PMID- 22517085 TI - Supplementing a training procedure with the use of a cadaver. PMID- 22517086 TI - Supplementing a training procedure with the use of a cadaver. Response to protocol review scenario: Passing the buck. PMID- 22517087 TI - Supplementing a training procedure with the use of a cadaver. Response to protocol review scenario: A word from USDA. PMID- 22517088 TI - Supplementing a training procedure with the use of a cadaver. Response to protocol review scenario: Compliance is a team effort. PMID- 22517089 TI - Supplementing a training procedure with the use of a cadaver. Response to protocol review scenario: Amendment is reasonable. PMID- 22517090 TI - Using vaginal wall impedance to determine estrous cycle phase in Lewis rats. AB - The use of Lewis rats in embryonic tissue transplantation experiments can present a challenge because of the fertility problems associated with this strain. The authors used estrous cycle phase determination to time pairings of reproductively active females and males in order to increase the likelihood that mating would occur. During a 24-month period, female rats in a production colony were evaluated for estrous phase by microscopic evaluation of vaginal smears and by vaginal impedance readings. Pairings that were arranged with females determined to be in the proestrous phase by vaginal smears resulted in a low rate of confirmed matings (14%). Serial vaginal smear sampling also produced a high incidence of pseudopregnancy. Pairings that were arranged with females determined to be in the proestrous phase by vaginal impedance readings resulted in a high rate of confirmed matings (48.1%) as well as a high rate of pregnancy (29.4%). An average of 7.2 embryos were produced per pregnancy. The vaginal impedance technique can be used to improve the breeding success rate of Lewis rats in order to maintain a stable production of embryos for experimentation. PMID- 22517091 TI - The effects of repeated oral gavage on the health of male CD-1 mice. AB - Oral gavage is a widely used method for administering substances to animals in pharmacological and toxicological studies. The authors evaluated whether oral gavage causes behavioral indicators of stress, increased mortality rate, alterations in food and water consumption and body weight or histological lesions in CD-1 mice. Gavage was carried out once per d for 5 d per week over 6 consecutive weeks. The mortality rate of mice in this study was 15%. Mice subjected to gavage did not undergo changes in food or water consumption during the study, and their mean body weights and relative organ weights were similar to those of mice in the control group. Serum cortisol levels at the time of euthanasia in mice in both groups were within the normal range. Histopathology showed acute esophagitis and pleurisy, indicative of perforation of the esophagus, in the two mice that died but no abnormalities in the other mice. The results suggest that animal stress and mortality related to oral gavage can be minimized when the procedure is carried out by an experienced technician. PMID- 22517092 TI - Applying mouse genetics expertise to research. PMID- 22517093 TI - CSF biomarkers for Alzheimer disease correlate with cortical brain biopsy findings. AB - OBJECTIVE: To assess the relationship between Alzheimer disease (AD)-related pathologic changes in frontal cortical brain biopsy and AD biomarkers in ventricular vs lumbar CSF, and to evaluate the relationships of AD biomarkers in CSF and cortical biopsy with the final clinical diagnosis of AD. METHODS: In 182 patients with presumed normal pressure hydrocephalus (152 with known APOE carrier status), Abeta plaques and tau in the cortical brain biopsies were correlated with the ventricular and lumbar CSF Abeta42, total tau, and p-tau levels measured by ELISA. In a median follow-up of 2.0 years, 51 patients developed AD dementia. RESULTS: The patients with Abeta plaques in the cortical biopsy had lower (p = 0.009) CSF Abeta42 levels than those with no Abeta plaques. The patients with tau in the cortical biopsy had lower (p = 0.014) Abeta42 but higher (p = 0.015) p-tau 181 in CSF as compared to those with no tau in the cortical biopsy. The patients with amyloid + tau + biopsies had the lowest Abeta42 and highest tau and p-tau 181 levels in CSF. The Abeta42 levels were lower and the tau and p-tau 181 higher in the ventricular vs corresponding lumbar CSF samples. In multivariate analysis, the presence of cortical Abeta was independently predicted by the APOE epsilon4 carrier status and age but not by CSF Abeta42 or tau levels. CONCLUSIONS: Amyloid plaques and hyperphosphorylated tau in cortical brain biopsies are reflected by low CSF Abeta42 and high CSF tau and p-tau levels, respectively. PMID- 22517094 TI - Development of a suspicion index to aid diagnosis of Niemann-Pick disease type C. AB - OBJECTIVES: Niemann-Pick disease type C (NP-C) is a rare, autosomal recessive lysosomal lipid storage disorder that is invariably fatal. NP-C diagnosis can be delayed for years due to heterogeneous presentation; adult-onset NP-C can be particularly difficult to diagnose. We developed a Suspicion Index tool, ranking specific symptoms within and across domains, including family members who have NP C, to provide a risk prediction score to identify patients who should undergo testing for NP-C. METHODS: A retrospective chart review was performed in 5 centers in Europe and 2 in Australia (n = 216). Three patient types were selected: classic or variant filipin staining NP-C cases (n = 71), NP-C noncases (confirmed negative by filipin staining; n = 64), or controls with at least 1 characteristic symptom of NP-C (n = 81). NP-C signs and symptoms were categorized into visceral, neurologic, or psychiatric domains. Logistic regression was performed on individual signs and symptoms within and across domains, and regression coefficients were used to develop prediction scores for NP-C. Internal validation was performed with the bootstrap resampling method. RESULTS: The Suspicion Index tool has good discriminatory performance with cutpoints for grading suspicion of NP-C. Neonatal jaundice/cholestasis, splenomegaly, vertical supranuclear gaze palsy, cataplexy, and cognitive decline/dementia were strong predictors of NP-C, as well as symptoms occurring in multiple domains in individual patients, and also parents/siblings or cousins with NP-C. CONCLUSIONS: The Suspicion Index tool is a screening tool that can help identify patients who may warrant further investigation for NP-C. A score >=70 indicates that patients should be referred for testing for NP-C. PMID- 22517095 TI - Two-year serial whole-brain N-acetyl-L-aspartate in patients with relapsing remitting multiple sclerosis. AB - OBJECTIVES: To test the hypotheses that 1) patients with relapsing-remitting multiple sclerosis (RR-MS) exhibit a quantifiable decline in their whole-brain concentration of the neural marker N-acetyl-L-aspartate (WBNAA), that is 2) more sensitive than clinical changes and 3) may provide a practical outcome measure for proof-of-concept and larger phase III clinical trials. METHODS: Nineteen patients (5 men and 14 women) with clinically definite RR-MS, who were 33 +/- 5 years old (mean +/- SD), had a disease duration of 47 +/- 28 months, and had a median Expanded Disability Status Scale (EDSS) score of 1.0 (range 0-5.5), underwent MRI and proton magnetic resonance spectroscopy ((1)H-MRS) semiannually for 2 years (5 time points). Eight matched control subjects underwent the protocol annually (3 time points). Their global N-acetyl-L-aspartate (1)H-MRS signal was converted into absolute amounts by phantom replacement and into WBNAA by dividing with the brain parenchymal volume, V(B), from MRI segmentation. RESULTS: The baseline WBNAA of the patients (10.5 +/- 1.7 mM) was significantly lower than that of the controls (12.3 +/- 1.3 mM; p < 0.002) and declined significantly (5%/year, p < 0.002) vs that for the controls who did not show a decline (0.4%/year, p > 0.7). Likewise, V(B) values of the patients also declined significantly (0.5%/year, p < 0.0001), whereas those of the controls did not (0.2%/year, p = 0.08). The mean EDSS score of the patients increased insignificantly from 1.0 to 1.5 (range 0-6.0) and did not correlate with V(B) or WBNAA. CONCLUSIONS: WBNAA of patients with RR-MS declined significantly at both the group and individual levels over a 2-year time period common in clinical trials. Because of the small sample sizes required to establish power, WBNAA can be incorporated into future studies. PMID- 22517096 TI - Increased risk of epilepsy in biopsy-verified celiac disease: a population-based cohort study. AB - OBJECTIVES: Celiac disease (CD) is associated with several neurologic disorders but it is unclear whether CD is associated with epilepsy. We therefore investigated whether biopsy-verified CD is associated with epilepsy. METHODS: Cohort study. Using biopsy report data from all Swedish pathology departments (n = 28), we identified individuals with CD who were diagnosed from 1969 to 2008 (Marsh 3: villous atrophy). Through Cox regression, we calculated hazard ratios (HRs) for epilepsy (defined as a diagnosis of epilepsy in the Swedish National Patient Register) in 28,885 individuals with CD and 143,166 controls matched for age, sex, calendar period, and county. RESULTS: Individuals with CD were at an increased risk of future epilepsy (HR = 1.42; 95% confidence interval [CI] = 1.24 1.62) (272 individuals with CD had a diagnosis of epilepsy vs an expected 192). The absolute risk of future epilepsy in patients with CD was 92/100,000 person years (excess risk = 27/100,000 person-years). This risk increase was seen in all ages, including children with CD. The HR for having at least 2 interactions with health care due to epilepsy was 1.41 (95% CI = 1.19-1.66). When we restricted epilepsy to those with both a diagnosis of epilepsy and an independent record of antiepileptic drug prescriptions, CD was associated with a 1.43-fold increased risk of epilepsy (95% CI = 1.10-1.86). CONCLUSION: Individuals with CD seem to be at a moderately increased risk of epilepsy. PMID- 22517097 TI - Identification of VPS35 mutations replicated in French families with Parkinson disease. PMID- 22517098 TI - Functional reorganization of sensorimotor cortex in early Parkinson disease. AB - OBJECTIVE: Compensatory reorganization of the nigrostriatal system is thought to delay the onset of symptoms in early Parkinson disease (PD). Here we sought evidence that compensation may be a part of a more widespread functional reorganization in sensorimotor networks, including primary motor cortex. METHODS: Several neurophysiologic measures known to be abnormal in the motor cortex (M1) of patients with advanced PD were tested on the more and less affected side of 16 newly diagnosed and drug-naive patients with PD and compared with 16 age-matched healthy participants. LTP-like effects were probed using a paired associative stimulation protocol. We also measured short interval intracortical inhibition, intracortical facilitation, cortical silent period, and input/output curves. RESULTS: The less affected side in patients with PD had preserved intracortical inhibition and a larger response to the plasticity protocol compared to healthy participants. On the more affected side, there was no response to the plasticity protocol and inhibition was reduced. There was no difference in input/output curves between sides or between patients with PD and healthy participants. CONCLUSIONS: Increased motor cortical plasticity on the less affected side is consistent with a functional reorganization of sensorimotor cortex and may represent a compensatory change that contributes to delaying onset of clinical symptoms. Alternatively, it may reflect a maladaptive plasticity that provokes symptom onset. Plasticity deteriorates as the symptoms progress, as seen on the more affected side. The rate of change in paired associative stimulation response over time could be developed into a surrogate marker of disease progression in PD. PMID- 22517099 TI - Being physically active may protect the brain from Alzheimer disease. PMID- 22517100 TI - Conglomerated beads shape of lacunar infarcts on diffusion-weighted MRI: what does it suggest? AB - OBJECTIVE: We aimed to analyze lesion patterns of lacunae-sized infarctions in the perforating arterial territory in terms of shape and to determine whether the particular pattern of conglomerated beads shape affected early neurologic deterioration. METHODS: We consecutively included acute ischemic stroke patients with confirmed lacunae-sized acute ischemic infarcts in the penetrating arterial territories on diffusion-weighted MRI. Based on diffusion-weighted MRI, the shape of ischemic infarcts was divided into oval or conglomerated beads shape. Demographics, risk factors, NIH Stroke Scale (NIHSS) score at admission and discharge, and stroke mechanisms were analyzed. Early neurologic deterioration was defined as any increase of NIHSS score at the time of discharge. RESULTS: Among 105 patients included, the conglomerated beads shape of infarcts was observed in 34 (32.4%) patients and the oval shape in 71 (67.6%) patients. The baseline characteristics were not different between the 2 groups. However, the maximal diameter of the lesion was significantly larger in the conglomerated beads shape group (12.8 +/- 3.3 mm vs 10.8 +/- 3.8 mm, p = 0.009). Early neurologic deterioration was also more commonly observed in the conglomerated beads shape group than in the oval shape group (20.6% vs 4.2%, p = 0.012). Multiple logistic regression analysis showed that the conglomerated beads shape was significantly associated with early neurologic deterioration (odds ratio 6.83, 95% confidence interval 1.53-30.55, p = 0.012). CONCLUSIONS: In 32.4% of all the lacunae-sized infarcts in the perforating artery territory, the conglomerated beads shape was observed. This shape was significantly associated with early neurologic deterioration. PMID- 22517101 TI - Decision support for diagnosis: co-evolution of tools and resources. PMID- 22517102 TI - High frequency of spinal involvement in patients with basal subarachnoid neurocysticercosis. AB - OBJECTIVE: To determine the frequency of spinal neurocysticercosis (NCC) in patients with basal subarachnoid NCC compared with that in individuals with viable limited intraparenchymal NCC (<=20 live cysts in the brain). METHODS: We performed a prospective observational case-control study of patients with NCC involving the basal cisterns or patients with only limited intraparenchymal NCC. All patients underwent MRI examinations of the brain and the entire spinal cord to assess spinal involvement. RESULTS: Twenty-seven patients with limited intraparenchymal NCC, and 28 patients with basal subarachnoid NCC were included in the study. Spinal involvement was found in 17 patients with basal subarachnoid NCC and in only one patient with limited intraparenchymal NCC (odds ratio 40.18, 95% confidence interval 4.74-340.31; p < 0.0001). All patients had extramedullary (intradural) spinal NCC, and the lumbosacral region was the most frequently involved (89%). Patients with extensive spinal NCC more frequently had ventriculoperitoneal shunt placement (7 of 7 vs 3 of 11; p = 0.004) and tended to have a longer duration of neurologic symptoms than those with regional involvement (72 months vs 24 months; p = 0.062). CONCLUSIONS: The spinal subarachnoid space is commonly involved in patients with basal subarachnoid NCC, compared with those with only intraparenchymal brain cysts. Spinal cord involvement probably explains serious late complications including chronic meningitis and gait disorders that were described before the introduction of antiparasitic therapy. MRI of the spine should be performed in basal subarachnoid disease to document spinal involvement, prevent complications, and monitor for recurrent disease. PMID- 22517103 TI - Randomized phase III study 306: adjunctive perampanel for refractory partial onset seizures. AB - OBJECTIVE: To evaluate the efficacy and safety of perampanel 2, 4, and 8 mg/day added to 1-3 concomitant antiepileptic drugs (AEDs) in patients with uncontrolled partial-onset seizures. METHODS: During this double-blind, placebo-controlled trial, patients with persisting seizures on 1-3 AEDs were randomized to perampanel 2, 4, and 8 mg/day or placebo following a 6-week baseline phase. Perampanel was titrated weekly by 2 mg/day and maintained at the dose achieved for 13 weeks. Primary endpoints were median percent change in seizure frequency and 50% responder rate. Analysis of covariance was performed on all treated patients with any seizure data (recorded in daily diaries) in the double-blind phase. RESULTS: A total of 706 patients were randomized and received trial medication; 623 completed the trial. Median percent change in seizure frequency the primary efficacy endpoint-was -10.7%, -13.6%, -23.3%, and -30.8% for placebo, perampanel 2, 4, and 8 mg/day, respectively. The difference from placebo was statistically significant for perampanel 4 mg/day (p = 0.0026) and 8 mg/day (p < 0.0001). The corresponding 50% responder rates were 17.9%, 20.6%, 28.5%, and 34.9%. The difference from placebo was statistically significant for perampanel 4 mg/day (p = 0.0132) and 8 mg/day (p = 0.0003). An apparent dose response was suggested for dizziness, which was the most frequent treatment-emergent adverse event. CONCLUSIONS: This trial demonstrated that adjunctive perampanel effectively reduced seizure frequency and possessed a favorable tolerability profile in patients >=12 years with partial-onset seizures (with or without secondary generalization), with a minimum effective dose of 4 mg/day. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that 4 and 8 mg/day doses of adjunctive perampanel are effective and tolerated in reducing partial-onset seizures. PMID- 22517104 TI - Simultaneous PML-IRIS after discontinuation of natalizumab in a patient with MS. AB - OBJECTIVE: Progressive multifocal leukoencephalopathy (PML) is a severe complication of natalizumab therapy in patients with multiple sclerosis (MS), which is often accompanied by an immune reconstitution inflammatory syndrome (IRIS) after removal of the drug. We describe a patient with MS who presented with simultaneous PML-IRIS 2 months after stopping natalizumab for other reasons. CASE REPORT AND RESULTS: The patient had widespread PML and severe IRIS. He received corticosteroids and displayed a vigorous JC virus-specific cellular immune response. Elevated myoinositol and lipid/creatine peaks measured in PML lesions by proton magnetic resonance spectroscopy ((1)H-MRS) corresponded to episodes of contrast enhancement on MRI scans and persisted after the enhancement subsided. He demonstrated steady clinical improvement, but developed marked residual atrophy in areas affected by PML and inflammation, as well as seizures. CONCLUSIONS: New enhancing white matter lesions, occurring after discontinuation of natalizumab, can be the manifestation of PML-IRIS rather than an MS exacerbation. Elevated myoinositol and lipid/creatine peaks appear to be more sensitive markers of inflammation in PML lesions than contrast enhancement. (1)H MRS may become useful as a biomarker for PML-IRIS by helping clinicians determine the need for corticosteroid administration and anticipate continuing clinical recovery. PMID- 22517105 TI - Hyperexcitability and amyotrophic lateral sclerosis. PMID- 22517106 TI - Decreased motor cortex gamma-aminobutyric acid in amyotrophic lateral sclerosis. AB - OBJECTIVES: To determine if there are in vivo differences in gamma-aminobutyric acid (GABA) in the motor cortex and subcortical white matter of patients with amyotrophic lateral sclerosis (ALS) compared with healthy controls using proton magnetic resonance spectroscopy (1H-MRS). METHODS: In this cross-sectional study, 10 patients with ALS and 9 age- and sex-matched healthy controls (HCs) underwent 3T edited 1H-MRS to quantify GABA centered on the motor cortex and the subcortical white matter. RESULTS: Compared with healthy controls, patients with ALS had significantly lower levels of GABA in the left motor cortex (1.42 +/- 0.27 arbitrary institutional units vs. 1.70 +/- 0.24 arbitrary institutional units, p = 0.038). There was no significant difference in GABA levels between groups in the subcortical white matter (p > 0.05). CONCLUSION: Decreased levels of GABA are present in the motor cortex of patients with ALS compared to HCs. Findings are consistent with prior reports of alterations in GABA receptors in the motor cortex as well as increased cortical excitability in the context of ALS. Larger, longitudinal studies are needed to confirm these findings and to further our understanding of the role of GABA in the pathogenesis of ALS. PMID- 22517107 TI - Impact of therapeutic hypothermia on MRI diffusion changes in neonatal encephalopathy. AB - OBJECTIVE: The objective of this work was to determine the impact of therapeutic hypothermia (TH) on the magnitude and time course of mean diffusivity (MD) changes following hypoxic-ischemic encephalopathy (HIE) in newborns. METHODS: Cerebral MRI scans of infants undergoing whole body TH for HIE from 2007 to 2010 were retrospectively reviewed. The data were analyzed identically to a control group of newborns with HIE previously published, prior to the development of TH. Anatomic injury was defined on T1- and T2-weighted ("late") MRI obtained after the fifth day of life. Since MD values vary regionally, the ratios of MD values for injured and normal tissue were calculated for areas of injury. Normal values were obtained from corresponding brain regions of 12 infants undergoing TH who had no injury on MRI studies. RESULTS: Twenty-three of 59 infants who underwent TH and MRI displayed cerebral injury on late MRI and were included in the study. MD ratios were decreased in all injured infants within the first 7 days of life. The return of MD to normal (pseudonormalization) occurred after the tenth day as compared to 6-8 days in the control group. Infants with severest injury demonstrated greater reduction in MD, but no difference in time to pseudonormalization. CONCLUSION: TH slows the evolution of diffusion abnormalities on MRI following HIE in term infants. PMID- 22517108 TI - Total daily physical activity and the risk of AD and cognitive decline in older adults. AB - OBJECTIVE: Studies examining the link between objective measures of total daily physical activity and incident Alzheimer disease (AD) are lacking. We tested the hypothesis that an objective measure of total daily physical activity predicts incident AD and cognitive decline. METHODS: Total daily exercise and nonexercise physical activity was measured continuously for up to 10 days with actigraphy (Actical(r); Philips Healthcare, Bend, OR) from 716 older individuals without dementia participating in the Rush Memory and Aging Project, a prospective, observational cohort study. All participants underwent structured annual clinical examination including a battery of 19 cognitive tests. RESULTS: During an average follow-up of about 4 years, 71 subjects developed clinical AD. In a Cox proportional hazards model adjusting for age, sex, and education, total daily physical activity was associated with incident AD (hazard ratio = 0.477; 95% confidence interval 0.273-0.832). The association remained after adjusting for self-report physical, social, and cognitive activities, as well as current level of motor function, depressive symptoms, chronic health conditions, and APOE allele status. In a linear mixed-effect model, the level of total daily physical activity was associated with the rate of global cognitive decline (estimate 0.033, SE 0.012, p = 0.007). CONCLUSIONS: A higher level of total daily physical activity is associated with a reduced risk of AD. PMID- 22517109 TI - GFAP and S100B in the acute phase of mild traumatic brain injury. AB - OBJECTIVE: The biomarkers glial fibrillary acid protein (GFAP) and S100B are increasingly used as prognostic tools in severe traumatic brain injury (TBI). Data for mild TBI are scarce. This study aims to analyze the predictive value of GFAP and S100B for outcome in mild TBI and the relation with imaging. METHODS: In 94 patients biomarkers were determined directly after admission. Collected data included injury severity, patient characteristics, admission CT, and MRI 3 months postinjury. Six months postinjury outcome was determined with Glasgow Outcome Scale Extended (GOSE) and return to work (RTW). RESULTS: Mean GFAP was 0.25 MUg/L (SD 1.08) and S100B 0.54 MUg/L (SD 1.18). In 63% GFAP was not discernible. GFAP was increased in patients with an abnormal CT (1.20 MUg/L, SD 2.65) compared to normal CT (0.05 MUg/L, SD 0.17, p < 0.05). Also in patients with axonal injury on MRI GFAP was higher (0.65 MUg/L, SD 0.91 vs 0.07 MUg/L, SD 0.2, p < 0.05). GFAP was increased in patients with incomplete RTW compared to complete RTW (0.69 MUg/L, SD 2.11 vs 0.12 MUg/L, SD 0.38, p < 0.05). S100B was not related to outcome or imaging studies. In multivariate analysis GFAP was not predictive for outcome determined by GOSE and RTW. CONCLUSIONS: A relation between GFAP with imaging studies and outcome (determined by RTW) was found in contrast to S100B. As the positive predictive value of GFAP is limited in this category of TBI patients, this biomarker is not suitable for prediction of individual patient outcome. PMID- 22517110 TI - When does responsiveness pique sexual interest? Attachment and sexual desire in initial acquaintanceships. AB - Three studies examined the contribution of attachment orientation and perceived partner responsiveness to sexual desire in initial acquaintanceships. In all studies, participants discussed a recent negative event with an unfamiliar, opposite-sex partner and then rated how responsive this partner had been during the interaction and their desire to have sex with him or her. Study 1 examined the association between perceived partner responsiveness and sexual desire in randomly paired strangers. Studies 2 and 3 experimentally manipulated partner responsiveness by standardized Instant Messages (Study 2) and a confederate's responsive or unresponsive reactions during face-to-face interviews (Study 3). Results indicated that perceiving a partner as responsive was associated with heightened interest in sex with this partner, primarily among less avoidant people. These results are consistent with research showing that secure individuals see sex as a means of becoming close to relationship partners, whereas avoidant individuals tend to approach sex in distancing ways. PMID- 22517111 TI - A cohort study on the association of early mutans streptococci colonisation and dental decay. AB - In children, a strong relationship between the timing of colonisation of mutans streptococci (MS) and future caries risk has been shown to exist. The aim of the study was to examine the association of early MS colonisation with dental decay and the need for restorative treatment. The subjects had been participants in an earlier Finnish mother-child study and assumed to be high-caries-risk subjects due to their mothers' high MS levels. The information on MS colonisation at 2 years of age was available for 164 children. Of them, comprehensive data on dental health, visits and treatments until 10 years of age were found in the registers for 147 subjects. The children who had not been colonised by MS at 2 years of age (n = 118) maintained their teeth caries-free longer than the MS colonised (n = 29) children. The median value for the caries-free time for MS colonised children was 4.6 years, in comparison with 8.0 years for non-MS colonised children (p < 0.001, hazard ratio 2.70; 95% CI 1.72-4.25, Cox regression). Until 10 years of age, the MS-colonised children had made on average 4.6 visits for restorative treatment, while the non-MS-colonised had made 2.8 visits (p = 0.005, Student's t test). The results suggest that the avoided early MS colonisation may lead to favourable long-term effects on caries experience and need for restorative treatment. PMID- 22517112 TI - Ultrasonography-based 2D motion-compensated HIFU sonication integrated with reference-free MR temperature monitoring: a feasibility study ex vivo. AB - Magnetic resonance imaging (MRI) and ultrasonography have been used simultaneously in this ex vivo study for the image-guidance of high intensity focused ultrasound (HIFU) treatment in moving tissue. A ventilator-driven balloon produced periodic and non-rigid (i.e. breathing-like) motion patterns in phantoms. MR-compatible ultrasound (US) imaging enabled near real-time 2D motion tracking based on optical flow detection, while near-harmonic reference-free proton resonance frequency shift (PRFS) MR thermometry (MRT) was used to monitor the thermal buildup on line. Reference-free MRT was applied to gradient-echo echo planar imaging phase maps acquired at the frame rate of 250 to 300 ms/slice with voxel size 1.25*1.25*5 mm(3). The MR-US simultaneous imaging was completely free of mutual interferences while minor RF interferences from the HIFU device were detected in the far field of the US images. The effective duty-cycle of the HIFU sonication was close to 100 % and no off-interval was required to temporally decouple it from the ultrasonography. The motion compensation of the HIFU sonication was achieved with an 8 Hz frame rate and sub-millimeter spatial accuracy, both for single-focus mode and for an iterated multi-foci line scan. Near harmonic reference-less PRFS MRT delivered motion-robust thermal maps perpendicular or parallel to the HIFU beam (0.7 degrees C precision, 0.5 degrees C absolute accuracy). Out-of-plane motion compensation was not addressed in this study. PMID- 22517113 TI - Palladium-catalyzed direct phosphonation of azoles with dialkyl phosphites. AB - The first Pd-catalyzed direct phosphonation of azoles with dialkyl phosphites has been achieved without addition of base or acid. This method involves the oxidative cleavage of C-H and P(O)-H bonds and represents an atom-efficiency alternative to the classical phosphonation of Ar-X. A Pd(II)/Pd(IV) mechanism has been studied and proposed. PMID- 22517114 TI - Abnormal response to cortical activation in early stages of Huntington disease. AB - BACKGROUND: We wished to identify noninvasive in vivo biomarkers of brain energy deficit in Huntington disease. METHODS: We studied 15 early affected patients (mean motor United Huntington Disease Rating Scale, 18 +/- 9) and 15 age- and sex matched controls. We coupled (31)phosphorus nuclear magnetic resonance spectroscopy with activation of the occipital cortex in order to measure the relative concentrations of adenosine triphosphate, phosphocreatine, and inorganic phosphate before, during, and after visual stimulation. RESULTS: In controls, we observed an 11% increase in the inorganic phosphate/phosphocreatine ratio (P = .024) and a 13% increase in the inorganic phosphate/adenosine triphosphate ratio (P = .016) during brain activation, reflecting increased adenosine diphosphate concentrations. Subsequently, controls had a return to baseline levels during recovery (P = .012 and .022, respectively). In contrast, both ratios were unchanged in patients during and after visual stimulation. CONCLUSIONS: (31)Phosphorus nuclear magnetic resonance spectroscopy could provide functional biomarkers of brain energy deficit to monitor therapeutic efficacy in Huntington disease. PMID- 22517115 TI - Exciton phase transitions in semiconductor quantum wells with disc-shaped electrode. AB - Phase transitions in a system of indirect excitons in semiconductor double quantum wells are studied for a set-up when one of the electrodes is of finite size and, in particular, has the shape of a disc. At voltage a region under the rim of the disc is created where excitons have lower energy, thus providing a macroscopic trap attractive for excitons while being repulsive for charged particles. The theory of the formation of patterns of the excitonic condensed phase under the disc is built based on the assumption of the existence of the inter-exciton range where the interaction between them is attractive. The finite value of the exciton lifetime is taken into account serving as a limiting factor for the size of the islands of the condensed phase. The calculations reveal complex restructuring of the patterns of the spatial distribution of exciton density with increasing pumping intensity: from the structureless gaseous phase to separate islands of the condensed phase within the gaseous phase, then to islands of the gaseous phase in the bulk of the condensed phase and finally to the continuous condensed phase. PMID- 22517116 TI - Dendritic cell-derived tumor necrosis factor alpha modifies airway epithelial cell responses. AB - Mucosal dendritic cells (DC) are intimately associated with the airway epithelium and thus are ideally situated to be first responders to pathogens. We hypothesize that DC drive innate immune responses through early release of tumor necrosis factor (TNF) alpha, which drives airway epithelial cell responses. In a mouse model, TNFalpha release was significantly increased following a single exposure to German cockroach (GC) frass, an event independent of neutrophil recruitment into the airways. While lung epithelial cells and alveolar macrophages failed to release TNFalpha following GC frass exposure, bone marrow-derived DC (BMDC) produced substantial amounts of TNFalpha suggesting their importance as early responding cells. This was confirmed by flow cytometry of pulmonary myeloid DC. Addition of GC frass-pulsed BMDC or conditioned media from GC frass-pulsed BMDC to primary mouse tracheal epithelial cells (MTEC) or MLE-15 cells induced chemokine (C-C) motif ligand (CCL) 20 and granulocyte macrophage (GM) colony stimulating factor (CSF), both of which are important for DC recruitment, survival and differentiation. Importantly, DC do not produce CCL20 or GM-CSF following allergen exposure. Blocking TNFalpha receptor 1 (TNFR1) completely abolished chemokine production, suggesting that BMDC-derived TNFalpha induced airway epithelial cell activation and enhancement of the innate immune response. Lastly, blocking TNFR1 in vivo resulted in significantly decreased CCL20 and GM CSF production in the lungs of mice. Together, our data strongly suggest that DC derived TNFalpha plays a crucial role in the initiation of innate immune responses through the modification of airway epithelial cell responses. PMID- 22517117 TI - Dietary phosphate binding and loading alter kidney angiotensin-converting enzyme mRNA and protein content in 5/6 nephrectomized rats. AB - BACKGROUND: Vitamin D receptor activation with paricalcitol can modulate the transcription of renin-angiotensin system components in the surgical 5/6 nephrectomy rat model (5/6 NX) of chronic renal insufficiency. We tested the hypothesis whether dietary modification of phosphate influences kidney renin angiotensin system gene expression at the mRNA level in 5/6 NX rats. METHODS: Fifteen weeks after surgery, rats were given control diet (0.3% calcium, 0.5% phosphate), phosphate-lowering diet (3% calcium as carbonate) or high-phosphate diet (1.5%) for 12 weeks. Sham-operated rats were on control diet. RESULTS: Blood pressure, plasma phosphate, parathyroid hormone, glomerulosclerosis, tubulointerstitial damage, and FGF-23 were increased in remnant kidney rats, whereas creatinine clearance was decreased. Phosphate, parathyroid hormone, glomerulosclerosis, tubulointerstitial damage, and FGF-23 were further elevated by the high-phosphate diet, but were reduced by the phosphate-lowering diet. Plasma calcium was increased with the phosphate-lowering diet and decreased with the high-phosphate diet. Remnant kidney rats on control diet showed upregulated kidney angiotensin-converting enzyme (ACE) and angiotensin (Ang) IV receptor (AT(4)) transcription, while ACE2, Ang II type 2 receptor and renin receptor transcription were downregulated in comparison with sham rats. Phosphate-lowering diet reduced whereas high-phosphate diet increased kidney ACE, and these effects were observed at both mRNA and protein levels. Dietary phosphate loading also resulted in lower AT(1a) gene transcription. CONCLUSION: Dietary phosphate loading was associated with elevated kidney ACE expression, increased tissue damage and lower AT(1a) transcription in 5/6 NX rats. Phosphate binding with 3% calcium carbonate had opposite effects on ACE and kidney damage. PMID- 22517118 TI - Experimental and theoretical study of the reaction of the ethynyl radical with nitrous oxide, C2H + N2O. AB - We investigated the rate constants and reaction mechanism of the gas phase reaction between the ethynyl radical and nitrous oxide (C(2)H + N(2)O) using both experimental methods and electronic structure calculations. A pulsed-laser photolysis/chemiluminescence technique was used to determine the absolute rate coefficient over the temperature range 570 K to 836 K. In this experimental temperature range, the measured temperature dependence of the overall rate constants can be expressed as: k(T) (C(2)H + N(2)O) = 2.93 * 10(-11) exp((-4000 +/- 1100) K/T) cm(3) s(-1) (95% statistical confidence). Portions of the C(2)H + N(2)O potential energy surface (PES), containing low-energy pathways, were constructed using the composite G3B3 method. A multi-step reaction route leading to the products HCCO + N(2) is clearly preferred. The high selectivity between product channels favouring N(2) formation occurs very early. The pathway corresponds to the addition of the terminal C atom of C(2)H to the terminal N atom of N(2)O. Refined calculations using the coupled-cluster theory whose electronic energies were extrapolated to the complete basis set limit CCSD(T)/CBS led to an energy barrier of 6.0 kcal mol(-1) for the entrance channel. The overall rate constant was also determined by application of transition-state theory and Rice-Ramsperger-Kassel-Marcus (RRKM) statistical analyses to the PES. The computed rate constants have similar temperature dependence to the experimental values, though were somewhat lower. PMID- 22517119 TI - Reverse phase protein array profiling reveals distinct proteomic signatures associated with chronic myeloid leukemia progression and with chronic phase in the CD34-positive compartment. AB - BACKGROUND: Chronic myeloid leukemia (CML) is a clonal stem cell malignancy whose pathogenesis is driven by constitutive activation of the breakpoint cluster region-v-abl Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL1) kinase. Although BCR-ABL1 activation is present in all patients with CML, patients can present in 3 different phases characterized by an increasingly worse prognosis and diminished responsiveness to tyrosine kinase inhibitors: chronic phase, accelerated phase, or blastic phase. The biologic basis for progression from chronic phase to blastic phase and for regulating the homeostasis of tyrosine kinase inhibitor-resistant CML stem cells is not entirely understood. METHODS: To shed some light into these aspects of CML biology, the authors used reverse phase protein arrays probed with 112 individual monoclonal antibodies to compare protein expression patterns in 40 samples of leukemia-enriched fractions from patients with CML (25 in chronic phase, 5 in accelerated phase, and 10 in phase). RESULTS: An analysis of variance (significance cutoff, P < .01) unveiled a set of proteins that were overexpressed in blastic phase, including heat-shock protein 90 (hsp90); retinoblastoma (Rb); apoptosis-inducing factor (AIF); serine/threonine-protein phosphatase 2A (PP2A); B-cell leukemia 2 (Bcl-2); X linked inhibitor of apoptosis protein (Xiap); human homolog of Drosophila Mad (mothers against decapentaplegic) and related Caenorhabditis elegans gene Sma, family member 1 (Smad1); single-stranded DNA binding protein 2 alpha (SSBP2alpha); poly(adenosine diphosphate-ribose) polymerase (PARP); GRB2 associated binding protein 2 (Gab2); and tripartite motif containing 24 (Trim24). It is noteworthy that several of these proteins also were overexpressed in the CD34-positive compartment, which putatively contains the CML stem cell population. CONCLUSIONS: The results from this study indicated that reverse phase protein array analysis can unveil differentially expressed proteins in advanced phase CML that can be exploited therapeutically with targeted approaches. PMID- 22517120 TI - Biological, preclinical and clinical characteristics of inhibitors of vascular endothelial growth factors. AB - Vascular endothelial growth factor (VEGF) plays an important role in the pathophysiology of several sight-threatening retinal disorders such as age related macular degeneration, diabetic macular edema and proliferative diabetic retinopathy. The discovery of anti-VEGF agents has revolutionized our treatment of these conditions. There are 4 anti-VEGF agents that are either approved or in common use in ophthalmology, namely pegaptanib (Macugen, Pfizer), ranibizumab (Lucentis, Novartis), aflibercept or VEGF Trap-Eye (EYLEA, Bayer) and bevacizumab (Avastin, Roche). There are differences between them. In this review, the differences are discussed in detail. Furthermore, an attempt is made to explain some of the clinical trial data based on their differences in ocular efficacy, duration of action, and local and systemic safety concerns. PMID- 22517121 TI - Neovascular age-related macular degeneration. AB - PURPOSE: Neovascular age-related macular degeneration (AMD) is a leading cause of blindness, with an increasing incidence as the elderly population expands. Large, multi-center, randomized, clinical trials have been conducted exploring the safety and efficacy of anti-VEGF treatments. This paper aims to discuss the safety and efficacy of pegaptanib, ranibizumab, aflibercept and bevacizumab. New therapeutic agents and treatment strategies are also discussed. PROCEDURES: Evidence available from prospective, multicenter, clinical studies and from a selective literature search is utilized to present the results of VEGF inhibition in neovascular AMD and to generate evidence-based recommendations. RESULTS: Anti VEGF treatment is indicated in choroidal neovascularization with active disease and produces a significant benefit in visual acuity. CONCLUSIONS: With the advent of anti-VEGF therapy, the prognosis of choroidal neovascularization has changed dramatically. Data from well-conducted clinical trials suggest that approved anti VEGF drugs are effective and well tolerated. PMID- 22517122 TI - Diabetic macular edema. AB - Diabetic retinopathy is one of the major complications of diabetes mellitus and a leading cause of visual loss. Diabetic macular edema (DME) is an ocular manifestation of the disease causing visual deterioration. The prevalence of visual impairment due to DME is estimated to be 5.4% in Europe. Vascular endothelial growth factor (VEGF) is overexpressed in diabetic eyes and plays a key role in the development of DME. VEGF levels were proven to be elevated in the vitreous and retina in patients with diabetic retinopathy. VEGF causes a breakdown of the blood-retinal barrier by influencing the tight junctions of retinal endothelial cells and leading to accumulation of fluid in the macula. Therefore, intravitreal VEGF inhibitors are ideal candidates to treat DME by counteracting VEGF overexpression. This review summarizes the results of the most recent prospective, controlled studies on DME with promising novel VEGF inhibitors. It focuses on the efficacy and safety aspects of anti-VEGF treatment of DME. PMID- 22517123 TI - Anti-vascular endothelial growth factor treatment for retinal vein occlusions. AB - Retinal vein occlusion (RVO) encompasses two conditions: central RVO, in which the major outflow vessel of the retina is obstructed, and branch RVO, in which a proximal branch of the central retinal vein is obstructed. In both conditions, there is increased intraluminal and interstitial pressure throughout the retina drained by the obstructed vessels, resulting in reduced arterial perfusion, which is exacerbated by preexistent arterial insufficiency, and in variable amounts of retinal ischemia. Retinal ischemia causes increased production of vascular endothelial growth factor (VEGF), which causes vascular leakage and macular edema. High levels of VEGF also promote retinal hemorrhages and exacerbate capillary nonperfusion. Intraocular injections of a VEGF-binding protein reduce vascular leakage, resulting in improvement in macular edema, accelerate resorption of retinal hemorrhages, and prevent worsening of capillary nonperfusion. The ideal regimen has not been defined, but it appears that monthly injections early in the course control edema and may help to limit disease severity in a large percentage of patients. Over time, treatment should be individualized based upon timing and severity of recurrent edema and/or progression of nonperfusion. The role of adjunctive treatments is yet to be defined, but it is clear that VEGF antagonists provide excellent first-line treatment that has dramatically improved visual outcomes in patients with RVO. PMID- 22517124 TI - Optical tracking of contrast medium bolus to optimize bolus shape and timing in dynamic computed tomography. AB - One of the biggest challenges in dynamic contrast-enhanced CT is the optimal synchronization of scan start and duration with contrast medium administration in order to optimize image contrast and to reduce the amount of contrast medium. We present a new optically based approach, which was developed to investigate and optimize bolus timing and shape. The time-concentration curve of an intravenously injected test bolus of a dye is measured in peripheral vessels with an optical sensor prior to the diagnostic CT scan. The curves can be used to assess bolus shapes as a function of injection protocols and to determine contrast medium arrival times. Preliminary results for phantom and animal experiments showed the expected linear behavior between dye concentration and absorption. The kinetics of the dye was compared to iodinated contrast medium and was found to be in good agreement. The contrast enhancement curves were reliably detected in three mice with individual bolus shapes and delay times of 2.1, 3.5 and 6.1 s, respectively. The optical sensor appears to be a promising approach to optimize injection protocols and contrast enhancement timing and is applicable to all modalities without implying any additional radiation dose. Clinical tests are still necessary. PMID- 22517126 TI - Justice for all. PMID- 22517125 TI - Risk factors for mesh complications after trocar guided transvaginal mesh kit repair of anterior vaginal wall prolapse. AB - AIMS: To identify risk factors for mesh exposures after anterior pelvic organ prolapse repair using a standardized trocar guided polypropylene mesh kit. METHODS: A secondary risk analysis combining patients from two prospective multicenter studies. Main outcome was clinical host-vs-implant reactions one year after surgery using a macroscopic inflammatory scale. RESULTS: 353 patients were included in the study. Mean age at surgery was 65.3 (+/- 9.6 SD) years and surgery was performed as a primary procedure in 224/353 (63.5%) patients. Mesh exposures, of which the majority were mild-moderate, occurred in a total of 30/349 patients (8.6%). Multivariate logistic regression showed increased odds for mesh exposures for women who smoked before surgery (OR 3.48, 95% CI 1.18 10.28), who had given birth to more than two children (OR 2.64, 95% CI 1.07-6.51) and those with somatic inflammatory disease (OR 5.11, 95% CI 1.17-22.23). Age, body mass index, and menopausal status showed no significant association with clinical mesh exposures. CONCLUSIONS: Smoking, multiple childbirth, and somatic inflammatory disease are possible risk factors for mesh exposure after trocar guided mesh kit surgery for anterior pelvic organ prolapse. Preoperative smoking cessation may decrease the risk for exposures. PMID- 22517127 TI - No shame. PMID- 22517128 TI - All together now. PMID- 22517129 TI - Deep-water drilling remains a risky business. PMID- 22517141 TI - European groups go global. PMID- 22517142 TI - Tsunami simulations scare Japan. PMID- 22517143 TI - A question of science. PMID- 22517144 TI - Japan gambles on displays. PMID- 22517145 TI - Gene hunt is on for mental disability. PMID- 22517146 TI - Science in court: Arrested development. PMID- 22517147 TI - Particle physics: A matter of detail. PMID- 22517148 TI - Astrophysics: Prepare for the coming space weather storm. PMID- 22517151 TI - Personalized medicine: Keep a way open for tailored treatments. PMID- 22517152 TI - Data accessibility: Getting a handle on biological data. PMID- 22517153 TI - Water accessibility: Boost water safety in rural China. PMID- 22517154 TI - Agriculture: Soil remedies for small-scale farming. PMID- 22517155 TI - Sensory biology: Search for the compass needles. PMID- 22517156 TI - Electronics: Carbon nanotubes finally deliver. PMID- 22517158 TI - Quantum physics: Tunnelling across a nanowire. PMID- 22517159 TI - Circadian rhythms: No lazing on sunny afternoons. PMID- 22517160 TI - Deformation cycles of subduction earthquakes in a viscoelastic Earth. AB - Subduction zones produce the largest earthquakes. Over the past two decades, space geodesy has revolutionized our view of crustal deformation between consecutive earthquakes. The short time span of modern measurements necessitates comparative studies of subduction zones that are at different stages of the deformation cycle. Piecing together geodetic 'snapshots' from different subduction zones leads to a unifying picture in which the deformation is controlled by both the short-term (years) and long-term (decades and centuries) viscous behaviour of the mantle. Traditional views based on elastic models, such as coseismic deformation being a mirror image of interseismic deformation, are being thoroughly revised. PMID- 22517162 TI - Coherent quantum phase slip. AB - A hundred years after the discovery of superconductivity, one fundamental prediction of the theory, coherent quantum phase slip (CQPS), has not been observed. CQPS is a phenomenon exactly dual to the Josephson effect; whereas the latter is a coherent transfer of charges between superconducting leads, the former is a coherent transfer of vortices or fluxes across a superconducting wire. In contrast to previously reported observations of incoherent phase slip, CQPS has been only a subject of theoretical study. Its experimental demonstration is made difficult by quasiparticle dissipation due to gapless excitations in nanowires or in vortex cores. This difficulty might be overcome by using certain strongly disordered superconductors near the superconductor-insulator transition. Here we report direct observation of CQPS in a narrow segment of a superconducting loop made of strongly disordered indium oxide; the effect is made manifest through the superposition of quantum states with different numbers of flux quanta. As with the Josephson effect, our observation should lead to new applications in superconducting electronics and quantum metrology. PMID- 22517163 TI - Formation of the 'Great Unconformity' as a trigger for the Cambrian explosion. AB - The transition between the Proterozoic and Phanerozoic eons, beginning 542 million years (Myr) ago, is distinguished by the diversification of multicellular animals and by their acquisition of mineralized skeletons during the Cambrian period. Considerable progress has been made in documenting and more precisely correlating biotic patterns in the Neoproterozoic-Cambrian fossil record with geochemical and physical environmental perturbations, but the mechanisms responsible for those perturbations remain uncertain. Here we use new stratigraphic and geochemical data to show that early Palaeozoic marine sediments deposited approximately 540-480 Myr ago record both an expansion in the area of shallow epicontinental seas and anomalous patterns of chemical sedimentation that are indicative of increased oceanic alkalinity and enhanced chemical weathering of continental crust. These geochemical conditions were caused by a protracted period of widespread continental denudation during the Neoproterozoic followed by extensive physical reworking of soil, regolith and basement rock during the first continental-scale marine transgression of the Phanerozoic. The resultant globally occurring stratigraphic surface, which in most regions separates continental crystalline basement rock from much younger Cambrian shallow marine sedimentary deposits, is known as the Great Unconformity. Although Darwin and others have interpreted this widespread hiatus in sedimentation on the continents as a failure of the geologic record, this palaeogeomorphic surface represents a unique physical environmental boundary condition that affected seawater chemistry during a time of profound expansion of shallow marine habitats. Thus, the formation of the Great Unconformity may have been an environmental trigger for the evolution of biomineralization and the 'Cambrian explosion' of ecologic and taxonomic diversity following the Neoproterozoic emergence of animals. PMID- 22517161 TI - An absence of neutrinos associated with cosmic-ray acceleration in gamma-ray bursts. AB - Very energetic astrophysical events are required to accelerate cosmic rays to above 10(18) electronvolts. GRBs (gamma-ray bursts) have been proposed as possible candidate sources. In the GRB 'fireball' model, cosmic-ray acceleration should be accompanied by neutrinos produced in the decay of charged pions created in interactions between the high-energy cosmic-ray protons and gamma-rays. Previous searches for such neutrinos found none, but the constraints were weak because the sensitivity was at best approximately equal to the predicted flux. Here we report an upper limit on the flux of energetic neutrinos associated with GRBs that is at least a factor of 3.7 below the predictions. This implies either that GRBs are not the only sources of cosmic rays with energies exceeding 10(18) electronvolts or that the efficiency of neutrino production is much lower than has been predicted. PMID- 22517166 TI - Continuous flow synthesis and scale-up of glycine- and taurine-conjugated bile salts. AB - A multi-gram scale protocol for the N-acyl amidation of bile acids with glycine and taurine has been successfully developed under continuous flow processing conditions. Selecting ursodeoxycholic acid (UDCA) as the model compound and N ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) as the condensing agent, a modular mesoreactor assisted flow set-up was employed to significantly speed up the optimization of the reaction conditions and the flow scale-up synthesis. The results in terms of yield, in line purification, analysis, and implemented flow set-up for the reaction optimization and large scale production are reported and discussed. PMID- 22517167 TI - Physicochemical characterization and structural evaluation of a specific 2:1 cocrystal of naproxen-nicotinamide. AB - Physicochemical characterization and structural evaluation of a 2:1 naproxen nicotinamide cocrystal were performed. The 2:1 cocrystal showed rapid naproxen dissolution and less water vapor adsorption, indicating better pharmaceutical properties of naproxen. The unique 2:1 cocrystal formation was evaluated by solid state nuclear magnetic resonance (NMR). The assignments of all H and (13) C peaks for naproxen and the cocrystal were performed using dipolar-insensitive nuclei enhanced by polarization transfer and (1) H-(13) C cross-polarization (CP) heteronuclear correlation (HETCOR) NMR measurements. The (13) C chemical shift revealed that two naproxen molecules and one nicotinamide molecule existed in the asymmetric unit of the cocrystal. The (1) H chemical shifts indicated that the carboxylic group of the naproxen in the cocrystal was nonionized, and the CH-pi interaction between naproxens was very strong. From the (1) H-(13) C CP-HETCOR NMR spectrum with contact time of 5 ms, two different synthons, carboxylic acid amide and carboxylic acid-pyridine ring, were found between naproxen and nicotinamide. Single-crystal X-ray analysis, which supported the solid-state NMR results, clarified the geometry and intermolecular interactions in more detail. The structure is unique among pharmaceutical cocrystals because each carboxyl group of the two naproxens formed different intermolecular synthons. PMID- 22517168 TI - Temperature-dependent Raman scattering study of the defect pyrochlores RbNbWO6 and CsTaWO6. AB - Lattice dynamics calculations and temperature-dependent Raman scattering experiments were performed on RbNbWO(6) and CsTaWO(6) pyrochlore oxides. The observed bands were assigned to the respective motions of atoms in the unit cell. The spectra showed the presence of additional Raman bands not allowed for by the [Formula: see text] cubic structure. We have shown that these bands appear due to both substitutional disorder in the 16c sites and displacive disorder of the A ions. Raman studies also revealed the presence of an additional 80 cm(-1) band at room temperature for RbNbWO(6), not observed for CsTaWO(6). The presence of this band has been attributed to off-center displacement of the Nb and W ions due to structural phase transition into a tetragonal ferroelectric phase. The temperature evolution of the 80 cm(-1) band intensity revealed that it disappeared at a much higher temperature (about 650 K) than the reported phase transition temperature (about 360 K). This behavior is reminiscent of chemically disordered perovskite ferroelectrics, including relaxor ferroelectrics, and was attributed to the presence of small polar regions with local tetragonal distortion embedded in the paraelectric matrix of the [Formula: see text] structure. PMID- 22517169 TI - Nanomaterials and lab-on-a-chip technologies. AB - Lab-on-a-chip (LOC) platforms have become important tools for sample analysis and treatment with interest for DNA, protein and cells studies or diagnostics due to benefits such as the reduced sample volume, low cost, portability and the possibility to build new analytical devices or be integrated into conventional ones. These platforms have advantages of a wide set of nanomaterials (NM) (i.e. nanoparticles, quantum dots, nanowires, graphene etc.) and offer excellent improvement in properties for many applications (i.e. detectors sensitivity enhancement, biolabelling capability along with other in-chip applications related to the specificities of the variety of nanomaterials with optical, electrical and/or mechanical properties). This review covers the last trends in the use of nanomaterials in microfluidic systems and the related advantages in analytical and bioanalytical applications. In addition to the applications of nanomaterials in LOCs, we also discuss the employment of such devices for the production and characterization of nanomaterials. Both framed platforms, NMs based LOCs and LOCs for NMs production and characterization, represent promising alternatives to generate new nanotechnology tools for point-of-care diagnostics, drug delivery and nanotoxicology applications. PMID- 22517170 TI - Enhanced trabeculectomy: the Moorfields Safer Surgery System. AB - Trabeculectomy with anti-fibrotic treatment is still the most popular incisional procedure for glaucoma filtration surgery (GFS) worldwide. The advent of anti fibrotic agents reduced failure due to scarring but resulted in increased complications. Advances in trabeculectomy surgery have been driven by the need to minimise the risk of: (1) complications and (2) surgical failure. This chapter covers preoperative, intraoperative and postoperative strategies, which improve the outcome of GFS. Strategies to reduce the risk of complications centre on the prevention of postoperative hypotony by minimising the risk of overdrainage, postoperative wound leaks and poor bleb morphology. Surgical techniques to reduce the risk of postoperative fibrosis by the use of anti-fibrotic agents (including mitomycin C) are discussed in detail. These techniques are based on a combination of considerable clinical experience, observation and laboratory research. The need to address pre-, intra- and postoperative issues in each individual patient is emphasised. These changes are embodied in the system we call the 'Moorfields Safer Surgery System'. The use of these strategies has considerably reduced the incidence of major complications including hypotony, cystic blebs and endophthalmitis in practices around the world. Most of these techniques are simple, require minimal equipment and can be easily mastered. They are associated with an improvement in overall outcome and it is hoped that this chapter will help the reader benefit from these advances. PMID- 22517171 TI - Deep sclerectomy. AB - Filtering surgery evolved from the classic trabeculectomy, in which penetration into the anterior chamber is a necessary step, toward nonpenetrating deep sclerectomy. The first procedure presents several serious complications such as durable hypotony, hyphema, flat anterior chamber, choroidal detachment, endophthalmitis and surgery-induced cataract. To avoid such drawbacks, a novel nonpenetrating technique was designed to improve predictability of the intraocular pressure-lowering action, while reducing the incidence of the immediate postoperative complications encountered with the penetrating method. This surgery works by building up new outflow pathways for the drainage of the aqueous humor while keeping intact the integrity of the anterior chamber. Deep sclerectomy acts at the bulk of main resistance to aqueous humor egress, located at the juxtacanalicular meshwork and the inner wall of Schlemm's canal. It consists of dissection of these two structures while keeping a thin filtering membrane though which aqueous humor is being drained. The membrane prevents overfiltration and ensures a reproducible postoperative intraocular pressure. This surgery is indicated for most of glaucoma except angle closure and neovascular cases. The procedure consists in opening the conjunctiva and Tenon's capsule and creating a 5 * 5 mm limbus-based superficial scleral flap. A deeper scleral flap measuring about 4 * 4 mm is dissected and the roof of Schlemm's canal is removed. A space maintainer is inserted and the flap and conjunctiva are closed. Results after 10 years are good with an IOP of 12.2 +/- 4.7 mmHg and an overall success rate of 77.6%with few complications. PMID- 22517172 TI - Glaucoma drainage implant surgery. AB - Glaucoma drainage implant (GDI) surgery represents a significant advance in the treatment of refractory glaucomas. Recent randomized clinical trials have compared the efficacy and safety of this technique to standard trabeculectomy. Several types of implants are currently available and differ in surface area, shape, composition, and presence or absence of a flow-restricting valve. A prospective, randomized clinical trial comparing two types of GDIs is ongoing. GDIs may be placed in the anterior chamber, ciliary sulcus, or pars plana. Several types of patch graft material may be utilized to prevent tube erosion. Potential complications of GDI surgery may relate to immediate or late-onset hypotony, motility disturbances, corneal decompensation, or tube erosion. PMID- 22517173 TI - Postoperative management of penetrating and nonpenetrating external filtering procedures. AB - Correct postoperative management is fundamental to prevent and treat complications and to optimize the success of filtering surgery: timely control visits and appropriate actions and prescriptions ensure the best outcomes, allow recovery from a number of untoward events, and can reestablish filtration when failure seems imminent. In contrast, a slack follow-up and wrong interventions or prescriptions can lead to failure of any surgery, no matter how accurately it had been carried out, sometimes jeopardizing vision and even the anatomy of the globe. The purpose of this review is to present a rational approach to postoperative follow-up and to synthetically describe how to prevent, recognize and address the most common complications of filtering surgery, pointing out the most common pitfalls in the management of the operated eye. PMID- 22517174 TI - Ocular surface and external filtration surgery: mutual relationships. AB - There is a large body of evidence from clinical and experimental studies that the long-term use of topical drugs may induce ocular surface changes, causing ocular discomfort, dry eye, conjunctival inflammation, subconjunctival fibrosis, corneal surface impairment, and, as a consequence of chronic ocular surface changes, the potential risk of failure for further glaucoma surgery. Subclinical inflammation has also been widely described in patients receiving antiglaucoma treatments for long periods of time, with inflammatory cell infiltration and fibroblast activation in the conjunctiva and subconjunctival space. The preservative, especially benzalkonium chloride, which has consistently demonstrated its toxic effects in laboratory, experimental, and clinical studies, could induce or enhance such inflammatory changes. As a quaternary ammonium, this compound causes tear film instability, loss of goblet cells, conjunctival squamous metaplasia and apoptosis, disruption of the corneal epithelium barrier, corneal nerve impairment, chronic inflammation and potential damage to deeper ocular tissues. Drug-induced adverse effects are therefore far from being restricted to only allergic reactions, but they are often very difficult to identify because they mostly occur in a delayed or poorly specific manner, and result from complex and multifactorial interactions between the drugs and the ocular surface. Postoperatively, the ocular surface also plays an important role, as the conjunctiva interacts with aqueous humor and subconjunctival fibrosis may block aqueous outflow and cause surgical failure. As preoperative inflammation underlies postoperative fibrosis and therefore surgical outcome, a better knowledge of ocular surface changes with appropriate evaluation and management should thus become a new paradigm in glaucoma care over the long term. PMID- 22517175 TI - Wound healing and glaucoma surgery: modulating the scarring process with conventional antimetabolites and new molecules. AB - Subconjunctival absorption of aqueous humor is an essential part of glaucoma filtration surgery. Mitomycin C (MMC) and 5-fluorouracil have been used to reduce postoperative episcleral fibrosis and scar formation in the filtering bleb area for more than two decades. Both antimetabolites have also been frequently injected before needling revision of failing filtering blebs. Recently, MMC was tried also in tube surgery and nonpenetrating filtering surgery, but its usefulness in these applications has not yet been determined. The main complications and side effects of antimetabolite-enhanced filtration surgery comprise development of thin-walled cystic blebs, late bleb leaks, bleb infections, endophthalmitis, chronic hypotony, hypotony maculopathy and corneal epithelial toxicity. Besides MMC and 5-fluorouracil, several other agents were proposed for decreasing episcleral healing after glaucoma filtering surgery. Only few were evaluated in randomized clinical trials, and none became generally accepted or widely used. PMID- 22517176 TI - Mini-drainage devices: the Ex-PRESS Mini-Glaucoma Device. AB - The Ex-PRESS Mini-Glaucoma Device is a glaucoma drainage device used to shunt aqueous from the anterior chamber into a subconjunctival reservoir that is created surgically. It has been used successfully over the last decade with approximately 60,000 implantations worldwide. In an ever-evolving microsurgical environment, the Ex-PRESS glaucoma device is on the forefront of intraocular pressure lowering technology. This chapter aims to review the surgical uses, techniques and considerations of the Ex-PRESS device as well as analyze the current literature detailing the advantages and disadvantages of the Ex-PRESS implant. Special attention will also be placed on the authors' own experience using the device. PMID- 22517177 TI - Laser-assisted techniques for penetrating and nonpenetrating glaucoma surgery. AB - The use of lasers is slowly pervading all sub-specialties of Ophthalmology, especially glaucoma, and lasers are slowly replacing many glaucoma surgeries. Conventional trabeculectomy has so far remained the gold standard for glaucoma surgery, and efforts are being made to develop a new surgical approach to overcome the limited success rate and safety issues of the traditional trabeculectomy. There is a great interest in using lasers to create an ab interno and ab externo penetrating and nonpenetrating filtering surgery. Theoretically, laser-assisted surgery offers the potential advantage of improved accuracy, repeatability, and safety, although the main drawback of using lasers for this purpose is the potential collateral damage induced by the scattered energy. Collateral thermal damage adjacent to the sclerostomy site is believed to be detrimental to the long-term success of the filtering procedure. Employing a laser with high water absorbance and low light scattering reduces the extent of collateral thermal damage and improves the long-term surgical success. An increasing number of different radiation sources were examined for penetrating and nonpenetrating glaucoma surgery with various success rates. PMID- 22517178 TI - Ab externo Schlemm's canal surgery: viscocanalostomy and canaloplasty. AB - Ab externo Schlemm's canal (SC) surgery (e.g. viscocanalostomy and canaloplasty) is a valuable alternative to glaucoma filtration surgery. It targets the abnormally high resistance to outflow in the trabecular meshwork and reestablishes the physiologic outflow system. In viscocanalostomy, viscoelastic substance is injected to dilate SC which in turn leads to microdisruptions of the inner wall. In canaloplasty, the additional intracanalicular suture stent keeps the canal patent and enhances the circumferential flow. A prerequisite for these procedures to work is the integrity of the distal outflow system, which can be evaluated by two clinical tests before surgery: provocative gonioscopy with blood reflux and fluorescein channelography. Ab externo SC surgery is suitable for open angle glaucoma, but also for angle closure glaucoma in combination with cataract extraction. IOP reduction to the mid-teens for viscocanalostomy, and to the lower teens for canaloplasty can be expected. The majority of complications seen in filtering surgery are largely eliminated by the nonpenetrating and bleb independent approach. Postoperative care is minimal as no bleb management like needling is required, and hypotony-related complications are largely avoided by the intrinsic resistance of the physiologic outflow system. For its efficacy and high safety profile, ab externo SC surgery will continue to play an increasing role and will change the current concept of glaucoma surgery towards earlier intervention. Surgeons will be well advised to implement these antimetabolite free procedures into their armamentarium to meet the expectations of the demanding glaucoma patient. PMID- 22517179 TI - Ab interno Schlemm's canal surgery: trabectome and i-stent. AB - In primary open-angle glaucoma, the site of greatest resistance to aqueous outflow is thought to be the trabecular meshwork. Augmentation of the conventional (trabecular) outflow pathway would facilitate physiologic outflow and subsequently lower intraocular pressure. Ab interno Schlemm's canal surgery including two novel surgical modalities, Trabectome (trabeculotomy internal approach) and Trabecular Micro-bypass Stent (iStent), is designed to reduce intraocular pressure by this approach. In contrast to external filtration surgeries such as trabeculectomy and aqueous tube shunt, these procedures are categorized as internal filtration surgeries and are both performed from an internal approach via gonioscopic guidance. Published results suggest that these surgical procedures are both safe and efficacious for the treatment of open-angle glaucoma. PMID- 22517180 TI - Surgical treatment of angle-closure glaucoma. AB - The main objective of surgical treatment in angle closure is to quickly decrease the intraocular pressure and therefore reduce the risk of further glaucomatous optic nerve damage. Surgical treatment of angle-closure glaucoma also helps to ensure that progressive angle closure does not occur, and that the risk of acute angle closure is abolished. The surgical options are diverse and include laser surgery, filtering surgery, lens extraction, combined lens extraction and filtering surgery, angle widening procedures such as goniosynechialysis, lens extraction combined with goniosynechialysis or a combination of procedures. PMID- 22517181 TI - Management of concomitant cataract and glaucoma. AB - The coexistence and management of cataract and glaucoma represents a challenging and unsolved problem. The surgical management of this problem is based on both visual field defect and loss of visual acuity. The surgical options currently available are: (1) cataract extraction alone; (2) cataract extraction followed by glaucoma surgery; (3) glaucoma surgery and afterwards, if necessary, cataract extraction; (4) combined surgery of cataract and glaucoma by one site or by two separate sites. Phacoemulsification alone is suggested when glaucoma can be sufficiently controlled by medication and visual field defect is moderate and not progressive. When glaucoma needs three or more types of medication to reduce intraocular pressure (IOP) or when the offset is unpredictable, phacoemulsification associated with glaucoma surgery at two different times allows a higher IOP reduction than that with a cataract extraction alone. Finally, when glaucoma is prevailing and the surgeon fears that an IOP spike after phacoemulsification may cause significant damage to the optic nerve, combined surgery allows to achieve a greater IOP decrease than phacoemulsification alone and a more predictable low-IOP range in the immediate postoperative period. PMID- 22517182 TI - Surgical management of pediatric glaucoma. AB - Pediatric glaucoma surgery is challenging because of the differences in anatomy from the adult, differences in the behavior of the tissues of a child's glaucomatous eye, the variety in causes of the disease, and difficulties with postoperative management. Goniotomy and trabeculotomy are the preferred initial treatments for primary congenital glaucoma. Trabeculectomy with adjunctive mitomycin C is more likely to succeed in older, phakic patients, but carries the long-term risk of bleb-associated endophthalmitis. Glaucoma drainage devices may be preferred in younger children and in patients with aphakic glaucoma, but these devices can cause tube-related complications. Lastly, cyclodestructive procedures are reserved for patients in whom filtering surgery has failed, given its more unpredictable effects and serious complications. PMID- 22517183 TI - When should we give up filtration surgery: indications, techniques and results of cyclodestruction. AB - PURPOSE: Cyclodestructive procedures are traditionally used in cases of glaucoma that are refractory to medical and surgical therapy. The goal of this chapter is to describe indications, contraindications, techniques, and pitfalls of cyclodestructive procedures including transscleral cyclophotocoagulation (TCP) and endoscopic cyclophotocoagulation (ECP). METHODS: A literature search for cyclophotocoagulation was performed. Relevant studies were included for evaluation and review. RESULTS: It is encouraging that TCP seems relatively efficacious even for patients who have been refractory to other treatments, depending on the energy setting, follow-up period, and definition of success. Repeated TCP is often required. TCP was more often used in eyes with limited visual potential caused by severe forms of glaucoma than in eyes with good visual potential. Serious complications were significant vision loss, inflammation, hypotony, and phthisis. ECP came later into clinical use for the treatment of refractory glaucoma. ECP is able to specifically target the ciliary epithelium under direct viewing as compared to TCP, which is an indirect cyclodestructive procedure. In the literature, it has been demonstrated that ECP has overall good success with relatively low complication rates when used for adult forms of glaucoma. There appeared to be a tendency to perform ECP earlier when combined with cataract surgery for controlling intraocular pressure. Serious complications of ECP were hypotony-related disorders, macular edema, and choroidal and retinal detachment. Recent publications have shown that both TCP and ECP may be reasonable first-line surgeries or even first-line treatments. CONCLUSIONS: Both TCP and ECP are effective cyclodestructive procedures and alternatives for the treatment of glaucoma refractory to medical and surgical therapy, though potential for serious complications exists. Recent studies have indicated that TCP and ECP are used increasingly as the primary surgery for various kinds and stages of glaucoma. PMID- 22517184 TI - Effects of pulse width, pulse rate and paired electrode stimulation on psychophysical measures of dynamic range and speech recognition in cochlear implants. AB - OBJECTIVES: In this article results are described of a study on the effects of stimulation rate (PR), pulse duration (PW), and paired pulsatile stimulation (PPS) versus continuous interleaved sampling (CIS) on speech perception and psychophysical loudness measures. METHODS: During 3 nonconsecutive days, 27 postlingually deafened patients, implanted with either a CII or a HiRes90K with a HiFocus electrode array, were fitted with nine 12-channel strategies after a Latin-square design, systematically investigating the effect of stimulation rate (774-3868 pps/channel), PW (11-43 usec/phase), and PPS versus CIS. Speech perception was measured in phonemes using open-set monosyllabic words. Minimum (T level) and maximum stimulation (M level) levels were measured. RESULTS: In general, performance was better with CIS strategies than with PPS strategies. There was little variation in speech perception performance between the different CIS strategies. As expected, PW and rate influenced the T and M levels in a systematic way for all electrode array positions. The T levels decreased by 2.11 dB per doubling of the pulse rate, whereas the M levels were considerably less influenced (slope -0.81 dB per doubling of the rate). T levels decreased 6.46 dB per doubling of pulse width, with an associated decrease in M levels of 5.58 dB, which is expressed in a closed-set formula. Changing from CIS to PPS led to a reduction of T levels by 1.34 dB and of M levels by 1.91 dB. This reduction was superimposed on the changes caused by doubling the rate, inherent to the PPS paradigm. CONCLUSIONS: CIS strategies tend to perform better than PPS strategies. PW, rate and paired stimulation have little effect on speech perception scores. However, they do have predictable and independent effects on both T and M levels for all strategies tested. The relationships found allow the improvement of the versatility of current fitting software and provide a basis to let the fitting software automatically adjust T and M levels if the PW or rate are adjusted in an existing program. PMID- 22517185 TI - Spatial acuity in 2-to-3-year-old children with normal acoustic hearing, unilateral cochlear implants, and bilateral cochlear implants. AB - OBJECTIVES: : To measure spatial acuity on a right-left discrimination task in 2 to-3-year-old children who use a unilateral cochlear implant (UCI) or bilateral cochlear implants (BICIs); to test the hypothesis that BICI users perform significantly better when they use two CIs than when using a single CI, and that they perform better than the children in the UCI group; to determine how well children with CIs perform compared with children who have normal acoustic hearing (NH); to determine the effect of intensity roving on spatial acuity. DESIGN: : Three groups of children between 26 and 36 months of age participated in this study: 8 children with NH (mean age: 30.9 months), 12 children who use a UCI (mean age: 31.9 months), and 27 children who use BICIs (mean age: 30.7 months). Testing was conducted in a large sound-treated booth with loudspeakers positioned in a horizontal arc with a radius of 1.2 m. The observer-based psychophysical procedure was used to measure the children's ability to identify the hemifield containing the sound source (right versus left). Two methods were used for quantifying spatial acuity, an adaptive-tracking method and a fixed-angle method. In Experiment 1 an adaptive tracking algorithm was used to vary source angle, and the minimum audible angle (MAA), the smallest angle at which right-left discrimination performance is better than chance, was estimated. All three groups participated in Experiment 1. In Experiment 2 source angles were fixed at +/-50 degrees, and performance was evaluated by computing the number of SDs above chance. Children in the UCI and BICI groups participated in Experiment 2. RESULTS: : In Experiment 1, when stimulus intensity was roved by 8 dB, MAA thresholds were 3.3 degrees to 30.2 degrees (mean = 14.5 degrees) and 5.7 degrees to 69.6 degrees (mean = 30.9 degrees) in the NH group and in the BICI group, respectively. When the intensity level was fixed for the BICI group, performance did not improve. Within the BICI group, 5 out of 27 children obtained MAA thresholds within one SD of their peers who have NH; all five had >12 months of bilateral listening experience. In Experiment 2, BICIs provided some advantages when the intensity level was fixed. First, the BICI group outperformed the UCI group. Second, children in the BICI group who repeated the task with their 1st CI alone had statistically significantly better performance when using both devices. In addition, when intensity roving was introduced, a larger percentage of children who had 12 or more months of BICI experience continued to perform above chance than children who had <12 months of BICI experience. Taken together, the results suggest that children with BICIs have spatial acuity that is better than when using their first CI alone and than that of their peers who use UCIs. In addition, longer durations of BICI use tend to result in better performance, although this cannot be generalized to all participants. CONCLUSION: : This report is consistent with a growing body of evidence that spatial-hearing skills can emerge in young children who use BICIs. The observation that these skills are not concomitantly emerging in age- and experience-matched children who use UCIs suggests that BICIs provide cues that are necessary for these spatial-hearing skills that UCIs do not provide. PMID- 22517186 TI - Leiomyosarcoma and sarcoma with myogenic differentiation: two different entities or 2 faces of the same disease? AB - BACKGROUND: The objective of this study was to evaluate whether the distinction between leiomyosarcomas (LMS) and sarcomas with myogenic differentiation (SMD), based on the expression of muscular markers, has any clinical implications. METHODS: Patients with localized LMS (excluding any gynecologic subtype) or SMD who underwent surgery at the authors' institution from 1994 to 2010 were analyzed. Overall survival (OS) and the crude cumulative incidence of local recurrence and distant metastasis (DM) were calculated, and multivariable analyses for DM and OS were carried out. RESULTS: In total, 327 patients were studied (71% LMS, 29% SMD). The median follow-up was 58 months (interquartile range, 31-97 months). The 5-year overall survival rate was 72.9% (95% confidence interval, 66.3%-80.2%) for the patients with LMS and 64.4% (95% confidence interval, 53.7%-77.1%) for the patients with SMD. The 5-year crude cumulative incidence of distant metastasis was 36.2% (95% confidence interval, 30.1%-43.5%) in the LMS group and 32.6% (95% confidence interval, 24%-44.2%) in the SMD group. Although tumor grade in LMS identified 3 distinct classes of risk, patients with grade 2 and grade 3 SMD had a similar course. The median postmetastasis survival was longer in patients with grade 3 LMS compared versus patients with grade 3 SMD (31 months vs 15 months, respectively). In patients who had grade 3 lesions, adjuvant chemotherapy yielded a better outcome in the SMD group compared with the LMS group (hazard ratio, 0.38). Patients who had superficial LMS had better outcomes compared with patients who had superficial SMD. CONCLUSIONS: The current results indicated that LMS and SMD do not share the same natural history. A limited prognostic impact of grade was observed in patients with SMD. Differences in response to chemotherapy should be taken into account in planning the therapeutic approach for patients with these tumors. The current clinical observations may correspond to the biology of a different disease and deserve further study. PMID- 22517187 TI - Ionic liquids promote PCR amplification of DNA. AB - A bicyclic imidazolium ionic liquid (4d), [b-4C-im][Br], was found to be highly effective not only for promoting PCR of GC-rich DNA by minimizing non-specific amplification, but also for facilitating PCR of normal-GC DNA under mild conditions. PMID- 22517188 TI - Racial differences in outcomes of the evaluation of potential live kidney donors: a retrospective cohort study. AB - BACKGROUND: In the USA, the lower rate of live donor kidney transplant among Black transplant candidates may stem from lower rates of donation among potential live donors who are Black. We determined whether outcomes of the evaluation of potential live kidney donors varied according to the potential donors' demographic characteristics. METHODS: We performed a single-center, retrospective observational cohort study of 1,179 potential live kidney donors, who came forward between 2000 and 2007. Potential donors' intended recipients were first time transplant recipients who were evaluated between 2000 and 2005. RESULTS: There were 268 (22.7%) potential live kidney donors who were Black, of whom 93.7% were recruited by Black transplant candidates. Donor outcomes included actual donation (38.3%), exclusion due to blood group or crossmatch incompatibility (20.4%), exclusion due to medical contraindication to donation (13.7%), and lack of further donor interest (11.2%). Black (vs. non-Black) potential donors were less likely to actually donate (27.2 vs. 41.6%, p < 0.001). Black potential donors were more likely to stop pursuing live donation (p = 0.047) or be excluded from donation for medical reasons (p = 0.008) or blood group or crossmatch incompatibility (p = 0.01). These racial differences persisted in a multivariable multinomial logistic regression model of factors associated with outcomes of the donor evaluation. CONCLUSIONS: Potential live kidney donors who are Black are less likely to actually donate. Future studies should determine whether paired exchange and desensitization programs decrease these racial differences and why Black potential donors appear more likely to stop pursuing live donation. PMID- 22517189 TI - Designing organometallic compounds for catalysis and therapy. AB - Bioorganometallic chemistry is a rapidly developing area of research. In recent years organometallic compounds have provided a rich platform for the design of effective catalysts, e.g. for olefin metathesis and transfer hydrogenation. Electronic and steric effects are used to control both the thermodynamics and kinetics of ligand substitution and redox reactions of metal ions, especially Ru(II). Can similar features be incorporated into the design of targeted organometallic drugs? Such complexes offer potential for novel mechanisms of drug action through incorporation of outer-sphere recognition of targets and controlled activation features based on ligand substitution as well as metal- and ligand-based redox processes. We focus here on eta(6)-arene, eta(5) cyclopentadienyl sandwich and half-sandwich complexes of Fe(II), Ru(II), Os(II) and Ir(III) with promising activity towards cancer, malaria, and other conditions. PMID- 22517191 TI - Tic-induced gait dysfunction. AB - BACKGROUND: Many neurological disorders impair gait, but only a few of them are episodic or paroxysmal, the most important ones being freezing of gait and paroxysmal dyskinesias. METHODS: We describe 4 patients with tic disorders (3 with Tourette syndrome, and 1 with a tic disorder secondary to vascular disease) in whom intrusion of complex motor tics interfered with normal progression of stepping, thus producing an episodic gait disorder. RESULTS: The involuntary movements that interfered with gait had features typical for tics, including their brief, sudden, irresistible, inapposite, and nonrhythmic recurrence. The motor behavior resembled tripping (n = 2), "blocking" of gait, or hip movements minimally interfering with gait. CONCLUSIONS: Tic-induced gait disturbance is an episodic gait disorder occurring in patients with tics and should be recognized as a possible cause of episodic gait disturbances. PMID- 22517190 TI - Separate and combined effects of very low nicotine cigarettes and nicotine replacement in smokers with schizophrenia and controls. AB - INTRODUCTION: The prevalence of smoking among people with schizophrenia in the United States is about 3 times that of the general population. Novel approaches are needed to reduce rates of smoking-related morbidity and mortality among these smokers. METHODS: This study used a within-subjects design to investigate the separate and combined effects of sensorimotor replacement for smoking (very low nicotine content [VLNC] cigarettes vs. no cigarettes) and transdermal nicotine replacement (42 mg nicotine [NIC] vs. placebo [PLA] patches) in smokers with schizophrenia (SS; n = 30) and control smokers without psychiatric illness (CS; n = 26). Each session contained a 5-hr controlled administration period in which participants underwent the following conditions, in counterbalanced order: VLNC + NIC, VLNC + PLA, no cigarettes + NIC, no cigarettes + PLA, usual-brand cigarettes + no patches. Next, participants completed measures of cigarette craving, nicotine withdrawal, smoking habit withdrawal, and cigarette subjective effects, followed by a 90-min period of ad libitum usual-brand smoking. RESULTS: Smoking VLNC cigarettes during the controlled administration periods reduced cigarette craving, nicotine withdrawal symptoms, habit withdrawal symptoms, and usual-brand smoking in SS and CS relative to the no cigarette conditions. VLNC cigarettes were well accepted by both groups and did not affect psychiatric symptom levels in SS. Transdermal nicotine significantly reduced cigarette craving but did not affect usual-brand smoking. CONCLUSIONS: These findings suggest that reducing the nicotine content of cigarettes to nonaddictive levels may be a promising approach for reducing nicotine dependence among people with schizophrenia. PMID- 22517192 TI - The foreign-language effect: thinking in a foreign tongue reduces decision biases. AB - Would you make the same decisions in a foreign language as you would in your native tongue? It may be intuitive that people would make the same choices regardless of the language they are using, or that the difficulty of using a foreign language would make decisions less systematic. We discovered, however, that the opposite is true: Using a foreign language reduces decision-making biases. Four experiments show that the framing effect disappears when choices are presented in a foreign tongue. Whereas people were risk averse for gains and risk seeking for losses when choices were presented in their native tongue, they were not influenced by this framing manipulation in a foreign language. Two additional experiments show that using a foreign language reduces loss aversion, increasing the acceptance of both hypothetical and real bets with positive expected value. We propose that these effects arise because a foreign language provides greater cognitive and emotional distance than a native tongue does. PMID- 22517193 TI - Retinal vascular calibre, geometry and progression of diabetic retinopathy in type 2 diabetes mellitus. AB - PURPOSE: To determine whether changes in retinal vascular calibre and geometry are associated with progression of diabetic retinopathy in type 2 diabetes (T2D). PROCEDURES: The retinal vascular calibre and geometry of 30 subjects with more than 20 years of diagnosed T2D with no retinopathy (NR) were compared to 30 subjects that progressed to proliferative diabetic retinopathy (PDR). The images of PDR subjects included in this study were those obtained before the onset of retinopathy. The diameter of retinal arterioles (CRAE), retinal venules (CRVE), tortuosity of retinal vessels, junctional exponent deviation (JE(a)) and fractal dimension (D(f)) were measured using Singapore I Vessel Assessment (SIVA 3.0) software and compared using Mann-Whitney U test. RESULTS: The median CRAE and the median CRVE were significantly wider in PDR subjects compared to NR subjects (p = 0.014 and 0.016), respectively. Curvature tortuosity of the retinal arteries and veins and D(f) were significantly decreased in the PDR subjects compared to NR subjects (p = 0.015, 0.016 and 0.03, respectively). The JE(a) was significantly increased in PDR subjects (p = 0.01). CONCLUSIONS: Retinal vessel calibre and geometry of the retinal vasculature may be important risk factors for the progression to PDR. More longitudinal prospective studies will be needed to further explore the findings of this study. PMID- 22517194 TI - MR, (18)F-FDG, and (18)F-AV45 PET correlate with AD PSEN1 original phenotype. AB - We report the case of a 37-year-old man suffering from insidious visual agnosia and spastic paraparesis due to a PSEN1 mutation. His mother was diagnosed with Alzheimer disease after a biopsy. He was assessed by multimodal neuroimaging, including new in vivo positron emission tomography amyloid imaging (F-AV45). His data were compared with those from healthy participants and patients with sporadic predemential Alzheimer disease. He exhibited posterior cortical thickness reduction, posterior hypometabolism, and increased amyloid ligand uptake in the posterior cortex and the striatum. We show that F-AV45 positron emission tomography allows visualization of the unusual pattern of amyloid deposits that co-localize with cortical atrophy in this genetic form of Alzheimer disease. PMID- 22517195 TI - Aromatic capping surprisingly stabilizes furan moieties in peptides against acidic degradation. AB - We herein describe the synthesis of furan containing peptides for further post synthetic derivatisation in solution through our recently developed furan oxidation-labeling technology. Previously, it was reported by others that during acidic cleavage of furan-modified peptides, furan moieties can suffer from degradation. We demonstrate here that this degradation is position dependent and can be fully suppressed through introduction of proximate aromatic residues. Versatile introduction of 2-furylalanine at internal, C-terminal as well as the sensitive N-terminal positions has now been proven possible. PMID- 22517196 TI - Stress urinary incontinence and quality of life: a reliability study of a condition-specific instrument in paper and web-based versions. AB - AIMS: Quality of life is an important outcome measure in studies of urinary incontinence. Electronic collection of data has several advantages. We examined the reliability of the Swedish version of the highly recommended condition specific quality of life questionnaire International Consultation on Incontinence Modular Questionnaire-Lower Urinary Tract Symptoms Quality of Life (ICIQ LUTSqol), in paper and web-based formats in women with stress urinary incontinence. METHODS: Women aged 18-70 years, with stress urinary incontinence at least once weekly, were recruited via the project's website and answered the ICIQ-LUTSqol questionnaire. Respondents completed either the paper version twice (n = 78), or paper and web-based versions once each (n = 54). The ICIQ validation protocol was followed. RESULTS: The mean interval between answers was 18.1 (SD = 3.1) days in the paper versus paper setting and 15.0 (SD = 7.8) days in the paper versus web-based setting. Internal consistency was excellent, with Cronbach's alpha coefficients of 0.87 for the paper version and 0.86 for the web-based version. There was a high degree of agreement of overall scores with intraclass correlations in the paper versus paper and paper versus web-based settings: 0.95 (P < 0.001) and 0.92 (P < 0.001), respectively. The mean of each individual item's weighted kappa value was 0.61 in both settings. CONCLUSIONS: The questionnaire is reliable in women with stress urinary incontinence, and it can be used in either a paper or a web-based version. PMID- 22517197 TI - Cell adhesion and glistening formation in hybrid copolymer intraocular lenses. AB - The purpose of this study is to investigate the cell adhesion and glistening formation properties of various foldable intraocular lenses (IOLs) in vitro. Three conventional hydrophobic methacrylate acrylic (MA) IOLs, a hydrophilic hydroxyethyl methacrylate (HEMA) IOL and a hybrid MA/HEMA copolymer IOL were investigated for immunologically activated cell adhesion and for formation of glistenings resulting from cavitation, by analysis of digital images using NIH Image J PC software. The MA IOLs exhibited a low level of adhering cells but a high level of glistening formation, the HEMA IOL exhibited the reverse tendency, and the MA/HEMA IOL exhibited a low level of both, thus indicating that hybrid MA/HEMA IOLs are less susceptible than HEMA IOLs to cell adhesion and less susceptible than MA IOLs to glistening formation. PMID- 22517199 TI - Resection margin involvement and tumour origin in pancreatic head cancer. AB - BACKGROUND: Assessment of the origin of adenocarcinoma in pancreatoduodenectomy specimens (pancreatic, ampullary or biliary) and resection margin status is not performed in a consistent manner in different centres. The aim of this review was to identify the impact of such variations on patient outcome. METHODS: A systematic literature search for articles on pancreatic, ampullary, distal bile duct and periampullary cancer was performed, with special attention to data on resection margin status, pathological examination and outcome. RESULTS: The frequent reclassification of tumour origin following slide review, and the wide variation in published incidence of pancreatic (33-89 per cent), ampullary (5-42 per cent) and distal bile duct (5-38 per cent) cancers indicate that the histopathological distinction between the three cancer groups is less accurate than generally believed. Recent studies have shown that the wide range of rates of microscopic margin involvement (R1) in pancreatoduodenectomy specimens (18-85, 0-27 and 0-72 per cent respectively for pancreatic, ampullary and distal bile duct cancers) is mainly caused by differences in pathological assessment rather than surgical practice and patient selection. As a consequence of the existing inconsistency in reporting of these data items, the clinical significance of microscopic margin involvement in each of the three cancer groups remains unclear. CONCLUSION: Inaccurate and inconsistent distinction between pancreatic, ampullary and distal bile duct cancer, combined with inaccuracies in resection margin assessment, results in obfuscation of key clinicopathological data. Specimen dissection technique plays a key role in the quality of the assessment of both tumour origin and margin status. Unless the pathological examination is meticulous and standardized, comparison of results between centres and observations in multicentre trials will remain of limited value. PMID- 22517200 TI - The philosophy of treatment of uveitis: past, present and future. AB - Treatment of inflammatory diseases of the eye is especially challenging. Although physicians in antiquity had recognized the existence of ocular inflammatory disease, their lack of understanding of the immune system made successful treatment almost impossible. Throughout the 20th century, great advances in the diagnosis and treatment of uveitis led to unique treatment options. The development of corticosteroids in 1949 and its application to the eye in 1950 revolutionized therapeutic strategies. As the use of corticosteroids became more prevalent in treating ocular inflammatory diseases, so did its side effects. Due to the high morbidity in conjunction with long-term corticosteroid use, physicians pursued other agents, specifically through the employment of chemotherapeutic agents. The shift from exclusive corticosteroid monotherapy to steroid-sparing immunomodulatory therapy reshaped the landscape of treating ocular inflammatory disease. Over time, with increased efforts, new therapies were studied, trialed, and brought to the market. Today, in comparison to any other time in history, physicians have available to them the largest array of effective agents for achieving the ultimate goal: corticosteroid-free, durable remission. PMID- 22517201 TI - The gold standard of noninfectious uveitis: corticosteroids. AB - Corticosteroids (CS) are considered to be the mainstay of therapy in noninfectious uveitis. They can be administered only after excluding an infectious origin or a possible masquerade syndrome. Different CS preparations can be used with various modes of administration: topical, periocular, intraocular, systemic or a combination of the above routes. Their indications depend upon numerous factors, among them the type (involving or not the posterior segment), the severity, the uni-/bilaterality, the chronicity of the intraocular inflammation. The induction treatment must be aggressive in order to overcome the intraocular inflammation as rapidly as possible avoiding permanent tissue damage. The dosage regimen is then tapered according to the clinical response and after a minimum period of quiescence. The maintenance CS treatment should not exceed 6-12 months under the threat of severe adverse effects. In chronic cases, high-dosage CS monotherapy cannot be used; it is important to add an immunomodulatory treatment on time when a long-term therapy is needed to control the disease. Although CS represent the first line of treatment, the type of clinical response to CS is not a reliable indicator of the effectiveness of immunomodulation: a noninfectious uveitis unresponsive to CS may respond to immunomodulation alone or combined with CS. PMID- 22517202 TI - Corticosteroid-sparing agents: conventional systemic immunosuppressants. AB - The introduction of corticosteroids in the mid-20th century to control inflammatory eye disease revolutionized treatment practices. As long-term use of corticosteroids became the backbone of immunosuppressive therapy, it soon became evident that it was associated with significant morbidity to the patient. For this reason, other immunosuppressant agents were sought. Thereafter, the first generation of immunosuppressive agents were born. The main action of all such agents involves the inhibition of lymphoid proliferation. The agents can be further subdivided into the following categories based on their specific mechanism of action: alkylating (cyclophosphamide and chlorambucil), antimetabolite (methotrexate, mycophenolate mofetil and azathioprine), and antibiotic/calcineurin inhibitor (cyclosporine, tacrolimus and sirolimus). These immunomodulating agents serve as the foundation to modern corticosteroid-sparing immunosuppressive therapy. Many times, these agents are now even indicated as first-line therapy for the treatment of systemic inflammatory diseases with destructive ocular sequela, e.g. Behcet's disease and granulomatosis with polyangiitis (Wegener's). Choosing the most appropriate immunomodulatory agent to initiate therapy can often be difficult; a multifactorial approach in the decision-making process is essential. Special attention must be given to the patient's medical history, type and severity of inflammatory disease, social history, compliance, age, and sex. Oftentimes, it takes a joint effort between the ophthalmologist and multiple sub-specialists (rheumatology, oncology, and hematology) to administer and monitor these therapies. Even though each of these systemic immunosuppressive agents has its own array of potential side effects, with careful monitoring and titration of dosages, such potential side effects can be minimized or avoided altogether. Ultimately, these patients are afforded a much more favorable long-term outcome, free of the devastating effects of chronic corticosteroid use. PMID- 22517203 TI - Corticosteroid-sparing agents: new treatment options. AB - Corticosteroids form the cornerstone of treatment for noninfectious uveitis, but their safety profile and adverse effects render their use a double-edged sword. As a result, the local benefits of treating ocular inflammation may be outweighed by systemic adverse effects, and it is mainly for this reason that steroid sparing agents are used. Most of these systemic immunomodulatory drugs used in ophthalmology have been adopted from other specialties, such as rheumatology and, while their safety profiles make them valid alternatives to long-term high-dose corticosteroids, systemic side effects still prove problematic for a significant proportion of patients. The desire to avoid these systemic side effects has driven the continuing search for effective agents with an improved safety profile, but also the increasing use of local drug administration, which avoids systemic side-effects, but may lead to ocular complications. Here we review both approaches and discuss the possible risks and benefits of each. PMID- 22517204 TI - Mycophenolate mofetil use in the treatment of noninfectious uveitis. AB - Mycophenolate mophetil (MMP) is a potent immunomodulatory drug that inhibits the function of T and B lymphocytes. It is used successfully in the treatment of recurrent noninfectious uveitis in adults and children. MMF can be used alone or in combination with other immunomodulatory drugs (biologics or calcineurin inhibitors) for moderate and severe cases of anterior, intermediate and posterior uveitis. It can also be used for treatment of patients with scleritis and ocular cicatricial pemphigoid. PMID- 22517205 TI - Anti-tumor necrosis factor-alpha agents in noninfectious uveitis. AB - Anti-tumor necrosis factor-alpha (anti-TNF-alpha) agents represent a major breakthrough for the therapeutic management of different autoimmune conditions. Noninfectious uveitis may lead to various sight threatening complications. Hence, from extrapolation of the benefit observed in autoimmune systemic diseases, anti TNF-alpha agents are widely used in the treatment of noninfectious uveitis. However, their use remains mostly 'off-label' in this indication, and the lack of evidence from randomized controlled studies limits a rationale choice. This review gives an update on the management of uveitis with TNF-alpha inhibitors, highlighting important issues, including initiation time, type of molecule, duration of therapy but also major adverse events. PMID- 22517206 TI - New biologic drugs: anti-interleukin therapy. AB - Interleukins (ILs) are cytokines which are defined by their capability to convey information between leukocytes, in this way directing proliferation, activation, and migration and also regulation of the cells. Data from anti-IL treatments in systemic autoimmune diseases have shown these drugs to be beneficial and to have a satisfactory safety profile and tolerance. Recent publications of small case series suggest that several anti-IL drugs have considerable efficacy in treating otherwise refractory uveitis. Anti-IL therapy, therefore, might constitute an option for the treatment of uveitis resistant to corticosteroids, classical immunosuppressives, or tumor necrosis factor-alpha inhibitors. However, due to high costs and possible long-term risks, anti-IL agents should currently be reserved to selected uveitis patients and be administered only under close interdisciplinary monitoring. PMID- 22517207 TI - Interferon-alpha therapy in noninfectious uveitis. AB - Interferon (IFN)-alpha and IFN-beta are naturally occurring cytokines which seem to have similar effects on the immune system. One of the effects of IFN seems to increase regulatory T cells. There are numerous case reports and studies reporting about the effect of IFN-alpha against Behcet's disease (BD), but also against chronic uveitic macular edema and a few other types of uveitis. Within 2 4 weeks, approximately 94% of patients reach complete or partial remission in the case of BD-associated uveitis. So far, IFN-alpha is the only drug that leads to stable remission even after discontinuation of the treatment. It is recommended to start treatment with 3-6 million IU per day. Administering less than daily dosages seems to increase the recurrence rate for BD-associated uveitis. Flu-like symptoms are expected in all patients as a sign of nonexisting anti-IFN antibodies. They are treated with nonsteroidal anti-inflammatory drugs like paracetamol and disappear normally after some days. Depression(8%) and mild leukopenia (30%) are additional side effects of concern; all other side effects are reported to appear in <=1% of cases. This chapter updates the mechanisms and pharmacology of IFN and its effects in experimental studies. This is followed by a summary of clinical studies in intraocular inflammation and the spectrum of side effects. PMID- 22517208 TI - Rituximab for noninfectious uveitis. AB - Rituximab (RTX) is a monoclonal antibody directed against the CD20 antigen expressed on B cells. This drug has been successfully employed in the treatment of non-Hodgkin's lymphoma and different systemic autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, granulomatosis with polyangiitis (Wegener's) and anti-neutrophil cytoplasmic antibody-associated vasculitis. At present, RTX may be used in patients with rheumatoid arthritis who qualify for treatment with tumor necrosis factor blockers and have had an inadequate response or intolerance to one or more of these agents. In ophthalmology, there is a growing amount of literature which suggests that RTX may be useful for inflammatory ocular diseases. Only few cases have been reported on treatment of ocular inflammatory disease mostly refractory scleritis, peripheral ulcerative keratitis, uveitis in adulthood and in children with juvenile idiopathic arthritis. RTX has also been employed in ocular surface diseases such as ocular cicatricial pemphigoid and conjunctival lymphoma. The tolerability and safety of RTX is good with the most common adverse events encountered being infusion reactions. RTX may be effective in the treatment of ocular inflammatory diseases, in particular the most aggressive, recalcitrant and sight-threatening forms of inflammation and uveitis. Although further studies are needed to assess the efficacy of RTX and the exact dosing regimen, RTX may be considered as a treatment alternative in patients with the most aggressive forms of inflammatory ocular diseases who fail to respond to conventional and other biologic agents. PMID- 22517209 TI - Intravitreal injection therapy in the treatment of noninfectious uveitis. AB - Uveitis is responsible for 5-20% of legal blindness in the United States and in Europe. In noninfectious uveitis, the most frequent uveitic complication that endangers sight is cystoid macular edema. Clinical characteristics, inflammation grading and visual acuity determine the choice of the correct therapy for each patient. We can utilize drugs either alone or in combination using different dosages and routes of administration. Intravitreal injection directly into the vitreous cavity leads to rapid therapeutic drug concentration in the retinal tissue and reduces systemic side effects. Intravitreally injected triamcinolone acetonide is the most powerful drug for the treatment of cystoid macular edema related to intraocular inflammation, but it also causes the most frequent and serious side effects. Due to the numerous side effects associated with the use of corticosteroids, there is a need to identify other anti-inflammatory agents with a better safety profile. Recent studies have demonstrated that intravitreal immunosuppressant injections of methotrexate or anti-VEGF agents may lead to fewer intraocular side effects, but also have a lower therapeutic activity for the reduction of macular edema. At present, intraocular anti-TNF-alpha drugs do not show promising results. As regards nonsteroidal anti-inflammatory drugs, further data are necessary to fully understand their efficacy and potential side effects. PMID- 22517210 TI - Corticosteroid intravitreal implants. AB - Intraocular implants developed for ocular inflammation which release glucocorticoids for a prolonged period within the vitreous cavity make use of either a bioerodible polymer (dexamethasone in polylactic acid-coglycolic acid matrix) or non-erodible implantable device (fluocinolone acetonide, FA, in a polyvinyl acetate/silicone laminate). Pharmacologically, both steroids are similar in their binding characteristics to glucocorticoid receptors (GR), their ability to transactivate the GR complex and their vitreous half-lives. They both possess neuroprotective properties for retina and retinal pigment epithelium which place them apart from triamcinolone acetonide. Triamcinolone acetonide's higher lipophilicity makes it possible to create an implant with prolonged release characteristics, but may be increasing the propensity for ocular side effects such as cataract and glaucoma. In clinical trials, both implants were shown to be effective at inhibiting intraocular inflammation in patients with intermediate or posterior uveitis. The Dexamethasone implant is inserted through a 22-gauge needle through the pars plana and can control inflammation for up to 6 months. The FA implant requires surgical insertion through the pars plana and can control inflammation for up to 3 years. The MUST trial has shown the FA implant when placed bilaterally to be slightly more effective than strict systemic therapy, though at the cost of additional ocular surgeries for cataract and glaucoma. Certain clinical situations particularly with asymmetric uveitis may in fact favor local vs. systemic therapy. PMID- 22517211 TI - New treatment options for noninfectious uveitis. AB - Autoimmune uveitis is a group of sight-threatening inflammatory diseases associated with an exacerbated immunological response to ocular proteins. The Standardization of Uveitis Nomenclature Working Group Guidelines have recommended the use of corticosteroids as the first line of therapy for patients who present with active uveitis. However, long-term use of corticosteroids is associated with numerous adverse effects including cataract, glaucoma and metabolic disorders. In this context, new drugs developed to treat rheumatic diseases, and other autoimmune diseases, are being employed often as monotherapy or combined with other immunosuppressive drugs in order to decrease the corticosteroid burden on patients and to manage refractive uveitis. These drugs are currently being evaluated in the framework of uveitis and may open a new horizon with less side effects and more responsiveness for chronic cases. Among others, calcineurin inhibitor voclosporin, mammalian target of rapamycin inhibitor sirolimus, and the IL-1 trap rilonacept, are among these new agents and will be scrutinized in detail in this chapter. More efficient modes of drug delivery are also being employed to deliver high concentration of drug locally and to minimize systemic side effects. The new modes of drug delivery that we will describe in the index chapter include nanoparticles and iontophoresis. PMID- 22517212 TI - Metamagnetism and weak ferromagnetism in nickel (II) oxalate crystals. AB - Microcrystals of orthorhombic nickel (II) oxalate dihydrate were synthesized through a precipitation reaction of aqueous solutions of nickel chloride and oxalic acid. Magnetic susceptibility exhibits a sharp peak at 3.3 K and a broad rounded maximum near 43 K. We associated the lower maximum with a metamagnetic transition that occurs when the magnetic field is about >=3.5 T. The maximum at 43 K is typical of 1D antiferromagnets, whereas weak ferromagnetism behavior was observed in the range of 3.3-43 K. PMID- 22517213 TI - Cooperative self-assembly of linear organogelators. Amplification of chirality and crystal growth of pharmaceutical ingredients. AB - Linear organogelators 1 and 2, which self-assemble cooperatively into fibrillar structures, act as efficient crystal growth media for common pharmaceutical ingredients like ASP, CAF, IND and CBZ. PMID- 22517214 TI - The lipid composition of isolated cytoplasmic lipid droplets from a human cancer cell line, BE(2)M17. AB - (1)H nuclear magnetic resonance spectroscopy (NMR) resonances from lipids in tumours are associated with tumour grade and treatment response. The origin of these NMR signals is mainly considered to be cytoplasmic lipid droplets (LDs). Techniques exist for isolating LDs but little is known about their composition and its relationship to NMR signals. In this work, density-gradient ultracentrifugation was performed on homogenised human cancer cells to isolate LDs. (1)H NMR was performed on whole cells, isolated LDs and their extracts. Heteronuclear single quantum coherence spectroscopy (HSQC) and liquid chromatography mass spectroscopy (LC-MS) were performed on lipid extracts of LDs. Staining and microscopy were used to characterize isolated LDs. An excellent agreement in chemical shift and relative signal intensity was observed between lipid resonances in cells and isolated LD spectra supporting that NMR-visible lipids originate primarily from LDs. Isolated LDs showed high concentrations of unsaturated lipids, a oleic-to-linoleic acid ratio greater than two and a cholesteryl ester (ChE)-to-cholesterol (Ch) ratio close to unity. These ratios were several-fold greater than respective ratios in whole cells, demonstrating isolation is important to characterize LD composition. LDs contain a specific group of lipid species that are likely to contribute to the (1)H NMR spectrum of cells. PMID- 22517215 TI - Lumbar computerized adaptive test and Modified Oswestry Low Back Pain Disability Questionnaire: relative validity and important change. AB - STUDY DESIGN: Retrospective analysis of longitudinal, observational cohort data. OBJECTIVES: To compare discriminating ability and minimal clinically important improvement (MCII) calculated using functional status (FS) measures estimated from the lumbar computerized adaptive test (LCAT) and Modified Oswestry Low Back Pain Disability Questionnaire (ODQ). BACKGROUND: The LCAT and ODQ are commonly used to estimate FS in patients seeking outpatient therapy but have not been compared directly. METHODS: Data from 8198 adult patients who completed the LCAT and ODQ at intake were analyzed, 3379 (41%) of whom completed both surveys at discharge. Global ratings of change data were available for 980 patients. Discriminating ability of FS estimates from the LCAT and ODQ was estimated using relative validity, calculated by dividing F values from LCAT and ODQ analyses of covariance for important risk-adjustment variables. MCII was estimated using receiver-operating-characteristic analyses by quartiles of intake FS values, and areas under the curves were compared. RESULTS: Relative validity ratios favored the LCAT for age (3.7; 95% confidence interval [CI]: 2.0, 8.9), acuity (1.3; 95% CI: 1.1, 1.6), comorbidities (1.8; 95% CI: 1.3, 2.6), and surgical history (1.8; 95% CI: 1.2, 2.9). MCII cut scores per quartile favored the LCAT. Receiver operating-characteristic areas under the curves were not different. CONCLUSION: FS measures estimated by both questionnaires had similar psychometric characteristics. The LCAT FS estimates tended to be more discriminating than ODQ FS estimates. MCII cut scores by quartile of intake FS favored the LCAT. Given the need to be efficient and precise in estimating measures of FS, particularly in older patients, results favor the LCAT in busy, automated outpatient therapy clinics, which are increasingly serving an aging population. PMID- 22517216 TI - Recursive partitioning analysis of prognostic factors for glioblastoma patients aged 70 years or older. AB - BACKGROUND: The most-used prognostic scheme for malignant gliomas included only patients aged 18 to 70 years. The purpose of this study was to develop a prognostic model for patients >=70 years of age with newly diagnosed glioblastoma. METHODS: A total of 437 patients >=70 years of age with newly diagnosed glioblastoma, pooled from 2 tertiary academic institutions, was identified for recursive partitioning analysis (RPA). The resulting prognostic model, based on the final pruned RPA tree, was validated using 265 glioblastoma patients >=70 years of age from a data set independently compiled by a French consortium. RESULTS: RPA produced 9 terminal nodes, which were pruned to 4 prognostic subgroups with markedly different median survivals: subgroup I = patients <75.5 years of age who underwent surgical resection (9.3 months); subgroup II = patients >=75.5 years of age who underwent surgical resection (6.4 months); subgroup III = patients with Karnofsky performance status of 70 to 100 who underwent biopsy only (4.6 months); and subgroup IV = patients with Karnofsky performance status <70 who underwent biopsy only (2.3 months). Application of this prognostic model to the French cohort also resulted in significantly different (P < .0001) median survivals for subgroups I (8.5 months), II (7.7 months), III (4.3 months), and IV (3.1 months). CONCLUSIONS: This model divides elderly glioblastoma patients into prognostic subgroups that can be easily implemented in both the patient care and the clinical trial settings. This purely clinical prognostic model serves as a backbone for the future incorporation of the increasing number of potential molecular prognostic markers. PMID- 22517217 TI - Long-term effects of calcium antagonists on augmentation index in hypertensive patients with chronic kidney disease: a randomized controlled study. AB - BACKGROUND: Our previous retrospective study showed that benidipine was superior to amlodipine (AM) for reducing proteinuria and preserving the augmentation index (AI) in patients with chronic kidney disease (CKD). METHODS: The present study enrolled CKD patients whose blood pressure was not well controlled by an angiotensin receptor blocker (ARB) and a calcium channel blocker other than AM or azelnidipine (AZ). Either AM (5 mg) or AZ (16 mg) was prescribed randomly. Clinical parameters, including proteinuria, serum creatinine, and AI, were measured before initiation of AM or AZ and 1 year later to assess the long-term effect on renal function and central blood pressure. RESULTS: Brachial and central blood pressures were similarly reduced in both groups. However, pulse rate increased in the AM group, but decreased in the AZ group (+3 +/- 1 vs. -2 +/ 1 bpm, p < 0.0001). The reduction of proteinuria was greater in the AZ group ( 29 +/- 2 vs. -38 +/- 3%, p < 0.01). Improvement of AI adjusted for a pulse rate of 75 bpm was larger in the AZ group than in the AM group (-4 +/- 1 vs. -9 +/- 1%, p < 0.05). In both groups, estimated GFR remained unchanged throughout the observation period. CONCLUSION: In hypertensive patients with CKD, combined treatment with AZ and an ARB decreases proteinuria and preferentially improves arterial reflection. PMID- 22517218 TI - Fracture and intra-cardiac embolisation of a totally implantable vascular access device. PMID- 22517219 TI - The course of delirium in older long-term care residents. AB - OBJECTIVE: The purpose of this study was to determine the course of delirium in older long-term care (LTC) residents. METHODS: A prospective cohort study of 279 residents in seven LTC facilities in Montreal and Quebec City, Canada, was conducted. The Mini Mental State Examination (MMSE), Confusion Assessment Method (CAM), Delirium Index (DI), Hierarchic Dementia Scale, Barthel Index, and Cornell Scale for Depression were completed at baseline. The MMSE, CAM, and DI were repeated weekly for 6 months. Information on medical problems and medication was abstracted from resident charts. Data were analyzed using descriptive statistics, Cox proportional hazard regression, and logistic regression. RESULTS: Of the 279 residents, 41 (14.7%) had 61 CAM-defined incident episodes of delirium: 28 (10%) had one episode and 13 (4.7%) had two or more episodes. Episode duration was 7-63 days, mean, 11.3 (SD, 10.1) days. The mean episode DI score was 11.5 (SD, 3.5). Rates of recovery at 1, 2, 4, and 24 weeks were 57.4%, 67.2% 77.1%, and 80.3%, respectively. Most episodes were preceded or followed by one or more CAM core symptoms of delirium, sometimes lasting many weeks. CONCLUSIONS: Confusion Assessment Method-defined incident episodes of delirium in older LTC residents appear to last longer than episodes in acute care hospital patients, but rates of recovery at 4 and 24 weeks are similar. Notably, most episodes were preceded or followed by one or more CAM core symptoms of delirium. These findings have implications for clinical practice and research in LTC settings. PMID- 22517220 TI - A sensitive and reliable detection of thrombin via enzyme-precipitate-coating linked aptamer assay. AB - Stable enzyme precipitate coatings (EPCs) with high enzyme loading were employed to develop a sensitive and reliable detection protocol, termed EPC-linked aptamer assay (EPC-LAA). EPC-LAA achieved the limit of detection to be 0.5 ng per mL of thrombin (13.5 pM), and maintained a reasonably stable detection signal even after storing all the reagents at 40 degrees C for 66 days. PMID- 22517221 TI - Photolysis, OH reactivity and ozone reactivity of a proxy for isoprene-derived hydroperoxyenals (HPALDs). AB - The C(5)-hydroperoxyenals (C(5)-HPALDs) are a newly-recognized class of multi functional hydrocarbons produced during the hydroxyl radical (OH)-initiated oxidation of isoprene. Recent theoretical calculations suggest that fast photolysis of these compounds may be an important OH source in high-isoprene, low NO regions. We report experimental constraints for key parameters of photolysis, OH reaction and ozone reaction of these compounds as derived from a closely related, custom-synthesized C(6)-HPALD. The photolysis quantum yield is 1.0 +/- 0.4 over the range 300-400 nm, assuming an absorption cross section equal to the average of those measured for several analogous enals. The yield of OH from photolysis was determined as 1.0 +/- 0.8. The OH reaction rate constant is (5.1 +/- 1.8) * 10(-11) cm(3) molecule(-1) s(-1) at 296 K. The ozone reaction rate constant is (1.2 +/- 0.2) * 10(-18) cm(3) molecule(-1) s(-1) at 296 K. These results are consistent with previous first-principles estimates, though the nature and fate of secondary oxidation products remains uncertain. Incorporation of C(5)-HPALD chemistry with the above parameters in a 0-D box model, along with experimentally-constrained rates for C(5)-HPALD production from isomerization of first-generation isoprene hydroxyperoxy radicals, is found to enhance modeled OH concentrations by 5-16% relative to the traditional isoprene oxidation mechanism for the chemical regimes of recent observational studies in rural and remote regions. This enhancement in OH will increase if C(5)-HPALD photo-oxidation products also photolyze to yield additional OH or if the C(5)-HPALD production rate is faster than has been observed. PMID- 22517222 TI - Communication: a matter of life and death: historical lessons are a standard for the future. PMID- 22517226 TI - Code it right or repay: place-of-service compliance. AB - All physicians/practitioners/suppliers should download and read CMS Transmittal 2407 in its entirety. In addition, a precise process to inform billers of the exact location where each wound care service was performed should be established. Billers should enter the correct POS code on every claim submitted to Medicare. Because the physician/practitioner/supplier is ultimately responsible for all claims submitted with the provider number, you should conduct internal audits of submitted claims to be certain that the POS code has been appropriately assigned and matches the actual location where your service was performed. If the internal audit identifies noncompliance with the POS code policy, correct your process and consider self-reporting the billing errors to Medicare. If the internal audit identifies compliance with the POS code policy, celebrate with your team! PMID- 22517227 TI - Anesthesia protocol for heel pressure ulcer debridement. AB - Heel ulcers are clinically challenging. Limited subcutaneous tissue covering the calcaneus bone makes the heel vulnerable to pressure injury. Adequate debridement of fibrotic, infected, and necrotic tissue is essential for healing. The authors report a standardized anesthesia protocol using regional anesthesia with sedation rather than general anesthesia for heel debridement. PMID- 22517228 TI - A prospective, single-center, nonblinded, comparative, postmarket clinical evaluation of a bovine-derived collagen with ionic silver dressing versus a carboxymethylcellulose and ionic silver dressing for the reduction of bioburden in variable-etiology, bilateral lower-extremity wounds. AB - OBJECTIVE: There are numerous dressings designed to manage the overabundance of matrix metalloproteinases, while also addressing the excessive bioburden found in chronic wounds. The authors compared the efficacy of 2 such dressings: a sodium carboxymethylcellulose/1.2% ionic silver (CMC), which theoretically reduces bacteria by providing silver ions, versus a bovine native collagen (BDC)/ionic silver dressing, which also delivers silver ions in an aqueous environment. Both dressings theoretically modulate the wound bed; CMC through moist wound care and fibrin ingrowth and BDC through matrix metalloproteinase balancing. METHODS: A prospective protocol was undertaken using patients as their own controls. Ten patients with bilateral venous stasis or diabetic foot ulcers were selected. One limb was randomized to treatment by either CMC or BDC, whereas the contralateral wound was treated with the other dressing. Biopsies for quantitative cultures were taken at weeks 1 and 4. Wound area was assessed at the weekly visits. RESULTS: The BDC wounds started with 1.0 * 10 (+/-1.2 * 10) bacteria, and the CMC wounds started with 1.4 * 10 (+/-1.3 * 10) bacteria. Over the 4-week period, the bacteria in the 3-ppm (parts per million) silver-treated wound increased 1.53 * 10, whereas in the 21-ppm silver-treated wound, the bacteria increased 1.42 * 10. The rates of closure for CMC-treated wounds was 0.79 +/- 0.735 cm/wk and for BDC treated wounds was 1.38 +/- 1.44 cm/wk. Only 1 wound treated with either dressing exhibited a decrease in bacteria. CONCLUSION: Both CMC and BDC silver dressings appeared to have statistically similar efficacy regarding the rate of wound healing and little impact on the actual bioburden in chronic lower-extremity wounds. Interestingly, there was no correlation in the size of the wound and any effect on bioburden. Although the BDC dressing showed a higher absolute rate of wound closure, neither technology demonstrated a statistically significant difference in wound closure rate when corrected for initial wound size. PMID- 22517229 TI - Measuring interface pressure and temperature in the operating room. AB - BACKGROUND: There is a high incidence of pressure ulcers (PrUs) during long hours of surgery. Interface pressure and temperature are considered risk factors for PrU development. OBJECTIVE: The objective of this study was to determine a methodology to measure interface pressure and temperature during long hours of surgery consistently. SAMPLE: Five patients undergoing liver transplants were recruited from the University of Pittsburgh Medical Center. METHODS AND OUTCOMES: Interface pressure and temperature were measured with pressure mapping and temperature mapping for the duration of the surgery. After the surgery, an 8-hour skin check over 48 hours was performed. RESULTS: Pressure mapping and temperature mapping are appropriate to quantify interface pressure and temperature during surgery. CONCLUSION: This study shows that measuring interface pressure and temperature using pressure and temperature mats is feasible. Further studies are necessary in order to validate the methodology in other types of surgery. PMID- 22517230 TI - Diagnosing and treating moisture-associated skin damage. AB - Certain types of moisture can cause debilitating damage to the skin. Terms such as perineal dermatitis, diaper rash, incontinence-associated dermatitis, or moisture-associated skin damage describe some of the conditions caused by moisture from wound drainage, fecal and/or urinary incontinence, and perspiration. It is important for clinicians to correctly diagnose and to locally treat the cause of skin damage, as well as promote appropriate cleaning techniques, to keep patients' skin healthy. PMID- 22517232 TI - Understanding the barriers to healing. PMID- 22517233 TI - Bladder inhibition by intermittent pudendal nerve stimulation in cat using transdermal amplitude-modulated signal (TAMS). AB - AIMS: To determine if intermittent stimulation of the pudendal nerve using a transcutaneous stimulation method can inhibit reflex bladder activity. Intermittent stimulation consumes less electrical power than continuous stimulation, requiring a smaller battery and reducing the size of the stimulator for neuromodulation therapy. METHODS: A non-invasive stimulation method employing a transdermal amplitude-modulated signal (TAMS) was used in 18 alpha-chloralose anesthetized cats to stimulate the pudendal nerve via electrodes attached to the skin surface. Intermittent stimulation of different duty cycles was applied during repeated cystometrograms (CMGs) to inhibit reflex bladder activity. The bladder capacity measured during each CMG was used to indicate the inhibitory effect induced by the stimulation. RESULTS: Continuous stimulation maximally increased bladder capacity to 172.6 +/- 15% of the control capacity, while intermittent stimulation at the duty cycles of 30/30, 5/5, and 1/1 ("on/off" in seconds) significantly (P < 0.05) increased bladder capacity to 132 +/- 7.5%, 154.2 +/- 20%, and 165.5 +/- 28%, respectively. The inhibitory effect was gradually reduced as the "on/off" ratio was decreased. CONCLUSIONS: This pre clinical study indicated that intermittent stimulation of the pudendal nerve could be as effective as continuous stimulation to inhibit reflex bladder activity. These results are useful for the design and development of new stimulator technology to treat overactive bladder, and are also important for understanding pudendal neuromodulation therapy. PMID- 22517234 TI - Classification of and cytoreductive surgery for low-grade appendiceal mucinous neoplasms. AB - BACKGROUND: Low-grade appendiceal mucinous neoplasm (LAMN) is a precursor lesion for pseudomyxoma peritonei (PMP), which, if treated suboptimally, may later disseminate throughout the abdominal cavity. The role of cytoreductive surgery for these relatively early lesions is unclear. METHODS: Clinicopathological details and treatment outcomes of patients with a LAMN and disease limited to the appendix or immediate periappendiceal tissues, referred to a national treatment centre between 2002 and 2009, were evaluated prospectively. RESULTS: Of 379 patients with a diagnosis of PMP, 43 (median age 49 years) had LAMNs localized to the appendix and periappendiceal tissue. Thirty-two patients initially presented with symptoms of acute appendicitis or right iliac fossa pain. Two distinct lesions were identified: type I (disease confined to the appendiceal lumen) and type II (mucin and/or neoplastic epithelium in the appendiceal submucosa, wall and/or periappendiceal tissue, with or without perforation). Type I lesions were managed by a watch-and-wait surveillance policy with serial measurement of tumour markers and computed tomography in 14 of 16 patients. Seventeen of 27 patients with type II lesions underwent risk-reducing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy with low morbidity. After a median follow-up of 40 months, there was no disease progression in either treatment pathway. CONCLUSION: This study identified two LAMN subtypes. Type II lesions have pathological features of increased risk for dissemination and should be considered for risk-reducing cytoreductive surgery. PMID- 22517235 TI - Clonidine-induced growth hormone and growth-hormone-releasing hormone release is mediated by tachykinin NK2 receptors in sheep. AB - Clonidine is an alpha(2)-adrenergic agonist, historically known to treat high blood pressure. Further studies showed that it could be used in the treatment of neuropsychiatric disorders. Afterwards, it has been reported that clonidine stimulated growth hormone (GH) release in many species including man. Using a transnasal surgery technique in awake sheep that allowed accessing hypothalamopituitary portal vessels, our laboratory previously reported that the injection of clonidine in sheep induced a significant, immediate and short lasting increase in peripheral GH and portal GH-releasing hormone (GHRH) levels. In this study, we show that the clonidine-induced peripheral GH and portal GHRH increase in sheep appears to be mediated by the tachykinin NK2 receptor. PMID- 22517236 TI - Measuring psychosocial distress and parenting concerns among adults with cancer: the Parenting Concerns Questionnaire. AB - BACKGROUND: A 2-phase, mixed methods study was conducted to develop a Parenting Concerns Questionnaire (PCQ) for adults with cancer. Limited information about this area of psychosocial distress highlights the need for a measurement tool that can identify adult oncology patients with heightened parenting concerns who could benefit from additional intervention. METHODS: Telephone focus groups were conducted with 16 oncology patients who had children 18 years old and younger. Group interview transcripts were analyzed to generate qualitative themes and candidate items for the PCQ. A 38-item version of the questionnaire was completed by 173 oncology outpatients who had children 18 years old and under. Participants also completed the Distress Thermometer, HADS (Hospital Anxiety and Depression Scale), and FACT-G (Functional Assessment of Cancer Therapy-General). Exploratory factor analyses revealed the emergence of 3 subscales of 5 items each, yielding a 15-item questionnaire. Associations between total PCQ scores, standardized measures of distress, depression, anxiety, quality of life, and demographic and illness characteristics were examined. RESULTS: The 15-item PCQ demonstrates good internal consistency (Cronbach's alpha = .83). PCQ scores were significantly associated (P < .01) with standardized measures of psychosocial distress (Distress Thermometer, HADS, and FACT-G) in the expected directions. Higher PCQ scores were associated with female sex, single parenthood, metastatic or recurrent cancer, subjective understanding of incurable disease, comorbid chronic health condition, and current mental health treatment. CONCLUSIONS: The PCQ proved a reliable and valid measure of parenting distress among cancer patients, and thus merits further study. PMID- 22517237 TI - First-principles calculations of interfacial and segregation energies in alpha Cr2O3. AB - The interfacial energies of three twin boundaries with low-index boundary planes: prismatic (101-0), basal O-terminated (0001), and basal Cr-terminated (0001), and the segregation energies of five doping elements (Ce, Hf, La, Y and Zr) have been calculated as a function of temperature. The static energies at 0 K were obtained through first-principles calculations and the energies at finite temperatures were derived based on the Debye model. The calculation results show that both the interfacial and segregation energies decrease as temperature increases and the segregation energies are found to be proportional to the ionic size mismatch and the interfacial energy. Our combined approaches suggest an efficient and less computationally intensive way to derive grain boundary energetics at finite temperatures. PMID- 22517238 TI - Development of colour and firmness in strawberry crops is UV light sensitive, but colour is not a good predictor of several quality parameters. AB - BACKGROUND: Strawberry (Fragaria * ananassa Duchesne var. Elsanta) plants were grown in polytunnels covered with three polythene films that transmitted varying levels of ultraviolet (UV) light. Fruit were harvested under near-commercial conditions and quality and yield were measured. During ripening, changes in the colour parameters of individual fruit were monitored, and the accuracy of using surface colour to predict other quality parameters was determined by analysing the correlation between colour and quality parameters within UV treatments. RESULTS: Higher exposure to UV during growth resulted in the fruit becoming darker at harvest and developing surface colour more quickly; fruit were also firmer at harvest, but shelf life was not consistently affected by the UV regime. Surface colour measurements were poorly correlated to firmness, shelf life or total phenolics, anthocyanins and ellagic acid contents. CONCLUSION: Although surface colour of strawberry fruits was affected by the UV regime during growth, and this parameter is an important factor in consumer perception, we concluded that the surface colour at the time of harvest was, contrary to consumer expectations, a poor indicator of firmness, potential shelf life or anthocyanin content. PMID- 22517239 TI - Inhibitory activity of plumbagin produced by Drosera intermedia on food spoilage fungi. AB - BACKGROUND: The aim of this study was to investigate the growth-inhibiting efficacy of Drosera intermedia extracts (water, methanol and n-hexane) against four food spoilage yeasts and five filamentous fungi strains responsible for food deterioration and associated with mycotoxin production, in order to identify potential antimycotic agents. RESULTS: The n-hexane extract showed a broad activity spectrum against all tested microorganisms, followed, in activity, by the methanol and water extracts. The major component of the n-hexane extract was purified using a solid-phase extraction column and identified as plumbagin. Results show that high-purity plumbagin can be produced from D. intermedia cultures following a simple and effective isolation procedure. A sample of purified plumbagin was tested against the same panel of microorganisms and high growth-inhibiting capacity was observed. Minimum inhibitory concentrations less than 2 ug mL(-1) were obtained against the filamentous fungi. In the case of the species Aspergillus fumigatus, A. niger and A. flavus, activities comparable to miconazole were obtained. CONCLUSION: The results obtained provided evidence of the antimycotic activity of plumbagin, suggesting that D. intermedia could be the source of an interesting compound for the food industry as an alternative to preservatives. PMID- 22517240 TI - Mucosal healing restores normal health and quality of life in patients with inflammatory bowel disease. AB - BACKGROUND: Inflammatory bowel disease (IBD) is a debilitating immune disorder that impairs function and health-related quality of life (HRQOL). A goal of IBD treatment is mucosal healing, but it is not known whether it achieves normalization of the patients' perception of health. This can be assessed by using a cut-off scoring threshold of the Inflammatory Bowel Disease Questonnaire 36 (IBDQ-36). AIMS: To determine whether patients with Crohn's disease (CD) and ulcerative colitis (UC) in clinical remission and with mucosal healing normalize their HRQOL. METHODS: This is a multicentric, prospective, observational, cross sectional study of patients who are in stable clinical remission and having mucosal healing. Patients completed the IBDQ-36, the EuroQol-5D, and the Daily Fatigue Impact Scale fatigue questionnaires. Complete restoration of health was believed to have occurred when the global score in the IBDQ-36 was at least 209 points. RESULTS: A total of 115 patients (48 with CD, 67 with UC) were included. The median activity index (the Harvey-Bradshaw or the colitis activity index) was 1.0 and the median endoscopic index (Simple Endoscopic Score for Crohn's disease or Mayo) was 0. Eighty percent of the patients (79% in CD and 82% in UC patients, P=NS) normalized their HRQOL. Type of treatment was not related to normalization of HRQOL. The lack of restoration of health was significantly related to fatigue and anxiety/depression. CONCLUSION: Mucosal healing is associated with a normalization of the perception of health by most IBD patients independently of treatment. However, a significant group of patients do not achieve restoration of HRQOL, which reinforces the necessity of a global care addressed to all patient concerns to achieve patients' complete health restoration. PMID- 22517241 TI - Nonanesthesiologist-administered propofol sedation for colonoscopy is safe and effective: a prospective Spanish study over 1000 consecutive exams. AB - BACKGROUND AND STUDY AIMS: Propofol is increasingly being used in sedated colonoscopy. This paper assesses the safety and efficacy of nonanesthesiologist administered propofol in a large series of colonoscopies. PATIENTS AND METHODS: A prospective registry of consecutive American Society of Anesthetics (ASA) class I and II outpatients undergoing colonoscopy was carried out. Propofol, administered by a nurse under an endoscopist's supervision, was the sole sedative agent used. RESULTS: Of the 1000 patients (563 women/437 men, mean age 57, range 8-89 years) included in the study, 57.4% showed ASA I and 42.6% ASA II characteristics. The cecal intubation rate was 96.9%. 48.2% of the procedures were for therapeutic purposes. The mean propofol dose was 177 mg (range 50-590 mg). Doses correlated inversely with patient age (r=-0.38; P<0.001) and were lower in ASA II patients (P<0.001) and in diagnostic (rather than therapeutic) exams (P<0.001). The average recovery time (from extracting the colonoscope to patient discharge) was 18.6 min (range 4-75) and longer in ASA II patients (P=0.05). A pulse oximetry saturation of less than 90% and a decrease in systolic blood pressure of more than 20 mmHg were observed in 24 (2.4%) and 385 (35.8%) patients, respectively. Both events were more frequent in patients older than 65 years (P<0.05); the latter was more common in ASA II patients. CONCLUSION: Colonoscopy under endoscopist-controlled propofol sedation in low-risk patients is safe and effective, allowing for a complete exploration, although patients at least 65 years old and/or classified as ASA II are more likely to present a decrease in blood pressure and have a prolonged recovery time. PMID- 22517242 TI - Association of nerve growth factor and vascular endothelial growth factor A with psychometric measurements of opiate dependence: results of a pilot study in patients participating in a structured diamorphine maintenance program. AB - Preclinical study results suggest that neurotrophic peptides like nerve growth factor (NGF) and vascular endothelial growth factor A (VEGF-A) may be associated with symptoms of addictive behavior like withdrawal symptoms and rewarding effects. We investigated alterations in NGF and VEGF-A serum levels in opiate dependent patients (25 male patients), who received diamorphine (DAM, heroin) treatment within a structured opiate maintenance program, and compared the results with the NGF and VEGF-A serum levels of healthy controls (23 male controls). NGF and VEGF-A serum levels were assessed before and after DAM administration twice a day (in the morning (16 h after last application--t1) and in the afternoon (7 h after last application--t3)) in order to detect a possible immediate or summative (in the afternoon) heroin effect on these two neuropeptides. Moreover, we investigated possible associations between the serum levels of these neurotrophic growth factors and psychometric dimensions of addictive behavior, e.g. craving, withdrawal, depression. Whereas there was no direct effect of DAM application on the serum levels of both neurotrophic growth factors neither in the morning nor in the afternoon, the NGF serum levels of the patient group were found to be significantly increased at all four time points of investigation compared with the healthy controls. In contrast, VEGF-A serum levels did not differ significantly in the patient and control groups. We found a significant positive association between the NGF serum levels and several items of the short opiate withdrawal scale as well as a negative association between self-reported mood (measured by visual analogue scale) and mood before heroin application (in the morning as in the afternoon). Moreover, we found a significant positive association between the NGF serum levels (t1 and t3) and the self-reported craving for methadone. In contrast, we found a negative association between the VEGF-A serum levels and avoidance, anxiety, suicide intentions of the SCL-90 as well as a positive association between the VEGF-A serum levels and the subscales of the heroin craving questionnaire measuring the rewarding effects of heroin. In conclusion, the results of this pilot study show that there might be an association between symptoms of opiate dependence and withdrawal and serum levels of VEGF-A and NGF. PMID- 22517243 TI - Synthesis and CO2/CH4 separation performance of Bio-MOF-1 membranes. AB - Herein we present the preparation of continuous and reproducible Bio-MOF-1 membranes supported on porous stainless steel tubes. These membranes displayed high CO(2) permeances for equimolar mixtures of CO(2) and CH(4). The observed CO(2)/CH(4) selectivities above one indicate that the separation is promoted by competitive adsorption. PMID- 22517244 TI - Mycophenolate as induction therapy in lupus nephritis with renal function impairment. AB - BACKGROUND: Mycophenolate (MF) is effective as induction therapy for lupus nephritis (LN) in patients with normal renal function; however, little is known about its role in patients with impaired renal failure. The purpose of this study was to evaluate the response to MF in LN and its association with baseline renal function. METHODS: Data were obtained for 90 patients from 12 Spanish renal units who were receiving MF as induction therapy for LN. Patients were classified into 2 groups: group 1 (estimated glomerular filtration rate [eGFR] >=60 ml/min/1.73 m(2)) and group 2 (eGFR <60 ml/min/ 1.73 m(2)). The primary outcome measure was the percentage of patients who achieved any response and its relationship with initial eGFR. The secondary outcome measures were the percentage of patients who achieved a complete response (CR) or partial response (PR) and the appearance of relapses during treatment and side effects. RESULTS: At initiation of MF treatment, there were no differences in the main parameters between group 1 (n = 63; eGFR 87 +/- 23 ml/min/ 1.73 m(2)) and group 2 (n = 27; eGFR 44 +/- 12 ml/min/1.73 m(2)). Exposure to prednisone and MF was similar. The percentages of patients who achieved a response in groups 1 and 2 were, respectively, 69.2 and 43.8% at 6 months and 81.3 and 73.7% at 12 months. CR was more frequent in group 1, whereas PR was similar in both groups. Four patients relapsed and side effects were unremarkable. CONCLUSIONS: MF is effective and safe as induction therapy for LN, and response is even achieved in patients with baseline renal impairment. PMID- 22517245 TI - Influence of inward pressure of the transducer on lateral abdominal muscle thickness during ultrasound imaging. AB - STUDY DESIGN: Controlled laboratory study, technical note. OBJECTIVES: The purpose of this study was to quantify changes in the thickness of the transversus abdominis, internal oblique, and external oblique muscles induced by different inward pressures of the transducer during ultrasound imaging (USI). BACKGROUND: USI of the lateral abdominal muscles is increasingly used in managing musculoskeletal dysfunction. However, to the best of our knowledge, no study has evaluated the influence of different inward pressures of the transducer on the lateral abdominal muscle thickness during USI. METHODS: Thirty healthy male volunteers participated in this study. The thickness of the transversus abdominis, internal oblique, and external oblique muscles was measured with USI by the same rater in 4 conditions of inward pressures of 0.5, 1.0, 2.0, and 4.0 N. Intraclass correlation coefficients (ICC1,1), with 95% confidence intervals, were calculated, and a repeated-measures analysis of variance was used to assess the influence of inward pressure on the thickness of the lateral abdominal muscles. RESULTS: The thickness of the transversus abdominis, internal oblique, and external oblique muscles was significantly different among the 4 conditions (P<.038). The mean difference between the 0.5-N and 4.0-N conditions was greater than the minimal detectable change of the 0.5-N condition in the lateral abdominal muscles. CONCLUSION: The difference in magnitude produced by the forces under different conditions was meaningful. When using a technique that involves a handheld transducer, the examiner should attempt to maintain consistent inward pressure of the transducer during USI to quantify the thickness of lateral abdominal muscles. J Orthop Sports Phys Ther 2012;42(9):815-818, Epub 19 April 2012. doi:10.2519/jospt.2012.4064. PMID- 22517246 TI - Organocatalytic stereocontrolled synthesis of 3,3'-pyrrolidinyl spirooxindoles by [3+2] annulation of isocyanoesters with methyleneindolinones. AB - A stereoselective [3+2] cycloaddition of isocyanoesters to methyleneindolinones catalyzed by a quinine-based thiourea-tertiary amine has been successfully developed. Just by tuning the protecting groups on substrates, a variety of optically enriched 3,3'-pyrrolidinyl spirooxindole diastereomers could be obtained in excellent enantioselectivities (up to 99% ee). PMID- 22517247 TI - Identifying structural distortion in doped VO2 with IR spectroscopy. AB - Doping VO(2) with tungsten can lower the metal-insulator transition (MIT) temperature and thus provide a controlled means for tailoring the MIT properties of VO(2) materials. Here, infrared spectroscopy has been employed as a tool for identifying structural changes in doped VO(2) as a way of lowering the MIT temperature. PMID- 22517249 TI - Surgical treatment of spinal extradural arachnoid cysts in the thoracolumbar spine. AB - BACKGROUND: Because an idiopathic spinal extradural arachnoid cyst (SEAC) is rare, its optimal surgical treatment remains controversial. OBJECTIVE: To evaluate the results of surgical treatments for SEACs and to clarify features of the disease associated with poor outcomes. METHODS: Twelve patients with SEACs who underwent surgery at our hospital between 1988 and 2008 were examined retrospectively. The mean follow-up period was 4.7 years. Total resection of the cyst was performed in 7 patients and closure of the dural defect without cyst resection in 5 patients. Surgical outcomes were evaluated with regard to the duration of symptoms, the size of the cyst, and the surgical procedure used. RESULTS: Neurological recovery was observed in all patients, and there was no recurrence. Poor outcomes were observed in patients with a long duration of symptoms (>1 year, P < .01) and large cyst size (>5 vertebrae, P < .05). The surgical procedure had no significant association with the postoperative neurological recovery. However, there was a significant difference in the degree of the mean postoperative kyphotic angle between the patients treated by total resection of the cyst (9.7 degrees) and those treated by closure of the dural defect without cyst resection through selective laminectomy (2.2 degrees) (P < .01). CONCLUSION: There was no significant difference in postoperative neurological recovery between the 2 surgical procedures. However, closure of the dural defect without cyst resection was less invasive, preventing postoperative kyphotic deformity of the thoracolumbar spine. PMID- 22517250 TI - Silent corticotroph adenomas: Emory University cohort and comparison with ACTH negative nonfunctioning pituitary adenomas. AB - BACKGROUND: Silent corticotroph adenomas (SCAs) are clinically nonfunctioning pituitary adenomas (NFPAs) with positive staining for corticotropin (ACTH) by immunohistochemistry. Whether SCAs behave more aggressively than NFPAs without ACTH immunoreactivity (ACTH negative) remains controversial. OBJECTIVE: To compare characteristics and outcomes of SCAs with ACTH-negative NFPAs and to identify predictors of aggressive outcome. Primary composite endpoint included the first of any of the following events: progression, recurrence, or death. METHODS: We reviewed all cases of SCAs and all ACTH-negative macroadenomas operated on between April 1995 and December 2007 by 1 neurosurgeon. RESULTS: Our retrospective cohorts included 33 SCAs followed for 42.5 months (median) (range, 6.7-179.0 months) and 126 ACTH-negative patients followed for 42 months (range, 6 142 months). SCA were younger (mean +/- SD; 49.6 +/- 14.1) than ACTH-negative patients (55.6 +/- 12.8, P = .02). Tumor diameter was similar (2.8 +/- 1.0 cm); cavernous sinus invasion was present in 45.5% of SCAs and 30.2% of ACTH-negative NFPAs (P = .09). Postoperative tumor residual was detected in 53.1% of SCAs and 49.6% of ACTH-negative patients. Radiation was administered in 40.6% of SCAs at 16 months (range, 3-149 months) and 33.3% of ACTH-negative patients at 13 months (range, 3-94) postoperatively. Progression of residual tumor occurred in 24.2% of SCAs and 11.1% of ACTH-negative patients (P = .08); recurrence was similar (6.0% SCAs vs 5.5% ACTH-negative patients). Cumulative event-free survival rates were not significantly different between the 2 groups (P = .3). Age, sex, tumor size, cavernous sinus invasion, or SCA subtypes were not associated with outcome. CONCLUSION: SCA patients were younger, but exhibited similar postoperative tumor regrowth rates as ACTH-negative macroadenomas while using a similar adjuvant radiation protocol. Long-term follow-up is warranted because predictors of regrowth are currently lacking. PMID- 22517251 TI - Use of a Yasargil mirror as an adjunct to indocyanine green angiography to evaluate the patency of elusive posterior communicating arteries during aneurysm clipping: case report. AB - BACKGROUND AND IMPORTANCE: Indocyanine green angiography (ICGA) has become a useful intraoperative tool during aneurysm surgery to determine parent, branching, and perforator vessel patency. Although extremely useful, ICGA is limited to the evaluation of vessels that are in direct view in the surgical field. CLINICAL PRESENTATION: We present 2 cases of patients who underwent a craniotomy for clipping of unruptured posterior communicating artery aneurysms. A Yasargil movable mirror was used as an adjuvant to ICGA to visualize the ventromedial posterior communicating vessels after clip placement to determine vessel patency. CONCLUSION: Although ICGA can be very useful during aneurysm surgery, it is limited to vessels directly visualized in the surgical field. A Yasargil movable mirror can be used during ICGA to visualize elusive vessels, in these cases on the ventromedial surface of the internal carotid artery. PMID- 22517252 TI - Thoracic myelopathy due to an intramedullary herniated nucleus pulposus: first case report and review of the literature. AB - BACKGROUND AND IMPORTANCE: Herniation of intervertebral discs is relatively common. Migration usually occurs in the ventral epidural space; very rarely discs migrate in the subdural space. No cases of intradural intramedullary disc have been reported in humans. CLINICAL PRESENTATION: A case of a herniated intervertebral disc directly into the spinal cord parenchyma is presented. The patient presented with 2 weeks of progressive bilateral lower extremity numbness and weakness, saddle hypoesthesia, urinary dysfunction and gait disturbance. Spine magnetic resonance imaging (MRI) with gadolinium revealed a solitary well defined intramedullary lesion (T7-T8 level) with ring enhancement and focal cord expansion with significant surrounding edema. Metastatic workup and neural axis imaging was negative. A thoracic laminectomy and myelotomy was performed; the lesion was pearlescent and well circumscribed. It was densely adherent to the ventral pia and gross totally removed. Pathology was consistent with nucleus pulposus. CONCLUSION: Intradural intramedullary migration of a herniated intervertebral disc is extremely rare but should be considered in the differential. It may present in a variety of clinical scenarios, including thoracic myelopathy, and mimic intramedullary spinal cord tumor. PMID- 22517253 TI - The importance and timing of optic canal exploration and decompression during endoscopic endonasal resection of tuberculum sella and planum sphenoidale meningiomas. AB - BACKGROUND: Suprasellar meningiomas often invade the optic canals (OCs). The feasibility of removing these tumors through a minimal-access endonasal route has been demonstrated, but the importance, safety, and timing of OC exploration and decompression are not well described. OBJECTIVE: To create a simple decision-tree algorithm for OC exploration and decompression in the endonasal endoscopic surgery for planum sphenoidale and tuberculum sella meningiomas. METHODS: We identified a consecutive series of 8 planum sphenoidale and tuberculum sella meningiomas resected endonasally. "Late" OC exploration and decompression was performed in 4 of 8 patients. The extent of resection, visual outcome, and complications were recorded. RESULTS: Five patients had OC invasion on magnetic resonance imaging. Endoscopic inspection did not reveal additional OC invasion. The OC was opened bilaterally in 2 patients and unilaterally in 2 patients. Gross total resection was achieved in 6 of 7 patients in whom it was the goal. Vision improved in 3 patients (3 of 3 OCs opened) and was stable in 4 (1 of 4 OCs opened). In 1 patient, the bitemporal hemianopsia improved, but there was unilateral deterioration (no OC invasion) because the tumor was extremely adherent to 1 optic nerve. After an average follow-up of 20.9 months, all patients had an Glasgow Outcome Scale score of 5, and there were no cerebrospinal fluid leaks. CONCLUSION: Exploration and decompression of the OC are feasible, safe, and important to optimize visual outcome and to minimize recurrence in planum sphenoidale and tuberculum sella meningiomas resected endonasally. It may not be important to open the canal early during surgery because tumor debulking can be performed without manipulating the optic nerves. Early decompression, however, is technically feasible. PMID- 22517254 TI - Differences in metabolism of fiber tract alterations in gliomas: a combined fiber density mapping and magnetic resonance spectroscopic imaging study. AB - BACKGROUND: Gliomas propagate diffusely throughout and along white matter structures. Glioma-related changes in structural integrity and metabolism are not detectable by standard magnetic resonance (MR) imaging. OBJECTIVE: To investigate differences in the metabolism of fiber tract alterations between gliomas grade II to IV by correlation of fiber density values with metabolite concentrations measured by fiber density mapping and MR spectroscopic imaging. METHODS: Fiber density mapping and MR spectroscopic imaging were performed in 48 patients with gliomas WHO grade II to IV. Fiber density mapping data were used to define fiber tracts in tumoral and peritumoral areas. Structural integrity of fiber tracts was assessed as fiber density ipsilateral-to-contralateral ratio (FD ICR). Metabolite concentrations for choline-containing compounds and N-acetyl-aspartate were computed and correlated to FD ICR values after coregistration with anatomic MR imaging. RESULTS: In tumoral areas, choline-containing compound concentrations of altered fiber tracts were significantly different between low- and high-grade glioma and showed different courses for the correlations of FD ICR and choline containing czeompounds. In high-grade glioma, increasing fiber destruction was associated with a massive progression in cell membrane proliferation. Peritumoral fiber structures showed significantly decreased N-acetyl-aspartate concentrations for all patients, but only patients with glioblastoma multiforme had significantly decreased fiber density compared with the contralateral side. Glioma grades II and III had significantly higher peritumoral FD ICR than glioblastoma multiforme. CONCLUSION: A multiparametric MR imaging strategy providing information about both structural integrity and metabolism of the tumor is required for detailed assessment of glioma-related fiber tract alterations, which in turn is essential for treatment planning. PMID- 22517255 TI - Mapping sensorimotor cortex with slow cortical potential resting-state networks while awake and under anesthesia. AB - BACKGROUND: The emerging insight into resting-state cortical networks has been important in our understanding of the fundamental architecture of brain organization. These networks, which were originally identified with functional magnetic resonance imaging, are also seen in the correlation topography of the infraslow rhythms of local field potentials. Because of the fundamental nature of these networks and their independence from task-related activations, we posit that, in addition to their neuroscientific relevance, these slow cortical potential networks could play an important role in clinical brain mapping. OBJECTIVE: To assess whether these networks would be useful in identifying eloquent cortex such as sensorimotor cortex in patients both awake and under anesthesia. METHODS: This study included 9 subjects undergoing surgical treatment for intractable epilepsy. Slow cortical potentials were recorded from the cortical surface in patients while awake and under propofol anesthesia. To test brain-mapping utility, slow cortical potential networks were identified with data driven (seed-independent) and anatomy-driven (seed-based) approaches. With electrocortical stimulation used as the gold standard for comparison, the sensitivity and specificity of these networks for identifying sensorimotor cortex were calculated. RESULTS: Networks identified with a data-driven approach in patients under anesthesia and awake were 90% and 93% sensitive and 58% and 55% specific for sensorimotor cortex, respectively. Networks identified with systematic seed selection in patients under anesthesia and awake were 78% and 83% sensitive and 67% and 60% specific, respectively. CONCLUSION: Resting-state networks may be useful for tailoring stimulation mapping and could provide a means of identifying eloquent regions in patients while under anesthesia. PMID- 22517257 TI - Covered carotid stents. PMID- 22517258 TI - "Statistically significant" does not necessarily mean 'clinically different' on pain/quality of life scales: opportune remarks on clinical outcomes measures in cervical spondylotic myelopathy. PMID- 22517259 TI - Fusion of single proteoliposomes with planar, cushioned bilayers in microfluidic flow cells. AB - Many biological processes rely on membrane fusion, and therefore assays to study its mechanisms are necessary. Here we report an assay with sensitivity to single vesicle, and even to single-molecule events using fluorescently labeled vesicle associated v-SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) liposomes and target-membrane-associated t-SNARE-reconstituted planar, supported bilayers (t-SBLs). Docking and fusion events can be detected using conventional far-field epifluorescence or total internal reflection fluorescence microscopy. In this assay, fusion is dependent on SNAP-25, one of the t-SNARE subunits that is required for fusion in vivo. The success of the assay is due to the use of: (i) bilayers covered with a thin layer of poly(ethylene glycol) (PEG) to control bilayer-bilayer and bilayer-substrate interactions, and (ii) microfluidic flow channels that present many advantages, such as the removal of nonspecifically bound liposomes by flow. The protocol takes 6-8 d to complete. Analysis can take up to 2 weeks. PMID- 22517260 TI - A simple and rapid nonviral approach to efficiently transfect primary tissue derived cells using polyethylenimine. AB - This protocol outlines steps for optimizing the transfection of adherent primary mammalian cells using the readily available off-the-shelf cationic polymer, 25 kDa branched polyethylenimine (bPEI25). Transfection efficiency of cationic polymers varies among cell lines and is highly dependent on the conditions and environment in which complexes are formed. Factors requiring optimization include the salt concentration, volume, incubation time, mixing order and ratio of polymer to DNA. In this transfection protocol, complexes are prepared in 30 min, with analysis 24 h later; thus, experiments can be completed in 2 d. In this protocol, as an example, we describe the parameters we have optimized for the transfection of bone marrow stromal cells and normal human foreskin fibroblasts. By using this protocol, we have obtained transfection efficiencies comparable to lipofection. An appropriately optimized protocol enhances the utility of cationic polymers in transfecting mammalian cells, thereby providing an effective alternative to expensive commercial reagents. PMID- 22517261 TI - Using the mitochondria-targeted ratiometric mass spectrometry probe MitoB to measure H2O2 in living Drosophila. AB - The role of hydrogen peroxide (H(2)O(2)) in mitochondrial oxidative damage and redox signaling is poorly understood, because it is difficult to measure H(2)O(2) in vivo. Here we describe a method for assessing changes in H(2)O(2) within the mitochondrial matrix of living Drosophila. We use a ratiometric mass spectrometry probe, MitoB ((3-hydroxybenzyl)triphenylphosphonium bromide), which contains a triphenylphosphonium cation component that drives its accumulation within mitochondria. The arylboronic moiety of MitoB reacts with H(2)O(2) to form a phenol product, MitoP. On injection into the fly, MitoB is rapidly taken up by mitochondria and the extent of its conversion to MitoP enables the quantification of H(2)O(2). To assess MitoB conversion to MitoP, the compounds are extracted and the MitoP/MitoB ratio is quantified by liquid chromatography-tandem mass spectrometry relative to deuterated internal standards. This method facilitates the investigation of mitochondrial H(2)O(2) in fly models of pathology and metabolic alteration, and it can also be extended to assess mitochondrial H(2)O(2) production in mouse and cell culture studies. PMID- 22517263 TI - Fetal vertebral artery Doppler reference values at 19-41 weeks of gestation. AB - OBJECTIVES: To establish Doppler reference values for the fetal vertebral artery resistance index (VA RI), pulsatility index (VA PI) and peak systolic velocity (VA PSV), and describe their normal ratios to the umbilical artery (UA) throughout the second and third trimester of pregnancy. METHODS: Between 19 and 41 weeks of gestation, 484 ultrasound examinations of the fetal VA and UA were performed on singleton pregnant women with uncomplicated pregnancies. The VA was examined at the anatomical point where the artery surrounds the lateral masses of the atlas between the first cervical vertebra and the occipital bone, and values were obtained for the VA RI, VA PI and VA PSV. The 10th, 50th and 90th percentiles were subsequently generated for these parameters and their ratios to the UA. RESULTS: The VA RI and VA PI reached their maximum values at the end of the second trimester. Both indexes subsequently decreased due to an increase in the diastolic flow. Conversely, the VA PSV values increased progressively until the end of gestation. As for the VA/UA ratios, the RI and PI were higher in the middle of the third trimester and decreased slightly afterwards. On the other hand, the PSV increased progressively until the end of pregnancy. CONCLUSIONS: The fetal VA can be visualized with Doppler ultrasound as early as 19 weeks' gestation. In this study, reference values of the VA RI, PI and PSV and their ratios to the UA during the second half of pregnancy have been provided for fetal research. However, future work is necessary to further explore the possible applications of VA Doppler examination in fetal medicine. PMID- 22517264 TI - HIV-1 protein Tat inhibits vesicular monoamine transporter-2 activity in rat striatum. PMID- 22517265 TI - Sequential photoisomerisation dynamics of the push-pull azobenzene Disperse Red 1. AB - The ultrafast dynamics of the push-pull azobenzene Disperse Red 1 following photoexcitation at lambda(pump) = 475 nm in solution in 2-fluorotoluene have been probed by broadband transient absorption spectroscopy and fluorescence up conversion spectroscopy. The measured two-dimensional spectro-temporal absorption map features a remarkable "fast" excited-state absorption (ESA) band at lambda ~ 570 nm appearing directly with the excitation laser pulse and showing a sub-100 fs lifetime with a rapid spectral blue-shift. Moreover, its ultrafast decay is paralleled by rising distinctive ESA at other wavelengths. Global fits to the absorption-time profiles using a consecutive kinetic model yielded three time constants, tau(1) = 0.08 +/- 0.03 ps, tau(2) = 0.99 +/- 0.02 ps, and tau(3) = 6.0 +/- 0.1 ps. Fluorescence-time profiles were biexponential with time constants tau(1)' = 0.12 +/- 0.06 ps and tau(2)' = 0.70 +/- 0.10 ps, close to the absorption results. Based on the temporal evolution of the transient spectra, especially the "fast" excited-state absorption band at lambda ~ 570 nm, and on the global kinetic analysis of the time profiles, tau(1) is assigned to an ultrafast transformation of the optically excited pipi* state to an intermediate state, which may be the npi* state, tau(2) to the subsequent isomerisation and radiationless deactivation time to the S(0) electronic ground state, and tau(3) to the eventual vibrational cooling of the internally "hot" S(0) molecules. PMID- 22517266 TI - Genome-scale genetic manipulation methods for exploring bacterial molecular biology. AB - Bacteria are diverse and abundant, playing key roles in human health and disease, the environment, and biotechnology. Despite progress in genome sequencing and bioengineering, much remains unknown about the functional organization of prokaryotes. For instance, roughly a third of the protein-coding genes of the best-studied model bacterium, Escherichia coli, currently lack experimental annotations. Systems-level experimental approaches for investigating the functional associations of bacterial genes and genetic structures are essential for defining the fundamental molecular biology of microbes, preventing the spread of antibacterial resistance in the clinic, and driving the development of future biotechnological applications. This review highlights recently introduced large scale genetic manipulation and screening procedures for the systematic exploration of bacterial gene functions, molecular relationships, and the global organization of bacteria at the gene, pathway, and genome levels. PMID- 22517268 TI - Early clearance of peripheral blood blasts predicts response to induction chemotherapy in acute myeloid leukemia. AB - BACKGROUND: Early marrow blast clearance 14 days after induction chemotherapy is an independent prognostic indicator of outcomes in acute myeloid leukemia (AML). METHODS: We evaluated the relationship between time to peripheral blood blast clearance after induction and disease status as assessed by day 14 and day 30 marrow biopsies in 162 patients with AML. Day 6 after induction was the optimal cutoff point determined by a receiver operating characteristic analysis and was selected to divide patients into early blast clearance (EBC; <=6 days; n = 119) and delayed blast clearance (DBC; >6 days; n = 43) groups. RESULTS: DBC patients were older, but otherwise the 2 groups were comparable. Marrow blast clearance on day 14 after induction chemotherapy was observed in 84% of patients in the EBC group and 60% in the DBC group. With a median follow-up of 1538 days, both relapse-free survival (RFS) (442 vs 202 days, P = .0017) and overall survival (OS) (930 vs 429 days, P < .0001) were longer in the EBC group, and a multivariable analysis showed that EBC independently predicted clearance of marrow blasts at day 14 (P = .0018), remission (P = .0179), RFS (P = .0171), and OS (P = .0122). CONCLUSIONS: Early clearance of peripheral blood blasts after induction chemotherapy predicts for early marrow blast clearance, complete remission, RFS, and OS. Cancer 2012. PMID- 22517267 TI - Lead induces an osteoarthritis-like phenotype in articular chondrocytes through disruption of TGF-beta signaling. AB - Lead remains a significant environmental toxin, and we believe we may have identified a novel target of lead toxicity in articular chondrocytes. These cells are responsible for the maintenance of joint matrix, and do so under the regulation of TGF-beta signaling. As lead is concentrated in articular cartilage, we hypothesize that it can disrupt normal chondrocyte phenotype through suppression of TGF-beta signaling. These experiments examine the effects of lead exposure in vivo and in vitro at biologically relevant levels, from 1 nM to 10 uM on viability, collagen levels, matrix degrading enzyme activity, TGF-beta signaling, and articular surface morphology. Our results indicate that viability was unchanged at levels <=100 uM Pb, but low and high level lead in vivo exposure resulted in fibrillation and degeneration of the articular surface. Lead treatment also decreased levels of type II collagen and increased type X collagen, in vivo and in vitro. Additionally, MMP13 activity increased in a dose dependent manner. Active caspase 3 and 8 were dose-dependently elevated, and treatment with 10 uM Pb resulted in increases of 30% and 500%, respectively. Increasing lead treatment resulted in a corresponding reduction in TGF-beta reporter activity, with a 95% reduction at 10uM. Levels of phosphoSmad2 and 3 were suppressed in vitro and in vivo and lead dose-dependently increased Smurf2. These changes closely parallel those seen in osteoarthritis. Over time this phenotypic shift could compromise maintenance of the joint matrix. PMID- 22517269 TI - Association between contralateral prophylactic mastectomy and breast cancer outcomes by hormone receptor status. AB - BACKGROUND: The effect of contralateral prophylactic mastectomy (CPM) on the survival of patients with early-stage breast cancer remains controversial. The objective of this study was to evaluate the benefits of CPM using a propensity scoring approach that reduces selection bias from the nonrandom assignment of patients in observational studies. METHODS: A total of 3889 female patients with stage I to III breast cancer were identified who were treated at The University of Texas MD Anderson Cancer Center from 1997 to 2009. We assessed the association between CPM and disease-free (DFS) and overall survival (OS), by using Cox proportional hazards models to estimate hazard ratios (HRs), and by matching patients in the CPM and no-CPM groups using propensity scores (n = 497 pairs). RESULTS: With a median follow-up time of 4.5 years, CPM was associated with improved DFS (HR, 0.75; 95% confidence interval [CI], 0.59-0.97) and OS (HR, 0.74; 95% CI, 0.56-0.99), adjusted for prognostic factors. The improved DFS was seen predominantly among hormone receptor-negative (HR, 0.60; 95% CI, 0.38-0.95) compared with hormone receptor-positive patients (HR, 0.80; 95% CI, 0.58-1.10). For the matched patient cohort, stratified survival analysis also showed an improvement in DFS with CPM (HR, 0.48; 95% CI, 0.22-1.01) in hormone receptor negative patients that was nearly statistically significant. CONCLUSIONS: CPM was associated with improved DFS for some patients with hormone receptor-negative breast cancer, after reducing selection bias. Identifying subsets of patients most likely to benefit from CPM may have important implications for a more personalized approach to treatment decisions about CPM. PMID- 22517270 TI - Joint latent class models for longitudinal and time-to-event data: a review. AB - Most statistical developments in the joint modelling area have focused on the shared random-effect models that include characteristics of the longitudinal marker as predictors in the model for the time-to-event. A less well-known approach is the joint latent class model which consists in assuming that a latent class structure entirely captures the correlation between the longitudinal marker trajectory and the risk of the event. Owing to its flexibility in modelling the dependency between the longitudinal marker and the event time, as well as its ability to include covariates, the joint latent class model may be particularly suited for prediction problems. This article aims at giving an overview of joint latent class modelling, especially in the prediction context. The authors introduce the model, discuss estimation and goodness-of-fit, and compare it with the shared random-effect model. Then, dynamic predictive tools derived from joint latent class models, as well as measures to evaluate their dynamic predictive accuracy, are presented. A detailed illustration of the methods is given in the context of the prediction of prostate cancer recurrence after radiation therapy based on repeated measures of Prostate Specific Antigen. PMID- 22517271 TI - Weight estimation and significance testing for three focused statistics. AB - Focused tests for clustering are designed to determine whether there is statistical evidence for raised incidence of some phenomenon around a prespecified location. The tests require definition of what is meant by 'around' the location, and this is achieved by specifying weights associated with surrounding locations. Different weight specifications will yield different levels of statistical significance, and because of the difficulty in knowing how to define the weights, it is tempting to try different definitions with the hope of finding one that is highly significant. This, however, introduces the problem of multiple testing; one will eventually be able to reject a null hypothesis if one tries often enough. This article describes approaches for adjusting the significance level when multiple tests, associated with varying definitions for the weights, are carried out. The approaches are developed for a local scan statistic, a maximum chi-square statistic, and a modified version of Stone's statistic. An illustration is provided using leukemia data from central New York State. PMID- 22517272 TI - Statistical approaches for farm and parasitic risk profiling in geographical veterinary epidemiology. AB - We address the problem of farm and parasitic risk profiling in the context of Veterinary Epidemiology. We take advantage of a cross-sectional study carried out in the Campania Region in order to study the spatial distribution of 16 parasites in 121 ovine farms. We propose a tri-level hierarchical Bayesian model, which account for multivariate spatially structured overdispersion, to obtain estimate of posterior classification probabilities, that is for each parasite and farm the probability to belong to the set of the null hypothesis. We explore four decision rules based on either posterior probabilities or posterior means and compare the results in terms of the number of false discoveries/non-discoveries or the rate of false discovery/non-discovery. Our approach proved useful for parasitological risk profiling and we show that decision rules can be easily handled. PMID- 22517273 TI - Atomistic modeling of an impurity element and a metal-impurity system: pure P and Fe-P system. AB - An interatomic potential for pure phosphorus, an element that has van der Waals, covalent and metallic bonding character, simultaneously, has been developed for the purpose of application to metal-phosphorus systems. As a simplification, the van der Waals interaction, which is less important in metal-phosphorus systems, was omitted in the parameterization process and potential formulation. On the basis of the second-nearest-neighbor modified embedded-atom method (2NN MEAM) interatomic potential formalism applicable to both covalent and metallic materials, a potential that can describe various fundamental physical properties of a wide range of allotropic or transformed crystalline structures of pure phosphorus could be developed. The potential was then extended to the Fe-P binary system describing various physical properties of intermetallic compounds, bcc and liquid alloys, and also the segregation tendency of phosphorus on grain boundaries of bcc iron, in good agreement with experimental information. The suitability of the present potential and the parameterization process for atomic scale investigations about the effects of various non-metallic impurity elements on metal properties is demonstrated. PMID- 22517274 TI - Evaluation of systemic redox states in patients carrying the MELAS A3243G mutation in mitochondrial DNA. AB - BACKGROUND/AIMS: To clarify the change of systemic redox states in patients carrying the A3243G mutation in mitochondrial DNA (A3243G), we evaluated oxidative stress and antioxidant activity in the serum of patients. METHODS: Oxidative stress and antioxidant activity in the serum samples obtained from 14 patients carrying A3243G and from 34 healthy controls were analyzed using the diacron-reactive oxygen metabolites (d-ROMs) and biological antioxidant potential (BAP) tests, respectively. RESULTS: The mean d-ROMs level of all patients was significantly greater than that of the controls (p < 0.005), and the mean BAP/d ROMs ratio of all patients was significantly lower than that of the controls (p < 0.02). In the patients with a history of stroke-like episodes (n = 10), both mean d-ROMs and BAP levels were increased compared with those of the controls (both p < 0.01). The mean BAP level of the patients without a history of stroke-like episodes (n = 4) was significantly decreased compared with that of the controls (p < 0.001), but the mean d-ROMs levels were not significantly different. CONCLUSION: d-ROMs and BAP tests indicated that patients carrying A3243G are always exposed to underlying oxidative stress, even at a remission state of stroke-like episodes. PMID- 22517275 TI - Proteinase-activated receptor-4 plays a major role in the recruitment of neutrophils induced by trypsin or carrageenan during pleurisy in mice. AB - BACKGROUND/AIMS: The activation of proteinase-activated receptors (PARs) has been implicated in the development of important hallmarks of inflammation, including in vivo leukocyte recruitment. Here, we examined the effects of aprotinin, a potent inhibitor of trypsin proteinase and the kallikrein-kinin system, and the PAR-4 antagonist YPGKF-NH(2) (tcY-NH(2)) on neutrophil recruitment in response to carrageenan and trypsin in the pleural cavity of mice. METHODS: BALB/c mice were intrapleurally injected with trypsin or PAR-4-activating peptide AY-NH(2), pretreated with aprotinin or tcY-NH(2) (1 MUg/cavity) prior to an intrapleural injection of trypsin or carrageenan, or pretreated with leukotriene B(4) antagonist U-75302 (3 MUg/cavity) prior to a trypsin injection. The number of infiltrating neutrophils was evaluated after 4 h. RESULTS: PAR-4-activating peptide AY-NH(2) and trypsin-induced neutrophil recruitment was inhibited by aprotinin, tcY-NH(2) or U-75302. Aprotinin and tcY-NH(2) also inhibited neutrophil recruitment induced by carrageenan. CONCLUSION: These data suggest a key role for PAR-4 in mediating neutrophil recruitment in a mouse model of pleurisy induced by the activity of trypsin or trypsin-like enzymes. PMID- 22517276 TI - Imaging the Belousov-Zhabotinsky reaction in real time using an ion sensitive array. AB - We show how an array of ion-sensitive-field-effect-transistors can be used to both spatially and temporally image the oscillating pH/ion waves produced by the Belousov-Zhabotinsky (BZ) reaction with high resolution. PMID- 22517277 TI - Oculomotor nerve enhancement after mild head trauma. PMID- 22517278 TI - Feasibility and efficacy of transcranial motor-evoked potential monitoring in neuroendovascular surgery. AB - BACKGROUND AND PURPOSE: Neurophysiological monitoring for neuroendovascular procedures typically involves EEG and SSEP monitoring via cutaneous electrodes. MEP monitoring has been used less frequently because, traditionally, this has required subdural electrode placement. With the advent of transcutaneous techniques, MEP monitoring use has increased. However, little has been published regarding the use of this technique in therapeutic neuroendovascular procedures. The purpose of this study was therefore to determine whether TcMEP monitoring is feasible and efficacious in therapeutic neuroendovascular procedures. MATERIALS AND METHODS: We retrospectively reviewed our data base of therapeutic neuroendovascular procedures performed with the use of TcMEP monitoring. We specifically determined the incidence of TcMEP changes compared with changes in either SSEP or EEG. We then correlated these changes to actual adverse neurologic events. RESULTS: Although TcMEP monitoring was technically successful in all of the 140 patients in which it was attempted, we observed significant changes in TcMEP signals in only 1 patient. This patient experienced changes involving all 3 monitoring modalities after intraprocedural aneurysm rupture. In contrast, changes in SSEP tracings alone were found in 9 patients. Of these, 2 patients were known to be moribund before their procedures and neither recovered. Among the remaining 7 patients, temporary SSEP changes tended to correlate with temporary neurologic deficits, while permanent changes were associated with permanent or long-lasting deficits. CONCLUSIONS: These results suggest that TcMEP monitoring is feasible in therapeutic neuroendovascular procedures. However, it appears that the addition of TcMEP monitoring provides no added benefit to SSEP and EEG monitoring alone. PMID- 22517279 TI - Endovascular treatment of ruptured intracranial aneurysms: factors affecting midterm quality anatomic results: analysis in a prospective, multicenter series of patients (CLARITY). AB - BACKGROUND AND PURPOSE: Recanalization is 1 drawback of the EVT of intracranial aneurysms. An analysis of the factors affecting the midterm anatomic results after EVT of ruptured intracranial aneurysms in a large multicenter series (CLARITY) is presented. MATERIALS AND METHODS: Of the 782 patients initially included in the CLARITY trial, 649 would theoretically undergo midterm follow-up examinations. Finally, 517/649 (79.7%) completed a midterm follow-up examination. Midterm anatomic results were independently and anonymously evaluated by 2 experienced neuroradiologists. RESULTS: In univariate analysis, factors affecting the quality of midterm occlusion were the quality of the postoperative occlusion (P < .001), hypertension (P = .018), aneurysm size (P = .007), neck size (P = .005), and ICA location (P = .049). In multivariate analysis, 3 factors were associated with the quality of postoperative aneurysm occlusion: neck size (P = .003), use of the balloon remodeling technique (P = .031), and the quality of postoperative occlusion (P < .001). In univariate analysis, the evolution of aneurysm occlusion was affected by age (P = .024) and neck size (P = .041). In multivariate analysis, it was associated with the same factors: age (P = .025) and neck size (P = .043). CONCLUSIONS: Among the many factors considered in this analysis, aneurysm neck size was identified as the single most important one in the quality of aneurysm occlusion at midterm follow-up after EVT. The present results suggest developing and evaluating new strategies of treatment and technique, especially for wide-neck aneurysms, with a focus on reinforcement and neoendothelialization at the level of the neck as objectives. PMID- 22517280 TI - Extracranial venous drainage patterns in patients with multiple sclerosis and healthy controls. AB - BACKGROUND AND PURPOSE: CCSVI hypothesizes an association between impaired extracranial venous drainage and MS. Published sonographic criteria for CCSVI are controversial, and no MR imaging data exist to support the CCSVI hypothesis. Our purpose was to evaluate possible differences in the extracranial venous drainage of MS and healthy controls using both TOF and contrast-enhanced TRICKS MRV. MATERIALS AND METHODS: Healthy subjects (n = 20) and patients with MS (n = 19) underwent axial 2D-TOF neck MRV (to assess flattening) and TRICKS MRV (to assess collaterals) at 3T. Two neuroradiologists blinded to cohort status scored IJV flattening and the severity of non-IJV collaterals by using a 4-point qualitative scale (normal = 0, mild = 1, moderate = 2, severe = 3). kappa was used to assess reader agreement. Comparisons between groups were performed by using the Wilcoxon rank sum test. The Spearman rank correlation was used to assess the relationship between IJV flattening and collateral scores and, in patients with MS, EDSS scores. RESULTS: The 2 groups were matched for age and sex (MS, 45 +/- 8 years, 79% female; healthy controls, 47 +/- 10 years, 65% female). Reader agreement for IJV flattening and collateral severity was good (kappa = 0.74) and moderate (kappa = 0.58), respectively. While IJV flattening was seen in both patients with MS and healthy controls, scores for the patients with MS were significantly higher (P = .002). Despite a trend, there was no significant difference in collateral scores between groups (P = .063). There was a significant positive correlation between flattening and collateral scores (rho = 0.32, P = .005) and EDSS and flattening scores (rho = 0.45, P = .004) but not between EDSS and collateral scores (rho = 0.01, P = .97). CONCLUSIONS: These results indicate that patients with MS have greater IJV flattening and a trend toward more non-IJV collaterals than healthy subjects. The role that this finding plays in the pathogenesis or progression of MS, if any, requires further study. PMID- 22517281 TI - Acute-onset migrainous aura mimicking acute stroke: MR perfusion imaging features. AB - BACKGROUND AND PURPOSE: In a very limited number of cases, acute migrainous aura may mimic acute brain infarction. The aim of this study was to recognize patterns of MR perfusion abnormalities in this presentation. MATERIALS AND METHODS: One thousand eight hundred fifty MR imaging studies performed for the suspicion of acute brain infarction were analyzed retrospectively to detect patients with acute migrainous aura not from stroke. All patients were examined clinically by 2 neurologists and underwent a standard stroke MR imaging protocol, including PWI. Two radiologists reviewed the perfusion maps visually and quantitatively for the presence, distribution, and grade of perfusion abnormalities. RESULTS: Among 1850 MR imaging studies, 20 (1.08%) patients were found to have acute migrainous aura. Hypoperfusion was found in 14/20 patients (70%) with delayed rMTT and TTP, decreased rCBF, and minimal decrease in rCBV. In contrast to the typical pattern in stroke, perfusion abnormalities were not limited to a single vascular territory but extended to >1. Bilateral hypoperfusion was seen in 3/14 cases. In 11/14 cases, hypoperfusion with a posterior predominance was found. TTP and rMTT were the best maps to depict perfusion changes at visual assessment, but also rCBF maps demonstrated significant hypoperfusion in quantitative analysis. In all patients, clinical and imaging follow-up findings were negative for stroke. CONCLUSIONS: Acute migrainous aura is rare but important in the differential diagnosis among patients with the suspicion of acute brain infarction. Atypical stroke perfusion abnormalities can be seen in these patients. PMID- 22517282 TI - Patient-specific 3D simulation of cyclic CSF flow at the craniocervical region. AB - BACKGROUND AND PURPOSE: Flow simulations in patient-specific models of the subarachnoid space characterize CSF flow in more detail than MR flow imaging. We extended previous simulation studies by including cyclic CSF flow and patient specific models in multiple patients with Chiari I. We compared simulation results with MR flow measurements. MATERIALS AND METHODS: Volumetric high resolution image sets acquired in 7 patients with Chiari I, 3 patients who had previous craniovertebral decompression, and 3 controls were segmented and converted to mathematical models of the subarachnoid space. CSF flow velocities and pressures were calculated with high spatial and temporal resolution during simulated oscillatory flow in each model with the Navier-Stokes equations. Pressures, velocities, and bidirectional flow were compared in the groups (with Student t test). Peak velocities in the simulations were compared with peak velocities measured in vivo with PCMR. RESULTS: Flow visualization for patients and volunteers demonstrated nonuniform reversing patterns resembling those observed with PCMR. Velocities in the 13 subjects were greater between C2 and C5 than in the foramen magnum. Chiari patients had significantly greater peak systolic and diastolic velocities, synchronous bidirectional flow, and pressure gradients than controls. Peak velocities measured in PCMR correlated significantly (P = .003; regression analysis) despite differences between them. CONCLUSIONS: In simulations of CSF, patients with Chiari I had significantly greater peak systolic and diastolic velocities, synchronous bidirectional flow, and pressure gradients than controls. PMID- 22517283 TI - Y-configuration stent placement (crossing and kissing) for endovascular treatment of wide-neck cerebral aneurysms located at 4 different bifurcation sites. AB - BACKGROUND AND PURPOSE: The Y-stent technique, including crossing-Y and kissing Y, is a promising therapeutic option for some complex bifurcation aneurysms. Here, its efficacy and safety are evaluated on the basis of 11 bifurcation aneurysms. MATERIALS AND METHODS: A retrospective review was conducted for all patients who underwent endovascular treatment of aneurysms in our department between January 2009 and June 2011 to identify and analyze cases with bifurcation aneurysms reconstructed by using Y-stents. RESULTS: Eleven patients (4 ruptured and 7 unruptured aneurysms) were identified (4 men, 7 women) with a mean age of 60.4 years. Nine aneurysms (2 AcomAs, 3 MCA-Bifs, 1 PcomA, 3 BA apexes) were treated by using the crossing-Y technique, and 2 (both BA apexes) were treated with the kissing-Y technique, achieving complete occlusion in 6 aneurysms, residual neck in 4, and partial occlusion in 1. Perioperatively, a single thromboembolic event occurred in 1 case without neurologic deficit, which required a salvaging second stent implantation. Means of 9.9 months of angiographic and 13.7 months of clinical follow-up were available. As a result, 9 (81.8) aneurysms were completely occluded, 1 with a residual neck remained stable, and 1 residual aneurysm sac was recanalized, which was retreated and achieved a complete occlusion. All patients were independent with an mRS score of 0-1 at discharge and follow-up. CONCLUSIONS: In selected patients, the reconstruction of bifurcation aneurysms by using the Y-stent can be successfully achieved with satisfactory midterm results. PMID- 22517284 TI - Comments on an article by Kamalian et al. PMID- 22517285 TI - Acute brain MRI findings in 120 Malawian children with cerebral malaria: new insights into an ancient disease. AB - BACKGROUND AND PURPOSE: There have been few neuroimaging studies of pediatric CM, a common often fatal tropical condition. We undertook a prospective study of pediatric CM to better characterize the MRI features of this syndrome, comparing findings in children meeting a stringent definition of CM with those in a control group who were infected with malaria but who were likely to have a nonmalarial cause of coma. MATERIALS AND METHODS: Consecutive children admitted with traditionally defined CM (parasitemia, coma, and no other coma etiology evident) were eligible for this study. The presence or absence of malaria retinopathy was determined. MRI findings in children with ret+ CM (patients) were compared with those with ret- CM (controls). Two radiologists blinded to retinopathy status jointly developed a scoring procedure for image interpretation and provided independent reviews. MRI findings were compared between patients with and without retinopathy, to assess the specificity of changes for patients with very strictly defined CM. RESULTS: Of 152 children with clinically defined CM, 120 were ret+, and 32 were ret-. Abnormalities much more common in the patients with ret+ CM were markedly increased brain volume; abnormal T2 signal intensity; and DWI abnormalities in the cortical, deep gray, and white matter structures. Focal abnormalities rarely respected arterial vascular distributions. Most of the findings in the more clinically heterogeneous ret- group were normal, and none of the abnormalities noted were more prevalent in controls. CONCLUSIONS: Distinctive MRI findings present in patients meeting a stringent definition of CM may offer insights into disease pathogenesis and treatment. PMID- 22517286 TI - Susceptibility-weighted imaging: a new tool in the diagnosis and evaluation of abnormalities of the vein of Galen in children. AB - We retrospectively identified 9 consecutive children, 3 males and 6 females (age 5.2 +/- 6.3 years, range 1 day to 18 years), with known or suspected AVGs who underwent MR imaging, including SWI, at our institution between January 2007 and March 2011. On the SWI sequence, arterialized blood flow was considered to be present in the vein of Galen or its tributaries when these showed abnormal signal hyperintensity from arteriovenous shunting. SWI findings were correlated with findings from DSA studies or findings from time-of-flight or contrast-enhanced MR angiography sequences. SWI was found to accurately differentiate between high flow and low-flow AVGs and was also useful in characterizing the arterial supply and venous drainage patterns associated with high-flow AVGs. PMID- 22517287 TI - FTSE, WHO Code and the infant formula industry. PMID- 22517288 TI - Templated synthesis of a large and flexible covalent porphyrinic cage bearing orthogonal recognition sites. AB - A large covalent cage incorporating two porphyrins attached by four long and flexible polyether chains each bearing two 3-pyridyl ligands was synthesized from a DABCO-templated olefin metathesis reaction. The X-ray structure of the cage with the DABCO coordinated inside the cavity to the two zinc(II) porphyrins reveals a highly symmetric structure. PMID- 22517289 TI - Unrecognized nonadherence masquerades as drug resistance. PMID- 22517290 TI - Predictors of asthma control: what can we modify? AB - PURPOSE OF REVIEW: One strategy to improve asthma control is to identify risk factors for uncontrolled asthma in epidemiologic studies and then consider those risk factors as potential targets for intervention. This article reviews predictors of impairment based on validated tools and predictors of severe asthma exacerbations. RECENT FINDINGS: Indirectly modifiable risk factors for poor asthma control include older age in adults, lower socioeconomic status, and poor perception of dyspnea. Modifiable risk factors for poor asthma control include allergy triggers, low adherence, comorbidities, absence of specialty care, and various aspects of asthma self-management education. SUMMARY: Intervention strategies are suggested for predictors that are directly or indirectly modifiable. It is hoped that attention to these factors will improve asthma control and reduce the burden of disease. PMID- 22517291 TI - Is vitamin D supplementation responsible for the allergy pandemic? AB - PURPOSE OF REVIEW: A link between vitamin D supplementation and allergy was already suspected soon after it became possible to chemically synthesise vitamin D2 by means of ultraviolet radiation. During the past decade, the assumed allergenic effect was confirmed by clinical and epidemiological studies although the most recent discussion has centred more on vitamin D insufficiency. The purpose of this review is to summarise studies published during the past year while attempting to reconcile some apparent inconsistencies. RECENT FINDINGS: Two new concepts are presented here - epigenetic programming of the fetal vitamin D system by low maternal vitamin D supply (Barker's paradox) and ubiquitous vitamin D exposure of the newborn (Rose's paradox). Taken together a misdirected epigenetic programming offers an explanation why also vitamin D insufficiency in pregnancy may be associated with increased allergy rates in the offspring.At least eight studies examined the association of early 25-hydroxy-vitamin D levels and atopic diseases in 2011, whereas no new study addressed the question of vitamin D supplementation in the newborn period. One study tested the whole range of 25-hydroxy-vitamin D levels in cord blood describing a U-shaped association with 2.4-fold odds ratio of low and 4-fold odds ratio of high levels to develop allergen-specific immunoglobulin E. SUMMARY: Randomised clinical trials with vitamin D supplements are therefore highly required. Several key points are presented for designing vitamin D trials. PMID- 22517292 TI - GABA(B) receptors do not internalize after baclofen treatment, possibly due to a lack of beta-arrestin association: study with a real-time visualizing assay. AB - The mechanism of agonist-induced GABA(B) receptor (GABA(B) R) internalization is not well understood. To investigate this process, we focused on the interaction of GABA(B) R with beta-arrestins, which are key proteins in the internalization of most of the G protein-coupled receptors, and the agonist-induced GABA(B) R internalization and the interaction of GABA(B) R with beta-arrestin1 and beta arrestin2 were investigated in real time using GABA(B) R and beta-arrestins both of which were fluorescent protein-tagged. We then compared these profiles with those of MU-opioid receptors (MUOR), well-studied receptors that associate and cointernalize with beta-arrestins. When stimulated by the specific GABA(B) R agonist baclofen, GABA(B) R composed of GABA(B1a) R (GB(1a) R) and fluorescent protein-tagged GABA(B2) R-Venus (GB2 R-V) formed functional GABA(B) R; they elicited G protein-activated inwardly rectifying potassium channels as well as nontagged GABA(B) R. In cells coexpressing GB(1a) R, GB2 R-V, and beta-arrestin1 Cerulean (betaarr1-C) or beta-arrestin2-Cerulean (betaarr2-C), real-time imaging studies showed that baclofen treatment neither internalized GB2 R-V nor mobilized betaarr1-C or betaarr2-C to the cell surface. This happened regardless of the presence of G protein-coupled receptor kinase 4 (GRK4), which forms a complex with GABA(B) R and causes GABA(B) R desensitization. On the other hand, in cells coexpressing MUOR-Venus, GRK2, and betaarr1-C or betaarr2-C, the MUOR molecule formed MUOR/betaarr1 or MUOR/betaarr2 complexes on the cell surface, which were then internalized into the cytoplasm in a time-dependent manner. Fluorescence resonance energy transfer assay also indicated scarce association of GB2 R-V and beta-arrestins-C with or without the stimulation of baclofen, while robust association of MUOR-V with beta-arrestins-C was detected after MUOR activation. These findings suggest that GABA(B) Rs failure to undergo agonist-induced internalization results in part from its failure to interact with beta-arrestins. PMID- 22517293 TI - Effect of L-arginine and selenium added to a hypocaloric diet enriched with legumes on cardiovascular disease risk factors in women with central obesity: a randomized, double-blind, placebo-controlled trial. AB - BACKGROUND/AIMS: We aimed to discover if L-arginine and selenium alone or together can increase the effect of a hypocaloric diet enriched in legumes (HDEL) on central obesity and cardiovascular risk factors in women with central obesity. METHODS: This randomized, double-blind, placebo-controlled trial was undertaken in 84 premenopausal women with central obesity. After a 2-week run-in period on an isocaloric diet, participants were randomly assigned to a control diet (HDEL), L-arginine (5 g/day) and HDEL, selenium (200 MUg/day) and HDEL or L-arginine, selenium and HDEL for 6 weeks. Cardiovascular risk factors were assessed before intervention and 3 and 6 weeks afterwards. RESULTS: After 6 weeks, L-arginine had significantly reduced waist circumference (WC); selenium had significantly lowered fasting concentrations of serum insulin and the homeostasis model assessment of insulin resistance index; the interaction between L-arginine and selenium significantly reduced the fasting concentration of nitric oxides (NO(x)), and HDEL lowered triglycerides (TG) and WC and significantly increased the fasting concentration of NO(x). HDEL reduced high-sensitivity C-reactive protein levels in the first half of the study and returned them to basal levels in the second half. CONCLUSION: These data indicate the beneficial effects of L arginine on central obesity, selenium on insulin resistance and HDEL on serum concentrations of NO(x) and TG. PMID- 22517294 TI - Controlling magnetoelectric coupling by nanoscale phase transformation in strain engineered bismuth ferrite. AB - The magnetoelectric coupling in multiferroic materials is promising for a wide range of applications, yet manipulating magnetic ordering by electric field proves elusive to obtain and difficult to control. In this paper, we explore the prospect of controlling magnetic ordering in misfit strained bismuth ferrite (BiFeO(3), BFO) films, combining theoretical analysis, numerical simulations, and experimental characterizations. Electric field induced transformation from a tetragonal phase to a distorted rhombohedral one in strain engineered BFO films has been identified by thermodynamic analysis, and realized by scanning probe microscopy (SPM) experiment. By breaking the rotational symmetry of a tip-induced electric field as suggested by phase field simulation, the morphology of distorted rhombohedral variants has been delicately controlled and regulated. Such capabilities enable nanoscale control of magnetoelectric coupling in strain engineered BFO films that is difficult to achieve otherwise, as demonstrated by phase field simulations. PMID- 22517295 TI - Highly enantioselective asymmetric hydrogenation of (E)-beta,beta-disubstituted alpha,beta-unsaturated Weinreb amides catalyzed by Ir(I) complexes of SpinPhox ligands. AB - The Ir(I) complexes of chiral spiro phosphino-oxazoline ligands (SpinPhox) have demonstrated good to excellent enantioselectivity in the asymmetric hydrogenation (AH) of a variety of (E)-beta,beta-disubstituted alpha,beta-unsaturated N-methoxy N-methylamides, affording the corresponding optically active Weinreb amides with up to 97% ee. PMID- 22517296 TI - Antiulcer activity of methanol extract of Melastoma malabathricum leaves in rats. AB - OBJECTIVE: To determine the potential antiulcer activity of methanol extract of Melastoma malabathricum leaves (MEMM) using various established rat models. MATERIALS AND METHODS: Ten groups of rats were used and orally administered 10% DMSO (negative control), 100 mg/kg ranitidine (positive control) or MEMM (50, 250 and 500 mg/kg) followed by gastric ulcer induction either using ethanol or indomethacin. The stomachs were collected and subjected to macroscopic and microscopic analyses. RESULTS: MEMM exhibited significant (p < 0.05) antiulcer activity in the ethanol, but not in the indomethacin-induced gastric ulcer model. The percentage of antiulcer activity for 50-500 mg/kg MEMM ranged between 3 and 75%, respectively. The gross observations were supported by histological findings. MEMM also aggravated the indomethacin-induced gastric ulcer, leading to an increase in ulcer area formation and ulcer score. CONCLUSION: The M. malabathricum leaves showed antiulcer activity, which could be attributed to their antioxidant and anti-inflammatory activities. This requires further in depth studies. PMID- 22517297 TI - Comparison of the FeO(2+) and FeS(2+) complexes in the cyanide and isocyanide ligand environment for methane hydroxylation. AB - A general comparison of fundamental distinctions between the FeO(2+) and FeS(2+) complexes in an identical cyanide or isocyanide ligand environment for methane hydroxylation has been probed computationally in this work in a series of hypothetical [Fe(IV)(X)(CN)5](3-), [Fe(IV)(X)(NC)5](3-), (X = O, S) complexes. We have detailed an analysis of the geometric and electronic structures using density functional theory calculations. In addition, their sigma- and pi mechanisms in C-H bond activation process have been described with the aid of the schematic molecular orbital diagram. From our theoretical results, it is shown that (a) the iron(IV)-sulfido complex apparently is able to hydroxylate C-H bond of methane as good as the iron(IV)-oxo species, (b) the O-CN, S-CN complexes have an inherent preference for the low-spin state, while for the case of O-NC and S NC in which S = 1 and S = 2 states are relatively close in energy, (c) each of the d block electron orbital plays an important role, which is not just spectator electron, and (d) in comparison to the cyanide and isocyanide ligand environment, we can see that the FeS(2+) species prefer the cyanide ligand environment, while the FeO(2+) species favor the isocyanide ligand environment. In addition, a remarkably good correlation of the sigma-/pi-mechanism for hydrogen abstraction from methane with the gap between the Fe-dz2 (alpha) and C-H (alpha) pair as well as the Fe-dxz/yz (beta) and C-H (beta) pair has been found. PMID- 22517298 TI - Lavender essential oil in the treatment of migraine headache: a placebo controlled clinical trial. AB - Lavender essential oil has been used as an anxiolytic drug, a mood stabilizer, a sedative, spasmolytic, antihypertensive, antimicrobial, analgesic agent as well as a wound healing accelerator. We have studied for the first time the efficacy of lavender essential oil inhalation for the treatment of migraine in a placebo controlled clinical trial. METHODS: Forty-seven patients with definite diagnosis of migraine headache were divided into cases and controls. Cases inhaled lavender essential oil for 15 min, whereas the control group used liquid paraffin for the same time period. Patients were asked to record their headache severity and associated symptoms in 30-min intervals for a total of 2 h. We matched the two groups for key confounding factors. RESULTS: The mean reduction of headache severity in cases was 3.6 +/- 2.8 based on Visual Analogue Scale score. The reduction was 1.6 +/- 1.6 in controls. This difference between the controls and cases was statistically significant with p < 0.0001. From 129 headache attacks in cases, 92 responded entirely or partially to lavender. In the control group, 32 out of 68 recorded headache attacks responded to placebo. The percentage of responders was significantly higher in the lavender group than the placebo group (p = 0.001). CONCLUSION: The present study suggests that inhalation of lavender essential oil may be an effective and safe treatment modality in acute management of migraine headaches. PMID- 22517299 TI - Sequential differentiation of mesenchymal stem cells in an agarose scaffold promotes a physis-like zonal alignment of chondrocytes. AB - Chondrocytes of the epiphyseal growth plate (physis) differentiate and mature in defined linear zones. The current study examines the differentiation of human bone marrow derived mesenchymal stem cells (hBMSCs) into zonal physeal cartilage. hBMSCs were embedded in an agarose scaffold with only the surface of the scaffold in direct contact with the culture medium. The cells were differentiated using a two-step system involving the sequential addition of TGFbeta followed by BMP2. The resultant samples displayed a heterogenic population of physis-like collagen type 2 positive cells including proliferating chondrocytes and mature chondrocytes showing hypertrophy, expression of early bone markers and matrix mineralization. Histological analysis revealed a physis-like linear zonal alignment of chondrocytes in varying stages of differentiation. The less mature chondrocytes were seen at the base of the construct while hypertrophic chondrocytes and matrix mineralization was observed closer to the surface of the construct. The described differentiation protocol using hBMSCs in an agarose scaffold can be used to study the factors and conditions that influence the differentiation, proliferation, maturation, and zonal alignment of physeal chondrocytes. PMID- 22517300 TI - Proportional hazards regression in epidemiologic follow-up studies: an intuitive consideration of primary time scale. AB - In epidemiologic cohort studies of chronic diseases, such as heart disease or cancer, confounding by age can bias the estimated effects of risk factors under study. With Cox proportional-hazards regression modeling in such studies, it would generally be recommended that chronological age be handled nonparametrically as the primary time scale. However, studies involving baseline measurements of biomarkers or other factors frequently use follow-up time since measurement as the primary time scale, with no explicit justification. The effects of age are adjusted for by modeling age at entry as a parametric covariate. Parametric adjustment raises the question of model adequacy, in that it assumes a known functional relationship between age and disease, whereas using age as the primary time scale does not. We illustrate this graphically and show intuitively why the parametric approach to age adjustment using follow-up time as the primary time scale provides a poor approximation to age-specific incidence. Adequate parametric adjustment for age could require extensive modeling, which is wasteful, given the simplicity of using age as the primary time scale. Furthermore, the underlying hazard with follow-up time based on arbitrary timing of study initiation may have no inherent meaning in terms of risk. Given the potential for biased risk estimates, age should be considered as the preferred time scale for proportional-hazards regression with epidemiologic follow-up data when confounding by age is a concern. PMID- 22517301 TI - Evaluation of residual CD34(+) Ph(+) progenitor cells in chronic myeloid leukemia patients who have complete cytogenetic response during first-line nilotinib therapy. AB - BACKGROUND: Compared with imatinib, nilotinib is a potent breakpoint cluster region/v-abl Abelson murine leukemia viral oncogene (bcr-abl) kinase inhibitor, and it induces higher rate and rapid complete cytogenetic response (CCyR), yet no clinical data are available regarding its efficacy against chronic myeloid leukemia (CML) stem cells. Earlier studies demonstrated that clusters of differentiation 34-positive, Philadelphia chromosome-positive (CD34(+) Ph(+) ) cells are detectable in about 45% of patients with CML, despite being on long term imatinib therapy and having achieved sustained CCyR. METHODS: CD34(+) cells from bone marrow of de novo CML patients in the chronic phase (n = 24) treated with nilotinib (median duration of therapy, 22 months) were isolated and scored for BCR-ABL by fluorescent in situ hybridization (FISH) analysis. Similar analysis was also performed in 5 de novo CML chronic phase patients who achieved CCyR within 3 months of nilotinib therapy. RESULTS: FISH evaluation of a median of 100 CD34(+) nuclei per patient revealed that only 1 of 20 (5%) evaluable patients showed residual Ph(+) progenitor cells. In this patient, just 1 of 140 (0.7%) CD34(+) interphase nuclei was found to be positive for BCR-ABL. Surprisingly, no CD34(+) Ph(+) cells were found even in those 5 patients evaluated after 3 months of nilotinib treatment. CONCLUSIONS: This study assessed for the first time the persistence of CD34(+) Ph(+) cells during nilotinib first line treatment. Preliminary results showed that in patients in CCyR, even after short-term nilotinib therapy, residual leukemic progenitors are very rarely detected compared with imatinib-treated CCyR patients. It is yet to be determined if these findings will have an impact in the path to a cure of CML with tyrosine kinase inhibitors. PMID- 22517302 TI - Generation and characterization of high-valent iron oxo phthalocyanines. AB - The first high-valent iron oxo complex on the phthalocyanine platform has been prepared from iron tetra-tert-butyl-phthalocyanine and m-chloroperbenzoic acid and characterized by low temperature UV-vis, cryospray MS, EPR, X-ray absorption and high resolution X-ray emission methods. PMID- 22517303 TI - Music to whose ears? The effect of social norms on young people's risk perceptions of hearing damage resulting from their music listening behavior. AB - Professional and community concerns about the potentially dangerous noise levels for common leisure activities has led to increased interest on providing hearing health information to participants. However, noise reduction programmes aimed at leisure activities (such as music listening) face a unique difficulty. The noise source that is earmarked for reduction by hearing health professionals is often the same one that is viewed as pleasurable by participants. Furthermore, these activities often exist within a social setting, with additional peer influences that may influence behavior. The current study aimed to gain a better understanding of social-based factors that may influence an individual's motivation to engage in positive hearing health behaviors. Four hundred and eighty-four participants completed questionnaires examining their perceptions of the hearing risk associated with listening to music listening and asking for estimates of their own and their peer's music listening behaviors. Participants were generally aware of the potential risk posed by listening to personal stereo players (PSPs) and the volumes likely to be most dangerous. Approximately one in five participants reported using listening volumes at levels perceived to be dangerous, an incidence rate in keeping with other studies measuring actual PSP use. However, participants showed less awareness of peers' behavior, consistently overestimating the volumes at which they believed their friends listened. Misperceptions of social norms relating to listening behavior may decrease individuals' perceptions of susceptibility to hearing damage. The consequences of hearing health promotion are discussed, along with suggestions relating to the development of new programs. PMID- 22517304 TI - Investigation of the relationship between aircraft noise and community annoyance in China. AB - A survey of community annoyance induced by aircraft noise exposure was carried out around Hangzhou Xiaoshan International Airport. To investigate the relationship curves between aircraft noise and the percentage of "highly annoyed" persons in China and also to get annoyance threshold of aircraft noise in China. Noise annoyance induced by aircraft noise exposure was assessed by 764 local residents around the airport using the International Commission on Biological Effect of Noise (ICBEN) scale. The status quo of aircraft noise pollution was measured by setting up 39 monitoring points. The interpolation was used to estimate the weighted effective continuous perceived noise levels (LWECPN) in different areas around the airport, and the graph of equal noise level contour was drawn. The membership function was used to calculate the annoyance threshold of aircraft noise. Data were analyzed using SPSS 16.0 and Origin 8.0. The results showed that if LWECPN was 64.3 dB (Ldn was 51.4 dB), then 15% respondents were highly annoyed. If LWECPN was 68.1 dB (Ldn was 55.0 dB), then 25% respondents were highly annoyed. The annoyance threshold of aircraft noise (LWECPN) was 73.7 dB, while the annoyance threshold of a single flight incident instantaneous noise level (LAmax) was 72.9 dB. People around the airport had felt annoyed before the aircraft noise LWECPN reached the standard limit. PMID- 22517305 TI - Review of the effect of aircraft noise on sleep disturbance in adults. AB - Noise exposure generated by air traffic has been linked with sleep disturbances. The purpose of this systematic review is to clarify whether there is a causal link between aircraft noise exposure and sleep disturbances. Only complete, peer reviewed articles published in scientific journals were examined. Papers published until December 2010 were considered. To be included, articles had to focus on subjects aged 18 or over and include an objective evaluation of noise levels. Studies were classified according to quality. Given the paucity of studies with comparable outcome measures, we performed a narrative synthesis using a best-evidence synthesis approach. The primary study findings were tabulated. Similarities and differences between studies were investigated. Of the 12 studies surveyed that dealt with sleep disturbances, four were considered to be of high quality, five were considered to be of moderate quality and three were considered to be of low quality. All moderate- to high-quality studies showed a link between aircraft noise events and sleep disturbances such as awakenings, decreased slow wave sleep time or the use of sleep medication. This review suggests that there is a causal relation between exposure to aircraft noise and sleep disturbances. However, the evidence comes mostly from experimental studies focusing on healthy adults. Further studies are necessary to determine the impact of aircraft noise on sleep disturbance for individuals more than 65 years old and for those with chronic diseases. PMID- 22517306 TI - Early occupational hearing loss of workers in a stone crushing industry: our experience in a developing country. AB - Noise-induced hearing loss (NIHL) is an irreversible sensorineural hearing loss associated with exposure to high levels of excessive noise. This paper aims to assess the prevalence of early NIHL and the awareness of the effects of noise on health among stone crushing industry workers. This was a comparative cross sectional study in Ghana of 140 workers from the stone crushing industry compared with a control group of 150 health workers. The stone workers and controls were evaluated using a structured questionnaire, which assessed symptoms of hearing loss, tinnitus, knowledge on the health hazards associated with work in noisy environment and the use of hearing protective device. Pure tone audiometric assessment was carried out for stone workers and controls. Noise levels at the work stations of the stone workers and of the controls were measured. Statistical Analysis of data was carried out using SPSS package version 16. The mean age of stone workers and controls was 42.58+/-7.85 and 42.19+/-12 years, respectively. Subjective hearing loss occurred in 21.5% of the workers and in 2.8% of the controls. Tinnitus occurred in 26.9% of stone workers and 21.5% of controls, while 87.5% stone workers had sound knowledge on the health hazards of a noisy environment. Early NIHL in the left ear occurred in 19.3% of the stone workers compared with 0.7% in controls and in the right ear, it occurred in 14.3% of the stone workers and in 1.3% of the controls; P<0.005. In conclusion, the prevalence rate of early NIHL among stone crushing workers is about 19.3% for the left ear and 14.3% for the right ear. PMID- 22517307 TI - Noise exposure and auditory effects on preschool personnel. AB - Hearing impairments and tinnitus are being reported in an increasing extent from employees in the preschool. The investigation included 101 employees at 17 preschools in Umea county, Sweden. Individual noise recordings and stationary recordings in dining rooms and play halls were conducted at two departments per preschool. The effects of noise exposures were carried out through audiometric screenings and by use of questionnaires. The average individual noise exposure was close to 71 dB(A), with individual differences but small differences between the preschools. The noise levels in the dining room and playing halls were about 64 dB(A), with small differences between the investigated types of rooms and preschools. The hearing loss of the employees was significantly higher for the frequencies tested when compared with an unexposed control group in Sweden. Symptoms of tinnitus were reported among about 31% of the employees. Annoyance was rated as somewhat to very annoying. The voices of the children were the most annoying noise source. The dB(A) level and fluctuation of the noise exposure were significantly correlated to the number of children per department. The preschool sound environment is complex and our findings indicate that the sound environment is hazardous regarding auditory disorders. The fluctuation of the noise is of special interest for further research. PMID- 22517308 TI - Multi-center study of noise in patients from hospitals in Spain: a questionnaire survey. AB - To identify the most annoying noises in the hospital environment. One hundred and ninety-three patients took part in the study. A questionnaire collected the perceptions of patients from four hospitals in Spain, with three distinct units. The most annoying noises were the repetitive ones and the most unbearable source was the people who talk loudly. The daily hours were the noisiest and the most annoying, especially when patients wanted to rest and indicated that noise was annoying for them to get to sleep. Our results demonstrate how sensitive patients are toward noise in Spain. We also suggest some strategies to reduce the noise and the harmful physiological effects of increased sound levels in order to improve the quality of life in a healthcare environment. PMID- 22517309 TI - Occupational noise exposure and regulatory adherence in music venues in the United Kingdom. AB - Noise in most working environments is an unwanted by-product of the process. In most countries, noise exposure for workers has been controlled by legislation for many years. In the music industry the "noise" is actually the "desired" product, and for a long time the UK entertainment industry was exempt from these regulations. From April 2008, however, it became regulated under the Noise at Work Regulations 2005, meaning that employers from orchestras to nightclubs are legally required to adhere to the same requirements (based on ISO 9612:2009) for controlling noise exposure for their staff that have been applied to other industries for many years. A key question is to what degree, 2 years after implementation, these employers are complying with their legal responsibilities to protect the staff from noise? This study assessed four public music venues where live and/or recorded music is regularly played. Thirty staff members in different roles in the venues were monitored using noise dosimetry to determine noise exposure. Questionnaires were used to determine work patterns, attitudes to noise and hearing loss, and levels of training about noise risk. Results showed that the majority of staff (70%) in all venues exceeded the daily noise exposure limit value in their working shift. Use of hearing protection was rare (<30%) and not enforced by most venues. The understanding of the hazard posed by noise was low, and implementation of the noise regulations was haphazard, with staff regularly exceeding regulatory limits. The implication is that the industry is failing to meet regulatory requirements. PMID- 22517310 TI - Primary care providers' perspectives on discontinuing prostate cancer screening. AB - BACKGROUND: Clinical guidelines recommend against routine prostate-specific antigen (PSA) screening for older men and for those with lower life expectancies. The authors of this report examined providers' decision-making regarding discontinuing PSA screening. METHODS: A survey of primary providers from a large, university-affiliated primary care practice was administered. Providers were asked about their current screening practices, factors that influenced their decision to discontinue screening, and barriers to discontinuing screening. Bivariate and multivariable logistic regression analyses were used to examine whether taking age and/or life expectancy into account and barriers to discontinuing were associated with clinician characteristics and practice styles. RESULTS: One hundred twenty-five of 141 providers (88.7%) participated in the survey. Over half (59.3%) took both age and life expectancy into account, whereas 12.2% did not consider either in their decisions to discontinue PSA screening. Providers varied in the age at which they typically stopped screening patients, and the majority (66.4%) reported difficulty in assessing life expectancy. Taking patient age and life expectancy into account was not associated with provider characteristics or practice styles. The most frequently cited barriers to discontinuing PSA screening were patient expectation (74.4%) and time constraints (66.4%). Black providers were significantly less likely than nonblack providers to endorse barriers related to time constraints and clinical uncertainty, although these results were limited by the small sample size of black providers. CONCLUSIONS: Although age and life expectancy often figured prominently in decisions to use screening, providers faced multiple barriers to discontinuing routine PSA screening. PMID- 22517311 TI - Anesthetic management in patients undergoing hyperthermic chemotherapy. AB - PURPOSE OF REVIEW: Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has become an important therapeutic option for selected patients with peritoneal surface malignancies. This aggressive multimodality treatment is complex, not only regarding surgical technique, but also regarding anesthesia. The present review represents our experience in anesthetic care. RECENT FINDINGS: Improved prognosis compared with systemic chemotherapy alone has recently been demonstrated for cytoreductive surgery when combined with intraoperative intracavitary hyperthermic chemotherapy. Anesthetic management of HIPEC is further impacted by these developments. In addition to the ambitious, long-lasting surgery, HIPEC causes significant fluid, blood and protein losses, increased intra-abdominal pressure, systemic hyperthermia, and increased metabolic rate, leading to relevant pathophysiological alterations, and therefore represents a challenge for anesthetist and critical care physicians. SUMMARY: Anesthetic management importantly contributes to the containment of the perioperative complications of HIPEC. An appreciation of the technical aspects and physiologic disruptions associated with intra-abdominal HIPEC is critical to ensure effective anesthetic management. Although data on this specialized surgical procedure are scarce, some referral centers have accumulated extensive experience. This article reviews the current knowledge about the anesthesiological and intensive care management of patients undergoing HIPEC. It pinpoints strategies for perioperative monitoring as well as illustrates alterations in hemodynamic, hematopoetic, and fluid hemostasis. PMID- 22517313 TI - Crystalline inverted membranes grown on surfaces by electrospray ion beam deposition in vacuum. AB - Crystalline inverted membranes of the nonvolatile surfactant sodium dodecylsulfate are found on solid surfaces after electrospray ion beam deposition (ES-IBD) of large SDS clusters in vacuum. This demonstrates the equivalence of ES IBD to conventional molecular beam epitaxy. PMID- 22517312 TI - Sprouty is a negative regulator of transforming growth factor beta-induced epithelial-to-mesenchymal transition and cataract. AB - Fibrosis affects an extensive range of organs and is increasingly acknowledged as a major component of many chronic disorders. It is now well accepted that the elevated expression of certain inflammatory cell-derived cytokines, especially transforming growth factor beta (TGFbeta), is involved in the epithelial-to mesenchymal transition (EMT) leading to the pathogenesis of a diverse range of fibrotic diseases. In lens, aberrant TGFbeta signaling has been shown to induce EMT leading to cataract formation. Sproutys (Sprys) are negative feedback regulators of receptor tyrosine kinase (RTK)-signaling pathways in many vertebrate systems, and in this study we showed that they are important in the murine lens for promoting the lens epithelial cell phenotype. Conditional deletion of Spry1 and Spry2 specifically from the lens leads to an aberrant increase in RTK-mediated extracellular signal-regulated kinase 1/2 phosphorylation and, surprisingly, elevated TGFbeta-related signaling in lens epithelial cells, leading to an EMT and subsequent cataract formation. Conversely, increased Spry overexpression in lens cells can suppress not only TGFbeta-induced signaling, but also the accompanying EMT and cataract formation. On the basis of these findings, we propose that a better understanding of the relationship between Spry and TGFbeta signaling will not only elucidate the etiology of lens pathology, but will also lead to the development of treatments for other fibrotic-related diseases associated with TGFbeta-induced EMT. PMID- 22517314 TI - Structure and stability of the complex formed by oligonucleotides. AB - Polycations and cationic lipids have been widely used as non-viral vectors for the delivery of plasmid DNA, siRNA and anti-sense oligonucleotides. To demonstrate that one polycation can form a complex with several types of DNA, we conducted a comparative study on the complexation of poly(L-lysine) (PLL) with 2000 bp salmon testes DNA (dsDNA), 21 bp double-stranded oligonucleotides (ds oligo), and 21 nt single-stranded oligonucleotides (ss-oligo) in PBS buffer. The complexes are prepared by a titration method and the process is monitored by laser light scattering. It was found that in most cases, ss-oligo and ds-oligo form complexes with higher molecular weights than the complex formed by dsDNA at the same +/- ratio immediately after mixing. More importantly, the complexes formed by oligonucleotides are not stable, the scattered intensity gradually decreases to the level of the solvent in weeks. Atomic force microscopy measurements also indicate that the freshly prepared complex is subject to environmental changes and could dissociate very quickly. The behaviour of oligonucleotides cannot be predicted by the classical polyelectrolyte theories. PMID- 22517315 TI - Pharmaceutical countermeasures have opposite effects on the utricles and semicircular canals in man. AB - INTRODUCTION: Sensory conflicts in the vestibular system lead to motion sickness of which space motion sickness (SMS) is a special case. SMS affects up to 70% of the astronauts during the first 3 days in space. The search for effective countermeasures has led to several nonpharmacological and pharmacological approaches. The current study focuses on the effects of lorazepam (1 mg), meclizine (25 mg), promethazine (25 mg), and scopolamine (0.4 mg) on the vestibular system, with special focus on the canal and otolith functions separately. METHODS: The study had a placebo-controlled, single blind, repeated measures design. Sixteen healthy volunteers were subjected to a total of 7 test sessions, the first and last being without intake of medication. Semicircular canal function was evaluated by means of electronystagmography and otolith function with unilateral centrifugation. The horizontal semicircular canal function was characterized by the vestibulo-ocular reflex (VOR) gain measured during earth vertical axis rotation as well as the total caloric response. The function of the utricles was represented by the utricular sensitivity, reflecting the ocular counter roll relative to the virtual induced head tilt. RESULTS: Promethazine significantly decreased the semicircular canal and utricular parameters. Both scopolamine and lorazepam caused only a decrease in the utricular sensitivity, whereas meclizine only decreased the semicircular canal induced VOR gain. DISCUSSION: The results show that the drugs affected different areas of the vestibular system and that the effects can thus be attributed to the specific pharmacological properties of each drug. Meclizine, as an antihistaminergic and weak anticholinergic drug, only affected the VOR gain, suggesting a central action on the medial vestibular nucleus. The same site of action is suggested for the anticholinergic scopolamine since acetylcholine receptors are present and utricular fibers terminate here. The global vestibular suppression caused by promethazine is probably a consequence of its anticholinergic, antihistaminergic, and antidopaminergic properties. Based on the fact that lorazepam increased the affinity of gamma-aminobutyric acid (GABA) for the GABA(A)-receptor and its effects on the utriculi, the site of action seems to be the lateral vestibular nucleus. CONCLUSION: Meclizine, scopolamine, and lorazepam selectively suppress specific parts of the vestibular system. Selective suppression of different parts of the vestibular system may be more beneficial for alleviating (space) motion sickness than general suppressive agents. Additionally, this knowledge may help the clinician in his therapeutic management of patients with either semicircular canal or otolith dysfunction. PMID- 22517316 TI - Gene-sharing networks reveal organizing principles of transcriptomes in Arabidopsis and other multicellular organisms. AB - Understanding tissue-related gene expression patterns can provide important insights into gene, tissue, and organ function. Transcriptome analyses often have focused on housekeeping or tissue-specific genes or on gene coexpression. However, by analyzing thousands of single-gene expression distributions in multiple tissues of Arabidopsis thaliana, rice (Oryza sativa), human (Homo sapiens), and mouse (Mus musculus), we found that these organisms primarily operate by gene sharing, a phenomenon where, in each organism, most genes exhibit a high expression level in a few key tissues. We designed an analytical pipeline to characterize this phenomenon and then derived Arabidopsis and human gene sharing networks, in which tissues are connected solely based on the extent of shared preferentially expressed genes. The results show that tissues or cell types from the same organ system tend to group together to form network modules. Tissues that are in consecutive developmental stages or have common physiological functions are connected in these networks, revealing the importance of shared preferentially expressed genes in conferring specialized functions of each tissue type. The networks provide predictive power for each tissue type regarding gene functions of both known and heretofore unknown genes, as shown by the identification of four new genes with functions in guard cell and abscisic acid response. We provide a Web interface that enables, based on the extent of gene sharing, both prediction of tissue-related functions for any Arabidopsis gene of interest and predictions concerning the relatedness of tissues. Common gene sharing patterns observed in the four model organisms suggest that gene sharing evolved as a fundamental organizing principle of gene expression in diverse multicellular eukaryotes. PMID- 22517317 TI - Dynamic antagonism between phytochromes and PIF family basic helix-loop-helix factors induces selective reciprocal responses to light and shade in a rapidly responsive transcriptional network in Arabidopsis. AB - Plants respond to shade-modulated light signals via phytochrome (phy)-induced adaptive changes, termed shade avoidance. To examine the roles of Phytochrome Interacting basic helix-loop-helix Factors, PIF1, 3, 4, and 5, in relaying such signals to the transcriptional network, we compared the shade-responsive transcriptome profiles of wild-type and quadruple pif (pifq) mutants. We identify a subset of genes, enriched in transcription factor-encoding loci, that respond rapidly to shade, in a PIF-dependent manner, and contain promoter G-box motifs, known to bind PIFs. These genes are potential direct targets of phy-PIF signaling that regulate the primary downstream transcriptional circuitry. A second subset of PIF-dependent, early response genes, lacking G-box motifs, are enriched for auxin-responsive loci, and are thus potentially indirect targets of phy-PIF signaling, mediating the rapid cell expansion induced by shade. Comparing deetiolation- and shade-responsive transcriptomes identifies another subset of G box-containing genes that reciprocally display rapid repression and induction in response to light and shade signals. These data define a core set of transcriptional and hormonal processes that appear to be dynamically poised to react rapidly to light-environment changes via perturbations in the mutually antagonistic actions of the phys and PIFs. Comparing the responsiveness of the pifq and triple pif mutants to light and shade confirms that the PIFs act with overlapping redundancy on seedling morphogenesis and transcriptional regulation but that each PIF contributes differentially to these responses. PMID- 22517318 TI - A transit peptide-like sorting signal at the C terminus directs the Bienertia sinuspersici preprotein receptor Toc159 to the chloroplast outer membrane. AB - Although Toc159 is known to be one of the key GTPase receptors for selective recognition of chloroplast preproteins, the mechanism for its targeting to the chloroplast surface remains unclear. To compare the targeting of these GTPase receptors, we identified two Toc159 isoforms and a Toc34 from Bienertia sinuspersici, a single-cell C4 species with dimorphic chloroplasts in individual chlorenchyma cells. Fluorescent protein tagging and immunogold studies revealed that the localization patterns of Toc159 were distinctive from those of Toc34, suggesting different targeting pathways. Bioinformatics analyses indicated that the C-terminal tails (CTs) of Toc159 possess physicochemical and structural properties of chloroplast transit peptides (cTPs). These results were further confirmed by fluorescent protein tagging, which showed the targeting of CT fusion proteins to the chloroplast surface. The CT of Bs Toc159 in reverse orientation functioned as a cleavable cTP that guided the fluorescent protein to the stroma. Moreover, a Bs Toc34 mutant protein was retargeted to the chloroplast envelope using the CTs of Toc159 or reverse sequences of other cTPs, suggesting their conserved functions. Together, our data show that the C terminus and the central GTPase domain represent a novel dual domain-mediated sorting mechanism that might account for the partitioning of Toc159 between the cytosol and the chloroplast envelope for preprotein recognition. PMID- 22517320 TI - Fern and lycophyte guard cells do not respond to endogenous abscisic acid. AB - Stomatal guard cells regulate plant photosynthesis and transpiration. Central to the control of seed plant stomatal movement is the phytohormone abscisic acid (ABA); however, differences in the sensitivity of guard cells to this ubiquitous chemical have been reported across land plant lineages. Using a phylogenetic approach to investigate guard cell control, we examined the diversity of stomatal responses to endogenous ABA and leaf water potential during water stress. We show that although all species respond similarly to leaf water deficit in terms of enhanced levels of ABA and closed stomata, the function of fern and lycophyte stomata diverged strongly from seed plant species upon rehydration. When instantaneously rehydrated from a water-stressed state, fern and lycophyte stomata rapidly reopened to predrought levels despite the high levels of endogenous ABA in the leaf. In seed plants under the same conditions, high levels of ABA in the leaf prevented rapid reopening of stomata. We conclude that endogenous ABA synthesized by ferns and lycophytes plays little role in the regulation of transpiration, with stomata passively responsive to leaf water potential. These results support a gradualistic model of stomatal control evolution, offering opportunities for molecular and guard cell biochemical studies to gain further insights into stomatal control. PMID- 22517322 TI - Chromatographic comparison of atenolol separation in reaction media on cellulose tris-(3,5-dimethylphenylcarbamate) chiral stationary phase using ultra fast liquid chromatography. AB - Because chiral liquid chromatography (LC) could become a powerful tool to estimate racemic atenolol quantity, excellent enantiomeric separation should be produced during data acquisition for satisfactory observation of atenolol concentrations throughout the racemic resolution processes. Selection of chiral LC column and analytical protocol that fulfill demands of the ultra fast LC analysis is essential. This article describes the characteristics of atenolol chromatographic separation that resulted from different resolution media and analytical protocols with the use of a Chiralcel(r) OD column. The chromatograms showed quite different characteristics of the separation process. The single enantiomer and racemic atenolol could be recognized by the Chiralcel(r) OD column in less than 20 min. Symmetrical peaks were obtained; however, several protocols produced peaks with wide bases and slanted baselines. Observations showed that efficient enantioresolution of racemic atenolol was obtained at slow mobile phase flow rate, decreased concentration of amine-type modifier but increased alcohol content in mobile phase and highest ultraviolet detection wavelength were required. The optimal ultra fast LC protocol enables to reduce and eliminate the peaks of either the atenolol solvent or the buffers and provided the highest peak intensities of both atenolol enantiomers. PMID- 22517321 TI - Mitogen-activated protein kinase signaling in plant-interacting fungi: distinct messages from conserved messengers. AB - Mitogen-activated protein kinases (MAPKs) are evolutionarily conserved proteins that function as key signal transduction components in fungi, plants, and mammals. During interaction between phytopathogenic fungi and plants, fungal MAPKs help to promote mechanical and/or enzymatic penetration of host tissues, while plant MAPKs are required for activation of plant immunity. However, new insights suggest that MAPK cascades in both organisms do not operate independently but that they mutually contribute to a highly interconnected molecular dialogue between the plant and the fungus. As a result, some pathogenesis-related processes controlled by fungal MAPKs lead to the activation of plant signaling, including the recruitment of plant MAPK cascades. Conversely, plant MAPKs promote defense mechanisms that threaten the survival of fungal cells, leading to a stress response mediated in part by fungal MAPK cascades. In this review, we make use of the genomic data available following completion of whole-genome sequencing projects to analyze the structure of MAPK protein families in 24 fungal taxa, including both plant pathogens and mycorrhizal symbionts. Based on conserved patterns of sequence diversification, we also propose the adoption of a unified fungal MAPK nomenclature derived from that established for the model species Saccharomyces cerevisiae. Finally, we summarize current knowledge of the functions of MAPK cascades in phytopathogenic fungi and highlight the central role played by MAPK signaling during the molecular dialogue between plants and invading fungal pathogens. PMID- 22517323 TI - Don't look back in anger! Responsiveness to missed chances in successful and nonsuccessful aging. AB - Life-span theories explain successful aging with an adaptive management of emotional experiences like regret. As opportunities to undo regrettable situations decline with age, a reduced engagement into these situations represents a potentially protective strategy to maintain well-being in older age. Yet, little is known about the underlying neurobiological mechanisms supporting this claim. We used a multimodal psychophysiological approach in combination with a sequential risk-taking task that induces the feeling of regret and investigated young as well as emotionally successfully and unsuccessfully (i.e., late-life depressed) aged participants. Responsiveness to regret was specifically reduced in successful aging paralleled by autonomic and frontostriatal characteristics indicating adaptive shifts in emotion regulation. Our results suggest that disengagement from regret reflects a critical resilience factor for emotional health in older age. PMID- 22517324 TI - The active site of methanol synthesis over Cu/ZnO/Al2O3 industrial catalysts. AB - One of the main stumbling blocks in developing rational design strategies for heterogeneous catalysis is that the complexity of the catalysts impairs efforts to characterize their active sites. We show how to identify the crucial atomic structure motif for the industrial Cu/ZnO/Al(2)O(3) methanol synthesis catalyst by using a combination of experimental evidence from bulk, surface-sensitive, and imaging methods collected on real high-performance catalytic systems in combination with density functional theory calculations. The active site consists of Cu steps decorated with Zn atoms, all stabilized by a series of well-defined bulk defects and surface species that need to be present jointly for the system to work. PMID- 22517325 TI - Strongly interacting Rydberg excitations of a cold atomic gas. AB - Highly excited Rydberg atoms have many exaggerated properties. In particular, the interaction strength between such atoms can be varied over an enormous range. In a mesoscopic ensemble, such strong, long-range interactions can be used for fast preparation of desired many-particle states. We generated Rydberg excitations in an ultra-cold atomic gas and subsequently converted them into light. As the principal quantum number n was increased beyond ~70, no more than a single excitation was retrieved from the entire mesoscopic ensemble of atoms. These results hold promise for studies of dynamics and disorder in many-body systems with tunable interactions and for scalable quantum information networks. PMID- 22517326 TI - The ancient drug salicylate directly activates AMP-activated protein kinase. AB - Salicylate, a plant product, has been in medicinal use since ancient times. More recently, it has been replaced by synthetic derivatives such as aspirin and salsalate, both of which are rapidly broken down to salicylate in vivo. At concentrations reached in plasma after administration of salsalate or of aspirin at high doses, salicylate activates adenosine monophosphate-activated protein kinase (AMPK), a central regulator of cell growth and metabolism. Salicylate binds at the same site as the synthetic activator A-769662 to cause allosteric activation and inhibition of dephosphorylation of the activating phosphorylation site, threonine-172. In AMPK knockout mice, effects of salicylate to increase fat utilization and to lower plasma fatty acids in vivo were lost. Our results suggest that AMPK activation could explain some beneficial effects of salsalate and aspirin in humans. PMID- 22517327 TI - Comparing central nervous system (CNS) and extra-CNS hemangiopericytomas in the Surveillance, Epidemiology, and End Results program: analysis of 655 patients and review of current literature. AB - BACKGROUND: Hemangiopericytomas (HPCs) are rare tumors in the central nervous system (CNS) and in extra-CNS sites. The authors of this report used the Surveillance, Epidemiology, and End Results (SEER) Program to study prognostic factors in patients with HPC. METHODS: The SEER database was analyzed for patients who were diagnosed with HPC tumors from 1973 to 2007. Patients were stratified into CNS and extra-CNS groups. Univariate and multivariate analyses were performed for the overall survival (OS) endpoint using major demographic factors (age, race, and sex) and disease factors (tumor site). RESULTS: In total, 655 patients with HPC were stratified into a CNS group (n = 199) and an extra-CNS group (n = 456). The patients with extra-CNS HPC were statistically older (mean age, 53 years vs 49 years; P = .008) and were more likely to have larger tumors (median greatest dimension, 7.0 cm vs 5.2 cm; P < .001). Patients who had CNS tumors had better OS and cause-specific survival (CSS) compared with patients who had extra-CNS tumors (P < .001 for both). Negative predictors of OS on multivariate analysis included extra-CNS tumor site (hazard ratio [HR], 1.6; P = .005) and older age (ages 40-59 years: HR, 2.08; P = .032; ages 60-79 years: HR, 3.9; P < .001; aged >=80 years: HR, 7.7; P < .001). CONCLUSIONS: The current analysis demonstrated that patients with extra-CNS HPCs had worse OS and CSS than patients with CNS HPCs. PMID- 22517328 TI - Facile synthesis of fluorescent porous zinc sulfide nanospheres and their application for potential drug delivery and live cell imaging. AB - Fabrication of intrinsically fluorescent porous nanocarriers that are simultaneously stable in aqueous solutions and photostable is critical for their application in drug delivery and optical imaging but remains a challenge. In this study, fluorescent porous zinc sulfide nanospheres were synthesized by a facile gum arabic-assisted hydrothermal procedure. The morphology, composition and properties of the nanospheres have been characterized by field-emission scanning electron microscopy, transmission electron microscopy, X-ray powder diffraction, N(2) adsorption-desorption analysis, thermal gravimetric analysis, fourier transform infrared spectrograph, optical measurement, dynamic light scattering, and cytotoxicity assay. They exhibit larger surface area, excellent colloidal stability, photostable fluorescent signals, and good biocompatibility, which makes them promising hosts for drug delivery and cellular imaging. The fluorescent dye safranine-T was employed as a drug model and loaded into the porous nanospheres, which were delivered to human cervical cancer HeLa cells in vitro for live cell imaging. PMID- 22517329 TI - Factors contributing to spousal and offspring caregiver burden in Parkinson's disease. AB - BACKGROUND/AIMS: Parkinson's disease (PD) is a common neurodegenerative disease with a chronic disease course. The increase in life expectancy of humans worldwide is expected to increase the prevalence and duration of PD; therefore, it is important to determine factors that contribute to the caregiver burden for both clinical and social reasons. METHODS: We surveyed 91 main caregivers of patients, and compared factors contributing to caregiver burden between 50 spouses and 41 offspring of patients. We determined Burden Interview, Depression Scale, Health-Related Quality of Life, and Obligation Scale scores, as well as the degree of functional social support of caregivers. RESULTS: Interestingly, the burden scores of the two groups were not significantly different. Correlation analysis revealed that depression, health-related quality of life, social support, subdivided parts of the Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr Scale, score of Mini-Mental State Examination, and Barthel index were correlated with burden in both spouses and offspring. However, in multiple regression, depression score and part 1 of the UPDRS were more significant predictors of burden in the spousal group, whereas social support of community and part 3 of the UPDRS were more important correlated factors in the offspring group. CONCLUSIONS: The caregiver burden of spousal and offspring caregivers of PD patients was not significantly different. However, different factors contributed to caregiver burden according to the caregiver's relationship with the patient. PMID- 22517330 TI - Outpatient laparoscopic repair of a Morgagni hernia. AB - INTRODUCTION: Morgagni hernia results from a rare congenital defect in the anterior diaphragm and can have symptomatic and/or asymptomatic presentation of abdominal viscera in the thorax. This is a case report of a Morgagni hernia repair done laparoscopically in the outpatient setting. PATIENT AND TECHNIQUE: The patient was a 43-year-old man who had an evaluation for upper respiratory symptoms and was found to have a Morgagni hernia on subsequent workup. He underwent laparoscopic primary suture repair of the defect under general anesthesia and was discharged the same day without complications. He has not had a recurrence of his hernia in over a year of follow-up. DISCUSSION: Laparoscopic repair of this patient's Morgagni hernia could be safely performed in an outpatient setting with excellent outcome. This may be a feasible management option in future cases in a similar patient population. PMID- 22517331 TI - A rigid disc for protection of exposed blood vessels during negative pressure wound therapy. AB - BACKGROUND: There are increasing reports of serious complications and deaths associated with negative pressure wound therapy (NPWT). Bleeding may occur when NPWT is applied to a wound with exposed blood vessels. Inserting a rigid disc in the wound may protect these structures. The authors examined the effects of rigid discs on wound bed tissue pressure and blood flow through a large blood vessel in the wound bed during NPWT. METHODS: Wounds were created over the femoral artery in the groin of 8 pigs. Rigid discs were inserted. Wound bed pressures and arterial blood flow were measured during NPWT. RESULTS: Pressure transduction to the wound bed was similar for control wounds and wounds with discs. Blood flow through the femoral artery decreased in control wounds. When a disc was inserted, the blood flow was restored. CONCLUSIONS: NPWT causes hypoperfusion in the wound bed tissue, presumably as a result of mechanical deformation. The insertion of a rigid barrier alleviates this effect and restores blood flow. PMID- 22517332 TI - Unlocking of interlocked heteropolymer gel by light: photoinduced volume phase transition in an ionic liquid from a metastable state to an equilibrium phase. AB - An azobenzene-containing heteropolymer gel in an ionic liquid exhibits thermally reversible volume phase transition when the azobenzene moiety mainly exists in the cis-state, whereas the transition becomes irreversible when it is in the trans-state and an interlocked collapsed state is stabilized; however, the unlocking of the metastable state occurs by UV light irradiation. PMID- 22517333 TI - Associations of apolipoprotein A5 (APOA5), glucokinase (GCK) and glucokinase regulatory protein (GCKR) polymorphisms and lifestyle factors with the risk of dyslipidemia and dysglycemia in Japanese - a cross-sectional data from the J-MICC Study. AB - This study examined the associations of the APOA5 T-1131C (rs662799), G553T (Cys185Gly, rs2075291), GCK G-30A (rs1799884), GCKR A/G at intron 16 (rs780094) and T1403C (Leu446Pro, rs1260326) polymorphisms with serum lipid and glucose levels in Japanese, considering lifestyle factors. Study subjects were 2,191 participants (aged 35-69 years, 1,159 males) enrolled in the Japan Multi Institutional Collaborative Cohort (J-MICC) Study. Dyslipidemia was defined as fasting serum triglycerides (FTG) >= 150 mg/dL and/or HDL-cholesterol (HDL-C) < 40 mg/dL, while dysglycemia was as fasting blood sugar (FBS) >= 110 mg/dL. When those with APOA5 -1131 T/T or 553 G/G were defined as references, those with APOA5 -1131 T/C, C/C or 553 G/T, T/T demonstrated significantly elevated risk of dyslipidemia (age- and sex-adjusted odds ratio: 1.77 [95% confidence interval:1.39-2.27], 3.35 [2.41-4.65], 2.23 [1.64-3.02] and 13.78 [3.44-55.18], respectively). Evaluation of FTG, HDL-C or FBS levels according to the genotype revealed that FTG and HDL-C levels were significantly associated with the APOA5 T 1131C and G553T polymorphisms, FTG with the GCKR rs780094 and rs1260326 polymorphisms, and FBS with the GCKR rs780094 and rs1260326 polymorphisms. Moreover, a significant positive interaction between APOA5 553 G/T+T/T genotypes and fat intake >= 25% of total energy for the risk of dyslipidemia was observed. Our cross-sectional study confirmed the essential roles of the polymorphisms of the APOA5, GCK and GCKR in the lipid or glucose metabolism disorders, and suggested the importance of fat intake control in the individualized prevention of dyslipidemia. PMID- 22517334 TI - Hans Christian Korting, 1952-2012. PMID- 22517335 TI - Tuberculosis in pediatric solid organ and hematopoietic stem cell transplant recipients. AB - The burden of tuberculosis after pediatric solid organ transplant or hematopoietic stem cell transplantation has not been well characterized. We report 7 pediatric cases with disseminated (4/7) or pulmonary (3/7) tuberculosis after solid organ transplant (n=6) or hematopoietic stem cell transplantation (n=1) during 26 years. The outcome was favorable in 6 patients. Isoniazid-induced hepatitis and rifampin interactions were common. PMID- 22517336 TI - Nasopharyngeal lactate dehydrogenase concentrations predict bronchiolitis severity in a prospective multicenter emergency department study. AB - We reexamined the finding of an inverse relationship between values of nasopharyngeal lactate dehydrogenase, a marker of the innate immune response, and bronchiolitis severity. In a prospective, multicenter study of 258 children, we found in a multivariable model that higher nasopharyngeal lactate dehydrogenase values in young children with bronchiolitis were independently associated with a decreased risk of hospitalization. PMID- 22517337 TI - Viral epidemiology and severity of respiratory infections in infants in 2009: a prospective study. AB - BACKGROUND: Viral respiratory infections are common in infants and can be severe. The new pandemic influenza virus H1N1v2009 was feared to cause particularly severe outcomes. OBJECTIVE: This study aimed at evaluating the impact of H1N1v2009 on the viral epidemiology, the clinical presentation and the severity of respiratory infections in infants. PATIENTS AND METHODS: This prospective epidemiologic study included all infants <2 years of age, both inpatients and outpatients, presenting with respiratory symptoms, from November 2009 through April 2010, at the pediatric emergency department of the University Hospital of Caen, France. A nasal swab was taken for viral detection and analyzed by immunofluorescence and, if negative, polymerase chain reaction. Severe respiratory infection was defined by a score of respiratory severity. RESULTS: One thousand twenty-one infectious episodes with a respiratory sample met inclusion criteria. Eight hundred thirty-four samples (81.7%) were positive. The viruses with the highest incidence were the respiratory syncytial virus (34.2%), the rhinoviruses (23.9%), the coronaviruses (9.3%) and H1N1v2009 (7.7%). Of all infections, 28.6% were severe and more frequent in infants with risk factors. H1N1v2009 infections had a low risk of severe respiratory disease (odds ratios = 0.15) and hospitalization (odds ratios = 0.40) compared with the other viruses. Respiratory syncytial virus infections had a high risk of respiratory severity (odds ratios = 7.85) and were responsible for 71.4% of admissions to the intensive care unit. CONCLUSION: Despite the modest impact of H1N1v2009 observed in this study, further surveillance is needed to detect virological factors that may increase its severity. PMID- 22517338 TI - Adenovirus respiratory infections in hospitalized children: clinical findings in relation to species and serotypes. AB - BACKGROUND: There are >50 adenovirus (ADV) serotypes that are divided into 7 species (A-G). The aim of this study was to characterize ADV serotypes and species in hospitalized infants and children in the City of Zagreb and Zagreb County and to describe clinical features and laboratory findings of ADV infections according to the causative ADV serotype. METHODS: During the 3-year period from January 2006 to November 2008, 135 children (<10 years of age) with ADV respiratory infection, based on virus isolation, were treated at 2 hospitals in Zagreb. Demographics, clinical presentations and laboratory findings were evaluated. RESULTS: Of the 135 ADV isolates, 77 (57.0%) were type 2, followed by 26 (19.3%) of type 1, 15 (11.1%) isolates of type 3, 2 (1.5%) of type 6 and only 1 (0.7%) was type 7. Male-to-female ratio was 3.2:1 (103 boys and 32 girls). The mean age was 22.9 months. The most common symptoms were fever (98%), rhinorrhea (89%) and cough (71%). The mean peak body temperature was 39.8 degrees C. Tonsillitis was present in 79 (59%) and acute otitis media in 37 (28%) patients. Leukocytosis (>15.0*109/L) was noted in 103 (77%) patients. Serum C-reactive protein was >40 mg/L in 74 patients (56%). The erythrocyte sedimentation rate was >=30 mm/h in 91 (71%) of the 127 patients tested. CONCLUSIONS: In this study, the most common isolated serotype was ADV type 2. Most affected children were younger than 3 years. ADV infections in young children can present with prolonged fever, leukocytosis and significantly elevated C-reactive protein and erythrocyte sedimentation rate, mimicking bacterial infections. PMID- 22517339 TI - Voriconazole-induced phototoxicity in children. AB - Voriconazole is used in antifungal prophylaxis. We performed a retrospective review of immunocompromised children receiving prophylaxis with voriconazole during major hospital renovation, who developed phototoxic skin reactions. The overall incidence of phototoxic skin reactions was 33%. A voriconazole dose of >=6 mg/kg of body weight per dose twice daily was associated with a significantly greater risk to develop phototoxic skin reactions compared with lower doses. PMID- 22517345 TI - Health care and the renaissance of holism. PMID- 22517346 TI - Ballistic, holistic nurses: developing ourselves as healers. PMID- 22517347 TI - Choose to Move for Positive Living: physical activity program for obese women. AB - The Choose to Move for + (Positive) Living program was implemented to increase physical activity among obese women. A holistic approach was used to promote stage of health behavior change, social support, and quality of life and reduce depression. Within 6 months, physical fitness improved and depressive symptoms decreased. PMID- 22517348 TI - Wellness promotion and the Institute of Medicine's Future of Nursing Report: are nurses ready? AB - This article highlights the gap between wellness in nursing practice and the mission statement of the Institute of Medicine's Future of Nursing Report. It explores wellness from 3 philosophical arguments, provides a historical evolution of wellness, and explores nurses' current understanding of wellness. Future directions for implementing wellness in nursing practice are provided for science, education, and leadership. PMID- 22517349 TI - Does yoga therapy reduce blood pressure in patients with hypertension?: an integrative review. AB - The aim of this article was to present a evidence-based integrative research review that validates yoga therapy as an effective complementary treatment in the management of high blood pressure (BP). The article also uses the theoretical framework of Dr Hans Selye's general adaptation syndrome. Yoga researchers demonstrate that yoga works because it modulates the physiological system of the body, specifically its effect on the heart rate. This review is significant because yoga presents an effective method of treating hypertension that is nonpharmacologic and therefore there are no adverse effects and there are other valuable health benefits. Research suggests that stress is a contributing factor to high BP; hence, the use of the general adaptation syndrome and the most important attribute of yoga, that is, it is a physical and mental exercise program, that is in sync with the philosophy of holistic nursing care where one treats the whole individual and not just the disease. The review was conducted with a search of computerized databases such as OVID, Academic Search Premier, CINAHL, MEDLINE, and Health Source: Nursing/Academic edition, PsychINFO, as well as reliable Web sites such as the cdc.gov, among others. An integrative review search was conducted, and 10 studies met the inclusion criteria. They include a combination of randomized controlled trials, quasi-experimental studies, and pilot studies. Yoga therapy is a multifunctional exercise modality with numerous benefits. Not only does yoga reduce high BP but it has also been demonstrated to effectively reduce blood glucose level, cholesterol level, and body weight, major problems affecting the American society. The completed integrative review provides guidelines for nursing implementation as a complementary treatment of high BP. PMID- 22517350 TI - The role of probiotics in diarrheal management. AB - Current evidence demonstrates that probiotics reduce diarrheal duration from a number of etiologies. Professional nursing practice based on evidence and clinical expertise supports a diet-containing probiotics to manage acute diarrhea. Dietary limitations included in the BRAT (bananas, rice, applesauce, and toast) diet recommended by many nurses need to be reexamined in light of the newest evidence. PMID- 22517351 TI - Efficacy of guided imagery to reduce stress via the Internet: a pilot study. AB - Multiple stressors are affecting the mental and physical health of entire populations. In this pilot study, the experience of a guided imagery presentation through the Internet reduced stress in a convenience sample of 29 adult participants as evidenced by a self-reported single-item rating scale question administered pre- and postintervention. Demographics are reported for descriptive statistics of the sample. PMID- 22517352 TI - A short guide to peer-reviewed, MEDLINE-indexed complementary and alternative medicine journals. AB - Complementary and alternative medicine (CAM) comprises a multitude of disciplines, for example, acupuncture, ayurvedic medicine, biofeedback, herbal medicine, and homeopathic medicine. While research on CAM interventions has increased and the CAM literature has proliferated since the mid-1990s, a number of our colleagues have expressed difficulties in deciding where to publish CAM articles. In response, we created a short guide to peer-reviewed MEDLINE-indexed journals that publish CAM articles. We examined numerous English-language sources to identify titles that met our criteria, whether specific to or overlapping CAM. A few of the resources in which we found the journal titles that we included are Alternative Medicine Foundation, American Holistic Nurses Association, CINAHL/Nursing Database, Journal Citation Reports database, MEDLINE, PubMed, and Research Council for Complementary Medicine. We organized the 69 selected titles for easy use by creating 2 user-friendly tables, one listing titles in alphabetical order and one listing them in topical categories. A few examples of the topical categories are Acupuncture, CAM (general), Chinese Medicine, Herbal/Plant/Phytotherapy, Neuroscience/Psychology, Nursing/Clinical Care. Our study is the first to list general CAM journals, specialty CAM journals, and overlapping mainstream journals that are peer reviewed, in English, and indexed in MEDLINE. Our goal was to assist both authors seeking publication and mainstream journal editors who receive an overabundance of publishable articles but must recommend that authors seek publication elsewhere due to space and priority issues. Publishing in journals indexed by and included in MEDLINE (or PubMed) ensures that citations to articles will be found easily. PMID- 22517353 TI - Red yeast rice: efficacy and tolerability of Monascus purpureus yeast, for treatment of hyperlipidemia in patients with statin-associated myalgias. PMID- 22517354 TI - Re-establishment of cytoskeletal tensional homeostasis in lax tendons occurs through an actin-mediated cellular contraction of the extracellular matrix. AB - Cytoskeletal tensional homeostasis is known to be an important factor in controlling catabolic gene expression in tendon cells. Loss of cell tension in lax rat tail tendon fascicles (RTTfs) has been associated with an upregulation of MMP-13 gene expression and protein synthesis. To determine the role of the actin cytoskeleton in re-establishing tensional homeostasis in lax tendons, RTTfs were allowed to freely contract in vitro for 8 days. The cultured RTTfs contracted rapidly, reaching 50% of their initial length by 3 days. This contraction was associated with the presence of alpha-smooth muscle actin positive cells within the tendon. Disruption of the actin network by cytochalasian D caused an immediate and significant elongation of the contracted RTTfs. Subsequent removal of the cytochalasian D re-initiated the contraction process. When lax RTTfs were allowed to contract between fixed clamps in culture and become taut, they demonstrated a marked decrease in MMP-13 staining intensity when compared to freely contracting RTTfs. The ability of native tendon cells to contract lax tendons and re-establish their homeostatic "set point" with respect to collagenase production may be an important mechanism in the recovery of tendons elongated by injury, surgical positioning, or cyclic, viscoelastic creep secondary to repetitive exercise. PMID- 22517355 TI - Frozen section-guided wide local excision in the treatment of recurrent scrotal extramammary Paget's disease. AB - BACKGROUND: A wide excision is generally accepted to be the standard modality of treatment for scrotal extramammary Paget's disease (EMPD). The disease has a recurrence rate of about 10% and a second wide excision is still the chief treatment. We investigated the therapeutic methods for recurrent scrotal EMPD. METHODS: We retrospectively studied the therapeutic methods and prognosis of 26 cases of recurrent EMPD. Seventy-two cases of primary scrotal EMPD served as controls. All of the cases were treated with frozen section-guided wide local excision. RESULTS: There was no significant difference in the follow-up period of the recurrent cases before recurrence (p=0.3228), local recurrence rate (p=0.449), and total recurrence rate (p=0.100) between the two groups, respectively. There is a favorable trend of worse mortality rate in the recurrence group (p=0.056). The rate of inguinal lymph node metastasis was higher in the group with recurrent disease than in the control group (p=0.017). CONCLUSION: Wide excision of the lesion still appears to be the most effective modality of treatment for recurrent scrotal Paget's disease. Inguinal lymphadenectomy or sentinel lymph node biopsy should be offered to patients with primary lesions. PMID- 22517356 TI - Proton block of the pore underlies the inhibition of hERG cardiac K+ channels during acidosis. AB - Human ether-a-go-go-related gene (hERG) potassium channels are critical determinants of cardiac repolarization. Loss of function of hERG channels is associated with Long QT Syndrome, arrhythmia, and sudden death. Acidosis occurring as a result of myocardial ischemia inhibits hERG channel function and may cause a predisposition to arrhythmias. Acidic pH inhibits hERG channel maximal conductance and accelerates deactivation, likely by different mechanisms. The mechanism underlying the loss of conductance has not been demonstrated and is the focus of the present study. The data presented demonstrate that, unlike in other voltage-gated potassium (Kv) channels, substitution of individual histidine residues did not abolish the pH dependence of hERG channel conductance. Abolition of inactivation, by the mutation S620T, also did not affect the proton sensitivity of channel conductance. Instead, voltage-dependent channel inhibition (delta = 0.18) indicative of pore block was observed. Consistent with a fast block of the pore, hERG S620T single channel data showed an apparent reduction of the single channel current amplitude at low pH. Furthermore, the effect of protons was relieved by elevating external K(+) or Na(+) and could be modified by charge introduction within the outer pore. Taken together, these data strongly suggest that extracellular protons inhibit hERG maximal conductance by blocking the external channel pore. PMID- 22517357 TI - Sat1 is dispensable for active oxalate secretion in mouse duodenum. AB - Mice deficient for the apical membrane oxalate transporter SLC26A6 develop hyperoxalemia, hyperoxaluria, and calcium oxalate stones due to a defect in intestinal oxalate secretion. However, the nature of the basolateral membrane oxalate transport process that operates in series with SLC26A6 to mediate active oxalate secretion in the intestine remains unknown. Sulfate anion transporter-1 (Sat1 or SLC26A1) is a basolateral membrane anion exchanger that mediates intestinal oxalate transport. Moreover, Sat1-deficient mice also have a phenotype of hyperoxalemia, hyperoxaluria, and calcium oxalate stones. We, therefore, tested the role of Sat1 in mouse duodenum, a tissue with Sat1 expression and SLC26A6-dependent oxalate secretion. Although the active secretory flux of oxalate across mouse duodenum was strongly inhibited (>90%) by addition of the disulfonic stilbene DIDS to the basolateral solution, secretion was unaffected by changes in medium concentrations of sulfate and bicarbonate, key substrates for Sat1-mediated anion exchange. Inhibition of intracellular bicarbonate production by acetazolamide and complete removal of bicarbonate from the buffer also produced no change in oxalate secretion. Finally, active oxalate secretion was not reduced in Sat1-null mice. We conclude that a DIDS-sensitive basolateral transporter is involved in mediating oxalate secretion across mouse duodenum, but Sat1 itself is dispensable for this process. PMID- 22517358 TI - Increased endogenous H2S generation by CBS, CSE, and 3MST gene therapy improves ex vivo renovascular relaxation in hyperhomocysteinemia. AB - Hydrogen sulfide (H(2)S) has recently been identified as a regulator of various physiological events, including vasodilation, angiogenesis, antiapoptotic, and cellular signaling. Endogenously, H(2)S is produced as a metabolite of homocysteine (Hcy) by cystathionine beta-synthase (CBS), cystathionine gamma lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3MST). Although Hcy is recognized as vascular risk factor at an elevated level [hyperhomocysteinemia (HHcy)] and contributes to vascular injury leading to renovascular dysfunction, the exact mechanism is unclear. The goal of the current study was to investigate whether conversion of Hcy to H(2)S improves renovascular function. Ex vivo renal artery culture with CBS, CSE, and 3MST triple gene therapy generated more H(2)S in the presence of Hcy, and these arteries were more responsive to endothelial dependent vasodilation compared with nontransfected arteries treated with high Hcy. Cross section of triple gene-delivered renal arteries immunostaining suggested increased expression of CD31 and VEGF and diminished expression of the antiangiogenic factor endostatin. In vitro endothelial cell culture demonstrated increased mitophagy during high levels of Hcy and was mitigated by triple gene delivery. Also, dephosphorylated Akt and phosphorylated FoxO3 in HHcy were reversed by H(2)S or triple gene delivery. Upregulated matrix metalloproteinases 13 and downregulated tissue inhibitor of metalloproteinase-1 in HHcy were normalized by overexpression of triple genes. Together, these results suggest that H(2)S plays a key role in renovasculopathy during HHcy and is mediated through Akt/FoxO3 pathways. We conclude that conversion of Hcy to H(2)S by CBS, CSE, or 3MST triple gene therapy improves renovascular function in HHcy. PMID- 22517359 TI - Inhibition of apolipoprotein(a) synthesis by farnesoid X receptor and fibroblast growth factor 15/19: a step toward selective lipoprotein(a) therapeutics. PMID- 22517360 TI - kNOXing on the door of selective insulin resistance. PMID- 22517361 TI - Orai1, STIM1, and iPLA2beta determine arterial vasoconstriction. PMID- 22517362 TI - Shining light and illuminating murine atherosclerosis via optical coherence tomography. PMID- 22517363 TI - ICAM-1 and nanomedicine: nature's doorway to the extravascular tissue realm. PMID- 22517364 TI - New developments in hepatic lipoprotein production and clinical relevance. PMID- 22517365 TI - Intrahepatic role of exchangeable apolipoproteins in lipoprotein assembly and secretion. AB - Exchangeable apolipoproteins, composed mainly of amphipathic alpha-helices, are associated with various plasma lipoproteins and play an important role in the metabolism of those lipoproteins to which they bind. Accumulating experimental evidence suggests that exchangeable apolipoproteins, such as apoE, apoA-IV, and apoC-III, also play a role intracellularly in facilitating lipid recruitment at different stages of very low-density lipoprotein assembly and trafficking through the endoplasmic reticulum-Golgi secretory compartments. Experimental evidence also suggests that apoA-I may become lipidated intracellularly through mechanisms dependent on or independent of ATP-binding cassette transporter A1. Thus, expression of these secretory proteins may exert an impact on hepatic triglyceride and cholesterol homeostasis during their transit from the endoplasmic reticulum through the Golgi apparatus. This review summarizes findings related to the modulation of intracellular assembly of very low-density lipoprotein and high-density lipoprotein by exchangeable apolipoproteins. PMID- 22517367 TI - Lumenal lipid metabolism: implications for lipoprotein assembly. AB - Overproduction of apolipoprotein B (apoB)-containing lipoproteins by the liver and the intestine is 1 of the hallmarks of insulin resistance and type 2 diabetes and a well-established risk factor of cardiovascular disease. The assembly of apoB lipoproteins is regulated by the availability of lipids that form the neutral lipid core (triacylglycerol and cholesteryl ester) and the limiting lipoprotein monolayer (phospholipids and cholesterol). Although tremendous advances have been made over the past decade toward understanding neutral lipid and phospholipid biosynthesis and neutral lipid storage in cytosolic lipid droplets (LDs), little is known about the mechanisms that govern the transfer of lipids to the lumen of the endoplasmic reticulum for apoB lipidation. ApoB synthesizing organs can deposit synthesized neutral lipids into at least 3 different types of LDs, each decorated with a subset of specific proteins: perilipin-decorated cytosolic LDs, and 2 types of LDs formed in the lumen of the endoplasmic reticulum, the secretion-destined LDs containing apoB, and resident lumenal LDs coated with microsomal triglyceride transfer protein and exchangeable apolipoproteins. This brief review will address the current knowledge of lumenal lipid metabolism in the context of apoB assembly and lipid storage. PMID- 22517366 TI - Intracellular trafficking and secretion of VLDL. AB - Steady increase in the incidence of atherosclerosis is becoming a major concern not only in the United States but also in other countries. One of the major risk factors for the development of atherosclerosis is high concentrations of plasma low-density lipoprotein, which are metabolic products of very low-density lipoprotein (VLDL). VLDLs are synthesized and secreted by the liver. In this review, we discuss various stages through which VLDL particles go from their biogenesis to secretion in the circulatory system. Once VLDLs are synthesized in the lumen of the endoplasmic reticulum, they are transported to the Golgi. The transport of nascent VLDLs from the endoplasmic reticulum to Golgi is a complex multistep process, which is mediated by a specialized transport vesicle, the VLDL transport vesicle. The VLDL transport vesicle delivers VLDLs to the cis-Golgi lumen where nascent VLDLs undergo a number of essential modifications. The mature VLDL particles are then transported to the plasma membrane and secreted in the circulatory system. Understanding of molecular mechanisms and identification of factors regulating the complex intracellular VLDL trafficking will provide insight into the pathophysiology of various metabolic disorders associated with abnormal VLDL secretion and identify potential new therapeutic targets. PMID- 22517368 TI - CIDE proteins and lipid metabolism. AB - Lipid homeostasis is maintained through the coordination of lipid metabolism in various tissues, including adipose tissue and the liver. The disruption of lipid homeostasis often results in the development of metabolic disorders such as obesity, diabetes mellitus, liver steatosis, and cardiovascular diseases. Cell death-inducing DNA fragmentation factor 45-like effector family proteins, including Cidea, Cideb, and Fsp27 (Cidec), are emerging as important regulators of various lipid metabolic pathways and play pivotal roles in the development of metabolic disorders. This review summarizes the latest cell death-inducing DNA fragmentation factor 45-like effector protein discoveries related to the control of lipid metabolism, with emphasis on the role of these proteins in lipid droplet growth in adipocytes and in the regulation of very low-density lipoprotein lipidation and maturation in hepatocytes. PMID- 22517369 TI - Hepatitis C virus: a new class of virus associated with particles derived from very low-density lipoproteins. AB - Hepatitis C virus (HCV) infects 3% of the world population and is the leading cause of liver failure in the United States. A unique feature of HCV is that the viral particles are integral to very low-density lipoprotein (VLDL)-derived lipoprotein particles. The virus is assembled into VLDL in hepatocytes and released out of the cells together with VLDL. The virus then infects more hepatocytes by entering the cells through the low-density lipoprotein receptor, which mediates uptake of majorities of VLDL-derived lipoprotein particles. These observations suggest that HCV may belong to a novel class of viruses that is associated with VLDL. Understanding the relationship between HCV and VLDL metabolism may reveal new strategies to treat HCV infection. PMID- 22517371 TI - Standardized uptake value by positron emission tomography/computed tomography as a prognostic variable in metastatic breast cancer. AB - BACKGROUND: In this retrospective, single-institution study, the authors examine the maximum standardized uptake value (SUVmax) on positron emission tomography/computed tomography (PET/CT) images as a prognostic variable in patients with newly diagnosed metastatic breast cancer (MBC). METHODS: Patients with >=1 metastatic lesion on PET/CT images that were obtained within 60 days of their MBC diagnosis between January 1, 2001 and December 31, 2008 were included. Patients were excluded if they had received chemotherapy <=30 days before the PET/CT images were obtained. Electronic medical reports were reviewed to determine the SUVmax and overall survival. Because of intraindividual variation in the SUV by body site, separate analyses were conducted by metastatic site. Relationships between site-specific PET/CT variable tertiles and overall survival were assessed using Cox regression; hazard ratios for the highest tertile versus the lowest tertile were reported. RESULTS: In total, 253 patients were identified, and their median age was 57 years (range, 27-90 years). Of these, 152 patients (60%) died, and the median follow-up was 40 months. On univariate analysis, SUVmax tertile was strongly associated with overall survival in patients who had bone metastases (N = 141; hazard ratio, 3.13; 95% confidence interval, 1.79-5.48; P < .001). This effect was maintained on multivariate analysis (HR = 3.19; 95% confidence interval, 1.64-6.20, P = .002) after correcting for known prognostic variables. A greater risk of death was associated with SUVmax tertile in patients who had metastases to the liver (N = 46; hazard ratio, 2.07; 95% confidence interval, 0.90-4.76), lymph nodes (N = 149; hazard ratio, 1.1; 95% confidence interval, 0.69-1.88), and lung (N = 62; hazard ratio, 2.2; 95% confidence interval, 0.97-4.95), although these results were not significant (P = .18, P = .31, and P = .095, respectively). CONCLUSIONS: The current results indicate that PET/CT has value as a prognostic tool in patients with newly diagnosed MBC to bone. PMID- 22517372 TI - Stereoselective metabolism of tetrahydropalmatine enantiomers in rat liver microsomes. AB - Tetrahydropalmatine (THP), with one chiral center, is an active alkaloid ingredient in Rhizoma Corydalis. The aim of the present paper is to study whether THP enantiomers are metabolized stereoselectively in rat, mouse, dog, and monkey liver microsomes, and then, to elucidate which Cytochrome P450 (CYP) isoforms are predominately responsible for the stereoselective metabolism of THP enantiomers in rat liver microsomes (RLM). The results demonstrated that (+)-THP was preferentially metabolized by liver microsomes from rats, mice, dogs, and monkeys, and the intrinsic clearance (Cl(int)) ratios of (+)-THP to (-)-THP were 2.66, 2.85, 4.24, and 1.67, respectively. Compared with the metabolism in untreated RLM, the metabolism of (-)-THP and (+)-THP was significantly increased in dexamethasone (Dex)-induced and beta-naphthoflavone (beta-NF)-induced RLM; meanwhile, the Cl(int) ratios of (+)-THP to (-)-THP in Dex-induced and beta-NF induced RLM were 5.74 and 0.81, respectively. Ketoconazole had stronger inhibitory effect on (+)-THP than (-)-THP, whereas fluvoxamine had stronger effect on (-)-THP in untreated and Dex-induced or beta-NF-induced RLM. The results suggested that THP enantiomers were predominately metabolized by CYP3A1/2 and CYP1A2 in RLM, and CYP3A1/2 preferred to metabolize (+)-THP, whereas CYP1A2 preferred (-)-THP. PMID- 22517373 TI - Treatment of pancreatic cancer using an oncolytic virus harboring the lipocalin-2 gene. AB - BACKGROUND: The 5-year survival rate for patients with pancreatic cancer is <5%, and it is always resistant to the current chemoradiotherapy. Therefore, new, effective agents for the treatment of pancreatic cancer are urgently needed. The promising strategy of cancer-targeting gene virotherapy (CTGVT) has demonstrated great anticancer potential. The objective of the current study was to determine whether 1 CTGVT approach, oncolytic virus (OV)-harboring lipocalin-2, is capable of treating pancreatic cancer. METHODS: Tissue microarrays were constructed to detect the expression of lipocalin-2 in 60 specimens of pancreatic adenocarcinoma. The clinical significance of lipocalin-2 was investigated in an analysis of correlations between lipocalin-2 expression and matched clinical characteristics. A lipocalin-2-expressing OV, ZD55-lipocalin-2, was constructed by deleting the adenoviral protein E1B55kD. The antitumor efficacy and mechanisms of the OV were investigated in pancreatic cancer cells with v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in vitro and in vivo. RESULTS: Lipocalin-2 expression was correlated with a good prognosis in patients with pancreatic adenocarcinoma. ZD55-lipocalin-2 dramatically inhibited the growth of pancreatic cancer in vitro and in vivo by inducing cytolysis and caspase dependent apoptosis. CONCLUSIONS: Higher lipocalin-2 expression predicted a better prognosis in patients with pancreatic cancer. The results indicated that ZD55-lipocalin-2, which specifically expressed higher levels of lipocalin-2 in tumor cells, may serve as a potent anticancer drug for pancreatic cancer therapy, especially for patients who have pancreatic adenocarcinoma with KRAS mutations. PMID- 22517374 TI - Biotemplated synthesis of perovskite nanomaterials for solar energy conversion. AB - A synthetic method of using genetically engineered M13 virus to mineralize perovskite nanomaterials, particularly strontium titanate (STO) and bismuth ferrite (BFO), is presented. Genetically engineered viruses provide effective templates for perovskite nanomaterials. The virus-templated nanocrystals are small in size, highly crystalline, and show photocatalytic and photovoltaic properties. PMID- 22517375 TI - Eleven years' experience with Korean cardiac myxoma patients: focus on embolic complications. AB - BACKGROUND: Cardiac myxomas are rare but are the most common cardiac tumors. This study is based on our clinical experience with cardiac myxomas over a period of 11 years at Sejong General Hospital. We focused on the embolic complications of patients with cardiac myxoma. METHODS: We retrospectively reviewed the medical records of 59 consecutive patients with cardiac myxoma who were treated between January 2000 and March 2011. The myxomas were divided into two types: type 1, with an irregular or villous surface and a soft consistency, and type 2, with a smooth surface and a compact consistency. The 59 investigated patients were classified into the embolic group and the non-embolic group. RESULTS: Cardiac obstructive symptoms, embolic events and constitutional symptoms were observed in 37 (62.7%), 13 (22.0%) and 10 (16.9%) patients, respectively. When the embolic and non-embolic groups were compared, there were no significant differences in vascular risk factors, the ejection fraction, the left atrial diameter or the tumor size. However, type 1 myxomas were significantly more frequent in the embolic group (p = 0.009 by Fisher's exact test). A binary logistic regression analysis showed that type 1 pathology alone was independently associated with myxoma-related embolism (p = 0.008; odds ratio 10.056; 95% confidence interval 1.828-55.337). There were no operative deaths in any of the 59 patients studied. Among the 13 patients with embolism, 11 (84.6%) had brain infarcts. The main patterns of the lesions were multiple lesions (8 out of 11 patients, 72.7%) and lesions in the middle cerebral artery territories (7 out of 11 patients, 63.6%). The other 2 patients were found to have occlusion of the left central retinal artery and left external iliac artery. Additionally, incidental cerebral aneurysms were found in the latter case. There was no recurrence of myxoma or myxoma-related symptoms in the 53 patients receiving outpatient management during the follow-up period (range 2 months to 11 years). CONCLUSIONS: The embolic potential of myxoma was associated with an irregular surface pathology but not with vascular risk factors. Echocardiography should be performed in patients with embolic events, especially when cerebral infarcts with multiple territorial lesions are detected. Surgical resection is a relatively safe and curative procedure for cardiac myxoma. PMID- 22517376 TI - Probing the electronic properties and structural evolution of anionic gold clusters in the gas phase. AB - Gold nanoparticles have been discovered to exhibit remarkable catalytic properties in contrast to the chemical inertness of bulk gold. A prerequisite to elucidate the molecular mechanisms of the catalytic effect of nanogold is a detailed understanding of the structural and electronic properties of gold clusters as a function of size. In this review, we describe joint experimental studies (mainly photoelectron spectroscopy) and theoretical calculations to probe the structural properties of anionic gold clusters. Electronic properties and structural evolutions of all known Au(n)(-) clusters as experimentally confirmed to date are summarized, covering the size ranges of n = 3-35 and 55-64. Recent experimental efforts in resolving the isomeric issues of small gold clusters using Ar-tagging, O(2)-titration and isoelectronic substitution are also discussed. PMID- 22517377 TI - Interference of different types of seats on postural control system during a forward-reaching task in individuals with paraplegia. AB - We aimed to evaluate the influence of different types of wheelchair seats on paraplegic individuals' postural control using a maximum anterior reaching test. Balance evaluations during 50, 75, and 90% of each individual's maximum reach in the forward direction using two different cushions on seat (one foam and one gel) and a no-cushion condition were carried out on 11 individuals with a spinal cord injury (SCI) and six individuals without SCI. Trunk anterior displacement and the time spent to perform the test were assessed. No differences were found for the three types of seats in terms of trunk anterior displacement and the time spent to perform the test when intragroup comparisons were made in both groups (P>0.05). The intergroup comparison showed that body displacement was less prominent and the time spent to perform the test was more prolonged for individuals with SCI (P<0.05), which suggests a postural control deficit. The seat type did not affect the ability of the postural control system to maintain balance during the forward-reaching task. PMID- 22517378 TI - Cyclic RGD peptidomimetics containing bifunctional diketopiperazine scaffolds as new potent integrin ligands. AB - The synthesis of eight bifunctional diketopiperazine (DKP) scaffolds is described; these were formally derived from 2,3-diaminopropionic acid and aspartic acid (DKP-1-DKP-7) or glutamic acid (DKP-8) and feature an amine and a carboxylic acid functional group. The scaffolds differ in the configuration at the two stereocenters and the substitution at the diketopiperazinic nitrogen atoms. The bifunctional diketopiperazines were introduced into eight cyclic peptidomimetics containing the Arg-Gly-Asp (RGD) sequence. The resulting RGD peptidomimetics were screened for their ability to inhibit biotinylated vitronectin binding to the purified integrins alpha(v)beta(3) and alpha(v)beta(5), which are involved in tumor angiogenesis. Nanomolar IC(50) values were obtained for the RGD peptidomimetics derived from trans DKP scaffolds (DKP-2-DKP-8). Conformational studies of the cyclic RGD peptidomimetics by (1)H NMR spectroscopy experiments (VT-NMR and NOESY spectroscopy) in aqueous solution and Monte Carlo/Stochastic Dynamics (MC/SD) simulations revealed that the highest affinity ligands display well-defined preferred conformations featuring intramolecular hydrogen-bonded turn motifs and an extended arrangement of the RGD sequence [Cbeta(Arg)-Cbeta(Asp) average distance >=8.8 A]. Docking studies were performed, starting from the representative conformations obtained from the MC/SD simulations and taking as a reference model the crystal structure of the extracellular segment of integrin alpha(v)beta(3) complexed with the cyclic pentapeptide, Cilengitide. The highest affinity ligands produced top-ranked poses conserving all the important interactions of the X-ray complex. PMID- 22517379 TI - Motor sequencing deficit as an endophenotype of speech sound disorder: a genome wide linkage analysis in a multigenerational family. AB - OBJECTIVES: The aim of this pilot study was to investigate a measure of motor sequencing deficit as a potential endophenotype of speech sound disorder (SSD) in a multigenerational family with evidence of familial SSD. METHODS: In a multigenerational family with evidence of a familial motor-based SSD, affectation status and a measure of motor sequencing during oral motor testing were obtained. To further investigate the role of motor sequencing as an endophenotype for genetic studies, parametric and nonparametric linkage analyses were carried out using a genome-wide panel of 404 microsatellites. RESULTS: In seven of the 10 family members with available data, SSD affectation status and motor sequencing status coincided. Linkage analysis revealed four regions of interest, 6p21, 7q32, 7q36, and 8q24, primarily identified with the measure of motor sequencing ability. The 6p21 region overlaps with a locus implicated in rapid alternating naming in a recent genome-wide dyslexia linkage study. The 7q32 locus contains a locus implicated in dyslexia. The 7q36 locus borders on a gene known to affect the component traits of language impairment. CONCLUSION: The results are consistent with a motor-based endophenotype of SSD that would be informative for genetic studies. The linkage results in this first genome-wide study in a multigenerational family with SSD warrant follow-up in additional families and with fine mapping or next-generation approaches to gene identification. PMID- 22517380 TI - Genome-wide linkage scan of antisocial behavior, depression, and impulsive substance use in the UCSF family alcoholism study. AB - OBJECTIVE: Epidemiological and clinical studies suggest that the rates of antisocial behavior, depression, and impulsive substance use are increased among individuals diagnosed with alcohol dependence relative to those who are not. Thus, the present study conducted genome-wide linkage scans of antisocial behavior, depression, and impulsive substance use in the University of California at San Francisco Family Alcoholism Study. METHODS: Antisocial behavior, depressive symptoms, and impulsive substance use were assessed using three scales from the Minnesota Multiphasic Personality Inventory - 2nd ed.: the Antisocial Practices content scale, the Depression content scale, and the revised MacAndrew Alcoholism scale. Linkage analyses were carried out using a variance components approach. RESULTS: Suggestive evidence of linkage to three genomic regions independent of alcohol and cannabis dependence diagnostic status was observed: the Antisocial Practices content scale showed evidence of linkage to chromosome 13 at 11 cM, the MacAndrew Alcoholism scale showed evidence of linkage to chromosome 15 at 47 cM, and all three scales showed evidence of linkage to chromosome 17 at 57-58 cM. CONCLUSION: Each of these regions has shown previous evidence of linkage and association to substance dependence as well as other psychiatric disorders such as mood and anxiety disorders, attention-deficit hyperactivity disorder, and schizophrenia, thus suggesting potentially broad relations between these regions and psychopathology. PMID- 22517381 TI - BDNF expression in lymphoblastoid cell lines carrying BDNF SNPs associated with bipolar disorder. AB - OBJECTIVE: To determine whether single nucleotide polymorphisms (SNPs) of the brain-derived neurotrophic factor (BDNF) that have been associated with bipolar illness are associated with physiological dysfunction. METHODS: Lymphoblastoid cell lines (n=30) obtained from bipolar I individuals carrying zero, one, or two copies of a BDNF SNP associated with bipolar illness (rs12273363) were utilized. RESULTS: Proapoptotic stressors of serum deprivation alone, or serum deprivation combined with the sodium ionophore, monensin, did not alter intracellular proBDNF. Monensin treatment increased mature-BDNF (mBDNF) protein levels (P<0.05). There were no differences related to the presence of SNP or copy number. CONCLUSION: rs12273363 does not appear to have functional consequences that would involve its role in bipolar illness. PMID- 22517382 TI - Attention-deficit hyperactivity disorder and binge eating disorder in a patient with 2q21.1-q22.2 deletion. AB - We report the case of a young male with attention-deficit hyperactivity disorder, oppositional defiant disorder, eating problems and overweight, and mild mental retardation. Karyotype analysis detected an apparently balanced translocation: t(1;2)(p34.1;q21.1) de novo. Array comparative genomic hybridization analysis defined a de-novo cryptic deletion of 2q21.1-q22.2 bands. The deletion, here first associated with this complex phenotype, encompasses several genes with a putative role in different domains of behavioral control and neurocognitive functions; their deregulated expression may influence metabolic pathways and the role of dopamine in reward, explaining the complex psychiatric phenotype and the pharmacotherapy response described in our patient. PMID- 22517383 TI - Clinical recognition of varicella zoster virus vasculopathy. AB - INTRODUCTION: It is important to recognize acutely evolving ischemic stroke attributable to reactivation of varicella zoster virus vasculopathy since antiviral agents are effective. METHODS: Three cases seen by the author over a 2 year period are highlighted. RESULTS: All patients presented with an evolving arterial or venous ischemia in the background of postherpetic neuralgia proceeding for weeks to months. CONCLUSION: Chronic neuralgic pain in a dermatomal distribution of an evolving central nervous system vasculopathy is an important clue to its recognition. PMID- 22517384 TI - Preventing venous thromboembolic disease in patients undergoing elective total hip and knee arthroplasty. PMID- 22517385 TI - A prospective randomized controlled trial of dynamic versus static progressive elbow splinting for posttraumatic elbow stiffness. AB - BACKGROUND: Both dynamic and static progressive (turnbuckle) splints are used to help stretch a contracted elbow capsule to regain motion after elbow trauma. There are advocates of each method, but no comparative data. This prospective randomized controlled trial tested the null hypothesis that there is no difference in improvement of motion and Disabilities of the Arm, Shoulder and Hand (DASH) scores between static progressive and dynamic splinting. METHODS: Sixty-six patients with posttraumatic elbow stiffness were enrolled in a prospective randomized trial: thirty-five in the static progressive and thirty one in the dynamic cohort. Elbow function was measured at enrollment and at three, six, and twelve months later. Patients completed the DASH questionnaire at enrollment and at the six and twelve-month evaluation. Three patients asked to be switched to static progressive splinting. The analysis was done according to intention-to-treat principles and with use of mean imputation for missing data. RESULTS: There were no significant differences in flexion arc at any time point. Improvement in the arc of flexion (dynamic versus static) averaged 29 degrees versus 28 degrees at three months (p = 0.87), 40 degrees versus 39 degrees at six months (p = 0.72), and 47 degrees versus 49 degrees at twelve months after splinting was initiated (p = 0.71). The average DASH score (dynamic versus static) was 50 versus 45 points at enrollment (p = 0.52), 32 versus 25 points at six months (p < 0.05), and 28 versus 26 points at twelve months after enrollment (p = 0.61). CONCLUSIONS: Posttraumatic elbow stiffness can improve with exercises and dynamic or static splinting over a period of six to twelve months, and patience is warranted. There were no significant differences in improvement in motion between static progressive and dynamic splinting protocols, and the choice of splinting method can be determined by the patients and their physicians. PMID- 22517386 TI - Implantation of allogenic synovial stem cells promotes meniscal regeneration in a rabbit meniscal defect model. AB - BACKGROUND: Indications for surgical meniscal repair are limited, and failure rates remain high. Thus, new ways to augment repair and stimulate meniscal regeneration are needed. Mesenchymal stem cells are multipotent cells present in mature individuals and accessible from peripheral connective tissue sites, including synovium. The purpose of this study was to quantitatively evaluate the effect of implantation of synovial tissue-derived mesenchymal stem cells on meniscal regeneration in a rabbit model of partial meniscectomy. METHODS: Synovial mesenchymal stem cells were harvested from the knee of one New Zealand White rabbit, expanded in culture, and labeled with a fluorescent marker. A reproducible 1.5-mm cylindrical defect was created in the avascular portion of the anterior horn of the medial meniscus bilaterally in fifteen additional rabbits. Allogenic synovial mesenchymal stem cells suspended in phosphate buffered saline solution were implanted into the right knees, and phosphate buffered saline solution alone was placed in the left knees. Meniscal regeneration was evaluated histologically at four, twelve, and twenty-four weeks for (1) quantity and (2) quality (with use of an established three-component scoring system). A similar procedure was performed in four additional rabbits with use of green fluorescent protein-positive synovial mesenchymal stem cells for the purpose of tracking progeny following implantation. RESULTS: The quantity of regenerated tissue in the group that had implantation of synovial mesenchymal stem cells was greater at all end points, reaching significance at four and twelve weeks (p < 0.05). Tissue quality scores were also superior in knees treated with mesenchymal stem cells compared with controls at all end points, achieving significance at twelve and twenty-four weeks (3.8 versus 2.8 at four weeks [p = 0.29], 5.7 versus 1.7 at twelve weeks [p = 0.008], and 6.0 versus 3.9 at twenty-four weeks [p = 0.021]). Implanted cells adhered to meniscal defects and were observed in the regenerated tissue, where they differentiated into type I and II collagen-expressing cells, at up to twenty-four weeks. CONCLUSIONS: Synovial mesenchymal stem cells adhere to sites of meniscal injury, differentiate into cells resembling meniscal fibrochondrocytes, and enhance both quality and quantity of meniscal regeneration. PMID- 22517387 TI - Incidence of symptomatic venous thromboembolism after elective knee arthroscopy. AB - BACKGROUND: Knee arthroscopy is the most commonly performed orthopaedic procedure in the United States and is usually considered to be a low-risk procedure. The purposes of this study were to describe the incidence of symptomatic deep venous thrombosis, symptomatic pulmonary embolism, and mortality after elective knee arthroscopy performed without thromboembolic prophylaxis, as well as to investigate the association of age, sex, procedure type, and oral contraceptive use with the odds of developing a venous thromboembolism. METHODS: A retrospective cohort study of elective arthroscopic knee procedures during a twenty-seven-month period (January 1, 2006, through March 31, 2008) was performed with use of the administrative database of a large health maintenance organization. Use of ICD-9-CM (International Classification of Diseases, Ninth Revision, Clinical Modification) procedure codes for arthroscopic surgery identified 21,794 arthroscopic knee procedures. The occurrence of a symptomatic deep venous thrombosis or pulmonary embolism within ninety days after surgery was identified by reviewing administrative and electronic medical record data for inpatient, outpatient, urgent care, and emergency encounters. Mortality and the cause of death were captured with use of electronic medical records, Social Security Administration Death Master Files, and county death certificates. Patient charts were reviewed for confirmation of the deep venous thrombosis, pulmonary embolism, or death. Patients who had a history of a venous thromboembolism or who had received anticoagulation therapy within fourteen days prior to the index surgery were excluded. RESULTS: The study cohort comprised 20,770 patients who met the inclusion criteria. Fifty-one patients (0.25%; 95% confidence interval, 0.18% to 0.31%) developed a deep venous thrombosis, and thirty-five (0.17%; 95% confidence interval, 0.11% to 0.22%) developed a pulmonary embolism. The incidence of venous thromboembolism was higher in patients who were fifty years of age or older (0.51% compared with 0.34% in younger patients), and the incidence in female patients was higher if they had been prescribed oral contraceptive medication (0.63% compared with 0.30% in female patients with no such prescription). No differences in the incidence of deep venous thrombosis or pulmonary embolism on the basis of sex or arthroscopic procedure code were noted. Nine patients (0.04%) died within ninety days of surgery, although only one death was confirmed to have resulted from a pulmonary embolism. CONCLUSIONS: The ninety-day incidence of symptomatic venous thromboembolism after elective knee arthroscopy was relatively low, with a 0.25% incidence of deep venous thrombosis and a 0.17% incidence of pulmonary embolism. The overall ninety-day mortality after arthroscopic knee surgery was 0.04%. PMID- 22517388 TI - Vascular safe zones for surgical dislocation in children with healed Legg-Calve Perthes disease. AB - BACKGROUND: Legg-Calve-Perthes disease consists of idiopathic osteonecrosis of the femoral head, causing proximal femoral growth deformity. Recent advances in surgical technique have permitted safe surgical dislocation of the hip, allowing for correction of femoracetabular impingement. The purpose of this study was to characterize the location and number of lateral epiphyseal arteries supplying the femoral head in children with healed Legg-Calve-Perthes disease. METHODS: This retrospective study included nineteen children (twenty-two hips) with a diagnosis of Legg-Calve-Perthes disease (the LCPD group) and a matched control group of seventeen children (twenty hips) with developmental hip dysplasia. All patients underwent high-resolution contrast-enhanced magnetic resonance imaging (MRI) to visualize the path of the medial femoral circumflex artery and the lateral epiphyseal artery branches supplying the femoral head. RESULTS: All patients in the LCPD group were classified as having Waldenstrom grade-4 disease. Their average age at the time of MRI was fifteen years (range, eleven to eighteen years). The lateral epiphyseal arteries reliably inserted on the posterior superior aspect of the femoral neck from a superior-anterior to a superior posterior position in both groups. An average of 2.63 (standard deviation [SD], 1.47) retinacular vessels were visualized in the LCPD group, compared with 5.20 (SD, 1.06) retinacular vessels in the dysplasia group (p < 0.0001). CONCLUSIONS: The lateral epiphyseal arteries of the femoral head reliably insert in a narrow anatomic window on the femoral neck. Reperfusion of the medial femoral circumflex artery does occur in patients with Legg-Calve-Perthes disease; however, the overall number of vessels is decreased as compared with that in patients with developmental hip dysplasia. PMID- 22517389 TI - Non-emergent orthopaedic injuries sustained by soldiers in Operation Iraqi Freedom. AB - BACKGROUND: The majority of soldiers deployed to the theater of combat operations return safely after completion of the deployment. Many of these soldiers sustain non-emergent musculoskeletal injuries that initially are treated nonoperatively and ultimately require surgery following their combat tour. METHODS: A prospective evaluation of the orthopaedic surgery consultations and surgical procedures required by soldiers returning from a full combat deployment was performed. Demographic information (including age and sex) as well as information on the mechanism of injury, the reason for orthopaedic consultation, and the procedures performed was collected for each soldier. The overall incidence of non emergent orthopaedic injuries was calculated, and multivariate Poisson regression analysis was utilized to determine the effect of age and sex on the type of orthopaedic injury sustained. RESULTS: There were 3787 soldiers who returned from combat operations at the end of a fifteen-month deployment without having been medically evacuated. There were 731 orthopaedic surgical consultations for the evaluation of a non-emergent musculoskeletal complaint, and 140 orthopaedic operations were performed as a result. An age of thirty years or more was an important risk factor for requiring an orthopaedic consultation (p < 0.0001). The most common surgical procedures were performed for shoulder stabilization, for superior labrum anterior to posterior lesion repair, for the treatment of internal derangement of the knee, and for the treatment of foot deformity. CONCLUSIONS: Nineteen percent of all soldiers who completed a combat deployment required an orthopaedic surgical consultation on return, and 4% of soldiers required orthopaedic surgery. More than half of the surgical procedures involved the knee or shoulder. This represents a large burden of care for returning soldiers on orthopaedic surgical services and has important implications for future resource utilization. PMID- 22517390 TI - Outcomes and prognostic factors for a consecutive case series of 115 patients with somatic leiomyosarcoma. AB - BACKGROUND: Leiomyosarcoma is an uncommon tumor that affects 500 to 1000 patients in the United States annually. The purpose of our study was to further define survival rates as well as to identify multivariable predictors of disease specific mortality, local recurrence, and development of distant metastasis following surgical resection. METHODS: We studied a consecutive series of patients treated for leiomyosarcoma at our institution (a tertiary-care referral center) over a ten-year period. Only patients with leiomyosarcoma of soft tissues, vasculature, or bone were included. Those with uterine, gastrointestinal, or cutaneous forms of the disease were excluded. This yielded a cohort of 115 patients with complete follow-up data on which statistical analysis was performed. RESULTS: One-year, five-year, and ten-year disease-specific survival rates were 87%, 57%, and 19%, respectively. Tumor depth (p < 0.01), histological grade (p < 0.01), and metastasis at presentation (p = 0.03) were found to be multivariable predictors of mortality. Both retroperitoneal location (p = 0.01) and mitotic rate (p < 0.001) were predictive of distant metastasis. Resection margin was the only multivariable significant predictor of local recurrence in the group treated with surgical resection (p < 0.001). CONCLUSIONS: Leiomyosarcoma is an aggressive disease, with a generally poor prognosis. Depth of tumor and high histological grade are indicators of a poor prognosis. Retroperitoneal tumors have a particularly high potential to metastasize. PMID- 22517391 TI - American Academy of Orthopaedic Surgeons clinical practice guideline on: preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. PMID- 22517392 TI - Revision open capsular shift for atraumatic and multidirectional instability of the shoulder. PMID- 22517393 TI - What's new in sports medicine. PMID- 22517394 TI - Repair integrity and functional outcomes after arthroscopic suture-bridge rotator cuff repair. AB - BACKGROUND: We evaluated the clinical and imaging outcomes of arthroscopic suture bridge repair of full-thickness rotator cuff tears. METHODS: From May 2007 to April 2008, seventy-nine patients with a full-thickness rotator cuff tear consecutively underwent arthroscopic suture-bridge repair. The mean age of the patients was 58.3 years (range, thirty-eight to seventy-eight years), and the mean duration of follow-up was 30.6 months (range, twenty-four to forty-four months). Seventy-three patients underwent postoperative ultrasonography or magnetic resonance imaging; seventy-one underwent the imaging at a minimum of two years postoperatively, and the remaining two did so after the operation because of persistent symptoms. The clinical results of seventy-seven patients (all except two who had undergone revision) were evaluated at a minimum of two years postoperatively. University of California at Los Angeles (UCLA), American Shoulder and Elbow Surgeons (ASES), and Constant-Murley scores were used for clinical and functional evaluations before surgery and at the time of final follow-up. RESULTS: The imaging follow-up rate was 92%, and the follow-up rate for clinical evaluation was 100%. The re-tear rate after suture-bridge repair was 15%. The re-tear rate of the medium, large, and massive tears (as classified according to the anterior-to-posterior diameter of the tear) was 12%, 21%, and 22%, respectively. Massive and large tears tended to show a higher re-tear rate than did medium tears, but the difference was not significant (p = 0.417 and p = 0.964, respectively). The mean UCLA, ASES, and Constant-Murley scores improved from 21.6, 50.4, and 52.7 preoperatively to 30.9, 86.2, and 74.7 at the time of final follow-up (p < 0.001). However, the clinical outcomes after the operation did not differ significantly between the patients who had healing of the tear and those who did not (p = 0.438, p = 0.625, and p = 0.898 for the UCLA, ASES, and Constant-Murley scores, respectively). CONCLUSIONS: Arthroscopic suture-bridge repair of full-thickness rotator cuff tears was followed by a re-tear rate of 15% as seen with imaging and resulted in significant improvement of functional outcomes and clinical results compared with the preoperative findings. PMID- 22517395 TI - Ulnar collateral ligament reconstruction in throwing athletes: a review of current concepts. AAOS exhibit selection. PMID- 22517396 TI - Level of evidence of presentations at American Academy of Orthopaedic Surgeons annual meetings. AB - BACKGROUND: The American Academy of Orthopaedic Surgeons (AAOS) Annual Meeting is a major international forum for scientific exchange and education. The purpose of this study was to evaluate the level of evidence of papers and posters presented at the 2001, 2004, 2007, and 2010 AAOS meetings to determine trends in the quality of study designs between the years 2001 and 2010. METHODS: Abstracts for AAOS presentations from 2001 (288 papers and 468 posters), 2004 (290 papers and 466 posters), 2007 (525 papers and 541 posters), and 2010 (720 papers and 569 posters) were independently evaluated by three reviewers. The level of evidence of each presentation was determined based on the AAOS classification system. The results were subdivided according to orthopaedic subspecialty and type of presentation. RESULTS: In subsequent years, there was a substantial increase in the percentage of Level I studies (2% in 2001, 3% in 2004, 5% in 2007, and 7% in 2010), Level II studies (15% in 2001, 18% in 2004, 23% in 2007, and 29% in 2010), and Level III studies (22% in 2001, 26% in 2004, 29% in 2007, and 33% in 2010), with a concomitant decrease in the percentage of Level IV studies (62% in 2001, 54% in 2004, 43% in 2007, and 31% in 2010). Overall, there was a significant nonrandom improvement in the level of evidence of presentations over the study period (p < 0.001). This trend was consistent across all orthopaedic subspecialties and in both the paper and the poster subgroups. CONCLUSIONS: The level of evidence of studies presented at the AAOS Annual Meeting is steadily increasing, which signifies a mark of continual improvement in the quality of the scientific program. PMID- 22517397 TI - Teaching professionalism in orthopaedic surgery residency programs. PMID- 22517398 TI - Is thromboprophylaxis after knee arthroscopy warranted? Commentary on an article by Gregory B. Maletis, MD, et al.: "Incidence of symptomatic venous thromboembolism after elective knee arthroscopy". PMID- 22517399 TI - A safety run-in and randomized phase 2 study of cilengitide combined with chemoradiation for newly diagnosed glioblastoma (NABTT 0306). AB - BACKGROUND: Cilengitide is a selective integrin inhibitor that is well tolerated and has demonstrated biologic activity in patients with recurrent malignant glioma. The primary objectives of this randomized phase 2 trial were to determine the safety and efficacy of cilengitide when combined with radiation and temozolomide for patients with newly diagnosed glioblastoma multiforme and to select a dose for comparative clinical testing. METHODS: In total, 112 patients were accrued. Eighteen patients received standard radiation and temozolomide with cilengitide in a safety run-in phase followed by a randomized phase 2 trial with 94 patients assigned to either a 500 mg dose group or 2000 mg dose group. The trial was designed to estimate overall survival benefit compared with a New Approaches to Brain Tumor Therapy (NABTT) Consortium internal historic control and data from the published European Organization for Research and Treatment of Cancer (EORTC) trial EORTC 26981. RESULTS: Cilengitide at all doses studied was well tolerated with radiation and temozolomide. The median survival was 19.7 months for all patients, 17.4 months for the patients in the 500 mg dose group, 20.8 months for patients in the 2000 mg dose group, 30 months for patients who had methylated O6-methylguanine-DNA methyltransferase (MGMT) status, and 17.4 months for patients who had unmethylated MGMT status. For patients aged <=70 years, the median survival and survival at 24 months was superior to what was observed in the EORTC trial (20.7 months vs 14.6 months and 41% vs 27%, respectively; P = .008). CONCLUSIONS: Cilengitide was well tolerated when combined with standard chemoradiation and may improve survival for patients newly diagnosed with glioblastoma multiforme regardless of MGMT methylation status. The authors concluded that, from an efficacy and safety standpoint, future trials of this agent in this population should use the 2000 mg dose. PMID- 22517401 TI - Monitoring peripheral perfusion in critically ill patients at the bedside. AB - PURPOSE OF REVIEW: The goal of circulatory monitoring is the use of an accurate, continuous and noninvasive method that can easily assess tissue perfusion under clinical conditions. As peripheral tissues are sensitive to alterations in perfusion, the noninvasive monitoring of peripheral circulation could be used as an early marker of systemic haemodynamic derangement. We, therefore, aim to discuss the currently available methods that can be used at the bedside as well as the role of peripheral perfusion monitoring in critically ill patients. RECENT FINDINGS: The deterioration of peripheral circulation has frequently been observed in critically ill patients with the use of subjective assessment and several optical techniques. In various patient categories, more severe and persistent alterations have been associated with worse outcomes, and these associations were independent of systemic haemodynamic parameters. Interventions aimed at systemic parameters have an unpredictable effect on peripheral circulation parameters, especially during hyperdynamic conditions. Thus, it appears that changes in peripheral perfusion reflect changes in regional vasomotor tone rather than systemic blood flow. SUMMARY: Subjective assessments and optical techniques provide important information regarding peripheral circulation. Moreover, these techniques are relatively easy to implement and interpret at the bedside and can be applied during acute conditions. Further research is warranted to investigate the effects of therapeutic interventions on peripheral perfusion parameters and patient outcome. PMID- 22517400 TI - Epidemiology and risk factors for perioperative mortality after total hip and knee arthroplasty. AB - The perioperative mortality of total knee and hip arthroplasties (TKA, THA) remains a major concern among health care providers and their patients. The increase in utilization of TKA and THA makes it imperative to be aware of factors that are associated with this unfortunate event. Therefore we analyzed the Nationwide Inpatient Sample data from 1998 to 2008 and compared admissions with perioperative mortality to those that survived their hospitalization. An estimated total of 4,438,213 TKA and 2,182,121 THA procedures were performed in the United States between 1998 and 2008. The average mortality rate for TKA was 0.13% and 0.18% for THA, or 0.34 and 0.44 events per 1,000 inpatient days, respectively. Independent risk factors for in-hospital mortality were advanced age, male gender, ethnic minority background, emergency admission as well as a number of comorbidities and complications. Furthermore, we demonstrated that the timing of death occurred earlier after TKA when compared to THA, with 50% of fatalities occurring by day 4 versus day 6 of the hospitalization, respectively. This study provides nationally representative information on risk factors for and timing of perioperative mortality after TKA and THA. Our data can be used to assess the risk for perioperative mortality and to develop targeted intervention to decrease such risk. PMID- 22517402 TI - Lactate as a hemodynamic marker in the critically ill. AB - PURPOSE OF REVIEW: An early quantitative resuscitation strategy improves outcome in critically ill patients. The hemodynamic endpoints of such a strategy have been a topic of debate in the literature. This review focuses on the use of lactate as a marker for risk stratification, lactate clearance as a hemodynamic endpoint, and its use compared to mixed venous oxygenation as a resuscitation goal. RECENT FINDINGS: Lactate clearance is associated with improved outcome across several cohorts of critically ill patients. Lactate levels and central venous oxygen saturations are frequently discordant. Targeting lactate clearance as part of a quantitative resuscitation strategy may be as effective as targeting central venous oxygen saturation. SUMMARY: Resuscitation of the critically ill patient should be aimed at the reversal of tissue hypoxia. The use of lactate as a hemodynamic marker and resuscitation endpoint makes physiologic sense, and is supported by the recent data. The use of lactate clearance versus other traditional endpoints of resuscitation, such as mixed venous oxygen saturation, should be based on the clinical characteristics and response of the individual patient. PMID- 22517403 TI - Recent efforts directed to the development of more sustainable asymmetric organocatalysis. AB - In line with the principles of "green" chemistry, organocatalysis seeks to reduce energy consumption and to optimize the use of the available resources, aiming to become a sustainable strategy in chemical transformations. Nevertheless, during the last decade diverse experimental protocols have made organocatalysis an even "greener" alternative by the use of friendlier reaction conditions, or via the application of solvent-free methodologies, or through the design and synthesis of more selective catalysts, or via the development of multicomponent one-pot organocatalytic reactions, or by the recycling and reuse of organocatalysts, or by means of the application of more energy-efficient activation techniques, among other approaches. In this feature article we review some of the remarkable advancements that have made it possible to develop even more sustainable asymmetric organocatalyzed methodologies. PMID- 22517404 TI - Automated quantification of white matter disease extent at 3 T: comparison with volumetric readings. AB - PURPOSE: To develop and validate an algorithm to automatically quantify white matter hyperintensity (WMH) volume. MATERIALS AND METHODS: Images acquired as part of the Dallas Heart Study, a multiethnic, population-based study of cardiovascular health, were used to develop and validate the algorithm. 3D magnetization prepared rapid acquisition gradient echo (MP-RAGE) and 2D fluid attenuated inversion recovery (FLAIR) images were acquired from 2082 participants. Images from 161 participants (7.7% of the cohort) were used to set an intensity threshold to maximize the agreement between the algorithm and a qualitative rating made by a radiologist. The resulting algorithm was run on the entire cohort and outlier analyses were used to refine the WMH volume measurement. The refined, automatic WMH burden estimate was then compared to manual quantitative measurements of WMH volume in 28 participants distributed across the range of volumes seen in the entire cohort. RESULTS: The algorithm showed good agreement with the volumetric readings of a trained analyst: the Spearman's Rank Order Correlation coefficient was r = 0.87. Linear regression analysis showed a good correlation WMHml[automated] = 1.02 * WMHml[manual] - 0.48. Bland-Altman analysis showed a bias of 0.34 mL and a standard deviation of 2.8 mL over a range of 0.13 to 41 mL. CONCLUSION: We have developed an algorithm that automatically estimates the volume of WMH burden using an MP-RAGE and a FLAIR image. This provides a tool for evaluating the WMH burden of large populations to investigate the relationship between WMH burden and other health factors. PMID- 22517405 TI - Self-disproportionation of enantiomers via achiral chromatography: a warning and an extra dimension in optical purifications. AB - This tutorial review describes the self-disproportionation of enantiomers (SDE) of chiral, non-racemic compounds, subjected to chromatography on an achiral stationary phase using an achiral eluent, which leads to the substantial enantiomeric enrichment and the corresponding depletion in different fractions, as compared to the enantiomeric composition of the starting material. The physicochemical background of SDE is a dynamic formation of homo- or heterochiral dimeric or oligomeric aggregates of different chromatographic behavior. This phenomenon is of a very general nature as the SDE has been reported for different classes of organic compounds bearing various functional groups and possessing diverse elements of chirality (central, axial and helical chirality). The literature data discussed in this review clearly suggest that SDE via achiral chromatography might be expected for any given chiral enantiomerically enriched compound. This presents two very important issues for organic chemists. First, chromatographic purification of reaction products can lead to erroneous determination of the stereochemical outcome of catalytic asymmetric reactions and second, achiral chromatography can be used as a new, nonconventional method for optical purifications. The latter has tremendous practical potential as the currently available techniques are limited to crystallization or chiral chromatography. However, a further systematic study of SDE is needed to develop understanding of this phenomenon and to design practical chromatographic separation techniques for optical purification of non-racemic mixtures by achiral phase chromatography. PMID- 22517406 TI - Secoscabronine M, a novel diterpenoid from the Chinese bitter mushroom Sarcodon scabrosus. AB - Secoscabronine M (1) is a hemiacetal cyathane diterpenoid that was isolated from the fruiting bodies of the basidiomycete Sarcodon scabrosus (Fr.) Karst. Compound 1 possesses a novel structure with a bond cleavage between C-3 and C-4. The structure of the new compound was elucidated by means of spectroscopic methods, including two-dimensional nuclear magnetic resonance experiments. The absolute configuration of 1 was established by analysis of circular dichroism spectroscopy and also by employing time-dependent density functional theory calculations. In addition, compound 1 was confirmed to be an equilibrium mixture of two epimers (15S and 15R) at position C-15 in polar solvents by one-dimensional nuclear magnetic resonance analysis. PMID- 22517407 TI - 'Normal' nuchal translucency: a justification to refrain from detailed scan? Analysis of 6858 cases with special reference to ethical aspects. AB - OBJECTIVE: To assess the prevalence and detection rate of major anomalies (MAs) by applying first trimester anomaly scan (FTAS) including first trimester fetal echocardiography (FTFE) to all fetuses and discuss ethical implications. METHODS: The study group included 6879 consecutive fetuses with known outcome of pregnancy (follow-up: 98%), 6565 with 'normal' nuchal translucency (NT) (<= P95), 314 with 'increased' NT (> P95). All fetuses received FTAS/FTFE. As MAs with the potential of being detected at FTAS/FTFE, we defined anomalies present at conception or developed during first trimester. RESULTS: Prevalence of MAs in fetuses with 'normal' NT reached 1.7%. Although 29.8% of chromosomal abnormalities were found in the group of 'normal' NT, 77% of MAs accompanied by a normal karyotype were found in this group. In fetuses with 'normal' NT and MA, diagnosis was made prenatally in 87.4% (FTAS/FTFE: 58.6%). CONCLUSION: A relevant number of MA is present in fetuses with 'normal' NT. More than half will be detected by FTAS/FTFE. As consequence, one should discuss a concept in which also in fetuses with 'normal' NT, FTAS/FTFE should be offered. This concept can also be justified from an ethical point of view, which focuses on the principles of nonmaleficence, justice and respect for autonomy of the pregnant woman. PMID- 22517408 TI - Life years lost--comparing potentially fatal late complications after radiotherapy for pediatric medulloblastoma on a common scale. AB - BACKGROUND: The authors developed a framework for estimating and comparing the risks of various long-term complications on a common scale and applied it to 3 different techniques for craniospinal irradiation in patients with pediatric medulloblastoma. METHODS: Radiation dose-response parameters related to excess hazard ratios for secondary breast, lung, stomach, and thyroid cancer; heart failure, and myocardial infarction were derived from large published clinical series. Combined with age-specific and sex-specific hazards in the US general population, the dose-response analysis yielded excess hazards of complications for a cancer survivor as a function of attained age. After adjusting for competing risks of death, life years lost (LYL) were estimated based on excess hazard and prognosis of a complication for 3-dimensional conformal radiotherapy (3D CRT), volumetric modulated arc therapy (VMAT), and intensity-modulated proton therapy (IMPT). RESULTS: Lung cancer contributed most to the estimated LYL, followed by myocardial infarction, and stomach cancer. The estimates of breast or thyroid cancer incidence were higher than those for lung and stomach cancer incidence, but LYL were lower because of the relatively good prognosis. Estimated LYL ranged between 1.90 years for 3D CRT to 0.28 years for IMPT. In a paired comparison, IMPT was associated with significantly fewer LYL than both photon techniques. CONCLUSIONS: Estimating the risk of late complications is associated with considerable uncertainty, but including prognosis and attained age at an event to obtain the more informative LYL estimate added relatively little to this uncertainty. PMID- 22517409 TI - Controlled chain polymerisation and chemical soldering for single-molecule electronics. AB - Single functional molecules offer great potential for the development of novel nanoelectronic devices with capabilities beyond today's silicon-based devices. To realise single-molecule electronics, the development of a viable method for connecting functional molecules to each other using single conductive polymer chains is required. The method of initiating chain polymerisation using the tip of a scanning tunnelling microscope (STM) is very useful for fabricating single conductive polymer chains at designated positions and thereby wiring single molecules. In this feature article, developments in the controlled chain polymerisation of diacetylene compounds and the properties of polydiacetylene chains are summarised. Recent studies of "chemical soldering", a technique enabling the covalent connection of single polydiacetylene chains to single functional molecules, are also introduced. This represents a key step in advancing the development of single-molecule electronics. PMID- 22517410 TI - Mycorrhizal networks: common goods of plants shared under unequal terms of trade. AB - Plants commonly live in a symbiotic association with arbuscular mycorrhizal fungi (AMF). They invest photosynthetic products to feed their fungal partners, which, in return, provide mineral nutrients foraged in the soil by their intricate hyphal networks. Intriguingly, AMF can link neighboring plants, forming common mycorrhizal networks (CMNs). What are the terms of trade in such CMNs between plants and their shared fungal partners? To address this question, we set up microcosms containing a pair of test plants, interlinked by a CMN of Glomus intraradices or Glomus mosseae. The plants were flax (Linum usitatissimum; a C(3) plant) and sorghum (Sorghum bicolor; a C(4) plant), which display distinctly different (13)C/(12)C isotope compositions. This allowed us to differentially assess the carbon investment of the two plants into the CMN through stable isotope tracing. In parallel, we determined the plants' "return of investment" (i.e. the acquisition of nutrients via CMN) using (15)N and (33)P as tracers. Depending on the AMF species, we found a strong asymmetry in the terms of trade: flax invested little carbon but gained up to 94% of the nitrogen and phosphorus provided by the CMN, which highly facilitated growth, whereas the neighboring sorghum invested massive amounts of carbon with little return but was barely affected in growth. Overall biomass production in the mixed culture surpassed the mean of the two monocultures. Thus, CMNs may contribute to interplant facilitation and the productivity boosts often found with intercropping compared with conventional monocropping. PMID- 22517411 TI - The plastid genome-encoded Ycf4 protein functions as a nonessential assembly factor for photosystem I in higher plants. AB - Photosystem biogenesis in the thylakoid membrane is a highly complicated process that requires the coordinated assembly of nucleus-encoded and chloroplast-encoded protein subunits as well as the insertion of hundreds of cofactors, such as chromophores (chlorophylls, carotenoids) and iron-sulfur clusters. The molecular details of the assembly process and the identity and functions of the auxiliary factors involved in it are only poorly understood. In this work, we have characterized the chloroplast genome-encoded ycf4 (for hypothetical chloroplast reading frame no. 4) gene, previously shown to encode a protein involved in photosystem I (PSI) biogenesis in the unicellular green alga Chlamydomonas reinhardtii. Using stable transformation of the chloroplast genome, we have generated ycf4 knockout plants in the higher plant tobacco (Nicotiana tabacum). Although these mutants are severely affected in their photosynthetic performance, they are capable of photoautotrophic growth, demonstrating that, different from Chlamydomonas, the ycf4 gene product is not essential for photosynthesis. We further show that ycf4 knockout plants are specifically deficient in PSI accumulation. Unaltered expression of plastid-encoded PSI genes and biochemical analyses suggest a posttranslational action of the Ycf4 protein in the PSI assembly process. With increasing leaf age, the contents of Ycf4 and Y3IP1, another auxiliary factor involved in PSI assembly, decrease strongly, whereas PSI contents remain constant, suggesting that PSI is highly stable and that its biogenesis is restricted to young leaves. PMID- 22517412 TI - Cross-linked multifunctional conjugated polymers prepared by in situ electrochemical deposition for a highly-efficient blue-emitting and electron transport layer. AB - An efficient and controllable approach to prepare cross-linked films from a conjugated polymer precursor by electrochemical deposition (ED) is reported for the first time. A novel polymer precursor with high solubility, high electroactivity, and electron-transport ability has been designed. The electrochemically deposited polymer film shows high thickness, smooth morphology, and high fluorescence. The single-layer pure-blue-emitting ED PLED exhibits a luminous efficiency of 3.8 cd A(-1) . PMID- 22517413 TI - The pharmacokinetics of lersivirine (UK-453,061) and HIV-1 protease inhibitor coadministration in healthy subjects. AB - OBJECTIVE: Lersivirine (UK-453,061) is a next-generation nonnucleoside reverse transcriptase inhibitor, active against wild-type HIV-1 and several nonnucleoside reverse transcriptase inhibitor-resistant strains. Four studies evaluated the pharmacokinetic (PK) interactions between lersivirine and various HIV-1 protease inhibitors. METHODS: Four phase I trials were conducted to assess the PK of lersivirine when coadministered with lopinavir/ritonavir, darunavir/ritonavir, or atazanavir with/without ritonavir, and to examine the effects of lersivirine on the PK of atazanavir with/without ritonavir. PK data included the area under the plasma concentration-time profile from time zero to the end of the dosing interval (AUC24), maximum plasma concentration (Cmax), minimum plasma concentration (Cmin, C24, or Ctrough), and time to Cmax (Tmax). Safety was assessed by recording adverse events, vital signs, and laboratory data. RESULTS: Coadministration of lersivirine with lopinavir/ritonavir, darunavir/ritonavir, or atazanavir/ritonavir decreased mean plasma lersivirine AUC24 by 43%, 22%, and 19%, respectively. Atazanavir had no effect on lersivirine exposure, except for a 16% decrease in lersivirine C24. Lersivirine had no effect on atazanavir AUC24 or Cmax, although Ctrough was reduced by 18% in the absence of ritonavir. CONCLUSIONS: Lersivirine exposure was reduced when coadministered with ritonavir boosted protease inhibitors; a dose adjustment may be warranted. Unboosted atazanavir had no effect on lersivirine exposure, except for a small decrease in lersivirine C24. Lersivirine had no effect on atazanavir (with/without ritonavir) exposure, except for a decrease in Ctrough. Caution should be applied when unboosted atazanavir is coadministered with lersivirine. Coadministration of lersivirine with lopinavir/ritonavir, darunavir/ritonavir, or atazanavir with/without ritonavir seems to be generally well tolerated. PMID- 22517414 TI - Association between missed early visits and mortality among patients of china national free antiretroviral treatment cohort. AB - BACKGROUND: China's National Free Antiretroviral Treatment program has scaled-up rapidly since 2002, leading to a significant reduction of mortality among its participants. However, few studies have evaluated indicators for patient access to medical care and their association with mortality. METHODS: Patients enrolled into this national program between June 2002 and June 2009 for at least 7.5 months were retrospectively analyzed. RESULTS: Twenty-seven thousand five hundred four patients were included into the analysis, among whom 10,034 (37%) had at least 1 missed visit during the first 6 months of treatment. In Cox proportional hazard regression analysis, controlled for baseline demographic and clinical factors, patients with more missed visits had a higher risk of mortality, with an adjusted hazard ratio of 1.3 (95% confidence interval: 1.1 to 1.5) for 1-2 missed visits and 1.7 (95% confidence interval 1.4 to 2.2) for >=3 missed visits compared with patients with no missed visits. In multivariate logistic regression models, factors independently associated with a higher likelihood of early missed visits included female gender, age >60, HIV transmission via injection drug use or via plasma donation compared with sexual transmission, baseline alanine aminotransferase >100 IU/L, having more symptoms at antiretroviral therapy initiation and receiving a didanosine-based regimen compared with lamivudine based regimen. Lower baseline CD4 count was protective against missed visits. CONCLUSIONS: Missing early visits occurred in a sizable number of patients in this cohort and was associated with a higher mortality rate. Early missed visits may serve as an early warning indicator to trigger additional outreach effort. PMID- 22517415 TI - What does U.S. health reform mean for HIV clinical care? AB - The Patient Protection and Affordable Care Act, more commonly known as health reform, is designed to expand health coverage to 32 million uninsured Americans by 2019 and makes significant changes to public and private health insurance systems that will affect providers of HIV care. We review the major features of the legislation and when they will be implemented, discuss the ways in which it will affect HIV care for different patient populations, and outline implementation challenges that are relevant for HIV care. We conclude with ways in which HIV providers can get involved to learn more about the law and help their patients take advantage of the new opportunities for health coverage. PMID- 22517416 TI - Permissive and protective factors associated with presence, level, and longitudinal pattern of cervicovaginal HIV shedding. AB - BACKGROUND: Cervicovaginal HIV level (CV-VL) influences HIV transmission. Plasma viral load (PVL) correlates with CV-VL, but discordance is frequent. We evaluated how PVL, behavioral, immunological, and local factors/conditions individually and collectively correlate with CV-VL. METHODS: CV-VL was measured in the cervicovaginal lavage fluid (CVL) of 481 HIV-infected women over 976 person visits in a longitudinal cohort study. We correlated identified factors with CV VL at individual person-visits and detectable/undetectable PVL strata by univariate and multivariate linear regression and with shedding pattern (never, intermittent, persistent >=3 shedding visits) in 136 women with >=3 visits by ordinal logistic regression. RESULTS: Of 959 person-visits, 450 (46.9%) with available PVL were discordant, 435 (45.3%) had detectable PVL with undetectable CV-VL, and 15 (1.6%) had undetectable PVL with detectable CV-VL. Lower CV-VL correlated with highly active antiretroviral therapy (HAART) usage (P = 0.01). Higher CV-VL correlated with higher PVL (P < 0.001), inflammation-associated cellular changes (P = 0.03), cervical ectopy (P = 0.009), exudate (P = 0.005), and trichomoniasis (P = 0.03). In multivariate analysis of the PVL-detectable stratum, increased CV-VL correlated with the same factors and friability (P = 0.05), while with undetectable PVL, decreased CV-VL correlated with HAART use (P = 0.04). In longitudinal analysis, never (40.4%) and intermittent (44.9%) shedding were most frequent. Higher frequency shedders were more likely to have higher initial PVL [odds ratio (OR) = 2.47/log10 increase], herpes simplex virus type 2 seropositivity (OR = 3.21), and alcohol use (OR = 2.20). CONCLUSIONS: Although PVL correlates strongly with CV-VL, discordance is frequent. When PVL is detectable, cervicovaginal inflammatory conditions correlate with increased shedding. However, genital shedding is sporadic and not reliably predicted by associated factors. HAART, by reducing PVL, is the most reliable means of reducing cervicovaginal shedding. PMID- 22517417 TI - Responses to hepatitis A virus vaccine in HIV-infected women: effect of hormonal contraceptives and HIV disease characteristics. PMID- 22517418 TI - Is there a drug-drug interaction between darunavir/ritonavir and raltegravir? PMID- 22517419 TI - Lack of association between concurrency and HIV infection: an artifact of study design. PMID- 22517421 TI - Influence of smoking combined with another risk factor on the risk of mortality from coronary heart disease and stroke: pooled analysis of 10 Japanese cohort studies. AB - BACKGROUND: In spite of the importance of a multifactorial approach to preventing cardiovascular disease in smokers, most information on the combined adverse effects of smoking and hypertension or high serum cholesterol on cardiovascular disease has been derived from Western populations, and coronary heart disease was often used as the only endpoint. Therefore, the present large-scale pooled analysis attempted to provide reliable information on the adverse effects of the coexistence of smoking and hypertension or high serum cholesterol on the risk of mortality from coronary heart disease and stroke in both, individuals and the entire population in Japan. METHODS: A total of 27,385 male and 39,207 female participants aged 40-89 years were enrolled from 10 well-qualified Japanese cohort studies with a mean follow-up of 10.1 years. Hazard ratios and their corresponding 95% confidence intervals in smokers who had hypertension or high serum cholesterol were estimated for men and women separately using a Cox proportional hazards regression model that included age, body mass index, cohort and either serum total cholesterol or systolic blood pressure as covariates. Fractions of deaths attributable to the coexistence of these risk factors were also calculated. RESULTS: The multivariate-adjusted hazard ratios in male and female current smokers with hypertension, compared with those with neither factor were 2.57 (95% confidence intervals, 1.51-4.38) and 6.14 (3.49-10.79) for coronary heart disease, and 3.28 (1.89-5.71) and 1.61 (0.81-3.18) for cerebral infarction, respectively. The fractions of deaths attributable to the coexistence of current smoking and hypertension in men and women were 24.6 and 9.6% for coronary heart disease and 28.1 and 2.0% for cerebral infarction, respectively. Smokers with high serum cholesterol were broadly comparable to hypertensive smokers only with respect to coronary mortality risk; the hazard ratios, compared with those with neither factor were 4.19 (2.33-7.53) for men and 3.90 (1.57-9.67) for women. The fraction of coronary deaths attributable to the coexistence of current smoking and high serum cholesterol was 6.3% in men and 2.2% in women. There was no interaction between smoking habit and blood pressure or serum total cholesterol for these two subtypes in both men and women. CONCLUSIONS: Particular attention should be given to smokers who have concomitant hypertension or high serum cholesterol for preventing deaths due to cardiovascular disease. From a public health perspective in Japan, priority should be given to hypertensive smokers, since this group makes a large contribution to the burden of both coronary and cerebral infarction deaths. PMID- 22517422 TI - Macrophages: Yolky beginnings. PMID- 22517423 TI - Regulation and function of mTOR signalling in T cell fate decisions. AB - The evolutionarily conserved kinase mTOR (mammalian target of rapamycin) couples cell growth and metabolism to environmental inputs in eukaryotes. T cells depend on mTOR signalling to integrate immune signals and metabolic cues for their proper maintenance and activation. Under steady-state conditions, mTOR is actively controlled by multiple inhibitory mechanisms, and this enforces normal T cell homeostasis. Antigen recognition by naive CD4(+) and CD8(+) T cells triggers mTOR activation, which in turn programmes the differentiation of these cells into functionally distinct lineages. This Review focuses on the signalling mechanisms of mTOR in T cell homeostatic and functional fates, and discusses the therapeutic implications of targeting mTOR in T cells. PMID- 22517425 TI - Dynamic contrast-enhanced MRI in advanced nonsmall-cell lung cancer patients treated with first-line bevacizumab, gemcitabine, and cisplatin. AB - PURPOSE: To investigate dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) of advanced nonsmall-cell lung cancer (NSCLC) patients treated with the antiangiogenic agent bevacizumab combined with gemcitabine and cisplatin as first-line treatment. MATERIALS AND METHODS: All patients were enrolled for MRI and computed tomography (CT) before and after the first three courses of bevacizumab combination chemotherapy. Pharmacokinetic parameters (K(trans), k(ep), v(e), v(p)) derived from DCE MRI were computed for the main mass. Parametric histogram analysis was obtained to evaluate changes of the internal tumor composition and for correlation with tumor response measured on CT. RESULTS: After three cycles of treatment, 11 patients showed decreased tumor size and a decreased value of all MR-derived pharmacokinetic parameters. Among these parameters, there was a significant decrease of mean and standard deviation of the K(trans) histogram as well as a decrease of mean of the k(ep) histogram (P < 0.05). Tumors with larger mean values of rate constant k(ep) (P < 0.0001) and smaller standard deviation of volume of extravascular extracellular space fraction v(e) (P < 0.0001) on histograms before chemotherapy were considered predictors for treatment response. CONCLUSION: DCE MRI enables a functional analysis of the treatment response of NSCLC. MRI parametric histogram has the potential to predict early treatment response of combined bevacizumab, gemcitabine, and cisplatin. PMID- 22517424 TI - Revisiting the role of the granuloma in tuberculosis. AB - The granuloma, which is a compact aggregate of immune cells, is the hallmark structure of tuberculosis. It is historically regarded as a host-protective structure that 'walls off' the infecting mycobacteria. This Review discusses surprising new discoveries--from imaging studies coupled with genetic manipulations--that implicate the innate immune mechanisms of the tuberculous granuloma in the expansion and dissemination of infection. It also covers why the granuloma can fail to eradicate infection even after adaptive immunity develops. An understanding of the mechanisms and impact of tuberculous granuloma formation can guide the development of therapies to modulate granuloma formation. Such therapies might be effective for tuberculosis as well as for other granulomatous diseases. PMID- 22517427 TI - Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration. AB - Data visualization is an essential component of genomic data analysis. However, the size and diversity of the data sets produced by today's sequencing and array based profiling methods present major challenges to visualization tools. The Integrative Genomics Viewer (IGV) is a high-performance viewer that efficiently handles large heterogeneous data sets, while providing a smooth and intuitive user experience at all levels of genome resolution. A key characteristic of IGV is its focus on the integrative nature of genomic studies, with support for both array-based and next-generation sequencing data, and the integration of clinical and phenotypic data. Although IGV is often used to view genomic data from public sources, its primary emphasis is to support researchers who wish to visualize and explore their own data sets or those from colleagues. To that end, IGV supports flexible loading of local and remote data sets, and is optimized to provide high performance data visualization and exploration on standard desktop systems. IGV is freely available for download from http://www.broadinstitute.org/igv, under a GNU LGPL open-source license. PMID- 22517426 TI - Motif discovery and transcription factor binding sites before and after the next generation sequencing era. AB - Motif discovery has been one of the most widely studied problems in bioinformatics ever since genomic and protein sequences have been available. In particular, its application to the de novo prediction of putative over represented transcription factor binding sites in nucleotide sequences has been, and still is, one of the most challenging flavors of the problem. Recently, novel experimental techniques like chromatin immunoprecipitation (ChIP) have been introduced, permitting the genome-wide identification of protein-DNA interactions. ChIP, applied to transcription factors and coupled with genome tiling arrays (ChIP on Chip) or next-generation sequencing technologies (ChIP Seq) has opened new avenues in research, as well as posed new challenges to bioinformaticians developing algorithms and methods for motif discovery. PMID- 22517428 TI - Bent spine syndrome: a phenotype of dysferlinopathy or a symptomatic DYSF gene mutation carrier. PMID- 22517429 TI - Proteasome inhibitor interacts synergistically with autophagy inhibitor to suppress proliferation and induce apoptosis in hepatocellular carcinoma. AB - BACKGROUND: The ubiquitin-proteasome system and autophagy-lysosome system are 2 major protein degradation pathways in eukaryotic cells, which are tightly linked to cancer. Proteasome inhibitors have been approved in clinical use against hematologic malignancies, but their application in solid tumors is uncertain. Moreover, the role of autophagy after proteasome inhibition is controversial. METHODS: Two proteasome inhibitors, 2 autophagy inhibitors, and 3 hepatocellular carcinoma (HCC) cell lines were investigated in the current study. In vitro, cell proliferation was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay, cell apoptosis was evaluated by flow cytometry analysis of annexin-V/propidium iodide staining, and autophagy was evaluated by green fluorescent protein-light chain 3 (GFP-LC3) redistribution and LC3 Western blot analysis. In vivo, Ki-67 staining was used to detect cell proliferation, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining was used to detect apoptosis, and electron microscopy and p62 immunohistochemical staining were used to detect autophagy. RESULTS: Proteasome inhibitors suppressed proliferation, induced apoptosis, and activated autophagy in HCC cell lines in vitro, and autophagy exerted a protective role after proteasome inhibition. In vivo, anticancer effects of bortezomib on the MHCC-97H orthotopic model (human HCC cells) were different from the effects observed on the Huh-7 subcutaneous model (human HCC cells). The autophagy inhibitor chloroquine interacted synergistically with bortezomib to suppress proliferation and induce apoptosis in both tumor models. CONCLUSIONS: The current results indicated that simultaneous targeting of the proteasome and autophagy pathways may represent a promising method for HCC treatment. PMID- 22517430 TI - Convenient syntheses and photophysical properties of 1-thio- and 1-seleno-1,3 butadiene fluorophores in rigid dibenzobarrelene and benzobarrelene skeletons. PMID- 22517431 TI - Phosphoproteomic analysis of cells treated with longevity-related autophagy inducers. AB - Macroautophagy is a self-cannibalistic process that enables cells to adapt to various stresses and maintain energy homeostasis. Additionally, autophagy is an important route for turnover of misfolded proteins and damaged organelles, with important implications in cancer, neurodegenerative diseases and aging. Resveratrol and spermidine are able to induce autophagy by affecting deacetylases and acetylases, respectively, and have been found to extend the life-span of model organisms. With the aim to reveal the signaling networks involved in this drug-induced autophagic response, we quantified resveratrol and spermidine induced changes in the phosphoproteome using SILAC and mass spectrometry. The data were subsequently analyzed using the NetworKIN algorithm to extract key features of the autophagy-responsive kinase-substrate network. We found that two distinct sequence motifs were highly responsive to resveratrol and spermidine and that key proteins modulating the acetylation, phosphorylation, methylation and ubiquitination status were affected by changes in phosphorylation during the autophagic response. Essential parts of the apoptotic signaling network were subjected to post-translational modifications during the drug-induced autophagy response, suggesting potential crosstalk and balancing between autophagy and apoptosis. Additionally, we predicted cellular signaling networks affected by resveratrol and spermidine using a computational framework. Altogether, these results point to a profound crosstalk between distinct networks of post translational modifications and provide a resource for future analysis of autophagy and cell death. PMID- 22517432 TI - Monocytes, viruses and metaphors: hanging the Trojan horse. PMID- 22517433 TI - An evaluation of small-molecule p53 activators as chemoprotectants ameliorating adverse effects of anticancer drugs in normal cells. AB - Pharmacological activation of wild-type p53 has been found to protect normal cells in culture from cytotoxicity and nuclear aberrations caused by conventional cancer therapeutics. Hence, small-molecule p53 activators could have clinical benefits as chemoprotectants for cancer patients bearing p53-mutant tumors. We have evaluated 16 p53-based cyclotherapy regimes combining p53 activators tenovin 6, leptomycin B, nutlin-3 and low dose actinomycin D, with clinically utilized chemotherapeutic agents (S- and M-phase poisons), vinblastine, vinorelbine, cytosine arabinoside and gemcitabine. All the p53 activators induce reversible cell-cycle arrest in primary human fibroblasts and protect them from both S- and M-phase poisons. Furthermore, studies with p53-mutant cancer cell lines show that nutlin-3 and low dose actinomycin D do not affect the sensitivity of these cells to any of the chemotherapeutics tested. Thus, these two small molecules could be suitable choices for cyclotherapy regimes involving S- or M-phase poisons. In contrast, pre-incubation of p53-mutant cells with tenovin-6 or leptomycin B reduces the efficacy of vinca alkaloids, suggesting that these p53 activators could be effective as chemoprotectants if combined with S- but not M-phase poisons. Discrepancies were observed between the levels of protection detected immediately after treatment and following recovery in fresh medium. This highlights the need to assess both short- and long-term effects when evaluating compounds as potential chemoprotectants for cancer therapy. PMID- 22517434 TI - TORC1-mediated protein synthesis regulates cilia size and function: implications for organelle size control by diverse signaling cascades. PMID- 22517435 TI - Serum autoantibodies to pancreatic cancer antigens as biomarkers of pancreatic cancer in a San Francisco Bay Area case-control study. AB - BACKGROUND: Screening and early diagnosis tools are lacking for pancreatic adenocarcinoma; most patients are diagnosed with metastatic disease. Autoantibodies to tumor-associated antigens (TAAs) can be present months to years before diagnosis and hold promise as biomarkers for early detection. METHODS: TAAs to pancreatic cancer autoantibodies CTDSP1 (carboxy-terminal domain, RNA polymerase II, polypeptide A, small phosphatase 1), MAPK9 (mitogen-activated protein kinase 9), and NR2E3 (nuclear receptor subfamily 2, group E, member 3), which were identified as potentially promising biomarkers in exploratory studies, were evaluated in serum from participants (300 cases, 300 controls) in a population-based case-control pancreatic cancer study in the San Francisco Bay Area. Patients were identified through cancer registry rapid case ascertainment, newly diagnosed from 1995 to 1999 and followed up through 2008. Autoantibody levels were analyzed as continuous and grouped (quartiles) variables. Multivariable unconditional logistic regression was used to compute odds ratios (ORs) as estimates of autoantibody levels associated with disease status. Kaplan Meier product limit estimates and multivariable Cox proportional hazards regression were used to assess autoantibody levels associated with case survival duration. RESULTS: Cases had higher levels of CTDSP1 (P = .004), MAPK9 (P = .0002), and NR2E3 (P <= .0001) autoantibodies than controls (fourth vs first quartile: CTDSP1 OR = 1.7, MAPK9 OR = 2.5, NR2E3 OR = 4.0). High body mass index and tobacco use were associated with levels in controls but were not statistical confounders. High CTDSP1 levels were somewhat associated with better survival (hazard ratio = 0.77, P = .07). CONCLUSIONS: Combined with previous results, this study contributes evidence that cancer-related host immune-response factors may be useful diagnostic screening tools and prognostic indicators for pancreatic cancer. Further studies are needed to critically assess the value of autoantibody panels to TAAs in diagnostic screening, prognosis, and immunotherapy of pancreatic and other cancers. PMID- 22517436 TI - Chiral analysis by online coupling of reversed-phase liquid chromatography to gas chromatography and mass spectrometry. AB - Enantiomeric composition of selected chiral compounds present in complex mixtures is determined by using the online coupling of reversed-phase liquid chromatography (LC) to gas chromatography (GC) and mass spectrometry. Integration of sample preparation into GC analysis, in a completely automated way, is achieved by means of the effective clean-up resulting from both the LC fractionation step and the eluent elimination provided by the through oven transfer adsorption desorption system used for LC-GC interfacing. The possibilities of the technique are illustrated through some examples concerning the stereodifferentiation in essential oils of major and minor chiral compounds via LC-GC transfer of different volume fractions, ranging from 0.5 to 1.9 ml, which show the significance of the window size for the determination of enantiomeric profiles. PMID- 22517437 TI - Non-invasive prenatal diagnosis of beta-thalassemia and sickle-cell disease using pyrophosphorolysis-activated polymerization and melting curve analysis. AB - OBJECTIVE: The aim of this study was to develop a pyrophosphorolysis-activated polymerization (PAP) assay for non-invasive prenatal diagnosis (NIPD) of beta thalassemia major and sickle-cell disease (SCD). PAP is able to detect mutations in free fetal DNA in a highly contaminating environment of maternal plasma DNA. METHODS: Pyrophosphorolysis-activated polymerization primers were designed for 12 informative SNPs, genotyped by melting curve analysis (MCA) in both parents. The PAP assay was tested in a series of 13 plasma DNA samples collected from pregnant women. A retrospective NIPD was performed in a couple at risk for SCD. RESULTS: All PAP reactions were optimized and able to detect <3% target gDNA in a background of >97% wildtype gDNA. In all 13 cases, the paternal allele was detected by PAP in maternal plasma at 10 to 18 weeks of gestation. For the couple at risk, PAP showed presence of the normal paternal SNP allele in maternal plasma, which was confirmed by results of the chorionic villus sampling analysis. CONCLUSIONS: In contrast to other methods used for NIPD, the combined PAP and MCA analysis detecting the normal paternal allele is also applicable for couples at risk carrying the same mutation, provided that a previously born child is available for testing to determine the linkage to the paternal SNPs. PMID- 22517438 TI - New vessels after stroke: postischemic neovascularization and regeneration. AB - The formation of new blood vessels after acute ischemic stroke is one of the most promising approaches to future therapies in the emerging field of stroke medicine. Angiogenesis and postnatal vasculogenesis are the underlying mechanisms of the formation of new blood vessels. Bone marrow-derived endothelial progenitor cells (EPCs) are thought to play an important role in neovascularization and during the regenerative processes after a vascular injury as well as in the maintenance of endothelial integrity. This review summarizes possible mechanisms of angiogenesis, postischemic neovascularization and regeneration with a focus on the potential role of EPCs as a risk marker and as a therapeutic target in stroke medicine. PMID- 22517439 TI - Theoretical study of the reduction of uranium(VI) aquo complexes on titania particles and by alcohols. AB - To provide insights into the adsorption and photoreduction of uranium(VI) on TiO(2), we have studied the structural and electronic properties of uranium(VI) aquo complexes adsorbed on stoichiometric and defected TiO(2) surfaces and nanoparticles. Plane wave calculations with the pure PBE density functional and the PBE+U approach were used to study U(VI) complexes on a periodic rutile (110) slab. In addition, a nanoparticulate Ti(38)O(76) cluster was used to simulate anatase nanoparticles. The electronic structures of the adsorbed U(VI) complexes indicate that the photoreduction process is a consequence of the photocatalytic properties of TiO(2). The reduction of the adsorbed complexes can only occur if the energy of the incident photon exceeds the semiconductor band gap. The gap states induced by single or neighboring hydrogen atoms and oxygen vacancies at the rutile (110) surface cannot reduce adsorbed U(VI) complexes as the unoccupied 5f orbitals are found deeper in the conduction band. In the absence of a solid substrate, photoreduction proceeds by abstraction of a hydrogen atom from water or organic molecules present in solution. Photoreduction by chlorophenol results in lower product yield than reduction by aliphatic alcohols. This is because the triplet uranyl-chlorophenol complex is much more stable than similar complexes formed with methanol and ethanol. In the case of water, the hydroxyl photoproduct easily re-oxidizes the pentavalent species formed. In addition, it is easier for the triplet uranyl-water complex to decompose to the photoreactants. PMID- 22517440 TI - A platform for nursing research on spirituality and religiosity: definitions and measures. AB - Spirituality or religiousness is important across the health trajectory, from promoting health and preventing disease, to coping with illness and end of life. Research on the relationship of religiousness or spirituality to health spans more than one discipline and applies many definitions and measures. The purpose of this multidisciplinary work is to facilitate research by nurses who seek to investigate the relationship between health and religiousness or spirituality, and provide evidence-based guidance for nursing practice. Senior researchers summarize the history of inquiry on this topic, discuss particular and persistent challenges posed by definitions of religion and spirituality, describe selected measures that have enjoyed wide application, and make recommendations for consideration by nurse researchers. Use of existing knowledge to select variables, definitions, and measures, and to link research questions and findings to the larger body of current inquiry, will advance nursing practice closer to fulfilling Nightingale's ideals for effective care. PMID- 22517441 TI - Fall risk-relevant functional mobility outcomes in dementia following dyadic tai chi exercise. AB - Whether persons with dementia benefit from fall prevention exercise is unclear. Applying the Positive Emotion-Motivated Tai Chi protocol, preliminary findings concerning adherence and effects of a dyadic Tai Chi exercise program on persons with Alzheimer's disease (AD) are reported. Using pre/posttest design, 22 community-dwelling AD-caregiver dyads participated in the program. Fall-risk relevant functional mobility was measured using Unipedal Stance Time (UST) and Timed Up and Go (TUG) tests. Results showed that 19/22 (86.4%) AD patients completed the 16-week program and final assessment; 16/19 dyads (84.2%) completed the prescribed home program as reported by caregivers. UST adjusted mean improved from 4.0 to 5.1 (Week 4, p < .05) and 5.6 (Week 16, p < .05); TUG improved from 13.2 to 11.6 (Week 4, p < .05) and 11.6 (Week 16, p > .05) post intervention. Retaining dementia patients in an exercise intervention remains challenging. The dyadic Tai Chi approach appears to succeed in keeping AD-caregiver dyads exercising and safe. PMID- 22517442 TI - Introduction to special issue. PMID- 22517443 TI - The integrative effects of population density, photoperiod, temperature, and host plant on the induction of alate aphids in Schizaphis graminum. AB - The wheat aphid Schizaphis graminum (Rondani) displays wing dimorphism with both winged and wingless adult morphs. The winged morph is an adaptive microevolutionary response to undesirable environmental conditions, including undesirable population density, photoperiod, temperature, and host plant. Here we studied the integrative effects of population density, photoperiod, temperature, and host plant on the induction of alate aphids in S. graminum. The present results show that these four factors all play roles in inducing alate aphids in S. graminum but population density is the most important under almost all circumstances. In importance, population density is followed by photoperiod, host plant, and temperature, in that order. These results indicate that ambient environmental factors are highly important to stimulation of alate aphids in S. graminum, especially when population density reaches 64 individuals per leaf. PMID- 22517444 TI - 20-hydroxyecdysone upregulates apoptotic genes and induces apoptosis in the Bombyx fat body. AB - During insect metamorphosis, obsolete larval tissues are removed by programed cell death (PCD), mainly apoptosis and autophagy, which is directed by the molting hormone, 20-hydroxyecdysone (20E) and the 20E-triggered transcriptional cascade. Here, we investigated how 20E regulates apoptosis at the transcriptional level in the fat body of the silkworm, Bombyx mori. As detected by TdT-mediated dUTP Nick-End Labeling (TUNEL), apoptosis weakly occurred during the fourth larval molting, decreased to undetected levels during the early fifth instar, and gradually increased from day 4 of fifth instar to the wandering stage to the prepupal stage. Meanwhile, as determined by quantitative real-time PCR, eight genes involved in apoptosis, including Apaf-1, Nedd2 like1, Nedd2 like2, ICE1, ICE3, ICE5, Arp, and IAP, were highly expressed during molting and pupation, when the 20E titer is high. Injection of 20E into day 2 of fifth instar larvae significantly induced apoptosis and upregulated apoptotic genes after 6 h of treatment, and in vitro treatment of larval fat body tissues with 20E upregulated all the eight apoptotic genes. Moreover, RNAi knockdown of USP, a component of the 20E receptor complex EcR-USP, at the early-wandering stage reduced apoptosis and downregulated apoptotic genes after 24 h of treatment. Taken together, we infer that 20E upregulates apoptotic genes and thus induces apoptosis in the Bombyx fat body during larval molting and the larval-pupal transition. PMID- 22517445 TI - Cloning and expression pattern of heat shock protein genes from the endoparasitoid wasp, Pteromalus puparum in response to environmental stresses. AB - Six heat shock protein (HSP) genes from five HSP families in the parasitoid, Pteromalus puparum, were evaluated for their response to temperature (-15 ~ 3 degrees C , and 30 ~ 42 degrees C for 1 h), heavy metals (0.5 ~ 5 mM Cd(2+) and Cu(2+) for 24 h and 60 h), and starvation (24 h). Compared with other insect HSPs, all conserved motifs are found in P. puparum HSPs, and they are very similar to those of the recently sequenced ectoparasitoid Nasonia vitripennis. The temporal gene expression patterns indicated that these six HSP genes were all heat-inducible, of which hsp40 was the most inducible. The temperatures for maximal HSP induction at high and low temperature zone were 36 or 39 degrees C and -3 degrees C, respectively. In the hot zone, all HSP genes have the same initial temperature (33 degrees C) for up-regulation. Low concentrations of Cd(2+) for a short-term promoted the expression of all HSP genes, but not high concentrations or long-term treatments. Cu(2+) stress for 24 h increased expression of nearly all HSP. Four HSP genes changed after starvation. We infer that all six HSP genes are sensitive to heat. This may help understand the absence of P. puparum during the summer and winter. The expression profiles of six HSP genes in P. puparum under heavy metal stress indicates that HSP is a short-term response to cellular distress or injury induced by Cd(2+) and Cu(2+). PMID- 22517446 TI - Acute simultaneous multiple lacunar infarcts: a severe disease entity in small artery disease. AB - BACKGROUND: We hypothesized that acute simultaneous multiple lacunar infarcts (sMLI) may have different clinico-radiological characteristics compared to acute single lacunar infarcts (SLI). METHODS: We retrospectively reviewed stroke patients with sMLI or SLI in a consecutively collected stroke registry with a predefined long-term clinical follow-up. Clinical characteristics, including vascular risk factors, rheological profiles, premorbid functional status, and clinical outcome were evaluated. In addition, radiological characteristics, including white matter ischemic changes, previous lacunes, microbleeds, and concomitant intra- or extracranial arterial stenosis were evaluated. RESULTS: Of the 548 acute ischemic stroke patients, sMLI was found in 23 (13.5%) and SLI in 148 (86.5%). There was no difference in vascular risk factors and rheological profiles between the two groups, except for advanced age and more frequent previous history of stroke in the sMLI group. The sMLI group also showed more previous lacunes (p < 0.001) and microbleeds (p < 0.001). A cardioembolic or atherothrombotic stroke mechanism was rare in both groups. Recurrent strokes were more frequent in the sMLI group. CONCLUSIONS: The main pathophysiology of sMLI may be small artery disease. However, clinico-radiological characteristics suggest that sMLI may be a more severe entity of small artery disease compared to SLI. PMID- 22517447 TI - Organocatalysis with dendrimers. AB - This review gives an overview of the use of dendrimers and dendrons as organocatalysts, i.e. as catalysts in the absence of any metal. A large variety of dendrimeric structures have already been used for such a purpose, varying in size (generation), type and location (core or surface) of the organocatalytic entities, and overall chemical composition. The main types of reactions catalyzed concern bond formation (in particular C-C bonds), bond cleavage (in particular of esters), reductions and oxidations. In many cases, good to excellent enantioselectivities have been observed, in some cases associated with a positive dendritic effect (better properties when the generation of the dendrimer increases). Due to their large size compared to products, the dendrimeric organocatalysts can be often recovered and reused several times. PMID- 22517448 TI - Tetraferrocenylporphyrins as active components of self-assembled monolayers on gold surface. AB - Novel tetraferrocenylporphyrins-containing self-assembled monolayers were prepared employing two different approaches. Self-assembled monolayers were characterized using UV-Vis spectroscopy and cyclic voltammetry (CV) whereas their photoelectrochemical properties were investigated by photocurrent generation (PG) experiments. PMID- 22517449 TI - Regression of cardiac hypertrophy in cyp1a1ren-2 transgenic rats. AB - PURPOSE: To evaluate the usefulness of the cyp1a1ren-2 transgenic rat model of inducible hypertension for studies of the development and regression of cardiac hypertrophy. MATERIALS AND METHODS: Cyp1a1ren-2 rats received a diet containing 0% or 0.167% indole-3-carbinonl (I3C) for 4 weeks to induce hypertension. Cardiac magnetic resonance imaging (MRI) at 7 T was performed every second week for 10 weeks to measure left ventricular mass and the ejection fraction. Concomitantly, in six cyp1a1ren-2 rats blood pressure was recorded telemetrically. RESULTS: Plasma prorenin concentrations rose from 138 +/- 38 to 15,490 +/- 3990 ng/angiotensin I/mL/h (P < 0.001) in I3C-treated transgenic rats and returned to basal levels after cessation of I3C. Mean blood pressure increased to a plateau of 169 +/- 11 mmHg by the second week of induction. After cessation of I3C (day 28), arterial pressure dropped to values slightly below those prior to induction within 4 days (basal: 106 +/- 7 mmHg, day 32: 103 +/- 21 mmHg; NS). At day 28, left ventricular mass was increased by 39% vs. 4% in controls (P < 0.001) without changes of the ejection fraction. Cardiac hypertrophy was completely reversed at day 70, as evaluated by MRI. CONCLUSION: The cyp1a1ren-2 transgenic rat is a useful model to study reversal and healing in the absence of surgical interventions. PMID- 22517450 TI - Development of a substance abuse program for opioid-dependent nonurban pregnant women improves outcome. AB - BACKGROUND: The goal of this study was to determine whether improved access to medication assisted therapy in the general population, with improved coordination of ancillary services for pregnant women, improved perinatal outcomes in a nonurban area. METHODS: The cohort of women treated for opioid dependence during pregnancy with medication-assisted therapy and delivered at a single institution between 2000 and 2006 were retrospectively identified (n = 149 women; n = 151 neonates). Access to opioid agonist therapy for the general population was determined as the combined number of available treatment positions for medication assisted therapy. Treatment during pregnancy (interim substitution therapy vs opioid treatment program) and pregnancy outcomes were noted from chart review. The primary outcome of trend of prenatal care indices and newborn birth weight over time was determined by Kendall's tau. RESULTS: As access to treatment in the general population expanded from 2000 to 2006, the number of women receiving treatment increased, the proportion of women receiving interim substitution therapy decreased (P < 0.001), gestational age at the initiation of treatment decreased (P < 0.001), and the proportion of women receiving treatment before pregnancy increased (P < 0.001). Infants delivered to mothers in a treatment program had improved birth weight z score compared with those receiving interim substitution therapy (P = 0.007). The proportion of infants discharged to the care of the mother and remaining in maternal care at 1 year improved both over time (P = 0.03; P = 0.004) and with treatment within a treatment program (P < 0.001; P = 0.004). CONCLUSIONS: Improved access to opioid agonist treatment programs for the general population in nonurban areas improves perinatal outcome and retention of maternal guardianship. PMID- 22517468 TI - Thyroid cancer incidence by histological type and related variants in a mildly iodine-deficient area of Northern Italy, 1998 to 2009. AB - BACKGROUND: The incidence of thyroid cancer is increasing in several countries. However, the issue of whether this applies to all different histological types and related variants is poorly addressed. METHODS: All incident thyroid cancers diagnosed between 1998 and 2009 in a mildly iodine-deficient area in northern Italy were derived from a population-based tumor registry. Stage of disease, size of the tumor, focality, and histological variants were recorded from a review of pathology reports and slides. The mean annual increase (MAI) of the standardized incidence rate was calculated over the entire 12-year period of observation and a standardized rate ratio was evaluated to compare the mean standardized incidence between 2 periods of 6 years each (1998-2003 vs 2004-2009). RESULTS: In total, 980 cases were considered. An increase in the incidence trend for all thyroid tumors was demonstrated; the increase was found to be continuous from 1998 to 2002 but not afterward. The cancer incidence increased in both male and female subjects. Papillary thyroid carcinoma (PTC), the follicular variant of PTC, the tall cell variant of PTC (TCV-PTC), and Hurthle cell carcinoma (HC) showed the most relevant changes in incidence whereas follicular carcinoma was not found to be significantly affected. TCV-PTC was the only histological type to demonstrated a significant (P < .01) proportional increase in the second 6-year period of observation. Only TCV-PTC and HC were found to display a significant MAI after 2002. CONCLUSIONS: The incidence of thyroid cancer has increased within the last decade, an increase that is accounted for mostly by differentiated tumors. The most significant increases were documented for aggressive variants of basic histotypes. PMID- 22517469 TI - Reversible 1,4-insertion of pyridine into a highly polar metal-carbon bond: effect of the second metal. PMID- 22517470 TI - Evaluation of "click" binaphthyl chiral stationary phases by liquid chromatography. AB - Two "click" binaphthyl chiral stationary phases were synthesized and evaluated by liquid chromatography. Their structures incorporate S-(-)-1,1'-binaphthyl moiety as the chiral selector and 1,2,3-triazole ring as the spacer. These chiral stationary phases (CSPs) allowed the efficient resolution for a wide range of racemic BINOL derivatives, particularly for nonpolar diether derivatives and 3 phenyl indolin-2-one analogs. The chromatographic data showed that the pi-pi interaction was crucial for enantiorecognition of these CSPs. Loss of enantioselectivity observed on CSP3, which are lacking the triazole ring linkage, indicated that the triazole ring linkage took part in the enantioseparation process, although it was remote from the chiral selector of the CSP. The substitution of the phenyl group at 6 and 6' positions can significantly improve the separation ability of the CSP. The chiral recognition mechanism was also investigated by tracking the elution orders and studying the thermodynamic parameters. PMID- 22517471 TI - High frame rate retrospectively triggered Cine MRI for assessment of murine diastolic function. AB - To assess left ventricular (LV) diastolic function in mice with Cine MRI, a high frame rate (>60 frames per cardiac cycle) is required. For conventional electrocardiography-triggered Cine MRI, the frame rate is inversely proportional to the pulse repetition time (TR). However, TR cannot be lowered at will to increase the frame rate because of gradient hardware, spatial resolution, and signal-to-noise limitations. To overcome these limitations associated with electrocardiography-triggered Cine MRI, in this paper, we introduce a retrospectively triggered Cine MRI protocol capable of producing high-resolution high frame rate Cine MRI of the mouse heart for addressing left ventricular diastolic function. Simulations were performed to investigate the influence of MRI sequence parameters and the k-space filling trajectory in relation to the desired number of frames per cardiac cycle. An optimized protocol was applied in vivo and compared with electrocardiography-triggered Cine for which a high-frame rate could only be achieved by several interleaved acquisitions. Retrospective high frame rate Cine MRI proved superior to the interleaved electrocardiography triggered protocols. High spatial-resolution Cine movies with frames rates up to 80 frames per cardiac cycle were obtained in 25 min. Analysis of left ventricular filling rate curves allowed accurate determination of early and late filling rates and revealed subtle impairments in left ventricular diastolic function of diabetic mice in comparison with nondiabetic mice. PMID- 22517472 TI - New insight into daylight photocatalysis of AgBr@Ag: synergistic effect between semiconductor photocatalysis and plasmonic photocatalysis. AB - Noble metal nanoparticles (NPs) are often used as electron scavengers in conventional semiconductor photocatalysis to suppress electron-hole (e(-)-h(+) ) recombination and promote interfacial charge transfer, and thus enhance photocatalytic activity of semiconductors. In this contribution, it is demonstrated that noble metal NPs such as Ag NPs function as visible-light harvesting and electron-generating centers during the daylight photocatalysis of AgBr@Ag. Novel Ag plasmonic photocatalysis could cooperate with the conventional AgBr semiconductor photocatalysis to enhance the overall daylight activity of AgBr@Ag greatly because of an interesting synergistic effect. After a systematic investigation of the daylight photocatalysis mechanism of AgBr@Ag, the synergistic effect was attributed to surface plasmon resonance induced local electric field enhancement on Ag, which can accelerate the generation of e(-) h(+) pairs in AgBr, so that more electrons are produced in the conduction band of AgBr under daylight irradiation. This study provides new insight into the photocatalytic mechanism of noble metal/semiconductor systems as well as the design and fabrication of novel plasmonic photocatalysts. PMID- 22517473 TI - Recurrence of myocarditis after mesalazine treatment for ulcerative colitis: a case report. PMID- 22517474 TI - Cooperative nucleophilic-electrophilic organocatalysis by ionic liquids. AB - The anionic and the cationic partners of ionic liquids may act cooperatively and independently as nucleophilic and electrophilic catalysts. This ambiphilic propensity was demonstrated by kinetically discriminating the contributions of the anion (nucleophilic catalyst) and of the cation (electrophilic catalyst) to the solvent-free Baylis-Hillman dimerization of cyclohexenone catalysed by ionic liquids. PMID- 22517475 TI - Adsorption of organic molecules on rutile TiO2 and anatase TiO2 single crystal surfaces. AB - The interaction of organic molecules with titanium dioxide surfaces has been the subject of many studies over the last few decades. Numerous surface science techniques have been utilised to understand the often complex nature of these systems. The reasons for studying these systems are hugely diverse given that titanium dioxide has many technological and medical applications. Although surface science experiments investigating the adsorption of organic molecules on titanium dioxide surfaces is not a new area of research, the field continues to change and evolve as new potential applications are discovered and new techniques to study the systems are developed. This tutorial review aims to update previous reviews on the subject. It describes experimental and theoretical work on the adsorption of carboxylic acids, dye molecules, amino acids, alcohols, catechols and nitrogen containing compounds on single crystal TiO(2) surfaces. PMID- 22517476 TI - Integrating the Institute of Medicine future of nursing report into the American Association of Neuroscience Nurses strategic plan. PMID- 22517477 TI - Free-breathing 3D whole-heart black-blood imaging with motion sensitized driven equilibrium. AB - PURPOSE: To assess the efficacy and robustness of motion sensitized driven equilibrium (MSDE) for blood suppression in volumetric 3D whole-heart cardiac MR. MATERIALS AND METHODS: To investigate the efficacy of MSDE on blood suppression and myocardial signal-to-noise ratio (SNR) loss on different imaging sequences, seven healthy adult subjects were imaged using 3D electrocardiogram (ECG) triggered MSDE-prep T(1) -weighted turbo spin echo (TSE), and spoiled gradient echo (GRE), after optimization of MSDE parameters in a pilot study of five subjects. Imaging artifacts, myocardial and blood SNR were assessed. Subsequently, the feasibility of isotropic spatial resolution MSDE-prep black blood was assessed in six subjects. Finally, 15 patients with known or suspected cardiovascular disease were recruited to be imaged using a conventional multislice 2D double inversion recovery (DIR) TSE imaging sequence and a 3D MSDE prep spoiled GRE. RESULTS: The MSDE-prep yielded significant blood suppression (75%-92%), enabling a volumetric 3D black-blood assessment of the whole heart with significantly improved visualization of the chamber walls. The MSDE-prep also allowed successful acquisition of black-blood images with isotropic spatial resolution. In the patient study, 3D black-blood MSDE-prep and DIR resulted in similar blood suppression in left ventricle and right ventricle walls but the MSDE-prep had superior myocardial signal and wall sharpness. CONCLUSION: MSDE prep allows volumetric black-blood imaging of the heart. PMID- 22517478 TI - Utility of serum tumor markers during surveillance for stage I seminoma. AB - BACKGROUND: The serum tumor markers alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (HCG), and lactate dehydrogenase (LDH) are often measured as part of surveillance protocols in patients with stage I seminoma. In this study, the authors evaluated the utility of routine measurement of these markers in the detection of disease relapse. METHODS: Data were gathered from a prospectively maintained database of patients who underwent surveillance for stage I testicular seminoma diagnosed between 1982 and 2005 at Princess Margaret Hospital. Patients were followed on a predefined schedule with physical examination (PE), serum tumor markers, abdominopelvic computed tomography, and chest x-rays. The records of patients who relapsed were examined for details of imaging and serum tumor markers throughout the period of follow-up until the time of relapse. RESULTS: Of the 527 patients who were managed by surveillance, 75 patients (14%) relapsed at a median follow-up of 72 months. Of these, 65 patients relapsed within the first 3 years and had routine serum tumor markers measured. In total, 11 patients had abnormal tumor markers at the time of relapse (AFP, 0 patients; HCG, 6 patients; LDH, 4 patients; and HCG and LDH, 1 patient). Only 1 patient had an elevated tumor marker (LDH) before relapse, as defined by an abnormal imaging study (n = 64) or physical examination (n = 1), for which the treatment and outcome were not affected. CONCLUSIONS: Serum tumor marker levels did not aid in the early diagnosis of disease relapse in patients with stage I seminoma who were managed with surveillance. The current results indicated that routine measurement of serum tumor markers can be discontinued safely in seminoma surveillance schedules. PMID- 22517479 TI - Electronic structures of one-dimensional metal-molecule hybrid chains studied using scanning tunneling microscopy and density functional theory. AB - The electronic structures of self-assembled hybrid chains comprising Ag atoms and organic molecules were studied using scanning tunneling microscopy (STM) and spectroscopy (STS) in parallel with density functional theory (DFT). Hybrid chains were prepared by catalytic breaking of Br-C bonds in 4,4"-dibromo-p terphenyl molecules, followed by spontaneous formation of Ag-C bonds on Ag(111). An atomic model was proposed for the observed hybrid chain structures. Four electronic states were resolved using STS measurements, and strong energy dependence was observed in STM images. These results were explained using first principles calculations based on DFT. PMID- 22517480 TI - Electronic monitoring improves brace-wearing compliance in patients with adolescent idiopathic scoliosis: a randomized clinical trial. AB - STUDY DESIGN: Randomized controlled trial. OBJECTIVE: To assess whether monitoring increases brace-wearing compliance in patients with adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: Noncompliance is a barrier to brace treatment of AIS. Studies have demonstrated that monitoring improves medication compliance; however, this has not been investigated in spinal braces. METHODS: Twenty-one patients (mean age = 12.4 +/- 2.0 years) with AIS were prescribed treatment with a custom-made Thoraco-Lumbo-Sacral-Orthosis for 18 hours a day using a standardized script. Before beginning treatment, 10 patients were randomized to be informed that their compliance was monitored, whereas 11 patients were unaware. Compliance was measured via a temperature probe embedded within the Thoraco-Lumbo-Sacral-Orthosis hidden from view. RESULTS: Patients who were notified that they had a monitor in their brace demonstrated significantly increased compliance during the first 14 weeks of treatment compared with those who were uninformed (85.7% vs. 56.5%, P = 0.029), corresponding to a mean difference of 5.24 hours of daily brace wear. CONCLUSION: Electronic monitoring can improve compliance with orthoses in patients with spinal deformity during a short observation period. PMID- 22517481 TI - Validity and reliability of an adapted Thai version of Scoliosis Research Society 22 questionnaire for adolescent idiopathic scoliosis. AB - STUDY DESIGN: Cross-sectional observational study to investigate psychometric properties of an adapted Thai version of the refined Scoliosis Research Society 22 (SRS-22) questionnaire. OBJECTIVE: To evaluate the reliability and validity of the adapted Thai version of the refined SRS-22 questionnaire. SUMMARY OF BACKGROUND DATA: The SRS-22 questionnaire is a valid instrument for assessing the health-related quality of life for patients with adolescent idiopathic scoliosis. Recently, the questionnaire has been translated and validated in many languages for non-English-speaking countries. METHODS: Translation/retranslation of the English version of the SRS-22 was conducted, and the cross-cultural adaptation process was performed. The Thai version SRS-22 and previously validated Thai version Short-Form survey version 2.0 (SF-36V2) questionnaires were administered to 77 patients with adolescent idiopathic scoliosis who had surgical treatment. Fifty-eight patients (52 adolescent girls) had filled out the first set of questionnaires. Thirty patients of the first-time responders completed the second set of questionnaires. The mean age at the time of operation was 14.6 years and the mean age at the time of the final follow-up was 18.7 years. The mean preoperative scoliosis curve magnitude was 55.4 degrees (range, 30 degrees -95 degrees ) and postoperative curve magnitude was 20.1 degrees (range, 0 degrees 60 degrees ). Internal consistency was determined with Cronbach alpha coefficient. Intraclass correlation coefficient was used for test-retest reliability. Concurrent validity was evaluated by comparing SRS-22 domains with relevant domains in the SF-36V2 questionnaire, using the Pearson correlation coefficient. RESULTS: The mean overall Cronbach alpha coefficient of the adapted Thai version SRS-22 was 0.76. The 2 of corresponding domains (mental health = 0.80 and self-image = 0.83) had satisfactory internal consistency and the remaining domains (pain = 0.78; function/activity = 0.74; and satisfaction = 0.76) were good. The intraclass correlation coefficient for 5 domains was ranged from 0.79 to 0.90, which demonstrated the satisfactory test/retest reproducibility. The concurrent validity, determined by the Pearson correlation coefficient between SRS-22 and SF-36V2 domains, had a good correlation for 15 relevant comparisons (r = 0.50-0.75). CONCLUSION: The adapted Thai version of the SRS-22 questionnaire had validity and reliability, which can be used to assess the outcome of treatment among Thai-speaking patients with adolescent idiopathic scoliosis. PMID- 22517482 TI - Midline anterior approach from the right side to the lumbar spine for interbody fusion and total disc replacement: a new mobilization technique of the vena cava. AB - STUDY DESIGN: Prospective study. OBJECTIVE: To describe a midline anterior approach to the lumbar spine from the right side, below the aortic bifurcation to L5-S1, and by mobilizing the vena cava from right to left between L2 and L5. Feasibility and complication rate related to the approach have been studied. SUMMARY OF BACKGROUND DATA: Midline anterior approach to the lumbar spine has developed during these last years, mainly for interbody fusion and disc arthroplasty surgery. This retroperitoneal approach is well described in publications and classically made from the left side. Major complications associated with the approach are known: retrograde ejaculation, venous injuries, and arterial thrombosis. METHODS: A total of 469 patients were included in a prospective study between August 2003 and November 2010, either for interbody fusion by anterior approach or for total disc replacement, on one or several levels between L2-L3 and L5-S1. RESULTS: On the 154 patients who had a mobilization of the vena cava, no injury occurred. Only 4 major venous injuries occurred. There was no arterial complication, and the oxygen saturation signal was interrupted in only 1 case. No case of retrograde ejaculation was found. CONCLUSION: The midline anterior retroperitoneal approach from the right side is a safe alternative compared with the classical approach from the left side. The low rate of venous injury is explained by the sidewall thickness of the vena cava compared with the left iliac vein sidewall. Contrary to what happens by left sided approach, the vascular retraction required for access to L4-L5 and above does not lead to arterial occlusion and therefore diminishes the risk in atheromatous patients. The absence of retrograde ejaculation confirms previous studies conducted on the left anastomosis of the superior hypogastric plexus, suggesting that its approach and mobilization by the left side are delicate. PMID- 22517484 TI - Clinical significance of SOD2 and GSTP1 gene polymorphisms in Chinese patients with gastric cancer. AB - BACKGROUND: Excessive reactive oxygen species (ROS) accumulation is a common phenomenon in carcinogenesis. However, the rationale behind ROS involvement in gastric cancer is unclear. In this study, the authors investigated the clinical significance of the single nucleotide polymorphisms (SNPs) of 2 ROS metabolic process-related genes: superoxide dismutase 2 (SOD2) and glutathione S transferase pi (GSTP1). METHODS: In total of 929 patients with gastric cancer who had definitive clinicopathologic and follow-up data were collected. SOD2 reference SNP 4880 (rs4880) and GSTP1 rs1695 genotyping were examined in DNA samples extracted from paraffin-embedded tumor tissue. Association of the 2 SNPs with each clinicopathologic feature was analyzed using the Pearson chi-square test and the independent Student t test. Gastric cancer-specific overall survival was analyzed using Kaplan-Meier curves and log-rank tests. Multivariate Cox regression analyses of these SNPs also were performed. RESULTS: The SOD2 rs4880 CT + CC genotypes were significantly associated with a high level of lymph node metastasis (P = .023), whereas the GSTP1 rs1695 GA + GG genotypes were significantly associated with larger tumor size (>5 cm long; P = .048). Kaplan Meier and Cox regression data indicated that the SOD2 rs4880 CT + CC genotypes alone (hazard ratio, 1.299; 95% confidence interval, 1.053-1.603; P = .015) and the GSTP1 rs1695 GA + GG combined genotypes (hazard ratio, 1.496; 95% CI, 1.078 2.074; P = .016) were independent predictors for overall survival. CONCLUSIONS: The current data, based on a large cohort (n = 929) of Chinese patients with gastric cancer, suggested that the presence of SOD2 rs4880 and GSTP1 rs1695 genotypes may contribute to cancer progression as well as tumor aggressiveness. The components of ROS metabolism pathways may be potential therapeutic targets for this aggressive malignancy. PMID- 22517485 TI - A strategy for dramatically enhancing the selectivity of molecules showing aggregation-induced emission towards biomacromolecules with the aid of graphene oxide. AB - By intelligently utilizing the different interacting strengths between different moieties according to the displacement method, general biosensors with aggregation-induced emission (AIE) characteristics for biomacromolecules without selectivity were converted to excellent, highly selective probes for one specific biomacromolecule with the aid of graphene oxide (GO) in an aqueous medium. Importantly, thanks to the different interactions between the AIE molecule and biomacromolecules, just by simply changing the AIE molecule the sensing system could detect different types of biomacromolecules, thereby providing a new approach to the development of AIE-based sensors with high selectivity and sensitivity. More specifically, the complex of A(2)HPS?HCl-a derivative of hexaphenylsilone (HPS) functionalized by two amino (A(2)) groups (N(CH(2)CH(3))(3))-and GO only gives an "off-on" response to DNA, with a detection limit of 2.3 MUg mL(-1) toward DNA-CT (calf thymus); interestingly, the complex of TPE-N(2)C(4) (1,2-bis{4-[4-(N,N,N-triethylammonium)butoxy]phenyl}-1,2 diphenylethene dibromide) and GO could only detect the presence of bovine serum albumin (BSA), whereas other biomacromolecules, including DNA, RNA, and even other proteins have very little influence. PMID- 22517486 TI - Prenatal diagnosis of CHARGE syndrome by identification of a novel CHD7 mutation in a previously unaffected family. AB - CHARGE syndrome comprises ocular coloboma (C), heart malformation (H), choanal atresia (A), retardation of growth and/or anomalies of the central nervous system (R), genital anomalies (G) and ear anomalies (E). Prenatal diagnosis of CHARGE syndrome may be suspected in the presence of specific major anomalies at ultrasound examination. We describe prenatal diagnosis of CHARGE syndrome confirmed by identification of a mutation in CHD7 gene in a previously unaffected family. PMID- 22517487 TI - SPECIAL semi-LASER with lipid artifact compensation for 1H MRS at 7 T. AB - The measurement of full metabolic profiles at ultrahigh fields including low concentrated or fast-relaxing metabolites is usually achieved by applying short echo time sequences. One sequence beside stimulated echo acquisition mode that was proposed in this regard is spin echo full intensity-acquired localized spectroscopy. Typical problems that are still persistent for spin echo full intensity-acquired localized spectroscopy are B(1) inhomogeneities especially for signal acquisition with surface coils and chemical shift displacement artifacts due to limited B(1) amplitudes when using volume coils. In addition, strong lipid contaminations in the final spectrum can occur when only a limited number of outer volume suppression pulses is used. Therefore, an adiabatic short echo time (= 19 ms) spin echo full intensity-acquired localized spectroscopy semilocalization by adiabatic selective refocusing sequence is presented that is less sensitive to strong B(1) variations and that offers increased excitation and refocusing pulse bandwidths than regular spin echo full intensity acquired localized spectroscopy. Furthermore, the existence of the systematic lipid artifact is identified and linked to unfavorable effects due to the preinversion localization pulse. A method to control this artifact is presented and validated in both phantom and in vivo measurements. The viability of the proposed sequence was further assessed for in vivo measurements by scanning 17 volunteers using a surface coil and moreover acquiring additional volume coil measurements. The results show well-suppressed lipid artifacts, good signal-to-noise ratio, and reproducible fitting results in accordance with other published studies. PMID- 22517488 TI - Cognitive function among sons of women who worked in dentistry. AB - OBJECTIVE: Exposure to elemental mercury vapor can impair neurological function as it is neurotoxic in doses higher than usually found in dentistry. Little is known about the potential effects of fetal exposure to elemental mercury among offspring of female dental workers. We investigated cognitive function among offspring of women working in dentistry at the time of their pregnancy. METHODS: We compared results for cognitive function examinations taken by the majority of young men in Sweden at the time of compulsory military enlistment (age 17-18 years). Sons of female dentists (N=365) and dental nurses (N=3181) born during the 1960-1970s were compared with sons of female physicians (N=378) and assistant nurses (N=12 667). RESULTS: Analysis by linear regression showed that sons of dental workers had similar or higher cognitive function test results compared to their matched cohorts. CONCLUSION: We found no evidence of poorer cognitive function among male offspring of female dentists or dental nurses. PMID- 22517489 TI - Impact of progression of Parkinson's disease on drooling in various ethnic groups. AB - BACKGROUND/AIMS: Drooling or sialorrhea is a common non-motor symptom of Parkinson's disease (PD), and is reported by 35-75% of patients. Drooling is primarily due to impaired swallowing rather than hypersecretion of saliva. In this study, we examined the prevalence of drooling in PD and its relation to various factors such as age, stage of disease, gender and ethnicity. METHODS: A retrospective cohort chart analysis of 307 patients with idiopathic PD was conducted. These patients were seen in the Parkinson's Disease and Movement Disorders Clinic between 2005 and 2010. RESULTS: 123 (40%) patients exhibited drooling. No correlation between age and development of drooling was observed. However, gender was found to be a significant factor in developing sialorrhea. Males are twice as more likely to develop sialorrhea than females. In addition, drooling becomes more prevalent with disease progression; Hoehn and Yahr stage 4 patients being the most at risk. Ethnicity and immigration status have no relationship in developing drooling. CONCLUSIONS: Sialorrhea is seen in a significant number of PD patients. This study, to the best of our knowledge, is the most extensive clinical assessment of drooling in PD to date. PMID- 22517490 TI - Tuning the electronic and spin complexity in organic-inorganic molecular hybrid compounds. PMID- 22517491 TI - Structure-charge transport relationship of 5,15-dialkylated porphyrins. AB - 5,15-Dialkyl-substituted porphyrins that are symmetrically capped with ethyl (C(2)-Por), butyl (C(4)-Por) and hexyl (C(6)-Por) were synthesized and characterized. Molecular structure versus physical property relationship has been established through the analysis of planar charge transport using thin film transistor (TFT) structure. PMID- 22517492 TI - Substituent effect on the photophysical properties, electrochemical properties and electroluminescence performance of orange-emitting iridium complexes. AB - A series of bis(2-phenylbenzothiozolato-N,C(2'))iridium(acetylacetonate) [(bt)(2)Ir(acac)] derivatives, 1-4, were synthesized. Different substituents (CF(3), F, CH(3), OCH(3)) were introduced in the benzothiazole ring to study the substituent effect on the photophysical, electrochemical properties and electroluminescent performance of the complexes, and finally to select high performance phosphors for use in organic light-emitting diodes (OLEDs). All complexes 1-4 and (bt)(2)Ir(acac) are orange-emitting with tiny spectral difference, despite the variation of the substituent. However, the phosphorescent quantum yield increases with the electron-withdrawing ability of the substituent. This is in contrast to the previous observation that the substituent in the phenyl ring bonded to the metal center of (bt)(2)Ir(acac) not only affected the luminescent quantum efficiency but also greatly tuned the emission color of the complexes. Quantum chemical calculations revealed that the substituents in this position do not make a significant contribution to both the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO), which probably accounts for the fact that they do no strongly influence the bandgap and emission color of the complexes. Orange OLEDs were fabricated using 1 4 as doped emitters. The electron-withdrawing CF(3) and F groups favor improving the electroluminescence efficiency in comparison with that of the parent (bt)(2)Ir(acac), while electron-donating CH(3) and OCH(3) are not favorable for light emission. The complex 1 based OLED exhibited a maximum luminance efficiency of 54.1 cd A(-1) (a power efficiency of 24 lm W(-1) and an external quantum efficiency of 20%), which are among the best results ever reported for vacuum deposited orange OLEDs so far. PMID- 22517493 TI - The use of single-agent sorafenib in the treatment of advanced hepatocellular carcinoma patients with underlying Child-Pugh B liver cirrhosis: a retrospective analysis of efficacy, safety, and survival benefits. AB - BACKGROUND: This study explored the efficacy, tolerability, and survival benefits of using sorafenib in patients with Child-Pugh class B (CPB) cirrhosis. METHODS: Patients with advanced hepatocellular carcinoma who were treated with sorafenib at Queen Mary Hospital, Hong Kong, China, were analyzed retrospectively. Treatment outcomes were analyzed according to their respective Child-Pugh status. Patients with CPB disease were further divided into CPB7 (those with a score of 7) and CPB8-9 (a score of 8 or 9) subgroups. RESULTS: The baseline demographic parameters were comparable between 108 patients with Child-Pugh class A (CPA) disease and 64 CPB patients. Both clinical benefit rate (21.3% vs 32.4% vs 14.8%; P = .23) and progression-free survival (median: 3.2 months vs 3.2 months vs 2.3 months; P = .26) were similar among CPA, CPB7, and CPB8-9 groups, respectively. The overall survival was different among these groups (P = .002) and showed a trend toward worse outcome in CPB patients: the median was 6.1, 5.4, and 2.7 months among CPA, CPB7, and CPB8-9 patients, respectively. The commonest grade 3/4 adverse events were hand-foot syndrome (13.5%), diarrhea (9.9%), and rash (7.0%). Grade 3/4 leukopenia, thrombocytopenia, and anemia occurred in 2.9%, 5.3%, and 8.8% of the patients, respectively. Overall, the 3 groups of patients experienced similar incidence of most of these adverse events. Nonetheless, CPB patients experienced more anemia (P = .01), gastrointestinal bleeding (P = .02), and hepatic encephalopathy (P = .02). CONCLUSIONS: CPA and CPB patients tolerated sorafenib similarly and derived similar clinical and progression-free survival benefit. Among CPB patients, most benefits were observed in patients with a score of 7. Nevertheless, CPB patients were more susceptible to developing cirrhotic complications, and thus more vigilant surveillance is needed. PMID- 22517494 TI - Insight from molecular modelling: does the polymer side chain length matter for transport properties of perfluorosulfonic acid membranes? AB - We present a detailed analysis of the nanostructure of the short side chain (SSC) perfluorosulfonic acid membrane and its effect on H(2)O clustering, H(3)O(+) and H(2)O diffusion, and mean residence times of H(2)O near SO(3)(-) groups based on molecular dynamics simulations. We studied a range of hydration levels (lambda) at temperatures of 300 and 360 K, and compare the results to our findings in the benchmark Nafion(r) membrane. The water cluster diameter is nearly the same in the two membranes, while the extent of SO(3)(-) clustering is more in the SSC membrane. The calculated cluster diameter of about 2.4 nm is in excellent agreement with the recently proposed cylindrical water channel model of these membranes. The diffusion coefficients of H(2)O and H(3)O(+) are similar in SSC and Nafion membranes. Raising the temperature of the SSC membrane from 300 to 360 K provides a much bigger increase in proton vehicular diffusion coefficient (by a factor of about 4) than changing the side chain length. H(3)O(+) ions are found to exchange more frequently with SO(3)(-) partners at the higher temperature. Our key findings are that (a) the hydrophobic-hydrophilic separation in the two membranes is surprisingly similar; (b) at all hydration levels studied, the long side chain of Nafion is bent and is effectively equivalent to a short side chain in terms of extension into the water domain; (c) vehicular proton transport occurs mainly between SO(3)(-) groups; and (d) changing the size of the simulation cell does not change the results significantly. The simulations are validated in good agreement with the corresponding experimental values for the simulated membrane density and diffusion coefficients of H(2)O. PMID- 22517495 TI - Reproducibility of total choline/water ratios in mouse U87MG xenograft tumors by 1H-MRS. AB - PURPOSE: To evaluate the reproducibility of the measurement of the total choline to-water ratio, and the effect of repositioning the subject between scans, using (1) H-magnetic resonance spectroscopy in a mouse U87MG xenograft model. MATERIALS AND METHODS: In vivo single-voxel MR spectra at 7T from xenograft tumors were obtained using both a water-suppressed and a nonwater-suppressed point-resolved spectroscopy (PRESS) sequence. Reproducibility of the total choline/water ratio was evaluated under the conditions of immediate rescan with no change in position of the animal or voxel, immediate reposition, and reposition after 1 or 7 days. RESULTS: Total choline-to-water ratios in U87MG tumor xenografts averaged ~0.018 across all of the groups. The average percent difference between the two scans in each condition was always less than ~3.0%, and the coefficient of variation was always less than ~12%. Bias was unrelated to the testing condition and relatively negligible in magnitude (<3%). Due to heteroscedasticity in the ratios, the limits of agreement were calculated after log transformation of the data and ranged from ~12% when animals were maintained in the same position and immediately rescanned to ~52% when the two scans were 7 days apart. CONCLUSION: The total choline-to-water ratio provides a reproducible measure of choline containing metabolites in subcutaneous U87MG xenograft tumors in mice. PMID- 22517496 TI - Birth outcomes among military personnel after exposure to documented open-air burn pits before and during pregnancy. AB - OBJECTIVE: To examine birth outcomes in military women and men with potential exposure to documented open-air burn pits before and during pregnancy. METHODS: Electronic data from the Department of Defense Birth and Infant Health Registry and the Defense Manpower Data Center were used to examine the prevalence of birth defects and preterm birth among infants of active-duty women and men who were deployed within a 3-mile radius of a documented open-air burn pit before or during pregnancy. RESULTS: In general, burn pit exposure at various times in relation to pregnancy and for differing durations was not consistently associated with an increase in birth defects or preterm birth in infants of active-duty military personnel. CONCLUSIONS: These analyses offer reassurance to service members that burn pit exposure is not consistently associated with these select adverse infant health outcomes. PMID- 22517497 TI - The PTSD Checklist-Civilian Version: reliability, validity, and factor structure in a nonclinical sample. AB - OBJECTIVES: We examined the reliability, validity, and factor structure of the posttraumatic stress diorder (PTSD) Checklist-Civilian Version (PCL-C; Blanchard, Jones-Alexander, Buckley, & Forneris, 1996) among unselected undergraduate students. PARTICIPANTS: Participants were 471 undergraduate students at a large university in the Eastern United States and were not preselected based on trauma history or symptom severity. RESULTS: The PCL-C demonstrated good internal consistency and retest reliability. Compared with alternative measures of PTSD, the PCL-C showed favorable patterns of convergent and discriminant validity. In contrast to previous research using samples with known trauma exposure, we found support for both 1-factor and 2-factor models of PTSD symptoms. CONCLUSIONS: Overall, the PCL-C appears to be a valid and reliable measure of PTSD symptoms, even among nonclinical samples, and is superior to some alternative measures of PTSD. The factor structure among nonclinical samples may not reflect each of the PTSD symptom "clusters" (i.e., reexperiencing, avoidance/numbing, and hyperarousal). PMID- 22517498 TI - Test-retest reproducibility of a rapid method to measure brain oxygen metabolism. AB - Cerebral metabolic rate of oxygen (CMRO(2)) is an important index of tissue viability and brain function, but this parameter cannot yet be measured routinely on clinical scanners. Recently, a noninvasive technique was proposed which estimates global CMRO(2) by concomitantly measuring oxygen-extraction-fraction using T(2)-relaxation-under-spin-tagging MRI and pulse oximetry, and cerebral blood-flow using phase-contrast MRI. This study sought to establish a standard acquisition procedure for this technique and to evaluate its test-retest reproducibility in healthy subjects. Each subject was examined in five sessions and each session included two measurements. Intrasession, intersession, and intersubject coefficients of variation for CMRO(2) were found to be 3.84 +/- 1.44% (N = 7, mean +/- standard deviation), 6.59 +/- 1.56%, and 8.80% respectively. These reproducibility values were comparable or slightly superior to (15) O positron emission tomography (PET) results reported in the literature. It was also found that oxygen-extraction-fraction and cerebral-blood-flow tended to co-vary across sessions (P = 0.002) and subjects (P = 0.01), and their coefficients of variation were greater than that of CMRO(2). The simplicity and reliability features may afford this global CMRO(2) technique great potential for immediate clinical applications. PMID- 22517499 TI - The exohedral Diels-Alder reactivity of the titanium carbide endohedral metallofullerene Ti2C2@D(3h)-C78: comparison with D(3h)-C78 and M3N@D(3h)-C78 (M=Sc and Y) reactivity. AB - The chemical functionalization of endohedral (metallo)fullerenes has become a main focus of research in the last few years. It has been found that the reactivity of endohedral (metallo)fullerenes may be quite different from that of the empty fullerenes. Encapsulated species have an enormous influence on the thermodynamics, kinetics, and regiochemistry of the exohedral addition reactions undergone by these species. A detailed understanding of the changes in chemical reactivity due to incarceration of atoms or clusters of atoms is essential to assist the synthesis of new functionalized endohedral fullerenes with specific properties. Herein, we report the study of the Diels-Alder cycloaddition between 1,3-butadiene and all nonequivalent bonds of the Ti(2)C(2)@D(3h)-C(78) metallic carbide endohedral metallofullerene (EMF) at the BP86/TZP//BP86/DZP level of theory. The results obtained are compared with those found by some of us at the same level of theory for the D(3h)-C(78) free cage and the M(3)N@D(3h)-C(78) (M=Sc and Y) metallic nitride EMFs. It is found that the free cage is more reactive than the Ti(2)C(2)@D(3h)-C(78) EMF and this, in turn, has a higher reactivity than M(3)N@D(3h)-C(78). The results indicate that, for Ti(2)C(2)@D(3h) C(78), the corannulene-type [5,6] bonds c and f, and the type B [6,6] bond 3 are those thermodynamically and kinetically preferred. In contrast, the D(3h)-C(78) free cage has a preference for addition to the [6,6] 1 and 6 bonds and the [5,6] b bond, whereas M(3)N@D(3h)-C(78) favors additions to the [6,6] 6 (M=Sc) and [5,6] d (M=Y) bonds. The reasons for the regioselectivity found in Ti(2)C(2)@D(3h)-C(78) are discussed. PMID- 22517500 TI - Fetal pyelectasis and corkscrew-shaped ureters: an association observed in postmortem fetal imaging studies of osteochondrodysplasia and trisomy 21. PMID- 22517501 TI - Rotating night shift work and polymorphism of genes important for the regulation of circadian rhythm. AB - OBJECTIVE: People living in industrialized societies have developed specific working schedules during the day and at night, including permanent night shifts and rotating night shifts. The aim of this study was to examine the association between circadian polymorphisms and rotating night shift work. METHODS: This cross-sectional study comprised 709 nurses and midwives (348 current rotating and 361 current day workers). Genetic polymorphism of selected clock genes BMAL1 (rs2279287), CLOCK (rs1801260), PER1 (rs2735611), PER2 (rs2304672), PER3 (rs10462020), CRY1 (rs8192440), CRY2 (rs10838527, rs10838527) was determined using real-time polymerase chain reaction (PCR) assays. RESULTS: There were no differences in BMAL1, CLOCK, CRY2, PER1, PER2, and PER3 genotypes among nurses and midwives working rotating night and day shifts. The frequency of women with rare CRY1 TT genotype was higher in the group of rotating night shift than day workers (17.0% versus 13.9%, P=0.06). Moreover, CRY1 TT genotype was associated with the total rotating shift-work duration, compared to women rarely working night shifts. CONCLUSIONS: These results suggest that CRY1 (rs8192440) polymorphism may influence the adaptation to the rotating night shift work among nurses and midwives. PMID- 22517502 TI - Supramolecular arrangement of guanosine/5-guanosine monophosphate binary mixtures studied by methods of circular dichroism. AB - Self-assembly of molecules is one of the fundamental processes in biology and in supramolecular chemistry. Guanosine (Guo) and its derivatives are among the widely studied molecules because of self-assembly abilities. Their tetrameric associates are the nature of telomeric DNA, and furthermore they are fundamental building blocks of supramolecular reversible gels, which may arise in certain physical and chemical conditions. Although poorly soluble in water, Guo forms interesting structures with guanosine 5'-monophosphate salt (GMP) in the TRIS buffer. We used electronic circular dichroism and vibrational circular dichroism to describe the thermal response of gels formed by the Guo/GMP binary mixture. Using these complementary techniques suitable to study conformational changes of chiral compounds, we obtained information about the involvement of functional groups and weak interactions in the guanosine quartet (G(4)) and stacked G(4) structures. PMID- 22517503 TI - Mucosal healing and clinical remission in inflammatory bowel diseases: are we missing something here? PMID- 22517504 TI - A "smart" catalyst: sinter-resistant supported iridium clusters visualized with electron microscopy. PMID- 22517505 TI - Data for cancer comparative effectiveness research: past, present, and future potential. AB - Comparative effectiveness research (CER) can efficiently and rapidly generate new scientific evidence and address knowledge gaps, reduce clinical uncertainty, and guide health care choices. Much of the potential in CER is driven by the application of novel methods to analyze existing data. Despite its potential, several challenges must be identified and overcome so that CER may be improved, accelerated, and expeditiously implemented into the broad spectrum of cancer care and clinical practice. To identify and characterize the challenges to cancer CER, the authors reviewed the literature and conducted semistructured interviews with 41 cancer CER researchers at the Agency for Healthcare Research and Quality's Developing Evidence to Inform Decisions about Effectiveness (DEcIDE) Cancer CER Consortium. Several data sets for cancer CER were identified and differentiated into an ontology of 8 categories and were characterized in terms of strengths, weaknesses, and utility. Several themes emerged during the development of this ontology and discussions with CER researchers. Dominant among them was accelerating cancer CER and promoting the acceptance of findings, which will necessitate transcending disciplinary silos to incorporate diverse perspectives and expertise. Multidisciplinary collaboration is required, including those with expertise in nonexperimental data, statistics, outcomes research, clinical trials, epidemiology, generalist and specialty medicine, survivorship, informatics, data, and methods, among others. Recommendations highlight the systematic, collaborative identification of critical measures; application of more rigorous study design and sampling methods; policy-level resolution of issues in data ownership, governance, access, and cost; and development and application of consistent standards for data security, privacy, and confidentiality. PMID- 22517506 TI - Metal-mediated self-assembly of tetrapyridyl porphyrins by Na+ ions. AB - In the presence of the sodium salt of a bulky anion, which allows the solubility of Na(+) in low polarity solvents, various tetra(4-pyridyl)porphyrin derivatives can spontaneously self-assemble from CH(2)Cl(2) into supramolecular nanostructures exhibiting a long-range order, through the coordination of Na(+) ions by the pyridyl moieties at the macrocycle periphery. PMID- 22517507 TI - Elucidating the structure-dependent photocatalytic properties of Bi2WO6: a synthesis guided investigation. AB - Polycrystalline microspheres and single-crystalline microplates of Bi(2)WO(6) have been synthesized by ultrasonic spray pyrolysis. Herein, these materials are evaluated as photocatalysts for the visible light mediated degradation of rhodamine B, a model pollutant, and the results compared to those obtained with Bi(2)WO(6) prepared by traditional methods. The microplates, which displayed the best crystallinity and highest surface area, were anticipated to facilitate the greatest rate of dye photodegradation. However, the polycrystalline microspheres outperformed both the Bi(2)WO(6) microplates and traditional samples. To understand the origin of this result, the local and macroscale structures of the Bi(2)WO(6) samples were comprehensively characterized by spectroscopy techniques (diffuse reflectance, fluorescence, Raman, and X-ray photoelectron spectroscopy) as well as electron microscopy and diffraction. This analysis found that the enhanced performance of the Bi(2)WO(6) microspheres results from the expression of a hydrophilic surface, a low concentration of point defects, and a moderate surface area. This finding highlights the significant role synthesis plays in imparting structure and functionality to solid materials. PMID- 22517508 TI - Estimation of the timing of carotid artery flow using peripheral pulse wave-gated MRI. AB - PURPOSE: To investigate the relationship between peripheral pulse wave (PPW) gating and the carotid systolic pulse wave in a large clinical patient cohort, and to establish a process for correct estimation of delay time from PPW-gating to foot (ie, beginning) or peak times of carotid systolic pulse waves. MATERIALS AND METHODS: Subjects comprised 209 patients scanned using 3T magnetic resonance imaging (MRI) for PPW-gated phase contrast images at the common carotid artery. Stepwise multiple regression analysis was conducted for the relationship between foot or peak times and the following factors after excluding correlated factors with coefficients >=0.5: pulse rate (PR); systolic blood pressure; diastolic blood pressure; height; body weight; body mass index; Brinkman index; diabetes mellitus; hypertension; and hyperlipidemia. RESULTS: PR showed significant correlation with foot (r = -0.86, P < 0.001) and peak (r = -0.87, P < 0.001) times. The following equations were derived: foot time (msec) = -8.55 * PR + 993.1 and peak time (msec) = -9.21 * PR + 1142.3. No other factors showed significant correlations. CONCLUSION: PR was the only factor showing significant relationships to foot and peak times of carotid artery flow. The derived equations will facilitate various kinds of noncontrast MR acquisition with simple PPW-gating. PMID- 22517509 TI - Isotretinoin treatment induces oxidative toxicity in blood of patients with acne vulgaris: a clinical pilot study. AB - Acne vulgaris is the one of the most common skin diseases. Although isotretinoin (13-cis-retinoic acid) is an effective and well-tolerated medication, it has a wide range of side effects. Because the effects of isotretinoin on oxidant and antioxidant systems have not yet been clarified, we investigated plasma and erythrocyte antioxidant vitamins, lipid peroxidation (LP), reduced glutathione (GSH) and glutathione peroxidase (GSH-Px) values in patients with acne vulgaris before and after isotretinoin treatment. The study was performed on the blood plasma and erythrocytes of 31 acne vulgaris patients. Blood samples were taken from the patients before treatment and after isotretinoin (oral and 0.5-0.7 mg.kg(-1)) treatment for 2 months. Plasma amtioxidant vitamins, erythrocyte malondialdehyde, GSH and GSH-Px levels were measured. Plasma vitamin E (p < 0.001), lipid peroxidation (LP) and serum high-density lipoprotein cholesterol (p < 0.001) values were significantly lower in the treatment group than in the pre treatment group, although erythrocyte LP (p < 0.001), GSH (p < 0.01) and GSH-Px (p < 0.001), aspartate aminotransferase (p < 0.05), alanine aminotransferase (p < 0.05), density lipoprotein cholesterol (p < 0.001) and total cholesterol (p < 0.01) levels were significantly higher in the treatment group than in the pre treatment group. Vitamins A, C and beta-carotene concentrations did not change significantly between the two groups. In conclusion, the results of the current study indicate that isotretinoin treatment induces oxidative stress and liver damage by decreasing plasma vitamin E and increasing erythrocytes GSH-Px, GSH and liver enzyme values. PMID- 22517510 TI - Acetylcholinesterase inhibition, antioxidant, antiinflammatory, antimicrobial and phytochemical properties of Huernia hystrix. AB - Huernia species are typical famine-food plants consumed in southern Ethiopia. H. hystrix is a heavily exploited ethnomedicinal succulent plant traded in traditional medicine systems especially on South Africa's eastern seaboard. This study investigated the acetylcholinesterase (AChE) inhibition, antioxidant, antiinflammatory and antimicrobial properties of extracts obtained from the stems and roots of this plant. At the same concentration level (625.0, 312.5 or 156.3 ug/mL), the whole plant extract showed higher AChE inhibitory activity when compared with the stem and root extracts; a finding suggesting the presence of AChE inhibitors acting additively or synergistically in the whole plant extract. The roots showed strong antioxidant activity (in DPPH and beta-carotene assays) comparable to that of butylated hydroxytoluene (BHT), indicating the presence of potent antioxidant compound(s) that can be exploited as alternatives for use in the food and cosmetic industries and/or as nutraceuticals. All the petroleum ether (PE) (except root PE) and dichloromethane (DCM) extracts demonstrated good inhibitory activity (> 70%) in cyclooxygenase (COX-1 and COX-2) assays at a 0.25 ug/MUL concentration. Most of the extracts showed broad-spectrum inhibitory and lethal activities against the microorganisms used in this study. The observed biological activities might be due to the iridoid, phenolic and flavonoid contents of the plants. PMID- 22517511 TI - Identification of molecular target proteins in berberine-treated cervix adenocarcinoma HeLa cells by proteomic and bioinformatic analyses. AB - In this study, the apoptosis of HeLa cells induced by berberine was investigated. Fifty-one differentially expressed proteins were identified before and after berberine treatment by a proteomic method, which either interacted with each other directly or through one intermediate protein to form a connected protein interaction sub-network. Nine of them were selected and validated. Compared with the cells in the control group, the expressions of 14-3-3sigma and lamin-A/C of the cells treated by berberine for 48 h increased by 94.12 and 5.24 times, respectively, and the expressions of annexin A5, cytokeratin 17, prohibitin, heat shock cognate 71 kDa protein (HSPA8), programmed cell death 6 and vimentin decreased by 4.1, 1.34, 23.8, 11.85, 4.63 and 5.24 times, respectively. In addition, tubulin-beta decreased from 9537 to 6908 ng/L. Furthermore, the inverse dock program (INVDOCK) was used to predict the possible drug-target of berberine's anticancer activity, and the results showed that HSPA8 and annexin A5 might be the drug targets. This study suggests that the anticancer effect of berberine on HeLa cells was a complex process based on affecting multiple protein expression and acting on an interaction network. Our work could be helpful to elucidate the mechanism of berberine's anticancer activity on HeLa cells. PMID- 22517512 TI - Exciplex formation and energy transfer in a self-assembled metal-organic hybrid system. AB - Exciting assemblies: A metal-organic self-assembly of pyrenebutyric acid (PBA), 1,10-phenanthroline (o-phen), and Mg(II) shows solid-state fluorescence originating from a 1:1 PBA-o-phen exciplex. This exciplex fluorescence is sensitized by another residual PBA chromophore through an excited-state energy transfer process. The solvent polarity modulates the self-assembly and the corresponding exciplex as well as the energy transfer, resulting in tunable emission of the hybrid (see figure). PMID- 22517513 TI - The prevalence of obesity-related hypertension and risk for new vascular events in patients with vascular diseases. AB - Higher body weight is associated with an increased prevalence of vascular risk factors. Obesity leads to hypertension by various mechanisms, often referred to as obesity-related hypertension. Aim of the present study was to evaluate the prevalence and the vascular risk of the combination of obesity and hypertension in patients with vascular diseases. A cohort of patients with various clinical manifest vascular diseases (n = 4,868) was screened for vascular risk factors and followed (median follow-up 4.2 years) for the occurrence of vascular events (stroke, myocardial infarction, and vascular death). The prevalence of obesity was 18% (95% confidence interval (CI) 17-19%) and the prevalence of hypertension was 83% (95% CI 82-84%). The prevalence of the combination of obesity and hypertension was 16% (95% CI 15-17%). Patients with high blood pressure (BP) combined with a high weight (highest tertile systolic BP (SBP) in the highest tertile BMI) were not at higher risk for new vascular events (hazard ratios (HR) 1.29; 95% CI 0.89-1.88) or mortality (HR 1.18; 95% CI 0.81-1.73) compared to patients without high BP and high weight (patients in the lowest tertile of SBP in the lowest tertile of BMI). Patients with only high weight did not have an elevated risk either for vascular events (HR 1.34; 95% CI 0.91-1.98) or mortality (HR 1.22; 95% CI 0.81-1.83) compared to patients without high BP and high weight. The prevalence of the combination of hypertension and obesity is low in patients with vascular diseases and does not confer a higher risk for recurrent vascular diseases and mortality than each risk factor alone. PMID- 22517514 TI - Jetstream(r) atherectomy for subacutely or chronically occluded femoro-popliteal prosthetic bypass grafts: a report of three cases. AB - A failed infrainguinal bypass is associated with poor prognosis for the limb in question, particularly if the graft was initially placed for limb salvage. Revascularization of occluded grafts is an important but challenging issue. We present three patients with occluded femoro-popliteal graft in whom the Jetstream((r)) system was used successfully to perform thromboatherectomy. The Jetstream((r)) system is minimally invasive and avoids use of thrombolytic therapy and its associated costs and complications. The device seems to be highly effective in removing thrombus beyond the acute setting. PMID- 22517516 TI - Mitomycin C in the therapy of recurrent esophageal strictures: hype or hope? AB - INTRODUCTION: Esophageal strictures refractory to conservative treatment represent a major problem in children. The application of Mitomycin C to the site of stricture has been introduced, but the experience with this novel approach remains very limited. METHODS: Systematic review of publications on the topical application of Mitomycin C in children with persistent esophageal stricture. RESULTS: We identified 11 publications including 31 cases. The underlying cause of stricture was caustic ingestion in 19 (61.2%), esophageal surgery in 7 (22.6%), and others in 5 children (16.2%). The median age of the patients was 48 months (range 4 to 276 months). In the majority of cases cotton pledgets soaked in solution of Mitomycin C were applied endoscopically. Various other techniques such as drug-eluting stents were used. Mitomycin C was applied from 1 to 12 times within intervals from 1 to 12 weeks. The concentrations of Mitomycin C varied considerably between 0.1 and 1 mg/mL. After a mean follow-up time of 22 (6 to 60) months complete relief of symptoms was reported for 21 children (67.7%), and 6 (19.4%) had a partial relief. In four children (12.9%) Mitomycin C treatment failed. No direct or indirect adverse effects were reported. CONCLUSION: The short-term results of topical Mitomycin C application for refractory esophageal stricture reported in the literature are very encouraging. Prospective studies are mandatory to determine the optimal time points, dosage, and modalities of treatment before a recommendation can be given. PMID- 22517515 TI - MicroRNA target site polymorphisms in the VHL-HIF1alpha pathway predict renal cell carcinoma risk. AB - Renal cell carcinoma (RCC) accounts for ~4% of all human malignancies and is the 9th leading cause of male cancer death in the United States. The purpose of this study was to determine the effect of variation within microRNA (miRNA)-binding sites of genes in the VHL-HIF1alpha pathway on RCC risk. We identified 429 miRNA binding site single-nucleotide polymorphisms (SNPs) in 102 pathway genes and assessed 53 tagging-SNPs for 31 of these genes for risk in a case-control study consisting of 894 RCC cases and 1,516 controls. Results showed that five SNPs were significantly associated with RCC risk. The most significant finding was rs743409 in MAPK1. Under the additive model, the variant was associated with a 10% risk reduction (OR: 0.90, 95% CI, 0.77-0.98). Other significant findings were for SNPs in CDCP1, TFRC, and DEC1. Cumulative effects analysis showed that subjects carrying four or five unfavorable genotypes had a 2.14-fold increase in risk (95% CI, 1.03-4.43, P = 0.04) than those with no unfavorable genotypes. Potential higher-order gene-gene interactions were identified and categorized subjects into different risk groups. The OR of the high-risk group defined by two SNPs: CDCP1:rs6773576 (GG) and DEC1:rs10982724 (GG) was 4.46 times higher than that of low-risk reference group (95% CI, 1.31-15.08). Overall, our study provides the first evidence supporting a connection between miRNA-binding site SNPs within the VHL-HIF1alpha pathway and RCC risk. These novel genetic risk factors might help identify individuals at high risk to enable detection of tumors at an early, curable stage. PMID- 22517517 TI - Inguinal hernias associated with biliary atresia. AB - INTRODUCTION: Infants with biliary atresia (BA) develop a degree of hepatic fibrosis as a consequence of their cholangiopathy. Some of them present clinically evident ascites that might predispose to inguinal hernias. We aimed to investigate whether infants with BA have a higher incidence of inguinal hernias. METHODS: Single-center retrospective review of all BA infants diagnosed between January 2006 and December 2010. Infants with a clinical diagnosis of inguinal hernia were identified and compared with those without. Data were expressed as median (range) and compared with nonparametric statistical tests. p <= 0.05 was regarded as significant. RESULTS: A total of 123 infants underwent Kasai portoenterostomy (KP) during the period. Of these, 10 (8.1%) infants (7 boys) developed inguinal hernias (bilateral n = 4, right n = 5, left n = 1); 9 were repaired (at KP [n = 3] and post-KP [n = 6] at 15 [7 to 30] days) using nonabsorbable sutures, and 1 died before repair. There was no difference in median age at KP (66 vs. 58 days, p = 0.31); cytomegalovirus (IgM positive) status (p = 1.0); use of postoperative corticosteroids (p = 0.49); or ultimate need for liver transplant (p = 1.0). However, aspartate aminotransferase-to platelet ratio (surrogate marker of liver fibrosis) was higher in hernia infants (2.0 vs. 1.0; p = 0.02). Recurrence has not been identified at a follow-up of 27 months (4 to 55). CONCLUSIONS: This is the first report to suggest that BA infants have a high incidence of inguinal hernias, which seems related to degree of liver fibrosis at presentation and presumably degree of ascites and increased intra-abdominal pressure. PMID- 22517518 TI - The expression of vascular endothelial growth factor and its receptors in congenital bronchopulmonary cystic malformations. AB - BACKGROUND: Bronchopulmonary sequestration (BPS) and congenital cystic adenomatoid malformation (CCAM) represent rare hamartomatous abnormalities of the lung. Dysregulation of cytokines that influence pulmonary vasculogenesis and epithelial growth, both known to be altered in BPS and CCAM, may play a role in their pathogenesis. OBJECTIVE: We hypothesized that expression of vascular endothelial growth factor (VEGF) or its receptors might be altered in CCAM and BPS, possibly distinguishing CCAM from BPS, or from controls. METHODS: Lung biopsy specimens obtained from infants who had undergone surgery for BPS (n = 4) or CCAM (n = 5) within the first month of life and normal lung autopsy samples (n = 4) serving as controls were investigated immunohistochemically for the protein expression levels of VEGF and its corresponding receptors. RESULTS: VEGF, vascular endothelial growth factor receptor 1 (VEGFR1), vascular endothelial growth factor receptor 2 (VEGFR2), and vascular endothelial growth factor receptor 3 (VEGFR3) staining was detected in CCAM and BPS specimens, as well as in control samples. VEGFR2 expression increased from controls to CCAM and from CCAM to BPS, the difference between controls and BPS being significant. The expression of VEGF, VEGFR1, and VEGFR3 was similar among the three groups. Consistent with a possible involvement of VEGFR2 in altered vasculogenesis bronchiogenesis interaction, its expression was predominantly found in bronchial but not alveolar regions. CONCLUSIONS: The data suggest a possible role of VEGF VEGFR2 interaction in the pathogenesis of congenital bronchopulmonary cystic malformations. However, VEGFR2 does not represent a suitable histochemical marker to distinguish between BPS and CCAM. PMID- 22517519 TI - Closing the appendicular stump with a polymeric clip in laparoscopic appendectomy: analysis of 121 pediatric patients. AB - INTRODUCTION: The purpose of this study was to evaluate the technical feasibility and other advantages of closing the appendicular stump with a polymeric clip in laparoscopic appendectomy (LA). METHODS: In this study, 121 pediatric patients who underwent LA between July 2009 and July 2011 were included. Age and gender of the patients, the number of clips, operative time and length of hospitalization, complications, and follow-up periods were evaluated retrospectively. RESULTS: Of appendicular stump of a total of 121 patients who were underwent LA, 71 were closed with double polymeric clips and 50 were closed with a single polymeric clip. Patients were between the ages of 3 and 15 years (mean 8.3 years). Out of the 121 patients, 54 were female and 67 were male. The duration of the operation was ranged from 13 to 55 minutes (mean 28 minutes). Of these, 83 patients were discharged in less than 24 hours. The cost of a single clip was 10 USD. The follow-up period of patients were ranged between 1 and 23 months (mean 13 months). No operative or postoperative complications occurred depending on the application of the polymeric clip. CONCLUSION: LA using polymeric clip/s to close appendicular stump in children is a safe, feasible, and inexpensive method. PMID- 22517520 TI - The use of mouth brushings for screening girls who present with inguinal hernia for complete androgen insensitivity syndrome. AB - INTRODUCTION: Published guidance recommends that all girls with inguinal hernia should be screened for complete androgen insensitivity syndrome (CAIS). We report a novel, noninvasive screening technique. METHODS: Retrospective review of all girls undergoing inguinal herniotomy from April 2009 to October 2010. Those screened using the novel technique of extraction of Y chromosome specific DNA from a buccal mucosal sample obtained by mouth brushing are reported. RESULTS: A total of 29 girls were screened by mouth brushing at median age 2.9 years (range 29 days to 9.3 years). Of the 29 samples, 25 were adequate for DNA extraction; 4 were inadequate and screening was repeated (3 repeat mouth brushing, 1 perioperative blood test). Mouth brushing was well tolerated by children and acceptable to parents. A preoperative blood test was avoided in all girls who had a mouth brushing. None of the girls in this study had CAIS. Turn-around time for mouth brushing was mean 4.9 days compared with a minimum of 10 days for a karyotype. This technique is cheaper than a karyotype (L 87 vs. L 205). CONCLUSION: Extraction of Y chromosome specific DNA from a mouth brushing sample is effective for screening girls with inguinal hernia for CAIS. It is acceptable, cheaper, and quicker than alternatives. PMID- 22517521 TI - Prophylactic treatment with proton pump inhibitors in children operated on for oesophageal atresia. AB - INTRODUCTION: Oesophageal stricture is a frequent complication following repair of oesophageal atresia (EA). The aim of this study was to conduct a pre- and postintervention study and analyze the incidence of stricture formation and need for balloon dilatation after introducing prophylactic proton pump inhibitor (PPI) treatment. CHILDREN AND DESIGN: All children operated for EA during 2001 to 2009 (n = 39) were treated with prophylactic PPIs (PPI group) for at least 3 months postoperatively. The frequency of stricture formation in the anastomosis and need for balloon dilatation was registered. A previously published group of children (n = 63) operated for EA during 1983 to 1995 not treated with prophylactic PPI was used as control group. Duration of follow-up time in the PPI group was equal to the one in the control group, and set to 1 year after the last oesophageal dilatation procedure. RESULTS: The PPI and control group were comparable regarding patient characteristics, gestational age and birth weight, prevalence of chromosomal aberration, and VACTERL (vertebral, and, cardiac, tracheal, esophageal, renal, limb) malformations. Also, survival rate and prevalence of surgery were similar in both groups. Mortality was mainly determined by associated malformations. The dilatation frequency needed in each child did not differ between the two groups. The prevalence of stricture formation was 42% in the control group compared with 56% in the PPI group, p = 0.25. Number of dilatations needed varied between 1 and 21, with a median value of 3 and 4, respectively, for the PPI and the control group. The children in the PPI group were significantly younger at the time of dilatation. This difference reflects a change in policy and increased experience. CONCLUSION: The incidence of anastomotic stricture following repair for esophageal atresia remains high also after introduction of PPI. The results cannot support that prophylactic treatment with PPI prevent anastomotic stricture formation. PMID- 22517522 TI - Treatment of benign bone defects in children with silicate-substituted calcium phosphate (SiCaP). AB - BACKGROUND: In children with benign bone defects, various treatment options are recommended. Whether these defects should be curetted, osteosynthetically stabilized and/or filled with allogenic or synthetic bone material is still a matter of controversy. METHODS: The reported study presents preliminary results of five children with benign bone lesions of the lower extremity. Curettage and filling of the defect with a commercially available silicate-substituted calcium phosphate (SiCaP) (Actifuse(r) by ApaTech Ltd., Elstree, United Kingdom) was performed. Patients were followed-up in the outpatient clinic. The healing process was assessed according to the clinical and radiological criteria. RESULTS: Clinical and radiological follow-up showed uneventful healing without intraoperative and short-term complications. All patients were capable of full weight bearing after a few weeks and currently did not experience any decreased range of movement among adjacent joints. Growth disturbances did not occur. In all patients increasing cancellous bone reconstruction of the defect, without signs of osteolysis could be shown radiologically. CONCLUSION: SiCaP represents a good and safe alternative to hitherto existing therapies in the management of defined symptomatic benign bone defects in the pediatric age group. PMID- 22517523 TI - Compensatory lung growth in NOS3 knockout mice suggests synthase isoform redundancy. AB - Nitric oxide synthase 3 (NOS3) produces nitric oxide (NO) in endothelial cells, which stimulates cyclic guanosine monophosphate (cGMP) production and thereby mediates pulmonary vasodilation. Inhibition of cGMP enzymatic cleavage by sildenafil might be involved in lung growth stimulating processes in pulmonary hypoplasia. The aim of this study was to discover insights into the transcriptional regulation of NOS3 in a mouse model of compensatory lung growth (CLG). CLG was studied in wild type animals (WT) and NOS3 knockout mice (NOS3-/-) by dry weight, DNA, and protein quantification as well as relative quantification of NOS mRNA. All assessments were done on adult female mice, 10 days after left pneumonectomy (PNX) or sham thoracotomy. Weight ratios of right NOS3-/- lungs were no different than controls. There was a compensatory increase in DNA and a noncompensating increase in protein ratios in NOS3-/- mice compared with controls. Pharmacological knockdown with the pan-NOS inhibitor l-NAME (nitro arginine methyl ester) reduced CLG by only 8% compared with the d-NAME treated control mice. Relative quantification of lung mRNA revealed no up-regulation of NOS3 expression in WT lungs after PNX, but NOS3-/- lungs showed a 2.6-fold higher inducible NOS2 expression compared with shams. These data suggest that NOS3 loss of function alone does not impair CLG in mice, possibly because of redundancy mechanisms involving NOS2. PMID- 22517524 TI - Undescended testis accompanying congenital Spigelian hernia: is it a reason, a result, or a new syndrome? AB - INTRODUCTION: Frequent reporting of cases of the coexistence of a Spigelian hernia (SH) with an undescended testis (UT) suggests that this phenomenon may be a syndrome. In this article, four pediatric cases in which an UT accompanies a congenital SH have been discussed in light of the literature. METHODS: In this study, four cases aged between 6 months and 5 years who had a SH accompanied by an UT were evaluated and underwent surgery. RESULT: The patient's ages were 6 months, 1 year, 2 years, and 5 years old. The testis was observed in the opened hernia sac. The patients did not have a gubernaculum or an inguinal canal on the side of the hernia. CONCLUSIONS: Neither the theories suggesting that SH leads to an UT nor those suggesting that an UT leads to a SH are satisfactory. We believe that this coexistence may be the congenital Spigelian-cryptorchidism syndrome seen in boys. As in the four cases presented here, elements of this syndrome are defects in the Spigelian fascia and the hernia sac enveloping the testis and an absence of the gubernaculum and the inguinal canal. PMID- 22517525 TI - Letter to the editor concerning article by A. A. Wheeler et al (Eur J Pediatr Surg 2011;21:381-385). PMID- 22517526 TI - RET genomic variants in infantile hypertrophic pyloric stenosis. PMID- 22517528 TI - A system dynamics approach for healthcare waste management: a case study in Istanbul Metropolitan City, Turkey. AB - Healthcare waste consists of various types of waste materials generated at hospitals, medical research centres, clinics and laboratories. Although 75-90% of this waste is classified as 'domestic' in nature, 20-25% is deemed to be hazardous, which if not disposed of appropriately, poses a risk to healthcare workers, patients, the environment and even the whole community. As long as healthcare waste is mixed with municipal waste and not segregated prior to disposal, costs will increase substantially. In this study, healthcare waste increases along with the potential to decrease the amounts by implementing effective segregation at healthcare facilities are projected to 2040. Our long term aim is to develop a system to support selection and planning of the future treatment capacity. Istanbul in Turkey was used as the case study area. In order to identify the factors affecting healthcare waste generation in Istanbul, observations were made and interviews conducted in Istanbul over a 3 month period. A system dynamics approach was adopted to build a healthcare waste management model using a software package, Vensim Ple Plus. Based on reported analysis, the non-hazardous municipal fraction co-disposed with healthcare waste is around 65%. Using the projected waste generation flows, reducing a municipal fraction to 30% has the potential to avoid some 8000 t year(-1) of healthcare waste by 2025 and almost 10 000 t year(-1) by 2035. Furthermore, if segregation practices ensured healthcare waste requiring incineration was also selectively managed, 77% of healthcare waste could be diverted to alternative treatment technologies. As the throughput capacity of the only existing healthcare waste treatment facility in Istanbul, Kemerburgaz Incinerator, has already been exceeded, it is evident that improved management could not only reduce overall flows and costs but also permit alternative and cheaper treatment systems (e.g. autoclaving) to be adopted for the healthcare waste. PMID- 22517529 TI - Personal and organizational predictors of physicians' knowledge, attitudes and practices related to medical waste management in Mazandaran province (northern Iran). AB - Medical waste management (MWM) is an important public health concern worldwide. Although physicians must participate in medical waste management, their personal and organizational predictors in this process are unknown. This study aimed to the determinants of physicians' knowledge, attitudes and practices related to MWM in eight hospitals of Mazandaran province, northern Iran. A validated, reliable self-administered questionnaire was used including 30 questions about the respondents' knowledge, attitudes and practices (KAP) and personal and professional variables. Of a total of 200 physicians, 150 persons completed the questionnaire (response rate of 75%). The average score (+/- SD) for physicians' knowledge was 6.50 (+/- 1.50) out of 10, whereas those for attitudes and practices were 4.44 (+/- 0.88) and 4.02 (+/- 1.35) out of 5, respectively. Surgeons and orthopaedists had the lowest scores, whereas para-clinical specialists and internal medicine specialists had the highest scores. The score of knowledge showed significant differences among speciality groups and the various speciality groups' scores differed significantly only for knowledge (P = 0.024) and the mean of total KAP was significantly different between educational and non-educational hospitals (P < 0.05). As hospital type and physician speciality was related to the KAP concerning MWM, therefore it is recommend that all hospitals should develop appropriate protocols for medical waste management based on the this variables using a participatory process with teamwork and continuous training. PMID- 22517530 TI - Estimating future generation of obsolete household appliances in China. AB - The estimate of future obsolete streams is one of the crucial issues for the establishment of an efficient waste collection and recycling system in China. Due to low availability of reliable data, information on discarded household appliances (HAs) is deficient in China. This study adopts a stocks-based prediction model based on material flow analysis. The model firstly models the lifetime distribution of HAs, and then the future stocks of HAs are extrapolated. By determining the initial year of calculation, the model makes a prediction of future obsolete HAs in China in the time period from 2010-2030. The results show that the discarded amount of the five major kinds of HAs will increase from 130 million units in 2010 to 216 to 221 million units by 2020, and 259 to 282 million units by 2030. A total of 4370 to 4528 million units (149 to 155 million tonnes) of obsolete HAs will be generated in China over the next 20 years. Urban households will generate significantly more obsolete HAs (about 2619 to 2723 million units) than rural households, mainly due to the difference in their HAs possession levels. Thus recycling capacity must increase if the rising quantity of domestic obsolete HAs is to be handled properly. The results of this study can help to develop the collection and recycling systems and facilities needed for the obsolete HAs generated in the future. From a methodological perspective, the stock-based model provides a suitable tool to predict the generation of discarded HAs in the future. PMID- 22517534 TI - Incidence of soft tissue sarcoma and beyond: a population-based prospective study in 3 European regions. AB - BACKGROUND: The objectives of this study were to measure the incidence of sarcomas, including viscerally sited tumors that are not reported in cancer statistics, and to draw explanatory clues from a large and reliable sarcoma incidence data set. METHODS: Cases of sarcomas regardless of primary site (except bone and joints) were collected during 2 years in 3 European regions totaling approximately 26,000,000 person-years. The sources used were pathology reports and hospital discharges forms. Diagnoses were reviewed by expert sarcoma pathologists and were classified according to 2002 World Health Organization criteria. Soft tissue sarcomas (STS) were considered those located in arms, legs, trunk, head, neck, and retroperitoneum; visceral sarcomas (VS) were considered those that arose in internal organs. Rates were age standardized using the European (ASR-E) and the USA standard population. The rate of coexistence of VS and STS was calculated by dividing the 2 corresponding ASRs. RESULTS: There were 1558 sarcomas, 968 STS, and 590 VS. The ASRs-USA per 100,000 person-years was 5.12 * 10(5) among males and 4.58 * 10(5) among females for all sarcomas. For males and females, respectively, the ASR-E per 100,000 person-years was 3.58 * 10(5) and 2.55 * 10(5) , respectively, for STS; 1.47 * 10(5) and 1.97 * 10(5) , respectively, for VS; and 0.55 * 10(5) and 0.10 * 10(5) , respectively, for Kaposi sarcoma. The coexistence rate of VS and STS was 0.41 for males and 0.77 for females. For dermatofibrosarcoma (both sexes), uterine sarcoma, liposarcoma (females), and leiomyosarcoma, including or excluding the uterus (females), the age-specific rates depicted a curve with a rapid increasing trend until ages 40 to 50 years and little variation thereafter. CONCLUSIONS: Compared with the incidence of STS, VS incidence made up an additional 41% in males and 77% in females. Because the shape of age-specific curves for some histotypes was similar to that of breast cancer, the authors concluded that sex hormones (plus many chemicals that act as endocrine disruptors) may be involved in carcinogenesis. This evidence could pave the way to investigate alternative treatments and to explore etiology. Cancer 2012. (c) 2012 American Cancer Society. PMID- 22517535 TI - Cycloaddition reactivity studies of first-row transition metal-azide complexes and alkynes: an inorganic click reaction for metalloenzyme inhibitor synthesis. AB - The studies described herein focus on the 1,3-dipolar cycloaddition reaction between first-row transition metal-azide complexes and alkyne reagents, i.e. an inorganic variant of the extensively used "click reaction". The reaction between the azide complexes of biologically-relevant metals (e.g., Fe, Co and Ni) found in metalloenzyme active sites and alkyne reagents has been investigated as a proof-of-principle for a novel method of developing metalloenzyme triazole-based inhibitors. Six Fe, Co and Ni mono-azide complexes employing salen- and cyclam type ligands have been synthesized and characterized. The scope of the targeted inorganic azide-alkyne click reaction was investigated using the electron deficient alkyne dimethyl acetylenedicarboxylate. Of the six metal-azide complexes tested, the Co and Ni complexes of the 1,4,8,11-tetrametyl-1,4,8,11 tetraazacyclotetradecane (Me(4)cyclam) ligand showed a successful cycloaddition reaction and formation of the corresponding metal-triazolate products, which were crystallographically characterized. Moreover, use of less electron deficient alkynes resulted in a loss of cycloaddition reactivity. Analysis of the structural parameters of the investigated metal-azide complexes suggests that a more symmetric structure and charge distribution within the azide moiety is needed for the formation of a metal-triazolate product. Overall, these results suggest that a successful cycloaddition reaction between a metal-azide complex and an alkyne substrate is dependent both on the ligand and metal oxidation state, that determine the electronic properties of the bound azide, as well as the electron deficient nature of the alkyne employed. PMID- 22517536 TI - 3-year prevalence of alcohol-related disorders in German patients treated with high-potency opioids. AB - PURPOSE: In November 2010, the European Medicines Agency's Committee for Medicinal Products for Human Use completed a review of the safety and effectiveness of modified-release oral high-potency opioids (HPO). The reason for this referral procedure was the concern that some of these controlled-release systems may be unstable when co-ingested with alcohol and that the active substance would be released too quickly. The aim of this study was to estimate the prevalence of alcohol-related disorders (ARD) in German patients treated with HPO approved for pain therapy. METHODS: The source of data was the German Pharmacoepidemiological Research Database including more than 14 million members of four statutory health insurances. The age and sex standardized 3-year prevalence of ARD in patients treated with any type of HPO and in patients receiving modified-release oral HPO was compared with the prevalence of ARD in the general population excluding HPO-treated patients. RESULTS: The age and sex standardized prevalence of ARD was significantly higher in patients treated with any type of HPO (5.5%, 95%confidence interval [CI]: 5.2%-5.9%) or with modified release HPO (5.4%, 95%CI: 4.8%-5.9%) than in persons belonging to the general population (2.2%, 95%CI: 2.2-2.2%). CONCLUSIONS: Interactions with alcohol in patients receiving modified-release HPO may be of relevance in a substantial number of patients. Physicians should be aware of this potentially dangerous interaction. PMID- 22517537 TI - Catalytic conversion of inulin and fructose into 5-hydroxymethylfurfural by lignosulfonic acid in ionic liquids. AB - In this work, we found that lignosulfonic acid (LS), which is a waste byproduct from the paper industry, in ionic liquids (ILs) can catalyze the dehydration of fructose and inulin into 5-hydroxymethylfurfural (HMF) efficiently, which is a promising potential substitute for petroleum-based building blocks. The effects of reaction time, temperature, catalyst loading, and reusability of the catalytic system were studied. It was found that a 94.3% yield of HMF could be achieved in only 10 min at 100 degrees C under mild conditions. The reusability study of the LS-IL catalytic system after removal of HMF by ethyl acetate extraction demonstrated that the catalytic activity decreased from 77.4 to 62.9% after five cycles and the catalytic activity could be recovered after simply removing the accumulated humins by filtration after adding ethanol to the LS-ILs. The integrated utilization of a biorenewable feedstock, catalyst, and ILs is an example of an ideal green chemical process. PMID- 22517538 TI - Long-term serial angiographic outcomes after sirolimus-eluting stent implantation. AB - OBJECTIVE: We evaluated, using quantitative coronary angiography, the natural history of change that occurred in target lesions after successful sirolimus eluting stent (SES) implantation. BACKGROUND: Percutaneous coronary intervention with drug-eluting stents (DES) has significantly reduced the rate of repeated target lesion revascularization. However, early studies have raised concerns regarding the "late catch-up" phenomenon of DES. METHODS: Between June 2004 and March 2007, consecutive 217 patients with 306 lesions without restenosis at early angiographic follow-up underwent late angiographic follow-up (early follow-up: 11.2 +/- 2.1 months and late follow-up: 29.4 +/- 5.2 months). Predictors of late catch-up were identified with univariate and multivariate regression analyses. RESULTS: Although reference vessel diameter did not significantly change during follow-up [3.15 mm (interquartile range (IQR): 2.81-3.49 mm), 3.12 mm (IQR: 2.79 3.47 mm), and 3.08 mm (IQR: 2.76-3.46 mm) at postprocedure, and early and late angiographic follow-up, respectively; P = 0.2653], late loss (LL) significantly increased during follow-up [0.05 mm (IQR: 0.00-0.13 mm) and 0.08 mm (IQR: 0.01 0.19 mm) at early and late follow-up, respectively; P < 0.0001]. Univariate analysis showed previous intervention, adjunctive use of cutting balloon, lesion length, and progression of MLD, LL, %DS at early follow-up as predictors of late catch-up. Multivariate regression analysis identified %DS at early follow-up as a predictor of late catch-up (OR 1.076, CI 1.039-1.114, P < 0.0001). CONCLUSION: Significant and continuous progression of neointima after SES implantation was observed in the present study. Larger LL may be a sign of late catch-up phenomenon. PMID- 22517539 TI - Tautomeric switching and metal-cation sensing of ligand-equipped 4-hydroxy-/4-oxo 1,4-dihydroquinolines. AB - Novel 4-hydroxyquinoline (4HQ) based tautomeric switches are reported. 4HQs equipped with coordinative side arms (8-arylimino and 3-piperidin-1-ylmethyl groups) were synthesized to access O- or N-selective chelation of Zn(2+) and Cd(2+) ions by 4HQ. In the case of the monodentate arylimino group, O chelation of metal ions induces concomitant switching of phenol tautomer to the keto form in nonpolar or aprotic media. This change is accompanied by selective and highly sensitive fluorometric sensing of Zn(2+) ions. In the case of the bidentate 8 (quinolin-8-ylimino)methyl side arm, NMR studies in CD(3) OD indicated that both Cd(2+) and Zn(2+) ions afford N chelation for 4HQ, coexisting with tautomeric switching from quinolin-4(1H)-one to quinolin-4-olate. In corroboration, UV/Vis monitored metal-ion titrations in toluene and methanol implied similar structural changes. Additionally, fluorescence measurements indicated that the metal triggered tautomeric switching is associated with compound signaling properties. The results are supported by DFT calculations at the B3LYP 6-31G* level. Several X-ray structures of metal-free and metal-chelating 4HQ are presented to support the solution studies. PMID- 22517540 TI - Maintaining glottic opening in multiple system atrophy: efficacy of serotonergic therapy. PMID- 22517542 TI - Placebo-controlled randomized clinical trial on the immunomodulating activities of low- and high-dose bromelain after oral administration - new evidence on the antiinflammatory mode of action of bromelain. AB - Bromelain has been used for treatment of inflammatory diseases for decades. However, the exact mechanism of action remains poorly understood. While in vitro investigations have shown conflicting effects on the release of various cytokines, no in vivo data were available. In this study, the effects on inflammation-related cytokines of two doses of bromelain were tested in a single dose placebo-controlled 3 * crossover randomized clinical trial. Cytokine circadian profiles were used to investigate the effects of bromelain on the human immune system by using stimulated whole-blood leukocytes. The effects seen in these cultures demonstrated a significant shift in the circadian profiles of the Th1 cell mediator interferon gamma (IFNgamma; p < 0.043) after bromelain 3000 FIP (Federation Internationale Pharmaceutique) units, and trends in those of the Th2 type cytokine IL-5 as well as the immunosuppressive cytokine interleukin (IL)-10. This suggests a general effect on the antigen-specific (T cell) compartment of the human immune system. This is the first time that bromelain has been shown to modulate the cellular responses of lymphocyte after oral use. It is postulated that the immunomodulating effect of bromelain observed in this trial is part of its known antiinflammatory activities. Further investigations will be necessary to verify the relevance of these findings to a diseased immune system. PMID- 22517541 TI - Reduction of inflammatory bowel disease-induced tumor development in IL-10 knockout mice with soluble epoxide hydrolase gene deficiency. AB - Soluble epoxide hydrolase (sEH) quickly inactivates anti-inflammatory epoxyeicosatrienoic acids (EETs) by converting them to dihydroxyeicosatrienoic acids (DHETs). Inhibition of sEH has shown effects against inflammation, but little is studied about the role of sEH in inflammatory bowel disease (IBD) and its induced carcinogenesis. In the present study, the effect of sEH gene deficiency on the development of IBD-induced tumor development was determined in IL-10 knockout mice combined with sEH gene deficiency. Tumor development in the bowel was examined at the age of 25 wk for male mice and 35 wk for female mice. Compared to IL-10(-/-) mice, sEH (-/-)/IL-10(-/-) mice exhibited a significant decrease of tumor multiplicity (2 +/- 0.9 tumors/mouse vs. 1 +/- 0.3 tumors/mouse) and tumor size (344.55 +/- 71.73 mm3 vs. 126.94 +/- 23.18 mm3), as well as a marked decrease of precancerous dysplasia. The significantly lower inflammatory scores were further observed in the bowel in sEH(-/-)/IL-10(-/-) mice as compared to IL-10(-/-) mice, including parameters of inflammation involved area (0.70 +/- 0.16 vs. 1.4 +/- 0.18), inflammation cell infiltration (1.55 +/- 0.35 vs. 2.15 +/- 0.18), and epithelial hyperplasia (0.95 +/- 0.21 vs. 1.45 +/- 0.18), as well as larger ulcer formation. qPCR and Western blotting assays demonstrated a significant downregulation of cytokines/chemokines (TNF alpha, MCP-1, and IL-12, 17, and 23) and NF-kappaB signals. Eicosanoid acid metabolic profiling revealed a significant increase of ratios of EETs to DHETs and EpOMEs to DiOMEs. These results indicate that sEH plays an important role in IBD and its-induced carcinogenesis and could serve as a highly potential target of chemoprevention and treatment for IBD. PMID- 22517543 TI - Cytometry for cells and particles in disease. PMID- 22517548 TI - Transient elastography and prognosis of cirrhosis. PMID- 22517549 TI - Transcription factor EB: a central regulator of both the autophagosome and lysosome. PMID- 22517550 TI - Dismantling the myth of "autoanticoagulation" in cirrhosis: an old dogma dies hard. PMID- 22517552 TI - Dehydroepiandrosterone prevents the aggregation of platelets obtained from postmenopausal women with type 2 diabetes mellitus through the activation of the PKC/eNOS/NO pathway. AB - The steroid hormone dehydroepiandrosterone (DHEA), suggested to be a cardioprotector, prevents platelet aggregation in healthy humans. This hormone is reduced in postmenopausal women by 60% of its normal value. Platelets in patients with type 2 diabetes (T2D) are more sensitive to aggregation, which has been attributed to a reduced ability to produce nitric oxide (NO). In light of these precedents and considering that DHEA is able to increase the production of NO in cultured endothelial cells, we suggest that DHEA prevents the aggregation of platelet from postmenopausal women with T2D through the activation of PKC/eNOS/NO/cGMP pathway. To determine the effect of DHEA in platelet aggregation, platelet-rich plasma (PRP) obtained from postmenopausal women with T2D was preincubated with DHEA, and aggregation induced by ADP was determined in the presence or absence of L-NNA (LNG-nitroarginine), Rottlerin, NOS, or PKC delta inhibitors, respectively. Platelet NO production was measured with the fluorescent probe DAF2DA and eNOS activation was determined by Western blot, using an anti-p-eNOS (ser 1177) antibody. DHEA 1) prevented platelet aggregation by 40% compared to control, 2) increased NO production by 63%, 3) increased p eNOS (phosphorylated endothelial nitric oxide synthase) levels, and 4) increased cGMP production. These effects were reduced in the presence of L-NNA or Rottlerin. DHEA prevents platelet aggregation induced by ADP. This effect is mediated by the activation of the PKCdelta/eNOS/NO/cGMP pathway. Our results suggest that DHEA could be considered to be a potential therapeutic tool in the prevention of atherothrombotic processes in postmenopausal women with T2D. PMID- 22517553 TI - PCB153 disrupts thyroid hormone homeostasis by affecting its biosynthesis, biotransformation, feedback regulation, and metabolism. AB - PCB153, one of the 3 dominant congeners in the food chain, causes the disruption of the endocrine system in humans and animals. In order to elucidate the effects of PCB153 on the biosynthesis, biotransformation, regulation, metabolism, and transport of thyroid hormones (THs), Sprague-Dawley (SD) rats were dosed with PCB153 intraperitoneally (i.p.) at 0, 4, 16 and 32 mg/kg/day for 5 consecutive days and sacrificed 24 h after the last dose. Results showed that after treatment with PCB153, serum total thyroxine (TT4), total triiodothyronine (TT3), and thyrotropin releasing hormone (TRH) decreased, whereas serum thyroid stimulating hormone (TSH) concentration did not alter. The serum sodium iodide symporter (NIS), thyroid peroxidase (TPO), and thyroglobulin (Tg) levels decreased. The mRNA expressions of type 2 and 3 deiodinases (D2 and D3) reduced, but the type 1 deiodinase (D1) showed no significant change. The TSH receptor (TSHr) and TRH receptor (TRHr) levels declined. PCB153 induced hepatic enzymes, and the UDPGTs, CYP2B1, and CYP3A1 mRNA levels were significantly elevated. Taken together, the observed results from the present study indicated that PCB153 disrupted thyroid hormone homeostasis through influencing synthesis-associated proteins (NIS, TPO and Tg), deiodinases, receptors (TSHr and TRHr), and hepatic enzymes, and the decrease of D3 expression might be the compensatory response of body. PMID- 22517554 TI - Screening of mutations in genes that predispose to hereditary paragangliomas and pheochromocytomas. AB - Thirty per cent of the paragangliomas and pheochromocytomas reported are hereditary. Mutations in SDHB, SDHC, SDHD, and more recently SDHAF2 and TMEM127 genes have been described in these hereditary tumors. We looked for mutations in these 5 genes in a series of 269 patients with paragangliomas and/or pheochromocytomas. The SDHB, SDHC, and SDHD genes were analyzed in a series of 269 unrelated index patients with paragangliomas and/or pheochromocytomas using dHPLC screening of point mutations followed by direct sequencing and Multiplex PCR Liquid Chromatography to detect large rearrangements confirmed by quantitative PCR. In a second phase, we adapted Multiplex PCR Liquid Chromatography to the SDHAF2 and TMEM127 genes. This method and direct sequencing were applied to 230 patients without the SDHB, C, D mutations. Of the 269 patients, 44 carried a mutation (16.3%). Thirty-seven different mutations were identified: 18 in SDHB (including 2 large deletions), 8 in SDHD, 6 in SDHC, 5 in TMEM127, and no mutations in SDHAF2. Thirteen mutations have not been published so far. An exhaustive study of the different genes is needed to make possible a familial genetic diagnosis in paraganglioma and pheochromocytoma hereditary syndromes. Although mutations in SDHC and TMEM127 are less frequent than mutations in SDHB and SDHD, they also have less evident clinical feature indicators. Analyzing SDHAF2 must be restricted to familial extra-adrenal paragangliomas. Multiplex PCR Liquid Chromatography is a sensitive, fast, and inexpensive method for screening large rearrangements, which are infrequent in these syndromes. PMID- 22517555 TI - Presymptomatic genetic testing in minors at risk of paraganglioma and pheochromocytoma: our experience of oncogenetic multidisciplinary consultation. AB - The aim of the work was to define quality criteria for presymptomatic genetic testing in minors at risk of paraganglioma/pheochromocytoma. A 3-step multidisciplinary procedure was developed: 1) preparatory consultations for parents, providing decision support and advice concerning the way of informing the children; 2) consultation with the minor and blood sampling; and 3) announcement of the result of the genetic test to the minor and his/her parents. Twenty-three minors (mean age=9.22) were tested. The result was positive in 16 cases (presence of the familial mutation) and negative in 7. The 23 procedures were classified according to emotional reactions at the announcement of the result: calm (18/23) or tense (5/23). In parallel, 4 criteria for a good testing procedure was defined: 1) both parents agreeing to have their child tested when they felt ready; 2) parents being given advice concerning the way to inform their child; 3) the most appropriate time for testing being discussed for each child; and 4) avoidance of testing during medical examination periods for the carrier parent. The frequencies of the above criteria were as follows: 1 (17/23); 2 (19/23); 3 (17/23); and 4 (17/23). The overall quality of the testing procedure, calculated as the sum of the four criteria, differed significantly between calm and tense announcements (p<0.01). This study highlights the important role of careful preparation with the parents in emotional acceptance of the result of testing. The 4 criteria identified should be evaluated in further prospective studies. PMID- 22517556 TI - High incidence of cardiovascular complications in pheochromocytoma. AB - Excess of catecholamines in pheochromocytoma is usually accompanied with classical symptoms and signs. In some cases, severe cardiovascular complications (e. g., heart failure, myocardial infarction) may occur. We performed a retrospective analysis focused on the incidence of cardiovascular complications (classified as follows: arrhythmias, myocardial involvement or ischemia and atherosclerosis, cerebrovascular impairment) before the establishment of diagnosis of pheochromocytoma among 145 subjects treated in our hospital. Cardiovascular complications occurred in 28 subjects, but these subjects did not differ significantly from subjects without complications in age, gender, body mass index, paroxysmal symptoms, symptom duration, tumor dimension, catecholamine secretory phenotype, and incidence of hypertension or diabetes mellitus. Arrhythmias occurred in 15 subjects (2 arrhythmia types in 2 subjects): atrial fibrillation in 9 subjects, supraventricular tachycardia in 3 cases, and ventricular tachycardia in 2 patients. Significant bradycardia was noted in 3 cases. Five subjects presented with heart failure with decreased systolic function (takotsubo-like cardiomyopathy found in 2 cases). One subject suffered from hypertrophic obstructive cardiomyopathy. Seven subjects presented with non ST-segment elevation myocardial infarction, 2 patients with ST-segment myocardial infarction, and 1 subject underwent coronary artery bypass grafting. Two subjects suffered from significant peripheral atherosclerosis. Among cerebrovascular complications, transient ischemic attack was found in 3 cases, 2 subjects suffered from stroke, and subarachnoidal bleeding occurred in 1 patient. One subject suffered from diffuse neurological impairment due to multiple ischemic white matter lesions. These data show relatively high incidence of cardiovascular complications (19.3%) in subjects with pheochromocytoma. Early diagnosis is mandatory to prevent severe complications in pheochromocytoma. PMID- 22517557 TI - A decade (2001-2010) of genetic testing for pheochromocytoma and paraganglioma. AB - The identification of 9 susceptibility genes for paraganglioma/pheochromocytoma between 2001 and 2010 has led to the development of routine genetic tests. To study the evolution in genetic screening for paraganglioma/pheochromocytoma over the past decade, we carried out a retrospective study on the tests performed in our laboratory from January 2001 to December 2010. A genetic test for paraganglioma/pheochromocytoma was assessed for 2 499 subjects, 1 620 index cases, and 879 presymptomatic familial genetic tests. A germline mutation in a PGL/PCC susceptibility gene was identified in 363 index cases (22.4%): 269 in SDHx genes (137 in SDHB, 100 in SDHD, 30 in SDHC, 2 in SDHA), 64 in VHL, 23 in RET, and 7 in TMEM127. A presymptomatic paraganglioma/pheochromocytoma test was positive in 427 subjects. Advances in molecular screening techniques led to an increase in the total number of mutation-carriers diagnosed each year. Overall, during the last decade, our laboratory identified a germline mutation in 44.7% of patients with a suspect hereditary PGL/PCC and in 8% of patients with an apparently sporadic PGL/PCC. During the past decade, the discoveries of new paraganglioma/pheochromocytoma susceptibility genes and the subsequent progress of molecular screening techniques have enabled us to diagnose a hereditary paraganglioma/pheochromocytoma in about 22% of patients tested in routine practice. This genetic testing is of major importance for the follow-up of affected patients and for the genetic counselling of their families. PMID- 22517558 TI - A change of osteocalcin (OC) and tartrate resistant acid phosphatase 5b (TRACP 5b) with the menstrual cycle. AB - Bone metabolism markers associated with 4 menstrual cycle phases were evaluated in 14 healthy young females without menstrual disorder. Menstrual cycle phases were confirmed with basal body temperature for 3 months, luteinizing hormone kits, and sexual hormone concentrations of serum. The bone metabolism markers used were osteocalcin (OC), which was measured by immunoradiometric assay (IRMA), and tartrate resistant acid phosphatase 5b (TRACP-5b), which was measured by enzyme immunometric assay (EIA). The highest values of OC and TRACP-5b were observed in the ovulation phase, and TRACP-5b increased significantly when compared with levels in the menstrual phase (p<0.05). Furthermore, the changes in sex-hormone secretion involved in OC and TRACP-5b showed specific patterns during the menstrual cycle. In other words, TRACP-5b levels are influenced by sex hormones produced during the menstrual period and are based on the bone-formation status. Therefore, it is presumed that the TRACP-5b levels during ovulation play a central role in bone formation and bone metabolism. PMID- 22517559 TI - Perioperative management of pheochromocytoma/paraganglioma: is there a state of the art? AB - Pheochromocytoma and paraganglioma are rare tumors of sympathetic or parasympathetic origin, presenting with a highly variable clinical picture. Rarity, as well as biological, clinical, and genetic heterogeneity are barriers to initiate prospective studies that help to establish clinical guidelines. The best management of these patients relies on the experience of a multidisciplinary team. The ultimate outcome can benefit from adequate pre-surgical evaluation and treatment as well as an accurate post-surgical follow-up. Long-term follow-up is mandatory in all patients, but is particularly important in specific familial cases such as those with an SDHB mutation where the risks of recurrence are higher. The surgical approach varies depending on tumor size, location, and surgeon's personal attitude and experience. In this paper, we summarize recommendations, based mostly on authors' and other experts' personal experiences, for the best possible management of patients prior, during and after surgery, as well as when pheochromocytoma is diagnosed during pregnancy. PMID- 22517560 TI - Palladium-catalyzed direct C-H arylation of enamides with simple arenes. PMID- 22517561 TI - Surface electronic structure of [XMIm]Cl probed by surface-sensitive spectroscopy. AB - We apply electron spectroscopy methods with different surface sensitivities to elucidate the DOS of the surface and the near-surface region of [XMIm]Cl (X=octyl, hexyl, butyl, and ethyl alkyl chain) ionic liquids. Using metastable induced electron spectroscopy (MIES) we are able to detect the density of states in front of the outermost surface, whereas ultraviolet and X-ray photoelectron spectroscopy (UPS and XPS) measurements provide lower surface sensitivity. The assignment of certain structures in the valence band spectra to particular atoms/functional groups of the ionic liquid based on DFT calculations and the reconstruction of PES spectra enables us to obtain information on the dominating groups at the surface, or in other words, on the molecular/ionic arrangement and orientation at the surface. From angular resolved XPS it is concluded that the alkyl chains dominate at the outermost surface. In agreement with this a decreasing chlorine signal is observed in the UPS spectra for ionic liquids with increasing alkyl chain length. The analysis of the MIES data shows that in case of [OMIm]Cl--in contrast to UPS and XPS--no Cl-induced features are visible in the MIES spectra at all and that the MIES spectra are dominated by the [OMIm](+) alkyl chain. PMID- 22517562 TI - Access to functionalised silver(I) and gold(I) N-heterocyclic carbenes by [2 + 3] dipolar cycloadditions. AB - A new strategy was developed for the modification of silver(I) and gold(I) N heterocyclic carbenes. Azido groups were grafted and used either by copper catalysed azide-alkyne cycloaddition before metallation or by thermal and "strain promoted" 1,3-dipolar cycloaddition after metallation to functionalise the metal NHCs. PMID- 22517563 TI - Using published criteria to develop a list of potentially inappropriate medications for elderly patients in Taiwan. AB - BACKGROUND: Explicit criteria for potentially inappropriate medications (PIMs) developed from other regions were often difficult to apply to a specific territory without significant modifications. PURPOSE: To describe a process of developing a country-specific explicit PIM criteria from quality review of several published PIM criteria, followed by consensus among regional experts in Taiwan. METHODS: After a review of the literature, we selected seven sets of published PIM criteria. Medications/medication classes listed in at least three of the seven sets of criteria were selected as preliminary core PIMs. We asked a group of 21 experts from various specialties to rate how appropriate they found inclusion of each medication/medication class in final PIM criteria after two rounds of modified Delphi methods. RESULTS: Table 1 of the instrument included 24 medication/medication classes to be generally avoided in older adults irrespective of co-morbidities, and Table 2 included 12 chronic conditions with six medication/medication classes that patients with these conditions should avoid. The Taiwan criteria contained only half the number of statements that were included in the Beers criteria (36 vs 68 statements) but detected nearly 70-75% as many PIMs in older patients with polypharmacy in a secondary data analysis. Features included straightforward statement arrangements, suggestions of alternatives, and clear definitions of long-acting benzodiazepine and anticholinergic drugs for Table 1 PIMs. CONCLUSION: A user-friendly instrument was developed to detect PIMs for Taiwanese older adults. Further prospective studies are needed to validate its use in clinical and research settings. PMID- 22517564 TI - Essential data and techniques for conducting microbial fuel cell and other types of bioelectrochemical system experiments. AB - Microbial fuel cells (MFCs) and other bioelectrochemical systems are new technologies that require expertise in a variety of technical areas, ranging from electrochemistry to biological wastewater treatment. There are certain data and critical information that should be included in every MFC study, such as specific surface area of the electrodes, solution conductivity, and power densities normalized to electrode surface area and volumes. Electrochemical techniques such as linear sweep voltammetry can be used to understand the performance of the MFC, but extremely slow scans are required for these biological systems compared to more traditional fuel cells. In this Minireview, the critical information needed for MFC studies is provided with examples of how results can be better conveyed through a full description of materials, the use of proper controls, and inclusion of a more complete electrochemical analysis. PMID- 22517565 TI - Electronic structure and aromaticity of graphene nanoribbons. AB - We analyse the electronic structure and aromaticity of graphene nanoribbons and carbon nanotubes through a series of delocalisation and geometry analysis methods. In particular, the six-centre index (SCI) is found to be in good agreement with the mean bond length (MBL) and ring bond dispersion (RBD) geometry descriptors. Based on DFT periodic calculations, three distinct classes of aromaticity patterns have been found for armchair graphene nanoribbons, appearing periodically as the width of the ribbon is increased. The periodicity in the band gap is found to be related to these aromaticity patterns. Also, the appearance of such distinct aromaticity distribution is explained within the framework of the Clar's sextet theory. Both delocalisation and geometry analysis methods are shown to be very fast and reliable tools for easily analysing the aromaticity in carbon nanosystems. PMID- 22517566 TI - Patient preferences for coronary artery bypass graft surgery or percutaneous intervention in multivessel coronary artery disease. AB - OBJECTIVES: Determine if patients prefer multivessel percutaneous coronary intervention (mv-PCI) over coronary artery bypass graft surgery (CABG) for treatment of symptomatic multivessel coronary artery disease (mv-CAD) despite high 1-year risk. BACKGROUND: Patient risk perception and preference for CABG or mv-PCI to treat medically refractory mv-CAD are poorly understood. We hypothesize that patients prefer mv-PCI instead of CABG even when quoted high mv-PCI risk. METHODS: 585 patients and 31 physicians were presented standardized questionnaires with a hypothetical scenario describing chest pain and medically refractory mv-CAD. CABG or mv-PCI was presented as treatment options. Risk scenarios included variable 1-year risks of death, stroke, and repeat procedures for mv-PCI and fixed risks for CABG. Participants indicated their preference of revascularization method based on the presented risks. We calculated the odds that patients or physicians would favor mv-PCI over CABG across a range of quoted risks of death, stroke, and repeat procedures. RESULTS: For nearly all quoted risks, patients preferred mv-PCI over CABG, even when the risk of death was double the risk with CABG or the risk of repeat procedures was more than three times that for CABG (P < 0.0001). Compared to patients, physicians chose mv-PCI less often than CABG as the risk of death and repeat procedures increased (P < 0.001 and P = 0.004, respectively). CONCLUSION: Patients favor mv-PCI over CABG to treat mv-CAD, even if 1-year risks of death and repeat procedures far exceed risk with CABG. Physicians are more influenced by actual risk and prefer mv-PCI less than patients despite similarly quoted 1-year risks. PMID- 22517567 TI - Task-specific tremor with use of scissors. PMID- 22517568 TI - High-grade dysplasia and intramucosal adenocarcinoma in Barrett's esophagus: the role of esophagectomy in the era of endoscopic eradication therapy. AB - PURPOSE OF REVIEW: The aim of this review is to evaluate the role of esophagectomy for high-grade dysplasia (HGD) and intramucosal adenocarcinoma (IMC) in light of recent advances in endoscopic therapy for Barrett's esophagus. RECENT FINDINGS: Radiofrequency ablation (RFA) and endoscopic mucosal resection (EMR) are proven well tolerated and effective, at least in midterm follow-up. The application of these techniques has opened a new road for the local treatment of esophageal HGD and IMC. To safely employ these techniques, reliable and accurate staging of the esophageal neoplasm is essential. EMR has taken a central role, as it allows the pathologist to provide tumor-staging information necessary for an appropriate clinical management decision process. Unfortunately, both RFA and EMR have limitations that preclude their universal use in the treatment of early esophageal cancer. In some cases, esophagectomy still remains the best treatment option. The evolution of the minimally invasive approach to esophagectomy may improve outcomes of this major operation. SUMMARY: A better understanding of the indications and limitations of endoscopic therapy for HGD and IMC permits a tailored approach to the management of patients with early esophageal adenocarcinoma. When indicated, the selection of a less morbid surgical technique has the potential to improve overall surgical and oncological outcomes. PMID- 22517569 TI - Two-photon fluorescence imaging super-enhanced by multishell nanophotonic particles, with application to subcellular pH. AB - A novel nanophotonic method for enhancing the two-photon fluorescence signal of a fluorophore is presented. It utilizes the second harmonic (SH) of the exciting light generated by noble metal nanospheres in whose near-field the dye molecules are placed, to further enhance the dye's fluorescence signal in addition to the usual metal-enhanced fluorescence phenomenon. This method enables demonstration, for the first time, of two-photon fluorescence enhancement inside a biological system, namely live cells. A multishell hydrogel nanoparticle containing a silver core, a protective citrate capping, which serves also as an excitation quenching inhibitor spacer, a pH indicator dye shell, and a polyacrylamide cladding are employed. Utilizing this technique, an enhancement of up to 20 times in the two photon fluorescence of the indicator dye is observed. Although a significant portion of the enhanced fluorescence signal is due to one-photon processes accompanying the SH generation of the exciting light, this method preserves all the advantages of infrared-excited, two-photon microscopy: enhanced penetration depth, localized excitation, low photobleaching, low autofluorescence, and low cellular damage. PMID- 22517570 TI - Small pneumoconiotic opacities on U.S. coal worker surveillance chest radiographs are not predominantly in the upper lung zones. AB - BACKGROUND: Radiographic shadows of coal workers' pneumoconiosis (CWP) are commonly described as predominantly in the upper lung zones. METHODS: We evaluated the lung distribution of small opacities on surveillance chest radiographs (CXRs) taken between 1981 and 2010 among 2,467 underground US coal miners. All had evidence of pneumoconiosis (category >=1/0), based on the contemporary International Labour Office Classification of Radiographs of Pneumoconioses. RESULTS: Small opacity involvement was approximately equal over all lung zones, with 30.7% of the total involvement reported in the upper zones, 37.1% in the middle zones, and 32.1% in the lower zones. Primarily rounded opacities were seen in 62.1% of miners and primarily irregular opacities were seen in 37.9%. Miners with primarily rounded opacities had a distribution with moderate upper zone predominance (upper = 36.8%, middle = 36.5%, and lower = 27.2%). In contrast, miners with primarily irregular opacities showed a lower zone preponderance (upper = 20.5%, middle = 38.4%, and lower = 41.1%). CONCLUSION: The distribution of small pneumoconiotic opacities on surveillance CXRs of working US coal miners is not consistent with the conventional expectations of upper lung zone predominance. PMID- 22517571 TI - Upper-limb lymphedema treated aesthetically with lymphaticovenous anastomosis using indocyanine green lymphography and noncontact vein visualization. AB - We have described a procedure to minimize surgical wounds, in which lymph vessels and skin venules are identified by indocyanine green (ICG) lymphography and the AV300 noncontact visualization system (AccuVein, Cold Spring Harbor, NY), respectively. This approach allows accurate decisions regarding sites of incision for lymphatic venous anastomosis (LVA). This method was applied in a patient with right upper-limb lymphedema after breast cancer therapy. The low-invasive procedure can be used before and during surgery. The incision size is minimal, and the incision site is at the joint area. Thus, we aim to establish this approach as a standard method for identifying lymph vessels and veins that are suitable for LVA. This innovative vascular-imaging machine makes LVA less invasive and more effective without side effects. PMID- 22517572 TI - Management of penile defects: a review. AB - Penile amputation is a rare injury. Although, in principle, penile replantation can be performed using a variety of methods, few, if any, standardized procedures exist to deal with this medical emergency. The value of the various microsurgical techniques for replantation of the penis remains uncertain. This article provides a review of the management of penile defects and complications. PMID- 22517573 TI - First dorsal metacarpal artery adiposofascial flap for venous conduit and soft tissue cover in an avulsed thumb: case report. AB - Skin loss, need for vein grafts, and secondary surgeries are often encountered in avulsion injuries of the thumb. We report a case of successful salvage of an avulsion type of near total amputation of the thumb following a conveyor belt injury in which the first dorsal metacarpal artery adiposofascial flap was used for combined soft tissue cover and venous conduit. PMID- 22517574 TI - Augmentation of venous drainage in deep inferior epigastric perforator flap breast reconstruction: efficacy and advancement. AB - Deep inferior epigastric perforator flap (DIEP) is the workhorse for autologous breast reconstruction because it is associated with less abdominal wall donor site morbidity; however, the high incidence of venous congestion of zone IV within the DIEP flap is the most important disadvantage. Venous augmentation may be an appropriate method for venous decompression of the DIEP flap. This study aims to assess retrospectively the efficacy of the venous augmented DIEP flap and to present an advanced technique for venous augmentation. A total of 79 breast reconstructions using DIEP flap from January 2006 to March 2011 were included. Thirty-two patients who underwent venous augmented DIEP flap were selected as the test group, and 47 patients who underwent the traditional DIEP flap were included as the control group. Three indices-operation time, flap size, and flap complication rate-were compared between the two groups. The operation time was 6.6 +/- 0.7 hours in the test group and 6.1 +/- 1.2 hours in the control group (p < 0.05). The mean flap size was 325.9 +/- 20.6 cm2 in the test group and 294.7 +/ 24.2 cm2 in the control group (p <0.05). In the test group, there was one partial flap loss (complication rate was 3.1%). In the control group, the total complication rate was 10.6% (p <0.05). Venous augmentation can successfully enhance the viability of a DIEP flap. The SIEV-SIEV (superficial inferior epigastric vein) reverse-flow anastomosis is an efficient and convenient method of venous augmentation for DIEP flap, with negligible drawbacks. PMID- 22517575 TI - Simultaneous contralateral breast adjustment in unilateral deep inferior epigastric perforator breast reconstruction. AB - BACKGROUND: Breast symmetry is a key factor in deep inferior epigastric perforator (DIEP) flap breast reconstruction, which necessitates in many cases contralateral breast adjustment, traditionally done at a second stage. We present our experience with simultaneous contralateral breast adjustment in unilateral DIEP breast reconstruction. METHODS: We retrospectively reviewed all consecutive unilateral DIEP breast reconstructions done in our institution. The patients were divided into three groups according to contralateral breast surgery performed: simultaneous adjustment, late adjustment, and no contralateral breast adjustment surgery. The groups were compared by aesthetic outcome and patient satisfaction using the BREAST-Q questionnaire. RESULTS: A total of 77 unilateral breast reconstructions were performed using the DIEP flap. Fifty-one eligible patients agreed to respond to the questionnaire by telephone and were enrolled in the study; 33 underwent simultaneous contralateral breast adjustment, eight underwent late adjustment procedure, and 10 had no contralateral surgery performed. Aesthetic outcome and patient satisfaction was comparable in the simultaneous and late adjustment groups, but was reduced during the latent period. CONCLUSION: Simultaneous contralateral breast adjustment in unilateral DIEP breast reconstruction is a safe and a worthwhile procedure that should be offered to the patient when appropriate. PMID- 22517576 TI - Vasodilatory effects of cinnamic acid via the nitric oxide-cGMP-PKG pathway in rat thoracic aorta. AB - Cinnamic acid (CA) and its derivatives have a broad therapeutic spectrum that includes antimicrobial, antifungal, and antitumoral activities. However, the vasodilative effect of CA has not been demonstrated. The present study characterizes the vasodilative activity and the mechanism of CA in rat thoracic aorta. The vasomotion of aortic strips following CA treatment was measured in an organ bath system. In addition, vascular strips and human umbilical vein endothelial cells (HUVECs) were used in organ bath, Western blot, nitrite, and cyclic guanosine monophosphate (cGMP) measurements. CA relaxed phenylephrine precontracted aortic strips in an endothelium-dependent manner. Pretreatment of the endothelium-intact aortic strips with N(G) -nitro-l-arginine methyl ester (10(-4) M), 1 H-[1,2,4]-oxadiazolole-[4,3-a] quinoxalin-10-one, (10(-6) M) and methylene blue (10(-5) M) inhibited CA-induced vasorelaxation. CA also increased the phosphorylation of endothelial nitric oxide synthase and nitric oxide generation in a concentration-dependent manner in HUVECs. In addition, cGMP generation and cGMP-dependent protein kinase G (PKG) expression in aortic strips were increased by CA treatment. Furthermore, CA-induced vasorelaxation was inhibited by the PKG inhibitor KT5823 (0.3 MUM) and the Ca(2+) -activated K(+) channel inhibitor tetraethylammonium (10(-3) M). These findings suggest that CA exerts an endothelium-dependent vasodilation effect via the nitric oxide-cGMP-PKG mediated pathway in rat thoracic aorta. PMID- 22517577 TI - A photochromic agonist of AMPA receptors. PMID- 22517578 TI - Double action: toward phosphorescence ratiometric sensing of chromium ion. AB - The phosphorescence double ratiometric sensor detects Cr(III) ions by taking advantage of reversible coordination binding and the biomimetic oxidation reaction. PMID- 22517579 TI - A novel method for investigating electrical breakdown enhancement by nm-sized features. AB - Electrical transport studies across nm-thick dielectric films can be complicated, and datasets compromised, by local electrical breakdown enhanced by nm-sized features. To avoid this problem we need to know the minimal voltage that causes the enhanced electrical breakdown, a task that usually requires numerous measurements and simulation of which is not trivial. Here we describe and use a model system, using a "floating" gold pad to contact Au nanoparticles, NPs, to simultaneously measure numerous junctions with high aspect ratio NP contacts, with a dielectric film, thus revealing the lowest electrical breakdown voltage of a specific dielectric-nanocontact combination. For a 48 +/- 1.5 A SiO(2) layer and a ~7 A monolayer of organic molecules (to link the Au NPs) we show how the breakdown voltage decreases from 4.5 +/- 0.4 V for a flat contact, to 2.4 +/- 0.4 V if 5 nm Au NPs are introduced on the surface. The fact that larger Au NPs on the surface do not necessarily result in significantly higher breakdown voltages illustrates the need for combining experiments with model calculations. This combination shows two opposite effects of increasing the particle size, i.e., increase in defect density in the insulator and decrease in electric field strength. Understanding the process then explains why these systems are vulnerable to electrical breakdown as a result of spikes in regular electrical grids. Finally we use XPS-based chemically resolved electrical measurements to confirm that breakdown occurs indeed right below the nm-sized features. PMID- 22517580 TI - Lignin model compounds as bio-based reactive diluents for liquid molding resins. AB - Lignin is a copious paper and pulping waste product that has the potential to yield valuable, low molecular weight, single aromatic chemicals when strategically depolymerized. The single aromatic lignin model compounds, vanillin, guaiacol, and eugenol, were methacrylated by esterification with methacrylic anhydride and a catalytic amount of 4-dimethylaminopyridine. Methacrylated guaiacol (MG) and methacrylated eugenol (ME) exhibited low viscosities at room temperature (MG: 17 cP and ME: 28 cP). When used as reactive diluents in vinyl ester resins, they produced resin viscosities higher than that of vinyl ester-styrene blends. The relative volatilities of MG (1.05 wt% loss in 18 h) and ME (0.96 wt% loss in 18 h) measured by means of thermogravimetric analysis (TGA) were considerably lower than that of styrene (93.7 wt% loss in 3 h) indicating the potential of these chemicals to be environmentally friendly reactive diluents. Bulk polymerization of MG and ME generated homopolymers with glass transition temperatures (T(g)s) of 92 and 103 degrees C, respectively. Blends of a standard vinyl ester resin with MG and ME (50 wt % reactive diluent) produced thermosets with T(g)s of 127 and 153 degrees C, respectively, which are comparable to vinyl ester-styrene resins, thus demonstrating the ability of MG and ME to completely replace styrene as reactive diluents in liquid molding resins without sacrificing cured-resin thermal performance. PMID- 22517581 TI - Formation of chiral environments by a mechanical induced vortex flow. AB - A chiral molecule absorbs preferentially right- or left-handed circularly polarized light in a circular dichroism (CD) measurement. Usually, the chirality of individual molecules is regarded as the origin of the CD signals. However, recently, several reports have suggested that the vortex flow of a solution of an achiral molecule gives rise to a CD signal, which is dependent on the stirring direction. This article introduces types of molecular architecture and material designs that show stir-induced chirality. We also discuss the effects of the molecular structure and alignment in vortex flows on this phenomena, reviewing the related issues. PMID- 22517583 TI - [From the expert's office: squamous cell carcinoma of the larynx from intensive and longlasting occupational exposure to aerosols of sulfic acid]. PMID- 22517584 TI - [Biology and relevance of stem cells in squamous head and neck cancer: latest insights and review of literature]. AB - The initiation, growth, recurrence and metastasis of head and neck squamous cell carcinomas (HNSCC) and other cancers have recently been related to the presence of cancer stem cells (CSC). Cancer stem cells have some characteristics in common with tissue stem cells like unlimited self renewal and the expression of stem cell factors. CSC express specific markers that vary considerably depending on tumor type or tissue of origin--the discovery of an universal marker has not yet been made. Compared to the bulk tumor mass, CSC are less sensitive to chemo- and radiotherapy and also have a lower immunogenicity. Another concept that explains the seeding of metastases is the epithelial-mesenchymal transition of CSC. CSC targeted therapies may change the prognosis of patients with HNSCC in the future. Recent knowledge on the role of CSC in HNSCC is reviewed, and known CSC markers as well as possible therapeutic targets are described. PMID- 22517585 TI - Novel use of an Amplatzer Vascular Occluder II to close an acquired fistula between a reconstructed aortic arch and the left atrial appendage in a patient with hypoplastic left heart syndrome. AB - An 8-month-old female with hypoplastic left heart syndrome had undergone bidirectional cavopulmonary anastomosis at the age of 4.5 months and presented with a new continuous flow murmur on routine follow-up. Diagnostic catheterization demonstrated a fistula between the left atrial appendage and the neo-aortic arch. The fistula was sealed with an Amplatzer Vascular Occluder II device without complications. PMID- 22517586 TI - Rapid perturbation of free-energy landscapes: from in vitro to in vivo. AB - Biological systems are often studied under the most "physiological" conditions possible. However, purposeful perturbation of biological systems can provide much information about their dynamics, robustness, and function. Such perturbations are particularly easy to apply at the interface of molecular biophysics and cellular biology, at which complex and highly regulated networks emerge from the behavior of individual biomolecules. Due to the size of diffusion coefficients and the length scale of biomolecules, the fastest timescales at this interface extend to below a microsecond. Thus perturbations must be induced and detected rapidly. We focus on examples of proteins and RNAs interacting with themselves (folding) or one another (binding, signaling). Beginning with general principles that have been learned from simple models and perturbation experiments in vitro, we progress to more complex environments that mimic aspects of the living cell, and finally rapid perturbation experiments in living cells. On the experimental side we highlight in particular two classes of rapid perturbation methods (nanoseconds to seconds) that have been traditionally employed in biophysical chemistry, but that will become increasingly important in cell biology and in vivo: fast relaxation techniques and phase-sensitive modulation techniques. These techniques are now increasingly married with imaging to produce a spatiotemporal map of biomolecular stability, dynamics and, in the near future, interaction networks inside cells. Many important chemical processes occur on biologically fast timescales, and yet have important ramifications for slower biological networks. PMID- 22517587 TI - Immune reconstitution after hematopoietic cell transplantation. AB - PURPOSE OF REVIEW: Successful immune reconstitution is important for decreasing posthematopoietic cell transplant (post-HCT) infections, relapse, and secondary malignancy, without increasing graft-versus-host disease (GVHD). Here we review how different parts of the immune system recover, and the relationship between recovery and clinical outcomes. RECENT FINDINGS: Innate immunity (e.g., neutrophils, natural killer cells) recovers within weeks, whereas adaptive immunity (B and T cells) recovers within months to years. This has been known for years; however, more recently, the pattern of recovery of additional immune cell subsets has been described. The role of these subsets in transplant complications like infections, GVHD and relapse is becoming increasingly recognized, as gleaned from studies of the association between subset counts or function and complications/outcomes, and from studies depleting or adoptively transferring various subsets. SUMMARY: Lessons learned from observational studies on immune reconstitution are leading to new strategies to prevent or treat posttransplant infections. Additional knowledge is needed to develop effective strategies to prevent or treat relapse, second malignancies and GVHD. PMID- 22517588 TI - Musashi 2 in hematopoiesis. AB - PURPOSE OF REVIEW: Recent work has shown that the Musashi 2 (Msi2) gene plays important roles in normal and malignant hematopoiesis. Here, we give an overview on the role of Msi2 in the regulation and function of primitive hematopoietic cells as well as in leukaemic progression. We also discuss the molecular pathways in which Msi2 acts in both normal and leukaemic blood cells. RECENT FINDINGS: Msi2 gain and loss of function experiments have shown that it plays an important role in regulating the heamatopoietic stem cell pool. Msi2 has also been found to be overexpressed in human myeloid leukaemias correlating with poor prognosis, therefore Msi2 may be considered as a prognostic marker for acute myeloid leukaemia. SUMMARY: Further studies into the molecular pathways through which Msi2 modulates primitive progenitor function will provide insight into the regulation of normal haematopoiesis and a better understanding of the mechanisms governing the leukaemic transformation process. This will be crucial for the development of effective therapies. PMID- 22517589 TI - The role of activation-induced cytidine deaminase in lymphomagenesis. AB - PURPOSE OF REVIEW: Activation-induced cytidine deaminase (AID) is expressed in germinal center B cells and initiates the events that lead to somatic hypermutation and class switch recombination of immunoglobulin genes. In addition to this fundamental role in immune diversification, aberrant targeting of AID activity contributes to point mutations and translocations of oncogenes associated with B-cell lymphoma. This review discusses recent findings on the role of AID in lymphomagenesis. RECENT FINDINGS: AID is expressed in many malignancies of mature B-cell origin and contributes to the development of lymphoma in several mouse models. The mechanism that guides AID to its genetic target is unknown and may be relatively nonspecific, as numerous nonimmunoglobulin genes appear to be targeted by AID in both normal and neoplastic B cells. Indeed, AID binds to genes on every chromosome throughout the genome and can induce double-stranded DNA breaks that lead to chromosome translocations at these sites. SUMMARY: Emerging evidence supports a key role of AID in lymphomagenesis through genome-wide off-target induction of point mutations and chromosome translocations. Additional work is needed to further define the full scope and consequences of off-target AID activity in human lymphoma as well as to understand the protective mechanisms that break down during the development and progression of disease. PMID- 22517590 TI - Bespoke latex allergen testing improves assessment of respiratory symptoms in textile-braiding workers. AB - BACKGROUND: Latex allergy is poorly understood in latex-exposed textile workers. METHODS: A cross-sectional study was carried out to better characterize respiratory symptoms, using personal breathing zone latex allergen measurement and specific IgE to latex allergens. RESULTS: Forty-four of the 86 (51% participation rate) participated. Ten of 39 workers who gave a blood sample (25.6%) were found to have IgE to at least one workplace allergen (5/39 positive to either latex braiding coated with silica or talc, 4/39 were positive to the dyed cotton extract, and 1/39 to latex braiding coated with silica or talc and dyed cotton extract), whilst only 2 of these 10 had specific IgE to the commercial latex extract. CONCLUSIONS: The presence of symptoms with evidence of sensitization was strongly dictated by current latex exposure. Bespoke workplace allergen IgE testing identified cases of WR respiratory symptoms with sensitization that otherwise would not have been identified. PMID- 22517591 TI - Energy efficiency enhancement of ethanol electrooxidation on Pd-CeO(2)/C in passive and active polymer electrolyte-membrane fuel cells. AB - Pd nanoparticles have been generated by performing an electroless procedure on a mixed ceria (CeO(2))/carbon black (Vulcan XC-72) support. The resulting material, Pd-CeO(2)/C, has been characterized by means of transmission electron microscopy (TEM), inductively coupled plasma atomic emission spectroscopy (ICP-AES), and X ray diffraction (XRD) techniques. Electrodes coated with Pd-CeO(2)/C have been scrutinized for the oxidation of ethanol in alkaline media in half cells as well as in passive and active direct ethanol fuel cells (DEFCs). Membrane electrode assemblies have been fabricated using Pd-CeO(2)/C anodes, proprietary Fe-Co cathodes, and Tokuyama anion-exchange membranes. The monoplanar passive and active DEFCs have been fed with aqueous solutions of 10 wt% ethanol and 2 M KOH, supplying power densities as high as 66 mW cm(-2) at 25 degrees C and 140 mW cm( 2) at 80 degrees C. A comparison with a standard anode electrocatalyst containing Pd nanoparticles (Pd/C) has shown that, at even metal loading and experimental conditions, the energy released by the cells with the Pd-CeO(2)/C electrocatalyst is twice as much as that supplied by the cells with the Pd/C electrocatalyst. A cyclic voltammetry study has shown that the co-support ceria contributes to the remarkable decrease of the onset oxidation potential of ethanol. It is proposed that ceria promotes the formation at low potentials of species adsorbed on Pd, Pd(I)-OH(ads), that are responsible for ethanol oxidation. PMID- 22517592 TI - A Parkinson's disease patient with camptocormia caused by an esophageal hiatal hernia. PMID- 22517593 TI - Simple and universal platform for logic gate operations based on molecular beacon probes. AB - A new platform technology is herein described with which to construct molecular logic gates by employing the hairpin-structured molecular beacon probe as a basic work unit. In this logic gate operation system, single-stranded DNA is used as the input to induce a conformational change in a molecular beacon probe through a sequence-specific interaction. The fluorescent signal resulting from the opening of the molecular beacon probe is then used as the output readout. Importantly, because the logic gates are based on DNA, thus permitting input/output homogeneity to be preserved, their wiring into multi-level circuits can be achieved by combining separately operated logic gates or by designing the DNA output of one gate as the input to the other. With this novel strategy, a complete set of two-input logic gates is successfully constructed at the molecular level, including OR, AND, XOR, INHIBIT, NOR, NAND, XNOR, and IMPLICATION. The logic gates developed herein can be reversibly operated to perform the set-reset function by applying an additional input or a removal strand. Together, these results introduce a new platform technology for logic gate operation that enables the higher-order circuits required for complex communication between various computational elements. PMID- 22517594 TI - Comparative evaluation of the drug interaction screening programs MediQ and ID PHARMA CHECK in neurological inpatients. AB - PURPOSE: The comparative evaluation of clinical decision support software (CDSS) programs regarding their sensitivity and positive predictive value for the identification of clinically relevant drug interactions. METHODS: In this research, we used a cross-sectional study that identified potential drug interactions using the CDSS MediQ and the ID PHARMA CHECK in 484 neurological inpatients. Interactions were reclassified according to the Zurich Interaction System, a multidimensional classification that incorporates the Operational Classification of Drug Interactions. RESULTS: In 484 patients with 2812 prescriptions, MediQ and ID PHARMA CHECK generated a total of 1759 and 1082 alerts, respectively. MediQ identified 658 unique potentially interacting combinations, 8 classified as "high danger," 164 as "average danger," and 486 as "low danger." ID PHARMA CHECK detected 336 combinations assigned to one or several of 12 risk and management categories. Altogether, both CDSS issued alerts relating to 808 unique potentially interacting combinations. According to the Zurich Interaction System, 6 of these were contraindicated, 25 were provisionally contraindicated, 190 carried a conditional risk, and 587 had a minimal risk of adverse events. The positive predictive value for alerts having at least a conditional risk was 0.24 for MediQ and 0.48 for ID PHARMA CHECK. CONCLUSIONS: CDSS showed major differences in the identification and grading of interactions, and many interactions were only identified by one of the two CDSS. For both programs, only a small proportion of all identified interactions appeared clinically relevant, and the selected display of alerts that imply management changes is a key issue in the further development and local setup of such programs. PMID- 22517595 TI - Promotion of hair growth by Rosmarinus officinalis leaf extract. AB - Topical administration of Rosmarinus officinalis leaf extract (RO-ext, 2 mg/day/mouse) improved hair regrowth in C57BL/6NCrSlc mice that experienced hair regrowth interruption induced by testosterone treatment. In addition, RO-ext promoted hair growth in C3H/He mice that had their dorsal areas shaved. To investigate the antiandrogenic activity mechanism of RO-ext, we focused on inhibition of testosterone 5alpha-reductase, which is well recognized as one of the most effective strategies for the treatment of androgenic alopecia. RO-ext showed inhibitory activity of 82.4% and 94.6% at 200 and 500 ug/mL, respectively. As an active constituent of 5alpha-reductase inhibition, 12-methoxycarnosic acid was identified with activity-guided fractionation. In addition, the extract of R. officinalis and 12-methoxycarnosic acid inhibited androgen-dependent proliferation of LNCaP cells as 64.5% and 66.7% at 5 ug/mL and 5 MUM, respectively. These results suggest that they inhibit the binding of dihydrotestosterone to androgen receptors. Consequently, RO-ext is a promising crude drug for hair growth. PMID- 22517596 TI - A molecular dynamics study of viscosity in ionic liquids directed by quantitative structure-property relationships. AB - A computational study into the molecular origin of viscosity in ionic liquids via a combined quantitative structure-property relationship (QSPR) and molecular dynamics (MD) approach is presented. QSPR models are developed for ionic liquids containing the bis[(trifluoromethyl)sulfonyl]imide (TFSI) anion using literature data. The best models thus developed are used to identify persistently well correlating molecular descriptors for further investigation by MD. By modifying the force field of a simple ionic liquid, 1-butyl-3-methylimidazolium hexafluorophosphate [bmim][PF(6)], the efficacy of the charged partial surface area (CPSA) descriptor is examined. Finally, by building QSPR models from the MD data and calculations derived from the CPSA descriptor, potential routes for improved prediction of ionic liquid viscosity are proposed. PMID- 22517597 TI - Molecular scaffolds using multiple orthogonal conjugations: applications in chemical biology and drug discovery. AB - Heteromultifunctional scaffolds that harness sequential "click" reactions will find significant utility in the areas of chemical biology and chemically enabled/enhanced biotherapeutics ("chemologics"). Here we review the existing synthetic technologies that illustrate the considerable potential of the field. PMID- 22517598 TI - Dairy consumption and risk of stroke in Swedish women and men. AB - BACKGROUND AND PURPOSE: Epidemiological studies of the associations of low-fat dairy and specific dairy food consumption with risk of stroke are sparse. Our aim was to examine the association between consumption of total, low-fat, full-fat, and specific dairy foods and risk of stroke in a prospective cohort study. METHODS: We followed 74,961 Swedish women and men who were free from cardiovascular disease and cancer and who completed a 96-item food frequency questionnaire in 1997. Incident cases of stroke were ascertained from the Swedish Hospital Discharge Registry. RESULTS: During a mean follow-up of 10.2 years, we ascertained 4089 cases of stroke, including 3159 cerebral infarctions, 583 hemorrhagic strokes, and 347 unspecified strokes. Consumption of low-fat dairy foods was inversely associated with risk of total stroke (P for trend=0.03) and cerebral infarction (P for trend=0.03). The multivariable relative risks for the highest compared with the lowest quintile of low-fat dairy consumption were 0.88 (95% CI, 0.80-0.97) for total stroke and 0.87 (95% CI, 0.78-0.98) for cerebral infarction. Consumption of total dairy, full-fat dairy, milk, sour milk/yogurt, cheese, and cream/creme fraiche was not associated with stroke risk. CONCLUSIONS: These results suggest that low-fat dairy consumption is inversely associated with the risk of stroke. PMID- 22517599 TI - Depressive symptoms, a time-dependent risk factor for coronary heart disease and stroke in middle-aged men: the PRIME Study. AB - BACKGROUND AND PURPOSE: To date, the association between depressive symptoms and the risk of cardiovascular diseases remains controversial. We investigated prospectively, within the same population, the time course of the association between baseline depressive symptoms and first stroke or coronary heart disease event. METHODS: In the Prospective Epidemiological Study of Myocardial Infarction (PRIME) Study, a multicenter, observational, prospective cohort, 9601 men from France and Northern Ireland were surveyed for the occurrence of first coronary heart disease (n=647) and stroke events (n=136) over 10 years. At baseline, the fourth quartile of a 13-item modified Center for Epidemiological Studies questionnaire was used to define the presence of depressive symptoms. We sought the best time-dependent function to assess the association between depressive symptoms and outcomes. Thus, the hazard ratios were estimated by a Cox proportional hazard model after splitting the follow-up before and after 5 years of follow-up time periods. RESULTS: Depressive symptoms at baseline were associated with coronary heart disease in the first 5 years of follow-up (hazard ratio, 1.43; 1.10-1.87) and with stroke in the second 5 years of follow up (hazard ratio, 1.96; 1.21-3.19) after adjustment for age, study centers, baseline socioeconomic factors, traditional vascular risk factors, and antidepressant treatment. The association was even stronger for ischemic stroke (n=108; hazard ratio, 2.48; 1.45-4.25). CONCLUSIONS: The current study suggests that in healthy, European, middle-aged men, baseline depressive symptoms are associated with an increased risk of coronary heart disease in the short-term, and for stroke in the long-term. PMID- 22517600 TI - Joint effect of modifiable risk factors on the risk of aneurysmal subarachnoid hemorrhage: a cohort study. AB - BACKGROUND AND PURPOSE: The joint effect of risk factors on the risk of aneurysmal SAH (aSAH) has been studied sparsely. METHODS: We examined the potential synergism between cigarette smoking, hypertension, and regular alcohol consumption and the risk of aSAH in a prospective, population-based cohort of participants from the Nord-Trondelag Health Study and the Tromso Study in Norway. Interaction was assessed on additive and multiplicative scales. RESULTS: We identified 122 cases of aSAH over 977 895 person-years of follow-up. Interaction was observed between current smoking and hypertension on the additive scale, (relative excess risk because of interaction, 6.40; 95% CI, 0.88-11.92, adjusted for sex and age). We found no significant interaction between hypertension and regular alcohol consumption or current cigarette smoking and regular alcohol consumption on the additive scale. No significant interaction was detected on the multiplicative scale. CONCLUSIONS: The joint effect of current smoking and hypertension on the risk of aSAH was stronger than was the sum of the independent effects of each factor. Persons at risk of aSAH should be advised of a markedly stronger risk for aSAH with the combination of current smoking and hypertension. In addition, the finding suggests that combining smoking cessation and blood pressure lowering may have an extra risk reduction effect on preventing aSAH. PMID- 22517601 TI - Initial findings of impact of strut width on stent coverage and apposition of sirolimus-eluting stents assessed by optical coherence tomography. AB - OBJECTIVES: We investigate the influence of stent design on stent coverage at 6-9 months after sirolimus eluting stent (SES) implantation using optical coherence tomography (OCT). BACKGROUND: Although some reports suggest that stent design may correlate with stent coverage of stent struts, there were few detailed data whether stent design impact on stent coverage in the same drug-eluting stent. METHODS: A total of 21 SESs (15 patients), who had implanted 2.5, 2.75, and 3.0 mm stents, underwent OCT at 6-9 months after stent implantation. SES is constructed by two different strut width-components; narrow strut width parts (59 MUm) and wide strut width parts (115 MUm). Thus, we divided stent struts of SESs into two groups: narrow strut width parts (narrow group) and wide ones (wide group). We compared the incidence of incomplete apposed struts, uncovered struts, and neointimal hyperplasia (NIH) thickness between the two groups. RESULTS: We could detect 2,948 struts (narrow group consisted of 1,132 struts and wide group consisted of 1,816 struts). Incidence of uncovered struts in the narrow group was significantly lower than in the wide group (30.2% vs. 40.8%, P < 0.001), and NIH thickness in the narrow group was significantly greater than in the wide group (127.5 +/- 93.4 MUm vs. 118.6 +/- 81.4 MUm, P = 0.03). CONCLUSIONS: Stent design, especially strut width, affects stent coverage of SES. The narrow strut may avoid the absence of stent coverage in SES, which correlates with stent thrombosis. PMID- 22517602 TI - Ionic liquids of cationic sandwich complexes. AB - Simple cationic sandwich complexes that contained alkyl- or halogen substituents provided ionic liquids (ILs) with the bis(perfluoroalkanesulfonyl)imide anion. Ferrocenium- and cobaltocenium ILs [M(C(5)H(4)R(1))(C(5)H(4)R(2))][Tf(2)N] (M=Fe, Co) and arene-ferrocenium ILs [Fe(C(5)H(4)R(1))(C(6)H(5)R(2))][Tf(2)N] were prepared and their physical properties were investigated. A detailed comparison of their thermal properties revealed the effects of molecular symmetry and substituents on their melting points. Their viscosity increased on increasing the length of the substituent on the cation and the perfluoroalkyl chain length on the anion. Upon cooling, ILs with low viscosities exhibited crystallization, whereas those with higher viscosities tended to exhibit glass transitions. Most of these salts showed phase transitions in the solid state. A magnetic-switching phenomenon was observed for the paramagnetic ferrocenium IL, which was associated with a liquid/solid transformation, based on the magnetic anisotropy of the ferrocenium cation. (57)Fe Mossbauer spectroscopy was applied to [Fe(C(5)H(4)nBu)(2)][Tf(2)N] to investigate the vibrational behavior of the iron atom in the crystal and glassy states of the ferrocenium IL. PMID- 22517603 TI - Use of pneumococcal polysaccharide vaccine in children: what is the evidence? AB - PURPOSE OF REVIEW: Pneumococcal glycoconjugate vaccines (PCVs) are now widely used in infant immunization schedules. These vaccines are also recommended for those at increased risk of pneumococcal infection and to provide optimal serotype coverage to those at increased risk of disease. The 23-valent polysaccharide vaccine (PPV23) is often advised from the second birthday to provide broader serotype coverage. The use of pneumococcal polysaccharide vaccines (PPVs) has in recent years become a topic of much debate, especially for use in children. RECENT FINDINGS: Although no effect of PPV23 on carriage has been reported, some protection against invasive pneumococcal disease (IPD) is possible. There is a theoretical risk of memory B-cell depletion to PCV serotypes following PPV23 vaccination, even in PCV-primed children, but the clinical significance is currently unknown. This risk is increased by PPV23 revaccination. SUMMARY: Whether the immune response to PPV23, non-PCV13 serotypes is sufficient to confer clinical benefit to at-risk children depends on their age, underlying disease and the immunogenicity of individual serotypes. Given the theoretical risk of memory B-cell depletion following PPV23 vaccination, it is not clear how best to maintain protection in those at-risk children who remain susceptible to IPD. PMID- 22517604 TI - Antibiotic dosing in children in Europe: can we grade the evidence from pharmacokinetic/pharmacodynamic studies - and when is enough data enough? AB - PURPOSE OF REVIEW: Antibiotics are prescribed more frequently to children than any other class of medication. Analysis of the evidence behind antimicrobial dosing regimes is imperative to improve clinical outcomes, minimize antimicrobial resistance development, and to identify priority research areas for the future. This review aims to promote debate amongst paediatricians, pharmacologists, and pharmacists about how to improve antimicrobial prescribing by considering methods to develop and disseminate optimal dosage information. RECENT FINDINGS: There has been increasing use of population analyses to understand pharmacokinetic/pharmacodynamic (PK/PD) parameters in children. Nonlinear mixed effects modelling is widely accepted to be the method of choice for analyses of PK/PD data. However, communicating the quality of PK/PD studies is an equally important factor to allow clinicians to gauge the robustness of the evidence. The possibility of grading PK/PD studies is discussed, along with using systematic reviews and PK/PD meta-analysis for generating high-quality evidence.Many doses in existing formularies (including the British National Formulary for Children) are based on outdated evidence. The need to update formularies to account for new evidence, population changes (e.g. obesity), and changing patterns of resistance requires a more systematic evaluation of antimicrobial PK/PD relationships in children. The possibility of e-formularies with links directly to the evidence should be considered and regulators must also play a role in supporting the re evaluation of off-patent dosing guidelines. SUMMARY: Advancing our understanding of the evidence behind paediatric antimicrobial therapeutic regimens is essential to improve both clinical outcomes and patient safety. Using a combination of international collaboration, electronic communication, and PK/PD modelling techniques, we can now define the gaps in our knowledge base and develop the techniques to answer them. PMID- 22517605 TI - Nanocomposites of graphene oxide and upconversion rare-earth nanocrystals with superior optical limiting performance. AB - Upconversion rare-earth nanomaterials (URENs) possess highly efficient near infrared (NIR), e.g., 980 nm, laser absorption and unique energy upconversion capabilities. On the other hand, graphene and its derivatives, such as graphene oxide (GO), show excellent performance in optical limiting (OL); however, the wavelengths of currently used lasers for OL studies mainly focus on either 532 or 1064 nm. To design new-generation OL materials working at other optical regions, such as the NIR, a novel nanocomposites, GO-URENs, which combines the advantages of both its components, is synthesized by a one-step chemical reaction. Transmission electron microscopy, X-ray diffraction, infrared spectroscopy, and fluorescence studies prove that the alpha-phase URENs uniformly attach on the GO surface via covalent chemical bonding, which assures highly efficient energy transfer between URENs and GO, and also accounts for the significantly improved OL performance compared to either GO or URENs. The superior OL effect is also observed in the proof-of-concept thin-film product, suggesting immediate applications in making high-performance laser-protecting products and optoelectronic devices. PMID- 22517607 TI - Profiles of steroidal saponins from the aerial parts of Tribulus pentandrus, T. megistopterus subsp. pterocarpus and T. parvispinus by LC-ESI-MS/MS. AB - INTRODUCTION: Tribulus is a well-known pharmaceutical herb that has been used for a long time in the traditional Chinese and Indian systems of medicine for the treatment of various diseases. It has been found that the genus Tribulus is rich in biologically active furostane-, cholestane- and spirostane-type steroidal saponins. OBJECTIVE: To develop a rapid, sensitive and accurate method based on liquid-phase extraction followed by high-performance liquid chromatography and electrospray ionisation mass spectrometry (HPLC-ESI-MS) to identify different saponins in three species of the genus Tribulus, and to quantify the compounds that are already known. METHODOLOGY: After extraction from the species studied, the extracts were subjected to HPLC analyses with an XTerra(r) MS C(18) -column and a binary mobile phase consisting of 0.05% formic acid in water and acetonitrile, and with an ESI-MS detection in the negative ion mode. Data were acquired and processed using the Xcalibur 1.3 software. RESULTS: The results exhibited that the profiles of native steroidal glycosides of both T. pentandrus and T. megistopterus subsp. pterocarpus were very similar to each other, but that of T. parvispinus was remarkably different. The fragmentation patterns provided evidence that the saponins possess spirostane-, cholestane- and furostane-type aglycones. Quantitative analyses suggested that these species are a rich source of steroidal saponins. CONCLUSION: HPLC-ESI-MS/MS allowed identification of the key compounds without preparative isolation of the components from the crude extract of Tribulus species. PMID- 22517608 TI - An ATR-FTIR study on the effect of molecular structural variations on the CO2 absorption characteristics of heterocyclic amines, part II. AB - This paper reports on an ATR-FTIR spectroscopic investigation of the CO(2) absorption characteristics of a series of heterocyclic diamines: hexahydropyrimidine (HHPY), 2-methyl and 2,2-dimethylhexahydropyrimidine (MHHPY and DMHHPY), hexahydropyridazine (HHPZ), piperazine (PZ) and 2,5- and 2,6 dimethylpiperazine (2,6-DMPZ and 2,5-DMPZ). By using in situ ATR-FTIR the structure-activity relationship of the reaction between heterocyclic diamines and CO(2) is probed. PZ forms a hydrolysis-resistant carbamate derivative, while HHPY forms a more labile carbamate species with increased susceptibility to hydrolysis, particularly at higher CO(2) loadings (>0.5 mol CO(2)/mol amine). HHPY exhibits similar reactivity toward CO(2) to PZ, but with improved aqueous solubility. The alpha-methyl-substituted MHHPY favours HCO(3)(-) formation, but MHHPY exhibits comparable CO(2) absorption capacity to conventional amines MEA and DEA. MHHPY show improved reactivity compared to the conventional alpha-methyl substituted primary amine 2-amino-2-methyl-1-propanol. DMHHPY is representative of blended amine systems, and its reactivity highlights the advantages of such systems. HHPZ is relatively unreactive towards CO(2). The CO(2) absorption capacity C(A) (mol CO(2)/mol amine) and initial rates of absorption R(IA) (mol CO(2)/mol amine min(-1)) for each reactive diamine are determined: PZ: C(A)=0.92, R(IA)=0.045; 2,6-DMPZ: C(A)=0.86, R(IA)=0.025; 2,5-DMPZ: C(A)=0.88, R(IA)=0.018; HHPY: C(A)=0.85, R(IA)=0.032; MHHPY: C(A)=0.86, R(IA)=0.018; DMHHPY: C(A)=1.1, R(IA)=0.032; and HHPZ: no reaction. Calculations at the B3LYP/6-31+G** and MP2/6 31+G** calculations show that the substitution patterns of the heterocyclic diamines affect carbamate stability, which influences hydrolysis rates. PMID- 22517609 TI - Assembly and absolute configuration of short-lived polyketides from Burkholderia thailandensis. PMID- 22517610 TI - Rosuvastatin pretreatment in patients undergoing elective PCI to reduce the incidence of myocardial periprocedural necrosis: the ROMA trial. AB - OBJECTIVES: The aim of this study is to assess the efficacy of the high-dose rosuvastatin preadministration in reducing periprocedural myocardial necrosis and major adverse cardiovascular and cerebrovascular events (MACCE) in patients undergoing elective percutaneous coronary intervention (PCI). BACKGROUND: Elective PCI may be complicated with an elevation of cardiac biomarkers. Several studies suggested that pretreatment with statins may be associated with a reduction in periprocedural myocardial necrosis. METHODS: One hundred and sixty patients with stable angina who underwent elective PCI were randomly assigned to receive either a preprocedural loading dose (40 mg) of rosuvastatin group (RG, n = 80) or a standard treatment [control group (CG), n = 80].The primary endpoint was the incidence of periprocedural myocardial necrosis. The secondary endpoint was the assessment of MACCE [cardiac death, all-myocardial infarction (MI), stroke, and target vessel revascularization (TVR)] at a 30-day and 12-month follow-up, as well as the rate of periprocedural rise of Troponin T-serum levels >3* upper limit of normal. RESULTS: Twelve and 24-hr post-PCI creatinine kinase MB isoform elevation >3* occurred more frequently in the CG than in the RG (22.7 vs. 7.1; P = 0.034 and 26.4 vs. 8.7; P = 0.003). At the 30-day and 12-month follow-up, the incidence of cumulative MACCE was higher in CG than in the RG (30.0% vs. 8.7%; P = 0.001 and 35.0% vs. 12.5%; P = 0.001).The difference between the groups was mainly due to the periprocedural MI incidence (26.4% vs. 8.7%; P = 0.003).The rate of cardiac death, spontaneous MI, TVR, and stroke were similar in the two groups. CONCLUSIONS: High loading dose of rosuvastatin within 24 hr before elective PCI seems to decrease the incidence of periprocedural myocardial necrosis during a period of 12-months compared to the standard treatment. PMID- 22517611 TI - Dual-luminophore-labeled gold nanoparticles with completely resolved emission for the simultaneous imaging of MMP-2 and MMP-7 in living cells under single wavelength excitation. AB - Although considerable effort has been devoted to the design of various nanoprobes for the fluorescent detection of multiple biomarkers in a single assay, they often suffer from emission-overlapping, owing to small Stokes shifts and wide emission spectra, which results in cross-talk and inaccurate quantification. Herein, we report the design and synthesis of a new nanoprobe for multienzyme detection with completely resolved emission peaks under single-wavelength excitation. The probe was assembled by attaching a cleavable peptide spacer, which was comprised from a matrix metalloproteinase-2 (MMP-2) substrate and a MMP 7 substrate, onto the surface of gold nanoparticles (AuNPs) through cysteine residues. A lanthanide complex, BCTOT-Eu(III) (BCTOT=1,10-bis(5'-chlorosulfo thiophene-2'-yl)-4,4,5,5,6,6,7,7-octafluorodecane-1,3,8,10-tetraone), and 7-amino 4-methylcoumarin (AMC) were attached to the N terminus and the C terminus of the peptide, respectively. In the presence of one or both targeting enzymes, the substrate was cleaved and fluorescence resonance energy transfer (FRET) between the dyes and AuNPs was prohibited, thereby resulting in the dramatic fluorescence emission of dyes. Importantly, there was no emission cross-talk between the two dyes, thereby ensuring accurate detection of each enzyme. Based on this, the simultaneous fluorescence image of MMP-2 and MMP-7 was accomplished in living cells under single wavelength excitation. The apparent differences in the fluorescence imaging indicated distinct differences between the expression levels of MMPs between the human normal liver cells and the human hepatoma cells. PMID- 22517612 TI - Clear cell adenocarcinoma of the lower urinary tract: cytopathologic characteristics and differential diagnoses. AB - Clear cell adenocarcinomas (CCAs) of the lower urinary tract are uncommon neoplasms that may present in routinely processed urinary cytology specimens. There is only limited discussion of the features of CCA of the lower urinary tract in the cytology literature. The authors report a series of 3 cases of this unusual tumor, and correlate cytomorphology with histologic specimens. Two of the cases were diagnosed accurately as adenocarcinoma, and 1 case was diagnosed as atypical cells of undetermined significance. Cytomorphologic features included variably cellular samples with 3-dimensional fragments of malignant cells that had enlarged nuclei, prominent nucleoli, and occasional hobnail configurations. Some fragments showed luminal formation with collections of neutrophils. CCA must be included in the differential diagnosis of malignant cells in a urinary specimen, particularly if the features are not typical of urothelial carcinoma. Other diagnostic considerations include metastatic adenocarcinomas, nephrogenic adenomas, and benign glandular lesions involving the bladder and urinary tract such as mullerianosis. PMID- 22517613 TI - Prebeta-1 HDL and coronary heart disease. AB - PURPOSE OF REVIEW: A negative correlation between HDL cholesterol levels and risk of coronary artery disease has long been recognized. Emerging knowledge of the molecular speciation and functional properties of HDL provides an opportunity to study the atheroprotective effects of specific metabolic processes. The discovery of the quantum particle among the molecular species of HDL (prebeta-1 HDL) and its role in cholesterol efflux from the artery wall, offer a means of assessing the efficiency of efflux. This review presents observations on the structure and metabolism of this particle and its emerging role as a predictor of risk for atherosclerotic vascular disease. RECENT FINDINGS: Prebeta-1 HDL is now recognized as the primary acceptor of cholesterol effluxed by the dominant ATP binding cassette A1 (ABCA1) transporter in arterial macrophages, a critical step in reverse cholesterol transport. Several studies have revealed an association between high levels of this particle and risk of globally defined coronary artery disease and carotid intima-media thickness. Recently, these findings have been confirmed and extended to include myocardial infarction. High levels of prebeta-1 HDL may serve as an index of functional impairment of cholesterol efflux or esterification, either of which would be expected to impede reverse cholesterol transport. SUMMARY: Recent studies underscore the critical role of prebeta-1 HDL in reverse cholesterol transport and its use as a marker of risk for structural coronary disease, myocardial infarction, and cerebral vascular disease. PMID- 22517614 TI - Rationale for cholesteryl ester transfer protein inhibition. AB - PURPOSE OF REVIEW: Raising HDL cholesterol (HDL-C) has become an attractive therapeutic target to lower cardiovascular risk in addition to statins. Inhibition of the cholesteryl ester transfer protein (CETP), which mediates the transfer of cholesteryl esters from HDL to apolipoprotein B-containing particles, leads to a substantial increase in HDL-C levels. Various CETP inhibitors are currently being evaluated in phase II and phase III clinical trials. However, the beneficial effect of CETP inhibition on cardiovascular outcome remains to be established. RECENT FINDINGS: Torcetrapib, the first CETP inhibitor tested in a phase III clinical trial (ILLUMINATE), failed in 2006 because of an increase in all-cause mortality and cardiovascular events that subsequently were attributed to nonclass-related off-target effects (particularly increased blood pressure and low serum potassium) related to the stimulation of aldosterone production. Anacetrapib, another potent CETP inhibitor, raises HDL-C levels by approximately 138% and decreases LDL cholesterol (LDL-C) levels by approximately 40%, without the adverse off-targets effects of torcetrapib (DEFINE study). The CETP modulator dalcetrapib raises HDL-C levels by approximately 30% (with only minimal effect on LDL-C levels) and proved safety in the dal-VESSEL and dal-PLAQUE trials involving a total of nearly 600 patients. Evacetrapib, a relatively new CETP inhibitor, exhibited favorable changes in the lipid profile in a phase II study. SUMMARY: The two ongoing outcome trials, dal-OUTCOMES (dalcetrapib) and REVEAL (anacetrapib), will provide more conclusive answers for the concept of reducing cardiovascular risk by raising HDL-C with CETP inhibition. PMID- 22517615 TI - Evaluation of different pulverisation methods for RNA extraction in squash fruit: lyophilisation, cryogenic mill and mortar grinding. AB - INTRODUCTION: Quality and integrity of RNA are critical for transcription studies in plant molecular biology. In squash fruit and other high water content crops, the grinding of tissue with mortar and pestle in liquid nitrogen fails to produce a homogeneous and fine powered sample desirable to ensure a good penetration of the extraction reagent. OBJECTIVE: To develop an improved pulverisation method to facilitate the homogenisation process of squash fruit tissue prior to RNA extraction without reducing quality and yield of the extracted RNA. METHODOLOGY: Three methods of pulverisation, each followed by the same extraction protocol, were compared. The first approach consisted of the lyophilisation of the sample in order to remove the excess of water before grinding, the second one used a cryogenic mill and the control one a mortar grinding of frozen tissue. The quality of the isolated RNA was tested by carrying out a quantitative real time downstream amplification. RESULTS: In the three situations considered, mean values for A(260) /A(280) indicated minimal interference by proteins and RNA quality indicator (RQI) values were considered appropriate for quantitative real time polymerase chain reaction (qRT-PCR) amplification. Successful qRT-PCR amplifications were obtained with cDNA isolated with the three protocols. CONCLUSION: Both apparatus can improve and facilitate the grinding step in the RNA extraction process in zucchini, resulting in isolated RNA of high quality and integrity as revealed by qRT-PCR downstream application. This is apparently the first time that a cryogenic mill has been used to prepare fruit samples for RNA extraction, thereby improving the sampling strategy because the fine powder obtained represents a homogeneous mix of the organ tissue. PMID- 22517616 TI - Synthesis, characterization, and direct intracellular imaging of ultrasmall and uniform glutathione-coated gold nanoparticles. AB - Gold nanoparticles (AuNPs) with core sizes below 2 nm and compact ligand shells constitute versatile platforms for the development of novel reagents in nanomedicine. Due to their ultrasmall size, these AuNPs are especially attractive in applications requiring delivery to crowded intracellular spaces in the cytosol and nucleus. For eventual use in vivo, ultrasmall AuNPs should ideally be monodisperse, since small variations in size may affect how they interact with cells and how they behave in the body. Here we report the synthesis of ultrasmall, uniform 144-atom AuNPs protected by p-mercaptobenzoic acid followed by ligand exchange with glutathione (GSH). Quantitative scanning transmission electron microscopy (STEM) reveals that the resulting GSH-coated nanoparticles (Au(GSH)) have a uniform mass distribution with cores that contain 134 gold atoms on average. Particle size dispersity is analyzed by analytical ultracentrifugation, giving a narrow distribution of apparent hydrodynamic diameter of 4.0 +/- 0.6 nm. To evaluate the nanoparticles' intracellular fate, the cell-penetrating peptide TAT is attached noncovalently to Au(GSH), which is confirmed by fluorescence quenching and isothermal titration calorimetry. HeLa cells are then incubated with both Au(GSH) and the Au(GSH)-TAT complex, and imaged without silver enhancement of the AuNPs in unstained thin sections by STEM. This imaging approach enables unbiased detection and quantification of individual ultrasmall nanoparticles and aggregates in the cytoplasm and nucleus of the cells. PMID- 22517617 TI - Re: Estimate of deaths due to valvular insufficiency attributable to the use of benfluorex in France. PMID- 22517618 TI - Prostaglandin E2 represses interleukin 1 beta-induced inflammatory mediator output from pregnant human myometrial cells through the EP2 and EP4 receptors. AB - Inflammatory mediators, including prostaglandins, cytokines, and chemokines, are strongly implicated in the mechanism of human labor, though their precise roles remain unknown. Here we demonstrate that interleukin 1 beta (IL-1beta) significantly increased the expression and release of interleukin-8 (CXCL8), monocyte chemotactic protein-1 (CCL2), and granulocyte macrophage colony stimulating factor (CSF2) by primary human myometrial cells. However, this effect was repressed by prostaglandin E(2) (PGE(2)). As PGE(2) can activate four distinct PGE(2) receptors (EP(1), EP(2), EP(3), and EP(4)) to elicit various responses, we sought to define the EP receptor(s) responsible for this repression. Using selective EP receptor agonists and a selective EP(4) antagonist, we show that PGE(2) mediates the repression of IL-1beta-induced release of CXCL8, CCL2, and CSF2 via activation of the EP(2) and EP(4) receptors. The use of siRNA gene-specific knockdown further confirmed a role for both receptors. Real-time RT-PCR demonstrated that EP(2) was the most highly expressed of all four EP receptors at the mRNA level in human myometrial cells, and immunocytochemistry showed that EP(2) protein is abundantly present throughout the cells. Interestingly, PGE(2) does not appear to reduce mRNA expression of CXCL8, CCL2, and CSF2. Our results demonstrate that PGE(2) can elicit anti inflammatory responses via activation of the EP(2) and EP(4) receptors in lower segment term pregnant human myometrial cells. Further elucidation of the EP receptor-mediated signaling pathways in the pregnant human uterus may be beneficial for optimizing the maintenance of pregnancy, induction of labor or indeed treatment of preterm labor. PMID- 22517619 TI - Conceptus-endometrium crosstalk during maternal recognition of pregnancy in cattle. AB - Successful growth and development of the posthatching blastocyst and pregnancy establishment are a result of the interaction between a competent embryo and a receptive uterine environment. We examined the global transcriptome profiles of the Day 16 bovine conceptus and pregnant endometrium tissues using RNA-Seq to identify genes that contribute to the dialogue during the period of pregnancy recognition. Using stringent filtering criterion, a total of 16 018 and 16 262 transcripts of conceptus and pregnant endometrium origin, respectively, were identified with distinct tissue-specific expression profiles. Of these, 2261 and 2505 transcripts were conceptus and endometrium specific. Using Cytoscape software, a total of 133 conceptus ligands that interact with corresponding receptors on the endometrium and 121 endometrium ligands that interact with corresponding receptors on the conceptus were identified. While 87 ligands were commonly detected, 46 were conceptus specific and 34 endometrium specific. This study is one of the first to provide a comprehensive list of potentially secreted molecules in the conceptus that interact with receptors on the endometrium and vice versa during the critical window of maternal recognition of pregnancy. The identified tissue-specific genes may serve as candidates to study pregnancy recognition and they or downstream products may represent potential early markers of pregnancy. PMID- 22517620 TI - Follicle-stimulating hormone accelerates mouse oocyte development in vivo. AB - During folliculogenesis, oocytes grow and acquire developmental competence in a mutually dependent relationship with their adjacent somatic cells. Follicle stimulating hormone (FSH) plays an essential and well-established role in the differentiation of somatic follicular cells, but its function in the development of the oocyte has still not been elucidated. We report here that oocytes of Fshb( /-) mice, which cannot produce FSH, grow at the same rate and reach the same size as those of wild-type mice. Consistent with this observation, the granulosa cells of Fshb(-/-) mice express the normal quantity of mRNA encoding Kit ligand, which has been implicated in oocyte growth. Oocytes of Fshb(-/-) mice also accumulate normal quantities of cyclin B1 and CDK1 proteins and mitochondrial DNA. Moreover, they acquire the ability to complete meiotic maturation in vitro and undergo transition from non-surrounded nucleolus to surrounded nucleolus. However, these events of late oocyte development are significantly delayed. Following in vitro maturation and fertilization, only a small number of embryos derived from oocytes of Fshb(-/-) mice reach the blastocyst stage. Administration of equine chorionic gonadotropin, which provides FSH activity, 48 h before in vitro maturation increases the number of blastocysts obtained subsequently. These results indicate that FSH is not absolutely required for oocyte development in vivo but that this process occurs more rapidly in its presence. We suggest that FSH may coordinate the development of the germline and somatic compartments of the follicle, ensuring that ovulation releases a developmentally competent egg. PMID- 22517621 TI - Sphingomyelinase activity in mother's milk is essential for juvenile development: a case from lactating tsetse flies. AB - Sphingosine is a structural component of sphingolipids. The metabolism of phosphoethanolamine ceramide (sphingomyelin) by sphingomyelinase (SMase), followed by the breakdown of ceramide by ceramidase (CDase) yields sphingosine. Female tsetse fly is viviparous and generates a single progeny within her uterus during each gonotrophic cycle. The mother provides her offspring with nutrients required for development solely via intrauterine lactation. Quantitative PCR showed that acid smase1 (asmase1) increases in mother's milk gland during lactation. aSMase1 was detected in the milk gland and larval gut, indicating this protein is generated during lactation and consumed by the larva. The higher levels of SMase activity in larval gut contents indicate that this enzyme is activated by the low gut pH. In addition, cdase is expressed at high levels in the larval gut. Breakdown of the resulting ceramide is likely accomplished by the larval gut-secreted CDase, which allows absorption of sphingosine. We used the tsetse system to understand the critical role(s) of SMase and CDase during pregnancy and lactation and their downstream effects on adult progeny fitness. Reduction of asmase1 by short interfering RNA negatively impacted pregnancy and progeny performance, resulting in a 4-5-day extension in pregnancy, 10%-15% reduction in pupal mass, lower pupal hatch rates, impaired heat tolerance, reduced symbiont levels, and reduced fecundity of adult progeny. This study suggests that the SMase activity associated with tsetse lactation and larval digestion is similar in function to that of mammalian lactation and represents a critical process for juvenile development, with important effects on the health of progeny during their adulthood. PMID- 22517622 TI - Conceptus-derived prostaglandins regulate endometrial function in sheep. AB - In sheep, the trophectoderm of the elongating conceptus secretes interferon tau (IFNT) and prostaglandins (PGE2, PGF2alpha, PGI2). The PGs are derived from PG synthase 2 (PTGS2), and inhibition of PTGS2 in utero prevents conceptus elongation. IFNT increases expression of many genes in the endometrial epithelia that regulate conceptus elongation. This study tested the hypothesis that PGs secreted by the conceptus regulate endometrial functions that govern conceptus elongation. Cyclic ewes received intrauterine infusions of control vehicle or early pregnancy levels of IFNT, PGE2, PGF2alpha, or PGI2 from Days 10-14 postestrus. Expression levels of endometrial GRP, IGFBP1, and LGALS15, whose products stimulate trophectoderm cell migration and attachment, were increased by PGE2, PGI2, and IFNT. All PGs and IFNT increased expression of the HEXB protease gene, but only IFNT increased the CST6 protease inhibitor gene. Differential effects of PGs were observed for expression of the CTSL protease gene and its inhibitor, CST3. IFNT, PGF2alpha, and PGI2 increased ANGPTL3 expression, but only IFNT and PGE2 increased HIF1A expression, both of which regulate angiogenesis. For glucose transporters, IFNT and all PGs increased SLC2A1 expression, but only PGs increased SLC2A5 expression, whereas endometrial SLC2A12 and SLC5A1 expression levels were increased by IFNT, PGE2, and PGF2alpha. Infusions of all PGs and IFNT increased the amino acid transporter SLC1A5, but only IFNT increased SLC7A2 expression. In the uterine lumen, only IFNT increased glucose levels, and only PGE2 and PGF2alpha increased total amino acids. These results indicate that PGs and IFNT from the conceptus coordinately regulate endometrial functions important for growth and development of the conceptus during the peri implantation period of pregnancy. PMID- 22517623 TI - Blastomere removal from cleavage-stage mouse embryos alters steroid metabolism during pregnancy. AB - Preimplantation genetic diagnosis (PGD) is a genetic screening of embryos conceived with assisted reproduction technologies (ART). A single blastomere from an early-stage embryo is removed and molecular analyses follow to identify embryos carrying genetic defects. PGD is considered highly successful for detecting genetic anomalies, but the effects of blastomere biopsy on fetal development are understudied. We aimed to determine whether single blastomere removal affects steroid homeostasis in the maternal-placental-fetal unit during mouse pregnancy. Embryos generated by in vitro fertilization (IVF) were biopsied at the four-cell stage, cultured to morula/early blastocyst, and transplanted into the oviducts of surrogate mothers. Nonbiopsied embryos from the same IVF cohorts served as controls. Cesarean section was performed at term, and maternal and fetal tissues were collected. Embryo biopsy affected the levels of steroids (estradiol, estrone, and progesterone) in fetal and placental compartments but not in maternal tissues. Steroidogenic enzyme activities (3beta-hydroxysteroid dehydrogenase, cytochrome P450 17alpha-hydroxylase, and cytochrome P450 19) were unaffected but decreased activities of steroid clearance enzymes (uridine diphosphate-glucuronosyltransferase and sulfotransferase) were observed in placentas and fetal livers. Although maternal body, ovarian, and placental weights did not differ, the weights of fetuses derived from biopsied embryos were lower than those of their nonbiopsied counterparts. The data demonstrate that blastomere biopsy deregulates steroid metabolism during pregnancy. This may have profound effects on several aspects of fetal development, of which low birth weight is only one. If a similar phenomenon occurs in humans, it may explain low birth weights associated with PGD/ART and provide a plausible target for improving PGD outcomes. PMID- 22517624 TI - Characterization of Wnt2 overexpression in a rat granulosa cell line (DC3): effects on CTNNB1 activation. AB - WNTs comprise a family of secreted glycoproteins that are essential for normal embryonic development of the female reproductive system. The functional role that WNTs play in the postnatal ovary is poorly defined. We have shown previously that Wnt2 and Fzd4 mRNAs are expressed in granulosa cells of the postnatal rat ovary. Here we examine the effects of Wnt2 overexpression in a rat granulosa cell line (DC3) that displays characteristics of granulosa cells at an early stage of follicular development. We show that DC3 cells express a 7.7-kb Fzd4 mRNA transcript similar in size to that detected in the rat and human ovary. Our results demonstrate that Wnt2 overexpression in DC3 promotes cytosolic and nuclear accumulation of beta-catenin (CTNNB1), but does not stimulate CTNNB1/TCF dependent (pGL3-OT) transcriptional activity. We show that chibby (CBY1), a nuclear CTNNB1-associated antagonist of the WNT pathway, is expressed in DC3 cells and associates with CTNNB1 in the presence and absence of Wnt2 overexpression, suggesting that Cby1 contributes to suppression of CTNNB1/TCF dependent transcription in these cells. Our results show that Wnt2 overexpression in DC3 cells increases follistatin (Fst) mRNA expression and promotes resistance to activin-induced cell deletion. Taken together, our results suggest that WNT2 opposes activin activity in granulosa cells by up-regulating expression of the activin antagonist Fst in a CTNNB1/TCF-independent manner, and that rat granulosa cells express factors, including Cby1, that suppress CTNNB1/TCF-dependent signal transduction in the presence of a WNT signal. PMID- 22517625 TI - From hyperkeratosis to apoptosis: lessons learned from 65 years of research. PMID- 22517626 TI - Rhox5 rules in an evolving saga of reproductive diversity. PMID- 22517627 TI - Nanomaterial-based treatments for medical device-associated infections. AB - Bacterial infections remain one of the biggest concerns to our society. Conventional antibiotic treatments showed little effect on the increasing number of antibiotic-resistant bacteria. Advances in synthetic chemistry and nanotechnology have resulted in a new class of nanometer-scale materials with distinguished properties and great potential to be an alternative for antibiotics. In this Minireview, we address the current situation of medical device-associated infections and the emerging opportunities for antibacterial nanomaterials in preventing these complications. Several important antimicrobial nanomaterials emergent from advances in synthesis chemistry are introduced and their bactericidal mechanisms are analyzed. In addition, concerns regarding the biocompatibility of such materials are also addressed. PMID- 22517628 TI - Towards a green process for bulk-scale synthesis of ethyl acetate: efficient acceptorless dehydrogenation of ethanol. PMID- 22517629 TI - Functionalized Fe3O4 nanoparticles for detecting zinc ions in living cells and their cytotoxicity. AB - The zinc tank: A new fluoro-chromogenic chemosensor based on BODIPY functionalized Fe(3)O(4) nanoparticles (1) has been prepared. Chemoprobe 1 exhibits high selectivity for Zn(2+) over other competing metal ions tested. Moreover, confocal microscopy experiments established that 1 can be used for detecting Zn(2+) levels in living cells (see figure). PMID- 22517630 TI - Real-time microscopy of graphene growth on epitaxial metal films: role of template thickness and strain. AB - Epitaxial transition metal films have recently been introduced as substrates for the scalable synthesis of transferable graphene. Here, real-time microscopy is used to study graphene growth on epitaxial Ru films on sapphire. At high temperatures, high-quality graphene grows in macroscopic (>100 MUm) domains to full surface coverage. Graphene nucleation and growth characteristics on thin (100 nm) Ru films are consistent with a pure surface chemical vapor deposition process, without detectable contributions from C segregation. Experiments on thicker (1 MUm) films show a systematic suppression of the C uptake into the metal to levels substantially below those expected from bulk C solubility data, consistent with a strain-induced reduction of the C solubility due to gas bubbles acting as stressors in the epitaxial Ru films. The results identify two powerful approaches--i) limiting the template thickness and ii) tuning the interstitial C solubility via strain--for controlling graphene growth on metals with high C solubility, such as Ru, Pt, Rh, Co, and Ni. PMID- 22517631 TI - Structure and dynamics in solution of the stop codon decoding N-terminal domain of the human polypeptide chain release factor eRF1. AB - The high-resolution NMR structure of the N-domain of human eRF1, responsible for stop codon recognition, has been determined in solution. The overall fold of the protein is the same as that found in the crystal structure. However, the structures of several loops, including those participating in stop codon decoding, are different. Analysis of the NMR relaxation data reveals that most of the regions with the highest structural discrepancy between the solution and solid states undergo internal motions on the ps-ns and ms time scales. The NMR data show that the N-domain of human eRF1 exists in two conformational states. The distribution of the residues having the largest chemical shift differences between the two forms indicates that helices alpha2 and alpha3, with the NIKS loop between them, can switch their orientation relative to the beta-core of the protein. Such structural plasticity may be essential for stop codon recognition by human eRF1. PMID- 22517633 TI - Hydrogen peroxide electrochemistry on platinum: towards understanding the oxygen reduction reaction mechanism. AB - Understanding the hydrogen peroxide electrochemistry on platinum can provide information about the oxygen reduction reaction mechanism, whether H(2)O(2) participates as an intermediate or not. The H(2)O(2) oxidation and reduction reaction on polycrystalline platinum is a diffusion-limited reaction in 0.1 M HClO(4). The applied potential determines the Pt surface state, which is then decisive for the direction of the reaction: when H(2)O(2) interacts with reduced surface sites it decomposes producing adsorbed OH species; when it interacts with oxidized Pt sites then H(2)O(2) is oxidized to O(2) by reducing the surface. Electronic structure calculations indicate that the activation energies of both processes are low at room temperature. The H(2)O(2) reduction and oxidation reactions can therefore be utilized for monitoring the potential-dependent oxidation of the platinum surface. In particular, the potential at which the hydrogen peroxide reduction and oxidation reactions are equally likely to occur reflects the intrinsic affinity of the platinum surface for oxygenated species. This potential can be experimentally determined as the crossing-point of linear potential sweeps in the positive direction for different rotation rates, hereby defined as the "ORR-corrected mixed potential" (c-MP). PMID- 22517632 TI - Retrospective multicenter observational study of the interventional management of coronary disease in the very elderly: the NINETY. AB - OBJECTIVES: The aim of this observational, multicenter study was to describe the outcome of very elderly patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: There is a paucity of data among nonagenarians undergoing PCI. METHODS: All consecutive patients 90 years of age or older undergoing PCI with stent implantation between April 2002 and June 2009 were included in the study. The primary endpoint was the long-term rate of net adverse cardiac events (NACE), that is, death, myocardial infarction (MI), target lesion revascularization, and life-threatening or major bleedings. RESULTS: One hundred forty-six nonagenarians were divided in three groups according to clinical setting: 27 (group A) stable angina or silent ischemia, 85 (group B) unstable angina or non-ST elevation MI, and 34 (group C) with ST elevation MI (STEMI). At 30 days, the incidence of NACE was significantly lower in patients in Group A vs. B or C (0% vs. 17.3% vs. 31.2%, P = 0.006), and the frequency of definite stent thrombosis was higher in Group C vs. A or B (9.4% vs. 0% vs. 0%, P = 0.007), respectively. Up to a median follow-up of 24 months, NACE rate was 33.3% in group A, 49.3% in group B, and 50% in group C (P = 0.32). There were no significant differences between groups in the individual components of the primary endpoint. CONCLUSIONS: PCI in nonagenarians is safe and feasible with acceptable major bleeding rates. However, long-term results show high mortality rates particularly in the STEMI group. PMID- 22517634 TI - Implementation of the new American Cancer Society process for creating cancer screening guidelines. PMID- 22517635 TI - Are the DSM-IV personality disorders related to mindfulness? An Italian study on clinical participants. AB - OBJECTIVES: This study aims to assess the relationships between measures of mindfulness, self-report, and interview measures of personality disorders (PDs) in a sample of 111 consecutively admitted adult outpatients. RESULTS: When PDs were assessed using the Structured Clinical Interview for DSM-IV Axis II Personality Disorders, Version 2.0, borderline and histrionic PD, as well as the overall number of PD criteria met by each participant, were significantly predicted by mindfulness measures. When the Personality Diagnostic Questionnaire 4+ (PDQ-4+) scale scores were entered in the regression equations as dependent variables, only the obsessive-compulsive PD seemed to be unrelated with mindfulness. The Mindful Attention Awareness Scale total score and the Five Facet Mindfulness Questionnaire Act with Awareness scale were consistent, negative, and nonredundant predictors of PDQ-4+ dimensionally assessed PDs. CONCLUSION: As a whole, our findings support the hypothesis that low levels of mindfulness play a significant role in personality psychopathology, and particularly in borderline PD. PMID- 22517637 TI - Online extraction and isolation of highly polar chemical constituents from Brassica napus L. pollen by high shear technique coupled with high-performance counter-current chromatography. AB - High shear technique coupled with high-performance counter-current chromatography was successfully used for the extraction and online isolation of seven highly polar chemical constituents from the Brassica napus L. The lower phase of ethyl acetate-n-butanol-water (1:4:5, v:v:v) was used as both the high shear technique solvent and high-performance counter-current chromatography mobile phase. Seven compounds of 14.2 mg of uridine, 4.6 mg of xanthosine, 7.8 mg of guanosine, 5.3 mg of adenosine, 19.5 mg of kaempferol-3,4'-di-O-beta-D-glucopyranoside, 17.7 mg of kaempferol-3-O-(2-O-beta-D-glucopyranosy1)-beta-D-glucopyranoside, and 25.7 mg of an unknown compound, with a high-performance liquid chromatography (HPLC) purity over 95.0%, were obtained in a one-step extraction-separation process within 130 min from 20.0 g of raw material of pollen of Brassica napus L. Moreover, the mode of elution-extrusion was employed for the separation of the last one compound. The isolated compounds were analyzed by HPLC, and the chemical structures of the compounds mentioned above were identified by UV and NMR. It is the first time to combine the high shear technique and high-performance counter current chromatography for the online isolation of the nature products. PMID- 22517638 TI - Ultra-high pressure LC determination of glucosamine in shrimp by-products and migration tests of chitosan films. AB - Chitosan, a multiple applications molecule, was isolated from shrimp by-products by fermentation. The amount of chitosan in the solid fraction of the fermented extract was measured after its conversion in the respective glucosamine units. The procedure includes an acid hydrolysis (110 degrees C, 4 h with HCl 8 M) and a derivatization with 9-fluorenylmethyl chloroformate (Fmoc-Cl). Ultra-high pressure liquid chromatography method was developed and optimized. Excellent peaks resolution was achieved in just 10 min. The method was evaluated in what concerns to validation parameters such as linearity, repeatability, quantification limit, and recovery. Migration tests of films prepared with chitosan were carried out in two simulants: ultrapure water and ethanol 95% (v/v). PMID- 22517639 TI - A new solid-phase extraction and HPLC method for determination of patulin in apple products and hawthorn juice in China. AB - A new solid-phase extraction (SPE) pretreatment method using a home-made polyvinylpolypyrrolidone-florisil (PVPP-F) column was developed for the analysis of patulin in apple and hawthorn products in China. Fifty samples (25 apple juices, 12 apple jams, and 13 hawthorn juices) were prepared using the new method and then analyzed by high performance liquid chromatography with diode array detection (HPLC-DAD) on an Agela Venusil MP C(18) reversed-phase column (4.6 mm * 250 mm, 5 MUm). The cleanup results for all samples using home-made PVPP-F column were compared with those obtained using a MycoSep(r)228 AflaPat column. The correlation coefficient R (0.9998) fulfilled the requirement of linearity for patulin in the concentration range of 2.5-250 MUg/kg. The limits of detection (LODs) and quantification (LOQs) of patulin were 3.99 and 9.64 MUg/kg for PVPP-F column, and 3.56 and 8.07 MUg/kg for MycoSep(r)228 AflaPat column, respectively. Samples were spiked with patulin at levels ranging from 25 to 250 MUg/kg, and recoveries using PVPP-F and MycoSep(r)228 AflaPat columns were in the range of 81.9-100.9% and 86.4-103.9%, respectively. Naturally occurring patulin was found in 2 of 25 apple juice samples (8.0%) and 1 of 13 hawthorn juice samples (7.7%) at concentrations ranging from 12.26 to 36.81 MUg/kg. The positive results were further confirmed by liquid chromatography electrospray ionization mass spectrometry (LC-ESI-MS). PMID- 22517640 TI - Determination of five priority haloacetic acids by capillary electrophoresis with contactless conductivity detection and solid phase extraction preconcentration. AB - A sensitive capillary electrophoretic separation method with contactless conductivity detection (C4D) for analysis of five priority haloacetic acids (HAA5) is presented. The analytes were baseline separated in an electrolyte composed of 20 mM 2-(N-Morpholino) ethanesulfonic acid (MES), 20 mM L-histidine (HIS), and 30 MUM cetyltrimethylammonium bromide (CTAB) at pH 6.0 in less than 4 min. A simplified solid-phase extraction (SPE) preconcentration procedure on highly cross-linked polystyrene-divinylbenzene (PS-DVB) type sorbent was developed and optimized with respect to short preconcentration time. HAA5 from a 25-mL sample aliquot of tap and swimming pool water could be preconcentrated in less than 5 min using an in-house made SPE column with recoveries ranging from 23 to 98%. Combining the SPE preconcentration procedure with capillary electrophoretic analysis, the attained limits of detection were between 6.1 and 12.2 MUg/L with total analysis time of less than 10 min. PMID- 22517641 TI - Inside needle capillary adsorption trap device for headspace solid-phase dynamic extraction based on polyaniline/hexagonally ordered silica nanocomposite. AB - Highly porous polyaniline/hexagonally ordered silica sorbent was used for fabrication of the inside needle capillary adsorption trap (INCAT) device. Polyaniline/SBA-15 nanocomposite was synthesized via chemical polymerization technique. The fabricated INCAT device was evaluated to the extraction of some polycyclic aromatic hydrocarbons (PAHs) from aqueous sample solutions in combination with gas chromatography (GC)-mass spectrometry (MS). A one at-the time optimization strategy was applied for optimizing the important extraction parameters such as extraction temperature, extraction time, ionic strength, sampling flow rate, desorption time, and desorption temperature. In optimum conditions (extraction temperature 55 degrees C, extraction time 20 min, ionic strength 20% (w/v), flow rate 4.5 mL min(-1), desorption temperature 270 degrees C, desorption time 3 min) the repeatability for one INCAT device (n = 4), expressed as relative standard deviation, was between 4.2 and 10.2% for the tested compounds. The quantitation limits for the studied compounds were between 1 and 5 pg mL(-1). The developed method was successfully applied to spring water sample which was spiked with PAHs with the relative recovery percentages of 87.3 109.1%. The developed method offers the advantage of being simple to use, with shorter analysis times, lower cost of equipment, and thermal stability. PMID- 22517642 TI - Analysis of quinolones by voltage-assisted liquid-phase microextraction combined with LC-MS. AB - The method of liquid-phase microextraction assisted with voltage was developed and applied on determination of quinolones in water sample in this study. Both of the reproducibility and extraction time were improved with the aid of applying voltage. Four analytes in neutral state such as cinoxacin, oxolinic acid, nalidixic acid, and flumequine were extracted from a sample solution at pH 2.0, through a polypropylene hollow fiber which was immobilized with 2-octanone, and then into a 25 MUL of the acceptor phase of 40 mM borate buffer at pH 10.0 by applying voltage of 100 V. Subsequently, the acceptor solution was directly subjected to analysis by LC-MS. The performance of the method for four quinolones was also evaluated. Linearity was obtained in the range of 1.0-25.0 ng/mL with R(2) > 0.996. Limits of detection were below 0.6 ng/mL, and recoveries of water sample were ranged from 90.8 to 109.6%. PMID- 22517643 TI - Determination of 4-methylpiperaine-1-carbodithioc acid 3-cyano-3,3-diphenylpropyl ester hydrochloride in rats' plasma by online-SPE-HPLC-DAD: application to a pharmacokinetic study. AB - A specific, simple, and fast online-solid-phase extraction-high performance liquid chromatography-diode array detector (SPE-HPLC-DAD) method was developed and validated to quantify 4-methylpiperaine-1-carbodithioc acid 3-cyano-3,3 diphenylpropyl ester hydrochloride (TM208) in small volume samples of rats' plasma for the first time. In this method, the 50-MUL plasma sample was taken to perform protein precipitation with 75 MUL methanol, and then 50 MUL supernatant containing the target analytes was injected and concentrated automatically in a C18 solid-phase extraction (SPE) cartridge. After that the sample was separated on a C18 RP analytical column and analyzed by DAD. The run cycle time is 6.0 min for each sample, and the calibration curve over the range of 0.03 to 25.00 MUg/mL has a good linear relationship (r > 0.9998). The recoveries of the quality control samples were all greater than 90%. The limit of detection and the lowest limit of quantification were 0.01 and 0.03 MUg/mL, respectively. Finally, this method was successfully applied to a pharmacokinetic study of TM208 in rats. PMID- 22517645 TI - Stereoselective synthesis of alpha- and beta-glycofuranosyl amides by traceless ligation of glycofuranosyl azides. AB - A highly stereoselective synthesis of alpha- or beta-glycofuranosyl amides based on the traceless Staudinger ligation of glycofuranosyl azides of the galacto, ribo, and arabino series with 2-diphenylphosphanyl-phenyl esters has been developed. Both alpha- and beta-isomers can be obtained with excellent selectivity from a common, easily available precursor. The process does not depend on the anomeric configuration of the starting azide but appears to be controlled by the C2 configuration and by the protection/deprotection state of the substrates. A mechanistic interpretation of the results, supported by (31)P NMR experiments, is offered and merged with our previous mechanistic analysis of pyranosyl azide ligation reactions. PMID- 22517646 TI - Remote ischemic preconditioning immediately before percutaneous coronary intervention does not impact myocardial necrosis, inflammatory response, and circulating endothelial progenitor cell counts: a single center randomized sham controlled trial. AB - AIMS: Percutaneous coronary intervention (PCI) is frequently accompanied by myocardial injury. The present study was performed to determine whether remote ischemic preconditioning (IP) induces cardioprotection during PCI. METHODS: We enrolled 95 patients requiring nonemergency PCI for stable disease or unstable angina into this prospective clinical trial. Patients were randomized to either remote IP (induced by three 3-min cycles of blood pressure cuff inflations to 200 mm Hg around the upper arm, followed by 3-min of reperfusion n = 47) or sham control (n = 48) immediately preceding PCI. The primary outcome measure was the frequency of post-PCI myonecrosis, defined as a peak postprocedural cTnT T >= 0.03 ng/dL. Secondary outcome measures were the change in plasma high-sensitivity C-reactive protein (hsCRP) levels following PCI and in endothelial progenitor cells (EPC) counts following IP. RESULTS: There was no difference in the primary endpoint of the frequency of PCI related myonecrosis which occurred in 22 (47%) and 19 (40%) patients in the remote IP and control groups, respectively, P = 0.42. There was significant increase in hsCRP post-PCI in both groups (P < 0.001), but there was no difference between the groups (median %change in hsCRP 46% vs. 54%, P = 0.73). There was no significant change in circulating early (CD34 -/CD133+/KDR+), intermediate (CD34+/CD133+/KDR+), or late (CD34+/CD133 /KDR+) EPC in the two groups immediately following IP. The composite rate of death, myocardial infarction, and target lesion revascularization at 1 year was 14.1% versus 13.7% (P = 0.90). CONCLUSIONS: Our study indicates that remote IP immediately before PCI does not induce cardioprotection in low to moderate risk patients. PMID- 22517647 TI - beta-cell-specific gene repression: a mechanism to protect against inappropriate or maladjusted insulin secretion? PMID- 22517648 TI - Paradigm shift or shifting paradigm for type 1 diabetes. PMID- 22517649 TI - PGC-1alpha: the missing ingredient for mesenchymal stem cell-mediated angiogenesis. PMID- 22517650 TI - Challenges of linking early-life conditions and disease susceptibility. PMID- 22517651 TI - Do acute exercise and diet reveal the molecular basis for metabolic flexibility in skeletal muscle? PMID- 22517652 TI - Selective insulin receptor modulators (SIRM): a new class of antidiabetes drugs? PMID- 22517653 TI - GLP-1-based therapies and the exocrine pancreas: more light, or just more heat? PMID- 22517654 TI - GLP-1 receptor agonist effects on normal and neoplastic pancreata. PMID- 22517655 TI - Mitochondria, diabetes, and Alzheimer's disease. PMID- 22517656 TI - A sweet new role for ubiquitin-specific protease 2 in controlling hepatic gluconeogenesis. PMID- 22517660 TI - Comment on: Marquez et al. Low-frequency variants in HMGA1 are not associated with type 2 diabetes risk. Diabetes 2012;61:524-530. PMID- 22517657 TI - The role of liver fructose-1,6-bisphosphatase in regulating appetite and adiposity. AB - Liver fructose-1,6-bisphosphatase (FBPase) is a regulatory enzyme in gluconeogenesis that is elevated by obesity and dietary fat intake. Whether FBPase functions only to regulate glucose or has other metabolic consequences is not clear; therefore, the aim of this study was to determine the importance of liver FBPase in body weight regulation. To this end we performed comprehensive physiologic and biochemical assessments of energy balance in liver-specific transgenic FBPase mice and negative control littermates of both sexes. In addition, hepatic branch vagotomies and pharmacologic inhibition studies were performed to confirm the role of FBPase. Compared with negative littermates, liver-specific FBPase transgenic mice had 50% less adiposity and ate 15% less food but did not have altered energy expenditure. The reduced food consumption was associated with increased circulating leptin and cholecystokinin, elevated fatty acid oxidation, and 3-beta-hydroxybutyrate ketone levels, and reduced appetite-stimulating neuropeptides, neuropeptide Y and Agouti-related peptide. Hepatic branch vagotomy and direct pharmacologic inhibition of FBPase in transgenic mice both returned food intake and body weight to the negative littermates. This is the first study to identify liver FBPase as a previously unknown regulator of appetite and adiposity and describes a novel process by which the liver participates in body weight regulation. PMID- 22517661 TI - Postradiation sarcoma: morphological findings on fine-needle aspiration with clinical correlation. AB - BACKGROUND: The current study was conducted to describe the clinical features and presentation, cytomorphological characteristics with histological correlation, and prognosis of patients who undergo fine-needle aspiration (FNA) for postradiation sarcoma (PRS). METHODS: A retrospective review was performed of 13 individual patients who were pooled from the FNA services of 3 academic institutions between 2001 and 2012. Cases were reviewed for the primary tumor, radiation history, latency period, and other distinguishing clinical features. The frequency of the various cytological preparations as well as the use of immunohistochemistry (IHC) on this material were reviewed. The cytopathology diagnosis was compared with the resection diagnosis, and the survival time was reviewed. RESULTS: The median age of the patients was 61 years (range, 35 years 94 years) and no significant gender predilection was noted. The median latency period was 11 years (range, 5 years to > 50 years). Patients generally presented with large tumors (median, 8 cm [range, 3 cm-12 cm]), and the median survival was 14 months (range, 6 months-46 months). Nine of 13 patients died of their disease and 1 was lost to follow-up. The tumors were morphologically heterogeneous. IHC played an important role in excluding other diagnoses in those cases in which sufficient material was available. CONCLUSIONS: PRS is a morphologically heterogeneous entity that can be diagnosed by FNA. It is a diagnosis of exclusion that requires a history of therapeutic radiation and often requires IHC to rule out locally recurrent malignancy. PMID- 22517662 TI - High-resolution crystal structure of FKBP12 from Aedes aegypti. AB - Dengue is one of the most infectious viral diseases prevalent mainly in tropical countries. The virus is transmitted by Aedes species of mosquito, primarily Aedes aegypti. Dengue remains a challenging drug target for years as the virus eludes the immune responses. Currently, no vaccines or antiviral drugs are available for dengue prevention. Previous studies suggested that the immunosuppressive drug FK506 shows antimalarial activity, and its molecular target, FK506-binding protein (FKBP), was identified in the Plasmodium parasite. Likewise, a FKBP family protein has been identified in A. aegypti (AaFKBP12) in which AaFKBP12 is assumed to play a similar role in its life cycle. FKBPs belong to a highly conserved class of proteins and are considered as an attractive pharmacological target. Herein, we present a high-resolution crystal structure of AaFKBP12 at 1.3 A resolution and discuss its structural features throwing light in facilitating the design of potential antagonists against the dengue-transmitting mosquito. PMID- 22517663 TI - Systematic investigation of the effect of lyophilizate collapse on pharmaceutically relevant proteins, part 2: stability during storage at elevated temperatures. AB - The objective of this work was to investigate the effect of lyophilizate collapse on the stability of freeze-dried protein pharmaceuticals. In the first part of this study, it was shown that collapse has no negative impact either on the properties of the freeze-dried cake or on protein stability [Schersch K, Betz O, Garidel P, Muehlau S, Bassarab S, Winter G. 2010. J Pharm Sci 99(5):2256-2278]. In order to further investigate the effect of collapse, its impact on lyophilizate's long-term stability during storage at various temperatures was evaluated at 2 degrees C-8 degrees C, 25 degrees C, 40 degrees C, and 50 degrees C for up to 6 months. Collapsed and noncollapsed lyophilizates of identical formulation and comparable residual moisture levels containing the following proteins were investigated: (1) a monoclonal immunoglobulin G antibody, (2) tissue-type plasminogen activator, and (3) the sensitive model protein l-lactic dehydrogenase. Protein stability was monitored using a comprehensive set of analytical techniques assessing the formation of soluble and insoluble aggregates, the biological activity, and the protein conformation. The properties of the freeze-dried cake--namely, the glass transition temperature, excipient crystallinity, reconstitution behavior, and the residual moisture content, were analyzed as well. Full protein stability in collapsed cakes was observed, and even enhanced protein stability was detected in collapsed cakes with regard to key stability-indicating parameters. PMID- 22517664 TI - Investigating attribute non-attendance and its consequences in choice experiments with latent class models. AB - A growing literature, mainly from transport and environment economics, has started to explore whether respondents violate some of the axioms about individuals' preferences in Discrete Choice Experiments (DCEs) and use simple strategies to make their choices. One of these strategies, termed attribute non attendance (ANA), consists in ignoring one or more attributes. Using data from a DCE administered to healthcare providers in Ghana to evaluate their potential resistance to changes in clinical guidelines, this study illustrates how latent class models can be used in a step-wise approach to account for all possible ANA strategies used by respondents and explore the consequences of such behaviours. Results show that less than 3% of respondents considered all attributes when choosing between the two hypothetical scenarios proposed, with a majority looking at only one or two attributes. Accounting for ANA strategies improved the goodness-of-fit of the model and affected the magnitude of some of the coefficient and willingness-to-pay estimates. However, there was no difference in the predicted probabilities of the model taking into account ANA and the standard approach. Although the latter result is reassuring about the ability of DCEs to produce unbiased policy guidance, it should be confirmed by other studies. PMID- 22517665 TI - Physically crosslinked nanocomposites from silicate-crosslinked PEO: mechanical properties and osteogenic differentiation of human mesenchymal stem cells. AB - The mechanical and biological properties of silicate-crosslinked PEO nanocomposites are studied. A strong correlation is observed between silicate concentration and mechanical properties. In vitro cell culture studies reveal that an increase in silicate concentration enhances the attachment and proliferation of human mesenchymal stem cells significantly. An upregulation in the expression of osteocalcin on nanocomposites compared to the tissue culture polystyrene control is observed. Together, these results suggest that silicate based nanocomposites are bioactive and have the potential to be used in a range of biotechnological and biomedical applications such as injectable matrices, biomedical coatings, drug delivery, and regenerative medicine. PMID- 22517666 TI - Recurrent coronary artery thrombosis after anomalous right coronary artery re implantation to the aorta. AB - Anomalous origin of the right coronary artery (RCA) from the pulmonary artery is a rare entity. The current recommendation is corrective operation even in asymptomatic patients when this cardiac malformation is found. We report a case of a 21-year-old male who initially presented with ST elevations. After surgical repair with re-implantation of the RCA to the aorta, he was found to have an acute thrombus in his left circumflex and several months later developed a thrombus in the proximal left anterior descending artery. We propose that the change from a hyperkinetic high flow state to a slow flow state in the setting of inadequate coronary flow reserve and endothelial function predisposed our patient to thrombus formation in the persistently dilated coronary arteries. It is expected that restoration of normal flow pattern in all coronary arteries will result in normalization of perfusion, decrease in feeding artery size, and return of endothelial function. Because this anomaly is rare, limited information exists on the effects of the procedure on myocardial perfusion. These findings raise the question of whether re-implantation of the anomalous artery is truly the superior approach. PMID- 22517667 TI - Synthesis and conformation of fluorinated beta-peptidic compounds. AB - Experimental and theoretical data indicate that, for alpha-fluoroamides, the F-C C(O)-N(H) moiety adopts an antiperiplanar conformation. In addition, a gauche conformation is favoured between the vicinal C-F and C-N(CO) bonds in N-beta fluoroethylamides. This study details the synthesis of a series of fluorinated beta-peptides (1-8) designed to use these stereoelectronic effects to control the conformation of beta-peptide bonds. X-ray crystal structures of these compounds revealed the expected conformations: with fluorine beta to a nitrogen adopting a gauche conformation, and fluorine alpha to a C=O group adopting an antiperiplanar conformation. Thus, the strategic placement of fluorine can control the conformation of a beta-peptide bond, with the possibility of directing the secondary structures of beta-peptides. PMID- 22517668 TI - Solution structure of the E3 ligase HOIL-1 Ubl domain. AB - The E3 ligases HOIL-1 and parkin are each comprised of an N-terminal ubiquitin like (Ubl) domain followed by a zinc-binding region and C-terminal RING-In between-RING-RING domains. These two proteins, involved in the ubiquitin-mediated degradation pathway, are the only two known E3 ligases to share this type of multidomain architecture. Further, the Ubl domain of both HOIL-1 and parkin has been shown to interact with the S5a subunit of the 26S proteasome. The solution structure of the HOIL-1 Ubl domain was solved using NMR spectroscopy to compare it with that of parkin to determine the structural elements responsible for S5a intermolecular interactions. The final ensemble of 20 structures had a beta-grasp Ubl-fold with an overall backbone RMSD of 0.59 +/- 0.10 A in the structured regions between I55 and L131. HOIL-1 had a unique extension of both beta1 and beta2 sheets compared to parkin and other Ubl domains, a result of a four-residue insertion in this region. A similar 15-residue hydrophobic core in the HOIL-1 Ubl domain resulted in a comparable stability to the parkin Ubl, but significantly lower than that observed for ubiquitin. A comparison with parkin and other Ubl domains indicates that HOIL-1 likely uses a conserved hydrophobic patch (W58, V102, Y127, Y129) found on the beta1 face, the beta3-beta4 loop and beta5, as well as a C-terminal basic residue (R134) to recruit the S5a subunit as part of the ubiquitin-mediated proteolysis pathway. PMID- 22517669 TI - Gold(I)-catalyzed rearrangement of 3-silyloxy-1,5-enynes: an efficient synthesis of benzo[b]thiophenes, dibenzothiophenes, dibenzofurans, and indole derivatives. AB - With the IPr ligand (IPr=1,3-bis-(2,6-diisopropylphenyl)imidazol-2-ylidene) on gold(I) excellent yields in the benzanellation of 2-substituted thiophenes, benzothiophenes, pyrroles, benzofurans, and indoles were achieved. The 1 siloxybut-3-ynyl side chains, incorporated in the anellation, are easily accessible by the addition of a propargyl metal reagent to a formyl group and silylation of the alcohol. This conveniently allows an anellation at the position of the formyl group under mild conditions. All reactions involve a 2,3-shift of the side chain in the anellation step and thus, provide an easy access to specific substitution patterns. Only in the case of 2-substituted indoles with their highly nucleophilic 3-position a direct hydroarylation without shift is observed. On the other hand, 3-substituted indoles give the same products as 2 substituted indoles. Then, a 3,2-shift in the indole ring system has to be involved. PMID- 22517670 TI - Changing strategies of the retrograde approach for chronic total occlusion during the past 7 years. AB - OBJECTIVE: We reviewed the technical changes and results achieved with the retrograde approach since we introduced it 7 years ago. SUBJECTS AND METHODS: The subjects were 1,268 patients who were treated for CTO between January 2004 and December 2010. They were investigated with respect to the success rate, the frequency of employing the retrograde approach and its outcome, and other factors. RESULTS: The retrograde approach was employed in ~30% of chronic total occlusion (CTO) patients (n = 281) and the retrograde guidewire success rate was 81.1%. The kissing wire technique was substituted for the retrograde approach in 126 of the 281 patients, with antegrade crossing of a guidewire being successful in 88 of them (70%). The retrograde approach was combined with the CART and reverse controlled antegrade retrograde tracking (CART) techniques in 22 and 21 patients, respectively. Among 83 patients treated with Corsair catheters, crossing of the CTO was achieved in 63. The overall procedural success rate was 79.7% (224 patients). Complications of the retrograde approach included collateral channel dissection (2.1%), channel perforation (1.7%), CTO perforation (1.7%), and donor artery occlusion (1.1%). CONCLUSION: The success rate and safety of the retrograde approach are both satisfactory if the appropriate devices and techniques are selected. PMID- 22517671 TI - Phenylboronic-acid-modified amphiphilic polyether as a neutral gene vector. AB - A phenylboronic-acid-modified amphiphilic block polyether is prepared via reaction of polyglycidol-block-poly(ethylene oxide)-block-poly(propylene oxide) block-poly(ethylene oxide)-block-polyglycidol (Pluronic-PG) with 2-(N,N dimethylaminomethyl)-5-aminomethyl phenylboronic acid using phosgene as a coupling reagent. The boronic-acid-modified non-cationic polymer binds plasmid pGL3 effectively, forms sub-um polymer/DNA complex particles, and greatly facilitates the cell uptake of the plasmid. The efficiency of the polymer as a gene vector is evaluated in vitro by transfection of pGL3 to HeLa, COS-7 and HepG2 cells. Pluronic-PG-BA enhances the transfection efficiency by 100 to 1000 times compared with Pluronic-PG. The presence of serum does not significantly affect the transfection efficiency. PMID- 22517672 TI - Does on-site adequacy evaluation reduce the nondiagnostic rate in endoscopic ultrasound-guided fine-needle aspiration of pancreatic lesions? AB - BACKGROUND: This retrospective study compared the nondiagnostic rate for endoscopic ultrasound-guided (EUS) fine-needle aspiration (FNA) of pancreatic lesions in 2 settings: 1 with and 1 without on-site evaluation. METHODS: The authors reviewed 381 consecutive cases and divided them into groups with and without on-site adequacy evaluation. For the group with on-site evaluation, cytopathology personnel prepared and evaluated Diff-Quik-stained direct smears and rinsed the remaining material in CytoLyt solution (Cytyc Corporation, Marlborough, Mass). The group without on-site evaluation was divided into 2 subgroups: the clinical team either prepared an air-dried smear for each FNA pass and then rinsed the remaining material in CytoLyt, or the entire sample was rinsed in CytoLyt. The cytologic diagnoses were reviewed and the nondiagnostic rates for each group were calculated. RESULTS: On-site evaluation was provided for 167 cases with a nondiagnostic rate of 25.8% (43 of 167 cases). On-site evaluation was not provided for 214 cases with a nondiagnostic rate of 24.3% (52 of 214 cases). The nondiagnostic rate for the subgroup with air-dried smears prepared by the clinical team was 25.6% (43 of 168 cases) and that for the subgroup with the entire sample rinsed in CytoLyt was 19.6% (9 of 46 cases). There were no significant statistical differences in nondiagnostic rates noted among the different groups or subgroups. CONCLUSIONS: The results of the current study indicate that when experienced operators perform EUS FNA of pancreatic lesions, on-site adequacy evaluation offers no benefit in reducing the nondiagnostic rate. Optimizing visualization of the sampled material by omitting the preparation of direct smears and rinsing the entire sample in liquid-based media demonstrated a trend toward improving the diagnostic rate. PMID- 22517673 TI - Design and synthesis of novel "orthogonally" functionalizable maleimide-based styrenic copolymers. AB - Polymers containing maleimide groups on their side chains have been synthesized by utilization of a novel styrenic monomer containing a masked-maleimide unit. AIBN initiated free radical polymerization and reverse addition-fragmentation chain transfer (RAFT) polymerization was utilized for synthesis of copolymers containing masked maleimide groups as side chains. The maleimide groups were unmasked via the retro Diels-Alder reaction. Orthogonally functionalizable copolymers were obtained by copolymerization of the maleimide-based monomer with other reactive monomers to yield copolymers that are reactive towards thiol- and amine-containing molecules, or two different thiol-containing molecules sequentially via the nucleophilic thiol-ene and the free-radical thiol-ene "click" reactions. PMID- 22517674 TI - Thermoresponsive poly(N-isopropylacrylamide)-based block copolymer coating for optimizing cell sheet fabrication. AB - Thermoresponsive surfaces are prepared via a spin-coating method with a block copolymer consisting of poly(N-isopropylacrylamide) (PIPAAm) and poly(butyl methacrylate) (PBMA) on polystyrene surfaces. The PBMA block suppresses the removal of deposited PIPAAm-based polymers from the surface. The polymer coating affects the temperature-dependent cellular behavior of the surfaces with respect to protein adsorption. By adjusting layer thicknesses, PBMA-b-PIPAAm-coated surfaces are optimized to regulate the adhesion/detachment of cells by temperature changes. Thus, thermoresponsive polymer-coated surfaces are able to harvest contiguous cell sheets with their basal extracellular matrix proteins. PMID- 22517675 TI - Immunoglobulin heavy-chain fluorescence in situ hybridization-chromogenic in situ hybridization DNA probe split signal in the clonality assessment of lymphoproliferative processes on cytological samples. AB - BACKGROUND: The human immunoglobulin heavy-chain (IGH) locus at chromosome 14q32 is frequently involved in different translocations of non-Hodgkin lymphoma (NHL), and the detection of any breakage involving the IGH locus should identify a B cell NHL. The split-signal IGH fluorescence in situ hybridization-chromogenic in situ hybridization (FISH-CISH) DNA probe is a mixture of 2 fluorochrome-labeled DNAs: a green one that binds the telomeric segment and a red one that binds the centromeric segment, both on the IGH breakpoint. In the current study, the authors tested the capability of the IGH FISH-CISH DNA probe to detect IGH translocations and diagnose B-cell lymphoproliferative processes on cytological samples. METHODS: Fifty cytological specimens from cases of lymphoproliferative processes were tested using the split-signal IGH FISH-CISH DNA probe and the results were compared with light-chain assessment by flow cytometry (FC), IGH status was tested by polymerase chain reaction (PCR), and clinicohistological data. RESULTS: The signal score produced comparable results on FISH and CISH analysis and detected 29 positive, 15 negative, and 6 inadequate cases; there were 29 true-positive cases (66%), 9 true-negative cases (20%), 6 false-negative cases (14%), and no false-positive cases (0%). Comparing the sensitivity of the IGH FISH-CISH DNA split probe with FC and PCR, the highest sensitivity was obtained by FC, followed by FISH-CISH and PCR. CONCLUSIONS: The split-signal IGH FISH-CISH DNA probe is effective in detecting any translocation involving the IGH locus. This probe can be used on different samples from different B-cell lymphoproliferative processes, although it is not useful for classifying specific entities. Cancer (Cancer Cytopathol) 2012;. (c) 2012 American Cancer Society. PMID- 22517676 TI - Avian predators as a biological control system of common vole (Microtus arvalis) populations in north-western Spain: experimental set-up and preliminary results. AB - BACKGROUND: Ecologically based rodent pest management using biological control has never been evaluated for vole plagues in Europe, although it has been successfully tested in other systems. The authors report on the first large-scale replicated experiment to study the usefulness of nest-box installation for increasing the breeding density of common kestrels (Falco tinnunculus) and barn owls (Tyto alba) as a potential biological control of common vole (Microtus arvalis) abundance in agricultural habitats in north-western Spain. RESULTS: The results show that: (1) population density of both predator species increased in response to both nest-site availability and vole density; (2) voles are a major prey for the common kestrels during the breeding period; (3) vole density during the increase phase of a population cycle may be reduced in crop fields near nest boxes. CONCLUSION: The installation of nest boxes provides nesting sites for barn owls and kestrels. Kestrel populations increased faster than in areas without artificial nests, and the common vole was one of their main prey during the breeding season. The results suggest that local (field) effects could be found in terms of reduced vole density. If so, this could be an environmentally friendly and cheap vole control technique to be considered on a larger scale. PMID- 22517677 TI - Forming interdisciplinary expertise: one organization's journey on the road to translational nanomedicine. AB - This paper provides a sociological account of how researchers of different disciplines become experts in translational nanomedicine. Using a case study of the Nanotechnology Characterization Laboratory (NCL) at the National Cancer Institute (NCI), the author argues that the relationship between the different disciplines involved in translational nanomedicine should be understood in the broader sociopolitical context of the boundary politics between the academy, industry, and government. This study suggests that the process of training the nanobio expert is not simply a process of inculcating skills; it is also a process of institution building. In the case of the NCL, sustaining the laboratory's existence at the interface between the university, industry, and government informed how researchers practiced interdisciplinarity and cultivated their interdisciplinary expertise. It required mobilizing institutional resources through administrative/managerial strategies. Viewing the formation of a professional identity as a social process helps clarify the meaning of interdisciplinarity and provides insight in evaluating the performance of interdisciplinary collaboration and the design of nanoscience education. PMID- 22517678 TI - Hexokinase II knockdown results in exaggerated cardiac hypertrophy via increased ROS production. AB - Hexokinase-II (HKII) is highly expressed in the heart and can bind to the mitochondrial outer membrane. Since cardiac hypertrophy is associated with a substrate switch from fatty acid to glucose, we hypothesized that a reduction in HKII would decrease cardiac hypertrophy after pressure overload. Contrary to our hypothesis, heterozygous HKII-deficient (HKII(+/-)) mice displayed increased hypertrophy and fibrosis in response to pressure overload. The mechanism behind this phenomenon involves increased levels of reactive oxygen species (ROS), as HKII knockdown increased ROS accumulation, and treatment with the antioxidant N acetylcysteine (NAC) abrogated the exaggerated response. HKII mitochondrial binding is also important for the hypertrophic effects, as HKII dissociation from the mitochondria resulted in de novo hypertrophy, which was also attenuated by NAC. Further studies showed that the increase in ROS levels in response to HKII knockdown or mitochondrial dissociation is mediated through increased mitochondrial permeability and not by a significant change in antioxidant defenses. Overall, these data suggest that HKII and its mitochondrial binding negatively regulate cardiac hypertrophy by decreasing ROS production via mitochondrial permeability. PMID- 22517679 TI - Adaptive organic nanoparticles of a teflon-coated iron (III) porphyrin catalytically activate dioxygen for cyclohexene oxidation. AB - Self-organized organic nanoparticles (ONP) are adaptive to the environmental reaction conditions. ONP of fluorous alkyl iron(III) porphyrin catalytically oxidize cyclohexene to the allylic oxidation products. In contrast, the solvated metalloporphyrin yields both allylic oxidation and epoxidation products. The ONP system facilitates a greener reaction because about 89% reaction medium is water, molecular oxygen is used in place of synthetic oxidants, and the ambient reaction conditions used require less energy. The enhanced catalytic activity of these ONP is unexpected because the metalloporphyrins in the nanoaggregates are in the close proximity and the TON should diminish by self-oxidative degradation. The fluorous alkyl chain stabilizes the ONP toward self-oxidative degradation. PMID- 22517682 TI - Propagation rate coefficients for homogeneous phase VDF-HFP copolymerization in supercritical CO2. AB - For the first time, propagation rate coefficients, k(p,COPO) , for the copolymerizations of vinylidene fluoride and hexafluoropropene have been determined. The kinetic data was determined via pulsed-laser polymerization in conjunction with polymer analysis via size-exclusion chromatography, the PLP-SEC technique. The experiments were carried out in homogeneous phase with supercritical CO(2) as solvent for temperatures ranging from 45 to 90 degrees C. Absolute polymer molecular weights were calculated on the basis of experimentally determined Mark-Houwink constants. The Arrhenius parameters of k(p,COPO) vary significantly compared with ethene, which is explained by the high electronegativity of fluorine and less intra- and intermolecular interactions between the partially fluorinated macroradicals. PMID- 22517683 TI - A novel flow-injection chemiluminescence method for determination of andrographolide in andrographis tablets. AB - A novel method for determination of andrographolide using flow-injection chemiluminescence (FI-CL) analysis is described in this paper. The chemiluminescence intensity of the solution was enhanced proportionally while the concentration of andrographolide increased. Under the selected experimental conditions, the calibration curve of andrographolide was linear within the range of 0.2 to 35.0 ug mL(-1) with a linear equation of DeltaI = 23.391x (ug mL(-1)) + 34.191, R(2) = 0.9965. The detection limit (3sigma) was 7.42 * 10(-2) ug mL(-1). At the case of continuous determination of andrographolide, the relative standard deviation (RSD, n =11) was less than 1.82%. The method has been successfully applied to the determination of andrographis tablets with satisfactory results. PMID- 22517685 TI - pH-induced shape-memory polymers. AB - A novel pH sensitive shape-memory polymer (SMP) is prepared by cross-linking the beta-cyclodextrin modified alginate (beta-CD-Alg) and diethylenetriamine modified alginate (DETA-Alg): The pH reversible beta-CD-DETA inclusion complexes serve as a reversible phase, and the cross-linked alginate chains serve as a fixing phase. It is shown that this material can be processed into temporary shape as we needs at pH 11.5 and recover to its initial shape at pH 7. The recovery ratio and the fixity ratio were 95.7 +/- 0.9% and 94.8 +/- 1.1%, respectively. Furthermore, this material showed good degradability and biocompatibility. Because the shape transition pH value is quite close to that of our body fluid and this pH triggered shape-memory effect is convenient and safe to use, this material has a high potential for medical application. PMID- 22517680 TI - Head-twitch response in rodents induced by the hallucinogen 2,5-dimethoxy-4 iodoamphetamine: a comprehensive history, a re-evaluation of mechanisms, and its utility as a model. AB - Two primary animal models persist for assessing hallucinogenic potential of novel compounds and for examining the pharmacological and neurobiological substrates underlying the actions of classical hallucinogens, the two-lever drug discrimination procedure and the drug-induced head-twitch response (HTR) in rodents. The substituted amphetamine hallucinogen, serotonin 2 (5-HT(2) ) receptor agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI) has emerged as the most popular pharmacological tool used in HTR studies of hallucinogens. Synthesizing classic, recent, and relatively overlooked findings, addressing ostensibly conflicting observations, and considering contemporary theories in receptor and behavioural pharmacology, this review provides an up-to-date and comprehensive synopsis of DOI and the HTR model, from neural mechanisms to utility for understanding psychiatric diseases. Also presented is support for the argument that, although both the two-lever drug discrimination and the HTR models in rodents are useful for uncovering receptors, interacting proteins, intracellular signalling pathways, and neurochemical processes affected by DOI and related classical hallucinogens, results from both models suggest they are not reporting hallucinogenic experiences in animals. PMID- 22517686 TI - Expandable tumor prostheses in children. AB - Any surgical resection in the lower extremities in children will cause a leg length discrepancy from physeal resection. To avoid the resulting functional deficit, leg length discrepancy must be reconciled with surgical techniques to approximate equal leg lengths at skeletal maturity. Currently there are several manufacturers who offer options for prosthetic reconstruction with expandable implants. These implants can be expanded to a length projected on the basis of three factors: the length of bone resected, the anticipated future growth of the contralateral extremity, and the estimated discrepancy of limb length at skeletal maturity. In this article, we review the basic principles and guidelines for prediction of remaining bone growth and planning lengthening in children, and present the currently available expandable prostheses and the evolution performed over time. PMID- 22517684 TI - Development of selective estrogen receptor modulator (SERM)-like activity through an indirect mechanism of estrogen receptor antagonism: defining the binding mode of 7-oxabicyclo[2.2.1]hept-5-ene scaffold core ligands. AB - Previously, we discovered estrogen receptor (ER) ligands with a novel three dimensional oxabicyclo[2.2.1]heptene core scaffold and good ER binding affinity act as partial agonists via small alkyl ester substitutions on the bicyclic core that indirectly modulate the critical switch helix in the ER ligand binding domain, helix 12, by interactions with helix 11. This contrasts with the mechanism of action of tamoxifen, which directly pushes helix 12 out of the conformation required for gene activation. We now report that a much larger substitution can be tolerated at this position of the bicyclic core scaffold, namely a phenyl sulfonate group, which defines a novel binding epitope for the estrogen receptor. We prepared an array of 14 oxabicycloheptene sulfonates, varying the phenyl sulfonate group. As with the parent compound, 5,6-bis-(4 hydroxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonic acid phenyl ester (OBHS), these compounds showed preferential affinity for ERalpha, and the disposition and size of the phenyl substituents were important determinants of the binding affinity and selectivity of these compounds, with those having ortho substituents giving the highest, and para substituents the lowest affinities for ERalpha. A few analogues exhibit ERalpha binding affinities that are comparable to or, in the case of the ortho-chloro analogue, higher than that of OBHS itself. In cell based studies, we found several compounds with activity profiles comparable to tamoxifen, but acting entirely as indirect antagonists, allosterically interfering with recruitment of coactivator proteins to the receptor. Thus, the OBHS binding epitope represents a novel approach to the development of estrogen receptor antagonists via an indirect mechanism of antagonism. PMID- 22517687 TI - Informal educational interventions for caregivers of adult cancer survivors. AB - This review study explores the available data relating to the informal education aspects of effective interventions applied in caregivers of adult cancer survivors to maintain their own health and quality of life (QoL) and as such to provide the optimal care to the cancer patient. The implications of these interventions in oncology practice are also discussed. Available data show that, over the last years, a significant proportion of caregivers of cancer survivors are increasingly offered informal education interventions towards the reduction of their burden. More specifically, educational, skills training, and therapeutic counseling interventions seem to positively affect caregivers' well-being and overall QoL. However, based on available data, one cannot generalize these interventions on improving caregivers' outcomes of daily living activities and QoL. As such, available intervention strategies should be further tested and validated in larger samples, whereas novel health promotion educational approaches are expected to be designed to effectively address and comply with the appropriate needs of caregivers of cancer patients. PMID- 22517688 TI - Clinical and pathological response to induction chemotherapy used as a prognostic factor in inflammatory breast cancer. Single institution experience. AB - PURPOSE: To evaluate clinical and pathological characteristics of patients with inflammatory breast carcinoma (IBC). Also, to evaluate the importance of achieved clinical and pathological responses to induction chemotherapy (iCT) and their role in the prognosis of IBC. METHODS: The medical records of 81 female patients with stage IIIB IBC, diagnosed between January 2008 and December 2010 at the Institute for Oncology and Radiology of Serbia (IORS) were evaluated. Almost all of the patients received anthracycline-based iCT. After 3-4 cycles of iCT, the clinical response (defined as complete response/CR, partial response/PR, stable disease/SD and disease progression/ PD) was assessed. Also, pathological response to iCT (defined as pathological complete response/pCR, near complete response/pNCR, partial response/pPR and no change/ pNC) was estimated in patients who had undergone surgery. All first metastatic sites were recorded. RESULTS: Clinical CR/PR was observed in 61.8% of the patients, while the pathological response (pCR, pNCR/near complete response, and pPR) rate in patients who had undergone surgery was 70%. During follow-up 22 (27.2%) patients developed PD (8 responders and 14 non-responders). Most common metastatic sites were the skeleton in non-responders and the liver in responders. Central nervous system (CNS) metastases developed in 24% of non-responders while no responder developed such metastases. Non-responders had shorter OS compared to responders, but without statistical significance. CONCLUSION: Although the number of the patients analysed in this study is relatively small, we believe that response to iCT could be used as a prognostic marker, since patients who initially failed to respond to iCT showed a higher risk for PD with development of distant metastases, primarily in bones and CNS, and shorter survival. PMID- 22517689 TI - Taxanes in the adjuvant treatment of node-negative breast cancer patients. AB - PURPOSE: Although the use of regimens with adjuvant taxanes is a standard approach in node-positive breast cancer, the use of taxanes in node-negative breast cancer is still controversial. In this search, we aimed to evaluate the data about the use of taxanes in high-risk node-negative patients. METHODS: Studies were retrieved by searching the Pubmed database. Randomized phase III studies on the use of regimens with adjuvant taxanes in early-stage breast cancer were screened and, among them, the studies that included node-negative patients were included in the evaluation. RESULTS: Data on the adjuvant use of taxanes in nodenegative patients were classified into 3 categories: a) studies that evaluated both node-positive and node-negative patients; b) meta-analyses on the use of adjuvant taxanes; and c) studies that included node-negative patients alone. The results of the studies that evaluated both node-positive and node negative patients and the meta-analyses were evaluated according to the node negative subgroup analyses. While two of these studies did not show difference in disease-free survival (DFS) for the node-negative subgroup, one study showed a difference in DFS. The only data for the adjuvant use of taxanes in only node negative breast cancers belong to GEICAM 9805 study and, according to its results, docetaxel provided a difference in DFS in high-risk node-negative patients. CONCLUSION: Data about the adjuvant use of taxanes in node-negative patients are limited compared to the studies in which both node-positive and node negative subgroups are evaluated. In the light of these studies, it is impossible to make a comment about the use of taxanes in node-negative patients. However, GEICAM 9805 study has shown positive results on DFS in high-risk node-negative breast cancer patients with adjuvant taxanes. PMID- 22517690 TI - The significance of HER-2 amplification and the size and type of pathological unicentric, initially operable clinical stage I and IIA/IIB breast cancer, in determining the treatment strategy. AB - PURPOSE: In order to determine the initial treatment strategies for primary operable unicentric breast cancer, the possible relationships of the amplification of human epidermal growth-factor receptor-2 (HER-2), with age, menstrual status, tumor pathological size (pT), histopathological tumor type (HP) and kind of surgical treatment were studied. METHODS: Analysed were 301 patients treated initially by surgery in the period 2006-2009. HP tumor type, pT and HER-2 status (using firstly immunohistochemistry and then chromogenic in situ hybridization/CISH) were determined. The patients were divided into 2 subgroups according to the presence (CISH+)/absence (CISH-) of HER-2 amplification. RESULTS: Data on pT and HER-2 analyses were available for 293/301 (98.3%) patients with ductal (DC) and lobular carcinoma (LC). Amplification of HER-2 was found in 66 (21.9%) patients. No significant difference between the two subgroups regarding age (p=0.08), menstrual status (p>0.05) and kind of operation (p>0.05) was found. HP showed statistically significant difference between DC (55; 83.3%) and LC (11; 16.7%) patients with HER-2 amplification (p<0.01). Further HP analysis of the type of cancer within the pT category as a subgroup showed significantly higher frequency of HER-2 amplification in DC patients for pT1 (p<0.01) and in pT2 + pT3pN0 (p<0.05) compared with patients with LC. CONCLUSION: This study showed a significantly higher incidence of HER-2 amplification in DC tumors, especially in pT1 and pT2, than in LC, which may influence the options in treatment strategies in primary unicentric operable DC type of breast cancer. PMID- 22517691 TI - Multifocal and multicentric breast cancer: is breast conserving surgery acceptable? AB - PURPOSE: The purpose of our study was to evaluate the significance of multifocal (MF) and multicentric (MC) breast cancer in the diagnosis and treatment of this condition. METHODS: This retrospective study was a combination of clinical and laboratory data. The patient population consisted of 274 women operated on with Madden mastectomy for breast cancer. Assessed were the following parameters: age, menstrual status, histopathological parameters, HER-2 status, estrogen receptor (ER) and progesterone receptor (PR) status, disease stage, quadrant(s) in which breast cancer was detected and axillary lymph nodes status. RESULTS: Of 274 patients 206 (85%) has unifocal disease, 41 (15%) suffered of MF (n=27; 9.9%)/MC (n=14; 5.1%) disease. MC disease was associated with metastatic axillary lymph nodes in 92.9% of the cases. MF/MC cases were primarily dependent on histology. MF/MC cancer was best related to the lobular type (85.7% of the cases), while ductal histological type was characteristic of unifocal tumors. CONCLUSION: Quadrantectomy as a form of conservative breast surgery is acceptable in cases of MF tumors, because all tumor foci can be removed. We suggest radical surgical treatment in all cases of suspected MC tumors because they are most often associated with metastasis to the axillary lymph nodes. Lobular histology characterizes MC breast cancer. PMID- 22517692 TI - The clinical role of micrometastatic disease in sentinel lymph nodes in breast cancer. AB - PURPOSE: Complete axillary lymph node dissection (cALND) is the standard procedure in treating the patients with tumor-positive sentinel nodes (SLNs). However, approximately half of these patients have not additional metastases in their axilla and therefore do not benefit from cALND. Our aim was to examine the outcome of patients with tumor-positive SLNs without cALND. METHODS: All patients (n=591) were women with clinically T1-2N0-1M0 breast cancer. SLN marking was performed with blue dye (Patentblau V) and radiotracer (antimony sulfide marked with Tc99m). Both contrast media were applied peritumorally or periareolarly. After SLN biopsy all patients underwent breast-conserving surgery or mastectomy with or without lymph node dissection of level I and II (depending on SLN status). RESULTS: In 37 (17.84%) out of 185 patients cases SLNs contained micrometastases. In 19 of 37 cases (57.58%) cALND was performed, and in 14 (42.42%) was not. The mean and median duration of follow-up were 50.59 and 55 months, respectively (range 4-108). Two cases without cALND developed ipsilateral enlarged lymph nodes at 26 and 59 months. Biopsy showed that the enlarged nodes were tumor-free. In all other cases with micrometastases in SLNs neither axillary lymphadenopathy nor distant metastases were seen. After performing surgical treatment, all patients received adjuvant chemotherapy or hormonotherapy and radiotherapy. CONCLUSION: Patients with SLN micrometastases who had not undergone cALND showed no regional recurrence and distant metastases. ALND is not necessary for regional control in patients with micrometastatic or isolated tumor cells in SLNs. By avoiding cALND the number of complications was reduced and the quality of life was improved. PMID- 22517693 TI - Male breast cancer: a retrospective study of 15 years. AB - PURPOSE: To retrospectively evaluate the 15-year experience with breast cancer in males at a single institution. METHODS: The data from 25 male patients who had undergone surgery for breast cancer at a single center were retrospectively analysed. Their medical records were studied for clinical characteristics, therapeutic modalities used and factors associated with disease free (DFS) and overall survival (OS), like local recurrence/distant metastasis. RESULTS: The median patient age was 67 years (range 38-83). The most frequent presenting symptom was a palpable lump. Eighteen (72%) patients underwent modified radical mastectomy (MRM), while sentinel lymph node biopsy (SLNB) was performed in 14 (56%) cases. Of 25 patients, 21 (84%) underwent axillary lymph node dissection (ALND) and 15 (71.4%) of them had pathological axillary lymph node involvement. Two of 25 (8%) patients with bone and liver metastases underwent toilet mastectomy due to breast ulceration. Estrogen receptor (ER) was positive in 15 (60%) patients, while progesterone receptor (PR) and C-erbB2 (HER-2) were positive in 10 (40%) and 2 (8%) patients, respectively. Ten patients (40%) had both ER(+) and PR(+). The median follow-up period was 19 months (range 3-102). Local recurrence developed in one (4%) patient and distant metastasis in 4 (16%). Five-year OS and DFS were 53 and 49%, respectively. In univariate and multivariate analysis, pathological tumor size (<2 vs. >2 cm), pathological lymph node involvement and preoperative skin involvement over the breast were not associated with breast recurrence. Only in univariate analysis local recurrence/distant metastasis were associated with poor OS. CONCLUSION: Large cooperative studies are needed using strict clinical and laboratory criteria to advance the understanding of this disease and to identify the most effective treatment approaches. PMID- 22517694 TI - Dynamic MRI-derived parameters for hot and cold spots: correlation with breast cancer histopathology. AB - PURPOSE: To identify the dynamic contrast-enhanced magnetic resonance (DCE-MR) imaging features that may predict the outcome of patients with breast cancer. METHODS: DCE-MR images from 87 patients newly diagnosed with primary breast cancer were reviewed. The kinetic parameters (including cold spot, hot spot, and heterogeneity parameters) were derived from the DCE-MRI data. These parameters were used to thoroughly reflect the tumor status. The association of dynamic MR features (including kinetic and morphological features) with established prognostic indicators was evaluated. RESULTS: Malignant tumors with poor histomorphological indicators showed higher values of hot spot parameters (maximal initial Slope [maxSlope(i)] and maximal Washout [maxWashout]), higher values of a heterogeneity parameter- initial slope ratio (Slope(i) ratio) and lower values of a cold spot parameter (minimal initial slope [minSlope(iM)]) than those with favorable prognostic indicators. The heterogeneous internal enhancement pattern and rim-like enhancement pattern were more frequently observed in patients with poor prognostic indicators. Moreover, binary logistic regression analysis showed that kinetic parameters Slope(i) ratio (p=0.021), minSlope(i) (p=0.024), internal homogeneity (p=0.001), and maxSlope(iM) (p<0.001) were independently and significantly associated with histological grade, lymph node status, tumor size, and Ki-67, respectively. CONCLUSION: Our results suggest that all hot spot, cold spot, and heterogeneity parameters may be useful to noninvasively identify highly aggressive breast carcinomas. More importantly, cold spot and heterogeneity parameters may serve as crucial indicators to predict the outcome of breast cancer. PMID- 22517695 TI - Breast MRI: intraindividual comparative study at 1.5 and 3.0T; initial experience. AB - PURPOSE: To prospectively and intraindividually compare breast magnetic resonance imaging (MRI) at 1.5 Tesla (T) and 3.0T. METHODS: A prospective intraindividual Ethics Committee- approved study was performed in 31 women (average age 58.6+/ 12.3 years), with 114 lesions (9 benign, 105 breast cancers; 24 patients with unilateral and 7 with bilateral cancers). Axial bilateral breast high-spatial resolution contrast-enhanced dynamic MRI was performed at 1.5T using 3 dimensional (3D) dynamic gradient-echo sequences in all patients (spatial resolution 1.1*0.7*2 mm; temporal resolution 41 sec per dynamic acquisition), and after 24-48 h at 3.0T (0.6*0.6*1.7 mm; temporal resolution 65 and 72 sec per dynamic acquisition). Contrast enhancement ratio, number and features of enhancing lesions, image quality and reliability were compared by two radiologists independently. RESULTS: 102 cancer lesions were detected at 1.5T and 105 cancer lesions were detected in 31 patients at 3.0T. One cancer lesion was observed at 1.5T which was missed at 3.0T, and 3 cancer lesions and one high-risk lesion (LCIS) were detected at 3.0T while missed at 1.5T. Enhancement rates were significantly higher at 1.5T (224.5+/-100.2) compared to 3.0T (133.7+/-38.3). Better image quality was observed at 3.0T. Interobserver reliability was higher at 3.0T (p= 0.684) compared to 1.5T (p= 0.351). CONCLUSION: Detection of breast cancer shows a trend of better performance at 3.0T than at 1.5T. PMID- 22517696 TI - Meta-analysis of the predictive value of KRAS mutations in treatment response using cetuximab in colorectal cancer. AB - PURPOSE: The monoclonal antibody cetuximab that targets epidermal growth factor receptor (EGFR) has been found effective in the treatment of colorectal cancer. However, mutations in exons 12 and 13 of KRAS oncogene have been reported as negative predictive factors for the treatment response using cetuximab. The purpose of this study was to conduct a meta-analysis of the published studies investigating the predictive value of KRAS mutations in the efficacy of cetuximab in patients suffering from colorectal cancer. METHODS: A systematic search of the literature was performed in PubMed, Medline, and Cochrane databases. Sensitivities, specificities and predictive values (negative and positive) of KRAS mutations as regards treatment response were calculated. RESULTS: Twenty-six studies were initially found during the literature search. After thorough evaluation, 13 papers were excluded for various reasons. Therefore, 13 studies were included in the present meta-analysis. In these studies, specificities were found much higher than sensitivities. Combining the data from the 13 studies, it was found that KRAS mutations comprise a negative predictive biomarker for response to cetuximab with very high specificity (0.96; 95% CI 0.84-0.99), and low sensitivity (0.47; 95% CI 0.43-0.50). Finally, the publication bias was found statistically significant. CONCLUSION: The results of the present meta-analysis suggest that cetuximab should be administered only to patients with colorectal cancer who have the wild type (KRASw) oncogene. Mutations in the KRAS gene are a negative predictive factor for response to cetuximab with very high specificity and low sensitivity. The latter may very well be attributed to additional mechanisms of resistance to anti-EGFR therapies such as mutations in BRAF. PMID- 22517697 TI - Worse histological grade of proximal colorectal tumors and its relation with stage. AB - PURPOSE: Accumulated data seem to support the concept that proximal and distal colorectal cancers (CRC) should be considered as different disease entities. We investigated a particular aspect of this assumption by examining variation of stage and grade distribution according to tumor site in a Greek patients' group. METHODS: A total of 200 cases having had undergone surgery for primary CRC was retrospectively analysed. Fifty-seven proximal tumors were compared to 143 distal lesions regarding tumor stage (TNM I-IV) and grade of differentiation (well, moderate and poor). Grade distribution by site was also examined within each particular stage and within additional stage categories (I-II, III-IV, I-III, II IV, II-III). RESULTS: There was an almost significant trend of distal tumors for earlier stage (I) presentation (p=0.055), whereas proximal cancers were more frequently diagnosed with stages II-III (p=0.08). Poorly differentiated lesions displayed a strong predilection for proximal site (p=0.002), while tumors with moderate differentiation were preferentially found distally (p=0.001). Such segmental differences in grade distribution were also ascertained within most particular stages and all additional stage subsets (especially the last three). Moreover, both the proximal and the poorly differentiated lesions showed a parallel decrease in their incidence during the study period. CONCLUSION: The consistently recorded worse histological pattern of proximal tumors implies a different biological behavior of these lesions possibly due to distinct tumorigenic pathways involved in their development, whereas their tendency for late stage presentation demands further investigation before considered supportive to this concept. PMID- 22517698 TI - Quantitative evaluation of stromal myofibroblasts and their significance for the metastatic capacity of colorectal carcinoma. AB - PURPOSE: To quantify the myofibroblasts in the tumor stroma of colorectal carcinomas using immunostaining with anti smooth muscle actin (SMA) as a marker for myofibroblasts. METHODS: The study was carried out on 46 surgically resected primary colorectal adenocarcinomas from the archive of the Centre for Pathology and Forensic Medicine of the Military Medical Academy in Belgrade, from 2008 2010. All samples were analysed by the scientific software "Image J". Myofibroblasts were visualized using anti-SMA antibody and quantified in order to predict tumor capacity for invasion and metastasis. Receiver Operator Characteristic (ROC) analysis was carried out, and a score of 5.72 was suggested as the score of SMA that is significant for the clinical outcome with lymph node involvement. RESULTS: Overall, the average SMA was 7.29 (range 0.39-16.84). Further analysis showed correlation of SMA with clinical and pathological tumor characteristics, i.e. SMA was significantly higher in tumors with more advanced stage, higher histological grade, greater amount of desmoplasia, smaller amount of inflammatory infiltrate, lymph node involvement, vascular and perineural invasion and infiltrative tumor growth. CONCLUSION: Our study suggests that it is possible to define the tumor capacity for invasion and metastasis by quantifying the myofibroblasts in the tumor stroma of colorectal carcinomas. Therefore, further investigations are needed to determine targeted therapies to signaling pathways in myofibroblasts. PMID- 22517699 TI - Expression of Smad4, E-cadherin and beta-catenin in advanced colorectal cancer: a retrospective study. AB - PURPOSE: To correlate the expression of E-cadherin and beta-catenin with alterations of expression of Smad4 in advanced colorectal cancer (CRC). METHODS: Tissue specimens from 75 colorectal cancer cases (Dukes stage C and D) were tested for Smad4, E-cadherin and beta-catenin by the Avidin-Biotin immunoperoxidase method. The results were correlated with patients' clinicopathological parameters. RESULTS: Smad4 expression was lost or reduced in roughly 1 out of every 3 Dukes C and D CRCs. Association of Smad4 expression with other clinicopathological parameters was not noted. Association of expression of E-cadherin with other clinicopathological parameters was not noted, apart from tumor location. Expression of beta-catenin was not associated with clinicopathological parameters. Lack of expression of Smad4 was associated with lack of expression of both E-cadherin (<0.000) and beta-catenin (p<0.000). As regards the relation between E-cadherin and beta-catenin, the expression of each seemed to parallel the expression of the other (p<0.000). Beta-catenin was overexpressed in 68.5% of the specimens studied. CONCLUSION: Clinically advanced CRC is associated with a reduced or complete lack of expression of Smad4. Ecadherin and beta-catenin are expressed in parallel with each other and also with Smad4. This tumor suppressor role of Smad4 by affecting both E-cadherin and beta-catenin may indicate a novel pathway for metastatic tumor via cellular reshaping. The precise underlined mechanism(s) and the clinical significance of these findings remain to be determined. PMID- 22517700 TI - The CD34-microvascular density in colorectal cancer patients. AB - PURPOSE: To investigate the influence of the angiogenesis parameter CD34 microvascular density (MVD) on overall survival of colorectal cancer (CRC) patients. METHODS: Thirty-one CRC patients were followed-up for 72 months after curative colorectal operation. Blood vessels measurement was done using the CD34 MVD immunochemistry method, and light microscopy. RESULTS: MVD was inversely correlated with patients' survival. MVD value < 35 proved as independent good prognostic factor, and patients with this value lived during the 72-month follow up after surgery, while a MVD value > 65 was an independent poor prognostic factor and such patients died within 11 months after radical surgery for CRC (p<0.01). CONCLUSION: According to these results, the CD34-MVD seems to be a significant prognosticator of overall survival in CRC patients. PMID- 22517701 TI - Prognostic factors in patients with advanced pancreatic cancer treated with gemcitabine alone or gemcitabine plus cisplatin: retrospective analysis of a multicenter study. AB - PURPOSE: The majority of patients with pancreatic cancer present with advanced disease. Systemic chemotherapy for patients with pancreatic cancer has limited impact on overall survival (OS). Patients eligible for chemotherapy should be selected carefully. The aim of this study was to analyse prognostic factors for OS in advanced pancreatic cancer patients treated with first-line palliative chemotherapy with gemcitabine alone or gemcitabine plus cisplatin. METHODS: We retrospectively reviewed 343 locally advanced or metastatic pancreatic cancer patients who were treated with gemcitabine or gemcitabine plus cisplatin as first line chemotherapy between December 2000 and June 2011. Fifteen potential prognostic variables were chosen for analysis. Univariate and multivariate analyses were conducted to identify prognostic factors associated with OS. Univariate and multivariate statistical methods were used to determine prognostic factors. RESULTS: Among the 15 variables of univariate analysis, 6 were identified to have prognostic significance: stage (p<0.001), cholestasis (p=0.02), weight loss, prior pancreatectomy, serum CEA level (p<0.001) and serum CA19-9 level (p>0.001). In addition, age, chemotherapy and liver metastasis were of borderline significance (p=0.06). Multivariate analysis (Cox proportional hazard model) included the 6 significant prognostic factors of univariate analysis and showed that stage was independent prognostic factor for OS, as were weight loss, and serum CEA level. CONCLUSION: Stage, weight loss, and serum CEA level were identified as important prognostic factors for OS in advanced pancreatic cancer patients. These findings may also facilitate pretreatment prediction of OS and can be used for selecting patients for treatment. PMID- 22517702 TI - The predictive role of Bcl-2 expression in operable locally advanced or metastatic gastric carcinoma. AB - PURPOSE: Gastric carcinoma is an aggressive disease with different epidemiologic and clinical profiles. Combination chemotherapy containing docetaxel, cisplatin and 5-fluorouracil/5-FU (DCF) is a frequently used regimen in metastatic gastric cancer. We studied the role of B-cell lymphoma 2 (Bcl-2) expression in predicting the response to DCF combination chemotherapy in metastatic gastric carcinoma. METHODS: This study included patients with pathologically confirmed locally advanced, surgically inoperable gastric carcinoma, or with metastatic disease. For immunohistochemical staining of Bcl-2 oncoprotein, lyophilized mouse monoclonal antibody (clone100/D5, 1:50, Thermo Scientific, Fremont, ABD) was used. Bcl-2 expression was evaluated with respect to the nuclear and cytoplasmic staining of the cells. Staining > 10% was accepted as positive and <= 10% as negative. RESULTS: Bcl-2 expression was positive in 5 (23.8%) patients and negative in 16 (76.2%), while partial response was achieved in 12 (57%) patients. No complete response was seen in any patient. The effect of positive Bcl-2 expression on survival was statistically significant by log-rank test (p=0.035). CONCLUSION: The patient group that expressed Bcl-2 survived longer confirming that Bcl-2 expression is a good prognostic factor in advanced-stage patients. We believe that Bcl-2 expression has an additional contribution in predicting response to this chemotherapy combination. PMID- 22517703 TI - Free light chains ratio as a marker to estimate prognosis and survival in patients with multiple myeloma and primary amyloidosis. AB - PURPOSE: The aim of this study was to evaluate the significance of free light chains ratio (FLC ratio) as a prognostic factor for remission, progression and survival in patients with multiple myeloma (MM) and primary amyloidosis. METHODS: The concentrations of immunoglobulins and FLC ratio were measured using immunonephelometry. A total of 101 patients from 3 different disease groups were investigated during a 7-year period: 1) MM (n=95); 2) nonsecretory multiple myeloma (NSMM) (n=3); and 3) primary amyloidosis (n=3). Reference range for FLC ratio was 0.26-1.65. RESULTS: According to the International Staging System (ISS) for MM, abnormal serum FLC ratio was < 0.03 or > 32. Patients with MM and highly or intermediately abnormal FLC ratio and a combination of adverse risk factors (56.9%) had median survival of 26 months (range 16-38), as opposed to patients with normal or slightly changed values of FLC ratio without adverse risk factors (43.1%) with median survival of 45 months (range 27-69). Also, all of the patients with NSMM had slightly changed values of FLC ratio corresponding to low risk of disease progression. In patients with primary amyloidosis, 33.3% had slightly changed values of FLC ratio corresponding to low risk of disease progression, as opposed to 66.7% with abnormal FLC ratio, corresponding to high risk. CONCLUSION: Abnormal FLC ratio in the examined groups could be an independent risk factor of disease progression and worse prognosis. PMID- 22517704 TI - Radiotherapy for Hodgkin's lymphoma: too hard to die? AB - The treatment of Hodgkin's lymphoma (HL) is associated with significant toxicity. The objective of high quality management is to keep the concept of combined modality, while trying to decrease the radiation dose, to diminish to a great extent the irradiated volume and at the same time to reduce the number of chemotherapy courses, introducing the so-called optimisation. New directives should be followed to obtain more effective treatments of HL. Shorter cycles of chemotherapy and the utilization of modern techniques in radiotherapy (RT) constitute fundamental steps to achieve this objective. Analysis of randomized studies supports the inclusion of reduced-field and dose of RT in the radiotherapeutic treatment options for HL. RT is an integral part of the combined modality therapy (CMT) of HL. PMID- 22517705 TI - Contribution of low-molecular weight heparin addition to concomitant chemoradiotherapy in the treatment of glioblastoma multiforme. AB - PURPOSE: Glioblastoma multiforme (GBM) is the most common brain tumor in adults and has a very aggressive course. Median survival is as short as 2 years with standard treatment (chemoradiotherapy followed by adjuvant temozolomide). The purpose of this study was to determine the contribution of low molecular weight heparin (LMWH) addition to concomitant chemoradiotherapy in the treatment of GBM. METHODS: All patients with newly diagnosed GBM between March 2004-May 2009 were evaluated. After surgical intervention (total, subtotal resection or only biopsy) all of them were treated with concomitant chemoradiotherapy (2 Gy daily, 5 days a week, 30 fractions, total tumor dose 60 Gy; and 75 mg/m2 temozolomide, 7 days a week), followed by adjuvant temozolomide (6 cycles, 150-200 mg/m2, 5 days every 28 days), with or without LMWH (4000 IU/day, 7 days a week, concomitant with radiotherapy) because of risk of thrombosis. The primary endpoint was the determination of progression-free survival (PFS) and overall survival (OS); secondary endpoints were 1- and 2-year OS survival. RESULTS: 30 patients (13 patients in the group non receiving LMWH (LMWH-) and 17 patients in the group receiving LMWH (LMWH+)) were included in the study. Median age was 54 years (range 24-75). Median PFS was 57 and 38 weeks in LMWH+ and LMWH- groups, respectively (p=0.068). Median OS was 69 and 44 weeks (p=0.095), 1-year OS survival 84.6 and 41.2% (p=0.016), and 2-year OS survival 38.5 and 5.9% in LMWH+ and LMWH-, respectively (p=0.061). No significant difference was noted between the two groups for grade 3-4 toxicity (p>0.05). CONCLUSION: Better PFS, OS and 2 year OS survival were obtained in present study with the addition of LMWH to concomitant chemoradiation for GBM but without statistical significance. One-year OS survival was statistically significant favoring the LMWH group. The addition of LMWH did not increase temozolomide toxicity. PMID- 22517706 TI - Local control of glomus tumors of the head & neck by radiation therapy and surgery. AB - PURPOSE: Glomus tumors are rare tumors, highly vascular and typically radiosensitive. Therapeutic options include surgery, radiation therapy (RT), embolisation or any combination of them, but the appropriate treatment still remains a challenge. The purpose of this study was to report the results of local control of 7 patients with glomus tumors treated with surgery and external beam RT (EBRT). METHODS: All of the patients underwent primary surgery and then postoperative EBRT. Follow-up was calculated from the date of initiation of EBRT and ranged from 3 to 15 years (mean 7.14, median 6.2). The likelihood of local control was analysed using the Kaplan-Meier product limit method. We also analysed the average duration of response between two groups of patients with different doses of EBRT as well as the presence of acute and late EBRT complications. RESULTS: Local control was obtained in 6/7 (85.7%) patients. Moreover, local control was achieved in 3/4 (75%) patients with recurrent glomus tumors, while in patients with postoperative residual disease local control was obtained in 3/3 (100%) of them. Patients who received <50 Gy (n=2) had shorter average duration of response compared to patients who received >50 Gy (n=5; p=0.248). There were no severe treatment complications. CONCLUSION: Surgery and RT represent an appropriate treatment approach for advanced glomus tumors with acceptable complications. PMID- 22517707 TI - Ki-67 expression in oral lichen planus. AB - PURPOSE: The monoclonal antibody Ki-67 detects a nuclear antigen that is present only in proliferating cells. This is of particular interest for the analysis of the proliferation rates of malignant tumors. The aim of this study was to investigate the malignant potential of oral lichen planus (OLP) on the basis of expression of Ki-67 in healthy individuals (HI), patients with OLP and patients with squamous cell carcinoma (SCC), and to see for any potential interdependence between Ki-67 expression and different clinical and histopathological parameters in OLP. METHODS: Immunohistochemistry for Ki-67 was carried out using an avidin biotin peroxidase complex method. RESULTS: Ki-67 was more expressed in keratinocytes and lymphocytes of OLP patients compared with HI, but less compared with patients with SCC. Keratinocytes and lymphocytes stained with Ki-67 in OLP patients were significantly higher in males, and in OLP specimens showed less developed civatte bodies (CB) and thickening of the basal membrane (TBM). CONCLUSION: Ki-67 may not serve as prognostic biomarker in oral cancer development from the initially diagnosed OLP, but it could help selecting patients with higher need of follow up for prevention of malignancy. PMID- 22517708 TI - Management of retroperitoneal sarcomas: main prognostic factors for local recurrence and survival. AB - PURPOSE: Retroperitoneal sarcomas (RPs) are characterized by slow indolent growth and metastasize at a late point in their natural course. The purpose of this study was to review our experience in the management of RSs and identify prognostic factors for local control and survival. METHODS: Between January 1990 and December 2010, the hospital records of 75 patients with RSs were retrospectively studied. Sixty-four (85.3%) patients had undergone surgical resection in our hospital for primary RS, whereas 11 (14.7%) were referred to our department for recurrent disease. RESULTS: The patient median age was 57 years. Median tumor size was 18.5 cm. The most common histologic type was liposarcoma (44%) followed by leiomyosarcoma (17%), paraganglioma (10%), malignant fibrous histiocytoma (6.5%) and rare tumors such as 2 chondrosarcomas and 1 pecoma. Complete initial resection with negative macroscopic margins (R0) was achieved in 39 (60.9%) patients. En bloc resection of adjacent organs was required in 8 (12.5%) patients with primary RS and in 8 (72.9%) with recurrent disease. Mortality rate was 4%. For the group of patients initially treated in our hospital, 1-year recurrence rate was 34.3%. The 3- and 5-year overall survival rates were 56.2% and 53.1%, respectively. Satellite tumors were recognised in 13 (20.3%) patients treated for primary RS, from whom 11 (84%) recurred within one year. Seven patients received adjuvant chemotherapy. CONCLUSION: Radical surgical resection is the treatment of choice for patients with primary and locally recurrent RSs. PMID- 22517709 TI - Effects on the immune system and toxicity of carboplatin/paclitaxel combination chemotherapy in patients with stage III-IV ovarian and non small cell lung cancer and its role in survival and toxicity. AB - PURPOSE: To examine the impact of paclitaxel and carboplatin combination chemotherapy on the parameters of the immune system in patients with non small cell lung cancer (NSCLC) and with ovarian cancer before, during and after chemotherapy, and the effect of this combination on the overall patient survival. METHODS: 24 patients with NSCLC and 20 with ovarian cancer (all in stage IIIb-IV) treated with 6 courses of paclitaxel and carboplatin combination chemotherapy were separated into two groups according to their survival group A: long survival (> 12 months for NSCLC; > 30 months for ovarian cancer) group B: short survival (<12 months for NSCLC; <30 months for ovarian cancer). At the same time we studied some immunological parameters (CD3, CD4, CD8, CD56, CD34, IL-3, IFN gamma) in relation with the induced toxicity during chemotherapy. The results were analysed using the ANOVA method. RESULTS: We observed a statistically significant difference of CD4 and CD4/CD8 after chemotherapy between groups A and B (p<0.001 and p< 0.006 respectively), implying that the further increase of T helper cells after chemotherapy had a positive impact on survival. In addition, statistically interesting was the difference in values of IFN-gamma between patients of groups A and B before and after chemotherapy (p< 0.039 and p< 0.027, respectively). Patients with high IL-3 had little chance of toxicity. CONCLUSION: Our findings support that with carboplatin/ paclitaxel combination chemotherapy, important parameters of the immune system (IFN-gamma, CD4, CD4/CD8) can be used as prognostic factors for survival, while others (IL-3) as indicators of toxicity. PMID- 22517710 TI - Informing cancer patient in relation his type of personality: the emotional hypothymic (depressive) patient. AB - Informing patients with cancer has been a subject of great scientific interest. Initially the research was aimed at quantity evaluation, in other words, the number of doctors who break the news to the patient, the number of patients seeking informing etc. Since the 1980s to present, research has shifted its focus equally on quality evaluation. In other words, serious efforts are being made to answer the question: "Is it possible to determine who should be told what, when and how?" It seems that deepening on the patient s character traits offers the best starting point for understanding the patient. The aim of this paper was to describe the character of personality types based on the question: "How could characters or personality types be used in informing patients with cancer?" As method of research was used the qualitative method through groups with doctors and nurses, while research within groups lasted for 5 years. The degree of informing is similar to the degree of the hyperthymic personality; initially, is "minimal, then "small" until it reaches "medium". The degree of denial varies between "large" and "very large" to sometimes "medium". Family: similar to the emotional-hyperthymic person, with the added difficulty of introversy. There is a discordance between what the patient shows and what the family reports about him, especially when the compensation mechanism is that of a controlling - orderly patient. PMID- 22517711 TI - Posttraumatic stress disorder and preparatory grief in advanced cancer. AB - PURPOSE: The purpose of the current study was to investigate the prevalence of posttraumatic stress disorder (PTSD) and its association with sociodemographic variables and preparatory grief in patients with advanced cancer. METHODS: 195 advanced cancer patients participated in the study. Out of them, 170 had PTSD and 25 had other anxiety disorders. The diagnoses were made in strict accordance with Structured Clinical Interview for DSM-IV Axis I disorders (SCID-I)-Clinician version. Patients completed also the Preparatory Grief in Advanced Cancer Patients (PGAC) scale. RESULTS: Patients with PTSD were younger (63.54 +/- 12.07 years) than those without PTSD (70.36 +/- 13.03 years, p=0.010). Patients with PTSD revealed more preparatory grief (37.69 +/- 12.11) than those without PTSD (29.58 +/- 14.04, p= 0.003). Multiple logistic regression analysis showed that preparatory grief (p=0.012), and metastatic disease (p=0.009) remained in the model whereas age showed a trend for independent significance (p=0.067). CONCLUSION: In advanced cancer stages, younger patients, those with metastatic disease or patients with elevated scores on preparatory grief seemed to have a greater likelihood to develop PTSD. Thus, given the prevalence of PTSD in advanced cancer patients, health care professionals should be able to better recognize those who are at risk for or exhibit symptoms of this disorder so that appropriate treatment referrals can be made. PMID- 22517712 TI - Can radiation-induced chronic oxidative stress in kidney and liver be prevented by dimethylsulfoxide? Biochemical determination by serum and tissue markers. AB - PURPOSE: To investigate the protective effects of dimethylsulfoxide (DMSO) on chronic oxidative stress in the liver, kidney and serum with biochemical parameters such as malondialdehyde (MDA), advanced oxidation protein product (AOPP), catalase, glutathione (GSH), and free-thiols (F-SH). METHODS: Thirty Wistar albino female rats were randomly divided into 3 groups: group I (control, n=10), group II (irradiation-alone group, n=10) and group III (DMSO and irradiation group, n=10). Rats in groups II and III were irradiated with a single dose of 6 Gy to the entire liver and right kidney. Group III received DMSO 4.5 g/kg by intraperitoneal injection 30 min before irradiation. At the end of the 24th week, the rats were sacrificed and their trunk blood, kidney and liver tissues were collected. RESULTS: Group II rats showed increased levels of lipid peroxidation and protein oxidation, with decreased GSH, FSH and catalase levels in all specimens when compared with group I. Serum and kidney MDA and AOPP levels were significantly lower in group III when compared with group II. However, serum and kidney GSH and F-SH levels were significantly higher in group III when compared with group II. The additive effect on catalase was seen only in the serum. CONCLUSION: DMSO is a protective agent on chronic oxidative stress in the serum and kidney tissue. No oxidant or antioxidant effect of DMSO in the liver was seen. PMID- 22517713 TI - Prognostic value of survivin expression in Wilms tumor. AB - PURPOSE: To determine survivin expression patterns in Wilms tumor (WT) and compare it with the expression in normal renal tissue. Also, to analyse cytoplasmic and nuclear survivin expression in relation to histological type, prognostic group and tumor stage. METHODS: Immunohistochemical expression of survivin was analysed in 59 cases of primary WT and in 10 normal kidney specimens, taken from the same patients, but distant from the tumor. RESULTS: 51 out of 59 cases of WT (86.44%) showed decreased cytoplasmic survivin expression and 4 out of 59 cases of WT (6.78%) showed nuclear overexpression of survivin. There was statistically significant difference in the frequency of decreased cytoplasmic expression of survivin in individual components of WT (p=0.005). Decreased cytoplasmic expression of survivin in epithelial, blastemal and stromal component was found significantly more often in low stage WT compared to high stage WT (Fisher exact test, p=0.0002, p=0.002, p=0.002, respectively). There was no statistically significant difference in the frequency of survivin nuclear overexpression between different stages of WT (Fisher exact test, p=0.564), histological types (Fisher exact test, p=0.915), or between different prognostic groups (Fisher exact test, p=1). CONCLUSION: Decreased survivin cytoplasmic expression or nuclear overexpression may be related to favorable prognosis of WT. PMID- 22517714 TI - Characteristics of the admissions of cancer patients to emergency department. AB - PURPOSE: To identify the characteristics of admission of patients with cancer in the emergency department of a university hospital. METHODS: The medical records of 468 emergency department admissions of 336 cancer patients due to medical conditions that were related either to their cancer or its treatment were reviewed and retrospectively analysed. RESULTS: There were 226 (67%) males and 110 females (37%), with a median age of 60 years (range 17-93). Regarding cancer staging, 156 (46%) patients had locoregional disease and 180 (54%) metastatic disease. Regarding performance status (PS), 321 (69%) were Eastern Cooperative Oncology Group (ECOG) 1-2, and 147 (31%) were ECOG 3-4. The main causes of emergency department admission were cancer progression in 188 (40%) patients, cancer-related signs and symptoms in 203 (43%) and treatment-related complications in 77 (16%). The most common primary cancer sites were the thorax, the gastrointestinal system and the genitourinary system. The medical condition necessitating emergency department admission was local tumor compression in 144 (31%) admissions, infection in 86 (19%) and end-of- life support in 63 (13%). CONCLUSION: Cancer patients seeking nonscheduled medical care and admitting to emergency departments present many challenges to the emergency physician. Due to the associated high morbidity and mortality, initial evaluation of the patient in the emergency department and therapy have utmost importance in the outcome of the patient. Accurate diagnosis and appropriate treatment of cancer-related problems can improve the quality of life dramatically in patients with cancer. PMID- 22517715 TI - George N. Papanicolaou (1883-1962): Fifty years after the death of a great doctor, scientist and humanitarian. AB - Fifty years have passed since the death of Dr George Nicholas Papanicolaou, who was born in Kyme at the island of Euboea in Greece in 1883 and became known for his innovative revolutionary invention of the Pap smear test performed at the Cornell University Medical College in the USA. To date, even after the introduction of HPV vaccination into the clinical practice, Dr George Papanicolaou's method remains an essential component of the prevention strategy against cancer and has resulted in a 70% decrease in cervical cancer mortality over the last 60 years. This article, which presents briefly his biography, is dedicated to him on the occasion of the 50th anniversary of his death. PMID- 22517716 TI - Medullary carcinoma of the breast: a brief report from a tertiary care center. PMID- 22517717 TI - Distribution of breast cancer diagnosis according to month of birth in Turkish population. PMID- 22517718 TI - Angiosarcoma of the breast. PMID- 22517719 TI - Epidemiological characteristics of acrochordons. PMID- 22517720 TI - Imatinib-induced anasarca without heart failure: capillary leakage? PMID- 22517721 TI - Clovis Vincent (1879-1947): founder of French neurosurgery and promoter of oncologic neurosurgery. AB - The eminent neurologist Clovis Vincent decided to become neurosurgeon at an advanced age. His is considered the founder of French neurosurgery and the Europe's first neurosurgeon. He was mainly interested in pituitary tumors and his work on oncologic neurosurgery remains valuable. PMID- 22517722 TI - Science ethics education: Part I: perception and attitude toward scientific fraud among medical researchers. PMID- 22517723 TI - Docetaxel nanotechnology in anticancer therapy. AB - Taxanes have been recognized as a family of very efficient anticancer drugs, but the formulation in use for the two main taxanes-Taxol for paclitaxel and Taxotere for docetaxel-have shown dramatic side effects. Whereas several new formulations for paclitaxel have recently appeared, such as Abraxane and others currently in various phases of clinical trials, there is no new formulation in clinical trials for the other main taxane, docetaxel, except BIND-014, a polymeric nanoparticle, which recently entered phase I clinical testing. Therefore, we review herein the state of the art and recent abundance in published results of academic approaches toward nanotechnology-based drug-delivery systems containing nanocarriers and targeting agents for docetaxel formulations. These efforts will certainly enrich the spectrum of docetaxel treatments in the near future. Taxotere's systemic toxicity, low water solubility, and other side effects are significant problems that must be overcome. To avoid the limitations of docetaxel in clinical use, researchers have developed efficient drug-delivery assemblies that consist of a nanocarrier, a targeting agent, and the drug. A wide variety of such engineered nanosystems have been shown to transport and eventually vectorize docetaxel more efficiently than Taxotere in vitro, in vivo, and in pre-clinical administration. Recent progress in drug vectorization has involved a combined therapy and diagnostic ("theranostic") approach in a single drug-delivery vector and could significantly improve the efficiency of such an anticancer drug as well as other drug types. PMID- 22517724 TI - Differential TERT promoter methylation and response to 5-aza-2'-deoxycytidine in acute myeloid leukemia cell lines: TERT expression, telomerase activity, telomere length, and cell death. AB - The catalytic subunit of human telomerase (TERT) is highly expressed in cancer cells, and correlates with complex cytogenetics and disease severity in acute myeloid leukemia (AML). The TERT promoter is situated within a large CpG island, suggesting that expression is methylation-sensitive. Studies suggest a correlation between hypermethylation and TERT overexpression. We investigated the relationship between TERT promoter methylation and expression and telomerase activity in human leukemia and lymphoma cell lines. DAC-induced demethylation and cell death were observed in all three cell lines, as well as telomere shortening in HL-60 cells. DAC treatment reduced TERT expression and telomerase activity in OCI/AML3 and HL-60 cells, but not in U937 cells. Control U937 cells expressed lower levels of TERT mRNA, carried a highly methylated TERT core promoter, and proved more resistant to DAC-induced repression of TERT expression and cell death. AML patients had significantly lower methylation levels at several CpGs than "well elderly" individuals. This study, the first to investigate the relationship between TERT methylation and telomerase activity in leukemia cells, demonstrated a differential methylation pattern and response to DAC in three AML cell lines. We suggest that, although DAC treatment reduces TERT expression and telomerase activity, this is unlikely to occur via direct demethylation of the TERT promoter. However, further investigations on the regions spanning CpGs 7-12 and 14-16 may reveal valuable information regarding transcriptional regulation of TERT. PMID- 22517725 TI - The role of effective mass of carrier in the photocatalytic behavior of silver halide-based Ag@AgX (X=Cl, Br, I): a theoretical study. AB - The recent discovery of Ag@AgX (X=Cl, Br, I) plasmonic photocatalysts motivates us to elucidate the origin of the higher photocatalytic performance compared to commonly used TiO(2) -based materials. Herein, the electronic structure and effective masses of electrons at the conduction band minimum (CBM) and holes at the valence band maximum (VBM) are studied along different directions in the silver halide for the first time by means of first-principles calculations. It is revealed that the smaller effective mass of electrons at the CBM in silver halides contributes to the higher photocatalytic performance. The remarkable dependence of the effective mass of holes on the direction and the anion of the silver halide explains well the experimental observed morphology and anion dependence of photocatalytic activities of Ag@AgX. The crystal field splitting of the Ag 4d bands in the valance band of silver halides is found to be a main factor leading to the large effective mass of the photogenerated holes and consequently to a weaker transfer ability. A new crystal design and exerting strain along the coordinate axis are proposed as solutions to decrease the effective mass of holes. The present work may be helpful in exploring this novel class of silver halide-based photocatalysts. PMID- 22517727 TI - Diastereoselective 1,3-dipolar cycloaddition of pyrylium ylides with chiral enamides. AB - Chiral enamides 5f-i were found to react with pyrylium ylides to give cycloadducts 6d-i in good yields with an excellent level of stereoselectivity. The chiral auxiliary was successfully removed on hydrogenolysis of compound 6f in continuous flow (H-Cube) resulting in the first asymmetric synthesis of complex amine 8. PMID- 22517726 TI - Modular assembly of RanBP2-type zinc finger domains to target single-stranded RNA. PMID- 22517728 TI - Application of a sensitive near-field microwave microprobe to the nondestructive characterization of microbial rhodopsin. AB - We study the opto-electrical properties of Natronomonas pharaonis sensory rhodopsin II (NpSRII) by using a near-field microwave microprobe (NFMM) under external light illumination. To investigate the possibility of application of NFMM to biological macromolecules, we used time dependent properties of NPSRII before/after light activation which has three distinct states - ground-state, M state, and O-state. The diagnostic ability of NFMM is demonstrated by measuring the microwave reflection coefficient (S(11)) spectrum of NpSRII under steady state illumination in the wavelength range of 350-650 nm. Moreover, we present microwave reflection coefficient S(11) spectra in the same wavelength range for two fast-photocycling rhodopsins: green light-absorbing proteorhodopsin (GPR) and Gloeobacter rhodopsin (GR). In addition the frequency sweep shift can be detected completely even for tiny amounts of sample (~10(-3) OD of rhodopsin). Based on these results NFMM shows both very high sensitivity for detecting conformational changes and produces a good time-resolved spectrum. PMID- 22517729 TI - Stabilizing H3-: or are we stabilizing a proton? PMID- 22517730 TI - The reaction of a high-valent nonheme oxoiron(IV) intermediate with hydrogen peroxide. PMID- 22517731 TI - Effect of hydration on assessment of early enamel lesion using swept-source optical coherence tomography. AB - Establishing reproducible methodologies for assessment of early enamel lesions using optical coherence tomography (OCT) appears to be challenging. This in vitro study longitudinally evaluated the subsurface enamel lesion progression after 3, 9 and 15 days by cross-sectional scanning using 1310 nm centered swept-source OCT (SS-OCT) under hydrated and dry conditions. The positive difference between the depth-integrated OCT signals at dry and hydrated conditions were calculated and adopted as dehydration parameter (DH). A linear regression was found between DH and the square root of demineralization time (R(2) = 0.99). Significant differences were found in DH between sound and demineralized enamel, and between different periods of demineralization (p < 0.001). Hydration state affects the reflectivity of demineralized porous enamel, and the effect can be potentially used for assessment of early enamel lesion using OCT. PMID- 22517732 TI - Grafting of cell-penetrating peptide to receptor-targeted liposomes improves their transfection efficiency and transport across blood-brain barrier model. AB - We report bifunctional liposomal delivery system, combining transferrin (Tf) mediated receptor targeting and poly-L-arginine (PR)-facilitated cell penetration, which overcomes the drawback of saturation of delivery. PR was conjugated to the distal end of distearoyl phosphoethanolamine-polyethylene glycol (PEG) 2000 and was incorporated with other phospholipids in chloroform/methanol (2:1) to form PR liposomes using thin-film hydration technique. Tf-PEG phospholipid micelles were incorporated into PR liposomes using postinsertion technique to form Tf-PR liposomes. The bifunctional liposomes demonstrated significantly (p < 0.05) higher cellular uptake by brain endothelial cells (bEnd.3) and about eightfold higher transfection in primary culture of glial cells as compared with the Tf liposomes. Cell viabilities of Tf-conjugated and bifunctional liposomes were not markedly different; however, transport across in vitro blood-brain barrier model improved considerably after dual modification. The study underlines the potential of bifunctional liposomes as high-efficiency and low-toxicity gene delivery system for the treatment of central nervous system disorders. PMID- 22517733 TI - Surface defects activating new reaction paths: formation of formate during methanol oxidation on Ru(0001). AB - Methanol was co-adsorbed with oxygen on Ru(0001) under conditions approaching those of real catalysts: at room temperature and at relatively high pressures and exposures, together with a comparative analysis of flat and defective surfaces. To clarify reaction routes, parallel exposures to formaldehyde and oxygen have also been analyzed. It is found that for both mixtures of gases, a new reaction path is activated on defective surfaces, in which methanol is oxidized to formate. Furthermore, at variance with pure methanol adsorption, apart from CO, various intermediates are observed in both flat and defective surfaces. On flat surfaces, formaldehyde and formyl are recognized whereas on defective ones methoxy and formate are detected. A model involving steering effects is presented, which accounts for the activity of surface defects towards the synthesis of formate. PMID- 22517734 TI - Alkylation of pyridone derivatives by nickel/Lewis acid catalysis. PMID- 22517735 TI - Development of a dual joystick-controlled laser trapping and cutting system for optical micromanipulation of chromosomes inside living cells. AB - A multi-joystick robotic laser microscope system used to control two optical traps (tweezers) and one laser scissors has been developed for subcellular organelle manipulation. The use of joysticks has provided a "user-friendly" method for both trapping and cutting of organelles such as chromosomes in live cells. This innovative design has enabled the clean severing of chromosome arms using the laser scissors as well as the ability to easily hold and pull the severed arm using the laser tweezers. PMID- 22517737 TI - Implications of a needs assessment intervention for people with progressive cancer: impact on clinical assessment, response and service utilisation. AB - OBJECTIVE: To assess the impact of the systematic use of the Palliative Care Needs Assessment Guidelines and Needs Assessment Tool: Progressive Disease-Cancer (NAT: PD-C) on clinical assessment, response and service utilisation. STUDY SETTING: Three major oncology treatment centres in NSW, Australia. STUDY DESIGN: Between March 2007 and December 2009, 219 people with advanced cancer were recruited to complete bi-monthly telephone interviews. The intervention, introduced after at least two baseline interviews, involved training health professionals to complete the NAT: PD-C with patients approximately monthly. DATA COLLECTION: Rates of service use and referrals were compared pre- and post introduction of the NAT: PD-C. Rates of completion of the tool; its impact on consultation length; and the types of needs and follow-up care to address these were also assessed. PRINCIPAL FINDINGS: The NAT: PD-C had a high rate of completion; identified needs consistent with those self-reported by patients in interviews; and did not alter consultation length. No changes in the number of health professionals seen by patients were found pre- and post-intervention. CONCLUSION: The NAT: PD-C is an efficient and acceptable strategy for supporting needs-based cancer care that can potentially be incorporated into standard routine care without increasing the burden on care providers. PMID- 22517738 TI - Cellular mechanism for selective vertical transmission of an obligate insect symbiont at the bacteriocyte-embryo interface. AB - Many insects are associated with obligate symbiotic bacteria, which are localized in specialized cells called bacteriocytes, vertically transmitted through host generations via ovarial passage, and essential for growth and reproduction of their hosts. Although vertical transmission is pivotal for maintenance of such intimate host-symbiont associations, molecular and cellular mechanisms underlying the process are largely unknown. Here we report a cellular mechanism for vertical transmission of the obligate symbiont Buchnera in the pea aphid Acyrthosiphon pisum. In the aphid body, Buchnera cells are transmitted from maternal bacteriocytes to adjacent blastulae at the ovariole tips in a highly coordinated manner. By making use of symbiont-manipulated strains of A. pisum, we demonstrated that the facultative symbiont Serratia is, unlike Buchnera, not transmitted from maternal bacteriocytes to blastulae, suggesting a specific mechanism for Buchnera transmission. EM observations revealed a series of exo /endocytotic processes operating at the bacteriocyte-blastula interface: Buchnera cells are exocytosed from the maternal bacteriocyte, temporarily released to the extracellular space, and endocytosed by the posterior syncytial cytoplasm of the blastula. These results suggest that the selective Buchnera transmission is likely attributable to Buchnera-specific exocytosis by the maternal bacteriocyte, whereas both Buchnera and Serratia are nonselectively incorporated by the endocytotic activity of the posterior region of the blastula. The sophisticated cellular mechanism for vertical transmission of Buchnera must have evolved to ensure the obligate host-symbiont association, whereas facultative symbionts like Serratia may coopt the endocytotic component of the mechanism for their entry into the host embryos. PMID- 22517739 TI - Profile of Lee D. Ross. Interview by Sandeep Ravindran. PMID- 22517736 TI - Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). PMID- 22517740 TI - Simultaneous mastering of two abstract concepts by the miniature brain of bees. AB - Sorting objects and events into categories and concepts is a fundamental cognitive capacity that reduces the cost of learning every particular situation encountered in our daily lives. Relational concepts such as "same," "different," "better than," or "larger than"--among others--are essential in human cognition because they allow highly efficient classifying of events irrespective of physical similarity. Mastering a relational concept involves encoding a relationship by the brain independently of the physical objects linked by the relation and is, therefore, consistent with abstraction capacities. Processing several concepts at a time presupposes an even higher level of cognitive sophistication that is not expected in an invertebrate. We found that the miniature brains of honey bees rapidly learn to master two abstract concepts simultaneously, one based on spatial relationships (above/below and right/left) and another based on the perception of difference. Bees that learned to classify visual targets by using this dual concept transferred their choices to unknown stimuli that offered a best match in terms of dual-concept availability: their components presented the appropriate spatial relationship and differed from one another. This study reveals a surprising facility of brains to extract abstract concepts from a set of complex pictures and to combine them in a rule for subsequent choices. This finding thus provides excellent opportunities for understanding how cognitive processing is achieved by relatively simple neural architectures. PMID- 22517741 TI - Tandem mass spectrometry identifies many mouse brain O-GlcNAcylated proteins including EGF domain-specific O-GlcNAc transferase targets. AB - O-linked N-acetylglucosamine (O-GlcNAc) is a reversible posttranslational modification of Ser and Thr residues on cytosolic and nuclear proteins of higher eukaryotes catalyzed by O-GlcNAc transferase (OGT). O-GlcNAc has recently been found on Notch1 extracellular domain catalyzed by EGF domain-specific OGT. Aberrant O-GlcNAc modification of brain proteins has been linked to Alzheimer's disease (AD). However, understanding specific functions of O-GlcNAcylation in AD has been impeded by the difficulty in characterization of O-GlcNAc sites on proteins. In this study, we modified a chemical/enzymatic photochemical cleavage approach for enriching O-GlcNAcylated peptides in samples containing ~100 MUg of tryptic peptides from mouse cerebrocortical brain tissue. A total of 274 O GlcNAcylated proteins were identified. Of these, 168 were not previously known to be modified by O-GlcNAc. Overall, 458 O-GlcNAc sites in 195 proteins were identified. Many of the modified residues are either known phosphorylation sites or located proximal to known phosphorylation sites. These findings support the proposed regulatory cross-talk between O-GlcNAcylation and phosphorylation. This study produced the most comprehensive O-GlcNAc proteome of mammalian brain tissue with both protein identification and O-GlcNAc site assignment. Interestingly, we observed O-beta-GlcNAc on EGF-like repeats in the extracellular domains of five membrane proteins, expanding the evidence for extracellular O-GlcNAcylation by the EGF domain-specific OGT. We also report a GlcNAc-beta-1,3-Fuc-alpha-1-O-Thr modification on the EGF-like repeat of the versican core protein, a proposed substrate of Fringe beta-1,3-N-acetylglucosaminyltransferases. PMID- 22517742 TI - Global impact of protein arginine phosphorylation on the physiology of Bacillus subtilis. AB - Reversible protein phosphorylation is an important and ubiquitous protein modification in all living cells. Here we report that protein phosphorylation on arginine residues plays a physiologically significant role. We detected 121 arginine phosphorylation sites in 87 proteins in the gram-positive model organism Bacillus subtilis in vivo. Moreover, we provide evidence that protein arginine phosphorylation has a functional role and is involved in the regulation of many critical cellular processes, such as protein degradation, motility, competence, and stringent and stress responses. Our results suggest that in B. subtilis the combined activity of a protein arginine kinase and phosphatase allows a rapid and reversible regulation of protein activity and that protein arginine phosphorylation can play a physiologically important and regulatory role in bacteria. PMID- 22517743 TI - Bats and white-nose syndrome. PMID- 22517744 TI - Nonthermal ATP-dependent fluctuations contribute to the in vivo motion of chromosomal loci. AB - Chromosomal loci jiggle in place between segregation events in prokaryotic cells and during interphase in eukaryotic nuclei. This motion seems random and is often attributed to brownian motion. However, we show here that locus dynamics in live bacteria and yeast are sensitive to metabolic activity. When ATP synthesis is inhibited, the apparent diffusion coefficient decreases, whereas the subdiffusive scaling exponent remains constant. Furthermore, the magnitude of locus motion increases more steeply with temperature in untreated cells than in ATP-depleted cells. This "superthermal" response suggests that untreated cells have an additional source of molecular agitation, beyond thermal motion, that increases sharply with temperature. Such ATP-dependent fluctuations are likely mechanical, because the heat dissipated from metabolic processes is insufficient to account for the difference in locus motion between untreated and ATP-depleted cells. Our data indicate that ATP-dependent enzymatic activity, in addition to thermal fluctuations, contributes to the molecular agitation driving random (sub)diffusive motion in the living cell. PMID- 22517746 TI - Degenerate Primer IDs and the birthday problem. PMID- 22517745 TI - Human fibrocytes coexpress thyroglobulin and thyrotropin receptor. AB - Thyroglobulin (Tg) is the macromolecular precursor of thyroid hormones and is thought to be uniquely expressed by thyroid epithelial cells. Tg and the thyroid stimulating hormone receptor (TSHR) are targets for autoantibody generation in the autoimmune disorder Graves disease (GD). Fully expressed GD is characterized by thyroid overactivity and orbital tissue inflammation and remodeling. This process is known as thyroid-associated ophthalmopathy (TAO). Early reports suggested that in TAO, both Tg and TSHR become overexpressed in orbital tissues. Previously, we found that CD34(+) progenitor cells, known as fibrocytes, express functional TSHR, infiltrate the orbit, and comprise a large subset of orbital fibroblasts in TAO. We now report that fibrocytes also express Tg, which resolves as a 305-kDa protein on Western blots. It can be immunoprecipitated with anti-Tg Abs. Further, (125)iodine and [(35)S]methionine are incorporated into Tg expressed by fibrocytes. De novo Tg synthesis is attenuated with a specific small interfering RNA targeting the protein. A fragment of the Tg gene promoter fused to a luciferase reporter exhibits substantial activity when transfected into fibrocytes. Unlike fibrocytes, GD orbital fibroblasts, which comprise a mixture of CD34(+) and CD34(-) cells, express much lower levels of Tg and TSHR. When sorted into pure CD34(+) and CD34(-) subsets, Tg and TSHR mRNA levels become substantially higher in CD34(+) cells. These findings indicate that human fibrocytes express multiple "thyroid-specific" proteins, the levels of which are reduced after they infiltrate tissue. Our observations establish the basis for Tg accumulation in orbital GD. PMID- 22517747 TI - Direct observation of stick-slip movements of water nanodroplets induced by an electron beam. AB - Dynamics of the first few nanometers of water at the interface are encountered in a wide range of physical, chemical, and biological phenomena. A simple but critical question is whether interfacial forces at these nanoscale dimensions affect an externally induced movement of a water droplet on a surface. At the bulk-scale water droplets spread on a hydrophilic surface and slip on a nonwetting, hydrophobic surface. Here we report the experimental description of the electron beam-induced dynamics of nanoscale water droplets by direct imaging the translocation of 10- to 80-nm-diameter water nanodroplets by transmission electron microscopy. These nanodroplets move on a hydrophilic surface not by a smooth flow but by a series of stick-slip steps. We observe that each step is preceded by a unique characteristic deformation of the nanodroplet into a toroidal shape induced by the electron beam. We propose that this beam-induced change in shape increases the surface free energy of the nanodroplet that drives its transition from stick to slip state. PMID- 22517748 TI - A core subunit of Polycomb repressive complex 1 is broadly conserved in function but not primary sequence. AB - Polycomb Group (PcG) proteins mediate heritable gene silencing by modifying chromatin structure. An essential PcG complex, PRC1, compacts chromatin and inhibits chromatin remodeling. In Drosophila melanogaster, the intrinsically disordered C-terminal region of PSC (PSC-CTR) mediates these noncovalent effects on chromatin, and is essential for viability. Because the PSC-CTR sequence is poorly conserved, the significance of its effects on chromatin outside of Drosophila was unclear. The absence of folded domains also made it difficult to understand how the sequence of PSC-CTR encodes its function. To determine the mechanistic basis and extent of conservation of PSC-CTR activity, we identified 17 metazoan PSC-CTRs spanning chordates to arthropods, and examined their sequence features and biochemical properties. PSC-CTR sequences are poorly conserved, but are all highly charged and structurally disordered. We show that active PSC-CTRs--which bind DNA tightly and inhibit chromatin remodeling efficiently--are distinguished from less active ones by the absence of extended negatively charged stretches. PSC-CTR activity can be increased by dispersing its contiguous negative charge, confirming the importance of this property. Using the sequence properties defined as important for PSC-CTR activity, we predicted the presence of active PSC-CTRs in additional diverse genomes. Our analysis reveals broad conservation of PSC-CTR activity across metazoans. This conclusion could not have been determined from sequence alignments. We further find that plants that lack active PSC-CTRs instead possess a functionally analogous PcG protein, EMF1. Thus, our study suggests that a disordered domain with dispersed negative charges underlies PRC1 activity, and is conserved across metazoans and plants. PMID- 22517749 TI - Alternative pathway for atmospheric particles growth. AB - Credible climate change predictions require reliable fundamental scientific knowledge of the underlying processes. Despite extensive observational data accumulated to date, atmospheric aerosols still pose key uncertainties in the understanding of Earth's radiative balance due to direct interaction with radiation and because they modify clouds' properties. Specifically, major gaps exist in the understanding of the physicochemical pathways that lead to aerosol growth in the atmosphere and to changes in their properties while in the atmosphere. Traditionally, the driving forces for particle growth are attributed to condensation of low vapor pressure species following atmospheric oxidation of volatile compounds by gaseous oxidants. The current study presents experimental evidence of an unaccounted-for new photoinduced pathway for particle growth. We show that heterogeneous reactions activated by light can lead to fast uptake of noncondensable Volatile Organic Compounds (VOCs) at the surface of particles when only traces of a photosensitizer are present in the seed aerosol. Under such conditions, size and mass increase; changes in the chemical composition of the aerosol are also observed upon exposure to volatile organic compounds such as terpenes and near-UV irradiation. Experimentally determined growth rate values match field observations, suggesting that this photochemical process can provide a new, unaccounted-for pathway for atmospheric particle growth and should be considered by models. PMID- 22517751 TI - Molecular genetic basis of pod corn (Tunicate maize). AB - Pod corn is a classic morphological mutant of maize in which the mature kernels of the cob are covered by glumes, in contrast to generally grown maize varieties in which kernels are naked. Pod corn, known since pre-Columbian times, is the result of a dominant gain-of-function mutation at the Tunicate (Tu) locus. Some classic articles of 20th century maize genetics reported that the mutant Tu locus is complex, but molecular details remained elusive. Here, we show that pod corn is caused by a cis-regulatory mutation and duplication of the ZMM19 MADS-box gene. Although the WT locus contains a single-copy gene that is expressed in vegetative organs only, mutation and duplication of ZMM19 in Tu lead to ectopic expression of the gene in the inflorescences, thus conferring vegetative traits to reproductive organs. PMID- 22517752 TI - Metaproteomics of a gutless marine worm and its symbiotic microbial community reveal unusual pathways for carbon and energy use. AB - Low nutrient and energy availability has led to the evolution of numerous strategies for overcoming these limitations, of which symbiotic associations represent a key mechanism. Particularly striking are the associations between chemosynthetic bacteria and marine animals that thrive in nutrient-poor environments such as the deep sea because the symbionts allow their hosts to grow on inorganic energy and carbon sources such as sulfide and CO(2). Remarkably little is known about the physiological strategies that enable chemosynthetic symbioses to colonize oligotrophic environments. In this study, we used metaproteomics and metabolomics to investigate the intricate network of metabolic interactions in the chemosynthetic association between Olavius algarvensis, a gutless marine worm, and its bacterial symbionts. We propose previously undescribed pathways for coping with energy and nutrient limitation, some of which may be widespread in both free-living and symbiotic bacteria. These pathways include (i) a pathway for symbiont assimilation of the host waste products acetate, propionate, succinate and malate; (ii) the potential use of carbon monoxide as an energy source, a substrate previously not known to play a role in marine invertebrate symbioses; (iii) the potential use of hydrogen as an energy source; (iv) the strong expression of high-affinity uptake transporters; and (v) as yet undescribed energy-efficient steps in CO(2) fixation and sulfate reduction. The high expression of proteins involved in pathways for energy and carbon uptake and conservation in the O. algarvensis symbiosis indicates that the oligotrophic nature of its environment exerted a strong selective pressure in shaping these associations. PMID- 22517756 TI - Improving biodiversity conservation through modern portfolio theory. PMID- 22517755 TI - Mitochondrial DNA variant associated with Leber hereditary optic neuropathy and high-altitude Tibetans. AB - The distinction between mild pathogenic mtDNA mutations and population polymorphisms can be ambiguous because both are homoplasmic, alter conserved functions, and correlate with disease. One possible explanation for this ambiguity is that the same variant may have different consequences in different contexts. The NADH dehydrogenase subunit 1 (ND1) nucleotide 3394 T > C (Y30H) variant is such a case. This variant has been associated with Leber hereditary optic neuropathy and it reduces complex I activity and cellular respiration between 7% and 28% on the Asian B4c and F1 haplogroup backgrounds. However, complex I activity between B4c and F1 mtDNAs, which harbor the common 3394T allele, can also differ by 30%. In Asia, the 3394C variant is most commonly associated with the M9 haplogroup, which is rare at low elevations but increases in frequency with elevation to an average of 25% of the Tibetan mtDNAs (odds ratio = 23.7). In high-altitude Tibetan and Indian populations, the 3394C variant occurs on five different macrohaplogroup M haplogroup backgrounds and is enriched on the M9 background in Tibet and the C4a4 background on the Indian Deccan Plateau (odds ratio = 21.9). When present on the M9 background, the 3394C variant is associated with a complex I activity that is equal to or higher than that of the 3394T variant on the B4c and F1 backgrounds. Hence, the 3394C variant can either be deleterious or beneficial depending on its haplogroup and environmental context. Thus, this mtDNA variant fulfills the criteria for a common variant that predisposes to a "complex" disease. PMID- 22517758 TI - Single amino acid radiocarbon dating of Upper Paleolithic modern humans. AB - Archaeological bones are usually dated by radiocarbon measurement of extracted collagen. However, low collagen content, contamination from the burial environment, or museum conservation work, such as addition of glues, preservatives, and fumigants to "protect" archaeological materials, have previously led to inaccurate dates. These inaccuracies in turn frustrate the development of archaeological chronologies and, in the Paleolithic, blur the dating of such key events as the dispersal of anatomically modern humans. Here we describe a method to date hydroxyproline found in collagen (~10% of collagen carbon) as a bone-specific biomarker that removes impurities, thereby improving dating accuracy and confidence. This method is applied to two important sites in Russia and allows us to report the earliest direct ages for the presence of anatomically modern humans on the Russian Plain. These dates contribute considerably to our understanding of the emergence of the Mid-Upper Paleolithic and the complex suite of burial behaviors that begin to appear during this period. PMID- 22517759 TI - Does water affect the acidity of surfaces? The proton-donating ability of silanol and carboxylic acid groups at mesoporous silica. PMID- 22517757 TI - MicroRNA-301a regulation of a T-helper 17 immune response controls autoimmune demyelination. AB - MicroRNAs (miRNAs) are an emerging group of short, noncoding RNAs that play an important role in regulating expression of classical genes. Thus far little is known about their role in autoimmune demyelination. In this study, we analyzed changes in the miRNA profile in CD4(+) T cells that occurred during the recognition of the myelin autoantigen, MOG(35-55). We found that, both in vivo and in vitro, myelin antigen stimulation resulted in significant up-regulation of miR-301a, miR-21, and miR-155. Furthermore, these three miRNAs were overexpressed in T cells infiltrating the CNS in animals with experimental autoimmune encephalomyelitis. Use of specific miRNA antagonists, antagomirs, revealed that miR-301a contributed to the development of the T-helper type 17 subset via targeting the IL-6/23-STAT3 pathway. This contribution appeared to be mediated by the miR-301a effect on the expression of the PIAS3, a potent inhibitor of the STAT3 pathway. Manipulation of miR-301a levels or PIAS3 expression in myelin specific CD4(+) T cells led to significant changes in the severity of experimental autoimmune encephalomyelitis. Thus, we have identified a role of miR 301a in regulating the function of myelin-reactive T-helper type 17 cells, supporting a role for miR-301a and PIAS3 as candidates for therapeutic targets for controlling of autoimmune demyelination. PMID- 22517760 TI - Selective detection of ethylene gas using carbon nanotube-based devices: utility in determination of fruit ripeness. PMID- 22517762 TI - Defects in MOFs: a thorough characterization. AB - As indicated by nearly perfect XRD data, but challenged by a two-signal IR spectrum of CO guest molecules, it is confirmed by computer simulations and XPS experiments that the most defect-free SURMOFs contain about 4% defective Cu sites. PMID- 22517763 TI - Isoindole-BODIPY dyes as red to near-infrared fluorophores. PMID- 22517761 TI - NGS catalog: A database of next generation sequencing studies in humans. AB - Next generation sequencing (NGS) technologies have been rapidly applied in biomedical and biological research since its advent only a few years ago, and they are expected to advance at an unprecedented pace in the following years. To provide the research community with a comprehensive NGS resource, we have developed the database Next Generation Sequencing Catalog (NGS Catalog, http://bioinfo.mc.vanderbilt.edu/NGS/index.html), a continually updated database that collects, curates and manages available human NGS data obtained from published literature. NGS Catalog deposits publication information of NGS studies and their mutation characteristics (SNVs, small insertions/deletions, copy number variations, and structural variants), as well as mutated genes and gene fusions detected by NGS. Other functions include user data upload, NGS general analysis pipelines, and NGS software. NGS Catalog is particularly useful for investigators who are new to NGS but would like to take advantage of these powerful technologies for their own research. Finally, based on the data deposited in NGS Catalog, we summarized features and findings from whole exome sequencing, whole genome sequencing, and transcriptome sequencing studies for human diseases or traits. PMID- 22517764 TI - In situ XPS monitoring of bulk ionic liquid reactions: shedding light on organic reaction mechanisms. AB - In the swim: until now, X-ray photoelectron spectroscopy (XPS) has been predominantly applied to the investigation of near-surface regions. Recent work has now brought XPS into a new domain with the direct monitoring of bulk reactions in the liquid phase. In the monitored reaction, the cation of an ionic liquid (IL) reacts with the anion of another IL. PMID- 22517765 TI - Butyrate suppresses colonic inflammation through HDAC1-dependent Fas upregulation and Fas-mediated apoptosis of T cells. AB - Butyrate, an intestinal microbiota metabolite of dietary fiber, has been shown to exhibit protective effects toward inflammatory diseases such as ulcerative colitis (UC) and inflammation-mediated colorectal cancer. Recent studies have shown that chronic IFN-gamma signaling plays an essential role in inflammation mediated colorectal cancer development in vivo, whereas genome-wide association studies have linked human UC risk loci to IFNG, the gene that encodes IFN-gamma. However, the molecular mechanisms underlying the butyrate-IFN-gamma-colonic inflammation axis are not well defined. Here we showed that colonic mucosa from patients with UC exhibit increased signal transducer and activator of transcription 1 (STAT1) activation, and this STAT1 hyperactivation is correlated with increased T cell infiltration. Butyrate treatment-induced apoptosis of wild type T cells but not Fas-deficient (Fas(lpr)) or FasL-deficient (Fas(gld)) T cells, revealing a potential role of Fas-mediated apoptosis of T cells as a mechanism of butyrate function. Histone deacetylase 1 (HDAC1) was found to bind to the Fas promoter in T cells, and butyrate inhibits HDAC1 activity to induce Fas promoter hyperacetylation and Fas upregulation in T cells. Knocking down gpr109a or slc5a8, the genes that encode for receptor and transporter of butyrate, respectively, resulted in altered expression of genes related to multiple inflammatory signaling pathways, including inducible nitric oxide synthase (iNOS), in mouse colonic epithelial cells in vivo. Butyrate effectively inhibited IFN-gamma-induced STAT1 activation, resulting in inhibition of iNOS upregulation in human colon epithelial and carcinoma cells in vitro. Our data thus suggest that butyrate delivers a double-hit: induction of T cell apoptosis to eliminate the source of inflammation and suppression of IFN-gamma-mediated inflammation in colonic epithelial cells, to suppress colonic inflammation. PMID- 22517766 TI - Ferritin upregulates hepatic expression of bone morphogenetic protein 6 and hepcidin in mice. AB - Hepcidin is a hepatocellular hormone that inhibits the release of iron from certain cell populations, including enterocytes and reticuloendothelial cells. The regulation of hepcidin (HAMP) gene expression by iron status is mediated in part by the signaling molecule bone morphogenetic protein 6 (BMP6). We took advantage of the low iron status of juvenile mice to characterize the regulation of Bmp6 and Hamp1 expression by iron administered in three forms: 1) ferri transferrin (Fe-Tf), 2) ferric ammonium citrate (FAC), and 3) liver ferritin. Each of these forms of iron enters cells by distinct mechanisms and chemical forms. Iron was parenterally administered to 10-day-old mice, and hepatic expression of Bmp6 and Hamp1 mRNAs was measured 6 h later. We observed that hepatic Bmp6 expression increased in response to ferritin but was unchanged by Fe Tf or FAC. Hepatic Hamp1 expression likewise increased in response to ferritin and Fe-Tf but was decreased by FAC. Exogenous ferritin increased Bmp6 and Hamp1 expression in older mice as well. Removing iron from ferritin markedly decreased its effect on Bmp6 expression. Exogenously administered ferritin and the derived iron localized in the liver primarily to sinusoidal lining cells. Moreover, expression of Bmp6 mRNA in isolated adult rodent liver cells was much higher in sinusoidal lining cells than hepatocytes (endothelial >> stellate > Kupffer). We conclude that exogenous iron-containing ferritin upregulates hepatic Bmp6 expression, and we speculate that liver ferritin contributes to regulation of Bmp6 and, thus, Hamp1 genes. PMID- 22517767 TI - Calcium-sensing receptor inhibits secretagogue-induced electrolyte secretion by intestine via the enteric nervous system. AB - Bacterial toxins such as cholera toxin induce diarrhea by both direct epithelial cell generation of cyclic nucleotides as well as stimulation of the enteric nervous system (ENS). Agonists of the extracellular calcium-sensing receptor (CaSR) can reduce toxin-stimulated fluid secretion in ENS-absent colonic epithelial crypts by increasing phosphodiesterase-dependent cyclic-nucleotide degradation. Here we show that the CaSR is also highly expressed in tetrodotoxin (TTX)-sensitive neurons comprising the ENS, suggesting that CaSR agonists might also function through neuronal pathways. To test this hypothesis, rat colon segments containing intact ENS were isolated and mounted on Ussing chambers. Basal and cyclic nucleotide-stimulated electrolyte secretions were monitored by measuring changes in short-circuit current (I(sc)). CaSR was activated by R-568 and its effects were compared in the presence and absence of TTX. Consistent with active regulation of anion secretion by the ENS, a significant proportion of I(sc) in the proximal and distal colon was inhibited by serosal TTX, both at basal and under cyclic AMP-stimulated conditions. In the absence of TTX, activation of CaSR with R-568 significantly reduced basal I(sc) and cyclic AMP stimulated I(sc); it also completely reversed the cAMP-stimulated secretory responses if the drug was applied after the forskolin stimulation. Such inhibitory effects of R-568 were either absent or significantly reduced when serosal TTX was present, suggesting that this agonist exerts its antisecretory effect on the intestine by inhibiting ENS. The present results suggest a new model for regulating intestinal fluid transport in which neuronal and nonneuronal secretagogue actions are modulated by the inhibitory effects of CaSR on the ENS. The ability of a CaSR agonist to reduce secretagogue-stimulated Cl(-) secretion might provide a new therapeutic approach for secretory and other ENS-mediated diarrheal conditions. PMID- 22517768 TI - Epidermal growth factor receptor transactivation is required for proteinase activated receptor-2-induced COX-2 expression in intestinal epithelial cells. AB - Proteinase-activated receptor (PAR)(2), a G protein-coupled receptor activated by serine proteinases, has been implicated in both intestinal inflammation and epithelial proliferation. Cyclooxygenase (COX)-2 is overexpressed in the gut during inflammation as well as in colon cancer. We hypothesized that PAR(2) drives COX-2 expression in intestinal epithelial cells. Treatment of Caco-2 colon cancer cells with the PAR(2)-activating peptide 2-furoyl-LIGRLO-NH(2) (2fLI), but not by its reverse-sequence PAR(2)-inactive peptide, for 3 h led to an increase in intracellular COX-2 protein expression accompanied by a COX-2-dependent increase in prostaglandin E(2) production. 2fLI treatment for 30 min significantly increased metalloproteinase activity in the culture supernatant. Increased epidermal growth factor receptor (EGFR) phosphorylation was observed in cell lysates following 40 min of treatment with 2fLI. The broad-spectrum metalloproteinase inhibitor marimastat inhibited both COX-2 expression and EGFR phosphorylation. The EGFR tyrosine kinase inhibitor PD153035 also abolished 2fLI induced COX-2 expression. Although PAR(2) activation increased ERK MAPK phosphorylation, neither ERK pathway inhibitors nor a p38 MAPK inhibitor affected 2fLI-induced COX-2 expression. However, inhibition of either Src tyrosine kinase signaling by PP2, Rho kinase signaling by Y27632, or phosphatidylinositol 3 (PI3) kinase signaling by LY294002 prevented 2fLI-induced COX-2 expression. Trypsin increased COX-2 expression through PAR(2) in Caco-2 cells and in an EGFR dependent manner in the noncancerous intestinal epithelial cell-6 cell line. In conclusion, PAR(2) activation drives COX-2 expression in Caco-2 cells via metalloproteinase-dependent EGFR transactivation and activation of Src, Rho, and PI3 kinase signaling. Our findings provide a mechanism whereby PAR(2) can participate in the progression from chronic inflammation to cancer in the intestine. PMID- 22517769 TI - Effect of a glucagon-like peptide 1 analog, ROSE-010, on GI motor functions in female patients with constipation-predominant irritable bowel syndrome. AB - The glucagon-like peptide 1 (GLP-1) analog ROSE-010 reduced pain during acute exacerbations of irritable bowel syndrome (IBS). Our objective was to assess effects of ROSE-010 on several gastrointestinal (GI) motor and bowel functions in constipation-predominant IBS (IBS-C). In a single-center, randomized, parallel group, double-blind, placebo-controlled, dose-response study, we evaluated safety, pharmacodynamics, and pharmacokinetics in female patients with IBS-C. ROSE-010 (30, 100, or 300 MUg sc) or matching placebo was administered once daily for 3 consecutive days and on 1 day 2-10 days later. We measured GI and colonic transit by validated scintigraphy and gastric volumes by single-photon emission computed tomography. The primary end points were half time of gastric emptying of solids, colonic transit geometric center at 24 h, and gastric accommodation volume. Analysis included intent-to-treat principle, analysis of covariance (with body mass index as covariate), and Dunnett-Hsu test for multiple comparisons. Exposure to ROSE-010 was approximately dose-proportional across the dose range tested. Demographic data in four treatment groups of female IBS-C patients (total 46) were not different. Gastric emptying was significantly retarded by 100 and 300 MUg of ROSE-010. There were no significant effects of ROSE-010 on gastric volumes, small bowel or colonic transit at 24 h, or bowel functions. The 30- and 100-MUg doses accelerated colonic transit at 48 h. Adverse effects were nausea (P < 0.001 vs. placebo) and vomiting (P = 0.008 vs. placebo). Laboratory safety results were not clinically significant. In IBS-C, ROSE-010 delayed gastric emptying of solids but did not retard colonic transit or alter gastric accommodation; the accelerated colonic transit at 48 h with 30 and 100 MUg of ROSE-010 suggests potential for relief of constipation in IBS-C. PMID- 22517770 TI - Physiology and pathophysiology of splanchnic hypoperfusion and intestinal injury during exercise: strategies for evaluation and prevention. AB - Physical exercise places high demands on the adaptive capacity of the human body. Strenuous physical performance increases the blood supply to active muscles, cardiopulmonary system, and skin to meet the altered demands for oxygen and nutrients. The redistribution of blood flow, necessary for such an increased blood supply to the periphery, significantly reduces blood flow to the gut, leading to hypoperfusion and gastrointestinal (GI) compromise. A compromised GI system can have a negative impact on exercise performance and subsequent postexercise recovery due to abdominal distress and impairments in the uptake of fluid, electrolytes, and nutrients. In addition, strenuous physical exercise leads to loss of epithelial integrity, which may give rise to increased intestinal permeability with bacterial translocation and inflammation. Ultimately, these effects can deteriorate postexercise recovery and disrupt exercise training routine. This review provides an overview on the recent advances in our understanding of GI physiology and pathophysiology in relation to strenuous exercise. Various approaches to determine the impact of exercise on the individual athlete's GI tract are discussed. In addition, we elaborate on several promising components that could be exploited for preventive interventions. PMID- 22517771 TI - Nitric oxide modifies chromatin to suppress ICAM-1 expression during colonic inflammation. AB - Nitric oxide (NO) is an established inflammatory mediator. However, it remains controversial whether NO enhances the inflammatory response in the colon or suppresses it. We investigated the epigenetic regulation of Icam-1 expression by NO following induction of colonic inflammation in rats by 2,4,6-trinitrobenzene sulfonic (TNBS) acid and obtaining colonic muscularis externae tissues 24 h later. TNBS inflammation induced intercellular adhesion molecule-1 (ICAM-1) expression by translocating NF-kappaB to the nucleus. The incubation of inflamed tissues with S-nitrosoglutathione (GSNO) did not affect the nuclear translocation of NF-kappaB; however, it suppressed the NF-kappaB binding to DNA. Chromatin immunoprecipitation analysis (ChIP)-qPCR assays showed that the increase in NF kappaB/DNA interaction following inflammation is due to the transcriptional downregulation of global HDAC3 and a decrease in its interaction with the DNA on the Icam-1 promoter containing the binding motifs of NF-kappaB. The decrease in the association of histone deacetylase (HDAC) 3 with the Icam-1 promoter increased the acetylation of histone 4 lysine residue 12 (H4K12), which would favor chromatin relaxation and greater access of NF-kappaB to its DNA binding sites. HDAC3 dissociation from the DNA did not affect the acetylation levels of H4K8 and H4K16. The NO release by GSNO countered the upregulation of Icam-1 by increasing the transcription of global HDAC3 and its association with the Icam-1 promoter, and by suppressing H4K12 acetylation. We conclude that chromatin modification by transcriptional downregulation of HDAC3 plays a critical role in the induction of the inflammatory response. NO may serve as an anti-inflammatory mediator during the acute stage of inflammation by blunting the downregulation of global HDAC3, increasing HDAC3 interaction with the nucleosomes containing the binding moieties of NF-kappaB, reducing H4K12Ac to restrict the access of NF kappaB to DNA, and suppressing ICAM-1 expression. PMID- 22517772 TI - The direct profibrotic and indirect immune antifibrotic balance of blocking the cannabinoid 2 receptor. AB - Cannabinoid 2 (CB2) receptors expressed on immune cells are considered to be antifibrogenic. Hepatic stellate cells (HSCs) directly interact with phagocytosis lymphocytes, but the nature of this interaction is obscure. We aimed to study the effects of CB2 receptors on hepatic fibrosis via their role in mediating immunity. Hepatic fibrosis was induced by carbon-tetrachloride (CCl(4)) administration in C57BL/6 wild-type (WT) and CB2 knockout (CB2(-/-)) mice. Irradiated animals were reconstituted with WT or CB2(-/-) lymphocytes. Lymphocytes from naive/fibrotic WT animals and healthy/cirrhotic hepatitis C virus were preincubated in vitro with or without CB2 antagonist, evaluated for proliferation and apoptosis, and then cocultured with primary mouse HSCs or a human HSC line (LX2), respectively. Lymphocyte phagocytosis was then evaluated. Following CCl(4)-administration, CB2(-/-) mice developed significant hepatic fibrosis but less necroinflammation. WT mice harbored decreased liver CD4(+) and NK(+) cells but increased CD8(+) subsets. Naive CB2(-/-) mice had significantly decreased T cell subsets. Adoptive transfer of CB2(-/-) lymphocytes led to decreased fibrosis in the irradiated WT recipient compared with animals receiving WT lymphocytes. Moreover, necroinflammation also tended to decrease. In vitro, a CB2-antagonist directly increased human HSC activation and increased apoptosis and decreased proliferation of mice/human T cells (healthy/fibrotic) and their phagocytosis. We concluded that CB2(-/-) lymphocytes exert an antifibrotic activity, whereas lack of CB2 receptor in HSCs promotes fibrosis. These findings broaden our understanding of cannabinoid signaling in hepatic fibrosis beyond their activity solely in HSCs. PMID- 22517773 TI - Impaired ghrelin signaling is associated with gastrointestinal dysmotility in rats with gastroesophageal reflux disease. AB - Gastroesophageal reflux disease (GERD) is often associated with decreased upper gastrointestinal motility, and ghrelin is an appetite-stimulating hormone known to increase gastrointestinal motility. We investigated whether ghrelin signaling is impaired in rats with GERD and studied its involvement in upper gastrointestinal motility. GERD was induced surgically in Wistar rats. Rats were injected intravenously with ghrelin (3 nmol/rat), after which gastric emptying, food intake, gastroduodenal motility, and growth hormone (GH) release were investigated. Furthermore, plasma ghrelin levels and the expression of ghrelin related genes in the stomach and hypothalamus were examined. In addition, we administered ghrelin to GERD rats treated with rikkunshito, a Kampo medicine, and examined its effects on gastroduodenal motility. GERD rats showed a considerable decrease in gastric emptying, food intake, and antral motility. Ghrelin administration significantly increased gastric emptying, food intake, and antral and duodenal motility in sham-operated rats, but not in GERD rats. The effect of ghrelin on GH release was also attenuated in GERD rats, which had significantly increased plasma ghrelin levels and expression of orexigenic neuropeptide Y/agouti-related peptide mRNA in the hypothalamus. The number of ghrelin-positive cells in the gastric body decreased in GERD rats, but the expression of gastric preproghrelin and GH secretagogue receptor mRNA was not affected. However, when ghrelin was exogenously administered to GERD rats treated with rikkunshito, a significant increase in antral motility was observed. These results suggest that gastrointestinal dysmotility is associated with impaired ghrelin signaling in GERD rats and that rikkunshito restores gastrointestinal motility by improving the ghrelin response. PMID- 22517774 TI - Ryanodine receptors contribute to bile acid-induced pathological calcium signaling and pancreatitis in mice. AB - Biliary pancreatitis is the most common etiology for acute pancreatitis, yet its pathophysiological mechanism remains unclear. Ca(2+) signals generated within the pancreatic acinar cell initiate the early phase of pancreatitis, and bile acids can elicit anomalous acinar cell intracellular Ca(2+) release. We previously demonstrated that Ca(2+) released via the intracellular Ca(2+) channel, the ryanodine receptor (RyR), contributes to the aberrant Ca(2+) signal. In this study, we examined whether RyR inhibition protects against pathological Ca(2+) signals, acinar cell injury, and pancreatitis from bile acid exposure. The bile acid tauro-lithocholic acid-3-sulfate (TLCS) induced intracellular Ca(2+) oscillations at 50 MUM and a peak-plateau signal at 500 MUM, and only the latter induced acinar cell injury, as determined by lactate dehydrogenase (LDH) leakage. Pretreatment with the RyR inhibitors dantrolene or ryanodine converted the peak plateau signal to a mostly oscillatory pattern (P < 0.05). They also reduced acinar cell LDH leakage, basolateral blebbing, and propidium iodide uptake (P < 0.05). In vivo, a single dose of dantrolene (5 mg/kg), given either 1 h before or 2 h after intraductal TLCS infusion, reduced the severity of pancreatitis down to the level of the control (P < 0.05). These results suggest that the severity of biliary pancreatitis may be ameliorated by the clinical use of RyR inhibitors. PMID- 22517776 TI - Structure of a novel PTH-related peptide hPTH' and its interaction with the PTH receptor. AB - We have previously shown that a recombinant human PTH fragment, Pro-Pro-[Arg11] hPTH (1-34)-Pro-Pro-Asp (hPTH'), could be a potentially better and more cost effective therapeutic agent than PTH (1-34) on osteoporosis. In this report, we characterized the solution conformations of hPTH' by NMR spectroscopy and modeled the interactions between the hPTH' and the PTH receptor. By comparing it with PTH (1-34) structures and their respective interactions with the PTH receptor, we identified two segments of helix extending from Ile5 to Met8 and from Glu22 to Gln29 with a divided kink between the two helixes around Arg20. Mutated arginine makes hPTH' fill the receptor cavity better as well as forms hydrogen bonds with Val193. Understanding the ligand receptor interactions will help us design small molecules to better mimic the activities of PTH. PMID- 22517777 TI - Diversity-oriented synthesis of diverse polycyclic scaffolds inspired by the logic of sesquiterpene lactones biosynthesis. PMID- 22517775 TI - Urocortins and CRF type 2 receptor isoforms expression in the rat stomach are regulated by endotoxin: role in the modulation of delayed gastric emptying. AB - Peripheral activation of corticotropin-releasing factor receptor type 2 (CRF(2)) by urocortin 1, 2, or 3 (Ucns) exerts powerful effects on gastric function; however, little is known about their expression and regulation in the stomach. We investigated the expression of Ucns and CRF(2) isoforms by RT-PCR in the gastric corpus (GC) mucosa and submucosa plus muscle (S+M) or laser captured layers in naive rats, their regulations by lipopolysaccharide (LPS, 100 MUg/kg ip) over 24 h, and the effect of the CRF(2) antagonist astresssin(2)-B (100 MUg/kg sc) on LPS induced delayed gastric emptying (GE) 2-h postinjection. Transcripts of Ucns and CRF(2b,) the most common wild-type CRF(2) isoform in the periphery, were expressed in all layers, including myenteric neurons. LPS increased Ucn mRNA levels significantly in both mucosa and S+M, reaching a maximal response at 6 h postinjection and returning to basal levels at 24 h except for Ucn 1 in S+M. By contrast, CRF(2b) mRNA level was significantly decreased in the mucosa and M+S with a nadir at 6 h. In addition, CRF(2a), reportedly only found in the brain, and the novel splice variant CRF(2a-3) were also detected in the GC, antrum, and pylorus. LPS reciprocally regulated these variants with a decrease of CRF(2a) and an increase of CRF(2a-3) in the GC 6 h postinjection. Astressin(2)-B exacerbated LPS-delayed GE (42-73%, P < 0.001). These data indicate that Ucn and CRF(2) isoforms are widely distributed throughout the rat stomach and inversely regulated by immune stress. The CRF(2) signaling system may act to counteract the early gastric motor alterations to endotoxemia. PMID- 22517778 TI - Sorption and dissipation of aged metolachlor residues in eroded and rehabilitated soils. AB - BACKGROUND: Sorption and dissipation of aged metolachlor were characterized in rehabilitated and eroded prairie soils using sequential batch slurry (conventional) and accelerated solvent extraction (ASE). RESULTS: In spite of an almost twofold difference in soil organic carbon (OC) content, S-metolachlor sorption coefficients (K(d)) and dissipation rates (DT(50)) were the same in soils from different landscape positions within an eroded landform. Soil was moved within the landform to increase productivity. In areas receiving topsoil addition, S-metolachlor K(d) was higher and DT(50) was longer than in eroded areas. The efficiency of extraction was higher for ASE than for conventional extractions. No consistent aging effect on K(d) was observed. Mineralization in 8 weeks accounted for < 10% of the applied metolachlor. CONCLUSION: The results of this laboratory study support a field dissipation study. Both showed that S metolachlor has the same retention and dissipation rate throughout an eroded landform, which was not expected owing to the large variability in soil properties, including OC concentrations. Altering soil properties by adding topsoil increased metolachlor sorption and persistence. The method of extraction (conventional versus ASE) affected calculated sorption coefficients and dissipation rates. In all cases, groundwater ubiquity scores (GUSs) categorized metolachlor as having intermediate mobility. PMID- 22517780 TI - Abstracts of the 35th Annual Scientific Sessions of the Society for Cardiovascular Angiography and Interventions. May 9-12, 2012. Las Vegas, Nevada, USA. PMID- 22517779 TI - Duodenal-pleural fistula in Crohn's disease: successful long-term medical management. PMID- 22517781 TI - N alkylation of tosylamides using esters as primary and tertiary alkyl sources: mediated by hydrosilanes activated by a ruthenium catalyst. PMID- 22517782 TI - Effect of therapist-based versus robot-assisted bilateral arm training on motor control, functional performance, and quality of life after chronic stroke: a clinical trial. AB - BACKGROUND: Although bilateral arm training (BAT) has been widely studied, the comparative effects of therapist-based BAT (TBAT) versus robot-assisted BAT (RBAT) remains unknown. OBJECTIVE: This study compared the efficacy of TBAT, RBAT, and a control treatment (CT) on motor control, functional performance, and quality of life after chronic stroke. DESIGN: A randomized, pretest-posttest, control group design was used. METHODS: Forty-two patients (mean age=54.49 years, SD=9.69; mean length of time since stroke onset=17.62 months, SD=10.50) were randomly assigned to TBAT, RBAT, and CT groups. Each group received treatment for 90 to 105 minutes per session, 5 sessions on weekdays, for 4 weeks. Outcome measures included kinematic analyses, the Fugl-Meyer Assessment (FMA), the Motor Activity Log, and the Stroke Impact Scale (SIS). RESULTS: Large and significant effects were found in the kinematic variables, distal part of upper-limb motor impairment, and certain aspects of quality of life in favor of TBAT or RBAT. Specifically, the TBAT group demonstrated significantly better temporal efficiency and smoothness, straighter trunk motion, and less trunk compensation compared with the CT and RBAT groups. The RBAT group had increased shoulder flexion compared with the CT and TBAT groups. On the FMA, the TBAT group showed higher distal part scores than the CT group. On the SIS, the RBAT group had better strength subscale, physical function domain, and total scores than the CT group. Limitations This study recruited patients with mild spasticity and without cognitive impairment. CONCLUSIONS: Compared with CT, TBAT and RBAT exhibited differential effects on outcome measures. Therapist-based BAT may improve temporal efficiency, smoothness, trunk control, and motor impairment of the distal upper limb. Robot-assisted BAT may improve shoulder flexion and quality of life. PMID- 22517783 TI - Cervical disk pathology in patients with multiple sclerosis: two case reports. AB - BACKGROUND AND PURPOSE: A patient with multiple sclerosis (MS) may be seen by a physical therapist for evaluation before the MS diagnosis is definitively made, after a relapse, or during a progression. The diagnosis of MS should be part of the differential diagnosis if the symptoms of a patient with neurological issues fit the pattern of a progressive disease. Multiple sclerosis can affect any part of the central nervous system. Cervical pathology can be confused with relapsing symptoms of MS. The purpose of this case report is to demonstrate how easily cervical pathology can be overlooked in a patient with MS. CASE DESCRIPTION: Two case reports of patients with relapsing MS are presented. Both patients were referred for physical therapy after not responding to standard treatment with intravenous methylprednisolone. One patient reported multiple falls and complained of increasing cervical pain and spasm, fatigue, bouts of diplopia, and difficulty ambulating. The other patient complained of headaches, visual disturbances, and cervical pain with radicular symptoms. Contrast magnetic resonance imaging (MRI) did not reveal new MS lesions or the extension of old MS lesions. The cervical herniations in the first patient, not previously documented, were old. The bulging disks in the second patient, seen in a previous study, were unchanged. The MRI findings did not support the diagnosis of acute inflammatory MS or acute cervical pathology. OUTCOMES: Both patients responded to physical therapy intervention once the cervical symptoms were directly addressed. As the cervical pain and spasm decreased, the relapsing MS symptoms of dysmetria, balance disturbance, and ataxic gait began to diminish. In both patients, eye function was slow to recover, with persistent impairment. Both patients returned to their premorbid activity and socialization level. DISCUSSION: Cervical disk disease should be considered in the differential diagnosis when a patient with MS has a history of trauma and displays abnormal postures, spastic weakness, and changes in pain complaints. In these 2 cases, treating the cervical pathology in addition to the MS symptoms provided the most effective approach for functional improvement. PMID- 22517784 TI - Assessing the integrated pest management practices of southeastern US ornamental nursery operations. AB - BACKGROUND: The Southern Nursery Integrated Pest Management (SNIPM) working group surveyed ornamental nursery crop growers in the southeastern United States to determine their pest management practices. Respondents answered questions about monitoring practices for insects, diseases and weeds, prevention techniques, intervention decisions, concerns about IPM and educational opportunities. Survey respondents were categorized into three groups based on IPM knowledge and pest management practices adopted. RESULTS: The three groups differed in the use of standardized sampling plans for scouting pests, in monitoring techniques, e.g. sticky cards, phenology and growing degree days, in record-keeping, in the use of spot-spraying and in the number of samples sent to a diagnostic clinic for identification and management recommendation. CONCLUSIONS: Stronger emphasis is needed on deliberate scouting techniques and tools to monitor pest populations to provide earlier pest detection and greater flexibility of management options. Most respondents thought that IPM was effective and beneficial for both the environment and employees, but had concerns about the ability of natural enemies to control insect pests, and about the availability and effectiveness of alternatives to chemical controls. Research and field demonstration is needed for selecting appropriate natural enemies for augmentative biological control. Two groups utilized cooperative extension almost exclusively, which would be an avenue for educating those respondents. PMID- 22517785 TI - Outcomes in patients with renal impairment undergoing percutaneous coronary intervention and implantation of the Endeavor zotarolimus-eluting stent: 1- and 2 year data from the E-Five Registry. AB - OBJECTIVES: Renal impairment (RI) is a predictor of poor outcomes in patients with cardiovascular disease, but its influence in the setting of percutaneous coronary intervention and zotarolimus-eluting stent (ZES) implantation has not been described. This study evaluated the impact of RI on clinical outcomes in patients participating in the E-Five Registry. BACKGROUND: E-Five was a prospective, multicenter, global registry of 8,314 patients; 2,116 patients were followed to 2 years. METHODS: Patients (excluding those who had undergone renal transplantation) were grouped according to renal function (normal function/mild RI, serum creatinine <110 MUmol/L; moderate RI, 110-200 MUmol/L; severe RI, >200 MUmol/L) and their outcomes evaluated retrospectively. Major adverse cardiac events (MACE; i.e., death, myocardial infarction, emergency cardiac bypass surgery, or target lesion revascularization) and stent thrombosis events at 1 and 2 years were compared between groups. RESULTS: The 1-year MACE rate in patients with mild RI was 6.8%, compared with 8.9 and 18.1% in patients with moderate and severe RI (P = 0.002 across groups). At 2 years, death occurred in 16% of those with severe RI, compared with 2.0 and 4.7% in those with mild and moderate RI (P = 0.002). There was no significant difference in the rates of target lesion revascularization or target vessel failure. CONCLUSIONS: Greater severity of RI at intervention is associated with greater mortality and MACE but unchanged revascularization rates after ZES implantation. PMID- 22517786 TI - Turning "on" and "off" a pyridoxal 5'-phosphate mimic using light. PMID- 22517787 TI - Next-generation regeneration: the hope and hype of lung stem cell research. AB - Research discoveries in the fields of stem cell biology and regenerative medicine are beginning to advance and refine our understanding of lung injury and repair. Although these emerging studies offer unprecedented opportunities to develop novel therapies for a variety of lung diseases, the quickening pace of work in this nascent field also makes it difficult to discern hope from hype when addressing the pleas of patients eager for clinical translation or when seeking information on the risk versus reward of participation in clinical trials. This perspective provides an overview of the latest advances in lung-related stem cell research and places the new discoveries in a historical context. Established, lineage-restricted epithelial progenitors of the conducting airways and gas exchanging alveoli are briefly reviewed, and controversial, newly proposed tissue specific candidate lung stem/progenitor cells with broader differentiation repertoire are introduced. Exogenous derivation of lung epithelia from embryonic stem cells or induced pluripotent stem cells is also presented as an alternative method for engineering lung tissue de novo in culture. PMID- 22517788 TI - A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients. AB - RATIONALE: The clinical relevance of Aspergillus-positive endotracheal aspirates in critically ill patients is difficult to assess. OBJECTIVES: We externally validate a clinical algorithm to discriminate Aspergillus colonization from putative invasive pulmonary aspergillosis in this patient group. METHODS: We performed a multicenter (n = 30) observational study including critically ill patients with one or more Aspergillus-positive endotracheal aspirate cultures (n = 524). The diagnostic accuracy of this algorithm was evaluated using 115 patients with histopathologic data, considered the gold standard. Subsequently, the diagnostic workout of the algorithm was compared on the total cohort (n = 524), with the categorization based on the diagnostic criteria of the European Organization for the Research and Treatment of Cancer/Mycoses Study Group. MEASUREMENTS AND MAIN RESULTS: Among 115 histopathology-controlled patients, 79 had proven aspergillosis. The algorithm judged 86 of 115 cases to have putative aspergillosis. This diagnosis was confirmed in 72 and rejected in 14 patients. The algorithm judged 29 patients to have Aspergillus colonization. This was confirmed in 22 and rejected in 7 patients. The algorithm had a specificity of 61% and a sensitivity of 92%. The positive and negative predictive values were 61 and 92%, respectively. In the total cohort (n = 524), 79 patients had proven invasive pulmonary aspergillosis (15.1%). According to the European Organization for the Research and Treatment of Cancer/Mycoses Study Group criteria, 32 patients had probable aspergillosis (6.1%) and 413 patients were not classifiable (78.8%). The algorithm judged 199 patients to have putative aspergillosis (38.0%) and 246 to have Aspergillus colonization (46.9%). CONCLUSIONS: The algorithm demonstrated favorable operating characteristics to discriminate Aspergillus respiratory tract colonization from invasive pulmonary aspergillosis in critically ill patients. PMID- 22517789 TI - The incidence of work-related asthma-like symptoms and dust exposure in Norwegian smelters. AB - RATIONALE: The prevalence of respiratory symptoms among employees in smelters is positively associated with dust exposure. OBJECTIVES: To investigate the association between the incidence of work-related asthma-like symptoms (WASTH) and dust exposure. METHODS: All the employees were invited to participate in a 5 year longitudinal study. The outcome of WASTH was defined as the combination of dyspnea and wheezing improving on rest days or vacation in an individual who had no asthma previously. Information about smoking and occupational status was obtained from a questionnaire. A job exposure matrix of total dust was developed. Multivariate data analyses were performed using Cox regression. MEASUREMENTS AND MAIN RESULTS: The total follow-up time of the employees (n = 2,476) was 8,469 years, and the median follow-up time for participants was 4.0 years. During the follow-up, 91 employees developed WASTH, and the corresponding incidence rate for WASTH per 1,000 person-years was 8.9 (7.3-10.9) (95% confidence interval in parentheses). The risk ratio of WASTH increased significantly (P = 0.0001) with dust exposure in the middle and high categories (1.0-2.9 and >= 3.0 mg/m(3)). Stratified analyses showed that the effect of current dust exposure varied with both previous exposure (PE) to dust and fumes (P = 0.006) and airflow limitation (AFL) (P = 0.033). The final analyses showed that the risk ratios for WASTH per 1 mg/m(3) increase in current dust exposure were 1.1 (0.93-1.2), 1.4 (1.1-1.8), 1.6 (1.1-2.3), and 1.9 (1.2-3.0) for the categories (PE+/AFL-), (PE-/AFL-), (PE+/AFL+, and (PE-/AFL+). CONCLUSIONS: In conclusion, dust exposure was associated with an increased incidence of WASTH. PMID- 22517790 TI - Prey consumption rates and compatibility with pesticides of four predatory mites from the family Phytoseiidae attacking Thrips palmi Karny (Thysanoptera: Thripidae). AB - BACKGROUND: Predatory mites (Amblyseius swirskii Athias-Henriot, Typhlodromips montdorensis Schicha, Neoseiulus cucumeris (Oudemans) and Iphiseius degenerans Berlese) were investigated for their potential to act as control agents for Thrips palmi Karny. Prey consumption rates and compatibility with pesticides were assessed. RESULTS: Second-instar larvae were the preferred life stage. Typhlodromips montdorensis consumed the most larvae (2.8) and also an average of 1.2 adult T. palmi per 5 day period. Both 24 and 48 h assessments following application of abamectin, spinosad and imazalil demonstrated mortality of predatory mites (across all species), which was significantly higher than with the other treatments (P < 0.001). Spraying with pymetrozine did not provide any increased mortality when compared with the water control. Application of thiacloprid proved detrimental only to I. degenerans. Following indirect exposure of predatory mites to pymetrozine and imazalil, no significant differences in mite mortality were obtained. Indirect exposure to spinosad was identified as the most detrimental treatment (P < 0.001) to all mites. Abamectin also proved detrimental, with only T. montdorensis showing any potential tolerance. CONCLUSION: All predatory mites investigated offer potential for controlling T. palmi. Compatibility with chemicals varied between the mites. The potential of incorporating the mites into eradication strategies for T. palmi is discussed. PMID- 22517791 TI - Synthesis of fluorene derivatives through rhodium-catalyzed dehydrogenative cyclization. PMID- 22517792 TI - Rebuttal: the CTO "no-controversy" controversy: should the field of CTO-PCI be allowed to expand? PMID- 22517794 TI - Martin Jansen. Interviewed by Bettina Lotsch. PMID- 22517793 TI - Patients with Fanconi anemia and AML have different cytogenetic clones than de novo cases of AML. AB - Specific cytogenetic clones might distinguish patients with unrecognized Fanconi anemia (FA) who present with acute myeloid leukemia (AML) from those with sporadic AML. Cytogenetic reports in literature cases of FA and AML were compared with de novo cases enrolled on CCG-2961. Gain of 1q, gain of 3q, monosomy 7, deleted 7q, gain of 13q, and deleted 20q were more frequent in FA AML; t(8;21), trisomy 8, t(9;11), t(6;9), and inversion 16 were exclusive to de novo AML cases. Observation of the FA AML cytogenetic clonal patterns should raise suspicion of an underlying leukemia predisposition syndrome and influence management. PMID- 22517795 TI - Chronic endotoxin exposure produces airflow obstruction and lung dendritic cell expansion. AB - Little is known about the mechanisms of persistent airflow obstruction that result from chronic occupational endotoxin exposure. We sought to analyze the inflammatory response underlying persistent airflow obstruction as a result of chronic occupational endotoxin exposure. We developed a murine model of daily inhaled endotoxin for periods of 5 days to 8 weeks. We analyzed physiologic lung dysfunction, lung histology, bronchoalveolar lavage fluid and total lung homogenate inflammatory cell and cytokine profiles, and pulmonary gene expression profiles. We observed an increase in airway hyperresponsiveness as a result of chronic endotoxin exposure. After 8 weeks, the mice exhibited an increase in bronchoalveolar lavage and lung neutrophils that correlated with an increase in proinflammatory cytokines. Detailed analyses of inflammatory cell subsets revealed an expansion of dendritic cells (DCs), and in particular, proinflammatory DCs, with a reduced percentage of macrophages. Gene expression profiling revealed the up-regulation of a panel of genes that was consistent with DC recruitment, and lung histology revealed an accumulation of DCs in inflammatory aggregates around the airways in 8-week-exposed animals. Repeated, low-dose LPS inhalation, which mirrors occupational exposure, resulted in airway hyperresponsiveness, associated with a failure to resolve the proinflammatory response, an inverted macrophage to DC ratio, and a significant rise in the inflammatory DC population. These findings point to a novel underlying mechanism of airflow obstruction as a result of occupational LPS exposure, and suggest molecular and cellular targets for therapeutic development. PMID- 22517796 TI - Indoleamine 2,3-dioxygenase and metabolites protect murine lung allografts and impair the calcium mobilization of T cells. AB - The enzyme indoleamine 2,3-dioxygenase (IDO) converts tryptophan into kynurenine metabolites that suppress effector T-cell function. In this study, we investigated IDO and its metabolite, 3-hydroxyanthranilic acid (3HAA), in regulating lung allograft rejection, using a murine orthotopic lung transplant model with a major mismatch (BALB/c donor and C57BL6 recipient). IDO was overexpressed in murine donor lungs, using an established nonviral (polyethylenimine carrier)-based gene transfer approach, whereas 3HAA was delivered daily via intraperitoneal injection. Increased IDO expression or its metabolite, 3HAA, resulted in a remarkable therapeutic effect with near normal lung function and little acute rejection, approximately A1, compared with A3 in untreated allografts (grading based on International Society for Heart and Lung Transplantation guidelines). We found that a high IDO environment for 7 days in lung allografts resulted in impaired T-cell activation, the production of multiple effector cytokines (IL-2, IL-4, IL-5, IL-6, IFN-gamma, TNF-alpha, IL-12, and IL-13), and the generation of effector memory T cells (CD62L(lo)CD44(hi) phenotype). In isolated murine splenocytes, we observed that IDO/3HAA impaired T cell receptor (TCR)-mediated T-cell activation, and more importantly, a decrease of intracellular calcium, phospholipase C-gamma1 phosphorylation, and mitochondrial mass was evident. This work further illustrates the potential role of a high IDO environment in lung transplantation, and that the high IDO environment directly impairs TCR activation via the disruption of calcium signaling. PMID- 22517797 TI - Hydroxyurea for the treatment of sickle cell disease: efficacy, barriers, toxicity, and management in children. AB - Hydroxyurea is the only approved medication in the United States for the treatment of sickle cell anemia (HbSS) and is widely used in children despite an indication limited to adults. We review the evidence of efficacy and safety in children with reference to pivotal adult studies. This evidence and expert opinion form the basis for recommended guidelines for the use of hydroxyurea in children including indications, dosing, therapeutic and safety monitoring, and interventions to improve adherence. However, there are substantial gaps in our knowledge to be addressed by on-going and planned studies in children. PMID- 22517798 TI - Transcatheter aortic valve implantation without balloon predilatation: not always feasible. AB - Balloon predilatation has been regarded as an essential step before implanting the self-expandable prosthesis during transcatheter aortic valve implantation (TAVI). Recent evidence showed that without balloon predilatation, an implantation success rate of >95% could be achieved. We report two cases in which balloon predilatation was not performed initially during TAVI but eventually required it to facilitate device crossing and implantation. They illustrated the importance of case selection and alerted us the potential limitation in performing TAVI without balloon predilatation. PMID- 22517799 TI - Developmental macular disorders: phenotypes and underlying molecular genetic basis. AB - The developmental macular disorders form part of a heterogeneous group of retinal conditions that are an important cause of visual impairment in children. The macular abnormality is present from birth and is usually non-progressive but visual loss may occur as a result of complications such as choroidal neovascularisation. To date, most of the causative genes have not been identified but with the advent of next generation sequencing, it is likely that the genetic basis of these disorders will soon be elucidated. Improved knowledge of the underlying molecular genetics and disease mechanisms will raise the possibility of future treatments for these disorders, for which there are no specific therapies available at the present time. PMID- 22517800 TI - Living with nystagmus: a qualitative study. AB - BACKGROUND/AIMS: To identify aspects of daily living affected by nystagmus. METHODS: Semistructured interviews were conducted at the University of Leicester, UK with participants with acquired and infantile nystagmus. In total 21, participants were purposively sampled and recruited. Transcript analysis was conducted using constant comparative technique, based upon the grounded theory, to identify specific areas of living affected by nystagmus. RESULTS: Analysis identified six domains that were adversely affected by nystagmus; visual function, restriction of movement, standing out/not fitting in, feelings about the inner self, negativity about the future and relationships. Cosmetic appearance of nystagmus, including others' avoidant response to this, was described (n=18), as was others' failure to recognise what it is like to have nystagmus (n=18). Driving issues were frequently raised (n=19) and restrictions in occupation choice/opportunities (n=17) were highlighted. Reliance on others (n=16) also emerged. Additional to other categories was an overarching and universal distress arising from nystagmus affecting every aspect of everyday life. CONCLUSION: Interviews revealed universally negative experiences of living with nystagmus that are previously unreported. Findings are similar to studies conducted for strabismus, in particular with respect to cosmetic impact. This study provides the content that is required to develop a nystagmus-specific quality of life tool. PMID- 22517801 TI - Future directions of sickle cell disease research: the NIH perspective. AB - Efforts to enhance therapy for children and adults with sickle cell disease (SCD) have proven more challenging than might have been predicted from the fact that an understanding of the underlying pathogenesis antedated that of many other diseases for which good treatments presently exist. The multi-organ injury that occurs with SCD certainly contributes to this clinical reality. Research over decades indicates that the primary defect in hemoglobin that results in polymerization of the protein under low oxygen conditions and resultant cellular deformity of the red blood cell initiates a complex downstream pathogenesis associated with vascular injury and organ ischemia. Deciphering this in a manner that informs successful therapies that improve all target organs continues to challenge hematologists. The National Heart, Lung and Blood Institute (NHLBI) is dedicated to support research across the basic science, translational and clinical spectrum to achieve these clinical outcomes. The following provides a brief summary of the research strategies which NHLBI is presently supporting and will support in the future to enhance care and ultimately, to effect cure of this hemoglobin disease that causes such suffering to those who inherit this monogenic disease. PMID- 22517802 TI - Organizational complements to electronic health records in ambulatory physician performance: the role of support staff. AB - In industries outside healthcare, highly skilled employees enable substantial gains in productivity after adoption of information technologies. The authors explore whether the presence of highly skilled, autonomous clinical support staff is associated with higher performance among physicians with electronic health records (EHRs). Using data from a survey of general internists, the authors assessed whether physicians with EHRs were more likely to be top performers on cost and quality if they worked with nurse practitioners or physician assistants. It was found that, among physicians with EHRs, those with highly skilled, autonomous staff were far more likely to be top performing than those without such staff (OR 7.0, 95% CI 1.7 to 34.8, p=0.02). This relationship did not hold among physicians without EHRs (OR 1.0). As we begin a national push towards greater EHR adoption, it is critical to understand why some physicians gain from EHR use and others do not. PMID- 22517806 TI - Spending on genetic tests grows: report calls for more genetics education and counselors. PMID- 22517803 TI - Cigarette advertising in the Republic of Korea: a case illustration of The One. PMID- 22517807 TI - Uncommon disorders in the spotlight: NIH and FDA celebrate Rare Disease Day. PMID- 22517809 TI - Role of tobacco use in the etiology of acoustic neuroma. AB - Two previous studies suggest that cigarette smoking reduces acoustic neuroma risk; however, an association between use of snuff tobacco and acoustic neuroma has not been investigated previously. The authors conducted a case-control study in Sweden from 2002 to 2007, in which 451 cases and 710 population-based controls completed questionnaires. Cases and controls were matched on gender, region, and age within 5 years. The authors estimated odds ratios using conditional logistic regression analyses, adjusted for education and tobacco use (snuff use in the smoking analysis and smoking in the snuff analysis). The risk of acoustic neuroma was greatly reduced in male current smokers (odds ratio (OR) = 0.41, 95% confidence interval (CI): 0.23, 0.74) and moderately reduced in female current smokers (OR = 0.70, 95% CI: 0.40, 1.23). In contrast, current snuff use among males was not associated with risk of acoustic neuroma (OR = 0.94, 95% CI: 0.57, 1.55). The authors' findings are consistent with previous reports of lower acoustic neuroma risk among current cigarette smokers than among never smokers. The absence of an association between snuff use and acoustic neuroma suggests that some constituent of tobacco smoke other than nicotine may confer protection against acoustic neuroma. PMID- 22517811 TI - Hormone therapy and different ovarian cancers: a national cohort study. AB - Postmenopausal hormone therapy use increases the risk of ovarian cancer. In the present study, the authors examined the risks of different histologic types of ovarian cancer associated with hormone therapy. Using Danish national registers, the authors identified 909,946 women who were followed from 1995-2005. The women were 50-79 years of age and had no prior hormone-sensitive cancers or bilateral oophorectomy. Hormone therapy prescription data were obtained from the National Register of Medicinal Product Statistics. The National Cancer and Pathology Register provided data on ovarian cancers, including information about tumor histology. The authors performed Poisson regression analyses that included hormone exposures and confounders as time-dependent covariates. In an average of 8.0 years of follow up, 2,681 cases of epithelial ovarian cancer were detected. Compared with never users, women taking unopposed oral estrogen therapy had increased risks of both serous tumors (incidence rate ratio (IRR) = 1.7, 95% confidence interval: 1.4, 2.2) and endometrioid tumors (IRR = 1.5, 95% confidence interval: 1.0, 2.4) but decreased risk of mucinous tumors (IRR = 0.3, 95% confidence interval: 0.1, 0.8). Similar increased risks of serous and endometrioid tumors were found with estrogen/progestin therapy, whereas no association was found with mucinous tumors. Consistent with results from recent cohort studies, the authors found that ovarian cancer risk varied according to tumor histology. The types of ovarian tumors should be given attention in future studies. PMID- 22517810 TI - Perfluorinated compounds in relation to birth weight in the Norwegian Mother and Child Cohort Study. AB - Perfluorooctane sulfonate and perfluorooctanoic acid are perfluorinated compounds (PFCs) widely distributed in the environment. Previous studies of PFCs and birth weight are equivocal. The authors examined this association in the Norwegian Mother and Child Cohort Study (MoBa), using data from 901 women enrolled from 2003 to 2004 and selected for a prior case-based study of PFCs and subfecundity. Maternal plasma samples were obtained around 17 weeks of gestation. Outcomes included birth weight z scores, preterm birth, small for gestational age, and large for gestational age. The adjusted birth weight z scores were slightly lower among infants born to mothers in the highest quartiles of PFCs compared with infants born to mothers in the lowest quartiles: for perfluorooctane sulfonate, beta = -0.18 (95% confidence interval: -0.41, 0.05) and, for perfluorooctanoic acid, beta = -0.21 (95% confidence interval: -0.45, 0.04). No clear evidence of an association with small for gestational age or large for gestational age was observed. Perfluorooctane sulfonate and perfluorooctanoic acid were each associated with decreased adjusted odds of preterm birth, although the cell counts were small. Whether some of the associations suggested by these findings may be due to a noncausal pharmacokinetic mechanism remains unclear. PMID- 22517812 TI - Phylogenetic relationships and generic delimitation of Eurasian Aster (Asteraceae: Astereae) inferred from ITS, ETS and trnL-F sequence data. AB - BACKGROUND AND AIMS: The classification and phylogeny of Eurasian (EA) Aster (Asterinae, Astereae, Asteraceae) remain poorly resolved. Some taxonomists adopt a broad definition of EA Aster, whereas others favour a narrow generic concept. The present study aims to delimit EA Aster sensu stricto (s.s.), elucidate the phylogenetic relationships of EA Aster s.s. and segregate genera. METHODS: The internal and external transcribed spacers of nuclear ribosomal DNA and the plastid DNA trnL-F region were used to reconstruct the phylogeny of EA Aster through maximum parsimony and Bayesian analyses. KEY RESULTS: The analyses strongly support an Aster clade including the genera Sheareria, Rhynchospermum, Kalimeris (excluding Kalimeris longipetiolata), Heteropappus, Miyamayomena, Turczaninowia, Rhinactinidia, eastern Asian Doellingeria, Asterothamnus and Arctogeron. Many well-recognized species of Chinese Aster s.s. lie outside of the Aster clade. CONCLUSIONS: The results reveal that EA Aster s.s. is both paraphyletic and polyphyletic. Sheareria, Rhynchospermum, Kalimeris (excluding K. longipetiolata), Heteropappus, Miyamayomena, Turczaninowia, Rhinactinidia, eastern Asian Doellingeria, Asterothamnus and Arctogeron should be included in Aster, whereas many species of Chinese Aster s.s. should be excluded. The recircumscribed Aster should be divided into two subgenera and nine sections. Kalimeris longipetiolata, Aster batangensis, A. ser. Albescentes, A. series Hersileoides, a two-species group composed of A. senecioides and A. fuscescens, and a six-species group including A. asteroides, should be elevated to generic level. With the Aster clade, they belong to the Australasian lineages. The generic status of Callistephus should be maintained. Whether Galatella (including Crinitina) and Tripolium should remain as genera or be merged into a single genus remains to be determined. In addition, the taxonomic status of A. auriculatus and the A. pycnophyllus-A. panduratus clade remains unresolved, and the systematic position of some segregates of EA Aster requires further study. PMID- 22517813 TI - Update in general internal medicine: evidence published in 2011. PMID- 22517820 TI - Targeting triple-negative breast cancer: optimising therapeutic outcomes. AB - BACKGROUND: Triple-negative breast cancer (TNBC) is a distinct subset of breast cancer (BC) defined by the lack of immunohistochemical expression of the estrogen and progesterone receptors and human epidermal growth factor receptor 2. It is highly heterogeneous and displays overlapping characteristics with both basal like and BC susceptibility gene 1 and 2 mutant BCs. This review evaluates the activity of emerging targeted agents in TNBC. DESIGN: A systematic review of PubMed and conference databases was carried out to identify randomised clinical trials reporting outcomes in women with TNBC treated with targeted and platinum based therapies. RESULTS AND DISCUSSION: Our review identified TNBC studies of agents with different mechanisms of action, including induction of synthetic lethality and inhibition of angiogenesis, growth, and survival pathways. Combining targeted agents with chemotherapy in TNBC produced only modest gains in progression-free survival, and had little impact on survival. Six TNBC subgroups have been identified and found to differentially respond to specific targeted agents. The use of biological preselection to guide therapy will improve therapeutic indices in target-bearing populations. CONCLUSION: Ongoing clinical trials of targeted agents in unselected TNBC populations have yet to produce substantial improvements in outcomes, and advancements will depend on their development in target-selected populations. PMID- 22517821 TI - Liquid biopsy to test new treatment strategies in breast cancer: are we there yet? PMID- 22517822 TI - Aspirin and cancer risk: a quantitative review to 2011. AB - BACKGROUND: Aspirin has been associated to a reduced risk of colorectal and possibly of a few other common cancers. METHODS: To provide an up-to-date quantification of this association, we conducted a meta-analysis of all observational studies on aspirin and 12 selected cancer sites published up to September 2011. RESULTS: Regular aspirin is associated with a statistically significant reduced risk of colorectal cancer [summary relative risk (RR) from random effects models = 0.73, 95% confidence interval (CI) 0.67-0.79], and of other digestive tract cancers (RR = 0.61, 95% CI = 0.50-0.76, for squamous cell esophageal cancer; RR = 0.64, 95% CI = 0.52-0.78, for esophageal and gastric cardia adenocarcinoma; and RR = 0.67, 95% CI = 0.54-0.83, for gastric cancer), with somewhat stronger reductions in risk in case-control than in cohort studies. Modest inverse associations were also observed for breast (RR = 0.90, 95% CI = 0.85-0.95) and prostate cancer (RR = 0.90, 95% CI = 0.85-0.96), while lung cancer was significantly reduced in case-control studies (0.73, 95% CI = 0.55-0.98) but not in cohort ones (RR = 0.98, 95% CI = 0.92-1.05). No meaningful overall associations were observed for cancers of the pancreas, endometrium, ovary, bladder, and kidney. CONCLUSIONS: Observational studies indicate a beneficial role of aspirin on colorectal and other digestive tract cancers; modest risk reductions were also observed for breast and prostate cancer. Results are, however, heterogeneous across studies and dose-risk and duration-risk relationships are still unclear. PMID- 22517823 TI - X-ACT: an important step on an unfinished journey. PMID- 22517824 TI - Standards for postdoc training. PMID- 22517829 TI - Agriculture. Dread citrus disease turns up in California, Texas. PMID- 22517830 TI - Stem cells. Texas Medical Board approves rules for controversial treatment. PMID- 22517831 TI - Biosecurity. Will Dutch allow 'export' of controversial flu study? PMID- 22517832 TI - Biomedicine. Nanoparticle treatment reverses cerebral palsy in rabbits. PMID- 22517833 TI - Newsmaker interview: Robert Groves. Saving money essential for next census, says departing director. Interview by Jeffrey Mervis. PMID- 22517834 TI - Hydropower. Trouble on the Yangtze. PMID- 22517835 TI - Hydropower. Evidence mounts for dam-quake link. PMID- 22517836 TI - American Chemical Society Spring Meeting. Nanoparticles offer 'open sesame' keys to new drugs and vaccines. PMID- 22517837 TI - American Chemical Society Spring Meeting. Biofuels and city air: a marginal effect. PMID- 22517838 TI - American Chemical Society Spring Meeting. New genetic letters augment DNA, and soon perhaps life. PMID- 22517839 TI - Environment-friendly reform in Myanmar. PMID- 22517840 TI - India's science: elitism prevails. PMID- 22517841 TI - India's science: excellence unrecognized. PMID- 22517843 TI - Comment on "Detection of emerging sunspot regions in the solar interior". AB - Ilonidis et al. (Reports, 19 August 2011, p. 993) report acoustic travel-time decreases associated with emerging sunspot regions before their appearance on the solar surface. An independent analysis using helioseismic holography does not confirm these travel-time anomalies for the four regions illustrated by Ilonidis et al. This negative finding is consistent with expectations based on current emerging flux models. PMID- 22517845 TI - Science and regulation. FDA's approach to regulation of products of nanotechnology. PMID- 22517846 TI - Applied physics. Solution-processible electrodes. PMID- 22517847 TI - Psychology. Tapping into the wisdom of the crowd--with confidence. PMID- 22517848 TI - Cancer. Heterogeneity and tumor history. PMID- 22517849 TI - Development. Making waves for segments. PMID- 22517850 TI - Evolution. Toward an alternative biology. PMID- 22517851 TI - Biochemistry. Visualizing amyloid assembly. PMID- 22517852 TI - The state and fate of Himalayan glaciers. AB - Himalayan glaciers are a focus of public and scientific debate. Prevailing uncertainties are of major concern because some projections of their future have serious implications for water resources. Most Himalayan glaciers are losing mass at rates similar to glaciers elsewhere, except for emerging indications of stability or mass gain in the Karakoram. A poor understanding of the processes affecting them, combined with the diversity of climatic conditions and the extremes of topographical relief within the region, makes projections speculative. Nevertheless, it is unlikely that dramatic changes in total runoff will occur soon, although continuing shrinkage outside the Karakoram will increase the seasonality of runoff, affect irrigation and hydropower, and alter hazards. PMID- 22517854 TI - Interplay of intra- and intermolecular H-bonding in a progressively solvated macrocyclic peptide. AB - Studying solvation of a large molecule on an atomic level is challenging because of the transient character and inhomogeneity of hydrogen bonding in liquid water. We studied water clusters of a protonated macrocyclic decapeptide, gramicidin S, which were prepared in the gas phase and then cooled to cryogenic temperatures. The experiment spectroscopically tracked fine structural changes of the clusters upon increasing the number of attached water molecules from 1 to 50 and distinguished vibrational fingerprints of different conformers. The data indicate that only the first two water molecules induce a substantial change of the gramicidin S structure by breaking two intramolecular noncovalent bonds. The peptide structure remains largely intact upon further solvation, reflecting the interplay between the strong intramolecular and weaker intermolecular hydrogen bonds. PMID- 22517853 TI - Oxidation of the guanine nucleotide pool underlies cell death by bactericidal antibiotics. AB - A detailed understanding of the mechanisms that underlie antibiotic killing is important for the derivation of new classes of antibiotics and clinically useful adjuvants for current antimicrobial therapies. Our efforts to understand why DinB (DNA polymerase IV) overproduction is cytotoxic to Escherichia coli led to the unexpected insight that oxidation of guanine to 8-oxo-guanine in the nucleotide pool underlies much of the cell death caused by both DinB overproduction and bactericidal antibiotics. We propose a model in which the cytotoxicity of beta lactams and quinolones predominantly results from lethal double-strand DNA breaks caused by incomplete repair of closely spaced 8-oxo-deoxyguanosine lesions, whereas the cytotoxicity of aminoglycosides might additionally result from mistranslation due to the incorporation of 8-oxo-guanine into newly synthesized RNAs. PMID- 22517855 TI - A universal method to produce low-work function electrodes for organic electronics. AB - Organic and printed electronics technologies require conductors with a work function that is sufficiently low to facilitate the transport of electrons in and out of various optoelectronic devices. We show that surface modifiers based on polymers containing simple aliphatic amine groups substantially reduce the work function of conductors including metals, transparent conductive metal oxides, conducting polymers, and graphene. The reduction arises from physisorption of the neutral polymer, which turns the modified conductors into efficient electron selective electrodes in organic optoelectronic devices. These polymer surface modifiers are processed in air from solution, providing an appealing alternative to chemically reactive low-work function metals. Their use can pave the way to simplified manufacturing of low-cost and large-area organic electronic technologies. PMID- 22517856 TI - Dislocation damping and anisotropic seismic wave attenuation in Earth's upper mantle. AB - Crystal defects form during tectonic deformation and are reactivated by the shear stress associated with passing seismic waves. Although these defects, known as dislocations, potentially contribute to the attenuation of seismic waves in Earth's upper mantle, evidence for dislocation damping from laboratory studies has been circumstantial. We experimentally determined the shear modulus and associated strain-energy dissipation in pre-deformed synthetic olivine aggregates under high pressures and temperatures. Enhanced high-temperature background dissipation occurred in specimens pre-deformed by dislocation creep in either compression or torsion, the enhancement being greater for prior deformation in torsion. These observations suggest the possibility of anisotropic attenuation in relatively coarse-grained rocks where olivine is or was deformed at relatively high stress by dislocation creep in Earth's upper mantle. PMID- 22517857 TI - Dynamic causes of the relation between area and age of the ocean floor. AB - The distribution of seafloor ages determines fundamental characteristics of Earth such as sea level, ocean chemistry, tectonic forces, and heat loss from the mantle. The present-day distribution suggests that subduction affects lithosphere of all ages, but this is at odds with the theory of thermal convection that predicts that subduction should happen once a critical age has been reached. We used spherical models of mantle convection to show that plate-like behavior and continents cause the seafloor area-age distribution to be representative of present-day Earth. The distribution varies in time with the creation and destruction of new plate boundaries. Our simulations suggest that the ocean floor production rate previously reached peaks that were twice the present-day value. PMID- 22517858 TI - Synthetic genetic polymers capable of heredity and evolution. AB - Genetic information storage and processing rely on just two polymers, DNA and RNA, yet whether their role reflects evolutionary history or fundamental functional constraints is currently unknown. With the use of polymerase evolution and design, we show that genetic information can be stored in and recovered from six alternative genetic polymers based on simple nucleic acid architectures not found in nature [xeno-nucleic acids (XNAs)]. We also select XNA aptamers, which bind their targets with high affinity and specificity, demonstrating that beyond heredity, specific XNAs have the capacity for Darwinian evolution and folding into defined structures. Thus, heredity and evolution, two hallmarks of life, are not limited to DNA and RNA but are likely to be emergent properties of polymers capable of information storage. PMID- 22517860 TI - Recent plant diversity changes on Europe's mountain summits. AB - In mountainous regions, climate warming is expected to shift species' ranges to higher altitudes. Evidence for such shifts is still mostly from revisitations of historical sites. We present recent (2001 to 2008) changes in vascular plant species richness observed in a standardized monitoring network across Europe's major mountain ranges. Species have moved upslope on average. However, these shifts had opposite effects on the summit floras' species richness in boreal temperate mountain regions (+3.9 species on average) and Mediterranean mountain regions (-1.4 species), probably because recent climatic trends have decreased the availability of water in the European south. Because Mediterranean mountains are particularly rich in endemic species, a continuation of these trends might shrink the European mountain flora, despite an average increase in summit species richness across the region. PMID- 22517861 TI - A yeast prion, Mod5, promotes acquired drug resistance and cell survival under environmental stress. AB - Prion conversion from a soluble protein to an aggregated state may be involved in the cellular adaptation of yeast to the environment. However, it remains unclear whether and how cells actively use prion conversion to acquire a fitness advantage in response to environmental stress. We identified Mod5, a yeast transfer RNA isopentenyltransferase lacking glutamine/asparagine-rich domains, as a yeast prion protein and found that its prion conversion in yeast regulated the sterol biosynthetic pathway for acquired cellular resistance against antifungal agents. Furthermore, selective pressure by antifungal drugs on yeast facilitated the de novo appearance of Mod5 prion states for cell survival. Thus, phenotypic changes caused by active prion conversion under environmental selection may contribute to cellular adaptation in living organisms. PMID- 22517862 TI - When are two heads better than one and why? AB - A recent study, using a perceptual task, indicated that two heads were better than one provided that the members could communicate freely, presumably sharing their confidence in their judgments. Capitalizing on recent work on subjective confidence, I replicated this effect in the absence of any dyadic interaction by selecting on each trial the decision of the more confident member of a virtual dyad. However, because subjective confidence monitors the consensuality rather than the accuracy of a decision, when most participants were in error, reliance on the more confident member yielded worse decisions than those of the better individual. Assuming that for each issue group decisions are dominated by the more confident member, these results help specify when groups will be more or less accurate than individuals. PMID- 22517863 TI - Structure of an intermediate state in protein folding and aggregation. AB - Protein-folding intermediates have been implicated in amyloid fibril formation involved in neurodegenerative disorders. However, the structural mechanisms by which intermediates initiate fibrillar aggregation have remained largely elusive. To gain insight, we used relaxation dispersion nuclear magnetic resonance spectroscopy to determine the structure of a low-populated, on-pathway folding intermediate of the A39V/N53P/V55L (A, Ala; V, Val; N, Asn; P, Pro; L, Leu) Fyn SH3 domain. The carboxyl terminus remains disordered in this intermediate, thereby exposing the aggregation-prone amino-terminal beta strand. Accordingly, mutants lacking the carboxyl terminus and thus mimicking the intermediate fail to safeguard the folding route and spontaneously form fibrillar aggregates. The structure provides a detailed characterization of the non-native interactions stabilizing an aggregation-prone intermediate under native conditions and insight into how such an intermediate can derail folding and initiate fibrillation. PMID- 22517864 TI - The power of monoclonal antibodies as agents of discovery: CD40 Revealed as a B lymphocyte costimulator. PMID- 22517859 TI - Nuclear genomic sequences reveal that polar bears are an old and distinct bear lineage. AB - Recent studies have shown that the polar bear matriline (mitochondrial DNA) evolved from a brown bear lineage since the late Pleistocene, potentially indicating rapid speciation and adaption to arctic conditions. Here, we present a high-resolution data set from multiple independent loci across the nuclear genomes of a broad sample of polar, brown, and black bears. Bayesian coalescent analyses place polar bears outside the brown bear clade and date the divergence much earlier, in the middle Pleistocene, about 600 (338 to 934) thousand years ago. This provides more time for polar bear evolution and confirms previous suggestions that polar bears carry introgressed brown bear mitochondrial DNA due to past hybridization. Our results highlight that multilocus genomic analyses are crucial for an accurate understanding of evolutionary history. PMID- 22517865 TI - Activation of human B cells mediated through two distinct cell surface differentiation antigens, Bp35 and Bp50. Proc. Natl. Acad. Sci. 1986. 83: 4494 4498. PMID- 22517867 TI - For once, truth in tobacco advertising: it is 'better to die' than to not smoke (better for tobacco companies, that is). PMID- 22517866 TI - The role of naive T cell precursor frequency and recruitment in dictating immune response magnitude. AB - Recent advances in technology have led to the realization that the populations of naive T cells specific for different foreign peptide:MHC (p:MHC) ligands vary in size. This variability is due, in part, to the fact that certain peptides contain amino acids that engage in particularly favorable interactions with TCRs. In addition, deletion of clones with cross-reactivity for self-p:MHC ligands may reduce the size of some naive populations. In many cases, the magnitude of the immune response to individual p:MHC epitopes correlates with the size of the corresponding naive populations. However, this simple relationship may be complicated by variability in the efficiency of T cell recruitment into the immune response. The knowledge that naive population size can predict immune response magnitude may create opportunities for production of more effective subunit vaccines. PMID- 22517868 TI - Detection of 'Candidatus Mycoplasma haemobos', Mycoplasma wenyonii and Anaplasma phagocytophilum from cattle in England. PMID- 22517869 TI - Unique approach for B lymphoma therapy. PMID- 22517870 TI - Avoiding intuxication. PMID- 22517871 TI - Inside platelet-leukocyte cross-talk. PMID- 22517872 TI - Applying the brakes to platelet activation. PMID- 22517873 TI - ADAMTS13 meets MR, then what? PMID- 22517874 TI - Improving on nature: redesigning ADAMTS13. PMID- 22517875 TI - MataHari reveals secrets of GVHD. PMID- 22517876 TI - Risk of second cancers in chronic myeloproliferative neoplasms. PMID- 22517877 TI - Regulation of human dendritic cells by B cells depends on the signals they receive. PMID- 22517878 TI - Rearrangement of NOTCH1 or BCL3 can independently trigger progression of CLL. PMID- 22517879 TI - Persistently high quality of life conferred by coexisting congenital deficiency of terminal complement C9 in a paroxysmal nocturnal hemoglobinuria patient. PMID- 22517881 TI - The power of one. AB - A single mouse Lgr5-positive colon stem cell can be expanded into a three dimensional organoid that, after transplant, contributes to the repair of injured colon epithelia in a mouse model of colitis. PMID- 22517882 TI - A baby step for nano. AB - Nanomedicine treatment postnatally in an inflammatory model of cerebral palsy ameliorates motor deficits (Kannan et al., this issue). PMID- 22517883 TI - Dendrimer-based postnatal therapy for neuroinflammation and cerebral palsy in a rabbit model. AB - Cerebral palsy (CP) is a chronic childhood disorder with no effective cure. Neuroinflammation, caused by activated microglia and astrocytes, plays a key role in the pathogenesis of CP and disorders such as Alzheimer's disease and multiple sclerosis. Targeting neuroinflammation can be a potent therapeutic strategy. However, delivering drugs across the blood-brain barrier to the target cells for treating diffuse brain injury is a major challenge. We show that systemically administered polyamidoamine dendrimers localize in activated microglia and astrocytes in the brain of newborn rabbits with CP, but not healthy controls. We further demonstrate that dendrimer-based N-acetyl-l-cysteine (NAC) therapy for brain injury suppresses neuroinflammation and leads to a marked improvement in motor function in the CP kits. The well-known and safe clinical profile for NAC, when combined with dendrimer-based targeting, provides opportunities for clinical translation in the treatment of neuroinflammatory disorders in humans. The effectiveness of the dendrimer-NAC treatment, administered in the postnatal period for a prenatal insult, suggests a window of opportunity for treatment of CP in humans after birth. PMID- 22517884 TI - Patient-specific induced pluripotent stem cells as a model for familial dilated cardiomyopathy. AB - Characterized by ventricular dilatation, systolic dysfunction, and progressive heart failure, dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy in patients. DCM is the most common diagnosis leading to heart transplantation and places a significant burden on healthcare worldwide. The advent of induced pluripotent stem cells (iPSCs) offers an exceptional opportunity for creating disease-specific cellular models, investigating underlying mechanisms, and optimizing therapy. Here, we generated cardiomyocytes from iPSCs derived from patients in a DCM family carrying a point mutation (R173W) in the gene encoding sarcomeric protein cardiac troponin T. Compared to control healthy individuals in the same family cohort, cardiomyocytes derived from iPSCs from DCM patients exhibited altered regulation of calcium ion (Ca(2+)), decreased contractility, and abnormal distribution of sarcomeric alpha actinin. When stimulated with a beta-adrenergic agonist, DCM iPSC-derived cardiomyocytes showed characteristics of cellular stress such as reduced beating rates, compromised contraction, and a greater number of cells with abnormal sarcomeric alpha-actinin distribution. Treatment with beta-adrenergic blockers or overexpression of sarcoplasmic reticulum Ca(2+) adenosine triphosphatase (Serca2a) improved the function of iPSC-derived cardiomyocytes from DCM patients. Thus, iPSC-derived cardiomyocytes from DCM patients recapitulate to some extent the morphological and functional phenotypes of DCM and may serve as a useful platform for exploring disease mechanisms and for drug screening. PMID- 22517885 TI - Targeted delivery of PLK1-siRNA by ScFv suppresses Her2+ breast cancer growth and metastasis. AB - A major obstacle to developing small interfering RNAs (siRNAs) as cancer drugs is their intracellular delivery to disseminated cancer cells. Fusion proteins of single-chain fragmented antibodies (ScFvs) and positively charged peptides deliver siRNAs into specific target cells. However, the therapeutic potential of ScFv-mediated siRNA delivery has not been evaluated in cancer. Here, we tested whether Polo-like kinase 1 (PLK1) siRNAs complexed with a Her2-ScFv-protamine peptide fusion protein (F5-P) could suppress Her2(+) breast cancer cell lines and primary human cancers in orthotopic breast cancer models. PLK1-siRNAs transferred by F5-P inhibited target gene expression, reduced proliferation, and induced apoptosis of Her2(+) breast cancer cell lines and primary human cancer cells in vitro without triggering an interferon response. Intravenously injected F5-P/PLK1 siRNA complexes concentrated in orthotopic Her2(+) breast cancer xenografts and persisted for at least 72 hours, leading to suppressed PLK1 gene expression and tumor cell apoptosis. The intravenously injected siRNA complexes retarded Her2(+) breast tumor growth, reduced metastasis, and prolonged survival without evident toxicity. F5-P-mediated delivery of a cocktail of PLK1, CCND1, and AKT siRNAs was more effective than an equivalent dose of PLK1-siRNAs alone. These data suggest that F5-P could be used to deliver siRNAs to treat Her2(+) breast cancer. PMID- 22517886 TI - Perceived risk of cervical cancer among pre-screening age women (18-24 years): the impact of information about cervical cancer risk factors and the causal role of HPV. AB - OBJECTIVES: Current National Health Service cervical screening information does not explain that the cause of cervical cancer is a sexually transmitted infection (human papillomavirus (HPV)). This study aimed to consider the impact that providing this information, in addition to risk factor information, might have on women's perceived risk of cervical cancer. METHODS: Female students aged 18-24 years (n=606) completed a web-based survey and were randomised to receive (1) control information about cervical cancer; (2) details of the link between HPV and cervical cancer; (3) risk factor information or (4) details about the link with HPV + risk factor information. Risk perceptions for cervical cancer were assessed before and after reading the information. RESULTS: There was a significant difference in perceived risk of cervical cancer between the four groups following information exposure (p=0.002). Compared with the control group, risk perceptions were significantly lower among women given risk factor information but not among those informed about HPV. There were significant group by risk factor interactions for smoking status (p<0.001), age of first sex (p=0.018) and number of sexual partners (p<0.001). Risk perceptions were lower among women considered at low risk and given risk factor information, but there was no association between information group and perceived risk for high-risk women. CONCLUSIONS: Providing risk factor information appears to reduce cervical cancer risk perceptions, but learning about the aetiological role of HPV appears to have no impact on risk perceptions. Incorporating brief information about HPV as the cause of cervical cancer should be in addition to, rather than in place of, risk factor information. PMID- 22517887 TI - What is the appropriate treatment for the management of rectal Chlamydia trachomatis in men and women? AB - BACKGROUND: There is no UK guidance specifically for the management of rectal Chlamydia trachomatis yet there is documented treatment failure with single-dose azithromycin suggesting that test of cure (TOC) and alternative treatment may be needed. OBJECTIVES: To evaluate the efficacy of single-dose azithromycin compared with 1 week of doxycycline in the treatment of rectal C trachomatis. METHODS: Data were collected prospectively on all patients diagnosed with rectal C trachomatis who received azithromycin 1 g stat between 1 January and 30 June 2010 and between 1 October 2010 and 31 March 2011 following a local change in treatment protocol to 1 week of doxycycline 100 mg twice a day. Information was collected on gender, concurrent sexually transmitted infections, treatment received, re-infection risk, re-treatment and TOC at 6 weeks. RESULTS: 11 patients (26.2%) had a positive TOC following treatment with stat azithromycin. The risk of re-infection was excluded in two, identifying nine of the 11 (81.8%) as treatment failures. Two patients had a positive TOC following treatment with 1 week of doxycycline, both were found to have a risk of re-infection. There was a significantly higher treatment failure rate in patients receiving azithromycin (p=0.0025). CONCLUSIONS: A higher treatment failure rate was found following azithromycin for rectal C trachomatis than previously published. If azithromycin is used for treatment of rectal C trachomatis, TOC may be required or alternative treatment with doxycycline may be preferable, but further data are required. PMID- 22517888 TI - Genotyping of Chlamydia trachomatis in rectal and pharyngeal specimens: identification of LGV genotypes in Finland. AB - OBJECTIVES: Lymphogranuloma venereum (LGV) infections caused by Chlamydia trachomatis L types have recently emerged in Europe among HIV-positive men having sex with men. Our aim was to introduce a genotyping strategy suitable for a diagnostic laboratory using nucleic acid amplification tests (NAATs) for detection of C trachomatis and to investigate the prevalence of LGV types in rectal and pharyngeal specimens in Finland. METHODS: Aptima Combo 2 (Gen-Probe) was used to detect C trachomatis in swabs. Altogether 140 C trachomatis NAAT positive rectal and pharyngeal samples were genotyped by pmpH and ompA real-time PCR. RESULTS: Of the 140 NAAT-positive rectal and pharyngeal specimens, 114 (81%) were successfully typed by pmpH PCR. One hundred and four samples contained non LGV, nine samples LGV and one sample both non-LGV and LGV C trachomatis types. The C trachomatis LGV types were mainly found in rectal samples. Six of the L types were confirmed to be genotype L2b and two were L2 with ompA PCR and sequencing. CONCLUSIONS: Our experience suggests that genotyping C trachomatis by pmpH PCR can be introduced as a function of a diagnostic laboratory already using NAAT for detection of C trachomatis. The data show that LGV infections occur also in Finland. LGV should be taken into account when considering treatment and management of rectal C trachomatis infections. PMID- 22517889 TI - Utility of post-treatment follow-up visit at 3 months in patients treated for early syphilis. PMID- 22517890 TI - SMS reminders improve re-screening in women and heterosexual men with chlamydia infection at Sydney Sexual Health Centre: a before-and-after study. AB - BACKGROUND: In 2009, Sydney Sexual Health Centre implemented a short message service (SMS) reminder system to improve re-screening after chlamydia infection. SMS reminders were sent at 3 months recommending the patient make an appointment for a re-screen. METHODS: Using a before-and-after study, the authors compared the proportion re-screened within 1-4 months of chlamydia infection in women and heterosexual men who were sent an SMS in January to December 2009 (intervention period) with a 18-month period before the SMS was introduced (before period). The authors used a chi(2) test and multivariate regression. Visitors and sex workers were excluded. RESULTS: In the intervention period, 141 of 343 (41%) patients were diagnosed with chlamydia and sent the SMS reminder. In the before period, 338 patients were diagnosed as having chlamydia and none received a reminder. The following baseline characteristics were significantly different between those sent the SMS in the intervention period and the before period: new patients (82% vs 72%, p=0.02), aged <25 years (51% vs 33% p<0.01), three or more sexual partners in the last 3 months (31% vs 27%, p<0.01) and anogenital symptoms (52% vs 38%, p<0.01). The proportion re-screened 1-4 months after chlamydia infection was significantly higher in people sent the SMS (30%) than the before period (21%), p=0.04, and after adjusting for baseline differences, the OR was 1.57 (95% CI 1.01 to 2.46). CONCLUSIONS: SMS reminders increased re-screening in patients diagnosed as having chlamydia at a sexual health clinic. The clinic now plans to introduce electronic prompts to maximise the uptake of the initiative and consider strategies to further increase re-screening. PMID- 22517891 TI - Individualized behavior management program for Alzheimer's/dementia residents using behavior-based ergonomic therapies. AB - Person-centered, nonpharmacological interventions for managing Alzheimer's/dementia-related behavioral disturbances have received significant attention. However, such interventions are quite often of a single type limiting their benefits. We develop a comprehensive nonpharmacological intervention, the Behavior-Based Ergonomic Therapy (BBET), which consists of multiple therapies. This low-cost, 24/7 program uses learning, personality, and behavioral profiles and cognitive function of each resident to develop a set of individualized therapies. These therapies are made available through an accessible resource library of music and video items, games and puzzles, and memory props to provide comfort or stimulation depending on an individual resident's assessment. The quantitative and qualitative benefits of the BBET were evaluated at the dementia care unit in a not-for-profit continuing care retirement community in west central Ohio. The 6-month pilot study reduced falls by 32.5% and markedly reduced agitation through increased resident engagement. PMID- 22517892 TI - Agrin is required for survival and function of monocytic cells. AB - Agrin, an extracellular matrix protein belonging to the heterogeneous family of heparan sulfate proteoglycans (HSPGs), is expressed by cells of the hematopoietic system but its role in leukocyte biology is not yet clear. Here we demonstrate that agrin has a crucial, nonredundant role in myeloid cell development and functions. We have identified lineage-specific alterations that affect maturation, survival and properties of agrin-deficient monocytic cells, and occur at stages later than stem cell precursors. Our data indicate that the cell autonomous signals delivered by agrin are sensed by macrophages through the alpha DC (DG) receptor and lead to the activation of signaling pathways resulting in rearrangements of the actin cytoskeleton during the phagocytic synapse formation and phosphorylation of extracellular signal-regulated kinases (Erk 1/2). Altogether, these data identify agrin as a novel player of innate immunity. PMID- 22517893 TI - RNA-dependent inhibition of ribonucleotide reductase is a major pathway for 5 azacytidine activity in acute myeloid leukemia. AB - 5-Azacytidine (5-azaC) is an azanucleoside approved for myelodysplastic syndrome. Approximately 80%-90% of 5-azaC is believed to be incorporated into RNA, which disrupts nucleic acid and protein metabolism leading to apoptosis. A smaller fraction (10%-20%) of 5-azaC inhibits DNA methylation and synthesis through conversion to decitabine triphosphate and subsequent DNA incorporation. However, its precise mechanism of action remains unclear. Ribonucleotide reductase (RR) is a highly regulated enzyme comprising 2 subunits, RRM1 and RRM2, that provides the deoxyribonucleotides required for DNA synthesis/repair. In the present study, we found for the first time that 5-azaC is a potent inhibitor of RRM2 in leukemia cell lines, in a mouse model, and in BM mononuclear cells from acute myeloid leukemia (AML) patients. 5-azaC-induced RRM2 gene expression inhibition involves its direct RNA incorporation and an attenuated RRM2 mRNA stability. Therefore, 5 azaC causes a major perturbation of deoxyribonucleotide pools. We also demonstrate herein that the initial RR-mediated 5-azaC conversion to decitabine is terminated through its own inhibition. In conclusion, we identify RRM2 as a novel molecular target of 5-azaC in AML. Our findings provide a basis for its more widespread clinical use either alone or in combination. PMID- 22517895 TI - Detectable minimal residual disease before hematopoietic cell transplantation is prognostic but does not preclude cure for children with very-high-risk leukemia. AB - In patients with acute leukemia, detection of minimal residual disease (MRD) before allogeneic hematopoietic cell transplantation (HCT) correlates with risk of relapse. However, the level of MRD that is most likely to preclude cure by HCT is unclear, and the benefit of further chemotherapy to reduce MRD before HCT is unknown. In 122 children with very-high-risk acute lymphoblastic leukemia (ALL; n = 64) or acute myeloid leukemia (AML, n = 58), higher MRD levels at the time of HCT predicted a poorer survival after HCT (P = .0019); MRD was an independent prognostic factor in a multivariate analysis (P = .0035). However, the increase in risk of death associated with a similar increment of MRD was greater in ALL than in AML, suggesting that a pretransplantation reduction of leukemia burden would have a higher impact in ALL. At any given MRD level, survival rates were higher for patients treated in recent protocols: the 5-year overall survival for patients with ALL was 49% if MRD was detectable and 88% if it was not and the corresponding rates for patients with AML were 67% and 80%, respectively. Although MRD before HCT is a strong prognostic factor, its impact has diminished and should not be regarded as a contraindication for HCT. PMID- 22517894 TI - Polyphosphate: an ancient molecule that links platelets, coagulation, and inflammation. AB - Inorganic polyphosphate is widespread in biology and exhibits striking prohemostatic, prothrombotic, and proinflammatory effects in vivo. Long-chain polyphosphate (of the size present in infectious microorganisms) is a potent, natural pathophysiologic activator of the contact pathway of blood clotting. Medium-chain polyphosphate (of the size secreted from activated human platelets) accelerates factor V activation, completely abrogates the anticoagulant function of tissue factor pathway inhibitor, enhances fibrin clot structure, and greatly accelerates factor XI activation by thrombin. Polyphosphate may have utility as a hemostatic agent, whereas antagonists of polyphosphate may function as novel antithrombotic/anti-inflammatory agents. The detailed molecular mechanisms by which polyphosphate modulates blood clotting reactions remain to be elucidated. PMID- 22517896 TI - O-linked glycosylation of von Willebrand factor modulates the interaction with platelet receptor glycoprotein Ib under static and shear stress conditions. AB - We have examined the effect of the O-linked glycan (OLG) structures of VWF on its interaction with the platelet receptor glycoprotein Ibalpha. The 10 OLGs were mutated individually and as clusters (Clus) on either and both sides of the A1 domain: Clus1 (N-terminal side), Clus2 (C-terminal side), and double cluster (DC), in both full-length-VWF and in a VWF construct spanning D' to A3 domains. Mutations did not alter VWF secretion by HEK293T cells, multimeric structure, or static collagen binding. The T1255A, Clus1, and DC variants caused increased ristocetin-mediated GPIbalpha binding to VWF. Platelet translocation rate on OLG mutants was increased because of reduced numbers of GPIbalpha binding sites but without effect on bond lifetime. In contrast, OLG mutants mediated increased platelet capture on collagen under high shear stress that was associated with increased adhesion of these variants to the collagen under flow. These findings suggest that removal of OLGs increases the flexibility of the hinge linker region between the D3 and A1 domain, facilitating VWF unfolding by shear stress, thereby enhancing its ability to bind collagen and capture platelets. These data demonstrate an important functional role of VWF OLGs under shear stress conditions. PMID- 22517897 TI - Identification of LMO2 transcriptome and interactome in diffuse large B-cell lymphoma. AB - LMO2 regulates gene expression by facilitating the formation of multipartite DNA binding complexes. In B cells, LMO2 is specifically up-regulated in the germinal center (GC) and is expressed in GC-derived non-Hodgkin lymphomas. LMO2 is one of the most powerful prognostic indicators in diffuse large B-cell (DLBCL) patients. However, its function in GC B cells and DLBCL is currently unknown. In this study, we characterized the LMO2 transcriptome and transcriptional complex in DLBCL cells. LMO2 regulates genes implicated in kinetochore function, chromosome assembly, and mitosis. Overexpression of LMO2 in DLBCL cell lines results in centrosome amplification. In DLBCL, the LMO2 complex contains some of the traditional partners, such as LDB1, E2A, HEB, Lyl1, ETO2, and SP1, but not TAL1 or GATA proteins. Furthermore, we identified novel LMO2 interacting partners: ELK1, nuclear factor of activated T-cells (NFATc1), and lymphoid enhancer-binding factor1 (LEF1) proteins. Reporter assays revealed that LMO2 increases transcriptional activity of NFATc1 and decreases transcriptional activity of LEF1 proteins. Overall, our studies identified a novel LMO2 transcriptome and interactome in DLBCL and provides a platform for future elucidation of LMO2 function in GC B cells and DLBCL pathogenesis. PMID- 22517898 TI - Methionine-induced hyperhomocysteinemia reverts fibrinolytic pathway activation in a murine model of acute promyelocytic leukemia. AB - Increased fibrinolysis is an important component of acute promyelocytic leukemia (APL) bleeding diathesis. APL blasts overexpress annexin II (ANXII), a receptor for tissue plasminogen activator (tPA), and plasminogen, thereby increasing plasmin generation. Previous studies suggested that ANXII plays a pivotal role in APL coagulopathy. ANXII binding to tPA can be inhibited by homocysteine and hyperhomocysteinemia can be induced by L-methionine supplementation. In the present study, we used an APL mouse model to study ANXII function and the effects of hyperhomocysteinemia in vivo. Leukemic cells expressed higher ANXII and tPA plasma levels (11.95 ng/mL in leukemic vs 10.74 ng/mL in wild-type; P = .004). In leukemic mice, administration of L-methionine significantly increased homocysteine levels (49.0 MUmol/mL and < 6.0 MUmol/mL in the treated and nontreated groups, respectively) and reduced tPA levels to baseline concentrations. The latter were also decreased after infusion of the LCKLSL peptide, a competitor for the ANXII tPA-binding site (11.07 ng/mL; P = .001). We also expressed and purified the p36 component of ANXII in Pichia methanolica. The infusion of p36 in wild-type mice increased tPA and thrombin-antithrombin levels, and the latter was reversed by L-methionine administration. The results of the present study demonstrate the relevance of ANXII in vivo and suggest that methionine-induced hyperhomocysteinemia may reverse hyperfibrinolysis in APL. PMID- 22517899 TI - SOCS1 cooperates with FLT3-ITD in the development of myeloproliferative disease by promoting the escape from external cytokine control. AB - Activating mutations in the receptor tyrosine kinase FLT3 are frequently found in acute myelogenous leukemia patients and confer poor clinical prognosis. It is unclear how leukemic blasts escape cytokine control that regulates normal hematopoiesis. We have recently demonstrated that FLT3-internal tandem duplication (ITD), when localized to the biosynthetic compartment, aberrantly activates STAT5. Here, we show that one of the target genes induced by STAT5 is suppressor of cytokine signaling (SOCS)1-a surprising finding for a known tumor suppressor. Although SOCS1 expression in murine bone marrow severely impaired cytokine-induced colony growth, it failed to inhibit FLT3-ITD-supported colony growth, indicating resistance of FLT3-ITD to SOCS1. In addition, SOCS1 coexpression did not affect FLT3-ITD-mediated signaling or proliferation. Importantly, SOCS1 coexpression inhibited interferon-alpha and interferon-gamma signaling and protected FLT3-ITD hematopoietic cells from interferon-mediated growth inhibitory effects. In a murine bone marrow transplantation model, the coexpression of SOCS1 and FLT3-ITD significantly shortened the latency of a myeloproliferative disease compared with FLT3-ITD alone (P < .01). Mechanistically, SOCS proteins shield FLT3-ITD from external cytokine control, thereby promoting leukemogenesis. The data demonstrate that SOCS1 acts as a conditional oncogene, providing novel molecular insights into cytokine resistance in oncogenic transformation. Restoring cytokine control may provide a new way of therapeutic intervention. PMID- 22517901 TI - Frequent somatic mosaicism of NEMO in T cells of patients with X-linked anhidrotic ectodermal dysplasia with immunodeficiency. AB - Somatic mosaicism has been described in several primary immunodeficiency diseases and causes modified phenotypes in affected patients. X-linked anhidrotic ectodermal dysplasia with immunodeficiency (XL-EDA-ID) is caused by hypomorphic mutations in the NF-kappaB essential modulator (NEMO) gene and manifests clinically in various ways. We have previously reported a case of XL-EDA-ID with somatic mosaicism caused by a duplication mutation of the NEMO gene, but the frequency of somatic mosaicism of NEMO and its clinical impact on XL-EDA-ID is not fully understood. In this study, somatic mosaicism of NEMO was evaluated in XL-EDA-ID patients in Japan. Cells expressing wild-type NEMO, most of which were derived from the T-cell lineage, were detected in 9 of 10 XL-EDA-ID patients. These data indicate that the frequency of somatic mosaicism of NEMO is high in XL ED-ID patients and that the presence of somatic mosaicism of NEMO could have an impact on the diagnosis and treatment of XL-ED-ID patients. PMID- 22517900 TI - How I treat acquired aplastic anemia. AB - Survival in severe aplastic anemia (SAA) has markedly improved in the past 4 decades because of advances in hematopoietic stem cell transplantation, immunosuppressive biologics and drugs, and supportive care. However, management of SAA patients remains challenging, both acutely in addressing the immediate consequences of pancytopenia and in the long term because of the disease's natural history and the consequences of therapy. Recent insights into pathophysiology have practical implications. We review key aspects of differential diagnosis, considerations in the choice of first- and second-line therapies, and the management of patients after immunosuppression, based on both a critical review of the recent literature and our large personal and research protocol experience of bone marrow failure in the Hematology Branch of the National Heart, Lung, and Blood Institute. PMID- 22517902 TI - Multiscale prediction of patient-specific platelet function under flow. AB - During thrombotic or hemostatic episodes, platelets bind collagen and release ADP and thromboxane A(2), recruiting additional platelets to a growing deposit that distorts the flow field. Prediction of clotting function under hemodynamic conditions for a patient's platelet phenotype remains a challenge. A platelet signaling phenotype was obtained for 3 healthy donors using pairwise agonist scanning, in which calcium dye-loaded platelets were exposed to pairwise combinations of ADP, U46619, and convulxin to activate the P2Y(1)/P2Y(12), TP, and GPVI receptors, respectively, with and without the prostacyclin receptor agonist iloprost. A neural network model was trained on each donor's pairwise agonist scanning experiment and then embedded into a multiscale Monte Carlo simulation of donor-specific platelet deposition under flow. The simulations were compared directly with microfluidic experiments of whole blood flowing over collagen at 200 and 1000/s wall shear rate. The simulations predicted the ranked order of drug sensitivity for indomethacin, aspirin, MRS-2179 (a P2Y(1) inhibitor), and iloprost. Consistent with measurement and simulation, one donor displayed larger clots and another presented with indomethacin resistance (revealing a novel heterozygote TP-V241G mutation). In silico representations of a subject's platelet phenotype allowed prediction of blood function under flow, essential for identifying patient-specific risks, drug responses, and novel genotypes. PMID- 22517904 TI - A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low dose dexamethasone (RdC) in AL amyloidosis. AB - In this phase 1/2 study, we explored the feasibility and activity of an oral regimen of lenalidomide with low-dose dexamethasone and low-dose oral cyclophosphamide (RdC) in patients with primary systemic light chain amyloidosis. RdC was given for up to 12 cycles in prespecified cohorts at escalated doses: 13 patients were treated in phase 1 and 24 in phase 2; 65% were previously untreated, and most had renal and/or cardiac involvement and elevated cardiac biomarkers. Lenalidomide 15 mg/d and cyclophosphamide 100 mg/d were further evaluated in phase 2. On intention to treat, 20 (55%) patients achieved a hematologic response, including 3 (8%) complete remissions. Hematologic responses were seen at all dose levels and in 4 of 5 patients who had received bortezomib previously. An organ response was recorded in 22% of patients on intention-to treat and in 40% of patients who survived at least 6 months. The median time to progression was 10 months and the 2-year survival was 41%. Fatigue, nonneutropenic infections, and rash were the most common toxicities. The results of the present study show that RdC is an oral regimen with activity in primary systemic light chain amyloidosis and may be an additional treatment option, especially for patients with preserved organ function or for patients who cannot receive or who relapse after bortezomib. This study is registered at www.clinicaltrials.gov as NCT00981708. PMID- 22517905 TI - A switch in infected erythrocyte deformability at the maturation and blood circulation of Plasmodium falciparum transmission stages. AB - Achievement of malaria elimination requires development of novel strategies interfering with parasite transmission, including targeting the parasite sexual stages (gametocytes). The formation of Plasmodium falciparum gametocytes in the human host takes several days during which immature gametocyte-infected erythrocytes (GIEs) sequester in host tissues. Only mature stage GIEs circulate in the peripheral blood, available to uptake by the Anopheles vector. Mechanisms underlying GIE sequestration and release in circulation are virtually unknown. We show here that mature GIEs are more deformable than immature stages using ektacytometry and microsphiltration methods, and that a switch in cellular deformability in the transition from immature to mature gametocytes is accompanied by the deassociation of parasite-derived STEVOR proteins from the infected erythrocyte membrane. We hypothesize that mechanical retention contributes to sequestration of immature GIEs and that regained deformability of mature gametocytes is associated with their release in the bloodstream and ability to circulate. These processes are proposed to play a key role in P falciparum gametocyte development in the host and to represent novel and unconventional targets for interfering with parasite transmission. PMID- 22517903 TI - Immunosuppression for acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2). AB - Acquired hemophilia A (AHA) is an autoimmune disease caused by an autoantibody to factor VIII. Patients are at risk of severe and fatal hemorrhage until the inhibitor is eradicated, and guidelines recommend immunosuppression as soon as the diagnosis has been made. The optimal immunosuppressive regimen is unclear; therefore, data from 331 patients entered into the prospective EACH2 registry were analyzed. Steroids combined with cyclophosphamide resulted in more stable complete remission (70%), defined as inhibitor undetectable, factor VIII more than 70 IU/dL and immunosuppression stopped, than steroids alone (48%) or rituximab-based regimens (59%). Propensity score-matched analysis controlling for age, sex, factor VIII level, inhibitor titer, and underlying etiology confirmed that stable remission was more likely with steroids and cyclophosphamide than steroids alone (odds ratio = 3.25; 95% CI, 1.51-6.96; P < .003). The median time to complete remission was approximately 5 weeks for steroids with or without cyclophosphamide; rituximab-based regimens required approximately twice as long. Immunoglobulin administration did not improve outcome. Second-line therapy was successful in approximately 60% of cases that failed first-line therapy. Outcome was not affected by the choice of first-line therapy. The likelihood of achieving stable remission was not affected by underlying etiology but was influenced by the presenting inhibitor titer and FVIII level. PMID- 22517906 TI - Multiple myeloma-related deregulation of bone marrow-derived CD34(+) hematopoietic stem and progenitor cells. AB - Multiple myeloma (MM) is a clonal plasma cell disorder frequently accompanied by hematopoietic impairment. We show that hematopoietic stem and progenitor cells (HSPCs), in particular megakaryocyte-erythrocyte progenitors, are diminished in the BM of MM patients. Genomic profiling of HSPC subsets revealed deregulations of signaling cascades, most notably TGFbeta signaling, and pathways involved in cytoskeletal organization, migration, adhesion, and cell-cycle regulation in the patients. Functionally, proliferation, colony formation, and long-term self renewal were impaired as a consequence of activated TGFbeta signaling. In accordance, TGFbeta levels in the BM extracellular fluid were elevated and mesenchymal stromal cells (MSCs) had a reduced capacity to support long-term hematopoiesis of HSPCs that completely recovered on blockade of TGFbeta signaling. Furthermore, we found defective actin assembly and down-regulation of the adhesion receptor CD44 in MM HSPCs functionally reflected by impaired migration and adhesion. Still, transplantation into myeloma-free NOG mice revealed even enhanced engraftment and normal differentiation capacities of MM HSPCs, which underlines that functional impairment of HSPCs depends on MM-related microenvironmental cues and is reversible. Taken together, these data implicate that hematopoietic suppression in MM emerges from the HSPCs as a result of MM related microenvironmental alterations. PMID- 22517908 TI - The interferon-dependent orchestration of innate and adaptive immunity after transplantation. AB - The therapeutic GVL effect after allogeneic stem cell transplantation is limited by the development of GVHD. The ultimate aim of current research is to separate the 2 processes in a meaningful fashion. The IFNs are a pleiotropic group of cytokines that were originally recognized because of their ability to interfere with viral replication. However, it is now established that these cytokines play an important role in orchestrating both innate and adaptive immunity. Multiple studies have investigated the effects of both types I and II IFN on GVHD and GVL in preclinical transplant models. The results indicate variable effects that are dependent on the period of activity within the developing immune response, the presence and type of pretransplant conditioning and the differential mechanisms, and IFN sensitivity of immune pathology within individual target organs during GVHD. This Perspective discusses the current literature on the IFNs and their potential modulation within clinical transplantation, focusing particularly on enhancing the therapeutic GVL effects. PMID- 22517907 TI - Non-cell-autonomous hedgehog signaling promotes murine B lymphopoiesis from hematopoietic progenitors. AB - The role of hedgehog (Hh) signaling in B lymphopoiesis has remained unclear. We observed that the proliferation of pro-B cells in stromal cocultures was impaired by interruption of Hh signaling, prompting us to investigate whether the target of Hh antagonism was intrinsic or extrinsic to the B-lymphoid compartment. In the present study, using conditional deletion of the pathway activator gene Smo, we found that cell-autonomous Hh signaling is dispensable for B-cell development, B lymphoid repopulation of the BM, and humoral immune function. In contrast, depletion of the Smo protein from stromal cells was associated with impaired generation of B-lymphoid cells from hematopoietic stem progenitor cells, whereas reciprocal removal of Smo from these cells had no effect on the production of B cell progenitors. Depletion of Smo from stromal cells was associated with coordinate down-regulation of genes for which expression is associated with osteoblastoid identity and B-lymphopoietic activity. The results of the present study suggest that activity of the Hh pathway within stromal cells promotes B lymphopoiesis in a non-cell-autonomous fashion. PMID- 22517909 TI - Consistency of patient preferences about a secure Internet-based patient communications portal: contemplating, enrolling, and using. AB - Internet-based secure communication portals (portal) have the potential to enhance patient care via improved patient-provider communications. This study examines differences among primary care patients' perceptions when contemplating using, enrolling to use, and using a portal for health care purposes. A total of 3 groups of patients from 1 Midwestern academic medical center were surveyed at different points in time: (1) Waiting Room survey asking about hypothetical interest in using a portal to communicate with their physicians; (2) patient portal Enrollment survey; and (3) Follow-up postenrollment experience survey. Those who enroll and use a patient portal have different demographic characteristics and interest levels in selected portal functions (eg, e-mailing providers, viewing medical records online, making appointments) and initially perceive only limited improvements in care because of the portal. These differences have potential market implications and provide insight into selecting and maintaining portal functions of greater interest to patients who use the portal. PMID- 22517911 TI - Classical sexually transmitted diseases drive the spread of HIV-1: back to the future. PMID- 22517910 TI - Symptomatic vaginal discharge is a poor predictor of sexually transmitted infections and genital tract inflammation in high-risk women in South Africa. AB - BACKGROUND: Diagnosis and treatment of sexually transmitted infections (STIs) is a public health priority, particularly in regions where the incidence of human immunodeficiency virus (HIV) infection is high. In most developing countries, STIs are managed syndromically. We assessed the adequacy of syndromic diagnosis of STIs, compared with laboratory diagnosis of STIs, and evaluated the association between STI diagnosis and the risk of HIV acquisition in a cohort of high-risk women. METHODS: HIV-uninfected high-risk women (n = 242) were followed for 24 months. Symptoms of STIs were recorded, and laboratory diagnosis of common STI pathogens was conducted every 6 months. Forty-two cytokines were measured by Luminex in cervicovaginal lavage specimens at enrollment. Human immunodeficiency virus type 1 (HIV-1) infection was evaluated monthly. RESULTS: Only 12.3% of women (25 of 204) who had a laboratory-diagnosed, discharge-causing STI had clinically evident discharge. Vaginal discharge was thus a poor predictor of laboratory-diagnosed STIs (sensitivity, 12.3%; specificity, 93.8%). Cervicovaginal cytokine concentrations did not differ between women with asymptomatic STIs and those with symptomatic STIs and were elevated in women with asymptomatic STIs, compared with women with no STIs or bacterial vaginosis. Although laboratory-diagnosed STIs were associated with increased risk of HIV infection (hazard ratio, 3.3 [95% confidence interval, 1.5-7.2)], clinical symptoms were not. CONCLUSIONS: Syndromic STI diagnosis dependent on vaginal discharge was poorly predictive of laboratory-diagnosed STI. Laboratory-diagnosed STIs were associated with increased susceptibility to HIV acquisition, while vaginal discharge was not. PMID- 22517912 TI - A protective role for interleukin 18 in interferon gamma-mediated innate immunity to Cryptosporidium parvum that is independent of natural killer cells. AB - Innate immunity against some intracellular parasitic protozoa involves interleukin 18 (IL-18)-mediated interferon gamma (IFN-gamma) production by natural killer (NK) cells, but the role of IL-18 in innate resistance to Cryptosporidium infection is unknown. Adult Rag2(-/-)gammac(-/-) mice that lack NK cells, T cells, and B cells demonstrated resistance to Cryptosporidium parvum infection that was IFN-gamma dependent. Treatment with anti-IL-18-neutralizing antibodies resulted in loss of resistance correlating with reduced intestinal IFN gamma expression. Intestinal mature IL-18 expression increased in vivo during infection and also in the intestinal epithelial cell line CMT-93 following combined IFN-gamma treatment/infection. Peritoneal macrophages produced IFN-gamma when stimulated with IL-18 combined with interleukin 12, and the latter was expressed in vivo during infection. Macrophage depletion in infected mice caused a rapid growth of infection with no increase in IFN-gamma expression. These findings provide evidence of an NK cell-independent, IFN-gamma-mediated innate immune pathway against C. parvum in which IL-18 and macrophages play prominent parts. PMID- 22517913 TI - Impact of human immunodeficiency virus on the natural history of human papillomavirus genital infection in South African men and women. AB - BACKGROUND: This study investigated genital human papillomavirus (HPV) incidence and clearance in 278 human immunodeficiency virus (HIV)-seropositive (HIV positive) women, 208 HIV-negative women, 161 HIV-positive men, and 325 HIV negative men, followed at 6-month intervals for up to 24 months. METHODS: HPV types were determined by the Roche Reverse Linear Array HPV genotyping assay. RESULTS: The rate of new HPV detection at the cervix and penis were 33.83 events/1000 person-months (95% confidence interval [CI], 26.39-43.46) and 55.68 events/1000 person-months (95% CI, 43.59-69.19), respectively. HIV infection was associated with increased risk of new HPV detection in women (relative risk [RR], 2.98; 95% CI, 2.07-4.29) and men (RR, 2.00; 95% CI, 1.49-2.69). The risk of new HPV detection increased in women (RR, 5.25; 95% CI, 3.52-7.81) and men (RR, 8.71; 95% CI, 6.19-12.24) when the sexual partner was infected with the same HPV type. The rate of clearing any HPV infection was 95.1 events/1000 person-months (95% CI, 83.3-108.1) in men and 66.9 events/1000 person-months (95% CI, 57.0-78.5) in women. HIV infection reduced the rate of HPV clearance in women (RR, 0.46; 95% CI, .34-.62) and men (RR, 0.71; 95% CI, .55-.93). CONCLUSIONS: HIV infection increases the risk of new HPV detection and decreases the rate of HPV clearance in both women and men. PMID- 22517914 TI - Leishmania-induced biphasic ceramide generation in macrophages is crucial for uptake and survival of the parasite. AB - The initial macrophage-Leishmania donovani interaction results in the formation of membrane platforms, termed lipid rafts, that help in the entry of the parasite. Therefore, it is imperative that the parasite designs a strategy to modulate its uptake and survival within the macrophages. Herein, we report Leishmania-triggered biphasic ceramide generation. In the first phase, L. donovani promastigotes induce activation of acid sphingomyelinase (ASMase), which catalyzes the formation of ceramide from sphingomyelin. Inhibition of ASMase resulted in reduced uptake and infection with the parasite. In the second phase, de novo synthesis generates ceramide that reduces the cellular cholesterol level and displaces the cholesterol from the membrane, leading to enhanced membrane fluidity, disruption of rafts, and impaired antigen-presentation to the T cells. The results reveal a novel role for ceramide in the perspective of L. donovani infection and help formulate an antileishmanial strategy that can possibly be applied to other intracellular infections as well. PMID- 22517915 TI - Risk factors for medically serious suicide attempts: evidence for a psychodynamic formulation of suicidal crisis. AB - This study explored a psychodynamic model for suicide risk by examining risk factors for medically serious suicide attempts, including assessments of affect flooding, negative self-schema / fragmentation, and impaired reality testing, closely approximating Maltsberger's psycho-dynamic formulation of suicide crisis. Baseline risk factors including age, gender, psychiatric symptoms, high-risk behaviors, and the Implicit Risk for Suicide Index (IRSI) were used to detect medically serious suicide attempts monitored for up to a year after the assessment. Twenty-five psychiatric inpatients who made life-threatening suicide attempts after assessment were compared to 25 inpatients and 25 psychotherapy outpatients who made no suicide attempts during follow-up. Statistical analysis revealed that a history of at least one suicide attempt and elevated IRSI scores accounted for 60 percent of the variance in detecting medically serious suicide attempts. Elevated IRSI accurately identified suicide attempt status above and beyond past suicide attempts and other empirically validated risk factors. Results are discussed in light of psychodynamic formulations of suicide risk. PMID- 22517916 TI - Cost effectiveness of alternative planned places of birth in woman at low risk of complications: evidence from the Birthplace in England national prospective cohort study. AB - OBJECTIVES: To estimate the cost effectiveness of alternative planned places of birth. DESIGN: Economic evaluation with individual level data from the Birthplace national prospective cohort study. SETTING: 142 of 147 trusts providing home birth services, 53 of 56 freestanding midwifery units, 43 of 51 alongside midwifery units, and a random sample of 36 of 180 obstetric units, stratified by unit size and geographical region, in England, over varying periods of time within the study period 1 April 2008 to 30 April 2010. PARTICIPANTS: 64,538 women at low risk of complications before the onset of labour. INTERVENTIONS: Planned birth in four alternative settings: at home, in freestanding midwifery units, in alongside midwifery units, and in obstetric units. MAIN OUTCOME MEASURES: Incremental cost per adverse perinatal outcome avoided, adverse maternal morbidity avoided, and additional normal birth. The non-parametric bootstrap method was used to generate net monetary benefits and construct cost effectiveness acceptability curves at alternative thresholds for cost effectiveness. RESULTS: The total unadjusted mean costs were L1066, L1435, L1461, and L1631 for births planned at home, in freestanding midwifery units, in alongside midwifery units, and in obstetric units, respectively (equivalent to about ?1274, $1701; ?1715, $2290; ?1747, $2332; and ?1950, $2603). Overall, and for multiparous women, planned birth at home generated the greatest mean net benefit with a 100% probability of being the optimal setting across all thresholds of cost effectiveness when perinatal outcomes were considered. There was, however, an increased incidence of adverse perinatal outcome associated with planned birth at home in nulliparous low risk women, resulting in the probability of it being the most cost effective option at a cost effectiveness threshold of L20 000 declining to 0.63. With regards to maternal outcomes in nulliparous and multiparous women, planned birth at home generated the greatest mean net benefit with a 100% probability of being the optimal setting across all thresholds of cost effectiveness. CONCLUSIONS: For multiparous women at low risk of complications, planned birth at home was the most cost effective option. For nulliparous low risk women, planned birth at home is still likely to be the most cost effective option but is associated with an increase in adverse perinatal outcomes. PMID- 22517917 TI - The effectiveness of SPARX, a computerised self help intervention for adolescents seeking help for depression: randomised controlled non-inferiority trial. AB - OBJECTIVE: To evaluate whether a new computerised cognitive behavioural therapy intervention (SPARX, Smart, Positive, Active, Realistic, X-factor thoughts) could reduce depressive symptoms in help seeking adolescents as much or more than treatment as usual. DESIGN: Multicentre randomised controlled non-inferiority trial. SETTING: 24 primary healthcare sites in New Zealand (youth clinics, general practices, and school based counselling services). PARTICIPANTS: 187 adolescents aged 12-19, seeking help for depressive symptoms, with no major risk of self harm and deemed in need of treatment by their primary healthcare clinicians: 94 were allocated to SPARX and 93 to treatment as usual. INTERVENTIONS: Computerised cognitive behavioural therapy (SPARX) comprising seven modules delivered over a period of between four and seven weeks, versus treatment as usual comprising primarily face to face counselling delivered by trained counsellors and clinical psychologists. OUTCOMES: The primary outcome was the change in score on the children's depression rating scale-revised. Secondary outcomes included response and remission on the children's depression rating scale-revised, change scores on the Reynolds adolescent depression scale-second edition, the mood and feelings questionnaire, the Kazdin hopelessness scale for children, the Spence children's anxiety scale, the paediatric quality of life enjoyment and satisfaction questionnaire, and overall satisfaction with treatment ratings. RESULTS: 94 participants were allocated to SPARX (mean age 15.6 years, 62.8% female) and 93 to treatment as usual (mean age 15.6 years, 68.8% female). 170 adolescents (91%, SPARX n = 85, treatment as usual n = 85) were assessed after intervention and 168 (90%, SPARX n = 83, treatment as usual n = 85) were assessed at the three month follow-up point. Per protocol analyses (n = 143) showed that SPARX was not inferior to treatment as usual. Post-intervention, there was a mean reduction of 10.32 in SPARX and 7.59 in treatment as usual in raw scores on the children's depression rating scale-revised (between group difference 2.73, 95% confidence interval -0.31 to 5.77; P=0.079). Remission rates were significantly higher in the SPARX arm (n = 31, 43.7%) than in the treatment as usual arm (n = 19, 26.4%) (difference 17.3%, 95% confidence interval 1.6% to 31.8%; P = 0.030) and response rates did not differ significantly between the SPARX arm (66.2%, n = 47) and treatment as usual arm (58.3%, n = 42) (difference 7.9%, -7.9% to 24%; P = 0.332). All secondary measures supported non-inferiority. Intention to treat analyses confirmed these findings. Improvements were maintained at follow-up. The frequency of adverse events classified as "possibly" or "probably" related to the intervention did not differ between groups (SPARX n = 11; treatment as usual n = 11). CONCLUSIONS: SPARX is a potential alternative to usual care for adolescents presenting with depressive symptoms in primary care settings and could be used to address some of the unmet demand for treatment. TRIAL REGISTRATION: Australian New Zealand Clinical Trials ACTRN12609000249257. PMID- 22517918 TI - Smac mimetic enables the anticancer action of BCG-stimulated neutrophils through TNF-alpha but not through TRAIL and FasL. AB - BCG, the current gold standard immunotherapy for bladder cancer, exerts its activity via recruitment of neutrophils to the tumor microenvironment. Many patients do not respond to BCG therapy, indicating the need to understand the mechanism of action of BCG-stimulated neutrophils and to identify ways to overcome resistance to BCG therapy. Using isolated human neutrophils stimulated with BCG, we found that TNF-alpha is the key mediator secreted by BCG-stimulated neutrophils. RT4v6 human bladder cancer cells, which express TNFR1, CD95/Fas, CD95 ligand/FasL, DR4, and DR5, were resistant to BCG-stimulated neutrophil conditioned medium but effectively killed by the combination of conditioned medium and Smac mimetic. rhTNF-alpha and rhFasL, but not rhTRAIL, in combination with Smac mimetic, generated signature molecular events similar to those produced by BCG-stimulated neutrophils in combination with Smac mimetic. However, experiments using neutralizing antibodies to these death ligands showed that TNF alpha secreted from BCG-stimulated neutrophils was the key mediator of anticancer action. These findings explain the mechanism of action of BCG and identified Smac mimetics as potential combination therapeutic agents for bladder cancer. PMID- 22517919 TI - Identification of hamster inducible nitric oxide synthase (iNOS) promoter sequences that influence basal and inducible iNOS expression. AB - IFN-gamma/LPS-activated hamster (Mesocricetus auratus) macrophages express significantly less iNOS (NOS2) than activated mouse macrophages, which contributes to the hamster's susceptibility to intracellular pathogens. We determined a mechanism responsible for differences in iNOS promoter activity in hamsters and mice. The HtPP (1.2 kb) showed low basal and inducible promoter activity when compared with the mouse, and sequences within a 100-bp region (-233 to -133) of the mouse and hamster promoters influenced this activity. Moreover, within this 100 bp, we identified a smaller region (44 bp) in the mouse promoter, which recovered basal promoter activity when swapped into the hamster promoter. The mouse homolog (100-bp region) contained a cis-element for NF-IL-6 (-153/ 142), which was absent in the hamster counterpart. EMSA and supershift assays revealed that the hamster sequence did not support the binding of NF-IL-6. Introduction of a functional NF-IL-6 binding sequence into the hamster promoter or its alteration in the mouse promoter revealed the critical importance of this transcription factor for full iNOS promoter activity. Furthermore, the binding of NF-IL-6 to the iNOS promoter (-153/-142) in vivo was increased in mouse cells but was reduced in hamster cells after IFN-gamma/LPS stimulation. Differences in the activity of the iNOS promoters were evident in mouse and hamster cells, so they were not merely a result of species-specific differences in transcription factors. Thus, we have identified unique DNA sequences and a critical transcription factor, NF-IL-6, which contribute to the overall basal and inducible expression of hamster iNOS. PMID- 22517920 TI - RLR-mediated production of interferon-beta by a human dendritic cell subset and its role in virus-specific immunity. AB - Cytosolic RIG-I-like helicases (RLR) are PRRs involved in type I IFN production and antiviral immunity. This study focuses to the comparison of the expression, function, and signaling cascades associated to RLR in the previously identified CD14(-)DC-SIGN(+)PPARgamma(low)CD1a(+) and CD14(low)DC SIGN(+)PPARgamma(high)CD1a(-) human moDC subsets. Our results revealed that the expression of RLR genes and proteins as well as the activity of the coupled signaling pathways are significantly higher in the CD1a(+) subset than in its phenotypically and functionally distinct counterpart. Specific activation of RLR in moDCs by poly(I:C) or influenza virus was shown to induce the secretion of IFN beta via IRF3, whereas induction of proinflammatory cytokine responses were predominantly controlled by TLR3. The requirement of RLR-mediated signaling in CD1a(+) moDCs for priming naive CD8(+) T lymphocytes and inducing influenza virus specific cellular immune responses was confirmed by RIG-I/MDA5 silencing, which abrogated these functions. Our results demonstrate the subset-specific activation of RLR and the underlying mechanisms behind its cytokine secretion profile and identify CD1a(+) moDCs as an inflammatory subset with specialized functional activities. We also provide evidence that this migratory DC subset can be detected in human tonsil and reactive LNs. PMID- 22517921 TI - Gender-related invariance of the Beck Depression Inventory II for Taiwanese adolescent samples. AB - The Chinese version of Beck Depression Inventory II (BDI-II-C) is one of the most used instruments to measure the severity of depression in Taiwan. The scarce literature regarding its psychometric properties (e.g., measurement invariance) highlighted the need and significance for such an investigation. The purpose of this study was to examine the gender-related measurement invariance of the BDI-II C in an adolescent sample facing an entrance examination in the following two ways: (a) examining configural, metric, and scalar invariance using multigroup confirmatory factor analyses and (b) estimating the effects of any detected noninvariance on mean differences. The participants included 827 (416 boys and 411 girls) Taiwanese adolescents. Results indicate that measurement invariance was established at the level of configural, metric, and partial scalar invariance. Seven noninvariant intercepts (Items 2, 3, 7, 9, 10, 12, and 19) were identified, showing that there was differential additive response style bias for the BDI-II-C across gender groups. Additionally, the results demonstrated that the noninvariance had significant effects on interpretation based on gender latent mean difference as well as observed mean difference. PMID- 22517922 TI - Measurement differences from rating posttraumatic stress disorder symptoms in response to differentially distressing traumatic events. AB - The authors explored differences in posttraumatic stress disorder (PTSD) symptoms as a result of rating symptoms from two separate, differentially distressing traumatic events. In an initial sample of 400 nonclinical participants, the authors inquired through a web survey about previous psychological trauma, instructing participants to nominate their most distressing and second most distressing traumatic events experienced. Using the PTSD Checklist, participants rated their PTSD symptoms separately from these worst and second worst events. Using the four-factor emotional numbing PTSD model in confirmatory factor analysis, results demonstrated evidence supporting separation of PTSD symptom rating sets from two differentially distressing traumas-specifically, the worst and second worst events. Measurement invariance tests revealed that factor loadings did not vary between the worst and second worst event PTSD ratings; item thresholds (indexing symptom severity) differed. Results generally support the recommended PTSD assessment protocol instructing participants to rate PTSD symptoms from a single, worst index event. PMID- 22517923 TI - Reliability and validity of the online continuous performance test among young adults. AB - Continuous Performance Tests (CPTs) are used in research and clinical contexts to measure sustained attention and response inhibition. Reliability and validity of a new Online Continuous Performance Test (OCPT) was assessed. The OCPT is designed for delivery over the Internet, thereby opening new opportunities for research and clinical application in naturalistic settings. In Study 1, participants completed the OCPT twice over a 1-week period. One test was taken at home and one in the laboratory. Construct validity was assessed against a gold standard CPT measure. Results indicate acceptable reliability between the home- and laboratory-administered tests. Modest to high correlations were observed between the OCPT scales and the corresponding scales of the gold standard CPT. Study 2 examined whether the OCPT may discriminate participants with attention deficit hyperactivity disorder from healthy controls. Results revealed significantly higher rates of omission and commission errors and greater response time variability in participants with attention deficit hyperactivity disorder relative to healthy controls. These results support the reliability and validity of the OCPT and suggest that it may serve as an effective tool for the assessment of attention function in naturalistic settings. PMID- 22517924 TI - Stereospecificity of fatty acid 2-hydroxylase and differential functions of 2 hydroxy fatty acid enantiomers. AB - FA 2-hydroxylase (FA2H) is an NAD(P)H-dependent enzyme that initiates FA alpha oxidation and is also responsible for the biosynthesis of 2-hydroxy FA (2-OH FA) containing sphingolipids in mammalian cells. The 2-OH FA is chiral due to the asymmetric carbon bearing the hydroxyl group. Our current study performed stereochemistry investigation and showed that FA2H is stereospecific for the production of (R)-enantiomers. FA2H knockdown in adipocytes increases diffusional mobility of raft-associated lipids, leading to reduced GLUT4 protein level, glucose uptake, and lipogenesis. The effects caused by FA2H knockdown were reversed by treatment with exogenous (R)-2-hydroxy palmitic acid, but not with the (S)-enantiomer. Further analysis of sphingolipids demonstrated that the (R) enantiomer is enriched in hexosylceramide whereas the (S)-enantiomer is preferentially incorporated into ceramide, suggesting that the observed differential effects are in part due to synthesis of sphingolipids containing different 2-OH FA enantiomers. These results may help clarify the mechanisms underlying the recently identified diseases associated with FA2H mutations in humans and may lead to potential pharmaceutical and dietary treatments. This study also provides critical information to help study functions of 2-OH FA enantiomers in FA alpha oxidation and possibly other sphingolipid-independent pathways. PMID- 22517925 TI - A comprehensive method for extraction and quantitative analysis of sterols and secosteroids from human plasma. AB - We describe the development of a method for the extraction and analysis of 62 sterols, oxysterols, and secosteroids from human plasma using a combination of HPLC-MS and GC-MS. Deuterated standards are added to 200 MUl of human plasma. Bulk lipids are extracted with methanol:dichloromethane, the sample is hydrolyzed using a novel procedure, and sterols and secosteroids are isolated using solid phase extraction (SPE). Compounds are resolved on C18 core-shell HPLC columns and by GC. Sterols and oxysterols are measured using triple quadrupole mass spectrometers, and lathosterol is measured using GC-MS. Detection for each compound measured by HPLC-MS was ? 1 ng/ml of plasma. Extraction efficiency was between 85 and 110%; day-to-day variability showed a relative standard error of <10%. Numerous oxysterols were detected, including the side chain oxysterols 22-, 24-, 25-, and 27-hydroxycholesterol, as well as ring-structure oxysterols 7alpha- and 4beta-hydroxycholesterol. Intermediates from the cholesterol biosynthetic pathway were also detected, including zymosterol, desmosterol, and lanosterol. This method also allowed the quantification of six secosteroids, including the 25 hydroxylated species of vitamins D2 and D3. Application of this method to plasma samples revealed that at least 50 samples could be extracted in a routine day. PMID- 22517926 TI - Effect of uremia and hemodialysis on proteome profile of blood platelets and plasma. AB - The aim of the present research was to assess the differences in blood platelet and plasma proteome profiles of patients with uremia in comparison with healthy participants. It was found that 23 peptides in the platelet proteome profiles of hemodialyzed patients and only 6 peptides in nondialyzed patients were upregulated. On the other hand, 18 peptides with reduced expression in nondialyzed patients and only 1 peptide in hemodialyzed patients were found. For serum, only 6 upregulated peptides in patients undergoing hemodialysis and 15 peptides in nondialyzed patients were found, most of these were about 10 kDa. A decrease in serum peptide expression was not observed. In conclusion, it should be noted that the process of hemodialysis modifies the platelet proteome to a greater extent than uremia alone, however the sera of nondialyzed patients have much larger amounts of low-molecular-weight peptides than those of hemodialyzed patients. PMID- 22517927 TI - The impact of perceived social support and sense of coherence on health-related quality of life in multimorbid primary care patients. AB - This study explores the impact of perceived social support and sense of coherence as positive resources for health-related quality of life in multimorbid primary care patients. We analysed cross-sectional survey data on health-related quality of life (EQ-5D), perceived social support (FSozU-K22), sense of coherence (SOC L9), social demographics and self reported morbidity of 103 multimorbid patients from 10 general practices in Germany. A multiple linear regression model was used to determine the impact of social support and sense of coherence on the health related quality of life while controlling for age, sex, educational level, marital status and number of chronic conditions. In the final regression model, higher sense of coherence scores were associated with higher health-related quality of life scores (standardized beta 0.34, p < 0.001) whereas a higher number of chronic conditions was associated with lower health-related quality of life scores (standardized beta -0.41, p < 0.001). In the bivariate model, higher perceived social support was associated with higher health-related quality of life scores (standardized beta 0.35, p < 0.001), whereas the model failed to show a significant association after controlling for sense of coherence which is a potential resource for improving health-related quality of life in multimorbid primary care patients. It emerged as a significant element contributing to the prediction of health-related quality of life. This issue may indicate the importance of internal resources for multimorbid patients. PMID- 22517928 TI - Dynamic assessment of ventilatory efficiency during recovery from peak exercise to enhance cardiopulmonary exercise testing. AB - BACKGROUND: While cardiopulmonary exercise testing (CPX) assessment is generally regarded as an optimal means to assess functional capacity in heart failure (HF) patients, strength parameters are omitted. CPX indices collected in recovery may provide additional insight regarding function, including strength. DESIGN AND METHODS: We performed a cross-sectional controlled study. Systolic HF patients (aged >= 50 years) and age-matched controls were assessed using CPX and strength evaluations. Standard CPX indices were assessed during exercise (peak oxygen consumption [VO2], first ventilatory threshold [1stVT], and ventilatory efficiency [VE/VCO2 slope]) as well as indices at 1-minute recovery (1 min VO2, 1 min VE/VCO2, and 1 min heart rate recovery [HRR]) and differences between peak and 1-minute recovery (DeltaVO2 and DeltaVE/VCO2). Lower extremity strength was evaluated using the 1-repetition maximum (1RM) and power. RESULTS: Seventy adults (31 HF; 39 controls), mean age 66.2 +/- 9.7 years were evaluated. Peak VO2 (15.4 +/- 4.2 versus 23.4 +/- 6.6 mlO2.kg(-1).min(-1), p < 0.0001) and 1stVT (10.9 +/- 2.1 versus 14.4 +/- 4.0 mlO2.kg(-1).min(-1), p < 0.0001) were diminished in HF versus controls and VE/VCO2 slope was increased (42.3 +/- 12.2 versus 35.4 +/- 8.3, p < 0.01). HF patients had reduced 1 minVO2 (13.1 +/- 2.9 versus 16.3 +/- 3.7 mlO2.kg(-1).min(-1), p < 0.0001), 1 min HRR (6.7 +/- 11.4 versus 12.4 +/- 7.6 beats, p < 0.02), and DeltaVO2 (2.43 +/- 2.3 versus 7.3 +/- 5.0 mlO2.kg(-1).min( 1), p < 0.0001) as well as increased 1 min VE/VCO2 (37 +/- 7.5 versus 31.5 +/- 4.4, p < 0.001) and DeltaVE/VCO2 (1.17 +/- 3.0 versus -0.5 +/- 1.3, p < 0.0001). Strength parameters were relatively lower in HF. While CPX exercise parameters correlated with strength, stronger correlations were observed between CPX recovery parameters and strength. CONCLUSIONS: CPX recovery indices corroborate disease-specific aerobic differences and distinguish differences in strength. Recovery ventilatory efficiency enhances CPX's value as a comprehensive physical function tool. PMID- 22517929 TI - Comparison of metformin and insulin versus insulin alone for type 2 diabetes: systematic review of randomised clinical trials with meta-analyses and trial sequential analyses. AB - OBJECTIVES: To compare the benefits and harms of metformin and insulin versus insulin alone as reported in randomised clinical trials of patients with type 2 diabetes. DESIGN: Systematic review of randomised clinical trials with meta analyses and trial sequential analyses. DATA SOURCES: The Cochrane Library, Medline, Embase, Science Citation Index Expanded, Latin American Caribbean Health Sciences Literature, and Cumulative Index to Nursing and Allied Health Literature until March 2011. We also searched abstracts presented at the American Diabetes Association and European Association for the Study of Diabetes Congresses, contacted relevant trial authors and pharmaceutical companies, hand searched reference lists of included trials, and searched the US Food and Drug Administration website. REVIEW METHODS: Two authors independently screened titles and abstracts for randomised clinical trials comparing metformin and insulin versus insulin alone (with or without placebo) in patients with type 2 diabetes, older than 18 years, and with an intervention period of at least 12 weeks. We included trials irrespective of language, publication status, predefined outcomes, antidiabetic interventions used before randomisation, and reported outcomes. RESULTS: We included 26 randomised trials with 2286 participants, of which 23 trials with 2117 participants could provide data. All trials had high risk of bias. Data were sparse for outcomes relevant to patients. Metformin and insulin versus insulin alone did not significantly affect all cause mortality (relative risk 1.30, 95% confidence interval 0.57 to 2.99) or cardiovascular mortality (1.70, 0.35 to 8.30). Trial sequential analyses showed that more trials were needed before reliable conclusions could be drawn regarding these outcomes. In a fixed effect model, but not in a random effects model, severe hypoglycaemia was significantly more frequent with metformin and insulin than with insulin alone (2.83, 1.17 to 6.86). In a random effects model, metformin and insulin resulted in reduced HbA(1c), weight gain, and insulin dose, compared with insulin alone; trial sequential analyses showed sufficient evidence for a HbA(1c) reduction of 0.5%, lower weight gain of 1 kg, and lower insulin dose of 5 U/day. CONCLUSIONS: There was no evidence or even a trend towards improved all cause mortality or cardiovascular mortality with metformin and insulin, compared with insulin alone in type 2 diabetes. Data were limited by the severe lack of data reported by trials for patient relevant outcomes and by poor bias control. PMID- 22517930 TI - Total hip arthroplasty versus resurfacing arthroplasty in the treatment of patients with arthritis of the hip joint: single centre, parallel group, assessor blinded, randomised controlled trial. AB - OBJECTIVES: To compare the clinical and cost effectiveness of total hip arthroplasty with resurfacing arthroplasty in patients with severe arthritis of the hip. DESIGN: Single centre, two arm, parallel group, assessor blinded, randomised controlled trial with 1:1 treatment allocation. SETTING: One large teaching hospital in the United Kingdom. PARTICIPANTS: 126 patients older than 18 years with severe arthritis of the hip joint, suitable for resurfacing arthroplasty of the hip. Patients were excluded if they were considered to be unable to adhere to trial procedures or complete questionnaires. INTERVENTIONS: Total hip arthroplasty (replacement of entire femoral head and neck); hip resurfacing arthroplasty (replacement of the articular surface of femoral head only, femoral neck remains intact). Both procedures replaced the articular surface of the acetabulum. MAIN OUTCOME MEASURES: Hip function at 12 months after surgery, assessed using the Oxford hip score and Harris hip score. Secondary outcomes were quality of life, disability rating, physical activity level, complications, and cost effectiveness. RESULTS: 60 patients were randomly assigned to hip resurfacing arthroplasty and 66 to total hip arthroplasty. Intention to treat analysis showed no evidence for a difference in hip function between treatment groups at 12 months (t test, P=0.242 and P=0.070 for Oxford hip score and Harris hip score, respectively); 95% of follow-up data was available for analysis. Mean Oxford hip score was 40.4 (95% confidence interval 37.9 to 42.9) in the resurfacing group and 38.2 (35.3 to 41.0) in the total arthroplasty group (estimated treatment effect size 2.23 (-1.52 to 5.98)). Mean Harris hip score was 88.4 (84.4 to 92.4) in the resurfacing group and 82.3 (77.2 to 87.5) in the total arthroplasty group (6.04 (-0.51 to 12.58)). Although we saw no evidence of a difference, we cannot definitively exclude clinically meaningful differences in hip function in the short term. Overall complication rates did not differ between treatment groups (P=0.291). However, we saw more wound complications in the total arthroplasty group (P=0.056) and more thromboembolic events in the resurfacing group (P=0.049). CONCLUSIONS: No evidence of a difference in hip function was seen in patients with severe arthritis of the hip, one year after receiving a total hip arthroplasty versus resurfacing arthroplasty. The long term effects of these interventions remain uncertain. TRIAL REGISTRATION: Current Controlled Trials ISRCTN33354155, UKCRN 4093. PMID- 22517931 TI - Hip resurfacing or stemmed arthroplasty for young active patients? PMID- 22517932 TI - Allergy risk from Royal Mint's new nickel plated steel coins should be publicly assessed. PMID- 22517933 TI - Don't ignore Coptic popes. PMID- 22517934 TI - Investigating the solitary pulmonary nodule. PMID- 22517935 TI - Lateral radiograph of the chest. PMID- 22517936 TI - Another shot to protect people with diabetes: add hepatitis B vaccination to the checklist. PMID- 22517937 TI - Type 2 diabetes: an epidemic requiring global attention and urgent action. PMID- 22517938 TI - Bidirectional association between depression and metabolic syndrome: a systematic review and meta-analysis of epidemiological studies. AB - OBJECTIVE: Epidemiological studies have repeatedly investigated the association between depression and metabolic syndrome (MetS). However, the results have been inconsistent. This meta-analysis aimed to summarize the current evidence from cross-sectional and prospective cohort studies that evaluated this association. RESEARCH DESIGN AND METHODS: MEDLINE, EMBASE, and PsycINFO databases were searched for articles published up to January 2012. Cross-sectional and cohort studies that reported an association between the two conditions in adults were included. Data on prevalence, incidence, unadjusted or adjusted odds ratio (OR), and 95% CI were extracted or provided by the authors. The pooled OR was calculated separately for cross-sectional and cohort studies using random-effects models. The I(2) statistic was used to assess heterogeneity. RESULTS: The search yielded 29 cross-sectional studies (n = 155,333): 27 studies reported unadjusted OR with a pooled estimate of 1.42 (95% CI 1.28-1.57; I(2) = 55.1%); 11 studies reported adjusted OR with depression as the outcome (1.27 [1.07-1.57]; I(2) = 60.9%), and 12 studies reported adjusted OR with MetS as the outcome (1.34 [1.18 1.51]; I(2) = 0%). Eleven cohort studies were found (2 studies reported both directions): 9 studies (n = 26,936 with 2,316 new-onset depression case subjects) reported adjusted OR with depression as the outcome (1.49 [1.19-1.87]; I(2) = 56.8%), 4 studies (n = 3,834 with 350 MetS case subjects) reported adjusted OR with MetS as the outcome (1.52 [1.20-1.91]; I(2) = 0%). CONCLUSIONS: Our results indicate a bidirectional association between depression and MetS. These results support early detection and management of depression among patients with MetS and vice versa. PMID- 22517939 TI - Understanding and addressing unique needs of diabetes in Asian Americans, native Hawaiians, and Pacific Islanders. PMID- 22517942 TI - Liraglutide treatment in a patient with HIV and uncontrolled insulin-treated type 2 diabetes. PMID- 22517940 TI - Pathophysiologic differences among Asians, native Hawaiians, and other Pacific Islanders and treatment implications. PMID- 22517943 TI - Double heterozygous germline HNF1A mutations in a patient with liver adenomatosis. PMID- 22517944 TI - Treatment of LADA with etanercept. PMID- 22517945 TI - Ramadan fasting: a study of changes in glucose profiles among patients with diabetes using continuous glucose monitoring. PMID- 22517946 TI - Comment on: Bopp et al. Routine data sources challenge International Diabetes Federation extrapolations of National Diabetes Prevalence in Switzerland. Diabetes Care 2011;34:2387-2389. PMID- 22517948 TI - Mental health conditions, individual and job characteristics and sleep disturbances among firefighters. AB - This study aimed to assess the associations between mental health conditions, individual and job characteristics and sleep disturbances among firefighters. Of 303 participants, 51.2% reported sleep disturbances. Psychological distress and psychosomatic disturbances were significantly associated with sleep disturbances. Suicidal ideation, unhealthy alcohol use and time as a firefighter were also associated with sleep disturbances but at a borderline level of significance (0.05 < p < .085). These findings may be related to the psychological and physical hazards of firefighting and indicate the importance of research on associated professions. PMID- 22517949 TI - Individuals' experiences of, and responses to, a negative genetic test result for familial hypercholesterolaemia. AB - This study aimed to explore the responses of individuals who have undergone genetic testing for familial hypercholesterolaemia (FH) where no genetic mutation has been identified. Semi-structured interviews were conducted with 11 patients and interpretative phenomenological analysis (IPA) was employed. This article describes three inter-related themes: 'feeling in limbo', 'exploring causes of raised cholesterol' and 'contradictions in talk about diet'. Although participants generally adhered to medication and engaged in healthy lifestyles, the findings have clinical implications for how genetic test results are communicated. PMID- 22517950 TI - Science to practice: Son et Lumiere--understanding tumor heterogeneity. AB - Treatment of cancer is often confounded by tumor heterogeneity.Variations in perfusion inhibit drug delivery to all parts of the tumor (1). Differences in oxygen tension (Po2)cause variations in response to radiation therapy (2).Understanding this tumor heterogeneity, which is caused by the interplay between the cancer cell's gene makeup and the tumor's environment (eg, stromal matrix, tissue vascularity),will likely enable improved treatment strategies.Whole-mount studies, in which the excised tumor is fixed or frozen and then sliced into thin sections - with subsequent staining and microscopic examination of the multiple sections-provide much information about tumor heterogeneity but cannot provide information about dynamic events, perfusion, metabolism, or those processes that exist in the tumor in vivo (including Po2). Intravital microscopy(3), in which a tumor or organ is exteriorized or viewed through a window cut in overlying tissue, can provide information on such dynamic processes; however, those studies are limited by scattering and diffusion of light as it penetrates tissue and so can only enable differentiation of surface structures and events. PMID- 22517951 TI - Variability in radiology practice in the United States: a former teleradiologist's perspective. PMID- 22517952 TI - The ABR and resident recall "cheating". PMID- 22517953 TI - Genitourinary applications of diffusion-weighted MR imaging in the pelvis. AB - Diffusion-weighted (DW) magnetic resonance (MR) imaging has a large number of potential clinical applications in the female and male pelvis and can easily be added to any routine MR protocol. In the female pelvis, DW imaging allows improvement of staging in endometrial and cervical cancer, especially in locally advanced disease and in patients in whom contrast medium administration should be avoided. It can also be helpful in characterizing complex adnexal masses and in depicting recurrent tumor after treatment of various gynecologic malignancies. DW imaging shows promising results in monitoring treatment response in patients undergoing radiation therapy of cervical cancer. An increase in apparent diffusion coefficient (ADC) values of responders precedes changes in size and may therefore allow early assessment of treatment success. In the male pelvis, the detection of prostate cancer in the peripheral zone is relatively easier than in the central gland based on the underlying ADC values, whereas overlapping values reported in the central gland still need further research. DW imaging might also be applied in the noninvasive evaluation of bladder cancer to differentiate between superficial and muscle-invasive tumors. Initial promising results have been reported in differentiating benign from malignant pelvic lymph nodes based on the ADC values; however, larger-scale studies will be needed to allow the detection of lymph node metastases in an individual patient. Prerequisites for successfully performing DW imaging of the female and male pelvis are standardization of the DW imaging technique, including the choice of b values, administration of an antiperistaltic drug, and comparison of DW findings with those of morphologic MR imaging. PMID- 22517955 TI - In vivo assessment of ductal carcinoma in situ grade: a model incorporating dynamic contrast-enhanced and diffusion-weighted breast MR imaging parameters. AB - PURPOSE: To develop a model incorporating dynamic contrast material-enhanced (DCE) and diffusion-weighted (DW) magnetic resonance (MR) imaging features to differentiate high-nuclear-grade (HNG) from non-HNG ductal carcinoma in situ (DCIS) in vivo. MATERIALS AND METHODS: This HIPAA-compliant study was approved by the institutional review board and requirement for informed consent was waived. A total of 55 pure DCIS lesions (19 HNG, 36 non-HNG) in 52 women who underwent breast MR imaging at 1.5 T with both DCE and DW imaging (b = 0 and 600 sec/mm(2)) were retrospectively reviewed. The following lesion characteristics were recorded or measured: DCE morphology, DCE maximum lesion size, peak initial enhancement at 90 seconds, worst-curve delayed enhancement kinetics, apparent diffusion coefficient (ADC), contrast-to-noise ratio (CNR) at DW imaging with b values of 0 and 600 sec/mm(2), and T2 signal effects (measured with CNR at b = 0 sec/mm(2)). Univariate and stepwise multivariate logistic regression modeling was performed to identify MR imaging features that optimally discriminated HNG from non-HNG DCIS. Discriminative abilities of models were compared by using the area under the receiver operating characteristic curve (AUC). RESULTS: HNG lesions exhibited larger mean maximum lesion size (P = .02) and lower mean CNR for images with b value of 600 sec/mm(2) (P = .004), allowing discrimination of HNG from non-HNG DCIS (AUC = 0.71 for maximum lesion size, AUC = 0.70 for CNR at b = 600 sec/mm(2)). Differences in CNR for images with b value of 0 sec/mm(2) (P = .025) without corresponding differences in ADC values were observed between HNG and non HNG lesions. Peak initial enhancement was the only kinetic variable to approach significance (P = .05). No differences in lesion morphology (P = .11) or worst curve delayed enhancement kinetics (P = .97) were observed. A multivariate model combining CNR for images with b value of 600 sec/mm(2) and maximum lesion size most significantly discriminated HNG from non-HNG (AUC = 0.81). CONCLUSION: The preliminary findings suggest that DCE and DW MR imaging features may aid in identifying patients with high-risk DCIS. Further study may yield a model combining MR characteristics with histopathologic data to facilitate lesion specific targeted therapies. (c) RSNA, 2012. PMID- 22517957 TI - Lymph node metastases from gastric cancer: gadofluorine M and gadopentetate dimeglumine MR imaging in a rabbit model. AB - PURPOSE: To compare the diagnostic performance of gadofluorine M with that of gadopentetate dimeglumine in the diagnosis of lymph node metastases with magnetic resonance (MR) imaging in a rabbit model of gastric cancer. MATERIALS AND METHODS: The study protocol was approved by the institutional animal care committee. VX2 carcinomas were inoculated into the wall of the stomach in 20 rabbits. Gadopentetate dimeglumine-enhanced MR imaging was performed 4-6 weeks after inoculation, and gadofluorine M-enhanced MR imaging was performed approximately 24 hours later. Both MR imaging sets were analyzed separately and independently by four radiologists with respect to confidence level regarding the presence of metastases in lymph nodes and lymph node conspicuity. Statistical analysis was performed by using multiple-reader multiple-case (MRMC) receiver operating characteristic curve analysis and the Wilcoxon signed rank test. RESULTS: Metastases were confirmed at pathologic analysis in 32 of 104 lymph nodes from 16 rabbits. The area under the receiver operating characteristic curve (AUC) for confidence regarding the presence of metastases in lymph nodes was significantly greater for gadofluorine M than for gadopentetate dimeglumine (AUC, 0.947 vs 0.894; P = .009). However, most (81%, 25 of 32) metastatic nodes were necrotic, and no significant difference was obtained in nonnecrotic nodes. For lymph node conspicuity, the gadofluorine M MR imaging set was assigned a significantly higher score than was the gadopentetate dimeglumine MR imaging set by all readers (P < .001). CONCLUSION: Gadofluorine M showed significantly higher accuracy and better conspicuity than gadopentetate dimeglumine in the diagnosis of metastatic nodes, most of which were necrotic, in this animal model of gastric cancer. PMID- 22517956 TI - Colonoscopy after CT diagnosis of diverticulitis to exclude colon cancer: a systematic literature review. AB - PURPOSE: To estimate the prevalence of underlying adenocarcinoma of the colon in patients in whom acute diverticulitis was diagnosed at computed tomography (CT) and to compare that to the prevalence of colon cancer in the general population. MATERIALS AND METHODS: A comprehensive literature review was performed to find articles in which patients with CT diagnosis of acute diverticulitis underwent surgery, colonoscopy, or barium enema study within 24 weeks. Patients meeting these criteria were included for analysis. A pooled prevalence of cancer was calculated on the basis of a random effects model and compared qualitatively with the prevalence of cancer in the general population. The 95% confidence intervals around the prevalence of cancer in the study populations were determined. RESULTS: Ten articles met the inclusion criteria. Data from these articles included only 771 patients who underwent surgery, colonoscopy, or barium enema study within 24 weeks of diagnosis. Fourteen patients were found to have colon cancer, for a prevalence of 2.1% (95% confidence interval: 1.2%, 3.2%). This compares to a calculated estimated prevalence of 0.68% among U.S. adults older than 55 years. CONCLUSION: There are limited data to support the recommendation to perform colonoscopy after a diagnosis of acute diverticulitis. PMID- 22517958 TI - Biliary complications after liver transplantation: addition of T1-weighted images to MR cholangiopancreatography facilitates detection of cast in biliary cast syndrome. AB - PURPOSE: To evaluate the diagnostic performance of T2-weighted magnetic resonance (MR) cholangiopancreatography pulse sequences in comparison with MR cholangiopancreatography sequences combined with nonenhanced T1-weighted images in the detection of biliary cast syndrome in liver transplant recipients. MATERIALS AND METHODS: This retrospective study was conducted in accordance with the declaration of Helsinki. Institutional review board approval was obtained. MR images in 95 patients who were examined after liver transplantation and who presented with symptoms of biliary obstruction were examined. Two separate sets of images, MR cholangiopancreatograms and MR cholangiopancreatograms plus T1 weighted images, were evaluated independently by three readers. Sensitivities, specificities, and positive and negative predictive values for biliary cast syndrome were calculated, and receiver operating characteristic curves were generated. The results of endoscopic retrograde cholangiopancreatography served as the reference standard. To determine interobserver agreement, kappa values were calculated. RESULTS: Cast appeared hyperintense on nonenhanced T1-weighted images. Sensitivities for T2-weighted MR cholangiopancreatography data alone were 0.65, 0.70, and 0.55 for the three readers. Adding unenhanced T1-weighted images resulted in sensitivities of 0.95, 0.90, and 0.90, respectively. Specificities for MR cholangiopancreatography alone and for MR cholangiopancreatography plus T1 weighted images were high on average (0.98, 0.97, and 0.97 vs 1.0 for all readers, respectively). Interobserver agreement was good for T2-weighted MR cholangiopancreatography (kappa for readers 1 and 2 = 0.589, kappa for readers 2 and 3 = 0.593, kappa for readers 1 and 3 = 0.734) and was excellent for MR cholangiopancreatography plus T1-weighted images (kappa for readers 1 and 2 = 0.806, kappa for readers 2 and 3 = 0.881, kappa for readers 1 and 3 = 0.848). CONCLUSION: The combination of T2-weighted MR cholangiopancreatography and T1 weighted imaging yields higher diagnostic performance than MR cholangiopancreatography alone. Therefore, readers evaluating liver MR images with regard to biliary complications after liver transplantation should also look at the bile ducts on unenhanced T1-weighted images, as biliary cast might be more easily depicted on these images. PMID- 22517959 TI - Preparative fasting for contrast-enhanced CT: reconsideration. AB - PURPOSE: To evaluate the evidence on the value of preparative fluid fasting for patients undergoing elective computed tomography (CT) with intravenous administration of contrast material and to survey leading institutions in a number of countries on their current policies in this regard. MATERIALS AND METHODS: This study qualified for exempt status by the institutional review board. First, 20 keyword combinations were entered into Medline to ascertain the correlation between fluid ingestion preceding contrast material-enhanced CT and development of aspiration pneumonia. The numbers of patients were summed up to estimate incidence of aspiration pneumonia attributable to ingestion of clear inert fluid before contrast-enhanced CT examination. Second, a multinational survey was conducted about the length of preparative fasting protocols, if any, for fluids and solids that they recommend to patients before elective non gastrointestinal contrast-enhanced CT. RESULTS: Aspiration was not noted in any of 2001 patients (13 studies in the literature) who underwent contrast-enhanced CT after fluid ingestion. Data were available from 69 (86.3%) of 80 institutions queried (17 Korean, 14 U.S., 11 French, 10 Australian, 10 German, and seven Egyptian hospitals). Two-thirds (14 of 21 [66.7%]) of the French and German hospitals had a no-restriction policy for both fluids and solids, while Australian hospitals had a policy liberal about fluids (no restrictions in eight of 10 [80%]) only. Policies on fluids were variable in Korea, the United States, and Egypt (restrictions of 0-8 hours, 0-4 hours, and 0-6 hours, respectively), as were policies on solids in Korea, the United States, Australia, and Egypt (restrictions of 0-8 hours, 0-6 hours, 0 to 4-6 hours, and 0 hours to overnight, respectively). The length of fasting was longer for solids than for fluids in 20 hospitals. CONCLUSION: There is little evidence that ingestion of clear inert fluid prior to contrast-enhanced CT is a cause of aspiration pneumonia; the length of fasting is variable in any country, being much longer in some hospitals than in others. PMID- 22517954 TI - Alzheimer disease: new concepts on its neurobiology and the clinical role imaging will play. AB - Alzheimer disease (AD) is one of, if not the most, feared diseases associated with aging. The prevalence of AD increases exponentially with age after 60 years. Increasing life expectancy coupled with the absence of any approved disease modifying therapies at present position AD as a dominant public health problem. Major advances have occurred in the development of disease biomarkers for AD in the past 2 decades. At present, the most well-developed AD biomarkers are the cerebrospinal fluid analytes amyloid-beta 42 and tau and the brain imaging measures amyloid positron emission tomography (PET), fluorodeoxyglucose PET, and magnetic resonance imaging. CSF and imaging biomarkers are incorporated into revised diagnostic guidelines for AD, which have recently been updated for the first time since their original formulation in 1984. Results of recent studies suggest the possibility of an ordered evolution of AD biomarker abnormalities that can be used to stage the typical 20-30-year course of the disease. When compared with biomarkers in other areas of medicine, however, the absence of standardized quantitative metrics for AD imaging biomarkers constitutes a major deficiency. Failure to move toward a standardized system of quantitative metrics has substantially limited potential diagnostic usefulness of imaging in AD. This presents an important opportunity that, if widely embraced, could greatly expand the application of imaging to improve clinical diagnosis and the quality and efficiency of clinical trials. PMID- 22517960 TI - Optical imaging of cancer heterogeneity with multispectral optoacoustic tomography. AB - PURPOSE: To investigate whether multispectral optoacoustic tomography (MSOT) can reveal the heterogeneous distributions of exogenous agents of interest and vascular characteristics through tumors of several millimeters in diameter in vivo. MATERIALS AND METHODS: Procedures involving animals were approved by the government of Upper Bavaria. Imaging of subcutaneous tumors in mice was performed by using an experimental MSOT setup that produces transverse images at 10 frames per second with an in-plane resolution of approximately 150 MUm. To study dynamic contrast enhancement, three mice with 4T1 tumors were imaged before and immediately, 20 minutes, 4 hours, and 24 hours after systemic injection of indocyanine green (ICG). Epifluorescence imaging was used for comparison. MSOT of a targeted fluorescent agent (6 hours after injection) and hemoglobin oxygenation was performed simultaneously (4T1 tumors: n = 3). Epifluorescence of cryosections served as validation. The accumulation owing to enhanced permeability and retention in tumors (4T1 tumors: n = 4, HT29 tumors: n = 3, A2780 tumors: n = 2) was evaluated with use of long-circulating gold nanorods (before and immediately, 1 hour, 5 hours, and 24 hours after injection). Dark-field microscopy was used for validation. RESULTS: Dynamic contrast enhancement with ICG was possible. MSOT, in contrast to epifluorescence imaging, showed a heterogeneous intratumoral agent distribution. Simultaneous imaging of a targeted fluorescent agent and oxy- and deoxyhemoglobin gave functional information about tumor vasculature in addition to the related agent uptake. The accumulation of gold nanorods in tumors seen at MSOT over time also showed heterogeneous uptake. CONCLUSION: MSOT enables live high-spatial-resolution observations through tumors, producing images of distributions of fluorochromes and nanoparticles as well as tumor vasculature. PMID- 22517962 TI - Radiation dose reduction with hybrid iterative reconstruction for pediatric CT. AB - PURPOSE: To assess image quality and radiation dose reduction with hybrid iterative reconstruction of pediatric chest and abdominal computed tomographic (CT) data compared with conventional filtered back projection (FBP). MATERIALS AND METHODS: A total of 234 patients (median age, 12 years; age range, 6 weeks to 18 years) underwent chest and abdominal CT in this institutional review board approved HIPAA-compliant retrospective study. CT was performed with a hybrid adaptive statistical iterative reconstruction (ASIR)-enabled 64-detector row CT scanner. Scanning protocols were adjusted for clinical indication and patient weight to enable acquisition of reduced-dose CT images in all patients, and tube current was further lowered for ASIR protocols. Weight, age, and sex were recorded, and objective noise was measured in the descending thoracic aorta for chest CT and in the liver for abdominal CT. Of the 234 consecutive patients who underwent ASIR-enabled CT (115 chest and 119 abdominal examinations), 70 patients had undergone prior FBP CT. ASIR and FBP CT studies (29 chest and 41 abdominal studies) in these 70 patients were reviewed for image quality, artifacts, and diagnostic confidence by two pediatric radiologists working independently. Data were analyzed with multiple paired t tests. RESULTS: Compared with FBP, ASIR enabled dose reduction of 46.4% (3.7 vs 6.9 mGy) for chest CT and 38.2% (5.0 vs 8.1 mGy) for abdominal CT (P < .0001). Both radiologists deemed image quality of and diagnostic confidence with ASIR and FBP CT images as acceptable, without any artifacts. Despite the lower radiation dose used, ASIR images (chest, 10.7 +/- 2.5 [mean +/- standard deviation]; abdomen, 11.8 +/- 3.4) had substantially less objective noise than did FBP images (chest, 13.3 +/- 3.8; abdomen, 13.8 +/- 5.2) (P = .001, P =.006, respectively). CONCLUSION: Use of a hybrid iterative reconstruction technique, such as ASIR, enables substantial radiation dose reduction for pediatric CT when compared with FBP and maintains image quality and diagnostic confidence. PMID- 22517961 TI - Longitudinal reproducibility and accuracy of pseudo-continuous arterial spin labeled perfusion MR imaging in typically developing children. AB - PURPOSE: To evaluate the longitudinal repeatability and accuracy of cerebral blood flow (CBF) measurements by using pseudo-continuous arterial spin-labeled (pCASL) perfusion magnetic resonance (MR) imaging in typically developing children. MATERIALS AND METHODS: Institutional review board approval with HIPAA compliance and informed consent were obtained. Twenty-two children aged 7-17 years underwent repeated pCASL examinations 2-4 weeks apart with a 3-T MR imager, along with in vivo blood T1 and arterial transit time measurements. Phase contrast (PC) MR imaging was performed as the reference standard for global blood flow volume. Intraclass correlation coefficient (ICC) and within-subject coefficient of variation (wsCV) were used to evaluate accuracy and repeatability. RESULTS: The accuracy of pCASL against the reference standard of PC MR imaging increased on incorporating subjectwise in vivo blood T1 measurement (ICC: 0.32 vs 0.58). The ICC further increased to 0.65 by using a population-based model of blood T1. Additionally, CBF measurements with use of pCASL demonstrated a moderate to good level of longitudinal repeatability in whole brain (ICC = 0.61, wsCV = 15%), in gray matter (ICC = 0.65, wsCV = 14%), and across 16 brain regions (mean ICC = 0.55, wsCV = 17%). The mean arterial transit time was 1538 msec +/- 123 (standard deviation) in the pediatric cohort studied, which showed an increasing trend with age (P = .043). CONCLUSION: Incorporating developmental changes in blood T1 is important for improving the accuracy of pCASL CBF measurements in children and adolescents; the noninvasive nature, accuracy, and longitudinal repeatability should facilitate the use of pCASL perfusion MR imaging in neurodevelopmental studies. PMID- 22517963 TI - Three-dimensional dual-phase whole-heart MR imaging: clinical implications for congenital heart disease. AB - PURPOSE: To identify which rest phase (systolic or diastolic) is optimum for assessing or measuring cardiac structures in the setting of three-dimensional (3D) whole-heart imaging in congenital heart disease (CHD). MATERIALS AND METHODS: The study was approved by the institutional review board; informed consent was obtained. Fifty children (26 male and 24 female patients) underwent 3D dual-phase whole-heart imaging. Cardiac structures were analyzed for contrast to-noise ratio (CNR) and image quality. Cross-sectional measurements were taken of the aortic arch, right ventricular (RV) outflow tract (RVOT) and pulmonary arteries. Normally distributed variables were compared by using paired t tests, and categorical data were compared by using Wilcoxon signed-rank test. RESULTS: Mean CNR and image quality were significantly (all P < .05) greater in systole for the right atrium (CNR, 8.9 vs 7.5; image quality, 438 vs 91), left atrium (CNR, 8.0 vs 5.3; image quality, 1006 vs 29), RV (CNR, 10.6 vs 8.2; image quality, 131 vs 23), LV (CNR, 9.4 vs 7.7; image quality, 125 vs 28), and pulmonary veins (CNR, 6.2 vs 4.9; image quality, 914 vs 32). Conversely, diastolic CNR was significantly higher in the aorta (9.2 vs 8.2; P = .013) and diastolic image quality was higher for the left pulmonary artery (238 vs 62; P = .007), right pulmonary artery (219 vs 35; P < .001), and for imaging of an area after an arterial stenosis (164 vs 7; P < .001). All aortic arch and RVOT cross sectional measurements were significantly (P < .05) greater in systole (narrowest point of arch, 70 vs 53 mm(2); descending aorta, 71 vs 58 mm(2); transverse arch, 293 vs 275 mm(2); valvar RVOT, 291 vs 268 mm(2); supravalvar RVOT, 337 vs 280 mm(2); prebifurcation RVOT, 329 vs 259 mm(2)). CONCLUSION: Certain structures in CHD are better imaged in systole and others in diastole, and therefore, the dual phase approach allows a higher overall success rate. This approach also allows depiction of diameter changes between systole and diastole and is therefore preferable to standard single-phase sequences for the planning of interventional procedures. PMID- 22517965 TI - Case 181: synovitis acne pustulosis hyperostosis osteitis (SAPHO) syndrome. PMID- 22517966 TI - Prudence in breast imaging. PMID- 22517967 TI - Incidental adrenal lesions. PMID- 22517968 TI - Choice of breast cancer screening examination. PMID- 22517969 TI - "Send three and fourpence...". PMID- 22517970 TI - Triangular cord sign in biliary atresia: does it have prognostic and medicolegal significance? PMID- 22517971 TI - Unusual glucuronides. AB - Glucuronidation reaction is catalyzed by mammalian uridine diphosphoglucuronosyl transferases by using uridine diphosphoglucuronic acid as a cosubstrate. Conjugation of glucuronic acid to nucleophilic functional groups in chemical entities results in formation of glucuronides. As anticipated, a number of nucleophilic functional groups such as hydroxyl, phenolic, acyl, primary secondary and tertiary amino, etc. in a diverse set of chemical compounds are known to form the corresponding glucuronides. Glucuronides have been reported to be formed at carbon atoms, selenium atoms, and upon N-carbamoylation of primary and secondary amino groups. Glucuronides are also believed to be the end products of metabolism. However, there are examples where glucuronidation results in further oxidative or conjugative biotransformation reactions. The objective of this review is to highlight unusual glucuronide conjugates. Diglucuronide conjugates reported in the literature fall under two distinct categories. Use of prefixes such as "bis" versus "di" has been previously proposed for separating the two types of diglucuronides. In spite of this, literature reports for diconjugative glucuronide metabolites reflect interchangeable use of "bisglucuronides" and "diglucuronides." Furthermore, the application of such prefixes does not adhere to recommendations of International Union of Pure and Applied Chemistry nomenclature for substituent groups. Therefore, an effort is made in this review to document the historic reports for diglucuronides into two distinct types for sake of clarity and to allow differentiation between the two types of diconjugative metabolites. Overall, this commentary centers on unusual glucuronide metabolites that result from conjugation at uncommon functional groups, glucuronides undergoing ensuing oxidative or conjugative metabolic transformations. Structural and mechanistic aspects are also discussed. PMID- 22517972 TI - Sequential metabolism of AMG 487, a novel CXCR3 antagonist, results in formation of quinone reactive metabolites that covalently modify CYP3A4 Cys239 and cause time-dependent inhibition of the enzyme. AB - CYP3A4-mediated biotransformation of (R)-N-(1-(3-(4-ethoxyphenyl)-4-oxo-3,4 dihydropyrido[2,3-d]pyrimidin-2-yl)ethyl)-N-(pyridin-3-ylmethyl)-2-(4 (trifluoromethoxy)phenyl)acetamide (AMG 487) was previously shown to generate an inhibitory metabolite linked to dose- and time-dependent pharmacokinetics in humans. Although in vitro activity loss assays failed to demonstrate CYP3A4 time dependent inhibition (TDI) with AMG 487, its M2 phenol metabolite readily produced TDI when remaining activity was assessed using either midazolam or testosterone (K(I) = 0.73-0.74 MUM, k(inact) = 0.088-0.099 min(-1)). TDI investigations using an IC(50) shift method successfully produced inhibition attributable to AMG 487, but only when preincubations were extended from 30 to 90 min. The shift magnitude was ~3* for midazolam activity, but no shift was observed for testosterone activity. Subsequent partition ratio determinations conducted for M2 using recombinant CYP3A4 showed that inactivation was a relatively inefficient process (r = 36). CYP3A4-mediated biotransformation of [(3)H]M2 in the presence of GSH led to identification of two new metabolites, M4 and M5, which shifted focus away from M2 being directly responsible for TDI. M4 (hydroxylated M2) was further metabolized to form reactive intermediates that, upon reaction with GSH, produced isomeric adducts, collectively designated M5. Incubations conducted in the presence of [(18)O]H(2)O confirmed incorporation of oxygen from O(2) for the majority of M4 and M5 formed (>75%). Further evidence of a primary role for M4 in CYP3A4 TDI was generated by protein labeling and proteolysis experiments, in which M4 was found to be covalently bound to Cys239 of CYP3A4. These investigations confirmed a primarily role for M4 in CYP3A4 inactivation, suggesting that a more complex metabolic pathway was responsible for generation of inhibitory metabolites affecting AMG 487 human pharmacokinetics. PMID- 22517973 TI - Call for government to cut bowel cancer deaths by 60% in the next 13 years. PMID- 22517974 TI - Development secretary says UK contribution to Global Fund depends on fund making progress on its reforms. PMID- 22517975 TI - Bevacizumab as adjuvant therapy for lung cancer does not help patients over 65. PMID- 22517976 TI - Disputes over payments for short stay patients are wasting NHS time, says watchdog. PMID- 22517977 TI - Scottish health board could face criminal charges over missing critical incident reports. PMID- 22517978 TI - Judges grill Big Tobacco's challenge to Australia's law on plain tobacco packaging. PMID- 22517979 TI - On the safety of persons accompanying nuclear medicine patients. AB - The presence of caretakers/comforters during nuclear medicine examinations is relatively common. These caretakers receive higher doses than the general public, who receive only environmental/background exposure. The aim of this research was to know about the doses received by two significant groups of caretakers: comforters of cancer patients (Group I) and mothers of small children (Group II). The patients were scheduled to undergo two different diagnostic studies: Inmuno Scintigraphy using a monoclonal antibody bound to (99m)Tc (for adults) and Renal Scintigraphy using (99m)Tc-dimercaptosuccinic acid (for children). The average effective doses were 0.27 and 0.29 mSv for Groups I and II, respectively. Additionally, environmental monitoring was performed in the waiting room for injected patients (Room I) and inside the procedure room (Room II). Equivalent environmental doses of 0.28 and 0.24 mSv for Rooms 1 and II, respectively, were found, which are similar to values reported by other authors. PMID- 22517980 TI - Inhaled hypertonic saline in adults hospitalised for exacerbation of cystic fibrosis lung disease: a retrospective study. AB - BACKGROUND: Inhaled hypertonic saline (HTS) improves quality of life and reduces pulmonary exacerbations when given long term in patients with cystic fibrosis (CF). While increasingly being offered for acute pulmonary exacerbations, little is known about the efficacy in this setting. OBJECTIVES: The authors examined the tolerability and efficacy of HTS use among adult subjects hospitalised with a CF pulmonary exacerbation and hypothesised that use of HTS would improve pulmonary function during the admission. DESIGN: Pilot retrospective non-randomised study. SETTING: Single tertiary care centre. PARTICIPANTS: 45 subjects admitted to the inpatient service for acute CF pulmonary exacerbation in 2006-2007. A subset of 18 subjects who were also admitted in 2005 when HTS was not available was included in the comparative study. PRIMARY OUTCOME: Change in forced expiratory volume in one second from admission to discharge. SECONDARY OUTCOMES: Change in weight from admission to discharge and time to next exacerbation. RESULTS: Mean age was 32.5 years, and mean length of stay was 11.5 days. HTS was offered to 33 subjects and was well tolerated for a total use of 336 days out of 364 days of hospital stay. Baseline demographics, lung function and sputum culture results were comparable in first and second visits. Use of HTS was not associated with an improvement in forced expiratory volume in one second (p=0.1), weight gain (p=0.24) or in the time to next admission (p=0.08). CONCLUSIONS: These pilot data suggest that HTS is well tolerated during CF pulmonary exacerbation but offers no clear outcome benefits. It is possible that HTS may not have much advantage above and beyond intensive rehabilitation and intravenous antibiotics and may add to hospital costs and treatment burden. PMID- 22517981 TI - Knowledge about epilepsy among health professionals: a cross-sectional survey in Sao Paulo, Brazil. AB - OBJECTIVE: To evaluate the epilepsy knowledge among health professionals in Sao Paulo, Brazil. DESIGN: This is a cross-sectional study. PARTICIPANTS: Professionals with academic degrees in physical education (n=134), nutrition (n=116), medicine (n=100), psychology (n=53), nursing (n=122) and physiotherapy (n=99) who lived in Sao Paulo City, Brazil. PRIMARY AND SECONDARY OUTCOME MEASURES: Knowledge of health professionals about epilepsy. METHODS: Professionals with academic degrees in physical education (n=134), nutrition (n=116), medicine (n=100), psychology (n=53), nursing (n=122) and physiotherapy (n=99) who lived in Sao Paulo City, Brazil, were invited to participate in the study. The subjects (n=624) answered a questionnaire composed of 25 simple closed ended questions from three areas: personal, educational and knowledge. RESULTS: Out of all subjects, 88.5% (n=552) had a postgraduate education, while 11.5% (n=72) had only an undergraduate degree. The authors found that physical educators, nutritionists and physiotherapists received lower scores on their epilepsy knowledge than other health professionals. CONCLUSIONS: Health professionals are considered better-educated group inside the society, especially with regards to healthcare issues. Thus, it is important they also have an accurate and correct knowledge about epilepsy. The findings of the present study indicate an imperative improvement in education about epilepsy, as well as an inclusion of formal programmes for epilepsy education especially for non-medical professionals. An improvement in epilepsy education might contribute to an improvement in epilepsy care and management. PMID- 22517982 TI - Management of isolated non-traumatic renal artery dissection: report of four cases. AB - BACKGROUND: Isolated non-traumatic renal artery dissection (RAD) is a rare disorder with uncertain natural history. The management may be surgical reconstruction, endovascular repair, or conservative medical treatment, yet no official consensus had been established. PURPOSE: To report the management of four cases of isolated non-traumatic RAD, emphasizing the beneficial role of conservative medical treatment. MATERIAL AND METHODS: From the year 2000 till 2011, four male patients with mean age of 42.5 years (range 34-48 years) presented with isolated non-traumatic RAD and were initially treated with medical therapy. Transcatheter in situ thrombolysis was performed in a case with thrombotic occlusion. RESULTS: Isolated non-traumatic RAD in four patients involving at least seven branches progressed to thrombotic occlusion in two branches, luminal narrowing in five, dual lumens in two, and aneurysmal dilatation in three. Medical treatment was efficacious in three patients, who showed persistent preserved renal function, controlled blood pressure, and favorable arterial remodeling. After failure of medical therapy, the fourth patient was referred to surgery. Thrombolysis was successful to dissolute an occluding thrombotic dissection. CONCLUSION: Conservative therapy is safe and effective when the renal artery is patent and blood pressure is controlled: we propose it as the first line of treatment, reserving interventional management for refractory cases. PMID- 22517983 TI - Ultra-low dose dual-source high-pitch computed tomography of the paranasal sinus: diagnostic sensitivity and radiation dose. AB - BACKGROUND: Today's gold standard for diagnostic imaging of inflammatory diseases of the paranasal sinus is computed tomography (CT). PURPOSE: To evaluate diagnostic sensitivity and radiation dose of an ultra-low dose dual-source CT technique. MATERIAL AND METHODS: Paranasal sinuses of 14 cadaveric heads were independently evaluated by two readers using a modern dual-source CT with lowest reasonable dosage in high-pitch mode (100 kV, 10 mAs, collimation 0.6 mm, pitch value 3.0). Additionally the head part of an anthropomorphic Alderson-Rando phantom was equipped with thermoluminiscent detectors to measure radiation exposure to the eye lenses and thyroid gland. RESULTS: Diagnostic accuracy regarding sinusoidal fluid, nasal septum deviation, and mucosal swelling was 100%. Mastoid fluid was detected in 76% and 92%, respectively. In the phantom study, average measured eye lens dosage was 0.64 mGy; radiation exposure of the thyroid gland was 0.085 mGy. CONCLUSION: Regarding evaluation of inflammatory diseases of the paranasal sinus this study indicates sufficient accuracy of the proposed CT protocol at a very low dosage level. PMID- 22517984 TI - Tie2-dependent knockout of alpha6 integrin subunit in mice reduces post-ischaemic angiogenesis. AB - AIMS: Integrins alpha6beta1 and alpha6beta4 are receptors for laminins, the main components of the basement membrane underlying the endothelial cells. In vitro, alpha6 integrin subunit (alpha6) expression at the surface of endothelial cells and their progenitors (EPCs) is up-regulated by pro-angiogenic growth factors and is crucial for adhesion, migration, and pseudotube formation. We investigated the role for alpha6 in post-ischaemic vascular repair in vivo. METHODS AND RESULTS: We used the cre-lox system to generate a mouse line with specific alpha6 gene deletion in Tie2-lineage cells. In a model of hind-limb ischaemia, Tie2-dependent alpha6 deletion reduced neovessel formation and reperfusion of the ischaemic limb. Concerning the role for alpha6 in post-ischaemic vasculogenesis, we showed previously that alpha6 was required for EPC recruitment at the site of ischaemia. Here, we found that alpha6 deletion also reduced EPC mobilization from the bone marrow after ischaemia. Examination of the ischaemic muscles showed that Tie2 dependent alpha6 deletion decreased the recruitment of pro-angiogenic Tie2 expressing macrophages. In the Matrigel plug assay, fibroblast growth factor-2 induced vascularization was diminished in mice lacking endothelial alpha6. To specifically investigate the role for alpha6 in angiogenesis, aortic rings were embedded in Matrigel or collagen and cultured ex vivo. In Matrigel, neovessel outgrowth from rings lacking alpha6 was strongly diminished, whereas no genotype dependent difference occurred for rings in collagen. CONCLUSION: alpha6 plays a major role in both post-ischaemic angiogenesis and vasculogenesis. PMID- 22517985 TI - Macrophages: cancer therapy's double-edged sword. PMID- 22517986 TI - The promise of protons in cancer therapy. PMID- 22517987 TI - Physician Data Query (PDQ(R)) update. PMID- 22517989 TI - Getting it right: BPA and the difficulty proving environmental cancer risks. PMID- 22517991 TI - Electroencephalogram-based anaesthetic depth monitoring in laboratory animals. AB - Objective measurements of physiological parameters controlled by the autonomic nervous system such as blood pressure, heart rate and respiration are easily obtained nowadays during anaesthesia by the use of monitors: oscillometers, pulseoximeters, electrocardiograms and capnographs are available for laboratory animals. However, the effect-site of hypnotic drugs that cause general anaesthesia is the central nervous system (the brain). In the present, the adjustment of hypnotic drugs in veterinary anaesthesia is performed according to subjective evaluation of clinical signs which are not direct reflexes of anaesthetic effects on the brain, making depth of anaesthesia (DoA) assessment a complicated task. The difficulties in assessing the real anaesthetic state of a laboratory animal may not only result in welfare-threatening situations, such as awareness and pain sensation during surgery, but also in a lack of standardization of experimental conditions, as it is not easy to keep all animals from an experiment in the same DoA without a measure of anaesthetic effect. A direct measure of this dose-effect relationship, although highly necessary, is still missing in the veterinary market. Meanwhile, research has been intense in this subject and methods based on the brain electrical activity (electroencephalogram) have been explored in laboratory animal species. The objective of this review is to explain the achievements made in this topic and clarify how far we are from an objective measure of DoA for animals. PMID- 22517990 TI - Staging and functional characterization of pheochromocytoma and paraganglioma by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography. AB - BACKGROUND: Pheochromocytomas and paragangliomas (PPGLs) are rare tumors of the adrenal medulla and extra-adrenal sympathetic chromaffin tissues; their anatomical and functional imaging are critical to guiding treatment decisions. This study aimed to compare the sensitivity and specificity of (18)F fluorodeoxyglucose positron emission tomography with computed tomography ((18)F FDG PET/CT) for tumor localization and staging of PPGLs with that of conventional imaging by [(123)I]-metaiodobenzylguanidine single photon emission CT ((123)I MIBG SPECT), CT, and magnetic resonance imaging (MRI). METHODS: A total of 216 patients (106 men, 110 women, aged 45.2 +/- 14.9 years) with suspected PPGL underwent CT or MRI, (18)F-FDG PET/CT, and (123)I-MIBG SPECT/CT. Sensitivity and specificity were measured as endpoints and compared by the McNemar test, using two-sided P values only. RESULTS: Sixty (28%) of patients had nonmetastatic PPGL, 95 (44%) had metastatic PPGL, and 61 (28%) were PPGL negative. For nonmetastatic tumors, the sensitivity of (18)F-FDG was similar to that of (123)I-MIBG but less than that of CT/MRI (sensitivity of (18)F-FDG = 76.8%; of (123)I-MIBG = 75.0%; of CT/MRI = 95.7%; (18)F-FDG vs (123)I-MIBG: difference = 1.8%, 95% confidence interval [CI] = -14.8% to 14.8%, P = .210; (18)F-FDG vs CT/MRI: difference = 18.9%, 95% CI = 9.4% to 28.3%, P < .001). The specificity was 90.2% for (18)F FDG, 91.8% for (123)I-MIBG, and 90.2% for CT/MRI. (18)F-FDG uptake was higher in succinate dehydrogenase complex- and von Hippel-Lindau syndrome-related tumors than in multiple endocrine neoplasia type 2 (MEN2) related tumors. For metastases, sensitivity was greater for (18)F-FDG and CT/MRI than for (123)I-MIBG (sensitivity of (18)F-FDG = 82.5%; of (123)I-MIBG = 50.0%; of CT/MRI = 74.4%; (18)F-FDG vs (123)I-MIBG: difference = 32.5%, 95% CI = 22.3% to 42.5%, P < .001; CT/MRI vs (123)I-MIBG: difference = 24.4%, 95% CI = 11.3% to 31.6%, P < .001). For bone metastases, (18)F-FDG was more sensitive than CT/MRI (sensitivity of (18)F-FDG = 93.7%; of CT/MRI = 76.7%; difference = 17.0%, 95% CI = 4.9% to 28.5%, P = .013). CONCLUSIONS: Compared with (123)I-MIBG SPECT and CT/MRI, both considered gold standards for PPGL imaging, metastases were better detected by (18)F-FDG PET. (18)F-FDG PET provides a high specificity in patients with a biochemically established diagnosis of PPGL. PMID- 22517992 TI - Anatomical description and morphometry of the skeleton of the common marmoset (Callithrix jacchus). AB - Callithrix jacchus (common marmoset) is regularly used in biomedical research, including for studies involving the skeleton. To support these studies, skeletons of healthy animals that had been euthanized for reasons not interfering with skeletal anatomy were prepared. The marmoset dental formula 2I-1C-3P-2M of each oral quadrant is atypical for New World monkeys which commonly possess a third molar. Seven cervical, 12-13 thoracic, 7-6 lumbar, 2-3 sacral and 26-29 caudal vertebrae are present, the thoracolumbar region always comprising 19 vertebrae. A sigmoid clavicle connects the scapula with the manubrium of the sternum. Depending on the number of thoracic vertebrae, 4-5 sternebrae are located between the manubrium and xiphoid process. Wide interosseous spaces separate the radius from the ulna, and the tibia from the fibula. A small sesamoid bone is inserted in the m. abductor digiti primi longus at the medial border of the carpus, a pair of ovoid sesamoid bones is located at the palmar/plantar sides of the trochleae of each metapodial bone, and round fabellae articulate with the proximal surfaces of the femoral condyles. Male marmosets possess a small penile bone. Both the front and hind feet have five digits. The hallux possesses a flat nail, whereas all other digits present curved claws. Interestingly, a central bone is present in both the carpus and tarsus. This study provides a description and detailed illustrations of the skeleton of the common marmoset as an anatomical guide for further biomedical research. PMID- 22517993 TI - Editorial ethical guidelines: what about the evaluation of the benefits to humans? PMID- 22517994 TI - Questionnaire surveys of dentists on radiology. AB - OBJECTIVES: Survey by questionnaire is a widely used research method in dental radiology. A major concern in reviews of questionnaires is non-response. The objectives of this study were to review questionnaire studies in dental radiology with regard to potential survey errors and to develop recommendations to assist future researchers. METHODS: A literature search with the software search package PubMed was used to obtain internet-based access to Medline through the website www.ncbi.nlm.nih.gov/pubmed. A search of the English language peer-reviewed literature was conducted of all published studies, with no restriction on date. The search strategy found articles with dates from 1983 to 2010. The medical subject heading terms used were "questionnaire", "dental radiology" and "dental radiography". The reference sections of articles retrieved by this method were hand-searched in order to identify further relevant papers. Reviews, commentaries and relevant studies from the wider literature were also included. RESULTS: 53 questionnaire studies were identified in the dental literature that concerned dental radiography and included a report of response rate. These were all published between 1983 and 2010. In total, 87 articles are referred to in this review, including the 53 dental radiology studies. Other cited articles include reviews, commentaries and examples of studies outside dental radiology where they are germane to the arguments presented. CONCLUSIONS: Non-response is only one of four broad areas of error to which questionnaire surveys are subject. This review considers coverage, sampling and measurement, as well as non-response. Recommendations are made to assist future research that uses questionnaire surveys. PMID- 22517995 TI - Three-dimensional segmentation of the upper airway using cone beam CT: a systematic review. AB - The objectives of this study were to systematically review the literature for studies that used cone beam CT (CBCT) to automatically or semi-automatically model the upper airway (including the pharyngeal, nasal and paranasal airways), and to assess their validity and reliability. Several electronic databases (MEDLINE(r), MEDLINE In-Process & Other Non-Indexed Citations, all evidence-based medicine reviews including the Cochrane database, and Scopus) were searched. Abstracts that appeared to meet the initial selection criteria were selected by consensus. The original articles were then retrieved and their references were searched manually for potentially suitable articles that were missed during the electronic search. Final articles that met all the selection criteria were evaluated using a customized evaluation checklist. 16 articles were finally selected. From these, five scored more than 50% based on their methodology. Although eight articles reported the reliability of the airway model generated, only three used intraclass correlation (ICC). Two articles tested the accuracy/validity of airway models against the gold standard, manual segmentation, using volumetric measurements; however, neither used ICC. Only three articles properly tested the reliability of the three-dimensional (3D) upper airway model generated from CBCT and only one article had sufficiently sound methodology to test the airway model's accuracy/validity. The literature lacks proper scientific justification of a solid and optimized CBCT protocol for airway imaging. Owing to the limited number of adequate studies, it is difficult to generate a strong conclusion regarding the current validity and reliability of CBCT-generated 3D models. PMID- 22517996 TI - Foramen tympanicum or foramen of Huschke: anatomical cone beam CT study. AB - OBJECTIVE: The foramen of Huschke (foramen tympanicum) represents a developmental defect in the antero-inferior aspect of the bony external auditory meatus. The foramen is located at the antero-inferior aspect of the external auditory canal, posteromedial to the temporomandibular joint. The aim of this study is to define the prevalence and location of the foramen of Huschke. METHODS: We retrospectively examined 207 cone beam CT (CBCT) studies (414 ears). We used flat panel detector (FPD)-based CBCT (New Tom FP; Quantitative Radiology, Verona, Italy) for imaging in our department. We noted the location of the foramen tympanicum and calculated its prevalence as a percentage. RESULTS: We found a foramen tympanicum in 37 (17.9%) of 207 patients. This was unilateral in 24 patients (11.6%) and bilateral in 13 patients (6.3%). Mean axial diameter was 5 mm and mean sagittal diameter was 2 mm. CONCLUSION: The foramen tympanicum is an uncommon disorder and is well demonstrated on CBCT. This is the first study to detect the foramen tympanicum using FPD-based CBCT. PMID- 22517997 TI - Clinical and MRI investigation of temporomandibular joint in major depressed patients. AB - OBJECTIVE: The aim of the present study was to describe the clinical and MRI findings of the temporomandibular joint (TMJ) in patients with major depressive disorders (MDDs) of the non-psychotic type. METHODS: 40 patients (80 TMJs) who were diagnosed as having MDDs were selected for this study. The clinical examination of the TMJs was conducted according to the research diagnostic criteria and temporomandibular disorders (TMDs). The MRIs were obtained bilaterally in each patient with axial, parasagittal and paracoronal sections within a real-time dynamic sequence. Two trained oral radiologists assessed all images. For statistical analyses, Fisher's exact test and chi(2) test were applied (alpha = 0.05). RESULTS: Migraine was reported in 52.5% of subjects. Considering disc position, statistically significant differences between opening patterns with and without alteration (p = 0.00) and between present and absent joint noises (p = 0.00) were found. Regarding muscular pain, patients with and without abnormalities in disc function and patients with and without abnormalities in disc position were not statistically significant (p = 0.42 and p = 0.40, respectively). Significant differences between mandibular pathway with and without abnormalities (p = 0.00) and between present and absent joint noises (p = 0.00) were observed. CONCLUSION: Based on the preliminary results observed by clinical and MRI examination of the TMJ, no direct relationship could be determined between MDDs and TMDs. PMID- 22517998 TI - Patient discomfort in bitewing examination with film and four digital receptors. AB - The aim was to compare patient discomfort during bitewing examination using five intra-oral receptors: a conventional film, a storage phosphor plate with a new soft cover, an already manufactured and sold sensor with a wire and two square and two rounded corners, a new version of a previously developed sensor with a wire and four square corners, and a newly developed sensor with a wire and four rounded corners. 60 patients participated in the study. The five receptors [a Kodak paper pack film (Eastman Kodak Company, Rochester, NY), a DIGORA(r) Optime phosphor plate (Soredex, Tuusula, Finland), and SuniRay (Suni Medical Imaging, Inc., San Jose, CA), DIGORA Toto (Soredex) and Snapshot (Instrumentarium Dental, Tuusula, Finland) complementary metal-oxide-semiconductors] with differences in ergonomic shape were placed in the mouth for a bitewing examination for approximately 10 s. The patients rated their discomfort on a 100 mm visual analogue scale after having had each receptor positioned. There was no significant difference in patient discomfort score between the conventional film and the Snapshot sensor (p > 0.05). Both conventional film and Snapshot were significantly less uncomfortable than the other receptors (p < 0.05). No significant difference was seen between the storage phosphor plate and the SuniRay sensor (p > 0.05). The storage phosphor plate was significantly less uncomfortable than the DIGORA Toto sensor (p < 0.05). There was no significant difference in the perception of discomfort between the conventional film and an ergonomically shaped wired sensor with rounded corners. PMID- 22517999 TI - Sinonasal cavernous haemangioma: a case report. AB - Cavernous haemangiomas arising in the paranasal sinuses are very rare. Even though the lesion is benign in nature, its imaging features are non-specific, leading to an incorrect pre-operative diagnosis in most patients. We present a case of a maxillary sinus cavernous haemangioma in a young male. The clinical presentation and imaging characteristics of this entity are reviewed. PMID- 22518000 TI - A case of cystadenocarcinoma of the ectopic salivary gland: comparison of pre operative ultrasound, CT and MR images with the pathological specimen. AB - Cystadenocarcinoma is a rare salivary gland tumour. Only a few case studies have provided pre-operative images of these tumours. This report demonstrates the case of a 28-year-old male with cystadenocarcinoma arising from an ectopic salivary gland with lymph node metastasis in the right upper neck. Ultrasound including Doppler images showed two masses with scant vascular flow. One was a hyperechoic mass enclosed within a low echoic cystic lesion and the other was a solid hypoechoic mass. Contrast enhancement CT scans demonstrated a ring enhanced mass and weakly homogeneous enhanced masses in the right upper neck. Dynamic studies showed increased enhancement in delayed phase CT that was the same as that in other malignant salivary gland tumours. Moderate to slightly high signal intensity was seen on T(1) weighted MR images and axial T(2) weighted MR images showed one heterogeneous mass in a high signal lesion and a moderate to high signal intensity mass. The authors discuss the pre-operative findings of ultrasound with Doppler imaging of this neoplasm, and CT findings including dynamic study images and MRI, comparing the findings with the post-operative pathological features of the tumour. PMID- 22518001 TI - Mutation conferring apical-targeting motif on AE1 exchanger causes autosomal dominant distal RTA. AB - Mutations in SLC4A1 that mislocalize its product, the chloride/bicarbonate exchanger AE1, away from its normal position on the basolateral membrane of the alpha-intercalated cell cause autosomal dominant distal renal tubular acidosis (dRTA). We studied a family exhibiting dominant inheritance and defined a mutation (AE1-M909T) that affects the C terminus of AE1, a region rich in potential targeting motifs that are incompletely characterized. Expression of AE1 M909T in Xenopus oocytes confirmed preservation of its anion exchange function. Wild-type GFP-tagged AE1 localized to the basolateral membrane of polarized MDCK cells, but AE1-M909T localized to both the apical and basolateral membranes. Wild type AE1 trafficked directly to the basolateral membrane without apical passage, whereas AE1-M909T trafficked to both cell surfaces, implying the gain of an apical-targeting signal. We found that AE1-M909T acquired class 1 PDZ ligand activity that the wild type did not possess. In summary, the AE1-M909T mutation illustrates the role of abnormal targeting in dRTA and provides insight into C terminal motifs that govern normal trafficking of AE1. PMID- 22518002 TI - Validation of reported predialysis nephrology care of older patients initiating dialysis. AB - The Centers for Medicare and Medicaid Services (CMS) Medical Evidence Report (form CMS-2728) queries providers about the timing of the patient's first nephrologist consultation before initiation of dialysis. The monitoring of disease-specific goals in the Healthy People 2020 initiative will use information from this question, but the accuracy of the reported information is unknown. We defined a cohort of 80,509 patients aged >=67 years who initiated dialysis between July 2005 and December 2008 with >=2 years of uninterrupted Medicare coverage as their primary payer. The primary referent, determined from claims data, was the first observed outpatient nephrologist consultation; secondary analyses used the earliest nephrology consultation, whether inpatient or outpatient. We used linear regression models to assess the associations among the magnitude of discrepant reporting and patient characteristics and we tested for any temporal trends. When using the earliest recorded outpatient nephrology encounter, agreement between the two sources of ascertainment was 48.2%, and the kappa statistic was 0.29 when we categorized the timing of the visit into four periods (never, <6, 6-12, and >12 months). When we dichotomized the timing of first predialysis nephrology care at >12 or <=12 months, accuracy was 70% (kappa=0.36), but it differed by patient characteristics and declined over time. In conclusion, we found substantial disagreement between information from the CMS Medical Evidence Report and Medicare physician claims on the timing of first predialysis nephrologist care. More-specific instructions may improve reporting and increase the utility of form CMS-2728 for research and public health surveillance. PMID- 22518003 TI - Protein kinase G inhibits flow-induced Ca2+ entry into collecting duct cells. AB - The renal cortical collecting duct (CCD) contributes to the maintenance of K(+) homeostasis by modulating renal K(+) secretion. Cytosolic Ca(2+) ([Ca(2+)](i)) mediates flow-induced K(+) secretion in the CCD, but the mechanisms regulating flow-induced Ca(2+) entry into renal epithelial cells are not well understood. Here, we found that atrial natriuretic peptide, nitric oxide, and cyclic guanosine monophosphate (cGMP) act through protein kinase G (PKG) to inhibit flow induced increases in [Ca(2+)](i) in M1-CCD cells. Coimmunoprecipitation, double immunostaining, and functional studies identified heteromeric TRPV4-P2 channels as the mediators of flow-induced Ca(2+) entry into M1-CCD cells and HEK293 cells that were coexpressed with both TRPV4 and TRPP2. In these HEK293 cells, introducing point mutations at two putative PKG phosphorylation sites on TRPP2 abolished the ability of cGMP to inhibit flow-induced Ca(2+) entry. In addition, treating M1-CCD cells with fusion peptides that compete with the endogenous PKG phosphorylation sites on TRPP2 also abolished the cGMP-mediated inhibition of the flow-induced Ca(2+) entry. Taken together, these data suggest that heteromeric TRPV4-P2 channels mediate the flow-induced entry of Ca(2+) into collecting duct cells. Furthermore, substances such as atrial natriuretic peptide and nitric oxide, which increase cGMP, abrogate flow-induced Ca(2+) entry through PKG mediated inhibition of these channels. PMID- 22518004 TI - Liver angiotensinogen is the primary source of renal angiotensin II. AB - Angiotensin II content in the kidney is much higher than in the plasma, and it increases more in kidney diseases through an uncertain mechanism. Because the kidney abundantly expresses angiotensinogen mRNA, transcriptional dysregulation of angiotensinogen within the kidney is one potential cause of increased renal angiotensin II in the setting of disease. Here, we observed that kidney-specific angiotensinogen knockout mice had levels of renal angiotensinogen protein and angiotensin II that were similar to those levels of control mice. In contrast, liver-specific knockout of angiotensinogen nearly abolished plasma and renal angiotensinogen protein and renal tissue angiotensin II. Immunohistochemical analysis in mosaic proximal tubules of megalin knockout mice revealed that angiotensinogen protein was incorporated selectively in megalin-intact cells of the proximal tubule, indicating that the proximal tubule reabsorbs filtered angiotensinogen through megalin. Disruption of the filtration barrier in a transgenic mouse model of podocyte-selective injury increased renal angiotensin II content and markedly increased both tubular and urinary angiotensinogen protein without an increase in renal renin activity, supporting the dependency of renal angiotensin II generation on filtered angiotensinogen. Taken together, these data suggest that liver-derived angiotensinogen is the primary source of renal angiotensinogen protein and angiotensin II. Furthermore, an abnormal increase in the permeability of the glomerular capillary wall to angiotensinogen, which characterizes proteinuric kidney diseases, enhances the synthesis of renal angiotensin II. PMID- 22518005 TI - Kidney injury accelerates cystogenesis via pathways modulated by heme oxygenase and complement. AB - AKI accelerates cystogenesis. Because cystogenic mutations induce strong transcriptional responses similar to those seen after AKI, these responses may accelerate the progression of cystic renal disease. Here, we modulated the severity of the AKI-like response in Cys1(cpk/cpk) mice, a model that mimics autosomal recessive polycystic kidney disease. Specifically, we induced or inhibited activity of the renoprotective enzyme heme oxygenase (HO) and determined the effects on renal cystogenesis. We found that induction of HO attenuated both renal injury and the rate of cystogenesis, whereas inhibition of HO promoted cystogenesis. HO activity mediated the response of NFkappaB, which is a hallmark transcriptional feature common to both cystogenesis and AKI. Among the HO-modulated effects we measured, expression of complement component 3 (C3) strongly correlated with cystogenesis, a functionally relevant association as suggested by Cys1(cpk/cpk) mice with genetically induced C3 deficiency. Because both C3 deficiency and HO induction reduce cyst number and cyst areas, these two factors define an injury-stimulated cystogenic pathway that may provide therapeutic targets to slow the formation of new renal cysts and the growth of existing cysts. PMID- 22518006 TI - Podocyte-specific loss of Cdc42 leads to congenital nephropathy. AB - Rho family GTPases are molecular switches best known for their pivotal role in dynamic regulation of the actin cytoskeleton. The prototypic members of this family are Cdc42, Rac1, and RhoA; these GTPases contribute to the breakdown of glomerular filtration and the resultant proteinuria, but their functions in normal podocyte physiology remain poorly understood. Here, mice lacking Cdc42 in podocytes developed congenital nephropathy and died as a result of renal failure within 2 weeks after birth. In contrast, mice lacking Rac1 or RhoA in podocytes were overtly normal and lived to adulthood. Kidneys from Cdc42-mutant mice exhibited protein-filled microcysts with hallmarks of collapsing glomerulopathy, as well as extensive effacement of podocyte foot processes with abnormal junctional complexes. Furthermore, we observed aberrant expression of several podocyte markers and cell polarity proteins in the absence of Cdc42, indicating a disruption of the slit diaphragm. Kidneys from Rac1- and RhoA-mutant mice, however, had normal glomerular morphology and intact foot processes. A nephrin clustering assay suggested that Cdc42 deficiency, but not Rac1 or RhoA deficiency, impairs the polymerization of actin at sites of nephrin aggregates. Taken together, these data highlight the physiological importance of Cdc42, but not Rac1 or RhoA, in establishing podocyte architecture and glomerular function. PMID- 22518007 TI - External light conditions and internal cell cycle phases coordinate accumulation of chloroplast and mitochondrial transcripts in the red alga Cyanidioschyzon merolae. AB - The mitochondria and chloroplasts in plant cells are originated from bacterial endosymbioses, and they still replicate their own genome and divide in a similar manner as their ancestors did. It is thus likely that the organelle transcription is coordinated with its proliferation cycle. However, this possibility has not extensively been explored to date, because in most plant cells there are many mitochondria and chloroplasts that proliferate asynchronously. It is generally believed that the gene transfer from the organellar to nuclear genome has enabled nuclear control of the organelle functions during the evolution of eukaryotic plant cells. Nevertheless, no significant relationship has been reported between the organelle transcriptome and the host cell cycle even in Chlamydomonas reinhardtii. While the organelle proliferation cycle is not coordinated with the cell cycle in vascular plants, in the unicellular red alga Cyanidioschyzon merolae that contains only one mitochondrion, one chloroplast, and one nucleus per cell, each of the organelles is known to proliferate at a specific phase of the cell cycle. Here, we show that the expression of most of the organelle genes is highly coordinated with the cell cycle phases as well as with light regimes in clustering analyses. In addition, a strong correlation was observed between the gene expression profiles in the mitochondrion and chloroplast, resulting in the identification of a network of functionally related genes that are co-expressed during organelle proliferation. PMID- 22518008 TI - Comparative evaluation of two hemagglutinating encephalomyelitis coronavirus vaccine candidates in mice. AB - Porcine hemagglutinating encephalomyelitis (PHE) is caused by the coronavirus hemagglutinating encephalomyelitis virus (PHE-CoV), and the recent, rapid spread of PHE-CoV in piglets from many countries emphasizes the urgent need for a PHE CoV vaccine. Here we use a murine model for evaluation of the induction of humoral and cellular immune responses by inactivated and PHE-CoV DNA vaccines in order to define the immune correlates for protection against PHE-CoV. The inactivated vaccine was composed of purified PHE-CoV and aluminum hydroxide gel (alum), which was chosen as an adjuvant because of its long history of safety for human use. The PHE-CoV DNA vaccine was constructed by subcloning the S1 gene of PHE-CoV into the pVAX1 vector to create the recombinant plasmid pV-S1. Our results showed that the inactivated PHE-CoV vaccine (IPV) elicited a high level of humoral immunity, resulting in good protection efficacy against PHE-CoV challenge. The IPV induced the IgG1 subclass of serum antibodies and expression of the cytokine interleukin-4 (IL-4), suggesting that the IPV generated a predominantly Th2-type immune response. The DNA vaccine was found to mediate primarily a cellular immune response with high levels of IgG2a and the cytokines IL-2 and gamma interferon (IFN-gamma). However, mice that were vaccinated twice with the DNA vaccine and boosted with the IPV could mount a sufficient neutralizing antibody response against live PHE-CoV, with little variation in IgG1 and IgG2a levels, and showed high levels of IL-2 and IL-4. This response may activate both B and T cells to mount a specific humoral and cellular immune response that could, in turn, elicit a phagocyte-mediated defense against PHE-CoV infections to achieve viral clearance. PMID- 22518009 TI - Memory B cell responses to Vibrio cholerae O1 lipopolysaccharide are associated with protection against infection from household contacts of patients with cholera in Bangladesh. AB - Vibrio cholerae O1 causes cholera, a dehydrating diarrheal disease. We have previously shown that V. cholerae-specific memory B cell responses develop after cholera infection, and we hypothesize that these mediate long-term protective immunity against cholera. We prospectively followed household contacts of cholera patients to determine whether the presence of circulating V. cholerae O1 antigen specific memory B cells on enrollment was associated with protection against V. cholerae infection over a 30-day period. Two hundred thirty-six household contacts of 122 index patients with cholera were enrolled. The presence of lipopolysaccharide (LPS)-specific IgG memory B cells in peripheral blood on study entry was associated with a 68% decrease in the risk of infection in household contacts (P = 0.032). No protection was associated with cholera toxin B subunit (CtxB)-specific memory B cells or IgA memory B cells specific to LPS. These results suggest that LPS-specific IgG memory B cells may be important in protection against infection with V. cholerae O1. PMID- 22518010 TI - Outbreak of transient conversions of the QuantiFERON-TB Gold In-Tube test in laboratory health care worker screenings. AB - Gamma interferon release assays were recently introduced in health care worker (HCWs) screenings for tuberculosis surveillance. In longitudinal surveys, conversions and reversions are seen, and yet whether these changes are unspecific or are an expression of new infections and microbial clearance remains unclear. In order to further elucidate these changes, we analyzed an outbreak of 15 transient conversions in 53 HCWs who operate in the same laboratory and handle specimens potentially containing Mycobacterium tuberculosis who underwent screening by the QuantiFERON-TB Gold In-Tube (QFT-GIT) test between 11 May and 30 June 2010: 15/46 (33%) negative HCWs showed a conversion and then reverted after 7 to 107 days. To validate these results, an evaluation of methodological procedures and test reliability, as well as an analysis of results obtained during the same period and processed by the same laboratory, was carried out. For the latter purpose, QFT-GIT results determined for 78 ward HCWs who underwent screening during the same period and were employed in departments with at least 3 infectious tuberculosis patients per year or had cared for an infectious patient without airborne precautions were analyzed with the following results: 6/63 (9%) HCWs with negative results in 3 different departments showed transient conversion (P = 0.002; odds ratio, 4.60; 95% confidence interval, 1.62 to 13.04). A retrospective survey of in-house biosafety practices led to determination of a single exposure factor within the laboratory. These data emphasize the validity of the hypothesis that a transient conversion demonstrates the presence of a real tubercular infection and could be an important indicator for occupational biosafety concerns. They also confirm that subjects with recent conversion should be retested before chest radiography and chemotherapy is offered. PMID- 22518011 TI - Serum IgG responses and seroconversion patterns to Cryptosporidium gp15 among children in a birth cohort in south India. AB - The correlates of protective immunity to cryptosporidiosis are not well understood. This study was conducted to assess the effect of maternal serum IgG against Cryptosporidium gp15 on responses to this antigen in children with (cases) and without (controls) PCR-confirmed cryptosporidial diarrhea. Maternal sera (n = 129) and sera from cases (n = 39) and controls (n = 90) collected at 3.5, 9, and 24 months of age were tested for serum IgG against Cryptosporidium gp15 by enzyme-linked immunosorbent assay (ELISA). Seroconversion patterns were evaluated by estimating probabilities of seroconversion along three time points based on the transition pathways by using a first-order Markov chain process and empirical Bayesian estimates. There was no difference in serum IgG levels or seropositivity rates to gp15 between cases and controls across all time points in children or in IgG levels to this antigen between mothers of cases and controls. The most common transition pathway can be described as a seronegative child at 3.5 months who seroconverts at 9 months and remains seropositive at 24 months. This pattern remained stable irrespective of the serological status of the mother or the case or control status of the child. Children were most likely to be exposed to Cryptosporidium for the first time between the ages of 3 and 9 months, and most of the children seroconverted by 24 months. The high degree of seroconversion among control children is suggestive of high rates of asymptomatic transmission in this region. PMID- 22518012 TI - Serological diagnosis of lung cystic hydatid disease using the synthetic p176 peptide. AB - Cystic hydatid disease (CHD) is a worldwide zoonosis caused by the larval stage of the dog tapeworm Echinococcus granulosus. Diagnosis is based on imagenological tools (abdominal ultrasound, chest X-rays, or computed tomography [CT] scan). Serological antibody-detecting assays, using diverse native antigens, have been used as a supportive diagnostic tool, but their sensitivities and specificities differ greatly. The use of synthetic peptides as antigens should provide more reliability and allow better assessment and comparison of test formats and case series. The synthetic peptide p176, corresponding to the N-terminal extreme of the subunit of antigen B (AgB8/1), has shown promising performances for diagnosis of CHD. We evaluated the performance of the synthetic peptide p176 for the diagnosis of pulmonary hydatid disease in an enzyme-linked immunosorbent assay (ELISA) format. Sixty-one serum samples from patients with a diagnosis of pulmonary hydatidosis confirmed by surgery and 128 from healthy volunteers were tested. The overall sensitivity and specificity of the p176 ELISA for lung CHD were 78.69% and 96.88%, respectively. On bivariate analysis, positive serum antibody reactions were associated with the presence of complications and with the number of cysts (single/multiple). Only the presence of persistent complications significantly associated with seropositivity on multivariate logistic regression analysis (odds ratio [OR], 9.58; 95% confidence interval [CI], 2.15 to 42.6; P = 0.003). The p176 ELISA performs well for the diagnosis of lung CHD and adds an easily reproducible diagnostic assay to the existing diagnostic tools. PMID- 22518013 TI - Identification and diagnostic utility of Leishmania infantum proteins found in urine samples from patients with visceral leishmaniasis. AB - Despite the clear need to control visceral leishmaniasis (VL), the existing diagnostic tests have serious shortcomings. Here, we introduce an innovative approach to directly identify Leishmania infantum antigens produced in vivo in humans with VL. We combined reverse-phase high-performance liquid chromatography (RP-HPLC) with mass spectrometry and categorized three distinct L. infantum proteins presumably produced in bone marrow/spleen/liver and excreted in the urine of patients with VL. The genes coding for these proteins (L. infantum iron superoxide dismutase, NCBI accession number XP_001467866.1; L. infantum tryparedoxin, NCBI accession number XP_001466642.1; and L. infantum nuclear transport factor 2, NCBI accession number XP_001463738.1) were cloned, and the recombinant molecules were produced in Escherichia coli. Antibodies to these proteins were produced in rabbits and chickens and were used to develop a capture enzyme-linked immunosorbent assay (ELISA) designed to detect these L. infantum antigens in the urine of VL patients. Specificity of the antibodies was confirmed by a Western blot analysis using both recombinant proteins and whole parasite extract. Importantly, a urinary antigen detection assay assembled with pairs of antibodies specific for each of these antigens identified 17 of 19 patients with VL. These results indicate that an improved antigen detection assay based on L. infantum proteins present in the urine of patients with VL may represent an important new strategy for the development of a specific and accurate diagnostic test that has the potential to both distinguish active VL from asymptomatic infection and serve as an important tool to monitor therapy efficacy. PMID- 22518014 TI - Mother-infant transfer of anti-human papillomavirus (HPV) antibodies following vaccination with the quadrivalent HPV (type 6/11/16/18) virus-like particle vaccine. AB - The exploratory immunogenicity objective of this analysis was to characterize the titer of vaccine human papillomavirus (HPV)-type immunoglobulins in both peripartum maternal blood and the cord blood of infants born to women who received blinded therapy. Data were derived from a randomized, placebo controlled, double-blind safety, immunogenicity, and efficacy study (protocol 019; NCT00090220). This study enrolled 3,819 women between the ages of 24 and 45 years from 38 international study sites between 18 June 2004 and 30 April 2005. Data in the current analysis are from subjects enrolled in Philippines and Thailand. For each of HPV types 6, 11, 16, and 18, maternal anti-HPV was found in cord blood samples. Furthermore, HPV titers in cord blood samples were highly positively correlated with maternal HPV titers. Additionally, there were instances when anti-HPV antibodies were no longer detectable in maternal serum samples and yet were detected in matched cord blood samples. These results demonstrate that quadrivalent HPV (qHPV) vaccine-induced antibodies cross the placenta and could potentially provide some benefit against vaccine-type HPV infection and related diseases such as recurrent respiratory papillomatosis. PMID- 22518015 TI - Development of a fourfold multiplexed opsonophagocytosis assay for pneumococcal antibodies against additional serotypes and discovery of serological subtypes in Streptococcus pneumoniae serotype 20. AB - Opsonophagocytic killing assays (OPAs) are important in vitro surrogate markers of protection in vaccine studies of Streptococcus pneumoniae. We have previously reported the development of a 4-fold multiplexed OPA (MOPA) for the 13 serotypes in Prevnar 13. Because new conjugate vaccines with increased valence are being developed, we developed 4-fold MOPAs for an additional 13 serotypes: serotypes 6C and 6D, plus the 11 serotypes contained in Pneumovax but not in Prevnar 13. A high level of nonspecific killing (NSK) was observed for three serotypes (10A, 15B, and 33F) in multiple batches of baby rabbit complement. The NSK could be reduced by preadsorbing the complement with encapsulated, as well as unencapsulated, pneumococcal strains. The MOPA results compared well with the results of single-serotype OPA for all serotypes except for serotype 3. For serotype 3, the results obtained from the MOPA format were ~40% higher than those of the single-serotype format. Interassay precision of MOPA was determined with 5 serum samples, and the coefficient of variation was generally <30% for all serotypes. MOPA was also specific for all serotypes except for serotype 20; i.e., free homologous polysaccharide (PS), but not unrelated PS, could completely and efficiently inhibit opsonization. However, serotype 20 PS from ATCC could efficiently inhibit opsonization of one serotype 20 target strain but not three other type 20 target strains even at a high (>80 mg/liter) PS concentration. This suggests the presence of serologic heterogeneity among serotype 20 strains. PMID- 22518016 TI - Early umbilical cord clamping increases the risk of neonatal anaemia and infant iron deficiency. PMID- 22518017 TI - Multisensory interactions between auditory and haptic object recognition. AB - Object manipulation produces characteristic sounds and causes specific haptic sensations that facilitate the recognition of the manipulated object. To identify the neural correlates of audio-haptic binding of object features, healthy volunteers underwent functional magnetic resonance imaging while they matched a target object to a sample object within and across audition and touch. By introducing a delay between the presentation of sample and target stimuli, it was possible to dissociate haptic-to-auditory and auditory-to-haptic matching. We hypothesized that only semantically coherent auditory and haptic object features activate cortical regions that host unified conceptual object representations. The left fusiform gyrus (FG) and posterior superior temporal sulcus (pSTS) showed increased activation during crossmodal matching of semantically congruent but not incongruent object stimuli. In the FG, this effect was found for haptic-to auditory and auditory-to-haptic matching, whereas the pSTS only displayed a crossmodal matching effect for congruent auditory targets. Auditory and somatosensory association cortices showed increased activity during crossmodal object matching which was, however, independent of semantic congruency. Together, the results show multisensory interactions at different hierarchical stages of auditory and haptic object processing. Object-specific crossmodal interactions culminate in the left FG, which may provide a higher order convergence zone for conceptual object knowledge. PMID- 22518019 TI - Method of most recent self-harm episode is related to risk of subsequent suicide. PMID- 22518020 TI - Being satisfied at work does affect burnout among psychiatrists: a national follow-up study from New Zealand. AB - BACKGROUND: Burnout and job satisfaction in psychiatrists has been an area of considerable interest. Longitudinal studies on the subject are lacking, rendering it difficult to establish whether burnout changes with time or whether low job satisfaction may predict high burnout with time in psychiatrists. AIMS: This longitudinal study of burnout and job satisfaction in a cohort of New Zealand psychiatrists was conducted to examine if initial scores on the Job Diagnostic Survey (JDS) predicted scores on the Maslach Burnout Inventory (MBI) three years later and vice versa. METHODS: Three questionnaires (a socio-demographic questionnaire, the JDS and the MBI) were sent to all registered psychiatrists in 2008, which included all those who had participated in a study three years earlier. Scores on these three questionnaires were compared for those who had participated in both studies. RESULTS: The overall number of psychiatrists reporting a high level of emotional exhaustion (EE) did not change across the two phases. The number of psychiatrists reporting high levels of depersonalization (DP) increased from 31 (13%) to 45 (20.2%); the mean DP score for the cohort significantly increased by 17.5% (p < .01). Those reporting reduced personal accomplishment (PA) increased from 90 (37.7%) to 98 (43.9%); the mean PA score for the cohort significantly reduced by 14.5% (p < .001). Low scores on skill variety, task Identity, and feedback of the JDS were significantly correlated with high EE scores three years later, whereas low scores on skill variety were significantly correlated with high scores on DP, and low scores on task significance and feedback were correlated with low scores on PA three years later. CONCLUSIONS: Paying attention to aspects of job satisfaction may assist us in developing specific interventions for psychiatrists who may score high on different dimensions of burnout. PMID- 22518021 TI - Repeated administration of a mutant cocaine esterase: effects on plasma cocaine levels, cocaine-induced cardiovascular activity, and immune responses in rhesus monkeys. AB - Previous studies have demonstrated the capacity of a long-acting mutant form of a naturally occurring bacterial double mutant cocaine esterase (DM CocE) to antagonize the reinforcing, discriminative, convulsant, and lethal effects of cocaine in rodents and reverse the increases in mean arterial pressure (MAP) and heart rate (HR) produced by cocaine in rhesus monkeys. This study was aimed at characterizing the immunologic responses to repeated dosing with DM CocE and determining whether the development of anti-CocE antibodies altered the capacity of DM CocE to reduce plasma cocaine levels and ameliorate the cardiovascular effects of cocaine in rhesus monkeys. Under control conditions, intravenous administration of cocaine (3 mg/kg) resulted in a rapid increase in the plasma concentration of cocaine (n = 2) and long-lasting increases in MAP and HR (n = 3). Administration of DM CocE (0.32 mg/kg i.v.) 10 min after cocaine resulted in a rapid hydrolysis of cocaine with plasma levels below detection limits within 5 to 8 min. Elevations in MAP and HR were significantly reduced within 25 and 50 min of DM CocE administration, respectively. Although slight (10-fold) increases in anti-CocE antibodies were observed after the fourth administration of DM CocE, these antibodies did not alter the capacity of DM CocE to reduce plasma cocaine levels or ameliorate cocaine's cardiovascular effects. Anti-CocE titers were transient and generally dissipated within 8 weeks. Together, these results suggest that highly efficient cocaine esterases, such as DM CocE, may provide a novel and effective therapeutic for the treatment of acute cocaine intoxication in humans. PMID- 22518022 TI - Arginine attenuates methylglyoxal- and high glucose-induced endothelial dysfunction and oxidative stress by an endothelial nitric-oxide synthase independent mechanism. AB - Methylglyoxal (MG), a reactive metabolite of glucose, has high affinity for arginine and is a precursor of advanced glycation endproducts (AGEs). We tested the hypothesis that L-arginine, and its inactive isomer D-arginine, can efficiently scavenge MG, administered exogenously or produced endogenously from high glucose, and attenuate its harmful effects including endothelial dysfunction and oxidative stress by an endothelial nitric-oxide synthase (eNOS)-independent mechanism. We used isolated aortic rings from 12-week-old male Sprague-Dawley rats and cultured human umbilical vein endothelial cells (HUVECs) and vascular smooth muscle cells (VSMCs). Both D-arginine and L-arginine prevented the attenuation of acetylcholine-induced endothelium-dependent vasorelaxation by MG and high glucose. However, the inhibitory effect of the NOS inhibitor N(omega) nitro-L-arginine methyl ester on vasorelaxation was prevented by L-arginine, but not D-arginine. MG and high glucose increased protein expression of arginase, a novel finding, NADPH oxidase 4, and nuclear factor kappaB and increased production of reactive oxygen species in HUVECs and VSMCs, which were attenuated by D-arginine and L-arginine. However, D-arginine and L-arginine did not attenuate MG- and high glucose-induced increased arginase activity in VSMCs and the aorta. D-arginine and L-arginine also attenuated the increased formation of the MG-specific AGE N(epsilon)-carboxyethyl lysine, caused by MG and high glucose in VSMCs. In conclusion, arginine attenuates the increased arginase expression, oxidative stress, endothelial dysfunction, and AGE formation induced by MG and high glucose by an eNOS-independent mechanism. The therapeutic potential of arginine against MG- and high glucose-induced pathology merits further investigation. PMID- 22518023 TI - Cocaine dose and self-administration history, but not initial cocaine locomotor responsiveness, affects sensitization to the motivational effects of cocaine in rats. AB - Cocaine addiction is a significant and complex disease. Part of this complexity is caused by the variability of the drug experience early in drug use (initial responsiveness, amount of use, etc.). In rats, individual differences in initial cocaine responsiveness and cocaine self-administration history both predict the development of cocaine sensitization, a putative mechanism contributing to the development of cocaine addiction. Here, we sought to determine the role of these factors and cocaine dose on the development of sensitization to cocaine's motivational effects during the earliest stages of self-administration. Rats were classified as either low or high cocaine responders (LCRs or HCRs, respectively) based on acute cocaine-induced locomotor activity (10 mg/kg i.p.) before learning to self-administer cocaine (0.6 mg/kg/infusion i.v.) under a fixed ratio 1 (FR1) schedule of reinforcement. After acquisition, rats self-administered cocaine (0.6 or 1.2 mg/kg/infusion) under a progressive ratio (PR) schedule of reinforcement either immediately or after an additional five FR1 sessions (0.6 or 1.2 mg/kg/infusion). No LCR/HCR differences in sensitization were observed. However, regardless of LCR/HCR classification, exposure to the higher dose of cocaine produced sensitization to cocaine's motivational effects on the PR schedule (i.e., increased break points) and an escalation of consumption on the FR schedule. Thus, our results reveal a novel model for studying escalation and sensitization very early after acquisition and suggest that sensitization may be important in the earliest stages of the cocaine addiction process. PMID- 22518024 TI - Role of TRPML and two-pore channels in endolysosomal cation homeostasis. AB - The transient receptor potential (TRP) channels TRPML1, TRPML2, and TRPML3 (also called mucolipins 1-3 or MCOLN1-3) are nonselective cation channels. Mutations in the Trpml1 gene cause mucolipidosis type IV in humans with clinical features including psychomotor retardation, corneal clouding, and retinal degeneration, whereas mutations in the Trpml3 gene cause deafness, circling behavior, and coat color dilution in mice. No disease-causing mutations are reported for the Trpml2 gene. Like TRPML channels, which are expressed in the endolysosomal pathway, two pore channels (TPCs), namely TPC1, TPC2, and TPC3, are found in intracellular organelles, in particular in endosomes and lysosomes. Both TRPML channels and TPCs may function as calcium/cation release channels in endosomes, lysosomes, and lysosome-related organelles with TRPMLs being activated by phosphatidylinositol 3,5-bisphosphate and regulated by pH and TPCs being activated by nicotinic acid adenine dinucleotide phosphate in a calcium- and pH-dependent manner. They may also be involved in endolysosomal transport and fusion processes, e.g., as intracellular calcium sources. Currently, however, the exact physiological roles of TRPML channels and TPCs remain quite elusive, and whether TRPML channels are purely endolysosomal ion channels or whether they may also be functionally active at the plasma membrane in vivo remains to be determined. PMID- 22518025 TI - A national ICU telemedicine survey: validation and results. AB - BACKGROUND: A recent ICU telemedicine research consensus conference identified the need for reliable methods of measuring structural features and processes of critical care delivery in the domains of organizational context and characteristics of ICU teams, ICUs, hospitals, and of the communities supported by an ICU. METHODS: The American College of Chest Physicians Critical Care Institute developed and conducted a survey of ICU telemedicine practices. A 32 item survey was delivered electronically to leaders of 311 ICUs, and 11 domains were identified using principal components analysis. Survey reliability was judged by intraclass correlation among raters, and validity was measured for items for which independent assessment was available. RESULTS: Complete survey information was obtained for 170 of 311 ICUs sent invitations. Analysis of a subset of surveys from 45 ICUs with complete data from more than one rater indicated that the survey reliability was in the excellent to nearly perfect range. Coefficients for measures of external validation ranged from 0.63 to 1.0. Analyses of the survey revealed substantial variation in the practice of ICU telemedicine, including ICU telemedicine center staffing patterns; qualifications of providers; case sign-out, ICU staffing models, leadership, and governance; intensivist review for new patients; adherence to best practices; use of quality and safety information; and ICU physician sign out for their patients. CONCLUSIONS: The American College of Chest Physicians ICU telemedicine survey is a reliable tool for measuring variation among ICUs with regard to staffing, structure, processes of care, and ICU telemedicine practices. PMID- 22518026 TI - The cardiopulmonary effects of vasopressin compared with norepinephrine in septic shock. AB - BACKGROUND: Vasopressin is known to be an effective vasopressor in the treatment of septic shock, but uncertainty remains about its effect on other hemodynamic parameters. METHODS: We examined the cardiopulmonary effects of vasopressin compared with norepinephrine in 779 adult patients with septic shock recruited to the Vasopressin and Septic Shock Trial. More detailed cardiac output data were analyzed for a subset of 241 patients managed with a pulmonary artery catheter, and data were collected for the first 96 h after randomization. We compared the effects of vasopressin vs norepinephrine in all patients and according to severity of shock (< 15 or >= 15 MUg/min of norepinephrine) and cardiac output at baseline. RESULTS: Equal BPs were maintained in both treatment groups, with a significant reduction in norepinephrine requirements in the patients treated with vasopressin. The major hemodynamic difference between the two groups was a significant reduction in heart rate in the patients treated with vasopressin (P <.0001), and this was most pronounced in the less severe shock stratum (treatment * shock stratum interaction, P =.03). There were no other major cardiopulmonary differences between treatment groups, including no difference in cardiac index or stroke volume index between patients treated with vasopressin and those treated with norepinephrine. There was significantly greater use of inotropic drugs in the vasopressin group than in the norepinephrine group. CONCLUSIONS: Vasopressin treatment in septic shock is associated with a significant reduction in heart rate but no change in cardiac output or other measures of perfusion. TRIAL REGISTRY: ISRCTN Register; No.: ISRCTN94845869; URL: www.isrctn.org PMID- 22518027 TI - Relation between COPD severity and global cardiovascular risk in US adults. AB - BACKGROUND: COPD is associated with the risk of cardiovascular events (CVEs), but its impact on overall mortality has not been well quantified. We determined the impact of global CVE risk assessment on CVE and total mortality in subjects with COPD. METHODS: We examined the severity of COPD in 6,266 US adult patients aged 40 years in relation to the estimated 10-year risk of CVEs. COPD was defi ned by spirometry, and severity was classified as mild (FEV1 >= 80%), moderate (50% <= FEV< 1 , 80%), or severe (FEV 1 , 50%). Cox proportional hazards regression was used to evaluate the relationship of global CVE risk combined with COPD status to CVE and all-cause mortality over a mean follow-up of 98.8 +/- 51.3 months. RESULTS: The proportion of individuals at high risk for CVEs ranged from 25% (without COPD)to . 50% (with moderate to severe COPD) ( P , .05). When global CVE risk scores were low, CVE mortality was also low ( , 10/1,000 person-years) regardless of COPD severity, and CVE mortality was high when CVE global risk was high ( . 40/1,000 person-years). Global CVE risk improved prediction for both CVEs and total mortality in patients with COPD ( P , .0001), with a net reclassification improvement of 17.1% ( P , .0001) and 13.0% ( P , .0001), respectively, beyond lung function measures. CONCLUSIONS: The addition of global CVE risk scores to lung function data significantly improves risk stratification of patients with COPD for CVE and total mortality and, thus, adds to predicting long-term survival of these patients. PMID- 22518028 TI - Primary care factors associated with cervical screening coverage in England. AB - BACKGROUND: The National Health Service Cervical Screening Programme was established to decrease the incidence and mortality of cervical cancer in England. METHODS: To identify socioeconomic and general practice factors associated with cervical screening coverage in England, a national cross sectional study was conducted using data on 26 497 476 female patients registered with 7970 practices in 152 English primary care trusts (PCTs). The 2008-09 data on cervical screening coverage rates from the quality and outcomes framework (QOF) database were used with data on QOF indicators, staffing levels and socioeconomic status. RESULTS: The mean cervical screening coverage rate was 78.5% at the PCT level and 83.5% at the practice level. At both levels, cervical screening coverage was significantly negatively associated with the index of multiple deprivation score, percentage of female patients aged 25-49 years and percentage of ethnic minority patients. Also, at the practice level, the percentage of female patients aged 50-64 years, overall QOF score and records and information score were significantly positively associated with cervical screening coverage. CONCLUSIONS: Cervical screening coverage was significantly lower in PCTs and practices serving higher percentages of younger-aged women, non Caucasian individuals and those living in socioeconomic deprivation. It is therefore important to adopt strategies to improve cervical screening coverage in these groups. PMID- 22518029 TI - Craniofacial pain and jaw-muscle activity during sleep. AB - This study compared the jaw-muscle electromyographic (EMG) activity during sleep in patients with craniofacial pain (n = 63) or no painful conditions (n = 52) and between patients with tension-type headache (TTH: n = 30) and healthy control individuals (n = 30). All participants used a portable single-channel EMG device (Medotech A/S) for four nights. There was no significant difference in EMG activity between craniofacial pain (24.5 +/- 17.9 events/hr) and no painful conditions (19.7 +/- 14.5), or between TTH (20.8 +/- 15.0) and healthy control individuals (15.2 +/- 11.6, p >.050). There were positive correlations between EMG activity and number of painful muscles (r = 0.188; p = 0.044), characteristic pain intensity (r = 0.187; p = 0.046), McGill Pain Questionnaire (r = 0.251; p = 0.008), and depression scores (r = 0.291; p = 0.002). Patients with painful conditions had significantly higher night-to-night variability compared with pain free individuals (p < 0.050). This short-term observational study suggests that there are no major differences between patients with different craniofacial pain conditions and pain-free individuals in terms of jaw-muscle EMG activity recorded with a single-channel EMG device during sleep. However, some associations may exist between the level of EMG activity and various parameters of craniofacial pain. Longitudinal studies are warranted to further explore the relationship between sleep bruxism and craniofacial pain. PMID- 22518030 TI - Effects of MMP inhibitors incorporated within dental adhesives. AB - Matrix metalloproteinase (MMP) inhibition has been shown to reduce adhesive bond degradation when applied as a pre-conditioner, adding to clinical steps in the placement of adhesives, but their incorporation within dental adhesives has not been fully explored. This study examined the effect of including 2 MMP inhibitors (BB94 and GM6001) within the primers of 3 commercially available adhesives. Fluorometric assay and zymography showed that adhesives with MMP inhibitors had high affinity toward both synthetic fluorogenic FRET peptides (95%) and dentin powder substrates, respectively. The immediate microtensile bond strength was enhanced for 2 types of adhesives following the addition of both inhibitors. However, no changes were detected between the control and the inhibitor groups following 3-month storage. The modified two-step etch-and-rinse and single-step systems showed less Rhodamine B penetration to the "hybrid layer" and to the "adhesive", respectively. The incorporation of BB94 and GM6001 within the primers resulted in the inhibition of dentin MMPs with improved initial bond strength and enhanced sealing ability. PMID- 22518031 TI - Nuclear miRNA regulates the mitochondrial genome in the heart. AB - RATIONALE: Mitochondria are semiautonomous cellular organelles with their own genome, which not only supply energy but also participate in cell death pathways. MicroRNAs (miRNAs) are usually 19 to 25 nt long, noncoding RNAs, involved in posttranscriptional gene regulation by binding to the 3'-untranslated regions of target mRNA, which impact on diverse cellular processes. OBJECTIVE: To determine if nuclear miRNAs translocate into the mitochondria and regulate mitochondrial function with possible pathophysiological implications in cardiac myocytes. METHODS AND RESULTS: We find that miR-181c is encoded in the nucleus, assembled in the cytoplasm, and finally translocated into the mitochondria of cardiac myocytes. Immunoprecipitation of Argonaute 2 from the mitochondrial fraction indicates binding of cytochrome c oxidase subunit 1 (mt-COX1) mRNA from the mitochondrial genome with miR-181c. Also, a luciferase reporter construct shows that mi-181c binds to the 3'UTR of mt-COX1. To study whether miR-181c regulates mt-COX1, we overexpressed precursor miR-181c (or a scrambled sequence) in primary cultures of neonatal rat ventricular myocytes. Overexpression of miR-181c did not change mt-COX1 mRNA but significantly decreased mt-COX1 protein, suggesting that miR-181c is primarily a translational regulator of mt-COX1. In addition to altering mt-COX1, overexpression of miR-181c results in increased mt-COX2 mRNA and protein content, with an increase in both mitochondrial respiration and reactive oxygen species generation in neonatal rat ventricular myocytes. Thus, our data show for the first time that miR-181c can enter and target the mitochondrial genome, ultimately causing electron transport chain complex IV remodeling and mitochondrial dysfunction. CONCLUSIONS: Nuclear miR-181c translocates into the mitochondria and regulates mitochondrial genome expression. This unique observation may open a new dimension to our understanding of mitochondrial dynamics and the role of miRNA in mitochondrial dysfunction. PMID- 22518032 TI - Electrical coupling and propagation in engineered ventricular myocardium with heterogeneous expression of connexin43. AB - RATIONALE: Spatial heterogeneity in connexin (Cx) expression has been implicated in arrhythmogenesis. OBJECTIVE: This study was performed to quantify the relation between the degree of heterogeneity in Cx43 expression and disturbances in electric propagation. METHODS AND RESULTS: Cell pairs and strands composed of mixtures of Cx43(-/-) (Cx43KO) or GFP-expressing Cx43(+/+) (WT(GFP)) murine ventricular myocytes were patterned using microlithographic techniques. At the interface between pairs of WT(GFP) and Cx43KO cells, dual-voltage clamp showed a marked decrease in electric coupling (approximately 5% of WT) and voltage gating suggested the presence of mixed Cx43/Cx45 channels. Cx43 and Cx45 immunofluorescence signals were not detectable at this interface, probably because of markedly reduced gap junction size. Macroscopic propagation velocity, measured by multisite high-resolution optical mapping of transmembrane potential in strands of cells of mixed Cx43 genotype, decreased with an increasing proportion of Cx43KO cells in the strand. A marked decrease in conduction velocity was observed in strands composed of <50% WT cells. Propagation at the microscopic scale showed a high degree of dissociation between WT(GFP) and Cx43KO cells, but consistent excitation without development of propagation block. CONCLUSIONS: Heterogeneous ablation of Cx43 leads to a marked decrease in propagation velocity in tissue strands composed of <50% cells with WT Cx43 expression and marked dissociation of excitation at the cellular level. However, the small residual electric conductance between Cx43 and WT(GFP) myocytes assures excitation of Cx43(-/-) cells. This explains the previously reported undisturbed contractility in tissues with spatially heterogeneous downregulation of Cx43 expression. PMID- 22518034 TI - How early can we repair pectus excavatum: the earlier the better? AB - OBJECTIVES: The optimal age for the repair of pectus excavatum using minimally invasive technique has yet to be determined. We hypothesized that the early repair of pectus excavatum may contribute in preserving chest wall integrity and also in enhancing patients' growth. The purpose of our present study was to verify a potential advantage of the early repair of pectus excavatum by using a minimally invasive technique. METHODS: For our study on minimally invasive pectus excavatum repair, 1571 patients from the period 1999 to 2011 were enrolled. Our strategy was to carry out routine repairs in patients older than 3 years of age. To examine the age factor on the results of the repairs the patients were divided into different age groups: Group 1 (<= 5 years, 618 (39.3%)), Group 2 (6-11 years, 322 (20.5%)), Group 3 (12-20 years, 401 (25.5%)) and Group 4 (>20 years, 230 (14.6%)). A comparative analysis was performed for factors such as complication rates; growth-percentile scores of height, weight and body mass index (BMI); incidence of asymmetry and costal flare score to determine the potential to resume the normal chest wall conformation by earlier repair. RESULTS: The mean age of the patients was 10.2 years (16 months to 51 years). The incidence of asymmetry was found to be lowest in Group 1 (24.3, 45.5, 58.7, 48.4%, respectively, P < 0.001). The complication rate after repair was also lowest in Group 1 (7.6, 11.5, 16.3, 19.1%, respectively, P < 0.001). The growth of body weight was significant in Groups 1 and 2 (0.53 +/- 1.02, P < 0.001). The costal flare score was found to have decreased in Groups 1 and 2 (Group 1: from 1.6 to 0.12, P < 0.001; Group 2: from 1.44 to 0.14, P < 0.001). In Groups 3 and 4, there was no improvement in costal flare after repair. CONCLUSIONS: Our results suggest that routine early repair of pectus excavatum in patients older than 3 years of age is safe and effective. We would recommend early repair to avoid asymmetry transformation of the deformity and to enhance the patients' growth potential. PMID- 22518033 TI - Label-free quantification and shotgun analysis of complex proteomes by one dimensional SDS-PAGE/NanoLC-MS: evaluation for the large scale analysis of inflammatory human endothelial cells. AB - To perform differential studies of complex protein mixtures, strategies for reproducible and accurate quantification are needed. Here, we evaluated a quantitative proteomic workflow based on nanoLC-MS/MS analysis on an LTQ-Orbitrap VELOS mass spectrometer and label-free quantification using the MFPaQ software. In such label-free quantitative studies, a compromise has to be found between two requirements: repeatability of sample processing and MS measurements, allowing an accurate quantification, and high proteomic coverage of the sample, allowing quantification of minor species. The latter is generally achieved through sample fractionation, which may induce experimental bias during the label-free comparison of samples processed, and analyzed independently. In this work, we wanted to evaluate the performances of MS intensity-based label-free quantification when a complex protein sample is fractionated by one-dimensional SDS-PAGE. We first tested the efficiency of the analysis without protein fractionation and could achieve quite good quantitative repeatability in single run analysis (median coefficient of variation of 5%, 99% proteins with coefficient of variation <48%). We show that sample fractionation by one dimensional SDS-PAGE is associated with a moderate decrease of quantitative measurement repeatability while largely improving the depth of proteomic coverage. We then applied the method for a large scale proteomic study of the human endothelial cell response to inflammatory cytokines, such as TNFalpha, interferon gamma, and IL1beta, which allowed us to finely decipher at the proteomic level the biological pathways involved in endothelial cell response to proinflammatory cytokines. PMID- 22518035 TI - Thoracolaparoscopy oesophagectomy and extensive two-field lymphadenectomy for oesophageal cancer: introduction and teaching of a new technique in a high-volume centre. AB - OBJECTIVES: The aim of this study was to assess the experience of a high-volume centre with thoracolaparoscopy radical oesophagectomy and to evaluate the feasibility, tumour clearance, the learning curve and reproducibility of this technique. METHODS: Eighty patients with thoracic oesophageal cancer who underwent thoracolaparoscopic oesophagectomy (TLE) were enrolled in this study. Two attending surgeons (Mingqiang Kang and Ruobai Lin) independently performed the procedure as operating surgeons. The 60 patients who had surgery performed on them by the senior attending surgeon, Mingqiang Kang, were divided into three groups of 20 patients: groups A, B and C. The results from the three groups were compared in order to detect any changes in the success of TLE as a way of monitoring the development of the surgeon's technical skill. Another 20 patients had surgery performed on them by the new attending surgeon, Ruobai Lin, and were classified into the fourth group, D. The results from Group D were compared with those of the other three groups to evaluate the reproducibility of our technique. RESULTS: There was no significant difference between the four groups with respect to age, gender, location of tumour or staging. The duration of both the thoracoscopic and laparoscopic procedures was significantly longer in Group A. The amount of estimated blood loss was significantly more in Group A than in the other groups. The number of lymph nodes dissected was similar in Groups A and D, whereas that of retrieved nodes was larger in Groups B and C. There was no significant difference in the incidence of respiratory complications, recurrent nerve palsy, anastomotic leaks, arrhythmia, chylothorax and delayed gastric emptying among the four groups. CONCLUSIONS: When TLE procedures are started in units with a large volume of oesophageal resections, and when there is support from colleagues within the unit, transition from open to TLE can be achieved safely, with a satisfactory oncological outcome. A plateau of TLE skill was reached after 40 cases had been performed. If mini-fellowship training with supervision from senior surgeons is used, it is possible for a new attending surgeon to attain the requisite basic skill to perform TLE in a relatively short period of time. PMID- 22518036 TI - A propensity-matched comparison of survival after lung resection in patients with a high versus low body mass index. AB - OBJECTIVES: An inverse relationship between body mass index (BMI) and the risk of lung cancer has been reported in several studies. In this study, we aimed to assess whether BMI can affect survival after lung resection for cancer. METHODS: We reviewed patient data for a 10-year period; 337 patients with BMI >= 30 who underwent lung resection for non-small cell lung cancer were identified. This group of patients was matched at a ratio of 1:1 to a group with BMI <30 and with similar characteristics such as sex, age, lung function test, history of smoking, diabetes, peripheral vascular disease, stroke, myocardial infarction, chronic obstructive pulmonary disease (COPD), procedure type, histology and stage of tumour. We also used the Kaplan-Meier survival curves before and after matching for the above mentioned patient characteristics. RESULTS: Before adjusting for the preoperative and operative characteristics, despite more history of diabetes, hypertension and renal impairment in patients with BMI >= 30 compared to those with BMI <30 (BMI = 18.5-30 and < 8.5), the survival rate was found to be significantly higher when analysed univariately (P = 0.02). This difference remained significant after adjusting for all the characteristics, suggesting a significantly higher survival rate in the group with BMI >= 30 (P = 0.04). CONCLUSIONS: Unlike in breast cancer, a high BMI in lung cancer patients after resection has protective effects. This may be due to the better nutritional status of the patient, a less aggressive cancer type that has not resulted in weight loss at the time of presentation or it may be due to certain hormones released from the adipose tissue. BMI can be a predictor of outcome after lung resection in cancer patients. PMID- 22518037 TI - Meta-analysis of 5,674 patients treated with percutaneous coronary intervention and drug-eluting stents or coronary artery bypass graft surgery for unprotected left main coronary artery stenosis. AB - OBJECTIVES: To compare the safety and efficacy of coronary artery bypass grafting (CABG) with percutaneous coronary intervention (PCI) using drug-eluting stents (DES) in patients with unprotected left main coronary artery (ULMCA) disease. METHODS: MEDLINE, EMBASE, CENTRAL/CCTR, SciELO, LILACS, Google Scholar and reference lists of relevant articles were searched for clinical studies that reported outcomes at the 1-year follow-up after PCI with DES and CABG for the treatment of ULMCA stenosis. Sixteen studies (three randomized controlled trials and 13 observational studies) were identified and included a total of 5674 patients (2331 for PCI with DES and 3343 for CABG). RESULTS: At the 1-year follow up, there was no significant difference between the CABG and DES groups in the risk for death (odds ratio [OR] 0.691, P = 0.051) or the composite endpoint of death, myocardial infarction or stroke (OR 0.832, P = 0.258). The risk for target vessel revascularization (TVR) was significantly higher in the PCI group compared with the CABG group (OR 3.597, P < 0.001). The risk of major adverse cardiac and cerebrovascular events (MACCE) was significantly higher in the PCI group compared with the CABG group (OR 1.607, P < 0.001). A publication bias was observed regarding the outcome of death and also a considerable heterogeneity effect on the composite endpoint of death, myocardial infarction or stroke and MACCE. CONCLUSIONS: CABG surgery remains the best option of treatment for patients with ULMCA disease, with less need of TVR and lower MACCE rates. PMID- 22518038 TI - Use of the Damus-Kaye-Stansel procedure prevents increased ventricular strain in Fontan candidates. AB - OBJECTIVES: In Fontan candidates, we have recently been aggressively performing the Damus-Kaye-Stansel procedure (DKS) to prevent increased afterload on the systemic ventricle. The present study investigated the efficacy of the DKS procedure in terms of the ventricular function following a Fontan operation. METHODS: Patients undergoing a Fontan operation were divided into three groups: DKS performed at the time of the bidirectional Glenn or Fontan operation (DKS group, n = 25); DKS not performed at any stage due to mild pulmonary stenosis (PS) (PS group, n = 23) and DKS not performed due to pulmonary atresia (PA) or severe PS (PA group, n = 24). Ventricular function, afterload on the systemic ventricle and atrioventricular valve regurgitation were compared between groups. RESULTS: Cardiac catheterization before a Glenn or Fontan operation and at 1-year following the Fontan revealed significantly decreased ventricular end-diastolic pressure in the DKS group. The ventricular ejection fraction was significantly deteriorated in the PS group. Effective arterial elastance, as an index of total ventricular afterload, was increased after a Fontan in all groups, with a substantial increase in the PS group. As an index of ventricular mechanical efficiency, ventriculoarterial coupling was significantly increased only in the PS group. Cardiac ultrasonography revealed atrioventricular valve regurgitation above grade 3 persisting in many patients from the PS group. Semilunar valve function after DKS operation did not progress to moderate or worse in any patients. CONCLUSIONS: The proactive performance of the DKS procedure prevents increased ventricular afterload, avoiding deterioration of cardiac function and contributing to improved long-term results following a Fontan operation. PMID- 22518039 TI - Accuracy of transthoracic ultrasound for the detection of pleural adhesions. AB - OBJECTIVES: In the era of minimally invasive surgery, preoperative detection of pleural adhesions can be very useful for the assessment of surgical approach, because pleural adhesions are the main contraindication to video-assisted thoracoscopy. The aim of this study was to assess the sensitivity and specificity of transthoracic ultrasound in the detection of pleural adhesions prior to thoracic surgery. METHODS: From February 2010 to January 2011, 142 consecutive patients (male, 98; female, 44; age range, 36-83 years, mean age, 63.4 years) undergoing surgical thoracic intervention (except for pneumothorax) were preoperatively scanned by two different surgeons. According to thoracic wall projections of lung segments, we created a nine-region topographic map, in which every pulmonary area was scanned to assess the presence or the absence of 'gliding sign' (lesion-by-lesion analysis). During operations the surgeon, blinded to the prediction, confirmed or excluded each suspected adhesion or documented other adhesions not previously identified. RESULTS: A total of 1192 predictions were made. Ultrasound predictions were confirmed 1124 times and refuted 68 times. Sensitivity was 80.6% (95% confidence interval, 0.740-0.872) and specificity 96.1% (95% confidence interval, 0.949-0.973). The positive predictive value was 73.2% and the negative predictive value was 97.4%. CONCLUSIONS: Transthoracic ultrasound is an effective method for predicting pleural adhesions before thoracic surgery in experienced hands. Its safety, feasibility and low cost make it a useful method for the planning of minimally invasive surgical interventions. PMID- 22518040 TI - A European training system in cardiothoracic surgery: is it time? AB - OBJECTIVE: Training in cardiothoracic surgery across Europe remains diverse and variable despite the ever closer integration of European countries at all levels and in all areas of life. Coupled with the increasing ease of movement across Europe, the need for uniform training programmes has arisen to allow for equivalent accreditation and certification. METHODS: We review the current training paradigms within the specialty across the world and in Europe and also explore the concept of competence. RESULTS: There are diverse training systems across the world and in Europe in particular. Competence-based training is the new model of training; however, competence remains difficult to define and measure. We propose a European Training Programme in Cardiothoracic Surgery that aims to standardize training across the European countries. CONCLUSIONS: The difficulties in unifying training across Europe are numerous, but it is time to implement a European Training System in Cardiothoracic Surgery that will deliver a competence-based curriculum. PMID- 22518041 TI - Are right ventricular risk scores useful? AB - OBJECTIVES: Left ventricular assist device (LVAD) implantation can be complicated by right ventricular (RV) failure. Several scores have been proposed to predict this event. Our aim was to validate three of these scores in a population which had received a rotary blood pump LVAD. METHODS: In a consecutive series of 59 full LVAD implantations, preoperative clinical, echocardiographic, laboratory and haemodynamic values were retrospectively collected. Three previously published predictive scores were calculated for all the patients. A logistic regression analysis was used to identify the predictors of RV support after LVAD implantation. RESULTS: Fourteen patients (23.7%) needed additional temporary RV support. The three scores did not present any significant difference between patients treated with LVAD plus right ventricular assist device or LVAD only (45.86 +/- 14.02 vs 42.1 +/- 17.34, P = 0.46; 4.57 +/- 3.37 vs 4.94 +/- 2.87, P = 0.69; 2.71 +/- 2.11 vs 2.92 +/- 2.99m P = 0.81) and they were not predictive for RV failure. High pulmonary vascular resistance and the presence of non-ischaemic cardiomyopathy were the only significant predictors in logistic regression. CONCLUSIONS: The use of risk scores failed to predict the need of RV support after LVAD. Stratification of the hazard with these scores should occur with extreme caution. PMID- 22518042 TI - Total arch replacement with long elephant trunk anastomosed at the base of the innominate artery: a single-centre longitudinal experience. AB - OBJECTIVE: Total arch replacement, with a long elephant trunk (ET) anastomosed at the base of the innominate artery using an undersized graft, is performed for a variety of arch aneurysms. We investigated the long-term clinical outcomes of this procedure, as well as its long-term effectiveness for preventing retrograde flow into the aneurysm and further dilation of the descending aorta. METHODS: We treated 127 consecutive patients with an arch aneurysm, who were divided into two groups according to the diameter of the descending aorta at the Th6-Th8 thoracic vertebral level: 35 mm or less (Single-ET, n = 94) and >35 mm (Staged-ET, n = 33). The graft diameter was undersized by 10-20% of the distal aortic diameter. ET length was determined by preoperative computed tomography (CT) to locate the distal end at Th6-Th8. Thrombosis around the ET and the descending aorta diameter around the distal end of the ET were evaluated using CT. RESULTS: Two patients (1.6%) died within 30 days, while seven (5.5%) died in the hospital, three (2.4%) had a new stroke, three (2.4%) had permanent paraplegia and one (0.8%) had paraparesis. CT demonstrated complete thrombosis of the perigraft space around the ET in 81 patients (86%) in the Single-ET group and 11 (33%) in the Staged-ET group within 1 month after surgery, but not in the remaining 35 patients. Twenty seven of the 35 patients without complete thrombosis underwent a subsequent second-stage operation. In those, the descending aorta showed no further dilation around the distal end of the ET, while new-onset perigraft perfusion occurred in two patients in the Single-ET group at 14 and 126 months, respectively. Overall survival was 89, 86, 78 and 74% at 1, 3, 5 and 7 years, respectively. CONCLUSIONS: Our operative strategy for extensive thoracic aortic aneurysms using a long ET technique yielded satisfactory short- and long-term outcomes. PMID- 22518043 TI - Editorial comment: From the left or from the right? PMID- 22518044 TI - Use of allogenous bone graft and osteosynthetic stabilization in treatment of massive post-sternotomy defects. AB - Thoracic stabilization using transverse plate fixation represents a modern and safe method of sternal dehiscence treatment. However, it still remains difficult to apply in cases of massive loss of bone tissue of the chest wall. An unsatisfactory stability of thorax often results in severe respiratory insufficiency, and also affects healing of soft tissue closure while increasing the risk of development of chronic fistulas and other dehiscences. In the reported case, we opted for a unique treatment of massive post-sternotomy defect using an allogenous bone graft of calva. Transverse titanium plates were applied to achieve stabilization of bone grafts and chest wall. PMID- 22518045 TI - A randomised controlled trial to compare opt-in and opt-out parental consent for childhood vaccine safety surveillance using data linkage. AB - INTRODUCTION: No consent for health and medical research is appropriate when the criteria for a waiver of consent are met, yet some ethics committees and data custodians still require informed consent. METHODS: A single-blind parallel-group randomised controlled trial: 1129 families of children born at a South Australian hospital were sent information explaining data linkage of childhood immunisation and hospital records for vaccine safety surveillance with 4 weeks to opt in or opt out by reply form, telephone or email. A subsequent telephone interview gauged the intent of 1026 parents (91%) in relation to their actions and the sociodemographic differences between participants and non-participants in each arm. RESULTS: The participation rate was 21% (n=120/564) in the opt-in arm and 96% (n=540/565) in the opt-out arm (chi(2) (1 df) = 567.7, p<0.001). Participants in the opt-in arm were more likely than non-participants to be older, married/de facto, university educated and of higher socioeconomic status. Participants in the opt-out arm were similar to non-participants, except men were more likely to opt out. Substantial proportions did not receive, understand or properly consider study invitations, and opting in or opting out behaviour was often at odds with parents' stated underlying intentions. CONCLUSIONS: The opt-in approach resulted in low participation and a biased sample that would render any subsequent data linkage unfeasible, while the opt-out approach achieved high participation and a representative sample. The waiver of consent afforded under current privacy regulations for data linkage studies meeting all appropriate criteria should be granted by ethics committees, and supported by data custodians. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry ACTRN12610000332022. PMID- 22518046 TI - Resolving the impasse on predictive genetic testing in minors: will more evidence be the solution? PMID- 22518047 TI - Comment on 'a capacity-based approach for addressing ancillary-care needs: implications for research in resource limited settings'. PMID- 22518048 TI - Reducing the harmful effects of alcohol misuse: the ethics of sobriety testing in criminal justice. AB - Alcohol use and abuse play a major role in both crime and negative health outcomes in Scotland. This paper provides a description and ethical and legal analyses of a novel remote alcohol monitoring scheme for offenders which seeks to reduce alcohol-related harm to both the criminal and the public. It emerges that the prospective benefits of this scheme to health and public order vastly outweigh any potential harms. PMID- 22518049 TI - Helping doctors become better doctors: Mary Lobjoit--an unsung heroine of medical ethics in the UK. AB - Medical Ethics has many unsung heros and heroines. Here we celebrate one of these and on telling part of her story hope to place modern medical ethics and bioethics in the UK more centrally within its historical and human contex. PMID- 22518050 TI - Vitamin D deficiency is not associated with early stages of thyroid autoimmunity. AB - CONTEXT: Vitamin D deficiency has been identified as a risk factor for a number of autoimmune diseases including type 1 diabetes and multiple sclerosis. OBJECTIVE: We hypothesized that low levels of vitamin D are related to the early stages of autoimmune thyroid disease (AITD). DESIGN: Two case-control studies were performed. In the cross-sectional study A, euthyroid subjects with genetic susceptibility for AITD but without thyroid antibodies were compared with controls. Cases were subjects from the Amsterdam AITD cohort (euthyroid women who had first- or second-degree relatives with overt AITD) who at baseline had normal TSH and no thyroid antibodies; controls were healthy women examined at the same period. In the longitudinal study B, subjects who developed de novo thyroid peroxidase antibody (TPO-Ab) were compared with those who did not. Cases and controls were subjects from the Amsterdam AITD cohort who at baseline had normal TSH and no thyroid antibodies and during follow-up developed TPO-Ab (cases) or remained without thyroid antibodies (controls). Controls in both studies were matched for age, BMI, smoking status, estrogen use, month of blood sampling, and in study B for the duration of follow-up. RESULTS: Serum 25(OH)D levels were as follows: study A: 21.0 +/- 7.9 vs 18.0 +/- 6.4 ng/ml (78 cases vs 78 controls, P=0.01); study B: baseline, 22.6 +/- 10.3 vs 23.4 +/- 9.1; follow-up 21.6 +/- 9.2 vs 21.2 +/- 9.3 ng/ml (67 cases vs 67 controls, NS). CONCLUSIONS: Early stages of thyroid autoimmunity (in study A genetic susceptibility and in study B development of TPO-Ab) are not associated with low vitamin D levels. PMID- 22518051 TI - Assessment of aortic valve complex by three-dimensional echocardiography: a framework for its effective application in clinical practice. AB - In the current era of expanding catheter-based and complex repair procedures to treat aortic valve (AV) diseases, growing consideration is being given to understanding the functional anatomy of the AV complex. Echocardiography is the primary imaging modality to assess and follow-up AV diseases, and the recent three-dimensional (3D) capabilities allow clinicians to appreciate the functional complexity of the aortic root in the beating heart. Despite being subject to several limitations, 3D echocardiography (3DE) holds promise as a more suitable imaging backup for aortic interventions of mounting complexity and for circumventing some of their current complications. In this review, we discuss the key principles of 3DE for assessing the AV pathology and the incremental clinical benefits in comparison with conventional 2DE and Doppler echocardiography, justifying its implementation in the diagnostic workup of aortic diseases. In view of an effective clinical use, a brief section is dedicated to the acquisition modalities, display, and interpretation of various abnormalities by 3DE. PMID- 22518052 TI - Coronary artery bypass grafting for the occlusion of left main trunk and right coronary artery guided by computed tomographic angiography. PMID- 22518053 TI - Screening for rheumatic heart disease: evaluation of a simplified echocardiography-based approach. AB - AIMS: Portable echocardiography has emerged as a potential tool to detect rheumatic heart disease (RHD) early. Complex echocardiographic criteria used in recent epidemiological studies may be difficult to translate into daily practice in areas where the burden of RHD is greatest and skilled practitioners are lacking. The aim of this study was to evaluate a simplified echo approach for RHD screening among children in low-income countries. METHODS AND RESULTS: Retrospective analysis of data from a cross-sectional echocardiography-based study carried out in 2005 through the examination of 2170 school children in Maputo, Mozambique. We aimed to evaluate the value of a reference set of criteria (defined as a combination of Doppler and morphological rheumatic features of the aortic and/or mitral valves) compared with an easy-to-use single mitral regurgitation jet-length criterion (simplified set of criteria). All suspected lesions (according to reference or simplified criteria) detected in the field by a portable echo machine were reassessed by non-portable echocardiography and then read by three independent experts. Definite RHD cases in both groups were finally ascertained according to the reference criteria. Portable echocardiography detected valve regurgitation in 208 children. According to the reference criteria, 18 children were detected with suspected RHD on site. Of these, 15 children (83%) were considered to have definite RHD, giving a prevalence of 6.9 per 1000 (95% CI: 3.9-11.4). The simplified mitral regurgitation jet-length criteria detected 12 children at school, 11 of whom were subsequently confirmed to have definite RHD, giving an estimated prevalence of 5.1 per 1000 (95% CI: 2.5 9.1) (P = 0.12, exact McNemar test). When compared with the reference criteria, the simplified approach yields a maximum sensitivity of 73% for case detection, with a positive predictive value of 92%. CONCLUSION: Simplified echocardiography based screening for RHD appears feasible, allowing rapid and appropriate detection of a significant number of RHD cases on site. PMID- 22518054 TI - Is NICE ageist? Highlights from this issue. PMID- 22518055 TI - Narrating stroke: the life-writing and fiction of brain damage. AB - Cerebro-vascular events are, after neurodegenerative disorders, the most frequent cause of brain damage that leads to the patient's impaired cognitive and/or bodily functioning. While the medico-scientific discourse related to stroke suggests that patients experience a change in identity and self-concept, the present analysis focuses on the patients' personal presentation of their experience to, first, highlight their way of thinking and feeling and, second, contribute to the clinician's actual understanding of the meaning of stroke within the life of each individual. As stroke 'victims' necessarily speak from the position of having undergone very abrupt degeneration followed by being confronted with a gradual relocation within their 'recovery', the present study addresses how narrative texts describe the condition, that is, the insult itself and its impairing consequences for body and mind, and how patients portray themselves within their illness. Furthermore, given that all illness narrative must remain non-representative, especially when exploring conditions that impair cognitive abilities, autobiographically inspired fiction, equally, contributes to neuroscientific perspectives on embodiment: it gives further insight into how the condition is perceived and alerts us to those aspects of the experience that are understood as particularly momentous. PMID- 22518056 TI - Pain and suffering: twins that can be managed using an interdisciplinary and biopsychosocial health model. PMID- 22518057 TI - Diagnostic value of a hand-carried ultrasound device for free intra-abdominal fluid and organ lacerations in major trauma patients. AB - BACKGROUND: Technological progress has led to the introduction of hand-carried ultrasound (HCU) imagers in clinical workflow. The aim of this study is to analyse whether examination with a HCU device is a rapid and reliable alternative to contrast-enhanced multidetector CT (MDCT) scans in diagnosis of free intra abdominal fluid and organ lacerations in major trauma patients. METHODS: 31 major trauma patients with an injury severity score >15 and the necessity of a MDCT scan (standard of reference) were enrolled prospectively to this study, and additionally examined with a HCU, according to 'focused assessment with sonography for trauma' principles for the assessment of organ lacerations and free intra-abdominal fluid. The HCU device employed was of the latest generation. Statistical analysis was performed using PASW V.18. RESULTS: Four patients were diagnosed with free intra-abdominal fluid (prevalence 12.9%). HCU showed a sensitivity and specificity of 75% and 100%, respectively. Positive predictive value and negative predictive value were 100% and 96%, respectively. Five patients had organ lacerations (prevalence 16.1%). In these cases, the HCU was able to detect organ lacerations with a sensitivity and specificity of 80% and 100%, respectively. Therefore, a positive predictive value and negative predictive value of 100% and 96%, respectively, were calculated. CONCLUSION: In major trauma patients, examination with HCU according to the 'focused assessment with sonography for trauma' principles for the diagnosis of organ lacerations and free intra-abdominal fluid is a reliable and rapid alternative to MDCT scans and can help save precious time in emergency situations, and should, additionally, be evaluated in the pre-clinical workflow. PMID- 22518058 TI - Intracranial air on plain films of the face--one sign not to miss! PMID- 22518059 TI - Current practices for paediatric procedural sedation and analgesia in emergency departments: results of a nationwide survey in Korea. AB - OBJECTIVE: Procedural sedation and analgesia (PSA) in children has become a standard tool in emergency settings, but no national PSA guidelines have been developed for the emergency department (ED) in Korea. Therefore, we investigated the practice of PSA and the level of adherence to institutional PSA guidelines in EDs of teaching hospitals. METHODS: This study was a cross-sectional, web-based survey. The study subjects were the faculty of EDs from 96 teaching hospitals. The questionnaire was posted on an internet site, and the participants were requested that the questionnaire be answered by email and telephone in May 2009. RESULTS: The questionnaires were completed by 67.7% of the participants. Only 20% of EDs had institutional PSA guidelines, 21.5% of those had discharge criteria and 13.8% of EDs had a discharge instruction form. Residents were administered PSA at 76.9% of EDs. The airway rescue equipment was near the area where PSA was performed in 76.9% of EDs. The most commonly used medication for both diagnostic imaging and painful procedure was oral chloral hydrate (87.7%, 61.5%). In 64.6% of EDs, patients were monitored. In only 21 cases, EDs (50.0%) monitored the patients to recovery after PSA or discharge. CONCLUSIONS: Current PSA for paediatric patients have not been appropriately applied in Korea. Unified PSA guidelines were rare in the hospitals surveyed, and many patients were not monitored over an appropriate duration, nor did they receive adequate medications for sedation by the best trained personnel. Therefore, the national PSA guidelines must be developed and implemented as early as possible. PMID- 22518060 TI - The impact of changing the 4 h emergency access standard on patient waiting times in emergency departments in England. AB - OBJECTIVE: To determine whether the process of emergency care waiting in England has changed following the modification of the operational standard for the 4 h waiting time target from 98% to 95% in June 2010. DESIGN: Retrospective analysis of publicly available 'total time spent in accident and emergency' data from Department of Health. SETTING AND PARTICIPANTS: Patients attending emergency departments (EDs) in England between October 2002 and September 2011. In 2005, the government set an operational standard that 98% of patients should wait <4 h in ED. In June 2010, the government announced that the operating standard would change to 95% immediately. OUTCOME MEASURES: Percentage of patients waiting <4 h (weekly and quarterly), and total number of patients waiting >4 h. RESULTS: The average percentage of patients waiting <4 h fell from 98% to 95% almost immediately following the operational standard change. Consequently, between October 2010 and September 2011, approximately 383 000 additional patients in England EDs waited in excess of 4 h than had the 98% standard been attained. The emergency care system appears to have been stabilised at this new level. CONCLUSIONS: The policy change for waiting times in EDs in England has resulted in the process of emergency care in England adjusting to the new operational standard of 95% of patients waiting <4 h. As a result, more patients are waiting >4 h to receive the care they need; consequently, outcomes are likely to suffer. PMID- 22518061 TI - The adult pituitary shows stem/progenitor cell activation in response to injury and is capable of regeneration. AB - The pituitary gland constitutes, together with the hypothalamus, the regulatory core of the endocrine system. Whether the gland is capable of cell regeneration after injury, in particular when suffered at adult age, is unknown. To investigate the adult pituitary's regenerative capacity and the response of its stem/progenitor cell compartment to damage, we constructed a transgenic mouse model to conditionally destroy pituitary cells. GHCre/iDTR mice express diphtheria toxin (DT) receptor after transcriptional activation by Cre recombinase, which is driven by the GH promoter. Treatment with DT for 3 d leads to gradual GH(+) (somatotrope) cell obliteration with a final ablation grade of 80-90% 1 wk later. The stem/progenitor cell-clustering side population promptly expands after injury, concordant with the immediate increase in Sox2(+) stem/progenitor cells. In addition, folliculo-stellate cells, previously designated as pituitary stem/progenitor cells and significantly overlapping with Sox2(+) cells, also increase in abundance. In situ examination reveals expansion of the Sox2(+) marginal-zone niche and appearance of remarkable Sox2(+) cells that contain GH. When mice are left after the DT-provoked lesion, GH(+) cells considerably regenerate during the following months. Double Sox2(+)/GH(+) cells are observed throughout the regenerative period, suggesting recovery of somatotropes from stem/progenitor cells, as further supported by 5-ethynyl-2' deoxyuridine (EdU) pulse-chase lineage tracing. In conclusion, our study demonstrates that the adult pituitary gland holds regenerative competence and that tissue repair follows prompt activation and plausible involvement of the stem/progenitor cells. PMID- 22518063 TI - Maximum occusal bite force for children in different dentition stages. AB - This study was carried out to record maximum occlusal bite force (MOBF) among different dentition stages in children and to study the relation of occlusal bite force to weight, height, and gender. A total of 1011 children (500 females and 511 males) aged from 3 to 18 years were examined. The subjects were divided into 5 groups according to their dentition stage as the following:- early primary dentition stage (100 males and 100 females, average age was 3.37 +/- 0.23 years), late primary dentition stage (104 males and 100 females, average age was 5.86 +/- 1.15 years), early mixed dentition stage (100 males and 100 females, average age was 8.15 +/- 0.67 years), late mixed dentition stage (100 males and 100 females, average age was 9.97 +/- 0.86 years ), and permanent dentition stage (107 males and 100 females, average age was 14.03 +/- 2.14 years). Occlusal bite force was measured using a hydraulic occlusal force gauge. The means of MOBF for the different dentition stages were:- 176 N in early primary stage, 240 N in late primary stage, 289 N in early mixed stage, 433 N in late mixed stage, and 527 N in the permanent dentition stage, respectively. Gender differences were detected in groups 2, 3 and 4. Height and age significantly correlated with the MOBF in all dentition stage groups except group 1. In conclusion, the MOBF increased with age. Age, gender, and height were significant predictors of the MOBF. PMID- 22518062 TI - The anorectic effect of CNTF does not require action in leptin-responsive neurons. AB - Leptin resistance is a feature of obesity that poses a significant therapeutic challenge. Any treatment that is effective to reduce body weight in obese patients must overcome or circumvent leptin resistance, which promotes the maintenance of excess body fat in obese individuals. Ciliary neurotrophic factor (CNTF) is unique in its ability to reduce food intake and body weight in obese, leptin-resistant humans and rodents. Although attempts to use CNTF as an obesity therapy failed due to the development of neutralizing antibodies to the drug, efforts to understand mechanisms for CNTF's anorectic effects provide an opportunity to develop new drugs for leptin-resistant individuals. CNTF and leptin share several structural, anatomic, and signaling properties, but it is not understood whether or how the two cytokines might interact to affect energy balance. Here, we conditionally deleted the CNTF receptor (CNTFR) subunit, CNTFRalpha, in cells expressing leptin receptors. We found that CNTFR signaling in leptin-responsive neurons is not required for endogenous maintenance of energy balance and is not required for the anorectic response to exogenous administration of a CNTF agonist. These results indicate that despite anatomical overlap for CNTF and leptin action, CNTF appears to act within a distinct neuronal population to elicit its potent anorectic effect. PMID- 22518064 TI - Elderly Care and Intrafamily Resource Allocation when Children Migrate. AB - This paper considers the intrafamily allocation of elderly care in the context of international migration where migrant children may be able to provide financial assistance to their parents, but are unable to offer physical care. To investigate the interaction between siblings, I take a non-cooperative view of family decision-making and estimate best response functions for individual physical and financial contributions as a function of siblings' contributions. I address the endogeneity of siblings' contributions and individual migration decisions by using siblings' characteristics as instrumental variables as well as models including family fixed effects. For both migrants and non-migrants, I find evidence that financial contributions function as strategic complements while siblings' time contributions operate as strategic substitutes. This suggests that children's contributions toward elderly care may be based on both strategic bequest and public good motivations. PMID- 22518065 TI - Diels-Alder reaction of maldoxin with an isopropenylallene. AB - The Diels-Alder reaction of maldoxin with an isopropenylallene at 60-75 degrees C afforded an adduct closely related to chloropestolide A (24%) and a second adduct (0-11%) that underwent an ene reaction to generate the chloropupukeanolide D (11-22%) skeleton. The Diels-Alder reaction occurred with good selectively (>5:1) from a single face of maldoxin under much milder conditions than previously reported for the analogous dimethoxycyclohexadienone. Furthermore, the ene reaction took place under mild conditions whereas the analogous Diels-Alder adduct from the dimethoxycyclohexadienone did not undergo an ene reaction. PMID- 22518066 TI - Identification of an Unexpected 2-Oxonia[3,3]sigmatropic Rearrangement/Aldol Pathway in the Formation of Oxacyclic Rings. Total Synthesis of (+)-Aspergillin PZ. AB - This paper reports the first unambiguous evidence that the cascade synthesis of tetrahydrofuran-containing oxacyclic molecules depicted in Scheme 12 can take place by a 2-oxonia[3,3]sigmatropic/aldol mechanism rather than by a Prins cyclization/pinacol rearrangement sequence. The 8-oxabicyclo[3.2.1]octyl aldehyde products of this reaction, 20 and 29, were employed to complete the first total synthesis of the structurally remarkable isoindolone alkaloid (+)-aspergillin PZ (1). The lack of activity seen in two tumor cell lines for synthetic (+) aspergillin PZ calls into question the suggestion that aspergillin PZ, like many aspochalasin diterpenes, might exhibit useful antitumor properties. PMID- 22518067 TI - Individual differences in temperament and behavioral management practices for nonhuman primates. AB - Effective behavioral management plans are tailored to unique behavioral patterns of each individual species. However, even within a species behavioral needs of individuals can vary. Factors such as age, sex, and temperament can affect behavioral needs of individuals. While some of these factors, such as age and sex, are taken into account, other factors, such as an individual's temperament, are rarely specifically provided for in behavioral management plans. However, temperament may affect how animals respond to socialization, positive reinforcement training and other forms of enrichment. This review will examine how individual differences in temperament might affect, or be affected by, behavioral management practices for captive primates. Measuring temperament may help us predict outcome of social introductions. It can also predict which animals may be difficult to train using traditional methods. Further, knowledge of temperament may be able to help identify individuals at risk for development of behavioral problems. Taken together, understanding individual differences in temperament of captive primates can help guide behavioral management decisions. PMID- 22518068 TI - Won't get fooled again: An event-related potential study of task and repetition effects on the semantic processing of items without semantics. AB - A growing body of evidence suggests that semantic access is obligatory. Several studies have demonstrated that brain activity associated with semantic processing, measured in the N400 component of the event-related brain potential (ERP), is elicited even by meaningless, orthographically illegal strings, suggesting that semantic access is not gated by lexicality. However, the downstream consequences of that activity vary by item type, exemplified by the typical finding that N400 activity is reduced by repetition for words and pronounceable nonwords but not for illegal strings. We propose that this lack of repetition effect for illegal strings is caused not by lack of contact with semantics, but by the unrefined nature of that contact under conditions in which illegal strings can be readily categorised as task-irrelevant. To test this, we collected ERPs from participants performing a modified Lexical Decision Task, in which the presence of orthographically illegal acronyms rendered meaningless illegal strings more difficult lures than normal. Confirming our hypothesis, under these conditions illegal strings elicited robust N400 repetition effects, quantitatively and qualitatively similar to those elicited by words, pseudowords, and acronyms. PMID- 22518069 TI - Multi-Method Assessment of ADHD Characteristics in Preschool Children: Relations between Measures. AB - Several forms of assessment tools, including behavioral rating scales and objective tests such as the Continuous Performance Test (CPT), can be used to measure inattentive and hyperactive/impulsive behaviors associated with Attention Deficit/Hyperactivity Disorder (ADHD). However, research with school-age children has shown that the correlations between parent ratings, teacher ratings, and scores on objective measures of ADHD-characteristic behaviors are modest at best. In this study, we examined the relations between parent and teacher ratings of ADHD and CPT scores in a sample of 65 preschoolers ranging from 50 to 72 months of age. No significant associations between teacher and parent ratings of ADHD were found. Parent-ratings of both inattention and hyperactivity/impulsivity accounted for variance in CPT omission errors but not CPT commission errors. Teacher ratings showed evidence of convergent and discriminant validity when entered simultaneously in a hierarchical regression. These tools may be measuring different aspects of inattention and hyperactivity/impulsivity. PMID- 22518070 TI - Subgroups of Adult Basic Education Learners with Different Profiles of Reading Skills. AB - The purpose of this study was to identify subgroups of adult basic education (ABE) learners with different profiles of skills in the core reading components of decoding, word recognition, spelling, fluency, and comprehension. The analysis uses factor scores of those 5 reading components from on a prior investigation of the reliability and construct validity of measures of reading component skills (MacArthur, Konold, Glutting, & Alamprese, 2010). In that investigation, confirmatory factor analysis found that a model with those 5 factors fit the data best and fit equally well for native and non-native English speakers. The study included 486 students, 334 born or educated in the United States (native) and 152 not born nor educated in the US (non-native) but who spoke English well enough to participate in English reading classes. The cluster analysis found an 8-cluster solution with good internal cohesion, external isolation, and replicability across subsamples. Of the 8 subgroups, 4 had relatively flat profiles (range of mean scores across factors < 0.5 SD), 2 had higher comprehension than decoding, and 2 had higher decoding than comprehension. Profiles were consistent with expectations regarding demographic factors. Non-native speakers were overrepresented in subgroups with relatively higher decoding and underrepresented in subgroups with relatively higher comprehension. Adults with self-reported learning disabilities were overrepresented in the lowest performing subgroup. Older adults and men were overrepresented in subgroups with lower performance. The study adds to the limited research on the reading skills of ABE learners and, from the perspective of practice, supports the importance of assessing component skills to plan instruction. PMID- 22518071 TI - Modeling Carbon-Black/Polymer Composite Sensors. AB - Conductive polymer composite sensors have shown great potential in identifying gaseous analytes. To more thoroughly understand the physical and chemical mechanisms of this type of sensor, a mathematical model was developed by combining two sub-models: a conductivity model and a thermodynamic model, which gives a relationship between the vapor concentration of analyte(s) and the change of the sensor signals. In this work, 64 chemiresistors representing eight different carbon concentrations (8-60 vol% carbon) were constructed by depositing thin films of a carbon-black/polyisobutylene composite onto concentric spiral platinum electrodes on a silicon chip. The responses of the sensors were measured in dry air and at various vapor pressures of toluene and trichloroethylene. Three parameters in the conductivity model were determined by fitting the experimental data. It was shown that by applying this model, the sensor responses can be adequately predicted for given vapor pressures; furthermore the analyte vapor concentrations can be estimated based on the sensor responses. This model will guide the improvement of the design and fabrication of conductive polymer composite sensors for detecting and identifying mixtures of organic vapors. PMID- 22518072 TI - Serum IL-18 is closely associated with renal tubulointerstitial injury and predicts renal prognosis in IgA nephropathy. AB - BACKGROUND: IgA nephropathy (IgAN) was thought to be benign but recently found it slowly progresses and leads to ESRD eventually. The aim of this research is to investigate the value of serum IL-18 level, a sensitive biomarker for proximal tubule injury, for assessing the histopathological severity and disease progression in IgAN. METHODS: Serum IL-18 levels in 76 IgAN patients and 36 healthy blood donors were measured by ELISA. We evaluated percentage of global and segmental sclerosis (GSS) and extent of tubulointerstitial damage (TID). The correlations between serum IL-18 levels with clinical, histopathological features and renal prognosis were evaluated. RESULTS: The patients were 38.85 +/- 10.95 years old, presented with 2.61 (1.43~4.08) g/day proteinuria. Serum IL-18 levels were significantly elevated in IgAN patients. Baseline serum IL-18 levels were significantly correlated with urinary protein excretion (r = 0.494, P = 0.002), Scr (r = 0.61, P < 0.001), and eGFR (r = -0.598, P < 0.001). TID scores showed a borderline significance with serum IL-18 levels (r = 0.355, P = 0.05). During follow-up, 26 patients (34.21%) had a declined renal function. Kaplan-Meier analysis found those patients with elevated IL-18 had a significant poor renal outcome (P = 0.03), and Cox analysis further confirmed that serum IL-18 levels were an independent predictor of renal prognosis (beta = 1.98, P = 0.003). PMID- 22518073 TI - Long-term outcome and structural integrity following open repair of massive rotator cuff tears. AB - BACKGROUND: Surgical repair of massive rotator cuff tears is associated with less favorable clinical results and a higher retear rate than repair of smaller tears, which is attributed to irreversible degenerative changes of the musculotendinous unit. MATERIALS AND METHODS: During the study period, 25 consecutive patients with a massive rotator cuff tear were enrolled in the study and the tears were repaired with an open suture anchor repair technique. Preoperative and postoperative clinical assessments were performed with the Constant score, the simple shoulder test (SST) and a pain visual analog scale (VAS). At the final follow-up, rotator cuff strength measurement was evaluated and assessment of tendon integrity, fatty degeneration and muscle atrophy was done using a standardized magnetic resonance imaging protocol. RESULTS: The mean follow-up period was 70 months. The mean constant score improved significantly from 42.3 to 73.1 points at the final follow-up. Both the SST and the pain VAS improved significantly from 5.3 to 10.2 points and from 6.3 to 2.1, respectively. The overall retear rate was 44% after 6 years. Patients with an intact repair had better shoulder scores and rotator cuff strength than those with a failed repair, and also the retear group showed a significant clinical improvement (each P<0.05). Rotator cuff strength in all testing positions was significantly reduced for the operated compared to the contralateral shoulder. Muscle atrophy and fatty infiltration of the rotator cuff muscles did not recover in intact repairs, whereas both parameters progressed in retorn cuffs. CONCLUSIONS: Open repair of massive rotator tears achieved high patient satisfaction and a good clinical outcome at the long-term follow-up despite a high retear rate. Also, shoulders with retorn cuffs were significantly improved by the procedure. Muscle atrophy and fatty muscle degeneration could not be reversed after repair and rotator cuff strength still did not equal that of the contralateral shoulder after 6 years. LEVEL OF EVIDENCE: Level IV. PMID- 22518074 TI - Validation of the Stanmore percentage of normal shoulder assessment. AB - BACKGROUND AND PURPOSE: The Stanmore Percentage of Normal Shoulder Assessment (SPONSA) is a patient-reported outcome measure (PROM). The score assesses pain, range of movement, strength, stability and function of the shoulder. The aim of this work was to formally validate the SPONSA. MATERIALS AND METHODS: Validation of this score was carried out by measuring reproducibility, construct validity and sensitivity to change. Time to completion was also recorded. The Oxford Shoulder Score (OSS) and Constant Score (CS) were used for comparison. These assessments were performed with 61 individuals undergoing shoulder interventions. RESULTS: There was excellent preoperative reproducibility in both intra- and inter-observer groups. The SPONSA had a 0.79 correlation with the OSS and 0.78 with the CS. The overall effect size of the SPONSA was 0.72, which was comparable to OSS (0.65) and greater than CS (0.34), implying equal or better sensitivity to change. CONCLUSIONS: The SPONSA is practical and quick to perform and also a reproducible and a sensitive instrument. This simple PROM is a commendable addition to the existing validated scoring methods for the shoulder. LEVEL OF EVIDENCE: I; testing of previously developed diagnostic criteria on consecutive patients (with universally applied reference "gold" standard). PMID- 22518075 TI - Partial-thickness articular surface rotator cuff tears in patients over the age of 35: Etiology and intra-articular associations. AB - PURPOSE: Partial-thickness articular-sided rotator cuff tears have a multifactorial etiology and are associated with degeneration of the tendon. They are often described as an injury of the young athlete, although they are also found in the older population. The aim of this study was to investigate the frequency and associations of partial-thickness articular-sided tears in patients over the age of 35 years. DESIGN: Retrospective MATERIALS AND METHODS: A retrospective study of all arthroscopic procedures for rotator cuff pathology in patients over the age of 35 years over a 2-year period by a single surgeon was performed. The included patients were divided into two groups based on the arthroscopic findings: those with a partial-thickness articular-sided rotator cuff tear and those with pure tendinopathy. The groups were then compared to identify the associated pathology with the rotator cuff lesions. 2*2 contingency table analysis and unpaired Student's t-test were used for statistical analysis. RESULTS: One hundred patients were included in the study of whom 62 had a partial articular-sided tear. Those with a partial articular-sided tear were older (P=0.0001), were more commonly associated with a documented injury (P=0.03), and more commonly had biceps degeneration (P=0.001) and synovitis (P=0.02) within the joint. CONCLUSION: Partial-thickness articular-sided tears are a common occurrence in patients requiring arthroscopic surgery for rotator cuff pathology over the age of 35 years. This probably reflects an injury in an already degenerate cuff. This would support the theory of intrinsic degeneration of the tendon in this age group and probably represent a different etiology to those seen in the young athletes. LEVEL OF EVIDENCE: Level 3. PMID- 22518076 TI - Myositis ossificans circumscripta of the triceps due to overuse in a female swimmer. AB - Myositis ossificans is a rare condition characterized by non-neoplastic heterotopic bone formation in soft tissue and skeletal muscle. It is a benign and often self-limiting disease with no need for surgery. Here, we describe a young female swimmer with myositis ossificans circumscripta of the triceps due to overuse. Because of the benign character of the lesion, conservative treatment was initiated with rest and anti-inflammatory drugs. She obtained complete resolution after 6 months and was able to return to normal sporting activities. Myositis ossificans circumscripta is a rare benign lesion with an excellent prognosis. Most lesions in athletes occur due to contusions or strains; however, overuse is now described as well. Spontaneous resolution is seen in almost all cases. Cases in which, despite conservative treatment, a painful mass persists, surgical excision can be considered. PMID- 22518077 TI - Giant cell tumor of the supraspinatus tendon sheath causing shoulder impingement. PMID- 22518078 TI - Effects of Cinnamomum zeylanicum (Ceylon cinnamon) on blood glucose and lipids in a diabetic and healthy rat model. AB - OBJECTIVES: To evaluate short- and long-term effects of Cinnamomum zeylanicum on food consumption, body weight, glycemic control, and lipids in healthy and diabetes-induced rats. MATERIALS AND METHODS: The study was conducted in two phases (Phase I and Phase II), using Sprague-Dawley rats in four groups. Phase I evaluated acute effects on fasting blood glucose (FBG) (Groups 1 and 2) and on post-oral glucose (Groups 3 and 4) blood glucose. Groups 1 and 3 received distilled-water and Groups 2 and 4 received cinnamon-extracts. Phase II evaluated effects on food consumption, body weight, blood glucose, and lipids over 1 month. Group A (n = 8, distilled-water) and Group B (n = 8, cinnamon-extracts) were healthy rats, while Group C (n = 5, distilled-water) and Group D (n = 5, cinnamon extracts) were diabetes-induced rats. Serum lipid profile and HbA1c were measured on D-0 and D-30. FBG, 2-h post-prandial blood glucose, body weight, and food consumption were measured on every fifth day. RESULTS: PHASE I: There was no significant difference in serial blood glucose values in cinnamon-treated group from time 0 (P > 0.05). Following oral glucose, the cinnamon group demonstrated a faster decline in blood glucose compared to controls (P < 0.05). Phase II: Between D0 and D30, the difference in food consumption was shown only in diabetes induced rats (P < 0.001). Similarly, the significant difference following cinnamon-extracts in FBG and 2-h post-prandial blood glucose from D0 to D30 was shown only in diabetes-induced rats. In cinnamon-extracts administered groups, total and LDL cholesterol levels were lower on D30 in both healthy and diabetes induced animals (P < 0.001). CONCLUSIONS: C. zeylanicum lowered blood glucose, reduced food intake, and improved lipid parameters in diabetes-induced rats. PMID- 22518079 TI - Antioxidant and antibacterial activities of the leaf essential oil and its constituents furanodienone and curzerenone from Lindera pulcherrima (Nees.) Benth. ex hook. f. AB - BACKGROUND: Lindera pulcherrima (Nees.) Benth. ex Hook. f. (Family: Lauraceae), an evergreen shrub, is an important medicinal plant distributed in temperate Himalayan regions. The leaves and bark are used as spice in cold, fever, and cough. MATERIALS AND METHODS: In this study, the terpenoid composition, antioxidant, and antibacterial activities of the leaf essential oil and its major constituents are being analyzed. CONCLUSION: The in vitro antioxidant activity showed a potent free radical scavenging activity for the essential oil as evidenced by a low IC(50) value for DPPH radical followed by furanodienone (0.087 +/- 0.03 and 1.164 +/- 0.58 mg/ml respectively) and the inhibition of lipid peroxidation for the oil and furanodienone also followed the same order (IC(50) 0.74 +/- 0.13 and 2.12 +/- 0.49 mg/ml, respectively). The oil and the constituents were also tested against three Gram negative (Escherichia coli, Salmonella enterica enterica, and (Pasturella multocida) and one Gram positive (Staphylococcus aureus) bacteria. The essential oil was effective against S. aureus (IZ = 19.0 +/- 0.34; MIC 3.90 MUl/ml) while furanodienone showed potent activity against E. coli and S. enterica enterica (IZ = 18.0 +/- 0.14 and 16.0 +/ 0.10 respectively). On the other hand, curzerenone was found to be slightly effective against E. coli (IZ = 10.8 +/- 0.52). The MIC value of the essential oil was least against S. aureus (MIC = 3.90 MUl/ml) and that of furanodienone against E. coli (MIC = 3.90 MUl/ml). PMID- 22518080 TI - Chemical and biological study of Manilkara zapota (L.) Van Royen leaves (Sapotaceae) cultivated in Egypt. AB - BACKGROUND: Manilkara zapota (L.) Van Royen is an evergreen tree, native to the tropical Americas and introduced to Egypt as a fruiting tree in 2002. No previous study was reported on the plant cultivated in Egypt. MATERIALS AND METHODS: In this study, the leaves of the plant cultivated in Egypt were subjected to phytochemical and biological investigations. The lipoidal matter was analyzed by GLC. Five compounds were isolated from the petroleum ether and ethyl acetate fractions of the alcoholic extract of the leaves by chromatographic fractionation on silica gel and sephadex, the structures of these compounds were identified using IR, UV, MS, (1)H-NMR and (13)C-NMR. The LD(50) of the alcoholic and aqueous extracts of the leaves was determined and their antihyperglycemic, hypocholesterolemic and antioxidant activities were tested by enzymatic colorimetric methods using specific kits. RESULTS: Unsaturated fatty acids represent 32.32 % of the total fatty acids, oleic acid (13.95%), linoleidic acid (10.18 %) and linoleic acid (5.96 %) were the major ones. The isolated compounds were identified as lupeol acetate, oleanolic acid, apigenin-7-O-alpha-L rhamnoside, myricetin-3-O-alpha-L-rhamnoside and caffeic acid. This is the first report about isolation of these compounds from Manilkara zapota except myricetin 3-O-alpha-L-rhamnoside, which was previously isolated from the plant growing abroad. The LD(50) recorded 80 g/Kg b. wt. for both the tested extracts, so they could be considered to be safe. They exhibited antihyperglycemic, hypocholesterolemic and antioxidant activities. CONCLUSION: The observed biological activities were attributed to the different chemical constituents present in the plant mainly its phenolic constituents. PMID- 22518081 TI - Medicinal plants use in central Togo (Africa) with an emphasis on the timing. AB - BACKGROUND: Plant-based remedies continue to play a key role in the health care of people in Togo; however, there is a lack of published data in medicinal plants and medical practices of the people in the country. OBJECTIVE: This study was aimed at documenting the plant utilization in the Tem folk medicine in the central region of Togo. MATERIALS AND METHODS: An ethnobotanical survey was conducted with traditional healers in the central region of Togo using a semi structured questionnaire. RESULTS: This study demonstrated that local specialists in the central region of Togo tend to agree with each other in terms of the plants used to treat diabetes (ICF = 0.38), infertility, and abdominal pains (ICF = 0.33), but cite a much more diverse groups of plants to treat problems related to arterial hypertension, sickle cell disease, and abscess. They use 144 herbal concoctions made of 72 plants, distributed among 36 botanical families. The Euphorbiaceae family with eight species was best represented in terms of the number of species. The species with the highest use value were Khaya senegalensis (Desr.) A. Juss. (Meliaceae) (UV = 0.36), Anthocleista djalonensis A. Chev. (Gentianaceae) (UV = 0.27), Trichilia emetica Vahl (Meliaceae) (UV = 0.25), and Sarcocephalus latifolius (Sm.) E. A. Bruce (Rubiaceae) (UV = 0.21). They also rely on the timing in the plant processing and the administration of herbal remedies. CONCLUSION: All these findings are based on empirical observations; laboratory screenings are needed to check the effectiveness of these plants. PMID- 22518082 TI - Phenolic compounds from Foeniculum vulgare (Subsp. Piperitum) (Apiaceae) herb and evaluation of hepatoprotective antioxidant activity. AB - OBJECTIVE: The study was designed to evaluate the antioxidant and hepatoprotective activities of the 80% methanolic extract as well as the ethyl acetate (EtOAc) and butanol (BuOH) fractions of the wild fennel (Foeniculum vulgare (Subsp; Piperitum)) and cultivated fennel (F. vulgare var. azoricum). In addition, quantification of the total phenolic content in the 80% methanol extract of fennel wild and cultivated herbs is measured. MATERIALS AND METHODS: An amount of 400 g of air dried powdered herb of wild and cultivated fennel were sonicated with aqueous methanol (80%), successively extracted with Hexane, EtOAc, and n-BuOH. The EtOAc and n-BuOH were subjected to repeated column chromatography on silica gel and Sephadex LH-20. The antioxidant effect was determined in vitro using 1,1-diphenyl-2-picrylhydrazyl (DPPH). Hepatoprotective activity was carried out using a Wistar male rat (250-300 g). Total phenolic and flavonoid contents were determined as chlorogenic acid and rutin equivalents, respectively. RESULTS: Two phenolic compounds, i.e., 3,4-dihydroxy-phenethylalchohol-6-O-caffeoyl-beta-D glucopyranoside and 3?,8?-binaringenin were isolated from the fennel wild herb, their structures were elucidated by spectral methods including 1D NMR, 2D NMR, and UV. The EtOAc and BuOH fractions of wild fennel were found to exhibit a radical scavenging activity higher than those of cultivated fennel. An in vitro method of rat hepatocytes monolayer culture was used for the investigation of hepatotoxic effects of the 80% methanol extract on the wild and cultivated fennel, which were >1000 and 1000 MUg/mL, respectively. As well as, their hepatoprotective effect against the toxic effect of paracetamol (25 mM) was exerted at 12.5 MUg/mL concentration. CONCLUSIONS: Fennel (F. Vulgare) is a widespread plant species commonly used as a spice and flavoring. The results obtained in this study indicated that the fennel (F. vulgare) herb is a potential source of natural antioxidant. Two phenolic compounds, i.e. 3,4-dihydroxy phenethylalchohol-6-O-caffeoyl-beta-D-glucopyranoside (A) and 3?,8?-binaringenin (B) were isolated from the fennel wild herb for the first time. PMID- 22518083 TI - Aloe barbadensis Mill. formulation restores lipid profile to normal in a letrozole-induced polycystic ovarian syndrome rat model. AB - BACKGROUND: Polycystic ovarian syndrome (PCOS), characterized by ovulatory infertility and hyperandrogenism, is associated with metabolic complications such as dyslipidemia, insulin resistance and endothelial dysfunction. Almost 70% PCOS women have abnormal serum lipid levels (dyslipidemia) and 50% of these women are obese. Several classes of pharmacological agents have been used to manage dyslipidemia. However, studies have shown adverse effects associated with these drugs. In the light of alternate therapy, many medicinal herbs have been reported to show hypoglycemic, anti-hyperlipidemic potential. Aloe barbadensis Mill. or Aloe vera is reported as one such herb. This study was to evaluate the lipid correcting effect of Aloe vera gel (AVG) in a PCOS rat model. MATERIALS AND METHODS: PCOS was induced in Charles Foster female rats by oral administration of non-steroidal aromatase inhibitor letrozole (0.5 mg/kg body weight, 21 days). All rats were hyperglycemic and 90% rats also showed elevated plasma triglycerides, elevated LDL cholesterol levels, and lowered plasma HDL cholesterol levels indicative of a dyslipidemic profile. PCOS positive rats with an aberrant lipid profile were selected for treatment. An AVG formulation (1 ml (10 mg)/day, 30 days) was administered orally. RESULTS AND CONCLUSION: AVG treated PCOS rats exhibited significant reduction in plasma triglyceride and LDL cholesterol levels, with an increase in HDL cholesterol. The gel treatment also caused reversion of abnormal estrous cyclicity, glucose intolerance, and lipid metabolizing enzyme activities, bringing them to normal. In conclusion, AVG has phyto components with anti-hyperlipidemic effects and it has shown efficacy in management of not only PCOS but also the associated metabolic complication : dyslipidemia. PMID- 22518084 TI - Screening Togolese medicinal plants for few pharmacological properties. AB - BACKGROUND: Terminalia macroptera Guill. et Perr. (Combretaceae), Sida alba L. (Malvaceae), Prosopis africana Guill et Perr. Taub. (Mimosaceae), Bridelia ferruginea Benth. (Euphorbiaceae), and Vetiveria nigritana Stapf. (Asteraceae) are traditionally used in Togolese folk medicine to treat several diseases including microbial infections. OBJECTIVE: This study aimed to investigate the antimicrobial, antioxidant, and hemolytic properties of the crude extracts of the above-mentioned plants. MATERIALS AND METHODS: The antimicrobial and the antioxidant activities were assayed using the NCCLS microdilution method and the DPPH free radical scavenging, respectively. Human A+ red blood cells were used to perform the hemolytic assay. Phenolics were further quantified in the extracts using spectrophotometric methods. RESULTS: Minimal inhibitory concentrations in the range of 230-1800 MUg/ml were recorded in the NCCLS broth microdilution for both bacterial and fungal strains with methanol extracts. The DPPH radical scavenging assay yielded interesting antioxidant activities of the extracts of P. africana and T. macroptera (IC(50) values of 0.003 +/- 0.00 MUg/ml and 0.05 +/- 0.03 MUg/ml, respectively). These activities were positively correlated with the total phenolic contents and negatively correlated with the proanthocyanidin content of the extracts. The hemolytic assay revealed that great hemolysis occurred with the methanol extracts of T. macroptera, S. longepedunculata, and B. ferruginea. CONCLUSION: These results support in part the use of the selected plants in the treatment of microbial infections. In addition, the plant showed an interesting antioxidant activity that could be useful in the management of oxidative stress. PMID- 22518085 TI - In vitro H(+) -K(+) ATPase inhibitory potential of methanolic extract of Cissus quadrangularis Linn. AB - OBJECTIVE: This study was undertaken to study in vitro H(+) -K(+) ATPase inhibitory potential of methanolic extract of Cissus quadrangularis Linn. MATERIALS AND MATHODS: Total phenolic and flavonoid contents from extract was quantified and H(+) -K(+) ATPase inhibition assay was performed in presence of different concentrations of standard (omeprazole) and methanol extract. RESULTS: Extract showed significant (*P < 0.05) proton pump inhibitory activity in the goat gastric mucosal homogenate which was comparable to standard. CONCLUSIONS: These findings showed that methanolic extract of C. quadrangularis Linn. is potent inhibitor of proton pump. PMID- 22518086 TI - A lossy compression technique enabling duplication-aware sequence alignment. AB - In spite of the recognized importance of tandem duplications in genome evolution, commonly adopted sequence comparison algorithms do not take into account complex mutation events involving more than one residue at the time, since they are not compliant with the underlying assumption of statistical independence of adjacent residues. As a consequence, the presence of tandem repeats in sequences under comparison may impair the biological significance of the resulting alignment. Although solutions have been proposed, repeat-aware sequence alignment is still considered to be an open problem and new efficient and effective methods have been advocated. The present paper describes an alternative lossy compression scheme for genomic sequences which iteratively collapses repeats of increasing length. The resulting approximate representations do not contain tandem duplications, while retaining enough information for making their comparison even more significant than the edit distance between the original sequences. This allows us to exploit traditional alignment algorithms directly on the compressed sequences. Results confirm the validity of the proposed approach for the problem of duplication-aware sequence alignment. PMID- 22518087 TI - Informational odds ratio: a useful measure of epidemiologic association in environment exposure studies. AB - The informational odds ratio (IOR) measures the post-exposure odds divided by the pre-exposure odds (ie, information gained after knowing exposure status). A desirable property of an adjusted ratio estimate is collapsibility (ie, the combined crude ratio will not change after adjusting for a variable that is not a confounder). Adjusted traditional odds ratios (TORs) are not collapsible. In contrast, Mantel-Haenszel adjusted IORs generally are collapsible. IORs are a useful measure of disease association in environmental case-referent studies, especially when the disease is common in the exposed and/or unexposed groups. PMID- 22518088 TI - Trastuzumab for HER2-Positive Metastatic Breast Cancer: Clinical and Economic Considerations. AB - Trastuzumab is a recombinant humanized monoclonal antibody that selectively targets the extra-cellular domain of the HER2 receptor. It was approved by the FDA in September 1998 as the first targeted therapy for HER2-positive metastatic breast cancer, and has since led to significant improvements in the overall prognosis for patients with HER2-positive metastatic disease. The favourable benefit/risk profile associated with palliative trastuzumab has been demonstrated in a number of clinical trials that examined trastusumab as monotherapy or in combination with chemotherapy, endocrine therapy and other HER2 targeted agents. The clinical benefits of trastuzumab, however should also be examined within the context of its significant drug acquisition costs. This review highlights the significant findings from the landmark clinical trials of trastuzumab for metastatic HER2-positive breast cancer, and the potential "value for money" associated with its use in clinical practice. PMID- 22518089 TI - Statistician expert witnesses in agreement on relative hazards. AB - 'If anticoagulants had been administered sooner, my client would not have died' was a central claim put to us, as statistician expert witnesses, by a Claimant's and Defendant's lawyers. To assist other litigants, and without identifying the specific case, we set out the study types that contribute to the evidence base, and their limitations. We then explain why it is difficult to adduce evidence about the relative risk of dying from pulmonary embolism within 12 hours of admission to accident and emergency even when it is well accepted that anticoagulation reduces the risk of dying within the next seven days of patients at objectively confirmed risk of pulmonary embolism. No matter how much we may want an answer, or how tragic an individual outcome, we can only work from the available evidence or work to improve the evidence base, which needs to be resourced. PMID- 22518090 TI - Global gene expression profiling of human osteosarcomas reveals metastasis associated chemokine pattern. AB - Global gene expression analysis was performed on a panel of 23 osteosarcoma samples of primary and metastatic origin using the Applied Biosystems Gene Expression Array System. When comparing the primary tumours with the metastases, we found a significantly increased expression of genes involved in immunological processes, for example coding for cytokines and chemokines, in the metastatic samples. In addition, a comparison of the gene expression in primary samples from patients with or without metastases demonstrated that patients who later developed metastases had high expression of the chemokine (C-X-C motif) receptor 4 (CXCR4), similar to the metastatic samples, suggesting that these signal molecules play an important role in promoting metastasis. Increased knowledge of mechanisms and interactions between specified molecular signalling pathways in osteosarcomas could lead to a more rational strategy for development of targeted therapy. PMID- 22518091 TI - The relationship between vocabulary and short-term memory measures in monolingual and bilingual speakers. AB - Previous studies have indicated that bilingualism may influence the efficiency of lexical access in adults. The goals of this research were (1) to compare bilingual and monolingual adults on their native-language vocabulary performance, and (2) to examine the relationship between short-term memory skills and vocabulary performance in monolinguals and bilinguals. In Experiment 1, English speaking monolingual adults and simultaneous English-Spanish bilingual adults were administered measures of receptive English vocabulary and of phonological short-term memory. In Experiment 2, monolingual adults were compared to sequential English-Spanish bilinguals, and were administered the same measures as in Experiment 1, as well as a measure of expressive English vocabulary. Analyses revealed comparable levels of performance on the vocabulary and the short-term memory measures in the monolingual and the bilingual groups across both experiments. There was a stronger effect of digit-span in the bilingual group than in the monolingual group, with high-span bilinguals outperforming low-span bilinguals on vocabulary measures. Findings indicate that bilingual speakers may rely on short-term memory resources to support word retrieval in their native language more than monolingual speakers. PMID- 22518092 TI - Extracted Fragment Ion Mobility Distributions: A New Method for Complex Mixture Analysis. AB - A new method is presented for constructing ion mobility distributions of precursor ions based upon the extraction of drift time distributions that are monitored for selected fragment ions. The approach is demonstrated with a recently designed instrument that combines ion mobility spectrometry (IMS) with ion trap mass spectrometry (MS) and ion fragmentation, as shown in a recent publication [J. Am. Soc. Mass Spectrom. 22 (2011) 1477-1485]. Here, we illustrate the method by examining selected charge states of electrosprayed ubiquitin ions, an extract from diesel fuel, and a mixture of phosphorylated peptide isomers. For ubiquitin ions, extraction of all drift times over small mass-to-charge (m/z) ranges corresponding to unique fragments of a given charge state allows the determination of precursor ion mobility distributions. A second example of the utility of the approach includes the distinguishing of precursor ion mobility distributions for isobaric, basic components from commercially available diesel fuel. Extraction of data for a single fragment ion is sufficient to distinguish the precursor ion mobility distribution of cycloalkyl-pyridine derivatives from pyrindan derivatives. Finally, the method is applied for the analysis of phosphopeptide isomers (LFpTGHPESLER and LFTGHPEpSLER) in a mixture. The approach alleviates several analytical challenges that include separation and characterization of species having similar (or identical) m/z values within complex mixtures. PMID- 22518093 TI - Analyzing a Mixture of Disaccharides by IMS-VUVPD-MS. AB - Comparative analyses utilizing collision induced dissociation (CID) and vacuum ultraviolet photodissociation (VUVPD) for seven isobaric disaccharides have been performed in order to differentiate the linkage type and anomeric configuration of the isomers. Although an individual CID spectrum of a disaccharide ion provides information related to its structure, CID does not sufficiently differentiate mixture components due to the identical mass-to-charge values of most of the intense fragments. In contrast to the ambiguity of the CID analyses for the disaccharide mixture, VUVPD (157 nm) generates unique fragments for each disaccharide ion that are useful for distinguishing individual components from the mixture. When combined with a gas-phase ion mobility separation of the ions, the identification of each component from the mixture can be obtained. PMID- 22518094 TI - On the correspondence between CAL and lagged cohort life expectancy. AB - It has been established that under certain mortality assumptions, the current value of the Cross-sectional Average length of Life (CAL) is equal to the life expectancy for the cohort currently reaching its life expectancy. This correspondence is important, because the life expectancy for the cohort currently reaching its life expectancy, or lagged cohort life expectancy (LCLE), has been discussed in the tempo literature as a summary mortality measure of substantive interest. In this paper, we build on previous work by evaluating the extent to which the correspondence holds in actual populations. We also discuss the implications of the CAL-LCLE correspondence (or lack thereof) for using CAL as a measure of cohort life expectancy, and for understanding the connection between CAL, LCLE, and underlying period mortality conditions. PMID- 22518095 TI - Implementation quality of whole-school mental health promotion and students' academic performance. AB - BACKGROUND: This paper argues for giving explicit attention to the quality of implementation of school-wide mental health promotions and examines the impact of implementation quality on academic performance in a major Australian mental health initiative. METHOD: Hierarchical linear modelling was used to investigate change in standardised academic performance across the 2-year implementation of a mental health initiative in 96 Australian primary (or elementary) schools that was focused on improving student social-emotional competencies. RESULTS: After controlling for differences in socioeconomic background, a significant positive relationship existed between quality of implementation and academic performance. The difference between students in high- and low-implementing schools was equivalent to a difference in academic performance of up to 6 months of schooling. KEY PRACTITIONER MESSAGE: Given the known relationship between student academic achievement and mental health, many nations are mounting school based mental health interventions: however, the quality of program implementation remains a concernThe Australian KidsMatter primary school mental health intervention enabled the development of an Implementation Index allowing schools to be grouped into low- to high- implementing schoolsThe quality of implementation of KidsMatter appears to be positively associated with the level of student academic achievement, equivalent to 6 months more schooling by Year 7, over and above any influence of socioeconomic background. PMID- 22518096 TI - Patterns and Predictors of Changes in Substance Use in Individuals with Schizophrenia and Affective Disorders. AB - OBJECTIVE: This study examined patterns and predictors of changes in substance use over one year in individuals with schizophrenia and affective disorders. We examined patterns of cocaine use over time, baseline predictors of continued cocaine use over one year, and predictors of transitions into and out of drug use and treatment. METHODS: We recruited 240 individuals with schizophrenia and affective disorders who met DSM-IV criteria for current cocaine dependence or cocaine dependence in early full or sustained full remission, and assessed them five times over twelve months. RESULTS: There was no change over time in either the proportion of the sample with at least one day of cocaine use in the past month or in the average number of days of cocaine use among those who reported any use. Baseline variables tapping actual substance use were found to predict a decreased likelihood of cocaine use. Several variables tapping actual substance use - including self- reported use of cocaine, positive urinalysis for marijuana, and positive urinalysis for cocaine - were predictive of transitions into and out of outpatient substance abuse treatment. Readiness to change variables such as self-efficacy and temptation to use drugs showed different predictive patterns for the schizophrenia and affective disorder groups. CONCLUSIONS: These findings illustrate how drug use may show a cyclical pattern for those with serious mental illness, in which more severe use - characterized by greater frequency of use and associated problems - is followed by decreased use over time. PMID- 22518097 TI - Comparison between Frame-Constrained Fix-Pixel-Value and Frame-Free Spiking Dynamic-Pixel ConvNets for Visual Processing. AB - Most scene segmentation and categorization architectures for the extraction of features in images and patches make exhaustive use of 2D convolution operations for template matching, template search, and denoising. Convolutional Neural Networks (ConvNets) are one example of such architectures that can implement general-purpose bio-inspired vision systems. In standard digital computers 2D convolutions are usually expensive in terms of resource consumption and impose severe limitations for efficient real-time applications. Nevertheless, neuro cortex inspired solutions, like dedicated Frame-Based or Frame-Free Spiking ConvNet Convolution Processors, are advancing real-time visual processing. These two approaches share the neural inspiration, but each of them solves the problem in different ways. Frame-Based ConvNets process frame by frame video information in a very robust and fast way that requires to use and share the available hardware resources (such as: multipliers, adders). Hardware resources are fixed- and time-multiplexed by fetching data in and out. Thus memory bandwidth and size is important for good performance. On the other hand, spike-based convolution processors are a frame-free alternative that is able to perform convolution of a spike-based source of visual information with very low latency, which makes ideal for very high-speed applications. However, hardware resources need to be available all the time and cannot be time-multiplexed. Thus, hardware should be modular, reconfigurable, and expansible. Hardware implementations in both VLSI custom integrated circuits (digital and analog) and FPGA have been already used to demonstrate the performance of these systems. In this paper we present a comparison study of these two neuro-inspired solutions. A brief description of both systems is presented and also discussions about their differences, pros and cons. PMID- 22518098 TI - Structural basis for the regulation of L-type voltage-gated calcium channels: interactions between the N-terminal cytoplasmic domain and Ca(2+)-calmodulin. AB - It is well-known that the opening of L-type voltage-gated calcium channels can be regulated by calmodulin (CaM). One of the main regulatory mechanisms is calcium dependent inactivation (CDI), where binding of apo-CaM to the cytoplasmic C terminal domain of the channel can effectively sense an increase in the local calcium ion concentration. Calcium-bound CaM can bind to the IQ-motif region of the C-terminal region and block the calcium channel, thereby providing a negative feedback mechanism that prevents the rise of cellular calcium concentrations over physiological limits. Recently, an additional Ca(2+)/CaM-binding motif (NSCaTE, N terminal spatial Ca(2+) transforming element) was identified in the amino terminal cytoplasmic region of Ca(v)1.2 and Ca(v)1.3. This motif exists only in Ca(v)1.2 and Ca(v)1.3 channels, and a pronounced N-lobe (Ca(2+)/CaM) CDI effect was found for Ca(v)1.3. To understand the molecular basis of this interaction, the complexes of Ca(2+)/CaM with the biosynthetically produced N-terminal region (residues 1-68) and NSCaTE peptide (residues 48-68) were investigated. We discovered that the NSCaTE motif in the N-terminal cytoplasmic region adopts an alpha-helical conformation, most likely due to its high alanine content. Additionally, the complex exhibits an unusual 1:2 protein:peptide stoichiometry when bound to Ca(2+)-CaM, and the N-lobe of CaM has a much stronger affinity for the peptide than the C-lobe. The complex structures of the isolated N- and C-lobe of Ca(2+)/CaM and the NSCaTE peptide were determined by nuclear magnetic resonance spectroscopy and data-driven protein-docking methods. Moreover, we also demonstrated that calcium binding protein 1, which competes with CaM for binding to the C-terminal cytoplasmic domain, binds only weakly to the NSCaTE region. The structures provide insights into the possible roles of this motif in the calcium regulatory network. Our study provides structural evidence for the CaM-bridge model proposed in previous studies. PMID- 22518099 TI - Negative modulation of NMDA receptor channel function by DREAM/calsenilin/KChIP3 provides neuroprotection? AB - N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels highly permeable to calcium and essential to excitatory neurotransmission. The NMDARs have attracted much attention because of their role in synaptic plasticity and excitotoxicity. Evidence has recently accumulated that NMDARs are negatively regulated by intracellular calcium binding proteins. The calcium-dependent suppression of NMDAR function serves as a feedback mechanism capable of regulating subsequent Ca(2+) entry into the postsynaptic cell, and may offer an alternative approach to treating NMDAR-mediated excitotoxic injury. This short review summarizes the recent progress made in understanding the negative modulation of NMDAR function by DREAM/calsenilin/KChIP3, a neuronal calcium sensor (NCS) protein. PMID- 22518100 TI - Molecular codes for neuronal individuality and cell assembly in the brain. AB - The brain contains an enormous, but finite, number of neurons. The ability of this limited number of neurons to produce nearly limitless neural information over a lifetime is typically explained by combinatorial explosion; that is, by the exponential amplification of each neuron's contribution through its incorporation into "cell assemblies" and neural networks. In development, each neuron expresses diverse cellular recognition molecules that permit the formation of the appropriate neural cell assemblies to elicit various brain functions. The mechanism for generating neuronal assemblies and networks must involve molecular codes that give neurons individuality and allow them to recognize one another and join appropriate networks. The extensive molecular diversity of cell-surface proteins on neurons is likely to contribute to their individual identities. The clustered protocadherins (Pcdh) is a large subfamily within the diverse cadherin superfamily. The clustered Pcdh genes are encoded in tandem by three gene clusters, and are present in all known vertebrate genomes. The set of clustered Pcdh genes is expressed in a random and combinatorial manner in each neuron. In addition, cis-tetramers composed of heteromultimeric clustered Pcdh isoforms represent selective binding units for cell-cell interactions. Here I present the mathematical probabilities for neuronal individuality based on the random and combinatorial expression of clustered Pcdh isoforms and their formation of cis tetramers in each neuron. Notably, clustered Pcdh gene products are known to play crucial roles in correct axonal projections, synaptic formation, and neuronal survival. Their molecular and biological features induce a hypothesis that the diverse clustered Pcdh molecules provide the molecular code by which neuronal individuality and cell assembly permit the combinatorial explosion of networks that supports enormous processing capability and plasticity of the brain. PMID- 22518101 TI - Enhanced functional synchronization of medial and lateral PFC underlies internally-guided action planning. AB - Actions are often internally guided, reflecting our covert will and intentions. The dorsomedial prefrontal cortex, including the pre-Supplementary Motor Area (pre-SMA), has been implicated in the internally generated aspects of action planning, such as choice and intention. Yet, the mechanism by which this area interacts with other cognitive brain regions such as the dorsolateral prefrontal cortex, a central node in decision-making, is still unclear. To shed light on this mechanism, brain activity was measured via fMRI and intracranial EEG in two studies during the performance of visually cued repeated finger tapping in which the choice of finger was guided by either a presented number (external) or self choice (internal). A functional-MRI (fMRI) study in 15 healthy participants demonstrated that the pre-SMA, compared to the SMA proper, was more active and also more functionally correlated with the dorsolateral prefrontal cortex during internally compared to externally guided action planning (p < 0.05, random effect). In a similar manner, an intracranial-EEG study in five epilepsy patients showed greater inter-regional gamma-related connectivity between electrodes situated in medial and lateral aspects of the prefrontal cortex for internally compared to externally guided actions. Although this finding was observed for groups of electrodes situated both in the pre-SMA and SMA-proper, increased intra cluster gamma-related connectivity was only observed for the pre-SMA (sign-test, p < 0.0001). Overall our findings provide multi-scale indications for the involvement of the dorsomedial prefrontal cortex, and especially the pre-SMA, in generating internally guided motor planning. Our intracranial-EEG results further point to enhanced functional connectivity between decision-making- and motor planning aspects of the PFC, as a possible neural mechanism for internally generated action planning. PMID- 22518102 TI - The hippocampus reevaluated in unconscious learning and memory: at a tipping point? AB - Classic findings from the neuropsychological literature invariably indicated that performances on tests of memory that can be accomplished without conscious awareness were largely spared in amnesia, while those that required conscious retrieval (e.g., via recognition or recall) of information learned in the very same sessions was devastatingly impaired. Based on reports of such dissociations, it was proposed that one of the fundamental distinctions between memory systems is whether or not they support conscious access to remembered content. Only recently have we come to realize that the putative systemic division of labor between conscious and unconscious memory is not so clean. A primary goal of this review is to examine recent evidence that has been advanced against the view that the hippocampus is selectively critical for conscious memory. Along the way, consideration is given to criticisms that have been levied against these findings, potential explanations for differences in the reported results are proposed, and methodological pitfalls in investigations of unconscious memory are discussed. Ultimately, it is concluded that a tipping point has been reached, and that while conscious recollection depends critically on hippocampal integrity, the reach of the hippocampus extends to unconscious aspects of memory performance when relational memory processing and representation are required. PMID- 22518103 TI - A Bird's Eye View of Human Language Evolution. AB - COMPARATIVE STUDIES OF LINGUISTIC FACULTIES IN ANIMALS POSE AN EVOLUTIONARY PARADOX: language involves certain perceptual and motor abilities, but it is not clear that this serves as more than an input-output channel for the externalization of language proper. Strikingly, the capability for auditory-vocal learning is not shared with our closest relatives, the apes, but is present in such remotely related groups as songbirds and marine mammals. There is increasing evidence for behavioral, neural, and genetic similarities between speech acquisition and birdsong learning. At the same time, researchers have applied formal linguistic analysis to the vocalizations of both primates and songbirds. What have all these studies taught us about the evolution of language? Is the comparative study of an apparently species-specific trait like language feasible? We argue that comparative analysis remains an important method for the evolutionary reconstruction and causal analysis of the mechanisms underlying language. On the one hand, common descent has been important in the evolution of the brain, such that avian and mammalian brains may be largely homologous, particularly in the case of brain regions involved in auditory perception, vocalization, and auditory memory. On the other hand, there has been convergent evolution of the capacity for auditory-vocal learning, and possibly for structuring of external vocalizations, such that apes lack the abilities that are shared between songbirds and humans. However, significant limitations to this comparative analysis remain. While all birdsong may be classified in terms of a particularly simple kind of concatenation system, the regular languages, there is no compelling evidence to date that birdsong matches the characteristic syntactic complexity of human language, arising from the composition of smaller forms like words and phrases into larger ones. PMID- 22518104 TI - Altered calcium signaling following traumatic brain injury. AB - Cell death and dysfunction after traumatic brain injury (TBI) is caused by a primary phase, related to direct mechanical disruption of the brain, and a secondary phase which consists of delayed events initiated at the time of the physical insult. Arguably, the calcium ion contributes greatly to the delayed cell damage and death after TBI. A large, sustained influx of calcium into cells can initiate cell death signaling cascades, through activation of several degradative enzymes, such as proteases and endonucleases. However, a sustained level of intracellular free calcium is not necessarily lethal, but the specific route of calcium entry may couple calcium directly to cell death pathways. Other sources of calcium, such as intracellular calcium stores, can also contribute to cell damage. In addition, calcium-mediated signal transduction pathways in neurons may be perturbed following injury. These latter types of alterations may contribute to abnormal physiology in neurons that do not necessarily die after a traumatic episode. This review provides an overview of experimental evidence that has led to our current understanding of the role of calcium signaling in death and dysfunction following TBI. PMID- 22518107 TI - The assumption of a reliable instrument and other pitfalls to avoid when considering the reliability of data. AB - The purpose of this article is to help researchers avoid common pitfalls associated with reliability including incorrectly assuming that (a) measurement error always attenuates observed score correlations, (b) different sources of measurement error originate from the same source, and (c) reliability is a function of instrumentation. To accomplish our purpose, we first describe what reliability is and why researchers should care about it with focus on its impact on effect sizes. Second, we review how reliability is assessed with comment on the consequences of cumulative measurement error. Third, we consider how researchers can use reliability generalization as a prescriptive method when designing their research studies to form hypotheses about whether or not reliability estimates will be acceptable given their sample and testing conditions. Finally, we discuss options that researchers may consider when faced with analyzing unreliable data. PMID- 22518108 TI - Finger counting and numerical cognition. PMID- 22518106 TI - Prevention of postoperative atrial fibrillation: novel and safe strategy based on the modulation of the antioxidant system. AB - Postoperative atrial fibrillation (AF) is the most common arrhythmia following cardiac surgery with extracorporeal circulation. The pathogenesis of postoperative AF is multifactorial. Oxidative stress, caused by the unavoidable ischemia-reperfusion event occurring in this setting, is a major contributory factor. Reactive oxygen species (ROS)-derived effects could result in lipid peroxidation, protein carbonylation, or DNA oxidation of cardiac tissue, thus leading to functional and structural myocardial remodeling. The vulnerability of myocardial tissue to the oxidative challenge is also dependent on the activity of the antioxidant system. High ROS levels, overwhelming this system, should result in deleterious cellular effects, such as the induction of necrosis, apoptosis, or autophagy. Nevertheless, tissue exposure to low to moderate ROS levels could trigger a survival response with a trend to reinforce the antioxidant defense system. Administration of n-3 polyunsaturated fatty acids (PUFA), known to involve a moderate ROS production, is consistent with a diminished vulnerability to the development of postoperative AF. Accordingly, supplementation of n-3 PUFA successfully reduced the incidence of postoperative AF after coronary bypass grafting. This response is due to an up-regulation of antioxidant enzymes, as shown in experimental models. In turn, non-enzymatic antioxidant reinforcement through vitamin C administration prior to cardiac surgery has also reduced the postoperative AF incidence. Therefore, it should be expected that a mixed therapy result in an improvement of the cardioprotective effect by modulating both components of the antioxidant system. We present novel available evidence supporting the hypothesis of an effective prevention of postoperative AF including a two-step therapeutic strategy: n-3 PUFA followed by vitamin C supplementation to patients scheduled for cardiac surgery with extracorporeal circulation. The present study should encourage the design of clinical trials aimed to test the efficacy of this strategy to offer new therapeutic opportunities to patients challenged by ischemia-reperfusion events not solely in heart, but also in other organs such as kidney or liver in transplantation surgeries. PMID- 22518109 TI - The frog vestibular system as a model for lesion-induced plasticity: basic neural principles and implications for posture control. AB - Studies of behavioral consequences after unilateral labyrinthectomy have a long tradition in the quest of determining rules and limitations of the central nervous system (CNS) to exert plastic changes that assist the recuperation from the loss of sensory inputs. Frogs were among the first animal models to illustrate general principles of regenerative capacity and reorganizational neural flexibility after a vestibular lesion. The continuous successful use of the latter animals is in part based on the easy access and identifiability of nerve branches to inner ear organs for surgical intervention, the possibility to employ whole brain preparations for in vitro studies and the limited degree of freedom of postural reflexes for quantification of behavioral impairments and subsequent improvements. Major discoveries that increased the knowledge of post lesional reactive mechanisms in the CNS include alterations in vestibular commissural signal processing and activation of cooperative changes in excitatory and inhibitory inputs to disfacilitated neurons. Moreover, the observed increase of synaptic efficacy in propriospinal circuits illustrates the importance of limb proprioceptive inputs for postural recovery. Accumulated evidence suggests that the lesion-induced neural plasticity is not a goal-directed process that aims toward a meaningful restoration of vestibular reflexes but rather attempts a survival of those neurons that have lost their excitatory inputs. Accordingly, the reaction mechanism causes an improvement of some components but also a deterioration of other aspects as seen by spatio-temporally inappropriate vestibulo-motor responses, similar to the consequences of plasticity processes in various sensory systems and species. The generality of the findings indicate that frogs continue to form a highly amenable vertebrate model system for exploring molecular and physiological events during cellular and network reorganization after a loss of vestibular function. PMID- 22518110 TI - Wegener's disease presenting with occipital condyle syndrome. AB - Tumors or chronic inflammatory lesions of the occipital condyle may cause occipital pain associated with an ipsilateral hypoglossal nerve injury (occipital condyle syndrome). We describe a young woman with recurrent otitis media and occipital condyle syndrome associated with a limited form of Wegener's disease. PMID- 22518105 TI - Physiology and pathology of calcium signaling in the brain. AB - Calcium (Ca(2+)) plays fundamental and diversified roles in neuronal plasticity. As second messenger of many signaling pathways, Ca(2+) as been shown to regulate neuronal gene expression, energy production, membrane excitability, synaptogenesis, synaptic transmission, and other processes underlying learning and memory and cell survival. The flexibility of Ca(2+) signaling is achieved by modifying cytosolic Ca(2+) concentrations via regulated opening of plasma membrane and subcellular Ca(2+) sensitive channels. The spatiotemporal patterns of intracellular Ca(2+) signals, and the ultimate cellular biological outcome, are also dependent upon termination mechanism, such as Ca(2+) buffering, extracellular extrusion, and intra-organelle sequestration. Because of the central role played by Ca(2+) in neuronal physiology, it is not surprising that even modest impairments of Ca(2+) homeostasis result in profound functional alterations. Despite their heterogeneous etiology neurodegenerative disorders, as well as the healthy aging process, are all characterized by disruption of Ca(2+) homeostasis and signaling. In this review we provide an overview of the main types of neuronal Ca(2+) channels and their role in neuronal plasticity. We will also discuss the participation of Ca(2+) signaling in neuronal aging and degeneration. PMID- 22518111 TI - In situ Spectroscopy on Intact Leptospirillum ferrooxidans Reveals that Reduced Cytochrome 579 is an Obligatory Intermediate in the Aerobic Iron Respiratory Chain. AB - Electron transfer reactions among colored cytochromes in intact bacterial cells were monitored using an integrating cavity absorption meter that permitted the acquisition of accurate absorbance data in suspensions of cells that scatter light. The aerobic iron respiratory chain of Leptospirillum ferrooxidans was dominated by the redox status of an abundant cellular cytochrome that had an absorbance peak at 579 nm in the reduced state. Intracellular cytochrome 579 was reduced within the time that it took to mix a suspension of the bacteria with soluble ferrous iron at pH 1.7. Steady state turnover experiments were conducted where the initial concentrations of ferrous iron were less than or equal to that of the oxygen concentration. Under these conditions, the initial absorbance spectrum of the bacterium observed under air-oxidized conditions was always regenerated from that of the bacterium observed in the presence of Fe(II). The kinetics of aerobic respiration on soluble iron by intact L. ferrooxidans conformed to the Michaelis-Menten formalism, where the reduced intracellular cytochrome 579 represented the Michaelis complex whose subsequent oxidation appeared to be the rate-limiting step in the overall aerobic respiratory process. The velocity of formation of ferric iron at any time point was directly proportional to the concentration of the reduced cytochrome 579. Further, the integral over time of the concentration of the reduced cytochrome was directly proportional to the total concentration of ferrous iron in each reaction mixture. These kinetic data obtained using whole cells were consistent with the hypothesis that reduced cytochrome 579 is an obligatory steady state intermediate in the iron respiratory chain of this bacterium. The capability of conducting visible spectroscopy in suspensions of intact cells comprises a powerful post reductionist means to study cellular respiration in situ under physiological conditions for the organism. PMID- 22518113 TI - Label fusion strategy selection. AB - Label fusion is used in medical image segmentation to combine several different labels of the same entity into a single discrete label, potentially more accurate, with respect to the exact, sought segmentation, than the best input element. Using simulated data, we compared three existing label fusion techniques STAPLE, Voting, and Shape-Based Averaging (SBA)-and observed that none could be considered superior depending on the dissimilarity between the input elements. We thus developed an empirical, hybrid technique called SVS, which selects the most appropriate technique to apply based on this dissimilarity. We evaluated the label fusion strategies on two- and three-dimensional simulated data and showed that SVS is superior to any of the three existing methods examined. On real data, we used SVS to perform fusions of 10 segmentations of the hippocampus and amygdala in 78 subjects from the ICBM dataset. SVS selected SBA in almost all cases, which was the most appropriate method overall. PMID- 22518114 TI - Poor Homologous Synapsis 1 Interacts with Chromatin but Does Not Colocalise with ASYnapsis 1 during Early Meiosis in Bread Wheat. AB - Chromosome pairing, synapsis, and DNA recombination are three key processes that occur during early meiosis. A previous study of Poor Homologous Synapsis 1 (PHS1) in maize suggested that PHS1 has a role in coordinating these three processes. Here we report the isolation of wheat (Triticum aestivum) PHS1 (TaPHS1), and its expression profile during and after meiosis. While the TaPHS1 protein has sequence similarity to other plant PHS1/PHS1-like proteins, it also possesses a unique region of oligopeptide repeat units. We show that TaPHS1 interacts with both single- and double-stranded DNA in vitro and provide evidence of the protein region that imparts the DNA-binding ability. Immunolocalisation data from assays conducted using antisera raised against TaPHS1 show that TaPHS1 associates with chromatin during early meiosis, with the signal persisting beyond chromosome synapsis. Furthermore, TaPHS1 does not appear to colocalise with the asynapsis protein (TaASY1) suggesting that these proteins are probably independently coordinated. Significantly, the data from the DNA-binding assays and 3 dimensional immunolocalisation of TaPHS1 during early meiosis indicates that TaPHS1 interacts with DNA, a function not previously observed in either the Arabidopsis or maize PHS1 homologues. As such, these results provide new insight into the function of PHS1 during early meiosis in bread wheat. PMID- 22518115 TI - Comparison between Capsule Endoscopy and Magnetic Resonance Enterography for the Detection of Polyps of the Small Intestine in Patients with Familial Adenomatous Polyposis. AB - Objective. The objective of this study was to assess the utility of magnetic resonance enterography (MRE) compared with capsule endoscopy (CE) for the detection of small-bowel polyps in patients with familial adenomatous polyposis (FAP). Methods. Patients underwent MRE and CE. The polyps were classified according to size of polyp: <5 mm (small size), 5-10 mm (medium size), or >10 mm (large size). The location (jejunum or ileum) and the number of polyps (1-5, 6 20, >20) detected by CE were also assessed. MRE findings were compared with the results of CE. Results. Small-bowel polyps, were detected by CE in 4 of the 6 (66%) patients. Three patients had small-sized polyps and one patient had medium sized polyps. CE detected polyps in four patients that, were not shown on MRE. Desmoid tumors were detected on anterior abdominal wall by MRE. Conclusion. In patients with FAP, CE can detect small-sized polyps in the small intestine not seen with MRE whereas MRE yields additional extraintestinal information. PMID- 22518112 TI - The function of introns. AB - The intron-exon architecture of many eukaryotic genes raises the intriguing question of whether this unique organization serves any function, or is it simply a result of the spread of functionless introns in eukaryotic genomes. In this review, we show that introns in contemporary species fulfill a broad spectrum of functions, and are involved in virtually every step of mRNA processing. We propose that this great diversity of intronic functions supports the notion that introns were indeed selfish elements in early eukaryotes, but then independently gained numerous functions in different eukaryotic lineages. We suggest a novel criterion of evolutionary conservation, dubbed intron positional conservation, which can identify functional introns. PMID- 22518116 TI - The role of pathology in small renal mass laparoscopic cryoablation. AB - Objective. We evaluated histological outcome of intraoperative biopsies at laparoscopic renal mass cryoablation (LCA), prevalence of peritumoral fat tissue invasion, and risk of tract seeding. Methods. Patients were biopsied 3-5 times (16-gauge). Histology was analyzed by general pathologists and reviewed. Peritumoral fat was histologically examined. The trocar used for biopsy-guidance was examined by cytology. Records were studied for reporting tract metastasis. Results. 77 biopsied renal masses with mean +/- SD diameter 30 +/- 7.4 mm were histologically classified by primary and review pathology revealing 64 and 62 malignancies, 13 and 15 benign lesions, respectively. In 30/34, the fat covered a carcinoma but revealed no malignancy. Cytology showed no malignant cells but was inconclusive in 1 case. No tract metastasis occurred. Conclusions. The use of an intraoperative biopsy protocol provides histological diagnosis of all renal masses. No existence of peritumoral fat tissue invasion or tract seeding was found. PMID- 22518117 TI - Development of screening tools for the interpretation of chemical biomonitoring data. AB - Evaluation of a larger number of chemicals in commerce from the perspective of potential human health risk has become a focus of attention in North America and Europe. Screening-level chemical risk assessment evaluations consider both exposure and hazard. Exposures are increasingly being evaluated through biomonitoring studies in humans. Interpreting human biomonitoring results requires comparison to toxicity guidance values. However, conventional chemical specific risk assessments result in identification of toxicity-based exposure guidance values such as tolerable daily intakes (TDIs) as applied doses that cannot directly be used to evaluate exposure information provided by biomonitoring data in a health risk context. This paper describes a variety of approaches for development of screening-level exposure guidance values with translation from an external dose to a biomarker concentration framework for interpreting biomonitoring data in a risk context. Applications of tools and concepts including biomonitoring equivalents (BEs), the threshold of toxicologic concern (TTC), and generic toxicokinetic and physiologically based toxicokinetic models are described. These approaches employ varying levels of existing chemical specific data, chemical class-specific assessments, and generic modeling tools in response to varying levels of available data in order to allow assessment and prioritization of chemical exposures for refined assessment in a risk management context. PMID- 22518118 TI - Morphological and histopathological changes in orofacial structures of experimentally developed acromegaly-like rats: an overview. AB - Tongue enlargement and mandibular prognathism are clinically recognized in almost all patients with acromegaly. An acromegaly-like rat model recently developed by exogenous administration of insulin-like growth factor I (IGF-I) was used to investigate morphological and histopathological changes in orofacial structures and to clarify whether these changes were reversible. Exogenous administration of IGF-I evoked specific enlargement of the tongue with identifiable histopathological changes (increased muscle bundle width, increased space between muscle bundles, and increased epithelial thickness), elongation of the mandibular alveolar bone and ascending ramus, and lateral expansion of the mandibular dental arch. Regarding histopathological changes in the mandibular condyle, the cartilaginous layer width, bone matrix ratio, and number of osteoblasts were all significantly greater in this rat model. After normalization of the circulating IGF-I level, tongue enlargement and histopathological changes in the tongue and mandibular condyle were reversible, whereas morphological skeletal changes in the mandible remained. PMID- 22518119 TI - Results of gamma knife radiosurgery in acromegaly. AB - Objective. Single-session radiosurgery with Gamma Knife (GK) may be a potential adjuvant treatment in acromegaly. We analyzed the safety and efficacy of GK in patients who had previously received maximal surgical debulking at our hospital. Methods. The study was a retrospective analysis of hormonal, radiological, and ophthalmologic data collected in a predefined protocol from 1994 to 2009. The mean age at treatment was 42.3 years (range 22-67 yy). 103 acromegalic patients participated in the study. The median follow-up was 71 months (IQ range 43-107). All patients were treated with GK for residual or recurrent GH-secreting adenoma. Results. Sixty-three patients (61.2%) reached the main outcome of the study. The rate of remission was 58.3% at 5 years (95% CI 47.6-69.0%). Other 15 patients (14.6%) were in remission after GK while on treatment with somatostatin analogues. No serious side effects occurred after GK. Eight patients (7.8%) experienced a new deficit of pituitary function. New cases of hypogonadism, hypothyroidism, and hypoadrenalism occurred in 4 of 77 patients (5.2%), 3 of 95 patients (3.2%), and 6 of 100 patients at risk (6.0%), respectively. Conclusion. In a highly selected group of acromegalic patients, GK treatment had good efficacy and safety. PMID- 22518120 TI - A cell model for conditional profiling of androgen-receptor-interacting proteins. AB - Partial androgen insensitivity syndrome (PAIS) is associated with impaired male genital development and can be transmitted through mutations in the androgen receptor (AR). The aim of this study is to develop a cell model suitable for studying the impact AR mutations might have on AR interacting proteins. For this purpose, male genital development relevant mouse cell lines were genetically modified to express a tagged version of wild-type AR, allowing copurification of multiprotein complexes under native conditions followed by mass spectrometry. We report 57 known wild-type AR-interacting proteins identified in cells grown under proliferating and 65 under nonproliferating conditions. Of those, 47 were common to both samples suggesting different AR protein complex components in proliferating and proliferation-inhibited cells from the mouse proximal caput epididymus. These preliminary results now allow future studies to focus on replacing wild-type AR with mutant AR to uncover differences in protein interactions caused by AR mutations involved in PAIS. PMID- 22518121 TI - Surgery and radiosurgery for acromegaly: a review of indications, operative techniques, outcomes, and complications. AB - Among multimodality treatments for acromegaly, the goals of surgical intervention are to balance maximal tumor resection while preserving normal pituitary function and maintaining patient safety. The resection of growth hormone-(GH-) secreting pituitary adenomas in the hands of experienced surgeons results in hormonal remission in 50-70% of patients. Acromegalic patients often have medical comorbidities and anatomical variations complicating anesthesia and surgical management. Despite these challenges, complications such as CSF leak or new hypopituitarism following surgery remain uncommon. Over the past decade, endoscopic approaches to pituitary tumors have improved visualization and facilitated identification of additional tumor using angled telescopes. Patients with persistent acromegaly following surgery require continued medical and/or radiation-based interventions. The adjunctive use of stereotactic radiosurgery offers hormonal remission in 40-50% of patients. In this article, the current preoperative evaluation, indications for surgery, surgical approaches, role of radiosurgery, complications, and remission criteria following operative resection of GH adenomas are reviewed. PMID- 22518122 TI - Previous gestational diabetes mellitus and markers of cardiovascular risk. AB - The prevalence of gestational diabetes mellitus (GDM) in the developed world has increased at an alarming rate over the last few decades. GDM has been shown to be associated with postpartum diabetes, insulin resistance, hypertension, and dyslipidemia. A history of previous GDM (pGDM), associated or not with any of these metabolic abnormalities, can increase the risk of developing not only type 2 diabetes mellitus but also cardiovascular disease (CVD) independent of a diagnosis of type 2 diabetes later in life. In this paper we discuss the relationship among inflammatory markers, metabolic abnormalities, and vascular dysfunction in women with pGDM. We also review the current knowledge on metabolic modifications occurring in normal pregnancy and the link between alterations of a normal metabolic state with the long-term maternal complications that may result in increased CVD risk. Our review of studies on pGDM prompts us to recommend that these women be considered a population at risk for later CVD events, which however could be avoided via the use of specially designed follow-up programs in the future. PMID- 22518123 TI - Stereotactic Irradiation of GH-Secreting Pituitary Adenomas. AB - Radiotherapy (RT) is often employed in patients with acromegaly refractory to medical and/or surgical interventions in order to prevent tumour regrowth and normalize elevated GH and IGF-I levels. It achieves tumour control and hormone normalization up to 90% and 70% of patients at 10-15 years. Despite the excellent tumour control, conventional RT is associated with a potential risk of developing late toxicity, especially hypopituitarism, and its role in the management of patients with GH-secreting pituitary adenomas remains a matter of debate. Stereotactic techniques have been developed with the aim to deliver more localized irradiation and minimize the long-term consequences of treatment, while improving its efficacy. Stereotactic irradiation can be given in a single dose as stereotactic radiosurgery (SRS) or in multiple doses as fractionated stereotactic radiotherapy (FSRT). We have reviewed the recent published literature on stereotactic techniques for GH-secreting pituitary tumors with the aim to define the efficacy and potential adverse effects of each of these techniques. PMID- 22518124 TI - Comparison of Endocrine Profile and In Vitro Fertilization Outcome in Patients with PCOS, Ovulatory PCO, or Normal Ovaries. AB - Aim. To compare the basic endocrine profile and outcomes of in vitro fertilization (IVF) in women with polycystic ovary syndrome (PCOS), ovulatory polycystic ovaries (PCO), or normal ovaries (NO). Methods. The basic clinical features and in vitro fertilization and embryo transfer outcome in patients receiving IVF or intracytoplasmic sperm injection (ICSI) were retrospectively analyzed. Results. The body mass index, basal luteinizing hormone, and testosterone levels were significantly lower in patients with ovulatory PCO compared to those in patients with PCOS. The PCOS patients exhibited the shortest duration of ovarian stimulation and lowest dose of gonadotropin, followed by the ovulatory PCO and NO patients. The ovulatory PCO and PCOS patients showed similar levels of E2 on the human chorionic gonadotropin treatment day and numbers of oocytes, which were both significantly higher than those of the NO patients. The fertilization rate of the PCOS patients was significantly lower than the other two groups. Compared to NO patients, the cleavage rate was lower in both PCOS and ovulatory PCO patients, however, the number of available embryos was significantly more in these two groups. The incidence of the moderate to severe ovarian hyperstimulation syndrome (OHSS) was markedly higher in the PCOS and ovulatory PCO patients. Conclusion. Ovulatory PCO patients do not express similar endocrine abnormalities as PCOS patients. Although the fertilization rate and cleavage rate were relatively low in PCOS patients, ultimately, all the three groups showed similar transferred embryo numbers, clinical pregnancy rates, and implantation rates. Since the incidence of OHSS was much higher in the PCOS and ovulatory PCO patients, we should take more care of these patients and try to prevent severe OHSS. PMID- 22518125 TI - Multigeneration Inheritance through Fertile XX Carriers of an NR0B1 (DAX1) Locus Duplication in a Kindred of Females with Isolated XY Gonadal Dysgenesis. AB - A 160 kb minimal common region in Xp21 has been determined as the cause of XY gonadal dysgenesis, if duplicated. The region contains the MAGEB genes and the NR0B1 gene; this is the candidate for gonadal dysgenesis if overexpressed. Most patients present gonadal dysgenesis within a more complex phenotype. However, few independent cases have recently been described presenting with isolated XY gonadal dysgenesis caused by relatively small NR0B1 locus duplications. We have identified another NR0B1 duplication in two sisters with isolated XY gonadal dysgenesis with an X-linked inheritance pattern. We performed X-inactivation studies in three fertile female carriers of three different small NR0B1 locus duplications identified by our group. The carrier mothers did not show obvious skewing of X-chromosome inactivation, suggesting that NR0B1 overexpression does not impair ovarian function. We furthermore emphasize the importance to investigate the NR0B1 locus also in patients with isolated XY gonadal dysgenesis. PMID- 22518126 TI - Clinical manifestations and diagnosis of acromegaly. AB - Acromegaly and gigantism are due to excess GH production, usually as a result of a pituitary adenoma. The incidence of acromegaly is 5 cases per million per year and the prevalence is 60 cases per million. Clinical manifestations in each patient depend on the levels of GH and IGF-I, age, tumor size, and the delay in diagnosis. Manifestations of acromegaly are varied and include acral and soft tissue overgrowth, joint pain, diabetes mellitus, hypertension, and heart and respiratory failure. Acromegaly is a disabling disease that is associated with increased morbidity and reduced life expectancy. The diagnosis is based primarily on clinical features and confirmed by measuring GH levels after oral glucose loading and the estimation of IGF-I. It has been suggested that the rate of mortality in patients with acromegaly is correlated with the degree of control of GH. Adequately treated, the relative mortality risk can be markedly reduced towards normal. PMID- 22518127 TI - Serum FSH Levels in Coasting Programmes on the hCG Day and Their Clinical Outcomes in IVF +/- ICSI Cycles. AB - Introduction. Coasting is the most commonly used strategy in prevention of severe OHSS. Serum FSH levels measurements during coasting may aid in optimizing the duration of coasting. Objective(s). To study live birth rates (LBRs), clinical pregnancy rates (CPRs), and optimal duration of coasting based on serum FSH levels on the hCG day. Materials and Methods. It is a retrospective study performed between 2005 and 2008 at Barts and The London Centre for Reproductive Medicine, NHS Trust, London, UK, on 349-coasted women undergoing controlled ovarian stimulation (COS) for IVF +/- ICSI. The serum FSH level measurements on the hCG day during coasting programme were analysed to predict the LBR and CPR. Result(s). LBR and CPR were significantly higher when the FSH levels on the hCG day were >2.5 IU/L (LBR: 32.5%, P = 0.045 and CPR: 36.9%, P = 0.027) compared to FSH <2.5 IU/L. The optimal FSH cut-off level for LBR and CPR is 5.6 IU/L on the hCG day. The optimal cutoff for coasting is 4 days. Conclusion(s). Coasting may be continued as long as either serum FSH level is > 2.5 IU/L on the hCG day without compromising the LBR and CPR or to maximum of 4 days. PMID- 22518128 TI - Exendin-4 Protects MIN6 Cells from t-BHP-Induced Apoptosis via IRE1-JNK-Caspase-3 Signaling. AB - Objectives. This study aimed to explore the effect of exendin-4 on t-BHP-induced apoptosis in pancreatic beta cells and the mechanism of action. Methods. Murine MIN6 pancreatic beta cells were treated with exendin-4 in the presence or absence of tert-butyl hydroperoxide (t-BHP). Cell survival was assessed by MTT staining. The percentage of apoptotic cells was determined by fluorescence microscopy analysis after Hoechst/PI staining and flow cytometric assay after Annexin V FITC/PI staining. The activity of caspase-3 was determined using a caspase-3 activity kit. Expression of P-IRE1alpha, IRE1alpha, C-Jun N-terminal kinase (JNK), P-JNK, C-JUN, and P-C-JUN was detected by western blotting. Results. Exendin-4 was found to inhibit t-BHP-induced apoptosis in pancreatic beta-cells by downregulating caspase-3 activity. Exendin-4 also inhibited the endoplasmic reticulum transmembrane protein IRE1, the apoptosis-related signaling molecule JNK, and c-Jun activation. Conclusions. Our findings suggest that exendin-4 ultimately reduces t-BHP-induced beta-cell apoptosis. IRE1-JNK-c-Jun signaling is involved in the exendin-4-mediated modulation of beta-cell apoptosis. PMID- 22518129 TI - Interactions between Serum Adipokines and Osteocalcin in Older Patients with Hip Fracture. AB - Introduction. Experiments on genetically modified animals have discovered a complex cross-regulation between adipokines (leptin, adiponectin) and osteocalcin. The relationships between these molecules in human osteoporosis are still unclear. We evaluated the hypothesis of a bidirectional link between adipokines and osteocalcin. Materials and Methods. In a cross-sectional study of 294 older patients with osteoporotic hip fracture, we estimated serum concentrations of leptin, adiponectin, resistin, osteocalcin, parameters of mineral metabolism, and renal function. Results. After adjustment for multiple potential confounders, serum osteocalcin concentration was inversely associated with resistin and positively with leptin, leptin/resistin ratio, and adiponectin/resistin ratio. In multivariate regression models, osteocalcin was an independent predictor of serum leptin, resistin, leptin/resistin, and adiponectin/resistin ratios. Conclusions. Our data support the bidirectional regulation between osteocalcin and adipokines, but contrary to the genetically modified animal models, in older subjects with osteoporotic hip fracture, serum osteocalcin is positively associated with leptin and inversely with resistin. PMID- 22518130 TI - Associations of Sun Exposure with 25-Hydroxyvitamin D and Parathyroid Hormone Levels in a Cohort of Hypertensive Patients: The Graz Endocrine Causes of Hypertension (GECOH) Study. AB - Sunlight-induced vitamin D, synthesis in the skin is the major source of vitamin D, but data on the relationship of sun-related behaviour with vitamin D and parathyroid hormone (PTH) levels are relatively sparse. We evaluated whether habitual sun exposure is associated with 25-hydroxyvitamin D (25[OH]D) and PTH levels and whether there exist seasonal variations. We examined 111 hypertensive patients in Austria (latitude 47 degrees N). Frequent sunbathing at home and outdoor sports were associated with higher 25(OH)D levels (P < 0.05 for both). Red or blond scalp hair as a child, memory of sunburns, preferring sunbathing, frequent stays on the beach or in open-air pools, and solarium use were associated with lower PTH levels (P < 0.05 for all). Multiple linear regression analyses including age, sex, and body mass index showed that sun exposure score was significantly associated with 25(OH)D (beta coefficient = 0.27; P = 0.004) and by trend with PTH (beta coefficient = -0.16; P = 0.09). These associations were more prominent in summer in which 25(OH)D levels were significantly higher compared to winter. Translation of these findings into recommendations for the prevention and treatment of vitamin D deficiency remains a challenge for the future. PMID- 22518131 TI - Connecting the Lines between Hypogonadism and Atherosclerosis. AB - Epidemiological studies show that atherosclerotic cardiovascular disease is a leading cause of morbidity and mortality worldwide and point to gender differences with ageing males being at highest risk. Atherosclerosis is a complex process that has several risk factors and mediators. Hypogonadism is a commonly undiagnosed disease that has been associated with many of the events, and risk factors leading to atherosclerosis. The mechanistic relations between testosterone levels, atherosclerotic events, and risk factors are poorly understood in many instances, but the links are clear. In this paper, we summarize the research journey that explains the link between hypogonadism, each of the atherosclerotic events, and risk factors. We look into the different areas from which lessons could be learned, including epidemiological studies, animal and laboratory experiments, studies on androgen deprivation therapy patients, and studies on testosterone-treated patients. We finish by providing recommendations for the clinician and needs for future research. PMID- 22518132 TI - Gamma knife radiosurgery for acromegaly. AB - Acromegaly is debilitating disease occasionally refractory to surgical and medical treatment. Stereotactic radiosurgery, and in particular Gamma Knife surgery (GKS), has proven to be an effective noninvasive adjunct to traditional treatments, leading to disease remission in a substantial proportion of patients. Such remission holds the promise of eliminating the need for expensive medications, along with side effects, as well as sparing patients the damaging sequelae of uncontrolled acromegaly. Numerous studies of radiosurgical treatments for acromegaly have been carried out. These illustrate an overall remission rate over 40%. Morbidity from radiosurgery is infrequent but can include cranial nerve palsies and hypopituitarism. Overall, stereotactic radiosurgery is a promising therapy for patients with acromegaly and deserves further study to refine its role in the treatment of affected patients. PMID- 22518133 TI - Markers of Sleep Disordered Breathing and Diabetes Mellitus in a Multiethnic Sample of US Adults: Results from the National Health and Nutrition Examination Survey (2005-2008). AB - We examined gender and ethnic differences in the association between sleep disordered breathing (SDB) and diabetes among 6,522 participants aged >=20 years from the National Health and Nutrition Examination Survey 2005-08. SDB severity was defined based on an additive summary score including sleep duration, snoring, snorting, and daytime sleepiness. We found that the summary SDB score was significantly associated with diabetes after adjusting for potential confounders in the whole population. Compared to those without any sleep disturbance, the multivariable odds ratio (OR) (95% confidence interval (CI)) of diabetes among those with >=3 sleep disturbances was 2.04 (1.46-2.87). In sex-specific analyses, this association was significant only in women (OR (95% CI) = 3.68 (2.01-6.72)) but not in men (1.10 (0.59-2.04)), P-interaction = 0.01. However, there were no ethnic differences in this association, P-interaction = 0.7. In a nationally representative sample of US adults, SDB was independently associated with diabetes only in women, but not in men. PMID- 22518134 TI - Metabolic syndrome in estonia: prevalence and associations with insulin resistance. AB - Recently, it has been suggested that metabolic syndrome should be considered a premorbid condition in younger individuals. We evaluated the prevalence of metabolic syndrome in Estonia and compared the characteristic profiles between morbid metabolic syndrome (previously established diabetes, hypertension, or dyslipidaemia) and premorbid metabolic syndrome subgroups. Our study was a cross sectional, population-based sample of the general population in Estonia aged 20 74 years (n = 495). Metabolic syndrome was diagnosed by National Cholesterol Education Program Adult Treatment Panel III criteria. Insulin resistance was estimated using the homeostasis model assessment (HOMA-IR). The crude and weighted prevalence of metabolic syndrome was 27.9% and 25.9%, respectively. Despite being significantly younger, the premorbid subgroup showed similar levels of insulin resistance as the morbid subgroup (mean HOMA-IR +/- SD 2.73 +/- 1.8 versus 2.97 +/- 2.1, P = 0.5). The most important attribute of metabolic syndrome is insulin resistance, which already characterises metabolic syndrome in the early stages of its metabolic abnormalities. PMID- 22518135 TI - The Metabolic Syndrome among Postmenopausal Women in Gorgan. AB - Introduction. The present study aimed to assess the metabolic syndrome among postmenopausal women in Gorgan, Iran. Materials and Methods. The study was conducted on hundred postmenopausal women who were referred to the health centers in Gorgan. Metabolic syndrome was diagnosed using Adult Treatment Panel III (ATP III) guidelines. Results. The mean body mass index, waist circumference, hip, circumference waist-to-hip ratio, diastolic blood pressure, and triglyceride and fasting blood glucose levels were significantly high among postmenopausal women with metabolic syndrome, but the mean HDL-cholesterol was significantly low (P < 0.05). Overall prevalence of metabolic syndrome was 31%. Body mass index and waist circumference had a positive correlation with a number of metabolic syndrome factors (P < 0.001). Body mass index, waist circumference, and waist-to hip ratio had a positive correlation with each other (P < 0.001). BMI had relatively high correlation with WC (P < 0.001). Conclusions. Our results show that postmenopausal status might be a predictor of metabolic syndrome. Low HDL cholesterol level and high abdominal obesity are the most frequent characteristics in comparison to other metabolic components. Our study also showed some related factors of metabolic syndrome among postmenopausal women. These factors may increase cardiovascular risk among postmenopausal women with metabolic syndrome. PMID- 22518136 TI - Taper preparation variability compared to current taper standards using computed tomography. AB - Introduction. The purpose of this study was to compare the taper variation in root canal preparations among Twisted Files and PathFiles-ProTaper .08 tapered rotary files to current standards. Methods. 60 root canals with severe angle of curvature (between 25 degrees and 35 degrees ) and short radius (r < 10 mm) were selected. The canals were divided randomly into two groups of 30 each. After preparation with Twisted Files and PathFiles-ProTaper to size 25 taper .08, the diameter was measured using computed tomography (CT) at 1, 3, and 16 mm. Canal taper preparation was calculated at the apical third and at the middle-cervical third. Results. Of the 2 file systems, both fell within the +/-.05 taper variability. All preparations demonstrated variability when compared to the nominal taper .08. In the apical third, mean taper was significantly different between TF and PathFiles-ProTaper (P value < 0.0001; independent t-test). Mean Taper was significantly higher with PathFile-ProTaper. In the middle-cervical third, mean Taper was significantly higher with TF (P value = 0.015; independent t-test). Conclusion. Taper preparations of the investigated size 25 taper .08 were favorable but different from the nominal taper. PMID- 22518137 TI - Application of Monoclonal Antibodies against Bioactive Natural Products: Eastern Blotting and Preparation of Knockout Extract. AB - Matrix-assisted laser desorption/ionization (MALDI) tof mass spectrometry was used for the confirmation of hapten number in synthesized antigen. As application of MAb, the MAbs against ginsenosides and glycyrrhizin have been prepared resulting in the development of two new techniques that we named the eastern blotting method and the knockout extract preparation. In eastern blotting technique, glycosides like ginsenosides and glycyrrhizin separated by silica gel TLC were blotted to PVDF membrane that was treated with a NaIO(4) solution followed by BSA resulted in glycoside-BSA conjugate on a PVDF membrane. The blotted spots were stained by MAb. Double staining of eastern blotting for ginsenosides using antiginsenoside Rb(1) and Rg(1) MAbs promoted complete identification of ginsenosides in Panax species. The immunoaffinity concentration of glycyrrhizin was determined by immunoaffinity column conjugated with antiglycyrrhizin MAb resulting in the glycyrrhizin-knockout extract, which was determined by the synergic effect with glycyrrhizin on NO production using the cell line. PMID- 22518138 TI - Cytoskeletal interactions at the nuclear envelope mediated by nesprins. AB - Nesprin-1 is a giant tail-anchored nuclear envelope protein composed of an N terminal F-actin binding domain, a long linker region formed by multiple spectrin repeats and a C-terminal transmembrane domain. Based on this structure, it connects the nucleus to the actin cytoskeleton. Earlier reports had shown that Nesprin-1 binds to nuclear envelope proteins emerin and lamin through C-terminal spectrin repeats. These repeats can also self-associate. We focus on the N terminal Nesprin-1 sequences and show that they interact with Nesprin-3, a further member of the Nesprin family, which connects the nucleus to the intermediate filament network. We show that upon ectopic expression of Nesprin-3 in COS7 cells, which are nearly devoid of Nesprin-3 in vitro, vimentin filaments are recruited to the nucleus and provide evidence for an F-actin interaction of Nesprin-3 in vitro. We propose that Nesprins through interactions amongst themselves and amongst the various Nesprins form a network around the nucleus and connect the nucleus to several cytoskeletal networks of the cell. PMID- 22518140 TI - Pseudomonas sp. as a Source of Medium Chain Length Polyhydroxyalkanoates for Controlled Drug Delivery: Perspective. AB - Controlled drug delivery technology represents one of the most rapidly advancing areas of science. They offer numerous advantages compared to conventional dosage forms including improved efficacy, reduced toxicity, improved patient compliance and convenience. Over the past several decades, many delivery tools or methods were developed such as viral vector, liposome-based delivery system, polymer based delivery system, and intelligent delivery system. Recently, nonviral vectors, especially those based on biodegradable polymers, have been widely investigated as vectors. Unlike the other polymers tested, polyhydroxyalkanoates (PHAs) have been intensively investigated as a family of biodegradable and biocompatible materials for in vivo applications as implantable tissue engineering material as well as release vectors for various drugs. On the other hand, the direct use of these polyesters has been hampered by their hydrophobic character and some physical shortcomings, while its random copolymers fulfilled the expectation of biomedical researchers by exhibiting significant mechanical and thermal properties. This paper reviews the strategies adapted to make functional polymer to be utilized as delivery system. PMID- 22518141 TI - Diversity of cellulolytic microbes and the biodegradation of municipal solid waste by a potential strain. AB - Municipal solid waste contains high amounts of cellulose, which is an ideal organic waste for the growth of most of microorganism as well as composting by potential microbes. In the present study, Congo red test was performed for screening of microorganism, and, after selecting a potential strains, it was further used for biodegradation of organic municipal solid waste. Forty nine out of the 250 different microbes tested (165 belong to fungi and 85 to bacteria) produced cellulase enzyme and among these Trichoderma viride was found to be a potential strain in the secondary screening. During the biodegradation of organic waste, after 60 days, the average weight losses were 20.10% in the plates and 33.35% in the piles. There was an increase in pH until 20 days. pH however, stabilized after 30 days in the piles. Temperature also stabilized as the composting process progressed in the piles. The high temperature continued until 30 days of decomposition, after which the temperature dropped to 40 degrees C and below during the maturation. Good quality compost was obtained in 60 days. PMID- 22518139 TI - Aggrephagy: selective disposal of protein aggregates by macroautophagy. AB - Protein aggregation is a continuous process in our cells. Some proteins aggregate in a regulated manner required for different vital functional processes in the cells whereas other protein aggregates result from misfolding caused by various stressors. The decision to form an aggregate is largely made by chaperones and chaperone-assisted proteins. Proteins that are damaged beyond repair are degraded either by the proteasome or by the lysosome via autophagy. The aggregates can be degraded by the proteasome and by chaperone-mediated autophagy only after dissolution into soluble single peptide species. Hence, protein aggregates as such are degraded by macroautophagy. The selective degradation of protein aggregates by macroautophagy is called aggrephagy. Here we review the processes of aggregate formation, recognition, transport, and sequestration into autophagosomes by autophagy receptors and the role of aggrephagy in different protein aggregation diseases. PMID- 22518142 TI - Social Behaviours under Anaerobic Conditions in Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is well adapted to grow in anaerobic environments in the presence of nitrogen oxides by generating energy through denitrification. Environmental cues, such as oxygen and nitrogen oxide concentrations, are important in regulating the gene expression involved in this process. Recent data indicate that P. aeruginosa also employs cell-to-cell communication signals to control the denitrifying activity. The regulation of denitrification by these signalling molecules may control nitric oxide production. Nitric oxide, in turn, functions as a signalling molecule by activating certain regulatory proteins. Moreover, under denitrifying conditions, drastic changes in cell physiology and cell morphology are induced that significantly impact group behaviours, such as biofilm formation. PMID- 22518143 TI - LiF Reduces MICs of Antibiotics against Clinical Isolates of Gram-Positive and Gram-Negative Bacteria. AB - Antibiotic resistance is an ever-growing problem yet the development of new antibiotics has slowed to a trickle, giving rise to the use of combination therapy to eradicate infections. The purpose of this study was to evaluate the combined inhibitory effect of lithium fluoride (LiF) and commonly used antimicrobials on the growth of the following bacteria: Enterococcus faecalis, Staphyloccoccus aureus, Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Serratia marcescens, and Streptococcus pneumoniae. The in vitro activities of ceftazidime, sulfamethoxazole trimethoprim, streptomycin, erythromycin, amoxicillin, and ciprofloxacin, doxycycline, alone or combined with LiF were performed by microdilution method. MICs were determined visually following 18-20 h of incubation at 37 degrees C. We observed reduced MICs of antibiotics associated with LiF ranging from two-fold to sixteen-fold. The strongest decreases of MICs observed were for streptomycin and erythromycin associated with LiF against Acinetobacter baumannii and Streptococcus pneumoniae. An eight-fold reduction was recorded for streptomycin against S. pneumoniae whereas an eight-fold and a sixteen-fold reduction were obtained for erythromycin against A. baumannii and S. pneumoniae. This suggests that LiF exhibits a synergistic effect with a wide range of antibiotics and is indicative of its potential as an adjuvant in antibiotic therapy. PMID- 22518144 TI - An MFS Transporter-Like ORF from MDR Acinetobacter baumannii AIIMS 7 Is Associated with Adherence and Biofilm Formation on Biotic/Abiotic Surface. AB - A major facilitator superfamily (MFS) transporter-like open reading frame (ORF) of 453 bp was identified in a pathogenic strain Acinetobacter baumannii AIIMS 7, and its association with adherence and biofilm formation was investigated. Reverse transcription PCR (RT-PCR) showed differential expression in surface attached biofilm cells than nonadherent cells. In vitro translation showed synthesis of a ~17 kDa protein, further confirmed by cloning and heterologous expression in E. coli DH5alpha. Up to 2.1-, 3.1-, and 4.1- fold biofilm augmentation was observed on abiotic (polystyrene) and biotic (S. cerevisiae/HeLa) surface, respectively. Scanning electron microscopy (SEM) and gfp-tagged fluorescence microscopy revealed increased adherence to abiotic (glass) and biotic (S. cerevisiae) surface. Extracellular DNA(eDNA) was found significantly during active growth; due to probable involvement of the protein in DNA export, strong sequence homology with MFS transporter proteins, and presence of transmembrane helices. In summary, our findings show that the putative MFS transporter-like ORF (pmt) is associated with adherence, biofilm formation, and probable eDNA release in A. baumannii AIIMS 7. PMID- 22518146 TI - Recent Advances in the Use of Drosophila melanogaster as a Model to Study Immunopathogenesis of Medically Important Filamentous Fungi. AB - Airborne opportunistic fungi, including Aspergillus and other less common saprophytic molds, have recently emerged as important causes of mortality in immunocompromised individuals. Understanding the molecular mechanisms of host fungal interplay in robust experimental pathosystems is becoming a research priority for development of novel therapeutics to combat these devastating infections. Over the past decade, invertebrate hosts with evolutionarily conserved innate immune signaling pathways and powerful genetics, such as Drosophila melanogaster, have been employed as a means to overcome logistic restrains associated with the use mammalian models of fungal infections. Recent studies in Drosophila models of filamentous fungi demonstrated that several genes implicated in fungal virulence in mammals also play a similarly important pathogenic role in fruit flies, and important host-related aspects in fungal pathogenesis are evolutionarily conserved. In view of recent advances in Drosophila genetics, fruit flies will become an invaluable surrogate model to study immunopathogenesis of fungal diseases. PMID- 22518148 TI - No-cook process for ethanol production using Indian broken rice and pearl millet. AB - No-cook process using granular starch hydrolyzing enzyme (GSHE) was evaluated for Indian broken rice and pearl millet. One-factor-at-a-time optimization method was used in ethanol production to identify optimum concentration of GSHE, under yeast fermentation conditions using broken rice and pearl millet as fermentation feedstocks. An acid fungal protease at a concentration of 0.2 kg per metric ton of grain was used along with various dosages of GSHE under yeast fermentation conditions to degrade the grain proteins into free amino nitrogen for yeast growth. To measure the efficacy of GSHE to hydrolyze no-cook broken rice and pearl millet, the chemical composition, fermentation efficiency, and ethanol recovery were determined. In both feedstocks, fermentation efficiency and ethanol recovery obtained through single-step no-cook process were higher than conventional multistep high-temperature process, currently considered the ideal industrial process. Furthermore, the no-cook process can directly impact energy consumption through steam saving and reducing the water cooling capacity needs, compared to conventional high-temperature process. PMID- 22518147 TI - Biological significance of HCV in various kinds of lymphoid cells. AB - It has been reported that HCV can infect not only hepatocytes but also various kinds of lymphoid cells. Although many reports have described the biological significance of lymphotropic HCV, the issue remains controversial since the target lymphoid cells might have various kinds of functions in the immune system. One of the important roles of lymphoid cells in HCV replication is being a reservoir of HCV. Several groups described the detection of HCV-RNA in lymphoid cells after HCV eradication in plasma. Another important role of lymphotropic HCV is that it acts as a carcinogenic agent and induces immune dysfunction. In this paper, we summarize the reports regarding the biological significance of lymphotropic HCV in representative lymphoid cells. PMID- 22518145 TI - Fungal biofilm resistance. AB - Fungal biofilm infections have become increasingly recognised as a significant clinical problem. One of the major reasons behind this is the impact that these have upon treatment, as antifungal therapy often fails and surgical intervention is required. This places a large financial burden on health care providers. This paper aims to illustrate the importance of fungal biofilms, particularly Candida albicans, and discusses some of the key fungal biofilm resistance mechanisms that include, extracellular matrix (ECM), efflux pump activity, persisters, cell density, overexpression of drug targets, stress responses, and the general physiology of the cell. The paper demonstrates the multifaceted nature of fungal biofilm resistance, which encompasses some of the newest data and ideas in the field. PMID- 22518149 TI - Isolation and Characterization of Nodule-Associated Exiguobacterium sp. from the Root Nodules of Fenugreek (Trigonella foenum-graecum) and Their Possible Role in Plant Growth Promotion. AB - One of the ways to increase the competitive survivability of rhizobial biofertilizers and thus achieve better plant growth under such conditions is by modifying the rhizospheric environment or community by addition of nonrhizobial nodule-associated bacteria (NAB) that cause better nodulation and plant growth when coinoculated with rhizobia. A study was performed to investigate the most commonly associated nodule-associated bacteria and the rhizospheric microorganisms associated with the Fenugreek (Trigonella foenum-graecum) plant. Isolation of nonrhizobial isolates from root nodules of Fenugreek was carried out along with the rhizospheric isolates. About 64.7% isolates obtained from Fenugreek nodules were gram-negative coccobacilli, 29.41% were gram-positive bacilli, and all rhizospheric isolates except one were gram-positive bacilli. All the isolates were characterized for their plant growth promoting (PGP) activities. Two of the NAB isolates M2N2c and B1N2b (Exiguobacterium sp.) showed maximum positive PGP features. Those NAB isolates when coinoculated with rhizobial strain-S. meliloti, showed plant growth promotion with respect to increase in plant's root and shoot length, chlorophyll content, nodulation efficiency, and nodule dry weight. PMID- 22518150 TI - The Design and Construction of K11: A Novel alpha-Helical Antimicrobial Peptide. AB - Amphipathic alpha-helical antimicrobial peptides comprise a class of broad spectrum agents that are used against pathogens. We designed a series of antimicrobial peptides, CP-P (KWKSFIKKLTSKFLHLAKKF) and its derivatives, and determined their minimum inhibitory concentrations (MICs) against Pseudomonas aeruginosa, their minimum hemolytic concentrations (MHCs) for human erythrocytes, and the Therapeutic Index (MHC/MIC ratio). We selected the derivative peptide K11, which had the highest therapeutic index (320) among the tested peptides, to determine the MICs against Gram-positive and Gram-negative bacteria and 22 clinical isolates including Acinetobacter baumannii, methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Staphylococcus epidermidis, and Klebsiella pneumonia. K11 exhibited low MICs (less than 10 MUg/mL) and broad spectrum antimicrobial activity, especially against clinically isolated drug resistant pathogens. Therefore, these results indicate that K11 is a promising candidate antimicrobial peptide for further studies. PMID- 22518151 TI - Temperature Depended Role of Shigella flexneri Invasion Plasmid on the Interaction with Acanthamoeba castellanii. AB - Shigella flexneri is a Gram-negative bacterium causing the diarrhoeal disease shigellosis in humans. The virulence genes required for invasion are clustered on a large 220 kb plasmid encoding type three secretion system (TTSS) apparatus and virulence factors such as adhesions and invasion plasmid antigens (Ipa). The bacterium is transmitted by contaminated food, water, or from person to person. Acanthamoebae are free-living amoebae (FLA) which are found in diverse environments and isolated from various water sources. Different bacteria interact differently with FLA since Francisella tularensis, Vibrio cholerae, Shigella sonnei, and S. dysenteriae are able to grow inside A. castellanii. In contrast, Pseudomonas aeruginosa induces both necrosis and apoptosis to kill A. castellanii. The aim of this study is to examine the role of invasion plasmid of S. flexneri on the interaction with A. castellanii at two different temperatures. A. castellanii in the absence or presence of wild type, IpaB mutant, or plasmid cured strain S. flexneri was cultured at 30 degrees C and 37 degrees C and the interaction was analysed by viable count of both bacteria and amoebae, electron microscopy, flow cytometry, and statistical analysis. The outcome of the interaction was depended on the temperature since the growth of A. castellanii was inhibited at 30 degrees C, and A. castellanii was killed by invasion plasmid mediated necrosis at 37 degrees C. PMID- 22518152 TI - Cochlear implantation in patients with neurofibromatosis type 2 and patients with vestibular schwannoma in the only hearing ear. AB - Cochlear implants are a new surgical option in the hearing rehabilitation of patients with neurofibromatosis type 2 (NF2) and patients with vestibular schwannoma (VS) in the only hearing ear. Auditory brainstem implant (ABI) has been the standard surgical treatment for these patients. We performed a literature review of patients with NF2 and patients with VS in the only hearing ear. Cochlear implantation (CI) provided some auditory benefit in all patients. Preservation of cochlear nerve integrity is crucial after VS resection. Results ranged from environmental sound awareness to excellent benefit with telephone use. Promontory stimulation is recommended although not crucial. MRI can be performed safely in cochlear implanted patients. PMID- 22518153 TI - Objective Assessment of Hypernasality in Patients with Cleft Lip and Palate with the NasalView System: A Clinical Validation Study. AB - Introduction. The objective of this investigation was to evaluate the reliability and validity of the NasalView system as a screening tool for hypernasality within the scope of a routine diagnostic procedure in cleft lip and palate patients. Material and Methods. In a collective of 95 patients with cleft and lip palate ranging from 4 to 25 years of age, hypernasality was exploited perceptually, patients were classified in four degrees, and nasalance was measured objectively with the NasalView system. Speech stimuli existed in one nasal and one nonnasal sentence; nasalance ratio and distance were calculated. Results. The test-retest error was within a range of 2%. Sensitivity ranged from 83.3% to 91.1% for the nonnasal sentence, from 70% to 78.4% for nasalance ratio and from 68.1% to 81.1% for nasalance distance. Specifity ranged from 87% to 93.1% for the nonnasal sentence, from 69.6% to 97.5% for nasalance ratio, and from 70.7% to 73.9% for nasalance distance. Conclusions. With a quick and gentle screening procedure, it is easily possible to identify hypernasal patients by an objective diagnostic tool of hypernasality, the NasalView system, with good reliability and validity. PMID- 22518154 TI - Maxillomandibular advancement in the management of obstructive sleep apnea. AB - Maxillomandibular advancement (MMA) is a surgical option for obstructive sleep apnea (OSA). MMA involves forward-fixing the maxilla and mandible approximately 10 mm via Le Fort I maxillary and sagittal split mandibular osteotomies. We retrospectively reviewed outcomes from 24 consecutive OSA patients who underwent MMA at our institution. MMA resulted in an 83% reduction in the group mean apnea hypopnea index (AHI) per polysomnography an average of 6.7 months after surgery. Forty-two percent of patients achieved a post-MMA AHI of less than 5 events/hour sleep and 71% achieved an AHI less than or equal to 10 events/hour sleep. The Epworth Sleepiness Scale score decreased by an average of 5 post-surgery. No parameters predictive of cure for OSA by MMA were identified. PMID- 22518155 TI - The role of atoh1 in mucous cell metaplasia. AB - A key issue in otitis media is mucous cell metaplasia which is responsible for mucous hypersecretion and persistence of the disease. However, little is known about the molecular mechanisms of mucous cell metaplasia in otitis media. Numerous studies of intestinal epithelial homeostasis have shown that Atonal homolog 1 (Atoh1), a basic helix-loop-helix (bHLH) transcription factor, is essential for the intestinal goblet cell differentiation. On the other hand, SAM pointed domain-containing Ets transcription factor (SPDEF), a member of the "Ets" transcription factor family, has been reported to trigger the mucous cell metaplasia of pulmonary infectious diseases or athsma. Recent studies have demonstrated the relation of these factors, that is, Spdef functions downstream of Atoh1. We could take the adventages of these findings for the study of otitis media because both middle ear and pulmonary epithelia belong to the same respiratory tract. Atoh1 and SPDEF could be the therapeutic targets for otitis media associated with mucous cell metaplasia which is frequently considered "intractable" in the clinical settings. PMID- 22518156 TI - Gram staining for the treatment of peritonsillar abscess. AB - Objective. To examine whether Gram staining can influence the choice of antibiotic for the treatment of peritonsillar abscess. Methods. Between 2005 and 2009, a total of 57 cases of peritonsillar abscess were analyzed with regard to cultured bacteria and Gram staining. Results. Only aerobes were cultured in 16% of cases, and only anaerobes were cultured in 51% of cases. Mixed growth of aerobes and anaerobes was observed in 21% of cases. The cultured bacteria were mainly aerobic Streptococcus, anaerobic Gram-positive cocci, and anaerobic Gram negative rods. Phagocytosis of bacteria on Gram staining was observed in 9 cases. The bacteria cultured from these cases were aerobic Streptococcus, anaerobic Gram positive cocci, and anaerobic Gram-negative rods. The sensitivity of Gram staining for the Gram-positive cocci and Gram-negative rods was 90% and 64%, respectively. The specificity of Gram staining for the Gram-positive cocci and Gram-negative rods was 62% and 76%, respectively. Most of the Gram-positive cocci were sensitive to penicillin, but some of anaerobic Gram-negative rods were resistant to penicillin. Conclusion. When Gram staining shows only Gram-positive cocci, penicillin is the treatment of choice. In other cases, antibiotics effective for the penicillin-resistant organisms should be used. PMID- 22518157 TI - A review of hearing loss in cleft palate patients. AB - Background. Cleft palate is associated with recurrent otitis media with effusion and hearing loss. This study analysed the way these patients' hearing is managed in Alder Hey Children's Hospital. Method. A retrospective audit was carried out on cleft palate patients in Alder Hey Children's Hospital. Audiology assessment and treatment options were reviewed. Comparisons were made between the use of ventilation tubes (VTs) and hearing aids (HAs). The types of cleft, types of hearing loss, and the management output of the audiology regions were also reviewed. Results. The audiology assessments of 254 patients were examined. The incidence of VT insertion in this group of patients was 18.9%. The hearing aid incidence rate was 10.1%. The VT-related complication rate was 25.5% and the HA related complication rate was 9.1%. Conclusion. The data demonstrates that both treatments are viable, and a new protocol which combines the short term benefit of VT insertion with the lower complication rate of HA is required. PMID- 22518158 TI - Interaction between Chronic Inflammation and Oral HPV Infection in the Etiology of Head and Neck Cancers. AB - Incidences of oral tongue, base of the tongue, and tonsil cancers have been increasing steadily in many parts of the world in spite of declining rates of tobacco use over the last four decades. A better understanding of the etiology, interactions between risk factors, and new approaches to prevention and treatment are necessary to change this course. This paper will present evidence supporting a potential role of chronic inflammation in the etiologies of oral human papillomavirus infection and head and neck squamous cell carcinoma, and it will discuss the implications for prevention and treatment. PMID- 22518159 TI - The dehiscent facial nerve canal. AB - Accidental injury to the facial nerve where the bony canal defects are present may result with facial nerve dysfunction during otological surgery. Therefore, it is critical to know the incidence and the type of facial nerve dehiscences in the presence of normal development of the facial canal. The aim of this study is to review the site and the type of such bony defects in 144 patients operated for facial paralysis, myringoplasty, stapedotomy, middle ear exploration for sudden hearing loss, and so forth, other than chronic suppurative otitis media with or without cholesteatoma, middle ear tumors, and anomaly. Correlation of intraoperative findings with preoperative computerized tomography was also analyzed in 35 patients. Conclusively, one out of every 10 surgical cases may have dehiscence of the facial canal which has to be always borne in mind during surgical manipulation of the middle ear. Computerized tomography has some limitations to evaluate the dehiscent facial canal due to high false negative and positive rates. PMID- 22518160 TI - Fungal rhinosinusitis: a retrospective microbiologic and pathologic review of 400 patients at a single university medical center. AB - Fungal Rhinosinusitis (FRS) is a well known entity, but only in more recent times have the types of FRS been more fully defined. In this study, we evaluate the diagnosis of FRS in a single medical center. Cases were divided into 2 main categories, non-invasive and invasive. Non-invasive FRS included fungus ball (FB) and allergic fungal rhinosinusitis (AFRS). Invasive FRS included acute invasive fungal rhinosinusitis (AIFRS), chronic invasive fungal rhinosinusitis (CIFRS), and chronic invasive granulomatous fungal rhinosinusitis (CGFRS). Fungal culture data, if available was reviewed. 400 patients with FRS were identified. 87.25% were non-invasive (45% AFRS, 40% FB, and 2% combined AFRS and FB and 12.5% were invasive 11% AIFRS 1.2% CIFRS 0.5% CGFRS. One patient (0.25%) had combined FB/CGFRS. Aspergillus sp. or dematiaceous species were the most common fungi isolated in AFS while Aspergillus sp. was most common in FB and AIFRS. In our experience, most FRS is non-invasive. In our patient population, invasive FRS is rare with AIFRS representing >90% of cases. Culture data supports that a variety of fungal agents are responsible for FRS, but Aspergillus sp. appears to be one of the most common organisms in patients with FRS. PMID- 22518161 TI - Unilateral auditory neuropathy caused by cochlear nerve deficiency. AB - Objective. To explore possible corelationship between the cochlear nerve deficiency (CND) and unilateral auditory neuropathy (AN). Methods. From a database of 85 patients with unilateral profound sensorineural hearing loss, eight who presented with evoked otoacoustic emissions (EOAEs) or cochlear microphonic (CM) in the affected ear were diagnosed with unilateral AN. Audiological and radiological records in eight patients with unilateral AN were retrospectively reviewed. Results. Eight cases were diagnosed as having unilateral AN caused by CND. Seven had type "A" tympanogram with normal EOAE in both ears. The other patient had unilateral type "B" tympanogram and absent OAE but CM recorded, consistent with middle ear effusion in the affected ear. For all the ears involved in the study, auditory brainstem responses (ABRs) were either absent or responded to the maximum output and the neural responses from the cochlea were not revealed when viewed by means of the oblique sagittal MRI on the internal auditory canal. Conclusion. Cochlear nerve deficiency can be seen by electrophysiological evidence and may be a significant cause of unilateral AN. Inclined sagittal MRI of the internal auditory canal is recommended for the diagnosis of this disorder. PMID- 22518162 TI - The Role of Postural Restrictions after BPPV Treatment: Real Effect on Successful Treatment and BPPV's Recurrence Rates. AB - Background. Canalith repositioning techniques are adequately established in the literature, as the treatment of choice for benign paroxysmal positional vertigo. However, the role of the posttreatment instructions is still not clearly defined. Patients and Methods. A retrospective chart review of 82 patients was conducted in order to determine the efficacy of postural restrictions, when combined with the classic canalith repositioning techniques, in terms of successful treatment and recurrence rates. Follow-up period reached at least 12 months after the initial treatment. Results. In this study, postural restrictions did not appear to significantly affect the outcomes of repositioning maneuvers, as well as the recurrence rate. Conclusions. Although this study, as well as most recent control studies, states that there is no significant effect of postmaneuver postural restrictions on both treatment and recurrence rates, larger multicentric research projects, adopting improved methodology, are still necessary in order to determine the contribution of such restrictions to both the therapeutic results and the prevention of recurrence. Adequate followup, focusing on the first six months after the initially successful repositioning maneuver, is also of paramount importance. PMID- 22518163 TI - The prevalence and clinical correlates of an auscultatory gap in systemic sclerosis patients. AB - Introduction. Accurate blood pressure (BP) measurement is essential to the diagnosis and management of hypertension in patients with systemic sclerosis (SSc) to help prevent renal and cardiovascular complications. The presence of an auscultatory gap during manual BP measurement-the temporary disappearance of the Korotkoff sounds during cuff deflation-leads to a potentially important underestimate of systolic BP if undetected. Objectives. Since the presence of an auscultatory gap is frequently associated with increased vascular stiffness, we investigated its presence and correlates in 50 consecutive SSc patients. Methods. For each patient, BP was measured sequentially using three different approaches performed in the same order. Results. Sixteen of 50 patients (32%) had an auscultatory gap which if undetected would have resulted in clinically important underestimates of systolic BP in 4 patients. The presence of an auscultatory gap was statistically associated with the presence of antibodies to RNA polymerase III (P<0.0068) and SSc diagnosis type (P<0.01). Conclusions. Our study demonstrates that auscultatory gaps are relatively common in SSc and correlate with markers for SSc vasculopathy. If undetected auscultatory gaps may result in clinically important underestimation of BP. Thus, electronic oscillometric BP may be preferred in SSc patients. PMID- 22518164 TI - Controversies in the management of endometrial carcinoma: an update. AB - Endometrial carcinoma is the commonest type of female genital tract malignancy in the developed countries. Endometrial carcinoma is usually confined to the uterus at the time of diagnosis and as such usually carries an excellent prognosis with high curability. Our understanding and management of endometrial cancer have continuously developed. Current controversies focus on screening and early detection, the extent of nodal surgery, and the changing roles of radiation therapy and chemotherapy and will be discussed in this paper. PMID- 22518165 TI - Headache in pregnancy: a nuisance or a new sense? AB - Headache is a very commonly encountered symptom in pregnancy and is usually due to primary headache disorders which are benign in nature. It can however be quite debilitating for some women who may need therapeutic treatment of which there are several options safe to use in pregnancy. It is equally important though to recognise that headache may be a sign of serious underlying pathology. This paper aims to provide a clinically useful guidance for differentiation between primary and secondary headaches in pregnancy. The primary headache disorders and their management in pregnancy are explored in depth with brief overviews of the causes for secondary headaches and their further investigation and management. PMID- 22518166 TI - Cryopreservation of ovarian tissue in pediatric patients. AB - Cancer treatments improve the survival rate of children and adolescents; however chemo- and radiotherapy result in gonadal damage leading to acute ovarian failure and sterility. Ovarian tissue cryopreservation allows long-term storage of primordial follicles and represents the only possibility of preserving the potential fertility in prepubertal girls. The aim of the present study is to describe our experience in ovarian tissue cryopreservation in 45 pediatric patients. The number of follicles per square millimeter of the overall section area and follicle quality were evaluated histologically. A strong negative correlation was found between age and follicular density in patients both prior to and after chemotherapy (P < 0.0001). Damage in follicular quality, that is, increased oocyte vacuolization and detachment of the oocyte from granulosa cells, was found after chemotherapy. Ovarian tissue cryopreservation, preferably performed before initiation of chemotherapy, should be offered to pediatric patients, including prepubertal girls, at risk of sterility. PMID- 22518168 TI - Information system and geographic information system tools in the data analyses of the control program for visceral leishmaniases from 2006 to 2010 in the sanitary district of venda nova, belo horizonte, minas gerais, Brazil. AB - The aim of this paper is to report a brief history of control actions for Visceral Leishmaniasis (VL) from 2006 to 2010 in the Sanitary District (DS) of Venda Nova, Belo Horizonte, Minas Gerais, Brazil, focusing on the use of information systems and Geographic Information System (GIS) tools. The analyses showed that the use of an automated database allied with geoprocessing tools may favor control measures of VL, especially with regard to the evaluation of control actions carried out. Descriptive analyses of control measures allowed to evaluating that the information system and GIS tools promoted greater efficiency in making decisions and planning activities. These analyses also pointed to the necessity of new approaches to the control of VL in large urban centers. PMID- 22518167 TI - Innovative oral treatments of uterine leiomyoma. AB - Uterine fibroids (leiomyoma), the benign tumors of the uterine wall, are very common cause of morbidity in reproductive age women usually in the form of excessive vaginal bleeding, chronic pelvic pain, miscarriage and infertility. These tumors are the leading indication for hysterectomy in the United States. Uterine fibroids are about 4 times higher in blacks compared to whites and constitute a major health disparity challenge. The estimated cost of uterine fibroids is up to $34.4 billion annually. Additionally, women who suffer from this disease and desire to maintain their future fertility have very limited treatment choices. Currently, there is no effective long-term medicinal treatment for uterine fibroids. While surgery has traditionally been the gold standard for the treatment of uterine fibroids, there is growing interest towards orally administered medications for the management of leiomyoma-related symptoms. In this paper, we will discuss these promising innovative oral medical treatments in detail. PMID- 22518169 TI - Childhood TB Surveillance: Bridging the Knowledge Gap to Inform Policy. AB - Tuberculosis (TB) is a leading cause of death globally. Natural history studies show that young children are at particularly high risk of progression to active TB and severe, disseminated disease following infection. Despite this, high quality regional and global surveillance data on the burden of childhood TB are lacking. We discuss the unique aspects of TB in children that make diagnosis and therefore surveillance challenging; the limitations of available surveillance data; other data which provide insights into the true burden of childhood TB. Improved surveillance is among the key research priorities identified for childhood TB, but progress to date has been slow. Recent advances in TB diagnostics, and standardized clinical diagnostic guidelines and case definitions, all provide opportunities for new strategies to improve surveillance. Better-quality data on the burden and trends of childhood TB will inform and improve both public health policy and clinical practice. PMID- 22518170 TI - A national baseline prevalence survey of schistosomiasis in the Philippines using stratified two-step systematic cluster sampling design. AB - For the first time in the country, a national baseline prevalence survey using a well-defined sampling design such as a stratified two-step systematic cluster sampling was conducted in 2005 to 2008. The purpose of the survey was to stratify the provinces according to prevalence of schistosomiasis such as high, moderate, and low prevalence which in turn would be used as basis for the intervention program to be implemented. The national survey was divided into four phases. Results of the first two phases conducted in Mindanao and the Visayas were published in 2008. Data from the last two phases showed three provinces with prevalence rates higher than endemic provinces surveyed in the first two phases thus changing the overall ranking of endemic provinces at the national level. Age and sex distribution of schistosomiasis remained the same in Luzon and Maguindanao. Soil-transmitted and food-borne helminthes were also recorded in these surveys. This paper deals with the results of the last 2 phases done in Luzon and Maguindanao and integrates all four phases in the discussion. PMID- 22518171 TI - Species distribution models and ecological suitability analysis for potential tick vectors of lyme disease in Mexico. AB - Species distribution models were constructed for ten Ixodes species and Amblyomma cajennense for a region including Mexico and Texas. The model was based on a maximum entropy algorithm that used environmental layers to predict the relative probability of presence for each taxon. For Mexico, species geographic ranges were predicted by restricting the models to cells which have a higher probability than the lowest probability of the cells in which a presence record was located. There was spatial nonconcordance between the distributions of Amblyomma cajennense and the Ixodes group with the former restricted to lowlands and mainly the eastern coast of Mexico and the latter to montane regions with lower temperature. The risk of Lyme disease is, therefore, mainly present in the highlands where some Ixodes species are known vectors; if Amblyomma cajennense turns out to be a competent vector, the area of risk also extends to the lowlands and the east coast. PMID- 22518172 TI - Molecular typing of dengue virus circulating in kolkata, India in 2010. AB - Dengue is one of the major public health threats in Kolkata. Every year, blood samples with dengue-like illness are referred to us from different medical colleges and hospitals in Kolkata for the detection of dengue infection in them. In 2010, a total of 378 samples were referred to us for that purpose. All the samples were tested for the detection of IgM antibodies by ELISA method, followed by RT-PCR test for the detection of serotypes. Only 173 samples were ELISA positive. Out of 378 samples, 108 were RT-PCR positive. Out of 108 samples, 74 samples had monotypic infection with different serotypes of DENV and 33 samples had dual infections with DENV-2 and DENV-3. Only one sample had the infection with DENV-1, DENV-2, and DENV-3. DHF was found mainly among the patients, infected with multiple dengue serotypes. Only 3 dengue monotypic infected patients had suffered from DHF. PMID- 22518173 TI - The experience in nicaragua: childhood leukemia in low income countries-the main cause of late diagnosis may be "medical delay". AB - Background. The event-free survival for pediatric leukemia in low-income Countries is much lower than in high-income countries. Late diagnosis, which is regarded as a contributing factor, may be due to "parental" or "medical" delay. Procedures. The present study analyses determinants of lag time from first symptoms to diagnosis of leukemia, comparing pediatric (0-16 years old) patients in two referral centers, one in Nicaragua and one in Italy. An observational retrospective study was conducted to assess factors influencing the time to diagnosis. Results. 81 charts of children diagnosed with acute myeloid leukemia or lymphoblastic leukemia were analyzed from each centre. Median lag time to diagnosis was higher in Nicaragua than in Italy (29 versus 14 days, P < 0.001) and it was mainly due to "physician delay" (16.5 versus 7 days, P < 0.001), whereas "patient delay" from symptoms to first medical assessment was similar in the two centers (7 versus 5 days, P = 0.27). Moreover, median lag time from symptoms to diagnosis was decreased in Nicaraguan districts were a specific training program upon childhood oncological diseases was carried out (20.5 versus 40 days, P = 0.0019). Conclusions. Our study shows that delay in diagnosis of childhood leukemia is mainly associated with "physician delay" and it may be overcome by programs of continuous medical education. PMID- 22518174 TI - Economic analysis of a pediatric ventilator-associated pneumonia prevention initiative in nicaragua. AB - We performed an economic analysis of an intervention to decrease ventilator associated pneumonia (VAP) prevalence in pediatric intensive care units (PICUs) at two Nicaraguan hospitals to determine the cost of the intervention and how effective it needs to be in order to be cost-neutral. A matched cohort study determined differences in costs and outcomes among ventilated patients. VAP cases were matched by sex and age for children older than 28 days and by weight for infants under 28 days old to controls without VAP. Intervention costs were determined from accounting and PICU staff records. The intervention cost was approximately $7,000 for one year. If VAP prevalence decreased by 0.5%, hospitals would save $7,000 and the strategy would be cost-neutral. The finding that the intervention required only modest effectiveness to be cost-neutral and has potential to generate substantial cost savings argues for implementation of VAP prevention strategies in low-income countries like Nicaragua on a broader scale. PMID- 22518175 TI - Cardiac troponin T and illness severity in the very-low-birth-weight infant. AB - Introduction. Respiratory distress are very common in Very-low-birth-weight (VLBW) infants and Myocardial injury may play a role in the disease outcome. Cardiac troponin T (cTnT) is the most useful marker of injury in adult population, but has not been extensively studied in this population. Aim. To study the role of cTnT in VLBW infants and its association with clinical outcomes. Methods. All VLBW infants admitted to our NICU were included in the study. Echocardiography and blood samples for cTnT determination were collected at 24 and 48 hours of life, and values >0.1 ng/mL were considered CTnT-positive values. Results. A total of 116 neonates had their blood samples collected. The median cTnT concentration within 24 hours was 0.191 (0.1-0.79) ng/mL and within 48 hours was 0.293 (0.1-1.0) ng/mL. A logistic regression analysis showed that PDA, low GA, and use of dopamine were independently associated with positive cTnT and abnormal Dopplerfluxometry and diuretics use had protective effects and was independently associated with troponin values. Conclusion. We observed a high prevalence of positivecTnT values in VLBW infants associated with illness severity. Our findings suggest that cTnT may be a useful and early marker of myocardial injury in VLBW infants. PMID- 22518176 TI - Outcomes of disconnective surgery in intractable pediatric hemispheric and subhemispheric epilepsy. AB - OBJECTIVES: To study the outcome of disconnective epilepsy surgery for intractable hemispheric and sub-hemispheric pediatric epilepsy. METHODS: A retrospective analysis of the epilepsy surgery database was done in all children (age <18 years) who underwent a peri-insular hemispherotomy (PIH) or a peri insular posterior quadrantectomy (PIPQ) from April 2000 to March 2011. All patients underwent a detailed pre surgical evaluation. Seizure outcome was assessed by the Engel's classification and cognitive skills by appropriate measures of intelligence that were repeated annually. RESULTS: There were 34 patients in all. Epilepsy was due to Rasmussen's encephalitis (RE), Infantile hemiplegia seizure syndrome (IHSS), Hemimegalencephaly (HM), Sturge Weber syndrome (SWS) and due to post encephalitic sequelae (PES). Twenty seven (79.4%) patients underwent PIH and seven (20.6%) underwent PIPQ. The mean follow up was 30.5 months. At the last follow up, 31 (91.1%) were seizure free. The age of seizure onset and etiology of the disease causing epilepsy were predictors of a Class I seizure outcome. CONCLUSIONS: There is an excellent seizure outcome following disconnective epilepsy surgery for intractable hemispheric and subhemispheric pediatric epilepsy. An older age of seizure onset, RE, SWS and PES were good predictors of a Class I seizure outcome. PMID- 22518177 TI - Prematurity-related hypertension in children and adolescents. AB - Due to the functional and structural immaturity of different organ systems, preterms have a higher rate of morbidity and mortality. The prevention and treatment of the complications of prematurity is a major challenge in perinatal health care. Recently, there have been several multicenter research trials analysing the impact of prematurity or low birth weight on the health problems of children and adolescents. Many of these studies deal with the issue of pediatric hypertension. An analysis of 15 studies conducted in the years 1998-2011, in which blood pressure values in ex-preterm children were measured, was performed. Comparison was based on several issues: measurement method, cohorts age, size, and birthweight. It has been proven that hypertension occurs more often in former preterm infants; however the etiologic pathways that cause this condition still remain unclear. Moreover, pediatric hypertension is a significant problem, because of its transformation into adult hypertension and increased cardiovascular risk later in life. Therefore it is crucial to introduce wide spread screening and detection of elevated blood pressure, especially among prematurely born children. PMID- 22518178 TI - Sleep endoscopy in the evaluation of pediatric obstructive sleep apnea. AB - Pediatric obstructive sleep apnea (OSA) is not always resolved or improved with adenotonsillectomy. Persistent or complex cases of pediatric OSA may be due to sites of obstruction in the airway other than the tonsils and adenoids. Identifying these areas in the past has been problematic, and therefore, therapy for OSA in children who have failed adenotonsillectomy has often been unsatisfactory. Sleep endoscopy is a technique that can enable the surgeon to determine the level of obstruction in a sleeping child with OSA. With this knowledge, site-specific surgical therapy for persistent and complex pediatric OSA may be possible. PMID- 22518179 TI - Managing the morbidity associated with respiratory viral infections in children with congenital heart disease. AB - Children with congenital heart disease (CHD) are at risk for increased morbidity from viral lower respiratory tract infections because of anatomical cardiac lesions than can worsen an already compromised respiratory status. Respiratory syncytial virus (RSV) remains an important pathogen in contributing toward the morbidity in this population. Although the acute treatment of RSV largely remains supportive, the development of monoclonal antibodies, such as palivuzumab, has reduced the RSV-related hospitalization rate in children with CHD. This review highlights the specific cardiac complications of RSV infection, the acute treatment of bronchiolitis in patients with CHD, and the search for new therapies against RSV, including an effective vaccine, because of the high cost associated with immunoprophylaxis and its lack of reducing RSV-related mortality. PMID- 22518180 TI - Protecting family interests: an interview study with foreign-born parents struggling on in childhood cancer care. AB - Sweden's population is gradually changing to become more multiethnic and diverse and that applies also for recipients of health care, including childhood cancer care. A holistic view on the sick child in the context of its family has always been a cornerstone in childhood cancer care in Sweden. The purpose of this study was to gain knowledge about the experiences and main concern of foreign-born parents in the context of paediatric cancer care. Interviews were performed with eleven foreign-born parents and data were analysed using a classic grounded theory approach. Foreign-born parents often feel in a position of powerless dependence, but family interests are protected in their approaches to interaction with healthcare staff, through cooperation, contesting, and reluctant resigning. Healthcare staff need to listen to foreign-born parents and deal with their concerns seriously to prevent powerless-dependence and work for trustful cooperation in the common fight against childhood cancer. PMID- 22518181 TI - Effectiveness of high fidelity video-assisted real-time simulation: a comparison of three training methods for acute pediatric emergencies. AB - Background. Video-assisted real-time simulation (VARS) offers the possibility of developing competence in acute medicine in a realistic and safe environment. We investigated the effectiveness of the VARS model and compared it with educational methods like Problem-Based Learning (PBL) and Pediatric Advanced Life Support (PALS). Methods. 45 fourth-year medical students were randomized for three educational methods. Level of knowledge and self-efficacy were measured before and after intervention. Clinical performance was measured by a blinded observer using a video checklist of prescripted scenarios on a high-fidelity simulator. Results. Knowledge test and self-efficacy scores improved significantly (P < 0.001) without differences between educational groups. The VARS group showed significantly (P < 0.05) higher scores on both postintervention scenarios concerning structure and time. Conclusion. VARS training is an effective educational method teaching pediatric acute care skills in the undergraduate curriculum. When compared to PBL and PALS training, VARS training appears to be superior in enhancing short-term clinical performance. PMID- 22518182 TI - Laryngomalacia: disease presentation, spectrum, and management. AB - Laryngomalacia is the most common cause of stridor in newborns, affecting 45-75% of all infants with congenital stridor. The spectrum of disease presentation, progression, and outcomes is varied. Identifying symptoms and patient factors that influence disease severity helps predict outcomes. Findings. Infants with stridor who do not have significant feeding-related symptoms can be managed expectantly without intervention. Infants with stridor and feeding-related symptoms benefit from acid suppression treatment. Those with additional symptoms of aspiration, failure to thrive, and consequences of airway obstruction and hypoxia require surgical intervention. The presence of an additional level of airway obstruction worsens symptoms and has a 4.5x risk of requiring surgical intervention, usually supraglottoplasty. The presence of medical comorbidities predicts worse symptoms. Summary. Most with laryngomalacia will have mild-to moderate symptoms and not require surgical intervention. Those with gastroesophageal reflux and/or laryngopharyngeal reflux have symptom improvement from acid suppression therapy. Those with severe enough disease to require supraglottoplasty will have minimal complications and good outcomes if multiple medical comorbidities are not present. Identifying patient factors that influence disease severity is an important aspect of care provided to infants with laryngomalacia. PMID- 22518183 TI - Risks to early childhood health and development in the postconflict transition of northern Uganda. AB - Research from numerous fields of science has documented the critical importance of nurturing environments in shaping young children's future health and development. We studied the environments of early childhood (birth to 3 years) during postconflict, postdisplacement transition in northern Uganda. The aim was to better understand perceived needs and risks in order to recommend targeted policy and interventions. Methods. Applied ethnography (interview, focus group discussion, case study, observational methods, document review) in 3 sites over 1 year. Results. Transition was a prolonged and deeply challenging phase for families. Young children were exposed to a myriad of risk factors. Participants recognized risks as potential barriers to positive long-term life outcomes for children and society but circumstances generally rendered them unable to make substantive changes. Conclusions. Support structures were inadequate to protect the health and development of children during the transitional period placing infants and young children at risk. Specific policy and practice guidelines are required that focus on protecting hard-to-reach, vulnerable, children during what can be prolonged and extremely difficult periods of transition. PMID- 22518184 TI - Clinical effectiveness of peramivir in comparison with other neuraminidase inhibitors in pediatric influenza patients. AB - The currently used antivirals in the treatment of influenza in Japan include amantadine, oseltamivir, zanamivir, laninamivir, and peramivir. We compared the efficacy of intravenous peramivir with that of other neuraminidase inhibitors for treating pediatric influenza. The present study included 223 influenza patients (<=18 years) who presented at the Hikita Pediatric Clinic between February and April 2011. We compared fever duration after starting treatment with antiviral drugs. Because inhalation drugs are difficult to use in <5-year-old patients and because of the potential adverse effects of oseltamivir in teenagers, we created two different age groups (<10-year-old group and 5-18-year-old group) to evaluate treatment results. In influenza A patients between 5 and 18 years old, the median fever duration after treatment with zanamivir was 2 days, compared with 1 day for peramivir (P = 0.0242). In influenza B patients between 5 and 18 years old, the median fever duration after treatment with laninamivir was 3 days, compared with 1 day for peramivir (P = 0.0097). We found no significant difference for any of the other combinations of drug/disease type/age groups. No adverse effects were observed with the antiviral drugs used. The results suggest that peramivir is very useful in pediatric influenza patients. PMID- 22518185 TI - Antenatal bartter syndrome: a review. AB - Antenatal Bartter syndrome (ABS) is a rare autosomal recessive renal tubular disorder. The defective chloride transport in the loop of Henle leads to fetal polyuria resulting in severe hydramnios and premature delivery. Early onset, unexplained maternal polyhydramnios often challenges the treating obstetrician. Increasing polyhydramnios without apparent fetal or placental abnormalities should lead to the suspicion of this entity. Biochemical analysis of amniotic fluid is suggested as elevated chloride level is usually diagnostic. Awareness, early recognition, maternal treatment with indomethacin, and amniocentesis allow the pregnancy to continue. Affected neonates are usually born premature, have postnatal polyuria, vomiting, failure to thrive, hypercalciuria, and subsequently nephrocalcinosis. Hypokalemia, metabolic alkalosis, secondary hyperaldosteronism and hyperreninaemia are other characteristic features. Volume depletion due to excessive salt and water loss on long term stimulates renin-angiotensin aldosterone system resulting in juxtaglomerular hyperplasia. Clinical features and electrolyte abnormalities may also depend on the subtype of the syndrome. Prenatal diagnosis and timely indomethacin administration prevent electrolyte imbalance, restitute normal growth, and improve activity. In this paper, authors present classification, pathophysiology, clinical manifestations, laboratory findings, complications, and prognosis of ABS. PMID- 22518186 TI - The effects of hypertension on cognitive function in children and adolescents. AB - Hypertension (HTN) is found in about 3-4% of the pediatric population with long term risks of end organ damage if untreated or poorly controlled. Although children with HTN are being more frequently screened for end organ damage (i.e., LVH), the cognitive effects of HTN and methods to screen for cognitive dysfunction have not been extensively explored. In recent years, there have been a small number of studies that have provided important insights that can guide future research in this area. These studies show that HTN can be associated with headaches, restlessness, sleep disturbance, anxiety, depression, decreased attention, and also poor executive functioning. By increasing the utilization of cognitive tests in hypertensive children and adolescents, important cognitive defects secondary to HTN may be detected. More research is needed in the area, and the results of future studies could have far reaching implications for long term outcomes in hypertensive children and adolescents. PMID- 22518187 TI - Maternal Music Exposure during Pregnancy Influences Neonatal Behaviour: An Open Label Randomized Controlled Trial. AB - Objective. This study evaluated the effect of antenatal music exposure to primigravida healthy mothers on the behaviour of their term appropriate-for-date newborns assessed using Brazelton Neonatal Behavioral Assessment Scale (BNBAS). Methods. This was a single-centre, randomized, open-label controlled trial. Primigravida mothers aged 19-29 years, free of chronic medical diseases or significant deafness, with singleton pregnancy, with a gestation of 20 weeks or less, were randomized to listen to a pre-recorded music cassette for approximately 1 hour/day in addition to standard antenatal care (intervention arm) or standard care only (control arm). Perinatal factors with adverse effect on neonatal behaviour were deemed as protocol violations. Outcome measure included scores on 7 clusters of BNBAS. Primary analysis was per protocol. The trial is registered with ClinicalTrials.gov (NCT01278329). Results. One hundred and twenty-six newborns in the music group and 134 in the control group were subjected to BNBAS assessment. The infants of mothers exposed to music during pregnancy performed significantly better on 5 of the 7 BNBAS clusters. The maximal beneficial effect was seen with respect to orientation (ES 1.13, 95% CI 0.82-1.44, P < 0.0001) and habituation (ES 1.05, 95% CI 0.53-1.57, P = 0.0001). Conclusion. Prenatal music exposure to mother significantly and favourably influences neonatal behaviour. PMID- 22518188 TI - Nephrogenic syndrome of inappropriate antidiuresis. AB - Mutations in the vasopressin V2 receptor gene are responsible for two human tubular disorders: X-linked congenital nephrogenic diabetes insipidus, due to a loss of function of the mutant V2 receptor, and the nephrogenic syndrome of inappropriate antidiuresis, due to a constitutive activation of the mutant V2 receptor. This latter recently described disease may be diagnosed from infancy to adulthood, as some carriers remain asymptomatic for many years. Symptomatic children, however, typically present with clinical and biological features suggesting inappropriate antidiuretic hormone secretion with severe hyponatremia and high urine osmolality, but a low plasma arginine vasopressin level. To date, only two missense mutations in the vasopressin V2 receptor gene have been found in the reported patients. The pathophysiology of the disease requires fuller elucidation as the phenotypic variability observed in patients bearing the same mutations remains unexplained. The treatment is mainly preventive with fluid restriction, but urea may also be proposed. PMID- 22518189 TI - Postmortem cerebrospinal fluid pleocytosis: a marker of inflammation or postmortem artifact? AB - The aim of this paper is to reassess the significance of postmortem cerebrospinal fluid pleocytosis. Published articles of CSF changes after death were reviewed, and reanalysis, in the light of modern views on the significance of bacterial postmortem isolates, was undertaken. There is theoretical and experimental evidence that the blood brain barrier to the movement of protein and cells is preserved in the first few hours after death. The number of mononuclear cells in the cerebrospinal fluid does rise in the first 24 hours after death, and this is most probably due to detachment of leptomeningeal lining cells. But the marked increase in lymphocyte counts seen in some cases of sudden infant death syndrome (SIDS) and in other deaths in the paediatric age range could well be a marker of inflammation. PMID- 22518190 TI - Respiratory support in meconium aspiration syndrome: a practical guide. AB - Meconium aspiration syndrome (MAS) is a complex respiratory disease of the term and near-term neonate. Inhalation of meconium causes airway obstruction, atelectasis, epithelial injury, surfactant inhibition, and pulmonary hypertension, the chief clinical manifestations of which are hypoxaemia and poor lung compliance. Supplemental oxygen is the mainstay of therapy for MAS, with around one-third of infants requiring intubation and mechanical ventilation. For those ventilated, high ventilator pressures, as well as a relatively long inspiratory time and slow ventilator rate, may be necessary to achieve adequate oxygenation. High-frequency ventilation may offer a benefit in infants with refractory hypoxaemia and/or gas trapping. Inhaled nitric oxide is effective in those with pulmonary hypertension, and other adjunctive therapies, including surfactant administration and lung lavage, should be considered in selected cases. With judicious use of available modes of ventilation and adjunctive therapies, infants with even the most severe MAS can usually be supported through the disease, with an acceptably low risk of short- and long-term morbidities. PMID- 22518191 TI - Leptin in anorexia and cachexia syndrome. AB - Leptin is a product of the obese (OB) gene secreted by adipocytes in proportion to fat mass. It decreases food intake and increases energy expenditure by affecting the balance between orexigenic and anorexigenic hypothalamic pathways. Low leptin levels are responsible for the compensatory increase in appetite and body weight and decreased energy expenditure (EE) following caloric deprivation. The anorexia-cachexia syndrome is a complication of many chronic conditions including cancer, chronic obstructive pulmonary disease, congestive heart failure, chronic kidney disease, and aging, where the decrease in body weight and food intake is not followed by a compensatory increase in appetite or decreased EE. Crosstalk between leptin and inflammatory signaling known to be activated in these conditions may be responsible for this paradox. This manuscript will review the evidence and potential mechanisms mediating changes in the leptin pathway in the setting of anorexia and cachexia associated with chronic diseases. PMID- 22518192 TI - Platelet-rich plasma peptides: key for regeneration. AB - Platelet-derived Growth Factors (GFs) are biologically active peptides that enhance tissue repair mechanisms such as angiogenesis, extracellular matrix remodeling, and cellular effects as stem cells recruitment, chemotaxis, cell proliferation, and differentiation. Platelet-rich plasma (PRP) is used in a variety of clinical applications, based on the premise that higher GF content should promote better healing. Platelet derivatives represent a promising therapeutic modality, offering opportunities for treatment of wounds, ulcers, soft-tissue injuries, and various other applications in cell therapy. PRP can be combined with cell-based therapies such as adipose-derived stem cells, regenerative cell therapy, and transfer factors therapy. This paper describes the biological background of the platelet-derived substances and their potential use in regenerative medicine. PMID- 22518193 TI - Spatial analysis of county-level breast cancer mortality in Texas. AB - OBJECTIVE: The objectives of the study were to detect high-risk areas and to examine how racial and ethnic status affect the geographic distribution of female breast cancer mortality in Texas. Analyses were based on county-level data for the years from 2000 to 2008. MATERIALS AND METHODS: Breast cancer mortality data were obtained from the Texas Cancer Registry, and the Spatial Scan Statistics method was used to run Purely Spatial Analyses using the Discrete Poisson, Bernoulli, and Multinomial models. RESULTS AND CONCLUSIONS: Highest rates of female breast cancer mortality in Texas have shifted over time from southeastern areas towards northern and eastern areas, and breast cancer mortality at the county level is distributed heterogeneously based on racial/ethnic status. Non Hispanic blacks were at highest risk in the northeastern region and lowest risk in the southern region, while Hispanics were at highest risk in the southern region along the border with Mexico and lowest risk in the northeastern region. PMID- 22518194 TI - Body massage performance investigation by brain activity analysis. AB - Massage has been widely applied to improve health and reduce stress. However, the performance difference between hands-on treatment and treatment by mechanical devices has been little mentioned. Therefore, the main aim of this paper is to investigate a subject's EEG performance under massage treatment applied by hand and treatment applied by mechanical devices. Massage was applied to four acupoints for three minutes each. The massage acupoint sequence was from left Jian-wai-yu, right Jian-wai-yu, left Zuo-fei-yu, and finally right Zuo-fei-yu. An EEG system of 32 channels was used. Twenty-four volunteers, mainly college students, were enrolled. EEG rhythm powers of each massage sessions were derived. Two-way ANOVA revealed that there were also significant interactions between the massage stage and the massage type on delta (P < 0.01), theta (P < 0.05), and beta rhythms (P < 0.01), and there were significant differences at different stages for the mechanical massage group (F = 5.557, P < 0.01). The mechanical massage group had more significant differences than the hands-on group for stage coherence of around coherence on alpha rhythm. Further rhythm power scalp topography between two massage methods is also investigated. PMID- 22518196 TI - Emotion understanding, theory of mind, and prosocial orientation: Relations over time in early childhood. AB - Data were collected when children were 42, 54, and 72 months of age (Ns=210, 191, and 172 for T1, T2, and T3, respectively). Children's emotion understanding (EU) and theory of mind (ToM) were examined as predictors of children's prosocial orientation within and across time. EU positively related to children's sympathy across 2.5 years, and T1 EU positively related to parent-reported prosocial orientation concurrently and across 1 year (T2). T2 ToM positively related to parents' reports of sympathy and prosocial orientation concurrently and 18 months later (T3); in contrast, T3 ToM did not relate to sympathy or prosocial orientation. T2 ToM accounted for marginally significant variance (p<0.058) in T3 mother-reported prosocial orientation over and above that accounted for by T2 prosocial orientation. Fostering the development of EU and ToM may contribute to children's prosocial orientation. PMID- 22518197 TI - Circulating microRNAs: next-generation biomarkers for early lung cancer detection. AB - Early diagnosis of lung cancer by low-dose computed tomography is an effective strategy to reduce cancer mortality in high-risk individuals. However, recruitment of at-risk individuals with asymptomatic lung cancer still remains challenging. We developed a minimal invasive serum test, based on the detection of circulating microRNAs, which can identify at-risk individuals with asymptomatic early stage non-small cell lung carcinomas with 80% accuracy. PMID- 22518195 TI - Multiple Pathways Linking Racism to Health Outcomes. AB - This commentary discusses advances in the conceptual understanding of racism and selected research findings in the social neurosciences. The traditional stress and coping model holds that racism constitutes a source of aversive experiences that, when perceived by the individual, eventually lead to poor health outcomes. Current evidence points to additional psychophysiological pathways linking facets of racist environments with physiological reactions that contribute to disease. The alternative pathways emphasize prenatal experiences, subcortical emotional neural circuits, conscious and preconscious emotion regulation, perseverative cognitions, and negative affective states stemming from racist cognitive schemata. Recognition of these pathways challenges change agents to use an array of cognitive and self-controlling interventions in mitigating racism's impact. Additionally, it charges policy makers to develop strategies that eliminate deep seated structural aspects of racism in society. PMID- 22518198 TI - A rare case of a phyllodes tumour of the breast converting to a fibrosarcoma with successful treatment. AB - A phyllodes tumour of the breast converting to fibrosarcoma of the breast is a rare entity. Prognosis of fibrosarcoma of the breast is poor and the role of various treatment modalities is not clearly defined due to the rarity of the disease. One such case, which was treated successfully with a combination of surgery, radiotherapy and chemotherapy, is presented here. PMID- 22518199 TI - Phase 0 clinical trials: towards a more complete ethics critique. AB - In efforts to modernise the entire drug-development process, making it more efficient, less costly, and ultimately of real benefit to patients, The Federal Drug Administration (FDA) authorised the use of exploratory IND or early Phase I (Phase 0) studies. Quite different in structure from Phase I, II, and III studies, the Phase 0 construct understandably poses a set of ethical problems not seen in the other research phases and so far not adequately addressed by ethicists. In an effort to deal with this deficiency, this paper proposes an ethics critique, based not on the usual concept of benefit, but on the means-end relation, and placed within an ethic of science derived from the practice of science. PMID- 22518201 TI - 30th german cancer congress, 22nd-25th february 2012, berlin. AB - "Securing quality - calling for and encouraging research". From 22nd to 25th February 2012 one of the largest multi-disciplinary cancer congresses took place in Berlin, Germany, attended by more than 10,000 healthcare professionals. "The German Cancer Congress is the only interdisciplinary congress of its kind in Germany and the second largest congress of its kind anywhere in the world" stated the congress president Professor Dr P Albers and the president of the German Cancer Society (DKG), Professor Dr Dr h.c. W Hohenberger in their greetings. Only the ASCO Annual Meeting is larger. At the 30th German Cancer Congress (DKK) established national and international experts presented latest data and discussed hot topics in the various oncology fields. Joint Symposia of the DKG together with the UICC (Union for International Cancer Control) and ASCO (American Society of Clinical Oncology) respectively stressed the importance of the meeting. The overreaching theme of the meeting was "Securing quality - calling for and encouraging research". This theme evolved from the idea, that only excellent research in clinics and medical practices can found the basis of future high quality efficient and effective structures in patient care and of the allocation of limited resources to meaningful measures for patient benefit. PMID- 22518202 TI - Measuring Media Exposure to Contradictory Health Information: A Comparative Analysis of Four Potential Measures. AB - There is increasing concern that the news media present conflicting health information on topics including cancer screening and nutrition, yet little is known about whether people notice such content. This study proposes four potential measures of media exposure to contradictory health information, using nutrition as an example (Measures I-IV). The measures varied on two dimensions: (1) content specificity, or whether specific nutrition topics and health consequences were mentioned in the question scripting, and (2) obtrusiveness, or whether "contradictory or conflicting information" was mentioned. Using data from the Annenberg National Health Communication Survey (ANHCS), we evaluated the performance of each measure against a set of validity criteria including nomological, convergent, and face validity. Overall, measure IV, which was moderately content-specific and obtrusive, performed consistently well and may prove most useful to researchers studying media effects of contradictory health information. Future directions and applications are discussed. PMID- 22518203 TI - Hyperbolic temperament and borderline personality disorder. AB - Zanarini and Frankenburg (2007) described the "essential nature" of borderline psychopathology as involving intense and chronic inner pain deriving from a hyperbolic temperament that is mediated through interpersonal behaviors. These interpersonal behaviors can either provoke kindling events that promote the expression of borderline pathology or buffer against borderline symptoms. This study was designed to test this general hypothesis and to articulate both the temperamental and the mediating constructs implicated in this theory more specifically. A questionnaire containing the elements of this theory was administered to non-clinical (N = 545), clinical (N = 316) and treatment (N = 50) samples. Covariance analyses supported a hyperbolic temperament factor and four mediating factors labeled passive, agentic, validation seeking, and detached. Overall, validity correlations conformed to predictions in showing a strong association between hyperbolic temperament and borderline and other forms of personality pathology, and in demonstrating varying relations between the mediating factors with adaptivity, including psychiatric improvements in a treatment trial. The place of this theoretical model of borderline pathology beside other theories that tend to emphasize personality traits or interpersonal patterns are discussed, and clinical implications of the model are highlighted. PMID- 22518204 TI - The Cognition Checklist for Mania-Revised (CCL-M-R): Factor-Analytic Structure and Links with Risk for Mania, Diagnoses of Mania, and Current Symptoms. AB - We conducted two studies to examine the Cognition Checklist for Mania-Revised (CCL-M-R; Beck, Colis, Steer, Madrak, & Goldberg, 2006). In the first, we gathered data in an undergraduate sample (N = 208) to examine the factor structure of the measure and the correlations of the subscales with the Hypomanic Personality Scale (HPS; Eckblad & Chapman, 1986). Factor analyses refined subscales, and three of the original four subscales developed by Beck and colleagues (2006) were retained. Persons with higher stores on the HPS were likely to endorse manic cognitions associated with overconfidence and excitement seeking. In a second study, we gathered data from 61 persons diagnosed with bipolar I disorder, 38 with major depressive disorder (MDD), and 33 with no history of mood disorder. Excitement-seeking scores were robustly related to current manic symptoms, as measured by the Internal State Scale (ISS; Bauer et al., 1991). Thus, CCL-M-R excitement-seeking scores appear to be related to risk for mania and to current symptoms of mania within a clinical sample. Other findings, though, suggest that problems with interpersonal relationships (feeling thwarted by others) may emerge among those clinically diagnosed with bipolar I disorder, even though not endorsed among those at risk. Moreover, difficulties with interpersonal relationships and diminished confidence in those with bipolar I disorder paralleled the difficulties observed among those with MDD. Findings suggest that cognitive profiles associated with mania may depend on mood state and course of the disorder. PMID- 22518205 TI - Quasi-least squares with mixed linear correlation structures. AB - Quasi-least squares (QLS) is a two-stage computational approach for estimation of the correlation parameters in the framework of generalized estimating equations. We prove two general results for the class of mixed linear correlation structures: namely, that the stage one QLS estimate of the correlation parameter always exists and is feasible (yields a positive definite estimated correlation matrix) for any correlation structure, while the stage two estimator exists and is unique (and therefore consistent) with probability one, for the class of mixed linear correlation structures. Our general results justify the implementation of QLS for particular members of the class of mixed linear correlation structures that are appropriate for analysis of data from families that may vary in size and composition. We describe the familial structures and implement them in an analysis of optical spherical values in the Old Order Amish (OOA). For the OOA analysis, we show that we would suffer a substantial loss in efficiency, if the familial structures were the true structures, but were misspecified as simpler approximate structures. To help bridge the interface between Statistics and Medicine, we also provide R software so that medical researchers can implement the familial structures in a QLS analysis of their own data. PMID- 22518206 TI - Our new journal. PMID- 22518207 TI - Covered stent graft for treatment of a pseudoaneurysm and carotid blowout syndrome. AB - BACKGROUND: Carotid blowout syndrome with pseudoaneurysm, a rapidly progressive pathology, may present emergently with massive oral hemorrhage. Use of an endograft prosthesis offers a treatment strategy with salvation of the carotid artery. CASE HISTORY: A 55 year old man with advanced squamous cell carcinoma of the head and neck presented with recurrent transoral hemorrhage, requiring endovascular treatment. TECHNICAL REPORT: Coil embolization was initially performed with little impact on the hemorrhage. A 7 x 40 mm Fluency(r) Plus covered stent (Bard Peripheral Vascular, Tempe, Arizona, USA) was placed and was supplemented by a second 8 x 40 mm Fluency Plus stent, with resulting cessation of active contrast extravasation. DISCUSSION: The risks and benefits of various treatment options of carotid pseudoaneurysm with blowout are discussed including the use or omission of antiplatelet and anticoagulant regimens, with reference to previously reported cases. CONCLUSION: Tandem, overlapping covered stent placement in the common carotid artery is feasible and offers a treatment option for carotid blowout syndrome. Risks of aggravation of hemorrhage versus long-term thromboembolic events without antiplatelet therapy must be considered in cases of active ongoing hemorrhage. PMID- 22518208 TI - A case of dural arteriovenous fistula with retrograde intracranial venous flow. AB - PRESENTATION: Dural arteriovenous fistulae are relatively rare lesions which can present a variety of different symptoms ranging from tinnitus to devastating intracranial hemorrhage. For those fistulae that require treatment, therapy is available in a wide range of options. We describe the case of a 60-year old patient who presented with a right occipital lesion presumably secondary to a dural arteriovenous fistula of the right transverse-sigmoid junction. The patient underwent successful endovascular treatment of the fistula. DISCUSSION: The participants in our discussion present their thoughts on how to evaluate and when and how to treat dural arteriovenous fistulae. PMID- 22518209 TI - Quantification and assessment of extracranial and intracranial occlusive disease. AB - BACKGROUND: Treatment planning for vascular occlusive disease depends in part on quantitative assessment of the degree of occlusion. Digital subtraction angiography is the gold standard for quantitative imaging although other modalities can also be used. DISCUSSION: Three different schemes for measuring percent stenosis of an occluded artery are all valid but may produce different results. CONCLUSION: The choise of method for measurement is less important than consistency of application. PMID- 22518210 TI - Anterior cerebral artery angioplasty for intracranial atherosclerosis. AB - BACKGROUND: Angioplasty of the intracranial vasculature has been well described for the middle cerebral artery and carotid terminus, primarily in the setting of vasospasm following subarachnoid hemorrhage. Endovascular therapy for anterior cerebral artery stenosis has not heretofore been described. CASE REPORT: We report the case of A1 segment angioplasty in a 77 year old man with presumed intracranial atherosclerosis. DISCUSSION: The proximal anterior cerebral artery serves the anterior caudate and lenticular nuclei; blockade produces motor symptoms. The anterior cerebral artery is smaller than the middle, making angioplasty more difficult. Anatomical variants are common. PMID- 22518211 TI - Stent placement to treat positional occlusion of the vertebral artery: A report of two cases. AB - Positional occlusion of the vertebral artery is suspected in patients who present with posterior circulation signs or symptoms related to a specific head position. So far, the only reported treatment is surgery with the aim of relieving the position-dependent pressure that is applied to the vessel. We report on two patients who were treated successfully with stent placement. PMID- 22518212 TI - Unruptured intracranial aneurysms and the Trial on Endovascular Aneurysm Management (TEAM): The principles behind the protocol. AB - BACKGROUND: With the widespread availability of non-invasive imaging of the brain in an aging population, we are increasingly confronted with the problem of the incidental discovery of unruptured aneurysms. The management of these patients remains controversial. Endovascular treatment can prevent rupture, but involves immediate risks. Furthermore, successful treatment does not eliminate all risk of rupture. The safety and efficacy of endovascular treatment of unruptured aneurysms remain undetermined. Hence the balance of the risks and benefits is uncertain. A randomized trial is needed to assess the potential benefits of endovascular management of unruptured aneurysms. THE TRIAL: TEAM (Trial on Endovascular Aneurysm Management) is a randomized trial comparing endovascular treatment versus conservative management of unruptured aneurysms. TEAM aims to recruit 2002 patients in 60 centers throughout the world over a 3-year period and to follow all patients for 10 years. The primary outcome is to verify if the clinical outcome (morbidity/mortality (modified Rankin scale > 2) related to the aneurysm or its treatment) can be improved from 8% to 4%. The study is funded by the Canadian Institutes of Health Research. PMID- 22518213 TI - The stroke and neurovascular program at the medical college of wisconsin and froedtert hospital. AB - The Stroke and Neurovascular Program at the Medical College of Wisconsin and Froedtert Hospital, in Milwaukee, is a comprehensive, interdisciplinary center for stroke medicine. The program encompasses an acute stroke team, a neuro intensive care unit, a stroke care unit, and a stroke rehabilitation program. The staff includes specialists with fellowship training in stroke, neurocritical care, neurointerventional therapy, vascular neurosurgery, interventional neuroradiology, and stroke rehabilitation. Fellowships are offered in interventional neurology, neurocritical care, and vascular neurology. In addition to clinical service and education, the faculty are actively engaged in research. The program is certified by the Joint Commission as a Primary Stroke Center. PMID- 22518214 TI - The significance of clinical trials. AB - BACKGROUND: Clinical trials are essential for the development of new treatments. Whether a person should participate depends on their understanding of the risks and benefits for themselves and for society as a whole. DISCUSSION: There are rules in place to protect human research subjects and all studies involving humans are reviewed locally to ensure that subjects are treated safely, fairly, and confidentially. Nevertheless, each subject should consider for themselves whether participation is consistent with their values. CONCLUSION: Clinical trials, when well-designed, can benefit the participants as well as the investigators, the sponsors, and the medical community. PMID- 22518215 TI - Can I drive after my stroke? AB - BACKGROUND: Stroke can advesely affect movements, sensations, alertness, awareness, coordination, and judgement, all of which may impair the ability to drive a car. DISCUSSION: Many stroke patients consider driving to be essential to their quality of life and want to drive if at all possible. Thus, the physician may be challenged with a tough decision about whether a patient should be allowed to drive. CONCLUSION: Referral to an occupational therapist can be of great help. PMID- 22518216 TI - The challenges of intracranial atherosclerotic disease. PMID- 22518217 TI - Endovascular embolization of paragangliomas: A safe adjuvant to treatment. AB - BACKGROUND AND PURPOSE: Paragangliomas are tumors of neural crest origin commonly arising from the carotid body, vagal nerve, or jugular bulb. The definitive treatment for these tumors is surgical resection, often augmented with pre operative embolization due their highly vascular nature. We present our experience examining the efficacy and safety of endovascular embolization of these rare tumors. METHODS: A review of patient's diagnosed with paragangliomas who underwent pre-operative embolization over a 5-year period (2002-2007) was conducted. The tumor subtype, efficacy of embolization, method of embolization, and rate of complication were noted. RESULTS: A total of 38 patients underwent selective arterial embolization of their paraganglioma using polyvinyl alcohol (PVA) particles ranging in size from 100-1000 microns. The tumor subtypes treated were carotid body (n = 20), glomus vagale (n = 10), and glomus jugulare (n = 8). The average age at presentation was 44 years (range, 15-81). Twenty-two patients were female and sixteen were male. The most common artery embolized was the ascending pharyngeal branch of the external carotid artery. Post-embolization angiography revealed an average decrease in blood flow to tumor of 75%. With the exception of transient facial pain documented in 1 patient, there were no known complications from embolization. CONCLUSIONS: The endovascular embolization of paragangliomas using PVA prior to surgical resection is a very safe and efficacious procedure that may reduce operative blood loss and associated morbidity. PMID- 22518218 TI - Treatment of unruptured intracranial aneurysms using internally expanding coils. AB - BACKGROUND AND PURPOSE: The International Subarachnoid Aneurysm Trial (ISAT) showed that patients with intracranial aneurysms treated with coil embolization have better clinical outcomes than those undergoing neurosurgical clipping. However some patients treated endovascularly have recurrence of aneurysms. Low packing density is often cited as a reason for recurrence. Coiling with hydrogel covered coils significantly improves the packing density. We report our initial experience in using a newly introduced design of hydrogel coils. METHODS: Three consecutive patients with unruptured aneurysms were treated with hydrogel coated coils. During embolization, a stable framework was first established with bare metal coils, and gel coated coils were used subsequently to increase the packing density. After the procedure, packing density was estimated by calculating the compaction ratio using an online calculator. RESULTS: Successful coil embolization was achieved in all 3 patients. Hydrogel coated coils comprised 11, 63 and 72% of the total coils deployed. One patient had coil herniation that required stent deployment. All patients remained neurologically intact during and after the procedure. Follow-up angiography in 2 patients at 6 months revealed aneurysm stability without any residual neck remnant. CONCLUSIONS: The softness of the hydrogel allowed us to deploy coated coils with good packing density. A slight expansion of these coils at the neck can be expected to reduce any neck remnant and potentially inhibit recurrence. PMID- 22518219 TI - Adjunct bivalirudin dosing protocol for neuro-endovascular procedures. AB - OBJECTIVE: To introduce a protocol for anticoagulation using bivalirudin in neuro endovascular procedures. METHODS: Three different bivalirudin dosing protocols were used in four consecutive patients undergoing neuro-endovascular procedures. Activated clotting time (ACT) was closely monitored to assess the effect of bivalirudin on ACT. Target ACT was set at 300-350 seconds. RESULTS: The first dosing protocol led to largely supra-therapeutic ACT values. With the second protocol, ACT remained sub-therapeutic for 25 minutes (33% of monitoring time). The third protocol was applied to two patients and it showed the best results with the ACT being in the therapeutic range for 72% of the combined monitoring time and never exceeding 366 seconds. CONCLUSIONS: The dosing of bivalirudin needs to be adjusted for the use in neuro-endovascular procedures. We are proposing a protocol that seems to provide safe and effective anticoagulation. The safety and efficacy of bivalirudin in neuroendovascular procedures will need to be further validated in future studies. PMID- 22518220 TI - Novel therapies in the pipeline: Directions of research into platelet inhibition. AB - BACKGROUND: Ischemic stroke is one of the foremost causes of death and disability in the industrialized world. Apart from both primary and secondary prevention with oral antiplatelet agents, acute treatment is currently limited to recombinant tissue plasminogen activator and interventional therapy. The occurrence of re-thrombosis during and after these interventions clearly indicate the need for further application of novel agents in the treatment of stroke. PLATELET FUNCTION: Current antiplatelet agents in use affect platelet aggregation at different steps. The common limiting factor is the observed occurrence of intracerebral hemorrhage in the setting of acute stroke. PLATELET INHIBITION: Selective inhibition of glycoproteins has been employed already (GP IIb/IIIa inhibitors) but there are other glycoproteins that can be targeted. This is based on research that shows that monoclonal antibody mediated inhibition decreases the burden of disease in mouse models of stroke. A new drug that targets the A1 domain of activated von Willebrand factor that attaches to GP Ib is potentially another way of solving the thrombosis puzzle with the promise that intracerebral hemorrhage would be limited. CONCLUSION: The continuing search for acceptable levels of platelet inhibition during cerebral ischemic events while minimizing the risk of potentially fatal hemorrhagic side effects is leading the way to selective targeting of the platelet signaling cascade. This raises hope that future therapy will be more effective while having a more favorable safety profile. PMID- 22518221 TI - Past, present, and future of anti-platelet therapy. AB - INTRODUCTION: Anti-platelet drugs are useful in preventing unwanted clots, but the complexities of platelet activation and clot formation are challenging. BACKGROUND: Platelets can be activated by a variety of agents, including natural biomolecules, foreign materials, and drugs. Calcium mediates a number of the intracellular processs Once activated, platelets release factors that act on other circulating cells and vascular endothelial cells to promote formation of a clot. The original anti-platelet drug, aspirin, inhibits cyclooxegenase, interfering with a crucial step in the biochemical cascade. Aspirin is cost effective but limited in its application. Newer drugs, ticlopidine and clopidogrel, act on the activation pathway at different points, so they can supplement aspirin. NEW DIRECTIONS: Abciximab represents a new generation of antiplatelet drug, being an antibody that binds to platelet surface receptors, thus inhibiting growth of thrombus. Other potential sites for antibody intervention are extracellular matrix and endothelial surface components. As new drugs are developed it becomes more imperative to find assays of platelet function that are sensitive and cost-effective. CONCLUSION: Although much progress has been made in anagement of clotting significant opportunities and challenges remain, both in treatment and in measurement of treatment effectiveness. PMID- 22518222 TI - The rising cost of falling: Strategies to combat a common post-stroke foe. AB - BACKGROUND: As a person ages, falls and strokes each become more likely, and because stroke patients are independently at increased risk for falling, the risk of falls is compounded in this population. DISCUSSION: There are a number of preventive measures that can be easily implemented to decrease the risk of falling. These are well known to physical and occupational therapists, so a consultation is well-advised. Four areas of focus are: (1) Exercise, to increase strength, balance, and coordination. (2) Vision, to assure that the subject sees as well as possible. (3) Medication, to minimize side effects that could influence falling. (4) Environment, to remove obstacles, add assists, and provide optimal lighting. CONCLUSION: Falls among stroke patients are costly in terms of risk to the individual and treatment demands on the healthcare system. However, simple attention to details can reduce the risk of falling. PMID- 22518223 TI - Why am I so tired after my stroke? AB - BACKGROUND: Fatigue is a common complaint after a stroke, and contributes to the large national burden of caring for stroke victims. Nevertheless, causes and cures for post-stroke fatigue are generally under-appreciated. DISCUSSION: Post stroke fatigue can be organic, psychological, emotional, or a combination of these. A precise diagnosis will aid in treatment planning for effective return to normal levels of activity. Depending on the cause of fatigue, a post-stroke patient may benefit from physical therapy, occupational therapy, anti depressants, counseling, and careful attention to basic needs. However, patients and care-givers should be patient and recognize that a stroke victims may never fully recover their abilities and dealing with fatigue may be a long-term issue. CONCLUSION: Post-stroke fatigue can be vexing but multi-modal rehabilitation often allows at least some improvement. Additional research on effective therapy for different sources of fatigue will benefit our stroke patients in the future. PMID- 22518224 TI - Cerebral hemodynamics in acute stroke: pathophysiology and clinical implications. AB - BACKGROUND: The capacity of the brain to regulate its blood flow in order to meet metabolic demands and to compensate for acute and chronic changes in cerebral perfusion pressure (cerebral autoregulation) is an essential protecting mechanism against cerebral ischemia. METHODS: We reviewed existing data on methods of assessing cerebral blood flow and autoregulation. RESULTS: Cerebral autoregulation is mechanistically complex and depends on myogenic, neuronal, endothelial, and metabolic factors. There are numerous methods of estimating cerebrovascular reserve (CVR) non-invasively including Positive Emission Tomography (gold standard), Transcranial Doppler ultrasound, dynamic contrast enhanced perfusion Magnetic Resonance Imaging, Single-Photon Emission Computed Tomography and Xenon Computed Tomography. Since each of these techniques has its advantages and disadvantages, selection of a specific method for CVR testing depends on availability, acquired experience in interpreting the study, required precision, and cost. Cerebral autoregulation may be impaired in patients with symptomatic or asymptomatic carotid stenosis or occlusion and is associated with a higher risk of stroke or transient ischemic attack (TIA) ipsilateral to the carotid artery disease. CONCLUSION: Assessment of CVR can help stratify patients based on their risk of stroke or TIA and select patients who may benefit from revascularization therapies. Cerebral vasoreactivity testing may be useful to evaluate cerebral autoregulation after revascularization procedures as a surrogate endpoint of vascular events related to hypoperfusion or hyperperfusion. PMID- 22518225 TI - Occurence and variability in acute formation of leptomeningeal collaterals in proximal middle cerebral artery occlusion. AB - BACKGROUND: We performed this study to semi-quantitatively characterize the formation of leptomeningeal collaterals in acute middle cerebral artery (MCA) occlusion caused by intravascular balloon inflation. METHODS: The anatomic extent of leptomeningeal collateral blood flow from the anterior cerebral artery territory to the MCA territory during occlusion of the M1 segment was graded based on angiographically visible retrograde reconstitution of the MCA segments on the delayed venous phase prior to and during inflation of the balloon. RESULTS: During MCA occlusion, the leptomeningeal collaterals markedly improved in 5 of 7 patients and were graded as 1 (retrograde filling of distal M1 segment) in 3 patients, 2 (retrograde filling of proximal M2 segment) in 1 patient, 4 (retrograde filling of M3 segment) in 1 patient and 5 (none or minimal) in 2 patients. CONCLUSION: Leptomeningeal collaterals from the anterior cerebral artery can form rapidly during MCA occlusion with considerable individual variability. PMID- 22518226 TI - Somnolence and stuttering as the primary manifestations of a midbrain stroke. AB - BACKGROUND: Stroke can occasionally manifest with non-lateralizing findings such as somnolence and stuttering. We describe a case and discuss the anatomical and physiological implications of this rare combination of symptoms. CASE REPORT: A 51-year-old woman presented with 3 days of "feeling drunk". She could further specify her symptoms as blurry vision, slurred speech, and gait instability. She had a history of hypertension and hyperlipidemia. Her examination at presentation was remarkable only for marked somnolence. Over the next several hours she developed mild upgaze limitation and vertical nystagmus. Non-enhanced computed tomography of the brain was normal. Brain magnetic resonance imaging (MRI) revealed a 5 mm acute infarct in the caudal midbrain. The first week the patient remained somnolent and manifested marked stuttering. The patient improved gradually with speech therapy. CONCLUSION: Strokes affecting the diencephalic mesencephalic junction can manifest with stuttering. Defective projections of the reticular formation to the supplementary motor area, damaged extrapyramidal circuits, and/or aberrant propioceptive feedback due to involvement of the mesencephalic nucleus of the trigeminal nerve are the proposed pathophysiological mechanisms. Somnolence can also be part of the presentation and is likely due to disruptions of sleep pathways subserved by the reticular activating system. The accurate diagnosis of these cases depends on careful clinical assessment and high index of suspicion for stroke, especially in lieu of preexisting vascular risk factors and lack of an alternative explanation such as toxic-metabolic encephalopathy. PMID- 22518227 TI - Hypertensive retinopathy and risk of cardiovascular diseases in a national cohort. AB - BACKGROUND: Retinal vascular examination using direct ophthalmoscopy can be used to determine the extent of hypertensive vascular changes. We studied the association of these changes in a large national cohort. METHODS: First National Health and Nutrition Survey (NHANES I) was conducted from 1971 through 1975. A subgroup (n=5500) of participants aged 25 to 74 years received standardized ophthalmologic examination and hypertensive changes were documented. Participants of the study had follow-up interviews and examinations up to 1992. All health care facility records and death certificates were ascertained and reviewed. Participants who were admitted with or died of primary diagnosis of either ischemic stroke or coronary heart disease were identified. We used Cox proportional-hazards regression to study the association of hypertensive retinopathy with cardiovascular disease. RESULTS: After excluding patients with previous history of stroke or myocardial infarction and/or missing blood pressure information, 4753 participants were included in the analysis. Participants with hypertensive retinopathy were older (61 +/- 11 vs 47 +/- 15) and more likely to be men (54% vs 62%). After adjustment for age, sex, race/ethnicity, body-mass index, cigarette smoking, systolic blood pressure, cholesterol, and diabetes mellitus patients with hypertensive retinopathy had a relative risk (RR) of 1.2 (95% confidence interval [CI] 1.0 - 1.3) for any cardiovascular disease and RR of 1.2(95% CI 0.9-1.5) for ischemic stroke. CONCLUSION: The presence of hypertensive retinal vascular changes is associated with increased risk of cardiovascular disease. Identification of such changes in the clinical setting can be used for stratification of high risk patients. PMID- 22518229 TI - Mode of arrival to the emergency department of stroke patients in the United States. AB - BACKGROUND: The modality of transport to the emergency department has implications for triage, evaluation, and treatment of patients with stroke. We performed this study to determine the national trends in modes of arrival in patients with stroke and its association with emergency department evaluation in a nationally representative sample of United States. METHODS: We used the data from the National Hospital Ambulatory Medical Care Survey (NHAMCS). The NHAMC is one of the largest studies designed to provide utilization and provision of services in hospital emergency departments (ED). Patients were categorized into three modes of arrival: 1) ambulance, either air or ground; 2) walk-in, this include car, taxi, bus, or foot; and 3) public services such as police car or social service vehicle/Unknown. RESULTS: Of the 630,402 patients evaluated with stroke in the ED, the mode of arrival was by ambulance [331,760 (53%)], walk-in [271,268 (43%)], and public services/unknown [27374 (4%)]. The mean time for evaluation by a physician was 30+/-37 minutes, 34+/-44 minutes, and 55+/-105 minutes for ambulance, walk-in (P=0.535), and public services/unknown (P=0.664) mode of arrival, respectively. There was a trend for more frequent utilization of brain imaging in the patients presenting by ambulance (73%) compared to walk-in (63%, P=0.64) and public services/unknown (59%, P=0.5). Patients transferred by ambulance were more often admitted to the intensive care unit (11%) compared to walk-in (0.2%, P=0.02) and public services/unknown (6%, P=0.47). CONCLUSION: Although arrival by ambulance was associated with a higher level of care, a prominent proportion of patients with suspected stroke are not arriving by ambulance to the ED. PMID- 22518228 TI - Traumatic Intracranial Aneurysm Formation following Closed Head Injury. AB - BACKGROUND: Traumatic intracranial aneurysms are rare conditions that can be a result of non-penetrating head trauma. We report the occurrence of intracranial aneurysms in patients with traumatic brain injury. METHODS: All diagnostic cerebral angiograms performed in patients with traumatic brain injury at a level I trauma center from January 2006 to July 2007 were reviewed. RESULTS: Diagnostic cerebral angiography was performed in 74 patients with the diagnosis of closed head injury. A total of 4 traumatic intracranial pseudoaneurysms were found in 4 patients, two in the supraclinoid segment of the internal carotid artery, one in the cavernous segment of the internal carotid artery and one in the paraophthalmic segment of the internal carotid artery. Two patients were treated with coil embolization. One patient had follow up imaging on which there was no change in the size and morphology of the aneurysm. CONCLUSION: Intracranial aneurysms can develop in patients with closed head injury presumably related to shear or rotational injury. It is unclear whether these aneurysms should be classified as traumatic intracranial aneurysms or pseudoaneurysms, but the pathological findings frequently reveal disruption of the three vascular layers fulfilling the definition of pseudoaneurysm. For these reason we favor the name of post-traumatic intracranial pseudoaneurysms. PMID- 22518230 TI - The basics of brain aneurysms: a guide for patients. PMID- 22518231 TI - Leptomeningeal collaterals in acute ischemic stroke. AB - INTRODUCTION: The leptomeningeal collaterals are a subsidiary network of vascular channels that act as anastomotic channels in conditions where cerebral blood flow is pathologically altered. These secondary collateral pathways may be utilized when collateral flow through the circle of Willis is inadequate. SUMMARY OF REVIEW: The review highlights the importance of leptomeningeal (pial) anastomoses in the brain especially in conditions of hemodynamic impairment such as ischemic stroke. The historical perspective regarding the role of these vessels is discussed. New advancements in the diagnostic and treatment modalities for the evaluation and optimization of these vessels are identified. CONCLUSION: Evaluation and optimization of the leptomeningeal collaterals in ischemic stroke represents an important venue in prevention and treatment of cerebral ischemia. PMID- 22518232 TI - Role of Multimodal Evaluation of Cerebral Hemodynamics in Selecting Patients with Symptomatic Carotid or Middle Cerebral Artery Steno-occlusive Disease for Revascularization. AB - BACKGROUND: The circle of Willis provides collateral pathways to perfuse the affected vascular territories in patients with severe stenoocclusive disease of major arteries. The collateral perfusion may become insufficient in certain physiological circumstances due to failed vasodilatory reserve and intracranial steal phenomenon, so-called 'Reversed-Robinhood syndrome'. We evaluated cerebral hemodynamics and vasodilatory reserve in patients with symptomatic distal internal carotid (ICA) or middle cerebral artery (MCA) severe steno-occlusive disease. METHODS: Diagnostic transcranial Doppler (TCD) and TCD-monitoring with voluntary breath-holding according to a standard scanning protocol were performed in patients with severe ICA or MCA steno-occlusive disease. The steal phenomenon was detected as transient, spontaneous, or vasodilatory stimuli-induced velocity reductions in affected arteries at the time of velocity increase in normal vessels. Patients with exhausted vasomotor reactivity and intracranial steal phenomenon during breath-holding were further evaluated by (99)technetium(m) hexamethyl propylene amine oxime single photon emission computed tomography (HMPAO-SPECT) with acetazolamide challenge. RESULTS: Sixteen patients (age 27-74 years, 11 men) fulfilled our TCD criteria for exhausted vasomotor reactivity and intracranial steal phenomenon during the standard vasomotor testing by breath holding. Acetazolamide-challenged HMPAO-SPECT demonstrated significant hypoperfusion in 12 patients in affected arterial territories, suggestive of failed vasodilatory reserve. A breath-holding index of <=0.3 on TCD was associated with an abnormal HMPAO-SPECT with acetazolamide challenge. TCD findings of a breath holding index of <=0.3 and intracranial steal during the procedure were determinants of a significant abnormality on HMPAO-SPECT with acetazolamide challenge. CONCLUSION: Multimodal evaluation of cerebral hemodynamics in symptomatic patients with severe steno-occlusive disease of the ICA or MCA is helpful in the identification and quantification of failed vasodilatory reserve. This approach may be useful in selecting patients for possible revascularization procedures. PMID- 22518233 TI - Bilateral tri-arterial embolization for the treatment of epistaxis. AB - BACKGROUND: Intractable epistaxis is treated by ipsilateral trans-arterial embolization of the internal maxillary artery, but there is 13-26% recurrence of bleeding. Preemptive embolization of both internal maxillary arteries along with the ipsilateral facial artery could provide maximal protection against recurrent epistaxis. We report our experience with 8 patients treated with bilateral tri arterial embolization. METHODS: We performed a retrospective review of the patients who were treated with bilateral internal maxillary artery and ipsilateral facial artery embolization from January 2005 to January 2007. All patients had bleeding that was refractory to nasal packing. RESULTS: Eight patients were treated with bilateral tri-arterial embolization. The median age was 65 years (range, 35-90 years). Risk factors included hypertension (n=4), smoking (n=2), alcohol (n=2), and use of anticoagulation (n=2). All but 2 of the patients were treated under local anesthesia. All patients had complete obliteration of bleeding during the procedure, with no residual vascular blush. No major peri- or post-procedural complications were noted. Patients stayed in the hospital for 2-4 days (average 2.6 days). One patient developed ipsilateral temporofacial pain which resolved during hospitalization. Another patient had minor recurrent epistaxis on post operative day 2 which resolved with temporary repacking and the patient was discharged the next day. CONCLUSION: In our experience with 8 cases, bilateral internal maxillary artery and/or ipsilateral facial artery embolization was achieved without complication and was associated with complete obliteration of vascular blush and no significant recurrent epistaxis. PMID- 22518234 TI - Accuracy of self-perception of cardiovascular risk in the community. AB - BACKGROUND: Assessment of individual risk is an important part of the primary prevention of coronary disease and stroke. The accuracy by which individuals perceive their risk is unclear. We aimed to explore the accuracy of self perceived cardiovascular risk in the community, and the value of one-to-one interview, using a risk assessment tool, in increasing the accuracy. METHODS: Participants in 2 community health fair events in 2006 were asked to assign their 5-year cardiovascular risk to one of 3 categories (high, moderate and low), before and after being counseled about their risk using a Framingham-based risk calculator. Agreement between perceived risk and calculated risk was studied using kappa analysis. Change in perception was the indicator of response to the study intervention. Predictors of accuracy, underestimation, and responsiveness to the study intervention were identified using logistic regression. RESULTS: There were 146 participants that were included in the analysis (mean age+/-SD, 47+/-15; 64% women). Rate of inaccuracy was 66% (mainly due to underestimation of risk n=86 participants). Agreement between perceived and objective risk was poor (kappa+/-standard error [SE] 09.0+/-4.3%). After the study intervention, the rate of accuracy significantly increased to 74% (n=108, p<0.0001). Post intervention kappa+/-SE 60.9+/-5.7%. Age >45 years predicted inaccuracy. Age > 45 years, non African-American race, and alcohol use predicted underestimation. Family history of cardiovascular diseases or risk factors predicted responsiveness. CONCLUSION: Self perception of the 5-year risk of cardiovascular events is inaccurate, mainly due to underestimation. A targeted educational session using a risk assessment tool improved the accuracy. PMID- 22518235 TI - Repeated dosing of 23.4% hypertonic saline for refractory intracranial hypertension. A case report. AB - BACKGROUND: Hypertonic saline (HTS) at a concentration of 23.4% is an emerging therapy for intracranial hypertension. Compared to mannitol which can be given as a single bolus or as repeated bolus dosing, little data exists regarding safety or efficacy of repeated dosing of 23.4% HTS. We report the first case of 16 doses of 23.4% HTS over a 5 day period in a patient with refractory intracranial hypertension. CASE REPORT: A 43-year-old woman with Fisher 3 subarachnoid hemorrhage and hydrocephalus requiring an external ventricular drain developed global cerebral edema on computed tomography. Medically refractory intracranial hypertension ensued which required repeated dosing of 23.4% HTS. Reductions in intracranial pressure (ICP) occurred after each dose of 23.4% HTS. No central nervous system complications occurred. Anasarca was the only observed complication, which responded to furosemide diuresis. CONCLUSION: Repeated dosing of 23.4% HTS was effective in reducing ICP in a case of medically refractory intracranial hypertension without major systemic complications. Prospective studies should address the safety and efficacy of repeat dose 23.4% HTS on serum sodium, intracranial pressure, and complications. PMID- 22518236 TI - Privation of Memory: What can be done to help stroke patients remember? PMID- 22518237 TI - Traumatic intracranial aneurysm formation following closed head injury. PMID- 22518238 TI - Primitive trigeminal artery. AB - A 29-year-old woman presented with a near-syncopal event, followed by right-sided weakness and numbness as well as dysarthria. The symptoms resolved over several hours. The patient had a history of migraine and cleidocranial dysostosis. Her work-up was negative for stroke and dissection. Computed tomographic angiography (Figure 1, A and B) showed a carotid to basilar artery anastomosis (persistent primitive trigeminal artery). This variant is present in 0.1% to 0.6% of angiograms1. Patients with cleidocranial synostosis may be prone to anomalies of the circle of Willis since they are more likely to harbor cerebral aneurysms (26%).2. PMID- 22518239 TI - A review of risk factors for stroke in patients with chronic kidney disease. AB - BACKGROUND: Patients with chronic kidney disease (CKD) are at higher risk for stroke because of higher prevalence of traditional and non-traditional cardiovascular risk factors. METHODS: We performed an extensive literature review with pre-defined keywords. We summarized the results of the studies evaluating for risk factors predisposing to stroke in CKD patients. RESULTS: The incidence of stroke and stroke-related mortality is higher in CKD patients compared with the general population. Presence of anemia, hypoalbuminemia, malnutrition, uremia, and hyperhomocysteinemia in patients with CKD is associated with higher incidence of stroke. Hemodialysis and renal transplant patients are at higher risk of developing stroke compared with those who do not require renal replacement therapy. CONCLUSION: The early recognition of risk factors associated with stroke in CKD population is imperative. Early interventions may potentially decrease the incidence and associated mortality of stroke in CKD patients. PMID- 22518240 TI - Cat ownership and the Risk of Fatal Cardiovascular Diseases. Results from the Second National Health and Nutrition Examination Study Mortality Follow-up Study. AB - BACKGROUND: The presence of pets has been associated with reduction of stress and blood pressure and therefore may reduce the risk of cardiovascular diseases. METHODS: Relative risks (RR) of all deaths, death due to myocardial infarction (MI), cardiovascular diseases (MI or stroke), and stroke during a 20 year follow up were determined by Cox proportional hazards analysis for categories of cat or dog ownership among participants after adjustment for potential confounding variables. RESULTS: Previous or present use of cats as domestic pets was reported by 2435 (55%) of the 4435 participants. After adjustment for differences in age, gender, ethnicity/race, systolic blood pressure, cigarette smoking, diabetes mellitus, serum cholesterol, and body mass index, a significantly lower RR for death due to MI was observed in participants with past cat ownership (RR, 0.63; 95% confidence interval [CI], 0.44 to 0.88) compared with those without cats as pet at any time. There was also a trend for decreased risk for death due to cardiovascular diseases among participants with past cat ownership (RR, 0.74; 95% CI, 0.55 to 1.0). CONCLUSIONS: A decreased risk for death due to MI and all cardiovascular diseases (including stroke) was observed among persons with cats. Acquisition of cats as domestic pets may represent a novel strategy for reducing the risk of cardiovascular diseases in high-risk individuals. PMID- 22518241 TI - Prevalence and clinical characteristics of intracerebral hemorrhages associated with clopidogrel. AB - BACKGROUND: As clopidogrel is being increasingly used, intracerebral hemorrhage (ICH) associated with clopidogrel are expected to increase. We assessed the prevalence and clinical characteristics of of ICH with clopidogrel in a consecutive series of patients in two hospitals. METHODS: We retrospectively reviewed the medication history of 204 patients (112 in one hospital and 92 in another - both individually consecutive) admitted with ICH. We identified the patients who were using clopidogrel prior to ICH occurrence. The etiology of the ICH was categorized on the basis of clinical history and diagnostic imaging, and outcome was subsequently evaluated. RESULTS: A total of 8 (4%) of the 204 patients were using clopidogrel prior to onset of ICH. Clopidogrel was the only medication in 3 patients and was used with aspirin or warfarin in 3 and 2 patients, respectively. Aspirin or warfarin was the only medication in 23 (%) and 14 (%) patients associated with ICH, respectively. The hematoma was located in the basal ganglia (n=2), lobes (n=2), thalamus (n=1), intraventricular (n=2), and cerebellar (n=2). One patient had secondary intraventricular extension. All patients using a combination of clopidogrel and warfarin prior to ICH died. CONCLUSION: The prevalence of ICH associated with clopidogrel is approximating the prevalence of aspirin- or warfarin-associated ICH. The mortality with clopidogrel related ICH appears to be high particularly when in combination with another antithrombotic agent. PMID- 22518242 TI - Cerebral vasospasm in intracerebral hemorrhage-case report. AB - BACKGROUND: Cerebral vasospasm is commonly seen in subarachnoid hemorrhage. However the vasospasm in spontaneous intracerebral hemorrhage without subarachnoid extension has not been described. REPORT: We report a patient who developed intracerebral hemorrhage associated with cerebral vasospasm demonstrated by conventional angiography. The vasospasm involved the superior and inferior divisions of the middle cerebral artery on the side of intracerebral hemorrhage. The vasospasm resolved in six days as documented by a repeat angiography. CONCLUSION: Cerebral vasospasm can be rarely seen in patients with intracerebral hemorrhage. Further elaboration is required to understand the pathophysiology and subsequent impact on outcome in such patients. PMID- 22518243 TI - Prolonged Mild-to-Moderate Hypothermia for Refractory Intracranial Hypertension. AB - BACKGROUND: Therapeutic hypothermia is an emerging therapy for brain injury and cerebral edema. Hypothermia is known to reduce death and neurologic morbidity in survivors of cardiac arrest from ventricular fibrillation. Traumatic brain injury (TBI) trials studies of short-term hypothermia (24 to 48hours) have had conflicting results. Recent evidence however suggests prolonged hypothermia (48 hours to 14 days) may be beneficial for TBI and select cases of nontraumatic brain injury especially when the duration of cerebral edema and intracranial hypertension is expected to last longer than 24 hours. CASE REPORT: A 43-year-old female presented with a Fisher grade 4 aneurysmal (anterior communicating artery) subarachnoid hemorrhage. The patient was comatose upon transfer to our hospital, was intubated, and had immediate aneurysm coiling. The patient had a right external ventricular drain (EVD) placed for acute hydrocephalus and intracranial pressure (ICP) monitoring. The patient developed severe vasospasm of several intracranial vessels requiring angioplasty on two consecutive days, and hypertensive, hypervolemic, hemodilution therapy (HHH). On the ninth day, ICP went above 20mmHg and computed tomography (CT) showed global cerebral edema. For the next 17 days, the patient had refractory intracranial hypertension, requiring sedation, neuromuscular blockade, hyperosmolar therapy (3% infusion, and 23.4% saline boluses), thiopental coma with burst suppression, and hypothermia (31 to 34C). Hypothermia continued for a total of 14 days before ICP and edema on CT normalized. CONCLUSION: We report the first case of prolonged therapeutic hypothermia over a total of 14days to control nontraumatic brain injury-related refractory intracranial pressure and global cerebral edema. More studies are needed comparing clinical outcomes and complication rates between short duration and prolonged hypothermia for brain injury. PMID- 22518244 TI - Spontaneous recanalization after complete occlusion of the common carotid artery with subsequent embolic ischemic stroke. AB - INTRODUCTION: Acute carotid artery occlusion carries a high morbidity and mortality. Acute angioplasty and stenting is a feasible option with little known about the long term outcome. Limiting factor for this approach is hyperperfusion syndrome or hemorrhagic infarction. Spontaneous early or late recanalization for extracranial vessel is in the range of 5% -30%, with no well defined clinical outcome data. We describe a case of spontaneous common carotid recanalization. CASE REPORT: An 88 year old man presented with right sided weakness, global aphasia and visual field loss and was discovered to have common carotid occlusion at its origin. Within 12 hours of symptom onset patient improved neurologically to his baseline exam and repeat imaging demonstrated spontaneous recanalization. This was followed symptomatic occlusion of left middle cerebral artery The patient was treated with multimodality approach resulting in complete revascularization of the middle cerebral artery and angioplasty and stent placement of the internal carotid artery. Patient had a good neurological outcome at 3 months followup. CONCLUSION: The present case report demonstrates the risk of spontaneous recanalization acutely in patients presenting with common carotid artery occlusion and associated risk of embolic strokes. In such a patient, concomitant treatment for intracranial occlusion and extracranial high grade stenosis may be performed safely after 30 hours from the initial symptom onset. PMID- 22518245 TI - Thrombolytic treatment after acute ischemic stroke. PMID- 22518246 TI - A new classification based on angiographic arterial supply to neoplasms. PMID- 22518248 TI - MRI can Predict the Response to Therapeutic Repetitive Transcranial Magnetic Stimulation (rTMS) in Stroke Patients. AB - BACKGROUND: Previous studies suggest that purposeful modulation of excitability by up regulation in primary motor area (M1) in the lesioned hemisphere or down regulation of excitability in M1 intact hemisphere can influence function in the paretic hand.. OBJECTIVES: 1- To determine if magnetic resonance imaging (MRI) delineation of lesion has an impact on the modality and site of rTMS stimulation, and 2- To determine whether MRI can predict the degree of recovery of motor function after rTMS treatment. METHODS: A total of 60 ischemic stroke patients were recruited. Physical examination, mini mental state examination, activities of daily living assessment, motor subscale of the activity index (AI) and fine hand movement assessment were performed initially and then 2 weeks later (after the end of therapeutic course), then at 4, 8, and 12 weeks. MRI was performed for all patients and used to localize the site and extent of lesion. The patients were divided to 3 group consisting of 20 patients each: group 1 received repetitive rTMS 5hz at 90% motor threshold for 2.5min on the infarcted hemisphere, group 2 received rTMS 1hz at 110% motor threshold for 2.5min on the intact hemisphere, and group 3 received sham stimulation. All patients received standard physical therapy following each rTMS session. RESULTS: Patients with total anterior circulation stroke demonstrated on MRI showed no significant improvement when compared to those with partial anterior circulation, lacunar or posterior circulation strokes. The patients with cortical strokes experienced less improvement when compared with those with subcortical strokes especially with 1 hz stimulation to intact hemisphere. CONCLUSION: MRI can help predict the response to rTMS for stroke rehabilitation and assist the clinician choose the mode and site of rTMS application. PMID- 22518249 TI - Asian cerebral venous thrombosis registry: study protocol. AB - INTRODUCTION: Cerebral venous thrombosis (CVT) is a well known but poorly reported entity. Most of the studies and registries related to CVT are reported from European countries. No large multi-center or multi- national data base or registry has been reported from Asian countries. CVT is not uncommon in Asia especially in south Asian subcontinent including India, Pakistan and Bangladesh. One study reported from India that CVT accounted for half of all strokes in the young and 40% of strokes in women. Review of CVT cases from Asian countries is suggestive of differences in risk factors profile and outcome in these patients as compared with European studies. These findings from multi- center data base in Asian countries will be extremely important in identifying risk factors for CVT in these countries. STUDY DESIGN: This is a prospective observational study. We plan to enroll more than 1000 patients from at least ten Asian countries (about 40-50 centers). Patients will be enrolled prospectively and followed for six months. Primary outcome would be death or dependence as assessed by modified Rankin scale (mRS). Data will be collected on a pre-defined data form. There will not be any laboratory test, investigation or treatment specified by the study. Only results of routinely performed studies and treatments will be recorded. Patient (aged 16 or above) will only be included in study if they have diagnosis of CVT proven by magnetic resonance imaging (MRI), magnetic resonance venography (MRV), computed tomography (CT) venography and cerebral venography according to established criteria. Follow up visits will be performed at 6 months, 12 months, and yearly thereafter, preferably by direct interview and observations by the local investigators. OUTCOME: Primary outcome is death or dependence (mRS >2) at the end of the follow-up period. Secondary outcomes are death and dependence at 6 months. Patients will be enrolled from January 2009 to June 2010. PMID- 22518247 TI - Mechanical properties of normal and diseased cerebrovascular system. AB - BACKGROUND: Blood vessel mechanics has traditionally been of interest to researchers and clinicians. Changes in mechanical properties of arteries have been associated with various diseases. OBJECTIVE: To provide a comprehensive review directed towards understanding the basic biomechanical properties of cerebral arteries under normal and diseased conditions. METHODS: Literature review supplemented by personal knowledge. RESULTS: The mechanical properties of vascular tissue may depend on several factors including macromolecular volume fraction, molecular orientation, and volume or number of cells such as smooth muscle cells. Mechanical properties of a blood vessel have been characterized using different methods such as in vitro tensile testing, non-invasive ultrasound examination, and mathematical models. Experiments are complicated by the variation in properties and content of materials that make up the vessel wall and more challenging as the size of the vessel of interest decreases. Therapeutic interventions aiming to alter the mechanical response are either pharmaceutical: including calcium channel blockers, angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), and beta-blockers; or, mechanical interventions such as angioplasty, stent placement, mechanical thrombectomy, or embolization procedures. CONCLUSION: It is apparent from the literature that macromolecular and cellular mechanics of blood vessels are not fully understood. Therefore, further studies are necessary to better understand contribution of these mechanisms to the overall mechanics of the vascular tissue. PMID- 22518250 TI - Clinical and radiological features of brainstem variant of hypertensive encephalopathy. AB - BACKGROUND: The "posterior reversible leukoencephalopathy" syndrome, generally observed in the setting of severe, acute hypertension, often correlates with radiological abnormalities that involve the occipital lobes and other hemispheric areas. A predominant involvement of the brainstem in this syndrome is rare. PATIENTS: We report three patients with previously known or newly diagnosed severe hypertension, who presented with a combination of headache and visual disturbances, along with diffuse abnormalities demonstrated on magnetic resonance imaging in the brainstem and cerebellum. The absence of clinical features of brainstem or cerebellar dysfunction contrasted with the severity of the radiological abnormalities. CONCLUSIONS: We discuss the pathophysiological, clinical, and radiographic features of this variant of posterior reversible leukoencephalopathy. PMID- 22518251 TI - A patient guide to brain stent placement. PMID- 22518252 TI - Congenital subclavian steal associated with atresia of a left innominate artery. AB - A 22-year-old woman presented with a history of multiple spells of dizziness, difficulty speaking and occasional loss of consciousness lasting for up to one hour. The patient had been initially diagnosed with epilepsy and treated with Levatiracetam without success. The physical finding of decreased left carotid and radial pulses raised suspicion for Takayasu arteriitis and the patient was referred to our center for further evaluation including cerebral angiography. Angiography was performed via two 5-French sheaths placed in the right femoral and left radial arteries. The patient was found to have only two great vessels originating from the aortic arch, while the left carotid and subclavian arteries shared a common origin and did not communicate with the arch. There was prominent subclavian steal through the vertebrobasilar junction and through hyper-trophied spinal arteries. The right internal carotid artery supplied the left hemisphere through the anterior communicating artery and also provided flow to the posterior cerebral arteries. No vascular lesions were identified to support the diagnosis of vasculitis. Atresia of a left innominate artery is an extremely rare aortic arch variant1, 2 which, as in this case can lead to symptomatic subclavian steal. Surgical options are being discussed with the patient1. PMID- 22518253 TI - A Classification Scheme for Assessing Recanalization and Collateral Formation following Cerebral Venous Thrombosis. PMID- 22518255 TI - Transcranial Doppler ultrasonography identifies symptomatic cavum septum pellucidum cyst: case report. AB - OBJECTIVE: Cavum Septum Pellucidum (CSP) cysts are considered normal anatomic variants, comprising as many as 15% of the adult and 85% of pediatric populations. On rare occasions, the cavum can obstruct CSF outflow from the lateral ventricles causing elevated intracranial pressure (ICP) and headaches. The purpose of this paper is to present a challenging case of new onset symptomatic CSP in a previously healthy adult male without papilledema and elevated ICP detected by transcranial Doppler (TCD) ultrasonography. CLINICAL PRESENTATION: A previously healthy 44 year-old man presented to the neurology service with debilitating positional headaches that were mitigated solely by recumbent positioning. A magnetic resonance imaging scan (MRI) of the brain revealed a cavum septum pellucidum. A lumbar puncture was performed and revealed normal ICP. No papilledema was evident on fundoscopic examination. A CSF flow study revealed normal dye opacification pattern without evidence of CSF leak. INTERVENTION: Without other clinical indicators of high ICP, but a history suspicious for symptomatic CSP, TCD study was performed and revealed abnormally low cerebral blood flow velocities (CBFV's) and significantly elevated pulsatility indices (PI's) for patient's age indicative of high ICP. Endoscopic fenestration of the septum pellucidum was performed improving the patient's headaches and normalization of the PI's and CBFV's to normal (p<0.01). CONCLUSIONS: Symptomatic CSP is a difficult diagnosis to make based on existing diagnostic paradigm. TCD in the absence of other objective confirmatory studies, can aid in the diagnosis and provide information about the success of fenestration of the cavum septum. PMID- 22518257 TI - Anticoagulation for stroke prevention in elderly patients with atrial fibrillation: risk-benefit ratio remains highly favorable. PMID- 22518254 TI - Trophic factors and stem cells for promoting recovery in stroke. AB - BACKGROUND: Stem cell therapy for stroke is in its initial stages as an option to restore lost neurological functions after stroke. OBJECTIVE: To provide a comprehensive review of studies involving stem cells in stroke treatment and to highlight new evidence from the ongoing clinical trials. METHODOLOGY: We performed a systematic study of various published journals in online medical libraries using Pubmed, Sciencedirect, and hajournal. Evidence synthesis is done with specific search words of - stem cell therapy, stroke, trophic factor, neural progenitor cell, pathophysiology, mechanism of action, clinical trial and mesenchymal stem cell in various combinations. Emphasis was given to articles published in year 2000 and onwards. RESULTS: Current research on stem cell therapy for stroke focuses on transplantation and endogenous neurogenesis of stem cells in brain. The sub-ventricular zone in the adult brain is identified as an endogenous resource of neuronal precursors that can be recruited to adjacent lesioned areas. Several factors can increase adult neurogenesis by stimulating formation or improving survival of new neurons, such as FGF-2, EGF, stem cell factor, erythropoietin, BDNF, caspase inhibitors, and anti-inflammatory drugs. Much of the beneficial effects of stem cell in stroke models are related to secretion of trophic factors. CONCLUSION: The complex pathophysiology involving various trophic factors, growth factor and gene modification in animal studies have showed promising result. Future research involving these trophic factors should open up new additional or clinically significant alternative for the treatment of stroke. PMID- 22518258 TI - Aberrant right subclavian artery and common carotid trunk. PMID- 22518256 TI - The effects of aortic coarctation on cerebral hemodynamics and its importance in the etiopathogenesis of intracranial aneurysms. AB - OBJECTIVES: Hemodynamic changes in the cerebral circulation in presence of coarctation of aorta (CoA) and their significance in the increased intracranial aneurysms (IAs) formation in these patients remain unclear. In the present study, we measured the flow-rate waveforms in the cerebral arteries of a patient with CoA, followed by an analysis of different hemodynamic indices in a coexisting IA. MATERIALS AND METHODS: Phase-contrast Magnetic Resonance (pc-MR) volumetric flow rate (VFR) measurements were performed in cerebral arteries of a 51 years old woman with coexisting CoA, and five healthy volunteers. Numerical predictions of a number of relevant hemodynamic indices were performed in an IA located in sub clinoid part of left internal carotid artery (ICA) of the patient. Computations were performed using Ansys((r))-CFX(TM) solver using the VFR values measured in the patient as boundary conditions (BCs). A second analysis was performed using the average VFR values measured in healthy volunteers. The VFR waveforms measured in the patient and healthy volunteers were compared followed by a comparison of the hemodynamic indices obtained using both approaches. The results are discussed in the background of relevant literature. RESULTS: Mean flow-rates were increased by 27.1% to 54.9% (2.66-5.44 ml/sec) in the cerebral circulation of patients with CoA as compared to healthy volunteers (1.2-3.95 ml/sec). Velocities were increased inside the IA by 35-45%. An exponential rise of 650% was observed in the area affected by high wall shear stress (WSS>15Pa) when flow-rates specific to CoA were used as compared to population average flow-rates. Absolute values of space and time averaged WSS were increased by 65%. Whereas values of maximum pressure on the IA wall were increased by 15% the area of elevated pressure was actually decreased by 50%, reflecting a more focalized jet impingement within the IA of the CoA patient. CONCLUSIONS: IAs can develop in patients with CoA several years after the surgical repair. Cerebral flow-rates in CoA patients are significantly higher as compared to average flow-rates in healthy population. The increased supra-physiological WSS (>15Pa), OSI (>0.2) and focalized pressure may play an important role in the etiopathogenesis of IAs in patients with CoA. PMID- 22518259 TI - Leptomeningeal collateral response and computed tomographic perfusion mismatch in acute middle cerebral artery occlusion. AB - OBJECTIVE: To identify the relationship between the magnitude of leptomeningeal collaterals (LMC) on digital subtraction angiography (DSA) and regional cerebral blood volume (rCBV)/regional cerebral blood flow (rCBF) mismatch on computed tomography perfusion (CTP) in patients with acute middle cerebral artery (MCA) occlusion. DESIGN/METHODS: We reviewed the clinical records, and neuroimaging studies in consecutive patients with proximal MCA (M1-segment) and proximal branch (M2-segment) occlusion undergoing endovascular treatment following the demonstration of mismatch on CTP. DSA images acquired prior to the treatment were used to grade collateral flow from the anterior cerebral artery to the MCA on a scale ranging from 1 to 5, based on retrograde reconstitution of MCA segments in the late arterial phase. CTP images were reviewed and rCBV/rCBF mismatch was categorized as minor (<= 1/3 of MCA territory), moderate (1/3-2/3 of MCA territory), or severe (> 2/3 to complete territory). Statistical association was assessed using Pearson exact test. RESULTS: A total of sixteen patients were studied (10 were men; mean age of 69 years). Mean time from symptom onset to CTP was 146 minutes. Patients with M1-segment occlusion (n=10) had more severe rCBV/rCBF mismatch compared to patients with M2-segment occlusion (p=0.016). There was no association between the magnitude of LMC and severity of rCBV/rCBF mismatch on CTP. CONCLUSIONS/RELEVANCE: The magnitude of LMC on DSA does not correlate with the severity of rCBV/rCBF mismatch in patients with MCA occlusion. This result suggests that additional factors, such as micro vascular failure, may contribute to altered cerebral perfusion. PMID- 22518260 TI - Atherosclerotic aortic arch plaques in acute ischemic stroke. AB - BACKGROUND: Atherosclerotic aortic arch plaques (AAP) have been linked to an increased risk of thrombo-embolic events as a cause of acute ischemic stroke of undetermined etiology. OBJECTIVES: To find out the presence of atherosclerotic plaques in aortic arch and their potential role as a source of embolism in cerebral infarction of undetermined etiology. METHODS: We performed trans esophageal echocardiography (TEE) and multislice computerized tomography (MSCT) of the aortic arch on 30 patients with acute ischemic stroke of undetermined cause from a total series of 150 non-selected patients with acute ischemic stroke studied prospectively by clinical evaluation, laboratory investigations, cranial computed tomography, color coded duplex ultrasonography of the carotid arteries and transcranial Doppler (TCD). RESULTS: Using trans-esophageal echocardiography eight patients (29.6%) had atherosclerotic aortic arch plaques, while using multislice computerized tomography atherosclerotic aortic arch plaques were revealed in twelve patients (40%). Atherosclerotic aortic arch plaques were significantly related to older age, male gender, hypertension, ischemic heart disease and low-grade atherosclerotic carotid lesions. Multislice computerized tomography of the aortic arch was more sensitive than trans-esophageal echocardiography in detecting the site, size and characters of atherosclerotic aortic arch plaques. CONCLUSION: Atherosclerotic aortic arch plaques are a frequent finding in patients with acute ischemic stroke of undetermined cause supporting the hypothesis that aortic plaques have embolic potential. In addition, multislice computerized tomography is more sensitive than trans esophageal echocardiography in detecting atherosclerotic aortic arch plaques and better characterization of these plaques especially relevant one. PMID- 22518261 TI - Pure motor upper limb weakness and infarction in the precentral gyrus: mechanisms of stroke. AB - BACKGROUND: Pure arm monoparesis is an uncommon presentation of stroke. Localization of the lesions is variable, including cortical, subcortical or deep brain infarcts. No particular risk factors or unifying mechanisms have been clearly identified. METHODS: Seven patients (5 women, 2 men) presented with isolated arm weakness and brain magnetic resonance imaging (MRI) documented an infarct in the precentral gyrus. All were evaluated for stroke risk factors, had telemetry monitoring, transthoracic echocardiogram (TTE) and magnetic resonance angiography (MRA) of the head and neck. Transesophageal echocardiogram (TEE) was performed in three cases. Hyper-coagulable work-up was performed in one case. Trans-cranial Doppler was performed in one case. RESULTS: Mean age was 73 years (range 55-88 years). Arm weakness in all patients was ranging from mild (-5/5) to moderate (2/5) and was predominantly distal (without plegia). None of the patients complained of limb pain or sensory deficit. Infarcts affected one gyrus (5/7) or, less often, 2 adjacent gyri (2/7), along the most distal aspect of the middle cerebral artery (MCA) territory. Risk factors included hypertension (6/7), diabetes (2/7), hyper-lipidemia (7/7), smoking (1/7) and prior TIA/stroke (3/7). The mechanisms of ischemic stroke were determined to be large artery atherosclerosis (2/5), cardioembolic (2/5), other determined etiology [hypoperfusion (1/5)] and undetermined etiology (2/5). CONCLUSIONS: Our series of patients with small cortical infarcts and pure motor arm weakness show heterogeneous etiologies of stroke mechanisms and related long term outcomes. The risk factors appear to distribute as in most stroke populations, without a pattern specific to this unusual clinical presentation. PMID- 22518262 TI - Earlier Hypothermia Attainment is Associated with Improved Outcomes after Cardiac Arrest. AB - INTRODUCTION: Therapeutic hypothermia (TH, 32-34oC) reduces mortality and improves neurologic outcomes after ventricular fibrillation cardiac arrest (CA). The relationship between time to achieve TH and outcomes remains undefined. We hypothesized that a shorter interval from CA to achieve TH would be associated with improved neurologic outcome. METHODS: We retrospectively reviewed subjects within or out-of-hospital CA treated with TH between November 2006 and April 2009 at our institution. The time to target temperature was defined as the interval between witnessed CA and first measurement of hypothermia (<= 34 oC) and further categorized as early (< 6 hours) or delayed (> 6 hours). Outcomes were assessed at the time of death or discharge using Cerebral Performance Category Score (CPC); good outcome was defined as CPC <= 2. Fisher's Exact test was used to assess the univariate relationship between time to TH and outcome. RESULTS: 26 patients achieved TH after in-hospital (39%) and out-of-hospital (61%) CA. Five patients (5/26) reached early target temperature; 80% (4/5) of those had a good neurological outcome. 24% (5/21) of subjects with delayed target temperature achieved a good neurological outcome. The univariate relationship between time to target temperature and neurological outcome was statistically significant (p=0.034). CONCLUSION: Attaining TH within 6 hours of in or out-of-hospital CA was associated with a greater likelihood of a good neurological outcome at discharge. Time from CA to achieved TH should be included as a clinically important covariate in future studies of predictors of outcome after CA. PMID- 22518263 TI - Application of Confocal Microscopy for 3D Assessment of Carotid Plaque Structure: Implications for Carotid Blood Flow and Stroke Research. AB - BACKGROUND: Little information is available on how forces resulting from fluid flow interact with structural stability of carotid atherosclerotic plaque and how such interactions may impact on stroke prevention; investigation of the 3D structure of plaque could help in such studies. The aim of this study was to investigate whether confocal microscopy can be used to obtain 3D visualization of the structure of atherosclerotic carotid plaques. METHODS: Carotid plaque specimens were collected from routine end-arterectomy surgical operations. Both bright-field microscopy and Laser Scanning Confocal Microscopy (LSCM) were used to generate 3D image data-sets and visualizations of surgically removed carotid plaques. RESULTS: Evidence of carotid plaque vulnerability was demonstrated by reduced fibrous cap thickness and large lipid-necrotic core with evidence of cracking. CONCLUSION: The generation of 3D images of carotid plaques could help in: (i) investigating key features that affect plaque structural stability; (ii) comparing 3D microstructure of the plaque with clinical imaging assessment and blood flow investigations; and (iii) developing markers to identify patients requiring clinical intervention. PMID- 22518264 TI - A Case Report of Thunderclap Headache with Sub-arachnoid Hemorrhage and Negative Angiography: A Review of Call-Fleming Syndrome and the use of Transcranial Dopplers in Predicting Morbidity. AB - INTRODUCTION: We present a case report in a patient with severe, recurrent, thunderclap with computed tomography (CT) evidence of subarachnoid blood and negative work-up for aneurysm. This case is an example of Call-Fleming syndrome with subarachnoid hemorrhage in which transcranial Doppler (TCD) was used for monitoring of cerebral vasoconstriction when angiography did not evidence vasoconstriction. We will review Call-Fleming syndrome and the utility of transcranial doppler imaging to assess cerebral vasoconstriction. METHODS: A review of the current literature regarding diagnostics, treatment, and morbidity in Call-Fleming (reversible cerebral vasoconstriction syndrome) as well as a review of the data using transcranial color-coded sonography and transcranial doppler imaging to assess vasospasm in these cases. RESULTS: The patient underwent computed tomography angiography (CTA) and venography (CTV), catheter angiography, lumbar puncture, and vasculitis work-up which were all negative. His magnetic resonance imaging (MRI) showed T2 weighted and fluid attenuation inversion recovery (FLAIR) hyper-intensities in the posterior frontal lobes as well as subarachnoid blood along bilateral occipital convexities. TCDs were obtained which showed elevated mean velocities. CONCLUSION: The use of bedside transcranial doppler imaging is a non-invasive means of assessing vasospasm in Call-Fleming syndrome; even in cases where angiography is negative. Determining the degree of vasospasm based on the data in subarachnoid hemorrhage, we are able to predict a patient's risk of complications related to vasospasm including reversible posterior leukoencephalopathy and ischemic events. PMID- 22518265 TI - Clinical outcome of patients with acute posterior circulation stroke and bilateral vertebral artery occlusion. AB - BACKGROUND AND INTRODUCTION: Patients presenting with posterior circulation acute ischemic events are occasionally noted to have occlusion of bilateral vertebral arteries with basilar artery blood flow entirely dependent from the anterior circulation. There is limited data about prognosis of such patients in literature. METHODS: Patients with acute posterior circulation ischemic stroke and bilateral vertebral artery occlusion (including contra-lateral hypoplastic vertebral artery without contribution to the basilar artery system) were identified prospectively from two academic centers. Data including clinical presentation, medical management, angiographic findings, recurrent events and outcome were collected and reported. RESULTS: A total of 4 patients presenting with acute ischemic events in the posterior circulation were identified to have bilateral vertebral artery occlusion at our center. One additional patient had a vertebral artery occlusion and a contra-lateral hypoplastic vertebral artery. In the functional evaluation of the blood flow with catheter angiography, the basilar artery was filling from the anterior circulation, with no antegrade flow from bilateral vertebral arteries injection in all 5 patients. Patients were treated with anti-platelets (n=4) or started on anti-coagulation after failing anti-platelet therapy (n=2). All patients had recurrent ischemic stroke with new ischemic lesions proven by diffusion weighted images on MRI within 2 to 70 days after the initial event. CONCLUSION: Patients with acute posterior circulation ischemic stroke and bilateral vertebral artery occlusion are at high risk of having early recurrent ischemic events. Reestablishment of the antegrade vertebro basilar blood flow through endovascular re-canalization might be an option to decrease stroke recurrence in selected patients with acute posterior circulation stroke and bilateral vertebral artery occlusion. PMID- 22518266 TI - Comparison of time to treatment between intravenous and endovascular thrombolytic treatments for acute ischemic stroke. AB - BACKGROUND: Intravenous (IV) recombinant tissue plasminogen activator (rt-PA) is used to treat acute ischemic stroke (AIS) within 4.5 hours of symptom onset. Endovascular treatment (ET) may provide higher rates of recanalization, but longer time to treatment may limit comparative clinical benefit and widespread applicability. OBJECTIVE: This retrospective study compares symptom onset to treatment times in patients who received both IV rt-PA and ET for AIS and its effect on clinical outcome. METHODS: AIS patients presenting to our facility who received both IV rt-PA and ET were reviewed using them as case and control to match other factors contributing to time to treatment. Good outcome was defined as modified Rankin Scale score 0 to 2 at discharge. RESULTS: Fifty patients received both treatments with significantly shorter mean symptom onset to time to IV rt-PA compared with symptom onset to time to ET (96.8 +/- 39.3 minutes versus 255.3 +/- 92.2 minutes, p < 0.001). Patients receiving ET in less time than the mean time had a higher rate of favorable outcome at discharge (45.5% versus 11.8%, p = 0.017) and a significantly lower rate of mortality at three months (15.2% versus 52.9%, p = 0.017) than those receiving it after the mean time. The symptom onset to times to ET was significantly longer in transferred patients compared to primary emergency department patients (299.3 minutes versus 230.5 minutes, p = 0.01) CONCLUSION: A considerable difference in symptom onset to treatment times between IV and ET was observed among patients with AIS, especially those who were transferred from another facility. Reducing the time to treatment for ET has the potential to improve outcomes among ischemic stroke patients. PMID- 22518267 TI - Tumefactive Multiple Sclerosis presenting as Acute Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Multiple sclerosis (MS) plaques appear as well demarcated, homogenous small ovoid lesions on magnetic resonance imaging (MRI). Atypical radiographic features of MS lesions include size greater than 2 cm, mass effect, and edema. Tumefactive MS lesions can radiographically mimic intra cranial neoplasms, infarction, as well as infections. In atypical cases of tumefactive demyelinating lesions, brain biopsy may be required for the diagnosis. METHODS: The authors describe the case of a 43 year old woman who presented with worsening right-gaze preference and left side weakness and was initially diagnosed with acute ischemic stroke. The patient underwent laboratory investigation and brain contrast-enhanced MRI before undergoing brain biopsy. RESULTS: Fluid attenuation inversion recovery (FLAIR) MRI showed an increase in signal intensity in the right frontal lobe sub-cortical region. Diffusion weighted imaging showed an area of restricted diffusion involving the white matter of the right-frontal lobe. Cerebrospinal fluid studies were normal except for the presence of oligo-clonal bands. Magnetic resonance spectroscopy (MRS) demonstrated an elevated choline (Cho)/creatine ratio, increase lactate, and normal N-acetylaspartate (NAA)/creatine ratio, findings suggestive of an inflammatory or a demyelinating disease. A brain biopsy of the right frontal lesion was performed and revealed well-demarcated foci of demyelination with axonal preservation. Peri-vascular and parenchymal CD3(+) T-cells were also identified within the demyelinated foci, findings that further supported the diagnosis of active multiple sclerosis. CONCLUSION: Tumefactive MS can be radiographically misdiagnosed as one of several conditions, among which are infarction, infections, and tumors. Brain biopsy may be needed for diagnosing challenging cases of tumefactive MS. PMID- 22518268 TI - Single Stage versus Multi-staged Stent-assisted Endovascular Repair of Intracranial Aneurysms. AB - BACKGROUND: Stent-assisted coiling of intracranial aneurysms is performed either as a single-stage or a multi-staged procedure. The objective of our study is to compare the complications between the in single-stage versus the multi-staged stent-assisted coiling of intracranial aneurysm. METHODS: From January 2003 to January 2010, consecutive patients treated with intracranial stent for aneurysms were prospectively enrolled. Patients' demographics including cerebrovascular risk factors, aneurysms size and locations were collected. Technical and clinical complications as well as outcomes were measured. Data were analyzed retrospectively using SPSS software version 11.5. RESULTS: 87 patients (87 aneurysms) with a mean of 51.2 +/- 13.6 years were treated with 90 intracranial (Neuroform 74, Enterprise 16) stents, single-stage 37 (42.5%) and multi-staged 50 (57.5%). Eight adverse events were observed without any mortality, 6 of which were in the single-stage group-rupture of aneurysm in 2, and thrombo-embolic events in 4. Both rupture occurred in basilar artery bifurcation aneurysms, required ventriculostomy and resuscitations. In single-stage, asymptomatic intra operative stent thrombosis developed in one, symptomatic stent thrombosis in one on day 14, transient ischemic attack on day 6 and immediate post operative stroke in one. Only two minor strokes were observed in the multi-staged group, one on post-procedure day 7 and other on day 60. Majority of the patients had good outcomes including those with events. CONCLUSION: Our study revealed that single stage stent-coiling technique is associated with a higher rate of complications than multistaged procedure. Therefore, staging the procedure may be an option whenever possible. PMID- 22518269 TI - The Relationship between Pulmonary Dysfunction and Age in Vasospasm Patients Receiving Triple H Therapy. AB - BACKGROUND AND INTRODUCTION: Triple H therapy is conventionally used to treat vasospasm following sub-arachnoid hemorrhage (SAH) but can sometimes have side effects. In order to investigate pulmonary complications in SAH patients and relationship with age we conducted the following study. METHODS: The charts of 121 sub-arachnoid hemorrhage patients who underwent clipping or coiling of an aneurysm were retrospectively reviewed. The diagnosis of vasospasm was documented based on Doppler and angiographic findings. All patients with vasospasm received the standard Triple H therapy (hematocrit 33-38%, central venous pressure 10-12 mmHg, systolic blood pressure 160-200 mmHg). We studied intravenous intake, artificial ventilation, hypoxemia/pulmonary edema, postoperative fever, pneumonia and death rates as outcome variables. RESULTS: Sixty five patients developed vasospasm (15 mild, 23 moderate, 27 severe). These were significantly younger than non-vasospasm patients (51 years vs. 61 years, p=0.004). The average daily intravenous input was 1,730 cc in novasospasm patients, 2,123 cc in the mild vasospasm group, 2,399 cc in the moderate vasospasm group, and 3,040 cc in the severe vasospasm group. Younger patients with moderate to severe vasospasm received more fluids than older patients. Ten patients (8.3%) developed hypoxemia or pulmonary edema. No patient developed hypoxemia/pulmonary edema in the mild vasospasm group and the rates did not show a trend and were not statistically different (7.1%, 0.0%, 13.0%, 11.1%, p>0.05) between vasospasm and non-vasospasm groups. Likewise, postoperative fever and pneumonia rates were not different between the vasospasm and non-vasospasm groups. Using the mean age as a threshold, pulmonary-related complications including death rates tended to be higher in the older group. The rates of postoperative ventilation (30.8% vs. 57.1%, P<0.01) and hypoxemia/pulmonary edema (3.1% vs. 14.3%, P<0.05) rates were statistically higher in the older group. Patients who developed hypoxemia/pulmonary edema in the vasospasm group tended to be younger than those who developed hypoxemia/pulmonary edema in the non-vasospasm group. CONCLUSION: Younger patients are at a higher risk of developing vasospasm than older patients possibly referable to vessel elasticity and reactive sensitivity factors. Likewise, patients who developed hypoxemia/pulmonary edema in the vasospasm group were younger than in the non-vasospasm group possibly secondary to fluid overload from triple H therapy. PMID- 22518270 TI - NAD(+) administration significantly attenuates synchrotron radiation X-ray induced DNA damage and structural alterations of rodent testes. AB - Synchrotron radiation (SR) X-ray has great potential for its applications in medical imaging and cancer treatment. In order to apply SR X-ray in clinical settings, it is necessary to elucidate the mechanisms underlying the damaging effects of SR X-ray on normal tissues, and to search for the strategies to reduce the detrimental effects of SR X-ray on normal tissues. However, so far there has been little information on these topics. In this study we used the testes of rats as a model to characterize SR X-ray-induced tissue damage, and to test our hypothesis that NAD(+) administration can prevent SR X-ray-induced injury of the testes. We first determined the effects of SR X-ray at the doses of 0, 0.5, 1.3, 4 and 40 Gy on the biochemical and structural properties of the testes one day after SR X-ray exposures. We found that 40 Gy of SR X-ray induced a massive increase in double-strand DNA damage, as assessed by both immunostaining and Western blot of phosphorylated H2AX levels, which was significantly decreased by intraperitoneally (i.p.) administered NAD(+) at doses of 125 and 625 mg/kg. Forty Gy of SR X-ray can also induce marked increases in abnormal cell nuclei as well as significant decreases in the cell layers of the seminiferous tubules one day after SR X-ray exposures, which were also ameliorated by the NAD(+) administration. In summary, our study has shown that SR X-ray can produce both molecular and structural alterations of the testes, which can be significantly attenuated by NAD(+) administration. These results have provided not only the first evidence that SR X-ray-induced tissue damage can be ameliorated by certain approaches, but also a valuable basis for elucidating the mechanisms underlying SR X-ray-induced tissue injury. PMID- 22518272 TI - New considerations in the design of clinical trials for traumatic brain injury. AB - Randomized controlled trials in traumatic brain injury (TBI) pose several complicated methodological challenges related to the heterogeneity of the population. Several strategies have been proposed to deal with these challenges. Recommendations presented by the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) study group include the use of relatively broad enrollment criteria combined with covariate adjustment for strong predictors of outcome in the analysis phase, rather than the use of strict enrollment criteria. Furthermore, an ordinal rather than a dichotomized analysis of the Glasgow Outcome Scale - the outcome measure in most TBI trials - will increase the statistical power significantly. This review discusses the issue of heterogeneity in TBI trials and summarizes the value of different innovative methods for the design and statistical analysis of randomized controlled trials in TBI. Future directions highlight the opportunities offered by alternative strategies, such as comparative effectiveness research, to investigate the clinical benefits of established and novel therapies in TBI. PMID- 22518273 TI - Processing Novel and Lexicalized Finnish Compound Words. AB - Participants read sentences in which novel and lexicalized two-constituent compound words appeared while their eye movements were measured. The frequency of the first constituent of the compounds was also varied factorially and the frequency of the lexicalized compounds was equated over the two conditions. The sentence frames prior to the target word were matched across conditions. Both lexicality and first constituent frequency had large and significant effects on gaze durations on the target word; moreover the constituent frequency effect was significantly larger for the novel words. These results indicate that first constituent frequency has an effect in two stages: in the initial encoding of the compound and in the construction of meaning for the novel compound. The difference between this pattern of results and those for English prefixed words (Pollatsek, Slattery, & Juhasz, 2008) is apparently due to differences in the construction of meaning stage. A general model of the relationship of the processing of polymorphemic words to how they are fixated is presented. PMID- 22518271 TI - Synergistic Catalysis: A Powerful Synthetic Strategy for New Reaction Development. AB - Synergistic catalysis is a synthetic strategy wherein both the nucleophile and the electrophile are simultaneously activated by two separate and distinct catalysts to afford a single chemical transformation. This powerful catalysis strategy leads to several benefits, specifically synergistic catalysis can (i) introduce new, previously unattainable chemical transformations, (ii) improve the efficiency of existing transformations, and (iii) create or improve catalytic enantioselectivity where stereocontrol was previously absent or challenging. This perspective aims to highlight these benefits using many of the successful examples of synergistic catalysis found in the literature. PMID- 22518274 TI - Sex differences in intimate relationships. AB - Social networks based on dyadic relationships are fundamentally important for understanding of human sociality. However, we have little understanding of the dynamics of close relationships and how these change over time. Evolutionary theory suggests that, even in monogamous mating systems, the pattern of investment in close relationships should vary across the lifespan when post weaning investment plays an important role in maximising fitness. Mobile phone data sets provide a unique window into the structure and dynamics of relationships. We here use data from a large mobile phone dataset to demonstrate striking sex differences in the gender-bias of preferred relationships that reflect the way the reproductive investment strategies of both sexes change across the lifespan, i.e. women's shifting patterns of investment in reproduction and parental care. These results suggest that human social strategies may have more complex dynamics than previously assumed and a life-history perspective is crucial for understanding them. PMID- 22518275 TI - Thymus atrophy and double-positive escape are common features in infectious diseases. AB - The thymus is a primary lymphoid organ in which bone marrow-derived T-cell precursors undergo differentiation, leading to migration of positively selected thymocytes to the T-cell-dependent areas of secondary lymphoid organs. This organ can undergo atrophy, caused by several endogenous and exogenous factors such as ageing, hormone fluctuations, and infectious agents. This paper will focus on emerging data on the thymic atrophy caused by infectious agents. We present data on the dynamics of thymus lymphocytes during acute Trypanosoma cruzi infection, showing that the resulting thymus atrophy comprises the abnormal release of thymic-derived T cells and may have an impact on host immune response. PMID- 22518276 TI - Subversion of Immunity by Leishmania amazonensis Parasites: Possible Role of Phosphatidylserine as a Main Regulator. AB - Leishmania amazonensis parasites cause progressive disease in most inbred mouse strains and are associated with the development of diffuse cutaneous leishmaniasis in humans. The poor activation of an effective cellular response is correlated with the ability of these parasites to infect mononuclear phagocytic cells without triggering their activation or actively suppressing innate responses of these cells. Here we discuss the possible role of phosphatidylserine exposure by these parasites as a main regulator of the mechanism underlying subversion of the immune system at different steps during the infection. PMID- 22518277 TI - Selective gene transfer to the retina using intravitreal ultrasound irradiation. AB - This paper aims to evaluate the efficacy of intravitreal ultrasound (US) irradiation for green fluorescent protein (GFP) plasmid transfer into the rabbit retina using a miniature US transducer. Intravitreal US irradiation was performed by a slight modification of the transconjunctival sutureless vitrectomy system utilizing a small probe. After vitrectomy, the US probe was inserted through a scleral incision. A mixture of GFP plasmid (50 MUL) and bubble liposomes (BLs; 50 MUL) was injected into the vitreous cavity, and US was generated to the retina using a SonoPore 4000. The control group was not exposed to US. After 72 h, the gene-transfer efficiency was quantified by counting the number of GFP-positive cells. The retinas that received plasmid, BL, and US showed a significant increase in the number (average +/- SEM) of GFP-positive cells (32 +/- 4.9; n = 7; P < 0.01 ). No GFP-positive cells were observed in the control eyes (n = 7). Intravitreal retinal US irradiation can transfer the GFP plasmid into the retina without causing any apparent damage. This procedure could be used to transfer genes and drugs directly to the retina and therefore has potential therapeutic value. PMID- 22518278 TI - The incidence of central serous chorioretinopathy after photorefractive keratectomy and laser in situ keratomileusis. AB - Purpose. To assess the incidence of central serous chorioretinopathy (CSCR) following laser in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK). Methods. A chart review was performed to identify all patients with CSCR and a previous history of LASIK or PRK. Results. Over the 6-year study period, 1 of 4,876 eyes which had LASIK or PRK at the Moran Eye Center was diagnosed with CSCR. One other patient was referred from an outside center, developed CSCR symptoms one month after PRK. Both patients were managed conservatively with a final visual acuity of 20/20 or better. All other patients presented 4 or more years after refractive surgery. Conclusions. We report the first 2 CSCR cases developing within one month after PRK. The low incidence argues against a causal association. Topical corticosteroids or anxiety may elevate cortisol levels presenting therapeutic challenges for the management of CSCR after PRK or LASIK. PMID- 22518280 TI - Vascular dysfunction as target organ damage in animal models of hypertension. AB - Endothelial dysfunction is one of the main characteristics of chronic hypertension and it is characterized by impaired nitric oxide (NO) bioactivity determined by increased levels of reactive oxygen species. Endothelial function is usually evaluated by measuring the vasodilation induced by the local NO production stimulated by external mechanical or pharmacological agent. These vascular reactivity tests may be carried out in different models of experimental hypertension such as NO-deficient rats, spontaneously hypertensive rats, salt sensitive rats, and many others. Wire myograph and pressurized myograph are the principal methods used for vascular studies. Usually, increasing concentrations of the vasodilator acetylcholine are added in cumulative manner to perform endothelium-dependent concentration-response curves. Analysis of vascular mechanics is relevant to identify arterial stiffness. Both endothelial dysfunction and vascular stiffness have been shown to be associated with increased cardiovascular risk. PMID- 22518279 TI - Novel insights into the vasoprotective role of heme oxygenase-1. AB - Cardiovascular risk factors contribute to enhanced oxidative stress which leads to endothelial dysfunction. These events trigger platelet activation and their interaction with leukocytes and endothelial cells, thus contributing to the induction of chronic inflammatory processes at the vascular wall and to the development of atherosclerotic lesions and atherothrombosis. In this scenario, endogenous antioxidant pathways are induced to restrain the development of vascular disease. In the present paper, we will discuss the role of heme oxygenase (HO)-1 which is an enzyme of the heme catabolism and cleaves heme to form biliverdin and carbon monoxide (CO). Biliverdin is reduced enzymatically to the potent antioxidant bilirubin. Recent evidence supports the involvement of HO 1 in the antioxidant and antiinflammatory effect of cyclooxygenase(COX)-2 dependent prostacyclin in the vasculature. Moreover, the role of HO-1 in estrogen vasoprotection is emerging. Finally, possible strategies to develop novel therapeutics against cardiovascular disease by targeting the induction of HO-1 will be discussed. PMID- 22518281 TI - Renal heme oxygenase-1 induction with hemin augments renal hemodynamics, renal autoregulation, and excretory function. AB - Heme oxygenases (HO-1; HO-2) catalyze conversion of heme to free iron, carbon monoxide, and biliverdin/bilirubin. To determine the effects of renal HO-1 induction on blood pressure and renal function, normal control rats (n = 7) and hemin-treated rats (n = 6) were studied. Renal clearance studies were performed on anesthetized rats to assess renal function; renal blood flow (RBF) was measured using a transonic flow probe placed around the left renal artery. Hemin treatment significantly induced renal HO-1. Mean arterial pressure and heart rate were not different (115 +/- 5 mmHg versus 112 +/- 4 mmHg and 331 +/- 16 versus 346 +/- 10 bpm). However, RBF was significantly higher (9.1 +/- 0.8 versus 7.0 +/ 0.5 mL/min/g, P < 0.05), and renal vascular resistance was significantly lower (13.0 +/- 0.9 versus 16.6 +/- 1.4 [mmHg/(mL/min/g)], P < 0.05). Likewise, glomerular filtration rate was significantly elevated (1.4 +/- 0.2 versus 1.0 +/- 0.1 mL/min/g, P < 0.05), and urine flow and sodium excretion were also higher (18.9 +/- 3.9 versus 8.2 +/- 1.0 MUL/min/g, P < 0.05 and 1.9 +/- 0.6 versus 0.2 +/- 0.1 MUmol/min/g, P < 0.05, resp.). The plateau of the autoregulation relationship was elevated, and renal vascular responses to acute angiotensin II infusion were attenuated in hemin-treated rats reflecting the vasodilatory effect of HO-1 induction. We conclude that renal HO-1 induction augments renal function which may contribute to the antihypertensive effects of HO-1 induction observed in hypertension models. PMID- 22518282 TI - Associations between High-Sensitivity C-Reactive Protein and Membrane Fluidity of Red Blood Cells in Hypertensive Elderly Men: An Electron Spin Resonance Study. AB - Recent evidence indicates that high-sensitivity C-reactive protein (hs-CRP), an acute phase of an inflammatory marker, might be associated with atherosclerosis, hypertension, and other cardiovascular diseases. The present study was performed to assess the possible link between plasma hs-CRP and membrane fluidity (a reciprocal value of membrane microviscosity) in hypertensive elderly men. We measured the membrane fluidity of red blood cells (RBCs) in hypertensive and normotensive elderly men using an electron spin resonance and spin-labeling method. Membrane fluidity of RBCs was decreased in hypertensive elderly men compared with normotensive elderly men. Plasma hs-CRP levels were significantly higher in hypertensive elderly men than in normotensive elderly men. In contrast, plasma nitric-oxide- (NO-) metabolite levels were lower in hypertensive elderly men than in normotensive elderly men. The reduced membrane fluidity of RBCs was associated with increased plasma hs-CRP and decreased plasma NO-metabolite levels. In a multivariate regression analysis, plasma hs-CRP was an independent determinant of membrane fluidity of RBCs after adjustment for general risk factors. The results suggest that CRP might have a close correlation with the rheologic behavior of RBCs and the microcirculation and would contribute, at least in part, to the circulatory dysfunction and vascular complications in hypertensive elderly men. PMID- 22518283 TI - Angiotensin converting enzyme 2, Angiotensin-(1-7), and receptor MAS axis in the kidney. AB - In the past few years the understanding of the renin-angiotensin system (RAS) has improved, helping to better define the role of this system in physiological conditions and in human diseases. Besides Angiotensin (Ang) II, the biological importance of other Ang fragments was progressively evidenced. In this regard, Angiotensin- (Ang-) (1-7) was recognized as a biologically active product of the RAS cascade with a specific receptor, the G-protein-coupled receptor Mas, and that is mainly formed by the action of the angiotensin-converting enzyme (ACE) homolog enzyme, ACE2, which converts Ang II into Ang-(1-7). Taking into account the biological effects of these two mediators, Ang II and Ang-(1-7), the RAS can be envisioned as a dual function system in which the vasoconstrictor/proliferative or vasodilator/antiproliferative actions are primarily driven by the balance between Ang II and Ang-(1-7), respectively. In this paper, we will discuss our current understanding of the ACE2/Ang-(1-7)/Mas axis of the RAS in renal physiology and in the pathogenesis of primary hypertension and chronic kidney disease. PMID- 22518284 TI - Recombinant Expression and Characterization of Human and Murine ACE2: Species Specific Activation of the Alternative Renin-Angiotensin-System. AB - Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase of the renin angiotensin-system (RAS) which is known to cleave several substrates among vasoactive peptides. Its preferred substrate is Angiotensin II, which is tightly involved in the regulation of important physiological functions including fluid homeostasis and blood pressure. Ang 1-7, the main enzymatic product of ACE2, became increasingly important in the literature in recent years, as it was reported to counteract hypertensive and fibrotic actions of Angiotensin II via the MAS receptor. The functional connection of ACE2, Ang 1-7, and the MAS receptor is also referred to as the alternative axis of the RAS. In the present paper, we describe the recombinant expression and purification of human and murine ACE2 (rhACE2 and rmACE2). Furthermore, we determined the conversion rates of rhACE2 and rmACE2 for different natural peptide substrates in plasma samples and discovered species-specific differences in substrate specificities, probably leading to functional differences in the alternative axis of the RAS. In particular, conversion rates of Ang 1-10 to Ang 1-9 were found to be substantially different when applying rhACE2 or rmACE2 in vitro. In contrast to rhACE2, rm ACE2 is substantially less potent in transformation of Ang 1-10 to Ang 1-9. PMID- 22518285 TI - Rumination as a mediator of chronic stress effects on hypertension: a causal model. AB - Chronic stress has been linked to hypertension, but the underlying mechanisms remain poorly specified. We suggest that chronic stress poses a risk for hypertension through repeated occurrence of acute stressors (often stemming from the chronic stress context) that cause activation of stress-mediating physiological systems. Previous models have often focused on the magnitude of the acute physiological response as a risk factor; we attempt to extend this to address the issue of duration of exposure. Key to our model is the notion that these acute stressors can emerge not only in response to stressors present in the environment, but also to mental representations of those (or other) stressors. Consequently, although the experience of any given stressor may be brief, a stressor often results in a constellation of negative cognitions and emotions that form a mental representation of the stressor. Ruminating about this mental representation of the stressful event can cause autonomic activation similar to that observed in response to the original incident, and may occur and persist long after the event itself has ended. Thus, rumination helps explain how chronic stress causes repeated (acute) activation of one's stress-mediating physiological systems, the effects of which accumulate over time, resulting in hypertension risk. PMID- 22518286 TI - Angiotensin-(1-7)-mediated signaling in cardiomyocytes. AB - The Renin-Angiotensin System (RAS) acts at multiple targets and has its synthesis machinery present in different tissues, including the heart. Actually, it is well known that besides Ang II, the RAS has other active peptides. Of particular interest is the heptapeptide Ang-(1-7) that has been shown to exert cardioprotective effects. In this way, great compilations about Ang-(1-7) actions in the heart have been presented in the literature. However, much less information is available concerning the Ang-(1-7) actions directly in cardiomyocytes. In this paper, we show the actual knowledge about Ang-(1-7) mediated signaling in cardiac cells more specifically we provide a brief overview of ACE2/Ang-(1-7)/Mas axis; and highlight the discoveries made in cardiomyocyte physiology through the use of genetic approaches. Finally, we discuss the protective signaling induced by Ang-(1-7) in cardiomyocytes and point molecular determinants of these effects. PMID- 22518287 TI - Current perspectives on the use of meditation to reduce blood pressure. AB - Meditation techniques are increasingly popular practices that may be useful in preventing or reducing elevated blood pressure. We reviewed landmark studies and recent literature concerning the use of meditation for reducing blood pressure in pre-hypertensive and hypertensive individuals. We sought to highlight underlying assumptions, identify strengths and weaknesses of the research, and suggest avenues for further research, reporting of results, and dissemination of findings. Meditation techniques appear to produce small yet meaningful reductions in blood pressure either as monotherapy or in conjunction with traditional pharmacotherapy. Transcendental meditation and mindfulness-based stress reduction may produce clinically significant reductions in systolic and diastolic blood pressure. More randomized clinical trials are necessary before strong recommendations regarding the use of meditation for high BP can be made. PMID- 22518288 TI - Blood pressure in old population. PMID- 22518289 TI - Blood Pressure Reactivity to an Anger Provocation Interview Does Not Predict Incident Cardiovascular Disease Events: The Canadian Nova Scotia Health Survey (NSHS95) Prospective Population Study. AB - We examined the association between blood pressure (BP) reactivity to an anger provocation interview and 10-year incident CVD events in 1,470 adults from the population-based 1995 Nova Scotia Health Survey (NSHS95). In an unadjusted model, those in the highest decile of systolic BP reactivity were more than twice as likely to have an incident CVD event compared to those in the decile with no reactivity (HR = 2.33, 95% CI = 1.15 - 4.69, P = 0.02). However, after adjusting for age and sex, and then also for Framingham risk score, body mass index, and education, this relationship was attenuated and not statistically significant. Diastolic BP reactivity was not associated with CVD incidence in any model. Individual differences in BP reactivity to a laboratory-induced, structured anger provocation interview may not play a major role in clinical CVD endpoints. PMID- 22518290 TI - From Brain to Behavior: Hypertension's Modulation of Cognition and Affect. AB - Accumulating evidence from animal models and human studies of essential hypertension suggest that brain regulation of the vasculature is impacted by the disease. Human neuroimaging findings suggest that the brain may be an early target of the disease. This observation reinforces earlier research suggesting that psychological factors may be one of the many contributory factors to the initiation of the disease. Alternatively or in addition, initial blood pressure increases may impact cognitive and/or affective function. Evidence for an impact of blood pressure on the perception and experience of affect is reviewed vis-a vis brain imaging findings suggesting that such involvement in hypertensive individuals is likely. PMID- 22518291 TI - Magnesium and vascular changes in hypertension. AB - Many factors have been implicated in the pathogenesis of hypertension, including changes in intracellular concentrations of calcium, sodium, potassium, and magnesium. There is a significant inverse correlation between serum magnesium and incidence of cardiovascular diseases. Magnesium is a mineral with important functions in the body such as antiarrhythmic effect, actions in vascular tone, contractility, glucose metabolism, and insulin homeostasis. In addition, lower concentrations of magnesium are associated with oxidative stress, proinflammatory state, endothelial dysfunction, platelet aggregation, insulin resistance, and hyperglycemia. The conflicting results of studies evaluating the effects of magnesium supplements on blood pressure and other cardiovascular outcomes indicate that the action of magnesium in the vascular system is present but not yet established. Therefore, this mineral supplementation is not indicated as part of antihypertensive treatment, and further studies are needed to better clarify the role of magnesium in the prevention and treatment of cardiovascular diseases. PMID- 22518292 TI - Deficiency of ACE2 in Bone-Marrow-Derived Cells Increases Expression of TNF-alpha in Adipose Stromal Cells and Augments Glucose Intolerance in Obese C57BL/6 Mice. AB - Deficiency of ACE2 in macrophages has been suggested to promote the development of an inflammatory M1 macrophage phenotype. We evaluated effects of ACE2 deficiency in bone-marrow-derived stem cells on adipose inflammation and glucose tolerance in C57BL/6 mice fed a high fat (HF) diet. ACE2 activity was increased in the stromal vascular fraction (SVF) isolated from visceral, but not subcutaneous adipose tissue of HF-fed mice. Deficiency of ACE2 in bone marrow cells significantly increased mRNA abundance of F4/80 and TNF-alpha in the SVF isolated from visceral adipose tissue of HF-fed chimeric mice, supporting increased presence of inflammatory macrophages in adipose tissue. Moreover, deficiency of ACE2 in bone marrow cells modestly augmented glucose intolerance in HF-fed chimeric mice and increased blood levels of glycosylated hemoglobin. In summary, ACE2 deficiency in bone marrow cells promotes inflammation in adipose tissue and augments obesity-induced glucose intolerance. PMID- 22518293 TI - Hypertension-Related Gene Polymorphisms of G-Protein-Coupled Receptor Kinase 4 Are Associated with NT-proBNP Concentration in Normotensive Healthy Adults. AB - G protein-coupled receptor kinase 4 (GRK4) with activating polymorphisms desensitize the natriuric renal tubular D1 dopamine receptor, and these GRK4 polymorphisms are strongly associated with salt sensitivity and hypertension. Meanwhile, N-terminal pro-B-type natriuretic peptide (NT-proBNP) may be useful in detecting slight volume expansion. However, relations between hypertension related gene polymorphisms including GRK4 and cardiovascular indices such as NT proBNP are not clear, especially in healthy subjects. Therefore, various hypertension-related polymorphisms and cardiovascular indices were analyzed in 97 normotensive, healthy Japanese adults. NT-proBNP levels were significantly higher in subjects with two or more GRK4 polymorphic alleles. Other hypertension-related gene polymorphisms, such as those of renin-angiotensin-aldosterone system genes, did not correlate with NT-proBNP. There was no significant association between any of the hypertension-related gene polymorphisms and central systolic blood pressure, cardioankle vascular index, augmentation index, plasma aldosterone concentration, or an oxidative stress marker, urinary 8-OHdG. Normotensive individuals with GRK4 polymorphisms show increased serum NT-proBNP concentration and may be at a greater risk of developing hypertension and cardiovascular disease. PMID- 22518294 TI - The Relationship between Multiple Health Behaviours and Brachial Artery Reactivity. AB - Background. The effects of smoking, alcohol consumption, obesity, and a sedentary lifestyle on endothelial function (EF) have only been examined separately. The relative contributions of these behaviours on EF have therefore not been compared. Purpose. To compare the relative associations between these four risk factors and brachial artery reactivity in the same sample. Methods. 328 patients referred for single-photon emission computed tomography (SPECT) exercise stress tests completed a nuclear-medicine-based forearm hyperaemic reactivity test. Self reported exercise behaviour, smoking habits, and alcohol consumption were collected and waist circumference was measured. Results. Adjusting for relevant covariates, logistic regression analyses revealed that waist circumference, abstinence from alcohol, and past smoking significantly predicted poor brachial artery reactivity while physical activity did not. Only waist circumference predicted continuous variations in EF. Conclusions. Central adiposity, alcohol consumption, and smoking habits but not physical activity are each independent predictors of poor brachial artery reactivity in patients with or at high risk for cardiovascular disease. PMID- 22518297 TI - Vasculitis, Atherosclerosis, and Altered HDL Composition in Heme-Oxygenase-1 Knockout Mice. AB - To elucidate roles of heme oxygenase-1 (HO-1) in cardiovascular system, we have analyzed one-year-old HO-1-knockout mice. Homozygous HO-1-knockout mice had severe aortitis and coronary arteritis with mononuclear cellular infiltration and fatty streak formation even on a standard chow diet. Levels of plasma total cholesterol and HDL were similar among the three genotypes. However, homozygous HO-1-knockout mice had lower body weight and plasma triglyceride. HO-1-deficiency resulted in alteration of the composition of HDL. The ratio of apolipoprotein AI to AII in HO-1-knockout mice was reduced about 10-fold as compared to wild-type mice. In addition, paraoxonase, an enzyme against oxidative stress, was reduced less than 50% in HO-1-knockout mice. The knockout mice also exhibited significant elevation of plasma lipid hydroperoxides. This study using aged HO-1-knockout mice strengthened the idea that HO-1 functions to suppress systemic inflammation in artery wall and prevents plasma lipid peroxidation. PMID- 22518296 TI - Oxidative stress and heme oxygenase-1 regulated human mesenchymal stem cells differentiation. AB - This paper describes the effect of increased expression of HO-1 protein and increased levels of HO activity on differentiation of bone-marrow-derived human MSCs. MSCs are multipotent cells that proliferate and differentiate into many different cell types including adipocytes and osteoblasts. HO, the rate-limiting enzyme in heme catabolism, plays an important role during MSCs differentiation. HO catalyzes the stereospecific degradation of heme to biliverdin, with the concurrent release of iron and carbon monoxide. Upregulation of HO-1 expression and increased HO activity are essential for MSC growth and differentiation to the osteoblast lineage consistent with the role of HO-1 in hematopoietic stem cell differentiation. HO-1 participates in the MSC differentiation process shifting the balance of MSC differentiation in favor of the osteoblast lineage by decreasing PPARgamma and increasing osteogenic markers such as alkaline phosphatase and BMP-2. In this paper, we define HO-1 as a target molecule in the modulation of adipogenesis and osteogenesis from MSCs and examine the role of the HO system in diabetes, inflammation, osteoporosis, hypertension, and other pathologies, a burgeoning area of research. PMID- 22518295 TI - Therapeutic potential of heme oxygenase-1/carbon monoxide in lung disease. AB - Heme oxygenase (HO), a catabolic enzyme, provides the rate-limiting step in the oxidative breakdown of heme, to generate carbon monoxide (CO), iron, and biliverdin-IXalpha. Induction of the inducible form, HO-1, in tissues is generally regarded as a protective mechanism. Over the last decade, considerable progress has been made in defining the therapeutic potential of HO-1 in a number of preclinical models of lung tissue injury and disease. Likewise, tissue protective effects of CO, when applied at low concentration, have been observed in many of these models. Recent studies have expanded this concept to include chemical CO-releasing molecules (CORMs). Collectively, salutary effects of the HO 1/CO system have been demonstrated in lung inflammation/acute lung injury, lung and vascular transplantation, sepsis, and pulmonary hypertension models. The beneficial effects of HO-1/CO are conveyed in part through the inhibition or modulation of inflammatory, apoptotic, and proliferative processes. Recent advances, however, suggest that the regulation of autophagy and the preservation of mitochondrial homeostasis may serve as additional candidate mechanisms. Further preclinical and clinical trials are needed to ascertain the therapeutic potential of HO-1/CO in human clinical disease. PMID- 22518298 TI - Induction of hemeoxygenase-1 reduces renal oxidative stress and inflammation in diabetic spontaneously hypertensive rats. AB - The renoprotective mechanisms of hemeoxygenase-1 (HO-1) in diabetic nephropathy remain to be investigated. We hypothesize that HO-1 protects the kidney from diabetic insult via lowering renal oxidative stress and inflammation. We used control and diabetic SHR with or without HO-1 inducer cobalt protoporphyrin (CoPP) treatment for 6 weeks. Urinary albumin excretion levels were significantly elevated in diabetic SHR compared to control and CoPP significantly attenuated albumin excretion. Immuno-histochemical analysis revealed an elevation in TGF beta staining together with increased urinary collagen excretion in diabetic versus control SHR, both of which were reduced with CoPP treatment. Renal oxidative stress markers were greater in diabetic SHR and reduced with CoPP treatment. The increase in renal oxidative stress was associated with an elevation in renal inflammation in diabetic SHR. CoPP treatment also significantly attenuated the markers of renal inflammation in diabetic SHR. In vitro inhibition of HO with stannous mesoporphyrin (SnMP) increased glomerular NADPH oxidase activity and inflammation and blocked the anti-oxidant and anti inflammatory effects of CoPP. These data suggest that the reduction of renal injury in diabetic SHR upon induction of HO-1 are associated with decreased renal oxidative stress and inflammation, implicating the role of HO-1 induction as a future treatment of diabetic nephropathy. PMID- 22518299 TI - AVE0991, a Nonpeptide Compound, Attenuates Angiotensin II-Induced Vascular Smooth Muscle Cell Proliferation via Induction of Heme Oxygenase-1 and Downregulation of p-38 MAPK Phosphorylation. AB - The nonpeptide AVE0991 is an agonist of the angiotensin-(1-7) (Ang-(1-7)) Mas receptor and is expected to be a putative new drug for treatment of cardiovascular disease. However, the mechanisms involved in the antiproliferative effects of AVE0991 are not fully understood. We saw that the compound attenuated proliferation in an angiotensin II-induced rat vascular smooth muscle cells (VSMC) proliferation model. Moreover, treatment with AVE0991 (10(-5) mol/L or 10( 7) mol/L) significantly attenuated reactive oxygen species (ROS) production, phosphorylation of p38 MAPK, and dose-dependently (10(-8) to 10(-5) mol/L) inhibited Ang II-induced VSMC proliferation. Meanwhile, heme oxygenase-1 (HO-1) expression increased in the AVE0991 + Ang II group (10(-5) mol/L or 10(-6) mol/L). However, the beneficial effects of AVE0991 were completely abolished when the VSMC were pretreated with A-779 (10(-6) mol/L). Furthermore, treatment with the HO-1 inhibitor ZnPPIX attenuated the inhibitory effect of AVE0991 on Ang II induced p38MAPK phosphorylation. These results suggest that AVE0991 attenuates Ang II-induced VSMC proliferation in a dose-dependent fashion and that this effect is associated with the Mas/HO-1/p38 MAPK signaling pathway. PMID- 22518300 TI - Targeting policy for obesity prevention: identifying the critical age for weight gain in women. AB - The obesity epidemic requires the development of prevention policy targeting individuals most likely to benefit. We used self-reported prepregnancy body weight of all women giving birth in Nova Scotia between 1988 and 2006 to define obesity and evaluated socioeconomic, demographic, and temporal trends in obesity using linear regression. There were 172,373 deliveries in this cohort of 110,743 women. Maternal body weight increased significantly by 0.5 kg per year from 1988, and lower income and rural residence were both associated significantly with increasing obesity. We estimated an additional 82,000 overweight or obese women in Nova Scotia in 2010, compared to the number that would be expected from obesity rates of just two decades ago. The critical age for weight gain was identified as being between 20 and 24 years. This age group is an important transition age between adolescence and adulthood when individuals first begin to accept responsibility for food planning, purchasing, and preparation. Policy and public health interventions must target those most at risk, namely, younger women and the socially deprived, whilst tackling the marketing of low-cost energy-dense foods at the expense of healthier options. PMID- 22518301 TI - (188)Re-SSS/Lipiodol: Development of a Potential Treatment for HCC from Bench to Bedside. AB - Hepatocellular carcinoma (HCC) is the 5th most common tumour worldwide and has a dark prognosis. For nonoperable cases, metabolic radiotherapy with Lipiodol labelled with beta-emitters is a promising therapeutic option. The Comprehensive Cancer Centre Eugene Marquis and the National Graduate School of Chemistry of Rennes (ENSCR) have jointly developed a stable and efficient labelling of Lipiodol with rhenium-188 (E(betamax) = 2.1 MeV) for the treatment of HCC. The major "milestones" of this development, from the first syntheses to the recent first injection in man, are described. PMID- 22518302 TI - (111)Indium Labelling of Recombinant Activated Coagulation Factor VII: In Vitro and Preliminary In Vivo Studies in Healthy Rats. AB - The aim of this study is to investigate whether (111)Indium-labelled recombinant FVIIa (rFVIIa) could be a potential radiopharmaceutical for localization of bleeding sources. DTPA-conjugated rFVIIa was radiolabelled with (111)In chloride. In vitro binding efficiency of (111)In-DTPA-rFVIIa to F1A2-Mab-sepharose was 99% in buffer, while it was 88-82% in serum. The binding efficiency of (111)In-DTPA rFVIIa to TF (1-209)-sepharose was 48% in buffer whereas 39%-36% in serum, respectively. In vivo experiment was conducted in healthy rats, and gamma camera images were taken immediately after iv. administration of 1.6-1.8 MBq (111)In DTPA-rFVIIa up to 120-130 min. Five min after administration of (111)In-DTPA rFVIIa, percentage of (111)In activity was 6.0% in the cardiac region and 24.5% in the liver region. After 2 hours activity was decreased to 3.3% in heart while it had increased to 42.0% in the liver. The (111)In-DTPA-rFVIIa might be a potential radiopharmaceutical for visualisation of tissues with significant TF expression such as acute bleeding lesions in the gastrointestinal tract. PMID- 22518303 TI - Feasibility evaluation of radioimmunoguided surgery of breast cancer. AB - Breast-conserving surgery involves completely excising the tumour while limiting the amount of normal tissue removed, which is technically challenging to achieve, especially given the limited intraoperative guidance available to the surgeon. This study evaluates the feasibility of radioimmunoguided surgery (RIGS) to guide the detection and delineation of tumours intraoperatively. The 3D point-response function of a commercial gamma-ray-detecting probe (GDP) was determined as a function of radionuclide ((131)I, (111)In,( 99m)Tc), energy-window threshold, and collimator length (0.0-3.0-cm). This function was used to calculate the minimum detectable tumour volumes (MDTVs) and the minimum tumour-to-background activity concentration ratio (T:B) for effective delineation of a breast tumour model. The GDP had larger MDTVs and a higher minimum required T:B for tumour delineation with (131)I than with (111)In or (99m)Tc. It was shown that for (111)In there was a benefit to using a collimator length of 0.5-cm. For the model used, the minimum required T:B required for effective tumour delineation was 5.2 +/- 0.4. RIGS has the potential to significantly improve the accuracy of breast-conserving surgery; however, before these benefits can be realized, novel radiopharmaceuticals need to be developed that have a higher specificity for cancerous tissue in vivo than what is currently available. PMID- 22518304 TI - The health of people with intellectual disability. PMID- 22518305 TI - Equity of access to quality of care in family medicine. PMID- 22518306 TI - Effects of self-empowered teams on rates of adverse drug events in primary care. AB - Background. Most safety issues in primary care arise from adverse drug events. Team Resource Management intervention was developed to identify systemic safety issues to design and implement interventions to address prioritized issues. Objectives. Evaluate impact of intervention on rates of events and preventable events in a vulnerable population. Design. Cluster randomized trial. 12 practices randomly assigned to either: (1) Intervention; (2) Intervention with Practice Enhancement Assistants; (3) No intervention. The intervention took 12 months. Main Outcome Measure. Rate and severity of events and preventable events measured using a Trigger Tool chart review method for the 12-month periods before and after the start of the intervention. Results. In the ''intervention with Assistants" group there was a statistically significant decrease in the overall rate of events and in the rate of moderate/severe events. Analysis of Variance with study arm and time as the factors and moderate/severe events as the outcome showed a significant interaction between arm and time supporting the notion that the ''Intervention with Assistants" practices had a greater reduction in moderate/severe preventable events. Conclusions. The intervention had a significant effect on medication safety as estimated using a trigger tool. Further exploration of role of Assistants and trigger tool is warranted. PMID- 22518307 TI - The CDM-Net Project: The Development, Implementation and Evaluation of a Broadband-Based Network for Managing Chronic Disease. AB - Background. In Australia most chronic disease management is funded by Medicare Australia through General Practitioner Management Plans (GPMPs) and Team Care Arrangements (TCAs). Identified barriers may be reduced effectively using a broadband-based network known as the Chronic Disease Management Service (CDMS). Aims. To measure the uptake and adherence to CDMS, test CDMS, and assess the adherence of health providers and patients to GPMPs and TCAs generated through CDMS. Methods. A single cohort before and after study. Results. GPMPs and TCAs increased. There was no change to prescribed medicines or psychological quality of life. Attendance at allied health professionals increased, but decreased at pharmacies. Overall satisfaction with CDMS was high among GPs, allied health professionals, and patients. Conclusion. This study demonstrates proof of concept, but replication or continuation of the study is desirable to enable the impact of CDMS on diabetes outcomes to be determined. PMID- 22518309 TI - The Phosphorus and the Vascular Calcification in ESRD between Old Adventures and New Horizons. PMID- 22518308 TI - Factors That Influence HIV Risk among Hispanic Female Immigrants and Their Implications for HIV Prevention Interventions. AB - Hispanics are the fastest growing minority group in North Carolina with increasing incidence of HIV infection. Gender roles, cultural expectations, and acculturation of women may explain some of Hispanic women's risks. The perspectives of Hispanic female immigrants and community-based providers were sought to identify services they offer, understand HIV risk factors, and support the adaptation of a best-evidence HIV behavioural intervention for Hispanic women. Two sets of focus groups were conducted to explicate risks and the opportunities to reach women or couples and the feasibility to conduct HIV prevention in an acceptable manner. Salient findings were that Hispanic female immigrants lacked accurate HIV/AIDS and STI knowledge and that traditional gender roles shaped issues surrounding sexual behaviour and HIV risks, as well as condom use, partner communication, and multiple sexual partnerships. Intervention implications are discussed such as developing and adapting culturally appropriate HIV prevention interventions for Hispanics that address gender roles and partner communication. PMID- 22518310 TI - Minimizing hemodialysis catheter dysfunction: an ounce of prevention. AB - The maintenance of tunneled catheter (TC) patency is critical for the provision of adequate hemodialysis in patients who are TC-dependent. TC dysfunction results in the need for costly and inconvenient interventions, and reduced quality of life. Since the introduction of TCs in the late 1980s, heparin catheter lock has been the standard prophylactic regimen for the prevention of TC dysfunction. More recently, alternative catheter locking agents have emerged, and in some cases have shown to be superior to heparin lock with respect to improving TC patency and reducing TC-associated infections. These include citrate, tissue plasminogen activator, and a novel agent containing sodium citrate, methylene blue, methylparaben, and propylparaben. In addition, prophylaxis using oral anticoagulants/antiplatelet agents, including warfarin, aspirin, ticlodipine, as well as the use of modified heparin-coated catheters have also been studied for the prevention of TC dysfunction with variable results. The use of oral anticoagulants and/or antiplatelet agents as primary or secondary prevention of TC dysfunction must be weighed against their potential adverse effects, and should be individualized for each patient. PMID- 22518312 TI - Calcific uremic arteriolopathy on multimodal combination therapy: still unmet goal. AB - Background. Calcific uremic arteriolopathy (CUA) or calciphylaxis though generally noted for its high mortality, recent case reports have shown promising results using single agent therapies. However, it is not clear whether combination therapeutic agents will improve course of the disease. Objective. To determine clinical outcome in subjects with CUA on multimodal treatment. Methods. All patients with end-stage renal failure (ESRF) at The Townsville Hospital, Australia, from April 1, 2006, to March 31, 2011, with diagnosis of CUA were retrospectively studied. Results. Six subjects with CUA (4 females and 2 males) were on various combination therapeutic agents comprising sodium thiosulphate, hyperbaric oxygen, prednisolone, cinacalcet, and parathyroidectomy in addition to intensified haemodialysis, specialist local wound care, and antibiotics. The wounds failed to heal in 3 patients while 5 of the 6 subjects died; cause of death being sepsis in 3 and myocardial infarction in 2. Conclusion. Prognosis of CUA remains poor in spite of multimodal combination therapy. Further prospective studies on a larger population are needed to verify our findings. PMID- 22518313 TI - Impact of hemodialysis catheter dysfunction on dialysis and other medical services: an observational cohort study. AB - Practice guidelines define hemodialysis catheter dysfunction as blood flow rate (BFR) <300 mL/min. We conducted a study using data from DaVita and the United States Renal Data System to evaluate the impact of catheter dysfunction on dialysis and other medical services. Patients were included if they had >=8 consecutive weeks of catheter dialysis between 8/2004 and 12/2006. Actual BFR <300 mL/min despite planned BFR >=300 mL/min was used to define catheter dysfunction during each dialysis session. Among 9,707 patients, the average age was 62,53% were female, and 40% were black. The median duration of catheter dialysis was 190 days, and the cohort accounted for 1,075,701 catheter dialysis sessions. There were 70,361 sessions with catheter dysfunction, and 6,33 1 (65.2%) patients had at least one session with catheter dysfunction. In multivariate repeated measures analysis, catheter dysfunction was associated with increased odds of missing a dialysis session due to access problems (Odds ratio [OR] 2.50; P < 0.001), having an access-related procedure (OR 2.10; P < 0.001), and being hospitalized (OR 1.10; P = 0.001). Catheter dysfunction defined according to NKF vascular access guidelines results in disruptions of dialysis treatment and increased use of other medical services. PMID- 22518314 TI - The effects of fetal gender on serum human chorionic gonadotropin and testosterone in normotensive and preeclamptic pregnancies. AB - INTRODUCTION: The aim of the present study was to evaluate the effects of fetal sex on serum human chorionic gonadotropin (hCG) and testosterone in normotensive and preeclamptic pregnancies. MATERIALS AND METHODS: This is a cross-sectional study and 139 women with singleton pregnancies in the third trimester were studied. Seventy-one pregnancies were uncomplicated; among those were 35 male and 36 female fetuses. Sixty-eight pregnancies were complicated by preeclampsia; among those were 35 male and 33 female fetuses. Human chorionic gonadotropin and total testosterone were measured in maternal peripheral blood. Data analyzed by SPSS software. RESULTS: In male-bearing pregnancies, maternal hCG and testosterone serum levels were significantly higher in preeclamptic than normotensive mothers (P < 0.001 and P < 0.001, resp.) in female-bearing pregnancies testosterone levels were significantly higher in preeclamptic than normotensive mothers (P < 0.001). Total testosterone levels were significantly higher in pregnancies with either gender and significantly higher in mlae-bearing than in female-bearing pregnancies. CONCLUSION: According to our results, there is a correlation between maternal serum hCG and testosterone levels and preeclampsia. Therefore these tests can be used as routine during 30-38 weeks of gestation. High maternal serum concentrations of these markers can predict preeclampsia. PMID- 22518311 TI - Reactive Oxygen Species Modulation of Na/K-ATPase Regulates Fibrosis and Renal Proximal Tubular Sodium Handling. AB - The Na/K-ATPase is the primary force regulating renal sodium handling and plays a key role in both ion homeostasis and blood pressure regulation. Recently, cardiotonic steroids (CTS)-mediated Na/K-ATPase signaling has been shown to regulate fibrosis, renal proximal tubule (RPT) sodium reabsorption, and experimental Dahl salt-sensitive hypertension in response to a high-salt diet. Reactive oxygen species (ROS) are an important modulator of nephron ion transport. As there is limited knowledge regarding the role of ROS-mediated fibrosis and RPT sodium reabsorption through the Na/K-ATPase, the focus of this review is to examine the possible role of ROS in the regulation of Na/K-ATPase activity, its signaling, fibrosis, and RPT sodium reabsorption. PMID- 22518315 TI - Elevated serum C-reactive protein and markers of sleep disordered breathing. AB - Background. Previous studies indicated sleep-disordered breathing (SDB) is associated with cardiovascular disease (CVD). Systemic inflammation is recognized as a risk factor for CVD. Studies examining SDB and inflammation are limited. Methods. We studied sleep duration, snoring, snorting, and daytime sleepiness, and an additive SDB score. The main outcome was a C-reactive protein (CRP) of >1 mg/dL. Results. Snoring, snorting, daytime sleepiness, and sleeping >7 or <7 hours, and the additive score were significantly associated with high CRP. The additive score was not associated in men but moderately associated in women in a multivariable model adjusting for age, gender, race/ethnicity, education, smoking, hypertension, alcohol intake, physical activity, body mass index, depression, diabetes, hypertension, and total cholesterol (P-interaction = 0.42). For race/ethnicity, the association was strongest in Mexican Americans/others, modest in Non-Hispanic whites, and absent in Non-Hispanic blacks (P-interaction = 0.07). Conclusions. The association between SDB and high CRP was present mainly in women and Mexican Americans, implying SDB has a residual, independent association with inflammation after controlling for lifestyle and metabolic risk factors like BMI, physical activity, depression, diabetes, and cholesterol. PMID- 22518316 TI - Microfabricated engineered particle systems for respiratory drug delivery and other pharmaceutical applications. AB - Particle Replication in Non-Wetting Templates (PRINT((r))) is a platform particle drug delivery technology that coopts the precision and nanoscale spatial resolution inherently afforded by lithographic techniques derived from the microelectronics industry to produce precisely engineered particles. We describe the utility of PRINT technology as a strategy for formulation and delivery of small molecule and biologic therapeutics, highlighting previous studies where particle size, shape, and chemistry have been used to enhance systemic particle distribution properties. In addition, we introduce the application of PRINT technology towards respiratory drug delivery, a particular interest due to the pharmaceutical need for increased control over dry powder characteristics to improve drug delivery and therapeutic indices. To this end, we have produced dry powder particles with micro- and nanoscale geometric features and composed of small molecule and protein therapeutics. Aerosols generated from these particles show attractive properties for efficient pulmonary delivery and differential respiratory deposition characteristics based on particle geometry. This work highlights the advantages of adopting proven microfabrication techniques in achieving unprecedented control over particle geometric design for drug delivery. PMID- 22518317 TI - A versatile polymer micelle drug delivery system for encapsulation and in vivo stabilization of hydrophobic anticancer drugs. AB - Chemotherapeutic drugs are widely used for the treatment of cancer; however, use of these drugs is often associated with patient toxicity and poor tumor delivery. Micellar drug carriers offer a promising approach for formulating and achieving improved delivery of hydrophobic chemotherapeutic drugs; however, conventional micelles do not have long-term stability in complex biological environments such as plasma. To address this problem, a novel triblock copolymer has been developed to encapsulate several different hydrophobic drugs into stable polymer micelles. These micelles have been engineered to be stable at low concentrations even in complex biological fluids, and to release cargo in response to low pH environments, such as in the tumor microenvironment or in tumor cell endosomes. The particle sizes of drugs encapsulated ranged between 30-80 nm, with no relationship to the hydrophobicity of the drug. Stabilization of the micelles below the critical micelle concentration was demonstrated using a pH-reversible crosslinking mechanism, with proof-of-concept demonstrated in both in vitro and in vivo models. Described herein is polymer micelle drug delivery system that enables encapsulation and stabilization of a wide variety of chemotherapeutic drugs in a single platform. PMID- 22518318 TI - Treatment of liver metastases in patients with neuroendocrine tumors of gastroesophageal and pancreatic origin. AB - Well-to-moderately differentiated neuroendocrine tumors of gastroesophageal and pancreatic origin (GEP-NETs) with liver metastasis are a heterogeneous group of malignancies for which a range of therapeutic options have been employed. Surgical resection of hepatic metastases or hepatic artery embolization may be beneficial in patients with hepatic-predominant metastatic disease. Patients with "carcinoid" syndrome and syndromes associated with functional pancreatic NET (PNET) can be effectively treated with somatostatin analogs. On the other hand, the efficacy of systemic chemotherapy for these patients is limited. A placebo controlled, double-blind, prospective, and randomized study showed that octreotide LAR improves progression-free survival in patients with advanced midgut functional "carcinoids." In patients with advanced pancreatic NET, randomized, placebo-controlled studies have recently demonstrated that treatment with the tyrosine kinase inhibitor sunitinib or with mTOR inhibitor everolimus is associated with improved progression-free survival. Based on these studies, octreotide LAR, sunitinib, or everolimus are now considered as first-line therapeutic options in patients with advanced NET. Future studies will likely further define the role of these agents in patients with carcinoid liver metastasis and pancreatic NET liver metastasis. PMID- 22518319 TI - Flow injection/sequential injection analysis systems: potential use as tools for rapid liver diseases biomarker study. AB - Flow injection/sequential injection analysis (FIA/SIA) systems are suitable for carrying out automatic wet chemical/biochemical reactions with reduced volume and time consumption. Various parts of the system such as pump, valve, and reactor may be built or adapted from available materials. Therefore the systems can be at lower cost as compared to other instrumentation-based analysis systems. Their applications for determination of biomarkers for liver diseases have been demonstrated in various formats of operation but only a few and limited types of biomarkers have been used as model analytes. This paper summarizes these applications for different types of reactions as a guide for using flow-based systems in more biomarker and/or multibiomarker studies. PMID- 22518320 TI - Potential Antioxidant Role of Tridham in Managing Oxidative Stress against Aflatoxin-B(1)-Induced Experimental Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most fatal cancers due to delayed diagnosis and lack of effective treatment options. Significant exposure to Aflatoxin B(1) (AFB(1)), a potent hepatotoxic and hepatocarcinogenic mycotoxin, plays a major role in liver carcinogenesis through oxidative tissue damage and p53 mutation. The present study emphasizes the anticarcinogenic effect of Tridham (TD), a polyherbal traditional medicine, on AFB(1)-induced HCC in male Wistar rats. AFB(1)-administered HCC-bearing rats (Group II) showed increased levels of lipid peroxides (LPOs), thiobarbituric acid substances (TBARs), and protein carbonyls (PCOs) and decreased levels of enzymic and nonenzymic antioxidants when compared to control animals (Group I). Administration of TD orally (300 mg/kg body weight/day) for 45 days to HCC-bearing animals (Group III) significantly reduced the tissue damage accompanied by restoration of the levels of antioxidants. Histological observation confirmed the induction of tumour in Group II animals and complete regression of tumour in Group III animals. This study highlights the potent antioxidant properties of TD which contribute to its therapeutic effect in AFB(1)-induced HCC in rats. PMID- 22518321 TI - MicroRNA Signature in Alcoholic Liver Disease. AB - Alcoholic liver disease (ALD) is a major global health problem. Chronic alcohol use results in inflammation and fatty liver, and in some cases, it leads to fibrosis and cirrhosis or hepatocellular carcinoma. Increased proinflammatory cytokines, particularly TNF alpha, play a central role in the pathogenesis of ALD. TNF alpha is tightly regulated at transcriptional and posttranscriptional levels. Recently, microRNAs (miRNAs) have been shown to modulate gene functions. The role of miRNAs in ALD is getting attention, and recent studies suggest that alcohol modulates miRNAs. Recently, we showed that alcohol induces miR-155 expression both in vitro (RAW 264.7 macrophage) and in vivo (Kupffer cells, KCs of alcohol-fed mice). Induction of miR-155 contributed to increased TNF alpha production and to the sensitization of KCs to produce more TNF alpha in response to LPS. In this paper, we summarize the current knowledge of miRNAs in ALD and also report increased expression of miR-155 and miR-132 in the total liver as well as in isolated hepatocytes and KCs of alcohol-fed mice. Our novel finding of the alcohol-induced increase of miRNAs in hepatocytes and KCs after alcohol feeding provides further insight into the evolving knowledge regarding the role of miRNAs in ALD. PMID- 22518322 TI - Treatment of liver metastases in patients with neuroendocrine tumors. PMID- 22518324 TI - Cyanamide potentiates the ethanol-induced impairment of receptor-mediated endocytosis in a recombinant hepatic cell line expressing alcohol dehydrogenase activity. AB - Ethanol administration has been shown to alter receptor-mediated endocytosis in the liver. We have developed a recombinant hepatic cell line stably transfected with murine alcohol dehydrogenase cDNA to serve as an in vitro model to investigate these ethanol-induced impairments. In the present study, transfected cells were maintained in the absence or presence of 25 mM ethanol for 7 days, and alterations in endocytosis by the asialoglycoprotein receptor were determined. The role of acetaldehyde in this dysfunction was also examined by inclusion of the aldehyde dehydrogenase inhibitor, cyanamide. Our results showed that ethanol metabolism impaired internalization of asialoorosomucoid, a ligand for the asialoglycoprotein receptor. The addition of cyanamide potentiated the ethanol induced defect in internalization and also impaired degradation of the ligand in the presence of ethanol. These results indicate that the ethanol-induced impairment in endocytosis is exacerbated by the inhibition of aldehyde dehydrogenase, suggesting the involvement of acetaldehyde in this dysfunction. PMID- 22518325 TI - Usefulness of the core outcome measures index in daily clinical practice for assessing patients with degenerative lumbar disease. AB - Introduction. Outcome evaluation is an important aspect of the treatment of patients with degenerative lumbar disease. We evaluated the usefulness of the Core Outcome Measures Index (COMI) in assessing people affected by degenerative lumbar disease in daily clinical practice. Methods. We evaluated 221 patients who had completed preoperatively and 2 years after surgery VAS pain, Short Form-36 (SF-36), Oswestry Disability Index (ODI) and COMI. We calculated the change of scores and its sensitivity to change. The internal consistency of the COMI items and the correlation between the COMI scores and the scores of the other measurements were assessed. Results. Statistically significant differences were observed between the mean scores of the preoperative and 2 years questionnaires for nearly all measurements. COMI showed a good internal consistency, except for the preoperative pain subscale. The sensitivity to change was high for the total COMI and its pain and well-being subscales and moderate for the rest. The COMI demonstrated strong correlation with the other measurements. Conclusions. The COMI is a useful tool for assessing the patient-based outcome in the studied population. Given its simplicity, good correlation with the SF-36 and ODI and its good sensitivity to change, it could replace more cumbersome instruments in daily clinical practice. PMID- 22518323 TI - A multimodal approach to the management of neuroendocrine tumour liver metastases. AB - Neuroendocrine tumours (NETs) are often indolent malignancies that commonly present with metastatic disease in the liver. Surgical, locoregional, and systemic treatment modalities are reviewed. A multidisciplinary approach to patient care is suggested to ensure all therapeutic options explored. PMID- 22518326 TI - Risk factors at birth for permanent obstetric brachial plexus injury and associated osseous deformities. AB - Purpose. To examine the most prevalent risk factors found in patients with permanent obstetric brachial plexus injury (OBPI) to identify better predictors of injury. Methods. A population-based study was performed on 241 OBPI patients who underwent surgical treatment at the Texas Nerve and Paralysis Institute. Results. Shoulder dystocia (97%) was the most prevalent risk factor. We found that 80% of the patients in this study were not macrosomic, and 43% weighed less than 4000 g at birth. The rate of instrument use was 41% , which is 4-fold higher than the 10% predicted for all vaginal deliveries in the United States. Posterior subluxation and glenoid version measurements in children with no finger movement at birth indicated a less severe shoulder deformity in comparison with those with finger movement. Conclusions. The average birth weight in this study was indistinguishable from the average birth weight reported for all brachial plexus injuries. Higher birth weight does not, therefore, affect the prognosis of brachial plexus injury. We found forceps/vacuum delivery to be an independent risk factor for OBPI, regardless of birth weight. Permanently injured patients with finger movement at birth develop more severe bony deformities of the shoulder than patients without finger movement. PMID- 22518327 TI - Strain echocardiography in early detection of Doxorubicin-induced left ventricular dysfunction in children with acute lymphoblastic leukemia. AB - Objective. To investigate the ability of two-dimensional longitudinal strain echocardiography (2DST), to detect the early doxorubicin cardiotoxicity. Patients and Methods. The study included 25 children with newly diagnosed acute lymphoblastic leukemia (ALL) aged 5-15 years and 30 healthy control children. They had echocardiographic examination with conventional 2-dimensional (2D), pulsed tissue Doppler (PTD), and 2DST echocardiography before and within 1 week after doxorubicin treatment. Results. There was no significant difference in left ventricle (LV) systolic and diastolic functions measured by conventional 2-D and PTD echocardiography between patients and controls. However, there was significant decrease in LV global and peak systolic strain detected by 2-DST echocardiography in study group than control. After doxorubicin treatment, there was no significant difference in LV systolic and diastolic functions measured by conventional 2-D and PTD echocardiography than before treatment except for prolonged IVCT and IVRT, but LV global and peak systolic strain was significantly lower after treatment. Conclusion. 2-D longitudinal strain echocardiography was more sensitive than conventional 2-D and PTD in detecting the early LV doxorubicin-induced cardiotoxicity in children with ALL. PMID- 22518328 TI - Neonatal deaths in rural southern Tanzania: care-seeking and causes of death. AB - Introduction. We report cause of death and care-seeking prior to death in neonates based on interviews with relatives using a Verbal Autopsy questionnaire. Materials and Methods. We identified neonatal deaths between 2004 and 2007 through a large household survey in 2007 in five rural districts of southern Tanzania. Results. Of the 300 reported deaths that were sampled, the Verbal Autopsy (VA) interview suggested that 11 were 28 days or older at death and 65 were stillbirths. Data was missing for 5 of the reported deaths. Of the remaining 219 confirmed neonatal deaths, the most common causes were prematurity (33%), birth asphyxia (22%) and infections (10%). Amongst the deaths, 41% (90/219) were on the first day and a further 20% (43/219) on day 2 and 3. The quantitative results matched the qualitative findings. The majority of births were at home and attended by unskilled assistants. Conclusion. Caregivers of neonates born in health facility were more likely to seek care for problems than caregivers of neonates born at home. Efforts to increase awareness of the importance of early care-seeking for a premature or sick neonate are likely to be important for improving neonatal health. PMID- 22518329 TI - High-Dose Therapy and Autologous Hematopoietic Progenitor Cells Transplantation for Recurrent or Refractory Hodgkin's Lymphoma: Analysis of King Hussein Cancer Center Results and Prognostic Variables. AB - Purpose. to evaluate the outcome of patients with Hodgkin's lymphoma who underwent autologous transplantation at KHCC bone marrow transplant program. Patients and Methods. Over 6 years, 63 patients with relapsed or refractory Hodgkin's lymphoma underwent high dose chemotherapy followed by autologous transplant. There were 25.4% patients in complete remission (CR), 71.4% with chemotherapy responsive disease at the time of transplant. Prior to conditioning regimen, 56% received two chemotherapy lines, and, 44% received more than two lines. Results. The main outcomes of the study are the rate of complete remission at day 100, overall survival (OS), relapse-free survival (RFS), The impact of the following variables on OS and RFS: (a) disease status at the time of transplant, (b) number of chemotherapy lines prior to conditioning, (c) age group, (d) time of relapse < or >12 months were investigated. The CR at day 100 was 57%. The median overall survival for the whole group was 40.6 months; the median RFS was 20 months. The only factor which significantly impacts the study outcomes was the number of chemotherapy lines prior to conditioning on OS in favor of patients received two lines. Conclusion. In our study only the number of chemotherapy lines received before conditioning had statistically significant impact on OS. PMID- 22518330 TI - Nutrition support for head and neck squamous cell carcinoma patients treated with chemoradiotherapy: how often and how long? AB - Background. Oral intake of many patients with locally advanced head and neck cancer (LAHNC) decrease during chemoradiotherapy (CRT). Although prophylactic percutaneous endoscopic gastrostomy (PEG) is recommended, not a few patients complete CRT without using PEG tube. Patients and Methods. The subjects were patients with LAHNC who received CRT. We retrospectively investigated the incidence and duration of nutritional support during and after CRT, and predicting factors of nutritional support. For patients who required nutritional support, we also checked the day of initiation and the duration of nutritional support. Results. Of 53 patients, 29 patients (55%) required nutritional support during and/or after CRT. While no clear relation between requirement of nutritional support and variables including age, T stage, N stage, clinical stage and chemotherapy regimen, there could be some relationships between tumor primary sites and the requirement and duration of nutritional support. 17 (77%) of 22 patients with oropharynx cancer(OP) required nutritional support and prolonged for 4.4 months, and 11 (46%) of 24 patients with hypopharynx cancer(HP) required nutritional support and prolonged for 21.9 months. Conclusion. Nutritional support is indicated many HNC patients treated with CRT and primary sites may have some relation to its indication and duration. PMID- 22518331 TI - Prognostic Biomarkers and EBV Infection Research in Diffuse Large B-Cell Lymphoma of the Palatine Tonsils. AB - Diffuse large B-cell lymphoma represents approximately 30%-40% of all diagnoses of non-Hodgkin's Lymphoma and may represent up to 80% of all lymphomas that arise in the palatine tonsils. Several studies have attempted to correlate clinical, laboratorial, and tissue factors with the prognosis of the lymphomas, such as the International Prognostic Index, the tissue expression of some proteins, and the lymphocyte count at the time of diagnosis, as well as to correlate Epstein-Barr virus (EBV) infection with worse prognoses. Patients with palatine tonsil DLBCL, from Salvador, Bahia, Brazil, were studied in order to identify prognostic factors. Twenty-four patients with DLBCL were studied. The factors that negatively influenced the patients' survival rates were the lymphocyte count at the time of diagnosis <1.000/mm(3) and the Bcl-2 protein expression. There was no CD5 expression in these lymphomas, and neither was there an association with EBV infection. PMID- 22518332 TI - Comparative analyses of homocitrate synthase genes of ascomycetous yeasts. AB - Most ascomycetous yeasts have 2 homocitrate synthases (HCSs). Among the fungal lysine biosynthesis-related genes, only the HCS gene was duplicated in the course of evolution. It was recently reported that HCS of Saccharomyces cerevisiae has an additional function in nuclear activities involving chromatin regulation related to DNA damage repair, which is not related to lysine biosynthesis. Thus, it is possible that the bifunctionality is associated with HCS gene duplication. Phylogenetic analysis showed that duplication has occurred multiple times during evolution of the ascomycetous yeasts. It is likely that the HCS gene duplication in S. cerevisiae occurred in the course of Saccharomyces evolution. Although the nucleosome position profiles of the two S. cerevisiae HCS genes were similar in the coding regions, they were different in the promoter regions, suggesting that they are subject to different regulatory controls. S. cerevisiae has maintained HCS activity for lysine biosynthesis and has obtained bifunctionality. PMID- 22518333 TI - DNA Barcoding and Molecular Phylogeny of Drosophila lini and Its Sibling Species. AB - Drosophila lini and its two sibling species, D. ohnishii and D. ogumai, are hardly distinguishable from one another in morphology. These species are more or less reproductively isolated. The mitochondrial ND2 and COI-COII and the nuclear ITS1-ITS2 regions were sequenced to seek for the possibility of DNA barcoding and to reconstruct the phylogeny of them. The character-based approach for DNA barcoding detected some diagnostic nucleotides only for monophyletic D. ogumai, but no informative sites for the other two very closely species, D. lini and D. ohnishii, of which strains intermingled in the molecular phylogenetic trees. Thus, this study provides another case of limited applicability of DNA barcoding in species delineation, as in other cases of related Drosophila species. The molecular phylogenetic tree inferred from the concatenated sequences strongly supported the monophyly of the cluster of the three species, that is, the lini clade. We propose some hypotheses of evolutionary events in this clade. PMID- 22518334 TI - Postzygotic Isolation Evolves before Prezygotic Isolation between Fresh and Saltwater Populations of the Rainwater Killifish, Lucania parva. AB - Divergent natural selection has the potential to drive the evolution of reproductive isolation. The euryhaline killifish Lucania parva has stable populations in both fresh water and salt water. Lucania parva and its sister species, the freshwater L. goodei, are isolated by both prezygotic and postzygotic barriers. To further test whether adaptation to salinity has led to the evolution of these isolating barriers, we tested for incipient reproductive isolation within L. parva by crossing freshwater and saltwater populations. We found no evidence for prezygotic isolation, but reduced hybrid survival indicated that postzygotic isolation existed between L. parva populations. Therefore, postzygotic isolation evolved before prezygotic isolation in these ecologically divergent populations. Previous work on these species raised eggs with methylene blue, which acts as a fungicide. We found this fungicide distorts the pattern of postzygotic isolation by increasing fresh water survival in L. parva, masking species/population differences, and underestimating hybrid inviability. PMID- 22518335 TI - Evolutionary Implications of Mechanistic Models of TE-Mediated Hybrid Incompatibility. AB - New models of TE repression in plants (specifically Arabidopsis) have suggested specific mechanisms by which TE misregulation in hybrids might result in the expression of hybrid inviability. If true, these models suggest as yet undescribed consequences for (1) mechanistic connections between hybrid problems expressed at different postzygotic stages (e.g., inviability versus sterility), (2) the predicted strength, stage, and direction of isolation between diverging lineages that differ in TE activity, and (3) the association between species attributes that influence TE dynamics (e.g., mode of reproduction, geographical structure) and the rate at which they could accumulate incompatibilities. In this paper, we explore these implications and outline future empirical directions for generating data necessary to evaluate them. PMID- 22518337 TI - Pancreatic Perfusion CT in Early Stage of Severe Acute Pancreatitis. AB - Early intensive care for severe acute pancreatitis is essential for improving SAP mortality rates. However, intensive therapies for SAP are often delayed because there is no ideal way to accurately evaluate severity in the early stages. Currently, perfusion CT has been shown useful to predict prognosis of SAP in the early stage. In this presented paper, we would like to review the clinical usefulness and limitations of perfusion CT for evaluation of local and systemic complications in early stage of SAP. PMID- 22518339 TI - Support of the laboratory in the diagnosis of fungal ocular infections. AB - This is a retrospective, and descriptive study about the support that the laboratory of microbiology aids can provide in the diagnosis of ocular infections in patients whom were attended a tertiary-care hospital in Mexico City in a 10 year-time period. We describe the microbiological diagnosis in palpebral mycose; in keratitis caused by Fusarium, Aspergillus, Candida, and melanized fungi; endophthalmitis; one Histoplasma scleritis and one mucormycosis. Nowadays, ocular fungal infections are more often diagnosed, because there is more clinical suspicion and there are easy laboratory confirmations. Correct diagnosis is important because an early medical treatment gives a better prognosis for visual acuity. In some cases, fungal infections are misdiagnosed and the antifungal treatment is delayed. PMID- 22518338 TI - Cataract surgery in uveitis. AB - Cataract surgery in uveitic eyes is often challenging and can result in intraoperative and postoperative complications. Most uveitic patients enjoy good vision despite potentially sight-threatening complications, including cataract development. In those patients who develop cataracts, successful surgery stems from educated patient selection, careful surgical technique, and aggressive preoperative and postoperative control of inflammation. With improved understanding of the disease processes, pre- and perioperative control of inflammation, modern surgical techniques, availability of biocompatible intraocular lens material and design, surgical experience in performing complicated cataract surgeries, and efficient management of postoperative complications have led to much better outcome. Preoperative factors include proper patient selection and counseling and preoperative control of inflammation. Meticulous and careful cataract surgery in uveitic cataract is essential in optimizing the postoperative outcome. Management of postoperative complications, especially inflammation and glaucoma, earlier rather than later, has also contributed to improved outcomes. This manuscript is review of the existing literature and highlights the management pearls in tackling complicated cataract based on medline search of literature and experience of the authors. PMID- 22518340 TI - Development of an inflammation-associated colorectal cancer model and its application for research on carcinogenesis and chemoprevention. AB - Chronic inflammation is a well-recognized risk factor for development of human cancer in several tissues, including large bowel. Inflammatory bowel disease, including ulcerative colitis and Crohn's disease, is a longstanding inflammatory disease of intestine with increased risk for colorectal cancer development. Several molecular events involved in chronic inflammatory process may contribute to multistep carcinogenesis of human colorectal cancer in the inflamed colon. They include overproduction of reactive oxygen and nitrogen species, overproduction and upregulation of productions and enzymes of arachidonic acid biosynthesis pathway and cytokines, and intestinal immune system dysfunction. In this paper, I will describe several methods to induce colorectal neoplasm in the inflamed colon. First, I will introduce a protocol of a novel inflammation associated colon carcinogenesis in mice. In addition, powerful tumor promotion/progression activity of dextran sodium sulfate in the large bowel of Apc(Min/+) mice will be described. Finally, chemoprevention of inflammation associated colon carcinogenesis will be mentioned. PMID- 22518336 TI - Carbohydrate Elimination or Adaptation Diet for Symptoms of Intestinal Discomfort in IBD: Rationales for "Gibsons' Conundrum". AB - THERAPEUTIC USE OF CARBOHYDRATES IN INFLAMMATORY BOWEL DISEASES (IBDS) IS DISCUSSED FROM TWO THEORETICAL, APPARENT DIAMETRICALLY OPPOSITE PERSPECTIVES: regular ingestion of prebiotics or withdrawal of virtually all carbohydrate components. Pathogenesis of IBD is discussed connecting microbial flora, host immunity, and genetic interactions. The best studied genetic example, NOD2 in Crohn's disease, is highlighted as a model which encompasses these interactions and has been shown to depend on butyrate for normal function. The role of these opposing concepts in management of irritable bowel syndrome (IBS) is contrasted with what is known in IBD. The conclusion reached is that, while both approaches may alleviate symptoms in both IBS and IBD, there is insufficient data yet to determine whether both approaches lead to equivalent bacterial effects in mollifying the immune system. This is particularly relevant in IBD. As such, caution is urged to use long-term carbohydrate withdrawal in IBD in remission to control IBS-like symptoms. PMID- 22518341 TI - IL-8 and MCP Gene Expression and Production by LPS-Stimulated Human Corneal Stromal Cells. AB - Purpose. To determine time course of effect of lipopolysaccharide (LPS) on production of interleukin-8 (IL-8) and monocyte chemotactic protein (MCP) by cultured human corneal stromal cells. Methods. Human corneal stromal cells were harvested from donor corneal specimens, and fourth to sixth passaged cells were used. Cell cultures were stimulated with LPS for 2, 4, 8, and 24 hours. Northern blot analysis of IL-8 and MCP gene expression and ELISA for IL-8 and MCP secretion were performed. ELISA results were analyzed for statistical significance using two-tailed Student's t-test. Results. Northern blot analysis demonstrated significantly increased IL-8 and MCP gene expression after 4 and 8 hours of exposure to LPS. ELISA for secreted IL-8 and MCP demonstrated statistically significant increases (P < 0.05) after corneal stromal cell stimulation with LPS. Conclusions. This paper suggests that human corneal stromal cells may participate in corneal inflammation by secreting potent leukocyte chemotactic and activating proteins in a time-dependent manner when exposed to LPS. PMID- 22518342 TI - Anti-inflammatory activity of lactobacillus on carrageenan-induced paw edema in male wistar rats. AB - Introduction. Lactobacillus casei and Lactobacillus acidophilus were used to assess the anti-inflammatory properties in carrageenan induced acute inflammatory model. Materials and Methods. Diclofenac sodium was used as standard drug at concentration of 150 mg/kg of body weight. Culture of Lactobacillus 2 * 10(7) CFU/ml was given orally. Edema was induced with 1% carrageenan to all the groups after one hour of the oral treatments. Paw thickness was checked at t = 1, 2, 3, 4, 5, and 24 hours. Stair climbing score and motility score were assessed at t = 24 hours. Cytokines assay for IL-6, IL-10, and TNF-alpha was performed on serum samples. Results. Lactobacillus showed a statistically significant decrease in paw thickness at P < 0.001. L. acidophilus and L. casei decreased by 32% and 28% in paw thickness. They both significantly increased the stair climbing and motility score. Lactobacillus treatment significantly downregulated IL-6 and TNF alpha while upregulated IL-10 at P < 0.0001. Conclusion. L. casei and L. acidophilus significantly decreased the inflammatory reactions induced by carrageenan. This study has also proposed that Lactobacillus ameliorated the inflammatory reaction by downregulating the proinflammatory cytokines pathway. PMID- 22518343 TI - Resident Corneal Cells Communicate with Neutrophils Leading to the Production of IP-10 during the Primary Inflammatory Response to HSV-1 Infection. AB - In this study we show that murine and human neutrophils are capable of secreting IP-10 in response to communication from the HSV-1 infected cornea and that they do so in a time frame associated with the recruitment of CD8(+) T cells and CXCR3 expressing cells. Cellular markers were used to establish that neutrophil influx corresponded in time to peak IP-10 production, and cellular depletion confirmed neutrophils to be a significant source of IP-10 during HSV-1 corneal infection in mice. A novel ex vivo model for human corneal tissue infection with HSV-1 was used to confirm that cells resident in the cornea are also capable of stimulating neutrophils to secrete IP-10. Our results support the hypothesis that neutrophils play a key role in T-cell recruitment and control of viral replication during HSV 1 corneal infection through the production of the T-cell recruiting chemokine IP 10. PMID- 22518345 TI - Cardiovascular inflammation. PMID- 22518344 TI - The Interface between Inflammation and Coagulation in Cardiovascular Disease. AB - The intimate connection between coagulation and inflammation in the pathogenesis of vascular disease has moved more and more into focus of clinical research. This paper focuses on the essential components of this interplay in the settings of cardiovascular disease and acute coronary syndrome. Tissue factor, the main initiator of the extrinsic coagulation pathway, plays a central role via causing a proinflammatory response through activation of coagulation factors and thereby initiating coagulation and downstream cellular signalling pathways. Regarding activated clotting factors II, X, and VII, protease-activated receptors provide the molecular link between coagulation and inflammation. Hereby, PAR-1 displays deleterious as well as beneficial properties. Unravelling these interrelations may help developing new strategies to ameliorate the detrimental reciprocal aggravation of inflammation and coagulation. PMID- 22518346 TI - Ultrasound of the small bowel in Crohn's disease. AB - Several radiological and endoscopic techniques are now available for the study of inflammatory bowel diseases. In everyday practice, the choice of the technique to be used depends upon its availability and a careful evaluation of diagnostic accuracy, clinical usefulness, safety, and cost. The recent development of innovative and noninvasive imaging techniques has led to a new and exciting area in the exploration of the gastrointestinal tract, especially in Crohn's disease patients by using ultrasound with oral or intravenous contrast. PMID- 22518347 TI - A risk prediction index for amiodarone-induced thyrotoxicosis in adults with congenital heart disease. AB - Amiodarone therapy in adults with congenital heart disease (CHD) is associated with a significant risk of amiodarone-induced thyrotoxicosis (AIT). We developed a risk index to identify those patients being considered for amiodarone treatment who are at high risk for AIT. We reviewed the health records of adults with CHD and assessed the association between potential clinical predictors and AIT. Significant predictors were included in multivariate analyses. The parameter estimates from multivariate analysis were subsequently used to develop a risk index. 169 adults met eligibility criteria and 23 developed AIT. The final model included age, cyanotic heart disease and BMI. The risk index developed identified 3 categories of risk. Their AIT likelihood ratios were: 0.37 for low risk (95% CI 0.15-0.92); 1.12 for medium risk (95% CI 0.65-1.91); and 3.47 for high risk (95% CI 1.7-7.11). The AIT predicted risk in our population was 5% for the low risk group, 15% for the medium risk group and 47% for the high risk group. Conclusions. We derived the first model to quantify the risk for developing AIT among adults with CHD. Before using it clinically to help selecting among alternative antiarrhythmic options, it needs validation in an independent population. PMID- 22518348 TI - Proteomic profiling of thyroid papillary carcinoma. AB - Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy. We performed shotgun liquid chromatography (LC)/tandem mass spectrometry (MS/MS) analysis on pooled protein extracts from patients with PTC and compared the results with those from normal thyroid tissue validated by real-time (RT) PCR and immunohistochemistry (IHC). We detected 524 types of protein in PTC and 432 in normal thyroid gland. Among these proteins, 145 were specific to PTC and 53 were specific to normal thyroid gland. We have also identified two important new markers, nephronectin (NPNT) and malectin (MLEC). Reproducibility was confirmed with several known markers, but the one of two new candidate markers such as MLEC did not show large variations in expression levels. Furthermore, IHC confirmed the overexpression of both those markers in PTCs compared with normal surrounding tissues. Our protein data suggest that NPNT and MLEC could be a characteristic marker for PTC. PMID- 22518349 TI - Altered Dynamic Postural Control during Step Turning in Persons with Early-Stage Parkinson's Disease. AB - Persons with early-stage Parkinson's disease (EPD) do not typically experience marked functional deficits but may have difficulty with turning tasks. Studies evaluating turning have focused on individuals in advanced stages of the disease. The purpose of this study was to compare postural control strategies adopted during turning in persons with EPD to those used by healthy control (HC) subjects. Fifteen persons with EPD, diagnosed within 3 years, and 10 HC participated. Participants walked 4 meters and then turned 90 degrees . Dynamic postural control was quantified as the distance between the center of pressure (COP) and the extrapolated center of mass (eCOM). Individuals with EPD demonstrated significantly shorter COP-eCOM distances compared to HC. These findings suggest that dynamic postural control during turning is altered even in the early stages of PD. PMID- 22518350 TI - Informational Needs of Head and Neck Cancer Patients. AB - Treatment for head and neck squamous cell carcinoma (HNSCC) can lead to considerable functional impairment. As a result, HNSCC patients experience significant decrements in quality of life, high levels of emotional distress, deteriorations in interpersonal relations, and increased social isolation. Studies suggest that HNSCC patients may have extensive informational and psychosocial needs that are not being adequately addressed. However, few programs have been developed to address the needs of HNSCC patients. Therefore, we conducted a pilot study of HNSCC patients to: 1) characterize patients' informational needs; and 2) describe preferred formats and time points for receiving such information. The majority of participants desired additional information regarding treatment options, managing changes in swallowing and speaking, and staying healthy after treatment. Overall, patients with early-stage disease reported more informational needs compared to patients with advanced disease. Female patients were more likely to desire information about coping with emotional stress and anxiety than male patients. Younger patients (29-49 years) were more interested in receiving information about sexuality after cancer compared to their older (50+) counterparts. Although information was requested throughout the cancer trajectory, most patients preferred to receive such information at diagnosis or within 1-3 months post-treatment. The majority of patients reported having computer and Internet access, and they were most receptive to receiving information delivered via the Internet, from a DVD, or from pamphlets and booklets. The relatively high percentage of patients with computer and Internet access reflects a growing trend in the United States and supports the feasibility of disseminating health information to this patient population via Internet-based programs. PMID- 22518351 TI - The major medical ethical challenges facing the public and healthcare providers in Saudi Arabia. AB - BACKGROUND: Despite the relatively high expenditure on healthcare in Saudi Arabia, its health system remains highly centralized in the main cities with its primary focus on secondary and tertiary care rather than primary care. This has led to numerous ethical challenges for the healthcare providers. This article reports the results of a study conducted with a panel of practitioners, and non clinicians, in Saudi Arabia, in order to identify the top ten ethical challenges for healthcare providers, patients, and their families. MATERIALS AND METHODS: The study design was a cross-sectional, descriptive, and qualitative one. The participants were asked the question: "What top ten ethical challenges are Saudis likely to face in health care?" The participants were asked to rank the top ten ethical challenges throughout a modified Delphi process, using a ranking Scale. A consensus was reached after three rounds of questions and an experts' meeting. RESULTS: The major 10 ethical issues, as perceived by the participants in order of their importance, were: (1) Patients' Rights, (2) Equity of resources, (3) Confidentiality of the patients, (4) Patient Safety, (5) Conflict of Interests, (6) Ethics of privatization, (7) Informed Consent, (8) Dealing with the opposite sex, (9) Beginning and end of life, and (10) Healthcare team ethics. CONCLUSION: Although many of the challenges listed by the participants have received significant public and specialized attention worldwide, scant attention has been paid to these top challenges in Saudi Arabia. We propose several possible steps to help address these key challenges. PMID- 22518352 TI - Metabolic syndrome among obese Qataris attending primary health care centers in Doha, 2010. AB - OBJECTIVES: To determine the prevalence of metabolic syndrome among obese patients using the IDF definition and to identify factors that are associated with it. MATERIALS AND METHODS: A cross-sectional randomized study was conducted at four primary care centers inside Doha, Qatar. One hundred and thirty-six Adults, >= 18 Qatari obese patients, were chosen by systematic random sampling. They were interviewed and screened for the presence of metabolic syndrome, which was diagnosed according to the International Diabetes Federation criteria: An abdominal circumference >= 94 cm in males or >= 80 cm in females, plus any two of the following: HDL cholesterol < 1.03 mmol / mL (< 40 mg / dL) [males] or < 1.3 mmol / mL (< 50 mg / dL) [females], Triglycerides >= 1.7 mmol / mL (>=150 mg / dL), Blood pressure >= 130 / 85 mmHg or the patient receiving antihypertensive treatment and baseline glycemia > 5.6 mmol / mL (> 100 mg / dL), or previously diagnosed type 2 diabetes mellitus. RESULTS: The overall prevalence of the metabolic syndrome among obese patients was 46.3%. The prevalence was higher in females (50%) than in males (42.4%). It was seen to increase with increasing body mass index class, from class 1 to class 2. The prevalence of metabolic comorbidities of abnormal waist circumference, raised blood pressure, raised fasting blood glucose, high triglycerides, and reduced high density lipoprotein was 88.2, 42.6, 32.4, 31.6, and 27.9%, respectively. Based on the logistic regression multivariable analysis, increasing age and being diabetic were the only significant associated factors that influenced the risk of having the metabolic syndrome. CONCLUSION: The prevalence of the metabolic syndrome was high, and the highest comorbidities were abnormal waist circumference and high blood pressure. Diabetes and increasing age were the only significant risk factors of having this syndrome. PMID- 22518353 TI - Dynamics of doctor-patient relationship: A cross-sectional study on concordance, trust, and patient enablement. AB - BACKGROUND: The rapid pace of medical advances coupled with specialization and super-specialization, is eroding the traditional doctor-patient relationship. OBJECTIVE: (a) To study the determinants of core dimensions, such as, concordance, trust, and enablement in a doctor-patient relationship; (b) to explore associations, if any, among these core dimensions. MATERIALS AND METHODS: A cross-sectional study design with both quantitative and qualitative methods was employed. One hundred and ninety-eight outdoor patients were interviewed as part of the quantitative study. Three dimensions of the doctor-patient relationship, that is, physician patient concordance, trust in physician, and patient enablement were assessed using validated tools. Focus group interviews using an open-ended format among few physicians was carried out as part of the qualitative study. RESULTS: In the quantitative analysis most of the sociocultural factors did not show any significant association with the doctor-patient relationship. However, gender was significantly and strongly associated with trust in the physician. Female patients showed a much lower trust in the physician (50%) as compared to male patients (75%) (OR = 0.33, 95% CI 0.17 - 0.64, Chi Sq = 12.86, P = 0.0003). A qualitative study revealed language and culture, alternative medicines, commercialization of medicine, and crowding at specialist and super specialist clinics as barriers to a good doctor-patient relationship. Better concordance was associated with improved trust in the doctor (OR = 5.30, 95% CI 2.06 - 13.98, Chi Sq = 14.46, P = 0.0001), which in turn was associated with improved patient enablement (OR = 3.89, 95% CI = 1.60 - 9.64, Chi Sq = 10.15, P = 0.001). CONCLUSION: Good doctor-patient concordance (agreement) leads to better trust in the physician, which in turn leads to better patient enablement, irrespective of the sociocultural determinants. PMID- 22518354 TI - Orthostatic hypotension before and after meal intake in diabetic patients and healthy elderly people. AB - OBJECTIVES: The symptoms of orthostatic hypotension may be ignored or go unnoticed and may predispose some diabetic or elderly people to repeated falls and trauma, leading to immobility and prolongation of rehabilitation. The present investigation is concerned mainly with testing the reaction of the cardiovascular system in response to physiological stimuli, such as, standing upright from a supine position before and after meal intake in diabetic patients and the healthy Saudi population. MATERIALS AND METHODS: Seventy-five healthy and 49 diabetic patients were selected for this study. Parameters of heart rate, systolic and diastolic blood pressures, and electrocardiograms (ECG) were obtained for each subject by Dinamap (an automatic recorder), after 10 minutes of rest in the supine position and then after one and two minutes of standing. All parameters were taken before and after an intake of a standard meal. The results were compared between the diabetic and non-diabetic groups, and between the elderly diabetic and the healthy elderly >= 65 year olds, and between the young adults <= 40 year olds and the elderly >= 65 year olds. RESULTS: The postural changes of blood pressure and heart rate between the diabetic and non-diabetic groups, and between the elderly diabetic and the healthy elderly groups, were not significant. However, a highly significant postural drop in blood pressure, and an increase in the resting heart rate were recorded before and after a meal intake in the elderly compared to the young adults. CONCLUSION: The highly significant postural drop in blood pressure and increase in the resting heart rate in the elderly diabetic and healthy elderly people can be attributed to a defect in the arterial baroreceptors control of blood pressure and parasympathetic control of heart rate in this population. PMID- 22518355 TI - Factors contributing to non-compliance among diabetics attending primary health centers in the Al Hasa district of Saudi Arabia. AB - PURPOSE: The purpose of the study was to measure the rate of non-compliance and the factors contributing to non-compliance among the diabetic patients in the Al Hasa region of Saudi Arabia. MATERIALS AND METHODS: A cross-sectional survey was conducted in the Al Hasa region during the period of June 2010 to June 2011. Random sampling was carried out for the selection of 535 diabetic patients from three chronic disease centers in different parts of Al Hasa. The data were collected by means of interviewing questionnaires and file records. Any patient who had been prescribed optimum treatment and was properly advised on diet and exercise for his / her diabetes, but did not follow the medical advice, with Hb1AC of more than 7% at the time of interview, was considered as non-compliant. RESULTS: The overall prevalence of therapeutic non-compliance of the participants was 67.9% (n = 318, 95% CI 63.59 - 72.02%). The non-compliance of males (69.34%) was higher than females (65.45%, P = .003). The non-compliance among the urban participants was significantly higher than (71.04 vs. 60.15%, P = .023) in the rural participants. There was a statistically significant difference in the prevalence rate of non-compliance among the participants with different levels of education. Factors found to be significantly associated with non-compliance on bi variate analysis were: female gender (OR = 1.90, CI =1.32-4.57),level of education (Illiteracy) (OR = 5.27, CI = 4.63 - 7.19), urban population (OR =5.22, CI= 3.65 - 8.22), irregularity of the follow-up (OR = 8.41, CI = 4.90 - 11.92), non-adherence to drug prescription (OR = 4.55 , CI = 3.54 - 5.56), non-adherence to exercise regimen (OR = 5.55, CI = 4.2 6 - 6.), insulin (OR = 1.29, CI = .71 - 1.87), and insulin with oral Metformin (OR = 1.20, CI = .65 - 1.75). CONCLUSION: The findings indicate that there is a high rate of non-compliance among the diabetes patients in the Al Hasa region of Saudi Arabia and there is a definite need for improvement in the healthcare system, health education, and training of diabetic patients. PMID- 22518356 TI - Reliability and validity of an Arabic version of the revised two-factor study process questionnaire R-SPQ-2F. AB - OBJECTIVE: How students accomplish their learning and what they learn is an indicator of the quality of student learning. An insight into the learning approaches of a student could assist educators of the health profession in their planning for the first year of study. The aim of this study was to develop a reliable and valid Arabic version of the revised two-factor study process questionnaire. MATERIALS AND METHODS: The translation of the revised two-Factor Study Process Questionnaire (R-SPQ-2F) into Arabic was done by an established forward-backward translation procedure. The Arabic version was then distributed to high school graduates applying for a place in the medical program at King Fahad Medical City. A total of 83 students voluntarily completed the questionnaire. The internal consistency and construct validity of the Arabic version of the R-SPQ-2F were computed. RESULTS: The exploratory factor analysis revealed two components. The two factors were similar to the main scales described in the original English questionnaire. The main scales were the deep and surface approach. The items for the subscales (deep motive, deep strategy and surface motive, surface strategy) had a high internal consistency of more than 0.80. CONCLUSIONS: The results of this study should provide a valid and reliable instrument for the evaluation of the study approaches of Arabic speaking students. PMID- 22518357 TI - A survey of the attitude and practice of research among doctors in Riyadh Military Hospital Primary Care Centers, Saudi Arabia. AB - OBJECTIVES: To assess the attitude and practice of doctors in the Military Hospital Primary Care Centers in Riyadh (RMH) toward research and to identify the main barriers to conduct research. MATERIALS AND METHODS: A cross-sectional study was conducted from March to April, 2010, at RMH primary care centers. The sample included all general practitioners (GPs) working in primary healthcare centers. A self-administered questionnaire was formulated from different sources and used as a tool for data collection. RESULTS: The response rate was 75%. Among the respondents 96.9% agreed that research in primary care was important for different reasons. Most of the GPs had a positive attitude toward research: 68% had been influenced by research in their clinical practice and 66% had an interest in conducting research, and74.2% of the respondents had plans to do research in the future. Insufficient time was the most frequently cited barrier (83.5%) for participating in research, followed by the lack of support (58.8%). CONCLUSIONS: Many of the GPs had a positive attitude toward research, but had no publications or plan for new research. Lack of time, support, and money were the main constraints for carrying out research. PMID- 22518358 TI - A study on rapid confirmation of pulmonary tuberculosis in smear-negative acid fast bacilli cases by using fiberoptic bronchoscopy, done through a trans oro pharyngeal spacer. AB - INTRODUCTION: The tuberculosis control program is based on a felt need-oriented basis. The diagnosis is mainly microbiological. However, sputum smear-negative Acid Fast Bacilli (AFB) cases with suspected radiological findings can be problematic in diagnosis. OBJECTIVES: To confirm the diagnosis of tuberculosis early, in smear-negative AFB cases by using a Fiberoptic Bronchoscope. MATERIALS AND METHODS: We embarked on Fiberoptic Bronchoscopy (FOB) and Spot Scopy smear Microscopy (SSM) for 533 suspected Pulmonary Tuberculosis (PT) cases (sputum smear negative and radiologically suggestive) from February 2007 to May 2010. FOB was performed using a special device, a Trans Oro Pharyngeal Spacer (TOPS), as a conduit. RESULTS: The yield for positivity for AFB was 341 (64%) out of 533 cases. CONCLUSION AND RECOMMENDATION: The specimens collected by using the fiberoptic bronchoscope confirmed the disease in the smear-negative cases. Hence, FOB was recommended in smear-negative cases, to avoid delay in the treatment of tuberculosis. PMID- 22518359 TI - Prevalence of mental disorders among high school students in National Guard Housing, Riyadh, Saudi Arabia. AB - BACKGROUND: Adolescents experience rapid biological, psychological, and social transitions that can be associated with mental health problems. During the high school period there are also more academic stressors. OBJECTIVE: (1) To study the prevalence of mental disorders in high school (grade 12) students. (2) To study some related sociodemographic data. MATERIALS AND METHODS: A cross-sectional study, using GHQ-28, that included 354 students randomly selected from grade 12 in four high schools - two male and two female high schools - in the National Guard Housing (Iskan), in Kashmalaan (suburb of Riyadh). RESULTS: The overall prevalence of mental disorders was found to be 48% (41% in males and 51% in females); more than 80% of these cases were mild to moderate. Females showed significantly more severe disorders than males (P = 0.017) and students with excellent performance degrees showed a significantly lower rate of mental disorders than others (P = 0.021). However, our study did not show a significant association between psychiatric disorders and other social variables (family size, birth order, and polygamous family) or smoking. CONCLUSION: The adolescent age groups in our community had high rates of mental disorders, which required more attention from the family, as well as the educational and health institutes in our country. PMID- 22518360 TI - Nicolau syndrome as an avoidable complication. PMID- 22518362 TI - Pain catastrophizing predicts poor response to topical analgesics in patients with neuropathic pain. AB - BACKGROUND: Previous research suggests that high levels of pain catastrophizing might predict poorer response to pharmacological interventions for neuropathic pain. OBJECTIVE: The present study sought to examine the clinical relevance of the relation between catastrophizing and analgesic response in individuals with neuropathic pain. Clinically meaningful reductions were defined in terms of the magnitude of reductions in pain through the course of treatment, and in terms of the number of patients whose end-of-treatment pain ratings were below 4/10. METHODS: Patients (n=82) with neuropathic pain conditions completed a measure of pain catastrophizing at the beginning of a three-week trial examining the efficacy of topical analgesics for neuropathic pain. RESULTS: Consistent with previous research, high scores on the measure of pain catastrophizing prospectively predicted poorer response to treatment. Fewer catastrophizers than noncatastrophizers showed moderate (>= 2 points) or substantial reductions in pain ratings through the course of treatment. Fewer catastrophizers than noncatastrophizers achieved end-of-treatment pain ratings below 4/10. CONCLUSIONS: The results of the present study suggest that the development of brief interventions specifically targeting catastrophic thinking might be useful for enhancing the effects of pharmacological interventions for neuropathic pain. Furthermore, failure to account for the level of catastrophizing might contribute to null findings in clinical trials of analgesic medication. PMID- 22518364 TI - The development of an electronic database for Acute Pain Service outcomes. AB - BACKGROUND: Quality assurance is increasingly important in the current health care climate. An electronic database can be used for tracking patient information and as a research tool to provide quality assurance for patient care. OBJECTIVE: An electronic database was developed for the Acute Pain Service, University of Alberta Hospital (Edmonton, Alberta) to record patient characteristics, identify at-risk populations, compare treatment efficacies and guide practice decisions. METHOD: Steps in the database development involved identifying the goals for use, relevant variables to include, and a plan for data collection, entry and analysis. Protocols were also created for data cleaning quality control. The database was evaluated with a pilot test using existing data to assess data collection burden, accuracy and functionality of the database. RESULTS: A literature review resulted in an evidence-based list of demographic, clinical and pain management outcome variables to include. Time to assess patients and collect the data was 20 min to 30 min per patient. Limitations were primarily software related, although initial data collection completion was only 65% and accuracy of data entry was 96%. CONCLUSIONS: The electronic database was found to be relevant and functional for the identified goals of data storage and research. PMID- 22518363 TI - Does pain necessarily have an affective component? Negative evidence from blink reflex experiments. AB - BACKGROUND: Experimental pain research has shown that the affective component of pain is influenced strongly by situational characteristics; affective pain processing appears to be particularly pronounced in situations that provoke a feeling of uncertainty and uncontrollability. OBJECTIVES: To determine whether the affective component of pain can be completely abolished if a 'safe', particularly predictable stimulation paradigm is applied. METHODS: Forty healthy volunteers recruited at the University of Bamberg (Bamberg, Germany) were assessed in two experiments. Tonic contact heat stimuli staged in three intensities (warmth, heat and pain) relative to the individual pain threshold was applied; these were predictable with regard to intensity and course, and the subjects had easy access to control. The startle reflex was assessed as an objective measure of affective response. In addition, the subjects provided unpleasantness ratings. To compare these results to a gold standard for affective response, affective pictures taken from the International Affective Picture System were presented during temperature stimulation in the second experiment. RESULTS: Both experiments showed no potentiation of the startle reflex under painful heat stimulation compared with the two nonpainful stimulus intensities (heat and warmth), although the painful stimulation was clearly rated as more unpleasant. CONCLUSIONS: Results suggest that it is possible to develop a 'safe' noxious stimulus, which is rated as clearly unpleasant, but lacks physiological indication of negative affect. This divergence might be explained by subjective ratings being influenced by the instructions. The possibility of reducing the pain affect by suggesting 'safety' may be of therapeutic interest. PMID- 22518365 TI - The hot foot syndrome: Evans' sign and the old way. AB - BACKGROUND: Pelvic cancers such as cancer of the cervix can spread locally to involve adjacent structures such as the lumbosacral plexus and the sympathetic chain. When this happens the prognosis is usually poor. An early suspicion of recurrence may result in investigation leading to earlier and better treatment. A physical sign that may be an early and only sign of recurrence is described. OBJECTIVE: To report the late Dr Ramon Evans' unpublished case series of the hot foot syndrome due to (mostly malignant) retroperitoneal disease. This unique contribution is an opportunity to pay tribute to a man who was a meticulous recorder of the patient narrative and practitioner of a detailed and comprehensive physical examination. METHODS: A longitudinal, observational, retrospective, descriptive study is reported. Data were collected from a convenience sample of 86 patients, 75 of whom had retroperitoneal cancer and 11 of whom were diagnosed with other conditions in that area. Patients referred to the Smythe Pain Clinic were seen at both the Princess Margaret Hospital and Toronto General Hospital in Toronto, Ontario, in the 1970s. They were referred with intractable pain in the leg or back and often a history of a treated abdominal or pelvic cancer in the previous months or years. Baseline demographic data were collected including age, sex, diagnosis, pain location, characteristics and severity, physical findings, investigations and mortality. RESULTS: The 86 subjects comprised 27 men and 59 women. Carcinoma of the cervix was the most common tumour. Most had a presenting complaint of leg pain. Neurological physical signs were demonstrated in the lower extremities in 44%; however, 56% (48 patients) had only an ipsilateral, warm, dry 'hot foot' due to sympathetic deafferentation. The prognosis for the underlying illness was poor for the malignant group. DISCUSSION: Sympathetic interruption by cancer is well known in apical lung cancer as the tumour spreads upwards to involve the inferior brachial plexus. An analogous situation occurs as cancers, such as that of the cervix, spread laterally to invade the lumbosacral plexus and sympathetic chain. Signs of sympathetic deafferentation (the 'hot foot') may be the earliest and only sign in this situation. This sign may be missed unless it is anticipated and a thorough physical examination carried out. CONCLUSION: Evans' sign is important because it may be an early and solitary sign of retroperitoneal recurrence of pelvic (cervix, rectum, bladder, ovary and prostate) cancers. Recognition of this finding when intractable pain in the back and leg occurs with a history of this type of cancer could lead to earlier and more successful treatment. PMID- 22518366 TI - A systematic review of early prognostic factors for persisting pain following acute orthopedic trauma. AB - BACKGROUND: Acute orthopedic trauma contributes substantially to the global burden of disease. OBJECTIVES: The present systematic review aimed to summarize the current knowledge concerning prognostic factors for the presence of persistent pain, pain severity and pain-related disability following acute orthopedic trauma involving a spectrum of pathologies to working-age adults. METHODS: The Ovid MEDLINE and EMBASE databases were searched for level II prognostic studies published between January 1996 and October 2010. Studies that were longitudinal and reported results with multivariate analyses appropriate for prognostic studies were included. Studies that addressed two specific injury types that have been the subject of previous reviews, namely, injuries to the spinal column and amputations, were excluded. RESULTS: The searches yielded 992 studies; 10 studies met the inclusion criteria and were rated for methodological quality. Seventeen factors were considered in more than one cohort. There was strong evidence supporting the association of female sex, older age, high pain intensity, preinjury anxiety or depression, and fewer years of education with persistent pain outcomes. There was moderate evidence supporting the association between postinjury depression or anxiety with persistent pain, and that injury severity was not a risk factor for ongoing pain. CONCLUSION: Many individuals experience persistent pain following acute trauma. Due to the lack of studies, the use of different constructs to measure the same factor and the methodological limitations associated with many of the studies, the present review was only able to reliably identify a limited set of factors that predicted persistent pain. Recommendations for the conduct of future methodologically rigorous studies of persistent pain are provided. PMID- 22518367 TI - The ventral striatum is implicated in the analgesic effect of mood changes. AB - BACKGROUND: The ventral striatum, particularly the nucleus accumbens, is commonly associated with the processing of reward and positive stimuli, positive affect as well as antinociceptive processes. OBJECTIVES: The present study examined whether the ventral striatum is implicated in analgesia resulting from positive mood change induced by pleasant odours. METHODS: Functional magnetic resonance imaging studies were conducted in healthy individuals receiving painful heat stimuli in the presence of pleasant or unpleasant odours, which were used to induce positive and negative mood states. Ventral striatum activity was examined in the two mood states. RESULTS: For most subjects, pleasant odours improved mood and reduced pain unpleasantness perception relative to unpleasant odours. In the pleasant odour condition, the maximum activation of both the left and right ventral striatum was positively correlated with the amount of pain reduction. Furthermore, the left and right ventral striatum activations positively covaried with one another, and the right ventral striatum activation positively correlated with that in the periaqueductal grey matter. Both ventral striatum activations negatively covaried with the activation of the right mediodorsal thalamus, left dorsal anterior cingulate cortex, left medial prefrontal cortex and right ventrolateral prefrontal cortex. CONCLUSIONS: Because both the mediodorsal thalamus and anterior cingulate are involved in pain affect perception, and activation within the prefrontal areas and periaqueductal grey matter were previously shown to correlate with mood-related pain modulation, it is concluded that the ventral striatum is likely implicated in the analgesic effect of positive mood changes induced by pleasant odours on pain unpleasantness. PMID- 22518368 TI - Use of a modified Comprehensive Pain Evaluation Questionnaire (CPEQ): characteristics and functional status of patients on entry to a tertiary care pain clinic. AB - BACKGROUND: With increasing knowledge of chronic pain, clinicians have attempted to assess chronic pain patients with lengthy assessment tools. OBJECTIVES: To describe the functional and emotional status of patients presenting to a tertiary care pain clinic; to assess the reliability and validity of a diagnostic classification system for chronic pain patients modelled after the Multidimensional Pain Inventory; to provide psychometric data on a modified Comprehensive Pain Evaluation Questionnaire (CPEQ); and to evaluate the relationship between the modified CPEQ construct scores and clusters with Diagnostic and Statistical Manual, Fourth Edition - Text Revision Pain Disorder diagnoses. METHODS: Data on 300 new patients over the course of nine months were collected using standardized assessment procedures plus a modified CPEQ at the Comprehensive Pain Program, Toronto Western Hospital, Toronto, Ontario. RESULTS: Cluster analysis of the modified CPEQ revealed three patient profiles, labelled Adaptive Copers, Dysfunctional, and Interpersonally Distressed, which closely resembled those previously reported. The distribution of modified CPEQ construct T scores across profile subtypes was similar to that previously reported for the original CPEQ. A novel finding was that of a strong relationship between the modified CPEQ clusters and constructs with Diagnostic and Statistical Manual, Fourth Edition - Text Revision Pain Disorder diagnoses. DISCUSSION AND CONCLUSIONS: The CPEQ, either the original or modified version, yields reproducible results consistent with the results of other studies. This technique may usefully classify chronic pain patients, but more work is needed to determine the meaning of the CPEQ clusters, what psychological or biomedical variables are associated with CPEQ constructs or clusters, and whether this instrument may assist in treatment planning or predict response to treatment. PMID- 22518369 TI - Long-acting morphine following hip or knee replacement: a randomized, double blind, placebo-controlled trial. AB - BACKGROUND: Patients undergoing total hip or knee replacement surgery experience unmanaged pain during postoperative physiotherapy sessions. It was theorized that a baseline opioid would improve pain management. OBJECTIVES: To examine the effectiveness of adding long-acting oral morphine to a routine postoperative regimen for total hip or knee replacement surgery. METHODS: The present study was a double-blind, randomized, placebo-controlled trial for patients undergoing total hip or knee replacement surgery. All patients received routine postoperative analgesia; in addition, the treatment group received long-acting oral morphine 30 mg orally twice daily for three days, while the control group received placebo capsules. The primary end point was a decrease in pain scores by two points on a 0- to 10-point pain rating scale. Secondary end points included adverse effects, acute confusion, pain-related interferences in function and sleep, length of stay and patient satisfaction. RESULTS: Two hundred patients were enrolled in the present study (March 2004 to March 2006). Although the groups were large enough to yield statistical significance, most pain scores did not reach the predetermined improvement for clinical significance. Additionally, there was an increase in opioid usage (P<0.0001), vomiting (P=0.0148) and oversedation (P=0.08). There were no statistically significant changes in function or sleep. Improved satisfaction with pain management was minimal (P=0.052). DISCUSSION: The present study was undertaken to determine the value of adding a long-acting opioid (morphine) to the usual care of patients undergoing total hip or total knee replacement surgery. The results yielded minimally improved pain scores and additional adverse effects (vomiting and oversedation). Published research in which long-acting opioids (oxycodone) were used for similar postoperative procedures did not robustly report improved pain scores. In addition, patients using a long-acting opioid (oxycodone) during the postoperative period reported somnolence, dizziness and confusion. Statistically, the patients in the present study showed higher confusion scores and no improvement for pain-related interferences with activity or walking. The treatment group did report increased satisfaction; however, the significance was weak. CONCLUSIONS: Thirty milligrams twice per day of long-acting morphine from days 1 to 3 following total hip and total knee replacement surgery provided minimal improvements in pain scores, and more adverse effects in the treatment group. The overall strength of evidence for improved outcomes is minimal and thus not supported. PMID- 22518370 TI - Evaluation of leptin levels among fibromyalgia patients before and after three months of treatment, in comparison with healthy controls. AB - BACKGROUND: Leptin, an adipocyte-produced cytokine, interacts with various hormones, including those of the hypothalamic-pituitary-adrenal axis. Fibromyalgia is a syndrome characterized by widespread pain accompanied by tenderness. The pathogenesis involves a disturbance in pain processing and transmission by the central nervous system, leading to a general increase in pain perception. OBJECTIVES: To analyze potential changes in leptin levels among female fibromyalgia patients compared with healthy controls, and to evaluate the changes in leptin levels during treatment. METHODS: Sixteen female fibromyalgia patients were recruited. Patients underwent clinical evaluation, physical examination, including manual dolorimetry, and were evaluated regarding quality of life, pain, fatigue, anxiety and depression. Plasma leptin levels were determined by ELISA. Patients were offered standard treatment for fibromyalgia. Clinical evaluation and leptin determination were repeated after three months. RESULTS: No significant difference was observed between leptin levels among fibromyalgia patients and controls; no significant correlation was observed between leptin levels and clinical parameters reflecting fibromyalgia severity; and no significant change was observed in leptin levels over three months of treatment. These results did not change after adjustment of leptin levels for body mass index values. CONCLUSIONS: The results of the present study do not support the existence of a significant relationship between leptin and fibromyalgia pathogenesis. Increasing the sample size or examining the interaction between leptin and additional hormones/mediators of metabolism and body weight control may yet uncover significant information in this field. PMID- 22518371 TI - Anxiety and impairment in a large sample of children and adolescents with chronic pain. AB - BACKGROUND: Anxiety is the most common psychiatric condition in children and adolescents, and is linked to significant disruptions across domains of function. Due to the avoidant nature of anxiety and pain-related disability, studying anxiety symptoms in children with chronic and recurrent pain conditions is important. OBJECTIVES: To examine anxiety symptoms in a large cohort of children and adolescents evaluated for complex chronic and recurrent pain conditions. METHODS: Through retrospective chart review, data on anxiety, pain and functional disability were collected from 655 children evaluated at a multidisciplinary pain clinic over a three-year period. RESULTS: Approximately 11% of children and adolescents reported clinically elevated anxiety symptoms, with elevated levels across dimensions of anxiety ranging from 14% (social anxiety, worry) to 27% (physiological). In addition, a notable 31% of the sample potentially minimized their anxiety by responding in a socially desirable manner. Anxiety was linearly associated with greater pain-related functional disability, but was not directly correlated with pain. Moderation analyses revealed that at low levels of worry, higher levels of pain were associated with greater functional disability, whereas at high levels of worry, pain no longer predicted the level of functional disability. CONCLUSIONS: These findings document the prevalence of anxiety in children and adolescents with chronic pain, and also extend recent studies examining the complex relationships among pain, anxiety and pain-related disability. PMID- 22518372 TI - Reliability of the conditioned pain modulation paradigm to assess endogenous inhibitory pain pathways. AB - BACKGROUND: Conditioned pain modulation paradigms are often used to assess the diffuse noxious inhibitory control (DNIC) system. DNICs provide one of the main supraspinal pain inhibitory pathways and are impaired in several chronic pain populations. Only one previous study has examined the psychometric properties of the conditioned pain modulation technique and this study did not evaluate intersession reliability. OBJECTIVES: To evaluate and compare the intra- and intersession reliability of two conditioned pain modulation paradigms using different conditioning stimuli, and to determine the time course of conditioned pain inhibition following stimulus removal. METHODS: An electronic pressure transducer was used to determine the pressure-pain threshold at the knee during painful conditioning of the opposite hand using the ischemic arm test and the cold pressor test. Assessments were completed twice on one day and repeated once approximately three days later. RESULTS: The two conditioning stimuli resulted in a similar increase in the pressure-pain threshold at the knee, reflecting presumed activation of the DNIC system. Intrasession intraclass correlation coefficients for the cold pressor (0.85) and ischemic arm tests (0.75) were excellent. The intersession intraclass correlation coefficient for the cold pressor test was good (0.66) but was poor for the ischemic arm test (-0.4). Inhibition of the pressure-pain threshold remained significant at 10 min following conditioning, but returned to baseline by 15 min. CONCLUSIONS: Within session reliability of DNIC assessment using conditioned pain modulation paradigms was excellent, but the applicability of assessing pain modulation over multiple sessions was influenced by the conditioning stimulus. The cold pressor test was the superior technique. PMID- 22518373 TI - Experimental pain responses in children with chronic pain and in healthy children: how do they differ? AB - BACKGROUND: Extant research comparing laboratory pain responses of children with chronic pain with healthy controls is mixed, with some studies indicating lower pain responsivity for controls and others showing no differences. Few studies have included different pain modalities or assessment protocols. OBJECTIVES: To compare pain responses among 26 children (18 girls) with chronic pain and matched controls (mean age 14.8 years), to laboratory tasks involving thermal heat, pressure and cold pain. Responses to cold pain were assessed using two different protocols: an initial trial of unspecified duration and a second trial of specified duration. METHODS: Four trials of pressure pain and of thermal heat pain stimuli, all of unspecified duration, were administered, as well as the two cold pain trials. Heart rate and blood pressure were assessed at baseline and after completion of the pain tasks. RESULTS: Pain tolerance and pain intensity did not differ between children with chronic pain and controls for the unspecified trials. For the specified cold pressor trial, 92% of children with chronic pain completed the entire trial compared with only 61.5% of controls. Children with chronic pain exhibited a trend toward higher baseline and postsession heart rate and reported more anxiety and depression symptoms compared with control children. CONCLUSIONS: Contextual factors related to the fixed trial may have exerted a greater influence on pain tolerance in children with chronic pain relative to controls. Children with chronic pain demonstrated a tendency toward increased arousal in anticipation of and following pain induction compared with controls. PMID- 22518374 TI - Influence of stimulation location and posture on the reliability and comfort of the nociceptive flexion reflex. AB - BACKGROUND: The lower limb nociceptive flexion reflex (NFR) is commonly used to assess the function of the nociceptive system. Currently, there is a lack of standardized stimulation procedures to determine the NFR threshold, making comparisons of thresholds across studies difficult. OBJECTIVES: To assess and compare the within- and between-session reliability of NFR threshold when elicited from two common stimulation locations: the medial arch of the foot (while standing) and the sural nerve (while seated). METHODS: A staircase procedure was used to determine NFR threshold in 20 healthy participants twice within one session and once more in a separate session approximately four days later. At both sessions, NFR threshold was determined from both medial arch and sural nerve stimulation. Comparisons of NFR threshold, reliability and participant discomfort ratings were made between the two stimulation locations. RESULTS: NFR thresholds were statistically equivalent at the two stimulation locations, but there were more nonresponders and ratings of participant discomfort were significantly higher during stimulation over the sural nerve. Within-session reliability measures were superior for stimulation over the sural nerve; however, between-session measures were more reliable using stimulation over the medial arch of the foot. CONCLUSIONS: The authors recommend stimulation over the medial arch of the foot while standing as the preferred location for eliciting the lower limb NFR, particularly if measurements are to be compared across multiple sessions. PMID- 22518376 TI - Immediate positioning of definitive abutments versus repeated abutment replacements in immediately loaded implants: effects on bone healing at the 1 year follow-up of a multicentre randomised controlled trial. AB - PURPOSE: To compare bone resorption around implants immediately loaded and restored using definitive abutments versus provisional abutments later replaced by custom-made abutments up to 12 months after implant placement. MATERIALS AND METHODS: 28 patients with partial edentulism were selected for a two-implant supported immediate restoration and randomised to provisional abutment (PA) and definitive abutment (DA) groups (14 patients for each group). In the PA group, implants were immediately restored using a platform-switched provisional titanium abutment. In the DA group, definitive platform-switched titanium abutments were tightened. In both groups, a provisional restoration was adapted, avoiding occlusal contacts. All implants were definitively restored after 3 months. In the PA group, patients underwent the standard prosthetic protocol: the abutments were removed and impressions were made directly on the implant platform. In the DA group, patients underwent the 'one abutment at one time' protocol: impressions were made of the abutments using a retraction cord. Peri-implant marginal bone levels were assessed immediately after surgery, and at 6- and 12-month follow-up examinations. RESULTS: At the 12-month follow-up no implant failed. In the PA group, peri-implant bone resorption was 0.359 mm after 6 months and 0.435 mm after 12 months. In the DA group, peri-implant bone resorption was 0.065 mm after 6 months and 0.094 mm after 12 months. There were statistically significant differences between the two groups for peri-implant bone level changes at the 6 month (P < 0.001) and the 12-month (P < 0.001) follow-up: 0.294 mm (CI 95% 0.276; 0.312) and 0.341 mm (CI 95% 0.322; 0.36), respectively. CONCLUSIONS: Within the limits of this study, it can be suggested that the non-removal of abutments placed at the time of surgery results in a statistically significant reduction of the crestal bone resorption around the immediately restored implants in cases of partial edentulism, however a difference of 0.3 mm may not have a clinical impact. PMID- 22518377 TI - Posterior atrophic jaws rehabilitated with prostheses supported by 6 mm-long, 4 mm-wide implants or by longer implants in augmented bone. Preliminary results from a pilot randomised controlled trial. AB - PURPOSE: To evaluate whether 6 mm-long by 4 mm-wide dental implants could be an alternative to at least 10 mm-long implants placed in bone augmented with bone substitutes in posterior atrophic jaws. MATERIALS AND METHODS: Twenty patients with bilateral atrophic mandibles and 20 patients with bilateral atrophic maxillae, having 5 to 7 mm of bone height above the mandibular canal or below the maxillary sinus, were randomised according to a split-mouth design to receive one to three 6 mm-long and 4 mm-wide implants or at least 10-mm long implants in augmented bone at two centres. Mandibles were vertically augmented with interpositional equine bone blocks and resorbable barriers, and implants were placed after 3 months. Maxillary sinuses were augmented with particulated porcine bone via a lateral window and implants were placed simultaneously. All implants were submerged and loaded, after 4 months, with provisional prostheses. Four months later, definitive screw-retained metal-ceramic prostheses were delivered. Outcome measures were prosthesis and implant failures, any complication, time needed to fully recover mental nerve function (only for mandibular implants) and patient preference. RESULTS: All screened patients had sufficient bone width to support 4 mm-diameter implants. Patients were followed up to 5 months post loading and none dropped out. There were no statistically significant differences in graft, implant or prosthesis failures, though significantly more intra- and postoperative complications occurred at grafted sites. Fourteen complications occurred in 12 patients at augmented sites versus none at short implants. All complications occurred before loading. Three complications were associated with the failure of the mandibular grafts (15%), determining the failures of 3 implants in one patient and 2 prostheses could not be delivered. One patient was re-grafted and 2 patients received short implants instead. Apart from those complications associated with graft failures, there were 4 perforations of the sinus membrane during sinus lifting and 7 temporary lower lip paraesthesiae lasting up to 4 days with no long-term consequences for the patients. All maxillary implants and prostheses were successful. All 20 patients treated with mandibular implants and 15 patients treated with maxillary implants preferred short implants, whereas 5 patients treated with maxillary implants described both procedures as equally acceptable. These differences were statistically significant. CONCLUSIONS: Short-term data (5 months after loading) indicate that 6 mm-long implants with a conventional diameter of 4 mm achieved similar if not better results than longer implants placed in augmented bone. Short implants might be a preferable choice to bone augmentation, especially in posterior mandibles since the treatment is faster, cheaper and associated with less morbidity. However, 5- to 10-year post-loading data are necessary before making reliable recommendations. PMID- 22518378 TI - Three-year outcome of a retrospective cohort study on the rehabilitation of completely edentulous atrophic maxillae with immediately loaded extra-maxillary zygomatic implants. AB - AIM: To report retrospectively on the 3-year follow-up results in the rehabilitation of completely edentulous atrophied maxillae using extra-maxillary zygomatic implants. MATERIALS AND METHODS: This retrospective report includes an initial cohort of 39 patients (30 women and 9 men), with a mean age of 53 years, which were followed up for 3 years. The patients were rehabilitated with 39 fixed prostheses and 169 implants (92 zygomatic and 77 regular implants). Final abutments were delivered at surgery stage and a provisional fixed dental prosthesis was manufactured and attached to the implants on the same day as surgery, achieving immediate function. Outcome measures were prosthesis success, implant success, complications, probing pocket depths (PPDs) and marginal bone levels (only for conventional implants). Data were analysed with descriptive and inferential analyses. RESULTS: Five patients dropped out of the study and 1 patient died after 30 months of follow-up due to causes unrelated to the oral rehabilitation. No prosthesis or implant was lost, though 1 implant presented mobility at the 1-year follow-up but remained stable on subsequent follow-ups. Six complications occurred (18%): 5 cases of sinusitis in 5 patients preoperatively diagnosed with sinusitis and whose sinus membrane was disrupted during surgery, and 1 oro-antral communication. Median PPD values were 3 mm in all follow-up appointments (2, 4 and 6 months, 1, 2 and 3 years), comparable to the values of probing depths assessed for standard implants. CONCLUSIONS: Within the limitations of this study, the medium-term outcome (3 years) indicates that severely atrophied completely edentulous maxilla rehabilitations supported by immediately loaded zygomatic implants are viable. PMID- 22518379 TI - Immediate loading of 2 (all-on-2) flapless-placed mandibular implants supporting cross-arch fixed prostheses: interim data from a 1-year follow-up prospective single cohort study. AB - PURPOSE: To evaluate the clinical outcome of 2 implants placed flapless in fully edentulous mandibles and immediately restored with a metal-resin screw-retained cross-arch prosthesis 1 year after loading. MATERIALS AND METHODS: Eighty consecutive patients were recruited. To be immediately loaded, implants had to be inserted with a minimum torque of 80 Ncm. Outcome measures, evaluated by two independent assessors, were prosthesis and implant failures, complications, marginal bone level changes, implant stability quotient (ISQ) values and patient satisfaction. RESULTS: Flaps were raised in 7 patients. Twelve implants in 7 patients did not reach the planned insertion torque. Four implants in 3 patients were immediately replaced by larger diameter implants and achieved the desired torque, whereas the remaining implants were immediately loaded anyway. Two implants failed early in 2 patients, but were successfully replaced and their prostheses remade. One month after loading, 72 (90%) patients declared to be completely satisfied with the therapy, 7 (9%) partially satisfied and 1 (1%) unsatisfied. One year after loading, all prostheses were in function, though one patient did not attend the 1-year control. Eight (10%) complications occurred, all successfully treated. After 1 year, the mean marginal bone loss was 0.3 mm and mean ISQ values decreased from 75.4 to 72.4. CONCLUSIONS: These short-term results at 1 year after loading suggest that immediately loaded mandibular cross arch fixed prostheses can be supported by only 2 dental implants. Longer follow ups (around 10 years) are needed to know the prognosis of this treatment modality. PMID- 22518380 TI - Immediate loading of two unsplinted implants retaining the existing complete mandibular denture in elderly edentulous patients: 1-year results from a multicentre prospective cohort study. AB - PURPOSE: To evaluate the outcome of two freestanding implants immediately loaded retaining an existing mandibular complete denture in elderly edentulous patients up to 1 year after loading. MATERIALS AND METHODS: 42 patients with a mean age of 76.5 years (range 71 to 89) were selected for stabilising their mandibular complete denture with two implants placed mesial to the mandibular canine position bilaterally. Individual ball abutments were connected and torqued at 30 Ncm and the existing complete denture was immediately attached. No postoperative limitations to chewing function were given. The patients were evaluated clinically and radiographically at implant placement and at 6- and 12-month follow-up examinations. RESULTS: At the 12-month follow-up no implant failed. Peri-implant bone resorption was 0.203 mm (CI 95% 0.322; 0.086) after 6 months and 0.298 mm (CI 95% 0.425; 0.173) after 12 months. Of the 42 cases, 3 had major prosthetic complications and 5 patients required minor extra maintenance appointments. CONCLUSIONS: Within the limits of this study, it can be suggested that the immediate loading of two unsplinted implants retaining the existing complete mandibular denture in elderly patients can result in favourable implant survival and peri-implant bone healing, however larger and longer follow-ups of 5 years or more are needed. PMID- 22518381 TI - A retrospective cohort study of 113 patients rehabilitated with immediately loaded maxillary cross-arch fixed dental prostheses in combination with immediate implant placement. AB - PURPOSE: To retrospectively evaluate the outcome of immediately loaded cross-arch fixed dental prostheses 6 months after loading. A second aim was to compare survival rates of implants placed in healed versus fresh extraction sites. MATERIALS AND METHODS: In total, 113 consecutive patients about to have their maxillae rendered fully edentulous (mean extractions per patient: 6.7 teeth) received four to eight implants each (total number = 675) which were immediately placed in healed sites (323 implants, 47.9%) or fresh sockets (352 implants, 52.1%). Immediate loading of provisional prostheses was performed and all patients were followed up for 6 months. The success criteria included prosthesis success, assessment of individual implant stability and complications. RESULTS: No patients dropped out and all 113 patients received definitive fixed prostheses after 6 months of loading. The overall implant survival rate after 6 months was 99.1%. Six implants were lost in 6 patients (5.3%). Five of them were inserted in fresh extraction sockets (1.4%) and one in a healed site (0.3%). No significant difference (P = 0.1621) was found for implants placed in healed sites versus fresh extraction sites. Ten patients had fractures of the provisional prostheses as complications. CONCLUSIONS: Immediate implant placement and loading resulted in high implant as well as prosthetic survival rates. Placement in healed or fresh extraction bone sites may not influence implant survival. PMID- 22518383 TI - Shear bond strength of self-etching adhesive systems with different pH values to bleached and/or CPP-ACP-treated enamel. AB - PURPOSE: To compare shear bond strengths of three different self-etching adhesive systems of different pH values to enamel bleached with carbamide peroxide, treated with casein phosphopeptide-amorphous calcium phosphate (CPP-ACP), or treated with CPP-ACP subsequent to bleaching with carbamide peroxide. MATERIALS AND METHODS: Thirty-six human third molars were cut into 4 sections and randomly assigned to 4 groups (n = 36): group I: no treatment; group II: bleaching; group III: CPP-ACP; group IV: bleaching and CPP-ACP. After surface treatments, the samples of each group were further divided into three subgroups (n = 12) based on the adhesive used. The adhesives Clearfil SE Bond (CSE), AdhesE (ADE), and Adper SE Plus (ADP) were applied, and resin composite cylinders with a diameter of 2 mm and a height of 4 mm were bonded to the enamel. Then the specimens were subjected to shear bond strength testing. Two-way ANOVA and a post-hoc Tukey's test were used for statistical analysis (alpha = 0.05). RESULTS: There were significant differences between the adhesive systems (p < 0.001) and surface treatments (p < 0.001), but no significant interactions were observed between these variables (p = 0.78). The CSE adhesive system showed the highest bond strength, and the bleaching procedure reduced bond strengths (p = 0.001). Furthermore, there were no significant differences in shear bond strength values between the control and CPP groups. However, the differences between other groups were statistically significant (p < 0.05). CONCLUSION: Bleaching reduced shear bond strength to enamel, but CPP-ACP application did not affect the bond strength to intact and previously bleached enamel. The bond strength of adhesives with different pH values to enamel was material dependent. PMID- 22518384 TI - Efficacy of air-abrasion technique and additional surface treatment at titanium/resin cement interface. AB - PURPOSE: To evaluate the effect of surface treatments on the shear bond strength (SBS) of a resin cement to commercially pure titanium (CP Ti). MATERIALS AND METHODS: Two hundred cast CP Ti disks were divided into 5 groups (n = 40), which were treated with one of the following air-abrasion techniques: (1) 50-um Al2O3 particles; (2) 120-um Al2O3 particles; (3) 250-um Al2O3 particles; (4) 30-um silica-modified Al2O3 particles (Cojet Sand); (5) 50-um Al2O3 particles followed by 110-um silica-modified Al2O3 particles (Rocatec Plus). For each air-abrasion technique, the following additional surface treatments were used (n = 10): (1) none; (2) adhesive Adper Single Bond 2; (3) silane RelyX Ceramic Primer; (4) silane plus adhesive. RelyX ARC resin cement was bonded to CP Ti surfaces. All specimens were thermocycled (5,000 cycles) before being tested in shear mode. Data (MPa) were analyzed using two-way ANOVA and Tukey's test (alpha = 0.05). Failure mode was determined with a stereomicroscope (20X). RESULTS: The results revealed that the air-abrasion technique (p < 0.001), additional surface treatment (p < 0.001) and their interaction were significant (p < 0.001). Except for the 50-um Al2O3 + adhesive group, 250-um Al2O3 particles promoted significantly higher SBS than 50-um Al2O3 particles (p < 0.001), while Rocatec Plus provided bond strengths that were similar to or higher than those of Cojet Sand. Of the additional surface treatments, the adhesive provided the best results in combination with the 3 air-abrasion techniques (50-um, 120-um, and 250 um Al2O3), whereas in the groups abraded with silica-modified Al2O3 particles (Cojet Sand and Rocatec Plus), the best results were obtained with additional silane. The two combinations that promoted the highest SBS were 250-um Al2O3 + adhesive and Rocatec Plus + silane. All groups showed 100% adhesive failure. CONCLUSION: The selection of the best additional surface treatment varied according to the air-abrasion technique. Particle size was the decisive factor in determining the bond strength when micromechanical retention was the only bonding mechanism. When both mechanisms were present, in addition to particle size, the material applied as the additional surface treatment also contributed to determining the bond strength. PMID- 22518385 TI - Effect of chlorhexidine incorporation into dental adhesive resin on durability of resin-dentin bond. AB - PURPOSE: This study evaluated the effect of chlorhexidine (CHX) incorporation into experimental dentin adhesives with different hydrophilicities on the microtensile bond strength (uTBS) to dentin. MATERIALS AND METHODS: Flat, deep dentin surfaces were prepared from 60 extracted human third molars. Three ethanol solvated (50 wt% ethanol/50 wt% comonomers) experimental adhesives with varying degrees of hydrophilicity were prepared for the CHX-free groups. For the CHX containing groups, chlorhexidine diacetate was further added to the ethanol solvated adhesives to form a concentration of 2.0 wt% CHX. Dentin surfaces were etched with 37% phosphoric acid for 15 s, rinsed and blot dried before bonding. The adhesives were generously applied to dentin with a microbrush for 15 s. A second application of fresh adhesive was made and light cured for 20 s (600 mW/cm2) after solvent evaporation. Composite buildups were made using Filtek Z250 (3M ESPE). The bonded teeth were sectioned into 0.9 mm x 0.9 mm beams and stressed to failure at a crosshead speed of 1 mm/min. Testing was performed 24 h after specimen preparation and 12 months after storage in artificial saliva. The uTBS data were analyzed using three-way ANOVA and Tukey's multiple comparison tests. Fractographic analysis was performed by SEM. RESULTS: Significant differences were observed for the three factors "adhesive hydrophilicity" (p < 0.001), "CHX incorporation" (p = 0.001), and "storage time" (p < 0.001). Interaction among these three factors was also significant (p < 0.001). Incorporation of CHX had no effect on the immediate bond strength of the three experimental adhesives (p > 0.05). After storage in artificial saliva, significant reduction in bond strength was observed in all adhesive groups, except for CHX-containing adhesive I (p < 0.001). The uTBS of the CHX-containing experimental adhesive III was significantly higher than the corresponding CHX free adhesive (p < 0.001) after aging. CONCLUSION: When incorporated into hydrophilic dental adhesives, chlorhexidine can partially reduce the degradation of the resin-dentin bonds. PMID- 22518386 TI - Time to abandon traditional bond strength testing? PMID- 22518387 TI - Is in vitro research in restorative dentistry useless? PMID- 22518388 TI - Experimental adhesives with different hydrophilicity: microshear test in after 1, 7, and 90 days' storage. AB - PURPOSE: To assess the microshear bond strength of 3 experimental adhesives with different degrees of hydrophilicity after 1, 7 and 90 days of storage. MATERIALS AND METHODS: The bonding effectiveness of three experimental two-step etch-and rinse adhesives (bis- GMA, bis-EMA/bis-GMA, polybutadiene [C6H12]) and one commercial adhesive (Single Bond) to sound hydrated dentin was determined using the microshear test with delimitation of the adhesive area after 1, 7, and 90 days of storage in water at 37 degrees C. Two-way ANOVA was performed at the 0.05 probability level. The fractures were classified as adhesive, cohesive in dentin, cohesive in resin, and mixed. RESULTS: The experimental adhesives showed values in the range of 11.31 to 12.96 MPa, with polybutadiene (PBH) showing the lowest bond strengths, bis-GMA the highest, and bis-EMA/bis-GMA intermediary values. Single Bond yielded bond strengths of approximately 24 MPa. Water storage decreased the bond strength in all adhesives. Adhesive fractures were predominant in experimental adhesives, while mixed fractures were the most frequent type in the Single Bond group. CONCLUSION: The experimental dentin adhesives of this study were able to form resin tags, but they could not penetrate into the collagen fibers and form hybrid layers. The resulting low bond strength decreased with increasing length of storage. PMID- 22518389 TI - RCPE UK Consensus Conference on 'Approaching the comprehensive management of atrial fibrillation: evolution or revolution?'. PMID- 22518390 TI - How can we best detect atrial fibrillation? AB - Atrial fibrillation (AF) is an arrhythmia of increasing prevalence associated with a reducible risk of stroke. We conducted a systematic review to address five questions relating to how we can best detect AF: 1. Are there useful screening tests to determine who should have a 12-lead electrocardiogram (ECG)? Potential screening tests, all with acceptable sensitivity, include pulse palpation, single lead ECG and newer technologies such as modified sphygmomanometers or a finger probe device. Pulse palpation has a high number of false positives, but is the cheapest method. 2. Is it more effective to offer 12-lead ECGs to the whole population (or specific sub-groups) or only to those who screen positive for AF? The cost-effectiveness of new devices, such as a modified blood pressure monitor, needs to be assessed. It is more cost-effective to opportunistically screen people rather than to offer a 12-lead ECG to everybody. 3. How accurate are different healthcare professionals and interpretative software at diagnosing AF on ECG? Definitive diagnosis of AF should be by 12-lead ECG, interpreted by someone with appropriate expertise. Computer software is not currently sensitive enough to be used alone to diagnose AF on ECG. Primary care practitioners may not accurately detect AF on ECG, but consistently high accuracy can be achieved by healthcare professionals with adequate training. 4. How best can we diagnose paroxysmal atrial fibrillation (PAF)? In patients in whom PAF is suspected, longer periods of monitoring will detect more cases of PAF. 5. What is the impact of the use of different ECG monitoring strategies (e.g. Holter monitoring, serial ECGs, continuous ECG) on AF detection rates post-stroke? In patients post-stroke, a single ECG will miss cases of PAF which can be detected by longer duration monitoring such as Holter monitoring, cardiac event recorders and serial ECGs. Further research into the cost-effectiveness of these methods, the duration of monitoring required and the clinical significance of the PAF detected is needed. PMID- 22518391 TI - Atrial fibrillation: the rate versus rhythm management controversy. AB - The fundamental management strategy for atrial fibrillation (AF) is still debated. There is no doubt that those patients at risk of thromboembolic events should be offered anticoagulant therapy. However, it is uncertain whether rhythm control (restoration and maintenance of sinus rhythm) or rate control (adjustment to a physiological ventricular rate while allowing AF to continue) is the preferred primary treatment option for the reduction of symptoms and major cardiovascular (CV) outcomes associated with AF. Several well conducted trials comparing the two strategies led to the conclusion that there was little to choose between them. However, guidelines leaned towards recommending rate control as the initial strategy, and reserved rhythm control for those who remained symptomatic. Recently this status quo is being increasingly challenged by the clear demonstration that left atrial catheter ablation is effective at suppressing AF resistant to traditional antiarrhythmic drugs, such as those that failed to demonstrate any superiority when compared with rate control. Also, recently introduced antiarrhythmic therapy may have superior efficacy with regard to reducing unexpected CV hospitalization, CV mortality and stroke. In addition, there is a growing perception that atrial remodelling should be best prevented by early rhythm control rather than delaying until rate control has proven unsatisfactory. For these reasons the results of large randomised clinical trials, which recruit patients soon after the presentation of AF and compare 'aggressive' modern rhythm control against the guideline approach of primary rate control, are eagerly awaited. In the meantime the pendulum of clinical opinion has begun to swing towards a rhythm control strategy. PMID- 22518392 TI - What is the most effective and safest delivery of thromboprophylaxis in atrial fibrillation? AB - The presence of atrial fibrillation (AF) increases the risk of stroke fivefold, but the risk is dependent upon the presence of stroke risk factors. The challenge is defining patients who would best benefit from thromboprophylaxis, and how to deliver it in the most effective and safe way. The objective of this brief overview is to address this question. Previously, attention has been directed towards identifying high-risk patients who could be subjected to an inconvenient (and potentially dangerous) drug, warfarin. Aspirin has been increasingly recognised as an inferior choice for stroke prevention, and may not be any safer than warfarin in terms of major bleeding, especially in the elderly. Thus, the focus more recently has been directed towards identifying truly low-risk patients who do not need any antithrombotic therapy, and all others with >= 1 stroke risk factors should be considered for oral anticoagulation therapy (whether as well controlled warfarin or one of the new oral anticoagulant drugs), as the most effective means of reducing the risk of stroke and thromboembolism in AF. PMID- 22518393 TI - What are the differences between physician and patient expectation with regard to the management of atrial fibrillation? AB - BACKGROUND: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, with approximately 840,000 people suffering from it nationally. People with AF have an increased risk of stroke which can be mitigated effectively with the use of anticoagulant therapy. Nevertheless, evidence suggests that less than 50% of eligible patients are receiving this form of intervention. METHOD: A comprehensive literature search was undertaken to assess the published evidence in order to understand why clinicians and patients underutilize an effective intervention such as anticoagulation in favor of the less effective antiplatelet agents. RESULTS: The decision to use anticoagulant drugs in patients with AF involves a consideration of the potential benefits versus the risks, inconveniences, and costs. There is however widespread variation in the importance placed on these factors across primary care practices, individual doctors and between and within different patient groups. There is a paucity of literature designed to examine patient expectations. Available studies suggest that patients are prepared to be placed at a higher risk of bleeding than their prescribing doctors would be prepared to accept. Given that this judgement depends on a range of factors, it is not surprising that attempts to understand clinician's barriers to prescribing take precedence. CONCLUSION: The barriers to anticoagulation can be identified, but we still don't understand the importance that clinicians and individuals give them. These barriers continue to limit the use of anticoagulation therapy, a potentially beneficial treatment. Due to these limitations it is unclear what impact the increased range of oral anticoagulants and the alternation to the Quality and Outcomes Framework (QoF) will have on the incentive to primary care physicians to anticoagulate those at risk. PMID- 22518820 TI - Air pollution shortens life expectancy and health expectancy for older adults: the case of China. AB - BACKGROUND: Outdoor air pollution is one of the most worrying environmental threats China faces today. Comprehensive and quantitative analyses of the health consequences of air pollution in China are lacking. This study reports age- and sex-specific life expectancy and health expectancies (HEs) corresponding to different levels of air pollution based on associations between air pollution and individual risks for a host of health conditions and mortality net of individual- and community-level confounders. METHODS: This is a multilevel prospective cohort study based a nationally representative sample of Chinese elders. The main outcome measures in this study include life expectancy estimated from mortality and HEs based on five health conditions including activity of daily living, instrumental activity of daily living, cognitive status, self-rated health, and chronic conditions. RESULTS: Net of the controls, exposure to outdoor air pollution corresponded to subsequent reductions of life expectancy and HEs for all five health conditions. These detrimental pollution effects were stronger for women. The gap in life expectancy between areas with good air quality and moderately heavily polluted areas was 3.78 years for women of age 65 and 0.93 years for men. The differences in HEs at age 65 were also large, ranging from 1.47 years for HE for good self-rated health in men to 5.20 years for activity of daily living disability-free HE in women. CONCLUSIONS: Air pollution has devastating health impacts on Chinese elders reducing longevity and shortening HEs. Women are more vulnerable than men. More strict air policy should be implemented to pursue sustainable development in China. PMID- 22518819 TI - Toward a positive aging phenotype for older women: observations from the women's health initiative. AB - BACKGROUND: To develop a positive aging phenotype, we undertook analyses to describe multiple dimensions of positive aging and their relationships to one another in women 65 years of age and older and evaluate the performance of individual indicators and composite factors of this phenotype as predictors of time to death, years of healthy living, and years of independent living. METHODS: Data from Women's Health Initiative clinical trial and observational study participants ages 65 years and older at baseline, including follow-up observations up to 8 years later, were analyzed using descriptive statistics and principal components analysis to identify the factor structure of a positive aging phenotype. The factors were used to predict time to death, years of healthy living (without hospitalization or diagnosis of a serious health condition), and years of independent living (without nursing home admission or use of special services). RESULTS: We identified a multidimensional phenotype of positive aging that included two factors: Physical-Social Functioning and Emotional Functioning. Both factors were predictive of each of the outcomes, but Physical-Social Functioning was the strongest predictor. Each standard deviation of increase in Physical-Social Functioning was accompanied by a 23.7% reduction in mortality risk, a 19.4% reduction in risk of major health conditions or hospitalizations, and a 26.3% reduction in risk of dependent living. CONCLUSIONS: Physical-Social Functioning and Emotional Functioning constitute important components of a positive aging phenotype. Physical-Social Functioning was the strongest predictor of outcomes related to positive aging, including years of healthy living, years of independent living, and time to mortality. PMID- 22518821 TI - Among dual eligibles, identifying the highest-cost individuals could help in crafting more targeted and effective responses. AB - The nearly nine million people who receive Medicare and Medicaid benefits, known as dual eligibles, constitute one of the nation's most vulnerable and costly populations. Several initiatives authorized by the Affordable Care Act are intended to improve the health care delivered to dual eligibles and, at the same time, to achieve greater control of spending growth for the two government programs. We examined the 2007 costs and service use associated with dual eligibles. Although the population is indeed costly, we found nearly 40 percent of dual eligibles had lower average per capita spending than non-dual-eligible Medicare beneficiaries. In addition, we found that about 20 percent of dual eligibles accounted for more than 60 percent of combined Medicaid and Medicare spending on the dual-eligible population. But even among these high-cost dual eligibles, we found subgroups. For example, fewer than 1 percent of dual eligibles were in high-cost categories for both Medicare and Medicaid. These findings suggest that decision makers should tailor reform initiatives to account for subpopulations of dual eligibles, their costs, and their service use. PMID- 22518823 TI - Semen quality in males with latent genital infections. PMID- 22518822 TI - Arthritogenic T cells drive the recovery of autoantibody-producing B cell homeostasis and the adoptive transfer of arthritis in SCID mice. AB - T cells orchestrate joint inflammation in rheumatoid arthritis (RA), but B cells/B cell-derived factors are also involved in disease pathogenesis. The goal of this study was to understand the role of antigen-specific T and B cells in the pathological events of arthritis, which is impossible to study in humans due to the small number of antigen-specific cells. To determine the significance of antigen-specific lymphocytes and antibodies in the development of an autoimmune mouse model of RA, we generated TCR transgenic (TCR-Tg) mice specific for the dominant arthritogenic epitope of cartilage proteoglycan (PG) and performed a series of combined transfers of T cells, B cells and autoantibodies into BALB/c.Scid mice. The adoptive transfer of highly purified T cells from naive TCR Tg, arthritic TCR-Tg or arthritic wild-type mice induced arthritis in SCID recipients, but the onset and severity of the disease were dependent on the sequential events of the T cell-supported reconstitution of PG-specific B cells and autoantibodies. The presence of activated PG-specific T cells was critical for disease induction, establishing a unique milieu for the selective homeostasis of autoantibody-producing B cells. In this permissive environment, anti-PG autoantibodies bound to cartilage and induced activation of the complement cascade, leading to irreversible cartilage destruction in affected joints. These findings may lead to a better understanding of the complex molecular and cellular mechanisms of RA. PMID- 22518824 TI - A unique patient presenting with concomitant Klinefelter syndrome, Alport syndrome, and craniopharyngioma. AB - A 31-year-old Caucasian male was referred for panhypopituitarism resulting from a surgically removed craniopharyngioma. The patient had been previously submitted to kidney transplantation for end-stage renal disease from X-linked Alport syndrome (ATS). Subsequent quantitative fluorescent polymerase chain reaction analysis indicated a 47,XXY karyotype consistent with Klinefelter syndrome (KS). The relevance of this unique case stems from several issues: 1) KS was an unexpected finding because of a previous diagnosis of hypogonadotropic hypogonadism resulting from craniopharyngioma; 2) the discovery of a de novo p.G406S substitution causing ATS; and 3) the multifactor origin of severe sexual dysfunction. This is the first description of the co-occurrence of KS, ATS, and craniopharyngioma. PMID- 22518825 TI - Perspectives and editorials: letter to the editor. PMID- 22518826 TI - Monthly variation in acute urinary retention incidence among patients with benign prostatic enlargement in Taiwan. AB - Acute urinary retention (AUR) is characterized by a sudden and painful inability to pass urine and is the most common urological emergency. However, according to our knowledge, no study to date has attempted to explore the monthly variation of AUR after adjusting for climatic parameters. This study aimed to examine the monthly variation of AUR due to benign prostatic enlargement (BPE) in Taiwan. The data used in this study were sourced from 2 datasets: the Longitudinal Health Insurance Database 2005 and a meteorological dataset supplied by the Taiwan Central Weather Bureau. We identified 1406 patients aged 40 years or more with a diagnosis of BPE that could all be followed throughout a 6-year study period (2003-2008). We used the autoregressive integrated moving average (ARIMA) method to examine the incidence of AUR for seasonality. The results show that January (midwinter) had the highest rates, decreasing in March to a trough in June (early summer). The incidence then increased again and reached a peak in December (early winter). The ARIMA test also revealed significant monthly variation in the incidence of AUR. In addition, the ARIMA regression revealed that January, February, August, October, November, and December had significantly higher monthly incidence rates of AUR compared with June, after adjusting for the time trend effect and climatic parameters. Our study concluded that significant monthly variation in the incidence of AUR occurred, and January (midwinter) had the highest rates. PMID- 22518827 TI - Transient receptor potential vanilloid type 1 channels contribute to reflex cutaneous vasodilation in humans. AB - Mechanisms underlying the cutaneous vasodilation in response to an increase in core temperature remain unresolved. The purpose of this study was to determine a potential contribution of transient receptor potential vanilloid type 1 (TRPV-1) channels to reflex cutaneous vasodilation. Twelve subjects were equipped with four microdialysis fibers on the ventral forearm, and each site randomly received 1) 90% propylene glycol + 10% lactated Ringer (vehicle control); 2) 10 mM l-NAME; 3) 20 mM capsazepine to inhibit TRPV-1 channels; 4) combined 10 mM l-NAME + 20 mM capsazepine. Whole body heating was achieved via water-perfused suits sufficient to raise oral temperature at least 0.8 degrees C above baseline. Maximal skin blood flow was achieved by local heating to 43 degrees C and infusion of 28 mM nitroprusside. Systemic arterial pressure (SAP) was measured, and skin blood flow was monitored via laser-Doppler flowmetry (LDF). Cutaneous vascular conductance (CVC) was calculated as LDF/SAP and normalized to maximal vasodilation (%CVC(max)). Capsazepine sites were significantly reduced compared with control (50 +/- 4%CVC(max) vs. 67 +/- 5%CVC(max), respectively; P < 0.05). l-NAME (33 +/- 3%CVC(max)) and l-NAME + capsazepine (30 +/- 4%CVC(max)) sites were attenuated compared with control (P < 0.01) and capsazepine (P < 0.05); however, there was no difference between l-NAME and combined l-NAME + capsazepine. These data suggest TRPV-1 channels participate in reflex cutaneous vasodilation and TRPV-1 channels may account for a portion of the NO component. TRPV-1 channels may have a direct neural contribution or have an indirect effect via increased arterial blood temperature. Whether the TRPV-1 channels directly or indirectly contribute to reflex cutaneous vasodilation remains uncertain. PMID- 22518828 TI - Absence of inspiratory laryngeal constrictor muscle activity during nasal neurally adjusted ventilatory assist in newborn lambs. AB - In nonsedated newborn lambs, nasal pressure support ventilation (nPSV) can lead to an active glottal closure in early inspiration, which can limit lung ventilation and divert air into the digestive system, with potentially deleterious consequences. During volume control ventilation (nVC), glottal closure is delayed to the end of inspiration, suggesting that it is reflexly linked to the maximum value of inspiratory pressure. Accordingly, the aim of the present study was to test whether inspiratory glottal closure develops at the end of inspiration during nasal neurally adjusted ventilatory assist (nNAVA), an increasingly used ventilatory mode where maximal pressure is also reached at the end of inspiration. Polysomnographic recordings were performed in eight nonsedated, chronically instrumented lambs, which were ventilated with progressively increasing levels of nPSV and nNAVA in random order. States of alertness, diaphragm, and glottal muscle electrical activity, tracheal pressure, Spo(2), tracheal Pet(CO(2)), and respiratory inductive plethysmography were continuously recorded. Although phasic inspiratory glottal constrictor electrical activity appeared during nPSV in 5 of 8 lambs, it was never observed at any nNAVA level in any lamb, even at maximal achievable nNAVA levels. In addition, a decrease in Pco(2) was neither necessary nor sufficient for the development of inspiratory glottal constrictor activity. In conclusion, nNAVA does not induce active inspiratory glottal closure, in contrast to nPSV and nVC. We hypothesize that this absence of inspiratory activity is related to the more physiological airway pressurization during nNAVA, which tightly follows diaphragm electrical activity throughout inspiration. PMID- 22518829 TI - Rapid microcomputed tomography suggests cardiac enlargement occurs during conductance catheter measurements in mice. AB - Conductance catheters (CC) represent an established method of determining cardiac function in mice; however, the potentially detrimental effects a catheter may have on the mouse heart have never been evaluated. The present study takes advantage of rapid three-dimensional (3D) microcomputed tomography (CT) to compare simultaneously acquired micro-CT and CC measurements of left ventricular (LV) volumes in healthy and infarcted mice and to determine changes in LV volume and function associated with CC insertion. LV volumes were measured in C57BL/6 mice (10 healthy, 10 infarcted, 2% isoflurane anesthesia) using a 1.4-Fr Millar CC. 3D micro-CT images of each mouse were acquired before CC insertion as well as during catheterization. Each CT scan produced high-resolution images throughout the entire cardiac cycle in <1 min, enabling accurate volume measurements as well as direct visualization of the CC within the LV. Bland-Altman analysis demonstrated that CC measurements underestimate volume compared with CT measurements in both healthy [bias of -18.4 and -28.9 MUl for end-systolic (ESV) and end-diastolic volume (EDV), respectively] and infarcted mice (ESV = -51.6 MUl and EDV = -71.7 MUl); underestimation was attributed to the off-center placement of the catheter. Individual evaluation of each heart revealed LV dilation following CC insertion in 40% of mice in each group. No change in ejection fraction was observed, suggesting the enlargement was caused by volume overload associated with disruption of the papillary muscles or chords. The enlargement witnessed was not significant; however, the results suggest the potential for CC insertion to detrimentally affect mouse myocardium, necessitating further investigation. PMID- 22518830 TI - Point: alterations in airway smooth muscle phenotype do/do not cause airway hyperresponsiveness in asthma. PMID- 22518831 TI - Deficiency of inducible nitric oxide synthase attenuates immobilization-induced skeletal muscle atrophy in mice. AB - The present study examined the effects of inducible nitric oxide synthase (iNOS) deficiency on skeletal muscle atrophy in single leg-immobilized iNOS knockout (KO) and wild-type (WT) mice. The left leg was immobilized for 1 wk, and the right leg was used as the control. Muscle weight and contraction-stimulated glucose uptake were reduced by immobilization in WT mice, which was accompanied with increased iNOS expression in skeletal muscle. Deficiency of iNOS attenuated muscle weight loss and the reduction in contraction-stimulated glucose uptake by immobilization. Phosphorylation of Akt, mTOR, and p70S6K was reduced to a similar extent by immobilization in both WT and iNOS KO mice. Immobilization decreased FoxO1 phosphorylation and increased mRNA and protein levels of MuRF1 and atrogin 1 in WT mice, which were attenuated in iNOS KO mice. Aconitase and superoxide dismutase activities were reduced by immobilization in WT mice, and deficiency of iNOS normalized these enzyme activities. Increased nitrotyrosine and carbonylated protein levels by immobilization in WT mice were reversed in iNOS KO mice. Phosphorylation of ERK and p38 was increased by immobilization in WT mice, which was reduced in iNOS KO mice. Immobilization-induced muscle atrophy was also attenuated by an iNOS-specific inhibitor N(6)-(1-iminoethyl)-l-lysine, and this finding was accompanied by increased FoxO1 phosphorylation and reduced MuRF1 and atrogin-1 levels. These results suggest that deficiency of iNOS attenuates immobilization-induced skeletal muscle atrophy through reduced oxidative stress, and iNOS-induced oxidative stress may be required for immobilization-induced skeletal muscle atrophy. PMID- 22518832 TI - Synergistic effect of obesity and lipid ingestion in suppressing the growth hormone response to exercise in children. AB - Diet plays an important role in modulating exercise responses, including activation of the growth hormone (GH)/insulin-like growth factor-I (IGF-1) axis. Obesity and fat ingestion were separately shown to reduce exercise GH responses, but their combined effect, especially important in children, has not been studied. We therefore measured the GH response to exercise [30-min intermittent cycling, ten 2-min bouts at ~80% maximal aerobic capacity (Vo(2max)), separated by 1-min rest], started 45 min after ingestion of a high-fat meal (HFM) in 16 healthy [controls; body mass index percentile (BMI%ile) 51 +/- 7], and 19 obese (Ob, BMI%ile 97 +/- 0.4) children. Samples were drawn at baseline (premeal), and at start, peak, and 30 min postexercise. In the Ob group, a marked ~75% suppression of the GH response (ng/ml) to exercise was observed (2.4 +/- 0.6 vs. 10.6 +/- 2.1, P < 0.001). This level of suppression was also significantly greater compared with age-, fitness-, and BMI-matched historical controls that had performed identical exercise in fasting conditions. Our data indicate that the reduction in the GH response to exercise, already present in obese children vs. healthy controls, is considerably amplified by ingestion of fat nutrients shortly before exercise, implying a potentially downstream negative impact on growth factor homeostasis and long-term modulation of physiological growth. PMID- 22518833 TI - Muscle atrophy is not always sarcopenia. PMID- 22518834 TI - MAPK signaling in the quadriceps of patients with chronic obstructive pulmonary disease. AB - Muscle atrophy in chronic obstructive pulmonary disease (COPD) is associated with reduced exercise tolerance, muscle strength, and survival. The molecular mechanisms leading to muscle atrophy in COPD remain elusive. The mitogen activated protein kinases (MAPKs) such as p38 MAPK and ERK 1/2 can increase levels of MAFbx/Atrogin and MuRF1, which are specifically involved in muscle protein degradation and atrophy. Our aim was to investigate the level of activation of p38 MAPK, ERK 1/2, and JNK in the quadriceps of patients with COPD. A biopsy of the quadriceps was obtained in 18 patients with COPD as well as in 9 healthy controls. We evaluated the phosphorylated as well as total protein levels of p38 MAPK, ERK 1/2, and JNK as well as MAFbx/Atrogin and MuRF1 in these muscle samples. The corresponding mRNA expression was also assessed by RT-PCR. Ratios of phosphorylated to total level of p38 MAPK (P = 0.02) and ERK 1/2 (P = 0.01) were significantly elevated in patients with COPD compared with controls. Moreover, protein levels of MAFbx/Atrogin showed a tendency to be greater in patients with COPD (P = 0.08). mRNA expression of p38 MAPK (P = 0.03), ERK 1/2 (P = 0.02), and MAFbx/Atrogin (P = 0.04) were significantly elevated in patients with COPD. In addition, phosphorylated-to-total p38 MAPK ratio (Pearson's r = -0.45; P < 0.05) and phosphorylated-to-total ERK 1/2 ratio (Pearson's r = -0.47; P < 0.05) were negatively associated with the mid-thigh muscle cross-sectional area. These data support the hypothesis that the MAPKs might play a role in the development of muscle atrophy in COPD. PMID- 22518835 TI - Resistance exercise load does not determine training-mediated hypertrophic gains in young men. AB - We have reported that the acute postexercise increases in muscle protein synthesis rates, with differing nutritional support, are predictive of longer term training-induced muscle hypertrophy. Here, we aimed to test whether the same was true with acute exercise-mediated changes in muscle protein synthesis. Eighteen men (21 +/- 1 yr, 22.6 +/- 2.1 kg/m(2); means +/- SE) had their legs randomly assigned to two of three training conditions that differed in contraction intensity [% of maximal strength (1 repetition maximum)] or contraction volume (1 or 3 sets of repetitions): 30%-3, 80%-1, and 80%-3. Subjects trained each leg with their assigned regime for a period of 10 wk, 3 times/wk. We made pre- and posttraining measures of strength, muscle volume by magnetic resonance (MR) scans, as well as pre- and posttraining biopsies of the vastus lateralis, and a single postexercise (1 h) biopsy following the first bout of exercise, to measure signaling proteins. Training-induced increases in MR measured muscle volume were significant (P < 0.01), with no difference between groups: 30%-3 = 6.8 +/- 1.8%, 80%-1 = 3.2 +/- 0.8%, and 80%-3= 7.2 +/- 1.9%, P = 0.18. Isotonic maximal strength gains were not different between 80%-1 and 80%-3, but were greater than 30%-3 (P = 0.04), whereas training-induced isometric strength gains were significant but not different between conditions (P = 0.92). Biopsies taken 1 h following the initial resistance exercise bout showed increased phosphorylation (P < 0.05) of p70S6K only in the 80%-1 and 80%-3 conditions. There was no correlation between phosphorylation of any signaling protein and hypertrophy. In accordance with our previous acute measurements of muscle protein synthetic rates a lower load lifted to failure resulted in similar hypertrophy as a heavy load lifted to failure. PMID- 22518836 TI - Mitochondrial dysfunction in skeletal muscle of amyloid precursor protein overexpressing mice. AB - Inclusion body myositis, the most common muscle disorder in the elderly, is partly characterized by abnormal expression of amyloid precursor protein (APP) and intracellular accumulation of its proteolytic fragments collectively known as beta-amyloid. The present study examined the effects of beta-amyloid accumulation on mitochondrial structure and function of skeletal muscle from transgenic mice (MCK-betaAPP) engineered to accumulate intramyofiber beta-amyloid. Electron microscopic analysis revealed that a large fraction of myofibers from 2-3-month old MCK-betaAPP mice contained numerous, heterogeneous alterations in mitochondria, and other cellular organelles. [(1)H-decoupled](13)C NMR spectroscopy showed a substantial reduction in TCA cycle activity and indicated a switch from aerobic to anaerobic glucose metabolism in the MCK-betaAPP muscle. Isolated muscle fibers from the MCK-betaAPP mice also exhibited a reduction in cytoplasmic pH, an increased rate of ROS production, and a partially depolarized plasmalemma. Treatment of MCK-betaAPP muscle cells with Ru360, a mitochondrial Ca(2+) uniporter antagonist, reversed alterations in the plasmalemmal membrane potential (V(m)) and pH. Consistent with altered redox state of the cells, treatment of MCK-betaAPP muscle cells with glutathione reversed the effects of beta-amyloid accumulation on Ca(2+) transient amplitudes. We conclude that structural and functional alterations in mitochondria precede the reported appearance of histopathological and clinical features in the MCK-betaAPP mice and may represent key early events in the pathogenesis of inclusion body myositis. PMID- 22518837 TI - Chaperonin cofactors, Cpn10 and Cpn20, of green algae and plants function as hetero-oligomeric ring complexes. AB - The chloroplast chaperonin system of plants and green algae is a curiosity as both the chaperonin cage and its lid are encoded by multiple genes, in contrast to the single genes encoding the two components of the bacterial and mitochondrial systems. In the green alga Chlamydomonas reinhardtii (Cr), three genes encode chaperonin cofactors, with cpn10 encoding a single ~10-kDa domain and cpn20 and cpn23 encoding tandem cpn10 domains. Here, we characterized the functional interaction of these proteins with the Escherichia coli chaperonin, GroEL, which normally cooperates with GroES, a heptamer of ~10-kDa subunits. The C. reinhardtii cofactor proteins alone were all unable to assist GroEL-mediated refolding of bacterial ribulose-bisphosphate carboxylase/oxygenase but gained this ability when CrCpn20 and/or CrCpn23 was combined with CrCpn10. Native mass spectrometry indicated the formation of hetero-oligomeric species, consisting of seven ~10-kDa domains. The cofactor "heptamers" interacted with GroEL and encapsulated substrate protein in a nucleotide-dependent manner. Different hetero oligomer arrangements, generated by constructing cofactor concatamers, indicated a preferential heptamer configuration for the functional CrCpn10-CrCpn23 complex. Formation of heptamer Cpn10/Cpn20 hetero-oligomers was also observed with the Arabidopsis thaliana (At) cofactors, which functioned with the chloroplast chaperonin, AtCpn60alpha(7)beta(7). It appears that hetero-oligomer formation occurs more generally for chloroplast chaperonin cofactors, perhaps adapting the chaperonin system for the folding of specific client proteins. PMID- 22518838 TI - Stapling mimics noncovalent interactions of gamma-carboxyglutamates in conantokins, peptidic antagonists of N-methyl-D-aspartic acid receptors. AB - Conantokins are short peptides derived from the venoms of marine cone snails that act as antagonists of the N-methyl-D-aspartate (NMDA) receptor family of excitatory glutamate receptors. These peptides contain gamma-carboxyglutamic acid residues typically spaced at i,i+4 and/or i,i+7 intervals, which by chelating divalent cations induce and stabilize helical conformation of the peptide. Introduction of a dicarba bridge (or a staple) can covalently stabilize peptide helicity and improve its pharmacological properties. To test the hypothesis that stapling can effectively replace gamma-carboxyglutamic acid residues in stabilizing the helical conformation of conantokins, we designed, synthesized, and characterized several stapled analogs of conantokin G (conG), with varying connectivities in terms of staple length and location along the face of the alpha helix. NMR studies confirmed that the ring-closing metathesis reaction yielded a single product with the Z configuration of the olefinic bond. Based on circular dichroism and molecular modeling, the stapled analogs exhibited significantly enhanced helicity compared with the native peptide in a metal-free environment. Stapling i,i+4 was benign with respect to effects on in vitro and in vivo pharmacological properties. One analog, namely conG[11-15,S(i,i+4)S(8)], blocked NR2B-containing NMDA receptors with IC(50) = 0.7 MUm and provided significant protection in the 6-Hz psychomotor model of pharmacoresistant epilepsy in mice. Remarkably, unlike native conG, conG[11-15,S(i,i+4)S(8)] produced no behavioral motor toxicity. Our results extend the applications of peptide stapling to helical peptides with extracellular targets and provide a means for engineering conantokins with improved pharmacological properties. PMID- 22518839 TI - Period of irreversible therapeutic intervention during sepsis correlates with phase of innate immune dysfunction. AB - Sepsis is a major health problem in the United States with high incidence and elevated patient care cost. Using an animal model of sepsis, cecum ligation, and puncture, we observed that mice became rapidly hypothermic reaching a threshold temperature of 28 degrees C within 5-10 h after initiation of the insult, resulting in a reliable predictor of mortality, which occurred within 30-72 h of the initial procedure. We also observed that the inflammatory gene expression in lung and liver developed early within 1-2 h of the insult, reaching maximum levels at 6 h, followed by a decline, approaching basal conditions within 20 h. This decrease in inflammatory gene expression at 20 h after cecal ligation and puncture was not due to resolution of the insult but rather was an immune dysfunction stage that was demonstrated by the inability of the animal to respond to a secondary external inflammatory stimulus. Removal of the injury source, ligated cecum, within 6 h of the initial insult resulted in increased survival, but not after 20 h of cecal ligation and puncture. We concluded that the therapeutic window for resolving sepsis is early after the initial insult and coincides with a stage of hyperinflammation that is followed by a condition of innate immune dysfunction in which reversion of the outcome is no longer possible. PMID- 22518840 TI - A stretch of polybasic residues mediates Cdc42 GTPase-activating protein (CdGAP) binding to phosphatidylinositol 3,4,5-trisphosphate and regulates its GAP activity. AB - The Rho family of small GTPases are membrane-associated molecular switches involved in the control of a wide range of cellular activities, including cell migration, adhesion, and proliferation. Cdc42 GTPase-activating protein (CdGAP) is a phosphoprotein showing GAP activity toward Rac1 and Cdc42. CdGAP activity is regulated in an adhesion-dependent manner and more recently, we have identified CdGAP as a novel molecular target in signaling and an essential component in the synergistic interaction between TGFbeta and Neu/ErbB-2 signaling pathways in breast cancer cells. In this study, we identified a small polybasic region (PBR) preceding the RhoGAP domain that mediates specific binding to negatively charged phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3). In vitro reconstitution of membrane vesicles loaded with prenylated Rac1 demonstrates that the PBR is required for full activation of CdGAP in the presence of PI(3,4,5)P3. In fibroblast cells, the expression of CdGAP protein mutants lacking an intact PBR shows a significant reduced ability of the protein mutants to induce cell rounding or to mediate negative effects on cell spreading. Furthermore, an intact PBR is required for CdGAP to inactivate Rac1 signaling into cells, whereas it is not essential in an in vitro context. Altogether, these studies reveal that specific interaction between negatively charged phospholipid PI(3,4,5)P3 and the stretch of polybasic residues preceding the RhoGAP domain regulates CdGAP activity in vivo and is required for its cellular functions. PMID- 22518841 TI - Factor H-related protein 4 activates complement by serving as a platform for the assembly of alternative pathway C3 convertase via its interaction with C3b protein. AB - Human complement factor H-related protein (CFHR) 4 belongs to the factor H family of plasma glycoproteins that are composed of short consensus repeat (SCR) domains. Although factor H is a well known inhibitor of the alternative complement pathway, the functions of the CFHR proteins are poorly understood. CFHR4 lacks SCRs homologous to the complement inhibitory domains of factor H and, accordingly, has no significant complement regulatory activities. We have previously shown that CFHR4 binds C-reactive protein via its most N-terminal SCR, which leads to classical complement pathway activation. CFHR4 binds C3b via its C terminus, but the significance of this interaction is unclear. Therefore, we set out to clarify the functional relevance of C3b binding by CFHR4. Here, we report a novel role for CFHR4 in the complement system. CFHR4 serves as a platform for the assembly of an alternative pathway C3 convertase by binding C3b. This is based on the sustained ability of CFHR4-bound C3b to bind factor B and properdin, leading to an active convertase that generates C3a and C3b from C3. The CFHR4 C3bBb convertase is less sensitive to the factor H-mediated decay compared with the C3bBb convertase. CFHR4 mutants containing exchanges of conserved residues within the C-terminal C3b-binding site showed significantly reduced C3b binding and alternative pathway complement activation. In conclusion, our results suggest that, in contrast to the complement inhibitor factor H, CFHR4 acts as an enhancer of opsonization by promoting complement activation. PMID- 22518842 TI - Genetic evidence for critical roles of P38alpha protein in regulating mast cell differentiation and chemotaxis through distinct mechanisms. AB - Mast cells mediate a range of immune responses. However, the mechanisms that contribute to their development remain poorly understood. Here, using a P38alpha conditional knockout system, we provide evidence to suggest that P38alpha plays critical roles in regulating mast cell differentiation and migration via distinct mechanisms. Induced deletion of P38alpha in bone marrow cells retards the maturation of mast cells in part by inhibiting the activation of cAMP response element-binding protein and expression of microphthalmia-associated transcription factor, which encourages the generation of basophils over mast cells. In fully differentiated mast cells, absence of P38alpha inhibits stem cell factor-induced activation of Akt and ERK, which is associated with reduced chemotaxis. In vivo, conditional deletion of P38alpha results in reduced numbers of mast cells in certain tissues and a failure to reconstitute these cells in W(sh) mice transplanted with P38alpha(-/-) Lin(-)c-kit(+)Sca-1(+) (LKS(+)) cells. Our findings suggest that P38alpha plays a dual role in mast cell development by regulating IL-3-induced differentiation of mast cell progenitor cells as well as by regulating stem cell factor-induced migration of fully differentiated mast cells. PMID- 22518843 TI - Soluble monomeric IgG1 Fc. AB - Antibody fragments are emerging as promising biopharmaceuticals because of their relatively small size and other unique properties. However, compared with full size antibodies, these antibody fragments lack the ability to bind the neonatal Fc receptor (FcRn) and have reduced half-lives. Fc engineered to bind antigens but preserve interactions with FcRn and Fc fused with monomeric proteins currently are being developed as candidate therapeutics with prolonged half lives; in these and other cases, Fc is a dimer of two CH2-CH3 chains. To further reduce the size of Fc but preserve FcRn binding, we generated three human soluble monomeric IgG1 Fcs (mFcs) by using a combination of structure-based rational protein design combined with multiple screening strategies. These mFcs were highly soluble and retained binding to human FcRn comparable with that of Fc. These results provide direct experimental evidence that efficient binding to human FcRn does not require human Fc dimerization. The newly identified mFcs are promising for the development of mFc fusion proteins and for novel types of mFc based therapeutic antibodies of small size and long half-lives. PMID- 22518844 TI - Transient aggregation of ubiquitinated proteins is a cytosolic unfolded protein response to inflammation and endoplasmic reticulum stress. AB - Failure to maintain protein homeostasis (proteostasis) leads to accumulation of unfolded proteins and contributes to the pathogenesis of many human diseases. Accumulation of unfolded proteins in the endoplasmic reticulum (ER) elicits unfolded protein response (UPR) that serves to attenuate protein translation, and increase protein refolding or degradation. In contrast to UPR in the ER, the regulatory molecules operative in cytosolic responses and their potential relation to ER stress are not well elucidated. Aggresome-like induced structures (ALIS) have been described as transient aggregation of ubiquitinated proteins in the cytosol. In this study, we show that cells respond to inflammation, infection or ER stress by cytosolic formation of ALIS, indicating that ALIS formation represents an early event in cellular adjustment to altered proteostasis that occurs under these conditions. This response was aided by rapid transcriptional up-regulation of polyubiqutin-binding protein p62. NF-kappaB and mTOR activation were also required for ALIS formation. Importantly, we show a cross talk between UPR in the ER and cytosolic ALIS. Down-regulation of ER UPR in XBP1 deficient cells increases cyotosolic ALIS formation. Furthermore, lysosomal activity but not macroautophagy is responsible for ALIS clearance. This study reveals the underlying regulatory mechanisms of ALIS formation and clearance, and provides a previously unrecognized common adaptive mechanism for cellular responses against inflammation and ER stress. PMID- 22518845 TI - Internucleosomal interactions mediated by histone tails allow distant communication in chromatin. AB - Action across long distances on chromatin is a hallmark of eukaryotic transcriptional regulation. Although chromatin structure per se can support long range interactions, the mechanisms of efficient communication between widely spaced DNA modules in chromatin remain a mystery. The molecular simulations described herein suggest that transient binary internucleosomal interactions can mediate distant communication in chromatin. Electrostatic interactions between the N-terminal tails of the core histones and DNA enhance the computed probability of juxtaposition of sites that lie far apart along the DNA sequence. Experimental analysis of the rates of communication in chromatin constructs confirms that long-distance communication occurs efficiently and independently of distance on tail-containing, but not on tailless, chromatin. Taken together, our data suggest that internucleosomal interactions involving the histone tails are essential for highly efficient, long-range communication between regulatory elements and their targets in eukaryotic genomes. PMID- 22518846 TI - Streptococcus uberis plasminogen activator (SUPA) activates human plasminogen through novel species-specific and fibrin-targeted mechanisms. AB - Bacterial plasminogen (Pg) activators generate plasmin to degrade fibrin blood clots and other proteins that modulate the pathogenesis of infection, yet despite strong homology between mammalian Pgs, the activity of bacterial Pg activators is thought to be restricted to the Pg of their host mammalian species. Thus, we found that Streptococcus uberis Pg activator (SUPA), isolated from a Streptococcus species that infects cows but not humans, robustly activated bovine but not human Pg in purified systems and in plasma. Consistent with this, SUPA formed a higher avidity complex (118-fold) with bovine Pg than with human Pg and non-proteolytically activated bovine but not human Pg. Surprisingly, however, the presence of human fibrin overrides the species-restricted action of SUPA. First, human fibrin enhanced the binding avidity of SUPA for human Pg by 4-8-fold in the presence and absence of chloride ion (a negative regulator). Second, although SUPA did not protect plasmin from inactivation by alpha(2)-antiplasmin, fibrin did protect human plasmin, which formed a 31-fold higher avidity complex with SUPA than Pg. Third, fibrin significantly enhanced Pg activation by reducing the K(m) (4-fold) and improving the catalytic efficiency of the SUPA complex (6 fold). Taken together, these data suggest that indirect molecular interactions may override the species-restricted activity of bacterial Pg activators; this may affect the pathogenesis of infections or may be exploited to facilitate the design of new blood clot-dissolving drugs. PMID- 22518847 TI - Mechanism of inhibition of the prothrombinase complex by a covalent antithrombin heparin complex. AB - Factor-Xa assembly into the prothrombinase complex decreases its availability for inhibition by antithrombin + unfractionated heparin (AT + UFH). We have developed a novel covalent antithrombin-heparin complex (ATH), with enhanced anticoagulant actions compared with AT + UFH. The present study was performed to extend understanding of the anticoagulant mechanisms of ATH by determining its inhibition of Xa within the critical prothrombinase. Discontinuous inhibition assays were performed to determine final k(2) values for inhibition of Xa. Fluorescent microscopy was conducted to evaluate inhibitor-prothrombinase interactions. The k(2) for inhibition of prothrombinase versus free Xa by AT + UFH was lower, whereas for ATH were much higher. Relative to intact prothrombinase, rates for Xa inhibition by AT + UFH in complexes devoid of prothrombin/vesicles/factor-Va were higher. For ATH, exclusion of prothrombin decreased k(2), removal of vesicles increased k(2) and exclusion of factor-Va gave no effect. While UFH may displace Xa from prothrombinase, Xa is detained within prothrombinase during ATH reactions. We confirm prothrombinase hinders inhibitory action of AT + UFH, whereas ATH is less affected with prothrombin being a key component in the complex responsible for the opposing effects. Overall, the results suggest that covalent linkage between AT-heparin assists access and neutralization of complexed Xa, with concomitant inhibition of prothrombinase function compared with conventional non-conjugated heparin. PMID- 22518848 TI - Genotypes and phenotypes of children with SHOX deficiency in France. AB - CONTEXT: The prevalence of SHOX deficiency in children with short stature (SS) is variable in the literature and various genotypes have been identified. OBJECTIVES: The aim of our study was to determine the frequency and distribution of SHOX genotypes in a large sample of children with SS in France. DESIGN, SETTING, AND PATIENTS: Children were enrolled in 38 French pediatric endocrinology centers and were either diagnosed with Leri-Weill syndrome (LWS), idiopathic short stature (ISS), or disproportionate short stature (DSS). INTERVENTION AND MAIN OUTCOME MEASURE: SHOX analysis was performed centrally as part of the Genetics and Neuroendocrinology of Short Stature International Study observational study. We compared patients with (SHOX-D) and without SHOX deficiency (non-SHOX-D). RESULTS: Among the 537 patients tested [58.3% females, mean age 11.0 (4.2) yr], 27.7% had SHOX deficiency (LWS, 48.9%; ISS, 16.9%; DSS, 18.8%). Mean height [-2.3 (0.9) sd score] was similar in SHOX-D and non-SHOX-D patients. The majority of SHOX-D patients with LWS had either a deletion encompassing SHOX or a point mutation (69%), whereas 59% of those with ISS had a deletion downstream of SHOX in the enhancer region. The height of the parents carrying a deletion downstream of SHOX was higher than the height of the parents carrying the other gene anomalies. CONCLUSIONS: SHOX deletions and point mutations as well as downstream SHOX enhancer deletions were identified in almost one third of the patients tested. An anomaly in this latter region seemed to be linked to a milder phenotype. Although further confirmation is needed, we suggest that the enhancer region should be systematically analyzed in patients suspected of SHOX deficiency. PMID- 22518849 TI - Incidence and clinical presentation of moderate to severe graves' orbitopathy in a Danish population before and after iodine fortification of salt. AB - CONTEXT: Population-based data on the incidence and clinical presentation of moderate to severe Graves' orbitopathy (GO) are scarce, and virtually nothing is known on the effect of an iodization program on the incidence and presentation of GO. OBJECTIVE: The objective of the study was to characterize incident moderate to severe GO in North Jutland County, Denmark, during the period 1992-2009, before and after the Danish salt iodization program. DESIGN AND PATIENTS: The design of the study was a prospective register of patients with incident moderate to severe GO in a population during 8.9 million persons * years of observation. SETTING: The study was conducted at a thyroid-eye clinic of university hospital. MAIN OUTCOME MEASURES: Clinical presentation and incidence before and after the year 2000 initiation of the mandatory Danish iodization of salt were measured. The incidence of GO was related to the incidence of Graves' hyperthyroidism (GH) in the same population. RESULTS: The incidence rate of moderate to severe GO was 16.1/million per year (women: 26.7; men: 5.4), with no change associated with iodization of salt. The moderate to severe GO incidence was 4.9% of the incidence of GH. The incidence rate ratio between women and men with GO (4.9) was not different from the ratio in GH. Compared with GH, only a few patients (<2%) suffered from moderate and severe GO below the age of 40 yr, whereas GO was relatively common in age groups 40-60 yr (~8%). CONCLUSIONS: Approximately 5% of the patients with Graves' disease develop moderate to severe GO, with a similar risk in women and men with Graves' disease. The risk of GO is much higher in patients aged 40-60 yr than in young patients with Graves' disease. Salt iodization was not associated with a change in the incidence of GO. PMID- 22518850 TI - Strategy for rapid identification and antibiotic susceptibility testing of gram negative bacteria directly recovered from positive blood cultures using the Bruker MALDI Biotyper and the BD Phoenix system. AB - Decreasing the time to species identification and antibiotic susceptibility determination of strains recovered from patients with bacteremia significantly decreases morbidity and mortality. Herein, we validated a method to identify Gram negative bacteria directly from positive blood culture medium using the Bruker MALDI Biotyper and to rapidly perform susceptibility testing using the BD Phoenix. PMID- 22518851 TI - OXA-163-producing Klebsiella pneumoniae in Cairo, Egypt, in 2009 and 2010. AB - Two genetically unrelated OXA-163-carrying Klebsiella pneumoniae strains were identified from two infection cases in June 2009 and May 2010 in Cairo, Egypt. OXA-163-producing Enterobacteriaceae had been previously reported in Argentina only. Both patients had no history of travel abroad. The emergence of this newly recognized OXA-48-related beta-lactamase able to hydrolyze cephalosporins and carbapenems is especially worrying in a geographic area where OXA-48 is endemic and effective surveillance for antibiotic resistance is largely unaffordable. PMID- 22518852 TI - Rapid detection of rpoB gene mutations conferring rifampin resistance in Mycobacterium tuberculosis. AB - Multidrug-resistant Mycobacterium tuberculosis strains are widespread and present a challenge to effective treatment of this infection. The need for a low-cost and rapid detection method for clinically relevant mutations in Mycobacterium tuberculosis that confer multidrug resistance is urgent, particularly for developing countries. We report here a novel test that detects the majority of clinically relevant mutations in the beta subunit of the RNA polymerase (rpoB) gene that confer resistance to rifampin (RIF), the treatment of choice for tuberculosis (TB). The test, termed TB ID/R, combines a novel target and temperature-dependent RNase H2-mediated cleavage of blocked DNA primers to initiate isothermal helicase-dependent amplification of a rpoB gene target sequence. Amplified products are detected by probes arrayed on a modified silicon chip that permits visible detection of both RIF-sensitive and RIF-resistant strains of M. tuberculosis. DNA templates of clinically relevant single nucleotide mutations in the rpoB gene were created to validate the performance of the TB ID/R test. Except for one rare mutation, all mutations were unambiguously detected. Additionally, 11 RIF-sensitive and 25 RIF-resistant clinical isolates were tested by the TB ID/R test, and 35/36 samples were classified correctly (96.2%). This test is being configured in a low-cost test platform to provide rapid diagnosis and drug susceptibility information for TB in the point-of-care setting in the developing world, where the need is acute. PMID- 22518853 TI - Evaluation of optimal storage temperature, time, and transport medium for detection of group B Streptococcus in StrepB carrot broth. AB - The performances of the ESwab and Amies transport media were evaluated for optimal survival of group B streptococcus (GBS) in StrepB carrot broth. ESwab was superior to Amies at all temperatures evaluated but was optimal at 21 degrees C and 24 degrees C, whereas recovery in Amies was significantly decreased at these temperatures. PMID- 22518854 TI - Rapid determination of methicillin resistance among Staphylococcus aureus clinical isolates by colorimetric methods. AB - In the present study, the effectiveness of a rapid and colorimetric nitrate reductase analysis (NRA) method and resazurin microplate assay (REMA) for rapid determination of methicillin resistance among Staphylococcus aureus was investigated. A total of 275 clinical isolates of S. aureus were included in the present study. Among these isolates, 151 had the mecA gene and were resistant to methicillin. The remaining 124 isolates were methicillin susceptible and did not have the mecA gene. Cefoxitin MICs of all isolates were detected by NRA, REMA, and reference broth microdilution methods. Category and essential agreement were determined as 100% and 99.6%, respectively, comparing both NRA and REMA with the reference method. No minor, major, or very major discrepancy was observed for either of the methods. The time necessary to have the MIC results was 5 h for NRA, whereas it was 6 h for REMA. Early detection of MRSA is an important public health concern, and the results of this study showed that both of the colorimetric methods are easy to perform and save time in the determination of MRSA. These methods have a potential use for early detection of MRSA for laboratories unable to use molecular techniques. PMID- 22518855 TI - Comparison of the Luminex xTAG RVP Fast assay and the Idaho Technology FilmArray RP assay for detection of respiratory viruses in pediatric patients at a cancer hospital. AB - Respiratory viruses are increasingly recognized as serious causes of morbidity and mortality in immunocompromised patients. The rapid and sensitive detection of respiratory viruses is essential for the early diagnosis and administration of appropriate antiviral therapy, as well as for the effective implementation of infection control measures. We compared the performance of two commercial assays, xTAG RVP Fast (Luminex Diagnostics, Toronto, Canada) and FilmArray RVP (FA RVP; Idaho Technology, Salt Lake City, UT), in pediatric patients at Memorial Sloan Kettering Cancer Center. These assays detect the following viruses: respiratory syncytial virus; influenza A and B viruses; parainfluenza viruses 1, 2, 3, and 4; human metapneumovirus; adenovirus; enterovirus-rhinovirus; coronaviruses NL63, HKU1, 229E, and OC43; and bocavirus. We tested a total of 358 respiratory specimens from 173 pediatric patients previously tested by direct fluorescence assay (DFA) and viral culture. The overall detection rate (number of positive specimens/total specimens) for viruses tested by all methods was 24% for DFA/culture, 45% for xTAG RVP Fast, and 51% for FA RVP. The agreement between the two multiplex assays was 84.5%, and the difference in detection rate was statistically significant (P < 0.0001). Overall, the FA RVP assay was more sensitive than the xTAG RVP Fast assay and had a turnaround time of approximately 1 h. The sensitivity, simplicity, and random-access platform make FA RVP an excellent choice for laboratory on-demand service with low to medium volume. PMID- 22518856 TI - First isolation of Mycobacterium kyorinense from clinical specimens in Brazil. AB - In this article, the first isolation of Mycobacterium kyorinense specimens in Brazil is described. M. kyorinense is a recently identified species, with a few strains reported only in Japan. The Brazilian isolates were initially identified as Mycobacterium celatum by PCR restriction enzyme pattern analysis (PRA) with hsp65. However, biochemical tests indicated the same profile of M. kyorinense and distinguished them from M. celatum and Mycobacterium branderi. The sequencing of the hsp65, rpoB, and 16S rRNA genes allowed the accurate identification of isolates as M. kyorinense. PMID- 22518857 TI - Rapid identification of Aspergillus terreus from bronchoalveolar lavage fluid by PCR and electrospray ionization with mass spectrometry. AB - We describe the application of PCR and electrospray-ionization with mass spectrometry (PCR/ESI-MS) to culture-negative bronchoalveolar lavage (BAL) fluid in order to identify septate hyphae noted by Gomori methenamine silver (GMS) staining of the fluid that was obtained from an immunocompromised woman with neutropenia following induction chemotherapy for treatment of acute myelogenous leukemia (AML). The patient was treated with empirical antifungal therapy, including intrathecal amphotericin B, while results of fungal cultures were pending. Ultimately, Aspergillus terreus, an amphotericin-resistant mold, was cultured from bilateral brain abscesses. PCR/ESI-MS correctly identified the mold. PMID- 22518858 TI - Analysis of a Streptococcus pyogenes puerperal sepsis cluster by use of whole genome sequencing. AB - Between June and November 2010, a concerning rise in the number of cases of puerperal sepsis, a postpartum pelvic bacterial infection contracted by women after childbirth, was observed in the New South Wales, Australia, hospital system. Group A streptococcus (GAS; Streptococcus pyogenes) isolates PS001 to PS011 were recovered from nine patients. Pulsed-field gel electrophoresis and emm sequence typing revealed that GAS of emm1.40, emm75.0, emm77.0, emm89.0, and emm89.9 were each recovered from a single patient, ruling out a single source of infection. However, emm28.8 GAS were recovered from four different patients. To investigate the relatedness of these emm28 isolates, whole-genome sequencing was undertaken and the genome sequences were compared to the genome sequence of the emm28.4 reference strain, MGAS6180. A total of 186 single nucleotide polymorphisms were identified, for which the phylogenetic reconstruction indicated an outbreak of a polyclonal nature. While two isolates collected from different hospitals were not closely related, isolates from two puerperal sepsis patients from the same hospital were indistinguishable, suggesting patient-to patient transmission or infection from a common source. The results of this study indicate that traditional typing protocols, such as pulsed-field gel electrophoresis, may not be sensitive enough to allow fine epidemiological discrimination of closely related bacterial isolates. Whole-genome sequencing presents a valid alternative that allows accurate fine-scale epidemiological investigation of bacterial infectious disease. PMID- 22518859 TI - Detection of methicillin-resistant Staphylococcus aureus in clinical specimens from cystic fibrosis patients by use of chromogenic selective agar. AB - We evaluated the use of a chromogenic selective medium (MRSA ID) as a useful tool for the detection of methicillin-resistant Staphylococcus aureus (MRSA) in cystic fibrosis (CF) patient samples. Fifty-four MRSA isolates were detected by MRSA ID, while only 24/54 (44%) (odds ratio [OR], 2.79; 95% confidence interval [CI], 1.63 to 4.76) were detected by conventional methods. A chromogenic selective medium for MRSA detection may improve its surveillance in CF patients. PMID- 22518860 TI - Novel approach to in vitro drug susceptibility assessment of clinical strains of Leishmania spp. AB - Resistance to antimonial drugs has been documented in Leishmania isolates transmitted in South America, Europe, and Asia. The frequency and distribution of resistance to these and other antileishmanial drugs are unknown. Technical constraints have limited the assessment of drug susceptibility of clinical strains of Leishmania. Susceptibility of experimentally selected lines and 130 clinical strains of Leishmania panamensis, L. braziliensis, and L. guyanensis to meglumine antimoniate and miltefosine was determined on the basis of parasite burden and percentage of infected U-937 human macrophages. Reductions of infection at single predefined concentrations of meglumine antimoniate and miltefosine and 50% effective doses (ED(50)s) were measured and correlated. The effects of 34 degrees C and 37 degrees C incubation temperatures and different parasite-to-host cell ratios on drug susceptibility were evaluated at 5, 10, and 20 parasites/cell. Reduction of the intracellular burden of Leishmania amastigotes in U-937 cells exposed to the predefined concentrations of meglumine antimoniate or miltefosine discriminated sensitive and experimentally derived resistant Leishmania populations and was significantly correlated with ED(50) values of clinical strains (for meglumine antimoniate, rho = -0.926 and P < 0.001; for miltefosine, rho = -0.906 and P < 0.001). Incubation at 37 degrees C significantly inhibited parasite growth compared to that at 34 degrees C in the absence of antileishmanial drugs and resulted in a significantly lower ED(50) in the presence of drugs. Susceptibility assessment was not altered by the parasite to-cell ratio over the range evaluated. In conclusion, measurement of the reduction of parasite burden at a single predetermined drug concentration under standardized conditions provides an efficient and reliable strategy for susceptibility evaluation and monitoring of clinical strains of Leishmania. PMID- 22518862 TI - Validation of increased blood storage times with the T-SPOT.TB assay with T-Cell Xtend reagent in individuals with different tuberculosis risk factors. AB - We compared the performance of the T-SPOT.TB assay with blood used within 0 to 3.5 h after collection (control) to its performance with blood stored for 0 to 3.5, 5 to 8, 18 to 21, or 31 to 33 h with the addition of T-Cell Xtend (experimental), using samples from 154 participants. The 95.4% concordance between paired specimens indicated that blood can be stored for up to 33 h prior to T-SPOT.TB testing. PMID- 22518861 TI - Recombinase polymerase amplification assay for rapid detection of Francisella tularensis. AB - Several real-time PCR approaches to develop field detection for Francisella tularensis, the infectious agent causing tularemia, have been explored. We report the development of a novel qualitative real-time isothermal recombinase polymerase amplification (RPA) assay for use on a small ESEQuant Tube Scanner device. The analytical sensitivity and specificity were tested using a plasmid standard and DNA extracts from infected rabbit tissues. The assay showed a performance comparable to real-time PCR but reduced the assay time to 10 min. The rapid RPA method has great application potential for field use or point-of-care diagnostics. PMID- 22518863 TI - Comparison of the Abbott RealTime High-Risk Human Papillomavirus (HPV), Roche Cobas HPV, and Hybrid Capture 2 assays to direct sequencing and genotyping of HPV DNA. AB - Infection with high-risk (HR) human papillomavirus (HPV) genotypes is an important risk factor for cervical cancers. We evaluated the clinical performances of two new real-time PCR assays for detecting HR HPVs compared to that of the Hybrid Capture 2 test (HC2). A total of 356 cervical swab specimens, which had been examined for cervical cytology, were assayed by Abbott RealTime HR and Roche Cobas HPV as well as HC2. Sensitivities and specificities of these assays were determined based on the criteria that concordant results among the three assays were regarded as true-positive or -negative and that the results of genotyping and sequencing were considered true findings when the HPV assays presented discrepant results. The overall concordance rate among the results for the three assays was 82.6%, and RealTime HR and Cobas HPV assays agreed with HC2 in 86.1% and 89.9% of cases, respectively. The two real-time PCR assays agreed with each other for 89.6% of the samples, and the concordance rate between them was equal to or greater than 98.0% for detecting HPV type 16 or 18. HC2 demonstrated a sensitivity of 96.6% with a specificity of 89.1% for detecting HR HPVs, while RealTime HR presented a sensitivity of 78.3% with a specificity of 99.2%. The sensitivity and specificity of Cobas HPV for detecting HR HPVs were 91.7% and 97.0%. The new real-time PCR assays exhibited lower sensitivities for detecting HR HPVs than that of HC2. Nevertheless, the newly introduced assays have an advantage of simultaneously identifying HPV types 16 and 18 from clinical samples. PMID- 22518864 TI - Performance of the cobas CT/NG test compared to the Aptima AC2 and Viper CTQ/GCQ assays for detection of Chlamydia trachomatis and Neisseria gonorrhoeae. AB - The next-generation amplification test for Chlamydia trachomatis and Neisseria gonorrhoeae (Roche cobas 4800), a fully automated system, was compared head to head, using female samples, to Gen-Probe Aptima Combo 2 and BD ProbeTec using Viper. Endocervical swabs, female urine, and endocervical samples in liquid-based cytology medium were run on at least two of three platforms. A total of 4,316 samples were evaluated, and 281 chlamydial and 69 gonococcal infections were identified. Estimates of sensitivity and specificity were obtained relative to the patient infection standard (PIS) and using latent class analysis (LCA). Chlamydia sensitivity estimates ranged from 86.9 to 95.6% using PIS and 97.6 to 98% using LCA. Specificity was >= 99.6% for all sample types. Sensitivity ranged from 95.6 to 100% using PIS and 96.9 to 100% using LCA for the detection of gonococcal infections. Specificity for gonococcal infections was >= 99.8%. cobas 4800 performance was equivalent to the comparator assays (all P values, >0.05), and the fully automated system provides high laboratory efficiency. PMID- 22518865 TI - Simultaneous detection of seven enteric viruses associated with acute gastroenteritis by a multiplexed Luminex-based assay. AB - Rapid and broad diagnostic methods are needed for the identification of viral agents of gastroenteritis. In this study, we used Luminex xMAP technology to develop a multiplexed assay for the simultaneous identification of major enteric viral pathogens, including rotavirus A (RVA), noroviruses (NoVs) (including genogroups GI and GII), sapoviruses (SaV), human astrovirus (HAstV), enteric adenoviruses (EAds), and human bocavirus 2 (HBoV2). The analytical sensitivity allowed detection of 10(3) (EAds, HBoV2, and RVA) and 10(4) (NoV GI and GII, SaV, and HAstV) copies per reaction mixture. Compared to conventional PCR, the Luminex based assay yielded greater than 75% sensitivity and 97% specificity for each virus, and the kappa correlation for detection of all viruses ranged from 0.75 to 1.00. In conclusion, this multiplexed Luminex-based assay provides a potentially rapid, high-throughput, and maneuverable diagnostic tool for major viral pathogens associated with gastroenteritis. PMID- 22518866 TI - Clinical significance of low cytomegalovirus DNA levels in human plasma. AB - The clinical significance of the detection of low copy numbers of cytomegalovirus (CMV) DNA in immune-suppressed patients remains unclear. In this study, we compared the artus CMV Rotor-Gene PCR, utilizing an automated nucleic acid extraction and assay setup (the artus CMV protocol), with the COBAS Amplicor CMV Monitor test (our reference protocol). We then analyzed the results of all CMV PCR tests ordered following the implementation of the artus CMV protocol at our institution and followed 91 adult patients with positive test results. The artus CMV protocol had a linear range extending from 2.0 to 7.0 log(10) copies/ml and had a lower limit of 95% detection of 57 copies/ml. With archived plasma samples, this protocol demonstrated 100% sensitivity and 94% specificity for the detection of CMV DNA. Following implementation of the artus CMV protocol, 320 of 1,403 (22.8%) plasma samples tested positive (compared with 323/3,579 [9.0%] samples in the preceding 6 months), and 227 (16.2%) samples had copy numbers of <400/ml. Ninety-one adult patients had at least one positive test. The data were analyzed using a threshold of 200 copies/ml, and in 22 episodes, the viral load increased from <200 copies/ml to >= 200 copies/ml on sequential tests. In 21 of these 22 episodes, either the viral load continued to increase or antiviral treatment was initiated in response to the repeat value. In summary, we evaluate the performance characteristics of a protocol utilizing the artus CMV PCR and identify clinically meaningful changes in CMV DNA copy numbers even when they are initially detected at a low level. PMID- 22518867 TI - Vibrio cholerae classical biotype strains reveal distinct signatures in Mexico. AB - Vibrio cholerae O1 classical (CL) biotype caused the fifth and sixth pandemics, and probably the earlier cholera pandemics, before the El Tor (ET) biotype initiated the seventh pandemic in Asia in the 1970s by completely displacing the CL biotype. Although the CL biotype was thought to be extinct in Asia and although it had never been reported from Latin America, V. cholerae CL and ET biotypes, including a hybrid ET, were found associated with areas of cholera endemicity in Mexico between 1991 and 1997. In this study, CL biotype strains isolated from areas of cholera endemicity in Mexico between 1983 and 1997 were characterized in terms of major phenotypic and genetic traits and compared with CL biotype strains isolated in Bangladesh between 1962 and 1989. According to sero- and biotyping data, all V. cholerae strains tested had the major phenotypic and genotypic characteristics specific for the CL biotype. Antibiograms revealed the majority of the Bangladeshi strains to be resistant to trimethoprim sulfamethoxazole, furazolidone, ampicillin, and gentamicin, while the Mexican strains were sensitive to all of these drugs, as well as to ciprofloxacin, erythromycin, and tetracycline. Pulsed-field gel electrophoresis (PFGE) of NotI digested genomic DNA revealed characteristic banding patterns for all of the CL biotype strains although the Mexican strains differed from the Bangladeshi strains in 1 to 2 DNA bands. The difference was subtle but consistent, as confirmed by the subclustering patterns in the PFGE-based dendrogram, and can serve as a regional signature, suggesting the pre-1991 existence and evolution of the CL biotype strains in the Americas, independent from Asia. PMID- 22518868 TI - Evaluation of macrolide resistance and enhanced molecular typing of Treponema pallidum in patients with syphilis in Taiwan: a prospective multicenter study. AB - Studies of macrolide resistance mutations and molecular typing using the newly proposed enhanced typing system for Treponema pallidum isolates obtained from HIV infected patients in the Asia-Pacific region are scarce. Between September 2009 and December 2011, we conducted a survey to detect T. pallidum using a PCR assay using clinical specimens from patients with syphilis at six major designated hospitals for HIV care in Taiwan. The T. pallidum strains were genotyped by following the enhanced molecular typing methodology, which analyzed the number of 60-bp repeats in the acidic repeat protein (arp) gene, T. pallidum repeat (tpr) polymorphism, and the sequence of base pairs 131 to 215 in the tp0548 open reading frame of T. pallidum. Detection of A2058G and A2059G point mutations in the T. pallidum 23S rRNA was performed with the use of restriction fragment length polymorphism (RFLP). During the 2-year study period, 211 clinical specimens were obtained from 136 patients with syphilis. T. pallidum DNA was isolated from 105 (49.8%) of the specimens, with swab specimens obtained from chancres having the highest yield rate (63.2%), followed by plasma (49.4%), serum (35.7%), and cerebrospinal fluid or vitreous fluid (18.2%) specimens. Among the 40 fully typed specimens, 11 subtypes of T. pallidum were identified. Subtype 14f/f (18 isolates) was the most common isolates, followed by 14f/c (3), 14b/c (3), and 14k/f (3). Among the isolates examined for macrolide resistance, none had the A2058G or A2059G mutation. In conclusion, we found that type 14 f/f was the most common T. pallidum strain in this multicenter study on syphilis in Taiwan and that none of the isolates exhibited 23S rRNA mutations causing resistance to macrolides. PMID- 22518869 TI - Cytology and human papillomavirus testing 6 to 12 months after ASCUS or LSIL cytology in organized screening to predict high-grade cervical neoplasia between screening rounds. AB - We carried out a prospective study comparing the performance of human papillomavirus (HPV) E6/E7 mRNA (PreTect HPV-Proofer; NorChip, Klokkarstua, Norway) and DNA (Amplicor HPV test; Roche Diagnostics, Basel, Switzerland) triage testing of women 6 to 12 months after atypical-squamous-cells-of-undetermined significance (ASCUS) or low-grade-squamous-intraepithelial-lesion (LSIL) cytology in organized screening to predict high-grade cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) between screening rounds. Between January 2005 and April 2008, 692 study women with screening-detected ASCUS/LSIL cytology 6 to 12 months earlier returned for HPV mRNA and DNA testing and repeat cytology. The median follow-up time was 3 years, using existing health care facilities. Follow up test results were available for 625 women. Of the 145 CIN2+ cases detected during the study period, 95 (65.5%) were HPV mRNA positive 6 to 12 months after screening-detected ASCUS/LSIL, 44 (30.4%) were HPV mRNA negative, and 6 (4.1%) were invalid. The corresponding HPV DNA results were 139 (95.9%), 5 (3.4%), and 1 (0.7%), respectively. The cumulative incidences of CIN2+ 3 years after a negative HPV mRNA and DNA test were 10.3% (95% confidence interval [CI], 7.2 to 13.3%) and 1.8% (95% CI, 0.0 to 3.6%), respectively. The cumulative incidences of CIN2+ 3 years after positive HPV mRNA and DNA tests were 52.8% (95% CI, 40.1 to 60.1%) and 41.3% (95% CI, 35.5 to 46.6%), respectively. In conclusion, both positive HPV mRNA and DNA test results have a high enough long-term prediction of CIN2+ risk to consider referral to colposcopy as good practice when performed in delayed triage of women with ASCUS/LSIL cytology. In addition, the low CIN2+ risk among women with a negative Amplicor HPV test in our study confirms its safe use in a clinical setting. PMID- 22518870 TI - Coccidioides thyroiditis in an HIV-infected patient. AB - We report a case of Coccidioides thyroiditis in an HIV-infected patient with a history of recent Coccidioides pneumonia but with negative Coccidioides serology determined by enzyme immunoassay at presentation. Diagnosis of Coccidioides thyroiditis was made based on histopathologic examination and culture of thyroid abscess material obtained by fine-needle aspiration biopsy. PMID- 22518871 TI - Early diagnosis of in utero and intrapartum HIV infection in infants prior to 6 weeks of age. AB - Early initiation of antiretroviral therapy reduces HIV-related infant mortality. The early peak of pediatric HIV-related deaths in South Africa occurs at 3 months of age, coinciding with the earliest age at which treatment is initiated following PCR testing at 6 weeks of age. Earlier diagnosis is necessary to reduce infant mortality. The performances of the Amplicor DNA PCR, COBAS AmpliPrep/COBAS TaqMan (CAP/CTM), and Aptima assays for detecting early HIV infection (acquired in utero and intrapartum) up to 6 weeks of age were compared. Dried blood spots (DBS) were collected at birth and at 2, 4, and 6 weeks from HIV-exposed infants enrolled in an observational cohort study in Johannesburg, South Africa. HIV status was determined at 6 weeks by DNA PCR on whole blood. Serial DBS samples from all HIV-infected infants and two HIV-uninfected, age-matched controls were tested with the 3 assays. Of 710 infants of known HIV status, 38 (5.4%) had in utero (n = 29) or intrapartum (n = 9) infections. By 14 weeks, when treatment should have been initiated, 13 (45%) in utero-infected and 2 (22%) intrapartum infected infants had died or were lost to follow-up. The CAP/CTM and Aptima assays identified 76.3% of all infants with early HIV infections at birth and by 4 weeks were 96% sensitive. DNA PCR demonstrated lower sensitivities at birth and 4 weeks of 68.4% and 87.5%, respectively. All assays had the lowest sensitivity at 2 weeks of age. CAP/CTM was the only assay with 100% specificity at all ages. Testing at birth versus 6 weeks of age identifies a higher total number of HIV infected infants, irrespective of the assay. PMID- 22518873 TI - Antimicrobial resistance, toxinotype, and genotypic profiling of Clostridium difficile isolates of swine origin. AB - The occurrence of Clostridium difficile infections in patients that do not fulfill the classical risk factors prompted us to investigate new risk factors of disease. The goal of this study was to characterize strains and associated antimicrobial resistance determinants of C. difficile isolated from swine raised in Ohio and North Carolina. Genotypic approaches used include PCR detection, toxinotyping, DNA sequencing, and pulsed-field gel electrophoresis (PFGE) DNA fingerprinting. Thirty-one percent (37/119) of isolates carried both tetM and tetW genes. The ermB gene was found in 91% of isolates that were resistant to erythromycin (68/75). Eighty-five percent (521/609) of isolates were toxin gene tcdB and tcdA positive. A total of 81% (494/609) of isolates were positive for cdtB and carry a tcdC gene (a toxin gene negative regulator) with a 39-bp deletion. Overall, 88% (196/223) of pigs carry a single C. difficile strain, while 12% (27/223) of pigs carried multiple strains. To the best of our knowledge, this is the first report of individual pigs found to carry more than one strain type of C. difficile. A significant difference in toxinotype profiles in the two geographic locations was noted, with a significantly (P < 0.001) higher prevalence of toxinotype V found in North Carolina (84%; 189/224) than in Ohio (55%; 99/181). Overall, the study findings indicate that significant proportions of C. difficile in swine are toxigenic and often are associated with antimicrobial resistance genes, although they are not resistant to drugs that are used to treat C. difficile infections. PMID- 22518872 TI - High mortality associated with Catabacter hongkongensis bacteremia. AB - Catabacter hongkongensis is a recently described catalase-positive, motile, anaerobic, nonsporulating, Gram-positive coccobacillus that was first isolated from blood cultures of four patients from Hong Kong and Canada. Although DNA sequences representing C. hongkongensis have been detected in environmental sources, only one additional case of human infection has been reported, in France. We describe five cases of C. hongkongensis bacteremia in Hong Kong, two presenting with sepsis, one with acute gangrenous perforated appendicitis, one with acute calculous cholecystitis, and one with infected carcinoma of colon. Three patients, with gastrointestinal malignancy, died during admission. All five isolates were catalase positive, motile, and negative for indole production and nitrate reduction and produced acid from arabinose, glucose, mannose, and xylose. They were unambiguously identified as C. hongkongensis by 16S rRNA gene analysis. Of the total of 10 reported cases of C. hongkongensis bacteremia in the literature and this study, most patients had underlying diseases, while two cases occurred in healthy young individuals with acute appendicitis. Six patients presented with infections associated with either the gastrointestinal or biliary tract, supporting the gastrointestinal tract as the source of bacteremia. C. hongkongensis bacteremia is associated with a poor prognosis, with a high mortality of 50% among reported cases, especially in patients with advanced malignancies. All reported isolates were susceptible to metronidazole. Identification of more C. hongkongensis isolates by 16S rRNA gene sequencing will help better define its epidemiology and pathogenesis. PMID- 22518874 TI - [Automobile driving in a cognitively impaired state]. PMID- 22518878 TI - Amber mutants of bacteriophage T4D: their isolation and genetic characterization. PMID- 22518879 TI - Manuel O. Mendez guides bioMerieux according to core principles and priorities. PMID- 22518880 TI - Crisis management. PMID- 22518881 TI - Shrinking cities: urban challenges of globalization. AB - Urban shrinkage is not a new phenomenon. It has been documented in a large literature analyzing the social and economic issues that have led to population flight, resulting, in the worse cases, in the eventual abandonment of blocks of housing and neighbourhoods. Analysis of urban shrinkage should take into account the new realization that this phenomenon is now global and multidimensional - but also little understood in all its manifestations. Thus, as the world's population increasingly becomes urban, orthodox views of urban decline need redefinition. The symposium includes articles from 10 urban analysts working on 30 cities around the globe. These analysts belong to the Shrinking Cities International Research Network (SCIRN), whose collaborative work aims to understand different types of city shrinkage and the role that different approaches, policies and strategies have played in the regeneration of these cities. In this way the symposium will inform both a rich diversity of analytical perspectives and country-based studies of the challenges faced by shrinking cities. It will also disseminate SCIRN's research results from the last 3 years. PMID- 22518882 TI - Declining suburbs in Europe and Latin America. AB - Suburban shrinkage, understood as a degenerative urban process stemming from the demise of the Fordist mode of urbanism, is generally manifested in a decline in population, industry and employment. It is also intimately linked to the global restructuring of industrial organization associated with the rise of the post Fordist mode of urbanism and, more recently, the thrust of Asian industrialization. Framed in the discourse of industrial urbanism, this article examines the first ring of industrial suburbs that developed around large cities in their most rapid Fordist urbanization phase. These industrial suburbs, although they were formed at different times, are today experiencing specific mutations and undergoing profound restructuring on account of their particular spatial position between the central area and the expanding peripheries of the post-Fordist metropolis. This article describes and compares suburban decline in two European cities (Glasgow and Paris) and two Latin American Cities (Sao Paulo, Brazil and Guadalajara, Mexico), as different instances of places asymmetrically and fragmentarily integrated into the geography of globalization. PMID- 22518883 TI - The shrinking mining city: urban dynamics and contested territory. AB - Shrinking mining cities - once prosperous settlements servicing a mining site or a system of mining sites - are characterized by long-term population and/or economic decline. Many of these towns experience periods of growth and shrinkage, mirroring the ebbs and flows of international mineral markets which determine the fortunes of the dominant mining corporation upon which each of these towns heavily depends. This dependence on one main industry produces a parallel development in the fluctuations of both workforce and population. Thus, the strategies of the main company in these towns can, to a great extent, determine future developments and have a great impact on urban management plans. Climate conditions, knowledge, education and health services, as well as transportation links, are important factors that have impacted on lifestyles in mining cities, but it is the parallel development with the private sector operators (often a single corporation) that constitutes the distinctive feature of these cities and that ultimately defines their shrinkage. This article discusses shrinking mining cities in capitalist economies, the factors underpinning their development, and some of the planning and community challenges faced by these cities in Australia, Canada, Japan and Mexico. PMID- 22518884 TI - Urban shrinkage in Germany and the USA: a comparison of transformation patterns and local strategies. AB - Many American and European cities have to deal with demographic and economic trajectories leading to urban shrinkage. According to official data, 13% of urban regions in the US and 54% of those in the EU have lost population in recent years. However, the extent and spatial distribution of declining populations differ significantly between Europe and the US. In Germany, the situation is driven by falling birth rates and the effects of German reunification. In the US, shrinkage is basically related to long-term industrial transformation. But the challenges of shrinking cities seldom appeared on the agendas of politicians and urban planners until recently. This article provides a critical overview of the development paths and local strategies of four shrinking cities: Schwedt and Dresden in eastern Germany; Youngstown and Pittsburgh in the US. A typology of urban growth and shrinkage, from economic and demographic perspectives, enables four types of city to be differentiated and the differences between the US and eastern Germany to be discussed. The article suggests that a new transatlantic debate on policy and planning strategies for restructuring shrinking cities is needed to overcome the dominant growth orientation that in most cases intensifies the negative consequences of shrinkage. PMID- 22518885 TI - The "housing question" and the state-socialist answer: city, class and state remaking in 1950s Bucharest. AB - Housing nationalization as a solution to urban inequalities has a long history in European social thought. This article describes housing nationalization in a state-socialist context. Using a political economy perspective and relying on recently released archival material about housing in 1950s Romania, I argue that nationalization may be regarded as a special type of urban process. Nationalization raised the occupancy rate and intensified the usage of existing housing, desegregated centrally located neighborhoods, turned some residential space into office space for state institutions, facilitated the degradation of the existing housing stock and gradually produced a socialist gentry. Aside from similarities with other state-socialist nationalizations from the same period, Romanian nationalization resembled the housing policies of other statist regimes. The data also suggest that, even in the context of revolutionary change, the state is a sum of multiple, often diverging projects, rather than a coherent actor. PMID- 22518887 TI - Dogs and the making of the American state: voluntary association, state power, and the politics of animal control in New York City, 1850-1920. PMID- 22518888 TI - The end of the asylum (town): community responses to the depopulation and closure of the Saskatchewan Hospital, Weyburn. AB - Never is the fraught relationship between the state-run custodial mental hospital and its host community clearer than during the period of rapid deinstitutionalization, when communities, facing the closure of their mental health facilities, inserted themselves into debates about the proper configuration of the mental health care system. Using the case of Weyburn, Saskatchewan, site in the 1960s of one of Canada's earliest and most radical experiments in rapid institutional depopulation, this article explores the government of Saskatchewan's management of the conflict between the latent functions of the old-line mental hospital as a community institution, an employer, and a generator of economic activity with its manifest function as a site of care made obsolete by the shift to community models of care. PMID- 22518889 TI - [The psychiatric revolution in Quebec, 1950-1962. From asylum to community psychiatry and the open door]. AB - Psychiatry opens to the world at a time when the very basis of psychiatric practice, namely the asylum, is called into question. Studies appear in Quebec and Canadian journals concurrent to the introduction of new formulas for care, such as the delivery of psychiatric services in general hospitals and clinics, that allow patients to be treated outside the walls of psychiatric hospitals. In addition, postwar psychiatry takes an optimistic view toward the future of children with impairments through the creation of specialized schools and workshops. From the mid-20th century onward, the thinking in psychiatry centres on the open door. PMID- 22518890 TI - Deinstitutionalization and vocational rehabilitation for mental health consumers in Nova Scotia since the 1950s. AB - In this paper we explore the broader policy determinants of the de hospitalization of mental patients in Nova Scotia between the 1950s and 1980s and trace the background to the development of occupational rehabilitation programs in the community. For employment programs, the government chose to rely on non profit NGOs as the suppliers of services. As a case study of such an organization, we examine the evolution of LakeCity Employment Services Association as a resource for people living with mental disabilities. PMID- 22518891 TI - [Diagnosis and treatment of group A beta-hemolytic streptococcal pharyngotonsillitis in pediatrics]. PMID- 22518892 TI - [Diagnosis and treatment of taste disorders]. PMID- 22518893 TI - [Diagnosis of dizziness at a clinic]. PMID- 22518894 TI - Clinical approach to leukoencephalopathies. AB - Recent advances in biochemical and molecular genetics have led to the discovery of new leukoencephalopathies. Despite these advances, many patients with leukoencephalopathy remain undiagnosed. A systematic approach to the investigation of these patients is needed to select the most appropriate testing strategy. In this article, the author presents a clinical and magnetic resonance imaging (MRI) based approach to the evaluation of patients with leukoencephalopathy. PMID- 22518895 TI - Clinical practice guidelines for mild traumatic brain injury and persistent symptoms. AB - OBJECTIVE: To outline new guidelines for the management of mild traumatic brain injury (MTBI) and persistent postconcussive symptoms (PPCS) in order to provide information and direction to physicians managing patients' recovery from MTBI. QUALITY OF EVIDENCE: A search for existing clinical practice guidelines addressing MTBI and a systematic review of the literature evaluating treatment of PPCS were conducted. Because little guidance on the management of PPCS was found within the traumatic brain injury field, a second search was completed for clinical practice guidelines and systematic reviews that addressed management of these common symptoms in the general population. Health care professionals representing a range of disciplines from across Canada and abroad were brought together at an expert consensus conference to review the existing guidelines and evidence and to attempt to develop a comprehensive guideline for the management of MTBI and PPCS. MAIN MESSAGE: A modified Delphi process was used to create 71 recommendations that address the diagnosis and management of MTBI and PPCS. In addition, numerous resources and tools were included in the guideline to aid in the implementation of the recommendations. CONCLUSION: A clinical practice guideline was developed to aid health care professionals in implementing evidencebased, best-practice care for the challenging population of individuals who experience PPCS following MTBI. PMID- 22518896 TI - Malignant wounds: managing odour. PMID- 22518897 TI - X-ray scans for nonspecific low back pain: a nonspecific pain? PMID- 22518898 TI - Acute breathlessness and chest pain following a harsh bout of coughing. PMID- 22518899 TI - Prediabetes and type 2 diabetes mellitus: assessing risks for physical activity clearance and prescription. PMID- 22518900 TI - [Day care service offered by public health clinics to psychiatric patients and its future prospect: from the results of a nationwide cross-sectional study following the implementation of the law to assist the handicapped for independent living]. PMID- 22518901 TI - [Health service research (17) "Industrial health and health service research"]. PMID- 22518902 TI - Rest area. PMID- 22518903 TI - [Public health for scientific study of society and health (13) "Connection between epidemiological and clinical studies"]. PMID- 22518904 TI - Primary health care models: medical students' knowledge and perceptions. AB - OBJECTIVE: To explore the knowledge and perceptions of fourth-year medical students regarding the new models of primary health care (PHC) and to ascertain whether that knowledge influenced their decisions to pursue careers in family medicine. DESIGN: Qualitative study using semistructured interviews. SETTING: The Schulich School of Medicine and Dentistry at The University of Western Ontario in London. Participants Fourth-year medical students graduating in 2009 who indicated family medicine as a possible career choice on their Canadian Residency Matching Service applications. METHODS: Eleven semistructured interviews were conducted between January and April of 2009. Data were analyzed using an iterative and interpretive approach. The analysis strategy of immersion and crystallization assisted in synthesizing the data to provide a comprehensive view of key themes and overarching concepts. MAIN FINDINGS: Four key themes were identified: the level of students' knowledge regarding PHC models varied; the knowledge was generally obtained from practical experiences rather than classroom learning; students could identify both advantages and disadvantages of working within the new PHC models; and although students regarded the new PHC models positively, these models did not influence their decisions to pursue careers in family medicine. CONCLUSION: Knowledge of the new PHC models varies among fourth year students, indicating a need for improved education strategies in the years before clinical training. Being able to identify advantages and disadvantages of the PHC models was not enough to influence participants' choice of specialty. Educators and health care policy makers need to determine the best methods to promote and facilitate knowledge transfer about these PHC models. PMID- 22518906 TI - Office-based ultrasound screening for abdominal aortic aneurysm. AB - OBJECTIVE: To assess the efficacy of an office-based, family physician administered ultrasound examination to screen for abdominal aortic aneurysm (AAA). DESIGN: A prospective observational study. Consecutive patients were approached by nonphysician staff. SETTING: Rural family physician offices in Grand Forks and Revelstoke, BC. PARTICIPANTS: The Canadian Society for Vascular Surgery screening recommendations for AAA were used to help select patients who were at risk of AAA. All men 65 years of age or older were included. Women 65 years of age or older were included if they were current smokers or had diabetes, hypertension, a history of coronary artery disease, or a family history of AAA. MAIN OUTCOME MEASURES: A focused "quick screen", which measured the maximal diameter of the abdominal aorta using point-of-care ultrasound technology, was performed in the office by a resident physician trained in emergency ultrasonography. Each patient was then booked for a criterion standard scan (i.e., a conventional abdominal ultrasound scan performed by a technician and interpreted by a radiologist). The maximal abdominal aortic diameter measured by ultrasound in the office was compared with that measured by the criterion standard method. The time to screen each patient was recorded. RESULTS: Forty five patients were included in data analysis; 62% of participants were men. The mean age was 73 years. The mean pairwise difference between the office-based ultrasound scan and the criterion standard scan was not statistically significant. The mean absolute difference between the 2 scans was 0.20 cm (95% CI 0.15 to 0.25 cm). Correlation between the scans was 0.81. The office-based ultrasound scan had both a sensitivity and a specificity of 100%. The mean time to screen each patient was 212 seconds (95% CI 194 to 230 seconds). CONCLUSION: Abdominal aortic aneurysm screening can be safely performed in the office by family physicians who are trained to use point-of- care ultrasound technology. The screening test can be completed within the time constraints of a busy family practice office visit. The benefit of screening for AAA in rural patients might be great if local diagnostic ultrasound service and emergent transport to a vascular surgeon are not available. PMID- 22518905 TI - Length of stay and hospital costs among patients admitted to hospital by family physicians. AB - OBJECTIVE: To compare length of stay and total hospital costs among patients admitted to hospital under the care of family physicians who were their usual health care providers in the community (group A) and patients admitted to the same inpatient service under the care of family physicians who were not their usual health care providers (group B). DESIGN: Retrospective observational study. SETTING: A large urban hospital in Vancouver, BC. PARTICIPANTS: All adult admissions to the family practice inpatient service between April 1, 2006, and June 30, 2008. MAIN OUTCOME MEASURES: Ratio of length of stay to expected length of stay and total hospital costs per resource intensity weight unit. Multivariate linear regression was performed to determine the effect of admitting group (group A vs. group B) on the natural logarithm transformations of the outcomes. RESULTS: The median acute length of stay was 8.0 days (interquartile range [IQR] 4.0 to 13.0 days) for group A admissions and 8.0 days (IQR 4.0 to 15.0 days) for group B admissions. The median (IQR) total hospital costs were $6498 ($4035 to $11,313) for group A admissions and $6798 ($4040 to $12,713) for group B admissions. Aftera djustment for patient characteristics, patients admitted to hospital under the care of their own family physicians did not significantly differ in terms of acute length of stay to expected length of stay ratio (percent change 0.6%, P = .942)or total hospital costs per resource intensity weight unit (percent change 2.0%, P = .722) compared with patients admitted under the care of other family physicians. CONCLUSION: These findings suggest that having networks of family physicians involved in hospital care for patients is not less efficient than having family physicians provide care for their own patients. PMID- 22518907 TI - [Psychosocial therapy needed by medial organizations--a proposal for model programs]. PMID- 22518908 TI - [Designing of social skill training (SST) in response to varied needs, such as those in an acute stage and in day care]. PMID- 22518909 TI - [Designing of a psychological education program to respond to varied needs, such as patients in acute stage or being treated by day care]. PMID- 22518910 TI - Addressing climate change through health promotion in Australia. PMID- 22518911 TI - Action on climate change requires strong leadership from the health sector. PMID- 22518912 TI - Health promotion interventions to address climate change using a primary health care approach: a literature review. AB - ISSUE ADDRESSED: This project explored the literature in which key concepts in primary health care and health promotion are overtly applied to the problem of climate change. This paper contains a discussion of the literature relevant to health promotion principles and intervention strategies for addressing climate change mitigation and adaptation in the primary health care sector. The concept of primary health care is that used by the World Health Organization, based on the Declaration of Alma Ata and often referred to as comprehensive primary health care to differentiate it from primary medical care. METHODS: This was a review of literature identified in electronic databases using two sets of search terms. Set A consisted of 'climate change or global warming or greenhouse effect' and set B consisted of 11 key concepts in primary health care and health promotion, for example community resilience, health promotion, social change, food security and economic development. Relevant literature was identified at the intersection of search term A with a term from set B. A search was completed for each set B term. RESULTS: This paper reports a discussion of major categories of health promotion interventions, namely health communication, community building and settings approaches and uses examples drawn from literature on community resilience and summer heat. These interventions are all applicable to the primary health care sector. CONCLUSION: There is a small literature on health promotion interventions for climate change mitigation and adaptation but it is incomplete and scattered across many sources. An important area for further research is to link the logic of service provision in primary health care to the logic of mitigation and adaptation in a changing environment. Interventions that link the logic must also link diverse services to provide coherent action on local and domestic scales, the scales at which primary health care acts. Another research gap is in regard to institutional change in the primary health care sector. How do the patterns of knowledge, practice and values need to change in the array of organisations that make up comprehensive primary health care? PMID- 22518913 TI - Residential air-conditioning and climate change: voices of the vulnerable. AB - ISSUE ADDRESSED: Decreasing the risk of heat-stress is an imperative in health promotion, and is widely accepted as necessary for successful adaptation to climate change. Less well understood are the vulnerabilities that air conditioning use exacerbates, and conversely, the need for the promotion of alternative strategies for coping with heat wave conditions. This paper considers these issues with a focus on the role of air-conditioning in the everyday life of elderly public housing tenants living alone, a sector of the population that has been identified as being at high risk of suffering heat stress. METHODS: A vulnerability analysis of domestic air-conditioning use, drawing on literature and policy on air-conditioning practices and ethnographic research with households. RESULTS: Residential air-conditioning exacerbated existing inequities. Case studies of two specifically selected low-income elderly single person households revealed that such households were unlikely to be able to afford this 'solution' to increasing exposure to heat waves in the absence of energy subsidies. Residential air-conditioning use during heat waves caused unintended side-effects, such as system-wide blackouts, which, in turn, led to escalating electricity costs as power companies responded by upgrading infrastructure to cope with periods of excess demand. Air-conditioning also contributed to emissions that cause climate change. CONCLUSIONS: Residential air conditioning is a potentially maladaptive technology for reducing the risk of heat stress. PMID- 22518914 TI - Older persons and heat-susceptibility: the role of health promotion in a changing climate. AB - ISSUE ADDRESSED: Many studies world wide have provided evidence that older persons are a sub-population at increased risk of heat-related morbidity and mortality. This article gives an overview of the current state of knowledge of risk factors and provides commentary on the role of health promotion in the prevention of a climate change-related increase in elderly heat casualties. METHODS: A search of peer-reviewed medical and epidemiological literature and community health websites was conducted in order to gain an in-depth understanding of heat-susceptibility in the elderly and preventive strategies. Key search words included: elderly, aged, older, heat, thermoregulation, heat wave, mortality, heat effects, dehydration, heat-related illness, adaptation, adaptive capacity. RESULTS: The reasons underlying reduced heat tolerance in this group are multi-faceted, comprising physiological, social and behavioural limitations, with comorbidities and polypharmacy being contributing factors. Additionally, some older persons may be unable or reluctant to undertake adaptations necessary to maintain thermal homeostasis due to diminished awareness of the heat, lowered thirst sensation, mobility or cognitive impairments, a lowered perception of risk, or economic concerns. CONCLUSION: With older persons in poor health being particularly vulnerable to heat, preventive messages need to promote protective behaviours and help build resilience as temperatures rise. PMID- 22518915 TI - Extreme heat arrangements in South Australia: an assessment of trigger temperatures. AB - ISSUE ADDRESSED: The high mortality and morbidity associated with the 2009 heat wave across South Eastern Australia highlighted the need for effective heat related health promotion and preventive strategies. The adverse health effects of extreme heat are largely preventable, and heat-related health promotion can advise the public about the dangers of hot weather and how to reduce health risks. The South Australian State Emergency Service has outlined a co-ordinated response system in their Extreme Heat Arrangements for South Australia. This paper evaluates the health impacts at the temperature trigger levels incorporated in this plan. METHODS: Heat events in Adelaide between 1994 and 2009 were compared in terms of heat duration, heat intensity and their impact on mortality and ambulance call-outs.The health impacts for events meeting specific temperature triggers were estimated. RESULTS: Individual heat events varied in terms of estimated excess mortality and ambulance call-outs. Increased mortality was associated with heat events of 3 or more consecutive days with maximum temperature (T(max)) > or = 43 degrees C or average daily temperature (ADT) > or = 34 degrees C, while ambulance call-outs increased significantly at lower T(max) levels.The two events reaching the temperature triggers for an extreme heat warning were associated with a 44% (95% CI 26-63%) increase in mortality. CONCLUSIONS: The results support the temperature trigger for an extreme heat warning within the Extreme Heat Arrangements for Adelaide, and indicate a limited health impact at lower temperature triggers. PMID- 22518916 TI - Core health promotion competencies in Australia: are they compatible with climate change action? AB - ISSUES ADDRESSED: Health promotion principles for practice are closely aligned with that of environmental sustainability. Health promotion practitioners are well positioned to take action on climate change. However, there has been scant discussion about practice synergies and subsequently the type and nature of professional competencies that underpin such action. METHODS: This commentary uses the Australian Health Promotion Association (AHPA) national core competencies for Health Promotion Practitioners as a basis to examine the synergies between climate change and health promotion action. RESULTS: We demonstrate that AHPA core competencies, such as program planning, evaluation and partnership building, are highly compatible for implementing climate change mitigation and adaptation strategies. We use food security examples to illustrate this case. CONCLUSIONS: There appears to be considerable synergy between climate change and health promotion action. This should be a key focus of future health promotion competency development in Australia. PMID- 22518917 TI - Why sustainable population growth is a key to climate change and public health equity. AB - Australia's population could reach 42 million by 2050. This rapid population growth, if unabated, will have significant social, public health and environmental implications. On the one hand, it is a major driver of climate change and environmental degradation; on the other it is likely to be a major contributor to growing social and health issues including a decline in quality of life for many residents. Disadvantaged and vulnerable groups will be most affected. The environmental, social and health-related issues include: pressure on the limited arable land in Australia; increased volumes of industrial and domestic waste; inadequate essential services; traffic congestion; lack of affordable housing; declining mental health; increased obesity problems; and inadequate aged care services. Many of these factors are related to the aggravation of climate change and health inequities. It is critical that the Australian Government develops a sustainable population plan with stabilisation of population growth as an option. The plan needs to ensure adequate hospitals and healthcare services, education facilities, road infrastructure, sustainable transport options, water quality and quantity, utilities and other amenities that are already severely overburdened in Australian cities. There is a need for a guarantee that affordable housing will be available and priority be given to training young people and Indigenous people for employment. This paper presents evidence to support the need for the stabilisation of population growth as one of the most significant measures to control climate change as well as to improve public health equity. PMID- 22518918 TI - Implications of climate change for skin cancer prevention in Australia. AB - It is estimated that nearly 450,000 Australians get skin cancer every year. Ultraviolet (UV) radiation from sunlight has been identified as the cause of more than 95% of skin cancers in Australia. Accordingly, the focus of skin cancer prevention programs is reducing exposure to UV radiation. In Victoria, improvements in sun protection behaviours and reductions in sunburn and melanoma incidence rates among younger people have been observed since the SunSmart program was established in 1988. However, climate change has the potential to undermine these successes. First, surface UVB radiation is dependent on stratospheric total ozone amounts. While signs of impact of international restrictions on the production of ozone-depleting substances have been observed, improvements have not yet returned ozone to pre-1970s levels. Interactions between ozone depletion and climate change may slow the recovery of the ozone layer and compound increases in UV radiation at some latitudes. Before recovery, it is expected that higher levels of UV radiation will continue in most Australian regions, with an associated higher risk of skin cancer. Indeed, recent data show increases in surface UV radiation throughout Australia since the 1970s. Second, mean temperatures in Australia have increased over the past 30 years and are projected to rise further by 2030. Australian data shows that with higher temperatures, adults spend more time outdoors, are less likely to wear covering clothing and more likely to be sunburnt. Hence, rising temperatures can be expected to result in increases in sun exposure, sunburn and correspondingly, skin cancer risk. PMID- 22518919 TI - A numbers game: lack of gendered data impedes prevention of disaster-related family violence. AB - ISSUE ADDRESSED: The lack of a systematic approach to collecting family violence data after a disaster impedes family violence prevention and response efforts. Without evidence, there is little chance that interventions will be planned and implemented to address increased family violence after disasters. METHODS: A literature review of international and Australian gendered disaster research was conducted, with a focus on family violence following disasters in developed countries. A case study was prepared exploring the complexity of gathering data about family violence in the aftermath of the Victorian Black Saturday bushfires. RESULTS: Although increases in family violence in the aftermath of the Black Saturday bushfire were observed and anecdotally reported by funded family violence agencies, recovery authorities and community leaders, attempts by Women's Health in the North and the researchers to quantify the increase were unsuccessful. The fragmented nature of the family violence data that was collected was a consequence of inconsistent data recording practices and the complex and multifaceted nature of the recovery effort. CONCLUSIONS: Health promotion theory and service planning demand a sound evidence base for interventions. In the absence of this, family violence following disasters will continue to be overlooked in the face of 'urgent' needs. PMID- 22518920 TI - Wrestling with 'doubt-sayers': a first step in leading community-wide climate change action for better health. AB - ISSUE ADDRESSED: Although the evidence base for climate change is indisputable and the potential human health impact is extremely concerning, to date public health professionals are playing little part in influencing community change to accept and act on the science. METHOD: In reviewing the techniques used to obstruct action on tobacco control by vested interests through constantly raising doubt about the science in this arena, a similar pattern is seen in obstructing action on climate change. RESULTS: It is clear that the raising of unverified doubt is the primary tool employed by profit-driven corporations to prevent constructive action in both these arenas, with the very high potential for the health of the whole population to suffer as a result. CONCLUSION: Those promoting the health of Australians have a responsibility to optimise health in this regard and need to think differently through embracing complexity science and then take action, with the first step being to provide constant counter-arguments to the unsubstantiated statements of the 'doubt-sayers'. PMID- 22518921 TI - The potential role of health impact assessment in tackling the complexity of climate change adaptation for health. AB - Managing an issue of the magnitude, scope and complexity of climate change is a daunting prospect, yet one which nations around the world must face. Climate change is an issue without boundaries--impacts will cut across administrative and geographical borders and be felt by every sector of society. Responses to climate change will need to employ system approaches that take into account the relationships that cross organisational and sectoral boundaries. Solutions designed in isolation from these interdependencies will be unlikely to succeed, squandering opportunities for long-term effective adaptation. Health Impact Assessment (HIA) provides a structural approach to identify, evaluate and manage health impacts of climate change that is inclusive of a wide range of stakeholders. Climate change will affect decision-making across every government level and sector and the health implications of these decisions can also be addressed with HIA. Given the nature of the issue, HIA of climate change will identify a large number of variables that influence the type and extent of health impacts and the management of these impacts. In order to implement the most effective adaptation measures, it is critica that an understanding of the interactions between these variables is developed. The outcome of HIA of climate change can therefore be strengthened by the introduction of system dynamics tools, such as causal loop diagrams, that are designed to examine interactions between variables and the resulting behaviour of complex systems. PMID- 22518922 TI - Networked resilience in rural Australia--a role for health promotion in regional responses to climate change. AB - ISSUES ADDRESSED: This paper provides a model for how health promotion teams might establish and support regional collaborations of organisations in a broad response to climate change that enables emergence of multiple strategies tailored to regional needs. METHODS: Complex Adaptive Systems Theory (CAS) and Organisational Learning informed action to foster a Climate Change Collaboration that engaged in strategies to improve transport options, food security and energy sustainability. Social Network Analysis was used to evaluate the degree to which member organisations became networked, the evolution of key network qualities and the way the organisations were affiliated via their participation in emergent strategies. RESULTS: Between 2005 and 2009 a highly connected network of organisations emerged and rapidly evolved to collaborate for action on climate change. There were significant improvements in network density, centralisation, clustering and reciprocity. Member organisations collaborated on a broad range of strategies. CONCLUSIONS: Reducing regional impact of climate change is complex. It requires long-term collaboration between organisations that may not usually work together. Sustain Northern Rivers provides a successful model for achieving such collaboration. PMID- 22518923 TI - It's here! Are we ready? Five case studies of health promotion practices that address climate change from within Victorian health care settings. AB - ISSUE ADDRESSED: Climate changes and environmental degradation caused by anthropogenic activities are having an irrefutable impact on human health. The critical role played by health promotion in addressing environmental challenges has a history in seminal charters--such as the Ottawa Charter for Health Promotion--that explicitly link human well-being with the natural environment. The lack of documented practice in this field prompted an investigation of health promotion practice that addresses climate change issues within health care settings. METHODS: This qualitative study involved five case studies of Victorian health care agencies that explicitly identified climate change as a priority. Individual and group interviews with ten health promotion funded practitioners as well as document analysis techniques were used to explore diverse practices across these rural, regional and urban health care agencies. RESULTS: Health promotion practice in these agencies was oriented toward: active and sustainable transport; healthy and sustainable food supply; mental health and community resilience; engaging vulnerable population groups such as women; and organisational development. CONCLUSION: Despite differences in approach, target population and context, the core finding was that health promotion strategies, competencies and frameworks were transferable to action on climate change in these health care settings. PMID- 22518924 TI - Schools, climate change and health promotion: a vital alliance. AB - Through an ongoing project, we have been reviewing the literature addressing school planning for climate change related ecological disruptions and disasters, particularly for the special needs of children with disabilities. We have also examined related state education department policies from across Australia. Our preliminary results suggest scant attention has been paid either by researchers or educational policy makers to the needs of children with disabilities and their caregivers in response to climate change induced disaster scenarios. Here, we advocate for better preparedness among institutions serving children with disabilities to support their health in the context of climate change, and describe how health promotion principles can be brought to bear on this issue. PMID- 22518925 TI - Changes in peroxidase and phenols activity in apple fruit inoculated with antagonistic Pseudomonas fluorescens isolates and Botrytis mali. AB - The biocontrol activity of three isolates of Pseudomonas fluorescens against gray mold of apple fruit caused by Botrytis mali and their ability to induce biochemical defense response in apple tissue were investigated. Apple fruit (Malus domestica) wounds were inoculated with 20 microL bacterial suspension (10(8) CFU mL(-1)) of Pseudomonas fluorescens followed 24 h later by 20 microL of conidial suspension of B. mali (10(5) conidia mL(-1)). The apples were then incubated at 20 degrees C for 11 days. Lesion diameters were evaluated 6 and 10 days after pathogen inoculation. In addition to controlling gray mold, these three isolates of P. fluorescens caused increase in peroxidase activities that reached maximum levels 2-6 days after pathogen inoculation. Phenolic accumulation was increased in apple fruit treated with antagonists and inoculated with B. mali and exhibited the highest level 6-8 days after treatment. The ability of P. fluorescens to increase activities of peroxidase and levels of phenol compounds maybe one of mechanism responsible its biocontrol activity. PMID- 22518926 TI - Susceptibility of field populations of Blattella germanica (Blattaria: Blattellidae) to spinosad. AB - The German cockroach is an important household insect pest worldwide and acts as a mechanical vector and reservoir for pathogenic agents. The aim of this study was to examine the basic laboratory toxicity of Blattella germanica to spinosad. The M, T, A22, AZAR4, BOOSTAN7 and ABAN21 strains were collected from field populations of six infested kitchen student dormitories and the SAMAN strain was collected from a residential area after insecticide spraying control failure in Tehran, Iran. Technical grade spinosad was delivered in 0.5 microL acetone to the first abdominal sternum of briefly CO2-anesthetize adult male cockroaches by topical application bioassay. Treated males monitored for mortality. Mortality data from the replicates was assessed by probit analysis. The average LD50 of susceptible strain was 494.3, 148.8 and 55.1 ng per insect after 24, 48 and 72 h, respectively. The LD50 of spinosad decreased with time in the field population strains. All German cockroach strains showed a similar susceptibility or lower tolerance (1.6-folds) for spinosad compared with the susceptible laboratory strain and the steep slopes of dose-response curves indicated that the field population of these German cockroach strains was homogenous in response to spinosad. These results indicated that the spinosad was relatively slow-acting in topical application bioassay, with LD50 values decreasing until 72 h and becoming stable thereafter. The effectiveness of spinosad against susceptible and the field population German cockroach strains in laboratory condition showed that spinosad probably could be useful for the control of the German cockroach. PMID- 22518927 TI - Effect of body mass index on severity and prevalence of varicocele. AB - Varicocele is classified as grade I-III regarding its severity. This study was aimed to determine the correlation between height and weight with varicocele grade in 18-30 years age group. We enrolled 400 persons aged 18-30 years referred to the specialist's clinics of Tabriz Medical Sciences University or Medical Commission Since Sep. 2004 to Mar. 2005. First we divided the volunteers in two groups including Varicocele Group and Non-varicocele Group, then varicocele patients were classified to three grades considering the severity of the disease: severe (Grade III), moderate (Grade II) and mild (Grade I). Finally, the correlation between height, weight and Body Mass Index (BMI) was evaluated. There was a significant relation between height and grades of left-side varicocele; in other words the severity of disease was increased with height (p = 0.004). Also, height increased the prevalence ofvaricocele (p = 0.011). On the other hand, low weight and BMI increased the prevalence of varicocele (p = 0.000, p = 0.004) but did not affect the severity of disease (p = 0.364, p = 0.172). In conclusion, the height of patients directly affected the prevalence and severity of left-side varicocele which probably is related to length of left internal spermatic veins in these patients and increased hydrostatic pressure in taller patients. Also, the weight and BMI is effective on the prevalence of varicocele. It seems that slim and tall persons will benefit from evaluation while puberty. PMID- 22518928 TI - Influence of agricultural practices on fruit quality of bell pepper. AB - An experiment was carried out under plastic house conditions to compare the effect of four fermented organic matter sources (cattle, poultry and sheep manure in addition to 1:1:1 mixture of the three organic matter sources) in which 4 kg organic matter m(-2) were used, with that of the conventional agriculture (chemical fertilizers) treatments on Marvello red pepper fruit quality, by using a Randomized Complete Block Design (RCBD) with four replicates. Pepper fruits characteristics cultivated in soil supplemented with manure were generally better than those from plants grown in soil only. Addition of animal manure increased bell pepper fruit content of soluble solids, ascorbic acid, total phenols, crude fibre and intensity of red color as compare with conventional agriculture that produced fruits with higher titratable acidity, water content, lycopene and bigger fruit size. In most cases of animal manure treatments, best results were obtained by the sheep manure treatment that produced the highest TSS, while the worst results were obtained by the poultry manure treatment that produced the smallest fruit and lowest fruit lycopene content. PMID- 22518929 TI - Potato disc bioassay and cytotoxic effect of Leptadenia pyrotechnica: comparative study of diverse extracts. AB - Comparative acute toxicity studies of the latex and sequential extracts of Leptadenia pyrotechnica (Forsk.) Decne (Asclepiadaceae) were recorded using brine shrimp. The higher toxicities were exhibited in latex; methanol, methanol/dichloromethane (1:1), defatted methanol/dichloromethane (1:1), defatted methanol and dichloromethane extracts. The other extracts; aqueous, alkaloids, ethyl acetate and n-butanol exhibited less toxicities compared with the other extracts. The estimated LC50 and its 95% confidence limits for these extracts expressed in ppm were: methanol, latex 18.84 (11.22-31.61), methanol/dichloromethane 19.95 (7.76-53.70), defatted methanol/dichloromethane 21.38 (7.24-63.10), defatted methanol 28.19 (16.27-48.81) and dichloromethane 30.90 (11.75-79.43). The anti-tumor activities; potato disc assays of methanol, ethyl acetate and alkaloids extracts showed good activities as anti-tumor agent which represented-49.30,-43.20 an -33.60%, respectively. While latex and aqueous extract represented-30.80 and-28.17%, respectively. PMID- 22518930 TI - Turning up the heat: immune brinksmanship in the acute-phase response. AB - The acutephase response (APR) is a systemic response to severe trauma, infection, and cancer, although many of the numerous cytokine-mediated components of the APR are incompletely understood. Some of these components, such as fever, reduced availability of iron and zinc, and nutritional restriction due to anorexia, appear to be stressors capable of causing harm to both the pathogen and the host. We review how the host benefits from differences in susceptibility to stress between pathogens and the host. Pathogens, infected host cells, and neoplastic cells are generally more stressed or vulnerable to additional stress than the host because: (a) targeted local inflammation works in synergy with APR stressors; (b) proliferation/growth increases vulnerability to stress; (c) altered pathogen physiology results in pathogen stress or vulnerability; and (d) protective heat shock responses are partially abrogated in pathogens since their responses are utilized by the host to enhance immune responses. Therefore, the host utilizes a coordinated system of endogenous stressors to provide additional levels of defense against pathogens. This model of immune brinksmanship can explain the evolutionary basis for the mutually stressful components of the APR. PMID- 22518931 TI - The costs of sex: facing real-world complexities. AB - Understanding the maintenance of sexual reproduction constitutes a difficult problem for evolutionary biologists because of the immediate costs that sex seems to incur. Typically, general benefits to sex and recombination are investigated that might outweigh these costs. However, several factors can strongly influence the complex balance between costs and benefits of sex; these include constraints on the evolution of asexuality, ecological differentiation, and certain lif history traits. We review these factors and their empirical support for the first time in a unified framework and find that they can reduce the costs of sex, circumvent them, or make them inapplicable. These factors can even tip the scales to a net benefit for sex. The reviewed factors affect species and species groups differently, and we conclude consequently that understanding the maintenance of sex could turn out to be more species-specific than commonly assumed. Interestingly, our study suggests that, in some species, no general benefits to sex and recombination might be needed to understand the maintenance of sex, as in our case study of dandelions. PMID- 22518932 TI - Prevalence of asthma in elementary school age children in Iran--a systematic review and meta analysis study. AB - Asthma is a common chronic disease of childhood which causes considerable morbidity. Asthma affects 1 in 13 school-age children and is a leading cause of office and emergency department visits, hospitalizations, and school absenteeism. Estimating the prevalence of asthma in the community is important in assessing the impact of asthma at the level of population. Since the pooled prevalence of asthma in Iranian elementary school age children (6-12 years old) was not identified, we decide to conduct a meta-analysis study to estimate the prevalence of asthma in elementary school age children in Iran. In order to gather the data, we searched a number of international electronic sources such as Pub Med, Embase, science direct, and ISI for English articles, and Iranian National Knowledge Infrastructure (scientific information) sources such as Iranmedx, Iran-doc, and SID for Persian articles from February 1995 to January 2010 to access the data. We used the words childhood, asthma, prevalence, and Iranian for searching relevant papers and used a data extraction form for the extracted data. The outcome in this Meta analysis study was response to the question, "Ever had asthma", based on the ISSAC program questionnaire. Eleven relevant articles were included for the Meta analysis. The pooled prevalence for girls, boys, and the two genders was obtained as 3.2% (CI; 2.5 to 3.9%), 4.3% (CI; 3.5 to 5.1%) and 3.9% (CI; 3.2 to 4.7%), respectively. The pooled prevalence of asthma in Iranian elementary school age children is low in comparison to the other reports. PMID- 22518933 TI - Phytochemical screening and in vitro amylase inhibitory effect of the leaves of Breynia retusa. AB - This study was proposed based on the folklore claim and on the scarcity of scientific evidence from the literature for the medicinal uses of Breynia retusa. The aim of the present study was to analyse the phytochemical constituents of the leaves of B. retusa. The fractions obtained by successive fractionation using solvents of varying polarity were studied for the presence of primary and secondary metabolites and the total phenolic content of the different fractions were determined by HPLC. The results of the study support the traditional acclaim of the therapeutic uses of B. retusa. The potential of B. retusa to inhibit alpha amylase, a prime enzyme involved in carbohydrate metabolism was analysed and it was observed that the ethyl acetate and methanolic extract of the leaves of B. retusa possessed in vitro amylase inhibitory activity. PMID- 22518934 TI - Effect of vitamin C supplementation on postprandial oxidative stress and lipid profile in type 2 diabetic patients. AB - Diabetes mellitus is one of the most wide spread endocrine disorders and an important developing health problem in the world. Cardiovascular disease is a common complication of type 2 diabetes. Several risk factors for coronary heart disease cosegregate in type 2 diabetes, including hyperglycemia, hyperlipaemia, increases production of free radical and decrease in antioxidant defense system. In this study we evaluated the effect of vitamin C supplementation on fasting and postprandial oxidative stress and lipid profile in type 2 diabetic patients. 30 patients with type 2 diabetes from Nader Kazemi Clinic, Shiraz, Iran were randomly divided into 2 groups; vitamin C treatment group (1000 mg d(-1)) and placebo group from May to September 2010. Fasting and postprandial lipid profile and Malondialdehyde (MDA) level were measured at the beginning of the study and after six weeks of supplementation. Data analysis was carried out using Mann Whitney U test with p < 0.05 being significant by SPSS software version 16.The result of the study showed a significantly decrease in fasting (p = 0.006) and postprandial MDA (p < 0.001) in vitamin C group compare to placebo group but not in lipid profile. This study suggests that vitamin C supplementation can decrease fasting and postprandial oxidative stress and may prevent diabetes complication. PMID- 22518935 TI - Phytochemical screening, cytotoxicity and antibacterial activities of two Bangladeshi medicinal plants. AB - The objectives of the present study were to investigate phytochemical screening and to assay cytotoxicity and antibacterial activities of ethanolic extracts of leaves of two medicinal plants, Aglaonema hookerianum Schott (Family: Araceae) and Lannea grandis Engl. (Family: Anacardiaceae) available in Bangladesh. The brine shrimp lethality bioassay showed that the ethanolic extracts of Aglaonema hookerianum and Lannea grandis possessed cytotoxic activities with LC50 5.25 (microg mL(-1)) and 5.75 (microg mL(-1)) and LC90 10.47 (microg mL(-1)) and 9.55 (microg mL(-1)), respectively. Two extracts obtained from leaves were examined for their antibacterial activities against some gram positive bacteria such as Bacillus subtilis, Bacillus megaterium and Staphylococcus aureus, also gram negative strains of Pseudomonas aeruginosa, Escherichia coli, Shigella dysenteriae, Salmonella typhi, Salmonella paratyphi and Vibrio cholerae. Agar disc diffusion method was applied to observe the antibacterial efficacy of the extracts. Results indicated that both plant extracts (500 microg disc(-1)) displayed antibacterial activity against all of the tested microorganisms. These results were also compared with the zones of inhibition produced by commercially available standard antibiotic, Amoxicillin at concentration of 10 microg disc( 1). Observed antibacterial properties of the ethanolic extract of Aglaonema hookerianum Schott and Lannea grandis Engl. showed that both plants might be useful sources for the development of new potent antibacterial agents. PMID- 22518936 TI - Antinociceptive and anti-inflammatory activity of the ethanolic extract of Cymbidium aloifolium (L.). AB - The ethanol leaf extract of Cymbidium aloifolium (L.) was evaluated for its analgesic and antiinflammatory activities. The extract, at the dose of 200 and 400 mg kg(-1) body weight, exerted the analgesic activity by observing the number of abdominal contractions and anti-inflammatory activity against Carrageenin induced paw edema in mice by measuring the paw volume. The ethanolic extract of Cymbidium aloifolium (L.) showed statistically significant (p < 0.05) reduction of percentage of writhing of 33.57 and 61.31% at 200 and 400 mg kg(-1) oral dose, respectively, when compared to negative control. The Ethanolic plant extract also showed significant (p < 0.05) dose dependent reduction of mean increase of formation of paw edema. The results of the experiment and its statistical analysis showed that the ethanolic plant extract had shown significant (p < 0.05) dose dependent analgesic and anti-inflammatory activities when compared to the control. PMID- 22518937 TI - Cyphostemma glaucophilla may serve as a cheap protectant of liver and kidney. PMID- 22518938 TI - Anti-colon activity in ethanolic extract of Phytolacca americana. PMID- 22518939 TI - Behavioral choices determines the fate of fish species. PMID- 22518940 TI - Intra-limb coordinative adaptations in cycling. AB - This study aimed to establish the nature of lower extremity intra-limb coordination variability in cycling and to investigate the coordinative adaptations that occur in response to changes in cadence and work rate. Six trained and six untrained males performed nine pedalling bouts on a cycle ergometer at various cadences and work rates (60, 90, and 120 revolutions per minute (rpm) at 120, 210, and 300W). Three-dimensional kinematic data were collected and flexion/extension angles of the ankle, knee, and hip joints were subsequently calculated. These data were used to determine two intra-limb joint couplings [hip flexion/extension-knee flexion/extension (HK) and knee flexion/extension-ankle plantar-flexion/dorsi-flexion (KA)], which were analysed using continuous relative phase analysis. Trained participants displayed significantly (p < 0.05) lower coordination variability (6.6 +/- 4.0 degrees) than untrained participants (9.2 +/- 4.7 degrees). For the trained subjects, the KA coupling displayed significantly more in-phase motion in the 120 rpm (19.2 +/- 12.3 degrees) than the 60 (30 +/- 7.1 degrees) or 90 rpm (33.1 +/- 7.4 degrees) trials and the HK coupling displayed significantly more in-phase motion in the 90 (33.3 +/- 3.4 degrees) and 120 rpm (27.9 +/- 13.6 degrees) than in the 60 rpm trial (36.4 +/- 3.5 degrees). The results of this study suggest that variability may be detrimental to performance and that a higher cadence is beneficial. However, further study of on-road cycling is necessary before any recommendations can be made. PMID- 22518941 TI - Muscle activity and pedal force profile of triathletes during cycling to exhaustion. AB - The purpose of this study was to analyze pedaling cadence, pedal forces, and muscle activation of triathletes during cycling to exhaustion. Fourteen triathletes were assessed at the power output level relative to their maximal oxygen uptake (355 +/- 23 W). Cadence, pedal forces, and muscle activation were analyzed during start, middle, and end test stages. Normal and tangential forces increased from the start to the end of the test (-288 +/- 33 to -352 +/- 42 N and -79 +/- 45 to -124 +/- 68 N, respectively) accompanied by a decrease in cadence (96 +/- 5 to 86 +/- 6 rpm). Muscle activation increased from the start to the middle and the end in the gluteus maximus (27 +/- 5.5% and 76 +/- 9.3%) and in the vastus lateralis (13 +/- 3.5% and 27 +/- 4.4%), similar increase was observed from the start to the end in the rectus femoris and the vastus medialis (50 +/- 9.3% and 20 +/- 5.7%, respectively). Greater normal force along with enhanced activation of knee and hip extensor muscles is linked with fatigue and declines in cadence of triathletes during cycling to exhaustion. PMID- 22518942 TI - Kinematic changes during learning the longswing on high bar. AB - The purpose of this study is to provide evidence of technique changes during learning a sports-specific skill, the looped bar longswing (LLS). Thirteen male participants with no previous high bar experience took part in a training study. Kinematic data were collected using a CODA motion analysis system (200 Hz) during eight weekly testing sessions. Analyses focused on the amplitude of swing and the functional phase (FP) actions, defined by the rapid flexion to extension of the shoulders and extension to flexion of the hips as the performer passed through the lower vertical. Three groups were identified based on the number of sessions it took each participant to perform the LLS (G1: most successful, G2: intermediate, and G3: least successful). All participants were able to significantly increase swing amplitude over the training period (p < 0.05). For each participant the hip FP started significantly: later for G1, earlier for G2, and did not change for G3. Extension actions at the shoulders were dissimilar to those reported for elite gymnasts performing the longswing. The FP of the hips provides a mechanism to distinguish between the learners of different skill levels. The study has provided support for a single-subject design when investigating technique changes during learning. PMID- 22518943 TI - Circles with a suspended aid: reducing pommel reaction forces. AB - The aim of this study was to investigate the influence of a suspended aid on the reaction forces during a basic skill on pommel horse. Twenty gymnasts performed three sets of 10 circles with and without a suspended aid on a pommel horse under which two force plates were set. The results confirmed that the suspended aid could reduce the magnitude of the pommel reaction forces during circles while maintaining the general loading pattern. On the left hand, the average and peak forces were attenuated to 0.59 body weight (BW) and 0.85 BW from 0.76 BW and 1.13 BW, respectively. The right hand experienced slightly larger forces with no-aid trials, but the asymmetry between the hands decreased with the aid. Despite a relatively large variability, all gymnasts experienced smaller impact peak forces with the aid. A suspended aid is most commonly used for a beginner gymnast as an introduction to pommel horse exercises. However, this study confirmed that it can also be useful for all levels of gymnasts who would like to practice pommel horse exercises with reduced pommel reaction forces for a purpose such as a progression for learning a new skill, control of training volume, or rehabilitation. PMID- 22518944 TI - Effects of previous lateral ankle sprain and taping on the latency of the peroneus longus. AB - The latency of the peroneus longus may be a key factor in the prevention of lateral ankle sprains (LASs). In addition, ankle taping is often applied to help prevent LASs. The purpose of this study was to determine the effects of a previous LAS and ankle taping on the latency of the peroneus longus after an inversion perturbation. Twenty-six participants, including 13 participants with no previous history of a LAS and 13 participants with a history of a single LAS completed the testing. Ankle taping was applied in a closed basket weave technique on one of the two testing days. The latency of the peroneus longus was determined by the onset of muscle activity exceeding 10 SD from baseline activity, after initiation of the 25 degrees inversion perturbation. A significant main effect (p < 0.05) was present for the ankle support condition, with ankle taping causing a significant reduction in latency of the peroneus longus (65.04 +/- 10.81 to 57.70 +/- 9.39 ms). There was no difference (p > 0.05) in latency between the injury groups. Ankle taping, immediately after application, reduces the latency of the peroneus longus among participants with and without a history of a LAS. PMID- 22518945 TI - Characterizing the mechanical parameters of forward and backward falls as experienced in snowboarding. AB - Wrist injuries are frequently observed after falls in snowboarding. In this study, laboratory experiments mimicking forward and backward falls were analysed. In six different falling scenarios, participants self-initiated falls from a static initial position. Eighteen volunteers conducted a total of 741 trials. Measurements were taken for basic parameters describing the kinematics as well as the biomechanical loading during impact, such as impact force, impact acceleration, and velocity. The effective mass affecting the wrist in a fall also was determined. The elbow angle at impact showed a more extended arm in backward falls compared to forward falls, whereas the wrist angle at impact remained similar in forward and backward falls. The study results suggest a new performance standard for wrist guards, indicating the following parameters to characterize an impact: an effective mass acting on one wrist of 3-5 kg, an impact angle of 75 degrees of the forearm relative to the ground, and an impact velocity of 3 m/s. PMID- 22518947 TI - Quantitative analysis of Brazilian football players' organisation on the pitch. AB - The purpose of this study was to characterise Brazilian teams' coverage area and spread on the pitch while attacking and defending and to analyse the teams' organisation in tackle and shot on goal situations. We obtained the trajectories of 223 players in eight games with a tracking method. Team area was defined as the area of the convex hull formed by players' positions. Team spread was defined as the Frobenius norm of the distance-between-player matrix. We calculated teams' area and spread over time and in situations of shots on goal (n = 233) and tackles (n = 1897). While the players attacked, spread and area (median +/- confidence interval) ranged from 322.9 +/- 0.8 to 387.8 +/- 1.0 m and from 905.4 +/- 4.4 to 1407.6 +/- 5.5 m2, respectively. On defence, the values were smaller (p < 0.05) and ranged from 283.4 +/- 0.9 to 325.8 +/- 0.9 m and from 773.8 +/- 4.6 to 1158.4 +/- 5.5 m2 for the spread and the area. In defending circumstances, the teams presented a greater area and spread when they suffered shots on goal than when the teams performed tackles. In attacking situations, the teams presented a greater area and spread when they suffered tackles than when they performed shots on goal. The results allowed showing the attacking-defending interaction between Brazilian teams. PMID- 22518946 TI - Biomechanics of walking with snowshoes. AB - Snowshoeing is a popular form of winter recreation due to the development of lightweight snowshoes that provide flotation, traction, and stability. The purpose of this study was to determine the effects of snowshoes on lower extremity kinematics during level walking. Twelve adults (6 males, 6 females, body mass = 67.5 +/- 10.7kg) completed six 3-minute level walking trials. Subjects walked overground without snowshoes and on packed snow using conventional and flexible tail snowshoes. We placed lightweight inertial/gyroscopic sensors on the sacrum, thigh, shank, and foot. We recorded sensor orientation and calculated hip, knee, and ankle joint angles and angular velocities. Compared to level overground walking, subjects had greater hip and knee flexion during stance and greater hip flexion during swing while snowshoeing. Ankle plantarflexion began during late swing when snowshoeing vs. heel strike during overground walking. Lower extremity kinematics were similar across snowshoe frame designs during level walking. Our results show that snowshoeing on packed snow results in a more flexed leg compared to overground walking and may reflect a strategy to limit the effects of walking with an extended heel. PMID- 22518948 TI - Does sensorimotor training improve the static balance of young volleyball players? AB - The aim of this investigation is to assess the effectiveness of a 6-week balance training (BT) protocol, integrated in regular training sessions, on postural sway of young female volleyball players (n = 26, age 13.0 +/- 0.2 years) divided into two groups (intervention and control; 13 per group). Trials were performed for bipedal and unipedal stance conditions before and after the BT protocol, using a pressure platform to collect center-of-pressure (COP) time series that were processed to calculate sway area, COP path length, and maximum displacement range in anteroposterior and mediolateral directions. The intervention group exhibited smaller sway areas in eyes closed conditions (intervention = 42.76 mm2, control = 67.60 mm2; p < 0.05) and Romberg quotients (intervention = 1.11 mm, control = 1.82 mm) in bipedal stance, while all the other parameters were unaffected. BT also reduced sway area (intervention = 122.70 mm2, control = 187.18 mm2) and anteroposterior COP displacements (intervention = 20.18 mm, control = 22.38 mm) of the non-dominant limb for single-leg stance. No significant change was found for the dominant limb. Although it is possible to hypothesize a beneficial effect of BT on young athletes, further investigations are required to clarify its actual effect on balance performance with respect to normal volleyball training. PMID- 22518949 TI - Does student learning style affect performance on different formats of biomechanics examinations? AB - Students' learning style preferences have been widely adapted into teaching and learning environments. The purpose of this study was to investigate the relationship between self-reported and assessed learning style preferences (visual, auditory, reading/writing, kinesthetic: VARK) on performance in different types of multiple-choice examinations (T1: text only format and T2: visual format) given in an introductory biomechanics class. Students who enrolled in three biomechanics classes at a state university were recruited to participate in the study. Ninety students (47 males and 43 females) completed a learning style survey and two types of examinations. Results showed that approximately half of the students were assessed and self-reported as kinesthetic for their preferred learning style. There was no significant difference in test performance between students who preferred visual and reading/writing learning styles (self reported and assessed). These students demonstrated similar learning and comprehension of biomechanical concepts regardless of whether the test material was presented in their preferred sensory mode or not. Interestingly, female students' perceptions of their learning style preference may have a positive effect on the test results when the test is presented in their preferred format. PMID- 22518950 TI - Comment on "Use of deterministic models in sports and exercise biomechanics research" by Chow and Knudson (2011). AB - Although deterministic models may provide a useful starting point for sports biomechanists examining the mechanical aspects of athletic performance, they have inherent weaknesses that limit their proctical application. Specifically, their inability to provide substantive information about coordinative movement patterns or 'technique' suggests that sports biomechanists must explore alternative paradigms and theoretical frameworks if they are to fulfil their main aims of improving performance and reducing injury risk. We believe that dynamical systems theory and its associated analytical tools can provide a useful adjunct to more traditional paradigms in sport biomechanics, such as deterministic modelling, which have only made a limit contribution to the enhancement of knowledge. PMID- 22518951 TI - [Future Psychiatry: a "think tank" for the Italian psychiatry]. AB - The Future Psychiatry Project was founded with the goal to address the critical ratio of research/training/clinic. In a series of regular meetings, each devoted to a specific clinical topic, data and more advanced models for the clinical area in question will be analyzed in an integrated and multidisciplinary approach and the real possibility of extension of development and prospects of scientific advances to the clinic and therapy will be evaluated. The primary methodological objective of the Future Psychiatry meetings is the training method to overcome the common type of teacher/learner classroom teaching, albeit divided into the various possibilities offered by different types of educational meetings. The structure is informal, with features of intensive seminars and suggested modes for better interaction. The objective is the "think tank", a common space for study and exchange of knowledge, experiences, opinions and expectations, aimed at producing an integrated and shared dynamic result, that can provide a real reference point for participants and for all researchers and clinicians engaged in improving their level of updating and best clinical activity. The first Future Psychiatry meeting was held in Sermoneta (Latina) in the halls of the Castello Caetani on September 16th to 18th 2010. The chosen topic was "The Future of Depression: the development of knowledge, the evolution of therapies". The currently most advanced data of research were discussed and developed in their potential to reach a shared model taking into account the etiological complexity of Depression and to be a real reference to the possibility of application to real clinical experience. The main guidelines of the current research and major prospects for development of this in the field Depression have been outlined, also in relation to the ongoing evolution and the future outlook of the models and tools of therapy. Psychiatrists' clinical needs and expectations in front of the development of scientific knowledge were analyzed in relation to the translational prospect of a better application of these in the clinical practice of present and future care of Depression. PMID- 22518952 TI - ["The future of depression: knowledge development, therapy evolution"]. PMID- 22518953 TI - Combined ultrasonic thermal ablation with interleaved ARFI image monitoring using a single diagnostic curvilinear array: a feasibility study. AB - The goal of this work is to demonstrate the feasibility of using a diagnostic ultrasound system (Siemens Antares and CH6-2 curvilinear array) to ablate ex vivo liver with a custom M-mode sequence and monitor the resulting tissue stiffening with 2-D Acoustic Radiation Force Impulse (ARFI) imaging. Images were taken before and after ablation, as well as in 5- s intervals during the ablation sequence in order to monitor the ablation lesion formation temporally. Ablation lesions were generated at depths up to 1.5 cm from the surface of the liver and were not visible in B-mode. ARFI images showed liver stiffening with heating that corresponded to discolored regions in gross pathology. As expected, the contrast of ablation lesions in ARFI images is observed to increase with ablation lesion size. This study demonstrated the ability of a diagnostic system using custom beam sequences to localize an ablation site, heat the site to the point of irreversible damage and monitor the formation of the ablation lesion with ARFI imaging. PMID- 22518954 TI - Ultrasonic attenuation and backscatter coefficient estimates of rodent-tumor mimicking structures: comparison of results among clinical scanners. AB - In vivo estimations of the frequency-dependent acoustic attenuation (alpha) and backscatter (eta) coefficients using radiofrequency (rf) echoes acquired with clinical ultrasound systems must be independent of the data acquisition setup and the estimation procedures. In a recent in vivo assessment of these parameters in rodent mammary tumors, overall agreement was observed among alpha and eta estimates using data from four clinical imaging systems. In some cases, particularly in highly-attenuating heterogeneous tumors, multisystem variability was observed. This paper compares alpha and eta estimates of a well-characterized rodent-tumor-mimicking homogeneous phantom scanned using seven transducers with the same four clinical imaging systems: a Siemens Acuson S2000, an Ultrasonix RP, a Zonare Z.one and a VisualSonics Vevo2100. alpha and eta estimates of lesion mimicking spheres in the phantom were independently assessed by three research groups, who analyzed their system's rf echo signals. Imaging-system-based estimates of alpha and eta of both lesion-mimicking spheres were comparable to through-transmission laboratory estimates and to predictions using Faran's theory, respectively. A few notable variations in results among the clinical systems were observed but the average and maximum percent difference between alpha estimates and laboratory-assessed values was 11% and 29%, respectively. Excluding a single outlier dataset, the average and maximum average difference between eta estimates for the clinical systems and values predicted from scattering theory was 16% and 33%, respectively. These results were an improvement over previous interlaboratory comparisons of attenuation and backscatter estimates. Although the standardization of our estimation methodologies can be further improved, this study validates our results from previous rodent breast-tumor model studies. PMID- 22518955 TI - Ultrasound attenuation measurements using a reference phantom with sound speed mismatch. AB - Ultrasonic attenuation may be measured accurately with clinical systems and array transducers by using reference phantom methods (RPM) to account for diffraction and other system dependencies on echo signals. Assumptions with the RPM are that the speeds of sound in the sample (c(sam)) and in the reference medium (c(ref)) are the same and that they match the speed assumed in the system beamformer (c(bf)). This work assesses the accuracy of attenuation measurements by the RPM when these assumptions are not met. Attenuation was measured for two homogeneous phantoms, one with a speed of sound of 1500 m/s and the other with a sound speed of 1580 m/s. Both have an attenuation coefficient approximately equal to that of the reference, in which the speed of sound is 1540 m/s. Echo signals from the samples and the reference were acquired from a Siemens S2000 scanner with a 9L4 linear array transducer. Separate acquisitions were obtained with c(bf) at its default value of 1540 m/s and when it was set at values matching the speeds of sound of the phantoms. Simulations were also performed using conditions matching those of the experiment. RPM-measured attenuation coefficients exhibited spatially-dependent biases when c(sam) differed from c(df) and c(ref). Mean errors of 19% were seen for simulated data, with the maximum errors in attenuation measurements occurring for regions of interest near the transmit focus. Biases were minimized (mean error with simulated data was 5.6%) using c(bf) that matched c(sam) and assuring that power spectra used for attenuation computations in the sample are from precisely the same depth as those from the reference. Setting the transmit focus well beyond the depth range used to compute attenuation values minimized the bias. PMID- 22518957 TI - [Coronary artery disease. Introduction]. PMID- 22518956 TI - Texture feature analysis for breast ultrasound image enhancement. AB - Texture analysis of breast ultrasound B-scans has been widely applied to the segmentation and classification of breast tumors. We present a parametric imaging method based on the texture features to preserve tumor edges and retain the texture information simultaneously. Four texture-feature parameters--homogeneity, contrast, energy and variance--were evaluated using the gray-level co-occurrence matrix. The local texture-feature parameter was assigned as the new pixel located at the center of the sliding window at each position. This process yielded the texture-feature parametric image as the map of texture-feature values. The signal to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were estimated to show the quality improvement of the images. The contours outlined from 11 experienced physicians and the gradient vector flow (GVF) snake algorithm segmentations were adopted to verify the edge enhancement of texture-feature parametric images. In addition, the Fisher's linear discriminant analysis (FLDA) and receiver-operating characteristic (ROC) curve were used to test the performance of breast tumor classifications between texture-feature parametric images and B-scan images. The results show that the variance images have higher CNR and SNR estimates than those in the B-scan images. There was a high agreement between the physician's manual contours and the GVF snake automatic segmentations in the variance images, and the mean area overlap was over 93%. The area under the ROC curve from the B scan images had 0.81 and 95% confidence interval of 0.72-0.88, and the texture feature parametric images had 0.90 and 95% confidence interval of 0.84-0.96. These findings indicate that the texture-feature parametric imaging method can be not only useful for determining the location of the lesion boundary but also as a tool to improve the accuracy of breast tumor classifications. PMID- 22518958 TI - [Historical change of the pathophysiological concept about "coronary artery disease"]. PMID- 22518959 TI - [The current situation of ischemic heart disease in Japan]. PMID- 22518960 TI - [Progress and future challenges in the study of coronary artery disease]. PMID- 22518961 TI - [Anatomy of coronary arteries]. PMID- 22518962 TI - [Intramyocardial microcirculatory system]. PMID- 22518963 TI - [ADAM8-dependent onset of blood circulation]. PMID- 22518964 TI - [Physiome in coronary circulation--links between function and structure, organ and molecule, and hopefully past and future]. PMID- 22518965 TI - [Regulatory mechanisms of coronary circulation]. PMID- 22518966 TI - [Coronary flow reserve]. PMID- 22518967 TI - [Metabolic remodeling in the ischemic and non-ischemic failing heart]. PMID- 22518968 TI - [The association between coronary circulation and cardiac function]. PMID- 22518969 TI - [Therapeutic angiogenesis for coronary artery]. PMID- 22518970 TI - [Component of coronary artery disease]. PMID- 22518971 TI - [Plaque development and destabilization in human coronary atherosclerotic lesions]. PMID- 22518972 TI - [Current evidence about lipid-lowering therapy and coronary plaque]. PMID- 22518973 TI - [Coronary plaque and endothelial function]. PMID- 22518974 TI - [Atherosclerotic plaque of coronary artery and vascular smooth muscle cells]. PMID- 22518975 TI - [Relationship between atherosclerotic plaque progression, vulnerability and vascular remodeling]. PMID- 22518976 TI - [Pathology and pathophysiology of coronary spasm]. PMID- 22518977 TI - [Thrombus formation/propagation in coronary artery]. PMID- 22518978 TI - [Coronary arterial thrombus formation: contributing role of coagulation cascade and fibrinolysis]. PMID- 22518979 TI - [Mechanical characteristic of ischemic myocardium]. PMID- 22518980 TI - [Concept, definition, and pathophysiology of the stunned and hibernating myocardium]. PMID- 22518981 TI - [No reflow phenomenon in acute myocardial infarction]. PMID- 22518982 TI - [Advancement in diagnosis of coronary artery disease]. PMID- 22518983 TI - [Unstable plaque markers]. PMID- 22518984 TI - [Markers of myocardial damage]. PMID- 22518985 TI - [Electrocardiography]. PMID- 22518986 TI - [Ambulatory electrocardiography]. PMID- 22518987 TI - [Stress electrocardiogram]. PMID- 22518988 TI - [Echocardiography]. PMID- 22518989 TI - [Angioscopy]. PMID- 22518990 TI - [Intravascular ultrasound; grayscale-IVUS and radiofrequency analysis]. PMID- 22518991 TI - [Intravascular optical coherence tomography]. PMID- 22518992 TI - [Coronary flow reserve (CFR) and fractional flow reserve (FFR)]. PMID- 22518993 TI - [Selective coronary angiography]. PMID- 22518994 TI - [Pathogenesis and prognosis of contrast-induced nephropathy (CIN)]. PMID- 22518995 TI - [Therapeutic strategy for prevention of contrast-induced nephropathy]. PMID- 22518996 TI - [Advancement and current status of coronary CT angiography]. PMID- 22518997 TI - [Cardiac magnetic resonance imaging]. PMID- 22518998 TI - [Nuclear cardiology]. PMID- 22518999 TI - [Genetic study of coronary artery disease]. PMID- 22519000 TI - [Transition of therapeutics in coronary artery disease: past and present]. PMID- 22519001 TI - [Basic treatment approach for coronary artery disease]. PMID- 22519002 TI - [Indication for percutaneous coronary intervention]. PMID- 22519003 TI - [Balloon angioplasty]. PMID- 22519004 TI - [Percutaneous coronary intervention--stent implantation]. PMID- 22519005 TI - [Percutaneous coronary intervention with drug eluting stent]. PMID- 22519006 TI - [Laser for coronary lesions]. PMID- 22519007 TI - [Overview of clinical use of Rotablator]. PMID- 22519008 TI - [Basic efficiently of drug eluting stent 2011]. PMID- 22519009 TI - [Sirolimis-eluting stent (SES)]. PMID- 22519010 TI - [Paclitaxel-eluting stent]. PMID- 22519011 TI - [Zotarolimus-eluting stent]. PMID- 22519012 TI - [Everolimus-eluting stent]. PMID- 22519013 TI - [Biolimus eluting stent]. PMID- 22519014 TI - [Pathological mechanisms of restenosis after drug-eluting stent implantation]. PMID- 22519015 TI - [Qualitative and quantitative assessment of DES restenosis by IVUS and OCT]. PMID- 22519016 TI - [Cilostazol]. PMID- 22519017 TI - [Impact of statins post percutaneous coronary intervention]. PMID- 22519018 TI - [Application of selective tyrosine kinase inhibitor to the prevention of coronary restenosis after PCI]. PMID- 22519019 TI - [The effect of erythropoietin on the improvement of cardiac function in patients with myocardial infarction]. PMID- 22519020 TI - [Pioglitazone]. PMID- 22519021 TI - [Current status of surgical myocardial revascularization]. PMID- 22519022 TI - [Indication criteria for coronary artery bypass grafting]. PMID- 22519023 TI - [Indications and limitations of coronary artery bypass grafting]. PMID- 22519024 TI - [Basic concept of pharmacological therapy of coronary artery disease]. PMID- 22519025 TI - [Aspirin]. PMID- 22519026 TI - [Fibrinolytic therapy for ST-elevation myocardial infarction]. PMID- 22519027 TI - [N-3 polyunsaturated fatty acids (EPA)]. PMID- 22519028 TI - [Renin-angiotensin system blocker: selective aldosterone blocker]. PMID- 22519029 TI - [Calcium antagonists]. PMID- 22519030 TI - [Vasodilators and nitrates]. PMID- 22519031 TI - [Beta-blocker]. PMID- 22519032 TI - [Prevention and treatment of gastric mucosal injury in patients taking low-dose aspirin]. PMID- 22519033 TI - [Implantable cardioverter defibrillator (ICD), automated external defibrillator (AED)]. PMID- 22519034 TI - [Intra-aortic balloon pumping]. PMID- 22519035 TI - [Percutaneous cardiopulmonary support]. PMID- 22519036 TI - [Ventricular assist device]. PMID- 22519037 TI - [Therapeutic hypothermia for post cardiac arrest care]. PMID- 22519038 TI - [Diet therapy]. PMID- 22519039 TI - [Exercise therapy for primary prevention of coronary heart disease]. PMID- 22519040 TI - [Smoking cessation treatment]. PMID- 22519041 TI - [Guidance of sexual life]. PMID- 22519042 TI - [Cardiac rehabilitation]. PMID- 22519043 TI - [Prevention and treatment of coronary artery disease in peri-operative period of non-cardiac surgery]. PMID- 22519044 TI - [The cardiovascular regeneration therapy for ischemic heart disease: road to heart repair]. PMID- 22519045 TI - [Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors]. PMID- 22519046 TI - [G-CSF therapy for acute myocardial infarction]. PMID- 22519047 TI - [Application of erythropoietin to cardiovascular diseases]. PMID- 22519048 TI - [Stem cell therapy using autologous myoblast sheets for severe heart failure]. PMID- 22519049 TI - [Epidemiological survey of ischemic heart disease in Japan]. PMID- 22519050 TI - [Cohort studies of cardiovascular disease in the Western countries]. PMID- 22519051 TI - [Cohort studies of ischemic heart disease in Japan]. PMID- 22519052 TI - [Hypertension]. PMID- 22519053 TI - [Obesity: visceral fat]. PMID- 22519054 TI - [Intensive glucose control and cardiovascular outcomes in diabetes and impaired glucose tolerance]. PMID- 22519055 TI - [Current concept of dyslipidemia in patients with coronary artery disease]. PMID- 22519056 TI - [Metabolic syndrome]. PMID- 22519057 TI - [Chronic kidney disease as a risk factor of coronary artery disease]. PMID- 22519058 TI - [Smoking is an important risk factor for cardiovascular disease in Japan]. PMID- 22519059 TI - [Coronary artery disease and depression]. PMID- 22519060 TI - [Psychological stress and physical stress]. PMID- 22519061 TI - [Ischemic heart disease: prognosis and QOL]. PMID- 22519062 TI - [Program for ischemic heart disease prevention]. PMID- 22519063 TI - [Healthcare economics in heart diseases: practice pattern, reimbursement and cost]. PMID- 22519064 TI - [How to take measures in Ningen Dock]. PMID- 22519065 TI - [Current status and future perspectives of ventricular assist system]. PMID- 22519066 TI - [Present situation and new horizons of the heart transplant]. PMID- 22519067 TI - [Gender differences in coronary artery disease]. PMID- 22519068 TI - Anatomical study of the human discomallear ligament using cone beam computed tomography imaging and morphological observations. AB - In the present study, the human discomallear ligament (DML) was observed in structures at both macroscopic and cone beam computed tomography levels. Assessments were made regarding the distribution of calcitonin-gene-related peptide (CGRP), protein gene-product (PGP) 9.5, and substance P (SP) of the DML based on immunohistochemical analyses of the anatomical properties of jaw movements using 27 Japanese human cadavers (mean, 79.3 +/- 8.6 years; male, 74.9 +/- 8.0; female, 82.8 +/- 7.5). The DML of the anterior region was connected to the TMJ disc. The DML of the posterior region was attached to both the head and the anterior process of the malleus through the petrotympanic fissure, which formed a narrow channel. The structure of the petrotympanic fissure through the DML was attached to the malleus, and this structure was associated with the mobility of the malleus. In the anterior and posterior parts of the disc associated connective tissue of the DML, CGRP-, PGP9.5- and SP-positive nerve fibers were located around numerous blood vessels, a condition which may be correlated with chronic pain syndrines disorders and the auditory system. PMID- 22519069 TI - A morphological study of the blood vessels associated with periodontal probing depth in human gingival tissue. AB - Gingival tissues in human cadavers were examined the blood vessel diameter in the depths of the gingival pockets such as three groups: gingiva adjacent to a sulcus of 2 mm (Group 1); gingiva adjacent to a 2-4-mm sulcus (Group 2); and gingiva adjacent to a sulcus of > 4 mm (Group 3). A meaningful significant difference was seen observed in gingival pocket side, intermediate and outer layer side regions of the gingiva. A meaningful significant difference was seen found in intermediate part and the outer layer of the gingiva in Group 3. Other gingival biopsies were performed on a human body donation specimen to examine CD-31 positive endothelial cells of blood vessels by an immnohistochemical method. Our results suggest that the periodontal probing depth reflect the blood vessel organization of human gingival tissue. PMID- 22519070 TI - Morphological study of the vasa nervorum in the peripheral branch of human facial nerve. AB - Given the length of axons reaching to distal regions, all peripheral nerves must derive nutrient supply not only for the nerve cell body, but also for the peripheral parts. Along the course of a peripheral nerve, in general, nutrient vessels accompany nerve fibers to peripheral regions in the form of "vasa nervorum" derived from the epineurium, reaching the endoneurium through the perineurium and forming a capillary plexus. In addition, in reconstructive procedures in plastic surgery, anastomosis of not only nerves, but also the vasa nervorum, has been reported to achieve improved outcomes. The present study therefore observed morphological features of the blood supply to the distal portion of the facial nerve in 14 sides of 14 adult cadavers (age at death, 46-86 years) under stereo microscopy after dye injection. The region of the epineurium was also observed under scanning electron microscopy (SEM). The vasa nervorum was seen to derive from a complex reticulation structure formed mainly by the superficial temporal, facial, transverse facial and zygomatico-orbital arteries with collateral supply from the supraorbital, deep temporal, buccal arteries and parotid branches. SEM showed that one capillary accompanied each perineurium in each nerve fascicle. PMID- 22519071 TI - Morphology of the lingual papillae in the Patagonian cavy. AB - We examined the dorsal lingual surfaces of an adult Patagonian cavy (Dolichotis patagonum) by scanning electron microscopy. The tongue of the Patagonian cavy is about 8 cm long and the lingual body had lingual prominence on the posterior third. There were no fungiform papillae in the lingual dorsal surface. The fungiform papillae were observed in both lateral sides of the lingual apex. The filiform papilla of the lingual body consisted of a large conical papilla. The connective tissue core of the filiform papilla showed many slender processes. The fungiform papillae were round in shape. The connective tissue core of the fungiform papilla was flower-bud shaped. Two vallate papillae were located on between lingual body and root, and insert in two grooves. The connective tissue core of the vallate papilla was covered with numerous small spines. Many foliate papillae were observed on the posterolateral regions of the tongue. After removing epithelium from the foliate papillae many vertical depressions became apparent. These findings suggest that in the structure of the lingual papillae of the Patagonian cavy there is similar to that of the capybara. PMID- 22519072 TI - Morphology of the lingual papillae in the roan antelope. AB - We examined the dorsal lingual surfaces of an adult roan antelope (Hippotragus equinus) by scanning electron microscopy. Filiform, fungiform and vallate papillae were observed. The filiform papillae consisted of a larger main papilla and smaller secondary papillae. A top of the connective tissue core of the filiform papilla showed several depressions. The connective tissue core of the papilla with a long process was rarely observed. The fungiform papillae were round in shape. The connective tissue core of the fungiform papilla was flower bud shaped. The lenticular papillae of large size were limited on the torus lingua. The connective tissue core of the lenticular papilla consisted of numerous small spines. The vallate papillae were located on both sides of the posterolateral aspects. The vallate papillae were flattened oval shaped and the papillae are surrounded by circular trench. The connective tissue core of the vallate papilla was covered with numerous small spines. PMID- 22519073 TI - Get ready for the games. PMID- 22519074 TI - Hospitals will receive funds for not admitting patients. PMID- 22519075 TI - Maintaining eye contact: how to communicate at handover. PMID- 22519076 TI - General practices may monitor data on emergency department attendance. PMID- 22519077 TI - 'Care in the air': the role of in-flight staff. AB - In-flight nursing offers emergency and intensive care nurses unique opportunities to enhance their knowledge and apply what they learn to their practice in the NHS. This article describes the work of a group of in-flight nurses, and a course that provides nurses with the skills they need to carry out a particularly demanding job. PMID- 22519078 TI - Prescribing prophylaxis to patients who have been exposed to HIV. AB - Emergency nurse practitioners should be prepared to prescribe post-exposure prophylaxis for sexual exposure (PEPSE) to people who may have been exposed to HIV, even where the number of such presentations is small. As this article makes clear, nurse prescribers require a sound knowledge of the drugs recommended in PEPSE protocols, and of their side effects, to relieve patients' anxiety and inform them about safe sexual practice. The article offers a case study and reflection to show that patients, particularly those who may have been exposed to HIV, who have been given the information they want are more likely to complete their courses of treatment. PMID- 22519079 TI - Is fever after infection part of the illness or the cure? AB - An increase in temperature above the normal range of 35.6 degrees C-38.2 degrees C (Ryan and Levy 2003) can indicate the presence of infection or sepsis. When the body detects infection, a series of responses to control infection are initiated that result in a rise in systemic temperature. Research suggests that this rise in temperature can be regarded as a cure, in that it is part of the autonomic response to remove infection and create a favourable environment for antibiotics. Nevertheless, it remains common practice to try to reduce fever with medication and physical cooling methods. This article explores the physiological changes that occur during bacterial sepsis that result in increased temperature, and discusses the pros and cons of administering antipyretic medication. The aim is to enable nurses to understand and support patients who present with fever. PMID- 22519080 TI - Mental health emergencies: using a structured assessment framework. AB - People who have mental health crises while attending emergency departments (EDs) require immediate assessment and management, and ED staff must be prepared to meet the specific needs of this client group. This article gives an overview of the public psychiatric emergency assessment tool (Wright et al 2008), which is used by, for example, the Lancashire Constabulary to share information with healthcare professionals. By using the tool, practitioners can organise and structure the information they acquire during patient assessments, and from accompanying carers, paramedics, or police. They can then pass this information on to mental health specialists. PMID- 22519081 TI - Agent of influence. PMID- 22519083 TI - Investigation of engine performance and emissions of a diesel engine with a blend of marine gas oil and synthetic diesel fuel. AB - This paper investigates diesel engine performance and exhaust emissions with marine gas oil (MGO) and a blend of MGO and synthetic diesel fuel. Ten per cent by volume of Fischer-Tropsch (FT), a synthetic diesel fuel, was added to MGO to investigate its influence on the diesel engine performance and emissions. The blended fuel was termed as FT10 fuel, while the neat (100 vol%) MGO was termed as MGO fuel. The experiments were conducted with a fourstroke, six-cylinder, turbocharged, direct injection, Scania DC 1102 diesel engine. It is interesting to note that all emissions including smoke (filter smoke number), total particulate matter (TPM), carbon monoxide (CO), total unburned hydrocarbon (THC), oxides of nitrogen (NOx) and engine noise were reduced with FT10 fuel compared with the MGO fuel. Diesel fine particle number and mass emissions were measured with an electrical low pressure impactor. Like other exhaust emissions, significant reductions in fine particles and mass emissions were observed with the FT10 fuel. The reduction was due to absence of sulphur and aromatic compounds in the FT fuel. In-cylinder gas pressure and engine thermal efficiency were identical for both FT10 and MGO fuels. PMID- 22519082 TI - Composition of intake sugars and emission of gases from paper sludges by Coptotermes formosanus Shiraki. AB - Paper sludge is a by-product of the pulping process and is landfilled or incinerated for disposal. In this study, we evaluated ingestion and digestibility of carbohydrates, by the termite Coptotermes formosanus, in two kinds of sludges: sludge C from the chemical pulp mill and sludge M from the mechanical pulp mill. The no-choice tests using the termite for three weeks showed that the mass loss of sludge C was significantly higher than that of the control samples: a bleached pulp and red pine wood. It is considered that the higher inorganic content of sludge C resulted in the higher mass loss when the same amount of carbohydrates was taken by the pulp- or wood-fed termite. Although the inorganic content of sludge M was almost the same as that of sludge C, the higher lignin content in sludge M is thought to have resulted in the lower mass loss. Analysis of sugar composition in the faecal materials of the termite showed that about 73% of glucose and 81% of xylose in sludge C were digested. It was concluded that the digestibility of these sugars in sludge C was the same as that of the control samples despite containing high amounts of inorganic compounds. However, the hydrogen conversion rate by the termites that were fed sludge was lower than that of the termites that were fed pulp in the no-choice test for three days: one mole of glucose from the sludge and pulp was converted to 0.51 and 0.80 moles of hydrogen, respectively. PMID- 22519084 TI - Copper emission during thermal treatment of simulated copper sludge. AB - This study evaluates Cu emissions in air-particulate and gas phases during thermal treatment of simulated copper sludge by a rotary kiln. Influences of operating parameters, including treatment temperature (400-700 degrees C), rotary speed (0.89-2.00 rpm) and copper content in sludge (1% to 5% by weight) on copper emissions were investigated. The toxicity characteristic leaching procedure (TCLP) and scanning electron microscopy (SEM) were also conducted to evaluate copper leaching and the surface structure of thermally treated sludge, respectively. The results indicated that (1) low Cu emissions in air-particulate and gas phases were associated with the two operating conditions of 400-500 degrees C at 0.89-1.39 rpm and 600-700 degrees C at 2.00 rpm; (2) temperatures and rotary speeds did not affect gaseous copper emission, except for the operating condition of 400 degrees C at 2.00 rpm; (3) rising copper content of sludge at 600 degrees C and 2.00 rpm increased the particulate copper emission, but not the gaseous copper emission; (5) the TCLP copper leaching concentrations of sludge treated at 400 degrees C were obviously higher than those treated at 500-700 degrees C; however, all of the thermally treated products agreed with the Taiwan EPA TCLP regulations. PMID- 22519085 TI - Mineralization of p-chlorophenol in water solution by AOPs based on UV irradiation. AB - Protection of clean aquifers requires radical minimization of water consumption, overall reduction of wastewater and, furthermore, minimization of wastewater loading. Many organic pollutants in wastewater present a specific problem because of their toxicity, bioaccumulation and poor biodegradability. The scope of this paper is to investigate and identify the benefits offered by advanced oxidation processes (AOPs) as destructive methods for treatment of wastewater loaded with recalcitrant organic pollutants. The study was performed on model wastewater containing p-chlorophenol as a representative of organic chemical industry intermediates. Several UV based AOPs were studied: UV, UV/H2O2, UV/O3, UV/H2O2/O3 and UV/Fenton. Optimal process conditions for the highest mineralization efficiency in the investigated range (pH, [H2O2] and [Fe2+]) have been determined on the basis of HPLC measurements and the following ecological parameters: total organic carbon (TOC), adsorbable organic halides (AOX), chemical oxygen demand (COD) and biochemical oxygen demand (BOD5). Toxicity is one of the most important ecological parameters in determining the level of water pollution. In this study, toxicity tests were performed on the zooplankton Daphnia magna in order to evaluate efficiency of the applied treatments. The UV/ Fenton and UV/H2O2/O3 processes were found to be the most appropriate processes for degradation and mineralization of p-chlorophenol. Complete degradation was achieved after 15 minutes ofUV/Fenton process treatment, while 92.1% TOC and 98.3% AOX removals were obtained after treatment of 60 minutes. PMID- 22519086 TI - Studies on synthesis and characteristics of zeolite prepared from Indian fly ash. AB - In the present study, samples of coal fly ash were obtained from seven major Indian thermal power plants. These samples were transformed into fly ash zeolite (FAZ) using hydrothermal activation by treatment with NaOH. All experiments were carried out at 100 degrees C, but with different solid:liquid ratios, different concentrations of alkali and different incubation times. The chemical composition, mineralogy and morphology of the fly ash and FAZ were determined by wet chemical method after Na2CO3 fusion, x-ray diffraction and scanning electron microscopy. The cation exchange capacity of fly ash and FAZ was determined using the ammonium acetate method (IS:2720). The ammonium exchange capacity was determined by the titrimetric method. The experiments demonstrate that zeolite can be synthesized at 100 degrees C using alkali. The cation exchange capacity and ammonium adsorption capacity of FAZ (up to 250 meq/100 g and 22.93 mg NH4+/g respectively) indicate that the FAZ may be potentially useful to reduce heavy metals and other pollutants from contaminated environments. Therefore, zeolitization at low temperature potentially allows waste fly ash to be used in an economically advantageous way. PMID- 22519087 TI - Response surface methodology for the modelling of 85Sr adsorption on zeolite 3A and pumice. AB - The adsorption of 85Sr from aqueous solutions on to zeolite 3A and three types of pumice materials (i.e. Kayseri, Isparta and Nevsehir) was investigated in this study. Experiments with radioactive 85Sr were performed to test the sorption ability of the sorbents to remove this radioisotope from liquid radioactive wastes. The influence of sorbent dosage and initial activity of feed solution on the decontamination factor were analysed and optimized by means of response surface methodology. The parameters of the experiments, namely temperature, pH, time, stirring efficiency, were selected in preliminary tests. The experimental results showed that the most efficient pumice sorbent for 85Sr is Isparta, for which a maximal decontamination factor of 76.92 was obtained by using the sorbent dosage of 0.5% w/v. However, the commercial zeolite 3A was 2.71-fold more efficient than Isparta pumice for decontamination of strontium radioactive solutions. Isparta pumice is a low-cost natural sorbent, and its ability to effectively bind strontium radioisotope from water solutions suggests that this material has further applications for radioactive waste treatment. PMID- 22519088 TI - Impacts upon soil quality and plant growth of bamboo charcoal addition to composted sludge. AB - In this research, the effects of bamboo charcoal on soil contaminant accumulation, soil fertility and plant growth were investigated. The results indicated that sludge composted with bamboo charcoal (BCS) significantly increased plant growth and decreased the mobility of Zn, Cu and polycyclic aromatic hydrocarbons (PAHs), compared with the composted sludge without bamboo charcoal (CS), with lower absorption and less accumulation of contaminants by the plants. Concentrations of Cu in turfgrass treated with CS were 11.7-23.4% higher than those of turfgrass treated with BCS. Concentrations of Zn in turfgrass treated with CS were 14.2-25.9% higher than those of turfgrass treated with BCS. The concentration of sigma 16PAHs (total contents of 16 PAHs that are listed by USEPA as priority pollutants for remediation based on their persistence and carcinogenic potential) in ryegrass grown in yellow loamy soil amended with CS was 680 microg kg(-1)) and was higher than that of ryegrass treated with BCS (only 439 microg kg(-1)). The biomass of fescue in BCS-treated soils increased by 13-16% compared with that of fescue in CS-treated soil. The biomass of ryegrass in BCS-treated soil was 20-27% higher than that in CS-treated soil. Chlorophyll content in turfgrass grown in CS-treated soil was lower than that in grass grown in BCS-treated soil. Compared with the control, chlorophyll contents in plants grown in soil with CS increased by about 13-22%, whereas those in plants grown in soil with BCS increased by about 20-32%. PMID- 22519089 TI - Coagulant properties of Moringa oleifera protein preparations: application to humic acid removal. AB - This work aimed to characterize the coagulant properties of protein preparations from Moringa oleifera seeds in the removal of humic acids from water. Three distinct preparations were assayed, namely extract (seeds homogenized with 0.15 M NaCl), fraction (extract precipitated with 60% w/v ammonium sulphate) and cMoL (protein purified with guar gel column chromatography). The extract showed the highest coagulant activity in a protein concentration between 1 mg/L and 180 mg/L at pH 7.0. The zeta potential of the extract (-10 mV to -15 mV) was less negative than that of the humic acid (-41 mV to -42 mV) in a pH range between 5.0 and 8.0; thus, the mechanism that might be involved in this coagulation activity is adsorption and neutralization of charges. Reduction of total organic carbon (TOC) and dissolved organic carbon (DOC) was observed in water samples containing 9 mg/L carbon as humic acid when treated with 1 mg/L of the extract. A decrease in colour and in the aromatic content of the treated water was also observed. These results suggested that the extract from M. oleifera seeds in a low concentration (1 mg/L) can be an interesting natural alternative for removing humic acid from water in developing countries. The extract dose determined in the present study does not impart odour or colour to the treated water. PMID- 22519090 TI - Evaluation of moisture effect on low-level CO2 adsorption by ion-exchanged zeolite. AB - To enhance the capture of low-level indoor CO2, a commercial zeolite (13X) was modified with alkali and alkaline earth metals using an ion-exchange method. Although the calcium-impregnated sorbent (zeo-Ca) showed the largest adsorption capacity, with a strong binding force for carbon dioxide, its regeneration by heat treatment was very difficult. Moisture in the gas flow caused significant decreases in CO2 adsorption capability as well as in the lifetime of the adsorbents. As for the regeneration gas, the test showed that nitrogen would hinder the CO2 adsorption more significantly than helium gas. Water vapour and nitrogen gas molecules are apt to competitively occupy the available sites of the adsorbent over the CO2 molecules. PMID- 22519091 TI - Agricultural potential of anaerobically digested industrial orange waste with and without aerobic post-treatment. AB - The potential of anaerobically digested orange waste with (AAD) and without (AD) aerobic post-treatment for use in agriculture was evaluated through chemical analyses, short-term phytotoxicity and long-term plant assays. Chemical analyses showed that AD contained ammonia and organic acids, and aerobic post-treatment did not significantly remove these phytotoxins. The N:P2O5:K2O ratio in AD was 1:0.26:0.96 and aerobic post-treatment did not change the composition in AAD except for K2O (1:0.26:1.24). Heavy metal contents in AD and AAD were more or less the same and were below the upper limit recommended for non-sewage sludge application on agricultural soils. Short-term phytotoxicity tests showed that seed germination and root elongation of Chinese cabbage and ryegrass were severely inhibited at digestate concentrations of 60-100%. Germination index values were well below the score of 50% required to indicate the phytotoxic-free nature of compost. Long-term plant assays showed that AD and AAD, when supplemented with a base fertilizer, resulted in higher plant growth, and fresh weight and dry matter production than AD without base fertilizer. The results thus indicate that aerobic post-treatment did not have any significant beneficial effect on reducing phytotoxicity, and AD could be used as such on agricultural soils, especially with high P. PMID- 22519092 TI - Solidification/stabilization of dredged marine sediments for road construction. AB - Cement/lime-based solidification is an environmentally sound solution for the management of dredged marine sediments, instead of traditional solutions such as immersion. Based on the mineralogical composition and physical characteristics of Dunkirk sediments, the effects of cement and lime are assessed through Atterberg limits, modified Proctor compaction, unconfined compressive strength and indirect tensile strength tests. The variation of Atterberg limits and the improvement in strength are discussed at different binder contents. The potential of sediments solidified with cement or lime for road construction is evaluated through a proposed methodology from two aspects: I-CBR value and material classification. The test results show the feasibility of solidified dredged sediments for beneficial use as a material in road construction. Cement is superior to lime in terms of strength improvement, and adding 6% cement is an economic and reasonable method to stabilize fine sediments. PMID- 22519093 TI - Continuous tank reactors in series: an improved alternative in the removal of phenolic compounds with immobilized peroxidase. AB - Immobilized derivatives of soybean peroxidase, covalently bound to a glass support, were used in a continuous stirred tank reactor in series, in order to study the removal of two phenolic compounds: phenol and 4-chlorophenol. The use of two reactors in series, rather than one continuous tank, improved the removal efficiencies of phenol and 4-chlorophenol. The distribution of different amounts of enzyme between the two tanks showed that the relative distributions influenced the removal efficiency reached and the degree of the enzyme deactivation. The highest removal percentages were reached at the outlet of the second tank for a distribution of 50% of the enzyme in each tank. However, with a distribution of 75% in the first tank and 25% in the second, the elimination percentage in the second tank was slightly lower than in the previous case, and the effects of deactivation of the enzyme in the first tank were less pronounced. In all the distributions assayed it was observed that the first tank acts as a filter for the second one, which receives a feed with a smaller load of phenolic compounds, thus diminishing enzyme deactivation in the second tank. PMID- 22519094 TI - Biosorption and biotransformation of chromium by Serratia sp. isolated from tannery effluent. AB - A bacterium isolated from soil and sediment ofa leather tanning mill's effluent was identified as Serratia sp. by the analysis of 16S rDNA. Scanning electron microscopy-energy dispersive X-ray analysis (SEM-EDX) and transmission electron microscopy (TEM) were used to assess morphological changes and confirm chromium biosorption in Serratia sp. both in a shake-flask culture containing chromium and in a tannery wastewater. The SEMEDX and the elemental analysis of the chromate containing samples confirmed the binding of chromium with the bacterial biomass. The TEM exhibited chromium accumulation throughout the bacterial cell, with some granular deposits in the cell periphery and in the cytoplasm. X-ray diffraction analysis (XRD) was used to quantify the chromium and to determine the chemical nature of the metal-microbe interaction. The XRD data showed the crystalline character of the precipitates, which consisted of mainly calcium chromium oxide, chromium fluoride phosphate and related organo-Cr(III) complex crystals. The XRD data also revealed a strong involvement of cellular carboxyl and phosphate groups in chromium binding by the bacterial biomass. The results of the study indicated that a combined mechanism of ion-exchange, complexation, croprecipitation and immobilization was involved in the biosorption of chromium by bacterial cells in contaminated environments. PMID- 22519095 TI - Oxidation of bisphenol A by UV/S2O8(2-): comparison with UV/H2O2. AB - The UV/S2O8(2-) process was applied to decompose bisphenol A (BPA), which is a representative endocrine-disrupting chemical (EDC), and was comared with the UV/H2O2 process. The BPA degradation efficiency by UV/S2O8(2-) was increased by increasing S2O8(2-) concentration or decreasing BPA concentration. The presence of humic acid caused an inhibitory effect. The BPA oxidation rate by UV/S2O8(2-) was increased in the following order: neutral pH (pH(i) = 7) < acidic pH (pH(i) = 4) < basic pH (pH(i) = 10). The main oxidizing species in the UV/S2O8(2-) system was sulphate radical (SO4(-*)), whereas the main oxidizing species in the UV/H2O2 system was OH radical (OH*). Compared with UV/H2O2, the UV/S2O8(2-) process showed higher performance for not only BPA degradation but also its mineralization, which means that SO4(-*) is a more effective oxidant for BPA than the OH*. The results shown in this study imply that the SO4(-*) -based UV/S2O8(2 ) process can be an excellent alternative process for the widely used UV/H2O2 process, with higher remediation performance. PMID- 22519096 TI - Strategies for selecting optimal sampling and work-up procedures for analysing alkylphenol polyethoxylates in effluents from non-activated sludge biofilm reactors. AB - Trace-level analysis of alkylphenol polyethoxylates (APEOs) in wastewater containing sludge requires the prior removal of contaminants and preconcentration. In this study, the effects on optimal work-up procedures of the types of alkylphenols present, their degree of ethoxylation, the biofilm wastewater treatment and the sample matrix were investigated for these purposes. The sampling spot for APEO-containing specimens from an industrial wastewater treatment plant was optimized, including a box that surrounded the tubing outlet carrying the wastewater, to prevent sedimented sludge contaminating the collected samples. Following these changes, the sampling precision (in terms of dry matter content) at a point just under the tubing leading from the biofilm reactors was 0.7% RSD. The findings were applied to develop a work-up procedure for use prior to a high-performance liquid chromatography-fluorescence detection analysis method capable of quantifying nonylphenol polyethoxylates (NPEOs) and poorly investigated dinonylphenol polyethoxylates (DNPEOs) at low microg L(-1) concentrations in effluents from non-activated sludge biofilm reactors. The selected multi-step work-up procedure includes lyophilization and pressurized fluid extraction (PFE) followed by strong ion exchange solid phase extraction (SPE). The yields of the combined procedure, according to tests with NP10EO spiked effluent from a wastewater treatment plant, were in the 62-78% range. PMID- 22519097 TI - Case study: heavy metals and fluoride contents in the materials of Syrian phosphate industry and in the vicinity of phosphogypsum piles. AB - This study focuses on the determination of heavy metals and fluoride concentrations in the Syrian phosphate industry and in the vicinity of the phosphogypsum (PG) piles. Four sampling campaigns were carried out, in which 86 soil, 139 plant, 30 air particulate, 16 water, 12 PG, 6 phosphate ore (raw and treated) and 3 fertilizer samples were collected. Differential pulse anode stripping voltammetry was used for Pb and Cd determination, atomic absorption spectrometry was used for Zn, Cr and Cu determination, and instrumental neutron activation analysis was used for Se, Ni, As and Hg determination. Fluoride concentration was determined via fluoride ion selective electrode. The data revealed that most of the heavy metals were retained in the fertilizer. Fluoride content in PG was 0.47%. The presence of PG piles showed no impact on the run-off and ground and lake waters in the area. However, fluoride concentration was double the permissible airborne threshold in the sites to the east of the PG piles because of the prevailing wind in the region. Similarly, enhanced concentrations of fluoride were recorded for the eastern soil samples. The content of heavy metals in plants was element- and plant-specific and influenced by the element concentration in soil, the soil texture and the pH. The maximal mean of fluoride was found in the plants species of the eastern sites (699 mg kg( 1)), which mainly related to PG erosion and airborne deposition. Thus, the main impact of the PG piles was to increase the concentration of fluoride in the surrounding area. A national action should be taken to regulate PG piles. PMID- 22519098 TI - Monitoring stress responses in cyanobacterial scytonemin--screening and characterization. AB - Scytonemin is believed to protect a variety of organisms against the negative effects of ultraviolet radiation. Cyanobacteria have evolved different strategies to minimize the potential damage caused by solar ultraviolet radiation. This includes the synthesis of the UV-absorbing compound scytonemin, which acts as a sunscreen. During the present study scytonemin was found in 9 out of 19 studied cyanobacterial strains. Aulosira fertilissima showed the maximum amount of scytonemin. The effect of environmental factors, including temperature, light intensity, UV-light and salt was studied on scytonemin synthesis of A. fertilissima. A remarkable change in scytonemin synthesis was observed under salt stress and UV-light stress. Scytonemin increased under all stress conditions but it increased maximally under yellow-light stress. PMID- 22519099 TI - Factorial experimental design application in modification of volcanic ash as a natural adsorbent with Fenton process for arsenic removal. AB - This paper describes an experimental design technique for the modification of volcanic ash with Fenton reagent (FMVA) to be used as a natural adsorbent in the removal of As(III) and As(V) from aqueous solution. The influence of pH, contact time and Fe(2+)/H2O2 on arsenic removal by the modified volcanic ash was investigated. It was observed that the arsenic removal efficiency was influenced by two of these parameters. The Fe(2+)/H2O2 ratio is an important factor that affects both As(III) and As(V) adsorption (P = 0.000). The pH affects As(V) adsorption (P = 0.003) more significantly than As (III) adsorption (P = 0.02). It was observed that the maximum As(III) adsorption by the FMVA was obtained at pH 2, Fe(+2)/H2O2 = 0.06 and 30 min of contact time (39 microg As(III) per mg FMVA), whereas the maximum As(V) adsorption was obtained under the conditions of pH 5, Fe(+2)/H2O2 = 0.06 and 30 min of contact time (41 microg As(V) per mg FMVA). PMID- 22519100 TI - Evaluation of vermicompost as a raw natural adsorbent for adsorption of pesticide methylparathion. AB - The assessment of vermicompost (VC) as a low-cost and alternative adsorbent for the removal of the pesticide methylparathion (MP) from an aqueous medium has been investigated by batch and column experiments. Parameters related to MP adsorption, i.e. equilibrium time (61.5 min) and adsorption pH (6.8) were optimized by using Doehlert design. The initial and final MP concentrations after adsorption assays were determined by square-wave adsorptive cathodic stripping voltammetry using an electrode composed of a multiwalled carbon nanotube dispersed in mineral oil. Batch adsorption experimental data were fitted to the Langmuir and Freundlich isotherm adsorptions, and a very good fit to the Langmuir linear model, giving a maximum adsorption capacity (MAC) of 0.17 mg g(-1). This result was very similar to that obtained with the column experiments. In order to evaluate the MP desorption from column packed VC, 100.0 ml of nitric acid solution (pH 3.0) has been percolated through material. No leaching of MP was observed, thus confirming the strong interaction between MP and VC. The satisfactory MAC obtained and low cost makes the VC a reliable natural material for the removal of MP from aqueous effluents. PMID- 22519101 TI - Removal of phosphorus and nitrogen from domestic wastewater using a mineralized refuse-based bioreactor. AB - Municipal solid waste used for landfill becomes stabilized, or aged, some years after placement, and can be safely excavated; the term 'mineralized refuse' is used in this study. The adsorptions of phosphorus, and the nitrification of the mineralized refuse and clay, were investigated by batch incubation. The variation of phosphorus adsorption in the mineralized refuse was fitted to the Freundlich adsorption isotherm equation, giving a maximum phosphorus adsorption capacity of 2310 mg kg(-1). Based on the Langmuir isotherm equation, maximum phosphorus adsorption capacity was calculated to be 1976 mg kg(-1), almost twice that of the clay. The equations for both the mineralized refuse and clay were fitted to zero order kinetics (R2 > 0.98, P < 0.01, n = 11), giving concentrations of phosphorus as phosphates less than 250 mg L(-1). The K value for the mineralized refuse was about 3.5 times higher than for the clay. The production of nitrogen as nitrates in both the mineralized refuse and the clay after 120 h incubation yielded a first-order reaction kinetics value of 100 mg kg(-1) NH4(+)-N from the initial concentration. The calculated net nitrification as nitrates for the mineralized refuse was 6.3 times higher than for the clay. Domestic wastewater was then treated in a mineralized refuse-based bioreactor for 30 days. The removal rates of COD(cr), total nitrogen and total phosphorus were 73.77 +/- 8.10%, 61.01 +/- 6.75%, and 69.14 +/- 9.25%, respectively. Large accumulations of nitrates occurred in the mineralized refuse-based bioreactor. For the full-scale design, a high column of mineralized refuse is recommended for the denitrification. PMID- 22519102 TI - Risk assessment--encapsulation of both the built and natural environments. AB - Although various risk assessment approaches have been adopted for landfill waste disposal sites, there are still wide-ranging knowledge gaps and limitations which need addressing by developing a holistic risk assessment methodology. This paper conceptually presents only a framework of such a risk analysis methodology for landfill leachate in a holistic format, thereby attempting to bridge these knowledge gaps. The conceptual framework or structure does not only draw together various sections and sub-sections of holistic risk assessment in one place but also categorizes and arranges them in a logical sequence. The holistic structure is to assist in performing the process of a risk analysis from start to end. Also, in order to place Risk Assessment (RA) in a broader perspective of the decision-making process, relationships between Risk Management (RM), Hazard Assessment (HA), and Risk Estimation (R Esti) are also presented. Although this paper attempts to cover the whole of the risk analysis methodology in the form of a fundamental framework, the study does not engage in in-depth detail of sections and sub-sections of the methodology due to brevity. PMID- 22519103 TI - Photoelectrocatalytic properties of a vertically aligned Ti-W alloy oxide nanotubes array and its applications in dye wastewater degradation. AB - A highly ordered and vertically oriented array of nanotubes (NTs) of mixed oxide was prepared in situ by Ti-W alloy anodization. Compared with the traditional TiO2 NTs, the photoelectrocatalytic activity of the resulting Ti-W-O NTs was greatly enhanced. Results indicated a narrowing of the band gap from 3.2 eV for pristine TiO2 to 2.7 eV for Ti-W-O NTs. Under irradiation with 254 and 365 nm UV lights, Ti-W-O NTs showed much higher photoelectroconversion efficiency (eta) than TiO2 NTs and TiO2-WO3 coating. The eta254 and eta365 on Ti-W-O NTs reached as high as 51.8% and 57.0% respectively, four to five times those on TiO2 NTs and TiO2-WO3 coating. As a result of its narrow band gap energy and fast electron hole separation, Ti-W-O NTs presented outstanding photoelectrocatalytic features. The electrochemically assisted photocatalytic degradation of highly concentrated Rhodamine 6G wastewaters was studied. The results showed that the rates of colour and TOC removal were much higher on Ti-W-O NTs than on TiO2 NTs and TiO2-WO3 coating. The photocatalytic material obtained by alloy anodization is of significance in the advanced oxidation of environmental pollutants. PMID- 22519104 TI - Characterization of Rapana thomasiana as an indicator of environmental quality of the Black Sea coast of Bulgaria. AB - The aim of this investigation was to determine the contents of polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), minerals, trace elements and bioactivity in the gastropod Rapana thomasiana, which can be used as an environmental bioindicator organism. The chemical differences between Rapana thomasiana from polluted (RapaPol) and non-polluted (RapaNPol) sites of the Black Sea coast in Bulgarian were investigated. Chromatography and high-resolution inductively coupled plasma mass spectrometry (HR-ICP-MS) were used for evaluation of PAHs, PCBs, minerals and trace elements. Methanol extracts from RapaPol and RapaNPol (to a lesser degree) contained relatively high amounts of free phenolics (2.50 +/- 0.3 and 1.57 +/- 0.18 mg GAE/g DW, respectively) and exhibited the following respective levels of antioxidant activities determined by two radical scavenging assays (microMTE/g DW): 1.8 +/- 0.2 and 0.98 +/- 0.08 by 1-diphenyl-2 picrylhydrazyl method (DPPH); 1.74 +/- 0.17 and 1.04 +/- 0.12 by cupric reducing antioxidant capacity (CUPRAC). The total amounts of elements, PAHs and PCBs were higher in RapaPol than in RapaNPol. The obtained indices of Rapana thomasiana can serve as a bioindicator of the environmental ecological quality. PMID- 22519105 TI - Management of wastewater from the vegetable dehydration industry in Egypt--a case study. AB - Management of wastewater from the vegetable dehydration industry was the subject of this study. A continuous monitoring programme for wastewater was carried out for almost four months. The characterization of the wastewater indicated that the vegetable dehydration wastewater contains moderate concentrations of organics, solids and nutrients. The wastewater was subjected to three different treatment processes, namely aerobic treatment, anaerobic treatment and chemical coagulation flocculation treatment. For aerobic treatment, the removal of chemical oxygen demand (COD), biochemical oxygen demand (BOD5) and total suspended solids (TSS) was accomplished within 5 h, and no further reduction was observed after that, with the steady state COD and BOD5 removal efficiencies being 95% +/- 10% and 97% +/- 8%, respectively. For anaerobic treatment, the removal efficiencies for COD, BOD5 and TSS were 67-81%, 70-86% and 56-69%, respectively at hydraulic retention times (HRTs) of 5, 6 and 8 h. Chemical coagulation-flocculation treatment also achieved good results. The COD removal efficiency was 72%, 51% and 75% for ferric chloride (56 g/m3 of wastewater), lime (140 g/m3 of wastewater) and ferric chloride aided with lime (100 g/m3 for ferric chloride and 200 g/m3 for lime), respectively. The corresponding TSS removal values were 92% +/- 17%, 20% +/- 7% and 93% +/- 9%. Based on the available results and the seasonally operated mode of this industry in Egypt, the chemical coagulation-flocculation process is therefore considered to be moste applicable from a technical point of view and for the simplicity of operation and maintenance. PMID- 22519106 TI - Research on the treatment of phosphoric wastewater by ultrasound-assisted microelectrolysis method. AB - In this research work, ultrasound was introduced to the microelectrolysis (ME) method to improve the treatment efficiency for phosphoric wastewater. The effects of treatment time, Fe/C ratio (v/v) and iron filings dosage on the efficiency of phosphorus removal from wastewater with different initial pH values were investigated. The results showed that the phosphorus removal efficiency by the ME method was significantly enhanced in the presence of ultrasound. The maximum removal rate of phosphorus (RRP) for the wastewater with an initial pH value of 4.0 was 92.4% after 60 min of treatment when the Fe/C and Fe/H2O volume ratio were 2/1 and 1/10, respectively. The reaction kinetics analysis indicated that the phosphorus degradation processes for the ultrasonic and ME methods as well as the ultrasonically assisted ME method (UME) were in accordance with the pseudo first-order kinetic model. The synergetic effect of the combined ultrasound and ME method for phosphorus removal was also studied by reaction kinetics analysis. PMID- 22519107 TI - Fate of nitrogen during volume reduction of human urine using an on-site volume reduction system. AB - This study was carried to assess the effect of a mixture of salts, urea and creatinine on water evaporation from urine using an on-site volume reduction system in long-term experiments. Subsequently, the fate of nitrogen during volume reduction of urine was also assessed. The water evaporation rate, salt accumulation in the gauze sheet, concentrations of urea and ammonia-N, and pH of urine were measured periodically. Based on the results, a mass balance of nitrogen in concentrated urine was calculated for a moderate evaporating condition. The results revealed that steady-state evaporation was observed throughout the experiment period without any inhibition due to salt accumulation. Salt concentration in the gauze sheet reached steady-state illustrating the possibility of salt falling back to the tank from the sheet. No significant reduction of urea was observed for a moderate evaporating condition, which indicates inhibition of urea hydrolysis by the high concentration of the mixture of salts, urea and creatinine in the urine. In contrast, for a low evaporating condition, the pH of the urine increased to 8.9, which indicates early urea hydrolysis, causing an offensive odour and ammonia loss to the air. In simple storage experiments, a mixture of salts, urea and creatinine amounting to 227-334 g L(-1) in urine inhibited urea hydrolysis, even with faecal contamination, at 25 degrees C, while urine samples containing a mixture of salts, urea and creatinine at less than 227 g L(-1) did not provide strong inhibition of hydrolysis. PMID- 22519108 TI - Nitrogen and phosphorus removal in a denitrifying phosphorus removal process in a sequencing batch reactor with a forced anoxic phase. AB - The objective of this study was to establish such operating conditions in a sequencing batch reactor (SBR) that will enable the achievement of the highest possible share of denitrifying P removal in nutrient elimination. Two different operating strategies for SBRs were analysed. Both of these strategies used a forced anoxic phase in the SBR treatment cycle. The first one was based on an intermittent aeration, which led to periodic occurrence of anoxic conditions when the uptake of P-PO4(3-) could occur. The second strategy was based on mimicking the A2O process and forcing an anoxic phase straight after an anaerobic phase. The experiments were performed in a laboratory reactor operating at a maximum fill of 26.8-27.7 litres and a constant temperature of 18 degrees C. It was found that a SBR configuration with intermittent aeration did not allow the achievement of significant denitrifying P removal, despite the DPAO/PAO ratio being equal to 50.5%. Almost the entire load of orthophosphates was being removed in aerobic conditions right after the anaerobic phase, even though this aerobic period lasted only 20 minutes. However, a SBR with a forced anoxic phase occurring after an anaerobic phase and created by an introduction of NO(x) rich stream of wastewater guaranteed the highest DPAO/PAO ratio of 82.8% and the highest share of denitrifying P removal (above 80%) in the total removal of phosphorus. PMID- 22519109 TI - Saline landfill leachate disposal in facultative lagoons for wastewater treatment. AB - This study was carried out to determine the effect of disposing of saline landfill leachates in a Facultative Lagoon Wastewater Treatment Plant (FLWTP). The FLWTP is near a landfill and presents two characteristics: a wastewater influent with low organic matter, and high lagoon salinity due to the soil characteristics. These characteristics made the FLWTP a viable candidate to evaluate the feasibility of adding landfill leachates to the wastewater influent. Different mixtures of leachate with raw wastewater using volumetric ratios of 4%, 6%, and 10% (v/v) were evaluated in facultative lagoon reactors (FLRs). A 10% concentration of leachates in raw wastewater increased BOD5 and COD in the influent from 45 to 110 mg L(-1) and from 219 to 711 mg L(-1), respectively. It was found that the increase in salinity given by the raw wastewater and leachate mixture did not inhibit algae diversity. The types of algae present were Microcystis sp., Merismopedia sp., Euglena sp., Scenedesmus sp., Chlorella, Diatomea and Anacystis sp. However, decreased algae densities were observed, as measured by the decrease in chlorophyll concentration. The results showed that a 100% leachate concentration combined with wastewater did not upset biological treatment in the FLRs. Mean removal efficiencies for BOD5 and COD were 75% and 35%, respectively, giving a final BOD5 lower than 25 mg L(-1). There was also a significant decrease in the leachate heavy metal content when diluted with raw wastewater as result of natural precipitation. PMID- 22519110 TI - A new collector for in situ pore water sampling in wetland sediment. AB - Currently available pore water samplers generally do not allow continuous monitoring of temporal variations in pore water composition. Therefore, a new type of pore water collector was designed and constructed. These collectors were constructed of polyvinyl chloride (PVC) materials, including PVC tubing with one end sealed and another end topped with a removable PVC screw-cap. A row of holes was drilled 10 cm from the sealed end of each collector. These new collectors were deployed in different layers of the sediment in a constructed wetland in Lake Taihu, China, to reveal variations in the nutrient composition of pore water with high spatial and temporal resolution. Specifically, the collectors were driven into the sediment, and the pore water flowed into the tubing via gravity. The pore water was then sampled from the PVC tubing using a portable vacuum pump, and then was taken to the lab within 20 min for analysis of the dissolved oxygen (DO) and nutrient concentration. The DO concentration of the pore water was below the detection limit for all samples, indicating that the pore water was probably not influenced by the air and that the water in the collector tube was representative of the pore water. These findings suggest that the collector is capable of measuring the temporal and spatial variations in the nutrient concentrations in pore water. Furthermore, the inexpensive material, ease of construction, minimal disturbance to the sediment and applicability for wetland sediments are advantages of the collector presented here compared with traditional pore water sampling techniques. PMID- 22519111 TI - Influence of operational parameters and kinetics analysis on the photocatalytic reduction of Cr(VI) by immobilized ZnO. AB - In the present work the performance of immobilized ZnO on a glass plate with the heat attachment method has been described for photoreduction of Cr(VI) to the less harmful Cr(III) at different operational parameters. The photoreduction of Cr(VI) on the surface of the immobilized ZnO catalyst was studied as a function of the pH of solution, initial Cr(VI) concentration and ultraviolet (UV) light intensity. Results indicated that the reduction rate decreases with increasing initial concentration of Cr(VI) and initial pH of solution, whereas it increases with increasing UV light intensity. The photoreduction rate of Cr(VI) on the surface of the immobilized ZnO in the presence of O2 as mobile gas is more than Ar and N2. The reduction process of Cr(VI) by immobilized ZnO also could be done under visible light irradiation. Pseudo first-order kinetics were observed for the photoreduction of Cr(VI) at different operational conditions. With non-linear regression analysis a mathematical kinetics model was developed for the pseudo first-order constant (k(ap)) as a function of operational parameters. PMID- 22519113 TI - Visualization of the exothermal VOC adsorption in a fixed-bed activated carbon adsorber. AB - Activated carbon fixed beds are classically used to remove volatile organic compounds (VOCs) present in gaseous emissions. In such use, an increase of local temperature due to exothermal adsorption has been reported; some accidental fires in the carbon bed due to the removal of high concentrations of ketones have been published. In this work, removal of VOCs was performed in a laboratory-scale pilot unit. In order to visualize the increase in local temperature, the adsorption front was tracked with a flame ionization detector and the thermal wave was simultaneously visualized with an infrared camera. In extreme conditions, fire in the adsorber and the combustion of activated carbon was achieved during ketone adsorption. Data have been extracted from these experiments, including local temperature, front velocity and carbon bed combustion conditions. PMID- 22519112 TI - Evaluation of compost and a mixture of compost and activated carbon as biofilter media for the treatment of indoor air pollution. AB - Indoor air pollution (IAP), defined by a lot of pollutants at low concentrations (microg m(-3)), is recognized as a major environmental health issue. In order to remove this pollution, biofiltration was investigated in this study. Two biofilters packed with compost and a mixture of compost and activated carbon (AC) were compared during the treatment of an influent with characteristics close to those of IAP. Very high removal efficiencies (RE) were achieved for the two biofilters (RE more than 90% for butyl acetate, butanol, formaldehyde, limonene, toluene and undecane at mass loading from 6-24mg m(-3) h(-1) and 19s empty bed retention time). The fact that high RE of hydrophobic compounds (undecane and limonene) were achieved, along with the results of an abiotic sorption study, lead us to suggest a mechanism including adsorption followed by biodegradation at the interface of the biofilm where microorganisms tend to concentrate near the available substrate. Both chemical reactions with the packing materials and biological degradation led to average RE greater than 91.4% for nitrogen dioxide. It was observed that adding AC to compost had significant effects. First, its buffering capacity led to shorter acclimation duration and more stable operation efficiencies than for the compost biofilter. Secondly, the only compound which was not removed by the compost biofilter, trichloroethylene, was strongly adsorbed by the compost/AC biofilter. Finally, the concentration profile along the two biofilters demonstrated that adding of AC could lead to a reduction of the retention time required to reach the maximal RE. PMID- 22519114 TI - Removal of lead from wastewater by adsorption using acid-activated clay. AB - The suitability of acid-activated clay for adsorbing lead from wastewater streams was tested by conducting experimental studies in the laboratory. The effect of initial concentration of the adsorbate on lead removal was analysed using solutions with lead concentrations ranging from 20-120 mg/l. Also, the effect of pH on removal of lead was studied in the pH range of 2-10 and the effect of adsorbent dosage was studied by varying the adsorbent dosage from 10-20 g/l. The tests were conducted at three different temperatures, 25 degrees C, 30 degrees C and 35 degrees C. The efficiency of lead removal was observed to be about 92.4% at an initial concentration of 100 mg/l of lead, at pH 6 and at a temperature of 30 degrees C. The adsorption isotherms were plotted. The Langmuir isotherm fitted the experimental data reasonably well. The adsorption process followed the pseudo second-order model. PMID- 22519115 TI - Drum composting of municipal solid waste. AB - The high initial C/N ratio (> 30) found in Indian municipal solid waste (MSW) leads to more time required for composting (> 3 months), with poor-quality compost production. Therefore, the effects of MSW amended with cattle manure (trial 1) and tree leaves (trial 2) were compared with unamended MSW (control) in a rotary drum composter. The initial C/N ratios of trial 1 and trial 2 were kept at 22, as compared to 32 for the MSW control sample. It was observed that trial 1 produced high-quality and stable compost within 20 days. It showed higher final total nitrogen (2.2%), final total phosphorus (3.2 g/kg) and low electrical conductivity (2.7 dS/m). At the end of 20 days, higher degradation caused lower final oxygen uptake rate (OUR) (1.8 mg/g volatile solids (VS)/day), final CO2 evolution (1.0 mg/g VS/day) and final C/N ratio (7.8). Trial 2 produced good quality and stable compost resulting in 1.9% of total nitrogen, 2.7% of total phosphorus and low OUR (2.0 mg/g VS/day), CO2 evolution (1.5 mg/g VS/day) and C/N ratio (10.1) after 20 days ofcomposting. However, the control sample with an initial C/N ratio of 32 showed higher OUR (3.6 mg/g VS/day) and CO2 evolution (2.6 mg/g VS/day) comprising a lower concentration of total nitrogen (1.6%) and total phosphorus (2.3 g/kg), which indicated an unstable and low-quality product as compared to trials 1 and 2. Therefore, results showed that the characteristics of MSW amended with cattle manure and tree leaves significantly influence the compost quality and process dynamics in a rotary drum composter. PMID- 22519116 TI - Photocatalytic degradation of reactive black-5 dye using TiO2-impregnated activated carbon. AB - The photocatalytic degradation of reactive black-5 (RB-5) dye was studied using hydrothermally prepared TiO2 impregnated on activated carbon (AC) (20%, 40% TiO2:AC). Photodegradation efficiency of the prepared TiO2:AC catalysts were studied and compared with the commercial TiO2 (P25). These catalysts were characterized by using X-ray diffraction and scanning election microscope techniques. The experimental results showed that the effect of TiO2 impregnation on AC helped to optimize the amount of TiO2 impregnated and the amount of catalyst used for the reaction. The effect of different parameters, such as the initial concentration of dye solution and the catalyst amount, on the rate of photodegradation was also studied. The reduction in the chemical oxygen demand (88%) proves the mineralization of the RB-5 dye along with the colour removal. PMID- 22519117 TI - Effect of COD/SO4(2-) ratio on anaerobic treatment of landfill leachate during the start-up period. AB - This study investigates the performance of an anaerobic baffled reactor (ABR) during the start-up period of raw young landfill leachate treatment at two chemical oxygen demand (COD) to SO4(2-) ratios of 20 and 4. The reactor was operated at ambient temperature and low organic loading rates (0.52, 0.76 and 1.05 kg COD/m3 per day). During the study, sulfate-reducing bacteria (SRB) activity increased at the lower ratio of COD/SO4(2-) producing higher levels of sulfide and alkalinity. The dissolved sulfide concentration reached an inhibitory level above 250 mg/L, which caused a sharp reduction in the total COD removal efficiency from 77-80% to 32%. Total volatile fatty acid (TVFA) production proceeded at a constant level despite increased organic loading. As the effluent total and organic COD concentrations increased, the inhibitory effect of the inborn sulfide was correlated to the limitation experienced in the hydrolysis/acidogenesis stages, and thus VFA production and organic matter removal. PMID- 22519118 TI - Sorption of phenanthrene on to soil fractions in the presence of Triton X-100. AB - The objective of this study was to evaluate the effect of soil fractions on surfactant-enhanced soil remediation. A soil sample was separated into humic acid (HA), humin (HM), base-extracted soil (BE) and mineral fraction through solution extraction. The sorption of phenanthrene (PHE) on to individual soil fractions in the presence of a nonionic surfactant, Triton X-100 (TX100) at two concentrations, was studied. The results showed that HA had the highest affinity for both PHE and TX100. The HM and BE presented a high sorption capacity for PHE but a low capacity for TX100, while mineral presented a low sorption capacity for PHE and a high sorption capacity for TX100. The sorption of PHE on different soil fractions was greatly influenced by the presence of TX100. With TX100 present in solution, the distribution parameters K(f) and K(d) of all the sorbents decreased, with the exception of the mineral fraction at the lower TX100 initial concentration. The sorption of PHE on to HA and the mineral fraction was particularly influenced by TX100, which is because of the corresponding high TX100 sorption capacity of HA and the mineral fraction. PMID- 22519119 TI - Determination of biodegradability of phenolic compounds, characteristic to wastewater of the oil-shale chemical industry, on activated sludge by oxygen uptake measurement. AB - The aim of this study was to investigate the biodegradation of phenol, o-cresol and p-cresol individually and as bi-substrate mixtures at low initial substrate concentrations. Activated sludge was taken from the Kohtla-Jarve wastewater treatment plant, Estonia, which is also treating phenolic wastewater from the oil shale chemical industry and is considered to be acclimated to the phenolic compounds. Respirometric data have been used for evaluation of the kinetic parameters describing the bio-oxidation of substrates. Activated sludge was able to degrade phenol and p-cresol faster than o-cresol, showing better affinity to p cresol. However, at higher concentrations, phenol and p-cresol exhibited also an inhibitory effect to the microorganisms. The highest values for maximum rate of oxygen uptake (V(O2,max)) were obtained for the bi-substrate system of phenol--p cresol among the mixtures containing both substrates at equal concentrations from 0.005 mM to 0.050 mM. Concerning the systems containing one substrate at 0.1 mM and the other substrate varied in the abovementioned range, the highest V(O2,max) values were found for phenol--o-cresol(0.1 mM). The interaction parameters indicated that phenol had a stronger inhibition effect on the biodegradation of p cresol than p-cresol had on the biodegradation of phenol. However, the obtained interaction parameters for systems of phenol--o-cresol indicated that o-cresol had a stronger inhibition effect on the biodegradation of phenol, which in turn had a mild inhibition or even enhancing effect on the biodegradation of o-cresol. In the case of a 1:1 mixture, phenol and o-cresol had a similar mild inhibition effect on each other's biodegradation. PMID- 22519120 TI - Reactive sorption of mercury(II) on to poly(m-phenylenediamine) microparticles. AB - Poly(m-phenylenediamine) (PmPD) microparticles, from the monomer with two amino groups, were synthesized through chemical oxidation, and the strong adsorbability of mercury ions on to PmPD was systematically examined. The results revealed a rapid adsorption process with an equilibrium time of 30 minutes. Also, the adsorption behaviour showed that the adsorption kinetics was in good agreement with the pseudo-second-order equation. The maximum uptake capacity for mercury (Q(max)) reached approximately 955 mg g(-1) at 0.02 M NaNO3 and 25 degrees C, which decreased appreciably with the increasing of salt concentration. The amount of mercury sorbed at equilibrium steadily increased as the temperature rose from 25 to 45 degrees C, which can be indicative of an endothermic process. The pH value of the solution seemed to exhibit little influence on the adsorption capacity. The adsorption mechanisms, including Hg2+ complexation with nitrogen and ion exchange between Hg2+ and H+ on PmPD chains, are proposed on the basis of Fourier transform infrared (FTIR) and X-ray photoelectron spectroscopy (XPS) analysis. PMID- 22519121 TI - Applications of soluble, encapsulated and cross-linked peroxidases from Sapindus mukorossi for the removal of phenolic compounds. AB - Peroxidases have been known to polymerize phenolic compounds and precipitate them from solution. Sapindus peroxidases (SPases) were extracted from the leaves of Sapindus mukorossi and precipitated with four volumes of chilled methanol. Soluble, encapsulated and cross-linked forms of enzymes were used for the removal of phenolic compounds (initial concentration 1.0 mM) in a stirred batch reactor. Calcium alginate beads were prepared using sodium alginate and calcium chloride at 1.5% and 5.0% (w/v), respectively. Sodium alginate and glutaraldehyde at 1.0% (w/v) and 0.8% (v/v), respectively, were optimized for cross-linking of SPases. The maximal removal of 2-chlorophenol was found in the buffers ofpH range 4-7 and at 30-60 degrees C in the presence of 1.2 mM H2O2 by soluble enzymes, but encapsulated and cross-linked enzymes worked well at pH 5 and at 50 degrees C in the presence of 0.8 mM H2O2. The optimized doses of soluble, encapsulated and cross-linked SPases were 1.2, 4.2 and 1.2 mg/mL, respectively, for the removal of phenolic compounds. Encapsulated and cross-linked enzymes showed a lower efficiency than soluble enzyme but can be reused in multiple cycles for the removal of phenolic compounds. PMID- 22519122 TI - Nickel-cadmium batteries: effect of electrode phase composition on acid leaching process. AB - At the end of their life, Ni-Cd batteries cause a number of environmental problems because of the heavy metals they contain. Because of this, recycling of Ni-Cd batteries has been carried out by dedicated companies using, normally, pyrometallurgical technologies. As an alternative, hydrometallurgical processes have been developed based on leaching operations using several types of leachants. The effect of factors like temperature, acid concentration, reaction time, stirring speed and grinding of material on the leaching yields of metals contained in anodic and cathodic materials (nickel, cadmium and cobalt) using sulphuric acid, is herein explained based on the structural composition of the electrode materials. The nickel, cobalt and cadmium hydroxide phases, even with a small reaction time (less than 15 minutes) and low temperature (50 degrees C) and acid concentration (1.1 M H2SO4), were efficiently leached. However, leaching of the nickel metallic phase was more difficult, requiring higher values of temperature, acid concentration and reaction time (e.g. 85 degrees C, 1.1 M H2SO4 and 5 h, respectively) in order to obtain a good leaching efficiency for anodic and cathodic materials (70% and 93% respectively). The stirring speed was not significant, whereas the grinding of electrode materials seems to promote the compaction of particles, which appears to be critical in the leaching of Ni degrees. These results allowed the identification and understanding of the relationship between the structural composition of electrode materials and the most important factors that affect the H2SO4 leaching of spent Ni-Cd battery electrodes, in order to obtain better metal-recovery efficiency. PMID- 22519123 TI - Violet diode laser-induced chlorophyll fluorescence: a tool for assessing mosaic disease severity in cassava (Manihot esculenta Crantz) cultivars. AB - Violet diode laser-induced chlorophyll fluorescence was used in agronomical assessment (disease severity and average yield per plant). Because cassava (Manihot esculenta Crantz) is of economic importance, improved cultivars with various levels of affinity for cassava mosaic disease were investigated. Fluorescence data correlated with cassava mosaic disease severity levels and with the average yield per plant. PMID- 22519124 TI - Characteristics of run-off quality and pollution loading from a highway toll gate. AB - The Ministry of Environment of the Republic of Korea has been seriously considering implementing a TMDL (Total Maximum Daily Load) as a mandatory requirement on watersheds because of the potential water pollution from highway toll-gates. The purpose of this study was to investigate the characteristics of run-off quality and pollution loading during rainfall events at a highway toll gate. Samples were analysed for run-off quantity and quality parameters such as COD(cr), TSS, total petroleum hydrocarbons, nutrients (TKN, NO3, TP and PO4) and several heavy metals (As, Cu, Cd, Ni, Pb and Zn). Based on a hydrograph and pollutant graph analysis, the pollutant concentration peak occurred in the run off 10 minutes after the onset of rainfall. The typical first flush effect on the concentration depended on the rainfall intensity and the number of antecedent dry days. The relationships between the run-off and the event mean concentrations of the pollutants (e.g. TSS and COD) were described by general nonlinear equations. For governmental implementation of TMDL policies, the estimation of the cumulative TSS load was 1032 kg/(ha x yr) in 2007, 963.44 kg/(ha x yr) in 2008 and 847.21 kg/(ha x yr) in 2009. This information can lead to improved practical water quality management practices and reduced costs of improving water quality. PMID- 22519125 TI - The policy of reducing the number of issues and to point to a better quality of published papers is seemingly paying dividends. PMID- 22519126 TI - Prevalence of allergic disorders in Italy: the Cotignola population study. AB - BACKGROUND: The worldwide prevalence of allergic diseases such as rhinitis, asthma, and atopic dermatitis is continuously increasing, while other allergic disorders such as urticaria and angioedema are less investigated. We performed a population study evaluating the prevalence of any kind of allergic disorders. METHODS: The entire population of 7,201 inhabitants of Cotignola (Ravenna, Italy) was surveyed by a questionnaire assessing symptoms related to rhinitis, asthma, anaphylaxis, skin symptoms and insect sting allergy as well as the features of clinical presentations, diagnosis, and treatment received. RESULTS: Valid questionnaires were obtained by 6,676 inhabitants (92.7%). The sample was formed by 3,266 males and 3,495 females, the mean age was 45.6 years; 1,035 subjects (15.5%) were aged less than 18 years; 404 subjects (6%) had at least one episode of wheezing/breathlessness in their lifetime, and 243 of them (60.1%) had a diagnosis of asthma; 1,002 subjects (14.8%) had nose symptoms in their lifetime, and 375 of them (37.4%) had a diagnosis of allergic rhinitis or rhinoconjunctivitis. For other allergic manifestations, data were obtained from 5,730 subjects; of them, 178 (3.1%) had skin symptoms, 59 (1.1%) had oral symptoms, and 37 (0.6%) had anaphylaxis; 207 (3.6%) had reactions to insect stings. There were no significant differences in prevalence between Italians and immigrants. Only 51.7% of subjects with asthma, 46.5% of those with rhinitis, 22.7% of those with other allergies, but 97.1% of those with insect allergy, received treatment. CONCLUSIONS: These findings confirm recent data on epidemiology of allergic diseases in Europe, particularly in Italy, and add some details on how such diseases are managed. PMID- 22519127 TI - Airways hyperresponsiveness to different inhaled combination therapies in adolescent asthmatics. AB - BACKGROUND: Inhaled combined therapy improves the pulmonary function in asthmatic patients. The effect on the airway hyperresponsiveness (AHR) and the efficacy of different pharmacological schedules is not well clarified on adolescent asthmatics. OBJECTIVE: Evaluate the responses to different combined inhaled therapies in adolescent asthmatics and study its impact on exercise induced AHR. METHODS: Basal lung function tests (LFT) were performed in 30 adolescents (13 to 16 years old; 19 female) with allergic asthma. They were submitted to exercise challenge test (EC) followed by bronchodilator test (BD). During 4 weeks, 15 adolescents were submitted to inhaled fluticasone/salmeterol (group A) and other 15 to inhaled budesonide/formoterol (group B). After this period, they underwent another functional evaluation as previous. RESULTS: Before treatment, pulmonary function was similar in both groups. After 4 weeks of treatment, these groups showed an improvement of the basal LFT (p = 0.001 for FEV1 in both), decrease on bronchoconstriction induced by exercise (NS for both) and less recovery on BD response (p = 0.001 and 0.002, for FEV1 respectively groups A and B). Group B showed a better performance, with higher improvement of basal FEF 25/75 (p = 0.001), reduced bronchoconstriction response to EC (p = 0.008 for FEV1) and fewer response to BD test (p < 0.0001 for FEV1 and 0.024 for FEF 25/75) No adverse events were observed. CONCLUSION: After 4 weeks of inhaled combined therapy, these patients improved their pulmonary function and bronchomotricity. Those under budesonide/formoterol showed the highest improvement. These medications are a safe measure in controlling the asthma in these patients. PMID- 22519128 TI - Adverse effects during specific oral tolerance induction: in-hospital "rush" phase. AB - BACKGROUND: Specific oral tolerance induction (SOTI) is a promising approach in the treatment of severe food allergies. Different protocols have demonstrated its efficacy. Nevertheless, SOTI is still considered an experimental method and should be limited to highly controlled settings. AIMS: To define the incidence and severity of adverse reactions, possible risk factors, and the safety and effectiveness of nebulized epinephrine as a first-line treatment of respiratory reactions during in-hospital SOTI for cow's milk allergy. MATERIALS AND METHODS: A retrospective study was conducted by reviewing the medical records of patients admitted for SOTI beginning in 2001. Reactions were classified as mild, moderate and severe on a partially modified Clark scale. Adverse reactions were treated following the International Guidelines with the introduction of nebulized epinephrine for level four reactions. RESULTS: Of 209 patients, 17 were excluded due to the absence of objective reactions. The remaining 192 were classified as follows: Mild Reactions (Clark Scale 1 to 3): 100 patients received either no treatment, oral antihistamines or nebulized steroids; Moderate Reactions (Clark Scale 4): 87 patients treated with nebulized epinephrine and, depending on their symptoms, oral antihistamines, corticosteroids (nebulized, oral or IV) or nebulized beta 2 agonists; Severe Reactions (Clark Scale 5): 5 children, 4 of whom initially underwent one nebulization of epinephrine and eventually required an IM dose. The fifth patient was immediately treated with IM epinephrine due to hypotension. DISCUSSION: adverse reactions during this in-hospital SOTI protocol were frequent but easily manageable. Nebulized epinephrine can play a relevant role in the treatment of respiratory reactions. PMID- 22519129 TI - Successful desensitization to natalizumab in a skin test--positive patient: a case report. AB - Relevant interest has been focused on rapid desensitization for drug hypersensitivity and on its use for reactions to monoclonal antibodies. Natalizumab is a highly effective therapy for multiple sclerosis but its use can be limited by hypersensitivity reactions. Herein we present a case of a 36-year old male patient with multiple sclerosis who started natalizumab therapy due to rapid neurological deterioration. During the second infusion he developed a reaction involving urticaria, erythema and angioedema. Natalizumab sensitization was demonstrated by a positive result on the intradermal test. The anti natalizumab IgG neutralizing antibody assay was negative. Lacking any alternative, equally effective treatment, he underwent a rapid intravenous desensitization protocol. Desensitization was successfully repeated eleven times and the patient's neurological conditions improved and remained stable after one year. This case demonstrates that rapid desensitization is a safe and effective procedure in the treatment of natalizumab hypersensitivity. PMID- 22519130 TI - A case of atopic dermatitis and erythema multiforme. AB - We report a case of a two-year-old boy with atopic dermatitis treated with antibiotics for pharyngitis and acute otitis media and subsequently developed targetoid and ulcerated blister mucocutaneous lesions. Diagnostic workup revealed eczema herpeticum and HSV viremia. To our knowledge, this is the first reported case of a patient with atopic dermatitis presenting with erythema multiforme likely secondary to eczema herpeticum and HSV viremia. PMID- 22519131 TI - [Leaving is not running away]. PMID- 22519132 TI - [Medicalization in the elderly, miracle or curse?]. PMID- 22519133 TI - [How to manage the parkinson patient with depression?]. PMID- 22519134 TI - [Using a cane for osteoarthritis of the knee]. PMID- 22519135 TI - [A joint committee to fight against pain]. AB - The crucial need to take into account the pain felt by elderly people is sometimes difficult to implement on the scale of small or medium-sized institutions. The pooling of resources which a joint committee to fight against pain could offer is an interesting avenue to explore. PMID- 22519136 TI - [Setting up of a modelling workshop in an Alzheimer's unit]. AB - Modelling is an original and creative form of therapy and above all one which is accessible when the limits of cognitive care have been reached. Salt dough is a malleable, sensitive and multi-sensory mediator which is forgiving of errors. Without the use of any known technique or objective as a reference, this activity avoids any notion of failure. This workshop is an area for expression and care and the mediation is interesting for its therapeutic potential. PMID- 22519137 TI - [Life history in a nursing home, a working tool]. AB - Elderly people suffering from Alzheimer's disease or related dementia sometimes testify to a difficult life. A life history recorded on arrival in the nursing home throws light on the behavioural disorders of the residents. It helps caregivers to take measures offering them some relief and to see the residents differently, beyond their illness. PMID- 22519138 TI - [Using the Leonetti Act to help caregivers]. PMID- 22519139 TI - [Gerontologic technologies and quality of life. When science helps the elderly]. PMID- 22519140 TI - [Gerontologic technologies and society]. AB - Gerontechnologies, a concept dating back to the 1990s, are a blend of gerontology and technology. They have a well-defined role, their main objective being one of observation and intervention. Even though gerontechnologies are directly aimed at elderly people, they are not necessarily suitable for everyone. PMID- 22519141 TI - [Remote medical consultations in gerontology]. AB - Experimental teleconsultations have been set up between a university hospital and a public geriatric hospital in Paris in order to facilitate elderly patients' access to specialist consultations. Caregivers have had to accept major changes to their professional practices (delegation of tasks, sharing of knowledge, etc.). This new telemedecine scheme represents huge progress in patient care. PMID- 22519143 TI - [Home automation for elderly people in the process of losing their autonomy]. AB - The safety of elderly people, particularly dependent at night, is a major factor in preventingthem from remaining in their own home. An experiment in Correze using domotics and advanced remote assistance services and involving around one hundred elderly people living at home, took place from summer 2009 to autumn 2010. PMID- 22519142 TI - [Alzheimer's disease and geolocation: initial results of the Estima study]. AB - Geolocation devices for patients suffering from Alzheimer's disease constitute an improvement in their care. However, this system arouses debate. The Estima study offers a series of results and recommendations concerning the use of these devices. It consists of three complementary sections: a sociological study, an observational retrospective study and an ethical analysis. PMID- 22519146 TI - [Musculoskeletal problems in the elderly]. PMID- 22519145 TI - [Gerontologic technologies and quality of life. Bibliography]. PMID- 22519144 TI - [Force platforms, a technological innovation]. AB - Falls in the elderly constitute a public health issue due to the seriousness of the physical and psychological consequences as well as the resulting financial cost. Static posturography with the help of a force platform helps to guide therapeutic decisions and to rehabilitate patients who have fallen. PMID- 22519147 TI - [Accomodation units]. PMID- 22519148 TI - Oral health and self-perceived oral treatment need of adults in Sweden. AB - The main aim of this thesis was to study the oral health and the self-perceived oral treatment need of adults in Sweden. The first step was to analyse the self perceived oral treatment need in a random national sample of young adults (20 to 25-year-olds). This study used one patient and one dentist questionnaire. The patient questionnaire was sent to 611 young adults and the response rate was 78%. After permission from 377 of these individuals, a questionnaire was sent to their dentists and answers were received from 85% (321 dentists). How the individuals perceived their oral treatment need was used as a dependent variable in a multivariate logistic regression model. Independent variables were self-assessed socio-economic situation, general health and dental attitudes together with information from the dentists on their patient's dental status. The results showed that having a high educational level, poorer oral health compared to one's peers, and being concerned about one's oral health significantly increased the odds for a high perceived oral treatment need. In this group of young adults, 33% perceived a high oral treatment need. In order to study if the oral treatment need was the same in all adult age groups and how the perceived oral health was in an adult Swedish population, a new questionnaire was sent to a random sample of 9 690 individuals, 20 to 89-year-olds, living in Skane, Sweden. The response rate was 63%. The results showed that a majority of the adult population in Skane had a positive perception of their oral health, in particular the individuals in the youngest age group. Most individuals had lost few teeth and removable dentures were uncommon. One third rated their dental treatment need as high. The highest proportion of individuals with a perceived high oral treatment need was found in the age group 70-79. In order to study the perceived oral treatment need in all adult age groups, the questionnaire was further analysed. The Andersen behavioural model was used as a theoretical framework for a multivariate logistic regression model. Questions that fit the components of individual characteristics, health behaviour and outcomes in the model were used as independent variables. The self-perceived oral treatment need was used as a dependent variable. The results showed that the Andersen behavioural model was found to be a useful tool when studying the perceived oral treatment need, and variables from all of the components in the model were significant. Important factors for the prediction of a high oral treatment need were a low educational level, previous unmet perceived oral treatment need, frequent visiting pattern, perception of worse oral health, external locus of control, and to have received information from one's dental caregiver about a need for oral treatment. The evaluated oral health was also studied using another sample of adults from the same region and of the same age. 966 individuals were invited to participate in a clinical study and 47% of the final sample was examined. Since socio-economic factors have been shown to be related to oral health, the clinical findings were studied in cross tabulations and chi-2 tests together with age, gender, ethnicity and educational level. The results showed that older age was related to a higher prevalence and an increased severity of oral diseases (except for caries) and a higher number of dental restorations. There were no significant differences between the genders. Individuals with a lower educational level had fewer teeth remaining, had more caries lesions, and had worse periodontal conditions and a higher DMFT. Individuals not born in Sweden had fewer teeth remaining, had worse periodontal conditions, more apical destructions and had received less dental fillings than those born in Sweden. CONCLUSIONS: The self-assessed and the professionally evaluated oral health of the adult population in Skane is good both in a historical and international perspective. The evaluated oral health is comparable to other Swedish studies. There is, however, a group of individuals that has an increased risk for oral diseases. The self-perceived oral treatment need is largely affected by the patient's socio-economic background and perceptions of oral health. PMID- 22519149 TI - Team leaders. Saluting the top collaborative building projects. PMID- 22519150 TI - Keeping pace. Time to retool the biomedical engineering department? PMID- 22519151 TI - The BIM revolution. Building information modeling expands, benefits to hospital design and operations. PMID- 22519152 TI - Air ways. Improvements in HVAC technology boost indoor air quality. PMID- 22519153 TI - Stepping up advocacy at the grass roots. PMID- 22519154 TI - Are you working with your ICP? PMID- 22519155 TI - Reliable delivery. Changes to medical gas and vacuum system requirements. PMID- 22519156 TI - Minimum impact. Reducing the detrimental effects of hospital waste. PMID- 22519157 TI - Trends of tuberculosis and HIV infections between 2004 and 2008 in Wolaita Sodo, southern Ethiopia. AB - BACKGROUND: In sub-Saharan Africa human immunodeficiency virus (HIV) epidemic has a major influence on tuberculosis (TB) epidemiology. Ethiopia is among the countries in the region most heavily affected by the HIV and TB. Recent evidence indicated that the HIV/AIDS epidemic may be more heterogeneous in different age categories, between males and females, across different risk groups, and/or in different geographical settings than previously believed. This heterogeneity implies that HIV/AIDS programs for a particular area should be based not only on national-level statistics, but it also needs to be geographically focused, and directed to those regions, districts or communities exhibiting higher prevalence. The current study was aimed to evaluate trends of the prevalence of HIV and TB infection in Wolaita Sodo town. METHOD: This is institution based retrospective study and it covered the period of 2004 to 2008. We reviewed the medical records of 7375 patients with a diagnosis of TB and 11447 individuals screened for HIV at three heath institutions located in Wolaita Sodo town. Statistical significance of trend in proportions over the study period was evaluated by chi2 test for trend using Epi-Info version 6.03. P-value less than 0.05 was reported as being statistically significant. RESULTS: The prevalence of TB was 17.1% (1262/7375), that of HIV was 10.7% (1220/11447) and the prevalence of HIV and TB co-infection was 7.8% (36/459). With the exception of 2008 annual TB cases, the prevalence of TB in Wolaita Sodo showed an overall significant decline over the study period (chi2 = 59.4, P < 0.001). The prevalence of TB (P = 0.003) and HIV (P < 0.001) has an increasing trend with age for study participants younger than 44 years and decrease then after (P < 0.001). Being a female was a significant risk factor for HIV infection (OR = 1.35; 95% CI: 1.23 to 1.47) but not for TB infection. CONCLUSION: In the study area annual prevalence of TB, HIV and TB/HIV co infection were significantly decreased from 2004 to 2008 in the age range of 25 44 years. However, the level of infection of these infections is still high and remains as being public health problems in the study area. Therefore, a good practice of TB and HIV control strategy adopted in the area should be strictly continued. PMID- 22519158 TI - HIV-associated anaemia before and after initiation of antiretroviral therapy at Art Centre of Minilik II Hospital, Addis Ababa, Ethiopia. AB - BACKGROUND: HIV associated anaemia is always overseen and it could be a challenge for prognosis of patients who are taking ART. The prevalence of anemia due to HIV at the early stage of infection is more prevalent than in the late stage. Knowing the impact of HIV on the haematopotosis of HIV infected patients is very essential for the management and care of people living with HIV/AIDS. HIV related anemia decreases the quality of life and survival rate of HIV patients. OBJECTIVE: The aim of this study is to determine prevalence of HIV associated anaemia before and after initiation of antiretroviral therapy (ART) in HIV infected adults. METHOD: A retrospective record review was conducted on HIV infected patients before ART and had follow up at the ART Clinic of Minilik II Hospital Addis Ababa, Ethiopia. Haemoglobin measurement and CD4+ T cell count was measured using standard methodology at baseline and after 4 months of antiretroviral therapy (ART). Paired t -test was used to assess mean differences for haemoglobin and CD4+ T cell count before and after ART initiation. RESULTS: Of the 230 study subjects 121 (52.6%) were anemic before ART. However, the prevalence of anemia after ART (37.4%) was significantly decreased (p < 0.05). The prevalence of anemia was higher in females than in males at base line (70.25% vs. 29.75%) (P = 0.017), and after ART treatment (69.23% vs. 30.77%) (P = 0.000). Mean CD4 cell count of study subjects was 112 cells/microl +/- 67/microl at baseline. The mean CD4+ T cell count is significantly increased after ART and found to be 211 cells/microl +/- 120/microl (p < 0.05). Significance association was observed between Hb aind CD4+ T cell count after ART (P = 0.011). CONCLUSIONS: There was a decline in the prevalence of anemia and increment of mean CD4+ T cell count among HIV infected patients after ART. However, a number of HIV/AIDS patients had still anemia and their CD4+ T cell count is not improved. Thus, there should be a large scale and longitudinal study for further characterization of HIV related anemia. PMID- 22519159 TI - Conjunctival impression cytology and detection of vitamin A deficiency in pregnant women, Gondar, Northwest Ethiopia. AB - BACKGROUNDS: Ethiopia has been classified by the WHO as a country where vitamin A deficiency is a public health problem. Vitamin A deficiency is labelled as a public health problem based on its extensively studied endemicity among children. Maternal vitamin A deficiency has received little attention. Thus the principal objective of this study is to assess the vitamin A status of pregnant Ethiopians based on Conjunctival Impression Cytology (CIC) and serum levels of vitamin A. METHODS: It is a descriptive study done among women attending ANC in the second and third trimesters of pregnancy at the ante-natal clinic of Gondar University Hospital. Women who appeared in July to October 2006 were recruited into the study based on inclusion criteria. Their socio-demographic and economic status, dietary, anthropometric and maternity data were collected with the help of structured questionnaire. Fasting blood samples were taken from the antecubital vein of each woman for determination of serum retinol. Furthermore, conjunctival cell samples were collected on Millipore Cellulose Acetate Filter to detect vitamin A deficiency related to Goblet cells and squamous metaplasia. RESULTS: A total of 303 pregnant mothers were included in this study. Twenty-six percent of the pregnant women had vitamin A deficiency or low serum retinol. Night blindness was found in 4.3% of the pregnant women. CIC results showed absence of goblet cells and/or mucin was seen more in those with low serum retinol but this was not statistically significant. CONCLUSION: Adequate nutrient supplementation to pregnant women is recommended based on the results. Further studies should be conducted to validate the importance of CIC. PMID- 22519160 TI - Demand for long acting and permanent contraceptive methods and associated factors among family planning service users, Batu town, Central Ethiopia. AB - BACKGROUND: Evidence suggests a high unsatisfied demand for long acting and permanent contraceptive methods in sub-Saharan Africa. However, there is limited knowledge on demand for long acting and permanent contraceptive methods and associated factors in Ethiopia. OBJECTIVE: The objective of this study was to assess demand for long acting and permanent contraceptive methods and associated factors among women of age group 18-49 years in Batu town, East Shoa Zone, Ethiopia. METHODOLOGY: A facility based cross-sectional survey was conducted in six service delivery points from March to April 2009 on 398 women of age 18-49 years old. RESULTS: Thirteen (3%) were using long acting and permanent contraceptive methods and 89 (22.4%) wanted no more child in the future making the total demand of long acting and permanent contraceptive methods 24.4%. Older age group, multiparty, that the provider asked about reproductive intention, and the provider explained side effects of method selected were significantly associated with using LA and MPs (P < 0.05). CONCLUSION: There is high total demand and several socio demographic and family planning service quality related factors were associated with demand for long acting and permanent contraceptive methods indicating that multi-dimensional measures are needed to improve the use of long acting and permanent contraceptive methods. PMID- 22519161 TI - Assessing the health system's capacity to conduct neonatal resuscitation in Ethiopia. AB - BACKGROUND: Globally and nationally approximately a quarter of neonatal deaths and an unknown number of intrapartum stillbirths are attributed to intrapartum complications known as birth asphyxia. Simple stimulation and resuscitation can save many of these lives. OBJECTIVE: To describe the capacity of the Ethiopian health system to provide neonatal resuscitation with bag and musk. METHODS: Cross sectional data were collected from 741 health facilities and one birth attendant at each facility was interviewed. This paper focuses on 711 nurses and midwives. Based on a guided interview, responses were converted into a knowledge index and we used multivariable linear regression to identify factors that predicted a high score. RESULTS: Nine out of 10 hospitals, but only 40% of health centers, had performed neonatal resuscitation in the three months prior to the survey. Barriers to performing neonatal resuscitation included missing essential equipment and inadequately trained staff. Half of the midwives interviewed reported having performed neonatal resuscitation in the past three months compared to only 20% of the nurses. After controlling for provider and facility characteristics, key predictors of a high knowledge score among providers were recent performance of neonatal resuscitation and geographic region. Whether the provider was a nurse or a midwife, was not associated with a higher knowledge score. CONCLUSION: Educators and program managers should insist on practical pre service and in-service training, ensure the availability of equipment to perform neonatal resuscitation, and prioritize certain regions of the country for these interventions. PMID- 22519162 TI - Review of lumbar disc diseases at Tikur Anbessa Hospital. AB - BACKGROUND: Disc degeneration is common, the pattern and prevalence of various signs of disc degeneration is unclear. Neither hospital nor population-based data or study is available on lumbar disc diseases in Ethiopia. The sequelae of disk degeneration are among the leading causes of functional incapacity in both sexes and are a common source of chronic disability in the working years. Lumbar disc disease refers to a collection of degenerative disorders that can lead to low back pain as people age. OBJECTIVE: Review the pattern, clinical manifestation, diagnostic method and management decision of patients with degenerative lumbar disc disease at the neurosurgical referral clinic of Tikur Anbessa Hospital during the fiscal year 2009. PATIENTS AND METHODS: This is a hospital based cross sectional study of patterns of patients with lumbar disc diseases seen at the neurosurgical referral clinic, Tikur Anbessa Specialized Teaching Hospital (TASTH), Department of Surgery, Addis Ababa, Ethiopia in the period between January and December 2009 (12 months). Data taken while clerking patients and patents' medical record at referral clinic were main source of information. Standardized and structured questionnaire prepared for this purpose were used to analyze the sociodemographic, clinical manifestation, diagnostic modalities such as lumbar myelography, CT and MRI, patterns of disc disease in lumbar spine at NSRC with reference to age, severity and level distribution were reviewed. Difference in proportions were examined using Chi-square test. RESULTS: The study reviews 364 patients with lumbar disc diseases at the neurosurgical referral clinic, TASH over the one-year period (2009), their age ranged from 20 to 82 years (median, 44.0). Pain, numbness and neurologic claudication were the three most common presenting symptoms, occurring in 337(92.5%), 232 (63.7.6%) and 111 (30.5%) respectively. Lumbar MRI was the statistically significant investigation modality of choice (p < 0.0001). Two hundred thirty-five (70.1%) patients had disc prolaps (P < 0.0001), 18.5% had disc bulge. Lumbar degenerative disc disease was most frequently seen at L4-L5 level in 309 (54.5%) patients (P < 0.0001). both L4-L5 and L5-S1 accounted for 79.1% of the disc displacements. On MRI, disc displacements, were central in 61.2%, lateral in 9.3% and posterolateral in 15.8%. PMID- 22519163 TI - Degree of bacterial contamination and antibiotic susceptibility pattern of isolates from housekeeping surfaces in operating rooms and surgical wards at Jimma University Specialized Hospital, south west Ethiopia. AB - BACKGROUND: The role of the hospital environment as a reservoir of potential pathogens has received increasing attention. There are several reports demonstrating contamination of a wide variety of environmental sites in operating rooms (ORs) and surgical wards (SWs) which lead to nosocomial spread. OBJECTIVES: To determine the degree of bacterial contamination and antibiotic susceptibility pattern of isolates from floor and tabletop surfaces in ORs and SWs at Jimma University Specialized Hospital (JUSH). METHODS: A cross sectional study was conducted on 144 floor and tabletop surfaces from October to January 2009/2010. Samples were investigated for identification of bacterial species following standard procedures and antimicrobial susceptibility tests were performed using disc diffusion technique. The data was analyzed using SPSS version 16 and compared with the proposed standard value. RESULTS: The mean aerobic colony counts (ACCs) for tabletop surfaces (34 CFU/cm2) and floors (19CFU/cm2) in SWs were significantly higher than the set ACC standard for hand contact surfaces (< 5 CFU/cm2) P < 0.00. The ACCs obtained from tabletop surfaces (6.2 CFU/cm2) and floors (10.1CFU/cm2) in ORs were also exceeding the standard. Over 55% of gram negative bacteria were identified from Critical Zone of ORs. Staphylococcus aureus was the must frequently isolated bacterium accounting 33.3% followed by Escherichia coli and Klebsiella spp each with 11.1%. Moreover, S. aureus showed 100% resistance to methicillin and multidrug resistant Enterobacteriaceae were also seen in more than 90 % of isolates. CONCLUSIONS: An increased bacterial contamination was measured in both ORs and SWs of the JUSH and the isolated bacteria were also resistant for most of the antibiotics used as a treatment options in the study area. Therefore, appropriate infection control measures needs to be taken to keep the contamination level within the proposed standard. PMID- 22519164 TI - Changes in nutritional, functional and immunological status of HIV-infected adults with antiretroviral therapy. AB - BACKGROUND: Literature has shown that there is vicious cycle between malnutrition and HIV infection. In Ethiopia, antiretroviral therapy (ART) was started about eight years back but, to the best of authors' knowledge, there was no published study that assessed treatment outcome indicators. OBJECTIVE: To assess the outcomes of ART from the perspective of nutritional, clinical, functional and immunological status. METHODS: A retrospective recored review was used to assess the nutritional status of adults before and after ART in Hawassa University referral hospital. This analysis included 358 living HIV positive adults who were on ART for 3 - 96 months. RESULTS: The mean age of the study participants was 33.75 +/- 9.12 years and the median duration of ART was 24 months (Inter-quartile range: 12, 36). After ART, cases with body mass index (BMI) < 18.5 kg/m2 dropped from 38% to about 20% and cases with CD4 count < 200/mm3 dropped from about 73% to about 9% (P < 0.0001 for each). However, there were 58 and 14 cases whose BMI and CD4 count were even below the Pre-ART levels, respectively. The regression line demonstrating an overall change in CD4 count showed a positive linear trend as the duration of ART increases but the change in BMI was a downward linear trend. In multiple linear regression, current nutritional status was found to have significant association with baseline low CD4 count, clinical stage III/ IV, low BMI and low meal frequency. Multiple logistic regression also demonstrated a significant association of low BMI after ART with low CD4 count before ART. With ART, decreased frequency of illness, baseline WHO clinical stage I/II and high BMI were independent predictors of improvement in functional status. CONCLUSION: Patients started on ART with low BMI, severely immunosuppressed and clinical stage III/IV illnesses were found to have poorer nutritional, functional and immunological response. This study provided another evidence to support the WHO recommendation on initiating ART before patients' nutritional, clinical and immunological statuses deteriorate. The nutritional care needs to be given more emphasis since the ART response was found to be unsatisfactory. PMID- 22519165 TI - Breast carcinoma in a 7-years- old girl. AB - This is a case report of a 7 years old female patient diagnosed to have secretory carcinoma of the breast and secondary axillary lymph nodes metastasis after she presented with compliant of left breast swelling that lasted for about 6 months. It is a rare (< 1%) type of breast carcinoma with distinct histologic features. Diagnosis of this carcinoma at fine needle aspiration cytology (FNAC) is quite difficult and it is not a particularly aggressive tumor with excellent prognosis even in the presence of metastasis. Axillary locoregional lymph node metastases are uncommon. Several authors, therefore, recommend a conservative and non aggressive treatment as much as possible. In her case, modified radical mastectomy with level II axillary dissection was done without hormonal or chemotherapy. So far, the therapeutic approach tends to be fairly flexible. PMID- 22519166 TI - Ruptured splenic artery aneurysm as a rare cause of acute abdomen; a case report done at Tikur Anbessa Specialized Hospital, Addis Ababa. AB - Splenic artery aneurysm is a rare phenomenon although it is the second most common visceral artery aneurysm. Usually it occurs in adults with an increase in incidence as age increases and the diagnosis is made incidentally during work-up of patients for other clinical conditions. When it ruptures life threatening hemorrhage occurs and patients usually die if the correct diagnosis is not made timely. Here we present a ruptured splenic artery aneurysm which was misdiagnosed as a hemorrhagic pancreatitis and finally the diagnosis was made on post contrast computed tomography scan. Physicians must include ruptured splenic artery aneurysm as one of the differential diagnosis of acute abdomen particularly in patients who are in shock state and anemic. PMID- 22519167 TI - Child healthcare in the United Kingdom and Nigeria. AB - Child healthcare differs widely from one country to another. The differences vary even more widely between developed and developing countries. The Nigerian and British child healthcare system share some similarities, but are significantly different in many areas. The structure of the healthcare system is quite similar and in the area of immunisation, the government of the two countries give childhood immunisation programme a priority. However, differences exist in areas of accessibility to child healthcare, parental attitude towards immunisation and efficiency of the child healthcare system. The aim of this paper is, to share with the medical community, the similarities and differences in child healthcare between the two countries. This would be of interest to colleagues who have not worked in both systems. PMID- 22519168 TI - [Preliminary analysis on respiratory syncytial virus identified in children with acute respiratory infections in Tibet Autonomous Region, China]. AB - To understand the role of respiratory syncytial virus (RSV) in children with acute respiratory infections (ARI) in Tibet Autonomous Region and the contribution of two major groups of RSV, nasopharyngeal aspirates (NPA) were collected from hospitalized children with ARI in Department of Pediatrics, Tibet People's Hospital in Lasa, Tibet from April to July in 2011 and tested for seven common respiratory viruses and human metapneumovirus (hMPV) by direct immunofluorescence assay (DFA). Total RNAs were extracted from RSV positive samples by DFA and reverse transcripted to cDNA. Nested-PCR was employed to determine the genogroups of RSV, which were confirmed by real time-PCR and sequence analysis for G protein encoding gene. The Characteristics and variations of G genes from RSV in this project were identified by sequence comparison with those G genes in GenBank. Out of 167 samples, 65 were positive for respiratory viruses with a total positive rate of 38.9%, including 45 (69.2%, 45/65)positive samples for RSV. Among 42 samples that were positive for RSV and genotyped, 40 were identified as group A and 2 as group B. Sequence analysis of full-length G genes for 7 RSV of group A indicated that all of these belonged to subgroup GA2. The nucleotide identities between RSVs from Tibet and prototype A2 strain were 90.7%-91.8%, with 86.5%-87.2% identities of amino acid. The mutations of amino acids were mainly located in both ends of a highly conserved region in the ectodomain of the G proteins. The data indicated that RSV was the most important viral etiologic agent of ARI in spring of 2011 in Tibet and group A of RSV was predominant during the study period. High divergence existed in the ectodomain of G proteins of RSVs from Tibet. PMID- 22519169 TI - [Study of the susceptibility of mice to Sendai strain Tianjin]. AB - To explore the infectivity characteristics and susceptibility of Sendai strain Tianjin in 129Sv, DBA/2, Kunming and BALB/c mice and determine the optimal small rodent animal model for strain Tianjin research, the Sendai strain Tianjin was propagated for 72h in 9-11 day-old chicken embryos, the allantoic fluids were then harvested and the virus titer (1:1280) was detected by hemagglutination assay. Four different kinds of mice were intranasally inoculated with 5 microl and the diluted 30 microl virus solution. The weight loss of mice was monitored for 12 consecutive days and the survival rate was observed. Kunming and BALB/c mice were sacrificed on the first day prior to infection and on the fourth and seventh days post infection of the diluted 30 microl Sendai strain Tianjin. Their left lobes of lung were fixed with 4% formalin for histopathologic examination. The maximum percentage of average weight loss of 129Sv, DBA/2 were 13.0%, 4.7% with 100% survival rate when 129Sv, DBA/2, Kunming and BALB/c were inoculated with 5 microl virus solution, while the mice were inoculated with diluted 30 microl virus solution, the maximum percentage of average weight loss reached 21.7%, 30.3%, 16.7% and 9.7% with the survival rate of 20%, 0%, 80% and 100%. Lung infections of mice Kunming on the fourth and seventh day post infection were more severe than that of BALB/c, showing a large number of inflammatory cell exudation and thickening of the submucosa. It suggested that DBA/2 was the most susceptible to the infection of strain Tianjin. The mice susceptibility ranked as DBA/2>129Sv>Kunming>BALB/c. Mice DBA/2 and 129Sv could be used as the optimal small rodent animal models in the research of pathogenicity and vaccine of Sendai strain Tianjin. PMID- 22519170 TI - [Complete genome sequence characteristics of human enterovirus 71 strain isolated in Yunnan, China]. AB - The complete nucleotide sequence of two human enterovirus 71 strains (KMM09 and KM186-09) isolated in Yunnan,China, were determined by RT-PCR and sequencing. As with other human enteroviruses, the genomes were 7 409 nucleotides (nts) in length and encoded 2 193 aa. Phylogenetic analysis based on VP1 regions revealed that the two isolates belonged to subgenotype C4a. In structural genomic regions, subgenotype C4 was most homologous to other strains of C genotype when compared to other genotypes. In non-structural genomic regions, subgenotype C4 was more homologous to CA16/G10 and other strains of B genotype than to other strains of C genotype. RDP3 and Blast analysis displayed evidence of recombination in non structural genomic regions between subgenotype B3 and C4, C4 and CA16/G10. The full-length genome of the human enterovirus 71 strains provided an overview of the diversity of genetic characteristics of a circulatinghuman enterovirus 71. PMID- 22519171 TI - [Molecular epidemiological analysis of species B enteroviruses isolated from Henan Province of China during the six months in 2010]. AB - This report presents an overview of human enterovirus B species in Henan Province. A total of 14 isolates of HEV-B species isolated under HFMD surveillance network during the six months in 2010 were examined. Based on molecular typing results targeting VP1 region, 14 isolates were classified into 6 serotypes of HEV-B. Furthermore, comparison of these 14 isolates with reference strains and strains in mainland China was conducted. The phylogenetic analysis revealed that E25, E11 and E6 showed homology with those from Shandong Province which adjoins Henan Province. E1 and E13 showed homology with those from Yunnan Province, and E30 showed homology with Henan strain isolated in 2008. Cocirculation of two lineages of echovirus 6 was observed. PMID- 22519172 TI - [Genomic characteristics of coxsakievirus A16 isolated in Henan Province]. AB - To reveal the genomic sequence characteristics of coxsackievirus A16 (CoxA16) strain isolated from patients with hand-foot-mouth disease (HFMD) in Henan province. A total of 406 samples were detected by reverse-transcription polymerase chain reaction (RT-PCR) and cell-culture-based isolation of coxsackievirus A16. The whole genome of CoxA16 isolate was amplified using 10 pairs of primers, the sequences were analyzed and phylogenetic tree was generated by bioinformatics software. The full length of HN1162/HN/CHN/2010 genome was 7411bp. Compared with the other CoxA16 strains released in GenBank, the nucleotide similarities were 87.0-97.9%, 77.0%-95.4%, 80.3%-96.9%, 77.9% 96.2%, 80.5-100% in 5'UTR, P1, P2, P3, 3'UTR region, respectively; The similarities of nucleotide and amino acid sequences in VP1 region were 91.4%-96.4% and 99.3% 99.7%, respectively. Phylogenetic tree analysis showed that CoxA16 strains isolated from Henan, Shenzhen, Guangzhou and Fujian belonged to the same cluster. The newly isolated CoxA16 from Henan province belonged to subgenotype C2/B-2. These results will have great significance in monitoring CoxA16 and for prevention and control of hand-foot-mouth disease. PMID- 22519173 TI - [Molecular epidemiological analysis of rubella virus isolates from 2001 to 2011 in Shanghai, China]. AB - Throat swabs collected from patients whose serum was measles IgM negative and rubella IgM positive during 2001-2011 were used to conduct cell culture for rubella virus. After identification of cell culture with RT-PCR, nucleotide of gene E1 of rubella virus was amplified and sequenced, followed by molecular epidemiological analysis. A total of 31 rubella viruses were isolated from 60 throat swabs. Compared 27 isolates with the WHO reference strains of all genotypes, phylogenetic tree was constructed based on the amplified 739 nucleotide fragment. These isolates belonged to two different genotypes respectively. Isolates 11009, 11052 and 11106 in 2011 belonged to genotype 2B, and others belonged to genotype 1E. Most of mutations were nonsense mutation, and sequence of amino acid was highly conserved. Amino acid sequence of most isolates of genotype 1E was identical, which suggested rubella viruses from same transmission chain might be transmitted continually since 2001. Rubella virus genotype 2B was found to be popular for the first time in Shanghai in 2011. The nucleotide sequences of these genotype 2B isolates showed 99% identity compared with that of isolates recently from Vietnam, Japan and Argentina. The resources of these strains were not confirmed due to the absence of rubella virus surveillance before. PMID- 22519174 TI - [Analysis of genetic characteristics of type II non-wild poliovirus in mainland China, 2010]. AB - To study the genetic characteristics of 123 type II non-wild polioviruses isolated from acute flaccid paralysis (AFP) cases in mainland China in 2010, provide the scientific basis for maintaining the "polio-free" status, and the switching use of polio vaccine for China. VP1 gene was amplified by reverse transcription-polymerase chain reaction (RT-PCR) and the PCR products were then sequenced. The sequence results were analyzed with Sequencher 4.8, BioEdit 7.0.9 and MEGA 5.0. Of 65 strains, nt2909 was found to be a mutation hotspot, and also a neurovirulence determinant in VP1 region. During 2010, two vaccine-derived polioviruses (VDPVs) were isolated from Yunnan province, China and no wild poliovirus (WPV) was isolated. The epidemiological studies and laboratory results of the two VDPVs showed that they were newly discovered VDPVs because of the genetic difference from other VDPVs strains isolated in the world, implying the sensitive poliovirus surveillance network could timely detect the transmission of VDPVs and the importation of WPV. PMID- 22519175 TI - [Genetic variation and pathogenicity analysis of highly pathogenic porcine reproductive and respiratory syndrome virus strain TJ in the course of attenuation]. AB - To develop an attenuated vaccine against the highly pathogenic porcine reproductive and respiratory syndrome (HP-PRRS) virus, the HP-PRRS virus strain TJ was attenuated by serial passages and plaque cloned every 5 to 10 passages in Marc-145 cells. Genetic variation and pathogenicity of HP-PRRSV strain TJ in the course of attenuation were analyzed. The results showed that the strain TJ sustained various sequence changes during the course of attenuation. Fifty-eight amino acids changes and a new continuous 120 amino acids deletion after the discontinuous 30 amino acids deletion (sites 481 and 533-561) occurred in strain TJ passages 140, and the position of 120 amino acids deletion was between 628 to 747 according to VR-2332. Animal test showed that the pathogenicity of strain TJ passages 20 was attenuated obviously, so we presume that genetic variation in nonstructural protein nsp2-nsp5, nsp7 and structural protein GP5 during the attenuation provides the molecular bases for the observed attenuated phenotype. PMID- 22519176 TI - [Biological characteristics of three Newcastle disease virus isolates and entire genome sequences analysis]. AB - Three Newcastle disease virus (NDV) strains recovered from ND outbreaks in chickens and duck flocks in north china during 2009 to 2011 were completely sequenced and biologically characterized. All the strains were velogenic and had the velogenic motif 112R-R-Q-K-R-F117 which was consistent with the results of biological tests. Analysis of the variable region (nucleotide 47 to 420) of the F gene indicated that the three isolates belonged to genotype VII d. Cross hemagglutination inhibition test indicated that the antigen homology between three isolates and LaSota were 82.5%-89.4%, the homology between the two isolates from chicken was 90%. A cross-protection experiment in which specific-pathogen free chickens vaccinated with LaSota were challenged by SDLY01 isolate showed that LaSota vaccine could provide complete protection against SDLY01, however virus discharge could be detected on fifth day. Challenge experiment in which Cherry Valley duck of 30 day old challenged with SD03 strain indicated that cherry valley duck had no disease in experiment period, but virus discharge could be detected from Larynx and cloaca until fifth day. Genome length of three NDV isolates was 15192bp and belonged to genotype VII d. Sequence analysis clarified that the whole genomic sequence of these three isolates shared high homology with NDV virus strains isolated from goose and duck over the same period, which elucidated that NDV isolated from goose, duck or chicken had close genetics and epidemiological relationship. PMID- 22519177 TI - [Development and identification of polyclonal antibodies against HIV-1 Vpr derived polypeptides]. AB - To develop polyclonal antibodies against predicted B cell epitopes in HIV-1 accessory protein Vpr, the prepared consensus Vpr amino acid sequence was used to predict potential B cell epitopes by online softwares (ABCpred and Bcepred), the synthesized polypeptides of B-cell epitopes were subsequently conjugated with keyhole limpet hemocyanin (KLH) and then used to immunize rabbits. The antibody titers were determined by ELISA, and antibody specifity was analyzed by Western Blotting and immunoprecipitation, respectively. Amino acid residues 3-19 (N) and 82-95 (C) of Vpr were predicted as the potential B cell epitopes. After inoculation of the conjugation of synthesized peptide to KLH, the antibody titers in rabbit sera against N and C peptides reached more than 1:100000 by ELISA. Western-Blotting analysis showed that the polyclonal antibodies reacted with both wild Vpr and fusion protein of GFP with Vpr, no matter Vpr was derived from HIV-1 B subtype or CRF07_BC recombinant form; Immunoprecipitation analysis showed similar reactions to Western-Blotting results. Two B cell epitopes of Vpr were successfully predicted by Bio-informatics methods and polyclonal antibodies against those peptides could be successfully prepared. PMID- 22519178 TI - [Sequence comparison of the hemagglutinin gene of the duck-origin H9N2 subtype avian influenza viruses]. AB - To demonstrate the phylogenetic evolution, the molecular characteristics of the motif of HA protein cleavage site and the varieties at the receptor binding sites of the hemagglutinin gene of the duck-origin H9N2 subtype avian influenza viruses, sequence alignment and phylogenetic analysis were performed by MEGA 4.1 Neighbor-Joining method.. The results revealed that the duck-origin H9N2 AIV viruses originated from CK/BJ/1/94-like and North-Ame-like, all the duck-origin H9N2 AIV viruses from mainland China belonged to CK/BJ/1/94-like and formed multiple genotypes through complicated re-assortment, while other duck-origin H9N2 AIV, isolated from other countries in Aisa, American and European such as Korea, Japan, Alberta, Austria, Switzerland, Iran, belonged to the North-Ame-like phylogenetic lineage. The amino acids at positions 183, 190, and 226 of the receptor binding sites of North-Ame-like group isolates had highly conserved H, E and Q respectively. In contrast with duck-origin H9N2 AIV viruses isolates from mainland China, the amino acids had N at positions 183, A, T, or V at 190, L or Q at 226, which was the same as the chicken-origin H9N2 AIV from mainland China. Most newly isolated chicken-origin H9N2 AIV in Fujian Province in Southern China had L at position 226 emphasized the higher risk of cross-infection between the chicken-origin and duck-origin H9N2 AIV in China. PMID- 22519179 TI - [Colorimetric detection of norovirus genotype GII by reverse transcription loop mediated isothermal amplification]. AB - A simple, rapid and sensitive colorimetric reverse transcription loop-mediated isothermal amplification (RT-LAMP) method was established to detect norovirus genotype GII. The method employed a set of six specially designed primers that recognized eight distinct sequences of RNA-dependant RNA polymerase and capsid protein gene for amplification of nucleic acid under isothermal conditions at 65 degrees C for 60 minutes. The amplification process of RT-LAMP was monitored by the addition of HNB (Hydroxy naphthol blue) dye prior to amplification. A positive reaction was indicated by a color change from violet to sky blue and confirmed by agarose electrophoresis. The specificity of the RT-LAMP was validated by detecting several different diarrhea viruses including norovirus genotype GII. The sensitivity was determined by serial dilutions of RNA molecules from in vitro transcription of norovirus genotype GII in parallel with conventional RT-PCR detection. The assay was further evaluated with 93 clinical specimens of diarrhea patients. The results showed that the sensitivity of RT LAMP was 1 000 copies/microL with a high specificity and the relative sensitivity was at the same level as that of conventional RT-PCR. Positive rate of RT-LAMP in analysis of clinical specimens was approximately the same as that of conventional RT-PCR as well. This colorimetric RT-LAMP assay was potential for rapid detection of norovirus genotype GII on spot due to the observation of visual result with high specificity and sensitivity, time-saving and cost benefit. PMID- 22519180 TI - [Localization of AcMNPV NLA genes in Sf9 cells]. AB - Nuclear actin which plays a key role in many nucleic processes has become a research hotspot. Baculovirus is the only reported pathogen using nuclear actin to replicate and proliferate. However, little is known about the mechanism of monomeric G-actin accumulation within nuclei of baculovirus-infected cells. It has been reported that AcMNPV ie-1, pe38, ac4, he65, ac102, and ac152 could be required for mediating nuclear localization of G-actin from transiently transfected results in TN-368 cells. In this paper, we found that IE1, AC152, PE38, AC102 localized in the whole cell and PE38, AC102 localized in the nuclear mainly, while both AC4 and HE65 localized in cytoplasm and could be mediated into the nucleus by AC102 and IE1 respectively for the first time. And ie-1 or pe38, ac4, he65 could mediate nuclear G-actin to accumulate partly, while these four genes were sufficient for recruiting G-actin accumulation within the nucleus when driven by promoter OpIE2. Determining the functions of each of these AcMNPV NLA gene products will advance our understanding of baculovirus biology and function of nuclear actin. PMID- 22519181 TI - [Cloning and expression of gp37 gene of avian leukosis virus subgroup J]. AB - The transmembrane protein (TM) encoded by gp37 gene plays a critical role when virus fusion with cell membrane occurs. Several highly conserved regions in TM are important targets for antivirus studies. Studies on structure and function of TM will provide basic information for anti-retrovirus, especially for avian leukosis virus. In the study, gp37 gene was amplified by PCR from the Chinese strain ALV-J-WS0701. The gp37 gene was cloned into pMD18-T vector, and was sequenced. Then, pFast-BacHTb-gp37 vector was constructed and expressed by baculovirus expression vector system. The expression product of gp37 gene was analyzed by indirect immunofluorescence assay and Western blot. The results showed that positive green fluorescence was present in sf9 cells infected with recombinant virus and a protein band with a molecular weight of 21kD was present in Western blot. It is concluded that gp37 gene was expressed in sf9 cells infected with recombinant virus successfully. PMID- 22519182 TI - [Roles of COPI related proteins during virus replication]. AB - COPI is a protein complex that transports vesicles from the Golgi complex back to endoplasmic reticulum. Many viruses such as RNA viruses, DNA viruses and retroviruses, hijack or adapt COPI related proteins including coatomer, ARF1 and GBF1 for their own benefits. Here, we summarize the current progress of the roles of COPI related proteins in virus replication. PMID- 22519183 TI - [Research advances in porcine bocavirus]. AB - Porcine bocavirus (PBoV) was considered as a new member of the genus Bocavirus of the subfamily Parvovirinae of the family Parvoviridae, which was discovered in Swedish swine herds with postweaning multisystemic wasting syndrome (PMWS) in 2009. At present, as an emerging pathogen, it was paid great attention by researchers at home and abroad. This paper referred to some published literatures and reviewed several aspects of PBoV including its finding, classification, genome structure and replication, epidemiology, associativity with diseases, cultural and diagnostic methods. PMID- 22519184 TI - Hysterectomy throughout history. AB - Hysterectomy, which is one of the most common surgeries performed on women, dates back to ancient times. The history of hysterectomy comprises biographies of many humble men and the significant individual efforts that they made to fight the skepticism of the medical communities of their times. Many of the pioneers were ignored. Although there are a number of alternatives to hysterectomy available, it remains one of the most frequently performed gynaecological operations. The introduction of antisepsis, anaesthesia, antibiotics and blood transfusion made hysterectomy a safe procedure. Nowadays, we distinguish three different surgical approaches to hysterectomy: vaginal, abdominal and laparoscopic. The limitations of conventional laparoscopy have led to the development of robotic surgery, which has evolved over the past decade from simple adjustable arms to support cameras in laparoscopic surgery to more sophisticated four-armed machines now being in use worldwide. PMID- 22519185 TI - [Pax-2 antigen expression in kidney tumours]. AB - Pax-2 transcriptional factor is expressed during kidney development and could re express in renal tumors. The aim of this study was to examine Pax-2 expression in different types of renal cell carcinoma (RCC) in order to see whether it is good immunohistochemical marker. METHOD: We analyzed 48 different renal tumours stained with Pax-2 antibody. Pax-2 positive reaction was noticed in nucleus or cytoplasm. Expression of this antigen in tumours tissue was correlated with tumour stage and nuc-lear grade. Pax-2 expression between different histological RCC types was analyzed by chi2 test and Fishers test for two in-depended samples. RESULTS: Pax-2 is expressed by a high percentage of re-nal tumors regardless of histologic type. Significant diffe-rence of Pax-2 expression between oncocytomas and chromofobe RCC was found. CONCLUSION: Nuclear expression of Pax-2 is useful diagnostic kidney tumour marker. Pax-2 showed stronger expression in lower malignancy kidney tumours and in oncocytomas, than in high grade RCC like in those with sarcomatoid differentiation PMID- 22519186 TI - The role of organ preservation in the surgical therapy of traumatic spleen injury. AB - BACKGROUND: New findings on immunological und haematological functions of the spleen, the postoperative risks following splenectomy, as well as improved surgical techniques resulted in an increased interest in organ preservative surgery after traumatic spleen injury in recent years. MATERIAL AND METHODS: The data of all patients who underwent surgery for traumatic spleen injuries between 1995-2009 were recorded prospectively and analysed concerning type of operation, intra-and postoperative complications and the postoperative course. RESULTS: A total of 214 patients with splenic trauma underwent surgery. The spleen could be preserved in 80 patients (37.4%, group 1), using thermocoagulation, suture, glue sealant, splenorhaphy and partial spleen resection or combined techniques. 4 of those patients (5%) required a revision operation, in which two spleens could be salvaged by application of glue sealant. Eight of the patients of group 1 could be treated laparoscopically (10%). CONCLUSION: Under consideration of the surgical segment anatomy of the spleen and the surgical techniques presented, organ preservation is possible with high success rates, even in patients with severe splenic damage. In stable patients with minor splenic injury, laparoscopic or conservative treatment can be considered. Splenectomy should be reserved for patients with complete shattering of the spleen or instable patients. PMID- 22519187 TI - Minimally invasive esophagectomy in the treatment of esophageal cancer. AB - In the Western countries, the incidence of esophaeal carcinoma is 3-6 cases per 100,000 persons. g Despite tremendous success of other therapeutic options, surgical treatment still represents the best therapeutic option whenever possible. For the long period, debate has centered on which of the a vailable surgical procedures is superior-transhiatal or transthoracic esophagectomy. Minimally invasive esophagectomy (MIE) could offer both minimally invasive approach and proper mediastinal lymph node dissection. Minimally invasive esophagectomy is safe and adequate, but time consuming and technically demanding procedure. It is procedure reserved for the surgeons experienced in open esophagectomy for cancer, and specially trained in advanced minimally invasive procedures. Even in that case, learning curve is steep. PMID- 22519188 TI - Ultrasound diagnosis of gallbladder polyps. AB - The most frequent benign gallbladder polyps are cholesterol polyps. Next in frequency were adenomas, which may have malignant potential. The aim of this study was to assess the possibility of ultrasonography in the diagnosis and differential diagnosis of cholesterol polyps compared to adenomas. Patients were examined during the period from October 2006. to December 2008. In Department of Ultrasound, Clinic for Gastroenterology and Hepatology, Belgrade. The group of 54 patients analyzed consisted of 30 women (56%) and 24 men (44%). Most (59%) had solitary polyps. In 92.6% of patients the size of polyps was below 10 mm. 74% of respondents were over 50 years. Ultrasonography is the method of choice and gold standard in diagnosis of gallbladder polyps. Based on echoic properties cholesterol polyps can not be distinguished from adenomas. Malignant alteration of polyps also could not be detected. Appropriate ultrasonographic characteristics such as size of polyps, appearance of a broad base that sits on the wall, concomitant lithiasis findings and patient age may be indicative for malignancy. PMID- 22519189 TI - Minimally invasive surgery in the treatment of gastric cancer. AB - Unlike benign pathology, progress of laparoscopy in performing cancer surgery has been slow because of fear of safety and oncological adequacy. However, the initial fear has been replaced by optimism as the results from a numerous studies have shown equivalent if not superior results to open surgery. Laparoscopic gastrectomy is safe and oncologic adequate, but time consuming and technically demanding procedure. Laparoscopic surgery has gained wide acceptance in the treatment of early gastric cancer, especially of the distal stomach. The use of laparoscopic surgery for the treatment of advanced gastric cancer remains controversial. Another open question that need complete evaluation is cost effectiveness analysis of minimally invasive and open approach. PMID- 22519190 TI - Dietary habits as a risk factor of gallstone disease in Serbia. AB - Gallstone formation is a multifactorial disease, caused by the interaction of genetic and enviromental factors. In order to prevent gallbladder stone disease, it is useful to detect modifable risk factors, which contribute to its development. The aim of this study is to analyze the potential relationship between nutrition and the development of gallstone disease, and to establish the possibility for its prevention. The study examined 114 patients; 55 of them suffered from gallstone disease, while 59 were healthy controls who were age- and sex- matched. Diagnosis of gallbladder stone disease was made by ultrasonography. Diet was established using a 24-hour dietary recall method. In the multivariate model, high energy intake (OR = 9.720, p < 0.001) and overnight fasting period (12 hours and longer) (OR = 4.285, p = 0.005) were the most important predictors of gallstone disease, after adjustment for Body Mass Index. These factors can be altered in order to prevent gallstone disease. PMID- 22519191 TI - Shoulder hemiarthroplasty rehabilitation with fractures. AB - Fractures of the upper end of the humerus are relatively common. They are predominant in the female population (85%), age over 50 years, where the force that leads to fractures in 90% of cases is moderate. Multifragmentary (three-part and four-part) fracture of the upper end of humerus, treated nonoperatively, often leaves behind a significant disability. MATERIALS AND METHODS: Between October 2003-2010, the rehabilitation of 34 patients with shoulder hemiarthroplasty was carried out. RESULTS: The achieved results are accompanied by a precise evaluation of Constant-score, after sixth month of operation. By scoring system, it estimates the pain, the mobility of the shoulder joint, the functional evaluation of the hand and grip strength. In 25 patients (73.5%) the Constant-score was >90 points. In 7 patients (20.6%) was 80-89, and in 2 patients (5.9%) the value of Constsant-score was < 60 points. CONCLUSION: The maximum possible restitution of shoulder function in patients with shoulder hemiarthroplasty is-provided by: well conducted operation--early started, adequate kinesiotherapeutic protocol, implemented long enough--a good motivation of patients for the treatment. PMID- 22519192 TI - Frequency and clinical caracteristics of colorectal adenoma and carcinoma in women. AB - INTRODUCTION: Available literature states that the incidence of colorectal adenomas and cancer is more common in men, however, lately has been observed increasing number of patients among women. AIM: to analyze the frequency and clinical characteristics of colorectal adenomas and cancer in women. MATERIALS AND METHODS: We performed a retrospective study in which data of 695 patients with colorectal adenomas and carcinomas have been analyzed from a total of 10,659 patients who underwent colonoscopy. RESULTS: Colonoscopy and colorectal neoplasms were more frequently diagnosed in man (71.88%/67.4%) than women (28.12%/32.65%), so the results must be interpreted with caution. CONCLUSION: The increase in the number of women who suffer from colorectal adenoma and carcinoma can be explained by balancing lifestyle and increasing the number of women who are examined, given up the initial resistance that women had to colonoscopy, which is a potentially painful and embarrassing. PMID- 22519193 TI - [Karakteristike pacijenata sa implantiranom totalnom protezom zgloba kuka i kolena]. AB - Osteoarthrosis is the most frequent joint disorder in the world. An increased incidence of total hip replacement (THR) and total knee replacement (TKR) has been noticed recently. AIM: To investigate demographic characteristics, comorbidities, surgical factors and postoperative complications of patients who received THR or TKR. MATERIAL AND METHOD: Patients aged at least 30 years hospitalized at the Clinics for Orthopaedic Surgery and Traumatology, Clinical Centre of Serbia, for THR or TKR between January 1, 2008 and January 1, 2010. were included in a retrospective cohort study. RESULTS: Out of 529 investigated patients, 421 (79.6%) were in the THR group, and 108 were in the TKR group. Patients in the TKR group were 68.7+7.8 year old in average and were significantly older than patients in the THR group (p<0.01). There were more women than men in both gro-ups, but no statistical significance was observed. Hyperte-nsion, which was the most frequent comorbidity, was noticed in 96 (18.1%) patients. 40% of patients were of poor physical condition (ASA 3 and more) approximately. Re-gional anaesthesia was performed more frequently in the TKR group than in the THR group (p < 0.01). The operations of knee replacement surgery lasted longer than hip replacement surgery (139.9 +/- 30.1 min; p < 0.01O). All patients received thromboprophylactic drugs. Five patients (0.9%) who were in the THR group had prosthesis dislocation as one of the observed postoperative complication. The mean duration of hospitalization of patients in the TKR group was 29.7+24.7 days which was longer than in the THR group (p < 0.01). CONCLUSION: Older population, especially women were operated on more frequently in the both groups. Regional anaesthesia was performed more frequently in the TKR group. Although a large percentage of patients had cardiovascular disorders and were of poor physical condition, postoperative complications were rare. PMID- 22519194 TI - [Surgical approach to parapharyngeal space tumors]. AB - INTRODUCTION: Parapharyngeal space tumors are very rare comprising 0.5% of head and neck tumors. Tumors of this symptomatology as well as considerable surgical issue owing to inaccessibility. PATIENTS AND METHODS: Retrospective twenty-year study of patients with parapharyngeal space tumors included 69 patients. Data were obtained from medical records, and were pointed to diagnostic procedures, surgical approach and pathohistological findings. Symptoms and clinical signs were also investigated. RESULTS: Preoperative diagnostics is very important for precise tumor localization and relation to adjacent structures. Computerized tomography was the most common method used, and recently, magnetic resonance imaging and indication-based contrast angiography have been applied. All of 69 patients with parapharyngeal space tumors were treated surgically. The most often approach to this tumor was transcervical (62%), then transoral approach and combination transcervical transoral approach. Pathohistological examination verified that most of the tumors were benign (75%) and origin of these tumors was most frequently salivary (42%). CONCLUSION: For making a decision on surgical approach, diagnostic methods, other than thorough examination, such as computerized tomography (CT) and/or magnetic resonance imaging (MR), are necessary to be applied. PMID- 22519195 TI - Preliminary experience with 18f-fluoro-deoxy-glucose positron emission tomography/computed tomography in pediatric oncology patients. AB - The aim of this study was to present preliminary experience with FDG PET/CT in pediatric oncology patients in National PET Center, Clinical Center of Serbia and to asses its impact on management of malignancies in children. 33 FDG PET/CT scans were performed on 30 pediatric patients. PET/CT imaging was performed for staging the disease, assessing therapy efficacy and diagnosing recurrent or metastatic disease. FDG PET/CT changed the stage of the disease in 60.6% (20/33) of the cases. 14 patients were down-staged after PET/CT, mostly patients with Hodgkin's disease, were in 7/10 cases PET/CT showed no activity in residual masses. Six scans led to upstage of the disease. In three cases PET/CT did not change the stage of disease, but has showed new distant metastases. In conclusion, FDG PET/CT showed important role in managing pediatric patients with different malignancies and was useful complementary diagnostic tool to conventional imaging methods. PMID- 22519196 TI - [Surgical treatment of the aseptic femoral shaft nonunion]. AB - Femoral shaft nonunions is difficult complication and a big challenge for the orthopaedic surgeons. These complications occur after open femoral fractures, comminuted fractures, segmental fractures, the infection, after the inadequate fixed osteosynthesis, the systemic disease, and smokers. The paper presents the results of treatment aseptic femoral shaft nonunion in 18 patients. They were primarily operated by the method of internal compresive plate fixation and external fixation (open fractures). For fixation we used dinamic internal fixator by Mitkovic. All nonunions treated by this method are healed. In patients with atrophic femoral shaft nonunions in addition to fixation was performed and bone grafting. This implant has proved successful in the treatment of femoral shaft nonunion. During the fixation no periostal and intramedullary vascularization damage, which is an important prerequisite for bone healing. Implant enables biological and mechanical conditions for nonunion healing. PMID- 22519198 TI - [The effect of patient age, the presence of infection and neoplastic disease on the occurrence of dehiscence laparotomy]. AB - BACKGROUND/AIM: Dehiscence after laparotomy is one of the major complications of laparotomy. Laparotomy is a partial or complete wound with disruption and evisceratio abdominal organs and require urgent reintervention. The aim of this study was to determine the impact of age, infection and neoplastic disease on the occurrence of dehiscence laparotomy. METHODS: A retrospective-prospective study were included 826 patients operated at the Clinic for General Surgery in Nis in the period from January 2008 to December 2009. The effect of patient age, the presence of infection and neoplastic disease on the occurrence of dehiscence laparotomy. Results are displayed numerically and in percentages. RESULTS: Of the total 32 patients with dehiscence laparotomy, 20 patients were male or 62.5% and 12 female patients, or 37.5%. Patients with dehiscence laparotomy were significantly younger than patients without dehiscence laparotomy (T-test t = 3.237, p < 0.05). The average age of respondents with dehiscence was 57.93 years, while patients without dehiscence 63.97 years. There is a statistically highly significant correlation between laparotomy dehiscence and infection (chi2 = 62.024, p < 0.01). There was a statistically significant association between dehiscence laparotomy and neoplastic diseases (chi2 = 42.196; p < 0.01). CONCLUSION: With respect to age, dehiscence laparotomy is significantly more common in younger patients. Infection was significantly more frequent in patients with dehiscence laparotomy. Inpatients with neoplastic diseases dehiscence laparotomy is common. PMID- 22519197 TI - Acinetobacter spp. colonization and infection risk factors in surgical patients. AB - INTRODUCTION: The results of numerous studies carried out over the last two decades have increasingly important cause of intrahospital infections (IHI). The aim of the study was to determine potential differences in distribution of individual risk factors between the group of patients in whom multiresistant Acinetobacter spp. was isolated and the group of patients in whom it was not. MATERIAL AND METHODS: A prospective cohort study of 64 patients hospitalized with recorded IHI at the University Hospital for Digestive Surgery, Clinical Center of Serbia in the period between January and July 2011. The subjects were divided into two groups: patients with IHI in whom multiresistant Acinetobacter spp. was isolated from the biological material samples, and those with IHI without the presence of Acinetobacter spp. RESULTS: Univariate data analysis indicated presence of statistically significant difference in distribution of certain types of surgeries (esophageal, pancreatic and hepatobiliary) among the two groups of subjects, distribution of CVC placement, application of mechanical ventilation and nasogastric tube placement, length of stay in ICU, lethal outcomes and administration of third generation cephalosporins. The results of multivariate analysis indicated that length of hospitalization in ICU (> 7 days), CVC, mechanical ventilation, esophageal, pancreatic and hepatobiliary surgeries as well as administration of third generation cephalosporins are independent risk factors for colonization and infection of patients with Acinetobacter spp. CONCLUSION: Colonized or infected patients with Acinetobacter spp. play a major role in contamination of hands of the medical staff in the course of care and treatment, while inadequate hand hygiene of the staff leads to cross transmission of the causative organism to infection-free patients. Selective antibiotic pressure, particularly administration of quinolones and broad-spectrum cephalosporins, favor onset of multiresistant species of Acinetobacter spp., and therefore appropriate prophylaxis and treatment represent basic preventive measures against the onset and spreading of the causative organisms. PMID- 22519199 TI - Heparin-induced thrombocytopenia with iliacofemoropopliteal thrombosis in a patient operated for colorectal carcinoma liver metastases. AB - We report a case of heparin-induced thrombocytopenia thrombosis (HITT) syndrome in a patient prophylactically treated with low molecular weight heparin. A 66 year-old men underwent radiofrequency-assisted partial liver resection for colorectal carcinoma liver metastases a year-and-a-half after he had been operated for rectal cancer. In the postoperative period, patient was prophilactically treated with reviparin sodium. On the 8th postoperative day, the platelet count decreased by more than 50% without clinical signs of thrombosis. HITT syndrome was suspected on the 19th postoperative day, after iliacofemoropopliteal thrombosis had developed, and related diagnosis was supported by the strongly positive particle gel agglutination technique immunoassay. Heparin was withdrawn and alternative anticoagulant, danaparoid sodium, was introduced in therapeutic doses. Despite delayed recognition, favorable clinical outcome was achieved. HITT syndrome should be considered with priority among the possible causes of thrombocytopenia in a surgical patient on heparin. PMID- 22519200 TI - [Development and treatment of cataract in myopic eye with phakic intraocular lens Fyodorov in the posterior chamber]. AB - This is a case report of a female patient who, due to high myopia, had silicone phakic intraocular lens type Fyodorov with plate-haptics implanted in the posterior chamber (PC pIOLs). The anterior subcapsular cataract (ASC) resulted in significant reduction of visual acuity and, therefore, the patient, after 16 years of the first surgery, underwent another surgical intervention. She had the pIOLs explantation, phacoemulsification and implantation of the flexible intraocular lens (IL) in the capsular bag. Explantation of the pIOLs, cataract surgery by phacoemulsification and IOL implantation were carried out through the same clear corneal incision and the intraoperative course was uneventful. The visual acuity of the operated eye was equal to pre-cataract period. PMID- 22519201 TI - Costovertebral rib disarticulation and pleurectomy in Askin's tumor: a mandatory approach to radical surgery in children? Case report and guiedelines to surgical treatment. AB - The case report of Askin's tumor in a 16-year-old girl is focused on the still debatable surgical contg roversy in the treatment of PNET tumor, i.e., whether disarticulation of involved rib at the costovertabral joint should be accepted as the mandatory surgical procedure. It was concluded that the procedure, if feasible, may offer better prognosis of PNET because progression-free survival rate of patients without costovertebral junction involvement reported in multicenter studies was statistically significantly better than in patients in whom PNET has involved the costovertebral junction or bone metastases were present at the diagnosis. The cartilage is a natural barrier for tumor spread and this property should be augmented by radical surgery. Disarticulation of involved rib or ribs and pleurectomy should be routinely performed if the surgery is contemplated with proper timing between the cycles of induction chemotherapy. PMID- 22519202 TI - A case of intussuscepted and incarcerated Meckel's diverticulum in to the cecum. AB - BACKGROUND: Intussusception with the Meckel's diverticulum is rare cause of small bowel obstruction in the adults. The Meckel diverticulum is the most common cause of intestinal obstruction in children. METHODS (CASE REPORT): We present a case of 18-year-old boy with developing signs of small bowel obstruction The onset of disease was the day before the first examination. There was no hystory of prior surgery. According to the clinical symptoms, physical examinations as well as radiographic and ultrasound examination, surgical treatment was indicated. Surgical approach was inferior medial laparotomy. Intussusceptions of the Meckel's diverticulum and into the coecum with incarceration were found. Desincarceration and simple diverticulectomy was done. CONCLUSION: The Meckels's diverticulum should be consider as a possible cause of the small bowel obs truction in previously healthy patient. PMID- 22519203 TI - [Appendicitis in puerperium--case report]. AB - Acute appendicitis in puerperium is often diagnosed too late, because clinical signs can be unrelaible. Abdominal wall rigidity is rarely noticed in puerpeium because of weak abdominal wall muscles, laboratory parameters are not enough relaible and atip cal appendix presentation makes dificulties in diagnosis. Knowing clinical signs and symptoms of appendicitis, possible complications and their early detection, make a chanse for a good surgical outcome. Measuring of axillar and rectal temperature can take confusion in, and prolong time until surgical treatment. Leucocytosis in puerperium is not valid for diagnosis. We report a case of patient in puerperium with high laboratory infection parameters. Diagnosis of appendicitis is made based on clinical signs and symptoms, that is proved intraoperatively and histologicaly. Appendectomy without perforation carries less risks for mother and fetus. PMID- 22519204 TI - [Gastroduodenal lymphoma]. AB - Gestroduodenal lymphoma are very rare and with small number of written scientific papers published. They can be found within chronic gastritis as mucose associated lymphoid tissue-MALT. MALT lesions are associated with Helicobacter Pylori infections. Misadraji first described case of primary duodenal lymphoma folikularnog in 1995. Since then, several studies suggested that MALT lymphoma is viewed as a separate clinical-pathological entity due to its localization, the nature of the disease and good prognosis. In this case report, authors presented duodenal MALT lymphoma in 70 year old patient in which was preoperatively diagnosed duodenal cancer. Cephalic duodenopancreatictomy was performed and pathohystological examination was conducted. Results was MALT lymphoma. In establishing the final diagnosis of duodenal MALT lymphoma should be used histochemical and immunostaining analysis. PMID- 22519205 TI - Looking forward. American College of Surgeons staff improvements. PMID- 22519207 TI - Cancer care closer to home: Dr. McKellar ensures rural patients get quality care. PMID- 22519206 TI - Common origins: The two ACSs--100 years of collaboration to improve the lives of cancer patient. PMID- 22519208 TI - Surgeons experience more ergonomic stress in the OR. PMID- 22519209 TI - Recycling the retired surgeon surgical assisting--a Canadian's perspective. PMID- 22519210 TI - Alliance leads thoracic surgery trials for lung cancer in 2012. PMID- 22519211 TI - New targeted solutions tool to prevent wrong site surgery. PMID- 22519212 TI - [Incidence and risk factors of the hushed weight to the being born on population once was attended in the Peru's hospitals of the health ministry]. AB - OBJECTIVE: Knowing incidence and risk factors of hushed weight to the being born on population that went once was attended in the Peru's hospitals of Health Ministry. MATERIAL AND METHODS: I study prospective, epidemiologic, of cases and controls. Compared with 14846 controls of 2500. Were examined to 3999 g total of 7423 alive newborns with younger weight to 2500 only pregnancy, tumors g. in 29 hospitals of Health Ministry of the Peru in the year 2007. Selected candidates at random. Came true analysis bivariado and intervening multivariado logistic regression, utilizing OR with intervals trustworthy to the 95%. Data base was utilized of the System Informatics Perinatal. RESULTS: He values it of hushed- weight incidence to the being born was 8.24 x 100 born living persons, with significant differences among geographic regions. The risk factors attended: Illness hipertensiva of the pregnancy (OR = 4.37), hemorrhage of the third trimester (OR = 4.28), chronic illness (OR = 2.92), premature rupture membrane (OR = 2.85), mother with bajo peso al nacer (OR = 2.27), antecedent of bajo peso al nacer (OR=1.66), absence or prenatal control inadequate (OR = 1.91), illiteracy or primary education (OR = 1.48), region saws or jungle (OR = 1.36), he carves maternal minor of 1.50 m (OR = 1.15) and interval younger two-years ntergenesicos (OR = 1.13). These risk factors have 68% of value predictive. He intends additive scale to identify women with bigger risk in order to bajo peso al nacer. CONCLUSION: He finds bajo peso al nacer'S incidence in hospitals of Health Ministry of the Peru in the average Latin-American and maternal nutritional, absence or prenatal control are associated to the deficient status inadequate and maternal pathology. PMID- 22519213 TI - [Preliminary results of effectiveness of two schemes of controlled ovarian hyperstimulation protocols with recombinant foliculle stimulating hormone in intrauterine insemination cycles]. AB - BACKGROUND: The intrauterine insemination (IUI) is the first line treatment in different infertility situations. OBJECTIVE: To compare the efficacy of two protocols of controlled ovarian hyper stimulation (COHS) with recombinant Follicle Stimulating hormone (rFSH) (75 vs. 150 UI/day) plus IUI, in terms of pregnancy rate, multiple pregnancies, ovarian hyper stimulation syndrome and ovarian stimulation features. MATERIALS AND METHODS: Prospective study, sequential assignment, included 35 patients that had 44 cycles of IUI. They were assigned in to two groups, group 1 that started controlled ovarian hiperestimulation with 75 and 2 with 150 UI/day of recombinant rFSH. RESULTS: We found statistically significant difference between groups in: dose of rFSH, amount of stimulation days, number of mature follicles and estradiol blood levels on the day of use of the GnRHant and hCG injection day. The pregnancy rate between group 1 and 2 were 9.1 vs. 27.2%, respectively. Of the 8 pregnancies, 75% were achieving in group 2. The twin pregnancy rate was 2.2% and there were no cases of OHSS. CONCLUSIONS: Although without significant difference between groups we found a clear trend to achieve a better pregnancy rate with the 150 UI/day protocol without a significant raise in multiple pregnancy rate nor OHSS. The multifollicular development was associated to group 2 seems to be related to the better pregnancy rate achieved by the same group. PMID- 22519214 TI - [Perinatal outcomes after prenatal ultrasound diagnosis of persistence of right umbilical vein]. AB - OBJECTIVE: To describe the ultrasound findings, maternal and perinatal variables in cases with a prenatal diagnosis of persistence of right umbilical vein. PATIENTS AND METHODS: A descriptive analysis of cases with prenatal diagnosis of persistence of right umbilical vein in the Fetal Medicine Unit, Department of Obstetrics and Gynecology, Hospital Universitario Severo Ochoa. We described ultrasound findings, maternal and perinatal variables. RESULTS: We explored 9198 fetuses and 6 cases (0.06%) were diagnosis prenatally of persistent right umbilical vein, between 20 and 29 weeks of gestation. The male/female ratio was 1/1. Ductus venosus was presented in all cases. Two fetuses (33%) were proved to have other structural anomalies and their parents opted for termination of the pregnancy. All cases had no chromosomal anomaly associated and after birth, neonatal developments were favorable. CONCLUSION: Based on our results and a literature review, after prenatal diagnosis of persistent right umbilical vein, an exhaustive morphological study, which included a fetal echocardiography, is mandatory in order to rule out other structural malformations. Indication for fetal karyotype study has to be individualized considering persistence right umbilical vein type and other ultrasound findings. PMID- 22519215 TI - [Placenta accreta: a surgical alternative that can save lives]. AB - The placenta accreta is the second leading cause of obstetric hemorrhage, which often require the implementation of emergency obstetric hysterectomy increased morbidity and mortality. We present a surgical alternative to hysterectomy obstetric allowed us to reduce to zero until our rate of maternal deaths from obstetric hemorrhage. Improving surgical times, associated morbidity, without altering perinatal outcomes. PMID- 22519216 TI - [Fetal ovarian cyst: prenatal diagnosis, perinatal outcome and treatment. Case series and literature review]. AB - BACKGROUND: Ovarian cysts in fetal abdominal tumors are more frequently diagnosed during pregnancy. Most of the time are usually small, asymptomatic and resolve spontaneously during pregnancy or in early neonatal life. OBJECTIVE: To describe the clinical and ultrasound cases with prenatal diagnosis of ovarian cyst treated in our center between 2002 and 2005. MATERIAL AND METHODS: Descriptive and observational cases of fetal ovarian cyst diagnosedbefore birth. The variables maternal and perinatal most relevant clinical data obtained at diagnosis and after birth. RESULTS: We explored 9.198 fetuses, of which there were 10 cases of ovarian cyst diagnosed between the second and third trimesters of pregnancy. All cases were unilateral andsonographic appearance homogeneous. In four cases there was spontaneous disappearance during the remaining gestational period. In the other six cases, four missing in the first 12 months and only two image persisted more than a year. CONCLUSIONS: Based on our results and in accordance with the literature, the prenatal diagnosis of fetal ovarian cyst is usually associated with a conservative approach with serialultrasound monitoring to rule out rare serious complications. During the neonatal period spontaneous disappearance is often the case and the surgical approach is indicated in cases with suspected persistent or torsion or hemorrhage, with cystectomy as first choice. PMID- 22519217 TI - [Asynchronous birth in twin pregnancy. Literature review and case report]. AB - BACKGROUND: The incidence of multiple pregnancy has grown, some of these cases are attributed to assisted reproduction techniques, with the consequent increase of maternal-fetal morbidity. There have been few reported cases of delayed interval delivery with different perinatal outcomes. This is a case report of a double twin pregnancy with delayed delivery of the second fetus after birth of the first one within 15.5 weeks of pregnancy, and the second one birth at 38.4 weeks, 158 days after the first one. Reported diagnosis, treatment and perinatal outcomes. CONCLUSIONS: The mean reported time to extend the pregnancy after the evacuation of the first one is 7 to 153 days. In this case the pregnancy was held 158 days, more than in the rest of the reported cases, maybe due to gestational delivery age of the first fetus (15.5 weeks) compared to fetuses of 20 to 28 weeks reported in the literature. The approach of these specific cases must be individualized. There have been no trials enough so we can't know with certainty which treatment is the best of all. PMID- 22519218 TI - [Utero-cutaneous fistula: a case report and literature review]. AB - Utero-cutaneous fistula is a rare clinical entity with less than 15 cases reported worldwide in the last 20 years and this is the first case reported in our country. In this article we review the worldwide literature addressing this condition and present the first case reported in Mexico and the first case reported worldwide in which the fistula is demonstrated using a combination of fistulogram and CT. PMID- 22519219 TI - [Axillary ectopic breast tissue fibroadenoma: report of three cases and review of the literature]. AB - BACKGROUND: Ninety-five percent of women have mammary tissue at the axilla. However, the fibroadenoma seldom occur in this area and there are only isolated case reports of this tumor. This paper presents a series of three cases of this rare entity. CASES REPORT: Three women came to our hospital by axillary lumps. The patients had a median age of 36 +/- 9-years-old with an average time of evolution of 34 +/- 53 months. One patient had the history of a breast phyllodes tumor previously excised, and two were nulliparous. In two cases, neither ultrasound nor mammogram gave useful information for its diagnosis. Mammary glands of all cases were normal. The tumors were firm and movable, similar to a lymphadenopathy, and one was evident. The mean tumor size was 28 +/- 18 mm; all were oval and with white appearance. Histological diagnosis for all cases was fibroadenoma. Our findings match with literature reports. CONCLUSIONS: The axillary fibroadenomas may occur in women aged 30 to 50-years-old, mimicking a lymphadenopathy. Finally, the ultrasound and the mammography are not useful tools for its diagnosis. PMID- 22519220 TI - [Rupture of umbilical cord chorioangioma, intraamniotic hemorrhage and fetal death: report of a case and review of the literature]. AB - The umbilical cord is exposed to a great variety of injuries and events throughout the pregnancy whose origin may be either structural, mechanical, hamartomatous or infectious (1). Some of these alterations unquestionably interfere directly with the fetoplacental circulation either blocking it or creating severe haemorrhage as a result of laceration or tumor rupture. True tumors of the umbilical cord interfere directly with the fetal development. Two true tumors of the umbilical cord are described in this paper: chorangioma and teratoma. Chorangioma is a benign tumor, but has a very high rate of rate of perinatal mortality. Its frequency is rare, reporting in literature it presence of 1:3500 pregnancies. Our objective was to review world-wide literature and to report a case of fetal death by chorangioma of umbilical cord. PMID- 22519221 TI - [Spontaneous hepatic hematoma in twin pregnancy]. AB - BACKGROUND: The hepatic hematoma or rupture appear in 1 of every 100,000 pregnancies. The most common causes of hepatic hematoma in pregnancy are severe preeclampsia and HELLP syndrome; some predisposing factors are seizures, vomiting, labor, preexistent hepatic disease and trauma. CASE: A 33 year old primigravid with a normal 33 week twin pregnancy presented abdominal pain and hypovolemic shock due to spontaneous subcapsular hepatic hematoma; laparoscopy was performed to evaluate the possibility of rupture, which was not found, later emergency cesarean section was carried out followed by hepatic hematoma drainage and abdominal packaging by laparoscopy. After surgery the flow through drainage was too high additionally hemodynamic instability and consumption coagulopathy. Abdominal panangiography was performed without identifying bleeding areas. Intesive care was given to the patient evolving satisfactorily, was discharged 19 days after the event. Seven months later she had laparoscopic cholecystectomy due to acute litiasic colecistitis. DISCUSSION: We found 5 cases in literatura about hepatic hematoma during pregnancy no related to hypertensive disorders of pregnancy; these were related to hepatoma, amebian hepatic abscess, falciform cell anemia, cocaine consumption and molar pregnancy. CONCLUSION: Hepatics hematomas have high morbidity and mortality so is significant early diagnosis and multidisciplinary approach. PMID- 22519222 TI - [Afibrinogenemia in obstetrics. 1957]. PMID- 22519223 TI - Screening for prostate cancer: throwing out the baby with the bathwater. PMID- 22519224 TI - HTLV-1 associated myelopathy/tropical spastic paraparesis: how far have we come? PMID- 22519225 TI - The effects of mild hypothermia on coagulation tests and haemodynamic variables in anaesthetized rabbits. AB - OBJECTIVE: Hypothermia has been associated with coagulation defects. The purpose of this experimental study was to investigate the effect of mild hypothermia on clinically used coagulation tests and on haemodynamic variables. METHODS: Nine New Zealand rabbits were subjected to mild core hypothermia by administration of general anaesthesia and exposure to room temperature of 22 degrees C for 60 minutes. Blood samples were obtained at normothermia and mild hypothermia for measurement of prothrombin time, activated partial thromboplastin time, fibrinogen levels, platelet count and haemoglobin concentration. Hypothermic values were compared to the normothermic values. Additionally, the progressive temperature drop and haemodynamic changes (blood pressure, heart rate) were recorded. RESULTS: Core temperature decreased significantly over time changing from 39.4 +/- 0.27 to 36.6 +/- 0.28 degrees C (p = 0.0001). Prothrombin time and activated partial thromboplastin time increased [corrected] at hypothermia, but the changes were not statistically significant (p = 0.203 and p = 0.109, respectively). Platelet count, fibrinogen levels and haemoglobin concentration decreased significantly (p = 0.0001, p = 0.03 and p = 0.027) but remained within normal limits. Mean arterial pressure and heart rate declined significantly over time (p = 0.0001 and p = 0.0001, respectively). CONCLUSION: The results of this study suggest that short term mild hypothermia may affect the coagulation mechanism to a clinically nonsignificant extent, while haemodynamic responses are significantly suppressed. PMID- 22519226 TI - Comparative analysis of thyroid carcinomas in Kingston and St Andrew, Jamaica, between two consecutive 15-year periods. AB - OBJECTIVE: To compare the distribution of histological subtypes of thyroid cancer in Kingston and St Andrew (KSA), Jamaica, within two consecutive 15-year periods. METHODS: We extracted all cases of thyroid carcinoma archived in the Jamaica Cancer Registry files over the 30-year period from 1978 to 2007. The cases were separated into two groups: 1978-1992 (Group I) and 1993-2007 (Group II). We analysed age, gender and histological subtype distribution within each group, and then made comparative analyses between the two periods. RESULTS: There were 311 cases in which the histological subtype was documented. The patients ranged in age from 12 to 94 years, with male to female ratios of 1:4.2 (group I) and 1:5.6 (group II). The highest frequencies of cases occurred in patients between the ages of 20 and 59 years. The commonest histological subtype in group I was follicular (52.7%); in group II, it was papillary (60%), followed by follicular (26.7%) and medullary (6.7%). There was an overall 263% increase in the papillary to follicular cancer ratio from group I (0.62) to group II (2.25). The increase in papillary carcinomas was statistically significant (p < 0.001) overall, and in patients less than 50 years of age (p < 0.001). CONCLUSION: The recent KSA thyroid cancer data show a histological profile similar to that described globally, with papillary carcinomas being commonest, followed by follicular and then medullary. The significant increase in papillary cancer frequency in KSA is most likely the result of gradual recognition of the entity follicular variant of papillary cancer PMID- 22519227 TI - Penile cancer in Jamaicans managed at the University Hospital of the West Indies. AB - OBJECTIVES: The aim of this study is to determine the prevalence and clinicopathological correlates of penile cancer as well as the clinical outcomes in a sample of Jamaicans managed at the University Hospital of the West Indies (UHWI). METHODS: All available records of patients diagnosed with penile cancer from 1998-2008 at the UHWI were obtained. Patient demographics, circumcision status, sexually transmitted infection status, lesion duration, location and size, and lymph node status were obtained. Histology, differentiation and stage were recorded. Information was obtained regarding treatment and outcome. The current data were compared with a previous report from UHWI in 1959. RESULTS: The records of 22 of 26 patients with penile cancer were available for review. Mean (SD) age of patients was 68 (13) years. Eighteen (86%) patients were uncircumcised Mean tumour size was 5.7 (2.6) cm; 8 (36%) lesions involved the entire penis. Sixteen (73%) lesions had clinically regional disease and 11 (52%) patients had advanced pathological stage. Surgical treatment was performed in 15 (68%) patients. Case fatality was 38%, with median survival following surgical intervention of 38 person-months. The major predictor of death in this series was increasing age (HR = 1.06, 95% CI 0.99, 1.1, p = 0.079). There was an increase in age and clinical stage of the cancer at presentation in the current series; however there was no difference in survival. CONCLUSION: Penile cancer is an uncommon cancer, seen at an advanced stage in Jamaicans. Overall survival is poor and advanced age is a major predictor of death. PMID- 22519228 TI - A ten-year assessment of anabolic steroid misuse among competitive athletes in Puerto Rico. AB - OBJECTIVE: Little is known about anabolic androgenic steroids (AAS) misuse in the Caribbean region in spite of increased popularity among athletes and adolescents. The present study examines the usage of AAS among competitive athletes in Puerto Rico. METHODS: Doping test results of competitive athletes obtained by random sampling out of competition during the 2000-2009 period were analysed. Doping tests were executed by the Centre for Sports, Health and Exercise Sciences (Albergue Olimpico, Salinas, Puerto Rico). A total of 550 athletes were monitored during 2000-2009. Information was collected with regard to competitive sport, gender and AAS compounds whenever a positive test result was encountered. RESULTS: From the total sample of monitored cases during the past decade, 5.4% showed adverse analytical findings. Anabolic androgenic steroids misuse was detected among male (62%) and female (38%) athletes. Weightlifting showed the greatest percentage of positive AAS doping test results (70% of total cases) and stanozolol was the most commonly misused exogenous androgen (60% of abused AAS whether alone or as part of a cocktail). Testosterone was the most common endogenous misused steroid (10% of misused compounds). CONCLUSION: In Puerto Rico, AAS misuse was detected across competitive sports for both genders. Although AAS misuse among Puerto Rican athletes shares some features that are consistent with the international sports community, it is imperative to address AAS misuse in the Caribbean region. PMID- 22519229 TI - Life after lower extremity amputation in diabetics. AB - Lower limb amputees typically have reduced mobility which affects their ability to perform daily tasks and to successfully reintegrate into community life. A major goal of rehabilitation for amputees is to improve quality of life (QOL). This study therefore focussed on QOL and functional independence for persons with lower limb amputations secondary to diabetes. OBJECTIVE: To determine the QOL and functional independence of lower limb diabetic amputees one to three years post amputation, using variables such as age, gender and amputation level. METHOD: A total of 87 participants were selected from the 2006-2009 physiotherapy records at the St Ann's Bay Hospital. These participants completed the World Health Organization Quality of Life Scale (WHO QOL-BREF) and the Functional Independence Measure (FIM). Data were analysed using SPSS (version 12) and the mean values for QOL and functional independence were calculated. Relationships between the variables: age, gender and level of amputation with QOL and functional independence were analysed using descriptive and inferential statistical techniques. RESULTS: Among the 35 males and 52 females participating in the study, below knee amputees recorded higher scores for QOL (p < 0.05) and functional independence (p < 0.0001) compared to the above knee amputees. The result also showed that females had a significantly higher average score than males among the four domains for QOL. Similar results were obtained from the FIM where women again had significantly higher scores than males (p < 0.0001). The majority of females across the age groups reported average to high QOL (p < 0.0001) compared to the males. A positive correlation (r = 0.5999, p < 0.0001) was found between functional independence and quality of life of all participants. CONCLUSION: The results showed that below knee amputees functioned better than those with above knee amputations and that females were more likely to cope and function with the disability than males. PMID- 22519230 TI - Glaucoma medication compliance issues in a Jamaican hospital eye clinic. AB - OBJECTIVE: To investigate the level of compliance with glaucoma medications in a clinic setting and the factors associated with failed compliance. METHOD: This was a prospective study done at the Glaucoma Clinic, University Hospital of the West Indies, between April and June 2005. Consecutive patients in the clinic were administered a questionnaire by the doctor Statistical analysis was done using cross-tabulations, Chi-square (Chi2) tests and odds ratio using SPSS version 11.0. RESULTS: One hundred glaucoma patients were recruited: 63% were female; 57% of the total group was in the 61-80-year age group. Forty-seven per cent had been attending the glaucoma clinic for over 10 years. Eighty-five per cent knew their diagnosis, although only 22% understood their diagnosis. Patients who did not have a full understanding of glaucoma were more likely to be non-compliant (odds ratio 0.771 (95% CI 0.298, 1.995, p = 0.591)). Females were more likely to be compliant than males (odds ratio was 1.64 (95% CI 0.72, 3.75, p = 0.24)). Patients who were clinic attendees for less than five years duration were less compliant than those attending the glaucoma clinic for 6-10 years. The reasons for reduced compliance were financial in 44%, forgetfulness in 20% and eye-drops being unimportant in 12% of cases. The educational level of patients was not related to compliance. CONCLUSION: The level of full compliance was 50% and partial compliance 43%. There was a 7% level of non-compliance. Higher levels of compliance were seen in females, patients who understood their diagnosis and those who had no co-morbid disease. PMID- 22519231 TI - Experimental study on the atlanto-axial joint and related structures with regional anatomy and medical imaging. AB - OBJECTIVE: To evaluate the anatomy and medical imaging characteristics in a study observing the atlanto-axial joint (AAJ) and related structures. METHODS: Eight cadaveric specimens of the AAJ segment were studied with both anatomical and imaging methods. The vertebral arteries of the AAJ segment (VA-A), the first and second cervical nerves (CN1, CN2) and synovial fold (SF) of the AAJ were observed and measured. RESULT: After extending from the vertebral canal, the CN1 goes between the posterior arch of the atlas and VA-A, and the CN2 passes between the posterior arch of the atlas and axis, and is posterior to VA-A. Among the eight cases, six were found in the SF in the central anterior AAJ and five in lateral. The vertebral arteries of the AAJ segment go along the AAJ with four curves, of which the second and fourth are away from the bone structure of the AAJ. The distance from CN1, CN2 to VA-A and that from the second, fourth curve of VA-A to AAJ is 0.0-2.2 mm, 0.0-3.6 mm and 0.0-4.8 mm, 2.0-7.9 mm respectively. There is no significant difference between the measurements made anatomically and those by the imaging method (p > 0.05). CONCLUSION: The anatomical method has advantages in observing the CN and SF, while the imaging method shows clearly and directly the VA-A and AAJ. Both are mutually complementary with consistent measurements. The combined use of the two provides a new way to study the complicated anatomy in this region. PMID- 22519232 TI - The epidemiology of end stage renal disease at a centre in Trinidad. AB - OBJECTIVE: The aim of this study is to estimate the trends in prevalence of end stage renal disease (ESRD) during the period 1999-2007 at one site in Trinidad, the Eric Williams Medical Sciences Complex (EWMSC), and to describe the epidemiological features, age, gender, ethnicity and comorbidities associated with ESRD. DESIGN AND METHODS: A retrospective cohort study design was used. There was a count of patients on haemodialysis at the EWMSC centre from 1999-2007 in order to demonstrate trends in prevalence but more detailed data were collected and analysed for patients with ESRD attending the nephrology clinic between January 2002 and December 2007. The data that were collected from the patients' records included: demographic data (age, gender and ethnicity), medical history (diabetes mellitus, hypertension, end stage renal disease and autoimmune disorders), history of dialysis (type of vascular access, frequency of dialysis), mortality and its cause. RESULTS: Records of 81 patients were retrieved. Their age range was 10-79 years. The survey showed that patients most affected in the study population were: males, aged 50-59 years, who were hypertensive and/or diabetic and of African descent. CONCLUSIONS: In conclusion, we provide epidemiological evidence of ESRD and the associated contributing factors at one hospital in Trinidad. PMID- 22519233 TI - Motorcycle trauma in a St Lucian hospital. AB - OBJECTIVE: A motorcycle is a single-track, two-wheeled motor vehicle that is used worldwide for transportation. The use of the motorcycle has resulted in trauma that is associated with significant morbidity and mortality. The aim of this study is to document the pattern of motorcycle accidents and the demographics of the cyclists in St Lucia. METHOD: This is a 15-month prospective study on all patients with motorcycle injuries that reported to the emergency room at the Victoria Hospital. Information on patients: age, gender helmet use, intake of alcohol/drugs before the motorcycling and mechanism of injury were obtained and filled into a prepared proforma by the attending physician. Those admitted were followed-up to know the outcome and complications of treatment. RESULTS: Total number of patients studied was 136 in 115 accidents, males (M) were 127 while females (F) were 9, with M:F ratio of 14.1:1.0. There were 105, 28 and 3 riders, passengers and pedestrians respectively; 87.5% of the patients were below the age of 35 years. Fifty-three per cent of the accidents occurred over the weekend. The limbs were mostly injured, constituting 81.9% of the parts of the body injured. CONCLUSION: The study revealed that young and productive males were mainly injured in motorcycle accidents and the injuries were more in the limbs. More than fifty per cent of the accidents were found to occur during the weekends and more than fifty per cent of the motorcyclists were not wearing crash helmets. PMID- 22519234 TI - First record of Anopheles albimanus from St Kitts. AB - OBJECTIVE: Previous mosquito surveys performed in the Federation of St Kitts and Nevis identified Anopheles albimanus in Nevis but there is no recorded occurrence of this mosquito in St Kitts. To determine the presence of this and other species in St Kitts and Nevis, a mosquito survey was conducted. METHODS: Surveys were performed in two phases--the dry season (March 16-23, 2010, in St Kitts), and the rainy season (October 18-25, 2010) in St Kitts and Nevis. BG Sentine mosquito traps baited with BG Lure and CO2 were set in a variety of habitats (urban, rural, semi-urban, dry forest and mangrove). Identification was performed using morphological keys. RESULTS: The most abundant species during both phases were Culex quinquefasciatus, Aedes taeniorhynchus and Aedes aegypti. A new record for St Kitts was Anopheles albimanus which was trapped during the rainy season near a mangrove site. CONCLUSION: This is the first time a potential malaria vector has been identified in St Kitts. PMID- 22519235 TI - Contraception and induced abortion in the West Indies: a review. AB - BACKGROUND: Most islands in the West Indies do not have liberal laws on abortion, nor laws on pregnancy prevention programmes (contraception). We present results of a literature review about the attitude of healthcare providers and women toward (emergency) contraception and induced abortion, prevalence, methods and juridical aspects of induced abortion and prevention policies. METHODS: Articles were obtained from PubMed, EMBASE, MEDLINE, PsychlNFO and Soclndex (1999 to 2010) using as keywords contraception, induced abortion, termination of pregnancy, medical abortion and West Indies. RESULTS: Thirty-seven articles met the inclusion criteria: 18 on contraception, 17 on induced abortion and two on both subjects. Main results indicated that healthcare providers' knowledge of emergency contraception was low. Studies showed a poor knowledge of contraception, but counselling increased its effective use. Exact numbers about prevalence of abortion were not found. The total annual number of abortions in the West Indies is estimated at 300 000; one in four pregnancies ends in an abortion. The use of misoprostol diminished the complications of unsafe abortions. Legislation of abortion varies widely in the different islands in the West Indies: Cuba, Puerto Rico, Martinique, Guadeloupe and St Martin have legal abortions. Barbados was the first English-speaking island with liberal legislation on abortion. All other islands have restrictive laws. CONCLUSION: Despite high estimated numbers of abortion, research on prevalence of abortion is missing. Studies showed a poor knowledge of contraception and low use among adolescents. Most West Indian islands have restrictive laws on abortion. PMID- 22519237 TI - Dental health knowledge and attitudes of primary school teachers toward developing dental health education. AB - OBJECTIVE: To assess the dental health knowledge of primary school teachers, their attitudes toward the prevention of dental diseases and to identify any barriers to the implementation of oral health promotion programmes in schools. METHOD: Teachers' knowledge of the causes and prevention of dental decay and gum disease, their attitudes toward oral health and barriers to the implementation of dental health education programmes were assessed using a self-administered questionnaire. RESULTS: School teachers were generally very well informed about the causes and prevention of dental decay and gum disease. Knowledge of the appropriate management of serious dental trauma was very poor among this group although they seemed to have greater awareness of the appropriate management for less serious dental injuries. The majority of teachers demonstrated positive attitudes toward dental health and its incorporation into the school curriculum. Teachers'attitudes to their own involvement in school-based dental health education were also positive. Lack of training and resources and time within the curriculum were identified as major barriers to the implementation of a dental health education programme in primary schools. CONCLUSION: Developing teacher training programmes that include oral health knowledge and an evidence-based approach to dental health education within a school setting could enable primary school teachers to play a significant part in oral health promotion for young children in Trinidad. PMID- 22519236 TI - Acute computed tomography findings in patients with acute confusion of non traumatic aetiology. AB - BACKGROUND: A retrospective review was undertaken of all patients referred for computed tomography (CT) scans of the head for acute onset of confusion, not consequent on head trauma, during the period June 1, 2004 to May 31, 2007. METHOD: Data were obtained by Microsoft Word search of the reports of the Radiology Department of the University Hospital of the West Indies, Kingston, Jamaica. Two hundred and twenty-one patients were reviewed: 103 men and 118 women. The mean age of the sample was 64 years; 168 patients (76%) were 50 years old or older. RESULT: Computed tomography scans were reported normal in 170 (76.9%) patients; 45 patients (20.4%) had definite acute intracranial CT findings. Findings were equivocal in three patients (1.4%) and unavailable for three (1.4%); 23.2% and 15.6% of patients above and below the age of 50 years respectively showed acute abnormalities on CT The most common acute finding on CT scan was an ischaemic infarct (68%). Other abnormalities included intracerebral haemorrhage and metastases 6.2% each, toxoplasmosis and primary brain tumour 4.2% each and subdural haematoma and meningitis 2.1% each. The diagnoses of toxoplasmosis were made based on appearances typical of toxoplasmosis on CT scans in patients whose request stated that they were HIV positive. CONCLUSION: In the sample reviewed, most patients who presented with acute confusion were above the age of 50 years. Overall, 20.4% of patients from all age groups had acute abnormalities on CT with a relative higher proportion, 23.2% versus 15.6% of those over 50 years, having acute pathology. The most common abnormality was an ischaemic infarct. This finding is similar to that in developed countries and unlike that seen in other developing countries where infectious aetiologies predominate. PMID- 22519238 TI - Relationship between body mass index and dental caries among adolescent children in South India. AB - OBJECTIVE: To evaluate the relationship between body mass index (BMI) and dental caries and to study the role of sweet consumption in predicting this relationship among adolescent children in Udupi district, India. METHODS: The study population consisted of 463 school children in the 13-15-year age group. Anthropometric (height in metres and weight in kilograms) and caries measurements and decayed missing filled teeth (DMFT) index, were carried out by a trained recorder according to standard criteria. RESULTS: The majority of the children were having low normal weight (BMI < 25) with 18.6% classified as overweight (BMI 25-29.9) and 3.5% as obese (BMI > 30). The frequency of sweet consumption significantly increased from low normal weight children to overweight and obese children. Analysis showed that the obese group of children had more caries than the overweight and low normal weight children. Correlation analysis showed significant positive relation with BMI, decayed teeth (DT) [r = 0.254, p < 0.001] and DMFT (r = 0.242, p < 0.001). Binomial logistic regression showed that males (OR = 2.09, CI = 1.01, 4.33), obese/overweight children (OR = 3.68, CI = 1.79, 7.56) and those who consumed sweets more than once a day (OR = 3.13, CI = 1.25, 7.85) were more likely to have high caries experience. CONCLUSION: There was a significant association between overweight/obesity and caries experience among school children of the Udupi district. Obesity and dental caries have common risk determinants and require a comprehensive multidisciplinary approach by both medical and dental healthcare professionals. PMID- 22519239 TI - Advanced abdominal pregnancy: a case report of good maternal and perinatal outcome. AB - Advanced abdominal pregnancy is understood to mean any extra-uterine pregnancy found within the peritoneal cavity that is greater than 20 weeks gestation. Its management is one of laparotomy with varying complications including poor perinatal outcome and increased maternal morbidity and mortality. There is no accepted consensus for the complete removal of the placenta at laparotomy. This paper reports the management of a unique case of advanced abdominal pregnancy that was diagnosed by ultrasound at 20 weeks gestation and treated conservatively until delivery of a viable female neonate at 33 weeks and 4 days by elective laparotomy. At the time of laparotomy, the placenta was removed completely with good maternal outcome. This, to the best of our knowledge, is the first case in the West Indian literature documenting complete removal of the placenta at the time of laparotomy with good maternal outcome. PMID- 22519240 TI - Laparoscopic cervicoisthmic cerclage for the treatment of cervical incompetence: case reports. AB - Cervical insufficiency/incompetence occurs in 0.5-1% of all pregnancies, often resulting in significant pregnancy lost. Three women with a history of second trimester miscarriages after failed transvaginal cervical cerclages were reviewed. A laparoscopic cervicoisthmic cerclage (LCC) was placed before pregnancy without any intra-operative or postoperative complications. Two patients have since delivered live babies at term by Caesarean section. This small case series supports the conclusion that LCC is a safe and cost-effective procedure in properly selected patients. Laparoscopic cervicoisthmic cerclage costs less, is less invasive, has fewer complications and should replace the traditional laparotomy technique. PMID- 22519241 TI - Fatal neutropenic enterocolitis due to clostridium septicum. AB - We describe a case of Clostridium septicum enterocolitis in a patient with pre-B acute lymphoblastic leukaemia undergoing autologous stem cell transplant. In the setting of neutropenia, Clostridium septicum should be suspected in patients who develop signs and symptoms of acute abdomen. PMID- 22519242 TI - Castor bean ingestion and ricin toxicity in a case of attempted suicide. PMID- 22519243 TI - Prostate cancer incidence in Jamaica before and after the introduction of prostate-specific antigen. PMID- 22519244 TI - Evaluation of certain food additives and contaminants. AB - This report represents the conclusions of a Joint FAO/WHO Expert Committee convened to evaluate the safety of various food additives, with a view to recommending acceptable daily intakes (ADIs) and to preparing specifications for identity and purity. The Committee also evaluated the risk posed by two food contaminants, with the aim of deriving tolerable intakes where appropriate and advising on risk management options for the purpose of public health protection. The first part of the report contains a general discussion of the principles governing the toxicological evaluation of and assessment of dietary exposure to food additives and contaminants. A summary follows of the Committee's evaluations of technical, toxicological and dietary exposure data for certain food additives (aluminium-containing food additives, Benzoe Tonkinensis, glycerol ester of gum rosin, glycerol ester of tall oil rosin, glycerol ester of wood rosin, octenyl succinic acid modified gum arabic, polydimethyl siloxane, Ponceau 4R, pullulan, pullulanase from Bacillus deromificans expressed in Bacillus licheniformis, Quinoline Yellow and Sunset Yellow FCF) and two food contaminants (cyanogenic glycosides and fumonisins). Specifications for the following food additives were revised: aluminium lakes of colouring matters; beta-apo-8'-carotenal; beta-apo-8' carotenoic acid ethyl ester; beta-carotene, synthetic; hydroxypropyl methyl cellulose; magnesium silicate, synthetic; modified starches; nitrous oxide; sodium carboxymethyl cellulose; and sucrose monoesters of lauric, palmitic or stearic acid. Annexed to the report are tables summarizing the Committee's recommendations for dietary exposures to and toxicological evaluations of the food additives and contaminants considered. PMID- 22519246 TI - [Clinical recommendations for treating and monitoring patients with renal cancer]. AB - Clear cell renal carcinoma is the most common kidney cancer. It is generally asymptomatic. A small percentage of patients present with hematuria, flank pain and abdominal mass. It is usually detected accidentally during radiologic examination. The diagnosis of kidney cancer is confirmed by pathohistological findings after completion of the diagnostic process. The decision about treatment is made based on clinical assessment of disease stage and other risk factors. Depending on that, treatment options include surgery, and considering high resistance of kidney cancer on chemotherapy and hormone therapy, use of targeted therapies (immunotherapy, tyrosine kinase inhibitors) and palliative radiotherapy. The following text presents the clinical guidelines in order to standardize procedures and criteria for the diagnosis, management, treatment and monitoring of patients with kidney cancer in the Republic of Croatia. PMID- 22519245 TI - [Clinical recommendations for diagnosis, treatment and monitoring of patients with invasive breast cancer]. AB - Breast cancer is the most common malignancy in women. Preventive measures, early diagnosis and development of all treatment modalities (surgery, radiotherapy, chemotherapy, hormonal and targeted biologic therapy) led to improvement in survival and quality of life of the patient. In order to standardize and optimize the approach, following good clinical practice standards, we bring consensus guidelines for diagnosis, treatment and monitoring of breast cancer patients as a result of consensus of a multidisciplinary team of experts for breast cancer. PMID- 22519247 TI - [Preemptive kidney transplantation in children--experience in UHC Zagreb]. AB - AIM: To discuss preemptive kidney transplantation outcomes in children with end stage kidney disease. METHODS: We present the data of patients younger than 18 years who were transplanted without previous dialysis in our Clinic. We retrospectively analyzed data available in medical health records. RESULTS: Preemptive living donor kidney transplantation was performed in 6 patients younger than 18 years. Creatinine clearance before transplantation was 9 +/- 4.15 ml/min (range = 2.7-12.3 ml/min, median = 8.5 ml/min). Currently, serum creatinine in patients with functioning graft is 139.4 +/- 60.9 micromol/l (range = 72-237 micromol/l, median = 130 micromol/l). One, three and five year graft survival was 100%. Overall graft and patient survival in the follow-up period was 83.3% and 100%, respectively. After 10 years one patient started with dialysis due to chronic graft rejection. CONCLUSION: From medical and socioeconomic point of view preemptive transplantation is optimal method for treatment of children with end-stage kidney disease. Membership in Eurotransplant should increase the number of preemptive transplantations in Croatia. PMID- 22519248 TI - [Stenting of dissected carotid arteries as a minimally invasive treatment modality]. AB - AIM: The purpose of this paper is to present our experiences with carotid artery stenting in the treatment of dissected carotid arteries, by means of self expandable stents and selective employment of cerebral protection devices. METHODS: In the period from June 1, 2006 to April 31, 2009, 6 patients with 6 dissected carotid arteries were treated with self-expandable stents (4 internal carotid artery dissections and 2 common carotid artery dissections). Two dissections were of spontaneous origin, 2 were traumatic, and 2 were iatrogenic. We applied cerebral protection filters selectively in 3 patients, based on morphological appearance of lesions. The criterion for the usage of protection devices was caudally oriented opening of the false lumen in order to prevent the possible migration of a thrombus from the false lumen during cranio-caudal deployment of self-expandable stents. We followed-up patients clinically and by means of duplex scanning throughout 12 months. RESULTS: Primary technical success was 100%. During the 12-month follow-up period no clinical or morphological signs of treatment failure were recorded. None of the patients suffered any complication (cerebral vascular insult, transitory ischemic attack, in-stent stenosis or occlusion). CONCLUSION: Carotid stenting, with selective employment of cerebral protection devices, is a successful, minimally invasive, and low risk procedure in the treatment of carotid dissections in cases when conservative treatment does not bring improvement to local finding or patients' general condition. PMID- 22519249 TI - [Why do treated hypertensives disregard our advice? A contribution to the "crash" initiative]. AB - Salt intake contributes to the rise in blood pressure and prevalence of hypertension. In this interventional trial on 110 treated hypertensives over three months a permanently elevated sodium excretion was found, averaging 187.9 +/- 81.5 mmol/day (range 103-297), because of inappropriate salt intake. The treated hypertensives, despite opposite claims, consume large amounts of salt, which, in addition to noncompliance, is the leading cause of poor hypertension control. Dietary education is an important part of preventive care in family medicine, and legal measures to enforce salt labeling on alimentary products are mandatory. PMID- 22519250 TI - [Intraductal papillary mucinous neoplasm of the pancreas: case report and review of the literature]. AB - Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is a relatively rare clinical entity with a main characteristic being mucus production. Extension of IPMN along pancretic ducts and mucus production lead to ductal obstruction and dilatation, resulting in recurrent episodes of acute pancreatitis. Molecular background of IPMN-a comprises several aberrations, with the K-ras gene mutation being the likely trigger that initiates further genetic changes. Due to its indolent nature, IPMN is most commonly diagnosed in the 7th decade of life. Depending on the histology type, IPMN has a malignant potential. Therefore, surgical therapy remains a "gold standard" of treatment. Insidious, slow progression of the disease and absence of symptoms in a certain number of patients makes diagnostic approach to this entity difficult. In this paper we present a patient with IPMN of the pancreas, in whom the episodes of acute pancreatitis had been present for 22 years. PMID- 22519251 TI - [Eccentric exercises in the treatment of overuse injuries of the musculoskeletal system]. AB - Overuse injuries of the musculoskeletal system are a common problem in both general population and among athletes. Researches made in the last decade have shown that overuse injuries are mainly caused by degenerative changes and not inflammation, as was thought before. Although they can be present everywhere in musculoskeletal system, overuse injuries are most often seen on tendons. The main goal of this article is to refer to latest guidelines in the treatment of overuse injuries, with special attention to eccentric exercise treatment program for most common tendinopathies (patellar tendinopathy, Achilles tendinopathy and lateral epicondylitis). The main reason is the fact that very good results are accomplished after eccentric exercises in the treatment of tendinopathies and are thus suggested as the first treatment option. PMID- 22519252 TI - [Mesenchymal stem cells: immunomodulatory properties and clinical application]. AB - Mesenchymal stem cells (MSCs) are multipotent nonhematopoietic cells that were first identified in bone marrow. Clinical interest for MSCs was initiated by the observation that MSCs are immunoprivileged cells that display immunomodulatory properties in vitro. Ex vivo expanded MSCs have therefore become a new type of cellular therapy in development with a wide range of potential clinical applications. So far many clinical studies confirmed safety of their use and showed that infused MSCs suppress graft versus host disease, support engraftment of transplanted allogeneic hematopoietic stem cells and stimulate growth in patients with osteogenesis imperfecta. Although underlying immunomodulatory mechanisms of action are not completely understood, potential benefit of MSC therapy justifies its clinical use in a broad range of disorders. In this report we give historical overview of MSC discovery and current scientific and clinical achievements in this field. Better insight into their biological properties and mechanisms of action are needed. PMID- 22519254 TI - [Baptism out of necessity--a medico-historiografic view]. PMID- 22519253 TI - [Coccygodynia: etiology, pathogenesis, clinical characteristics, diagnosis and therapy]. AB - The term 'coccygodynia' means the pain in the tailbone area (os coccygis; coccyx). Due to the sitting intolerance, coccygodynia can significantly disturb the quality of life. Coccygeal disorders that could be manifested in coccygodynia are injuries (fracture, subluxation, luxation), abnormal mobility (hypermobility, anterior and posterior subluxation or luxation of the coccyx), disc degeneration at sacrococcygeal (SC) and intercoccygeal (IC) segments, coccygeal spicule (bony excrescence), osteomyelitis and tumors. Abnormal mobility of coccyx, which can be seen on dynamic radiograph (lateral X-rays of the coccyx in the standing and sitting position), is the most common pathological finding in patients with coccygodynia (70% of patients). It can be a result of an injury and chronic static and dynamic overload of the coccyx (obesity, prolonged sitting, bicycling, rowing, riding etc). Coccygeal origin of the pain can be confirmed by injections of the local anesthetic in the structures that can be a source of the pain (SC disc, first IC disc, Walther's ganglion, muscle attachments around the top of the coccyx etc). Extracoccygeal disorders that can be manifested by coccygodynia are: pilonidal cyst, perianal abscess, hemorrhoids, and diseases of pelvic organs as well as disorders of lumbosacral spine, sacroiliac joints, piriformis muscle and sacrum. In 30% of patients with coccygodynia, the cause of pain cannot be found (idiopathic coccygodynia). Therapy for coccygodynia can be conservative and surgical (partial or total coccygectomy). Conservative therapy includes: rest, medicamentous therapy, acupuncture, coccyx cushion, physical therapy, manual therapy (massage and stretching of the levator ani muscle; mobilization of the coccyx) and therapeutic interventions (injections of local anesthetic and corticosteroid in the painful structures; radiofrequency ablation of coccygeal discs and Walther's ganglion). Using different modalities of conservative therapy, satisfactory results are achieved in the majority of patients with coccygodynia. Coccygectomy is indicated in refractory cases, first of all in patients with abnormal mobility of the coccyx and spicules who respond best to surgical treatment. PMID- 22519255 TI - [The use of biological therapy in the SAPHO syndrome]. PMID- 22519256 TI - [Dose calculation of anticancer drugs in the obese]. PMID- 22519257 TI - [Mental health of persons with intellectual disabilities]. PMID- 22519258 TI - [Challenges and barriers in the promotion of quality in health care services]. AB - The promotion of quality and safety in health care faces many challenges and barriers including lack of cooperation by physicians. Complexity and uncertainty in measuring quality raise methodological difficulties. Lack of sufficient awareness about these limitations, also among those who measure quality, contributes to physicians lack of interest, suspicion and mistrust. Strategic issues associated with quality assessment in the Israeli health care system derive from lack of regulation and evasiveness about the accountability of executives and governing bodies regarding the quality of the services provided to patients in hospitals and clinics. Some of these challenges relate to the intrusion of market forces into the world of medicine without needed adaptations, so that reimbursement is often conveniently linked to the quantity of services and not to their quality. Efficiency, which characterizes competitive markets, is not easily translated in the clinical world where empathy, listening skills, and capability of explaining are critical physician attributes. This clinical world values giving beyond monetary compensation, and cooperation between institutions- rather than competition--all crucial for the continuity of patient's care. The interface between economics and health care calls for creative thinking, with a novel definition for the social value of medical and nursing care according to their quality and not their quantity. PMID- 22519259 TI - [Identifying ways to address the crisis facing a medical specialty: a case study of general surgery]. AB - BACKGROUND: In a previous study we defined criteria for a medical specialty in crisis' and measures to assess the scale of the problem, and possible resolutions suggested based on experience abroad. This study seeks to gain further knowledge by exploring how front-line Israeli surgeons envisage the problems and possible solutions. OBJECTIVES: To identify ways to address the workforce crisis in general surgery (GS) white focusing on issues that can be dealt with at the department and the hospital levels. METHODOLOGY: An action study of GS conducted in two stages: (1) Semi-structured interviews with 180 GS residents. (2) The use of the retrospective method of "Learning from success" in five general surgical departments recognized as "successful" in attracting residents and integrating them into the departments while providing high-level training. FINDINGS: The factors attracting medical students to specialize in GS are presented along with the problems perceived by residents during their residency. AdditionaLLy, 12 general principles identified in the study are presented, which can be transmitted to and implemented by other GS departments. They are related to three key topics: the mode and quality of residency training; work schedules, departmental organization of work and departmental atmosphere; and the comportment of senior physicians. The value of implementing these principles should be weighed in terms of being identified as constituting "leverage for change". CONCLUSIONS: Study findings will facilitate recommendations on internal organizational/professional factors of attracting and integrating residents to the specialty and the department. The study can serve as a basis for similar action research in other medical specialties. PMID- 22519260 TI - [Birth and pregnancy outcomes of drug addicted women]. AB - INTRODUCTION: Illegal drug abuse causes significant health problems with consequences to the mother and the neonate, and an economic burden to the health system. OBJECTIVES: The present study aimed to investigate pregnancy and perinatal outcome in women using illegal drugs prior to and during pregnancy. METHODS: A retrospective cohort study comparing pregnancy and neonatal outcomes of drug addicted women to the outcomes of other Jewish women. The study population includes all women who gave birth between the years 1989-2008 at the Soroka University Medical Center. RESULTS: From a total of 106,000 deliveries, 119 women were known to be drug addicted. No significant differences were found between the groups regarding maternal age and origin, but more women in the addicted group smoked, and tacked prenatal care. More women in the addicted group had obstetrics complications such as: recurrent abortions, placenta previa, pLacental abruption and preterm labor. Illegal drug abuse was significantly associated with adverse perinatal outcomes such as low birth weight, congenital anomalies, peripartum death and prolonged hospitalizations. CONCLUSIONS: Illegal drug abuse is an independent risk factor for adverse obstetric and perinatal outcomes. DISCUSSION: This study investigated a significant problem that may be underestimated in our population. The higher incidence of pLacental abruption, placenta previa, preterm tabor and low birth weight could be a sign for placentaL insult. SUMMARY: Illegal drug abuse is an independent risk factor for adverse perinatal outcomes and causes an economic burden. Further national studies are needed to characterize the problem, and to develop appropriate intervention programs. PMID- 22519261 TI - [What do ultrasound performers in Israel know regarding safety of ultrasound, in comparison to the end users in the United States?]. AB - OBJECTIVE: The goal was to examine the knowledge of ultrasound end users regarding safety of ultrasound in pregnancy, and to compare it to ultrasound end users in the United States. METHODS: A questionnaire was distributed to ultrasound users at obstetrics and gynecology conventions and wards throughout the country, between the years 2008-2010, and compared to an identical questionnaire distributed in the United States. RESULTS: A total of 143 end users completed the questionnaire; 92% of them are physicians, 71% gynecologists; 3.5% routinely perform Doppler ultrasound in the first trimester. Overall, 36% of the ultrasound end users thought that the number of ultrasounds performed in low-risk pregnancy should be limited. Although 44.1% were familiar with the term thermal index, only 22.4% answered the related question correctly; 26.6% were familiar with the term mechanical index, but only 4.9% described it correctly. More than 80% of the end users did not know where to find the acoustic indices while performing the examination. No significant difference in knowledge was found between the ultrasound end users in Israel and the United States. CONCLUSIONS: The poor level of knowledge regarding safety issues, found both in Israel and United States, raises the necessity to reexamine the methods of informing the relevant audience on the courses and training programs available on these matters. PMID- 22519262 TI - [Preschool diagnostic process and changes in diagnosis of autism spectrum disorder]. AB - BACKGROUND: Autism spectrum disorders [ASD] are characterized by a wide range of neuropsychiatric comorbid disorders which change during early development. Coordinated collaboration between therapists from various disciplines and integrating measurements, may Lead to a comprehensive diagnosis of ASD. A diagnostic kindergarten set-up for children with a preliminary diagnosis of ASD or communication disorder can facilitate a multidisciplinary diagnosis, as an integral part of the child and parental intervention process. GOALS: To examine the changes in the diagnosis of children after one year of observation and treatment in a special education set-up, including aspects such as common neuropsychiatric comorbidity, differential diagnosis and subsequent placement recommendations. METHODS: Changes in the frequencies of ASD diagnoses were calculated prior to and following participation in the kindergarten for 76 children, who studied in the diagnostic kindergarten for ASD at the Weinberg Child Development Center during the last decade. Frequencies of neuropsychiatric comorbid disorders and differential diagnosis were calculated. RESULTS: It was found that: half (44.7%) of the preliminary diagnoses changed after a year of treatment; 14.2% of the children admitted with other developmental diagnoses, were subsequently diagnosed with ASD and in the cases of 25% of the children with ASD, their diagnosis was removed. Neuropsychiatric comorbid disorders appeared in 66% of cases. The most common differential diagnosis was Language disability, which appeared in 76% of the cases. CONCLUSIONS: This study reinforces the importance of a thorough assessment process conducted by a multidisciplinary team during and after treatment. A quarter of the children diagnosed with ASD in early childhood may have a different diagnosis later, usually milder, probably as a consequence of developmental changes combined with intensive treatment. PMID- 22519263 TI - [Assessing the effect of compulsory ambulatory treatment orders on the time lapse out of hospitalization for patients suffering from schizophrenia]. AB - INTRODUCTION: Schizophrenia is the most severe mental disorder, characterized in many cases by poor insight and low adherence to drug treatment. In Israel, as in many countries, Laws have been Legislated to allow the issuance of compuLsory ambulatory treatment orders (CATO) to patients whose medical condition poses a risk to themselves or the environment. In the Limited existing literature, no conclusive evidence has been found on the efficacy of CATO on patients' outcome. METHODS AND AIMS: We examined the medical files of all the patients in "Shalvata" Mental Health Center, who were treated under the compulsory ambulatory treatment order during the years 2003-2010. We examined the effect of the CATO on the time Lapse out of hospitalization during a 3 year period before and after issuing the order. The study group was composed of 77 patients and each patient served as his own control. RESULTS: We conducted paired samples t-test and found that the average time lapse out of hospitalization after issuing CATO was higher (M = 426 days, SD = 3921 compared to the average time lapse out of hospitalization before issuing CATO (M = 345 days, SD = 366, N = 77), but the difference was not statistically significant (t = -1.34, p = 0.2). CONCLUSIONS: Our research shows that there was no significant beneficial effect of the CATO in the group of patients that we examined. We found that the average time lapse out of hospitalization did not increase significantly. Our study raises questions regarding the importance of the compulsory ambulatory treatment and its implementation measures. PMID- 22519264 TI - [Sudden death due to eosinophilic arteritis of a major coronary artery]. AB - Coronary arteritis is the fourth most common cause of fatal cardiac disease, after coronary atheroscLerosis, congenital anomalies and coronary dissection. Eosinophilic inflammation of the coronary arteries is extremely rare, involves the major coronaries and occurs as an isolated disease or as part of Churg Strauss syndrome or Wegener's granulomatosis with involvement of other internal organs. A case of sudden and unexpected death of a healthy young woman is presented. Autopsy revealed eosinophilic inflammation of Left coronary artery with thrombosis of the lumen, causing a fatal cardiac failure. No other pathology was detected. We discuss the importance of performing a full autopsy, including microscopic inspection of the tissues, in order to glean the cause of death and learn about new and rare pathologies. PMID- 22519265 TI - [Autism spectrum disorders--a syndrome on the rise: risk factors and advances in early detection and intervention]. AB - Autism spectrum disorders [ASD] are complex neurobehavioraL disorders defined by social and communication deficits and repetitive and stereotyped behaviors. The current estimated prevalence of ASD is approximately 1:100, which reflects a 15 fold increase from studies published a half-century ago. ASD is a highly heritable disorder, however, the exact cause of ASD is still unknown. ASD is associated with altered functional and structural connectivity patterns in the frontal and temporo-limbic brain regions that occur early in life. It is now believed that environmental factors may modulate phenotypical expression of ASD that are associated with the genetic predisposition. Several possible risk factors for ASD were investigated and included advanced parental age, birth complications, prematurity, Low birth weight and assisted conception. Numerous epidemioLogical reports have failed to confirm any association between immunizations and MMR specifically or thimerosaL exposure and risk for ASD. The diagnosis of ASD can be reLiably made in the second year of Life and appears to be relatively stable over time. However, diagnosis of very young children can be quite complex due to their clinical heterogeneity and varying patterns of onset that can differ from the typical autism symptoms of an older child. It is further challenging to distinguish between developmental and/or speech delay and ASD at this early age. Standardized tests for ASD diagnosis, developmental level and adaptive skiLls have been successfully used for accurate diagnosis of ASD. Research has recently focused on possible basic measures and/or biological markers that can assist with early diagnosis of ASD. Recent studies suggest that substantial gains can be achieved by intensive behavioral intervention initiated prior to 24 months, as neural plasticity is increased and chaLLenging behaviors are less prominent. Effective early intervention should begin soon after the diagnosis is made, and be individualized, intensive, and comprehensive and should include parent education, and behavioral intervention. It is highly important for pediatricians and experts in child neurology, development and child psychiatry to recognize the early signs of ASD, diagnostic tools and effective intervention methods. PMID- 22519266 TI - [Involuntary outpatient treatment]. AB - Much has been written about involuntary outpatient treatment, both in Israel and abroad. Since the amendment of the law in Israel in 1991, there is an option for compulsory outpatient treatment that is Less confining than hospitalization. Research has noted its efficacy in avoiding exacerbation of the mental state, repeat hospitalizations and involvement in dangerous activities among patients with low compliance to treatment. In practice, there is no mechanism for implementation or enforcement. Thus, the main difficulty noted by Spinzy and Krieger, is the lack of tools to supervise involuntary outpatient treatment, thereby making it difficult to implement the law of involuntary outpatient treatment ordered by the regional psychiatrist. In addition, the court interpreted the law in a manner that prevents taking measures against the patient who does not comply with compulsory outpatient treatment unless his condition is so severe that it requires court ordered hospitalization. The issue becomes more problematic with court ordered compulsory outpatient treatment. In the United States there is Assisted Outpatient Treatment (AOT) in 42 states. The criteria include dangerousness to the environment, harm to self, or severe inability to care for one's self. AOT helps prevent hospitalizations and improves the outcome of treatment. According to "Kendra's Law" in the United States, the Court detaiLs the biological and psychosocial treatment programs in the court order recommendations: The recommendations include: create uniformity, determine a mechanism of action, assign skilled manpower to implement compulsory outpatient treatment, establish a plan for compulsory outpatient treatment, and create a legal mechanism to supervise patients in court ordered outpatient treatment. In conclusion, determining a mechanism for intervention, implementation and supervision of compulsory outpatient treatment is first and foremost in the best interest of: the patient, who does not want his condition to deteriorate to rehospitalization, the caregivers, for whom the mechanism will help provide medical care, and for society, which will be better protected. PMID- 22519267 TI - [Autism spectrum disorders: updates and new definitions]. AB - Autism spectrum disorders (ASD) include several clinically different disorders. Despite the impression that in recent years there has been a rise in the incidence of this disorder, it seems that the apparent rise stems from the widening of diagnostic criteria rather than from a true rise in disorder incidence. Notwithstanding the wide range of clinical symptoms, reliabLe information on the etiology of this disorder is lacking. However, new data points to an important genetic component and to structural changes in the brain. There is a wide range of comorbidities with additional neurodevelopmental disorders. The currently offered treatment is multi-disciplinary and includes primarily behavioral therapy and symptomatic treatment with psychotropic drugs. PMID- 22519268 TI - [IgM enriched immunoglobulins as a therapy for sepsis and autoimmune diseases]. AB - The importance of natural autoreactive antibodies of the immunogtobulin M (IgM) isotype, raised the issue of the innate immune response being immunoregulatory. These antibodies have low affinity and a wide range of specificity, thus acting as protective autoantibodies. Bearing this in mind, many have proposed the therapeutics potential of IgM enriched intravenous immunoglobulin (IVIg) in sepsis and in autoimmune diseases. We will summarize the emerging knowledge of these natural autoreactive IgM antibodies, their role and mechanisms of action in the above mentioned diseases. PMID- 22519269 TI - [Tuberculosis and AIDS in labor migrants in Israel--are we really facing a new challenge?]. AB - Israel has absorbed labor migrants (LM), mostly originating from developing countries endemic for tuberculosis and AIDS. This trend has increased in the last 4 years, and included LM from the horn of Arica. Public opinion towards LM is ambivalent and is based on incomplete data and prejudice. Those who support LM deportation emphasize the burden of infectious diseases (ID) and raise concerns regarding possible exposure of Israeli citizens. This article will elucidate the process of data monitoring and the risk of ID transmission to the citizens of the hosting country. Of all individuals infected with tuberculosis and AIDS in Israel, 13% and 17% respectively are LM. LM are screened prior to arrival or upon incarceration in Israel Female LM are advised to perform an HIV test during their pregnancy. As a consequence of the active screening, more LM are diagnosed than Israelis, who are not routinely tested. The risk of ID transmission to the citizens of the hosting country is Limited, as M. tuberculosis is transmitted only to close (mainly domestic) contacts and HIV is mainly transmitted during sexual contact. These intimate contacts are rare between LM and Israelis. The Israeli Ministry of Health operates services for LM and supports treatment for tuberculosis patients and for pregnant HIV-infected females. Nevertheless, the unique medical needs of LM should be addressed and health authorities should appropriate a health infrastructure to support LM. Early detection of infectious diseases will lead to correct treatment and will reduce the risk of ID transmission in the community. PMID- 22519270 TI - [Mast cell proliferation and activation in disease processes]. AB - Mast cells are well known as pivotal players in the development of allergic diseases. Their most acknowledged mechanism of activation is cross-bridging of the IgE receptor. However, in recent years, the complex structure and function of these cells have been recognized as well as their diverse pathophysiological contributions. This review attempts to delineate the various ways in which mast cell proliferation and activation are involved in disease processes. PMID- 22519271 TI - [How to access and generate resources for medical research?]. PMID- 22519272 TI - Hemodialysis vascular access infection and mortality in maintenance hemodialysis patients. AB - Infectious complications associated with vascular access are a well known cause of increased morbidity and mortality in hemodialysis patients. The aim of the study was to evaluate the incidence of hemodialysis vascular access infections and patients survival in the group of maintenance hemodialysis patients during a one year observation period. The study group consisted of 213 patients (126 male, 87 female; aged 57.4 +/- 14.9 years being on renal replacement therapy for 54 months; range: 2 to 384 months) treated by maintenance hemodialysis at the Nephrology Department of the University Hospital. From the study group 181 patients (84.9%) had created arterio-venous fistulas (AVF); 28 (13.2%) permanent central venous catheters (CVC) implanted and 4 (1.9%) arterio-venous grafts (AVG). Vascular access infectious complications were monitored during a one year observation period. Infections of CVC were observed in 4 (14.3%) of the patients with CVC; 4 (2.2%) of patients with AVF and 2 (50%) of AVG. In the group of patients with signs of AVF infection the following pathogens were found: S. epidermidis 50%, S. aureus 25% and negative culture in 25%. The common pathogens in the group of patients with AVG were as follows: S. aureus and S. hemoliticus. Patients that had infections of implanted CVCin 75% were found to have Gram positive bacteria (50% S. aureus, 25% S. coagulazo-negative), while 25% had Gram negative infections (E. coli). In the analyzed period 30 deaths (14.1%) were noted; 23 (12.7%) in patients with AVF and 7 (25%) with CVC. Mortality due to cardio-vascular events in dialyzed patients using permanent catheters came to 43%; death due to catheter infections 14%. In the group of patients with AVF from 23 deaths 83% were of cardio-vascular origin, and 4% due to infections. No deaths were occurred during the observation period in the group of patients with AVG. One should note that only 4 patients with AVG during the study period were evaluated. CONCLUSIONS: 1. Types of vascular access has some influence on infectious complications and survival in the group of hemodialized patients. 2. High rate of CVC infections and associated increased mortality and better patients outcome with AVF, indicate that fistula should be constructed in all cases where it is possible. PMID- 22519273 TI - [Cardiovascular calcification and five-years mortality in patients on maintenance hemodialysis]. AB - The very high cardiovascular mortality and morbidity in hemodialyzed patients (HD) is strongly associated with cardiovascular calcification. The aim of the study was to find the predictors of mortality in HD patients during 5-years observation period. The study group was composed of 64 patients (35 F, 29 M) aged 25-75 years (mean 48.9) hemodialyzed three times a week for 12-275 months (mean 77.8). The levels of hemoglobin, total protein, albumin, Ca, P, Ca x P, iPTH, cholesterol, triglycerides, fibrinogen, insulin, homocysteine, leptin, procalcitonin, CRP, IL-6, TGF-beta, PDGF were assessed and all patients underwent Calcium Score (CS) of coronary arteries (CACS) calculation using MSCT and B-mode ultrasound of carotid arteries for intima-media thickness (CCA-IMT), as well as echocardiographic assessment with LVMI calculation and heart valves evaluation at the start of observation. The self-elaborated Cumulative Calcification Index (CCl) was calculated as a sum of CACS Index according to Rumberger et al. (CS<10 0, 10400 - 3 points); number of calcified plaques in carotid arteries (0-0, 1 - 1, 2 - 2, 3 and more - 3 points) and the number of calcified heart valves. At the start of the study the median value of CCl was 4 and interquartile range 4. Only 2 (3%) patients were free of any type of cardiovascular calcification (CCl =0), 15 (23%) patients had minimal calcification (CCl 1 to 2 points), 33 (52%) average (2 - 6 points) and 14 (22%) patients had severe calcification (CCl>6). 21 (32,8%) patients died during observation period. Patients who died were older (56.9 vs. 45.3 yrs.) and had higher CS at the start (1275 vs. 356), higher CCA-IMT (0.948 vs. 0.687 mm) and CCl (6.15 vs. 3.63) values. Those patients had also higher CRP (0.645 vs. 0.245 mg/dl) and IL-6 (10.16 vs. 4.15 pg/ml) levels (p<0.05). LVMI and mean: hemoglobin, total protein, albumin, Ca, P, Ca x P, iPTH, cholesterol, triglycerides, fibrinogen, insulin, homocysteine, leptin, procalcitonin, TGF-beta as well as PDGF levels did not differ between the groups. In logistic regression model (p<0.00002), among tested parameters only CCl was an independent and statistically significant factor of mortality with OR=1.82 per every point of CCl (p<0.0003). Cardiovascular calcification expressed as CCl confirmed to be a strong predictor of mortality in HD patients. PMID- 22519274 TI - [Prevalence of metastatic lymph nodes in the central compartment of the neck following prophylactic clearance for papillary thyroid cancer]. AB - INTRODUCTION: Clinical suspicion of regional lymph nodes' involvement is present in approximately 10% of patients with papillary thyroid cancer (PTC). Nevertheless, among the remaining 90% of individuals staged pre-, or intraoperatively as node negative, some cases of metastatic lymph nodes from PTC are found on final pathological report. Both quality of life and survival can be influence by eventual nodal recurrence in this group of patients. AIMS: To evaluate the prevalence of metastatic lymph nodes in patients with PTC in stage cT1-3NxMx undergoing prophylactic central compartment lymph nodes' clearance, and to assess associated morbidity. METHODS: Clinical database of patients with thyroid cancer undergoing surgery in 2009 and 2010 was retrospectively analyzed. 116 (78.9%) patients with PTC, with pre-, or intraoperatively not suspected lymph nodes were identified. Total extracapsular thyroidectomy with one-stage prophylactic bilateral level VI lymph nodes clearance was performed in all patients. The numbers of excised and metastatic lymph nodes within the surgical specimen were analyzed. In addition, surgical morbidity was evaluated. RESULTS: Metastatic level VI lymph nodes' involvement was found in 22 of 116 (19%) patients. Mean number of lymph nodes within the surgical specimen was 4.5 +/- 3.3 (1-17, median 4). Mean number of 1 +/- 2 metastatic lymph nodes were identified (0-7, median 1). Transient vs. permanent hypoparathyroidism was found in 31 (26.7%) vs. 2 (1.7%) and temporary vs. permanent recurrent laryngeal nerve injury was found in 7 (3.0%) vs. 2 (0.9%) of 232 nerves at risk. CONCLUSIONS: One fifth of PTC patients with clinically and intraoperatively non-suspected lymph nodes within the central compartment are positive for metastatic nodal de- posits in surgical specimen following prophylactic level VI clearance. PMID- 22519276 TI - [Acute kidney injury in cancer patients]. AB - Acute kidney injury is a common and serious complication of cancer. We analyzed medical records of 335 cancer patients who were treated in Internal Diseases and Nephrology Department with Dialysis Center at St. Lucas Hospital in Tarnow in years 2009 and 2010. AKI was diagnosed according to the RIFLE classification in 91 cases (43 woman and 48 men). The average age was 68.7 years (from 18 to 93 years). 54 patients were classified as category F, 23 as category I and 14 as category R of the RIFLE classification. 60.4% of the patients were diagnosed with metastatic cancer, 12.1% with a regionally developed disease, 18.7% with cancer limited to one organ and in 8.8% the stage of the disease could not be established. The highest incidence of AKI was observed in patients with cancer of the cervix, ovary, prostate, breast, stomach and of unknown primary site. The most common risk factor of AKI was hypovolemia diagnosed in 35% of cases. Obstruction of the urinary tract, the second most frequent risk factor was observed in 26% of cases. 14.5% of the patients required hemodialysis. In the group of dialysed patients 38.5% of them died, 61.5% were discharged from hospital after improvement of renal function. In the group of non-dialysed patients mortality rate was 25.6%; survivors in that group presented improvement in renal function. Evaluation of the renal function in patients with cancer is essential. PMID- 22519278 TI - [Disadvantages and benefits of early initiation of dialysotherapy]. AB - Along with dialysis therapy evolvement and its widespread availability, highly economically developed countries have shown a tendency to initiate dialysis therapy earlier. In the light of available data, this does not seem to be a tendency worth recommending. The key to improvement of quality of life and patient survival in chronic kidney disease (CKD) are: prophylactic measures of CKD, quicker diagnosis of kidney disease and early patient referral to the nephrologist. These measures permit for the delay of initiation of renal replacement therapy. When it becomes mandatory to start therapy, preemptive renal transplantation should be the choice especially for patients having a living related donor. When it is impossible start dialysis therapy based on peritoneal dialysis or hemodialysis. PMID- 22519277 TI - [How to effectively change health behaviours of patients at old age]. AB - In the frame of the international CHANGE Project a training course for nurses has been elaborated in order to improve their interpersonal communication skills in motivating older patients to change their health behaviours. Family nurses, caring for community-dwelling older patients applied their newly-developed competences to promote healthy nutrition and regular physical activity among their patients. OBJECTIVES: To assess the effectiveness of the nurse training. Changes in physical activity and nutritional habits of older patients resulting from nurses' performance were evaluated as well as patients' intentions to change those behaviours. METHODS: During the 2 weeks following the training 108 older patients at age avg. 69.6 (SD 60-87) in Krakow city, were initially interviewed by nurses with a questionnaire assessing health behaviours (frequency of intake of particular food products, frequency of different types of physical activity) and motivation to change those behaviours. The nurses provided consultancy directly after questionnaire interviews, then visited patients for consultancy at least once and repeated their assessment 6-8 weeks after the first one. Wilcoxon's matched pairs test and paired t-test were applied to measure the effectiveness of the intervention. RESULTS: The results have shown a significant improvement in duration (p<0.04) and frequency (p=0.0531) of walking, change of attitudes toward physical activity (p<0.003), and intentions to exercise regularly (p<0.01), higher level of self-satisfaction with personal physical capacity (p<0.006) and well-being (p<0.005). The frequency of intake of fresh fruit, vegetables and water (p<0.0001), pasta, cereal or bread (p<0.02) has also increased significantly. CONCLUSIONS: The nurses' training in motivating older patients to change their health behaviours exerted an effect on patients' health beliefs, intentions and health behaviours. PMID- 22519279 TI - [Metabolic disorders in patients with psoriasis]. AB - Psoriasis is a chronic, relapsing, inflammatory - proliferative disease, belonging to the group of autoimmune disorders. Although the disease process concerns mainly the skin, this is a systemic inflammation. In psoriasis there is an increased synthesis of proinflammatory proteins, such as: C-reactive protein (CRP), interleukin 1 (IL-1), IL-2, IL-6, IL-8, tumor necrosis factor alpha (TNF alpha), interferon gamma (IFN-gamma), alpha2-macroglobulin, alpha1-antitrypsin and ceruloplasmin. Many studies have shown increased incidence of the metabolic syndrome in patients with psoriasis. There is also relationship between severity of psoriasis and severity of the various components of metabolic syndrome (impaired glucose tolerance or diabetes, abdominal obesity, atherogenic dyslipidemia and hypertension). Chronic inflammation seems to be a link between psoriasis and various components of metabolic syndrome. Proinflammatory cytokines may cause atherosclerosis, insulin resistance, hypertension and type 2 diabetes. Presence of obesity and particular components of the metabolic syndrome may also play an important role in the pathogenesis of chronic kidney disease in patients with psoriasis. The primary intervention in patients with psoriasis and metabolic syndrome in order to reduce cardiovascular risk are lifestyle modifications, i.e. increased physical activity and dietary treatment of obesity, in combination with pharmacotherapy of particular components of metabolic syndrome. PMID- 22519280 TI - [Atypical causes of myocardial infarction--Kounis syndrome]. AB - The first reports about correlation between acute coronary syndromes and allergic reactions were originally published in 1950 and involved the use of penicillin. In 1991, Kounis and Zavras described the case of an allergic reaction which led to a myocardial infarction. Kounis syndrome is defined as an acute coronary syndrome which occurs during the course of an allergic reaction, and is caused by the contraction of the epicardial artery or the destabilization of the atherosclerotic plaque. Both of these processes are the consequence of a violent allergic reaction and the release of inflammatory markers such as histamine, proteolytic enzymes, and the products of arachidonic acid metabolism. PMID- 22519281 TI - [Post transplant lymphoproliferative disorder (PTLD)--10 years follow-up]. AB - PTLD is a very severe, life threatening complication after organ transplantation. A 17 years old female patient with kidney transplanted (KTx) 7th months ago on immunosuppression therapy: Tacrolimus (TAC), Cell Cept (MMF), Encorton (Enc) was described. She was admitted to the hospital due to: fever, abdominal pain, diarrhea and enlarged cervical and inguinal lymph nodes on palpation. Histopathological diagnosis revealed monomorphic PTLD; diffuse large B cell lymphoma, immunoblastic. Treatment of PTLD was started immediatly after the final diagnosis. MMF was stopped, dose of TAC was reduced (blood level 3-4 ng/ ml), Enc were continued. Anti-CD20 antibodies (Rituximab) were administered. After 7 days of treatment the patient developed signs of diffuse peritonitis. In the course of surgery, perforation in six sites of the small intestine and sigmoid colon were discovered. The Hartman's surgery was performed (sigmoidectomy) with formation of temporary sigmoideostomy. Resected parts of intestine and sigmoid colon were infiltrated by immnunoblasts and revealed diffuse necrosis - the same process was seen in lymph nodes. After the wounds healed, Rituksymab was continued (8 doses) and chemotherapy was started - CHOP - 6 cycles every month. Eight months after surgery, full remission was obtained, TAC was change to rapamycine (RAP) and closure of sigmoideostomy was performed. At present, almost 10 years after first symptoms of PTLD, the patient remains in full remission of the disease. PMID- 22519282 TI - [Clinical implication of residual mesoaxial polydactyly of the foot--case report]. AB - The aim of our study was to estimate influence of anatomical malformations in foot (characterised by mesoaxial polydactyly) in 26-year old female patient on clinical condition and biomechanical motion. Clinical, radiological and pedobarographic examinations were used in the patient's analysis. The postural pedobarographics examinations revealed persistent disturbances in underfoot pressure distribution despite pain recovered, which has been achieved by discontinued of wearing tight shoes. PMID- 22519283 TI - [Transplantation as a care about neighbour health and life]. AB - Taking into account current developments in medicine and the increasingly extended lifespan of our patients, the role of transplantation and the related issues have become increasingly more urgent and have demanded more attention in recent years. Transplantation is a branch of medical studies which has been developed as a result of the need to find answers to unsuccessful organ transplants. Transplants are the future of the contemporary medicine and provide better prospects for patients with defective organs. In spite of the rapid development and huge successes achieved in the field of transplantation, the major problem we are facing, both in terms of the legal and ethical aspects, is the lack of the organ donors. Developing social awareness and continuous education can bring about positive changes to the current shortage of donors. The role of the church and the media in promoting the importance of organ donation will also greatly contribute to the future success of transplantation thus saving human lives. PMID- 22519275 TI - [Results of QC vs QL study (quality of care vs quality of life) 2006-2009. The way of providing hemodialysis and a concomitant therapy]. AB - Healthcare development is the fact in the present world. Because of this the improvement of the quality of care and life of patients is of great importance. Since six years in our country, the study concerning quality of life and care of hemodialysed patients (QC vs QL) is performed annually. In three subsequent papers results of studies performed between 2006 and 2009 are summarised. Almost 7000 patients were studies in the analysed period. This was more than 10% of dialysed patients in every year. In the present paper we focused on the hemodialysis modalities and concomitant therapy. The increase of high-flux hemodialysis usage as well as plasmapheresis but not hemodiafiltration was noticed in the analysed period. Adequacy of the therapy was evaluated as Kt/V and was stable in the whole study. Treatment with erythropoesis stimulating agents (ESA) was provided in 100% of dialysis units, the dosage frequency was connected with long acting ESA. Because of changed trends and the payer requirements apart from frequency the route has also changed. The average haemoglobin level reflected European and county guidelines and changed during the observation. Additional help from psychologist and dietician is available in too small number of dialysis units. Summarizing, based on performed analysis the development of hemodialysis treatment and a high level of provided therapy comparable to other European countries was observed in Poland. Support for further development and improvement of renal replacement therapy is needed to achieve also better quality of life of our patients. PMID- 22519284 TI - A zero-cost approach to reducing costly registration errors. PMID- 22519285 TI - Reviewing revenue cycle operations in an age of payer audits. PMID- 22519286 TI - Beware of the ZPIC: tips for revenue cycle leaders. PMID- 22519287 TI - Hospital could be held liable for nursing negligence in failing to use leg cuffs. Tisdale. v. Toledo Hospital, 2012-Ohio 1110 L-15-1005 (3/16/2012)-OH. PMID- 22519288 TI - Cerebral palsy does not mean nurse or Dr. negligent. Case on point: Trudeau v. Physicians Ins. Co. of Wisconsin, Inc., 201AP2615 (3/6/2012)-WI. PMID- 22519289 TI - OH: Plaintiff failed to identify unknown parties: dismissal of suit vs. RN & MD affirmed. Henik V. Robinson Memorial Hospital, 2012-Ohio-1169 C.A. 25701 (3/21/2012)-OH. PMID- 22519290 TI - FL: Could stroke victim have survived? Verdict for estate reversed for lack of causation. Hollywood Medical Center v. Alfred, 4D09-4878, 4D10-1003 (2/1/2012) FL. PMID- 22519291 TI - PACU refused to aid ventilator-dependent pt.: death resulted. Case on point: Dixon-Gates v. Brooklyn Hospial Center, 2012-22063 (3/7/2012)-NY. PMID- 22519292 TI - Redox properties of lysine- and methionine-coordinated hemes ensure downhill electron transfer in NrfH2A4 nitrite reductase. AB - The multiheme NrfHA nitrite reductase is a menaquinol:nitrite oxidoreductase that catalyzes the 6-electron reduction of nitrite to ammonia in a reaction that involves eight protons. X-ray crystallography of the enzyme from Desulfovibrio vulgaris revealed that the biological unit, NrfH2A4, houses 28 c-type heme groups, 22 of them with low spin and 6 with pentacoordinated high spin configuration. The high spin hemes, which are the electron entry and exit points of the complex, carry a highly unusual coordination for c-type hemes, lysine and methionine as proximal ligands in NrfA and NrfH, respectively. Employing redox titrations followed by X-band EPR spectroscopy and surface-enhanced resonance Raman spectroelectrochemistry, we provide the first experimental evidence for the midpoint redox potential of the NrfH menaquinol-interacting methionine coordinated heme (-270 +/- 10 mV, z = 0.96), identified by the use of the inhibitor HQNO, a structural analogue of the physiological electron donor. The redox potential of the catalytic lysine-coordinated high spin heme of NrfA is -50 +/- 10 mV, z = 0.9. These values determined for the integral NrfH2A4 complex indicate that a driving force for a downhill electron transfer is ensured in this complex. PMID- 22519293 TI - Concentration-dependent photoredox conversion of As(III)/As(V) on illuminated titanium dioxide electrodes. AB - The photoconversion of As(III) (arsenite) and As(V) (arsenate) over a mesoporous TiO(2) electrode was investigated in a photoelectrochemical (PEC) cell for a wide range of concentrations (MUM-mM), under nonbiased (open-circuit potential measurements) and biased (short-circuit current measurements) conditions. Not only As(III) can be oxidized, but also As(V) can be reduced in the anoxic condition under UV irradiation. However, the reversible nature of As(III)/As(V) photoconversion was not observed in the normal air-equilibrated condition because the dissolved O(2) is far more efficient as an electron acceptor than As(V). Although As(III) should be oxidized by holes, its presence did not increase the photooxidation current in a monotonous way: the photocurrent was reduced by the presence of As(III) in the micromolar range but enhanced in the millimolar range. This abnormal concentration-dependent behavior is related with the fate of the intermediate As(IV) species which can be either oxidized or reduced depending on the experimental conditions, combined with surface deactivation for the water photooxidation process. The lowering of the photooxidation current in the presence of micromolar As(III) is ascribed to the role of As(IV) as a charge recombination center. Being an electron acceptor, the addition of As(V) consistently lowers the photocurrent in the entire concentration range. A global concentration-dependent mechanism is proposed accounting for all the PEC results and its relation with the photocatalytic oxidation mechanism is discussed. PMID- 22519294 TI - Immobilized sialyloligo-macroligand and its protein binding specificity. AB - We report a chemoenzymatic synthesis of chain-end functionalized sialyllactose containing glycopolymers with different linkages and their oriented immobilization for glycoarray and SPR-based glyco-biosensor applications. Specifically, O-cyanate chain-end functionalized sialyllactose-containing glycopolymers were synthesized by enzymatic alpha2,3- and alpha2,6-sialylation of a lactose-containing glycopolymer that was synthesized by cyanoxyl-mediated free radical polymerization. (1)H NMR showed almost quantitative alpha2,3- and alpha2,6-sialylation. The O-cyanate chain-end functionalized sialyllactose containing glycopolymers were printed onto amine-functionalized glass slides via isourea bond formation for glycoarray formation. Specific protein binding activity of the arrays was confirmed with alpha2,3- and alpha2,6-sialyl specific binding lectins together with inhibition assays. Further, immobilizing O-cyanate chain-end functionalized sialyllactose-containing glycopolymers onto amine modified SPR chip via isourea bond formation afforded SPR-based glyco-biosensor, which showed specific binding activity for lectins and influenza viral hemagglutinins (HA). These sialyloligo-macroligand derived glycoarray and SPR based glyco-biosensor are closely to mimic 3D nature presentation of sialyloligosaccharides and will provide important high-throughput tools for virus diagnosis and potential antiviral drug candidates screening applications. PMID- 22519296 TI - Cleaning and decontamination efficacy of wiping cloths and silver dihydrogen citrate on food contact surfaces. AB - AIMS: To test the efficacy of four wipe cloth types (cotton bar towel, nonwoven, microfibre and blended cellulose/cotton) with either quaternary ammonia cleaning solution or silver dihydrogen citrate (SDC) in cleaning food contact surfaces. METHODS: Swab samples collected from untreated, cloth-treated and cloth disinfectant-treated surfaces were subjected to hygiene monitoring using adenosine triphosphate (ATP) bioluminescence and aerobic total plate counting (TPC) assays. RESULTS: Adenosine triphosphate measurements taken after wiping the surfaces showed poor cleaning by nonwoven cloths (2.89 RLU 100 cm(-2) ) than the microfibre (2.30 RLU 100 cm(-2) ), cotton terry bar (2.26 RLU 100 cm(-2) ) and blended cellulose/cotton cloth types (2.20 RLU 100 cm(-2) ). The cellulose/cotton cloth showed highest log reduction in ATP-B RLU values (95%) and CFU values (98.03%) when used in combination with SDC disinfectant. CONCLUSIONS: Cleaning effect of wiping cloths on food contact surfaces can be enhanced by dipping them in SDC disinfectant. ATP-B measurements can be used for real-time hygiene monitoring in public sector, and testing microbial contamination provides more reliable measure of cleanliness. SIGNIFICANCE AND IMPACT OF THE STUDY: Contaminated food contact surfaces need regular hygiene monitoring. This study could help to estimate and establish contamination thresholds for surfaces at public sector facilities and to base the effectiveness of cleaning methods. PMID- 22519295 TI - Neuroprotective and neurotrophic actions of glucagon-like peptide-1: an emerging opportunity to treat neurodegenerative and cerebrovascular disorders. AB - Like type-2 diabetes mellitus (T2DM), neurodegenerative disorders and stroke are an ever increasing, health, social and economic burden for developed Westernized countries. Age is an important risk factor in all of these; due to the rapidly increasing rise in the elderly population T2DM and neurodegenerative disorders, both represent a looming threat to healthcare systems. Whereas several efficacious drugs are currently available to ameliorate T2DM, effective treatments to counteract pathogenic processes of neurodegenerative disorders are lacking and represent a major scientific and pharmaceutical challenge. Epidemiological data indicate an association between T2DM and most major neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Likewise, there is an association between T2DM and stroke incidence. Studies have revealed that common pathophysiological features, including oxidative stress, insulin resistance, abnormal protein processing and cognitive decline, occur across these. Based on the presence of shared mechanisms and signalling pathways in these seemingly distinct diseases, one could hypothesize that an effective treatment for one disorder could prove beneficial in the others. Glucagon-like peptide-1 (GLP-1)-based anti-diabetic drugs have drawn particular attention as an effective new strategy to not only regulate blood glucose but also to reduce apoptotic cell death of pancreatic beta cells in T2DM. Evidence supports a neurotrophic and neuroprotective role of GLP-1 receptor (R) stimulation in an increasing array of cellular and animal neurodegeneration models as well as in neurogenesis. Herein, we review the physiological role of GLP-1 in the nervous system, focused towards the potential benefit of GLP-1R stimulation as an immediately translatable treatment strategy for acute and chronic neurological disorders. PMID- 22519297 TI - Design, synthesis, and antiviral evaluation of purine-beta-lactam and purine aminopropanol hybrids. AB - Purine-beta-lactam chimera were prepared as a novel class of hybrid systems through N-alkylation of 6-benzylamino- or 6-benzyloxypurine with (omega haloalkyl)-beta-lactams, followed by reductive ring opening of the beta-lactam ring by LiEt(3)BH to provide an entry into the class of purine-aminopropanol hybrids. Both new types of hybrid systems were assessed for their antiviral activity and cytotoxicity, resulting in the identification of eight purine-beta lactam hybrids and two purine-aminopropanol hybrids as promising lead structures. PMID- 22519300 TI - The impact of HIV/AIDS on children's educational outcome: a critical review of global literature. AB - The number of children losing one or both parents to HIV/AIDS has continued to rise in the past decade, with most of them being school-aged children. This study reviews global literature on the effects of HIV/AIDS (e.g., parental HIV-related illness or death) on children's schooling. Systematic review procedures generated 23 studies for examination. Existing studies show educational disadvantages among children affected by AIDS in various educational outcomes, including school enrollment and attendance, school behavior and performance, school completion, and educational attainment. A number of individual and contextual factors potentially moderate or mediate the effect of HIV/AIDS on children's education. These factors include gender of child, pattern of parental loss (maternal vs. paternal vs. dual), living arrangement (relationship with caregivers, gender of the household head), and household poverty. Current literature indicates limitations in number and scope of existing studies and in educational outcome measurements. There is a lack of studies with longitudinal design and data collection from multiple sources (e.g., students, teachers, caregivers), and a lack of studies on the relationship between psychosocial well-being of children affected by AIDS and their educational outcomes. Future studies need to employ more rigorous methodology and incorporate both individual and contextual factors for children affected by AIDS in various regions. More efforts are needed to design and implement culturally appropriate and context-specific approaches to improve the educational outcomes of children affected by AIDS. PMID- 22519299 TI - Osteogenic potential of poly(ethylene glycol)-poly(dimethylsiloxane) hybrid hydrogels. AB - Growth factors have been shown to be potent mediators of osteogenesis. However, their use in tissue-engineered scaffolds not only can be costly but also can induce undesired responses in surrounding tissues. Thus, the ability to specifically induce osteogenic differentiation in the absence of exogenous growth factors through manipulation of scaffold material properties would be desirable for bone regeneration. Previous research indicates that addition of inorganic or hydrophobic components to organic, hydrophilic scaffolds can enhance multipotent stem cell (MSC) osteogenesis. However, the combined impact of scaffold inorganic content and hydrophobicity on MSC behavior has not been systematically explored, particularly in three-dimensional (3D) culture systems. The aim of the present study was therefore to examine the effects of simultaneous increases in scaffold hydrophobicity and inorganic content on MSC osteogenic fate decisions in a 3D culture environment toward the development of intrinsically osteoinductive scaffolds. Mouse 10T1/2 MSCs were encapsulated in a series of novel scaffolds composed of varying levels of hydrophobic, inorganic poly(dimethylsiloxane) (PDMS) and hydrophilic, organic poly(ethylene glycol) (PEG). After 21 days of culture, increased levels of osteoblast markers, runx2 and osteocalcin, were observed in scaffolds with increased PDMS content. Bone extracellular matrix (ECM) molecules, collagen I and calcium phosphate, were also elevated in formulations with higher PDMS:PEG ratios. Importantly, this osteogenic response appeared to be specific in that markers for chondrocytic, smooth muscle cell, and adipocytic lineages were not similarly affected by variations in scaffold PDMS content. As anticipated, the increase in scaffold hydrophobicity accompanying increasing PDMS levels was associated with elevated scaffold serum protein adsorption. Thus, scaffold inorganic content combined with alterations in adsorbed serum proteins may underlie the observed cell behavior. PMID- 22519301 TI - Alkaline phosphatase immobilization onto Bio-Gide(r) and Bio-Oss(r) for periodontal and bone regeneration. AB - AIM: To evaluate the effect of alkaline phosphatase (ALP) immobilization onto Bio Gide((r)) in vitro, and to study the in vivo performance of ALP-enriched Bio Gide((r)) and/or Bio-Oss((r)) with the purpose to enhance periodontal regeneration. MATERIALS AND METHODS: Alkaline phosphatase ALP was immobilized onto Bio-Gide((r)) and Bio-Oss((r)) . Forty-eight rats received periodontal defects, which were treated according to one of the following strategies: Bio Gide((r)), Bio-Gide((r)) -ALP, Bio-Gide((r)) -ALP/Bio-Oss((r)), Bio-Gide((r)) /Bio-Oss((r)) -ALP, Bio-Gide((r)) -ALP/Bio-Oss((r)) -ALP, or empty. Micro-CT and histological analysis were performed. RESULTS: A 30 min ALP-deposition time was determined as optimal from mineralization capacity assessment and consequently used as Bio-Gide((r)) -ALP membranes in the animal experiment. In vivo results showed that after 2 weeks, the defect and implanted materials were still visible, an inflammatory response was present, and membrane degradation was ongoing. Bone formation, although limited, was observed in the majority of Bio-Gide((r)) -ALP specimens and all of the Bio-Gide((r)) /Bio-Oss((r)) -ALP specimens, and was significantly higher compared with Bio-Gide((r)) and empty controls. After 6 weeks, the defects and particles were still visible, whereas membranes were completely degraded. The inflammatory response was decreased and bone formation appeared superior for Bio-Gide((r)) -ALP treated defects. CONCLUSION: Immobilization of ALP onto guided tissue regeneration (GTR)/ guided bone regeneration (GBR)-materials (Bio-Gide((r)) and Bio-Oss((r))) can enhance the performance of these materials in GTR/GBR procedures. PMID- 22519302 TI - An investigation on knowledge-attitude-practice about injury and the related factors among school children's parents in Jinan, China. AB - The aim of this study was to investigate the knowledge-attitude-practice (KAP) and their related factors on injury prevention and safety promotion among children's parents in the city area, in order to provide scientific data for the development of Safe School in mainland China. A total of 3617 subjects were investigated in Jinan with the help of a self-administered questionnaire which included parental demographic characteristics and 40 questions related to KAP about injury prevention and safety promotion. Responses to each question included only one correct answer. A score of 1 was given if the participant answered correctly, otherwise the score was 0. Therefore, the total KAP score was 40 if all the 40 questions were answered correctly by one respondent. The total KAP scores were classified into two categories for which the cutoff value was the mean of the total KAP scores. The results showed that the KAP scores ranged from 13 to 39, with an average of 30.79 +/- 3.54. Higher KAP scores were statistically associated with mothers (odds ratio [OR] = 1.79) and higher education level (OR = 1.34). It was concluded that parental KAP about injury prevention and safety promotion was unsatisfactory, and health education on KAP about injury prevention and safety promotion for parents, especially among fathers and parents with low education levels, should be strengthened further by Safe School programmes. PMID- 22519303 TI - Solid dosage forms for active antiretroviral therapy (HAART): dissolution profile study of nevirapine by experimental factorial design. AB - Nevirapine is the first antiretroviral member of non-nucleoside reverse transcriptase inhibitor used in active antiretroviral therapy (HAART). The aim of this work was the evaluation of the dissolution profile of nevirapine tablets by means of the Disk Intrinsic Dissolution Rate (DIDR) using a 2(3) factorial design. This study used a triplicate in central point and was based on three independent variables: the rotational speed of the apparatus, the compression force of nevirapine disk, and the distance of the tank dissolution. The dependent variable was set as intrinsic dissolution speed (IDS). IDS was strongly dependent on the rotational speed, compression force, and distance of the apparatus, analyzed by Student's t test with 95% confidence, and confirmed by ANOVA. The rotational speed of nevirapine disks was the main factor contributing to the IDS, whereas the compression force and the distance of disks on the dissolution apparatus revealed no effects. PMID- 22519304 TI - Receptor protein tyrosine phosphatase sigma regulates synapse structure, function and plasticity. AB - The mechanisms that regulate synapse formation and maintenance are incompletely understood. In particular, relatively few inhibitors of synapse formation have been identified. Receptor protein tyrosine phosphatase sigma (RPTPsigma), a transmembrane tyrosine phosphatase, is widely expressed by neurons in developing and mature mammalian brain, and functions as a receptor for chondroitin sulfate proteoglycans that inhibits axon regeneration following injury. In this study, we address RPTPsigma function in the mature brain. We demonstrate increased axon collateral branching in the hippocampus of RPTPsigma null mice during normal aging or following chemically induced seizure, indicating that RPTPsigma maintains neural circuitry by inhibiting axonal branching. Previous studies demonstrated a role for pre-synaptic RPTPsigma promoting synaptic differentiation during development; however, subcellular fractionation revealed enrichment of RPTPsigma in post-synaptic densities. We report that neurons lacking RPTPsigma have an increased density of pre-synaptic varicosities in vitro and increased dendritic spine density and length in vivo. RPTPsigma knockouts exhibit an increased frequency of miniature excitatory post-synaptic currents, and greater paired-pulse facilitation, consistent with increased synapse density but reduced synaptic efficiency. Furthermore, RPTPsigma nulls exhibit reduced long-term potentiation and enhanced novel object recognition memory. We conclude that RPTPsigma limits synapse number and regulates synapse structure and function in the mature CNS. PMID- 22519305 TI - The main determinant of hypotension in nitroglycerine tilt-induced vasovagal syncope. AB - BACKGROUND: The aim of the study was to assess the main determinant of the fall in blood pressure (BP) responsible for the head-up tilt testing-induced syncope. METHODS AND RESULTS: The study involved 200 patients (mean age 42 +/- 3; 81 male) with syncope of unknown origin after the first evaluation. According to the response to the diagnostic tilt test, the population study was divided into four groups: Group I with mixed vasovagal syncope; Group II with cardioinhibitory syncope; Group III with vasodepressive syncope; Group IV: 40 patients with clinical syncope but no tilt-induced syncope. Finger arterial BP (Portapres, TNO, Amsterdam, the Netherlands) was recorded during tilt testing. Left ventricular stroke volume (SV), cardiac output (CO), and total peripheral resistance (TPR) were computed from the pressure pulsations (Modelflow, TNO, Amsterdam, the Netherlands). During syncopal phase, the TPR decreased significantly in Group III, and increased in Group I and in Group II. CO decreased in Group I and in Group II and did not change significantly in Group III. SV decreased significantly in all groups. CONCLUSIONS: Our data showed that the arterial system appears to be the main determinant of the BP fall in vasodepressive vasovagal syncope; while the impaired constrictive response of the venous system, leading to reduced venous return to the heart, appears to be the main determinant of BP fall in mixed and cardioinhibitory vasovagal syncope. PMID- 22519306 TI - Perspective on density functional theory. AB - Density functional theory (DFT) is an incredible success story. The low computational cost, combined with useful (but not yet chemical) accuracy, has made DFT a standard technique in most branches of chemistry and materials science. Electronic structure problems in a dazzling variety of fields are currently being tackled. However, DFT has many limitations in its present form: too many approximations, failures for strongly correlated systems, too slow for liquids, etc. This perspective reviews some recent progress and ongoing challenges. PMID- 22519307 TI - Perspective: relativistic effects. AB - This perspective article discusses some broadly-known and some less broadly-known consequences of Einstein's special relativity in quantum chemistry, and provides a brief outline of the theoretical methods currently in use, along with a discussion of recent developments and selected applications. The treatment of the electron correlation problem in relativistic quantum chemistry methods, and expanding the reach of the available relativistic methods to calculate all kinds of energy derivative properties, in particular spectroscopic and magnetic properties, requires on-going efforts. PMID- 22519308 TI - Communication: The highest frequency hydrogen bond vibration and an experimental value for the dissociation energy of formic acid dimer. AB - The highest frequency hydrogen bond fundamental of formic acid dimer, nu(24) (B(u)), is experimentally located at 264 cm(-1). FTIR spectra of this in-plane bending mode of (HCOOH)(2) and band centers of its symmetric D isotopologues (isotopomers) recorded in a supersonic slit jet expansion are presented. Comparison to earlier studies at room temperature reveals the large influence of thermal excitation on the band maximum. Together with three B(u) combination states involving hydrogen bond fundamentals and with recent progress for the Raman-active modes, this brings into reach an accurate statistical thermodynamics treatment of the dimerization process up to room temperature. We obtain D(0) = 59.5(5) kJ/mol as the best experimental estimate for the dimer dissociation energy at 0 K. Further improvements have to wait for a more consistent determination of the room temperature equilibrium constant. PMID- 22519309 TI - A geometrical correction for the inter- and intra-molecular basis set superposition error in Hartree-Fock and density functional theory calculations for large systems. AB - A semi-empirical counterpoise-type correction for basis set superposition error (BSSE) in molecular systems is presented. An atom pair-wise potential corrects for the inter- and intra-molecular BSSE in supermolecular Hartree-Fock (HF) or density functional theory (DFT) calculations. This geometrical counterpoise (gCP) denoted scheme depends only on the molecular geometry, i.e., no input from the electronic wave-function is required and hence is applicable to molecules with ten thousands of atoms. The four necessary parameters have been determined by a fit to standard Boys and Bernadi counterpoise corrections for Hobza's S66*8 set of non-covalently bound complexes (528 data points). The method's target are small basis sets (e.g., minimal, split-valence, 6-31G*), but reliable results are also obtained for larger triple-zeta sets. The intermolecular BSSE is calculated by gCP within a typical error of 10%-30% that proves sufficient in many practical applications. The approach is suggested as a quantitative correction in production work and can also be routinely applied to estimate the magnitude of the BSSE beforehand. The applicability for biomolecules as the primary target is tested for the crambin protein, where gCP removes intramolecular BSSE effectively and yields conformational energies comparable to def2-TZVP basis results. Good mutual agreement is also found with Jensen's ACP(4) scheme, estimating the intramolecular BSSE in the phenylalanine-glycine-phenylalanine tripeptide, for which also a relaxed rotational energy profile is presented. A variety of minimal and double-zeta basis sets combined with gCP and the dispersion corrections DFT D3 and DFT-NL are successfully benchmarked on the S22 and S66 sets of non covalent interactions. Outstanding performance with a mean absolute deviation (MAD) of 0.51 kcal/mol (0.38 kcal/mol after D3-refit) is obtained at the gCP corrected HF-D3/(minimal basis) level for the S66 benchmark. The gCP-corrected B3LYP-D3/6-31G* model chemistry yields MAD=0.68 kcal/mol, which represents a huge improvement over plain B3LYP/6-31G* (MAD=2.3 kcal/mol). Application of gCP corrected B97-D3 and HF-D3 on a set of large protein-ligand complexes prove the robustness of the method. Analytical gCP gradients make optimizations of large systems feasible with small basis sets, as demonstrated for the inter-ring distances of 9-helicene and most of the complexes in Hobza's S22 test set. The method is implemented in a freely available FORTRAN program obtainable from the author's website. PMID- 22519310 TI - Adaptive Green-Kubo estimates of transport coefficients from molecular dynamics based on robust error analysis. AB - We present a rigorous Green-Kubo methodology for calculating transport coefficients based on on-the-fly estimates of: (a) statistical stationarity of the relevant process, and (b) error in the resulting coefficient. The methodology uses time samples efficiently across an ensemble of parallel replicas to yield accurate estimates, which is particularly useful for estimating the thermal conductivity of semi-conductors near their Debye temperatures where the characteristic decay times of the heat flux correlation functions are large. Employing and extending the error analysis of Zwanzig and Ailawadi [Phys. Rev. 182, 280 (1969)] and Frenkel [in Proceedings of the International School of Physics "Enrico Fermi", Course LXXV (North-Holland Publishing Company, Amsterdam, 1980)] to the integral of correlation, we are able to provide tight theoretical bounds for the error in the estimate of the transport coefficient. To demonstrate the performance of the method, four test cases of increasing computational cost and complexity are presented: the viscosity of Ar and water, and the thermal conductivity of Si and GaN. In addition to producing accurate estimates of the transport coefficients for these materials, this work demonstrates precise agreement of the computed variances in the estimates of the correlation and the transport coefficient with the extended theory based on the assumption that fluctuations follow a Gaussian process. The proposed algorithm in conjunction with the extended theory enables the calculation of transport coefficients with the Green-Kubo method accurately and efficiently. PMID- 22519311 TI - A perturbation density functional theory for the competition between inter and intramolecular association. AB - Using the framework of Wertheim's thermodynamic perturbation theory we develop the first density functional theory which accounts for intramolecular association in chain molecules. To test the theory new Monte Carlo simulations are performed at a fluid solid interface for a 4 segment chain which can both intra and intermolecularly associate. The theory and simulation results are found to be in excellent agreement. It is shown that the inclusion of intramolecular association can have profound effects on interfacial properties such as interfacial tension and the partition coefficient. PMID- 22519312 TI - Density functional theory with fractional orbital occupations. AB - In contrast to the original Kohn-Sham (KS) formalism, we propose a density functional theory (DFT) with fractional orbital occupations for the study of ground states of many-electron systems, wherein strong static correlation is shown to be described. Even at the simplest level represented by the local density approximation (LDA), our resulting DFT-LDA is shown to improve upon KS LDA for multi-reference systems, such as dissociation of H(2) and N(2), and twisted ethylene, while performing similar to KS-LDA for single-reference systems, such as reaction energies and equilibrium geometries. Because of its computational efficiency (similar to KS-LDA), this DFT-LDA is applied to the study of the singlet-triplet energy gaps (ST gaps) of acenes, which are "challenging problems" for conventional electronic structure methods due to the presence of strong static correlation effects. Our calculated ST gaps are in good agreement with the existing experimental and high-level ab initio data. The ST gaps are shown to decrease monotonically with the increase of chain length, and become vanishingly small (within 0.1 kcal/mol) in the limit of an infinitely large polyacene. In addition, based on our calculated active orbital occupation numbers, the ground states for large acenes are shown to be polyradical singlets. PMID- 22519313 TI - A study of the accuracy of moment-closure approximations for stochastic chemical kinetics. AB - Moment-closure approximations have in recent years become a popular means to estimate the mean concentrations and the variances and covariances of the concentration fluctuations of species involved in stochastic chemical reactions, such as those inside cells. The typical assumption behind these methods is that all cumulants of the probability distribution function solution of the chemical master equation which are higher than a certain order are negligibly small and hence can be set to zero. These approximations are ad hoc and hence the reliability of the predictions of these class of methods is presently unclear. In this article, we study the accuracy of the two moment approximation (2MA) (third and higher order cumulants are zero) and of the three moment approximation (3MA) (fourth and higher order cumulants are zero) for chemical systems which are monostable and composed of unimolecular and bimolecular reactions. We use the system-size expansion, a systematic method of solving the chemical master equation for monostable reaction systems, to calculate in the limit of large reaction volumes, the first- and second-order corrections to the mean concentration prediction of the rate equations and the first-order correction to the variance and covariance predictions of the linear-noise approximation. We also compute these corrections using the 2MA and the 3MA. Comparison of the latter results with those of the system-size expansion shows that: (i) the 2MA accurately captures the first-order correction to the rate equations but its first-order correction to the linear-noise approximation exhibits the wrong dependence on the rate constants. (ii) the 3MA accurately captures the first- and second-order corrections to the rate equation predictions and the first-order correction to the linear-noise approximation. Hence while both the 2MA and the 3MA are more accurate than the rate equations, only the 3MA is more accurate than the linear-noise approximation across all of parameter space. The analytical results are numerically validated for dimerization and enzyme-catalyzed reactions. PMID- 22519314 TI - Anisotropic behavior of organic molecules on prepatterned surfaces. AB - The nucleation of organic molecules on surfaces, prepatterned with stripes, is investigated with emphasis on anisotropy effects. Representing the molecules as ellipsoids, the related particle-particle interaction is modeled by means of a generalized Gay-Berne potential for similar biaxial particles. The orientation behavior of these ellipsoidal molecules induced by the stripe pattern is studied for the first monolayer by performing kinetic Monte Carlo simulations. It is shown how the properties of the particle alignment depend on energy scales, temperature, and flux. Based on the fact the particles strictly arrange in rows, it is furthermore instructive to analyze the orientation behavior within the different rows. Finally, the transfer of orientation from a preset row of molecules with fixed orientation to other nucleating particles is examined. PMID- 22519315 TI - Quantization and fractional quantization of currents in periodically driven stochastic systems. I. Average currents. AB - This article studies Markovian stochastic motion of a particle on a graph with finite number of nodes and periodically time-dependent transition rates that satisfy the detailed balance condition at any time. We show that under general conditions, the currents in the system on average become quantized or fractionally quantized for adiabatic driving at sufficiently low temperature. We develop the quantitative theory of this quantization and interpret it in terms of topological invariants. By implementing the celebrated Kirchhoff theorem we derive a general and explicit formula for the average generated current that plays a role of an efficient tool for treating the current quantization effects. PMID- 22519316 TI - Quantization and fractional quantization of currents in periodically driven stochastic systems. II. Full counting statistics. AB - We study Markovian stochastic motion on a graph with finite number of nodes and adiabatically periodically driven transition rates. We show that, under general conditions, the quantized currents that appear at low temperatures are a manifestation of topological invariants in the counting statistics of currents. This observation provides an approach for classification of topological properties of the counting statistics, as well as for extensions of the phenomenon of the robust quantization of currents at low temperatures to the properties of the counting statistics which persist to finite temperatures. PMID- 22519317 TI - Long-range corrected hybrid meta-generalized-gradient approximations with dispersion corrections. AB - We propose a long-range corrected hybrid meta-generalized-gradient approximation (GGA) functional, based on a global hybrid meta-GGA functional, M05 [Y. Zhao, N. E. Schultz, and D. G. Truhlar, J. Chem. Phys. 123, 161103 (2005)], and empirical atom-atom dispersion corrections. Our resulting functional, omegaM05-D, is shown to be accurate for a very wide range of applications, such as thermochemistry, kinetics, noncovalent interactions, equilibrium geometries, frontier orbital energies, fundamental gaps, and excitation energies. In addition, we present three new databases, IP131 (131 ionization potentials), EA115 (115 electron affinities), and FG115 (115 fundamental gaps), consisting of experimental molecular geometries and accurate reference values, which will be useful in the assessment of the accuracy of density functional approximations. PMID- 22519318 TI - Dual-etalon frequency-comb cavity ringdown spectrometer. AB - We have demonstrated a spectroscopic technique for simultaneously obtaining broad spectral bandwidth and high frequency resolution absorption measurements, with 5 MUs temporal resolution, continuously for tens of microseconds in an apparatus with no active stabilization. The technique utilizes two passive air-gap etalons to imprint two frequency comb patterns onto a single pulsed light source. The air gap etalons also serve as cavity ringdown cells increasing the sensitivity of the absorption spectroscopy by increasing the interrogation path length. Here, we demonstrate the operation of the spectrometer utilizing a ~0.15 cm(-1) bandwidth pulsed dye laser and two nearly identical 300 MHz free-spectral range confocal air-gap etalons each with a finesse of ~1 * 10(5), to investigate the (1,1,3) overtone of water and the R(7) transition of the O(2) b(1)Sigma(g)(+)< X(3)Sigma(g)(-) (2,0) band with high spectral resolution. PMID- 22519319 TI - Source of slow lithium atoms from Ne or H2 matrix isolation sublimation. AB - We have studied, via laser absorption spectroscopy, the velocity distribution of (7)Li atoms released from cryogenic matrices of solid neon or molecular hydrogen. The Li atoms are implanted into the Ne or H(2) matrices--grown onto a sapphire substrate--by laser ablation of a solid Li or LiH precursor. A heat pulse is then applied to the sapphire substrate sublimating the matrix together with the isolated atoms. With a NiCr film resistor deposited directly onto the sapphire substrate we are able to transfer high instantaneous power to the matrix, thus reaching a fast sublimation regime. In this regime the Li atoms can get entrained in the released matrix gas, and we were also able to achieve matrix sublimation times down to 10 MUs for both H(2) or Ne matrix, enabling us to proceed with the trapping of the species of our interest such as atomic hydrogen, lithium, and molecules. The sublimation of the H(2) matrix, with its large center-of-mass velocity, provides evidence for a new regime of one-dimensional thermalization. The laser ablated Li seems to penetrate the H(2) matrix deeper than it does in Ne. PMID- 22519320 TI - Electronic, vibrational, and rotational structures in the S0 1A1 and S1 1A1 states of phenanthrene. AB - Electronic and vibrational structures in the S(0) (1)A(1) and S(1) (1)A(1) states of jet-cooled phenanthrene-h(10) and phenanthrene-d(10) were analyzed by high resolution spectroscopy using a tunable nanosecond pulsed laser. The normal vibrational energies and molecular structures were estimated by ab initio calculations with geometry optimization in order to carry out a normal-mode analysis of observed vibronic bands. The rotational structure was analyzed by ultrahigh-resolution spectroscopy using a continuous-wave single-mode laser. It has been demonstrated that the stable geometrical structure is markedly changed upon the S(1) <- S(0) electronic excitation. Nonradiative internal conversion in the S(1) state is expected to be enhanced by this structural change. The observed fluorescence lifetime has been found to be much shorter than the calculated radiative lifetime, indicating that the fluorescence quantum yield is low. The lifetime of phenanthrene-d(10) is longer than that of phenanthrene-h(10) (normal deuterium effect). This fact is in contrast with anthracene, which is a structural isomer of phenanthrene. The lifetime at the S(1) zero-vibrational level of anthracene-d(10) is much shorter than that of anthracene-h(10) (inverse deuterium effect). In phenanthrene, the lifetime becomes monotonically shorter as the vibrational energy increases for both isotopical molecules without marked vibrational dependence. The vibrational structure of the S(0) state is considered to be homogeneous and quasi-continuous (statistical limit) in the S(1) energy region. PMID- 22519321 TI - Spectroscopy and dynamics of barium-doped helium nanodroplets. AB - Excitation spectra up to the ionization threshold are reported for barium atoms located on the surface of helium nanodroplets. For states with low principal quantum number, the resonances are substantially broadened and shifted towards higher energy with respect to the gas phase. This has been attributed to the repulsive interaction of the excited atom with the helium at the Franck-Condon region. In contrast, for states with high principal quantum number the resonances are narrower and shifted towards lower energies. Photoelectron and ZEKE spectroscopy reveal that the redshift results from a lowering of the ionization threshold due to polarization of the helium by the barium ionic core. As a result of the repulsive interaction with the helium, excited barium atoms desorb from the surface of the droplets. Only when excited to the 6s6p (1)P(1) state, which reveals an attractive interaction with the helium, the atoms remain attached to the droplets. PMID- 22519322 TI - Near-threshold shape resonance in the photoionization of 2-butyne. AB - Photoelectron velocity map imaging is combined with one- and two-photon ionization to study the near threshold photoionization of the 2-butyne molecule. In this region, the photoabsorption and photoionization cross sections display a very intense broad feature that is assigned to an l = 4, pi(g) shape resonance. The effect of this shape resonance on the vibrational branching ratios and photoelectron angular distributions is explored. Theoretical calculations of the photoionization cross section and photoelectron angular distributions are in good agreement with the experiments. The results for 2-butyne are compared with those of acetylene, propyne, and 1-butyne, none of which show such significant enhancements near threshold, and the differences are rationalized in terms of the symmetries and orbital angular momenta of the highest occupied orbitals and the corresponding shape resonances. Expectations for larger alkynes and alkynyl radicals are also discussed. A preliminary measurement of the ionization energy of the 2-butyne dimer is also presented. PMID- 22519323 TI - A new method for investigating infrared spectra of protonated benzene (C6H7+) and cyclohexadienyl radical (c-C6H7) using para-hydrogen. AB - We use protonated benzene (C(6)H(7)(+)) and cyclohexadienyl radical (c-C(6)H(7)) to demonstrate a new method that has some advantages over other methods currently used. C(6)H(7)(+) and c-C(6)H(7) were produced on electron bombardment of a mixture of benzene (C(6)H(6)) and para-hydrogen during deposition onto a target at 3.2 K. Infrared (IR) absorption lines of C(6)H(7)(+) decreased in intensity when the matrix was irradiated at 365 nm or maintained in the dark for an extended period, whereas those of c-C(6)H(7) increased in intensity. Observed vibrational wavenumbers, relative IR intensities, and deuterium isotopic shifts agree with those predicted theoretically. This method, providing a wide spectral coverage with narrow lines and accurate relative IR intensities, can be applied to larger protonated polyaromatic hydrocarbons and their neutral species which are difficult to study with other methods. PMID- 22519324 TI - Vibrational Fano resonances in dipole-bound anions. AB - This paper explores Fano resonances due to non-adiabatic coupling of vibrational modes and the electron continuum in dipole-bound anions. We adopt a simple one electron model consisting of a point dipole and an auxiliary potential to represent the electron interaction with the neutral core. Nuclear motion is added by assuming that harmonic vibrations modulate the dipole moment. When the model is parameterized to simulate key features of the water tetramer anion, the resultant photodetachment lineshape closely resembles that observed experimentally and analyzed as a Fano resonance with a parameter q close to -1. Other parameterizations are explored for the model and it is found that large changes in the auxiliary potential are required to change the sign of q. This is consistent with the experimental finding that q is negative for all water cluster sizes studied. PMID- 22519325 TI - Photoelectron spectroscopy of the molecular anions, ZrO-, HfO-, HfHO-, and HfO2H . AB - Negative ion photoelectron spectra of ZrO(-), HfO(-), HfHO(-), and HfO(2)H(-) are reported. Even though zirconium- and hafnium-containing molecules typically exhibit similar chemistries, the negative ion photoelectron spectral profiles of ZrO(-) and HfO(-) are dramatically different from one another. By comparing these data with relevant theoretical and experimental studies, as well as by using insights drawn from atomic spectra, spin-orbit interactions, and relativistic effects, the photodetachment transitions in the spectra of ZrO(-) and HfO(-) were assigned. As a result, the electron affinities of ZrO and HfO were determined to be 1.26 +/- 0.05 eV and 0.60 +/- 0.05 eV, respectively. The anion photoelectron spectra of HfHO(-) and HfO(2)H(-) are similar to one another and their structural connectivities are likely to be H-Hf-O(-) and O-Hf-OH(-), respectively. The electron affinities of HfHO and HfO(2)H are 1.70 +/- 0.05 eV and 1.73 +/- 0.05 eV, respectively. PMID- 22519326 TI - A systematic investigation of the ground state potential energy surface of H3+. AB - Based on different ab initio electronic structure calculations (CI-R12 and Gaussian Geminals) of the Born-Oppenheimer electronic energy E(BO) of H(3)(+) from high to highest quality, we build up a potential energy surface which represents a highly reliable form of the topology of the whole potential region, locally and globally. We use the CI-R12 method in order to get within reasonable CPU-time a relatively dense grid of energy points. We demonstrate that CI-R12 is good enough to give an accurate surface, i.e., Gaussian Geminals are not absolutely necessary. For different types of potential energy surface fits, we performed variational calculations of all bound vibrational states, including resonances above the dissociation limit, for total angular momentum J = 0. We clarify the differences between different fits of the energy to various functional forms of the potential surface. Small rms-values (<1 cm(-1)) of the fit do not provide precise information about the interpolatory behaviour of the fit functions. PMID- 22519327 TI - Resonant Auger spectroscopy at the carbon and nitrogen K-edges of pyrimidine. AB - The resonant Auger electron spectra obtained after photoexcitation below the C and N 1s ionization thresholds in the pyrimidine molecule have been measured at several photon energies. The results show the relevance of the localization of the inner hole and of the matching between the symmetries of the intermediate and final states in the decay spectra via participator transitions. The comparison with the Auger electron spectra suggests some assignment for the two-hole-one particle states reached via spectator transitions. The analysis of the participator decay is supported by state-of-the art density functional theory calculations. PMID- 22519330 TI - Vibrational mode frequencies of silica species in SiO2-H2O liquids and glasses from ab initio molecular dynamics. AB - Vibrational spectroscopy techniques are commonly used to probe the atomic-scale structure of silica species in aqueous solution and hydrous silica glasses. However, unequivocal assignment of individual spectroscopic features to specific vibrational modes is challenging. In this contribution, we establish a connection between experimentally observed vibrational bands and ab initio molecular dynamics (MD) of silica species in solution and in hydrous silica glass. Using the mode-projection approach, we decompose the vibrations of silica species into subspectra resulting from several fundamental structural subunits: The SiO(4) tetrahedron of symmetry T(d), the bridging oxygen (BO) Si-O-Si of symmetry C(2v), the geminal oxygen O-Si-O of symmetry C(2v), the individual Si-OH stretching, and the specific ethane-like symmetric stretching contribution of the H(6)Si(2)O(7) dimer. This allows us to study relevant vibrations of these subunits in any degree of polymerization, from the Q(0) monomer up to the fully polymerized Q(4) tetrahedra. Demonstrating the potential of this approach for supplementing the interpretation of experimental spectra, we compare the calculated frequencies to those extracted from experimental Raman spectra of hydrous silica glasses and silica species in aqueous solution. We discuss observed features such as the double-peaked contribution of the Q(2) tetrahedral symmetric stretch, the individual Si-OH stretching vibrations, the origin of the experimentally observed band at 970 cm(-1) and the ethane-like vibrational contribution of the H(6)Si(2)O(7) dimer at 870 cm(-1). PMID- 22519328 TI - Structures of small bismuth cluster cations. AB - The structures of bismuth cluster cations in the range between 4 and 14 atoms have been assigned by a combination of gas phase ion mobility and trapped ion electron diffraction measurements together with density functional theory calculations. We find that above 8 atoms the clusters adopt prolate structures with coordination numbers between 3 and 4 and highly directional bonds. These open structures are more like those seen for clusters of semiconducting-in-bulk elements (such as silicon) rather than resembling the compact structures typical for clusters of metallic-in-bulk elements. An accurate description of bismuth clusters at the level of density functional theory, in particular of fragmentation pathways and dissociation energetics, requires taking spin-orbit coupling into account. For n = 11 we infer that low energy isomers can have fragmentation thresholds comparable to their structural interconversion barriers. This gives rise to experimental isomer distributions which are dependent on formation and annealing histories. PMID- 22519329 TI - A pure H2O isolated line-shape model based on classical molecular dynamics simulations of velocity changes and semi-classical calculations of speed dependent collisional parameters. AB - It is well known that the Voigt profile does not well describe the (measured) shapes of isolated lines. This is due to the neglect of the intermolecular collision-induced velocity changes and of the speed dependence of the collisional parameters. In this paper, we present a new line profile model for pure H(2)O which takes both of these effects into account. The speed dependence of the collisional parameters has been calculated by a semi-classical method. The velocity changes have been modeled by using the Keilson-Storer collision kernel with two characteristic parameters. The latter have been deduced from classical molecular dynamics simulations which also indicate that, for pure H(2)O, the correlation between velocity-changing and state-changing collisions is not negligible, a result confirmed by the analysis of measured spectra. A partially correlated speed-dependent Keilson-Storer model has thus been adopted to describe the line-shape. Comparisons between simulated spectra and measurements for four self-broadened lines in the near-infrared at various pressures show excellent agreements. PMID- 22519332 TI - Bridge function for the dipolar fluid from simulation. AB - The exact bridge function of the Lennard-Jones dipolar (Stockmayer) fluid is extracted from Monte Carlo simulation data. The projections g(mnl)(r) onto rotational invariants of the non-spherically symmetric pair distribution function g(r, Omega) are accumulated during simulation. Making intensive use of anisotropic integral equation techniques, the molecular Ornstein-Zernike equation is then inverted in order to derive the direct correlation function c(mnl)(r), the cavity function y(mnl)(r), the negative excess potential of mean force lny|(mnl)(r), and the bridge function b(mnl)(r) projections. b(r, Omega) presents strong, non-universal anisotropies at high dipolar coupling. This simulation data analysis may serve as reference and guide for approximated bridge function theories of dipolar fluids and is a valuable step towards the case of more refined, nonlinear water-like geometries. PMID- 22519333 TI - Geometric influence on Ruderman-Kittel-Kasuya-Yosida interactions in zigzag carbon nanotubes. AB - We derive an analytic description of the spin susceptibility in finite length zigzag carbon nanotubes (CNT) with chirality (n, 0). The spin susceptibility is proportional to the Ruderman-Kittel-Kasuya-Yosida (RKKY) interactions which describes indirect carrier mediated exchange coupling between localized magnetic moments. We show that the strongest RKKY interactions are along the edges of the nanotube and in the thermodynamic limit at half filling with spin symmetry the shape of the susceptibility curve about the edge of the CNT can be determined solely by the lattice geometry represented by the parameter n and a parameter L which describes the nanotube length. We also show that the introduction of Zeeman splitting or doping may have no effect on the spin susceptibility, provided n is small. A detailed knowledge of magnetic interactions, such as RKKY interactions, in CNT is of vital importance to the development of nanotechnology applications. PMID- 22519331 TI - Entropic estimate of cooperative binding of substrate on a single oligomeric enzyme: an index of cooperativity. AB - Here we have systematically studied the cooperative binding of substrate molecules on the active sites of a single oligomeric enzyme in a chemiostatic condition. The average number of bound substrate and the net velocity of the enzyme catalyzed reaction are studied by the formulation of stochastic master equation for the cooperative binding classified here as spatial and temporal. We have estimated the entropy production for the cooperative binding schemes based on single trajectory analysis using a kinetic Monte Carlo technique. It is found that the total as well as the medium entropy production shows the same generic diagnostic signature for detecting the cooperativity, usually characterized in terms of the net velocity of the reaction. This feature is also found to be valid for the total entropy production rate at the non-equilibrium steady state. We have introduced an index of cooperativity, C, defined in terms of the ratio of the surprisals or equivalently, the stochastic system entropy associated with the fully bound state of the cooperative and non-cooperative cases. The criteria of cooperativity in terms of C is compared with that of the Hill coefficient of some relevant experimental result and gives a microscopic insight on the mechanism of cooperative binding of substrate on a single oligomeric enzyme which is usually estimated from the macroscopic reaction rate. PMID- 22519334 TI - Solvation free energies and hydration structure of N-methyl-p-nitroaniline. AB - Solvation Gibbs energies of N-methyl-p-nitroaniline (MNA) in water and 1-octanol are calculated using the expanded ensemble molecular dynamics method with a force field taken from the literature. The accuracy of the free energy calculations is verified with the experimental Gibbs free energy data and found to reproduce the experimental 1-octanol/water partition coefficient to within +/-0.1 in log unit. To investigate the hydration structure around N-methyl-p-nitroaniline, an independent NVT molecular dynamics simulation was performed at ambient conditions. The local organization of water molecules around the solute MNA molecule was investigated using the radial distribution function (RDF), the coordination number, and the extent of hydrogen bonding. The spatial distribution functions (SDFs) show that the water molecules are distributed above and below the nitrogen atoms parallel to the plane of aromatic ring for both the methylamino and nitro functional groups. It is found that these groups have a significant effect on the hydration of MNA with water molecules forming two weak hydrogen bonds with both the methylamino and nitro groups. The hydration structures around the functional groups in MNA in water are different from those that have been found for methylamine, nitrobenzene, and benzene in aqueous solutions, and these differences together with weak hydrogen bonds explain the lower solubility of MNA in water. The RDFs together with SDFs provide a tool for the understanding the hydration of MNA (and other molecules) and therefore their solubility. PMID- 22519335 TI - Time dependent stretching of aging dynamics in a generalized hydrodynamic model for supercooled liquids. AB - The nonequilibrium dynamics and aging behavior of a supercooled liquid is investigated from an analysis of the correlation of density fluctuations at two different times. The dynamic correlation functions are computed by solving numerically the equations of nonlinear fluctuating hydrodynamics. The aging time dependence follows a modified stretched exponential form with a relaxation time which is dependent on the aging time. This is similar to the behavior seen in the aging data of dielectric response functions of a typical glass forming liquid. PMID- 22519336 TI - Computer simulation of sedimentation of ionic systems using the Wolf method. AB - We present computer simulation results for 1:1 and 2:1 electrolyte solutions in the presence of a gravitational field, using the Monte Carlo method in the NVT ensemble for the restrictive primitive model. Coulombic interactions were taken into account comparing the Ewald and Wolf methods. Three variations of Ewald summations were considered: the exact method for slab geometries (EW2D), and the three-dimensional (3D) versions with and without a dipolar correction (EW3DC and EW3D, respectively). The equivalent 3D Wolf protocols were applied under the same conditions (WF3DC and WF3D, respectively). The Wolf and Ewald methods agree accurately in the prediction of several thermodynamic and structural properties for these inhomogeneous systems: excess internal energies, isochoric heath capacities, and density and electrostatic potential profiles. The main advantage using the Wolf method is the significant saving in computing time, which is approximately six times faster than EW3D and EW3DC, and sixty times faster than EW2D. PMID- 22519337 TI - Molecular dynamics determination of the surface tension of silver-gold liquid alloys and the Tolman length of nanoalloys. AB - Using molecular dynamics simulations, an embedded-atom model potential, and the mechanistic route, we have computed the pressure tensor and the surface tension gamma of Ag-Au liquid alloys. Although the model generally underestimates gamma for pure metals, calculations for a bulk planar slab exhibit nonlinear variations of gamma with increasing gold concentration, which agree with experiments and can be accounted for by a perfect solution model. Calculations for various nanoscale droplets containing between 100 and 3200 atoms show a systematic decrease of gamma with increasing droplet radius R. The positive Tolman length of the alloy determined from these size variations is estimated to vary slightly with gold concentration. The effects of temperature in the range 1300-1700 K are discussed. PMID- 22519338 TI - Interfacial and coexistence properties of soft spheres with a short-range attractive Yukawa fluid: molecular dynamics simulations. AB - Molecular dynamics simulations have been carried out to obtain the interfacial and coexistence properties of soft-sphere attractive Yukawa (SAY) fluids with short attraction range, kappa = 10, 9, 8, 7, 6, and 5. All our simulation results are new. These data are also compared with the recently reported results in the literature of hard-core attractive Yukawa (HAY) fluids. We show that the interfacial and coexistence properties of both potentials are different. For the surveyed systems, here we show that all coexistence curves collapse into a master curve when we rescale with their respective critical points and the surface tension curves form a single master curve when we plot gamma* vs. T/T(c). PMID- 22519339 TI - Inhomogeneous charge transfer within monolayer zinc phthalocyanine absorbed on TiO2(110). AB - The d-orbital contribution from the transition metal centers of phthalocyanine brings difficulties to understand the role of the organic ligands and their molecular frontier orbitals when it adsorbs on oxide surfaces. Here we use zinc phthalocyanine (ZnPc)/TiO(2)(110) as a model system where the zinc d-orbitals are located deep below the organic orbitals leaving room for a detailed study of the interaction between the organic ligand and the substrate. A charge depletion from the highest occupied molecular orbital is observed, and a consequent shift of N1s and C1s to higher binding energy in photoelectron spectroscopy (PES). A detailed comparison of peak shifts in PES and near-edge X-ray absorption fine structure spectroscopy illustrates a slightly uneven charge distribution within the molecular plane and an inhomogeneous charge transfer screening between the center and periphery of the organic ligand: faster in the periphery and slower at the center, which is different from other metal phthalocyanine, e.g., FePc/TiO(2). Our results indicate that the metal center can substantially influence the electronic properties of the organic ligand at the interface by introducing an additional charge transfer channel to the inner molecular part. PMID- 22519340 TI - Creation and recovery of a W(111) single atom gas field ion source. AB - Tungsten single atom tips have been prepared from a single crystal W(111) oriented wire using the chemical assisted field evaporation and etching method. Etching to a single atom tip occurs through a symmetric structure and leads to a predictable last atom unlike etching with polycrystalline tips. The single atom tip formation procedure is shown in an atom by atom removal process. Rebuilds of single atom tips occur on the same crystalline axis as the original tip such that ion emission emanates along a fixed direction for all tip rebuilds. This preparation method could be utilized and developed to prepare single atom tips for ion source development. PMID- 22519341 TI - Growth and electronic structure of Sm on thin Al2O3/Ni3Al(111) films. AB - The growth and electronic structure of vapor-deposited Sm on a well-ordered Al(2)O(3)/Ni(3)Al(111) ultrathin film under ultrahigh vacuum conditions at room temperature have been studied comprehensively using synchrotron radiation photoemission spectroscopy, X-ray photoelectron spectroscopy, work function measurements, scanning tunneling microscopy, and low-energy electron diffraction. Our results indicate that at room temperature Sm grows in a layer-by-layer fashion up to at least 1 ML, followed by three-dimensional growth. The interaction of Sm with Al(2)O(3) thin films leads to an initial oxidation of Sm, accompanied by a parallel reduction of the Al(2)O(3) substrate. Both the oxidation states of Sm(2+) and Sm(3+) are found at low coverage (<1 ML). The concentration of Sm(2+) saturates below 0.4 ML, while that of Sm(3+) keeps increasing until the metallic state of Sm appears at high coverages. PMID- 22519342 TI - Atomic imaging of atomic layer deposition oxide nucleation with trimethylaluminum on As-rich InGaAs(001) 2 * 4 vs Ga/In-rich InGaAs(001) 4 * 2. AB - Formation of a contaminant free, flat, electrically passive interface to a gate oxide such as a-Al(2)O(3) is the critical step in fabricating III-V metal oxide semiconductor field effect transistors; while the bulk oxide is amorphous, the interface may need to be ordered to prevent electrical defect formation. A two temperature in situ cleaning process is shown to produce a clean, flat group III or group V rich InGaAs surface. The dependence of initial surface reconstruction and dosing temperature of the seeding of aluminum with trimethylaluminum dosing is observed to produce an ordered unpinned passivation layer on InGaAs(001)-(4 * 2) surface at sample temperatures below 190 degrees C. Conversely, the InGaAs(001)-(2 * 4) surface is shown to generate an unpinned passivation layer with a seeding temperature up to 280 degrees C. For both reconstructions, the chemical drive force is consistent with formation of As-Al-As bonds. The optimal seed layer protects the surface from background contamination. PMID- 22519343 TI - Hofmeister effects in micromolar electrolyte solutions. AB - Ions induce both specific (Hofmeister) and non-specific (Coulomb) effects at aqueous interfaces. More than a century after their discovery, the origin of specific ion effects (SIE) still eludes explanation because the causal electrostatic and non-electrostatic interactions are neither local nor separable. Since direct Coulomb effects essentially vanish below ~10 MUM (i.e., at >50 nm average ion separations in water), we decided to investigate whether SIE operate at, hitherto unexplored, lower concentrations. Herein, we report the detection of SIE above ~0.1 MUM in experiments where relative iodide/bromide populations, chi = I(-)/Br(-), were determined on the surface of aqueous (NaI + NaBr) jets by online electrospray mass spectrometry in the presence of variable XCl (X = H, Na, K, Cs, NH(4), and N(C(4)H(9))(4)) and NaY (Y = OH, Cl, NO(3), and ClO(4)) concentrations. We found that (1) all tested electrolytes begin to affect chi below ~1 MUM and (2) I(-) and Br(-) are preferentially suppressed by co-ions closely matching their interfacial affinities. We infer that these phenomena, by falling outside the reach of even the longest ranged electrostatic interactions, are dynamical in nature. PMID- 22519344 TI - Temperature divergence of the dynamics of a poly(vinyl acetate) glass: dielectric vs. mechanical behaviors. AB - The dynamics of glass forming liquids as the glass transition temperature (T(g)) is traversed has become of special interest because of the continuing question as to whether or not the dynamics diverge towards an ideal glass transition/Kauzmann temperature or if the apparent Vogel-Fulcher-Tammann (VFT) divergence is lost as one goes below the conventional T(g) but remains in equilibrium. Here we examine the response of a poly(vinyl acetate) PVAc polymer glass-former using both dielectric and mechanical methods in the vicinity of T(g). Isothermal measurements were performed to study the aging behavior of the PVAc and to assure that the equilibrium state was achieved for temperatures as much as 16 K below the calorimetric T(g). Surprisingly, we found that the mechanical response took much longer to age into its equilibrium than did the dielectric response. Also, the temperature dependence of the time-temperature shift factors obtained from the two methods is different and the dielectric response shows a turnover to an apparent Arrhenius behavior rather than a continuation of the VFT extrapolated divergence at the lowest temperatures tested. PMID- 22519345 TI - Theory of nonlinear elasticity, stress-induced relaxation, and dynamic yielding in dense fluids of hard nonspherical colloids. AB - We generalize the microscopic naive mode coupling and nonlinear Langevin equation theories of the coupled translation-rotation dynamics of dense suspensions of uniaxial colloids to treat the effect of applied stress on shear elasticity, cooperative cage escape, structural relaxation, and dynamic and static yielding. The key concept is a stress-dependent dynamic free energy surface that quantifies the center-of-mass force and torque on a moving colloid. The consequences of variable particle aspect ratio and volume fraction, and the role of plastic versus double glasses, are established in the context of dense, glass-forming suspensions of hard-core dicolloids. For low aspect ratios, the theory provides a microscopic basis for the recently observed phenomenon of double yielding as a consequence of stress-driven sequential unlocking of caging constraints via reduction of the distinct entropic barriers associated with the rotational and translational degrees of freedom. The existence, and breadth in volume fraction, of the double yielding phenomena is predicted to generally depend on both the degree of particle anisotropy and experimental probing frequency, and as a consequence typically occurs only over a window of (high) volume fractions where there is strong decoupling of rotational and translational activated relaxation. At high enough concentrations, a return to single yielding is predicted. For large aspect ratio dicolloids, rotation and translation are always strongly coupled in the activated barrier hopping event, and hence for all stresses only a single yielding process is predicted. PMID- 22519346 TI - Memory effects during the unbiased translocation of a polymer through a nanopore. AB - Through a detailed Langevin dynamics simulation study, the role of memory effects during unbiased translocation is explored. Tests are devised to uncover the presence of memory effects by directly measuring forward/backward-correlated motion as well as the associated change in the dynamics. Conducting these tests at low and high viscosities, a range of behaviours across different time scales is revealed: short-time forward correlations at all viscosities, quasi-static behaviour at low viscosity, and long-time backward correlations at high viscosity. By applying these tests at different portions of the translocation process, these memory effects are also shown to vary as translocation proceeds. Combining this information with standard measurements, a physical picture of unbiased translocation as the diffusion of a local minimum is proposed. PMID- 22519347 TI - Analytical model for the dynamics of semiflexible dendritic polymers. AB - We study the dynamics of semiflexible dendritic polymers following the method of Dolgushev and Blumen [J. Chem. Phys. 131, 044905 (2009)]. The scheme allows to formulate in analytical form the corresponding Langevin equations. We determine the eigenvalues by first block-diagonalizing the problem, which allows to treat even very large dendritic objects. A basic ingredient of the procedure is the observation that a set of eigenmodes in the semiflexible case is similar to that chosen by Cai and Chen [Macromolecules 30, 5104 (1997)] for fully flexible dendritic structures. Varying the flexibility of the macromolecules allows us to better understand their mechanical loss moduli G"(omega) based on their eigenvalue spectra. We present the G"(omega) for a series of stiffness parameters and for different functionalities of the branching points. PMID- 22519348 TI - Ordering of anisotropic polarizable polymer chains on the full many-body level. AB - We study the effect of dielectric anisotropy of polymers on their equilibrium ordering within mean-field theory, but with a formalism that takes into account the full n-body nature of van der Waals (vdW) forces. Dielectric anisotropy within polymers is to be expected as the electronic properties of the polymer will typically be different along the polymer than across its cross section. It is therefore physically intuitive that larger charge fluctuations can be induced along the chain than perpendicular to it. We show that this dielectric anisotropy leads to n-body interactions which can induce an isotropic-nematic transition. The two body and three body components of the full vdW interaction are extracted and it is shown how the two body term behaves like the phenomenological self aligning-pairwise nematic interaction. At the three body interaction level we see that the nematic phase that is energetically favorable is discotic, however, on the full n-body interaction level we find that the normal axial nematic phase is always the stable ordered phase. The n-body nature of our approach also shows that the key parameter driving the nematic-isotropic transition is the bare persistence length of the polymer chain. PMID- 22519349 TI - Elasticity of flexible and semiflexible polymers with extensible bonds in the Gibbs and Helmholtz ensembles. AB - Stretching experiments on single molecules of arbitrary length opened the way for studying the statistical mechanics of small systems. In many cases in which the thermodynamic limit is not satisfied, different macroscopic boundary conditions, corresponding to different statistical mechanics ensembles, yield different force displacement curves. We formulate analytical expressions and develop Monte Carlo simulations to quantitatively evaluate the difference between the Helmholtz and the Gibbs ensembles for a wide range of polymer models of biological relevance. We consider generalizations of the freely jointed chain and of the worm-like chain models with extensible bonds. In all cases we show that the convergence to the thermodynamic limit upon increasing contour length is described by a suitable power law and a specific scaling exponent, characteristic of each model. PMID- 22519350 TI - A formalism for scattering of complex composite structures. II. Distributed reference points. AB - Recently, we developed a formalism for the scattering from linear and acyclic branched structures build of mutually non-interacting sub-units. [C. Svaneborg and J. S. Pedersen, J. Chem. Phys. 136, 104105 (2012)] We assumed each sub-unit has reference points associated with it. These are well-defined positions where sub-units can be linked together. In the present paper, we generalize the formalism to the case where each reference point can represent a distribution of potential link positions. We also present a generalized diagrammatic representation of the formalism. Scattering expressions required to model rods, polymers, loops, flat circular disks, rigid spheres, and cylinders are derived, and we use them to illustrate the formalism by deriving the generic scattering expression for micelles and bottle-brush structures and show how the scattering is affected by different choices of potential link positions and sub-unit choices. PMID- 22519351 TI - The interaction between colloids in polar mixtures above Tc. AB - We calculate the interaction potential between two charged colloids immersed in an aqueous mixture containing salt near or above the critical temperature. We find an attractive interaction far from the coexistence curve due to the combination of preferential solvent adsorption at the colloids' surface and preferential ion solvation. We show that the ion-specific interaction strongly depends on the amount of salt added as well as on the mixture composition. The calculations are in good agreement with recent experiments. For a highly antagonistic salt of hydrophilic anions and hydrophobic cations, a repulsive interaction at an intermediate inter-colloid distance is predicted even though both the electrostatic and adsorption forces alone are attractive. PMID- 22519352 TI - Deoxycholate induced tetramer of alphaA-crystallin and sites of phosphorylation: fluorescence correlation spectroscopy and femtosecond solvation dynamics. AB - Structure and dynamics of acrylodan labeled alphaA-crystallin tetramer formed in the presence of a bile salt (sodium deoxycholate, NaDC) has been studied using fluorescence correlation spectroscopy (FCS) and femtosecond up-conversion techniques. Using FCS it is shown that, the diffusion constant (D(t)) of the alphaA-crystallin oligomer (mass ~800 kDa) increases from ~35 MUm(2) s(-1) to ~68 MUm(2) s(-1). This corresponds to a decrease in hydrodynamic radius (r(h)) from ~6.9 nm to ~3.3 nm. This corresponds to about 10-fold decrease in molecular mass to ~80 kDa and suggests formation of a tetramer (since mass of alphaA-crystallin monomer is ~20 kDa). The steady state emission maximum and average solvation time () of acrylodan labeled at cysteine 131 position of alphaA-crystallin is markedly affected on addition of NaDC, while the tryptophan (trp-9) becomes more exposed. This suggests that NaDC binds near the cys-131 and makes the terminal region of alphaA-crystallin exposed. This may explain the enhanced auto phosphorylation activity of alphaA-crystallin near the terminus of the 173 amino acid protein (e.g., at the threonine 13, serine 45, or serine 169 and 172) and suggests that phosphorylation at ser-122 (close to cys-131) is relatively less important. PMID- 22519353 TI - The nature of the low energy band of the Fenna-Matthews-Olson complex: vibronic signatures. AB - Based entirely upon actual experimental observations on electron-phonon coupling, we develop a theoretical framework to show that the lowest energy band of the Fenna-Matthews-Olson complex exhibits observable features due to the quantum nature of the vibrational manifolds present in its chromophores. The study of linear spectra provides us with the basis to understand the dynamical features arising from the vibronic structure in nonlinear spectra in a progressive fashion, starting from a microscopic model to finally performing an inhomogeneous average. We show that the discreteness of the vibronic structure can be witnessed by probing the diagonal peaks of the nonlinear spectra by means of a relative phase shift in the waiting time resolved signal. Moreover, we demonstrate that the photon-echo and non-rephasing paths are sensitive to different harmonics in the vibrational manifold when static disorder is taken into account. Supported by analytical and numerical calculations, we show that non-diagonal resonances in the 2D spectra in the waiting time, further capture the discreteness of vibrations through a modulation of the amplitude without any effect in the signal intrinsic frequency. This fact generates a signal that is highly sensitive to correlations in the static disorder of the excitonic energy albeit protected against dephasing due to inhomogeneities of the vibrational ensemble. PMID- 22519354 TI - Coarse-grained modeling of the structural states and transition underlying the powerstroke of dynein motor domain. AB - This study aims to model a minimal dynein motor domain capable of motor function, which consists of the linker domain, six AAA+ modules (AAA1-AAA6), coiled coil stalk, and C-terminus domain. To this end, we have used the newly solved X-ray structures of dynein motor domain to perform a coarse-grained modeling of dynein's post- and pre-powerstroke conformation and the conformational transition between them. First, we have used normal mode analysis to identify a single normal mode that captures the coupled motions of AAA1-AAA2 closing and linker domain rotation, which enables the ATP-driven recovery stroke of dynein. Second, based on the post-powerstroke conformation solved crystallographically, we have modeled dynein's pre-powerstroke conformation by computationally inducing AAA1 AAA2 closing and sliding of coiled coil stalk, and the resulting model features a linker domain near the pre-powerstroke position and a slightly tilted stalk. Third, we have modeled the conformational transition from pre- to post powerstroke conformation, which predicts a clear sequence of structural events that couple microtubule binding, powerstroke and product release, and supports a signaling path from stalk to AAA1 via AAA3 and AAA4. Finally, we have found that a closed AAA3-AAA4 interface (compatible with nucleotide binding) is essential to the mechano-chemical coupling in dynein. Our modeling not only offers unprecedented structural insights to the motor function of dynein as described by past single-molecule, fluorescence resonance energy transfer, and electron microscopy studies, but also provides new predictions for future experiments to test. PMID- 22519355 TI - A molecular dynamics study of the lateral free energy profile of a pair of cholesterol molecules as a function of their distance in phospholipid bilayers. AB - Free energy profile of a pair of cholesterol molecules in a leaflet of 1 palmitoyl-2-oleoyl-phosphatidylcholine (POPC) bilayers in the liquid-crystalline phase has been calculated as a function of their lateral distance using a combination of NPT-constant atomistic molecular dynamics calculations (P = 1 atm and T = 310.15 K) and the thermodynamic integration method. The calculated free energy clearly shows that the two cholesterol molecules form a dimer separated by a distance of 1.0-1.5 nm in POPC bilayers. Well depth of the free energy profile is about 3.5 kJ/mol, which is comparable to the thermal energy k(B)T at 310.15 K. This indicates that the aggregation of cholesterol molecules in the bilayers depends on the temperature as well as the concentration of the system. The free energy function obtained here may be used as a reference when coarse grained potential model is investigated for this two-component system. Local structure of POPC molecules around two cholesterol molecules has also been investigated. PMID- 22519356 TI - Empirically determining the sample size for large-scale gene network inference algorithms. AB - The performance of genome-wide gene regulatory network inference algorithms depends on the sample size. It is generally considered that the larger the sample size, the better the gene network inference performance. Nevertheless, there is not adequate information on determining the sample size for optimal performance. In this study, the author systematically demonstrates the effect of sample size on information-theory-based gene network inference algorithms with an ensemble approach. The empirical results showed that the inference performances of the considered algorithms tend to converge after a particular sample size region. As a specific example, the sample size region around ?64 is sufficient to obtain the most of the inference performance with respect to precision using the representative algorithm C3NET on the synthetic steady-state data sets of Escherichia coli and also time-series data set of a homo sapiens subnetworks. The author verified the convergence result on a large, real data set of E. coli as well. The results give evidence to biologists to better design experiments to infer gene networks. Further, the effect of cutoff on inference performances over various sample sizes is considered. [Includes supplementary material]. PMID- 22519357 TI - Growth-related model of the GAL system in Saccharomyces cerevisiae predicts behaviour of several mutant strains. AB - The genetic regulatory network responds dynamically to perturbations in the intracellular and extracellular environments of an organism. The GAL system in the yeast Saccharomyces cerevisiae has evolved to utilise galactose as an alternative carbon and energy source, in the absence of glucose in the environment. This work contains a modified dynamic model for GAL system in S. cerevisiae, which includes a novel mechanism for Gal3p activation upon induction with galactose. The modification enables the model to simulate the experimental observation that in absence of galactose, oversynthesis of Gal3p can also induce the GAL system. Subsequently, the model is related to growth on galactose and glucose in a structured manner. The growth-related models are validated with experimental data for growth on individual substrates as well as mixed substrates. Finally, the model is tested for its prediction of a variety of known mutant behaviours. The exercise shows that the authors' model with a single set of parameters is able to capture the rich behaviour of the GAL system in S. cerevisiae. [Includes supplementary material]. PMID- 22519358 TI - Spatial localisation of chaperone distribution in the endoplasmic reticulum of yeast. AB - In eukaryotes, the endoplasmic reticulum (ER) serves as the first membrane enclosed organelle in the secretory pathway, with functions including protein folding, maturation and transport. Molecular chaperones, of the Hsp70 family of proteins, participate in assisting these processes and are essential to cellular function and survival. BiP is a resident Hsp70 chaperone in the ER of Saccharomyces cerevisiae. In this study the authors have created a partial differential equation model to examine how BiP interacts with the membrane-bound co-chaperone Sec63 in translocation, a process in which BiP assists in guiding a nascent protein into the ER lumen. It has been found that when Sec63 participates in translocation through localisation at the membrane, the spatial distribution of BiP is inhomogeneous, with more BiP at the surface. When translocation is inhibited through a disabling of Sec63's membrane tether, the concentration of BiP throughout the ER becomes homogeneous. The computational simulations suggest that Sec63's localisation and the resulting binding to BiP near the membrane surface of the ER enable a heterogeneous distribution of BiP within the ER, and may facilitate BiP's role in translocation. [Includes supplementary material]. PMID- 22519359 TI - New approaches to expand hematopoietic stem and progenitor cells. AB - INTRODUCTION: Hematopoietic stem cells (HSCs) are defined by their capacity to self-renew and to differentiate into all blood cell lineages, and are currently the foundation of HSC transplantation therapy. A variety of methods have recently been explored to find a way to expand hematopoietic stem and progenitor cells (HSCs/PCs) ex vivo in order to improve the efficiency and outcome of HSC transplantation. AREAS COVERED: Recent studies of HSCs/PCs have led to the development of new ways to detect and purify HSCs/PCs and have also revealed several intrinsic and extrinsic factors that control the molecular signals fundamental to self-renewal and differentiation of HSCs. These findings have provided new approaches for expanding HSCs/PCs ex vivo utilizing protein factors and small-molecule compounds (SMCs) and have also demonstrated promising outcomes in clinical trials. EXPERT OPINION: Although further technical innovation is still needed, elucidation of the whole picture of signaling pathways critical to HSCs/PCs and manipulation of such pathways by SMCs could establish efficient, cost-effective, riskless and robust methods for ex vivo expansion of HSCs/PCs. With these efforts, more sophisticated HSC transplantation would be possible in the near future. PMID- 22519360 TI - Association of XPC polymorphisms with susceptibility and clinical outcome to chemotherapy in breast cancer patients. AB - The aim of the current study was to evaluate the relation between xeroderma pigmentosum complementation group C (XPC) polymorphisms and susceptibility to breast cancer (BC), the development and progression of disease, and response to different individualized drug treatments. We investigated two polymorphisms in XPC Ala499Val and Lys939Gln using PCR-RFLP assays including 618 cases and 622 controls. The frequency of the TT genotype of Ala499Val (adjusted odds ratio = 1.575; 95% confidence interval, 1.104-2.245; P = 0.012) and the AC genotype of Lys939Gln (adjusted odds ratio = 1.330; 95% confidence interval, 1.045-1.694; P = 0.020) were found to significantly increase the risk of developing BC. The CT+TT genotypes of Ala499Val were associated with estrogen receptor positive, and Her-2 and p53 negative status, and the AC+CC genotypes of Lys939Gln were associated with BRCA1 negative status. Moreover, a significantly increased chance of treatment with neoadjuvant anthracycline-based chemotherapy response was found in women carrying TT genotype of Ala499Val, or CC and AC genotypes of Lys939Gln. In addition, a significantly longer overall survival after chemotherapy was observed in patients who had XPC Lys939Gln AC+CC genotypes with estrogen receptor positive (log-rank test, P = 0.086) and p53 negative (log-rank test, P = 0.020). The current data suggested that XPC Ala499Val and Lys939Gln polymorphisms may contribute to the identification of patients with increased risk for BC. Moreover, the polymorphisms were associated with the prognosis of BC patients. PMID- 22519361 TI - Comparative efficacy and safety of palonosetron with the first 5-HT3 receptor antagonists for the chemotherapy-induced nausea and vomiting: a meta-analysis. AB - A number of studies have reported the difference between the 5-HT3 receptor antagonists and palonosetron in preventing the chemotherapy-induced nausea and vomiting (CINV). Through analysing the efficacy and safety in palonosetron treated patients, it can provide evidence for palonosetron administration. We identified randomised controlled clinical trials comparing palonosetron with the first-generation 5-HT3 receptor antagonists in the prevention of CINV in cancer patients. Nine studies investigated the outcomes in a total of 3463 cases. Compared with the first-generation 5-HT3 receptor antagonists, the cumulative incidences of emesis were significantly reduced in the patients treated with palonosetron (0.25 mg i.v.) on the first day [relative risk (RR) = 1.11, 95% confidence interval (CI): 1.05-1.17], from 2 to 5 days (RR = 1.26, 95% CI: 1.16 1.36) and the overall five days (RR = 1.23, 95% CI: 1.13-1.34). Regarding the drug safety, there was no significant difference between palonosetron-treated group and the first-generation 5-HT3 receptor antagonists-treated group. Results from the analysis suggest that palonosetron is highly effective in preventing nausea and vomiting in the days after administration of moderately or highly emetogenic chemotherapy agents. PMID- 22519362 TI - Immunonutrition: does it have a role in improving recovery in patients receiving a stem cell transplant? AB - Numerous clinical trials have demonstrated that immunomodulating diets (IMDs) reduce treatment complications such as the risk of acquired infections, length of hospital stay, and wound complications in patients receiving planned surgery. These complications are possibly exacerbated by malnutrition at the time of surgery, resulting in decreased cell-mediated and humoral immune responses, which can be improved with the utilization of IMDs both prior to and following surgery. Although numerous randomized studies have investigated IMDs in the surgical setting, IMDs have not been well studied to evaluate whether their use improves outcomes for other patient groups with high incidence of malnutrition and acquired infections. Patients receiving stem cell transplantation following preparative myeloablative chemotherapy for treatment of a hematologic malignancy would be a prime example of another patient group who would share these characteristics. Given the proposed mechanism of action by which IMDs have aided recovery after surgery, it is reasonable to expect that IMDs may aid recovery after stem cell transplantation, and current preclinical and clinical data support the need for further clinical studies. PMID- 22519363 TI - Serum MMPs 7-9 and their inhibitors during glucocorticoid and anti-TNF-alpha therapy in pediatric inflammatory bowel disease. AB - OBJECTIVES: In inflammatory bowel diseases (IBD), matrix metalloproteinases (MMPs) participate in intestinal tissue damage and regenerative processes. MMP activity is inhibited by tissue inhibitors of MMPs (TIMPs) and plasma inhibitor, alpha2-macroglobulin (alpha2M). We evaluated serum MMPs, their inhibitors and markers of neutrophil activity, myeloperoxidase (MPO) and human neutrophil elastase (HNE), during glucocorticoid (GC) and anti-TNF-alpha therapies in pediatric IBD, in aim to find new tools for assessment of therapeutic response. METHODS: Serum samples were collected before and within a month after the start of therapy with oral GC (n = 19) or anti-TNF-alpha agent (n = 16), and from 32 pediatric control patients. Serum levels of MMP-7, MMP-9, TIMP-1, TIMP-2, alpha2M, MPO, and HNE were analyzed with enzyme-linked immunoabsorbent assays (ELISA) and MMP-8 by immunofluorometric assay (IFMA). Disease activity was monitored with erythrocyte sedimentation rate (ESR), CRP, fecal calprotectin (FC), and physician's global assessment of clinical disease activity (PGA). RESULTS: In IBD, pretreatment serum MMP-7, MMP-8, MMP-9, alpha2M, MPO, and HNE were elevated compared with controls. During GC therapy, MMP-7, TIMP-1, and MMP 7/TIMP-2 decreased (all p < 0.05). During anti-TNF-alpha therapy, MMP-7 decreased (p = 0.063), but remained higher than that after GC therapy (p < 0.05). alpha2M (p < 0.05) and HNE (p < 0.05) increased, the former higher than that in GC treated patients. The levels of MMPs and their inhibitors did not markedly associate with inflammatory markers in blood or feces. CONCLUSIONS: In pediatric IBD, serum MMP-7 mirrors disease activity, and together with TIMP-1, reflects GC therapy response. alpha2-Macroglobulin expression parallels the anti-TNF-alpha response. PMID- 22519364 TI - Neonatal mortality and morbidity in preterm infants born from assisted reproductive technologies. AB - AIM: Premature birth is frequent in infants conceived with assisted reproductive technologies (ART). We sought to determine whether neonatal outcome in ART preterm infants differs from that of spontaneously conceived (SC) preterm infants. METHODS: Data were prospectively collected in infants born <= 32 weeks after ART or SC. We calculated a composite index of severe morbidity (based on occurrences of severe necrotizing enterocolitis, severe intraventricular haemorrhage, periventricular leukomalacia or bronchopulmonary dysplasia). Survival rate without severe morbidity was compared between the two groups. RESULTS: Six hundred and twelve preterm infants were hospitalized in our tertiary care centre: 81 in ART group and 521 in SC group. In the ART group, twin pregnancy (69.1% vs. 15.9%, p < 0.001) and inborn delivery (98.8% vs. 90.0%, p < 0.01) were more frequent. Gestational age (29 vs. 28 weeks, p < 0.05) and birth weight (1100 vs. 1020 g, p < 0.001) were also higher. Survival without severe morbidity was significantly higher in ART infants (76.5% vs. 55.2%, p < 0.001), with the difference mainly observed in infants born <= 28 weeks (22.9% vs. 55.7%, p < 0.001). CONCLUSION: Assisted reproductive technologies was not associated with adverse neonatal outcome. Differences in pregnancy and neonatal characteristics probably explain the increased survival without severe morbidity in ART infants. PMID- 22519365 TI - Patient involvement in blood transfusion safety: patients' and healthcare professionals' perspective. AB - BACKGROUND: Blood transfusion is one of the major areas where serious clinical consequences, even death, related to patient misidentification can occur. In the UK, healthcare professional compliance with pre-transfusion checking procedures which help to prevent misidentification errors is poor. Involving patients at a number of stages in the transfusion pathway could help prevent the occurrence of these incidents. OBJECTIVES: To investigate patients' willingness to be involved and healthcare professionals' willingness to support patient involvement in pre transfusion checking behaviours. MEASURES: A cross-sectional design was employed assessing willingness to participate in pre-transfusion checking behaviours (patient survey) and willingness to support patient involvement (healthcare professional survey) on a scale of 1-7. PARTICIPANTS: One hundred and ten patients who had received a transfusion aged between 18 and 93 (60 male) and 123 healthcare professionals (doctors, nurses and midwives) involved in giving blood transfusions to patients. RESULTS: Mean scores for patients' willingness to participate in safety-relevant transfusion behaviours and healthcare professionals' willingness to support patient involvement ranged from 4.96-6.27 to 4.53-6.66, respectively. Both groups perceived it most acceptable for patients to help prevent errors or omissions relating to their hospital identification wristband. Neither prior experience of receiving a blood transfusion nor professional role of healthcare staff had an effect on attitudes towards patient participation. CONCLUSION: Overall, both patients and healthcare professionals view patient involvement in transfusion-related behaviours quite favourably and appear in agreement regarding the behaviours patients should adopt an active role in. Further work is needed to determine the effectiveness of this approach to improve transfusion safety. PMID- 22519366 TI - Transfusion-related mortality after primary hip arthroplasty--an analysis of mechanisms and confounders. AB - BACKGROUND AND OBJECTIVES: Bleeding and postoperative anaemia after total hip arthroplasty (THA) may trigger transfusion of red blood cells (RBC). However, large observational studies have reported associations between RBC transfusion and increased postoperative morbidity and mortality. As major bleeding or severe postoperative anaemia is intrinsically linked with RBC transfusion, direct causality between transfusion and adverse outcomes remains unclear. This study aimed to identify possible relations between RBC transfusion, severe bleeding or anaemia and mortality in all patients who died <90 days after THA in Denmark in 2008. MATERIALS AND METHODS: Nationwide review of patient records. Cases of adverse transfusion events, infections following transfusion, severe perioperative bleeding or anaemia and possible causal relations to mortality were identified by two independent reviewers. RESULTS: Of 6932 THA patients, 45 (0.6%) were transfused within 30 days and died <90 days from surgery. Three patients (7%) died from causes possibly related to either severe anaemia, major bleeding alone or major bleeding with transfusion-related acute lung injury, while five (11%) died from infections occurring after RBC transfusion. Mortality in the remaining 37 patients (82%) was of unknown cause (nine patients) or related to patient or surgical factors (28 patients). CONCLUSION: Transfusion-related mortality after THA included cases of major perioperative bleeding or severe postoperative anaemia with delayed RBC transfusion in addition to possible complications to RBC transfusion per se. Future studies should account for pretransfusion haemoglobin and perioperative blood loss when evaluating RBC transfusion-associated outcomes after surgery. PMID- 22519367 TI - Strategies for improving the quantitative bioanalytical performance of LC-MS in pharmacokinetic studies. AB - Quantitative bioanalysis is urgently required for the evaluation of pharmacokinetic properties of a drug and to demonstrate the body exposure to the parent drug and/or metabolite for interpretation of the efficacy and toxicity. New trends in drug discovery and development will be always posing challenges on LC-MS-based quantitative bioanalysis. The focus of this minireview is to highlight the commonly used strategies for improving the quantitative bioanalytical performance including overcoming matrix effects and improving MS detectability. "LC-electrolyte effects" and "pulse gradient chromatography" proposed by our group are new approaches that have also showed potential efficiencies on improving overall bioassay performance, including lowering lower limit of quantification (LLOQ), enlarging upper limit of quantification (ULOQ), decreasing matrix effects, and overcoming elutropic effects, etc.. They should also work well in metabolic profiling studies and other important analytical fields, such as food pesticide residue analysis, environmental analysis, clinical and forensic toxicology, doping control, and so on. PMID- 22519368 TI - Isotopic labeling of metabolites in drug discovery applications. AB - Understanding the metabolic and pharmacokinetic fate of a drug in humans is a key factor in its development and registration, as well as in the elaboration of new therapeutic agents. To carry out these studies, stable isotope labeling techniques have been effectively used by drug metabolism scientists and toxicologists in order to gain better understanding of the drugs' disposition, bioavailability and toxicity in in vivo studies. Among the different analytical techniques used, mass spectrometry (MS) coupled to separation techniques has become the detection method of choice due to its high sensitivity and selectivity. In vitro quantification of metabolite levels in biofluids by MS is often difficult if a proper internal standard is not available due to the inherent problems associated with the technique (e.g. chromatographic coelutions, ion suppression, low reproducibility etc.). Stable isotope coding approaches alleviate these drawbacks and allow comparative drug metabolomics studies similarly to the differential proteomic techniques developed in the last decade. This review describes a selection of methodological improvements in the use of stable isotopes labeling in combination with MS to detect drug metabolites. In the first part of the paper, the application of labeled compounds to study the absorption, distribution, metabolism, excretion and toxicology of drugs (ADMET) in addition to the elucidation of metabolic pathways is presented. In the second part, recent developments of stable isotope coded tags for the in vitro relative metabolite quantification in biofluids are presented. PMID- 22519369 TI - Liquid chromatography-mass spectrometric multiple reaction monitoring-based strategies for expanding targeted profiling towards quantitative metabolomics. AB - Recent advances in analytical methodologies have made it possible to bring metabolomic profiling into quantitative metabolomics that permits precise measurements of comprehensive small-molecule profiles. Modern liquid chromatography-tandem mass spectrometry (LC-MS/MS) with multiple reaction monitoring (MRM) mode serves as the foundation for accurate simultaneous multi analyte quantitation across large sample sets to provide high-quality information on target molecular profiles in complex systems. Despite the intrinsic multiplexing potential of the LC-MRM-MS technique, the key bottleneck in current LC-MRM-based assays is generally the limited analyte coverage and throughput capacity. Nowadays, the MRM-based approach has emerged as an attractive strategy for quantitative proteomic analysis and high-throughput biomarker discovery. So far, the full potential of the contemporary LCMRM methodology unleashed for quantitative metabolite profiling and metabolomic measurements of non-peptidic small molecules is rarely discussed. In this review we attempt to provide an overview on the major recent developments in LC-MRM-based strategies for quantitative profiling of multi- and non-target small molecules in biological samples. This article highlights the utility and power of the LC-MRM-based targeted approaches as valuable bioanalytical tools for low-cost, multiplexed quantitation on a large scale, with special emphasis on the promise of combining various strategies for expanding coverage and throughput of the LC-MRM-based assays to cover the gap between a widely targeted profiling and large-scale unknown screening towards comparative or quantitative metabolomics. General issues raised in metabolite profiling, such as basic aspects of bioanalysis, methodological dilemmas and challenges in quantitative metabolomics are addressed, and different strategies to circumvent the existing bottleneck and potential pitfalls of the current LC-MRM-MS techniques are outlined. In addition, the rudiments of LC-MRM-MS and its recent applications in combination with such strategies for biomarker quantitation and verification is also described. PMID- 22519370 TI - LC/MS based tools and strategies on qualitative and quantitative analysis of herbal components in complex matrixes. AB - Accompanying with hot discussions on developing multi-target drugs for the therapy of multi-gene diseases, herbal medicines are receiving more and more attention worldwide in both academic and industrial fields. Pharmacokinetic and metabolic research is one of the important issues for intensive understanding of therapeutic benefits/risks of herbal medicines. The qualitative and quantitative analysis of herbal medicines, which is a prerequisite for pharmacokinetic and metabolic evaluations, remains a great challenge because of the intrinsic complexity of herbal medicines. This paper provides a review on the recent development of qualitative and quantitative methodologies on herbal medicines analysis. Powerful hybrid mass spectrometric tools such as Q-TOF and IT-TOF are highly useful for both the qualitative and quantitative analysis of complicated components. In the past decade, some universal useful strategies to the qualitative and quantitative analysis and pharmacokinetic assessment of complicated herbal components have been also proposed. Nonetheless, it is urgent to develop additional strategies to resolve the critical challenges underlying herbal analyses, such as the lack of authentic compounds, the difficulties in information processing, and the elimination of complex matrixes interferences. PMID- 22519371 TI - LC-MS based screening and targeted profiling methods for complex plant: coffee a case study. AB - In the recent years the way of thinking about human health necessarily passes by human food. Recent discoveries are not only concerned about valuable biomolecules but also contaminants. Thus, the screening of substances in animal and vegetable matrices by analytical techniques is focused on the presence and absence of target substance. In both cases, the majority of these substances are present as traces or in very low levels. Contaminants could be naturally present in the food, inserted on it or even developed on it as a consequence of food processing or cooking. Pesticides, mycotoxins, dioxins, acrylamide, Sudan red, melamine and now 4(5)-methylimidazole can be, at present, be listed as some of the world big problems related to food contaminants and adulterants. With the development of liquid chromatography coupled to mass spectrometry (LC-MS-MS), in the last few decades, analysis of some food contaminants in trace levels trace become less laborious, more accurate and precise. The multiple approach of those techniques make possible to obtain many results in one single run. On the other hand, European Union (2002/657/EC) established regulations for analytical methods regarding mass spectrometry as detection tool, showing the importance of this technique in food quality control. The EU criteria uses identification points (IPs) that could be achieved basically with four product ions (including molecular ion) or reduced with the use of high resolution equipments. This kind of mass spectrometers made the IPs criteria more accessible, as the exact mass information is a differential tool. In view of this the aim of this review is to present the actual scenario for mass spectrometry analysis in a complex vegetable food matrix such as roasted coffee, with emphasis on needs and challenges regarding the LC-MS technique in order to meet and contribute to food safety standards in this complex matrix. PMID- 22519372 TI - Hepatitis C in Iran. How extensive of a problem is it? PMID- 22519373 TI - When are patients with common bile duct stones referred for surgery? PMID- 22519374 TI - High prevalence of hepatitis C infection among high risk groups in Kohgiloyeh and Boyerahmad Province, Southwest Iran. AB - BACKGROUND: Detection of Hepatitis C virus (HCV)-infected people in each community assists with infection prevention and control. This study aims to evaluate the prevalence of HCV infection among high risk groups in Kohgiloyeh and Boyerahmad Province, Southwest Iran. METHODS: This was a cross-sectional study conducted from 2009-2010 in Kohgiloyeh and Boyerahmad Province. High risk groups for HCV were the subjects of this study. Blood samples were taken from 2009 individuals at high risk for HCV that included inmates, injecting drug users (IDUs), health care workers, patients on maintenance hemodialysis, hemophilic patients, and those with histories of blood transfusions. Patients were residents of Yasuj, Gachsaran, and Dehdasht (3 main townships in the province). Samples were analyzed by ELISA for anti-HCV antibodies. Demographic features of participants were recorded by a questionnaire during sample collection. Data were analyzed by SPSS version 13 software. RESULTS: Of 2009 subjects, HCV antibodies were detected in 172 (8.6%). Rate of infection was higher in males (11.4%) compared to females (3.2%). Rate of infection in inmates was 11.7% while this rate was 42.4% in IDUs, 4.2% in health care workers, and 6.1% in thalassemic patients. Significant correlation was found between HCV infection, history of imprisonment, and thalassemia. CONCLUSION: Results of this study have provided epidemiologic features of HCV and its risk factors in Kohgiloyeh and Boyerahmad Province, Southwest Iran. This information may assist in preventing the spread of HCV infection in this and other similar settings in the region. The findings of this study may help in improving surveillance and infection control in the community through management and monitoring of infected individuals. PMID- 22519375 TI - Assessment and treatment of choledocholithiasis when endoscopic sphincterotomy is not successful. AB - BACKGROUND: Choledocholithiasis exists in approximately 15% of patients with gallstones and is present in 3%-10% of those undergoing cholecystectomy. METHODS: In this study, we retrospectively analyzed the outcome patients with choledocholithiasis that were managed by open common bile duct (CBD) exploration according to our center's protocol. Endoscopic retrograde cholangiopancreatography (ERCP) was performed for CBD stone clearance. If ERCP and sphincterotomy were not successful, open surgical exploration of CBD was performed with T-tube insertion without routine intraoperative cholangiography (IOC). RESULTS: We studied 1462 patients with choledocholithiasis. ERCP was successful in in 1276 (87.2%) patients. A total of 186 (12.8%) underwent surgery. Of these, 82 (45.2%) had CBD exploration and T-tube insertion without IOC. Choledochoduodenostomy was performed in 82 (44.1%) patients and choledochojejunostomy was performed in 20 (10.8%). Retained stones were found only in 4 cases which were treated by ERCP. CONCLUSION: ERCP is successful in most cases with choledocholithiasis. If ERCP fails, open exploration of CBD and T tube insertion, or biliary-enteric anastomosis are acceptable ways for CBD drainage. The rate of retained stone is not more than expected, thus elective IOC is more acceptable than routine IOC. Routine IOC is time-consuming and particularly difficult in elderly patients and emergency conditions. PMID- 22519376 TI - Reliability and validity of the Modifiable Activity Questionnaire (MAQ) in an Iranian urban adult population. AB - BACKGROUND: The purpose of this study is to evaluate the validity and reliability of a Persian translation of the Modifiable Activity Questionnaire (MAQ) in a sample of adults from Tehran, Iran. METHODS: There were 48 adults (53.1% males) enrolled to test the physical activity questionnaire. A sub-sample included 33 participants (45.5% males) who assessed the reliability of the physical activity questionnaire.The validity was tested in 25 individuals (48.0% males). The reliability of two MAQs was calculated by intraclass correlation coefficients. The validation study was evaluated with the Spearman correlation coefficients to compare data between the means of 2 MAQs and the means of 4 physical activity records. RESULTS: Intraclass correlation coefficients between 2 MAQs for the previous year's leisure time was 0.94; for occupational, it was 0.98; and for total (leisure and occupational combined) physical activity, it was 0.97. The Spearman correlation coefficients between the means of the 2 MAQs and means of the 4 physical activity records was 0.39 (P = 0.05) for leisure time, 0.36 (P = 0.07) for occupational, and 0.47 (P = 0.01) for total (leisure and occupational combined) physical activities. CONCLUSION: High reliability and relatively moderate validity were found for the Persian translated MAQ in adults from Tehran. However, further studies with larger sample sizes are suggested to more precisely assess the validity of the MAQ. PMID- 22519377 TI - Efficacy of harm reduction programs among patients of a smoking cessation clinic in Tehran, Iran. AB - BACKGROUND: Recently, harm reduction programs have been used to reduce mortality and morbidity among smokers. The main objective of this study was to evaluate the effect of harm reduction programs on the smoking patterns of subjects who presented to a smoking cessation clinic in Tehran, Iran. METHODS: This observational study was conducted between September 2008-September 2009 on 132 patients who were unable to quit smoking. Patients were enrolled by the first come first service method. During the study period, subjects were assigned to either group or individual visits every 15 days in conjunction with the use of nicotine gum. The main objective of this study was to evaluate at the third and sixth months of follow-up: the number of smoked cigarettes, level of expired carbon monoxide (CO), and numbers of nicotine gum used. Data were analyzed by the Wilcoxon rank, Fisher's exact, and Pearson's chi-square tests and SPSS version 17 software. RESULTS: A total of 87.1% of the subjects were males. We noted decreases in the number of cigarettes smoked daily and the level of expired CO, whereas the amount of nicotine gum used significantly increased during the time interval between the first session and the third and sixth month follow-up visits (p < 0.001 for all variables). During the follow up sessions, 64.4% of subjects reduced the number of cigarettes they smoked daily by at least 50% and 12.9% of subjects quit smoking. CONCLUSION: Behavioral and pharmacological therapy in harm reduction programs result in a decrease in the number of cigarettes smoked daily and a reduction in the amount of expired CO. Therefore, these methods can be beneficial in achieving complete smoking cessation. PMID- 22519378 TI - Validity, reliability and factor structure of Hepatitis B Quality of Life Questionnaire version 1.0: findings in a large sample of 320 patients. AB - BACKGROUND: Quality of life is of significant importance in chronic hepatitis B (CHBV). We aimed to assess the psychometric properties of the Hepatitis B Quality of Life Questionnaire v1.0 (HBQOL) in a large sample of 320 Iranian patients with CHBV. METHODS: After adapting the Iranian version through forward-backward translation and expert panel discussion, we administered HBQOL together with Short-Form 36 (SF-36), Medical Outcome Study Social Support Questionnaire (MOS SS), Hospital Anxiety and Depression Scale (HADS), and the Iowa Fatigue Scale (IFS) to 320 non-cirrhotic Iranian patients. We used principal component analysis with Varimax rotation to determine the factor structure. To evaluate the psychometric properties of HBQOL, test-retest and internal consistency reliabilities, divergent and convergent validity with other instruments, and discriminatory power were calculated. RESULTS: Thirty-one questions loaded on to six factors (Anticipation anxiety, Stigma, Psychological well-being, Vitality, Transmissibility and Vulnerability) which explained 63.6% of total variance. Test retest reliability was 0.66. Cronbach's alpha was 0.94 for the overall scale and between 0.7 and 0.9 for subscales, with the exception of the Vulnerability subscale. HBQOL and its subscales showed acceptable convergent and divergent validity with other instruments. Furthermore, Vulnerability subscale of HBQOL discriminated between patients with chronic active and chronic inactive hepatitis. CONCLUSION: The Iranian version of HBQOL is reliable, valid, and sensitive to the clinical conditions of the patients. This instrument has acceptable factor structure to measure several aspects of quality of life in patients with chronic HBV. PMID- 22519379 TI - A new technical approach to cancers of the cervical esophagus. AB - BACKGROUND: The aim of this study was to assess the possibility of a primary end to-end pharyngoesophageal anastomosis after standard tumor resection of the cervical esophagus by acute flexion of the neck. METHODS: A total of 34 consecutive patients with primary cervical esophageal cancer, none having received prior radio- or chemotherapy, were treated by two methods based on intraoperative findings. In 18 patients, reconstruction after esophageal resection was carried out by the standard gastric pull-through technique (control group). In 16 patients, acute flexion of the neck after tumor resection allowed for reconstruction by primary end-to-end pharyngoesophagostomy (experimental group). RESULTS: There was no operative mortality in either group. The mean operative time for the experimental group was about 50 minutes less compared to the control group. Self-limited postoperative anastomotic leakage in the neck was twice as common in the experimental group. Postoperative dysphagia was about three times as common in the experimental group [5 patients (31%)] compared to the control group [2 patients (11%)]. CONCLUSION: In selected cases, segmental resection of primary cervical esophageal cancers reconstructed by end-to-end pharyngoesophagostomy is technically feasible by bending the neck acutely forward during anastomosis and maintaining it in the flexed position during a postoperative period of about 7 days. The advantages are reduced scope and duration of the operation. The downside is doubling of the frequency of postoperative cervical leakage. PMID- 22519380 TI - Severe thrombocytopenia and hemorrhagic diathesis due to brucellosis. AB - BACKGROUND: We aimed to examine cases of brucellosis that presented with severe thrombocytopenia and hemorrhagic diathesis. METHODS: A total of 10 brucellosis cases with severe thrombocytopenia were included in this case-series study. Patients' files were reviewed for their clinical and laboratory findings, as well as clinical outcomes and complications. Platelet counts of < 20,000/mm3 were diagnosed as severe thrombocytopenia. RESULTS: The lowest thrombocyte count was 3000/mm3 while the highest was 19,000/mm3 (mean: 12,000/mm3). Patients had the following symptoms: epistaxis (7 cases), petechia with epistaxis (4 cases), bleeding gums (3 cases), ecchymosis with epistaxis (2 cases), melena and renal failure (2 cases), and hematuria (1 case). Patients were given rifampicin and doxycycline along with supportive hematological therapy. All were treated successfully with no evidence of recurrence at follow-up visits. CONCLUSION: Since brucellosis is endemic in developing countries, it must be considered in the differential diagnosis of cases that present with severe thrombocytopenia and hemorrhagic diathesis. PMID- 22519381 TI - Acute administration of Zn, Mg, and thiamine improves postpartum depression conditions in mice. AB - BACKGROUND: Postpartum depression (PPD) affects approximately half of new mothers. Chronic exposure to progesterone during pregnancy and its withdrawal following delivery increases depression and anxiety. In addition, there are complex interactions between hormones, neurotransmitters, and trace elements. Zinc (Zn) and magnesium (Mg) influence the nervous system by impacting synaptic neurotransmission in the brain. Thiamine (Vit B1) deficiency results in a high percentage of depressive behaviors. Elevated levels of reactive oxygen species in pregnancy are implicated in the pathogenesis of major depression. METHODS: We examined the effects of different combinations of Zn, Mg, and Vit B1 in an animal model of PPD. ZnCl, MgCl, and thiamine-HCl were administered to PPD-induced mice. Depression, anxiety-related behavior, and total antioxidant capacity (TAC) were assessed. Depression and anxiety-like behavior were evaluated by the forced swimming test (FST) and elevated plus-maze, respectively. RESULTS: The acute combined administration of Zn, Mg, and Vit B1 significantly decreased immobility time in FST, increased the percentage of both time spent in- and entries to open arms in the elevated plus-maze, and augmented TAC. CONCLUSION: Our data suggest that acute administration of combined treatment with Zn, Mg, and Vit B1 on postpartum day 3 improves depressive symptoms and anxiety-like behaviors. Our evaluation of TAC is in accordance with behavioral results. PMID- 22519382 TI - Microbial susceptibility, virulence factors, and plasmid profiles of uropathogenic Escherichia coli strains isolated from children in Jahrom, Iran. AB - BACKGROUND: Urinary tract infections (UTIs), including cystitis and pyelonephritis, are the most common infectious diseases in childhood. Escherichia coli (E. coli) accounts for as much as 90% of the community-acquired and 50% of nosocomial UTIs. Therefore, identification of E. coli strains is important for both clinical and epidemiological implications. Understanding antibiotic resistance patterns and molecular characterization of plasmids and other genetic elements is also epidemiologically useful. METHODS: To characterize uropathogenic strains of E. coli, we studied 96 E. coli strains recovered from urine samples of children aged 1 month to 14 years with community-acquired UTIs in Jahrom, Iran. We assessed virulence factors (VFs), drug sensitivities, and plasmid profiles. RESULTS: Drug sensitivities of the isolates were: 19.8% (ampicillin), 24% (trimethoprim-sulfamethoxazole), 29.2% ( tetracycline), 75.5% (nalidixic acid), 80.4% (cefixime), 84.6% (gentamicin), 91.4% (ciprofloxacin), 96.8% (nitrofurantoin), 96.8% (amikacin) and 100% (imipenem). Totally, 76 isolates harbored plasmids with an average of 5.5 plasmids (range: 1-10) in each strain. Plasmid profiling distinguished 22 different E. coli genotypes in all isolates that ranged in similarity from 50% to 100%. PCR showed that the prevalence of virulence genes ranged from 15.62% for hly to 30.2% for pap. CONCLUSION: These data mandate local monitoring of drug resistance and its consideration in empirical therapy of E. coli infections. Plasmid analysis of representative E. coli isolates also demonstrates the presence of a wide range of plasmid sizes, with no consistent relationship between plasmid profiles and resistance phenotypes. Plasmid profiles distinguished more strains than did the antimicrobial susceptibility pattern. PMID- 22519383 TI - A report of the injuries sustained in Iran Air Flight 277 that crashed near Urmia, Iran. AB - BACKGROUND: On January 9, 2011 Iran Air Flight 277 crashed during approach to Urmia, Iran. Out of 105 passengers, 27 survived. This brief report presents a perspective of the passengers' sustained injuries. METHODS: We reviewed the recorded injuries of all passengers as provided by the Legal Medicine Organization authorities. The Injury Severity Score (ISS), an anatomical scoring system, was used to provide an overall code for those who survived with multiple anatomical injuries. RESULTS: There were a total of 96 ISS body region injuries among those who survived. Facial injuries (83%) were the most frequent injuries noted among fatalities, which was statistically significant (P = 0.000). In those who survived, injuries to the head and neck (37%) and facial (33%) regions were relatively less frequent than other anatomical regions. The most serious injuries among survivors belonged to the extremity (85%) region, particularly lower limb fractures (62%). Differences in extremity injuries between the survivors and fatalities were not statistically significant. CONCLUSION: The findings of this study were similar to other studies where the most frequent serious injuries were fractures of the extremities, particularly the lower limbs. PMID- 22519384 TI - Advocacy strategies and action plans for reducing salt intake in Iran. PMID- 22519385 TI - A rare case of perforated Meckel's diverticulum presenting as a gatrointestinal stromal tumor. AB - Meckel's diverticulum is located on the antimesentric border of the ileum, approximately 45 to 60 cm proximal to the ileocecal valve, and results from incomplete closure of the omphalomesentric or viteline duct. Common complications presenting in adults include bleeding, obstruction, diverticulitis, and perforation. Tumors within Meckel's diverticulum are a rare, but recognized complication. A 62 year-old woman presented with peri-umbilical pain that had localized to the right iliac fossa. On examination, she was tender in the right iliac fossa, with localized peritonism. At surgery,a perforated Meckel's diverticulum was found that was associated with free intra-abdominal fluid and hemorrhage. A 25 mm nodule was found at the apex of Meckel's diverticulum. We resected 100 mm of the small bowel and a primary anastamosis was performed. Histopathological examination of the resected lesion revealed a mesenchymal tumor categorized as a gastrointestinal stromal tumor (GISTs). GISTs arising from Meckel's diverticulum are an extremely rare, but recognized complication. Surgery is considered the standard treatment for non-metastatic GISTs with enbloc resection and clear margins. PMID- 22519386 TI - Primary adrenal hydatid cyst presenting with arterial hypertension. AB - Hydatid disease is an endemic illness in some countries. The main sites of involvement are the liver and lungs, but rarely, it can be seen in other organs as well. Herein, we report a case of primary adrenal hydatid cyst accompanied by arterial hypertension. PMID- 22519387 TI - Primary intrathoracic biphasic synovial sarcoma. AB - Synovial sarcomas are most frequently observed in the extremities. Although synovial sarcomas are the third most common histological type of soft-tissue sarcomas of the extremities, primary mediastinal synovial sarcoma is extremely rare. Monophasic synovial sarcoma is the most commonly observed subtype. whereas the biphasic subtype is less common. We present our case which was diagnosed as biphasic synovial sarcoma located in the anterior mediastinum, which is considered to be a rare entity. The patient underwent surgical resection together with multimodal adjuvant radiotherapy and chemotherapy. PMID- 22519388 TI - Photoclinic. PMID- 22519389 TI - Intraamniotic inflammatory response to bacteria: analysis of multiple amniotic fluid proteins in women with preterm prelabor rupture of membranes. AB - OBJECTIVE: To analyse whether intraamniotic inflammation in response to bacteria is different below and above gestational age 32 weeks in pregnancies complicated by preterm prelabor rupture of membranes (PPROM). METHODS: A prospective study was performed, and 115 women with singleton pregnancies complicated by PPROM at gestational ages between 24(0/7) and 36(6/7) weeks were included in the study. Transabdominal amniocenteses were performed. Amniotic fluid was analysed using polymerase chain reactions for genital mycoplasmas and cultured for aerobic and anaerobic bacteria. The concentrations of 26 proteins in the amniotic fluid were determined simultaneously using multiplex technology. RESULTS: Bacteria were found in the amniotic fluid of 43% (49/115) of the women. The women were stratified into two subgroups according to gestational age 32 weeks. The amniotic fluid levels of four (interleukin-6, interleukin-10, CC chemokine ligands 2, and 3) and one specific (CC chemokine ligands 2) proteins were higher in women with the presence of bacteria in the amniotic fluid below and above 32 gestational weeks, respectively. CONCLUSIONS: An intraamniotic inflammatory response to bacteria in pregnancies complicated by PPROM seems to be different below and above 32 weeks of gestation. PMID- 22519390 TI - Metabolic outcomes of elderly patient populations initiating exenatide BID versus insulin glargine in an ambulatory care setting. AB - AIMS: The safety and efficacy of exenatide BID (exenatide) and insulin glargine (glargine) have been studied in clinical trials with few elderly patients. This study examined the clinical effectiveness of exenatide compared to glargine in patients 65 years and older with type 2 diabetes mellitus (T2DM). METHODS: A retrospective analysis was conducted using the General Electric electronic medical record database. Patients aged 65 years and older with T2DM who initiated exenatide or glargine were identified between November 1, 2006 and April 30, 2009 with 12 months of pre- and post-index continuous eligibility. Propensity-score matching (1:1) was used to balance baseline differences between the cohorts. The effectiveness endpoints were changes in A1C (primary endpoint), weight, body mass index (BMI), and blood pressure (BP). Matched cohorts were compared using paired t tests and nonparametric tests as appropriate. RESULTS: The matched exenatide and glargine patients (n = 804 each) were comparable in their baseline characteristics, including age (70 vs. 71 years), and male sex (44.9% vs. 45.2%). In the 12-month follow-up, exenatide patients experienced significantly greater mean reductions in A1C (-0.5 vs. -0.2%), weight (-2.8 vs. -0.2 kg), BMI (-1.0 vs. -0.1 kg/m(2)), and systolic BP (-2.2 vs. 1.0 mmHg) (all: P < 0.05). More exenatide-treated patients reached the A1C goal of <7% (53.9% vs. 43.0%, P < 0.01). Diastolic BP was similar between the cohorts. LIMITATIONS: Unmeasured confounding bias may still exist and thus findings should be interpreted as associations instead of causations. Due to incomplete data, adverse events and medication use were not examined. CONCLUSION: Exenatide was associated with significant improvement in A1C, weight, BMI and BP compared to glargine for management of T2DM in an elderly patient population treated in ambulatory care settings. PMID- 22519391 TI - Comparability and biosimilarity: considerations for the healthcare provider. AB - BACKGROUND: Healthcare providers use recombinant biologics such as monoclonal antibodies to treat a variety of serious illnesses. Manufacturing of approved biotechnology products is complex, and the quality of the resulting biologic is dependent on careful control of process inputs and operating conditions. Biosimilars, which are similar but not identical to innovator biologics, are entering regulatory evaluation, approval, and marketing in regions with biosimilar approval pathways. SCOPE AND FINDINGS: This article describes the evaluation and potential impact of manufacturing process changes and biosimilar product development, and explores the similarities and distinctions between the two. Regulatory agencies generally require a comparability exercise following a manufacturing process change. This comparability is focused primarily on analytical characterization of the approved product before and after the manufacturing process change, with non-clinical and clinical confirmation required when determined necessary. When developing a biosimilar, the manufacturer does not have access to key information including the innovator manufacturer's cell line, cell culture conditions, purification procedures, and fill and finish processes. Further, the biosimilar manufacturer does not have access to information about the innovator manufacturer's product development history, including knowledge about the quality attributes of lots used in non clinical and clinical development. We define the biosimilar manufacturer's lack of information as the knowledge gap. As a result, a biosimilarity exercise to compare a biosimilar to an approved innovator biologic requires a rigorous evaluation to ensure the safety and efficacy of the biosimilar. CONCLUSION: Given the knowledge gap under which biosimilars are developed, data to establish biosimilarity should go beyond a simple comparability exercise. PMID- 22519392 TI - Avoidance of swallowing saliva: a symptom related to aberrant basal ganglia functions? AB - We report two patients with avoidance of swallowing saliva despite intact swallowing functions. One, with mild, de novo Parkinson's disease, had a fear that his saliva was contaminated and would harm him. The other, with a history of CNS germinoma in remission for 3 years following chemotherapy, expectorated because his saliva was distasteful and disgusting. He had a lesion involving the left pallidum. Both appeared obsessed with the idea of saliva contamination and both expectorated compulsively, presenting obsessive-compulsive disorder (OCD) symptoms. OCD-like behavior may be induced in association with pathological conditions in which aberrant basal ganglia functions are present. PMID- 22519394 TI - Some recent approaches of biologically active substituted pyridazine and phthalazine drugs. AB - Nitrogen atom containing heterocyclic compounds, pyridazines, pyridazinones and phthalazines are important structural feature of many biologically active compounds and show diverse pharmacological properties. Pyridazines and phthalazines hold considerable interest relative to the preparation of organic intermediates and physiologically active compounds. On the basis of literature, pyridazines, pyridazinone and phthalazines further focus our attention because of their easy fictionalization at various ring positions, which makes them attractive synthetic compounds for designing and development of the novel pyridazines and phthalazines drugs in future. PMID- 22519395 TI - Protocatechuic acid and human disease prevention: biological activities and molecular mechanisms. AB - Epidemiological evidence has shown that a high dietary intake of vegetables and fruit rich in polyphenols is associated with a reduction of cancer incidence and mortality from coronary heart disease. The healthy effects associated with polyphenol consumption have made the study of the mechanisms of action a matter of great importance. In particular, the hydroxybenzoic acid protocatechuic acid (PCA) has been eliciting a growing interest for several reasons. Firstly, PCA is one of the main metabolites of complex polyphenols such as anthocyanins and procyanidins that are normally found at high concentrations in vegetables and fruit, and are absorbed by animals and humans. Since the daily intake of anthocyanins has been estimated to be much higher than that of other polyphenols, the nutritional value of PCA is increasingly recognized. Secondly, a growing body of evidence supports the concept that PCA can exert a variety of biological effects by acting on different molecular targets. It has been shown that PCA possesses antioxidant, anti-inflammatory as well as antihyperglycemic and neuroprotective activities. Furthermore, PCA seems to have chemopreventive potential because it inhibits the in vitro chemical carcinogenesis and exerts pro apoptotic and anti-proliferative effects in different tissues. This review is aimed at providing an up-dated and comprehensive report on PCA giving a special emphasis on its biological activities and the molecular mechanisms of action most likely responsible for a beneficial role in human disease prevention. PMID- 22519396 TI - Discovery of selective small molecular TACE inhibitors for the treatment of rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic, inflammatory disease that afflicts 1-2% of the world population, characterized by an immune mediated inflammatory synovitis that leads to joint destruction, functional impairment, and reduced quality of life. The treatment goals of RA should be longterm substantial relief of pain, arrested joint inflammation and damage, and improved function. Current treatment can be divided into four classes, namely general analgesics and non steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, disease modifying anti-rheumatic drugs (DMARDs) and biological agents (tumor-necrosis factor modifiers). However, gastrointestinal (GI) side effects of NSAIDs cannot be neglected, direct joint injections of glucocorticoids cannot be injected more than once every 3 months, synthetic DMARDs is far from optimal and only minority of patients achieved longterm remission, the biologics are very expensive to manufacture, need to be injected, and can cause allergic reactions. An alternative and good approach to the treatment of this disease is to lower the levels of tumour necrosis factor-alpha (TNF-alpha) in RA, which can be achieved by selectively inhibiting the tumour necrosis factor-alpha converting enzyme (TACE) that generate these cytokines using cheaper small molecules. This review focuses on the current status of selective small molecule inhibitors of TACE, with respect to lead compound search, inhibitors design approach, structure activity relationship (SAR) and pharmacological studies in animals and humans. Through these methods, new hope is emerging for the treatment of RA through selective inhibition of TACE. PMID- 22519397 TI - Mechanisms involved in the protective effects of metformin against nonalcoholic fatty liver disease. AB - Metformin is an antidiabetic drug used widely in clinical practice. Its main clinical effect is to reduce blood glucose levels by improving insulin resistance. Nonalcoholic fatty liver disease is characterized by chronic liver damage and can develop into liver cirrhosis. Nonalcoholic fatty liver disease is associated with obesity and contributes to insulin resistance, and metformin is used to treat individuals with these conditions. The mechanisms underlying the clinical effects of metformin in treating nonalcoholic fatty liver disease are unclear. This article summarizes the literature on the mechanisms associated with liver glucose metabolism and the beneficial effects of metformin on this common liver disease. PMID- 22519398 TI - Intracellular signaling pathways modulated by phenolic compounds: application for new anti-inflammatory drugs discovery. AB - Extensive research within the last two decades revealed that most chronic illnesses, including cancer, neurological, autoimmune and cardiovascular diseases are mediated through chronic inflammation. Thus, suppressing chronic inflammation has the potential to delay, prevent, and treat those diseases. However, side effects and high costs of current anti-inflammatory drugs force the development of new drugs. Natural products represent an important source of new bioactive compounds. Among them, phenolic compounds, which are widely distributed in plants, have been described as having many therapeutic effects. Several reviews have addressed the anti-inflammatory activity of phenols, attributing their properties not only to the antioxidant capacity, but also to inflammatory mediators' modulation, namely cytokines and pro-inflammatory proteins, such as inducible nitric oxide synthase and cyclooxygenase-2. Signal transduction pathways precede changes in inflammatory mediators' expression. However, only a restricted number of studies have addressed the effect of phenols on a specific signal transduction pathway. The present review attempts to summarize and highlight a broad range of inflammation-associated signaling pathways modulated by phenols namely: nuclear factor (NF)-kappaB, activator protein (AP)-1, peroxisome proliferator-activated receptor (PPAR) and nuclear factor erythroid 2 related factor 2 (Nrf2) transcription factors; mitogen-activated protein kinases (MAPKs); protein tyrosine kinases (PTKs); tyrosine phosphatidylinositol 3-kinase (PI3K)/Akt and ubiquitin-proteasome system. As a consequence of phenols effect on signaling pathways, described above, their action on inflammatory mediators' production is mentioned. Finally, it is established that the structure-activity relationships of phenolic compounds are a valuable information source on the development of new anti-inflammatory drugs from natural products. PMID- 22519399 TI - Recent advances in the medicinal chemistry of aurones. AB - The first review regarding the potential of aurones as promising drug candidates was reported in 2003. Since, considerable efforts have been made to explore the pharmacological and therapeutical activities of aurones. In this regard, many biological areas were concerned, including major pathological, such as cancer and neurodegenerative disorders. The aim of the present report is to highlight the progress made during the last ten years on the medicinal chemistry of aurones. A special focus will be made on the structure-activity relationship aspects among aurones and especially in case where aurones were found highly active than the corresponding flavones and chalcones. PMID- 22519400 TI - Recent progress and future potential for metal complexes as anticancer drugs targeting G-quadruplex DNA. AB - Now cisplatin and its analogs are some of the most effective chemotherapeutic agents in clinical use as the first line of treatment in testicular and ovarian cancers. Unfortunately, they have several major drawbacks, such as cumulative toxicities of nephrotoxicity and ototoxicity, inherent or treatment-induced resistance. This has provided the motivation for developing novel metal complexes as anticancer agents with different mechanism of action. In recent years, significant attention has been devoted to the role of G-quadruplexes in cancer. It was found that the stabilization of G-quadruplexes by small molecules has been shown to inhibit the transcriptional activity of some oncogenes. Thus, the G quadruplex motif has emerged as a promising target for the design of selective anticancer drugs. Apart from the purely organic heteroaromatic compounds reported as G-quadruplex binders, it has recently been shown that metal complexes can also interact strongly and selectively with quadruplex DNA and have potential anticancer activity. This review will highlight recent progress of the metal complexes as anticancer drugs targeting G-quadruplex DNA, and discuss their future potential in the medical fields. Considering the significant roles of the metal ions, the metal complexes will be discussed as follows: (1) Ruthenium(II) complexes; (2) Nickel(II) complexes; (3) Zinc(II) complexes; (4) Manganese(III) complexes; (5) Copper(II) complexes; (6) Palladium(II)/Platinum(II); (7) Other metal complexes. PMID- 22519401 TI - Extraction, characterization and in vivo neuromodulatory activity of phytosterols from microalga Dunaliella tertiolecta. AB - In recent years, a great deal of research has been devoted to identify new natural sources of phytosterols and to improve methods for their recovery and purification. In this regard, unexplored natural sources of bioactive ingredients are gaining much attention since they can lead to the isolation of new compounds or bioactivities. The field of available natural sources has been further increased by including algae and, even more interestingly, microalgae. In the present study, a multidisciplinary approach has been used considering, in an integrated view, extraction, chemical composition and bioactivity of phytosterols from the microalga Dunaliella tertiolecta. A novel methodology to extract, separate and characterize microalgal-derived phytosterols has been developed. In addition, recoverable and reusable eluents have been selected in order to reduce the quantities of employed organic solvents. Finally, we addressed the question whether orally administered phytosterols reach the brain and if those interfere with the major neurotransmitter systems, such as the dopaminergic, serotoninergic and noradrenergic ones, in several brain areas of rats. Flash Liquid Chromatography has been used to separate the Total Sterol (TS) fraction, composed of twelve sterols, with a purity of 97.87% and a recovery percentage of 98%, while the "flash version" of Silver Ion Liquid Chromatography has been used to purify the most abundant phytosterols in TS, (22E,24R)- methylcholesta-5,7,22 trien-3beta-ol (ergosterol) and (22E,24R)-ethylcholesta-5,7,22-trien-3beta-ol (7 dehydroporiferasterol), with a purity of 97.4%. These two combined methods did not need sophisticated technologies but only cheap laboratory supplies. Moreover, the possibility of recovering and recycling the solvents used as eluents made it a cleaner process. Finally, for the first time, a neuromodulatory action of Dunaliella tertiolecta-derived phytosterols has been found in selective brain areas of rats. PMID- 22519402 TI - Screening of 64 tryptamines at NMDA, 5-HT1A, and 5-HT2A receptors: a comparative binding and modeling study. AB - Tryptamine (T) and several T derivatives (Ts) inhibit in a voltage-dependent manner the NMDA receptor (NR). This effect is influenced by substituents at various positions, but has not yet been subjected to a detailed SAR study. Here, 64 Ts have been tested as inhibitors of [3H]MK-801 binding to NRs on rat brain membranes. For comparison, they were also tested as inhibitors of [3H]8-OHDPAT binding to 5-HT1A and of [3H]ketanserin binding to 5-HT2A receptors. Since most of these Ts have not been tested before at any of these receptors, we start with a review of the effects of Ts on 5-HT1A and 5-HT2A binding sites. NRs were inhibited with IC50s from 2 to 7 MUM by Ts with alkyl or halogen at positions 2, 5, and/or 7. Inhibition by some Ts was attenuated more than 10-fold by 30 MUM spermine. The most potent inhibitors at 5-HT1A receptors were 5-carboxamido-T (IC50 0.00015 MUM) and serotonin (0.0016 MUM), at 5-HT2A receptors 2-Me-4,7-Cl2-T (1.2 MUM) and 2,7-Me2-4-Cl-T (2.0 MUM). Fujita-Ban modified Free-Wilson analyses pointed to the individual significance of particular substituents. Also QSARs based on molecular operating environment descriptors resulted in sound correlations at all 4 targets. No similarities between the NR and 5-HT receptors could be found. At the NR, only L-Trp-NH2 bound 10 times better than at both 5-HT receptors studied. L-Trp-NH2 may be a structural lead to endogenous non competitive NR antagonists. PMID- 22519403 TI - Determination of the intracellular stability of gold nanoparticle monolayers using mass spectrometry. AB - Monolayer stability of core-shell nanoparticles is a key determinant of their utility in biological studies such as imaging and drug delivery. Intracellular thiols (e.g., cysteine, cysteamine, and glutathione) can trigger the release of thiolate-bound monolayers from nanoparticles, a favorable outcome for controllable drug release applications but an unfavorable outcome for imaging agents. Here, we describe a method to quantify the monolayer release of gold nanoparticles (AuNPs) in living cells using parallel measurements by laser desorption/ionization (LDI) and inductively coupled plasma (ICP) mass spectrometry. This combination of methods is tested using AuNPs with structural features known to influence monolayer stability and on cells types with varying concentrations of glutathione. On the basis of our results, we predict that this approach should help efforts to engineer nanoparticle surface monolayers with tunable stability, providing stable platforms for imaging agents and controlled release of therapeutic monolayer payloads. PMID- 22519404 TI - Pulmonary surfactant suppressed phenanthrene adsorption on carbon nanotubes through solubilization and competition as examined by passive dosing technique. AB - Adsorption of phenanthrene on carbon nanotubes (CNTs) was examined in the presence of pulmonary surfactant (Curosurf) and its main components, dipalmitoyl phosphatidylcholine (DPPC) and bovine serum albumin (BSA). A passive-dosing method based on equilibrium partitioning from a preloaded polymer was successfully employed to measure phenanthrene binding and speciation at controlled freely dissolved concentrations while avoiding phase separation steps. Curosurf, DPPC, and BSA could all linearly solubilize phenanthrene, and phenanthrene solubilization by Curosurf was 4 times higher than individual components (DPPC or BSA). In the presence of Curosurf, DPPC or BSA, adsorption of phenanthrene by multiwalled CNTs (MWCNTs) was suppressed, showing competitive adsorption between pulmonary surfactant (or DPPC, BSA) and phenanthrene. Competitive adsorption between Curosurf and phenanthrene was the strongest. Therefore, when phenanthrene-adsorbed CNTs enter the respiratory tract, phenanthrene can be desorbed due to both solubilization and competition. The bioaccessibility of phenanthrene adsorbed on three MWCNTs in the respiratory tract would be positively related to the size of their outer diameters. Moreover, the contribution of solubilization and competition to desorption of phenanthrene from MWCNTs was successfully separated for the first time. These findings demonstrate the two mechanisms on how pulmonary surfactants can enhance desorption and thus possibly biological absorption of phenanthrene adsorbed on CNTs. PMID- 22519405 TI - Vascular endothelial growth factor secretion by nonmyocytes modulates Connexin-43 levels in cardiac organoids. AB - We previously showed that the sequential, but not simultaneous, culture of endothelial cells (ECs), fibroblasts (FBs), and cardiomyocytes (CMs) resulted in elongated, beating cardiac organoids. We hypothesized that the expression of Cx43 and contractile function are mediated by vascular endothelial growth factor (VEGF) released by nonmyocytes during the preculture period. Cardiac organoids (~200 MUm diameter) were cultivated in microchannels to enable rapid screening. Three experimental groups were formed: (i) Simultaneous Preculture (ECs+FBs for 48 h, followed by CMs), (ii) Sequential Preculture (ECs for 24 h, FBs for 24 h, followed by CMs), and (iii) Simultaneous Triculture (ECs+FBs+CMs). Controls included CMs only, FBs only, and ECs only groups, and preculture with ECs only or FBs only. The highest VEGF levels were found in the Preculture groups [Simultaneous Preculture, 8.9+/-2.7 ng/(mL.h(-1)); Sequential Preculture, 16.6+/ 3.4 ng/(mL.h(-1))], as compared with Simultaneous Triculture where VEGF was not detectable, as shown by enzyme-linked immunosorbent assay. Analytical flow cytometry showed that VEGFR2 was expressed by ECs (86%+/-2 VEGFR2+), FBs (44%+/-1 VEGFR2+), and CMs (49%+/-2 VEGFR2+), showing that all three cell types were capable of responding to changes in VEGF. Addition of anti-VEGF neutralizing IgG (0.4 MUg/mL) to Simultaneous Preculture resulted in 3-fold decrease in Cx43 mRNA and 1.5-fold decrease in Cx43 protein, while Simultaneous Triculture supplemented with VEGF ligand (30 ng/mL) had a threefold increase in Cx43 mRNA and a twofold increase in Cx43 protein. Addition of a small molecule inhibitor of the VEGFR2 receptor (19.4 nM) to Sequential Preculture caused a 1.4-fold decrease in Cx43 mRNA and a 4.1-fold decrease in Cx43 protein. Cx43 was localized within CMs, and not within FBs or ECs. Enriched CM organoids and Sequential Preculture organoids grown in the presence of VEGFR2 inhibitor displayed low levels of Cx43 and poor functional properties. Taken together, these results suggest that endogenous VEGF VEGFR2 signaling enhanced Cx43 expression and cardiac function in engineered cardiac organoids. PMID- 22519406 TI - Cetuximab in non-melanoma skin cancer. AB - INTRODUCTION: Non-melanoma skin cancer (NMSC) has become the most common cancer with squamous cell carcinoma (SCC) as the major cause of morbidity and mortality. REVIEW AREAS COVERED: The chimeric human-mouse monoclonal antibody Cetuximab against epidermal growth factor receptor (EGFR) has been approved for advanced head and neck cancer (HNC). Since SCC has been shown to express the EGFR, EGFR targeted therapy is an option. METHODOLOGY: A PUBMED research 2000 - 2012 have been conducted using the following items: "Non-melanoma skin cancer AND cetuximab," "cutaneous squamous cell carcinoma AND cetuximab," and "basal cell carcinoma AND cetuximab." RESULTS: Current evidence of cetuximab efficacy in NMSC results from a Phase II trial and case reports. Cetuximab can be combined with radiotherapy in analogy to HNC. The total response rate is almost 50% in patients with SCC. The combination with radiotherapy resulted in a complete response rate of 50%. Management of adverse reactions in SCC with particular emphasis on cutaneous toxicities is necessary. Further controlled trials are needed. EXPERT OPINION: EGFR inhibitor cetuximab is an option for recurrent or advanced SCC of skin. The combination with radiotherapy seems to be superior to cetuximab alone. PMID- 22519407 TI - Reformulation of Stmerin((r)) D CFC formulation using HFA propellants. AB - Stmerin((r)) D was reformulated using hydrofluoroalkanes (HFA-134a and HFA-227) as alternative propellants instead of chlorofluorocarbons (CFCs), where the active ingredients were suspended in mixed CFCs (CFC-11/CFC-12/CFC-114). Here, we report the suspension stability and spray performance of the original CFC formulation and a reformulation using HFAs. We prepared metered dose inhalers (MDI) using HFAs with different surfactants and co-solvents, and investigated the effect on suspension stability by visual testing. We found that the drug suspension stability was poor in both HFAs, but was improved, particularly for HFA-227, by adding a middle chain fatty acid triglycerides (MCT) to the formulation. However, the vapor pressure of HFA-227 is higher than a CFC mixture and this increased the fine particle dose (FPD). Spray performance was adjusted by altering the actuator configuration, and the performance of different actuators was tested by cascade impaction. We found the spray performance could be controlled by the configuration of the actuator. A spray performance comparable to the original formulation was obtained with a 0.8 mm orifice diameter and a 90 degrees cone angle. These results demonstrate that the reformulation of Stmerin((r)) D using HFA-227 is feasible, by using MCT as a suspending agent and modifying the actuator configuration. PMID- 22519408 TI - Ras signaling pathway in the chemopreventive action of different ratios of fish oil and corn oil in experimentally induced colon carcinogenesis. AB - Dietary factors play a significant role in colon cancer. The essential polyunsaturated fatty acids (PUFAs), n-3 PUFAs, and n-6 PUFAs exert inverse effect on cancer. This study was designed to understand the mechanism of chemopreventive action of different ratios of fish oil (FO) and corn oil (CO) in colon carcinoma. Wistar rats were divided into 3 groups: Group 1 received purified diet whereas Groups 2 and 3 received modified diet with FO:CO (1:1) and FO:CO (2.5:1), respectively. The groups were further subdivided into controls receiving ethylenediamine-tetra acetic-acid and treated groups received dimethylhydrazine-dihydrochloride (DMH)/wk for 4 wk. Animals sacrificed 48 h after last injection constituted initiation phase and that sacrificed after 16 wk constituted post-initiation phase. Differential effect of different ratios of FO and CO was analyzed in isolated colonocytes. In both phases, DMH treatment showed an increase in pan Ras, Raf, MEK1/2, extracellular signal regulated kinase (Erk)1/2, and c-fos levels. Akt levels were increased in post-initiation phase only. Treatment with FO + CO (1:1) + DMH decreased pan Ras, MEK1/2 and Erk1/2 levels in post-initiation phase whereas Raf and c-fos were decreased in both phases. Treatment with FO + CO (2.5:1) + DMH decreased Ras, Raf, MEK1/2, Erk1/2, and c-fos levels in both phases. Akt was decreased in post-initiation phase only. The chemo-preventive action of FO and CO may be mediated by time- and dose dependent effect. PMID- 22519409 TI - Medical students on long-term regional and rural placements: what is the financial cost to supervisors? AB - INTRODUCTION: Medical student education is perceived as utilising significant amounts of preceptors' time, negatively impacting on clinical productivity. Most studies have examined short-term student rotations in urban settings, limiting their generalisability to other settings and educational models. To test Worley and Kitto's hypothetical model which proposed a 'turning point' when students become financially beneficial, this study triangulated practice financial data with the perspectives of clinical supervisors before and after regional/rural longitudinal integrated community-based placements. METHODS: Gross practice financial data were compared before and during the year-long placement. Interview data pre- and post-placement were analysed by two researchers who concurred on emergent themes and categories. METHODS: This study suggested a financial 'turning point' of 1-2 months when the student became beneficial to the practice. Most preceptors (66%) perceived the longitudinal placement as financially neutral or favourable. Nineteen per cent of supervisors reported a negative financial impact, some attributing this to reduced patient throughput, inadequacy of the government teaching subsidy and/or time spent on assessment preparation. Other supervisors were unconcerned about costs, perceiving that minor financial loss was outweighed by personal satisfaction. CONCLUISONS: Senior students learning in long-term clerkships are legitimate members of regional/rural communities of practice. These students can be cost-neutral or have a small positive financial impact on the practice within a few months. Further financial impact research should include consideration of different models of supervisor teaching subsidies. The ultimate financial benefit of a model may lie in the recruitment and retention of much-needed regional and rural practitioners. PMID- 22519411 TI - Incorporation of silver nanoparticles into the bulk of the electrospun ultrafine polyimide nanofibers via a direct ion exchange self-metallization process. AB - This paper reports our works on the preparation of the silver-nanoparticle incorporated ultrafine polyimide (PI) ultrafine fibers via a direct ion exchange self-metallization technique using silver ammonia complex cation ([Ag(NH(3))(2)](+)) as the silver precursor and pyromellitic dianhydride (PMDA)/4,4'-oxidianiline (4,4'-ODA) polyimide as the matrix. The polyimide precursor, poly(amic acid) (PAA), was synthesized and then electrospun into ultrafine fibers. By thermally treating the silver(I)-doped PAA ultrafine fibers, where the silver(I) ions were loaded through the ion exchange reactions of the carboxylic acid groups of the PAA macromolecules with the [Ag(NH(3))(2)](+) cations in an aqueous solution, ultrafine polyimide fibers embedded with silver nanoparticles with diameters less than 20 nm were successfully fabricated. The fiber-electrospinning process, the ion exchange process, and various factors influencing the hybrid ultrafine fibers preparation process such as the thermal treatment atmospheres and the thermal catalytic oxidative degradation effect of the reduced silver nanoparticles were discussed. The ultrafine fibers were characterized by attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), inductively coupled plasma atomic emission spectroscopy (ICP AES), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and thermogravimetric analysis (TGA). PMID- 22519410 TI - Undernotification of anaphylaxis deaths in Brazil due to difficult coding under the ICD-10. AB - BACKGROUND: Undernotification is well recognized as a key challenge to the study of anaphylaxis mortality, but it is seldom mentioned that one of its reasons is the difficult coding of the condition under the tenth revision of the international classification of diseases (ICD-10), given that there are no anaphylaxis-specific ICD-10, which are considered valid for coding underlying causes-of-death, and that official mortality statistics consider exclusively the underlying and disregard the contributing causes-of-death data recorded on death certificates. Brazilian mortality data were used as a case study to call attention to the inadequacy of the ICD-10 for the measurement of anaphylaxis deaths. METHODS: Underlying and contributing causes-of-death data were used to estimate the rates of anaphylaxis deaths in the country over the years 2008-2010. RESULTS: Of 498 anaphylaxis deaths were found, of which 75% were classified as 'definite' and 25% as 'possible anaphylaxis deaths'. The average national rate for these years was 0.87 per million per year. None of these deaths would have been found had we exclusively considered information from the underlying cause-of death field. CONCLUSION/RECOMMENDATIONS: The study of anaphylaxis mortality using secondary data requires the use of information derived from the underlying as well as from the contributing causes-of-death fields. Coding definitions should be standardized with a view of enabling trend analyses and international comparisons. The ICD-11 revision is a unique opportunity to improve the coding system so as to facilitate epidemiological studies of anaphylaxis mortality. Educational interventions targeted at improving the quality of death certificate completion are urgently needed. PMID- 22519412 TI - Isoprene hydrocarbons production upon heterologous transformation of Saccharomyces cerevisiae. AB - AIMS: Isoprene (2-methyl-1,3-butadiene; C(5) H(8) ) is naturally produced by photosynthesis and emitted in the atmosphere by the leaves of many herbaceous, deciduous and woody plants. Fermentative yeast and fungi (Ascomycota) are not genetically endowed with the isoprene production process. The work investigated whether Ascomycota can be genetically modified and endowed with the property of constitutive isoprene production. METHODS AND RESULTS: Two different strategies for expression of the IspS gene in Saccharomyces cerevisiae were employed: (i) optimization of codon usage of the IspS gene for specific expression in S. cerevisiae and (ii) multiple independent integrations of the IspS gene in the rDNA loci of the yeast genome. Copy number analysis showed that IspS transgenes were on the average incorporated within about 25% of the endogenous rDNA. Codon use optimization of the Pueraria montana (kudzu vine) IspS gene (SckIspS) for S. cerevisiae showed fivefold greater expression of the IspS protein compared with that of nonoptimized IspS (kIspS). With the strategies mentioned earlier, heterologous expression of the kudzu isoprene synthase gene (kIspS) in S. cerevisiae was tested for stability and as a potential platform of fermentative isoprene production. The multi-copy IspS transgenes were stably integrated and expressed for over 100 generations of yeast cell growth and constitutively produced volatile isoprene hydrocarbons. Secondary chemical modification of isoprene to a number of hydroxylated isoprene derivatives in the sealed reactor was also observed. CONCLUSION: Transformation of S. cerevisiae with the Pueraria montana var. lobata (kudzu vine) isoprene synthase gene (IspS) conferred to the yeast cells constitutive isoprene hydrocarbons production in the absence of adverse or toxic effects. SIGNIFICANCE AND IMPACT OF THE STUDY: First-time demonstration of constitutive isoprene hydrocarbons production in a fermentative eukaryote operated through the mevalonic acid pathway. The work provides concept validation for the utilization of S. cerevisiae, as a platform for the production of volatile hydrocarbon biofuels and chemicals. PMID- 22519413 TI - Photoresponsive poly(S-(o-nitrobenzyl)-L-cysteine)-b-PEO from a L-cysteine N carboxyanhydride monomer: synthesis, self-assembly, and phototriggered drug release. AB - A photoresponsive S-(o-nitrobenzyl)-l-cysteine N-carboxyanhydride (NBC-NCA) monomer was for the first time designed, and the related poly(S-(o-nitrobenzyl)-l cysteine)-b-poly(ethylene glycol) (PNBC-b-PEO) block copolymers were synthesized from the ring-opening polymerization (ROP) of NBC-NCA in DMF solution at 25 degrees C. Their molecular structures, physical properties, photoresponsive self assembly, and drug release of PNBC-b-PEO were thoroughly investigated. The beta sheet conformational PNBC block within copolymers presented a thermotropic liquid crystal phase behavior, and the crystallinity of PEO block was progressively suppressed over the PNBC composition. The characteristic absorption peaks of these copolymers at about 310 and 350 nm increased over UV irradiation time and then leveled off, indicating that the o-nitrobenzyl groups were gradually photocleaved from copolymers until the completion of photocleavage. The PNBC-b PEO copolymers self-assembled into spherical nanoparticles in aqueous solution, presenting a photoresponsive self-assembly behavior, together with a size reduction of nanoparticles after irradiation. The anticancer drug doxorubicin can be released in a controlled manner by changing the light irradiation time, which was induced by gradually photocleaving the PNBC core of nanoparticles. This work provides a facile strategy not only for the synthesis of photoresponsive polypeptide-based block copolymers but also for the fabrication of photoresponsive nanomedicine potential for anticancer therapy. PMID- 22519415 TI - Factors associated with changes in quality of life in patients undergoing allogeneic haematopoietic stem cell transplantation. AB - It is well known that patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) experience changes in quality of life. We investigated factors associated with quality of life changes in adult HSCT patients. The Functional Assessment of Cancer Therapy - Bone Marrow Transplantation (FACT-BMT) scale, supplemented with the Functional Assessment of Chronic Illness Therapy - Spiritual Well-being (FACIT-Sp) subscale, was administered on three occasions, immediately before transplantation, 100 days and 12 months after transplantation. Analyses of nine selected factors were made where changes in quality of life were found. Seventy-five patients were included and 40 of these completed the study. Emotional well-being was found to improve between the baseline and 100 days, while all other dimensions deteriorated, including overall quality of life. Physical and social/family well-being deteriorated between the baseline and the 12-month follow-up, while emotional well-being improved. The main factors associated with deteriorating quality of life over time were found to be significant infections, female gender and transplantation with stem cells from a sibling donor. In our further studies we aim to focus on the relationships between patients and sibling donors in order to improve the care. Careful attention must be paid to continuous adequate information during the transplantation procedure. PMID- 22519414 TI - Allosteric inhibition of cobalt binding to albumin by fatty acids: implications for the detection of myocardial ischemia. AB - The biomarker "ischemia-modified albumin" (IMA), measured by the albumin-cobalt binding assay (ACB assay), is the only FDA-approved biomarker for early diagnosis of myocardial ischemia. On the basis of the hypothesis that high levels of free fatty acids are directly responsible for reduction in cobalt binding by albumin, chemically defined model systems consisting of bovine serum albumin, Co(2+), and myristate were studied by isothermal titration calorimetry, (111)Cd NMR spectroscopy, and ACB assays. Significantly reduced Co(2+) binding to albumin, as demonstrated by an increase in the absorption of the Co-dithiothreitol adduct, elicited by adding ca. 3 mol equiv of myristate, was comparable to that observed in clinical ACB assays. Levels of free fatty acids are elevated during myocardial ischemia but also in other conditions that have been correlated with high IMA values. Hence, IMA may correspond to albumin with increased levels of bound fatty acids, and all clinical observations can be rationalized by this molecular mechanism. PMID- 22519416 TI - Drug-induced gingival overgrowth: a study in the French Pharmacovigilance Database. AB - BACKGROUND: Gingival overgrowth is an adverse drug reaction (ADR) well known with phenytoin, cyclosporine or calcium channel blockers but can be related to other drugs. AIM: We reviewed spontaneous notifications of drug-induced gingival overgrowth (DIGO), in France. MATERIAL & METHODS: We selected DIGO cases registered in the French Pharmacovigilance Database, between 1984 and 2010. RESULTS: We found 147 DIGO cases (0.04% of all cases), most of them (86.4%) "non serious". Patients were more frequently men (58.5%) and between 40 and 69 years (58.5%). Evolution was favourable in 47.5% of cases. The most frequently "suspected" drugs were calcium channel blockers (30.6%) followed by immunosuppressants (15.2%) and anticonvulsants (10.1%). The DIGO was also reported with drugs for which the ADR was "unlabelled" (mycophenolate mofetil, valproic acid, clarithromycin, ethynylestradiol, levonorgestrel, desogestrel, etc.). There were two peaks of occurrence (0-3 and >12 months) for immunosuppressants or calcium channel blockers and only one (>12 months) for anticonvulsants. CONCLUSION: Gingival overgrowth is often a "non serious" ADR but evolution was favourable in only half of cases. This ADR is "labelled" for calcium channel blockers, cyclosporine and phenytoin but can also occur with other immunosuppressants or anticonvulsants, antibiotics, oral contraceptives, etc. PMID- 22519417 TI - Flexible multilevel resistive memory with controlled charge trap B- and N-doped carbon nanotubes. AB - B- and N-doped carbon nanotubes (CNTs) with controlled workfunctions were successfully employed as charge trap materials for solution processable, mechanically flexible, multilevel switching resistive memory. B- and N-doping systematically controlled the charge trap level and dispersibility of CNTs in polystyrene matrix. Consequently, doped CNT device demonstrated greatly enhanced nonvolatile memory performance (ON-OFF ratio >10(2), endurance cycle >10(2), retention time >10(5)) compared to undoped CNT device. More significantly, the device employing both B- and N-doped CNTs with different charge trap levels exhibited multilevel resistive switching with a discrete and stable intermediate state. Charge trapping materials with different energy levels offer a novel design scheme for solution processable multilevel memory. PMID- 22519418 TI - Blockade of beta-adrenoceptors restores the GRK2-mediated adrenal alpha(2) adrenoceptor-catecholamine production axis in heart failure. AB - BACKGROUND AND PURPOSE: Sympathetic nervous system (SNS) hyperactivity is characteristic of chronic heart failure (HF) and significantly worsens prognosis. The success of beta-adrenoceptor antagonist (beta-blockers) therapy in HF is primarily attributed to protection of the heart from the noxious effects of augmented catecholamine levels. beta-Blockers have been shown to reduce SNS hyperactivity in HF, but the underlying molecular mechanisms are not understood. The GPCR kinase-2 (GRK2)-alpha(2) adrenoceptor-catecholamine production axis is up-regulated in the adrenal medulla during HF causing alpha(2) -adrenoceptor dysfunction and elevated catecholamine levels. Here, we sought to investigate if beta-blocker treatment in HF could lower SNS activation by directly altering adrenal GRK2 levels. EXPERIMENTAL APPROACH: Four weeks after myocardial infarction-induced HF, adult rats were randomized to 10-week treatment with vehicle (HF/C) or bisoprolol (HF/B). Cardiac function and dimensions were measured. In heart and adrenal gland, GRK2 levels were assessed by RT-PCR and Western blotting and adrenoceptors studied with radioligand binding. Catecholamines and alpha(2) adrenoceptors in adrenal medulla chromaffin cell cultures were also measured. KEY RESULTS: Bisoprolol treatment ameliorated HF related adverse cardiac remodelling and reduced plasma catecholamine levels, compared with HF/C rats. Bisoprolol also attenuated adrenal GRK2 overexpression as observed in HF/C rats and increased alpha(2) adrenoceptor density. In cultures of adrenal medulla chromaffin cells from all study groups, bisoprolol reversed HF related alpha(2) adrenoceptor dysfunction. This effect was reversed by GRK2 overexpression. CONCLUSION AND IMPLICATIONS: Blockade of beta-adrenoceptors normalized the adrenal alpha(2) adrenoceptor-catecholamine production axis by reducing GRK2 levels. This effect may contribute significantly to the decrease of HF-related sympathetic overdrive by beta-blockers. PMID- 22519419 TI - Fecal calprotectin and S100A12 have low utility in prediction of small bowel Crohn's disease detected by wireless capsule endoscopy. AB - OBJECTIVE: Data on fecal calprotectin and S100A12 in predicting wireless capsule endoscopy (WCE) findings in suspicion of Crohn's disease (CD) are scarce. Our aim was to study the role of calprotectin and S100A12 in predicting inflammatory lesions of small bowel in patients undergoing WCE. MATERIAL AND METHODS: 84 patients undergoing WCE (77 for suspicion of CD and 7 CD patients for evaluation of disease extent) were prospectively recruited. WCE findings were scored. Patients provided a stool sample for measurements of biomarkers. Patients underwent an esophagogastroduodenoscopy and ileocolonoscopy before WCE. RESULTS: WCE was abnormal in 35 (42%) of 84 patients: 14 patients with CD, 8 with NSAID enteropathies, 8 with angioectasias, 4 with polyps or tumors, and 1 with ischemic stricture. Median calprotectin concentration in the study population was 22 MUg/g (range 2-342) and S100A12 concentration 0.048 MUg/g (range 0.003-1.215). Fecal calprotectin was significantly higher in CD patients (median 91, range 2-312) compared with those with normal WCE or other abnormalities (p = 0.008), whereas fecal S100A12 (0.087 MUg/g, range 0.008-0.896) did not differ between the groups (p = 0.166). In detecting inflammatory small bowel lesions, sensitivity, specificity, positive predictive value, and negative predictive value for fecal calprotectin (cutoff 50 MUg/g) were 59%, 71%, 42%, and 83%, and for S100A12 (cutoff 0.06 MUg/g) these were 59%, 66%, 38%, and 82%. CONCLUSIONS: In predicting small bowel inflammatory changes, fecal biomarkers calprotectin and S100A12 have moderate specificity, but low sensitivity. Neither fecal calprotectin nor S100A12 can be used for screening or excluding small bowel CD. PMID- 22519420 TI - Trehalose glycopolymers for stabilization of protein conjugates to environmental stressors. AB - Herein, we report the synthesis of trehalose side chain polymers for stabilization of protein conjugates to environmental stressors. The glycomonomer 4,6-O-(4-vinylbenzylidene)-alpha,alpha-trehalose was synthesized in 40% yield over two steps without the use of protecting group chemistry. Polymers containing the trehalose pendent groups were prepared via reversible addition-fragmentation chain transfer (RAFT) polymerization using two different thiol-reactive chain transfer agents (CTAs) for subsequent conjugation to proteins through disulfide linkages. The resulting glycopolymers were well-defined, and a range of molecular weights from 4200 to 49 500 Da was obtained. The polymers were conjugated to thiolated hen egg white lysozyme and purified. The glycopolymers when added or covalently attached to protein significantly increased stability toward lyophilization and heat relative to wild-type protein. Up to 100% retention of activity was observed when lysozyme was stressed ten times with lyophilization and 81% activity when the protein was heated at 90 degrees C for 1 h; this is in contrast to 16% and 18% retention of activity, respectively, for the wild-type protein alone. The glycopolymers were compared to equivalent concentrations of trehalose and poly(ethylene glycol) (PEG) and found to be superior at stabilizing the protein to lyophilization and heat. In addition, the protein-glycopolymer conjugates exhibited significant increases in lyophilization stability when compared to adding the same concentration of unconjugated polymer to the protein. PMID- 22519421 TI - Intragastric pressure as a determinant of food intake. AB - BACKGROUND: Different studies indicated a correlation between intragastric pressure (IGP) and satiation. Our aim was to investigate this correlation while artificially increasing the IGP. METHODS: In 12 fasted healthy volunteers an infusion catheter and a manometry probe were positioned intragastrically. Intragastric pressure was increased using a custom-made belt before or progressively during intragastric nutrient infusion. Nutrient drink (1.5 kcal mL( 1)) was intragastrically infused at 60 mL min(-1) . The subjects scored satiation using a 6-point Likert scale until maximum, when the infusion ended and the belt was released. Results are presented as mean +/- S.E.M. and compared using a paired t-test. KEY RESULTS: When the belt was tightened before the nutrient infusion, fasting IGP was significantly increased (13.6 +/- 1.3 vs 9.6 +/- 0.9 mmHg; P < 0.05) but no differences in satiation could be observed. When progressively tightening the belt during nutrient infusion the IGP increased with 0.43 +/- 0.04 mmHg per minute while in control experiments this was 0.28 +/- 0.05 mmHg per minute (P < 0.01). During the latter experiment satiation linearly increased with 0.35 +/- 0.03 and 0.29 +/- 0.02 units per minute until maximal satiation (P < 0.01) while maximum volume consumed was 926 +/- 66 and 1095 +/- 82 mL when progressively increasing the IGP vs control respectively (P < 0.01). CONCLUSIONS & INFERENCES: These findings indicate that IGP per se does not affect satiation but that a gradual IGP increase during food intake is associated with decreased food intake, indicating that gastric accommodation is an important determinant of food intake. PMID- 22519422 TI - Enhancement of immunoassay's fluorescence and detection sensitivity using three dimensional plasmonic nano-antenna-dots array. AB - Protein detection is universal and vital in biological study and medical diagnosis (e.g., cancer detection). Fluorescent immunoassay is one of the most widely used and most sensitive methods in protein detection (Giljohann, D. A.; Mirkin, C. A. Nature2009, 462, 461-464; Yager, P.; et al. Nature2006, 442, 412 418). Improvements of such assays have many significant implications. Here, we report the use of a new plasmonic structure and a molecular spacer to enhance the average fluorescence of an immunoassay of Protein A and human immunoglobulin G (IgG) by over 7400-fold and the immunoassay's detection sensitivity by 3,000,000 fold (the limit of detection is reduced from 0.9 * 10(-9) to 0.3 * 10(-15) molar (i.e., from 0.9 nM to 300 aM), compared to identical assays performed on glass plates). Furthermore, the average fluorescence enhancement has a dynamic range of 8 orders of magnitude and is uniform over the entire large sample area with a spatial variation +/-9%. Additionally, we observed that, when a single molecule fluorophore is placed at a "hot spot" of the plasmonic structure, its fluorescence is enhanced by 4 * 10(6)-fold, thus indicating the potential to further significantly increase the average fluorescence enhancement and the detection sensitivity. Together with good spatial uniformity, wide dynamic range, and ease to manufacture, the giant enhancement in immunoassay's fluorescence and detection sensitivity (orders of magnitude higher than previously reported) should open up broad applications in biology study, medical diagnosis, and others. PMID- 22519423 TI - Can AV node ablation help save AV conduction? PMID- 22519424 TI - The role of glia in retinal vascular disease. AB - Retinal vascular diseases collectively represent a leading cause of blindness. Unsurprisingly, pathological characterisation and treatment of retinal 'vascular' diseases have primarily focused on the aetiology and consequences of vascular dysfunction. Far less research has addressed the contribution of neuronal and glial dysfunction to the disease process of retinal vascular disorders. Ample evidence now suggests that retinal vasculopathy only uncommonly occurs in isolation, usually existing in concert with neuropathy and gliopathy. Retinal glia (Muller cells, astrocytes and microglia) have been reported to exhibit morphological and functional changes in both early and advanced phases of almost every retinal vascular disease. It is anticipated that identifying the causes of glial activation and dysfunction, and their contribution to loss of vision in retinal vascular disease, will lead to a better understanding of retinal vascular diseases, which might ultimately be translated into novel clinical therapies. PMID- 22519425 TI - Memory impairment exhibited by veterans with Gulf War Illness. AB - Roughly 26-32% of US veterans, who served in the first Gulf War, report suffering from chronic health problems ( Golomb, 2008 , Proceedings of the National Academies of Science, 105, 4295). The present study investigated the memory deficits reported by these ill Gulf War veterans (GWV) using a face-name associative memory paradigm administered during functional magnetic resonance imaging (fMRI). The fMRI data confirmed memory performance on the memory task to be related to the amount of activation in the left hippocampus observed during the study. In addition, ill-GWV demonstrated decreased memory performance relative to unaffected GWV on this memory test, providing evidence of memory deficits using an objective measure of memory. PMID- 22519426 TI - Immunohistochemical characterization of perineal melanoma in Kilis goats. AB - We describe the clinical, histopathological and immunohistochemical features of the malignant melanomas in the perineal regions of Kilis goats from Sanliurfa province in Turkey. We studied 13 female Kilis goats between 3 and 8 years old that were brought to Harran University Veterinary School, Department of Surgery, between 2002 and 2010. By macroscopic examination, the masses were determined to have elastic consistency, dark brown-black color, necrotic surfaces and ulceration. Microscopically, pleomorphic cells were observed under the basal layer and these advanced toward the dermis. These cells were polyhedral, round or spindle-shaped, anaplastic, and their cytoplasm contained varying amounts of dark brown-black pigments. Immunohistochemical staining was obtained with anti-melan A, vimentin and S100 antibodies. PMID- 22519427 TI - The indoleamine 2,3-dioxygenase (IDO) pathway controls allergy. AB - A series of recent studies have demonstrated that the immunoregulatory pathway of tryptophan catabolism, initiated by the enzyme indoleamine 2,3-dioxygenase (IDO), is a critical participant in allergic inflammation. Originally known for its regulatory function during pregnancy and during chronic inflammation in tumorigenesis and infection, the activity of IDO seems to positively modify the inflammatory state of atopy or allergy. The tryptophan degradation pathway is important for tolerance induction during systemic allergen immunotherapy. Here, we focus on recent findings that establish the IDO pathway as central to allergic inflammation. PMID- 22519428 TI - Romaphobia among Serbian and Dutch adolescents: the role of perceived threat, nationalistic feelings, and integrative orientations. AB - This study examines the relationships between nationalism and integration attitudes on one hand, and anti-Roma prejudice on the other. Using Stephan and Stephan's threat theory, the study analyzes whether and to what extent these relationships are mediated by perceived economic and symbolic threats. Data were collected among 16- and 17-year-old students in Serbia and The Netherlands. A path analysis shows that perceived economic and symbolic threats mediate the relationships between nationalism and integration on one hand, and Romaphobia on the other. Moreover, the findings show that these relationships are comparable between Serbian and Dutch youth. Levels of threat and Romaphobia differ between countries. Youth in the Netherlands, who barely have contact opportunities with Roma, are characterized by higher threat and Romaphobia scores than Serbian youth, who have proportionally more contact opportunities. Explanations are discussed as well as implications for theory and prejudice reduction in diverse intercultural settings. PMID- 22519430 TI - Neurolasermicroscopy. PMID- 22519429 TI - Human umbilical cord matrix stem cells efficiently rescue acute liver failure through paracrine effects rather than hepatic differentiation. AB - There is increasing evidence that mesenchymal stem cells (MSCs) derived from different tissues could act as an alternative source of mature hepatocytes for treatment of acute liver failure (ALF). Human umbilical cord matrix stem cells (hUCMSCs) represent a novel source of MSCs. We examined the therapeutic potential and the different mechanisms of hUCMSCs by their transplantation into nonobese diabetic severe combined-immunodeficient (NOD-SCID) mice with carbon tetrachloride (CCl(4))-induced ALF in comparison to adult human hepatocytes (AHHs). The characteristics of isolated hUCMSCs were determined from MSCs and hepatocyte marker expression, hepatic function, and differentiation. Native hUCMSCs constitutively expressed some hepatic markers, though weaker hepatocyte specific functions were observed when compared to AHHs. When native hUCMSCs or AHHs were transplanted into livers of NOD-SCID mice with ALF induced by CCl(4), both hUCMSCs and AHHs provided a significant survival benefit and prevented the release of liver injury biomarkers. hUCMSCs were found to engraft within the recipient liver and differentiated into functional hepatocytes, whereas the HepPar1-/albumin (ALB)-positive cells of the hUCMSC group were less than the AHH group in the recipient liver. Higher values of human ALB in the serum of mice transplanted AHHs were determined in comparison with levels in mice-transplanted hUCMSCs. The analysis of mouse serum cytokine levels showed that hUCMSC transplantation was even more effective than treatment with AHHs and successfully downregulated the systemic inflammatory cytokines such as interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, IL-6, IL-10, and IL-1 receptor antagonist (IL 1RA). Furthermore, paracrine effects produced by hUCMSCs were identified by indirect coculture with damaged mouse hepatocytes (MHs) induced by CCl(4). Coculture with hUCMSCs significantly increased the viability, ALB secretion of damaged MHs, and greatly enhanced the regeneration of MHs in vitro when compared with AHHs. These data suggest that direct transplantation of native hUCMSCs can rescue ALF and repopulate livers of mice through paracrine effects to stimulate endogenous liver regeneration rather than hepatic differentiation for compensated liver function, which is the primary effect of AHHs. Thus, hUCMSCs can be a potential alternative source of AHHs for cell therapy of ALF and eliminate the shortage of hepatocytes. PMID- 22519431 TI - Natural history of unruptured intracranial aneurysms. PMID- 22519432 TI - Long-term benefits in quality of life after unilateral thalamic deep brain stimulation for essential tremor. AB - OBJECT: The goal of this study was to evaluate short- and long-term benefits in quality of life (QOL) after unilateral deep brain stimulation (DBS) for essential tremor (ET). METHODS: Patients who received unilateral DBS of the ventral intermediate nucleus of the thalamus between 1997 and 2010 and who had at least 1 follow-up evaluation at least 1 year after surgery were included. Their QOL was assessed with the Parkinson Disease Questionnaire-39 (PDQ-39), and ET was measured with the Fahn-Tolosa-Marin tremor rating scale (TRS) prior to surgery and then postoperatively with the stimulation in the on mode. RESULTS: Ninety-one patients (78 at 1 year; 42 at 2-7 years [mean 4 years]; and 22 at >7-12 years [mean 9 years]) were included in the analysis. The TRS total, targeted tremor, and activities of daily living (ADL) scores were significantly improved compared with presurgical scores up to 12 years. The PDQ-39 ADL, emotional well-being, stigma, and total scores were significantly improved up to 7 years after surgery compared with presurgical scores. At the longest follow-up, only the PDQ-39 stigma score was significantly improved, and the PDQ-39 mobility score was significantly worsened. CONCLUSIONS: Unilateral thalamic stimulation significantly reduces ET and improves ADL scores for up to 12 years after surgery, as measured by the TRS. The PDQ-39 total score and the domains of ADL, emotional well-being, and stigma were significantly improved up to 7 years. Although scores were improved compared with presurgery, other than stigma, these benefits did not remain significant at the longest (up to 12 years) follow-up, probably related in part to changes due to aging and comorbidities. PMID- 22519433 TI - Optimized angiographic computed tomography with intravenous contrast injection: an alternative to conventional angiography in the follow-up of clipped aneurysms? AB - OBJECT: The purpose of this study was to evaluate the diagnostic accuracy of an optimized angiographic CT (ACT) program with intravenous contrast agent injection (ivACT) in the assessment of potential aneurysm remnants after neurosurgical clipping compared with conventional digital subtraction angiography (DSA). METHODS: The authors report on 14 patients with 19 surgically clipped cerebral aneurysms who were scheduled to undergo angiographic follow-up. For each patient, the authors performed ivACT with dual rotational acquisition and conventional angiography including a 3D rotational run. The ivACT and 3D DSA data were reconstructed with different imaging modes, including a newly implemented subtraction mode with motion correction. Thereafter, the data sets were merged by the dual-volume technique, and freely rotatable 3D images were obtained for further analysis. Observed aneurysm remnants were electronically measured and classified for each modality by 2 experienced neuroradiologists. RESULTS: Digital subtraction angiography and ivACT both provided high-quality images without motion artifacts. Artifact disturbances from the aneurysm clips led to a compromised, but still sufficient, image quality in 1 case. The ivACT assessed all aneurysm remnants as true-positive up to a minimal size of 2.6*2.4 mm in accordance with the DSA findings. There was a tendency for ivACT to overestimate the size of the aneurysm remnants. All cases without aneurysm remnants on DSA were scored correctly as true-negative by ivACT. CONCLUSIONS: By using an optimized image acquisition protocol as well as enhanced postprocessing algorithms, the noninvasive ivACT seems to achieve results comparable to those of conventional angiography in the follow-up of clipped cerebral aneurysms. The authors have shown that ivACT can provide reliable diagnostic information about potential aneurysm remnants after neurosurgical clipping with high sensitivity and specificity, sufficient for clinical decision making, at least for aneurysms in the anterior circulation located distal to the internal carotid artery. These preliminary results may be a promising step to replace conventional angiography by a noninvasive imaging technique in selected cases after aneurysm clipping. PMID- 22519435 TI - Prognostic impact of circulating miR-21 and miR-375 in plasma of patients with esophageal squamous cell carcinoma. AB - BACKGROUND: miR-21 and miR-375 are reported to be highly and poorly expressed in esophageal squamous cell carcinoma (ESCC) tissues, respectively. Recently, we demonstrated that circulating miR-21 and miR-375 were stably detectable in plasma and reflected tumor dynamics as a tumor marker for ESCC. We hypothesized that these plasma miRNA concentrations contributed to prognostic markers in patients with ESCC. METHODS: Between 2008 and 2010, 50 preoperative plasma samples were collected from consecutive patients with ESCC, who underwent curative esophagectomy in our hospital. We examined the association between plasma miRNA concentrations and prognosis retrospectively. RESULTS: i) The postoperative cause specific survival rate of patients with high plasma miR-21 concentration tended to be poorer than low group (3-yr survival rate: 53.4 and 81.5%, p = 0.1038), while that of high plasma miR-375 group was better than low group (3-yr survival rate: 100 and 65.2%). ii) Patients with high miR-21 and low miR-375 concentrations in plasma had significantly poorer prognosis than other patients (3-yr survival rate: 48.4 and 83.1%, p = 0.039). Multivariate analysis revealed that the presence of high miR-21 and low miR-375 concentrations in plasma was an independent prognostic factor (p = 0.029, hazard ratio 3.8 (1.14-12.5)). CONCLUSION: Circulating miR-21 and miR-375 could be reliable prognostic markers for ESCC. These plasma markers might facilitate clinical decision-making to select prospective candidates, which need meticulous follow-up for early detection of recurrences and additional treatments such as neo-adjuvant chemotherapy and postoperative chemotherapy in ESCC. PMID- 22519434 TI - Rupture rate for patients with untreated unruptured intracranial aneurysms in South Korea during 2006-2009. AB - OBJECT: The authors investigated the rupture rate among patients with untreated unruptured intracranial aneurysms (UIAs) in South Korea during 2006-2009. METHODS: A longitudinal study using national representative health-claim data, including all hospital records for every Korean citizen, was used. Patients with a UIA who were 18-80 years old in 2006 were identified using the I67.1 ICD-10 code. To select eligible patients, a historical period of 1 year prior to the first diagnosis of a UIA in 2006 was utilized. Patients with a previous UIA diagnosis, subarachnoid hemorrhage (SAH), or treatments, such as clipping or coiling, during the historical period were excluded from analysis. Patients with head trauma or a brain tumor during the historical period were also excluded. Eligible patients were followed up for at least 3 years from the index date. Rupture was defined as SAH events with at least 14 days of hospitalization, using the I60 ICD-10 code and excluding the I60.8 code, or death within 14 days of hospitalization. RESULTS: Seven thousand four hundred four patients with UIAs were identified, including 1441 treated patients (20%) and 5963 untreated patients (80%), with a median follow-up of 3.3 years. Rupture events occurred in 163 (0.9 cases/100 person-years) of the 5963 untreated patients. The rupture rate was highest in the 1st year after UIA diagnosis. An older age was a risk factor for rupture among patients with UIAs. CONCLUSIONS: The overview of the incidence of rupture indicates the need for a preventive strategy and future studies to prevent rupture in Asian patients with UIAs. PMID- 22519436 TI - Diallyl trisulfide induces apoptosis of human basal cell carcinoma cells via endoplasmic reticulum stress and the mitochondrial pathway. AB - Diallyl trisulfide (DATS), an active component of garlic oil, has attracted much attention because of its anticancer effect on several types of cancers. However, the mechanism of DATS-induced apoptosis of basal cell carcinoma (BCC) is not fully understood. In the present study, we revealed that DATS-mediated dose dependent induction of apoptosis in BCC cells was associated with intracellular reactive oxygen species accumulation and disrupted mitochondrial membrane potential. Western analysis demonstrated concordant expression of molecules involved in mitochondrial apoptosis, including DATS-associated increases in phospho-p53, proapoptotic Bax, and decreases in antiapoptotic Bcl-2 and Bcl-xl in BCC cells. Moreover, DATS induced the release of cytochrome c, apoptosis-inducing factor, and HtrA2/Omi into the cytoplasm, and activated factors downstream of caspase-dependent and caspase-independent apoptosis, including nuclear translocation of apoptotic-inducing factor and endonuclease G and the caspase cascade. These results were confirmed by pretreatment with the antioxidant N acetyl-L-cysteine and the caspase inhibitor (z-VAD-fmk), the latter of which did not completely enhance the viability of DATS-treated BBC cells. Exposure to DATS additionally induced endogenous endoplasmic reticulum stress markers and intracellular Ca2+ mobilization, upregulation of Bip/GRP78 and CHOP/GADD153, and activation of caspase-4. Our findings suggest that DATS exerts chemopreventive potential via ER stress and the mitochondrial pathway in BCC cells. PMID- 22519437 TI - Thiol-mediated anchoring of silver cations to DNA for construction of nanofibers on DNA scaffold. AB - The formation of metal-containing Ag-mercaptoethanol (-Ag-S(R)-)(n) complexes on DNA chain scaffold was studied by UV spectroscopy, zeta potential measurement, and fluorescence and transmission electron microscopies. Experimental results made clear the mechanism of DNA mineralization and compaction, according to which intercalation of silver cations into DNA scaffold and further formation of (-Ag S(R)-)(n) oligomeric complexes on DNA induce efficient DNA chain compaction by terminal Ag(+) cations. By transmission electron microscopy the formation of fiber-like DNA-templated nanostructures was observed. DNA-Ag-thiol complexes are promising for DNA-templated engineering of hybrid 1D nanostructures with adjustable chemical functionalities by choosing appropriate thiol ligand. PMID- 22519438 TI - Diversity and antibacterial activity of bacteria isolated from the coastal marine sponges Amphilectus fucorum and Eurypon major. AB - AIMS: To assess the diversity and antimicrobial activity of culturable bacteria associated with two temperate-water marine sponges, Amphilectus fucorum and Eurypon major. METHODS AND RESULTS: Sponge samples were collected in August 2008 and bacteria were cultured on several different media. The 16S rRNA gene of representative strains was sequenced to allow classification. It was found that Proteobacteria were the dominant group of bacteria cultured from both sponges, but overall, the bacterial composition was diverse and distinct between the sponges. The most notable features were the significantly higher proportion of firmicutes in E. major and the low frequency of actinobacteria in both sponges. Four bacterial isolates were identified as potentially novel species and will be characterised in future studies. Approximately 400 cultured bacteria were screened for antimicrobial activity against a collection of indicator strains, with only eight strains, all Pseudovibrio spp., displaying any such activity. These strains were active against Escherichia coli and Bacillus subtilis but not Staphylococcus aureus or a selection of fungal strains. CONCLUSIONS: Diverse and distinct populations of culturable bacteria are present in the coastal sponges A. fucorum and E. major. Only a minority of isolates produce antibacterial metabolites in culture, but this activity is common in Pseudovibrio spp. SIGNIFICANCE AND IMPACT OF THE STUDY: This study illustrates the diversity of sponge-associated bacteria and the need to increase our knowledge about the function of these symbiotic bacteria. The data suggest that production of antibacterial metabolites is restricted to a subset of species, with the majority involved in other functions. The importance of Pseudovibrio as a reservoir of antibacterial metabolites is also highlighted. PMID- 22519439 TI - Self-assembled poly(ethylene glycol)-co-acrylic acid microgels to inhibit bacterial colonization of synthetic surfaces. AB - We explored the use of self-assembled microgels to inhibit the bacterial colonization of synthetic surfaces both by modulating surface cell adhesiveness at length scales comparable to bacterial dimensions (~1 MUm) and by locally storing/releasing an antimicrobial. Poly(ethylene glycol) [PEG] and poly(ethylene glycol)-co-acrylic acid [PEG-AA] microgels were synthesized by suspension photopolymerization. Consistent with macroscopic gels, a pH dependence of both zeta potential and hydrodynamic diameter was observed in AA-containing microgels but not in pure PEG microgels. The microgels were electrostatically deposited onto poly(l-lysine) (PLL) primed silicon to form submonolayer surface coatings. The microgel surface density could be controlled via the deposition time and the microgel concentration in the parent suspension. In addition to their intrinsic antifouling properties, after deposition, the microgels could be loaded with a cationic antimicrobial peptide (L5) because of favorable electrostatic interactions. Loading was significantly higher in PEG-AA microgels than in pure PEG microgels. The modification of PLL-primed Si by unloaded PEG-AA microgels reduced the short-term (6 h) S. epidermidis surface colonization by a factor of 2, and the degree of inhibition increased when the average spacing between microgels was reduced. Postdeposition L5 peptide loading into microgels further reduced bacterial colonization to the extent that, after 10 h of S. epidermidis culture in tryptic soy broth, the colonization of L5-loaded PEG-AA microgel modified Si was comparable to the very small level of colonization observed on macroscopic PEG gel controls. The fact that these microgels can be deposited by a nonline-of-sight self-assembly process and hinder bacterial colonization opens the possibility of modifying the surfaces of topographically complex biomedical devices and reduces the rate of biomaterial-associated infection. PMID- 22519440 TI - Mercury stable isotopes in seabird eggs reflect a gradient from terrestrial geogenic to oceanic mercury reservoirs. AB - Elevated mercury concentrations ([Hg]) were found in Alaskan murre (Uria spp.) eggs from the coastal embayment of Norton Sound relative to insular colonies in the northern Bering Sea-Bering Strait region. Stable isotopes of Hg, carbon, and nitrogen were measured in the eggs to investigate the source of this enrichment. Lower delta(13)C values in Norton Sound eggs (-23.30/00 to -20.00/00) relative to eggs from more oceanic colonies (-20.90/00 to -18.70/00) indicated that a significant terrestrial carbon source was associated with the elevated [Hg] in Norton Sound, implicating the Yukon River and smaller Seward Peninsula watersheds as the likely Hg source. The increasing [Hg] gradient extending inshore was accompanied by strong decreasing gradients of delta(202)Hg and Delta(199)Hg in eggs, indicating lower degrees of mass-dependent (MDF) and mass-independent Hg fractionation (MIF) (respectively) in the Norton Sound food web. Negative or zero MDF and MIF signatures are typical of geological Hg sources, which suggests murres in Norton Sound integrated Hg from a more recent geological origin that has experienced a relatively limited extent of aquatic fractionation relative to more oceanic colonies. The association of low delta(202)Hg and Delta(199)Hg with elevated [Hg] and terrestrial delta(13)C values suggested that Hg stable isotopes in murre eggs effectively differentiated terrestrial/geogenic Hg sources from oceanic reservoirs. PMID- 22519441 TI - Editorial: matrix metalloproteinases in cardiovascular disease. PMID- 22519442 TI - Molecular mechanisms regulating matrix metalloproteinases. AB - The family of matrix metalloproteinases (MMPs) comprises 24 multidomain enzymes with a zinc-dependent activity. Their structural diversity over the archetypal domain organization confers variable biological function to these molecules ranging from cellular homeostasis and control of tissue turnover to implication in multiple pathological conditions such as inflammation, arthritis, cardiovascular disease and cancer. MMP expression and activity exhibits high tissue-species- and signal-specificity and involves multiple regulatory mechanisms that co-ordinate zymogen activation, endogenous inhibition and gene transcription. In this article, we provide an overview of the molecular mechanisms that regulate MMPs gene expression at transcriptional and post transcriptional level through integration of signals from multiple pathways to cis-acting elements present in MMP promoters, epigenetic modifications, mRNA stability mechanisms and microRNA modulation. Loss of MMP activity through mutations and single nucleotide polymorphisms is further discussed in the context of disease susceptibility. PMID- 22519443 TI - Myocardial structure and matrix metalloproteinases. AB - Metalloproteinases (MMPs) are enzymes which enhance proteolysis of extracellular matrix proteins. The pathophysiologic and prognostic role of MMPs has been demonstrated in numerous studies. The present review covers a wide a range of topics with regards to MMPs structural and functional properties, as well as their role in myocardial remodeling in several cardiovascular diseases. Moreover, the clinical and therapeutic implications from their assessment are highlighted. PMID- 22519444 TI - Inflammatory mechanisms in atherosclerosis: the impact of matrix metalloproteinases. AB - Inflammatory process is essential for the initiation and progression of vascular remodeling, entailing degradation and reorganization of the extra-cellular matrix (ECM) scaffold of the vessel wall, leading to the development of atherosclerotic lesions. Matrix metalloproteinases (MMPs) are zing dependent endo-peptidases found in most living organisms and act mainly by degrading ECM components. Most MMPs are formed as inactive proenzymes and are activated by proteolysis. This process depends and is regulated by other proteases and endogenous MMP inhibitors (TIMPs). MMPs and TIMPs play a major role not only in ECM degradation but also in mediating cell migration, proliferation, tissue remodeling; acting as a signal for the production and secretion of growth factors and cytokines. More importantly MMPs through proteolysis and degradation of ECM contribute in many physiological and pathological processes including organ development, wound healing, tissue support, vascular remodeling and restenosis, atherosclerosis progression, acute coronary syndromes, myocardial infarction, cardiomyopathy, aneurysms remodeling, cancer, arthritis, and chronic inflammatory diseases. A substantial body of evidence support the notion that imbalance between the activity of MMPs and their tissue inhibitors (TIMPs) contribute to the pathogenesis of cardiovascular diseases such as atherosclerosis, vascular remodeling and progression of heart failure. In this review, we will discuss the relationship between MMPs, inflammation and atherosclerosis under the topic of cardiovascular disease. PMID- 22519445 TI - The role of matrix metalloproteinases in essential hypertension. AB - The matrix metalloproteinases/tissue inhibitors of metalloproteinases system is involved in the regulation of extracellular matrix metabolism, which plays a crucial role with regards to maintenance of tissue integrity. During the occurrence of vascular pathologies including hypertension, the balance between proteases and their inhibitors is temporally destroyed. Even though there are conflicting data in the literature regarding the expression pattern of the vascular matrix metalloproteinase system, the occurring extracellular matrix turnover leads to the change of arterial mechanical properties. For example, hypertension plays crucial role in the formation of cardiovascular remodeling which seems to be characterized by an increase in extracellular matrix. Changes in arterial stiffness, a predictor for cardiovascular morbidity and mortality, are determined by alterations in vascular extracellular matrix due to hemodynamic, genetic, or other factors. It has become increasingly evident that blockade of the renin-angiotensin-aldosterone system and other pharmacological strategies, seem to be particularly effective in reducing vascular stiffness and collagen content in human and animal models. However, the relationship between extracellular matrix metabolism and the effects of therapy in hypertensive patients needs to be further explored in larger trials over a longer period of time. PMID- 22519446 TI - The role of matrix metalloproteinases in diabetes mellitus. AB - Diabetes mellitus (DM) is a leading risk factor for cardiovascular disease that adversely affects multiple vascular components from early in its course. Current evidence implicates matrix metalloproteinases (MMPs) and their endogenous inhibitors in diverse pathways associated with the development and progression of diabetic microvascular complications. In diabetic nephropathy, altered MMPs expression contributes to extracellular matrix deposition and glomerular hypertrophy that eventually lead to proteinuria and renal insufficiency. In diabetic cardiomyopathy, MMPs participate in the breakdown of collagen and elastin, myocardial remodelling as well as the vulnerability of the coronary plaque. The development of diabetic peripheral arterial disease is mediated by the impaired angiogenesis caused by the activity of MMPs. Experimental data support an integral role of MMPs in cerebral circulation and stroke volume in diabetes. An excess of MMPs may contribute in poor diabetic wound healing. Future research should further clarify the role of MMPs within the pathophysiological substrate of diabetes, as well as potential therapeutic options. PMID- 22519447 TI - Matrix metalloproteinases and vulnerable atheromatous plaque. AB - Atherosclerotic coronary artery disease, the underlying basis for ischemic heart disease, is the leading cause of death and disability in the USA and recent trends indicate that coronary artery disease is also becoming a major public health problem in developing countries [1]. Atherosclerosis is a continuous process that is initiated early in life, which gradually progresses with potentially devastating consequences: atherosclerotic plaque rupture is the most common underlying pathological mechanism creating acute ischemic coronary syndromes [2]. This term refers to the process of disruption of the endothelial surface and the exposure of the underlying prothrombotic vessel wall to circulating platelets and coagulation factors. In order to identify the high-risk plaque we need to recognize its specific morphological and functional characteristics. The morphological characteristics have been identified in several human histopathological and in vivo studies, and include: 1) a large lipid core (>=40% plaque volume) composed of free cholesterol crystals, cholesterol esters, and oxidized lipids impregnated with tissue factor, 2) a thin fibrous cap depleted of smooth muscle cells and collagen, 3) an outward (positive) remodeling, 4) inflammatory cell infiltration of fibrous cap and adventitia (mostly monocyte- macrophages, activated T cells and mast cells), and 5) increased neovascularization. The terms vulnerable, unstable or 'high-risk' are now widely used to describe plaques that exhibit such features, irrespective of whether rupture of the fibrous cap is present [3]. PMID- 22519448 TI - Matrix metallopropteinases in heart failure. AB - Heart failure (HF) represents a complex multifactorial syndrome, characterized by crucial structural and functional abnormalities of the myocardium. Matrix metalloproteinases are associated with left ventricular dysfunction, adverse left ventricular remodelling and prognosis after acute myocardial infarction. There is a strong association between oxidative stress and MMPs in the pathophysiology of HF. As MMPs are strongly associated to the pathogenesis and pathophysiology of HF, several agents have been proposed as potential modulators of these molecules. Classical agents such as statins, angiotensin converting enzyme inhibitors (ACEIS) and beta-blockers and a variety of novel agents have been implicated in the pathogenesis and progression of heart failure via the matrix metalloproteinases pathway and consist of possible future therapeutic targets. PMID- 22519449 TI - Matrix metalloproteinases in acute coronary syndromes: current perspectives. AB - Matrix metalloproteinases (MMPs) are a family of zinc metallo-endopeptidases secreted by cells and are responsible for much of the turnover of matrix components. Several studies have shown that MMPs are involved in all stages of the atherosclerotic process, from the initial lesion to plaque rupture. Recent evidence suggests that MMP activity may facilitate atherosclerosis, plaque destabilization, and platelet aggregation. In the heart, matrix metalloproteinases participate in vascular remodeling, plaque instability, and ventricular remodelling after cardiac injury. The aim of the present article is to review the structure, function, regulation of MMPs and to discuss their potential role in the pathogenesis of acute coronary syndromes, as well as their contribution and usefullness in the setting of the disease. PMID- 22519450 TI - Genetic variability of matrix metalloproteinase genes in cardiovascular disease. AB - It is well established that matrix metalloproteinases (MMPs) contribute to the degradation of the extracellular matrix of coronary plaque and contribute to the thinning of the fibrous cap. As a result, the atheromatous plaque becomes unstable and prone to rupture with consequent clinical manifestations including acute coronary syndromes. Moreover, genetic polymorphisms of MMPs have been found to be associated with the concentration of circulating MMPs, and over the past decade, considerable efforts have been devoted to explore the relationships between MMPs polymorphisms and myocardial infarction risk among various populations. However, existing studies have yielded inconsistent results. Some observations have suggested that genetic variation that affects the expression of MMPs may contribute to the occurrence of myocardial infarction, whereas others reported no support for an association of MMPs polymorphisms with myocardial infarction susceptibility. Furthermore, the interpretation of these studies has been complicated by the use of different populations or different control sources. Therefore, further studies are required to evaluate the role of matrix metalloproteinases and especially the associated genetic polymorphisms in cardiovascular disease. PMID- 22519451 TI - Novel therapeutic approaches targeting matrix metalloproteinases in cardiovascular disease. AB - Matrix metalloproteinases (MMPs), are proteinases that participate in extracellular matrix remodelling and degradation. Under normal physiological conditions, the activities of MMPs are regulated at the level of transcription, of activation of the pro-MMP precursor zymogens and of inhibition by endogenous inhibitors (tissue inhibitors of metalloproteinases; TIMPs). Alteration in the regulation of MMP activity is implicated in atherosclerotic plaque development, coronary artery disease and heart failure. The pathological effects of MMPs and TIMPs in cardiovascular diseases involve vascular remodelling, atherosclerotic plaque instability and left ventricular remodelling after myocardial infarction. Since excessive tissue remodelling and increased matrix metalloproteinase activity have been demonstrated during atherosclerotic lesion progression, MMPs represent a potential target for therapeutic intervention aimed at modification of vascular pathology by restoring the physiological balance between MMPs and TIMPs. This review discusses pharmacological approaches to MMP inhibition. PMID- 22519453 TI - Study of correlation between maternal fatigue and uterine contraction pattern in the active phase of labour. AB - AIMS AND OBJECTIVES: To evaluate the correlation between maternal fatigue and uterine contraction pattern at the beginning of the active phase of labour. BACKGROUND: Fatigue is one of the most common complaints in pregnant women that often continues until delivery. Maternal fatigue prolongs the labour process and increases the rate of cesarian section. Studies on the pattern of uterine contractions have shown that the length of the fall time is longer in prolonged labours than in normal deliveries. DESIGN: A cross-sectional study. METHODS: This study was conducted on 100 primiparous women who were referred to Ommolbanin Hospital (Mashhad, Iran) in 2011. Maternal fatigue was assessed at the beginning of the active phase of labour. Then, the pattern of uterine contractions was monitored for 30 minutes by an external tocodynamometer. The F/R ratio was determined by measuring the time for a contraction to return to its baseline from its peak and the time for a contraction to rise to its peak. The data were analysed by chi-square and anova tests. RESULTS: The results showed that there was a significant relationship between maternal fatigue and uterine contraction pattern. The F/R ratio was increased with increase in fatigue severity. CONCLUSIONS: Fatigue causes changes in the pattern of uterine contractions. The return time of a contraction from its peak to its baseline (fall) is increased with increase in fatigue severity. RELEVANCE TO CLINICAL PRACTICE: Offering strategies to prevent tiredness and reduce the related fatigue complications. PMID- 22519452 TI - Modulation of PAR(1) signalling by benzimidazole compounds. AB - BACKGROUND AND PURPOSE: Recently, a small molecule (Q94) was reported to selectively block PAR(1) /Galpha(q) interaction and signalling. Here, we describe the pharmacological properties of Q94 and two analogues that share its benzimidazole scaffold (Q109, Q89). Q109 presents a modest variation from Q94 in the substituent group at the 2-position, while Q89 has quite different groups at the 1- and 2-positions. EXPERIMENTAL APPROACH: Using human microvascular endothelial cells, we examined intracellular Ca(2+) mobilization and inositol 1,4,5-trisphosphate accumulation as well as isoprenaline- or forskolin-stimulated cAMP production in response to thrombin. KEY RESULTS: Q89 (10 uM) produced a leftward shift in the thrombin-mediated intracellular Ca(2+) mobilization concentration-response curve while having no effect on the E(max) . Both Q94 (10 uM) and Q109 (10 uM) reduced intracellular Ca(2+) mobilization, leading to a decrease in E(max) and an increase in EC(50) values. Experiments utilizing receptor-specific activating peptides confirmed that Q94 and Q109 were selective for PAR(1) as they did not alter the Ca(2+) response mediated by a PAR(2) activating peptide. Consistent with our Ca(2+) results, micromolar concentrations of either Q94 or Q109 significantly reduced thrombin-induced inositol 1,4,5-trisphosphate production. Neither Q94 nor Q109 diminished the inhibitory effects of thrombin on cAMP production, indicating they inhibit signalling selectively through the G(q) pathway. Our results also suggest the 1,2-disubstituted benzimidazole derivatives act as 'allosteric agonists' of PAR(1) . CONCLUSIONS AND IMPLICATIONS: The Q94 and Q109 benzimidazole derivatives represent a novel scaffold for the development of new PAR(1) inhibitors and provide a starting point to develop dual signalling pathway-selective positive/negative modulators of PAR(1) . PMID- 22519455 TI - Gastroesophageal and laryngopharyngeal reflux profiles in patients with obstructive sleep apnea/hypopnea syndrome as determined by combined multichannel intraluminal impedance-pH monitoring. AB - BACKGROUND: The profiles of gastroesophageal reflux (GER) and laryngopharyngeal reflux (LPR) in patients with obstructive sleep apnea/hypopnea syndrome (OSAHS) have never been explored. The aim of the study was to investigate the reflux profile in OSAHS patients. METHODS: Consecutive snoring out-patients suspected with having OSAHS and 20 healthy volunteers were included. All subjects underwent simultaneous 24-h combined multichannel intraluminal impedance-pH (MII-pH) monitoring and polysomnography. Obstructive sleep apnea/hypopnea syndrome was defined when the apnea/hypopnea index was over 5. Stepwise multiple logistic regression analysis was performed to determine the predictor for OSAHS. KEY RESULTS: Fifty-three patients were included, 37 with and 16 without OSAHS. The prevalence of reflux symptoms was similar between OSAHS (35.1%) and non-OSHAS (37.5%) patients. More OSAHS patients, compared with non-OSAHS patients and healthy volunteers, had pathologic acid GER, nocturnal acid GER, and prolonged acid clearance (P < 0.001). However, no difference in non-acid reflux episodes was observed among the three groups. Laryngopharyngeal reflux was detected in 51.4%, 43.8%, and 35.0% of OSAHS, non-OSAHS, and healthy volunteers, respectively (P = 0.034). In OSAHS patients, there was no difference in the sleep parameters between patients with and without LPR. Body mass index was the only predictor of OSAHS in the regression analysis. CONCLUSIONS & INFERENCES: OSAHS patients have more pathologic acid GER and prolonged acid clearance than non-OSAHS patients whereas non-acid reflux was similar between the two groups. However, BMI, not GER, is the only independent predictor for OSAHS. Laryngopharyngeal reflux occurs in more than half of OSAHS patients despite no significant association with OSAHS. PMID- 22519456 TI - Hematopoietic stem cell transplantation for curing children with severe autoimmune diseases: is this a valid option? AB - The cure of children with severe AD, especially patients with severe, progressive, and therapy-resistant autoimmunity, represents a challenge for current medical practice. The idea of HSCT as a promising therapeutic opportunity was borne accidentally from finding patients who, after undergoing HSCT for a hematological indication, were cured of a concomitant AD. Thus, over the last two decades, HSCT has been extensively investigated, and it has become an appealing therapy for rheumatological (juvenile rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis) and hematological diseases (immune cytopenias). Recently, interesting results have been also described in type 1 diabetes mellitus and Crohn's disease. Although the use of HSCT has been steadily rising in the last few years, many questions are still open, especially after the discoveries of many new biological agents. Given the low incidence of ADs in children, most of the data about the use of the HSCT for these diseases are taken from a mixed cohort of adults and children. The aim of this review is to summarize the published studies and to try to answer the question as to whether this procedure can be considered a promising approach. PMID- 22519457 TI - Nafamostat mesilate, a noncalcium compound, as an anticoagulant, induces calcium dependent haemolysis when infused with packed erythrocytes. AB - BACKGROUND: Nafamostat mesilate (NM), a protease inhibitor, is available for acute pancreatitis and disseminated intravascular coagulopathy and is used as an anticoagulant for haemodialysis in Japan. Co-infusion of red cell concentrates (RCC) and intravenous drugs is usually contraindicated. Because of limited venous access, adherence to the guidelines may be compromised in some clinical settings. Therefore, we investigated the influence of co-infusion of RCC and various anticoagulants on haemolysis in vitro. METHODS: We investigated the effect of co incubation of RCC and various anticoagulant drugs [NM, gabexate mesilate (GM), heparin] in packed erythrocytes. We evaluated haemolysis using lactate dehydrogenase and free haemoglobin. In addition, we also evaluated the influence of co-incubation on phosphatidylserine (PS) expression on the erythrocyte membrane. RESULTS: GM and NM induced haemolysis in a dose-dependent manner, which was inhibited by removal of citrate and pretreatment with the calcium chelator, ethylenediaminetetraacetic acid. In a dynamic experiment using an infusion pump, NM not only induced haemolysis during co-infusion with RCC but also elevated PS expression dependent on extracellular calcium. CONCLUSION: NM and GM induce haemolysis in packed erythrocytes in the presence of citrate that is dependent on extracellular calcium. PMID- 22519458 TI - Clinical characteristics and mutational analysis of the RyR2 gene in seven Czech families with catecholaminergic polymorphic ventricular tachycardia. AB - BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare hereditary arrhythmia. The onset of clinical symptoms usually occurs during childhood, and is typically related to exercise. The aim of our study was to describe the clinical characteristics of seven Czech families with CPVT and the results of mutational analysis of the RyR2 gene in these families. METHODS: The subjects and their relatives were investigated at the participating departments. They underwent basic clinical investigation, and history was focused on possible CPVT symptoms, that is, syncopes during exercise. Bicycle ergometry was performed to obtain electrocardiogram recording during adrenergic stimulation. In all the investigated individuals, blood samples were taken for mutation analysis of the RyR2 gene. RESULTS: To date, seven families have been investigated, comprising 11 adults and 13 children. In seven CPVT patients, the indication for examination was syncope during exercise. Diagnosis was confirmed by bicycle ergometry-induced polymorphic ventricular tachycardia. In one relative, polymorphic ventricular tachycardia was also induced. All eight affected individuals were treated with beta-blockers and in two, a cardioverter-defibrillator was implanted due to recurrent syncopi. Coding variants of the RyR2 gene were found in four probands. CONCLUSIONS: This is a systematic description of CPVT families in the Czech Republic. Our data support the importance of exercise testing for the diagnosis of CPVT. In addition, RyR2 gene coding variants were found in 50% of affected individuals. PMID- 22519459 TI - Expedient synthesis of electronically modified luciferins for bioluminescence imaging. AB - Bioluminescence imaging with luciferase enzymes requires access to light emitting, small-molecule luciferins. Here, we describe a rapid method to synthesize d-luciferin, the substrate for firefly luciferase (Fluc), along with a novel set of electronically modified analogues. Our procedure utilizes a relatively rare, but synthetically useful dithiazolium reagent to generate heteroaromatic scaffolds in a divergent fashion. Two of the luciferin analogues produced with this approach emit light with Fluc in vitro and in live cells. Collectively, our work increases the number of substrates that can be used for bioluminescence imaging and provides a general strategy for synthesizing new collections of luciferins. PMID- 22519460 TI - Short comments on the statistical method used in the paper: difference in angiotensinogen haplotype frequencies... PMID- 22519464 TI - Left thoracotomy approach for implantation of the Abiomed left ventricular assist device. AB - We describe a left thoracotomy approach for implantation of the Abiomed AB5000 left ventricular assist device (LVAD). The technique is easily performed and spares the patient a sternotomy in anticipation of future transplantation or LVAD exchange. PMID- 22519463 TI - A case of hyperthymesia: rethinking the role of the amygdala in autobiographical memory. AB - Much controversy has been focused on the extent to which the amygdala belongs to the autobiographical memory (AM) core network. Early evidence suggested the amygdala played a vital role in emotional processing, likely helping to encode emotionally charged stimuli. However, recent work has highlighted the amygdala's role in social and self-referential processing, leading to speculation that the amygdala likely supports the encoding and retrieval of AM. Here, cognitive as well as structural and functional magnetic resonance imaging data was collected from an extremely rare individual with near-perfect AM, or hyperthymesia. Right amygdala hypertrophy (approximately 20%) and enhanced amygdala-to-hippocampus connectivity (>10 SDs) was observed in this volunteer relative to controls. Based on these findings and previous literature, we speculate that the amygdala likely charges AMs with emotional, social, and self-relevance. In heightened memory, this system may be hyperactive, allowing for many types of autobiographical information, including emotionally benign, to be more efficiently processed as self-relevant for encoding and storage. PMID- 22519465 TI - Effects of poly-ether B on proteome and phosphoproteome expression in biofouling Balanus amphitrite cyprids. AB - Biofouling is ubiquitous in marine environments, and the barnacle Balanus amphitrite is one of the most recalcitrant and aggressive biofoulers in tropical waters. Several natural antifoulants that were claimed to be non-toxic have been isolated in recent years, although the mechanism by which they inhibit fouling is yet to be investigated. Poly-ether B has shown promise in the non-toxic inhibition of larval barnacle attachment. Hence, in this study, multiplex two dimensional electrophoresis (2-DE) was applied in conjunction with mass spectrometry to investigate the effects of poly-ether B on barnacle larvae at the molecular level. The cyprid proteome response to poly-ether B treatment was analyzed at the total proteome and phosphoproteome levels, with 65 protein and 19 phosphoprotein spots found to be up- or down-regulated. The proteins were found to be related to energy-metabolism, oxidative stress, and molecular chaperones, thus indicating that poly-ether B may interfere with the redox-regulatory mechanisms governing the settlement of barnacle larvae. The results of this study demonstrate the usefulness of the proteomic technique in revealing the working mechanisms of antifouling compounds. PMID- 22519467 TI - Six-channel ECG-based pulse wave velocity for assessing whole-body arterial stiffness. AB - BACKGROUND: Despite the proposal of different means of non-invasive arterial stiffness assessment, none offers simultaneous information on whole-body peripheral arterial condition. We investigated the validity of applying a six channel electrocardiogram-based pulse wave velocity (ECG-PWV) measurement system for this purpose. METHODS: The study consisted of two parts. Part One enrolled hypertensive (Group 1, n = 32) and normal (Group 2, n = 32) subjects, whereas Part Two recruited diabetic (Group 3, n = 50) and normal (Group 4, n = 50) subjects. To validate the application of ECG-PWV in assessing peripheral arterial stiffness in different parts of body, ECG-PWV data were compared with three other parameters including the cardio-ankle vascular index (CAVI), pulse wave velocity digital volume pulse (PWV-DVP) and intima-media thickness (IMT). RESULTS: ECG-PWV in healthy subjects in Part One correlated significantly with CAVI and PWV-DVP (p < 0.05), whereas ECG-PWV and CAVI were significantly different between the hypertensive and normal subjects. Moreover, comparison of IMT and ECG-PWV from different sites showed significant correlation only between IMT and ECG-PWV from earlobe (r = 0.495, p = 0.004). No significant association, however, was noted between IMT and CAVI. For Part Two, significant differences existed between diabetic and normal subjects in body weight, waist circumference, level of HbA1c, fasting blood sugar, serum creatinine and ECG-PWV from the foot. However, no significant difference was noted in PWV-DVP between two groups. CONCLUSIONS: Six channel ECG-PWV measurement system showed remarkable correlation with IMT in hypertensive subjects and with key anthropometric and biochemical parameters in diabetic patients, suggesting its validity in assessing whole-body arterial stiffness in subjects with peripheral arterial diseases within 10 min. PMID- 22519466 TI - Efficacy and safety of infliximab and adalimumab in Crohn's disease: a single centre study. AB - BACKGROUND: Infliximab and adalimumab are highly effective in Crohn's Disease (CD). This is supported by clinical trials and open-label studies using either infliximab or adalimumab, thus not allowing a proper comparison between these anti-TNFs in CD. AIM: To evaluate the efficacy and safety of infliximab and adalimumab in active CD. METHODS: In a longitudinal study, CD patients with indication for anti-TNFs were treated with infliximab or adalimumab. RESULTS: Ninety-three patients were treated with infliximab (n = 44) or adalimumab (n = 49). In the infliximab group, the induction was completed by 77.3% of patients, due to no response (n = 2), delayed hypersensitivity reactions (DHR) or infusion reactions (n = 8). Maintenance with infliximab was completed by 60% of patients, due to clinical worsening or loss of efficacy (n = 5), DHR or infusion reactions (n = 5). In the adalimumab group, all patients completed the induction, while maintenance was completed by 67% of patients, due to clinical worsening or loss of efficacy (n = 8), DHR (n = 1), other causes (n = 7). In both groups, the CDAI significantly reduced at baseline vs. each visit (P < 0.04). The Kaplan-Meier survival analysis performed to evaluate the risk of steroid-free remission in patients treated with infliximab vs. adalimumab detected no differences (log-rank test P = 0.4). Cox proportional-hazards regression identified two predictors of steroid-free remission using anti-TNFs: no smokers [HR = 2.94 (1.52-5.70), P = 0.001] and non stricturing non penetrating behaviour [HR = 3.116 (1.06-9.13), P = 0.03826]. CONCLUSIONS: Infliximab and adalimumab showed a similar efficacy. No smoking and non-stricturing non-penetrating behaviour were predictors of steroid free remission. PMID- 22519468 TI - IsoQuant: a software tool for stable isotope labeling by amino acids in cell culture-based mass spectrometry quantitation. AB - Accurate protein identification and quantitation are critical when interpreting the biological relevance of large-scale shotgun proteomics data sets. Although significant technical advances in peptide and protein identification have been made, accurate quantitation of high-throughput data sets remains a key challenge in mass spectrometry data analysis and is a labor intensive process for many proteomics laboratories. Here, we report a new SILAC-based proteomics quantitation software tool, named IsoQuant, which is used to process high mass accuracy mass spectrometry data. IsoQuant offers a convenient quantitation framework to calculate peptide/protein relative abundance ratios. At the same time, it also includes a visualization platform that permits users to validate the quality of SILAC peptide and protein ratios. The program is written in the C# programming language under the Microsoft .NET framework version 4.0 and has been tested to be compatible with both 32-bit and 64-bit Windows 7. It is freely available to noncommercial users at http://www.proteomeumb.org/MZw.html . PMID- 22519469 TI - Metabonomic variations associated with AOM-induced precancerous colorectal lesions and resveratrol treatment. AB - Resveratrol (Res), 3,5,4'-trihydroxy-trans-stilbene, is an antioxidant found in the skin of red grapes and in several other plants. This phenolic compound has been recently reported to possess cancer chemopreventive activity that inhibits the process of carcinogenesis. However, the mechanisms underlying its anticancer effects remain largely unresolved. In this study, we investigated the chemoprotective effects of dietary Res in an azoxymethane (AOM) induced precancerous colorectal lesion model in male Wistar rats. The metabolic alterations in urine, sera, and colonic tissues of experimental rats perturbed by AOM intervention as well as the Res treatment were measured by a gas chromatography time-of-flight mass spectrometry (GC-TOFMS) analysis. Significant alterations of metabolites were observed in AOM group in urine, sera, and colonic tissues, which were attenuated by Res treatment and concurrent with the histopathological improvement with significantly decreased aberrant crypt foci (ACF) incidence. Representative metabolites include depleted glucose, beta hydroxybutyrate (ketone body), hypoxanthine, and elevated branched chain amino acids (isoleucine and valine) and tryptophan in colonic tissue, as well as elevated serum aminooxyacetate and urinary 4-hydroxyphenylacetate and xanthurenate. These metabolic changes suggest that the preventive effect of Res is associated with attenuation of impaired glucose and lipid metabolism and elevated protein breakdown in colonic tissues from AOM-exposed rats. It also appears that Res induced significant metabolic alterations independent of the AOM induced metabolic changes. The significantly altered metabolites identified in Res-AOM group relative to AOM group include arachidonate, linoleate, glutamate, docosahexaenoate, palmitelaidate, 2-aminobutyrate, pyroglutamate, and threonate, all of which are involved in inflammation and oxidation processes. This suggests that Res exerts the chemopreventive effects on ACF formation by anti-inflammatory and antioxidant mechanisms in addition to amelioration of AOM-induced mitochondrial disruption. PMID- 22519470 TI - Self-focused cognitive emotion regulation style as associated with widespread diminished EEG fractal dimension. AB - The cognitive regulation of emotions is important for human adaptation. Self focused emotion regulation (ER) strategies have been linked to the development and persistence of anxiety and depression. A vast array of research has provided valuable knowledge about the neural correlates of the use of specific self focused ER strategies; however, the resting neural correlates of cognitive ER styles, which reflect an individual's disposition to engage in different forms of ER in order to manage distress, are largely unknown. In this study, associations between theoretically negative ER style (self-focused or not) and the complexity (fractal dimension, FD) of the resting EEG at frontal, central, parietal, and occipital regions were investigated in 58 healthy volunteers. The Cognitive Emotion Regulation Questionnaire was used as the self-report measure of ER style. Results showed that a diminished FD over the scalp significantly correlated with self-focused ER style scores, even after controlling for negative affect, which has been also considered to influence the use of ER strategies. The lower the EEG FD, the higher were the self-focused ER style scores. Correlational analyses of specific self-focused ER strategies showed that self-blaming and rumination were negatively associated with diminished FD of the EEG, but catastrophizing and blaming others were not. No significant correlations were found for ER strategies more focused on situation or others. Results are discussed within the self organized criticality theory of brain dynamics: The diminished FD of the EEG may reflect a disposition to engage in self-focused ER strategies as people prone to ruminate and self-blame show a less complex resting EEG activity, which may make it more difficult for them to exit their negative emotional state. PMID- 22519471 TI - Glial cell line-derived neurotrophic factor promotes invasive behaviour in testicular seminoma cells. AB - The glial cell line-derived neurotrophic factor (GDNF) has multiple functions that promote cell survival, proliferation and migration in different cell types. The experimental over-expression of GDNF in mouse testis leads to infertility and promotes seminomatous germ cell tumours in older animals, which suggests that deregulation of the GDNF pathway may be implicated in germ cell carcinogenesis. GDNF activates downstream pathways upon binding to its specific co-receptor GDNF family receptor-a 1 (GFRA1). This complex then interacts with Ret and other co receptors to activate several intracellular signalling cascades. To explore the involvement of the GDNF pathway in the onset and progression of testicular germ cell tumours, we analysed GFRA1 and Ret expression patterns in seminoma samples. We demonstrated, via immunohistochemistry, that GFRA1, but not Ret, is over expressed in in situ carcinoma (CIS) and in intratubular and invasive seminoma cells compared with normal human germ cells. Functional analysis of the GDNF biological activity was performed on TCam-2 seminoma cell line. Reverse transcription-PCR (RT-PCR) and immunohistochemical analyses demonstrate that TCam 2 cells express both GFRA1 and Ret mRNA, but only GFRA1 was detected at the protein level. In TCam-2 cells, although GDNF is not mitogenic, it is able to induce migration, as demonstrated by a Boyden chamber assay, possibly through the Src and MEK pathways. Moreover, GDNF promotes invasive behaviour, an effect dependent on pericellular protease activity, possibly through the activity of matrix metalloproteinases. GFRA1 over-expression in CIS and seminoma cells, along with the functional analyses in TCam-2 cells, suggests an involvement of the GDNF pathway in the progression of testicular germ cell cancer. PMID- 22519472 TI - Safety of hormone replacement therapy in gynaecological cancer survivors. AB - Therapy for endometrial, ovarian and cervical cancer in young women can cause sudden onset of intense menopausal symptoms, such as hot flushes, emotional disorders and sexual dysfunction. In order to overcome these unpleasant and sometimes severe symptoms, hormone replacement therapy (HRT) has proven to be very effective. However, its safety remains controversial. We reviewed English literature and examined whether administration of HRT in this specific population is related with more recurrences and worse prognosis. Current scientific data, comprising mainly retrospective studies, suggest that recurrence rates and survival are comparable between HRT users and non-users. However, large randomised trials are missing and definitive conclusions cannot be drawn. Gynaecological cancer survivors using HRT, although they seem to have little if any risk for recurrence, should be correctly informed about the lack of strong evidence. PMID- 22519473 TI - Readiness of obstetric professionals to inform parents regarding potential outcome of premature infants. AB - Parents often regard obstetric professionals as an important source of information regarding prematurity. However, there is no information regarding the readiness of these obstetric professionals to inform expectant parents of the potential outcomes of premature infants. Using a self-report questionnaire, we determined the knowledge of obstetric professionals regarding outcomes of premature infants, and gauged their confidence in providing this information to expectant parents. Some 50% of obstetric professionals reported that they 'struggle to answer parental questions' regarding premature infants. The majority of obstetric professionals correctly identified potential morbidities of prematurity, but compared to neonatal professionals, they were less likely to discuss this information with parents. When they do provide information to parents, obstetric professionals were least likely to discuss neurological morbidities. Our study has identified an important barrier to the effective transfer of neonatal outcomes information to expectant parents. This limitation requires further investigation and intervention. PMID- 22519474 TI - Does high maternal first trimester iron status have an effect on the 50 g oral glucose test? AB - We aimed to test the hypothesis that 1st trimester high body iron status is associated with a high positive 50 g oral glucose tolerance test. In this study, 29 pregnant women with positive 50 g oral glucose tolerance test were compared with 94 negative 50 g OGTT patients as the control group in terms of 1st trimester iron status. Both groups had similar age, weight, height, body mass index and also median gravidity and parity values. Our results showed that there were no differences between groups in mean haemoglobin, haematocrit, serum iron, serum ferritin, total iron binding capacity and transferrin. Since it seems that free radicals have much influence on oxidative stress and glucose metabolism, prospective, randomised clinical trials should be designed to demonstrate the possible relation between maternal iron status and glucose intolerance. PMID- 22519475 TI - Time of birth and delivery outcomes: a retrospective cohort study. AB - Studies performed previously have attributed increased risk of intrapartum anoxia to delivery outside the normal working week. We sought to determine if the time of delivery effects outcome with respect to delivery characteristics and neonatal condition at birth. We identified a cohort of 14,426 deliveries over a 3-year period. These were analysed as three groups: night (00:00-07:59); day (08:00 15:59) and twilight (16:00-23:59). We found significantly more deliveries at night 36.3% (n = 5,240; p =0.01). At night, there were non-significantly more 'normal' deliveries compared with during the day and twilight hours (78.4%, 76.2%, 77.3%, respectively; p = 0.27). The caesarean section rate did not differ significantly between the groups (14.2%, 15.6%, 14.8%; p = 0.147). There were significantly fewer assisted deliveries in the night-time period (6.6%, 8.0%, 7.3%; p = 0.03). Women who delivered at night were more likely to have a normal delivery and less likely to have obstetric intervention in the form of assisted or operative delivery. There were no significant differences in the need for resuscitation to be performed at birth across the three groups (14.3%, 13.3%, 14.8%; p = 0.111). There was no significant difference in the numbers of babies directly admitted to the neonatal intensive care unit (NICU) (5.9%, 6.8%, 6.3%; p = 0.198) in the three respective time periods. PMID- 22519476 TI - The B-Lynch technique for the management of intraoperative uterine atony. AB - This paper reports the experience of 150 B-Lynch suture applications for the management of uterine atony during caesarean section that did not respond to conventional therapeutical measures. Technique was considered effective if the need for hysterectomy was avoided. High-risk antenatal obstetrical conditions included: pre-eclampsia (12%), oligohydramnios (8%), polyhydramnios (4.7%). A total of 36% were primigravid, 66% had been in active labour, 4.7% received misoprostol and 26.7% used oxytocin for labour augmentation. Suture was successful in 95.3%, with only five cases requiring hysterectomy combined with uterine artery ligation and two uterine artery ligations alone to control bleeding and uterine atony ('floppiness'). Although 26.7% of cases required transfusions, no maternal deaths were reported, and overall women were discharged after a median 4-day hospital stay without further complications upon follow-up. The B-Lynch technique was an effective intraoperative measure to control uterine atony. Despite the encouraging results, long term assessment on a larger sample is needed in our clinical scenario. PMID- 22519478 TI - Shoulder pain after caesarean section: comparison between general and spinal anaesthesia. AB - This study investigated shoulder pain as a maternal complication after caesarean section (CS), evaluation of its prevalence and comparison between spinal anaesthesia (SA) and general anaesthesia (GA) groups. A total of 200 women as CS candidates were allocated into two equal groups; SA and GA. The total prevalence of shoulder pain was 39.45%. The two groups were matched according to demographic data. However, the incidence of shoulder pain in the GA group was more than that in the SA group (p =0.004). Shoulder pain in the right shoulder in the GA group was more prevalent than the left shoulder (p <0.001). Moderate severity of shoulder pain was significantly more in the GA group (p =0.000), while in the SA group, the mild severity was significant (p <0.001). Our study revealed that the incidence of shoulder pain after CS is significant. Moreover, shoulder pain was significantly more common in the GA group than the SA group. PMID- 22519477 TI - Identification of maternal characteristics associated with the use of epidural analgesia. AB - The present survey aims to identify predictors associated with the use of epidural analgesia (EA). Therefore, from October 2007 to June 2008, a survey was conducted in 193 pregnant women (mean age 31.7 years (SD 4.9); 64.8% primipara) attending a German general hospital with a specialisation in integrative medicine. Questionnaires, including Antonovsky's sense of coherence (SOC) were delivered antepartum. Delivery data were recorded within the hospital quality management programme. The adjusted odds ratio (OR) for EA use was significantly greater than one for women who had previously used EA (adjusted OR =4.1; CI: 1.03 16.31) and for the desire for a delivery without pain (adjusted OR =3.05; CI: 1.36-6.83). The likelihood of EA use decreased in multipara (adjusted OR =0.05; CI: 0.01-0.22). SOC was not found to be an independent predictor for EA use. However, women with high SOC more often preferred a delivery without EA (p for trend =0.037). In conclusion, first time labour, the desire for a delivery without pain and previous use of EA are independent predictors for the use of EA in labour. Further studies should clarify the predictive role of SOC in pregnancy. PMID- 22519479 TI - Persistence of perinatal mortality due to congenital malformations in resource poor settings. AB - Every year, half a million babies are born with malformations, one-third of these life-threatening. The present study aims at analysing trends of perinatal mortality (PM) due to major congenital malformations (MCM) at a rural institute, for preventive possibilities. Records of all perinatal deaths due to MCM over 24 years were analysed. Perinatal deaths (PD) due to MCM were 346; overall 8.3% of PD (287 (82.94%) stillbirths; 59 (17.06%) neonatal deaths). There was a decreasing trend of contribution of MCM to PM: 9.52% in Block A to 6.95% in Block H; 26.87% of PD were due to nervous system anomalies: 3.76% in Block A to 2.02% in Block H. PM due to congenital heart disease increased from 0.87% in Block A to 6.94% in Block H. It is essential that a system exists to diagnose MCM at a gestation when abortion is possible. Research for prevention of anomalies needs to be continued. PMID- 22519480 TI - Resumption of vaginal intercourse in the early postpartum period: determinants and considerations for child spacing in a Nigerian population. AB - A total of 860 mothers were interviewed during their first postnatal clinic visit to determine the factors that influenced their resumption of sexual intercourse as well as their family planning practices in the early postpartum period. Some 255 (29.7%) women had resumed sexual intercourse with a mean delivery - resumption interval of 5.4 +/- 2.6 weeks. Resumption of menses and HIV-negative status were the factors most significantly associated with resumption of sexual intercourse. Other significant determinants were urban residence and vaginal delivery without tears. Only 21.5% of the sexually active mothers used a modern contraceptive in the form of a male condom, while 56.9% did not consider contraception at all. The major reason for prolonged abstinence was fear of another pregnancy. In this group of women, child spacing appears to be the major consideration for resumption of coitus, even over the fear of painful discomfort. PMID- 22519481 TI - A service evaluation of women attending the menopause/premature ovarian failure clinic of a tertiary referral centre. AB - This service evaluation aimed to characterise the referrals to the premature ovarian failure clinic, including the type of referral and patient needs, in order to plan for future service provision. The majority of women seen in the clinic experienced idiopathic premature ovarian failure, were aged 30-39 and were nulliparous at the time of diagnosis. Our service requires to be tailored to their needs. For many women, this includes a fertility consultation in the clinic and this part of the service is well used. Our data support the long-term follow up of women both on treatment and those who initially decline treatment. Most women who initially decline treatment accept it after a few clinic visits. This may be due to consistent advice on the benefits of oestrogen treatment or due to yearly bone scans showing a change in bone density. There was a high non attendance rate in this group: 21% of appointments were not attended. PMID- 22519482 TI - Relationship between the expression of fibulin-3 and anterior vaginal wall prolapse. AB - Anterior vaginal wall prolapse is the most common type of pelvic organ prolapse. Vaginal wall samples were obtained from women with (n =12) and without (n =12) anterior vaginal wall prolapse. No reports have been published on the content of fibulin-3 in the vaginal walls of patients with prolapse; thus, we compared the expression of fibulin-3 in the vaginal walls of women with and without anterior vaginal wall prolapse. RT-PCR was performed to measure mRNA expression and the expression of protein was assessed by immunohistochemistry. Statistical analysis was performed to determine differences between the two groups of women. Age, parity and menopausal status did not differ between women with and without prolapse. The expressions of fibulin-3 mRNA and protein were not different between the prolapse and no prolapse groups. It is unlikely that abnormal expression of fibulin-3 has a major role in the pathogenesis of anterior vaginal wall prolapse. PMID- 22519483 TI - Evidence of biochemical hyperandrogenism in women: the limitations of serum testosterone quantitation. AB - Hyperandrogenism in women is a common clinical scenario and is characterised by menstrual disturbance, hirsutism and infertility. Accurate measurement of serum testosterone is often used in these patients to diagnose polycystic ovary syndrome (PCOS) and to prompt further investigation in patients with suspected androgen-secreting tumours. Immunoassay methods are commonly used for serum testosterone quantitation, although the 'gold standard' reference method is mass spectrometry (MS), which is only available at certain tertiary centres. In this retrospective observational study, 57 female patients were investigated for possible hyperandrogenism. Biochemical testing for testosterone using an immunoassay was compared to an MS method. Correlation between the immunoassay and MS method was worse at lower testosterone concentrations, however overall, gave a reasonably strong correlation coefficient of 0.73. This study highlights the ongoing controversy over the most reliable test for hyperandrogenism in clinical practice. It is vital that clinicians are aware of the limitations of these methods and the clinical repercussions. PMID- 22519484 TI - An evaluation of the simultaneous use of the levonorgestrel-releasing intrauterine device (LNG-IUS, Mirena(r)) combined with endometrial ablation in the management of menorrhagia. AB - The objective of our study was to document the efficacy and possible complications in women who were treated for menorrhagia with the simultaneous use of endometrial ablation and the levonorgestrel-releasing intrauterine device. Women were offered this combined treatment if they complained of menorrhagia and needed contraception. A structured questionnaire was mailed to 150 women who had undergone this combined treatment; 105 (70%) returned a completed questionnaire. The mean duration of follow-up was 25 months (range 6-54 months). Following treatment, 53 women (50.5%) described their periods as being lighter than normal and 49 (46%) had become amenorrhoeic. Overall, 101 (96%) stated that they were satisfied with the treatment. Of the women, 95 (90.5%) said that the treatment had been a 'complete success'; eight (7.6%) 'partly successful' and two women (1.9%) said the treatment had been a 'failure'. One woman subsequently required a hysterectomy. This observational study supports the hypothesis that combined endometrial ablation and insertion of a levonorgestrel-releasing intrauterine device is an effective treatment for menorrhagia and has some advantages when compared with the individual use of these treatments. PMID- 22519485 TI - National survey of the current management of infertility in women aged 40 and over in the UK. AB - We conducted a national survey to identify the variation in the management of infertility in women aged 40 and over among the assisted conception units in the UK. A total of 44 out of 69 IVF units replied by filling in a questionnaire. Nearly half of the units (49%) offer treatment to this age group 6 months after trying for a pregnancy. As first-line management, 71.7% would offer conventional in vitro fertilisation (IVF) and 17.9% intrauterine insemination (IUI). On average, the doctors would move on from IUI to the next step after three attempts. The survey revealed a mean age of 45 as the upper limit for application of IVF (own eggs), and 43% of the units will recommend three cycles of IVF using own eggs before moving to egg donation. Among interventions to improve outcome, 33.3% would consider blastocyst transfer, 5.9% pre-implantation genetic screening (PGS) and 3.9% assisted zona hatching (AZH). PMID- 22519486 TI - Multiple transvaginal ascitic fluid aspirations improves the clinical and reproductive outcome in patients undergoing in vitro fertilisation treatment complicated by severe early ovarian hyperstimulation syndrome. AB - The objective of this study is to examine the effect of repeated transvaginal ascitic fluid aspiration on the reproductive outcome in patients undergoing in vitro fertilisation treatment complicated with severe ovarian hyperstimulation syndrome. A total of 65 women with severe early OHSS were hospitalised and managed with transvaginal ascitic fluid aspiration either in < 3 occasions (control group; n = 29) or >= 3 occasions (multiple aspirations) (study group; n = 36). All patients in both groups received intravenous fluid, human albumin and thromboprophylaxis. Patients in the study group received significantly lower amounts of parenteral fluid (p < 0.05), human albumin (p < 0.01), and LMWH (p < 0.001). In addition, they had significantly lower days of hospitalisation (p < 0.01) as compared with the control group. There was no significant difference in the cancellation rate between the two groups, but patients who underwent multiple aspiration had a significantly higher pregnancy rate (82.8% vs 41.7%, p < 001) and significantly lower abortion rate (10.3% vs 40%, p < 0.05) compared with the control group. Repeated transvaginal asitic fluid aspiration even with large amounts is safe and effective in the treatment of symptomatic patients with severe OHSS. The pregnancy rate increased significantly along with a significant decrease in the abortion rate was observed after multiple aspirations compared with < 3 aspirations. PMID- 22519487 TI - Minilaparotomy female sterilisation in a rural setup: a comparison of two antibiotic regimens. AB - Female sterilisation is the world's most popular contraceptive method. With present advances in contraceptive technology, surgical contraception seems to be the most popular and safest method of fertility control all over the world. The advent of laparoscopy has made the procedure easier in developed countries but not so widely in a developing country like India. Current study was carried out to compare two antibiotic regimens on patients undergoing minilaparotomy tubal ligation and also to see whether local anaesthesia and intravenous sedation/analgesia can be safely practised in a rural setup, where the infrastructure of a tertiary level institution was unavailable. Out of 729 patients, none were referred to a higher centre due to any surgical or anaesthetic problem and a lower rate of infection in the group receiving postoperative combination antibiotic supports the fact that female sterilisation can be performed safely with common antibiotic coverage available in the rural hospitals of developing countries with limited operative facilities. PMID- 22519488 TI - Predictors of female genital cutting among university students in northern Nigeria. AB - Female genital cutting (FGC) is a harmful cultural practice that is perpetrated against women and children. Little is known about the extent of this custom among university students in northern Nigeria. Using self-administered questionnaires, we studied the prevalence and determinants of FGC among female university students in Kano, Nigeria (n =359). The prevalence of FGC was 12.1% (95% confidence interval =8.8-15.8%). Awareness and disapproval of FGC among the study population was very high (96% and 91%, respectively). In multivariate regression models, ethnicity and geographic origin were significant predictors of female circumcision. A comprehensive legal and educational framework and the support of civil society, governments and development partners is required to address this form of gender discrimination. PMID- 22519489 TI - A complex case of Down syndrome in mother and fetus: obstetric and ethical considerations. PMID- 22519490 TI - A new technology in the diagnosis of small ventricular septal defects. PMID- 22519491 TI - Large desmoid tumour causing unstable lie in pregnancy. PMID- 22519492 TI - Placenta percreta invading the urinary bladder and parametrium. PMID- 22519493 TI - Acrania associated with amniotic bands in a fetus. PMID- 22519494 TI - Cardiac rhabdomyoma presenting with fetal bradycardia: is immediate delivery always the answer? PMID- 22519495 TI - Instillagel as vaginal contrast for MRI of a stenosed vagina. PMID- 22519496 TI - Unusual finding of a metallic intrauterine device in postmenopausal bleeding. PMID- 22519498 TI - A case of pelvic actinomycosis with bilateral hydronephrosis and renal failure associated with prolonged intrauterine contraceptive systems use. PMID- 22519497 TI - Emergency laparoscopic sigmoid colectomy for perforation secondary to intrauterine contraceptive device. PMID- 22519499 TI - Profuse and persistent vaginal discharge following fibroid embolisation. PMID- 22519500 TI - Giant fibroepithelial polyp of the uterine cervix. PMID- 22519501 TI - Giant cystic adenomatoid tumour of the uterus. PMID- 22519502 TI - Parasitic fibroid and pseudo-Meigs' syndrome: co-existence of two rare entities. PMID- 22519503 TI - Spectroscopy analysis of cervical carcinoma originated from endometrial carcinoma. PMID- 22519504 TI - Amazing pelvic inflammatory disease... PMID- 22519506 TI - Understanding the value of the arts in the education of mental health professionals: Georg Lukacs, Samuel Beckett and the aesthetic category of specific particularity. AB - The manner in which the arts can enhance the practical, therapeutic concerns of mental health professionals is becoming well established in the health care literature. What gets discussed less frequently, however, are those aesthetic frameworks that propose to give an account of the possible 'meaning' and 'purpose' of art. In response, this paper will elucidate the aesthetic theory of the Hungarian philosopher Georg Lukacs and will suggest that his concept of specific particularity enables an understanding of how art, and literature, poetry and drama in particular, can be employed as an educational resource that can contribute to the development of the 'emotional capabilities' of practitioners. However, insofar as Lukacs' works are philosophically complex and challenging, his concept of specific particularity will be discussed within the context of Samuel Beckett's dramatic work Ohio Impromptu. In doing so, it will be suggested that Ohio Impromptu is not only productive for the elucidation of Lukacs' aesthetics, but also illustrates how the arts provides practitioners with a valuable educative opportunity to engage with, and critically reflect upon, a multiplicity of affective dimensions, thereby enhancing the practitioner's ability to move towards achieving an empathic understanding of, and 'emotional resonance' with, those receiving mental health care. PMID- 22519507 TI - Amphiphilic polymeric micelles as the nanocarrier for peroral delivery of poorly soluble anticancer drugs. AB - INTRODUCTION: Many amphiphilic copolymers have recently been synthesized as novel promising micellar carriers for the delivery of poorly water-soluble anticancer drugs. Studies on the formulation and oral delivery of such micelles have demonstrated their efficacy in enhancing drug uptake and absorption, and exhibit prolonged circulation time in vitro and in vivo. AREAS COVERED: In this review, literature on hydrophobic modifications of several hydrophilic polymers, including polyethylene glycol, chitosan, hyaluronic acid, pluronic and tocopheryl polyethylene glycol succinate, is summarized. Parameters influencing the properties of polymeric micelles for oral chemotherapy are discussed and strategies to overcome main barriers for polymeric micelles peroral absorption are proposed. EXPERT OPINION: During the design of polymeric micelles for peroral chemotherapy, selecting or synthesizing copolymers with good compatibility with the drug is an effective strategy to increase drug loading and encapsulation efficiency. Stability of the micelles can be improved in different ways. It is recommended to take permeability, mucoadhesion, sustained release, and P glycoprotein inhibition into consideration during copolymer preparation or to consider adding some excipients in the formulation. Furthermore, both the copolymer structure and drug loading methods should be controlled in order to get micelles with appropriate particle size for better absorption. PMID- 22519508 TI - Rho kinase inhibitor Y-27632 prolongs the life span of adult human keratinocytes, enhances skin equivalent development, and facilitates lentiviral transduction. AB - The use of tissue-engineered human skin equivalents (HSE) for fundamental research and industrial application requires the expansion of keratinocytes from a limited number of skin biopsies donated by adult healthy volunteers or patients. A pharmacological inhibitor of Rho-associated protein kinases, Y-27632, was recently reported to immortalize neonatal human foreskin keratinocytes. Here, we investigated the potential use of Y-27632 to expand human adult keratinocytes and evaluated its effects on HSE development and in vitro gene delivery assays. Y 27632 was found to significantly increase the life span of human adult keratinocytes (up to five to eight passages). The epidermal morphology of HSEs generated from high-passage, Y-27632-treated keratinocytes resembled the native epidermis and was improved by supplementing Y-27632 during the submerged phase of HSE development. In addition, Y-27632-treated keratinocytes responded normally to inflammatory stimuli, and could be used to generate HSEs with a psoriatic phenotype, upon stimulation with relevant cytokines. Furthermore, Y-27632 significantly enhanced both lentiviral transduction efficiency of primary adult keratinocytes and epidermal morphology of HSEs generated thereof. Our study indicates that Y-27632 is a potentially powerful tool that is used for a variety of applications of adult human keratinocytes. PMID- 22519510 TI - Exceptionally strong multiphoton-excited blue photoluminescence and lasing from ladder-type oligo(p-phenylene)s. AB - We report the synthesis and investigation of multiphoton absorption properties of a novel series of diphenylamino-end-capped ladder-type oligo(p-phenylene)s which exhibit greatly enhanced and efficient multiphoton (from two- to five-photon) upconverted blue photoluminescence with which the record-high intrinsic three photon absorption cross-section of 4.56 * 10(-76) cm(6) s(2) in the femtosecond regime has been obtained. Exceptionally efficient two- to five-photon-excited lasing in the blue region has also been demonstrated in which the highest two photon-excited lasing efficiency of 0.34% has been achieved. PMID- 22519509 TI - Nucleotide excision repair is reduced in oral epithelial tissues compared with skin. AB - Ultraviolet radiation (UVR) exposure to internal tissues for diagnostic, therapeutic and cosmetic procedures has increased dramatically over the past decade. The greatest increase in UVR exposure of internal tissues occurs in the cosmetic industry where it is combined with oxidizing agents for teeth whitening, often in conjunction with indoor tanning. To address potential carcinogenic risks of these procedures, we analyzed the formation and repair of the DNA photoproducts associated with the signature mutations of UVR. Radioimmunoassay was used to quantify the induction and repair of cyclobutane pyrimidine dimers and pyrimidine(6-4)pyrimidone photoproducts in DNA purified from three reconstructed tissues, EpiDerm(TM) , EpiGingival(TM) and EpiOral(TM) . We observed comparable levels of DNA damage in all tissues immediately after UVR exposure. In contrast, repair was significantly reduced in both oral tissues compared with EpiDerm(TM) . Our data suggest that UVR exposure of oral tissues can result in accumulation of DNA damage and increase the risk for carcinoma and melanoma of the mouth. Because NER is a broad-spectrum defense against DNA damage caused by a variety of agents in addition to UVR, our data suggest that the relatively low NER efficiency observed in oral tissues may have wide-ranging consequences in this highly exposed environment. PMID- 22519511 TI - Boron containing compounds as protease inhibitors. PMID- 22519512 TI - A simple approach to guide factor retention decisions when applying principal component analysis to biomechanical data. AB - The use of principal component analysis (PCA) as a multivariate statistical approach to reduce complex biomechanical data-sets is growing. With its increased application in biomechanics, there has been a concurrent divergence in the use of criteria to determine how much the data is reduced (i.e. how many principal factors are retained). This short communication presents power equations to support the use of a parallel analysis (PA) criterion as a quantitative and transparent method for determining how many factors to retain when conducting a PCA. Monte Carlo simulation was used to carry out PCA on random data-sets of varying dimension. This process mimicked the PA procedure that would be required to determine principal component (PC) retention for any independent study in which the data-set dimensions fell within the range tested here. A surface was plotted for each of the first eight PCs, expressing the expected outcome of a PA as a function of the dimensions of a data-set. A power relationship was used to fit the surface, facilitating the prediction of the expected outcome of a PA as a function of the dimensions of a data-set. Coefficients used to fit the surface and facilitate prediction are reported. These equations enable the PA to be freely adopted as a criterion to inform PC retention. A transparent and quantifiable criterion to determine how many PCs to retain will enhance the ability to compare and contrast between studies. PMID- 22519514 TI - Bilateral eyelid erythema associated with false eyelash glue. AB - We report an unusual case of bilateral eyelid erythema caused by eyelash glue. A 22-year-old woman presented with a 3-day history of bilateral eyelid dermatitis after attaching false eyelashes by using latex-containing glue. Slit-lamp examination revealed erythema and swelling of the upper lids of both eyes. The skin prick test was positive for eyelash glue and her total tear IgE score was high. To the best of our knowledge, this is the first report of bilateral eyelid dermatitis caused by eyelash glue. PMID- 22519517 TI - Anaerobic transformation kinetics and mechanism of steroid estrogenic hormones in dairy lagoon water. AB - Wastewater from concentrated animal feeding operations (CAFOs) frequently contains high concentrations of steroid estrogenic hormones. Release of these hormones into the environment may occur when CAFO wastewater is applied to agricultural lands as a nutrient and water source for crop production. To assess the potential risk of hormone contaminants derived from animal wastewater, we investigated the transformation kinetics and mechanisms of three natural estrogenic hormones (17alpha-estradiol, 17beta-estradiol, and estrone) in aqueous solutions blended with dairy lagoon water under anaerobic conditions. Initial transformations of the three hormones in the dairy lagoon water were dominated by biodegradation and the degradation rates were temperature-dependent. The total amounts of hormones (initial concentration at 5 mg L(-1)) remaining in the solution after 52 days at 35 degrees C accounted for approximately 85%, 78%, and 77% of the initial amounts of 17alpha-estradiol, 17beta-estradiol, and estrone, respectively. This observation suggests that these hormones are relatively stable over time and may accumulate in anaerobic or anoxic environments and anaerobic CAFO lagoons. A racemization reaction between 17alpha-estradiol and 17beta estradiol via estrone was observed in aqueous solutions in the presence of CAFO wastewater under anaerobic conditions. The initial hormone concentrations did not affect this degradation mechanism. A reversible reaction kinetic model was applied to fit the observed transformation dynamics. The degradation and regeneration of the parent hormone and its metabolites were successfully simulated by this model. The information in this study is useful for assessing the environmental risk of steroid hormones released from CAFO wastewater and to better understand why these hormone contaminants persist in many aquatic environments. PMID- 22519516 TI - Percutaneous extraction of cardiac implantable electronic devices (CIEDs) in octogenarians. AB - BACKGROUND: As the population receiving cardiac device therapy ages, the number of extraction procedures performed in octogenarians is increasing. This group has more comorbidities and may be at higher risk of such procedures. OBJECTIVES: Document the safety and success of percutaneous lead extraction in octogenarians. METHODS: All extraction cases performed between January 2001 and April 2011 entered into a computer database were analyzed for patient characteristics and indications, extraction technique, procedural success, and complications. Success and complications were classified according to the Heart Rhythm Society consensus statement. Outcomes in octogenarians were compared to younger patients undergoing extraction during the same period. RESULTS: Four hundred and six cases were performed: 72 procedures in octogenarians (mean age 84, range 80-95) and 334 in younger adults (mean age 62, range 20-79). Octogenarians had a greater number of comorbidities per case. Infection was the commonest indication for extraction in both groups. One hundred forty-one leads were extracted in octogenarians and 657 in younger patients. Laser assistance was required in 51.4% of octogenarians versus 49.7% of younger patients. Procedural success was achieved in 71/72 (98.6%) octogenarians versus 329/334 (98.5%) younger patients. No procedural mortality occurred in either group. Overall, complications were more frequent in octogenarians with major and minor complications occurring in 2.8 and 8.3% of octogenarians versus 0.6 and 3.0% of younger patients (P = 0.014). CONCLUSIONS: Procedural success was equally high in octogenarians and younger patients. Percutaneous lead extraction can be performed effectively and safely in octogenarians and is associated with a higher complication rate but no increased mortality. PMID- 22519518 TI - Organ donor screening using parallel nucleic acid testing allows assessment of transmission risk and assay results in real time. AB - Expansion of the donor pool may lead to utilization of donors with risk factors for viral infections. Donor laboratory screening relies on serological and nucleic acid testing (NAT). The increased sensitivity of NAT in low prevalence populations may result in false-positive results (FPR) and may cause unnecessary discard of organs.We developed a screening algorithm to deal, in real time, with potential FPR. Three NAT assays: COBAS AmpliScreen assay (CAS), AmpliPrep Total Nucleic Acid Isolation/CAS, and AmpliPrep/TaqMan assays, were validated and used in parallel for prospective screening of increased-risk donors (IRD), and the probability of FPR was calculated. The lower limit of detection of this algorithm was 9.79, 21.02, and 4.31 IU/mL for human immunodeficiency virus-1, hepatitis C virus, and hepatitis B virus, respectively, with an average turn-around-time of 7.67 h from sample receipt to result reporting. The probability that a donor is potentially infectious with two NAT concordant results was >90%. NAT screening of 35 IRD within 18 months resulted in transplantation of 102 additional organs that without screening would either not be used or used with restrictions in Australia. Using a parallel testing algorithm, real-time confirmation of seropositive donors allows use of organs from IRD and safer expansion of the donor pool. PMID- 22519519 TI - Host-jump drives rapid and recent ecological speciation of the emergent fungal pathogen Colletotrichum kahawae. AB - Ecological speciation through host-shift has been proposed as a major route for the appearance of novel fungal pathogens. The growing awareness of their negative impact on global economies and public health created an enormous interest in identifying the factors that are most likely to promote their emergence in nature. In this work, a combination of pathological, molecular and geographical data was used to investigate the recent emergence of the fungus Colletotrichum kahawae. C. kahawae emerged as a specialist pathogen causing coffee berry disease in Coffea arabica, owing to its unparalleled adaptation of infecting green coffee berries. Contrary to current hypotheses, our results suggest that a recent host jump underlay the speciation of C. kahawae from a generalist group of fungi seemingly harmless to coffee berries. We posit that immigrant inviability and a predominantly asexual behaviour could have been instrumental in driving speciation by creating pleiotropic interactions between local adaptation and reproductive patterns. Moreover, we estimate that C. kahawae began its diversification at <2200 bp leaving a very short time frame since the divergence from its sibling lineage (c. 5600 bp), during which a severe drop in C. kahawae's effective population size occurred. This further supports a scenario of recent introduction and subsequent adaptation to C. arabica. Phylogeographical data revealed low levels of genetic polymorphism but provided the first geographically consistent population structure of C. kahawae, inferring the Angolan population as the most ancestral and the East African populations as the most recently derived. Altogether, these results highlight the significant role of host specialization and asexuality in the emergence of fungal pathogens through ecological speciation. PMID- 22519513 TI - The solute carrier 6 family of transporters. AB - The solute carrier 6 (SLC6) family of the human genome comprises transporters for neurotransmitters, amino acids, osmolytes and energy metabolites. Members of this family play critical roles in neurotransmission, cellular and whole body homeostasis. Malfunction or altered expression of these transporters is associated with a variety of diseases. Pharmacological inhibition of the neurotransmitter transporters in this family is an important strategy in the management of neurological and psychiatric disorders. This review provides an overview of the biochemical and pharmacological properties of the SLC6 family transporters. PMID- 22519520 TI - Proteomic identification of in vivo interactors reveals novel function of skin cornification proteins. AB - Protection against injurious external insults and loss of vital fluids is essential for life and is in all organisms, from bacteria to plants and humans, provided by some form of barrier. Members of the small proline-rich (SPRR) protein family are major components of the cornified cell envelope (CE), a structure responsible for the barrier properties of our skin. These proteins are efficient reactive oxygen species (ROS) quenchers involved not only in the establishment of the skin's barrier function but also in cell migration and wound healing. Here, a proteomic analysis of in vivo SPRR-interacting proteins confirmed their function in CE-formation and ROS-quenching and also revealed a novel unexpected role in DNA-binding. Direct in vitro and in vivo evidence proved that the DNA-binding capacity of SPRRs is regulated by the oxidation state of the proteins. At low ROS levels, nuclear SPRR is able to bind DNA and prevent ROS induced DNA damage. When ROS levels increase, SPRR proteins multimerize and form an effective antioxidant barrier at the cell periphery, possibly to prevent the production or infiltration of ROS. At even higher ROS exposure, DNA-binding is restituted. A molecular model explaining how the intracellular oxidation state of SPRRs likely influences their selective protective function is provided. PMID- 22519521 TI - Is a lone right hemisphere enough? Neurolinguistic architecture in a case with a very early left hemispherectomy. AB - We studied the linguistic profile and neurolinguistic organization of a 14-year old adolescent (EB) who underwent a left hemispherectomy at the age of 2.5 years. After initial aphasia, his language skills recovered within 2 years, with the exception of some word finding problems. Over the years, the neuropsychological assessments showed that EB's language was near-to-normal, with the exception of lexical competence, which lagged slightly behind for both auditory and written language. Moreover, EB's accuracy and speed in both reading and writing words and non-words were within the normal range, whereas difficulties emerged in reading loan words and in tasks with homophones. EB's functional magnetic resonance imaging (fMRI) patterns for several linguistic and metalinguistic tasks were similar to those observed in the dominant hemisphere of controls, suggesting that his language network conforms to a left-like linguistic neural blueprint. However, a stronger frontal recruitment suggests that linguistic tasks are more demanding for him. Finally, no specific reading activation was found in EB's occipitotemporal region, a finding consistent with the surface dyslexia-like behavioral pattern of the patient. While a lone right hemisphere may not be sufficient to guarantee full blown linguistic competences after early hemispherectomy, EB's behavioral and fMRI patterns suggest that his lone right hemisphere followed a left-like blueprint of the linguistic network. PMID- 22519522 TI - Association between chemical pattern in breast milk and congenital cryptorchidism: modelling of complex human exposures. AB - During the past four decades, there has been an increase in the incidence rate of male reproductive disorders in some, but not all, Western countries. The observed increase in the prevalence of male reproductive disorders is suspected to be ascribable to environmental factors as the increase has been too rapid to be explained by genetics alone. To study the association between complex chemical exposures of humans and congenital cryptorchidism, the most common malformation of the male genitalia, we measured 121 environmental chemicals with suspected or known endocrine disrupting properties in 130 breast milk samples from Danish and Finnish mothers. Half the newborns were healthy controls, whereas the other half was boys with congenital cryptorchidism. The measured chemicals included polychlorinated biphenyls (PCBs), polybrominated diphenyl-ethers, dioxins (OCDD/PCDFs), phthalates, polybrominated biphenyls and organochlorine pesticides. Computational analysis of the data was performed using logistic regression and three multivariate machine learning classifiers. Furthermore, we performed systems biology analysis to explore the chemical influence on a molecular level. After correction for multiple testing, exposure to nine chemicals was significantly different between the cases and controls in the Danish cohort, but not in the Finnish cohort. The multivariate analysis indicated that Danish samples exhibited a stronger correlation between chemical exposure patterns in breast milk and cryptorchidism than Finnish samples. Moreover, PCBs were indicated as having a protective effect within the Danish cohort, which was supported by molecular data recovered through systems biology. Our results lend further support to the hypothesis that the mixture of environmental chemicals may contribute to observed adverse trends in male reproductive health. PMID- 22519523 TI - eHealth interventions for HIV prevention. AB - The rapidly changing media landscape and proliferation of new technologies creates vast new opportunities for HIV prevention. The fast growth of the relatively new eHealth field is a testament to the excitement and promise of these new technologies. eHealth interventions in HIV prevention tested to date include computer- and Internet-based interventions; chat room interventions; text messaging interventions; and social media. The current article provides a brief review of these types of interventions in HIV prevention, including their unique advantages and evidence of efficacy. Implications for future research in the eHealth HIV prevention field are discussed. PMID- 22519524 TI - Construction of a gene screening system using giant unilamellar liposomes and a fluorescence-activated cell sorter. AB - We have constructed a gene screening system composed of an in vitro transcription translation system encapsulated within giant unilamellar liposomes and a fluorescence-activated cell sorter (FACS), which allows high-throughput screening of genes encoding proteins of interest. A mock gene library of beta-glucuronidase (GUS) was compartmentalized into liposomes at the single-molecule level, and liposomes exhibiting green fluorescence derived from hydrolysis of the fluorogenic substrate by the synthesized enzyme were sorted using FACS. More than 10-fold enrichment of GUS gene with higher catalytic activity was obtained when a single copy of the GUS gene was encapsulated in each liposome. Quantitative analysis of the enrichment factors and their liposome size dependencies showed that experimentally obtained and theoretical values were in agreement. Using this method, genes encoding active GUS were then enriched from a gene library of randomly mutated GUS genes. Only three rounds of screening were required, which was also consistent with our theoretical estimation. PMID- 22519525 TI - Primary cutaneous CD56 positive lymphoma: a diagnostic conundrum in an unusual case of lymphoma. AB - We present an unusual case of a CD56-positive T-cell lymphoma exhibiting immunophenotypic characteristics of both gammadelta T-cell lymphoma and extranodal NK/T-cell lymphoma, nasal-type. The patient presented with a 2-month history of rapidly progressive, pruritic and cutaneous nodules on his arms. A biopsy showed a dense pan-dermal infiltrate of markedly atypical CD3-positive lymphocytes, compatible with tumor stage cutaneous T-cell lymphoma. Retrospective review of a preceding biopsy and flow cytometric analysis, performed at an outside institution, showed strong expression of surface CD3, CD7, CD43 and gammadelta T-cell receptor (TCR), findings consistent with a diagnosis of cutaneous gammadelta T-cell lymphoma. In light of these data, we performed additional studies that showed diffuse positive staining of the atypical lymphocytes for CD56, CD4 and CD43 as well as Epstein-Barr virus-encoded small nonpolyadenylated RNA (EBER). Interestingly, this case displays characteristic features of gammadelta T-cell lymphoma, with strong surface expression of CD3 and gammadelta-TCR, as well as characteristics of natural killer (NK)/T-cell lymphoma, including expression of CD4 and EBER positivity, that represent two separate categories in the current classification of cutaneous lymphomas. Taken together, these findings underscore the difficulty of rendering an unambiguous classification of the presented neoplasm given the close ontogenetic relationship between NK and cytotoxic T-cells and highlight the need for continued reevaluation of the current classification system. PMID- 22519526 TI - Modified anastomosis for repair of supracardiac total anomalous pulmonary venous connection in infants. AB - Recurrent pulmonary venous obstruction after repair of total anomalous pulmonary venous connection (TAPVC) is usually restricted to the anastomosis between the pulmonary venous confluence and the left atrium. We describe a modified technique for repair of supracardiac TAPVC in infants. An L-shaped incision of left atrium is utilized and the right-sided anastomosis is enlarged by using autologous pericardium to create a large and tension-free anastomosis. PMID- 22519527 TI - Trait emotional intelligence and mental distress: the mediating role of positive and negative affect. AB - Over the past decade, emotional intelligence (EI) has received much attention in the literature. Previous studies indicated that higher trait or ability EI was associated with greater mental distress. The present study focused on mediating effects of positive and negative affect on the association between trait EI and mental distress in a sample of Chinese adults. The participants were 726 Chinese adults (384 females) with an age range of 18-60 years. Data were collected by using the Wong Law Emotional Intelligence Scale, the Positive Affect and Negative Affect Scale, and the General Health Questionnaire. Hierarchical regression analysis showed that EI was a significant predictor of positive affect, negative affect and mental distress. Further mediation analysis showed that positive and negative affect acted as partial mediators of the relationship between EI and mental distress. Furthermore, effect contrasts showed that there was no significant difference between the specific indirect effects through positive affect and through negative affect. This result indicated that positive affect and negative affect played an equally important function in the association between EI and distress. The significance and limitations of the results are discussed. PMID- 22519528 TI - Proprotein convertase subtilisin kexin9 (PCSK9): a novel target for cholesterol regulation. AB - Proprotein Convertase Subtilisin Kexin9 (PCSK9), originally called Neural Apoptosis-Regulated Convertase1 (NARC1), is the latest member of mammalian subtilase super-family. Since its discovery in 2003, it has drawn significant attention because of its function in the degradation of Low Density Lipoprotein Receptor (LDL-R). LDL-R removes circulating LDL-cholesterol (LDL-C) in the blood. Increased level of PCSK9 functional activity will lead to an accumulation of cholesterol in the blood - a high risk factor for cardiovascular disease. This is confirmed by PCSK9 knock out and transgenic animals, various biochemical and clinical studies involving "gain and loss of function" genetic mutations of PCSK9 found in various subset of populations. Owing to this finding, development of strategies for inhibition of PCSK9 function has drawn significant research interest for therapeutic intervention of hypercholesterolemia. Thus PCSK9 is a target for the development of new cholesterol lowering drugs. PMID- 22519529 TI - Effect of amidation on the antimicrobial peptide aurein 2.5 from Australian southern bell frogs. AB - Aurein 2.5 is a naturally C-terminally amidated amphibian antimicrobial peptide. C-terminal amidation can increase efficacy and hence a comparison was made between aurein 2.5-CONH2 and its nonamidated analogue. Amidation of the C terminal carboxyl of aurein 2.5 enhanced antimicrobial activity 2.5- fold against Klebsiella pneumonia. Our results demonstrate that both peptide analogues had high surface activities (23 mN m-1for aurein 2.5-COOH and 26 mN m-1 aurein 2.5 CONH2). Circular dichroism measurements suggest that the helical content of the amidated form, in the presence of trifluoroethanol, was significantly enhanced (33.66 % for aurein 2.5-COOH and 60.89 % aurein 2.5-CONH2). The interaction of aurein 2.5 with bacterial cell membrane mimics was investigated using Langmuir monolayers. Aurein 2.5-CONH2 induced stable surface pressure changes in monolayers formed from K. pneumonia (circa 4.7 mN m-1), however, lower surface pressure changes were observed for aurein 2.5- COOH (circa 3.8 mN m-1). The data shows that in the case of aurein 2.5, amidation is able to enhance antibacterial activity and it is proposed that the increase in effectiveness is due to stabilization of the alpha-helical structure at the membrane interface. PMID- 22519530 TI - D-serine-dehydratase from Saccaromyces cerevisiae: a pyridoxal 5'- phosphate dependent enzyme for advanced biotech applications. AB - The Saccaromices cerevisiae D-serine dehydratase is a pyridoxal 5'-phosphate dependent enzyme that requires zinc for its function. It catalyses the conversion of D-serine into pyruvate and ammonia with the K(m) and k(cat) values of 0.39 mM and 13.1 s(-1) respectively. In this work, a new methodology for monitoring D serine is presented. Our results show that this enzyme could be successfully used as a biological probe for detection of D-serine via fluorescence spectroscopy. PMID- 22519531 TI - Mechanism of action and relationship between structure and biological activity of Ctx-Ha: a new ceratotoxin-like peptide from Hypsiboas albopunctatus. AB - The increase in bacterial resistance to current antibiotics has led to the development of new active molecules. We have isolated the antimicrobial peptide Ctx-Ha from the skin secretion of the frog Hypsiboas albopunctatus. The aim of the present work was to elucidate the mechanism of action of this new antimicrobial peptide. The sequence similarity with Ceratotoxin, the pore size, and the pore-like release of carboxyfluorescein from vesicles indicated that Ctx(Ile21)-Ha has a mechanism of action based on the barrel- stave model. In a second part of this work, we synthesized three analogues to provide information about the relationship between the peptide's structure and its biological activity. Ctx(Ile21)-Ha-VD 16, Ctx(Ile21)- Ha-VD 5,16 and Ctx(Ile21)-Ha-I9K were designed to disrupt the peptide's helical structure and change the hydrophobicity/ hydrophilicity and amphipathicity of the apolar face in order to uncouple the antimicrobial activity of Ctx(Ile21)-Ha from its hemolytic activity. To evaluate the effects of the amino acid substitutions on peptide conformation, secondary structure was accessed using CD measurements. The peptides presented a high amount of alpha-helical structure in the presence of TFE and LPC. The CD data showed that destruction of the amphipathic alpha-helix by the replacing isoleucine by lysine is less harmful to the structure than D-amino acid substitutions. Biological tests demonstrated that all peptides have activity. Nevertheless, the peptide Ctx(Ile21)-Ha-I9K showed the highest value of therapeutic index. Our findings suggest that these peptides are potential templates for the development of new antimicrobial drugs. These studies highlight the importance of single amino acid modification as a tool to modulate the biological activity of antimicrobial peptides. PMID- 22519532 TI - Study of the interaction between fisetin and human serum albumin: a biophysical approach. AB - The binding of fisetin with human serum albumin (HSA) has been studied at different pH using UV-Vis, FTIR, CD and fluorescence spectroscopic techniques. The binding constants were found to increase with the rise in pH of the media. The negative DeltaH degrees (kJ mol-1) and positive DeltaS degrees (J mol-1 K 1) indicate that fisetin binds to HSA via electrostatic interactions with an initial hydrophobic association that result in a positive DeltaS degrees . In presence of potassium chloride (KCl) the binding constants were found to be decrease. The alpha-helical content of HSA increased after binding with fisetin as analyzed from both CD and FTIR methods. The site marker displacement studies using fluorescence anisotropy suggest that fisetin binds to the hydrophobic pocket (Site 1, subdomain IIA) of HSA which is in good accordance with the molecular docking study. The change in accessible surface area (ASA) of residues of HSA was calculated to get a better insight into the binding. PMID- 22519533 TI - Role of Hsp70 in cancer growth and survival. AB - Hsp70 is a highly conserved protein that refolds misfolded proteins and has numerous housekeeping functions which regulate apoptosis and other cell activities. Hsp70 consists of a nucleotide binding domain which binds ATP and a substrate binding domain that binds misfolded proteins. The substrate binding domain contains a peptide binding pocket which is covered by a helical lid. In humans, there are three major cytosolic Hsp70 isotypes, Hsp70-8, Hsp70-1 and Hsp70-2. Leukemic and numerous other cancer cells have a greater amount of Hsp70 1 and -2, which help the cancer cells inhibit apoptosis in response to stress. This review summarizes the structure and role of Hsp70 proteins in cancer survival. PMID- 22519534 TI - Proteomic characterization of the hyaluronidase (E.C. 3.2.1.35) from the venom of the social wasp Polybia paulista. AB - Polybia paulista wasp venom possesses three major allergens: phospholipase A1, hyaluronidase and antigen-5. To the best of our knowledge, no hyaluronidase from the venom of Neotropical social wasps was structurally characterized up to this moment, mainly due to its reduced amount in the venom of the tropical wasp species (about 0.5% of crude venom). Four different glycoproteic forms of this enzyme were detected in the venom of the wasp Polybia paulista. In the present investigation, an innovative experimental approach was developed combining 2-D SDS-PAGE with in-gel protein digestion by different proteolytic enzymes, followed by mass spectrometry analysis under collision-induced dissociation CID) conditions for the complete assignment of the protein sequencing. Thus, the most abundant form of this enzyme in P. paulista venom, the hyaluronidase-III, was sequenced, revealing that the first 47 amino acid residues from the N-terminal region, common to other Hymenoptera venom hyaluronidases, are missing. The molecular modeling revealed that hyaluronidase-III has a single polypeptide chain, folded into a tertiary structure, presenting a central (beta/alpha)5 core with alternation of beta-strands and alpha-helices; the tertiary structure stabilized by a single disulfide bridge between the residues Cys189 and Cys201. The structural pattern reported for P. paulista venom hyaluronidase-III is compatible with the classification of the enzyme as member of the family 56 of glycosidase hydrolases. Moreover, its structural characterization will encourage the use of this protein as a model for future development of "component-resolved diagnosis". PMID- 22519535 TI - A novel monoclonal antibody against the C-terminus of beta-tubulin recognizes endocytic organelles in Trypanosoma cruzi. AB - Microtubule cytoskeleton is a dynamic structure involved in the maintenance of eukaryote cell shape, motion of cilia and flagellum, and intracellular movement of vesicles and organelles. Many antibodies against tubulins have been described, most of them against the C-terminal portion, which is exposed at the outside of the microtubules. By generating a novel set of monoclonal antibodies against the cytoskeleton of Trypanosoma cruzi, a flagellate protozoan that causes Chagas' disease, we selected a clone (mAb 3G4) that recognizes beta-tubulin. The epitope for mAb 3G4 was mapped by pepscan to a highly conserved sequence motif found between alpha-helices 11 and 12 of the C-terminus of beta-tubulin in eukaryotes. It labels vesicular structures in both T. cruzi and mammalian cells, colocalizing respectively with a major cysteine protease (Cruzipain) and lysosome associated protein (LAMP2) respectively, but it does not label regular microtubules on these cellular models. We propose that the epitope recognized by mAb 3G4 is exposed only in a form of tubulin associated with endosomes. PMID- 22519537 TI - Protein & peptide letters. Editorial. PMID- 22519536 TI - Using protein-protein interaction network information to predict the subcellular locations of proteins in budding yeast. AB - The information of protein subcellular localization is vitally important for in depth understanding the intricate pathways that regulate biological processes at the cellular level. With the rapidly increasing number of newly found protein sequence in the Post-Genomic Age, many automated methods have been developed attempting to help annotate their subcellular locations in a timely manner. However, very few of them were developed using the protein-protein interaction (PPI) network information. In this paper, we have introduced a new concept called "tethering potential" by which the PPI information can be effectively fused into the formulation for protein samples. Based on such a network frame, a new predictor called Yeast-PLoc has been developed for identifying budding yeast proteins among their 19 subcellular location sites. Meanwhile, a purely sequence based approach, called the "hybrid-property" method, is integrated into Yeast PLoc as a fall-back to deal with those proteins without sufficient PPI information. The overall success rate by the jackknife test on the 4,683 yeast proteins in the training dataset was 70.25%. Furthermore, it was shown that the success rate by Yeast- PLoc on an independent dataset was remarkably higher than those by some other existing predictors, indicating that the current approach by incorporating the PPI information is quite promising. As a user-friendly web server, Yeast-PLoc is freely accessible at http://yeastloc.biosino.org/. PMID- 22519538 TI - Studies of histidine residues in soybean (Glycine max) urease. AB - Soybean urease has been investigated extensively to reveal the presence of histidine residue (s) in the active site and their potential role in the catalysis. The spectrophotometric studies using diethylpyrocarbonate (DEP) showed the modification of 11.76 +/- 0.1 histidine residues per mole of native urease. Therefore, the results are indicative of the presence of twelve histidine residues per urease molecule. It is presumed that the soybean urease, being a hexameric protein possess two histidine residues per subunit. Correlation plot showed that the complete inactivation of soybean urease corresponds to the modification of 1.97 histidine residues per subunit. Further, double logarithmic plot of kapp versus DEP concentration has resulted in a linear correlation and thereby demonstrating that only one of the two histidine residues per subunit is catalytically essential. Significant protection has been observed against inactivation when urea or acetohydroxamate (AHA) is incubated with DEP treated urease. The studies have demonstrated the presence of one histidine residue at the active site of soybean urease and its significance in catalysis. PMID- 22519540 TI - Terminal sequence importance of de novo proteins from binary-patterned library: stable artificial proteins with 11- or 12-amino acid alphabet. AB - Successful approaches of de novo protein design suggest a great potential to create novel structural folds and to understand natural rules of protein folding. For these purposes, smaller and simpler de novo proteins have been developed. Here, we constructed smaller proteins by removing the terminal sequences from stable de novo vTAJ proteins and compared stabilities between mutant and original proteins. vTAJ proteins were screened from an alpha3beta3 binary-patterned library which was designed with polar/ nonpolar periodicities of alpha-helix and beta-sheet. vTAJ proteins have the additional terminal sequences due to the method of constructing the genetically repeated library sequences. By removing the parts of the sequences, we successfully obtained the stable smaller de novo protein mutants with fewer amino acid alphabets than the originals. However, these mutants showed the differences on ANS binding properties and stabilities against denaturant and pH change. The terminal sequences, which were designed just as flexible linkers not as secondary structure units, sufficiently affected these physicochemical details. This study showed implications for adjusting protein stabilities by designing N- and C-terminal sequences. PMID- 22519539 TI - Comparison of the neutrophil proteome in trauma patients and normal controls. AB - Neutrophils have an impressive array of microbicidal weapons, and in the presence of a pathogen, progress from a quiescent state in the bloodstream to a completely activated state. Failure to regulate this activation, for example, when the blood is flooded with cytokines after severe trauma, causes inappropriate neutrophil activation that paradoxically, is associated with tissue and organ damage. Acidic proteomic maps of quiescent human neutrophils were analyzed and compared to those of activated neutrophils from severe trauma patients. The analysis revealed 114 spots whose measured volumes differed between activated and quiescent neutrophils, with 27 upregulated and 87 downregulated in trauma conditions. Among the identified proteins, grancalcin, S100-A9 and CACNB2 reinforce observed correlations between motility and ion flux, ANXA3, SNAP, FGD1 and Zfyve19 are involved in vesicular transport and exocytosis, and GSTP1, HSPA1 HSPA1L, MAOB, UCH-L5, and PPA1 presented evidence that activated neutrophils may have diminished protection against oxidative damage and are prone to apoptosis. These are discussed, along with proteins involved in cytoskeleton reorganization, reactive oxygen species production, and ion flux. Proteins such as Zfyve19, MAOB and albumin- like protein were described for the first time in the neutrophil. In this work we achieved the identification of several proteins potentially involved in inflammatory signaling after trauma, as well as proteins described for the first time in neutrophils. PMID- 22519541 TI - Isolation and identification of novel neutrophil-activating cryptides hidden in mitochondrial cytochrome C. AB - Although it is known that neutrophils infiltrate damaged sites immediately after tissue injury, the endogenous factors that induce their acute transmigration and activation have not been thoroughly investigated. For the candidates of those factors, we recently discovered two novel neutrophil-activating cryptides, mitocryptide-1 (MCT-1) and mitocryptide-2 (MCT-2), hidden in mitochondrial proteins. In addition, many unknown neutrophil-activating peptides other than MCT 1 and MCT-2 were also observed during their purification. Here, we isolated and purified a novel neutrophil-activating peptide from porcine hearts, which we showed by structural analyses to have an identical primary structure to porcine mitochondrial cytochrome c (68-85). We named this novel functional octadecapeptide as mitocryptide-CYC (MCT-CYC). Structure-activity relationships of cytochrome c on beta-hexosaminidase (beta-HA) release from neutrophilic differentiated HL- 60 cells demonstrated that peptides derived from the C terminal part of cytochrome c induced beta-HA release and that cytochrome c (70 85) was the most potent cryptide among them. Since cytochrome c is known to be involved in the apoptotic process, our results suggest that cryptides, including MCT-CYC, derived from mitochondrial cytochrome c are possible factors that induce scavenging of toxic debris produced from apoptotic cells by neutrophils. PMID- 22519542 TI - Local flexibility facilitates oxidization of buried methionine residues. AB - In proteins, all amino acid residues are susceptible to oxidation by various reactive oxygen species (ROS), with methionine and cysteine residues being particularly sensitive to oxidation. Methionine oxidation is known to lead to destabilization and inactivation of proteins, and oxidatively modified proteins can accumulate during aging, oxidative stress, and in various age-related diseases. Although the efficiency of a given methionine oxidation can depend on its solvent accessibility (evaluated from a protein structure as the accessible surface area of the corresponding methionine residue), many experimental results on oxidation rate and oxidation sites cannot be unequivocally explained by the methionine solvent accessible surface area alone. In order to explore other possible mechanisms, we analyzed a set of seventy-one oxidized methionines contained in thirty-one proteins by various bioinformatics tools. In which, 41% of the methionines are exposed, 15% are buried but with various degree of flexibility, and the rest 44% are buried and structured. Buried but highly flexible methionines can be oxidized. Buried and less flexible methionines can acquire additional local structural flexibility from flanking regions to facilitate the oxidation. Oxidation of buried and structured methionine can also be promoted by the oxidation of neighboring methionine that is more exposed and/or flexible. Our data are consistent with the hypothesis that protein structural flexibility represents another important factor favoring the oxidation process. PMID- 22519543 TI - Subcutaneous nadroparin calcium in the treatment of recent onset retinal vein occlusion: a pilot study. AB - PURPOSE: Optimal management of retinal vein occlusion (RVO) is still a matter of debate. The purpose of this pilot study was to investigate whether nadroparin calcium may play some role in the treatment of recent onset (<=3 weeks' duration) RVO. METHODS: Twenty-four RVO patients were treated with subcutaneous nadroparin calcium (200 I.U./kg/day) for 6 weeks. Best corrected visual acuity (BCVA) and macular thickness in the affected eye were measured at baseline, and after 3 and 6 months. Twenty-four RVO patients treated with oral pentoxifylline, matched for age, gender, RVO type, eye involvement, and BCVA at presentation, randomly selected from the RVO register, were used as controls. RESULTS: Median BCVAs at baseline, month 3, and month 6 were 20/70 (range: 20/1,000-20/20), 20/40 (range: 20/100-20/20), and 20/30 (range: 20/200-20/20) in cases and 20/70 (range: 20/1,000-20/20), 20/60 (range: 20/320-20/25), and 20/60 (range: 20/500-20/20) in controls. Differences between groups were statistically significant at months 3 (P=0.025) and 6 (P=0.024). In the study group, the mean macular thickness was 510+/-207 MUm at baseline, 384+/-198 MUm after 3 months, and 313+/-170 MUm after 6 months. Differences between baseline and months 3 and 6 were statistically significant (P=0.004 and P<0.001). CONCLUSIONS: Results suggest that nadroparin calcium might become a potential candidate for the treatment of RVO. Larger trials are necessary to confirm these preliminary findings. PMID- 22519544 TI - Involvement of redox-signalling in endogenous hydrogen sulfide production. AB - Recently, cystathionine-gamma-lyase (CSE) was found to provide the major physiological pathway for H(2) S, the third member of the gasotransmitter family. In various pathophysiological conditions, H(2) S exerted protective effects based on its antioxidant, anti-inflammatory, anti-hypertensive and other regulatory functions. Interestingly, CSE expression had been only poorly studied and only in relation with inflammatory processes. Therefore, the study by Hassan et al. in this issue of the BJP, provides a considerable advance by furnishing direct experimental evidence for the involvement of redox signalling in the regulation of CSE gene expression. They found that PDGF up-regulated CSE expression and activity that was abolished by antioxidants and by deletion of the transcription factor nuclear erythroid-2-related factor-2 (Nrf2). Furthermore, PDGF induced Nrf2 binding to its consensus sequence that was again reversed by antioxidants. As Nrf2 also governs CO biosynthesis, and PDGF inversely affects H(2) S and NO production, these data could indicate a concerted regulation of the three gasotransmitters by redox signalling. LINKED ARTICLE: This article is a commentary on Hassan et al., pp. 2231-2242 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2012.01949.x. PMID- 22519546 TI - Validation of a full body finite element model (THUMS) for running-type impacts to the lower extremity. AB - The purpose of this study was to determine whether modifying an existing, highly biofidelic full body finite element model [total human model for safety (THUMS)] would produce valid amplitude and temporal shock wave characteristics as it travels proximally through the lower extremity. Modifying an existing model may be more feasible than developing a new model, in terms of cost, labour and expertise. The THUMS shoe was modified to more closely simulate the material properties of a heel pad. Relative errors in force and acceleration data from experimental human pendulum impacts and simulated THUMS impacts were 22% and 54%, respectively, across the time history studied. The THUMS peak acceleration was attenuated by 57.5% and took 19.7 ms to travel proximally along the lower extremity. Although refinements may be necessary to improve force and acceleration timing, the modified THUMS represented, to a certain extent, shock wave propagation and attenuation demonstrated by living humans under controlled impact conditions. PMID- 22519545 TI - Cationic tricoordinate boron intermediates: borenium chemistry from the organic perspective. PMID- 22519547 TI - The bidirectional relationship between headache and chronic musculoskeletal complaints: an 11-year follow-up in the Nord-Trondelag Health Study (HUNT). AB - BACKGROUND AND PURPOSE: Chronic daily headache (CDH) and chronic musculoskeletal complaints (CMSCs) are associated disorders, but whether there is a causal relationship between them is unclear. OBJECTIVE: To determine whether CMSCs are associated with the subsequent development of CDH and vice versa. METHODS: This longitudinal population-based cohort study used data from two consecutive surveys in the Nord-Trondelag Health Study (HUNT 2 and 3) performed in 1995-1997 and 2006 2008. Amongst the 51 383 participants aged >= 20 years at baseline, 41 766 were eligible approximately 11 years later. Of these, 26 197 (63%) completed the questions regarding headache and CMSCs in HUNT 3. RESULTS: A bidirectional relationship was found between headache and CMSCs. In the multivariate analyses adjusting for known potential confounders, a nearly two fold risk (OR 1.8; 95% CI 1.5-2.3) for developing CDH was found for those with CMSCs at baseline. Vice versa, a similarly elevated risk of CMSCs (OR 1.8; 95% CI 1.2-2.6), and even higher risk of chronic widespread MSCs (OR 2.7; 95% CI 1.6-4.7), was found at follow-up amongst those with CDH at baseline. CONCLUSION: CMSCs predispose to CDH and CDH predisposes to CMSCs 11 years later. This may have relevance to understanding the pathophysiology of these disorders. CMSCs should be treated not only to relieve them but also to prevent the development of CDH, and vice versa. PMID- 22519548 TI - Perylene-3-ylmethanol: fluorescent organic nanoparticles as a single-component photoresponsive nanocarrier with real-time monitoring of anticancer drug release. AB - We report for the first time the use of perylene-3-ylmethanol fluorescent organic nanoparticles as a drug delivery system. In the present system, perylene-3 ylmethanol nanoparticles performed four important roles: (i) "nanocarriers" for drug delivery; (ii) "phototriggers" for the drug release; (iii) fluorescent chromophores for cell imaging; and (iv) detectors for real time-monitoring of drug release. In vitro biological studies revealed that the newly developed perylene-3-ylmethanol nanoparticles exhibit good biocompatibility and cellular uptake as well as efficient photoregulated anticancer drug release ability. Such fluorescent organic nanoparticles may open up new perspectives for designing a new class of promising photoresponsive nanocarriers for drug delivery. PMID- 22519549 TI - Substrate stiffness modulates gene expression and phenotype in neonatal cardiomyocytes in vitro. AB - Biomaterials to be used as cell delivery systems for cardiac tissue engineering should be able to comply with cardiac muscle contractile activity, while favoring cell survival and neo-angiogenesis in a hostile environment. Biocompatible synthetic materials can be tailored to mimic cardiac tissue three-dimensional organization in the micro- and nanoscales. Nonetheless, they usually display mechanical properties that are far from those of the native myocardium and thus could affect host cell survival and activity. In the present investigation, inert poly-epsilon-caprolactone planar layers were manufactured to change the surface stiffness (with Young's modulus ranging from 1 to 133 MPa) without changing matrix chemistry. These substrates were challenged with neonatal murine cardiomyocytes to study the possible effect of substrate stiffness on such cell behavior without changing biological cues. Interestingly, softer substrates (0.91+/-0.08 and 1.53+/-0.16 MPa) were found to harbor mostly mature cardiomyocytes having assembled sarcomeres, as shown by the expression of alpha actinin and myosin heavy chain in typical striations and the upregulation of sarcomeric actin mRNA. On the other hand, a preferential expression of immature cardiac cell genes (Nkx-2.5) and proteins (GATA-4) in cardiac cells grown onto stiffer materials (49.67+/-2.56 and 133.23+/-8.67 MPa) was detected. This result could not be ascribed to significant differences in cell adhesion or proliferation induced by the substrates, but to the stabilization of cardiomyocyte differentiated phenotype induced by softer layers. In fact, cardiac cell electromechanical coupling was shown to be more organized on softer surfaces, as highlighted by connexin 43 distribution. Moreover, a differential regulation of genes involved in extracellular matrix remodeling was detected on soft films (0.91+/-0.08 MPa) as compared with the stiffest (133.23+/-8.67 MPa). Finally, the upregulation of a number of genes involved in inflammatory processes was detected when the stiffest polymer is used. These events highlight the differences in cell mechanosensitivity in a heterogeneous cell preparation and are likely to contribute to the differences encountered in cardiac cell phenotype induced by substrate stiffness. PMID- 22519550 TI - Angiotensin II type 2 receptor agonists--where should they be applied? AB - It is now widely accepted that the renin-angiotensin system (RAS) not only contributes to pathological mechanisms involved, e.g. in hypertension or hypertensive and diabetic end-organ damage, but also harbors a "protective arm" represented mainly by two receptors, the AT2 (angiotensin type 2) receptor and the Mas receptor, both mediating tissue-protective and pro-regenerative actions. Several compounds are currently in preclinical and clinical development, which aim at targeting the "protective RAS" by agonism on the AT2 or the Mas receptor. In a recent issue of Expert Opinion on Investigational Drugs Koen Verdonk and co authors review the physiology and patho-physiology of the AT2 receptor and discuss potential future clinical indications and putative adverse effects of AT2 receptor agonists. This article comments the review by Verdonk et al., suggests some additional possible indications, and particularly re-reviews whether there is preclinical in vivo evidence for adverse effects of AT2 receptor agonists. PMID- 22519551 TI - Direct volumetric flow cytometric quantitation of CD34+ stem and progenitor cells. AB - OBJECTIVES: In this study, we compared a classic single-platform (SP) method applying beads for enumeration of CD45+ or CD34+ cells with a new device allowing direct volumetric measurements of stem and progenitor cells. BACKGROUND: Following apheresis and cyropreservation, the precise enumeration of CD34+ cells as key parameter of graft quality is mandatory for the clinical course after transplantation. Currently, flow cytometry with SP technique represents the 'gold standard' for such determinations. METHODS/MATERIALS: Fresh samples, 14 from mobilised peripheral blood (PB), 9 from apheresis products (AP) and 13 samples from frozen-thawed (FT) haematopoietic progenitor cell grafts, were analysed for CD34+ cells, CD45+ cells, and in frozen-thawed samples for viability by a bead based flow cytometric method and in parallel by a direct, volumetric flow cytometric method. RESULTS: Comparison of CD34+ analyses revealed a significant correlation (P < 0.01) for each material between both techniques with r = 0.95 (PB), r = 0.933 (AP) and r = 0.929 (FT). Also, for analysis of CD45+ cells uL(-1) , the measured numbers evaluated with the different techniques did not significantly differ for all three materials analysed. In frozen-thawed samples, the analysis of viability was comparable for both techniques. CONCLUSIONS: The results of this study demonstrate that a direct volumetric analysis of CD34+ cells uL(-1) or CD45+ cells uL(-1) is feasible. This technique represents a simple and economical approach for standardisation of progenitor and stem cell analyses. PMID- 22519552 TI - Mercury distribution across 14 U.S. forests. Part II: Patterns of methyl mercury concentrations and areal mass of total and methyl mercury. AB - This study characterized distribution patterns of monomethyl mercury (MeHg) and areal mass of total mercury (THg) and MeHg across U.S. upland forests. MeHg concentrations increased from surface litter (average: 0.14 MUg kg(-1)) to intermediate (0.47 MUg kg(-1)) and deeper, decomposed litter (1.43 MUg kg(-1)). MeHg concentrations were lower in soils (0.10 MUg kg(-1) at 0-20 cm depth; 0.06 MUg kg(-1) at >20 cm depth). Ratios of MeHg to THg were higher in litter compared to soils. In soils, MeHg concentrations positively correlated with THg across all sites, and MeHg concentrations also increased with C content and latitude. THg areal mass ranged from 41.6 g ha(-1) to 268.8 g ha(-1). Largest THg mass at all sites was sequestered in soils (average of 91%), followed by litter (8%) and aboveground biomass (<1%). MeHg mass (litter plus soils only) ranged from 75 to 443 mg ha(-1), of which 88% was found in soils. Both THg and MeHg mass correlated with latitude, with average mass increases of 10.6 g ha(-1) (THg) and 20 MUg ha( 1) (MeHg) per degree latitude, indicating that highest THg and MeHg accumulation in upland forests are expected in northern sites. PMID- 22519553 TI - On an equal footing: adults' accounts of the experience of using assistive devices for standing. AB - PURPOSE: The aim of the study was to illuminate the meaning that standing holds for persons who require standing devices. METHOD: The phenomenological/hermeneutical analysis of the interviews was carried out using a life world-approach. Fifteen users of standing devices lacking the ability to stand independently participated in the interviews. RESULT: Each person's lived experiences of standing in their devices indicated that the upright body position opens up an opportunity for connection to the outside world. An upright body position (i) alters the person's sense of self, (ii) augments the person's availability to the outside world, (iii) strengthens social interplay, and (iv) changes a person's motivation and their expectations over time. CONCLUSION: Standing may be something that unites the body and self. Understanding the meaning of the altered body position that the use of standing devices opens up is vital for physiotherapists and occupational therapists prescribing these devices. Furthermore, it is important to take account of the subjective body, as well as the biological one, to enhance the adoption of different body positions and the person's experiences. PMID- 22519554 TI - In vivo sodium release and saltiness perception in solid lipoprotein matrices. 1. Effect of composition and texture. AB - Reducing the sodium content in foods is complex because of their multidimensional sensory characteristics and the multifunctionality of sodium chloride. The aim of this study was to elucidate how food composition may influence in-mouth sodium release and saltiness perception. Lipoprotein matrices (LPM) were produced using milk constituents and characterized by means of rheological measurements, texture, and taste sensory profiles. Texture and taste perceptions were affected differently by variations in the salt level, dry matter, and fat contents. Composition and textural changes also modified temporal sodium release and saltiness perception recorded in five subjects, but the effects varied as a function of the salt content. The water content mainly appeared to influence the amount of sodium released, whereas saltiness perception was mainly related to fat content. Elasticity, coating, and granularity were found to be correlated with temporal sodium release and/or saltiness parameters. PMID- 22519555 TI - Differences in transcription levels among wild, domesticated, and hybrid Atlantic salmon (Salmo salar) from two environments. AB - Escaped domesticated individuals can introduce disadvantageous traits into wild populations due to both adaptive differences between population ancestors and human-induced changes during domestication. In contrast to their domesticated counterparts, some endangered wild Atlantic salmon populations encounter during their marine stage large amounts of suspended sediments, which may act as a selective agent. We used microarrays to elucidate quantitative transcriptional differences between a domesticated salmon strain, a wild population and their first-generation hybrids during their marine life stage, to describe transcriptional responses to natural suspended sediments, and to test for adaptive genetic variation in plasticity relating to a history of natural exposure or nonexposure to suspended sediments. We identified 67 genes differing in transcription level among salmon groups. Among these genes, processes related to energy metabolism and ion homoeostasis were over-represented, while genes contributing to immunity and actin-/myosin-related processes were also involved in strain differentiation. Domestic-wild hybrids exhibited intermediate transcription patterns relative to their parents for two-thirds of all genes that differed between their parents; however, genes deviating from additivity tended to have similar levels to those expressed by the wild parent. Sediments induced increases in transcription levels of eight genes, some of which are known to contribute to external or intracellular damage mitigation. Although genetic variation in plasticity did not differ significantly between groups after correcting for multiple comparisons, two genes (metallothionein and glutathione reductase) tended to be more plastic in response to suspended sediments in wild and hybrid salmon, and merit further examination as candidate genes under natural selection. PMID- 22519557 TI - Perceptions of family members of children with cleft lip and palate in hyderabad, India, and its rural outskirts regarding craniofacial anomalies: a pilot study. AB - Objective : This pilot study aimed to understand cultural perspectives on cleft anomalies in the community of Hyderabad, India, and its rural outskirts. Design : Interviews focusing on perceptions of cleft lip and palate were conducted using a 21-item interview guide approved by the director of the Gosla Srinivas Reddy Institute of Craniofacial Surgery (GSR). Settings : Interviews were conducted at GSR, a specialty surgical center located in Hyderabad, India. Patients and Participants : All patients who presented to GSR with either cleft lip, cleft palate, or cleft lip and palate at the time of this study were included. Results : Of the 23 families interviewed, 12 mothers believed the cleft was caused by an eclipse, and two believed the scientific explanation their physician offered. Fourteen families were offered no explanation for the cleft lip and/or palate at the time of their first physician visit. No families practiced non-Western methods for treatment of the cleft. One family identified beliefs held in the community that their child with a cleft lip was bad luck. Conclusion : A commonly held belief in this community in India is that cleft lip, cleft palate, or cleft lip and palate are caused by an eclipse. Physicians appear to be providing families with insufficient education on cleft impairments. Data generated from studies similar to this can be used to design educational protocols that address this gap in community understanding of orofacial clefting. PMID- 22519556 TI - Recovery in a letter-by-letter reader: more efficiency at the expense of normal reading strategy. AB - Although changes in reading performance of recovering letter-by-letter readers have been described in some detail, no prior research has provided an in-depth analysis of the underlying adaptive word processing strategies. Our work examined the reading performance of a letter-by-letter reader, FH, over a period of 15 months, using eye movement methodology to delineate the recovery process at two different time points (T1, T2). A central question is whether recovery is characterized either by moving back towards normal word processing or by refinement and possibly automatization of an existing pathological strategy that was developed in response to the impairment. More specifically, we hypothesized that letter-by-letter reading may be executed with at least four different strategies and our work sought to distinguish between these alternatives. During recovery significant improvements in reading performance were achieved. A shift of fixation positions from the far left to the extreme right of target words was combined with many small and very few longer regressive saccades. Apparently, 'letter-by-letter reading' took the form of local clustering, most likely corresponding to the formation of sublexical units of analysis. This pattern was more pronounced at T2, suggesting that improvements in reading efficiency may come at the expense of making it harder to eventually return to normal reading. PMID- 22519558 TI - Vasectomy reversal using a microsurgical three-layer technique: one surgeon's experience over 18 years with 1300 patients. AB - The technique and the results of microsurgical vasectomy reversal in a single centre study over 18 years are presented. Both vasovasostomy (VV) and epididymovasostomy (EV) were carried out in a three-layer technique. With strict adherence to the strategy, end-to-end VV was only performed if spermatozoa had been demonstrated at the epididymal stump of the vas. In all other cases, EV was carried out in a preocclusive region of the epididymal tubule. The outpatient procedure of refertilization was associated with a very low complication rate, which underlines its minimal-invasive character. The follow-up rate was 71%, the overall patency rate was 89% and the pregnancy rate was 59%. Secondary azoospermia was only observed in 1% of the patients. In relation to the intervals of obstruction, the patency and pregnancy rates were higher after short-term obstruction than after long-term obstruction. Correspondingly, higher success rates were found after VV than after EV. This is understandable because the probability for indication of EV increases with longer periods of obstruction. There is a significant discrepancy between patency and pregnancy rates that is likely to be caused by a relevant number of patients with post-operative asthenozoospermia. The duration of obstruction is an important factor concerning epididymal damage, but it only disproportionately affects the results of refertilization if the technology of EV is implemented consistently in case of an epididymal granuloma. Good clinical results are achieved with this strategy, as evidenced by pregnancy rates and semen analyses. PMID- 22519559 TI - Biventricular defibrillator patients have higher complication rates after revision of recalled leads. AB - BACKGROUND: Since the 2009 revised advisory statement regarding Sprint Fidelis(r) Defibrillator Lead failure rates (Medtronic Inc., Minneapolis, MN, USA), there has been a significant increase in revision of these leads. We sought to establish the frequency of major procedural complications and determine what patient characteristics were associated with these outcomes. METHODS: We retrospectively reviewed the charts of 621 patients with Fidelis(r) leads being followed in the University of Pittsburgh Medical Center through January 1, 2010. The population was then examined for rates of lead malfunction, revision, and complication. RESULTS: The average time from implantation of Fidelis(r) lead to endpoint was 32 +/- 16 months. Overall lead survival rates were 89% at 41 months and were lower in biventricular implantable cardioverter defibrillator (BiVICD) as compared to standard implantable cardioverter defibrillator patients (log rank P = 0.053). Prophylactic revisions increased dramatically during 2009 (9.4% vs 1.4%, P < 0.001). Among the 131 patients who underwent revision during the entire time of follow-up, 11 patients had postoperative complications (8.5%). The only significant variable found between patients who did and did not have complications was the presence of a BiVICD (81.8 vs 48.7%, P = 0.036). Of the 40 total patients who underwent lead extraction, all three complications occurred in patients with BiVICDs. CONCLUSION: The number of prophylactic Fidelis(r) lead revisions has increased dramatically since 2008, and procedure-related complications have been higher than anticipated. Major procedural complication rates are greater among patients with BiVICDs. Overall, lead extraction does not appear to increase procedural risk as compared to abandonment. PMID- 22519560 TI - Comparative proteomic analysis of primary schwann cells and a spontaneously immortalized schwann cell line RSC 96: a comprehensive overview with a focus on cell adhesion and migration related proteins. AB - Schwann cells (SCs) are the principal glial cells of the peripheral nervous system (PNS). As a result of tissue heterogeneity and difficulties in the isolation and culture of primary SCs, a considerable understanding of SC biology is obtained from SC lines. However, the differences between the primary SCs and SC lines remain uncertain. In the present study, quantitative proteomic analysis based on isobaric tags for relative and absolute quantitation (iTRAQ) labeling was conducted to obtain an unbiased view of the proteomic profiles of primary rat SCs and RSC96, a spontaneously immortalized rat SC line. Out of 1757 identified proteins (FDR < 1%), 1702 were quantified, while 61 and 78 were found to be, respectively, up- or down-regulated (90% confidence interval) in RSC96. Bioinformatics analysis indicated the unique features of spontaneous immortalization, illustrated the dedifferentiated state of RSC96, and highlighted a panel of novel proteins associated with cell adhesion and migration including CADM4, FERMT2, and MCAM. Selected proteomic data and the requirement of these novel proteins in SC adhesion and migration were properly validated. Taken together, our data collectively revealed proteome differences between primary SCs and RSC96, validated several differentially expressed proteins with potential biological significance, and generated a database that may serve as a useful resource for studies of SC biology and pathology. PMID- 22519561 TI - Pilot programme for the rapid initiation of antiretroviral therapy in pregnancy in Cape Town, South Africa. AB - Initiation of antiretroviral therapy (ART) in pregnancy is an important intervention to prevent the mother-to-child transmission (MTCT) of HIV and to promote maternal health. Early initiation of ART is particularly important to achieve viral suppression rapidly before delivery. However, current approaches to start ART in pregnancy may be problematic in many settings, with referrals between antenatal care (ANC) and ART services, and delays for patient preparation before ART initiation. These steps contribute to a sizable proportion of women failing to receive adequate duration of ART before delivery, increasing the risk of MTCT. To address these limitations, we developed the rapid initiation of antiretroviral therapy in pregnancy (RAP) programme. The programme featured the use of point-of-care CD4 testing to identify ART-eligible women with CD4 cell counts <= 350 cells/ul; immediate ART initiation in women on the same day that eligibility was determined, if possible; and intensive counselling and support for ART initiation during the first few weeks on ART. We implemented RAP in an antenatal clinic setting in Cape Town South Africa. Between February and August 2011, a total of 221 HIV-infected women were referred to the programme for CD4 cell count testing and 101 (46%) were eligible for ART. Of these, 98 women (97%) started therapy during pregnancy, 89 (91%) on the day of referral to the service. In-depth interviews suggested that although there were substantial challenges facing HIV-infected women initiating ART in pregnancy, the availability of immediate services and counselling support played an important role in addressing these. While further research is needed, this evaluation demonstrates that a novel service delivery approach may facilitate rapid ART initiation in pregnancy. PMID- 22519562 TI - Microbial strain prioritization using metabolomics tools for the discovery of natural products. AB - Natural products profoundly impact many research areas, including medicine, organic chemistry, and cell biology. However, discovery of new natural products suffers from a lack of high throughput analytical techniques capable of identifying structural novelty in the face of a high degree of chemical redundancy. Methods to select bacterial strains for drug discovery have historically been based on phenotypic qualities or genetic differences and have not been based on laboratory production of secondary metabolites. Therefore, untargeted LC/MS-based secondary metabolomics was evaluated to rapidly and efficiently analyze marine-derived bacterial natural products using LC/MS principal component analysis (PCA). A major goal of this work was to demonstrate that LC/MS-PCA was effective for strain prioritization in a drug discovery program. As proof of concept, we evaluated LC/MS-PCA for strain selection to support drug discovery, for the discovery of unique natural products, and for rapid assessment of regulation of natural product production. PMID- 22519563 TI - Matrix metalloproteinase inhibition affects adipose tissue mass in obese mice. AB - 1. Because the development of adipose tissue involves remodelling of the extracellular matrix (ECM), which requires matrix metalloproteinase (MMP) activity, we examined whether MMP inhibitors may have the potential to affect adipose tissue mass in obese mice. 2. Administration of the relatively gelatinase specific MMP inhibitor tolylsam ((R)-3-methyl-2-[4-(3-p-tolyl-[1,2,4]oxadiazol-5 yl)-benzenesulphonylamino]-butyric acid; 100 mg/kg per day) for 7 weeks to obese wild-type mice on a high-fat diet resulted in significantly lower bodyweight (P < 0.05), lower subcutaneous (SC) and gonadal (GON) adipose tissue mass (both P < 0.05) and smaller adipocytes in both SC (P < 0.005) and GON (P < 0.0005) adipose tissues. 3. Magnetic resonance imaging confirmed a lower total body fat content in tolylsam-treated mice (P < 0.0005). In addition, tolylsam treatment of wild type mice was associated with a marked enhancement in metabolic rate. 4. Electron microscopy analysis of tissue sections at the end of the 7 week feeding period revealed significantly higher collagen accumulation in the ECM of SC adipose tissues of tolylsam-treated mice (P < 0.001). 5. Thus, the relatively gelatinase specific MMP inhibitor tolylsam has the potential to affect fat tissue growth in obese mice. PMID- 22519564 TI - Percutaneous mitral valve repair in patients with prior cardiac surgery. AB - BACKGROUND AND AIM OF THE STUDY: The safety of percutaneous mitral valve repair with the MitraClip system has been documented. However, few data are available on high-risk patients not amenable to surgery. The aim of this study was to evaluate the outcomes of patients with prior cardiac surgery undergoing MitraClip therapy (Abbott, Abbott Park, Chicago, IL, USA) for severe mitral regurgitation. METHODS: We reported two cases of percutaneous treatment of severe mitral regurgitation performed in patients who had previously undergone cardiac surgery with the implantation of mechanical prosthetic aortic valve. RESULTS: In both the reported cases a sustained reduction in mitral regurgitation severity was obtained at two year follow-up, with a relevant improvement in terms of clinical status and quality of life. CONCLUSIONS: Percutaneous mitral valve repair using the MitraClip system represents a viable treatment choice for severe mitral regurgitation in high-risk patients who have previously undergone cardiac surgery. PMID- 22519565 TI - Comparing different boosters of planning interventions on changes in fat consumption in overweight and obese individuals: a randomized controlled trial. AB - Single planning interventions have been found to promote short-term dietary change. Repeated planning interventions may foster long-term effects on behavior change. It remains unknown whether there is a critical number of boosters to establish long-term maintenance of behavioral changes. This study aimed at investigating what social-cognitive variables mediate the effects of the interventions on dietary behavior change. Overall, 373 participants (n = 270 women, 72.4%; age M = 52.42, SD = 12.79) were randomly allocated to one of five groups: a control group, a single planning group, and three groups with 3, 6, or 9 weeks' repeated planning interventions. Follow-ups took place 4, 6, and 12 months after baseline. Change in fat consumption was not promoted by any of the interventions. In terms of social-cognitive variables, intentions, self-efficacy and coping planning displayed a time * group interaction, with the 9 weeks' planning group showing the most beneficial effects. Effect sizes, however, were very small. None of the tested planning interventions successfully promoted change in fat consumption across the 12 month period. This, however, could not be explained by problems with adherence to the intervention protocol. Potential explanations for this unexpected result are discussed. PMID- 22519566 TI - Neuroanatomical correlates of the progressive supranuclear palsy corticobasal syndrome hybrid. AB - BACKGROUND: The progressive supranuclear palsy syndrome (PSPS) and corticobasal syndrome (CBS) are associated with relatively specific patterns of atrophy; the former predominantly involving the brainstem, the latter frontoparietal regions. However, it has become apparent that there are subjects that meet criteria for PSPS and CBS. We refer to subjects with this presentation as Hybrids. The hybrid presentation is not rare, yet there are no studies that have assessed the neuroanatomical correlates of the hybrid syndrome to explain its occurrence. METHOD: In this study of 41 subjects and controls, we utilized the technique of voxel-based morphometry to assess both gray and white matter volume loss in six prospectively recruited Hybrids that underwent 3.0 T volumetric head magnetic resonance image scanning to determine the neuroanatomical correlates of the syndrome. We compared patterns of atrophy in three prospectively recruited groups: the Hybrid group (n = 6), a PSPS group (n = 10), and CBS group (n = 5). All 21 subjects had completed the same standardized batteries assessing cognition, and motor, behavioral, executive, oculomotor and limb praxis function. RESULTS: The Hybrid group showed imaging features of both PSPS and CBS, with volume loss observed in the brainstem (superior cerebellar peduncle) and cortex (medial and lateral premotor, prefrontal and motor cortex). As expected, typical patterns of loss were observed in PSPS and CBS. CONCLUSIONS: These findings explain the neuroanatomical basis of the overlapping presenting signs and symptoms of PSPS and CBS, in Hybrids. PMID- 22519567 TI - Characterization of DDRI-18 (3,3'-(1H,3'H-5,5'-bibenzo[d]imidazole-2,2' diyl)dianiline), a novel small molecule inhibitor modulating the DNA damage response. AB - BACKGROUND AND PURPOSE: Recently, the DNA damage response (DDR) has emerged as a promising target for anticancer drug development. In our previous study, we identified several DDR-inhibiting compounds via high-content screening of a small molecule library using gammaH2AX foci as a biomarker. Here, we studied the effects of the DNA damage response inhibitor DDRI-18 (3,3'-(1H,3'H-5,5' bibenzo[d]imidazole-2,2'-diyl)dianiline) on DDR. EXPERIMENTAL APPROACH: Osteosarcoma U2OS cells were treated with etoposide to induce DDR. The nuclear foci of gammaH2AX and other signalling molecules in DDR were visualized by immunofluorescence and quantified using an IN Cell Analyzer. The DNA repair capacity of cells was analysed using the comet assay and in vivo DNA end-joining assay. Cell survival after drug treatment was quantified using the MTT assay, and apoptotic cell death was analysed by Annexin V staining and flow cytometry. KEY RESULTS: DDRI-18 inhibited the non-homologous end-joining (NHEJ) DNA repair process and delayed the resolution of DNA damage-related proteins (gammaH2AX, ATM and BRCA1) from DNA lesions at a later phase of DDR. Furthermore, DDRI-18 enhanced the cytotoxic effects of anticancer DNA-damaging drugs, including etoposide, camptothecin, doxorubicin and bleomycin. This synergistic effect on cell death was shown to be due to caspase-dependent apoptosis. CONCLUSIONS AND IMPLICATIONS: We identified a chemical compound, DDRI-18, that has chemosensitization activity. Although the target molecule and mechanism of action of DDRI-18 remain unknown, DDRI-18 is an effective chemosensitizing agent and may improve the therapy with classical anticancer drugs. PMID- 22519569 TI - Good choices, great future: an applied theatre prevention program to reduce alcohol-related risky behaviours during Schoolies. AB - INTRODUCTION AND AIMS: The contextual and temporal factors of post-school celebratory events ('Schoolies') place young people at elevated risk of excessive drinking compared with other social occasions. This study investigates the impact of an applied theatre prevention program 'Choices' in reducing the risk of drinking and other risk behaviours during Schoolies celebrations. DESIGN AND METHODS: Choices was delivered in the last term of Year 12 across 28 North Queensland schools. A total of 352 school leavers (43.1% male, mean age = 17.14 years) completed a questionnaire at Whitsunday Schoolies, Queensland, Australia on 23-24 November 2010. Nearly 49% of respondents had attended Choices. The survey included measures of alcohol use, illicit drug use and associated problems during Schoolies and a month prior to Schoolies. RESULTS: After controlling for gender and pre-Schoolies drinking, school leavers who attended Choices were significantly less likely to report illicit drug use (OR = 0.51, P < 0.05) and problem behaviours (OR = 0.40, P < 0.01) than those who did not attend Choices. There was, however, no intervention effect in risky drinking (i.e. drank on 5 or more days, typical amount five or more standard drink and binge drank on 3 or more days) at Schoolies (OR = 0.92, P = 0.80). DISCUSSION AND CONCLUSIONS: Delivery of a youth-specific applied theatre prevention program employing a harm minimisation framework may be effective in reducing high-risk behaviours associated with alcohol consumption at celebratory events, even if young people expect to engage in excessive alcohol consumption. PMID- 22519568 TI - Autoimmune gastritis: histology phenotype and OLGA staging. AB - BACKGROUND: Among Western populations, the declining incidence of Helicobacter pylori infection coincides with a growing clinical impact of autoimmune gastritis. AIMS: To describe the histological phenotype of autoimmune gastritis, also to test the prognostic impact of OLGA staging in the autoimmune setting. METHODS: A single-institutional series (spanning the years 2003-2011) of 562 consecutive patients (M:F ratio: 1:3.7; mean age = 57.6 +/- 14.4 years) with serologically confirmed autoimmune gastritis underwent histology review and OLGA staging. RESULTS: Helicobacter pylori infection was ascertained histologically in 44/562 cases (7.8%). Forty six biopsy sets (8.2%) featured OLGA stages III-IV; they included all four cases of incidental epithelial neoplasia (three intraepithelial and one invasive; three of these four cases had concomitant H. pylori infection). There were 230 (40.9%) and 139 (24.7%) cases, respectively, of linear and micro-nodular enterochromaffin-like cell hyperplasia; 19 (3.4%) type I carcinoids were detected. The series included 116 patients who underwent repeated endoscopy/biopsy sampling (mean time elapsing between the two procedures = 54 months; range 24-108). Paired histology showed a significant (P = 0.009) trend towards a stage progression [the stage increased in 25/116 cases (22%); it remained unchanged in 87/116 cases (75%)]. CONCLUSIONS: In autoimmune gastritis, the cancer risk is restricted to high-risk gastritis stages (III-IV), and is associated mainly with concomitant H. pylori infection. OLGA staging consistently depicts the time-dependent organic progression of the autoimmune disease and provides key information for secondary gastric cancer prevention strategies. PMID- 22519570 TI - A system for predicting and preventing work-related musculoskeletal disorders among dentists. AB - Work-related musculoskeletal disorders (WMSDs) have become increasingly common among dentists and initiate a series of events that could result in a career ending. This study aims to construct a system for predicting and preventing WMSD among dentists. We used Bayesian network (BN) that describes the mutual relationships among multiple variables contributing to WMSDs. The data-sets were prepared from direct measurements of dentist's movements and a questionnaire survey. We applied BN learning algorithms to the training data-sets to develop WMSD prediction model using 10-fold cross-validation. To evaluate the system performance, 16 dentists were randomly assigned into a 2 * 2 crossover trial scheduled to each of two sequences of dental working: receiving feedback or no feedback including the probability of WMSD and related risk factors from the system. The group that received feedback decreased significantly (t-test, p < 0.05) the extensions of neck and upper back in the y-axis as well as the WMSD probability on the post-test. In conclusion, the system for predicting and preventing WMSD aids the correction of neck and upper back extensions and reduction in WMSD probability, which may potentially contribute to reduce the risk of WMSD among dentists. PMID- 22519571 TI - Microbiome analysis among bats describes influences of host phylogeny, life history, physiology and geography. AB - Metagenomic methods provide an experimental approach to inform the relationships between hosts and their microbial inhabitants. Previous studies have provided the conceptual realization that microbiomes are dynamic among hosts and the intimacy of relation between micro- and macroorganisms. Here, we present an intestinal microflora community analysis for members of the order Chiroptera and investigate the relative influence of variables in shaping observed microbiome relationships. The variables ranged from those considered to have ancient and long-term influences (host phylogeny and life history) to the relatively transient variable of host reproductive condition. In addition, collection locality data, representing the geographic variable, were included in analyses. Results indicate a complex influence of variables in shaping sample relationships in which signal for host phylogeny is recovered at broad taxonomic levels (family), whereas intrafamilial analyses disclosed various degrees of resolution for the remaining variables. Although cumulative probabilities of assignment indicated both reproductive condition and geography influenced relationships, comparison of ecological measures among groups revealed statistical differences between most variable classifications. For example, ranked ecological diversity was associated with host phylogeny (deeper coalescences among families were associated with more microfloral diversity), dietary strategy (herbivory generally retained higher diversity than carnivory) and reproductive condition (reproductively active females displayed more diverse microflora than nonreproductive conditions). Overall, the results of this study describe a complex process shaping microflora communities of wildlife species as well as provide avenues for future research that will further inform the nature of symbiosis between microflora communities and hosts. PMID- 22519572 TI - Empowering HIV testing as a prevention tool: targeting interventions for high risk men who have sex with men. AB - In France, HIV testing can be easily performed in free and anonymous voluntary counselling testing (VCT) centres. The recent national study among French men who have sex with men (MSM) showed that 73% of those already tested for HIV had been tested in the previous two years. Nothing is known about the risk behaviours of MSM attending VCT centres. This study aimed to characterize sexual risk behaviours of MSM tested for HIV in such centres and identify factors associated with inconsistent condom use (ICU). A cross-sectional study was conducted from March to December 2009 in four VCT centres where a self-administered questionnaire was proposed to all MSM about to have a HIV test. ICU was defined as reporting non-systematic condom use during anal intercourse with casual male partners. Among the 287 MSM who fully completed their questionnaire, 44% reported ICU in the previous six months. Among those who had been already tested, 63% had had their test in the previous two years. Factors independently associated with ICU included: never avoiding one-night stands, not having been recently HIV tested, experiencing difficulty in using condoms when with a HIV negative partner or when under the influence of drugs or alcohol and finally, reporting to have had a large number of casual male partners in the previous six months. The rate of recently tested MSM was high in our study. Nevertheless, this rate was lower than that found in the last national study. Furthermore those not recently tested were significantly more likely to report high risk behaviours. We therefore recommend that further efforts be made to adapt the offer of both HIV testing and counselling to meet the specific needs of hard-to-reach MSM. Accordingly, an additional community-based offer of HIV testing to reach most-at-risk MSM is forthcoming in France. PMID- 22519573 TI - Emergency-department-initiated palliative care consults: a descriptive analysis. AB - BACKGROUND: To provide optimal palliative care (PC) services in the acute setting of the emergency department (ED), it may be beneficial for the consult team to delineate the most commonly requested ED-PC services and understand why ED clinicians currently request palliative care consults (PCC). METHODS: Using a retrospective review of data gathered by the PC team on services and consults we studied patterns of ED-initiated PCC (EDI-PCC) and describe here the use of PC services in an urban tertiary-care-center ED. We then compare these with PC services provided in the traditional in-patient consult setting. RESULTS AND CONCLUSIONS: EDI-PCC patients are young, likely secondary to traumatic and critical, sudden events. In-hospital mortality rate for EDI-PCC patients is very high (most die early and in the ED setting), signifying a trend for ED clinicians to request PC consults in those who are imminently dying. PC consult teams called to the ED should expect to provide high-priority, time-sensitive services and anticipate a high level of bereavement/emotional support for distraught and unprepared families, with major discussions around end-of-life care. PMID- 22519574 TI - "Heart rate-dependent" electrocardiographic diagnosis of left ventricular hypertrophy. AB - A case is presented revealing the common phenomenon of heart rate-dependent diagnosis of electrocardiographic (ECG) diagnosis of left ventricular hypertrophy (LVH), which consists of satisfaction of LVH criteria only at faster rates whereas ECGs with a slow heart rate do not satisfy such criteria. The mechanism of the phenomenon has been attributed to the tachycardia-mediated underfilling of the left ventricle bringing the electrical "centroid" of the heart closer to the recording electrodes, which results in augmentation of the amplitude of QRS complexes, particularly in leads V2-V4. PMID- 22519575 TI - Mercury distribution and deposition in glacier snow over western China. AB - Western China is home to the largest aggregate of glaciers outside the polar regions, yet little is known about how the glaciers in this area affect the transport and cycling of mercury (Hg) regionally and globally. From 2005 to 2010, extensive glacier snow sampling campaigns were carried out in 14 snowpits from 9 glaciers over western China, and the vertical distribution profiles of Hg were obtained. The Total Hg (THg) concentrations in the glacier snow ranged from <1 to 43.6 ng L(-1), and exhibited clear seasonal variations with lower values in summer than in winter. Spatially, higher THg concentrations were typically observed in glacier snows from the northern region where atmospheric particulate loading is comparably high. Glacier snowpit Hg was largely dependent on particulate matters and was associated with particulate Hg, which is less prone to postdepositional changes, thus providing a valuable record of atmospheric Hg deposition. Estimated atmospheric Hg depositional fluxes ranged from 0.74 to 7.89 MUg m(-2) yr(-1), agreeing very well with the global natural values, but are one to two orders of magnitude lower than that of the neighboring East Asia. Elevated Hg concentrations were observed in refrozen ice layers in several snowpits subjected to intense melt, indicating that Hg can be potentially released to meltwater. PMID- 22519576 TI - ICT: this transformer isn't science fiction. PMID- 22519579 TI - Whey protein nanofibrils: the environment-morphology-functionality relationship in lyophilization, rehydration, and seeding. AB - Amyloid-like fibrils from beta-lactoglobulin have potential as efficient thickening and gelling agents for food and biomedical applications, but the link between fibril morphology and bulk viscosity is poorly understood. We examined how lyophilization and rehydration affects the morphology and rheological properties of semiflexible (i.e., straight) and highly flexible (i.e., curly) fibrils, the latter made with 80 mM CaCl(2). Straight fibrils were fractured into short rods by lyophilization and rehydration, whereas curly fibrils sustained little damage. This was reflected in the viscosities of rehydrated fibril dispersions, which were much lower for straight fibrils than for curly fibrils. Lyophilized straight or curly fibrils seeded new fibril growth, but viscosity enhancement due to seeding was negligible. We believe that the increase in fibril concentration caused by seeding was counterbalanced by a decrease in fibril length, reducing the ability of fibrils to form physical entanglement networks. PMID- 22519580 TI - Asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and L arginine in patients with arteriogenic and non-arteriogenic erectile dysfunction. AB - The plasma concentration of asymmetrical dimethylarginine (ADMA), an inhibitor of nitric oxide synthase, has been linked to endothelial dysfunction. We investigated the relation between ADMA, symmetric dimethylarginine (SDMA) and L arginine concentrations and erectile dysfunction. We compared plasma levels of ADMA, SDMA and L-arginine in 61 men in good health with erectile dysfunction of arteriogenic and non-arteriogenic origin. Diagnosis of erectile dysfunction was based on the International Index of Erectile Function Score and its aetiology was classified with penile echo-colour-Doppler in basal condition and after intracavernous injection of prostaglandin E1. The ADMA and SDMA concentrations were significantly higher in men with arteriogenic erectile dysfunction compared with those with erectile dysfunction of non-arteriogenic origin (p < 0.05) and the concentrations in both subgroups were significantly higher than in controls (p < 0.001). There was a negative correlation between ADMA and International Index of Erectile Function Score only in arteriogenic erectile dysfunction subgroup. L-arginine did not differ significantly neither between the two erectile dysfunction subgroups (p > 0.05) nor between each of the two erectile dysfunction subgroups and controls (p > 0.05). The L-arginine/ADMA and the L arginine/SDMA ratios in arteriogenic erectile dysfunction subgroups were significantly lower than both in controls (p < 0.05) and in non-arteriogenic erectile dysfunction patients (p < 0.05); the two ratios in non-arteriogenic erectile dysfunction patients did not differ from those in the controls (p > 0.05). We conclude that ADMA and SDMA concentrations are significantly higher and L-arginine/ADMA ratio lower in patients who have arteriogenic erectile dysfunction compared with both patients with non-arteriogenic erectile dysfunction and controls. The negative correlation between ADMA and severity of erectile dysfunction is present only in patients with arteriogenic erectile dysfunction. This study supports the importance to always distinguish arteriogenic from non-arteriogenic erectile dysfunction patients to study the complicate erectogenic mechanisms that lead to erectile dysfunction and also to provide potential therapeutic agents for patients with arteriogenic erectile dysfunction. PMID- 22519581 TI - Relating fatty acid composition in human fingertip blood to age, gender, nationality and n-3 supplementation in the Scandinavian population. AB - This study investigated data obtained from whole blood fatty acid (FA) composition of 3476 Norwegian and Swedish individuals, which provided background information including age, gender, nationality and self-motivated n-3 supplement consumption. The aim of this paper was to statistically relate this background information on the subjects to their whole blood FA profile, focusing mainly on the n-3 polyunsaturated FA (PUFA). Results showed that age had significant effects on the content of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in blood lipids for the Norwegian individuals, while n-3 PUFA supplementation had a positive effect on EPA and DHA content in whole blood for the investigated population. Gender differences were also found for individual FA. A correlation also exists with previous studies on the FA profiling of blood lipids, further validating the test procedure. PMID- 22519582 TI - The impact of substrate stiffness and mechanical loading on fibroblast-induced scaffold remodeling. AB - Fibroblasts as many other cells are known to form, contract, and remodel the extracellular matrix (ECM). The presented study aims to gain an insight into how mechanical boundary conditions affect the production of ECM components, their remodeling, and the feedback of the altered mechanical cell environment on these processes. The influence of cyclic mechanical loading (f=1 Hz, 10% axial compression) and scaffold stiffness (E=1.2 and 8.5 kPa) on the mechanical properties of fibroblast-seeded scaffold constructs were investigated in an in vitro approach over 14 days of culture. To do so, a newly developed bioreactor system was employed. While mechanical loading resulted in a clear upregulation of procollagen-I and fibronectin production, scaffold stiffness showed to primarily influence matrix metalloproteinase-1 (MMP-1) secretion and cell-induced scaffold contraction. Higher stiffness of the collagen scaffolds resulted in an up to twofold higher production of collagen-degrading MMP-1. The changes of mechanical parameters like Young's modulus, maximum compression force, and elastic portion of compression force over time suggest that from initially distinct mechanical starting conditions (scaffold stiffness), the construct's mechanical properties converge over time. As a consequence of mechanical loading a shift toward higher construct stiffness was observed. The results suggest that scaffold stiffness has only a temporary effect on cell behavior, while the impact of mechanical loading is preserved over time. Thus, it is concluded that the mechanical environment of the cell after remodeling is depending on mechanical loading rather than on initial scaffold stiffness. PMID- 22519583 TI - An all-gas-phase approach for the fabrication of silicon nanocrystal light emitting devices. AB - We present an all-gas-phase approach for the fabrication of nanocrystal-based light-emitting devices. In a single reactor, silicon nanocrystals are synthesized, surface-functionalized, and deposited onto substrates precoated with a transparent electrode. Devices are completed by evaporation of a top metal electrode. The devices exhibit electroluminescence centered at a wavelength of lambda = 836 nm with a peak external quantum efficiency exceeding 0.02%. This all gas-phase approach permits controlled deposition of dense, functional nanocrystal films suitable for application in electronic devices. PMID- 22519584 TI - Psychosocial wellbeing in the Central and Eastern European transition: an overview and systematic bibliographic review. AB - This paper presents the results of a systematic review of literature on the psychosocial wellbeing of populations in Central and Eastern Europe during the transition period subsequent to the fall of the SovietBloc. A revision of research addressing emotional wellbeing trends in this period and theoretical models was carried in order to verify their validity in the analysis of empirical studies. Hence, a systematic bibliographic review was conducted, aiming to find possible subjective mediators between social variables derived from change sand emotional wellbeing. The results of the review show that subjective mediators such as locus of control,perceived control, self-efficacy beliefs, perceived familial support, and the subjective evaluation of social change explain part of the relationship between macrosocial changes and emotional wellbeing. Results appear coherent with proposed multidimensional models of social change and mental health, although further research should be conducted to determine the specific weight of these phenomena in individual emotional wellbeing. PMID- 22519586 TI - Effects of river-flow regulation on anuran occupancy and abundance in riparian zones. AB - The natural flow regimes of rivers worldwide have been heavily altered through anthropogenic activities, and dams in particular have a pervasive effect on riverine ecosystems. Flow-regulation effects of dams negatively affect species diversity and abundance of a variety of aquatic animals, including invertebrates and fishes. However, the effects on semiaquatic animals are relatively unknown. We conducted anuran calling surveys at 42 study locations along the Broad and Pacolet Rivers in South Carolina to address the potential effects of flow regulation by damming on anuran occupancy and abundance. We estimated occupancy and abundance with Program PRESENCE. Models incorporated distance upstream and downstream from the nearest dam as covariates and urbanization pressure as an alternative stressor. Distance from dam was associated with occupancy of 2 of the 9 anuran species in our analyses and with abundance of 6 species. In all cases, distance downstream from nearest dam was a better predictor of occupancy and abundance than distance upstream from nearest dam. For all but one species, distance downstream from nearest dam was positively correlated with both occupancy and abundance. Reduced occupancy and abundance of anurans likely resulted from downstream alterations in flow regime associated with damming, which can lead to reduced area of riparian wetlands that serve as anuran breeding habitat. Our results showed that damming has a strong negative effect on multiple anuran species across large spatial extents and suggest that flow regulation can affect semiaquatic animals occupying riparian zones. PMID- 22519585 TI - Protonation and concerted proton-electron transfer reactivity of a bis benzimidazolate ligated [2Fe-2S] model for Rieske clusters. AB - A model system for biological Rieske clusters that incorporates bis benzimidazolate ligands ((Pr)bbim)(2-) has been developed ((Pr)bbimH(2) = 4,4 bis(benzimidazol-2-yl)heptane). The diferric and mixed-valence clusters have been prepared and characterized in both their protonated and deprotonated states. The thermochemistry of interconversions of these species has been measured, and the effect of protonation on the reduction potential is in good agreement to that observed in the biological systems. The mixed-valence and protonated congener [Fe(2)S(2)((Pr)bbim)((Pr)bbimH)](Et(4)N)(2) (4) reacts rapidly with TEMPO or p benzoquinones to generate diferric and deprotonated [Fe(2)S(2)((Pr)bbim)(2)](Et(4)N)(2) (1) and 1 equiv of TEMPOH or 0.5 equiv of p benzohydroquinones, respectively. The reaction with TEMPO is the first well defined example of concerted proton-electron transfer (CPET) at a synthetic ferric/ferrous [Fe-S] cluster. PMID- 22519587 TI - Epitope-specific anti-nuclear antibodies are expressed in a mouse model of primary biliary cirrhosis and are cytokine-dependent. AB - Although the hallmark of primary biliary cirrhosis (PBC) is the presence of anti mitochondrial antibodies (AMA), a significant number of patients have anti nuclear antibodies (ANA) directed primarily against two nuclear proteins, gp210 and sp100. In PBC, there are considerable data on the specificity of these anti nuclear antibodies as well as suggestive evidence that antibodies to gp210 predict a poor outcome. However, a further understanding of the significance of these autoantibodies has been hampered by limitations in accessing human subjects in a preclinical or early asymptomatic stage. To overcome this limitation, we have taken advantage of transgenic mice with abrogated transforming growth factor beta signalling in T cells (dnTGF-betaRII) that develop histological features of PBC as well as the same AMA specificity. We studied these mice for serum ANA, including specific autoantibodies against gp210 and sp100. We further examined sera from dnTGF-betaRII mice with concurrent deletions of the genes encoding interleukin (IL)-12p35, IL-12p40, IL-23p19, IL-17, IL-6, interferon (IFN)-gamma or tumour necrosis factor (TNF)-alpha. Sera from all the dnTGF-betaRII mouse lines contained antibodies against gp210 and sp100. Of significance, mice with germline deletions of the genes encoding IL-12p40, IL-23p19, IL-17, IL-6 and TNF alpha had significantly lower titres of anti-gp210 antibodies. These results provide a platform to dissect the mechanisms of gp210 and sp100 autoantibody production in dnTGF-betaRII mice as well as to study the possible role of ANA in the pathophysiology of PBC. PMID- 22519588 TI - Prophylactic and therapeutic efficacies of a selective inhibitor of the immunoproteasome for Hashimoto's thyroiditis, but not for Graves' hyperthyroidism, in mice. AB - Major histocompatibility complex (MHC) class I-restricted T cell epitopes are generated mainly by the immunoproteasome in antigen-presenting cells. Therefore, inhibition of activity of this proteolytic complex molecule is thought to be a potential treatment for cell-mediated autoimmune diseases. We therefore studied the efficacy of an immunoproteasome inhibitor, ONX 0914 (formerly PR-957), for the treatment of autoimmune thyroid diseases, including cell-mediated Hashimoto's thyroiditis and autoantibody-mediated Graves' hyperthyroidism using mouse models. Our data show that ONX 0914 was effective prophylactically and therapeutically at suppressing the degree of intrathyroidal lymphocyte infiltration and, to a lesser degree, the titres of anti-thyroglobulin autoantibodies in non-obese diabetic (NOD)-H2(h4) mice, an iodine-induced autoimmune thyroiditis model. It also inhibited differentiation of T cells to T helper type 1 (Th1) and Th17 cells, effector T cell subsets critical for development of thyroiditis in this mouse strain. In contrast, its effect on the Graves' model was negligible. Although ONX 0914 exerts its immune-suppressive effect through not only suppression of immune proteasome but also other mechanism(s), such as inhibition of T cell differentiation, the present results suggest that the immunoproteasome is a novel drug target in treatment of Hashimoto's thyroiditis in particular and cell mediated autoimmune diseases in general. PMID- 22519589 TI - The effect of gestation and fetal mismatching on the development of autoimmune diabetes in non-obese diabetic mice. AB - The impact of gestation and fetal-maternal interactions on pre-existent autoimmune beta cell destruction is widely unknown. The aim of this study was to investigate the influence of gestation per se and fetal mismatching on the onset of autoimmune diabetes in female non-obese diabetic (NOD) mice. We examined cumulative diabetes frequencies of NOD dams mated to syngeneic NOD, haploidentical CByB6F1/J and fully mismatched C57BL/6J male mice. Pregnancy from NOD males neither increased nor accelerated the diabetes onset of NOD dams (71% by age 28 weeks) compared to unmated female NOD mice (81% by age 28 weeks; P = 0.38). In contrast, delayed diabetes onset was observed when NOD dams were mated at 10 weeks of age with major histocompatibility complex (MHC) haploidentical CByB6F1/J male mice (38% at age 28 weeks; P = 0.01). Mating with fully MHC mismatched C57BL/6J male mice (72% diabetes by age 28 weeks; P = 0.22) or mating with the haploidentical males at the later time-point of age 13 weeks (64% versus 91% in unmated litter-matched controls; P = 0.13) did not delay diabetes significantly in NOD females. Because infusion of haploidentical male mouse splenocytes was found previously to prevent diabetes in NOD mice we looked for, but found no evidence of, persistent chimeric lymphocytes from haploidentical paternal origin within the dams' splenocytes. Gestation per se appears to have no aggravating or ameliorating effects on pre-existent autoimmune beta cell destruction, but pregnancy from MHC partially mismatched males delays diabetes onset in female NOD mice. PMID- 22519590 TI - The role of natural killer (NK) and NK T cells in the loss of tolerance in murine primary biliary cirrhosis. AB - One of the major obstacles in dissecting the mechanism of pathology in human primary biliary cirrhosis (PBC) has been the absence of animal models. Our laboratory has focused on a model in which mice, following immunization with a xenobiotic chemical mimic of the immunodominant autoepitope of the E2 component of pyruvate dehydrogenase complex (PDC-E2), develop autoimmune cholangitis. In particular, following immunization with 2-octynoic acid (a synthetic chemical mimic of lipoic acid-lysine located within the inner domain of PDC-E2) coupled to bovine serum albumin (BSA), several strains of mice develop typical anti mitochondrial autoantibodies and portal inflammation. The role of innate immune effector cells, such as natural killer (NK) cells and that NK T cells, was studied in this model based on the hypothesis that early events during immunization play an important role in the breakdown of tolerance. We report herein that, following in-vivo depletion of NK and NK T cells, there is a marked suppression of anti-mitochondrial autoantibodies and cytokine production from autoreactive T cells. However, there was no change in the clinical pathology of portal inflammation compared to controls. These data support the hypothesis that there are probably multiple steps in the natural history of PBC, including a role of NK and NK T cells in initiating the breakdown of tolerance. However, the data suggest that adaptive autoimmune effector mechanisms are required for the progression of clinical disease. PMID- 22519591 TI - Oral treatment with Hev b 13 prevents experimental arthritis in mice. AB - Hev b 13 is an allergenic esterase obtained from the rubber tree Hevea brasiliensis, which has been shown recently to induce human monocytes to release interleukin (IL)-10 in vitro, and to exert a potent anti-inflammatory effect in vivo. Moreover, Hev b 13 has been shown to reduce clinical signs of inflammation and also histological damage to the distal colon of mice with 2,4,6-trinitrobenze sulphonic acid (TNBS)-induced colitis after its oral administration. The aim of this study was to investigate the effect of Hev b 13 on human mononuclear cells, as well as its therapeutic use in the methylated bovine serum albumin (mBSA) model of antigen-induced arthritis. Five days before the intra-articular challenge, and daily thereafter for 8 days, Hev b 13 was administered by oral gavage. In mice treated with a dose of 0.5 mg/kg of Hev b 13, the severity of oedema, leucocyte infiltration, pannus formation and cartilage erosion were reduced significantly. These findings underscore the anti-inflammatory activity suggested previously for Hev b 13, an activity speculated to be related to its interaction with monocytes/macrophages and the consequent stimulation of IL-10 release and reduction of tumour necrosis factor (TNF) release. The study also opens a wide range of possible applications in the field of immune-mediated inflammatory diseases. PMID- 22519593 TI - Safety and efficacy of icatibant self-administration for acute hereditary angioedema. AB - We evaluated the efficacy and safety of icatibant self-administration in 15 patients with hereditary angioedema (HAE) types I or III, for 55 acute attacks (mostly severe or very severe). Icatibant self-administration was generally effective: first symptom improvement occurred in 5 min-2 h (HAE type I; n = 17) and 8 min-1 h (HAE type III; n = 9) for abdominal attacks and 5-30 min (HAE type I; n = 4) and 10 min-12 h (HAE type III; n = 6) for laryngeal attacks. Complete symptom resolution occurred in 15 min-19 h (HAE type I; n = 8) and 15 min-48 h (HAE type III; n = 9) for abdominal attacks and 5-48 h (HAE type I; n = 3) and 8 48 h (HAE type III; n = 5) for laryngeal attacks. No patient required emergency hospitalization. The only adverse events were mild, spontaneously resolving injection site reactions. Patients reported that carrying icatibant with them gave them greater confidence in managing their condition. PMID- 22519592 TI - Up-regulation of fas and fasL pro-apoptotic genes expression in type 1 diabetes patients after autologous haematopoietic stem cell transplantation. AB - Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by T cell mediated destruction of pancreatic beta cells, resulting in insulin deficiency and hyperglycaemia. Recent studies have described that apoptosis impairment during central and peripheral tolerance is involved in T1D pathogenesis. In this study, the apoptosis-related gene expression in T1D patients was evaluated before and after treatment with high-dose immunosuppression followed by autologous haematopoietic stem cell transplantation (HDI-AHSCT). We also correlated gene expression results with clinical response to HDI-AHSCT. We observed a decreased expression of bad, bax and fasL pro-apoptotic genes and an increased expression of a1, bcl-x(L) and cIAP-2 anti-apoptotic genes in patients' peripheral blood mononuclear cells (PBMCs) compared to controls. After HDI-AHSCT, we found an up regulation of fas and fasL and a down-regulation of anti-apoptotic bcl-x(L) genes expression in post-HDI-AHSCT periods compared to pre-transplantation. Additionally, the levels of bad, bax, bok, fasL, bcl-x(L) and cIAP-1 genes expression were found similar to controls 2 years after HDI-AHSCT. Furthermore, over-expression of pro-apoptotic noxa at 540 days post-HDI-AHSCT correlated positively with insulin-free patients and conversely with glutamic acid decarboxylase autoantibodies (GAD65) autoantibody levels. Taken together, the results suggest that apoptosis-related genes deregulation in patients' PBMCs might be involved in breakdown of immune tolerance and consequently contribute to T1D pathogenesis. Furthermore, HDI-AHSCT modulated the expression of some apoptotic genes towards the levels similar to controls. Possibly, the expression of these apoptotic molecules could be applied as biomarkers of clinical remission of T1D patients treated with HDI-AHSCT therapy. PMID- 22519594 TI - CD137 deficiency does not affect development of airway inflammation or respiratory tolerance induction in murine models. AB - The co-stimulatory molecule CD137 (4-1BB) plays a crucial role in the development and persistence of asthma, characterized by eosinophilic airway inflammation, mucus hypersecretion, airway hyperreactivity, increased T helper type 2 (Th2) cytokine production and serum immunoglobulin (Ig)E levels. We have shown previously that application of an agonistic CD137 monoclonal antibody (mAb) prevented and even reversed an already established asthma phenotype. In the current study we investigated whether deficiency of the CD137/CD137L pathway affects the development of allergic airway inflammation or the opposite immune reaction of respiratory tolerance. CD137-/- and wild-type (WT) mice were sensitized and challenged with the model allergen ovalbumin (OVA) and analysed for the presence of allergic disease parameters (allergy protocol). Some animals were tolerized by mucosal application of OVA prior to transferring the animals to the allergy protocol to analyse the effect of CD137 loss on tolerance induction (tolerance protocol). Eosinophilic airway inflammation, mucus hypersecretion, Th2 cytokine production and elevated allergen-specific serum IgE levels were increased equally in CD137-/- and WT mice. Induction of tolerance resulted in comparable protection from the development of an allergic phenotype in both mouse strains. In addition, no significant differences could be identified in CD4+, CD8+ and forkhead box protein 3 (FoxP3+) regulatory T cells, supporting the conclusion that CD137-/- mice show equal Th2-mediated immune responses compared to WT mice. Taken together, CD137-/- mice and WT mice develop the same phenotype in a murine model of Th2-mediated allergic airway inflammation and respiratory tolerance. PMID- 22519595 TI - Increased plasma LIGHT levels in patients with atopic dermatitis. AB - LIGHT [the name of which is derived from 'homologous to lymphotoxins, exhibits inducible expression, competes with herpes simplex virus glycoprotein D for herpes simplex virus entry mediator (HVEM), and expressed by T lymphocytes'], is a member of the tumour necrosis factor superfamily that is involved in various inflammatory diseases. We aimed to estimate the relevance of plasma LIGHT levels as a biomarker for atopic dermatitis (AD). In order to understand the putative role of LIGHT in AD pathogenesis, we also investigate the effects of LIGHT on a monocytic cell line, human acute monocytic leukaemia cell line (THP-1). We examined plasma LIGHT levels, total serum IgE, serum value of CCL17 and peripheral blood eosinophil counts in patients with AD and healthy subjects. The effects of LIGHT on activation and apoptosis in THP-1 cells were also investigated. The plasma concentrations of LIGHT in AD patients were significantly higher than those in healthy individuals and the concentrations decreased as the symptoms were improved by treatment. The LIGHT plasma concentrations correlated with IgE levels and the Severity Scoring of AD (SCORAD) index. In addition, LIGHT stimulation increased expression of CD86 and induced production of interleukin-1beta in THP-1 cells. Apoptosis was inhibited, the Bcl 2 level increased and the caspase-3 level decreased in THP-1 cells stimulated with LIGHT, compared to unstimulated control cells. These results suggest that plasma LIGHT levels may be one of the promising biomarkers for AD. PMID- 22519596 TI - Cordycepin as a sensitizer to tumour necrosis factor (TNF)-alpha-induced apoptosis through eukaryotic translation initiation factor 2alpha (eIF2alpha)- and mammalian target of rapamycin complex 1 (mTORC1)-mediated inhibition of nuclear factor (NF)-kappaB. AB - Cordycepin (3'-deoxyadenosine) is one of the major bioactive substances produced by Cordyceps militaris, a traditional medicinal mushroom. Cordycepin possesses several biological activities, including both pro-apoptotic and anti-apoptotic properties. In the present report, we investigated an effect of cordycepin on the survival of cells exposed to tumour necrosis factor (TNF)-alpha. We found that subtoxic doses of cordycepin increased susceptibility of cells to TNF-alpha induced apoptosis. It was associated with suppression of nuclear factor-kappaB (NF-kappaB), a major prosurvival component involved in TNF-alpha signalling. The adenosine transporter and A3 adenosine receptor, but not A1 and A2 adenosine receptors, mediated both anti-NF-kappaB and pro-apoptotic effects. We found that cordycepin had the potential to phosphorylate eukaryotic translation initiation factor 2alpha (eIF2alpha) and that activation of eIF2alpha mimicked the suppressive effect of cordycepin on the NF-kappaB pathway. Furthermore, activation of eIF2alpha sensitized cells to TNF-alpha-induced apoptosis. To identify molecular events downstream of eIF2alpha, the role of mammalian target of rapamycin complex 1 (mTORC1) was examined. Selective activation of 3eIF2alpha, as well as treatment with cordycepin, caused phosphorylation of mTORC1. Rapamycin, an inhibitor of mTORC1, significantly reversed the suppressive effects of eIF2alpha on NF-kappaB. These results suggest that cordycepin sensitizes cells to TNF-alpha-induced apoptosis, at least in part, via induction of the eIF2alpha mTORC1 pathway and consequent suppression of NF-kappaB. PMID- 22519598 TI - The need for calcium channels in cell proliferation. AB - Both increases in the basal cytosolic calcium concentration ([Ca2+]cyt) and [Ca2+]cyt transients play a major role in cell cycle progression, cell proliferation and division. Calcium influx and release from endoplasmic reticulum are the major routes involved in the variations in [Ca2+]cyt and past studies have clearly shown that calcium influx controls cell growth and proliferation in several cell types. Furthermore, various studies in the past thirty years have demonstrated that calcium channel expression levels, as well as cell specific expression, were determinant in these physiological processes. Cell proliferation is directly linked to cell cycle progression, and again, it became evident that calcium channel expression interferes here. It is also clear that calcium influx and cell proliferation relationship can be uncoupled in transformed and cancer cells, resulting in an external calcium-independent proliferation. Other divalent cations such as iron and zinc involved in cell proliferation permeating some calcium channels may interfere in this cellular process. This patent review is focused on transient receptor potential and ORAI channels, and, as calcium influx regulates several other transduction pathways, we assume that specific signalization complexes are needed to trigger activation of proliferation and cell division in mammalian cells. PMID- 22519599 TI - General asymmetric hydrogenation of 2-alkyl- and 2-aryl-substituted quinoxaline derivatives catalyzed by iridium-difluorphos: unusual halide effect and synthetic application. AB - A general asymmetric hydrogenation of a wide range of 2-alkyl- and 2-aryl substituted quinoxaline derivatives catalyzed by an iridium-difluorphos complex has been developed. Under mild reaction conditions, the corresponding biologically relevant 2-substituted-1,2,3,4-tetrahydroquinoxaline units were obtained in high yields and good to excellent enantioselectivities up to 95%. With a catalyst ratio of S/C = 1000 and on a gram scale, the catalytic activity of the Ir-difluorphos complex was maintained showing its potential value. Finally, we demonstrated the application of our process in the synthesis of compound (S)-9, which is an inhibitor of cholesteryl ester transfer protein (CETP). PMID- 22519600 TI - beta-lactam pharmacokinetics and pharmacodynamics in critically ill patients and strategies for dose optimization: a structured review. AB - 1. Infections and related sepsis are two of the most prevalent issues in the care of critically ill patients, with mortality as high as 70%. Appropriate antibiotic selection, as well as adequate dosing, is important to improve the clinical outcome for these patients. 2. beta-Lactams are the most common antibiotic class used in critically ill sepsis patients because of their broad spectrum of activity and high tolerability. beta-Lactams exhibit time-dependent antibacterial activity. Therefore, concentrations need to be maintained above the minimum inhibitory concentration (MIC) of pathogenic bacteria. beta-Lactams are hydrophilic antibiotics with small distribution volumes similar to extracellular water and are predominantly excreted through the renal system. 3. Critically ill patients experience a myriad of physiological changes that result in changes in the pharmacokinetics (PK) of hydrophilic drugs such as beta-lactams. A different approach to dosing with beta-lactams may increase the likelihood of positive outcomes considering the pharmacodynamics (PD) of beta-lactams, as well as the changes in PK in critically ill patients. 4. The present review describes the strategies for dose optimization of beta-lactams in critically ill patients in line with the PK and PD of these drugs. PMID- 22519597 TI - Matrix metalloproteinases in diabetic retinopathy: potential role of MMP-9. AB - INTRODUCTION: Diabetic retinopathy remains one of the most feared complications of diabetes. Despite extensive research in the field, the molecular mechanism responsible for the development of this slow progressing disease remains unclear. In the pathogenesis of diabetic retinopathy, mitochondria are damaged and inflammatory mediators are elevated before the histopathology associated with the disease can be observed. Matrix metalloproteinases (MMPs) regulate a variety of cellular functions including apoptosis and angiogenesis. Diabetic environment stimulates the secretion of several MMPs that are considered to participate in complications, including retinopathy, nephropathy and cardiomyopathy. Patients with diabetic retinopathy and also animal models have shown increased MMP-9 and MMP-2 in their retina and vitreous. Recent research has shown that MMPs have dual role in the development of diabetic retinopathy; in the early stages of the disease (pre-neovascularization), MMP-2 and MMP-9 facilitate the apoptosis of retinal capillary cells, possibly via damaging the mitochondria, and in the later phase, they help in neovascularization. AREAS COVERED: This article reviews the literature to evaluate the role of MMPs, especially MMP-9, in the development of diabetic retinopathy, and presents existing evidence that the inhibitors targeted toward MMP-9, depending on the duration of diabetes at the times their administration could have potential to prevent the progression of this blinding disease, and protect the vision loss. EXPERT OPINION: Inhibitors of MMPs could have dual role: in the early stages of the diseases, inhibit capillary cell apoptosis, and if the disease has progressed to the angiogenic stage, inhibit the growth of new vessels. PMID- 22519601 TI - Botulinum neurotoxin A impairs neurotransmission following retrograde transynaptic transport. AB - The widely used botulinum neurotoxin A (BoNT/A) blocks neurotransmission via cleavage of the synaptic protein SNAP-25 (synaptosomal-associated protein of 25 kDa). Recent evidence demonstrating long-distance propagation of SNAP-25 proteolysis has challenged the idea that BoNT/A remains localized to the injection site. However, the extent to which distant neuronal networks are impacted by BoNT/A retrograde trafficking remains unknown. Importantly, no studies have addressed whether SNAP-25 cleavage translates into structural and functional changes in distant intoxicated synapses. Here we show that the BoNT/A injections into the adult rat optic tectum result in SNAP-25 cleavage in retinal neurons two synapses away from the injection site, such as rod bipolar cells and photoreceptors. Retinal endings displaying cleaved SNAP-25 were enlarged and contained an abnormally high number of synaptic vesicles, indicating impaired exocytosis. Tectal injection of BoNT/A in rat pups resulted in appearance of truncated-SNAP-25 in cholinergic amacrine cells. Functional imaging with calcium indicators showed a clear reduction in cholinergic-driven wave activity, demonstrating impairments in neurotransmission. These data provide the first evidence for functional effects of the retrograde trafficking of BoNT/A, and open the possibility of using BoNT/A fragments as drug delivery vehicles targeting the central nervous system. PMID- 22519602 TI - Hemiplegia and thrombolysis. AB - BACKGROUND AND PURPOSE: Hemiplegia at stroke onset may be considered a contraindication for thrombolytic therapy. We describe the outcome of patients with ischaemic stroke presenting with hemiplegia and treated with intravenous alteplase (tPA). METHODS: All patients treated with tPA for acute ischaemic stroke between 1995 and 2010 were prospectively recorded in the Helsinki Stroke Thrombolysis Registry. Patients with basilar artery occlusion (BAO) were excluded. Hemiplegia was defined as no visible voluntary movement on ipsilateral arm and leg. RESULTS: Of all treated patients (n = 1579), we excluded those with BAO (n = 152). Of remaining 1427 patients, 81 (6%) had hemiplegia at baseline. By 24 h, three had died and 20 retained their total hemiplegia. At day 7, a further nine had died, and 10 had persistent hemiplegia. A good 3-month outcome, modified Rankin Scale (mRS, 0-2), was observed in 23%, independence in ambulatory function (mRS 3) in further 16%, while 9% were bedridden and 20% dead. A wide clinical spectrum of neurological deficits coexisted with hemiplegia. With advanced age, more neurological functions lost, and with early radiological signs, the prognosis of patients with hemiplegia deteriorated. With combined fixed eye deviation (n = 23), half were either bedridden (n = 3) or dead (n = 9) by 3 months, and fatal intracerebral haemorrhage were common (n = 5). CONCLUSIONS: Hemiplegia at presentation should not prevent thrombolytic therapy by itself, as limb movements are likely to return, and two of five thrombolysis-treated patients will walk independently by 3 months. With combined fixed eye deviation, the outcome is poorer and haemorrhagic complications are common. PMID- 22519603 TI - Update on EPA's ToxCast program: providing high throughput decision support tools for chemical risk management. AB - The field of toxicology is on the cusp of a major transformation in how the safety and hazard of chemicals are evaluated for potential effects on human health and the environment. Brought on by the recognition of the limitations of the current paradigm in terms of cost, time, and throughput, combined with the ever increasing power of modern biological tools to probe mechanisms of chemical biological interactions at finer and finer resolutions, 21st century toxicology is rapidly taking shape. A key element of the new approach is a focus on the molecular and cellular pathways that are the targets of chemical interactions. By understanding toxicity in this manner, we begin to learn how chemicals cause toxicity, as opposed to merely what diseases or health effects they might cause. This deeper understanding leads to increasing confidence in identifying which populations might be at risk, significant susceptibility factors, and key influences on the shape of the dose-response curve. The U. S. Environmental Protection Agency (EPA) initiated the ToxCast, or "toxicity forecaster", program 5 years ago to gain understanding of the strengths and limitations of the new approach by starting to test relatively large numbers (hundreds) of chemicals against an equally large number of biological assays. Using computational approaches, the EPA is building decision support tools based on ToxCast in vitro screening results to help prioritize chemicals for further investigation, as well as developing predictive models for a number of health outcomes. This perspective provides a summary of the initial, proof of concept, Phase I of ToxCast that has laid the groundwork for the next phases and future directions of the program. PMID- 22519604 TI - Understanding the mental lexicon through neglect dyslexia: a study on compound noun reading. AB - The present study employs neglect dyslexia (ND) as an experimental model to study compound-word processing; in particular, it investigates whether compound constituents are hierarchically organized at mental level and addresses the possibility of whole-word representation. Seven Italian-speaking patients suffering from ND participated in a word naming task. Both left-headed (pescespada, swordfish) and right-headed (astronave, spaceship) Italian compound nouns were used as stimuli. Non-existent compounds, which were generated by substituting the leftmost constituent of a compound with an orthographically similar word (e.g., *pestespada, *plaguesword), were also employed. A significant headedness effect emerged in the group analysis: patients read left-headed compounds better than right-headed compounds. A significant lexicality effect was also found: the participants read real compounds better than their non-existent compound pairs. Moreover, logit mixed-effects analyses indicated a left-hand constituent frequency effect. Results are discussed in terms of hierarchical representation of compounds and direct access to compound lemma nodes. PMID- 22519606 TI - Improving quality in healthcare--current trends and innovations. PMID- 22519605 TI - Proximity to HIV is associated with a high rate of HIV testing among men who have sex with men living in Douala, Cameroon. AB - In low- and middle-income countries, men who have sex with men (MSM) are 19 times more likely to be HIV positive compared with background populations. Criminalisation and social rejection of homosexuality in most sub-Saharan African countries reinforce stigma and exclude MSM from prevention activities, including HIV testing. This paper's purpose is to identify factors associated with never having been HIV tested (NHT), among a sample of Cameroonian MSM. In 2008, a community-based study was conducted in Douala, the economic capital city of Cameroon, by a local NGO Alternatives-Cameroun, recruiting participants through the snowball technique and administering a questionnaire during face-to-face interviews. Proximity to HIV was investigated according to the following criteria: knowing at least one person living with HIV and having been exposed to HIV prevention interventions. NHT was defined as reporting to have never been HIV tested. A logistic regression was used to identify factors associated with NHT. Among the 165 MSM of our study group who reported that they were not HIV positive, 19% reported NHT. Factors independently associated with NHT were as follows: being younger, being Muslim, not having a steady male partner, not knowing any person living with HIV and never having been exposed to HIV prevention interventions. In this MSM population, a small proportion reported that they had never been HIV tested and among these, the percentage was higher among individuals not in proximity to HIV. Despite the hostile context of sub Saharan African countries towards MSM, local and national HIV testing campaigns to date may have played a substantial role in raising HIV awareness in the MSM population living in Douala, and peer-based counselling may have educated those in contact with Alternatives-Cameroun regarding the positive value of HIV testing. This result is a further argument for continuing community-based prevention and extending it to difficult-to-reach MSM. PMID- 22519607 TI - Patient transfers in Australia: implications for nursing workload and patient outcomes. AB - AIM: To discuss the impact of patient transfers on patient outcomes and nursing workload. BACKGROUND: Many patient transfers are essential and occur in response to patients' clinical changes. However, increasingly within Australia transfers are performed in response to reductions in bed numbers, resulting in 'bed block'. EVALUATION: A discussion of the literature related to inpatient transfers, nursing workload and patient safety. KEY ISSUES: Measures to increase patient flow such as short-stay units may result in an increase in patient transfers and nursing workload. Frequent patient transfers may also increase the risk of medication incidents, health-care acquired infections and patient falls. CONCLUSIONS: The continuing demand for health care has led to a reactionary bed management system that, in an attempt to accommodate patients, has resulted in increased transfers between wards. This can have a negative effect on nursing workload and affect patient outcomes. IMPLICATIONS FOR NURSING MANAGEMENT: High nursing workload is cited as one reason for nurses leaving the profession. Reductions in non-essential transfers may reduce nurse workload, improve patient outcomes and enhance continuity of patient care. PMID- 22519608 TI - Nursing accreditation system and patient safety. AB - AIMS: This study investigated whether nursing accreditation level affects patient safety. BACKGROUND: The nursing accreditation system evaluates the capabilities of nursing professionals in Taiwan. While this system has been in place for years, few studies have investigated whether nursing accreditation level is associated with patient safety indicators. This study can help in understanding how nursing capabilities affect patient safety and can subsequently contribute to improvements in patient safety. METHODS: This study adopted a cross-sectional research design using questionnaires to collect responses from nurses working in two major medical centres in northern Taiwan. Regression analyses were conducted to test the study hypothesis. RESULTS: The analytical results show that nursing accreditation level is positively related to patient safety indicators. CONCLUSION: Health services managers should encourage nurses to advance their knowledge, skills, and professional capabilities because these may be positively related to patient safety. IMPLICATIONS FOR NURSING MANAGEMENT: Nursing managers who seek to improve patient safety should consider encouraging nurses to advance their accreditation level. PMID- 22519609 TI - The influence of a person-centred psychosocial unit climate on satisfaction with care and work. AB - AIM: To describe nurses' satisfaction with care and work and to explore the extent to which a person-centred unit climate influenced this satisfaction. BACKGROUND: Although the concept of person-centred care is used to describe high quality care, there is a shortage of studies exploring the relationship between person-centredness and nurses' satisfaction with care and work in acute care settings. METHODS: Registered nurses within a university hospital in Sweden (n = 206) completed the Satisfaction with Nursing Care and Work Assessment Scale and the Person-centred Climate Questionnaire. The data collected was analysed using descriptive and analytical statistics. DESIGN: Cross-sectional explorative study. RESULTS: The majority of respondents were satisfied with the care and work situation. Nurses with more than 9 years of work experience were more satisfied with care and work, and there were a significant association between a person centred psychosocial climate of units and nurses' satisfaction with care and work. CONCLUSIONS: This study provided evidence for a significant association between person-centredness and the satisfaction with care and work of nurses in acute care environments. IMPLICATIONS FOR NURSING MANAGEMENT: Promoting and implementing a person-centred philosophy of care can be one way to improve nurses' satisfaction with care and work. PMID- 22519610 TI - Avoidable interruptions during drug administration in an intensive rehabilitation ward: improvement project. AB - AIMS: To record the frequency of interruptions and their causes, to identify 'avoidable' interruptions and to build an improvement project to reduce 'avoidable' interruptions. BACKGROUND: In Italy each year 30,000-35,000 deaths per year are attributed to health-care system errors, of which 19% are caused by medication errors. The factors that contribute to drug management error also include interruptions and carelessness during treatment administration. METHODS: A descriptive study design was used to record the frequency of interruptions and their causes and to identify 'avoidable' interruptions in an intensive rehabilitation ward in Northern Italy. A data collection grid was used to record the data over a 6-month period. RESULTS: A total of 3000 work hours were observed. During the study period 1170 interruptions were observed. The study identified 14 causes of interruption. CONCLUSIONS: The study shows that of the 14 cases of interruptions at least nine can be defined as 'avoidable'. An improvement project has been proposed to reduce unnecessary interruptions and distractions to avoid making errors. IMPLICATIONS FOR NURSING MANAGEMENT: An additional useful step to reduce the incidence of treatment errors would be to implement the use of a single patient medication sheet for the recording of drug prescription, preparation and administration and also the incident reporting. PMID- 22519611 TI - Paradoxical effects of a hospital-based, multi-intervention programme aimed at reducing medication round interruptions. AB - AIM: The main aim of the present study was to evaluate interruptions that occurred during medication rounds within a hospital-based, multi-intervention programme. BACKGROUND: There are no standardized ways to reduce medication interruptions during medication rounds and no guidelines or standards on the use of tabards during medication rounds. MATERIALS AND METHODS: In 2006, a preliminary baseline evaluation (T0) was conducted at the hospital level observing the occurrence of interruptions during medication rounds in daily practice. Subsequently, a hospital-based policy for a multi-intervention medication round programme was implemented at of the beginning of 2008 (T1). After 18 months, an evaluation of the frequency of interruptions was repeated (T2). RESULTS: At T0, 298 interruptions were observed for 945 medications administered, or one for every 3.2 medications given. At T2, 385 interruptions were observed for 895 medications given, an interruption for every 2.3 medications administered (P = 0.041). At T0, the mean interruption duration per medication round was 10.48 min whereas at T2 it was 5.08 min. Patient interruptions were reduced (26.5-14.0%, P = 0.05); in spite of this effect, staff member interruptions increased (15.8-40.5%, P = 0.01). CONCLUSIONS: With the implementation of the multi-intervention programme, the interruptions changed their pattern. While wearing the red tabard was paradoxically effective with patients, it was ineffective with other staff members. IMPLICATIONS FOR NURSING MANAGEMENT: Before introducing new strategies, an evaluation of their appropriateness with regard to the culture of the patients and nurses is recommended: in the present study, patients seem to have considered the warning message worn by nurses as mainly intended for them. PMID- 22519612 TI - Weathering the storm: nurses' satisfaction with a mobile admission nurse service. AB - AIM: To evaluate nurses' satisfaction with, and perceptions of, a practice innovation introducing a Mobile Admission Nurse service. BACKGROUND: Staff nurses identified that the admission process, while crucial to initiating safe and appropriate acute care, can be disruptive and interfere with care in progress. A pilot project implementing the role of a Mobile Admission Nurse was introduced to address this need. METHOD: A self-developed web-based survey was administered to a convenience sample of 104 RNs who had used the services during the pilot project. RESULTS: Staff nurses (n = 78) reported a chaotic, demanding work environment within which the admission process disrupts the flow of care. The Mobile Admission Nurse helped them in 'weathering the storm', which was the overarching theme that emerged during data analysis. CONCLUSIONS: Having an admission nurse complete the admission process steadied workflow processes for nurses. Improved patient safety and increased staff and family satisfaction were also reported. The strongly positive feedback led to expansion of the service. IMPLICATIONS FOR NURSING MANAGEMENT: Proactively redesigning work processes, using a structured theoretical model such as the (Plan-Do-Study-Act) PDSA approach, may improve outcomes in a chaotic practice environment. PMID- 22519613 TI - The 'Releasing Time to Care--the Productive Ward' programme: participants' perspectives. AB - AIM: The aim of this study was to explore the perceptions of nursing staff concerning the implementation of the 'Releasing Time to Care - the Productive Ward' programme in a specialist cardiothoracic hospital. BACKGROUND: The 'Releasing Time to Care - the Productive Ward' programme uses the 'lean' philosophy originally developed in the Japanese motor industry to improve the efficiency of hospital wards. Its aim is to increase the proportion of time that nurses are able to spend in direct patient care. METHOD: This study used a descriptive qualitative method with a sample size of four nurses and two health care support workers. Thematic analysis of the interview transcripts was undertaken using the procedure developed by Burnard. RESULTS: Thematic content analysis identified five major themes: starting to implement the programme, anxiety and defensiveness, the importance of leadership and communication, challenges, and learning and personal development. CONCLUSION: Overall, the programme had a positive impact on both the wards studied. Challenges that were identified included the need to sustain momentum once the initial enthusiasm had waned. IMPLICATIONS FOR NURSING MANAGEMENT: This study highlighted the importance of key transformational leadership skills at ward manager level, such as the ability to inspire nurses to approach old problems in new ways, in the implementation of the 'Releasing Time to Care - the Productive Ward' programme. PMID- 22519614 TI - Speaking up, being heard: registered nurses' perceptions of workplace communication. AB - AIMS: The aim of the present study was to explore nurses' perceptions of their own ability to speak up and be heard in the workplace. BACKGROUND: Nurses are central to patient care and patient safety in hospitals. Their ability to speak up and be heard greatly impacts their own work satisfaction, team work as well as patient safety. METHOD: The present study utilized a qualitative approach, consisting of focus group interviews of 33 registered nurses (RNs), in staff or management positions from a variety of healthcare settings in California, USA. Data were analysed using thematic content analysis. RESULTS: Findings were organized into three categories: influences on speaking up, transmission and reception of a message and outcomes or results. The present study supported the importance of the manager in setting the culture of open communication. IMPLICATIONS FOR NURSE MANAGERS: It is anticipated that findings from the present study may increase understandings of nurse views of communication within healthcare settings. The study highlights the importance of nurse managers in creating the communication culture that will allow nurses to speak up and be heard. These open communication cultures lead to better patient care, increased safety and better staff satisfaction. PMID- 22519615 TI - Does nursing leadership affect the quality of care in the community setting? AB - AIM: To examine perceptions about how nursing leadership affects quality of care in the community setting. BACKGROUND: Quality care is considered an essential component of nursing work and recent policy has emphasized the role of leadership in meeting the quality agenda. As shifting the balance of nursing care from the hospital to the community occurs in the UK, there is an imperative to confirm more effectively the quality of care that patients and families receive from nurses working in the community. METHODS: A qualitative study involving community nurse leaders (n = 12) and community nurses (n = 27) in semi-structured individual interviews (n = 31) and three focus groups (n = 13). RESULTS: Tensions exist between 'leading' for quality care and 'delivering' for quality care. Organisational decision making is challenged by limited measures of quality of care in the diverse roles of community nursing. CONCLUSIONS: Frontline community nurses and nurse leaders need to articulate how they intend quality of nursing care to be appreciated and actively indicate ways to show this. IMPLICATIONS FOR NURSING MANAGEMENT: Mechanisms to monitor patient safety, a key aspect of the policy agenda for quality care and other technical aspects of care are important for nurse leaders to develop with frontline community nurses. PMID- 22519616 TI - Measuring the impact of the advanced practitioner role: a practical approach. AB - AIM: This paper aims to illuminate difficulties in evaluating the advanced practitioner role and to offer a practical solution. BACKGROUND: The advanced practice role has been part of the workforce strategy in the Northwest of England since 2005. However capturing hard evidence of the impact of this role has been problematic. Current restrictions on resources require the provision of evidence of the value of roles and services. EVALUATION: Critical analysis of literature has identified challenges in evaluating the advanced practice role. The case study design takes account of current policy initiatives, notably QIPP. KEY ISSUES: There is no common approach to evaluating the role of advanced practitioners. The case study has the potential to be a useful tool to organise evidence of the impact of advanced practitioner roles. CONCLUSIONS: Advanced practitioners need to have appropriate knowledge and skills to provide evidence of the impact of their role. There is potential for this work to be applied to other roles across the NHS. IMPLICATIONS FOR NURSING MANAGEMENT: Managers need to work in partnership with workforce planners and educationalists to support advanced practitioners to utilise their skills in methods of providing evidence that they do work of value. Clear strategic direction for advanced practitioners is advised as part of the workforce strategy. PMID- 22519617 TI - Assessing RN-to-RN peer review on clinical units. AB - AIM: The primary purpose of this study was to measure informal registered nurse (RN)-to-RN peer review (defined as collegial communication about the quality of nursing care) at the work-unit level. METHODS: Survey design with cluster sampling of 28 hospital or ambulatory care units (n = 541 respondents). Results were compared with existing patient safety and satisfaction data. A chi-squared test was used to compare responses against nurse characteristics. RESULTS: Nurses agreed that RN-to-RN peer review takes place on their units, but no correlation with patient safety and satisfaction data was found. Misunderstandings about the meaning of peer review were evident. Open-ended comments revealed barriers to peer review: fear of retribution, language barriers and lack of professionalism. CONCLUSIONS: Nurses need clarification of peer review. Issues with common language in a professional environment need to be addressed and nurses can learn collaboration from each other's cultures. IMPLICATIONS FOR NURSING MANAGEMENT: Managers should support RN-to-RN peer review on clinical units. Methods used here may be useful to assess current departmental nurse peer review. PMID- 22519618 TI - Does clinical supervision promote medical-surgical nurses' well-being at work? A quasi-experimental 4-year follow-up study. AB - AIM: The aim of the present paper is to report results of a quasi-experimental study exploring the effects of clinical supervision (CS) on the development of medical-surgical nurses' well-being at work over a 4-year period. BACKGROUND: Effective workplace interventions are needed to prevent stress and burnout. More robust scientific evidence is needed to confirm the restorative effects of CS in nursing. METHODS: A questionnaire survey on the perceptions of work and health was conducted in 2003 and 2007 on 14 units of a Finnish university hospital where 19 CS group processes had been completed between 2004 and 2007. RESULTS: Improvement in job resources as well as reduction in professional inefficacy and psychological distress were found among nurses who received effective CS (n = 41), but were not present among the nurses who found their CS less effective (n = 43) or who did not attend CS (n = 82). CONCLUSIONS: The results provide robust evidence for the positive effects of CS on medical-surgical nurses' well-being at work. IMPLICATIONS FOR NURSING MANAGEMENT: Stress is a developmental challenge in the professional growth of individual nurses. One option for management to sustain nurses' well-being at work is to develop a learning organization in the workplace making use of CS. PMID- 22519619 TI - Measuring tele-ICU impact: does it optimize quality outcomes for the critically ill patient? AB - AIMS: To determine the relationship between tele-ICU (intensive care unit) implementations and improvement in quality measures and patient outcomes. BACKGROUND: Tele-ICUs were designed to leverage scarce critical-care experts and promised to improve patient quality. EVALUATION: Abstracts and peer-reviewed articles were reviewed to identify the associations between tele-ICU programmes and clinical outcomes, cost savings, and customer satisfaction. KEY ISSUES: Few peer-reviewed studies are available and many variables in each study limit the ability to associate study conclusions to the overall tele-ICU programme. Further research is required to explore the impact of the tele-ICU on patient/family satisfaction. Research findings are highly dependent upon the level of ICU acceptance. CONCLUSIONS: The tele-ICU, in collaboration with the ICU team, can be a valuable tool for the enhancement of quality goals although the ability to demonstrate cost savings is extremely complex. Studies clearly indicate that tele ICU nursing vigilance can enhance patient safety by preventing potential patient harm. IMPLICATIONS FOR NURSING MANAGEMENT: Nursing managers and leaders play a vital part in optimizing the quality role of the tele-ICU through supportive modelling and the maximization of ICU integration. PMID- 22519620 TI - Re: Overcoming ignorance and stigma relating to intellectual disability in healthcare: a potential solution. PMID- 22519621 TI - Integrated platform for proteome profiling with combination of microreversed phase based protein and peptide separation via online solvent exchange and protein digestion. AB - An online integrated platform for proteome profiling was established, with the combination of protein separation by microreversed phase liquid chromatography (MURPLC), online acetonitrile (ACN) removal, and pH adjustment by a hollow fiber membrane interface (HFMI), online digestion by an immobilized enzymatic microreactor (IMER), as well as peptide separation and proteins identification by MURPLC or nano-RPLC-electrospray ionization tandem mass spectrometry (MURPLC-ESI MS/MS). To evaluate the performance of such a platform, a three-protein mixture with mass ranging from 5 to 500 ng was analyzed automatically. Compared to the offline counterpart, although similar protein sequence coverages were obtained by the integrated platform, the signal intensity of total ion chromatogram was improved by almost 4 times. In addition, such an integrated platform was further applied for the analysis of extracted proteins from rat brain. Compared to the results obtained by offline counterpart and traditional MudPIT approach under similar conditions, by the integrated platform, the identified protein group number was comparable, but the analysis time was shortened to less than half of that taken by the traditional approaches. All these results demonstrated that our developed integrated platform might offer a promising tool for high-throughput and large-scale profiling of proteomes. PMID- 22519622 TI - Synthesis, crystal structure, and luminescent properties of 2-(2,2,2 trifluoroethyl)-1-indone lanthanide complexes. AB - A new beta-diketone, 2-(2,2,2-trifluoroethyl)-1-indone (TFI), which contains a trifluorinated alkyl group and a rigid indone group, has been designed and employed for the synthesis of two series of new TFI lanthanide complexes with a general formula [Ln(TFI)(3)L] [Ln = Eu, L = (H(2)O)(2) (1), bpy (2), and phen (3); Ln = Sm, L = (H(2)O)(2) (4), bpy (5), and phen (6); bpy = 2,2'-bipyridine, phen = 1,10-phenanthroline]. X-ray crystallographic analysis reveals that complexes 1-6 are mononuclear, with the central Ln(3+) ion eight-coordinated by six oxygen atoms furnished by three TFI ligands and two O/N atoms from ancillary ligand(s). The room-temperature photoluminescence (PL) spectra of complexes 1-6 show strong characteristic emissions of the corresponding Eu(3+) and Sm(3+) ions, and the substitution of the solvent molecules by bidentate nitrogen ligands essentially enhances the luminescence quantum yields and lifetimes of the complexes. PMID- 22519623 TI - Coronary sinus lead fragmentation and migration. AB - We report the case of a patient with ischemic cardiomyopathy who several years before underwent cardiac resynchronization therapy. He was admitted for surgical revision of the system due to coronary sinus lead failure. Percutaneous extraction of the lead was performed but an unusual complication related to the damaged lead occurred with relatively positive outcomes. PMID- 22519625 TI - [Foreword. Invasive aspergillosis: diagnosis and therapy in stationary and ambulatory venues]. PMID- 22519624 TI - Subclinical endothelial dysfunction and low-grade inflammation play roles in the development of erectile dysfunction in young men with low risk of coronary heart disease. AB - The purpose of this study is to investigate the possible underlying pathogenesis of erectile dysfunction(ED) in young men with low risk of coronary heart disease and no well-known aetiology. To conduct this study, 122 patients with ED under the age of 40 were enrolled, along with 33 age-matched normal control subjects. The patients with ED had significantly higher levels of systolic blood pressure (SBP), total cholesterol and triglyceride, high sensitivity C-reactive protein (hs-CRP), greater carotid intima-media thickness (CIMT) and Framingham risk score (FRS) than the control group, though all of these values were within the respective normal range. Further, the brachial artery flow- mediated vasodilation (FMD) values were significantly lower in ED patients and correlated positively with the severity of ED (r = 0.714, p < 0.001). When these significant factors were studied in the multivariate logistic regression model, FMD, SBP, hs-CRP and FRS remained the statistical significance. The receiver-operating characteristic (ROC) analysis demonstrated that FMD had a high ability to predict ED in young male with low FRS [area under the curve (AUC) 0.921, p < 0.001]. The cutoff value of FMD <10.25% had sensitivity of 82.8% and specificity of 100% for diagnosis of ED. FRS and hs- CRP were also proven to be predictors of ED (AUC 0.812, p < 0.001; AUC 0.645, p = 0.011, respectively). The results of this study validated that subclinical endothelial dysfunction and low-grade inflammation may be the underlying pathogenesis of ED with no well-known aetiology. Young patients complaining of ED should be screened for cardiovascular risk factors and possible subclinical atherosclerosis. Measurement of FMD, hs-CRP and FRS can improve our ability to predict and treat ED, as well as subclinical cardiovascular disease early for young male. PMID- 22519626 TI - [Diagnosis of Aspergillus infections in hematology and oncology]. PMID- 22519627 TI - [Diagnostic imaging methods and therapy options for cerebral aspergillosis]. PMID- 22519628 TI - [Early antimycotic therapy strategies: empirical or diagnostically driven]. PMID- 22519629 TI - [Pulmonary and other aspergilloses in patients in the intensive care unit]. PMID- 22519630 TI - [Ambulatory therapy of aspergillosis in hematological and oncological patients]. PMID- 22519631 TI - An integrated power pack of dye-sensitized solar cell and Li battery based on double-sided TiO2 nanotube arrays. AB - We present a new approach to fabricate an integrated power pack by hybridizing energy harvest and storage processes. This power pack incorporates a series-wound dye-sensitized solar cell (DSSC) and a lithium ion battery (LIB) on the same Ti foil that has double-sided TiO(2) nanotube (NTs) arrays. The solar cell part is made of two different cosensitized tandem solar cells based on TiO(2) nanorod arrays (NRs) and NTs, respectively, which provide an open-circuit voltage of 3.39 V and a short-circuit current density of 1.01 mA/cm(2). The power pack can be charged to about 3 V in about 8 min, and the discharge capacity is about 38.89 MUAh under the discharge density of 100 MUA. The total energy conversion and storage efficiency for this system is 0.82%. Such an integrated power pack could serve as a power source for mobile electronics. PMID- 22519632 TI - Depression and cardiovascular disease in women. PMID- 22519633 TI - Expression of BMP-receptor type 1A correlates with progress of osteoarthritis in human knee joints with focal cartilage lesions. AB - BACKGROUND AIMS: Bone morphogenetic protein-2 (BMP-2) and its receptor type 1A (BMPR-1A) play significant roles in cartilage metabolism. The aim of this study was to evaluate a possible correlation between intra-articular expression of these proteins and the degree of osteoarthritis (OA) in human knees. METHODS: Biopsies of synovia and debrided cartilage were taken in 15 patients undergoing autologous chondrocyte implantation. Expression of BMP-2 and BMPR-1A was evaluated semi-quantitatively by immunohistologic staining. These data were complemented by grading of cartilage lesions according to International Cartilage Repair Society (ICRS), defect size, duration of complaints, knee osteoarthritis scoring system (KOSS) and Henderson and Kellgren-Lawrence scores. General histologic stainings were used to determine Mankin, Pritzker and Krenn scores. RESULTS: The expression of BMPR-1A but not of BMP-2 was significantly higher in cartilage biopsies taken in type 3 lesions with intact subchondral layer compared with type 4 defects (P < 0.05). In cartilage areas of bordering sectors, the intensity of immunohistologic staining of BMPR-1A was statistically significantly higher in mature cartilage compared with repair zones (P < 0.05). Expression of BMP-2 and its receptor 1A correlated in the cartilage biopsies (P < 0.02) but not in the synovia. The degree of OA was scored in all biopsies according to Mankin and Pritzker, and these scores correlated statistically significantly with BMPR 1A expression in the synovia (P < 0.05). In patients with an osteochondritis dissecans, the degree of OA was higher compared with other causes of chondromalacia, as evaluated by defect size, ICRS score, duration of complaints, Pritzker score and expression of BMPR-1A in cartilage (P < 0.05). CONCLUSIONS: These data support the role of BMPR-1A as an indicator of OA progression in human knees with circumscribed cartilage lesions. PMID- 22519634 TI - Cryopreservation of umbilical cord mesenchymal cells in xenofree conditions. AB - BACKGROUND AIMS: Mesenchymal stromal cells (MSC) are being used to treat and prevent a variety of clinical conditions. To be readily available, MSC must be cryopreserved until infusion. However, the optimal cryopreservation methods, cryoprotector solutions and MSC sensitivity to dimethyl sulfoxide (DMSO) exposure are unknown. This study investigated these issues. METHODS: MSC samples were obtained from human umbilical cord (n = 15), expanded with Minimal Essential Medium-alpha (alpha-MEM) 10% human serum (HS), resuspended in 25 mL solution (HS, 10% DMSO, 20% hydroxyethyl starch) and cryopreserved using the BioArchive(r) system. After a mean of 18 +/- 7 days, cell suspensions were thawed and diluted until a DMSO concentration of 2.5% was reached. Samples were tested for cell quantification and viability, immunophenotype and functional assays. RESULTS: Post-thaw cell recovery: 114 +/- 2.90% (mean +/- SEM). Recovery of viable cells: 93.46 +/- 4.41%, 90.17 +/- 4.55% and 81.03 +/- 4.30% at 30 min, 120 min and 24 h post-thaw, respectively. Cell viability: 89.26 +/- 1.56%, 72.71 +/- 2.12%, 70.20 +/- 2.39% and 63.02 +/- 2.33% (P < 0.0001) pre-cryopreservation and 30 min, 120 min and 24 h post-thaw, respectively. All post-thaw samples had cells that adhered to culture bottles. Post-thaw cell expansion was 4.18 +/- 0.17 *, with a doubling time of 38 +/- 1.69 h, and their capacity to inhibit peripheral blood mononuclear cells (PBMC) proliferation was similar to that observed before cryopreservation. Differentiation capacity, cell-surface marker profile and cytogenetics were not changed by the cryopreservation procedure. CONCLUSIONS: A method for cryopreservation of MSC in bags, in xenofree conditions, is described that facilitates their clinical use. The MSC functional and cytogenetic status and morphologic characteristics were not changed by cryopreservation. It was also demonstrated that MSC are relatively resistant to exposure to DMSO, but we recommend cell infusion as soon as possible. PMID- 22519635 TI - Determination of carotenoids, total phenolic content, and antioxidant activity of Araza (Eugenia stipitata McVaugh), an Amazonian fruit. AB - The fruit of Araza (Eugenia stipitata McVaugh) native to the Colombian Amazon is considered a potentially economically valuable fruit for the Andean economy due to its novel and unique taste. The fruit has an intense yellow color, but its chemical composition and properties have not been well studied. Here we report the identification and quantitation of carotenoids in the ripe fruit using high performance liquid chromatography (HPLC) with photodiode array detector (PDA) and atmospheric pressure chemical ionization (APcI) mass spectrometry (MS/MS). The qualitative carotenoid profile of the fruit according to maturity stage was also observed. Furthermore, antioxidant activity of the peel and pulp were assessed using the ferric reducing ability of plasma (FRAP), 2,2'-azino-bis(3 ethylbenzothiazoline-6-sulfonic acid) (ABTS), and 1,1-diphenyl-2-picrylhydrazyl (DPPH) methods, in addition to chemical indexes and total phenolic content. Multiple carotenoids were identified in the peel and pulp including four xanthophylls (free and esterified as their mono and diesters) and two carotenes. One of the xanthophylls was tentatively identified as zeinoxanthin, while the others were identified as lutein, zeaxanthin, and beta-cryptoxanthin. Carotenes included alpha-carotene and beta-carotene. The total carotenoid content was significantly higher in the peel (2484 +/- 421 MUg/100 g FW) than in the pulp (806 +/- 348 MUg/100 g FW) with lutein, beta-cryptoxanthin, and zeinoxanthin as the major carotenoid components. The unique carotenoid composition of this fruit can differentiate it from other carotenoid-rich fruits and perhaps be useful in authentication procedures. Overall, results from this study suggest that Colombian Araza may be a good edible source of carotenoids important in retinal health as well as carotenoids with provitamin A activity. Therefore, Araza fruit can be used as a nutraceutical ingredient and in production of functional foods in the Colombian diet. PMID- 22519636 TI - Evaluation of potential responses to invasive non-native species with structured decision making. AB - In managing invasions and colonizations of non-native species, eradication or control efforts must proceed quickly. There are 2 challenges in taking such quick action. First, managers frequently have to choose among complex and often competing environmental, social, and economic objectives. Second, the effects are highly uncertain. We applied participatory structured decision making (SDM) to develop a response plan for the recent invasion of non-native myrtle rust (Uredo rangelii) in Australia. Structured decision making breaks a complex decision process into 5 steps: identify problems (i.e., decisions to be made), formulate objectives, develop management alternatives, estimate consequences of implementing those alternatives, and select preferred alternatives by evaluating trade-offs among alternatives. To determine the preferred mid- to long-term alternatives to managing the rust, we conducted 2 participatory workshops and 18 interviews with individuals to elicit stakeholders' key concerns and convert them into 5 objectives (minimize management cost, minimize economic cost to industry, minimize effects on natural ecosystems and landscape amenities, and minimize environmental effects associated with use of fungicide) and to identify the 5 management alternatives (full eradication, partial eradication, slow spread, live with it [i.e., major effort invested in mitigation of effects], and do nothing). We also developed decision trees to graphically represent the essence of the decision by displaying the relations between uncertainties and decision points. In the short term or before local expansion of myrtle rust, the do-nothing alternative was not preferred, but an eradication alternative was only recommended if the probability of eradication exceeded about 40%. After the expansion of myrtle rust, the slow-the-spread alternative was preferred regardless of which of the short-term management alternatives was selected at an earlier stage. The participatory SDM approach effectively resulted in informed and transparent response plans that incorporated multiple objectives in decision making processes under high uncertainty. PMID- 22519637 TI - Regulation of oxidative stress in long-lived lipopolysaccharide-activated microglia. AB - 1. Previously, we reported that an optimal dose of lipopolysaccharide (LPS) markedly extends the life span of mouse primary-cultured microglia by suppressing apoptotic and autophagic cell death pathways. The aim of the present study was to assess how these cells protect themselves against reactive oxygen species (ROS) generated by LPS treatment. 2. The study was conducted in microglia obtained from murine neonate brain, which are destined to die within a few days under ordinary culture conditions. 3. The generation of ROS was maximal after 15 h LPS treatment (1 ng/mL LPS and 100 ng/mL LPS). The expression of inducible nitric oxide (NO) synthase protein was significantly increased by Day 1 of LPS treatment and was followed by the production of NO. The expression of either Cu/Zn- or Mn superoxide dismutase protein (SOD) was also increased by 16 h and Day 1 of LPS treatment. LPS did not affect the expression of Cu/Zn- and Mn-SOD proteins, nor did it extend the life span of microglia that had mutated Toll-like receptor (TLR) 4. 4. The findings of the present study suggest that SODs function as a potent barrier to overcome ROS generated in primary-cultured microglia following LPS treatment and that TLR4 may be significantly involved in inducing these proteins. The microglia may be able to protect themselves against oxidative stress, allowing them to live for more than 1 month. Because long-lived microglia may play a critical role in the exacerbation of neurodegeneration, bringing activated microglia back to their resting stage could be a new and promising strategy to inhibit the deterioration underlying neurodegenerative disorders. PMID- 22519638 TI - Open rotator cuff repairs in patients 70 years and older. AB - BACKGROUND: Symptomatic rotator cuff tear is a commonly diagnosed problem in patients over the age of 70; however, there is controversy regarding the management of this condition. We set out to investigate whether this group has satisfactory results with operative management of their rotator cuff tears. METHODS: Retrospective review of one surgeon's patients who have undergone an open rotator cuff repair at age 70 or older. Outcome assessment included history of work and recreational activities, review of medical records, clinical examination, the Simple Shoulder Test (SST) and the Constant Shoulder Score (CSS). RESULTS: A total of 96 patients (104 shoulders) underwent open rotator cuff repair during the study period. Sixteen patients (16 shoulders) were lost to follow-up leaving 80 patients (88 shoulders) for review. Mean duration of symptoms was 18.3 months, mean age at surgery was 74.2 years and mean time to follow-up was 40.8 months. The mean SST and CSS scores were 9.8 and 80.1, respectively. In both tests, patients scored best in the pain relief categories and worst in strength-measuring areas. A total of 73 patients (92.7%) reported satisfaction with their surgery. None of these were limited by their shoulders in returning to pre-injury independence, work or recreations. They were either completely pain free or had only mild symptoms. CONCLUSION: Patients in our study reflected a high satisfaction rate of 92.7% as well as excellent pain relief and a high level of function when related to their daily activities, independence and recreations or work. LEVEL OF EVIDENCE: Level IV (observational study without control - retrospective study). PMID- 22519640 TI - The saposin-like protein SPP-12 is an antimicrobial polypeptide in the pharyngeal neurons of Caenorhabditis elegans and participates in defence against a natural bacterial pathogen. AB - Caenopores are antimicrobial and pore-forming polypeptides in Caenorhabditis elegans belonging to the saposin-like protein superfamily and are considered important elements of the nematode's intestinal immune system. In the present study, we demonstrate that, unlike the other members of the multifarious gene family (spps) coding for caenopores, spp-12 is expressed exclusively in two pharyngeal neurons. Recombinantly expressed SPP-12 binds to phospholipid membranes and forms pores in a pH-dependent manner characteristic of caenopores. Moreover, SPP-12 kills viable Gram-positive bacteria, yeast cells and amoebae by permeabilizing their membranes, suggesting a wide-target cell spectrum. A spp-12 knockout mutant is more susceptible to pathogenic Bacillus thuringiensis than wild-type worms and is tolerant to non-pathogenic bacteria. By contrast, SPP-1, a caenopore, whose gene is expressed only in the intestine and reported to be regulated by the same pathway as spp-12, is apparently non-protective against pathogenic B. thuringiensis, although it also does display antimicrobial activity. The transcription of spp-1 is down-regulated in wild-type worms in the presence of pathogenic B. thuringiensis and a spp-1 knockout mutant is hyposusceptible to this bacterium. This implies that SPP-12, but not SPP-1, contributes to resistance against B. thuringiensis, a natural pathogen of the nematode. PMID- 22519641 TI - Anti-angiogenic therapies for malignant pleural mesothelioma. AB - INTRODUCTION: Malignant pleural mesothelioma (MPM) is a disease with a dismal prognosis. Currently available treatments have modest results. Therefore, new agents and new treatment strategies are eagerly awaited by patients and clinicians. Preclinical and clinical studies have shown that angiogenesis plays a very important role in MPM. Therefore, a great hope has been placed in the use of anti-angiogenic agents in this disease. AREAS COVERED: Studies regarding anti angiogenic treatments in MPM with bevacizumab, tyrosine-kinase inhibitors (TKIs) and other agents were critically analyzed, with an overview of ongoing trials and future perspectives, including research on biomarkers. EXPERT OPINION: The clinical use of angiogenesis inhibitors in MPM patients has resulted more challenging than anticipated. The intrinsic complexity of neo-angiogenesis, and its redundant regulatory mechanisms, suggests that multiple and different biomarkers are needed to predict efficacy of anti-angiogenic agents and to monitor their biological and therapeutic effects. The growing understanding of the molecular alterations and key pathways that underlie the resistance to VEGF inhibitors will allow to design studies of the combination of agents targeting these pathways with anti-VEGF therapies. Only a tight integration of preclinical and clinical studies will allow to achieve a real progress in MPM patients with this therapeutic strategy. PMID- 22519642 TI - Unified total syntheses of fawcettimine class alkaloids: fawcettimine, fawcettidine, lycoflexine, and lycoposerramine B. AB - The total syntheses of the lycopodium alkaloids fawcettimine, fawcettidine, lycoflexine, and lycoposerramine B have been accomplished through an efficient, unified, and stereocontrolled strategy that relies on a Diels-Alder reaction to construct the cis-fused 6,5-carbocycles with one all-carbon quaternary center. Access to the enantioselective syntheses of both antipodes of those alkaloids can be achieved by kinetic resolution of the earliest intermediate via a Sharpless asymmetric dihydroxylation (Sharpless AD). Compared to existing approaches to these alkaloids, our synthetic route possesses superior stereocontrol over the C 4 and C-15 stereogenic centers as well as allowing for more functional variation on the 6-membered ring. PMID- 22519644 TI - Oxidation state and symmetry of magnesia-supported Pd13O(x) nanocatalysts influence activation barriers of CO oxidation. AB - Combining temperature-programmed reaction measurements, isotopic labeling experiments, and first-principles spin density functional theory, the dependence of the reaction temperature of catalyzed carbon monoxide oxidation on the oxidation state of Pd(13) clusters deposited on MgO surfaces grown on Mo(100) is explored. It is shown that molecular oxygen dissociates easily on the supported Pd(13) cluster, leading to facile partial oxidation to form Pd(13)O(4) clusters with C(4v) symmetry. Increasing the oxidation temperature to 370 K results in nonsymmetric Pd(13)O(6) clusters. The higher symmetry, partially oxidized cluster is characterized by a relatively high activation energy for catalyzed combustion of the first CO molecule via a reaction of an adsorbed CO molecule with one of the oxygen atoms of the Pd(13)O(4) cluster. Subsequent reactions on the resulting lower-symmetry Pd(13)O(x) (x < 4) clusters entail lower activation energies. The nonsymmetric Pd(13)O(6) clusters show lower temperature-catalyzed CO combustion, already starting at cryogenic temperature. PMID- 22519643 TI - Muscle development and differentiation in the urodele Ambystoma mexicanum. AB - Muscle differentiation has been widely described in zebrafish and Xenopus, but nothing is known about this process in amphibian urodeles. Both anatomical features and locomotor activity in urodeles are known to show intermediate features between fish and anurans. Therefore, a better understanding of myogenesis in urodeles could be useful to clarify the evolutionary changes that led to the formation of skeletal muscle in the trunk of land vertebrates. We report here a detailed morphological and molecular investigation on several embryonic stages of Ambystoma mexicanum and show that the first differentiating muscle fibers are the slow ones, originating from a myoblast population initially localized close to the notochord that forms a superficial layer on the somitic surface afterwards. Subsequently, fast fibers differentiation ensues. We also identified and cloned A. mexicanum Myf5 as a muscle-specific transcriptional factor likely involved in urodele muscle differentiation. PMID- 22519645 TI - Refractory semantic access dysphasia resulting from resection of a left frontal glioma. AB - The existence of semantic access disorders is now well established, however the precise cognitive and anatomical underpinnings are still debated. Here we describe the case of a patient that became aphasic after the resection of a left frontal glioma. Detailed lesion reconstruction indicates that the lesion was mostly restricted to the left dorsal and ventral prefrontal cortices and the underlying white matter, but sparing temporal lobes. Critically, the patient showed all the signs of refractory semantic access dysphasia, supporting the association between this syndrome and damage to left prefrontal areas likely to subserve retrieval and selection mechanisms for verbal material. PMID- 22519646 TI - Pivotal role of the AREB/ABF-SnRK2 pathway in ABRE-mediated transcription in response to osmotic stress in plants. AB - Water availability is one of the main limiting factors for plant growth and development. The phytohormone abscisic acid (ABA) fulfills a critical role in coordinating the responses to reduced water availability as well as in multiple developmental processes. Endogenous ABA levels increase in response to osmotic stresses such as drought and high salinity, and ABA activates the expression of many genes via ABA-responsive elements (ABREs) in their promoter regions. ABRE binding protein/ABRE-binding factor (AREB/ABF) transcription factors (TFs) regulate the ABRE-mediated transcription of downstream target genes. Three subclass III sucrose non-fermenting-1 related protein kinase 2 (SnRK2) protein kinases (SRK2D/SnRK2.2, SRK2E/SnRK2.6/OST1 and SRK2I/SnRK2.3) phosphorylate and positively control the AREB/ABF TFs. Substantial progress has been made in our understanding of the ABA-sensing system mediated by Pyrabactin resistance1/PYR1 like/regulatory components of ABA receptor (PYR/PYL/RCAR)-protein phosphatase 2C complexes. In addition to PP2C-PYR/PYL/RCAR ABAreceptor complex, the AREB/ABF SnRK2 pathway, which is well conserved in land plants, was recently shown to play a major role as a positive regulator of ABA/stress signaling through ABRE mediated transcription of target genes implicated in the osmotic stress response. This review focuses on current progress in the study of the AREB/ABF-SnRK2 positive regulatory pathway in plants and describes additional signaling factors implicated in the AREB/ABF-SnRK2 pathway. Moreover, to help promote the link between basic and applied studies, the nomenclature and phylogenetic relationships between the AREB/ABFs and SnRK2s are summarized and discussed. PMID- 22519647 TI - Evaluation of online training for the provision of opioid substitution treatment by community pharmacists in New Zealand. AB - INTRODUCTION AND AIMS: The role of community pharmacists in the provision of opioid substitution treatment (OST) is pivotal and integral to addiction treatment. An online training program for pharmacists in OST management was piloted in New Zealand in 2010, following recognition of the difficulty in recruitment and retention of community pharmacists to provide OST services. Our aim was to evaluate the OST online training that was made available for any community pharmacist in New Zealand and to establish the feasibility and acceptability of this format of training for community pharmacists. The evaluation explored participants' attitudes, skills and knowledge both pre- and post-training in OST. DESIGN AND METHODS: All pharmacists registering to participate in the training program were asked to complete an evaluation questionnaire immediately before (pre) and immediately after (post) completing the training. Participants were also invited to participate in a brief 10 min structured telephone interview about their training experience. RESULTS: In the first 4 months 190 pharmacists commenced the training; 101 completed both evaluations. Improvements in the confidence and skills of pharmacists were demonstrated through both the quantitative and qualitative analyses. Statistically significant changes in attitudes were also demonstrated. Overall the OST training was well received and the online format was feasible and highly acceptable. DISCUSSION AND CONCLUSION: Online training is an appropriate and economical method of improving pharmacists' clinical skills with respect to this client group, and has the potential to reach a wider audience of pharmacists. Further research is required to investigate OST client experiences in community pharmacy. PMID- 22519648 TI - 3D porous sol-gel matrix incorporated microdevice for effective large volume cell sample pretreatment. AB - In this study, we demonstrated an effective sample pretreatment microdevice that could perform the capture, purification, and release of pathogenic bacteria with a large-volume sample and at a high speed and high-capture yield. We integrated a sol-gel matrix into the microdevice which forms three-dimensional (3D) micropores for the cell solution to pass through and provides a large surface area for the immobilization of antibodies to capture the target Staphylococcus aureus (S. aureus) cells. The antibody was linked to the surface of the sol-gel via a photocleavable linker, allowing the cell-captured antibody moiety to be released by UV irradiation. In addition to the optimization of the antibody immobilization and UV cleavage processes, the cell-capture efficiency was maximized by controlling the sample flow rate with a pumping scheme (3 steps, 5 steps: 3 steps with one flutter step, 7 steps: 3 steps with two flutter steps) and the pumping time (100, 200, and 300 ms). A quantitative capture analysis was performed by targeting a specific gene site of protein A of S. aureus in real-time PCR (RT PCR). While the 3-step process with an actuation time of 100 ms showed the fastest flow rate (1 mL sample processing time in 10 min), the pumping scheme with the 7-step process and the 300 ms actuation time revealed the highest cell capture efficiency. A limit of detection study with the 7-step and the 300 ms pumping scheme demonstrated that 100 cells per 100 MUL were detected with a 70% yield, and even a single cell could be analyzed via on-chip sample preparation. Thus, our novel sol-gel based microdevice was proven more cost-effective, simple, and efficient in terms of its sample pretreatment ability compared to the use of a conventional 2D flat microdevice. This proposed sample pretreatment device can be further incorporated to an analytical functional unit to realize a micrototal analysis system (MUTAS) with sample-in-answer-out capability in the fields of biomedical diagnostics, food safety testing, and environmental pollutant screening. PMID- 22519649 TI - Determination of solvation layer thickness by a magnetophotonic approach. AB - Derjaguin-Landau-Verwey-Overbeek (DLVO) theory fails in explaining the superior stability of colloid particles in aqueous suspensions under conditions of high ionic strengths where electrostatic forces are effectively screened. Accumulating evidence shows that the formation of a thin rigid layer of solvent molecules in the vicinity of a colloidal particle surface provides an additional repulsive interaction when the interparticle distance is reduced to several nanometers. The effective determination of the thickness of the solvation layer however remains a challenge. Here, we demonstrate a simple yet powerful magnetophotonic technique that can be used to study the thickness of the solvation layers formed on the colloidal silica surface in various polar solvents. A relationship between the hydrogen-bonding ability of the solvents and the thickness of solvation layer on colloidal silica surfaces has been identified; this observation is found to be consistent with the previously proposed hydrogen-bonding origin of the solvation force. PMID- 22519650 TI - Increased incidence of Guillain-Barre syndrome after surgery. AB - BACKGROUND AND PURPOSE: Antecedent surgery has been described to trigger Guillain Barre syndrome (GBS), but its evidence is poor and based on case reports only. METHODS: We performed a retrospective analysis of 63 patients with GBS admitted to the University Hospital Basel and University Children's Hospital Basel from January 2005 to December 2010. We calculated and compared the incidences of post surgical and non-exposed patients with GBS in the study population and those reported previously in literature. RESULTS: Six of 63 (9.5%) GBS cases had had a surgery within 6 weeks prior to GBS. The relative risk of developing GBS during the 6-week period after surgery is 13.1 times higher than the normal incidence in the study population (95% confidence interval: 5.68, 30.3; P <= 0.0001), suggesting an attributable risk of 4.1 cases per 100, 000 surgeries. In addition, the incidence of post-surgical GBS is significantly higher than influenza vaccine associated GBS in the study population (P = 0.01) as well as in comparison with previous reported vaccine-associated GBS (P <= 0.0001) and background incidences (P <= 0.0001). CONCLUSION: Surgery must be considered to be a potential risk factor for developing GBS. PMID- 22519652 TI - "Something of the two of us". The emotionally loaded embryo disposition decision making of patients who view their embryo as a symbol of their relationship. AB - OBJECTIVES: This paper describes a recently identified conception of the cryopreserved embryo as a symbol of one's relationship (SOR). METHODS: A questionnaire was sent together with the embryo disposition decision (EDD) form to patients for whom embryos were cryopreserved at the department in Ghent, Belgium. We collected data on patient characteristics, their EDD attitudes and the reasons for their willingness or unwillingness to consider each of the disposition options (donation to others for reproduction, donation for science and discarding). RESULTS: The SOR view was found more often in patients who were less educated and whose last treatment was less than 3 years ago. Viewing the embryo as a SOR was not linked to more difficult decision making, but to more emotionally loaded decision making. In particular, patients with this view more often reported feelings of grief. This view was also linked to the outcome of the decision making process. CONCLUSION: The conception of the embryo as a SOR is part of an affective attitude towards embryos that has an impact on patients' disposition decisions. Alongside patients' values and principles, it is important that counselors acknowledge and clarify patients' affective conceptualizations. PMID- 22519653 TI - From a Dy(III) single molecule magnet (SMM) to a ferromagnetic [Mn(II)Dy(III)Mn(II)] trinuclear complex. AB - The Schiff base compound 2,2'-{[(2-aminoethyl)imino]bis[2,1-ethanediyl nitriloethylidyne]}bis-2-hydroxy-benzoic acid (H(4)L) as a proligand was prepared in situ. This proligand has three potential coordination pockets which make it possible to accommodate from one to three metal ions allowing for the possible formation of mono-, di-, and trinuclear complexes. Reaction of in situ prepared H(4)L with Dy(NO(3))(3).5H(2)O resulted in the formation of a mononuclear complex [Dy(H(3)L)(2)](NO(3)).(EtOH).8(H(2)O) (1), which shows SMM behavior. In contrast, reaction of in situ prepared H(4)L with Mn(ClO(4))(2).6H(2)O and Dy(NO(3))(3).5H(2)O in the presence of a base resulted in a trinuclear mixed 3d 4f complex (NHEt(3))(2)[Dy{Mn(L)}(2)](ClO(4)).2(H(2)O) (2). At low temperatures, compound 2 is a weak ferromagnet. Thus, the SMM behavior of compound 1 can be switched off by incorporating two Mn(II) ions in close proximity either side of the Dy(III). This quenching behavior is ascribed to the presence of the weak ferromagnetic interactions between the Mn(II) and Dy(III) ions, which at T > 2 K act as a fluctuating field causing the reversal of magnetization on the dysprosium ion. Mass spectrometric ion signals related to compounds 1 and 2 were both detected in positive and negative ion modes via electrospray ionization mass spectrometry. Hydrogen/deuterium exchange (HDX) reactions with ND(3) were performed in a FT-ICR Penning-trap mass spectrometer. PMID- 22519654 TI - The use of extracorporeal shock wave-stimulated periosteal cells for orthotopic bone generation. AB - The cambium cells of the periosteum, which are known osteoprogenitor cells, have limited suitability for clinical applications of tissue engineering in their native state due to their low cell number (2-5 cells thick). Extracorporeal shock waves (ESWs) have been shown to cause rapid periosteal cambium cell proliferation and subsequent periosteal osteogenesis. This work investigates a novel strategy for orthotopic bone generation: applying ESW therapy as a noninvasive, inexpensive, and rapid method for stimulating cambium cell proliferation, and combining these cells with a bioactive scaffold for bone growth. ESWs applied to the rabbit medial tibia resulted in a significant 2.7-fold increase in cambium cell number and a 4-fold increase in cambium cell thickness at 4 days post-ESW. ESW-stimulated, or nontreated control, periosteal cells were elevated in situ and overlaid on an anorganic bovine bone scaffold to interrogate their ability to form bone. At 2 weeks post-surgery, there was a significant increase in all key outcome variables for the ESW-stimulated group when compared with controls: a 4 fold increase in osseous tissue in the upper half of the scaffold underlying the periosteum; a 12-fold increase in osseous tissue overlying the scaffold; and a 2 fold increase in callus size. These results successfully demonstrated the efficacy of ESW-stimulated periosteum for orthotopic bone generation. PMID- 22519655 TI - Surface investigation of intermetallic PdGa(111). AB - The intermetallic PdGa is a highly selective and potent catalyst in the semihydrogenation of acetylene, which is attributed to the surface stability and isolated Pd atom ensembles. In this context PdGa single crystals of form B with (111) orientation were investigated by means of X-ray photoelectron spectroscopy (XPS), ultraviolet photoelectron spectroscopy (UPS), scanning tunneling microscopy (STM), X-ray photoelectron diffraction (XPD), and low-energy electron diffraction (LEED) to study the electronic and geometric properties of this surface. UPS and thermal desorption spectroscopy (TDS) were used to probe the chemisorption behavior of CO. The PdGa(111) surface exhibits a (1 * 1) LEED and a pronounced XPD pattern indicating an unreconstructed bulk-truncated surface. Low temperature STM reveals a smooth surface with a (1 * 1) unit cell. No segregation occurs, and no impurities are detected by XPS. The electronic structure and the CO adsorption properties reveal PdGa(111) to be a bulk-truncated intermetallic compound with Pd-Ga partial covalent bonding. PMID- 22519656 TI - The "Swiss Statement": who knows about it? How do they know? What are its effects on people living with HIV/AIDS? AB - The publication of the "Swiss Statement" in 2008 shook the international HIV prevention and advocacy scene. HIV behavioral research has provided us with some studies focusing on the potential changes that new prevention strategies can produce, but results are not conclusive. Besides, there is a lack of data concerning awareness of these kinds of prevention strategies on real-life settings, studying mainly the behavior of people recruited in different types of trials (e.g., circumcision, pre and post-exposure prophylaxis). The present study aims to (1) identify the factors associated with awareness of the "Swiss Statement" among PLWHA, (2) determine in which setting they became aware of it, and (3) look for potential, behavioral, and/or emotional changes as a consequence of this awareness. In order to achieve these three objectives, we used the data collected by a community-based survey called "HIV, Hepatitis and you." In order to determine the factors associated with the awareness of the Swiss Statement, univariate and multivariate logistic regression were performed. Main results show that among the 997 HIV-positive people answering the questionnaire, 57% knew about the Swiss Statement, and that their main source of information was the associative setting, while 30% declared having found out about it from their doctor. As for the factors associated with the awareness of the Swiss Statement, we found that the following variables were significantly associated with such awareness: living in stable housing, having a CD4 count above 350 cell/mm(3), having an undetectable viral load, being in contact with a HIV-solidarity network, feeling of belonging to the LGBT community, and filling out the questionnaire online. The results of this study point out that interventions addressed to improve access to health-related information for PLWHA facing socioeconomical difficulties and isolation are strongly needed. PMID- 22519657 TI - Guideline vulvovaginal candidosis (2010) of the German Society for Gynecology and Obstetrics, the Working Group for Infections and Infectimmunology in Gynecology and Obstetrics, the German Society of Dermatology, the Board of German Dermatologists and the German Speaking Mycological Society. AB - Candida (C.) species colonize the estrogenized vagina in at least 20% of all women. This statistic rises to 30% in late pregnancy and in immunosuppressed patients. The most often occurring species is Candida albicans. Host factors, especially local defense deficiencies, gene polymorphisms, allergic factors, serum glucose levels, antibiotics, psychosocial stress and estrogens influence the risk for a Candida vulvovaginitis. In less than 10% of all cases, non albicans species, especially C. glabrata, but in rare cases also Saccharomyces cerevisiae, cause a vulvovaginitis, often with fewer clinical signs and symptoms. Typical symptoms include premenstrual itching, burning, redness and non-odorous discharge. Although pruritus and inflammation of the vaginal introitus are typical symptoms, only less than 50% of women with genital pruritus suffer from a Candida vulvovaginitis. Diagnostic tools are anamnesis, evaluation of clinical signs, the microscopic investigation of the vaginal fluid by phase contrast (400 x), vaginal pH-value and, in clinically and microscopically uncertain or in recurrent cases, yeast culture with species determination. The success rate for treatment of acute vaginal candidosis is approximately 80%. Vaginal preparations containing polyenes, imidazoles and ciclopiroxolamine or oral triazoles, which are not allowed during pregnancy, are all equally effective. C. glabrata is resistant to the usual dosages of all local antimycotics. Therefore, vaginal boric acid suppositories or vaginal flucytosine are recommended, but not allowed or available in all countries. Therefore, high doses of 800 mg fluconazole/day for 2-3 weeks are recommended in Germany. Due to increasing resistence, oral posaconazole 2 * 400 mg/day plus local ciclopiroxolamine or nystatin for 15 days was discussed. C. krusei is resistant to triazoles. Side effects, toxicity, embryotoxicity and allergy are not clinically important. A vaginal clotrimazole treatment in the first trimester of pregnancy has shown to reduce the rate of preterm births in two studies. Resistance of C. albicans does not play a clinically important role in vulvovaginal candidosis. Although it is not necessary to treat vaginal candida colonization in healthy women, it is recommended in the third trimester of pregnancy in Germany, because the rate of oral thrush and diaper dermatitis in mature healthy newborns, induced by the colonization during vaginal delivery, is significantly reduced through prophylaxis. Chronic recurrent vulvovaginal candidosis requires a "chronic recurrent" suppression therapy, until immunological treatment becomes available. Weekly to monthly oral fluconazole regimes suppress relapses well, but cessation of therapy after 6 or 12 months leads to relapses in 50% of cases. Decreasing dose maintenance regime of 200 mg fluconazole from an initial 3 times a week to once monthly (Donders 2008) leads to more acceptable results. Future studies should include candida autovaccination, antibodies against candida virulence factors and other immunological trials. Probiotics should also be considered in further studies. Over the counter (OTC) treatment must be reduced. PMID- 22519659 TI - The relationship between anogenital distance and azoospermia in adult men. AB - Anogenital distance (AGD) is a marker for endocrine disruption in animal studies in which decreased male AGD has been associated with testicular dysfunction. The objective of the study was to investigate whether anogenital distance could distinguish men with obstructive azoospermia (OA) from those with nonobstructive azoospermia (NOA). To accomplish this, azoospermic men were recruited and evaluated at a men's reproductive health clinic in Houston, TX. Anogenital distance (the distance from the posterior aspect of the scrotum to the anal verge) and penile length (PL) were measured using digital calipers. Testis size was estimated by physical examination. Logistic regression was used to compare AGD lengths in men with OA and men with NOA. A total of 69 OA men (mean age: 44.2 +/- 9.2) and 29 NOA men (mean age: 32.8 +/- 4.8) were recruited. The NOA men possessed significantly shorter mean AGD than the men with OA (AGD: 36.3 vs. 41.9 mm, p = 0.01). An AGD of less than 30 mm, had a 91% specificity in accurately classifying NOA. Moreover, after adjustment for age, race, and BMI, an AGD of less than 30 mm yielded a significantly increased odds of NOA compared to OA (OR 5.6, 95% CI 1.0, 30.7). In summary, AGD may provide a novel metric for assessing testicular function in men and in distinguishing OA from NOA. PMID- 22519658 TI - Rapid clinical induction of bupropion hydroxylation by metamizole in healthy Chinese men. AB - AIMS: This study aimed to investigate the effect of metamizole on bupropion hydroxylation related to different CYP2B6 genotype groups in healthy volunteers. METHODS: Sixteen healthy male volunteers (6 CYP2B6*1/*1, 6 CYP2B6*1/*6 and 4 CYP2B6*6/*6) received orally administered bupropion alone and during daily treatment with metamizole 1500 mg day(-1) (500 mg tablet taken three times daily) for 4 days. Serial blood samples were obtained up to 48 h after each bupropion dose. RESULTS: After metamizole treatment relative to bupropion alone, the geometric mean ratios (GMRs) and 90% confidence interval (CI) of the AUC(0,infinity) ratio of 4-hydroxybupropion over bupropion were 1.99 (1.57, 2.55) for the CYP2B6*1/*1 group, 2.15 (1.53, 3.05) for the CYP2B6*1/*6 group and 1.86 (1.36, 2.57) for the CYP2B6*6/*6 group. The GMRs and 90% CI of bupropion were 0.695 (0.622, 0.774) for AUC(0,infinity) and 0.400 (0.353, 0.449) for C(max) , respectively. The corresponding values for 4-hydroxybupropion were 1.43 (1.28, 1.53) and 2.63 (2.07, 2.92). The t(1/2) value was significantly increased for bupropion and decreased for 4-hydroxybupropion. The t(max) values of bupropion and 4-hydroxybupropion were both significantly decreased. The mean percentage changes in pharmacokinetic parameters among the CYP2B6 genotype groups were not significantly different. CONCLUSIONS: Oral administration of metamizole for 4 days significantly altered the pharmacokinetics of both bupropion and its active metabolite, 4-hydroxybupropion, and significantly increased the CYP2B6-catalyzed bupropion hydroxylation in all of the subjects. Cautions should be taken when metamizole is co-administered with CYP2B6 substrate drugs. PMID- 22519660 TI - Marine-freshwater transitions are associated with the evolution of dietary diversification in terapontid grunters (Teleostei: Terapontidae). AB - The ecological opportunities associated with transitions across the marine freshwater interface are regarded as an important catalyst of diversification in a range of aquatic taxa. Here, we examined the role of these major habitat transitions and trophic diversification in a radiation of Australasian fishes using a new molecular phylogeny incorporating 37 Terapontidae species. A combined mitochondrial and nuclear gene analysis yielded a well-supported tree with most nodes resolved. Ancestral terapontids appear to have been euryhaline in habitat affiliation, with a single transition to freshwater environments producing all Australasian freshwater species. Mapping of terapontid feeding modes onto the molecular phylogeny-predicted carnivorous dietary habits was displayed by ancestral terapontids, which subsequently diversified into a range of additional carnivorous, omnivorous, herbivorous and detritivorous dietary modes upon transition to freshwater habitats. Comparative analyses suggested that following the freshwater invasion, the single freshwater clade has exhibited an increased rate of diversification at almost three times the background rate evident across the rest of the family. The marine-freshwater transition within Terapontidae appears to have resulted in substantial dietary radiation in freshwater environments, as well as increased lineage diversification rates relative to euryhaline-marine habitats. PMID- 22519661 TI - Origin matters: widely distributed native and non-native species benefit from different functional traits. AB - Recently, ecologists debated whether distinguishing native from non-native species is sensible or not. One argument is that widespread and less widespread species are functionally different, whether or not they are native. An opposing statement points out ecologically relevant differences between native and non native species. We studied the functional traits that drive native and non-native vascular plant species frequency in Germany by explaining species grid-cell frequency using traits and their interaction with status. Native and non-native species frequency was equally driven by life span, ploidy type and self compatibility. Non-native species frequency rose with later flowering cessation date, whereas this relationship was absent for native species. Native and non native species differed in storage organs and in the number of environmental conditions they tolerate. We infer that environmental filters drive trait convergence of native and non-native species, whereas competition drives trait divergence. Meanwhile, introduction pathways functionally bias the frequency of non-native species. PMID- 22519662 TI - Multicolor single molecule tracking of stochastically active synthetic dyes. AB - Single particle tracking can reveal dynamic information at the scale of single molecules in living cells but thus far has been limited either in the range of potential protein targets or in the quality and number of tracks attainable. We demonstrate a new approach to single molecule tracking by using the blinking properties of synthetic dyes targeted to proteins of interest with genetically encoded tags to generate high-density tracks while maintaining flexibility in protein labeling. We track membrane proteins using different combinations of dyes and show that the concept can be extended to three-color imaging. Moreover, we show that this technique is not limited to the membrane by performing live tracking of proteins in intracellular compartments. PMID- 22519663 TI - Investigation for the amorphous state of ER-34122, a dual 5 lipoxygenase/cyclooxygenase inhibitor with poor aqueous solubility, in HPMC solid dispersion prepared by the solvent evaporation method. AB - ER-34122, a poorly water-soluble dual 5-lipoxygenase/cyclooxygenase inhibitor, exists as a crystalline form. According to an Oak Ridge thermal ellipsoid plot drawing, carbonyl oxygen O (5) makes an intermolecular hydrogen bond with the hydrogen bonded to N (3) in the crystal structure. The FTIR and the solid-state 13C NMR spectra suggest that the network is spread out in the amorphous state and the hydrogen bonding gets weaker than that in the crystalline phase, because the carbonyl signals significantly shift in both spectra. When amorphous ER-34122 was heated, crystallization occurred at around 140 degrees C. Similar crystallization happened in the solid dispersion; however, the degree of crystallization was much lower than that observed in the pure amorphous material. Also, the DSC thermogram of the solid dispersion did not show any exothermic peaks implying crystallization. The heat of fusion (DeltaHf) determined in the pure amorphous material was nearly equal to that for the crystalline form, whereas the DeltaHf value obtained in the solid dispersion was less than a third of them. These data prove that crystallization of the amorphous form is dramatically restrained in the solid dispersion system. The carbonyl wavenumber shifts in the FTIR spectra indicate that the average hydrogen bond in the solid dispersion is lower than that in the pure amorphous material. Therefore, HPMC will suppress formation of the intermolecular network observed in ER-34122 crystal and preserve the amorphous state, which is thermodynamically less stable, in the solid dispersed system. PMID- 22519664 TI - Robust climate policies under uncertainty: a comparison of robust decision making and info-gap methods. AB - This study compares two widely used approaches for robustness analysis of decision problems: the info-gap method originally developed by Ben-Haim and the robust decision making (RDM) approach originally developed by Lempert, Popper, and Bankes. The study uses each approach to evaluate alternative paths for climate-altering greenhouse gas emissions given the potential for nonlinear threshold responses in the climate system, significant uncertainty about such a threshold response and a variety of other key parameters, as well as the ability to learn about any threshold responses over time. Info-gap and RDM share many similarities. Both represent uncertainty as sets of multiple plausible futures, and both seek to identify robust strategies whose performance is insensitive to uncertainties. Yet they also exhibit important differences, as they arrange their analyses in different orders, treat losses and gains in different ways, and take different approaches to imprecise probabilistic information. The study finds that the two approaches reach similar but not identical policy recommendations and that their differing attributes raise important questions about their appropriate roles in decision support applications. The comparison not only improves understanding of these specific methods, it also suggests some broader insights into robustness approaches and a framework for comparing them. PMID- 22519665 TI - How do we teach pediatric topics in transfusion medicine: curriculum development, learners, and instructional strategies. PMID- 22519666 TI - Genomic organization and dynamics of repetitive DNA sequences in representatives of three Fagaceae genera. AB - Oaks, chestnuts, and beeches are economically important species of the Fagaceae. To understand the relationship between these members of this family, a deep knowledge of their genome composition and organization is needed. In this work, we have isolated and characterized several AFLP fragments obtained from Quercus rotundifolia Lam. through homology searches in available databases. Genomic polymorphisms involving some of these sequences were evaluated in two species of Quercus, one of Castanea, and one of Fagus with specific primers. Comparative FISH analysis with generated sequences was performed in interphase nuclei of the four species, and the co-immunolocalization of 5-methylcytosine was also studied. Some of the sequences isolated proved to be genus-specific, while others were present in all the genera. Retroelements, either gypsy-like of the Tat/Athila clade or copia-like, are well represented, and most are dispersed in euchromatic regions of these species with no DNA methylation associated, pointing to an interspersed arrangement of these retroelements with potential gene-rich regions. A particular gypsy-sequence is dispersed in oaks and chestnut nuclei, but its confinement to chromocenters in beech evidences genome restructuring events during evolution of Fagaceae. Several sequences generated in this study proved to be good tools to comparatively study Fagaceae genome organization. PMID- 22519668 TI - Effect of nature and location of defects on bandgap narrowing in black TiO2 nanoparticles. AB - The increasing need for new materials capable of solar fuel generation is central in the development of a green energy economy. In this contribution, we demonstrate that black TiO(2) nanoparticles obtained through a one-step reduction/crystallization process exhibit a bandgap of only 1.85 eV, which matches well with visible light absorption. The electronic structure of black TiO(2) nanoparticles is determined by the unique crystalline and defective core/disordered shell morphology. We introduce new insights that will be useful for the design of nanostructured photocatalysts for energy applications. PMID- 22519667 TI - Structure and activity of the cold-active and anion-activated carboxyl esterase OLEI01171 from the oil-degrading marine bacterium Oleispira antarctica. AB - The uncharacterized alpha/beta-hydrolase protein OLEI01171 from the psychrophilic marine bacterium Oleispira antarctica belongs to the PF00756 family of putative esterases, which also includes human esterase D. In the present paper we show that purified recombinant OLEI01171 exhibits high esterase activity against the model esterase substrate alpha-naphthyl acetate at 5-30 degrees C with maximal activity at 15-20 degrees C. The esterase activity of OLEI01171 was stimulated 3 8-fold by the addition of chloride or several other anions (0.1-1.0 M). Compared with mesophilic PF00756 esterases, OLEI01171 exhibited a lower overall protein thermostability. Two crystal structures of OLEI01171 were solved at 1.75 and 2.1 A resolution and revealed a classical serine hydrolase catalytic triad and the presence of a chloride or bromide ion bound in the active site close to the catalytic Ser148. Both anions were found to co-ordinate a potential catalytic water molecule located in the vicinity of the catalytic triad His257. The results of the present study suggest that the bound anion perhaps contributes to the polarization of the catalytic water molecule and increases the rate of the hydrolysis of an acyl-enzyme intermediate. Alanine replacement mutagenesis of OLEI01171 identified ten amino acid residues important for esterase activity. The replacement of Asn225 by lysine had no significant effect on the activity or thermostability of OLEI01171, but resulted in a detectable increase of activity at 35-45 degrees C. The present study has provided insight into the molecular mechanisms of activity of a cold-active and anion-activated carboxyl esterase. PMID- 22519669 TI - Controllable p-n switching behaviors of GaAs nanowires via an interface effect. AB - Due to the extraordinary large surface-to-volume ratio, surface effects on semiconductor nanowires have been extensively investigated in recent years for various technological applications. Here, we present a facile interface trapping approach to alter electronic transport properties of GaAs nanowires as a function of diameter utilizing the acceptor-like defect states located between the intrinsic nanowire and its amorphous native oxide shell. Using a nanowire field effect transistor (FET) device structure, p- to n-channel switching behaviors have been achieved with increasing NW diameters. Interestingly, this oxide interface is shown to induce a space-charge layer penetrating deep into the thin nanowire to deplete all electrons, leading to inversion and thus p-type conduction as compared to the thick and intrinsically n-type GaAs NWs. More generally, all of these might also be applicable to other nanowire material systems with similar interface trapping effects; therefore, careful device design considerations are required for achieving the optimal nanowire device performances. PMID- 22519670 TI - Acetone precipitation of the scrapie agent results in successful recovery of PrP(Sc) but decreased infectivity. AB - Bioassay is considered the most sensitive method for evaluating prion inactivation procedures. Because prions are resistant to methods effective at inactivating conventional microorganisms, prion inactivation research has focused on relatively harsh alternatives, such as concentrated sodium hypochlorite or sodium hydroxide. Often, bioassay for residual infectivity in these studies requires dilution or biochemical alteration of the treated sample in order to maintain subject health and survival. Ideally, prions from treated samples could be sufficiently separated from the inactivating agent without alteration of the sample and with negligible loss of infectivity prior to inoculation into the bioassay host. The current study was designed to evaluate acetone precipitation of the disease-associated form of the prion protein (PrP(Sc)) from brain homogenate derived from mice with the RML (Rocky Mountain Laboratory) strain of scrapie. The ability to recover PrP(Sc) was evaluated by Western blot. Dilutions of acetone-precipitated RML-positive brain homogenate were compared to nonprecipitated RML homogenate, resulting in similar PrP(Sc) detection levels down to 0.025 mg equivalents of brain tissue. The impact of the method on infectivity was investigated by bioassay in intracranially inoculated tga20 mice. Additionally, contributions to infectivity from the pellet and supernatant fractions were investigated. Acetone precipitation resulted in a 1-log10 reduction in infectivity. Infectivity could not be reconstituted by the acetone soluble fraction of the infectious sample or uninfected brain. This study demonstrates that PrP(Sc) can successfully be precipitated out of infected brain homogenate using acetone but that there is a reduction in infectivity attributable to the procedure that would need to be considered when evaluating bioassay results. PMID- 22519671 TI - Marginal public health gain of screening for colorectal cancer: modelling study, based on WHO and national databases in the Nordic countries. AB - AIMS: To estimate the potential gain of national screening programmes for colorectal cancer (CRC) by stool occult blood testing in the Nordic countries, with comparative reference to the burden of other causes of premature death. METHODS: Implementation of national screening programmes for CRC was modelled among people 55-74 years in accordance with the 2011 Cochrane review of biannual screening, using the faecal occult blood test (FOBT) for 10 years, resulting in 15% relative risk reduction in CRC deaths among all those invited [intention-to treat; relative risk 0.85; confidence interval (CI) 0.78 to 0.92]. Our calculations are based on the World Health Organization and national databanks on death causes (ICD-10) and the mid-year number of inhabitants in the target group. For Finland, Denmark, Norway and Sweden, we used data for 2009. For Iceland, due to the population's small size, we calculated mean mortality for the period 2005 2009. RESULTS: Invitation to a CRC screening programme for 10 years could influence 0.5-0.9% (95%CI 0.4-1.2) of all deaths in the age group 65-74 years. Among the remaining 99% of premature deaths, around 50% were caused by lung cancer, other lung diseases, cardiovascular diseases and accidents, with some national variations. CONCLUSIONS AND IMPLICATIONS: Establishment of a screening programme for CRC for people aged 55-74 can be expected to affect only a minor proportion of all premature deaths in the Nordic setting. From a public health perspective, prioritizing preventive strategies targeting more prevalent causes of premature death may be a superior approach. PMID- 22519672 TI - Assessing nutritional status of acute intermittent porphyria patients. AB - BACKGROUND: Acute intermittent porphyria (AIP) is a metabolic disease of haem synthesis, whose haem precursors may accumulate in the body. A well-balanced diet may prevent the symptoms, so that porphyric patients should be monitored closely during therapy for possible complications concerning any progression of acute porphyria. The aim was to evaluate the nutritional status of patients with AIP and to assess their compliance with nutritional recommendations, comparing the findings with a control group and assessing any possible nutritional deficiency. MATERIAL AND METHODS: Sixteen patients with AIP and a control group were evaluated by means of a lifestyle questionnaire, the Nutrition Screening Initiative checklist and a dietary questionnaire. The following diet quality indicators were calculated: animal and vegetal proteins, protein quality index, PUFA/SFA and MUFA + PUFA/SFA ratios, insoluble dietary fibre (DF)/total DF, soluble DF/total DF and insoluble DF/soluble DF ratios, thiamine, riboflavin and niacin density and the vitamin B6/protein ratio. STATISTICAL METHODS: Differences in continuous variables were compared using the unpaired Student's t-test and the chi-square test for nonparametric variables. The odds ratio (OR) of malnutrition was also used. RESULTS: Our patients showed a low intake of carbohydrates, a high lipid intake and very high protein intake, and accompanied by an inadequate intake of zinc, folic acid and tocopherol, increasing the risk of malnutrition for energy, Ca, Fe, Mg, K, folic acid and tocopherols. CONCLUSIONS: The patients with AIP studied individually show an increased risk of malnutrition and, given the potential increase of oxidative stress in patients with porphyria, it is recommended that they should increase their intake of carbohydrates, minerals and antioxidant nutrients. PMID- 22519673 TI - Drug hypersensitivity reactions targeting the skin in dogs and cats. AB - Adverse drug reactions (ADRs) can be dose dependent or idiosyncratic. Most idiosyncratic reactions are believed to be immune-mediated; such drug hypersensitivities and allergies are unpredictable. Cutaneous reactions are the most common presentation of drug allergies. In veterinary medicine it can be difficult to assess the true prevalence of adverse drug reactions, although reports available suggest that they occur quite commonly. There are multiple theories that attempt to explain how drug allergies occur, because the pathogenesis is not yet well understood. These include the (pro)-hapten hypothesis, the Danger Theory, the pi concept, and the viral reactivation theory. Cutaneous drug allergies in veterinary medicine can have a variety of clinical manifestations, ranging from pruritus to often fatal toxic epidermal necrolysis. Diagnosis can be challenging, as the reactions are highly pleomorphic and may be mistaken for other dermatologic diseases. One must rely heavily on history and physical examination to rule out other possibilities. Dechallenge of the drug, histopathology, and other diagnostic tests can help to confirm the diagnosis. New diagnostic tools are beginning to be used, such as antibody or cellular testing, and may be used more in the future. There is much yet to learn about drug allergies, which makes future research vitally important. Treatment of drug allergies involves supportive care, and additional treatments, such as immunosuppressive medications, depend on the manifestation of the disease. Of utmost importance is to avoid the use of the incriminating drug in future treatment of the patient, as subsequent reactions can be worse, and ultimately can prove fatal. PMID- 22519674 TI - Noise, artifact, and oversensing related inappropriate ICD shock evaluation: ALTITUDE noise study. AB - BACKGROUND: Approximately 12-21% of implantable cardioverter defibrillator (ICD) patients receive inappropriate shocks. We sought to determine the incidence and causes of noise/artifact and oversensing (NAO) resulting in ICD shocks. METHODS: A random sample of 2,000 patients who received ICD and cardiac resynchronization therapy defibrillator shocks and were followed by a remote monitoring system was included. Seven electrophysiologists analyzed stored electrograms from the 5,279 shock episodes. Episodes were adjudicated as appropriate or inappropriate shocks. RESULTS: Of the 5,248 shock episodes with complete adjudication, 1,570 (30%) were judged to be inappropriate shocks. Of these 1,570, 134 (8.5%) were a result of NAO. The 134 NAO episodes were determined to be due to external noise in 76 (57%), lead connector-related in 37 (28%), muscle noise in 11 (8%), oversensing of atrium in seven (5%), T-wave oversensing in two (2%), and other noise in one (1%). The ICD shock itself resulted in a marked decrease in the level of noise in 60 of 134 (45%) NAO episodes, and the magnitude of this effect varied with the type of NAO (58% for external noise, 35% for muscle, 27% for lead/connector, and 0% for oversensing; P = 0.03). There was no significant difference in NAO likelihood based on type of lead (integrated bipolar 89/1,802 vs dedicated bipolar 9/140, P = 0.67). CONCLUSIONS: External noise and lead/connector noise were the primary causes, while T-wave oversensing was the least common cause of NAO resulting in ICD shock. Noise/artifact decreased immediately after a shock in nearly half of episodes. The specific ICD lead type did not impact the likelihood of NAO. PMID- 22519675 TI - Sperm chromatin integrity may predict future fertility for unexplained recurrent spontaneous abortion patients. AB - The pathogenesis of recurrent spontaneous abortion (RSA) is multi-factorial, complex and poorly understood. In the present study, semen parameters, including sperm chromatin integrity, sperm concentration, sperm motility and sperm morphology, were compared between 111 men whose partners had a history of unexplained RSA (RSA group) and 30 healthy fertile men (control group). The RSA group was further separated into three subgroups, depending on their reproductive outcome during the 12 months after they were enrolled in the study: the pregnancy subgroup consisted of 43 men whose partners achieved a successful pregnancy up to at least the 24th week of gestation; the abortion subgroup included 31 men whose partners experienced further abortions; and the infertile subgroup had 37 men whose partners did not have any positive pregnancy test after regular, unprotected intercourse. Significantly lower proportion of sperm with normal morphology was found in the abortion subgroup (14.7 +/- 4.3%) than in the control group (17.5 +/- 5.0%). Sperm concentrations were significantly lower in the infertile subgroup (55.7 +/- 24.1%) than in the controls (68.6 +/- 27.8%). The rates of abnormal sperm chromatin integrity were significantly higher in the abortion (16.7 +/- 7.7%) and infertile (16.3 +/- 6.6%) subgroups, compared to the control group (13.0 +/- 4.4%). Logistic regression analysis showed that the subsequent reproductive outcome of the 111 RSA patients was negatively correlated to the rates of abnormal sperm chromatin integrity. In conclusion, sperm chromatin integrity, sperm morphology, and sperm concentration were associated with future reproductive outcome of RSA patients. The sperm chromatin integrity was a significant predictor for future abortion and infertility. PMID- 22519676 TI - Word regularity affects orthographic learning. AB - Share's self-teaching hypothesis proposes that orthographic representations are acquired via phonological decoding. A key, yet untested, prediction of this theory is that there should be an effect of word regularity on the number and quality of word-specific orthographic representations that children acquire. Thirty-four Grade 2 children were exposed to the sound and meaning of eight novel words and were then presented with those words in written form in short stories. Half the words were assigned regular pronunciations and half irregular pronunciations. Lexical decision and spelling tasks conducted 10 days later revealed that the children's orthographic representations of the regular words appeared to be stronger and more extensive than those of the irregular words. PMID- 22519677 TI - Changes in isoflavone profiles of soybean treated with gamma irradiation. AB - Soybean is an important Brazilian agricultural commodity that contains a high concentration of isoflavones. Many studies showed that isoflavones are active in the prevention of many human diseases. However, the correct processing techniques used to prepare the soy foodstuffs are important to maintain the active forms. The objective of this study was to evaluate the effect of gamma irradiation on the isoflavone contents of the defatted soybean flour when compared with soybean molasses, a derivative from the soybean food production. After extracting phenolic compounds with methanol aqueous solution (80%), isoflavones were detected by reverse-phase high-performance liquid chromatography/diode-array detector. The radiation doses of 2 and 5 kGy presented a small effect on the isoflavones content of defatted soy flour. Samples irradiated at 50 kGy showed lower isoflavone contents. The observed reduction in the concentration of isoflavones-daidzein, glycitein and genistein-induced by gamma radiation in soy molasses was not significant in defatted soy flour, thus suggesting that isoflavones in defatted soy flour were not eliminated by gamma radiation at rates up to 50 kGy. PMID- 22519678 TI - Determination of catechin in lotus rhizomes by high-performance liquid chromatography. AB - A novel method was developed to analyze lotus rhizome polyphenolic catechin using high-performance liquid chromatography (HPLC). The retain time of catechin was 14.72 min under the optimized condition. Mass spectrometry was further employed to qualify and quantify the purity of the catechin peak. Good linearity (R=0.9997) was obtained within the range of 50-1,000 ng. The coefficient of variance was determined as 5.2%, with a recovery rate of 97%. The detection and quantification limitations of catechin were 23 ng and 50 ng, respectively. The catechin level was 0.0025% in the lotus rhizome, and 0.011% in the knot of the lotus rhizome (Nelumbo nucifera cv. 'damao jie'). The optimized conditions of HPLC for catechin detection in the lotus rhizome matrix were as follows: the SuperlcosILTM LC-18 analytical column (150 mm*4.6 mm, 5 um), methanol-water acetic acid (10:90:1, volume ratio) as the mobile phase, an UV detector at 280 nm, a flow rate of 0.8 ml/min, column temperature at 30 degrees C, and an injection volume of 10 ul. PMID- 22519679 TI - In vitro antifungal activity of Indian liposomal amphotericin B against clinical isolates of emerging species of yeast and moulds, and its comparison with amphotericin B deoxycholate, voriconazole, itraconazole and fluconazole. AB - Fungisome(TM) is a liposomal preparation of amphotericin B (AMB), already marketed in India. However, its antifungal activity has not been evaluated against a wide range of fungal pathogens. The study was planned to elucidate the in vitro antifungal activity of Fungisome(TM) against wide range of fungi and compare it with AMB deoxycholate (AMB-d), voriconazole (VOR), itraconazole (ITR) and fluconazole (FLU). Minimum inhibitory concentrations (MICs) of the drugs were determined for 262 clinical fungal isolates, including yeast, dimorphic and filamentous fungi, by broth microdilution method approved by Clinical and Laboratory Standards Institute, USA (yeast, M27-A3; filamentous fungi, M38-A2). The MIC(90s) of Fungisome(TM) were 0.125, 0.5 and 0.25 mg l(-1) against yeast, filamentous and dimorphic fungi respectively. In comparison, MIC(90s) of AMB-d, FLU, ITR and VOR were 1, 1 and 1 mg l(-1) (AMB-d), 4, 64 and 64 mg l(-1) (FLU), 1, 16 and 16 mg l(-1) (ITR) and 0.5, 4 and 16 mg l(-1) (VOR) against yeast, filamentous and dimorphic fungi respectively. The MIC of Fungisome(TM) was two to 16-fold lower than AMB-d. These results reveal an efficient in vitro activity of Fungisome(TM). PMID- 22519680 TI - Condom use problems during anal sex among men who have sex with men (MSM): findings from the Safe in the City study. AB - Our research aims were to: (1) assess the prevalence of two condom use problems: breakage or slippage and partial use (delayed application or early removal) among men who have sex with men (MSM) seeking services in urban US STD clinics; and (2) examine the association between these condom use problems and participant, partner and partnership characteristics. Analysis was restricted to HIV-negative MSM who reported having anal sex at least once in the preceding 3 months and who completed both the baseline and 3 month follow-up assessments. Two models were fitted using the generalized estimating equations (GEE) approach. A total of 263 MSM (median age=32 years) reported 990 partnerships. Partnerships with no condom use 422 (42.6%) were excluded. Thus, 207 MSM and 568 partnerships were included. Among condom users, 100% use was reported within 454 partnerships (79.9%) and <100% within 114 (20.1%), and 21(3.7%) reported both condom use problems, 25 (4.4%) reported only breakage, 67 (11.8%) reported only partial use, and 455 (80.1%) reported no errors. The breakage or slippage and partial use rates per condom used were 3.4% and 11.2%, respectively. A significantly higher rate of breakage or slippage occurred among non-main partnerships. Characteristics associated with increased odds for condom breakage or slippage were: lower education level (OR=2.78; CI: 1.1-7.5), non-main partner status (OR=4.1; CI: 1.5 11.7), and drunk or high during sex (OR=2.0; CI: 1.1-3.8), and for partial use: lower education level (OR=2.6; CI: 1.0-6.6), perceived partner sexually transmitted infections (STI) risk (OR=2.4; CI: 1.3-4.2), and inconsistent condom use (OR=3.7; CI: 2.0-6.6). A high percentage of MSM partnerships reported no condom use and among condom users, a sizable proportion did not use them consistently or correctly. MSM may benefit from interventions designed to increase proficiency for condom use with a particular focus on the behaviors of inconsistent and partial condom use. PMID- 22519681 TI - Morphology and separation efficiency of low-aspect-ratio capillary ultrahigh pressure liquid chromatography columns. AB - We derive a quantitative relationship between the bed morphology and the chromatographic separation efficiency of capillary columns packed with sub-2 MUm particles, covering capillary inner diameters from 10 to 75 MUm. Our study focuses on wall effects and their impact on band broadening at increasing column to-particle diameter (aspect) ratios. We approach these complex effects by a morphological analysis of reconstructed column segments composed of several thousand particles that were imaged by confocal laser scanning microscopy. Radial interparticle porosity profiles including wall effects are quantified through an integral porosity deviation, a scalar measure that proves to be a general descriptor of transcolumn porosity heterogeneity. It correlates with the associated transcolumn eddy dispersion, which dominates band broadening in the capillaries and is visualized in the plate height curves by a simple velocity proportional term. Our comprehensive approach identifies the packing structure features that contribute to decreased efficiency as reflected, e.g., in subtle variations of the wall effect at different aspect ratios, or a particle size segregation effect in larger-diameter columns as a result of an increased number of packing voids near the wall-bed interface. PMID- 22519682 TI - The BioStent: novel concept for a viable stent structure. AB - OBJECTIVES: Percutaneous stenting of occluded peripheral vessels is a well established technique in clinical practice. Unfortunately, the patency rates of small-caliber vessels after stenting remain unsatisfactory. The aim of the BioStent concept is to overcome in-stent restenosis by excluding the diseased vessel segment entirely from the blood stream, in addition to providing an intact endothelial cell layer. DESIGN: The concept combines the principles of vascular tissue engineering with a self-expanding stent: casting of the stent within a cellularized fibrin gel structure, followed by bioreactor conditioning, allows complete integration of the stent within engineered tissue. MATERIALS AND METHODS: Small-caliber BioStents (O=6 mm; n=4) were produced by casting a nitinol stent within a thin fibrin/vascular smooth muscle cell (vSMC) mixture, followed by luminal endothelial cell seeding, and conditioning of the BioStent within a bioreactor system. The potential remodeling of the fibrin component into tissue was analyzed using routine histological methods. Scanning electron microscopy was used to assess the luminal endothelial cell coverage following the conditioning phase and crimping of the stent. RESULTS: The BioStent was shown to be noncytotoxic, with no significant effect on cell proliferation. Gross and microscopic analysis revealed complete integration of the nitinol component within a viable tissue structure. Hematoxylin and eosin staining revealed a homogenous distribution of vSMCs throughout the thickness of the BioStent, while a smooth, confluent luminal endothelial cell lining was evident and not significantly affected by the crimping/release process. CONCLUSIONS: The BioStent concept is a platform technology offering a novel opportunity to generate a viable, self-expanding stent structure with a functional endothelial cell lining. This platform technology can be transferred to different applications depending on the luminal cell lining required. PMID- 22519683 TI - Development and validation of a prediction model for low hemoglobin deferral in a large cohort of whole blood donors. AB - BACKGROUND: Each year, approximately 5% of the invited blood donors is eventually deferred from donation because of low hemoglobin (Hb) levels. Estimating the risk of Hb deferral in blood donors can be helpful in the management of the donation program. We developed and validated a prediction model for Hb deferral in whole blood donors, separately for men and women. STUDY DESIGN AND METHODS: Data from a Dutch prospective cohort of 220,946 whole blood donors were used to identify predictors for Hb deferral using multivariable logistic regression analyses. Validity of the prediction models was assessed with a cross-validation. RESULTS: A total of 12,865 donors (5.8%) were deferred because of a low Hb level. The strongest predictors of Hb deferral were Hb level measured at the previous visit, age, seasonality, difference in Hb levels between the previous two visits, time since the previous visit, deferral at the previous visit, and the total number of whole blood donations in the past 2 years for both men and women. The prediction models had an area under the receiver operating characteristic curve of 0.89 for men and 0.84 for women. Cross-validation showed similar results and good calibration. CONCLUSION: Using a limited number of easy-to-measure characteristics enables a good prediction of Hb deferral risk in whole blood donors. The prediction models may guide the decision which donors to invite for a next donation and for which donors the invitation should be postponed. Potentially, this could decrease the number of Hb deferrals in blood donors. PMID- 22519684 TI - 'Do more, smoke less!' Harm reduction in action for smokers with mental health/substance use problems who cannot or will not quit. AB - Although smoking rates among mental health/substance abusing populations are very high, the focus of treatment and research has tended to be on substances other than tobacco. A range of harm-reduction strategies is needed, including long-term nicotine maintenance, smokeless tobacco and 'clean' nicotine products. For those who cannot or will not quit, assistance in reducing smoking should be given. Interventions for smoking among people with mental health/substance use problems may best be delivered by addressing multiple health-risk behaviours, especially physical activity, around the same time. PMID- 22519686 TI - Acute and long-term cardiomyopathy and delayed neurotoxicity after accidental lasalocid poisoning in horses. AB - BACKGROUND: Horses are extremely susceptible to ionophore intoxication. Although numerous reports are available regarding monensin, little is known about lasalocid toxicity. OBJECTIVES: To describe accidental lasalocid poisoning on a farm in Belgium. ANIMALS: Eighty-one horses, of which 14 demonstrated clinical signs from day 0-21 after being fed a new concentrate batch. One horse died on day 20 and another on day 27. METHODS: The most severe cases (n = 7), admitted to the clinic on day 29-46, underwent cardiac examination and blood biochemical analysis, including determination of plasma cardiac troponin I (cTnI) at admission and during follow-up. On day 57-70, cardiac examination, cTnI determination or both were undertaken on 72 remaining horses. RESULTS: Short-term effects of lasalocid intoxication included inappetance, lethargy, sweating, and muscular weakness. All 7 horses admitted to the clinic demonstrated signs of myocardial degeneration such as increased cTnI, dysrhythmia and reduced myocardial contractility. Four horses developed ataxia on day 40-50. Five horses died or were euthanized on day 30-370, 2 horses recovered fully and returned to previous athletic use. None of the 72 remaining horses exhibited clinical signs between day 57-70, but 34 had dysrhythmia and 13 had increased cTnI concentrations. After a period of rest, all horses returned to their previous work. Lasalocid was detected in hepatic tissue of 2 necropsied horses. CONCLUSIONS AND CLINICAL IMPORTANCE: Lasalocid intoxication induced myocardial and neurological damage. Although uncommon, this should be included as differential diagnosis for unexplained inappetance, signs of depression, cardiomyopathy, and ataxia in horses. PMID- 22519687 TI - Space confinement and rotation stress induced self-organization of double-helix nanostructure: a nanotube twist with a moving catalyst head. AB - Inorganic materials with double-helix structure have attracted intensive attention due to not only their elegant morphology but also their amazing morphology-related potential applications. The investigation on the formation mechanism of the inorganic double-helix nanostructure is the first step for the fundamental studies of their materials or physical properties. Herein, we demonstrated the space confinement and rotation stress induced self-organization mechanism of the carbon nanotube (CNT)-array double helices under scanning electron microscopy by directly observing their formation process from individual layered double hydroxide flakes, which is a kind of hydrotalcite-like material composed of positively charged layers and charge-balancing interlayer anions. Space confinement is considered to be the most important extrinsic factor for the formation of CNT-array double helices. Synchronous growth of the CNT arrays oppositely from LDH flakes with space confinement on both sides at the same time is essential for the growth of CNT-array double helices. Coiling of the as-grown CNT arrays into double helices will proceed by self-organization, tending to the most stable morphology in order to release their internal rotation stress. Based on the demonstrated mechanism, effective routes were carried out to improve the selectivity for CNT-array double helices. The work provides a promising method for the fabrication of double-helix nanostructures with their two helices connected at the end by self-assembly. PMID- 22519685 TI - Paediatric use of mycophenolate mofetil. AB - A number of medications do not have a licence, or label, for use in the paediatric age group nor for the specific indication for which they are being used in children. Over recent years, mycophenolate mofetil has increasingly been used off-label (i.e. off-licence) in adults for a number of indications, including autoimmune conditions; progressively, this wider use has been extended to children. This review summarizes current use of mycophenolate mofetil (MMF) in children, looking at how MMF works, the pharmacokinetics, the clinical conditions for which it is used, the advantages it has when compared with other immunosuppressants and the unresolved issues remaining with use in children. The review aims to focus on off-label use in children so as to identify areas that require further research and investigation. The overall commercial value of MMF is limited because it has now come off patent in adults. Given the increasing knowledge of the pharmacodynamics, pharmacokinetics and pharmacogenomics demonstrating the clinical benefits of MMF, new, formal, investigator-led studies, including trials focusing on the use of MMF in children, would be of immense value. PMID- 22519688 TI - Syntheses and structures of three complexes of formulas [L3Co(MU2 O2P(Bn)2)3CoL'][L"], featuring octahedral and tetrahedral cobalt(II) geometries; variable-temperature magnetic susceptibility measurement and analysis on [(py)3Co(MU2-O2PBn2)3Co(py)][ClO4]. AB - The syntheses and structural properties of three dinuclear complexes [L(3)Co(MU(2)-O(2)P(Bn)(2))(3)CoL'][L"] [one ionic L(3) = py(3), L' = py, L" = ClO(4)(-) (1) and two molecular L(3) = py(3), L' = Cl (2) and L(3) = py, MU(2) NO(3)(-), L' = py (3)] are reported. Complexes feature octahedral Co(II) sites bridged by three dibenzylphosphinate ligands to a tetrahedrally ligated Co(II) site, with the remaining coordination sites occupied by py, nitrato, and Cl ligands. The Co-Co distances are 4.248 A at 291 K and 4.265 A at 100 K for 1 and 4.278 and 4.0313(7) A for 2 and 3, respectively at 100 K. A fit of the low temperature magnetic susceptibility data was derived for complex 1 with g = 2.25, TIP = 700 * 10(-6) cm(3) mol (-1), lambda = -173 cm(-1), kappa = 0.93, nu = -3.9, Delta = 630 cm(-1), J = 0.15 cm(-1), and theta = -1.8 resulting in R(chi(M)) = 2.5 * 10(-5) and R(chi(M)T) = 5.8 * 10(-5). PMID- 22519689 TI - Is there a difference in laterality during robot-assisted radical prostatectomy? Assessment of lymph node yield and neurovascular bundle dissection. AB - BACKGROUND AND PURPOSE: The da Vinci Surgical System (dVSS) has been reported to eliminate innate hand dominance of the surgeon. There are no studies to date, however, that specifically address whether the dVSS has its own inherent "handedness" resulting from the fixed left-right preference of specific instrument docking and assistant positioning. We identified the pelvic lymph node (LN) and neurovascular bundle (NVB) dissections as well as positive surgical margin rates as procedure points during robot-assisted radical prostatectomy (RARP) that could be influenced by laterality and sought to illustrate left-right consistency. PATIENTS AND METHODS: Patients who underwent RARP by a single right handed surgeon (KKB) between 2008 and 2010 were identified. Surgeon instrument preference and port placement were consistent across all cases. Pathologic LN yield was stratified by the intended limits of dissection (limited or extended) and laterality. In addition, fascial widths (FW) were prospectively measured for 93 consecutive patients, a narrower FW indicating a more precise intended NVB dissection. The pathologists were blinded to intended dissections. RESULTS: A total of 340 limited, 11 bilateral extended, 11 right extended, and 5 left extended LN dissections were performed. For patients undergoing limited LN dissection, the mean LN yield was greater on the right compared with the left (3.26 vs 2.76, P=0.010). This difference was not seen in the extended LN dissection (P=0.96). Average FW was narrower on the right surgical margin compared with the left (1.99 vs 2.64 mm, P<0.001). CONCLUSIONS: Our findings suggest that a greater number of LNs and a closer NVB dissection are achieved on the right compared with the left using the dVSS during RARP. This can be attributed to surgeon handedness, robotic instrument laterality, or assistant instrument laterality. Surgeon awareness of these potential differences is important for the preoperative planning before RARP. PMID- 22519690 TI - Ultrasonic measurement of the effects of adhesive application and power density on the polymerization behavior of core build-up resins. AB - OBJECTIVE: To use ultrasonic measurements to monitor the effects of adhesive application and power density on the polymerization behavior of dual-cured core build-up resins. METHODS: Ultrasonic measurements were carried out using a pulser receiver, transducers and an oscilloscope. The core build-up resins were mixed, inserted into a transparent mold and then placed onto a sample stage with or without self-etch adhesive. Power densities of 0 (no light irradiation), 200 and 600 mW/cm(2) were used for curing. The transit time through the core build-up resin disk was divided by the specimen thickness to obtain the longitudinal sound velocity (V). RESULTS: Light irradiation of the core build-up resins at a power density of 600 mW/cm(2) caused V values to rise to an initial plateau of 1550 1650 m/s, then to rise rapidly to a second plateau of 2800-3200 m/s. The rate of V increase was slower when the resin cements were light-irradiated and became faster when irradiated at a higher power density. There were no significant differences between the groups with or without adhesive. CONCLUSIONS: The polymerization behavior of the core build-up resins was affected by the power density of the curing unit. The influence of adhesive application differed among the core build-up resins tested. PMID- 22519691 TI - Assessment of phylogenetic structure in genome size--gene content correlations. AB - Gene content and gene-coding percentage can be predicted from genome size in newly sequenced organisms. Here, we investigate whether these predictions are influenced by phylogenetic relationships between the involved species. Combining a highly resolved phylogenetic tree with a large compilation of gene content data, our results reveal the presence of significant phylogenetic structure in the correlations between genome size and gene content in both bacteria and eukaryotes. The variation in log(gene content) explained by log(genome size) in combination with phylogeny was found to be 97% in bacteria and 55% in eukaryotes. Further, in bacteria, gene-coding percentages are only significantly correlated to genome size if phylogenetic information is taken into account in the analyses. These findings support the usage of phylogenetic correlation models for gene content predictions. PMID- 22519692 TI - Effect of drying technique on some physical properties of cross-linked high amylose/pectin mixtures. AB - Polymers mixtures as well as cross-linking reactions are approaches that have been used successfully to modulate the polymers characteristics in order to improve the control over drug release rate. High amylose and pectin are polysaccharides frequently used to prepare drug delivery systems. Since the drying technique can strongly influence the properties of such systems, the aim of this work was to characterize high amylose/pectin mixtures cross-linked with sodium trimetaphosphate and dried by different techniques - oven and lyophilization. The results showed that samples dried by lyophilization presented reduced particle size, higher porosity and higher swelling ability than the samples dried in oven. Besides, lower thermal stability and different diffraction patterns showed by the former particles should reflect the structural changes as a function of drying technique. PMID- 22519693 TI - Risk communication, public engagement, and climate change: a role for emotions. AB - This article discusses the potential role that emotions might play in enticing a lifestyle that diminishes climate change. Climate change is an important challenge for society. There is a growing consensus that climate change is due to our behavior, but few people are willing to significantly adapt their lifestyle. Empirical studies show that people lack a sense of urgency: they experience climate change as a problem that affects people in distant places and in a far future. Several scholars have claimed that emotions might be a necessary tool in communication about climate change. This article sketches a theoretical framework that supports this hypothesis, drawing on insights from the ethics of risk and the philosophy of emotions. It has been shown by various scholars that emotions are important determinants in risk perception. However, emotions are generally considered to be irrational states and are hence excluded from communication and political decision making about risky technologies and climate change, or they are used instrumentally to create support for a position. However, the literature on the ethics of risk shows that the dominant, technocratic approach to risk misses the normative-ethical dimension that is inherent to decisions about acceptable risk. Emotion research shows that emotions are necessary for practical and moral decision making. These insights can be applied to communication about climate change. Emotions are necessary for understanding the moral impact of the risks of climate change, and they also paradigmatically provide for motivation. Emotions might be the missing link in effective communication about climate change. PMID- 22519694 TI - Aberration-corrected transmission electron microscopy of the intergranular phase in magnetic recording media. AB - In perpendicular hard disk memory media, nanometric magnetic Co-rich grains are separated by a ~1 nm thick nonmagnetic and preferably amorphous intergranular phase (IP). Attempts at observing the IP structure at high resolution using TEM have been obstructed by the superposition of lattice fringes from the crystalline grains extending into the IP region in images. Here we present the first images of a magnetic recording medium produced using a spherical aberration-corrected TEM showing the true amorphous IP structure in contrast to the crystalline grains, allowing the accurate determination of the grain-IP interface and the grain and IP dimensions. It is shown that these aberration-corrected TEM images are functionally superior for analyzing certain features of the ultrahigh capacity data recording media. PMID- 22519695 TI - High prevalence of androgen deficiency and abnormal lipid profile in infertile men with non-obstructive azoospermia. AB - In men with non-obstructive azoospermia (NOA), the risk of hypogonadism is often overlooked. Testicular sperm extraction (TESE) may increase this risk. The objective of this study was to elucidate the prevalence of hypogonadism in NOA patients, the impact of TESE on hormone balance and the association between testosterone deficiency and dyslipidaemia. Men with NOA who had undergone TESE during the period 2004-2009 were eligible. Hypogonadism was defined as total testosterone <10 nmol/L and/or LH >10 IU/L and/or ongoing androgen replacement therapy. Sixty-five consecutive men who had undergone TESE owing to NOA and from whom post-TESE serum testosterone levels measured before 1100 h were available. Furthermore, 141 fertile men served as controls. Serum concentrations of testosterone, LH and lipids were assessed. Odds ratios (OR) for biochemical hypogonadism were calculated. Pre- and post-TESE hormone levels were compared. Lipid profile was related to testosterone levels. Hypogonadism was found in 47% (95% CI, 0.36, 0.59) of the NOA-men. As compared with fertile controls, the OR for hypogonadism post-TESE was 17 (95% CI 6.6-45). Serum LH (p = 0.03), but not testosterone (p = 0.43), differed significantly pre- and post-TESE. Compared with eugonadal NOA-men, the OR for having deviations in lipid profile was 3.3 (95% CI 1.3-8.8) for the hypogonadal NOA-men. NOA-men are at very high risk of androgen deficiency, which even in young subjects is associated with dyslipidaemia. Medical management of these men should therefore include endocrinological evaluation and follow-up after completion of infertility treatment. PMID- 22519696 TI - Exploring the question-behaviour effect: randomized controlled trial of motivational and question-behaviour interventions. AB - PURPOSE: Measuring intentions and other cognitions to perform a behaviour can promote performance of that behaviour (the question-behaviour effect, QBE). It has been suggested that this effect may be amplified for individuals motivated to perform the behaviour. The present research tested the efficacy of combining a motivational intervention (providing personal risk information) with measuring intentions and other cognitions in a fully crossed 2 * 2 design with an objective measure of behaviour in an at-risk population using a randomized controlled trial (RCT). METHODS: Participants with elevated serum cholesterol levels were randomized to one of four conditions: a combined group receiving both a motivational intervention (personalized cardiovascular disease risk information) and a QBE manipulation (completing a questionnaire about diet), one group receiving a motivational intervention, one group receiving a QBE intervention, or one group receiving neither. All participants subsequently had the opportunity to obtain a personalized health plan linked to reducing personal risk for coronary heart disease. RESULTS: Neither the motivational nor the QBE manipulations alone significantly increased rates of obtaining the health plan. However, the interaction between conditions was significant. Decomposition of the interaction indicated that the combined condition (motivational plus QBE manipulation) produced significantly higher rates of obtaining the health plan (96.2%) compared to the other three groups combined (80.3%). CONCLUSIONS: The findings provide insights into the mechanism underlying the QBE and suggest the importance of motivation to perform the behaviour in observing the effect. STATEMENT OF CONTRIBUTION: What is already known on this subject? Research has indicated that merely asking questions about a behaviour may be sufficient to produce changes in that or related behaviours (referred to as the question-behaviour effect; QBE). Previous studies have suggested that the QBE may be moderated by the individual's motivation to change the behaviour, i.e., the QBE will only produce increases in the behaviour among those with strong motivation to perform the behaviour. However, no study has directly tested this prediction by manipulating motivation and examining impacts on the QBE. What does this study add? The present study tested the individual and combined effects of a motivational and a QBE intervention in a fully crossed design using a randomized controlled trial (RCT) and showed that: a combined intervention significantly increased behaviour. effect partially mediated by cognitions. PMID- 22519697 TI - Forced bachelors, migration and HIV transmission risk in the context of China's gender imbalance: a meta-analysis. AB - China has experienced continual increase in the sex ratio at birth (SRB) since the 1980s, which has led to a serious gender imbalance. To identify whether the future forced bachelors, especially those who migrate to cities, will increase the risk of HIV spread, a systematic review was carried out of studies published since 2000 that include the sexual risks of male migrants of China. Five studies comparing risk differences between migrants and non-migrants showed male migrants had greater risk of having multiple sexual partners and engaging in commercial sex. Ten studies concerning the relationship between sexual risks and socio demographic characteristics showed that unmarried male migrants were more likely to engage in commercial sex and be infected with STDs than married migrants, while male migrants with higher income were more likely to have multiple sexual partners and be infected with STDs. In an analysis stratified by sample characteristics, the association between marriage and sexual risk was greater among samples with lower mean age, higher average income and education. In addition, the risk selection on education and income disappeared in the samples of migrants of whom more than half were unmarried. PMID- 22519698 TI - Reduced inbreeding depression in peripheral relative to central populations of a monocarpic herb. AB - Many temperate taxa were confined to warmer latitudes during the last glacial maximum. As their ranges expanded when climates warmed, genetic drift and inbreeding in relatively small peripheral populations are expected to have reduced genetic diversity and the segregating genetic load. Therefore, inbreeding depression in peripheral populations might be lower than in centrally located sites. We evaluated the consequences of inbreeding for fitness traits in six central and six northern peripheral populations of the herb Campanulastrum americanum. Inbreeding reduced performance for all traits. Inbreeding depression in peripheral populations was lower than in central populations. This difference increased across the life cycle from similar levels for germination, to central populations having three times the inbreeding depression for adult traits. Geographical patterns of inbreeding depression suggest that mating system variation and potential future mating system evolution in many temperate taxa might reflect, at least in part, nonequilibrium conditions associated with historic range changes. PMID- 22519699 TI - Electrochemical aptamer-based sandwich assays for the detection of explosives. AB - Electrochemical impedance spectroscopy (EIS) is used to detect 2,4,6 trinitrotoluene (TNT) in a novel sandwiched structure which relies on the specific interactions between (i) primary amine with TNT and (ii) TNT and anti TNT aptamer. With pure targets, the assay has a sensitivity of 10(-14) M, a dynamic range of 10(-14)-10(-3) M, and employs a small sample volume (25 MUL). The method's sensitivity is comparable to state of the art optical methods with the added advantages of electrochemical detection, which can be easily miniaturized and implemented into a hand-held device. PMID- 22519700 TI - Implementation of proteomic biomarkers: making it work. AB - While large numbers of proteomic biomarkers have been described, they are generally not implemented in medical practice. We have investigated the reasons for this shortcoming, focusing on hurdles downstream of biomarker verification, and describe major obstacles and possible solutions to ease valid biomarker implementation. Some of the problems lie in suboptimal biomarker discovery and validation, especially lack of validated platforms with well-described performance characteristics to support biomarker qualification. These issues have been acknowledged and are being addressed, raising the hope that valid biomarkers may start accumulating in the foreseeable future. However, successful biomarker discovery and qualification alone does not suffice for successful implementation. Additional challenges include, among others, limited access to appropriate specimens and insufficient funding, the need to validate new biomarker utility in interventional trials, and large communication gaps between the parties involved in implementation. To address this problem, we propose an implementation roadmap. The implementation effort needs to involve a wide variety of stakeholders (clinicians, statisticians, health economists, and representatives of patient groups, health insurance, pharmaceutical companies, biobanks, and regulatory agencies). Knowledgeable panels with adequate representation of all these stakeholders may facilitate biomarker evaluation and guide implementation for the specific context of use. This approach may avoid unwarranted delays or failure to implement potentially useful biomarkers, and may expedite meaningful contributions of the biomarker community to healthcare. PMID- 22519701 TI - Hydrogen-bond symmetry in difluoromaleate monoanion. AB - The symmetry of the hydrogen bond in hydrogen difluoromaleate monoanion is probed by X-ray crystallography and by the NMR method of isotopic perturbation in water, in two aprotic organic solvents, and in an isotropic liquid crystal. The X-ray crystal structure of potassium hydrogen difluoromaleate shows a remarkably short O-O distance of 2.41 A and equal O-H distances of 1.206 A, consistent with a strong and symmetric hydrogen bond. Incorporation of (18)O into one carboxyl group allows investigation of the symmetry of the H-bond in solution by the method of isotopic perturbation. The (19)F NMR spectra of the mono-(18)O substituted monoanion in water, CD(2)Cl(2), and CD(3)CN show an AB spin system, corresponding to fluorines in different environments. The difference is attributed to the perturbation of the acidity of a carboxylic acid by (18)O, not to the mere presence of the (18)O, because the mono-(18)O dianion shows equivalent fluorines. Therefore, it is concluded that the monoanion exists as an equilibrating pair of interconverting tautomers and not as a single symmetric structure not only in water but also in organic solvents. However, in the isotropic liquid crystal phase of 4-cyanophenyl 4-heptylbenzoate, tetrabutylammonium hydrogen difluoromaleate-(18)O shows equivalent fluorines, consistent with a single symmetric structure. These results support earlier studies, which suggested that the symmetry of hydrogen bonds can be determined by the local environment. PMID- 22519703 TI - Strengthening national laboratory health systems in the Caribbean Region. AB - The President's Emergency Plan for AIDS Relief (PEPFAR) programme for the Caribbean Region was established in 2008 to address health system challenges, including fragile laboratory services and systems. The laboratory component of this programme consisted of several phases: assessment of laboratory needs of all 12 countries engaged in the programme; addressing gaps identified during the assessment; and monitoring and evaluation of the progress achieved. After one year of PEPFAR collaboration with national governments and other partners, laboratory services and systems greatly improved. Some of the milestones include: (1) the accreditation of a public laboratory; (2) improved access to HIV diagnosis with faster turnaround time; (3) establishment of capacity for platforms for DNA PCR, viral load and HIV drug resistance; (4) development of the laboratory workforce; and (5) establishment of a framework for implementation of sustainable quality management systems for laboratory accreditation. The progress recorded in strengthening laboratory health systems after one year of initiating this collaboration shows that with a rigorous initial assessment, programme design and intervention and strategic partnership, national laboratory health systems can be greatly enhanced to support programme implementation. Continued collaboration and country leadership is critical to create an integrated and sustainable laboratory network in the Caribbean. PMID- 22519702 TI - SP-1 regulation of MMP-9 expression requires Ser586 in the PEST domain. AB - Rac1, a small GTPase, regulates macrophage MMP (matrix metalloproteinase)-9 in an ERK (extracellular-signal-regulated kinase)- and SP (specificity protein)-1 dependent manner. SP-1 contains a PEST (Pro-Glu-Ser-Thr) domain that may modulate protein stability. We hypothesize that Thr578, Ser586 and/or Ser587 in the PEST domain are required for SP-1 stability and MMP-9 expression secondary to activation of ERK, a serine/threonine kinase. We determined the effects of Rac1 and ERK on MMP-9 expression driven by SP-1WT (wild-type) and the SP-1 mutants T578A, S586A and S587A. Expression of WT and mutant SP-1 increased MMP9 promoter activity in alveolar macrophages. However, constitutively active Rac1 suppressed MMP9 promoter activity in cells expressing SP-1WT, SP-1T578A and SP-1S587A, but not SP-1S586A. Furthermore, constitutive ERK activation, which was inhibited by Rac1, significantly increased MMP9 transcription in cells expressing SP-1WT, but not SP-1S586A. As Rac1 activation and ERK inactivation increased degradation of SP-1WT and not SP-1S586A, the results of the present study suggest that SP-1 stability mediated at Ser586 regulates MMP9 transcription. Ex vivo, alveolar macrophages obtained from patients with asbestosis had less MMP-9 expression that was associated with decreased SP-1 expression and ERK activation. These observations demonstrate that Ser586 in the PEST domain of SP-1 is important for MMP9 gene expression in alveolar macrophages and highlight the importance of these proteins in pulmonary fibrosis. PMID- 22519705 TI - Levonorgestrel-releasing intrauterine system versus laparoscopic supracervical hysterectomy for the treatment of heavy menstrual bleeding: a randomized study. AB - BACKGROUND: The optimal treatment of heavy menstrual bleeding (HMB) remains a challenge for the physician. There is a need for further trials to compare the effectiveness and compliance between a levonorgestrel-releasing intrauterine system (LNG-IUS) and minimally invasive types of hysterectomy, for example, laparoscopic supracervical hysterectomy (LSH), in women with HMB. This article is the first to report a randomized trial aimed at comparing postoperative outcomes and effects on quality of life after LNG-IUS or LSH in women with HMB. METHODS: The trial was performed at Tor Vergata University Hospital, Rome. Seventy-two women requiring treatment for HMB were randomly allocated into two treatment arms: LNG-IUS (n=36) or LSH (n=36). The primary outcome was the comparison of the effects on menstrual bleeding (pictorial blood loss assessment chart [PBAC]) at 12 months after the two procedures. The secondary outcome measures were the quality of life, improvement in bleeding patterns, intensity of postoperative pain, and early postoperative complications. A p<0.05 was considered statistically significant. RESULTS: The PBAC score was significantly reduced in both treatment groups. The Medical Outcomes Survey Short Form 36 (SF-36) score improved in both groups. A more significant improvement in the parameters Role and Mental health was observed after LNG-IUS. CONCLUSIONS: LNG-IUS can be considered as first option for the treatment of HMB unresponsive to drug therapy, and it is particularly suitable for women who want to preserve an acceptable menstrual flow. LSH may be considered the best surgical option in women with HMB unresponsive to any medical treatment. PMID- 22519704 TI - Differences in barriers to mammography between rural and urban women. AB - BACKGROUND: Few studies have examined differences between rural and urban women in mammography barriers, knowledge, and experiences. Exploring differences can help inform tailored interventions. METHODS: Women, aged >=40, who had not been screened in the past 2 years were recruited from eight federally qualified health centers across Louisiana. They were given a structured interview assessing mammography knowledge, beliefs, barriers, experiences, and literacy. RESULTS: Of the 1189 patients who participated, 65.0% were African American, 61.6% were rural, and 44.0% had low literacy. Contrary to guidelines, most believed mammography should be done annually (74.3%) before age 40 (70.5%). Compared to urban women, rural participants were more likely to believe mammography will find small breast lumps early (34.4% vs. 6.5%, p<0.0001) and strongly disagree that mammography is embarrassing (14.6% vs. 8.4%, p=0.0002) or that they are afraid of finding something wrong (21.2% vs.12.3%, p=0.007). Rural women were more likely to report a physician recommendation for mammography (84.3% vs. 76.5%, p=0.006), but they were less likely to have received education (57.2% vs. 63.6%, p=0.06) or to have ever had a mammogram (74.8% vs. 78.1%, p=0.007). In multivariate analyses controlling for race, literacy, and age, all rural/urban differences remained significant, except for receipt of a mammogram. CONCLUSIONS: Most participants were unclear about when they should begin mammography. Rural participants reported stronger positive beliefs, higher self-efficacy, fewer barriers, and having a physician recommendation for mammography but were less likely to receive education or screening. PMID- 22519707 TI - Role of globin moiety in the chemical structure of curing pigment. AB - In this study, the role of the globin moiety in the structure of this pigment has been evaluated, using myoglobin and hemin as model systems. After the synthesis of the cured pigment from the compounds used in this study, the absorption spectra, Fourier transform infrared spectroscopy (FTIR), and electrospray ionization (ESI)/MS spectroscopy were used to evaluate the chemical structure. Results indicated that the UV/visible, IR absorption, and mass spectroscopy of the cured pigment produced from myoglobin and its counterpart without the globin moiety, hemin, are different. Whereas myoglobin produced mononitrosylheme, hemin converted to dinitrosylheme, but probably the second nitric oxide group attached to the propionate side chain of the heme ring. It seems that the globin moiety protected heme ring against the second nitric oxide group. PMID- 22519706 TI - The rice hydroperoxide lyase OsHPL3 functions in defense responses by modulating the oxylipin pathway. AB - As important signal molecules, jasmonates (JAs) and green leaf volatiles (GLVs) play diverse roles in plant defense responses against insect pests and pathogens. However, how plants employ their specific defense responses by modulating the levels of JA and GLVs remains unclear. Here, we describe identification of a role for the rice HPL3 gene, which encodes a hydroperoxide lyase (HPL), OsHPL3/CYP74B2, in mediating plant-specific defense responses. The loss-of function mutant hpl3-1 produced disease-resembling lesions spreading through the whole leaves. A biochemical assay revealed that OsHPL3 possesses intrinsic HPL activity, hydrolyzing hydroperoxylinolenic acid to produce GLVs. The hpl3-1 plants exhibited enhanced induction of JA, trypsin proteinase inhibitors and other volatiles, but decreased levels of GLVs including (Z)-3-hexen-1-ol. OsHPL3 positively modulates resistance to the rice brown planthopper [BPH, Nilaparvata lugens (Stal)] but negatively modulates resistance to the rice striped stem borer [SSB, Chilo suppressalis (Walker)]. Moreover, hpl3-1 plants were more attractive to a BPH egg parasitoid, Anagrus nilaparvatae, than the wild-type, most likely as a result of increased release of BPH-induced volatiles. Interestingly, hpl3-1 plants also showed increased resistance to bacterial blight (Xanthomonas oryzae pv. oryzae). Collectively, these results indicate that OsHPL3, by affecting the levels of JA, GLVs and other volatiles, modulates rice-specific defense responses against different invaders. PMID- 22519708 TI - Bone regeneration related to calcium phosphate-coated implants in osteoporotic animal models: a meta-analysis. AB - BACKGROUND: Osteoporosis is a frequent human metabolic bone disorder. Prospectively, global ageing of populations will lead to a major increase of subjects being diagnosed with osteoporosis and in need for dental rehabilitation. However, as local osteoporosis of the jaws affects bone quantity and quality of edentulous regions, osseointegration of dental implants might be hampered. Consequently, calcium phosphate ceramic-coated implants have been suggested to compensate for low bone quantity/density and for impaired bone healing in osteoporosis. Nonetheless, up to now no meta-analytical assessment of the relevant preclinical literature to quantify such a possible positive effect has been undertaken. MATERIALS AND METHODS: PubMed search, limited to animal models, to identify a possible positive effect of calcium phosphate-coated implants on bone regeneration, was carried out. Further, the reference lists of related review articles and publications selected for inclusion in this review were systematically screened. The primary outcome variables were bone-to-implant contact percentage as assessed histomorphometrically and mechanical stability testing. RESULTS: The electronic search in the database of the National Library of Medicine resulted in the identification of 2704 titles. These titles were initially screened by the two independent reviewers for possible inclusion, resulting in further consideration of 51 publications. Screening the abstracts led to 22 full-text articles. From these articles, 16 reports were excluded. Finally, six of these original research reports could be selected for evaluation. Additionally, eight publications were identified by manual search. Thus, a total of 14 articles were included for analysis. CONCLUSIONS: It was concluded that (1) in osteoporotic animal models calcium phosphate ceramic-coated implants are associated with improved bone-to-implant healing as compared to noncoated implants. Moreover, (2) essentially due to quality characteristics of the analyzed original research articles a negative impact of osteoporosis on bone-to implant healing could not be confirmed. Besides, (3) the established positive bone-to-implant healing effect of calcium phosphate ceramic coatings does not differ between osteoporotic and nonosteoporotic, healthy animal models. PMID- 22519709 TI - Susceptibility to etravirine of HIV type 1 subtype C isolates from nevirapine/efavirenz-experienced patients: comparative interpretation of ANRS and STANFORD algorithms. AB - Abstract We analyzed subtype C HIV-1 isolates from patients at failure of a regimen including nevirapine or efavirenz for their susceptibility or resistance to etravirine according to the ANRS and STANFORD algorithms. Statistical analysis showed a consensus that more than 45% of these viral strains are potentially resistant to etravirine. PMID- 22519710 TI - Will clinical studies elucidate the connection between the length of storage of transfused red blood cells and clinical outcomes? An analysis based on the simulation of randomized controlled trials. AB - BACKGROUND: The temporal pattern of the biologic mechanism linking red blood cell (RBC) storage duration with clinical outcomes is yet unknown. This study investigates how such a temporal pattern can affect the power of randomized controlled trials (RCT) to detect a relevant clinical outcome mediated by the transfusion of stored RBCs. STUDY DESIGN AND METHODS: This study was a computer simulation of four RCTs, each using a specific categorization of the RBC storage time. The trial's endpoint was evaluated assuming five hypothetical temporal patterns for the biologic mechanism linking RBC storage duration with clinical outcomes. RESULTS: Power of RCTs to unveil a significant association between RBC storage duration and clinical outcomes was critically dependent on a complex interaction among three factors: 1) the way the RBC storage time is categorized in the trial design, 2) the temporal pattern assumed for the RBC storage lesion, and 3) the age distribution of RBCs in the inventory from which they are picked up for transfusion. For most combinations of these factors, the power of RCTs to detect a significant treatment effect was below 80%. All the four simulated RCTs had a very low power to disclose a harmful clinical effect confined to last week of the maximum 42-day shelf life of stored RBCs. CONCLUSIONS: Ongoing RCTs may lack enough power to settle the issue of whether or not the transfusion of stored blood has a negative clinical impact. A precautionary reduction of the maximum storage time to 35 days is advisable. PMID- 22519711 TI - Prevalence of gastroesophageal reflux disease in premature calves. AB - BACKGROUND: Gastroesophageal reflux (GER) is the presence of gastric contents proximal to the stomach. Pathologic consequences secondary to GER are termed gastroesophageal reflux disease (GERD). OBJECTIVES: The purpose of this study was to determine the prevalence of GER and GERD in premature calves by endoscopic examination. ANIMALS: Ten healthy and 51 premature calves were included in the study. All premature calves also had respiratory distress syndrome. METHODS: Esophagoscopy of premature calves was conducted by fiber optic endoscopy. Abnormalities such as increased saliva, hyperemia, hemorrhage, petechiae, presence of abomasal content in the esophagus, and relaxation of the lower esophageal sphincter (LES) were evaluated by endoscopy. RESULTS: The prevalence of GERD and GER in the premature calves was 55 and 67%, respectively. Hyperemia and hyperemia with hemorrhage or petechiation of the esophageal mucosa were determined by endoscopic examination. Hyperemia was commonly observed in the distal esophageal mucosa, although a few hyperemic areas also were observed in other portions of the esophagus. In addition to these abnormalities, LES relaxation, abomasal fluid in the distal esophagus, abomasal content in the esophagus, and increased saliva also were observed in premature calves with GER. CONCLUSIONS: The prevalence of both GER (67%) and GERD (55%) in premature calves was high in the study. Endoscopy provides a practical, rapid, noninvasive, and reasonably accurate method for determining the presence of GER and GERD in premature calves. PMID- 22519712 TI - Nanostructured hybrid transparent conductive films with antibacterial properties. AB - Here, we demonstrate that the assembly of nanostructures with different dimensionalities yields "multicomponent hybrid" transparent conductive films (TCFs) with sheet resistance and optical transmittance comparable to that of indium tin oxide (ITO) films. It was shown that sheet resistance of single component Ag nanowire (NW) films can be further decreased by introducing gold decorated reduced graphene oxide (RG-O) nanoplatelets that bridge the closely located noncontacting metal NWs. RG-O nanoplatelets can act as a protective and adhesive layer for underneath metal NWs, resulting in better performance of hybrid TCFs compared to single-component TCFs. Additionally, these hybrid TCFs possess antibacterial properties, demonstrating their multifunctional characteristics that might have a potential for biomedical device applications. Further development of this strategy paves a way toward next generation TCFs composed of different nanostructures and characterized by multiple (or additional) functionalities. PMID- 22519713 TI - Healthcare utilization by abused women: a case control study. AB - BACKGROUND: Previous studies observed an association between intimate partner violence (IPV) and increased health problems. Early detection of IPV by general practitioners (GPs) is required to prevent further harm and provide appropriate support. In general practice, a limited number of studies are available on healthcare utilization of abused women. OBJECTIVES: The aim of the study was to investigate the healthcare utilization of abused women compared to non-abused. METHODS: The study was designed as a matched case-control study in 16 general practices in deprived areas in Rotterdam (The Netherlands). Electronic medical files of 50 victims of IPV were analysed for consultation frequency, referrals, medical prescription and reasons for encounter over a period of five years. Controls (n= 50) were non-abused women matched for general practice, age, number of children, and country of origin and education level. RESULTS: Abused women visited their GP almost twice as often than non-abused, in particular for social problems (OR= 3.5; 95%CI: 1.2-10.5; P= 0.01), substance abuse (OR= 4.6; 95%CI: 0.9-22.7; P= 0.05) and reproductive health problems (OR= 3.0; 95%CI: 1.3-6.8; P= 0.009). Victims of IPV were significantly more often referred for additional diagnostics (OR= 3.6; 95%CI: 1.1-12.2; P= 0.03), to mental healthcare (OR= 2.9; 95%CI: 1.2-7.1; P= 0.02) than non-victims. Abused women received 4.1 times more often a prescription for anti-depressants (95%CI: 1.5-11.6; P= 0.005) than non abused women. CONCLUSION: As compared to non-abused women, female victims of IPV visited their GP more frequently and exhibited a typical pattern of healthcare utilization. This could alert GPs to inquire about partner abuse in the past. PMID- 22519714 TI - EFPC: European Forum for Primary Care. Innovation in health professional education. PMID- 22519715 TI - High-resolution 1H NMR investigations of the oxidative consumption of salivary biomolecules by oral rinse peroxides. AB - BACKGROUND: A multicomponent evaluation of the oxidative consumption of salivary biomolecules by a tooth-whitening oral rinse preparation has been performed using high-resolution proton ((1)H) nuclear magnetic resonance spectroscopy (NMR). METHODS: Unstimulated human saliva samples (n = 12) were treated with aliquots of the oral rinse tested and 600 MHz (1)H NMR spectra acquired on these samples demonstrated that hydrogen peroxide (H(2)O(2)) and/or peroxodisulphate (S(2)O(8) (2-)) present in this product gave rise to the oxidative decarboxylation of the salivary electron-donor pyruvate (to acetate and CO(2)), and also oxidized methionine (a precursor to volatile sulphur compounds responsible for oral malodour), and malodourous trimethylamine to methionine sulphoxide and trimethylamine-N-oxide, respectively (reductions observed in the salivary concentrations of each biomolecular peroxide-scavenging agent were all extremely statistically significant, p < 0.005). RESULTS: Experiments conducted on chemical model systems confirmed the consumption of pyruvate by this product, and also revealed that the amino acids cysteine and methionine were oxidatively transformed to cystine and methionine sulphoxide, respectively. CONCLUSIONS: High field (1)H NMR analysis provides much valuable molecular information regarding the fate of tooth-whitening oxidants in human saliva and permits an assessment of the mechanisms of action of oral healthcare products containing these agents. The biochemical and potential therapeutic significance of the results obtained are discussed. PMID- 22519716 TI - Uranyl heteropolyoxometalate: synthesis, structure, and spectroscopic properties. AB - A novel uranium heteropolyoxometalate, [H(3)O](4)[Ni(H(2)O)(3)](4){Ni[(UO(2))(PO(3)C(6)H(4)CO(2))](3)(PO(4)H)}(4).2.72H( )O, has been prepared under mild hydrothermal conditions using the diethyl(2 ethoxycarbonylphenyl)phosphonate ligand and in situ ligand synthesis of the HPO(4)(2-) anion. The cluster is derived from a common UO(7), pentagonal bipyramid and is constructed by employing nickel(II) metal ions as linkers. The 3d-5f heteropolyoxometalate core incorporates 12 classical pentagonal uranyl groups and four Ni(2+) octahedral units. PMID- 22519717 TI - Specificity of the ester bond forming condensation enzyme SgcC5 in C-1027 biosynthesis. AB - The SgcC5 condensation enzyme catalyzes the attachment of SgcC2-tethered (S)-3 chloro-5-hydroxy-beta-tyrosine (2) to the enediyne core in C-1027 (1) biosynthesis. It is reported that SgcC5 (i) exhibits high stereospecificity toward the (S)-enantiomers of SgcC2-tethered beta-tyrosine and analogues as donors, (ii) prefers the (R)-enantiomers of 1-phenyl-1,2-ethanediol (3) and analogues, mimicking the enediyne core, as acceptors, and (iii) can recognize a variety of donor and acceptor substrates to catalyze their regio- and stereospecific ester bond formations. PMID- 22519718 TI - Predictive value of attenuation coefficients measured as Hounsfield units on noncontrast computed tomography during flexible ureteroscopy with holmium laser lithotripsy: a single-center experience. AB - PURPOSE: To assess the utility of attenuation coefficients as predictors of surgical outcome after a single flexible ureteroscopy (URS) with holmium laser lithotripsy. Many reports indicate that the efficacy of extracorporeal shockwave lithotripsy (SWL) can be predicted by the target's radiofrequency attenuation, measured as Hounsfield units (HUs) on noncontrast CT (NCCT). Studies of flexible URS, however, have not assessed the predictive value of attenuation coefficients on NCCT. PATIENTS AND METHODS: Patients with renal stones who were treated by flexible URS with holmium laser lithotripsy between December 2009 and October 2011 at a single institute were retrospectively evaluated. Stone-free (SF) status was determined by kidneys-ureters-bladder (KUB) radiography at postoperative month 3. Correlations of possible predictors with SF status were analyzed using a logistic regression model. The comparison between groups with low and high HUs was examined using the Mann-Whitney U test. RESULTS: There were 219 eligible procedures. According to the logistic regression model, the maximum attenuation coefficient (P=0.105) and average attenuation coefficient (P=0.175) did not significantly, independently predict SF status. Fragmentation efficiency was significantly different between cases with low and high attenuation coefficients (P=0.001). In groups with less than 20.0-mm diameter stones, overall operative time (P<0.001 and P=0.001) and the time from starting fragmentation (P<0.001 and P=0.002) were significantly high in both attenuation groups. In groups with stones greater than 20.0 mm diameter, the two definitions of operative time revealed no differences between the low and high attenuation groups. The retrospective study design was the major limitation of this study. CONCLUSIONS: We found that both the maximum and average attenuation coefficients on NCCT are significantly related to the fragmentation efficiency. In addition, this study showed that, in patient groups with stone a burden <20.0 mm in diameter, both the maximum and average attenuation coefficients were significantly predictive of operative time. PMID- 22519719 TI - Fertility preservation. PMID- 22519720 TI - Sensitivity and specificity of a blood and urine galactomannan antigen assay for diagnosis of systemic aspergillosis in dogs. AB - BACKGROUND: Diagnosis of canine systemic aspergillosis requires fungal culture from a sterile site, or confirmatory histopathology from a nonsterile site. Invasive specimen collection techniques may be necessary. OBJECTIVE: To evaluate the sensitivity and specificity of a serum and urine Aspergillus galactomannan antigen (GMA) ELISA assay for diagnosis of systemic aspergillosis in dogs. DESIGN: Multicenter study. ANIMALS: Thirteen dogs with systemic aspergillosis and 89 dogs with other diseases. Thirty-seven of the 89 dogs had signs that resembled those of systemic aspergillosis and 52 dogs were not suspected to have aspergillosis. PROCEDURE: The GMA ELISA was performed on serum specimens from all dogs and urine specimens from 67 dogs. Galactomannan indices (GMI) >= 0.5 were considered positive. Results for dogs in each group were compared. RESULTS AND CONCLUSIONS: The sensitivity and specificity of the assay for serum were 92 and 86%, respectively, and for urine were 88 and 92%, respectively. False negatives were seen only in dogs with localized pulmonary aspergillosis. Use of a cutoff GMI of 1.5 increased specificity to 93% for both serum and urine without loss of sensitivity for diagnosis of disseminated infection. High-level false positives (> 1.5) occurred in dogs with other systemic mycoses and those treated with Plasmalyte. CLINICAL RELEVANCE: Serum and urine Aspergillus GMA ELISA is a noninvasive, sensitive, and specific test for the diagnosis of disseminated aspergillosis in dogs when a cutoff GMI of >= 1.5 is used. PMID- 22519721 TI - A simple method of microneedle array fabrication for transdermal drug delivery. AB - The outermost layer of skin, stratum corneum, being lipophilic limits the passive transport of hydrophilic and large molecular weight drugs. Microfabrication technology has been adapted to fabricate micron scale needles, which are minimally invasive, yet able to deliver the drugs across this barrier layer. In this study, we fabricated microneedles from a biocompatible polymer, namely, poly (ethylene glycol) diacrylate. A simple lithographical approach was developed for microneedle array fabrication. Several factors including polymerization time, ultraviolet light intensity and distance from light source were studied for their effects on microneedle formation. The microneedle length and tip diameter can be controlled by varying these factors. The microneedles were shown to be able to penetrate cadaver pig skin. Model drug rhodamine B was encapsulated in the range of 50 ug to 450 ug per microneedle array. The fabricated microneedles containing rhodamine B increased the permeability by four times than the control. Altogether, we demonstrated that the microneedle arrays can be fabricated through a simple single-step process and needles were mechanically strong to penetrate skin, increasing the permeability of encapsulated drug through skin. PMID- 22519722 TI - Involvement of the autophagy pathway in trafficking of Mycobacterium tuberculosis bacilli through cultured human type II epithelial cells. AB - Interactions between Mycobacterium tuberculosis bacilli and alveolar macrophages have been extensively characterized, while similar analyses in epithelial cells have not been performed. In this study, we microscopically examined endosomal trafficking of M. tuberculosis strain Erdman in A549 cells, a human type II pneumocyte cell line. Immuno-electron microscopic (IEM) analyses indicate that M. tuberculosis bacilli are internalized to a compartment labelled first with Rab5 and then with Rab7 small GTPase proteins. This suggests that, unlike macrophages, M. tuberculosis bacilli traffic to late endosomes in epithelial cells. However, fusion of lysosomes with the bacteria-containing compartment appears to be inhibited, as illustrated by IEM studies employing LAMP-2 and cathepsin-L antibodies. Examination by transmission electron microscopy and IEM revealed M. tuberculosis-containing compartments surrounded by double membranes and labelled with antibodies against the autophagy marker Lc3, providing evidence for involvement and intersection of the autophagy and endosomal pathways. Interestingly, inhibition of the autophagy pathway using 3-methyladenine improved host cell viability and decreased numbers of viable intracellular bacteria recovered after 72 h post infection. Collectively, these data suggest that trafficking patterns for M. tuberculosis bacilli in alveolar epithelial cells differ from macrophages, and that autophagy is involved this process. PMID- 22519723 TI - A new partially deprotonated mixed-valence manganese(II,III) hydroxide-arsenate with electronic conductivity: magnetic properties of high- and room-temperature sarkinite. AB - A new three-dimensional hydroxide-arsenate compound called compound 2 has been synthesized by heating (in air) of the sarkinite phase, Mn(2)(OH)AsO(4) (compound 1), with temperature and time control. The crystal structure of this high temperature compound has been solved by Patterson-function direct methods. A relevant feature of this new material is that it is actually the first member of the adamite-type family with mixed-valence manganese(II,III) and electronic conductivity. Crystal data: a = 6.7367(5) A, b = 7.5220(6) A, c = 9.8117(6) A, alpha = 92.410(4) degrees , beta = 109.840(4) degrees , gamma = 115.946(4) degrees , P1. The unit cell content derived from Rietveld refinement is Mn(8)(O(4)H(x))(AsO(4))(4). Its framework, projected along [111], is characterized by rings of eight Mn atoms with the OH(-)/O(2-) inside the rings. These rings form an almost perfect hexagonal arrangement with the AsO(4) groups placed in between. Bond-valence analysis indicates both partial deprotonation (x ? 3) and the presence of Mn in two different oxidation states (II and III), which is consistent with the electronic conductivity above 300 degrees C from electrochemical measurements. The electron paramagnetic resonance spectra of compound 1 and of its high-temperature form compound 2 show the presence of antiferromagnetic interactions with stronger magnetic coupling for the high temperature phase. Magnetization measurements of room-temperature compound 1 show a complex magnetic behavior, with a three-dimensional antiferromagnetic ordering and magnetic anomalies at low temperatures, whereas for compound 2, an ordered state is not reached. Magnetostructural correlations indicate that superexchange interactions via oxygen are present in both compounds. The values of the magnetic exchange pathways [Mn-O-Mn] are characteristic of antiferromagnetic couplings. Notwithstanding, the existence of competition between different magnetic interactions through superexchange pathways can cause the complex magnetic behavior of compound 1. The loss of three-dimensional magnetic ordering by heating of compound 1 could well be based on the presence of Mn(3+) ions (d(4)) in compound 2. PMID- 22519724 TI - 'I quit' versus 'I'm sorry I used': a preliminary investigation of variations in narrative ending and transportation. AB - A narrative experience can partly depend on how a narrative ends or concludes. This study examined prevention effects of personal drug use narratives varying by type of ending and gender of protagonist. Additionally, the role of transportation in the persuasion process, particularly the association between transportation and cocaine use intentions, both directly and indirectly, through the mediation of anti-drug and pro-drug expectancies was assessed. A total of 500 undergraduate students at a large northern university in the UK participated in the experiment which was a 2 * 2 * 2 mixed design with ending (progressive vs. regressive) and gender of protagonist (male vs. female) as within-participants factors and participant gender (male vs. female) as between-participants factors. The results demonstrated significant main effects for ending, gender of protagonist in the narrative and participant gender, but no interaction effects. Finally, greater transportation was associated with stronger anti-cocaine expectancies, which were further associated with lower cocaine use intentions. Important theoretical and empirical implications are discussed. PMID- 22519725 TI - Genetic sequence data identifies the cercaria of Drepanocephalus spathans (Digenea: Echinostomatidae), a parasite of the double-crested cormorant (Phalacrocorax auritus), with notes on its pathology in juvenile channel catfish (Ictalurus punctatus). AB - An unidentified xiphidio-type cercaria, previously thought inconsequential to catfish health, was found to be released from marsh rams-horn snails (Planorbella trivolvis) inhabiting ponds on a commercial catfish operation in the Mississippi Delta. A preliminary challenge of cohabiting channel catfish ( Ictalurus punctatus ) with snails actively shedding the unidentified cercariae resulted in death of some fish. A second cohabitation trial yielded similar results, as did a third challenge of 250 cercariae/fish. Histopathology revealed developing metacercariae concentrated in the cranial region, especially within the branchial chamber, with several metacercariae at the base of the branchial arches within, or adjacent to, blood vessels, possibly the proximate cause of death. Genetic sequence analysis of the 18S small subunit ribosomal DNA (ssDNA), 28S large subunit rDNA (lsDNA), and cytochrome oxidase (Cox1) genes all matched the cercariae to Drepanocephalus spathans (Digenea: Echinostomatidae), a parasite of the double-crested cormorant (Phalacrocorax auritus), a piscivorous bird endemic on most catfish farms. This is the first commentary regarding pathology of D. spathans in juvenile channel catfish as well as the first report of the marsh rams-horn snail as an intermediate host in the D. spathans life cycle. The data presented here suggest this parasite could have limiting effects on catfish production, further supporting the need for adequate snail control programs to reduce trematode prevalence on commercial catfish operations. PMID- 22519726 TI - Multilevel resistive switching in planar graphene/SiO2 nanogap structures. AB - We report a planar graphene/SiO(2) nanogap structure for multilevel resistive switching. Nanosized gaps created on a SiO(2) substrate by electrical breakdown of nanographene electrodes were used as channels for resistive switching. Two terminal devices exhibited excellent memory characteristics with good endurance up to 10(4) cycles, long retention time more than 10(5) s, and fast switching speed down to 500 ns. At least five conduction states with reliability and reproducibility were demonstrated in these memory devices. The mechanism of the resistance switching effect was attributed to a reversible thermal-assisted reduction and oxidation process that occurred at the breakdown region of the SiO(2) substrate. In addition, the uniform and wafer-size nanographene films with controlled layer thickness and electrical resistivity were grown directly on SiO(2) substrates for scalable device fabrications, making it attractive for developing high-density and low-cost nonvolatile memories. PMID- 22519727 TI - Total synthesis of mycocyclosin. AB - The first total synthesis of mycocyclosin, a diketopiperazine natural product isolated from M. tuberculosis, is described. While direct oxidative coupling of tyrosine phenolic groups was unsuccessful, construction of the highly strained bicyclic framework was successfully accomplished through an intramolecular Miyaura-Suzuki cross-coupling to generate the biaryl linkage. PMID- 22519728 TI - Seeing things differently: expert and consumer mental models evaluating combined oral contraceptives. AB - Communication regarding the benefits and risks of combined oral contraceptives (COCs) remains a challenge in view of persistent misconceptions about the 'pill'. The aim of this study was to investigate how women understand the benefits and risks of COCs, comparing their assessments with an expert model created from literature- and guideline-based research and reviewed by a sample of gynaecologists using the mental models approach. Two qualitative studies were conducted in Germany - a questionnaire-based study involving 30 gynaecologists with a mean of 218 COC prescriptions on average per month, and in-depth interviews (plus the use of a questionnaire) with 21 women aged 18-24 years. As expected, women reported only a few concepts of benefits and risks unprompted, but further prompting revealed beliefs of many other associations. The women stated an overall positive valence even if the number of negative concepts predominated indicating a latent cognitive dissonance. The major differences compared with the expert model included: (a) a negative association with weight gain, subfertility and teratogenicity, (b) only a partial association of COC intake with thromboembolic conditions, (c) a confusing, rather negative perception of a COC-related effect on cancer and (d) a partial lack of basic knowledge of the active ingredients, time to excretion and mode of action of COCs. Appropriate COC counselling should cover these discrepancies. PMID- 22519729 TI - Laparoscopic urorectal fistula repair: value of the salvage prostatectomy and review of current approaches. AB - BACKGROUND AND PURPOSE: The surgical approach and repair for urorectal fistula (URF) is a challenging task. A variety of techniques have been described to treat URFs, and the laparoscopic approach has been approved as an efficient tool for even some complex fistulas. We aimed to report our laparoscopic experience for complex URF repair with special emphasis on salvage prostatectomy. PATIENTS AND METHODS: The study included four men (59-75 years), with laparoscopic repair for complex URFs. URF developed after transurethral resection of the prostate in patients 2 and 3 and after radical prostatectomy in patient 4. Patient 1 had received combined radiotherapy and chemotherapy for the rectal carcinoma; a prostatic abscess developed that resulted at the end in URF. Laparoscopic salvage prostatectomy was performed for patients 1 and 2. A transvesical laparoscopic approach was performed for patient 3, and a transperitoneal transvesical technique was performed for patient 4. A tunica vaginalis flap was used for patient 1, and peritoneal interposition flaps were developed in patients 2 and 4 mL, and no patients needed intraoperative blood transfusion. Postoperative hospital stay was 12 to 34 days. The urethral catheter was removed on postoperative day 11 to 32, and cystography showed no leakage of contrast except in patient 1. CONCLUSIONS: Laparoscopic URF repair is safe and efficacious in experienced hands even in complex cases, and salvage laparoscopic prostatectomy seems like a valuable operative option. The technique requires advanced experience, however, particularly with pelvic surgery and intracorporeal suturing. PMID- 22519730 TI - Unfolding the damping behavior of multilayer graphene membrane in the low frequency regime. AB - The damping behavior of few-layered graphene membrane in the low-frequency regime of mechanical loading is investigated in the present study. Damping of graphene has significant applications in micro/nanoscale devices and macroscale dynamic systems for absorbing shock-generated energies. Damping behavior of graphene is experimentally evaluated, for the first time, by dynamic mechanical analysis at the nanoscale with cyclic mechanical loading in the range 0.1-50 MUN applied at a frequency range of 10-250 Hz. This study reveals 260% higher damping on graphene membranes than a silicon surface. The damping shows excellent reproducibility and remains steady even after 100,000 cycles. The damping of multilayer graphene membrane, supported on a Si/SiO(2) substrate, shows a strong dependence on the frequency of cyclic loading. The mechanism governing impressive damping of a graphene membrane is elucidated by structural changes such as ripple formation, ripple wave propagation, and z-axis compression. Damping behavior of a graphene membrane in this low-frequency regime is also found to depend on the number of graphene layers and is explained as the interplay between in-plane sp(2) and out of-plane van der Waals forces. These findings are important for establishing the potential of graphene for applications in macro- to nanoscale structures that require continuous absorption of shock waves without destruction/failure. PMID- 22519731 TI - IQGAP1 mediates the disruption of adherens junctions to promote Escherichia coli K1 invasion of brain endothelial cells. AB - The transcellular entry of Escherichia coli K1 through human brain microvascular endothelial cells (HBMEC) is responsible for tight junction disruption, leading to brain oedema in neonatal meningitis. Previous studies demonstrated that outer membrane protein A (OmpA) of E. coli K1 interacts with its receptor, Ecgp96, to induce PKC-alpha phosphorylation, adherens junction (AJ) disassembly (by dislodging beta-catenin from VE-cadherin), and remodelling of actin in HBMEC. We report here that IQGAP1 mediates beta-catenin dissociation from AJs to promote actin polymerization required for E. coli K1 invasion of HBMEC. Overexpression of C-terminal truncated IQGAP1 (IQDeltaC) that cannot bind beta-catenin prevents both AJ disruption and E. coli K1 entry. Of note, phospho-PKC-alpha interacts with the C-terminal portion of Ecgp96 as well as with VE-cadherin after IQGAP1 mediated AJ disassembly. HBMEC overexpressing either C-terminal truncated Ecgp96 (Ecgp96Delta200) or IQDeltaC upon infection with E. coli showed no interaction of phospho-PKC-alpha with Ecgp96. These data indicate that the binding of OmpA to Ecgp96 induces PKC-alpha phosphorylation and association of phospho-PKC-alpha with Ecgp96, and then signals IQGAP1 to detach beta-catenin from AJs. Subsequently, IQGAP1/beta-catenin bound actin translocates to the site of E. coli K1 attachment to promote invasion. PMID- 22519732 TI - In vitro cercariae transformation: comparison of mechanical and nonmechanical methods and observation of morphological changes of detached cercariae tails. AB - Schistosomula, the larval stage of schistosomes in vertebrate hosts, are highly vulnerable and considered an ideal target for vaccine and drug development. Although the schistosomule stage is essential for biological studies, collecting sufficient numbers of schistosomula from their definitive hosts in vivo is difficult to accomplish. However, in vitro collection via cercariae transformation can effectively yield high numbers of schistosomula. We compared a current and widely used double-ended-needle mechanical transformation method to a culture medium based on a nonmechanical method. We found the rates of transformed cercariae, i.e., separated cercariae heads from tails, differed by only 2-7% at 0.5, 1, and 2 days in culture and that there was no significant difference in the number of transformed cercariae between the transformation methods at 3 and 4 days in culture. Notably, the mechanical and nonmechanical cercariae transformation methods both yielded significantly large and similar quantities of viable schistosomula. Given that the nonmechanical method is simpler and less damaging to the parasites, we recommend the use of it as an alternative way for in vitro cercariae transformation. In addition, we also observed morphological changes of the detached cercariae tails in culture medium. Interestingly, the tails are able to regenerate head-like organs/tissues and survive for at least 4 days. This intriguing change suggests unique biological features of the cells in the tails. PMID- 22519733 TI - Imino-phenolic-pyridyl conjugates of calix[4]arene (L1 and L2) as primary fluorescence switch-on sensors for Zn2+ in solution and in HeLa cells and the recognition of pyrophosphate and ATP by [ZnL2]. AB - Pyridyl-based triazole-linked calix[4]arene conjugates, viz. L(1) and L(2), were synthesized and characterized. These two conjugates were shown to be selective and sensitive for Zn(2+) among the 12 metal ions studied in HEPES buffer medium by fluorescence, absorption, and visual color change with the detection limit of ~31 and ~112 ppb, respectively, by L(1) and L(2). Moreover, the utility of the conjugates L(1) and L(2) in showing the zinc recognition in live cells has also been demonstrated using HeLa cells as monitored by fluorescence imaging. The zinc complexes of L(1) and L(2) were isolated, and the structure of [ZnL(1)] has been established by single-crystal XRD and that of [ZnL(2)] by DFT calculations. TDDFT calculations were performed in order to demonstrate the electronic properties of receptors and their zinc complexes. The isolated zinc complexes, viz. [ZnL(1)] and [ZnL(2)], have been used as molecular tools for the recognition of anions on the basis of their binding affinities toward Zn(2+). [ZnL(2)] was found to be sensitive and selective toward phosphate-bearing ions and molecules and in particular to pyrophosphate (PPi) and ATP among the other 18 anions studied; however, [ZnL(1)] was not sensitive toward any of the anions studied. The selectivity has been shown on the basis of the changes observed in the emission and absorption spectral studies through the removal of Zn(2+) from [ZnL(2)] by PPi. Thus, [ZnL(2)] has been shown to detect PPi up to 278 +/- 10 ppb at pH 7.4 in aqueous methanolic (1/2 v/v) HEPES buffer. PMID- 22519734 TI - Expression of the polyalanine expansion mutant of nuclear poly(A)-binding protein induces apoptosis via the p53 pathway. AB - The PABPN1 [nuclear poly(A)-binding protein 1] is ubiquitous, binds to the nascent mRNA transcript and controls the poly(A) tract elongation process in multicellular organisms. Expansion of GCG repeats that encode first 6 of the 10 alanine residues of a polyalanine tract at the N-terminus of wild-type PABPN1 to 12-17 alanine residues causes aggregation of the protein and cell death. Patients with the adult onset autosomal dominant OPMD (oculopharyngeal muscular dystrophy) carry the GCG expansion mutation in their PABPN1 gene. The symptoms of OPMD include drooping eye lids and difficulty swallowing. The severity of symptoms increases with the length of the expansion. We have investigated the mechanism of cell death in HeLa and HEK-293 (human embryonic kidney) cultured cells expressing the mutant PABPN1 with a polyalanine tract containing 17 alanine residues (PABPN1 A17). In cells expressing PABPN1-A17, the abundance of pro-apoptotic proteins, p53, PUMA (p53 up-regulated modulator of apoptosis) and Noxa, are up-regulated. This was associated with the redistribution of p53 to the nucleus and mitochondria. Concomitantly Bax was translocated to the mitochondria, followed by the release of cytochrome c and the cleavage of caspase 3. Furthermore, blocking p53-mediated transcription using pifithrin significantly reduced apoptosis. Our findings suggest a key role of p53-mediated apoptosis in death of cells expressing the polyalanine expansion mutant of PABPN1. PMID- 22519735 TI - A comparison of pharmacokinetics and pharmacodynamics of insulin aspart, biphasic insulin aspart 70, biphasic insulin aspart 50, and human insulin: a randomized, quadruple crossover study. AB - BACKGROUND: We compared the pharmacokinetic and pharmacodynamic profiles of insulin aspart, biphasic insulin aspart 70 (BIAsp70) and 50 (BIAsp50) (containing 70% and 50% rapid-acting insulin aspart, respectively), and soluble human insulin under experimental conditions. SUBJECTS AND METHODS: In this randomized, four period crossover study, 19 type 1 diabetes patients received subcutaneous injections of identical doses (0.2 U/kg) of insulin aspart, BIAsp70, or BIAsp50 immediately before a standardized meal or human insulin 30 min before meal. Plasma glucose and serum insulin were measured for 12 h postprandially. RESULTS: The pharmacokinetic and pharmacodynamic profiles of human insulin differed from those of insulin aspart, BIAsp70, and BIAsp50. The three different aspart preparations had easily distinguishable features with regard to onset and duration of action. Insulin aspart preparations were, on average, absorbed twice as fast as human insulin. In the initial phases (0-4 h and 0-6 h), the insulin area under the concentration-time curve (AUC(ins)) was significantly higher during insulin aspart treatment compared with the others, whereas insulin aspart had a significantly lower AUC(ins) over the last 6 h (P<0.05). BIAsp70 and BIAsp50 provided insulin coverage comparable to that of human insulin over the last 6 h. Insulin aspart had the most pronounced onset of action and the shortest duration. Comparing with insulin aspart and BIAsp70, BIAsp50 revealed a closer treatment ratio to human insulin on pharmacodynamic end points. CONCLUSIONS: BIAsp70 and BIAsp50 injected immediately before a meal are at least as effective as human insulin injected 30 min earlier in controlling postprandial glycemic excursions. BIAsp50 showed the greatest similarity to human insulin with regard to pharmacokinetic and pharmacodynamic profiles. PMID- 22519736 TI - Differential effects of alpha-glucosidase inhibitors on postprandial plasma glucose and lipid profile in patients with type 2 diabetes under control with insulin lispro mix 50/50. AB - BACKGROUND: The additive effect of alpha-glucosidase inhibitors (alpha-GIs) was investigated in patients with type 2 diabetes (T2D) under control with rapid acting insulin analog. SUBJECTS AND METHODS: Thirty-six poorly controlled T2D patients were recruited, and plasma glucose (PG) was controlled by three times daily injection of insulin lispro mix 50/50 (Mix50) to maintain fasting PG <130 mg/dL and 2-h postprandial PG (PPG) <180 mg/dL. Another group of 20 patients was randomly assigned to either 0.3 mg of voglibose or 50 mg of miglitol, which was administered at breakfast every other day. Another group of 16 patients was assigned to a crossover study, in which each alpha-GI was switched every day during the 6-day study. PPG, C-peptide, and lipid profile were analyzed. RESULTS: The addition of voglibose had no effect on PPG, but miglitol blunted the PPG rise and significantly decreased 1-h and 2-h postprandial C-peptide levels compared with Mix50 alone. In addition, miglitol significantly decreased the 1-h postprandial triglyceride rise and the remnant-like particle-cholesterol rise, while it increased the 1-h postprandial high-density lipoprotein-cholesterol and apolipoprotein A-I levels in the crossover study. CONCLUSIONS: Miglitol appears to have rapid action, which appears earlier than that of lispro. The combination of miglitol and Mix50 seems effective for the control of PPG and lipid profile in T2D. PMID- 22519737 TI - Serum D-lactate concentrations in cats with gastrointestinal disease. AB - BACKGROUND: Increased D-lactate concentrations cause neurological signs in humans with gastrointestinal disease. HYPOTHESIS/OBJECTIVES: To determine if serum D lactate concentrations are increased in cats with gastrointestinal disease compared to healthy controls, and if concentrations correlate with specific neurological or gastrointestinal abnormalities. ANIMALS: Systematically selected serum samples submitted to the Gastrointestinal Laboratory at Texas A&M University from 100 cats with clinical signs of gastrointestinal disease and abnormal gastrointestinal function tests, and 30 healthy cats. METHODS: Case control study in which serum D- and L-lactate concentrations and retrospective data on clinical signs were compared between 30 healthy cats and 100 cats with gastrointestinal disease. Association of D-lactate concentration with tests of GI dysfunction and neurological signs was evaluated by multivariate linear and logistic regression analyses, respectively. RESULTS: All 100 cats had a history of abnormal gastrointestinal signs and abnormal gastrointestinal function test results. Thirty-one cats had definitive or subjective neurological abnormalities. D-lactate concentrations of cats with gastrointestinal disease (median 0.36, range 0.04-8.33 mmol/L) were significantly higher than those in healthy controls (median 0.22, range 0.04-0.87 mmol/L; P = .022). L-lactate concentrations were not significantly different between the 2 groups of cats with gastrointestinal disease and healthy controls. D-lactate concentrations were not significantly associated with fPLI, fTLI, cobalamin, folate, or neurological abnormalities (P > .05). CONCLUSIONS AND CLINICAL IMPORTANCE: D-lactate concentrations can be increased in cats with gastrointestinal disease. These findings warrant additional investigations into the role of intestinal microbiota derangements in cats with gastrointestinal disease, and the association of D-lactate and neurological abnormalities. PMID- 22519738 TI - Streptocarbazoles A and B, two novel indolocarbazoles from the marine-derived actinomycete strain Streptomyces sp. FMA. AB - Streptocarbazoles A (1) and B (2), two novel indolocarbazoles featuring unprecedented cyclic N-glycosidic linkages between 1,3-carbon atoms of the glycosyl moiety and two indole nitrogen atoms of the indolocarbazole core, were isolated from the marine-derived actinomycetes strain Streptomyces sp. FMA. Their structures were established by spectroscopic methods, CD spectra, and ECD quantum mechanical calculations. Compound 1 was cytotoxic on HL-60 and A-549 cell lines and could arrest the cell cycle of Hela cells at the G(2)/M phase. PMID- 22519739 TI - A case of systemic anaplastic lymphoma kinase-negative anaplastic large cell lymphoma associated with hypereosinophilia, granulomatous myositis and vasculitis. PMID- 22519740 TI - Discussions of viral load in negotiating sexual episodes with primary and casual partners among men who have sex with men. AB - Recent studies suggest that people living with HIV with lower viral load are at reduced risk for transmitting HIV to their sexual partners. As information about the association between viral load and risk for HIV transmission disseminates throughout high-risk communities, viral load discussions may be used more often as a risk reduction strategy. The overall purpose of this study was to determine the frequency of viral load discussions and unprotected anal intercourse (UAI) in primary and casual sexual partnerships among men who have sex with men (MSM). An online survey was completed by 326 MSM (82% Caucasian, 62% college educated, 7% HIV-positive or thought they were HIV positive) in January 2011. Results showed that viral load discussions occurred in 93% of primary partnerships in which at least one partner was HIV-positive; UAI was reported with 46% of all primary partners and 25% of serodiscordant primary partners with whom viral load was discussed. Viral load discussions occurred in 53% of the three recent sexual episodes with casual sex partners with whom participants had either sex with once or had sex with multiple times in the past three months. UAI was more common in sexual encounters with casual sex partners when viral load was not discussed than when viral load was discussed (75% v. 56% of encounters). The finding that casual sexual episodes that did not include viral load discussions had a higher percentage of UAI than those that did include viral load discussions suggests either that men who do not discuss viral load may be higher risk-takers than men who do, or that the former are less adept at negotiating safer sex with casual sex partners than men who do discuss viral load. More research is needed to understand the role of viral load discussions in negotiating sexual activities among MSM. PMID- 22519741 TI - Outcome of dual flange metallic urethral stents in the treatment of neuropathic bladder dysfunction after spinal cord injury. AB - PURPOSE: To review the results of metallic urethral stents used in patients with neuropathic bladder dysfunction after spinal cord injury (SCI). PATIENTS AND METHODS: In a rehabilitation unit for SCI and stroke in Cape Town, South Africa, we performed a case note review of dual flange Memokath stents placed from March 2008 until October 2011. Stents were placed rather than performing an external sphincterotomy in selected patients. With the patient under deep general anesthesia, a thermosensitive expandable metallic stent was positioned over the internal and external urethral sphincters. RESULTS: In total, 33 stents were placed in 28 male patients. SCI was cervical in 23 patients and thoracic in 5. Average follow-up was 18 months (range 1-40 months, median 18 months). The most common indications were repeated catheter blockage in eight patients and urinary tract infection in six. The average time from SCI to stent insertion was 79 months (range 1-468 months, median 21 months). Severe autonomic dysreflexia was present in 17 cases before stent placement and in 7 after stents were placed (P=0.003). Stents failed in 15 patients (45%) and were removed. The most common reason for failure was stone formation. Comparing the group of patients with stents lasting >20 months (n=11) to the group with stent removal before 20 months (n=10), the mean time between SCI and stent placement was 31 vs 119 months (P=0.057). Medium term results (up to 27 months) were significantly influenced by earlier stent placement (P=0.0484). One major complication was stent migration that caused an urethrocutaneous fistula. PMID- 22519743 TI - A new Sarcocystis species (Apicomplexa: Sarcocystidae) from the rock gecko Bunopus tuberculatus in Saudi Arabia. AB - Sarcocystis bunopusi n. sp. from the muscle fibres of the rock gecko ( Bunopus tuberculatus ) in Saudi Arabia is described. Sarcocysts were found in skeletal muscles of the tail and fore and hind limbs in 3 of 30 geckos. Sarcocysts were microscopic, 42-45 um long and 22-25 um wide. Using light microscopy, the cyst wall was thin and smooth. Ultrastructurally, the primary cyst wall consisted of a thin parasitophorous vacuolar membrane with osmiophilic 100 nm * 50 nm knob-like papillae, and no perpendicular protrusions. Septae were indistinct. Bradyzoites were 5-7 * 1.5-2.0 um in size. This is the first description of a Sarcocystis species from this gecko. PMID- 22519742 TI - Rh2(II)-catalyzed intramolecular aliphatic C-H bond amination reactions using aryl azides as the N-atom source. AB - Rhodium(II) dicarboxylate complexes were discovered to catalyze the intramolecular amination of unactivated primary, secondary, or tertiary aliphatic C-H bonds using aryl azides as the N-atom precursor. While a strong electron withdrawing group on the nitrogen atom is typically required to achieve this reaction, we found that both electron-rich and electron-poor aryl azides are efficient sources for the metal nitrene reactive intermediate. PMID- 22519744 TI - Human papillomavirus infection in men who have sex with men in Lima, Peru. AB - Human papillomavirus (HPV) infection among men who have sex with men (MSM) is the primary risk factor for anal cancer. Of 105 Peruvian MSM examined, 77.1% were infected with HPV; of these 79.0% were coinfected with two or more types and 47.3% were infected by a carcinogenic type. HPV types 53, 6, 16, and 58 were the most frequent HPV infections detected. High-risk HPV type infection was associated with sex work, HIV status, and having rectal chlamydial or gonorrheal infection. These findings support broadening HPV vaccine coverage and increasing surveillance for the development of cancer in MSM infected with HPV. PMID- 22519745 TI - Suspension culture of human pluripotent stem cells in controlled, stirred bioreactors. AB - Therapeutic and industrial applications of pluripotent stem cells and their derivatives require large cell quantities generated in defined conditions. To this end, we have translated single cell-inoculated suspension cultures of human pluripotent stem cells (hPSCs; including human induced pluripotent stem cells [hiPS] and human embryonic stem cells [hESC]) to stirred tank bioreactors. These systems that are widely used in biopharmaceutical industry allow straightforward scale up and detailed online monitoring of key process parameters. To ensure minimum medium consumption, but in parallel functional integration of all probes mandatory for process monitoring, that is, for pO2 and pH, experiments were performed in 100 mL culture volume in a "mini reactor platform" consisting of four independently controlled vessels. By establishing defined parameters for tightly controlled cell inoculation and aggregate formation up to 2*108 hiPSCs/100 mL were generated in a single process run in 7 days. Expression of pluripotency markers and ability of cells to differentiate into derivates of all three germ layers in vitro was maintained, underlining practical utility of this new process. The presented data provide key steps toward scalable mass expansion of human iPS and ES cells thereby enabling translation of stem cell research to (pre)clinical application in relevant large animal models and valuable in vitro assays for drug development and validation as well. PMID- 22519746 TI - Bypassing proximal health care facilities for acute care: a survey of patients in a Ghanaian Accident and Emergency Centre. AB - OBJECTIVE: To characterise the population that presents to the Accident and Emergency Centre (AEC) at Komfo Anokye Teaching Hospital (KATH) and to identify risk factors associated with bypassing proximal care facilities. METHODS: A structured questionnaire was verbally administered to patients presenting to the AEC over 2 weeks. The questionnaire focused on the use of health care resources and characteristics of current illness or injury. Measures recorded include demographics, socioeconomic status, chief complaint, transportation and mobility, reasons for choosing KATH and health care service utilisation and cost. RESULTS: The total rate of bypassing proximal care was 33.9%. On multivariate analysis, factors positively associated with bypassing included age older than 38 years (OR: 2.18, P 0.04) and prior visits to facility (OR 2.88, P 0.01). Bypassers were less likely to be insured (OR 0.31, P 0.01), to be seeking care due to injury (OR 0.42, P 0.03) and to have previously sought care for the problem (OR 0.10, P < 0.001). CONCLUSIONS: Patients who bypass facilities near them to seek care at an urban AEC in Ghana do so for a combination of reasons including familiarity with the facility, chief complaint and insurance status. Understanding bypassing behaviour is important for guiding health care utilisation policy decisions and streamlining cost-effective, appropriate access to care for all patients. PMID- 22519747 TI - Minimum inhibitory concentrations of amphotericin B against Candida krusei isolates from a French teaching hospital laboratory: a retrospective study over 8 years. AB - Recent studies have shown decreased susceptibility of Candida krusei to amphotericin B (AmB), in addition to its inherent resistance to fluconazole. The susceptibility of C. krusei to AmB was studied in the Parasitology-Mycology laboratory of Grenoble Teaching Hospital, France. Between 2003 and 2011, we analysed 200 C. krusei isolates from 130 patients. The isolates were mainly collected in intensive care, cardio-thoracic and cancer/haematology units. Minimum inhibitory concentrations (MICs) were determined by the E-test method. The modal MIC was 0.5 MUg ml(-1); the MIC(50) and MIC(90) (MICs encompassing 50% and 90% of all isolates tested, respectively) were 0.5 MUg ml(-1) and 1 MUg ml( 1). The Cuzick's and Kendall's tests showed a significant increase in MIC values between 2003 and 2011 (P = 0.001 and P <= 0.001, respectively), regardless of age or gender. No statistical difference was reached with these tests when the first 100 or 50 data were excluded. Despite the increase observed in the first period of the study, our results confirm the low AmB MICs reported in previous studies. However, some authors have recently reported much higher MICs. This discrepancy cannot be explained by method biases and could reflect C. krusei epidemiological differences among populations. PMID- 22519748 TI - Selection in a fluctuating environment leads to decreased genetic variation and facilitates the evolution of phenotypic plasticity. AB - Changes in the environment are expected to induce changes in the quantitative genetic variation, which influences the ability of a population to adapt to environmental change. Furthermore, environmental changes are not constant in time, but fluctuate. Here, we investigate the effect of rapid, continuous and/or fluctuating temperature changes in the seed beetle Callosobruchus maculatus, using an evolution experiment followed by a split-brood experiment. In line with expectations, individuals responded in a plastic way and had an overall higher potential to respond to selection after a rapid change in the environment. After selection in an environment with increasing temperature, plasticity remained unchanged (or decreased) and environmental variation decreased, especially when fluctuations were added; these results were unexpected. As expected, the genetic variation decreased after fluctuating selection. Our results suggest that fluctuations in the environment have major impact on the response of a population to environmental change; in a highly variable environment with low predictability, a plastic response might not be beneficial and the response is genetically and environmentally canalized resulting in a low potential to respond to selection and low environmental sensitivity. Interestingly, we found greater variation for phenotypic plasticity after selection, suggesting that the potential for plasticity to evolve is facilitated after exposure to environmental fluctuations. Our study highlights that environmental fluctuations should be considered when investigating the response of a population to environmental change. PMID- 22519749 TI - Bartonella entry mechanisms into mammalian host cells. AB - The Gram-negative genus Bartonella comprises arthropod-borne pathogens that typically infect mammals in a host-specific manner. Bartonella bacilliformis and Bartonella quintana are human-specific pathogens, while several zoonotic bartonellae specific for diverse animal hosts infect humans as an incidental host. Clinical manifestations of Bartonella infections range from mild symptoms to life-threatening disease. Following transmission by blood-sucking arthropods or traumatic contact with infected animals, bartonellae display sequential tropisms towards endothelial and possibly other nucleated cells and erythrocytes, the latter in a host-specific manner. Attachment to the extracellular matrix (ECM) and to nucleated cells is mediated by surface-exposed bacterial adhesins, in particular trimeric autotransporter adhesins (TAAs). The subsequent engulfment of the pathogen into a vacuolar structure follows a unique series of events whereby the pathogen avoids the endolysosomal compartments. For Bartonella henselae and assumingly most other species, the infection process is aided at different steps by Bartonella effector proteins (Beps). They are injected into host cells through the type IV secretion system (T4SS) VirB/D4 and subvert host cellular functions to favour pathogen uptake. Bacterial binding to erythrocytes is mediated by Trw, another T4SS, in a strictly host-specific manner, followed by pathogen-forced uptake involving the IalB invasin and subsequent replication and persistence within a membrane-bound intra-erythrocytic compartment. PMID- 22519750 TI - Smoking-specific communication and children's smoking onset: an extension of the theory of planned behaviour. AB - The aim of this study was to test whether maternal smoking-specific communication and parental smoking related to smoking cognitions (i.e. attitude, self-efficacy and social norm) derived from the Theory of Planned Behaviour in association with smoking onset during preadolescence. A total of 1478 pairs of mothers and children participated (mean age: 10.11; standard deviation = 0.78). Structural equation models in Mplus were used to examine whether smoking-specific communication influences children's smoking cognitions, which in turn, affect smoking onset. A positive association was found between pro-smoking attitudes and smoking onset. Smoking-specific communication and parental smoking were related to smoking cognitions. Specifically, frequency of communication was negatively associated with pro-smoking attitudes, social norms of mother and best friend. Quality of communication related negatively to pro-smoking attitudes and positively to self-efficacy and norms of friends. Parental smoking was positively associated with pro-smoking attitudes and norms of mother and (best) friends. Additionally, more frequent communication and higher levels of parental smoking were associated with higher smoking onset. In conclusion, smoking-specific communication and parental smoking were associated with smoking cognitions and smoking onset. Already during preadolescence, parents contribute to shaping the smoking cognitions of their children, which may be predictive of smoking later in life. PMID- 22519752 TI - Dislocation-driven CdS and CdSe nanowire growth. AB - We report the synthesis of CdS and CdSe nanowires (NWs) and nanoribbons (NRs) with gold catalysts by H(2)-assisted chemical vapor deposition. Nanopods and nanocones were obtained without catalysts at higher system pressure. Transmission electron microscopy (TEM) studies, including two-beam TEM and displaced-aperture dark-field TEM characterization, were used to investigate the NW growth mechanism. Dislocation contrast and twist contours have been routinely observed within the synthesized one-dimensional (1D) CdS and CdSe NWs, suggesting the operation of the dislocation-driven NW growth mechanism under our experimental conditions. The Burgers vectors of dislocations and the associated Eshelby twists were measured and quantified. We hypothesize that gold nanoparticles provide nucleation sites to initiate the growth of CdS/CdSe NWs and lead to the formation of dislocations that continue to drive and sustain 1D growth at a low supersaturation level. Our study suggests that the dislocation-driven mechanism may also contribute to the growth of other 1D nanomaterials that are commonly considered to grow via the vapor-liquid-solid mechanism. PMID- 22519751 TI - Nanoflow low pressure high peak capacity single dimension LC-MS/MS platform for high-throughput, in-depth analysis of mammalian proteomes. AB - The use of narrow bore LC capillaries operated at ultralow flow rates coupled with mass spectrometry provides a desirable convergence of figures of merit to support high-performance LC-MS/MS analysis. This configuration provides a viable means to achieve in-depth protein sequence coverage while maintaining a high rate of data production. Here we explore potential performance improvements afforded by use of 25 MUm * 100 cm columns fabricated with 5 MUm diameter reversed phase particles and integrated electrospray emitter tips. These columns achieve a separation peak capacity of ~750 in a 600-min gradient, with average chromatographic peak widths of less than 1 min. At room temperature, a pressure drop of only ~1500 psi is sufficient to maintain an effluent flow rate of <=10 nL/min. Using mouse embryonic stem cells as a model for complex mammalian proteomes, we reproducibly identify over 4000 proteins across duplicate 600 min LC-MS/MS analyses. PMID- 22519753 TI - The bHLH transcription factor MdbHLH3 promotes anthocyanin accumulation and fruit colouration in response to low temperature in apples. AB - Low environmental temperatures promote anthocyanin accumulation and fruit colouration by up-regulating the expression of genes involved in anthocyanin biosynthesis and regulation in many fruit trees. However, the molecular mechanism by which fruit trees regulate this process in response to low temperature (LT) remains largely unknown. In this study, the cold-induced bHLH transcription factor gene MdbHLH3 was isolated from an apple tree and was found to interact physically and specifically through two regions (amino acids 1-23 and 186-228) at the N terminus with the MYB partner MdMYB1 (allelic to MdMYB10). Subsequently, MdbHLH3 bound to the promoters of the anthocyanin biosynthesis genes MdDFR and MdUFGT and the regulatory gene MdMYB1 to activate their expression. Furthermore, the MdbHLH3 protein was post-translationally modified, possibly involving phosphorylation following exposure to LTs, which enhanced its promoter-binding capacity and transcription activity. Our results demonstrate the molecular mechanism by which MdbHLH3 regulates LT-induced anthocyanin accumulation and fruit colouration in apple. PMID- 22519754 TI - Histone H1 affects gene imprinting and DNA methylation in Arabidopsis. AB - Imprinting, i.e. parent-of-origin expression of alleles, plays an important role in regulating development in mammals and plants. DNA methylation catalyzed by DNA methyltransferases plays a pivotal role in regulating imprinting by silencing parental alleles. DEMETER (DME), a DNA glycosylase functioning in the base excision DNA repair pathway, can excise 5-methylcytosine from DNA and regulate genomic imprinting in Arabidopsis. DME demethylates the maternal MEDEA (MEA) promoter in endosperm, resulting in expression of the maternal MEA allele. However, it is not known whether DME interacts with other proteins in regulating gene imprinting. Here we report the identification of histone H1.2 as a DME interacting protein in a yeast two-hybrid screen, and confirmation of their interaction by the in vitro pull-down assay. Genetic analysis of the loss-of function histone h1 mutant showed that the maternal histone H1 allele is required for DME regulation of MEA, FWA and FIS2 imprinting in Arabidopsis endosperm but the paternal allele is dispensable. Furthermore, we show that mutations in histone H1 result in an increase of DNA methylation in the maternal MEA and FWA promoter in endosperm. Our results suggest that histone H1 is involved in DME mediated DNA methylation and gene regulation at imprinted loci. PMID- 22519756 TI - How do I allocate blood products at the end of life? An ethical analysis with suggested guidelines. AB - Blood products are scarce resources requiring prudent and reasoned allocation. The utilization of red blood cells and platelets in terminally ill patients can be complicated and requires guidelines tempered by individualized considerations. Representative cases are discussed in which blood products are requested or utilized by patients at the end of life. Relevant literature is reviewed and ethical issues pertaining to each case are discussed. A practical approach to blood product utilization at the end of life is suggested. PMID- 22519755 TI - A human embryonic stem cell-derived clonal progenitor cell line with chondrogenic potential and markers of craniofacial mesenchyme. AB - AIMS: We screened 100 diverse human embryonic stem-derived progenitor cell lines to identify novel lines with chondrogenic potential. MATERIALS & METHODS: The 4D20.8 cell line was compared with mesenchymal stem cells and dental pulp stem cells by assessing osteochondral markers using immunohistochemical methods, gene expression microarrays, quantitative real-time PCR and in vivo repair of rat articular condyles. RESULTS: 4D20.8 expressed the site-specific gene markers LHX8 and BARX1 and robustly upregulated chondrocyte markers upon differentiation. Differentiated 4D20.8 cells expressed relatively low levels of COL10A1 and lacked IHH and CD74 expression. Transplantation of 4D20.8 cells into experimentally induced defects in the femoral condyle of athymic rats resulted in cartilage and bone differentiation approximating that of the original tissue architecture. Relatively high COL2A1 and minimal COL10A1 expression occurred during differentiation in HyStem-C hydrogel with TGF-beta3 and GDF-5. CONCLUSION: Human embryonic stem cell-derived embryonic progenitor cell lines may provide a novel means of generating purified site-specific osteochondral progenitor cell lines that are useful in research and therapy. PMID- 22519757 TI - Interplay between arrhythmias originating in the right ventricular outflow tract and the left coronary cusp. AB - A 35-year-old man was referred for ablation of ventricular tachycardia with two different morphologies triggering each other. After elimination of the first arrhythmia in the right ventricular outflow tract, ablation of the second morphology was performed 8 mm below the left main stem after contrast injection into the left coronary cusp through the irrigated-tip ablation catheter. PMID- 22519758 TI - Intrauterine growth restriction promotes vascular remodelling following carotid artery ligation in rats. AB - Epidemiological studies revealed an association between IUGR (intrauterine growth restriction) and an increased risk of developing CVDs (cardiovascular diseases), such as atherosclerosis or hypertension, in later life. Whether or not IUGR contributes to the development of atherosclerotic lesions, however, is unclear. We tested the hypothesis that IUGR aggravates experimentally induced vascular remodelling. IUGR was induced in rats by maternal protein restriction during pregnancy (8% protein diet). To detect possible differences in the development of vascular injury, a model of carotid artery ligation to induce vascular remodelling was applied in 8-week-old intrauterine-growth-restricted and control rat offspring. Histological and immunohistochemical analyses were performed in the ligated and non-ligated carotid arteries 8 weeks after ligation. IUGR alone neither caused overt histological changes nor significant dedifferentiation of VSMCs (vascular smooth muscle cells). After carotid artery ligation, however, neointima formation, media thickness and media/lumen ratio were significantly increased in rats after IUGR compared with controls. Moreover, dedifferentiation of VSMCs and collagen deposition in the media were more prominent in ligated carotids from rats after IUGR compared with ligated carotids from control rats. We conclude that IUGR aggravates atherosclerotic vascular remodelling induced by a second injury later in life. PMID- 22519759 TI - Oral anticoagulant therapy in Italian patients 80 yr of age or older with atrial fibrillation: a pilot study of low vs. standard PT/INR targets. AB - BACKGROUND: Oral anticoagulation therapy (OAT), which aims to prevent thromboembolism in patients with atrial fibrillation (AF), is underused in subjects who are over the age of 80 yr because of the associated bleeding risk. The aim of this study was to evaluate the efficacy and safety of OAT with low (2.0) vs. standard (2.5) PT/international normalised ratio (INR) targets in patients over the age of 80. MATERIALS AND METHODS: Of 233 patients aged 80 yr or older with AF on OAT, 58 had unstable PT/INR values and achieved reduced targets. These patients were enrolled as a group (A) in a case-control study and were treated with a low (2.0) PT/INR target. They were compared with a second group (B) of 58 additional patients who were matched for age and CHADS scores and treated with a standard (2.5) PT/INR target. Group A OAT parameters were also compared before and after the PT/INR reduction. The time in the therapeutic range (TTR%), PT/INR values >5, haemorrhages and strokes were prospectively evaluated in the two groups after 2 yr of follow-up. RESULTS: Of the 116 enrolled patients, 55 group A and 57 group B patients were evaluated. The TTR was 72.59% in group A and 64.43% in group B (P < 0.01). The percent of PT/INR values >5 was 0.68% for group A and 1.42% for group B (P < 0.05). Haemorrhages and thromboses occurred only in group B patients. The before and after analysis in group A showed that a low INR target produced an increase in the TTR (53.05% vs. 72.59%; P < 0.0001) and a reduction in the PT/INR values > 5 (1.72% vs. 0.68%; P < 0.001). CONCLUSIONS: A low PT/INR target seems effective and safe in Italian patients with AF over the age of 80. Further trials are needed to confirm the hypothesis generated by this study. PMID- 22519760 TI - Theory-guided strategy for nanolatex synthesis. AB - The synthesis of waterborne nanocomposites in semicontinuous emulsion polymerization was investigated using a theory-guided strategy with the aim of achieving the best balance among small particle size, low surfactant concentration, and sufficiently high solids content. It was found that both kinetic (monomer feeding rate, radical generation rate, and temperature) and colloidal (ionic strength and polymer hydrophilicity) aspects were critical in the process. Waterborne nanoparticles as small as 13 nm were obtained with a solids content/(surfactant/polymer) ratio higher than 7. PMID- 22519761 TI - DNA binding studies of 3, 5, 6-trichloro-2-pyridinol pesticide metabolite. AB - 3, 5, 6-Trichloro-2-pyridinol (TCP) is a stable metabolite of two major pesticides, Chlopyrifos insecticide and Triclopyr herbicide, which are widely used in the world. The potential health hazard associated with TCP is identified due to its high affinity to the DNA molecule. Therefore, in this study, the interaction of native calf thymus DNA with TCP has been investigated using spectrophotometric, circular dichroism (CD), spectrofluorometric, viscometric and voltametric techniques. It was found that TCP molecules could interact with DNA via a groove-binding mode, as evidenced by hyperchromism, with no red shift in the UV absorption band of TCP, no changes in K(b) values in the presence of salt, no significant changes in the specific viscosity and CD spectra of DNA, and a decrease in peak currents with no shift in the voltamogram. In addition, TCP is able to release Hoechst 33258, a strong groove binder, in the DNA solutions. The results are indicative of the groove-binding mode of TCP to DNA. PMID- 22519763 TI - Biotechnological potential and conservatory of extremophiles from climatically wide ranged developing countries: Lesson from Pakistan. AB - Abstract Technological advances, in developing countries, without considering environmental health issues have generated microsites uninhabitable to organisms including usual bacteria. While extremophilic microorganisms thrive in such locations. It is the high time to isolate and conserve the extremophilic biodiversity from such man made habitats before the environmental awareness treats them to the level of "destructiona. For biotechnology processes to be geared by employing extremophilic microorganisms, locations characterized with high/low temperature for most part of the year, hypersaline brine and abneutral pH environments may render the respective microbes to do their allotted/required jobs with minimal of extraneous investments. Besides, many known and expected potentials of extremophilic bacteria for biotechnological applications, major attraction lies in operating bioprocesses under non-aseptic conditions for making them economically feasible. This review after giving a thumbnail picture of extremophilies' known features is centered on the triad of biodiversity richness, environmental availabilities/managements of locations suitable for respective biotechnological bioprocesses and their non-aseptic designing for a developing country like Pakistan. PMID- 22519762 TI - Prevalence and change in psychiatric disorders among perinatally HIV-infected and HIV-exposed youth. AB - As the pediatric HIV epidemic in resource-rich countries evolves into an adolescent epidemic, there is a substantive need for studies elucidating mental health needs of perinatally HIV-infected (PHIV +) youth as they transition through adolescence. This article examines the role of perinatal HIV infection in influencing mental health by comparing the changes in psychiatric disorders and substance use disorders (SUD) in PHIV + and perinatally HIV-exposed, but uninfected (PHIV -) youth over time. Participants were recruited from four medical centers in New York City. Individual interviews were administered at baseline and 18-month follow-up to 166 PHIV + and 114 PHIV- youth (49% male, age 9-16 years at baseline). Youth psychiatric disorder was assessed using the caregiver and youth versions of the Diagnostic Interview Schedule for Children (DISC-IV). Over two-thirds of participants met criteria for at least one psychiatric disorder at either baseline or follow-up, with few group differences. Among PHIV + youth, there was a significant decrease in the prevalence of any psychiatric disorder, as well as anxiety disorders specifically over time, whereas the prevalence of any psychiatric disorder among PHIV- youth remained the same and mood disorders increased. Rates of SUD were low in both groups, increasing slightly by follow-up. PHIV + youth reported more use of mental health services at follow-up. CD4 count and HIV RNA viral load were not associated with the presence or absence of disorder at either time point. In conclusion, among PHIV + and PHIV- youth, the rates of psychiatric disorder were high, even compared to other vulnerable populations, suggesting that factors other than perinatal HIV infection may be important determinants of mental health. PHIV + youth were more likely to improve over the observation period. The data underscore the critical need for mental health interventions for both PHIV + and PHIV- youth. PMID- 22519765 TI - Inhaled prostanoid therapy for pulmonary arterial hypertension - a promise unfulfilled? PMID- 22519766 TI - Tyrosine kinase inhibitors in acute and chronic leukemias. AB - INTRODUCTION: Since the initial approval of imatinib much has been learned about its resistance mechanisms, and efforts have continued to improve upon BCR-ABL tyrosine kinase inhibitor therapy. Targeted therapy with TKIs has continued to be an area of active research and development in the care of acute and chronic leukemia patients. AREAS COVERED: This article reviews current approved and investigational TKI treatments for chronic myelogenous leukemia (CML), Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph + ALL) and acute myelogenous leukemia (AML). EXPERT OPINION: There are now more potent BCR ABL TKIs approved, which allow for additional options when determining front-line and second-line CML and Ph + ALL treatments. The T315I mutation is an ever present challenge. Ponatinib, a pan BCR-ABL TKI, while still under investigation, is very hopeful with its ability to overcome T315I mutations in resistant CML and Ph + ALL patients. Because nilotinib and dasatinib have not been directly compared, at present we recommend selecting one or the other based on the side effect profile, drug interactions, patient comorbidities, and mutational status. FLT-3 inhibition is of particular interest in AML patients with FLT-3 internal tandem duplication mutations; this type of targeted therapy continues to be studied. PMID- 22519767 TI - Current treatment of nontuberculous mycobacteriosis: an update. AB - INTRODUCTION: Nontuberculous mycobacteria (NTM) are becoming increasingly important. A growing number of patients with underlying conditions that make them prone to diseases caused by NTM. These diseases include the appearance of new syndromes, such as mesotherapy and other cosmetic-related infections, or diseases that affect patients who are being treated with tumor necrosis factor. AREAS COVERED: A literature search has been performed for each mycobacterium species. An introduction to the different aspects of the species and the diseases is provided, along with a review of the current therapeutic options; special emphasis is put on new research and discoveries. EXPERT OPINION: Recognition of the current role of NTM isolates remains the key step in the management of NTM infections. After recognition, treatment must be guided by attending to the isolated species, the specific syndromes, clinical experience and - for some species - the results of in-vitro susceptibility tests. Surgical therapy is also important for some species (Mycobacterium ulcerans, Mycobacterium scrofulaceum) and for localized infections. The treatment of uncommon species is not yet well defined and recent research on resistance mechanisms has described their importance. The role of biofilms is currently of special concern for various specific infections. PMID- 22519768 TI - Rilpivirine: a next-generation non-nucleoside analogue for the treatment of HIV infection. AB - INTRODUCTION: HIV therapy has evolved rapidly since the 1990s; the arrival of more potent and safer antiretroviral drugs has transformed HIV infection into a chronic condition, which is rarely fatal. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are frequently used as a third agent - as part of a triple combination therapy. Side effects and low barriers to resistance have been the major drawbacks of NNRTIs. Rilpivirine (RPV) is a next-generation non-nucleoside analogue, the unique features of which might favor choosing this drug over other NNRTIs. RPV is the latest NNRTI approved for the treatment of HIV infection. Along with its high efficacy and good safety profile, data on pharmacokinetics and drug interactions make RPV particularly attractive. AREAS COVERED: This article aims to provide an in-depth analysis of the main features and data available from recent clinical trials that have tested the performance of RPV. EXPERT OPINION: RPV is a safe and efficacious antiretroviral drug with a better neuropsychiatric and metabolic profile than efavirenz, which is currently the most widely used NNRTI. The availability of a fixed-dose coformulation of RPV with tenofovir/emtricitabine makes the use of RPV even more attractive. The efficacy of RPV in patients with a high baseline viral load remains to be clarified in further trials. PMID- 22519769 TI - Oxycodone for the treatment of postoperative pain. AB - INTRODUCTION: Pain is a likely outcome of any surgical procedure. In several countries the use of oxycodone has surpassed that of morphine in postoperative pain management. AREAS COVERED: This review summarizes the recent pharmacological and clinical data on oxycodone use for postoperative pain management. The benefits and the impact oxycodone may have on outcome in different patient groups is addressed. As oxycodone is available on different pharmaceutical formulations and as a new combination product with naloxone, the different approaches that may be used with oxycodone in postoperative pain management are also reviewed. EXPERT OPINION: The recent interest in oxycodone is based on its favorable pharmacokinetics and pharmacodynamics, especially in the central nervous system. Moreover, relatively high enteral bioavailability allows an easy switch from one drug formulation to another during the course of pain management. Oxycodone is highly effective and well tolerated in different types of surgical procedures and patient groups, from preterm to aged patients. In the future, the use of transmucosal administration and enteral oxycodone-naloxone controlled-release tablets is likely to increase, and an appropriate concurrent use of different enteral drug formulations will decrease the need for more complex administration techniques, such as intravenous patient-controlled analgesia. PMID- 22519770 TI - Sorafenib in liver cancer. AB - INTRODUCTION: With growing knowledge of the molecular pathway of carcinogenesis, targeted therapies have become the 'blue ocean' of cancer treatment. sorafenib is an oral multikinase inhibitor that targets Raf/mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK) (Raf/MEK/ERK) and several tyrosine kinases (VEGFR-2, VEGFR-3, PDGFR-beta) that has shown efficacy in hepatocellular carcinoma (HCC). AREAS COVERED: An updated summary of the preclinical and clinical experience with sorafenib in HCC is presented in this paper. Data are based on abstracts from international conferences and journal articles found in a PubMed search of literature published up to December 2011. EXPERT OPINION: Based on favorable data from preclinical and clinical trials, sorafenib has been approved as a standard therapy in advanced HCC. However, further efforts to understand the additional roles of sorafenib in the treatment of HCC are still necessary. Data for sorafenib will guide the development of new drugs for the treatment of HCC. PMID- 22519771 TI - Retraction. Treatment of osteoporosis and reduction in risk of invasive breast cancer in postmenopausal women with raloxifene. PMID- 22519772 TI - Do trade-offs have explanatory power for the evolution of organismal interactions? AB - The concept of a trade-off has long played a prominent role in understanding the evolution of organismal interactions such as mutualism, parasitism, and competition. Given the complexity inherent to interactions between different evolutionary entities, ecological factors may especially limit the power of trade off models to predict evolutionary change. Here, we use four case studies to examine the importance of ecological context for the study of trade-offs in organismal interactions: (1) resource-based mutualisms, (2) parasite transmission and virulence, (3) plant biological invasions, and (4) host range evolution in parasites and parasitoids. In the first two case studies, mechanistic trade-off models have long provided a strong theoretical framework but face the challenge of testing assumptions under ecologically realistic conditions. Work under the second two case studies often has a strong ecological grounding, but faces challenges in identifying or quantifying the underlying genetic mechanism of the trade-off. Attention is given to recent studies that have bridged the gap between evolutionary mechanism and ecological realism. Finally, we explore the distinction between ecological factors that mask the underlying evolutionary trade-offs, and factors that actually change the trade-off relationship between fitness-related traits important to organismal interactions. PMID- 22519774 TI - Determination of the cost of worker reproduction via diminished life span in the ant Diacamma sp. AB - Workers of social Hymenoptera can usually produce male offspring, but rarely do so in the presence of a queen despite the potential individual fitness benefit. Various mechanisms have been hypothesized to regulate worker reproduction, including avoiding the colony-level cost of worker reproduction. However, firm quantitative evidence is lacking to support that hypothesis. Here, we accurately quantified this cost by studying an ant species (Diacamma sp.) in which worker reproduction is rare in the presence of the gamergate (the functional queen). A series of experiments to manipulate worker-gamergate contact revealed that short term brood-production efficiency is not changed by the presence of worker reproduction. However, when workers reproduce, their average life span is reduced to between 74% and 88% of that in the absence of reproduction, indicating a long term cost to the colony. In theory, this cost can explain the policing of worker reproduction under a queen-single mating system, but the cost does not appear to be high enough to stop worker reproduction. When contact with the gamergate is lost, it is only the nonreproductive workers whose life span was reduced; the reproductive workers lived as long as nonorphaned workers. We suggest that an increased workload can account for the reduction in life span better than a trade off between reproduction and longevity. PMID- 22519773 TI - Evolutionary perspectives in a mutualism of sepiolid squid and bioluminescent bacteria: combined usage of microbial experimental evolution and temporal population genetics. AB - The symbiosis between marine bioluminescent Vibrio bacteria and the sepiolid squid Euprymna is a model for studying animal-bacterial Interactions. Vibrio symbionts native to particular Euprymna species are competitively dominant, capable of outcompeting foreign Vibrio strains from other Euprymna host species. Despite competitive dominance, secondary colonization events by invading nonnative Vibrio fischeri have occurred. Competitive dominance can be offset through superior nonnative numbers and advantage of early start host colonization by nonnatives, granting nonnative vibrios an opportunity to establish beachheads in foreign Euprymna hosts. Here, we show that nonnative V. fischeri are capable of rapid adaptation to novel sepiolid squid hosts by serially passaging V. fischeri JRM200 (native to Hawaiian Euprymna scolopes) lines through the novel Australian squid host E. tasmanica for 500 generations. These experiments were complemented by a temporal population genetics survey of V. fischeri, collected from E. tasmanica over a decade, which provided a perspective from the natural history of V. fischeri evolution over 15,000-20,000 generations in E. tasmanica. No symbiont anagenic evolution within squids was observed, as competitive dominance does not purge V. fischeri genetic diversity through time. Instead, abiotic factors affecting abundance of V. fischeri variants in the planktonic phase sustain temporal symbiont diversity, a property itself of ecological constraints imposed by V. fischeri host adaptation. PMID- 22519775 TI - Experimental tests of sex allocation theory with two species of simultaneously hermaphroditic acorn barnacles. AB - Sex allocation theory for simultaneous hermaphrodites predicts increases in relative allocation to male-specific function as competition for fertilizations increases. Theoretical models developed specifically for competing acorn barnacles predict that the proportional allocation to male function increases toward an asymptote of 50% as the number of competitors for fertilizations increases. Experimental manipulations were used to investigate how mate competition affected both relative and absolute allocation to the sex functions for two species of acorn barnacle: Semibalanus balanoides and Balanus glandula. The ratio of male to female allocation did not increase with the number of competitors for either species. However, both species showed increased allocation to male function (estimated as total mass of sex-specific tissues) with increased crowding. Allocation to female function seemed to be limited by other factors and did not vary with mating group size as predicted. Allocation to male and female function were both positively related to body size, but a trade-off between male and female function, a key assumption of prior models, was not observed. PMID- 22519776 TI - Selection on floral design in Polemonium brandegeei (Polemoniaceae): female and male fitness under hawkmoth pollination. AB - Plant-pollinator interactions promote the evolution of floral traits that attract pollinators and facilitate efficient pollen transfer. The spatial separation of sex organs, herkogamy, is believed to limit sexual interference in hermaphrodite flowers. Reverse herkogamy (stigma recessed below anthers) and long, narrow corolla tubes are expected to promote efficiency in male function under hawkmoth pollination. We tested this prediction by measuring selection in six experimental arrays of Polemonium brandegeei, a species that displays continuous variation in herkogamy, resulting in a range of recessed to exserted stigmas. Under glasshouse conditions, we measured pollen removal and deposition, and estimated selection gradients (beta) through female fitness (seeds set) and male fitness (siring success based on six polymorphic microsatellite loci). Siring success was higher in plants with more nectar sugar and narrow corolla tubes. However, selection through female function for reverse herkogamy was considerably stronger than was selection through male function. Hawkmoths were initially attracted to larger flowers, but overall preferred plants with reverse herkogamy. Greater pollen deposition and seed set also occurred in reverse herkogamous plants. Thus, reverse herkogamy may be maintained by hawkmoths through female rather than male function. Further, our results suggest that pollinator attraction may play a considerable role in enhancing female function. PMID- 22519778 TI - How depressed? Estimates of inbreeding effects during seed development depend on reproductive conditions. AB - Inbreeding depression can reduce the performance of offspring produced by mating between relatives, with consequences for population dynamics and sexual-system evolution. In flowering plants, inbreeding depression commonly acts most intensely during seed development. This predispersal component is typically estimated by comparing seed production following exclusive self- and cross pollination, but such estimates are unbiased only if seed production is limited by ovule availability, rather than by pollen receipt or seed-development resources. To overcome this problem, we propose experimental and statistical methods based on a model of ovule fertilization and seed development that accounts for differential fertilization by self- and cross-pollen, limited ovule viability or receptivity, differential survival of self- and cross-zygotes and limited resource availability. Simulations illustrate that the proposed methods eliminate bias in estimated predispersal inbreeding depression caused by pollen limitation and can improve estimates under resource limitation. Application of these methods to two orchid species further demonstrates their utility in identifying and estimating diverse influences on reproductive performance under typical conditions. Although our theoretical results raise questions about the reported intensity of predispersal inbreeding depression, our proposed methods guard against bias while also providing insight into plant reproduction. PMID- 22519777 TI - Genetic architecture and adaptive significance of the selfing syndrome in Capsella. AB - The transition from outcrossing to predominant self-fertilization is one of the most common evolutionary transitions in flowering plants. This shift is often accompanied by a suite of changes in floral and reproductive characters termed the selfing syndrome. Here, we characterize the genetic architecture and evolutionary forces underlying evolution of the selfing syndrome in Capsella rubella following its recent divergence from the outcrossing ancestor C. grandiflora. We conduct genotyping by multiplexed shotgun sequencing and map floral and reproductive traits in a large (N= 550) F2 population. Our results suggest that in contrast to previous studies of the selfing syndrome, changes at a few loci, some with major effects, have shaped the evolution of the selfing syndrome in Capsella. The directionality of QTL effects, as well as population genetic patterns of polymorphism and divergence at 318 loci, is consistent with a history of directional selection on the selfing syndrome. Our study is an important step toward characterizing the genetic basis and evolutionary forces underlying the evolution of the selfing syndrome in a genetically accessible model system. PMID- 22519779 TI - Relating hybrid advantage and genome replacement in unisexual salamanders. AB - Unisexual vertebrates are model systems for understanding the evolution of sex. Many predominantly clonal lineages allow occasional genetic recombination, which may be sufficient to avoid the accumulation of deleterious mutations and parasites. Introgression of paternal DNA into an all-female lineage represents a one-way flow of genetic material. Over many generations, this could result in complete replacement of the unisexual genomes by those of the donor species. The process of genome replacement may be counteracted by contemporary dispersal or by positive selection on hybrid nuclear genomes in ecotones. I present a conceptual model that relates nuclear genome replacement, positive selection on hybrids and biogeography in unisexual systems. I execute an individual-based simulation of the fate of hybrid genotypes in contact with a single host species. I parameterize these models for unisexual salamanders in the Ambystoma genus, for which the frequency of genome replacement has been a source of ongoing debate. I find that, if genome replacement occurs at a rate greater than 1/10,000 in Ambystoma, then there must be compensating positive selection in order to maintain observed levels of hybrid nuclei. Future researchers studying unisexual systems may use this framework as a guide to evaluating the hybrid superiority hypothesis. PMID- 22519780 TI - Genetic variation and evolution of secondary compounds in native and introduced populations of the invasive plant Melaleuca quinquenervia. AB - We examined multivariate evolution of 20 leaf terpenoids in the invasive plant Melaleuca quinquenervia in a common garden experiment. Although most compounds, including 1,8-Cineole and Viridiflorol, were reduced in home compared with invaded range genotypes, consistent with an evolutionary decrease in defense, one compound (E-Nerolidol) was greater in invaded than home range genotypes. Nerolidol was negatively genetically correlated with Cineole and Viridiflorol, and the increase in this compound in the new range may have been driven by this negative correlation. There was positive selection on all three focal compounds, and a loss of genetic variation in introduced range genotypes. Selection skewers analysis predicted an increase in Cineole and Viridiflorol and a decrease or no change in Nerolidol, in direct contrast to the observed changes in the new range. This discrepancy could be due to differences in patterns of selection, genetic correlations, or the herbivore communities in the home versus introduced ranges. Although evolutionary changes in most compounds were consistent with the evolution of increased competitive ability hypothesis, changes in other compounds as well as selection patterns were not, indicating that it is important to understand selection and the nature of genetic correlations to predict evolutionary change in invasive species. PMID- 22519782 TI - Asymmetrical patterns of speciation uniquely support reinforcement in Drosophila. AB - Understanding how often natural selection directly favors speciation, a process known as reinforcement, has remained an outstanding problem for over 70 years. Although reinforcement has been strongly criticized in the past, it is once again seen as more realistic due to the seminal discovery of enhanced prezygotic isolation among sympatric species and to a handful of well-studied examples. Nevertheless, the pattern of enhanced isolation in sympatry has alternative explanations, highlighting the need to uncover unique signatures of reinforcement to determine its overall frequency in nature. Using a novel dataset on asymmetrical prezygotic and postzygotic isolation among Drosophila species, I uncover new patterns explicitly predicted by reinforcement. Broadly, I found that almost all sympatric species had concordant isolation asymmetries, where the more costly reciprocal mating has greater prezygotic isolation relative to the less costly mating. No such patterns exist in allopatry. Using simulations, I ruled out alternative explanations and showed that concordant isolation asymmetries in sympatry are likely unique signatures of reinforcement. These results allowed me to estimate that reinforcement may impact 60-83% of all sympatric Drosophila and enhance premating isolation by 18-26%. These findings suggest that reinforcement plays a key role in Drosophila speciation. PMID- 22519781 TI - Population genetics and objectivity in species diagnosis. AB - Species as evolutionary lineages are expected to show greater evolutionary independence from one another than are populations within species. Two measures of evolutionary independence that stem from the study of isolation-with-migration models, one reflecting the amount of gene exchange and one reflecting the time of separation, were drawn from the literature for a large number of pairs of closely related species and pairs of populations within species. Both measures, for gene flow and time, showed broadly overlapping distributions for pairs of species and for pairs of populations within species. Species on average show more time and less gene flow than populations, but the similarity of the distributions argues against there being a qualitative difference associated with species status, as compared to populations. The two measures of evolutionary independence were similarly correlated with F(ST) estimates, which in turn also showed similar distributions for species comparisons relative to population comparisons. The measures of gene flow and separation time were examined for the capacity to discriminate intraspecific differences from interspecific differences. If used together, the two measures could be used to develop an objective (in the sense of being repeatable) measure for species diagnosis. PMID- 22519784 TI - Reconciling extremely strong barriers with high levels of gene exchange in annual sunflowers. AB - In several cases, estimates of gene flow between species appear to be higher than we might predict given the strength of interspecific barriers separating these species pairs. However, as far as we are aware, detailed measurements of reproductive isolation have not previously been compared with a coalescent-based assessment of gene flow. Here, we contrast these two measures in two species of sunflower, Helianthus annuus and H. petiolaris. We quantified the total reproductive barrier strength between these species by compounding the contributions of the following prezygotic and postzygotic barriers: ecogeographic isolation, reproductive asynchrony, niche differentiation, pollen competition, hybrid seed formation, hybrid seed germination, hybrid fertility, and extrinsic postzygotic isolation. From this estimate, we calculated the probability that a reproductively successful hybrid is produced: estimates of P(hyb) range from 10( 4) to 10(-6) depending on the direction of the cross and the degree of independence among reproductive barriers. We then compared this probability with population genetic estimates of the per generation migration rate (m). We showed that the relatively high levels of gene flow estimated between these sunflower species (N(e) m= 0.34-0.76) are mainly due to their large effective population sizes (N(e) > 10(6)). The interspecific migration rate (m) is very small (<10( 7)) and an order of magnitude lower than that expected based on our reproductive barrier strength estimates. Thus, even high levels of reproductive isolation (>0.999) may produce genomic mosaics. PMID- 22519785 TI - Strong selection against hybrids maintains a narrow contact zone between morphologically cryptic lineages in a rainforest lizard. AB - Phenotypically cryptic lineages comprise an important yet understudied part of biodiversity; in particular, we have much to learn about how these lineages are formed and maintained. To better understand the evolutionary significance of such lineages, we studied a hybrid zone between two morphologically cryptic phylogeographic lineages in the rainforest lizard, Lampropholis coggeri. Analyzing a multilocus genetic dataset through cline inference, individual-based methods and population measures of disequilibrium and using simulations to explore our genetic results in context of theoretical expectations, we inferred the processes maintaining this hybrid zone. We find that these lineages meet in a hybrid zone that is narrow (~400 m) relative to inferred dispersal rate. Further, the hybrid zone exhibits substantial genetic disequilibrium and sharply coincident and largely concordant clines. Based on our knowledge about the region's biogeography, the species' natural history, and our simulation results, we suggest that strong selection against hybrids structures this system. As all clines show a relatively narrow range of introgression, we posit that this hybrid zone might not yet be in equilibrium. Nonetheless, our results clearly show that phylogeographic lineages can evolve substantial reproductive isolation without concomitant morphological diversification, suggesting that such lineages can constitute a significant component of evolutionary diversity. PMID- 22519786 TI - Hybridization and barriers to gene flow in an island bird radiation. AB - While reinforcement may play a role in all major modes of speciation, relatively little is known about the timescale over which species hybridize without evolving complete reproductive isolation. Birds have high potential for hybridization, and islands provide simple settings for uncovering speciation and hybridization patterns. Here we develop a phylogenetic hypothesis for a phenotypically diverse radiation of finch-like weaver-birds (Foudia) endemic to the western Indian Ocean islands. We find that unlike Darwin's finches, each island-endemic Foudia population is a monophyletic entity for which speciation can be considered complete. In explaining the only exceptions-mismatches between taxonomy, mitochondrial, and nuclear data-phylogenetic and coalescent methods support introgressive hybridization rather than incomplete lineage sorting. Human introductions of known timing of one island-endemic species, to all surrounding archipelagos provide two fortuitous experiments; (1) population sampling at known times in recent evolutionary history, (2) bringing allopatric lineages of an island radiation into secondary contact. Our results put a minimum time bound on introgression (235 years), and support hybridization between species in natural close contact (parapatry), but not between those in natural allopatry brought into contact by human introduction. Time in allopatry, rather than in sympatry, appears key in the reproductive isolation of Foudia species. PMID- 22519787 TI - Modularity, noise, and natural selection. AB - Most biological systems are formed by component parts that are to some degree interrelated. Groups of parts that are more associated among themselves and are relatively autonomous from others are called modules. One of the consequences of modularity is that biological systems usually present an unequal distribution of the genetic variation among traits. Estimating the covariance matrix that describes these systems is a difficult problem due to a number of factors such as poor sample sizes and measurement errors. We show that this problem will be exacerbated whenever matrix inversion is required, as in directional selection reconstruction analysis. We explore the consequences of varying degrees of modularity and signal-to-noise ratio on selection reconstruction. We then present and test the efficiency of available methods for controlling noise in matrix estimates. In our simulations, controlling matrices for noise vastly improves the reconstruction of selection gradients. We also perform an analysis of selection gradients reconstruction over a New World Monkeys skull database to illustrate the impact of noise on such analyses. Noise-controlled estimates render far more plausible interpretations that are in full agreement with previous results. PMID- 22519788 TI - Roles for modularity and constraint in the evolution of cranial diversity among Anolis lizards. AB - Complex organismal structures are organized into modules, suites of traits that develop, function, and vary in a coordinated fashion. By limiting or directing covariation among component traits, modules are expected to represent evolutionary building blocks and to play an important role in morphological diversification. But how stable are patterns of modularity over macroevolutionary timescales? Comparative analyses are needed to address the macroevolutionary effect of modularity, but to date few have been conducted. We describe patterns of skull diversity and modularity in Caribbean Anolis lizards. We first diagnose the primary axes of variation in skull shape and then examine whether diversification of skull shape is concentrated to changes within modules or whether changes arose across the structure as a whole. We find no support for the hypothesis that cranial modules are conserved as species diversify in overall skull shape. Instead we find that anole skull shape and modularity patterns independently converge. In anoles, skull modularity is evolutionarily labile and may reflect the functional demands of unique skull shapes. Our results suggest that constraints have played little role in limiting or directing the diversification of head shape in Anolis lizards. PMID- 22519789 TI - Invasion of gene duplication through masking for maladaptive gene flow. AB - Gene duplication can increase an organism's ability to mask the effect of deleterious alleles present in the population, but this is typically a small effect when the source of the genetic variation is mutation. Migration can introduce orders of magnitude more deleterious alleles per generation and may therefore be an important force acting on the structure of genomes. Using formal analytical methods, we study the invasion of haplotypes containing two copies of the resident allele, assuming that a single-locus equilibrium is already established in a continent-island model of migration. Provided that the immigrant allele can be completely masked by multiple functional gene copies, a new duplication will deterministically spread so long as duplicate haplotypes are, on average, fitter than single-copy haplotypes. When fitness depends on the number of immigrant allele copies and their masking ability then the threshold for invasion depends on the rate of immigration and the rate of recombination between the gene copies. Results from several special cases, including formation of protein dimers and Dobzhansky-Muller incompatibilities, suggest that duplications can invade in a wide range of selection regimes. We hypothesize that duplication in response to gene flow may provide an explanation for the high levels of polymorphism in gene copy number observed in natural populations. PMID- 22519783 TI - Dynamics of drift, gene flow, and selection during speciation in Silene. AB - The mechanics of speciation with gene flow are still unclear. Disparity among genes in population differentiation (F(ST)) between diverging species is often interpreted as evidence for semipermeable species boundaries, with selection preventing "key" genes from introgressing despite ongoing gene flow. However, F(ST) can remain high before it reaches equilibrium between the lineage sorting of species divergence and the homogenizing effects of gene flow (via secondary contact). Thus, when interpreting F(ST), the dynamics of drift, gene flow, and selection need to be taken into account. We illustrate this view with a multigenic analyses of gene flow and selection in three closely related Silene species, S. latifolia, S. dioica, and S. diclinis. We report that although S. diclinis appears to have evolved in allopatry, isolation with (bidirectional) gene flow between S. latifolia and S. dioica is likely, perhaps as a result of parapatric speciation followed by more extensive sympatry. Interestingly, we detected the signatures of apparently independent instances of positive selection at the same locus in S. latifolia and S. dioica. Despite gene flow between the species, the adaptive alleles have not crossed the species boundary, suggesting that this gene has independently undergone species-specific (diversifying or parallel) selection. PMID- 22519790 TI - Gene duplication in the evolution of sexual dimorphism. AB - Males and females share most of the same genes, so selection in one sex will typically produce a correlated response in the other sex. Yet, the sexes have evolved to differ in a multitude of behavioral, morphological, and physiological traits. How did this sexual dimorphism evolve despite the presence of a common underlying genome? We investigated the potential role of gene duplication in the evolution of sexual dimorphism. Because duplication events provide extra genetic material, the sexes each might use this redundancy to facilitate sex-specific gene expression, permitting the evolution of dimorphism. We investigated this hypothesis at the genome-wide level in Drosophila melanogaster, using the presence of sex-biased expression as a proxy for the sex-specific specialization of gene function. We expected that if sexually antagonistic selection is a potent force acting upon individual genes, duplication will result in paralog families whose members differ in sex-biased expression. Gene members of the same duplicate family can have different expression patterns in males versus females. In particular, duplicate pairs containing a male-biased gene are found more frequently than expected, in agreement with previous studies. Furthermore, when the singleton ortholog is unbiased, duplication appears to allow one of the paralog copies to acquire male-biased expression. Conversely, female-biased expression is not common among duplicates; fewer duplicate genes are expressed in the female-soma and ovaries than in the male-soma and testes. Expression divergence exists more in older than in younger duplicates pairs, but expression divergence does not correlate with protein sequence divergence. Finally, genomic proximity may have an effect on whether paralogs differ in sex-biased expression. We conclude that the data are consistent with a role of gene duplication in fostering male-biased, but not female-biased, gene expression, thereby aiding the evolution of sexual dimorphism. PMID- 22519791 TI - A model for genomic imprinting in the social brain: elders. AB - Genomic imprinting refers to the process whereby genes are silenced when inherited via sperm or egg. The most widely accepted theory for the evolution of genomic imprinting-the kinship theory-argues that conflict between maternally inherited and paternally inherited genes over phenotypes with asymmetric effects on matrilineal and patrilineal kin results in self-imposed silencing of one of the copies. This theory was originally developed in the context of fitness interactions within nuclear families, to understand intragenomic conflict in the embryo and infant, but it has recently been extended to encompass interactions within wider social groups, to understand intragenomic conflict over the social behavior of juveniles and adults. Here, we complete our model of genomic imprinting in the social brain by considering age-specific levels of expression in a society were generations overlap, to determine how intragenomic conflict plays out in older age. We determine the role of sex bias in juvenile dispersal, reproductive success, and adult mortality in mediating the direction and intensity of conflict over the competing demands of parental and communal care as the individual ages. We discover that sex-specific asymmetries in these demographic parameters result in intragenomic conflict at early age but this conflict gradually decays with age. Although individuals are riven by internal conflict in their youth and middle age, they put their demons to rest in later life. PMID- 22519792 TI - The evolutionary epidemiology of multilocus drug resistance. AB - The evolution of resistance to drugs is a major public health concern as it erodes the efficacy of our therapeutic arsenal against bacterial, viral, and fungal pathogens. Increasingly, it is recognized that the evolution of resistance involves genetic changes at more than one locus, both in cases where multiple changes are required to obtain high-level resistance, and where compensatory changes at secondary loci ameliorate the costs of resistance. Similarly, multiple loci are often involved in the evolution of multidrug resistance. There has been widespread interest recently in understanding the evolutionary consequences of multilocus resistance, with many empirical studies documenting extensive patterns of genetic interactions (i.e., epistasis) among the loci involved. Currently, however, there are few general theoretical results available that bridge the gap between classical multilocus population genetics and mathematical epidemiology. Here, such theory is developed to shed new light on these previous studies, and to provide further guidance on the type of data required to predict the evolution of pathogens in response to drug pressure. Our results reveal the importance of feedbacks between the epidemiological and evolutionary dynamics, and illustrate how these feedbacks can be exploited to control resistance. In particular, we show how interventions such as social distancing and isolation can influence rates of recombination, and how this then can slow the spread of multilocus resistance and increase the likelihood of reversion to drug sensitivity once drug therapy has ceased. PMID- 22519793 TI - Environmental robustness and the adaptability of populations. AB - Recent work has shown that genetic robustness can either facilitate or impede adaptation. But the impact of environmental robustness on adaptation remains unclear. Environmental robustness helps ensure that organisms consistently develop the same phenotype in the face of "environmental noise" during development. Under purifying selection, those genotypes that express the optimal phenotype most reliably will be selectively favored. The resulting reduction in genetic variation tends to slow adaptation when the population is faced with a novel target phenotype. However, environmental noise sometimes induces the expression of an alternative advantageous phenotype, which may speed adaptation by genetic assimilation. Here, we use a population-genetic model to explore how these two opposing effects of environmental noise influence the capacity of a population to adapt. We analyze how the rate of adaptation depends on the frequency of environmental noise, the degree of environmental robustness in the population, the distribution of environmental robustness across genotypes, the population size, and the strength of selection for a newly adaptive phenotype. Over a broad regime, we find that environmental noise can either facilitate or impede adaptation. Our analysis uncovers several surprising insights about the relationship between environmental noise and adaptation, and it provides a general framework for interpreting empirical studies of both genetic and environmental robustness. PMID- 22519794 TI - Two measures of effective population size for graphs. AB - Effective population size is a key parameter in population ecology because it allows prediction of the dynamics of genetic variation and the rate of genetic drift and inbreeding. It is important for the definition of "nearly neutral" mutations and, hence, has consequences for the fixation or extinction probabilities of advantageous and deleterious mutations. As graph-based population models become increasingly popular for studying evolution in spatially or socially structured populations, a neutral theory for evolution on graphs is called for. Here, we derive formulae for two alternative measures of effective population size, the variance effective and inbreeding effective size of general unweighted and undirected graphs. We show how these two quantities relate to each other and we derive effective sizes for the complete graph the cycle and bipartite graphs. For one-dimensional lattices and small-world graphs, we estimate the inbreeding effective size using simulations. The presented method is suitable for any structured population of haploid individuals with overlapping generations. PMID- 22519795 TI - Evolution of social versus individual learning in an infinite island model. AB - We model the evolution of learning in a population composed of infinitely many, finite-sized islands connected by migration. We assume that there are two discrete strategies, social and individual learning, and that the environment is spatially homogeneous but varies temporally in a periodic or stochastic manner. Using a population-genetic approximation technique, we derive a mathematical condition for the two strategies to coexist stably and the equilibrium frequency of social learners under stable coexistence. Analytical and numerical results both reveal that social learners are favored when island size is large or migration rate between islands is high, suggesting that spatial subdivision disfavors social learners. We also show that the average fecundity of the population under stable coexistence of the two strategies is in general lower than that in the absence of social learners and is minimized at an intermediate migration rate. PMID- 22519796 TI - The evolutionary diversification of seed size: using the past to understand the present. AB - The Devonian origin of seed plants and subsequent morphological diversification of seeds during the late Paleozoic represents an adaptive radiation into unoccupied ecological niche space. A plant's seed size is correlated with its life-history strategy, growth form, and seed dispersal syndrome. The fossil record indicates that the oldest seed plants had relatively small seeds, but the Mississippian seed size envelope increased significantly with the diversification of larger seeded lineages. Fossil seeds equivalent to the largest extant gymnosperm seeds appeared by the Pennsylvanian, concurrent with morphological diversification of growth forms and dispersal syndromes as well as the clade's radiation into new environments. Wang's Analysis of Skewness indicates that the evolutionary trend of increasing seed size resulted from primarily passive processes in Pennsylvanian seed plants. The distributions of modern angiosperms indicate a more diverse system of active and some passive processes, unbounded by Paleozoic limits; multiple angiosperm lineages independently evolved though the upper and lower bounds. Quantitative measures of preservation suggest that, although our knowledge of Paleozoic seeds is far from complete, the evolutionary trend in seed size is unlikely to be an artifact of taphonomy. PMID- 22519799 TI - Tuning nonlinear optical and optoelectronic properties of vinyl coupled triazene chromophores: a density functional theory and time-dependent density functional theory investigation. AB - Triazenes are a unique class of polyazo compounds containing three consecutive nitrogen atoms in an acyclic arrangement and are promising NLO candidates. In the present work, a series of 15 donor-pi-acceptor type vinyl coupled triazene derivatives (VCTDs) with different acceptors (-NO(2), -CN, and -COOH) have been designed, and their structure, nonlinear response, and optoelectronic properties have been studied using density functional theory and time-dependent density functional theory methods. B3LYP/6-311g(d,p) optimized geometries of the designed candidates show delocalization from the acceptor to donor through a pi-bridge. Molecular orbital composition analysis reveals that HOMO is stabilized by the pi bridge, whereas acceptors play a major role in the stabilization of LUMO. Among the three acceptors, nitro derivatives are found to be efficient NLO candidates, and tri- and di-substituted cyano and carboxylic acid derivatives also show reasonably good NLO response. The effect of solvation on these properties has been studied using PCM calculations. From TDDFT calculations, the computed absorption spectra of these candidates lie in the range of 350-480 nm in the gas phase and have positive solvatochromism. The ground-state stabilization interactions are accounted from NBO calculations. In an effort to substantiate the thermal stability of the designed candidates, computations have been done to identify the weak interactions in the systems through NCI and AIM analysis. In summary, 10 out of 15 designed candidates are found to have excellent NLO and optoelectronic properties. PMID- 22519798 TI - The evolution of conflict resolution between plasmids and their bacterial hosts. AB - It has recently been proposed that mobile elements may be a significant driver of cooperation in microorganisms. This may drive a potential conflict, where cooperative genes are transmitted independently of the rest of the genome, resulting in scenarios where horizontally spread cooperative genes are favored, whereas a chromosomal equivalent would not be. This can lead to the whole genome being exploited by surrounding noncooperative individuals. Given that there are costs associated with mobile elements themselves, infection with a plasmid carrying a cooperative trait may lead to a significant conflict within the host genome. Here, we model the mechanisms that allow the host to resolve this conflict, either by exhibiting complete resistance to the mobile element or by controlling its gene expression via a chromosomally based suppressor. We find that the gene suppression mechanism will be more stable than full resistance, implying that suppressing the expression of costly genes within a cell is preferable to preventing the acquisition of the mobile element, for the resolution of conflict within a genome. PMID- 22519797 TI - Convergence, recurrence and diversification of complex sperm traits in diving beetles (Dytiscidae). AB - Sperm display remarkable morphological diversity among even closely related species, a pattern that is widely attributed to postcopulatory sexual selection. Surprisingly few studies have used phylogenetic analyses to discern the details of evolutionary diversification in ornaments and armaments subject to sexual selection, and the origins of novel sperm traits and their subsequent modification are particularly poorly understood. Here we investigate sperm evolution in diving beetles (Dytiscidae), revealing dramatic diversification in flagellum length, head shape, presence of sperm heteromorphism, and the presence/type of sperm conjugation, an unusual trait where two or more sperm unite for motility or transport. Sperm conjugation was found to be the ancestral condition in diving beetles, with subsequent diversification into three forms, each exhibiting varying degrees of evolutionary loss, convergence, and recurrence. Sperm head shape, but not length or heteromorphism, was found to evolve in a significantly correlated manner with conjugation, consistent with the different mechanisms of head alignment and binding required for the different forms of conjugation. Our study reveals that sperm morphological evolution is channeled along particular evolutionary pathways (i.e., conjugate form), yet subject to considerable diversification within those pathways through modification in sperm length, head shape, and heteromorphism. PMID- 22519801 TI - The smallest stable fullerene, M@C28 (m = Ti, Zr, U): stabilization and growth from carbon vapor. AB - The smallest fullerene to form in condensing carbon vapor has received considerable interest since the discovery of Buckminsterfullerene, C(60). Smaller fullerenes remain a largely unexplored class of all-carbon molecules that are predicted to exhibit fascinating properties due to the large degree of curvature and resulting highly pyramidalized carbon atoms in their structures. However, that curvature also renders the smallest fullerenes highly reactive, making them difficult to detect experimentally. Gas-phase attempts to investigate the smallest fullerene by stabilization through cage encapsulation of a metal have been hindered by the complexity of mass spectra that result from vaporization experiments which include non-fullerene clusters, empty cages, and metallofullerenes. We use high-resolution FT-ICR mass spectrometry to overcome that problem and investigate formation of the smallest fullerene by use of a pulsed laser vaporization cluster source. Here, we report that the C(28) fullerene stabilized by encapsulation with an appropriate metal forms directly from carbon vapor as the smallest fullerene under our conditions. Its stabilization is investigated, and we show that M@C(28) is formed by a bottom-up growth mechanism and is a precursor to larger metallofullerenes. In fact, it appears that the encapsulating metal species may catalyze or nucleate endohedral fullerene formation. PMID- 22519802 TI - Cancer clusters in the USA: what do the last twenty years of state and federal investigations tell us? AB - BACKGROUND: Cancer clusters garner considerable public and legislative attention, and there is often an expectation that cluster investigations in a community will reveal a causal link to an environmental exposure. At a 1989 national conference on disease clusters, it was reported that cluster studies conducted in the 1970s and 1980s rarely, if ever, produced important findings. We seek to answer the question: Have cancer cluster investigations conducted by US health agencies in the past 20 years improved our understanding of cancer etiology, or informed cancer prevention and control? METHODS: We reviewed publicly available cancer cluster investigation reports since 1990, obtained from literature searches and by canvassing all 50 states and the District of Columbia. Investigations were categorized with respect to cancer type(s), hypothesized exposure, whether perceived clusters were confirmed (e.g. by elevated incidence), and conclusions about a link between cancer(s) of concern and hypothesized environmental exposure(s). RESULTS: We reviewed 428 investigations evaluating 567 cancers of concern. An increase in incidence was confirmed for 72 (13%) cancer categories (including the category "all sites"). Three of those were linked (with variable degree of certainty) to hypothesized exposures, but only one investigation revealed a clear cause. CONCLUSIONS: It is fair to state that extensive efforts to find causes of community cancer clusters have not been successful. There are fundamental shortcomings to our current methods of investigating community cancer clusters. We recommend a multidisciplinary national dialogue on creative, innovative approaches to understanding when and why cancer and other chronic diseases cluster in space and time. PMID- 22519803 TI - Postprandial triglyceride profile after a standardized oral fat load is altered in growth hormone (GH)-deficient adult patients and is not improved after short term GH replacement therapy. AB - OBJECTIVE: Adult growth hormone deficiency (GHD) has detrimental effects on metabolic profile, leading to an increased cardiovascular mortality and morbidity. Above all, disturbance in postprandial triglyceride metabolism is of major concern because of the crucial role of triglyceride-rich lipoproteins in atherogenesis. The majority of previous studies on GH replacement have shown favourable changes in the fasting lipid profile. Aim of this study is to investigate whether this beneficial effect is exerted also on postprandial triglyceride (TG) metabolism. PATIENTS AND METHODS: We challenged nine GHD patients with a standardized fat loading meal at baseline and after 6 months of GH replacement therapy. Nine healthy control subjects were similarly tested under baseline conditions. Blood samples were obtained before and up to 8 h after fat loading for serum lipid analysis. RESULTS: We found that GHD patients with fasting TG level in the normal range (1.29 +/- 0.31 mm) had a delayed postprandial TG clearance compared to healthy controls (triglyceride level at 8 h, 3.82 +/- 0.83 vs 1 +/- 0.06 mm P < 0.01), and the postprandial hypertriglyceridaemia was not corrected by 6 months of GH therapy. CONCLUSIONS: This study has shown for the first time that GHD adult patients have a higher postprandial triglyceridaemia compared to healthy controls when challenged by a standardized fat load and that this atherogenic feature is not normalized by short-term GH treatment despite a decrease in visceral fat mass described during the replacement therapy. PMID- 22519804 TI - Measures to assess maladaptive variants of the five-factor model. AB - The five-factor model (FFM) is the predominant dimensional model of general personality structure. A considerable body of research supports the hypothesis that personality disorders can be conceptualized as extreme or maladaptive variants of the domains and facets of the FFM. However, existing measures of the FFM are confined largely to the normal variants. The purpose of this special section of the Journal of Personality Assessment is to provide the development and initial validation of self-report inventory scales to assess obsessive compulsive, borderline, narcissistic, avoidant, and dependent personality traits from the perspective of the FFM, which complement the similarly constructed existing measures for psychopathic, histrionic, and schizotypal personality traits. PMID- 22519805 TI - Molecular control of the nanoscale: effect of phosphine-chalcogenide reactivity on CdS-CdSe nanocrystal composition and morphology. AB - We demonstrate molecular control of nanoscale composition, alloying, and morphology (aspect ratio) in CdS-CdSe nanocrystal dots and rods by modulating the chemical reactivity of phosphine-chalcogenide precursors. Specific molecular precursors studied were sulfides and selenides of triphenylphosphite (TPP), diphenylpropylphosphine (DPP), tributylphosphine (TBP), trioctylphosphine (TOP), and hexaethylphosphorustriamide (HPT). Computational (DFT), NMR ((31)P and (77)Se), and high-temperature crossover studies unambiguously confirm a chemical bonding interaction between phosphorus and chalcogen atoms in all precursors. Phosphine-chalcogenide precursor reactivity increases in the order: HPTE < TOPE < TBPE < DPPE =500-fold) and good accuracy [relative error (RE) < 18.8%] and precision [interbatch relative standard deviation (RSD) < 18.1%, intrabatch RSD < 17.2%]. The quantitative method was applied to a comprehensive investigation of the steady-state tissue distribution of 8c2 in wild-type mice versus those deficient in FcRn alpha-chain, FcgammaIIb, and FcgammaRI/FcgammaRIII, following a chronic dosing regimen. This work represents the first extensive quantification of mAb in tissues by an LC/MS-based method. PMID- 22519811 TI - Substratum preference of Philophthalmus sp. cercariae for cyst formation under natural and experimental conditions. AB - Selection on parasites should favor adaptations that maximize the probability of transmission to the definitive host, such as the preference for and use of intermediate hosts or encystment substrata that are likely to be consumed by the definitive host. Eye flukes in the genus Philophthalmus are passed to their definitive avian host through the ingestion of metacercariae encysted on hard substrata. The life cycle of these parasites is generally well understood; however, there is almost no information on substratum use or preference of the cercariae of these parasites. In this study, we combine a survey of naturally occurring substrata with experimental, laboratory-based choice tests to determine the preferred substratum of Philophthalmus sp. and whether this preference is affected by the presence and density of pre-existing cysts. A concordance between natural and experimental data show a preference for the shells of multiple species of snail over other hard substrata that are common at the field site, including seaweed, other molluscs, and crustaceans. In addition, we found that cercariae preferred substrata with pre-existing cysts and that this preference seemed to increase with increasing cyst density. Such a preference should lead to an aggregated distribution of cysts among snail shells that may benefit the parasite by increasing the number of potential mates that become established in the definitive host. The identification of a preferred substratum also may help to identify potential definitive hosts that were previously unknown. PMID- 22519812 TI - Regulation of Helicobacter pylori adherence by gene conversion. AB - Genetic diversification of Helicobacter pylori adhesin genes may allow adaptation of adherence properties to facilitate persistence despite host defences. The sabA gene encodes an adhesin that binds sialyl-Lewis antigens on inflamed gastric tissue. We found variability in the copy number and locus of the sabA gene and the closely related sabB and omp27 genes due to gene conversion among 51 North American paediatric H. pylori strains. We determined that sabB to sabA gene conversion is predominantly the result of intra-genomic recombination and RecA, RecG and AddA influence the rate at which it occurs. Although all clinical strains had at least one sabA gene copy, sabA and sabB were lost due to gene conversion at similar rates in vitro, suggesting host selection to maintain the sabA gene. sabA gene duplication resulted in increased SabA protein production and increased adherence to sialyl-Lewis antigens and mouse gastric tissue. In conclusion, gene conversion is a mechanism for H. pylori to regulate sabA expression level and adherence. PMID- 22519814 TI - Development of sandwich enzyme-linked immunosorbent assay for the detection of Cronobacter muytjensii (formerly called Enterobacter sakazakii). AB - This study aimed to produce a polyclonal antibody against Cronobacter muytjensii (C. muytjensii, formerly called Enterobacter sakazakii) and to develop an immunoassay for its detection. The optimum production of rabbit anti-C. muytjensii immunoglobulin G (IgG) and chicken anti-C. muytjensii IgY was reached in weeks 8 and 9, respectively. Purification of rabbit anti-C. muytjensii IgG from immunized rabbit sera was accomplished using the caprylic acid and ammonium sulfate precipitation method. As a result, sodium dodecyl sulfate-polyacrylamide gel electrophoresis produced two bands around 25 and 50 kDa, corresponding to a light and a heavy chain, respectively. The optimized conditions for sandwich enzyme-linked immunosorbent assay were using rabbit anti-C. muytjensii IgG (1 MUg/mL) as a detection antibody and chicken anti-C. muytjensii IgY (10 MUg/mL) as a capture antibody. In this assay, no cross-reactivity was observed with the other genera of pathogenic bacteria tested, which included Escherichia coli O157:H7, Salmonella typhimurium, Staphylococcus aureus, Bacillus cereus and Listeria monocytogenes. The developed assay did not show cross-reactivity with other tested species of Cronobacter and Enterobacter genera such as C. turicensis, C. sakazakii, E. aerogenes, E. pulveris and E. helveticus. The detection limit of sandwich ELISA for C. muytjensii was found to be 2.0 * 10(4) colony forming units (CFU)/mL. In addition, detection of C. muytjensii in infant formula powder showed a low matrix effect on the detection curve of sandwich ELISA for C. muytjensii, the detection limit being found to be 6.3 * 10(4) CFU/mL. These findings demonstrate that the developed method is able to detect all strains of C. muytjensii. Hence, this ELISA technique has potent application for the rapid and accurate detection of C. muytjensii in dietary foods. PMID- 22519815 TI - Adenosine modification may be preferred for reducing siRNA immune stimulation. AB - The immune stimulation induced by short interfering RNAs (siRNAs) has been reported to be quieted or abrogated by methoxy or fluoro modifications of the 2' position of the ribose sugar. However, variables such as the type of modification, nucleotide preference, and strand bias have not been systematically evaluated. Here, we report the results of a screen of several modified siRNAs via a human peripheral blood monocyte cytokine induction assay. Unlike corresponding modifications of guanosine, cytidine, or uridine, 2'-fluoro modification of adenosine significantly reduced cytokine induction while retaining siRNA knockdown activity. The results of this study suggest adenosine as an optimal target for modification. PMID- 22519816 TI - An overlooked aspect on metabolic acidosis at birth: blood gas analyzers calculate base deficit differently. AB - OBJECTIVE: Metabolic acidosis (MA) at birth is commonly defined as umbilical cord arterial pH < 7.0 plus base deficit (BD) >= 12.0 mmol/L. Base deficit is not a measured entity but is calculated from pH and Pco(2) values, with the hemoglobin (Hb) concentration [Hb] included in the calculation algorithm as a fixed or measured value. Various blood gas analyzers use different algorithms, indicating variations in the MA diagnosis. The objective was therefore to calculate the prevalence of MA in blood and extracellular fluid with algorithms from three blood gas analyzer brands relative to the Clinical and Laboratory Standards Institute (CLSI) algorithm. DESIGN: Comparative study. SETTING: University hospital. SAMPLE: Arterial cord blood from 15 354 newborns. MAIN OUTCOME MEASURE: Prevalence of MA. METHODS: Blood was analyzed in a Radiometer ABL 735 analyzer. Base deficit was calculated post hoc with algorithms from CLSI and Corning and Roche blood gas analyzers, and with measured and fixed (9.3 mmol/L) values of [Hb]. RESULTS: The prevalence of BD >=12.0 mmol/L in blood was with the CLSI algorithm 1.97%, Radiometer 5.18%, Corning 3.84% and Roche 3.29% (CLSI vs. other; McNemar test, p < 0.000001). Likewise, MA prevalences were 0.58, 0.66, 0.64 and 0.64%, respectively (p<= 0.02). Base deficit >= 12.0 mmol/L and MA rates were lower in extracellular fluid than in blood (p<= 0.002). Algorithms with measured or fixed Hb concentration made no differences to MA rates (p>= 0.1). CONCLUSIONS: The neonatal metabolic acidosis rate varied significantly with blood gas analyzer brand and fetal fluid compartment for calculation of BD. PMID- 22519817 TI - Phosphorylation of histone H2A is associated with centromere function and maintenance in meiosis. AB - Histone phosphorylation is dynamically regulated during cell division, for example phosphorylation of histone H3 (H3)-Ser10, H3-Thr11 and H3-Ser28. Here we analyzed maize (Zea mays L) for Thr133-phosphorylated histone H2A, which is important for spindle checkpoint control and localization of the centromere cohesion protector Shugoshin in mammals and yeast. Immunostaining results indicate that phosphorylated H2A-Thr133 signals bridged those of the centromeric H3 histone variant CENH3 by using a plant displaying yellow fluorescent protein CENH3 signals and H2A-Thr133 is phosphorylated in different cell types. During mitosis, H2A-Thr133 phosphorylation becomes strong in metaphase and is specific to centromere regions but drops during later anaphase and telophase. Immunostaining for several maize dicentric chromosomes revealed that the inactive centromeres have lost phosphorylation of H2A-Thr133. During meiosis in maize meiocytes, H2A phosphorylation becomes strong in the early pachytene stage and increases to a maximum at metaphase I. In the maize meiotic mutant afd1 (absence of first division), sister chromatids show equational separation at metaphase I, but there are no changes in H2A-Thr-133 phosphorylation during meiosis compared with the wild type. In sgo1 mutants, sister chromatids segregate randomly during meiosis II, and phosphorylation of H2A-Thr-133 is observed on the centromere regions during meiosis II. The availability of such mutants in maize that lack sister cohesion and Shugoshin indicate that the signals for phosphorylation are not dependent on cohesion but on centromere activity. PMID- 22519818 TI - Benzisoxazole analogs as glycogen synthase activators, a patent evaluation (WO2011057956). AB - A small series of benzisoxazole analogs that effectively activate glycogen synthase (GS) was prepared in WO2011057956. These novel GS activators are claimed to be beneficial for the treatment or prophylaxis of metabolic disease and disorders. The 1,2-benzisoxazole-3-ol moiety is utilized in the present patent as a bioisoster of benzoic acid, which has often been employed in prior examples of the GS activators. PMID- 22519819 TI - Host sialoglycans and bacterial sialidases: a mucosal perspective. AB - Sialic acids are nine-carbon-backbone sugars that occupy outermost positions on vertebrate cells and secreted sialoglycoproteins. These negatively charged hydrophilic carbohydrates have a variety of biological, biophysical and immunological functions. Mucosal surfaces and secretions of the mouth, airway, gut and vagina are especially sialoglycan-rich. Given their prominent positions and important functions, a variety of microbial strategies have targeted host sialic acids for adherence, mimicry and/or degradation. Here we review the roles of bacterial sialidases (neuraminidases) during colonization and pathogenesis of mammalian mucosal surfaces. Evidence is presented to support the myriad roles of mucosal sialoglycans in protecting the host from bacterial infection. In opposition, many bacteria hydrolyse sialic acids during associations with the gastrointestinal, oral, respiratory and reproductive tracts. Sialidases promote bacterial survival in mucosal niche environments in several ways, including: (i) nutritional benefits of sialic acid catabolism, (ii) unmasking of cryptic host ligands used for adherence, (iii) participation in biofilm formation and (iv) modulation of immune function. Bacterial sialidases are among the best-studied enzymes involved in pathogenesis and may also drive commensal and/or symbiotic host associations. Future studies should continue to define host substrates of bacterial sialidases and the mechanisms of their pathologic, commensal and symbiotic interactions with the mammalian host. PMID- 22519820 TI - Influence of nanoparticle surface functionalization on the thermal stability of colloidal polystyrene films. AB - The installation of large scale colloidal nanoparticle thin films is of great interest in sensor technology or data storage. Often, such devices are operated at elevated temperatures. In the present study, we investigate the effect of heat treatment on the structure of colloidal thin films of polystyrene (PS) nanoparticles in situ by using the combination of grazing incidence small-angle X ray scattering (GISAXS) and optical ellipsometry. In addition, the samples are investigated with optical microscopy, atomic force microscopy (AFM), and field emission scanning electron microscopy (FESEM). To install large scale coatings on silicon wafers, spin-coating of colloidal pure PS nanoparticles and carboxylated PS nanoparticles is used. Our results indicate that thermal annealing in the vicinity of the glass transition temperature T(g) of pure PS leads to a rapid loss in the ordering of the nanoparticles in spin-coated films. For carboxylated particles, this loss of order is shifted to a higher temperature, which can be useful for applications at elevated temperatures. Our model assumes a softening of the boundaries between the individual colloidal spheres, leading to strong changes in the nanostructure morphology. While the nanostructure changes drastically, the macroscopic morphology remains unaffected by annealing near T(g). PMID- 22519821 TI - CO2 capture by metal-organic frameworks with van der Waals density functionals. AB - We use density functional theory calculations with van der Waals corrections to study the role of dispersive interactions on the structure and binding of CO(2) within two distinct metal-organic frameworks (MOFs): Mg-MOF74 and Ca-BTT. For both classes of MOFs, we report calculations with standard gradient-corrected (PBE) and five van der Waals density functionals (vdW-DFs), also comparing with semiempirical pairwise corrections. The vdW-DFs explored here yield a large spread in CO(2)-MOF binding energies, about 50% (around 20 kJ/mol), depending on the choice of exchange functional, which is significantly larger than our computed zero-point energies and thermal contributions (around 5 kJ/mol). However, two specific vdW-DFs result in excellent agreement with experiments within a few kilojoules per mole, at a reduced computational cost compared to quantum chemistry or many-body approaches. For Mg-MOF74, PBE underestimates adsorption enthalpies by about 50%, but enthalpies computed with vdW-DF, PBE+D2, and vdW-DF2 (40.5, 38.5, and 37.4 kJ/mol, respectively) compare extremely well with the experimental value of 40 kJ/mol. vdW-DF and vdW-DF2 CO(2)-MOF bond lengths are in the best agreement with experiments, while vdW-C09(x) results in the best agreement with lattice parameters. On the basis of the similar behavior of the reduced density gradients around CO(2) for the two MOFs studied, comparable results can be expected for CO(2) adsorption in BTT-type MOFs. Our work demonstrates for this broad class of molecular adsorbate-periodic MOF systems that parameter-free and computationally efficient vdW-DF and vdW-DF2 approaches can predict adsorption enthalpies with chemical accuracy. PMID- 22519823 TI - The association between ethnicity and late presentation to antenatal care among pregnant women living with HIV in the UK and Ireland. AB - UK and Ireland guidelines state that all pregnant women should have their first antenatal care appointment by 13 weeks of pregnancy (antenatal booking). We present the results of an analysis looking at the association between maternal ethnicity and late antenatal booking in HIV-positive women in the UK and Ireland. We analysed data from the National Study of HIV in Pregnancy and Childhood (NSHPC). We included all pregnancies in women who were diagnosed with HIV before delivery and had an estimated delivery date between 1 January 2008 and 31 December 2009. Late booking was defined as antenatal booking at 13 weeks or later. The baseline reference group for all analyses comprised women of "white" ethnicity. Logistic regression models were fitted to estimate adjusted odds ratios (AOR). There were 2721 eligible reported pregnancies; 63% (1709) had data available on antenatal care booking date. In just over 50% of pregnancies (871/1709), the antenatal booking date was >=13 weeks of pregnancy (i.e., late booking). Women diagnosed with HIV during the current pregnancy were more likely to present for antenatal care late than those previously diagnosed (59.1% vs. 47.5%, p<0.001). Where women knew their HIV status prior to becoming pregnant, the risk of late booking was raised for those of African ethnicity (AOR 1.80; 95% confidence interval (CI) 1.14, 2.82; p=0.011). In women diagnosed with HIV during pregnancy, the risk of late booking was also higher for women of African ethnicity (AOR 2.98: 95% CI 1.45, 6.11; p=0.003) and for women of other black ethnicity (AOR 3.74: 95% CI 1.28, 10.94; p=0.016). Overall, women of African or other black ethnicity were more likely to book late for antenatal care compared with white women, regardless of timing of diagnosis. This may have an adverse effect on maternal and infant outcomes, including mother-to-child transmission of HIV. PMID- 22519824 TI - Selective synthesis of a [3]rotaxane consisting of size-complementary components and its stepwise deslippage. AB - An alpha-cyclodextrin-based size-complementary [3]rotaxane with an alkylene axle was selectively synthesized in one pot via an end-capping reaction with 2 bromophenyl isocyanate in water. Thermal degradation of the [3]rotaxane product yielded not only the original components but also the [2]rotaxane. Thermodynamic studies suggested a stepwise deslippage process. PMID- 22519825 TI - Sc2S@C(s)(10528)-C72: a dimetallic sulfide endohedral fullerene with a non isolated pentagon rule cage. AB - A non isolated pentagon rule metallic sulfide clusterfullerene, Sc(2)S@C(s)(10528)-C(72), has been isolated from a raw mixture of Sc(2)S@C(2n) (n = 35-50) obtained by arc-discharging graphite rods packed with Sc(2)O(3) and graphite powder under an atmosphere of SO(2) and helium. Multistage HPLC methods were utilized to isolate and purify the Sc(2)S@C(72). The purified Sc(2)S@C(s)(10528)-C(72) was characterized by mass spectrometry, UV-vis-NIR absorption spectroscopy, cyclic voltammetry, and single-crystal X-ray diffraction. The crystallographic analysis unambiguously elucidated that the C(72) fullerene cage violates the isolated pentagon rule, and the cage symmetry was assigned to C(s)(10528)-C(72). The electrochemical behavior of Sc(2)S@C(s)(10528)-C(72) shows a major difference from those of Sc(2)S@C(s)(6) C(82) and Sc(2)S@C(3v)(8)-C(82) as well as the other metallic clusterfullerenes. Computational studies show that the Sc(2)S cluster transfers four electrons to the C(72) cage and C(s)(10528)-C(72) is the most stable cage isomer for both empty C(72)(4-) and Sc(2)S@C(72), among the many possibilities. The structural differences between the reported fullerenes with C(72) cages are discussed, and it is concluded that both the transfer of four electrons to the cage and the geometrical requirements of the encaged Sc(2)S cluster play important roles in the stabilization of the C(s)(10528)-C(72) cage. PMID- 22519822 TI - Epigenetic mechanisms in commonly occurring cancers. AB - Cancer is a collection of very complex diseases that share many traits while differing in many ways as well. This makes a universal cure difficult to attain, and it highlights the importance of understanding each type of cancer at a molecular level. Although many strides have been made in identifying the genetic causes for some cancers, we now understand that simple changes in the primary DNA sequence cannot explain the many steps that are necessary to turn a normal cell into a rouge cancer cell. In recent years, some research has shifted to focusing on detailing epigenetic contributions to the development and progression of cancer. These changes occur apart from primary genomic sequences and include DNA methylation, histone modifications, and miRNA expression. Since these epigenetic modifications are reversible, drugs targeting epigenetic changes are becoming more common in clinical settings. Daily discoveries elucidating these complex epigenetic processes are leading to advances in the field of cancer research. These advances, however, come at a rapid and often overwhelming pace. This review specifically summarizes the main epigenetic mechanisms currently documented in solid tumors common in the United States and Europe. PMID- 22519826 TI - Perfusion practices and education of perfusionists for open heart surgery in Turkey--current practices and future suggestions. AB - Our objective is to compare our current findings with the findings of our former study in 2004 and to make new suggestions for the development of cardiovascular perfusion in Turkey according to the results of the survey in 2011. PMID- 22519827 TI - Gene-environment interaction in teacher-rated internalizing and externalizing problem behavior in 7- to 12-year-old twins. AB - BACKGROUND: Internalizing and externalizing problem behavior at school can have major consequences for a child and is predictive for disorders later in life. Teacher ratings are important to assess internalizing and externalizing problems at school. Genetic epidemiological studies on teacher-rated problem behavior are relatively scarce and the reported heritability estimates differ widely. A unique feature of teacher ratings of twins is that some pairs are rated by different and others are rated by the same teacher. This offers the opportunity to assess gene environment interaction. METHODS: Teacher ratings of 3,502 7-year-old, 3,134 10 year-old and 2,193 12-year-old twin pairs were analyzed with structural equation modeling. About 60% of the twin pairs were rated by the same teacher. Twin correlations and the heritability of internalizing and externalizing behavior were estimated, separately for pairs rated by the same and different teachers. Socioeconomic status and externalizing behavior at age 3 were included as covariates. RESULTS: Twin correlations and heritability estimates were higher when twin pairs were in the same class and rated by the same teacher than when pairs were rated by different teachers. These differences could not be explained by twin confusion or rater bias. When twins were rated by the same teacher, heritability estimates were about 70% for internalizing problems and around 80% in boys and 70% in girls for externalizing problems. When twins were rated by different teachers, heritability estimates for internalizing problems were around 30% and for externalizing problems around 50%. CONCLUSIONS: Exposure to different teachers during childhood may affect the heritability of internalizing and externalizing behavior at school. This finding points to gene-environment interaction and is important for the understanding of childhood problem behavior. In addition, it could imply an opportunity for interventions at school. PMID- 22519829 TI - A five-factor measure of obsessive-compulsive personality traits. AB - This study provides convergent, discriminant, and incremental validity data for the Five-Factor Obsessive-Compulsive Inventory (FFOCI), a newly developed measure of traits relevant to obsessive-compulsive personality disorder (OCPD) from the perspective of the Five-factor model (FFM). Twelve scales were constructed as maladaptive variants of specific FFM facets (e.g., Perfectionism as a maladaptive variant of FFM competence). On the basis of data from 407 undergraduates (oversampled for OCPD symptoms) these 12 scales demonstrated convergent correlations with established measures of OCPD and the FFM. Further, they obtained strong discriminant validity with respect to facets from other FFM domains. Most important, the individual scales and total score of the FFOCI obtained incremental validity beyond existing measures of the FFM and OCPD for predicting a composite measure of obsessive-compulsive symptomatology. The findings support the validity of the FFOCI as a measure of obsessive-compulsive personality traits, as well as of maladaptive variants of the FFM. PMID- 22519828 TI - Indoleamine 2,3-dioxygenase expression and functional activity in dendritic cells exposed to cholera toxin. AB - Indoleamine 2,3-dioxygenase (IDO), a tryptophan-metabolizing enzyme expressed by dendritic cells (DC), has the potential to inhibit T cell responses and to promote tolerance. In contrast, cholera toxin (CT), the enterotoxin produced by Vibrio cholerae, promotes T cell responses, partly through its ability to induce DC maturation and promote antigen presentation. We hypothesized that the adjuvant activity of CT is associated with a lack of induction of IDO in DC. To test this hypothesis, monocyte-derived DC were pulsed with CT, and the IDO mRNA expression, IDO functional activity and cytokine production were measured as well as the ability of DC to induce T cell responses in vitro. Cholera toxin exposure induced enhanced levels of IDO mRNA in DC but no functional IDO protein activity. Cholera toxin pulsing however primed DC for CD40L-induced IDO protein activity. CD40L stimulation of CT-pulsed DC induced a modest IL-12p40 production, but not IL 12p70 or IL-23 secretion. Furthermore, CT-pulsed DC induced strong allogeneic and autologous T cell responses in vitro, which were not affected by the IDO-specific inhibitor 1-methyl tryptophan. Our results show that CT per se does not induce the expression of functional IDO protein, although it primes DC for CD40L mediated IDO production and IL-12p40 secretion. Furthermore, CT-treated DC were equally powerful in their T cell stimulatory capacity as cytokine-matured DC. PMID- 22519830 TI - Lower alloimmunization rates in pediatric sickle cell patients on chronic erythrocytapheresis compared to chronic simple transfusions. AB - BACKGROUND: Erythrocytapheresis (ECP), automated red blood cell exchange, is increasingly being used for chronic transfusion therapy in sickle cell disease (SCD) as it is an isovolumetric transfusion, is more effective in lowering hemoglobin (Hb)S, and can limit iron overload. Because ECP requires increased blood exposure compared to simple transfusions there is concern for increased transfusion complications, including alloimmunization. We compared alloimmunization rates between patients receiving simple or exchange chronic transfusions. STUDY DESIGN AND METHODS: Data were retrospectively collected for 45 SCD patients (n = 23 simple, n = 22 ECP) on a chronic transfusion program as of December 2010 to determine the rate of antibody formation (antibodies formed per 100 units transfused). RESULTS: The 45 patients received 10,949 units and formed six new alloantibodies during the study period (1994-2010); therefore, the overall alloimmunization rate was 0.055 alloantibodies per 100 U. There were three antibodies formed in three patients on ECP, one allo (anti-rh(i) ) and two autoantibodies. There were six antibodies in four patients on a simple transfusion program, five allo (anti-Le(a) , M, D, C, and Kp(a) ) and one autoantibody. The ECP group received significantly more blood (338.5 units/patient vs. 152.2 units/patient, p = 0.001). The rate of antibody formation (auto plus allo) was 0.040 antibodies per 100 U in the ECP group and 0.171 antibodies per 100 U in the simple transfusion group (p = 0.04). The alloantibodies formed per 100 units was 0.013 in the ECP group and 0.143 in the simple transfusion group (p = 0.03). CONCLUSION: Chronic ECP should be considered in patients requiring optimal management of HbS levels and iron burden. Concerns about increased alloimmunization with ECP may be unjustified. PMID- 22519831 TI - Antitumor effect of arsenic trioxide in human K562 and K562/ADM cells by autophagy. AB - Arsenic trioxide (As(2)O(3)) has been reported to have potent antitumor effects in vitro and in vivo by inducing cell death via cell cycle arrest and apoptosis in leukemia cells, but the mechanisms of As(2)O(3)-mediated cell death are not fully understood. In this study, we provided in vitro evidence that As(2)O(3) was a potent inducer of autophagy in leukemia K562 and its drug-resistant line K562/ADM cells. As(2)O(3) significantly activated autophagic cell death (programmed cell death type II) in leukemia cell lines. Numerous large cytoplasmic inclusions, abundant autophagic vacuoles, phagocytizing cytoplasm and organelles were observed in As(2)O(3)-treated cells using electron microscope. MDC-labeled autophagic vacuoles were observed by fluorescent inverted phase contrast microscopy and the enhanced MDC fluorescent staining was detected by flow cytometry in As(2)O(3)-treated cells. Furthermore, real-time quantitative RT PCR revealed that the expression levels of Beclin-1 and LC3 genes, which play key roles in autophagy, increased in As(2)O(3) treated samples than in controls, indicating that autophagy can potentially be involved in the antitumor properties of As(2)O(3). The expression level of Bcl-2 gene, an anti-apoptotic molecule, decreased in As(2)O(3) treated samples than in controls, suggesting that Bcl-2 may be involved in accumulating Beclin-1 and triggering autophagic cell death in As(2)O(3)-treated leukemia cells. Western blotting also showed that As(2)O(3) up regulated Beclin-1. Altogether, our data provide direct evidence that autophagic cell death is critical for the effects of As(2)O(3) on acute myelogenous leukemia cells. PMID- 22519832 TI - Functional identification of the phosphorylation sites of Arabidopsis PIN-FORMED3 for its subcellular localization and biological role. AB - Directional cell-to-cell movement of auxin is mediated by asymmetrically localized PIN-FORMED (PIN) auxin efflux transporters. The polar localization of PINs has been reported to be modulated by phosphorylation. In this study, the function of the phosphorylation sites of the PIN3 central hydrophilic loop (HL) was characterized. The phosphorylation sites were located in two conserved neighboring motifs, RKSNASRRSF(/L) and TPRPSNL, where the former played a more decisive role than the latter. Mutations of these phosphorylatable residues disrupted in planta phosphorylation of PIN3 and its subcellular trafficking, and caused defects in PIN3-mediated biological processes such as auxin efflux activity, auxin maxima formation, root growth, and root gravitropism. Because the defective intracellular trafficking behaviors of phospho-mutated PIN3 varied according to cell type, phosphorylation codes in PIN3-HL are likely to operate in a cell-type-specific manner. PMID- 22519833 TI - Dermatoglyphic asymmetries and fronto-striatal dysfunction in young adults reporting non-clinical psychosis. AB - OBJECTIVE: Growing evidence indicates that non-clinical psychotic-like experiences occur in otherwise healthy individuals, suggesting that psychosis may occur on a continuum. However, little is known about how the diathesis for formal psychosis maps on to individuals at the non-clinical side of this continuum. Our current understanding of the pathophysiology of schizophrenia implicates certain key factors such as early developmental abnormalities and fronto-striatal dysfunction. To date, no studies have examined these core factors in the context of non-clinical psychosis. METHOD: A total of 221 young adults were assessed for distressing attenuated positive symptoms (DAPS), dermatoglyphic asymmetries (a marker of early developmental insult), and procedural memory (a proxy for fronto striatal function). RESULTS: Participants reporting DAPS (n = 16; 7.2%) and no DAPS (n = 205; 92.7%) were split into two groups. The DAPS group showed significantly elevated depression, elevated dermatoglyphic asymmetries, and a pattern of procedural learning consistent with other studies with formally psychotic patients. CONCLUSION: The results indicate that the non-clinical side of the psychosis continuum also shares key vulnerability factors implicated in schizophrenia, suggesting that both early developmental disruption and abnormalities in fronto-striatal function are core aspects underlying the disorder. PMID- 22519834 TI - Assessment of airborne exposures and health in flooded homes undergoing renovation. AB - In June 2008, the Cedar River crested flooding more than 5000 Cedar Rapids homes. Residents whose homes were flooded were invited to participate in this study. Household assessments and resident interviews were conducted between November 2008 and April 2009. We characterized exposures and symptoms experienced by individuals inhabiting 73 flood-damaged homes. Active air sampling and passive electrostatic dust collectors were used to assess exposures to culturable mold, culturable bacteria, fungal spores, inhalable particulate matter (iPM), endotoxin, glucans, allergens, lead, asbestos, radon, carbon dioxide, and carbon monoxide. Wall moisture levels and relative humidity were also measured. Exposures and questionnaire-based health assessments were compared at two levels of remediation, in-progress and completed. Homes with remediation in-progress (N = 24), as compared to the completed homes (N = 49), had significantly higher airborne concentrations of mold, bacteria, iPM, endotoxin, and glucan. Residents of in-progress homes had a significantly higher prevalence of doctor-diagnosed allergies (adjusted OR = 3.08; 95% CI: 1.05, 9.02) and all residents had elevated prevalence of self-reported wheeze (adjusted OR = 3.77; 95% CI: 2.06, 6.92) and prescription medication use for breathing problems (adjusted OR = 1.38; 95% CI: 1.01, 1.88) after the flood as compared to before. Proper post-flood remediation led to improved air quality and lower exposures among residents living in flooded homes. PRACTICAL IMPLICATIONS: The number and severity of floods is on the rise, and health departments need evidence-based information to advise homeowners on recovery after such disasters. Our study suggests that proper remediation of flood-damaged homes can reduce bioaerosols to acceptable levels but exposures are significantly increased while remediation is in-progress leading to an increased burden of allergy and allergic rhinitis. PMID- 22519836 TI - Effect of thermal cycling and disinfection on colour stability of denture base acrylic resin. AB - OBJECTIVES: The purpose of this study was to investigate the effect of thermal cycling and disinfection on the colour change of denture base acrylic resin. MATERIALS AND METHODS: Four different brands of acrylic resins were evaluated (Onda Cryl, QC 20, Classico and Lucitone). All brands were divided into four groups (n = 7) determined according to the disinfection procedure (microwave, Efferdent, 4% chlorhexidine or 1% hypochlorite). The treatments were conducted three times a week for 60 days. All specimens were thermal cycled between 5 and 55 degrees C with 30-s dwell times for 1000 cycles before and after disinfection. The specimens' colour was measured with a spectrophotometer using the CIE L*a*b* system. The evaluations were conducted at baseline (B), after first thermal cycling (T1 ), after disinfection (D) and after second thermal cycling (T2 ). Colour differences (DeltaE) were calculated between T1 and B (T1 B), D and B (DB), and T2 and B (T2 B) time-points. RESULTS: The samples submitted to disinfection by microwave and Efferdent exhibited the highest values of colour change. There were significant differences on colour change between the time points, except for the Lucitone acrylic resin. CONCLUSIONS: The thermal cycling and disinfection procedures significantly affected the colour stability of the samples. However, all values obtained for the acrylic resins are within acceptable clinical parameters. PMID- 22519837 TI - Behavior of double emulsions in a cross-type optical separation system. AB - The behavior of double emulsions in a cross-type optical particle separation system was studied for different combinations of refractive indices and different inner and outer layer radii. The radii and refractive indices of the double emulsions were easily adjusted by taking advantage of the coflowing geometry of a cross-type optical particle separation device. An analytical expression of the optical forces on a pair of concentric spheres was derived using the photon stream method in the ray optics regime. The predicted trajectories of the double emulsions by the optical force agreed well with the experimental data. This work has potential uses in cell separation by morphometry, drug delivery vehicle, and emulsion-based biomedical applications. PMID- 22519838 TI - Targeting pain mediators induced by injured nerve-derived COX2 and PGE2 to treat neuropathic pain. AB - INTRODUCTION: Neuropathic pain (NeP) is an intractable chronic pain condition which severely deteriorates the quality of life of 6% of the population. Caused by direct physical damage or diseases of the nervous system responsible for pain generation and transmission, NeP is manifested as spontaneous pain, hyperalgesia and allodynia. Its treatment is a challenging and unmet medical need. It is generally accepted that inflammatory mediators over-produced in injured nerves play a crucial role in the initiation and maintenance of NeP. AREAS COVERED: Among numerous inflammatory mediators, cyclooxygenase 2 (COX2) and its end product prostaglandin E2 (PGE2) are persistently up-regulated in infiltrating macrophages and Schwann cells in injured nerves and contribute to the development of NeP. In a NeP rat model and an ex vivo model of sensory ganglion explant culture, injured nerve-derived COX2 and PGE2 facilitate the synthesis of pain mediators including neuropeptides, ion channels, cytokines and neurotrophins in primary sensory neurons. EXPERT OPINION: Stimulating the synthesis of pain mediators in primary sensory neurons is a novel mechanism underlying the contribution of injured nerve-derived COX2 and PGE2 to the genesis of NeP. Targeting COX2/PGE2/EP signaling in injured nerves through local administration could open a novel therapeutic avenue to treat this debilitating disease. PMID- 22519839 TI - An in vivo evaluation of the auto apical reverse function of the Root ZX II. AB - AIM: To evaluate in vivo the accuracy of the Root ZX II (J. Morita) apex locator in controlling the apical extent of rotary instrumentation when using the Auto Apical Reverse (AAR) set at the levels 0.5, 1.0 and 1.5. METHODOLOGY: Thirty single-rooted premolar teeth scheduled for extraction were divided into three groups (n = 10), according to the AAR setting 0.5, 1.0 and 1.5. The root canals were prepared using ProTaper (Dentsply Maillefer). After rotary instrumentation, the last file used (F3) was manually introduced into the extent of the root canal preparation and fixed before tooth extraction. The apical third of the root was dissected until exposure of the file. The distance from the file tip to the major apical foramen was obtained. RESULTS: Measurements within the range -1.0 to 0.0 mm were obtained in 30% of the teeth with AAR 0.5, 50% with AAR 1.0 and in 0% with AAR 1.5. The proportions test revealed a significant difference between the AAR settings 1.0 and 1.5 (P = 0.0188). Overinstrumentation occurred in 70% of the teeth with AAR 0.5 and in 40% with AAR 1.0. The measurements short of the acceptable range occurred in 10% of the teeth with setting AAR 1.0 and in 100% of the cases with AAR 1.5. A significant difference was found when comparing the percentage of teeth in which the file tip was short and beyond the established range between groups, except when comparing AAR 0.5 and AAR 1.0. CONCLUSION: The AAR function of the Root ZX II was not an accurate method for controlling the apical extent of rotary instrumentation in vivo. The setting 0.5 presented overinstrumentation in most of the canals, the setting 1.5 was short in all cases, and the setting 1.0 provided an adequate working length in only 50% of the teeth. PMID- 22519840 TI - Susceptibility status of malaria vectors to insecticides commonly used for malaria control in Tanzania. AB - OBJECTIVE: The aim of the study was to monitor the insecticide susceptibility status of malaria vectors in 12 sentinel districts of Tanzania. METHODS: WHO standard methods were used to detect knock-down and mortality in the wild female Anopheles mosquitoes collected in sentinel districts. The WHO diagnostic doses of 0.05% deltamethrin, 0.05% lambdacyhalothrin, 0.75% permethrin and 4% DDT were used. RESULTS: The major malaria vectors in Tanzania, Anopheles gambiae s.l., were susceptible (mortality rate of 98-100%) to permethrin, deltamethrin, lambdacyhalothrin and DDT in most of the surveyed sites. However, some sites recorded marginal susceptibility (mortality rate of 80-97%); Ilala showed resistance to DDT (mortality rate of 65% [95% CI, 54-74]), and Moshi showed resistance to lambdacyhalothrin (mortality rate of 73% [95% CI, 69-76]) and permethrin (mortality rate of 77% [95% CI, 73-80]). CONCLUSIONS: The sustained susceptibility of malaria vectors to pyrethroid in Tanzania is encouraging for successful malaria control with Insecticide-treated nets and IRS. However, the emergency of focal points with insecticide resistance is alarming. Continued monitoring is essential to ensure early containment of resistance, particularly in areas that recorded resistance or marginal susceptibility and those with heavy agricultural and public health use of insecticides. PMID- 22519841 TI - Tag-free microfluidic separation of cells against multiple markers. AB - Conventional cell separation against multiple markers generally requires the attachment of antibody tags, typically fluorescent or magnetic, to selected cell types in a heterogeneous suspension. This work describes how such separation can be accomplished in a series of microfluidic systems without the need for such tags. Two capture stages containing antibody-functionalized alginate hydrogels are utilized for the isolation of CD34+ and Flk1+ cells from untreated, whole human blood. The capture-release capability of these degradable coatings is harnessed by a mixing chamber and a simple valving system such that the suspension emerging from the first capture stage is prepared for the second capture stage for further enrichment. With this configuration, we demonstrate the isolation of CD34+/Flk1+ endothelial progenitor cells from blood enabled by the depletion of CD34+/Flk1-hematopoietic stem cells population. This ability to achieve isolation of cells against multiple markers in an untagged separation method is of particular significance in applications involving cell implantation based therapeutics including tissue engineering and molecular analysis. PMID- 22519842 TI - A two-piece sectional interim obturator. A clinical report. AB - Prosthetic rehabilitation of acquired maxillary defects can be achieved satisfactorily if all facets of treatment planning and design considerations are taken into account before the rehabilitation process. Complications associated with maxillary defects limit treatment protocols to a great extent. The prosthodontist has to identify these problem areas and suitably devise feasible options and incorporate them in the design. In this report, an acquired maxillary defect with unfavorable undercuts in the defect was successfully treated by making a two-piece sectional obturator. The two pieces were connected by the use of double-die pin system. The methodology greatly reduced chairside time and number of visits, and effective obturation was satisfactorily achieved. PMID- 22519843 TI - Tuning photophysics and nonlinear absorption of bipyridyl platinum(II) bisstilbenylacetylide complexes by auxiliary substituents. AB - The photophysics of six bipyridyl platinum(II) bisstilbenylacetylide complexes with different auxiliary substituents are reported. These photophysical properties have been investigated in detail by UV-vis, photoluminescence (both at room temperature and at 77 K) and transient absorption (nanosecond and femtosecond) spectroscopies, as well as by linear response time-dependent density functional theory (TD-DFT) calculations. The photophysics of the complexes are found to be dominated by the singlet and triplet pi,pi* transitions localized at the stilbenylacetylide ligands with strong admixture of the metal-to-ligand (MLCT) and ligand-to-ligand (LLCT) charge-transfer characters. The interplay between the pi,pi* and MLCT/LLCT states depends on the electron-withdrawing or donating properties of the substituents on the stilbenylacetylide ligands. All complexes exhibit remarkable reverse saturable absorption (RSA) at 532 nm for nanosecond laser pulses, with the complex that contains the NPh(2) substituent giving the strongest RSA and the complex with NO(2) substituent showing the weakest RSA. PMID- 22519844 TI - Wives without husbands: gendered vulnerability to sexually transmitted infections among previously married women in India. AB - Using population-based and family structural data from a high HIV-prevalence district of Southern India, this paper considers four suggested social scenarios used to explain the positive correlation between HIV prevalence and previously married status among Indian women: (1) infection from and then bereavement of an infected husband; (2) abandonment after husbands learn of their wives' HIV status; (3) economic instability after becoming previously married, leading women to seek financial support through male partners; and (4) the social status of being previously married exposing women to sexual harassment and predation. By also considering seroprevalence of two other common sexually transmitted infections (STIs), herpes and syphilis, in a combined variable with HIV, we limit the likelihood of the first two scenarios accounting for the greater part of this correlation. Through a nuanced analysis of household residences patterns (family structure), standard of living, and education, we also limit the probability that scenario three explains a greater portion of the correlation. Scenario four emerges as the most likely explanation for this correlation, recognizing that other scenarios are also possible. Further, the interdisciplinary literature on the social position of previously married women in India strongly supports the suggestion that, as a population, previously married women are sexually vulnerable in India. Previously married status as an STI risk factor requires further biosocial research and warrants concentrated public health attention. PMID- 22519845 TI - Multinuclear Cu-catalysts based on SPINOL-PHOS in asymmetric conjugate addition of organozinc reagents. AB - Multinuclear Cu/Zn complex-catalyzed efficient asymmetric conjugate addition of organozinc reagents to acyclic and cyclic enones has been developed in the presence of a wide variety of regioisomeric chiral diols bearing phosphorus moieties as ligands. The regioisomeric SPINOL-PHOS ligands based on a SPINOL architecture showed an unexpected inversion of stereoselectivity. PMID- 22519846 TI - A five-factor measure of avoidant personality: the FFAvA. AB - A new self-report assessment of the basic traits of avoidant personality disorder (AVD) was developed using a general trait model of personality (Five-factor model; FFM) as a framework. Scales were written to assess maladaptive variants of 10 FFM traits found to be robustly related to AVD across a variety of methods. In a sample of 291 undergraduates, the scales from the Five Factor Avoidant Assessment (FFAvA) proved to be internally consistent and strongly related to the original FFM scales from which they were derived. The FFAvA scales also demonstrated substantial incremental validity in the prediction of existing AVD measures and indexes of social discomfort over their FFM counterparts. The FFAvA provides an opportunity to examine AVD and its correlates using smaller, more basic units of personality rather than more global symptoms that might blend these elements. PMID- 22519847 TI - Unlocking the binding and reaction mechanism of hydroxyurea substrates as biological nitric oxide donors. AB - Hydroxyurea is the only FDA approved treatment of sickle cell disease. It is believed that the primary mechanism of action is associated with the pharmacological elevation of nitric oxide in the blood; however, the exact details of this are still unclear. In the current work, we investigate the atomic level details of this process using a combination of flexible-ligand/flexible receptor virtual screening coupled with energetic analysis that decomposes interaction energies. Utilizing these methods, we were able to elucidate the previously unknown substrate binding modes of a series of hydroxyurea analogs to hemoglobin and the concomitant structural changes of the enzyme. We identify a backbone carbonyl that forms a hydrogen bond with bound substrates. Our results are consistent with kinetic and electron paramagnetic resonance (EPR) measurements of hydroxyurea-hemoglobin reactions, and a full mechanism is proposed that offers new insights into possibly improving substrate binding and/or reactivity. PMID- 22519848 TI - New photolabile BAPTA-based Ca2+ cages with improved photorelease. AB - The efficient synthesis, physicochemical and photolytical properties of a photoactivable BAPTA-based Ca(2+) cage containing two photosensitive o nitrobenzhydryl groups attached to the aromatic core are described. Ca(2+) release in living cells was evaluated. The double substitution with the chromophores caused a significant improvement of the Ca(2+) release properties of nitr-T versus singly substituted reported nitr-x derivatives without compromising Ca(2+)/Mg(2+) selectivity or pH insensitivity. Our results demonstrate a general strategy to improve light-triggered Ca(2+) release which may result in more efficient, selective, and pH-insensitive photolabile Ca(2+) chelators. PMID- 22519850 TI - Variables associated with corneal confocal microscopy parameters in healthy volunteers: implications for diabetic neuropathy screening. AB - AIM: Corneal confocal microscopy is a promising screening method for diabetic neuropathy. Although much research in this field has been accomplished, we aimed to determine and confirm the known clinical and eyewear variables associated with the parameters of corneal confocal microscopy specifically in healthy volunteers, in particular associations with corneal nerve fibre length. METHODS: Clinical characteristics, electrophysiological examination and a general clinical eye history were collected from 64 healthy volunteers. Corneal confocal microscopy was performed to determine corneal nerve fibre length, corneal nerve branch density, corneal nerve fibre density and tortuosity coefficient. Univariate and multivariate linear regression analysis was used to determine clinical variables associated with corneal nerve fibre length parameters. RESULTS: We observed that corneal nerve fibre length has a broad distribution in healthy volunteers (18 +/- 4 mm/mm(2), 95% confidence interval, 12.3-25.7 mm/mm(2)). Multivariate regression analysis demonstrated that HbA(1c) was the only independent clinical factor to account for variations in corneal nerve fibre length, independent of age and status of contact lens wear. CONCLUSIONS: This study does not provide convincing evidence that corneal nerve fibre length is independently associated with age or the wearing of contact lenses, and that these factors are therefore unlikely to hinder valid screening for polyneuropathies such as diabetic neuropathy. Furthermore, the strong inverse association of corneal nerve fibre length with glycaemic exposure may support the use of this parameter to detect subclinical pre-diabetic nerve injury. PMID- 22519849 TI - Comparison of the antitussive effect of remifentanil during recovery from propofol and sevoflurane anaesthesia. AB - This prospective randomised study compared the antitussive effect of remifentanil during recovery from either propofol or sevoflurane anaesthesia. Seventy-four female patients undergoing thyroidectomy were anaesthetised with either propofol and remifentanil or sevoflurane and remifentanil. During recovery, remifentanil was maintained at an effect-site concentration of 2 ng.ml(-1) until extubation and the occurrence of coughing, haemodynamic parameters and recovery profiles were compared between the two groups. During recovery, neither the incidence nor the severity of cough (incidence 20% with propofol; 24% with sevoflurane, p = 0.77), nor the haemodynamic parameters were different between the two groups. Time to awakening and time to extubation were significantly shorter in the propofol group (4.7 min, 6.1 min min, respectively) compared with the sevoflurane group (7.9 min and 8.9 min respectively) (p < 0.001 and p = 0.002, respectively). An effect-site concentration of 2 ng.ml(-1) of remifentanil was associated with smooth emergence from both propofol and sevoflurane anaesthesia. PMID- 22519851 TI - Microarray analysis revealed upregulation of nitrate reductase in juvenile cuttings of Eucalyptus grandis, which correlated with increased nitric oxide production and adventitious root formation. AB - The loss of rooting capability following the transition from the juvenile to the mature phase is a known phenomenon in woody plant development. Eucalyptus grandis was used here as a model system to study the differences in gene expression between juvenile and mature cuttings. RNA was prepared from the base of the two types of cuttings before root induction and hybridized to a DNA microarray of E. grandis. In juvenile cuttings, 363 transcripts were specifically upregulated, enriched in enzymes of oxidation/reduction processes. In mature cuttings, 245 transcripts were specifically upregulated, enriched in transcription factors involved in the regulation of secondary metabolites. A gene encoding for nitrate reductase (NIA), which is involved in nitric oxide (NO) production, was among the genes that were upregulated in juvenile cuttings. Concomitantly, a transient burst of NO was observed upon excision, which was higher in juvenile cuttings than in mature ones. Treatment with an NO donor improved rooting of both juvenile and mature cuttings. A single NIA gene was found in the newly released E. grandis genome sequence, the cDNA of which was isolated, overexpressed in Arabidopsis plants and shown to increase NO production in intact plants. Therefore, higher levels of NIA in E. grandis juvenile cuttings might lead to increased ability to produce NO and to form adventitious roots. Arabidopsis transgenic plants constantly expressing EgNIA did not exhibit a significantly higher lateral or adventitious root formation, suggesting that spatial and temporal rather than a constitutive increase in NO is favorable for root differentiation. PMID- 22519852 TI - Simulation-aided design and synthesis of hierarchically porous membranes. AB - Free-standing silica membranes with hierarchical porosity (ca. 300 nm macropores surrounded by 6-8 nm mesopores) and controllable mesopore architecture were prepared by a dual-templating method, with the structural design aided by mesoscale simulation. To create a two-dimensional, hexagonal macropore array, polymeric colloidal hemisphere arrays were synthesized by a two-step annealing process starting with non-close-packed polystyrene sphere arrays on silicon coated with a sacrificial alumina layer. A silica precursor containing a poly(ethylene) oxide-poly(propylene oxide)-poly(ethylene) oxide (PEO-PPO-PEO) triblock-copolymer surfactant as template for mesopore creation was spin-coated onto the support and aged and then converted into the free-standing membranes by dissolving both templates and the alumina layer. To test the hypothesis that the mesopore architecture may be influenced by confinement of the surfactant containing precursor solution in the colloidal array and by its interactions with the polymeric colloids, the system was studied theoretically by dissipative particle dynamics (DPD) simulations and experimentally by examining the pore structures of silica membranes via electron microscopy. The DPD simulations demonstrated that, while only tilted columnar structure can be formed through tuning the interaction with the substrate, perfect alignment of 2D hexagonal micelles perpendicular to the plane of the membrane is achievable by confinement between parallel walls that interact preferentially with the hydrophilic components (PEO blocks, silicate, and solvent). The simulations predicted that this alignment could be maintained across a span of up to 10 columns of micelles, the same length scale defined by the colloidal array. In the actual membranes, we manipulated the mesopore alignment by tuning the solvent polarity relative to the polar surface characteristics of the colloidal hemispheres. With methanol as a solvent, columnar mesopores parallel to the substrate were observed; with a methanol-water mixed solvent, individual spherical mesopores were present; and with water as the only solvent, twisted columnar structures were seen. PMID- 22519853 TI - Long-term effects of malaria prevention with insecticide-treated mosquito nets on morbidity and mortality in African children: randomised controlled trial. AB - OBJECTIVE: The objective is to investigate the effect of malaria control with insecticide-treated mosquito nets (ITNs) regarding possible higher mortality in children protected during early infancy, due to interference with immunity development, and to assess long-term effects on malaria prevalence and morbidity. METHODS: Between 2000 and 2002, a birth cohort was enrolled in 41 villages of a malaria holoendemic area in north-western Burkina Faso. All neonates (n = 3387) were individually randomised to ITN protection from birth (group A) vs. ITN protection from age 6 months (group B). Primary outcome was all-cause mortality. In 2009, a survey took place in six sentinel villages, and in 2010, a census was conducted in all study villages. RESULTS: After a median follow-up time of 8.3 years, 443/3387 (13.1%) children had migrated out of the area and 484/2944 (16.4%) had died, mostly at home. Long-term compliance with ITN protection was good. There were no differences in mortality between study groups (248 deaths in group A, 236 deaths in group B; rate ratio 1.05, 95% CI: 0.889-1.237, P = 0.574). The survey conducted briefly after the rainy season in 2009 showed that more than 80% of study children carried asexual malaria parasites and up to 20% had clinical malaria. CONCLUSION: Insecticide-treated mosquito net protection in early infancy is not a risk factor for mortality. Individual ITN protection does not sufficiently reduce malaria prevalence in high-transmission areas. Achieving universal ITN coverage remains a major challenge for malaria prevention in Africa. PMID- 22519854 TI - Transcranial magnetic stimulation reveals modulation of corticospinal excitability when observing actions with the intention to imitate. AB - Studies using transcranial magnetic stimulation have demonstrated that action observation can modulate the activity of the corticospinal system. This has been attributed to the activity of an 'action observation network', whereby premotor cortex activity influences corticospinal excitability. Neuroimaging studies have demonstrated that the context in which participants observe actions (i.e. whether they simply attend to an action, or observe it with the intention to imitate) modulates action observation network activity. The study presented here examined whether the context in which actions were observed revealed similar modulatory effects on corticospinal excitability. Eight human participants observed a baseline stimulus (a fixation cross), observed actions in order to attend to them, or observed the same actions with the intention to imitate them. Whereas motor evoked potentials elicited from the first dorsal interosseus muscle of the hand were facilitated by attending to actions, observing the same actions in an imitative capacity led to no facilitation effect. Furthermore, no motor facilitation effects occurred in a control muscle. Electromyographic data collected when participants physically imitated the observed actions revealed that the activity of the first dorsal interosseus muscle increased significantly during action execution compared with rest. These data suggest that an inhibitory mechanism acts on the corticospinal system to prevent the immediate overt imitation of observed actions. These data provide novel insight into the properties of the human action observation network, demonstrating for the first time that observing actions with the intention to imitate them can modulate the effects of action observation on corticospinal excitability. PMID- 22519855 TI - Is pride a prosocial emotion? Interpersonal effects of authentic and hubristic pride. AB - Pride is associated with both prosocial and antisocial behaviour. Do others also infer such behaviours when pride is expressed and does this affect their own prosocial behaviour? We expected that authentic pride (i.e., confidence, accomplishment) would signal and elicit more prosocial behaviour than hubristic pride (i.e., arrogance, conceit). In a first laboratory experiment, a target in a public-good dilemma was inferred to have acted less prosocially when displaying a nonverbal expression of pride versus no emotion. As predicted, inferences of hubristic pride-but not authentic pride-mediated this effect. Participants themselves also responded less prosocially. A second laboratory experiment where a target verbally expressed authentic pride, hubristic pride, or no emotion replicated the effects of hubristic pride and showed that authentically proud targets were assumed to have acted prosocially, but especially by perceivers with a dispositional tendency to take the perspective of others. We conclude that authentic pride is generally perceived as a more prosocial emotion than hubristic pride. PMID- 22519856 TI - Comparison and evaluation of urinary biomarkers for occupational exposure to spray adhesives containing 1-bromopropane. AB - Three metabolites of 1-bromopropane (1-BP) were measured in urine samples collected from 30 workers exposed to 1-BP at two facilities making furniture seat cushions and evaluated for use as biomarkers of exposure. The mercapturic acid metabolite, N-acetyl-S-(n-propyl)-l-cysteine (AcPrCys), 3-bromopropionic acid (3 BPA), and bromide ion levels (Br(-)) were quantitated for this evaluation. The high exposure group consisted of 13 workers employed as adhesive sprayers who assembled foam cushions using 1-BP containing spray adhesives and the low exposure group consisted of 17 non-sprayers, who worked in various jobs without spraying adhesives. All workers' urine voids were collected over the same 48 h period at work, and at home before bedtime, and upon awakening. Urinary AcPrCys and Br(-) levels were elevated in the sprayers compared to that of non-sprayers. Following HPLC-MS/MS analysis of mercapturic acid metabolite levels, 50 urine samples having the highest levels of AcPrCys were analyzed for 3-BPA. No 3-BPA was detected in any of the samples. The data collected from this study demonstrate that AcPrCys and Br(-) are effective biomarkers of 1-BP exposure, but 3-BPA is not. PMID- 22519857 TI - Automatic disulfide bond assignment using a1 ion screening by mass spectrometry for structural characterization of protein pharmaceuticals. AB - An automatic method for disulfide bond assignment using dimethyl labeling and computational screening of a(1) ions with customized software, RADAR, is developed. By utilization of the enhanced a(1) ions generated from labeled peptides, the N-terminal amino acids from disulfide-linked peptides can be determined. In this study, we applied this method for structural characterization of recombinant monoclonal antibodies, an important group of therapeutic proteins. In addition to a(1) ion screening and molecular weight match, new RADAR is capable of confirming the matched peptide pairs by further comparing the collision-induced dissociation (CID) fragment ions. With the N-terminal amino acid identities as a threshold, the identification of disulfide-linked peptide pairs can be achieved rapidly at a higher confidence level. Unlike most current approaches, prior knowledge of disulfide linkages or a high-end mass spectrometer is not required, and tedious work or deliberate interpretation can be avoided in this study. Our approach makes it possible to analyze unknown disulfide bonds of protein pharmaceuticals as well as their degraded forms without further protein separation. It can be used as a convenient quality examination tool during biopharmaceutical development and manufacturing processes. PMID- 22519858 TI - Extended-spectrum beta-lactamase-producing and AmpC-producing Escherichia coli from livestock and companion animals, and their putative impact on public health: a global perspective. AB - The possible zoonotic spread of antimicrobial-resistant bacteria is controversial. This review discusses global molecular epidemiological data combining both analyses of the chromosomal background, using multilocus sequence typing (MLST), and analyses of plasmid (episomal) extended-spectrum beta lactamase (ESBL)/AmpC genes in Escherichia coli present in humans and animals. For consideration of major epidemiological differences, animals were separated into livestock and companion animals. MLST revealed the existence of ESBL producing isolates thoughout the E. coli population, with no obvious association with any ancestral EcoR group. A similar distribution of major ESBL/AmpC types was apparent only in human isolates, regardless of their geographical origin from Europe, Asia, or the Americas, whereas in animals this varied extensively between animal groups and across different geographical areas. In contrast to the diversity of episomal ESBL/AmpC types, isolates from human and animals mainly shared identical sequence types (STs), suggesting transmission or parallel micro evolution. In conclusion, the opinion that animal ESBL-producing E. coli is a major source of human infections is oversimplified, and neglects a highly complex scenario. PMID- 22519859 TI - Nanomodification of mineral trioxide aggregate for enhanced physiochemical properties. AB - AIM: To analyse the physicochemical properties of a Nano white mineral trioxide aggregate (NWMTA) and compare it with white mineral trioxide aggregate (WMTA). METHODOLOGY: White mineral trioxide aggregate and NWMTA were prepared and mixed according to the manufacturer's instructions. Surface area of powder before hydration, setting time, X-ray diffraction and microhardness at pH values of 4.4 and 7.4 were evaluated by Brunauer-Emmett-Teller, ISO Specification no.6876, Vickers microhardness, and energy-dispersive X-ray spectroscopy equipped with X ray colour (dot) map for both cements. anova and Mann-Whitney were used for statistical analysis at a significance level of 0.5. RESULTS: The mean +/- SD of surface area and setting time were 1.8 +/- 0.2 m(2) g(-1) and 43 +/- 2 min for WMTA and 7.8 +/- 1.2 m(2) g(-1) and 6 +/- 1 min for NWMTA, respectively. Mean +/- SD of Microhardness were 16 +/- 2, 51 +/- 1, 69 +/- 1 and 81 +/- 2 for WMTA at pH values of 4.4 and 7.4 and for NWMTA correspondingly. Numbers of open porosity over the surface were 88 +/- 24 and 44 +/- 13 for WMTA and NWMTA, respectively. Statistical tests revealed significant differences between the groups (P < 0.001) in surface area, setting time and surface hardness for both cements. Uniform distribution of strontium was only observed in NWMTA. However, other compounds were not significantly different. CONCLUSION: Increasing surface area of powder can reduce setting time and increase microhardness even at lower pH values after hydration. PMID- 22519860 TI - 6-Deoxyerythronolide B synthase thioesterase-catalyzed macrocyclization is highly stereoselective. AB - Macrocyclic polyketide natural products are an indispensable source of therapeutic agents. The final stage of their biosynthesis, macrocyclization, is catalyzed regio- and stereoselectively by a thioesterase. A panel of substrates were synthesized to test their specificity for macrocyclization by the erythromycin polyketide synthase TE (DEBS TE) in vitro. It was shown that DEBS TE is highly stereospecific, successfully macrocyclizing a 14-member ring substrate with an R configured O-nucleophile, and highly regioselective, generating exclusively the 14-member lactone over the 12-member lactone. PMID- 22519861 TI - Systemic delivery of transthyretin siRNA mediated by lactosylated dendrimer/alpha cyclodextrin conjugates into hepatocyte for familial amyloidotic polyneuropathy therapy. AB - RNA interference (RNAi) is a sequence-specific gene-silencing mechanism triggered by double-stranded RNA and powerful tools for a gene function study and RNAi therapy. Although siRNAs offer several advantages as potential new drugs to treat various diseases, the efficient delivery system of siRNAs in vivo remains a crucial challenge for achieving the desired RNAi effect in clinical development. In particular, when considering the siRNA therapeutics for familial amyloidotic polyneuropathy (FAP) caused by the deposition of variant transthyretin (TTR) in various organs, hepatocyte-selective siRNA delivery is desired because TTR is predominantly synthesized by hepatocytes. In this study, to reveal the potential use of lactosylated dendrimer (G3)/alpha-cyclodextrin conjugate (Lac-alpha-CDE (G3)) as novel hepatocyte-selective siRNA carriers in order to treat FAP, we evaluated the RNAi effect of siRNA complex with Lac-alpha-CDE (G3) both in vitro and in vivo. PMID- 22519862 TI - Prevalence and clinical characteristics of diabetic peripheral neuropathy in hospital patients with Type 2 diabetes in Korea. AB - AIMS: Diabetic peripheral neuropathy is a common complication of diabetes. This cross-sectional study investigated the prevalence and clinical characteristics of this neuropathy in patients with Type 2 diabetic mellitus treated at hospitals in Korea. METHODS: Questionnaires and medical records were used to collect data on 4000 patients with Type 2 diabetes from the diabetes clinics of 40 hospitals throughout Korea. Diabetic peripheral neuropathy was diagnosed based on a review of medical records or using the Michigan Neuropathy Screening Instrument score and monofilament test. RESULTS: The prevalence of neuropathy was 33.5% (n = 1338). Multivariate analysis revealed that age, female sex, diabetes duration, lower glycated haemoglobin, treatment with oral hypoglycaemic agents or insulin, presence of retinopathy, history of cerebrovascular or peripheral arterial disease, presence of hypertension or dyslipidaemia, and history of foot ulcer were independently associated with diabetic peripheral neuropathy. Of the patients with neuropathy, 69.8% were treated for the condition and only 12.6% were aware of their neuropathy. CONCLUSION: There was a high prevalence of peripheral neuropathy in patients with Type 2 diabetes in Korea and those patients were far more likely to have complications or co-morbidities. The proper management of diabetic peripheral neuropathy deserves attention from clinicians to ensure better management of diabetes in Korea. PMID- 22519863 TI - Impact of the mobilization regimen and the harvesting technique on the granulocyte yield in healthy donors for granulocyte transfusion therapy. AB - BACKGROUND: Granulocyte mobilization and harvesting, the two major phases of granulocyte collection, have not been standardized. STUDY DESIGN AND METHODS: The data on 123 granulocyte collections were retrospectively investigated for the effect of the mobilization regimen and the harvesting technique. After a single subcutaneous dose (600 ug) of granulocyte-colony-stimulating factor (G-CSF) with (n = 68) or without (n = 40) 8 mg of orally administered dexamethasone, 108 granulocyte donors underwent granulocyte collections. Moreover, 15 peripheral blood stem cell (PBSC) donors who had received 400 ug/m2 or 10 ug/kg G-CSF for 5 days underwent granulocyte collections on the day after the last PBSC collections (PBSC-GTX donors). Granulocyte harvesting was performed by leukapheresis with (n = 108) or without (n = 15) using high-molecular-weight hydroxyethyl starch (HES). RESULTS: Granulocyte donors who received mobilization with G-CSF plus dexamethasone produced significantly higher granulocyte yields than those who received G-CSF alone (7.2 * 10(10) +/- 2.0 * 10(10) vs. 5.7 * 10(10) +/- 1.7 * 10(10) , p = 0.006). PBSC-GTX donors produced a remarkably high granulocyte yield (9.7 * 10(10) +/- 2.3 * 10(10) ). The use of HES was associated with better granulocyte collection efficiency (42 +/- 7.8% vs. 10 +/- 9.1%, p < 0.0001). CONCLUSION: G-CSF plus dexamethasone produces higher granulocyte yields than G CSF alone. Granulocyte collection from PBSC donors appears to be a rational strategy, since it produces high granulocyte yields when the related patients are at a high risk for infection and reduces difficulties in finding granulocyte donors. HES should be used in apheresis procedures. PMID- 22519866 TI - Effects of magnesium sulphate on postoperative coagulation, measured by rotational thromboelastometry (ROTEM((r))). AB - We investigated the effects of magnesium sulphate on blood coagulation profiles using rotational thromboelastometry in gynaecological patients undergoing pelviscopic surgery. Patients were randomly allocated to the magnesium group (n = 20) or control group (n = 20). The magnesium group received magnesium sulphate (50 mg.kg(-1) followed by continuous infusion of 15 mg.kg(-1).h(-1)), whereas the control group received the same volume of isotonic saline according to the same methods. Mean (SD) postoperative serum magnesium levels were 1.58 (0.17) mmol.l( 1) in the magnesium group compared with 0.98 (0.06) mmol.l(-1) in the control group (p < 0.001). Postoperative clotting time, clot formation time, alpha-angle and maximum clot firmness of INTEM, and clot formation time, alpha-angle, and maximum clot firmness of EXTEM were significantly different between the two groups (p < 0.05). Intra-operative infusion of magnesium sulphate seems to attenuate postoperative hypercoagulability by maintaining magnesium levels at the upper limit of the normal range. PMID- 22519864 TI - Default mode network connectivity in children with a history of preschool onset depression. AB - BACKGROUND: Atypical Default Mode Network (DMN) functional connectivity has been previously reported in depressed adults. However, there is relatively little data informing the developmental nature of this phenomenon. The current case-control study examined the DMN in a unique prospective sample of school-age children with a previous history of preschool depression. METHODS: DMN functional connectivity was assessed using resting state functional connectivity magnetic resonance imaging data and the posterior cingulate (PCC) as a seed region of interest. Thirty-nine medication naive school age children (21 with a history of preschool depression and 18 healthy peers) and their families who were ascertained as preschoolers and prospectively assessed over at least 4 annual waves as part of a federally funded study of preschool depression were included. RESULTS: Decreased connectivity between the PCC and regions within the middle temporal gyrus (MTG), inferior parietal lobule, and cerebellum was found in children with known depression during the preschool period. Increased connectivity between the PCC and regions within the subgenual and anterior cingulate cortices and anterior MTG bilaterally was also found in these children. Additionally, a clinically relevant 'brain-behavior' relationship between atypical functional connectivity of the PCC and disruptions in emotion regulation was identified. CONCLUSIONS: To our knowledge, this is the first study to examine the DMN in children known to have experienced the onset of a clinically significant depressive syndrome during preschool. Results suggest that a history of preschool depression is associated with atypical DMN connectivity. However, longitudinal studies are needed to clarify whether the current findings of atypical DMN connectivity are a precursor or a consequence of preschool depression. PMID- 22519865 TI - A case-control nutrigenomic study on the synergistic activity of folate and vitamin B12 in cervical cancer progression. AB - The present study was designed to identify the role of folate, B12, homocysteine, and polymorphisms of methylene tetrahydrofolatereductase (MTHFR) gene in cervical carcinogenesis among 322 women from Kerala, South India. Serum folate, vitamin B12 (chemiluminescence assay), and homocysteine (EIA) along with genetic polymorphisms of MTHFR gene (polymerase chain reaction/restriction fragment length polymorphism) were analyzed for 136 control subjects, 92 low-grade squamous intraepithelial lesions (LSIL) subjects, and 94 invasive cervical cancer cases (ICC). Statistically significant associations between MTHFR polymorphisms, serum homocysteine, and folate levels with cervical carcinogenesis were not evident, but we found that these parameters acted as effect modifiers of serum vitamin B12. The risk estimates observed for B12 became prominent only when there was a deficiency in serum folate levels [LSIL-odds ratio (OR): 14.9 (95% CI: 2.65 to 84.4); ICC-OR = 8.72 (95% CI = 1.55 to 48.8)] or when MTHFR A1298C polymorphic variant was present [LSIL-OR = 9.8 (95% CI = 2.61 to 36.7); ICC-OR = 10.0 (95%CI = 2.5 to 39.3)]. The statistical significance of this effect modification was further studied using an interaction model, where only folate was observed to have an influence on B12 levels as suggested by the odds ratio of 7.11 (95% CI = 0.45 to 111.9) obtained for ICC group, implicating a synergistic role of these 2 vitamins in invasive cervical cancer. PMID- 22519867 TI - Nano-sized cationic polymeric magnetic liposomes significantly improves drug delivery to the brain in rats. AB - In recent years, cationic polymeric magnetic liposomes have shown greater stability and prolonged circulation half-life over traditional liposomes. Here, we examined the capability of cationic polymeric magnetic liposomes in delivering drugs into the brain under magnetic targeting with paclitaxel as the loaded agent. We found that the fabricated paclitaxel-loaded magnetic liposomes had a uniform diameter of 20 nm and were superparamagnetic. After they were injected into rats by the caudal vein, brain paclitaxel concentration increased 2-5 folds without magnetic targeting and 5-15 folds after magnetic targeting. The high brain concentration was maintained for more than 8 h, which was significantly longer than that for pure paclitaxel injection. When the liposomes were given via the internal carotid artery at 10% of the dose given via the caudal vein, paclitaxel in the brain was increased by 1.5 folds, indicating that intra arterial administration enhanced delivery efficiency remarkably. Prussian blue staining of the cortex showed that the magnetic liposomes were aggregated in the cortex vasculature and the cortex cells were under magnetic targeting, indicating that the drugs were delivered across the nearly impermeable blood-brain barrier. These results showed that the nano-sized cationic polymeric magnetic liposomes are potential tools for magnetic drug delivery to the brain. PMID- 22519868 TI - Identification of psychiatric disorders among human immunodeficiency virus infected individuals in Taiwan, a nine-year nationwide population-based study. AB - A previous survey had shown a high level of psychiatric morbidity among human immunodeficiency virus (HIV)-infected individuals, but the number of patients that are actually identified as having a psychiatric disorder in the medical service in Taiwan is unknown. Using the claims data of a nationally representative cohort from the Taiwan National Health Insurance Research Database, the diagnoses of psychiatric disorders among newly diagnosed HIV infected individuals were investigated from 1998 through 2006. Two hundred and seventy-four (23.8%) of 1153 newly diagnosed HIV-infected patients were identified as having psychiatric disorders, with an average latency of 3.33+/ 2.47 years after HIV infection. Anxiety and depressive disorders were the leading diagnoses. Male patients had lower morbidity (21.0% vs. 25.3%, p=0.056), but a shorter latency to be identified with a psychiatric disorder (2.1+/-2.13 vs. 3.9+/-2.40 years, p<0.001) than females. This first population-based cohort study showed a high morbidity of psychiatric disorders among HIV-infected individuals, but with a long latency after infection, and a gender effect was noted. Regular psychiatric evaluation and follow-up and prompt intervention are necessary for HIV-infected individuals. PMID- 22519869 TI - Adult tooth loss for residents of US coal mining and Appalachian counties. AB - OBJECTIVES: The authors compared rates of tooth loss between adult residents of Appalachian coal-mining areas and other areas of the nation before and after control for covariate risks. METHODS: The authors conducted a cross-sectional secondary data analysis that merged 2006 national Behavioral Risk Factor Surveillance System data (BRFSS) (N = 242 184) with county coal-mining data and other county characteristics. The hypothesis tested was that adult tooth loss would be greater in Appalachian mining areas after control for other risks. Primary independent variables included main effects for coal-mining present (yes/no) residence in Appalachia (yes/no), and their interaction. Data were weighted using the BRFSS final weights and analyzed using SUDAAN Proc Multilog to account for the multilevel complex sampling structure. The odds of two measures of tooth loss were examined controlling for age, race?ethnicity, drinking, smoking, income, education, supply of dentists, receipt of dental care, fluoridation rate, and other variables. RESULTS: After covariate adjustment, the interaction variable for the residents of Appalachian coal-mining counties showed a significantly elevated odds for any tooth loss [odds ratio (OR) = 1.19, 95% CI = 1.02, 1.38], and greater tooth loss measured by a 4-level edentulism scale (OR = 1.20, 95% CI = 1.05, 1.36). The main effect for Appalachia was also significant for both measures, but the main effect for coal mining was not. CONCLUSIONS: Greater risk of tooth loss among adult residents of Appalachian coal-mining areas is present and is not explained by differences in reported receipt of dental care, fluoridation rates, supply of dentists or other behavioral or socioeconomic risks. Possible contributing factors include mining-specific disparities related to access, behavior or environmental exposures. PMID- 22519870 TI - Modulation of doxorubicin-induced oxidative stress by a grape (Vitis vinifera L.) seed extract in normal and tumor cells. AB - The major limitation of Doxorubicin (Dox) clinical use is the development of chronic and acute toxic side effects induced through the generation of reactive oxygen species. The present work was designated to investigate in vitro effects of a red grape-seed hydroethanolic extract Burgund Mare (BM), in associated administration with Dox (30 min before drug administration) in normal (Hfl-1) and tumor cell lines (HepG2 and Mls). The BM concentrations administered were below the level of the extract cytotoxiciy threshold (40 MUg gallic acid [GA] Eq/mL; 37.5, 25.0, and 12.5 MUg GA Eq/mL). The antioxidant capacity of the BM extract was assessed by measuring the acute toxicity at 24 h, lipid peroxides (LP), and protein oxidation. In normal cells, the product statistically decreased cytotoxicity and markedly inhibited LP and protein carbonyl (PC) formation, in a dose-dependent relationship. On contrary, in tumor cells, such treatment resulted in a reversed effect, cell death, malondialdehyde, and PC contents increasing with BM dose enhancement. BM extract treatment prior to subsequent administration of Dox afforded a differential protection against Dox-negative toxic side effects in normal cells without weakening (even enhancing) Dox's antitumor activity. PMID- 22519872 TI - Editorial Comment to Paratesticular extrarenal Wilms' tumor. PMID- 22519874 TI - Health-related quality of life in advanced non-small cell lung cancer: correlates and comparisons to normative data. AB - The aim was to describe self-reported health-related quality of life (HRQoL) in patients with advanced non-small cell lung cancer and to investigate the associations to stage of disease, age, gender, weight loss and performance status. Further, the study aimed to compare patients' HRQoL with that of the Swedish general population. Data on HRQoL were collected within a multi-centre randomised controlled trial. A total of 334 patients were included between 1998 and 2001. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Questionnaire (EORTC QLQ-C30) and Lung Cancer Questionnaire (EORTC QLQ-LC13) were used to assess HRQoL. HRQoL data for comparison with the Swedish population were derived from a random sample of the Swedish population. Patients reported a markedly impaired HRQoL compared to the normal population. There were statistically and clinically significant differences with regard to almost all QLQ-C30 functional and symptom scales. Global health status, physical functioning, role functioning and emotional functioning were markedly deteriorated. The most prominent symptoms were dyspnoea, fatigue, coughing, insomnia, appetite loss and pain. A low performance status, younger age, female gender and a more advanced disease were independently associated with a worse HRQoL. Additional studies are required to gain increased insight into this seriously ill group of patients and their need of supportive care. PMID- 22519875 TI - Preferential processing of threatening facial expressions using the repetition blindness paradigm. AB - BACKGROUND: Neuroanatomical evidence suggests that the human brain has dedicated pathways to rapidly process threatening stimuli. This processing bias for threat was examined using the repetition blindness (RB) paradigm. RB (i.e., failure to report the second instance of an identical stimulus rapidly following the first) has been established for words, objects and faces but not, to date, facial expressions. METHODS: 78 (Study 1) and 62 (Study 2) participants identified repeated and different, threatening and non-threatening emotional facial expressions in rapid serial visual presentation (RSVP) streams. RESULTS: In Study 1, repeated facial expressions produced more RB than different expressions. RB was attenuated for threatening expressions. In Study 2, attenuation of RB for threatening expressions was replicated. Additionally, semantically related but non-identical threatening expressions reduced RB relative to non-threatening stimuli. CONCLUSIONS: These findings suggest that the threat bias is apparent in the temporal processing of facial expressions, and expands the RB paradigm by demonstrating that identical facial expressions are susceptible to the effect. PMID- 22519877 TI - Syntheses of water-soluble octahedral, truncated octahedral, and cubic Pt-Ni nanocrystals and their structure-activity study in model hydrogenation reactions. AB - We developed a facile strategy to synthesize a series of water-soluble Pt, Pt(x)Ni(1-x) (0 < x < 1), and Ni nanocrystals. The octahedral, truncated octahedral, and cubic shapes were uniformly controlled by varying crystal growth inhibition agents such as benzoic acid, aniline, and carbon monoxide. The compositions of the Pt(x)Ni(1-x) nanocrystals were effectively controlled by choice of ratios between the Pt and Ni precursors. In a preliminary study to probe their structure-activity dependence, we found that the shapes, compositions, and capping agents strongly influence the catalyst performances in three model heterogeneous hydrogenation reactions. PMID- 22519876 TI - Temporomandibular joint-evoked responses by spinomedullary neurons and masseter muscle are enhanced after repeated psychophysical stress. AB - Psychological stress is a risk factor for the development of musculoskeletal pain of the head and neck; however, the basis for this relationship remains uncertain. This study tested the hypothesis that psychophysical stress alone was sufficient to alter the encoding properties of spinomedullary dorsal horn neurons and masseter muscle activity in male rats. Repeated forced swim conditioning increased markedly both the background firing rate and temporomandibular joint (TMJ)-evoked activity of neurons in deep dorsal horn, while neurons in superficial laminae were less affected. Stress also increased the responses to stimulation of facial skin overlying the TMJ of neurons in deep and superficial dorsal horn. TMJ-evoked masseter muscle activity was enhanced significantly in stressed rats, an effect that was reduced by prior blockade of the spinomedullary junction region. These data indicated that repeated psychophysical stress induced widespread effects on the properties of medullary dorsal horn neurons and masseter muscle activity. The effects of stress were seen preferentially on neurons in deep dorsal horn and included enhanced responses to chemosensory input from the TMJ and mechanical input from overlying facial skin. The stress-induced elevation in TMJ-evoked masseter muscle activity matched well with the changes seen in dorsal horn neurons. It is concluded that the spinomedullary junction region plays a critical role in the integration of psychophysical stress and sensory information relevant for nociception involving deep craniofacial tissues. PMID- 22519878 TI - Mini-nutritional assessment predicts functional status and quality of life of patients with hepatocellular carcinoma in Taiwan. AB - This study aimed to determine the possibility of using the Mini-Nutritional Assessment (MNA) to evaluate the quality of life and functional status in patients with hepatocellular carcinoma (HCC). The study recruited 300 outpatients with HCC from a teaching hospital in Central Taiwan to serve as subjects. All subjects were interviewed with a structured questionnaire for rating the nutritional status with the MNA (long-form and short-form), and for evaluating quality of life and functional status with Global Quality of Life (GQL) and Global Functional Status (GFS), respectively, of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 version-3. Cancer staging and liver cirrhosis indicators, blood biochemical indicators, and self-rated health status and mobility were used as reference standards. Results showed that based on the strength of the correlation and association with the reference standards, both the long-form and short-form of the MNA performed better than GQL and GFS in predicting quality of life and functional status of patients with HCC. These results suggest that the MNA is suitable for identifying the risk of deteriorating quality of life or functional status, in addition to identifying the risk of malnutrition, in patients with HCC. PMID- 22519880 TI - In vitro skin permeation and decontamination of the organophosphorus pesticide paraoxon under various physical conditions--evidence for a wash-in effect. AB - Misuse of various chemicals, such as chemical warfare agents, industrial chemicals or pesticides during warfare or terrorists attacks requires adequate protection. Thus, development and evaluation of novel decontamination dispositives and techniques are needed. In this study, in vitro permeation and decontamination of a potentially hazardous compound paraoxon, an active metabolite of organophosphorus pesticide parathion, was investigated. Skin permeation and decontamination experiments were carried out in modified Franz diffusion cells. Pig skin was used as a human skin model. Commercially produced detergent-based washing solutions FloraFree(TM) and ArgosTM were used as decontamination means. The experiments were done under "warm", "cold", "dry" and "wet" skin conditions in order to determine an effect of various physical conditions on skin permeation of paraoxon and on a subsequent decontamination process. There was no significant difference in skin permeation of paraoxon under warm, cold and dry conditions, whereas wet conditions provided significantly higher permeation rates. In the selected conditions, decontamination treatments performed 1 h after a skin exposure did not decrease the agent volume that permeated through the skin. An exception were wet skin conditions with non significant decontamination efficacy 18 and 28% for the FloraFree(TM) and Argos(TM) treatment, respectively. In contrast, the skin permeation of paraoxon under warm, cold and dry conditions increased up to 60-290% following decontamination compared to non-decontaminated controls. This has previously been described as a skin wash-in effect. PMID- 22519879 TI - Prophylactic platelet transfusions. PMID- 22519881 TI - Activation of PPARdelta counteracts angiotensin II-induced ROS generation by inhibiting rac1 translocation in vascular smooth muscle cells. AB - Angiotensin II (Ang II)-mediated modification of the redox milieu of vascular smooth muscle cells (VSMCs) has been implicated in several pathophysiological processes, including cell proliferation, migration and differentiation. In this study, we demonstrate that the peroxisome proliferator-activated receptor (PPAR) delta counteracts Ang II-induced production of reactive oxygen species (ROS) in VSMCs. Activation of PPARdelta by GW501516, a specific ligand for PPARdelta, significantly reduced Ang II-induced ROS generation in VSMCs. This effect was, however, reversed in the presence of small interfering (si)RNA against PPARdelta. The marked increase in ROS levels induced by Ang II was also eliminated by the inhibition of phosphatidylinositol 3-kinase (PI3K) but not of protein kinase C, suggesting the involvement of the PI3K/Akt signalling pathway in this process. Accordingly, ablation of Akt with siRNA further enhanced the inhibitory effects of GW501516 in Ang II-induced superoxide production. Ligand-activated PPARdelta also blocked Ang II-induced translocation of Rac1 to the cell membrane, inhibiting the activation of NADPH oxidases and consequently ROS generation. These results indicate that ligand-activated PPARdelta plays an important role in the cellular response to oxidative stress by decreasing ROS generated by Ang II in vascular cells. PMID- 22519882 TI - Condyle fossa relationship associated with functional posterior crossbite, before and after rapid maxillary expansion. AB - OBJECTIVE: To investigate condylar symmetry and condyle fossa relationships in subjects with functional posterior crossbite comparing findings before and after rapid maxillary expansion (RME) treatment through low-dose computed tomography (CT). MATERIALS AND METHODS: Twenty-six patients (14 girls and 12 boys, mean age 9.6 +/- 1.4 years) with functional posterior crossbite (FPXB) diagnosis underwent rapid palatal expansion with a Hyrax appliance. Patients' temporomandibular joints (TMJ) underwent multislice CT scans before rapid palatal expansion (T0) and after (T1). Joint spaces were compared with those of a control sample of 13 subjects (7 girls and 5 boys, mean age 11 +/- 0.6 years). RESULTS: Anterior space (AS), superior space (SS), and posterior space (PS) joint space measurements at T0 between the FPXB side and contralateral side demonstrated no statistically significant differences. After RME treatment (T1), all three joint spaces increased on both the FPXB side and the non-crossbite side. However, differences were statistically significant only for the SS when comparing the two sides at T1. SS increased more than AS and PS in the non-crossbite condyle (0.28 mm) and FPXB condyle (0.37 mm), and PS increased only on the FPXB side (0.34 mm). CONCLUSIONS: There were no statistically significant differences in condyle position within the glenoid fossa between the FPXB and non-crossbite side before treatment. Increases in joint spaces were observed after treatment with RME on both sides. These changes were, however, of small amounts. PMID- 22519883 TI - Chlorhexidine, ethanol, lipopolysaccharide and nicotine do not enhance the cytotoxicity of a calcium hydroxide pulp capping material. AB - AIM: To determine whether cells pre-stressed by known cytotoxic or inflammatory agents are more susceptible to the deleterious effects of a calcium hydroxide formulation used in pulp capping. METHODOLOGY: Adult human dermal fibroblasts were treated for 48 h with 0.001% chlorhexidine, 0.2% ethanol, 5 MUg mL(-1) Escherichia coli lipopolysaccharide (LPS) or 0.05 mmol L(-1) nicotine. Cells were subsequently treated with the soluble materials extracted from Dycal pellets for an additional 24 h. Controls included cells cultured in medium only and cells exposed to Dycal only. Cytotoxicity was measured using colorimetric MTT, WST and secreted lactate dehydrogenase assays. In addition, mitotic activity was evaluated using a colorimetric histone H3 phosphorylation assay. Data were statistically analysed using anova with Tukey's multiple comparison post-test and significance at P <= 0.05. RESULTS: For all assays, measured values for cells treated with chlorhexidine, ethanol, LPS or nicotine plus the soluble materials extracted from Dycal pellets were significantly lower compared to control (P < 0.05) for all comparisons between experimental conditions. However, between treatments and for comparisons of treatments with Dycal, there were no differences observed for any assay. CONCLUSIONS: Calcium hydroxide in a formulation used in dental clinical procedures is highly cytotoxic to cultured cells, as evidenced by several cellular assays. However, other known toxic agents, including chlorhexidine, ethanol, bacterial LPS and nicotine, do not appear to function synergistically to increase the deleterious cellular effects of the calcium hydroxide in an in vitro model of cytotoxicity. PMID- 22519884 TI - Commentary: Psychopathic traits enhance adolescents' influence on others and make them less easily influenced by others?--reflections on Kerr et al. (2012). PMID- 22519885 TI - Basal autophagy decreased during the differentiation of human adult mesenchymal stem cells. AB - Autophagy plays an important role in homeostasis, development, and disease, functioning both as a survival and cell death pathway. However, despite its importance in cell physiology, there is little information about the role of autophagy in stem cells and, in particular, on its implication in their survival and/or cell death. We describe here that in vitro, human mesenchymal stem cells (hMSCs) exhibited a high level of constitutive autophagy. Inhibitors of autophagy such as Bafilomycin A1 (Baf-A1) inhibited the proteolytic degradation associated with autophagy in these cells. In addition, we show that a knockdown in the expression of Bcl-xL is accompanied by a loss of autophagic proteolytic ability. Indeed, Bcl-xL seems to exert a tight control on autophagy regulation, since its reintroduction by a protein construct PTD-Bcl-xL resulted in the reacquisition of autophagy. We show that the suppression of autophagy through the knockdown of Bcl xL influenced hMSC survival and differentiation. This study expands our knowledge on the control exerted by Bcl-xL on autophagy and illustrates the important role of autophagy in the maintenance and differentiation of adult hMSCs. PMID- 22519886 TI - Prenatal diagnosis of right diaphragmatic eventration associated with fetal hydrops. AB - Congenital diaphragmatic eventration (CDE) is a rare diaphragmatic abnormality. Clinical manifestations of CDE may mimic congenital diaphragmatic hernia. Prenatal differential diagnosis of eventration is critical because postnatal managing and prognosis of these conditions vary significantly. Sonographic features of CDE involve presence of abdominal organs in the thorax, shift of cardiac axis and mediastinum. Non-immune hydrops fetalis (NIHF) has been previously reported to be associated with intrathoracic masses as well as CDE. In this report, we present a case of congenital right diaphragmatic eventration associated with NIHF. PMID- 22519887 TI - The impact of intrinsic and extrinsic factors on the job satisfaction of dentists. AB - The Two-Factor Theory of job satisfaction distinguishes between intrinsic motivation (i.e. recognition, responsibility) and extrinsic-hygiene (i.e. job security, salary, working conditions) factors. The presence of intrinsic motivation facilitates higher satisfaction and performance, whereas the absences of extrinsic factors help mitigate against dissatisfaction. The consideration of these factors and their impact on dentists' job satisfaction is essential for the recruitment and retention of dentists. OBJECTIVES: The objective of the study is to assess the level of job satisfaction of German dentists and the factors that are associated with it. METHODS: This cross-sectional study was based on a job satisfaction survey. Data were collected from 147 dentists working in 106 dental practices. Job satisfaction was measured with the 10-item Warr-Cook-Wall job satisfaction scale. Organizational characteristics were measured with two items. Linear regression analyses were performed in which each of the nine items of the job satisfaction scale (excluding overall satisfaction) were handled as dependent variables. A stepwise linear regression analysis was performed with overall job satisfaction as the dependent outcome variable, the nine items of job satisfaction and the two items of organizational characteristics controlled for age and gender as predictors. RESULTS: The response rate was 95.0%. Dentists were satisfied with 'freedom of working method' and mostly dissatisfied with their 'income'. Both variables are extrinsic factors. The regression analyses identified five items that were significantly associated with each item of the job satisfaction scale: 'age', 'mean weekly working time', 'period in the practice', 'number of dentist's assistant' and 'working atmosphere'. Within the stepwise linear regression analysis the intrinsic factor 'opportunity to use abilities' (beta = 0.687) showed the highest score of explained variance (R(2) = 0.468) regarding overall job satisfaction. CONCLUSIONS: With respect to the Two Factor Theory of job satisfaction both components, intrinsic and extrinsic, are essential for dentists but the presence of intrinsic motivating factors like the opportunity to use abilities has most positive impact on job satisfaction. The findings of this study will be helpful for further activities to improve the working conditions of dentists and to ensure quality of care. PMID- 22519888 TI - Engineered allosteric ribozymes that sense the bacterial second messenger cyclic diguanosyl 5'-monophosphate. AB - A series of allosteric ribozymes that respond to the bacterial second messenger cyclic diguanosyl-5'-monophosphate (c-di-GMP) have been created by using in vitro selection. An RNA library was generated by using random-sequence bridges to join a hammerhead self-cleaving ribozyme to an aptamer from a natural c-di-GMP riboswitch. Specific bridge sequences, called communication modules, emerged through two in vitro selection efforts that either activate or inhibit ribozyme self-cleavage upon ligand binding to the aptamer. Representative RNAs were found that exhibit EC(50) (half-maximal effective concentration) values for c-di-GMP as low as 90 nM and IC(50) (half-maximal inhibitory concentration) values as low as 180 nM. The allosteric RNAs display molecular recognition characteristics that mimic the high discriminatory ability of the natural aptamer. Some engineered RNAs operate with ribozyme rate constants approaching that of the parent hammerhead ribozyme. By use of these allosteric ribozymes, cytoplasmic concentrations of c-di-GMP in three mutant strains of Escherichia coli were quantitatively estimated from cell lysates. Our findings demonstrate that engineered c-di-GMP-sensing ribozymes can be used as convenient tools to monitor c-di-GMP levels from complex biological or chemical samples. Moreover, these ribozymes could be employed in high-throughput screens to identify compounds that trigger c-di-GMP riboswitch function. PMID- 22519889 TI - What factors are associated with patient self-reported health status among HIV outpatients? A multi-centre UK study of biomedical and psychosocial factors. AB - Patient self-reported outcomes are increasingly important in measuring disease, treatment and care outcomes. It is unclear what constitutes well-being using a combined biomedical and psychosocial approach for patients with antiretroviral therapy (ART) access. This study aimed to determine the variance within the visual analogue scale (VAS) measure of health status using the existing five dimensions of the EuroQOL-5D, to identify which domains have the greatest effect on self-reported health status and to identify associations with the VAS using both biomedical and psychosocial factors among HIV outpatients. Consecutive patients in five UK clinics were recruited to a cross-sectional survey, n=778 (86% response rate). Patients self-completed validated measures, with treatment variables extracted from file. On the EuroQOL-5D, nearly one-third (28.1%) had mobility problems, one-fifth (18.7%) self-care problems, one-third (37.4%) difficulty in performing usual tasks and one-half (44.4%) reported pain/discomfort. In the regression model to determine associations with self reported health status (VAS score), neither CD4 count nor ART status was associated with the outcome. However, in addition to four dimensions of the EuroQOL-5D, poorer health status was associated with worse physical symptom burden, treatment optimism and psychological symptoms. There is a relatively high prevalence of psychological morbidity and poor physical function, and these burdens of disease are associated with worse self-reported health status. As HIV management focuses on treatment for extended survival and a chronic model of disease, clinical attention to physical and psychological dimensions of patient care are essential to achieve optimal well-being. PMID- 22519891 TI - Cerebral hypoperfusion and cognitive impairment: the pathogenic role of vascular oxidative stress. AB - Alzheimer's disease (AD) and vascular dementia (VaD) are the most frequent causes of cognitive impairment in the elderly. In the pathogenesis of cognitive impairment, the association of neurodegenerative and vascular factors indicates a major role of hemodynamic abnormalities including cerebral hypoperfusion. There is also ample evidence that oxidative stress of vascular origin leads to profound alterations in cerebrovascular regulation and is crucial to cerebrovascular dysfunction in a variety of conditions that result in chronic hypoperfusion of the brain. In rodents, experimental chronic cerebral hypoperfusion (CCH) can be initiated by occlusion of the major arterial supply. This way CCH brings about mitochondrial dysfunction and protein synthesis inhibition. These effects may destroy the balance of antioxidases and reactive oxygen species (ROS) and produce oxidative damage. At the same time, oxidative injury to vascular endothelial cell, glia, and neuron impairs vascular function and neurovascular coupling, which may result in a vicious cycle of further reduction of cerebral perfusion. In clinical cases of severe cognitive dysfunction, vascular risk factors are commonly present, while cerebral hypoperfusion is often associated with vascular oxidative damage. Thus we hypothesize that cerebral hypoperfusion is one of the key factors in the development of cognitive impairment, in which vascular oxidative stress plays a major role. The approaches against cerebrovascular dysfunction, combined with antioxidants and others, might make a promising contribution to the treatment of cognitive impairment. PMID- 22519892 TI - End-of-life preferences in advanced cancer patients willing to discuss issues surrounding their terminal condition. AB - The aim of the present study is to describe end-of-life preferences of advanced cancer patients willing to talk about death issues. Eighty-eight advanced cancer patients were interviewed through End of Life Preferences Interview (ELPI), a 23 item interview covering a wide range of end-of-life care issues. Most interviewed subjects were home care patients and their median survival after ELPI administration was 69 days. In total, 100% of responders expressed the will to receive some kind of information on the disease process and/or the treatments proposed. Approximately 77% declared to be willing to talk about what it is important at the end of life in case of worsening of their conditions and 31% prefer to be left alone in difficult moments. Approximately 67% choose home as the preferred place of death and 63% think it is preferable to die in a state of unconsciousness induced by drugs. About half of responders declare to believe in any kind of life after death and 40% consider very important to find any meaning at the end of life. ELPI can be a useful instrument to adapt the model of care to the specific needs and values of each patient. PMID- 22519890 TI - Positron emission tomography imaging of tumor angiogenesis with a 66Ga-labeled monoclonal antibody. AB - The goal of this study was to develop a (66)Ga-based positron emission tomography (PET) tracer for noninvasive imaging of CD105 expression during tumor angiogenesis, a hallmark of cancer. (66)Ga was produced using a cyclotron with (nat)Zn or isotopically enriched (66)Zn targets. TRC105, a chimeric anti-CD105 monoclonal antibody, was conjugated to 2-S-(4-isothiocyanatobenzyl)-1,4,7 triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) and labeled with (66)Ga. No difference in CD105 binding affinity or specificity was observed between TRC105 and NOTA-TRC105 based on flow cytometry analysis. Reactivity of (66)Ga for NOTA, corrected to the end of bombardment, was between 74 and 222 GBq/MUmol for both target enrichments with <2 ppb of cold gallium. (66)Ga-labeling was achieved with >80% radiochemical yield. Serial PET imaging revealed that the murine breast cancer 4T1 tumor uptake of (66)Ga-NOTA-TRC105 was 5.9 +/- 1.6, 8.5 +/- 0.6, and 9.0 +/- 0.6% ID/g at 4, 20, and 36 h postinjection, respectively (n = 4). At the last time point, tumor uptake was higher than that of all organs, which gave excellent tumor contrast with a tumor/muscle ratio of 10.1 +/- 1.1. Biodistribution data as measured by gamma counting were consistent with the PET findings. Blocking experiment, control studies with (66)Ga-NOTA-cetuximab, as well as ex vivo histology all confirmed the in vivo target specificity of (66)Ga NOTA-TRC105. Successful PET imaging with high specific activity (66)Ga (>700 GBq/MUmol has been achieved) as the radiolabel opens many new possibilities for future PET research with antibodies or other targeting ligands. PMID- 22519893 TI - Immunoliposomal delivery of doxorubicin can overcome multidrug resistance mechanisms in EGFR-overexpressing tumor cells. AB - Immunoliposomes (ILs) can be constructed to target the epidermal growth factor receptor (EGFR) to provide efficient intracellular drug delivery in tumor cells. We hypothesized that this approach might be able to overcome drug resistance mechanisms, which remain an important obstacle to better outcomes in cancer therapy. ILs were evaluated in vitro and in vivo against EGFR-overexpressing pairs of human cancer cells (HT-29 and MDA-MB-231) that either lack or feature the multidrug resistance (mdr) phenotype. In multidrug-resistant cell lines, ILs loaded with doxorubicin (DOX) produced 19-216-fold greater cytotoxicity than free DOX, whereas in nonresistant cells, immunoliposomal cytotoxicity of DOX was comparable with that of the free drug. In intracellular distribution studies, free DOX was efficiently pumped out of the multidrug-resistant tumor cells, whereas immunoliposomal DOX leads to 3.5-8 times higher accumulation of DOX in the cytoplasm and 3.5-4.9 times in the nuclei compared with the free drug. Finally, in vivo studies in the MDA-MB-231 Vb100 xenograft model confirmed the ability of anti-EGFR ILs-DOX to efficiently target multidrug-resistant cells and showed impressive antitumor effects, clearly superior to all other treatments. In conclusion, ILs provide efficient and targeted drug delivery to EGFR overexpressing tumor cells and are capable of completely reversing the multidrug resistant phenotype of human cancer cells. PMID- 22519894 TI - Absence of somatization in non-coeliac gluten sensitivity. AB - OBJECTIVE: In contrast to coeliac disease (CD), the mechanism behind non-coeliac gluten sensitivity (NCGS) is unclear. The aims of the study were to measure the presence of somatization, personality traits, anxiety, depression, and health related quality of life in NCGS individuals compared with CD patients and healthy controls, and to compare the response to gluten challenge between NCGS and CD patients. MATERIAL AND METHODS: We examined 22 CD patients and 31 HLA-DQ2+ NCGS patients without CD, all on a gluten-free diet. All but five CD patients were challenged orally for 3 days with gluten; symptom registration was performed during challenge. A comparison group of 40 healthy controls was included. Patients and healthy controls completed questionnaires regarding anxiety, depression, neuroticism and lie, hostility and aggression, alexithymia and health locus of control, physical complaints, and health-related quality of life. RESULTS: The NCGS patients reported more abdominal (p = 0.01) and non-abdominal (p < 0.01) symptoms after gluten challenge than CD patients. There were no significant differences between CD and NCGS patients regarding personality traits, level of somatization, quality of life, anxiety, and depressive symptoms. The somatization level was low in CD and NCGS groups. Symptom increase after gluten challenge was not related to personality in NCGS patients. CONCLUSIONS: NCGS patients did not exhibit a tendency for general somatization. Personality and quality of life did not differ between NCGS and CD patients, and were mostly at the same level as in healthy controls. NCGS patients reported more symptoms than CD patients after gluten challenge. PMID- 22519896 TI - A qualitative analysis of job burnout in eating disorder treatment providers. AB - Although job burnout is common in mental health care settings, almost no research has examined burnout in eating disorder treatment providers. Using qualitative methodology, this study examined a) perceived contributors of burnout, b) efforts to manage burnout, and c) recommendations for avoiding burnout in a sample of professional eating disorder treatment providers. Recruited via professional organizations, 298 participants completed an online questionnaire designed by the authors. Qualitative responses were coded and grouped into themes. Results indicated that almost all participants worried about their patients' health, which frequently resulted in negative affect (e.g., anxiety, sadness). The most frequently cited contributors to burnout were common characteristics of eating pathology (e.g., chronicity, relapse, symptom severity); patient characteristics (e.g., personality conflict); work-related factors (e.g., time demands); and, financial issues (e.g., inadequate compensation). To avoid burnout, over 90% of participants engaged in self-care behaviors (e.g., exercise, social support). Early-career practitioners were encouraged to utilize supervision, create a work/life balance, engage in self-care, and limit caseloads. These results suggest that supervision and training of eating disorder treatment providers should include burnout management. PMID- 22519895 TI - Closed and open breathing circuit function in healthy volunteers during exercise at Mount Everest base camp (5300 m). AB - We present a randomised, controlled, crossover trial of the Caudwell Xtreme Everest (CXE) closed circuit breathing system vs an open circuit and ambient air control in six healthy, hypoxic volunteers at rest and exercise at Everest Base Camp, at 5300 m. Compared with control, arterial oxygen saturations were improved at rest with both circuits. There was no difference in the magnitude of this improvement as both circuits restored median (IQR [range]) saturation from 75%, (69.5-78.9 [68-80]%) to > 99.8% (p = 0.028). During exercise, the CXE closed circuit improved median (IQR [range]) saturation from a baseline of 70.8% (63.8 74.5 [57-76]%) to 98.8% (96.5-100 [95-100]%) vs the open circuit improvement to 87.5%, (84.1-88.6 [82-89]%; p = 0.028). These data demonstrate the inverse relationship between supply and demand with open circuits and suggest that ambulatory closed circuits may offer twin advantages of supplying higher inspired oxygen concentrations and/or economy of gas use for exercising hypoxic adults. PMID- 22519897 TI - A systematic review of dialectical behavior therapy for the treatment of eating disorders. AB - Dialectical behavior therapy (DBT) has been proposed as an effective treatment for eating disorders (EDs). We conducted a systematic literature review to locate refereed journal articles testing DBT for the treatment of EDs. We identified 13 studies empirically evaluating treatment efficacy across various settings. Findings, based on mostly uncontrolled trials, indicate that DBT treatments appear effective in addressing ED behaviors and other forms of psychopathology in ED samples. The expectation that improvements in emotion regulation capabilities drive reductions in ED pathology was not fully supported. Further research is necessary to confirm the efficacy of modified DBT treatments for EDs. PMID- 22519898 TI - Eating disorders and social support: perspectives of recovered individuals. AB - Eating disorder researchers have focused more on the etiology and treatment and less on what happens for individuals during the recovery process from an eating disorder. For this qualitative study, we examined how social supports were helpful and hurtful during the eating disorder recovery process and learned about varying experiences with social supports from the perspectives of 22 recovered women. Participants reported that eating disorder recovery is largely influenced by the individual's sense of connection to self and others. In addition, participants shared that the focus of care from providers influenced their recovery process in powerful ways. Clinical implications and future research ideas are presented for clinicians and researchers working in the area of eating disorders. PMID- 22519899 TI - What components of perfectionism predict drive for thinness? AB - Perfectionism and drive for thinness have both been described as predictors of eating disorders, but the relationship between these two constructs over time requires further investigation, as does the an understanding of what components of perfectionism are important in this relationship. Using a longitudinal design, a population of 175 young adults was followed up over a 4 month period. Structural equation modelling indicated a unidirectional relationship between evaluative concerns and drive for thinness, with evaluative concerns, measured at Time 1 predicting an increase in drive for thinness at Time 2. This finding has potential implications for understanding psychological symptoms that precede eating disorder symptoms, and may help build models about prevention and treatment. As a first study to prospectively examine this relationship, further research is needed to assess the generalisability of the findings, and to explore additional variables that may mediate the relationship between evaluative concerns and drive for thinness. PMID- 22519903 TI - Come play with me: an argument to link autism spectrum disorders and anorexia nervosa through early childhood pretend play. AB - This article builds on the argument of a link between behaviours observed in persons with autism spectrum disorders and persons with anorexia nervosa. In describing these behaviours, a link is made between deficits in social cognition, lack of flexible and creative thinking, theory of mind, and deficits in early pretend play ability. Early pretend play ability is a strong avenue to the development and strengthening of social cognition, problem solving, language, logical sequential thought, and understanding social situations. Currently, there is no literature on the pretend play ability of persons who develop anorexia nervosa. This article argues for research into this area which may potentially contribute to developments in new intervention strategies for these persons. PMID- 22519904 TI - Diabetes mellitus and cancer risk in a network of case-control studies. AB - Diabetes has been associated to the risk of a few cancer sites, though quantification of this association in various populations remains open to discussion. We analyzed the relation between diabetes and the risk of various cancers in an integrated series of case-control studies conducted in Italy and Switzerland between 1991 and 2009. The studies included 1,468 oral and pharyngeal, 505 esophageal, 230 gastric, 2,390 colorectal, 185 liver, 326 pancreatic, 852 laryngeal, 3,034 breast, 607 endometrial, 1,031 ovarian, 1,294 prostate, and 767 renal cell cancer cases and 12,060 hospital controls. The multivariate odds ratios (OR) for subjects with diabetes as compared to those without-adjusted for major identified confounding factors for the cancers considered through logistic regression models-were significantly elevated for cancers of the oral cavity/pharynx (OR = 1.58), esophagus (OR = 2.52), colorectum (OR = 1.23), liver (OR = 3.52), pancreas (OR = 3.32), postmenopausal breast (OR = 1.76), and endometrium (OR = 1.70). For cancers of the oral cavity, esophagus, colorectum, liver, and postmenopausal breast, the excess risk persisted over 10 yr since diagnosis of diabetes. Our data confirm and further quantify the association of diabetes with colorectal, liver, pancreatic, postmenopausal breast, and endometrial cancer and suggest forthe first time that diabetes may also increase the risk of oral/pharyngeal and esophageal cancer. PMID- 22519905 TI - Nucleophile- or light-induced synthesis of 3-substituted phthalides from 2 formylarylketones. AB - The surprisingly facile conversion (isomerization) of 2-formyl-arylketones into 3 substituted phthalides, as observed for the marine natural product pestalone and its per-O-methylated derivative, was investigated using a series of simple 2 acylbenzaldehydes as substrates. The transformation generally proceeds smoothly in DMSO, either in a Cannizarro-Tishchenko-type reaction under nucleophile catalysis (NaCN) or under photochemical conditions (DMSO, 350 nm). PMID- 22519906 TI - Longer term safety of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes mellitus: systematic review and meta-analysis. AB - Dipeptidyl peptidase-4 (DPP-4) inhibitors are oral antidiabetic agents that hold the potential of slowing the progress of type 2 diabetes mellitus. Their long term safety is still a subject of debate. A systematic review of randomized, controlled trials was undertaken to comprehensively profile the safety of chronic treatment of type 2 diabetes mellitus with DPP-4 inhibitors. We searched data sources including MEDLINE, CENTRAL, publishers' and manufacturers' databases. Eligible trials were double-blind, randomized, placebo or active-controlled trials with >=18 weeks duration in patients with type 2 diabetes reporting safety outcomes. Meta-analysis was performed separately for trials in which the control group received placebo (44 studies), another gliptin (3 studies) and any other antidiabetic drug (20 studies). Risk ratios with 95% confidence intervals were computed using a Mantel-Haenszel fixed-effect model for general safety outcomes, hypoglycaemia and adverse events by system organ class. Of 307 publications retrieved, 67 randomized, controlled trials met the eligibility criteria and were included in this review (4 alogliptin, 8 linagliptin, 8 saxagliptin, 20 sitagliptin, and 27 vildagliptin trials). Adverse events with gliptin treatment were at placebo level (relative risk (RR) 1.02 [0.99, 1.04]). No increased risk of infections was detectable (RR 0.98 [0.93, 1.05] compared to placebo and 1.02 [0.97, 1.07] compared to other antidiabetic drugs). Asthenia (RR 1.57 [1.09, 2.27]) as well as cardiac (RR 1.37 [1.00, 1.89]) and vascular disorders (RR 1.74 [1.05, 2.86] for linagliptin) emerged as adverse events associated with DPP-4 inhibitor treatment. The risk of hypoglycaemia was low with DPP-4 inhibitor treatment (RR 0.92 [0.74, 1.15] compared to placebo, RR 0.20 [0.17, 0.24] compared to sulphonylureas) in the absence of sulphonylurea or insulin co therapy, but significantly elevated for combination therapy of sulphonylurea or insulin with sitagliptin or linagliptin (RR 1.86 [1.46, 2.37] compared to placebo). A large body of data supports the long-term safety of gliptin treatment and refutes an increased risk of infections. Further research is needed to clarify a possible link to asthenia, cardiac and vascular events. For combination therapy with insulin or insulin secretagogues, a careful choice of the agent used may limit the risk of hypoglycaemia. PMID- 22519907 TI - Moderate-intensity, premeal cycling blunts postprandial increases in monocyte cell surface CD18 and CD11a and endothelial microparticles following a high-fat meal in young adults. AB - High-fat meals promote transient increases in proatherogenic factors, implicating the postprandial state in cardiovascular disease (CVD) progression. Although low grade inflammation is associated with CVD, little research has assessed postprandial inflammation. Because of its anti-inflammatory properties, premeal exercise may counteract postprandial inflammation. The purpose of this study was to determine postprandial alterations in monocytes and circulating markers of endothelial stress and inflammation following a high-fat meal in young adults with or without premeal cycle exercise. Each subject completed two trials and was randomized to rest or cycle at a moderate intensity prior to eating a high fat meal. Flow cytometry was used to assess monocyte cell surface receptor expression and concentration of endothelial microparticles (EMP). Plasma cytokines were assessed using Luminex MagPix. Statistical analysis was completed using separate linear mixed models analyses with first-order autoregressive (AR(1)) heterogeneous covariance structure. Significance was set at P <= 0.05. Percentage increases in classic monocyte CD11a and CD18 were greater overall in the postprandial period in the meal-only condition compared with the meal + exercise condition (P < 0.05). EMP concentration was 47% greater 3 h after the meal compared with premeal values in the meal-only condition (P < 0.05); no significant increase was observed in the meal + exercise condition. Premeal cycling blunted postprandial increases in EMP and CD11a and CD18. Acute, moderate intensity exercise may help counteract possibly deleterious postprandial monocyte and endothelial cell activation. PMID- 22519908 TI - Site-specific mapping and time-resolved monitoring of lysine methylation by high resolution NMR spectroscopy. AB - Methylation and acetylation of protein lysine residues constitute abundant post translational modifications (PTMs) that regulate a plethora of biological processes. In eukaryotic proteins, lysines are often mono-, di-, or trimethylated, which may signal different biological outcomes. Deconvoluting these different PTM types and PTM states is not easily accomplished with existing analytical tools. Here, we demonstrate the unique ability of NMR spectroscopy to discriminate between lysine acetylation and mono-, di-, or trimethylation in a site-specific and quantitative manner. This enables mapping and monitoring of lysine acetylation and methylation reactions in a nondisruptive and continuous fashion. Time-resolved NMR measurements of different methylation events in complex environments including cell extracts contribute to our understanding of how these PTMs are established in vitro and in vivo. PMID- 22519909 TI - Combined treatment with a dipeptidyl peptidase-IV inhibitor (sitagliptin) and an angiotensin II type 1 receptor blocker (losartan) promotes islet regeneration via enhanced differentiation of pancreatic progenitor cells. AB - AIM: The existence of pancreatic progenitor cells (PPCs) with differentiation capacity in the adult pancreas has rendered that promotion of islet regeneration is feasible. The dipeptidyl peptidase-IV inhibitor sitagliptin and the angiotensin II type 1 receptor (AT(1) receptor) blocker losartan have a common target action in the pancreata. Thus, we evaluated the synergistic/additive effects of these two drugs on the differentiation of islet progenitors. METHODS: The acute and chronic effects of sitagliptin and losartan, individually or in combination, on islet regeneration in vivo were investigated by using a streptozotocin-induced type 1 diabetes mouse model. Their effects were also examined on an in vitro PPCs model derived from human foetal pancreas. RESULTS: A chronic combination treatment enhanced glucose tolerance in diabetic mice associated with an increased ratio of beta cells to islet; an acute combination treatment resulted in a marked increase in the production of neurogenin 3 (NGN3(+)) cells in proximity to CK7(+) ductal cell and an increased presence of insulin(+) /CK7(+) cells. The in vitro study revealed that a combination treatment significantly enhanced mRNA expression of NGN3, NKX6.1 and PDX-1 during PPCs differentiation into human islet-like cell clusters (ICCs). Despite no apparent changes in insulin release, the combined treatment resulted in increasing production of peroxisome proliferator-activated receptor gamma (PPARgamma) during PPC differentiation. CONCLUSIONS: These data indicate that combined sitagliptin-losartan treatment can improve islet function by promoting the differentiation of PPCs into ICCs, perhaps via a mechanism involving PPARgamma production, and could thereby, contribute to islet regeneration. PMID- 22519911 TI - Factors associated with work outcome for survivors from haematological malignancies--a systematic literature review. AB - Recent years have seen a growing number of survivors from haematological malignancies. As biology and treatment for these malignancies differ from other malignancies, we performed a systematic literature review of factors associated with work outcome for these survivors. A systematic literature search was conducted. Eight studies with different methodology and characteristics met the inclusion criteria. Three prospective studies agreed, to a high extent, on their findings, whereas results of five cross-sectional studies collectively were inconclusive. Overall, this review - like reviews on other cancer survivors - found no certain association of single factors with work outcome. However, based on possible explanations of the converging findings, this review pinpointed a number of issues that may inform future studies. The design should preferably be prospective, including comparison with age-paired cancer-free individuals. The role of co-morbidity and of differences between haematological diagnoses ought to be established, and work outcomes must be well defined and recorded with valid methods. To establish cause-effect relations, factors possibly associated to work outcome should be evaluated at an early time point after diagnosis. Such studies would assist identification of individuals at increased risk of encountering work related problems and would hence help establish knowledge on which rehabilitation measures could rest. PMID- 22519910 TI - The advent of AAV9 expands applications for brain and spinal cord gene delivery. AB - INTRODUCTION: Straightforward studies compared adeno-associated virus (AAV) serotypes to determine the most appropriate one for robust expression in the CNS. AAV9 was efficient when directly injected into the brain, but more surprisingly, AAV9 produced global expression in the brain and spinal cord after a peripheral, systemic route of administration to neonatal mice. AREAS COVERED: Topics include AAV9 gene delivery from intraparenchymal, intravenous, intrathecal and intrauterine routes of administration, and related preclinical studies and disease models. Systemic AAV9 gene transfer yields remarkably consistent neuronal expression, though only in early development. AAV9 is versatile to study neuropathological proteins: microtubule-associated protein tau and transactive response DNA-binding protein 43 kDa (TDP-43). EXPERT OPINION: AAV9 will be more widely used based on current data, although other natural serotypes and recombineered vectors may also support or improve upon wide-scale expression. A peripheral-to-central gene delivery that can affect the entire CNS without having to inject the CNS is promising for basic functional experiments, and potentially for gene therapy. Systemic or intra-cerebrospinal fluid routes of AAV9 administration should be considered for spinal muscular atrophy, lysosomal storage diseases and amyotrophic lateral sclerosis, if more neuronal expression can be achieved in adults, or if glial expression can be exploited. PMID- 22519912 TI - New (99m)Tc(CO)(3) mannosylated dextran bearing S-derivatized cysteine chelator for sentinel lymph node detection. AB - The aim of the present study is to synthesize new mannosylated dextran derivative that can be labeled with Tc-99m for potential use in sentinel lymph node detection (SLND). The compound was designed to have a dextran with molecular weight of 10 kDa as a backbone, mannose for binding to mannose receptors of the lymph node and S-derivatized cysteine as a suitable chelator for labeling with [(99m)Tc(H(2)O)(3)(CO)(3)](+) precursor. Reaction of allyl bromide with dextran (MW 11800) yielded the intermediate allyl-dextran (1) with about 40% coupling. Addition of cysteine to allyl-dextran resulted in the S-derivatized cysteine, compound DC15 (2). The final product DCM20 (3) was obtained in good yield after in situ hydrolysis and activation of cyanomethyl tetraacetyl-1-thio-d mannopyranoside and coupling to DC15. All derivatives were purified by ultrafiltration and characterized by NMR. DC15 and DCM20 were quantitatively labeled with (99m)Tc (>95% radiochemical purity) using the fac [(99m)Tc(OH(2))(3)(CO)(3)](+) precursor and ligand concentration of 1.5 * 10(-6) M at neutral pH. Both (99m)Tc-labeled compounds (99m)Tc(CO)(3)-DC15 (6) and (99m)Tc(CO)(3)-DCM20 (7) remained stable after 6 h incubation at 37 degrees C in the presence of excess histidine or cysteine, as well as even after 20-fold dilution and incubation for 24 h at room temperature. The characterization of the compounds 6 and 7 was performed by comparing their HPLC radiochromatograms with those of their rhenium surrogates Re(CO)(3)-DC15 (4) and Re(CO)(3)-DCM20 (5) respectively that were prepared using the precursor [NEt(4)](2)fac [ReBr(3)(CO)(3)] and characterized by IR and NMR spectroscopy. When injected subcutaneously from the foot pad of mice, (99m)Tc-labeled mannosylated dextran (7) showed accumulation in the popliteal lymph node (SLN in this model) higher than that of non-mannosylated analogue (6) and the (99m)Tc-phytate serving as standard. Compound 7 also exhibited lower radioactivity levels at the injection site compared to (99m)Tc-phytate. The SPECT/CT studies in mice confirmed that 7 accumulated in the popliteal lymph node allowing its clear visualization. The present findings demonstrate that compound 7 ((99m)Tc(CO)(3)-DCM20) is promising and merits further evaluation as a radiopharmaceutical for sentinel lymph node detection. PMID- 22519913 TI - Barriers to involvement of men in ANC and VCT in Khayelitsha, South Africa. AB - We used qualitative methods to assess pregnant women and men's attitudes, feelings, beliefs, experiences and reactions to male partners' involvement in antenatal clinic (ANC) in Khayelitsha, Cape Town, South Africa. The aims of these studies were to determine barriers to male partners' attendance of ANC with their pregnant female partners and to identify possible strategies to overcome these barriers. Findings from the qualitative studies demonstrated that pregnant women were keen to invite their male sexual partners and that men would attend if invited. The main barrier to male participation was lack of awareness and the healthcare facility environment. The findings of these studies emphasized the need to increase awareness among men in Khayelitsha of the need for male attendance of ANC and the need to address the barriers to male attendance of ANC. It was clear that community sensitization programmes coupled with improvement of the health facility environment to be receptive to men are essential for increasing male attendance of ANC. PMID- 22519914 TI - The need for worldwide policy and action plans for rare diseases. AB - There are more than 6000 rare diseases (defined as affecting <5/10 000 individuals in Europe, <200 000 people in the United States). The rarity can create problems including: difficulties in obtaining timely, accurate diagnoses; lack of experienced healthcare providers; useful, reliable and timely information may be hard to find; research activities are less common; developing new medicines may not be economically feasible; treatments are sometimes very expensive; and in developing countries, the problems are compounded by other resource limitations. Emphasis is required to support appropriate research and development leading to better prevention, diagnosis and treatments of rare diseases. Notably, clinical trials using already existing drugs may result in new, affordable, treatment strategies. Moreover, rare diseases may teach us about common disorders. CONCLUSIONS: Countries are encouraged to implement specific research and development activities within their individual capabilities, so that patients worldwide have equal access to necessary interventions to maximize the potential of every individual. PMID- 22519915 TI - DOTAGA-trastuzumab. A new antibody conjugate targeting HER2/Neu antigen for diagnostic purposes. AB - Improved bifunctional chelating agents (BFC) are required for indium-111 radiolabeling of monoclonal antibodies (mAbs) under mild conditions to yield stable, target-specific agents. 2,2',2"-(10-(2,6-Dioxotetrahydro-2H-pyran-3-yl) 1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (DOTAGA-anhydride) was evaluated for mAb conjugation and labeling with indium-111. The DOTA analogue was synthesized and conjugated to trastuzumab-which targets the HER2/neu receptor-in mild conditions (PBS pH 7.4, 25 degrees C, 30 min) and gave a mean degree of conjugation of 2.6 macrocycle per antibody. Labeling of this immunoconjugate with indium-111 was performed in 75% yield after 1 h at 37 degrees C, and the proportion of (111)In-DOTAGA-trastuzumab reached 97% after purification. The affinity of DOTAGA-trastuzumab was 5.5 +/- 0.6 nM as evaluated by in vitro saturation assays using HCC1954 breast cancer cell line. SPECT/CT imaging and biodistribution studies were performed in mice bearing breast cancer BT-474 xenografts. BT-474 tumors were clearly visualized on SPECT images at 24, 48, and 72 h postinjection. The tumor uptake of [(111)In-DOTAGA]-trastuzumab reached 65%ID/g 72 h postinjection. These results show that the DOTAGA BFC appears to be a valuable tool for biologics conjugation. PMID- 22519916 TI - Inhibitory effect of liquiritigenin on migration via downregulation proMMP-2 and PI3K/Akt signaling pathway in human lung adenocarcinoma A549 cells. AB - Liquiritigenin (LQ) is a flavanone extracted from Glycyrrhizae, which has multiple biological effects, such as antiinflammation and anticancer. This study is the first to investigate the effect of LQ on the migration of human lung adenocarcinoma A549 cells in vitro. First, LQ exhibited inhibitory effects on the adhesion and migration of A549 cells in the absence of cytotoxicity. Gelatin zymography and Western blot analysis showed that LQ significantly reduced the expression of promatrix metalloproteinase-2 (proMMP-2) in A549 cells in terms of both activity and protein level. Second, LQ inhibited the phosphorylation of Akt and activated the phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2). Furthermore, the treatment of inhibitors specific for Akt (LY294002) and ERK1/2 (U0126) to A549 cells resulted in reduced activity of proMMP-2. These results suggested that the inhibition on proMMP-2 expression by LQ may be through suppression on PI3K/Akt signaling pathway, which in turn led to the inhibition of lung adenocarcinoma A549 cells migration. However, activation of ERK might not be involved in the regulation of proMMP-2. Taken together, LQ may be considered as a potential interfering agent of cancer progression. PMID- 22519917 TI - Gastroesophageal reflux disease in primary care: using changes in proton pump inhibitor therapy as an indicator of partial response. AB - OBJECTIVE: Up to one-third of patients with gastroesophageal reflux disease (GERD) in primary care have residual symptoms despite proton pump inhibitor (PPI) therapy. We aimed to characterize partial response to PPIs among adult patients in UK primary care. MATERIAL AND METHODS: Newly diagnosed GERD patients aged 20 79 years who were prescribed PPI for treatment of GERD were identified in The Health Improvement Network. Those with a treatment change suggesting partial response to PPIs (new treatment added to PPI, increased PPI dose, or switching PPI) during the subsequent 6 months were identified as potential cases and confirmed after manual review of each patient's complete computer medical record including free-text comments. Patients without these treatment changes were study controls. A nested case-control analysis was conducted using logistic regression. RESULTS: The proportion of newly diagnosed GERD patients with partial response to PPI therapy was 18.6% (1201/6453). Partial response was associated with female gender (odds ratio [OR]: 1.20; 95% confidence interval [CI]: 1.05-1.37), anxiety or depression (OR: 1.15; 95% CI: 1.00-1.31), and prescription of >= 6 drugs in the month before GERD diagnosis (OR: 1.42; 95% CI: 1.14-1.78). Among new PPI users (n = 2907), partial response was associated with esophageal ulcer or Barrett's esophagus at initial diagnosis (OR: 3.14; 95% CI: 1.60-6.17). CONCLUSIONS: Approximately one in five newly diagnosed patients with GERD appear to have a partial response to PPI therapy. Female gender, polymedication, and a severe initial diagnosis may be associated with partial response. PMID- 22519918 TI - Non-Luer connectors: are we nearly there yet? AB - The Department of Health aims to eliminate the use of devices with a Luer connector firstly from 'single shot' neuraxial procedures (April 2012) and subsequently from all neuraxial and regional anaesthesia procedures (April 2013). This initiative is important for all anaesthetists, oncologists, paediatricians and neurologists. Once achieved, non-Luer connectors for neuraxial procedures will create one more barrier to wrong-route errors. The period until full implementation and market stability remains problematic. Avoidance of unintended consequences requires professional and individual attention to detail. Considerable progress has been made by manufacturers in the last year in improving the quality and range of equipment available, but despite this not all the necessary equipment is available and there remains a lack of independent evaluation, which is urgently needed to enable clinicians to judge the absolute and relative performance of different connectors. Initial evaluation of devices with new connectors can (and should) take place in a laboratory with rigs and manikins, with patient-based evaluation following after the results of the technical and usability evaluations are available. A structured evaluation of all five current connectors is urgently needed. Non-Luer connectors, however successful, will not create barriers to several type of wrong-route error and solutions to these should also be actively sought. It is clear that the initiative has been more complex than the Health Select Committee, the National Patient Safety Agency and the External Reference Group anticipated, but while there is still much work to be done, we should acknowledge that much progress has been made. PMID- 22519919 TI - Imeglimin, a novel glimin oral antidiabetic, exhibits a good efficacy and safety profile in type 2 diabetic patients. AB - AIMS: Imeglimin is the first in a new tetrahydrotriazine-containing class of oral antidiabetic agents, the glimins. It has been shown to act on the liver, muscle and pancreatic beta-cells to uniquely target the key defects of type 2 diabetes. Two studies were performed to compare the safety and efficacy of imeglimin with metformin and placebo on glycaemic control in type 2 diabetes patients. METHODS: In a 4-week phase IIa, three-arm parallel group study, patients were randomized to imeglimin 2000 mg once daily (od), imeglimin 1000 mg twice daily (bid) or metformin 850 mg bid and responses to an oral glucose tolerance test (OGTT) were measured. In an 8-week phase IIa, four-arm controlled multi-centre study, patients were randomized to imeglimin 500 mg bid, imeglimin 1500 mg bid, metformin 850 mg bid or placebo. Glycaemic assessments included area under the curve (AUC) up to 6 h (AUC(0-6h)) for glucose during a prolonged meal, fasting plasma glucose (FPG) and HbA1c. Safety and tolerability were assessed in both studies through adverse event recording and laboratory parameters, vital signs and electrocardiogram. RESULTS: Imeglimin was found to be as effective as metformin at reducing the AUC(PG) and AUC(0-6h) , FPG and HbA1c. Imeglimin exhibited a favourable tolerability profile in comparison to metformin. CONCLUSIONS: The results from both studies confirm that imeglimin displays a superior benefit : risk profile compared with metformin in type 2 diabetes patients. The encouraging tolerability profile of imeglimin could make it suitable for combination with other classes of antidiabetic agents and may increase availability to a wider patient population. PMID- 22519920 TI - Measures to prevent transfusion-related acute lung injury (TRALI). PMID- 22519921 TI - Taking the negative view of current migraine treatments: the unmet needs. AB - Acute migraine treatment is given to abolish ongoing attacks, while prophylactic migraine treatment is given on a daily basis to prevent the occurrence of migraine attacks as far as possible. The majority of migraine patients do not use the specific acute anti-migraine drugs, the triptans. Thus, only 10% (Denmark) to 35% (France) of migraine patients use triptans. This is most likely due to relatively low efficacy. Thus, in randomized controlled trials (RCTs) pain freedom after 2 hours ranges from 12% (frovatriptan 2.5 mg) to 40% (rizatriptan 10 mg). For prophylactic treatment (propranolol, valproate, topiramate) a response (at least a 50% reduction in migraine frequency) is observed in 40-50%. In addition, prophylactic treatment is hampered by adverse events and withdrawals. There is a need for new acute anti-migraine drugs and targets are already available and there are more to come. It has been estimated that approximately 2% of the adult population need prophylactic treatment because of frequent migraine attacks. For prophylactic migraine drugs there is an even greater need for new drugs than for acute drug treatment. PMID- 22519922 TI - Randomized clinical study of a histamine H3 receptor antagonist for the treatment of adults with attention-deficit hyperactivity disorder. AB - BACKGROUND: Psychostimulants, including methylphenidate and amphetamine preparations, are commonly prescribed for the treatment of attention-deficit hyperactivity disorder (ADHD) in children and adults. Histamine H3 receptors reside on non-histamine neurons and regulate other neurotransmitters (e.g. acetylcholine, noradrenaline [norepinephrine]) suggesting that H3 antagonists have the potential to improve attention and impulsivity. Research indicates that H3 receptor antagonists due to their novel mechanism of action may have a unique treatment effect offering an important alternative for the treatment of ADHD. Bavisant (JNJ-31001074) is a highly selective, orally active antagonist of the human H3 receptor with a novel mechanism of action, involving wakefulness and cognition, with potential as a treatment for ADHD. OBJECTIVE: The objective of this study was to evaluate the efficacy, safety and tolerability of three dosages of bavisant compared with placebo in adults with ADHD. STUDY DESIGN: This randomized, double-blind, placebo- and active-controlled, parallel-group, multicentre study evaluated three dosages of bavisant (1 mg/day, 3 mg/day or 10 mg/day) and two active controls in adults with ADHD. The study consisted of a screening phase of up to 14 days, a 42-day double-blind treatment phase and a 7 day post-treatment follow-up phase. Efficacy and safety assessments were performed. SETTING: The study was conducted at 37 study centres in the US from April 2009 through January 2010. PARTICIPANTS: Men and women aged 18-55 years with an established diagnosis of ADHD as confirmed by clinician and self-report diagnostic measures were enrolled. INTERVENTION: Participants were randomly assigned equally to one of six treatment groups: placebo, bavisant 1 mg/day, 3 mg/day or 10 mg/day, atomoxetine hydrochloride 80 mg/day or osmotic-release oral system (OROS) methylphenidate hydrochloride 54 mg/day. MAIN OUTCOME MEASURE: The primary efficacy endpoint was the change in the Attention Deficit Hyperactivity Disorder Rating Scale, Version IV (ADHD-RS-IV) total score from baseline (day 1) to the end of the treatment phase (day 42), and included all randomized participants who received one or more doses of study drug and had baseline and one or more post-baseline assessments (intent-to-treat [ITT] population). Safety assessments included treatment-emergent adverse events (TEAEs), laboratory tests and ECG readings. RESULTS: 430 participants were randomized, 424 received one or more doses of study medication and 335 (78%) of those randomized completed the study. Study participants had a mean age of 33.9 years and were predominantly White men. Mean treatment duration ranged from 31.4 to 38.8 days across groups. Mean change from baseline in the total ADHD-RS-IV score at day 42 (primary efficacy endpoint) was -8.8 in the placebo group versus -9.3, -11.2 and -12.2 in the bavisant 1 mg/day, 3 mg/day and 10 mg/day groups, respectively; the change in the 10 mg/day group was not statistically superior to placebo (p=0.161), and hence statistical comparisons of the 1 mg/day and 3 mg/day groups with placebo based on a step-down closed testing procedure were not performed. Mean change from baseline in the total ADHD-RS-IV score at day 42 was superior to placebo in the atomoxetine (-15.3) and OROS methylphenidate (-15.7) groups (p<0.005). Secondary efficacy assessments demonstrated a similar pattern with a non significant trend towards improvement in the bavisant groups. The two lower dosages showed a good tolerability profile, but the higher dosage of bavisant was less well tolerated, as evidenced by the incidence of total TEAEs (61.8%, 82.4%, 89.0%), and discontinuations due to TEAEs (4.4%, 7.4%, 19.2%) in the bavisant 1 mg/day, 3 mg/day and 10 mg/day groups, respectively, compared with 58.9% and 2.7%, respectively on placebo. In the atomoxetine and OROS methylphenidate groups, the incidence of total TEAEs was 83.8% and 82.4% and discontinuations due to TEAEs was 10.8% and 8.8%, respectively. CONCLUSION: Bavisant, a highly selective, wakefulness-promoting H3 antagonist, did not display significant clinical effectiveness in the treatment of adults with ADHD. CLINICAL TRIAL REGISTRATION NUMBER: NCT00880217. PMID- 22519923 TI - Quetiapine: a review of its use in the management of bipolar depression. AB - Quetiapine (Seroquel(r)) is an orally administered atypical antipsychotic that is indicated for the treatment of schizophrenia and bipolar disorder, including bipolar depression. An extended-release (XR) formulation of quetiapine is also available. This review summarizes the pharmacological properties, efficacy and tolerability of quetiapine and quetiapine XR in patients with bipolar depression. Quetiapine is an antagonist at both serotonin 5-HT2 and dopamine D2 receptors, and its antipsychotic effects are thought to stem from interactions at these receptors. The antidepressant effects of quetiapine are poorly understood, but may be related to antagonism of 5-HT2A receptors in cortical regions, partial agonism of 5-HT1A in the prefrontal cortex in association with increased extracellular dopamine release in the region, or to reduced synaptic reuptake of noradrenaline resulting from inhibition of the noradrenaline reuptake transporter by the quetiapine metabolite norquetiapine. The efficacy and tolerability of quetiapine was evaluated in five 8-week, randomized, double-blind, placebo controlled, multicentre or multinational trials in patients with a major depressive episode (MDE) associated with bipolar disorder. Across trials, monotherapy with oral quetiapine 300 or 600 mg/day (or quetiapine XR 300 mg/day) produced significantly greater improvements than placebo in depressive symptoms (primary endpoint), according to the change in the Montgomery-Asberg Depression Rating Scale total score. In general, quetiapine and quetiapine XR were also associated with significantly higher MDE response and remission rates than placebo. Across trials, quetiapine and quetiapine XR produced significantly greater improvements in global severity of illness scores than placebo, according to changes in the Clinical Global Impressions scale score. There were no differences in treatment outcomes between quetiapine 300 mg/day and 600 mg/day dosage groups. Patients with bipolar depression who responded to quetiapine during two 8-week acute treatment trials also benefited from continuing quetiapine therapy for up to 52 weeks. Compared with quetiapine responders randomized to placebo, quetiapine responders who continued quetiapine 300 or 600 mg/day had a significantly reduced risk of recurrence of any mood events and of depression mood events, but not of hypomanic/manic events. In a randomized, double-blind, placebo-controlled trial, quetiapine maintenance therapy for up to 104 weeks was more efficacious than placebo or lithium in prolonging the time to recurrence of any mood event (primary endpoint). Patients in this trial had bipolar I disorder with mania, depression or a mixed episode as the index episode, and the trial included only patients who were responsive to acute phase quetiapine, which may have introduced a positive bias in favour of quetiapine over lithium during maintenance therapy. Quetiapine 300 or 600 mg/day and quetiapine XR 300 mg/day was generally well tolerated in patients with bipolar depression, with most treatment-emergent adverse events being of mild to moderate severity. The most frequent adverse events occurring during the acute treatment phase were dry mouth, sedation, somnolence, dizziness (quetiapine and quetiapine XR), constipation (quetiapine) and increased appetite (quetiapine XR). Extrapyramidal symptoms (EPS) occurred across quetiapine and placebo groups, but there were no significant differences between quetiapine and placebo recipients on objective measures of EPS and akathisia. In some trials, quetiapine recipients experienced significantly greater weight gain than placebo recipients. Across trials, some quetiapine recipients had clinically relevant increases in blood glucose or lipid parameters, although these also occurred in patients from other treatment groups. The clinical significance of these changes is uncertain. In conclusion, quetiapine and quetiapine XR are valuable additions to the first-line treatments for bipolar depression. Further head-to-head trials of quetiapine versus other drug regimens that are effective in bipolar depression would be of considerable interest. PMID- 22519924 TI - Improved differentiation between ductal and acinar prostate cancer using three dimensional histology and biomarkers. AB - OBJECTIVE: The aim of the study was to refine the methodology for discriminating the ductal (DAP) and acinar adenocarcinomas (AAP) of the prostate and confirm that prostate carcinoma of ductal origin is a more aggressive subtype. MATERIAL AND METHODS: A retrospective analysis of 110 consecutive radical prostatectomy cases operated on between 2000 and 2006 and worked up using large-format "two dimensional" (2D; 4 MUm thick) and "three-dimensional" (3D; 1500 MUm thick) histology sections was carried out, with an average follow-up of 5.1 years. The same material was also analysed for selected biomarkers in tissue microarray blocks. The most discriminatory biomarkers were then tested on preoperative core biopsy specimens from 24 of these patients. RESULTS: 3D histology classified 97/110 (88%) cases of AAP and 13/110 (12%) DAP, which was then confirmed in 2D specimens. The DAP cases had a significantly greater frequency of pT3a and more advanced cancers, > 20 mm tumour focus, high-grade prostatic intraepithelial neoplasia, Gleason score >= 7, positive margin, extracapsular extension, vascular invasion, seminal vesicle infiltration, biochemical/local recurrence, regional lymph-node metastases and distant metastases. Three biomarkers in combination (chromogranin A, epidermal growth factor receptor and p53] distinguished DAP from AAP with an accuracy of 94% (area under the curve 0.94, 95% confidence interval 0.88-0.99). The same high accuracy was achieved using these three biomarkers on the preoperative specimens. CONCLUSIONS: Both 3D histology and the three selected biomarkers can help in accurately distinguishing DAP from AAP. The clear-cut distinction of two forms of prostate cancers by the approach advocated in this paper would allow AAP patients to undergo less radical treatment and would segregate DAP patients into a subset requiring more effective treatment regimens. PMID- 22519925 TI - Rapid and simple DNA extraction method for the detection of enterotoxigenic Staphylococcus aureus directly from food samples: comparison of PCR and LAMP methods. AB - AIMS: The study describes the development of simple and rapid DNA extraction method in combination with loop-mediated isothermal amplification (LAMP) to detect enterotoxigenic Staphylococcus aureus in food samples. METHODS AND RESULTS: In this study, isolation of genomic DNA of enterotoxigenic Staph. aureus from spiked milk, milk burfi, khoa, sugarcane juice and boiled rice was carried out by boiling the isolated sample pellets for 10 min with 1% Triton X 100. The isolated DNA was evaluated by polymerase chain reaction (PCR) and LAMP method. The LAMP was found to be 100 times more sensitive than PCR. The LAMP assay was very specific for Staph. aureus, and the presence of other contaminating bacterial DNAs and food matrix did not interfere or inhibit the LAMP assay. CONCLUSIONS: The template DNA extraction method developed in this study for food samples is simple, rapid and cost-effective. LAMP was found to be less sensitive to matrix effect of food, compared to PCR. SIGNIFICANCE AND IMPACT OF THE STUDY: The method is suitable for direct detection of Staph. aureus without any enrichment in contaminated food samples and hence finds its application in food safety analysis, in permutation with LAMP. PMID- 22519926 TI - Anatomical parameters of subaxial percutaneous transfacet screw fixation based on the analysis of 50 computed tomography scans: Clinical article. AB - OBJECT: Cervical transfacet screw placement has been described in the literature. Although the technique shows promise for percutaneous application, parameters for screw placement have not been well delineated. This study used reconstructed CT scans with imaging software to assess the feasibility of percutaneous transfacet screw placement, analyzing potential entry angles, transfacet lengths, and sex differences at each subaxial level. METHODS: Fifty consecutive cervical CT scans (obtained in 26 males and 24 females [mean age 41.5 years]) were reformatted using OsiriX software, and transfacet lengths, entry angles, and potential occipital clearance were analyzed at all subaxial levels. Statistical analyses were used to determine the differences, if any, between transfacet lengths, entry angle, and occipital clearance across individual cervical levels. Repeatability was quantified by calculating the intraclass correlation coefficient and Cohen kappa value. RESULTS: A total of 200 transfacet lengths and 200 entry angles in 50 patients were analyzed. The mean transfacet lengths were 17.9 +/- 2.6, 17.6 +/ 3.2, 16.3 +/- 3.6, and 13.1 +/- 2.2 mm at C3-4, C4-5, C5-6, and C6-7, respectively, with mean entry angles at 52.7 degrees +/- 7.8 degrees , 56.5 degrees +/- 8.0 degrees , 55.0 degrees +/- 8.8 degrees , and 53.0 degrees +/- 8.7 degrees , respectively. Analysis of variance revealed a significant difference between the mean transfacet lengths, while post hoc analysis revealed significantly larger transfacet lengths in the upper 2 cervical levels (C3-4 and C4-5) than in the lower 2 cervical levels (C5-6 and C6-7). Analysis of variance demonstrated no significant difference between the entry angles. Males had significantly larger transfacet lengths at C5-6 (17.4 vs 15.1 mm) and C6-7 (13.7 vs 12.4 mm) than females. The occiput would have blocked percutaneous screw placement in 86%, 78%, 54%, and 20% of the cases at C3-4, C4-5, C5-6, and C6-7, respectively. Transfacet lengths may accommodate longer screws in the upper cervical spine, but potential screw sizes decrease in the lower subaxial levels. A transfacet entry angle of approximately 50 degrees or greater was associated with a higher incidence of occipital clearance. Additionally, the occiput may pose a significant obstruction to percutaneous transfacet fixation in upper subaxial levels. Interrater reliability was poor for screw angle and length measurements, but was satisfactory in intrarater analysis in 6 of 8 measurements. There was moderate to good agreement of occipital clearance in all but one measurement. CONCLUSIONS: Cervical transfacet screw placement is possible from C 3 to C-7. Because occipital clearance can be difficult at C3-4 and C6-7, the use of curved or flexible instruments may be necessary to obtain the appropriate screw trajectory. Screw lengths varied with spinal level and the sex of the patient. PMID- 22519927 TI - Development of a large-animal model to measure dynamic cerebrospinal fluid pressure during spinal cord injury: Laboratory investigation. AB - OBJECT: Spinal cord injury (SCI) often results in considerable permanent neurological impairment, and unfortunately, the successful translation of effective treatments from laboratory models to human patients is lacking. This may be partially attributed to differences in anatomy, physiology, and scale between humans and rodent models. One potentially important difference between the rodent and human spinal cord is the presence of a significant CSF volume within the intrathecal space around the human cord. While the CSF may "cushion" the spinal cord, pressure waves within the CSF at the time of injury may contribute to the extent and severity of the primary injury. The objective of this study was to develop a model of contusion SCI in a miniature pig and establish the feasibility of measuring spinal CSF pressure during injury. METHODS: A custom weight-drop device was used to apply thoracic contusion SCI to 17 Yucatan miniature pigs. Impact load and velocity were measured. Using fiber optic pressure transducers implanted in the thecal sac, CSF pressures resulting from 2 injury severities (caused by 50-g and 100-g weights released from a 50-cm height) were measured. RESULTS: The median peak impact loads were 54 N and 132 N for the 50-g and 100-g injuries, respectively. At a nominal 100 mm from the injury epicenter, the authors observed a small negative pressure peak (median 4.6 mm Hg [cranial] and -5.8 mm Hg [caudal] for 50 g; -27.6 mm Hg [cranial] and 27.2 mm Hg [caudal] for 100 g) followed by a larger positive pressure peak (median 110.5 mm Hg [cranial] and 77.1 mm Hg [caudal] for 50 g; 88.4 mm Hg [cranial] and 67.2 mm Hg [caudal] for 100 g) relative to the preinjury pressure. There were no significant differences in peak pressure between the 2 injury severities or the caudal and cranial transducer locations. CONCLUSIONS: A new model of contusion SCI was developed to measure spinal CSF pressures during the SCI event. The results suggest that the Yucatan miniature pig is an appropriate model for studying CSF, spinal cord, and dura interactions during injury. With further development and characterization it may be an appropriate in vivo large animal model of SCI to answer questions regarding pathological changes, therapeutic safety, or treatment efficacy, particularly where humanlike dimensions and physiology are important. PMID- 22519928 TI - Biomechanical analysis in a human cadaveric model of spinous process fixation with an interlaminar allograft spacer for lumbar spinal stenosis: Laboratory investigation. AB - OBJECT: Traditional posterior pedicle screw fixation is well established as the standard for spinal stabilization following posterior or posterolateral lumbar fusion. In patients with lumbar spinal stenosis requiring segmental posterior instrumented fusion and decompression, interlaminar lumbar instrumented fusion (ILIF) is a potentially less invasive alternative with reduced morbidity and includes direct decompression assisted by an interlaminar allograft spacer stabilized by a spinous process plate. To date, there has been no biomechanical study on this technique. In the present study the biomechanical properties of the ILIF construct were evaluated using an in vitro cadaveric biomechanical analysis, and the results are presented in comparison with other posterior fixation techniques. METHODS: Eight L1-5 cadaveric specimens were subjected to nondestructive multidirectional testing. After testing the intact spine, the following conditions were evaluated at L3-4: bilateral pedicle screws, bilateral laminotomy, ILIF, partial laminectomy, partial laminectomy plus unilateral pedicle screws, and partial laminectomy plus bilateral screws. Intervertebral motions were measured at the index and adjacent levels. RESULTS: Bilateral pedicle screws without any destabilization provided the most rigid construct. In flexion and extension, ILIF resulted in significantly less motion than the intact spine (p < 0.05) and no significant difference from the laminectomy with bilateral pedicle screws (p = 0.76). In lateral bending, there was no statistical difference between ILIF and laminectomy with unilateral pedicle screws (p = 0.11); however, the bilateral screw constructs were more rigid (p < 0.05). Under axial rotation, ILIF was not statistically different from laminectomy with unilateral or bilateral pedicle screws or from the intact spine (p > 0.05). Intervertebral motions adjacent to ILIF were typically lower than those adjacent to laminectomy with bilateral pedicle screws. CONCLUSIONS: Stability of the ILIF construct was not statistically different from bilateral pedicle screw fixation following laminectomy in the flexion and extension and axial rotation directions, while adjacent segment motions were decreased. The ILIF construct may allow surgeons to perform a minimally invasive, single-approach posterior decompression and instrumented fusion without the added morbidity of traditional pedicle screw fixation and posterolateral fusion. PMID- 22519929 TI - Conservative treatment for pediatric lumbar spondylolysis to achieve bone healing using a hard brace: what type and how long?: Clinical article. AB - OBJECT: Various kinds of trunk braces have been used to achieve bone healing in cases of pediatric lumbar spondylolysis. However, the optimal brace for achieving bone healing is unclear. The purpose of the present study was to determine in what types of spondylolysis bone healing can be achieved and how long it takes. METHODS: In this prospective study, 63 pars interarticularis defects (spondylolysis) among 37 patients who were younger than 18 years (mean 13.5 +/- 2.7 years) were treated using a hard brace. The youngest patient was 8 years old. Based on the results of CT scanning, the lyses were classified into 3 categories: early, progressive, and terminal defects. Progressive defects were further divided into 2 types according to STIR MRI findings: those with high signal intensity at the adjacent pedicle and those with low signal intensity (that is, a normal appearance). A hard brace, such as a molded plastic thoracolumbosacral orthosis, was used to immobilize the trunk. Approximately every 3 months, CT scanning was performed to evaluate bone healing until approximately 6 months. RESULTS: The union rates were 94%, 64%, 27%, and 0% for the early, progressive with high signal intensity, progressive with low signal intensity, and terminal defects, respectively. It was noted that no terminal defect was healed using conservative treatment. The mean time to healing among the defects that showed bone healing was 3.2, 5.4, and 5.7 months for the early, progressive with high signal intensity, and progressive with low signal intensity groups, respectively. CONCLUSIONS: Patients with early-stage defects are the best candidates for conservative treatment with a hard brace because more than 90% of such cases can be healed in 3 months. PMID- 22519930 TI - Factors influencing initial choice of insulin therapy in a large international non-interventional study of people with type 2 diabetes. AB - AIM: To use baseline characteristics of the Cardiovascular Risk Evaluation in people with type 2 Diabetes on Insulin Therapy study population to identify factors that could explain the choice of insulin therapy when beginning insulin. METHODS: The source, non-interventional, longitudinal, long-term study involves 314 centres in 12 countries in five regions. People were enrolled having started any insulin regimen in the previous 12 months. To identify factors associated with the choice of insulin regimen, multivariable backward logistic regression was performed on eligible physician and participant explanatory variables. RESULTS: Participants (N = 3031) had mean age 62 years, diabetes duration 11 years, body mass index 29.3 kg/m2 and an HbA1c of 9.5%. Participants in Japan had less hypertension, smoked more and used fewer concomitant medications than those of other regions. Only physician location (rural or urban) influenced the choice of insulin in Japan. In the other four-regions-combined, physician location, specialty, sex and practice type influenced choice of insulin as did participant location, baseline HbA1c, use of glucose-lowering therapies and prior insulin secretagogue use. CONCLUSION: Choice of initial insulin regimen was influenced by several physician and participant characteristics in Canada and Europe, but only by physician location in Japan. PMID- 22519931 TI - Cell transplantation for spinal cord injury focusing on iPSCs. AB - INTRODUCTION: Reports of functional recovery from spinal cord injury (SCI) after the transplantation of neural stem cells (NSCs) derived from fetus/embryonic stem cells (ESCs), has raised great expectations for the successful clinical use of stem cell transplantation therapy. However, the ethical issues involved in destroying human embryos or fertilized oocytes to obtain NSCs have been a major obstacle to developing clinically useful stem cell sources, and the transplantation of stem cells isolated from other human embryonic tissues has not yet been developed for use in clinical applications. AREAS COVERED: Recently, induced pluripotent stem cells (iPSCs), which can serve as a source of cells for autologous transplantation, have been attracting a great deal of attention as a clinically viable alternative to stem cells obtained directly from tissues. In this review, the authors outline the neural induction of ESC/iPSC, their therapeutic efficacy in SCI and their safety in vivo. EXPERT OPINION: Although iPSCs offer great promise as the cell source for autologous transplantation for SCI, safety issues including tumorigenicity should be determined prior to the clinical trial. PMID- 22519932 TI - Characterization of a bilateral penetrating brain injury in rats and evaluation of a collagen biomaterial for potential treatment. AB - Penetrating brain injury (PBI) encountered in both the military and civilian sectors results in high morbidity and mortality due to the absence of effective treatment options for survivors of the initial trauma. Developing therapies for such injuries requires a better understanding of the complex pathology involved when projectiles enter the skull and disrupt the brain parenchyma. This study presents a histological characterization of bilateral PBI using a relatively new injury model in the rat, and also investigates the implantation of a collagen scaffold into the PBI lesion as a potential treatment option. At 1 week post-PBI, the lesion was characterized by dense macrophage infiltration, evolving astrogliosis, hypervascularity, and an absence of viable neurons, oligodendrocytes, and myelinated axons. Histomorphometric analysis revealed that the PBI lesion volume expanded by 29% between 1 week and 5 weeks post-injury, resulting in formation of a large acellular cavity. Immunohistochemistry showed a decrease in the presence of CD68-positive macrophages from 1 to 5 weeks post-PBI as the necrotic tissue in the lesion was cleared, while persistent glial scarring remained in the form of upregulated GFAP expression surrounding the PBI cavity. Implanted type I collagen scaffolds remained intact with open pores after time periods of 1 week and 4 weeks in vivo, and were found to be sparsely infiltrated with macrophages, astrocytes, and endothelial cells. Collagen scaffolds appear to be an appropriate delivery vehicle for cellular and pharmacological therapeutic agents in future studies of PBI. PMID- 22519933 TI - Effect of surface roughness and softness on water capillary adhesion in apolar media. AB - The roughness and softness of interacting surfaces are both important parameters affecting the capillary condensation of water in apolar media, yet are poorly understood at present. We studied the water capillary adhesion between a cellulose surface and a silica colloidal probe in hexane by AFM force measurements. Nanomechanical measurements show that the Young's modulus of the cellulose layer in water is significantly less (~7 MPa) than in hexane (~7 GPa). In addition, the cellulose surface in both water and hexane is rather rough (6-10 nm) and the silica probe has a comparable roughness. The adhesion force between cellulose and silica in water-saturated hexane shows a time-dependent increase up to a waiting time of 200 s and is much (2 orders of magnitude) lower than that expected for a capillary bridge spanning the whole silica probe surface. This suggests the formation of one or more smaller bridges between asperities on both surfaces, which is confirmed by a theoretical analysis. The overall growth rate of the condensate cannot be explained from diffusion mediated capillary condensation alone; thin film flow due to the presence of a wetting layer of water at both the surfaces seems to be the dominant contribution. The logarithmic time dependence of the force can also be explained from the model of the formation of multiple capillary bridges with a distribution of activation times. Finally, the force-distance curves upon retraction show oscillations. Capillary condensation between an atomically smooth mica surface and the silica particle show less significant oscillations and the adhesion force is independent of waiting time. The oscillations in the force-distance curves between cellulose and silica may stem from multiple bridge formation between the asperities present on both surfaces. The softness of the cellulose surface can bring in additional complexities during retraction of the silica particle, also resulting in oscillations in the force-distance curves. PMID- 22519934 TI - Barebacking and sexual health in the French setting: "NoKondom Zone" workshops. AB - Barebacking has been, since its emergence in the 1990s, a very controversial issue, and has as many definitions as authors writing about it. In France, sexual risk reduction strategies have been very contentious, and the advent of the bareback phenomenon increased this conflictual situation. This state of affairs has prevented the identification of needs and development of adequate programs for people not using condoms. In December 2008, a peer sexual health workshop, organized on a monthly basis and taking place over 1 year was launched and facilitated by a group of people who declared not using condoms (n approximate = 15). These workshops were hosted and organized by AIDES, the largest French HIV/AIDS community-based organization. The main objective was to create a safe place for exchanging about sexuality and health concerns. Most of the participants, who were mainly HIV positive, referred to being discriminated against in healthcare settings and in the gay community because of prevention policies and stereotypes about barebacking. This experience was extremely challenging for group members, for the facilitator and for the organisation. Main results show that taking part in the groups allowed participants to break their feelings of isolation, to discuss risk reduction strategies and, in some cases, to improve communication with medical staff. Besides, a political dimension related to implementing this kind of intervention was discussed. Participants declared that, in one way or another, they were more in need of this support than people not taking risks. Further interventions are needed in order to compare and contrast the present results. PMID- 22519935 TI - The reliability of the Health Related Quality Of Life questionnaire PedsQL 3.0 Diabetes ModuleTM for Swedish children with type 1 diabetes. AB - AIM: The overall aim of the study was to assess reliability and accomplish a limited validation of the Pediatric Quality of Life Inventory 3.0 Diabetes Module Scales (PedsQL 3.0), Swedish version in a sample of Swedish children diagnosed with Type 1 diabetes (T1DM). A secondary aim was to assess whether the children's Health Related Quality of Life (HRQOL) was associated with children's gender and age and whether the child self- and parent proxy reports were consistent. METHODS: One hundred and thirty families from four diabetes centres participated in this study. The Pediatric Quality of Life Inventory 4.0 Generic Core Scales (PedsQL 4.0) and the PedsQL 3.0 were administered to 108 children (aged 5-18 years) with T1DM and 130 parents (of children with T1DM aged 2-18 years). RESULTS: The internal consistency of the PedsQL 3.0, Swedish version, reached or exceeded Cronbach's alpha values of 0.70 for both child self- and proxy reports- and parent proxy-reports. The PedsQL 4.0 and PedsQL 3.0 were highly correlated (r = 0.76), indicating convergent validity. The parents reported lower diabetes specific HRQOL than the children themselves (p < 0.01). The girls in the study reported lower psychological functioning and treatment adherence compared with the boys (p < 0.05). The oldest children (between 13 and 18 years of age) reported significantly lower diabetes-specific HRQOL, as compared with younger children (p < 0.05). CONCLUSIONS: PedsQL 3.0 Diabetes Module can be used as a valuable tool for measuring diabetes-specific HRQOL in child populations, both in research and in clinical practice. PMID- 22519937 TI - Commentary: Does a clinical diagnosis of ASD make a difference to outcomes in adolescence? A response to Russell et al. (2012). PMID- 22519936 TI - Paramagnetic Cu(II) for probing membrane protein structure and function: inhibition mechanism of the influenza M2 proton channel. AB - Paramagnetic Cu(II) ions enhance nuclear spin relaxation in a distance-dependent fashion and can be used as a structural probe of proteins. Cu(II) can also serve as a functionally important ligand in proteins. Here we investigate the structural basis of Cu(II) inhibition of the influenza M2 proton channel through Cu(II)-induced paramagnetic relaxation enhancement (PRE). (13)C T(1) relaxation rates of the central residues of the transmembrane (TM) domain of M2 are significantly enhanced by Cu(II), and pronounced spectral broadening is observed for the proton-selective residue, His37. These data yielded quantitative distances of (13)C spins to the Cu(II) center and identified the Cu(II) binding site to be Nepsilon2 of His37. This binding site is surrounded by four imidazole rings from the top and four indole rings of Trp41 from the bottom, thus explaining the high affinity of Cu(II) binding. Bound at this location, Cu(II) can inhibit proton currents by perturbing histidine-water proton exchange, preventing histidine conformational dynamics, and interfering with His-Trp cation pi interaction. The Cu(II) binding site is distinct from the binding site of the hydrophobic drug amantadine, which is about 10 A N-terminal to His37. Consistently, Cu(II) and amantadine induce distinct conformational changes at several key residues, suggesting the possibility of designing new drugs that target the His37 site to inhibit amantadine-resistant mutant M2 proteins. In addition to the high-affinity His37 binding site, we also examined the weaker and nonspecific binding of Cu(II) to membrane-surface lipid phosphates and the extent of the resulting PRE to surface-proximal protein residues. This study demonstrates the feasibility of NMR studies of paramagnetic-ion-complexed membrane proteins, where the ion serves as both a functional ligand and a distance probe. PMID- 22519938 TI - Preoperative metastatic status, level of thrombus and body mass index predict overall survival in patients undergoing nephrectomy and inferior vena cava thrombectomy. AB - Study Type - Prognosis (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Little is known about the prognostic impact of body mass index (BMI) and obesity on patients with locally advanced kidney cancer. Previous studies suggest that clinical/pathological stage, the proximal extent of the tumour thrombus, direct vascular wall invasion, and preoperative performance status may all constitute important prognostic factors within this patient population. The present study shows that a patient's metastatic status, higher level of tumour thrombus, and lower BMI all constitute adverse predictors of overall survival in patients who have RCC with inferior vena cava tumour thrombus. OBJECTIVE: * To determine which clinical variables, including body mass index (BMI), predict overall survival (OS) after nephrectomy with inferior vena cava (IVC) thrombectomy for renal cell carcinoma (RCC) with tumour thrombus. PATIENTS AND METHODS: * After institutional review board approval, a retrospective analysis of all patients (N= 100) undergoing nephrectomy and IVC thrombectomy for RCC from 1989 to 2010 were reviewed. One patient was excluded owing to missing clinical information leaving 99 patients in the study cohort. * Patients were placed into one of two subgroups, based on their preoperative BMI (BMI <=30 kg/m(2) or BMI >30 kg/m(2) ). * Complications, blood loss, level of tumour thrombus, side of tumour and follow-up data were tabulated. RESULTS: * Fifty-six patients had a BMI <=30 kg/m(2) and 43 patients had a BMI >30 kg/m(2) . Intraoperative complications occurred in 14% of those with BMI >30 kg/m(2) and 5.4% of those with a BMI <=30 kg/m(2) (P= 0.171). * On multivariate analysis, a higher thrombus level (III/IV vs I/II) and the presence of metastatic disease at time of diagnosis was associated with a worse OS (P= 0.041 and P < 0.001, respectively). * The subgroup with a higher preoperative BMI had a significantly better OS (hazard ratio 0.42; 95% confidence interval 0.22-0.80, P= 0.009). * Similarly, our Kaplan-Meier survival analysis showed an improved OS in the patient cohort with a BMI >30 kg/m(2) (P= 0.016). CONCLUSION: * Important predictors of outcome in patients undergoing nephrectomy with IVC thrombectomy for RCC with tumour thrombus include preoperative BMI, level of IVC tumour thrombus, and metastatic status at time of surgery. PMID- 22519939 TI - Coagulometer international sensitivity index (ISI) derivation, a rapid method using the prothrombin time/international normalized ratio (PT/INR) Line: a multicenter study. AB - BACKGROUND: The original WHO procedure for prothrombin time (PT) standardization has been almost entirely abandoned because of the universal use of PT coagulometers. These often give different international normalized ratio (INR) results from the manual method, between individual makes of instruments and with instruments from the same manufacture. METHOD: A simple procedure is required to derive local INR with coagulometers. The PT/INR Line method has recently been developed using five European Concerted Action on Anticoagulation (ECAA) certified plasmas to derive local INR. This procedure has been modified to derive a coagulometer PT/INR Line providing International Sensitivity Index (ISI) and mean normal PT (MNPT) for coagulometers and give local INR. Results have been compared with conventional ISI calibrations at the same laboratories. RESULTS: With human thromboplastins, mean ISI by local calibration was 0.93 (range: 0.77 1.16). With the PT/INR Line, mean coagulometer ISI was higher, for example 0.99 (0.84-1.23) but using the PT/INR Line derived MNPT there was no difference in local INR. Between-centre INR variation of a certified validation plasma was reduced with human and bovine reagents after correction with local ISI calibrations and the PT/INR Line. CONCLUSION: The PT/INR Line-ISI with its derived MNPT is shown to provide reliable local INR with the 13 different reagent/coagulometer combinations at the 28 centres in this international study. PMID- 22519941 TI - Prion reduction of red-blood-cells. PMID- 22519940 TI - Sickle cell disease in children. AB - Early identification of infants with sickle cell disease (SCD) by newborn screening, now universal in all 50 states in the US, has improved survival, mainly by preventing overwhelming sepsis with the early use of prophylactic penicillin. Routine transcranial Doppler screening with the institution of chronic transfusion decreases the risk of stroke from 10% to 1% in paediatric SCD patients. Hydroxyurea decreases the number and frequency of painful crises, acute chest syndromes and number of blood transfusions in children with SCD. Genetic research continues to be driven toward the prevention and ultimate cure of SCD before adulthood. This review focuses on clinical manifestations and therapeutic strategies for paediatric SCD as well as the evolving topic of gene-focused prevention and therapy. PMID- 22519942 TI - Emergency capnography monitoring: comparing ergonomic design of intensive care unit ventilator interfaces and specific training of staff in reducing time to activation. AB - Modern ventilators provide capnography monitoring in patients with tracheal tubes, in compliance with national and international recommendations. This technology is often not used when patients' lungs are non-invasively ventilated; however, it should be accessed immediately following tracheal intubation to confirm tube placement. This study assessed the effect of ventilation interface design on the speed with which capnography can be activated by comparing the Drager Evita 4 and Drager V500 before and after a specific training episode. We configured the V500 to have a capnography activation button on the front screen in contrast to the Evita 4 which requires a sequence of actions to access capnography monitoring. We used a randomised crossover design, measuring time to monitoring activation, and repeated the study after 3 months. Survival analysis showed significantly quicker activation associated with ventilator choice (V500, p < 0.0001) and training (p = 0.0058). The training improved activation speed with both machines, though this was only significant for the Evita 4 (p = 0.0097). PMID- 22519943 TI - Cardioversion of intraatrial reentrant tachycardia using rate response. AB - Intraatrial reentrant tachycardia (IART) is the most common long-term, surgical arrhythmia sequela in patients with complex congenital heart disease. The management of IART is challenging. Medications, catheter ablation therapy, and pacemaker therapy have all been utilized as treatment options. Slower tachycardia cycle lengths and 1:1 atrioventricular conduction provide even more challenges with regard to detection and antitachycardia pacing. We describe the use of the rate response feature as a means of patient-initiated cardioversion. PMID- 22519944 TI - One-piece zirconia oral implants: one-year results from a prospective cohort study. 1. Single tooth replacement. AB - AIM: To investigate the clinical and radiographic outcome of a one-piece zirconia oral implant for single tooth replacement after 1 year. MATERIALS AND METHODS: A total of 65 patients received a one-stage implant surgery with immediate temporization. Standardized radiographs were taken at implant insertion and after 1 year to monitor peri-implant bone loss. A univariate analysis of the influence of different baseline parameters on marginal bone loss from implant insertion to 12 months was performed. Soft tissue parameters were evaluated at prosthesis insertion and at the 1-year follow-up. RESULTS: After 1 year, three implants were lost, giving a cumulative survival rate of 95.4%. The marginal bone loss after 1 year was 1.31 mm. Thirty-four per cent of the implants lost at least 2 mm bone, and 14% more than 3 mm. The univariate analysis could not depict any parameter influencing marginal bone loss. Probing depth, Clinical Attachment Level, Bleeding and Plaque Index decreased over 1 year. CONCLUSIONS: The cumulative survival rate of the presented ceramic implant was comparable to the reported survival rate of titanium implants when immediately restored. However, the frequency of increased radiographic bone loss (>2 mm) after 1 year was considerably higher as compared to conventional two-piece titanium implants. The presented zirconia implant can therefore not be recommended for clinical usage. PMID- 22519946 TI - Something's happening here; what it is ain't exactly clear. PMID- 22519945 TI - The influence of stigma on HIV risk behavior among men who have sex with men in Chennai, India. AB - Stigma has been shown to increase vulnerability to HIV acquisition in many settings around the world. However, limited research has been conducted examining its role among men who have sex with men (MSM) in India, whose HIV prevalence is far greater than the general population. In 2009, 210 MSM in Chennai completed an interviewer-administered assessment, including questions about stigma, sexual risk, demographics, and psychosocial variables. More than one fifth of the MSM reported unprotected anal sex (UAS) in the past three months. Logistic regression procedures were used to examine correlates of having experienced stigma. The 11 item stigma scale had high internal consistency reliability (Cronbach's alpha=0.99). Almost 2/5 (39%) reported a high-level of experienced stigma (>=12 mean scale-score) in their lifetime, and the mean stigma scale score was 12 (SD=2.0). Significant correlates of having experienced prior stigma, after adjusting for age and educational attainment, included the following: identifying as a kothi (feminine acting/appearing and predominantly receptive in anal sex) compared to a panthi (masculine appearing, predominantly insertive) (AOR=63.23; 95% CI: 15.92-251.14; p<0.0001); being "out" about one's MSM behavior (AOR=5.63; 95% CI: 1.46-21.73; p=0.01); having clinically significant depressive symptoms (AOR=2.68; 95% CI: 1.40-5.12; p=0.003); and engaging in sex work in the prior three months (AOR=4.89; 95% CI: 2.51-9.51; p<0.0001). These findings underscore the need to address psychosocial issues of Indian MSM. Unless issues such as stigma are addressed, effective HIV prevention interventions for this hidden population remain a challenge. PMID- 22519947 TI - Orally administered heat-killed Lactobacillus gasseri TMC0356 alters respiratory immune responses and intestinal microbiota of diet-induced obese mice. AB - AIMS: To investigate the influence of heat-killed Lactobacillus gasseri TMC0356 on changes in respiratory immune function and intestinal microbiota in a diet induced obese mouse model. METHODS AND RESULTS: Male C57BL/6J mice were fed a high-fat diet for 16 weeks. After 8 weeks, the high-fat-diet-induced obese mice (DIO mice) were randomly divided into two 0067roups, the DIO and DIO0356 groups. DIO0356 group mice were orally fed with heat-killed TMC0356 every day for 8 weeks, while DIO group mice were exposed to 0.85% NaCl over the same time period as controls. After intervention, the pulmonary mRNA expression of cytokines and other immune molecules in DIO0356 mice compared to those in DIO group mice was significantly increased (P < 0.05, P < 0.01). In faecal bacterial profiles, analysed using the terminal restriction fragment length polymorphism (T-RFLP) method, T-RFLP patterns in 75% of the DIO0356 group mice were apparently changed compared with those in control group mice. CONCLUSION: These results suggest that inactive lactobacilli may stimulate the respiratory immune responses of obese host animals to enhance their natural defences against respiratory infection, partially associating with their potent impact on intestinal microbiota. SIGNIFICANCE AND IMPACT OF THE STUDY: We have demonstrated that oral administration of inactive lactobacilli may protect host animals from the lung immune dysfunction caused by obesity. PMID- 22519948 TI - A prospective evaluation of the role of transient elastography for the detection of hepatic fibrosis in type 2 diabetes without overt liver disease. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is a major risk factor for the development of non-alcoholic fatty liver disease (NAFLD) and subsequently hepatic fibrosis. Transient elastography (TE) is a rapid, reproducible non-invasive test that may be appropriate as a screening tool for the presence of hepatic fibrosis. AIM: Assess the utility of TE as a screening tool for the presence of hepatic fibrosis in a T2DM population with no known liver disease. METHODS: T2DM patients without known liver disease were included. Patients were assessed with TE in addition to biochemical parameters. RESULTS: A successful TE evaluation could be obtained in 74 of 81 (91%) included subjects. Of these, 26 (35%) had a liver stiffness measurement (LSM) >= 7.65 kPa. Sixteen of these subjects had confirmatory liver biopsies with significant (>= F2 fibrosis) present in 12 (75%) and cirrhosis diagnosed in 2 subjects. 15/16 (94%) had histological steatohepatitis. Compared with those with a lower LSM, subjects with an LSM >= 7.65 kPa had higher ALT levels (38.0 +/- 21.7 vs 26.1 +/- 11.1 U/L, p = 0.021) and increased prevalence of hepatic steatosis by ultrasound (85% vs 63%, p = 0.005). CONCLUSION: Significant hepatic fibrosis in the T2DM population is frequently under-recognized. TE may be a feasible tool for the screening of T2DM patients for the presence of hepatic fibrosis. PMID- 22519949 TI - Antidiabetic and antihypertensive effect of a polyphenol-rich fraction of Thymelaea hirsuta L. in a model of neonatal streptozotocin-diabetic and N(G) nitro-l-arginine methyl ester-hypertensive rats. AB - BACKGROUND: The present study examined the effect of the polyphenol-rich fraction from Thymelaea hirsuta (PRF-Th) in a rat model of streptozotocin (STZ) diabetes and nitric oxide (NO)-deficient hypertension. METHODS: Diabetes was induced by a single dose of STZ (90 mg/kg, i.p.). To induce NO-deficient hypertension, rats were treated with the NO synthase inhibitor N(G) -nitro-l arginine methyl ester; l-NAME; 30 mg/kg per day, p.o. for 3 weeks. The effects of 21 days treatment with 80 mg/kg per day PRF-Th in the drinking water were evaluated in diabetic-hypertensive (DH) rats. In all groups (n = 6 in each), glycemia and systolic blood pressure were determined weekly. At the end of the experiment, hepatic glycogen was determined. RESULTS: Blood glucose levels decreased gradually from baseline until the end of the experiment in untreated DH rats (from 1.92 +/- 0.09 to 1.3 +/- 0.1 g/L; P < 0.05). Administration of PRF-Th concomitantly with l-NAME prevented the blood pressure increase in rats. After 21 days, blood pressure in PRF-Th + l-NAME- and l-NAME-treated rats was 132 +/- 1 and 157 +/- 1 mmHg, respectively (P < 0.001). Administration of 2 mL/kg per day PRF-Th to DH rats significantly increased hepatic glycogen levels compared with levels in untreated DH rats (13.65 +/- 1.84 vs 6.34 +/- 0.75 mg/g tissue, respectively; P < 0.01). Moreover, PRF-Th significantly reduced the amount of glucose absorbed in in situ perfused jejunum segments compared with control (by 33.6%; P <0.001). This effect of PRF-Th was comparable with that of acarbose, an alpha-glucosidase inhibitor. CONCLUSIONS: The findings of the present study indicate that T. hirsuta has antidiabetic and antihypertensive activity in STZ diabetic, NO-deficient hypertensive rats. This effect seems to be due to its rich polyphenol content. Therefore, T. hirsuta may be useful as a food supplement for the prevention of type 2 diabetes and hypertension. PMID- 22519951 TI - One-year evolution of ulnar somatosensory potentials after trauma in 365 tetraplegic patients: early prediction of potential upper limb function. AB - Early prediction of hand function is crucial for efficient rehabilitation of cervical spinal cord injury (cSCI). This study investigated correlations between ulnar somatosensory evoked potentials (ulnar SSEPs) and functional outcome of hand function following acute traumatic cervical cord injury. Neurological assessment of sensory scores and hand function were compared with five ulnar SSEP categories of similar persistence and quality in 365 patients throughout the first year after cSCI. Of the 365 patients, 218 (68%) exhibited ulnar SSEP potentials at any one stage during the year, and in 147 patients (40.3%) ulnar SSEPs were obtainable at every assessment stage. While ulnar SSEP latency and amplitude assessments remained largely unchanged over time in the majority of patients, hand function improved remarkably during the first year following cSCI. One year outcome of hand function was predetermined by ulnar SSEP category due to distinct differences in the ulnar SSEP parameters. Additionally, an early prognostic group allocation by ulnar SSEP criteria at the first assessment stage within 4 weeks after spinal trauma allowed reliable prediction of hand function outcome after 1 year. We conclude that early assessment of ulnar SSEP as a non invasive and objective neurophysiological test is a valuable marker of prospective hand function and independence 1 year after cSCI. This could be most relevant for planning neurorehabilitation, and in prospective clinical SCI trials. PMID- 22519950 TI - Evaluation of a moisturising micro-gel spray for prevention of cell dryness in oral mucosal cells: an in vitro study and evaluation in a clinical setting. AB - A moisturising micro-gel spray for prevention of dryness was compared with commercial products and artificial saliva in vitro and in a clinical setting in patients with cancer. Survival of cultured human gingival epithelial cells was evaluated after treatment with each product for 15 min. A dry test was performed for products giving a 50% survival rate, in which cell survival was measured after drying of cells treated with each product. The survival rates of cells treated with the micro-gel spray and artificial saliva were significantly higher than those of control cells. The micro-gel spray was then evaluated for 1 week in patients with symptoms of dry mouth caused by cancer treatment. There was significant improvement of these symptoms at night and on awakening and of subjective symptoms of decreased salivary volume (P < 0.05). Mean visual analogue scale scores also significantly decreased (P < 0.01). These data suggest that evaluation of moisturising products for dryness prevention can be performed in cultured cells, since products that performed well in vitro also showed good efficacy for symptoms of dry mouth. The micro-gel spray was particularly effective for relieving symptoms of dry mouth in patients with cancer. PMID- 22519953 TI - Molecular modeling of fluoropropene refrigerants. AB - Different fluoropropenes are currently considered as refrigerants, either as pure compounds or as components in low GWP (global warming potential) refrigerant mixtures. Due to their limited commercial production, experimental data for the thermophysical properties of fluoropropenes and their mixtures are in general rare, which hampers the exploration of their performance in technical applications. In principle, molecular simulation can be used to predict the relevant properties of refrigerants and refrigerant blends, provided that adequate intermolecular potential functions ("force fields") are available. In our earlier work (Raabe, G.; Maginn, E. J., J. Phys. Chem. B2010, 114, 10133 10142), we introduced a transferable force field for fluoropropenes comprising the compounds 3,3,3-trifluoro-1-propene (HFO-1243zf), 2,3,3,3-tetrafluoro-1 propene (HFO-1234yf), and hexafluoro-1-propene (HFO-1216). In this paper, we provide an extension of the force field model to the trans- and cis-1,3,3,3 tetrafluoro-1-propene (HFO-1234ze(E), HFO-1234ze) and the cis-1,2,3,3,3 pentafluoro-1-propene (HFO-1225ye(Z)) as well as revised simulation results for HFO-1216. We present Gibbs ensemble simulation results on the vapor pressures, saturated densities, and heats of vaporization of these compounds in comparison with experimental results. The simulation results show that the force field model enables reliable predictions of the properties of the different fluoropropenes and also reproduces well the differing vapor-liquid coexistence and vapor pressure curve of the cis- and trans-isomers of 1,3,3,3-tetrafluoro-1-propene, HFO-1234ze and HFO-1234ze(E). For these two isomers, we also present molecular dynamics simulation studies on their local structure. PMID- 22519952 TI - Distal arthrogryposis: clinical and genetic findings. AB - AIM: Distal arthrogryposis is characterized by congenital contractures predominantly in hands and feet. Mutations in sarcomeric protein genes are involved in several types of distal arthrogryposis. Our aim is to describe clinical and molecular genetic findings in individuals with distal arthrogryposis and evaluate the genotype-phenotype correlation. METHOD: We investigated 39 patients from 21 families. Clinical history, including neonatal findings, joint involvement and motor function, was documented. Clinical examination was performed including evaluation of muscle strength. Molecular genetic investigations were carried out in 19 index cases. Muscle biopsies from 17 patients were analysed. RESULTS: A pathogenic mutation was found in six families with 19 affected family members with autosomal dominant inheritance and in one child with sporadic occurrence. In three families and in one child with sporadic form, the identified mutation was de novo. Muscle weakness was found in 17 patients. Ambulation was affected in four patients and hand function in 28. Fourteen patients reported pain related to muscle and joint affection. CONCLUSION: The clinical findings were highly variable between families and also within families. Mutations in the same gene were found in different syndromes suggesting varying clinical penetrance and expression, and different gene mutations were found in the same clinical syndrome demonstrating genetic heterogeneity. PMID- 22519954 TI - Printable optical sensors based on H-bonded supramolecular cholesteric liquid crystal networks. AB - A printable H-bonded cholesteric liquid crystal (CLC) polymer film has been fabricated that, after conversion to a hygroscopic polymer salt film, responds to temperature and humidity by changing its reflection color. Fast-responding humidity sensors have been made in which the reflection color changes between green and yellow depending on the relative humidity. The change in reflection band is a result of a change in helix pitch in the film due to absorption and desorption of water, resulting in swelling/deswelling of the film material. When the polymer salt was saturated with water, a red-reflecting film was obtained that can potentially act as a time/temperature integrator. Finally, the films were printed on a foil, showing the potential application of supramolecular CLC materials as low-cost, printable, battery-free optical sensors. PMID- 22519955 TI - Circulating nucleic acids and Darwin's gemmules. PMID- 22519956 TI - Protein Ser/Thr phosphatases--the ugly ducklings of cell signalling. AB - This review traces the historical origins and conceptual developments leading to the current state of knowledge of the three superfamilies of protein Ser/Thr phosphatases. 'PR enzyme' was identified as an enzyme that inactivates glycogen phosphorylase, although it took 10 years before this ugly duckling was recognized for its true identity as a protein Ser/Thr phosphatase. Ethanol denaturation for purification in the 1970s yielded a phosphatase that exhibited broad specificity, which was resolved into type-1 and type-2 phosphatases in the 1980s. More recent developments show that regulation and specificity are achieved through assembly of multisubunit holoenzymes, transient phosphorylation and the action of inhibitor proteins. Still not widely appreciated, there are hundreds of discrete protein Ser/Thr phosphatases available to counteract protein kinases, offering potential therapeutic targets. Signalling networks and modelling schemes need to incorporate the full gamut of protein Ser/Thr phosphatases and their interconnections. PMID- 22519957 TI - Effect of topical anesthesia on evaluation of corneal sensitivity and intraocular pressure in rats and dogs. AB - OBJECTIVE: To determine the effect of 0.5% proparacaine in tonometry by evaluating corneal touch threshold (CTT) and intraocular pressure (IOP). ANIMAL STUDIED: Nine rats (18 eyes, Sprague-Dawley) and 10 dogs (20 eyes, Beagle) PROCEDURES: The IOP and CTT were measured in each eye before and after topical anesthesia with 0.5% proparacaine. The IOP was evaluated using Tonopen for dogs and Tonolab for rats. The corneal sensitivity was evaluated by CTT through a Cochet-Bonnet aesthesiometer. RESULTS: The mean IOP was not significantly changed in rats or dogs before and after topical anesthesia. However, after application of proparacaine, CTT was significantly increased in both animal groups compared with that before application of proparacaine. CONCLUSION: From this study, topical anesthesia was found to significantly lower the corneal sensitivity but have little effect on IOP measurements. In ophthalmologic examination, topical anesthesia can be used to reduce corneal sensation without an effect on IOP. PMID- 22519959 TI - C-reactive protein as a prognostic marker FOR mCRPC. PMID- 22519958 TI - Programme level implementation of malaria rapid diagnostic tests (RDTs) use: outcomes and cost of training health workers at lower level health care facilities in Uganda. AB - BACKGROUND: The training of health workers in the use of malaria rapid diagnostic tests (RDTs) is an important component of a wider strategy to improve parasite based malaria diagnosis at lower level health care facilities (LLHFs) where microscopy is not readily available for all patients with suspected malaria. This study describes the process and cost of training to attain competence of lower level health workers to perform malaria RDTs in a public health system setting in eastern Uganda. METHODS: Health workers from 21 health facilities in Uganda were given a one-day central training on the use of RDTs in malaria case management, including practical skills on how to perform read and interpret the test results. Successful trainees subsequently integrated the use of RDTs into their routine care for febrile patients at their LLHFs and transferred their acquired skills to colleagues (cascade training model). A cross-sectional evaluation of the health workers' competence in performing RDTs was conducted six weeks following the training, incorporating observation, in-depth interviews with health workers and the review of health facility records relating to tests offered and antimalarial drug (AMD) prescriptions pre and post training. The direct costs relating to the training processes were also documented. RESULTS: Overall, 135 health workers were trained including 63 (47%) nursing assistants, a group of care providers without formal medical training. All trainees passed the post-training concordance test with >= 80% except 12 that required re-training. Six weeks after the one-day training, 51/64 (80%) of the health workers accurately performed the critical steps in performing the RDT. The performance was similar among the 10 (16%) participants who were peer-trained by their trained colleagues. Only 9 (14%) did not draw the appropriate amount of blood using pipette. The average cost of the one-day training was US$ 101 (range $92-$112), with the main cost drivers being trainee travel and per-diems. Health workers offered RDTs to 76% of febrile patients and AMD prescriptions reduced by 37% six weeks post-training. CONCLUSION: One-day training on the use of RDTs successfully provided adequate skill and competency among health workers to perform RDTs in fever case management at LLHF in a Uganda setting. The cost averaged at US$101 per health worker trained, with the main cost drivers being trainee travel and per diems. Given the good peer training noted in this study, there is need to explore the cost-effectiveness of a cascade training model for large scale implementation of RDTs. PMID- 22519961 TI - Fibrinogen levels during trauma hemorrhage, response to replacement therapy, and association with patient outcomes. AB - BACKGROUND: Low fibrinogen levels are known to occur in trauma. However, the extent of fibrinogen depletion during trauma hemorrhage, the response to replacement therapy and association with patient outcomes remain unclear. OBJECTIVES: The study aims were to: characterize admission fibrinogen level and correlate it with factors associated with injury; describe the time course of fibrinogen depletion and response to replacement therapy; determine the correlation of fibrinogen level with rotational thromboelastography (ROTEM) parameters; evaluate the effect of fibrinogen supplementation ex vivo; and establish the association between fibrinogen level and clinical outcomes. METHODS: This was a prospective cohort study of 517 patients. Blood samples were drawn on admission and after admistration of every 4 units of packed red blood cells. Fibrinogen levels were determined with the Clauss method, and global hemostatic competence was assessed with thromboelastometry. The effect of fibrinogen supplementation was assessed in a subgroup of coagulopathic patients. RESULTS: Low admission fibrinogen level was independently associated with injury severity score (P < 0.01), shock (P < 0.001), and prehospital fluid volume (P < 0.001). Fibrinogen supplementation during transfusion maintained but did not augment fibrinogen levels. Administration of cryoprecipitate was associated with improved survival. ROTEM parameters correlated with fibrinogen level, and ex vivo fibrinogen administration reversed coagulopathic ROTEM parameters. Fibrinogen level was an independent predictor of mortality at 24 h and 28 days (P < 0.001). CONCLUSIONS: Fibrinogen level is decreased in injured patients on admission and is associated with poor outcomes. ROTEM is a rapid means of assessing hypofibrinogenemia. Earlier administration of specific fibrinogen replacement may improve outcomes, and prospective controlled trials are urgently needed. PMID- 22519960 TI - BB0324 and BB0028 are constituents of the Borrelia burgdorferi beta-barrel assembly machine (BAM) complex. AB - BACKGROUND: Similar to Gram-negative bacteria, the outer membrane (OM) of the pathogenic spirochete, Borrelia burgdorferi, contains integral OM-spanning proteins (OMPs), as well as membrane-anchored lipoproteins. Although the mechanism of OMP biogenesis is still not well-understood, recent studies have indicated that a heterooligomeric OM protein complex, known as BAM (beta-barrel assembly machine) is required for proper assembly of OMPs into the bacterial OM. We previously identified and characterized the essential beta-barrel OMP component of this complex in B. burgdorferi, which we determined to be a functional BamA ortholog. RESULTS: In the current study, we report on the identification of two additional protein components of the B. burgdorferi BAM complex, which were identified as putative lipoproteins encoded by ORFs BB0324 and BB0028. Biochemical assays with a BamA-depleted B. burgdorferi strain indicate that BB0324 and BB0028 do not readily interact with the BAM complex without the presence of BamA, suggesting that the individual B. burgdorferi BAM components may associate only when forming a functional BAM complex. Cellular localization assays indicate that BB0324 and BB0028 are OM-associated subsurface lipoproteins, and in silico analyses indicate that BB0324 is a putative BamD ortholog. CONCLUSIONS: The combined data suggest that the BAM complex of B. burgdorferi contains unique protein constituents which differ from those found in other proteobacterial BAM complexes. The novel findings now allow for the B. burgdorferi BAM complex to be further studied as a model system to better our understanding of spirochetal OM biogenesis in general. PMID- 22519962 TI - Proteomic profiling of the rat hypothalamus. AB - BACKGROUND: The hypothalamus plays a pivotal role in numerous mechanisms highly relevant to the maintenance of body homeostasis, such as the control of food intake and energy expenditure. Impairment of these mechanisms has been associated with the metabolic disturbances involved in the pathogenesis of obesity. Since rodent species constitute important models for metabolism studies and the rat hypothalamus is poorly characterized by proteomic strategies, we performed experiments aimed at constructing a two-dimensional gel electrophoresis (2-DE) profile of rat hypothalamus proteins. RESULTS: As a first step, we established the best conditions for tissue collection and protein extraction, quantification and separation. The extraction buffer composition selected for proteome characterization of rat hypothalamus was urea 7 M, thiourea 2 M, CHAPS 4%, Triton X-100 0.5%, followed by a precipitation step with chloroform/methanol. Two dimensional (2-D) gels of hypothalamic extracts from four-month-old rats were analyzed; the protein spots were digested and identified by using tandem mass spectrometry and database query using the protein search engine MASCOT. Eighty six hypothalamic proteins were identified, the majority of which were classified as participating in metabolic processes, consistent with the finding of a large number of proteins with catalytic activity. Genes encoding proteins identified in this study have been related to obesity development. CONCLUSION: The present results indicate that the 2-DE technique will be useful for nutritional studies focusing on hypothalamic proteins. The data presented herein will serve as a reference database for studies testing the effects of dietary manipulations on hypothalamic proteome. We trust that these experiments will lead to important knowledge on protein targets of nutritional variables potentially able to affect the complex central nervous system control of energy homeostasis. PMID- 22519963 TI - Discovery of a potent and selective GPR120 agonist. AB - GPR120 is a receptor of unsaturated long-chain fatty acids reported to mediate GLP-1 secretion, insulin sensitization, anti-inflammatory, and anti-obesity effects and is therefore emerging as a new potential target for treatment of type 2 diabetes and metabolic diseases. Further investigation is however hindered by the lack of suitable receptor modulators. Screening of FFA1 ligands provided a lead with moderate activity on GPR120 and moderate selectivity over FFA1. Optimization led to the discovery of the first potent and selective GPR120 agonist. PMID- 22519964 TI - Is there a link between diabetic glomerular injury and crescent formation? A case report and literature review. AB - Glomerular crescents are most commonly associated with rapidly progressive crescentic glomerulonephritis; however, they also develop in response to a wide range of primary and secondary glomerular injuries. Since various kind of glomerulopathies occasionally overlay diabetic glomerular injuries, the presence of crescents in renal biopsy specimens of diabetics may have stimulated a search for etiologies other than diabetes. In this report, we describe an unusual case of diabetic glomerulosclerosis with peculiar extracapillary proliferation. Although such a relationship has so far been ignored in most of the literature, the etiological linkage between diabetic glomerulosclerosis and the development of crescents may not be exceptional. We have reviewed the previous literature and herein discuss the pathological implications of the development of crescents in patients with diabetic glomerulosclerosis. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3950457896920255. PMID- 22519965 TI - A partitioning deletion/substitution/addition algorithm for creating survival risk groups. AB - Accurately assessing a patient's risk of a given event is essential in making informed treatment decisions. One approach is to stratify patients into two or more distinct risk groups with respect to a specific outcome using both clinical and demographic variables. Outcomes may be categorical or continuous in nature; important examples in cancer studies might include level of toxicity or time to recurrence. Recursive partitioning methods are ideal for building such risk groups. Two such methods are Classification and Regression Trees (CART) and a more recent competitor known as the partitioning Deletion/Substitution/Addition (partDSA) algorithm, both of which also utilize loss functions (e.g., squared error for a continuous outcome) as the basis for building, selecting, and assessing predictors but differ in the manner by which regression trees are constructed. Recently, we have shown that partDSA often outperforms CART in so called "full data" settings (e.g., uncensored outcomes). However, when confronted with censored outcome data, the loss functions used by both procedures must be modified. There have been several attempts to adapt CART for right-censored data. This article describes two such extensions for partDSA that make use of observed data loss functions constructed using inverse probability of censoring weights. Such loss functions are consistent estimates of their uncensored counterparts provided that the corresponding censoring model is correctly specified. The relative performance of these new methods is evaluated via simulation studies and illustrated through an analysis of clinical trial data on brain cancer patients. The implementation of partDSA for uncensored and right-censored outcomes is publicly available in the R package, partDSA. PMID- 22519967 TI - Intrinsic terahertz plasmons and magnetoplasmons in large scale monolayer graphene. AB - We show that in graphene epitaxially grown on SiC the Drude absorption is transformed into a strong terahertz plasmonic peak due to natural nanoscale inhomogeneities, such as substrate terraces and wrinkles. The excitation of the plasmon modifies dramatically the magneto-optical response and in particular the Faraday rotation. This makes graphene a unique playground for plasmon-controlled magneto-optical phenomena thanks to a cyclotron mass 2 orders of magnitude smaller than in conventional plasmonic materials such as noble metals. PMID- 22519966 TI - Asthma treatment outcome in children is associated with vascular endothelial growth factor A (VEGFA) polymorphisms. AB - BACKGROUND: Asthma is a common chronic disease characterized by airway inflammation and structural remodeling. Vascular endothelial growth factor (VEGF), a major regulator of angiogenesis, is elevated in asthma patients. VEGF contributes to airway responsiveness and remodeling. It has been shown that treatment of asthma patients decreases VEGF levels, and inhibition of VEGF diminishes asthma symptoms in mice. Therefore, polymorphisms in the vascular endothelial growth factor A (VEGFA) gene might be associated with asthma treatment response. METHODS: This study enrolled 131 children with asthma treated with different therapies - specifically, the inhaled corticosteroid (ICS) fluticasone propionate or the leukotriene receptor antagonist (LTRA) montelukast. We performed an association analysis between improvement of lung function - assessed by measurement of the percentage of the predicted forced expiratory volume in 1 second (%predicted FEV(1)), the ratio between the FEV(1) and the forced vital capacity (FEV(1)/FVC) after 6 and 12 months of treatment, and asthma control after 12 months of treatment - and two polymorphisms, rs2146323 and rs833058, in the VEGFA gene. RESULTS: Polymorphism rs2146323 A>C in VEGFA was associated with response to ICS therapy. Asthma patients with the AA genotype had a greater improvement in the %predicted FEV(1) than those with the AC or CC genotype (p = 0.018). Conversely, the AA genotype in rs2146323 was associated with uncontrolled asthma in patients regularly receiving LTRA therapy (p = 0.020) and a worse FEV(1)/FVC ratio in patients who episodically used LTRA therapy (p = 0.044). Furthermore, polymorphism rs833058 C>T was associated with treatment response to episodically used LTRA therapy. A subgroup of patients with the TT genotype had an improvement in the %predicted FEV(1), compared with no improvement in patients with the CT or CC genotype (p = 0.029). CONCLUSIONS: Our results showed that treatment response to commonly used asthma therapies (ICS or LTRA) is associated with polymorphisms rs2146323 and rs833058 in VEGFA. With additional replication of this preliminary study, our findings could contribute to the development of individualized asthma therapy. PMID- 22519968 TI - Quorum sensing activity in Ophiostoma ulmi: effects of fusel oils and branched chain amino acids on yeast-mycelial dimorphism. AB - AIMS: For Ophiostoma (Ceratocystis) ulmi, the ability to undergo morphological change is a crucial factor for its virulence. To gain an understanding of quorum sensing activity in O. ulmi as it relates to yeast-mycelium dimorphism control, this study examines the effects of branched-chain amino acids as well as their fusel alcohols and fusel acids as quorum sensing molecules. METHODS AND RESULTS: In a defined medium containing glucose, proline and salts, O. ulmi grew as yeasts when the culture was inoculated with a high density of spores (2 * 10(7) CFU ml(-1) ) and as mycelia when inoculated with a low spore density (4 * 10(5) CFU ml(-1) ). The cultures displaying yeast morphology secreted a quorum-sensing factor that shifted the morphology from mycelia to yeast. This quorum-sensing molecule was lipophilic and extractable by organic solvents from the spent medium. Using GC/MS analysis, it was determined that the major compound in the extract was 2-methyl-1-butanol. A similar effect was observed when the branched chain amino acids (fusel alcohol precursors) were used as the nitrogen source. E, E-farnesol had no effect on the morphology of O. ulmi. CONCLUSIONS: Addition of the branched-chain amino acids or one of the compounds detected in the spent medium, 2-methyl-1-butanol or 4-hydroxyphenylacetic acid, or methylvaleric acid, decreased germ tube formation by more than 50%, thus demonstrating a quorum sensing molecule behaviour in O. ulmi cultures. SIGNIFICANCE AND IMPACT OF THE STUDY: This study presents advances in the investigation of dimorphism in O. ulmi, complementing the existing scientific basis, for studying, understanding and controlling this phenomenon. PMID- 22519969 TI - Preliminary evidence for the dedifferentiation of RAW 264.7 cells into mesenchymal progenitor-like cells by a purine analog. AB - Dedifferentiation of cells to multipotential cells is of interest since they have a potential regenerative capacity. Our purpose was to de- and redifferentiate murine RAW 264.7 cells, a committed macrophage cell line of hematopoietic origin, into mesenchymal-like cells such as osteoblasts. RAW 264.7 cells in culture were treated with 5 MUM reversine, a purine analog that was shown to dedifferentiate myoblasts in osteoblasts. Treatment with reversine resulted in a significant increase in the expression of the STRO-1 antigen, a marker of mesenchymal stem/progenitor cells: from 0.6%+/-0.5% cells in untreated RAW cells to 19.0%+/ 8.6% in treated cells, but there was no increase in the expression of SH-2 (CD105), an earlier marker of mesenchymal stem cells. The effects of reversine were significantly curtailed by 67% when cultures were pretreated with the c-Jun N-terminal kinase pathway blocker SP600125. These STRO-1+ cells retained a multipotential status and were capable of redifferentiating into cells with osteogenic and lipogenic characteristics under inductive conditions. We showed that STRO-1+ cells in an osteogenic medium significantly increased expression of the osteoblast marker osteocalcin, and formed mineralized nodules. When seeded on a demineralized scaffold of human bone in vitro, these cells deposited a calcium matrix. Under adipogenic conditions, expression of the adipocyte marker peroxisome proliferator-activated receptor gamma 2 on STRO-1+ cells was elevated, and cultures stained positive with Oil red O. Our results demonstrated that treating a committed hematopoietic cell line with a purine analog can alter cell development and result in cellular reverse transformation into stage-limited multipotential cells. These cells could subsequently be redifferentiated into cells with characteristics of the mesenchymal lineage, such as those of an osteoblast and/or adipocyte, under inductive conditions. PMID- 22519970 TI - Bismuth nitrate-induced microwave-assisted expeditious synthesis of vanillin from curcumin. AB - BACKGROUND: Curcumin and vanillin are the two useful compounds in food and medicine. Bismuth nitrate pentahydrate is an economical and ecofriendly reagent. METHOD: Bismuth nitrate pentahydrate impregnated montmorillonite KSF clay and curcumin were subjected to microwave irradiation. RESULTS: Microwave-induced bismuth nitrate-promoted synthesis of vanillin from curcumin has been accomplished in good yield under solvent-free condition. Twenty-five different reaction conditions have been studied to optimize the process. CONCLUSION: The present procedure for the synthesis of vanillin may find useful application in the area of industrial process development. PMID- 22519971 TI - Nucleobases and prebiotic molecules in organic residues produced from the ultraviolet photo-irradiation of pyrimidine in NH(3) and H(2)O+NH(3) ices. AB - Although not yet identified in the interstellar medium (ISM), N-heterocycles including nucleobases-the information subunits of DNA and RNA-are present in carbonaceous chondrites, which indicates that molecules of biological interest can be formed in non-terrestrial environments via abiotic pathways. Recent laboratory experiments and ab initio calculations have already shown that the irradiation of pyrimidine in pure H(2)O ices leads to the formation of a suite of oxidized pyrimidine derivatives, including the nucleobase uracil. In the present work, NH(3):pyrimidine and H(2)O:NH(3):pyrimidine ice mixtures with different relative proportions were irradiated with UV photons under astrophysically relevant conditions. Liquid- and gas-chromatography analysis of the resulting organic residues has led to the detection of the nucleobases uracil and cytosine, as well as other species of prebiotic interest such as urea and small amino acids. The presence of these molecules in organic residues formed under abiotic conditions supports scenarios in which extraterrestrial organics that formed in space and were subsequently delivered to telluric planets via comets and meteorites could have contributed to the inventory of molecules that triggered the first biological reactions on their surfaces. PMID- 22519972 TI - Nitrogen incorporation in CH(4)-N(2) photochemical aerosol produced by far ultraviolet irradiation. AB - Nitrile incorporation into Titan aerosol accompanying hydrocarbon chemistry is thought to be driven by extreme UV wavelengths (lambda<120 nm) or magnetospheric electrons in the outer reaches of the atmosphere. Far UV radiation (120-200 nm), which is transmitted down to the stratosphere of Titan, is expected to affect hydrocarbon chemistry only and not initiate the formation of nitrogenated species. We examined the chemical properties of photochemical aerosol produced at far UV wavelengths, using a high-resolution time-of-flight aerosol mass spectrometer (HR-ToF-AMS), which allows for elemental analysis of particle-phase products. Our results show that aerosol formed from CH(4)/N(2) photochemistry contains a surprising amount of nitrogen, up to 16% by mass, a result of photolysis in the far UV. The proportion of nitrogenated organics to hydrocarbon species is shown to be correlated with that of N(2) in the irradiated gas. The aerosol mass greatly decreases when N(2) is removed, which indicates that N(2) plays a major role in aerosol production. Because direct dissociation of N(2) is highly improbable given the immeasurably low cross section at the wavelengths studied, the chemical activation of N(2) must occur via another pathway. Any chemical activation of N(2) at wavelengths >120 nm is presently unaccounted for in atmospheric photochemical models. We suggest that reaction with CH radicals produced from CH(4) photolysis may provide a mechanism for incorporating N into the molecular structure of the aerosol. Further work is needed to understand the chemistry involved, as these processes may have significant implications for how we view prebiotic chemistry on early Earth and similar planets. PMID- 22519973 TI - Microbially induced iron precipitation associated with a neutrophilic spring at Borra Caves, Vishakhapatnam, India. AB - The present investigation uncovers various pieces of evidence for the possible biologically induced mineralization in iron mats associated with a pH-neutral spring in the Borra caves, Vishakhapatnam, India. Electron microscopy [scanning electron microscopy (SEM) and transmission electron microscopy (TEM)] demonstrated large numbers of (i) hollow tubes (diameter ~1 MUm) resembling sheaths of the iron-oxidizing bacteria Leptothrix, (ii) thin (diameter <<1 MUm) solid fibers of uncertain origin, (iii) nanoscale subspherical to irregularly shaped particles encrusting tubes and fibers, and (iv) aggregates of broken and partially disintegrated sheaths, fibers, and particles embedded in extracellular polymeric substances (EPS) occasionally including microbial cells. X-ray microanalyses by energy dispersive spectroscopy (EDS) revealed that the mat accumulated largely Fe but also smaller amounts of Si and traces of P and Ca. Particles rich in Si and Al (possibly kaolinite) and Ca (carbonate) were also observed. High-resolution TEM/EDS of unstained ultrathin sections suggests that microbial sheaths were highly mineralized by amorphous to cryptocrystalline Fe rich phases and less frequently by other fine-grained and fibrous authigenic claylike minerals. Total number of microorganisms in the iron mats was 5.8*10(5) cells, g sed(-1) (wet weight). Analysis of the 16S rRNA gene diversity revealed microorganisms assigned to eight different phyla [Proteobacteria (62%), Chloroflexi (8%), Bacteroidetes (7%), Planctomycetes (1%), Actinobacteria (5%), Acidobacteria (6%), Nitrospira (1%), Firmicutes (5%)]. Within the Proteobacteria, Betaproteobacteria was the predominant class, which accounted for 28% of the sequences. Within this class some obvious similarities between the obtained sequences and sequences from other cave systems could be seen, especially sequences affiliated with Leptothrix, Siderooxidans, Crenothrix, Comamonadaceae, Dechloromonas, and many uncultured Betaproteobacteria. Four (4%) of the sequences could not be assigned to phylum level but were affiliating with the candidate division TM7 (2%), candidate division OP11 (1%), and candidate division WWE3 (1%). The results allow us to infer a possible relationship of microbial sheaths, EPS, and the iron precipitates to microbial community diversity in the Borra cave springs. Understanding biogenic iron oxides in caves has important astrobiological applications as it provides a potential tool for the detection of extraterrestrial life. PMID- 22519974 TI - Life at the wedge: the activity and diversity of arctic ice wedge microbial communities. AB - The discovery of polygonal terrain on Mars underlain by ice heightens interest in the possibility that this water-bearing habitat may be, or may have been, a suitable habitat for extant life. The possibility is supported by the recurring detection of terrestrial microorganisms in subsurface ice environments, such as ice wedges found beneath tundra polygon features. A characterization of the microbial community of ice wedges from the high Arctic was performed to determine whether this ice environment can sustain actively respiring microorganisms and to assess the ecology of this extreme niche. We found that ice wedge samples contained a relatively abundant number of culturable cells compared to other ice habitats (~10(5) CFU.mL(-1)). Respiration assays in which radio-labeled acetate and in situ measurement of CO(2) flux were used suggested low levels of microbial activity, though more sensitive techniques are required to confirm these findings. Based on 16S rRNA gene pyrosequencing, bacterial and archaeal ice wedge communities appeared to reflect surrounding soil communities. Two Pseudomonas sp. were the most abundant taxa in the ice wedge bacterial library (~50%), while taxa related to ammonia-oxidizing Thaumarchaeota occupied 90% of the archaeal library. The tolerance of a variety of isolates to salinity and temperature revealed characteristics of a psychrotolerant, halotolerant community. Our findings support the hypothesis that ice wedges are capable of sustaining a diverse, plausibly active microbial community. As such, ice wedges, compared to other forms of less habitable ground ice, could serve as a reservoir for life on permanently cold, water-scarce, ice-rich extraterrestrial bodies and are therefore of interest to astrobiologists and ecologists alike. . PMID- 22519975 TI - Reflections on astrobiology, exobiology, bioastronomy, and cosmobiology. PMID- 22519976 TI - The cofactor preference of glucose-6-phosphate dehydrogenase from Escherichia coli--modeling the physiological production of reduced cofactors. AB - In Escherichia coli, the pentose phosphate pathway is one of the main sources of NADPH. The first enzyme of the pathway, glucose-6-phosphate dehydrogenase (G6PDH), is generally considered an exclusive NADPH producer, but a rigorous assessment of cofactor preference has yet to be reported. In this work, the specificity constants for NADP and NAD for G6PDH were determined using a pure enzyme preparation. Absence of the phosphate group on the cofactor leads to a 410 fold reduction in the performance of the enzyme. Furthermore, the contribution of the phosphate group to binding of the transition state to the active site was calculated to be 3.6 kcal.mol(-1). In order to estimate the main kinetic parameters for NAD(P) and NAD(P)H, we used the classical initial-rates approach, together with an analysis of reaction time courses. To achieve this, we developed a new analytical solution to the integrated Michaelis-Menten equation by including the effect of competitive product inhibition using the omega-function. With reference to relevant kinetic parameters and intracellular metabolite concentrations reported by others, we modeled the sensitivity of reduced cofactor production by G6PDH as a function of the redox ratios of NAD/NADH (rR(NAD)) and NADP/NADPH (rR(NADP)). Our analysis shows that NADPH production sharply increases within the range of thermodynamically feasible values of rR(NADP), but NADH production remains low within the range feasible for rR(NAD). Nevertheless, we show that certain combinations of rR(NADP) and rR(NAD) sustain greater levels of NADH production over NADPH. PMID- 22519979 TI - A phase I study of low-pressure hyperbaric oxygen therapy for blast-induced post concussion syndrome and post-traumatic stress disorder: a neuropsychiatric perspective. PMID- 22519978 TI - Conformational landscape of N-glycosylated peptides detecting autoantibodies in multiple sclerosis, revealed by Hamiltonian replica exchange. AB - Synthetic N-glycosylated CSF114(Glc) and related peptides were proved to be able to recognize specific and high-affinity autoantibodies circulating in blood of relapsing-remitting multiple sclerosis (MS) patients and correlating with disease activity. The effect of these peptides has been linked to the beta-turn structure around the minimal epitope Asn(Glc). In this work we performed Hamiltonian replica exchange molecular dynamics simulations on the central heptapeptide fragment of a CSF114(Glc)-derived peptide in water and in a water/hexafluoroacetone mixture, confirming a significant incidence of beta-turn structures in both solvents. The structural similarity of the glycosylated and unglycosylated forms in all environments proves that the conformation of the heptapeptide is only marginally affected by the presence of the sugar. Moreover, the presence of a significant amount of bioactive hairpin-like conformations in the water environment suggests a possible use not only in the diagnosis but also in the treatment of MS. PMID- 22519980 TI - Bone marrow or peripheral blood stem cell transplantation from unrelated donors in adult patients with acute myeloid leukaemia, an Acute Leukaemia Working Party analysis in 2262 patients. AB - BACKGROUND: No survival benefit of using blood stem cells instead of bone marrow (BM) has been shown in matched unrelated donor (MUD) transplantation. DESIGN AND METHODS: In a retrospective registry analysis, we compared the use of blood stem cells (n = 1502) and BM (n = 760) from unrelated donors in patients aged 18-60 years with acute myeloid leukaemia (AML) undergoing myeloablative conditioning between 1997 and 2008. The blood stem cell recipients were older (P < 0.01), had more advanced disease (P < 0.0001) and received less total body irradiation (P < 0.0001) and more antithymocyte globulin (P = 0.01). RESULTS: Recovery of neutrophils and platelets was faster with blood stem cells (P < 0.0001). The incidence of acute graft-versus-host disease (GVHD) was similar, but there was more chronic GVHD in the blood stem cell group [hazard ratio (HR) = 1.29, P = 0.02]. There were no significant differences in nonrelapse mortality (NRM), relapse incidence and leukaemia-free survival (LFS) between the two groups amongst patients with AML in remission. In patients with advanced leukaemia, NRM was lower (HR = 0.61, P = 0.02) and LFS was prolonged (HR = 0.67, P = 0.002) when blood stem cells were used. At 3 years, LFS for all patients, regardless of remission status, was 41% for both treatment groups. The outcome was not affected after multivariable analysis adjusted for confounders. CONCLUSION: Blood stem cells compared with BM in MUD transplantation for patients with AML in remission resulted in the same rates of LFS. In patients with advanced leukaemia, the blood stem cell group had reduced NRM and improved LFS. PMID- 22519981 TI - Feasibility and tolerance of sequential chemoradiotherapy in squamous cell carcinoma of the head and neck. AB - This paper evaluates the feasibility and tolerance of sequential chemoradiotherapy in patients with squamous cell carcinoma of the head and neck and ascertains whether the use of induction chemotherapy compromises delivery of subsequent radiotherapy with or without concurrent chemotherapy. We also compared sequential chemoradiotherapy treatment adherence between the elderly and younger patients with squamous cell carcinoma of the head and neck. One hundred and ninety-four patients with head and neck squamous cell carcinoma who received induction chemotherapy with cisplatin and 5-fluorouracil were included in this study. Treatment-related death rate from induction chemotherapy was 1.5%. One hundred and ninety-one patients (98.5%) proceeded to radical radiotherapy, with 90.1% also receiving planned concomitant chemotherapy. One hundred and seventy eight patients (93.2%) completed radiotherapy with no prolongation of the treatment duration. There were no statistical differences in sequential chemoradiotherapy treatment adherence and tolerance between the elderly and younger patients apart from the proportion who required hospitalisation during radiotherapy. Induction chemotherapy in head and neck squamous cell carcinoma does not compromise delivery of definitive radiotherapy with or without concurrent chemotherapy. Elderly patients with head and neck squamous cell carcinoma are able to tolerate aggressive treatments such as sequential chemoradiotherapy. Treatment 'deintensification' based solely on chronological age is not recommended. PMID- 22519982 TI - Comparison of metabolism-mediated effects of pyrrolizidine alkaloids in a HepG2/C3A cell-S9 co-incubation system and quantification of their glutathione conjugates. AB - 1. Toxicity of pyrrolizidine alkaloids (PAs) largely depends on their metabolic activation by hepatic enzymes, including cytochrome P450s, to become chemically reactive pyrrolic derivatives. These then spontaneously release the esterifying acids to generate carbonium ions that form covalent adducts with cellular nucleophiles to exhibit toxicity. 2. In our investigation, metabolism-mediated toxicity of monocrotaline, retrorsine, lycopsamine, echimidine (retronecine-type PAs), heliotrine (a heliotridine-type PA) and senkirkine (an otonecine-type PA) was studied using an in vitro co-incubation assay. 3. Human hepatocarcinoma (HepG2/C3A) cells were incubated with PAs in the presence and absence of rat liver S9 fraction and the toxicity was assessed as lowered mitochondrial activity. 4. Bioactivation potential was measured by incubating PAs with rat liver S9 fraction, NADPH and GSH in a cell free system. Pyrrolic metabolites generated were entrapped as glutathione conjugates (7-GSH-DHP and 7,9-di-GSHDHP) which were quantified using LC-MS-MS analysis. 5. Our results indicated that PAs were metabolized by rat liver S9 fraction into reactive pyrrolic derivatives which were toxic to HepG2/C3A cells. This approach can be used to determine and compare bioactivation potential and metabolism-mediated toxicity of various PAs. PMID- 22519984 TI - Monocyte-derived and CD34+/KDR+ endothelial progenitor cells in heart failure. AB - BACKGROUND: Endothelial progenitor cells (EPCs) are known to be altered in heart failure (HF), but monocyte-derived EPCs in HF have not been assessed. We aimed to characterize monocyte-derived EPCs in systolic HF. METHODS AND RESULTS: We recruited 128 subjects with systolic HF: 50 South Asian (SA), 50 white, and 28 African-Caribbean (AC), for interethnic comparisons. Additionally, SAs with HF were compared with 40 SAs with coronary artery disease (CAD) without HF (disease controls [DCs]) and 40 SA healthy controls (HCs). Counts of CD34(+) and kinase domain receptor (KDR)(+) monocytes attributed to specific monocyte subsets (CD14(++) /CD16(-) [Mon1], CD14(++)/CD16(+) [Mon2], and CD14(+)/CD16(++) [Mon3]) and monocyte expression of vascular endothelial growth factor (VEGF) receptor 1 were analyzed by flow cytometry. We also enumerated CD34(+)/KDR(+) EPCs derived from mononuclear cells ('classic' EPC definition). RESULTS: SAs with HF had significantly reduced counts of CD34(+) monocytes, attributed to the Mon1 and Mon2 subsets. KDR(+) Mon1 counts were 4.5-fold increased in DCs as compared with HCs, but significantly reduced in HF subjects vs. DCs. VEGF receptor type 1 expression on Mon1 and Mon2 cells was significantly reduced in HF patients as compared with DCs. Also, CD34(+)/KDR(+) EPC numbers were reduced in HF subjects. Whites had significantly fewer KDR(+) Mon3 cells than ACs, but significantly more CD34(+) Mon2 cells than SAs and ACs. VEGF receptor type 1 expression by Mon1 cells was predictive for left ventricular ejection fraction after adjustment for ethnicity (beta = - 0.25. P = 0.039). CD34(+) Mon2 counts correlated with measures of microvascular endothelial function, and were predictive of the future risk of hospital admission. CONCLUSIONS: Circulating counts of monocyte-derived EPCs are significantly altered in HF, with significant ethnic differences in the levels of monocyte-derived EPCs. PMID- 22519983 TI - Evaluation of shock wave lithotripsy injury in the pig using a narrow focal zone lithotriptor. AB - What's known on the subject? and What does the study add? Of all the SW lithotriptors manufactured to date, more research studies have been conducted on and more is known about the injury (both description of injury and how to manipulate injury size) produced by the Dornier HM-3 than any other machine. From this information have come suggestions for treatment protocols to reduce shock wave (SW)-induced injury for use in stone clinics. By contrast, much less is known about the injury produced by narrow-focus and high-pressure lithotriptors like the Storz Modulith SLX. In fact, a careful study looking at the morphology of the injury produced by the SLX itself is lacking, as is any study exploring ways to reduce renal injury by manipulating SW delivery variables of this lithotriptor. The present study quantitates the lesion size and describes the morphology of the injury produced by the SLX. In addition, we report that reducing the SW delivery rate, a manoeuvre known to lower injury in the HM-3, does not reduce lesion size in the SLX. OBJECTIVE: * To assess renal injury in a pig model after treatment with a clinical dose of shock waves using a narrow focal zone (~3 mm) lithotriptor (Modulith SLX, Karl Storz Lithotripsy). MATERIALS AND METHODS: * The left kidney of anaesthetized female pigs were treated with 2000 or 4000 shock waves (SWs) at 120 SWs/min, or 2000 SWs at 60 SWs/min using the Storz SLX. * Measures of renal function (glomerular filtration rate and renal plasma flow) were collected before and 1 h after shock wave lithotripsy (SWL) and the kidneys were harvested for histological analysis and morphometric quantitation of haemorrhage in the renal parenchyma with lesion size expressed as a percentage of functional renal volume (FRV). * A fibre-optic probe hydrophone was used to determine acoustic output and map the focal width of the lithotriptor. * Data for the SLX were compared with data from a previously published study in which pigs of the same age (7-8 weeks) were treated (2000 SWs at 120 or 60 SWs/min) using an unmodified Dornier HM3 lithotriptor. RESULTS: * Treatment with the SLX produced a highly focused lesion running from cortex to medulla and often spanning the full thickness of the kidney. Unlike the diffuse interstitial haemorrhage observed with the HM3, the SLX lesion bore a blood filled core of near-complete tissue disruption devoid of histologically recognizable kidney structure. * Despite the intensity of tissue destruction at the core of the lesion, measures of lesion size based on macroscopic determination of haemorrhage in the parenchyma were not significantly different from kidneys treated using the HM3 (2000 SWs, 120 SWs/min: SLX, 1.86 +/- 0.52% FRV; HM3, 3.93 +/- 1.29% FRV). * Doubling the SW dose of the SLX from 2000 to 4000 SWs did not significantly increase lesion size. In addition, slowing the firing rate of the SLX to 60 SWs/min did not reduce the size of the lesion (2.16 +/- 0.96% FRV) compared with treatment at 120 SWs/min, as was the case with the HM3 (0.42 +/- 0.23% FRV vs 3.93 +/- 1.29% FRV). * Renal function fell significantly below baseline in all treated groups but was similar for both lithotriptors. * Focal width of the SLX (~2.6 mm) was about one-third that of the HM3 (~8 mm) while peak pressures were higher (SLX at power level 9: P+~90 MPa, P ~-12 MPa; HM3 at 24 kV: P+~46 MPa, P-~-8 MPa). CONCLUSIONS: * The lesion produced by the SLX (narrow focal width, high acoustic pressure) was a more focused, more intense form of tissue damage than occurs with the HM3. * Slowing the SW rate to 60 SWs/min, a strategy shown to be effective in reducing injury with the HM3, was not protective with the SLX. * These findings suggest that the focal width and acoustic output of a lithotriptor affect the renal response to SWL. PMID- 22519985 TI - Antiadhesion therapy for urinary tract infections--a balanced PK/PD profile proved to be key for success. AB - The initial step for the successful establishment of urinary tract infections (UTIs), predominantly caused by uropathogenic Escherichia coli, is the adhesion of bacteria to urothelial cells. This attachment is mediated by FimH, a mannose binding adhesin, which is expressed on the bacterial surface. To date, UTIs are mainly treated with antibiotics, leading to the ubiquitous problem of increasing resistance against most of the currently available antimicrobials. Therefore, new treatment strategies are urgently needed, avoiding selection pressure and thereby implying a reduced risk of resistance. Here, we present a new class of highly active antimicrobials, targeting the virulence factor FimH. When the most potent representative, an indolinylphenyl mannoside, was administered in a mouse model at the low dosage of 1 mg/kg (corresponding to approximately 25 MUg/mouse), the minimal therapeutic concentration to prevent UTI was maintained for more than 8 h. In a treatment study, the colony-forming units in the bladder could be reduced by almost 4 orders of magnitude, comparable to the standard antibiotic treatment with ciprofloxacin (8 mg/kg, sc). PMID- 22519986 TI - Surgical treatment of epibulbar melanocytomas by complete excision and homologous corneoscleral grafting in dogs: 11 cases. AB - OBJECTIVE: The aim of the study was to evaluate the efficacy, outcome, and complications following penetrating sclerokeratoplasty and frozen homologous corneoscleral grafting for the management of extensive canine epibulbar melanocytomas. METHODS: Medical records of canine patients treated at three different veterinary hospitals between 1999 and 2010 were reviewed. Signalment, location and extent of melanocytomas, recurrence rate, and early and late complications were reported. Patients were re-examined postoperatively to provide follow-up information. RESULTS: Patients included one intact male, three castrated males, six intact females, and one spayed female, with a median age of 5 years (range, 3-9). German Shepherds were overrepresented. Tumors extended from 2 to 4 clock hours at the limbus and up to 17 mm from clear cornea to globe equator. One case showed iridocorneal angle invasion; corneal involvement was present in all cases, and lipid keratopathy was present in four cases. In two cases, there was incomplete resection owing to tumor extent. Follow-up time ranged from 3 to 72 months (median, 17 months), with one case of intraocular tumor progression. Early complications included anterior uveitis (11/11), intracameral fibrin (5/11), hyphema (4/11), corneal edema (4/11), exuberant corneal granulation tissue (2/11), focal retinal edema (1/11), dyscoria (1/11), and partial suture dehiscence (1/11). Late complications included corneal fibrosis and/or pigmentation (11/11), faint anterior cortical cataracts (3/11), and lipid keratopathy (1/11). Vision was retained in all cases. CONCLUSIONS: This technique offers a surgically challenging but effective treatment for extensive epibulbar melanocytomas. In this case series, complications were mild and transient, with preservation of ocular anatomy and function. PMID- 22519987 TI - A single tyrosine hydroxyl group almost entirely controls the NADPH specificity of Plasmodium falciparum ferredoxin-NADP+ reductase. AB - Plasmodium falciparum ferredoxin-NADP(+) reductase (FNR) is a FAD-containing enzyme that, in addition to be a promising target of novel antimalarial drugs, represents an excellent model of plant-type FNRs. The cofactor specificity of FNRs depends on differences in both k(cat) and K(m) values for NADPH and NADH. Here, we report that deletion of the hydroxyl group of the conserved Y258 of P. falciparum FNR, which interacts with the 2'-phosphate group of NADPH, selectively decreased the k(cat) of the NADPH-dependent reaction by a factor of 2 to match that of the NADH-dependent one. Rapid-reaction kinetics, active-site titrations with NADP(+), and anaerobic photoreduction experiments indicated that this effect may be the consequence of destabilization of the catalytically competent conformation of bound NADPH. Moreover, because the Y258F replacement increased the K(m) for NADPH 4-fold and decreased that for NADH 3-fold, it led to a drop in the ability of the enzyme to discriminate between the coenzymes from 70- to just 1.5-fold. The impact of the Y258F change was not affected by the presence of the H286Q mutation, which is known to enhance the catalytic activity of the enzyme. Our data highlight the major role played by the Y258 hydroxyl group in determining the coenzyme specificity of P. falciparum FNR. From the general standpoint of engineering the kinetic properties of plant-type FNRs, although P. falciparum FNR is less strictly NADPH-dependent than its homologues, the almost complete abolishment of coenzyme selectivity reported here has never been accomplished before through a single mutation. PMID- 22519988 TI - sAPPalpha rescues deficits in amyloid precursor protein knockout mice following focal traumatic brain injury. AB - The amyloid precursor protein (APP) is thought to be neuroprotective following traumatic brain injury (TBI), although definitive evidence at moderate to severe levels of injury is lacking. In the current study, we investigated histological and functional outcomes in APP-/- mice compared with APP+/+ mice following a moderate focal injury, and whether administration of sAPPalpha restored the outcomes in knockout animals back to the wildtype state. Following moderate controlled cortical impact injury, APP-/- mice demonstrated greater impairment in motor and cognitive outcome as determined by the ledged beam and Barnes Maze tests respectively (p < 0.05). This corresponded with the degree of neuronal damage, with APP-/- mice having significantly greater lesion volume (25.0 +/- 1.6 vs. 20.3 +/- 1.6%, p < 0.01) and hippocampal damage, with less remaining CA neurons (839 +/- 245 vs. 1353 +/- 142 and 1401 +/- 263). This was also associated with an impaired neuroreparative response, with decreased GAP-43 immunoreactivity within the cortex around the lesion edge compared with APP+/+ mice. The deficits observed in the APP-/- mice related to a lack of sAPPalpha, as treatment with exogenously added sAPPalpha post-injury improved APP-/- mice histological and functional outcome to the point that they were no longer significantly different to APP+/+ mice (p < 0.05). This study shows that endogenous APP is potentially protective at moderate levels of TBI, and that this neuroprotective activity is related to the presence of sAPPalpha. Importantly, it indicates that the mechanism of action of exogenously added sAPPalpha is independent of the presence of endogenous APP. PMID- 22519989 TI - Congenital cytomegalovirus infection - a common cause of hearing loss of unknown aetiology. AB - AIM: The aim of this study was to investigate the role of congenital cytomegalovirus (CMV) infection as a cause of various types of sensorineural hearing loss (SNHL) in a group of nonsyndromic children with otherwise unknown aetiology of hearing loss. Furthermore, the occurrence of combined congenital CMV infection and connexin 26 (Cx26) mutations was investigated. METHODS: The dried blood spot (DBS) cards of 45 children with various degrees of hearing deficits and 46 children with severe/profound hearing loss were tested for CMV DNA with polymerase chain reaction (PCR) technique. The DBS cards of the 46 children with severe/profound hearing loss were also analysed for Cx26 mutations. RESULTS: Of the 45 children with various degrees of hearing loss, nine were positive for CMV DNA (20%). The nine children represented severe/profound, mild and unilateral hearing loss. From the 46 children with severe/profound hearing loss, nine of 46 (20%) were positive for CMV DNA. In addition, three of the CMV DNA-positive children were carriers of mutations of Cx26. CONCLUSION: Congenital CMV infection is a high risk factor in hearing impairment among children. PMID- 22519994 TI - Adrenal and renal physiology, and medical renal disease. PMID- 22519995 TI - Urological oncology: renal, ureteral and retroperitoneal tumors. PMID- 22519996 TI - Geriatrics. PMID- 22519997 TI - Urological oncology: prostate cancer. PMID- 22519998 TI - Imaging. PMID- 22519999 TI - Laparoscopy/new technology. PMID- 22520000 TI - Geriatrics. PMID- 22520002 TI - Urological oncology: testis cancer. PMID- 22520001 TI - Socioeconomic factors, urological epidemiology and practice patterns. PMID- 22520003 TI - Bladder, penis and urethral cancer, and basic principles of oncology. PMID- 22520004 TI - Voiding function and dysfunction, bladder physiology and pharmacology, and female urology. PMID- 22520005 TI - Benign prostatic hyperplasia. PMID- 22520006 TI - Renal transplantation and renovascular hypertension. PMID- 22520007 TI - Male and female sexual function and dysfunction; andrology. PMID- 22520008 TI - Male infertility. PMID- 22520009 TI - Socioeconomic factors, urological epidemiology and practice patterns. PMID- 22520010 TI - Diagnostic urology, urinary diversion and perioperative care. PMID- 22520011 TI - Pediatric urology. PMID- 22520012 TI - Uro-science. PMID- 22520013 TI - Infection and inflammation of the genitourinary tract. PMID- 22520015 TI - Voiding function and dysfunction, bladder physiology and pharmacology, and female urology. PMID- 22520017 TI - Suicide ideators and attempters with schizophrenia--the role of 5-HTTLPR, rs25531, and 5-HTT VNTR Intron 2 variants. AB - AIM: To examine the role of 5-HTTLPR, rs25531 and 5-HTT VNTR Intron 2 variants in subjects with psychotic disorders manifesting suicide ideation and behaviour. METHODS: The study included 519 subsequently hospitalized subjects who were genotyped for 5-HTTLPR, rs25531 and 5-HTT VNTR In2 variants. Clinical assessments included structured psychiatric interview, sociodemographic characteristics, suicide ideation and behaviour (SIBQ), severity of psychopathology (PANSS) and depression (CDSS). RESULTS: Three subgroups were identified: suicide attempters (N = 161), suicide ideators (N = 174) and subjects who never reported suicide ideation or behaviour (comparative group, N = 184). MAJOR FINDINGS: 1) Suicide attempters scored highest on the CDSS, while no differences between the three clinical subgroups were detected in the PANSS scores; 2) Suicide attempters were more frequently the carriers of L(A) allele, while subjects in the comparative group were more frequently the carriers of low expression 5-HTTLPR/5-HTT rs25531 haplotype SL(G); 3) No difference was found between the three clinical groups in the 5-HTT VNTR In2 variants; 4) Subjects with 5-HTTLPR/5-HTT rs25531 intermediate expression haplotype (L(A)L(G,)SL(A)) scored higher on the PANSS general psychopathology subscale; 5) There was no association between suicide attempt or ideation and 5-HTTLPR/In2 or 5-HTTLPR/rs25531/In2 haplotype distribution. CONCLUSION: The suicide ideators, attempters and controls did not differ significantly in 5-HTTLPR or 5-HTT VNTR In 2 variants, but 5-HTTLPR/5-HTT rs25531 haplotype might be a useful genetic marker in distinguishing these three clinical groups. PMID- 22520016 TI - Microparticle-associated tissue factor activity, venous thromboembolism and mortality in pancreatic, gastric, colorectal and brain cancer patients. AB - BACKGROUND: Tissue factor (TF) expression by tumors contributes to tumor growth. Release of TF-positive microparticles (MPs) may contribute to venous thromboembolism (VTE). OBJECTIVES: To conduct a prospective cohort study to determine whether elevated MP-associated TF (MP-TF) activity is predictive of VTE and mortality in four cancer types. PATIENTS/METHODS: We determined MP-TF activity in pancreatic, gastric, colorectal and brain cancer patients. We used a chromogenic endpoint assay for all patients and also a chromogenic kinetic assay for patients with pancreatic and brain cancer. RESULTS: During follow-up, 12/60 (20%) pancreatic, 6/43 (14%) gastric, 12/126 (10%) colorectal and 19/119 (16%) brain cancer patients developed VTE; 46/60 (77%), 30/43 (70%), 47/126 (37%) and 67/119 (56%), respectively, died. MP-TF activity levels were highest in pancreatic cancer. We did not find a statistically significant association of MP TF activity with the risk of VTE in any of the four cancer types by using two statistical methods. An association of MP-TF activity with the risk of mortality was detected in pancreatic cancer with the endpoint assay (hazard ratio [HR] 1.8 and 95% confidence interval [CI] 1.4-2.3 per doubling of activity, P < 0.001) and the kinetic assay (HR 1.2, 95% CI 1.1-1.4, P < 0.001); adjustment for type of treatment was not performed. In pancreatic cancer, MP-TF activity correlated with D-dimer level (endpoint assay, r = 0.51; chromogenic assay, r = 0.48), and a correlation between assays (r = 0.61) was found. CONCLUSION: MP-TF activity was not associated with future VTE in pancreatic, gastric, colorectal and brain cancer. However, we found a strong association of MP-TF activity with mortality in pancreatic cancer. MP-TF activity might be reflective of an aggressive pancreatic cancer phenotype. PMID- 22520018 TI - Oxidation mechanism of methionine by HO* radical: a theoretical study. AB - A theoretical investigation at the MP2/6-311++G(2d,2p)//MP2/6-31+G(d,p) level was employed in order to study the one-electron oxidation mechanism of methionine in aqueous solution. Three reaction paths corresponding to the HO(*), O(2) attack and hydrolysis were considered. Results show that all the processes are exothermic and that the rate determining step can be associated with the hydrolysis reaction. DFT computations with different exchange-correlation potentials were performed in order to verify their reliability in the description of the cyclic adduct produced in the HO(*) attack step. PMID- 22520019 TI - Frequency of the CHEK2 1100delC mutation among women with early-onset and bilateral breast cancer. PMID- 22520020 TI - A case of oculo-cerebral B-cell lymphoma in a cat. AB - PURPOSE: To describe a case of a cat with primary B-cell lymphoma affecting the eye and brain and which shared features similar to oculo-cerebral lymphoma in humans. METHODS: A 13-year-old castrated male Persian cat presented with clinical signs of anterior uveitis and increased intraocular pressure (IOP) in the left eye (OS). A complete diagnostic work-up was declined, and left-eye enucleation was performed. The globe was submitted for histopathology. One week after surgery, the cat became inappetent, hypothermic, and aggressive. Euthanasia was requested by the owner, and a necropsy was permitted. RESULTS: Histopathology of the enucleated globe revealed an extensive neoplastic infiltration consistent with large-cell lymphoma, affecting the anterior uvea, neuroretina and optic nerve. At necropsy, all organs were unremarkable except for the brain, where there was a neoplastic cell population consistent with that described in the left eye, infiltrated and expanded meninges, and perivascular spaces. Immunohistochemically, the neoplastic cells were positive for B-cell marker (CD20) and negative for T-cell marker (CD3). Histology and immunophenotyping suggested a diagnosis of primary central nervous system and ocular large B-cell lymphoma. DISCUSSION: The lymphoma in this cat resembled oculo-cerebral lymphoma in humans, sharing similar clinical features and histopathological findings, including the perivascular pattern of neoplastic cell infiltration. To the best of the authors' knowledge, this is the first description of a primary oculo cerebral B-cell lymphoma in a cat. PMID- 22520021 TI - Light on the horizont: biologicals in Behcet uveitis. AB - Relapsing ocular involvement is one of the major manifestations in Behcet disease (BD). When ocular BD is left untreated, it often results in blindness in <5 years. Combining systemic corticosteroids with cyclosporine A and other conventional immune modulating agents has been the only choice for treatment. More recently, the introduction of 'biologics' seems to be an effective therapy in patients affected with BD, especially in those with ocular disease. Our purpose was to survey the current knowledge regarding the biological therapeutic approaches for Behcet uveitis. We focused on the most commonly used biological agents: 'tumor necrosis factor-alpha antagonists' and 'interferon alpha'. We attempted to compare the effectiveness of these two biologicals and tried to balance on the pros and cons of these agents in clinical practice. The impressive efficacy of both approaches in sight-threatening BD argues for their expanding role. Earlier introduction of these agents in the course of disease may prevent irreversible structural damage and may result in improved long-term prognosis. PMID- 22520022 TI - Replication in aquatic biology: the result is often pseudoreplication. PMID- 22520024 TI - Intraduodenal sarcoma recurrence of retroperitoneal origin: an unusual cause for a duodenal obstruction. AB - Soft tissue sarcomas are uncommon tumors, and intraduodenal soft tissue sarcoma manifestation is even more rare. Only three cases of intraduodenal sarcomas have been reported in the literature thus far. Here, we report a case of an intraduodenal recurrence of a retroperitoneal sarcoma causing bowel obstruction. This unusual recurrence pattern likely relates to the patient's previous resection and radiation treatment, and highlights the benefits, limitations and follow-up strategies after multimodality treatment. PMID- 22520025 TI - Innovative enzymatic approach to resolve homogalacturonans based on their methylesterification pattern. AB - Three series of model homogalacturonans (HGs) covering a large range of degree of methylesterification (DM) were prepared by chemical and/or enzymatic means. Randomly demethylesterified HGs, HGs containing a few long demethylesterified galacturonic acid stretches, and HGs with numerous but short demethylesterified blocks were recovered. The analysis of the degradation products generated by the action of a purified pectin lyase allowed the definition of two new parameters, the degree of blockiness, and the absolute degree of blockiness of the highly methylesterified stretches (DBMe and DB(abs)Me, respectively). By combining this information with that obtained by the more traditional endopolygalacturonase digestion, the total proportion of degradable zones for a given DM was measured and was shown to permit a clear differentiation of the three types of HG series over a large range of DM. This double enzymatic approach will be of interest to discriminate industrial pectin samples exhibiting different functionalities and to evaluate pectin fine structure dynamics in vivo in the plant cell wall, where pectin plays a key mechanical role. PMID- 22520023 TI - The effect of reactive oxygen species on whole blood aggregation and the endothelial cell-platelet interaction in patients with coronary heart disease. AB - BACKGROUND: The effect of reactive oxygen species (ROS) on platelet function in coronary heart disease (CHD) is complex and poorly defined. Platelet aggregation studies in healthy volunteers have demonstrated contrasting results when platelets are exposed to ROS. We investigated the effect of ROS on whole blood aggregation (WBA) and the endothelial cell-platelet interaction in patients with CHD. METHODS AND RESULTS: ROS generated by xanthine and xanthine oxidase caused a concentration-dependent inhibition of WBA in blood from healthy donors and patients with CHD. In patients with CHD, 100 MUM xanthine and 100 mU/ml xanthine oxidase inhibited WBA in response to 3 MUg/ml collagen by 28.9% (95% CI 15.9% 41.8%, p<0.001) and in response to 5 MUM ADP by 36.0% (95% CI 9.6%-62.4%, p=0.005). Using nitrotyrosine expression, platelets isolated from patients with CHD were found to be susceptible to peroxynitrite damage. The addition of 1 * 10(5) cultured endothelial cells inhibited WBA in response to 3 MUg/ml collagen by 31.2% (95% CI 12.2%-50.2%, p<0.05) and in response to 5 MUM ADP by 31.6% (95% CI 2.5-60.7%, p<0.05). Addition of xanthine and xanthine oxidase did not alter this effect, however pre-treatment of endothelial cells with a nitric oxide synthase inhibitor (L-NAME) partly reversed the inhibition. CONCLUSION: ROS inhibit WBA in blood from patients with CHD. Whilst endothelial cells also inhibit WBA, the effect is attenuated by L-NAME, suggesting that nitric oxide is likely to remain an important protective mechanism against thrombosis in CHD. PMID- 22520026 TI - The evolutionary relationship of the transcriptionally active fabp11a (intronless) and fabp11b genes of medaka with fabp11 genes of other teleost fishes. AB - Here we describe the structure of the fatty acid-binding protein 11a and 11b genes (fabp11a and fabp11b) in medaka, and their evolutionary relationship to fabp11 genes from other teleost fishes. Initial studies indicated that the medaka fabp11a gene is intronless, but the fabp11b gene consists of four exons separated by three introns, a genomic organization that is characteristic of most members of the intracellular lipid-binding protein family. Based on genomic sequence, we conclude that the intronless fabp11a gene most likely arose as a result of reverse transcription of its mRNA transcript into cDNA followed by integration into chromosomal DNA. The ancestral intron-containing fabp11a gene was presumably lost from the medaka genome. The duplicated fabp11 genes extant in medaka encode polypeptides of 134 amino acids, which share highest sequence identity and similarity, and cluster in a distinct phylogenetic clade, with their orthologs in other teleost fishes. The fabp11a and fabp11b genes in medaka are therefore orthologs of the fabp11a and fabp11b genes, respectively, of other teleost fishes. No conserved gene synteny was found between medaka fabp11a and fabp11a genes from other teleost fishes, supporting our suggestion as to how this intronless gene arose. However, conserved gene synteny was evident between medaka fabp11b and fabp11b genes from other teleost fishes. The tissue-specific distribution of transcripts for medaka and zebrafish fabp11a and fabp11b genes revealed acquisition of a new function(s) in various tissues by the medaka fabp11b gene, which may explain the retention of sister duplicates of fabp11 in the medaka genome. PMID- 22520027 TI - High heterogeneity of HIV-related sexual risk among transgender people in Ontario, Canada: a province-wide respondent-driven sampling survey. AB - BACKGROUND: Studies of HIV-related risk in trans (transgender, transsexual, or transitioned) people have most often involved urban convenience samples of those on the male-to-female (MTF) spectrum. Studies have detected high prevalences of HIV-related risk behaviours, self-reported HIV, and HIV seropositivity. METHODS: The Trans PULSE Project conducted a multi-mode survey using respondent-driven sampling to recruit 433 trans people in Ontario, Canada. Weighted estimates were calculated for HIV-related risk behaviours, HIV testing and self-reported HIV, including subgroup estimates for gender spectrum and ethno-racial groups. RESULTS: Trans people in Ontario report a wide range of sexual behaviours with a full range of partner types. High proportions - 25% of female-to-male (FTM) and 51% of MTF individuals - had not had a sex partner within the past year. Of MTFs, 19% had a past-year high-risk sexual experience, versus 7% of FTMs. The largest behavioural contributors to HIV risk were sexual behaviours some may assume trans people do not engage in: unprotected receptive genital sex for FTMs and insertive genital sex for MTFs. Overall, 46% had never been tested for HIV; lifetime testing was highest in Aboriginal trans people and lowest among non-Aboriginal racialized people. Approximately 15% of both FTM and MTF participants had engaged in sex work or exchange sex and about 2% currently work in the sex trade. Self report of HIV prevalence was 10 times the estimated baseline prevalence for Ontario. However, given wide confidence intervals and the high proportion of trans people who had never been tested for HIV, estimating the actual prevalence was not possible. CONCLUSIONS: Results suggest potentially higher than baseline levels of HIV; however low testing rates were observed and self-reported prevalences likely underestimate seroprevalence. Explicit inclusion of trans people in epidemiological surveillance statistics would provide much-needed information on incidence and prevalence. Given the wide range of sexual behaviours and partner types reported, HIV prevention programs and materials should not make assumptions regarding types of behaviours trans people do or do not engage in. PMID- 22520028 TI - Epididymis rhabdomyoma: a case report and literature review. AB - Genital rhabdomyoma is very rare tumor that usually occurs in the vulvar of young women. Epididymis rhabdomyoma in a young man is extremely uncommon and has rarely been reported. Here, we report a case of epididymis rhabdomyoma of a 17-year-old man and review the literatures. PMID- 22520031 TI - Consent to transfusion: patients' and healthcare professionals' attitudes towards the provision of blood transfusion information. AB - BACKGROUND: Patients should be informed about the risks and benefits of blood transfusion and their consent should be documented. However, this is not routinely practised in the UK, and there have been few studies to investigate patients' and healthcare professionals' attitudes towards this process. OBJECTIVES: To investigate patients' and healthcare professionals' attitudes towards the information patients are provided with about transfusion and obtaining consent for transfusion. MEASURES: A cross-sectional qualitative survey design was employed. Attitudes towards transfusion-related information and consenting to transfusion were assessed using a patient survey and healthcare professional survey. PARTICIPANTS: One hundred and ten patients who had received a transfusion aged between 18 and 93 (60 males and 50 females) and 123 healthcare professionals (doctors, nurses and midwives) involved in administering transfusions. RESULTS: Sixty-one patients recalled consenting transfusion. The majority said they were just told they needed a transfusion (N = 67) and only 1 patient said a full discussion about the risks and the benefits of the transfusion took place. However, although 82 patients said they were satisfied with the information, 22 patients reported they would have liked to have been given more details. The majority of healthcare professionals (N = 83) felt that patients were often not given sufficient information about transfusion. CONCLUSION: Greater efforts should be made to provide information to patients about the risks and benefits of blood transfusions. Future research should explore the most effective ways of delivering this information to patients in an appropriate and timely manner. PMID- 22520032 TI - Aestivation and hypoxia-related events share common silent neuron trafficking processes. AB - BACKGROUND: The availability of oxygen is a limiting factor for neuronal survival since low levels account not only for the impairment of physiological activities such as sleep-wake cycle, but above all for ischemic-like neurodegenerative disorders. In an attempt to improve our knowledge concerning the type of molecular mechanisms operating during stressful states like those of hypoxic conditions, attention was focused on eventual transcriptional alterations of some key AMPAergic silent neuronal receptor subtypes (GluR1 and GluR2) along with HSPs and HIF-1alpha during either a normoxic or a hypoxic aestivation of a typical aquatic aestivator, i.e. the lungfish (Protopterus annectens). RESULTS: The identification of partial nucleotide fragments codifying for both AMPA receptor subtypes in Protopterus annectens displayed a putative high degree of similarity to that of not only fish but also to those of amphibians, birds and mammals. qPCR and in situ hybridization supplied a very high (p < 0.001) reduction of GluR1 mRNA expression in diencephalic areas after 6 months of aerial normoxic aestivation (6mAE). Concomitantly, high (p < 0.01) levels of HSP70 mRNAs in hypothalamic, mesencephalic and cerebellar areas of both 6mAE and after 6 months of mud hypoxic aestivation (6mMUD) were detected together with evident apoptotic signals. Surprisingly, very high levels of GluR2 mRNAs were instead detected in thalamic along with mesencephalic areas after 6 days of normoxic (6dAE) and hypoxic (6dMUD) aestivation. Moreover, even short- and long-term hypoxic states featured high levels of HIF-1alpha and HSP27 transcripts in the different brain regions of the lungfish. CONCLUSIONS: The distinct transcriptional variations of silent neurons expressing GluR1/2 and HSPs tend to corroborate these factors as determining elements for the physiological success of normoxic and hypoxic aestivation. A distinct switching among these AMPA receptor subtypes during aestivation highlights new potential adaptive strategies operating in key brain regions of the lungfish in relation to oxygen availability. This functional relationship might have therapeutic bearings for hypoxia-related dysfunctions, above all in view of recently identified silent neuron-dependent motor activity ameliorations in mammals. PMID- 22520033 TI - Diagnostic and radiological management of cystic pancreatic lesions: important features for radiologists. AB - Cystic pancreatic neoplasms are often an incidental finding, the frequency of which is increasing. The understanding of such lesions has increased in recent years, but the numerous types of lesions involved can hinder differential diagnosis. They include, in particular, intraductal papillary mucinous neoplasms (IPMN), serous cystic neoplasms (SCN), and mucinous cystic neoplasms (MCN). Knowledge of their histological and radiological structure, as well as distribution in terms of localization, age, and sex, helps to differentiate such tumours from common pancreatic pseudocysts. Several types of cystic pancreatic neoplasms can undergo malignant transformation and, therefore, require differentiated radiological management. This review aims to develop a broader understanding of the pathological and radiological characteristics of cystic pancreatic neoplasms, and provide a guideline for everyday practice based on current concepts in the radiological management of the given lesions. PMID- 22520034 TI - Intravenous contrast medium administration at 128 multidetector row CT pulmonary angiography: bolus tracking versus test bolus and the implications for diagnostic quality and effective dose. AB - AIM: To investigate the effects of a test bolus protocol contrast medium administration on diagnostic image quality in computed tomography pulmonary angiography (CTPA). MATERIALS AND METHODS: Fifty patients referred for exclusion of pulmonary embolism underwent CTPA using a test bolus protocol CTPA at 120 kVp and were compared with 50 patients undergoing CTPA using a standard bolus tracking protocol at 120 kVp, via assessment of attenuation, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) seen in the pulmonary arteries (PAs). An additional group of 10 non-obese patients who underwent CTPA using a test bolus protocol performed at 100 kVp were also analysed. Mean effective dose was calculated from the dose-length product, using standard conversion factors. RESULTS: The test bolus protocol showed significantly higher attenuation, SNR, and CNR in the pulmonary vasculature down to the segmental level compared to bolus-tracking CTPA (p < 0.0001). There was no significant difference in effective dose between the test bolus and bolus tracking cohorts. The additional group of test bolus CTPA examinations performed at 100 kVp had a significantly reduced effective dose in comparison to both test bolus CTPA at 120 kVp and bolus tracking CTPA at 120 kVp (p < 0.005) yet maintained mean PA attenuation to segmental level significantly better than bolus-tracking CTPA performed at 120 kVp and comparable to the test bolus cohort performed at 120 kVp. CONCLUSION: Test bolus contrast administration should be used as an optimal protocol. Performing test bolus CTPA at 100 kVp, as opposed to 120 kVp, significantly reduces dose without compromising PA attenuation in non-obese subjects. PMID- 22520035 TI - Roles of a hospital for community safety promotion. AB - It is not easy for any health professional to be aware of injury problems and safety issues within their own communities if their main responsibility is not in this field. Health professionals, however, can play an important role in all aspects of injury prevention and safety promotion. This includes not only medical or surgical treatment for the injured patients but also risk assessment, health education, community action, organisational development and advocacy for policy to promote safety at a multi-level in the society. This can be accomplished most efficiently through collaboration with diverse sectors within a community, including hospitals, public health professionals, policy makers, school boards, police departments, fire departments, citizens' coalitions and others. Since 2002, Ajou University School of Medicine and Public Health in Suwon, Korea, has introduced a Safe Community model to many countries in Asia, including Korea, Japan, China, Vietnam, Thailand, among others, which is led by The World Health Organization Collaborating Centre on Community Safety Promotion at Karolinska Institutet, Stockholm, Sweden. PMID- 22520036 TI - Obituary - David Bennett. PMID- 22520037 TI - Elevated prepartum fibrinogen levels are not associated with a reduced risk of postpartum hemorrhage. PMID- 22520038 TI - Vitamin K1 enhances sorafenib-induced growth inhibition and apoptosis of human malignant glioma cells by blocking the Raf/MEK/ERK pathway. AB - BACKGROUND: The combined effects of anticancer drugs with nutritional factors against tumor cells have been reported previously. This study characterized the efficacy and possible mechanisms of the combination of sorafenib and vitamin K1 (VK1) on glioma cell lines. METHODS: We examined the effects of sorafenib, VK1 or their combination on the proliferation and apoptosis of human malignant glioma cell lines (BT325 and U251) by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, flow cytometry and 4',6-diamidino-2-phenylindole (DAPI) assay. The signaling pathway changes were detected by western blotting. RESULTS: Sorafenib, as a single agent, showed antitumor activity in a dose dependent manner in glioma cells, but the effects were more pronounced when used in combination with VK1 treatment. Sorafenib in combination with VK1 treatment produced marked potentiation of growth inhibition and apoptosis, and reduced expression of phospho-mitogen-activated protein kinase kinase (MEK) and phospho extracellular signal-regulated kinase (ERK). Furthermore, the expression levels of antiapoptotic proteins Bcl-2 and Mcl-1 were significantly reduced. CONCLUSIONS: Our findings indicated that VK1 enhanced the cytotoxicity effect of sorafenib through inhibiting the Raf/MEK/ERK signaling pathway in glioma cells, and suggested that sorafenib in combination with VK1 maybe a new therapeutic option for patients with gliomas. PMID- 22520039 TI - Bone marrow cells and CD117-positive haematopoietic stem cells promote corneal wound healing. AB - PURPOSE: The present study was conducted to evaluate the therapeutic effects of topically applied bone marrow (BM) cells and CD117-positive haematopoietic stem (CD117(+)) cells on alkali-induced corneal ulcers. METHODS: Bone marrow cells and CD117(+) cells were isolated from syngenic mice and labelled with an intracellular cell tracer. Defined corneal wounds were produced in 89 eyes of syngenic mice and allowed to partially heal in vivo for 6 hr. The alkali-burned eyes were enucleated 6 hr postinjury and randomly divided into three groups. Control group (33 eyes) was incubated with medium only. The treatment groups received either BM cells (30 eyes) or CD117(+) cells (26 eyes) suspended in medium. Re-epithelialization process of corneal defects was qualitatively and quantitatively assessed and statistically analysed. The corneas were examined by histological and immunohistochemical methods. RESULTS: We found that the re epithelialization of corneal wounds in both treatment groups was significantly accelerated as compared to the control group. During the follow-up period (85 hr), the corneal transparency was comparable in all groups. Morphological investigations of corneas from control and treatment group showed no evident differences in the phenotype of the regenerated epithelium. Additionally, corneas in the treatment groups were devoid of donor-derived BM cells and CD117(+) cells, respectively. CONCLUSIONS: This study provides evidence that topical application of BM cells or CD117(+) cells can be used to reconstruct corneal surfaces. Because neither BM cells nor CD117(+) cells were integrated into the corneal epithelium, we suggest that soluble factors could be responsible for the positive effect of BM cells and CD117(+) cells on corneal wound healing. PMID- 22520040 TI - Management of spontaneous chronic corneal epithelial defects (SCCEDs) in dogs with diamond burr debridement and placement of a bandage contact lens. AB - Objective To describe the outcome of canine spontaneous chronic corneal epithelial defects (SCCED) treated with diamond burr debridement (DBD) and bandage contact lens placement (BCL). Animal studied Forty eyes of 36 dogs presenting to a single private practice. Procedures A retrospective review of medical records was performed. Cases were eligible for inclusion if they were newly diagnosed with SCCED by a veterinary ophthalmologist and treated with DBD/BCL. All patients received a complete ocular examination followed by DBD using a battery-powered, handheld motorized burr (Algerbrush((r)) , Alger Equipment Company, Lago Vista, TX, USA). A BCL was placed post-debridement in all patients. Data were analyzed for sex, age, breed, duration of clinical signs prior to DBD; number of debridements required before healing was achieved; contact lens retention, complications attributed to DBD, and additional surgical interventions were required to achieve healing. Results The median time to first recheck examination was 7 days (IQR 7-9 days) with 28/40 (70%) of cases healed at this examination. The mean time to second recheck examination was 15.5 +/- 5.5 days with 37/40 (92.5%) healed by this examination. The median time to final recheck examination was 19 days (IQR 18-35.5 days) with a range of 18-52 days. All cases resolved by the third and final recheck examination. A second DBD/BCL was performed in 5/40 (12.5%) of cases. The BCL retention rate was 95% over all examination time points. No case required a keratectomy or other surgical intervention to achieve healing. The only complication observed was one case of suspected bacterial keratitis post-DBD/BCL. Conclusions Results suggest that DBD/BCL is safe and effective for treatment of canine SCCED. PMID- 22520041 TI - [Initial experience of a series of robotic-assisted laparoscopic adrenalectomy]. AB - OBJECTIVES: We present our initial experience using robotic-assisted laparoscopic adrenalectomy in the surgical treatment of adrenal masses. MATERIAL AND METHODS: A total of 18 patients (11 women and 7 men) diagnosed of a functioning or non functioning adrenal tumor mass were operated on in our facilities between October 2009 and October 2011. Surgical variables, intra-hospital recovery time, pathological findings and peri- and post-operatory findings were evaluated. RESULTS: Mean age of the population intervened was 51.2 years (range 18-81), average ASA score 2.11 (range 1-4) and BMI 27.0 (range 18.8-36.1). Of the 18 patients, 11 were operated on the left side and 7 on the right. Mean surgery time was 150 (range 84-329) min and intra-operatory bleeding 121 (range 10-1500) ml, with a mean loss of hemoglobin and hematocrits of 2.11g/dl and 6.33%, respectively. Two patients were converted to conventional surgery. The factors influencing surgical conversion were: normal size (>10cm), tumor weight (>100g.), active pheochromocytoma and left localization of the tumor. Seven functioning cortical adenomas, 6 metastatic adrenal tumors, 3 pheochromocytoma and 2 incidental tumors were excised. Mean tumor size was 5.39 (range 3-15) cm. Median hospital stay was 6 days (range 4-14). Five patients had peri-operatory complication. Of these, only one (5%) had major complications (Clavien III). Mean follow-up was 6 months (range 2-24). CONCLUSIONS: Robotic technology for laparoscopic adrenalectomies is a valid option for adrenal tumor treatment. In our experience with a relatively short learning curve, it makes it possible to reduce hospital treatment times and the intra- and post-operatory complications, without affecting the oncological and post-operatory functional results. PMID- 22520042 TI - [Advances in uro-oncology "Oncoforum": the best of 2011]. AB - OBJECTIVE: To put forth new findings in urologic oncology with impact in the clinical practice, presented in the principal annual meetings (EAU, ESTRO, AUA, ASCO and ASTRO). METHODS: The reporters of the OncoUrology Forum select and classify the summaries on genitourinary cancer based on the impact on present or future practice. This document includes the summaries having the highest scores. RESULTS: The OncoUrology Forum committee considered the following messages important. The PIVOT study shows that radical prostatectomy reduces the specific mortality of prostate cancer (PCa) compared to follow-up in observation, in localized high risk PCa or PSA >10 ng/mL. Dissection of the pelvic lymph nodes should be done in all the patients with bladder cancer treated by radical cystectomy, regardless of the tumor stage, in accordance with baseline analysis of the Surveillance, Epidemiology and End Results (SEER) data. An analysis of the SEER of patients with renal cancer concluded that the radical nephrectomy is associated to worse cardiovascular and overall survival compared to those treated with partial nephrectomy in localized renal cell carcinoma of <=2 cm. In patients with nonseminomatous germ cells cancer, retroperitoneal lymph node dissection should not be omitted when the residual tumor size is <=1 cm because of the considerably high risk of teratoma and viable cancer. CONCLUSIONS: Although these studies do not offer a final response for all the oncourological subjects, these results will have an impact on the daily clinical practice. PMID- 22520043 TI - [Prostate cancer: promising biomarkers related to aggressive disease]. AB - BACKGROUND: Although a rapidly growing number of candidate biological markers of prognosis and/or response to specific treatments in prostate cancer, none have to date showed ability to completely prognosticate prostate cancer on evidence based urology. OBJECTIVE: To review the pertinent literature on the issue. ACQUISITION OF EVIDENCE: A comprehensive review of the current literature was done focusing on promising biomarkers related to aggressive prostate cancer. SUMMARY OF EVIDENCE: Combined with the heterogeneous nature of the disease, mixed case series are the most common study design, impeding robust results and the development of an effective therapeutic strategy. Improvement in prostate cancer patient survival requires not only the identification of new therapeutic target based on detailed understanding of the biological mechanisms involved in metastatic dissemination and tumor growth but strong clinical studies as well. CONCLUSION: Better study design involving potential markers and including well classified and staged patients with robust methodology and adequate outcomes (mainly survival) are necessary to the field evolution. PMID- 22520044 TI - [Prostatic involvement by urothelial carcinoma in patients with bladder cancer and their implications in the clinical practice]. AB - OBJECTIVES: Urothelial carcinoma (UC) is a multifocal disease that may develop in any location of the urinary tract, including the prostate. We analyze the types of prostate involvement due to UC, their diagnosis, risk factors and the clinical implications of this entity. MATERIAL AND METHODS: Analysis of original, review articles and publications related to prostate involvement due to UC. The study included works published in the period of 1985-2011, most of which were obtained from the search in PubMed. RESULTS: Prostate involvement due to UC has been observed frequently in both non-muscle invasive bladder cancer (NMIBC) series and prolonged follow-up (39%) as in radical cystectomy series (15-48%). Prostatic involvement may occur in the mucosa and ducts (superficial involvement) or prostate stroma (invasive involvement), a fact that has prognostic and therapeutic implications. Stromal involvement may have both a bladder and intraurethral origin. Carcinoma in situ, multifocality, bladder neck/trigone cancer, and previous history of tumor recurrence are the factors that have been m ore consistently associated to prostate involvement due to UC. The incidence of prostatic involvement by UC in patients with NMIBC increases over time when risk factors exist. In these cases, a prostatic urethral biopsy should be performed during the follow-up. Conservative treatment with transurethral resection and BCG is possible in case of superficial involvement of the prostatic urethra, assuming its risk of progression. Patients subjects to cystectomy and with prostate involvement due to UC have a greater risk of urethral recurrence. The elevated incidence of prostatic adenocarcinoma and prostatic involvement by UC in cystectomy specimens makes it necessary to be very selective when indicating prostate-sparing cystectomy. Chemotherapy may be an option in an attempt to improve survival of patients with prostatic stromal involvement. CONCLUSIONS: Prostatic involvement by UC is not uncommon and it has important implications in the management of patients with NMIBC and in those who have an indication for or have undergone radical cystectomy. PMID- 22520045 TI - Factors influencing heterogeneity of radiation-induced DNA-damage measured by the alkaline comet assay. AB - BACKGROUND: To investigate whether different conditions of DNA structure and radiation treatment could modify heterogeneity of response. Additionally to study variance as a potential parameter of heterogeneity for radiosensitivity testing. METHODS: Two-hundred leukocytes per sample of healthy donors were split into four groups. I: Intact chromatin structure; II: Nucleoids of histone-depleted DNA; III: Nucleoids of histone-depleted DNA with 90 mM DMSO as antioxidant. Response to single (I-III) and twice (IV) irradiation with 4 Gy and repair kinetics were evaluated using %Tail-DNA. Heterogeneity of DNA damage was determined by calculation of variance of DNA-damage (V) and mean variance (Mvar), mutual comparisons were done by one-way analysis of variance (ANOVA). RESULTS: Heterogeneity of initial DNA-damage (I, 0 min repair) increased without histones (II). Absence of histones was balanced by addition of antioxidants (III). Repair reduced heterogeneity of all samples (with and without irradiation). However double irradiation plus repair led to a higher level of heterogeneity distinguishable from single irradiation and repair in intact cells. Increase of mean DNA damage was associated with a similarly elevated variance of DNA damage (r = +0.88). CONCLUSIONS: Heterogeneity of DNA-damage can be modified by histone level, antioxidant concentration, repair and radiation dose and was positively correlated with DNA damage. Experimental conditions might be optimized by reducing scatter of comet assay data by repair and antioxidants, potentially allowing better discrimination of small differences. Amount of heterogeneity measured by variance might be an additional useful parameter to characterize radiosensitivity. PMID- 22520046 TI - Results from a community-based program evaluating the effect of changing smoking status on asthma symptom control. AB - BACKGROUND: Cigarette smoking has been associated with accelerated decline in lung function, increased health services use and asthma severity in patients with asthma. Previous studies have provided insight into how smoking cessation improves lung function among asthma patients, however, fail to provide measurable asthma symptom-specific outcomes after smoking cessation. The objective of this study was to measure the effect of changing smoking status on asthma symptom control and health services use in adults with asthma. METHODS: The study was conducted in eight primary care practices across Ontario, Canada participating in a community-based, participatory, and evidence-based Asthma Care Program. Patients aged 18 to 55 identified with physician-diagnosed mild to moderate asthma were recruited. In addition to receiving clinical asthma care, participants were administered a questionnaire at baseline and 12-month follow-up visits to collect information on demographics, smoking status, asthma symptoms and routine health services use. The effect of changing smoking status on asthma symptom control was compared between smoking groups using Chi-square and Fisher's exact tests where appropriate. Mixed effect models were used to measure the impact of the change in smoking status on asthma symptom and health services use while adjusting for covariates. RESULTS: This study included 519 patients with asthma; 11% of baseline smokers quit smoking while 4% of baseline non-smokers started smoking by follow-up. Individuals who quit smoking had 80% lower odds of having tightness in the chest (Odds ratio (OR) = 0.21, 95% CI: 0.06, 0.82) and 76% lower odds of night-time symptoms (OR = 0.24, 95% CI: 0.07, 0.85) compared to smokers who continued to smoke. Compared to those who remained non-smokers, those who had not been smoking at baseline but self-reported as current smoker at follow-up had significantly higher odds of chest tightness (OR = 1.36, 95% CI: 1.10, 1.70), night-time symptoms (OR = 1.55, 95% CI: 1.09, 2.20), having an asthma attack in the last six months (OR = 1.43, 95% CI: 1.17, 1.75) and visiting a walk-in clinic for asthma (OR = 4.57, 95% CI: 1.44, 14.49). CONCLUSIONS: This study provides practitioners measurable and clinically important findings that associate smoking cessation with improved asthma control. Health practitioners and asthma programs can use powerful education messages to emphasize the benefits of smoking cessation as a priority to current smokers. PMID- 22520047 TI - Metabolite profiling of plasma and urine from rats with TNBS-induced acute colitis using UPLC-ESI-QTOF-MS-based metabonomics--a pilot study. AB - The incidence of inflammatory bowel disease, a relapsing intestinal condition whose precise etiology is still unclear, has continually increased over recent years. Metabolic profiling is an effective method with high sample throughput that can detect and identify potential biomarkers, and thus may be useful in investigating the pathogenesis of inflammatory bowel disease. In this study, using a metabonomics approach, a pilot study based on ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOF-MS) was performed to characterize the metabolic profile of plasma and urine samples of rats with experimental colitis induced by 2,4,6-trinitrobenzene sulfonic acid. Acquired metabolic profile data were processed by multivariate data analysis for differentiation and screening of potential biomarkers. Five metabolites were identified in urine: two tryptophan metabolites [4-(2-aminophenyl)-2,4-dioxobutanoic acid and 4,6 cihydroxyquinoline], two gut microbial metabolites (phenyl-acetylglycine and p cresol glucuronide), and the bile acid 12alpha-hydroxy-3-oxocholadienic acid. Seven metabolites were identified in plasma: three members of the bile acid/alcohol group (cholic acid, 12alpha-hydroxy-3-oxocholadienic acid and cholestane-3,7,12,24,25-pentol) and four lysophosphatidylcholines [LysoPC(20:4), LysoPC(16:0), LysoPC(18:1) and LysoPC(18:0)]. These metabolites are associated with damage of the intestinal barrier function, microbiota homeostasis, immune modulation and the inflammatory response, and play important roles in the pathogenesis of inflammatory bowel disease. Our results positively support application of the metabonomic approach in study of the pathophysiological mechanism of inflammatory bowel disease. PMID- 22520049 TI - [Thromboembolic risk factors in geriatrics: study of 155 cases]. PMID- 22520050 TI - [Postexercise duplex ultrasound to diagnose external iliac endofibrosis]. AB - Arterial endofibrosis is a disease of recent discovery which concerns high performance athletes, predominantly competitive cyclists. The preferential location is the external iliac artery. The symptoms are diverse (pain, edema, paresthesia), always linked to an effort. The diagnosis may be delayed due to atypical symptoms in athletes. Complementary tests are measure of the systolic pressure index after exercise, duplex ultrasound, CT angiography, MR angiography and arteriography. We report a case of endofibrosis where late diagnosis was established with postexercise duplex ultrasound, while CT angiography and arteriography failed to reveal characteristic abnormalities. PMID- 22520048 TI - The family of Deg/HtrA proteases in plants. AB - BACKGROUND: The Deg/HtrA family of ATP-independent serine endopeptidases is present in nearly all organisms from bacteria to human and vascular plants. In recent years, multiple deg/htrA protease genes were identified in various plant genomes. During genome annotations most proteases were named according to the order of discovery, hence the same names were sometimes given to different types of Deg/HtrA enzymes in different plant species. This can easily lead to false inference of individual protease functions based solely on a shared name. Therefore, the existing names and classification of these proteolytic enzymes does not meet our current needs and a phylogeny-based standardized nomenclature is required. RESULTS: Using phylogenetic and domain arrangement analysis, we improved the nomenclature of the Deg/HtrA protease family, standardized protease names based on their well-established nomenclature in Arabidopsis thaliana, and clarified the evolutionary relationship between orthologous enzymes from various photosynthetic organisms across several divergent systematic groups, including dicots, a monocot, a moss and a green alga. Furthermore, we identified a "core set" of eight proteases shared by all organisms examined here that might provide all the proteolytic potential of Deg/HtrA proteases necessary for a hypothetical plant cell. CONCLUSIONS: In our proposed nomenclature, the evolutionarily closest orthologs have the same protease name, simplifying scientific communication when comparing different plant species and allowing for more reliable inference of protease functions. Further, we proposed that the high number of Deg/HtrA proteases in plants is mainly due to gene duplications unique to the respective organism. PMID- 22520051 TI - The mammalian kidney. PMID- 22520053 TI - Distant metastases from head and neck squamous cell carcinoma. Part II. Diagnosis. AB - The detection of distant metastases is critical for prognostication and for the choice of treatment in patients with head and neck squamous cell carcinoma (HNSCC). Pretreatment screening for distant metastases should be conducted particularly for patients with high risk factors, prior to locoregional treatment decisions. Different diagnostic techniques are discussed. Unfortunately, most studies lack sufficient follow-up to reliably assess false-negative results. Moreover, the designs of most studies vary substantially with regard to homogeneity of groups (tumor types and stages), timing (pretreatment, follow-up) and definition of risk factors (patient selection). Therefore, only a few studies are comparable. The combination of F-18 fluoro-d-glucose-positron emission tomography (FDG-PET) and a dedicated CT (at least of the chest) is the most important imaging protocol at the present time. Eventually, whole-body-MRI (WB MRI) may possibly replace PET-CT for screening patients for distant metastases. PMID- 22520054 TI - Distant metastases from head and neck squamous cell carcinoma. Part I. Basic aspects. AB - The incidence of distant metastasis in head and neck squamous cell carcinoma (HNSCC) is relatively low but remains a major determinant of prognosis and therefore an important factor in clinical decision making. The most frequently involved sites for distant metastasis are the lung (approximately 70% of cases), followed by bone and liver. There are often conflicting reports on which parameters are risk factors for distant metastasis, but the most important predictive factors appear to be the site of the primary tumor (hypopharynx in particular), advanced T- and N-classification, histological grade and the ability to achieve locoregional disease control. Metastasis results from a selection of tumor cells that have acquired the properties to withstand multiple and often unfavorable circumstances and settle in distant organs. Most of these processes involve interaction between tumor cells, their microenvironment and host factors. Increasing knowledge of the biology of distant metastasis may result in the development of diagnostic and therapeutic strategies targeted to this usually terminal stage for patients with HNSCC. PMID- 22520052 TI - Using angiogenic factors and their soluble receptors to predict organ dysfunction in patients with disseminated intravascular coagulation associated with severe trauma. AB - INTRODUCTION: Disseminated intravascular coagulation (DIC) is characterized by the concomitant activation of coagulofibrinolytic disorders and systemic inflammation associated with endothelial dysfunction-induced microvascular permeability. Angiogenic factors, including vascular endothelial growth factor (VEGF), angiopoietin (Ang), and their receptors, play crucial roles in angiogenesis and microvascular permeability. The aim of the study was to assess the relationship between angiogenic factors, their soluble receptors and organ dysfunction associated with DIC after severe trauma. MATERIALS AND METHODS: A total of 57 patients with severe trauma were divided into two subgroups; 30 DIC patients and 27 non-DIC patients. The DIC was diagnosed based on the Japanese Association for Acute Medicine (JAAM) DIC and the International Society on Thrombosis and Haemostasis (ISTH) overt DIC criteria. The serum levels of angiogenic factors were measured at the time of admission (Day 1), Day 3 and Day 5. This study compared levels of these angiogenic factors between the two DIC groups, and evaluated their predictive value for organ dysfunction. RESULTS: DIC patients, especially those with ISTH DIC, showed higher Sequential Organ Failure Assessment (SOFA) scores and lactate levels. There were lower levels of VEGF, Ang1 and the soluble Tie2 in the ISTH DIC patients than the non-DIC patients. The levels of soluble VEGF receptor-1 (sVEGFR1), Ang2 and the Ang2/Ang1 ratio in the ISTH DIC patients were higher than in non-DIC patients. The relationship between the presence of massive transfusion and angiogenic factors indicated the same results. The levels of sVEGFR1, Ang2 and the Ang2/Ang1 ratio correlated with the SOFA scores. In particular, sVEGFR1 and Ang2 were independent predictors of an increase in the SOFA score. The lactate levels independently predicted increases in the levels of sVEGFR1 and Ang2. The decrease in the platelet counts also independently predicted the increase in Ang2 levels in DIC patients. CONCLUSIONS: Angiogenic factors and their soluble receptors, particularly sVEGFR1 and Ang2, are considered to play pivotal roles in the development of organ dysfunction in DIC associated with severe trauma. DIC-induced tissue hypoxia and platelet consumption may play crucial roles in inducing sVEGFR1 and Ang2, and in determining the prognosis of the severity of organ dysfunction. PMID- 22520055 TI - Dose-effect and metabolism of docosahexaenoic acid: pathophysiological relevance in blood platelets. AB - Docosahexaenoic acid (DHA) is known as a major nutrient from marine origin. Considering its beneficial effect in vascular risk prevention, the effect of DHA on blood components, especially platelets, will be reviewed here. Investigating the dose-effect of DHA in humans shows that daily intake lower than one gram/day brings several benefits, such as inhibition of platelet aggregation, resistance of monocytes against apoptosis, and reinforced antioxidant status in platelets and low-density lipoproteins. However, higher daily intake may be less efficient on those parameters, especially by losing the antioxidant effect. On the other hand, a focus on the inhibition of platelet aggregation by lipoxygenase end products of DHA is made. The easy conversion of DHA by lipoxygenases and the formation of a double lipoxygenation product named protectin DX, reveal an original way for DHA to contribute in platelet inhibition through both the cyclooxygenase inhibition and the antagonism of thromboxane A2 action. PMID- 22520056 TI - Curcumin protects against sepsis-induced acute lung injury in rats. AB - The present study aimed to investigate the effect of curcumin on sepsis-induced acute lung injury (ALI) in rats, and explore its possible mechanisms. Male Sprague-Dawley rats were randomly divided into the following five experimental groups (n = 20 per group): animals undergoing a sham cecal ligature puncture (CLP) (sham group); animals undergoing CLP (control group); or animals undergoing CLP and treated with vehicle (vehicle group), curcumin at 50 mg/kg (low-dose curcumin [L-Cur] group), or curcumin at 200 mg/kg (high-dose curcumin [H-Cur] group).At 6, 12, 24 h after CLP, blood, bronchoalveolar lavage fluid (BALF) and lung tissue were collected. The lung wet/dry weight (W/D) ratio, protein level, and the number of inflammatory cells in the BALF were determined. Optical microscopy was performed to examine the pathologic changes in lungs. Myeloperoxidase (MPO) activity, malondialdehyde (MDA) content, as well as superoxidase dismutase (SOD) activity were measured in lung tissues. The expression of inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha), interluekin-8 (IL-8), and macrophage migration inhibitory factor (MIF) were determined in the BALF. Survival rates were recorded at 72 h in the five groups in another experiment. Treatment with curcumin significantly attenuated the CLP induced pulmonary edema and inflammation, as it significantly decreased lung W/D ratio, protein concentration, and the accumulation of the inflammatory cells in the BALF, as well as pulmonary MPO activity. This was supported by the histopathologic examination, which revealed marked attenuation of CLP-induced ALI in curcumin treated rats. In addition, curcumin significantly increased SOD activity with significant decrease in MDA content in the lung. Also, curcumin caused down-regulation of the inflammatory cytokines TNF-alpha, IL-8, and MIF levels in the lung. Importantly, curcumin improved the survival rate of rats by 40%-50% with CLP-induced ALI. Taken together, these results demonstrate the protective effects of curcumin against the CLP-induced ALI. This effect can be attributed to curcumin ability to counteract the inflammatory cells infiltration and, hence, ROS generation and regulate cytokine effects. PMID- 22520058 TI - Hip and knee joint kinematics during a diagonal jump landing in anterior cruciate ligament reconstructed females. AB - Anterior cruciate ligament (ACL) injury is a common injury encountered by sport medicine clinicians. Surgical reconstruction is the recommended treatment of choice for those athletes wishing to return to full-contact sports participation and for sports requiring multi-directional movement patterns. The aim of ACL reconstruction is to restore knee joint mechanical stability such that the athlete can return to sporting participation. However, knowledge regarding the extent to which lower limb kinematic profiles are restored following ACL reconstruction is limited. In the present study the hip and knee joint kinematic profiles of 13 ACL reconstructed (ACL-R) and 16 non-injured control subjects were investigated during the performance of a diagonal jump landing task. The ACL-R group exhibited significantly less peak knee joint flexion (P=0.01). Significant between group differences were noted for time averaged hip joint sagittal plane (P<0.05) and transverse plane (P<0.05) kinematic profiles, as well as knee joint frontal plane (P<0.05) and sagittal plane (P<0.05) kinematic profiles. These results suggest that aberrant hip and knee joint kinematic profiles are present following ACL reconstruction, which could influence future injury risk. PMID- 22520057 TI - Ischemia postconditioning and mesenchymal stem cells engraftment synergistically attenuate ischemia reperfusion-induced lung injury in rats. AB - BACKGROUND: It has been reported that ischemic postconditioning (IPO) or mesenchymal stem cell (MSC) engraftment could protect organs from ischemia/reperfusion (I/R) injury. We investigated the synergetic effects of combined treatment on lung injury induced by I/R. METHODS: Adult Sprague-Dawley rats were randomly assigned to one of the following groups: sham-operated control, I/R, IPO, MSC engraftment, and IPO plus MSC engraftment. Lung injury was assessed by arterial blood gas analysis, the wet/dry lung weight ratio, superoxide dismutase level, malondialdehyde content, myeloperoxidase activity, and tissue histologic changes. Cytokine expression was detected using real-time polymerase chain reaction, Western blotting, and enzyme-linked immunosorbent assay. Cell apoptosis was determined by terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate-biotin nick end assay and annexin V staining. RESULTS: MSC engraftment or IPO alone markedly attenuated the lung wet/dry weight ratio, malondialdehyde and myeloperoxidase production, and lung pathologic injury and enhanced arterial partial oxygen pressure, superoxide dismutase content, inhibited pro-inflammatory cytokine levels, and decreased cell apoptosis in lung tissue, compared with the I/R group. In contrast, IPO pretreatment enhanced the protective effects of MSC on I/R-induced lung injury compared with treatment alone. Moreover, in the combined treatment group, the number of MSC engraftments in the lung tissue was increased, associated with enhanced survival of MSCs compared with MSC treatment alone. Additional investigation showed that IPO treatment increased expression of vascular endothelial growth factor and stromal cell-derived factor-1 in I/R lung tissue. CONCLUSIONS: IPO might contribute to the homing and survival of transplanted MSCs and enhance their therapeutic effects through improvement of the microenvironment of I/R injury. PMID- 22520059 TI - Viewing a needle pricking a hand that you perceive as yours enhances unpleasantness of pain. AB - "Don't look and it won't hurt" is commonly heard advice when receiving an injection, which implies that observing needle pricks enhances pain perception. Throughout our lives, we repeatedly learn that sharp objects cause pain when penetrating our skin, but situational expectations, like information given by the clinician prior to an injection, may also influence how viewing needle pricks affects forthcoming pain. How both previous experiences and acute situational expectations related to viewing needle pricks modulate pain perception is unknown. We presented participants with video clips of a hand perceived as their own being either pricked by a needle or touched by a Q-tip, while concurrently applying painful or nonpainful electrical stimuli. Intensity and unpleasantness ratings, as well as pupil dilation responses, were monitored. Effects of situational expectations about the strength of electrical stimuli were investigated by manipulating the contingency between clips and electrical stimuli across experimental blocks. Participants were explicitly informed about the contingency. Intensity ratings of electrical stimuli were higher when a clip was associated with expectation of painful compared to nonpainful stimuli, suggesting that situational expectations about forthcoming pain bias perceived intensity. Unpleasantness ratings and pupil dilation responses were higher when participants viewed a needle prick, compared to when they viewed a Q-tip touch, suggesting that previous experiences with viewing needle pricks primarily act upon perceived unpleasantness. Thus, remote painful experiences with viewing needle pricks, together with information given prior to an injection, differentially shape the impact of viewing a needle prick on pain perception. PMID- 22520061 TI - Evaluating ritual efficacy: evidence from the supernatural. AB - Rituals pose a cognitive paradox: although widely used to treat problems, rituals are causally opaque (i.e., they lack a causal explanation for their effects). How is the efficacy of ritual action evaluated in the absence of causal information? To examine this question using ecologically valid content, three studies (N=162) were conducted in Brazil, a cultural context in which rituals called simpatias are used to treat a great variety of problems ranging from asthma to infidelity. Using content from existing simpatias, experimental simpatias were designed to manipulate the kinds of information that influences perceptions of efficacy. A fourth study (N=68) with identical stimuli was conducted with a US sample to assess the generalizability of the findings across two different cultural contexts. The results provide evidence that information reflecting intuitive causal principles (i.e., repetition of procedures, number of procedural steps) and transcendental influence (i.e., presence of religious icons) affects how people evaluate ritual efficacy. PMID- 22520060 TI - Expression of the G protein-coupled estrogen receptor (GPER) in endometriosis: a tissue microarray study. AB - BACKGROUND: The G protein-coupled estrogen receptor (GPER) is thought to be involved in non-genomic estrogen responses as well as processes such as cell proliferation and migration. In this study, we analyzed GPER expression patterns from endometriosis samples and normal endometrial tissue samples and compared these expression profiles to those of the classical sex hormone receptors. METHODS: A tissue microarray, which included 74 samples from different types of endometriosis (27 ovarian, 19 peritoneal and 28 deep-infiltrating) and 30 samples from normal endometrial tissue, was used to compare the expression levels of the GPER, estrogen receptor (ER)-alpha, ER-beta and progesterone receptor (PR). The immunoreactive score (IRS) was calculated separately for epithelium and stroma as the product of the staining intensity and the percentage of positive cells. The expression levels of the hormonal receptors were dichotomized into low (IRS < 6) and high (IRS > = 6) expression groups. RESULTS: The mean epithelial IRS (+/- standard deviation, range) of cytoplasmic GPER expression was 1.2 (+/- 1.7, 0-4) in normal endometrium and 5.1 (+/- 3.5, 0-12) in endometriosis (p < 0.001), of nuclear GPER 6.4 (+/- 2.6, 0-12) and 6.8 (+/- 2.9, 2-12; p = 0.71), of ER-alpha 10.6 (+/- 2.4, 3-12) and 9.8 (+/- 3.0, 2-12; p = 0.26), of ER-beta 2.4 (+/- 2.2; 0-8) and 5.6 (+/- 2.6; 0-10; p < 0.001), and of PR 11.5 (+/- 1.7; 3-12) and 8.1 (+/- 4.5; 0-12; p < 0.001), respectively. The mean stromal IRS of nuclear GPER expression was 7.7 (+/- 3.0; 2-12) in endometrium and 10.8 (+/- 1.7; 6-12) in endometriosis (p < 0.001), of ER-alpha 8.7 (+/- 3.1; 2-12) and 10.6 (+/- 2.4; 2 12; p = 0.001), of ER-beta 1.8 (+/- 2.0; 0-8) and 5.4 (+/- 2.5; 0-10; p < 0.001), and of PR 11.7 (+/- 0.9; 8-12) and 10.9 (+/- 2.0; 3-12; p = 0.044), respectively. Cytoplasmic GPER expression was not detectable in the stroma of endometrium and endometriosis. The observed frequency of high epithelial cytoplasmic GPER expression levels was 50% (n = 30/60) in the endometriosis and none (0/30) in the normal endometrium samples (p < 0.001). High epithelial cytoplasmic GPER expression levels were more frequent in endometriomas (14/20, 70%; p = 0.01), as compared to peritoneal (9/18, 50%) or deep-infiltrating endometriotic lesions (7/22, 31.8%). The frequency of high stromal nuclear GPER expression levels was 100% (n = 74/74) in endometriosis and 76.7% (n = 23/30) in normal endometrium (p < 0.001). The frequency of high epithelial nuclear GPER expression levels did not differ between endometriosis and normal endometrium. CONCLUSIONS: The present data indicate a unique GPER expression pattern in endometriosis, especially in endometriomas as compared to the normal endometrium. The overexpression of GPER in endometriotic lesions suggests a potential role for GPER in the hormonal regulation of endometriosis, which should be taken into consideration for future hormonal treatment strategies. PMID- 22520064 TI - Detection of methicillin-resistant Staphylococcus aureus (MRSA) in the microbial flora from the conjunctiva of healthy donkeys from Sicily (Italy). AB - OBJECTIVE: To describe the bacterial flora present in the normal conjunctiva of donkeys from Sicily (Italy). ANIMALS STUDIED: A total of 46 healthy donkeys housed in 3 locations within the territory of Palermo (Sicily, Italy) were studied. Donkeys ranged from 2 to 13 years of age, with a median age of 6 years. PROCEDURES: Forty-six conjunctival swabs were obtained from both eyes of each animal, and specimens were cultured for aerobic bacteria. Furthermore, the antimicrobial activity of methicillin (1 MUg) and oxacillin (5 MUg) on Staphylococcus spp. isolates was evaluated, and a specific PCR assay, which allows the detection of mecA gene specific for methicillin-resistant Staphylococcus aureus (MRSA) strains, was performed. RESULTS: Forty of 46 (86.9%) donkeys were positive for bacteria. Eighty bacterial isolates, representing 9 bacteria genera, were successfully cultured. The most frequently recovered bacterial genus was Staphylococcus (52/80 isolates; 65%). Several strains (20/80 isolates; 25%) belonging to the Enterobacteriaceae family were also isolated, among which the most frequently isolated genus was Enterobacter (eight isolates). Of the 52 Staphylococcus spp. isolates, 14 (26.9%) strains were oxacillin/methicillin resistant. The mecA gene was detected in 6/52 (11.5%) strains. CONCLUSIONS: This study contributes to the knowledge about normal ocular flora and MRSA occurrence in donkey farms in Sicily. PMID- 22520065 TI - Influence of the paraoxonase-1 Q192R genetic variant on clopidogrel responsiveness and recurrent cardiovascular events: a systematic review and meta analysis. AB - BACKGROUND: A poor biological response to clopidogrel is associated with an increased risk of major cardiovascular ischemic events (MACE). Paraoxonase 1 (PON1) enzyme activity is modulated by the PON1-Q192R variant (rs662) and was recently suggested to be strongly involved in clopidogrel bioactivation, but the influence of the PON1-Q192R variant on the risk of MACE in clopidogrel-treated patients is controversial. OBJECTIVES: To determine whether the PON1-Q192R variant influences clopidogrel biological responsiveness and the risk of MACE in patients treated with clopidogrel. METHODS: Systematic review and meta-analysis of studies of the association between the PON1-Q192R polymorphism and the biological response to clopidogrel and/or the risk of MACE during clopidogrel administration. RESULTS: Seventeen studies were included. In the 12 studies of the biological response to clopidogrel (n = 5302 patients), there was no significant difference between 192QQ and 192QR + 192RR subjects, whatever the laboratory method used (global mean standardized difference = 0.10 [-0.06; 0.25], P = 0.22). Eleven studies assessed the risk of MACE, four using a case-control design (n = 2739 patients) and seven a prospective design (n = 5353 patients). Overall, MACE occurred in 19% of patients in case-control studies and in 6% of patients in prospective cohort studies, with no significant difference between 192QQ and 192QR + 192RR patients (OR = 1.28 [0.97; 1.68], P = 0.08). Similar results were obtained when study design was taken into account. Heterogeneity was mainly driven by one publication. CONCLUSIONS: This meta-analysis suggests that the PON1-Q192R polymorphism has no major impact on the risk of MACE and does not alter the biological response to clopidogrel in clopidogrel-treated patients. PMID- 22520066 TI - Perceived crime and traffic safety is related to physical activity among adults in Nigeria. AB - BACKGROUND: Neighborhood safety is inconsistently related to physical activity, but is seldom studied in developing countries. This study examined associations between perceived neighborhood safety and physical activity among Nigerian adults. METHODS: In a cross-sectional study, accelerometer-based physical activity (MVPA), reported walking, perceived crime and traffic safety were measured in 219 Nigerian adults. Logistic regression analysis was conducted, and the odds ratio for meeting health guidelines for MVPA and walking was calculated in relation to four safety variables, after adjustment for potential confounders. RESULTS: Sufficient MVPA was related to more perception of safety from traffic to walk (OR=2.28, CI=1.13- 6.25) and more safety from crime at night (OR=1.68, CI=1.07-3.64), but with less perception of safety from crime during the day to walk (OR=0.34, CI=0.06- 0.91). More crime safety during the day and night were associated with more walking. CONCLUSIONS: Perceived safety from crime and traffic were associated with physical activity among Nigerian adults. These findings provide preliminary evidence on the need to provide safe traffic and crime environments that will make it easier and more likely for African adults to be physically active. PMID- 22520067 TI - How Norwegian casualty clinics handle contacts related to mental illness: A prospective observational study. AB - BACKGROUND: Low-threshold and out-of-hours services play an important role in the emergency care for people with mental illness. In Norway casualty clinic doctors are responsible for a substantial share of acute referrals to psychiatric wards. This study's aim was to identify patients contacting the casualty clinic for mental illness related problems and study interventions and diagnoses. METHODS: At four Norwegian casualty clinics information on treatment, diagnoses and referral were retrieved from the medical records of patients judged by doctors to present problems related to mental illness including substance misuse. Also, routine information and relation to mental illness were gathered for all consecutive contacts to the casualty clinics. RESULTS: In the initial contacts to the casualty clinics (n = 28527) a relation to mental illness was reported in 2.5% of contacts, whereas the corresponding proportion in the doctor registered consultations, home-visits and emergency call-outs (n = 9487) was 9.3%. Compared to other contacts, mental illness contacts were relatively more urgent and more frequent during night time. Common interventions were advice from a nurse, laboratory testing, prescriptions and minor surgical treatment. A third of patients in contact with doctors were referred to in-patient treatment, mostly non-psychiatric wards. Many patients were not given diagnoses signalling mental problems. When police was involved, they often presented the patient for examination. CONCLUSIONS: Most mental illness related contacts are managed in Norwegian casualty clinics without referral to in-patient care. The patients benefit from a wide range of interventions, of which psychiatric admission is only one. PMID- 22520068 TI - Enhancement potential of sucrose laurate (L-1695) on intestinal absorption of water-soluble high molecular weight compounds. AB - PURPOSE: The potential of sucrose fatty acid esters (SEs) to enhance intestinal absorption was investigated in order to identify their utility for the intestinal absorption of water-soluble high molecular weight compounds. METHODS: Fluorescein isothiocyanate-labeled dextran (FD) with a molecular weight (MW) of 4,000 (FD-4) was used as a model compound, and several SEs were tested as absorption enhancers. After FD-4 was administered intra-duodenally at 10 % (w/v) with the non-loop method in situ in rats in the absence or presence of SEs, the plasma concentration-time profiles of FD-4 were examined. As to sucrose laurate (L 1695), the relationship between concentration and enhancement effect was investigated. In addition, the enhancement effect after dosing into the different small intestinal regions, the effect on FDs with different MWs and the influence of N-acetyl-cysteine (NAC) co-existence were examined. RESULTS: Low water-soluble SEs exhibited slight and/or slow absorption enhancement effects, while L-1695, being highly water-soluble, had good potential to enhance the absorption rate and extent. The enhancement effect became greater as the concentration of L1695 increased. L-1695 displayed high enhancement potential in wide intestinal areas. The enhancement effect of L-1695 (10 %, w/v) depended on MWs of FDs; the mean values of the area under the plasma concentration curve from 0-120 min (AUC0-120 mins) increased by 14 and 8 times for FD-4 and FD-10 (MW 10,000), while it was hardly changed as for FD-70 (MW 70,000). The enhancement effect of L-1695 (10 %, w/v) was similar to that of sodium caprate (10 %, w/v), and was influenced to some extent by the co-existence of NAC (5 %, w/v). CONCLUSION: The absorption enhancement potential of SEs depended on their water-solubility. L-1695, being highly water-soluble, showed a good enhancement effect, and its absorption profiles were elucidated. This study proposes the possibility of SEs, in particular, L-1695, as intestinal absorption enhancers. As far as the present non loop method is concerned, the intestinal damage was not observed macroscopically with the addition of L1695 at 2.5-20 % (w/v). PMID- 22520069 TI - Oral targeting of protein kinase C receptor: promising route for diabetic retinopathy? AB - In patients with diabetes, hyperglycemia is known to promote high levels of diacylglycerol which activates protein kinase C (PKC) in the vascular tissues and leads to the production of vascular endothelial growth factor (VEGF) in the retina. PKC activation and increased concentration of VEGF are likely to play a key role in diabetic microvascular complications, particularly change in vascular permeability, inflammation, fluid leakage and ischemia in the retina. PKC comprises a super family of isoenzymes that is activated in response to various stimuli. The PKC family consists of 12 isomers that possess distinct differences in structure, substrate requirement, expression and localization. PKC isomer selective inhibitors and VEGF trap are likely to be new therapeutics, which can delay the onset or stop the progression of diabetic vascular disease. A new promising therapy for diabetic retinopathy is undergoing Phase III trials, in which they proposed to target PKC betaII isomer using Ruboxistaurin by oral administration. Besides retina, PKC betaII isomer is found in higher concentration in brain, spleen, etc. So, oral targeting may be a questionable approach since generalized inhibitors may prove toxic in the treatment of diabetic retinopathy and ocular delivery may be a better alternative approach. PMID- 22520070 TI - Preparation and in vitro in vivo evaluation of aceclofenac loaded alginate microspheres: an investigation of effects of polymer using multiple comparison analysis. AB - The aim of this present research work was to prepare and evaluate alginate microspheres of aceclofenac by ionic gelation method for targeting the drug release in intestinal region and decrease distinct tissue protection in the stomach. This method offers to prepare microspheres which are important in controlling the release rate and the absorption of aceclofenac from the intestinal region. Variation in polymer concentration was studied systemically for their influence on the encapsulation efficacy, particle size and in vitro drug release. The enteric nature of the microspheres showed very less amount of drug released in acidic medium. The mucoadhesion property was strongly dependent on the pH of the medium and the polymer concentration in the formulations. In vitro drug release study proposed a mixed drug release mechanism, partially involving the sphere matrix disintegration and drug diffusion of the microspheres. Holm-Sidak multiple comparison analysis suggested a significant difference in measured t50% values among all the microsphere formulations. In vivo studies revealed that the anti-inflammatory effect induced by the aceclofenac loaded alginate microspheres was significantly high and prolonged than that induced by the pure aceclofenac. So, this aceclofenac loaded alginate microspheres exhibited promising properties to improve the patient compliance by controlling and prolonging the systemic absorption of aceclofenac along with a distinct tissue protection in the stomach. PMID- 22520071 TI - Her2/neu small interfering RNA delivered in culture by a streptavidin nanoparticle. AB - A three-component nanoparticle consisting of biotinylated Trastuzumab antiHer2 antibody, tat transferring peptide and radiolabeled antisense oligomer, linked together through streptavidin, have shown promise in the delivery to Her2+ tumor in mice following intravenous administration and with evidence of radiotherapeutic efficacy. These results have encouraged us to consider the nanoparticle as a delivery vehicle for RNA interference therapy in which the radiolabeled antisense oligomer is replaced with an unlabeled siRNA duplex. The siRNA stability within the nanoparticle was first confirmed by incubation with RNase A. The interferon responses, that indicate off-target cytotoxicity, were evaluated by quantitative real-time RT-PCR in BT-474 (Her2+) human breast cancer cells by measuring the mRNA expression of 2', 5'-oligoadenylate synthetase (OAS1) and Stat-1, two key interferon-responsive genes. Thereafter the cytotoxicity induced by the siRNA nanoparticle was evaluated by a clonogenic survival assay in BT-474 cells while the Her2 expression of these target cells was evaluated for evidence of specific gene silencing. The siRNA within the three-component anti- Her2/neu siRNA nanoparticle was largely protected from RNase-dependent degradation and did not activate an interferon response. The nanoparticle effectively and significantly inhibited colony formation of the target cells and silenced the Her2 gene expression at 5 nM compared with the identical nanoparticle with a scrambled siRNA. Our delivery nanoparticle, with tumor targeting provided by the antibody and its accumulation without entrapment, possibly due to the transfecting peptide, delivered an siRNA duplex to the proper subcellular localization for specific and effective gene silencing in culture by what appears to be an siRNA mechanism. PMID- 22520073 TI - Degradation of high energetic and insensitive munitions compounds by Fe/Cu bimetal reduction. AB - A reductive technology based on a completely mixed two-phase reactor (bimetallic particles and aqueous stream) was developed for the treatment of aqueous effluents contaminated with nitramines and nitro-substituted energetic materials. Experimental degradation studies were performed using solutions of three high energetics (RDX, HMX, TNT) and three insensitive-munitions components (NTO, NQ, DNAN). The study shows that, on laboratory scale, these energetic compounds are easily degraded in solution by suspensions of bimetallic particles (Fe/Ni and Fe/Cu) prepared by electro-less deposition. The type of bimetal pair (Fe/Cu or Fe/Ni) does not appear to affect the degradation kinetics of RDX, HMX, and TNT. The degradation of all components followed apparent first-order kinetics. The half-lives of all compounds except NTO were under 10 min. Additional parameters affecting the degradation processes were solids loading and initial pH. PMID- 22520074 TI - Quasi-Monte Carlo based global uncertainty and sensitivity analysis in modeling free product migration and recovery from petroleum-contaminated aquifers. AB - This paper presents a global uncertainty and sensitivity analysis (GUSA) framework based on global sensitivity analysis (GSA) and generalized likelihood uncertainty estimation (GLUE) methods. Quasi-Monte Carlo (QMC) is employed by GUSA to obtain realizations of uncertain parameters, which are then input to the simulation model for analysis. Compared to GLUE, GUSA can not only evaluate global sensitivity and uncertainty of modeling parameter sets, but also quantify the uncertainty in modeling prediction sets. Moreover, GUSA's another advantage lies in alleviation of computational effort, since those globally-insensitive parameters can be identified and removed from the uncertain-parameter set. GUSA is applied to a practical petroleum-contaminated site in Canada to investigate free product migration and recovery processes under aquifer remediation operations. Results from global sensitivity analysis show that (1) initial free product thickness has the most significant impact on total recovery volume but least impact on residual free product thickness and recovery rate; (2) total recovery volume and recovery rate are sensitive to residual LNAPL phase saturations and soil porosity. Results from uncertainty predictions reveal that the residual thickness would remain high and almost unchanged after about half year of skimmer-well scheme; the rather high residual thickness (0.73-1.56 m 20 years later) indicates that natural attenuation would not be suitable for the remediation. The largest total recovery volume would be from water pumping, followed by vacuum pumping, and then skimmer. The recovery rates of the three schemes would rapidly decrease after 2 years (less than 0.05 m(3)/day), thus short-term remediation is not suggested. PMID- 22520075 TI - Physico-chemical properties of chars obtained in the co-pyrolysis of waste mixtures. AB - The present work aims to perform a multistep upgrading of chars obtained in the co-pyrolysis of PE, PP and PS plastic wastes, pine biomass and used tires. The quality of the upgraded chars was evaluated by measuring some of their physico chemical properties in order to assess their valorisation as adsorbents' precursors. The crude chars were submitted to a sequential solvent extraction with organic solvents of increasing polarity (hexane, mixture 1:1 v/v hexane:acetone and acetone) followed by an acidic demineralization procedure with 1M HCl solution. The results obtained showed that the upgrading treatment allow the recovery of 63-81% of the pyrolysis oils trapped in the crude chars and a reduction in the char's ash content in the range of 64-86%. The textural and adsorption properties of the upgraded chars were evaluated and the results indicate that the chars are mainly mesoporous and macroporous materials, with adsorption capacities in the range of 3.59-22.2 mg/g for the methylene blue dye. The upgrading treatment allowed to obtain carbonaceous materials with quality to be reused as adsorbents or as precursors for activated carbon. PMID- 22520076 TI - A phase I clinical study of inhaled nitric oxide in healthy adults. AB - BACKGROUND: Nitric oxide (NO) is an approved pulmonary vasodilator for neonates and full term infants up to a dose of 80 ppm. At 100 ppm to 200 ppm, NO has potent antimicrobial activities in vitro and in animal studies which suggest its therapeutic use for infectious diseases in humans. However, whether inhaled NO is safe at 160 ppm in healthy human adults is unknown. The aim of the phase I study was to assess the safety of delivery and the physiologic effects of intermittent 160 ppm NO in healthy human adults. METHODS: Ten healthy adult volunteers (5 males, 5 females; 20-62 years) were recruited and inhaled 163.3 ppm (SD: 4.0) NO for 30 min, 5 times daily, for 5 consecutive days. Lung function and blood levels of methemoglobin, nitrites/nitrates, prothrombin, pro-inflammatory cytokines and chemokines were determined before and during treatment. RESULTS: All individuals tolerated the NO treatment courses well. No significant adverse events occurred and three minor adverse events, not attributable to NO, were reported. Forced expiratory volume in 1 sec % predicted and other lung function parameters, serum nitrites/nitrates, prothrombin, pro-inflammatory cytokine and chemokine levels did not differ between baseline and day 5, while methemoglobin increased significantly during the study period to a level of 0.9% (SD: 0.08) (p<0.001). CONCLUSION: These data suggest that inhalation of 160 ppm NO for 30 min, 5 times daily, for 5 consecutive days, is safe and well tolerated in healthy individuals. PMID- 22520078 TI - Amino acid screening based on structural modeling identifies critical residues for the function, ion selectivity and structure of Arabidopsis MTP1. AB - Arabidopsis thaliana MTP1 is a vacuolar membrane Zn(2+)/H(+) antiporter of the cation diffusion facilitator family. Here we present a structure-function analysis of AtMTP1-mediated transport and its remarkable Zn(2+) selectivity by functional complementation tests of more than 50 mutant variants in metal sensitive yeast strains. This was combined with homology modeling of AtMTP1 based on the crystal structure of the Escherichia coli broad-specificity divalent cation transporter YiiP. The Zn(2+)-binding sites of EcYiiP in the cytoplasmic C terminus, and the pore formed by transmembrane helices TM2 and TM5, are conserved in AtMTP1. Although absent in EcYiiP, Cys31 and Cys36 in the extended N-terminal cytosolic domain of AtMTP1 are necessary for complementation of a Zn-sensitive yeast strain. On the cytosolic side of the active Zn(2+)-binding site inside the transmembrane pore, Ala substitution of either Asn258 in TM5 or Ser101 in TM2 non selectively enhanced the metal tolerance conferred by AtMTP1. Modeling predicts that these residues obstruct the movement of cytosolic Zn(2+) into the intra membrane Zn(2+)-binding site of AtMTP1. A conformational change in the immediately preceding His-rich cytosolic loop may displace Asn258 and permit Zn(2+) entry into the pore. This would allow dynamic coupling of Zn(2+) transport to the His-rich loop, thus acting as selectivity filter or sensor of cytoplasmic Zn(2+) levels. Individual mutations at diverse sites within AtMTP1 conferred Co and Cd tolerance in yeast, and included deletions in N-terminal and His-rich intra-molecular cytosolic domains, and mutations of single residues flanking the transmembrane pore or participating in intra- or inter-molecular domain interactions, all of which are not conserved in the non-selective EcYiiP. PMID- 22520079 TI - Transcriptome analysis of stem development in the tumourous stem mustard Brassica juncea var. tumida Tsen et Lee by RNA sequencing. AB - BACKGROUND: Tumourous stem mustard (Brassica juncea var. tumida Tsen et Lee) is an economically and nutritionally important vegetable crop of the Cruciferae family that also provides the raw material for Fuling mustard. The genetics breeding, physiology, biochemistry and classification of mustards have been extensively studied, but little information is available on tumourous stem mustard at the molecular level. To gain greater insight into the molecular mechanisms underlying stem swelling in this vegetable and to provide additional information for molecular research and breeding, we sequenced the transcriptome of tumourous stem mustard at various stem developmental stages and compared it with that of a mutant variety lacking swollen stems. RESULTS: Using Illumina short-read technology with a tag-based digital gene expression (DGE) system, we performed de novo transcriptome assembly and gene expression analysis. In our analysis, we assembled genetic information for tumourous stem mustard at various stem developmental stages. In addition, we constructed five DGE libraries, which covered the strains Yong'an and Dayejie at various development stages. Illumina sequencing identified 146,265 unigenes, including 11,245 clusters and 135,020 singletons. The unigenes were subjected to a BLAST search and annotated using the GO and KO databases. We also compared the gene expression profiles of three swollen stem samples with those of two non-swollen stem samples. A total of 1,042 genes with significantly different expression levels occurring simultaneously in the six comparison groups were screened out. Finally, the altered expression levels of a number of randomly selected genes were confirmed by quantitative real time PCR. CONCLUSIONS: Our data provide comprehensive gene expression information at the transcriptional level and the first insight into the understanding of the molecular mechanisms and regulatory pathways of stem swelling and development in this plant, and will help define new mechanisms of stem development in non-model plant organisms. PMID- 22520080 TI - [Recommendations against prostate cancer screening with PSA]. PMID- 22520081 TI - An anatomical study of normal meniscal roots with isotropic 3D MRI at 3T. AB - OBJECTIVES: To clarify the morphological features of normal meniscal roots on magnetic resonance (MR) imaging with an isotropic 3D proton density-weighted (PDW) sequence. MATERIALS: 3D PDW MR was performed in sixty-two patients at 3T before knee arthroscopy. MR images of 34 normal medial menisci and 33 intact lateral menisci confirmed by arthroscopy were retrospectively evaluated. MR signals, insertion sites, dimensions and courses of four meniscal roots were recorded. RESULTS: The anterior root of medial meniscus (ARMM) was typically hypointense, while the posterior root of medial meniscus (PRMM) and the anterior root of lateral meniscus (ARLM) were prone to be hyperintense or showing a comblike signal, and the posterior root of lateral meniscus (PRLM) was usually hypointense or comblike on PDW MR images. ARMM and PRLM had more complex and diverse insertion patterns than ARLM and PRMM. There were significant statistical differences of the lengths, widths, heights and course angles among four meniscal roots (all P<0.001). CONCLUSIONS: The signal intensity of each meniscal root can be hypointense, hyperintense, or comblike on 3D PDW MR images. ARMM and PRLM have more complex and diverse insertion patterns than ARLM and PRMM. The dimensions and courses of four meniscal roots all differ. PMID- 22520082 TI - Differentiation between benign and malignant solid pseudopapillary tumor of the pancreas by MDCT. AB - PURPOSE: The purpose of this study was to determine if characteristic features on computed tomographic and (or) magnetic resonance imaging can differentiate benign and malignant solid pseudopapillary neoplasms (SPN). MATERIALS AND METHODS: A total of 82 pathologically diagnosed SPN patients were included. CT and MRI were reviewed by 3 radiologists. Each tumor was analyzed through the clinical and imaging features. RESULTS: The highest occurrence of malignant SPN was observed in the group of patients (11-19 years old) followed by the group of patients (50 65 years old). When the tumor was located in the tail and the size was equal or larger than 6.0 cm, the positive and predictive value, the predictive value, sensitivity and specificity for a malignant SPN were 61.5%, 100%, 100% and 78.6%, respectively. Presence of complete encapsulation was more frequent in benign SPNs, but focal discontinuity in the malignant SPNs. Amorphous or scattered calcifications, all near-solid tumors and presence of upstream pancreatic ductal was found in the benign SPNs. CONCLUSION: A focal discontinuity of the capsule, large tumor size (>6.0 cm) and a pancreatic tail location may suggest malignancy of SPN. In contrast, tumors with amorphous or scattered calcifications, and all near-solid tumors may be indicative of benignancy. Age (less than 20 or more than 50 years old) is a possible risk factor of SPN. In comparison to other pancreatic neoplasms, such as ductal adenocarcinoma, a complete/incomplete pseudo-capsule, without upstream pancreatic duct dilatation and lymph nodes metastasis, and the presence of internal calcification and hemorrhage are more likely SPN. PMID- 22520083 TI - Early neurovascular uncoupling in the brain during community acquired pneumonia. AB - INTRODUCTION: Sepsis leads to microcirculatory dysfunction and therefore a disturbed neurovascular coupling in the brain. To investigate if the dysfunction is also present in less severe inflammatory diseases we studied the neurovascular coupling in patients suffering from community acquired pneumonia. METHODS: Patients were investigated in the acute phase of pneumonia and after recovery. The neurovascular coupling was investigated with a simultaneous electroencephalogram (EEG)-Doppler technique applying a visual stimulation paradigm. Resting EEG frequencies, visual evoked potentials as well as resting and stimulated hemodynamic responses were obtained. Disease severity was characterized by laboratory and cognitive parameters as well as related scoring systems. Data were compared to a control group. RESULTS: Whereas visually evoked potentials (VEP) remained stable a significant slowing and therefore uncoupling of the hemodynamic responses were found in the acute phase of pneumonia (Rate time: control group: 3.6 +/- 2.5 vs. acute pneumonia: 1.6 +/- 2.4 s; P < 0.0005). In the initial investigation, patients who deteriorated showed a decreased hemodynamic response as compared with those who recovered (gain: recovered: 15% +/- 4% vs. deteriorated: 9% +/- 3%, P < 0.05; control: 14% +/- 5%). After recovery the coupling normalized. CONCLUSIONS: Our study underlines the role of an early microcirculatory dysfunction in inflammatory syndromes that become evident in pre-septic conditions with a gradual decline according to disease severity. PMID- 22520084 TI - Efficacy and optimal dosing interval of the long-acting beta2 agonist, vilanterol, in persistent asthma: a randomised trial. AB - BACKGROUND: Vilanterol (VI) is a novel once-daily long-acting beta2 agonist with inherent 24-h activity. The aim of this study was to evaluate the efficacy of three once-daily doses and one twice-daily dose of VI used concurrently with ICS in adult patients (>=18 years) with persistent asthma. Safety was also assessed. METHODS: Multicentre, randomised, double-blind, placebo-controlled, five-period crossover study consisting of 7-day treatment periods separated by 7-day wash-out periods. Seventy-five patients, maintained on ICS, received VI 6.25, 12.5 and 25 mcg once-daily (evening), VI 6.25 mcg twice-daily (morning/evening), and placebo. The primary endpoint was trough forced expiratory volume in 1 s (FEV(1)) (mean of 23 h and 24 h post evening dose) on Day 7; secondary endpoint was weighted mean 24-h serial FEV(1) on Day 7. RESULTS: All VI groups demonstrated statistically significant increases in trough FEV(1) versus placebo (p < 0.001). There was a statistically significant increase in weighted mean 24-h FEV(1) for each VI group versus placebo (p < 0.001). The effects of once-daily VI on trough FEV(1) and weighted mean 24-h FEV(1) were dose dependent. The incidence of adverse events (AEs) was low in each VI treatment group and was not dose dependent (5-9%; placebo = 18%); no drug-related AEs or serious AEs were reported. CONCLUSION: Once-daily treatment with VI was well tolerated and associated with improvements in lung function. The VI 6.25 mcg twice-daily dose showed the greatest change in trough FEV(1), however, similar changes in weighted mean 24-h FEV(1) with VI 12.5 mcg once-daily were observed. Although our study was not powered to demonstrate non-inferiority of once- versus twice-daily dosing of VI, the data suggest no advantage over a 24-h period of twice-daily over once-daily dosing for the same total daily dose. ClinicalTrials.gov: NCT00980200. PMID- 22520085 TI - Health-related quality of life as measured by the child health questionnaire in adolescents with bipolar disorder treated with olanzapine. AB - AIM: To examine health-related quality of life (HRQoL) in adolescents with bipolar disorder before and after double-blind treatment with olanzapine or placebo. METHODS: Parents or legal guardians of 160 adolescents with a manic or mixed episode associated with bipolar I disorder were asked to rate their child's health using the Child Health Questionnaire-Parental Form 50 at baseline, before receiving medication, and then again at the end of participation in a 3-week double-blind placebo-controlled study of olanzapine. RESULTS: Adolescents in both treatment groups began and ended the study with significantly lower scores than normalized values of healthy peers on several HRQoL subscales (lower ratings indicate more impaired functioning), especially those assessing psychosocial factors. However, participants receiving olanzapine exhibited greater improvement than those in the placebo group across multiple HRQoL subscales, including the Behavior, Family activities, and Mental health subscales. Reduction in manic symptoms was associated with improvement in HRQoL values. CONCLUSIONS: As expected, manic adolescents with bipolar disorder exhibit abnormalities in psychosocial, rather than physical factors associated with HRQoL. Treatment with olanzapine had a greater effect on multiple domains of psychosocial functioning compared with placebo, suggesting that in addition to improving manic symptoms, pharmacologic interventions may lessen some of psychosocial deficits experienced by adolescents with bipolar disorder. However, following 3 weeks of treatment, adolescents with bipolar disorder continued to exhibit deficits in several aspects of psychosocial functioning, indicating that additional pharmacologic and psychosocial interventions may be necessary to further improve functional outcome. PMID- 22520086 TI - Outcomes of compulsorily admitted schizophrenia patients who agreed or disagreed to prolong their hospitalization. AB - BACKGROUND: Compulsory admission is practiced around the world with legislative variations. The legal status during compulsory hospitalization might be changed to consent or the patient might be discharged against medical advice (AMA), if he no longer poses a risk. OBJECTIVE: In the present study, we investigated the outcome of compulsory admitted patients who left the hospital after commitment period despite request by the treating psychiatrist to remain in the hospital (AMA) vs those who agreed to prolong their hospitalization. RESULTS: Of 320 patients with schizophrenia admitted involuntarily, 157 (49%) were discharged without converting to consent, and 163 (51%) agreed to stay in the hospital. There was no difference in baseline clinical and demographic characteristics and outcome measures (rate of readmission, legal status of next admission, and length of stay in the next admission) between the 2 groups. CONCLUSIONS: Prolongation of length of stay in compulsorily psychiatrist-ordered schizophrenia patients did not affect their rate of rehospitalizations or the length of next admission compared with those who left the hospital immediately after the change in their legal status AMA. PMID- 22520087 TI - Autonomic reactivity and hypothalamic pituitary adrenal axis dysregulation in spouses of Oklahoma City bombing survivors 7 years after the attack. AB - OBJECTIVE: The objective of this exploratory pilot study was to examine autonomic reactivity and hypothalamic pituitary adrenal axis dysregulation in spouses of highly exposed survivors of the 1995 Oklahoma City bombing. METHODS: This study compared psychiatric diagnoses and biological stress markers (physiological reactivity and cortisol measures) in spouses of bombing survivors and matched community participants. Spouses were recruited through bombing survivors who participated in prior studies. Individuals with medical illnesses and those taking psychotropic medications that would confound biological stress measures were excluded. The final sample included 15 spouses and 15 community participants. The primary outcome measures were psychiatric diagnoses assessed with the Diagnostic Interview Schedule for DSM-IV (DIS-IV). Biological stress markers were physiological reactivity and recovery in heart rate and blood pressure responses to a trauma interview and cortisol (morning, afternoon, and diurnal variation). RESULTS: Compared to the community participants, spouses evidenced greater reactivity in heart rate, systolic blood pressure, and diastolic blood pressure; delayed recovery in systolic blood pressure; and higher afternoon salivary cortisol. CONCLUSIONS: The results support the need for further research in this area to clarify post-disaster effects on biological stress measures in the spouses of survivors and the potential significance of these effects and to address the needs of this important population which may be overlooked in recovery efforts. PMID- 22520088 TI - Personality disorder--not otherwise specified evidence of validity and consideration for DSM-5. AB - Personality disorder-not otherwise specified (PD-NOS) has received little study despite being a very prevalent diagnosis of personality disorder (PD). Although some studies suggest that PD-NOS is intermediate in severity between subjects with, and without, formal PD, studies examining a comprehensive set of measures and control subjects have not been reported. Nearly 800 subjects were studied with semi-structured diagnostic interviews and with a variety of measures of temperament, character, and specific dimensions of personality and behavior. The subjects were divided into healthy controls (n = 176), Axis I controls (n = 87), PD subjects (n = 344) and PD-NOS subjects (n = 177). Subjects who met General Diagnostic Criteria for Personality Disorder (GDCPD), but not criteria for any one, specific PD, were designated as PD-NOS. On nearly all measures, PD-NOS differed from Healthy and from Axis I Controls in the direction of more pathology. Although subjects meeting criteria for specific PDs appeared more pathological than PD-NOS, this was always due to severity of PD as reflected by the Structured Interview for the Diagnosis of DSM Personality 4 severity score. When compared with subjects with only one specific PD diagnosis, subjects with PD NOS did not differ in any way. When diagnosed by GDCPD, subjects with PD-NOS are similar to subjects with specific personality disorders and differ, as expected, from Healthy and Axis I Controls on measures of psychosocial function and on various dimensions of personality and related behavior. Accordingly, PD-NOS by GDCPD is as valid a PD as any other specific PD by DSM criteria. PMID- 22520089 TI - Risk factors for medical deterioration of psychiatric inpatients: opportunities for early recognition and prevention. AB - BACKGROUND: Medical deterioration during admission to free-standing psychiatric hospitals is distressing for patients, interrupts bio-behavioral interventions, and places a substantial burden on health care resources. Emergency transfers to a general hospital are a reasonable marker of significant medical deterioration, but have not been assessed systematically. OBJECTIVE: To use clinical data available at the time of psychiatric admission to identify risk factors for transfers to a general hospital. METHOD: Retrospective review of the hospital course of 1000 adults consecutively admitted for an average of 19.1 +/- 21.3 days to a single free-standing psychiatric hospital in 2010. RESULTS: One hundred forty-four patients (14.4%) were transferred to a general hospital. Transferred and not-transferred groups differed significantly with regard to age, presence of dementia, number of comorbid medical disorder, history of arterial hypertension, blood urea nitrogen (BUN), creatinine, albumin, glucose, calcium, hemoglobin, and hematocrit (P < .001). In a multiple logistic regression analysis, blood urea nitrogen (odds ratio [OR], 63.2), hemoglobin (OR, 35.3), albumin (OR, 7.3) and age (OR, 5.73) were independently associated with transfers. Acute medical deteriorations occurred in 46.2% of patients with azotemia (BUN >24 mg/dL), 32.7% of those with anemia (Hb <12 g/L), 37.5 % of those with hypoalbuminemia (albumin <3.7 g/dL), and 37.4% of patients 65 and older. CONCLUSION: Medical deterioration of psychiatric inpatients correlates with higher BUN, lower albumin and hemoglobin, and older age. Baseline azotemia, anemia or hypoalbuminemia should trigger prompt medical evaluation and enhanced monitoring to prevent, identify, and treat somatic disorders. PMID- 22520091 TI - Determining remission from depression on two self-report symptom scales: a comparison of the Quick Inventory of Depressive Symptomatology and the Clinically Useful Depression Outcome Scale. AB - To answer fundamental questions regarding the effectiveness of treatments for depression in real-world clinical practice, it is necessary to incorporate the measurement of outcome. Self-report questionnaires are a cost-effective option to systematically, reliably, and validly evaluate clinical status because they are inexpensive in terms of professional time needed for administration, and do not require special training for administration. While there are many self administered depression scales, only a limited number cover all of the diagnostic criteria for major depressive disorder (MDD) and have had cutoff scores derived corresponding to the Hamilton Depression Rating Scale (HAM-D) definition of remission. In the present study from the Rhode Island Methods to Improve Diagnostic Assessment and Services project, we compared 2 scales in their respective ability to identify remission as defined by the HAM-D. We administered the 17-item HAM-D to 274 depressed outpatients in ongoing treatment. The patients completed the Quick Inventory of Depressive Symptomatology (QIDS) and the Clinically Useful Depression Outcome Scale (CUDOS). Based on the cutoffs recommended by the developers of the scales to identify remission, the 2 scales performed similarly overall though the sensitivity was higher for the QIDS than the CUDOS (95.5% vs. 78.7%), whereas specificity was higher for the CUDOS than the QIDS (73.0% vs. 50.0%). On the CUDOS, the cutoff that maximized the sum of sensitivity and specificity was similar to cutoff initially derived for this purpose; however, for the QIDS, the optimal cutoff was higher than the cutoff originally derived for this purpose. In conclusion, the CUDOS and the QIDS were equally highly related to the HAM-D definition of remission. The CUDOS takes less time to complete than the QIDS and, therefore, may be preferable to use in routine clinical practice. PMID- 22520092 TI - Association between kinase insert domain-containing receptor gene polymorphisms and silent brain infarction: a Korean study. AB - BACKGROUND: Kinase insert domain-containing receptor (KDR), vascular endothelial growth factor receptor-2, play a pivotal role in endothelial dysfunction, which may lead to silent brain infarction (SBI). We evaluated whether single nucleotide polymorphisms (SNPs) of KDR genes are associated with increased risk of SBI in a Korean population. METHODS: A total of 383 patients with SBI and 387 controls were genotyped for the KDR -604T>C, 1192G>A, and 1719A>T SNPs. We separately analyzed this association according to the age (age>=65 and age<65) and the gender. We also compared haplotype frequencies between SBI patients and controls. RESULTS: Genotype frequencies for three SNPs did not differ significantly between SBI patients and controls. In addition, haplotype analysis for three SNPs did not show a difference between patients and controls. However, the frequency of genotype of KDR -604T>C was significantly associated with an increased risk of SBI in the age<65 years old group (AOR=1.515, 95% CI, 1.003 to 2.289, p=0.048) and in male group (AOR=1.596, 95% CI, 1.018 to 2.503, p=0.042). CONCLUSIONS: KDR 604T>C SNP may serve as genetic markers for the increased risk of SBI among the younger (<65 years) or male only Korean subpopulations. PMID- 22520090 TI - Reliability and validity of the Center for Epidemiological Studies Depression Scale in 2 special adult samples from rural China. AB - Few studies on the validation of the Center for Epidemiological Studies Depression Scale (CES-D) in Chinese have been conducted in the samples from rural area, whereas the mental health problems among rural Chinese deserve more attention. For instance, the suicide rate in rural China is about 3 times that of the urban rate. This study aimed at assessing reliability and validity of the CES D in 2 special adult samples in rural China, with data obtained by face-to-face interviews. One sample consisted of the proxy informants for subjects who committed suicide, and the other was of the proxy informants for living controls. For each person who committed suicide and each control, a family member and close friend served as informants. This study focused on informants themselves (not the persons who committed suicide or the living control himself/herself). Suicide informants (n = 781) who had experienced the suicide of a relative or close friend in the past 6 months were compared with the control informants (n = 832) who had no such experience. Internal reliability was satisfactory (Cronbach coefficients were .949 for suicide informants and .880 for control informants). Good concurrent validity and criterion validity were found by analyzing the relations to negative life events and the Scale for Suicide Ideation. Confirmatory factor analyses indicated that 3-factor structure (positive affect, interpersonal problems, depressive mood and somatic symptoms combined) had good fit in rural Chinese. These findings suggested that the CES-D had good reliability and validity when applied in these 2 adult samples in rural China. Factor structure analyses of the CES-D indicated that "somatization" process of expressing depressive symptoms still existed among rural Chinese. PMID- 22520093 TI - Analysis of spinocerebellar ataxias due to expanded triplet repeats in Greek patients with cerebellar ataxia. AB - The relative frequency of different autosomal dominant cerebellar ataxias, commonly referred to as spinocerebellar ataxias (SCAs), varies considerably among populations of different ethnic origin. No data exist at present on the frequency of different SCAs in the Greek population. In the present study we investigated the presence of triplet repeat expansion SCAs (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17 and DRPLA) in a cohort of 83 Greek patients with slowly progressive cerebellar ataxia. Twenty patients came from autosomal dominant (AD) pedigrees, seven displayed recessive or unclear inheritance and 56 were sporadic. We found four patients with pathological SCA expansions, all from AD pedigrees. Two patients had SCA1, one SCA2 and one SCA7 (10.0, 5.0 and 5.0% of the AD group, respectively). The clinical features of these patients were within the expected spectrum. In total, a pathological expansion was detected in 20% of patients from AD pedigrees. Interestingly, no cases of SCA3 or SCA6 were detected in the AD group. No expansions were found in other familial cases or in sporadic patients. Overall, no cases of SCA3, SCA6, SCA12, SCA17 or DRPLA were identified in the Greek population. In conclusion, SCA1, SCA2 and SCA7 are present in Greek patients with AD cerebellar ataxia in frequencies similar to those observed in other populations. SCA3 and SCA6 appear however to be rare in Greece. The genetic cause for the majority of AD ataxias remains to be identified. PMID- 22520094 TI - Correlation between thyroid autoantibodies and intracranial arterial stenosis in stroke patients with hyperthyroidism. AB - We performed a retrospective case review of stroke patients with diagnosis of hyperthyroidism admitted in our hospital from January 2008 to December 2010. We reviewed their routine assessments of intracranial and extracranial arteries or heart and then compared the demographic profiles, thryroid function test, and thyroid autoantibody status between stroke patients with and without intracranial stenosis. We also compared the baseline characteristics, thyroid function test (TFT), and prevalence of intracranial arterial stenosis between patients with or without elevated TPO-Ab level. We use the Wicoxon rank sum test for nonparametric and Fisher's exact test for categorical comparisons. A total of 17 acute ischemic stroke patients with hyperthyroidism were included and 8 (47.0%) patients was found to have intracranial stenosis. The patients with intracranial stenosis had a higher prevalence of elevated antithyroperoxidase antibody (TPO-Ab), compared with those without intracranial stenosis (100% versus 33.3%, p=0.004), while thyroid function tests were not significantly different between two groups. So we come to the conclusion that elevated thyroid autoantibody, especially TPO-Ab, is associated with the development of intracranial stenosis in hyperthyroid patients and therefore monitoring of intracranial vessels is suggested in hyperthyroid patients with high level of thyroid autoantibodies. PMID- 22520096 TI - [A new phase]. PMID- 22520097 TI - [Second parts were also good: Note from the SENEC Board of Directors at the beginning of the new age of Neurosurgery]. PMID- 22520095 TI - CT cisternography in intracranial symptomatic arachnoid cysts: classification and treatment. AB - OBJECTIVES: The symptom and neuroimaging as indications for treating arachnoid cysts (ACs) are not adequate. Understanding the communication between cyst and subarachnoid space is helpful for decision-making. We took a dynamic study of ACs using CT cisternography (CTC) and proposed a classification of arachnoid cysts. MATERIALS AND METHODS: Total 52 symptomatic patients with ACs were enrolled in this prospective study. CTC images were ordered, in all enrolled patients, at the 1, 3, 6, 12, 24 and 48 h after the intrathecal Omnipaque administration. Enhancement in cysts was measured quantitatively and was compared with neighboring subarachnoid spaces. All enrolled patients were allocated randomly in 2 groups. The CTC result was considered before treatment in one group (CTC group), while another group was surgically treated without considering CTC results (surgical group). RESULTS: ACs in our study were classified into 3 types: complete (cyst filling time at 1 h), incomplete (filling time began at 3 h) and noncommunicating cysts (no or slight filling after 24 h). Twenty-two patients in CTC group with incomplete communicating, or noncommunicating cysts underwent surgeries. And other 6 patients with complete communicating cysts were closely observed. In CTC group, the symptom of all surgical patients was relieved, and 5 out of 6 observational patients showed clinical improvement or no deterioration during the follow-up. In surgical group, only 18 out of 24 patients showed clinical improvement after surgeries, and there were 6 patients showing no difference before and after surgeries in symptom and in imaging. CONCLUSIONS: This classification based on dynamic CT cisternography is useful for the decision of surgical indication. Some symptomatic patients with complete communicating ACs may not need surgical intervention. PMID- 22520098 TI - Bypass surgery for the prevention of ischemic stroke: current indications and techniques. AB - INTRODUCTION: Although most ischemic strokes are thromboembolic in origin and their management is endovascular or medical, some are haemodynamic in origin and their management may be surgical. We reviewed bypass indications, patient selection and surgical techniques used in our current practice. METHODS: Extracranial-intracranial (EC-iC) bypass with superior temporal artery-to-middle cerebral artery (STA-MCA) bypass, high-flow interposition grafts and reconstructive techniques were used to treat patients with symptomatic ischemia. RESULTS: During a 13-year period, 152 bypasses were performed for ischemia in 129 patients. Specific diagnoses included: (1) internal carotid artery (iCA) occlusion (58 bypasses); (2) MCA occlusion and, rarely, high-grade MCA stenosis (22 bypasses); (3) vertebrobasilar atherosclerotic steno-occlusive disease (2 bypasses); (4) moyamoya disease (65 bypasses); and (5) ischemic complications after aneurysm treatment (5 bypasses). of the 152 bypasses, 137 were conventional STA-MCA bypasses. fourteen patients had high-flow bypasses that included 4 "double-barrel" STA-MCA bypasses, 6 bypasses with interposition grafts to the cervical carotid artery, 2 subclavian artery-to-MCA bypasses, 1 MCA-to-posterior cerebral artery (PCA) bypass and 1 aorto-carotid bypass. The bypass patency rate was 96.1%. CONCLUSIONS: Bypass surgery for the prevention of ischemic stroke is safe and elegant techniques have been developed. Patients with athero-occlusive disease, ischemic symptoms and haemodynamic insufficiency have significant risk of stroke if managed medically or left untreated. However, surgical intervention lacks supporting evidence from the recent Carotid occlusion Surgery Study (CoSS). Patients will be caught in a difficult position between a dismal natural history and an unproven surgical intervention. Clinicians must individualise their management until additional data are published or further consensus develops. PMID- 22520099 TI - [Antibiotic-impregnated catheters. A useful tool against infection]. AB - Progress in the treatment of hydrocephalus and particularly of cerebrospinal fluid (CSF) diversion surgery has been continuous and significant from cranial bandaging, which was one of the initial hydrocephalus treatments in the 16th century, to last-generation CSF shunts. However, infection currently remains the most frequent and serious complication despite the efforts made to prevent it. One of these current prevention measures is the use of antibiotic-impregnated catheters. A retrospective cohort study including shunts and external ventricular drains was designed to assess their efficacy in our scenario. The results show that rifampicin- and clindamycin-impregnated catheters are a helpful tool against CSF shunt-derived infection. PMID- 22520100 TI - 5-aminolevulinic acid and neuronavigation in high-grade glioma surgery: results of a combined approach. AB - In high-grade glioma surgery, several techniques are used to achieve the maximum cytoreductive treatment preserving neurological functions. However, the effectiveness of all the methods used alone is reduced by specific limitations of each. We assessed the reliability of a multimodal strategy based on 5 aminolevulinic acid (5-ALA) and neuronavigation. We prospectively studied 18 patients with suspected, non eloquent-area malignant gliomas amenable for complete resection. Conventional illumination was used until the excision appeared complete. The cavity was then systematically inspected in violet-blue light to identify any residual tumour. Multiple biopsies of both fluorescent and non-fluorescent tissue were performed in all cases. Each specimen was labelled according to the sampling location (inside or outside the boundary set by the neuronavigator). The samples were analysed by a neuropathologist blinded to the intraoperative classification. We reviewed the results of both methods, either singly or in combination. Individual analysis showed higher 5-ALA reliability compared to neuronavigation. However, several false-negative fluorescent specimens were detected. With the combined use of fluorescence and neuroimaging, only 1 sample (negative for both 5-ALA and navigation) was tumoral tissue. In our experience, the combined approach showed the best sensitivity and it is recommended in cases of lesions involving non-eloquent areas. PMID- 22520101 TI - [Primary prophylaxis of early seizures after surgery of cerebral supratentorial tumors: Group for the Study of Functional-Sterotactic Neurosurgery of The Spain Society of Neurosurgery recommendations]. AB - Our review of the literature is basically focused on the primary prophylaxis of early seizures after surgery of cerebral supratentorial tumors, with the aim of suggesting several recommendations in medical antiepileptic treatment to avoid this kind of seizures which occur immediately after surgery. In conclusion, it is recommended to provide criteria for prophylaxis of early seizures after surgery of cerebral supratentorial tumors. Its recommended a one week treatment with antiepileptic drugs in patients who didnt have seizures jet, starting immediately after the surgical treatment. If seizures appear during progress of the disease, a large period treatment will be needed. Preferred antiepileptic treatment is intravenous and with a low interactions profile. Levetiracetam, followed by valproic acid seem to be most appropriated drugs due to their properties and protective effects, particularly for our patients requirements. These recommendations are considered a general proposal to effective clinical management of early seizures after surgery, not taking into account the single circumstances of our patients. Always, clinical features of the patients could modify even significantly these guides in the benefit of each patient. PMID- 22520102 TI - [Penetrating spinal injury with glass fragments causing CSF leak: case report]. AB - Penetrating injuries to the spine are important causes of spinal cord traumatism. There are two varieties: gunshot or stab wounds. Within the second category, sharp knifelike objects and, rarely, glass are found. This article presents a case of penetrating glass injury to the lumbar spine in an 18-year-old girl, with the migration of pieces of glass within muscles and spinous process until reaching the dural sac. PMID- 22520103 TI - Cerebral salt wasting syndrome: postoperative complication in tumours of the cerebellopontine angle. AB - Cerebral salt wasting (CSW) is a rare complication in posterior fossa tumour surgery. We present two patients with cerebellopontine angle (CPA) tumours who developed cerebral salt wasting postoperatively. Both patients deteriorated in spite of intensive fluid and salt replacement. On CT scan the patients presented mild to moderate ventricular dilation, which was treated with an external ventricular drainage. After the resolution of hydrocephalus, fluid balance rapidly returned to normal in both patients and the clinical status improved. Identification and treatment of secondary obstructive hydrocephalus may contribute to the management of CSW associated to posterior fossa tumour surgery. PMID- 22520104 TI - [Neuronavigation in the surgery for atlantoaxial instability: "the spinal shift"]. PMID- 22520105 TI - [Authors' reply]. PMID- 22520108 TI - Novel robotic renorrhaphy technique for hilar tumours: 'V' hilar suture (VHS). PMID- 22520110 TI - Ureteroscopy assisted retrograde nephrostomy: a new technique for percutaneous nephrolithotomy (PCNL). PMID- 22520111 TI - Impact of urethral ultrasonography on decision-making in anterior urethroplasty. PMID- 22520114 TI - "Childhood overweight and obesity: maternal perceptions of the time for engaging in child weight management". AB - BACKGROUND: There is an increasing awareness of the impact of parental risk perception on the weight course of the child and the parent's readiness to engage in preventive efforts, but only less is known about factors related to the parental perception of the right time for the implementation of preventive activities. The aim of this study was to examine parental perceptions of the appropriate time to engage in child weight management strategies, and the factors associated with different weight points at which mothers recognize the need for preventive actions. METHODS: 352 mothers with children aged 2-10 years took part in the study. We assessed mothers' perceptions of the actual and preferred weight status of their child, their ability to identify overweight and knowledge of its associated health risks, as well as perceptions of the right time for action to prevent overweight in their child. A regression analysis was conducted to examine whether demographic and weight related factors as well as the maternal general risk perception were associated with recognizing the need to implement prevention strategies. RESULTS: Although most of the parents considered a BMI in the 75th to 90th percentile a valid reason to engage in the prevention of overweight, 19% of the mothers were not willing to engage in prevention until their child reached the 97th percentile. Whereas the child's sex and the identification of an elevated BMI were significant predictors for parents' recognition of the 75th percentile as right point to engage in prevention efforts, an inability to recognize physical health risks associated with overweight silhouettes emerged as a significant factor predicting which parents would delay prevention efforts until a child's BMI reached the 97th percentile. CONCLUSION: Parental misperceptions of overweight and associated health risks constitute unfavorable conditions for preventive actions. Feedback on the health risks associated with overweight could help increase maternal readiness for change. PMID- 22520115 TI - Subcutaneous emphysema causing inefficient ultrasound guidance during central vein cannulation. PMID- 22520116 TI - Exogenous surfactant therapy in acute lung injury/acute respiratory distress syndrome: the need for a revised paradigm approach. PMID- 22520117 TI - Rotavirus vaccines for children in developing countries: understanding the science, maximizing the impact, and sustaining the effort. PMID- 22520118 TI - Malnutrition levels among vaccinated and unvaccinated children between 2 and 3 years of age following enrollment in a randomized clinical trial with the pentavalent rotavirus vaccine (PRV) in Bangladesh. AB - A double-masked, individually randomized Phase 3 clinical trial to assess the efficacy, safety and immunogenicity of the pentavalent rotavirus vaccine (PRV), RotaTeqTM, was conducted in rural Matlab, Bangladesh (NCT00362648). A total of 1136 infants were enrolled and randomized to receive either vaccine or placebo in a 1:1 ratio administered with the standard EPI vaccines at a mean age of approximately 8, 12, and 16 weeks. Weight was collected at four time points (study vaccine doses 1, 2, and 3, and a close-out visit in March 2009 at 15-26 months of age), and birth weight was retrospectively collected from information contained on the mother's health card when available. Approximately one year following trial completion a separate study was conducted to collect anthropometry measurements, including weight and height. These measurements were linked with Phase 3 trial data and a post hoc analysis was conducted to assess the effects of rotavirus vaccination on malnutrition among enrolled children who could be located when they were between 27 and 38 months old. Among the 1033 (91%) children located, and measured, for this analysis height-for-age and weight for-height Z scores were calculated and compared between vaccine and placebo recipients at the anthropometry follow-up 1-year post-trial, and weight-for-age Z scores were calculated at four trial time points in addition to the anthropometry follow-up. The data indicated that there was no effect of rotavirus vaccination on malnutrition in this population at any of the measured time points. PRV, estimated to have about 43% efficacy against severe rotavirus gastroenteritis in this population, may not reduce the overall burden of diarrheal illness sufficiently among all vaccinees to appreciably measure impact on growth compared with non-vaccinees. Regardless of the impact on malnutrition indicators, rotavirus vaccines are an important intervention for reducing morbidity and mortality in children in developing countries. PMID- 22520119 TI - Immunogenicity of the pentavalent rotavirus vaccine among infants in two developing countries in Asia, Bangladesh and Vietnam. AB - BACKGROUND: We evaluated the immunogenicity of the pentavalent rotavirus vaccine (PRV) in two GAVI-eligible Asian countries, Bangladesh and Vietnam, nested in a larger randomized, double-blind, placebo-controlled efficacy trial conducted over a two-year period from 2007 through 2009. METHODS: 2036 infants were randomly assigned, in a 1:1 ratio, to receive three oral doses of PRV or placebo approximately at 6, 10, and 14 weeks of age. Concomitant use of EPI vaccines, including oral poliovirus vaccine (OPV) and diphtheria-tetanus-whole cell pertussis (DTwP) vaccine, was encouraged in accordance to the local EPI schedule. A total of 303 infants were evaluated for immunogenicity and blood samples were collected before the first dose (pD1) and approximately 14 days following the third dose (PD3). The seroresponse rates (>=3-fold rise from pD1 to PD3) and geometric mean titers (GMTs) were measured for anti-rotavirus immunoglobulin A (IgA) and serum neutralizing antibody (SNA) to human rotavirus serotypes G1, G2, G3, G4, and P1A[8], respectively. RESULTS: Nearly 88% of the subjects showed a >=3-fold increase in serum anti-rotavirus IgA response in the analysis of the two countries combined. When analyzed separately, the IgA response was lower in Bangladeshi children (78.1% [95% CI: 66.0, 87.5]) than in Vietnamese children (97.0% [95% CI: 89.6, 99.6]), with a PD3 GMT of 29.1 (units/mL) and 158.5 (units/mL), respectively. In the combined population, the SNA responses to the individual serotypes tested ranged from 10 (G3) to 50 (G1) percentage points lower than the responses shown in the developed countries. However, the SNA response to G3 in Vietnamese subjects was 37.3% (95% CI: 25.8, 50.0), which was similar to the G3 response rate in developed countries. CONCLUSIONS: Three oral doses of PRV were immunogenic in two GAVI-eligible Asian countries: Bangladesh and Vietnam. The GMTs of both the serum anti-rotavirus IgA and SNA responses were generally higher in Vietnamese than in Bangladeshi children. The SNA responses varied by individual serotypes and were lower than the results from developed countries. The clinical significance of these observations is not understood because an immune correlate of protection has not been established. PMID- 22520120 TI - A dose-escalation safety and immunogenicity study of a new live attenuated human rotavirus vaccine (Rotavin-M1) in Vietnamese children. AB - We tested a candidate live, oral, rotavirus vaccine (Rotavin-M1TM) derived from an attenuated G1P [8] strain (KH0118-2003) isolated from a child in Vietnam. The vaccine was tested first for safety in 29 healthy adults. When deemed safe, it was further tested for safety and immunogenicity in 160 infants (4 groups) aged 6 12 weeks in a dose and schedule ranging study. The vaccine was administered in low titer (10(6.0)FFU/dose) on a 2-dose schedule given 2 months apart (Group 2L) and on a 3-dose schedule given 1 month apart (Group 3L) and in high titer (10(6.3)FFU/dose) in 2 doses 2 months apart (Group 2H) and in 3 doses 1 month apart (Group 3H). For comparison, 40 children (group RotarixTM) were given 2 doses of the lyophilized RotarixTM vaccine (10(6.5)CCID(50)/dose) 1 month apart. All infants were followed for 30 days after each dose for clinical adverse events including diarrhea, vomiting, fever, abdominal pain, irritability and intussusception. Immunogenicity was assessed by IgA seroconversion and viral shedding was monitored for 7 days after administration of each dose. Two doses of Rotavin-M1 (10(6.3)FFU/dose) were well tolerated in adults. Among infants (average 8 weeks of age at enrollment), administration of Rotavin-M1 was safe and did not lead to an increased rate of fever, diarrhea, vomiting or irritability compared to RotarixTM, indicating that the candidate vaccine virus had been fully attenuated by serial passages. No elevation of levels of serum transaminase, blood urea, or blood cell counts were observed. The highest rotavirus IgA seroconversion rate (73%, 95%CI (58-88%)) was achieved in group 2H (2 doses- 10(6.3)FFU/dose, 2 months apart). The 2 dose schedules performed slightly better than the 3 dose schedules and the higher titer doses performed slightly better than the lower titer doses. These rates of seroconversion were similar to that of the RotarixTM group (58%, 95%CI (42-73%)). However more infants who received RotarixTM (65%) shed virus in their stool after the first dose than those who received Rotavin-M1 (44-48%) (p<0.05) and the percent shedding decreased after subsequent doses of either vaccine. Rotavin-M1 vaccine is safe and immunogenic in Vietnamese infants. A trial in progress will assess the safety, immunogenicity and efficacy of Rotavin-M1 (2 doses at 10(6.3)FFU/dose) in a larger number of infants. The trial registration numbers are NCT01375907 and NCT01377571. PMID- 22520121 TI - Systematic review of regional and temporal trends in global rotavirus strain diversity in the pre rotavirus vaccine era: insights for understanding the impact of rotavirus vaccination programs. AB - Recently, two rotavirus vaccines have been recommended for routine immunization of infants worldwide. These vaccines proved efficacious during clinical trials and field use in both developing and developed countries, and appear to provide good protection against a range of rotavirus genotypes, including some that are not included in the vaccines. However, since conclusive data that the vaccines will protect against a wide variety of rotavirus strains are still lacking and since vaccines may exert some selection pressure, a detailed picture of global strain prevalence from the pre-rotavirus vaccine era is important to evaluate any potential changes in circulating strains observed after widespread introduction of rotavirus vaccines. Thus, we systematically reviewed rotavirus genotyping studies spanning a 12-year period from 1996 to 2007. In total, ~110,000 strains were genotyped from 100 reporting countries. Five genotypes (G1-G4, and G9) accounted for 88% of all strains, although extensive geographic and temporal differences were observed. For example, the prevalence of G1 strains declined from 2000 onward, while G3 strains re-emerged, and G9 and G12 strains emerged during the same period. When crude strain prevalence data were weighted by region based on the region's contribution to global rotavirus mortality, the importance of genotypes G1 and G9 strains that were more prevalent in regions with low mortality was reduced and conversely the importance of G8 strains that were more prevalent in African settings with greater contribution to global rotavirus mortality was increased. This study provides the most comprehensive, up-to-date information on rotavirus strain surveillance in the pre-rotavirus vaccine era and will provide useful background to examine the impact of rotavirus vaccine introduction on future strain prevalence. PMID- 22520122 TI - A systematic review of rotavirus strain diversity in India, Bangladesh, and Pakistan. AB - Of the estimated half-million deaths from rotavirus globally each year, approximately one-third (N = 160,000 deaths) occur in the Indian subcontinent (defined as India, Bangladesh, and Pakistan). Two commercial vaccines are available for use and recommended by WHO, although the prohibitive vaccine price has limited their introduction into routine childhood immunization programs. New rotavirus vaccines are in late clinical development, including two advanced candidates in India. As significant shifts in rotavirus strain diversity have occurred in the past three decades and questions remain regarding whether strain replacement may occur following introduction of rotavirus vaccines, it is important to understand the temporal and regional strain diversity profile before vaccine introduction. We reviewed 33 peer-reviewed manuscripts from the Indian subcontinent and found that the most common G-types (G1-4) and P-types (P[4] and P[8]) globally accounted for three-fourths of all strains in the subcontinent. However, strains varied by region, and temporal analysis showed the decline of G3 and G4 in recent years and the emergence of G9 and G12. Our findings underscore the large diversity of rotavirus strains in the Indian subcontinent and highlight the need to conduct surveillance on a regional scale to better understand strain diversity before and after rotavirus vaccine introduction. PMID- 22520123 TI - Molecular characterization of rotavirus strains detected during a clinical trial of a human rotavirus vaccine in Blantyre, Malawi. AB - The human, G1P[8] rotavirus vaccine (RotarixTM) significantly reduced severe rotavirus gastroenteritis episodes in a clinical trial in South Africa and Malawi, but vaccine efficacy was lower in Malawi (49.5%) than reported in South Africa (76.9%) and elsewhere. The aim of this study was to examine the molecular relationships of circulating wild-type rotaviruses detected during the clinical trial in Malawi to RIX4414 (the strain contained in RotarixTM) and to common human rotavirus strains. Of 88 rotavirus-positive, diarrhoeal stool specimens, 43 rotaviruses exhibited identifiable RNA migration patterns when examined by polyacrylamide gel electrophoresis. The genes encoding VP7, VP4, VP6 and NSP4 of 5 representative strains possessing genotypes G12P[6], G1P[8], G9P[8], and G8P[4] were sequenced. While their VP7 (G) and VP4 (P) genotype designations were confirmed, the VP6 (I) and NSP4 (E) genotypes were either I1E1 or I2E2, indicating that they were of human rotavirus origin. RNA-RNA hybridization using 21 culture-adapted strains showed that Malawian rotaviruses had a genomic RNA constellation common to either the Wa-like or the DS-1 like human rotaviruses. Overall, the Malawi strains appear similar in their genetic make-up to rotaviruses described in countries where vaccine efficacy is greater, suggesting that the lower efficacy in Malawi is unlikely to be explained by the diversity of circulating strains. PMID- 22520124 TI - Distributional impact of rotavirus vaccination in 25 GAVI countries: estimating disparities in benefits and cost-effectiveness. AB - BACKGROUND: Other studies have demonstrated that the impact and cost effectiveness of rotavirus vaccination differs among countries, with greater mortality reduction benefits and lower cost-effectiveness ratios in low-income and high-mortality countries. This analysis combines the results of a country level model of rotavirus vaccination published elsewhere with data from Demographic and Health Surveys on within-country patterns of vaccine coverage and diarrhea mortality risk factors to estimate within-country distributional effects of rotavirus vaccination. The study examined 25 countries eligible for funding through the GAVI Alliance. METHODS: For each country we estimate the benefits and cost-effectiveness of vaccination for each wealth quintile assuming current vaccination patterns and for a scenario where vaccine coverage is equalized to the highest quintile's coverage. In the case of India, variations in coverage and risk proxies by state were modeled to estimate geographic distributional effects. RESULTS: In all countries, rates of vaccination were highest and risks of mortality were lowest in the top two wealth quintiles. However countries differ greatly in the relative inequities in these two underlying variables. Similarly, in all countries examined, the cost-effectiveness ratio for vaccination ($/Disability-Adjusted Life Year averted, DALY) is substantially greater in the higher quintiles (ranging from 2-10 times higher). In all countries, the greatest potential benefit of vaccination was in the poorest quintiles. However, due to reduced vaccination coverage, projected benefits for these quintiles were often lower. Equitable coverage was estimated to result in an 89% increase in mortality reduction for the poorest quintile and a 38% increase overall. CONCLUSIONS: Rotavirus vaccination is most cost-effective in low-income groups and regions. However in many countries, simply adding new vaccines to existing systems targets investments to higher income children, due to disparities in vaccination coverage. Maximizing health benefits for the poorest children and value for money require increased attention to these distributional effects. PMID- 22520125 TI - Characterisation of a G9P[8] rotavirus strain identified during a gastroenteritis outbreak in Alice Springs, Australia post RotarixTM vaccine introduction. AB - A large rotavirus gastroenteritis outbreak occurred in the Alice Springs region of the Northern Territory, Australia from the 12th of March until the 11th of July 2007. The outbreak occurred five months after the introduction of the RotarixTM vaccine. Electropherotype and sequence analysis demonstrated that a single G9P[8] strain was responsible for the outbreak and that the strain remained highly conserved during the outbreak period. The outbreak strain contained amino acid changes in regions of the VP7 and NSP4 genes, with known biological function, when compared to previously characterised G9P[8] strains from Australia and other international locations. The recent vaccine introduction was unlikely to have influenced genotype selection in this setting. Importantly, RotarixTM vaccine was highly effective against the G9P[8] outbreak strain. PMID- 22520127 TI - Severity of rotavirus gastroenteritis in Indian children requiring hospitalization. AB - INTRODUCTION: The burden of rotavirus gastroenteritis is greatest in India and other developing countries. With the availability of two licensed vaccines and a number of additional vaccines in various stages of development and trial, analysis of detailed clinical information is essential for the development of a uniform method of severity assessment. METHODS: Diarrhoeal stool samples from 1001 children <5 years of age hospitalized with gastroenteritis were screened for rotavirus using a commercial enzyme immunoassay. Positive samples were confirmed by genotyping using hemi nested multiplex RT-PCR. Detailed clinical data was collected for gastroenteritis assessment for 934 children and extraintestinal presentations were analyzed in 470 children. Severity scoring was carried out for all children using the Vesikari score and in a subset by Clark's scoring system. RESULTS: Rotavirus was detected in 35.4% of samples tested between December 2005 and November 2008. Clark's and Vesikari scores showed moderate correlation but varied greatly in the categorization of severe disease. Using Clark's scoring, only 1.6% were categorized as presenting with severe disease in comparison to 66.1% by the Vesikari score. Association of extraintestinal symptoms with rotavirus gastroenteritis was not documented in this study. CONCLUSION: The assessment of disease severity using two common severity scoring systems highlights the difference in the categorization of "severe" disease. This underscores the need for a robust scoring system which is needed for vaccine trial and in post-licensure surveillance, because vaccine efficacy is estimated for protection against severe rotavirus gastroenteritis. PMID- 22520126 TI - Comparison of two clinical severity scoring systems in two multi-center, developing country rotavirus vaccine trials in Africa and Asia. AB - BACKGROUND: Clinical severity scoring systems are used in rotavirus vaccine efficacy and effectiveness studies to define the primary endpoint, severe rotavirus gastroenteritis (RVGE). Understanding how scoring systems perform in diverse settings is critical for proper design and interpretation. This investigation aims to understand how the Vesikari scoring system (VSS) and Clark scoring system (CSS) categorize severe disease among children under 2 years of age using data from two Phase III efficacy trials conducted in five developing countries in Africa and Asia. METHODS: Signs and symptoms were collected on trial participants who presented to a medical facility with study-defined gastroenteritis. Severity scores were calculated using pre-established VSS and CSS criteria and compared to identify differences in the proportions of severe RVGE within regions and sites, and by gender and age. RESULTS: In Africa and Asia, 40.6% and 56.0% of rotavirus-positive episodes were severe according to the VSS, while 9.5% and 6.3% of episodes were severe according to the CSS (Fisher's Exact, p <= 0.001). Using the mean scores in these trials (VSS: >= 10 Africa, >= 11 Asia; CSS: Africa and Asia >= 10) as the severity thresholds, agreement between scoring system severity classifications improved substantially within each region (Africa: kappa = 0.67; Asia: kappa = 0.78) as compared to the original severity classification (Africa: kappa = 0.27; Asia: kappa = 0.10). Using the mean score, 17.1% and 9.5% of severe VSS cases in Africa and Asia, respectively, were classified as not severe according to the CSS and 14.7% and 9.5% of severe CSS cases in Africa and Asia were classified as not severe according to the VSS. CONCLUSION: The two scoring systems performed differently among developing country populations in Africa and Asia, with the VSS classifying more cases as severe in both regions. One accurate and reliable scoring system should be developed and implemented for all trials so that results may be more comparable. PMID- 22520128 TI - Five-year cohort study on the burden of hospitalisation for acute diarrhoeal disease in African HIV-infected and HIV-uninfected children: potential benefits of rotavirus vaccine. AB - INTRODUCTION: Diarrhoea remains an important cause of death in children under five years of age, including in areas with high prevalence of HIV infection. Rotavirus contributes significantly to childhood diarrhoea in South Africa but data on the burden of rotavirus disease in HIV-infected children are limited. METHODS: This secondary data analysis, involving a cohort of 39,879 children enrolled into a pneumococcal conjugate vaccine efficacy trial, evaluated the incidence of hospitalisation for acute gastroenteritis in HIV-infected and HIV uninfected children under five years of age from Soweto, South Africa. The data were used to evaluate the potential burden of hospitalisation that would be preventable with rotavirus vaccine. RESULTS: Acute gastroenteritis (AGE) was identified as a leading cause of hospitalisation in the cohort and was associated with 21% of all hospitalisations. Twenty-six percent of the AGE hospitalisations occurred in HIV-infected children. The incidence of AGE was greatest in the under 6 months age group and 90% of cases occurred within the first two years of life. The overall incidence of AGE was 5.4 fold (CI(95%) 4.9, 6.0) higher in HIV infected compared to HIV-uninfected children. In addition, the estimates of rotavirus incidence were 2.3 fold (CI(95%) 1.8, 2.9) higher in HIV-infected compared to HIV-uninfected children. HIV-infected children were 1.8 fold (CI(95%) 1.4, 2.4) more likely to have prolonged hospitalisation and the case fatality rate was 4.0 (CI(95%) 2.0, 7.8) fold higher in HIV-infected compared to HIV uninfected children. CONCLUSION: Despite rotavirus reportedly being less frequently identified in hospitalised HIV-infected children, the absolute burden of rotavirus-associated hospitalisation is likely to be greater compared to HIV uninfected children. The introduction of rotavirus vaccine into the national immunisation program in South Africa is likely to benefit HIV-infected and HIV uninfected children and reduce the overall burden of AGE hospitalisation in our childhood population. PMID- 22520129 TI - Research priorities regarding rotavirus vaccine and intussusception: a meeting summary. AB - Currently available rotavirus vaccines have been associated with a small increased risk of intussusception (~1-2 cases per 100,000 vaccinated infants) in some populations. In response to this newly emerging data on intussusception related to current rotavirus vaccines, a group of technical experts convened by the Program for Applied Technology in Health met to review the data, establish what gaps in knowledge exist, and identify what future research is needed. This manuscript outlines the evidence that is currently available and the research agenda that was generated during this meeting. It also highlights the need for countries that are using or considering introducing the rotavirus vaccine to evaluate both the benefits and risks of vaccination. PMID- 22520130 TI - Workshop on intussusception in African countries--meeting report. AB - Rotavirus causes approximately 450,000 deaths annually among children less than 5 years of age worldwide, almost half of which occur in Africa. After the recent completion of successful trials of 2 new rotavirus vaccines, the World Health Organization has recommended these vaccines for all children worldwide. Because a previous rotavirus vaccine, Rotashield((r)), was associated with intussusception, a form of intestinal obstruction among infants, the current rotavirus vaccines were tested in large clinical trials and found to be safe. However, due to the past Rotashield((r)) experience, post licensure monitoring of intussusception is considered to be crucial after the introduction of future oral rotavirus vaccines. Thus, in planning for future introductions of rotavirus vaccine in Africa, a workshop of experts working on intussusception was convened by the World Health Organization in May 2004 in association with the Pan-African Association of Paediatric Surgeons (PAPSA) in Malawi. In brief, delegates from ten countries presented data from retrospective record reviews of intussusception events from 1993 to 2003 at selected hospitals in their respective countries. This review showed that age of intussusception onset during infancy varies markedly with peak prevalence between 4 and 6 months of life. Diagnostic modality (e.g., contrast enema, ultrasound) was employed in <20% of the events; nearly 70% of the intussusception events were diagnosed at the time of surgery. Overall, case-fatality was high, ~13%, in these African countries. The findings of this meeting highlight the challenges in implementing surveillance for intussusception after rotavirus vaccine introduction in Africa. The deliberations identified some concrete steps necessary to establish active surveillance at sentinel sites in African countries. This is becoming more urgent now that many countries are expressing interest in introducing rotavirus vaccines. PMID- 22520131 TI - Retrospective hospital based surveillance of intussusception in children in a sentinel paediatric hospital: benefits and pitfalls for use in post-marketing surveillance of rotavirus vaccines. AB - Evaluation of the safety of rotavirus vaccines, particularly with respect to the risk of intussusception, is recommended for countries planning to introduce rotavirus vaccines into the National Immunisation Program. However, as prospective studies are costly, require time to conduct and may be difficult to perform in some settings, retrospective hospital based surveillance at sentinel sites has been suggested as an option for surveillance for intussusception following introduction of rotavirus vaccines. OBJECTIVE: To assess the value of retrospective hospital based surveillance to describe clinical and epidemiological features of intussusception in children aged <24 months and to investigate any temporal association between receipt of a rotavirus vaccine and intussusception. METHODS: A retrospective chart review of all patients diagnosed with intussusception at Royal Children's Hospital, Melbourne, Australia over an 8 year period including before and after rotavirus vaccine introduction into the National Immunisation Program, was conducted using patients identified by a medical record database (ICD-10-CM 56.1). Patient profile, clinical presentation, treatment and outcome were analysed along with records of immunisation status obtained using the Australian Childhood Immunisation Register. RESULTS: A 9% misclassification rate of discharge diagnosis of intussusception was identified on critical chart review. The incidence rate of intussusception at the Royal Children's Hospital over the study period was 1.91 per 10,000 infants <24 months (95% CI 1.65-2.20). Intestinal resection was required in 6.5% of infants (95% CI 3.6%, 11.0%). Intussusception occurred within 30 days after vaccination in 2 of 27 patients who had received at least 1 dose of a rotavirus vaccine. CONCLUSIONS: Valuable data on the incidence, clinical presentation and treatment outcomes of intussusception can be obtained from data retrieved from hospital medical records in a sentinel paediatric hospital using standardised methodology. However, there are methodological limitations and the quality of the data is highly dependent on the accuracy and completeness of the patient information recorded, the system of coding and record retrieval. PMID- 22520132 TI - Analyses of health outcomes from the 5 sites participating in the Africa and Asia clinical efficacy trials of the oral pentavalent rotavirus vaccine. AB - BACKGROUND: Efficacy of the pentavalent rotavirus vaccine (PRV), RotaTeq((r)), against severe rotavirus gastroenteritis (RVGE) was evaluated in two double blind, placebo-controlled, multicenter Phase III clinical trials conducted in GAVI-eligible countries in Africa (Ghana, Kenya, and Mali) and in Asia (Bangladesh and Vietnam) from March 2007 through March 2009. The findings from each continent have been analyzed and presented separately, according to a single identical protocol. Ad hoc analyses combining data from the five sites were performed to further assess the impact of PRV. METHODS: 6674 infants (4705 infants from Africa and 1969 infants from Asia), randomized 1:1 to receive 3 doses of PRV/placebo at approximately 6-, 10-, and 14-weeks of age according to each country's EPI schedule, were included in the per protocol efficacy analysis. Breastfeeding and concomitant administration of EPI vaccines, including OPV, were allowed. Episodes of gastroenteritis (GE) in infants who presented to study facilities were captured and scored using the 20-point Vesikari scale. Stool samples were analyzed by rotavirus-specific EIA to detect presence of rotavirus antigen and RT-PCR to determine the G/P genotypes. We assessed efficacy to prevent all-cause GE and RVGE at a variety of cut-off points (score>=11, severe; score>=15, very severe). RESULTS: Vaccine efficacy (VE) against RVGE, regardless of serotype, through the entire follow-up period for any severity, severe (score>=11), and very severe (score>=15) was 33.9%, 95% CI (22.7, 43.5), 42.5%, 95% CI (27.4, 54.6), and 51.2%, 95% CI (26.3, 68.2), respectively. Through the first year of life, VE against severe RVGE was 58.9%, 95% CI (40.0, 72.3) and against all-cause severe GE was 23.0%, 95% CI (5.4, 37.3). VE against severe RVGE caused by non-vaccine G serotypes, G8 and G9, through the entire follow-up period was 87.5%, 95% CI (6.8, 99.7) and 48.0%, 95% CI (-5.5, 75.6), respectively. All G8 strains were associated with P2A[6] (a P-type not contained in PRV), while the majority of the G9 strains were associated with P1A[8] (a P-type contained in PRV). CONCLUSIONS: Combining data from the 5 sites strengthens the precision of VE estimates and reveals rising VE with increased RVGE severity. Extrapolating data from VE against severe GE and RVGE suggest that 39% of severe GE episodes during the first year of life were due to rotavirus, highlighting substantial, potentially preventable, public health burden of RVGE. PRV provides protection against non-vaccine serotypes (G8P2A[6]). PMID- 22520133 TI - Rotavirus vaccines in developing countries: the potential impact, implementation challenges, and remaining questions. AB - Diarrhoeal disease is one of the commonest causes of death in children, especially in developing countries in Africa and Asia. Rotavirus has been consistently identified as the commonest pathogen associated with severe diarrhoea. Hence, the availability of vaccines against this organism provides the opportunity to reduce child mortality. Data from efficacy trials in developing countries in Africa and Asia showed that the vaccine efficacy was lower than that observed in other countries. Nevertheless, the vaccines are expected to be of significant benefit in high mortality countries in these regions. While the reports published in this supplement add to our understanding about the performance of these vaccines in developing countries in these regions, questions remain over the overall impact of these vaccines when used in national programmes of developing countries in Africa and Asia, the optimal vaccination schedules and the impact of age restrictions for vaccine use on immunization coverage. Additional research is required to improve understanding on the performance of these vaccines in developing countries in Africa and Asia and measures that may improve performance. Data that will assist in the definition of the optimal immunization schedule and possibly allow relaxation of the age restrictions for vaccine use may help in enhancing the impact of the vaccines in these countries. Finally, disease surveillance and studies are required to document the impact of vaccination and monitor changes in disease epidemiology. PMID- 22520134 TI - Influence of oral polio vaccines on performance of the monovalent and pentavalent rotavirus vaccines. AB - In recent years, two live, oral rotavirus vaccines have been successfully tested in developing and industrialized countries, and both vaccines are now recommended by the World Health Organization for all children worldwide. Both immunogenicity and efficacy of these rotavirus vaccines has been lower in developing compared to industrialized settings. We reviewed the data on the effect of trivalent OPV on the immunogenicity and efficacy of two rotavirus vaccines currently recommended by the WHO. While rotavirus vaccines have not affected immune responses to OPV, in general, the immune responses (i.e., antibody levels) to rotavirus vaccination were lower when rotavirus vaccines were co-administered with OPV. Limited data suggests that the interference is greater after the first dose of OPV, presumably because the first dose is associated with greatest intestinal replication of vaccine polio virus strains, and this interference is largely overcome with subsequent rotavirus vaccine doses. Despite the lower immunogenicity, one large efficacy study in middle income Latin American countries showed no decrease in protective efficacy of rotavirus vaccine in infants receiving concurrent OPV. While these data are encouraging and support simultaneous administration of rotavirus vaccines and OPV, additional evidence should be gathered as rotavirus vaccines are used more widely in developing country settings, where OPV is routinely used, rather than inactivated polio vaccine. PMID- 22520135 TI - Efficacy of human rotavirus vaccine against severe gastroenteritis in Malawian children in the first two years of life: a randomized, double-blind, placebo controlled trial. AB - Rotavirus gastroenteritis is a major cause of morbidity and mortality among African infants and young children. A phase III, placebo-controlled, multi-centre clinical trial of a live, oral G1P[8] human rotavirus vaccine (RIX4414) undertaken in Malawi and South Africa significantly reduced the incidence of severe rotavirus gastroenteritis in the first year of life. We now report on vaccine efficacy in the Malawi cohort of children who were followed into the second year of life. A total of 1773 healthy infants were enrolled in Blantyre, Malawi into three groups. Two groups received three doses of RIX4414 or placebo at age 6, 10, and 14 weeks and the third group received placebo at 6 weeks and RIX4414 at age 10 and 14 weeks. Subjects were followed by weekly home visits for episodes of gastroenteritis until 1 year of age, and were then re-consented for further follow-up to 18-24 months of age. Severity of gastroenteritis episodes was graded according to the Vesikari scoring system. Seroconversion for anti rotavirus IgA was determined on a subset of children by using ELISA on pre- and post-vaccine blood samples. Rotavirus VP7 (G) and VP4 (P) genotypes were determined by RT-PCR. A total of 70/1030 (6.8%, 95% CI 5.3-8.5) subjects in the pooled (2 dose plus 3 dose) RIX4414 group compared with 53/483 (11.0%, 8.3-14.1) subjects in the placebo group developed severe rotavirus gastroenteritis in the entire follow-up period (vaccine efficacy 38.1% (9.8-57.3)). The point estimate of efficacy in the second year of life (17.6%; -59.2 to 56.0) was lower than in the first year of life (49.4%; 19.2-68.3). There were non-significant trends towards a higher efficacy in the second year of life among children who received the three-dose schedule compared with the two-dose schedule, and a higher anti rotavirus IgA seroresponse rate in the three-dose RIX4414 group. Rotavirus strains detected included genotype G12 (31%); G9 (23%); and G8 (18%); only 18% of strains belonged to the G1P[8] genotype. While the optimal dosing schedule of RIX4414 in African infants requires further investigation, vaccination with RIX4414 significantly reduced the incidence of severe gastroenteritis caused by diverse rotavirus strains in an impoverished African population with high rotavirus disease burden in the first two years of life. PMID- 22520136 TI - Efficacy and immunogenicity of two or three dose rotavirus-vaccine regimen in South African children over two consecutive rotavirus-seasons: a randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: Human rotavirus vaccine (HRV; i.e., Rotarix) reduced the incidence of severe rotavirus gastroenteritis (RVGE) by 77% (95% Confidence interval: 56-88%) during the first year of life in South Africa. Persistence of HRV-derived protection against RVGE during subsequent rotavirus seasons, although evident in industrialized settings, remains to be established in African settings. This study reports on the efficacy of HRV against severe RVGE over two consecutive rotavirus seasons in South African children. METHODS: A prospective, double blind, placebo controlled multi-centered trial in South Africa and Malawi randomly assigned infants in a 1:1:1 ratio to receive either two (10 and 14 weeks; HRV_2D) or three (6, 10 and 14 weeks; HRV_3D) doses of HRV or placebo. The primary analysis involved pooling of HRV_2D and HRV_3D arms. Episodes of gastroenteritis caused by wild-type rotavirus were identified through active follow-up surveillance and graded by the Vesikari scale. RESULTS: 1339 infants (447 in the HRV_2D group, 447 in the HRV_3D group and 445 in the placebo group) were enrolled in Year 2 of the study, including 1035 (77.3%) who were followed up over two consecutive rotavirus seasons (i.e., Cohort 2 subjects). Rotarix was associated with ongoing protection against severe RVGE, preventing 2.5 episodes per 100 vaccinated children over two consecutive rotavirus seasons; vaccine efficacy: 59% (95% Confidence interval: 1-83%). An exploratory analysis indicated better immunogenicity (among Cohort 1 subjects) and a higher point-efficacy estimate over two seasons in the HRV_3D compared to HRV_2D arms of the study in Cohort 2 subjects. CONCLUSION: Rotarix is associated with significant reductions in severe gastroenteritis episodes through 2 years of life among South African children. Further research is needed to determine the optimal dosing schedule of Rotarix in providing long-term protection against rotavirus illness in African children. PMID- 22520137 TI - Efficacy of pentavalent rotavirus vaccine in a high HIV prevalence population in Kenya. AB - BACKGROUND: Rotavirus gastroenteritis (RVGE) is a leading cause of death in African children. The efficacy of pentavalent rotavirus vaccine (PRV) against severe RVGE evaluated in Ghana, Kenya, and Mali in a randomized, double-blind, placebo-controlled trial, showed a combined regional efficacy of 39.3% (95% confidence interval [CI]: 19.1,54.7) in nearly 2 years of follow-up. This report concentrates on the Kenya findings. METHODS: Infants received 3 doses of PRV/placebo at approximately 6-, 10-, and 14-weeks of age. HIV testing was offered to all participants. Data on illness symptoms and signs were collected upon presentation to healthcare facilities, where stools were collected, and analyzed by rotavirus-specific enzyme-linked immunosorbent assay. The primary endpoint was severe RVGE (Vesikari score >= 11), occurring >= 14 days following the third dose. At monthly home visits, symptoms of illnesses during the past 2 weeks were solicited and limited physical exams were performed; dehydration was defined by WHO's Integrated Management of Childhood Illness. FINDINGS: Vaccine efficacy (VE) against severe RVGE through nearly 2 years of follow-up among 1308 Kenyan children was 63.9% (95% CI: -5.9,89.8). Through the first year of life, VE against severe RVGE was 83.4% (95% CI: 25.5,98.2). From home visits, VE against all-cause gastroenteritis with severe dehydration was 34.4% (95% CI: 5.3,54.6) through the first year and 29.7% (95% CI: 2.5,49.3) through the entire follow-up period. The reduction in incidence of gastroenteritis with severe dehydration in the community during the first year of life (19.0 cases/100 person-years) was almost six times greater than the reduction in severe RVGE presenting to the clinic (3.3/100 person-years). Oral rehydration solution use was lower among PRV recipients (VE 23.1%, 95% CI: 8.8,35.1). An estimated 41% of gastroenteritis with severe dehydration in the first year reported at home was rotavirus-related. CONCLUSIONS: PRV significantly reduced severe RVGE in Kenya. The impact of PRV might be greatest in rural Africa in protecting the many children who develop severe gastroenteritis and cannot access health facilities. PMID- 22520138 TI - Safety of the pentavalent rotavirus vaccine (PRV), RotaTeq((r)), in Kenya, including among HIV-infected and HIV-exposed infants. AB - Two multicenter Phase III trials were conducted in five countries from March 2007 to March 2009 to evaluate the safety and efficacy of the pentavalent rotavirus vaccine (PRV), RotaTeq((r)), in Africa and Asia. In this report, we evaluate the safety of this vaccine, including among HIV-infected and HIV-exposed infants, in Kenya. 1308 Infants were randomized 1:1 to receive 3 doses of PRV/placebo at approximately 6, 10, and 14 weeks of age. HIV counseling and testing were offered to all participants. A positive PCR result indicated HIV infection; the presence of HIV antibody in PCR-negative children indicated HIV exposure without HIV infection. All serious adverse events (SAE) within 14 days of any dose, and vaccine-related SAEs, intussusception, and deaths occurring at any time during the study, were reported ("SAE surveillance"). In addition, 297 participants were followed for 42 days after any dose for any adverse event (AE), regardless of severity ("intensive safety surveillance"). The safety evaluation was stratified by HIV status. SAEs were reported in 20/649 vaccine recipients (3.1%) and 21/643 placebo recipients (3.3%) within 14 days following vaccination (p = 0.9). The most common SAE in the vaccinated group was pneumonia (1.7%). No individual SAE was significantly more common among vaccine vs. placebo recipients. Seventy-two deaths were reported, 38 (5.9%) and 34 (5.3%) among vaccine and placebo recipients, respectively (p = 0.66). No cases of intussusception were reported. During intensive safety surveillance, 137/147 (93.2%) vaccine recipients and 147/150 (98.0%) placebo recipients experienced one or more AEs (risk ratio = 0.95; 95% CI: 0.91-1.0; p = 0.05). 88.5% of the infants were tested for HIV infection; 21/581 (3.6%) children in the vaccine group and 17/577 (2.9%) in the placebo group were HIV-infected. Among the 37 HIV-infected infants with full safety follow-up, 5/21 (23.8%) vaccine recipients and 2/16 (12.5%) placebo recipients reported an SAE (p = 0.67). In total, 12 deaths occurred among identified HIV-infected infants: 8 (38%) receiving vaccine vs. 4 (23.5%) receiving placebo (RR = 1.6, 95% CI: 0.59-4.5). Among the 21 HIV-infected infants in the vaccine group, 2 of 8 deaths were gastroenteritis-related; among the 17 HIV-infected infants in the placebo group, 3 of 4 deaths were gastroenteritis related. There were no significant differences in serious or non-serious AEs, including vaccine-related SAEs, between the 88 HIV-exposed vaccine recipients vs. the 89 HIV-exposed placebo recipients. PRV appears to be a safe intervention against rotavirus gastroenteritis among infants in Kenya. AEs, including serious AEs, were not associated with receipt of vaccine. Further, SAEs were not significantly more common among HIV-infected or HIV-exposed participants; however, the low number of HIV-infected infants did not provide sufficient power to fully assess safety in HIV-infected vaccine recipients. PMID- 22520139 TI - Projected health and economic impact of rotavirus vaccination in GAVI-eligible countries: 2011-2030. AB - Rotavirus is the leading cause of diarrheal disease in children under 5 years of age. It is responsible for more than 450,000 deaths each year, with more than 90% of these deaths occurring in low-resource countries eligible for support by the GAVI Alliance. Significant efforts made by the Alliance and its partners are providing countries with the opportunity to introduce rotavirus vaccines into their national immunization programs, to help prevent childhood illness and death. We projected the cost-effectiveness and health impact of rotavirus vaccines in GAVI-eligible countries, to assist decision makers in prioritizing resources to achieve the greatest health benefits for their populations. A decision-analytic model was used to project the health outcomes and direct costs of a birth cohort in the target population, with and without a rotavirus vaccine. Current data on disease burden, vaccine efficacy, immunization rates, and costs were used in the model. Vaccination in GAVI-eligible countries would prevent 2.46 million childhood deaths and 83 million disability-adjusted life years (DALYs) from 2011 to 2030, with annual reductions of 180,000 childhood deaths at peak vaccine uptake. The cost per DALY averted is $42 for all GAVI countries combined, over the entire period. Rotavirus vaccination would be considered very cost effective for the entire cohort of GAVI countries, and in each country individually, as cost-effectiveness ratios are less than the gross domestic product (GDP) per capita. Vaccination is most cost-effective and has the greatest impact in regions with high rotavirus mortality. Rotavirus vaccination in GAVI eligible countries is very cost-effective and is projected to substantially reduce childhood mortality in this population. PMID- 22520140 TI - Efficacy of the oral pentavalent rotavirus vaccine in Mali. AB - The oral, pentavalent rotavirus vaccine (PRV), RotaTeq was assessed for prevention of severe rotavirus gastroenteritis (RVGE) in young children in two multi-site, randomized, placebo-controlled field trials; one in Asia (Vietnam and Bangladesh) and the other in sub-Saharan Africa (Ghana, Kenya and Mali). The efficacy results for the Mali site of the multi-country trial are presented here. We randomly assigned infants in a 1:1 ratio to receive 3 doses of PRV/placebo at approximately 6, 10, and 14 weeks of age. Gastroenteritis episodes were captured passively at the local health centers and by home visits. The primary study outcome was severe RVGE, as defined by a score of >= 11 using the Vesikari Clinical Scoring System occurring >= 14 days after the third dose until the end of the study. Other efficacy analyses included efficacy against severe RVGE through the first year and during the second years of life, as well as efficacy after receiving at least one dose of vaccine. In total, 1960 infants were enrolled in the trial at the Mali site and sera were collected on a subset of infants (approximately 150) for immunogenicity testing. In the first year of follow-up, largely due to cultural practices to visit traditional healers as the first point of care, the point estimate of efficacy was unreliable: the per protocol vaccine efficacy against severe RVGE was 1% (95% confidence interval [CI]: -431.7, 81.6); the intention-to-treat vaccine efficacy was 42.9% (95% CI: 125.7, 87.7). During the second year of follow-up, after the surveillance system was modified to adapt to local customs and health care seeking practices, the point estimate of per-protocol vaccine efficacy was 19.2% (95% CI: -23.1,47.3%). 82.5% of Malian infants (95% CI: 70.1,91.3%) who received PRV mounted a seroresponse (>= 3-fold rise from baseline (prevaccination) to post-dose 3 vaccination) of anti-rotavirus immunoglobulin A antibody, with a post third-dose geometric mean titer (GMT) of 31.3 units/mL. By contrast, only 20.0% of placebo recipients (95% CI: 10.0, 33.7%) developed a seroresponse and the post-third dose GMT was 3.2 units/mL. None of the serious clinical adverse events observed were considered to be vaccine-related. PMID- 22520141 TI - Secondary efficacy endpoints of the pentavalent rotavirus vaccine against gastroenteritis in sub-Saharan Africa. AB - The efficacy of the pentavalent rotavirus vaccine (PRV), RotaTeq((r)), was evaluated in a double-blind, placebo-controlled, multicenter Phase III clinical trial conducted (April 2007-March 2009) in 3 low-income countries in Africa: Ghana, Kenya, and Mali. In total, 5468 infants were randomized 1:1 to receive 3 doses of PRV/placebo at approximately 6, 10, and 14 weeks of age; concomitant administration with routine EPI vaccines, including OPV, was allowed. HIV infected infants were not excluded. The primary endpoint, vaccine efficacy (VE) against severe-rotavirus gastroenteritis (RVGE), as measured by Vesikari scoring system (VSS, score >=11), from >=14 days following Dose 3 through a follow-up period of nearly 2 years in the combined 3 African countries, and secondary endpoints by total follow-up period have been previously reported. In this study, we report post hoc subgroup analyses on secondary endpoints of public health importance. VE against RVGE of any severity was 49.2% (95%CI: 29.9, 63.5) through the first year of life and 30.5% (95%CI: 16.7, 42.2) through the complete follow up period. VE against severe-gastroenteritis of any etiology was 21.5% (95%CI: <0, 38.4) through the first year of life and 10.6% (95%CI: <0, 24.9) through the complete follow-up period. Through the complete follow-up period, VE against severe-RVGE caused by (i) vaccine-contained G and P types (G1-G4, P1A[8]), (ii) non-vaccine G types (G8, G9, G10), and (iii) non-vaccine P types (P1B[4], P2A[6]) was 34.0% (95%CI:11.2, 51.2), 81.8% (95%CI:16.5, 98.0) and 40.7% (95%CI:8.4, 62.1), respectively. There was a trend towards higher VE with higher disease severity, although in some cases the numbers were small. In African countries with high under-5 mortality rates, PRV significantly reduced RVGE through nearly 2 years of follow-up; more modest reductions were observed against gastroenteritis of any etiology. PRV provides protection against severe-RVGE caused by diverse rotavirus genotypes, including those not contained in the vaccine. PMID- 22520142 TI - Immunogenicity of the pentavalent rotavirus vaccine in African infants. AB - We recently completed a double-blind, placebo-controlled, multicenter Phase III clinical trial of the pentavalent rotavirus vaccine (PRV) in three African countries, Ghana, Kenya, and Mali, from April 2007 to March 2009. The immunogenicity of PRV in African infants is described. In total, 5468 infants were randomized 1:1 to receive 3 doses of PRV or placebo at approximately 6, 10, and 14 weeks of age. Breastfeeding and concomitant administration of EPI vaccines, including OPV, were allowed, and HIV-infected infants were not excluded. Immunogenicity of PRV was assessed by measuring serum anti-rotavirus IgA responses, as well as serum neutralization antibody (SNA) to the human rotavirus serotypes G1, G2, G3, G4 and P1A[8] in approximately 150 infants per country. Sera were collected pre-dose 1 (pD1) and approximately 14 days post-dose 3 (PD3) for immunological analysis. For the sero-response rates (>= 3-fold rise from pD1 to PD3), the number of subjects evaluable included those with both pD1 and PD3 data available. PRV was immunogenic in African children and significantly reduced severe RVGE in African children through the first two years of life. The pooled anti-rotavirus IgA sero-response rate was 78.3%, with consistent rates in each of the African sites: 73.8% (Kenya), 78.9% (Ghana), and 82.5% (Mali); but generally lower than that reported in Europe and USA. PD3 GMTs (28.2 dilution units) were 5-10 times lower than those assessed in subjects in clinical trials in developed countries. SNA responses to human rotavirus serotypes G1-G4 and P1A[8] ranged from 6.3% (G3) to 26.5% (G4). PD3 SNA GMTs to G1 and P1A[8] were 4 fold and 3-fold lower respectively, when compared to the corresponding GMTs in subjects who received PRV in similar studies conducted in developed countries. PRV was immunogenic in African infants, and the anti-rotavirus IgA sero-response rates were similar across all three African sites although lower than those observed in Europe and USA. While immune correlates of protection have not been established for rotavirus, the findings are consistent with lower efficacy rates demonstrated during this trial. Further investigation is needed to understand the reason for the lower immunogenicity observed. PMID- 22520143 TI - Methodology and lessons-learned from the efficacy clinical trial of the pentavalent rotavirus vaccine in Bangladesh. AB - An efficacy clinical trial with pentavalent rotavirus vaccine (PRV), RotaTeq((r)), was conducted at Matlab field site of ICDDR,B, Bangladesh from March 2007 to March 2009. The methodology, including operation logistics, and lessons-learned are described in this report. Vaccination was organized at 41 fixed-site clinics twice/month. A total of 1136 infants were randomized 1:1 to receive 3 doses of PRV/placebo at approximately 6-, 10-, and 14-weeks of age with routine vaccines of the Expanded Programme on Immunization (EPI) schedule. Twelve field-workers routinely visited study participants for safety and efficacy follow up. The study was conducted following good clinical practices and maintaining cold-chain requirements. There were no temperature deviations of clinical vaccine supplies. Data entry was done using the source documents to a central database developed by the sponsor which was linked to web. Among enrolled infants, 1128 (99.3%) received 3 doses of PRV/placebo and efficacy follow-up was conducted for a median of 554 days. For the evaluation of immunogenicity, blood samples were collected from 150 participants predose 1 and from 147 (98%) of the same participants post dose 3. Stool samples were collected from 778 (99.9%) acute gastroenteritis episodes among children who reported to diarrhoea treatment centres. Thirty-nine serious adverse events, including 6 deaths, occurred among study participants. The efficacy of PRV against severe rotavirus gastroenteritis was 42.7% through the entire follow-up period; serum anti-rotavirus IgA response was 78.1%. Inclement weather, difficult transportation, and movement of study participants were some of the challenges identified. This is the first vaccine trial in rural Bangladesh with online data entry. The study was well accepted in the community and was completed successfully. PMID- 22520144 TI - Ladies from hell, Aberdeen free gardeners, and the Russian influenza: an anthropometric analysis of WWI-era Scottish soldiers and civilians. AB - We analyze data on the height of Scottish men, both civilians and members of the military forces serving in World War I measured in the 1910s, in order to provide another window into the biological well-being of late nineteenth-century birth cohorts. The evidence indicates that rural residents still had a distinct height advantage over their urban counterparts and that military men displayed a slower growth profile than did civilians, but mean heights for the two groups of adults were similar. Mean stature for both groups is well above those found by Floud for British troops born in the 1880s and greater than that of Scottish convicts from the 1830s. Men who were in utero between 1889 and 1893 were slightly stunted, "marked for life" by an encounter with the Russian influenza which struck the region repeatedly. PMID- 22520145 TI - Patients satisfaction with laboratory services at antiretroviral therapy clinics in public hospitals, Addis Ababa, Ethiopia. AB - BACKGROUND: Despite the fact that Ethiopia has scale up antiretroviral treatment (ART) program, little is known about the patient satisfaction with ART monitoring laboratory services in health facilities. We therefore aimed to assess patient satisfaction with laboratory services at ART clinics in public hospitals. METHODS: Hospital based, descriptive cross sectional study was conducted from October to November 2010 among clients attending in nine public hospitals ART clinics in Addis Ababa Ethiopia. Patients' satisfaction towards laboratory services was assessed using exit interview structured questionnaire. Data were coded and entered using EPI info 2002 (Centers for Disease Control and Prevention Atlanta, GA) and analyzed using SPSS version 15 software (SPSS INC, Chicago, IL, USA). RESULTS: A total of 406 clients were involved in the study. Of these 255(62.8%) were females. The overall satisfaction rate for ART monitoring laboratory services was (85.5%). Patients were satisfied with measures taken by health care providers to keep confidentiality and ability of the person drawing blood to answer question (98.3% and 96.3% respectively). Moreover, the finding of this study revealed, statistical significant associations between the overall patients' satisfaction with waiting time to get blood drawing service, availability of ordered laboratory tests and waiting time to get laboratory result with (p < 0.05). Patients receiving blood drawing service less than 30 minute were 7.59 times (95% CI AOR: 3.92-14.70) to be more satisfied with ART monitoring laboratory services compared to those who underwent for more than 30 minutes. CONCLUSIONS: Overall, the satisfaction survey showed, most respondents were satisfied with ART monitoring laboratory services. However, factors such as improving accessibility and availability of latrines should be taken into consideration in order to improve the overall satisfaction. PMID- 22520146 TI - Long-term control of a MEN1 prolactin secreting pituitary carcinoma after temozolomide treatment. AB - We report here a rare case of a young male patient presenting with a Multiple Endocrine Neoplasia Type 1 - prolactin-secreting pituitary carcinoma, controlled long-term after temozolomide withdrawal. Initial presentation was pituitary apoplexy leading to surgery. Dopamine agonists and radiotherapy allowed control of prolactin secretion and pituitary remnant. Metastasis appeared 10 years after initial presentation, leading to the diagnosis of pituitary carcinoma. At that time, dopamine agonists were no more effective; temozolomide, an oral alkylating agent, was administered for 24 cycles, and allowed decrease of the volume of the pituitary lesion and metastases. The patient is still currently followed in our department, 3 years after temozolomide withdrawal: prolactin level and pituitary tumor volume remain controlled without any chemotherapy. To our knowledge, this is the first case of MEN1 prolactin secreting pituitary carcinoma controlled long term after temozolomide discontinuation. PMID- 22520147 TI - Prevalence and incidence of pituitary adenomas. AB - Reliable epidemiological data on pituitary adenomas (PAs) are of major importance for estimating the burden on the Health Care System and for designing optimal resource distribution for clinical care and for research activities. Cross sectional studies from Switzerland, Belgium and the UK have shown that PAs have a prevalence of 78 to 94 cases/100,000 inhabitants (three to five times higher than previously thought). Furthermore, data from Northern Finland show an overall standardized incidence rate of 4 per 100,000 with the incidentally discovered ones demonstrating an increase. The enhanced awareness of pituitary disease and the recent advances in the diagnostic technologies have contributed to the earlier recognition of PAs. Studies from diverse populations and of larger sample size are needed to expand our insight on the epidemiology of PAs. PMID- 22520148 TI - Predictive factors for visual outcome after resection of spheno-orbital meningiomas: a long-term review. PMID- 22520149 TI - Regional anaesthesia with sedation protocol to safely debride sacral pressure ulcers. AB - A treatment challenge for patients with sacral pressure ulcers is balancing the need for adequate surgical debridement with appropriate anaesthesia management. We are functioning under the hypothesis that regional anaesthesia has advantages over general anaesthesia. We describe our regional anaesthesia protocol for perioperative and postoperative management. PMID- 22520150 TI - Parental compliance--an emerging problem in Liverpool community child health surveys 1991-2006. AB - BACKGROUND: Compliance is a critical issue for parental questionnaires in school based epidemiological surveys and high compliance is difficult to achieve. The objective of this study was to determine trends and factors associated with parental questionnaire compliance during respiratory health surveys of school children in Merseyside between 1991 and 2006. METHODS: Four cross-sectional respiratory health surveys employing a core questionnaire and methodology were conducted in 1991, 1993, 1998 and 2006 among 5-11 year old children in the same 10 schools in Bootle and 5 schools in Wallasey, Merseyside. Parental compliance fell sequentially in consecutive surveys. This analysis aimed to determine the association of questionnaire compliance with variation in response rates to specific questions across surveys, and the demographic profiles for parents of children attending participant schools. RESULTS: Parental questionnaire compliance was 92% (1872/2035) in 1991, 87.4% (3746/4288) in 1993, 78.1% (1964/2514) in 1998 and 30.3% (1074/3540) in 2006. The trend to lower compliance in later surveys was consistent across all surveyed schools. Townsend score estimations of socio-economic status did not differ between schools with high or low questionnaire compliance and were comparable across the four surveys with only small differences between responders and non-responders to specific core questions. Respiratory symptom questions were mostly well answered with fewer than 15% of non-responders across all surveys. There were significant differences between mean child age, maternal and paternal smoking prevalence, and maternal employment between the four surveys (all p < 0.01). Out-migration did not differ between surveys (p = 0.256) with three quarters of parents resident for at least 3 years in the survey areas. CONCLUSION: Methodological differences or changes in socio-economic status of respondents between surveys were unlikely to explain compliance differences. Changes in maternal employment patterns may have been contributory. This analysis demonstrates a major shift in community parental questionnaire compliance over a 15 year period to 2006. Parental questionnaire compliance must be factored into survey designs and methodologies. PMID- 22520151 TI - Investigation on the pharmacological profile of 2,6-diacetylpyridine bis(benzoylhydrazone) derivatives and their antimony(III) and bismuth(III) complexes. AB - Complexes [Sb(HAcPh)Cl(2)] (1), [Sb(HAcpClPh)Cl(2)] (2), [Sb(HAcpNO(2)Ph)Cl(2)] (3) and [Bi(HAcPh)Cl(2)] (4), [Bi(HAcpClPh)Cl(2)] (5), [Bi(HAcpNO(2)Ph)Cl(2)] (6) were obtained with 2,6-diacetylpyridine bis(benzoylhydrazone) (H(2)AcPh), 2,6 diacetylpyridine bis(para-chlorobenzoylhydrazone) (H(2)AcpClPh), and 2,6 diacetylpyridine bis(para-nitrobenzoylhydrazone) (H(2)AcpNO(2)Ph). The bis(benzoylhydrazones) were inactive as antimicrobial agents against gram positive and gram-negative bacteria and against Candida albicans but upon coordination to antimony(III) and bismuth(III) antimicrobial activity was demonstrated. The studied compounds were tested for their cytotoxic activities against Jurkat and HL60 (leukemia), MCF-7 (breast tumor), HCT-116 (colorectal carcinoma) and peripheral blood mononuclear (PBMC) cells. All bis(benzoylhydrazones) proved to be poorly cytotoxic. Upon coordination of the bis(benzoylhydrazones) to antimony(III) and bismuth(III) cytotoxicity significantly improved. Complex (5) presented high therapeutic indexes (TI = 11 508) against all cell lineages. PMID- 22520152 TI - Quinazoline-tyrphostin as a new class of antitumor agents, molecular properties prediction, synthesis and biological testing. AB - A new series of substituted quinazolin-4-(3H)-one-tyrphostin derivatives was prepared and screened for their cytotoxic activity against three tumor cell lines, namely human breast cancer cell line (MCF-7), human cervical cancer cell line (HeLa) and human hepatocellular liver carcinoma cell line (HepG2) using the colorimetric MTT assay. Among the current series, 10 compounds exhibited remarkable in vitro antiproliferative activity against the three tested cell lines with the IC(50) values ranging from 0.009 to 0.015 mM. All the compounds showed suitable drug like characteristics according to Lipinski's rule. PMID- 22520153 TI - Benzothiazoles as probes for the 5HT1A receptor and the serotonin transporter (SERT): a search for new dual-acting agents as potential antidepressants. AB - The synthesis and evaluation of several benzothiazole-based compounds are described in an attempt to identify novel dual-acting 5HT(1A) receptor and SERT inhibitors as new antidepressants. Binding affinities at the 5HT(1A) receptor and the serotonin transporter do not appear to be congruent and other areas of the binding sites would need to be explored in order to improve binding simultaneously at both sites. Compounds 20 and 23 show moderate binding affinity at the 5HT(1A) receptor and the SERT site and thus, have the potential to be further explored as dual-acting agents. In addition, compound 20 binds with low affinity to the dopamine transporter (DAT), the norepinephrine transporter (NET) and 5HT(2C) receptor, which are desirable properties as selectivity for SERT (and not DAT or NET) is associated with an absence of cardiovascular side effects. PMID- 22520154 TI - [Bloodstream infection in the up to 80 year-old-patients]. AB - INTRODUCTION: The aim of our study was to describe the characteristics of bacteremia detected in patients over 79 years and to identify possible factors associated with the mortality. METHODS: A retrospective cohort study, which included all patients over 17 years of age with bacteremia detected between 2004 7 was performed. Demographic variables, comorbidities, source of bacteremia, causing microorganism, severity and hospital mortality were recorded. Patients were classified into three age groups: 18 to 64 years (G1), 65 to 79 (G2) and >=80 years (G3). RESULTS: We analyzed 1594 episodes of bacteremia (35% in G1, 35% in G2 and 29% in G3). In G3, 47% had renal failure, 83% solid neoplasm, 2% immunosuppression 5% malnutrition and 38% decubitus ulcers. These proportions were 27, 30, 5 and 2%, respectively in G2, and 15, 16, 12 and 5% in G1 (P<.01). The urinary focus accounted for 28%, 43% and 44% in G1, G2 and G3, respectively (P<.01) and biliary focus 6, 11 and 16% (P<.01), in each group. E. coli accounted for 32% in G1, 44% in G2 and 51% in G3. Mortality in each age group was 9, 16 and 21%. In multivariate analysis, mortality in the >=80 years was associated with renal failure, malnutrition, the presence of ulcers and shock. CONCLUSIONS: Bacteremia in the elderly are mainly of urinary origin. Mortality in these cases depends primarily on the patient's baseline status rather than their age. PMID- 22520155 TI - Exploring professionalization among Brazilian oral health technicians. AB - Professional dental auxiliaries emerged in the early 20th century in the United States of America and quickly spread to Europe and other regions of the world. In Brazil, however, oral health technicians (OHTs), who occupy a similar role as dental hygienists, had a long journey before the occupation achieved legal recognition: Brazilian Law 11.889, which regulates this occupation in the country, was only enacted in 2008. The aim of this paper is to review the literature on the professionalization of OHTs, highlighting the triggering, limiting and conflicting aspects that exerted an influence on the historical progress of these professionals in Brazil. We have tested Abbott's and Larson's theory on professionalization, against the history of OHTs. A number of different dental corporative interests exerted an influence over professionalization, especially in discussions regarding the permissible activities of these professionals in the oral cavity of patients. With primary health care advances in Brazil, the importance of these professionals has once again come to the forefront. This seems to be a key point in the consolidation of OHTs in the area of human resources for health in Brazil. PMID- 22520156 TI - Childhood obesity in modern China. PMID- 22520157 TI - How to reliably deliver narrow individual-patient error bars for optimization of pacemaker AV or VV delay using a "pick-the-highest" strategy with haemodynamic measurements. AB - Intuitive and easily-described, "pick-the-highest" is often recommended for quantitative optimization of AV and especially VV delay settings of biventricular pacemakers (BVP; cardiac resynchronization therapy, CRT). But reliable selection of the optimum setting is challenged by beat-to-beat physiological variation, which "pick-the-highest" combats by averaging multiple heartbeats. Optimization is not optimization unless the optimum is identified confidently. This document shows how to calculate how many heartbeats must be averaged to optimize reliably by pick-the-highest. Any reader, by conducting a few measurements, can calculate for locally-available methods (i) biological scatter between replicate measurements, and (ii) curvature of the biological response. With these, for any clinically-desired precision of optimization, the necessary number of heartbeats can be calculated. To achieve 95% confidence of getting within +/-?x of the true optimum, the number of heartbeats needed is 2(scatter/curvature)(2)/?x(4) per setting. Applying published scatter/curvature values (which readers should re evaluate locally) indicates that optimizing AV, even coarsely with a 40ms-wide band of precision, requires many thousand beats. For VV delay, the number approaches a million. Moreover, identifying the optimum twice as precisely requires 30-fold more beats. "Pick the highest" is quick to say but slow to do. We must not expect staff to do the impossible; nor criticise them for not doing so. Nor should we assume recommendations and published protocols are well designed. Reliable AV or VV optimization, using "pick-the-highest" on commonly recommended manual measurements, is unrealistic. Improving time-efficiency of the optimization process to become clinically realistic may need a curve-fitting strategy instead, with all acquired data marshalled conjointly. PMID- 22520158 TI - Coronary computed tomography versus exercise testing in patients with stable chest pain: comparative effectiveness and costs. AB - BACKGROUND: To determine the comparative effectiveness and costs of a CT-strategy and a stress-electrocardiography-based strategy (standard-of-care; SOC-strategy) for diagnosing coronary artery disease (CAD). METHODS: A decision analysis was performed based on a well-documented prospective cohort of 471 outpatients with stable chest pain with follow-up combined with best-available evidence from the literature. Outcomes were correct classification of patients as CAD- (no obstructive CAD), CAD+ (obstructive CAD without revascularization) and indication for Revascularization (using a combination reference standard), diagnostic costs, lifetime health care costs, and quality-adjusted life years (QALY). Parameter uncertainty was analyzed using probabilistic sensitivity analysis. RESULTS: For men (and women), diagnostic cost savings were ?245 (?252) for the CT-strategy as compared to the SOC-strategy. The CT-strategy classified 82% (88%) of simulated men (women) in the appropriate disease category, whereas 83% (85%) were correctly classified by the SOC-strategy. The long-term cost-effectiveness analysis showed that the SOC-strategy was dominated by the CT-strategy, which was less expensive (-?229 in men, -?444 in women) and more effective (+0.002 QALY in men, +0.005 in women). The CT-strategy was cost-saving (-?231) but also less effective compared to SOC (-0.003 QALY) in men with a pre-test probability of >= 70%. The CT strategy was cost-effective in 100% of simulations, except for men with a pre test probability >= 70% in which case it was 59%. CONCLUSIONS: The results suggest that a CT-based strategy is less expensive and equally effective compared to SOC in all women and in men with a pre-test probability <70%. PMID- 22520160 TI - High-resolution metabolic profiling towards G protein-coupled receptors: rapid and comprehensive screening of histamine H4 receptor ligands. AB - In the past years we developed high-resolution screening platforms involving separation of bioactive mixtures and on-line or at-line bioassays for a wide variety of biological targets with parallel mass spectrometric detection and identification. In the current research, we make a major step forward in the development of at-line bioassays by implementation of radioligand receptor binding and functional cellular assays to evaluate bioactvity and selectivity. We demonstrate a new platform for high-resolution metabolic profiling of lead compounds for functional activity and selectivity toward the human histamine H(4) receptor (hH(4)R), a member of the large family of membrane-bound G protein coupled receptors. In this platform analytical chemistry, cell biology and pharmacology are merged. The methodology is based on chromatographic separation of metabolic mixtures by HPLC coupled to high-resolution fractionation onto (multiple) microtiter well plates for complementary assaying. The methodology was used for efficient and rapid metabolic profiling of the drug clozapine and three selective hH(4)R lead compounds. With this new platform metabolites with undesired alterations in target selectivity profiles can be readily identified. Moreover, the parallel identification of metabolite structures, with accurate mass measurements and MS/MS, allowed identification of liable metabolic 'hotspots' for further lead optimization and plays a central role in the workflow and in this study. The methodology can be easily adapted for use with other receptor screening formats. The efficient combination of pharmacological assays with analytical techniques by leveraging high-resolution at-line fractionation as a linking technology will allow implementation of comprehensive metabolic profiling in an early phase of the drug discovery process. PMID- 22520159 TI - Sample displacement chromatography as a method for purification of proteins and peptides from complex mixtures. AB - Sample displacement chromatography (SDC) in reversed-phase and ion-exchange modes was introduced approximately twenty years ago. This method takes advantage of relative binding affinities of components in a sample mixture. During loading, there is a competition among different sample components for the sorption on the surface of the stationary phase. SDC was first used for the preparative purification of proteins. Later, it was demonstrated that this kind of chromatography can also be performed in ion-exchange, affinity and hydrophobic interaction mode. It has also been shown that SDC can be performed on monoliths and membrane-based supports in both analytical and preparative scale. Recently, SDC in ion-exchange and hydrophobic interaction mode was also employed successfully for the removal of trace proteins from monoclonal antibody preparations and for the enrichment of low abundance proteins from human plasma. In this review, the principals of SDC are introduced, and the potential for separation of proteins and peptides in micro-analytical, analytical and preparative scale is discussed. PMID- 22520161 TI - Evaluation of the biomethane potential of solid fish waste. AB - Manufacturing processes in fish canning industries generate a considerable amount of solid waste that can be digested anaerobically. The aim of this research was to study the biochemical methane potential of different solid fish waste. For tuna, sardine and needle fish waste, around 0.47g COD-CH(4)/g COD(added) was obtained in batch experiments with 1%TS; whereas for mackerel waste, the methane production attained 0.59g COD-CH(4)/g COD(added). The increase in the waste/inoculum ratio, from 1.1-1.3 to 2.8-3.3g VS(waste)/g VS(inoculum), led to overload due to VFA and LCFA accumulation. Afterward, co-digestion assays of fish waste with gorse were undertaken but the biochemical methane potential did not improve. PMID- 22520162 TI - Estimating the value of estimation. PMID- 22520163 TI - Quantitative studies of lower motor neuron degeneration in amyotrophic lateral sclerosis: evidence for exponential decay of motor unit numbers and greatest rate of loss at the site of onset. AB - OBJECTIVE: To use our Bayesian method of motor unit number estimation (MUNE) to evaluate lower motor neuron degeneration in ALS. METHODS: In subjects with ALS we performed serial MUNE studies. We examined the repeatability of the test and then determined whether the loss of MUs was fitted by an exponential or Weibull distribution. RESULTS: The decline in motor unit (MU) numbers was well-fitted by an exponential decay curve. We calculated the half life of MUs in the abductor digiti minimi (ADM), abductor pollicis brevis (APB) and/or extensor digitorum brevis (EDB) muscles. The mean half life of the MUs of ADM muscle was greater than those of the APB or EDB muscles. The half-life of MUs was less in the ADM muscle of subjects with upper limb than in those with lower limb onset. CONCLUSIONS: The rate of loss of lower motor neurons in ALS is exponential, the motor units of the APB decay more quickly than those of the ADM muscle and the rate of loss of motor units is greater at the site of onset of disease. SIGNIFICANCE: This shows that the Bayesian MUNE method is useful in following the course and exploring the clinical features of ALS. PMID- 22520165 TI - Predicting participation in and successful outcome of a penile rehabilitation programme using a phosphodiesterase type 5 inhibitor with a vacuum erection device after radical prostatectomy. AB - Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? The role of the vacuum erection device (VED) has increased with its use in combined therapy with a phosphodiesterase type 5 inhibitor (PDE5i) for penile rehabilitation after radical prostatectomy (RP) and radiotherapy. The advantages of the VED are non-invasive, cost effective, and a possibility of preventing shrinkage of penis length. Albeit current widespread use of penile rehabilitation programmes for post-RP erectile dysfunction, independent predictors for the rehabilitation participants, as well as for its treatment success have not been fully investigated. In the present study, we have added several new predictors for rehabilitation participation, e.g. African-Americans and higher preoperative sexual function. Conversely, higher preoperative PSA concentrations and the presence of positive surgical margins were predictors for avoidance of rehabilitation. Notably, there was a primary surgeon difference, which had a trend for predicting outcome of the rehabilitation among the participants, implying their surgical technique and follow-up might influence success of the rehabilitation. OBJECTIVES: * To investigate baseline demographic and clinicopathological characteristics of men who participate in our penile rehabilitation programme after radical prostatectomy (RP). * To determine predictors for participation in rehabilitation, as well as successful rehabilitation outcome using multivariable logistic regression analyses. PATIENTS AND METHODS: * We analysed data on 2345 consecutive patients who underwent RP between 2001 and 2009 in our institution. * The decision to participate in penile rehabilitation using phosphodiesterase type 5 inhibitor (PDE5i) with a vacuum erection device (VED) was based on the patient's choice after post-RP discussions. * Rehabilitation success was defined using the following criteria: (i) patients who continued the penile rehabilitation programme and did not switch treatment from PDE5i to other erectile aids, (ii) success was noted in men who had an Expanded Prostate Cancer Index Composite (EPIC) sexual function (SF) score of >75% of the patient's baseline EPIC score, and (iii) patients who answered that they achieved adequate erections with a PDE5i. * Logistic regression analysis was used to identify factors associated with treatment participation and its success. RESULTS: * Of 676 patients, 354 (53.2%) men participated in a penile rehabilitation programme. Among 329 rehabilitation participants with available data, 96 (29.2%) had treatment success. * In multivariable regression analysis, African-Americans (odds ratio [OR] 3.47, P < 0.001), and higher preoperative SF (OR 1.02, P < 0.001) were associated with participation in rehabilitation. * Higher preoperative PSA concentration (OR 0.50, P = 0.004) and presence of positive surgical margins (OR 0.68, P = 0.042) were found to be independent predictors for non-participation in the rehabilitation. * For rehabilitation outcomes, being older at surgery (OR 0.93, P = 0.001) and adjuvant therapy (OR 0.34, P = 0.047) had a negative association with successful outcome. * There was a trend in the relationship between primary surgeon and rehabilitation success (OR 1.05, P = 0.053) CONCLUSIONS: * Those patients who have risk factors, e.g. adverse prostate cancer features, need to be carefully counselled and encouraged to participate in the penile rehabilitation programme. * Clinicians could lead patients toward successful outcomes if appropriate surgical techniques and rehabilitation are provided. PMID- 22520166 TI - [Diabetes insipidus induced by pregnancy. A case report]. PMID- 22520167 TI - Bariatric surgery in type 1 diabetes. PMID- 22520168 TI - [Tachycardia-induced cardiomyopathy associated to thyroid hormone resistance]. PMID- 22520169 TI - Pituitary apoplexy. A case report. PMID- 22520170 TI - Molecular xenomonitoring of Dirofilaria immitis and Dirofilaria repens in mosquitoes from north-eastern Italy by real-time PCR coupled with melting curve analysis. AB - BACKGROUND: Dirofilaria immitis and Dirofilaria repens are transmitted by bloodsucking culicid mosquitoes belonging to Culex, Aedes, Ochlerotatus, Anopheles and Mansonia genera. The detection of filarioids in mosquitoes for assessing distribution of vectors and/or of pathogens in a given area (also known as "xenomonitoring"), when based on individual dissection of wild-caught female mosquitoes is time consuming and hardly applicable in large epidemiological surveys. Our study aimed to evaluate the recently developed duplex real-time PCR for screening large number of culicids and to assess their positivity for D. immitis and D. repens in an area where both species are endemic. METHODS: A duplex real-time PCR was used to detect and differentiate D. immitis and D. repens in mosquitoes collected in six provinces of the Veneto region using 43 carbon dioxide-baited traps under the frame of an entomological surveillance program to monitor the vectors of West Nile disease. From early May till October 2010, unfed female mosquitoes (n = 40,892) were captured in 20 selected sites. RESULTS: Mosquitoes identified as Culex pipiens, Ochlerotatus caspius, Aedes vexans and Culex modestus were grouped into 995 pools according to species, day and site of collection (from minimum of 1 to maximum of 57). Out of 955 pools, 23 (2.41 %) scored positive for Dirofilaria spp. of which, 21 (2.2 %) for D. immitis and two (0.21 %) for D. repens. An overall Estimated Rate of Infection (ERI) of 0.06 % was recorded, being higher in Och. caspius and Ae. vexans (i.e., 0.18 % and 0.14 %, respectively). At least one mosquito pool was positive for Dirofilaria spp. in each province with the highest ERI recorded in Vicenza and Padova provinces (i.e., 0.42% and 0.16 %, respectively). Mosquitoes collected in all provinces were positive for D. immitis whereas, only two (i.e., Padova and Rovigo) provinces scored positive for D. repens. All mosquito species, except for Cx. modestus, were positive for D. immitis, whereas D. repens was only found in Cx. pipiens. CONCLUSIONS: The results suggest that both Dirofilaria species are endemic and may occur in sympatry in the examined area. The molecular approach herein used represents a powerful tool for surveillance programs of D. immitis and D. repens in the culicid vectors towards a better understanding of the epidemiology of the infections they cause and their seasonal transmission patterns. PMID- 22520171 TI - Partners of people on ART - a New Evaluation of the Risks (The PARTNER study): design and methods. AB - BACKGROUND: It is known that being on antiretroviral therapy reduces the risk of HIV transmission through sex. However it remains unknown what the absolute level of risk of transmission is in a person on ART with most recent measured HIV plasma viral load<50 c/mL in the absence of condom use. There are no data on risk of transmission for anal sex in MSM when the index partner is on ART. METHODS/DESIGN: The PARTNER study is an international, observational multi-centre study, taking place from 2010 to 2014 in which HIV serodifferent partnerships who at enrolment reported recently having had condom-less vaginal or anal sexual intercourse are followed over time, with 46 monthly reporting of transmission risk behaviour through a confidential self completed risk behaviour questionnaire and with 46 monthly HIV testing for the HIV negative partner. The objective is to study (i) the risk of HIV transmission to partners, in particular in partnerships that continue not to use condoms consistently and the HIV-positive partner is on therapy with a viral load<50 copies/mL and (ii) why some partnerships do not use condoms, to describe the proportion who begin to adopt consistent condom use, and factors associated with this. For any negative partner who becomes infected phylogenetic analysis will be used following anonymisation of the samples to assess if transmission had been from the HIV infected partner. DISCUSSION: This observational study will provide missing information on the absolute risk of HIV transmission for both vaginal and anal sex when the index case is on ART with a VL<50 copies/mL in the absence of condom use. PMID- 22520172 TI - Selective impairment of spinal mu-opioid receptor mechanism by plasticity of serotonergic facilitation mediated by 5-HT2A and 5-HT2B receptors. AB - Opioid analgesia is compromised by intracellular mediators such as protein kinase C (PKC). The phosphatidylinositol hydrolysis-coupled serotonin receptor 5-HT2 is ideally suited to promote PKC activation. We test the hypothesis that 5-HT2A and 5-HT2B receptors, which have been previously shown to become pro-excitatory after spinal nerve ligation (SNL), can negatively influence the ability of opioids to depress spinal excitation evoked by noxious input. Spinal superfusion with (100 nM) mu-opioid receptor (MOR)-agonist DAMGO significantly depressed C fiber-evoked spinal field potentials. Simultaneous administration of subclinical 5-HT2AR antagonist 4F 4PP (100 nM) or 5-HT2BR antagonist SB 204741 (100 nM) significantly reduced the IC50 value for DAMGO in nerve-ligated rats (97.56 nM +/- 1.51 and 1.20 nM +/- 1.28 respectively, relative to 104 nM +/- 1.08 at the baseline condition), but not in sham-operated rats. Both antagonists failed to alter depression induced by delta-opioid receptor (DOR)-agonist D-ala2-deltorphin II after SNL as well as in the sham condition. Western blot analysis of dorsal horn homogenates revealed bilateral upregulation of 5-HT2AR and 5-HT2BR protein band densities after SNL. As assessed from double immunofluorescence labeling for confocal laser scanning microscopy, scarce dorsal horn cell processes showed co localization color overlay for 5-HT2AR/MOR, 5-HT2BR/MOR, 5-HT2AR/DOR, or 5 HT2BR/DOR in sham-operated rats. Intensity correlation-based analyses showed significant increases in 5-HT2AR/MOR and 5-HT2BR/MOR co-localizations after SNL. These results indicate that plasticity of spinal serotonergic neurotransmission can selectively reduce spinal MOR mechanisms via 5-HT2A and 5-HT2B receptors, including upregulation of the latter and increased expression in dorsal horn neurons containing MOR. PMID- 22520173 TI - Selecting representative affective dimensions using Procrustes analysis: an application to mobile phone design. AB - Collecting affective responses (ARs) from consumers is crucial to designers aspiring to produce an appealing product. Adjectives are frequently used by researchers as an affective means by which consumers can describe their subjective feelings regarding a specific product design. This study proposes a Kansei engineering (KE) approach for selecting representative affective dimensions using factor analysis (FA) and Procrustes analysis (PA). A semantic differential (SD) experiment is used to examine consumers' ARs toward a set of representative product samples. FA is employed to extract the underlying latent factors using an initial set of affective dimensions. A backward elimination process based on PA is used to determine the relative significance of adjectives in each step according to the calculated residual sum of squared differences (RSSDs) to finally obtain the ranking of the initial set of adjectives. Additionally, the results of the proposed approach are compared to the method that combines FA and two-stage cluster analysis (CA). A case study of mobile phone design is provided to demonstrate the analysis results. PMID- 22520175 TI - Periorbital necrotizing fasciitis -- a review. AB - Necrotizing fasciitis (NF) is a severe infection characterized by rapidly progressing necrotizing infection of the superficial fascia with secondary necrosis of the overlying skin. Periorbital NF is uncommon because of the excellent blood supply to that area; nevertheless, it can sometimes result in death. The aim of this study is to present a systematic review and analyse the factors associated with death. We carried out a systematic literature review of all cases of periorbital NF published in the English language over the past 20 years and present the predisposing conditions, triggering factors, organisms causing NF, presence or absence of toxic shock and the prognosis. The significance of various risk factors leading to death was analysed. We traced a total of 94 patients with periorbital NF from 61 reports. There were no triggering incidents in 25 cases (26.6%). In 48 cases (51.1%), the organism responsible for NF was Group A beta haemolytic Streptococcus. Toxic shock occurred in 29 (30.9%) cases, and loss of vision in 13 (13.8%). Surgical debridement was carried out in 80 (85.1%) cases. There were eight cases (8.5%) of death. This seems to be less than previously reported figures. Toxic shock syndrome (p < 0.001), type 1 infections (p = 0.018), facial involvement (p = 0.032) and blindness because of periorbital NF (p = 0.035) were significantly associated with mortality. Mortality caused by NF arising from the periorbital area seems to be on the decline. However, it is important to recognize it early and institute treatment to avoid toxic shock that leads to death. Type 1 infections, although rare in periorbital area, are not associated with immunocompromised status and nevertheless carry a significant risk of mortality. Major morbidity is loss of vision followed by soft-tissue defects affecting function and cosmesis. PMID- 22520174 TI - Ergonomic analysis of fastening vibration based on ISO Standard 5349 (2001). AB - Hand-held power tools used for fastening operations exert high dynamic forces on the operator's hand-arm, potentially causing injuries to the operator in the long run. This paper presents a study that analyzed the vibrations exerted by two hand held power tools used for fastening operations with the operating exhibiting different postures. The two pneumatic tools, a right-angled nut-runner and an offset pistol-grip, are used to install shearing-type fasteners. A tri-axial accelerometer is used to measure the tool's vibration. The position and orientation of the transducer mounted on the tool follows the ISO-5349 Standard. The measured vibration data is used to compare the two power tools at different operating postures. The data analysis determines the number of years required to reach a 10% probability of developing finger blanching. The results indicate that the pistol-grip tool induces more vibration in the hand-arm than the right-angled nut-runner and that the vibrations exerted on the hand-arm vary for different postures. PMID- 22520176 TI - [Iron metabolism and tools for the iron status assessment]. PMID- 22520177 TI - The importance of obtaining truly consensual informed consent. PMID- 22520178 TI - Acidification of drinking water inhibits indirect transmission, but not direct transmission of Campylobacter between broilers. AB - In this study the effect of acidification of the drinking water of broiler chickens on both direct and indirect transmission of Campylobacter was evaluated. In the direct transmission experiment both susceptible and inoculated animals were housed together. In the indirect transmission experiment the susceptible animals were spatially separated from the inoculated animals and no direct animal to animal contact was possible. The transmission parameter beta was estimated for the groups supplied with acidified drinking water and for the control groups. The results showed that acidification of the drinking water had no effect on direct transmission (beta=3.7 day(-1) for both control and treatment). Indirect transmission however was influenced by acidification of the drinking water. A significant decrease in transmission was observed (p<0.05), with control vs. treatment point estimates being beta=0.075 day(-1) vs. beta=0.011 day(-1). Apart from providing quantitative estimations of both direct and indirect transmission of Campylobacter in broilers, this study also demonstrates the use of an experimental setup for indirect transmission of Campylobacter between broilers to assess the efficacy of candidate measures to reduce transmission. PMID- 22520179 TI - Validation of a fecal scoring scale in puppies during the weaning period. AB - In puppies weaning is a high risk period. Fecal changes are frequent and can be signs of infection by digestive pathogens (bacteria, viruses, parasites) and indicators of nutritional and environmental stress. The aim of this study was to define a pathological fecal score for weaning puppies, and to study the impact on that score of two intestinal viruses (canine parvovirus type 2 and canine coronavirus). For this, the quality of stools was evaluated on 154 puppies between 4 and 8 weeks of age (100 from small breeds and 54 from large breeds). The scoring was performed immediately after a spontaneous defecation based on a 13-point scale (from 1; liquid to 13; dry and hard feces). Fecal samples were frozen for further viral analysis. Each puppy was weighed once a week during the study period. The fecal score regarded as pathological was the highest score associated with a significant reduction in average daily gain (ADG). Fecal samples were checked by semi-quantitative PCR or RT-PCR for canine parvovirus type 2 and canine coronavirus identification, respectively. The quality of feces was affected by both age and breed size. In small breeds, the ADG was significantly reduced under a fecal score of 6 and 7 for puppies at 4-5 and 6-8 weeks of age, respectively. In large breeds, the ADG was significantly reduced under a fecal score of 5 whatever the age of the puppy. Whereas a high viral load of canine parvovirus type 2 significantly impacted feces quality, no effect was recorded for canine coronavirus. This study provides an objective threshold for evaluation of fecal quality in weaning puppies. It also emphasizes the importance to be given to age and breed size in that evaluation. PMID- 22520180 TI - Assimilating knowledge - food and nutrition in early modern physiologies. PMID- 22520181 TI - Food for healing: Convalescent cookery in the early modern era. AB - Despite major theoretical shifts in early modern nutritional theory, from humoralism to chemical and mechanical systems, the form and structure of convalescent cookery remained remarkably constant throughout the era and to a large extent even down to the present. In medical texts, cookbooks and in the popular imagination convalescent food generally mirrored food for infants, being soft and bland, based on dairy and grains, as well as foods considered highly nutritious yet easy to digest like concentrated broths. This article traces the development of ideas about convalescent food and how little they change over time. PMID- 22520182 TI - Chemical and mechanical theories of digestion in early modern medicine. AB - The aim of this paper is to survey the iatrochemists' and iatromechanists' explanations of digestion, from the sixteenth to the early decades of the eighteenth century. The iatrochemists substituted the Galenic thermal digestion with a series of chemical processes, the same as those produced in the laboratory. Jean Baptiste van Helmont marked a turning point in the chemical understanding of digestion, indicating the acid ferment in the stomach as the digestive agent. In the wake of van Helmont, an increasing number of physicians rejected the traditional Galenic theory of digestion, turning to the chemical reactions taking place in the ventricles. The iatrochemists saw nutrition as the outcome of the separation of an active invisible substance, i.e., spirits, from a thick inert covering. The emergence of the mechanical physiology, with its emphasis on the shape, size and motion of parts, did not bring about a decline of the chemical investigations of digestion. Descartes ruled out chemistry in the study of physiology, while a number of physiologists-notably in England-adopted a compromise between iatrochemical and mechanical theories. In the second half of the seventeenth century, the view of acid as an agent of gastric digestion became popular among physiologists. Late in the century, the acid-alkali doctrine spurred further investigations on digestion and nutrition. PMID- 22520183 TI - Diet, embodiment, and virtue in the mechanical philosophy. AB - This paper considers the relationship between diet, embodiment, nature and virtue in several seventeenth-century natural philosophers, all of whom sought to overcome or to radically reform inherited ideas about the self as a hylomorphic compound of form and matter, but who nonetheless were not entirely ready to discard the notion that the self is intimately united with the body. One implication of this intimate union, for them, is that what one does with the body, including what one puts into it, is directly relevant to the supreme end of achieving a virtuous life. I thus consider food--its preparation and its consumption--as a link between natural and moral philosophy in the early modern period, showing in particular the parallels between the search for the diet that is 'natural to man', on the one hand, and the project of establishing rules of virtue on the other. Key to discerning these parallels, I argue, is an understanding of early modern ideas about diet and eating as rooted in the Stoic notion of oikeiosis, which may be translated as 'assimilation' or 'appropriation', and which, as recent work by Lisa Shapiro has shown, played an important role in early modern ideas about a bodily contribution to the human good. The most general thesis is that dietary questions were far more important in early modern philosophy than has yet been recognized: nearly every prominent natural philosopher was preoccupied with them. A narrower thesis is that this parallelism between natural philosophy and moral philosophy is reflected in the conception of cooking as both a fundamental physiological process ('coction') as well as the most basic form of social existence. PMID- 22520184 TI - Health, national character and the English diet in 1700. AB - By 1750, the 'roast beef of Old England' had become a byword. Half a century earlier, however, debate raged about the appropriate diet for the English temperament, a term laden with medical as well as political implications. John Evelyn's Acetaria (1699, 2nd ed. 1706) valorized a rural society that subsisted mostly on vegetables, while the physician Martin Lister's preface to his edition of the Roman cookery book of Apicius (1705) praised the imperial Roman diet and its use of sauces and spices as healthful. The Grub Street writer William King satirized Lister in The Art of Cookery (1708), claiming that a pre-Roman British diet of grilled meats was the most suited to the English character. But the politics of meat-eating was complex: Evelyn's emphasis on vegetables had earlier been endorsed by the radical Thomas Tryon, while the Royal Society stalwart Edward Tyson argued that although the human body seemed best suited for a vegetable diet, human free will trumped nature. PMID- 22520185 TI - The fluid mechanics of nutrition: Herman Boerhaave's synthesis of seventeenth century circulation physiology. AB - This paper investigates the theory of nutrition of Herman Boerhaave, the famous professor of medicine and chemistry at the university of Leyden. Boerhaave's work, which systematized and synthesized the knowledge of the time, represents a shift from a humoral to a hydraulic model of the body in medicine and culture around 1700. This epistemological reconfiguration of early modern physiological thinking is exemplified with respect to the changing meanings of milk. While over centuries the analogy between blood and milk played an essential role in understanding the hidden workings of the nutritional faculties, following the discovery of the blood circulation the blood-milk analogy was transformed into a chyle-milk analogy. Yet Boerhaave's interpretations show that the use of new knowledge tools did not simply displace the old ways of reasoning. Instead, analogies continued to serve as epistemic instruments. Old theories and new insights overlapped, and contemporary knowledge assimilated past ideas. PMID- 22520186 TI - 'Abhorreas pinguedinem': Fat and obesity in early modern medicine (c. 1500-1750). AB - Contrary to a widely held belief, the medicalization of obesity is not a recent development. Obesity was extensively discussed in leading early modern medical textbooks, as well as in dozens of seventeenth- and eighteenth-century dissertations. Drawing upon ancient and medieval writings, these works discussed the negative impact of obesity upon health and linked it with premature death. Obesity was particularly associated with apoplexy, paralysis, asthma and putrid fevers, and a range of therapeutic options was proposed. This paper offers a first survey of the medical understanding of the causes, effects and treatment of obesity in the early modern period. It examines the driving forces behind the physicians' interest and traces the apparently rather limited response to their claims among the general public. Comparing early modern accounts of obesity with the views and stereotypes prevailing today, it notes the impact of changing medical, moral and aesthetic considerations and identifies, among other things, a shift in the early modern period from concepts of pathological compression to images of the obese body as lax and boundless. PMID- 22520187 TI - Balancing acts: Picturing perspiration in the long eighteenth century. AB - This essay examines the historical fortunes of an image that throughout the seventeenth and eighteenth centuries became a landmark of the medical doctrine and practice of static medicine advanced by the physician Santorio Santorio (1561 1636). The image depicted a man sitting on a large Roman steelyard, which allowed the weighing of bodily discharges and gave guidance on the intake of food. Well into the eighteenth century, the image of the weight-watching man accompanied Santorio's work on the art of static medicine and, most likely, contributed to its success. It appeared in a variety of medical works and navigated across competing medical theories and different medical genres, while remaining largely unscathed. This essay explores the success and the historical agency of this image. Focusing on the history of its copies and variants, it investigates how the image came to symbolize the attempt to transform dietetics into an experimental practice, and accordingly preserve its pivotal significance in the medical world. PMID- 22520188 TI - Sciences of appetite in the Enlightenment, 1750-1800. AB - Advice about diet has been an important part of Western medicine from its inception. Although based partly on the presumed qualities and effects of foodstuffs, such advice rested chiefly on the constitution and circumstances of individual patients, including their unique appetites and eating habits. In the eighteenth century the nature of appetite itself came to be a subject of growing interest in the sciences, especially in medicine, natural history, and physiology. Within these sciences attention to the eating proclivities of individuals began to be displaced by interest in uniform processes of ingestion and digestion. In turn dietary advice came increasingly to rely on general standards of health and the digestibility of foodstuffs. Central to the promotion of uniform standards was the increasing credence given to experimental procedures that claimed to offer new certainties about the digestive process. As experimental science took hold, appetite, long regarded as a perplexing blend of psychic and somatic elements, assumed subordinate status as an object of inquiry to phenomena thought readily susceptible to laboratory manipulation. These eighteenth-century developments stand at the origin of the modern nutritional science that denigrates individual appetites in favor of universal rules of 'healthy eating.' PMID- 22520189 TI - The emergence of Nervennahrung: Nerves, mind and metabolism in the long eighteenth century. AB - Morphological assumptions concerning the form, structure and internal life of the brain and nervous system profoundly influenced contemporary physiological concepts about nerve actions throughout the 'long eighteenth century'. This article investigates some early theories of mind and metabolism. In a bottom-up fashion, it asks how eighteenth-century theories regarding the physiological actions of the body organs shaped the conceptions of the structure of the brain and nervous tissue themselves. These proposed that a healthy Nervennahrung (the German word for 'nerve nutrition', which might be rendered as brain food in modern English), not only guaranteed the integrity and stability of neuronal structures in the body, but also explained the complex texture of the brain and spinal cord in physiological terms. Eighteenth-century nerve theories already embodied a Leitmotiv of neurology and brain psychiatry from the later nineteenth century: 'Without phosphorus there is no thought!' PMID- 22520190 TI - 'A matter of so great importance to my health': Alimentary knowledge in practice. AB - The early modern period persists in being the neglected era for concerted study of what the editors have called 'alimentary knowledge' and its applications. Using the details of a regimen penned by a Sussex school teacher in the middle of the eighteenth century, this short afterword considers how far some of the features of that alimentary knowledge-scape, as debated by the contributors to this volume, penetrated into quotidian practice. The possibilities for other forms of research, which might enrich our mapping of these foodways and their impacts, are briefly discussed in conclusion. PMID- 22520191 TI - Crisis discussions in psychology--New historical and philosophical perspectives. AB - In this introductory article, we provide a historical and philosophical framework for studying crisis discussions in psychology. We first trace the various meanings of crisis talk outside and inside of the sciences. We then turn to Kuhn's concept of crisis, which is mainly an analyst's category referring to severe clashes between theory and data. His view has also dominated many discussions on the status of psychology: Can it be considered a "mature" science, or are we dealing here with a pre- or multi-paradigmatic discipline? Against these Kuhnian perspectives, we point out that especially, but not only in psychology distinctive crisis declarations and debates have taken place since at least the late 19th century. In these, quite different usages of crisis talk have emerged, which can be determined by looking at (a) the content and (b) the dimensions of the declarations, as well as (c) the functions these declarations had for their authors. Thus, in psychology at least, 'crisis' has been a vigorous actor's category, occasionally having actual effects on the future course of research. While such crisis declarations need not be taken at face value, they nevertheless help to break the spell of Kuhnian analyses of psychology's history. They should inform ways in which the history and philosophy of psychology is studied further. PMID- 22520192 TI - Wundt contested: The first crisis declaration in psychology. AB - When reflecting on the history and the present situation of their field, psychologists have often seen their discipline as being in a critical state. The first author to warn of a crisis was, in 1897, the now scarcely known philosopher Rudolf Willy. He saw a crisis in psychology resulting, firstly, from a profuse branching out of psychology. Adopting a radical empiriocriticist point of view, he, secondly, made the metaphysical stance of scholars like Wilhelm Wundt responsible for the crisis. Meanwhile, the priest Constantin Gutberlet responded to the claim of crisis arguing, on the contrary, that the crisis resulted from research that was empirical only. Throughout the discipline psychologists felt troubled by a widespread sense of fragmentation in the field. I will argue that this is due to psychology's early social success and popularization in modern society. Moreover the paper shows that the first declaration of crisis emerged at a time when a discussion of fundamentals was already underway between Wundt and the empiriocriticist Richard Avenarius. The present historical research reveals the depth of the confrontation between Wundt and Willy, entailing a clash of two worldviews that embrace psychological, epistemological, and political aspects. PMID- 22520193 TI - Has psychology "found its true path"? Methods, objectivity, and cries of "crisis" in early twentieth-century French psychology. AB - This article explores how French psychologists understood the state of their field during the first quarter of the twentieth century, and whether they thought it was in crisis. The article begins with the Russian-born psychologist Nicolas Kostyleff and his announcement in 1911 that experimental psychology was facing a crisis. After briefly situating Kostyleff, the article examines his analysis of the troubles facing experimental psychology and his proposed solution, as well as the rather muted response his diagnosis received from the French psychological community. The optimism about the field evident in many of the accounts surveying French psychology during the early twentieth century notwithstanding, a few others did join Kostyleff in declaring that all was not well with experimental psychology. Together their pronouncements suggest that under the surface, important unresolved issues faced the French psychological community. Two are singled out: What was the proper methodology for psychology as a positive science? And what kinds of practices could claim to be objective, and in what sense? The article concludes by examining what these anxieties reveal about the type of science that French psychologists hoped to pursue. PMID- 22520194 TI - Hans Driesch and the problems of "normal psychology". Rereading his Crisis in Psychology (1925). AB - In 1925, the German biologist and philosopher Hans Driesch published a booklet entitled The Crisis in Psychology. It was originally published in English and was based on lectures given at various universities in China, Japan and the USA. The "crisis" in psychology of that time, in Driesch's opinion, lies in the necessity to decide about "the road which psychology is to follow in the future". This necessity refers to five "critical points", namely (1) to develop the theory of psychic elements to a theory of meaning by phenomenological analysis, (2) the overcoming of association theory, (3) to acknowledge that the unconscious is a fact and a "normal" aspect of mental life, (4) to reject "psychomechanical parallelism" or any other epiphenomenalistic solution of the mind-body problem, and (5) the extension of psychical research to new facts as described by parapsychology, for instance. Driesch saw close parallels between the development of modern psychology and that of biology, namely in a theoretical shift from "sum concepts" like association and mechanics, to "totality-concepts" like soul and entelechy. The German translation of 1926 was entitled Grundprobleme der Psychologie (Fundamental Problems of Psychology) while "the crisis in psychology" forms just the subtitle of this book. This underlines that Driesch's argumentation--in contrast to that of Buehler--dealt with ontological questions rather than with paradigms. PMID- 22520195 TI - Buhler and Popper: Kantian therapies for the crisis in psychology. AB - I analyze the historical background and philosophical considerations of Karl Buhler and his student Karl Popper regarding the crisis of psychology. They share certain Kantian questions and methods for reflection on the state of the art in psychology. Part 1 outlines Buhler's diagnosis and therapy for the crisis in psychology as he perceived it, leading to his famous theory of language. I also show how the Kantian features of Buhler's approach help to deal with objections to his crisis diagnosis and to aspects of his linguistic theory. Part 2 turns to Popper's dissertation, completed in 1928 under Buhler. I analyze Popper's disapproval of Schlick's physicalism in psychology, as well as Popper's attempt to extend Buhler's Kantian strategy to the domain of the psychology of thinking. In conclusion, I indicate how these approaches to the crisis in psychology differ from Thomas Kuhn's notions of crisis and revolution, which are still all too popular in current philosophical discussions of psychology. PMID- 22520196 TI - Vygotsky's Crisis: Argument, context, relevance. AB - Vygotsky's The Historical Significance of the Crisis in Psychology (1926-1927) is an important text in the history and philosophy of psychology that has only become available to scholars in 1982 in Russian, and in 1997 in English. The goal of this paper is to introduce Vygotsky's conception of psychology to a wider audience. I argue that Vygotsky's argument about the "crisis" in psychology and its resolution can be fully understood only in the context of his social and political thinking. Vygotsky shared the enthusiasm, widespread among Russian leftist intelligentsia in the 1920s, that Soviet society had launched an unprecedented social experiment: The socialist revolution opened the way for establishing social conditions that would let the individual flourish. For Vygotsky, this meant that "a new man" of the future would become "the first and only species in biology that would create itself." He envisioned psychology as a science that would serve this humanist teleology. I propose that The Crisis is relevant today insofar as it helps us define a fundamental problem: How can we systematically account for the development of knowledge in psychology? I evaluate how Vygotsky addresses this problem as a historian of the crisis. PMID- 22520197 TI - Koffka, Kohler, and the "crisis" in psychology. AB - This paper examines the claims of the Gestalt psychologists that there was a crisis in experimental psychology ca. 1900, which arose because the prevailing sensory atomism excluded meaning from among psychological phenomena. The Gestaltists claim that a primary motivation of their movement was to show, against the speculative psychologists and philosophers and Verstehen historians, that natural scientific psychology can handle meaning. Purportedly, they revealed this motivation in their initial German-language presentations but in English emphasized their scientific accomplishments for an American audience. The paper finds that: there was a recognized crisis in the new experimental psychology ca. 1900 pertaining especially to sensory atomism; that the Gestaltists responded to the crisis with new experimental findings and theoretical concepts (Gestalten) that challenged atomism; in both languages, they raised problems of meaning and discussed the contest with speculative psychology and philosophy only after presenting their scientific case; that they introduced phenomenological observations on meaning and perceptual organization into their psychology but did not develop a theory of meaning or solve philosophical problems; that they argued "philosophically," that is, using abstract, conceptual arguments; and that this aspect of their cognitive style was not received well by some prominent members of their American audience. PMID- 22520198 TI - Husserl's Crisis as a crisis of psychology. AB - This paper places Husserl's mature work, The Crisis of the European Sciences, in the context of his engagement with--and critique of--experimental psychology at the time. I begin by showing (a) that Husserl accorded psychology a crucial role in his philosophy, i.e., that of providing a scientific analysis of subjectivity, and (b) that he viewed contemporary psychology--due to its naturalism--as having failed to pursue this goal in the appropriate manner. I then provide an analysis of Husserl's views about naturalism and scientific philosophy. Some central themes of the Crisis are traced back to Husserl's earlier work and to his relationship with his teacher, Franz Brentano, with whom he disagreed about the status of "inner perception" as the proper scientific method for a phenomenological analysis. The paper then shows that Husserl was well aware of at least one publication about the crisis of psychology (Buhler's 1927 book), and it teases out some aspects of the complicated relationship between Husserl and members of the Wurzburg School of thought psychology: The latter had drawn on Husserl's writings, but Husserl felt that they had misunderstood his central thesis. I conclude by placing Husserl's work in the wider context of scientific, cultural, and political crisis-discourses at the time. PMID- 22520199 TI - Buhler revisited in times of war--Peter R. Hofstatter's The Crisis of Psychology (1941). AB - During World War II in 1941, the psychologist P. R. Hofstatter added an article to the debate on the crisis of psychology in a distinctly Nazi academic journal. After introducing Hofstatter and the journal, the core elements of his diagnosis and therapy recommendation beneath the National-Socialist-verbiage will be expounded. Hofstatter, a student of Karl Buhler's, ties on to his teacher's crisis well-known publication, but perceives the crisis in a broader perspective and connects it to the decline of theology and of pastoral guidance. Hofstatter's central, new aspect is the practice of psychology without which he sees it doomed. A central feature of psychological practice should be secular, non therapeutic guidance of individuals. Various contextual facets are illuminated, Hofstatter's thwarted attempts to get a university position, the recent establishment of psychology in Germany as a discipline teaching professionals, the abolition of German military psychology, the battle for the Berlin university chair of Wolfgang Kohler. PMID- 22520200 TI - American social psychology: Examining the contours of the 1970s crisis. AB - Throughout the 1960s and 1970s, social psychologists diagnosed their field as suffering a state of disciplinary crisis. The crisis was a multifaceted one, but issues of methodology, social relevance, and disciplinary, philosophical, and theoretical orientation were the primary areas of concern. Given that these issues have been prominent ones throughout the history of the social and behavioral sciences, it becomes necessary to look to the immediate context of the 1970s crisis to understand how and why a disciplinary crisis came to be diagnosed. The present analysis suggests that the crisis reflected the larger crisis in American society and also drew on the language of crisis prevalent at the time. Employing this language may have offered the field a method of making sense of, reframing, and redirecting internal and external critiques of the discipline. PMID- 22520201 TI - Stages in the development of a model organism as a platform for mechanistic models in developmental biology: Zebrafish, 1970-2000. AB - Model organisms became an indispensable part of experimental systems in molecular developmental and cell biology, constructed to investigate physiological and pathological processes. They are thought to play a crucial role for the elucidation of gene function, complementing the sequencing of the genomes of humans and other organisms. Accordingly, historians and philosophers paid considerable attention to various issues concerning this aspect of experimental biology. With respect to the representational features of model organisms, that is, their status as models, the main focus was on generalization of phenomena investigated in such experimental systems. Model organisms have been said to be models for other organisms or a higher taxon. This, however, presupposes a representation of the phenomenon in question. I will argue that prior to generalization, model organisms allow researchers to built generative material models of phenomena - structures, processes or the mechanisms that explain them - through their integration in experimental set-ups that carve out the phenomena from the whole organism and thus represent them. I will use the history of zebrafish biology to show how model organism systems, from around 1970 on, were developed to construct material models of molecular mechanisms explaining developmental or physiological processes. PMID- 22520202 TI - Development and mechanistic explanation. AB - Within modern philosophy of biology the topic of mechanistic explanation has become a central theme for critical discussion. The neo-mechanical philosophers have developed accounts that emphasize intervention and manipulation as the central epistemic tools that allow gaining epistemic access upon the mechanisms and have argued that the processes of inter-field integration across disciplines can be understood through the analysis of mechanisms spanning multiple levels. In this paper I revisit current proposals on mechanistic explanation in order to show some of their limitations when dealing with developmental mechanisms. I basically argue that (i) developmental mechanisms cannot be accommodated within a framework centered upon the mutual manipulation principle, (ii) the distinction between causal relations vs. constitutive relations cannot be easily demarcated within developmental biology and (iii) the notion of "part" underlying the neo mechanical accounts on explanation is not suitable for developmental biology. PMID- 22520203 TI - Intervention, causal reasoning, and the neurobiology of mental disorders: Pharmacological drugs as experimental instruments. AB - In psychiatry, pharmacological drugs play an important experimental role in attempts to identify the neurobiological causes of mental disorders. Besides being developed in applied contexts as potential treatments for patients with mental disorders, pharmacological drugs play a crucial role in research contexts as experimental instruments that facilitate the formulation and revision of neurobiological theories of psychopathology. This paper examines the various epistemic functions that pharmacological drugs serve in the discovery, refinement, testing, and elaboration of neurobiological theories of mental disorders. I articulate this thesis with reference to the history of antipsychotic drugs and the evolution of the dopamine hypothesis of schizophrenia in the second half of the twentieth century. I argue that interventions with psychiatric patients through the medium of antipsychotic drugs provide researchers with information and evidence about the neurobiological causes of schizophrenia. This analysis highlights the importance of pharmacological drugs as research tools in the generation of psychiatric knowledge and the dynamic relationship between practical and theoretical contexts in psychiatry. PMID- 22520204 TI - Transcending disciplines: Scientific styles in studies of the brain in mid twentieth century America. AB - Much scholarship in the history of cybernetics has focused on the far-reaching cultural dimensions of the movement. What has garnered less attention are efforts by cyberneticians such as Warren McCulloch and Norbert Wiener to transform scientific practice in an array of disciplines in the biomedical sciences, and the complex ways these efforts were received by members of traditional disciplines. In a quest for scientific unity that had a decidedly imperialistic flavour, cyberneticians sought to apply practices common in the exact sciences mainly theoretical modeling-to problems in disciplines that were traditionally defined by highly empirical practices, such as neurophysiology and neuroanatomy. Their efforts were met with mixed, often critical responses. This paper attempts to make sense of such dynamics by exploring the notion of a scientific style and its usefulness in accounting for the contrasts in scientific practice in brain research and in cybernetics during the 1940s. Focusing on two key institutional contexts of brain research and the role of the Rockefeller and Macy Foundations in directing brain research and cybernetics, the paper argues that the conflicts between these fields were not simply about experiment vs. theory but turned more closely on the questions that defined each area and the language used to elaborate answers. PMID- 22520205 TI - The negative view of natural selection. AB - An influential argument due to Elliott Sober, subsequently strengthened by Denis Walsh and Joel Pust, moves from plausible premises to the bold conclusion that natural selection cannot explain the traits of individual organisms. If the argument were sound, the explanatory scope of selection would depend, surprisingly, on metaphysical considerations concerning origin essentialism. I show that the Sober-Walsh-Pust argument rests on a flawed counterfactual criterion for explanatory relevance. I further show that a more defensible criterion for explanatory relevance recently proposed by Michael Strevens lends support to the view that natural selection can be relevant to the explanation of individual traits. PMID- 22520206 TI - Arthroprosthetic cobaltism and cardiomyopathy. AB - Cobaltism related to athroplasty implants has been anecdotally documented in at least six cases presenting with a combination of neurological, endocrine and cardiac symptoms with improvement in most symptoms after revision. Causality however has not been well established. This report documents the case of a 75 year-old male farmer who presents with possible cobalt cardiomyopathy from severe cobalt poisoning in the setting of arthroprosthetic cobaltism with symptomatic improvement upon revision of the hip. PMID- 22520207 TI - Remote monitoring for implantable cardiac electronic devices. AB - Pacemaker and implantable defibrillator implantation rates have increased significantly over the last decade. This, along with increasing complexity of the devices, has placed a large burden on the physicians and technicians that provide the follow up services for these patients. Recently technological advances have allowed remote interrogation of pacemakers and defibrillators with subsequent transmission of this information to a remote location for assessment. The technology behind remote device follow up, the potential advantages and the status of this technology is addressed in this article. PMID- 22520209 TI - Fluorescence study of drug-carrier interactions in CTAB/PBS buffer model systems. AB - The well-known cationic surfactant hexadecyltrimethylammonium bromide (CTAB) was used as a model carrier to study drug-carrier interactions with fluorescence probes (5-hexadecanoylaminofluorescein (HAF) and 2,10-bis-(3 aminopropyloxy)dibenzo[a,j]perylene-8,16-dione (NIR 628) by applying ensemble as well as single molecule fluorescence techniques. The impact of the probes on the micelle parameters (critical micelle concentration, average aggregation number, hydrodynamic radius) was investigated under physiological conditions. In the presence of additional electrolytes, such as buffer, the critical micelle concentration decreased by a factor of about 10. In contrast, no influence of the probes on the critical micelle concentration and on average aggregation number was observed. The results show that HAF does not affect the characteristics of CTAB micelles. Analyzing fluorescence correlation spectroscopy data and time resolved anisotropy decays in terms of the "two-step" in combination with the "wobbling-in-cone" model, it was proven that HAF and NIR 628 are differently associated with the micelles. Based on ensemble and single molecule fluorescence experiments, intra- and intermicellar energy transfer process between the two dyes were probed and characterized. PMID- 22520208 TI - Mesoporous silica SBA-15 modified with copper as an efficient NO2 adsorbent at ambient conditions. AB - Copper oxide particles were synthesized by precipitation in sodium hydroxide and dispersed simultaneously in mesoporous SBA-15 silica. The materials were then submitted to thermal treatment under nitrogen at different temperatures. They were tested as novel NO(2) adsorbents in dynamic condition at room temperature. The surface of the initial and exhausted materials was characterized using N(2) adsorption, XRD, TEM, thermal analysis and FT-IR. The addition of Cu(2)O particles leads to a significant increase in the NO(2) adsorption capacity. However, no trend between the NO(2) capacity and the temperature of the thermal treatment of the materials has been observed. The amount of NO released during the NO(2) adsorption was found to be lower on the materials submitted to a low temperature treatment. On these materials, the formation of copper nitrites is favored, whereas on materials treated at higher temperature, copper nitrates are formed as a predominant species. The results suggest that silanol groups of the silica matrix play an important role in NO(2) adsorption and NO retention at room temperature. PMID- 22520210 TI - Shear and dilational interfacial rheology of surfactant-stabilized droplets. AB - A new measurement method is suggested that is capable of probing the shear and dilational interfacial rheological responses of small droplets, those of size comparable to real emulsion applications. Freely suspended aqueous droplets containing surfactant and non-surface-active tracer particles are transported through a rectangular microchannel by the plane Poiseuille flow of the continuous oil phase. Optical microscopy and high-speed imaging record the shape and internal circulation dynamics of the droplets. Measured circulation velocities are coupled with theoretical descriptions of the droplet dynamics in order to determine the viscous (Boussinesq) and elastic (Marangoni) interfacial effects. A new Marangoni-induced stagnation point is identified theoretically and observed experimentally. Particle velocimetry at only two points (including gradients) in the droplet is sufficient to determine the amplitudes of the dilational and shear responses. We investigate the sensitivity for measuring interfacial properties and compare results from droplets stabilized by a small-molecule surfactant (butanol) and those stabilized by relatively large block copolymer molecules. Future increased availability of shear and dilational interfacial rheological properties is anticipated to lead to improved rules of thumb for emulsion preparation, stabilization, and general practice. PMID- 22520211 TI - Dynamic characterization of extremely bidisperse magnetorheological fluids. AB - In this work, we investigate the stability and redispersibility of magnetorheological fluids (MRFs). These are disperse systems where the solid is constituted by ferro- or ferri-magnetic microparticles. Upon the application of external magnetic field, they experience rapid and reversible increases in yield stress and viscosity. The problem considered here is first of all the determination of their stability against sedimentation, an essential issue in their practical application. Although this problem is typically faced through the addition of thixotropic agents to the liquid medium, in this work, we propose the investigation of the effect of magnetic nanoparticles addition, so that the dispersion medium is in reality a ferrofluid. It is found that a volume fraction of nanoparticles not higher than 3% is enough to provide a long-lasting stabilization to MRFs containing above 30% iron microparticles. In the, in fact unavoidable, event of settling, the important point is the ease of redispersion of the sediment. This is indirectly evaluated in the present investigation by measuring the penetration force in the suspension, using a standard hardness needle. Again, it is found that the nanoparticles addition produces soft sediments by avoiding short-range attractions between the large iron particles. Finally, the performance of the designed MRFs is evaluated by obtaining their steady-state rheograms for different volume fractions of magnetite and different magnetic field strengths. The yield stress is found to be strongly field dependent, and it can achieve the high values expected in standard magnetorheological fluids but with improved stability and redispersibility. PMID- 22520212 TI - Interfacial jumps and pressure bursts during fluid displacement in interacting irregular capillaries. AB - The macroscopically regular motion of fluid displacement fronts in porous media often results from numerous pore scale interfacial jumps and associated pressure fluctuations. Such rapid pore scale dynamics defy postulated slow viscous energy dissipation and may shape phase entrapment and subsequent macroscopic transport properties. Certain displacement characteristics are predictable from percolation theory; however, insights into rapid interfacial dynamics require mechanistic models for hydraulically interacting pores such as found along fluid displacement fronts. A model for hydraulically coupled sinusoidal capillaries was used to analyze stick-jump interfacial motions with a significant inertial component absent in Darcy-based description of fluid front displacement. High-speed camera provided measurements of rapid interfacial dynamics in sintered glass beads cell during drainage. Interfacial velocities exceeding 50 times mean front velocity were observed in good agreement with model predictions for a pair of sinusoidal capillaries. In addition to characteristic pinning-jumping behavior, interfacial dynamics were sensitive to initial positions within pores at the onset of a jump. Even for a pair of sinusoidal capillaries, minute variations in pore geometry and boundary conditions yield rich behavior of motions, highlighting challenges and potential new insights offered by consideration of pore scale mechanisms in macroscopic description of fluid displacement fronts in porous media. PMID- 22520213 TI - Precipitation, stabilization and molecular modeling of ZnS nanoparticles in the presence of cetyltrimethylammonium bromide. AB - ZnS nanoparticles were precipitated in aqueous dispersions of cationic surfactant cetyltrimethylammonium bromide (CTAB). The sphere radii of ZnS nanoparticles calculated by using band-gap energies steeply decreased from 4.5 nm to 2.2 nm within CTAB concentrations of 0.4-1.5 mmol L(-1). Above the concentration of 1.5 mmol L(-1), the radii were stabilized at R=2.0 nm and increased up to R=2.5 nm after 24 h. The hydrodynamic diameters of CTAB-ZnS structures observed by the dynamic light scattering (DLS) method ranged from 130 nm to 23 nm depending on CTAB concentrations of 0.5-1.5 mmol L(-1). The complex structures were observed by transmission electron microscopy (TEM). At the higher CTAB concentrations, ZnS nanoparticles were surrounded by CTA(+) bilayers forming positively charged micelles with the diameter of 10nm. The positive zeta-potentials of the micelles and their agglomerates were from 16 mV to 33 mV. Wurtzite and sphalerite nanoparticles with R=2.0 nm and 2.5 nm covered by CTA(+) were modeled with and without water. Calculated sublimation energies confirmed that a bilayer arrangement of CTA(+) on the ZnS nanoparticles was preferred to a monolayer. PMID- 22520214 TI - Treatment of adult MPSI mouse brains with IDUA-expressing mesenchymal stem cells decreases GAG deposition and improves exploratory behavior. AB - BACKGROUND: Mucopolysaccharidosis type I (MPSI) is caused by a deficiency in alpha-L iduronidase (IDUA), which leads to lysosomal accumulation of the glycosaminoglycans (GAGs) dermatan and heparan sulfate. While the currently available therapies have good systemic effects, they only minimally affect the neurodegenerative process. Based on the neuroprotective and tissue regenerative properties of mesenchymal stem cells (MSCs), we hypothesized that the administration of MSCs transduced with a murine leukemia virus (MLV) vector expressing IDUA to IDUA KO mouse brains could reduce GAG deposition in the brain and, as a result, improve neurofunctionality, as measured by exploratory activity. METHODS: MSCs infected with an MLV vector encoding IDUA were injected into the left ventricle of the brain of 12- or 25-month-old IDUA KO mice. The behavior of the treated mice in the elevated plus maze and open field tests was observed for 1 to 2 months. Following these observations, the brains were removed for biochemical and histological analyses. RESULTS: After 1 or 2 months of observation, the presence of the transgene in the brain tissue of almost all of the treated mice was confirmed using PCR, and a significant reduction in GAG deposition was observed. This reduction was directly reflected in an improvement in exploratory activity in the open field and the elevated plus maze tests. Despite these behavioral improvements and the reduction in GAG deposition, IDUA activity was undetectable in these samples. Overall, these results indicate that while the initial level of IDUA was not sustainable for a month, it was enough to reduce and maintain low GAG deposition and improve the exploratory activity for months. CONCLUSIONS: These data show that gene therapy, via the direct injection of IDUA-expressing MSCs into the brain, is an effective way to treat neurodegeneration in MPSI mice. PMID- 22520218 TI - Simultaneous nitrogen and carbon removal from swine digester liquor by the Canon process and denitrification. AB - A laboratory-scale completely autotrophic nitrogen removal over nitrite (Canon) biofilm reactor was applied to remove nitrogen and organic carbon from swine digester liquor for 150 d. A stable nitrogen removal rate was reached after a three-week adaptation period. The nitrogen loading rate of influent were 0.20+/ 0.04, 0.26+/-0.04, 0.26+/-0.07 kg N m(-3) d(-1) in period I, II and III, respectively. Nitrogen removal rates reached 0.096, 0.133 and 0.104 kg N m(-3) d( 1) when the C/N ratios of liquor were maintained at 0.81, 0.65, and 1.24, respectively. The Canon process was better than the denitrification process for nitrogen elimination when the C/N ratio of the influent was controlled below 0.8. PCR-DGGE analysis showed a decrease in microbial diversity of Planctomycetes during long-term operation. In contrast, the aerobic ammonium-oxidizing bacteria species were resistant to the changes due to replacement of synthetic wastewater with swine digester liquor. PMID- 22520219 TI - Effects of cellulose, hemicellulose and lignin on thermochemical conversion characteristics of the selected biomass. AB - The objective of this study was to investigate effects of biomass constituents (cellulose, hemicellulose and lignin) on biomass thermal decomposition and gas evolution profiles of four biomass materials. Switchgrass, wheat straw, eastern redcedar and dry distilled grains with solubles (DDGS) were selected as the biomass materials. No significant difference was observed in the weight loss profiles of switchgrass, wheat straw and eastern redcedar even though their cellulose, hemicellulose and lignin contents were considerably different. The weight loss kinetic parameters were also not significantly different except for activation energy of the eastern redcedar. However, biomass composition did significantly affect gas evolution profiles. The higher contents of cellulose and hemicellulose in switchgrass and wheat straw may have resulted in their higher CO and CO(2) concentrations as compared to eastern redcedar. On the other hand, higher lignin content in eastern redcedar may have resulted in significantly its high CH(4) concentration. PMID- 22520220 TI - Nitrate reduction by organotrophic Anammox bacteria in a nitritation/anammox granular sludge and a moving bed biofilm reactor. AB - The effects of volatile fatty acids (VFAs) on nitrogen removal and microbial community structure in nitritation/anammox process were compared within a granular sludge reactor and a moving bed biofilm reactor. Nitrate productions in both systems were lower by 40-68% in comparison with expected nitrate production. Expected sludge production on VFAs was estimated to be 67-77% higher if heterotrophs were the main acetate degraders suggesting that Anammox bacteria used its organotrophic capability and successfully competed with general heterotrophs for organic carbon, which led to a reduced sludge production. FISH measurements showed a population consisting of mainly Anammox and AOB in both reactors and oxygen uptake rate (OUR) tests also confirmed that flocculent biomass consisted of a minor proportion of heterotrophs with a large proportion of AOBs. The dominant Anammox bacterium was Candidatus "Brocadia fulgida" with a minor fraction of Candidatus "Anammoxoglobus propionicus", both known to be capable of oxidizing VFAs. PMID- 22520221 TI - Oil-in-water microemulsions enhance the biodegradation of DDT by Phanerochaete chrysosporium. AB - A novel approach was developed using oil-in-water (O/W) microemulsions formed with non-ionic surfactant, cosurfactant (1-pentanol) and linseed oil, at the cosurfactant to surfactant ratio (C/S ratio, w/w) of 1:3 and oil to surfactant ratio (O/S ratio, w/w) of 1:10, to enhance the biodegradation of DDT by the white rot fungus Phanerochaete chrysosporium. Results showed that microemulsions formed with Tween 80 effectively enhanced the biodegradation of DDT by P. chrysosporium and the enhancement was about two times that of Tween 80 solution, while microemulsion formed with Triton X-100 exhibited negative effect. Further studies revealed that microemulsion formed with Tween 80 enhanced the biodegradation of DDT through transporting DDT from crystalline phase to mycelium as well as their positive effect on the growth of P. chrysosporium; of these, the former is likely the most important and pre-requisite for the biodegradation of DDT by P. chrysosporium. PMID- 22520222 TI - Study of the anti-sapstain fungus activity of Bacillus amyloliquefaciens CGMCC 5569 associated with Ginkgo biloba and identification of its active components. AB - An endophytic bacterium, designated strain Bacillus amyloliquefaciens CGMCC 5569 was isolated from Chinese medicinal Ginkgo biloba collected from Xuzhou, China. Both the filtrate and the ethyl acetate extract of strain CGMCC 5569 showed growth inhibition activity against the sapstain fungi Lasiodiplodia rubropurpurea, L. crassispora, and L. theobromae obviously (>65%) based on the comparison of the length of zones on the petri dish. From the ethyl acetate extract of the filtrate, the antifungal compounds were obtained as a series of lipopeptides, which including series of fengycin, surfactin and bacillomycin. It showed strong growth inhibition activity in vitro against the L. rubropurpurea, L. crassispora and L. theobromae by about 70.22%, 69.53% and 78.76%, respectively. The strong anti-sapstain fungus activity indicated that the endophytic B. amyloliquefaciens CGMCC 5569 and its bioactive components might provide an alternative bio-resource for the bio-control of sapstain. PMID- 22520223 TI - Anammox sludge immobilized in polyvinyl alcohol (PVA) cryogel carriers. AB - This study evaluated the use of PVA cryogels to encapsulate slow-growing anammox bacteria for deammonification treatment of wastewater. The cryogel pellets were prepared by freezing-thawing at -8 degrees C. On average, pellets contained 11.8 mg-TSS/g-pellet of enriched anammox sludge NRRL B-50286 (Candidatus Brocadia caroliniensis) in 4-mm cubes. They were tested with synthetic and partially nitrified swine wastewater using continuous stirred-tank reactors packed at 20% (w/v). The immobilized gel was retained inside the reactor by a screen that eliminated the need of sludge recycling. The stoichiometry of anammox reaction was maintained for more than 5 months under non-sterile conditions. The process was not limited by substrates availability unless quite low N concentration (<5 mg/L) achieving >93% removal efficiency. In mass balances, >80% of the potential N conversion activity was achieved (2920 mg-N/kg-pellet/d). In addition, the immobilized bacteria were resilient to inhibition at high nitrite concentrations (244-270 mg-N/L). PMID- 22520224 TI - Non-catalytic heterogeneous biodiesel production via a continuous flow system. AB - This study provides a novel methodology for biodiesel (FAME) production under ambient pressure, which resolves most drawbacks of current commercialized biodiesel conversion via the transesterification reaction. This has been achieved by means of a thermo-chemical process and a true continuous flow system. This also enables combination of esterification of free fatty acids (FFAs) and transesterification of triglycerides into a single process without utilizing a catalyst, and leads to a 98-99+/-0.5 % conversion efficiency of FAME within 1 min in the temperature range of 350-500 degrees C. High FFA content in oil feedstock is not a matter of the new process, which enables the use of a broader variety of feedstocks, including all edible and inedible fats. Another feature of this novel method is that it does not produce wastewater. Thus, the new process has potential to spur a breakthrough in the lowest cost of biodiesel production. Moreover, this method also requires utilization of carbon dioxide during biodiesel production, an additional environmental benefit. PMID- 22520225 TI - Immobilization of Chlorella sorokiniana GXNN 01 in alginate for removal of N and P from synthetic wastewater. AB - High costs and issues such as a high cell concentrations in effluents are encountered when utilizing microalgae for wastewater treatment. The present study analyzed nitrogen and phosphate removal under autotrophic, heterotrophic, mixotrophic and micro-aerobic conditions by Chlorella sorokiniana GXNN 01 immobilized in calcium alginate. The immobilized cells grew as well as free living cells under micro-aerobic conditions and better than free-living cells under the other conditions. The immobilized cells had a higher ammonium removal rate (21.84%, 43.59% and 41.46%) than free living cells (14.35%, 38.57% and 40.59%) under autotrophic, heterotrophic, and micro-aerobic conditions, and higher phosphate removal rate (87.49%, 88.65% and 84.84%) than free living cells (20.21%, 42.27% and 53.52%) under heterotrophic, mixotrophic and micro-aerobic conditions, respectively. The data indicate that immobilized Chlorella sorokiniana GXNN 01 is a suitable species for use in wastewater treatment. PMID- 22520226 TI - Methicillin-resistant Staphylococcus aureus ST80-IV clone in children from Jordan. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of infections that are becoming increasingly difficult to combat because of emerging resistance. In this study, 103 S. aureus, 41 MRSA and 62 methicillin-sensitive Staphylococcus aureus isolates, were collected from children in Jordan. Genotyping based on spa and multilocus sequence typing (MLST) revealed 48 different spa types and identified distinct allelic profiles or STs, with the majority belonging to ST80. Pulsed-field gel electrophoresis (PFGE) of 15 different spa types revealed 8 different PFGE types, while SCCmec showed the predominance (53%) of subtype IV. Clustering SCCmec along with MLST revealed that ST80-MRSA-IV was the dominant type. Results obtained suggest that a significant amount of clonal spread is occurring in Jordan. The mechanism of spread of the ST80-IV clone is not known, and control measures are needed to reduce further spread of this or of other clones among children in Jordan. PMID- 22520227 TI - Effect of multiple firing and silica deposition on the zirconia-porcelain interfacial bond strength. AB - OBJECTIVES: To test the hypothesis that multiple firing and silica deposition on the zirconia surface influence the bond strength to porcelain. MATERIALS AND METHODS: Specimens were cut from yttria-stabilized zirconia blocks and sintered. Half of the specimens (group S) were silica coated (physical vapor deposition (PVD)) via reactive magnetron sputtering before porcelain veneering. The remaining specimens (group N) had no treatment before veneering. The contact angle before and after silica deposition was measured. Porcelain was applied on all specimens and submitted to two (N2 and S2) or three firing cycles (N3 and S3). The resulting porcelain-zirconia blocks were sectioned to obtain bar-shaped specimens with 1mm(2) of cross-sectional area. Specimens were attached to a universal testing machine and tested in tension until fracture. Fractured surfaces were examined using optical microscopy. Data were statistically analyzed using two-way ANOVA, Tukey's test (alpha=0.05) and Weibull analysis. RESULTS: Specimens submitted to three firing cycles (N3 and S3) showed higher mean bond strength values than specimens fired twice (N2 and S2). Mean contact angle was lower for specimens with silica layer, but it had no effect on bond strength. Most fractures initiated at porcelain-zirconia interface and propagated through the porcelain. SIGNIFICANCE: The molecular deposition of silica on the zirconia surface had no influence on bond strength to porcelain, while the number of porcelain firing cycles significantly affected the bond strength of the ceramic system, partially accepting the study hypothesis. Yet, the Weibull modulus values of S groups were significantly greater than the m values of N groups. PMID- 22520228 TI - Production of non-glycosylated recombinant proteins in Nicotiana benthamiana plants by co-expressing bacterial PNGase F. AB - Application of tools of molecular biology and genomics is increasingly leading towards the development of recombinant protein-based biologics. As such, it is leading to an increased diversity of targets that have important health applications and require more flexible approaches for expression because of complex post-translational modifications. For example, Plasmodium parasites may have complex post-translationally modified proteins such as Pfs48/45 that do not carry N-linked glycans (Exp. Parasitol. 1998; 90, 165.) but contain potential N linked glycosylation sites that can be aberrantly glycosylated during expression in mammalian and plant systems. Therefore, it is important to develop strategies for producing non-glycosylated forms of these targets to preserve biological activity and native conformation. In this study, we are describing in vivo deglycosylation of recombinant N-glycosylated proteins as a result of their transient co-expression with bacterial PNGase F (Peptide: N-glycosidase F). In addition, we show that the recognition of an in vivo deglycosylated plant produced malaria vaccine candidate, Pfs48F1, by monoclonal antibodies I, III and V raised against various epitopes (I, III and V) of native Pfs48/45 of Plasmodium falciparum, was significantly stronger compared to that of the glycosylated form of plant-produced Pfs48F1. To our knowledge, neither in vivo enzymatic protein deglycosylation has been previously achieved in any eukaryotic system, including plants, nor has bacterial PNGase F been expressed in the plant system. Thus, here, we report for the first time the expression in plants of an active bacterial enzyme PNGase F and the production of recombinant proteins of interest in a non-glycosylated form. PMID- 22520229 TI - Retinol-binding protein 4, insulin resistance and pregnancy. PMID- 22520230 TI - Atorvastatin and pitavastatin enhance lipoprotein lipase production in L6 skeletal muscle cells through activation of adenosine monophosphate-activated protein kinase. AB - Pravastatin and atorvastatin increase the serum level of lipoprotein lipase (LPL) mass in vivo but do not increase LPL activity in 3T3-L1 preadipocytes in vitro. LPL is mainly produced by adipose tissue and skeletal muscle cells. Metformin enhances LPL in skeletal muscle through adenosine monophosphate-activated protein kinase (AMPK) activation but not in adipocytes. This study aimed to examine the effect of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) on LPL production and to investigate the mechanism by which statins enhance skeletal muscle cell LPL production. L6 skeletal muscle cells were incubated with pravastatin, simvastatin, atorvastatin or pitavastatin. LPL activity, protein levels and mRNA expression were measured. Atorvastatin and pitavastatin significantly increased LPL activity, protein levels and mRNA expression in L6 skeletal muscle cells at 1 MUmol/L, but neither statin had an effect at 10 MUmol/L. We measured AMPK to clarify the mechanism by which statins increase LPL production in skeletal muscle cells. At 1 MUmol/L, both atorvastatin and pitavastatin enhanced AMPK activity, but this enhancement was abolished when AMPK signaling was blocked by compound C. The increased expressions of LPL protein and mRNA by atorvastatin and pitavastatin were reduced by compound C. In addition, mevalonic acid abolished atorvastatin- and pitavastatin-induced AMPK activation and LPL expression. These results suggest that atorvastatin and pitavastatin increase LPL activity, protein levels and LPL mRNA expression by activating AMPK in skeletal muscle cells. PMID- 22520231 TI - "Sometimes they used to whisper in our ears": health care workers' perceptions of the effects of abortion legalization in Nepal. AB - BACKGROUND: Unsafe abortion has been a significant cause of maternal morbidity and mortality in Nepal. Since legalization in 2002, more than 1,200 providers have been trained and 487 sites have been certified for the provision of safe abortion services. Little is known about health care workers' views on abortion legalization, such as their perceptions of women seeking abortion and the implications of legalization for abortion-related health care. METHODS: To complement a quantitative study of the health effects of abortion legalization in Nepal, we conducted 35 in-depth interviews with physicians, nurses, counsellors and hospital administrators involved in abortion care and post-abortion complication treatment services at four major government hospitals. Thematic analysis techniques were used to analyze the data. RESULTS: Overall, participants had positive views of abortion legalization - many believed the severity of abortion complications had declined, contributing to lower maternal mortality and morbidity in the country. A number of participants indicated that the proportion of women obtaining abortion services from approved health facilities was increasing; however, others noted an increase in the number of women using unregulated medicines for abortion, contributing to rising complications. Some providers held negative judgments about abortion patients, including their reasons for abortion. Unmarried women were subject to especially strong negative perceptions. A few of the health workers felt that the law change was encouraging unmarried sexual activity and carelessness around pregnancy prevention and abortion, and that repeat abortion was becoming a problem. Many providers believed that although patients were less fearful than before legalization, they remained hesitant to disclose a history of induced abortion for fear of judgment or mistreatment. CONCLUSIONS: Providers were generally positive about the implications of abortion legalization for the country and for women. A focus on family planning and post-abortion counselling may be welcomed by providers concerned about multiple abortions. Some of the negative judgments of women held by providers could be tempered through values-clarification training, so that women are supported and comfortable sharing their abortion history, improving the quality of post-abortion treatment of complications. PMID- 22520232 TI - A pill for cholesterol and a capsule for bleeding. PMID- 22520233 TI - Anthelmintic resistance in sheep farms: update of the situation in the American continent. AB - The present paper reviews the frequency of anthelmintic resistance in sheep farms in different countries of the American continent and describes some aspects that might influence the trend in sheep farms. The situation of anthelmintic resistance in sheep farms has been explored mainly in south of the continent (Argentina, Brazil and Uruguay) where sheep farming is an important industry. In those three countries, as well as in Paraguay, the first comprehensive surveys of anthelmintic resistance were performed among countries in the continent, which showed evidence of high frequency of sheep farms with anthelmintic resistance. Today, it is common to find sheep flocks with multiple-resistant worms. In North and Central America, a similar situation has been reported in sheep farms in the south of the United States of America, parts of Mexico and Costa Rica. On the other hand, other areas of the continent show low frequency of farms with anthelmintic resistance. From many areas no results have been published regarding situation on anthelmintic resistance or, alternatively, published results have received limited dissemination. Although the diagnosis of anthelmintic resistance is important for decision making of helminth management/control at the farm level, this is still an aspiration rather than a reality. For decades, researchers working on anthelmintic resistance in the American continent have expressed the need to change farmers' attitudes towards anthelmintic drugs. A common advice has been to check the anthelmintic drug efficacy regularly and reduce the dependence on these with alternative control measures. In spite of such advice, the challenge to stop/delay the advancement of anthelmintic resistance against the available anthelmintic drugs is still present. The evidence suggests that anthelmintic resistance is a growing phenomenon in the American continent. The situation described might be the tip of the iceberg, as anthelmintic resistance is still largely under-diagnosed. Hence, a different approach to tackle the advancement of anthelmintic resistance in sheep farms must be found. Awareness of farmers on the importance of diagnosis of anthelmintic resistance is not enough. Technical support schemes that provide the diagnostic service cheaply and timely must be implemented together with the research aiming at the adoption of control methods to reduce the dependence on conventional anthelmintic drugs. Unless these elements are readily available for producers, the negative consequences of anthelmintic resistance on sheep farming in America will continue to worsen with time. PMID- 22520234 TI - Chick embryo tracheal organ: a new and effective in vitro culture model for Cryptosporidium baileyi. AB - In the present study, chick embryo tracheal organ (TOCs) was used to cultivate oocysts or sporozoites of Cryptosporidium baileyi. Approximately 5 * 10(4) sporozoites and oocysts mixture for group I; 5 * 10(5), 1 * 10(6), 2 * 10(6) purified sporozoites for group II, group III and group IV, respectively, were inoculated into respective chick embryo tracheal rings maintained in RPMI 1640 supplemented with 5% heat-inactivated FBS, and cultivated in each well of the 24 well culture plate at 40 degrees C and 5% CO(2). The tracheal rings in four experimental groups (I-IV) were successfully infected with C. baileyi, and different stages of parasites were also observed under light and electron microscopy. Parasite infection and cytological alterations were noted as early as PI 72 h. The Cryptosporidium were seen attached to the edge of the tracheal epithelium, with more number of parasites in group I than that in group II, group III and group IV. The moderate nuclear swelling and chromatin margination were also detected, and the normal vertical orientation and basilar location of the nuclei of the epithelial cells were almost lost. C. baileyi that has been passed by TOCs exhibited similar immunity and molecular features with parasites before intratracheal inoculation. These results suggest that chick embryo tracheal organ is a new and effective in vitro culture model for C. baileyi and other respiratory pathogens. PMID- 22520235 TI - Establishment and evaluation of an iELISA using the recombinant membrane protein LHD-Sj23 for the serodiagnosis of Schistosoma japonicum infection in cattle in China. AB - Schistosomiasis is an important zoonosis and some livestock especially cattle play a crucial role in disease transmission in endemic areas. In order to establish an effective diagnostic method for detecting Schistosoma japonicum infection in cattle, the gene encoding large hydrophilic domain of Sj23 (LHD Sj23) was cloned and expressed in Escherichia coli as a fusion protein with GST tag. The purified rLHD-Sj23-GST was used as an antigen in an indirect enzyme linked immunosorbent assay (iELISA). The sera samples collected from cattle experimentally infected with S. japonicum from week 0 to week 54 post-infection were examined by rLHD-Sj23-GST iELISA. Furthermore, 484 clinical sera samples collected from cattle in schistosomiasis epidemic and free areas in China were tested by this method with a positive rate of 18.4% and 3.44%, respectively. The findings from this study indicated the established iELISA is a useful method for diagnosing S. japonicum infection in cattle and could be used in serological surveys to map out the prevalence of this disease. PMID- 22520236 TI - Protective effect of annexin-A1 against irreversible damage to cavernous tissue after cavernous nerve injury in the rat. AB - Study Type - Aetiology (case control) Level of Evidence 3b. What's known on the subject? and What does the study add? Penile rehabilitation is still controversial regarding good results. Our study shows a non-invasive treatment option to recovery after cavernous nervous damage. The assessment of changes in the intracavernous pressure and karyometry demonstrates the protective effect of annexin-A1 in an animal model of cavernous nerve injury. We found that annexin-A1 effectively preserved erectile function, evidently through significantly protecting the corpus cavernosum tissue against fibrosis. OBJECTIVE: * To evaluate the protective effect of annexin-A1 against irreversible damage to cavernous tissue after cavernous nerve injury. PATIENTS AND METHODS: * Thirty Sprague-Dawley male rats were divided into 3 groups; sham-operated rats (n= 10), bilateral cavernous nerve injury treated intravenously with 100 ug/kg annexin-A1 (n= 10), and a crush group of rats submitted to bilateral cavernous nerve injury and vehicle (n= 10). Groups were compared in respect to intracavernous pressure and karyometric parameters. RESULTS: * After annexin-A1 treatment, the maximum changes in intracavernous pressure responses were significantly higher in the annexin-A1 group compared to the vehicle-only group on the 7(th) postoperative day (p-value <0.05). Hematoxylin-eosin staining showed that the percentage of cavernosal smooth muscle was higher in the annexin-A1 group. Karyometry showed that the nuclear volume was greater in the annexin-A1 group, as was the major/minor smooth muscle cell diameter ratio compared to the vehicle-only group on the 7(th) postoperative day (p-value <0.05). CONCLUSION: * This is the first report that, by assessing changes in the intracavernous pressure and karyometry, demonstrates the protective effect of annexin-A1 in an animal model of cavernous nerve injury. We found that annexin-A1 effectively preserved erectile function, evidently through significantly protecting the corpus cavernosum tissue against fibrosis. PMID- 22520237 TI - Teaching human parasitology in China. AB - China has approximately one-fifth of the world's population. Despite the recent success in controlling major parasitic diseases, parasitic diseases remain a significant human health problem in China. Hence, the discipline of human parasitology is considered as a core subject for undergraduate and postgraduate students of the medical sciences. We consider the teaching of human parasitology to be fundamental to the training of medical students, to the continued research on parasitic diseases, and to the prevention and control of human parasitic diseases. Here, we have summarized the distribution of educational institutions in China, particularly those that teach parasitology. In addition, we have described some existing parasitology courses in detail as well as the teaching methods used for different types of medical students. Finally, we have discussed the current problems in and reforms to human parasitology education. Our study indicates that 304 regular higher education institutions in China offer medical or related education. More than 70 universities have an independent department of parasitology that offers approximately 10 different parasitology courses. In addition, six universities in China have established excellence-building courses in human parasitology. PMID- 22520238 TI - Cultivating understanding of health issues for adults with intellectual disability. AB - Going into hospital may be a frightening experience. Fears and anxieties may be particularly compounded when the patient has an existing health diagnosis such as a mental health condition or intellectual disabilities (ID). While people with ID often have worse health than other people, they can experience more difficulty accessing healthcare. OBJECTIVES: The aim of this paper is to describe the self evaluation process and outcome of a series of workshops designed to cultivate understanding of the health needs of adults with ID. DESIGN: The research was designed to explore the impact of the workshops for generic healthcare professionals, using a mixed methods inquiry. SETTINGS: The workshops were interactive, and facilitated by health care clinicians, three people with an ID, advocates and academics. SAMPLE: Participants were mainly qualified and unqualified nurses and other allied health professionals (N=157). METHODS: Quantitative questionnaires comprised of 16 questions with multiple choice answers were distributed to all participants (pre and post workshop). A qualitative feedback sheet to promote shared dialogues was circulated on completion of each workshop. RESULTS: Triangulated research methods of data collection demonstrate a positive impact of the workshops and the learning experienced from a participant perspective. CONCLUSIONS: While resources alone will never replace nurse education and training, they can reinforce best practice, and the resource developed in this paper was maximized by workshops to explore its potential. The remaining challenge is measuring the impact of this work on clinical practice in the longer term. PMID- 22520239 TI - The nursing students' attitude toward using blogs in a nursing clinical practicum in Taiwan: a 3-R framework. AB - BACKGROUND: Some nursing educators have been using blogs as a channel to reflect on, share, and discuss questions and ideas for educational purpose. There were not many studies focused on the application of blog technology to the professional development of nursing education in Taiwan. OBJECTIVES: The major goal of this study was to use a blog platform for students, writing their reflection notes, and observing the feedbacks from peers during their clinical practicum. Then we tried to probe the nursing students' attitude toward adopting 3-R categories based blog, which included wRiting reflection notes, Reading peers' notes, and Receiving peers' feedback. PARTICIPANTS: Of the 179 fourth grade from one five-year technical college students enrolled in a clinical practice course in Taiwan were used as a pool of sampling. Four-eight students were invited by the researcher to take part in this project. RESULTS: 90% of the participants agreed that blogs provided them with opportunities to share personal experiences with others. 81% of them valued that blogs provided opportunities to offering encouragement and emotional support to their peers. A majority of the participants believed that reading peers' journals was helpful in enhancing their professional development. In addition, all of them agreed that reading peers' journals can help them understand their peer's viewpoints. Most of the participants agreed that they were benefited through receiving feedbacks on the blogs. About 98% of them agreed that feedbacks can promote interaction with peers. CONCLUSIONS: The findings of this study generally indicated the participants' positive attitude toward using blogs in their clinical practicum. A majority of the participants also claimed that blogs provided them the opportunities to share personal experiences with their peers as well as to see things from their peers' viewpoints. They believed that reading peers' notes was helpful in enhancing their professional development. In addition, most of them agreed that receiving feedbacks could promote in-depth reflections; therefore, they were encouraged to write more reflective notes. Thus, future clinical practicum design should exert efforts to foster students' collaboration, reflections, and dialogues by providing blog platform. PMID- 22520240 TI - Simulation-based education (SBE) within postgraduate emergency on-call physiotherapy in the United Kingdom. AB - BACKGROUND: The application and extent of simulation-based education use within cardiorespiratory physiotherapy postgraduate education (in-house/regional provisions) and emergency oncall services were previously unexplored. OBJECTIVES: This survey aimed to investigate the extent to which simulation-based education is currently utilised by physiotherapy services in the UK. DESIGN: A national postal questionnaire-based survey. SETTING: All 280 National Health Service Critical/Intensive Care Units in England, Northern Ireland, Scotland and Wales, providing emergency on-call physiotherapy services were included in the survey. PARTICIPANTS: Emergency on-call physiotherapy service leads. METHOD: A self administered 20-item postal questionnaire survey was designed to establish the extent to which simulation-based education was currently being used within cardio respiratory physiotherapy post-registration training. RESULTS: A useable response rate of 55% (155/280) was achieved, representing a range of respiratory and emergency on-call service leads. Sixty-one Trusts (39%) currently use simulation within acute respiratory or emergency on-call postgraduate training. The provision of simulation equipment varied with respect to type, fidelity and accessible to the physiotherapy service. Simulation-based education featured in emergency on-call induction, updates, competency assessment, assessment skills, treatment skills and scenarios (75, 92, 39, 28, 82, 48% respectively). CONCLUSIONS: Simulation is currently used to teach a wide variety of cardio respiratory physiotherapy skills relevant to the acute respiratory and on-call environments. Adoption was dependent upon local facilities, needs and training requirements. National inconsistencies in availability, fidelity and accessibility were identified. The evidence base surrounding the current use of simulation-based education within physiotherapy is limited and evidence of transferability to the practice arena remains relatively unknown. Future research is warranted to determine the education outcomes, impact on skill performance, competency, retention and patient safety when integrating SBE within EOC training activities. PMID- 22520241 TI - Improving student learning on a midwifery education programme by using a benchmark course portfolio as a means of reflection and peer review. AB - The idea of scholarship within disciplines has long been discussed in the relevant literature. The concept of scholarship in teaching and learning has its foundations in Boyer's (1990) seminal work Scholarship Reconsidered. In this, Boyer made the case for teaching to be enhanced and made public and to be credited with equal weight as research activity within academic institutions. The activities of teaching and learning are truly academia's raison d'etre however they get obscured in the mists of the importance placed on research activity. To this end it is vital that educators begin to critically examine their teaching to fully inform research and practice. One of the lenses through which this can be done is through the act of reflection. Reflection on action as a process first described by Schon in 1983 (Schon, 2005) necessitates not only the critical examination of what we do but also what are the underlying assumptions about why we do what we do. The paper outlines such reflective portfolio submitted as part requirement for Postgraduate Diploma in Teaching and Learning in Higher Education. It examines student midwives learning using the reflective lens of the benchmark course portfolio. PMID- 22520242 TI - Advances in shaking technologies. AB - Shaking bioreactors are the most frequently used reactor system for screening and process optimization on a small scale. Their success can be attributed to their simple and functional design, which make shaking systems suitable for a large number of cost-efficient parallel experiments. Recently reported findings for oxygen transfer, power input, out-of-phase operation, hydromechanical stress and mixing in shaken bioreactors are summarized in this article. Novel monitoring techniques for the control of culture conditions in shake flasks and microtiter plates are described. The methods for characterizing culture conditions and the novel online measurement techniques that are summarized in this article can be utilized to tap the full potential of shaking reactor systems. PMID- 22520243 TI - Macular thickness in Chinese. PMID- 22520244 TI - Ultrasonography and color Doppler in juvenile idiopathic arthritis: diagnosis and follow-up of ultrasound-guided steroid injection in the wrist region. A descriptive interventional study. AB - BACKGROUND: The wrist region is one of the most complex joints of the human body. It is prone to deformity and functional impairment in juvenile idiopathic arthritis (JIA), and is difficult to examine clinically. The aim of this study was to evaluate the role of ultrasonography (US) with Doppler in diagnosis of synovitis, guidance of steroid injections, and follow-up examinations of the wrist in JIA. METHODS: In 11 patients (median age 12.5 years, range 2-16), 15 wrists with clinically active arthritis were assessed clinically by US and color Doppler (Logiq 9, GE, 16-4 MHz linear transducer) prior to and 1 and 4 weeks after US-guided steroid injection. RESULTS: US detected synovitis in the radio carpal joints, the midcarpal joints, and the tendon sheaths in 87%, 53% and 33% of the wrists, respectively. Multiple compartments were involved in 67%. US guidance allowed accurate placement of steroid in all 21 injected compartments, with a low rate of subcutaneous atrophy. Synovial hypertrophy was normalized in 86% of the wrists, hyperemia in 91%, and clinically active arthritis in 80%. CONCLUSIONS: US enabled detection of synovial inflammation in compartments that are difficult to evaluate clinically and exact guidance of injections, and it was valuable for follow-up examinations. Normalization of synovitis was achieved in most cases, which supports the notion that US is an important tool in management of wrist involvement in JIA. PMID- 22520245 TI - Doctors cheating on exams: a tempest in a teacup? PMID- 22520246 TI - Case of the month #176: pseudoaneurysm of the cystic artery. PMID- 22520247 TI - Case of the month #177: bipolar clavicular dislocation: radiologic evaluation of a rare traumatic injury. PMID- 22520248 TI - The AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial: to believe or not to believe? PMID- 22520249 TI - Niacin and statin combination therapy for atherosclerosis regression and prevention of cardiovascular disease events: reconciling the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial with previous surrogate endpoint trials. AB - Despite substantial risk reductions targeting low-density lipoprotein cholesterol with statins, there remains significant residual risk as evidenced by incident and recurrent cardiovascular disease (CVD) events among statin-treated patients. Observational studies have shown that low levels of high-density lipoprotein cholesterol (HDL-C) are associated with increased CVD risk. It remains unclear whether strategies aimed at increasing HDL-C in addition to background statin therapy will further reduce risk. The AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial, which compared combined niacin/simvastatin with simvastatin alone, failed to demonstrate an incremental benefit of niacin among patients with atherosclerotic CVD and on-treatment low-density lipoprotein cholesterol values <70 mg/dl, but this study had some limitations. Previously, small randomized, clinical trials of niacin plus statins showed that modest regression of carotid atherosclerosis is possible in individuals with CVD, CVD risk equivalents, or atherosclerosis. This viewpoint summarizes these imaging trials studying niacin and places them in the context of the failure of AIM-HIGH to support the HDL-C increasing hypothesis. PMID- 22520251 TI - Concerns about data reporting and interpretation in "Efficacy and tolerability of the novel triple reuptake inhibitor amitifadine in the treatment of patients with major depressive disorder: a randomized, double-blind, placebo-controlled trial". PMID- 22520250 TI - A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study. AB - OBJECTIVES: This study sought to investigate the efficacy, safety, and antiplatelet effect of prasugrel as compared with clopidogrel in patients with high on-treatment platelet reactivity (HTPR) after elective percutaneous coronary intervention (PCI). BACKGROUND: The extent to which prasugrel can correct HTPR and improve clinical outcomes in patients undergoing elective PCI is unknown. METHODS: Stable coronary artery disease (CAD) patients with HTPR (>208 P2Y(12) reaction units [PRU] by the VerifyNow test) after elective PCI with at least 1 drug-eluting stent (DES) were randomly assigned to either prasugrel 10 mg daily or clopidogrel 75 mg daily. Platelet reactivity of the patients on the study drug was reassessed at 3 and 6 months. The study was stopped prematurely for futility because of a lower than expected incidence of the primary endpoint. RESULTS: In 212 patients assigned to prasugrel, PRU decreased from 245 (225 to 273) (median [interquartile range]) at baseline to 80 (42 to 124) at 3 months, whereas in 211 patients assigned to clopidogrel, PRU decreased from 249 (225 to 277) to 241 (194 to 275) (p < 0.001 vs. prasugrel). The primary efficacy endpoint of cardiac death or myocardial infarction at 6 months occurred in no patient on prasugrel versus 1 on clopidogrel. The primary safety endpoint of non-coronary artery bypass graft Thrombolysis In Myocardial Infarction major bleeding at 6 months occurred in 3 patients (1.4%) on prasugrel versus 1 (0.5%) on clopidogrel. CONCLUSIONS: Switching from clopidogrel to prasugrel in patients with HTPR afforded effective platelet inhibition. However, given the low rate of adverse ischemic events after PCI with contemporary DES in stable CAD, the clinical utility of this strategy could not be demonstrated. PMID- 22520253 TI - Primary nasal histiocytic sarcoma of macrophage-myeloid cell type in a cat. AB - A 16-year-old neutered male Burmese cat was presented with a locally invasive nasal mass. The cytological and histological findings on incisional biopsy of this mass were suggestive of histiocytic sarcoma. Tumour cells expressed CD18, major histocompatibility complex class II, lysozyme and alpha-naphthyl acetate esterase; and lacked expression of CD3, CD79a, CD1a, CD1b, calprotectin, CD11c and E-cadherin. These findings are consistent with a myeloid-macrophage lineage. Metastasis to the bone marrow was present on necropsy examination. Histiocytic sarcoma should be considered in cats presented with primary round cell neoplasia of the nasal cavity. PMID- 22520254 TI - Infiltrative myxoma of the stifle joint and thigh in a domestic rabbit (Oryctolagus cuniculus). AB - A 5-year-old male domestic rabbit had severe swelling of the left hindlimb. Radiographs demonstrated a proliferative, infiltrative lesion involving the stifle joint, femur and soft tissues of the thigh. Osteomyelitis or neoplasia was suspected and the limb was amputated. Grossly, there was a multilobular mass comprised of cystic spaces containing yellow mucinous material. Microscopically, the mass formed coalescing lobules of stellate to rounded cells embedded in varying amounts of myxoid to collagenous matrix, and some rimmed by narrow walls of metaplastic bone and/or cartilage, and some infiltrated by plasma cells, lymphocytes, heterophils and histiocytes. Immunohistochemically, neoplastic cells expressed vimentin but not cytokeratin, sarcomeric actin, Mac387 or BLA36. Cytokeratin was not detected in normal synovial cells. The radiographic, gross and histological findings were most consistent with synovial myxoma; however, because of the extensive involvement of the limb in the absence of confirmed metastatic disease, the term infiltrative synovial myxoma was applied. PMID- 22520255 TI - Pathological features of Mycobacterium kansasii infection in black bearded sakis (Chiropotes satanas). AB - Two black bearded sakis (Chiropotes satanas), kept in the same cage in a zoological park, developed multifocal subcutaneous nodular lesions and were diagnosed as having mycobacterial infection by microscopical examination of tissues and 16S rRNA polymerase chain reaction (PCR) and subsequent sequencing of amplicons. One animal died despite both being treated with prolonged antimicrobial therapy. This animal had disseminated disease with lesions in the liver, spleen, lymph nodes and brain. The lesions were granulomatous in nature, but organisms were not identified by acid-fast staining other than on an impression smear of one of the skin nodules. The granulomatous lesions lacked epithelioid macrophages, multinucleated giant cells and fibrous encapsulation. Mycobacterium kansasii was identified by PCR in the lymph nodes of the animal with disseminated disease. Mycobacterial speciation was not as readily achieved in the animal with cutaneous nodules only. PMID- 22520257 TI - Structure-activity relationship in the antitumor activity of 6-, 8- or 6,8 substituted 3-benzylamino-beta-carboline derivatives. AB - We synthesized 47 kinds of 3-amino- or 3-benzylamino-beta-carboline derivatives with a substituent on the 6-, 8-, or 6,8-carbon atoms and evaluated their antitumor activities for Hela S-3 and Sarcoma 180 cell lines using a 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Consequently, we succeeded to develop 3-benzylamino-8-methylamino-beta-carboline (17a) and 8 methylamino-3-(3-phenoxybenzyl)amino-beta-carboline (17c) with antitumor activity with IC(50) values of 0.046, 0.032 MUM, respectively, against HeLa S-3 cell line, which are higher than that of previously reported 3-(3-phenoxybenzyl)amino-beta carboline (10e) of 0.074 MUM. Furthermore, effects of Cl group at 6-carbon atom on the type of cell death was evaluated using 3-benzylamino-6-chloro-beta carboline (10b), 3-benzylamino-beta-carboline (10d), N-(3-benzylamino)-6-chloro 9H-beta-carbolin-8-yl)benzamide (14g), and N-(3-benzylamino-9H-beta-carbolin-8 yl)benzamide (17b) to show no effect. Hoechst 33342 staining and DNA fragmentation assay suggested that these compounds induced cell death by apoptosis. In addition, using flow cytometry analysis, we established that the cell death pathway was through the arrest of the cell cycle in the G(2)/M phase. PMID- 22520258 TI - A novel pyrimidine derivatives with aryl urea, thiourea and sulfonamide moieties: synthesis, anti-inflammatory and antimicrobial evaluation. AB - A series of novel 4-(3-(trifluoromethyl)phenylamino-6-(4-(3 arylureiodo/arylthioureido/arylsulfonamido)-pyrimidine derivatives of biological interest were prepared by the sequential Suzuki cross coupling, acid amination, reduction followed by reaction of resulting amine with different arylisocyantes or arylisothiocyantes or arylsulfonyl chlorides. All the synthesized compounds (1 25) were screened for their pro-inflammatory cytokines (TNF-alpha and IL-6) and antimicrobial activity (antibacterial and antifungal). Biological data revealed that among all the compounds screened, compounds 5, 6, 11, 12, 16 and 20 were found to have moderate to potent anti-inflammatory activity (up to 48-78% TNF alpha and 56-96% IL-6 inhibitory activity) with reference to standard dexamethasone at 10 MUM. The compounds 10, 12, 13, 18, 20, 22, 24 and 25 found to have promising antimicrobial activity against all the selected pathogenic bacteria and fungi. PMID- 22520259 TI - Identification of ETP-46321, a potent and orally bioavailable PI3K alpha, delta inhibitor. AB - Phosphoinositide-3-kinase (PI3K) is an important target for cancer therapeutics due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein, we describe the optimization of imidazo [1,2-a] pyrazines, which allow us to identify compound 14 (ETP-46321), with potent biochemical and cellular activity and good pharmacokinetic properties (PK) after oral dosing. ETP 46321 PK/PD studies showed time dependent downregulation of AKT(Ser473) phosphorylation, which correlates with compound levels in tumor tissue and demonstrating to be efficacious in a GEMM mouse tumor model driven by a K Ras(G12V) oncogenic mutation. Treatment with ETP-46321 resulted in significant tumor growth inhibition. PMID- 22520260 TI - Synthesis and biological evaluation of some novel thiazole substituted benzotriazole derivatives. AB - A series of novel hybrid molecules 4a-y containing thiazole and benzotriazole templates were designed and synthesized. The structures of the synthesized compounds were elucidated by IR, (1)H NMR, (13)C NMR and mass spectral data. All the synthesized compounds were tested for their antimicrobial activity (zone of inhibition) against Gram-positive, Gram-negative strains of bacteria as well as fungal strains. After that minimum inhibitory concentrations (MICs), minimum bactericidal concentrations (MBCs) and minimum fungicidal concentrations (MFCs) of all the synthesized compounds were determined. The investigation of antimicrobial screening data revealed that most of the tested compounds showed moderate to good microbial inhibitions. PMID- 22520261 TI - Synthesis, biological evaluation and structure-activity relationships of glycyrrhetinic acid derivatives as novel anti-hepatitis B virus agents. AB - Fifty-seven derivatives of glycyrrhetinic acid (GA) were synthesized, and their anti-hepatitis B virus (HBV) activity was evaluated in HepG 2.2.15 cells. Among them, sixteen compounds showed greater anti-HBV activity than GA, especially, compounds 29, 32, 35, 41 exhibited significantly inhibitory activities against HBV DNA replication with IC(50) values of 5.71, 5.36, 8.90 and 9.08 MUM, respectively. The structure-activity relationships (SARs) of GA derivatives were discussed for exploring novel anti-HBV agents. PMID- 22520262 TI - Comparative clinical benefits of systemic adjuvant therapy for paradigm solid tumors. AB - Adjuvant therapy employing cytotoxic chemotherapy, molecularly targeted agents, immunologic, and hormonal agents has shown a significant impact upon a variety of solid tumors. The principles that guide adjuvant therapy differ among various tumor types and specific modalities, but generally indicate a greater impact of therapy in the postsurgical setting of micrometastatic disease, for which adjuvant therapy is commonly pursued, vs. the setting of gross unresectable disease. This review of adjuvant therapies in current use for five major solid tumors highlights the rationale for current effective adjuvant therapy, and draws comparisons between the adjuvant regimens that have found application in solid tumors. PMID- 22520263 TI - Magnetically controlled growing rods for spinal deformity. PMID- 22520264 TI - Magnetically controlled growing rods for severe spinal curvature in young children: a prospective case series. AB - BACKGROUND: Scoliosis in skeletally immature children is often treated by implantation of a rod to straighten the spine. Rods can be distracted (lengthened) as the spine grows, but patients need many invasive operations under general anaesthesia. Such operations are costly and associated with negative psychosocial outcomes. We assessed the effectiveness and safety of a new magnetically controlled growing rod (MCGR) for non-invasive outpatient distractions. METHODS: We implanted the MCGR in five patients, two of whom have now reached 24 months' follow-up. Each patient underwent monthly outpatient distractions. We used radiography to measure the magnitude of the spinal curvature, rod distraction length, and spinal length. We assessed clinical outcome by measuring the degree of pain, function, mental health, satisfaction with treatment, and procedure-related complications. FINDINGS: In the two patients with 24 months' follow-up, the mean degree of scoliosis, measured by Cobb angle, was 67 degrees (SD 10 degrees ) before implantation and 29 degrees (4 degrees ) at 24 months. Length of the instrumented segment of the spine increased by a mean of 1.9 mm (0.4 mm) with each distraction. Mean predicted versus actual rod distraction lengths were 2.3 mm (1.2 mm) versus 1.4 mm (0.7 mm) for patient 1, and 2.0 mm (0.2 mm) and 2.1 mm (0.7 mm) versus 1.9 mm (0.6 mm) and 1.7 mm (0.8 mm) for patient 2's right and left rods, respectively. Throughout follow-up, both patients had no pain, had good functional outcome, and were satisfied with the procedure. No MCGR-related complications were noted. INTERPRETATION: The MCGR procedure can be safely and effectively used in outpatient settings, and minimises surgical scarring and psychological distress, improves quality of life, and is more cost-effective than is the traditional growing rod procedure. The technique could be used for non-invasive correction of abnormalities in other disorders. FUNDING: Ellipse Technologies. PMID- 22520266 TI - Do we need to obtain consent for penile shortening as a complication of treatment for organ-confined prostate cancer? AB - OBJECTIVE: To establish an evidence base to guide consenting for treatment of organ-confined prostate cancer with regard to penile shortening. MATERIALS AND METHODS: We performed literature searches using the EMBASE, MEDLINE, AHMED and PsycINFO databases up to October 2011, looking for articles relating to surgical treatment of prostate cancer and penile shortening and articles relating to radiotherapy for prostate cancer and penile shortening. We also looked at further references in the papers identified. RESULTS: We found 16 original papers and three review articles with measurements of penile shortening after total prostatectomy (TP). Penile shortening was generally considered in conjunction with erectile dysfunction (ED). Three further articles address psychological and consent issues. We found two articles regarding penile shortening after radiotherapy for prostate cancer. CONCLUSIONS: There is no doubt that TP leads to penile shortening in some patients, but the mechanism remains debatable. Given current evidence, it is likely that several factors contribute and early penile rehabilitation for ED, by any method, appears to positively influence the changes leading to penile shortening. We advise explicit mentioning of penile shortening in the consent process for TP and potentially also for radiotherapy for prostate cancer. We also advise early penile rehabilitation to improve the patient's own body image and, in turn, quality of life, even in patients who do not seek treatment specifically for ED. The choice of treatment method should be left to the patient. PMID- 22520265 TI - Public health concern behind the exposure to persistent organic pollutants and the risk of metabolic diseases. AB - BACKGROUND: Persistent organic pollutants (POPs) are hazardous chemicals omnipresent in our food chain, which have been internationally regulated to ensure public health. Initially described for their potency to affect reproduction and promote cancer, recent studies have highlighted an unexpected implication of POPs in the development of metabolic diseases like type 2 diabetes and obesity. Based on this novel knowledge, this article aims at stimulating discussion and evaluating the effectiveness of current POP legislation to protect humans against the risk of metabolic diseases. Furthermore, the regulation of POPs in animal food products in the European Union (EU) is addressed, with a special focus on marine food since it may represent a major source of POP exposure to humans. DISCUSSION: There is mounting scientific evidence showing that current POP risk assessment and regulation cannot effectively protect humans against metabolic disorders. Better regulatory control of POPs in dietary products should be of high public health priority. SUMMARY: The general population is exposed to sufficient POPs, both in term of concentration and diversity, to induce metabolic disorders. This situation should attract the greatest attention from the public health and governmental authorities. PMID- 22520267 TI - The dose-response of the anal sphincter region--an analysis of data from the MRC RT01 trial. AB - PURPOSE: Most studies investigating the dose-response of the rectum focus on rectal bleeding. However, it has been reported that other symptoms such as urgency or sphincter control have a large impact on quality-of-life and that different symptoms are related to the dose to different parts of the anorectal wall. In this study correlations between the 3D dose distribution to the anal sphincter region and radiation-induced side-effects were quantified. MATERIALS AND METHODS: Dose-surface maps of the anal canal were generated. Next, longitudinal and lateral extent and eccentricity were calculated at different dose levels; DSHs and DVHs were also determined. Correlations between these dosimetric measures and seven clinically relevant endpoints were determined by assessing dosimetric constraints. Furthermore, an LKB model was generated. The study was performed using the data of 388 prostate patients from the RT01 trial (ISRCTN 47772397). RESULTS: Subjective sphincter control was significantly correlated with the dose to the anal surface. The strongest correlations were found for lateral extent at 53 Gy (p=0.01). Outcome was also significantly correlated with the DSH and the mean dose to the anal surface. CONCLUSIONS: The dose to the anal sphincter region should be taken into account when generating treatment-plans. This could be done using shape-based tools, DSH/DVH-based tools or an NTCP model. PMID- 22520269 TI - Profile of intraocular tumour necrosis factor-alpha and interleukin-6 in diabetic subjects with different degrees of diabetic retinopathy. AB - PURPOSE: To assess and correlate the levels of inflammatory mediators in the eyes from non-diabetic and diabetic subjects without retinopathy (NDR), with non proliferative diabetic retinopathy (NPDR) or with proliferative diabetic retinopathy (PDR) to corresponding erum levels. METHODS: The levels of interleukin 1beta, interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF alpha) were analysed by an ELISA-mimicking technique in the vitreous from 26 diabetic subjects with active PDR and 27 non-diabetic subjects, or by a multiplex bead assay in the aqueous humour from 35 diabetic subjects with NDR/NPDR and 40 non-diabetic subjects. Intraocular protein production was estimated in vitreous specimens by calculating a vitreous/serum ratio. RESULTS: In the vitreous, IL-6 was higher in diabetic [157.5 (25.0-1401.0) pg/ml; median (min-max)] than in non diabetic subjects [44.0 (5.0-4425) pg/ml; p = 0.021]. The vitreous/serum ratio was high (55.5:1 and 16:1, respectively), suggesting intraocular production. TNF alpha was lower in diabetic [18.0 (8.0-46.0) pg/ml] than in non-diabetic subjects [22.0 (13.0-47.0) pg/ml; p = 0.034], but the vitreous/serum ratio was elevated in both groups (2:1 and 3.4:1, respectively). TNF-alpha levels were higher in serum from diabetic subjects [9.0 (5.0-53.0) pg/ml versus 6.7 (3.0-11.0) pg/ml; p < 0.001]. Aqueous levels of inflammatory mediators did not differ between diabetic subjects with NDR/NPDR and non-diabetic subjects despite elevated TNF-alpha in serum [27.8 (6.8-153.7) pg/ml versus 16.4 (4.1-42.4) pg/ml; p = 0.021]. CONCLUSION: Intraocular inflammation seems to be involved in PDR but does not seem to be prominent in early retinopathy stages, i.e. NDR or NPDR. Diabetic subjects have an overall increased inflammatory activity compared to non-diabetic subjects, as demonstrated by increased serum levels of TNF-alpha. PMID- 22520268 TI - Protein misfolding and aggregation in cataract disease and prospects for prevention. AB - The transparency of the eye lens depends on maintaining the native tertiary structures and solubility of the lens crystallin proteins over a lifetime. Cataract, the leading cause of blindness worldwide, is caused by protein aggregation within the protected lens environment. With age, covalent protein damage accumulates through pathways thought to include UV radiation, oxidation, deamidation, and truncations. Experiments suggest that the resulting protein destabilization leads to partially unfolded, aggregation-prone intermediates and the formation of insoluble, light-scattering protein aggregates. These aggregates either include or overwhelm the protein chaperone content of the lens. Here, we review the causes of cataract and nonsurgical methods being investigated to inhibit or delay cataract development, including natural product-based therapies, modulators of oxidation, and protein aggregation inhibitors. PMID- 22520271 TI - Uncommitted role of enterococcal surface protein, Esp, and origin of isolates on biofilm production by Enterococcus faecalis isolated from bovine mastitis. AB - PURPOSE: This study was conducted in order to determine the occurrence of esp and biofilm formation among Enterococcus faecalis causing mastitis isolated from different bovine and environmental origins. MATERIALS AND METHODS: A total of 41 E. faecalis isolates were obtained from clinical mastitis before antibiotic therapy, subclinical mastitis, dried manure bedding samples, and postpartum milk samples. Isolates were screened for biofilm formation using microtiter plate method using tryptic soy broth with 0.25% glucose as media. Isolates were tested for the presence of the esp gene, which has been reported to be essential for biofilm formation in enterococci, by means of the polymerase chain reaction. RESULTS: Analysis of the relationship between the presence of esp and the biofilm formation capacity in E. faecalis showed that the esp gene was not identified in any of the 18 biofilm-producing E. faecalis isolates. Moreover, two of the three non-biofilm-producing E. faecalis strains were esp positive. In addition, the biofilm assay mean values were not changed with different origins of isolation. CONCLUSIONS: These results suggest the following: (1) lack of strict association between the presence of esp and biofilm formation and (2) widespread biofilm formation capacity among different sources of E. faecalis isolates derived from bovine mastitis. PMID- 22520270 TI - Phase I evaluation of TNFerade biologic plus chemoradiotherapy before esophagectomy for locally advanced resectable esophageal cancer. AB - BACKGROUND: Neoadjuvant chemoradiotherapy followed by surgery is the primary treatment option for patients with locally advanced esophageal cancer. This multicenter phase I trial examined intratumoral injection of TNFerade biologic, an adenoviral vector that expresses the human tumor necrosis factor-alpha gene, with chemoradiotherapy in locally advanced esophageal cancer. OBJECTIVES: To assess pathologic complete response (pCR), time to disease progression, progression-free survival, survival, and safety and tolerance in patients treated with preoperative chemoradiation combined with endoscopy or EUS-guided intratumoral injection of TNFerade biologic. DESIGN/INTERVENTION: Five weekly injections of TNFerade biologic, dose-escalated logarithmically from 4 * 10(8) to 4 * 10(11) particle units (PU), were given in combination with cisplatin 75 mg/m(2) and intravenous 5-fluorouracil 1000 mg/m(2)/d for 96 hours on days 1 and 29, and concurrent radiation therapy to 45 Gy. Surgery was performed 9 to 15 weeks after treatment. SETTING: U.S. multicenter study. PATIENTS: Patients with stage II and III esophageal cancer were enrolled. MAIN OUTCOME MEASUREMENTS: Primary outcome measures were safety, feasibility, tolerability, and rate of pCR. Secondary outcome measures were overall survival (OS) and disease-free survival. RESULTS: Twenty-four patients with a median age of 61 years were enrolled; 88% of the patients were men, 21% were stage II, and 79% were stage III. Six (29%) had a pCR, observed among 21 patients (20 who underwent esophagectomy and 1 at autopsy). Dose-limiting toxicities were not observed. The most frequent potentially related adverse events were fatigue (54%), fever (38%), nausea (29%), vomiting (21%), esophagitis (21%), and chills (21%). At the top dose of 4 * 10(11) PU, thromboembolic events developed in 5 of 8 patients. The median OS was 47.8 months. The 3- and 5-year OS rates and disease-free survival rates were 54% and 41% and 38% and 38%, respectively. LIMITATIONS: We included primarily adenocarcinoma. CONCLUSIONS: Preoperative TNFerade, in combination with chemoradiotherapy, is active and safe at doses up to 4 * 10(10) PU and is associated with long survival. This regimen warrants additional studies. PMID- 22520272 TI - Comparison between patients under hemodialysis with community-onset bacteremia caused by community-associated and healthcare-associated methicillin-resistant Staphylococcus aureus strains. AB - BACKGROUND/PURPOSE(S): Patients receiving hemodialysis infected with methicillin resistant Staphylococcus aureus (MRSA) have been considered to have healthcare associated (HA) infections, but strains with community-associated (CA) characteristics have also been identified in this population. The authors compared infections of the two strains among patients with end-stage renal disease. METHODS: From January 2004 to December 2008 the authors analyzed the demographic and microbiologic data of 57 patients with community-onset (defined as a positive culture obtained <= 48 hours after admission) MRSA bacteremia and end-stage renal disease at a 2900-bed tertiary medical center. MRSA isolate with staphylococcal cassette chromosome mec (SCCmec) type II/III was classified as HA strains, and SCCmec type IV/V as CA strains. RESULTS: Forty-seven patients (82%) had HA-MRSA strains and 10 patients (18%) had CA-MRSA strains. The major clones of HA-MRSA were sequence type (ST) 5 with SCCmec type II and staphylococcal protein A (spa) t002 as well as ST239 carrying SCCmec type III and spa t037. The CA-MRSA strains were predominantly ST59, more susceptible to non-beta-lactam antimicrobial agents, and had a higher percentage of carrying the Panton Valentine leukocidin gene in comparision with the HA-MRSA strains. Patients infected with HA-MRSA isolates had a higher overall mortality (57.4%, p = 0.012). In multivariate analysis, male patients were more likely to be infected with HA MRSA isolates than CA-MRSA strains (p = 0.037), and a history of receiving urinary catheterization within 1 year prior to bacteremia onset (p = 0.047) is an independent risk factor to acquiring HA-MRSA strains. CONCLUSION: Patients undergoing dialysis and infected with HA-MRSA strains had higher mortality rates and were more commonly associated with urinary catheterization within 1 year before bacteremia. PMID- 22520273 TI - Radiation effect on viscous flow of a nanofluid and heat transfer over a nonlinearly stretching sheet. AB - In this work, we study the flow and heat transfer characteristics of a viscous nanofluid over a nonlinearly stretching sheet in the presence of thermal radiation, included in the energy equation, and variable wall temperature. A similarity transformation was used to transform the governing partial differential equations to a system of nonlinear ordinary differential equations. An efficient numerical shooting technique with a fourth-order Runge-Kutta scheme was used to obtain the solution of the boundary value problem. The variations of dimensionless surface temperature, as well as flow and heat-transfer characteristics with the governing dimensionless parameters of the problem, which include the nanoparticle volume fraction phi, the nonlinearly stretching sheet parameter n, the thermal radiation parameter NR, and the viscous dissipation parameter Ec, were graphed and tabulated. Excellent validation of the present numerical results has been achieved with the earlier nonlinearly stretching sheet problem of Cortell for local Nusselt number without taking the effect of nanoparticles. PMID- 22520274 TI - Insecticide resistance in Culex quinquefasciatus from Zanzibar: implications for vector control programmes. AB - BACKGROUND: Zanzibar has a long history of lymphatic filariasis (LF) caused by the filarial parasite Wuchereria bancrofti, and transmitted by the mosquito Culex quinquefasciatus Say. The LF Programme in Zanzibar has successfully implemented mass drug administration (MDA) to interrupt transmission, and is now in the elimination phase. Monitoring infections in mosquitoes, and assessing the potential role of interventions such as vector control, is important in case the disease re-emerges as a public health problem. Here, we examine Culex mosquito species from the two main islands to detect W. bancrofti infection and to determine levels of susceptibility to the insecticides used for vector control. METHODS: Culex mosquitoes collected during routine catches in Vitongoji, Pemba Island, and Makadara, Unguja Island were tested for W. bancrofti infection using PCR. Insecticide bioassays on Culex mosquitoes were performed to determine susceptibility to permethrin, deltamethrin, lambda-cyhalothrin, DDT and bendiocarb. Additional synergism assays with piperonyl butoxide (PBO) were used for lambda-cyhalothrin. Pyrosequencing was used to determine the kdr genotype and sequencing of the mitochondrial cytochrome oxidase I (mtCOI) subunit performed to identify ambiguous Culex species. RESULTS: None of the wild-caught Culex mosquitoes analysed were found to be positive for W. bancrofti. High frequencies of resistance to all insecticides were found in Wete, Pemba Island, whereas Culex from the nearby site of Tibirinzi (Pemba) and in Kilimani, Unguja Island remained relatively susceptible. Species identification confirmed that mosquitoes from Wete were Culex quinquefasciatus. The majority of the Culex collected from Tibirinzi and all from Kilimani could not be identified to species by molecular assays. Two alternative kdr alleles, both resulting in a L1014F substitution were detected in Cx. quinquefasciatus from Wete with no homozygote susceptible detected. Metabolic resistance to pyrethroids was also implicated by PBO synergism assays. CONCLUSIONS: Results from the xenomonitoring are encouraging for the LF programme in Zanzibar. However, the high levels of pyrethroid resistance found in the principle LF vector in Pemba Island will need to be taken into consideration if vector control is to be implemented as part of the elimination programme. PMID- 22520275 TI - A family outreach intervention for engaging young out-of-treatment drug users: pre- versus post-treatment comparison. AB - Only a small fraction of drug users worldwide enter treatment each year. We evaluated the efficacy of a systemic family outreach intervention (SFOI) for young, untreated drug users, using a quasi-experimental design in which the experimental group (EG) received SFOI and the control group (CG) received traditional outreach work (OW). Both pre- and post-treatment, we administered the Addiction Severity Index-6 (ASI-6), the Family Environment Scale (FES), and tests of parental practices and risky behavior. Post-treatment, there was a fivefold improvement on the ASI-6 and a significant worsening on the conflict sub-scale of the FES in the EG as compared with the CG. SFOI was more efficacious than OW in reducing drug use in the drug user's home environment. The increased conflict in the EG might be explained by parents' increased awareness of abnormal behaviors and implementation of strategies to protect their children. PMID- 22520277 TI - A qualitative analysis of case managers' use of harm reduction in practice. AB - The harm reduction approach has become a viable framework within the field of addictions, yet there is limited understanding about how this approach is implemented in practice. For people who are homeless and have co-occurring psychiatric and substance use disorders, the Housing First model has shown promising results in employing such an approach. This qualitative study utilizes ethnographic methods to explore case managers' use of harm reduction within Housing First with a specific focus on the consumer-provider relationship. Analysis of observational data and in-depth interviews with providers and consumers revealed how communication between the two regarding the consumer's substance use interacted with the consumer-provider relationship. From these findings emerged a heuristic model of harm reduction practice that highlighted the profound influence of relationship quality on the paths of communication regarding substance use. This study provides valuable insight into how harm reduction is implemented in clinical practice that ultimately has public health implications in terms of more effectively addressing high rates of addiction that contribute to homelessness and health disparities. PMID- 22520276 TI - Pilot trial of a recovery management intervention for heroin addicts released from compulsory rehabilitation in China. AB - China faces the challenge of dual epidemics of drug use and HIV/AIDS. Despite the high relapse rate among heroin addicts released from compulsory rehabilitation facilities, there are few programs available in China to assist these addicts in the community. We pilot-tested in China a Recovery Management Intervention (RMI) program designed to facilitate early detection of relapse and prompt linkage from compulsory rehabilitation to the community and, if participants relapse, to community-based methadone maintenance treatment (MMT) programs. One hundred heroin addicts were randomly assigned to either the Standard Care group (n = 50) or the RMI group (n = 50). At the end of the 3-month trial, participants in the RMI group, relative to the standard care group, demonstrated positive outcomes in recidivism due to relapse (0 vs. 6%, p = .08; d = 0.354), MMT participation (8% vs. 0, p = 0.06; d = 0.417), and employment (33% vs. 2%, p < .001; d = 0.876), although no difference was found in urine testing results (8.5% vs. 8.7%; d = 0.013) among interviewed participants. These pilot study results were based on a small sample size and short-term observation, suggesting the need for more research to further improve and test RMI effectiveness with larger samples over a longer period of time in order to provide evidence in support of RMI as an effective strategy for community reintegration among addicts released from rehabilitation facilities in China. PMID- 22520278 TI - Feasibility and impact of brief interventions for frequent cannabis users in Canada. AB - Cannabis use is prevalent among young people, and frequent users are at an elevated risk for health problems. Availability and effectiveness of conventional treatment are limited, and brief interventions (BIs) may present viable alternatives. One hundred thirty-four young high-frequency cannabis users from among university students were randomized to either an oral (C-O; n = 25) or a written experimental cannabis BI (C-W; n = 47) intervention group, or to either an oral (H-O; n = 25) or written health BI (H-W; n = 37) control group. Three month follow-up assessments based on repeated measures analysis of variance techniques found a decrease in the mean number of cannabis use days in the total sample (p = 0.024), reduced deep inhalation/breathholding use in the C-O group (p = 0.003), reduced driving after cannabis use in the C-W group (p = 0.02), and a significant reduction in deep inhalation/breathholding in the C-O group (p = 0.011) compared with controls. Feasibility and short-term impact of the BIs were demonstrated, yet more research is needed. PMID- 22520279 TI - Revascularization and tissue regeneration of an empty root canal space is enhanced by a direct blood supply and stem cells. AB - BACKGROUND: Regenerative endodontics is an innovative treatment concept aiming to regenerate pulp, dentin and root structures. In the diseased or necrotic tooth, the limitation in vascular supply renders successful tissue regeneration/generation in a whole tooth challenging. The aim of this study is to evaluate the ability of vascularized tissue to develop within a pulpless tooth using tissue engineering techniques. MATERIALS AND METHODS: A pulpless tooth chamber, filled with collagen I gel containing isolated rat dental pulp cells (DPC) and angiogenic growth factors, was placed into a hole created in the femoral cortex or into its own tooth socket, respectively. The gross, histological and biochemical characteristics of the de novo tissue were evaluated at 4 and 8 weeks post-transplantation. RESULTS: Tooth revascularization and tissue generation was observed only in the femur group, confirming the important role of vascular supply in tissue regeneration. The addition of cells and growth factors significantly promoted connective tissue production in the tooth chamber. CONCLUSION: Successful revascularization and tissue regeneration in this model demonstrate the importance of a direct vascular supply and the advantages of a stem cell approach. PMID- 22520280 TI - Sequestration of MBNL1 in tissues of patients with myotonic dystrophy type 2. AB - The pathogenesis of myotonic dystrophy type 2 includes the sequestration of MBNL proteins by expanded CCUG transcripts, which leads to an abnormal splicing of their target pre-mRNAs. We have found CCUG(exp) RNA transcripts of the ZNF9 gene associated with the formation of ribonuclear foci in human skeletal muscle and some non-muscle tissues present in muscle biopsies and skin excisions from myotonic dystrophy type 2 patients. Using RNA-FISH and immunofluorescence-FISH methods in combination with a high-resolution confocal microscopy, we demonstrate a different frequency of nuclei containing the CCUG(exp) foci, a different expression pattern of MBNL1 protein and a different sequestration of MBNL1 by CCUG(exp) repeats in skeletal muscle, vascular smooth muscle and endothelia, Schwann cells, adipocytes, and ectodermal derivatives. The level of CCUG(exp) transcription in epidermal and hair sheath cells is lower compared with that in other tissues examined. We suppose that non-muscle tissues of myotonic dystrophy type 2 patients might be affected by a similar molecular mechanism as the skeletal muscle, as suggested by our observation of an aberrant insulin receptor splicing in myotonic dystrophy type 2 adipocytes. PMID- 22520281 TI - Anatomy and physiology of the thoracic lymphatic system. AB - The thoracic lymphatic system is one of the most complex and poorly understood systems of the human body, and much is still to be learned, especially in lymphatic physiology. Knowledge of the normal anatomy of this system as well as of its variations is nevertheless important for thoracic surgeons investigating and treating patients with lung or esophageal neoplasms. PMID- 22520282 TI - Computed tomography and magnetic resonance imaging of the thoracic lymphatic system. AB - Several radiographic diagnostic techniques are currently available to assess the potential involvement of mediastinal lymph nodes in thoracic oncology. In particular, computed tomography and magnetic resonance imaging have been repeatedly validated; these techniques allow adequate imaging with a reasonable accuracy. The morphologic information provided by these techniques is crucial to stage lung cancer and plan treatment. These techniques are also extremely useful to evaluate other disorders and differentiate malignancy from benign disease. PMID- 22520283 TI - PET staging of mediastinal lymph nodes in thoracic oncology. AB - There is an extensive and growing body of literature about the role of positron emission tomography (PET) in the management of non-small cell lung cancer and esophageal cancer. This article focuses on the use of PET in mediastinal staging of these common thoracic malignancies. PET is the most accurate noninvasive approach to staging mediastinal lymph nodes in non-small cell lung cancer. The role of PET in mediastinal lymph node staging in esophageal cancer is less clear, since it has been largely supplanted by endoscopic ultrasonography. A review of the evidence for and against the use of PET in mediastinal staging is provided and the use of PET in practice is discussed. PMID- 22520284 TI - MicroRNAs and lymph node metastatic disease in lung cancer. AB - Lymphatic and distant metastases are primary factors in determining survival in patients with lung cancer. The identification of novel molecular biomarkers that can predict the presence of micrometastasis in lymph nodes and their incorporation in traditional histologic staging is needed. MicroRNAs are emerging as powerful biomarkers for several neoplastic disorders. This article reports the experimental results that have recently led to the identification of several microRNAs deregulated in lung cancer that are strongly associated with lymph node metastasis and advanced clinical stage. This evidence indicates that microRNAs are a promising tool for the clinical management of lung cancer. PMID- 22520285 TI - Invasive staging of mediastinal lymph nodes: mediastinoscopy and remediastinoscopy. AB - Nodal status in lung cancer is essential for planning therapy and assessing prognosis. The involvement of ipsilateral and contralateral mediastinal lymph nodes is associated with poor prognosis and usually excludes patients from upfront surgical treatment. Mediastinoscopy is a time-honored procedure that allows the surgeon to access the upper mediastinal lymph nodes for either biopsy or removal. Remediastinoscopy is mainly indicated to assess objective tumor response in mediastinal lymph nodes after induction therapy for locally advanced lung cancer and to indicate further therapy. PMID- 22520286 TI - Ultrasound-guided transbronchial and transesophageal needle biopsy in the mediastinal staging of lung cancer. AB - This review presents the current state of two endosonographic techniques, endobronchial ultrasonography (EBUS) and endoscopic ultrasonography (EUS), and their application in the mediastinal staging of patients with lung cancer. The technique for these procedures is presented and their diagnostic yield is discussed, based on the published evidence. EBUS and EUS, especially in combination with needle aspiration biopsy, emerge as the primary modalities for mediastinal staging because of their high diagnostic yield, minimal invasiveness, low cost, and avoidance of disruption of mediastinal lymphatic pathways before the final treatment. PMID- 22520287 TI - Sentinel lymph node in lung cancer surgery. AB - The greatest utility of sentinel lymph node (SLN) assessment is the avoidance of lymph node dissection and related morbidity. Another potential utility is the ability to direct pathologic examination and more sensitive techniques to detect occult micrometastatic disease. New pathologic methods can identify single tumor cells or even genetic material within a single lymph node station, bringing the concept of ultrastaging and micrometastasis in the field on staging. This article describes the SLN technique in patients with early non-small-cell lung cancer, as unique and useful targeting enables pathologists to localize micrometastatic foci within an otherwise normal lymph node. PMID- 22520288 TI - Thoracoscopic and robotic dissection of mediastinal lymph nodes. AB - Understanding the anatomy of the lymphatic channels and lymph nodes in the mediastinum is relevant to many disease processes as well as therapeutic interventions for thoracic malignancies. A brief review of the anatomy of the mediastinal lymph nodes is presented and the indications for mediastinal lymph node dissection are discussed, followed by a more detailed description of the technical aspects of thoracoscopic and robotic mediastinal lymph node dissection. PMID- 22520289 TI - Video-assisted mediastinoscopic lymphadenectomy and transcervical extended mediastinal lymphadenectomy. AB - This article describes in detail the operative technique of the new surgical methods, video-assisted mediastinoscopic lymphadenectomy (VAMLA) and transcervical extended mediastinal lymphadenectomy (TEMLA). Both techniques enable the removal of the mediastinal nodes with the surrounding fatty tissue. VAMLA and TEMLA have very high diagnostic yield and can be combined with minimally invasive video-assisted lobectomy. PMID- 22520290 TI - The role of lymphadenectomy in lung cancer surgery. AB - Adequate lymphadenectomy represents a fundamental procedure in lung cancer surgery for accurate staging and potential survival benefit. Various techniques are used in current surgical practice for the intraoperative lymph node removal associated with pulmonary resection, without definitive indications concerning the preferable option. Different studies in the last decades have compared complete mediastinal lymph node dissection with lymph node sampling regarding their effect on long-term survival, recurrence rate, accuracy of pathologic staging, and surgical morbidity. Literature data and technical aspects of lymph node dissection are reported and discussed in this article. PMID- 22520291 TI - The impact of complete lymph node dissection for lung cancer on the postoperative course. AB - The role of lymph node dissection (LND) for non-small cell lung cancers (NSCLCs) remains controversial. LND adds little morbidity to a pulmonary resection for NSCLC, although it requires an additional 15 to 20 minutes of operative time. Four prospective randomized trials have been performed to compare lymph node sampling and LND; 3 trials showed no difference in survival and 1 showed survival benefit of LND. It is recommended that all patients with resectable NSCLC undergo LND because the procedure provides patients with the most accurate staging and the opportunity for effective adjuvant therapy. PMID- 22520292 TI - The impact of chemotherapy on the lymphatic system in thoracic oncology. AB - Non-small-cell lung cancer remains the leading cause of cancer-related mortality in the United States and Europe. Most patients are diagnosed with metastatic disease for which chemotherapy remains the cornerstone of treatment. In non metastatic disease, surgery is the most potentially curative therapeutic option, but its outcome is still poor, in particular for patients with lymph node involvement. Therefore, several randomized adjuvant/neoadjuvant trials using chemotherapy and/or radiotherapy investigated the possibility of increasing the overall survival of patients with surgically treated lung cancer. The findings are reviewed in this article. PMID- 22520293 TI - The lymphatic system in thoracic oncology. PMID- 22520295 TI - Sleep apnea, cardiac arrhythmias, and conduction disorders. AB - Sleep apnea (SA) is a common breathing disorder. It is associated with a myriad of medical conditions including increased cardiovascular morbidity and mortality. Recent studies have shown that cardiac arrhythmias and conduction disorders are common in patients with SA. Sleep apnea has also been also linked to heart failure, hypertension, coronary artery disease, and stroke. The purpose of this brief review is to analyze the available information that links SA with different cardiac arrhythmias and conduction disorders and the role of intracardiac devices for the diagnosis and management of this condition. PMID- 22520296 TI - Characterization and neural differentiation of mouse embryonic and induced pluripotent stem cells on cadherin-based substrata. AB - A suitable culture condition using advanced biomaterials has the potential to improve stem cell differentiation into selective lineages. In this study, we evaluated the effects of recombinant extracellular matrix (ECM) components on the mouse embryonic stem (mES) and induced pluripotent stem (miPS) cells' self renewal and differentiation into neural progenitors, comparing conventional culture substrata. The recombinant ECMs were established by immobilizing two chimera proteins of cadherin molecules, E-cadherin-Fc and N-cadherin-Fc, either alone or in combination. We report that the completely homogeneous population of mES and miPS cells could be maintained on E-cadherin-based substrata under feeder and serum-free culture conditions to initiate neural differentiation. Using defined monolayer differentiation conditions on E-cadherin and N-cadherin (E-/N cad-Fc) hybrid substratum, we routinely obtained highly homogeneous population of primitive ectoderm and neural progenitor cells. Moreover, the differentiated cells with higher expression of betaIII-tubulin, Pax6, and tyrosine hydroxylase (TH) in absence of GFAP (a glial cell marker) expression suggesting the presence of a lineage restricted to neural cells. Our improved culture method should provide a homogeneous microenvironment for differentiation and obviate the need for protocols based on stromal feeders or embryoid bodies. PMID- 22520298 TI - The hidden dimensions of the competition effect: basal cortisol and basal testosterone jointly predict changes in salivary testosterone after social victory in men. AB - Dominance struggles appear to affect hormone concentrations in many mammalian species, such that higher concentrations of testosterone are seen in winners of competitions, compared to losers. This so-called, "competition effect" has received inconsistent empirical support, suggesting that additional psychological (e.g., mood), situational (i.e., nature of the competition) and physiological (e.g., cortisol) variables might intervene in modulating testosterone fluctuations after social contests. We investigated possible interactions between the hypothalamic-pituitary-gonadal (HPG) axis and the hypothalamic-pituitary adrenal (HPA) stress axis in predicting transient changes in testosterone after social victory or defeat on a familiar competitive task. In particular, the present study examined the dual-hormone hypothesis - proposing that baseline cortisol potently modulates the competition effect (Mehta and Josephs, 2010) - in a sample of healthy young men engaged in head-to-head competition on a widely played commercial videogame, Tetris. We found a significant interaction between HPG and HPA axes status and the competition effect on testosterone in the randomly assigned videogame winners, such that winners with a pre-competition combination of high baseline testosterone and low baseline cortisol exhibited significantly greater post-competition testosterone concentrations. The randomly assigned videogame losers showed significantly decreased post-competition levels of testosterone. Possible biological and evolutionary mechanisms underlying this phenomenon are discussed. PMID- 22520300 TI - Ectasia risk: barriers to understanding. PMID- 22520299 TI - Pubertal testosterone predicts mental rotation performance of young adult males. AB - Robust sex differences in some spatial abilities that favor males have raised the question of whether testosterone contributes to those differences. There is some evidence for prenatal organizational effects of testosterone on male-favoring spatial abilities, but not much is known about the role of pubertal testosterone levels on adult cognitive abilities. We studied the association between pubertal testosterone (at age 14) and cognitive performance in young adulthood (at age 21 23), assessing male-favoring, female-favoring, and sex-neutral cognitive domains in a population-based sample of 130 male and 178 female twins. Pubertal testosterone was negatively associated with performance in the Mental Rotation Test in young adult men (r=-.27), while among women no significant associations between testosterone and cognitive measures were detected. The significant association among men remained after controlling for pubertal development. Confirmatory within-family comparisons with one-sided significance testing yielded a negative correlation between twin pair differences in testosterone levels and Mental Rotation Test performances in 35 male twin pairs (r=-.32): the twin brother with higher testosterone performed less well on the Mental Rotation Test. That association was evident in 18 pairs of dizygotic male twin pairs (r= .42; analysis controlling for shared environmental effects). In contrast, the association of differences was not evident among 17 monozygotic male twin pairs (r=-.07; analysis controlling for shared genetic influences). Results suggest that pubertal testosterone levels are related specifically to male-favoring spatial ability and only among men. Within-family analyses implicated possible shared genetic effects between pubertal testosterone and mental rotation ability. PMID- 22520301 TI - Modified technique for removal of Soemmerring ring and in-the-bag secondary intraocular lens placement in aphakic eyes. AB - We describe modifications to previously described techniques for evacuation of Soemmerring ring during secondary intraocular lens (IOL) implantation in aphakic eyes following previous pediatric cataract surgery. A new anterior capsulotomy is initiated using a cystotome to incise the anterior capsule close to its attachment to the posterior capsule. A curved microscissor is used to cut circumferentially, completing the capsulotomy, and a dispersive ophthalmic viscoelastic device (OVD) is used to viscoexpress Soemmerring ring material from the capsular bag. A 2-handed maneuver is used to manually divide the Soemmerring ring. Finally, slow-motion phacoemulsification is used to emulsify and remove the pieces. Viscoexpression of fragments of Soemmerring ring is done if there is a posterior capsulotomy. The residual capsular bag is filled with OVD and a foldable 3-piece IOL injected into the bag and dialed in. This technique allows complete evacuation of Soemmerring ring and placement of a secondary IOL in the capsular bag. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 22520302 TI - Visual outcomes and corneal changes after intrastromal femtosecond laser correction of presbyopia. AB - PURPOSE: To assess the effect of intrastromal femtosecond laser presbyopia treatment on uncorrected near visual acuity (UNVA) and corneal integrity over an 18-month period. SETTING: Department of Ophthalmology, International Vision Correction Research Centre, University of Heidelberg, Heidelberg, Germany. DESIGN: Clinical trial. METHODS: The UNVA (at 40 cm), corneal pachymetry, and true net power were evaluated preoperatively and 1, 3, 6, 12, and 18 months after femtosecond intrastromal presbyopic treatment (Intracor). Endothelial cell density (ECD) was measured preoperatively and 3, 6, and 12 months postoperatively. Data were analyzed with the Wilcoxon test at a P=.01 level of significance. RESULTS: The median UNVA improved significantly from 0.7 logMAR preoperatively to 0.4 logMAR, 0.2 logMAR, 0.2 logMAR, 0.3 logMAR, and 0.2 logMAR at 1, 3, 6, 12, and 18 months, respectively (all P<.001). The median corneal true net power increased significantly by 1.1 diopters (D) to 0.7 D, 0.8 D, 1.0 D, and 0.9 D, respectively (all P<.001); pachymetry showed no significant thinning postoperatively. There was no significant difference in ECD between preoperatively and postoperatively. CONCLUSIONS: Intrastromal femtosecond presbyopic treatment yielded a significant and stable gain of UNVA and corneal steepening without significant loss of endothelial cells or corneal thinning up to 18 months postoperatively. No significant regression of visual acuity or further corneal steepening occurred during the follow-up period. FINANCIAL DISCLOSURE: Dr. Auffarth and Dr. Holzer received lecture and consulting fees from Technolas Perfect Vision GmbH. No author has a financial or proprietary interest in any material or method mentioned. PMID- 22520303 TI - Visual simulation through different intraocular lenses in patients with previous myopic corneal ablation using adaptive optics: effect of tilt and decentration. AB - PURPOSE: To evaluate visual quality differences between intraocular lenses (IOLs) in patients with previous myopic laser ablations and assess the impact of IOL decentration and tilt on visual quality. SETTING: University of Valencia, Burjassot, Spain. DESIGN: Cohort study. METHODS: An adaptive optics visual simulator was used to simulate the wavefront aberration pattern of 1 aberration correcting IOL (Acrysof IQ SN60WF), 1 aberration-free IOL (Akreos Adapt AO), and 1 spherical IOL (Triplato) under 5 IOL situations: centered, 0.2 mm and 0.4 mm decentered, and 2 degrees and 4 degrees tilted in eyes with simulated low or high myopic laser corneal ablations. Monocular distance visual acuity at 100%, 50%, and 10% contrast were measured. RESULTS: Ten eyes of 10 patients were evaluated. When the IOLs were centered, the aberration-correcting IOL provided the best visual quality results in both groups. When the IOLs were misaligned, there was a decrease of visual quality with all simulated IOLs except the aberration-free IOL in the high myopia group. In the misaligned situations, all simulated IOLs obtained comparable visual quality results in both groups. CONCLUSIONS: The results suggest that in patients with previous myopic laser corneal ablation, aberration-correcting IOLs should be implanted. The decrease in visual quality when these IOLs are decentered or tilted demonstrates the importance of accurate implantation of these IOLs. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22520304 TI - Evaluating teaching methods of cataract surgery: validation of an evaluation tool for assessing surgical technique of capsulorhexis. AB - PURPOSE: To develop and assess the validity of an evaluation tool to quantitatively assess the capsulorhexis portion of cataract surgery performed by residents. SETTING: University of California at Los Angeles (UCLA), Department of Ophthalmology, Jules Stein Eye Institute, Los Angeles, California, USA. DESIGN: Masked prospective case series. METHODS: Ophthalmology faculty members at UCLA were surveyed and literature was reviewed to develop a grading tool comprising 12 questions to evaluate surgical technique, including 4 from the Global Rating Assessment of Skills in Intraocular Surgery and 2 from the International Council of Ophthalmology's Ophthalmology Surgical Competency Assessment Rubric. Video clips of continuous curvilinear capsulorhexis (CCC) performed by 2 postgraduate year (PGY) 3 residents, 2 PGY 4 residents, and 2 advanced surgeons were independently graded in a masked fashion by a 7-member faculty panel. RESULTS: Four questions had low interobserver variability and a significant correlation with surgical skill level (intraclass correlation coefficient >0.75; P<.05, analysis of variance; 42 observations). The 4 questions were visual Likert-scale questions grading flow of operation, set up for regrasp, commencement of flap and formation, and circular completion of the CCC. CONCLUSIONS: Surgical performance can be validly measured using an evaluation tool. However, not all evaluation questions produced reliable results. The reliability and accuracy of the measurements appear to depend on the form and content of the question. Studies to optimize assessment tools identifying the best questions for evaluating each step of cataract surgery may help ophthalmic educators more precisely measure outcomes for improving teaching interventions. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22520305 TI - Effects of a blue light-filtering intraocular lens on driving safety in glare conditions. AB - PURPOSE: To evaluate whether the previously established benefit of blue light filtering intraocular lenses (IOLs) when driving in glare conditions is maintained in patients previously implanted with a blue light-filtering toric IOL. SETTING: Department of Applied Psychology, Arizona State University, Mesa, Arizona, USA. DESIGN: Comparative case series. METHODS: The study comprised patients with a blue light-filtering toric IOL (test IOL) or an ultraviolet (UV) only filtering nontoric IOL (control IOL). All patients had good visual acuity and a valid driver's license. While wearing best spherocylindrical correction, patients performed left-turn maneuvers in front of oncoming traffic in a driving simulator. The safety margin was defined as the time to collision less the time taken to turn at an intersection with oncoming traffic. Measures were repeated with a glare source simulating low-angle sun conditions (daytime driving). RESULTS: Of the 33 evaluable patients, 18 had a test IOL and 15 had a control IOL. In the presence of glare, patients with test IOLs had significantly greater safety margins (mean 2.676 seconds +/- 0.438 [SD]) than patients with control IOLs (mean 2.179 +/- 0.343 seconds) and significantly lower glare susceptibility (P<.05). In no-glare and glare conditions, patients with test IOLs had significantly lower glare susceptibility than patients with control IOLs. CONCLUSION: The blue light-filtering toric IOL produced a significantly greater reduction in glare disability than the UV-only filtering nontoric IOL and increased the ability of drivers to safely execute left turns in low-sun conditions. FINANCIAL DISCLOSURE: Dr. Houtman is an employee of Alcon Laboratories, Inc. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 22520306 TI - Visual quality assessment in patients with orange-tinted blue light-filtering and clear ultraviolet light-filtering intraocular lenses. AB - PURPOSE: To evaluate potential differences in the quality of vision after implantation of a blue light-filtering intraocular lens (IOL) and an ultraviolet (UV) light-filtering IOL. SETTING: Department of Ophthalmology, Ruhr-University, Bochum, Germany. DESIGN: Prospective randomized cohort study. METHODS: Patients with age-related cataract had bilateral standardized small-incision Kelman phacoemulsification-based cataract surgery with implantation of a blue light filtering IOL (Oculaid PC 440Y Orange Series) in 1 eye and a UV light-filtering IOL (Oculaid PC 430 Elite Series) in the other eye. Outcome measures included scotopic and photopic corrected distance visual acuity (CDVA) and photopic uncorrected distance visual acuity (UDVA), color discrimination, and contrast sensitivity with and without glare. A questionnaire was used to assess patient satisfaction. Postoperative follow-up visits were scheduled at 1, 3, and 6 months. RESULTS: Twenty-two patients (44 eyes) completed the study. There were no statistically significant differences in UDVA, CDVA, or contrast sensitivity with or without glare between the 2 IOL groups. Color discrimination was significantly decreased in eyes with blue light-filtering IOLs compared with UV light-filtering IOLs, except along the red-green axis (P=.118). No subjective differences in color or light perception were found. CONCLUSIONS: Both IOL types provided similar postoperative visual function except color perception, which was slightly better in eyes with a clear IOL. Although differences were not clinically significant, information about potential disturbances in color vision might be provided before implanting an orange blue light-filtering IOL. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22520307 TI - Comparison of the effect of torsional and microburst longitudinal ultrasound on clear corneal incisions during phacoemulsification. AB - PURPOSE: To compare incision integrity after clear corneal microcoaxial phacoemulsification using longitudinal and torsional ultrasound (US). SETTING: Iladevi Cataract & IOL Research Centre, Ahmedabad, India. DESIGN: Prospective randomized experimental clinical trial. METHODS: Part 1 comprised an experimental study of rabbit eyes. Group 1 received longitudinal US. Group 2 received torsional US. The right eye of each rabbit served as a control. Samples were processed for histomorphology and collagen I denaturation by immunofluorescence. Part 2 comprised a clinical trial of patients. Group 1 received torsional US. Group 2 received longitudinal US. At the end of surgery, trypan blue 0.0125% was instilled. After 2 minutes, 0.1 mL of aqueous was aspirated and its optical density measured. RESULTS: In part 1, incision histomorphology was comparable in both modalities. Collagen denaturation tests (immunofluorescence, dot blot analysis) showed no irregularity in collagen arrangement in either group. In Group 2, Descemet membrane was detached and endothelial cells were minimal at the roof of the incision. In part 2, trypan blue ingress into the anterior chamber was significantly greater in Group 1 than in Group 2 (mean 3.40 + 0.6 log units versus and 3.77 + 0.82 log units) (P<.007). CONCLUSIONS: Incision histomorphology in the torsional group showed minimal Descemet membrane detachment and minimal endothelial cell loss at the roof of the incision. Minimal ingress of trypan blue into the anterior chamber was observed with torsional US, indicating better wound integrity than with longitudinal US. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22520308 TI - Straylight measurements as an indication for cataract surgery. AB - PURPOSE: To assess adding straylight measurements to the indication for cataract surgery. SETTING: Onze Lieve Vrouwe Hospital, Amsterdam, and Zonnestraal Eye Clinic, Hilversum, The Netherlands. DESIGN: Prospective interventional cohort study. METHODS: Before and after cataract extraction, corrected distance visual acuity (CDVA) and straylight were recorded in all patients. Subjective complaints were documented by the 39-item National Eye Institute Visual Function Questionnaire (NEI VFQ-39) and a straylight questionnaire. RESULTS: The population comprised 217 patients with a mean age of 72 years +/- 9.12 (SD) (range 29 to 90 years). Preoperatively, the mean straylight was 1.55 +/- 0.29 log(s) and the mean CDVA, 0.28 +/- 0.21 logMAR. Visual acuity and straylight showed little correlation (R(2) = 0.08). The mean postoperative improvement in CDVA was 0.26 +/- 0.20 logMAR (range -0.12 to 1.12 logMAR) and in straylight, 0.31 +/- 0.32 log(s) (range -0.50 to 1.27 log[s]). The preoperative breakeven point (50% chance of postoperative improvement) was 0.06 logMAR for CDVA and 1.29 log(s) for straylight. Preoperative and postoperative questionnaires showed straylight had almost the same influence as visual acuity on quality of vision. CONCLUSIONS: Straylight and visual acuity measure different aspects of quality of vision and influenced subjective visual quality almost equally. When straylight was added to preoperative considerations of cataract extraction, postoperative results were more predictable. FINANCIAL DISCLOSURE: The Netherlands Academy of Arts and Sciences has a proprietary interest in the C-Quant Straylight meter. No author has a financial or proprietary interest in any material or method mentioned. PMID- 22520309 TI - Outcomes of pediatric cataract surgery in anterior persistent fetal vasculature. AB - PURPOSE: To report the intraoperative performance and postoperative outcomes in eyes with anterior persistent fetal vasculature (PFV). SETTING: Iladevi Cataract & IOL Research Centre, India, and Filatov Institute Odessa, Ukraine. DESIGN: Prospective interventional case series. METHODS: Eyes with anterior PFV had surgery using a standardized surgical technique. Plaque peeling was used for small plaques and partial excision for larger plaques. In eyes in which the entire lens converted into a fibrovascular tissue, extensive capsulectomy with anterior 2-port limbal vitrectomy was performed. Microphthalmic eyes had no intraocular lens implantation. RESULTS: This study comprised 33 eyes. The mean age at surgery was 6.30 months +/- 5.16 (SD). Microcornea was observed in 10 eyes (30.3%). Within the morphology of cataract, 10 eyes (30.3%) had the lens converted into fibrovascular mass, of which 4 had associated prominent ciliary process. Anterior continuous curvilinear capsulorhexis (CCC) and manual posterior CCC were performed in 23 eyes (69.7%) and 3 eyes (9.1%), respectively. Intraoperatively, posterior capsule plaque was seen in 20 eyes (60.6%). In 31 eyes (93.9%), 2-port limbal anterior vitrectomy was performed and in 2 eyes (6.1%), pars plana vitrectomy was performed. Intraocular lens implantation was performed in 16 eyes (48.5%); 17 eyes (51.5%) were left aphakic. Visual axis obscuration was observed in 6 eyes (18.2%). At the 3-year follow-up, visual acuity remained stable in 11 eyes (33.3%) and improved in 22 eyes (66.6%). CONCLUSION: The results suggest that good visual outcomes can be obtained in PFV eyes after surgical intervention, with an acceptable rate of serious postoperative complications. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22520310 TI - Outcomes of Descemet membrane endothelial keratoplasty in phakic eyes. AB - PURPOSE: To determine the clinical outcomes of isolated Descemet membrane transplantation (ie, Descemet membrane endothelial keratoplasty [DMEK]) in phakic eyes. SETTING: Tertiary referral center. DESIGN: Cohort study. METHODS: Phakic eyes from a larger group of consecutive eyes that had DMEK for Fuchs endothelial dystrophy were examined. The examination included corrected distance visual acuity (CDVA), subjective and objective refractions, endothelial cell density (ECD), and intraoperative and postoperative complications at 1, 3, and 6 months. RESULTS: The study enrolled 52 phakic eyes from a group of 260 DMEK eyes. Of the phakic eyes, 69% reached a CDVA equal to or better than 20/40 (>=0.5) within 1 week and 85% reached equal to or better than 20/25 (>=0.8) at 6 months. Compared with an age-matched control group of pseudophakic eyes, phakic eyes had a similar visual rehabilitation rate, final visual outcome, mean ECD at 6 months (1660 cells/mm(2) +/- 470 [SD]), minor hyperopic shift (+0.74 diopter), and graft detachment rate (4%). Visual acuity equal to or better than 20/13 (>=1.5) was limited to phakic eyes, suggesting better optical quality with the crystalline lens in situ. Temporary mechanical angle-closure glaucoma due to air-bubble dislocation behind the iris was the main complication (11.5%). Two eyes (4%) required phacoemulsification after DMEK. CONCLUSIONS: In phakic eyes, DMEK may give excellent visual outcomes without an increased risk for complications. Visual acuities equal to or better than 20/13 (>=1.5) may indicate that the almost anatomic repair after DMEK is associated with near perfect optical quality of the transplanted cornea. FINANCIAL DISCLOSURE: Dr. Melles is a consultant to D.O.R.C. International/Dutch Ophthalmic USA. No author has a financial or proprietary interest in any material or method mentioned. PMID- 22520311 TI - Evaluation of transepithelial stromal riboflavin absorption with enhanced riboflavin solution using spectrophotometry. AB - PURPOSE: To assess transepithelial stromal riboflavin absorption with an enhanced riboflavin solution (riboflavin 0.1%, 15% dextran T500 with trometamol (Tris [hydroxymethyl]aminomethane) and sodium ethylenediaminetetraacetic acid by analyzing light-transmission properties of ex vivo rabbit corneas. SETTING: School of Optometry and Vision Sciences, Cardiff, Wales. DESIGN: Experimental study. METHODS: The enhanced riboflavin drops (Ricrolin TE) were applied every 3 minutes for 1 hour to 12 corneas (4 with intact epithelium, 4 with superficial scratches, 4 with 8.0 mm epithelial debridement). As a comparison, riboflavin drops without the enhancers (riboflavin 0.1%, 20% dextran T500) (normal riboflavin group) were applied to 12 corneas (4 with intact epithelium, 4 with superficial scratches, 4 with central epithelial debridement). A control group of 4 corneas with intact epithelium received balanced saline 0.9%. To assess enhanced riboflavin absorption, light-transmission spectra of the corneas were analyzed with a spectrophotometer. RESULTS: The spectra in corneas with intact epithelium in both riboflavin groups and in eyes with superficial scratches treated with normal riboflavin were similar to controls. Those with enhanced riboflavin and superficial scratches showed a homogeneous yellow discoloration of the cornea with a dip in light transmission between 400 and 490 nm, similar to that of the enhanced riboflavin solution. This was also seen, albeit of a greater magnitude, with complete epithelial removal, with eyes receiving enhanced riboflavin having a greater dip in transmission than eyes receiving normal riboflavin. CONCLUSIONS: Administration of enhanced riboflavin and superficial epithelial scratches allowed sufficient riboflavin stromal absorption to homogeneously alter the transmission spectra of rabbit corneas. This did not occur to the same extent with an intact epithelium or normal riboflavin with superficial scratches. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22520312 TI - Intrastromal corneal ring segment implantation for irregular astigmatism after laser in situ keratomileusis. AB - We describe the case of a 56-year-old man with a previously decentered laser in situ keratomileusis ablation in his right eye that induced associated vision threatening problems. After intrastromal corneal ring segment implantation, both topography and visual acuity significantly improved. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22520313 TI - Consultation section. Intraocular lens power calculation after refractive surgery. PMID- 22520321 TI - Flaporhexis. PMID- 22520322 TI - Back to the surface? PMID- 22520324 TI - Let us be clear: a cornea has no axis; a cornea has meridians. PMID- 22520326 TI - Optimized constants for an ultraviolet light-adjustable intraocular lens. PMID- 22520328 TI - Other factors in PCO prevention. PMID- 22520329 TI - Advantages of bevel-down technique. PMID- 22520331 TI - Association analysis between HOXD9 genes and the development of developmental dysplasia of the hip in Chinese female Han population. AB - BACKGROUND: Developmental dysplasia of the hip (DDH) is a congenital or acquired deformation or misalignment of the hip joint which affects mainly females. We hypothesized that HOXD9 gene could be regulated in acetabular size or shape and related in DDH developing. METHODS: Two hundred and nine Chinese Han female DDH patients and 173 ethnic, age matched healthy female controls were genotyped for HOXD9 two tag SNPs using sequenom method. RESULTS: One of the two tag SNPs, rs711822, was not shown significantly differences in genotypic or allelic distribution between case and control group. Comparing the genotypic distribution of rs711819, there was significant differences between DDH patients group and control group (chi2 = 7.54, df =2, P =0.023), and the association to DDH developing reached significance (P =0.045, OR =1.79, 95 % CI: 1.01-3.17 by dominant mode). CONCLUSION: In conclusion, the association between one tag SNP of HOXD9 gene and the development of DDH reach significant in our study population, this result indicate the positive correlation between HOXD9 gene and DDH developing. Further study in larger sample size and different population as well as functional studies will help to understand the pathogenesis of DDH. PMID- 22520332 TI - A highly soluble matrix metalloproteinase-9 inhibitor for potential treatment of dry eye syndrome. AB - Dry eye syndrome (DES) or keratoconjunctivitis sicca is an eye disease caused by the chronic lack of lubrication and moisture of the eye. The pathogenesis of DES involves the over-expression and over-activity of corneal Matrix Metalloproteinase 9 (MMP-9). We propose herein a new, non-symptomatic approach for the treatment of DES based on the inhibition of MMP-9 by a new highly soluble molecule, designed as PES_103 that has been shown to inhibit MMP-9 both in vitro and in vivo. The efficacy of PES_103 in vivo and the potential benefits of this treatment in restoring tear production were studied in this work using an animal model of reduced lacrimation. PES_103 did not show any significant corneal toxicity. PMID- 22520333 TI - Transcriptional activation of Brassica napus beta-ketoacyl-ACP synthase II with an engineered zinc finger protein transcription factor. AB - Targeted gene regulation via designed transcription factors has great potential for precise phenotypic modification and acceleration of novel crop trait development. Canola seed oil composition is dictated largely by the expression of genes encoding enzymes in the fatty acid biosynthetic pathway. In the present study, zinc finger proteins (ZFPs) were designed to bind DNA sequences common to two canola beta-ketoacyl-ACP Synthase II (KASII) genes downstream of their transcription start site. Transcriptional activators (ZFP-TFs) were constructed by fusing these ZFP DNA-binding domains to the VP16 transcriptional activation domain. Following transformation using Agrobacterium, transgenic events expressing ZFP-TFs were generated and shown to have elevated KASII transcript levels in the leaves of transgenic T(0) plants when compared to 'selectable marker only' controls as well as of T(1) progeny plants when compared to null segregants. In addition, leaves of ZFP-TF-expressing T(1) plants contained statistically significant decreases in palmitic acid (consistent with increased KASII activity) and increased total C18. Similarly, T(2) seed displayed statistically significant decreases in palmitic acid, increased total C18 and reduced total saturated fatty acid contents. These results demonstrate that designed ZFP-TFs can be used to regulate the expression of endogenous genes to elicit specific phenotypic modifications of agronomically relevant traits in a crop species. PMID- 22520334 TI - A new fractioning process to decrease the price of ranibizumab. PMID- 22520335 TI - [Information to the readers]. PMID- 22520336 TI - Metastatic breast cancer: we do need primary cost data. AB - The lifetime cost of metastatic breast cancer is a key component for the economic evaluations of targeted therapies and biomarkers. In the literature, only few cost studies are available and provide discordant cost estimates for the management of metastatic recurrences. Our objective was to assess the lifetime costs of metastatic breast cancer and to investigate cost variability using primary cost data. We used individual data from a cohort of 290 French women treated at the Gustave Roussy Institute and who had died between 2005 and 2008. We separately analysed the determinants for survival after metastatic recurrence and for the monthly cost using two different models. The mean survival time after recurrence was 24.8 months. The mean hospital cost per patient amounted to ? 36,516 and the mean cost per month ? 3764. We identified three prognostic factors: age at breast cancer diagnosis, the histological grade and the site of the first recurrence. The factors significantly associated with the cost per month were hospitalisation in a palliative care unit, trastuzumab treatment, the number of sites of recurrence and whether or not the patient had died during the last hospital stay. We identified cost drivers of the lifetime costs of metastatic breast cancer. This provides useful information for the design of future economic studies. We also provide cost estimates in homogeneous subgroups of patients defined by patient characteristics and by the type of care received. PMID- 22520337 TI - Auditory hallucinations: expectation-perception model. AB - In this paper, we aimed to present a hypothesis that would explain the mechanism of auditory hallucinations, one of the main symptoms of schizophrenia. We propose that auditory hallucinations arise from abnormalities in the predictive coding which underlies normal perception, specifically, from the absence or attenuation of prediction error. The suggested deficiencies in processing prediction error could arise from (1) abnormal modulation of thalamus by prefrontal cortex, (2) absence or impaired transmission of external input, (3) dysfunction of the auditory and association cortex, (4) neurotransmitter dysfunction and abnormal connectivity, and (5) hyperactivity activity in auditory cortex and broad prior probability. If there is no prediction error, the initially vague prior probability develops into an explicit percept in the absence of external input, as a result of a recursive pathological exchange between auditory and prefrontal cortex. Unlike existing explanations of auditory hallucinations, we propose concrete mechanisms which underlie the imbalance between perceptual expectation and external input. Impaired processing of prediction error is reflected in reduced mismatch negativity and increased tendency to report non-existing meaningful language stimuli in white noise, shown by those suffering from auditory hallucinations. We believe that the expectation-perception model of auditory hallucinations offers a comprehensive explanation of the underpinnings of auditory hallucinations in both patients and those not diagnosed with mental illness. Therefore, our hypothesis has the potential to fill the gaps in the existing knowledge about this distressing phenomenon and contribute to improved effectiveness of treatments, targeting specific mechanisms. PMID- 22520338 TI - Efficacy of slow-release collar formulations of imidacloprid/flumethrin and deltamethrin and of spot-on formulations of fipronil/(s)-- methoprene, dinotefuran/pyriproxyfen/permethrin and (s) -methoprene/amitraz/fipronil against Rhipicephalus sanguineus and Ctenocephalides felis felis on dogs. AB - BACKGROUND: Two studies evaluating the efficacy of an imidacloprid/flumethrin collar (Seresto(r), Bayer Animal Health, IVP), a deltamethrin collar (Scalibor(r), MSD, CP1), a fipronil/(s)-methoprene spot-on (Frontline Combo(r), Merial, CP2), a dinotefuran/pyriproxyfen/permethrin spot-on (Vectra 3D(r), Ceva, CP3) and an amitraz/fipronil/(s)-methoprene spot-on (Certifect(r), Merial, CP4/CP5) against repeated infestations with Rhipicephalus sanguineus and Ctenocephalides felis felis on dogs were conducted over periods of 226 days and 71 days respectively. METHODS: The first study comprised 4 groups of treated dogs and one untreated control group, and the second 3 groups of treated dogs and one control group. Each group consisted of 8 dogs. All dogs were infested with ticks and fleas at regular intervals. Ticks were counted 6 h, 18 h or 48 h after infestations and fleas 24 h after infestations. Efficacies of the treatments were calculated by comparison with the untreated control groups using standard descriptive statistics. RESULTS: The protective 48 h tick efficacy was 97.8% to 100% for the IVP (226 days), 69.3% to 97.4% for CP1 (170 days), 99.6% to 43.4% for CP2 (35 days) and 98% to 61.4% for CP3 (35 days).The protective 18 h tick efficacy was 98% to 99.6% for the IVP (71 days), 100% to 86.5% for CP4 (29 days), 100% to 72.8% for CP4 after re-treatment (35 days) and 98.8% to 54.3% for CP5 (35 days).The protective 6 h tick efficacy was 85.6% at Day 7 and 90.1% to 97.1% from Day 14 onwards for the IVP (70 days), 92.3% to 70.7% for CP4 (35 days), 97.5% to 65.2% for CP4 after re-treatment (35 days) and 95.1% to 51.8% for CP5 (35 days).The protective 24 h flea efficacy was 99.5/90.9% to 100% for the IVP (71/226 days), 66.7% to 83% for CP1 (170 days), 100% to 88.5% for CP2 (35 days), 100% to 73.3% for CP3 (35 days), 100% to 98.7% for CP4 (35 days), 100% to 87.5% for CP4 after re-treatment (35 days) and 100% to 79.5% for CP5 (35 days). CONCLUSIONS: These data suggest that the long-term efficacy provided by a medicated collar that is effective, is a means to overcome the fluctuating efficacy of spot-on treatments resulting from a lack of pet owner re-treatment compliance, and consequently protect animals successfully against ectoparasites and probably vector-borne diseases. PMID- 22520339 TI - Perspectives - March 2012. PMID- 22520340 TI - Extranodal marginal zone lymphoma of the CNS arising after a long-standing history of atypical white matter disease. PMID- 22520341 TI - Adverse impact of IDH1 and IDH2 mutations in primary AML: experience of the Spanish CETLAM group. AB - The study of genetic lesions in AML cells is helpful to define the prognosis of patients with this disease. This study analyzed the frequency and clinical impact of recently described gene alterations, isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) mutations, in a series of homogeneously treated patients with primary (de novo) AML. Two-hundred and seventy-five patients enrolled in the CETLAM 2003 protocol were analyzed. IDH1 and IDH2 mutations were investigated by well-established melting curve-analysis and direct sequencing (R140 IDH2 mutations). To establish the percentage of the mutated allele a pyrosequencing method was used. Patients were also studied for NPM, FLT3, MLL, CEBPA, TET2 and WT1 mutations. IDH1 or IDH2 mutations were identified in 23.3% AML cases and in 22.5% of those with a normal karyotype. In this latter group, mutations were associated with short overall survival. This adverse effect was even more evident in patients with the NPM or CEBPA mutated/FLT3 wt genotype. In all the cases analyzed, the normal allele was detected, suggesting that both mutations act as dominant oncogenes. No adverse clinical impact was observed in cases with TET2 mutations. IDH1 and IDH2 mutations are common genetic alterations in normal karyotype AML. Favourable genotype NPM or CEBPA mutated/FLT3 wt can be further categorized according to the IDH1 and IDH2 mutational status. PMID- 22520342 TI - The impact of appearance-focused social comparisons on body image disturbance in the naturalistic environment: the roles of thin-ideal internalization and feminist beliefs. AB - Drawing on Festinger's (1954) social comparison theory and its modern applications, this research investigated the relationship between upward appearance-focused social comparisons and body image disturbance using ecological momentary assessment, which allows for examination of these phenomena in their natural context. Participants were 91 undergraduate women who answered questionnaires five times per day for five days using Palm Personal Data Assistant (PDA) devices. Analyses were conducted using hierarchical linear modeling, which allows for examination of longitudinal data both within and across participants. Results revealed a positive relationship between upward appearance-focused social comparisons and body image disturbance. Upward appearance-focused social comparisons were associated with greater body image disturbance for those with higher levels of thin-ideal internalization and with greater body checking for women with lower levels of feminist beliefs. These findings further illuminate the nature of the relationship between social comparisons and body image disturbance. PMID- 22520343 TI - Neuroeconomics and the study of addiction. AB - We review the key findings in the application of neuroeconomics to the study of addiction. Although there are not "bright line" boundaries between neuroeconomics and other areas of behavioral science, neuroeconomics coheres around the topic of the neural representations of "Value" (synonymous with the "decision utility" of behavioral economics). Neuroeconomics parameterizes distinct features of Valuation, going beyond the general construct of "reward sensitivity" widely used in addiction research. We argue that its modeling refinements might facilitate the identification of neural substrates that contribute to addiction. We highlight two areas of neuroeconomics that have been particularly productive. The first is research on neural correlates of delay discounting (reduced Valuation of rewards as a function of their delay). The second is work that models how Value is learned as a function of "prediction-error" signaling. Although both areas are part of the neuroeconomic program, delay discounting research grows directly out of behavioral economics, whereas prediction-error work is grounded in models of learning. We also consider efforts to apply neuroeconomics to the study of self control and discuss challenges for this area. We argue that neuroeconomic work has the potential to generate breakthrough research in addiction science. PMID- 22520344 TI - Translation equations to compare ActiGraph GT3X and Actical accelerometers activity counts. AB - BACKGROUND: This study aimed to develop a translation equation to enable comparison between Actical and ActiGraph GT3X accelerometer counts recorded minute by minute. METHODS: Five males and five females of variable height, weight, body mass index and age participated in this investigation. Participants simultaneously wore an Actical and an ActiGraph accelerometer for two days. Conversion algorithms and R(2) were calculated day by day for each subject between the omnidirectional Actical and three different ActiGraph (three dimensional) outputs: 1) vertical direction, 2) combined vector, and 3) a custom vector. Three conversion algorithms suitable for minute/minute conversions were then calculated from the full data set. RESULTS: The vertical ActiGraph activity counts demonstrated the closest relationship with the Actical, with consistent moderate to strong conversions using the algorithm: y = 0.905x, in the day by day data (R(2) range: 0.514 to 0.989 and average: 0.822) and full data set (R(2) = 0.865). CONCLUSIONS: The Actical is most sensitive to accelerations in the vertical direction, and does not closely correlate with three-dimensional ActiGraph output. Minute by minute conversions between the Actical and ActiGraph vertical component can be confidently performed between data sets and might allow further synthesis of information between studies. PMID- 22520346 TI - Emerging treatments in the management of tuberous sclerosis complex. AB - Tuberous sclerosis complex is a genetic disorder characterized by the formation of nonmalignant hamartomas in the brain, heart, skin, kidney, lung, and other organs. It is associated with autism, epilepsy, and other neurocognitive and behavioral disabilities. Wide phenotypic variation occurs in disease severity and natural course: some patients demonstrate minimal effects, e.g., skin changes; others manifest profound seizures and mental retardation. Tuberous sclerosis complex is caused by mutations in either the tuberous sclerosis complex 1 or 2 gene (coding for hamartin and tuberin, respectively). The tuberous sclerosis complex 1/tuberous sclerosis complex 2 protein dimer complex is a crucial inhibitory element in the mammalian target of rapamycin pathway, regulating cell growth and proliferation. Until recently, few options existed, other than surgery, for treating symptoms of tuberous sclerosis complex related to the growth of hamartomas. Increased understanding of the genetic cause of the disease and underlying dysregulation of the mammalian target of rapamycin pathway has led to clinical trials of mammalian target of rapamycin inhibitors, including sirolimus and everolimus. This review gives an overview of tuberous sclerosis complex and its molecular causes, and summarizes results from recent clinical trials of mammalian target of rapamycin inhibitors in patients with the disease. PMID- 22520347 TI - Outcomes of epileptic spasms in patients aged less than 3 years: single-center United States experience. AB - Retrospective review was performed of children aged <3 years with epileptic spasms at our center from 2004-2010. Short-term (<6 months) and long-term (>=6 months) outcomes were assessed. We included 173 children (104 boys; median age of onset, 6.8 months) with epileptic spasms of known (62%) and unknown (38%) etiology. Treatments included adrenocorticotropic hormone (n = 103), vigabatrin (n = 82), phenobarbital (n = 34), and other agents (n = 121). Short-term treatment with adrenocorticotropic hormone and vigabatrin provided better epileptic spasm control in groups with known and unknown etiology than other agents. At follow-up (6-27 months), 54% of children manifested seizures, and 83% manifested developmental delay. Known etiology was a predictor of poor developmental outcome (P = 0.006), whereas bilateral/diffuse brain lesions predicted both poor development and seizures (P = 0.001 and 0.005, respectively). Initial presentations of epileptic spasms with hypotonia or developmental delay most strongly predicted both seizures and neurodevelopmental outcomes (P < 0.001). In a child presenting with epileptic spasms with developmental delay or hypotonia, no specific treatment may offer superior benefit. PMID- 22520348 TI - Utilization of antiepileptic drugs in Hong Kong children. AB - This study investigated the prescribing patterns of antiepileptic drugs, especially the uptake of newer drugs, among children and adolescents in Hong Kong. Data were retrieved from the Clinical Data Analysis and Reporting System. Children aged 0-19 years who received at least one prescription of anticonvulsants were selected. The study period extended from April 1, 2005 to March 31, 2009. The overall prevalence of anticonvulsants prescribing was 2.23/1000 children in 2005. A slight but steady decline in anticonvulsants prevalence was observed throughout the study period. Valproic acid was the most frequently prescribed drug, followed by carbamazepine and benzodiazepine derivatives. The use of newer anticonvulsants rose significantly, by 26.9%. The use of valproic acid remained unchanged, whereas the use of carbamazepine declined by 20%. Among newer drugs, the use of levetiracetam increased fourfold, and that of oxcarbazepine increased 15-fold. In the youngest age group, phenobarbital was the second most frequently used drug. A significant increase in lamotrigine prescriptions was not observed among adolescents. The persistent increase in using newer antiepileptic drugs implies not only an increase in drug expenditure. It also reflects the need to assess cost-effectiveness in terms of long-term outcomes, quality of life, and health economic outcomes. PMID- 22520345 TI - Clamp loader ATPases and the evolution of DNA replication machinery. AB - Clamp loaders are pentameric ATPases of the AAA+ family that operate to ensure processive DNA replication. They do so by loading onto DNA the ring-shaped sliding clamps that tether the polymerase to the DNA. Structural and biochemical analysis of clamp loaders has shown how, despite differences in composition across different branches of life, all clamp loaders undergo the same concerted conformational transformations, which generate a binding surface for the open clamp and an internal spiral chamber into which the DNA at the replication fork can slide, triggering ATP hydrolysis, release of the clamp loader, and closure of the clamp round the DNA. We review here the current understanding of the clamp loader mechanism and discuss the implications of the differences between clamp loaders from the different branches of life. PMID- 22520349 TI - Automatic detection of childhood absence epilepsy seizures: toward a monitoring device. AB - Automatic detections of paroxysms in patients with childhood absence epilepsy have been neglected for several years. We acquire reliable detections using only a single-channel brainwave monitor, allowing for unobtrusive monitoring of antiepileptic drug effects. Ultimately we seek to obtain optimal long-term prognoses, balancing antiepileptic effects and side effects. The electroencephalographic appearance of paroxysms in childhood absence epilepsy is fairly homogeneous, making it feasible to develop patient-independent automatic detection. We implemented a state-of-the-art algorithm to investigate the performance of paroxysm detection. Using only a single scalp electroencephalogram channel from 20 patients with a total of 125 paroxysms >2 seconds, 97.2% of paroxysms could be detected with no false detections. This result leads us to recommend further investigations of tiny, one-channel electroencephalogram systems in an ambulatory setting. PMID- 22520350 TI - Clinical profile of Malay children with optic neuritis. AB - Limited data are available on optic neuritis in Asian children. Clinical profiles tend to vary with different races. We aimed to determine the clinical manifestations, visual outcomes, and etiologies of optic neuritis in Malaysian children, and discuss the literature of optic neuritis in Asian children. A retrospective study involving 14 children with optic neuritis was performed at Hospital Universiti Sains Malaysia between July 2005 and January 2010 (follow-up, 18-60 months). Clinical features, laboratory results, possible etiologies, and visual acuity after 1 year were studied. Females were predominant (mean age at presentation, 11.1 years). All patients manifested bilateral involvement. Swollen optic discs were observed in 92.9% of eyes; 60.7% of patients demonstrated a visual acuity of 6/60 (or 20/200) or worse on presentation, whereas 14.3% remained at 6/60 (or 20/200) or worse, 1 year after their attack. Cecocentral scotoma comprised the most common visual field defect. Infection contributed to 50.0% of cases; 14.3% progressed to multiple sclerosis during follow-up, with no evidence of recurrent optic neuritis. The clinical profiles and etiologies of optic neuritis in Malay children differ slightly compared with other optic neuritis studies of Asian children. The frequency of progression to multiple sclerosis is relatively lower. PMID- 22520351 TI - Later onset phenotypes of Krabbe disease: results of the world-wide registry. AB - The majority of newborns screening positive for Krabbe disease have not exhibited the expected early infantile phenotype, with most clinically normal despite low galactocerebrosidase activity and two mutations. Most are expected to develop the later onset phenotypes. The World-Wide Krabbe Registry was developed in part to expand our understanding of the natural history of these rare variants. As of June 2011, 122 patients were enrolled in the registry: 62% manifested early infantile onset (previously reported), 10% manifested onset at 7-12 months (late infantile), 22% manifested onset at 13 months to 10 years (later onset), and 5% manifested adolescent/adult onset. Data on disease course, galactocerebrosidase activity, DNA mutations, and results of neurodiagnostic studies were obtained from questionnaires and medical records. Initial signs (late infantile) included loss of milestones and poor feeding, whereas later onset and adolescent/adult phenotypes presented with changes in gait. Elevated cerebrospinal fluid protein and abnormal magnetic resonance imaging results were present in most, but not all, patients at diagnosis. Phenotypic variability occurred in four sibships. Five-year and 10-year survivals for all later onset phenotypes were at least 50%. The later onset Krabbe phenotypes differ from those with early infantile disease, but no specific predictor of phenotype was identified. PMID- 22520352 TI - Head circumference growth reference charts for Turkish children aged 0-84 months. AB - This study sought to produce updated head circumference references in a representative population of Turkish children aged 0 to <84 months. Head circumference measurements are very important in monitoring child growth, to evaluate macrocephaly and microcephaly. Primary sampling units involved family health centers in the city center and suburbs of Kayseri. In total, 2989 children (1479 boys and 1510 girls) were included. Head circumference was measured with a nonelastic tape on a line passing over the glabella and posterior occipital protrusion in children aged 0-2 years lying on a bed, and children aged more than 2 years standing up. We compared the 50th percentile of our cross-sectional data with longitudinal Belgian and American data. The comparison indicated that Turkish head circumference percentiles were similar to, or not much lower than, Belgian and American percentiles. Head circumference percentiles can be used to evaluate children with microcephaly and macrocephaly (+/-2 standard deviations), and to monitor growth. PMID- 22520354 TI - Kikuchi-Fujimoto disease complicated by peripheral neuropathy. AB - Kikuchi-Fujimoto disease is a necrotizing lymphadenitis, mainly characterized by lymphadenopathy, fever, hepatosplenomegaly, nocturnal sweats, myalgia, weight loss, and arthralgia. Its diagnosis is most often based on lymph node biopsy. Differential diagnoses with several other diseases, e.g., malignant lymphoma, necrotizing lymphadenitis, and infective lymphadenopathies, may be challenging. Neurologic involvement is rarely reported in patients diagnosed with Kikuchi Fujimoto disease. In this subset of patients, the great majority manifest signs involving the central nervous system. We present a 14-year-old boy with a severe form of Kikuchi-Fujimoto disease, complicated by peripheral neuropathy. This patient is interesting for both his age and his peculiar complication. PMID- 22520353 TI - Short-term response of sleep-potentiated spiking to high-dose diazepam in electric status epilepticus during sleep. AB - We describe the short-term effects of high-dose oral diazepam on sleep potentiated epileptiform activity in patients with electric status epilepticus during sleep. We enrolled patients treated with high-dose oral bedtime diazepam from 2001-2009. We defined spike percentage as the percentage of 1-second bins containing at least one spike, and calculated it during three randomly selected 5 minute samples of wakefulness throughout the day and during the first 5 minutes of every hour of non-rapid eye movement sleep at night. In this study, patients were considered to demonstrate sleep-potentiated epileptiform activity when their spike percentage during sleep was increased by >=50% compared with wakefulness. Twenty-nine children (18 boys) were included (median age, 7.4 years). Twenty-four hours after receiving high-dose diazepam, epileptiform activity was significantly reduced (76.7% at baseline vs 40.8% 24 hours after high-dose diazepam; Wilcoxon signed ranks test, Z = -4.287, P < 0.0001). Seven patients (24.1%) manifested mild, reversible side effects during the first 48 hours after diazepam administration. High-dose oral diazepam effectively and safely reduced epileptiform activity in patients with electric status epilepticus during sleep. PMID- 22520355 TI - Ataxia-telangiectasia presenting with a novel immunodeficiency. AB - Ataxia-telangiectasia is a rare autosomal recessive disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasias, and variable degrees of immunodeficiency. Immunologic evaluations of affected patients often reveal anomalies of humoral and cell-mediated immunity. We describe a case of ataxia-telangiectasia with an atypical immunodeficiency and a novel mutation in the ATM gene. The patient presented at age 3 years with a perineal cellulitis associated with profound neutropenia and T-cell lymphopenia. Serum immunoglobulin levels and antibody titers were normal. Neurologic evaluation revealed minimal hypotonia and wide-based gait, without other signs of cerebellar dysfunction. The alpha-fetoprotein level was elevated, and molecular genetic testing confirmed the diagnosis of ataxia-telangiectasia, uncovering a novel ATM gene mutation c.3931C>T (p.Gln1311X) in exon 28. This patient presents a unique immunologic pattern with normal immunoglobulin levels, significant lymphopenia, and profound neutropenia. The diagnosis of ataxia-telangiectasia should be considered in children presenting with gait disorder and immunologic defects, regardless of subtype and severity. PMID- 22520356 TI - Novel neuroimaging finding in palmitoyl protein thioesterase-1-related neuronal ceroid lipofuscinosis. AB - Palmitoyl protein thioesterase-1 (PPT1)-related neuronal ceroid lipofuscinosis is a type of neuronal ceroid lipofuscinosis caused by a deficiency of the enzyme palmitoyl protein thioesterase-1. Cranial magnetic resonance imaging reveals more severe atrophy in the cerebral hemispheres than in the cerebellum. The basal ganglia and particularly the thalamus demonstrate low signal intensity on T(2) weighted images from an early age. We present three patients with PPT1-related neuronal ceroid lipofuscinosis who exhibited isolated, symmetric signal changes in the bilateral dentate nucleus as sole early neuroimaging abnormality. Neither cerebral or cerebellar atrophy nor signal changes in the thalamus/basal ganglia were evident. This neuroimaging finding in PPT1-related neuronal ceroid lipofuscinosis was not previously reported. PMID- 22520357 TI - Childhood-onset myasthenia gravis with thymoma. AB - Juvenile myasthenia gravis is an acquired, autoimmune disease occurring before age 16 years. Thymoma is exceedingly rare in children, especially in association with juvenile myasthenia gravis. We describe a 14-year-old boy with juvenile myasthenia gravis and thymoma. He presented with difficulties chewing and swallowing, nasal speech, and fluctuating weakness of the leg muscles. Neurologic examination revealed masticatory and bulbar muscle weakness with nasal speech, proximal muscle weakness, fatigability of the arms and legs, and distal muscle weakness of the legs. A diagnosis of juvenile myasthenia gravis was confirmed by a positive neostigmine test, a decremental response on repetitive nerve stimulation, and increased titers of serum anti-acetylcholine receptor antibodies. The patient received anticholinesterases, corticosteroids, azathioprine, and thymectomy. A pathohistologic analysis of the thymus gland indicated thymoma, Masaoka grade II. After 2 years of an unstable disease course, remission was achieved. Because only 10 cases of thymoma-associated myasthenia gravis are described in the pediatric population, this report offers an important contribution to a better understanding of this rare association. PMID- 22520358 TI - Predisposition to subdural hemorrhage in X-linked myotubular myopathy. AB - X-linked myotubular myopathy is a severe congenital myopathy that can involve multiple organs. We report on a 10-month-old boy who manifested X-linked myotubular myopathy with subdural hemorrhage. The diagnosis of X-linked myotubular myopathy was based on typical muscle pathology and MTM1 missense mutation. The patient had undergone no traumatic episodes or bleeding diathesis. Axial growth acceleration is known to occur in X-linked myotubular myopathy, potentially leading to dolichocephaly. In our patient, an enlarged subdural space apparently stretched the bridging veins, increasing susceptibility to subdural hemorrhage. Patients who manifest X-linked myotubular myopathy with typical dolichocephaly are at increased risk for subdural hemorrhage. PMID- 22520360 TI - Reactivation of varicella presenting as pseudotumor cerebri: three cases and a review of the literature. PMID- 22520361 TI - Use of MRI and CT for fat imaging in children and youth: what have we learned about obesity, fat distribution and metabolic disease risk? AB - Childhood obesity is a matter of great concern for public health. Efforts have been made to understand its impact on health through advanced imaging techniques. An increasing number of studies focus on fat distribution and its associations with metabolic risk, in interaction with genetics, environment and ethnicity, in children. The present review is a qualitative synthesis of the existing literature on visceral and subcutaneous abdominal, intrahepatic and intramuscular fat. Our search revealed 80 original articles. Abdominal as well as ectopic fat depots are prevalent already in childhood and contribute to abnormal metabolic parameters, starting early in life. Visceral, hepatic and intramuscular fat seem to be interrelated but their patterns as well as their independent contribution on metabolic risk are not clear. Some ethnic-specific characteristics are also prevalent. These results encourage further research in childhood obesity by using imaging techniques such as magnetic resonance imaging and computed tomography. These imaging methods can provide a better understanding of fat distribution and its relationships with metabolic risk, compared to less detailed fat and obesity assessment. However, studies on bigger samples and with a prospective character are warranted. PMID- 22520362 TI - Clear cell chondrosarcoma of the head and neck. AB - Clear cell chondrosarcoma is a rare variant of chondrosarcoma that mostly involves the end of long bones. However, nine cases have been reported in the head and neck: four in larynx, two in nasal septum, two in maxilla and one in the skull. These cases form the basis of this review. Head and neck cases accounts for less than 5% of Clear cell chondrosarcomas in the whole body and the larynx is the most common place. The histological findings of head and neck cases are consistent with general features of this entity in the whole body and nearly all tumors in this case series had a component of conventional chondrosarcoma. Clear cell chondrosarcoma is an intracompartmental tumor and retains "Grenz zone" just beneath the epithelium. Therefore, the overlying mucosa remained intact in all laryngeal cases. Nasal tumor caused ballooning of the septum and the maxillary lesion did not involve the oral mucosa. This tumor presents various radiographic features in the head and neck area. Chondroblastoma, chondroma, osteoblastoma, osteosarcoma and metastatic renal cell carcinoma are included in the histologic differential diagnoses. Differentiation from chondroblastic osteosarcoma is important in the maxilla. A wide resection is adequate in most cases. However, some laryngeal cases show tendency to recur. Clear cell chondrosarcoma is a slow growing tumor and this necessitates a long time follow-up of patients. Due to the extreme rarity in the head and neck, diagnosis of Clear cell chondrosarcoma in this area, must be confirmed by histochemical and immunohistochemical studies. PMID- 22520363 TI - Assessment of leukemia inhibitory factor and glycoprotein 130 expression in endometrium and uterine flushing: a possible diagnostic tool for impaired fertility. AB - BACKGROUND: Uterine receptivity and implantation are complex processes requiring coordinated expression of molecules by zygote and uterus. Our objective was to evaluate the role of the endometrial expression of leukemia inhibitory factor (LIF) and its glycoprotein 130 (gp130) receptor molecules and their secretion in uterine flushing during the window of implantation in cases of primary unexplained infertility CASE PRESENTATION: The study was conducted on 25 infertile women with unexplained infertility for at least two years and 10 normal fertile women as a control group . Endometrial tissue and uterine flushing were obtained. Each tissue specimen was divided into two pieces; one piece was used for histological dating of the endometrium and for immunostaining of progesterone receptors, and the second was used for RNA extraction and PCR assay of LIF and gp130 mRNA expression. Serum estrogen and progesterone were measured for all subjects. LIF mRNA was expressed in the endometrium of all normal fertile women but significantly decreased in infertile women. LIF was not detectable in 88% of infertile women while it was fairly detectable in 12% of them. Gp130 mRNA was hardly detectable in both fertile and infertile women with no difference between them. Infertile women secreted significantly less LIF and gp130 molecules in the uterine flushing compared with normal fertile women. CONCLUSIONS: Expression of LIF mRNA in endometrium could be used as a molecular marker of unexplained infertility. Assessment of secreted LIF and gp130 molecules in uterine flushing could be another useful and safe method for predicting successful implantation as well as for diagnosing and eventually treating women with impaired fertility using recombinant human LIF. PMID- 22520364 TI - The aviation model of vascular surgery education. PMID- 22520365 TI - Pylephlebitis and acute mesenteric ischemia in a young man with inherited thrombophilia and suspected foodborne illness. AB - We report on a young man who developed complicated pylephlebitis after foodborne illness. Despite antibiotics and resection of the focus of infectious colitis, he developed extensive small bowel infarction. He was treated with anticoagulation, local thrombolytic infusion, and resection of irreversibly ischemic small bowel. Thrombophilia workup demonstrated heterozygosity for factor V Leiden and the prothrombin G20210A mutation. The complications of pylephlebitis can be minimized by using systemic anticoagulation, thrombectomy, and/or local thrombolytic infusion along with antibiotics and surgical management of the infection. Evaluation for thrombophilic states should be considered, particularly if a patient does not respond to initial therapy. PMID- 22520366 TI - Renal oncocytoma growth rates before intervention. AB - OBJECTIVE: To describe the growth rates of oncocytomas before treatment with surgical resection or percutaneous ablation. PATIENTS AND METHODS: This single institution retrospective study included 33 consecutive, pathologically proven renal oncocytomas with serial contrast-enhanced computed tomography scans spanning at least 1 year before intervention, from 2000 to 2009. Tumours were measured by two radiologists, and growth rates and interobserver variability were calculated. The mean (range) pre-procedural imaging surveillance period was 36 (12-124) months (median 33 months). RESULTS: The mean (SD) oncocytoma size was 17 (11) mm (range 4-47 mm, median 15 mm) in maximum transverse diameter on initial imaging and grew to a mean (SD) of 26 (5) mm (range 10-83 mm, median 23 mm) by the time of treatment. Overall, the mean (SD) and median growth rates were 2.9 (2.6) mm/year and 2.7 mm/year, respectively (range -1.2-10.9 mm/year). After weighting by the se of each tumour's growth rate, the mean (SD) change was 2.1 (1.2) mm/year. The mean (range) interobserver variability for each tumour measurement was 1 (0-7) mm with an intraclass correlation coefficient of 0.99. CONCLUSIONS: Renal oncocytomas grow at a rate similar to reported growth rates of renal cell carcinoma. As the observation of growth does not distinguish between benign and malignant renal tumours, growth of small renal masses under active surveillance should be carefully considered before a switch is made to intervention. PMID- 22520367 TI - Why is dracunculiasis eradication taking so long? AB - The long time needed for global eradication of dracunculiasis (Guinea worm disease) was not anticipated at the outset. The successful eradication of smallpox in 10 years compares with the target date set in 1985 for dracunculiasis eradication - 1995. Seventeen years after that date, transmission continues. Why? Various factors are responsible, mainly lack of resources, or resources ineffectively used. The example of Ghana, where the programme stagnated for a decade, sheds light on this delay. When more resources were put into Ghana's programme in 2007, transmission of the disease was interrupted in 3 years. The variable success of dracunculiasis eradication in different countries provides lessons for future disease eradication programmes. PMID- 22520368 TI - Acute mesenteric ischaemia and unexpected death. AB - Acute mesenteric ischaemia is a vascular emergency that arises when blood flow to the intestine is compromised leading to tissue necrosis. It is primarily a condition of the elderly associated with significant morbidity and mortality. Causes include arterial thromboembolism, venous thrombosis and splanchnic vasoconstriction (so-called nonocclusive mesenteric ischaemia). Reperfusion injury and breakdown of the intestinal mucosal barrier lead to metabolic derangements, sepsis and death from multiorgan failure. The diagnosis may be difficult to make clinically and numbers of cases are increasing due to ageing of the population. The clinical and pathological features are reviewed with discussion of predisposing conditions. Careful dissection of the mesenteric vasculature is required at autopsy with appropriate histologic sampling and documentation of associated comorbidities. Other organs need to be checked for thrombi and the possibility of testing for inherited thombophilias should be considered. Toxicological evaluation, particularly in younger individuals, may reveal evidence of cocaine use. On occasion no obstructive lesions will be demonstrated, however the confounding effects of post-mortem autolytic and putrefactive changes may mean that nonocclusive mesenteric ischaemia may be difficult to diagnose. PMID- 22520369 TI - Testamentary capacity: A practical guide to assessment of ability to make a valid will. AB - Medical practitioners are occasionally requested to provide opinions on people's ability to make a valid will. Moreover, if a will is challenged subsequent to the death of the testator, the evidence of a medical practitioner may be pivotal to a decision by the courts on the validity of the will. Litigation can be avoided if a well-founded expert opinion, based on thorough medical assessment, is available. The combination of an aging population, a consequent increase in the prevalence of dementia, an increase in per capita wealth, and more complex family structures with increasing rates of divorce and remarriage, is likely to result in a greatly increased frequency of demands on medical practitioners to provide opinion in this regard. In order for the result of a medical assessment of testamentary capacity to be legally valid, it is imperative that medical practitioners have adequate guidance on what is expected of them in their assessment. As there is no standardised tool for medical practitioners to which to refer, a synthesis of relevant literature is presented to guide medical practitioners in the assessment of testamentary capacity. Medical practitioners' roles in this medico-legal process are elaborated and elucidated. PMID- 22520370 TI - Abusing female children by circumcision is continued in Egypt. AB - Female circumcision is a frank picture of female child abuse that is practised widely in many countries especially in Africa. This procedure is considered a fundamental violation of human rights. The procedure is expected to be declining in Egypt in response to the recent medicolegal litigation in 2007. The aim of this study is to record the prevalence of female circumcision in 2010, in the region of Cairo and Giza, seeking to show if there is difference in the practice after the change in the law and banning of the procedure. A formatted questionnaire for 244 female volunteers was conducted. Statistical analysis revealed that 63.9% of the sample had been victimised by circumcision. The mean age of circumcision was 10.846+/-1.98 years. Circumcision took place at victim's home in 56.5%, private clinics in 38.5% or at hospitals in 5%. The procedure was performed by medical personnel in the majority of cases. The motivation behind the practice was primarily traditional beliefs (64.1%) followed by religious considerations (35.9%). Experienced complications were emotional trauma in 94.9%, haemorrhage in 33.3% and dysuria in 7.7%. Sexual problems were exclusively reported by the victimised subjects in 72.7% of sexually experienced subjects. PMID- 22520371 TI - Osmium impregnation detection of pulmonary intravascular fat in sudden death: A study of 65 cases. AB - Pulmonary fat embolism is widely recognised in forensic pathology. Pulmonary fat embolism requires mobilisation of free fat, entry of free fat into the circulation and lodging of fat globules in fine venous capillaries. This paradigm of fat embolisation has been used to support the evidence of antemortem fat depot disruption when the presence of intravascular fat is confirmed at autopsy. However, sporadic reports of intravascular fat in various medical conditions, which contradict the above mechanism, have opened questions about the alternative pathogenesis. In this study, 65 cases of sudden deaths were examined for the presence of pulmonary intravascular fat (PIF) by osmium impregnation. Cases were selected based on the criteria that were designed to eliminate the possible confounding effect from medical intervention or postmortem changes. Slides were graded based on their ease of search and only the fat droplets confined by the blood vessel or capillary wall were considered as a positive finding. The results show surprisingly high PIF incidences of varying degrees in all the categories of sudden deaths. Further study is needed to devise criteria for diagnosis of fatal fat embolism since the histological appearance of the high-grade PIF in natural sudden death may not be easily distinguishable from the traumatic fat embolism. PMID- 22520372 TI - Study of defence injuries in homicidal deaths - An autopsy study. AB - In order to determine specific patterns and distribution of defence injuries, this study was conducted on 121 homicidal deaths which showed defence injuries in 40 (33%) cases. Of these 40 victims, 72.5% were males and 27.5% were females. Maximum numbers of victims were in the age group of 20-29 years. In 70% of cases, more than one assailant was involved. It was found that in 77.5% cases, sharp weapons were alone used, whereas, in 10% and 12.5% of victims, blunt weapons and multiple (sharp and blunt) weapons, respectively, were used. Fatal wounds were seen most commonly on the head and neck region. In 42.5% of cases, defence injuries were seen on the right side only, whereas in 27.5% of cases both sides were involved. Victim's right forearm and hand were more commonly involved because these are nearest to the perpetrator and consistent with the preponderance of right-handed individuals in the population. PMID- 22520373 TI - Multiplication factor versus regression analysis in stature estimation from hand and foot dimensions. AB - Estimation of stature is an important parameter in identification of human remains in forensic examinations. The present study is aimed to compare the reliability and accuracy of stature estimation and to demonstrate the variability in estimated stature and actual stature using multiplication factor and regression analysis methods. The study is based on a sample of 246 subjects (123 males and 123 females) from North India aged between 17 and 20 years. Four anthropometric measurements; hand length, hand breadth, foot length and foot breadth taken on the left side in each subject were included in the study. Stature was measured using standard anthropometric techniques. Multiplication factors were calculated and linear regression models were derived for estimation of stature from hand and foot dimensions. Derived multiplication factors and regression formula were applied to the hand and foot measurements in the study sample. The estimated stature from the multiplication factors and regression analysis was compared with the actual stature to find the error in estimated stature. The results indicate that the range of error in estimation of stature from regression analysis method is less than that of multiplication factor method thus, confirming that the regression analysis method is better than multiplication factor analysis in stature estimation. PMID- 22520374 TI - Evaluating the functional impairment of assault survivors in a judicial context - A retrospective study. AB - BACKGROUND: The description of traumatic injuries and the outcome on functioning are major items of the evaluation of assault survivors. French law quantifies the seriousness of committed violence through the duration of the victims' inability to fulfil their usual daily activities, in days of 'Total incapacity to work' (TIW). Physicians are provided with a limited number of recommendations. In this study, we searched for determinants of TIW. METHODS: We reviewed 1145 consecutives files of victims evaluated between 10/01/2010 and 11/22/2010. People reporting repeated assaults, or assessed more than 30 days after the facts were excluded. Data collected were: gender, age, TIW, type of traumatic injuries, time to evaluation, patient category, type of assailant, and presence of aggravating factors. Univariate associations with TIW were assessed, while generalised linear models including relevant covariables were proposed. RESULTS: The population (718 men, 427 women, median age 29) included 236 detainees, 74 police officers, and 835 other individuals. Mean duration of TIW was 4.3 days. The time to evaluation was correlated to TIW. Patient category (police officers, detainees, or other individuals), presence of traumatic injuries, and type of assailant were associated with TIW. In patients presenting no evidence of bone fracture, duration of TIW (2.0 days vs. 2.6 and 3.8, p < 0.001) and time to evaluation (10.9 h vs. 21.2 and 58.5, p < 0.001) differed in detainees, police officers, and other individuals. CONCLUSION: We suggest that the outcome of assaults should be evaluated in similar conditions in all victims, including time to evaluation. PMID- 22520375 TI - The value of radius bone in prediction of sex and height in the Iranian population. AB - OBJECTIVE: Measurement of anthropometric parameters of long bones can be applied in sex determination and height prediction. The aim of this study was to investigate the value of length of the radius in forensic identification. MATERIALS AND METHODS: Cross-sectional analysis of anthropometric parameters of the radius was done by Legal Medicine Organization of Tehran, Iran studying fresh cadavers of Iranian population during 2009 and 2010. RESULTS: This study surveyed length of radius of 106 fresh Iranian cadavers, 61 men and 45 women, in the age range of 10-85 years old. The study showed that genders can be distinguished using the length of radius with a sensitivity of 83% and specificity of 96%. Using the regression test, there was significant relation between the height of persons and the length of radius bone. The equations were obtained to estimate the height of the individuals on the basis of radius bone length in different age groups, with an exception in females of 40-64 Years old. CONCLUSION: In the cases of fresh cadavers, by using the length of radius, we could be able to determine the length of height and gender with high confidence. PMID- 22520376 TI - Postmortem burning of the corpses following homicide. AB - Although there have been a great number of studies focussing on antemortem burns or fire-related deaths, the present study is the first dealing exclusively with postmortem burnings aiming to cover up a homicidal action. This study aims to draw attention to postmortem burning following homicide by determining the general characteristics of a series of burned corpses. Thirteen cases of homicide involving postmortem burning were included in the scope of the study. The cases were examined with regard to age, gender, place of death or discovery, autopsy findings, accompanying injuries and manner of death. Eleven of the cases were male and two were female. Victims' ages ranged between 24 and 62 years with a mean age of 43.5 years. All of the victims were discovered in unfamiliar places. Autopsy findings indicated postmortem burning of corpses to cover homicide. Discovering a burned body in an unfamiliar, outdoor or abandoned place, scene or autopsy findings attributable to a violent death, presence of accelerant use and absence of vitality signs are factors indicative of postmortem burning following homicide. PMID- 22520377 TI - Medico-legal considerations in a case of splenic injury that occurred during colonoscopy. AB - Colonoscopy has became the gold standard diagnostic and therapeutic treatment for rectum and colon diseases. The splenic injury is a rare complication of colonoscopy and relatively few cases (less than 70) have been reported in the literature so far. Here we present a case of splenic rupture identified in an 80 year-old man few hours after an apparently uneventful colonoscopy. Acknowledging a causal relationship between the lesion and the diagnostic procedures, we discuss the possible medico-legal implications with regard to professional liability considering the exceptional nature of such an event and the stance recently taken by the Italian law. PMID- 22520378 TI - Homicidal smothering on toilet paper: A case report. AB - Toilet paper is a ubiquitous personal hygiene product that is usually considered harmless. It was reported however to have been used as a mean of self-destruction in two unusual suicides, and is here reported to have been used to commit homicide. The body of a 91-year-old woman suffering from Alzheimer's disease was found in the bedroom of her nursing home, a roll of toilet paper near the body and toilet paper protruding from the mouth. At autopsy, pellets of toilet paper were impacted in the buccal cavity and the laryngopharynx above the epiglottis. The cause of death was established as smothering on toilet paper, whereas the manner of death was ruled as homicidal. Non-lethal blunt head injuries were considered to be a contributive factor, by lowering the victim's resistance. The perpetrator was another elderly woman, also suffering from Alzheimer's disease. PMID- 22520379 TI - Adenomyomatous polyp of the uterus: Report of an autopsy case and review of the literature. AB - Adenomyomatous polyps of the endometrium are a rare subtype of endometrial polyps. In addition to the usual features of endometrial polyps, they also contain a smooth muscle component. Grossly they appear no different than ordinary endometrial polyps. In the case reported herein, a 23-year-old nulliparous female was killed in a traffic accident. In the course of the medicolegal autopsy, a small pedunculated growth was identified in the fundus of the endometrial cavity. Histologically the mass consisted of endometrial glands intimately mixed with smooth muscle and thick walled blood vessels, consistent with an adenomyomatous polyp. There was no history of tamoxifen use in this individual. To our knowledge this is the first report of post-mortem diagnosis of an adenomyomatous polyp. Furthermore, this is the first report of an individual with this diagnosis younger than the fourth decade. In the medicolegal setting, forensic pathologists are constantly faced with entities that, while they may not have caused death, may serve to educate practitioners about rare lesions. This individual's finding serves as one of those entities. This case reiterates the importance of the autopsy as not only the answer to an individual's death, but as an avenue for the discovery of entities that may have relevance to those who are still living. PMID- 22520380 TI - Tobacco toxicity ignored as a cause of death. Why? PMID- 22520381 TI - An alternative model of a forensic autopsy service. PMID- 22520382 TI - Reponse to: L. Love., "My experience of the DFCASA exam including recommendations to potential candidates" [J Forensic Legal Med 2011;19:4]. PMID- 22520383 TI - On 'atypical suicidal' cut throat injuries. PMID- 22520384 TI - Porphyromonas gingivalis and its lipopolysaccharide differentially regulate the expression of cathepsin B in endothelial cells. AB - Porphyromonas gingivalis infection and cathepsins protease upregulation are independently implicated in atherosclerosis worsening. In this study, we evaluated the effects of P. gingivalis infection and P. gingivalis -purified lipopolysaccharide (Pg-LPS) stimulation on the expression of cathepsin B (CATB) in endothelial cells (ECs). Analysis of the enzymatic activity and expression of CATB were investigated at the messenger RNA, protein and protein-phosphorylation levels. Effects of Toll-like receptors 2 and 4 blocking on CATB activity were also analysed. Our results showed that P. gingivalis and Pg-LPS significantly increased the activity of CATB but with different kinetics. The peak of CATB activity was observed 3 h after P. gingivalis infection but it appeared 48 h after Pg-LPS stimulation. The increase of CATB activity was related to its rapid tyrosine-dephosphorylation during P. gingivalis infection, whereas the levels of CATB messenger RNAs and proteins did not vary after P. gingivalis infection or Pg LPS stimulation. Inhibition of Toll-like-receptors 2 and 4 differentially decreased P. gingivalis and Pg-LPS CATB activations. These results showed for the first time that P. gingivalis infection rapidly affects ECs and modulates CATB activity, whereas Pg-LPS effects appear to be delayed. This study suggests that direct infection of ECs by P. gingivalis may worsen atherosclerotic plaque formation via activation of the CATB pathway. PMID- 22520385 TI - Tumor necrosis factor-alpha and interleukin-1beta expression pathway induced by Streptococcus mutans in macrophage cell line RAW 264.7. AB - Streptococcus mutans, a major etiological agent of dental caries, frequently causes systemic disease, such as subacute bacterial endocarditis, if it enters the bloodstream. In this study, the production pathways of the proinflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL 1beta), induced by S. mutans in mouse macrophage were examined using a quantitative real-time polymerase chain reaction and an enzyme-linked immunosorbent assay. The S. mutans stimulated the expression of TNF-alpha and IL 1beta mRNA at a multiplicity of infection of 1 : 100, which increased at 2 and 4 h, respectively, to 24 h. It also induced the production of high levels of the TNF-alpha and IL-1beta proteins, which increased at 2 h and reached a peak at 4 and 24 h, respectively. Nuclear factor-kappaB (NF-kappaB) was activated and reached a maximum level 30 min after the S. mutans treatment. The expression of TNF-alpha and IL-1beta mRNA and protein was suppressed by the treatment with pyrrolidine dithiocarbamate, an NF-kappaB inhibitor. The S. mutans-induced TNF alpha expression was suppressed by the presence of SB203580, a p38 mitogen activated protein (MAP) kinase inhibitor, or SP600125, a Jun N-terminal kinase (JNK) MAP kinase inhibitor. On the other hand, IL-1beta expression was inhibited by extracellular signal-regulated kinase (ERK)/p38/JNK MAP kinase inhibitor pretreatment. In addition, TNF-alpha production was suppressed more in the Toll like receptor 2(-/-) (TLR2(-/-)) macrophages than in the TLR4(-/-) macrophages, whereas IL-1beta production was suppressed more in the TLR4(-/-) macrophages than in the TLR2(-/-) macrophages. These results show that S. mutans stimulates the production of TNF-alpha and IL-1beta in the mouse macrophage cell line, RAW 264.7, by activating ERK/p38/JNK, and NF-kappaB through TLR2 and TLR4, respectively. PMID- 22520386 TI - Streptococcus pyogenes infection of tonsil explants is associated with a human beta-defensin 1 response from control but not recurrent acute tonsillitis patients. AB - Host defence peptides (HDP), including the defensins and hCAP-18, function as part of the innate immune defences, protecting the host epithelia from microbial attachment and invasion. Recurrent acute tonsillitis (RAT), in which patients suffer repeated symptomatic tonsil infections, is linked to Streptococcus pyogenes, a group A streptococcus, and may reflect the impaired expression of such peptides. To address this, the defensin and hCAP-18 messenger RNA expression profiles of 54 tonsils excised from control and RAT patients undergoing tonsillectomy were quantified and compared. Marked variation in expression was observed between individuals from the two groups, but statistically no significant differences were identified, suggesting that at the time of surgery the tonsil epithelial HDP barrier was not compromised in RAT subjects. Surgical removal of the tonsils occurs in a quiescent phase of disease, and so to assess the effects of an active bacterial infection, HaCaT cells an in vitro model of the tonsil epithelium, and explants of patient tonsils maintained in vitro were challenged with S. pyogenes. The HaCaT data supported the reduced expression of hCAP-18/LL-37, human beta-defensin 1 (HBD1;P < 0.01) and HBD2 (P < 0.05), consistent with decreased protection of the epithelial barrier. The tonsil explant data, although not as definitive, showed similar trends apart from HBD1 expression, which in the control tonsils but not the RAT patient tonsils was characterized by increased expression (P < 0.01). These data suggest that in vivo HBD1 may play a critical role in protecting the tonsil epithelia from S. pyogenes. PMID- 22520387 TI - The Pst system of Streptococcus mutans is important for phosphate transport and adhesion to abiotic surfaces. AB - The Pst system is a high-affinity inorganic phosphate transporter found in many bacterial species. Streptococcus mutans, the etiological agent of tooth decay, carries a single copy of the pst operon composed of six cistrons (pstS, pstC1, pstC, pstB, smu.1134 and phoU). Here, we show that deletion of pstS, encoding the phosphate-binding protein, reduces phosphate uptake and impairs cell growth, which can be restored upon enrichment of the medium with high concentrations of inorganic phosphate. The relevance of Pst for growth was also demonstrated in the wild-type strain treated with an anti-PstS antibody. Nevertheless, a reduced ability to bind to saliva-coated surfaces was observed, along with the reduction of extracellular polysaccharide production, although no difference on pH acidification was observed between mutant and wild-type strains. Taken together, the present data indicate that the S. mutans Pst system participates in phosphate uptake, cell growth and expression of virulence-associated traits. PMID- 22520388 TI - Using high throughput sequencing to explore the biodiversity in oral bacterial communities. AB - High throughput sequencing of 16S ribosomal RNA gene amplicons is a cost effective method for characterization of oral bacterial communities. However, before undertaking large-scale studies, it is necessary to understand the technique-associated limitations and intrinsic variability of the oral ecosystem. In this work we evaluated bias in species representation using an in vitro assembled mock community of oral bacteria. We then characterized the bacterial communities in saliva and buccal mucosa of five healthy subjects to investigate the power of high throughput sequencing in revealing their diversity and biogeography patterns. Mock community analysis showed primer and DNA isolation biases and an overestimation of diversity that was reduced after eliminating singleton operational taxonomic units (OTUs). Sequencing of salivary and mucosal communities found a total of 455 OTUs (0.3% dissimilarity) with only 78 of these present in all subjects. We demonstrate that this variability was partly the result of incomplete richness coverage even at great sequencing depths, and so comparing communities by their structure was more effective than comparisons based solely on membership. With respect to oral biogeography, we found inter subject variability in community structure was lower than site differences between salivary and mucosal communities within subjects. These differences were evident at very low sequencing depths and were mostly caused by the abundance of Streptococcus mitis and Gemella haemolysans in mucosa. In summary, we present an experimental and data analysis framework that will facilitate design and interpretation of pyrosequencing-based studies. Despite challenges associated with this technique, we demonstrate its power for evaluation of oral diversity and biogeography patterns. PMID- 22520390 TI - Relationship between plasma homocysteine and the morphological and immunohistochemical study of carotid plaques in patients with carotid stenosis over 70%. AB - BACKGROUND: Several clinical and epidemiological studies describe hyperhomocysteinemia as an independent cardiovascular risk factor. Implication of cellular immunity in atherosclerosis also seems clear. This study aimed to analyze the association among plasma hyperhomocysteinemia, neurological clinical events, and the morphology and immunocytology of carotid plaques in patients with carotid stenosis >70% receiving surgical treatment. METHODS: Sixty-two patients with carotid stenosis >70% receiving surgical treatment were studied; 58% had a history of stroke in the ipsilateral carotid territory. Plasma homocysteine concentrations were determined by considering pathological values >12.4 MUmol/L. Histopathological (stable and unstable plaques) and immunohistochemical (macrophages, T lymphocytes, and active T lymphocytes counts) studies were performed. Hyperhomocysteinemia prevalence was calculated in this population, as were the possible relationships between homocysteine plasma concentrations, and the carotid plaque type and the cell types in it. The relationship between this risk factor and the presence of a neurological event relating to carotid stenosis was also investigated. RESULTS: Hyperhomocysteinemia prevalence was 43.5%, with a mean value of 11.8 MUmol/L (median; range = 2-41.8 MUmol/L). No significant differences were found between homocysteine levels and the plaque's morphological characteristics, or between the cell types analyzed. Elevated concentrations of homocysteine were not significantly higher in patients with a history of stroke. CONCLUSION: The present study confirms high hyperhomocysteinemia prevalence in patients with extracranial cerebrovascular disease, although no relationship between plaque complication phenomena and this cardiovascular risk factor was observed. PMID- 22520389 TI - Role of the Porphyromonas gingivalis extracytoplasmic function sigma factor, SigH. AB - Little is known about the regulatory mechanisms that allow Porphyromonas gingivalis to survive in the oral cavity. Here we characterize the sigma (sigma) factor SigH, one of six extracytoplasmic function (ECF) sigma factors encoded in the P. gingivalis genome. Our results indicate that sigH expression is upregulated by exposure to molecular oxygen, suggesting that sigH plays a role in adaptation of P. gingivalis to oxygen. Furthermore, several genes involved in oxidative stress protection, such as sod, trx, tpx, ftn, feoB2 and the hemin uptake hmu locus, are downregulated in a mutant deficient in SigH designated as V2948. ECF sigma consensus sequences were identified upstream of the transcriptional start sites of these genes, consistent with the SigH-dependent regulation of these genes. Growth of V2948 was inhibited in the presence of 6% oxygen when compared with the wild-type W83 strain, whereas in anaerobic conditions both strains were able to grow. In addition, reduced growth of V2948 was observed in the presence of peroxide and the thiol-oxidizing reagent diamide when compared with the W83 strain. The SigH-deficient strain V2948 also exhibited reduced hemin uptake, consistent with the observed reduced expression of genes involved in hemin uptake. Finally, survival of V2948 was reduced in the presence of host cells compared with the wild-type W83 strain. Collectively, our studies demonstrate that SigH is a positive regulator of gene expression required for survival of the bacterium in the presence of oxygen and oxidative stress, hemin uptake and virulence. PMID- 22520391 TI - A modular branched stent-graft system for sutureless anastomoses in extensive aortic arch replacement--a porcine study. AB - BACKGROUND: We developed a modular branched stent-graft system to test whether it is feasible for sutureless anastomoses in extensive aortic arch replacement. METHODS: Extensive aortic arch replacement was performed using the three-branched stent-graft system in eight pigs. Under deep hypothermic circulatory arrest, sutureless anastomoses were established at the distal aortic arch and the two supra-aortic arteries with the modular branched stent-graft system. External bandings on the distal arches were applied in six pigs (banding group) and not applied in two pigs (control group). No external banding was applied on the two supra-aortic arteries. RESULTS: Successful procedures were achieved in all pigs in the banding group, whereas failures were seen in the control group owing to leakage from the distal arch anastomoses. The anastomosis at each distal aortic arch was completed in 10 minutes in the banding group and in 5 minutes in the control group; the anastomosis of each supra-aortic artery was achieved in 5 minutes. Median durations of the circulatory arrest, aortic cross-clamping, and cardiopulmonary bypass were 30, 67, and 174 minutes, respectively. The postoperative computed tomography revealed adequate alignment of the stents and appropriate size matching between stent-graft and native aorta. Histological examinations revealed no pressure necrosis at the sutureless anastomotic sites. CONCLUSIONS: This study confirmed the technical feasibility of sutureless anastomoses with the modular branched stent-graft system in porcine extensive aortic arch replacement. An external banding is essential for the secure hemostasis of the distal arch anastomosis, but it is not required for the supra aortic arteries. PMID- 22520392 TI - Hyperspectral image measurements of skin hemoglobin compared with transcutaneous PO2 measurements. AB - BACKGROUND: Objective measurements of skin blood flow would have predictive value in assessing the potential for wound healing. In this study, we evaluated the relationship between transcutaneous PO(2) (tcPO(2)) measurements and hyperspectral reflectance spectroscopy measurements of oxygenated hemoglobin (OxyHgb), deoxygenated hemoglobin (DeOxyHgb), total hemoglobin (Sum = OxyHgb + DeOxyHgb), and hemoglobin saturation (Sat = 100 * OxyHgb/Sum). The effect of varying tcPO(2) probe temperatures (37 degrees C, 41 degrees C, and 45 degrees C) was also assessed. METHODS: A Hypermed Oxy-Vu system was used for hyperspectral imaging, with measurements performed 2 minutes after removing tcPO(2) probes (Radiometer). Twenty-three sections of foot or wrist skin in four healthy volunteers were measured at 37 degrees C, 41 degrees C, and 45 degrees C using both modalities. RESULTS: TcPO(2) at 37 degrees C was 23.1 +/- 24.8 mm Hg, increasing to 63.0 +/- 27.3 mm Hg at 45 degrees C. OxyHgb levels increased from 52.4 +/- 25.4 at 37 degrees C to 101.3 +/- 23.8 at 45 degrees C. Linear regression analysis of the HSI data at 37 degrees C showed a positive correlation between tcPO(2) and OxyHgb (r(2) = 0.35, P = 0.003), tcPO(2) and DeOxyHgb (r(2) = 0.63, P < 0.0001), and tcPO(2) and Sum (r(2) = 0.60, P < 0.0001), but not Sat (r(2) = 0.001, P = 0.92). As the probe temperature increased, the correlations of tcPO(2) with OxyHgb, DeoxyHgb, and Sum became progressively much weaker. CONCLUSION: A marked increase in the HSI measurements of OxyHgb in skin exposed to heated tcPO(2) probes was observed, with tcPO(2), Sat, and Sum measurements also observed to increase with temperature. These measurements were influenced by heat inducing vasodilatation in the superficial skin layers. HSI measurements may be clinically useful for measuring wound healing potential, as they correlate with tcPO(2) levels under normal physiological conditions. PMID- 22520393 TI - Lysophosphatidic acid pretreatment prevents micromolar atorvastatin-induced endothelial cell death and ensures the beneficial effects of high-concentration statin therapy on endothelial gene expression. AB - Because of the pleiotropic effects of statins, it may potentially be used as a locoregional adjuvant in vascular revascularization, tissue engineering, and regenerative procedures. Electron probe X-ray microanalyses and oligonucleotide microarrays were used to identify the global effects of micromolar concentrations of atorvastatin on the gene expression and cell viability of endothelial cells in different states of lysophosphatidic acid (LPA)-induced activation. Treatment with 1-MUM atorvastatin for 24 hours significantly reduced the viability of human vascular endothelial cells (HUVECs). However, the same treatment of LPA preactivated HUVECs produced elevated cell viability levels and an optimal vascular gene expression profile, including endothelial nitric oxide synthase overexpression, endothelin-1 repression, an anti-inflammatory genetic pattern, and upregulation of molecules involved in maintaining the endothelial barrier (vascular endothelial cadherin, claudin 5, tight junction protein 1, integrin beta4). The atorvastatin treatment also produced a repression of microRNA 21 and genes involved in cell proliferation and neointimal formation (vascular endothelial growth factor [VEGF] A, VEGF receptor 1, VEGFC). Results obtained suggest that micromolar atorvastatin therapy can enhance global endothelial function, but its effects on cell viability vary according to the baseline state of cell activation (preactivated, postactivated, or not activated). Preactivation with LPA protects HUVECs against atorvastatin-induced apoptosis and delivers optimal levels of cell viability and functionality. PMID- 22520394 TI - Protective effect of antithrombin III against lung and myocardial injury in lower limb ischemia-reperfusion syndrome. AB - BACKGROUND: Restoration of blood flow to an acutely ischemic limb can trigger systemic inflammation. We investigated whether antithrombin III (AT-III) exerts a protective action against remote lung and myocardial injury in an experimental animal model of lower-limb ischemia-reperfusion. METHODS: Ischemia was induced by lower-limb arterial occlusion for 6 hours in 60 male Wistar rats. Animals were divided into those receiving AT-III (dose, 250 mg/kg) 30 minutes before the reperfusion (group A, n = 30) and those receiving placebo (group B, n = 30). Animals were then sacrificed, and lung and myocardial tissue samples were taken at baseline, 30 minutes, and 4 hours after reperfusion. Levels of malondialdehyde (MDA), a compound used as indirect index of oxygen free radicals, were estimated in lung and myocardium, and the two groups were compared at different time points using the independent sample t test. RESULTS: Animals administered AT-III had significantly lower levels of lung MDA compared with the placebo group at baseline and at 30 minutes, but not at 4 hours (P = 0.001, P = 0.01, and P = 0.9, respectively), indicating a protective action of AT-III against remote lung injury early in the reperfusion phase. With regard to myocardial MDA levels, no statistically significant differences existed between the AT-III and placebo groups at baseline, at 30 minutes, and at 4 hours (P = 0.07, P = 0.07, and P = 0.2, respectively) after reperfusion. CONCLUSIONS: In this experimental animal model, AT-III appears to exert a protective effect against remote ischemia reperfusion injury in the lung tissue, but not in the myocardium. PMID- 22520395 TI - Hybrid repair of a hepatic artery aneurysm. AB - Visceral arterial aneurysm is a rare pathology. Currently, there are no sufficient data to support the superiority of surgical or endovascular treatment. The choice depends mainly on patient characteristics and the anatomy of the aneurysm. We present a case of a 12-cm fusiform aneurysm of the common hepatic artery. A combined approach including endovascular exclusion of the celiac trunk and surgical closure of the aneurysm was chosen. The postoperative course was uneventful. To our knowledge, this is the first case in the literature describing this combined approach. PMID- 22520396 TI - Deformations, mechanical strains and stresses across the different hierarchical scales in weight-bearing soft tissues. AB - Sustained internal tissue loads (deformations, mechanical strains and stresses) which develop during immobile weight-bearing postures such as while in bed or in a chair were identified as a fundamental cause for the onset and progression of pressure ulcers (PUs), particularly of the deep tissue injury (DTI) type. The sustained loading may compromise tissue viability either directly, by geometrically distorting cells, or indirectly, by distorting the vasculature or lymphatic networks or, at the micro-scale, by distorting cellular organelles involved in regulating transport, e.g. the plasma membrane, since transport control-mechanisms are essential for adequate biological function of cells. In this article we provide a comprehensive, rigorous review of the up-to-date published computational-modeling-work as well as relevant experimental studies concerning tissue deformations, strains and stresses across the different hierarchical scales: tissue-scale [cm], meso-scale [mm] and cell-scale [MUm]. Viability of tissues exposed to sustained loading should be investigated in all dimensional scales, from the macro to micro, in order to provide complete understanding of the etiology of PUs and DTIs and in particular, for identifying individuals for whom and conditions at which the susceptibility to these injuries might be greater. Emerging relevant bioengineering methods of computer simulation such as multiscale and multiphysics modeling will undoubtedly contribute to the aetiological research in this field in the near future. PMID- 22520397 TI - Vascular calcification: the price to pay for anticoagulation therapy with vitamin K-antagonists. AB - Vitamin K-antagonists (VKA) are the most widely used anti-thrombotic drugs with substantial efficacy in reducing risk of arterial and venous thrombosis. Several lines of evidence indicate, however, that VKA inhibit not only post-translational activation of vitamin K-dependent coagulation factors but also synthesis of functional extra-hepatic vitamin K-dependent proteins thereby eliciting undesired side-effects. Vascular calcification is one of the recently revealed side-effects of VKA. Vascular calcification is an actively regulated process involving vascular cells and a number of vitamin K-dependent proteins. Mechanistic understanding of vascular calcification is essential to improve VKA-based treatments of both thrombotic disorders and atherosclerosis. This review addresses vitamin K-cycle and vitamin K-dependent processes of vascular calcification that are affected by VKA. We conclude that there is a growing need for better understanding of the effects of anticoagulants on vascular calcification and atherosclerosis. PMID- 22520398 TI - Cerebral haemodynamics, cognition and brain volumes in patients with type 2 diabetes. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with cognitive impairment and brain abnormalities on MRI. The underlying mechanisms are unclear. We examined the relationship between cerebral haemodynamics (cerebral blood flow (CBF) and cerebrovascular reactivity (CVR)) and cognitive performance and brain volumes in patients with T2DM, at baseline and after four years. METHODS: 114 patients with T2DM, aged 56-80 years, underwent a detailed cognitive assessment and MRI scan. In 68 patients the evaluation was repeated after four years. CBF (two-dimensional flow-encoded phase-contrast MRI) and CVR (carbogen breathing response middle cerebral artery; transcranial Doppler) were measured at baseline. Cognitive performance was expressed as composite z-score and regression based index score. Brain volumes were measured on MRI by automated segmentation. The relationship of haemodynamics with cognition and brain volumes was examined with linear regression analyses adjusted for age, sex and IQ. RESULTS: Mean CVR was 51.8% +/- 18.0% and mean rCBF 53.3 +/- 11.3 ml/min/100 ml brain tissue. CBF was associated with baseline cognitive performance (standardized regression coefficient beta (95% CI): 0.17 (0.00; 0.32) and total brain volume (0.23 (0.05; 0.41)). No correlation was found between CVR and baseline cognitive performance. Neither CBF nor CVR predicted change in cognition (CBF 0.11 (-0.21; 0.44); CVR 0.07 (-0.21; 0.36)) or total brain volume (CBF 0.09 (-0.22; 0.39); CVR 0.13 ( 0.13; 0.40)) over four years. CONCLUSIONS: CBF was associated with impaired cognition and total brain volume in cross-sectional analyses, but did not predict changes in cognition or brain volumes over time. Apparently, alterations in cerebral haemodynamics play no major etiological role in cognitive decline or change in brain volumes in non-demented individuals with T2DM. PMID- 22520399 TI - Scanning laser edema index: a reliable tool to correlate with diabetic retinopathy and systemic risk factors? AB - To correlate Heidelberg Retina Tomograph (HRT) derived macular edema (DME) index with severity of diabetic retinopathy and systemic factors. A total of 300 diabetic patients were recruited for the study for each of them a value for the macular edema index was obtained using the HRT II. Patients' age, gender, duration and type of diabetes mellitus, latest HbA1c result and presence or absence of co-morbid factors (hypertension, ischemic heart disease, nephropathy) were recorded together with the stage of diabetic retinopathy. These were correlated with DME. Out of 300 patients, HRT defined macula edema was seen in 68 patients (22.6%). There is a wider and higher range (95% percentile) of macula edema index in the severe non proliferative diabetic retinopathy (NPDR) group. Independent samples t test showed significant difference between the severe NPDR group and no DR group (p<0.001), mild NPDR group (p<0.05) and moderate NPDR group (p<0.05). A higher macula edema index was also found to have a low degree of correlation with more advanced stages of retinopathy (r=0.310; p<0.001). Also nephropathy showed a strong and significant correlation with DME. Hypertension had moderately significant correlation with DME. This study found no correlation between ischemic heart disease and DME. HRT derived scanning laser edema index is a reliable objective tool to evaluate diabetic retinopathy and systemic risk factors. PMID- 22520400 TI - Human C-reactive protein accentuates macrophage activity in biobreeding diabetic rats. AB - OBJECTIVE: Type 1 diabetes (T1DM) is a pro-inflammatory state characterized by high C-reactive protein (CRP) levels. However, there is a paucity of data examining the role of CRP in promoting the pro-inflammatory state of diabetes. Thus, we examined the pro-inflammatory effects of human CRP using spontaneously diabetic bio-breeding (BB) rats. METHODS: Diabetic rats (n=9/group) were injected with Human serum albumin (huSA) or Human CRP (hCRP, 20 mg/kg body weight; i.p.) for 3 consecutive days. Blood and peritoneal macrophages (MO) were obtained following euthanasia. Peritoneal macrophages were used for measuring superoxide anion release, NF-kappaB DNA binding activity, proinflammatory mediator secretion. RESULTS: hCRP administration resulted in significantly increased superoxide anion production, along with increased release of cytokines/chemokines, and plasminogen activator inhibitor (PAI-1) and Tissue Factor (TF) activity in diabetic rats compared to huSA. hCRP-treated BB rat MO showed significant induction of protein kinase C (PKC)-alpha, PKC-delta and p47 phox expression and NF-kappaB compared to huSA. CONCLUSIONS: Thus, our data suggest that human CRP exacerbates in-vivo the pro-inflammatory, pro-oxidant and procoagulant states of diabetes predominantly via increased macrophage activity and this could have implications with respect to vascular complications and anti inflammatory therapies. PMID- 22520401 TI - Aerobic physical training restores biomechanical properties of Achilles tendon in rats chemically induced to diabetes mellitus. AB - The aim of this study is to evaluate if the application of a moderate aerobic exercise protocol reverses the damage caused by diabetes on the mechanical properties of the Achilles tendon. METHODS: Forty-four rats were divided randomly into four groups as follows: Sedentary Control Group-SCG, Sedentary Diabetic Group-SDG, Trained Control Group-TCG and Trained Diabetic Group-TDG, the trained groups were submitted to a protocol of moderate physical training on a continuous treadmill. For mechanical testing the tendons were fixed in a conventional mechanical testing machine and pulled to the point of failure of the specimen, the cell load of 500N. The parameters were: Elastic Modulus (MPa), Stress Maximum Strength (MPa), Strain Specific Maximum Force (mm), Energy / Tendon Area (N.mm/mm(2)) and Cross-sectional Area (mm(2)). RESULTS: The evaluation of the biomechanical properties of the Achilles tendon of the SDG indicated that the elastic modulus (MPa) is decreased when compared to the TDG and the other groups (p<0.01). However, the specific deformation (%), the deformation at maximum force (mm), and energy / tendon area (N.mm/mm(2)) of the SDG were significantly higher than in the other groups (p<0.01). Moreover, moderate aerobic training on a treadmill caused the biomechanical property values to move closer to the values shown by the control groups (p>0.01). CONCLUSION: In summary, our study indicates that moderate-intensity aerobic training restored the normal mechanical properties of tendons in diabetic animals, since the elastic modulus (MPa), the specific deformation (%), the deformation of the maximum force (mm) and energy / tendon area (N.mm/mm(2)) approached the values shown by the control groups. PMID- 22520402 TI - Retrospective comparative analysis of metabolic control and early complications in familial and sporadic type 1 diabetes patients. AB - BACKGROUND: Genetic susceptibility and lifestyle are associated with glycemic control and diabetic complications in type 1 diabetes (T1D). OBJECTIVES: To investigate metabolic control and occurrence of acute and microvascular complications among familial and sporadic T1D patients. PATIENTS AND METHODS: Retrieved from our institutional registry of new T1D cases for the years 1979 2008 were 226 familial patients belonging to 121 families (58 parent-offspring, 63 sib-pairs) and 226 sporadic cases matched for age, gender, and year of diagnosis. Extracted from medical files were clinical course and therapeutic regimen. RESULTS: Mean age at diagnosis of diabetes of the cohort was 10.8 +/- 5.7 years. Throughout follow-up (11.1 +/- 8.7 years) mean HbA1c values were significantly higher in familial than in sporadic cases (8.18%+/- 1.15% vs. 7.85%+/- 1.15%, p=0.005). Diabetic ketoacidosis (DKA) rates were higher in familial than sporadic cases (2.8 vs. 1.9 events per 100 patient-years; incidence rate ratio (IRR)=1.5, 95% CI [1.03, 2.22, p=0.03]). Severe hypoglycemia events per 100 patient-years were comparable in familial and sporadic groups (3.7 vs. 4.0 events); sib-pairs had higher rates than parent-offspring (4.8 vs. 2.4 events; (IRR)=2, 95% CI [1.03, 3.25, p=0.03]). The percentage of patients with microvascular complications was similar in the familial (21.7%) and sporadic (26.7%) groups. In both familial and sporadic cases the most significant predictor for metabolic control and microvascular complications was diabetes duration; a higher mean HbA1c level was the predictor for DKA events. CONCLUSIONS: The worse metabolic control and increased rate of DKA in familial T1D patients as compared to those in the sporadic T1D patients warrant intensified surveillance in this population. PMID- 22520404 TI - How reliable are cultures of specimens from superficial swabs compared with those of deep tissue in patients with diabetic foot ulcers? AB - PURPOSE: To assess the reliability of cultures of superficial swabs (SS) by comparing them with cultures of concomitantly obtained deep tissue (DT) specimens in patients with diabetic foot ulcers. METHODS: We reviewed clinical and microbiological data from patients with diabetes who presented during a two-year period to our hyperbaric medicine center with a foot ulcer. We identified patients who had at least one concomitantly collected SS and DT pair of specimens sent for culture. RESULTS: A total of 89 culture pairs were available from 54 eligible patients, 33 (61.1%) of whom were hospitalized. Wounds were infected in 47 (87.0%) of the patients and 28 (51.9%) patients had received antibiotic therapy within the previous month. Overall, 65 (73%) of the SS and DT pairs had identical culture results, but in 11 (16.9%) cases the cultures were sterile; thus, only 54 (69.2%) of the 78 culture-positive pairs had identical results. Compared with DT, SS cultures yielded >=1 extra organism in 10 (11.2%) cases, missed at least one organism in 8 (9.0%), and were completely different in 6 (6.7%). When compared to DT culture results, SS cultures had a positive predictive value of 84.4%, negative predictive value of 44.0%, and overall accuracy of 73.0%. CONCLUSIONS: In patients with diabetic foot ulcers, results of specimens for culture taken by SS did not correlate well with those obtained by DT. This suggests that SS specimens may be less reliable for guiding antimicrobial therapy than DT specimens. PMID- 22520403 TI - Factors associated with poor glycemic control in older Mexican American diabetics aged 75 years and older. AB - OBJECTIVE: This study examines the prevalence and correlates of poor glycemic control in Mexican Americans aged 75 years and older with diabetes. METHODS: Data are from the 5(th) wave (2004-05) of the Hispanic Established Population for the Epidemiological Study of the Elderly (H-EPESE). A total of 2,069 Mexican Americans aged 75 and over were interviewed. Six hundred eighty nine subjects (33.5%) reported having been diagnosed with diabetes and 209 (30.3%) subjects agreed to a blood test of their HbA(1)c level. RESULTS: Of the 209 diabetic subjects with an HbA(1)c test, 73 (34.9%) had good glycemic control (HbA(1)c <7%) and 136 (65.1%) had poor glycemic control (HbA(1)c >7%). Bivariate analysis revealed that subjects with poor control had longer disease duration, had lower education, used the glucometer more frequently, and had more diabetes complications when compared to those in the good glycemic control group. Multivariable logistic regression analysis found the following factors associated with poor glycemic control: <8 years of education, foreign-born, smoking, obesity, longer disease duration, daily glucometer use, and having macro complications. DISCUSSION: Prevalence of poor glycemic control is very high in this population with very high and rising prevalence of diabetes. Further studies are needed to explore the effect of these and other characteristics on glycemic control among older Mexican Americans and to develop appropriate interventions to improve diabetes outcomes and increase life-expectancy. PMID- 22520405 TI - Extra-osseous Ewing sarcoma of the thyroid gland mimicking lymphoma recurrence: a case report. AB - Extra-osseous Ewing sarcomas/peripheral primitive neuroectodermal tumors (EOES/pPNETs) are high-grade malignant tumors found in various organs, such as the lung, skin, intestine, kidney and female genital tract; however, to the best of our knowledge, only two cases have previously been identified in the thyroid gland. We describe a case of primary EOES/PNET of the thyroid gland in a 66-year old man with a previous history of large B cell lymphoma. During a routine follow up examination, the patient underwent an ultrasound cervical scan showing a solid nodule of the left thyroid lobe. The fine-needle aspiration biopsy of the nodule suggested a neuroendocrine tumor. Histological and immunohistochemical examination of the surgical specimen supported a diagnosis of EOES/PNET, which was further confirmed by the demonstration of EWSR1 gene translocation by means of fluorescent in situ hybridization and by the detection of glycogen particles and neurosecretory granules by means of electron microscopy. Total body computed tomography and magnetic resonance imaging excluded the involvement of other sites, and therefore a diagnosis of primary EOES/PNET of the thyroid gland was made.This paper also discusses the main differential diagnoses, including lymphoma recurrence, other small round cell tumors (primary or metastatic), and a thyroid localization of an EWS/PNET from another organ. PMID- 22520406 TI - Unilateral gynecomastia and pseudoangiomatous stromal hyperplasia in neurofibromatosis: case report and review of the literature. AB - In this article, we describe unilateral gynecomastia and pseudoangiomatous stromal hyperplasia (PASH) in a case of type-1 neurofibromatosis (NF-1). It is important to distinguish PASH from fibroadenoma clinically, and from true blood capillaries and angiosarcoma histologically. In the present case, giant multinucleated cells lined the pseudovascular spaces, which was markedly different from that of conventional breast PASH. The origin of PASH has been reported to be either the fibroblast or the myofibroblast phenotype and may be affected by endocrine signaling because many cases have been reported in premenopausal women, and cases are often estrogen (ER) and progesterone receptor (PR) positive. However, previous reports have identified PASH in NF-1 in juvenile males only, and the cases were negative for alpha-SMA, ER and PR. The cause and prognosis of PASH in NF-1 may be distinguished from that of conventional PASH, and mast cells, histiocytes and CD54 may play roles. PMID- 22520414 TI - Influence of in situ TiB reinforcements and role of heat treatment on mechanical properties and biocompatibility of beta Ti-alloys. AB - The effect of heat treatment on the mechanical properties of Ti-35Nb-5.7Ta-7.2Zr (TNZT) and Ti-35Nb-5.7Ta-7.2Zr-0.5B (TNZTB) alloys has been investigated. In the case of TNZT alloy, the presence of omega phase in the matrix has a greater effect on strength and hardness than the presence of secondary alpha precipitates. The TNZTB alloy shows higher hardness and tensile strength than the TNZT alloy due to the formation of hard TiB precipitates in the matrix of the former. However, the boron free alloy offers higher ductility than the boron containing alloy. Presence of TiB precipitates in the matrix increases the strength of the TNZTB alloy when omega precipitates are present in the matrix. However, the boride precipitates have no substantial influence on the strength of the TNZTB alloy when omega phase in the matrix is replaced by the alpha phase. The elastic modulus of the TNZT samples shows a very small variation with different heat treatment conditions. The TNZT alloy samples containing beta and omega phases show higher elastic modulus than the samples containing beta and alpha phases. The elastic modulus of the TNZTB alloy is higher than that of the TNZT alloy due to the formation of high modulus TiB particles in the matrix. Both the alloys show better cell adhesion and spreading than the control material (polystyrene). However, the boron free Ti-alloy shows better cell attachment than the boron containing Ti-alloy. PMID- 22520415 TI - Wear performance of dental ceramics after grinding and polishing treatments. AB - AIM: The aim of this in vitro study was to determine the two-body wear resistance of different dental ceramics after grinding and polishing treatments. MATERIAL AND METHODS: Standardized specimens were prepared from three zirconia and two veneering ceramics and were subjected to different surface treatments. Zirconia ceramics were polished, ground and repolished, veneering ceramics were ground and repolished. One zirconia ceramic was investigated with a superficial glaze. Human enamel was used for reference. Surface roughness R(a) was determined using a profilometric contact surface measurement device. Two-body wear tests were performed in a chewing simulator with steatite and enamel antagonists, respectively. Specimens were loaded pneumatically in a pin-on-block design for 1.2x10(5) mastication cycles (50 N, 1.2 Hz, lateral movement: 1 mm, mouth opening: 2 mm) under simultaneous thermal cycling (600 cycles, 5/55 degrees C). Wear depths of specimens were determined using a 3D laser scanning device, wear areas of steatite antagonists were measured by means of light-optical micrographs. Means and standard deviations were calculated, and statistical analysis was performed using one-way analysis of variance (ANOVA) and the Bonferroni multiple comparison test for post hoc analysis (alpha=0.05). Scanning electron microscopy was applied for evaluating the wear performance of ceramics and antagonists. RESULTS: No wear was found for polished, ground and repolished zirconia. Compared to the wear depths of the enamel reference with 274.1+/-187.4 MUm versus steatite and 123.3+/-131.0 MUm versus enamel, relative wear depths of porcelains ranged between 0.54+/-0.07 and 0.62+/-0.09 with steatite antagonists and between 0.66+/-0.26 and 1.04+/-0.27 with enamel antagonists. Relative wear areas of steatite antagonists (enamel reference: 1.25 mm(2)) varied between 0.84+/-0.13 and 1.90+/-0.29 for zirconia and between 1.97+/-0.38 and 2.47+/-0.40 for porcelains. Enamel antagonists generally showed wear, cracks or even fractures, but revealed smooth surfaces when opposed to polished/ground/repolished zirconia and ploughed surfaces when opposed to ground/repolished porcelains or glaze. CONCLUSIONS: Zirconia ceramics yielded superior wear behavior and lower antagonistic wear compared to porcelains. A trend to higher ceramic and antagonistic wear was shown after grinding treatments. PMID- 22520416 TI - Mechanical characterization of brain tissue in compression at dynamic strain rates. AB - Traumatic brain injury (TBI) occurs when local mechanical load exceeds certain tolerance levels for brain tissue. Extensive research has been done previously for brain matter experiencing compression at quasistatic loading; however, limited data is available to model TBI under dynamic impact conditions. In this research, an experimental setup was developed to perform unconfined compression tests and stress relaxation tests at strain rates <=90/s. The brain tissue showed a stiffer response with increasing strain rates, showing that hyperelastic models are not adequate. Specifically, the compressive nominal stress at 30% strain was 8.83 +/- 1.94, 12.8 +/- 3.10 and 16.0 +/- 1.41 kPa (mean +/- SD) at strain rates of 30, 60 and 90/s, respectively. Relaxation tests were also conducted at 10%-50% strain with the average rise time of 10 ms, which can be used to derive time dependent parameters. Numerical simulations were performed using one-term Ogden model with initial shear modulus MU(o)=6.06+/-1.44, 9.44 +/- 2.427 and 12.64 +/- 1.227 kPa (mean +/- SD) at strain rates of 30, 60 and 90/s, respectively. A separate set of bonded and lubricated tests were also performed under the same test conditions to estimate the friction coefficient MU, by adopting combined experimental-computational approach. The values of MU were 0.1 +/- 0.03 and 0.15 +/- 0.07 (mean +/- SD) at 30 and 90/s strain rates, respectively, indicating that pure slip conditions cannot be achieved in unconfined compression tests even under fully lubricated test conditions. The material parameters obtained in this study will help to develop biofidelic human brain finite element models, which can subsequently be used to predict brain injuries under impact conditions. PMID- 22520417 TI - Failure and behavior in water of hydroxyapatite whisker-reinforced bis-GMA-based resin composites. AB - Failure mode under Hertzian indentation and the behavior on immersion in water of bis-GMA-based composites with HA whiskers or nanoscopic HA powder as filler were evaluated. Failure load decreased with increase in filler loading, but the decrease was smaller for whiskers, which showed a different failure mode both macroscopically and microscopically. Particle-filled composites failed mainly by radial cracking and cone cracking, with some plastic deformation at low filler loading, with fracture into irregular segments. For whisker-filled materials, crack propagation was inhibited by the well-dispersed whiskers by the usual toughening mechanisms; cone cracking was the dominant failure mode, at higher loads than for the powder, and fracture was incomplete. The filler reduced both water-uptake and elution of soluble materials, as expected, but both were lower for the whisker-filled material. Such composites might form the basis of viable materials for dental load-bearing restorations and other applications. PMID- 22520418 TI - Tri-layered vascular grafts composed of polycaprolactone, elastin, collagen, and silk: Optimization of graft properties. AB - The purpose of this study was to create seamless, acellular, small diameter bioresorbable arterial grafts that attempt to mimic the extracellular matrix and mechanical properties of native artery using synthetic and natural polymers. Silk fibroin, collagen, elastin, and polycaprolactone (PCL) were electrospun to create a tri-layered structure for evaluation. Dynamic compliance testing of the electrospun grafts ranged from 0.4-2.5%/100 mmHg, where saphenous vein (1.5%/100 mmHg) falls within this range. Increasing PCL content caused a gradual decrease in medial layer compliance, while changes in PCL, elastin, and silk content in the adventitial layer had varying affects. Mathematical modeling was used to further characterize these results. Burst strength results ranged from 1614-3500 mmHg, where some exceeded the capacity of the pressure regulator. Four week degradation studies demonstrated no significant changes in compliance or burst strength, indicating that these grafts could withstand the initial physiological conditions without risk of degradation. Overall, we were able to manufacture a multi-layered graft that architecturally mimics the native vascular wall and mechanically matches the gold standard of vessel replacement, saphenous vein. PMID- 22520419 TI - Investigating the morphological, mechanical and degradation properties of scaffolds comprising collagen, gelatin and elastin for use in soft tissue engineering. AB - Collagen-based scaffolds can be used to mimic the extracellular matrix (ECM) of soft tissues and provide support during tissue regeneration. To better match the native ECM composition and mechanical properties as well as tailor the degradation resistance and available cell binding motifs, other proteins or different collagen types may be added. The present study has explored the use of components such as gelatin or elastin and investigated their effect on the bulk physical properties of the resulting scaffolds compared to those made from pure collagen type I. The effect of altering the composition and crosslinking was evaluated in terms of the scaffold structure, mechanical properties, swelling, degradation and cell attachment. Results demonstrate that scaffolds based on gelatin had reduced tensile stiffness and degradation time compared with collagen. The addition of elastin reduced the overall strength and stiffness of the scaffolds, with electron microscopy results suggesting that insoluble elastin interacts best with collagen and soluble elastin interacts best with gelatin. Carbodiimide crosslinking was essential for structural stability, strength and degradation resistance for scaffolds of all compositions. In addition, preliminary cell adhesion studies showed these highly porous structures (pore size 130-160 MUm) to be able to support HT1080 cell infiltration and growth. Therefore, this study suggests that the use of gelatin in place of collagen, with additions of elastin, can tailor the physical properties of scaffolds and could be a design strategy for reducing the overall material costs. PMID- 22520420 TI - Mechano-rheological properties of the murine thrombus determined via nanoindentation and finite element modeling. AB - Deep vein thrombosis, pulmonary embolism, and abdominal aortic aneurysms are blood-related diseases that represent a major public health problem. These diseases are characterized by the formation of a thrombus (i.e., blood clot) that either blocks a major artery or causes an aortic rupture. Identifying the mechanical properties of thrombi can help determine when these incidents will occur. In this investigation, a murine thrombus, formed from platelet-rich plasma, calcium, and thrombin, was nanoindented and the elastic modulus was estimated via elastic contact theory. This information was used as input to an inverse finite element simulation, which determined optimal values for the elastic modulus and viscosity of the thrombus using a viscoelastic material model. A sensitivity analysis was also performed to determine which material parameters have the greatest affect on the simulation. Results from this investigation demonstrate the feasibility of the mechanical characterization of a murine thrombus using nanoindentation. PMID- 22520421 TI - Dynamic mechanical properties of dental nanofilled light-cured resin composites: Effect of food-simulating liquids. AB - This work is aimed at the study by dynamic mechanical analysis (DMA) of viscoelastic properties that is, the elastic modulus (E'), the loss modulus (E"), the loss tangent (tandelta) and the glass transition temperature (T(g)), of two current commercial light-cured resin composites, Filtek Supreme Body and Filtek Supreme Translucent, characterized as nanofilled. These composites show differences in the filler content and type. For DMA analysis the bar-shaped specimens were divided into groups of three samples each. The first group consisted of dry samples measured 1 h after light-curing (at room temperature) during which they were placed in a desiccator at 37 degrees C. The other groups consisted of samples which had been stored in air, distilled water, artificial saliva SAGF or ethanol/water solution (75 v/v), at 37+/-1 degrees C for 1, 7, 30 or 90 days. DMA tests were performed on a Diamond Dynamic Mechanical Analyzer (Perkin-Elmer) in bending mode. A frequency of 1 Hz was applied and a temperature range of 25-185 degrees C, while a heating rate of 2 degrees C/min were selected to cover mouth temperature and the materials' likely T(g). The studied dry composites showed comparable values for their properties in spite of their differences in the filler content and type. Storage of composites in air 37 degrees C for 1 day caused a significant post curing which was not continued during storage up to 90 days. Water and artificial saliva showed the same effect on composites. They caused both post curing and plasticization. Ethanol/water solution 75% v/v had a more strong effect than water and artificial saliva due to its organophilic nature. It caused post curing, plasticization and most probably degradation of the bond filler-silane coupling agent. PMID- 22520422 TI - Tribological behavior study on Ti-Nb-Sn/hydroxyapatite composites in simulated body fluid solution. AB - In this study, Ti-35Nb-2.5Sn/xhydroxyapatite (HA) composites were sintered by pulse current activated sintering (PCAS) from powders milled for different time. These sintered composites were expected to be potential biomaterials. Ca(3)(PO(4))(2) phase which could increase hardness of sintered composites was found in the Ti-35Nb-2.5Sn/15HA composite sintered from 12 h milled powders. The sintered composites had low elastic modulus (18~26 GPa) and high compression strength. Due to the importance of friction and wear in biomaterials application, the tribological behavior of sintered composites was studied in simulated body fluid (SBF) solution. Results revealed that milling time and HA content of powders could affect wear properties of sintered composites. The major wear mechanism was abrasive wear in the wear test. The wear rate and friction coefficient decreased when milling time and HA content of powders increased. The lowest friction coefficient (0.1223) was obtained in the Ti-35Nb-2.5Sn/15HA composite sintered from 12 h milled powders, and this composite had superior wear resistance. PMID- 22520423 TI - Computational load estimation of the femur. AB - The density distribution and, thus, mechanical properties of long bones such as the femur are dependent on their loading. Many bone tissue adaptation theories are proposed to describe the density distribution that results from a given set of loading parameters. It is relatively easy to measure the density distribution of long bones, for example, using Computed Tomography (CT). However, there is no easy non-invasive method for in-vivo measurement of musculoskeletal loads. It is therefore interesting to investigate whether or not it is possible to predict the musculoskeletal loads that have resulted in a certain measured density distribution using bone tissue adaptation models. An inverse problem has to be solved for that purpose. In this paper, we use Artificial Neural Networks (ANNs) to solve the associated inverse problem and estimate the loading parameters that have resulted in the CT-measured three-dimensional density distribution of a proximal femur. An ANN is trained using a dataset generated by solving the forward tissue adaptation model for a large number of loading parameters. Before training the ANN with the generated training dataset, a Gaussian noise component is added to the density distribution. This improves the robustness of the trained ANN against deviations of the measured density distribution from the predictions of the forward bone tissue adaptation model. It is shown that the proposed technique is capable of predicting loading parameters that result in a density distribution close to the measured density distribution. PMID- 22520424 TI - Impact of measurement errors on the determination of the linear modulus of human meniscal attachments. AB - For the development of meniscal substitutes and related finite element models it is necessary to know the mechanical properties of the meniscus and its attachments. Measurement errors can falsify the determination of material properties. Therefore the impact of metrological and geometrical measurement errors on the determination of the linear modulus of human meniscal attachments was investigated. After total differentiation the error of the force (+0.10%), attachment deformation (-0.16%), and fibre length (+0.11%) measurements almost annulled each other. The error of the cross-sectional area determination ranged from 0.00%, gathered from histological slides, up to 14.22%, obtained from digital calliper measurements. Hence, total measurement error ranged from +0.05% to -14.17%, predominantly affected by the cross-sectional area determination error. Further investigations revealed that the entire cross-section was significantly larger compared to the load-carrying collagen fibre area. This overestimation of the cross-section area led to an underestimation of the linear modulus of up to -36.7%. Additionally, the cross-sections of the collagen-fibre area of the attachments significantly varied up to +90% along their longitudinal axis. The resultant ratio between the collagen fibre area and the histologically determined cross-sectional area ranged between 0.61 for the posterolateral and 0.69 for the posteromedial ligament. The linear modulus of human meniscal attachments can be significantly underestimated due to the use of different methods and locations of cross-sectional area determination. Hence, it is suggested to assess the load carrying collagen fibre area histologically, or, alternatively, to use the correction factors proposed in this study. PMID- 22520425 TI - Effects of backward extrusion on mechanical and degradation properties of Mg-Zn biomaterial. AB - Backward extrusion was used to improve the properties of Mg-based biomaterials. The microstructures, mechanical performance and corrosion properties of as-cast and backward extruded Mg-xZn (x=0.5, 1, 1.5, 2, wt.%) alloys were investigated. The secondary dendrite arm spacing of as-cast Mg-xZn alloys and the grain size of backward extruded Mg-xZn alloys were decreased with the increment of Zn content. Meanwhile, both strength and elongation were improved by backward extruded treatment. With increasing Zn addition, the corrosion properties of both as-cast and backward extruded Mg-xZn alloys were decreased. However, the corrosion performance of backward extruded sample was improved obviously compared to the corresponding as-cast one. More importantly, the degradation rate of the backward extruded alloy was stable, which was mainly associated with the fine second precipitates and the homogeneous microstructure. It was demonstrated that backward extrusion was an effective approach to manufacture high performance Mg based biomaterials. PMID- 22520426 TI - Cervical spine segment finite element model for traumatic injury prediction. AB - Many detailed cervical spine models have been developed and primarily used to investigate kinematic response of the neck in impact scenarios. However, the goal of detailed models is to predict both kinematic response and provide insights into injury mechanisms and thresholds through tissue-level response. The objective of this study was to verify and validate an enhanced cervical spine segment finite element model to predict tissue-level failure under four load conditions: tension, flexion, and extension using a C4-C5 segment, and compression using a C5-C6-C7 segment. Mechanical tissue test data in relevant modes of loading was used in the model, and this data was also used to model ultimate tissue failure. The predicted failure locations were representative of reported cervical spine injuries for the different modes of loading, and the predicted peak failure forces were within the reported experimental corridors. The displacement to failure of the tension simulation was lower than expected in some cases, attributed to limitations in the constitutive model. This study provided a validated approach to predict tissue-level failure for cervical spine segments, predicting the location and sequence of tissue failure, and can be applied to future full cervical spine models for the prediction of injurious loading in automotive crash scenarios. PMID- 22520427 TI - Towards a biomimetism of abdominal healthy and aneurysmal arterial tissues. AB - The aim of this work is to develop a new hyperelastic and anisotropic material mimicking histological and mechanical features of healthy and aneurysmal arterial tissues. The material is constituted by rhombic periodic lattices of hyperelastic fibres embedded into a soft elastomer membrane. To fit bi-axial experimental data obtained from the literature, with normal or pathologic human abdominal aortic tissues, the microstructure of the periodic lattices (fibre length, angle between fibres) together with the mechanical behaviour of the fibres (fibre tension elongation curve) were optimised by using theoretical results arising from a multi-scale homogenisation process. It is shown that (i) a material constituted by only one periodic lattice of fibres is clearly not sufficient to describe all the experimental data set, (ii) a quantitative agreement between measurements and theoretical predictions is obtained by using a material with two fibre lattices, (iii) the optimised microstructures and mechanical properties of the fibrous lattices are strongly different for the abdominal healthy and aneurysmal arterial tissues, (iv) the anisotropic mechanical behaviour of the optimised material is described by only five parameters and (v) the optimal angles between fibres in the case of the healthy aorta are consistent with histological data. Several technical solutions of fibres can be considered as relevant candidates: this is illustrated in the particular cases of straight and wavy fibres. PMID- 22520428 TI - Influence of geometrical parameters on radial force during self-expanding stent deployment. Application for a variable radial stiffness stent. AB - The goal of this work is to study the influence of the main geometrical parameters on the radial force of a self-expanding stent, and using them to advance towards a new design of a variable radial force stent to improve the interaction vessel-device. Using finite element simulations, a parametric analysis of a commercial stent model (Acculink, Abbot Vascular) was developed to estimate the influence of geometrical variables, mainly radial and circumferential strut thicknesses and the initial diameter of the stent. The radial expansion force was compared for the different values of each geometrical variable. The previous results were used to propose a new stent design with variable radial stiffness. Their effects on healthy and atheromatous vessels were studied and compared for both stent models, constant and variable radial stiffness respectively. The developed analysis reveals a notable decrease of the contact pressure over the inner arterial wall in healthy areas using a variable radial force (VF) stent with respect to the same model with a constant expansion force (CF) stent. In the case of a vessel model with a fibrotic core plaque, the lumen healthy areas that suffer a contact pressure higher than 0.25 MPa are reduced from 36.86% to 22.38% for the left healthy area (LHA), and from 40.13% to 21.36% in the right healthy area (RHA). Furthermore, this pressure reduction in the healthy areas does not cause a decrease in the expansion pressure in an atheromatous section, where it is necessary to maintain a recovery of the lumen section. In the case of lipid core, the flow section with plaque is 70.8% of the healthy flow section using a VF stent, and 70.9% with a CF stent, while 66.87% and 66.89% were found respectively in the case of a calcified core. PMID- 22520429 TI - Orientation and deformation of mineral crystals in tooth surfaces. AB - Tooth enamel is the hardest material in the human body, and it is mainly composed of hydroxyapatite (HAp)-like mineral particles. As HAp has a hexagonal crystal structure, X-ray diffraction methods can be used to analyze the crystal structure of HAp in teeth. Here, the X-ray diffraction method was applied to the surface of tooth enamel to measure the orientation and strain of the HAp crystals. The c axis of the hexagonal crystal structure of HAp was oriented to the surface perpendicular to the tooth enamel covering the tooth surface. Thus, the strain of HAp at the surface of teeth was measured by X-ray diffraction from the (004) lattice planes aligned along the c-axis. The X-ray strain measurements were conducted on tooth specimens with intact surfaces under loading. Highly accurate strain measurements of the surface of tooth specimens were performed by precise positioning of the X-ray irradiation area during loading. The strains of the (004) lattice plane were measured at several positions on the surface of the specimens under compression along the tooth axis. The strains were obtained as tensile strains at the labial side of incisor tooth specimens. In posterior teeth, the strains were different at different measurement positions, varying from tensile to compressive types. PMID- 22520430 TI - An analytical solution for the stress state at stent-coating interfaces. AB - In this paper an analytical solution for the stress state in a coated stent is presented, with a particular focus on the interface stresses between the coating and stent. As a first step a simplified stent architecture consisting of a bi layered composite elastic arch is considered. The variations of normal and shear stress at the interface as functions of the boundary conditions at the base of the arch are explored. Depending on applied displacement and rotation, very distinct distributions of stress occur along the interface: dominant shear or dominant normal stress, compressive or tensile normal stress. A bi-layered composite elastic strut is then added to the composite elastic arch in order to create a realistic coated stent geometry. A displacement is applied to the bottom of the strut to simulate stent deployment. The addition of the strut is found to increase the normal stress and decrease the shear stress at all points on the interface. The influence of the various geometrical and material parameters on interface stress is explored using the analytical procedure developed in the paper, providing practical insight for stent-coating design. PMID- 22520431 TI - Characterization of multi-principal-element (TiZrNbHfTa)N and (TiZrNbHfTa)C coatings for biomedical applications. AB - Multi-principal-element (TiZrNbHfTa)N and (TiZrNbHfTa)C coatings were deposited on Ti6Al4V alloy by co-sputtering of Ti, Zr, Nb, Hf and Ta metallic targets in reactive atmosphere. The coatings were analyzed for elemental and phase compositions, crystalline structure, morphology, residual stress, hardness, friction performance, wear-corrosion resistance and cell viability. For all the films, only simple fcc solid solutions with (111) preferred orientations were found, with crystallite sizes in the range 7.2-13.5 nm. The coatings were subjected to compressive stress, with values ranging from 0.8 to 1.6 GPa. The carbide coating with the highest carbon content (carbon/metal ~1.3) exhibited the highest hardness of about 31 GPa, the best friction behavior (MU = 0.12) and the highest wear resistance (wear rate K=0.2*10(-6)mm(3)N(-1)m(-1)), when testing in simulated body fluids (SBFs). Cell viability tests proved that the osteoblast cells were adherent to the coated substrates, and a very high percentage of live cells were observed on sample surfaces, after 72 h incubation time. PMID- 22520432 TI - Investigation of structure-property relationships of polyisobutylene-based biomaterials: Morphology, thermal, quasi-static tensile and long-term dynamic fatigue behavior. AB - This study examines the morphology, thermal, quasi-static and long-term dynamic creep properties of one linear and three arborescent polyisobutylene-based block copolymers (L_SIBS31, D_IBS16, D_IBS27 and D_IBS33). Silicone rubber, a common biopolymer, was considered as a benchmark material for comparison. A unique hysteretic testing methodology of Stepwise Increasing Load Test (SILT) and Single Load Test (SLT) was used in this study to evaluate the long-term dynamic fatigue performance of these materials. Our experimental findings revealed that the molecular weight of polyisobutylene (PIB) and polystyrene (PS) arms [M(n)(PIB(arm)) and M(n)(PS(arm))], respectively had a profound influence on the nano-scaled phase separation, quasi-static tensile, thermal transition, and dynamic creep resistance behaviors of these PIB-based block copolymers. However, silicone rubber outperformed the PIB-based block copolymers in terms of dynamic creep properties due to its chemically crosslinked structure. This indicates a need for a material strategy to improve the dynamic fatigue and creep of this class of biopolymers to be considered as alternative to silicone rubber for biomedical devices. PMID- 22520433 TI - Strain rate dependent properties of younger human cervical spine ligaments. AB - The cervical spine ligaments play an essential role in limiting the physiological ranges of motion in the neck; however, traumatic loading such as that experienced in automotive crash scenarios can lead to ligament damage and result in neck injury. The development of detailed neck models to evaluate the response and the potential for injury requires accurate ligament mechanical properties at relevant loading rates. The objective of this study was to measure the mechanical properties of the cervical spine ligaments, by performing tensile tests at elongation rates relevant to car crash scenarios, using younger specimens (<=50 years), in simulated in vivo conditions, and to provide a comprehensive investigation of gender and spinal level effects. The five ligaments investigated were the anterior longitudinal ligament, posterior longitudinal ligament, capsular ligament, ligamentum flavum, and interspinous ligament. Ligaments were tested in tension at quasi-static (0.5 s(-1)), medium (20 s(-1)) and high (150 250 s(-1)) strain rates. The high strain rates represented typical car crash scenarios as determined using an existing cervical spine finite element model. In total, 261 ligament tests were performed, with approximately even distribution within elongation rate, spinal level, and gender. The measured force-displacement data followed expected trends compared to previous studies. The younger ligaments investigated in this study demonstrated less scatter, and were both stiffer and stronger than comparable data from older specimens reported in previous studies. Strain rate effects were most significant, while spinal level effects were limited. Gender effects were not significant, but consistent trends were identified, with male ligaments having a higher stiffness and failure force than female ligaments. PMID- 22520434 TI - Evaluation of flexural strength of hipped and presintered zirconia using different estimation methods of Weibull statistics. AB - OBJECTIVES: This study determined the flexural strength of one hipped and eight presintered zirconia and evaluated the results using different estimation methods of Weibull statistics. MATERIALS AND METHODS: Presintered zirconia specimens were prepared in white state and sintered according to each manufacturer's instructions. One hipped zirconia acted as the control group. The specimens were loaded in a Universal Testing Machine (ISO 6872, 2008). Data were analysed using "normal" (Levene test, one-way ANOVA, Scheffe test) and "Weibull distribution" estimated by either Least Squares (LS) (mean (Excel) and median rank (MINITAB)), Maximum Likelihood (ML) (MINITAB) or ML (MINITAB) with a correction of BS EN 843 5 (2006) (MLC) (alpha=0.05). RESULTS: According to normal (sigma) and Weibull distribution (s), three-point flexural strength (MPa) of the hipped zirconia (sigma=1643 (1507; 1782), s(LS mean rank): 1772, s(LS median rank): 1751 (1619; 1894), s(ML): 1733 (1645; 1826) and s(MLC): (1625; 1848) showed significantly higher results compared to all other presintered zirconia groups (p<0.001). The lowest mean and characteristic strength was observed with GC (sigma=817(803;953), s(LS mean rank): 935, s(LS median rank): 935(868; 1007), s(ML): 932(875; 994) and s(MLC): (862; 1009)). The highest Weibull modulus estimated by LS for mean and median rank was observed with LZ (8.9 and 9.8(7.5; 12.9), respectively) and the lowest with ZE (5.1 and 5(3; 8.2), respectively). According to ML and MLC estimation, the control group showed the highest (10.1(6.6; 15.6), 9.2(5.8; 14.2), respectively), and CZ the lowest (5.6(3.8; 8.2), 5.0(3.2; 7.8), respectively) Weibull modulus. No differences in estimates of standard deviations of the normal distribution and the estimates of Weibull moduli for different estimation methods were found between all tested groups. CONCLUSIONS: Flexural strength of the tested hipped zirconia was higher than those of presintered ones according to both normal and Weibull distribution. LS (median rank) and ML estimates can be compared by a global test and by means of 95% CI. For corrected ML estimates the 95% CI can be interpreted. Estimate calculations in Excel (LS, mean rank) provides information on 95% CI for the Weibull parameters. PMID- 22520435 TI - Heterogeneous structure and mechanical hardness of biomedical beta-type Ti-29Nb 13Ta-4.6Zr subjected to high-pressure torsion. AB - A novel beta-type titanium alloy, Ti-29Nb-13Ta-4.6Zr (TNTZ), has been developed as a candidate for biomedical applications. TNTZ exhibits non-toxicity and a low Young's modulus close to that of bone (10-30 GPa). Such a low Young's modulus of this alloy is achieved by comprising a single metastable beta phase. Greater mechanical biocompatibility, which implies higher mechanical strength and hardness while maintaining a low Young's modulus, has been aimed for TNTZ. Therefore, strengthening by grain refinement and increasing dislocation density is expected to provide TNTZ high mechanical strength while keeping a low Young's modulus because they keep the original beta phase. In this case, high-pressure torsion (HPT) processing is one of the effective ways to obtain these properties simultaneously in TNTZ. Thus, in this study, the effect of HPT processing on the microstructure and mechanical hardness of TNTZ was systematically investigated at rotation numbers (N) of 1 to 20 under a pressure of around 1.25 GPa at room temperature. On the cross sections of TNTZ subjected to HPT processing (TNTZ(HPT)) after cold rolling (TNTZ(CR)) at any rotation number, a heterogeneous microstructure consisting of a matrix and a non-etched band, which is not corroded by etching solution, can be observed. The thickness of non-etched band increases as rotation number and distance from specimen center increase. Both matrix and non-etched band comprise a single beta phase, but their grain geometries are different each other. Equiaxed grains and elongated grains are observed in the matrix and the non-etched band, respectively. The equiaxed grain diameter, which is ranged from 155 nm to 44 nm, in the matrix decreases with increasing rotation number. Contrastingly, the elongated grains with a length of around 300 nm and a width of 30 nm, which are nearly constant with rotation number, are observed in the non-etched band. The mechanical hardness of TNTZ(HPT) is consistently much higher than that of TNTZ(CR). The mechanical hardness distribution on the surface of TNTZ(HPT) is heterogeneous in the radial and depth directions, while that of TNTZ(CR) is homogeneous; the mechanical hardness is higher in the peripheral region than in the central region on the surfaces of TNTZ(HPT) at all N. Further, the mechanical hardness distribution on the cross sections of TNTZ(HPT) at all N is also heterogeneous in depth direction; the mechanical hardness is higher in the peripheral region than in the central region. The heterogeneous mechanical hardness distribution depending on the position on the surface and cross section of TNTZ(HPT) is considered to be related to grain refinement and imposed strain due to HPT processing. PMID- 22520436 TI - The processing of number and gender agreement in Spanish: an event-related potential investigation of the effects of structural distance. AB - Previous research suggests that the processing of agreement is affected by the distance between the agreeing elements. However, the unique contribution of structural distance (number of intervening syntactic phrases) to the processing of agreement remains an open question, since previous investigations do not tease apart structural and linear distance (number of intervening words). We used event related potentials (ERPs) to examine the extent to which structural distance impacts the processing of Spanish number and gender agreement. Violations were realized both within the phrase and across the phrase. Across both levels of structural distance, linear distance was kept constant, as was the syntactic category of the agreeing elements. Number and gender agreement violations elicited a robust P600 between 400 and 900 ms, a component associated with morphosyntactic processing. No amplitude differences were observed between number and gender violations, suggesting that the two features are processed similarly at the brain level. Within-phrase agreement yielded more positive waveforms than across-phrase agreement, both for agreement violations and for grammatical sentences (no agreement by distance interaction). These effects can be interpreted as evidence that structural distance impacts the establishment of agreement overall, consistent with sentence processing models which predict that hierarchical structure impacts the processing of syntactic dependencies. However, due to the lack of an agreement by distance interaction, the possibility cannot be ruled out that these effects are driven by differences in syntactic predictability between the within-phrase and across-phrase configurations, notably the fact that the syntactic category of the critical word was more predictable in the within-phrase conditions. PMID- 22520437 TI - MPTP-induced hippocampal effects on serotonin, dopamine, neurotrophins, adult neurogenesis and depression-like behavior are partially influenced by fluoxetine in adult mice. AB - In Parkinson's disease the loss of dopamine induces motor impairment but also leads to non-motor symptoms such as cognitive impairment, anxiety and depression. Selective serotonine reuptake inhibitors (SSRI) are so far first line therapy for mood alterations in PD and have also been shown to influence cognition, however with often insufficient results due to yet not fully understood underlying pathomechanisms of the symptoms. Deficits in the generation and maturation of new neurons in the adult hippocampus seem to be key mechanisms of major depression and cognitive decline and are robustly influenced by serotonergic pharmacotherapy. In this study we analyzed the effects of a short- and long-term treatment with the SSRI fluoxetine on changes of hippocampal precursor maturation, neurotransmitter-receptor mRNA-expression, neurotrophin levels and clinical symptoms in the MPTP-mouse model for PD. The generation of neuronal precursors as well as the absolute numbers of endogenous immature neurons increased following MPTP and were further elevated by fluoxetine. Net neurogenesis however, impaired after MPTP, remained unchanged by fluoxetine treatment. Fluoxetine induced microenvironmental changes in the hippocampus that might be involved in enhanced precursor generation involved increased contents of the neurotrophins VEGF and BDNF and decreased hippocampal expression of the 5HT1a receptor mRNA and the D2 receptor mRNA. Clinically, we were not able to detect any differences in anxiety or depressive behavior in MPTP animals compared to controls which is in line with previous studies indicating that neuropsychiatric symptoms in PD are difficult to assess in rodents due to their clinical characteristics and involvement of several brain regions. Taken together, we show that fluoxetine partially enhances brain's capacity to counteract MPTP-induced neurodegeneration by increasing the endogenous pool of immature neurons and upregulating neural precursor cell generation. The mechanisms underlying this phenomenon and the link to the clinical use of fluoxetine in PD remain to be further elucidated. PMID- 22520438 TI - Age-related changes in force and power associated with balance of women in quiet bilateral stance on a firm surface. AB - Quantitative assessment of the fluctuations of the body centre of mass (CM) while in a stationary bilateral stance on a firm surface is an important criterion of the functional state of human motor-vestibular and sensory apparatus. From analysis of the literature we conclude that more objective characteristics of human balance in quiet standing may be the amount of energy used to maintain the CM in a constant position. Further analysis of the references showed that these characteristics have not been investigated in neurological practice. In this study, the displacement of CM in participants standing in a normal anatomical position was analysed. Forty-five healthy women in three age groups: 18-24, 45-55 and over 60 years participated in the experiments, which consisted of recording changes in partial body weight on the force platform (under one leg) in situations with opened and closed eyes. The specific power of oscillation of body sway and force of lateral swing of CM were calculated. Results indicated that the maximum specific power of oscillation and force of lateral swing were observed in the group of women older than 60 years, especially in the absence of vision. Minimum values occurred in the group of 18-24 years. We also found a considerable variability in all indices in all age groups. This indicates that the stability of the vertical posture in humans depends also on the individual biological characteristics of the central nervous and muscular systems. PMID- 22520440 TI - Gene silencing in parasites: current status and future prospects. AB - Parasitic diseases cause important losses in public and veterinary health worldwide. Novel drugs, more reliable diagnostic techniques and vaccine candidates are urgently needed. Due to the complexity of parasites and the intricate relationship with their hosts, development of successful tools to fight parasites has been very limited to date. The growing information on individual parasite genomes is now allowing the use of a broader range of potential strategies to gain deeper insights into the host-parasite relationship and has increased the possibilities to develop molecular-based tools in the field of parasitology. Nevertheless, functional studies of respective genes are still scarce. The RNA interference phenomenon resulting in the regulation of protein expression through the specific degradation of defined mRNAs, and more specifically the possibility of artificially induce it, has shown to be a powerful tool for the investigation of proteins function in many organisms. Recent advances in the design and delivery of targeting molecules allow efficient and highly specific gene silencing in different types of parasites, pointing out this technology as a powerful tool for the identification of novel vaccine candidates or drug targets at the high-throughput level in the near future, and could enable researchers to functionally annotate parasite genomes. The aim of this review is to provide a comprehensive overview on the current advances and pitfalls in gene silencing mechanisms, techniques, applications and prospects in animal parasites. PMID- 22520439 TI - Prenatal stress causes alterations in the morphology of microglia and the inflammatory response of the hippocampus of adult female mice. AB - BACKGROUND: Stress during fetal life increases the risk of affective and immune disorders later in life. The altered peripheral immune response caused by prenatal stress may impact on brain function by the modification of local inflammation. In this study we have explored whether prenatal stress results in alterations in the immune response in the hippocampus of female mice during adult life. METHODS: Pregnant C57BL/6 mice were subjected three times/day during 45 minutes to restraint stress from gestational Day 12 to delivery. Control non stressed pregnant mice remained undisturbed. At four months of age, non-stressed and prenatally stressed females were ovariectomized. Fifteen days after surgery, mice received an i.p. injection of vehicle or of 5 mg/kg of lipopolysaccharide (LPS). Mice were sacrificed 20 hours later by decapitation and the brains were removed. Levels of interleukin-1beta (IL1beta), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), interferon gamma-inducible protein 10 (IP10), and toll-like receptor 4 mRNA were assessed in the hippocampus by quantitative real-time polymerase chain reaction. Iba1 immunoreactivity was assessed by immunocytochemistry. Statistical significance was determined by one-way or two way analysis of variance. RESULTS: Prenatal stress, per se, increased IL1beta mRNA levels in the hippocampus, increased the total number of Iba1-immunoreactive microglial cells and increased the proportion of microglial cells with large somas and retracted cellular processes. In addition, prenatally stressed and non stressed animals showed different responses to peripheral inflammation induced by systemic administration of LPS. LPS induced a significant increase in mRNA levels of IL-6, TNF-alpha and IP10 in the hippocampus of prenatally stressed mice but not of non-stressed animals. In addition, after LPS treatment, prenatally stressed animals showed a higher proportion of Iba1-immunoreactive cells in the hippocampus with morphological characteristics of activated microglia compared to non-stressed animals. In contrast, LPS induced similar increases in expression of IL1beta and toll-like receptor 4 in both prenatally stressed and non-stressed animals. CONCLUSION: These findings indicate that prenatal stress induces long lasting modifications in the inflammatory status of the hippocampus of female mice under basal conditions and alters the immune response of the hippocampus to peripheral inflammation. PMID- 22520441 TI - Giardia--from genome to proteome. AB - In this review, the current status of genomic and proteomic research on Giardia is examined in terms of evolutionary biology, phylogenetic relationships and taxonomy. The review also describes how characterising genetic variation in Giardia from numerous hosts and endemic areas has provided a better understanding of life cycle patterns, transmission and the epidemiology of Giardia infections in humans, domestic animals and wildlife. Some progress has been made in relating genomic information to the phenotype of Giardia, and as a consequence, new information has been obtained on aspects of developmental biology and the host parasite relationship. However, deficiencies remain in our understanding of pathogenesis and host specificity, highlighting the limitations of currently available genomic datasets. PMID- 22520442 TI - Malaria ecotypes and stratification. AB - To deal with the variability of malaria, control programmes need to stratify their malaria problem into a number of smaller units. Such stratification may be based on the epidemiology of malaria or on its determinants such as ecology. An ecotype classification was developed by the World Health Organization (WHO) around 1990, and it is time to assess its usefulness for current malaria control as well as for malaria modelling on the basis of published research. Journal and grey literature was searched for articles on malaria or Anopheles combined with ecology or stratification. It was found that all malaria in the world today could be assigned to one or more of the following ecotypes: savanna, plains and valleys; forest and forest fringe; foothill; mountain fringe and northern and southern fringes; desert fringe; coastal and urban. However, some areas are in transitional or mixed zones; furthermore, the implications of any ecotype depend on the biogeographical region, sometimes subregion, and finally, the knowledge on physiography needs to be supplemented by local information on natural, anthropic and health system processes including malaria control. Ecotyping can therefore not be seen as a shortcut to determine control interventions, but rather as a framework to supplement available epidemiological and entomological data so as to assess malaria situations at the local level, think through the particular risks and opportunities and reinforce intersectoral action. With these caveats, it does however emerge that several ecotypic distinctions are well defined and have relatively constant implications for control within certain biogeographic regions. Forest environments in the Indo-malay and the Neotropics are, with a few exceptions, associated with much higher malaria risk than in adjacent areas; the vectors are difficult to control, and the anthropic factors also often converge to impose constraints. Urban malaria in Africa is associated with lower risk than savanna malaria; larval control may be considered though its role is not so far well established. In contrast, urban malaria in the Indian subcontinent is associated with higher risks than most adjacent rural areas, and larval control has a definite, though not exclusive, role. Simulation modelling of cost effectiveness of malaria control strategies in different scenarios should prioritize ecotypes where malaria control encounters serious technical problems. Further field research on malaria and ecology should be interdisciplinary, especially with geography, and pay more attention to juxtapositions and to anthropic elements, especially migration. PMID- 22520445 TI - Patellofemoral alignment and anterior knee pain after closing- and opening-wedge valgus high tibial osteotomy. AB - PURPOSE: The purpose of this study was to compare the clinical and radiographic outcomes of opening- and closing-wedge valgus high tibial osteotomy (HTO) for the treatment of medial unicompartmental knee osteoarthritis with a minimum follow-up of 3 years, with a focus on patellofemoral alignment and anterior knee pain. METHODS: We performed a retrospective comparison of 50 patients who underwent closing-wedge HTO and 50 patients who underwent opening-wedge HTO for isolated medial joint arthritis of the knee with varus deformity. All patients were evaluated and the 2 study groups were compared after a minimum follow-up of 3 years with a focus on patellofemoral alignment, patellofemoral osteoarthritis, and anterior knee pain while climbing stairs. RESULTS: Patellar alignment (patellar tilt and lateral patellar displacement) was not significantly different in the 2 groups either preoperatively or at follow-up. Furthermore, there were no significant differences in the extent of patellofemoral arthritis and incidence of anterior knee pain at follow-up between the 2 groups. In addition, no significant intergroup difference was found in terms of the incidence of anterior knee pain (28% in closing-wedge group and 32% in opening-wedge group at follow up). CONCLUSIONS: The results of closing- and opening-wedge valgus HTO were not found to be significantly different with respect to patellar alignment, osteoarthritis of the patellofemoral joint, or anterior knee pain. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 22520444 TI - A polymorphic indel containing the RS3 microsatellite in the 5' flanking region of the vasopressin V1a receptor gene is associated with chimpanzee (Pan troglodytes) personality. AB - Vasopressin is a neuropeptide that has been strongly implicated in the development and evolution of complex social relations and cognition in mammals. Recent studies in voles have shown that polymorphic variation in the promoter region of the arginine vasopressin V1a receptor gene (avpr1a) is associated with different dimensions of sociality. In humans, variation in a repetitive sequence element in the 5' flanking region of the AVPR1A, known as RS3, have also been associated with variation in AVPR1a gene expression, brain activity and social behavior. Here, we examined the association of polymorphic variation in this same 5' flanking region of the AVPR1A on subjective ratings of personality in a sample of 83 chimpanzees (Pan troglodytes). Initial analyses indicated that 34 females and 19 males were homozygous for the short allele, which lacks RS3 (DupB(-/-)), while 18 females and 12 males were heterozygous and thus had one copy of the long allele containing RS3 (DupB(+/-)), yielding overall allelic frequencies of 0.82 for the DupB(-) allele and 0.18 for the DupB(+) allele. DupB(+/+) chimpanzees were excluded from the analysis because of the limited number of individuals. Results indicated no significant sex difference in personality between chimpanzees homozygous for the deletion of the RS3-containing DupB region (DupB( /-)); however, among chimpanzees carrying one allele with the DupB present (DupB(+/-)), males had significantly higher dominance and lower conscientiousness scores than females. These findings are the first evidence showing that the AVPR1A gene plays a role in different aspects of personality in male and female chimpanzees. PMID- 22520447 TI - Comparison of existing syncope rules and newly proposed anatolian syncope rule to predict short-term serious outcomes after syncope in the Turkish population. AB - BACKGROUND: We wished to compare the San Francisco Syncope Rule (SFSR), Evaluation of Guidelines in Syncope Study (EGSYS) and the Osservatorio Epidemiologico sulla Sincope nel Lazio (OESIL) risk scores and to assess their efficacy in recognising patients with syncope at high risk for short-term adverse events (death, the need for major therapeutic procedures, and early readmission to the hospital). We also wanted to test those variables to designate a local risk score, the Anatolian Syncope Rule (ASR). METHODS: This prospective, cohort study was conducted at the emergency department of a tertiary care centre. Between December 1 2009 and December 31 2010, we prospectively collected data on patients of ages 18 and over who presented to the emergency department with syncope. RESULTS: We enrolled 231 patients to the study. A univariate analysis found 23 variables that predicted syncope with adverse events. Dyspnoea, orthostatic hypotension, precipitating cause of syncope, age over 58 years, congestive heart failure, and electrocardiogram abnormality (termed DO-PACE) were found to predict short-term serious outcomes by logistic regression analysis and these were used to compose the ASR. The sensitivity of ASR, OESIL, EGSYS and SFSR for mortality were 100% (0.66 to 1.00); 90% (0.54 to 0.99), 80% (0.44 to 0.97) and 100% (0.66 to 1.00), respectively. The specificity of ASR, OESIL, EGSYS and SFSR for mortality were 78% (0.72 to 0.83); 76% (0.70 to 0.82); 80% (0.74 to 0.85) and 70% (0.63 to 0.76). The sensitivity of ASR, OESIL, EGSYS and SFSR for any adverse event were 97% (0.85 to 1.00); 70% (0.52 to 0.82); 56% (0.40 to 0.72) and 87% (0.72 to 0.95). The specificity of ASR, OESIL, EGSYS and SFSR for any adverse event were 72% (0.64 to 0.78); 82% (0.76 to 0.87); 84% (0.78 to 0.89); 78% (0.71 to 0.83), respectively. CONCLUSION: The newly proposed ASR appears to be highly sensitive for identifying patients at risk for short-term serious outcomes, with scores at least as good as those provided by existing diagnostic rules, and it is easier to perform at the bedside within the Turkish population. If prospectively validated, it may offer a tool to aid physicians' decision making. PMID- 22520446 TI - Gene expression profiling of flaxseed in mouse lung tissues-modulation of toxicologically relevant genes. AB - BACKGROUND: Flaxseed (FS), a nutritional supplement consisting mainly of omega-3 fatty acids and lignan phenolics has potent anti-inflammatory, anti-fibrotic and antioxidant properties. The usefulness of flaxseed as an alternative and complimentary treatment option has been known since ancient times. We have shown that dietary FS supplementation ameliorates oxidative stress and inflammation in experimental models of acute and chronic lung injury in mice resulting from diverse toxicants. The development of lung tissue damage in response to direct or indirect oxidant stress is a complex process, associated with changes in expression levels of a number of genes. We therefore postulated that flaxseed might modulate gene expression of vital signaling pathways, thus interfering with the development of tissue injury. METHODS: We evaluated gene expression in lungs of flaxseed-fed (10%FS) mice under unchallenged, control conditions. We reasoned that array technology would provide a powerful tool for studying the mechanisms behind this response and aid the evaluation of dietary flaxseed intervention with a focus on toxicologically relevant molecular gene targets. Gene expression levels in lung tissues were analyzed using a large-scale array whereby 28,800 genes were evaluated. RESULTS: 3,713 genes (12.8%) were significantly (p < 0.05) differentially expressed, of which 2,088 had a >1.5-fold change. Genes affected by FS include those in protective pathways such as Phase I and Phase II. CONCLUSIONS: The array studies have provided information on how FS modulates gene expression in lung and how they might be related to protective mechanisms. In addition, our study has confirmed that flaxseed is a nutritional supplement with potentially useful therapeutic applications in complementary and alternative (CAM) medicine especially in relation to treatment of lung disease. PMID- 22520448 TI - Ehrlichia chaffeensis presenting with bilateral anterior thigh pain (Louria's sign). AB - Bilateral anterior thigh pain may indicate bacteremia (Louria's Sign). We present a case of Ehrlichiosis due to Ehrlichia chaffeensis whose predominant presenting symptom was localized bilateral anterior thigh pain. PMID- 22520443 TI - The changing limits and incidence of malaria in Africa: 1939-2009. AB - Understanding the historical, temporal changes of malaria risk following control efforts in Africa provides a unique insight into what has been and might be archived towards a long-term ambition of elimination on the continent. Here, we use archived published and unpublished material combined with biological constraints on transmission accompanied by a narrative on malaria control to document the changing incidence of malaria in Africa since earliest reports pre second World War. One result is a more informed mapped definition of the changing margins of transmission in 1939, 1959, 1979, 1999 and 2009. PMID- 22520449 TI - The selection of search sources influences the findings of a systematic review of people's views: a case study in public health. AB - BACKGROUND: For systematic reviews providing evidence for policy decisions in specific geographical regions, there is a need to minimise regional bias when seeking out relevant research studies. Studies on people's views tend to be dispersed across a range of bibliographic databases and other search sources. It is recognised that a comprehensive literature search can provide unique evidence not found from a focused search; however, the geographical focus of databases as a potential source of bias on the findings of a research review is less clear. This case study describes search source selection for research about people's views and how supplementary searches designed to redress geographical bias influenced the findings of a systematic review. Our research questions are: a) what was the impact of search methods employed to redress potential database selection bias on the overall findings of the review? and b) how did each search source contribute to the identification of all the research studies included in the review? METHODS: The contribution of 25 search sources in locating 28 studies included within a systematic review on UK children's views of body size, shape and weight was analysed retrospectively. The impact of utilising seven search sources chosen to identify UK-based literature on the review's findings was assessed. RESULTS: Over a sixth (5 out of 28) of the studies were located only through supplementary searches of three sources. These five studies were of a disproportionally high quality compared with the other studies in the review. The retrieval of these studies added direction, detail and strength to the overall findings of the review. All studies in the review were located within 21 search sources. Precision for 21 sources ranged from 0.21% to 1.64%. CONCLUSIONS: For reducing geographical bias and increasing the coverage and context-specificity of systematic reviews of people's perspectives and experiences, searching that is sensitive and aimed at reducing geographical bias in database sources is recommended. PMID- 22520450 TI - Large-conductance calcium-activated potassium channel activity, as determined by whole-cell patch clamp recording, is decreased in urinary bladder smooth muscle cells from male rats with partial urethral obstruction. AB - OBJECTIVES: To examine the effect of partial urethral obstruction (PUO) on bladder smooth muscle outward potassium current and the contribution of the large conductance calcium-activated potassium (Maxi-K, BKCa) channel to this activity in smooth muscle cells isolated from bladders of sham-operated and PUO male rats using whole-cell patch clamp recording techniques. To determine the effect of PUO on the expression of the Maxi-K channel alpha and beta1 subunits and in vitro detrusor contractility. MATERIALS AND METHODS: Twenty adult male Sprague-Dawley rats were divided equally into two groups and subjected to surgical ligation of the urethra (PUO) or sham surgery (SHAM). After 2 weeks, the detrusors from PUO and SHAM rats were used for molecular analyses (mRNA and protein quantification of Maxi-K subunits) or organ bath contractility studies, or myocytes were isolated for conventional whole-cell patch clamp analyses. RESULTS: PUO increased bladder mass 2.5-fold and detrusor strips exhibited a more tonic-type contraction and increased contractility compared with controls (SHAM). Iberiotoxin (300 nM) sensitive Maxi-K channel current comprised about 40% of the outward whole-cell current in SHAM bladders but only about 8% in PUO bladders. Expression of the alpha subunit of the Maxi-K channel was significantly decreased ~40% while the expression of the beta1 subunit was increased ~2-fold at the mRNA level. The increase in beta1 expression was confirmed by Western blotting. CONCLUSIONS: Our findings show that obstruction of the rat bladder is associated with decreased Maxi-K channel activity of bladder smooth muscle cells, determined via direct current measurement. Increased expression of the beta1 subunit points to a compensatory reaction to decreased Maxi-K channel activity. Maxi-K channel openers or gene therapy may therefore provide therapeutic benefit for the overactive bladder. PMID- 22520451 TI - Biomarker measurements in Trifolium repens and Eisenia fetida to assess the toxicity of soil contaminated with landfill leachate: a microcosm study. AB - To assess the toxicity of a soil contaminated with landfill leachate, biomarker measurements in two species living in close contact with the soil, i.e. a plant species Trifolium repens and an animal species Eisenia fetida, were conducted. Briefly, both species were studied after simultaneous exposure conducted in microcosms. The organisms were exposed to soil supplemented with pure leachate, leachate diluted to 50%; leachate diluted to 25% and without leachate. After a 10 weeks exposure period, we observed an increase in the Olive Trail Moment in T. repens, compared to the reference, for 50% and pure leachate. The response observed appears to be dose-dependent and linear in our experimental conditions. Addition of the leachate to the reference soil induced an increase in Cd Metallothionein-coding mRNA quantity in E. fetida. In addition, expression level of another gene implied in detoxification and coding Phytochelatin synthase was significantly induced in worms exposed to the reference soil spiked with the leachate, regardless presence of T. repens. Thus, T. repens and E. fetida can be used in a complementary manner to assess soil quality. Sensitivities of the test species yield sensitive bioassays as both species responded at low doses despite the buffering effect of the soil. PMID- 22520452 TI - Effects of herbicides and the chytrid fungus Batrachochytrium dendrobatidis on the health of post-metamorphic northern leopard frogs (Lithobates pipiens). AB - Effects of exposure to contaminants such as pesticides along with exposure to pathogens have been listed as two major contributors to the global crisis of declining amphibian populations. These two factors have also been linked in explanations of the causes of these population declines. We conducted a combined exposure experiment to test the hypothesis that exposure to two agricultural herbicides would increase the susceptibility of post-metamorphic northern leopard frogs (Lithobates pipiens) to the amphibian fungal pathogen Batrachochytrium dendrobatidis (Bd). We assessed the independent and interactive effects of these exposures on the health and survival of the frogs. Wild-caught frogs underwent a 21-day exposure to a nominal concentration of either 2.1 MUg/L atrazine (Aatrex((r)) Liquid 480) or 100 MUg a.e./L glyphosate (Roundup((r)) Original), followed by Bd, and then were observed until 94 days post-initial exposure to the herbicides. Actual levels of atrazine were between 4.28 +/- 0.04 MUg/L and 1.70 +/- 0.26 MUg/L while glyphosate degraded from 100 MUg a.e./L to approximately 7 MUg a.e./L within 6 days of initial exposure to the herbicides. Compared to controls, the glyphosate formulation reduced the snout-vent length of frogs during the pesticide exposure (at Day 21), and the atrazine formulation reduced gain in mass up to Day 94. No treatment affected survival, splenosomatic or hepatosomatic indices, the densities and sizes of hepatic and splenic melanomacrophage aggregates, the density and size of hepatic granulomas, proportions of circulating leucocytes, the ratio of neutrophils to lymphocytes, or the ratio of leucocytes to erythrocytes. Histological assessment of samples collected at Day 94 revealed no evidence of Bd infection in any Bd-exposed frogs, while real-time PCR detected only one case of light infection in a single atrazine- and Bd-exposed frog. Frogs exposed to Bd shed their skin significantly more frequently than Bd-unexposed frogs, which may have helped them resist or clear infection, and could explain why no interaction between the herbicides and Bd was detected. The results suggest that these frogs were resistant to Bd infection and that pre-exposure to the herbicides did not alter this resistance. The effects seen on the growth following herbicide exposure is a concern, as reduced growth can lower the reproductive success and survival of the amphibians. PMID- 22520453 TI - Dissipation of pyraclostrobin and its metabolite BF-500-3 in maize under field conditions. AB - The dissipation and residue of pyraclostrobin and its metabolite BF-500-3 in maize under field conditions were investigated. A sensitive, simple and fast method for simultaneous determination of pyraclostrobin and BF-500-3 in maize matrix was established by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The average recoveries of pyraclostrobin and BF-500-3 were found in the range of 83.6-104.9% with relative standard deviations (RSDs) of 2.3-10.0%. The results showed that pyraclostrobin dissipated quickly in maize plant with half-lives of 1.6-1.7 days. Its metabolite BF-500-3 showed a tendency of rapid increasing initially and decreasing afterwards. At harvest time, the terminal residues of pyraclostrobin were below the maximum residue limit (MRL) set by USA and Canada in maize grain when measured 7 days after the final application, which suggested that the use of this fungicide was safe for humans. The results could provide guidance to safe and reasonable use of pyraclostrobin in agriculture. PMID- 22520454 TI - Long-term management of CKD-mineral and bone disorder. AB - Chronic kidney disease-mineral and bone disorder (CKD-MBD) is the term used to describe the abnormalities of bone and mineral metabolism that occur in the setting of kidney disease. The spectrum of these abnormalities is wide, ranging from severe high-turnover bone disease on one end to marked low bone turnover bone disease on the other. Similarly, some patients have severe vascular calcifications while others do not, and the values for biochemistry determinations, including calcium, phosphorus, and parathyroid hormone, also may vary widely among patients. This variability may be influenced by such things as the chronicity of the particular kidney disease, effects of therapies such as corticosteroids on modifying the course of kidney disease, and comorbid conditions, such as diabetes, heart disease, age, and osteoporosis. The heterogeneity of CKD-MBD makes strict protocol-driven therapeutic approaches difficult; accordingly, considerable individualized therapy is required. Using a case history, we explore several of the variables and difficulties involved in patient management. PMID- 22520455 TI - Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures. AB - Cannabis sativa has been associated with contradictory effects upon seizure states despite its medicinal use by numerous people with epilepsy. We have recently shown that the phytocannabinoid cannabidiol (CBD) reduces seizure severity and lethality in the well-established in vivo model of pentylenetetrazole-induced generalised seizures, suggesting that earlier, small scale clinical trials examining CBD effects in people with epilepsy warrant renewed attention. Here, we report the effects of pure CBD (1, 10 and 100mg/kg) in two other established rodent seizure models, the acute pilocarpine model of temporal lobe seizure and the penicillin model of partial seizure. Seizure activity was video recorded and scored offline using model-specific seizure severity scales. In the pilocarpine model CBD (all doses) significantly reduced the percentage of animals experiencing the most severe seizures. In the penicillin model, CBD (>= 10 mg/kg) significantly decreased the percentage mortality as a result of seizures; CBD (all doses) also decreased the percentage of animals experiencing the most severe tonic-clonic seizures. These results extend the anti-convulsant profile of CBD; when combined with a reported absence of psychoactive effects, this evidence strongly supports CBD as a therapeutic candidate for a diverse range of human epilepsies. PMID- 22520456 TI - Diffusion tensor imaging in radiosurgical callosotomy. AB - Callosotomy by radioneurosurgery induces slow and progressive axonal degeneration of white matter fibers, a key consequence of neuronal or axonal injury (radionecrosis). However, the acute effects are not apparent when using conventional MRI techniques. Diffusion tensor imaging (DTI) during the first week following radioneurosurgical callosotomy allowed evaluation of these microstructural changes. The present report details that the use of sequential DTI to evaluate axonal degeneration following radioneurosurgical callosotomy in a patient normalized with the data of six healthy subjects. We describe a 25-year old woman with symptomatic generalized epilepsy who underwent a radioneurosurgical callosotomy using LINAC (Novalis(r) BrainLAB). DTI was acquired at the baseline, 3 and 9 months and showed a progressive decrease of the fractional anisotropy values in the irradiated areas compared to the controls that could be interpreted as a progressive disconnection of callosal fibers related to the outcome. PMID- 22520457 TI - The influence of heel height on patellofemoral joint kinetics during walking. AB - Although wearing high-heeled shoes has long been considered a risk factor for the development for patellofemoral pain (PFP) in women, patellofemoral joint kinetics during high-heeled gait has not been examined. The purpose of this study was to determine if heel height increases patellofemoral joint loading during walking. Eleven healthy women (mean age 25.0+/-3.1 yrs) participated. Lower extremity kinematics and kinetics were obtained under 3 different shoe conditions: low heel (1.27 cm), medium heel (6.35 cm), and high heel (9.53 cm). Patellofemoral joint stress was estimated using a previously described biomechanical model. Model outputs included patellofemoral joint reaction force, patellofemoral joint stress and utilized contact area as a function of the gait cycle. One-way ANOVAs with repeated measures were used to compare the model outputs and knee joint angles among the 3 shoe conditions. Peak patellofemoral joint stress was found to increase significantly (p=0.002) with increasing heel height (low heel: 1.9+/-0.7 MPa, medium heel: 2.6+/-1.2 MPa, and high heel: 3.6+/-1.5 MPa). The increased patellofemoral joint stress was mainly driven by an increase in joint reaction force owing to higher knee extensor moments and knee flexion angles. Our findings support the premise that wearing high-heeled shoes may be a contributing factor with respect to the development of PFP. PMID- 22520458 TI - Shigella navigates tight corners. AB - In this issue, Fukumatsu and colleagues (2012) find that Shigella preferentially spread from cell-to-cell at unique intercellular junctions. Shigella protrusions invade adjacent cells at junctions where three cells meet, the tricellular junction. The tight junction protein tricellulin marks these sites and is important for Shigella spread. PMID- 22520459 TI - UnZIPping mechanisms of effector-triggered immunity in animals. AB - The mechanisms by which epithelial cells distinguish pathogens from commensal microbes have long puzzled us. Now, McEwan et al. (2012) and Dunbar et al. (2012), in this issue of Cell Host & Microbe, demonstrate that in C. elegans, microbial toxin-induced inhibition of host cellular functions, especially blockade of protein translation, activates the effector-triggered immune response dependent on the transcription factor ZIP-2. PMID- 22520460 TI - Be a good neighbor: organ-to-organ communication during the innate immune response. AB - Local infection in the Drosophila larval intestine elicits a systemic immune reaction in fat bodies. In this issue, Wu and colleagues (2012) show that this is a reactive oxygen species-dependent communication. PMID- 22520461 TI - Shigella targets epithelial tricellular junctions and uses a noncanonical clathrin-dependent endocytic pathway to spread between cells. AB - Bacteria move between cells in the epithelium using a sequential pseudopodium mediated process but the underlying mechanisms remain unclear. We show that during cell-to-cell movement, Shigella-containing pseudopodia target epithelial tricellular junctions, the contact point where three epithelial cells meet. The bacteria-containing pseudopodia were engulfed by neighboring cells only in the presence of tricellulin, a protein essential for tricellular junction integrity. Shigella cell-to-cell spread, but not pseudopodium protrusion, also depended on phosphoinositide 3-kinase, clathrin, Epsin-1, and Dynamin-2, which localized beneath the plasma membrane of the engulfing cell. Depleting tricellulin, Epsin 1, clathrin, or Dynamin-2 expression reduced Shigella cell-to-cell spread, whereas AP-2, Dab2, and Eps15 were not critical for this process. Our findings highlight a mechanism for Shigella dissemination into neighboring cells via targeting of tricellular junctions and a noncanonical clathrin-dependent endocytic pathway. PMID- 22520462 TI - Yersinia pseudotuberculosis effector YopJ subverts the Nod2/RICK/TAK1 pathway and activates caspase-1 to induce intestinal barrier dysfunction. AB - Yersinia pseudotuberculosis is an enteropathogenic bacteria that disrupts the intestinal barrier and invades its host through gut-associated lymphoid tissue and Peyer's patches (PP). We show that the Y. pseudotuberculosis effector YopJ induces intestinal barrier dysfunction by subverting signaling of the innate immune receptor Nod2, a phenotype that can be reversed by pretreating with the Nod2 ligand muramyl-dipeptide. YopJ, but not the catalytically inactive mutant YopJ(C172A), acetylates critical sites in the activation loops of the RICK and TAK1 kinases, which are central mediators of Nod2 signaling, and decreases the affinity of Nod2 for RICK. Concomitantly, Nod2 interacts with and activates caspase-1, resulting in increased levels of IL-1beta. Finally, IL-1beta within PP plays an essential role in inducing intestinal barrier dysfunction. Thus, YopJ alters intestinal permeability and promotes the dissemination of Yersinia as well as commensal bacteria by exploiting the mucosal inflammatory response. PMID- 22520463 TI - Strong immunogenicity and cross-reactivity of Mycobacterium tuberculosis ESX-5 type VII secretion: encoded PE-PPE proteins predicts vaccine potential. AB - The genome of Mycobacterium tuberculosis (Mtb) encodes five type VII secretion systems, ESX-1 to ESX-5, most of which are associated with genes encoding PE/PPE proteins, named after their N-terminal Pro-Glu (PE) or Pro-Pro-Glu (PPE) motifs. Here, we describe the strong T cell immunogenicity of the ESX-5-encoded PE/PPE proteins, which share a large panel of cross-reactive CD4(+) epitopes with substantial numbers of their ESX-5-nonassociated PE/PPE homologs. The immunogenicity of these numerous PE/PPE proteins is dependent on their export by a functional EccD(5), the predicted transmembrane channel of the ESX-5 secretion apparatus. The Mtb Deltappe25-pe19 mutant deleted for all ESX-5-associated pe and ppe genes, although highly attenuated in immunocompetent mice, remains able to induce immunity against the ESX-5-associated PE/PPE virulence factors, via cross reactivity with their numerous homologs, and against the ESX-1 virulence factors ESAT-6/CFP-10. The Deltappe25-pe19 strain is strongly protective against Mtb infection in mice and represents a potential antituberculosis vaccine candidate. PMID- 22520464 TI - Host translational inhibition by Pseudomonas aeruginosa Exotoxin A Triggers an immune response in Caenorhabditis elegans. AB - Intestinal epithelial cells are exposed to both innocuous and pathogenic microbes, which need to be distinguished to mount an effective immune response. To understand the mechanisms underlying pathogen recognition, we investigated how Pseudomonas aeruginosa triggers intestinal innate immunity in Caenorhabditis elegans, a process independent of Toll-like pattern recognition receptors. We show that the P. aeruginosa translational inhibitor Exotoxin A (ToxA), which ribosylates elongation factor 2 (EF2), upregulates a significant subset of genes normally induced by P. aeruginosa. Moreover, immune pathways involving the ATF-7 and ZIP-2 transcription factors, which protect C. elegans from P. aeruginosa, are required for preventing ToxA-mediated lethality. ToxA-responsive genes are not induced by enzymatically inactive ToxA protein but can be upregulated independently of ToxA by disruption of host protein translation. Thus, C. elegans has a surveillance mechanism to recognize ToxA through its effect on protein translation rather than by direct recognition of either ToxA or ribosylated EF2. PMID- 22520465 TI - C. elegans detects pathogen-induced translational inhibition to activate immune signaling. AB - Pathogens commonly disrupt host cell processes or cause damage, but the surveillance mechanisms used by animals to monitor these attacks are poorly understood. Upon infection with pathogenic Pseudomonas aeruginosa, the nematode C. elegans upregulates infection response gene irg-1 using the zip-2 bZIP transcription factor. Here we show that P. aeruginosa infection inhibits mRNA translation in the intestine via the endocytosed translation inhibitor Exotoxin A, which leads to an increase in ZIP-2 protein levels. In the absence of infection we find that the zip-2/irg-1 pathway is upregulated following disruption of several core host processes, including inhibition of mRNA translation. ZIP-2 induction is conferred by a conserved upstream open reading frame in zip-2 that could derepress ZIP-2 translation upon infection. Thus, translational inhibition, a common pathogenic strategy, can trigger activation of an immune surveillance pathway to provide host defense. PMID- 22520466 TI - Lactocepin secreted by Lactobacillus exerts anti-inflammatory effects by selectively degrading proinflammatory chemokines. AB - The intestinal microbiota has been linked to inflammatory bowel diseases (IBD), and oral treatment with specific bacteria can ameliorate IBD. One bacterial mixture, VSL#3, containing Lactobacillus, Bifidobacterium, and Streptococcus, was clinically shown to reduce inflammation in IBD patients and normalize intestinal levels of IP-10, a lymphocyte-recruiting chemokine, in a murine colitis model. We identified Lactobacillus paracasei prtP-encoded lactocepin as a protease that selectively degrades secreted, cell-associated, and tissue-distributed IP-10, resulting in significantly reduced lymphocyte recruitment after intraperitoneal injection in an ileitis model. A human Lactobacillus casei isolate was also found to encode lactocepin and degrade IP-10. L. casei feeding studies in a murine colitis model (T cell transferred Rag2(-/-) mice) revealed that a prtP-disruption mutant was significantly less potent in reducing IP-10 levels, T cell infiltration and inflammation in cecal tissue compared to the isogenic wild-type strain. Thus, lactocepin-based therapies may be effective treatments for chemokine-mediated diseases like IBD. PMID- 22520468 TI - Infection-induced intestinal oxidative stress triggers organ-to-organ immunological communication in Drosophila. AB - Local infections can trigger immune responses in distant organs, and this interorgan immunological crosstalk helps maintain immune homeostasis. We find that enterobacterial infection or chemically and genetically stimulating reactive oxygen species (ROS)-induced stress responses in the Drosophila gut triggers global antimicrobial peptide (AMP) responses in the fat body, a major immune organ in flies. ROS stress induces nitric oxide (NO) production in the gut, which triggers production of the AMP Diptericin, but not Drosomycin, in the fat body. Hemocytes serve as a signaling relay for communication between intestinal ROS/NO signaling and fat body AMP responses. The induction of AMP responses requires Rel/NF-kappaB activation within the fat body. Although Rel-mediated Drosomycin induction is repressed by the AP-1 transcription factor, this repressor activity is inhibited by intestinal ROS. Thus, intestinal ROS signaling plays an important role in initiating gut-to-fat body immunological communication in Drosophila. PMID- 22520467 TI - Nondegradative role of Atg5-Atg12/ Atg16L1 autophagy protein complex in antiviral activity of interferon gamma. AB - Host resistance to viral infection requires type I (alpha/beta) and II (gamma) interferon (IFN) production. Another important defense mechanism is the degradative activity of macroautophagy (herein autophagy), mediated by the coordinated action of evolutionarily conserved autophagy proteins (Atg). We show that the Atg5-Atg12/Atg16L1 protein complex, whose prior known function is in autophagosome formation, is required for IFNgamma-mediated host defense against murine norovirus (MNV) infection. Importantly, the direct antiviral activity of IFNgamma against MNV in macrophages required Atg5-Atg12, Atg7, and Atg16L1, but not induction of autophagy, the degradative activity of lysosomal proteases, fusion of autophagosomes and lysosomes, or the Atg8-processing protein Atg4B. IFNgamma, via Atg5-Atg12/Atg16L1, inhibited formation of the membranous cytoplasmic MNV replication complex, where Atg16L1 localized. Thus, the Atg5 Atg12/Atg16L1 complex performs a pivotal, nondegradative role in IFNgamma mediated antiviral defense, establishing that multicellular organisms have evolved to use portions of the autophagy pathway machinery in a cassette-like fashion for host defense. PMID- 22520469 TI - Simulating a base population in honey bee for molecular genetic studies. AB - BACKGROUND: Over the past years, reports have indicated that honey bee populations are declining and that infestation by an ecto-parasitic mite (Varroa destructor) is one of the main causes. Selective breeding of resistant bees can help to prevent losses due to the parasite, but it requires that a robust breeding program and genetic evaluation are implemented. Genomic selection has emerged as an important tool in animal breeding programs and simulation studies have shown that it yields more accurate breeding value estimates, higher genetic gain and low rates of inbreeding. Since genomic selection relies on marker data, simulations conducted on a genomic dataset are a pre-requisite before selection can be implemented. Although genomic datasets have been simulated in other species undergoing genetic evaluation, simulation of a genomic dataset specific to the honey bee is required since this species has a distinct genetic and reproductive biology. Our software program was aimed at constructing a base population by simulating a random mating honey bee population. A forward-time population simulation approach was applied since it allows modeling of genetic characteristics and reproductive behavior specific to the honey bee. RESULTS: Our software program yielded a genomic dataset for a base population in linkage disequilibrium. In addition, information was obtained on (1) the position of markers on each chromosome, (2) allele frequency, (3) chi(2) statistics for Hardy Weinberg equilibrium, (4) a sorted list of markers with a minor allele frequency less than or equal to the input value, (5) average r(2) values of linkage disequilibrium between all simulated marker loci pair for all generations and (6) average r2 value of linkage disequilibrium in the last generation for selected markers with the highest minor allele frequency. CONCLUSION: We developed a software program that takes into account the genetic and reproductive biology specific to the honey bee and that can be used to constitute a genomic dataset compatible with the simulation studies necessary to optimize breeding programs. The source code together with an instruction file is freely accessible at http://msproteomics.org/Research/Misc/honeybeepopulationsimulator.html. PMID- 22520470 TI - Small molecule bromodomain inhibitors: extending the druggable genome. PMID- 22520471 TI - TRPV1 antagonists: clinical setbacks and prospects for future development. PMID- 22520472 TI - Multivalent dual pharmacology muscarinic antagonist and beta2 agonist (MABA) molecules for the treatment of COPD. PMID- 22520473 TI - Hematopoietic prostaglandin D synthase inhibitors. PMID- 22520474 TI - The large scale restructuring of pharmaceutical company research function. Preface. PMID- 22520475 TI - Changes in cervical cancer FDG uptake during chemoradiation and association with response. AB - PURPOSE: Previous research showed that pretreatment uptake of F-18 fluorodeoxyglucose (FDG), as assessed by the maximal standardized uptake value (SUVmax) and the variability of uptake (FDGhetero), predicted for posttreatment response in cervical cancer. In this pilot study, we evaluated the changes in SUVmax and FDGhetero during concurrent chemoradiation for cervical cancer and their association with post-treatment response. METHODS AND MATERIALS: Twenty five patients with stage Ib1-IVa cervical cancer were enrolled. SUVmax, FDGhetero, and metabolic tumor volume (MTV) were recorded from FDG-positron emission tomography (PET)/computed tomography (CT) scans performed pretreatment and during weeks 2 and 4 of treatment and were evaluated for changes and association with response assessed on 3-month post-treatment FDG-PET/CT. RESULTS: For all patients, the average pretreatment SUVmax was 17.8, MTV was 55.4 cm3, and FDGhetero was -1.33. A similar decline in SUVmax was seen at week 2 compared with baseline and week 4 compared with week 2 (34%). The areas of highest FDG uptake in the tumor remained relatively consistent on serial scans. Mean FDGhetero decreased during treatment. For all patients, MTV decreased more from week 2 to week 4 than from pretreatment to week 2. By week 4, the average SUVmax had decreased by 57% and the MTV had decreased by 30%. Five patients showed persistent or new disease on 3-month post-treatment PET. These poor responders showed a higher average SUVmax, larger MTV, and greater heterogeneity at all 3 times. Week 4 SUVmax (P=.037), week 4 FDGhetero (P=.005), pretreatment MTV (P=.008), and pretreatment FDGhetero (P=.008) were all significantly associated with post-treatment PET response. CONCLUSIONS: SUVmax shows a consistent rate of decline during treatment and declines at a faster rate than MTV regresses. Based on this pilot study, pretreatment and week 4 of treatment represent the best time points for prediction of response. PMID- 22520476 TI - Prediction of liver function by using magnetic resonance-based portal venous perfusion imaging. AB - PURPOSE: To evaluate whether liver function can be assessed globally and spatially by using volumetric dynamic contrast-enhanced magnetic resonance imaging MRI (DCE-MRI) to potentially aid in adaptive treatment planning. METHODS AND MATERIALS: Seventeen patients with intrahepatic cancer undergoing focal radiation therapy (RT) were enrolled in institution review board-approved prospective studies to obtain DCE-MRI (to measure regional perfusion) and indocyanine green (ICG) clearance rates (to measure overall liver function) prior to, during, and at 1 and 2 months after treatment. The volumetric distribution of portal venous perfusion in the whole liver was estimated for each scan. We assessed the correlation between mean portal venous perfusion in the nontumor volume of the liver and overall liver function measured by ICG before, during, and after RT. The dose response for regional portal venous perfusion to RT was determined using a linear mixed effects model. RESULTS: There was a significant correlation between the ICG clearance rate and mean portal venous perfusion in the functioning liver parenchyma, suggesting that portal venous perfusion could be used as a surrogate for function. Reduction in regional venous perfusion 1 month after RT was predicted by the locally accumulated biologically corrected dose at the end of RT (P<.0007). Regional portal venous perfusion measured during RT was a significant predictor for regional venous perfusion assessed 1 month after RT (P<.00001). Global hypovenous perfusion pre-RT was observed in 4 patients (3 patients with hepatocellular carcinoma and cirrhosis), 3 of whom had recovered from hypoperfusion, except in the highest dose regions, post-RT. In addition, 3 patients who had normal perfusion pre-RT had marked hypervenous perfusion or reperfusion in low-dose regions post-RT. CONCLUSIONS: This study suggests that MR-based volumetric hepatic perfusion imaging may be a biomarker for spatial distribution of liver function, which could aid in individualizing therapy, particularly for patients at risk for liver injury after RT. PMID- 22520477 TI - Low p53 binding protein 1 (53BP1) expression is associated with increased local recurrence in breast cancer patients treated with breast-conserving surgery and radiotherapy. AB - PURPOSE: To investigate whether the expression of p53 binding protein 1 (53BP1) has prognostic significance in a cohort of early-stage breast cancer patients treated with breast-conserving surgery and radiotherapy (BCS+RT). METHODS AND MATERIALS: A tissue microarray of early-stage breast cancer treated with BCS+RT from a cohort of 514 women was assayed for 53BP1, estrogen receptor, progesterone receptor, and HER2 expression by immunohistochemistry. Through log-rank tests and univariate and multivariate models, the staining profile of each tumor was correlated with clinical endpoints, including ipsilateral breast recurrence-free survival (IBRFS), distant metastasis-free survival (DMFS), cause-specific survival (CSS), recurrence-free survival (RFS), and overall survival (OS). RESULTS: Of the 477 (93%) evaluable tumors, 63 (13%) were scored as low. Low expression of 53BP1 was associated with worse outcomes for all endpoints studied, including 10-year IBRFS (76.8% vs. 90.5%; P=.01), OS (66.4% vs. 81.7%; P=.02), CSS (66.0% vs. 87.4%; P<.01), DMFS (55.9% vs. 87.0%; P<.01), and RFS (45.2% vs. 80.6%; P<.01). Multivariate analysis incorporating various clinico-pathologic markers and 53BP1 expression found that 53BP1 expression was again an independent predictor of all endpoints (IBRFS: P=.0254; OS: P=.0094; CSS: P=.0033; DMFS: P=.0006; RFS: P=.0002). Low 53BP1 expression was also found to correlate with triple-negative (TN) phenotype (P<.01). Furthermore, in subset analysis of all TN breast cancer, negative 53BP1 expression trended for lower IBRFS (72.3% vs. 93.9%; P=.0361) and was significant for worse DMFS (48.2% vs. 86.8%; P=.0035) and RFS (37.8% vs. 83.7%; P=.0014). CONCLUSION: Our data indicate that low 53BP1 expression is an independent prognostic indicator for local relapse among other endpoints in early-stage breast cancer and TN breast cancer patients treated with BCS+RT. These results should be verified in larger cohorts of patients to validate their clinical significance. PMID- 22520478 TI - Molecular profiling to optimize treatment in non-small cell lung cancer: a review of potential molecular targets for radiation therapy by the translational research program of the radiation therapy oncology group. AB - Therapeutic decisions in non-small cell lung cancer (NSCLC) have been mainly based on disease stage, performance status, and co-morbidities, and rarely on histological or molecular classification. Rather than applying broad treatments to unselected patients that may result in survival increase of only weeks to months, research efforts should be, and are being, focused on identifying predictive markers for molecularly targeted therapy and determining genomic signatures that predict survival and response to specific therapies. The availability of such targeted biologics requires their use to be matched to tumors of corresponding molecular vulnerability for maximum efficacy. Molecular markers such as epidermal growth factor receptor (EGFR), K-ras, vascular endothelial growth factor (VEGF), mammalian target of rapamycin (mTOR), and anaplastic lymphoma kinase (ALK) represent potential parameters guide treatment decisions. Ultimately, identifying patients who will respond to specific therapies will allow optimal efficacy with minimal toxicity, which will result in more judicious and effective application of expensive targeted therapy as the new paradigm of personalized medicine develops. PMID- 22520479 TI - Clinical value of [11C]methionine PET for stereotactic radiation therapy with intensity modulated radiation therapy to metastatic brain tumors. AB - PURPOSE: This study investigated the clinical impact of (11)C-labeled methionine positron emission tomography (MET-PET) for stereotactic radiation therapy with intensity modulated radiation therapy (SRT-IMRT) in metastatic brain tumors. METHODS AND MATERIALS: Forty-two metastatic brain tumors were examined. All tumors were treated with SRT-IMRT using a helical tomotherapy system. Gross tumor volume (GTV) was defined and drawn on the stereotactic magnetic resonance (MR) image, taking into account the respective contributions of MR imaging and MET PET. Planning target volume (PTV) encompassed the GTV-PET plus a 2-mm margin. SRT IMRT was performed, keeping the dose for PTV at 25-35 Gy in 5 fractions. The ratio of the mean value of MET uptake to the contralateral normal brain (L/N ratio) was plotted for the PTV prior to SRT-IMRT, at 3 months following SRT-IMRT, and at 6 months following SRT-IMRT. Tumor characteristic changes of MET uptake before and after SRT-IMRT were evaluated quantitatively, comparing them with MRI examination. RESULTS: Mean +/- SD L/N ratios were 1.95 +/- 0.83, 1.18 +/- 0.21, and 1.12 +/- 0.25 in the pre-SRT-IMRT group, in the 3 months post-SRT-IMRT group, and in the 6 months post-SRT-IMRT group, respectively. Differences in the mean L/N ratio between the pre-SRT-IMRT group and the 3-month post-SRT-IMRT group and between the pre-SRT-IMRT group and the 6 month post-SRT-IMRT group were statistically significant, irrespective of MRI examination. CONCLUSIONS: We showed examples of metastatic lesions demonstrating significant decreases in MET uptake following SRT-IMRT. MET-PET seems to have a potential role in providing additional information, although MRI remains the gold standard for diagnosis and follow-up after SRT-IMRT. The present study is a preliminary approach, but to more clearly define the impact of PET-based radiosurgical assessment, further experimental and clinical analyses are required. PMID- 22520480 TI - Excellence in Radiation Research for the 21st Century (EIRR21): description of an innovative research training program. AB - PURPOSE: To describe and assess an interdisciplinary research training program for graduate students, postdoctoral fellows, and clinical fellows focused on radiation medicine; funded by the Canadian Institutes for Health Research since 2003, the program entitled "Excellence in Radiation Research for the 21st Century" (EIRR21) aims to train the next generation of interdisciplinary radiation medicine researchers. METHODS AND MATERIALS: Online surveys evaluating EIRR21 were sent to trainees (n=56), mentors (n=36), and seminar speakers (n=72). Face-to-face interviews were also conducted for trainee liaisons (n=4) and participants in the international exchange program (n=2). RESULTS: Overall response rates ranged from 53% (mentors) to 91% (trainees). EIRR21 was well received by trainees, with the acquisition of several important skills related to their research endeavors. An innovative seminar series, entitled Brainstorm sessions, imparting "extracurricular" knowledge in intellectual property protection, commercialization strategies, and effective communication, was considered to be the most valuable component of the program. Networking with researchers in other disciplines was also facilitated owing to program participation. CONCLUSIONS: EIRR21 is an innovative training program that positively impacts the biomedical community and imparts valuable skill sets to foster success for the future generation of radiation medicine researchers. PMID- 22520481 TI - Radiotherapy for management of extremity soft tissue sarcomas: why, when, and where? AB - This critical review will focus on published data on the indications for radiotherapy in patients with extremity soft tissue sarcomas and its role in local control, survival, and treatment complications. The differences between pre and postoperative radiotherapy will be discussed and consensus recommendations on target volume delineation proposed. PMID- 22520482 TI - Magnetic resonance lymphography findings in patients with biochemical recurrence after prostatectomy and the relation with the Stephenson nomogram. AB - PURPOSE: To estimate the occurrence of positive lymph nodes on magnetic resonance lymphography (MRL) in patients with a prostate-specific antigen (PSA) recurrence after prostatectomy and to investigate the relation between score on the Stephenson nomogram and lymph node involvement on MRL. METHODS AND MATERIALS: Sixty-five candidates for salvage radiation therapy were referred for an MRL to determine their lymph node status. Clinical and histopathologic features were recorded. For 49 patients, data were complete to calculate the Stephenson nomogram score. Receiver operating characteristic (ROC) analysis was performed to determine how well this nomogram related to the MRL result. Analysis was done for the whole group and separately for patients with a PSA <1.0 ng/mL to determine the situation in candidates for early salvage radiation therapy, and for patients without pathologic lymph nodes at initial lymph node dissection. RESULTS: MRL detected positive lymph nodes in 47 patients. ROC analysis for the Stephenson nomogram yielded an area under the curve (AUC) of 0.78 (95% confidence interval, 0.61-0.93). Of 29 patients with a PSA <1.0 ng/mL, 18 had a positive MRL. Of 37 patients without lymph node involvement at initial lymph node dissection, 25 had a positive MRL. ROC analysis for the Stephenson nomogram showed AUCs of 0.84 and 0.74, respectively, for these latter groups. CONCLUSION: MRL detected positive lymph nodes in 72% of candidates for salvage radiation therapy, in 62% of candidates for early salvage radiation therapy, and in 68% of initially node negative patients. The Stephenson nomogram showed a good correlation with the MRL result and may thus be useful for identifying patients with a PSA recurrence who are at high risk for lymph node involvement. PMID- 22520483 TI - [Renal abnormalities in ankylosing spondylitis]. AB - We will study the epidemiologic, clinical, biological, therapeutic, prognostic characteristics and predictive factors of development of nephropathy in ankylosing spondylitis patients. We retrospectively reviewed the medical record of 32 cases with renal involvement among 212 cases of ankylosing spondylitis followed in our service during the period spread out between 1978 and 2006. The renal involvement occurred in all patients a mean of 12 years after the clinical onset of the rheumatic disease. Thirty-two patients presented one or more signs of renal involvement: microscopic hematuria in 22 patients, proteinuria in 23 patients, nephrotic syndrome in 11 patients and decreased renal function in 24 patients (75%). Secondary renal amyloidosis (13 patients), which corresponds to a prevalence of 6,1% and tubulointerstitial nephropathy (7 patients) were the most common cause of renal involvement in ankylosing spondylitis followed by IgA nephropathy (4 patients). Seventeen patients evolved to the end stage renal disease after an average time of 29.8 +/- 46 months. The average follow-up of the patients was 4,4 years. By comparing the 32 patients presenting a SPA and renal disease to 88 with SPA and without nephropathy, we detected the predictive factors of occurred of nephropathy: tobacco, intense inflammatory syndrome, sacroileite stage 3 or 4 and presence of column bamboo. The finding of 75% of the patients presented a renal failure at the time of the diagnosis of renal involvement suggests that evidence of renal abnormality involvement should be actively sought in this disease. PMID- 22520484 TI - [Potentialisation of hyperkalemia effects by cinacalcet-induced hypocalcemia on dialysis]. AB - We report on two patients on chronic hemodialysis, who presented with typical symptoms of hyperkalemia (lower limb paresia and characteristic electrocardiogram [ECG]) for an only mildly increased kalemia (6.1 and 6.2 mEq/L), values that are frequently seen in asymptomatic patients on chronic hemodialysis. Their common denominator was a concomitant hypocalcemia (7.5 et 6.4mg/dL) induced by cinacalcet treatment. Hypocalcemia has very likely precipitated the occurrence of clinical and electrocardiological manifestations of hyperkalemia. This observation is in agreement with previous publications showing that, in other clinical situations than the use of cinacalcet, hypocalcemia potentiates the effect of hyperkalemia on muscle membrane. Nephrologists should be aware of this complication and pay most attention in their patients on chronic dialysis with a calcemia less than 8mg/dL induced by cinacalcet treatment. PMID- 22520485 TI - [Estimating glomerular filtration rate in 2012: which adding value for the CKD EPI equation?]. AB - Measuring or estimating glomerular filtration rate (GFR) is still considered as the best way to apprehend global renal function. In 2009, the new Chronic Kidney Disease Epidemiology (CKD-EPI) equation has been proposed as a better estimator of GFR than the Modification of Diet in Renal Disease (MDRD) study equation. This new equation is supposed to underestimate GFR to a lesser degree in higher GFR levels. In this review, we will present and deeply discuss the performances of this equation. Based on articles published between 2009 and 2012, this review will underline advantages, notably the better knowledge of chronic kidney disease prevalence, but also limitations of this new equation, especially in some specific populations. We eventually insist on the fact that all these equations are estimations and nephrologists should remain cautious in their interpretation. PMID- 22520486 TI - Primary mitochondrial arteriopathy. AB - AIM: Whether arteries are affected in mitochondrial disorders (MIDs) was under debate for years but meanwhile there are strong indications that large and small arteries are primarily or secondarily affected in MIDs. DATA SYNTHESIS: When reviewing the literature for appropriate studies it turned out that vascular involvement in MIDs includes primary or secondary micro- or macroangiopathy of the cerebral, cervical, and retinal arteries, the aorta, the iliac arteries, the brachial arteries, or the muscular arteries. Arteriopathy in MIDs manifests as atherosclerosis, stenosis, occlusion, dissection, ectasia, aneurysm formation, or arteriovenous malformation. Direct evidence for primary cerebral microangiopathy comes from histological studies and indirect evidence from imaging and perfusion studies of the brain. Microangiopathy of the retina is highly prevalent in Leber's hereditary optic neuropathy. Macroangiopathy of the carotid arteries may be complicated by stroke. Arteriopathy of the aorta may result in ectasia, aneurysm formation, or even rupture. Further evidence for arteriopathy in MIDs comes from the frequent association of migraine with MIDs and the occurrence of premature atherosclerosis in MID patients without classical risk factors. CONCLUSIONS: Mitochondrial arteriopathy most frequently concerns the cerebral arteries and may result from the underlying metabolic defect or secondary from associated vascular risk factors. Vascular involvement in MIDs has a strong impact on the prognosis and outcome of these patients. PMID- 22520487 TI - A method for estimation of plasma albumin concentration from the buffering properties of whole blood. AB - PURPOSE: Hypoalbuminemia is strongly associated with poor clinical outcome. Albumin is usually measured at the central laboratory rather than point of care, but in principle, information exists in the buffering properties of whole blood to estimate plasma albumin concentration from point of care measurements of acid base and oxygenation status. This article presents and evaluates a new method for doing so. MATERIALS AND METHODS: The mathematical method for estimating plasma albumin concentration is described. To evaluate the method at numerous albumin concentrations, blood from 19 healthy subjects was diluted at 3 different levels giving 57 data sets. Calculated and measured plasma albumin concentrations were compared using correlation coefficient (r(2)), regression line, and Bland-Altman bias and limits of agreement. RESULTS: Albumin levels covered the clinically interesting range from 8.8 to 53.3 g/L. Calculated and measured plasma albumin concentrations compared well with r(2) = 0.9, a regression line of albumin calculated = 1.05 * albumin-measured - 2.25, a small average bias between measured and calculated values of 0.7 g/L, and Bland-Altman limits of agreement of 10 g/L. CONCLUSIONS: This new method may be a valuable tool in screening and monitoring plasma albumin concentration in acutely ill patients, from measurements taken at the point of care. PMID- 22520488 TI - Pharmacokinetic changes in patients receiving extracorporeal membrane oxygenation. AB - Extracorporeal membrane oxygenation (ECMO) is a form of prolonged cardiopulmonary bypass used to temporarily sustain cardiac and/or respiratory function in critically ill patients. Extracorporeal membrane oxygenation further complicates the management of critically ill patients who already have profound physiologic derangements with consequent altered pharmacokinetics. The purpose of this study is to identify and critically review the published literature describing pharmacokinetics in the presence of ECMO. This review revealed a dearth of data describing pharmacokinetics during ECMO in critically ill adults, with most of the available data originating in neonates. Of concern, the present data indicate substantial variability and a lack of predictability in drug behavior in the presence of ECMO. The most common mechanisms by which ECMO affects pharmacokinetics are sequestration in the circuit, increased volume of distribution, and decreased drug elimination. While lipophilic drugs and highly protein-bound drugs (eg, voriconazole and fentanyl) are significantly sequestered in the circuit, hydrophilic drugs (eg, beta-lactam antibiotics, glycopeptides) are significantly affected by hemodilution and other pathophysiologic changes that occur during ECMO. Although the published literature is insufficient to make any meaningful recommendations for adjusting therapy for drug dosing, this review systematically describes the available data enabling clinicians to make conclusions based on available data. Furthermore, this review serves to highlight the need for well-designed and conducted clinical and laboratory-based studies to provide the data from which robust dosing guidance can be developed to improve clinical outcomes in this most unwell cohort of patients. PMID- 22520489 TI - Predicting the need for mechanical ventilation in acute exacerbations of chronic obstructive pulmonary disease: comparing the CURB-65 and BAP-65 scores. AB - PURPOSE: Clinicians lack a validated tool for risk stratification for need for mechanical ventilation (MV) in acute exacerbations of chronic obstructive pulmonary disease (AECOPD). We sought to compare 2 risk scores, BAP-65 and CURB 65, at predicting a need for MV in AECOPDs. MATERIALS AND METHODS: We analyzed 34,478 AECOPD admissions to 195 US hospitals (2007). We compared the rates of MV at admission and at any point during hospitalization based on the respective BAP 65 and CURB-65 scores. We compared the accuracy of the 2 scores via the area under the receiver operating characteristic curves. RESULTS: The overall MV rate at admission was 7.9%, and the rate of MV any time equaled 9.3%. Use of MV increased with escalating BAP-65 and CURB-65 scores. The area under the receiver operating characteristic curve for BAP-65 was higher than that for CURB-65 for both early MV, 0.81 (95% confidence interval [CI], 0.80-0.82) vs 0.76 (95% CI, 0.75-0.77), P < .0001, and MV any time, 0.78 (95% CI, 0.77-0.79) vs 0.74 (95% CI, 0.73-0.75), P < .0001. CONCLUSIONS: BAP-65 identifies patients with AECOPD at high risk for need of MV more accurately than does CURB-65. BAP-65 may represent a useful tool for initial MV risk stratification in AECOPD. PMID- 22520490 TI - Muscle strength assessment in critically ill patients with handheld dynamometry: an investigation of reliability, minimal detectable change, and time to peak force generation. AB - PURPOSE: Dynamometry is an objective tool for volitional strength evaluation that may overcome the limited sensitivity of the Medical Research Council scale for manual muscle tests, particularly at grades 4 and 5. The primary aims of this study were to investigate the reliability, minimal detectable change, and time to peak muscle force, measured with portable dynamometry, in critically ill patients. MATERIALS AND METHODS: Isometric hand grip, elbow flexion, and knee extension were measured with portable dynamometry. RESULTS: Interrater consistency (intraclass correlation coefficient [95% confidence interval]) (0.782 [0.321-0.930] to 0.946 [0.840-0.982]) and test-retest agreement (0.819 [0.390 0.943] to 0.918 [0.779-0.970]) were acceptable for all dynamometry forces, with the exception of left elbow flexion. Despite generally good reliability, a mean change (upper 95% confidence interval) of 2.8 (7.8) kg, 1.9 (5.2) kg, and 2.6 (7.1) kg may be required from a patient's baseline force measurement of right grip, elbow flexion, and knee extension to reflect real force changes. There was also a delay in the time for critically ill patients to generate peak muscle forces, compared with healthy controls (P <= .001). CONCLUSIONS: Dynamometry can provide reliable measurements in alert critically ill patients, but moderate changes in strength may be required to overcome measurement error, during the acute recovery period. Deficits in force timing may reflect impaired neuromuscular control. PMID- 22520491 TI - Fractional excretion of urea as a diagnostic index in acute kidney injury in intensive care patients. AB - PURPOSE: Acute kidney injury (AKI) is a dynamic process that evolves from an early reversible condition to an established disease. Value of urine indices in the event of AKI is uncertain in critically ill patients. The aim of this study was to evaluate the performance of fractional excretion of urea (FeU) for differentiating persistent from transient AKI in patients admitted to the intensive care unit. METHODS: This was an observational study. Forty-seven patients with AKI according to the RIFLE classification were included. Transient AKI was defined as AKI resolved within 3 days after inclusion. Persistent AKI was defined as persistent serum creatinine elevation or oliguria. RESULTS: Fractional excretion of urea was lower in case of transient, 33% (25-39), than persistent AKI, 47% (36-61) (P = .001). Areas under the receiver operating characteristic curve for FeU in case of transient AKI were better than those for other urinary indexes, 0.78 (95% confidence interval, 0.63-0.92). Optimal cutoff point according to the receiver operating characteristic curve was 40%. In patients treated with diuretics, FeU was the only predictive index of transient AKI. Fractional excretion of urea gradually increased from days 1 to 7 in transient AKI, whereas plasma creatinine decreased. CONCLUSIONS: Fractional excretion of urea less than 40% was found to be a sensitive and specific index in differentiating transient from persistent AKI in intensive care unit patients especially if diuretics had been administered. PMID- 22520492 TI - Integrating lung ultrasound in the hemodynamic evaluation of acute circulatory failure (the fluid administration limited by lung sonography protocol). AB - In circulatory failure, fluid administration limited by lung sonography protocol uses lung ultrasound artifacts and makes sequential diagnosis of obstructive, cardiogenic, hypovolemic, and septic shock. Lung ultrasound is used along with simple cardiac and vena cava analysis. Whenever echocardiography cannot be performed, fluid administration limited by lung sonography protocol is favored because of its simplicity and could prove contributive. It is based on the presence (B profile) or the absence (A profile) of interstitial pulmonary edema. However, the latter does not represent actual alveolar edema, and transthoracic echocardiography is still used by intensivists as a pivotal hemodynamic measure. Tissue Doppler imaging facilitates the estimation of left ventricular filling pressures, whereas assessing right ventricular function is of prognostic value in states of shock due to massive pulmonary embolism and acute respiratory distress syndrome. In mechanically ventilated patients, poor acoustic windows are evident and performing transesophageal echocardiography may be necessary. Whenever noninvasive hemodynamic measures are inconclusive, in a deteriorating patient, a pulmonary artery catheter may be placed. Ultrasound is not a therapy but a guide for treatment, and physicians should aim to treat underlying pathologies. Despite its limitations, general chest ultrasound (lung and cardiac ultrasound) is a powerful diagnostic and monitoring tool reflecting an era of genuine "visual" medicine. PMID- 22520493 TI - Impact of pattern of admission on outcomes after aneurysmal subarachnoid hemorrhage. AB - OBJECTIVE: Patients with aneurysmal subarachnoid hemorrhage (aSAH) require management in centers with neurosurgical expertise necessitating emergent interhospital transfer (IHT). Our objective was to compare outcomes in aSAH IHTs to our institution with aSAH admissions from our institutional emergency department (ED). METHODS: Data for consecutive patients with aSAH admitted to Johns Hopkins Medical Institutions between 1991 and 2009 were analyzed from a prospectively obtained database. We compared in-hospital mortality and functional outcomes at first clinical appointment post-aSAH (30-120 days) using dichotomized Glasgow Outcome Scale (good outcome: Glasgow Outcome Scale 4-5) in ED admissions with IHTs. RESULTS: A total of 1134 consecutive patients with aSAH were included in analysis (ED 40.1%, IHT 59.9%). Direct ED admissions had a higher incidence of poor Hunt and Hess grade (4/5) and major medical comorbidities, with no significant differences between the 2 groups in age, intraventricular hemorrhage, and hydrocephalus. In-hospital mortality for ED admissions (14.9%) was significantly lower than that for IHTs (20.5%), with 1.8 times greater adjusted odds of survival after multivariate analysis (P = .001). Emergency department admissions had nearly 2-fold greater odds of good outcomes (odds ratio, 1.89; P < .001) after multivariate analysis. CONCLUSIONS: Our institutional ED SAH admissions had significantly better outcomes than did IHTs, suggesting that delays in optimizing care before transfer could deleteriously impact outcomes. PMID- 22520494 TI - Response to a bolus of conivaptan in patients with acute hyponatremia after brain injury. AB - PURPOSE: The aim of the study was to analyze the response to the vasopressin receptor antagonist conivaptan in a large cohort of brain-injured patients with acute hyponatremia. MATERIALS AND METHODS: The natremic response (rise in serum sodium) to an initial bolus of conivaptan was retrospectively evaluated in 124 patients over a 3-year period in our neurosciences intensive care unit. Variables associated with this response were identified using linear regression. RESULTS: Median pretreatment sodium was 132 mEq/L, and duration of hyponatremia before dose was 1 day. Median natremic response was +4 mEq/L (interquartile range, 2-7 mEq/L), measured a median of 9 hours (interquartile range, 6-12 hours) after conivaptan administration. This was associated with significant urine output (median, 2.6 L over 12 hours), with degree of aquaresis associated with natremic response (regression coefficient, B = 1.8 change in sodium per liter; 95% confidence interval, 1.3-2.4; P < .001). Seventy-four patients (60%) responded with a rise of at least 4 mEq/L. Response was predicted by higher baseline urine output (B = 0.018 per mL; 0.004-0.032; P = .01) and lack of oral fluid intake (B = 2.06; 0.44-3.68; P = .01) but not tonicity of intravenous fluids or creatinine clearance. CONCLUSIONS: Conivaptan given as a bolus can effectively treat acute hyponatremia in brain-injured patients. PMID- 22520495 TI - The American Rare Donor Program. AB - The American Rare Donor Program (ARDP), headquartered in Philadelphia, Pennsylvania, maintains a comprehensive database of donors with "rare blood types." The ARDP secures blood and blood products for difficult-to-transfuse patients. Remarkably, a significant number of physicians, both in the United States and abroad, remain unaware of the unique and critical services that the ARDP provides to critical care specialists and their patients. PMID- 22520496 TI - Changes in heart rate, mean arterial pressure, and oxygen saturation after open and closed endotracheal suctioning: a prospective observational study. AB - PURPOSE: It is widely assumed that closed suction systems (CSSs), as compared with open suction systems (OSSs), better guarantee optimal oxygenation with less disturbance of physiologic parameters in mechanically ventilated intensive care patients. We, therefore, quantified changes in heart rate (HR), mean arterial pressure (MAP), and peripheral oxygen saturation (Spo(2)) in patients undergoing endotracheal suctioning (ES) with CSS and OSS. MATERIALS AND METHODS: We performed a prospective observational study nested within a crossover trial in 4 intensive care units between January 2007 and February 2008. Per unit, 50 ES procedures were selected at random, and HR, MAP, and Spo(2) were measured before and after ES. RESULTS: In total, 197 complete ES procedures (103 OSS and 94 CSS) were monitored. Mean HR, MAP, and Spo(2) changed directly after ES and returned to baseline after 5 minutes. Changes in HR and MAP were comparable after using CSS and OSS, whereas in Spo(2), slightly better values were monitored 3 and 5 minutes after OSS, these differences being rather small (0.3%-0.7%) and clinically not relevant. CONCLUSIONS: Changes in HR, MAP, and Spo(2) were comparable and mild during and after CSS and OSS. Both systems can be considered equally safe. PMID- 22520497 TI - Use of an abnormal laboratory value-drug combination alert to detect drug-induced thrombocytopenia in critically Ill patients. AB - PURPOSE: The aim of this study was to assess the performance of a commercially available clinical decision support system (CDSS) drug-laboratory result alert in detecting drug-induced thrombocytopenia in critically ill patients. MATERIALS AND METHODS: Adult patients admitted to the medical and cardiac intensive care unit during an 8-week period and identified by 1 of 3 signals in the CDSS, TheraDoc, were eligible. Alerts were generated when the patient had a low platelet count and was ordered a potentially causal drug. Patients were evaluated in real time for the occurrence of an adverse drug reaction using 3 causality instruments. Positive predictive values were calculated for the alert. RESULTS: Sixty-four patients with a mean age of 54 years met the inclusion criteria, generating 350 alerts. Positive predictive values were 0.36, 0.83, and 0.40 for signals 1, 2, and 3, respectively. Overall, there were 137 adverse drug reactions identified in the 350 alerts, with heparin, vancomycin, and famotidine as the 3 most common potential causes. CONCLUSIONS: A commercial CDSS drug-laboratory alert is effective at identifying drug-induced thrombocytopenia in the intensive care unit and may improve patient safety. Compared with previous studies, the combination alert performs better than alerts based exclusively on laboratory values and should be considered to reduce alert fatigue. PMID- 22520498 TI - The usefulness of immunohistochemistry to differentiate between nasal carcinoma and lymphoma in cats: 140 cases (1986-2000). AB - A retrospective evaluation of 232 feline nasal biopsies initially diagnosed as either carcinoma or lymphoma was performed by two pathologists. One or both pathologists disagreed with the original diagnosis in 15 cases (7%), 14 of which had original diagnoses of carcinoma. Out of the 232 cases, 140, including the disputed ones, were subjected to immunohistochemical staining with epithelial and lymphoid markers. Immunohistochemical staining of the 15 disputed cases showed that the original diagnoses were incorrect in 67% (10/15), unverified in 13% (2/15) and correct in 20% (3/15). Among the consensual diagnoses, immunohistochemistry revealed that 3% (4/125) of diagnoses were unverified because they did not stain for any of the markers evaluated. This report demonstrates the importance of immunohistochemistry in establishing a correct histologic diagnosis for nasal neoplasms in cats. PMID- 22520499 TI - Phytochemicals to suppress Fusarium head blight in wheat-chickpea rotation. AB - Fusarium diseases cause major economic losses in wheat-based crop rotations. Volatile organic compounds (VOC) in wheat and rotation crops, such as chickpea, may negatively impact pathogenic Fusarium. Using the headspace GC-MS method, 16 VOC were found in greenhouse-grown wheat leaves: dimethylamine, 2-methyl-1 propanol, octanoic acid-ethyl ester, acetic acid, 2-ethyl-1-hexanol, nonanoic acid-ethyl ester, nonanol, N-ethyl-benzenamine, naphthalene, butylated hydroxytoluene, dimethoxy methane, phenol, 3-methyl-phenol, 3,4-dimethoxy-phenol, 2,4-bis (1,1-dimethyethyl)-phenol, and 1,4,7,10,13,16-hexaoxacyclooctadecane; and 10 VOC in field-grown chickpea leaves: ethanol, 1-penten-3-ol, 1-hexanol, cis-3 hexen-1-ol, trans-2-hexen-1-ol, trans-2-hexenal, 3-methyl-1-butanol, 3-hydroxy-2 butanone, 3-methyl-benzaldehyde and naphthalene. Also found was 1-penten-3-ol in chickpea roots and in the root nodules of two of the three cultivars tested. Chickpea VOC production pattern was related (P=0.023) to Ascochyta blight severity, suggesting that 1-penten-3-ol and cis-3-hexen-1-ol were induced by Ascochyta rabiei. Bioassays conducted in Petri plates established that chickpea produced VOC used in isolation were generally more potent against Fusarium graminearum and Fusarium avenaceum than wheat-produced VOC, except for 2-ethyl-1 hexanol, which was rare in wheat and toxic to both Fusarium and tetraploid wheat. Whereas exposure to 1-penten-3-ol and 2-methyl-1-propanol could suppress radial growth by over 50% and octanoic acid-ethyl ester, nonanol, and nonanoic acid ethyl ester had only weak effects, F. graminearum and F. avenaceum growth was completely inhibited by exposure to trans-2-hexenal, trans-2-hexen-1-ol, cis-3 hexen-1-ol, and 1-hexanol. Among these VOC, trans-2-hexenal and 1-hexanol protected wheat seedlings against F. avenaceum and F. graminearum, respectively, in a controlled condition experiment. Genetic variation in the production of 2 ethyl-1-hexanol, a potent VOC produced in low amount by wheat, suggests the possibility of selecting Fusarium resistance in wheat on the basis of leaf VOC concentration. Results also suggests that the level of Fusarium inoculum in chickpea-wheat rotation systems may be reduced by growing chickpea genotypes with high root and shoot levels of trans-2-hexen-1-ol and 1-hexanol. PMID- 22520500 TI - Recent trends in assistive technology for mobility. AB - Loss of physical mobility makes maximal participation in desired activities more difficult and in the worst case fully prevents participation. This paper surveys recent work in assistive technology to improve mobility for persons with a disability, drawing on examples observed during a tour of academic and industrial research sites in Europe. The underlying theme of this recent work is a more seamless integration of the capabilities of the user and the assistive technology. This improved integration spans diverse technologies, including powered wheelchairs, prosthetic limbs, functional electrical stimulation, and wearable exoskeletons. Improved integration is being accomplished in three ways: 1) improving the assistive technology mechanics; 2) improving the user-technology physical interface; and 3) sharing of control between the user and the technology. We provide an overview of these improvements in user-technology integration and discuss whether such improvements have the potential to be transformative for people with mobility impairments. PMID- 22520501 TI - Association of RASSF1A genotype and haplotype with the progression of clear cell renal cell carcinoma in Japanese patients. AB - What's known on the subject? and What does the study add? Ras association domain family 1A (RASSF1A) is a tumour suppressor and regulates cell cycle, apoptosis and microtubule stability. This is the first study to identify associations between RASSF1A polymorphisms and clinicopathological parameters and survival in patients with clear cell renal cell carcinoma (CCRCC). RASSF1A genotyping may be useful for predicting the prognosis of the clinical course of CCRCC, and this finding might provide a better understanding of the mechanism underlying the development and progression of CCRCC. However, functional and prospective studies with a larger number of patients are needed to confirm the results. OBJECTIVE: To compare Ras association domain family 1A (RASSF1A) genotypes or haplotypes with clinicopathological characteristics and survival rates of patients with clear cell renal cell carcinoma (CCRCC). PATIENTS AND METHODS: The study cohort comprised 224 Japanese patients who underwent radical nephrectomy and had CCRCC confirmed by histopathological analysis. * Three common polymorphisms in the RASSF1A gene, 133Ala/Ser (G/T), -710C/T and -392C/T, were genotyped using TaqMan assays and haplotypes were analysed using appropriate software. RESULTS: Patients with CCRCC with RASSF1A -710TT genotype exhibited a significantly higher tumour stage and higher stage grouping than those with -710CC or -710CT (P = 0.005 and P = 0.032, respectively). * There was no significant association between 133Ala/Ser or -392C/T genotype and clinicopathological characteristics. * RASSF1A 133Ala 710T-392T haplotype and -710TT genotype were significantly associated with poorer recurrence-free survival rates (P = 0.038 and P = 0.007, respectively). CONCLUSIONS: This is the first study to identify associations between RASSF1A polymorphisms and clinicopathological parameters and survival in patients with CCRCC. * RASSF1A genotyping may be useful in predicting the prognosis of the clinical course of CCRCC, and this finding might provide a better understanding of the mechanism underlying the development and progression of CCRCC. * Functional and prospective studies with a larger number of patients are needed to confirm the results. PMID- 22520502 TI - Characterization of antimicrobial resistance and virulence genes in Enterococcus spp. isolated from retail meats in Alberta, Canada. AB - The objective of this study was to characterize antimicrobial resistance (AMR) and virulence genotypes of Enterococcus spp. particularly Enterococcus faecalis isolated from retail meats purchased (2007-2008) in Alberta, Canada. Unconditional statistical associations between AMR pheno- and genotypes and virulence genotypes were determined. A total of 532 enterococci comprising one isolate from each positive sample were analyzed for antimicrobial susceptibility. A customized enterococcal microarray was used for species identification and the detection of AMR and virulence genes. E. faecalis was found in >94% of poultry samples and in about 73% of beef and 86% of pork samples. Enterococcus faecium was not found in turkey meat and its prevalence was 2% in beef and pork and 4% in chicken samples. None of the enterococci isolates were resistant to the clinically important drugs ciprofloxacin, daptomycin, linezolid and vancomycin. Multiresistance (>=3 antimicrobials) was more common in E. faecalis (91%) isolated from chicken and turkey (91%) than those isolated from beef (14%) or pork (45%). Resistance to aminoglycosides was also noted at varying degrees. The most common resistance genes found in E. faecalis were aminoglycosides (aac, aphA3, aadE, sat4, aadA), macrolides (ermB, ermA), tetracyclines (tetM, tetL, tetO), streptogramin (vatE), bacitracin (bcrR) and lincosamide (linB). Virulence genes expressing aggregation substances (agg) and cytolysin (cylA, cylB, cylL, cylM) were found more frequently in poultry E. faecalis and were unconditionally associated with tetM, linB and bcrR resistance genes. Other virulence genes coding for adhesion (ace, efaAfs), gelatinase (gelE) were also found in the majority of E. faecalis. Significant statistical associations were found between resistance and virulence genotypes, suggesting their possible physical link on a common genetic element. This study underscores the importance of E. faecalis as a reservoir of resistance and virulence genes and their potential transfer to humans through consumption of contaminated undercooked meat. PMID- 22520503 TI - Structure and gene cluster of the O-antigen of Escherichia coli O120. AB - The acidic O-polysaccharide (O-antigen) of Escherichia coli O120 was isolated from the lipopolysaccharide and studied by sugar analysis and NMR spectroscopy. The following structure of the branched hexasaccharide repeating unit was established, which is unique among the known structures of bacterial polysaccharides: [formula see text] The O-antigen gene cluster of E. coli O120 was sequenced. The gene functions were tentatively assigned by comparison with sequences in the available databases and found to be in full agreement with the O polysaccharide structure. PMID- 22520504 TI - Cytotoxic activity of some glycoconjugates including saponins and anthracyclines. AB - Many different glycoconjugates, including saponins (e.g., hellebrin) and anthracyclines (e.g., doxorubicin), are known to display cytotoxic activities. In recent work, we have developed synthetic protocols for the synthesis of various glycoconjugates, focusing on glycosylation methods for different classes of biomolecules. Simultaneously a number of saponins and anthracyclines have been generated. In this note, the cytotoxic activities of these synthesized compounds are briefly addressed. PMID- 22520505 TI - Structural analysis of methyl 6-O-benzyl-2-deoxy-2-dimethylmaleimido-alpha-D allopyranoside by X-ray crystallography, NMR, and QM calculations: hydrogen bonding and comparison of density functionals. AB - The crystal structure of methyl 6-O-benzyl-2-deoxy-2-dimethylmaleimido-alpha-D allopyranoside was solved in order to gain insight into the hydrogen bond features which can be determining features in the glycosylation regioselectivity observed for this compound. An intramolecular hydrogen bond between the hydroxyl H(O)3 and a carbonyl oxygen from the dimethylmaleoyl (DMM) group was observed. This was in agreement with previous NMR temperature shift determinations and molecular modeling. The determination has also found an intermolecular hydrogen bond between the second hydroxyl H(O)4 and the other carbonyl oxygen (generated by symmetry) from DMM. The crystal structure was optimized by five different functionals, namely the hybrid methods B3LYP, M06-2X, B3PW91, and PBE0, and the pure functional PBE, and the optimized geometries were compared with the crystal geometry and with MM3. An excellent coincidence of the geometries was found with the five quantum methods, with minor details deviating from this coincidence. PBE tends to yield larger bond distances, whereas M06-2X fails slightly to match the exocyclic torsion angles for the sugar moiety. In any case, the differences are small, implying that any of these functionals can accurately emulate the geometries of a complex carbohydrate derivative like this one. PMID- 22520506 TI - Essential role of glutamate 317 in galactosyl transfer by alpha3GalT: a computational study. AB - Retaining glycosyltransferases (ret-GTs) are the enzymes responsible for the biosynthesis of highly specific glycosidic bonds and have drawn the interest of the scientific community. The catalytic mechanism of such enzymes is not yet fully understood and its study remains a challenge for both experimental and theoretical researches. In the case of ret-GTs where a well defined nucleophilic agent is identified in the vicinity of the anomeric center, a double-displacement mechanism via a covalent enzyme-glycosyl intermediate is commonly assumed and has received some experimental support, although not direct and univocal evidence has been obtained so far. This is the case for alpha-(1->3)-galactosyltransferase (alpha3GalT), a ret-GT from Bos taurus where a glutamate (Glu317) is in suitable position to act as a nucleophile. Here we perform density functional theory (DFT) quantum mechanics/molecular mechanics (QM/MM) calculations on the full alpha3GalT enzyme to analyze the role of Glu317 in the catalytic process. This is done not only for the double-displacement mechanism, where the function of the nucleophile is obvious, but also in the scenario of a front-side attack mechanism (via an oxocarbenium ion-like transition state (S(N)i) or an ion-pair oxocarbenium intermediate (S(N)i-like)). Glu317 is found to be essential in both cases. For a front-side attack, this residue would have a key role in leaving group departure and consequent stabilization of the increasing positive charge at the anomeric center. This finding alerts on the interpretation of the mutagenesis data as both, the formation of a covalent intermediate and a S(N)i or a S(N)i-like mechanism 'assisted' by a nucleophile, could be consistent with experiment. In addition, it could explain why the covalent enzyme-glycosyl intermediate has never been isolated. PMID- 22520507 TI - Genetic suppression of agrin reduces mania-like behavior in Na+ , K+ -ATPase alpha3 mutant mice. AB - Myshkin mice heterozygous for an inactivating mutation in the neuron-specific Na(+) ,K(+) -ATPase alpha3 isoform show behavior analogous to mania, including an abnormal endogenous circadian period. Agrin is a proteoglycan implicated as a regulator of synapses that has been proposed to inhibit activity of Na(+) ,K(+) ATPase alpha3. We examined whether the mania-related behavior of Myshkin mice could be rescued by a reduction in the expression of agrin through genetic knockout. The suppression of agrin reduced hyperambulation and holeboard exploration, restored anxiety-like behavior (or reduced risk-taking behavior), improved prepulse inhibition and shortened the circadian period. Hence, agrin is important for regulating mania-like behavior and circadian rhythms. In Myshkin mice, the suppression of agrin increased brain Na(+) ,K(+) -ATPase activity by 11 +/- 4%, whereas no effect on Na(+) ,K(+) -ATPase activity was detected when agrin was suppressed in mice without the Myshkin mutation. These results introduce agrin as a potential therapeutic target for the treatment of mania and other neurological disorders associated with reduced Na(+) ,K(+) -ATPase activity and neuronal hyperexcitability. PMID- 22520508 TI - The Y chromosome and the heartache of males. PMID- 22520509 TI - Inflammatory bowel disease in children and adolescents: assessing the diagnostic performance and interreader agreement of magnetic resonance enterography compared to histopathology. AB - RATIONALE AND OBJECTIVES: The purpose of this study was to determine the accuracy of magnetic resonance enterography (MRE) compared to histopathology in the evaluation of pediatric inflammatory bowel disease and to assess interreader reliability for image interpretation. MATERIALS AND METHODS: All magnetic resonance enterography studies performed for known or suspected inflammatory bowel disease between July 2009 and July 2010 were retrospectively reviewed by two pediatric radiologists. Exams were evaluated for signs of enteric inflammation and extraenteric disease. A five-point, Likert-type scale was used to assess the overall likelihood of active inflammation, with scores >= 3 considered positive. Cohen's kappa coefficient was calculated to assess interreader agreement. A subset of patients who had undergone ileocolonoscopy or surgery with confirmed histopathology within 45 days of MRE were used to assess the accuracy of MRE for detecting active inflammation in the terminal ileum and large bowel. RESULTS: A total of 91 magnetic resonance enterography studies were reviewed. Of these, 45 had comparison histopathology within 45 days. The overall sensitivity of MRE for detecting active inflammation compared to ileocolonoscopy was 92% for both readers, while specificity was 100% for reader 1 and 75% for reader 2. Of the individual parameters evaluated, mucosal hyperenhancement and bowel wall thickening were the most sensitive indicators of active inflammation, each having sensitivity of 86% and specificity of 88%. Cohen's kappa coefficient was 0.59, indicating moderate agreement between the readers. CONCLUSIONS: MRE has high overall diagnostic accuracy for detecting active bowel inflammation in pediatric patients compared to ileocolonoscopy and demonstrates moderate interreader reliability. PMID- 22520510 TI - Inhibitory effect of Yukmijihwang-tang, a traditional herbal formula against testosterone-induced benign prostatic hyperplasia in rats. AB - BACKGROUND: Yukmijihwang-tang, a traditional herbal formula, has been used for treating disorder, diabetic mellitus and neurosis in China (Liu-wei-di-huang-tang in Chinese), Japan (Lokumijio-to in Japanese) and Korea for many years. In this study, we investigated the effects of Yukmijihwang-tang water extract (YJT) on the development of benign prostatic hyperplasia (BPH) using a rat model of testosterone propionate (TP)-induced BPH. METHODS: A total of 30 rats were divided into five groups. One group was used as a control and the other groups received subcutaneous injections of TP for 4 weeks to induce BPH. YJT (200 or 400 mg/kg) was administered daily for 4 weeks to two groups by oral gavage concurrently with the TP. The animals were euthanized, the prostate and body weights were recorded, and tissues were subjected to hormone assays and histomorphology. In addition, we investigated proliferating cell nuclear antigen (PCNA) expression in the prostate using immunoblotting. RESULTS: Animals with BPH showed significantly increased absolute and relative prostate weights, increased dihydrotestosterone levels in the serum or prostate and increased PCNA expression in the prostate; however, YJT-treated animals showed significant reductions compared with the animals with TP-induced BPH. Histomorphology also showed that YJT inhibited TP-induced prostatic hyperplasia. CONCLUSIONS: These findings indicate that YJT effectively inhibited the development of BPH and might be a useful drug clinically. PMID- 22520511 TI - Innovations in modeling influenza virus infections in the laboratory. AB - Respiratory viruses represent one of the most substantial infectious disease burdens to the human population today, and in particular, seasonal and pandemic influenza viruses pose a persistent threat to public health worldwide. In recent years, advances in techniques used in experimental research have provided the means to better understand the mechanisms of pathogenesis and transmission of respiratory viruses, and thus more accurately model these infections in the laboratory. Here, we briefly review the model systems used to study influenza virus infections, and focus particularly on recent advances that have increased our knowledge of these formidable respiratory pathogens. PMID- 22520512 TI - Similarities in serum oxidative stress markers and inflammatory cytokines in patients with overt schizophrenia at early and late stages of chronicity. AB - Schizophrenia (SZ) is a debilitating neurodevelopmental disorder that strikes at a critical period of a young person's life. Its pathophysiology could be the result of deregulation of synaptic plasticity, with downstream alterations of inflammatory immune processes regulate by cytokines, impaired antioxidant defense and increased lipid peroxidation. The aim of this study was to examine serum oxidative stress markers and inflammatory cytokines in early and late phases of chronic SZ. Twenty-two patients at early stage (within first 10 years of a psychotic episode), 39 at late stage (minimum 10 years after diagnosis of SZ) and their respective matched controls were included. Each subject had 5 ml blood samples collected by venipuncture to examined thiobarbituric acid-reactive substances (TBARS), total reactive antioxidant potential (TRAP), protein carbonyl content (PCC), Interleukins 6 and 10 (IL-6, IL-10) and tumor necrosis factor alpha (TNF-alpha). TBARS, IL-6 and PCC levels were significantly higher in patients with SZ at early and late stages than in controls. There were no differences for TRAP and TNF-alpha levels in patients with SZ at early and late stages than in controls. IL-10 levels were decreased in patients at late stage and a decrease trend in early stage was found. Results provided evidence consistent with comparable biological markers across chronic SZ. The concept of biochemical staging proposed by others for bipolar disorder is not seen in this cohort of patients with SZ, at least for cytokines and oxidative stress markers. Our findings reinforce the need of assessment of individuals in ultra high risk to develop psychosis and first-episode population. PMID- 22520513 TI - mGluR1 interacts with cystic fibrosis transmembrane conductance regulator and modulates the secretion of IL-10 in cystic fibrosis peripheral lymphocytes. AB - Cystic fibrosis (CF) is caused by the mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. CFTR dysfunction in T cells could lead directly to aberrant immune responses. The action of glutamate on the secretion of IL-8 and IL-10 by lymphocytes derived from healthy subjects and cystic CF patients, as well as the expression of metabotropic glutamate receptor subtype 1 (mGluR1) in the membrane fractions of lymphocytes was investigated. Our results have shown that CF-derived T-cells in the presence of IL-2 produce more IL-8 and IL-10, than T-cell from healthy control. However, only in normal lymphocytes a significant increase (144%) in the IL-10 secretion during exposure to high concentration of glutamate (10(-4)M) was detected. Glutamate-dependent secretion of IL-10 was not inhibited either by NMDA receptor (NMDAR), or by AMPA-receptor (AMPAR) antagonist. Only mGluR1 antagonist, LY367385, strongly decreases the production of IL-10. Furthermore, the content of mGluR1, as well as cystic fibrosis transmembrane conductance regulator-associated ligand (CAL), Na(+)/H(+) exchanger regulatory factor 1 (NHERF-1), was analyzed in plasma membrane of lymphocytes after immunoprecipitation of CFTR. We have found that normal, non-mutated CFTR, as well as mutated forms of CFTR were associated with metabotropic mGluR1, but the level of surface exposed mGluR1 in CF lymphocytes was much lower than in normal cells. Besides, our results have shown that normal, non-mutated CFTR, as well as mutated forms of CFTR were associated with NHERF-1 and CAL; however in lymphocytes with CFTR mutation the amount of cell-surface expressed CFTR-CAL complex was greatly decreased. We have concluded that CFTR and mGluR1 could compete for binding to CAL, which in turn downregulates the post-synthetic trafficking of mGluR1 and decreases the synthesis of IL-10. PMID- 22520514 TI - A retrospective analysis of the clinicopathologic characteristics of uterine cellular leiomyomas in China. AB - OBJECTIVE: To investigate the clinicopathologic features of uterine cellular leiomyomas (CLs) by comparing them with those of uterine leiomyosarcomas (LMSs). METHODS: A case-control study comparing 78 cases of CL with 10 cases of LMS was conducted. The patients' records were reviewed to abstract information on tumors features and treatment, immunohistochemical findings, and disease prognosis. RESULTS: The mean age at diagnosis was 45.3 +/- 8.41 years in the CL group. The main clinical CL manifestations were menstrual abnormalities (56.4%), abdominal pain or distension (14.1%), and pelvic pressure (8.9%). Abdominal pain or distension was significantly more common in the LMS than in the CL group (P<0.05). Generally, CL tumors were smaller in diameter than LMS tumors (P<0.05). Moreover, lower levels of Ki-67 and PCNA expression were measured in CL than in LMS tumors (P<0.05). There were no cases of malignant transformation or metastasis in 41 patients with CL who adhered to long-tern follow-up. CONCLUSION: No symptoms were found to be specifically associated with CL, and management of CL does not need to differ from that of ordinary leiomyoma. In contrast to malignant disease, CL has a favorable long-term prognosis. However, given its "borderline" pathologic nature, patients with CL require clinical surveillance. PMID- 22520515 TI - Heritability of cortisol response to confinement stress in European sea bass dicentrarchus labrax. AB - BACKGROUND: In fish, the most studied production traits in terms of heritability are body weight or growth, stress or disease resistance, while heritability of cortisol levels, widely used as a measure of response to stress, is less studied. In this study, we have estimated heritabilities of two growth traits (body weight and length) and of cortisol response to confinement stress in the European sea bass. FINDINGS: The F1 progeny analysed (n = 922) belonged to a small effective breeding population with contributions from an unbalanced family structure of just 10 males and 2 females. Heritability values ranged from 0.54 (+/- 0.21) for body weight to 0.65 (+/- 0.22) for standard body length and were low for cortisol response i.e. 0.08 (+/- 0.06). Genetic correlations were positive (0.94) between standard body length and body weight and negative between cortisol and body weight and between cortisol and standard body length (-0.60 and -0.55, respectively). CONCLUSION: This study confirms that in European sea bass, heritability of growth-related traits is high and that selection on such traits has potential. However, heritability of cortisol response to stress is low in European sea bass and since it is known to vary greatly among species, further studies are necessary to understand the reasons for these differences. PMID- 22520516 TI - Triple antithrombotic therapy after coronary stenting in the elderly with atrial fibrillation: necessary or too hazardous? PMID- 22520517 TI - Rationale and design of a Global Rheumatic Heart Disease Registry: the REMEDY study. AB - BACKGROUND: Rheumatic heart disease (RHD) is the principal cause of valvular heart disease-related mortality and morbidity in low- and middle-income countries. The disease predominantly affects children and young adults. It is estimated that RHD may potentially be responsible for 1.4 million deaths annually worldwide and 7.5% of all strokes occurring in developing countries. Despite the staggering global burden, there are no contemporary data documenting the presentation, clinical course, complications, and treatment practices among patients with RHD. METHODS: The REMEDY study is a prospective, international, multicenter, hospital-based registry planned in 2 phases: the vanguard phase involving centers in Africa and India will enroll 3,000 participants with RHD over a 1-year period. We will document clinical and echocardiographic characteristics of patients at presentation. Over a 2-year follow-up, we will document disease progression and treatment practices with particular reference to adherence to secondary prophylaxis and oral anticoagulation regimens. With 3,000 patients, we will be able to reliably determine the incidence of all-cause mortality, worsening heart failure requiring hospitalization, systemic embolism (including stroke), and major bleeding individually among all participants. We will identify barriers to care in a subgroup of 500 patients. CONCLUSION: The REMEDY study will provide comprehensive, contemporary data on patients with RHD and will help in the development of strategies to prevent and manage RHD and its complications. PMID- 22520518 TI - Target Temperature Management after out-of-hospital cardiac arrest--a randomized, parallel-group, assessor-blinded clinical trial--rationale and design. AB - BACKGROUND: Experimental animal studies and previous randomized trials suggest an improvement in mortality and neurologic function with induced hypothermia after cardiac arrest. International guidelines advocate the use of a target temperature management of 32 degrees C to 34 degrees C for 12 to 24 hours after resuscitation from out-of-hospital cardiac arrest. A systematic review indicates that the evidence for recommending this intervention is inconclusive, and the GRADE level of evidence is low. Previous trials were small, with high risk of bias, evaluated select populations, and did not treat hyperthermia in the control groups. The optimal target temperature management strategy is not known. METHODS: The TTM trial is an investigator-initiated, international, randomized, parallel-group, and assessor-blinded clinical trial designed to enroll at least 850 adult, unconscious patients resuscitated after out-of-hospital cardiac arrest of a presumed cardiac cause. The patients will be randomized to a target temperature management of either 33 degrees C or 36 degrees C after return of spontaneous circulation. In both groups, the intervention will last 36 hours. The primary outcome is all-cause mortality at maximal follow-up. The main secondary outcomes are the composite outcome of all-cause mortality and poor neurologic function (cerebral performance categories 3 and 4) at hospital discharge and at 180 days, cognitive status and quality of life at 180 days, assessment of safety and harm. DISCUSSION: The TTM trial will investigate potential benefit and harm of 2 target temperature strategies, both avoiding hyperthermia in a large proportion of the out-of-hospital cardiac arrest population. PMID- 22520519 TI - Design and rationale for the PREVAIL study: effect of e-Health individually tailored encouragements to physical exercise on aerobic fitness among adolescents with congenital heart disease--a randomized clinical trial. AB - Intensive exercise may be an important part of rehabilitation in patients with congenital heart disease (CHD). However, performing regular physical exercise is challenging for many adolescent patients. Consequently, effective exercise encouragements may be needed. Little is known on the effect of e-Health encouragements on physical fitness, physical activity, and health-related quality of life in adolescents. This trial is a nationwide interactive e-Health rehabilitation study lasting 1 year, centered on interactive use of mobile phone and Internet technology. We hypothesize that e-Health encouragements and interactive monitoring of intensive exercise for 1 year can improve physical fitness, physical activity, and health-related quality of life. Two hundred sixteen adolescents (age, 13-16 years) with surgically corrected complex CHD but without significant hemodynamic residual defects and no restrictions to participate in physical activity are in the process of being enrolled by invitation after informed consent. Physical fitness is measured as the maximal oxygen uptake (Vo(2)) at baseline and after 12 months by an assessor blinded to the randomization group. After baseline testing, the patients are 1:1 randomized to an intervention group or a control group. Individually fully automated tailored e-Health encouragements--SMS, Internet, and mobile applications--aimed at increasing physical activity are delivered to the participants in the intervention group once a week. The Bandura's Social Cognitive Theory inspires the behavioral theoretical background. The e-Health intervention and the Godfrey cycle ergometer protocol have been feasibility tested and seem applicable to adolescents with CHD. The trial is expected to contribute with new knowledge regarding how physical activity in adolescents with CHD can be increased and, possibly, comorbidity be reduced. PMID- 22520520 TI - DUrable polymer-based sTent CHallenge of Promus ElemEnt versus ReSolute integrity (DUTCH PEERS): rationale and study design of a randomized multicenter trial in a Dutch all-comers population. AB - BACKGROUND: Drug-eluting stents (DES) are increasingly used for the treatment of coronary artery disease. An optimized DES performance is desirable to successfully treat various challenging coronary lesions in a broad population of patients. In response to this demand, third-generation DES with an improved deliverability were developed. Promus Element (Boston Scientific, Natick, MA) and Resolute Integrity (Medtronic Vascular, Santa Rosa, CA) are 2 novel third generation DES for which limited clinical data are available. Accordingly, we designed the current multicenter study to investigate in an all-comers population whether the clinical outcome is similar after stenting with Promus Element versus Resolute Integrity. METHODS: DUTCH PEERS is a multicenter, prospective, single blinded, randomized trial in a Dutch all-comers population. Patients with all clinical syndromes who require percutaneous coronary interventions with DES implantation are eligible. In these patients, the type of DES implanted will be randomized in a 1:1 ratio between Resolute Integrity versus Promus Element. The trial is powered based on a noninferiority hypothesis. For each stent arm, 894 patients will be enrolled, resulting in a total study population of 1,788 patients. The primary end point is the incidence of target vessel failure at 1 year follow-up. SUMMARY: DUTCH PEERS is the first randomized multicenter trial with a head-to-head comparison of Promus Element and Resolute Integrity to investigate the safety and efficacy of these third-generation DES. PMID- 22520521 TI - Reinfarction after percutaneous coronary intervention or medical management using the universal definition in patients with total occlusion after myocardial infarction: results from long-term follow-up of the Occluded Artery Trial (OAT) cohort. AB - BACKGROUND: The OAT study randomized 2,201 patients with a totally occluded infarct-related artery on days 3 to 28 (>24 hours) after myocardial infarction (MI) to percutaneous coronary intervention (PCI) or medical treatment (MED). There was no difference in the primary end point of death, reinfarction, or heart failure at 2.9 or 6-year mean follow-up. However, in patients randomized to PCI, there was a trend toward a higher rate of reinfarction. METHODS: We analyzed the characteristics and types of reinfarction according to the universal definition. Independent predictors of reinfarction were determined using Cox proportional hazard models with follow-up up to 9 years. RESULTS: There were 169 reinfarctions: 9.4% PCI vs 8.0% MED, hazard ratio 1.31, 95% CI 0.97-1.77, P = .08. Spontaneous reinfarction (type 1) occurred with similar frequency in the groups: 4.9% PCI vs 6.7% MED, hazard ratio 0.78, 95% CI 0.53-1.15, P = .21. Rates of type 2 (secondary) and 3 (sudden death) MI were similar in both groups. There was an increase in type 4a reinfarctions (related to protocol or other PCI) (0.8% PCI vs 0.1% MED, P = .01) and type 4b reinfarctions (stent thrombosis) (2.7% PCI vs 0.6% MED, P < .001). Multivariate predictors of reinfarction were history of PCI before study entry (P = .001), diabetes (P = .005), and absence of new Q waves with the index infarction (P = .01). CONCLUSIONS: There was a trend for reinfarctions to be more frequent with PCI. Opening an occluded infarct-related artery in stable patients with late post-MI may expose them to a risk of subsequent reinfarction related to reocclusion and stent thrombosis. PMID- 22520522 TI - Differences in symptom presentation and hospital mortality according to type of acute myocardial infarction. AB - BACKGROUND: Chest pain/discomfort (CP) is the hallmark symptom of acute myocardial infarction (MI), but some patients with MI present without CP. We hypothesized that MI type (ST-segment elevation MI [STEMI] or non-STEMI [NSTEMI]) may be associated with the presence or absence of CP. METHODS: We investigated the association between CP at presentation and MI type, hospital care, and mortality among 1,143,513 patients with MI in the National Registry of Myocardial Infarction (NRMI) from 1994 to 2006. RESULTS: Overall, 43.6% of patients with NSTEMI and 27.1% of patients with STEMI presented without CP. For both MI type, patients without CP were older, were more frequently female, had more diabetes or history of heart failure, were more likely to delay hospital arrival, and were less likely to receive evidence-based medical therapies and invasive cardiac procedures. Multivariable analysis indicated that NSTEMI (vs STEMI) was the strongest predictor of atypical symptoms (adjusted odds ratio [95% CI], 1.93 [1.91-1.95]). Within the 4 CP/MI type categories, hospital mortality was highest for no CP/STEMI (27.8%), followed by no CP/NSTEMI (15.3%) and CP/STEMI (9.6%), and was lowest for CP/NSTEMI (5.4%). The adjusted odds ratio of mortality was 1.38 (1.35-1.41) for no CP (vs CP) in the STEMI group and 1.31 (1.28-1.34) in the NSTEMI group. CONCLUSIONS: Hospitalized patients with NSTEMI were nearly 2-fold more likely to present without CP than patients with STEMI. Patients with MI without CP were less quickly diagnosed and treated and had higher adjusted odds of hospital mortality, regardless of whether they had ST-segment elevation. PMID- 22520523 TI - Heart rate recovery in pulmonary arterial hypertension: relationship with exercise capacity and prognosis. AB - BACKGROUND: Delayed postexercise heart rate recovery (HRR) has been associated with disability and poor prognosis in chronic cardiopulmonary diseases. The usefulness of HRR to predict exercise impairment and mortality in patients with pulmonary arterial hypertension (PAH), however, remains largely unexplored. METHODS: Seventy-two patients with PAH of varied etiology (New York Heart Association classes I-IV) and 21 age- and gender-matched controls underwent a maximal incremental cardiopulmonary exercise test (CPET), with heart rate being recorded up to the fifth minute of recovery. RESULTS: Heart rate recovery was consistently lower in the patients compared with the controls (P < .05). The best cutoff for HRR in 1 minute (HRR(1 min)) to discriminate the patients from the controls was 18 beats. Compared with patients with HRR(1 min) <= 18 (n = 40), those with HRR(1 min) >18 (n = 32) had better New York Heart Association scores, resting hemodynamics and 6-minute walking distance. In fact, HRR(1 min) >18 was associated with a range of maximal and submaximal CPET variables indicative of less severe exercise impairment (P < .05). The single independent predictor of HRR(1 min) <= 18 was the 6-minute walking distance (odds ratio [95% CI] 0.99 [0.98-1.00], P < .05). On a multiple regression analysis that considered only CPET-independent variables, HRR(1 min) <= 18 was the single predictor of mortality (hazard ratio [95% CI] 1.19 [1.03-1.37], P < .05). CONCLUSIONS: Preserved HRR(1 min) (>18 beats) is associated with less impaired responses to incremental exercise in patients with PAH. Conversely, a delayed HRR(1 min) response has negative prognostic implications, a finding likely to be clinically useful when more sophisticated (and costlier) analyses provided by a full CPET are not available. PMID- 22520524 TI - Current practice for determining pulmonary capillary wedge pressure predisposes to serious errors in the classification of patients with pulmonary hypertension. AB - BACKGROUND: Accurate measurement of left ventricular filling pressure is important to distinguish between category 1 pulmonary arterial hypertension (PAH) and category 2 pulmonary hypertension (PH) from left heart diseases (PH-HFpEF). We hypothesized that the common practice of relying on the digitized mean pulmonary capillary wedge pressure (PCWP-digital) results in erroneous recordings, whereas end-expiratory PCWP measurements (PCWP-end Exp) provide a reliable surrogate measurement for end-expiratory left ventricular end-diastolic pressure (LVEDP-end Exp-end Exp). METHODS: We prospectively performed left and right cardiac catheterization on 61 patients referred for evaluation of PH and compared the LVEDP-end Exp to end-expiration to the (a) PCWP-end Exp and (b) PCWP digital. RESULTS: The PCWP-end Exp was a more reliable reflection of LVEDP-end Exp (mean 13.2 mm Hg vs 12.4 mm Hg; P, nonsignificant) than PCWP-digital (mean 8.0 mm Hg vs 12.4 mm Hg, P < .05). Bland-Altman analysis of PCWP-digital and LVEDP-end Exp revealed a mean bias of -4.4 mm Hg with 95% limits of agreement of 11.3 to 2.5 mm Hg. Bland-Altman analysis of PCWP-end Exp and LVEDP-end Exp revealed a mean bias of 0.9 mm Hg with 95% limits of agreement of -5.2 to 6.9 mm Hg. If PCWP-digital were used to define LVEDP-end Exp, 14 (27%) of 52 patients would have been misclassified as having PAH rather than PH-HFpEF. Patients with obesity and hypoxia were particularly more likely to be misclassified as PAH instead of PH-HFpEF if PCWP-digital was used to define LVEDP-end Exp (odds ratio 8.1, 95% CI 1.644-40.04, P = .01). CONCLUSIONS: The common practice of using PCWP digital instead of PCWP-end Exp results in a significant underestimation of LVEDP end Exp. In our study, this translated to nearly 30% of patients being misclassified as having PAH rather than PH from HFpEF. PMID- 22520525 TI - Use of a highly sensitive assay for cardiac troponin T and N-terminal pro-brain natriuretic peptide to diagnose acute rejection in pediatric cardiac transplant recipients. AB - BACKGROUND: Biomarkers have been proposed to augment or replace endomyocardial biopsy (EMB) to diagnose acute transplant rejection (AR). A new, highly sensitive assay for troponin T detects levels of cardiac troponin T (cTnT) 10- to 100-fold lower than standard assays but has not been investigated in transplant patients. N-terminal pro-brain natriuretic peptide (NT-proBNP) has not been evaluated in pediatric transplant patients. The purpose of this pilot study was to evaluate the association of cTnT and NT-proBNP with AR in pediatric cardiac transplant patients. METHODS: Plasma was obtained at the time of EMB from pediatric patients >= 1 year old. N-terminal pro-brain natriuretic peptide was measured in fresh plasma at the time of biopsy, and cTnT was measured from frozen, stored samples using the highly sensitive assay for troponin T. Biomarker data were correlated with EMB results. Cellular AR was defined as an International Society for Heart and Lung Transplantation biopsy score of grade >= 2R. RESULTS: Fifty-three blood samples were obtained from 42 patients (mean age 11 years). Seven episodes of AR occurred in 5 patients. Biopsies with vs without AR were associated with higher cTnT (median [interquartile range {IQR}] 66 [45-139] vs 7 [2-13] pg/mL, P = .001) and NT-proBNP (median [IQR] 11,169 [280-23,317] vs 334 [160-650] pg/mL, P < .01). After successful treatment of AR in 5 patients, cTnT fell markedly (median [IQR] 53.5 [44.8-66.5] to 10.7 [1.5-16.4], P = .05). CONCLUSION: In this pilot study, we found marked elevation of cTnT and NT-proBNP among children with AR. Moreover, reduction in cTnT levels after treatment paralleled improvement in EMB results. If these findings are confirmed in larger prospective studies, monitoring with these biomarkers may obviate surveillance EMB. PMID- 22520526 TI - ComparisOn of neointimal coVerage betwEen zotaRolimus-eluting stent and everolimus-eluting stent using Optical Coherence Tomography (COVER OCT). AB - BACKGROUND: Data on strut surface coverage of second-generation drug-eluting stents (DES) are limited. We investigated stent strut coverage of resolute zotarolimus-eluting stent (ZES-R) or everolimus-eluting stent (EES) at 9 months after implantation using optical coherence tomography (OCT). METHODS: ComparisOn of neointimal coVerage betwEen zotaRolimus-eluting stent and everolimus-eluting stent using Optical Coherence Tomography (COVER OCT) is a prospective, randomized, multicenter trial comparing ZES-R to EES using OCT at 9 months after stent implantation. The primary end point was the rate of stent strut coverage at 9 months. RESULTS: A total of 51 patients were randomized to receive either ZES-R (ZES-R group) or EES (EES group), and 47 stents (24 ZES-R and 23 EES) in 44 of 51 patients were evaluated by OCT both immediately after stent implantation and at 9 months. The neointimal thickness was not significantly different between the 2 groups at 9 months (ZES-R vs EES: 139 +/- 58 vs 124 +/- 42 MUm, P = .31). The mean percentages of uncovered stent struts were 3.3% for ZES-R versus 3.4% for EES at 9 months (P = .51). The proportions of malapposed struts immediately after stent implantation (P = .89) and at 9-month follow-up (P = .34) were 0.8% and 0.7% for ZES-R versus 1.0% and 0.1% for EES, respectively. Thrombi were documented in 1 stent (1 [4.2%] in ZES-R vs 0 [0%] in EES). CONCLUSION: According to the sequential OCT evaluation, ZES-R and EES showed comparable neointimal thickness and the rate of uncovered stent strut at 9 months after stent implantation. PMID- 22520528 TI - Use and overuse of left ventriculography. AB - BACKGROUND: Left ventriculography provided the first imaging of left ventricular function and was historically performed as part of coronary angiography despite a small but significant risk of complications. Because modern noninvasive imaging techniques are more accurate and carry smaller risks, the routine use of left ventriculography is of questionable utility. We sought to analyze the frequency that left ventriculography was performed during coronary angiography in patients with and without a recent alternative assessment of left ventricular function. METHODS: We performed a retrospective analysis of insurance claims data from the Aetna health care benefits database including all adults who underwent coronary angiography in 2007. The primary outcome was the concomitant use of left ventriculography during coronary angiography. RESULTS: Of 96,235 patients who underwent coronary angiography, left ventriculography was performed in 78,705 (81.8%). Use of left ventriculography was high in all subgroups, with greatest use in younger patients, those with a diagnosis of coronary disease, and those in the Southern United States. In the population who had undergone a very recent ejection fraction assessment by another modality (within 30 days) and who had had no intervening diagnosis of new heart failure, myocardial infarction, hypotension, or shock (37,149 patients), left ventriculography was performed in 32,798 patients (88%)-a rate higher than in the overall cohort. CONCLUSIONS: Left ventriculography was performed in most coronary angiography cases and often when an alternative imaging modality had been recently completed. New clinical practice guidelines should be considered to decrease the overuse of this invasive test. PMID- 22520527 TI - Effect of strut thickness on neointimal atherosclerotic change over an extended follow-up period (>= 4 years) after bare-metal stent implantation: intracoronary optical coherence tomography examination. AB - BACKGROUND: Neointima inside the bare-metal stents (BMSs) can transform into atherosclerotic tissue during an extended follow-up because of a persistent inflammatory reaction to the metal. We sought to investigate whether strut thickness may impact on the atherosclerotic change in neointima 4 years or more after BMS implantation using optical coherence tomography. METHODS: Forty-six stented lesions of 41 patients with BMS >= 4 years after implantation who underwent optical coherence tomography were enrolled in the study. The strut was defined as thin when less than 100 MUm and thick when >= 100 MUm. According to these criteria, stents were divided into 2 groups (thin strut n = 19, thick strut n = 27). Neointimal tissue was categorized into normal neointima, characterized by a signal-rich band without signal attenuation, or lipid-laden intima, with marked signal attenuation and a diffuse border. Intimal disruption, thrombus, and neovascularization were also evaluated. RESULTS: The mean period after implantation was 98.2 +/- 25.8 months in the thin-strut group and 91.1 +/- 22.8 months in the thick-strut group (P = .330). Lipid-laden intima (70% vs 32%, P = .016), thin-cap fibroatheroma-like intima (59% vs 16%, P = .0056), and intimal disruption (48% vs 16%, P = .031) were observed more frequently in the thick strut group than in the thin-strut group, but no significant difference was observed in the frequency of thrombus. Although peristrut neovascularization was a common finding in both groups (thick vs thin 81% vs 79%, P = 1.000), the frequency of intraintima neovascularization tended to be higher in the thick strut group (67% vs 42%, P = .135). CONCLUSIONS: A thinner strut thickness may have favorable effects on neointimal atherosclerotic changes after BMS implantation. PMID- 22520529 TI - An intravascular ultrasound appraisal of atherosclerotic plaque distribution in diseased coronary arteries. AB - BACKGROUND: The assumption that atherosclerosis accumulates in the proximal coronary arteries and that distal segments are spared has yet to be systematically shown in vivo. METHODS: We used intravascular ultrasound to analyze complete proximal, mid, and distal segments from 75 diseased left anterior descending arteries (LADs) and 61 diseased right coronary arteries (RCAs) (including either the posterolateral [PLA; n = 38] or posterior descending artery [PDA; n = 23]) to document that distal coronary arteries are more often free of disease vs proximal vessels. External elastic membrane, lumen, and plaque and media areas were measured every 0.4 mm (median), and plaque burden (plaque and media/external elastic membrane) and percentage of normal (plaque and media thickness <0.3 mm) cross sections/segment were determined. RESULTS: Left anterior descending artery plaque was heaviest in proximal and mid segments, diminishing significantly in distal segments; plaque burden was 46% +/- 9% in proximal, 39% +/- 8% in mid, and 31% +/- 9% in distal LAD (P < .0001), with 93% (median) of distal LAD cross sections being normal compared with 21% of mid and 0% of proximal cross sections (P < .0001). Right coronary artery plaque gradient was less pronounced vs the LAD; plaque burden was 37% +/- 13% in proximal, 40% +/- 10% in mid, and 36% +/- 10% in distal RCA, followed by 31% +/- 11% in PDA and 33% +/- 10% in PLA. This was supported by the median percentage of normal cross sections/segment: 0% proximal, 0% mid, and 23% distal RCA sections plus 100% PDA and 48% PLA sections. CONCLUSIONS: Intravascular ultrasound data indicated a proximal-to-distal LAD plaque gradient; significant disease was uncommon in the distal LAD. Conversely, the proximal-to-distal RCA plaque gradient was less distinct than the LAD, although disease in the PDA was still reduced compared with proximal segments. PMID- 22520530 TI - Comparison of transradial and femoral approaches for percutaneous coronary interventions: a systematic review and hierarchical Bayesian meta-analysis. AB - BACKGROUND: Despite lower risks of access site-related complications with transradial approach (TRA), its clinical benefit for percutaneous coronary intervention (PCI) is uncertain. We conducted a systematic review and meta analysis of clinical studies comparing TRA and transfemoral approach (TFA) for PCI. METHODS: Randomized trials and observational studies (1993-2011) comparing TRA with TFA for PCI with reports of ischemic and bleeding outcomes were included. Crude and adjusted (for age and sex) odds ratios (OR) were estimated by a hierarchical Bayesian random-effects model with prespecified stratification for observational and randomized designs. The primary outcomes were rates of death, combined incidence of death or myocardial infarction, bleeding, and transfusions, early (<= 30 days) and late after PCI. RESULTS: We collected data from 76 studies (15 randomized, 61 observational) involving a total of 761,919 patients. Compared with TFA, TRA was associated with a 78% reduction in bleeding (OR 0.22, 95% credible interval [CrI] 0.16-0.29) and 80% in transfusions (OR 0.20, 95% CrI 0.11 0.32). These findings were consistent in both randomized and observational studies. Early after PCI, there was a 44% reduction of mortality with TRA (OR 0.56, 95% CrI 0.45-0.67), although the effect was mainly due to observational studies (OR 0.52, 95% CrI 0.40-0.63, adjusted OR 0.49 [95% CrI 0.37-0.60]), with an OR of 0.80 (95% CrI 0.49-1.23) in randomized trials. CONCLUSION: Our results combining observational and randomized studies show that PCI performed by TRA is associated with substantially less risks of bleeding and transfusions compared with TFA. Benefit on the incidence of death or combined death or myocardial infarction is found in observational studies but remains inconclusive in randomized trials. PMID- 22520531 TI - Safety and efficacy of rescue angioplasty for ST-elevation myocardial infarction with high utilization rates of glycoprotein IIb/IIIa inhibitors. AB - BACKGROUND: Fibrinolytic therapies remain widely used for ST-elevation myocardial infarction, and for "failed reperfusion," rescue percutaneous coronary intervention (PCI) is guideline recommended to improve outcomes. However, these recommendations are based on data from an earlier era of pharmacotherapy and procedural techniques. METHODS AND RESULTS: To determine factors affecting prognosis after rescue PCI, we studied 241 consecutive patients (median age 55 years, interquartile range [IQR] 48-65) undergoing procedures between 2001 and 2009 (53% anterior ST-elevation myocardial infarction and 78% transferred). The median treatment-related times were 1.2 hours (IQR 0.8-2.2) from symptom onset to door, 2 hours (IQR 1.3-3.2) from symptom onset to fibrinolysis (93% tenecteplase), and 3.9 hours (IQR 3.1-5.2) from fibrinolysis to balloon. Procedural characteristics were stent deployment in 95% (11.6% drug eluting) and 78% glycoprotein IIb/IIIa inhibitor use, and Thrombolysis In Myocardial Infarction (TIMI) 3 flow rates pre-PCI and post-PCI were 41% and 91%, respectively (P < .001). At 30 days, TIMI major bleeding occurred in 16 (6.6%) patients, and 23 (9.5%) patients received transfusions; nonfatal stroke occurred in 4 (1.7%) patients (2 hemorrhagic). Predictors of TIMI major bleeding were female gender (odds ratio 3.194, 95% CI 1.063-9.597; P = .039) and pre-PCI shock (odds ratio 3.619, 95% CI,1.073-12.207; P = .038). Mortality at 30 days was 6.2%, and 3.2% in patients without pre-PCI shock. One-year mortality was 8.2% (5.3% in patients without pre-PCI cardiogenic shock), 5.2% had reinfarction, and the target vessel revascularization rate was 6.4% (2.6% in arteries >= 3.5 mm in diameter). Pre-PCI shock, female gender, and post-PCI TIMI flow grades <= 2 were significant predictors of 1-year mortality on multivariable regression modeling, but TIMI major bleeding was not. CONCLUSIONS: Rescue PCI with contemporary treatments can achieve mortality rates similar to rates for contemporary primary PCI in patients without pre-PCI shock. Whether rates of bleeding can be reduced by different pharmacotherapies and interventional techniques needs clarification in future studies. PMID- 22520533 TI - Exercise intervention and inflammatory markers in coronary artery disease: a meta analysis. AB - BACKGROUND: Inflammatory activity plays a role in the development and progression of coronary artery disease (CAD), and exercise confers survival benefit. We performed a meta-analysis of changes in inflammatory biomarkers over the course of exercise interventions in patients with CAD. METHODS: We searched MEDLINE, Embase, the Cochrane Collaboration, AMED, and CINAHL for studies reporting peripheral inflammatory biomarker concentrations before and after exercise interventions of >= 2 weeks in patients with CAD. Data were summarized using standard mean differences (SMD) and 95% CIs. RESULTS: Twenty-three studies were included. Concentrations of C-reactive protein (CRP; SMD -0.345, 95% CI -0.444 to -0.246, n = 1,466, P < .001), interleukin 6 (SMD -0.546, 95% CI -0.739 to -0.353, n = 280, P < .001), fibrinogen (SMD -0.638, 95% CI -0.953 to -0.323, n = 247, P < .001), and vascular cell adhesion molecule 1 (SMD -0.413, 95% CI -0.778 to 0.048, n = 187, P = .027) were lower postintervention. Higher total cholesterol (B = -0.328, 95% CI -0.612 to -0.043, P = .026) and higher total/high-density lipoprotein cholesterol ratios (B = -0.250, 95% CI -0.425 to -0.076, P = .008) at baseline were associated with greater reductions in CRP. In controlled studies, follow-up concentrations of CRP (SMD -0.500, 95% CI -0.844 to -0.157, n(exercise/control) = 485/284, P = .004), and fibrinogen (SMD -0.544, 95% CI 1.058 to -0.030, n(exercise/control) = 148/100, P = .038) were lower in subjects who exercised compared with controls. CONCLUSION: Exercise training is associated with reduced inflammatory activity in patients with CAD. C-reactive protein and fibrinogen have provided the strongest evidence. Higher baseline CRP and adverse baseline lipid profiles predicted greater reductions in CRP. PMID- 22520532 TI - Patient-focused intervention to improve long-term adherence to evidence-based medications: a randomized trial. AB - BACKGROUND: Nonadherence to cardiovascular medications is a significant public health problem. This randomized study evaluated the effect on medication adherence of linking hospital and community pharmacists. METHODS: Hospitalized patients with coronary artery disease discharged on aspirin, beta-blocker, and statin who used a participating pharmacy were randomized to usual care or intervention. The usual care group received discharge counseling and a letter to the community physician; the intervention group received enhanced in-hospital counseling, attention to adherence barriers, communication of discharge medications to community pharmacists and physicians, and ongoing assessment of adherence by community pharmacists. The primary end point was self-reported use of aspirin, beta-blocker, and statin at 6 months postdischarge; the secondary end point was a >= 75% proportion of days covered (PDC) for beta-blocker and statin through 6 months postdischarge. RESULTS: Of 143 enrolled patients, 108 (76%) completed 6-month follow-up, and 115 (80%) had 6-month refill records. There was no difference between intervention and control groups in self-reported adherence (91% vs 94%, respectively, P = .50). Using the PDC to determine adherence to beta blockers and statins, there was better adherence in the intervention versus control arm, but the difference was not statistically significant (53% vs 38%, respectively, P = .11). Adherence to beta-blockers was statistically significantly better in intervention versus control (71% vs 49%, respectively, P = .03). Of 85 patients who self-reported adherence and had refill records, only 42 (49%) were also adherent by PDC. CONCLUSIONS: The trend toward better adherence by refill records with the intervention should encourage further investigation of engaging pharmacists to improve continuity of care. PMID- 22520534 TI - The relationship between perceived discrimination and coronary artery obstruction. AB - BACKGROUND: Chronic stressors such as perceived discrimination might underlie race disparities in cardiovascular disease. This study focused on the relationship between perceived discrimination and risk of severe coronary obstruction while also accounting for multiple psychosocial variables and clinical factors. METHODS: Data from 793 (629 white and 164 black) male veterans with positive nuclear imaging studies were analyzed. Participants were categorized as being at low/moderate or high risk for severe coronary obstruction based on results of their nuclear imaging studies. Hierarchical logistic regression models were tested separately for blacks and whites. The first step of the models included clinical factors. The second step included the psychosocial variables of optimism, religiosity, negative affect, and social support. The final step included perceived discrimination. RESULTS: Perceived discrimination was positively related to risk of severe obstruction among blacks but not among whites after controlling for clinical and psychosocial variables. Similar results were found in patients who underwent coronary angiography (n = 311). CONCLUSIONS: Perceived discrimination was associated with risk of severe coronary obstruction among black male veterans and could be an important target for future interventions. PMID- 22520535 TI - Accuracy of intracardiac echocardiography for aortic root assessment in patients undergoing transcatheter aortic valve implantation. AB - BACKGROUND: Multislice computed tomography (MSCT) has generally been accepted as the most accurate modality fulfilling this purpose with good reproducibility. A major drawback of MSCT consists in the use of contrast dye, which may be unsafe in transcatheter aortic valve implantation (TAVI) patients who frequently are affected by renal failure. We sought to appraise the accuracy of intracardiac echocardiography (ICE) in measurements of structures in the aortic root in patients undergoing TAVI. METHODS: Aortic annulus and sinus of Valsalva diameters were measured using ICE, performed during standard invasive preprocedural assessment in 30 consecutive patients with severe aortic stenosis referred for TAVI. Multislice computed tomography was performed in all patients afterward, and aortic root measurements were made by an independent radiologist. RESULTS: Effective ICE measurements were obtained in all patients, easily and without any complication. Mean aortic annulus diameters were 21.9 +/- 1.8 mm using ICE, 22.0 +/- 1.9 mm using MSCT (3-chamber [3-C] view) and 22.8 +/- 1.8 mm using the mean of long-axis and short-axis (L-ax/S-ax) view MSCT (P = .192, ICE vs 3-C MSCT; P < .001, ICE vs L-ax/S-ax MSCT, respectively). Correlation between ICE and both MSCT measurements was good (r(2) = 0.83, P < .001; r(2) = 0.80, P < .001, respectively). Mean sinus of Valsalva diameters were 32.3 +/- 3.3 mm using ICE and 32.5 +/- 3.1 mm using 3-C MSCT view (P = .141). Even in this case, correlation between ICE and both MSCT measurements was excellent (r(2) = 0.96, P < .001). CONCLUSIONS: In patients referred for TAVI, measurements of the aortic annulus and the sinus of Valsalva using ICE compare favorably with those made at MSCT. This approach might be a useful and reproducible strategy in patients with severe renal impairment to avoid the administration of contrast dye during MSCT. PMID- 22520536 TI - Effect of lipid lowering on new-onset atrial fibrillation in patients with asymptomatic aortic stenosis: the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. AB - BACKGROUND: Lipid-lowering drugs, particularly statins, have anti-inflammatory and antioxidant properties that may prevent atrial fibrillation (AF). This effect has not been investigated on new-onset AF in asymptomatic patients with aortic stenosis (AS). METHODS: Asymptomatic patients with mild-to-moderate AS (n = 1,421) were randomized (1:1) to double-blind simvastatin 40 mg and ezetimibe 10 mg combination or placebo and followed up for a mean of 4.3 years. The primary end point was the time to new-onset AF adjudicated by 12-lead electrocardiogram at a core laboratory reading center. Secondary outcomes were the correlates of new-onset AF with nonfatal nonhemorrhagic stroke and a combined end point of AS related events. RESULTS: During the course of the study, new-onset AF was detected in 85 (6%) patients (14.2/1,000 person-years of follow-up). At baseline, patients who developed AF were, compared with those remaining in sinus rhythm, older and had a higher left ventricular mass index a smaller aortic valve area index. Treatment with simvastatin and ezetimibe was not associated with less new onset AF (odds ratio 0.89 [95% CI 0.57-1.97], P = .717). In contrast, age (hazard ratio [HR] 1.07 [95% CI 1.05-1.10], P < .001) and left ventricular mass index (HR 1.01 [95% CI 1.01-1.02], P < .001) were independent predictors of new-onset AF. The occurrence of new-onset AF was independently associated with 2-fold higher risk of AS-related outcomes (HR 1.65 [95% CI 1.02-2.66], P = .04) and 4-fold higher risk of nonfatal nonhemorrhagic stroke (HR 4.04 [95% CI 1.18-13.82], P = .03). CONCLUSIONS: Simvastatin and ezetimibe were not associated with less new onset AF. Older age and greater left ventricular mass index were independent predictors of AF development. New-onset AF was associated with a worsening of prognosis. PMID- 22520537 TI - Simple regional strain pattern analysis to predict response to cardiac resynchronization therapy: rationale, initial results, and advantages. AB - BACKGROUND: A classical strain pattern of early contraction in one wall and prestretching of the opposing wall followed by late contraction has previously been associated with left bundle branch block (LBBB) activation and short-term response to cardiac resynchronization therapy (CRT). Aims of this study were to establish the long-term predictive value of an LBBB-related strain pattern and to identify changes in contraction patterns during short-term and long-term CRT. METHODS AND RESULTS: Sixty-seven patients with standard CRT criteria were prospectively enrolled between early 2009 and late 2010. Echocardiography including regional strain analysis by 2-dimensional speckle tracking was performed 1 week before implantation, at day 1, and 6 months after. Response was defined as a decrease in left ventricular end-systolic volume >= 15%. The predictive ability of a classical pattern was compared with time-to-peak measurements from velocity and deformation analysis. Forty-three patients (65%) were classified as responders. The presence of a classical pattern showed 91% specificity and 95% sensitivity for response and performed significantly better than time-to-peak parameters in prediction of response to CRT (P < .001, all). In responders, CRT acutely increased septal longitudinal peak systolic strain (-8.7% +/- 3.6% to -11.1% +/- 3%, P < .001) but not in nonresponders. CONCLUSIONS: The classical pattern is highly predictive of response to CRT and superior to time-to peak methods. Patients who obtain long-term reverse remodeling are characterized by short-term reversal of the classical strain pattern. These findings emphasize the value of recognizing potentially reversible strain patterns in selection of CRT candidates. PMID- 22520538 TI - The impact of high-density lipoprotein cholesterol levels on long-term outcomes after non-ST-elevation myocardial infarction. AB - BACKGROUND: Low serum high-density lipoprotein cholesterol (HDL-C) level is a potent risk factor for developing atherosclerosis, yet it is uncertain if HDL-C level at the time of non-ST-segment elevation myocardial infarction (NSTEMI) has downstream prognostic importance. METHODS: We evaluated 24,805 patients with NSTEMI aged >= 65 years enrolled at 434 Can Rapid Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology/American Heart Association Guidelines (CRUSADE) participating hospitals between February 15, 2003, and December 30, 2006, who had clinical data linked to Medicare files through December 31, 2008. Unadjusted and adjusted hazard ratios (HRs) were calculated to determine the association between HDL-C level at initial hospitalization and all-cause mortality, as well as a combined outcome of all-cause mortality or recurrent myocardial infarction (MI). RESULTS: Overall, 50% of patients had low HDL-C (<= 40 mg/dL) and 18% had very low HDL-C (<= 30 mg/dL). The rate of all-cause mortality was 39.5% during a median follow-up of 2.9 years; death or recurrent MI occurred in 43% in this older population with NSTEMI. Compared with patients who had normal HDL-C, those with very low HDL-C had a modest but significantly higher long-term mortality risk (adjusted HR 1.12, 95% CI 1.06-1.19, P = .0001). The adjusted HR for mortality or recurrent MI was the same. When modeled as a continuous variable, every 5-mg/dL decrement in HDL-C below 40 mg/dL was associated with a 5% increased risk of long-term mortality, as well as the combined end point. CONCLUSIONS: Older patients with NSTEMI with low levels of HDL-C are at increased risk for downstream mortality or recurrent MI. Future studies are needed to evaluate strategies to reduce this residual risk. PMID- 22520539 TI - Preventing cardiovascular disease in primary care: role of a national risk factor management program. AB - BACKGROUND: Heartwatch, a structured risk factor modification program for secondary prevention of cardiovascular (CV) disease (CVD) in primary care, is associated with improvements in CV risk factors in participating patients. However, it is not known whether Heartwatch translates into reductions in clinically important CV events. OBJECTIVE: The aim of the study was to determine the association between participation in Heartwatch and future risk of CV events in patients with CVD. METHODS: The study consisted of a prospective cohort of 1,609 patients with CVD in primary care practices. Of these, 97.5% had data available on Heartwatch participation status, of whom 15.2% were Heartwatch participants. Cox proportional hazards models were used to determine the association between Heartwatch participation and risk of the CV composite (CV death, nonfatal myocardial infarction, heart failure, and nonfatal stroke). All cause mortality and CV mortality were secondary outcome measures. RESULTS: During follow-up, the CV composite occurred in 208 patients (13.6%). Of Heartwatch participants, 8.4% experienced the CV composite compared with 14.5% of nonparticipants (P = .003). Participation in Heartwatch was associated with a significantly reduced risk of the CV composite (hazard ratio [HR] 0.52, 95% CI, 0.31-0.87), CV mortality (HR 0.31, 95% CI, 0.11-0.89), and all-cause mortality (HR 0.32, 95% CI, 0.15-0.68). Heartwatch participation was also associated with greater reductions in mean systolic blood pressure (P = .047), mean diastolic blood pressure (P < .001), and greater use of secondary preventative therapies for CVD, such as lipid-lowering agents (P < .001), beta-blockers (P < .001), and angiotensin-converting enzyme inhibitors (P < .001). CONCLUSION: Heartwatch is associated with a reduced risk of major vascular events and improved risk factor modification, supporting its potential as a nationwide program for secondary prevention of CVD. PMID- 22520540 TI - Safety and effectiveness of antithrombotic strategies in older adult patients with atrial fibrillation and non-ST elevation myocardial infarction. AB - BACKGROUND: We aimed to study the comparative safety and effectiveness of various antithrombotic treatment strategies among older adults with non-ST elevation myocardial infarction (NSTEMI) and atrial fibrillation (AF). METHODS: Using the CRUSADE registry linked to longitudinal Medicare claims data, we examined NSTEMI patients aged >= 65 years with a concomitant diagnosis of AF. Multivariable Cox analysis was used to compare risk of rehospitalization for bleeding and a major cardiac composite end point of death, readmission for myocardial infarction, or stroke, according to discharge antithrombotic strategy. RESULTS: Among 7619 NSTEMI patients with AF, 29% were discharged on aspirin alone; 37%, on aspirin + clopidogrel; 7%, on warfarin alone; 17%, on aspirin + warfarin; and 10%, on warfarin + aspirin + clopidogrel. There was no difference in predicted stroke risk between groups. By 1 year, 12.2% of patients were rehospitalized for bleeding, and 33.1% had a major cardiac event. Relative to aspirin alone, antithrombotic intensification was associated with increased bleeding risk (aspirin + clopidogrel adjusted HR 1.22, 95% CI 1.03-1.46 and warfarin + aspirin HR 1.46, 95% CI 1.21-1.80). Patients treated with aspirin + clopidogrel + warfarin had the highest observed bleeding risk (HR 1.65, 95% CI 1.30-2.10). One year risk of the major cardiac end point was similar between groups, although, relative to aspirin only, there was a trend toward lower risk for the warfarin + aspirin group (HR 0.88, 95% CI 0.78-1.00). CONCLUSIONS: Older NSTEMI patients with AF are at high risk for subsequent bleeding and major cardiac events. Increased antithrombotic management was associated with increased bleeding risk. Further investigation is needed to clarify whether these risks are counterbalanced by reduced thromboembolic events in this population. PMID- 22520541 TI - Age of natural menopause and atrial fibrillation: the Framingham Heart Study. AB - BACKGROUND: Early menopausal age is associated with risk of cardiovascular events including myocardial infraction, stroke, and increased mortality. Relations between menopausal age and atrial fibrillation (AF) have not been investigated. We examined the association between menopausal age and AF. METHODS: Framingham Heart Study women >= 60 years old without prevalent AF and natural menopause were followed up for 10 years or until incident AF. Menopausal age was modeled as a continuous variable and by categories (<45, 45-53, and >53 years). We used Cox proportional hazards regression to determine associations between menopausal age and AF risk. RESULTS: In 1,809 Framingham women (2,662 person-examinations, mean baseline age 71.4 +/- 7.6 years, menopausal age 49.8 +/- 3.6 years), there were 273 unique participants with incident AF. We did not identify a significant association between the SD of menopausal age (3.6 years) and AF (hazard ratio [HR] per SD 0.94, 95% CI 0.83-1.06; P = .29). In a multivariable model with established risk factors for AF, menopausal age was not associated with incident AF (HR per SD 0.97, 95% CI 0.86-1.09; P = .60). Examining categorical menopausal age, earlier menopausal age (<45 years) was not significantly associated with increased AF risk compared with older menopausal age >53 years (HR 1.20, 95% CI 0.74-1.94; P = .52) or menopausal age 45 to 53 years (HR 1.38, 95% CI 0.93-2.04; P = .11). CONCLUSION: In our moderate-sized, community-based sample, we did not identify menopausal age as significantly increasing AF risk. However, future larger studies will need to examine whether there is a small effect of menopausal age on AF risk. PMID- 22520542 TI - Relationship of antihypertensive treatment to plasma markers of vascular inflammation and remodeling in the Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis study. AB - BACKGROUND: Antihypertensive agents lower the risk of cardiovascular events, but whether they affect pathways important in inflammation and plaque remodeling in atherosclerosis is uncertain. We assessed whether 2 commonly used antihypertensive agents affected plasma biomarkers reflecting specific inflammatory and remodeling processes over 2 years in the Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis (CAMELOT) study. METHODS: The study was a randomized controlled trial of 2 antihypertensives (amlodipine and enalapril) compared with placebo in patients with coronary artery disease and diastolic blood pressure less than 100 mm Hg. In 196 subjects who had baseline and 2-year intravascular coronary ultrasound examinations, we measured plasma interleukin 18, interleukin 1 receptor antagonist, matrix metalloproteinase 9, neopterin, and C-reactive protein. Results for both treatment groups were pooled and compared with placebo. RESULTS: Antihypertensive treatment with either agent significantly lowered diastolic blood pressure (-4.7 vs placebo 1.3 mm Hg, P = .002) and progression of coronary atheroma (Delta percent atheroma volume 0.6 vs placebo 2.1, P = .031). Antihypertensive therapy did not affect plasma biomarkers of inflammation or plaque remodeling in the 135 subjects with baseline and 2-year biomarker samples. Progression in percent atheroma volume was significantly less in subjects taking statins at baseline ( 2.5%, P = .0008). CONCLUSIONS: In patients with coronary artery disease and well controlled risk factors, antihypertensive therapy lowered blood pressure and progression of coronary atherosclerosis but did not affect plasma biomarkers of inflammation and remodeling. Antihypertensives may decrease atheroma progression by mechanisms other than those reflected by these plasma biomarkers. PMID- 22520543 TI - Regarding the impact of left ventricular size on response to cardiac resynchronization therapy. PMID- 22520544 TI - Cognitive decline and ischemic microlesions after coronary catheterization: a comparison to coronary artery bypass. PMID- 22520545 TI - A need, also, for transformative innovation in the definition of hypertension. PMID- 22520547 TI - Could radial instead of femoral access for coronary angiography change renal outcome? Nephrologists call for help. PMID- 22520549 TI - The not so "ideal" body weight-based dosing of Integrilin in obesity. PMID- 22520551 TI - Improvement in ejection fraction--but do not forget the basics, the medications. PMID- 22520553 TI - Reducing transfusion-related acute lung injury risk: evidence for and approaches to transfusion-related acute lung injury mitigation. AB - Transfusion-related acute lung injury (TRALI) is a major cause of transfusion related morbidity and mortality. Although the pathogenesis of TRALI is incompletely understood, substantial data from hemovigilance systems, large case series, clinical trials, and animal models have identified antileukocyte antibodies as a major precipitant and have contributed to the development of concrete interventions to reduce the risk of TRALI. This review presents the clinical data supporting specific donor management strategies to reduce TRALI risk and their observed clinical efficacy. Novel strategies that use the donor health questionnaire combined with testing are discussed, and important challenges that remain going forward are explored. PMID- 22520554 TI - Gastric cancer cell supernatant causes apoptosis and fibrosis in the peritoneal tissues and results in an environment favorable to peritoneal metastases, in vitro and in vivo. AB - BACKGROUND: In this study, we examined effects of soluble factors released by gastric cancer cells on peritoneal mesothelial cells in vitro and in vivo. METHODS: HMrSV5, a human peritoneal mesothelial cell line, was incubated with supernatants from gastric cancer cells. Morphological changes of HMrSV5 cells were observed. Apoptosis of HMrSV5 cells was observed under a transmission electron microscope and quantitatively determined by MTT assay and flow cytometry. Expressions of apoptosis-related proteins (caspase-3, caspase-8, Bax, bcl-2) were immunochemically evaluated. RESULTS: Conspicuous morphological changes indicating apoptosis were observed in HMrSV5 cells 24 h after treatment with the supernatants of gastric cancer cells. In vivo, peritoneal tissues treated with gastric cancer cell supernatant were substantially thickened and contained extensive fibrosis. CONCLUSIONS: These findings demonstrate that supernatants of gastric cancer cells can induce apoptosis and fibrosis in HMrSV5 human peritoneal mesothelial cells through supernatants in the early peritoneal metastasis, in a time-dependent manner, and indicate that soluble factors in the peritoneal cavity affect the morphology and function of mesothelial cells so that the resulting environment can become favorable to peritoneal metastases. PMID- 22520555 TI - [Classification and characteristics of interval cancers in the Principality of Asturias's Breast Cancer Screening Program]. AB - OBJECTIVE: To review and classify the interval cancers found in the Principality of Asturias's Breast Cancer Screening Program (PDPCM). A secondary objective was to determine the histological characteristics, size, and stage of the interval cancers at the time of diagnosis. MATERIAL AND METHODS: We included the interval cancers in the PDPCM in the period 2003-2007. Interval cancers were classified according to the breast cancer screening program protocol, with double reading without consensus, without blinding, with arbitration. Mammograms were interpreted by 10 radiologists in the PDPCM. RESULTS: A total of 33.7% of the interval cancers could not be classified; of the interval cancers that could be classified, 40.67% were labeled true interval cancers, 31.4% were labeled false negatives on screening, 23.7% had minimal signs, and 4.23% were considered occult. A total of 70% of the interval cancers were diagnosed in the year of the period between screening examinations and 71.7% were diagnosed after subsequent screening. A total of 76.9% were invasive ductal carcinomas, 61.1% were stage II when detected, and 78.7% were larger than 10mm when detected. CONCLUSIONS: The rate of interval cancers and the rate of false negatives in the PDPCM are higher than those recommended in the European guidelines. Interval cancers are diagnosed later than the tumors detected at screening. Studying interval cancers provides significant training for the radiologists in the PDPCM. PMID- 22520557 TI - Hexanic lipidosterolic extract of Serenoa repens inhibits the expression of two key inflammatory mediators, MCP-1/CCL2 and VCAM-1, in vitro. AB - What's known on the subject? and What does the study add? Pervasive inflammatory infiltrates, mainly composed of chronically activated T cells and monocytes/macrophages, have been observed in benign prostatic hyperplasia (BPH). Permixon(r), a hexanic lipidosterolic extract of Serenoa repens (hexanic LSESr) used to treat urinary dysfunction in BPH patients, has anti-inflammatory activities. This paper provides new insights into the anti-inflammatory properties of Permixon(r). We report that hexanic LSESr inhibits early steps of leukocyte infiltration in vitro by downregulating MCP-1/CCL2 and VCAM-1 expression. OBJECTIVE: To investigate the mechanisms by which hexanic lipidosterolic extract of Serenoa repens (hexanic LSESr) may prevent leukocyte infiltration in benign prostatic hyperplasia by studying its impact on monocyte chemoattractant protein 1/chemokine (C-C motif) ligand 2 (MCP-1/CCL2) and vascular cell adhesion molecule 1 (VCAM-1) expression in vitro. MATERIALS AND METHODS: After pretreatment with hexanic LSESr, human prostate (epithelial and myofibroblastic) cells and vascular endothelial cells were stimulated with proinflammatory cytokines. MCP-1/CCL2 and VCAM-1 mRNA expression was quantified by real-time PCR. ELISA kits were used to determine MCP-1/CCL2 levels in culture supernatants and VCAM-1 expression in living cells. RESULTS: Hexanic LSESr reduced MCP-1/CCL2 mRNA levels in both epithelial (BPH-1) and myofibroblastic (WPMY-1) prostate cell lines. Hexanic LSESr downregulated MCP1/CCL2 secretion by WPMY-1 cells in a concentration-dependent manner, more efficiently than Serenoa repens extracts obtained by supercritical carbon dioxide extraction. Hexanic LSESr inhibited tumour-necrosis-factor-alpha-induced MCP-1/CCL2 secretion by the human vascular endothelial cell line EAhy.926, as well as surface VCAM-1 protein expression, in a concentration-dependent manner. CONCLUSIONS: Hexanic LSESr impedes key steps of monocyte and T cell attraction and adherence by inhibiting MCP-1/CCL2 and VCAM-1 expression by human prostate and vascular cells in an inflammatory environment. These findings provide new insights into the anti inflammatory effects of the hexanic lipidosterolic extract of Serenoa repens, Permixon(r), in benign prostatic hyperplasia. PMID- 22520556 TI - Evaluation of the postoperative lumbar spine. AB - Given the prevalence of low back pain, surgical interventions on the lumbar spine are becoming more common. Among the many surgical procedures available for these interventions, the most common are laminectomy and discectomy. In 10 to 40% of patients who undergo surgical interventions on the lumbar spine, low back pain is not completely alleviated or it recurs, and these cases fall into the category of " failed back surgery syndrome ". This syndrome can have many different causes and multiple factors are often involved. It is important not to confuse the normal postoperative findings with those specific to failed back surgery syndrome. Deciding which imaging technique to use will depend on the type of surgical intervention, whether metallic orthopedic material was used, and the clinical suspicion. It is essential to know the advantages and limitations of the available imaging techniques to ensure the optimal evaluation of these patients, especially after interventions carried out with instrumentation to minimize the artifacts due to these materials. PMID- 22520558 TI - Cardiovascular abnormalities in obstructive cholestasis: the possible mechanisms. AB - Cholestatic liver disease is associated with widespread derangements in the cardiovascular system, such as bradycardia, hypotension, QT prolongation and peripheral vasodilation; it is also associated with increased susceptibility to postoperative renal failure and haemorrhagic shock. A number of cellular signalling pathways have been shown to contribute to these abnormalities. In this article, we briefly review recent in vivo and in vitro findings in the field in an attempt to highlight the areas of agreement and areas of controversy. In this review, we will summarize pathogenic mechanisms underlying cardiac and vascular abnormalities in obstructive cholestasis. It seems that cardiovascular dysfunction is likely because of bile acids as one of the predominant factors. Other important factors which might play roles in these abnormalities are increased nitric oxide, endogenous opioids and endocannabinoids. These three factors interact with each other to exert vasodilation and impaired cardiovascular responses to sympathetic stimulation. PMID- 22520560 TI - [Initial experience of a program of clipping the sympathetic nervous system for the treatment of hyperhidrosis and facial flush]. AB - INTRODUCTION AND OBJECTIVE: To evaluate the results of our program of clipping the thoracic sympathetic nervous system (TSNS) for the treatment of facial flush and/or hyperhidrosis (HH), and to compare the methodology-results of the program development phase (A: January 2007-April 2009) and its consolidation phase (B: May 2009-March 2010). MATERIAL AND METHODS: The program included a total of 44 patients (88 procedures) subjected to videothoracoscopy and clipping of the TSNS in a one day surgery unit. Data were collected and analysed retrospectively, and a descriptive and comparative statistical analysis was performed between the two periods (A and B). RESULTS: The overall morbidity was 5 cases (11.3%). The post surgical occurrence rate of HH was 4.54% (2 cases), and the incidence of compensatory sweating was 65.9% (minimal in 26 of the 29 cases). On comparing period B with period A, there was a significant decrease in surgical time, disappearance of recurrence of HH, a decrease of 30% in morbidity, reduction by half in the incidence of moderate to severe compensatory sweating, and an increase in the level of satisfaction. The clamps were removed in one of the poorly tolerated compensatory sweating cases, resulting in its disappearance. CONCLUSIONS: Clipping the TSNS is a safe technique in the one day surgery unit, with a short learning curve (20 cases) after which comparable, or even better, results are obtained than those of sympatholysis. These results, together with their potential reversibility, makes it, in our opinion, the technique of choice in the surgery of the TSNS. PMID- 22520559 TI - A review of wearable sensors and systems with application in rehabilitation. AB - The aim of this review paper is to summarize recent developments in the field of wearable sensors and systems that are relevant to the field of rehabilitation. The growing body of work focused on the application of wearable technology to monitor older adults and subjects with chronic conditions in the home and community settings justifies the emphasis of this review paper on summarizing clinical applications of wearable technology currently undergoing assessment rather than describing the development of new wearable sensors and systems. A short description of key enabling technologies (i.e. sensor technology, communication technology, and data analysis techniques) that have allowed researchers to implement wearable systems is followed by a detailed description of major areas of application of wearable technology. Applications described in this review paper include those that focus on health and wellness, safety, home rehabilitation, assessment of treatment efficacy, and early detection of disorders. The integration of wearable and ambient sensors is discussed in the context of achieving home monitoring of older adults and subjects with chronic conditions. Future work required to advance the field toward clinical deployment of wearable sensors and systems is discussed. PMID- 22520561 TI - [Bowel intussusception in a gastric by-pass patient]. PMID- 22520562 TI - Adult sporadic burkitt lymphoma of the oral cavity: a case report and literature review. PMID- 22520563 TI - Osteonecrosis of the jaws unrelated to bisphosphonate exposure: a series of 4 cases. PMID- 22520564 TI - Congenital mucocele in the tongue: report of a case. PMID- 22520565 TI - Sialoendoscopy-assisted sialolithectomy for submandibular hilar calculi. AB - PURPOSE: To assess the clinical effects of endoscopy-assisted sialolithectomy for submandibular hilar calculi. MATERIALS AND METHODS: The present study was undertaken in 70 patients with symptomatic stones in the hilum of submandibular glands who underwent endoscopy-assisted sialolithectomy from December 2005 through March 2011 in the Peking University School and Hospital of Stomatology. The operative data were analyzed retrospectively. All patients were followed periodically postoperatively. Submandibular gland function was investigated by postoperative symptoms, clinical examinations, sialography, and scintigraphy. RESULTS: Submandibular stones were successfully removed in 65 patients, with a success rate of 92.9%. Temporary lingual nerve injury occurred in 1 patient. Two patients developed ranulae and underwent an uneventful sublingual gland excision. During a mean follow-up of 23 months (range, 6 to 55 mo), 52 of 65 patients were symptom free, whereas 11 patients complained of occasional swelling of the affected gland at mealtimes and 2 patients developed a recurrent stone. Thirty patients underwent postoperative sialography. The sialographic appearances included 4 types: 1) approximately normal; 2) the main duct was significantly dilated at the hilum, but no persistent contrast was seen on the functional film; 3) the main duct was significantly dilated in the hilar region, and persistent contrast was seen at the dilated hilum of the functional film; 4) the main duct was dilated or strictured, and persistent contrast was seen on the functional film. Three of the 4 patients who underwent scintigraphy exhibited good function. CONCLUSIONS: Sialoendoscopy-assisted sialolithectomy is a safe and effective gland-preservation technique for patients with hilar stones of the Wharton's duct. PMID- 22520566 TI - Analysis of 3D soft tissue changes after 1- and 2-jaw orthognathic surgery in mandibular prognathism patients. AB - PURPOSE: Orthognathic surgery has the objective of altering facial balance to achieve esthetic results in patients who have severe disharmony of the jaws. The purpose was to quantify the soft tissue changes after orthognathic surgery, as well as to assess the differences in 3D soft tissue changes in the middle and lower third of the face between the 1- and 2-jaw surgery groups, in mandibular prognathism patients. MATERIALS AND METHODS: We assessed soft tissue changes of patients who have been diagnosed with mandibular prognathism and received either isolated mandibular surgery or bimaxillary surgery. The quantitative surface displacement was assessed by superimposing preoperative and postoperative volumetric images. An observer measured a surface-distance value that is shown as a contour line. Differences between the groups were determined by the Mann Whitney U test. The Spearman correlation coefficient was used to evaluate a potential correlation between patients' surgical and cephalometric variables and soft tissue changes after orthognathic surgery in each group. RESULTS: There were significant differences in the middle third of the face between the 1- and 2-jaw surgery groups. Soft tissues in the lower third of the face changed in both surgery groups, but not significantly. The correlation patterns were more evident in the lower third of the face. CONCLUSION: The overall soft tissue changes of the midfacial area were more evident in the 2-jaw surgery group. In 2-jaw surgery, significant changes would be expected in the midfacial area, but caution should be exercised in patients who have a wide alar base. PMID- 22520568 TI - Comparative study of different osteotomy modalities in maxillary distraction osteogenesis for cleft lip and palate. AB - PURPOSE: Conventional maxillary distraction osteogenesis and anterior maxillary segmental distraction were applied in the treatment of severe maxillary hypoplasia secondary to cleft clip and palate. The aim of the present study was to compare the difference between these 2 osteotomy modalities used for rigid external distraction. PATIENTS AND METHODS: Ten patients with severe maxillary hypoplasia secondary to CLP were enrolled in our study. They were randomly divided into 2 groups. Conventional maxillary distraction osteogenesis was performed in 5 patients and anterior maxillary segmental distraction in 5 patients. The preoperative and postoperative lateral cephalograms were compared, and cephalometric analysis was performed. The independent sample t test was used to evaluate the differences between the 2 groups. RESULTS: All patients healed uneventfully, and the maxillae moved forward satisfactorily. The sella-nasion point A angles, nasion-point A-Frankfort horizontal plane angles, overjets, and 0 meridian to subnasale distances had increased significantly after distraction osteogenesis. Significant differences were found in the changes in palatal length between the 2 groups (P < .05). A mean increase of 7.50 mm in palatal length was found in the anterior maxillary segmental distraction group. No significant difference in the changes in palatopharyngeal depth or soft palatal length was found. CONCLUSIONS: With the ability of increasing the palatal and arch length, avoiding changes in palatopharyngeal depth, and preserving palatopharyngeal closure function, anterior maxillary segmental distraction has great value in the treatment of maxillary hypoplasia secondary to CLP. It is a promising and valuable technique in this potentially complicated procedure. PMID- 22520567 TI - Periapical tissue response after use of intermediate restorative material, gutta percha, reinforced zinc oxide cement, and mineral trioxide aggregate as retrograde root-end filling materials: a histologic study in dogs. AB - PURPOSE: To investigate the periapical tissue response of 4 different retrograde root-filling materials, ie, intermediate restorative material, thermoplasticized gutta-percha, reinforced zinc oxide cement (Super-EBA), and mineral trioxide aggregate (MTA), in conjunction with an ultrasonic root-end preparation technique in an animal model. MATERIALS AND METHODS: Vital roots of the third and fourth right mandibular premolars in 6 healthy mongrel dogs were apicectomized and sealed with 1 of the materials using a standardized surgical procedure. After 120 days, the animals were sacrificed and the specimens were analyzed radiologically, histologically, and scanning electron microscopically. The Fisher exact test was performed on the 2 outcome values. RESULTS: Twenty-three sections were analyzed histologically. Evaluation showed better re-establishment of the periapical tissues and generally lower inflammatory infiltration in the sections from teeth treated with the intermediate restorative material and the MTA. New root cement on the resected dentin surfaces was seen on all sections regardless of the used material. New hard tissue formation, directly on the surface of the material, was seen only in the MTA sections. There was no statistical difference in outcome among the tested materials. CONCLUSIONS: The results from this dog model favor the intermediate restorative material and MTA as retrograde fillings when evaluating the bone defect regeneration. MTA has the most favorable periapical tissue response when comparing the biocompatibility of the materials tested. PMID- 22520569 TI - Does swallowing function recover in the long term in patients with surgically treated tongue carcinomas? AB - PURPOSE: The present study aimed to measure postsurgical swallowing function in patients 5 years after the surgical treatment of tongue carcinoma. PATIENTS AND METHODS: Using a retrospective cohort study design, the investigators enrolled postsurgical patients treated for tongue carcinomas in Hokkaido University Hospital. The primary outcome variable was oropharyngeal swallow efficiency (OPSE) determined by videofluoroscopic evaluation, and OPSE at follow-up was compared with that at discharge. Other variables included current nutritional status (body mass index, serum albumin), dietary intake, self-rating of current swallowing function, and occurrence of pneumonia. Statistical analysis used the paired t test and the Spearman rank correlation. RESULTS: Swallowing function was assessed in 20 patients (11 men and 9 women) who underwent the surgical treatment of tongue carcinomas; the median age was 70 years (range, 56 to 90 yrs). The mean OPSE values for liquid and paste at follow-up were 26.6 +/- 21.2 and 21.9 +/- 22.5, respectively. The mean values for the body mass index and serum albumin at presentation were 22.2 +/- 3.4 kg/m(2) and 4.5 +/- 0.3 g/dL, respectively. All patients had a full oral intake of foods, with a mean self-rated value of 6.4 +/- 2.5, a value acceptable to the patients. Pneumonia requiring hospitalization did not occur in these patients. CONCLUSIONS: The long-term follow-up of patients after the surgical treatment of tongue carcinomas showed acceptable levels of oral function and nutritional status despite objective measurements of poor swallowing efficiency assessed using videofluoroscopy. PMID- 22520570 TI - Can the humanities mend medicine? PMID- 22520571 TI - Lateral meniscal tear resulting from the femoral cross-pin used for hamstring graft fixation in anterior cruciate ligament reconstruction. AB - We report a case of lateral meniscal tear resulting from the femoral cross-pin used for hamstring graft fixation in anterior cruciate ligament (ACL) reconstruction. A 29 year old man presented with symptoms of knee pain, catching and locking, 13 months following an ACL reconstruction. Magnetic resonance imaging (MRI) and arthroscopy confirmed the broken femoral cross-pin abutting the lateral meniscus and the resulting meniscal tear. Removal of the broken femoral cross-pin and repair of the lateral meniscal tear resulted in resolution of symptoms. Distal femoral cross-pin fracture and its intra-articular position are postulated as the cause of this lateral meniscal tear. Hence, we recommend a low threshold to investigate with a MRI scan any new symptoms following ACL reconstruction with cross-pin fixation. PMID- 22520572 TI - The effect of exogenous corticosterone on West Nile virus infection in Northern Cardinals (Cardinalis cardinalis). AB - The relationship between stress and disease is thought to be unambiguous: chronic stress induces immunosuppression, which likely increases the risk of infection. However, this link has not been firmly established in wild animals, particularly whether stress hormones affect host responses to zoonotic pathogens, which can be transmitted to domesticated animal, wildlife and human populations. Due to the dynamic effects of stress hormones on immune functions, stress hormones may make hosts better or poorer amplifying hosts for a pathogen contingent on context and the host species evaluated. Using an important zoonotic pathogen, West Nile virus (WNV) and a competent host, the Northern Cardinal (Cardinalis cardinalis), we tested the effects of exogenous corticosterone on response to WNV infection. Corticosterone was administered at levels that individuals enduring chronic stressors (i.e., long-term inclement weather, food shortage, anthropogenic pollution) might experience in the wild. Corticosterone greatly impacted mortality: half of the corticosterone-implanted cardinals died between five - 11 days post-inoculation whereas only one of nine empty-implanted (control) birds died. No differences were found in viral titer between corticosterone- and empty implanted birds. However, cardinals that survived infections had significantly higher average body temperatures during peak infection than individuals that died. In sum, this study indicates that elevated corticosterone could affect the survival of WNV-infected wild birds, suggesting that populations may be disproportionately at-risk to disease in stressful environments. PMID- 22520573 TI - Inverted papilloma of the bladder: a review and an analysis of the recent literature of 365 patients. AB - OBJECTIVES: Until the 1970s, inverted urothelial papilloma (IUP) of the bladder was generally regarded as a benign neoplasm. However, in the 1980s, several reported cases suggested the malignant potential of these papillomas, including cases with features indicative of malignancy, recurrent cases, and cases of IUP synchronous or metachronous with transitional cell carcinoma. The aim of this systematic review and analysis of the literature since 1990 to date is to contribute to unresolved issues regarding the biological behavior and prognosis of these neoplasms to establish some key points in the clinical and surgical management of IUP. MATERIALS AND METHODS: Database searches yielded 109 references. Exclusion of irrelevant references left 10 references describing studies that fulfilled the predefined inclusion criteria. RESULTS: One problem regarding these neoplasms is the difficulty of obtaining a correct histopathologic diagnosis. The main differential diagnosis is endophytic urothelial neoplasia, including papillary urothelial neoplasia of low malignant potential or urothelial carcinoma of low or high grade, while other considerably rare differential diagnoses include nephrogenic adenoma, paraganglioma, carcinoid tumor, cystitis cystica, cystitis glandularis, and Brunn's cell nests. The size of the lesions ranged from 1 to 50 mm (mean 12.8 mm). Most cases occurred in the fifth and sixth decade of life. The mean age of affected patients was 59.3 years (range 20-88 years). Analysis of the literature revealed a strong male predominance with a male/female ratio of 5.8:1. The most commonly reported sites of IUP were the bladder neck region and trigone. Of 285 cases included in 8 studies, 12 cases (4.2%) were multiple. Out of the total of 348 patients, 6 patients (1.72%) had a previous history of transitional cell carcinoma of the urinary bladder, 5 patients (1.43%) had synchronous transitional cell carcinoma of the urinary bladder, and 4 patients (1.15%) had subsequent transitional cell carcinoma of the urinary tract. The time before recurrence was <45 months (range 5-45 months, mean 27.7 months) after surgery. CONCLUSIONS: Inverted papilloma could be considered a risk factor for transitional cell carcinoma, and it is clinically prudent to exclude transitional cell cancer when it is diagnosed. Follow-up is needed if the histologic diagnosis is definitive or doubtful. We recommend 4-monthly flexible cystoscopy for the first year and then every 6 months for the subsequent 3 years. Routine surveillance of the upper urinary tract in cases of inverted papilloma of the lower part of the urinary tract is not deemed necessary. PMID- 22520574 TI - Epidermal growth factor receptor (EGFR) biology and Wnt developmental signaling highlight research endeavors of SCBA award winners. AB - This months Cell and Bioscience highlights review articles by Mien-Chie Hung on EGFR biology and Yingzi Yang on Wnt signaling. Dr. Hung was the 2011 Society of Chinese Bioscientists in America (SCBA) Presidential Award winner. Dr. Yang was the 2011 SCBA Outstanding Young Investigator Award winner. PMID- 22520575 TI - The prognostic value of detecting symptomatic or asymptomatic recurrence in patients with gastric cancer after a curative gastrectomy. AB - BACKGROUND: Although studies have investigated whether a routine follow-up should be performed after a gastrectomy, no consensus has been reached on the significance of the follow-up or the optimal surveillance protocol. In the present study, we evaluated the significance of the presence or absence of symptoms in the detection of recurrences after curative gastrectomy for gastric cancer. METHODS: We retrospectively analyzed 173 patients with recurrent gastric cancer who underwent radical gastrectomy. We evaluated the prognostic significance of the presence of cancer-related symptoms at the diagnosis of recurrence, and the relationship between the presence of symptoms and other clinicopathological factors. RESULTS: We detected a symptomatic recurrence in 42.2% of patients. The presence of symptoms were significantly correlated with tumor size, pT stage, pN stage, pathologic stage, and short disease-free interval (<12 mo). The median disease-free survival (DFS), post-recurrence survival (PRS), and overall survival (OS) times for patients with asymptomatic recurrence were significantly longer than those of patients with symptomatic recurrence (disease free survival was corrected as DFS, 11.1 versus 9.3 mo, P < 0.001; PRS, 4.9 versus 3.1 mo, P = 0.02; OS, 18.3 versus 12.3 mo, P = 0.001, respectively). Multivariate analysis showed that the presence of cancer-related symptoms (P = 0.033; hazard ratio [HR], 0.81) was an independent prognostic factor for PRS, as were short disease-free intervals (P < 0.001; HR, 2.42), age (P = 0.02; HR, 1.53), and the presence of chemotherapy in recurrence (P = 0.001; HR, 0.49). In addition, multivariate analysis indicated that the presence of symptoms, short disease-free interval, and age were also independent prognostic indicators for OS. CONCLUSIONS: Our results demonstrate that symptomatic recurrence is an important prognostic factor for PRS of patients with gastric cancer after a curative gastrectomy. The presence of symptomatic recurrence may be a new and beneficial prognostic marker to evaluate biologic aggressiveness, which is an important determinant of survival at the time of recurrence diagnosis during a follow-up for gastric cancer. PMID- 22520576 TI - Heterotopic abdominal heart transplantation in rats for functional studies of ventricular unloading. AB - INTRODUCTION: Chronic changes in mechanical load regulate long-term cardiac function. Chronic overload of the ventricle results in myocardial failure. Clinical use of ventricular assist devices shows that chronic reduction in load has a number of different consequences on the myocardium, including beneficial reverse remodeling as well as undesired remodeling (e.g., myocardial atrophy and fibrosis, both of which could have negative functional implications). The complex response to mechanical unloading necessitates reproducible animal models of mechanical unloading for use in the laboratory. This article aims to describe the operative technique of two animal models of mechanical unloading in detail, to enable the reproducible use of these animal models. METHODS: In 1964, Abbott et al first described the heterotopic abdominal heart transplantation technique as a means to study the biology of transplanted cardiac grafts. This involves an aorto aortic anastomosis and a pulmonary artery to inferior vena cava anastomosis. In this model, the left ventricle is virtually completely volume unloaded, receiving only thebesian venous return, and substantially but not entirely pressure unloaded. In this report we describe two refined techniques for mechanical unloading of healthy or failing hearts based on experience with over 500 operations. RESULTS: We describe an operative technique, including cardioprotective strategies, that provides a model of mechanical unloading with no immunological rejection and allows measurements of parameters of myocardial structure and function for many months. We describe a refined technique that achieves a lesser degree of left ventricular volume unloading, involving transplantation of both heart and lungs via a single aorto-aortic anastomosis. CONCLUSIONS: This article is the first to describe these two techniques in sufficient detail to enable novices to attempt and understand these operations and the differences between them. The technique we describe provides an effective and reproducible model of complete and partial mechanical unloading. PMID- 22520577 TI - Nicotine stimulates proliferation and inhibits apoptosis in colon cancer cell lines through activation of survival pathways. AB - BACKGROUND: Colorectal cancer is one of the leading causes of cancer-related death throughout the world, and the risk to develop this malignant disease seems to be associated with long-term cigarette smoking. Nicotine, one of the major components of cigarette smoking, can stimulate cell proliferation and suppress apoptosis both in normal cells and in several human cancer cell lines derived from various organs. However, although nicotine appears to have a role in stimulating cell proliferation of colon cancer cells, there is no information on its role in inhibiting apoptosis in these cells. MATERIALS AND METHODS: Human colorectal cancer cell lines Caco-2 and HCT-8 were treated with 1 MUM nicotine alone or in combination with 1 MUM alpha-BTX in complete or in serum free medium. Cell proliferation and apoptosis were determined by cell count performed with a cell counter and by cytofluorimetric assay respectively. PI3K/Akt and PKC/ERK1/2 pathways, survivin, and P-Bcl2 (Ser70) were investigated by Western blot analysis. RESULTS: Nicotine induced an increase in cell proliferation and a decrease of apoptosis in Caco-2 and HCT-8 cells. Both cell growth and apoptosis appear to be mediated by alpha7-nicotinic acetylcholine receptors, since treatment with alpha-Bungarotoxin inhibited these processes. Nicotine induced a statistically significant increase in the expression of PI3K and in P-Akt/Akt ratio as well as in the expression of PKC, ERK1/2, survivin, and P-Bcl2 (Ser70) in both cell lines. CONCLUSIONS: Nicotine, contained in cigarette smoking, could participate in colon cancer development and progression by stimulating cell proliferation and suppressing physiological apoptosis. PMID- 22520578 TI - Mesh shift following laparoscopic ventral hernia repair. AB - INTRODUCTION: Traditionally, laparoscopic ventral hernia repair (LVHR) is performed by placing the trocars on one side of the abdomen. Tacking the mesh on the operative side can be challenging. We hypothesized that mesh shift may occur as a result of this approach. We define mesh shift as any mesh off-center, where the center is the hernia defect. Our objectives were to evaluate whether mesh shift occurs after LVHR, and to develop a grading system to describe this phenomenon. METHODS: We conducted a retrospective review of patients who underwent LVHR from 2000 to 2010. We examined patient demographics, comorbidities, radiographic data, surgical data, and outcomes. Using analysis of variance, we analyzed continuous data; we used Chi squared to analyze categorical data. Of the 201 patients, we reviewed 78 postoperative computed tomography (CT) scans. Two surgeons measured mesh overlap of the fascia bilaterally at the level of the hernia defect. We compared a ratio of the two sides of overlap (least overlap/greatest overlap) and classified patients into four grades: grade I, no mesh shift (ratio of 0.5-1.00); grade II, mild mesh shift (ratio of 0.20-0.49); grade III, moderate mesh shift (>0-0.19); and grade IV, major mesh shift with recurrence (<0). Any recurrence was classified as a grade IV shift. RESULTS: A total of 48% of patients had mesh shift (grade II = 23%; grade III = 10%; and grade IV = 17%). In 92% of the patients with mesh shift, the mesh migrated away from the port placement site, resulting in decreased mesh/fascial overlap. Patients in the four groups had similar demographics, comorbid conditions, hernia characteristics, operative technique, and outcomes (excluding recurrences, which were all grade IV by definition). Whereas differences in time to follow-up CT scan in the different grades were not statistically significant, there was a trend toward increasing shift with time (mean: grade I, 20 mo; grade II, 38 mo; grade III, 50 mo; and grade IV, 26 mo; P = 0.07). A total of 26 patients (33%) had multiple postoperative CT scans. With time, it appears that mesh tended to shift with time (grade I, 68%-46%; grade II, 12%-19%; grade III, 12%-8%, and grade 4, 8%-23%). CONCLUSIONS: Mesh can shift from the ideal central placement after LVHR. Mesh tends to shift away from the operative side and recurrences tend to occur on the operative side. Mesh shift may be a precursor to hernia recurrence. Recurrence may be a two-step process, beginning first with intra operative mesh shift followed by additional factors (such mesh contraction) that may accentuate the shift and lead to recurrence. Potential solutions include increasing mesh overlap (>= 6 cm), performing transcutaneous closure of central defect, securing trans-fascial sutures before tacking, placing operative side tacks first, and consider placing contralateral ports to secure the mesh. PMID- 22520579 TI - Compromised margins following mastectomy for stage I-III invasive breast cancer. AB - BACKGROUND: We investigated factors associated with positive margins following mastectomy and the impact on outcomes. METHODS: We identified 240 patients with stage I-III invasive breast cancer who underwent mastectomy from 1999 to 2009. Data included patient and tumor characteristics, pathologic margin assessment, and outcomes. Margin positivity was defined as the presence of in situ or invasive malignancy at any margin. Descriptive statistics were used for data summary and were compared using chi(2). RESULTS: Of the 240 patients, 132 (55%) had a simple mastectomy with sentinel lymph node biopsy and 108 (45%) had a modified radical mastectomy. Overall, 21 patients (9%) had positive margins, including 12 (57%) with one positive margin, 3 (14%) with two positive margins, and 6 (29%) with three or more positive margins. The most commonly affected margin was the deep margin (48% of patients). Eight of the 21 patients (38%) received adjuvant chest wall irradiation. There were no differences between patients who had a positive margin and those who did not with respect to patient age, race, percentage of in situ component, tumor size, tumor grade, lymphovascular invasion, or immunostain profile (P > 0.05 for all). None of the patients with positive margins experienced a local recurrence. CONCLUSIONS: Positive margins following mastectomy occurred in nearly 10% of our patients. No specific patient or tumor characteristics predicted a risk for having a positive margin. Despite the finding that only approximately 40% of patients received adjuvant radiation in the setting of a positive margin, no local recurrences have been observed. PMID- 22520580 TI - HLA gene and haplotype frequencies in Russians, Bashkirs and Tatars, living in the Chelyabinsk Region (Russian South Urals). AB - We have characterized the HLA-A, -B, -DRB1, -DQA1 and -DQB1 profiles of three major ethnic groups living in Chelyabinsk Region of Russian South Urals, viz., Russians (n = 207), Bashkirs (n = 146) and Tatars (n = 135). First field level typing was performed by PCR using sequence-specific primers. Estimates included carriage and gene frequencies, linkage disequilibrium and its significance and related values. Population comparisons were made between the allele family frequencies of the three populations and between these populations and 20 others using a dendrogram. Chelyabinsk Region Russians demonstrate all the features typical of a Caucasoid population, but also have some peculiarities. Together with Tatars, Russians have high frequencies of allele families and haplotypes characteristic of Finno-Ugric populations. This presupposes a Finno-Ugric impact on Russian and Tatar ethnogenesis. However, this was not apparent in Bashkirs, the first of the three populations to live in this territory, and implies admixture with populations of a Finno-Ugric origin with precursors of Russians and Tatars before they came to the South Urals. The Bashkirs appear close to Mongoloids in allele and haplotype distribution. However, Bashkirs cannot be labelled either as typical Mongoloids or as Caucasoids. Thus, Bashkirs possess some alleles and haplotypes frequent in Mongoloids, which supports the Turkic impact on Bashkir ethnogenesis, but also possess the AH 8.1 haplotype, which could evidence an ancient Caucasoid population that took part in their ethnic formation or of recent admixture with adjacent populations (Russians and Tatars). Bashkirs showed no features of populations with a substantial Finno-Ugric component, for example Chuvashes or Russian Saami. This disputes the commonly held belief of a Finno-Ugric origin for Bashkirs. Tatars appeared close to many European populations. However, they possessed some characteristics of Asiatic populations possibly reflecting a Mongoloid influence on Tatar ethnogenesis. Some aspects of HLA in Tatars appeared close to Chuvashes and Bulgarians, thus supporting the view that Tatars may be descendents of ancient Bulgars. PMID- 22520581 TI - Severe ictal hypoxemia following focal, subclinical temporal electrographic scalp seizure activity. AB - Ictal hypoxemia has been reported in focal seizures and can be particularly severe during sustained seizure activity involving both hemispheres. Oxygen desaturations have been linked to sudden unexplained death in epilepsy (SUDEP). We report a 71-year-old patient with subclinical electrographic seizure discharges involving the left temporal lobe. Electrographic seizures were followed by apneas and severe oxygen desaturations below 70% SpO(2) even after cessation of electrographic scalp seizure activity, suggesting inhibition of respiratory brainstem centers outlasting neocortical seizure activity. Seizures led to disrupted night's sleep due to arousals. Our case illustrates that severe hypoxemia can occur in association with subclinical seizures involving the temporal lobe and after scalp EEG seizure activity has terminated. Electrographic seizures followed by hypoxemia, such as observed in our patient, could contribute to SUDEP without overt clinical seizure activity. PMID- 22520582 TI - Coping strategies and health-related quality of life in epilepsy: a clinical reflection from a pilot study. PMID- 22520583 TI - Patient reporting of suspected adverse drug reactions to antiepileptic drugs: factors affecting attribution accuracy. AB - This study was aimed to assess the frequency and number of suspected ADRs reported by patients taking antiepileptic drugs (AEDs) and to explore the factors that may affect patients' symptom attribution accuracy. A validated questionnaire containing an extensively checklist of symptoms was distributed to outpatients prescribed one or more AEDs. Data on concomitant drugs and diseases were obtained from outpatient records. All symptoms identified were assessed for causality. Of 1388 questionnaires distributed to 1214 patients, 830 completed questionnaires were returned (59.8%) from 727 patients. In total, 7815 symptoms were identified on 757 questionnaires (91.2%). Symptom severity ratings were positively related to the number of symptoms reported (p=0.003). Causality assessment found that 71.9% of the symptoms were 'true' ADRs and 28.1% were 'false' ADRs. Attribution accuracy was primarily influenced by the number of symptoms identified and indication for AED therapy, fewer symptoms and use for non-epilepsy indications being associated with greater attribution accuracy. PMID- 22520584 TI - Ventricular tachycardia manifested as tonic seizure. AB - Nonepileptic seizures are sudden changes in behavior that resemble epileptic seizures but are not associated with the typical neurophysiological changes that characterize epileptic seizures. Cardiovascular disorders may cause loss of consciousness complicated by abnormal movements due to generalized cerebral hypoxia, leading to the initial impression of seizure. We report a case where a patient suffered from frequent loss of consciousness together with generalized tonic postures manifesting as leg extension, arm flexion or extension and upward gazing. These episodes were confirmed to be nonepileptic and caused by ventricular tachycardia. PMID- 22520585 TI - Emotion in psychogenic nonepileptic seizures: responses to affective pictures. AB - We examined emotional responses to standard affective pictures in 18 psychogenic nonepileptic seizure (PNES) patients. Given reports of trauma and posttraumatic stress symptoms (PTS) in many PNES patients, comparison groups were seizure-free individuals high and low in PTS (PTS-high, PTS-low; n=18 per group). Patients with psychogenic nonepileptic seizures (1) reported more emotional intensity to neutral and pleasant pictures than PTS-low and more intensity to neutral pictures than PTS-high, and (2) showed less positive emotional behavior to pleasant pictures than PTS-high. Groups did not differ in pleasantness/unpleasantness ratings, negative emotional behavior, cardiac interbeat interval, or respiratory sinus arrhythmia (RSA) reactivity to the pictures. Patients with psychogenic nonepileptic seizures reported more general emotion regulation difficulties and showed lower baseline RSA than PTS-low but not PTS-high. In sum, intense emotional experience and diminished positive emotional behavior characterized PNES patients' emotional responses. PMID- 22520586 TI - Auras in temporal lobe epilepsy with hippocampal sclerosis: relation to seizure focus laterality and post surgical outcome. AB - We examined the relationship between presence and frequency of different types of auras and side of lesion and post surgical outcomes in 205 patients with medically intractable mesial temporal lobe epilepsy (MTLE) with unilateral hippocampal sclerosis (HS). With respect to the number of auras, multiple auras were not associated with side of lesion (p=0.551). The side of HS was not associated with the type of auras reported. One hundred fifty-seven patients were operated. The occurrence of multiple auras was not associated with post-surgical outcome (p=0.740). The presence of extratemporal auras was significantly higher in patients with poor outcome. In conclusion, this study suggests that the presence of extratemporal auras in patients with MTLE-HS possibly reflects extratemporal epileptogenicity in these patients, who otherwise showed features suggestive of TLE. Therefore, TLE-HS patients undergoing pre-surgical evaluation and presenting clinical symptoms suggestive of extratemporal involvement should be more extensively evaluated to avoid incomplete resection of the epileptogenic zone. PMID- 22520587 TI - Musculotendon lengths and moment arms for a three-dimensional upper-extremity model. AB - Generating muscle-driven forward dynamics simulations of human movement using detailed musculoskeletal models can be computationally expensive. This is due in part to the time required to calculate musculotendon geometry (e.g., musculotendon lengths and moment arms), which is necessary to determine and apply individual musculotendon forces during the simulation. Modeling upper-extremity musculotendon geometry can be especially challenging due to the large number of multi-articular muscles and complex muscle paths. To accurately represent this geometry, wrapping surface algorithms and/or other computationally expensive techniques (e.g., phantom segments) are used. This paper provides a set of computationally efficient polynomial regression equations that estimate musculotendon length and moment arms for thirty-two (32) upper-extremity musculotendon actuators representing the major muscles crossing the shoulder, elbow and wrist joints. Equations were developed using a least squares fitting technique based on geometry values obtained from a validated public-domain upper extremity musculoskeletal model that used wrapping surface elements (Holzbaur et al., 2005). In general, the regression equations fit well the original model values, with an average root mean square difference for all musculotendon actuators over the represented joint space of 0.39 mm (1.1% of peak value). In addition, the equations reduced the computational time required to simulate a representative upper-extremity movement (i.e., wheelchair propulsion) by more than two orders of magnitude (315 versus 2.3 s). Thus, these equations can assist in generating computationally efficient forward dynamics simulations of a wide range of upper-extremity movements. PMID- 22520588 TI - Passive elastic properties of the rat ankle. AB - Passive properties of muscles and tendons, including their elasticity, have been suggested to influence motor control. We examine here the potential role of passive elastic muscle properties at the rat ankle joint, focusing on their potential to specify an equilibrium position of the ankle. We measured the position-dependent passive torques at the rat ankle before and after sequential cuts of flexor (a.k.a. dorsiflexor) and extensor (a.k.a. plantarflexor) ankle muscles. We found that there was a passive equilibrium position of the ankle that shifted systematically with the cuts, demonstrating that the passive torques produced by ankle flexor and extensor muscles work in opposition in order to maintain a stable equilibrium. The mean equilibrium position of the intact rat ankle ranged from 9.3 degrees to 15.7 degrees in extension relative to the orthogonal position, depending on the torque metric. The mean shift in equilibrium position due to severing extensors ranged from 4.4 degrees to 7.7 degrees , and the mean shift due to severing flexors was smaller, ranging from 0.9 degrees to 2.5 degrees . The restoring torques generated by passive elasticity are large enough (approximately 1.5-5 mNm for displacements of 18 degrees from equilibrium) to affect ankle movement during the swing phase of locomotion, and the asymmetry of larger extension vs. flexion torques is consistent with weight support, demonstrating the importance of accounting for passive muscle properties when considering the neural control of movement. PMID- 22520589 TI - Cortical bone failure mechanisms during screw pullout. AB - An experimental and computational study of screw pullout from cortical bone has been conducted. A novel modification of standard pullout tests providing real time image capture of damage mechanisms during screw pullout was developed. Pullout forces, measured using the novel test rig, have been validated against standard pullout tests. Pullout tests were conducted, considering osteon alignment, to investigate the effect of osteons aligned parallel to the axis of the orthopaedic screw (longitudinal pullout) as well as the effect of osteons aligned perpendicular to the axis of the screw (transverse pullout). Distinctive alternate failure mechanisms, for longitudinally and transversely orientated cortical bone during screw pullout, were uncovered. Vertical crack propagation, parallel to the axis of the screw, was observed for a longitudinal pullout. Horizontal crack propagation, perpendicular to the axis of the screw, was observed for a transverse pullout. Finite element simulation of screw pullout, incorporating material damage and crack propagation, was also performed. Simulations revealed that a homogenous material model for cortical bone predicts vertical crack propagation patterns for both longitudinal and transverse screw pullout. A bi-layered composite model representing cortical bone microstructure was developed. A unique set of material and damage properties was used for both transverse and longitudinal pullout simulations, with only layer orientations being changed. Simulations predicted: (i) higher pullout forces for transverse pullout; (ii) horizontal crack paths perpendicular to screw axis for transverse pullout, whereas vertical crack paths were computed for longitudinal pullout. Computed results agreed closely with experimental observations in terms of pullout force and crack propagation. PMID- 22520590 TI - Self-reported cost-prohibitive dental care needs among Canadians. AB - OBJECTIVES: To explore self-reported cost-prohibitive dental treatment needs among Canadians. METHODS: Data were collected through a national telephone interview survey of 1006 randomly selected Canadian adults. Descriptive analyses based on socio-demographic characteristics and dental-related behaviours were undertaken. Logistic regression was used to determine the predictors of experiencing a cost-prohibitive dental care need. Chi-square tests were used to determine significant differences in the treatments reported as unaffordable by socio-demographic characteristics and dental-related behaviours. RESULTS: Those of low income, no insurance coverage and poor self-rated oral health were more likely to report having a cost-prohibitive dental care need. The top needs reported as unaffordable were fillings, cleanings and check-ups. Comparatively, preventive services were selected as cost-prohibitive more often by the insured, dentures by the oldest group and extractions by those with a high school education or less. CONCLUSIONS: This study confirms that there are significant relationships between socio-demographic factors, dental-related behaviours and the types of dental services that are selected as unaffordable. Indirectly, this shows us how socio-demographic factors may influence the types of dental services that are reported as 'needed' by certain groups. Difficulties in distinguishing between the services that are 'needed' from and those that are 'wanted' demonstrate some of the policy complexity associated with publicly financed dental care. PMID- 22520591 TI - Single port laparoscopic subtotal colectomy and ileostomy in an adolescent with ulcerative colitis. AB - INTRODUCTION: Single port laparoscopic surgery has been increasingly used for complex surgical procedures. To our knowledge, this is the first published report of a single port laparoscopic subtotal colectomy and ileostomy in an adolescent patient with ulcerative colitis. CASE REPORT: A 13-year old female patient with ulcerative colitis resistant to maximal medical therapy underwent a single port laparoscopic subtotal colectomy and ileostomy. Both the procedure and the postoperative recovery were uneventful and the patient was discharged home on the sixth postoperative day. Follow-up at 3 and 8 weeks after surgery identified no early complications with a 4 kg weight gain. DISCUSSION: Single port laparoscopic surgery is feasible in the adolescent population if there is appropriate surgical expertise and strict patient selection. PMID- 22520592 TI - Efficacy of Adalimumab as a long term maintenance therapy in ulcerative colitis. AB - INTRODUCTION: Adalimumab is a recombinant human IgG1 monoclonal antibody to TNF alpha. There are limited data with regard to its efficacy in ulcerative colitis. We report experience of adalimumab in ulcerative colitis in a single centre with a focus on the ability of this agent to maintain response and avoid colectomy in the medium to long-term. METHODS: Twenty-three ulcerative colitis patients (mean age 32 years; 7 female) who received adalimumab were identified from a prospectively maintained database of over 2700 IBD patients. The primary study endpoint was treatment failure defined as discontinuation of adalimumab due to lack of efficacy, as defined by requiring an alternative maintenance therapy or colectomy, or intolerance. Colectomy rate was recorded as a secondary endpoint. RESULTS: Most patients (96%) had received immunosuppressants prior to adalimumab therapy (infliximab 20/23 87%). Sixteen of 23 patients (70%) discontinued adalimumab. Six primary failures, 8 secondary loss of response, one had unacceptable side effects and one discontinued treatment after 6 months but remains in remission. Overall estimated cumulative treatment failure rates at 6, 12 and 24 months were 50%, 65% and 72% respectively. Median follow-up in patients continuing adalimumab is 23 months (IQR 17-31 months). Treatment failure was unrelated to patient age, gender, disease extent, smoking status or CRP. Colectomy free survival was 59% at 2 years. No patient experienced a major adverse event. CONCLUSION: Adalimumab shows some efficacy as a maintenance strategy in Ulcerative Colitis, but only a limited proportion of patients remain well on continued treatment at 2 years. PMID- 22520593 TI - Pathogenic free-living amoebae: epidemiology and clinical review. AB - Free-living amoebae are widely distributed in soil and water. Small number of them was implicated in human disease: Acanthamoeba spp., Naegleria fowleri, Balamuthia mandrillaris and Sappinia diploidea. Some of the infections were opportunistic, occurring mainly in immunocompromised hosts (Acanthamoeba and Balamuthia encephalitis) while others are non opportunistic (Acanthamoeba keratitis, Naegleria meningoencephalitis and some cases of Balamuthia encephalitis). Although, the number of infections caused by these amoebae is low, their diagnosis was still difficult to confirm and so there was a higher mortality, particularly, associated with encephalitis. In this review, we present some information about epidemiology, ecology and the types of diseases caused by these pathogens amoebae. PMID- 22520596 TI - Major trends in mobility technology research and development: overview of the results of the NSF-WTEC European study. AB - Mobility technologies, including wheelchairs, prostheses, joint replacements, assistive devices, and therapeutic exercise equipment help millions of people participate in desired life activities. Yet, these technologies are not yet fully transformative because many desired activities cannot be pursued or are difficult to pursue for the millions of individuals with mobility related impairments. This WTEC study, initiated and funded by the National Science Foundation, was designed to gather information on European innovations and trends in technology that might lead to greater mobility for a wider range of people. What might these transformative technologies be and how might they arise? Based on visits to leading mobility technology research labs in western Europe, the WTEC panel identified eight major trends in mobility technology research. This commentary summarizes these trends, which are then described in detail in companion papers appearing in this special issue. PMID- 22520594 TI - Orthopaedic applications of nanoparticle-based stem cell therapies. AB - Stem cells have tremendous applications in the field of regenerative medicine and tissue engineering. These are pioneering fields that aim to create new treatments for disease that currently have limited therapies or cures. A particularly popular avenue of research has been the regeneration of bone and cartilage to combat various orthopaedic diseases. Magnetic nanoparticles (MNPs) have been applied to aid the development and translation of these therapies from research to the clinic. This review highlights contemporary research for the applications of iron-oxide-based MNPs for the therapeutic implementation of stem cells in orthopaedics. These MNPs comprise of an iron oxide core, coated with a choice of biological polymers that can facilitate the uptake of MNPs by cells through improving endocytic activity. The combined use of these oxides and the biological polymer coatings meet biological requirements, effectively encouraging the use of MNPs in regenerative medicine. The association of MNPs with stem cells can be achieved via the process of endocytosis resulting in the internalisation of these particles or the attachment to cell surface receptors. This allows for the investigation of migratory patterns through various tracking studies, the targeting of particle-labelled cells to desired locations via the application of an external magnetic field and, finally, for activation stem cells to initiate various cellular responses to induce the differentiation. Characterisation of cell localisation and associated tissue regeneration can therefore be enhanced, particularly for in vivo applications. MNPs have been shown to have the potential to stimulate differentiation of stem cells for orthopaedic applications, without limiting proliferation. However, careful consideration of the use of active agents associated with the MNP is suggested, for differentiation towards specific lineages. This review aims to broaden the knowledge of current applications, paving the way to translate the in vitro and in vivo work into further orthopaedic clinical studies. PMID- 22520597 TI - [Integrative pathology, an important field of development of clinical pathology]. PMID- 22520595 TI - In vitro antiplasmodial, antileishmanial and antitrypanosomal activities of selected medicinal plants used in the traditional Arabian Peninsular region. AB - BACKGROUND: Worldwide particularly in developing countries, a large proportion of the population is at risk for tropical parasitic diseases. Several medicinal plants are still used traditionally against protozoal infections in Yemen and Saudi Arabia. Thus the present study investigated the in vitro antiprotozoal activity of twenty-five plants collected from the Arabian Peninsula. METHODS: Plant materials were extracted with methanol and screened in vitro against erythrocytic schizonts of Plasmodium falciparum, intracellular amastigotes of Leishmania infantum and Trypanosoma cruzi and free trypomastigotes of T. brucei. Cytotoxic activity was determined against MRC-5 cells to assess selectivity. The criterion for activity was an IC(50) < 10 MUg/ml (<5 MUg/ml for T. brucei) and selectivity index of >4. RESULTS: Antiplasmodial activity was found in the extracts of Chrozophora oblongifolia, Ficus ingens, Lavandula dentata and Plectranthus barbatus. Amastigotes of T. cruzi were affected by Grewia erythraea, L. dentata, Tagetes minuta and Vernonia leopoldii. Activity against T. brucei was obtained in G. erythraea, L. dentata, P. barbatus and T. minuta. No relevant activity was found against L. infantum. High levels of cytotoxicity (MRC-5 IC(50) < 10 MUg/ml) and hence non-specific activities were noted in Cupressus sempervirens, Kanahia laniflora and Kniphofia sumarae. CONCLUSION: The results endorse that medicinal plants can be promising sources of natural products with antiprotozoal activity potential. The results support to some extent the traditional uses of some plants for the treatment of parasitic protozoal diseases. PMID- 22520598 TI - [KRAS analysis management: Process and delays]. AB - INTRODUCTION: The prescription of some anti-cancer therapies is now based on the detection of specific genetic alterations that should be determined as early as possible not to put patients at a disadvantage. In 2009, the 'Aquitaine platform of molecular tumour genetics' (PGMC) developed a programme to evaluate and to improve the organisation of molecular cancer analyses, particularly the analysis of the KRAS gene. The objective was to describe the analysis process, the organization of pathology laboratories and the delays between the different phases of the process. METHODS: We established a working group to describe the different steps between the prescription of molecular biology analyses and the analysis report. A retrospective study based on the first quarter of 2009 allowed us to measure management delays. In addition, a pathology laboratory organisational questionnaire allowed us to identify organisational features hindering rapid delivery. RESULTS: The median delay between the analysis prescription and the results was 15 days (range: 7-78 days). Practices explaining longer delays were highlighted not only in the pathology laboratories (for example, pending of the prescription before sending the analysis, waiting for several cases before sending the material, sample slicing, sending by standard mail), but also within the PGMC (for example, sample testing by another technique or new extraction for non-contributory samples). CONCLUSION: The results of this study emphasise the necessity of speeding up pre-analytical phases, and of creating an electronic procedure and regional facilities in order to provide results more rapidly to clinicians. PMID- 22520599 TI - [Setting up indicators in biobanking: why and how?]. AB - The biobanking area is highly complex, and its complexity is increasing along with its growth and demand. Due to the advancements in genetic research, stem cell research and regenerative medicine, biobanking has become ever more important and plays a key role in biomedical research. The robustness and the reproducibility of research results depend greatly on the quality and on the number of the samples used, and thus on the expertise of biobanks having supplied these samples. Undoubtedly, the recognition of a research biobank depends on the impact of the research projects conducted with samples obtained from tumour bank(s), but also on many other criteria. It thus seems important to determine a number of indicators within a biobank to estimate objective criteria for the performance of these structures. These indicators can allow to make some strategic decisions knowing that biobanks are expensive structures to maintain in the present hospital context. The use of these indicators could also contribute to the elaboration of an "biobank impact factor of" or so called "bioresource research impact factor" (BRIF). We describe here four major categories of indicators (quality, activity, scientific production, visibility), which seem to be useful for the evaluation of a biobank by making a proposition of allocation of coefficients for the various considered items. PMID- 22520601 TI - [Diagnostic issues of prostate biopsies. Introduction]. PMID- 22520602 TI - [Diagnostic issues of prostate biopsies. Case 1. Limited adenocarcinoma]. PMID- 22520603 TI - [Diagnostic issues of prostate biopsies. Case 2. Atypical adenomatous hyperplasia (adenosis)]. PMID- 22520604 TI - [Diagnostic issues of prostate biopsies. Case 3. Atrophic carcinoma]. PMID- 22520605 TI - [Diagnostic issues of prostate biopsies. Case 4. Pseudo-hyperplasic carcinoma]. PMID- 22520606 TI - [Diagnostic issues of prostate biopsies. Case 5. Foamy cell carcinoma, associated with xanthomatous inflammation]. PMID- 22520607 TI - Diagnostic issues of prostate biopsies. Case 6. PIN-like ductal adenocarcinoma. PMID- 22520608 TI - [Diagnostic issues of prostate biopsies. Case 7. Gleason grade 4 adenocarcinoma, with ill-defined glands and poorly formed glandular lumina]. PMID- 22520609 TI - [Diagnostic issues of prostate biopsies. Case 8. How to report the different grades observed on prostate biopsies?]. PMID- 22520611 TI - [Secondary gliosarcoma: case report]. AB - Gliosarcoma is a rare tumor of the central nervous system, consisting of gliomatous and sarcomatous elements. The glioblastoma can undergo a change in phenotype, transforming into a gliosarcoma, especially when the tumor has been treated with radiotherapy. Features unique to gliosarcoma compared to glioblastoma include their potential to appear similar to a meningioma at macroscopy, repeated reports of metastases and infrequency of EGFR mutations. We present a case of secondary gliosarcoma to emphasize on the specificities, essentially diagnostical of this rare entity. PMID- 22520612 TI - [An odontogenic tumor of the upper jaw]. PMID- 22520613 TI - [A rare lesion of the vulva]. PMID- 22520614 TI - [An unusual endobronchial lesion]. PMID- 22520615 TI - [A particular lesion not to be misdiagnosed]. PMID- 22520616 TI - A milestone. PMID- 22520617 TI - Nutrition label reading tips for CKD patients (English and Korean). PMID- 22520618 TI - Electrocardiographic abnormalities in centenarians: impact on survival. AB - BACKGROUND: The centenarian population is gradually increasing, so it is becoming more common to see centenarians in clinical practice. Electrocardiogram abnormalities in the elderly have been reported, but several methodological biases have been detected that limit the validity of their results. The aim of this study is to analyse the ECG abnormalities in a prospective study of the centenarian population and to assess their impact on survival. METHOD: We performed a domiciliary visit, where a medical history, an ECG and blood analysis were obtained. Barthel index (BI), cognitive mini-exam (CME) and Charlson index (ChI) were all determined. Patients were followed up by telephone up until their death. RESULTS: A total of 80 centenarians were studied, 26 men and 64 women, mean age 100.8 (SD 1.3). Of these, 81% had been admitted to the hospital at least once in the past, 81.3% were taking drugs (mean 3.3, rank 0-11). ChI was 1.21 (SD 1.19). Men had higher scores both for BI (70 -SD 34.4- vs. 50.4 -SD 36.6-, P = .005) and CME (16.5 -SD 9.1- vs. 9.1 -SD 11.6-, P = .008); 40.3% of the centenarians had anaemia, 67.5% renal failure, 13% hyperglycaemia, 22.1% hypoalbuminaemia and 10.7% dyslipidaemia, without statistically significant differences regarding sex. Only 7% had a normal ECG; 21 (26.3%) had atrial fibrillation (AF), 30 (37.5%) conduction defects and 31 (38.8%) abnormalities suggestive of ischemia, without sex-related differences. A history of heart disease was significantly associated with the presence of AF (P = .002, OR 5.2, CI 95% 1.8 to 15.2) and changes suggestive of ischemia (P = .019, OR 3.2, CI 95% 1.2-8.7). Mean survival was 628 days (SD 578.5), median 481 days. Mortality risk was independently associated with the presence of AF (RR 2.0, P = .011), hyperglycaemia (RR 2.2, P = .032), hypoalbuminaemia (RR 3.5, P < .001) and functional dependence assessed by BI (RR 1.8, P = .024). CONCLUSION: Although ECG abnormalities are common in centenarians, they are not related to sex, functional capacity or cognitive impairment. The only abnormality that has an impact on survival is AF. PMID- 22520619 TI - Risk assessment of metastatic recurrence in patients with prostate cancer by using the Cancer of the Prostate Risk Assessment score: results from 2937 European patients. AB - Study Type--Prognosis (case series) Level of Evidence 4. What's known on the subject? and What does the study add? Different tools allow the individual estimation of the various endpoints in patients with prostate cancer. The Cancer of the Prostate Risk Assessment (CAPRA) score is an easy to calculate prediction tool, based on a large population based database. However, little is known about the performance of this prediction tool in European patients. The data obtained in the present study demonstrate differences in tumour characteristics between European patients and the initial development cohort from the USA. However, the concordance index of the CAPRA scores for predicting biochemical recurrence and metastatic recurrence was 76.2 and 78.5, respectively, in European patients. Therefore, the CAPRA score also allows reliable prediction of the examined endpoints in European patients. OBJECTIVES: * To assess the ability of the Cancer of the Prostate Risk Assessment Score (CAPRA) score for predicting biochemical recurrence (BCR) and metastatic recurrence (MR) by using a large cohort of European patients with prostate cancer. * The CAPRA score was initially developed using patients treated in community-based hospitals in the USA and allows a prediction of the risk of different clinical endpoints, without incorporating the surgical margin status. PATIENTS AND METHODS: * BCR and metastatic recurrence rates were studied in 2937 patients who underwent radical prostatectomy in a tertiary referral centre after a mean (median, range) follow-up of 49 (56, 12 220) months. * The association between the examined endpoints, individual CAPRA scores and pathological features was analyzed by using Kaplan-Meier, proportional hazard and logistic regressions analyses. * Graphical representation assessed the calibration of the CAPRA score for predicting both endpoints. RESULTS: * Compared to the initial development cohort, worse tumour characteristics and a lower overall positive surgical margin rate (17.2% vs 32.4%) were detected in the European cohort. * Overall, 530 (18.4%) and 58 (1.9%) of patients developed BCR and MR. Increasing CAPRA scores were related to less favourable pathological characteristics and higher BCR and metastatic recurrence rates. * For example, the 5-year BCR and metastatic recurrence rates were markedly different at the extremes of 0-1 vs >= 8 (9.2% vs 70.8% and 0.7% vs 16.4%, respectively). * The concordance index for the prediction of BCR and metastatic recurrence was 76.2 and 78.5, respectively. CONCLUSIONS: * Despite differences between the present cohort and the initial development cohort with respect to clinical features and the outcomes achieved, the data obtained in the present study shows the generalizability of the CAPRA score. * Specifically, the data allow the precise identification of those European patients who are at high risk for BCR and MR. PMID- 22520620 TI - Finding words in a language that allows words without vowels. AB - Across many languages from unrelated families, spoken-word recognition is subject to a constraint whereby potential word candidates must contain a vowel. This constraint minimizes competition from embedded words (e.g., in English, disfavoring win in twin because t cannot be a word). However, the constraint would be counter-productive in certain languages that allow stand-alone vowelless open-class words. One such language is Berber (where t is indeed a word). Berber listeners here detected words affixed to nonsense contexts with or without vowels. Length effects seen in other languages replicated in Berber, but in contrast to prior findings, word detection was not hindered by vowelless contexts. When words can be vowelless, otherwise universal constraints disfavoring vowelless words do not feature in spoken-word recognition. PMID- 22520621 TI - One-year consumption of a grape nutraceutical containing resveratrol improves the inflammatory and fibrinolytic status of patients in primary prevention of cardiovascular disease. AB - The search for complementary treatments in primary prevention of cardiovascular disease (CVD) is a high-priority challenge. Grape and wine polyphenol resveratrol confers CV benefits, in part by exerting anti-inflammatory effects. However, the evidence in human long-term clinical trials has yet to be established. We aimed to investigate the effects of a dietary resveratrol-rich grape supplement on the inflammatory and fibrinolytic status of subjects at high risk of CVD and treated according to current guidelines for primary prevention of CVD. Seventy-five patients undergoing primary prevention of CVD participated in this triple blinded, randomized, parallel, dose-response, placebo-controlled, 1-year follow up trial. Patients, allocated in 3 groups, consumed placebo (maltodextrin), a resveratrol-rich grape supplement (resveratrol 8 mg), or a conventional grape supplement lacking resveratrol, for the first 6 months and a double dose for the next 6 months. In contrast to placebo and conventional grape supplement, the resveratrol-rich grape supplement significantly decreased high-sensitivity C reactive protein (-26%, p = 0.03), tumor necrosis factor-alpha (-19.8%, p = 0.01), plasminogen activator inhibitor type 1 (-16.8%, p = 0.03), and interleukin 6/interleukin-10 ratio (-24%, p = 0.04) and increased anti-inflammatory interleukin-10 (19.8%, p = 0.00). Adiponectin (6.5%, p = 0.07) and soluble intercellular adhesion molecule-1 (-5.7%, p = 0.06) tended to increase and decrease, respectively. No adverse effects were observed in any patient. In conclusion, 1-year consumption of a resveratrol-rich grape supplement improved the inflammatory and fibrinolytic status in patients who were on statins for primary prevention of CVD and at high CVD risk (i.e., with diabetes or hypercholesterolemia plus >=1 other CV risk factor). Our results show for the first time that a dietary intervention with grape resveratrol could complement the gold standard therapy in the primary prevention of CVD. PMID- 22520622 TI - One-year results of health-related quality of life among patients undergoing transcatheter aortic valve implantation. AB - Recently, it has been demonstrated that transcatheter aortic valve implantation (TAVI) can result in significant improvement in patients' quality of life (QOL) in the short term. At present, however, little is known about the long-term improvements in QOL after TAVI. Thus, our aim was to prospectively assess the 1 year QOL outcome of patients undergoing TAVI. We performed a prospective analysis of 186 patients with symptomatic severe aortic valve stenosis ineligible for conventional aortic valve replacement, who underwent TAVI with either the Medtronic CoreValve or Edwards Sapien device. A total of 106 patients completed the 1-year follow-up protocol. The QOL was measured using the Medical Outcomes Study 36-item short-form health survey questionnaire at baseline and at 3 months and 1 year of follow-up. At 1 year of follow-up, significant improvements in the Medical Outcomes Study 36-item short-form health survey questionnaire scores for physical functioning (baseline 34.6 +/- 2.3 vs 1 year of follow-up 45.6 +/- 2.7; p <0.001), role physical (20 +/- 3.0 vs 34.2 +/- 4.4; p <0.001), bodily pain (59.9 +/- 3 vs 70 +/- 2.7; p <0.01), general health (47.3 +/- 1.5 vs 55.2 +/- 2.1, p <0.001), vitality (35.9 +/- 2 vs 48.5 +/- 2; p <0.001), and mental health (62.2 +/- 2.2 vs 67.3 +/- 1.8; p <0.05) were observed compared to baseline. No significant improvement could be detected for social functioning (75.4 +/- 2.5 vs 76.5 +/- 2.6; p = 0.79) and role emotional (61.1 +/- 4.3 vs 66.5 +/- 4.7; p = 0.29). At 1 year of follow-up, the various physical and mental scores were comparable to an age-matched standard population. In conclusion, the present study has demonstrated that TAVI can improve the QOL status of high-surgical risk patients with severe aortic valve stenosis that can be maintained for <=1 year postproceduraly in survivors. Although the mental subscales improved slightly, the mental component summary score failed to reach statistical significance in our study population. PMID- 22520623 TI - Diabetes and depressive symptoms among Korean American older adults: the mediating role of subjective health perceptions. AB - PURPOSE: In recognition of the impact of chronic diseases on mental health and the lack of research on Asian American subgroups, the present study examined subjective perceptions of health as a potential mediator in the association between diabetes and depressive symptoms in Korean American older adults. METHODS: Multivariate analysis with data from 672 Korean American older adults in Florida explored the mediation model of health perceptions. RESULTS: The presence of diabetes was associated with negative perceptions of health and elevated symptoms of depression. The proposed mediation model was also supported: negative perceptions of health served as an intervening step between diabetes and depressive symptoms. CONCLUSIONS: The intervening role of health perceptions yields implications for developing health promotion interventions targeting older individuals with diabetes. Results suggest that even in the presence of chronic health conditions, mental well-being of older adults can be maintained by having optimistic beliefs and positive attitudes towards their own health. PMID- 22520624 TI - Residential crowding and severe respiratory syncytial virus disease among infants and young children: a systematic literature review. AB - BACKGROUND: The objective of this literature review was to determine whether crowding in the home is associated with an increased risk of severe respiratory syncytial virus (RSV) disease in children younger than 5 years. METHODS: A computerized literature search of PubMed and EMBASE was conducted on residential crowding as a risk factor for laboratory-confirmed RSV illness in children younger than 5 years. Study populations were stratified by high-risk populations, defined by prematurity, chronic lung disease of prematurity, hemodynamically significant congenital heart disease, or specific at-risk ethnicity (i.e. Alaska Native, Inuit), and mixed-risk populations, including general populations of mostly healthy children. The search was conducted for articles published from January 1, 1985, to October 8, 2009, and was limited to studies reported in English. To avoid indexing bias in the computerized databases, the search included terms for multivariate analysis and risk factors to identify studies in which residential crowding was evaluated but was not significant. Methodological quality of included studies was assessed using a Cochrane risk of bias tool. RESULTS: The search identified 20 relevant studies that were conducted in geographically diverse locations. Among studies of patients in high-risk populations, 7 of 9 found a statistically significant association with a crowding variable; in studies in mixed-risk populations, 9 of 11 found a significant association with a crowding variable. In studies of high-risk children, residential crowding significantly increased the odds of laboratory-confirmed RSV hospitalization (i.e. odds ratio ranged from 1.45 to 2.85). In studies of mixed risk populations, the adjusted odds ratios ranged from 1.23 to 9.1. The findings on the effect of residential crowding on outpatient RSV lower respiratory tract infection were inconsistent. CONCLUSIONS: Residential crowding was associated with an increased risk of laboratory-confirmed RSV hospitalization among high risk infants and young children. This association was consistent despite differences in definitions of residential crowding, populations, or geographic locations. PMID- 22520626 TI - Stroke subtyping for genetic association studies? A comparison of the CCS and TOAST classifications. AB - BACKGROUND: A reliable and reproducible classification system of stroke subtype is essential for epidemiological and genetic studies. The Causative Classification of Stroke system is an evidence-based computerized algorithm with excellent inter-rater reliability. It has been suggested that, compared to the Trial of ORG 10172 in Acute Stroke Treatment classification, it increases the proportion of cases with defined subtype that may increase power in genetic association studies. We compared Trial of ORG 10172 in Acute Stroke Treatment and Causative Classification of Stroke system classifications in a large cohort of well-phenotyped stroke patients. METHODS: Six hundred ninety consecutively recruited patients with first-ever ischemic stroke were classified, using review of clinical data and original imaging, according to the Trial of ORG 10172 in Acute Stroke Treatment and Causative Classification of Stroke system classifications. RESULTS: There was excellent agreement subtype assigned by between Trial of ORG 10172 in Acute Stroke Treatment and Causative Classification of Stroke system (kappa = 0.85). The agreement was excellent for the major individual subtypes: large artery atherosclerosis kappa = 0.888, small-artery occlusion kappa = 0.869, cardiac embolism kappa = 0.89, and undetermined category kappa = 0.884. There was only moderate agreement (kappa = 0.41) for the subjects with at least two competing underlying mechanism. Thirty-five (5.8%) patients classified as undetermined by Trial of ORG 10172 in Acute Stroke Treatment were assigned to a definite subtype by Causative Classification of Stroke system. Thirty-two subjects assigned to a definite subtype by Trial of ORG 10172 in Acute Stroke Treatment were classified as undetermined by Causative Classification of Stroke system. CONCLUSIONS: There is excellent agreement between classification using Trial of ORG 10172 in Acute Stroke Treatment and Causative Classification of Stroke systems but no evidence that Causative Classification of Stroke system reduced the proportion of patients classified to undetermined subtypes. The excellent inter-rater reproducibility and web-based semiautomated nature make Causative Classification of Stroke system suitable for multicenter studies, but the benefit of reclassifying cases already classified using the Trial of ORG 10172 in Acute Stroke Treatment system on existing databases is likely to be small. PMID- 22520625 TI - Nuclear functions and subcellular trafficking mechanisms of the epidermal growth factor receptor family. AB - Accumulating evidence suggests that various diseases, including many types of cancer, result from alteration of subcellular protein localization and compartmentalization. Therefore, it is worthwhile to expand our knowledge in subcellular trafficking of proteins, such as epidermal growth factor receptor (EGFR) and ErbB-2 of the receptor tyrosine kinases, which are highly expressed and activated in human malignancies and frequently correlated with poor prognosis. The well-characterized trafficking of cell surface EGFR is routed, via endocytosis and endosomal sorting, to either the lysosomes for degradation or back to the plasma membrane for recycling. A novel nuclear mode of EGFR signaling pathway has been gradually deciphered in which EGFR is shuttled from the cell surface to the nucleus after endocytosis, and there, it acts as a transcriptional regulator, transmits signals, and is involved in multiple biological functions, including cell proliferation, tumor progression, DNA repair and replication, and chemo- and radio-resistance. Internalized EGFR can also be transported from the cell surface to several intracellular compartments, such as the Golgi apparatus, the endoplasmic reticulum, and the mitochondria, in addition to the nucleus. In this review, we will summarize the functions of nuclear EGFR family and the potential pathways by which EGFR is trafficked from the cell surface to a variety of cellular organelles. A better understanding of the molecular mechanism of EGFR trafficking will shed light on both the receptor biology and potential therapeutic targets of anti-EGFR therapies for clinical application. PMID- 22520627 TI - Clinical effects of an essential oil solution used as a coolant during ultrasonic root debridement. AB - AIM: The use of chlorhexidine and povidone iodine solutions applied as a coolant during ultrasonic root debridement for the treatment of chronic periodontitis has been described. Hitherto, this application has not yet been extensively investigated for essential oil solutions. The goal was to clinically explore this and to compare to water irrigation. MATERIALS AND METHODS: Thirty-five chronic periodontitis patients participated in a single-blind randomized controlled clinical study. Patients were randomly allocated to the control group (n=18) or test group (n=17) receiving oral hygiene instructions and ultrasonic root debridement using water as a coolant, respectively, a pure essential oil solution. Oral hygiene was reinforced if necessary at each occasion, and clinical parameters were collected at baseline and after 1 and 3 months. RESULTS: Significant pocket reduction (control, 1.02 mm; test, 0.89 mm) and clinical attachment gain (control and test, 0.48 mm) were shown in both groups. However, there were no significant differences between the groups at any point in time for any of the parameters. CONCLUSION: Essential oil solutions do not offer a clinical benefit over water when used as a coolant during ultrasonic root debridement for the treatment of chronic periodontitis. PMID- 22520629 TI - A highly selective Hsp90 affinity chromatography resin with a cleavable linker. AB - Over 200 proteins have been identified that interact with the protein chaperone Hsp90, a recognized therapeutic target thought to participate in non-oncogene addiction in a variety of human cancers. However, defining Hsp90 clients is challenging because interactions between Hsp90 and its physiologically relevant targets involve low affinity binding and are thought to be transient. Using a chemo-proteomic strategy, we have developed a novel orthogonally cleavable Hsp90 affinity resin that allows purification of the native protein and is quite selective for Hsp90 over its immediate family members, GRP94 and TRAP 1. We show that the resin can be used under low stringency conditions for the rapid, unambiguous capture of native Hsp90 in complex with a native client. We also show that the choice of linker used to tether the ligand to the insoluble support can have a dramatic effect on the selectivity of the affinity media. PMID- 22520630 TI - Synthesis, biological evaluation and molecular docking studies of 1,3,4 oxadiazole derivatives as potential immunosuppressive agents. AB - A series of 1,3,4-oxadiazole derivatives derived from 4-methoxysalicylic acid or 4-methylsalicylic acid (6a-6z) have been first synthesized for their potential immunosuppressive activity. Among them, compound 6z displayed the most potent biological activity against lymph node cells (inhibition=38.76% for lymph node cells and IC(50)=0.31 MUM for PI3Kgamma). The preliminary mechanism of compound 6z inhibition effects was also detected by flow cytometry (FCM) and the compound exerted immunosuppressive activity via inducing the apoptosis of activated lymph node cells in a dose dependent manner. Docking simulation was performed to position compound 6z into the PI3Kgamma structure active site to determine the probable binding model. PMID- 22520631 TI - Ability of C-reactive protein to complement multiple prognostic classifiers in men with metastatic castration resistant prostate cancer receiving docetaxel based chemotherapy. AB - What's known on the subject? and What does the study add? Serum C-reactive protein (C-reactive protein) is emerging as a potential novel prognostic factor in metastatic castration-resistant prostate cancer (mCRPC). In the present study, a prospective trial was investigated retrospectively and a significant prognostic impact for C-reactive protein that was independent of multiple published prognostic models was identified in men receiving docetaxel-based chemotherapy for mCRPC. Prospective validation is warranted. OBJECTIVE: * Given the recent emergence of C-reactive protein levels as a novel prognostic factor in men with metastatic castration-resistant prostate cancer (mCRPC), we sought to evaluate the independent prognostic ability of C-reactive protein in the context of published prognostic nomograms, risk grouping and disease state models in men receiving docetaxel-based chemotherapy for mCRPC. PATIENTS AND METHODS: * A large randomized phase II trial (CS-205) of mCRPC patients who received docetaxel prednisone + AT-101 (Bcl-2 inhibitor) or docetaxel-prednisone + placebo was analyzed retrospectively (n= 220). * Overall survival (OS), progression-free survival (PFS) and measures of discriminatory ability were assessed in a hypothesis-generating analysis using Cox regression and concordance probabilities. * Patients from both treatment groups were combined for this analysis because no significant differences in outcomes were observed. * Because some factors used in nomograms were not collected or defined differently, risk was estimated based on slightly modified versions of nomograms. RESULTS: * C reactive protein was independently prognostic for OS and PFS (P <= 0.002) after adjusting for all modeled risk estimates and classifiers. * C-reactive protein showed a concordance probability of 0.65 for both OS and PFS. * A 10-factor modified prognostic model based on the TAX327 trial had the greatest observed discrimination ability for OS and PFS (concordance probability = 0.623 and 0.603, respectively) among the modified nomograms or classifiers. * Adding the TAX327 model risk estimates to C-reactive protein did not substantially increase discrimination ability over C-reactive protein alone. CONCLUSIONS: * Current prognostic classifications provide modest discrimination of outcomes in mCRPC receiving docetaxel-based chemotherapy, highlighting the need for improved risk based models. * Baseline C-reactive protein appears to be an useful, independent prognostic factor and prospective external validation is warranted. PMID- 22520632 TI - Using video-cases to assess student reflection: development and validation of an instrument. AB - BACKGROUND: Reflection is a meta-cognitive process, characterized by: 1. Awareness of self and the situation; 2. Critical analysis and understanding of both self and the situation; 3. Development of new perspectives to inform future actions. Assessors can only access reflections indirectly through learners' verbal and/or written expressions. Being privy to the situation that triggered reflection could place reflective materials into context. Video-cases make that possible and, coupled with a scoring rubric, offer a reliable way of assessing reflection. METHODS: Fourth and fifth year undergraduate medical students were shown two interactive video-cases and asked to reflect on this experience, guided by six standard questions. The quality of students' reflections were scored using a specially developed Student Assessment of Reflection Scoring rubric (StARS(r)). Reflection scores were analyzed concerning interrater reliability and ability to discriminate between students. Further, the intra-rater reliability and case specificity were estimated by means of a generalizability study with rating and case scenario as facets. RESULTS: Reflection scores of 270 students ranged widely and interrater reliability was acceptable (Krippendorff's alpha = 0.88). The generalizability study suggested 3 or 4 cases were needed to obtain reliable ratings from 4th year students and >= 6 cases from 5th year students. CONCLUSION: Use of StARS(r) to assess student reflections triggered by standardized video cases had acceptable discriminative ability and reliability. We offer this practical method for assessing reflection summatively, and providing formative feedback in training situations. PMID- 22520633 TI - Postoperative treatment of critical limb ischemia. PMID- 22520634 TI - Highly sensitive fast determination of entecavir in rat urine by means of hydrophilic interaction chromatography-ultra-high-performance liquid chromatography-tandem mass spectrometry. AB - Entecavir is a deoxyguanosine nucleotide antiviral agent with the activity against hepatitis B virus (HBV). The agent possesses a polar structure, which is predetermined for hydrophilic interaction chromatography (HILIC). Novel, fast and sensitive HILIC-UHPLC method developed in this study included separation from matrix component on BEH Amide stationary phase by isocratic elution using binary mobile phase composed of acetonitrile/5mM ammonium acetate pH 4.0 (75:25) at flow rate 0.3 ml/min. Analysis under RP-UHPLC conditions was also possible on BEH C18 stationary phase with mostly aqueous binary mobile phase composed of (4:96) acetonitrile/0.01% formic acid. The comparison of sensitivity of the two UHPLC MS/MS methods both using selected reaction monitoring (SRM) for quantitation revealed only slightly higher sensitivity for HILIC determination, however much better method linearity, repeatability and accuracy. HILIC separation mode provided also more convenient conditions for straightforward coupling with solid phase extraction (SPE). Entecavir was extracted on Oasis HLB cartridge (1 ml, 30 mg) and eluted by 75% acetonitrile in water, which is actually the HILIC mobile phase used in this study. Therefore the evaporation/reconstitution step was omitted, which substantially accelerated the sample preparation step. The method was validated using stable isotopically labeled internal standard entecavir C(2)(13) N(15), which is the most appropriate internal standard. Validation results demonstrated good method accuracy (with < 5% error, and 26% at LOQ), recovery (87-114%), precision (<4% RSD), selectivity and sensitivity (LOQ=100 pg/ml). The matrix effects determined by both post-column infusion method as well as post-extraction addition method were negligible (<15%). PMID- 22520635 TI - Separation of unsaturated organic compounds using silver-thiolate chromatographic material. AB - Separation of organic compounds containing various numbers of double bonds (DB) can be readily achieved by using silver ion impregnated silica gel, often called silver-ion or argentation chromatography. However, the practical application of silver-ion liquid chromatography in analytical and preparative separations has been limited by the concerns about the stability and mobility of silver ions and the widespread use of reversed phase high performance liquid chromatography. Silver covalently anchored onto the thiol moiety of mercaptopropyl modified silica gel has been tested for the separation of polycyclic aromatic hydrocarbons by ring numbers, but has never been shown to separate mixtures of alkenes having different number of double bonds. We report here that silver-thiolate chromatographic material (AgTCM; including, but not limited to, silver(I) mercaptopropyl silica gel) is also highly efficient in liquid chromatographic separation of alkane/alkenes differing by one double bond. AgTCM displays exceptionally high selectivity for unsaturated compounds and high stability under extended heat and light exposure, while silver is virtually immobile during solvent elution. Compared to ionic silver, silver-thiolate interacts with double bonds less strongly, allowing AgTCM to efficiently separate olefins using less polar (and often less viscous and lower cost) solvents. The interaction energy between silver and ethylene is calculated using established computational methods and the results are in full agreement with our experimental results. Importantly, the exceptional stability of AgTCM gives rise to much higher compound recovery than conventional silver-ion silica gel during the chromatographic elution. Our results pave the way for the development of novel covalently bonded, transition metal-containing chromatographic materials. PMID- 22520636 TI - Cumulative solid phase microextraction sampling for gas chromatography olfactometry of Shiraz wine. AB - Solid phase microextraction (SPME) coupled to gas chromatography-olfactometry (GC O) is now commonly used for determination of aroma-active compounds, but the method sensitivity and selectivity is restricted by the small volume and limited type of fibre coating phases. In an attempt to enhance the method performance, a cryogenic trapping (CT) approach was investigated in this study by coupling multiple SPME sampling events for wine headspace using GC-O analysis. By performing multiple SPME sampling employing different chemical polymer coatings, desorbed solute from the integrated sampling is accumulated by the CT at the front section of a Wax separation capillary column prior to chromatographic analysis. Results show that the CT was capable of retaining apolar alkane volatiles of decane and greater, and tested polar alcohols, including methanol. Chromatographic signals eluting later than the ethanol peak were found to progressively increase in response, and correlated well, with the cumulative number of SPME samplings. The approach was developed for GC-O screening of potent odorants in Shiraz wine collected from fibre coatings of polyacrylate (PA) and the triple-phase coated polydimethylsiloxane/divinylbenzene/carboxen (PDC). The aromagram for solute derived from a combined introduction of both PA plus PDC fibres (i.e. sequential fibre introduction into the injector; termed as PADC) compared well to the sum of those sampled by using a single fibre coating alone, which comprised of odorants derived from both fibre coatings. Accumulation in the CT of volatile solutes derived from up to 6 repeat PADC sampling events revealed a similar pattern of their aromagrams, though with stronger olfactory stimulus response. This study demonstrated a simple and effective way for enhancing SPME sensitivity and potentially less discrimination during the analysis of wine volatiles. However, the single dimensional GC separation method requires development of an improved separation strategy to better separate individual compounds. PMID- 22520637 TI - High-performance liquid chromatography-mass spectrometry and evaporative light scattering detector to compare phenolic profiles of muscadine grapes. AB - Evaporative light scattering detector (ELSD) is considered as a universal detector able to detect almost any compound. This study successfully established a HPLC-ELSD method for the simultaneous determination of phenolic acids, flavonoids and anthocyanins in muscadine grape. Twenty-four phenolics, including 5 anthocyanins, were identified by HPLC-UV-MS, ten of them were selected to calibrate the ELSD. Results from the ELSD quantification suggested that gallic acid, proanthocyanidins, and ellagic acid were the main phenolics in muscadines. In addition, antioxidant tests suggested that the extracts of muscadine grapes possessed strong antioxidant activities. All extracts had a high total phenolic content (TPC). High total anthocyanins contents (TAC) were found in Noble muscadine, and high proanthocyanidins content (TPA) in the seed portion. PMID- 22520638 TI - High resolution ultra high pressure liquid chromatography-time-of-flight mass spectrometry dereplication strategy for the metabolite profiling of Brazilian Lippia species. AB - Plants belonging to the Lippia genus have been widely used in ethnobotany throughout South and Central America and in tropical Africa as foods, medicines, sweeteners and in beverage flavouring. Various taxonomic problems involving some genera from Verbenaceae, including Lippia, have been reported. In this study, the metabolite profiling of fifteen extracts of various organs of six Lippia species was performed and compared using UHPLC-PDA-TOF-MS. Fourteen phenolic compounds that were previously isolated from L. salviaefolia Cham. and L. lupulina Cham. were used as references. The annotation of the remaining LC peaks was based on concomitant online high mass accuracy measurements and subsequent molecular formula assignments following these different steps: (i) elimination of non coherent putative molecular formulae by heuristic filtering, (ii) verification of the occurrence of remaining molecular formulae in databases, (iii) cross search with reported compounds in the Lippia genus, (iv) match with reported UV spectra, (v) estimation of the chromatographic retention behaviour based on the log P parameter of reference compounds. This strategy is generic and time-saving, avoids isolation/purification procedures, enables an efficient LC peak annotation of most of the studied compounds and is well adapted for plant chemotaxonomic studies. Within this study, the interconversion of four flavanone glucoside isomers was additionally highlighted by analytical HPLC isolation and immediate analysis using fast UHPLC gradients. Dereplication results and hierarchical data analysis demonstrated that L. salviaefolia, L. balansae, L. velutina and L. sidoides displayed significant chemical similarities, while the compositions of L. lasiocalicyna and L. lupulina differed substantially. PMID- 22520639 TI - Comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry for the forensic study of cadaveric volatile organic compounds released in soil by buried decaying pig carcasses. AB - This article reports on the use of comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry (GC*GC-TOFMS) for forensic geotaphonomy application. Gravesoil samples were collected at various depths and analyzed for their volatile organic compound (VOC) profile. A data processing procedure was developed to highlight potential candidate marker molecules related to the decomposition process that could be isolated from the soil matrix. Some 20 specific compounds were specifically found in the soil sample taken below the carcass and 34 other compounds were found at all depths of the gravesoil samples. The group of the 20 compounds consisted of ketones, nitriles, sulfurs, heterocyclic compounds, and benzene derivatives like aldehydes, alcohols, ketones, ethers and nitriles. The group of the 34 compounds consisted of methyl branched alkane isomers including methyl-, dimethyl-, trimethyl-, tetramethyl-, and heptamethyl-isomers ranging from C(12) to C(16). A trend in the relative presence of these alkanes over the various layers of soils was observed, with an increase in the amount of the specific alkanes when coming from the carcass to the surface. Based on the specific presence of these methyl-branched alkanes in gravesoils, we created a processing method that applies a specific script to search raw data for characteristic mass spectral features related to recognizable mass fragmentation pattern. Such screening of soil samples for cadaveric decomposition signature was successfully applied on two gravesoil sites and clearly differentiates soils at proximity of buried decaying pig carcasses from control soils. PMID- 22520640 TI - Dispersive microextraction based on water-coated Fe3O4 followed by gas chromatography-mass spectrometry for determination of 3-monochloropropane-1,2 diol in edible oils. AB - In the present work, we developed a novel dispersive microextraction technique by combining the advantages of liquid-phase microextraction (LPME) and magnetic solid-phase extraction (MSPE). In this method, trace amount of water directly absorbed on bare Fe3O4 to form water-coated Fe3O4 (W-Fe3O4) and rapid extraction can be achieved while W-Fe3O4 dispersed in the sample solution. The analyte adsorbed W-Fe3O4 can be easily collected and isolated from sample solution by application of a magnet. It was worth noting that in the proposed method water was used as extractant and Fe3O4 served as the supporter and retriever of water. The performance of the method was evaluated by extraction of 3-monochloropropane 1,2-diol (3-MCPD) from edible oils. The extracted 3-MCPD was then derived by a silylanization reagent (1-trimethylsilylimidazole) before gas chromatography-mass spectrometry (GC-MS) analysis. Several parameters that affected the extraction and derivatization efficiency were investigated. Our results showed that the limit of detection for 3-MCPD was 1.1 ng/g. The recoveries in spiked oil samples were in the range of 70.0-104.9% with the RSDs less than 5.6% (intra-day) and 6.4% (inter-day). Taken together, the simple, rapid and cost-effective method developed in current study, offers a potential application for the extraction and preconcentration of hydrophilic analytes from complex fatty samples. PMID- 22520641 TI - Ultrasonographic fatty liver indicator, a novel score which rules out NASH and is correlated with metabolic parameters in NAFLD. AB - BACKGROUND: Differentiating steatosis from NASH is key in deciding treatment and follow-up schedules. We hypothesized that sonographic grading of steatosis will correlate with metabolic and pathologic changes of NASH. METHODS: Fifty-three non consecutive patients had a semi-quantitative evaluation of hepatic steatosis through ultrasonographic Fatty Liver Indicator (US-FLI) just prior to liver biopsy. All biopsies demonstrated NAFLD. US-FLI is a new scoring system ranging 2 8 based on the intensity of liver/kidney contrast, posterior attenuation of ultrasound beam, vessel blurring, difficult visualization of gallbladder wall, difficult visualization of the diaphragm and areas of focal sparing. NAFLD is diagnosed by the minimum score >=2. Ultrasonographic findings were correlated with metabolic and histological data. Inter-observer US-FLI score agreement, evaluated by three different operators in 31 consecutive patients with steatosis, showed "almost perfect/substantial" agreement (P < 0.001). RESULTS: US-FLI showed a positive correlation with HOMA, insulin, uric acid, ferritin, ALT and bilirubin and was associated with steatosis extent assessed histologically and histological features of NASH, except for fibrosis. US-FLI was an independent predictor of NASH (OR 2.236; P = 0.007) and a US-FLI < 4 had a high negative predictive value (94%) in ruling out the diagnosis of severe NASH according to Kleiner's criteria. CONCLUSION: Data confirm the hypothesis that US-FLI significantly correlates with metabolic derangements and individual pathologic criteria for NASH and may better select patients for liver biopsy. PMID- 22520642 TI - Effects of hormonal contraception on vaginal flora. AB - BACKGROUND: The sector of the market that deals with contraception offers a long list of different contraceptive methods. Within the estroprogestinic choice, the routes of administration are oral, transdermic and vaginal one. Even though efficacy is comparable with these methods, secondary and adverse effects are directly involved in the acceptability of the method. STUDY DESIGN: This was a prospective comparative study. During 1 year, we enrolled 60 asymptomatic women who voluntarily requested combined oral contraception (COC) or combined contraceptive vaginal ring (CCVR group). After a baseline study of vaginal milieu prior to starting hormonal contraception, we performed a follow-up. For each woman, we examined vaginal pH; quantification of leukocytes, lactobacilli, Candida and cocci on saline microscopy fluid; Gram stain with Nugent score and the presence of vaginal infection [culture for Trichomonas vaginalis, albicans and nonalbicans Candida, Group B Streptococcus (GBS)]. RESULTS: At the end of follow-up, there was a little change of vaginal milieu in both groups. We noted an increase of lactobacilli in the CCVR users and an increase of GBS in COC users. CONCLUSION: CCVR compared to COC users showed an increase of the number of lactobacilli in vaginal flora. It means that an increase of leukorrhea in that group could be protective in terms of prevention of vaginal imbalance/infection. PMID- 22520643 TI - Tubal sterilization during cesarean section or as an elective procedure? Effect on the ovarian reserve. AB - BACKGROUND: The purpose of this study is to compare the effects of tubal sterilization on the ovarian reserve by means of hormonal and ultrasonographic evaluation during a cesarean section or when performed as a planned interval procedure. STUDY DESIGN: Fifty women who had undergone tubal sterilization during a cesarean section (n=24) and by minilaparotomy as an elective procedure (n=26) were included in the study. Tubes were ligated with the Pomeroy technique in both groups. The women who had chosen to use barrier method or intrauterine device for contraception (n=30) constituted the control group. Among the women in the control group, two separate control groups were constituted (control 1 and control 2) who were age matched with the women in each study group. Hormone levels including antimullerian hormone (AMH) and inhibin B and ultrasonographic evaluations were performed on the third day of the menstrual cycle 1 year after the tubal sterilization procedure. RESULTS: Mean blood estradiol, follicle stimulating hormone and luteinizing hormone levels on the third day of the cycle postoperative 12 months after the surgical intervention did not show any significant differences in the groups with respect to their age-matched controls. There was no significant difference in terms of mean serum AMH and inhibin B levels between the groups and their age-matched controls. However, significantly higher postoperative levels of mean AMH levels were detected in the tubal sterilization during cesarean section group when compared with the minilaparotomy group, and significantly lower postoperative levels of mean inhibin B were detected in the elective tubal sterilization via minilaparotomy group when compared with the cesarean section group. Statistically significant differences were observed in terms of number of antral follicles and mean ovarian volumes being less in the elective tubal sterilization via minilaparotomy group when compared with age-matched controls. CONCLUSION: Intraoperative cesarean section tubal sterilization seems to be a practical and safe method, and has less effect on the ovarian reserve when compared with planned tubal sterilization by minilaparotomy. PMID- 22520644 TI - Effect of letrozole on uterine tonus and contractility: a randomized controlled trial. AB - BACKGROUND: Letrozole inhibits estrogen production. It has been shown to increase efficacy in medical abortion when used with misoprostol. This study investigated if letrozole acts as an abortifacient due to a synergistic effect with misoprostol on uterine contractility. STUDY DESIGN: Sixteen healthy women requesting surgical abortion were randomized to receive either no pretreatment or treatment with letrozole 7.5 mg daily for 3 days prior to the abortion. All women received misoprostol 400 mcg vaginally 3.5 h prior to surgery. Intrauterine pressure was measured for 30 min before and 3.5 h after misoprostol was given using an intrauterine pressure catheter. Main outcome measure was uterine contractility analyzed by repeated-measures analysis of variance. RESULTS: At baseline, uterine contractions were absent and tonus was low. No significant difference was seen between the two groups in tonus (p=.818) or in contractility (p=.423) after misoprostol administration. CONCLUSION: Letrozole does not appear to act as an abortifacient through an effect on uterine contractility or increased sensitivity to misoprostol of the uterine myometrium. PMID- 22520645 TI - Reproductive health preventive screening among clinic vs. over-the-counter oral contraceptive users. AB - BACKGROUND: Interest is growing in moving oral contraceptives over-the-counter (OTC), although concerns exist about whether women would continue to get preventive health screening. STUDY DESIGN: We recruited cohorts of US-resident women who obtained oral contraceptives from US family planning clinics (n=532) and OTC from pharmacies in Mexico (n=514) and interviewed them four times over 9 months. Based on self-reports of having a Pap smear within 3 years or ever having had a pelvic exam, clinical breast exam and testing for sexually transmitted infections (STIs), we assessed the prevalence of preventive screening using Poisson regression models. RESULTS: The prevalence of screening was high for both groups (>88% for Pap smear, pelvic exam and clinical breast exam and >71% for STI screening), while the prevalence ratios for screening were higher for clinic users, even after multivariable adjustment. CONCLUSIONS: Results suggest that most women would obtain reproductive health preventive screening if oral contraceptives were available OTC, and also highlight the need to improve access to preventive screening for all low-income women. PMID- 22520646 TI - Chronicity of partner violence, contraceptive patterns and pregnancy risk. AB - BACKGROUND: Partner violence may interfere with a woman's ability to maintain continuous contraception and therefore contribute to increased risk of pregnancy among childbearing women. STUDY DESIGN: A retrospective review of medical records (N=2000) was conducted from four family planning clinics in the northeast United States. Eligibility criteria for inclusion were as follows: (1) female, (2) reproductive age (menarche through menopause), (3) seeking reproductive services and (4) clinic visit for annual gynecologic exam between 2006 and 2011. RESULTS: Partner violence was documented in 28.5% (n=569) of medical records. Chronicity of violence influenced contraceptive patterns and pregnancy risk. Women reporting past year partner violence only [odds ratio (OR)=10.2] and violence during the last 5 years (OR=10.6) had the highest odds of not using a current method of contraception. Women reporting recent exposure to violence were most likely to change birth control methods and use emergency contraception (OR=6.5). Women experiencing any history of violence reported more frequent contraceptive method changes during the previous year. CONCLUSIONS: A history of partner violence was common among women utilizing family planning services. The chronicity of violence appeared to play a significant role in contraceptive method changes, types of methods used and pregnancy risk. These results may be one explanation for increased pregnancies among women who experience partner violence. PMID- 22520647 TI - European study of research and development in mobility technology for persons with disabilities. AB - ?In the fall of 2010, the National Science Foundation, the National Institutes of Health and the U.S. Veteran's Administration jointly supported a review of mobility technology in Europe. A delegation of American Scientists traveled to Europe to visit a number of research centers and engaged in a demonstration and dialogue related to the global state-of-the-art for mobility impairment rectification and augmentation. From the observations and exchanges between the U.S. delegation and host institutions, the researchers were able to derive a series of papers which are now published in this thematic series of Journal of NeuroEngineering and Rehabilitation. The papers describe the main themes of the European mobility technology research activities showing a healthy picture of research and innovation in the field. PMID- 22520648 TI - Cell-based analysis of Chikungunya virus E1 protein in membrane fusion. AB - BACKGROUND: Chikungunya fever is a pandemic disease caused by the mosquito-borne Chikungunya virus (CHIKV). E1 glycoprotein mediation of viral membrane fusion during CHIKV infection is a crucial step in the release of viral genome into the host cytoplasm for replication. How the E1 structure determines membrane fusion and whether other CHIKV structural proteins participate in E1 fusion activity remain largely unexplored. METHODS: A bicistronic baculovirus expression system to produce recombinant baculoviruses for cell-based assay was used. Sf21 insect cells infected by recombinant baculoviruses bearing wild type or single-amino acid substitution of CHIKV E1 and EGFP (enhanced green fluorescence protein) were employed to investigate the roles of four E1 amino acid residues (G91, V178, A226, and H230) in membrane fusion activity. RESULTS: Western blot analysis revealed that the E1 expression level and surface features in wild type and mutant substituted cells were similar. However, cell fusion assay found that those cells infected by CHIKV E1-H230A mutant baculovirus showed little fusion activity, and those bearing CHIKV E1-G91D mutant completely lost the ability to induce cell-cell fusion. Cells infected by recombinant baculoviruses of CHIKV E1 A226V and E1-V178A mutants exhibited the same membrane fusion capability as wild type. Although the E1 expression level of cells bearing monomeric-E1-based constructs (expressing E1 only) was greater than that of cells bearing 26S-based constructs (expressing all structural proteins), the sizes of syncytial cells induced by infection of baculoviruses containing 26S-based constructs were larger than those from infections having monomeric-E1 constructs, suggesting that other viral structure proteins participate or regulate E1 fusion activity. Furthermore, membrane fusion in cells infected by baculovirus bearing the A226V mutation constructs exhibited increased cholesterol-dependences and lower pH thresholds. Cells bearing the V178A mutation exhibited a slight decrease in cholesterol dependence and a higher-pH threshold for fusion. CONCLUSIONS: Cells expressing amino acid substitutions of conserved protein E1 residues of E1-G91 and E1-H230 lost most of the CHIKV E1-mediated membrane fusion activity. Cells expressing mutations of less-conserved amino acids, E1-V178A and E1-A226V, retained membrane fusion activity to levels similar to those expressing wild type E1, but their fusion properties of pH threshold and cholesterol dependence were slightly altered. PMID- 22520650 TI - Cost minimization minilaparotomy vs laparoscopic sacral colpopexy. PMID- 22520651 TI - Risk factors for abnormal anal cytology over time in HIV-infected women. AB - OBJECTIVE: The objective of the study was to assess the incidence of, and risk factors for, abnormal anal cytology and anal intraepithelial neoplasia (AIN) 2-3 in human immunodeficiency virus (HIV)-infected women. STUDY DESIGN: This prospective study assessed 100 HIV-infected women with anal and cervical specimens for cytology and high-risk human papillomavirus (HPV) testing over 3 semiannual visits. RESULTS: Thirty-three women were diagnosed with an anal cytologic abnormality at least once. Anal cytology abnormality was associated with current CD4 count less than 200 cells/mm(3), anal HPV infection, and a history of other sexually transmitted infections (STIs). Twelve subjects were diagnosed with AIN2-3: 4 after AIN1 diagnosis and 4 after 1 or more negative anal cytology. AIN2-3 trended toward an association with history of cervical cytologic abnormality and history of STI. CONCLUSION: Repeated annual anal cytology screening for HIV-infected women, particularly for those with increased immunosuppression, anal and/or cervical HPV, a history of other STIs, or abnormal cervical cytology, will increase the likelihood of detecting AIN2-3. PMID- 22520652 TI - Induction of labor in a contemporary obstetric cohort. AB - OBJECTIVE: We sought to describe details of labor induction, including precursors and methods, and associated vaginal delivery rates. STUDY DESIGN: This was a retrospective cohort study of 208,695 electronic medical records from 19 hospitals across the United States, 2002 through 2008. RESULTS: Induction occurred in 42.9% of nulliparas and 31.8% of multiparas and elective or no recorded indication for induction at term occurred in 35.5% and 44.1%, respectively. Elective induction at term in multiparas was highly successful (vaginal delivery 97%) compared to nulliparas (76.2%). For all precursors, cesarean delivery was more common in nulliparas in the latent compared to active phase of labor. Regardless of method, vaginal delivery rates were higher with a ripe vs unripe cervix, particularly for multiparas (86.6-100%). CONCLUSION: Induction of labor was a common obstetric intervention. Selecting appropriate candidates and waiting longer for labor to progress into the active phase would make an impact on decreasing the national cesarean delivery rate. PMID- 22520654 TI - Evaluation of the clinical value of ELISA based on MPT64 antibody aptamer for serological diagnosis of pulmonary tuberculosis. AB - BACKGROUND: Presently, tuberculosis (TB) poses a global threat to human health. The development of reliable laboratory tools is vital to the diagnosis and treatment of TB. MPT64, a protein secreted by Mycobacterium tuberculosis complex, is highly specific for TB, making antibody to MPT64 a reagent specific for the diagnosis of TB. METHOD: Antibody to MPT64 was obtained by a combination of genetic engineering and immunization by the system evolution of ligands by exponential enrichment. A high-affinity aptamer of antibody to MPT64 was selected from a random single-stranded DNA library, and a sandwich ELISA method based on this aptamer was developed. This ELISA method was used to detect TB in 328 serum samples, 160 from patients with pulmonary TB (PTB) and 168 from non-tuberculous controls. RESULTS: The minimum limit of detection of the ELISA method was 2.5 mg/L, and its linear range varied from 10 mg/L to 800 mg/L. Its sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and area under the curve, with 95 % confidence intervals, were 64.4 % (56.7 %-71.4 %), 99.4 % (96.7 %-99.9 %), 108.2 (15.3-765.9), 0.350 (0.291-0.442) and 0.819 (0.770-0.868), respectively. No significant difference in sensitivity was observed between sputum smear positive (73/112, 65.2 %) and negative (30/48, 62.5 %) individuals. CONCLUSIONS: This sandwich ELISA based on an MPT64 antibody aptamer may be useful for the serological diagnosis of PTB, both in sputum smear positive and negative patients. PMID- 22520655 TI - Is healthy eating for obese children necessarily more costly for families? AB - BACKGROUND: During consultations on weight management in childhood obesity clinics, the additional costs incurred by healthy eating are often cited, as an economic barrier to achieving a better nutritional balance. AIM: To examine whether adopting an improved theoretical, balanced diet compared to current dietary habits in children incurs additional cost. DESIGN AND SETTING: Children aged 5-16 years (body mass index [BMI] >=98th percentile) recruited to a randomised trial comparing a hospital-based and primary care childhood obesity clinics provided data for this study. METHOD: Three-day dietary diaries collected at baseline were analysed for energy and fat intake and then compared to a theoretical, adjusted healthy-eating diet based on the Food Standards Agency, 'Eatwell plate'. Both were priced contemporaneously using the appropriate portion size, at a neighbourhood, mid-range supermarket, at a budget supermarket, and on the local high street. RESULTS: The existing diet purchased at a budget supermarket was cheapest (L2.48/day). The healthier, alternative menu at the same shop cost an additional 33 pence/day (L2.81). The same exercise in a mid range supermarket, incurred an additional cost of 4 pence per day (L3.40 versus L3.44). Switching from an unhealthy mid-range supermarket menu to the healthier, budget-outlet alternative saved 59 pence per day. The healthier, alternative menu was cheaper than the existing diet if purchased on the high street (L3.58 versus L3.75), although for both menus this was most expensive. CONCLUSION: For many obese children, eating healthily would not necessarily incur prohibitive, additional financial cost, although a poor diet at a budget supermarket remains the cheapest of all options. Cost is a possible barrier to healthy eating for the most economically disadvantaged. PMID- 22520657 TI - Obesity and chronic disease in younger people: an unfolding crisis. PMID- 22520658 TI - Evaluating the transferability of a hospital-based childhood obesity clinic to primary care: a randomised controlled trial. AB - BACKGROUND: The Care Of Childhood Obesity (COCO) clinic at the Bristol Royal Hospital for Children (BRHC) uses a multidisciplinary approach comprising a consultant, dietitian, and exercise specialist. The clinic has demonstrated efficacy in managing children's weight but similar clinics are scarce in the UK. AIM: This pilot randomised controlled trial (RCT) aimed to examine the feasibility of undertaking a fully powered RCT and to gauge whether the COCO model could be effective as a nurse-led clinic in primary care settings. DESIGN AND SETTING: Patients were randomised to a hospital-based childhood obesity clinic or a nurse-led clinic in a primary care setting in south-west England. METHOD: Children aged 5-16 years with a body mass index (BMI) >=98th centile were referred by GPs to the consultant in charge of the COCO clinic at BRHC. Referred children were clinically screened for suitability and invited into the study. Consenting families were randomised to BRHC or a primary care clinic (PCC) and offered five appointments over 12 months. Clinical effectiveness was measured by change in body mass index standard deviation score (BMI SDS) at 12 months. Other measures included: treatment adherence, quality of life (QOL), and satisfaction. Feasibility was examined by assessing referral, screening, and recruitment data. RESULTS: A total 152 patients were referred by GPs: 31 (20%) were screened out; 45 (30%) declined to participate. Seventy-six (50%) patients were randomised and 68 provided baseline data (PCC = 42; BRHC = 26); 52 provided outcome data (PCC = 29; BRHC = 23). Mean change in BMI SDS was PCC -0.17 (95% confidence interval [CI] = -0.27 to -0.07); BRHC -0.15 (95% CI = -0.26 to -0.05). QOL, adherence, and satisfaction data indicated similar positive patterns in both trial arms. CONCLUSION: Screening and recruitment data indicate that primary care is a clinically appropriate setting and acceptable to families. The primary clinical outcome measure (reduction in BMI SDS), along with secondary outcome measures, indicate that primary care has the potential to be effective in providing weight management for children, using the COCO model. PMID- 22520659 TI - Reflections at the deep end. PMID- 22520660 TI - Training for leadership. PMID- 22520661 TI - Methodological issues in pragmatic trials of complex interventions in primary care. PMID- 22520662 TI - From patient advocate to gatekeeper: understanding the effects of the NHS reforms. PMID- 22520663 TI - From patient advocate to gatekeeper: understanding the effects of the NHS reforms. PMID- 22520664 TI - Counselling patients about behaviour change: the challenge of talking about diet. AB - BACKGROUND: As obesity levels increase, opportunistic behaviour change counselling from primary care clinicians in consultations about healthy eating is ever more important. However, little is known about the approaches clinicians take with patients. AIM: To describe the content of simulated consultations on healthy eating in primary care, and compare this with the content of smoking cessation consultations. DESIGN AND SETTING: Qualitative study of 23 audiotaped simulated healthy eating and smoking cessation consultations between an actor and primary care clinicians (GPs and nurses) within a randomised controlled trial looking at behaviour change counselling. METHOD: Consultations were audiotaped and transcribed verbatim, then analysed inductively using thematic analysis. A thematic framework was developed by all authors and applied to the data. The content of healthy eating consultations was contrasted with that given for smoking cessation. RESULTS: There was a lack of consistency and clarity when clinicians discussed healthy eating compared with smoking; in smoking cessation consultations, the content was clearer to both the clinician and patient. There was a lack of specificity about what dietary changes should be made, how changes could be achieved, and how progress could be monitored. Barriers to change were addressed in more depth within the smoking cessation consultations than within the healthy eating encounters. CONCLUSION: At present, dietary counselling by clinicians in primary care does not typically contain consistent, clear suggestions for specific change, how these could be achieved, and how progress would be monitored. This may contribute to limited uptake and efficacy of dietary counselling in primary care. PMID- 22520665 TI - Olympic absurdities. PMID- 22520666 TI - Screening for sickle cell and thalassaemia in primary care: a cost-effectiveness study. PMID- 22520667 TI - G.O.D and inventing the wheel. PMID- 22520668 TI - Urgent suspected cancer referrals from general practice. PMID- 22520669 TI - The Fremantle Primary Prevention Study: a multicentre randomised trial of absolute cardiovascular risk reduction. AB - BACKGROUND: Cardiovascular disease (CVD) is the leading cause of global mortality. Risk factor management in clinical practice often relies on relative risk modification rather than the more appropriate absolute risk assessment. AIM: To determine whether patients receiving more-frequently designated GP visits had increased benefit in terms of their absolute CVD risk assessment, as compared with patients in receipt of their usual GP care. DESIGN AND SETTING: Prospective, open, pragmatic block randomised study in a 1:1 group allocation ratio in three Western Australian general practices. METHOD: A convenience sample (n = 1200) of patients aged 40-80 years were randomised to 3-monthly GP visits (five in total for the intensive) or usual GP care (two in total for the opportunistic), with 12 months' follow-up. The main outcome was absolute CVD risk scores based on the New Zealand Cardiovascular Risk Calculator. Others outcome measures were weight, height, waist circumference, blood pressure, and fasting blood lipids and glucose. RESULTS: There were 600 patients per group at baseline. At 12 months' analysis there were 543 in the intensive group and 569 in the opportunistic group. Mean (standard deviation [SD]) absolute CVD risk reduced significantly between baseline and 12 months in the intensive group (6.28% [5.11] to 6.10% [4.94]) but not in the opportunistic group (6.27% [5.10] to 6.24% [5.38]). There was a significant reduction between baseline and 12 months in mean (SD) total cholesterol (5.28 mmol/l [0.94] to 5.08 mmol/l [0.96]); low-density lipoprotein cholesterol (3.08 mmol/l [0.87] to 2.95 mmol/l [0.89]); triglyceride (1.45 mmol/l [0.86] to 1.36 mmol/l [0.84]); and in mean (SD) waist circumference in men (98.74 cm [10.70] to 97.13 cm [10.20]) and females (90.64 cm [14.62] to 88.96 cm [14.00]) in the intensive group. CONCLUSION: A targeted approach using absolute risk calculators can be used in primary care to modify global CVD risk assessment. PMID- 22520671 TI - Turn something bad into something good. PMID- 22520670 TI - Identifying patients with suspected colorectal cancer in primary care: derivation and validation of an algorithm. AB - BACKGROUND: Earlier diagnosis of colorectal cancer could help improve survival so better tools are needed to help this. AIM: To derive and validate an algorithm to quantify the absolute risk of colorectal cancer in patients in primary care with and without symptoms. DESIGN AND SETTING: Cohort study using data from 375 UK QResearch(r) general practices for development and 189 for validation. METHOD: Included patients were aged 30-84 years, free at baseline from a diagnosis of colorectal cancer and without rectal bleeding, abdominal pain, appetite loss, or weight loss in the previous 12 months. The primary outcome was incident diagnosis of colorectal cancer recorded in the next 2 years. Risk factors examined were age, body mass index, smoking status, alcohol status, deprivation, diabetes, inflammatory bowel disease, family history of gastrointestinal cancer, gastrointestinal polyp, history of another cancer, rectal bleeding, abdominal pain, abdominal distension, appetite loss, weight loss, diarrhoea, constipation, change of bowel habit, tiredness, and anaemia. Cox proportional hazards models were used to develop separate risk equations in males and females. Measures of calibration and discrimination assessed performance in the validation cohort. RESULTS: There were 4798 incident cases of colorectal cancer from 4.1 million person-years in the derivation cohort. Independent predictors in males and females included family history of gastrointestinal cancer, anaemia, rectal bleeding, abdominal pain, appetite loss, and weight loss. Alcohol consumption and recent change in bowel habit were also predictors in males. On validation, the algorithms explained 65% of the variation in females and 67% in males. The receiver operating curve statistics were 0.89 (females) and 0.91 (males). The D statistic was 2.8 (females) and 2.9 (males). The 10% of patients with the highest predicted risks contained 71% of all colorectal cancers diagnosed over the next 2 years. CONCLUSION: The algorithm has good discrimination and calibration and could potentially be used to help identify those at highest risk of current colorectal cancer, to facilitate early referral and investigation. PMID- 22520672 TI - Working in a primary care based antiretroviral team in KwaZulu-Natal, South Africa. PMID- 22520674 TI - Identifying patients with suspected pancreatic cancer in primary care: derivation and validation of an algorithm. AB - BACKGROUND: Pancreatic cancer has the worst survival for any cancer and is often diagnosed late when the cancer is advanced. Chances of survival are more likely if patients can be diagnosed earlier. AIM: To derive and validate an algorithm to estimate absolute risk of having pancreatic cancer in patients with and without symptoms in primary care. DESIGN AND SETTING: Cohort study using data from 375 UK QResearch(r) general practices for development and 189 for validation. METHOD: Included patients were aged 30-84 years, free at baseline from a diagnosis of pancreatic cancer and had not had dysphagia, abdominal pain, abdominal distension, appetite loss, or weight loss recorded in the preceding 12 months. The primary outcome was incident diagnosis of pancreatic cancer recorded in the following 2 years. Risk factors examined included: age, body mass index, smoking status, alcohol, deprivation, diabetes, pancreatitis, previous diagnosis of cancer apart from pancreatic cancer, dysphagia, abdominal pain, abdominal distension, appetite loss, weight loss, diarrhoea, constipation, tiredness, itching, and anaemia. Cox proportional hazards models were used to develop separate risk equations in males and females. Measures of calibration and discrimination assessed performance in the validation cohort. RESULTS: There were a total of 1415 incident cases of pancreatic cancer from 4.1 million person-years in the derivation cohort. Independent predictors in both males and females were age, smoking, type 2 diabetes, chronic pancreatitis, abdominal pain, appetite loss, and weight loss. Abdominal distension was a predictor for females only; dysphagia and constipation were predictors for males only. On validation, the algorithms explained 59% of the variation in females and 62% in males. The receiver operating characteristic statistics were 0.84 (females) and 0.87 (males). The D statistic was 2.44 (females) and 2.61 (males). The 10% of patients with the highest predicted risks contained 62% of all pancreatic cancers diagnosed over the following 2 years. CONCLUSION: The algorithm has good discrimination and calibration and could potentially be used to help identify those at highest risk of pancreatic cancer to facilitate early referral and investigation. PMID- 22520677 TI - Medical care: elitism or social commitment? PMID- 22520678 TI - Nothing about me without me ...? PMID- 22520679 TI - Reforming primary care: innovation or destruction? PMID- 22520680 TI - Association between primary care organisation population size and quality of commissioning in England: an observational study. AB - BACKGROUND: The ideal population size of healthcare commissioning organisations is not known. AIM: To investigate whether there is a relationship between the size of commissioning organisations and how well they perform on a range of performance measures. DESIGN AND SETTING: Cross-sectional, observational study of performance in all 152 primary care trusts (PCTs) in England. METHOD: Comparison of PCT size against 36 indicators of commissioning performance, including measures of clinical and preventative effectiveness, patient centredness, access, cost, financial ability, and engagement. RESULTS: Fourteen of the 36 indicators have an unadjusted relationship (P<0.05) with size of the PCT. With 10 indicators, there was increasing quality with larger size. However, when population factors including deprivation, ethnicity, rurality, and age were included in the analysis, there was no relationship between size and performance for any measure. CONCLUSION: There is no evidence to suggest that there is an optimum size for PCT performance. Observed variations in PCT performance with size were explained by the characteristics of the populations they served. These findings suggest that configuration of clinical commissioning groups should be geared towards producing organisations that can function effectively across their key responsibilities, rather than being based on the size of their population alone. PMID- 22520681 TI - Common mental health disorders--identification and pathways to care: NICE clinical guideline. PMID- 22520682 TI - Tips for GP trainees working in oral and maxillofacial surgery. PMID- 22520684 TI - James Mackenzie Lecture 2010: Beyond the numbers game--the call of leadership. PMID- 22520683 TI - What we talk about when we talk about depression: doctor-patient conversations and treatment decision outcomes. AB - BACKGROUND: Efforts to address depression in primary care settings have focused on the introduction of care guidelines emphasising pharmacological treatment. To date, physician adherence remains low. Little is known of the types of information exchange or other negotiations in doctor-patient consultations about depression that influence physician decision making about treatment. AIM: The study sought to understand conversational influences on physician decision making about treatment for depression. DESIGN: A secondary analysis of consultation data collected in other studies. Using a maximum variation sampling strategy, 30 transcripts of primary care consultations about distress or depression were selected from datasets collected in three countries. Transcripts were analysed to discover factors associated with prescription of medication. METHOD: The study employed two qualitative analysis strategies: a micro-analysis approach, which examines how conversation partners shape the dialogue towards pragmatic goals; and a narrative analysis approach of the problem presentation. RESULTS: Patients communicated their conceptual representations of distress at the outset of each consultation. Concepts of depression were communicated through the narrative form of the problem presentation. Three types of narratives were identified: those emphasising symptoms, those emphasising life situations, and mixed narratives. Physician decision making regarding medication treatment was strongly associated with the form of the patient's narrative. Physicians made few efforts to persuade patients to accept biomedical attributions or treatments. CONCLUSION: Results of the study provide insight into why adherence to depression guidelines remains low. Data indicate that patient agendas drive the 'action' in consultations about depression. Physicians appear to be guided by common-sense decision-making algorithms emphasising patients' views and preferences. PMID- 22520685 TI - Wnt signaling in development and disease. AB - Cell signaling mediated by morphogens is essential to coordinate growth and patterning, two key processes that govern the formation of a complex multi cellular organism. During growth and patterning, cells are specified by both quantitative and directional information. While quantitative information regulates cell proliferation and differentiation, directional information is conveyed in the form of cell polarities instructed by local and global cues. Major morphogens like Wnts play critical roles in embryonic development and they are also important in maintaining tissue homeostasis. Abnormal regulation of these signaling events leads to a diverse array of devastating diseases including cancer. Wnts transduce their signals through several distinct pathways and they regulate vertebrate embryonic development by providing both quantitative and directional information. Here, taking the developing skeletal system as an example, we review our work on Wnt signaling pathways in various aspects of development. We focus particularly on our most recent findings that showed that in vertebrates, Wnt5a acts as a global cue to establishing planar cell polarity (PCP). Our work suggests that Wnt morphogens regulate development by integrating quantitative and directional information. Our work also provides important insights in disease like Robinow syndrome, brachydactyly type B1 (BDB1) and spina bifida, which can be caused by human mutations in the Wnt/PCP signaling pathway. PMID- 22520686 TI - [18F]fluoromethylcholine (FCH) positron emission tomography/computed tomography (PET/CT) for lymph node staging of prostate cancer: a prospective study of 210 patients. AB - Study Type--Diagnostic (exploratory cohort) Level of Evidence 2a. What's known on the subject? and What does the study add? Staging of patients with prostate cancer is the cornerstone of treatment. However, after curative intended therapy a high portion of patients relapse with local and/or distant recurrence. Therefore, one may question whether surgical lymph node dissection (LND) is sufficiently reliable for staging of these patients. Several imaging methods for primary LN staging of patients with prostate cancer have been tested. Acceptable detection rates have not been achieved by CT or MRI or for that matter with PET/CT using the most common tracer fluoromethylcholine (FCH). Other more recent metabolic tracers like acetate and choline seem to be more sensitive for assessment of LNs in both primary staging and re-staging. However, previous studies were small. Therefore, we assessed the value of [(18) F]FCH PET/CT for primary LN staging in a prospective study of a larger sample and with a 'blinded' review. After a study period of 3 years and >200 included patients, we concluded that [(18) F]FCH PET/CT did not reach an optimal detection rate compared with LND, and, therefore, it cannot replace this procedure. However, we did detect several bone metastases with [(18) F]FCH PET/CT that the normal bone scans had missed, and this might be worth pursuing. OBJECTIVES: * To assess the value of [(18) F]fluoromethylcholine (FCH) positron emission tomography/computed tomography (PET/CT) for lymph node (LN) staging of prostate cancer. * To evaluate if FCH PET/CT can replace LN dissection (LND) for LN staging of prostate cancer, as about one-third of patients with prostate cancer who receive intended curative therapy will have recurrence, one reason being undetected LN involvement. PATIENTS AND METHODS: * From January 2008 to December 2010, 210 intermediate- or high-risk patients had a FCH PET/CT scan before regional LND. * After dissection, the result of histological examination of the LNs (gold standard) was compared with the result of FCH PET/CT obtained by 'blinded review'. * Sensitivity, specificity, positive (PPV), and negative predictive values (NPV) of FCH PET/CT were measured for detection of LNe metastases. RESULTS: * Of the 210 patients, 76 (36.2%) were in the intermediate-risk group and 134 (63.8%) were in the high-risk group. A medium (range) of 5 (1-28) LNs were removed per patient. * Histological examination of removed LNs showed metastases in 41 patients. Sensitivity, specificity, PPV, and NPV of FCH PET/CT for patient-based LN staging were 73.2%, 87.6%, 58.8% and 93.1%, respectively. * Corresponding values for LN-based analyses were 56.2%, 94.0%, 40.2%, and 96.8%, respectively. * The mean diameter of the true positive LN metastases was significantly larger than that of the false negative LNs (10.3 vs 4.6 mm; P < 0.001). * In addition, FCH PET/CT detected a high focal bone uptake, consistent with bone metastases, in 18 patients, 12 of which had histologically benign LNs. CONCLUSIONS: * Due to a relatively low sensitivity and a correspondingly rather low PPV, FCH PET/CT is not ideal for primary LN staging in patients with prostate cancer. * However, FCH PET/CT does convey important additional information otherwise not recognised, especially for bone metastases. PMID- 22520687 TI - (+)-naloxone, an opioid-inactive toll-like receptor 4 signaling inhibitor, reverses multiple models of chronic neuropathic pain in rats. AB - Previous work demonstrated that both the opioid antagonist (-)-naloxone and the non-opioid (+)-naloxone inhibit toll-like receptor 4 (TLR4) signaling and reverse neuropathic pain expressed shortly after chronic constriction injury. The present studies reveal that the TLR4 contributes to neuropathic pain in another major model (spinal nerve ligation) and to long established (2-4 months) neuropathic pain, not just to pain shortly after nerve damage. Additionally, analyses of plasma levels of (+)-naloxone after subcutaneous administration indicate that (+) naloxone has comparable pharmacokinetics to (-)-naloxone with a relatively short half-life. This finding accounts for the rapid onset and short duration of allodynia reversal produced by subcutaneous (+)-naloxone. Given that toll-like receptor 2 (TLR2) has also recently been implicated in neuropathic pain, cell lines transfected with either TLR4 or TLR2, necessary co-signaling molecules, and a reporter gene were used to define whether (+)-naloxone effects could be accounted for by actions at TLR2 in addition to TLR4. (+)-Naloxone inhibited signaling by TLR4 but not TLR2. These studies provide evidence for broad involvement of TLR4 in neuropathic pain, both early after nerve damage and months later. Additional, they provide further support for the TLR4 inhibitor (+) naloxone as a novel candidate for the treatment of neuropathic pain. PERSPECTIVE: These studies demonstrated that (+)-naloxone, a systemically available, blood brain barrier permeable, small molecule TLR4 inhibitor can reverse neuropathic pain in rats, even months after nerve injury. These findings suggest that (+) naloxone, or similar compounds, be considered as a candidate novel, first-in class treatment for neuropathic pain. PMID- 22520688 TI - Autonomic nervous system function in young children with functional abdominal pain or irritable bowel syndrome. AB - Adults with irritable bowel syndrome (IBS) have been reported to have alterations in autonomic nervous system function as measured by vagal activity via heart rate variability. Whether the same is true for children is unknown. We compared young children 7 to 10 years of age with functional abdominal pain (FAP) or IBS to healthy children (HC) and explored the relationship of vagal activity and sympathovagal balance to psychological distress and stool type. Children completed questionnaires, kept a 2-week pain/stool diary, and wore a 24-hour Holter monitor to assess vagal activity. Group comparisons on vagal activity were controlled for age and body mass index. Indicators of vagal activity and sympathovagal balance did not differ between FAP/IBS children (70 girls, 30 boys) and HC (44 girls, 18 boys). Psychological distress measures were generally higher in FAP/IBS than HC, primarily in girls. Exploratory analyses suggest a potential negative correlation between vagal activity and psychological distress in FAP/IBS girls but not boys. In contrast to reports in women, no differences were found in vagal activity between FAP/IBS and HC. Preliminary findings suggest that in girls with FAP/IBS there is an inverse relationship between vagal activity and psychological distress. PERSPECTIVE: The results from this study suggest a possible relationship between emotional state and vagal activity in prepubertal girls (but not boys) with FAP/IBS. Age and/or duration of symptoms may explain our contrasting findings versus adults with IBS. PMID- 22520689 TI - Application of extrapolation chambers in low-energy X-rays as reference systems. AB - Extrapolation chambers are instruments designed to measure doses of low-energy radiations, mainly beta radiation. In this work, a commercial extrapolation chamber and a homemade extrapolation chamber were applied in measurements using standard radiotherapy X-ray beams. Saturation curves and polarity effect as well as short- and medium-term stabilities were obtained, and these results are within the recommendations of the International Electrotechnical Commission (IEC). The response linearity and the extrapolation curves were also obtained, and they presented good behavior. The results show the usefulness of these extrapolation chambers in low-energy X-ray beams. PMID- 22520690 TI - Cognitive ability in early adulthood as a predictor of habitual drug use during later military service and civilian life: the Vietnam Experience Study. AB - BACKGROUND: Recent reports have linked cognitive ability (IQ) with alcohol dependency, but the relationship with illegal drug use is not well understood. METHODS: Participants were 14,362 male US Vietnam veterans with IQ test results at entry into military service in 1965-1971 (mean age 22.58) who participated in a telephone interview in 1985-1986. A structured diagnostic telephone interview was used to ascertain habitual drug use during military service (for once a week, >= 3 months) and in civilian life (in the past 12 months, >= once a week), combat exposure, and post-traumatic stress disorder according to established Diagnostic and Statistical Manual of Mental disorders criteria (version III). RESULTS: In unadjusted analysis, men with high IQ scores were less likely to be habitual users of cannabis (OR=0.89, 95% CI=0.86, 0.93), cocaine (OR=0.69, 95% CI=0.61, 0.78), heroin (OR=0.80, 95% CI=0.73, 0.88), amphetamines (OR=0.90, 95% CI=0.83, 0.98), barbiturates (OR=0.79, 95% CI=0.72, 0.86) and LSD (OR=0.91, 95% CI=0.82, 0.99) during military service and civilian life. These associations were markedly attenuated after adjustment for socioeconomic status in early and later civilian life. CONCLUSION: In this cohort, socioeconomic position might lie on the pathway linking earlier IQ and later habitual drug use but might also act as a surrogate for IQ. This suggests interventions to prevent drug use could attempt to improve early life IQ and opportunities for employment. PMID- 22520691 TI - A tripling of readers: Acta Physiologica takes off. PMID- 22520692 TI - Oxygen sensing, uptake, delivery, consumption and related disorders. PMID- 22520693 TI - Early platelet dysfunction: an unrecognized role in the acute coagulopathy of trauma. AB - BACKGROUND: Our aim was to determine the prevalence of platelet dysfunction using an end point of assembly into a stable thrombus after severe injury. Although the current debate on acute traumatic coagulopathy has focused on the consumption or inhibition of coagulation factors, the question of early platelet dysfunction in this setting remains unclear. STUDY DESIGN: Prospective platelet function in assembly and stability of the thrombus was determined within 30 minutes of injury using whole blood samples from trauma patients at the point of care using thrombelastography-based platelet functional analysis. RESULTS: There were 51 patients in the study. There were significant differences in the platelet response between trauma patients and healthy volunteers, such that there was impaired aggregation to these agonists. In trauma patients, the median ADP inhibition of platelet function was 86.1% (interquartile range [IQR] 38.6% to 97.7%) compared with 4.2 % (IQR 0 to 18.2%) in healthy volunteers. After trauma, the impairment of platelet function in response to arachidonic acid was 44.9% (IQR 26.6% to 59.3%) compared with 0.5% (IQR 0 to 3.02%) in volunteers (Wilcoxon nonparametric test, p < 0.0001 for both tests). CONCLUSIONS: In this study, we show that platelet dysfunction is manifest after major trauma and before substantial fluid or blood administration. These data suggest a potential role for early platelet transfusion in severely injured patients at risk for postinjury coagulopathy. PMID- 22520695 TI - Laparoscopic liver resection. PMID- 22520694 TI - Younger boys have a higher risk of inguinal hernia after ventriculo-peritoneal shunt: a 13-year nationwide cohort study. AB - BACKGROUND: Few studies associate ventriculo-peritoneal shunt (VPS) in children with higher incidence of inguinal hernia (IH). These institutional-based data have small numbers and provided little information about the effects of age and sex. This study aims to examine the incidences and risk factors of IH in children with hydrocephalus treated with VPS. STUDY DESIGN: Using a 13-year nationwide database, a cohort of 1,568 children younger than 5 years of age who received VPS were followed up for IH. Of these, 194 received IH repair. Kaplan-Meier analysis and Cox regression were conducted. RESULTS: Overall incidence of IH after VPS in children younger than 5 years old was 22.9 per 1,000 person-years. The average follow-up time was 5.41 years, and the mean time interval between VPS and IH repair was 1.14 years. Age-specific incidences were 45.0, 21.3, 18.5, and 4.1 per 1000 person-years for neonates, infants, toddlers, and preschool children, respectively. Compared with preschool children, neonates, infants, and toddlers, were more likely to have IH (crude hazard ratio = 9.8, 5.3, and 4.4; p < 0.001, p = 0.001, and p = 0.006, respectively). Sex and age were significantly different in children with and without IH (both, p < 0.001). Differences of cumulative incidence rates in the 4 age groups were significant in both male and female patients (p < 0.001 and p = 0.023, respectively). CONCLUSIONS: The patient's age on VPS surgery significantly affects the likelihood of subsequent IH development. IH is more likely to develop in neonates after VPS than in infants, toddlers, and preschool-aged children. This age-related effect is more prominent in boys than in girls. PMID- 22520697 TI - Appropriate use of emergency department thoracotomy. PMID- 22520698 TI - Ultrasound-guided core needle biopsy of axillary lymph nodes in breast cancer. PMID- 22520700 TI - End-of-life care decisions. PMID- 22520703 TI - A new single-port approach to perform a transperitoneal step and an extraperitoneal para-aortic lymphadenectomy with a single incision. PMID- 22520704 TI - Difficulties and countermeasures of transumbilical single incision laparoscopic cholecystectomy. PMID- 22520705 TI - Treatment received, satisfaction with health care services, and psychiatric symptoms 3 months after hospitalization for self-poisoning. AB - BACKGROUND: Patients who self-poison have high repetition and high mortality rates. Therefore, appropriate follow-up is important. The aims of the present work were to study treatment received, satisfaction with health care services, and psychiatric symptoms after hospitalization for self-poisoning. METHODS: A cohort of patients who self-poisoned (n = 867) over a period of 1 year received a questionnaire 3 months after discharge. The Beck Depression Inventory (BDI), Beck Hopelessness Scale (BHS), and Generalized Self-Efficacy Scale (GSE) were used. The participation rate was 28% (n = 242); mean age, 41 years; 66% females. RESULTS: Although only 14% of patients were registered without follow-up referrals at discharge, 41% reported no such measures. Overall, satisfaction with treatment was fairly good, although 29% of patients waited more than 3 weeks for their first appointment. A total of 22% reported repeated self-poisoning and 17% cutting. The mean BDI and BHS scores were 23.3 and 10.1, respectively (both moderate to severe). The GSE score was 25.2. BDI score was 25.6 among patients with suicide attempts, 24.9 for appeals, and 20.1 for substance-use-related poisonings. CONCLUSIONS: Despite plans for follow-up, many patients reported that they did not receive any. The reported frequency of psychiatric symptoms and self harm behavior indicate that a more active follow-up is needed. PMID- 22520706 TI - Characterization of magnetic nanoparticles modified with thiol functionalized PAMAM dendron for DNA recovery. AB - Magnetic nanoparticles (MNPs) modified with the thiol functionalized polyamidoamine (PAMAM) dendron were synthesized to estimate their DNA recovery capabilities. Aminosilane-modified MNPs and MNPs surrounded by a phospholipid (distearoylphosphatidylethanolamine (DSPE)) bilayer were used as core particles. Cystamine-core PAMAM dendrimers were reduced by dithiothreitol to dendron thiols and chemically conjugated to the core particles. Characterization of the synthesis revealed an increase of the surface amine charge from generation 1 (G1) to G6, starting with an aminosilane initiator. Particle size distribution analysis indicated that G6 PAMAM-modified MNPs exhibited monodispersity in an aqueous solution. G6 PAMAM-MNPs and G6 PAMAM-PE-MNPs synthesized by the proposed method have equivalent DNA recovery abilities to PAMAM-MNPs prepared by the conventional divergent synthesis method. In optimized conditions, 96% of lambdaDNA was recovered using G6 PAMAM-PE-MNPs. Therefore, the method for preparing PAMAM-MNPs and PAMAM-PE-MNPs proposed in this study will be a novel approach for producing DNA carriers for efficient DNA purification by magnetic separation. PMID- 22520707 TI - Evaporative micro-particle self assembly influenced by capillary evacuation. AB - As evaporation does not incur energy introduction, the droplet coffee-stain patterning approach is attractive for biochemical tests conducted in the field or in third world environments. A practical strategy uses chemically functionalized microbeads for the coffee stain deposition process. From an application perspective, it will be necessary to minimize the coffee stain deposition time, as evaporation, depending on the volume of the droplet, can be a slow process. The introduction of a porous media will generate a capillary flow (or wicking) that removes any remnant liquid in the droplet, thus permitting it to be done inexpensively and in the field. Using optical profilometry, we were able to establish that polystyrene microspheres developed more copious and defined single ring coffee depositions than silica of the same size and concentration in a suspension. In analyzing the droplet capillary evacuation process with a porous media, we found the liquid bridge formed during the later stages to rupture and leave behind some liquid material for a second stage evaporation process. This was responsible for a two ring structure that was more visible with silica microspheres. A high degree of hysteresis of the contact angle was found to develop at the contact line in which values below 5 degrees could be achieved. Dynamic observations showed the copious and dense packing of polystyrene particles to be more resistant to ring break up from the evacuation flow. Nevertheless, erosion of the back array portions of the ring was evident notwithstanding either type of microsphere used. PMID- 22520708 TI - Magnetic alpha-Fe2O3/MCM-41 nanocomposites: preparation, characterization, and catalytic activity for methylene blue degradation. AB - Catalysts based on nanosized magnetic iron oxide stabilized inside the pore system of ordered mesoporous silica MCM-41 have been prepared. The obtained materials were characterized by powder X-ray diffraction analysis (XRD), scanning electron microscopy (SEM), vibrating sample magnetometer (VSM), and N(2) adsorption-desorption isotherm. XRD analysis showed that the obtained materials consist from the pure hematite crystalline phase (alpha-Fe(2)O(3)) dispersed within ordered mesoporous silica MCM-41. Magnetic measurements show that the obtained nanocomposites exhibit at room temperature weak ferromagnetic behavior with slender hysteresis. The catalytic activity of the magnetic alpha Fe(2)O(3)/MCM-41 nanocomposites was evaluated by the degradation of methylene blue (MB) aqueous solution. For this purpose, an ultrasound-assisted Fenton-like process was used. The effect of solution pH on degradation of MB was investigated. The results indicated that US-H(2)O(2)-alpha-Fe(2)O(3)/MCM-41 nanocomposite system is effective for the degradation of MB, suggesting its great potential in removal of dyes from wastewater. It was found that the degradation rate of MB increases with decrease in the pH value of the solution. PMID- 22520709 TI - Synthesis of core-shell composites using an inverse surfmer. AB - Anilinium dodecylsulfate was prepared from aniline and sodium dodecylsulfate. The critical micellar concentration of the salt was determined using electrical conductimetry, which revealed that the change of countercation, sodium by anilinium, reduced the critical micellar concentration with respect to the conventional counterpart, sodium dodecylsulfate. The anilinium dodecylsulfate was used as the surfmer in the synthesis of polystyrene/polyaniline core-shell composites, first performing as the surfactant to stabilize the emulsion polymerization of styrene, and later as the monomer to synthesize polyaniline via oxidative polymerization. Here, the surfmer function was directed toward the external phase instead of to the internal phase, as with conventional surfmers with carbon-carbon double bonds. Consequently, the term inverse surfmer is proposed. Analyses of its composite microstructure using electron microscopy and thermogravimetric analysis confirmed the core-shell arrangement. PMID- 22520710 TI - Protein adsorption-desorption on electrospray capillary walls--no influence on aggregate distribution. AB - Adsorbed proteins on walls of glass capillaries used for electrospray (ES) can desorb and potentially affect size distributions and, thus, quantification of aggregates of proteins. In this study we use differential mobility analysis (DMA) to investigate the size distribution of various proteins eluting from bare and passivated glass capillaries. We found no significant differences in aggregate distributions from unpassivated capillaries at 'steady state' when compared to aggregate distributions from passivated capillaries implying that desorbing proteins do not influence protein aggregate distribution. Surface passivation with gelatin was found to be considerably more effective in limiting adsorption of two antibodies (Rituxan and polyclonal human IgG) compared to passivation with BSA. Gelatin passivation was also found to be stable for a few days and from a pH range of 4.8-9.0. PMID- 22520711 TI - Mathematical modeling of a hydrophilic cylinder floating on water. AB - In this paper, a hydrostatic model of the surface profile anchored to the upper edge of a vertical cylinder is proposed to explain why coins can float on water surface. The sharp edge of a cylinder is thus modeled as a round smooth surface on which the contact line may be anchored at a position according to the weight of the cylinder. The mathematical model of the surface profile is established based on the hydrostatics and a third order ordinary differential equation is resulted. Numerical solution of the model demonstrates under practical conditions the existence of the surface profiles that provide reasonable uplifting force at the contact line so that the force is available for floating coins on water surface. The proposed model explains the obviously enlarged apparent contact angle and the edge effect in the literature. The numerical simulation is found in very good agreement with the experimental data in the literature. PMID- 22520712 TI - Immobilization of anionic iron(III) porphyrins onto in situ obtained zinc oxide. AB - A family of anionic iron(III) porphyrins (FePor) was immobilized onto zinc oxide (ZnO) obtained by the in situ hydrothermal decomposition of zinc hydroxide nitrate, a layered hydroxide salt. The immobilization probably occurred via the interaction between the anionic charges on the porphyrins and the positively charged surface of the ZnO, in slightly acidic to neutral pH. The resulting solids were characterized by transmission electron microscopy (TEM), X-ray powder diffraction (XRDP), Fourier transform infrared spectroscopy (FTIR), electron paramagnetic resonance (EPR), and ultraviolet-visible spectroscopy (UV-Vis) (solid samples), which confirmed the formation of ZnO and the immobilization of the FePor. The prepared materials were employed as catalysts for the heterogeneous catalytic oxidation of cyclooctene, cyclohexane, and n-heptane, using iodosylbenzene as the oxygen donor. Good catalytic results were achieved for all the substrates, and selectivity for the alcohol was verified during the oxidation of alkanes. The reuse capacity of the solid catalyst was also investigated. PMID- 22520713 TI - General one-pot strategy to prepare multifunctional nanocomposites with hydrophilic colloidal nanoparticles core/mesoporous silica shell structure. AB - A general and facile strategy was developed to coat hydrophilic inorganic nanoparticles directly with mesoporous silica nanoparticles (MSNs). The cationic surfactant of cetyltrimethylammonium bromide (CTAB) was adsorbed to various negatively charged CdTe quantum dots, Fe(3)O(4) nanocrystals or Au nanoparticles, introducing the bilayer of CTAB overcoating with positive charge. The subsequent sol-gel reaction of TEOS with the basic catalyst resulted in uniform nanocomposites. The concentration of CTAB and NH(4)OH in the recipe strongly influenced the number of inorganic nanoparticles in the nanocomposites and the homogeneity of MSNs shell. One dimensional Au nanorods and larger size of solid SiO(2) nanoparticles were also able to coat with MSNs using a similar synthetic procedure. The proposed method was greatly simplified without the help of any mediators or silane coupling agents and excellent mesostructural performance was readily achieved. Compared to the methods known from the literatures for the coating of hydrophobic nanoparticles, this efficient way is especially useful for trapping different hydrophilic nanoparticles with arbitrary sizes and shapes into MSNs. These highly versatile multifunctional nanocomposites, together with the pH responsible drug release behaviors, non-toxicity to normal cells and ease of uptake into cancer cells, are expected to be utilized as drug delivery system for simultaneous imaging and therapeutic applications. PMID- 22520714 TI - The risk-benefit task of research ethics committees: an evaluation of current approaches and the need to incorporate decision studies methods. AB - BACKGROUND: Research ethics committees (RECs) are tasked to assess the risks and the benefits of a trial. Currently, two procedure-level approaches are predominant, the Net Risk Test and the Component Analysis. DISCUSSION: By looking at decision studies, we see that both procedure-level approaches conflate the various risk-benefit tasks, i.e., risk-benefit assessment, risk-benefit evaluation, risk treatment, and decision making. This conflation makes the RECs' risk-benefit task confusing, if not impossible. We further realize that RECs are not meant to do all the risk-benefit tasks; instead, RECs are meant to evaluate risks and benefits, appraise risk treatment suggestions, and make the final decision. CONCLUSION: As such, research ethics would benefit from looking beyond the procedure-level approaches and allowing disciplines like decision studies to be involved in the discourse on RECs' risk-benefit task. PMID- 22520715 TI - Hyperthyroidism presenting as mixed affective state: a case report. AB - Thyroid disorders have long been associated with psychiatric illness, commonly mood disorders. In bipolar disorder, hypothyroidism is quite a common abnormality. Little is known about the association of thyroid disorders and mixed affective states. We present a case of hyperthyroidism presenting as a mixed affective state and the successful resolution of psychiatric symptoms with antithyroid medication along with a mood-stabilizing agent. PMID- 22520716 TI - Risperidone-induced leukopenia: a case report and brief review of literature. AB - A Caucasian, male, young adult with recurrent agitated depression and suicidal ideation received lithium and oral olanzapine. His white blood cell count was normal at that time. Due to unsatisfactory response, he received 4 mg/day risperidone. While symptoms improved, leukopenia emerged, specifically directed towards neutrophils. Upon risperidone discontinuation, white blood cell count returned to reference values within 1 week. As symptom control was satisfactory, we attempted no risperidone rechallenge. Accurate blood testing must accompany atypical antipsychotic drug administration since blood dyscrasias are always possible with these drugs. PMID- 22520717 TI - Effects of various drug therapies on Kleine-Levin syndrome: a case report. AB - Kleine-Levin syndrome (KLS) is a rare sleep disorder, predominantly affecting adolescent males, which presents as recurrent episodes of hypersomnia, behavioral and cognitive disturbances, hyperphagia and sometimes hypersexuality (Lisk, "Kleine-Levin syndrome." Pract Neurol 2009;9:42-45). Modafinil has been reported to show an effect in shortening the duration of symptomatic periods, but does not affect the recurrence rate (Huang et al., "Kleine-Levin syndrome: current status." Med Clin N Am 2010;94:557-562). However, no single drug therapy has been consistently successful, despite various psychotropic agents, including lithium, anticonvulsants and antidepressants, having been systematically tried (Arnulf et al., "Kleine-Levin syndrome: a systematic study of 108 patients." Ann Neurol 2008;63:482-492). This study reports a male adolescent with KLS who received several courses of drug therapy, providing a chance to compare differential drug effects over time. PMID- 22520718 TI - Utility of autopsy in uncovering unexpected neuropathology. AB - Autopsy rates have declined in the last several decades for a variety of reasons. The purpose of this study is to compare autopsy neuropathologic findings from 2 periods to assess the prevalence of unexpected neuropathologic findings and unexpected neuropathologic diagnoses determined to be the major cause of death. Retrospective review of autopsies with examination of the central nervous system was performed in 2007 to 2008 (n = 289) and 1984 to 1985 (n = 328). Unexpected neuropathologic diagnoses were found at autopsy in 42.4% of cases from 1984 to 1985 vs 38.8% of cases from 2007 to 2008. The neuropathology was felt to contribute to the cause of death in 22% of cases from 1984 to 1985 vs 19.7% of cases from 2007 to 2008. Unexpected neuropathologic findings were the cause of death in 5.2% of cases from 1984 to 1985 vs 3.1% of cases from 2007 to 2008. These findings underscore the continued use of brain and spinal cord examination at autopsy despite advances in "modern" medicine. PMID- 22520719 TI - Vascular access for chronic hemodialysis in a patient with epidermolysis bullosa dystrophica Hallopeau-Siemens. AB - Epidermolysis bullosa is a rare genetic hereditary disease characterized with mechanobullous dermatosis. Except cutaneous, these patients have various extracutaneous manifestations and some types of epidermolysis bullosa comprise almost all organ systems. Because of prolonged life span, chronic renal insufficiency has become an important cause of morbidity and death in these patients. Establishment of functional vascular dialysis access is a great challenge for both the doctors and the patients. Multidisciplinary approach is essential. We present a case of successful establishment of dialysis access via Tesio catheter in a young woman suffering from epidermolysis bullosa dystrophica Hallopeau-Siemens and end-stage renal disease. Since then, the Tesio catheter inserted via the right internal jugular vein has been the functional mean of dialysis. The patient was given the opportunity to lead a quality and active life in spite of disabling disease. Several cases of successful dialysis access establishment with dialysis catheters via central veins have been reported. We report the successful establishment of long-term dialysis access via Tesio catheter and suggest this approach as ideal for these patients. This is the first report dealing with vascular access in this group of patients. PMID- 22520720 TI - How should I wean my next intra-aortic balloon pump? Differences between progressive volume weaning and rate weaning. AB - OBJECTIVE: Although the intra-aortic balloon pump is the most used ventricular assist device, no study has ever evaluated the best weaning method. We compared 2 different intra-aortic balloon pump weaning methods. METHODS: Thirty consecutive patients needing an intra-aortic balloon pump because of perioperative low-output cardiac syndrome were randomized to be weaned by ratio (4 consecutive hours of a 1:2 assisting ratio followed by 1 hour of a 1:3 ratio; group R) or by progressive volume deflation (10% of total volume every hour for 5 consecutive hours; 15 patients, group V). A duration of 5 hours was set a priori as the weaning duration. The weaning protocol was started when the cardiac index was greater than 2.5 L/min/m(2), the central venous pressure was 12 mm Hg or less, the blood lactate was less than 2.5 mmol/L, the mean arterial pressure was greater than 65 mm Hg, and the preserved urine output (>=1 mL/kg/hr) lasted for at least 5 consecutive hours before weaning. The cardiac index, indexed systemic vascular resistance, cardiac cycle efficiency, and central venous pressure were registered at 9 points (T0, start; T1 to T5, the first 5 weaning hours; T6, 2 hours after withdrawal; T7, 12 hours after withdrawal; and T8, at intensive care unit discharge) using the pressure recording analytical method. The interval from intra-aortic balloon pump withdrawal to intensive care unit discharge, weaning failure, perioperative troponin I, and lactate (same points) were compared. RESULTS: All patients, except for 1 belonging to group R (P = 1.0), were successfully weaned. Group V had better preserved cardiac index, indexed systemic vascular resistance, cardiac cycle efficiency, and central venous pressure (group*time P = .0001). Group R had worse cardiac index from T5 to T8 (P <= .0001), indexed systemic vascular resistance from T2 to T8 (P <= .004), cardiac cycle efficiency from T3 to T8 (P <= .001), central venous pressure from T4 to T8 (P <= .0001), and a longer interval from intra-aortic balloon pump withdrawal to intensive care unit discharge (P = .0001). The lactate level was lower in group V from T5 to T8 (P <= .027; group*time P = .001). CONCLUSIONS: Intra-aortic balloon pump weaning by volume deflation allowed better hemodynamic and metabolic parameters. PMID- 22520721 TI - Intra-aortic balloon pump inserted through the subclavian artery: A minimally invasive approach to mechanical support in the ambulatory end-stage heart failure patient. AB - OBJECTIVE: Intra-aortic balloon pumps are traditionally inserted through the femoral artery, limiting the patient's mobility. We used alternate approaches of intra-aortic balloon pump insertion to provide temporary and minimally invasive support for patients with decompensating, end-stage heart failure. The present study describes the outcomes with closed-chest, transthoracic intra-aortic balloon pumps by way of the subclavian artery. METHODS: During a 3-year period, 20 patients underwent subclavian artery-intra-aortic balloon pump in the setting of end-stage heart failure. The balloon was inserted through a polytetrafluoroethylene graft sutured to the right subclavian artery in 19 patients (95%) and to the left subclavian artery in 1 patient (5%). The goal of support was to bridge to transplantation in 17 patients (85%) and bridge to recovery in 3 patients (15%). The primary outcome measure was death during subclavian artery-intra-aortic balloon pump support. The secondary outcomes included survival to the intended endpoint of bridge to transplantation/bridge to recovery, complications during subclavian artery-intra-aortic balloon pump support (eg, stroke, limb ischemia, brachial plexus injury, dissection, bleeding requiring reoperation, and device-related infection), emergent surgery for worsening heart failure, and ambulation during intra-aortic balloon pump support. RESULTS: The duration of balloon support ranged from 3 to 48 days (mean, 17.3 +/- 13.1 days). No patients died during subclavian artery-intra-aortic balloon pump support. Of the 20 patients, 14 (70%) were successfully bridged to transplant or left ventricular-assist device. Two patients (10%) required emergent left ventricular-assist device for worsening heart failure. CONCLUSIONS: An intra aortic balloon pump inserted through the subclavian artery is a simple, minimally invasive approach to mechanical support and is associated with limited morbidity and facilitates ambulation in patients with end-stage heart failure. PMID- 22520722 TI - Cryoablation during left ventricular assist device implantation reduces postoperative ventricular tachyarrhythmias. AB - BACKGROUND: The number of patients undergoing implantation of a HeartMate II left ventricular assist device (LVAD; Thoratec Corporation, Pleasanton, Calif) is rising. Ventricular tachyarrhythmia (VA) after placement of the device is common, especially among patients with preoperative VA. We sought to determine whether intraoperative cryoablation in select patients reduces the incidence of postoperative VA. METHODS: From January 2009 through September 2010, 50 consecutive patients undergoing implantation of the HeartMate II LVAD were examined. Fourteen of these patients had recurrent preoperative VA. Of those patients with recurrent VA, half underwent intraoperative cryoablation (Cryo: n = 7) and half did not (NoCryo: n = 7). Intraoperatively, patients underwent localized epicardial and endocardial cryoablation via LVAD ventriculotomy. Cryothermal lesions were created to connect scar to fixed anatomic borders in the region of clinical VA. Demographics, risk factors, intraoperative features, and outcomes were analyzed to investigate the feasibility of cryoablation. RESULTS: Thirty-day mortality remained low (n = 1, 2%) among all LVAD recipients. There were no differences in risk factors between groups except that preoperative inotropes were less prevalent in Cryo patients (P = .09). Compared with NoCryo, the Cryo group had significantly decreased postoperative resource use and complications (P < .05). Recurrent postoperative VA did not develop in any of the Cryo patients (P = .02). CONCLUSIONS: Postoperative VA can be minimized by preoperative risk assessment and intraoperative treatment. Localized cryoablation in select patients offers promising early feasibility when performed during HeartMate II LVAD implantation. Further prospective analysis is required to investigate this novel approach. PMID- 22520724 TI - Two different opinions on a published systematic review. PMID- 22520723 TI - Orthodontic measurements and nasal respiratory function after surgically assisted rapid maxillary expansion: an acoustic rhinometry and rhinomanometry study. AB - The present study sought to assess nasal respiratory function in adult patients with maxillary constriction who underwent surgically assisted rapid maxillary expansion (SARME) and to determine correlations between orthodontic measurements and changes in nasal area, volume, resistance, and airflow. Twenty-seven patients were assessed by acoustic rhinometry, rhinomanometry, orthodontic measurements, and use of a visual analogue scale at three time points: before surgery; after activation of a preoperatively applied palatal expander; and 4 months post-SARME. Results showed a statistically significant increase (p<0.001) in all orthodontic measurements. The overall area of the nasal cavity increased after surgery (p<0.036). The mean volume increased between assessments, but not significantly. Expiratory and inspiratory flow increased over time (p<0.001). Airway resistance decreased between assessments (p<0.004). Subjective analysis of the feeling of breathing exclusively through the nose increased significantly from one point in time to the next (p<0.05). There was a statistical correlation between increased arch perimeter and decreased airway resistance. Respiratory flow was the only variable to behave differently between sides. The authors conclude that the SARME procedure produces major changes in the oral and nasal cavity; when combined, these changes improve patients' quality of breathing. PMID- 22520725 TI - Hemimandibulectomy and vascularized fibula flap in bisphosphonate-induced mandibular osteonecrosis with polycythaemia rubra vera. AB - This report presents the successful management of an advanced and refractory bisphosphonate-related osteonecrosis of the jaws (BRONJ) by hemimandibulectomy and an osteocutaneous fibula flap reconstruction in a patient with polycythaemia rubra vera, a rare haematological condition in which there is increased risk of thrombosis and haemorrhage. Union of the vascularized bone with the mandible depends on obtaining a BRONJ-free margin and rigid fixation of the bony ends. Magnetic resonance imaging can provide accurate delineation of necrotic bone and area of osteomyelitis. Placement of a 1cm margin beyond this can envisage a BRONJ free margin. Aggressive medical management of polycythaemia rubra vera by venesection, asprin and cytoreduction therapy along with anticoagulant prophylaxis against thromboembolic events in the first 2 weeks following major surgery can provide the basis of a good surgical and flap outcome. Nevertheless, the possibility of unpredictable haemorrhage must be considered throughout. PMID- 22520726 TI - Bacterial communication and human communication: what can we learn from quorum sensing? PMID- 22520727 TI - A step-by-step guide to dopamine. PMID- 22520728 TI - Functional network endophenotypes of psychotic disorders. PMID- 22520730 TI - The genomics of speciation-with-gene-flow. AB - The emerging field of speciation genomics is advancing our understanding of the evolution of reproductive isolation from the individual gene to a whole-genome perspective. In this new view it is important to understand the conditions under which 'divergence hitchhiking' associated with the physical linkage of gene regions, versus 'genome hitchhiking' associated with reductions in genome-wide rates of gene flow caused by selection, can enhance speciation-with-gene-flow. We describe here a theory predicting four phases of speciation, defined by changes in the relative effectiveness of divergence and genome hitchhiking, and review empirical data in light of the theory. We outline future directions, emphasizing the need to couple next-generation sequencing with selection, transplant, functional genomics, and mapping studies. This will permit a natural history of speciation genomics that will help to elucidate the factors responsible for population divergence and the roles that genome structure and different forms of hitchhiking play in facilitating the genesis of new biodiversity. PMID- 22520729 TI - Replication timing and its emergence from stochastic processes. AB - The temporal organization of DNA replication has puzzled cell biologists since before the mechanism of replication was understood. The realization that replication timing correlates with important features, such as transcription, chromatin structure and genome evolution, and is misregulated in cancer and aging has only deepened the fascination. Many ideas about replication timing have been proposed, but most have been short on mechanistic detail. However, recent work has begun to elucidate basic principles of replication timing. In particular, mathematical modeling of replication kinetics in several systems has shown that the reproducible replication timing patterns seen in population studies can be explained by stochastic origin firing at the single-cell level. This work suggests that replication timing need not be controlled by a hierarchical mechanism that imposes replication timing from a central regulator, but instead results from simple rules that affect individual origins. PMID- 22520731 TI - The treatment of glioblastoma multiforme through activation of microglia and TRAIL induced by rAAV2-mediated IL-12 in a syngeneic rat model. AB - BACKGROUND: Microglial cells are the predominant immune cells in malignant brain tumors, but tumors may release some factors to reduce their defensive functions. Restoration of the anti-cancer function of microglia has been proposed as a treatment modality for glioblastoma. We examined the effect of intra-cranially administered recombinant adeno-associated virus encoding interleukin-12 (rAAV2/IL12) on transfection efficiency, local immune activity and survival in a rat model of glioblastoma multiforme. METHODS: F344 rats were injected with rAAV2/IL12 and implanted with syngeneic RG2 cells (glioblastoma cell line). Intracerebral interleukin-12 and interferon-gamma concentrations were determined by ELISA. Activation of microglia was determined by expressions of ED1 and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) which were evaluated by Western blotting and immunohistochemistry. The proliferation of cancer cells was evaluated with Ki67 immunohistochemistry and apoptosis of cancer cells with TUNEL. RESULTS: The brains treated with rAAV2/IL-12 maintained high expression of interleukin-12 and interferon-gamma for at least two months. In syngeneic tumor model, brains treated with rAAV2/IL12 exhibited more infiltration of activated microglia cells as examined by ED1 and TRAIL stains in the tumor. In addition, the volume of tumor was markedly smaller in AAV2/IL12-treated group and the survival time was significantly longer in this group too. CONCLUSION: The intra cerebrally administered rAAV2/IL-12 efficiently induces long lasting expression of IL-12, the greater infiltration of activated microglia cells in the tumor associated improved immune reactions, resulting in the inhibited growth of implanted glioblastoma and the increased survival time of these rats. PMID- 22520732 TI - Impact of C-reactive protein kinetics on survival of patients with advanced urothelial carcinoma treated by second-line chemotherapy with gemcitabine, etoposide and cisplatin. AB - OBJECTIVE: To assess the impact of C-reactive protein (CRP) kinetics, the effect of dynamic changes of CRP concentration on the survival of patients with locally advanced or metastatic urothelial carcinoma (UC) treated by single chemotherapeutic regimen including cisplatin was examined. PATIENTS AND METHODS: Eighty patients with advanced UC, who failed treatment of advanced UC with the first-line chemotherapy or who received perioperative treatment of neoadjuvant or adjuvant settings, were treated with gemcitabine, etoposide and cisplatin (GEP) as second-line chemotherapy. Patients were divided into three groups according to CRP kinetics based on baseline and nadir CRP concentrations. Patients whose baseline CRP levels were <5 mg/L, patients whose baseline CRP levels were >=5 mg/L and normalized (<5 mg/L), and patients whose baseline CRP levels were >=5 mg/L and never normalized were assigned to non-elevated, normalized and non normalized CRP groups, respectively. The prognostic impact of CRP kinetics and the correlation between normalized CRP period and overall survival period were determined. RESULTS: In 46 (57%) of the 80 patients, CRP levels were elevated at the diagnosis of advanced UC. During treatment, after a median follow-up period of 12 months CRP levels were normalized in 24 (71%) of 34 patients, whereas CRP levels remained elevated in the remaining 10 patients. Overall survival rates were significantly different between the non-elevated, normalized, and non normalized CRP groups (P < 0.001), with 1-year survival rates of 72, 51 and 14%, respectively. On multivariate analysis including Eastern Cooperative Oncology Group performance status, visceral metastasis, number of metastatic sites, previous definitive surgery, anaemia, baseline and nadir CRP levels (mg/L), and CRP kinetics status, CRP kinetics was an independent and significant factor for overall survival. The normalized CRP period was significantly correlated with the overall survival period in 52 patients who died. CONCLUSIONS: CRP kinetics is significantly associated with the prognosis and survival period of patients with advanced UC treated by chemotherapy. Although larger confirmatory studies are warranted to validate our results, CRP can potentially be a useful biomarker for patients with advanced UC. PMID- 22520734 TI - Small-cell cancer of the breast: what is the optimal treatment? A report and review of outcomes. PMID- 22520733 TI - Metronomic chemotherapy combined with bevacizumab and erlotinib in patients with metastatic HER2-negative breast cancer: clinical and biological activity. AB - The aim of this study was to determine the safety and efficacy of metronomic chemotherapy combined with targeted drugs in patients with metastatic breast cancer (MBC). We included 26 untreated patients with HER2-negative (HER-) MBC and poor hormone receptor expression. The analysis of the results suggests that the metronomic chemotherapy combined with bevacizumab and erlotinib is effective and well tolerated. BACKGROUND: The object of this study was to evaluate the safety and efficacy of metronomic chemotherapy in combination with bevacizumab and erlotinib in patients with HER2-negative (HER2(-)) metastatic breast cancer (MBC) and poor hormone receptor expression. PATIENTS AND METHODS: Patients with untreated MBC were candidates to receive metronomic oral capecitabine (500 mg thrice daily) and cyclophosphamide (50 mg daily) plus bevacizumab (15 mg/kg every 3 weeks) and erlotinib (100 mg daily). RESULTS: Of 24 patients assessable for response, we observed 1 complete response (CR, 4%), 14 partial responses (58%), 5 patients with stable disease greater than 9 weeks' duration (SD, 21%), and 1 patient (4%) with early progression of disease. The overall clinical benefit (CB) (CR + partial response + SD > 24 weeks) was 75% (95% confidence interval [CI], 53%-90%). Median time to progression was 43 weeks (95% CI, 21-69). Patients with low levels of circulating endothelial progenitors (CEPs) at baseline had a significantly improved progression-free survival (PFS). Toxicity was generally mild. Grade 3 toxicity included diarrhea (n = 1), thrombosis (n = 1), and hypertension (n = 2). Grade 2 adverse events included diarrhea (n = 5), hand-foot syndrome (n = 13), and hypertension (n = 4). CONCLUSION: Treatment with metronomic chemotherapy in combination with bevacizumab and erlotinib was effective in HER2(-), estrogen receptor (ER)- and progesterone receptor (PR)-poor advanced breast cancer. PMID- 22520735 TI - Colorectal and uterine movement and tension of the inferior hypogastric plexus in cadavers. AB - BACKGROUND: Hypotheses on somatovisceral dysfunction often assume interference by stretch or compression of the nerve supply to visceral structures. The purpose of this study is to examine the potential of pelvic visceral movement to create tension of the loose connective tissue that contains the fine branches of the inferior hypogastric nerve plexus. METHODS: Twenty eight embalmed human cadavers were examined. Pelvic visceral structures were displaced by very gentle 5 N unidirectional tension and the associated movement of the endopelvic fascia containing the inferior hypogastric plexus that this caused was measured. RESULTS: Most movement of the fascia containing the inferior hypogastric plexus was obtained by pulling the rectosigmoid junction or broad ligament of the uterus. The plexus did not cross any vertebral joints and the fascia containing it did not move on pulling the hypogastric nerve. CONCLUSIONS: Uterine and rectosigmoid displacement produce most movement of the fascia containing the hypogastric nerve plexus, potentially resulting in nerve tension. In the living this might occur as a consequence of menstruation, pregnancy or constipation. This may be relevant to somatovisceral reflex theories of the effects of manual therapy on visceral conditions. PMID- 22520736 TI - Genetics and diagnosis of central diabetes insipidus. AB - Most of the central diabetes insipidus cases seen in general practice are acquired but the rare cases of hereditary autosomal dominant or recessive neurohypophyseal diabetes insipidus have provided further cellular understanding of the mechanisms responsible for pre-hormone folding, maturation and release. Autosomal dominant central diabetes insipidus is secondary to the toxic accumulation of vasopressin mutants as fibrillar aggregates in the endoplasmic reticulum of hypothalamic magnocellular neurons producing vasopressin. As well, Trpv1(-/-) and Trpv4(-/-) mice have shed new light on the perception of tonicity through the stretch receptors TRPVs expressed both in central and peripheral neurons. The genomic information provided by sequencing the AVP gene is key to the routine care of these patients and, as in other genetic diseases, reduces health costs and provides psychological benefits to patients and families. In addition, simple, inexpensive blood and urine measurements together with clinical characteristics and brain magnetic resonance imaging (MRI) could distinguish between central, nephrogenic and polydipsic cases. PMID- 22520738 TI - Prediction of the outcome of short- and long-term psychotherapy based on socio demographic factors. AB - BACKGROUND: Socio-demographic factors predict the outcome of short-term psychotherapy (STT) in the treatment of mood and anxiety disorders, but information on the prediction for long long-term therapy (LPP) is lacking. We aimed to compare the prediction of changes in psychiatric symptoms afforded by socio-demographic factors across two treatment conditions, short- versus long term psychotherapy. METHODS: In the Helsinki Psychotherapy Study, 326 outpatients with mood or anxiety disorders, aged 20-46 years, were randomly assigned to STT or LPP. Socio-demographic factors (i.e. age, gender, education, employment status, marital status, and living arrangement) were self-reported. Psychiatric symptoms were measured by the Symptom Check List, Global Severity Index (SCL-90 GSI) and Anxiety scale (SCL-90-Anx), and the Beck Depression Inventory (BDI) at baseline and seven times during a three-year follow-up period. RESULTS: Socio demographic factors were found to predict symptom development during follow-up irrespective of the baseline symptom level. Patients in a relatively good position, i.e. married and highly educated patients benefited from STT, whereas patients in less advantaged positions, i.e. homemakers, lone parents, and divorced patients needed LPP or did not benefit from either therapy. In several categories of socio-demographic factors, the extent to which a patient's background predicted the outcome of the psychotherapy varied according to whether general, anxiety or depressive symptoms were studied. LIMITATIONS: We were unable to assess widows and pensioners. For ethical reasons, a no-treatment control group with a long follow-up could not be included in the study design. CONCLUSIONS: Socio-demographic factors may need to be considered in the selection of patients for short- and long-term therapy. PMID- 22520739 TI - Contrasting chronic with episodic depression: an analysis of distorted socio emotional information processing in chronic depression. AB - BACKGROUND: The specific features that differentiate chronic and episodic depression are widely unknown. This study compares the chronic and episodic form of depression with regard to two domains of socio-emotional information processing: Decoding of other people's emotional states (Theory of Mind) and the perception of own emotions (alexithymia). METHOD: This study compares 30 chronically and 29 episodically depressed patients by tapping into Theory of Mind deficits with a multi-method approach and by assessing alexithymic deficits. Furthermore, a retrospective assessment of adverse relational childhood experiences is administered. RESULTS: The observed results reveal distorted information processing in only one of the two domains: Chronically depressed patients scored higher in alexithymia than episodically depressed patients, while no group differences in the domain of Theory of Mind were found. Moreover, alexithymia was found to mediate the influence of adverse relational childhood experiences on depression type (chronic vs. episodic). LIMITATIONS: Due to the reliance on retrospective and self-report data, results should be interpreted with due caution. In addition, the cross-sectional design limits causal conclusions. CONCLUSIONS: These results suggest a potentially central role of the deficient perception of own emotions in causing or maintaining chronic depression. Derived practical implications include a focus on the perception of own emotions in the psychotherapy of chronic depression. If future research continues to uncover systematic differences in the psychopathology of chronic and episodic depression, chronicity should be more strongly considered when classifying unipolar depressive disorders. PMID- 22520740 TI - The concept of temperament in psychoactive substance use among college students. AB - BACKGROUND: Substance abuse is among the leading causes of preventable diseases and premature death but reasons and conditions leading to substance abuse are complex and multifaceted. Different models of abuse and dependence assume an underlying emotional vulnerability. Individual behavioral and emotional reactivity patterns of personality are considered in the concept of temperament but studies linking different types of temperament with substance use are rare. METHODS: In this study we investigated 1380 inhabitants (59.7% females; 40.3% males) of residential student homes in Austria, using Akiskals TEMPS-M auto questionnaire. Further, we administered the CAGE- and the HSI-questionnaire and assessed other psychoactive substance use to examine associations between traits of temperament and substance abuse using ordered logistic regression. RESULTS: Temperaments follow different distributions in both genders: Women have higher scores on the depressive, cyclothymic, and anxious subscales and lower scores on the hyperthymic scale than men. The cyclothymic and particularly irritable temperament serve as predictors of self-reported nicotine dependence, alcohol abuse and cannabis use. Interestingly, the depressive temperament seems to be protective against self-reported cannabis use. LIMITATIONS: Substance abuse assessment is based on self-reports only and urine drug and blood tests were not performed. Also, the history of substance abuse is not documented thus temperamental factors could have been influenced by substance abuse if the time of onset was in early adolescence. The study design was cross-sectional, thus limiting causal interpretations. CONCLUSIONS: It might be important to consider temperamental traits as protective- and risk factors in the etiology, prevention and therapy of substance abuse in future. PMID- 22520741 TI - Development and study of novel non-contact ultrasonic motor based on principle of structural asymmetry. AB - The article presents novel design of non-contact rotary ultrasonic motor consisting of ring-shaped stator vibrating in in-plane flexural mode and rotor provided with blades. In contrast to other motors with similar design proposed motor relies on the use of standing ultrasonic waves. This simplifies design and electronic control of motor and becomes possible due to introduction of artificial asymmetry, for example by tilting one or several blades of the rotor relative to the surface normal. Operating principle of the proposed motor is based on acoustic radiation torque exerted on rotor by ultrasonic waves propagating in air or fluid gap between rotor and stator. This torque is calculated using finite element method by means of COMSOL Multiphysics software. Dynamics of rotor is studied using MathCad software and general theory of nonlinear conservative oscillators. Role of asymmetry is explained on the basis of comparative analysis of potential functions and phase trajectories for symmetric and asymmetric cases. It is shown that direction of rotation is determined by structural parameters of motor, particularly tilting direction (clockwise or counter-clockwise) of the blades. Conceptual design of motor with bidirectional rotation is described. Direction and velocity of rotation in the proposed conceptual design can be potentially controlled by changing excitation frequency of stator. PMID- 22520742 TI - Health-related quality of life in cancer patients at the end of life, translation, validation, and longitudinal analysis of specific tools: study protocol for a randomized controlled trial. AB - BACKGROUND: The end of life for cancer patients is the ultimate stage of the disease, and care in this setting is important as it can improve the wellbeing not only of patients, but also the patients' family and close friends. As it is a matter of profoundly personal concerns, patients' perception of this phase of the disease is difficult to assess and has thus been insufficiently studied. Nonetheless, caregivers are required to provide specific care to help patients and to treat them in order to improve their wellbeing during this period.While tools to assess health-related quality of life (QoL) in cancer patients at the end of life exist in English, to our knowledge, no validated tools are available in French. METHODS/DESIGN: This randomized multicenter cohort study will be carried out to cross-culturally adapt and validate a French version of the English QUAL-E and the Missoula Vitas Quality Of Life Index (MVQOLI) questionnaires for advanced cancer patients in a palliative setting. A randomized clinical trial component in addition to a cohort study is implemented in order to test psychometric hypotheses: order effect and improvement of sensibility to change.The validation procedure will ensure that the psychometric properties are maintained.The main criterion to assess the reliability of the questionnaires will be reproducibility (test-retest method) using intraclass correlation coefficients. It will be necessary to include 372 patients. The sensitivity to change, discriminant capability as well as convergent validity will be also investigated. DISCUSSION: If the cross-cultural validation of the MVQOLI and QUAL E questionnaires for advanced cancer patients in a palliative setting have satisfactory psychometric properties, it will allow us to assess the specific dimensions of QoL at the end of life. TRIAL REGISTRATION: Current Controlled Trials NCT01545921. PMID- 22520744 TI - Can physicians' judgments of futility be accepted by patients? A comparative survey of Japanese physicians and laypeople. AB - BACKGROUND: Empirical surveys about medical futility are scarce relative to its theoretical assumptions. We aimed to evaluate the difference of attitudes between laypeople and physicians towards the issue. METHODS: A questionnaire survey was designed. Japanese laypeople (via Internet) and physicians with various specialties (via paper-and-pencil questionnaire) were asked about whether they would provide potentially futile treatments for end-of-life patients in vignettes, important factors for judging a certain treatment futile, and threshold of quantitative futility which reflects the numerical probability that an act will produce the desired physiological effect. Also, the physicians were asked about their practical frequency and important reasons for futile treatments. RESULTS: 1134 laypeople and 401 (80%) physicians responded. In all vignettes, the laypeople were more affirmative in providing treatments in question significantly. As the factors for judging futility, medical information and quality of life (QOL) of the patient were rather stressed by the physicians. Treatment wish of the family of the patient and psychological impact on patient side due to the treatment were rather stressed by laypeople. There were wide variations in the threshold of judging quantitative futility in both groups. 88.3% of the physicians had practical experience of providing futile treatment. Important reasons for it were communication problem with patient side and lack of systems regarding futility or foregoing such treatment. CONCLUSION: Laypeople are more supportive of providing potentially futile treatments than physicians. The difference is explained by the importance of medical information, the patient family's influence to decision-making and QOL of the patient. The threshold of qualitative futility is suggested to be arbitrary. PMID- 22520743 TI - Impact of antiviral treatment and hospital admission delay on risk of death associated with 2009 A/H1N1 pandemic influenza in Mexico. AB - BACKGROUND: Increasing our understanding of the factors affecting the severity of the 2009 A/H1N1 influenza pandemic in different regions of the world could lead to improved clinical practice and mitigation strategies for future influenza pandemics. Even though a number of studies have shed light into the risk factors associated with severe outcomes of 2009 A/H1N1 influenza infections in different populations, analyses of the determinants of mortality risk spanning multiple pandemic waves and geographic regions are scarce. Between-country differences in the mortality burden of the 2009 pandemic could be linked to differences in influenza case management, underlying population health, or intrinsic differences in disease transmission. Additional studies elucidating the determinants of disease severity globally are warranted to guide prevention efforts in future influenza pandemics.In Mexico, the 2009 A/H1N1 influenza pandemic was characterized by a three-wave pattern occurring in the spring, summer, and fall of 2009 with substantial geographical heterogeneity. A recent study suggests that Mexico experienced high excess mortality burden during the 2009 A/H1N1 influenza pandemic relative to other countries. However, an assessment of potential factors that contributed to the relatively high pandemic death toll in Mexico are lacking. Here, we fill this gap by analyzing a large series of laboratory confirmed A/H1N1 influenza cases, hospitalizations, and deaths monitored by the Mexican Social Security medical system during April 1 through December 31, 2009 in Mexico. In particular, we quantify the association between disease severity, hospital admission delays, and neuraminidase inhibitor use by demographic characteristics, pandemic wave, and geographic regions of Mexico. METHODS: We analyzed a large series of laboratory-confirmed pandemic A/H1N1 influenza cases from a prospective surveillance system maintained by the Mexican Social Security system, April-December 2009. We considered a spectrum of disease severity encompassing outpatient visits, hospitalizations, and deaths, and recorded demographic and geographic information on individual patients. We assessed the impact of neuraminidase inhibitor treatment and hospital admission delay (<= > 2 days after disease onset) on the risk of death by multivariate logistic regression. RESULTS: Approximately 50% of all A/H1N1-positive patients received antiviral medication during the Spring and Summer 2009 pandemic waves in Mexico while only 9% of A/H1N1 cases received antiviral medications during the fall wave (P < 0.0001). After adjustment for age, gender, and geography, antiviral treatment significantly reduced the risk of death (OR = 0.52 (95% CI: 0.30, 0.90)) while longer hospital admission delays increased the risk of death by 2.8 fold (95% CI: 2.25, 3.41). CONCLUSIONS: Our findings underscore the potential impact of decreasing admission delays and increasing antiviral use to mitigate the mortality burden of future influenza pandemics. PMID- 22520745 TI - Targeted therapies for hepatitis C reach the clinic. PMID- 22520746 TI - Biology evolves to fight chemistry. AB - A human enzyme variant, PON1-G3C9, accidentally catalyzes the hydrolysis of organophosphorus chemical weapons. In this issue of Chemistry & Biology, Goldsmith and coworkers describe a new PON1 variant with improved hydrolysis by several hundred fold; enough that it may protect animals from a toxic dose. PMID- 22520747 TI - Selective inhibition of USP7. AB - The deubiquitinating enzyme USP7 is an emerging oncology and antiviral target. Reverdy et al., in this issue of Chemistry & Biology, disclose the first small molecule inhibitor selective for USP7, which recapitulates its knockdown in cancer cells and hence demonstrates the therapeutic feasibility of USP7 inhibitors. PMID- 22520748 TI - Evolution finds shelter in small spaces. AB - When RNA is replicated in cell-free systems, a ubiquitous problem is the hijacking of the system by short parasitic RNA sequences. In this issue of Chemistry & Biology, Bansho et al. show that compartmentalization into water-in oil droplets can ameliorate this problem, but only if the droplets are small. This result helps to both recapitulate abiogenesis and optimize synthetic biology. PMID- 22520749 TI - Designing chimeric LOV photoswitches. AB - The LOV domain from Avena sativa has a C-terminal (Jalpha) helix that dissociates and unfolds when the protein is exposed to blue light. Using computational protein design methods, Lungu et al., in this issue of Chemistry & Biology, created chimeric Jalpha sequences that show photo-controlled interactions with chosen targets. PMID- 22520750 TI - Insights into quinaldic acid moiety formation in thiostrepton biosynthesis facilitating fluorinated thiopeptide generation. AB - Thiostrepton (TSR), often referred as to a parent compound in the thiopeptide family, is a bimacrocyclic member that features a quinaldic acid (QA) moiety containing side ring appended to the characteristic core system. QA biosynthesis requires an unusual ring-expanding conversion, showing a methyl transfer onto and a rearrangement of the indole part of L-tryptophan to give a quinoline ketone. Herein, we report that the process involves the activities of the radical methyltransferase TsrT, aminotransferase TsrA, dehydrogenase TsrE, and cyclase TsrD. TsrU, a stereospecific oxidoreductase, catalyzes the further conversion of the ketone into an enantiomerically pure S-alcohol. Elucidation of this chemistry, which is common in the biosynthesis of a number of thiopeptides sharing a QA side ring system, facilitates analog generation, as shown by the achievement of region-specific fluorination of thiostrepton with the improved antibacterial activity. PMID- 22520751 TI - Structure-based design of supercharged, highly thermoresistant antibodies. AB - Mutation of surface residues to charged amino acids increases resistance to aggregation and can enable reversible unfolding. We have developed a protocol using the Rosetta computational design package that "supercharges" proteins while considering the energetic implications of each mutation. Using a homology model, a single-chain variable fragment antibody was designed that has a markedly enhanced resistance to thermal inactivation and displays an unanticipated ~30 fold improvement in affinity. Such supercharged antibodies should prove useful for assays in resource-limited settings and for developing reagents with improved shelf lives. PMID- 22520752 TI - Evolved stereoselective hydrolases for broad-spectrum G-type nerve agent detoxification. AB - A preferred strategy for preventing nerve agents intoxication is catalytic scavenging by enzymes that hydrolyze them before they reach their targets. Using directed evolution, we simultaneously enhanced the activity of a previously described serum paraoxonase 1 (PON1) variant for hydrolysis of the toxic S(P) isomers of the most threatening G-type nerve agents. The evolved variants show <=340-fold increased rates and catalytic efficiencies of 0.2-5 * 10(7) M(-1) min( 1). Our selection for prevention of acetylcholinesterase inhibition also resulted in the complete reversion of PON1's stereospecificity, from an enantiomeric ratio (E) < 6.3 * 10(-4) in favor of the R(P) isomer of a cyclosarin analog in wild type PON1, to E > 2,500 for the S(P) isomer in an evolved variant. Given their ability to hydrolyze G-agents, these evolved variants may serve as broad-range G agent prophylactics. PMID- 22520753 TI - Discovery of specific inhibitors of human USP7/HAUSP deubiquitinating enzyme. AB - The human USP7 deubiquitinating enzyme was shown to regulate many proteins involved in the cell cycle, as well as tumor suppressors and oncogenes. Thus, USP7 offers a promising, strategic target for cancer therapy. Using biochemical assays and activity-based protein profiling in living systems, we identified small-molecule antagonists of USP7 and demonstrated USP7 inhibitor occupancy and selectivity in cancer cell lines. These compounds bind USP7 in the active site through a covalent mechanism. In cancer cells, these active-site-targeting inhibitors were shown to regulate the level of several USP7 substrates and thus recapitulated the USP7 knockdown phenotype that leads to G1 arrest in colon cancer cells. The data presented in this report provide proof of principle that USP7 inhibitors may be a valuable therapeutic for cancer. In addition, the discovery of such molecules offers interesting tools for studying deubiquitination. PMID- 22520754 TI - Importance of parasite RNA species repression for prolonged translation-coupled RNA self-replication. AB - Increasingly complex reactions are being constructed by bottom-up approaches with the aim of developing an artificial cell. We have been engaged in the construction of a translation-coupled replication system of genetic information from RNA and a reconstituted translation system. Here a mathematical model was established to gain a quantitative understanding of the complex reaction network. The sensitivity analysis predicted that the limiting factor for the present replication reaction was the appearance of parasitic replicators. We then confirmed experimentally that repression of such parasitic replicators by compartmentalization of the reaction in water-in-oil emulsions improved the duration of self-replication. We also found that the main source of the parasite was genomic RNA, probably by nonhomologous recombination. This result provided experimental evidence for the importance of parasite repression for the development of long-lasting genome replication systems. PMID- 22520755 TI - Blockade of inflammatory responses by a small-molecule inhibitor of the Rac activator DOCK2. AB - Tissue infiltration of activated lymphocytes is a hallmark of transplant rejection and organ-specific autoimmune diseases. Migration and activation of lymphocytes depend on DOCK2, an atypical Rac activator predominantly expressed in hematopoietic cells. Although DOCK2 does not contain Dbl homology domain typically found in guanine nucleotide exchange factors, DOCK2 mediates the GTP GDP exchange reaction for Rac through its DHR-2 domain. Here, we have identified 4-[3'-(2"-chlorophenyl)-2'-propen-1'-ylidene]-1-phenyl-3,5-pyrazolidinedione (CPYPP) as a small-molecule inhibitor of DOCK2. CPYPP bound to DOCK2 DHR-2 domain in a reversible manner and inhibited its catalytic activity in vitro. When lymphocytes were treated with CPYPP, both chemokine receptor- and antigen receptor-mediated Rac activation were blocked, resulting in marked reduction of chemotactic response and T cell activation. These results provide a rational of and a chemical scaffold for development of the DOCK2-targeting immunosuppressant. PMID- 22520756 TI - MmpL genes are associated with mycolic acid metabolism in mycobacteria and corynebacteria. AB - Mycolic acids are vital components of the cell wall of the tubercle bacillus Mycobacterium tuberculosis and are required for viability and virulence. While mycolic acid biosynthesis is studied extensively, components involved in mycolate transport remain unidentified. We investigated the role of large membrane proteins encoded by mmpL genes in mycolic acid transport in mycobacteria and the related corynebacteria. MmpL3 was found to be essential in mycobacteria and conditional depletion of MmpL3 in Mycobacterium smegmatis resulted in loss of cell wall mycolylation, and of the cell wall-associated glycolipid, trehalose dimycolate. In parallel, an accumulation of trehalose monomycolate (TMM) was observed, suggesting that mycolic acids were transported as TMM. In contrast to mycobacteria, we found redundancy in the role of two mmpL genes, in Corynebacterium glutamicum; a complete loss of trehalose-associated and cell wall bound corynomycolates was observed in an NCgl0228-NCgl2769 double mutant, but not in individual single mutants. Our studies highlight the role of mmpL genes in mycolic acid metabolism and identify potential new targets for anti-TB drug development. PMID- 22520757 TI - Designing photoswitchable peptides using the AsLOV2 domain. AB - Photocontrol of functional peptides is a powerful tool for spatial and temporal control of cell signaling events. We show that the genetically encoded light sensitive LOV2 domain of Avena Sativa phototropin 1 (AsLOV2) can be used to reversibly photomodulate the affinity of peptides for their binding partners. Sequence analysis and molecular modeling were used to embed two peptides into the Jalpha helix of the AsLOV2 domain while maintaining AsLOV2 structure in the dark but allowing for binding to effector proteins when the Jalpha helix unfolds in the light. Caged versions of the ipaA and SsrA peptides, LOV-ipaA and LOV-SsrA, bind their targets with 49- and 8-fold enhanced affinity in the light, respectively. These switches can be used as general tools for light-dependent colocalization, which we demonstrate with photo-activable gene transcription in yeast. PMID- 22520758 TI - Identification and characterization of small molecule antagonists of pRb inactivation by viral oncoproteins. AB - The retinoblastoma protein pRb is essential for regulating many cellular activities through its binding and inhibition of E2F transcription activators, and pRb inactivation leads to many cancers. pRb activity can be perturbed by viral oncoproteins including human papillomavirus (HPV) that share an LxCxE motif. Because there are no treatments for existing HPV infection leading to nearly all cervical cancers and other cancers to a lesser extent, we screened for compounds that inhibit the ability of HPV-E7 to disrupt pRb/E2F complexes. This lead to the identification of thiadiazolidinedione compounds that bind to pRb with mid-high nanomolar dissociation constants, are competitive with the binding of viral oncoproteins containing an LxCxE motif, and are selectively cytotoxic in HPV-positive cells alone and in mice. These inhibitors provide a promising scaffold for the development of therapies to treat HPV-mediated pathologies. PMID- 22520759 TI - Small-molecule inhibitors of the c-Fes protein-tyrosine kinase. AB - The c-Fes protein-tyrosine kinase modulates cellular signaling pathways governing differentiation, the innate immune response, and vasculogenesis. Here, we report the identification of types I and II kinase inhibitors with potent activity against c-Fes both in vitro and in cell-based assays. One of the most potent inhibitors is the previously described anaplastic lymphoma kinase inhibitor TAE684. The crystal structure of TAE684 in complex with the c-Fes SH2-kinase domain showed excellent shape complementarity with the ATP-binding pocket and a key role for the gatekeeper methionine in the inhibitory mechanism. TAE684 and two pyrazolopyrimidines with nanomolar potency against c-Fes in vitro were used to establish a role for this kinase in osteoclastogenesis, illustrating the value of these inhibitors as tool compounds to probe the diverse biological functions associated with this unique kinase. PMID- 22520760 TI - The antidepressant drug fluoxetine inhibits persistent sodium currents and seizure-like events. AB - The antidepressant drug fluoxetine (FLX) has been shown to exert antiepileptic effects in several animal models, but mixed preclinical findings and occasional reports of proconvulsant effects have led to hesitation towards its use in epileptic people. Despite being developed as a selective serotonin reuptake inhibitor, FLX has numerous other targets in the brain. One of the proposed targets is the neuronal sodium channel, which is inhibited by many existing antiepileptic drugs. In this study, we used electrophysiological methods in a brain slice model of seizures to test for anticonvulsant and Na(+) channel blocking effects of FLX. This approach allowed us to use a single biological system to study the effects of FLX on (1) epileptiform activity, (2) Na(+) dependent action potential generation, and (3) the persistent Na(+) current (I(NaP)). We found that FLX was anticonvulsant in a dose- and time-dependent manner, and that this action was accompanied by strong I(NaP) inhibition and impairment of repetitive firing. These findings suggest that the effect of FLX on active membrane properties is similar to that of many antiepileptic drugs, and that this action may contribute to anticonvulsant effects. PMID- 22520762 TI - COPD in primary care: from episodic to continual management. PMID- 22520763 TI - Preventing unintentional injuries: what does NICE guidance mean for primary care? PMID- 22520764 TI - Dementia: commissioning for quality. PMID- 22520765 TI - Shisha guidance for GPs: eliciting the hidden history. PMID- 22520766 TI - Difficulties in differential diagnosis of COPD and asthma in primary care. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) and asthma treatment must be based on appropriate diagnosis. However, patients receiving inhaled therapy in primary care may not be accurately diagnosed according to current guidelines. AIM: To analyse the characteristics of patients treated with inhaled medication, the concordance of tools for differential diagnosis, and the adequacy of prescription of inhaled corticosteroids (ICs) in primary care. DESIGN AND SETTING: Cross-sectional, multicentre, non-interventional study conducted in 10 primary care centres in Barcelona, Spain. METHOD: Patients with chronic respiratory disease, aged >40 years were treated with ICs. They provided sociodemographic and clinical information and performed forced spirometry with a bronchodilator test (BDT). The diagnostic accuracy of asthma and COPD diagnoses were tested using two differential diagnosis questionnaires. RESULTS: A total of 328 patients were initially classified as having COPD (64.8%), asthma (15.4%), or indeterminate (19.8%) by their GPs. After spirometry, 40% of patients had moderate-severe airflow obstruction according to the GOLD classification; mean reversibility of forced expiratory volume in 1 second (FEV1) was 8.4%; 18.6% had a positive BDT; and 39.8% had post-bronchodilator FEV1/forced vital capacity >0.7. Concordance of the differential diagnosis tools was moderate (clinical diagnosis versus spirometry and between the two questionnaires), low (clinical diagnosis versus questionnaires), and very low (spirometry versus differential diagnosis). Of the patients diagnosed with COPD, 71.4% were treated with ICs, and 12% of those classified as having asthma were not receiving ICs. CONCLUSION: Most patients can be classified as having COPD or asthma by primary care physicians. The use of the two questionnaires did not provide a better differential diagnostic compared with symptoms and spirometry with a BDT. Misdiagnosis may lead to inadequate treatment. PMID- 22520767 TI - A systematic review: the role of spirituality in reducing depression in people living with HIV/AIDS. PMID- 22520768 TI - Buprenorphine versus methadone use in opiate detoxification, are there other factors that should be considered? PMID- 22520769 TI - QOF should be more about disease and risk factors prevention. PMID- 22520770 TI - What do we actually know about the referral process? PMID- 22520771 TI - A non-traditional method of teaching general practice to medical students: notes summarising. PMID- 22520772 TI - Physical activity and health: it is a democratic right to ignore scientific evidence and common sense, but it is not wise. PMID- 22520773 TI - Effect of ethnicity on the prevalence, severity, and management of COPD in general practice. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) remains a major cause of mortality and hospital use. Little is known in the UK about the variation in COPD prevalence, severity, and management depending on ethnicity. AIM: To examine differences by ethnicity in COPD prevalence, severity, and management. DESIGN & SETTING: Cross-sectional study using routinely collected computerised data from general practice in three east-London primary care trusts (Newham, Tower Hamlets, and City and Hackney) with multiethnic populations of people who are socially deprived. METHOD: Routine demographic, clinical, and hospital admission data from 140 practices were collected. RESULTS: Crude COPD prevalence was 0.9%; the highest recorded rates were in the white population. Severity of COPD, measured by percentage-predicted forced expiratory volume in 1 second, did not vary by ethnicity. South Asians and black patients were less likely than white patients to have breathlessness, indicated by a Medical Research Council dyspnoea grade of >=4 (odds ratio [OR] 0.7 [95% confidence interval (CI) = 0.6 to 0.9] and 0.6 [95% CI = 0.4 to 0.8]). Black patients were less likely than white patients to receive inhaled medications. Influenza and pneumococcal vaccine rates were highest among groups of South Asians (OR 3.0 [95% CI = 2.1 to 4.3] and 1.8 [95% CI = 1.4 to 2.3] respectively). Both minority ethnic groups had low referral rates to pulmonary rehabilitation. In Tower Hamlets, black patients were more likely to be admitted to hospital for respiratory causes. CONCLUSION: Differences in COPD prevalence and severity by ethnicity were identified, and significant differences in drug and non-drug management and hospital admissions observed. Systematic ethnicity recording in general practice is needed to be able to explore such differences and monitor inequalities in healthcare by ethnicity. PMID- 22520774 TI - Making a successful return to work: the UK burden of injury multicentre longitudinal study. AB - BACKGROUND: Injuries are common and make a significant contribution to sickness absence, but little is known about problems experienced by injured people on return to work (RTW). AIM: To quantify work problems on RTW and explore predictors of such problems. DESIGN & SETTING: Multicentre longitudinal study in four UK hospitals. METHOD: Prospective study of injured participants aged 16-65 years who were employed or self-employed prior to the injury and had RTW at 1 or 4 months post injury. RESULTS: At 1 month, most (59%) had only made a partial RTW. By 4 months, 80% had fully RTW. Those who had partially RTW had problems related to physical tasks (work limited for median of 25% of time at 1 month, 18% at 4 months), time management (10% at 1 month, 20% at 4 months) and output demands (10% at 1 month, 15% at 4 months). Productivity losses were significantly greater among those with partial than full RTW at 1 month (median 3.3% versus 0.9%, P<0.001) and 4 months (median 4.6% versus 1.1% P = 0.03). Moderate/severe injuries (relative risk [RR] 1.93, 95% confidence interval [CI] = 1.35 to 2.77) and sports injuries (RR 1.73, 95% CI = 1.12 to 2.67) were associated with significantly greater productivity losses at 1 month while pre-existing long-term illnesses (RR 2.12, 95% CI = 1.38 to 3.27) and upper limb injuries (RR 1.64, 95% CI = 1.06 to 2.53) were at 4 months. CONCLUSION: Injuries impact on successful RTW for at least 4 months. Those who have only partially RTW experience the most problems and GPs should pay particular attention to identifying work problems in this group and ways of minimising such problems. PMID- 22520775 TI - Quality of care provided to people with dementia: utilisation and quality of the annual dementia review in general practice. AB - BACKGROUND: Primary care services are often the main healthcare service for people with dementia; as such, good-quality care at this level is important. AIM: To measure the quality of care provided to people with dementia in general practice using routinely collected data, and to explore associated patient and practice factors. DESIGN AND SETTING: Observational, cross-sectional review of medical records from general practices (n = 52) in five primary care trusts. METHOD: A total of 994 people with dementia were identified from dementia registers. An unweighted quality-of-care score was constructed using information collected in the annual dementia review, together with pharmacological management of cognitive and non-cognitive symptoms. Multilevel modelling was carried out to identify factors associated with quality-of-care scores. RESULTS: In total, 599 out of 745 (80%) patients with dementia had received an annual dementia review; however, a social care review or discussion with carers was evident in just 305 (51%) and 367 (61%) of those 599 cases, respectively. Despite high prevalence of vascular disease, over a quarter (n = 259, 26%) of all patients with dementia were prescribed antipsychotics; only 57% (n = 148) of these had undergone medication review in the previous 6 months. Those with vascular dementia who were registered with single-handed practices received poorer quality of care than those registered with practices that had more than one GP. CONCLUSION: Although the number of people with dementia with a record of an annual dementia review is high, the quality of these reviews is suboptimal. The quality score developed in this study could be used as one source of data to identify weaknesses in practice activity that need to be corrected, and so would be of value to commissioners and regulators, as well as practices themselves. PMID- 22520776 TI - Why bother talking to teenagers? PMID- 22520777 TI - Good health has little to do with doctors, Mr Lansley. PMID- 22520778 TI - Choosing to die. PMID- 22520780 TI - Denunciation: a new threat to access to health care for undocumented migrants. PMID- 22520783 TI - Healthy new year. PMID- 22520782 TI - Prevalence of causes of insomnia in primary care: a cross-sectional study. AB - BACKGROUND: As a result of a research interest in primary insomnia, the prevalence of other causes of insomnia in primary care must be ascertained. No source was found in the literature. It is also essential to know the epidemiology of the common causes of a condition to make an accurate diagnosis in primary care. AIM: To determine the prevalence of causes of insomnia in primary care, as part of a method of identifying patients with primary insomnia. DESIGN AND SETTING: Cross-sectional study in three general practices in Auckland, New Zealand. METHOD: Consecutive patients from the waiting room were asked to complete a nine-page questionnaire on possible causes of insomnia. RESULTS: In total, 1517 patients were approached and 955 completed the nine-page questionnaire (63%). Of the 41% (388) who reported difficulty with sleeping, primary insomnia occurred in 12% (45) of the population (95% confidence interval = 9% to 15%); 50% (195) had depression, 48% (185) had anxiety and 43% (165) had general (physical) health problems. Obstructive sleep apnoea occurred in 9% (34) and delayed sleep phase disorder in 2% (7). Only primary insomnia and delayed sleep phase disorder are mutually exclusive; the others can co-exist. CONCLUSION: This is the first description of the prevalence of causes of insomnia in primary care. It is hoped that the focus on primary insomnia will result in more behavioural treatments and lower the use of hypnotics in primary care; it should also assist in the appropriate detection and treatment of other causes of insomnia in primary care. PMID- 22520784 TI - Factors associated with duration of new antidepressant treatment: analysis of a large primary care database. AB - BACKGROUND: It is not known how much the duration of newly prescribed antidepressant treatment is influenced by patient characteristics or practice variation. AIM: To describe the relationship between patient characteristics and the duration of new antidepressant treatment by general practices. DESIGN AND SETTING: Large primary care database cohort study of all patients with a newly initiated course of eligible antidepressant treatment during 1 year, from a database of 237 Scottish practices. METHOD: Detailed prescription data were used to estimate the duration of new antidepressant treatment for each patient. Cox proportional hazards regression was used to estimate the influence of patient characteristics on continuation of treatment and, by multilevel modelling, the variation between practices. RESULTS: A total of 28 027 (2.2%) patients commenced antidepressant treatment during the year; 75% continued beyond 30 days, 56% beyond 90 days, and 40% beyond 180 days. Treatment was less likely to be continued in patients from areas of high socioeconomic deprivation: hazard ratio 1.22 (95% confidence interval [CI] = 1.16 to 1.29); in patients under 35 years, 1.33 (95% CI = 1.28 to 1.37); and in those for whom the GP recorded no relevant diagnostic code, 1.16 (95% CI = 1.13 to 1.18). Models accounted for between 2.2% and 3.9% of the variation in treatment duration. CONCLUSION: Patient demographic characteristics account for relatively little variation in the duration of new antidepressant treatment, though treatment was shorter in younger patients and those with greater socioeconomic deprivation. There is variation in treatment duration between practices and according to whether patients have a depression diagnosis coded in their records. PMID- 22520785 TI - How to afford a just health service. PMID- 22520786 TI - Air travel for patients with chronic obstructive pulmonary disease: a case report. PMID- 22520787 TI - Tips for GP trainees working in respiratory medicine. PMID- 22520789 TI - Important treatment aims at the end of life: a nationwide study among GPs. AB - BACKGROUND: Little is known about treatment aims during the last 3 months of life. AIM: To investigate important treatment aims in the last 3 months of patients' lives in cases of non-sudden death. DESIGN AND SETTING: Mortality follow-back study in The Netherlands. METHOD: Data were collected retrospectively in 2009 within the representative Sentinel Network of GPs in The Netherlands. GPs completed a standardised registration form. RESULTS: Data for 279 patients were studied. Of these, 55% died of cancer and 45% of another disease. Treatment was aimed at palliation for 73% of the patients in months 2 and 3 before death, and for 95% of the patients in the last week of life. Seven per cent received treatment aimed at cure in the last week of life. In a minority of patients, cure/life prolongation and palliation were simultaneously important treatment aims. In the last week of life and in the 2-4 weeks before death, cure was more frequently reported as an important treatment aim in patients with a non-cancer disease than in patients with cancer. In the 2-4 weeks before death, palliation was an important treatment aim for a larger proportion of patients with cancer than patients with other diseases. CONCLUSION: Registration by GPs show that, in the last weeks and days of life, cure was more frequently reported as an important treatment aim in patients with a non-cancer disease than in patients with cancer. For a small number of patients, palliation and cure/life prolongation were simultaneously important treatment aims. PMID- 22520788 TI - Anticipatory care planning and integration: a primary care pilot study aimed at reducing unplanned hospitalisation. AB - BACKGROUND: Anticipatory care for older patients who are frail involves both case identification and proactive intervention to reduce hospitalisation. AIM: To identify a population who were at risk of admission to hospital and to provide an anticipatory care plan (ACP) for them and to ascertain whether using primary and secondary care data to identify this population and then applying an ACP can help to reduce hospital admission rates. DESIGN AND SETTING: Cohort study of a service intervention in a general practice and a primary care team in Scotland. METHOD: The ACP sets out patients' wishes in the event of a sudden deterioration in health. If admitted, a proactive approach was taken to transfer and discharge patients into the community. Cohorts were selected using the Nairn Case Finder, which matched patients in two practices for age, sex, multiple morbidity indexes, and secondary care outpatient and inpatient activity; 96 patients in each practice were studied for admission rate, occupied bed days and survival. RESULTS: Survivors from the ACP cohort (n = 80) had 510 fewer days in hospital than in the 12 months pre-intervention: a significant reduction of 52.0% (P = 0.020). There were 37 fewer admissions of the survivors from that cohort post intervention than in the preceding 12 months, with a significant reduction of 42.5% (P = 0.002). Mortality rates in the two cohorts were similar, but the number of patients who died in hospital and the hospital bed days used in the last 3 months of life were significantly lower for the decedents with an ACP than for the controls who had died (P = 0.007 and P = 0.045 respectively). CONCLUSION: This approach produced statistically significant reductions in unplanned hospitalisation for a cohort of patients with multiple morbidities. It demonstrates the potential for providing better care for patients as well as better value for health and social care services. It is of particular benefit in managing end-of-life care. PMID- 22520790 TI - Primary-care based participatory rehabilitation: users' views of a horticultural and arts project. AB - BACKGROUND: Participation in horticulture and arts may improve wellbeing in those with mental and physical illness. AIM: To conduct an in-depth exploration of the views and experience of participants of a primary-care-based horticultural and participatory arts rehabilitation project (Sydenham Garden). DESIGN AND SETTING: Qualitative interview study of a primary-care-based horticultural and participatory arts rehabilitation project in South London. METHOD: Semi structured interviews were conducted with 16 participants (referred to as 'coworkers') of Sydenham Garden. Seven were female. Participants were aged between 38 and 91 years and had a range of severe mental and physical health problems; most had depression. The interviews were analysed using constant comparison and thematic analysis. RESULTS: Data were overwhelmingly positive concerning participation. Coworkers considered participation in the project to promote wellbeing by providing purposeful and enjoyable activity and interest, improving mood and self-perceptions, and providing an escape from life's pressures. Being outdoors was considered therapeutic. The most-valued aspect of participation was the social contact derived as a result of it. Many of the coworkers who were interviewed developed transferable skills, including nationally recognised qualifications, which they valued highly. CONCLUSION: Delivery of horticultural therapy and participatory arts is a feasible model for improving wellbeing in patients in primary care who have serious illness. Longer term studies are needed to address what happens to people after leaving such projects. PMID- 22520791 TI - Patients' experiences of self-monitoring blood pressure and self-titration of medication: the TASMINH2 trial qualitative study. AB - BACKGROUND: Self-management of hypertension, comprising self-monitoring of blood pressure with self-titration of medication, improves blood pressure control, but little is known regarding the views of patients undertaking it. AIM: To explore patients' views of self-monitoring blood pressure and self-titration of antihypertensive medication. DESIGN AND SETTING: Qualitative study embedded within the randomised controlled trial TASMINH2 (Telemonitoirng and Self Management in the Control of Hypertension) trial of patient self-management of hypertension from 24 general practices in the West Midlands. METHOD: Taped and transcribed semi-structured interviews with 23 intervention patients were used. Six family members were also interviewed. Analysis was by a constant comparative method. RESULTS: Patients were confident about self-monitoring and many felt their multiple home readings were more valid than single office readings taken by their GP. Although many patients self-titrated medication when required, others lacked the confidence to increase medication without reconsulting with their GP. Patients were more comfortable with titrating medication if their blood pressure readings were substantially above target, but were reluctant to implement such a change if readings were borderline. Many planned to continue self-monitoring after the study finished and report home readings to their GP, but few wished to continue with a self-management plan. CONCLUSION: Participants valued the additional information and many felt confident in both self-monitoring blood pressure and self-titrating medication. The reluctance to change medication for borderline readings suggests behaviour similar to the clinical inertia seen for physicians in analogous circumstances. Additional support for those lacking in confidence to implement prearranged medication changes may allow more patients to undertake self-management. PMID- 22520792 TI - Ethics of the ordinary: a class response. PMID- 22520793 TI - Fit for work? Changing fit note practice among GPs. PMID- 22520794 TI - Transcatheter aortic valve replacement: a breakthrough medical therapy! The 20 year odyssey, and now, a 10-year anniversary. PMID- 22520795 TI - Prospective analysis of 30-day safety and performance of transfemoral transcatheter aortic valve implantation with Edwards SAPIEN XT versus SAPIEN prostheses. AB - BACKGROUND: A new generation of balloon-expandable valves (e.g. Edwards SAPIEN XT) enables the use of a decreased sheath size using the NovaFlexTM delivery system for transfemoral transcatheter aortic valve implantation (TAVI). However, there are few data analysing the efficacy and safety of this new prosthesis. AIMS: To evaluate periprocedural and 30-day clinical outcomes using the Edwards SAPIEN XT compared with the first-generation Edwards SAPIEN prosthesis. METHODS: Between May 2006 and October 2011, consecutive high-risk or non-operable patients with severe aortic stenosis had TAVI using an Edwards SAPIEN or SAPIEN XT prosthesis. Valve Academic Research Consortium endpoints were used. RESULTS: Of 250 patients who underwent TAVI, 190 were performed transfemorally (78 SAPIEN and 112 SAPIEN XT). Transfemoral access was possible more often using SAPIEN XT (112/123 [91.1%] vs 78/127 [61.4%]; P<0.001). Mean logistic EuroSCORE was significantly lower in the SAPIEN XT group (18.1+/-11.0% vs 27.3+/-11.1%; P<0.0001), and the iliofemoral artery minimal lumen diameter was smaller (6.7+/ 1.2 vs 8.5+/-1.3mm; P<0.0001). Device success was similar in both groups (95.5% for SAPIEN XT and 93.6% for SAPIEN), as was the 30-day combined safety endpoint (15.2% and 17.9%, respectively). At 30days, prosthesis performance was similar in both groups. CONCLUSIONS: Short-term safety and performance analysis of the latest generation of balloon-expandable valve, the SAPIEN XT, seem similar to the previous generation. However, transfemoral implantation is more often possible, related to sheath size reduction. PMID- 22520796 TI - Transapical aortic valve implantation in Rouen: four years' experience with the Edwards transcatheter prosthesis. AB - BACKGROUND: The first French transapical transcatheter aortic valve implantation (TAVI) was performed in July 2007 in our department. AIMS: To report 4-year outcomes of transapical implantation with the Edwards transcatheter bioprosthesis. METHODS: We prospectively evaluated consecutive patients who underwent transapical implantation with an Edwards transcatheter bioprosthesis between July 2007 and October 2011. Patients were not suitable for conventional surgery (due to severe comorbidities) or transfemoral implantation (due to poor femoral access). RESULTS: Among 61 patients (59.0% men), mean logistic EuroSCORE was 27.5 +/- 14.9% and mean age was 81.0 +/- 6.8 years. Successful valve implantation was achieved in 59/61 patients (96.7%) of patients. The other two patients required conversion to conventional surgery due to prosthesis embolization and died. Six additional patients died in the postoperative period. Causes of perioperative death were two septic shocks (one of peritonitis), two multi-organ failure, one ventricular fibrillation and one respiratory insufficiency. Intraprocedural stroke was not observed in any patient. The actuarial survival rates at 1, 2 and 4 years were 73.8%, 67.2% and 41.0%. During this 4-year period, four patients died of cardiovascular events, but no impairment of transprosthesis gradient was observed. CONCLUSION: Our series of 61 patients who underwent transapical implantation of the Edwards transcatheter bioprosthesis shows satisfactory results, similar to other reports, considering the high level of severity of patients referred for this method. Transapical access is a reliable alternative method for patients that cannot benefit from a transfemoral approach. PMID- 22520797 TI - Development of transcatheter aortic valve implantation (TAVI): a 20-year odyssey. AB - The development of transcatheter aortic valve implantation (TAVI) by our group has been a 20-year odyssey. In 1993, postmortem studies validated the concept of intravalvular stenting in calcific aortic stenosis. The first prototypes of balloon-expandable valves were tested in an animal model in 2000. The first-in man implantation was performed in Rouen in 2002, rapidly followed by two prospective series in compassionate cases in our centre. TAVI took flight in 2004 in the hands of Edwards Lifesciences, with major improvements in devices and approaches. At the same time, the self-expanding CoreValve was launched. Thousands of high-surgical-risk patients were enrolled in feasibility studies, leading to the Conformite Europeenne (CE) mark being granted in 2007 for the two devices. A number of postmarketing registries have shown dramatic improvements in procedural and midterm results and decreased complication rates, with more experience and improved technology. The results of the randomized PARTNER study in the USA recently confirmed the important place of TAVI in non-operable and high-surgical-risk patients. To date, more than 50,000 patients have benefited from TAVI worldwide (2300 patients in 33 centres in France in 2011) and the number is consistently increasing. An optimal multidisciplinary collaboration and formally trained experienced physicians are the keys to success. An extension of indications to lower-risk patients might be expected in the coming years but should be cautiously investigated. Ten years after the first-in-man case, TAVI is here to stay and the future is promising. PMID- 22520798 TI - Transcatheter aortic valve implantation: the evolution of prostheses, delivery systems and approaches. AB - It is two decades since the first report of transcatheter implantation of a stented aortic valve in an animal. The first implantation of a transcatheter aortic valve in a human was accomplished just one decade ago dramatically demonstrating the promise and feasibility of this new therapy. Over the past 10 years, there have been rapid developments in valves, delivery systems and technical approaches. Today, transcatheter valve implantation is a technical possibility for the great majority of patients with aortic stenosis. The next 10 years may well see this become the dominant therapy for aortic stenosis. PMID- 22520799 TI - The development of transcatheter aortic valve replacement in the USA. AB - The penetration rate of devices in general, and in transcatheter aortic valve replacement (TAVR) specifically, is significantly delayed in the United States of America (USA) compared with in Europe. This is mostly due to the mission statement of the regulatory agencies in the USA, which requires very rigorous clinical testing of a device prior to its approval. The USA had a major role in the development and evaluation of this technology and USA research has enabled clinicians inside and outside of the USA to conduct a concise scientifically based assessment of the performance of TAVR devices in terms of safety and efficacy. In the following review, we provide data on the development of TAVR in the USA, revealing the critical role the USA has played in this extraordinary process. PMID- 22520800 TI - Patient selection for transcatheter aortic valve implantation: patient risk profile and anatomical selection criteria. AB - Patient selection plays a crucial role in the success of transcatheter aortic valve implantation (TAVI). It requires meticulous attention to the smallest of details and needs to be performed in a systematic manner for every patient. In essence, the patient must be assessed from access to implantation site. Becoming over "complacent" and "routine" may lead to failure and impact patient safety. TAVI is indicated for high or prohibitive surgical risk patients with severe aortic stenosis. Some patients, however, are too high risk even for TAVI. In addition to patient risk evaluation, anatomical selection criteria need to be considered. Multimodality imaging, using a combination of angiography, echocardiography and multislice computed tomography, is necessary to determine the anatomical suitability for the procedure. PMID- 22520801 TI - Transcatheter aortic valve implantation: surgical perspectives. AB - Aortic valve replacement (AVR) is a routine procedure for decades to treat patients with symptomatic aortic stenosis. The introduction of transcatheter aortic valve implantation (TAVI) by Professor Alain Cribier has paved the way for minimally invasive therapeutic options for elderly and high-risk patients with aortic stenosis. Transfemoral and transapical aortic valve implantations have become routine procedures in many centres around Europe. TAVI is usually being performed together by experienced cardiologists and cardiac surgeons who build the interdisciplinary 'Heart Team'. In the future, improved devices together with advanced fusion imaging will lead to a further improvement in clinical outcomes for the sake of our patients. PMID- 22520802 TI - Transcatheter aortic valve implantation: our vision of the future. AB - Transcatheter aortic valve implantation (TAVI), introduced 10 years ago by Alain Cribier, has now been performed in more than 50,000 patients worldwide. Our vision of the main directions for the future are fourfold. Firstly, the 'Heart Team' is and will remain, essential for patient selection and the performance of the procedure. Careful training and controlled diffusion of the technique to medico-surgical centres are also keys to success. Secondly, patient selection must be refined, in order to predict the risk of surgery and that of TAVI. The technique is currently limited to very high-risk patients or those with contraindications to surgery. It will be extended to include lower risk patients once there are adequate trial data, the safety of the procedure has been improved and better knowledge of long-term outcomes from the procedure has been obtained. Thirdly, the procedure will be simplified, and should also be safer with an expected decrease in the occurrence of strokes, vascular complications and perivalvular regurgitation. Fourthly, the devices will also improve, with the addition of the potential for repositioning and improvement in durability. The role of imaging with the use of multimodality techniques will no doubt increase and ease the efficacy and safety of the procedure. Overall, the use of TAVI will undoubtedly increase over time, enabling a larger number of patients with severe aortic stenosis to be treated in an effective and safe way, in complement to surgical aortic valve replacement. PMID- 22520803 TI - A rare case of aortic stenosis in adulthood. PMID- 22520804 TI - Cardiac multislice computed tomography after transcatheter aortic valve implantation: features after "valve-in-valve" implantation for degenerative stented aortic bioprosthesis. PMID- 22520805 TI - Spontaneous endometriosis in a mandrill (Mandrillus sphinx). AB - A 25-year-old female mandrill (Mandrillus sphinx) died after exhibiting weakness and recumbency with serosanguineous ascites. Gross findings included haemoperitoneum and multifocal to diffuse serosal thickening with petechiae and ecchymoses throughout the peritoneum. The uterus was covered entirely with large blood clots and was adherent to the ovaries and pelvic wall. Microscopical and immunohistochemical examination revealed extra- and intra-uterine growth of ectopic endometrial tissue with marked fibrosis. The ectopic endometrial tissues predominantly consisted of stromal cells expressing CD10 and progesterone receptor and variably-sized glands lined by the epithelium with occasional slight expression of oestrogen receptor alpha. A diagnosis of endometriosis was made. This is the first report of naturally occurring endometriosis in a mandrill. PMID- 22520806 TI - Toll-like receptor gene expression in fresh and archived ovine pseudoafferent lymph DEC205+ dendritic cells. AB - Toll-like receptors (TLRs) are key regulators of the innate and adaptive immune response to bacterial, viral and fungal pathogens. To date, 10 human TLRs and 13 mouse TLRs have been identified and they exhibit tissue-specific mRNA/protein expression patterns. We recently cloned and characterized 10 ovine TLR genes. The present study was carried out to determine the expression profile of TLRs 1-10 in fresh and archived ovine pseudoafferent lymph (pAL) cells and pAL dendritic cells (pALDCs) using two-step quantitative reverse transcriptase polymerase chain reaction (RT-PCR) with ovine specific primer/probe sets. Dendritic cells are important in the initiation and maintenance of immune responses and express a spectrum of pattern-recognition receptors (that includes the TLRs). Fresh and archived total pAL cells expressed all 10 ovine TLRs to a broadly similar extent and TLR1-10 mRNA expression was observed in DEC205(hi) pALDCs. In addition, there were changes in particular TLR transcript levels in DEC205(hi) pALDC in archived lymph samples at two time points after orf virus reinfection. The results show that frozen archived cells can be used for retrospective TLR gene expression analysis. Furthermore, changes in TLR gene expression in DEC205(hi) pALDC after orf virus reinfection in the skin of sheep suggests that more detailed analyses of TLR gene expression changes during disease processes are worthwhile. These data will be useful to inform future studies on the role of TLRs in disease pathogenesis and control. PMID- 22520807 TI - Osteosarcoma of the maxilla with concurrent osteoma in a southern sea otter (Enhydra lutris nereis). AB - Southern sea otters (Enhydra lutris nereis) are threatened marine mammals that belong to the family Mustelidae and are native to the coast of Central California. Neoplasia is reported infrequently in sea otters. An adult female free-ranging southern sea otter was found alive at Pebble Beach, Monterey County, California, on January 1st, 1994 and died soon after capture. The carcass was submitted to the US Geological Survey - National Wildlife Health Center for necropsy examination. Grossly, a mass with rubbery texture was firmly attached to the left maxillary region of the skull and the nasopharynx was occluded by soft neoplastic tissue. Post-mortem skull radiographs showed an oval, smoothly marginated mineralized opaque mass centered on the left maxilla, extending from the canine tooth to caudal to the molar and replacing portions of the zygomatic arch and palatine and temporal bones. The majority of the mass protruded laterally from the maxilla and was characterized by central homogeneous mineral opacity. Microscopically, the mass was characterized by fully differentiated lamellar non-osteonal bone that expanded beyond the margins of the adjacent normal osteonal bone. Sections of the nasopharyngeal mass were comprised of moderately pleomorphic cells with bony stroma. Gross, microscopical and radiological findings were compatible with maxillary osteosarcoma with concurrent osteoma. PMID- 22520808 TI - Gonadoblastoma in the ovaries of a lesser galago (Galago senegalensis braccatus). AB - An enlarged right ovary was removed from a 14-year-old lesser galago (Galago senegalensis braccatus). Cytological preparations consisted of a heterogeneous population of neoplastic cells admixed with extracellular hyaline structures and cell-free nuclei. Microscopically, the ovary was replaced with gonadoblastoma and was composed of nests of germinal cells, including large oocyte-like cells, and sex cord-stromal cells arranged in palisading patterns around the germinal cells, the periphery of the nests and around extracellular hyaline material. The animal died 2 years after initial diagnosis. Necropsy examination revealed gonadoblastoma in the left ovary. The germinal cells of the tumour in the right and left ovaries were immunoreactive for calretinin, OCT3/4, PGP 9.5, Ki67 and/or faintly for cytokeratins. Sex cord-stromal cells were immunoreactive for calretinin, OCT3/4, GATA-4, E-cadherin and vimentin. Luteinized sex cord-stromal cells were immunoreactive for inhibin-alpha. The extracellular hyaline material was immunoreactive for laminin. This is the first case of gonadoblastoma in a non human primate. PMID- 22520809 TI - Experimental foot-and-mouth disease virus infection in white tailed deer. AB - White tailed deer (Odocoileus virginianus) were inoculated with foot-and-mouth disease virus (FMDV) O UKG 11/2001 and monitored for the development of clinical signs, histopathological changes and levels of virus replication. All FMDV infected deer developed clinical signs starting at 2 days post inoculation and characterized by an increase in body temperature, increased salivation and lesions in the mouth and on the feet. Virus spread to various tissues was determined by quantifying the amount of FMDV RNA using quantitative reverse transcriptase polymerase chain reaction. Virus or viral antigen was also detected in tissues using traditional isolation techniques, enzyme linked immunosorbent assay and immunohistochemistry. Deer-to-cattle transmission of the virus was observed in this experimental setting; however, inoculated deer were not found to become carriers of FMDV. PMID- 22520810 TI - Fibroepithelial polyps of the vagina in bitches: a histological and immunohistochemical study. AB - The histological and immunohistochemical features of 13 cases of suspected vaginal fibroepithelial polyps are reported. The characteristic microscopical features of these lesions were an abundant oedematous or fibrous stroma containing spindle-shaped and stellate cells and the presence of variable inflammation and haemorrhage. There was often a superficial layer of compressed tissue, but the stroma in the peripheral areas of the masses was generally more loosely arranged than in central areas. The connective tissue cells expressed vimentin and desmin, but did not express smooth muscle actin or calponin. Individual cases had additional changes including granulomatous inflammation, epithelial dysplasia suggestive of papillomavirus infection and a lesion resembling phyllodes tumour in women. PMID- 22520811 TI - Malignant pilomatricoma in a dog. AB - An 11-year-old female German shepherd dog was presented with a history of lameness and pain in the left forelimb. Clinical examination revealed ataxia of the hindlimbs and a subcutaneous mass in the left prescapular region. Radiography revealed metastatic foci in the left humerus, lung and abdomen. Gross necropsy examination revealed a firm, white mass in the left prescapular region. Multiple nodules with similar characteristics were observed in the lung, liver and spleen. Bone lysis was noted in the humerus and the fifth to seventh lumbar vertebrae. Microscopical examination revealed a proliferation of basal cells forming irregular islands of various sizes and surrounding extensive zones of keratinized 'ghost' cells. A definitive diagnosis of malignant pilomatricoma was made. This is a rare tumour in dogs with no previous report of metastasis to the spleen and liver. PMID- 22520812 TI - Pancreatic carcinosarcoma in a cat. AB - A 10-year-old female American shorthair cat was presented for evaluation of weight loss. An intra-abdominal mass was found on ultrasonography and laparotomy was performed. The mass was located in the left uterine horn and further masses were found in the pancreas, greater omentum and diaphragm. Microscopical examination revealed that the pancreatic mass had epithelial and mesenchymal components, which on immunohistochemistry expressed cytokeratin and vimentin, respectively. In addition, some spindle cells expressed vimentin and E-cadherin, which might suggest epithelial to mesenchymal transition. In contrast, the uterine, omental and diaphragmatic masses had only mesenchymal composition. The pancreatic lesion is proposed to be a primary carcinosarcoma with metastasis of only the mesenchymal component to distant sites. This the first report of pancreatic carcinosarcoma in a cat. PMID- 22520813 TI - Intrathoracic myxosarcoma in a dog. AB - A 3-year-old Labrador retriever dog was presented with pyrexia, dyspnoea and tachycardia. A pleural effusion was detected radiographically and ultrasonography showed pleural fluid with floating material. The fluid was drained, revealing a soft tissue mass adjacent to the left ventricle. The aspirated fluid had a proteinaceous and gelatinous appearance. Cytological examination revealed atypical mesenchymal cells in a dense eosinophilic background, interpreted as consistent with the presence of a matrix-secreting tumour, probably a myxosarcoma. Thoracoscopy confirmed the presence of the mass adjacent to the left ventricle, but showed additional smaller pleural masses. Microscopical and immunohistochemical evaluation of a biopsy sample from the mass supported the diagnosis of a myxosarcoma, which was further confirmed by transmission electron microscopy. PMID- 22520814 TI - Recurrent bacteraemia in sheep infected persistently with Anaplasma phagocytophilum. AB - Following experimental or natural infection with Anaplasma phagocytophilum, the causative agent of tick-borne fever (TBF), sheep may be infected persistently for several months or years. In the present study, quantitative real-time polymerase chain reaction was used to investigate the duration and magnitude of primary bacteraemia and to establish whether the organism is present continuously in the peripheral blood after the period of primary bacteraemia and the cessation of clinical signs. Persistent infection was characterized by a clearly defined period of primary bacteraemia followed by recurrent cycles of bacteraemia, usually lasting a few days and of lower magnitude, interspersed by negative periods of variable duration in which bacterial DNA could not be detected. During a 150-day period of consecutive sampling of four sheep, A. phagocytophilum was detected on 64.25 +/- 4.9 occasions, which means that on average bacterial DNA was detected in 42.8 +/- 3.3 percent of all samples, with the positive days falling into 15-20 distinct cycles. Primary bacteraemia lasted for 15.5 +/- 2.33 days, but secondary and subsequent cycles of bacteraemia were short-lived, with 61% of the cycles lasting only 1-2 days and 39% lasting for 3 or more days. Secondary and subsequent cycles of bacteraemia were not accompanied by febrile responses or other clinical features of TBF. For three animals, bacterial DNA was detected at 311, 318 and 358 days post infection, indicating the long-term persistence of A. phagocytophilum within peripheral blood. PMID- 22520815 TI - Recurrent outbreaks of myelodysplasia in newborn calves. AB - The present study records recurrent outbreaks of myelodysplasia of unknown origin occurring in a specific geographical location in the north of Spain, and involving up to 30% of the calves born in affected herds. The affected calves were of different breeds and displayed non-progressive signs of spinal cord dysfunction. The disease has occurred annually in February-March over a period of at least 15 years. Only calves born to cattle grazed on mountainside pastures and under high grazing pressure were affected. Seven calves were subjected to necropsy examination. Myelodysplasia was not associated with vertebral defects or arthrogryposis and involved the entire length of the spinal cord. Microscopically, there was abnormal distribution of the grey matter, aberrations of the central canal and failure of formation of the ventral median fissure. Infectious, nutritional and physical disorders were ruled out as possible aetiologies. A critical period of embryonic susceptibility to the causal agent was identified. This was during the time of secondary neurulation when cows in the early stages of gestation were grazed on mountainside pastures. Consequently, the presence of neuroteratogenic plants in these pastures is proposed as a likely cause. Two plants, Carex brevicollis and Erythronium dens-canis, which contain alkaloids, were identified on the mountainsides where affected cattle were grazed and not in other pastures, and are proposed as the possible aetiology of the disease. PMID- 22520816 TI - Comparative analysis of peptidylarginine deiminase-2 expression in canine, feline and human mammary tumours. AB - The peptidylarginine deiminase (PAD) enzyme family converts arginine residues in proteins to citrulline. In the canine mammary gland, PAD2 expression is first detected in epithelial cells in oestrus and becomes more widely expressed during dioestrus. PAD2 appears to modify nuclear histones, suggesting a role for the enzyme in chromatin remodelling and gene regulation. Recent evidence suggests that PAD2 plays a role in gene regulation in primary human breast epithelial cells. PAD2 may therefore be involved in gene regulation as it relates to mammary development, the oestrus cycle and potentially to neoplasia. The aim of the present study was to determine whether PAD2 expression was increased or decreased in mammary carcinoma compared with normal mammary tissue. A human mammary tissue microarray and archival surgical biopsy tissues from canine and feline mammary tumours were used to demonstrate differential expression of PAD2 in mammary carcinoma that appeared to be consistent across species. Normal human and canine mammary epithelium showed strong cytoplasmic and nuclear expression of PAD2, but there was reduced PAD2 expression in mammary carcinomas from both species. Feline mammary carcinomas had complete loss of nuclear PAD2 expression. Loss of nuclear PAD2 expression may therefore represent a marker of progression towards more aggressive neoplasia. PMID- 22520817 TI - Expression of matrix metalloproteinases, tissue inhibitors of metalloproteinases and vascular endothelial growth factor in canine mast cell tumours. AB - Degradation of the extracellular matrix and angiogenesis are associated with tumour invasion and metastasis in human and canine neoplasia. Matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs) and vascular endothelial growth factor-A (VEGF-A) are key mediators of these respective processes. Mast cell tumour (MCT) is the most common malignant cutaneous tumour in dogs. MCTs are always considered potentially malignant, but their true metastatic potential is unknown. In the present study, samples from seven grade 1, 22 grade 2 and six grade 3 MCTs were subjected to quantitative real-time polymerase chain reaction and immunohistochemistry (IHC) to evaluate MMP-2, MMP-9, membrane-type 1 MMP (MT1-MMP), TIMP-2 and VEGF-A mRNA and protein expression. Gelatin zymography (GZ) was also performed to evaluate MMP-2 and MMP 9 activity. MMP-9 and VEGF-A mRNA increased with histological grade, while TIMP-2 decreased with increasing grade. Gene expression data obtained for MMP-9, VEGF-A and TIMP-2 were confirmed by IHC for evaluation of the respective proteins. In contrast, MMP-2 and MT1-MMP had variable, but similar, expression for both mRNA and protein. Despite the high variability observed, there was correlation between MMP-2 and MT1-MMP mRNA expression (r=+0.91, P<0.0001). The MMP-2:TIMP-2 and MMP 9:TIMP-1 mRNA ratios showed an imbalance between MMPs and their specific inhibitors in MCTs, which increased with the histological grade. Finally, the activities of both latent and active forms of MMP-2 and MMP-9 were evaluated by GZ and there were significant increases in their activities with increasing histological grade and immunohistochemical expression. This study demonstrates that MMP-9, TIMP-2 and VEGF-A expression is related to histological grade and suggests that these markers are possible indicators of malignancy and targets for therapeutic strategies. PMID- 22520818 TI - Distribution of bovine viral diarrhoea virus antigen in persistently infected white-tailed deer (Odocoileus virginianus). AB - Infection with bovine viral diarrhoea virus (BVDV), analogous to that occurring in cattle, is reported rarely in white-tailed deer (Odocoileus virginianus). This study evaluated the distribution of BVDV antigen in persistently infected (PI) white-tailed deer and compared the findings with those from PI cattle. Six PI fawns (four live-born and two stillborn) from does exposed experimentally to either BVDV-1 or BVDV-2 were evaluated. Distribution and intensity of antigen expression in tissues was evaluated by immunohistochemistry. Data were analyzed in binary fashion with a proportional odds model. Viral antigen was distributed widely and was present in all 11 organ systems. Hepatobiliary, integumentary and reproductive systems were respectively 11.8, 15.4 and 21.6 times more likely to have higher antigen scores than the musculoskeletal system. Pronounced labelling occurred in epithelial tissues, which were 1.9-3.0 times likelier than other tissues to contain BVDV antigen. Antigen was present in >90% of samples of liver and skin, suggesting that skin biopsy samples are appropriate for BVDV diagnosis. Moderate to severe lymphoid depletion was detected and may hamper reliable detection of BVDV in lymphoid organs. Muscle tissue contained little antigen, except for in the cardiovascular system. Antigen was present infrequently in connective tissues. In nervous tissues, antigen expression frequency was 0.3 0.67. In the central nervous system (CNS), antigen was present in neurons and non neuronal cells, including microglia, emphasizing that the CNS is a primary target for fetal BVDV infection. BVDV antigen distribution in PI white-tailed deer is similar to that in PI cattle. PMID- 22520819 TI - Lack of prognostic significance of angiogenesis in canine melanocytic tumours. AB - The prognostic significance of angiogenesis in some canine tumours has been investigated, but little is known about its relevance in canine melanocytic tumours (MTs). The aim of this study was to evaluate the prognostic significance of angiogenesis in canine MTs. A total of 36 cutaneous melanocytomas (benign MTs), 40 cutaneous melanomas (malignant MTs) and 43 oral melanomas were studied. Survival data were available for a subset of 59 cases. Microvessel density (MVD) and endothelial area (EA) were determined by immunolabelling using an antibody specific for von Willebrand factor (vWF). Mean MVD (expressed as the number of microvessels per mm(2)) was 129 +/- 14 in melanocytomas, 191 +/- 16 in cutaneous melanomas and 208 +/- 16 in oral melanomas. Mean EA (expressed as the percentage of the total area) was 1.5 +/- 0.14 in melanocytomas, 2.6 +/- 0.2 in cutaneous melanomas and 2.4 +/- 0.3 in oral melanomas. The differences in MVD and EA between melanocytomas and melanomas were significant (P = 0.001 and P = 0.003, respectively). MVD and EA were significantly correlated between cutaneous and oral MTs (r = 0.54; P <0.001 and r = 0.63; P <0.001, respectively). MVD and EA were not related to survival in cutaneous and oral MTs. In conclusion, tumour vascularization was higher in melanomas than in melanocytomas, but it seemed to have no prognostic significance in these tumours. PMID- 22520820 TI - Bovine epizootic encephalomyelitis caused by Akabane virus infection in Korea. AB - A large-scale epidemic of Akabane virus (AKAV) encephalomyelitis in cattle aged 4 72 months occurred in the southern part of Korea from late summer to late autumn in 2010. Affected cattle exhibited neurological signs including locomotor ataxia, astasia, tremor and hypersensitivity. Samples of brain (n = 116), spinal cord (n = 116) and whole blood (n = 205) were submitted to the National Veterinary Research and Quarantine Service for diagnosis. Microscopical analysis of the brains and spinal cords revealed the presence of non-suppurative encephalomyelitis in 99 of 116 brains and/or spinal cords (85%). The brains and spinal cords were evaluated by reverse transcriptase polymerase chain reaction and AKAV antigens were detected by immunohistochemistry using rabbit antiserum against AKAV strain OBE-1. Fifteen AKAVs were isolated from the brain and spinal cord samples. Antibodies against AKAV in a virus neutralization test were detected in 188 of 205 serum samples (91.7%). This is the first report of a large scale outbreak of bovine epidemic encephalomyelitis caused by AKAV infection in Korea. PMID- 22520821 TI - Immunohistochemical expression of E-cadherin and beta-catenin in feline mammary tumours. AB - E-cadherin and beta-catenin have been studied in carcinogenesis and tumour progression and reduced membrane expression of these molecules in canine mammary tumours has been associated with a poor prognosis. The present study investigated immunohistochemically the expression of E-cadherin and beta-catenin in 53 mammary tumours and 48 hyperplastic or dysplastic lesions from 57 queens. E-cadherin and beta-catenin expression was membranous in all samples and there was a significant decrease in expression in malignant tumours and metastases. Cytoplasmic expression of both markers was inversely correlated to the membrane localization. beta-catenin nuclear labelling was detected in one lymph node metastasis (60% positive cells) and in the basal/myoepithelial cells of 6/7 ductal tumours. No correlation with survival was found for either marker. These results confirm the role of these proteins in maintaining tissue architecture and in inhibiting cell invasiveness and potentially indicate the oncogenic potential of the Wnt/beta catenin transduction pathway in feline mammary tumours. In addition, specific independent expression of beta-catenin in the nuclei of basal/myoepithelial cells might suggest that this molecule is involved in regulation of the mammary stem/pluripotent cell component. Further studies should include more cases of benign mammary neoplasia and further investigate beta-catenin nuclear expression in ductal tumours. PMID- 22520822 TI - Cerebral cryptococcomas in a cow. AB - Cerebral cryptococcomas are described in a 5-year-old mixed-breed cow without manifestations of systemic cryptococcosis. Two cryptococcomas were observed grossly. Microscopical examination revealed accumulations of yeast that were morphologically consistent with Cryptococcus neoformans. Immunohistochemistry characterized the organisms as C. neoformans var. grubii. PMID- 22520823 TI - Left ventricular mass index and aortic arch calcification score are independent mortality predictors of maintenance hemodialysis patients. AB - To analyze predictive factors for all-cause mortality, cardiovascular (CV) mortality, nonfatal CV events (CVE) in maintenance hemodialysis (MHD) patients, and to compare the effects of standard hemodialysis (HD) and online hemodiafiltration (HDF) on these factors and outcomes. A total of 333 MHD patients were prospectively followed up for 50 +/- 15 months and all-cause death, CV death and CVE were registered. At the baseline, demographic, clinical, and laboratory data of the whole population were recorded. Then, patients were stratified into two groups according to the dialysis modalities, HD (n = 268) and HDF (n = 65). At the end of 6th month, clinical and laboratory data were recorded again. The predictive factors at baseline for all-cause mortality, CV mortality, and CVE were analyzed by Cox regression. The effects of HD and HDF on these factors at the 6th month and long-term outcomes were compared by t-test and Kaplan-Meier method, respectively. Age, gender, left ventricular mass index (LVMI), aortic arch calcification score (AoACS), hemoglobin (Hb) <10 g/dL, and ferritin >500 ng/mL maintained independent associations with all-cause mortality. C-reactive protein (CRP), LVMI, AoACS, and Hb <10 g/dL were associated with CV mortality. Prior cardiovascular disease (CVD), AoACS and LVMI were independent predictors of nonfatal CVE. Higher body mass index (BMI), body weight, total serum cholesterol, Hb concentration, and lower CRP level, LVMI, and AoACS were found in patients on HDF at the end of the 6th month. Improved outcomes with longer survival time for all-cause mortality, CV mortality, and CVE were found in HDF group. Age, gender, LVMI, AoACS, Hb, and ferritin were predictors of all cause mortality in MHD patients. CRP, LVMI, AoACS, and Hb were associated with CV mortality. Prior CVD, AoACS, and LVMI were independent predictors of nonfatal CVE. HDF could improve BMI, body weight, total serum cholesterol, Hb, CRP, LVMI, AoACS, and long-term outcomes, including all-cause mortality, CV mortality, and CVE. PMID- 22520824 TI - Modeling population exposure to community noise and air pollution in a large metropolitan area. AB - Epidemiologic studies have shown that both air pollution and community noise are associated with cardiovascular disease mortality. Because road traffic is a major contributor to these environmental pollutants in metropolitan areas, it is plausible that the observed associations may be confounded by coexistent pollutants. As part of a large population-based cohort study to address this concern, we used a noise prediction model to assess annual average community noise levels from transportation sources in metropolitan Vancouver, Canada. The modeled annual average noise level was 64 (inter quartile range 60-68) dB(A) for the region. This model was evaluated by comparing modeled annual daytime A weighted equivalent continuous noise levels (L(day)) with measured 5-min daytime A-weighted equivalent continuous noise levels (L(eq,day,5 min)) at 103 selected roadside sites in the study region. On average, L(day) was 6.2 (95% CI, 6.0-7.9) dB(A) higher than, but highly correlated (r=0.62; 95% CI, 0.48-0.72) with, L(eq,day,5 min). These results suggest that our model-based noise exposure assessment could approximately reflect actual noise exposure in the study region. Overall, modeled noise levels were not strongly correlated with land use regression estimates of traffic-related air pollutants including black carbon, particulate matter with aerodynamic diameter <=2.5 MUm (PM(2.5)), NO(2) and NO; the highest correlation was with black carbon (r=0.48), whereas the lowest correlation was with PM(2.5) (r=0.18). There was no consistent effect of traffic proximity on the correlations between community noise levels and traffic-related air pollutant concentrations. These results, consistent with previous studies, suggest that it is possible to assess potential adverse cardiovascular effects from long-term exposures to community noise and traffic-related air pollution in prospective epidemiologic studies. PMID- 22520825 TI - Real time emotion aware applications: a case study employing emotion evocative pictures and neuro-physiological sensing enhanced by Graphic Processor Units. AB - In this paper the feasibility of adopting Graphic Processor Units towards real time emotion aware computing is investigated for boosting the time consuming computations employed in such applications. The proposed methodology was employed in analysis of encephalographic and electrodermal data gathered when participants passively viewed emotional evocative stimuli. The GPU effectiveness when processing electroencephalographic and electrodermal recordings is demonstrated by comparing the execution time of chaos/complexity analysis through nonlinear dynamics (multi-channel correlation dimension/D2) and signal processing algorithms (computation of skin conductance level/SCL) into various popular programming environments. Apart from the beneficial role of parallel programming, the adoption of special design techniques regarding memory management may further enhance the time minimization which approximates a factor of 30 in comparison with ANSI C language (single-core sequential execution). Therefore, the use of GPU parallel capabilities offers a reliable and robust solution for real-time sensing the user's affective state. PMID- 22520827 TI - The relationship between anogenital distance and the efficacy of varicocele repair. AB - Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? Anogenital distance (AGD) is a marker of genital development and adult testicular function. To date, there is no data on the clinical utility of using such an anthropomorphic variable. About 30% of men will have no improvement in semen parameters after varicocele repair. It is currently difficult to assess which patients are most likely to benefit from surgical repair. The present study showed that men with a longer AGD had a higher likelihood of improvement after varicocelectomy. As such, AGD may allow clinicians to better counsel men on the efficacy of varicocele repair. OBJECTIVE: * To investigate whether anogenital distance (AGD) can identify men most likely to show improved semen parameters after varicocele ligation, as AGD has been shown to correlate with intrinsic adult testicular function. PATIENTS AND METHODS: * Men with varicoceles who were evaluated at a men's reproductive health clinic in Houston were recruited. * AGD (the distance from the posterior aspect of the scrotum to the anal verge) was measured using digital callipers. * Logistic regression was used to compare outcomes after stratifying men based on AGD. RESULTS: * In all, 46 men with a mean (sd) age of 33.1 (6.3) years with postoperative semen data were recruited. * Semen concentration, motility, and total motile sperm count all showed significant improvement postoperatively (P < 0.01). * While 48% of men with a shorter AGD had improvements in sperm concentration postoperatively, 84% of men with a longer AGD improved (P = 0.01). * There was a trend toward a lower percentage of men (62% vs 84%) with shorter AGDs showing improvements in total motile sperm count (P = 0.09). CONCLUSION: * AGD may provide a novel metric to assess intrinsic testicular function and predict efficacy of varicocele repair. PMID- 22520826 TI - Evolution of variation in presence and absence of genes in bacterial pathways. AB - BACKGROUND: Bacterial genomes exhibit a remarkable degree of variation in the presence and absence of genes, which probably extends to the level of individual pathways. This variation may be a consequence of the significant evolutionary role played by horizontal gene transfer, but might also be explained by the loss of genes through mutation. A challenge is to understand why there would be variation in gene presence within pathways if they confer a benefit only when complete. RESULTS: Here, we develop a mathematical model to study how variation in pathway content is produced by horizontal transfer, gene loss and partial exposure of a population to a novel environment. CONCLUSIONS: We discuss the possibility that variation in gene presence acts as cryptic genetic variation on which selection acts when the appropriate environment occurs. We find that a high level of variation in gene presence can be readily explained by decay of the pathway through mutation when there is no longer exposure to the selective environment, or when selection becomes too weak to maintain the genes. In the context of pathway variation the role of horizontal gene transfer is probably the initial introduction of a complete novel pathway rather than in building up the variation in a genome without the pathway. PMID- 22520828 TI - Biventricular repair with the Yasui operation (Norwood/Rastelli) for systemic outflow tract obstruction with two adequate ventricles. AB - BACKGROUND: The Yasui procedure is employed in neonates with interrupted aortic arch and left ventricular outflow tract obstruction (IAA/LVOTO) or aortic atresia severe stenosis with ventricular septal defect (AA/VSD) and 2 adequate-sized ventricles. This combines a Norwood arch reconstruction with a Rastelli operation establishing a biventricular repair. METHODS: From 2002 to 2011, 21 neonates aged 3 to 55 days (mean 12.2 days, median 7 days) had IAA/LVOTO (n=13), AA/VSD (n=7), or AA/IAA with aortopulmonary window (n=1); ten (48%) had genetic abnormalities (8 with DiGeorge syndrome). Based on clinical characteristics and surgeon preference, 6 had a primary Yasui repair (4 AA/VSD, 2 IAA/LVOTO); 15 were staged with an initial Norwood repair (3 AA/VSD, 12 IAA) followed by Yasui completion in 13 (2 await completion) 4.3 to 26.6 months later (median 6.9 months). RESULTS: Early mortality was zero with no interstage deaths in the staged patients. One patient died 2 months after staged repair. Since biventricular repair, 8 survivors (44%) had reoperation for conduit replacement (n=6), recurrent LVOTO (n=1), or a residual VSD (n=1). No patient requires a pacemaker. There were 3 late deaths after biventricular repair, all in patients with genetic syndromes and IAA/LVOTO. Actuarial survival after initial operation was 100% at 1 year and 75% at 5 years. Actuarial freedom from reoperation or death after biventricular repair was 14% at 5 years. CONCLUSIONS: The Yasui operation is effective for patients with IAA/LVOTO and AA/VSD. Primary and staged repair have comparable results. Reoperation after biventricular repair seems inevitable, mostly for conduit replacement. Genetic factors may affect long-term survival. PMID- 22520829 TI - The effect of additional pulmonary blood flow on timing of the total cavopulmonary connection. AB - BACKGROUND: The staged Fontan procedure is used to palliate functionally univentricular hearts. The effect of additional pulmonary blood flow combined with a bidirectional cavopulmonary shunt in these patients remains a controversial subject. METHODS: This retrospective study included all 82 patients with a unilateral or bilateral bidirectional cavopulmonary shunt at our institution between April 1990 and July 2010. Patients with hypoplastic left heart syndrome were excluded. Two groups, based on the presence (n=57) or absence (n=25) of additional pulmonary blood flow after the bidirectional cavopulmonary shunt, were compared. RESULTS: Patients with a bidirectional cavopulmonary shunt combined with additional pulmonary blood flow had higher arterial oxygen saturations postoperatively (86% [interquartile range, 85% to 90%] vs 82% [80% to 85%]; p=0.001) and had a longer median interval before the total cavopulmonary connection (3.42 [2.43 to 4.89] years vs 2.90 [2.08 to 3.32] years; p=0.06). At the total cavopulmonary connection, they were older (4.59 [3.88 to 6.49] years vs 3.94 [3.10 to 4.57] years; p=0.03) and had a larger median body surface area (0.73 [0.65 to 0.87] m2 vs 0.68 [0.59 to 0.73] m2; p=0.04). CONCLUSIONS: Patients with a bidirectional cavopulmonary shunt and additional pulmonary blood flow have a longer interval before the total cavopulmonary connection without evident untoward effects. This may theoretically be advantageous for the pulmonary artery growth needed for a successful Fontan circulation. Furthermore, postponement of the final Fontan may ensure the insertion of a larger extracardiac conduit to avoid prosthesis-patient mismatch. PMID- 22520830 TI - Previous percutaneous coronary interventions increase mortality and morbidity after coronary surgery. AB - BACKGROUND: This multicenter study investigated the impact of previous percutaneous coronary interventions (PCI) on postoperative outcome and 5-year survival of subsequent coronary artery bypass grafting. METHODS: Among 7,855 patients who underwent isolated first-time coronary artery bypass grafting between January 2000 and December 2005, 6,834 (87%) had no previous PCI and 1,021 (13%) had previous PCI with stenting. Logistic multiple regression and propensity score analyses were used to assess the risk-adjusted impact of prior PCI on in hospital mortality and major adverse cardiac events. The Cox regression model was used to assess the effect of prior PCI on 3-year and 5-year survival. RESULTS: After risk-adjusted multivariate analysis, age over 70 years, female sex, 3 vessel or 2-vessel plus left main coronary disease, multivessel PCI, ejection fraction 0.40 or less, diabetes mellitus, previous myocardial infarction, and chronic obstructive pulmonary disease were identified as independent predictors of both hospital mortality and major adverse cardiac events. After propensity score matching, conditional logistic regression analysis identified history of previous PCI as significantly associated with an increased risk for hospital mortality (odds ratio, 2.8; 95% confidence interval 1.4 to 4.8; p=0.003) and major adverse cardiac events (odds ratio 2.1; 95% confidence interval 1.2 to 3.6; p<0.001). Survival at 3 and 5 years was lower in patients with previous PCI compared with the no-PCI patients (97.4%+/-0.01% vs 96.5%+/-0.02% and 94.2%+/ 0.03% vs 92.1%+/-0.05%; log-rank test: p=0.03). CONCLUSIONS: Our results provided further evidence that history of PCI before coronary artery bypass grafting increases risk of both operative death and perioperative complications, and decreases survival at 5 years follow-up. PMID- 22520831 TI - Pilot study: Effects of drinking hydrogen-rich water on muscle fatigue caused by acute exercise in elite athletes. AB - BACKGROUND: Muscle contraction during short intervals of intense exercise causes oxidative stress, which can play a role in the development of overtraining symptoms, including increased fatigue, resulting in muscle microinjury or inflammation. Recently it has been said that hydrogen can function as antioxidant, so we investigated the effect of hydrogen-rich water (HW) on oxidative stress and muscle fatigue in response to acute exercise. METHODS: Ten male soccer players aged 20.9 +/- 1.3 years old were subjected to exercise tests and blood sampling. Each subject was examined twice in a crossover double-blind manner; they were given either HW or placebo water (PW) for one week intervals. Subjects were requested to use a cycle ergometer at a 75 % maximal oxygen uptake (VO2) for 30 min, followed by measurement of peak torque and muscle activity throughout 100 repetitions of maximal isokinetic knee extension. Oxidative stress markers and creatine kinase in the peripheral blood were sequentially measured. RESULTS: Although acute exercise resulted in an increase in blood lactate levels in the subjects given PW, oral intake of HW prevented an elevation of blood lactate during heavy exercise. Peak torque of PW significantly decreased during maximal isokinetic knee extension, suggesting muscle fatigue, but peak torque of HW didn't decrease at early phase. There was no significant change in blood oxidative injury markers (d-ROMs and BAP) or creatine kinease after exercise. CONCLUSION: Adequate hydration with hydrogen-rich water pre-exercise reduced blood lactate levels and improved exercise-induced decline of muscle function. Although further studies to elucidate the exact mechanisms and the benefits are needed to be confirmed in larger series of studies, these preliminary results may suggest that HW may be suitable hydration for athletes. PMID- 22520832 TI - The modular endoprosthesis for mandibular body replacement. Part 1: mechanical testing of the reconstruction. AB - INTRODUCTION: In this paper we present the results of the mechanical testing of a new generation modular endoprosthesis, which has been designed to improve the results of mandibular reconstruction. MATERIALS AND METHODS: The new cementless endoprosthesis consists of a male part, a female part (both with screws on the stems), connected via a dove-tailed connection and secured with a coronal screw. The endoprosthesis was fitted into standardized blocks of synthetic bone (Synbone AG, Malans, Switzerland). The set-up was fixed to an ElectroPuls testing machine at one end and loaded at the other end 25 mm away. Three specimens were loaded continuously until failure to determine the average load to failure of the construct. Five specimens were then loaded cyclically between 10 and 150 N until either failure or 500,000 cycles. A finite element analysis was also performed on the set-up. RESULTS: Of the five specimens in the fatigue testing, only one survived while the other four either were bent or fractured at the stem of the clamped portion. The specimen that survived had very good bony contact with the prosthesis at the lower border. The connection of the modules via the dove-tailed design did not show any loosening. Finite element analysis showed areas of stress concentration at the superior surface of the stems to 188.8 MPa. This was well below the yield strength of titanium alloy of 897 MPa. Statistical analysis performed for specimens 1 to 4 to calculated lower tolerance bounds on cycles to failure, representing the estimated minimum achievable cycles to failure at 90, 95, and 99% of the population at 90 and 95% confidence levels, showed that the estimated mean cycles to failure was 10,132 cycles at the mean, minimum and maximum loads of 120 N and 18.4 N respectively. CONCLUSION: Good bony contact seems to be essential at the lower border for long-term survival of the reconstruction. Small gaps increase the bending forces and thus shear stresses at the stem. The new design of the modular endoprosthesis is prone to stress concentrations at the superior surface of the stems. This is accentuated by the sharp screw threads of the stems. The loosening of the module connection seemed to have been stopped with the dove-tailed design. PMID- 22520833 TI - Different immune response of pigs to Mycobacterium avium subsp. avium and Mycobacterium avium subsp. hominissuis infection. AB - Mycobacterium avium subsp. avium (MAA) and Mycobacterium avium subsp. hominissuis (MAH) are the most common mycobacterial species isolated from granulomatous lesions in swine in countries with controlled bovine tuberculosis. This study is focused on the immunological aspect of MAA and MAH infection in pigs. We detected induction of humoral and cell-mediated immunity in experimentally infected pigs. Specific antibodies were analyzed in serum by ELISA and the IFN-gamma release assay was used for evaluation of cell-mediated immunity. While MAA induced a significant increase of both types of immune responses, MAH-infected pigs had an unvarying level of specific antibodies and showed low cell-mediated immunity with high individual variability. The subsequent in vitro experiment confirmed the lower immunogenicity of the MAH strain in comparison to MAA. MAH-infected porcine monocyte-derived macrophages showed a weaker induction of pro-inflammatory mediators in comparison to MAA, which included mRNA for IL-1beta, TNF-alpha, IL 23p19, IL-18 and chemokines CCL-3, CCL-5, CXCL-8 and CXCL-10. Additionally, qualitative proteomic analysis revealed 28 proteins exclusively in MAA and 7 proteins unique to MAH. In conclusion, closely related M. avium subspecies MAA and MAH showed different capacities to stimulate the porcine immune system. From a diagnostic point of view, the IFN-gamma release assay showed higher sensitivity than the detection of specific antibodies by ELISA and seems to be an effective tool for discrimination of MAA-infected pigs. In the case of MAH infection, the IFN-gamma release assay could fail because of the low immunogenic capacity of the MAH strain. PMID- 22520836 TI - Molecular characterization of two mitoviruses co-infecting a hypovirulent isolate of the plant pathogenic fungus Sclerotinia sclerotiorum [corrected]. AB - The complete nucleotide sequences of two double-stranded RNA (dsRNA) segments, isolated from the same hypovirulent strain (KL-1) of Sclerotinia sclerotiorum, were determined. Sequence analysis showed that dsRNAs 1 to be 2513 nts long and is A-U rich (61.7%). Excluding the poly(A) tail, dsRNAs2 is 2421 nts long and its AU content is 53.1%. The 5' and 3'-terminal sequences of the positive-strand of each dsRNA could be folded into predicted stable stem-loop structures. Mitochondrial codon usage revealed that each dsRNA has a single large open reading frame coding for a protein containing RNA-dependent RNA polymerase conserved motifs. Furthermore, dsRNAs 1 and 2 share sequence similarities with other mitoviruses. These results suggest that dsRNAs 1 and 2 represent two distinct new mitoviruses, designated Sclerotinia sclerotiorum mitovirus 1 (SsMV1/KL-1) and SsMV2/KL-1, respectively. The hypovirulence traits of strain KL 1 and the two mitoviruses could be co-transmitted to a virus-free virulent strain via hyphal anastomosis. PMID- 22520837 TI - The N-terminus of the Montano virus nucleocapsid protein possesses broadly cross reactive conformation-dependent epitopes conserved in rodent-borne hantaviruses. AB - The hantavirus nucleocapsid (N) protein is an important immunogen that stimulates a strong and cross-reactive immune response in humans and rodents. A large proportion of the response to N protein has been found to target its N-terminus. However, the exact nature of this bias towards the N-terminus is not yet fully understood. We characterized six monoclonal antibodies (mAbs) against the N protein of Montano virus (MTNV), a Mexican hantavirus. Five of these mAbs recognized eight American hantaviruses and six European and Asian hantaviruses, but not the Soricomorpha-borne Thottapalayam hantavirus. The N protein-reactive binding regions of the five mAbs were mapped to discontinuous epitopes within the N-terminal 13-51 amino acid residues, while a single serotype-specific mAb was mapped to residues 1-25 and 49-75. Our findings suggest that discontinuous epitopes at the N-terminus are conserved, at least in rodent-borne hantaviruses, and that they contribute considerably to N protein cross-reactivity. PMID- 22520838 TI - Effects of sequence changes in the HIV-1 gp41 fusion peptide on CCR5 inhibitor resistance. AB - A rare pathway of HIV-1 resistance to small molecule CCR5 inhibitors such as Vicriviroc (VCV) involves changes solely in the gp41 fusion peptide (FP). Here, we show that the G516V change is critical to VCV resistance in PBMC and TZM-bl cells, although it must be accompanied by either M518V or F519I to have a substantial impact. Modeling VCV inhibition data from the two cell types indicated that G516V allows both double mutants to use VCV-CCR5 complexes for entry. The model further identified F519I as an independent determinant of preference for the unoccupied, high-VCV affinity form of CCR5. From inhibitor free reversion cultures, we also identified a substitution in the inner domain of gp120, T244A, which appears to counter the resistance phenotype created by the FP substitutions. Examining the interplay of these changes will enhance our understanding of Env complex interactions that influence both HIV-1 entry and resistance to CCR5 inhibitors. PMID- 22520839 TI - Dumbbell-shaped nonpsammomatous malignant melanotic schwannoma of the cervical spinal root. AB - BACKGROUND CONTEXT: Melanotic schwannoma is a very rare tumor of Schwann cell origin, which can develop in various locations, similar to conventional schwannoma. This tumor has a malignant potential and therefore careful therapy is required. PURPOSE: To describe a case of melanotic schwannoma with a histopathologically and clinically malignant behavior. STUDY DESIGN: Case report. METHODS: A 64-year-old man presented with sensory changes in his arm and gait disturbance. Magnetic resonance imaging revealed a dumbbell-shaped tumor at the left C7 spinal root, which was hyperintense on T1-weighted images and generally hypointense on T2-weighted images in comparison with conventional schwannoma; however, the peripheral zone was relatively hyperintense, and the central zone was hypointense like a target sign. RESULTS: The tumor was partially resected and diagnosed to be nonpsammomatous malignant melanotic schwannoma. The patient experienced local recurrence and metastases to the bone and lung and finally developed quadriplegia. Radiation therapy failed to palliate the symptoms. CONCLUSIONS: Some melanotic schwannomas present with an aggressive behavior, which thus leads to poor prognosis. We should therefore be familiar with its characteristic clinical imaging and pathologic findings to provide a correct diagnosis and appropriate treatment for such patients. PMID- 22520840 TI - Interaction between Ca(2+) channel blockers and isoproterenol on L-type Ca(2+) current in canine ventricular cardiomyocytes. AB - AIM: The aim of this work was to study antagonistic interactions between the effects of various types of Ca(2+) channel blockers and isoproterenol on the amplitude of L-type Ca(2+) current in canine ventricular cells. METHODS: Whole cell version of the patch clamp technique was used to study the effect of isoproterenol on Ca(2+) current in the absence and presence of Ca(2+) channel blocking agents, including nifedipine, nisoldipine, diltiazem, verapamil, CoCl(2) and MnCl(2) . RESULTS: Five micromolar Nifedipine, 1 MUM nisoldipine, 10 MUM diltiazem, 5 MUM verapamil, 3 mM CoCl(2) and 5 mM MnCl(2) evoked uniformly a 90 95% blockade of Ca(2+) current in the absence of isoproterenol. Isoproterenol (100 nM) alone increased the amplitude of Ca(2+) current from 6.8 +/- 1.3 to 23.7 +/- 2.2 pA/pF in a reversible manner. Isoproterenol caused a marked enhancement of Ca(2+) current even in the presence of nifedipine, nisoldipine, diltiazem and verapamil, but not in the presence of CoCl(2) or MnCl(2) . CONCLUSION: The results indicate that the action of isoproterenol is different in the presence of organic and inorganic Ca(2+) channel blockers. CoCl(2) and MnCl(2) were able to fully prevent the effect of isoproterenol on Ca(2+) current, while the organic Ca(2+) channel blockers failed to do so. This has to be born in mind when the effects of organic Ca(2+) channel blockers are evaluated either experimentally or clinically under conditions of increased sympathetic tone. PMID- 22520841 TI - The Naive nurse: revisiting vulnerability for nursing. AB - BACKGROUND: Nurses in the Western world have given considerable attention to the concept of vulnerability in recent decades. However, nurses have tended to view vulnerability from an individualistic perspective, and have rarely taken into account structural or collective dimensions of the concept. As the need grows for health workers to engage in the global health agenda, nurses must broaden earlier works on vulnerability, noting that conventional conceptualizations and practical applications on the notion of vulnerability warrant extension to include more collective conceptualizations thereby making a more complete understanding of vulnerability in nursing discourse. DISCUSSION: The purpose of this paper is to examine nursing contributions to the concept of vulnerability and consider how a broader perspective that includes socio-political dimensions may assist nurses to reach beyond the immediate milieu of the patient into the dominant social, political, and economic structures that produce and sustain vulnerability. SUMMARY: By broadening nurse's conceptualization of vulnerability, nurses can obtain the consciousness needed to move beyond a peripheral role of nursing that has been dominantly situated within institutional settings to contribute in the larger arena of social, economic, political and global affairs. PMID- 22520842 TI - Beta catenin and cytokine pathway dysregulation in patients with manifestations of the "PTEN hamartoma tumor syndrome". AB - BACKGROUND: The "PTEN hamartoma tumor syndrome" (PHTS) includes a group of syndromes caused by germline mutations within the tumor suppressor gene "phosphatase and tensin homolog deleted on chromosome ten" (PTEN), characterized by multiple polyps in the gastrointestinal tract and by a highly increased risk of developing malignant tumours in many tissues. The current work clarifies the molecular basis of PHTS in three unrelated Italian patients, and sheds light on molecular pathway disregulation constitutively associated to PTEN alteration. METHODS: We performed a combination of RT-PCR, PCR, sequencing of the amplified fragments, Real Time PCR and western blot techniques. RESULTS: Our data provide the first evidence of beta-catenin accumulation in blood cells of patients with hereditary cancer syndrome caused by germ-line PTEN alteration. In addition, for the first time we show, in all PHTS patients analysed, alterations in the expression of TNFalpha, its receptors and IL-10. Importantly, the isoform of TNFRI that lacks the DEATH domain (TNFRSF1beta) was found to be overexpressed. CONCLUSION: In light of our findings, we suggest that the PTEN pathway disregulation could determine, in non-neoplastic cells of PHTS patients, cell survival and pro-inflammatory stimulation, mediated by the expression of molecules such as beta-catenin, TNFalpha and TNFalpha receptors, which could predispose these patients to the development of multiple cancers. PMID- 22520843 TI - Beneficial effect of branched-chain amino acid supplementation on glycemic control in chronic hepatitis C patients with insulin resistance: implications for type 2 diabetes. AB - Branched-chain amino acids (BCAAs) improve disorders of albumin metabolism, quality of life, subjective symptoms, and prognosis in patients with chronic hepatitis. However, it remains unclear whether they improve insulin resistance. We examined the effects of BCAAs on glucose tolerance and insulin sensitivity in patients with chronic hepatitis C and insulin resistance. Individuals with a definitive diagnosis of chronic hepatitis C and insulin resistance were eligible for participation. Eligible participants were randomly assigned to the BCAA group or a control group. Participants were then crossed over to the other treatment for a further 12 weeks. Baseline clinical features, laboratory markers, fatty acid levels, and insulin sensitivity, assessed with oral glucose tolerance tests and a hyperinsulinemic euglycemic clamp, were also examined before and 12 and 24 weeks after the beginning of the study. Of the 27 patients who completed the study, 14 began in the BCAA group and 13 began as controls. There were no significant differences in glucose metabolism parameters or lipid profiles between the groups. HbA1c values were improved in 10 patients and worsened or remained unchanged in 17 patients. The only predictive variable for change in HbA1c was the baseline Matsuda index: the lower the index, the greater the improvement in HbA1c values. BCAA therapy did not have adverse effects on glucose tolerance or insulin sensitivity in patients with chronic hepatitis C and insulin resistance. Moreover, it had a therapeutic effect on HbA1c values in patients with marked peripheral (primarily muscle) insulin resistance. PMID- 22520844 TI - The JAK-STAT pathway at twenty. AB - We look back on the discoveries that the tyrosine kinases TYK2 and JAK1 and the transcription factors STAT1, STAT2, and IRF9 are required for the cellular response to type I interferons. This initial description of the JAK-STAT pathway led quickly to additional discoveries that type II interferons and many other cytokines signal through similar mechanisms. This well-understood pathway now serves as a paradigm showing how information from protein-protein contacts at the cell surface can be conveyed directly to genes in the nucleus. We also review recent work on the STAT proteins showing the importance of several different posttranslational modifications, including serine phosphorylation, acetylation, methylation, and sumoylation. These remarkably proficient proteins also provide noncanonical functions in transcriptional regulation and they also function in mitochondrial respiration and chromatin organization in ways that may not involve transcription at all. PMID- 22520846 TI - Janus kinase deregulation in leukemia and lymphoma. AB - Genetic alterations affecting members of the Janus kinase (JAK) family have been discovered in a wide array of cancers and are particularly prominent in hematological malignancies. In this review, we focus on the role of such lesions in both myeloid and lymphoid tumors. Oncogenic JAK molecules can activate a myriad of canonical downstream signaling pathways as well as directly interact with chromatin in noncanonical processes, the interplay of which results in a plethora of diverse biological consequences. Deciphering these complexities is shedding unexpected light on fundamental cellular mechanisms and will also be important for improved diagnosis, identification of new therapeutic targets, and the development of stratified approaches to therapy. PMID- 22520845 TI - Inborn errors of human JAKs and STATs. AB - Inborn errors of the genes encoding two of the four human JAKs (JAK3 and TYK2) and three of the six human STATs (STAT1, STAT3, and STAT5B) have been described. We review the disorders arising from mutations in these five genes, highlighting the way in which the molecular and cellular pathogenesis of these conditions has been clarified by the discovery of inborn errors of cytokines, hormones, and their receptors, including those interacting with JAKs and STATs. The phenotypic similarities between mice and humans lacking individual JAK-STAT components suggest that the functions of JAKs and STATs are largely conserved in mammals. However, a wide array of phenotypic differences has emerged between mice and humans carrying biallelic null alleles of JAK3, TYK2, STAT1, or STAT5B. Moreover, the high degree of allelic heterogeneity at the human JAK3, TYK2, STAT1, and STAT3 loci has revealed highly diverse immunological and clinical phenotypes, which had not been anticipated. PMID- 22520848 TI - M(odu)LLating the innate response. AB - The integration of chromatin modifiers into specific regulatory networks is not fully understood. In this issue of Immunity, Austenaa et al. (2012) demonstrate a specific role for the histone methyltransferase MLL4 (Wbp7) in controlling the expression of critical molecules in the Toll-like receptor pathway. PMID- 22520849 TI - STATus report on tetramers. AB - STAT proteins bind DNA as dimers to regulate gene expression. Cooperative recruitment of pairs of dimers (tetramers) to adjacent DNA sites has also been documented. In this issue, Lin et al. (2012) examined tetramer function in vivo and showed that STAT5 tetramers function primarily as transcriptional activators. PMID- 22520847 TI - JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. AB - The discovery of the Janus kinase (JAK)-signal transducer and activator of transcripton (STAT) signaling pathway, a landmark in cell biology, provided a simple mechanism for gene regulation that dramatically advanced our understanding of the action of hormones, interferons, colony-stimulating factors, and interleukins. As we learn more about the complexities of immune responses, new insights into the functions of this pathway continue to be revealed, aided by technology that permits genome-wide views. As we celebrate the 20(th) anniversary of the discovery of this paradigm in cell signaling, it is particularly edifying to see how this knowledge has rapidly been translated to human immune disease. Not only have genome-wide association studies demonstrated that this pathway is highly relevant to human autoimmunity, but targeting JAKs is now a reality in immune-mediated disease. PMID- 22520850 TI - Toll signaling in flies and mammals: two sorts of MyD88. AB - The mammalian MyD88 signaling molecule participates in Toll receptor signaling within the cytoplasm. In this issue of Immunity, Marek and Kagan (2012) report that Drosophila (d)MyD88 acts instead at the plasma membrane to sort the signaling adaptor Tube. PMID- 22520851 TI - Actin' as a death signal. AB - Cell death needs to be detected by immune cells. In this issue of Immunity, Ahrens et al. (2012) and Zhang et al. (2012) show that actin filaments become exposed on necrotic cells and act as ligands for the C-type lectin receptor Clec9a. PMID- 22520853 TI - Episodic autobiographical memory in normal aging and mild cognitive impairment: a population-based study. AB - While episodic memory impairment has been extensively studied in normal and pathological aging, studies investigating age-related episodic autobiographical memory among representative samples are scarce. We therefore investigated episodic autobiographical memory in a sample of 395 participants of a population based prospective study of aging. Three groups were compared, consisting of 194 middle-aged participants, 138 healthy old-aged participants and 63 patients with mild cognitive impairment (MCI). Results showed a significant impairment of episodic autobiographical memory performance associated with MCI, but not with normal aging. These deficits were significantly correlated with verbal memory performances, but not with measures of executive functions. PMID- 22520852 TI - Critical Role of STAT5 transcription factor tetramerization for cytokine responses and normal immune function. AB - Cytokine-activated STAT proteins dimerize and bind to high-affinity motifs, and N terminal domain-mediated oligomerization of dimers allows tetramer formation and binding to low-affinity tandem motifs, but the functions of dimers versus tetramers are unknown. We generated Stat5a-Stat5b double knockin (DKI) N-domain mutant mice in which STAT5 proteins form dimers but not tetramers, identified cytokine-regulated genes whose expression required STAT5 tetramers, and defined dimer versus tetramer consensus motifs. Whereas Stat5-deficient mice exhibited perinatal lethality, DKI mice were viable; thus, STAT5 dimers were sufficient for survival. Nevertheless, STAT5 DKI mice had fewer CD4(+)CD25(+) T cells, NK cells, and CD8(+) T cells, with impaired cytokine-induced and homeostatic proliferation of CD8(+) T cells. Moreover, DKI CD8(+) T cell proliferation after viral infection was diminished and DKI Treg cells did not efficiently control colitis. Thus, tetramerization of STAT5 is critical for cytokine responses and normal immune function, establishing a critical role for STAT5 tetramerization in vivo. PMID- 22520854 TI - Hashimoto encephalopathy diagnosis after 40 years of a schizophrenia-like disorder. PMID- 22520855 TI - Association study of a new schizophrenia susceptibility locus of 10q24.32-33 in a Han Chinese population. AB - Recently, a new schizophrenia susceptibility locus 10q24.32-q24.33, containing two single-nucleotide polymorphisms (SNPs: rs7914558 and rs11191580), was identified in a genome-wide association study. To examine if this locus is associated with schizophrenia in the Han Chinese population, we analyzed six SNPs, including two SNPs within the region of interest. The sample consisted of 1430 schizophrenia cases and 1570 controls from genetically independent members of the Han population. Single-SNP association, haplotype association and sex specific association analyses were performed. Three SNPs, rs7914558 (p=1.41*10( 4); OR=1.11; 95% CI 1.05-1.17), rs12220375 (p=1.18*10(-4); OR=1.06; 95% CI 1.03 1.09) and rs11191580 (p=3.03*10(-4); OR=1.05; 95% CI 1.02-1.10), mapped to the locus and were significantly associated in our sample set. Further genotype and haplotype association analyses suggested a similar pattern. Similar to results from European populations, our results provide further evidence that this region associated with schizophrenia in Han Chinese. Results also confirm previous reports suggesting that 10q24.32-q24.33 offers an intriguing new insight into the pathogenesis of schizophrenia and may play an important role in its etiology. PMID- 22520856 TI - Frontal delta power associated with negative symptoms in ultra-high risk individuals who transitioned to psychosis. AB - It has recently been shown that treatment with long-chain omega-3 polyunsaturated fatty acids (PUFAs) could decrease the rate of transition to psychosis, and improve psychiatric symptoms and global functioning in people at ultra-high risk (UHR) for psychosis. Previous studies have suggested that resting state brain activity measured with electroencephalography (EEG) may represent an objective biomarker of changes in neural function associated with supplementation with omega-3 PUFAs. It has also been proposed that although resting state EEG cannot, by itself, predict transition to psychosis in UHR individuals, the combination of resting state EEG with negative symptoms may be a valid predictor of transition. The present study investigated whether treatment with omega-3 PUFAs influenced resting state EEG in UHR participants, and whether or not the association of the participants' resting state EEG with their levels of negative symptoms was dependent on their transition status. The brain activity of 73 UHR participants was recorded in the context of a randomized, placebo-controlled trial of the effects of supplementation with omega-3 PUFAs. The UHR participants who subsequently transitioned to psychosis (UHR+) did not differ from those who did not transition (UHR-) in terms of resting state EEG power in any frequency band. However, negative symptom scores were associated with increased delta activity in the frontal region of the UHR+ participants, but not in the UHR- participants. Treatment with omega-3 PUFAs did not induce changes in resting state EEG in either group. The results suggest that decreased frontal delta activity, in combination with high levels of negative symptoms, may be a risk factor for subsequent transition to psychosis in UHR individuals. PMID- 22520857 TI - Charting a course for equal access to immunization. PMID- 22520858 TI - The impact of increased oxygen conditions on metal-contaminated sediments part II: effects on metal accumulation and toxicity in aquatic invertebrates. AB - The present study evaluated the effect of increasing oxygen concentrations in overlying surface water on the accumulation and toxicity of sediment-bound metals in the aquatic invertebrates Lumbriculus variegatus, Asellus aquaticus and Daphnia magna. A 54 days experiment using three experimental treatments (90% O(2) in overlying surface water, 40% O(2) and a non-polluted control) was conducted. At 6 different time points (after 0, 2, 5, 12, 32 and 54 days) acid volatile sulfides (AVS), simultaneously extracted metals (SEM) and total organic carbon (TOC) were measured in the superficial sediment layer (0-1 cm). At each time point, accumulated metal levels as well as the available energy stores were measured in L. variegatus and A. aquaticus and each time D. magna was exposed to surface water in a 24 h toxicity test. Additionally metallothionein-like protein (MTLP) induction was quantified in L. variegatus. Oxygen induced changes in sediment AVS resulted in faster accumulation of metals from contaminated sediments in A. aquaticus, while no differences in toxicity in this species were observed. Ag, Cr, As and Co accumulation as well as toxicity in water exposed D. magna were clearly enhanced after 54 days, caused by oxidation of metal-sulfide complexes. Due to their feeding and burrowing behaviour, metal accumulation and toxicity in L. variegatus was not influenced by geochemical characteristics. Nevertheless, a rapid induction of MTLP was observed in both the 90% O(2) and the 40% O(2) treatment. The present study showed that elevated oxygen concentrations in overlying surface water can directly enhance metal accumulation and toxicity in aquatic invertebrates, however this is highly dependent on the organisms ecology and most dominant metal exposure route (water vs. sediment). PMID- 22520859 TI - N2O production rate of an enriched ammonia-oxidising bacteria culture exponentially correlates to its ammonia oxidation rate. AB - The relationship between the ammonia oxidation rate (AOR) and nitrous oxide production rate (N(2)OR) of an enriched ammonia-oxidising bacteria (AOB) culture was investigated. The AOB culture was enriched in a nitritation system fed with synthetic anaerobic digester liquor. The AOR was controlled by adjusting the dissolved oxygen (DO) and pH levels and also by varying the initial ammonium (NH(4)(+)) concentration in batch experiments. Tests were also performed directly on the parent reactor where a stepwise decrease/increase in DO was implemented to alter AOR. The experimental data indicated a clear exponential relationship between the biomass specific N(2)OR and AOR. Four metabolic models were used to analyse the experimental data. The metabolic model formulated based on aerobic N(2)O production from the decomposition of nitrosyl radical (NOH) predicted the exponential correlation observed experimentally. The experimental data could not be reproduced by models developed on the basis of N(2)O production through nitrite (NO(2)(-)) and nitric oxide (NO) reduction by AOB. PMID- 22520860 TI - Automatic control systems for submerged membrane bioreactors: a state-of-the-art review. AB - Membrane bioreactor (MBR) technology has become relatively widespread as an advanced treatment for both industrial and municipal wastewater, especially in areas prone to water scarcity. Although operational cost is a key issue in MBRs, currently only a few crucial papers and inventions aimed to optimise and enhance MBR efficiency have been published. The present review summarises the available solutions in the area of automatic control systems and widely explores the advances in automation and control for MBRs. In this review of state of the art, different control systems are evaluated comparatively, distinguishing between control systems used for the filtration process and those used for the biological process of MBRs and describing the challenge faced by integrated control systems. The existing knowledge is classified according to the manipulated variables, the operational mode (open-loop or closed-loop) and the controlled variables used. PMID- 22520861 TI - Understanding how brass ball valves passing certification testing can cause elevated lead in water when installed. AB - The lead leaching potential of new brass plumbing devices has come under scrutiny as a significant source of lead in drinking water (>300 MUg/L) of new buildings around the world. Experiments were conducted using ball valves that were sold as certified and known to have caused problems in practice, in order to better understand how installed products could create such problems, even if they passed "leaching tests" such as National Sanitation Foundation (NSF) Standard 61 Section 8. Diffusion of lead from within the device into water when installed can increase lead leaching by orders of magnitude relative to results of NSF testing, which once only required exposure of very small volumes of water within the device. "Normalization" of the lead-in-water result tended to produce estimates of lead concentration that were much lower than actual lead measured at the tap. Finally, the presence of flux could also dramatically increase lead leaching, whereas high water velocity had relatively little effect. PMID- 22520862 TI - Spectroscopic studies of photosynthetic responses of tomato plants to the interaction of zinc and cadmium toxicity. AB - The in vivo chlorophyll (Chl) fluorescence spectra of Solanum lycopersicum leaves were recorded in the spectral region 650-800nm using a spectroscopic method based on ultraviolet light emitting diode induced fluorescence spectroscopy (UV-LED IFS). These spectra have been used to analyze the interactive functions of cadmium (Cd(2+)) and zinc (Zn(2+)) on photosynthetic activities of S. lycopersicum plants. The fluorescence intensity ratios (F(690)/F(735)) of the chlorophyll bands at 685 and 730nm were calculated by evaluating curve fitted parameters using a Gaussian spectral function, for control as well as treated plants. The fluorescence induction kinetics (Kautsky effect) was also measured on dark adapted intact plant leaves at the chlorophyll bands for determining the variable chlorophyll fluorescence decrease ratio (R(Fd) values) and the stress adaptation index (Ap). In addition, metal accumulation in plants, plant growth and photosynthetic pigments content were estimated. It was found that the R(Fd)(690), R(Fd)(730) and Ap values decreased whereas the F(690)/F(735) ratio increased in the case of 10MUM Cd(2+) treated plants, indicating an impairment of the photosynthetic efficiency. Zn(2+) supplementation, at low concentration (10 and 50MUM), in combination with Cd(2+) protect the photochemical functions. However, the high Zn(2+) concentration exacerbated the negative effects of Cd(2+) and showed a severe decrease of R(Fd)(690), R(Fd)(730) and Ap values compared to Cd(2+) alone. It is seen that F(690)/F(735) ratios are strongly correlated with chlorophyll contents. The results demonstrate the usefulness of F(690)/F(735), Ap and R(Fd) values in determining the potential photosynthetic activity of an intact attached leaf in a non-destructive way. PMID- 22520863 TI - Effect of sequential treatment with syndrome differentiation on acute exacerbation of chronic obstructive pulmonary disease and "AECOPD Risk-Window": study protocol for a randomized placebo-controlled trial. AB - BACKGROUND: Frequent chronic obstructive pulmonary disease (COPD) exacerbation is a major cause of hospital admission and mortality. It has been reported that Traditional Chinese Medicine (TCM) may relieve COPD symptoms and reduce the incidence of COPD exacerbations, thus improving life quality of COPD patients. The acute exacerbation of COPD risk-window (AECOPD-RW) is the period after an exacerbation and before the patient returns to baseline. In the AECOPD-RW, patients are usually at increased risk of a second exacerbation, which may lead to hospital admission and high mortality. It may be beneficial for acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients to receive interventions during AECOPD-RW. During exacerbations the treatment principle is to eliminate exogenous pathogens, whereas the AECOPD-RW treatment principle focuses on enhancing body resistance. METHODS/DESIGN: A prospective, multi-center, single-blinded, double-dummy and randomized controlled clinical trial is being conducted to test the therapeutic effects of a sequential two stage treatment, which includes eliminating pathogen and strengthening vital qi with syndrome differentiation. A total of 364 patients will be enrolled in this study with 182 in each treatment group (TCM and control). Patients received medication (or control) according to their assigned group. TCM for AECOPD were administered twice daily to patients with AECOPD over 7 to 21 days, followed by TCM for AECOPD-RW over 28 days. All patients were followed for six months. The clinical symptoms, the modified medical research council dyspnea (MMRC) scale and exacerbations were used as the primary outcome measures. Pulmonary function, quality of life and mortality rate were used as secondary outcome measures. DISCUSSION: It is hypothesized that sequentially eliminating pathogens and strengthening vital qi treatments with syndrome differentiation will have beneficial effects on reducing the frequency and duration of acute exacerbation, relieving symptoms and improving quality of life for COPD patients. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov, ChiCTR-TRC 11001460. PMID- 22520864 TI - Comparative karyotype analysis and chromosome evolution in the genus Aplastodiscus (Cophomantini, Hylinae, Hylidae). AB - BACKGROUND: The frogs of the Tribe Cophomantini present, in general, 2n = 24 karyotype, but data on Aplastodiscus showed variation in diploid number from 2n = 24 to 2n = 18. Five species were karyotyped, one of them for the first time, using conventional and molecular cytogenetic techniques, with the aim to perform a comprehensive comparative analysis towards the understanding of chromosome evolution in light of the phylogeny. RESULTS: Aplastodiscus perviridis showed 2n = 24, A. arildae and A. eugenioi, 2n = 22, A. callipygius, 2n = 20, and A. leucopygius, 2n = 18. In the metaphase I cells of two species only bivalents occurred, whereas in A. arildae, A. callipygius, and A. leucopygius one tetravalent was also observed besides the bivalents. BrdU incorporation produced replication bands especially in the largest chromosomes, and a relatively good banding correspondence was noticed among some of them. Silver impregnation and FISH with an rDNA probe identified a single NOR pair: the 11 in A. perviridis and A. arildae; the 6 in A. eugenioi; and the 9 in A. callipygius and A. leucopygius. C-banding showed a predominantly centromeric distribution of the heterochromatin, and in one of the species distinct molecular composition was revealed by CMA3. The telomeric probe hybridised all chromosome ends and additionally disclosed the presence of telomere-like sequences in centromeric regions of three species. CONCLUSIONS: Based on the hypothesis of 2n = 24 ancestral karyotype for Aplastodiscus, and considering the karyotype differences and similarities, two evolutionary pathways through fusion events were suggested. One of them corresponded to the reduction of 2n = 24 to 22, and the other, the reduction of 2n = 24 to 20, and subsequently to 18. Regarding the NOR, two conditions were recognised: plesiomorphy, represented by the homeologous small-sized NOR-bearing pairs, and derivation, represented by the NOR in a medium-sized pair. In spite of the apparent uniformity of C-banding patterns, heterogeneity in the molecular composition of some repetitive regions was revealed by CMA3 staining and by interstitial telomeric labelling. The meiotic tetravalent might be due to minute reciprocal translocations or to non-chiasmatic ectopic pairing between terminal repetitive sequences. The comparative cytogenetic analysis allowed to outline the chromosome evolution and contributed to enlighten the relationships within the genus Aplastodiscus. PMID- 22520865 TI - Aquatic biosystems: reactions and actions. AB - Aquatic biological systems are a critical part of the structure and function of earth's biosphere. While attention of the scientific community is often focused on the reaction of biological systems to changes in the environment, these systems also have profound effects, or actions, on the environment. Throughout the evolutionary history of earth, the rise and/or fall of different aquatic biosystems has impacted the character of the biosphere. At no time have environmental changes been more important to all life on earth than in the modern era, which underscores the need for the new journal, Aquatic Biosystems. We welcome submission of original research manuscripts, reviews, and commentaries to the journal. PMID- 22520866 TI - Genesis of spermatodesms in Tylopsis liliifolia (Orthoptera: Phaneropterinae) and their transit in the male genital tract. AB - The spermatodesms of Tylopsis liliifolia form in the most proximal follicular cysts and are composed of a large number of sperm held together by a cap located in the anterior region of the acrosome. The cap is formed by short thin fibrils, loosely arranged at random, probably derived from secretory activity of cells of the cyst wall. Compared to other Tettigoniidae, a peculiar feature is acrosomal wings that twist gradually around the anterior region of the nucleus; at the end of the twisting process, the region of the sperm acrosome, observed in cross section, shows a typical spiral form. Spermatodesms do not undergo any substantial changes in the spermiduct. The epithelial cells of the wall have secretory activity and many show marked spermiophagic activity, which is conducted by epithelial cell protrusions that envelop the gametes, taking them into the cytoplasm. When removed from seminal vesicles and observed in vivo, spermatodesms show accentuated corkscrew movement, and when observed by SEM, slight torsion. Thus organized, spermatodesms are transferred to the spermatophore during mating, where they are transformed before reaching the seminal receptacle. PMID- 22520867 TI - Do Patients With High Vascular Risk Take Antihypertensive Medication Correctly? Cumple-MEMS Study. AB - INTRODUCTION AND OBJECTIVES: To assess compliance with treatment inhibit the renin-angiotensin system (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) in uncontrolled hypertension in patients at high cardiovascular risk. METHODS: Prospective, longitudinal, multicenter study, carried out in 102 Spanish primary care centers. We included 808 uncontrolled hypertensive patients treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers who were at high vascular risk; 4 visits were conducted: baseline and 1, 3, and 6 months later. Compliance was measured by electronic monitors. We calculated the mean percentage compliance, the overall percentage of compliers, once-daily compliers, compliers with the prescribed time frame, and antihypertensive coverage. We considered a patient to be a complier when the percentage compliance was 80%-100%. RESULTS: In all, 701 patients completed the study (mean age, 63.7 [11.1] years). The systolic and diastolic blood pressures decreased significantly (P<.0001) to 18.8 mmHg and 9.8 mmHg, respectively. The control rate was 70% (95% confidence interval, 65.6%-74.4%) (P=.0001). The rate of control was significantly higher among compliers than noncompliers (P<.05). The mean percentage of doses taken was 87.9% (95% confidence interval, 84.8%-91%) and the mean therapeutic coverage was 82.4% (95% confidence interval, 78.7%-86.1%). Overall, 73.3% of the patients were compliers (95% confidence interval, 69%-77.6%), 52.8% (95% confidence interval, 48%-57.6%) were once-daily compliers, and 46.5% (95% confidence interval, 41.9%-51.1%) complied with the prescribed time frame. Noncompliance was associated with a higher number of drugs prescribed (P<.001). CONCLUSIONS: In hypertensive patients at high vascular risk, the rate of therapeutic noncompliance was very high, mainly when they took 5 or more pills daily. PMID- 22520868 TI - The evolution of early animal embryos: conservation or divergence? AB - There is a remarkable similarity in the appearance of groups of animal species during periods of their embryonic development. This classic observation has long been viewed as an emphatic realization of the principle of common descent. Despite the importance of embryonic conservation as a unifying concept, models seeking to predict and explain different patterns of conservation have remained in contention. Here, we focus on early embryonic development and discuss several lines of evidence, from recent molecular data, through developmental networks to life-history strategies, that indicate that early animal embryos are not highly conserved. Bringing this evidence together, we argue that the nature of early development often reflects adaptation to diverse ecological niches. Finally, we synthesize old and new ideas to propose a model that accounts for the evolutionary process by which embryos have come to be conserved. PMID- 22520869 TI - A four-year, systems-wide intervention promoting interprofessional collaboration. AB - BACKGROUND: A four-year action research study was conducted across the Australian Capital Territory health system to strengthen interprofessional collaboration (IPC) though multiple intervention activities. METHODS: We developed 272 substantial IPC intervention activities involving 2,407 face-to-face encounters with health system personnel. Staff attitudes toward IPC were surveyed yearly using Heinemann et al's Attitudes toward Health Care Teams and Parsell and Bligh's Readiness for Interprofessional Learning scales (RIPLS). At study's end staff assessed whether project goals were achieved. RESULTS: Of the improvement projects, 76 exhibited progress, and 57 made considerable gains in IPC. Educational workshops and feedback sessions were well received and stimulated interprofessional activities. Over time staff scores on Heinemann's Quality of Interprofessional Care subscale did not change significantly and scores on the Doctor Centrality subscale increased, contrary to predictions. Scores on the RIPLS subscales of Teamwork & Collaboration and Professional Identity did not alter. On average for the assessment items 33% of staff agreed that goals had been achieved, 10% disagreed, and 57% checked neutral. There was most agreement that the study had resulted in increased sharing of knowledge between professions and improved quality of patient care, and least agreement that between professional rivalries had lessened and communication and trust between professions improved. CONCLUSIONS: Our longitudinal interventional study of IPC involving multiple activities supporting increased IPC achieved many project specific goals. However, improvements in attitudes over time were not demonstrated and neutral assessments predominated, highlighting the difficulties faced by studies targeting change at the systems level and over extended periods. PMID- 22520870 TI - Screening for distant metastases before salvage surgery in patients with recurrent head and neck squamous cell carcinoma: a retrospective case series comparing thoraco-abdominal CT, positron emission tomography and abdominal ultrasound. AB - OBJECTIVES: To evaluate the role of 18-fluoro-deoxy-d-glucose (FDG)-positron emission tomography (PET) scan for detecting distant metastases in the preoperative assessment of patients with recurrent head and neck squamous cell carcinoma (HNSCC). DESIGN: Retrospective study. SETTING: University Teaching Hospital. MAIN OUTCOME MEASURES: Thirty-seven consecutive patients who presented, between April 2008 and April 2010, a local and/or regional recurrence of head and neck squamous cell carcinoma after treatment with radio-chemotherapy were studied. The work-up included thoraco-abdominal computed tomography (CT), fluoro-deoxy-D-glucose-positron emission tomography scan and abdominal ultrasound. The imaging results, when positive, were compared to histology or cytology (conducted during targeted examinations, for example, fiberoptic oesophago-gastro-duodenal search, colonoscopy, bronchoscopy, liver biopsy) or targeted imaging examination (Abdominal MRI, sonography) combined with clinical follow-up. All patients were followed-up for at least 6 months. Positron emission tomography performances were then analysed and compared with those of conventional imaging for detecting distant metastases. RESULTS: Among the 37 patients, 9 (24%) had visceral metastases. The sensitivity, specificity, positive predictive value and negative predictive value for detecting metastasis or second primary were, respectively, 100%, 94%, 86% and 100% for CT and 92%, 87%, 74% and 97% for positron emission tomography. Computed tomography and positron emission tomography were strictly concordant in 32/37 (86%) of cases. No false-negative result was found for CT, while we found one case of false-negative positron emission tomography. The number of false-positive results was two for CT and four for positron emission tomography. CONCLUSIONS: From our study, positron emission tomography does not appear to offer a first-choice technique for the detection of metastases before salvage surgery as CT detected all lesions visible on positron emission tomography. PMID- 22520871 TI - [Spontaneous arterial systemic tumor embolism]. PMID- 22520872 TI - [Primary cutaneous nocardiosis caused by Nocardia farcinica]. PMID- 22520876 TI - Ultrathin transnasal endoscopy without sedation: the straight skinny. PMID- 22520877 TI - Usefulness of endoscopic radial incision and cutting method for refractory esophagogastric anastomotic stricture (with video). AB - BACKGROUND: There is no effective treatment for gastroesophageal anastomotic strictures that are refractory to repeated endoscopic balloon dilation (EBD). However, EBD is still selected worldwide to manage such refractory strictures. To relieve the symptoms of dysphagia and keep a wide lumen, we developed a new incisional treatment, radial incision and cutting (RIC). OBJECTIVE: To evaluate the efficacy and safety of the RIC method for the treatment of refractory anastomotic strictures. DESIGN: Retrospective cohort study. SETTING: National Cancer Center and University Hospital. PATIENTS: This study involved 54 consecutive patients with refractory anastomotic stricture after esophagogastric surgery. INTERVENTION: RIC. MAIN OUTCOME MEASUREMENTS: The safety and clinical success of RIC and the long-term patency after RIC compared with those of continued EBD. RESULTS: The median procedure time of RIC was 14 minutes (range, 4 40 minutes). No serious adverse events associated with RIC were observed. Immediately after RIC, 81.3% (26/32) of patients were able to eat solid food without symptoms of dysphagia. As a short-term effect, the dysphagia improved after RIC in 93.8% (30/32) of the patients. As a long-term effect, 63% (17/27) and 62% (13/21) of patients were able to eat solid food 6 and 12 months after RIC, respectively. The 6-month and 12-month patency rates were significantly different between the RIC group and the continued EBD group (65.3% vs 19.8%, P < .005; 61.5% vs 19.8%, P < .005). LIMITATIONS: Nonrandomized retrospective study. CONCLUSIONS: RIC is an effective and safe method. The demonstration of the validity of this method may place RIC as a new medical treatment for patients with refractory stricture after surgical resection for esophagogastric diseases. PMID- 22520878 TI - Magnetic endoscope imaging colonoscope: a new modality for hypothesis testing in unsedated colonoscopy. PMID- 22520879 TI - Teaching the endoscopic and paraendoscopic skills of gastroenterology. PMID- 22520880 TI - An unsolved conundrum: the ideal follow-up strategy after curative surgery for colorectal cancer. PMID- 22520881 TI - Inverted diverticulum or adenomatous lesion? Identification using confocal laser endomicroscopy. PMID- 22520883 TI - Post-ERCP mortality and provider volume in England. PMID- 22520884 TI - Better stent function with chemotherapy: effects of chemotherapy or just a better prognosis? PMID- 22520886 TI - Autoimmune pancreatitis presenting with gastric outlet obstruction. PMID- 22520887 TI - Duodenal web: complications and failure of endoscopic treatment. PMID- 22520888 TI - Recurrent esophageal web in Plummer-Vinson syndrome successfully treated with postdilation intralesional injection of mitomycin C. PMID- 22520889 TI - A single-center experience with spiral enteroscopy: a note of caution. PMID- 22520891 TI - Telling the truth: why disclosure matters in chronic kidney disease. PMID- 22520892 TI - Privatisation: an exercise in ambiguity and ideology. PMID- 22520893 TI - Out of hours and primary care: closer and closer apart. PMID- 22520894 TI - Not just another primary care workforce crisis .... PMID- 22520895 TI - The Fremantle Primary Prevention Study: a multicentre randomised trial of absolute cardiovascular risk reduction. PMID- 22520896 TI - Why bother talking to teenagers? PMID- 22520897 TI - The one and the many. PMID- 22520898 TI - Aiming to reduce late detection of head and neck cancer. PMID- 22520899 TI - Italian lessons: exploring general practice in Italy. PMID- 22520900 TI - The other side. PMID- 22520901 TI - The private finance initiative: a case study of wastage in the NHS in Wandsworth. PMID- 22520905 TI - Learning from the experts. PMID- 22520906 TI - Communicating risk to patients and the public. PMID- 22520907 TI - Syphilitic tonsillitis in primary care: a case report. PMID- 22520908 TI - Tips for GP trainees wishing to undertake an international experience. PMID- 22520909 TI - Treatment needs and diagnosis awareness in primary care patients with chronic kidney disease. AB - BACKGROUND: GPs in England are required to keep a register of patients with chronic kidney disease (CKD). National Institute for Health and Clinical Excellence (NICE) guidelines recommend regular follow-up, but patients are perceived to be low risk and not requiring active management. AIM: To assess treatment needs of CKD stage 3 patients in primary care, as well as their awareness of CKD. DESIGN AND SETTING: A cross-sectional analysis from a longitudinal prospective study in 32 general practices. METHOD: A total of 1741 participants underwent clinical assessment including urine and blood tests. Participants were asked about awareness of their CKD. Results were reviewed and a letter recommending treatment in line with NICE guidelines was sent to their GP. RESULTS: The mean age of participants was 73 +/- 9 years; 60% (n = 1052) were female and diabetes was present in 17%; 67% of participants required further intervention. Most required improved control of hypertension (n = 1576; 33.1% of cohort). Other recommendations included advice to investigate anaemia (n = 1142; 8.2%) or stop nephrotoxic drugs (n = 1120; 7.5%). Less than 6% of participants met NICE criteria for referral to nephrology services and 41% were unaware of their CKD diagnosis. Multivariable analysis identified subjects with formal educational qualifications, age <75 years, estimated glomerular filtration rate (eGFR) 30-44 ml/min/1.73 m(2), and significant albuminuria as more likely to be aware of their diagnosis. CONCLUSION: The study data show that the majority of patients required at least one intervention to improve the management of their CKD. Most interventions could be delivered in primary care and only a minority required nephrology referral. Many patients were unaware of their CKD diagnosis, and efforts should be made to improve this to facilitate involvement in their care. PMID- 22520910 TI - Understanding the management of early-stage chronic kidney disease in primary care: a qualitative study. AB - BACKGROUND: Primary care is recognised to have an important role in the delivery of care for people with chronic kidney disease (CKD). However, there is evidence that CKD management is currently suboptimal, with a range of practitioner concerns about its management. AIM: To explore processes underpinning the implementation of CKD management in primary care. DESIGN AND SETTING: Qualitative study in general practices participating in a chronic kidney disease collaborative undertaken as part of the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for Greater Manchester. METHOD: Semi-structured interviews were conducted with GPs and practice nurses (n = 21). Normalisation Process Theory provided a framework for generation and analysis of the data. RESULTS: A predominant theme was anxiety about the disclosure of early-stage CKD with patients. The tensions experienced related to identifying and discussing CKD in older people and patients with stage 3A, embedding early-stage CKD within vascular care, and the distribution of work within the practice team. Participants provided accounts of work undertaken to resolve the difficulties encountered, with efforts having tended to focus on reassuring patients. Analysis also highlighted how anxiety surrounding disclosure influenced, and was shaped by, the organisation of care for people with CKD and associated long-term conditions. CONCLUSION: Offering reassurance alone may be of limited benefit, and current management of early stage CKD in primary care may miss opportunities to address susceptibility to kidney injury, improve self-management of vascular conditions, and improve the management of multimorbidity. PMID- 22520911 TI - Predicting the risk of chronic kidney disease in the UK: an evaluation of QKidney(r) scores using a primary care database. AB - BACKGROUND: Chronic kidney disease is a major health concern that, if left untreated, may progress to end-stage kidney failure (ESKF). Identifying individuals at an increased risk of kidney disease and who might benefit from a therapeutic or preventive intervention is an important challenge. AIM: To evaluate the performance of the QKidney(r) scores for predicting 5-year risk of developing moderate-severe kidney disease and ESKF in an independent UK cohort of patients from general practice records. DESIGN AND SETTING: Prospective cohort study to evaluate the performance of two risk scores for kidney disease in 364 practices from the UK, contributing to The Health Improvement Network (THIN) database. METHOD: Data were obtained from 1.6 million patients registered with a general practice surgery between 1 January 2002 and 1 July 2008, aged 35-74 years, with 43,186 incident cases of moderate-severe kidney disease and 2663 incident cases of ESKF. This is the first recorded evidence of moderate-severe chronic kidney and ESKF as recorded in general practice records. RESULTS: The results from this independent and external validation of QKidney scores indicate that both scores showed good performance data for both moderate-severe kidney disease and ESKF, on a large cohort of general practice patients. Discrimination and calibration statistics were better for models including serum creatinine; however, there were considerable amounts of missing data for serum creatinine. QKidney scores both with and without serum creatinine were well calibrated. CONCLUSION: QKidney scores have been shown to be useful tools to predict the 5 year risk of moderate-severe kidney disease and ESKF in the UK. PMID- 22520912 TI - Identifying patients with suspected renal tract cancer in primary care: derivation and validation of an algorithm. AB - BACKGROUND: Earlier diagnosis of renal tract cancer could help improve survival so better tools are needed to help this. AIM: To derive and validate an algorithm to estimate the absolute risk of renal tract cancer in patients with and without symptoms in primary care. DESIGN: Cohort study using data from 375 UK QResearch(r) general practices for development and 189 for validation. METHOD: Included patients were aged 30-84 years free at baseline of a diagnosis of renal tract cancer (bladder, kidney, ureter, or urethra) and without haematuria, abdominal pain, appetite loss, or weight loss in previous 12 months. The primary outcome was incident diagnosis of renal tract cancer recorded in the next 2 years. Risk factors examined were age, body mass index, smoking, alcohol, deprivation, treated hypertension, renal stones, structural kidney problems, diabetes, previous diagnosis of cancer apart from renal tract cancer, haematuria, abdominal pain, appetite loss, weight loss, diarrhoea, constipation, tiredness, and anaemia. Cox proportional hazards models were used to develop separate risk equations in males and females. Measures of calibration and discrimination assessed performance in the validation cohort. RESULTS: There were 2878 incident cases of renal tract cancer from 4.1 million person-years in the derivation cohort. Independent predictors in both males and females were age, smoking status, haematuria, abdominal pain, weight loss, and anaemia. A history of prior cancer other than renal tract cancer, and appetite loss were predictors for females only. On validation, the algorithms explained 75% of the variation in females and 76% in males. The receiver operating curve statistics were 0.91 (females) and 0.95 (males). The D statistic was 3.53 (females) and 3.60 (males). The 10% of patients with the highest predicted risks contained 87% of all renal tract cancers diagnosed over the next 2 years. CONCLUSION: The algorithm has good discrimination and calibration and could potentially be used to identify those at highest risk of renal tract cancer, to facilitate more timely referral and investigation. PMID- 22520913 TI - Experiences of carers managing childhood eczema and their views on its treatment: a qualitative study. AB - BACKGROUND: Childhood eczema causes significant impact on quality of life for some families, yet non-concordance with treatment is common. AIM: To explore parents' and carers' views of childhood eczema and its treatment. DESIGN AND SETTING: Qualitative interview study in primary care in the south of England. METHOD: Carers of children aged <=5 years with a recorded diagnosis of eczema, who reported that eczema was still a problem, were invited to participate. Thirty one parents were interviewed from 28 families. RESULTS: Many parents expressed frustration with both medical care and prescribed treatments. They felt their child's suffering was not 'taken seriously', and experienced messages about a 'trial and error' prescribing approach and assurance that their child would 'grow out of it' as a further 'fobbing off', or dismissal. Many carers were ambivalent about eczema treatments, mainly topical corticosteroids but also emollients. Dietary exclusions as a potential cure were of interest to most families, although they perceived healthcare professionals as uninterested in this. Families varied in the extent to which they felt able to manage eczema and the length of time taken to gain control. In some instances, this was linked to not understanding advice or receiving conflicting advice from different healthcare providers. CONCLUSION: Poor concordance with treatments seems unsurprising in the presence of such dissonance between carers' and healthcare providers' agendas. Acknowledging the impact of the condition, greater attention to how key messages are delivered and addressing carers' treatment beliefs are likely to improve engagement with effective self-care. PMID- 22520914 TI - Prophylactic treatment of migraine by GPs: a qualitative study. AB - BACKGROUND: Despite the considerable impact of migraine, the use of preventive medication in primary care is limited. Only about 5% of migraine patients who qualify for prophylaxis actually receive it, and adherence is far from optimal. AIM: To explore the opinions of GPs regarding preventive medication for migraine. DESIGN AND SETTING: A qualitative focus group study in Dutch general practice. METHOD: Four focus groups (six GPs each) were formed. GPs were purposively sampled to acquire a range of participants, reflecting the more general GP population. RESULTS: GPs perceived patients' concerns about the impact of migraine and the potential benefits of prophylaxis. However, some were hesitant to start prescribing prophylaxis due to doubts about effectiveness, potential side effects, and the risk of developing drug dependency. GPs' decisions were often based on considerations other than those presented in national guidelines, for example, the patient's need to control their own problem. Many GPs placed responsibility for initiating prophylaxis with the patient. CONCLUSION: Various considerations hamper GPs from managing migraine with preventive medication, and various patient-related concerns cause GPs to deviate from national headache guidelines. PMID- 22520915 TI - The compatibility of prescribing guidelines and the doctor-patient partnership: a primary care mixed-methods study. AB - BACKGROUND: UK policy expects health professionals to involve patients in decisions about their care (including medicines use) and, at the same time, to follow prescribing guidelines. The compatibility of these approaches is unclear. AIM: To explore the relationship between prescribing guidelines and patient partnership by exploring the attitudes of patients, GPs and primary care trust (PCT) prescribing advisors. DESIGN AND SETTING: A mixed-methods study using qualitative, semi-structured interviews followed by a quantitative, questionnaire survey in primary care in Northern England. METHOD: Interviews were conducted with 14 patients taking a statin or a proton pump inhibitor, eight GPs and two prescribing advisors. A multi-variate sampling strategy was used. Qualitative findings were analysed using framework analysis. Questionnaires based on themes derived from the interviews were distributed to 533 patients and 305 GPs of whom 286 (54%) and 142 (43%) responded. RESULTS: Areas of tension between guidelines and patient partnership were identified, including potential damage to trust in the doctor and reduced patient choice, through the introduction of the policy maker as a third stakeholder in prescribing decisions. Other areas of tension related to applying single condition guidelines to patients with multiple illnesses, competition for doctors' time and the perception of cost containment. Many GPs coped with these tensions by adopting a flexible approach or prioritising the doctor-patient relationship over guidelines. CONCLUSION: Rigidly applied guidelines can limit patient choice and may damage the doctor-patient relationship. GPs need flexibility in order to optimise the implementation of prescribing guidelines, while responding to individuals' needs and preferences. PMID- 22520916 TI - Experience of contractual change in UK general practice: a qualitative study of salaried GPs. AB - BACKGROUND: General practice in the UK underwent major change in 2004, with the introduction of new contracts and a significant element of pay for performance. Although salaried GPs form an increasing proportion of the general practice workforce, little is known of their experiences. AIM: To explore the views and experiences of salaried GPs working in English general practice. DESIGN AND SETTING: Qualitative study using semi-structured interviews in 17 practices across England, between July 2007 and September 2009. METHOD: Interviews were conducted with 23 salaried GPs. A topic guide included questions on motivations for a career in general practice, descriptions of their daily working environment and duties, practice relationships, and future aspirations. RESULTS: The new ability to opt out of out-of-hours responsibilities was deemed positive for the profession but not a major driver for choosing medical speciality. Views regarding the impact of the Quality and Outcomes Framework were ambivalent. Differences in pay were regarded as largely reflective of differences in responsibility between salaried GPs and principals. Most participants reported conducting varied work in collaborative practices. Participants held varying career aspirations. CONCLUSION: Salaried GPs' working experiences were dependent upon personal aspirations and local context. Most salaried GPs were reportedly content with their current position but many also had aspirations of eventually attaining GP principal status. The current lack of available partnerships threatens to undo recent positive workforce progress and may lead to deep dissatisfaction within the profession and a future workforce crisis. Further large-scale quantitative work is required to assess the satisfaction and future expectations of those in salaried posts. PMID- 22520917 TI - Delivering a national programme of anticipatory care in primary care: a qualitative study. AB - BACKGROUND: Primary prevention often occurs against a background of inequalities in health and health care. Addressing this requires practitioners and systems to acknowledge the contribution of health-related and social determinants and to deal with the lack of interconnectedness between health and social service providers. Recognising this, the Scottish Government has implemented a national programme of anticipatory care targeting individuals aged 45-64 years living in areas of socioeconomic deprivation and at high risk of cardiovascular disease. This programme is called Keep Well. AIM: To explore the issues and tensions underpinning the implementation of a national programme of anticipatory care. DESIGN AND SETTING: A qualitative study in five Wave 1 Keep Well pilot sites, located in urban areas of Scotland, and involving 79 general practices. METHOD: Annual semi-structured interviews were conducted with 74 key stakeholders operating at national government level, local pilot level and within general practices, resulting in 118 interviews. Interview transcripts were analysed using the framework approach. RESULTS: Four underlying tensions were identified. First, those between a patient-focused general-practice approach versus a population-level health-improvement approach, linking disparate health and social services; secondly, medical approaches versus wider social approaches; thirdly, a population-wide approach versus individual targeting; and finally, reactive versus anticipatory care. CONCLUSION: Implementing an anticipatory care programme to address inequalities in cardiovascular disease identified several tensions, which need to be understood and resolved in order to inform the development of such approaches in general practice and to develop systems that reduce the degree of fragmentation across health and social services. PMID- 22520918 TI - Multimorbidity in primary care: a systematic review of prospective cohort studies. AB - BACKGROUND: Primary care increasingly deals with patients with multimorbidity, but relevant evidence-based interventions are scarce. Knowledge about multimorbidity over time is required to inform the development of effective interventions. AIM: This review identifies prospective cohort studies of multimorbidity in primary care to determine: their nature, scope and key findings; the methodologies used; and gaps in knowledge. DESIGN: Systematic review. METHOD: Studies were identified by searching electronic databases, reviewing citations, and writing to authors. Searches were limited to adult populations with no restrictions on publication date or language. In total, 996 articles were identified and screened. RESULTS: Of the 996 articles, six detailing five completed prospective cohort studies were selected as appropriate. Three of the studies were undertaken in the US and two in The Netherlands; none was nationally representative. The main focus of the studies was: healthcare utilisation and/or costs (n = 3); patients' physical functioning (n = 1); and risk factors for developing multimorbidity (n = 1). The conditions that were included varied widely. The findings of these studies showed that multimorbidity increased healthcare costs (n = 2), inpatient admission (n = 1), death rates (n = 1), and service use (n = 3), and reduced physical functioning (n = 1). One study identified psychosocial risk factors for multimorbidity. No study used random sampling, sample sizes were relatively small (414-3745 patients at baseline), and study duration was relatively short (1-4 years). No study focused on prevalence, treatment use, patient safety, service models, cultural or socioeconomic factors, and patient experience, and no study collected qualitative data. CONCLUSION: Few longitudinal studies based in primary care have investigated multimorbidity. Further large, long-term prospective studies are required to inform healthcare commissioning, planning, and delivery. PMID- 22520919 TI - Can sex during pregnancy cause a miscarriage? A concise history of not knowing. PMID- 22520920 TI - Situating general practice training in the general practice context. PMID- 22520921 TI - Genotyping of a tri-allelic polymorphism by a novel melting curve assay in MTHFD1L: an association study of nonsyndromic Cleft in Ireland. AB - BACKGROUND: Polymorphisms within the MTHFD1L gene were previously associated with risk of neural tube defects in Ireland. We sought to test the most significant MTHFD1L polymorphisms for an association with risk of cleft in an Irish cohort. This required the development of a new melting curve assay to genotype the technically challenging MTHFD1L triallelic deletion/insertion polymorphism (rs3832406). METHODS: Melting curve analysis was used to genotype the MTHFD1L triallelic deletion/insertion polymorphism (rs3832406) and a Single Nucleotide Polymorphism rs17080476 in an Irish cohort consisting of 981 Irish case-parent trios and 1,008 controls. Tests for association with nonsyndromic cleft lip with or without cleft palate and cleft palate included case/control analysis, mother/control analysis and Transmission Disequilibrium Tests of case-parent trios. RESULTS: A successful melting curve genotyping assay was developed for the deletion/insertion polymorphism (rs3832406). The TDT analysis initially showed that the rs3832406 polymorphism was associated with isolated cleft lip with or without cleft palate. However, corrected p-values indicated that this association was not significant. CONCLUSIONS: Melting Curve Analysis can be employed to successfully genotype challenging polymorphisms such as the MTHFD1L triallelic deletion/insertion polymorphism (DIP) reported here (rs3832406) and is a viable alternative to capillary electrophoresis. Corrected p-values indicate no association between MTHFD1L and risk of cleft in an Irish cohort. PMID- 22520924 TI - Arsenic and chromium speciation in an urban contaminated soil. AB - The distribution and speciation of As and Cr in a contaminated soil were studied by synchrotron-based X-ray microfluorescence (MU-XRF), microfocused X-ray absorption spectroscopy (MU-XAS), and bulk extended X-ray absorption fine structure spectroscopy (EXAFS). The soil was taken from a park in Wilmington, DE, which had been an important center for the leather tanning industry along the Atlantic seaboard of the United States, until the early 20th century. Soil concentrations of As, Cr, and Pb measured at certain locations in the park greatly exceeded the background levels of these heavy metals in the State of Delaware. Results show that Cr(III) and As(V) species are mainly present in the soil, with insignificant amounts of Cr(VI) and As(III). Micro-XRF maps show that Cr and Fe are distributed together in regions where their concentrations are diffuse, and at local spots where their concentrations are high. Iron oxides, which can reduce Cr(VI) to Cr(III), are present at some of these hot spots where Cr and Fe are highly concentrated. Arsenic is mainly associated with Al in the soil, and to a minor extent with Fe. Arsenate may be sorbed to aluminum oxides, which might have transformed after a long period of time into an As-Al precipitate phase, having a structure and chemical composition similar to mansfieldite (AlAsO(4)?2H(2)O). The latter hypothesis is supported by the fact that only a small amount of As present in the soil was desorbed using the characteristic toxicity leaching procedure tests. This suggests that As is immobilized in the soil. PMID- 22520925 TI - NGF-p75 and neuropsin/KLK8 pathways stimulate each other to cause hyperkeratosis and acanthosis in inflamed skin. PMID- 22520926 TI - Over-expression of kallikrein related peptidases in palmoplantar pustulosis. PMID- 22520927 TI - Relationship between microstructure of the skin surface and surface reflection based on geometric optics. AB - BACKGROUND: The behavior of reflected light in skin affects skin appearance and provides clues as to the internal condition of the skin. Surface topography is one of the central physical factors contributing to surface reflection. OBJECTIVE: We tried to clarify the relationship between microstructure of the skin surface and surface reflection based on geometric optics. METHODS: Microstructures and surface reflections in the left cheeks of adult females were evaluated. Skin topography was acquired measuring replicas using confocal laser microscopy. Surface topography was used to calculate arithmetical mean deviation of the surface (S(a)), and geometric index from gradient of the surface (S(grad)), which is expected to correlate with the directionality of surface reflection (DoSR) based on geometric optics. A surface reflection image was acquired from differently polarized pictures of a face, and the index of surface reflection (I(obs)) was calculated as the average pixel value of the area of shine. Correlations between indices were then evaluated. RESULTS: S(grad) and S(a) showed significant correlation (p<0.01) with I(obs). However, S(grad) showed a higher correlation with the simulated surface reflection from the reflection model than S(a). In addition, S(grad) can explain differences in DoSR for some panelists even in the case of an identical S(a). CONCLUSIONS: The topographic element involved in DoSR was extracted from height mapping. S(grad) reflects the ratio of flat area, offering a more effective indicator than S(a) for distinguishing topographic characteristics with respect to surface reflection. PMID- 22520928 TI - Long TSLP transcript expression and release of TSLP induced by TLR ligands and cytokines in human keratinocytes. AB - BACKGROUND: Thymic stromal lymphopoietin (TSLP), highly expressed in keratinocytes in atopic dermatitis patients and bronchial epithelial cells in asthma patients, plays a key role in allergic diseases. Two forms of TSLP mRNA (long and short) have been reported. OBJECTIVE: We compared the expression of the long-form and total TSLP transcripts in primary human keratinocytes. METHODS: Primary human keratinocytes were stimulated with Toll-like receptor (TLR) ligands, cytokines, and vitamin D receptor agonists. Gene expression was analyzed by quantitative real-time PCR. The amount of TSLP released was measured by ELISA. RESULTS: PolyI:C (TLR3 ligand), FSL-1 (TLR2-TLR6 ligand) and flagellin (TLR5 ligand) upregulated long-form TSLP expression, which predominantly contributed to upregulation of total TSLP expression. A glucocorticoid or an endosomal acidification inhibitor inhibited the polyI:C-dependent upregulation of total TSLP and the decrease of the total TSLP was due to the decrease of the long-form. An atopic cytokine milieu (TNF-alpha+IL-4+IL-13) or TNF-alpha alone also upregulated the long-form. These stimuli also induced the release of TSLP. In contrast, a high concentration of calcitriol (1,25-dihydroxyvitamin D(3), the active form of vitamin D(3)) or its analog MC903 upregulated total TSLP significantly but not the long-form, and did not induce the release of TSLP. CONCLUSION: TLR ligands or cytokines predominantly upregulate the gene expression of the long TSLP form, which contributes to the TSLP protein production, in primary human keratinocytes. Specific measurement of the long-form rather than total TSLP should be useful for accurate detection of functional human TSLP gene expression. PMID- 22520929 TI - Molecular taxonomy of Dunaliella (Chlorophyceae), with a special focus on D. salina: ITS2 sequences revisited with an extensive geographical sampling. AB - We used an ITS2 primary and secondary structure and Compensatory Base Changes (CBCs) analyses on new French and Spanish Dunallela salina strains to investigate their phylogenetic position and taxonomic status within the genus Dunaliella. Our analyses show a great diversity within D. salina (with only some clades not statistically supported) and reveal considerable genetic diversity and structure within Dunaliella, although the CBC analysis did not bolster the existence of different biological groups within this taxon. The ITS2 sequences of the new Spanish and French D. salina strains were very similar except for two of them: ITC5105 "Janubio" from Spain and ITC5119 from France. Although the Spanish one had a unique ITS2 sequence profile and the phylogenetic tree indicates that this strain can represent a new species, this hypothesis was not confirmed by CBCs, and clarification of its taxonomic status requires further investigation with new data. Overall, the use of CBCs to define species boundaries within Dunaliella was not conclusive in some cases, and the ITS2 region does not contain a geographical signal overall. PMID- 22520930 TI - From the editor. PMID- 22520931 TI - Disparities in adherence to and persistence with antihypertensive regimens: an exploratory analysis from a community-based provider network. AB - Despite the availability of effective antihypertensive therapies, adherence to and persistence with treatment is suboptimal. As such, there is a need to better understand factors associated with adherence and persistence, such as race/ethnicity. In a retrospective, exploratory analysis of 51,772 hypertensive adult subjects identified in the electronic medical record, we examined medication possession ratio and proportion of days covered as proxies for adherence and persistence, respectively. Logistic regression analyses were performed to assess the role of race/ethnicity in adherence to and persistence with antihypertensive treatments. Relative to white subjects, Asian American/Pacific Islander, black, Hispanic, and "other" subjects were significantly less likely to be adherent to and persistent with their antihypertensive regimens. Black and Hispanic subjects had the lowest odds of adherence (0.46, 95% CI: 0.43-0.49 and 0.58, 95% CI: 0.54-0.62, respectively) and persistence (0.70, 95% CI: 0.65-0.75 and 0.70, 95% CI: 0.66-0.74, respectively) relative to white subjects. Other factors significantly associated with both lower adherence and persistence included younger age and lower chronic disease score. Disparities were found with regard to adherence to and persistence with antihypertensive regimens. Future studies should address these disparities by designing interventions to improve medication-taking behavior in high-risk populations. PMID- 22520932 TI - Home and clinic blood pressure responses in elderly individuals with systolic hypertension. AB - Home blood pressure (BP) monitoring may enhance assessment of BP control. In this 16-week study, men and women 70 years or older with systolic BP between 150 and 200 mm Hg were randomized to receive valsartan/hydrochlorothiazide (V/HCTZ) 160/12.5 mg (n = 128), HCTZ 12.5 mg (n = 128), or V 160 mg (n = 128) for 4 weeks. Participants whose BP was 140/90 mm Hg or higher at weeks 4, 8, or 12 were uptitrated to a maximum of V/HCTZ 320/25 mg. Participants were evaluated by home BP monitoring using an automated device weekly before taking daily study medication (n = 301). Baseline BP +/- SD for clinic (165.5 +/- 11.8/85.1 +/- 9.5 mm Hg) was approximately 3/1 mm Hg greater than home readings (162.5 +/- 15.8/84.3 +/- 10.2 mm Hg). Reductions in BP +/- SEM at week 4 were similar for clinic (12.6 +/- 1.0/4.7 +/- 0.5 mm Hg) and home (10.9 +/- 1.1/3.8 +/- 0.5 mm Hg) readings (P = .25/P = .23; clinic versus home); differences between V/HCTZ and HCTZ or V were also similar for both home and clinic readings and results by either technique correlated significantly (P < .0001). Home BP measurements confirm that treatment initiated with V/HCTZ versus monotherapy resulted in greater antihypertensive efficacy. Home BP monitoring, if done with proper technique, provides a reliable indicator of BP control in elderly patients and may help guide drug dosing and titration. PMID- 22520933 TI - The present and future of the American Society of Hypertension: 2012. PMID- 22520934 TI - Independent and incremental value of severely enlarged left atrium in risk stratification of very elderly patients with chronic systolic heart failure. AB - The authors sought to assess the impact on survival of demographic, clinical, and echo-Doppler parameters in patients with chronic heart failure due to left ventricular systolic dysfunction divided according to age groups. This study included 734 patients (age 69+/-11 years) who were classified into tertiles of age: I (22-66 years), II (67-76 years), and III (77-94 years). Severely enlarged left atrial size was defined as >=52 mm in men and >=47 mm in women. Multivariable analysis identified male sex (P=.018) and severely enlarged left atrium (P=.024) as significant correlates of all-cause mortality in the very elderly cohort, while restrictive filling pattern (RFP) (P=.004) and New York Heart Association class III or IV (P=.005) among patients of the first tertile and RFP (P=.028) among patients in the second tertile were independently associated with mortality after 30+/-21 months of follow-up. At the interactive stepwise model in the very elderly population, a severely enlarged left atrium, added to the model after clinical parameters and ejection fraction, moved the chi square value from 20.7 to 25.8 (P=.048). RFP emerged as the single best predictor of all-cause mortality in the younger and intermediate ranges, whereas severely enlarged left atrium was the best predictor in the very elderly. PMID- 22520935 TI - Statistical properties of interval mapping methods on quantitative trait loci location: impact on QTL/eQTL analyses. AB - BACKGROUND: Quantitative trait loci (QTL) detection on a huge amount of phenotypes, like eQTL detection on transcriptomic data, can be dramatically impaired by the statistical properties of interval mapping methods. One of these major outcomes is the high number of QTL detected at marker locations. The present study aims at identifying and specifying the sources of this bias, in particular in the case of analysis of data issued from outbred populations. Analytical developments were carried out in a backcross situation in order to specify the bias and to propose an algorithm to control it. The outbred population context was studied through simulated data sets in a wide range of situations.The likelihood ratio test was firstly analyzed under the "one QTL" hypothesis in a backcross population. Designs of sib families were then simulated and analyzed using the QTL Map software. On the basis of the theoretical results in backcross, parameters such as the population size, the density of the genetic map, the QTL effect and the true location of the QTL, were taken into account under the "no QTL" and the "one QTL" hypotheses. A combination of two non parametric tests - the Kolmogorov-Smirnov test and the Mann-Whitney-Wilcoxon test - was used in order to identify the parameters that affected the bias and to specify how much they influenced the estimation of QTL location. RESULTS: A theoretical expression of the bias of the estimated QTL location was obtained for a backcross type population. We demonstrated a common source of bias under the "no QTL" and the "one QTL" hypotheses and qualified the possible influence of several parameters. Simulation studies confirmed that the bias exists in outbred populations under both the hypotheses of "no QTL" and "one QTL" on a linkage group. The QTL location was systematically closer to marker locations than expected, particularly in the case of low QTL effect, small population size or low density of markers, i.e. designs with low power. Practical recommendations for experimental designs for QTL detection in outbred populations are given on the basis of this bias quantification. Furthermore, an original algorithm is proposed to adjust the location of a QTL, obtained with interval mapping, which co located with a marker. CONCLUSIONS: Therefore, one should be attentive when one QTL is mapped at the location of one marker, especially under low power conditions. PMID- 22520936 TI - [The myopic vitreous. Why is its examination so difficult?]. AB - The examination of a high myopic vitreous is difficult for several reasons, including optic phenomena and vitreous liquefaction. The diagnosis of a posterior vitreous detachment may be problematic and confused with the observation of a large lacuna posterior margin. PMID- 22520937 TI - Intravenous magnesium prevents atrial fibrillation after coronary artery bypass grafting: a meta-analysis of 7 double-blind, placebo-controlled, randomized clinical trials. AB - BACKGROUND: Postoperative atrial fibrillation (POAF) is the most common complication after coronary artery bypass grafting (CABG). The preventive effect of magnesium on POAF is not well known. This meta-analysis was undertaken to assess the efficacy of intravenous magnesium on the prevention of POAF after CABG. METHODS: Eligible studies were identified from electronic databases (Medline, Embase, and the Cochrane Library). The primary outcome measure was the incidence of POAF. The meta-analysis was performed with the fixed-effect model or random-effect model according to heterogeneity. RESULTS: Seven double-blind, placebo-controlled, randomized clinical trials met the inclusion criteria including 1,028 participants. The pooled results showed that intravenous magnesium reduced the incidence of POAF by 36% (RR 0.64; 95% confidence interval (CI) 0.50-0.83; P = 0.001; with no heterogeneity between trials (heterogeneity P = 0.8, I2 = 0%)). CONCLUSIONS: This meta-analysis indicates that intravenous magnesium significantly reduces the incidence of POAF after CABG. This finding encourages the use of intravenous magnesium as an alternative to prevent POAF after CABG. But more high quality randomized clinical trials are still need to confirm the safety. PMID- 22520938 TI - Cancer incidence and mortality trends in Australian adolescents and young adults, 1982-2007. AB - BACKGROUND: Increasing incidence and lack of survival improvement in adolescents and young adults (AYAs) with cancer have led to increased awareness of the cancer burden in this population. The objective of this study was to describe overall and type-specific cancer incidence and mortality trends among AYAs in Western Australia from 1982-2007. METHODS: Age-adjusted incidence and mortality rates were calculated for all malignancies combined and for each of the most common diagnostic groups, using five-year age-specific rates. Joinpoint regression analysis was used to derive annual percentage changes (APC) for incidence and mortality rates. RESULTS: The annual incidence rate for all cancers combined increased in males from 1982 until 2000 (APC = 1.5%, 95%CI: 0.9%; 2.1%) and then plateaued, whilst rates for females remained stable across the study period (APC = -0.1%; 95%CI: -0.2%; 0.4%) across the study period. For males, significant incidence rate increases were observed for germ cell tumors, lymphoblastic leukemia and thyroid cancer. In females, the incidence of Hodgkin's lymphoma, colorectal and breast cancers increased. Significant incidence rate reductions were noted for cervical, central nervous system and lung cancers. Mortality rates for all cancers combined decreased from 1982 to 2005 for both males (APC = -2.6%, 95%CI:-3.3%;-2.0%) and females (APC = -4.6%, 95%CI:-5.1%;-4.1%). With the exception of bone sarcoma and lung cancer in females, mortality rates for specific cancer types decreased significantly for both sexes during the study period. CONCLUSIONS: Incidence of certain AYA cancers increased, whilst it decreased for others. Mortality rates decreased for most cancers, with the largest improvement observed for breast carcinomas. Further research is needed to identify the reasons for the increasing incidence of certain cancers. PMID- 22520939 TI - Measuring paediatric intensive care nursing knowledge in Australia and New Zealand: how the Basic Knowledge Assessment Tool for pediatric critical care nurses (PEDS-BKAT4) performs. AB - Validated professional knowledge measures are limited in paediatric intensive care unit (PICU) nursing. The Basic Knowledge Assessment Tool for Pediatric Critical Care Nurses (PEDS-BKAT4) measures knowledge, however content and practice differences exist between various PICUs. The study aim was to evaluate the PEDS-BKAT4 in the Australian and New Zealand setting. A panel of 10 experts examined item and scale content validity. Items were evaluated for 31 evidence based item writing flaws and for cognitive level, by a 4-person expert panel. Thirty-six PICU nurses completed the PEDS-BKAT4, with reliability and item analysis conducted. Mean item content validity was 0.70, and 43% of items had content validity less than 0.8. Overall (Scale) content validity was 0.71. Thirty five percent of items were classified as flawed. Thirty-five percent of items were written at the 'knowledge' level, and 58% at 'understanding'. The mean PEDS BKAT4 score was 60.8 (SD=9.6), KR-20 reliability 0.81. The mean item difficulty was 0.62, and the mean discrimination index was 0.23. The PEDS-BKAT4 was not a reliable and valid measure of basic PICU nursing knowledge in Australian and New Zealand. Further research into the types of knowledge and skills required of PICU nurses in this setting are needed to inform the development of a future tool. PMID- 22520941 TI - Modulation of hepatitis C virus release by the interferon-induced protein BST 2/tetherin. AB - Hepatitis C virus is a leading cause of chronic hepatitis and liver cancer. Little information exists on the interplay between innate defense mechanisms and viral antagonists that promote viral egress. Herein, the effects of Tetherin/BST 2 on HCV release were investigated. In Huh-7.5 hepatocytes, low expression levels of BST-2 were detected. Treatment of Huh-7.5 cells with IFNalpha, elevated BST-2 expression levels. However, HCV could not alter the expression of IFNalpha induced BST-2, nor of stably over-expressed BST-2. Significantly, over expressed BST-2 moderately blocked HCV production and release from Huh-7.5 cells. Functional analysis of BST-2, confirmed its ability to inhibit the release of HIV delta-Vpu from Huh-7.5-BST-2 cells. HIV-Vpu antagonized BST-2 activity and rescued HIV delta-Vpu release from Huh-7.5-BST-2 cells. However, vpu slightly rescued HCV release and production from Huh-7.5-BST-2. We conclude that BST-2 moderately restricts HCV production and release from Huh-7.5 hepatocytes, while the virus lacks mechanisms to counteract this restriction. PMID- 22520940 TI - Apolipoprotein E gene polymorphism: effects on plasma lipids and risk of type 2 diabetes and coronary artery disease. AB - BACKGROUND: The most common apolipoprotein E (apoE) gene polymorphism has been found to influence plasma lipid concentration and its correlation with coronary artery disease (CAD) has been extensively investigated in the last decade. It is, however, unclear whether apoE gene polymorphism is also associated with increased risk of type 2 diabetes mellitus (T2DM). The knowledge of this study may provide the primary prevention for T2DM and CAD development before its initiation and progression. Therefore, this study was carried out to determine the association between apoE gene polymorphism and T2DM with and without CAD and its role in lipid metabolism. METHODS: The case-control study was carried out on a total of 451 samples including 149 normal control subjects, 155 subjects with T2DM, and 147 subjects with T2DM complicated with CAD. The apoE gene polymorphism was tested by polymerase chain reaction-restriction fragment length polymorphism (PCR RFLP). Univariable and multivariable logistic regression analyses were used to identify the possible risks of T2DM and CAD. RESULTS: A significantly increased frequency of E3/E4 genotype was observed only in T2DM with CAD group (p = 0.0004), whereas the epsilon4 allele was significantly higher in both T2DM (p = 0.047) and T2DM with CAD (p = 0.009) as compared with controls. E3/E4 genotype was also the independent risk in developing CAD after adjusting with established risk factors with adjusted odds ratio (OR) 2.52 (95%CI 1.28-4.97, p = 0.008). The independent predictor of individuals carrying epsilon4 allele still remained significantly associated with both CAD (adjusted OR 2.32, 95%CI 1.17-4.61, p = 0.016) and T2DM (adjusted OR 2.04, 95%CI 1.07-3.86, p = 0.029). After simultaneously examining the joint association of E3/E4 genotype combined with either obesity or smoking the risk increased to approximately 5-fold in T2DM (adjusted OR 4.93, 95%CI 1.74-13.98, p = 0.003) and 10-fold in CAD (adjusted OR 10.48, 95%CI 3.56-30.79, p < 0.0001). The association between apoE genotypes on plasma lipid levels was compared between E3/E3 as a reference and E4-bearing genotypes. E4-bearing genotypes showed lower HDL-C and higher VLDL-C and TG, whereas other values of plasma lipid concentrations showed no significant difference. CONCLUSIONS: These results indicate that epsilon4 allele has influence on lipid profiles and is associated with the development of both T2DM with and without CAD, and furthermore, it increased the risk among the subjects with obesity and/or smoking, the conditions associated with high oxidative stress. PMID- 22520942 TI - The energetic contributions of scaffolding and coat proteins to the assembly of bacteriophage procapsids. AB - In vitro assembly of bacteriophage P22 procapsids requires coat protein and sub stoichiometric concentrations of the internal scaffolding protein. If there is no scaffolding protein, coat protein assembles aberrantly, but only at higher concentrations. Too much scaffolding protein results in partial procapsids. By treating the procapsid as a lattice that can bind and be stabilized by scaffolding protein we dissect procapsid assembly as a function of protein concentration and scaffolding/coat protein ratio. We observe that (i) the coat coat association is weaker for procapsids than for aberrant polymer formation, (ii) scaffolding protein makes a small but sufficient contribution to stability to favor the procapsid form, and (iii) there are multiple classes of scaffolding protein binding sites. This approach should be applicable to other heterogeneous virus assembly reactions and will facilitate our ability to manipulate such in vitro reactions to probe assembly, and for development of nanoparticles. PMID- 22520943 TI - Mutation in the platelet-derived growth factor receptor alpha inhibits adeno associated virus type 5 transduction. AB - Due to its non-pathogenic lifecycle, little is known about the cellular determinants of infection by adeno-associated virus (AAV). To identify these critical cellular factors, we took advantage of the gene transfer abilities of AAV in combination with a forward genetic selection to identify proteins critical for transduction by this virus. AAV serotype 5 (AAV5) vectors encoding the furin gene were used to transduce furin-deficient cells followed by selection with furin-dependent toxins. A population of cells specifically resistant to AAV5 transduction was identified and sequence analysis suggested all had a single amino acid mutation in the leader sequence of the platelet-derived growth factor receptor alpha (PDGFRalpha) gene. Characterization of this mutation suggested it inhibited PDGFRalpha trafficking resulting in limited expression on the plasma membrane. Mutagenesis and transfection experiments confirmed the effect of this mutation on PDGFRalpha trafficking, and the AAV5 resistant phenotype could be rescued by transfection with wild type PDGFRalpha. PMID- 22520944 TI - Migration of gammadelta T cells in steady-state conditions. AB - The orchestrated migration of T lymphocytes is important for generating immunity and maintaining immunological tolerance. T lymphocytes can be divided into two populations, alphabeta T cells and gammadelta T cells, on the basis of their expression of different forms of the T cell receptor (TCR). gammadelta T cells represent an innate subset of T lymphocytes that play an important role in early immune response against a variety of pathogens, including bacteria and viruses. gammadelta T cells are abundant in the epithelial tissues. In ruminants and pigs, they constitute a major proportion of the blood lymphocyte pool, unlike in rodents and humans. Although recent studies using large animals have suggested that epithelial gammadelta T cells are the major source of gammadelta T cells in peripheral blood, and that they recirculate between epithelial tissues and blood via lymphatics, the migration pattern of these cells is largely unknown. The aim of this review is to provide an overview of the current knowledge on gammadelta T cell migration under steady-state conditions. A deeper understanding of gammadelta T cell migration may enable therapeutic modulation of innate immune responses. PMID- 22520945 TI - Safety and tolerability of a 6-week course of oseltamivir prophylaxis for seasonal influenza in children. AB - In an open-label study, 49 children aged 1-12 years received oseltamivir (30-75 mg once daily depending on bodyweight) for 6 weeks for influenza prophylaxis. Seventeen participants reported 22 adverse events (AEs); in three participants, AEs were considered probably drug related (nausea or vomiting). No serious AEs were reported. The tolerability profile was similar to pooled safety data from treatment studies (duration of 5 days) in children. PMID- 22520947 TI - Splenic B-cell lymphomas with more than 55% prolymphocytes in blood: evidence for prolymphocytoid transformation. AB - We describe 4 patients aged 62 to 79 years with splenomegaly and bone marrow involvement by splenic B-cell lymphoma who developed more than 55% prolymphocytes in blood. The diagnosis of B-cell prolymphocytic leukemia was considered clinically based on a markedly elevated leukocyte (up to 131.5*10(9)/L) or prolymphocyte (up to 86%) count. Splenectomy was performed in all patients, and spleen weight ranged from 1500 to 2380 g. In 3 patients, the neoplasms were classified as splenic marginal zone lymphoma, and in 1 patient, the neoplasm was classified as splenic diffuse red pulp small B-cell lymphoma. In 2 patients, splenectomy preceded a B-cell prolymphocytic leukemia-like picture, and the spleen showed splenic marginal zone lymphoma or splenic diffuse red pulp small B cell lymphoma with increased (10%-20%) nucleolated cells consistent with prolymphocytes. In the other 2 patients, a B-cell prolymphocytic leukemia-like picture prompted splenectomy. Initial examination of bone marrow in these patients suggested splenic marginal zone lymphoma. The spleen specimens showed extensive involvement by splenic marginal zone lymphoma with numerous prolymphocytes. Flow cytometry immunophenotyping in all cases showed lymphocytes positive for monotypic surface immunoglobulin (bright), pan-B-cell antigens, CD11c, CD22, and FMC7. Immunohistochemical analysis in all patients showed moderate to bright p53 expression in the spleen (n=3) or bone marrow (n=2). Annexin A1 and cyclin D1 were negative in all cases. Conventional cytogenetic analysis showed del(7q) in 3 patients. We conclude that splenic B-cell lymphoma of various types can undergo prolymphocytoid transformation with more than 55% prolymphocytes in the blood mimicking B-cell prolymphocytic leukemia. PMID- 22520948 TI - A review of adenoid cystic carcinoma of the breast with emphasis on its molecular and genetic characteristics. AB - Breast carcinomas that do not express estrogen receptor alpha, progesterone receptor, or human epidermal growth factor receptor 2 are frequently grouped together as "triple negative" and considered an aggressive type of breast malignancy; however, this group is not homogeneous. Adenoid cystic carcinoma of the breast is a rare type of breast cancer with such triple-negative features and, generally, a more favorable clinical course. This comprehensive review describes diagnostic, molecular, and clinical features of adenoid cystic carcinoma and compares them with those of triple-negative breast carcinomas of no special type. PMID- 22520949 TI - Signal transduction pathway analysis in fibromatosis: receptor and nonreceptor tyrosine kinases. AB - Despite reports of receptor tyrosine kinase activation in desmoid-type fibromatosis, therapeutic benefits of kinase inhibitor therapy are unpredictable. Variability in signal transduction or cellular kinases heretofore unevaluated in desmoid tumors may be responsible for these inconsistent responses. In either case, a better understanding of growth regulatory signaling pathways is necessary to assess the theoretical potential of inhibitor therapy. Immunohistochemical analysis of tyrosine kinases and activated isoforms of downstream signal transduction proteins was performed on a tissue microarray containing 27 cases of desmoid-type fibromatosis and 14 samples of scar; 6 whole sections of normal fibrous tissue were studied for comparison. Platelet-derived growth factor receptor, beta type, and focal adhesion kinase 1 were expressed in all desmoid tumors and healing scars but only 80% and 50% of nonproliferative fibrous tissue samples, respectively. Hepatocyte growth factor receptor was detected in 89% of desmoids and all scars tested, but not in any of the fibrous tissue samples. Epidermal growth factor receptor was detected in only 12% of desmoids and not in scar or fibrous tissue. Mast/stem cell growth factor receptor, receptor tyrosine protein kinase erbB-2, and phosphorylated insulin-like growth factor 1 receptor/insulin receptor were negative in all study cases. Variable levels of phosphorylated downstream signal transduction molecules RAC-alpha/beta/gamma serine/threonine-protein kinase, mitogen-activated protein kinase, and signal transducer and activator of transcription-3 were observed in desmoids (58%, 62%, and 67%), scar tissues (100%, 86%, and 86%), and fibrous tissue (33%, 17%, and 17%). These results indicate that tyrosine kinase signaling is active in both fibromatosis and healing scar, but not in most nonproliferating fibrous tissues. Although platelet-derived growth factor receptor, beta type, is expressed ubiquitously in desmoids, the kinases driving cell proliferation in desmoids remain unresolved. PMID- 22520950 TI - Clinicopathologic significance of DNA methyltransferase 1, 3a, and 3b overexpression in Tunisian breast cancers. AB - DNA methyltransferase 1, 3a, and 3b affect DNA methylation, and it is thought that they play an important role in the malignant transformation of various cancers. The current study was designed to analyze DNA methyltransferase expression by immunohistochemistry in a series of 94 Tunisian sporadic breast carcinomas. Results were correlated to clinicopathologic parameters and promoter methylation status of 8 tumor suppressor genes (BRCA1, BRCA2, RASSFA1, TIMP3, CDH1, P16, RARbeta2, and DAPK). Overexpression of DNA methyltransferase 1, 3a, and 3b was detected in 46.8%, 32%, and 44.7% of cases, respectively. A significant correlation was found between DNA methyltransferase 1 overexpression and Scarff-Bloom-Richardson histologic grade III (P = .01). DNA methyltransferase 3a overexpression was significantly associated with menopausal status (P = .01), Scarff-Bloom-Richardson histologic grade III (P = .0001), estrogen (P = .04) and progesterone (P = .007) receptor negativity, and HER2 overexpression (P = .004). However, DNA methyltransferase 3a overexpression was found less frequently in the luminal A intrinsic breast cancer subtype (9.7%) than in luminal B (53%), HER2 (41%), and triple-negative (50%) subtypes (P = .001). DNA methyltransferase 3b overexpression shows significant correlation with promoter hypermethylation of BRCA1 (P = .03) and RASSFA1 (P = .04) and with the hypermethylator phenotype (more than 4 methylated genes, P = .01). These data suggest that overexpression of various DNA methyltransferases might represent a critical event responsible for the epigenetic inactivation of multiple tumor suppressor genes, leading to the development of aggressive forms of sporadic breast cancer. PMID- 22520951 TI - Immunohistochemical analysis of polycomb group protein expression in advanced gastric cancer. AB - The polycomb group proteins have recently captured the attention of cancer biologists. enhancer of zeste homologue 2 (EZH2) and B lymphoma Mo-MLV insertion region 1 homolog (BMI-1) are the best-characterized polycomb group proteins; their deregulation contributes to the development of many malignancies including gastric cancers. H3 trimethylation at lysine 27 and DNA methylase DNA methyltransferase 3B proteins are associated with the recruitment of polycomb group proteins. Overexpression of polycomb group proteins is associated with poor prognoses in some types of cancers but with favorable prognoses in others. In the present study, we investigated the expression of the polycomb group proteins EZH2 and BMI-1 and the associated proteins H3 trimethylation at lysine 27 and DNA methyltransferase 3B in advanced gastric cancers. Based on immunohistochemical detection, we evaluated the clinical relevance of these proteins in 178 cases of advanced gastric cancers that were managed with radical surgery and adjuvant systemic chemotherapy. BMI-1, enhancer of zeste homologue 2, H3 trimethylation at lysine 27, and DNA methyltransferase 3B proteins were overexpressed in the nuclei of gastric carcinoma compared with adjacent nonneoplastic gastric parenchyma. The high-level expression of BMI-1, enhancer of zeste homologue 2, H3 trimethylation at lysine 27, and DNA methyltransferase 3B proteins were frequently noted in advanced gastric cancer tissues (70.8%, 92.1%, 58.4%, and 64.6% of cases, respectively) and well intercorrelated in expression (P < .05). The expression level of BMI-1, enhancer of zeste homologue 2, and DNA methyltransferase 3B showed correlation with sex, gross type, and histologic type of the tumor among clinicopathologic variables. In terms of patient survival, low-level expression of enhancer of zeste homologue 2 was associated with cancer-related death (P = .018) and shorter overall survival (P = .005). Low-level expression of enhancer of zeste homologue 2 may represent a negative prognostic marker (P = .005) and indicate high risk in patients with advanced gastric cancer after surgery and adjuvant chemotherapy. PMID- 22520952 TI - Complementary dietary treatment using lysine-free, arginine-fortified amino acid supplements in glutaric aciduria type I - A decade of experience. AB - The cerebral formation and entrapment of neurotoxic dicarboxylic metabolites (glutaryl-CoA, glutaric and 3-hydroxyglutaric acid) are considered to be important pathomechanisms of striatal injury in glutaric aciduria type I (GA-I). The quantitatively most important precursor of these metabolites is lysine. Recommended therapeutic interventions aim to reduce lysine oxidation (low lysine diet, emergency treatment to minimize catabolism) and to enhance physiologic detoxification of glutaryl-CoA via formation of glutarylcarnitine (carnitine supplementation). It has been recently shown in Gcdh(-/-) mice that cerebral lysine influx and oxidation can be modulated by arginine which competes with lysine for transport at the blood-brain barrier and the inner mitochondrial membrane [Sauer et al., Brain 134 (2011) 157-170]. Furthermore, short-term outcome of 12 children receiving arginine-fortified diet showed very promising results [Strauss et al., Mol. Genet. Metab. 104 (2011) 93-106]. Since lysine free, arginine-fortified amino acid supplements (AAS) are commercially available and used in Germany for more than a decade, we evaluated the effect of arginine supplementation in a cohort of 34 neonatally diagnosed GA-I patients (median age, 7.43 years; cumulative follow-up period, 221.6 patient years) who received metabolic treatment according to a published guideline [Kolker et al., J. Inherit. Metab. Dis. 30 (2007) 5-22]. Patients used one of two AAS product lines during the first year of life, resulting in differences in arginine consumption [group 1 (Milupa Metabolics): mean=111 mg arginine/kg; group 2 (Nutricia): mean=145 mg arginine/kg; p<0.001]. However, in both groups the daily arginine intake was increased (mean, 137 mg/kg body weight) and the dietary lysine-to arginine ratio was decreased (mean, 0.7) compared to infants receiving human milk and other natural foods only. All other dietary parameters were in the same range. Despite significantly different arginine intake, the plasma lysine-to arginine ratio did not differ in both groups. Frequency of dystonia was low (group 1: 12.5%; group 2: 8%) compared with patients not being treated according to the guideline, and gross motor development was similar in both groups. In conclusion, the development of complementary dietary strategies exploiting transport competition between lysine and arginine for treatment of GA-I seems promising. More work is required to understand neuroprotective mechanisms of arginine, to develop dietary recommendations for arginine and to evaluate the usefulness of plasma monitoring for lysine and arginine levels as predictors of cerebral lysine influx. PMID- 22520955 TI - Prey items and predation behavior of killer whales (Orcinus orca) in Nunavut, Canada based on Inuit hunter interviews. AB - BACKGROUND: Killer whales (Orcinus orca) are the most widely distributed cetacean, occurring in all oceans worldwide, and within ocean regions different ecotypes are defined based on prey preferences. Prey items are largely unknown in the eastern Canadian Arctic and therefore we conducted a survey of Inuit Traditional Ecological Knowledge (TEK) to provide information on the feeding ecology of killer whales. We compiled Inuit observations on killer whales and their prey items via 105 semi-directed interviews conducted in 11 eastern Nunavut communities (Kivalliq and Qikiqtaaluk regions) from 2007-2010. RESULTS: Results detail local knowledge of killer whale prey items, hunting behaviour, prey responses, distribution of predation events, and prey capture techniques. Inuit TEK and published literature agree that killer whales at times eat only certain parts of prey, particularly of large whales, that attacks on large whales entail relatively small groups of killer whales, and that they hunt cooperatively. Inuit observations suggest that there is little prey specialization beyond marine mammals and there are no definitive observations of fish in the diet. Inuit hunters and elders also documented the use of sea ice and shallow water as prey refugia. CONCLUSIONS: By combining TEK and scientific approaches we provide a more holistic view of killer whale predation in the eastern Canadian Arctic relevant to management and policy. Continuing the long-term relationship between scientists and hunters will provide for successful knowledge integration and has resulted in considerable improvement in understanding of killer whale ecology relevant to management of prey species. Combining scientists and Inuit knowledge will assist in northerners adapting to the restructuring of the Arctic marine ecosystem associated with warming and loss of sea ice. PMID- 22520956 TI - Childhood trauma and distress experiences associate with psychotic symptoms in patients attending primary and psychiatric outpatient care. Results of the RADEP study. AB - GOAL: We studied the prevalence of and association between psychotic symptoms and childhood trauma experiences in primary care patients compared with psychiatric care patients. PATIENTS AND METHODS: We note 911 primary care and psychiatric care patients over 16 years of age filled in a questionnaire including a list of lifetime psychotic symptoms of the Composite International Diagnostic Interview (CIDI) and the childhood Trauma and Distress Scale (TADS). Prevalence of and correlations between psychotic symptoms and childhood trauma and stressful experiences were calculated. Association between the sum of CIDI symptoms and the TADS sum score was analysed by Anova. RESULTS: In primary care, more than half of the patients had had at least one psychotic symptom during their lifetime, and nearly 70% of patients had experienced a childhood trauma at some time or more often. In psychiatric care patients, CIDI symptoms were more prevalent and TADS scores were higher than in primary care patients. In the whole sample, CIDI symptoms correlated with TADS scores. The association remained even when the effects of age, service, and patient's functioning were taken into account. There was a dose-response between TADS scores and CIDI symptoms. CONCLUSION: Childhood trauma experiences associate with psychotic symptoms. In clinical work, it is important to acknowledge that psychotic symptoms and childhood trauma experiences are common not only in psychiatric care but also in primary care patients, and thus require adequate attention. PMID- 22520957 TI - [Disinvestment and efficiency: no green sprouts yet]. PMID- 22520958 TI - International Congress on Electrocardiology 2011 in Kingston, Ontario, Canada. PMID- 22520959 TI - Compensatory properties of heart rate asymmetry. AB - BACKGROUND: Heart rate asymmetry (HRA) is a physiologic phenomenon that reflects a systematic and 1-directional difference between heart rate accelerations and decelerations. In terms of variance-based descriptors, HRA causes the contributions from heart rate decelerations to contribute more to short-term variability than accelerations, and for the long-term variability, the relation is reversed. The hypothesis tested in the present article is that this reversal is caused by a compensatory mechanism whose function is to keep the system in relative balance. METHODS: Thirty-minute electrocardiographic recordings from 420 young healthy volunteers were analyzed. The variance-based HRA descriptors were calculated. Cases with both short- and long-term HRAs were considered to show compensation. In the binomial test, we looked for statistically significant departures from independence in the distribution of cases possessing both types of asymmetry. RESULTS: Short-term asymmetry was observed in 77.6% of subjects (P < .0001), and long-term asymmetry, in 69.3% (P < .0001); both types of HRA coexisted in 66.9% (P < .0001) of the whole group. This result is significantly different (P < .0001) from the independent case (53.78%). CONCLUSION: The compensation effect between the short- and long-term asymmetries is present in supine resting electrocardiographic recordings in young healthy people. PMID- 22520960 TI - Alterations in the QRS complex in the offspring of patients with metabolic syndrome and diabetes mellitus: early evidence of cardiovascular pathology. AB - OBJECTIVE: This study was undertaken to evaluate the nature and onset of changes in the QRS complex in the offspring of patients with diabetes mellitus (DM) and metabolic syndrome (MetS). METHODS AND METHODS: A total of 529 subjects, divided into 5 groups, were included in the study: (i) group DM (n = 92), patients with DM; (ii) group MetS (n = 125), patients with MetS; (iii) group O-DM (n = 109), offspring of patients with DM; (iv) group O-MetS (n = 122), offspring of patients with MetS; and (v) group HO (n = 81), offspring of healthy subjects. QRS parameters analyzed included amplitude, maximum QRS spatial vector magnitude, electrical axis (EA), and 3 electrocardiogram (ECG) criteria for left ventricular hypertrophy based on amplitude criteria: Sokolow-Lyon index, Cornell voltage, and Gubner criterion. RESULTS: Patients with DM and MetS showed a significant leftward shift of the EA when compared with the control group. A modest but significant leftward shift of EA was also observed in both offspring groups. These EA and maximum QRS spatial vector magnitude changes were reflected in the individual leads of the 12-lead ECG. The prevalence of a positive diagnosis by accepted electrocardiographic criteria (ECG left ventricular hypertrophy) was low. CONCLUSION: Patients with DM and MetS displayed significant changes in QRS complex that suggest depolarization sequence deterioration. Similar changes were observed also in the offspring of patients with DM and MetS, which suggests early subclinical cardiovascular damage. These findings have implications for prevention, early diagnosis, and treatment in the offspring of patients with DM and MetS. PMID- 22520961 TI - Circadian autophagy rhythm: a link between clock and metabolism? AB - Nutrient and energy metabolism in mammals exhibits a strong diurnal rhythm that aligns with the body clock. Circadian regulation of metabolism is mediated through reciprocal signaling between the clock and metabolic regulatory networks. Recent work has demonstrated that autophagy is rhythmically activated in a clock dependent manner. Because autophagy is a conserved biological process that contributes to nutrient and cellular homeostasis, its cyclic induction may provide a novel link between clock and metabolism. This review discusses the mechanisms underlying circadian autophagy regulation, the role of rhythmic autophagy in nutrient and energy metabolism, and its implications in physiology and metabolic disease. PMID- 22520962 TI - An expanded family of arrestins regulate metabolism. AB - The classical visual and beta-arrestins belong to a larger family of proteins that likely share structural similarity. Humans have an additional six related proteins sometimes termed the alpha-arrestins, whose functions are now emerging. Surprisingly, several alpha-arrestins play prominent roles in the regulation of metabolism and obesity. One alpha-arrestin, thioredoxin-interacting protein (Txnip), has crucial functions in regulating glucose uptake and glycolytic flux through the mitochondria. Another alpha-arrestin, Arrdc3, is linked to obesity in men and was recently identified in mice as a regulator of body mass, adiposity, and energy expenditure. Here we discuss recent evidence suggesting potential common themes for all arrestins, including physiological roles for classical arrestins in metabolism and the functions of alpha-arrestins in receptor signaling and endocytosis. PMID- 22520963 TI - Factors contributing to therapeutic effects evaluated in acupuncture clinical trials. AB - Acupuncture treatment has been widely used for many conditions, while results of the increasing numbers of randomized trials and systematic reviews remain controversial. Acupuncture is a complex intervention of both specific and non specific factors associated with therapeutic benefit. Apart from needle insertion, issues such as needling sensation, psychological factors, acupoint specificity, acupuncture manipulation, and needle duration also have relevant influences on the therapeutic effects of acupuncture. Taking these factors into consideration would have considerable implications for the design and interpretation of clinical trials. PMID- 22520964 TI - Antifreeze protein gene amplification facilitated niche exploitation and speciation in wolffish. AB - During winter, the coastal waters of Newfoundland can be considered a 'freeze risk ecozone' for teleost fishes, where the shallower habitats pose a high (and the deeper habitats a low) risk of freezing. Atlantic (Anarhichas lupus) and spotted (Anarhichas minor) wolffish, which inhabit these waters, reside at opposite ends of this ecozone, with the Atlantic wolffish being the species facing the greatest risk, because of its shallower niche. In order to resist freezing, this species secretes five times the level of antifreeze protein (AFP) activity into the plasma than does the spotted wolffish. The main basis for this interspecific difference in AFP levels is gene dosage, as the Atlantic wolffish has approximately three times as many AFP gene copies as the spotted wolffish. In addition, AFP transcript levels in liver (the primary source of circulating AFPs) are several times higher in the Atlantic wolffish. One explanation for the difference in gene dosage and transcript levels is the presence of tandemly arrayed repeats in the latter, which make up two-thirds of its AFP gene pool. Such repeats are not present in the spotted wolffish. The available evidence indicates that the two species diverged from a common ancestor at a time when the ebb and flow of northern glaciations would have resulted in the emergence of shallow water 'freeze risk ecozones'. The results of this study suggest that the duplication/amplification of AFP genes in a subpopulation of ancestral wolffish would have facilitated the exploitation of this high-risk habitat, resulting in the divergence and evolution of modern-day Atlantic and spotted wolffish species. PMID- 22520965 TI - Characterization of a novel chaperone/usher fimbrial operon present on KpGI-5, a methionine tRNA gene-associated genomic island in Klebsiella pneumoniae. AB - BACKGROUND: Several strain-specific Klebsiella pneumoniae virulence determinants have been described, though these have almost exclusively been linked with hypervirulent liver abscess-associated strains. Through PCR interrogation of integration hotspots, chromosome walking, island-tagging and fosmid-based marker rescue we captured and sequenced KpGI-5, a novel genomic island integrated into the met56 tRNA gene of K. pneumoniae KR116, a bloodstream isolate from a patient with pneumonia and neutropenic sepsis. RESULTS: The 14.0 kb KpGI-5 island exhibited a genome-anomalous G + content, possessed near-perfect 46 bp direct repeats, encoded a gamma1-chaperone/usher fimbrial cluster (fim2) and harboured seven other predicted genes of unknown function. Transcriptional analysis demonstrated expression of three fim2 genes, and suggested that the fim2A-fim2K cluster comprised an operon. As fimbrial systems are frequently implicated in pathogenesis, we examined the role of fim2 by analysing KR2107, a streptomycin resistant derivative of KR116, and three isogenic mutants (Deltafim, Deltafim2 and DeltafimDeltafim2) using biofilm assays, human cell adhesion assays and pair wise competition-based murine models of intestinal colonization, lung infection and ascending urinary tract infection. Although no statistically significant role for fim2 was demonstrable, liver and kidney CFU counts for lung and urinary tract infection models, respectively, hinted at an ordered gradation of virulence: KR2107 (most virulent), KR2107?fim2, KR2107?fim and KR2107?fim?fim2 (least virulent). Thus, despite lack of statistical evidence there was a suggestion that fim and fim2 contribute additively to virulence in these murine infection models. However, further studies would be necessary to substantiate this hypothesis. CONCLUSION: Although fim2 was present in 13% of Klebsiella spp. strains investigated, no obvious in vitro or in vivo role for the locus was identified, although there were subtle hints of involvement in urovirulence and bacterial dissemination from the respiratory tract. Based on our findings and on parallels with other fimbrial systems, we propose that fim2 has the potential to contribute beneficially to pathogenesis and/or environmental persistence of Klebsiella strains, at least under specific yet-to-be identified conditions. PMID- 22520966 TI - Estimating the genetic variance of major depressive disorder due to all single nucleotide polymorphisms. AB - Genome-wide association studies of psychiatric disorders have been criticized for their lack of explaining a considerable proportion of the heritability established in twin and family studies. Genome-wide association studies of major depressive disorder in particular have so far been unsuccessful in detecting genome-wide significant single nucleotide polymorphisms (SNPs). Using two recently proposed methods designed to estimate the heritability of a phenotype that is attributable to genome-wide SNPs, we show that SNPs on current platforms contain substantial information concerning the additive genetic variance of major depressive disorder. To assess the consistency of these two methods, we analyzed four other complex phenotypes from different domains. The pattern of results is consistent with estimates of heritability obtained in twin studies carried out in the same population. PMID- 22520968 TI - Influence of root-exudates concentration on pyrene degradation and soil microbial characteristics in pyrene contaminated soil. AB - The effect of ryegrass (Lolium perenne L.) root-exudates concentration on pyrene degradation and the microbial ecological characteristics in the pyrene contaminated soil was investigated by simulating a gradually reducing concentration of root exudates with the distance away from root surface in the rhizosphere. Results showed that, after the root-exudates were added 15 d, the pyrene residue in contaminated soil responded nonlinearly in the soils with the same pyrene contaminated level as the added root-exudates concentration increased, which decreased first and increased latter with the increase of the added root-exudates concentration. The lowest pyrene concentration appeared when the root exudates concentration of 32.75 mg kg(-1) total organic carbon (TOC) was added. At the same time, changes of microbial biomass carbon (MBC, C(mic)) and microbial quotient (C(mic)/C(org)) were opposite to the trend of pyrene degradation as the added root-exudates concentration increased. Phospholipid fatty acid (PLFA) analysis revealed that bacteria was the dominating microbial community in pyrene contaminated soil, and the changing trends of pyrene degradation and bacteria number were the same. The changing trend of endoenzyme dehydrogenase activity was in accordance with that of soil microbe, indicating which could reflect the quantitative characteristic of detoxification to pyrene by soil microbe. The changes in the soils microbial community and corresponding microbial biochemistry characteristics were the ecological mechanism influencing pyrene degradation with increasing concentration of the added root-exudates in the pyrene contaminated soil. PMID- 22520969 TI - Using a physiologically based pharmacokinetic model to link urinary biomarker concentrations to dietary exposure of perchlorate. AB - Exposure to perchlorate is widespread in the United States and many studies have attempted to character the perchlorate exposure by estimating the average daily intakes of perchlorate. These approaches provided population-based estimates, but did not provide individual-level exposure estimates. Until recently, exposure activity database such as CSFII, TDS and NHANES become available and provide opportunities to evaluate the individual-level exposure to chemical using exposure surveillance dataset. In this study, we use perchlorate as an example to investigate the usefulness of urinary biomarker data for predicting exposures at the individual level. Specifically, two analyses were conducted: (1) using data from a controlled human study to examine the ability of a physiologically based pharmacokinetic (PBPK) model to predict perchlorate concentrations in single-spot and cumulative urine samples; and (2) using biomarker data from a population based study and a PBPK model to demonstrate the challenges in linking urinary biomarker concentrations to intake doses for individuals. Results showed that the modeling approach was able to characterize the distribution of biomarker concentrations at the population level, but predicting the exposure-biomarker relationship for individuals was much more difficult. The type of information needed to reduce the uncertainty in estimating intake doses, for individuals, based on biomarker measurements is discussed. PMID- 22520967 TI - Linkage analysis followed by association show NRG1 associated with cannabis dependence in African Americans. AB - BACKGROUND: A genetic contribution to cannabis dependence (CaD) has been established but susceptibility genes for CaD remain largely unknown. METHODS: We employed a multistage design to identify genetic variants underlying CaD. We first performed a genome-wide linkage scan for CaD in 384 African American (AA) and 354 European American families ascertained for genetic studies of cocaine and opioid dependence. We then conducted association analysis under the linkage peak, first using data from a genome-wide association study from the Study of Addiction: Genetics and Environment, followed by replication studies of prioritized single nucleotide polymorphisms (SNPs) in independent samples. RESULTS: We identified the strongest linkage evidence with CaD (logarithm of odds = 2.9) on chromosome 8p21.1 in AAs. In the association analysis of the Study of Addiction: Genetics and Environment sample under the linkage peak, we identified one SNP (rs17664708) associated with CaD in both AAs (odds ratio [OR] = 2.93, p = .0022) and European Americans (OR = 1.38, p = .02). This SNP, located at NRG1, a susceptibility gene for schizophrenia, was prioritized for further study. We replicated the association of rs17664708 with CaD in an independent AAs sample (OR = 2.81, p = .0068). The joint analysis of the two AA samples demonstrated highly significant association between rs17664708 and CaD with adjustment for either global (p = .00044) or local ancestry (p = .00075). CONCLUSIONS: Our study shows that NRG1 is probably a susceptibility gene for CaD, based on convergent evidence of linkage and replicated associations in two independent AA samples. PMID- 22520970 TI - 2,5,6,9,10-Pentabromocyclododecanols (PBCDOHs): a new class of HBCD transformation products. AB - Pentabromocyclododecanols (PBCDOHs) are potential environmental transformation products of hexabromocyclododecanes (HBCDs). They are also potential stage one metabolites of biological HBCD transformations. Herein, we present analytical evidence that PBCDOHs are also constituents of technical HBCDs and flame-proofed polystyrenes (FP-PSs). PBCDOHs are possibly formed during the synthesis of technical HBCD, presumably during the bromination of cyclododecatrienes in aqueous isobutanol together with isobutoxypentabromocyclododecanes (iBPBCDs), which have been identified in these materials recently. Of the 64 stereoisomers possible, eight pairs of enantiomers, named alpha-, beta-, gamma-, delta-, epsilon-, zeta-, eta-, and theta-PBCDOHs were separated with a combination of normal-, reversed- and chiral-phase LC. Crystal structure analysis revealed the stereochemistry of the alpha-PBCDOH pair of enantiomers, which was assigned to (1S,2S,5R,6S,9S,10R)-2,5,6,9,10-pentabromocyclododecanol and its enantiomer. Mass spectrometric data are in accordance with the expected isotope patterns. On a C(18)-RP-column, the polar PBCDOHs eluted before the HBCD and iBPBCD classes of compounds. PBCDOHs were also found in FP-PS materials. The stereoisomer patterns varied considerably in these materials like those of HBCDs and iBPBCDs. Expanded polystyrenes were rich in late-eluting stereoisomers, similar to technical HBCD mixtures. Extruded polystyrenes contained more of the polar, faster-eluting isomers. The presented chromatographic and analytical methods allow a stereoisomer-specific search for PBCDOHs in biota samples, which might have experienced metabolic HBCD transformation reactions. Besides this potential source, it has to be recognized that PBCDOHs are by-products in technical HBCDs and in flame-proofed polystyrenes. Therefore, it is likely that PBCDOHs and iBPBCDs are released to the environment together with HBCD-containing plastic materials. PMID- 22520971 TI - The removal of hydrogen sulfide in solution by ferric and alum water treatment residuals. AB - This work investigated the characteristics and mechanisms of hydrogen sulfide adsorption by ferric and alum water treatment residuals (FARs) in solution. The results indicated that FARs had a high hydrogen sulfide adsorption capacity. pH 7 rather than higher pH (e.g. pH 8-10) was favorable for hydrogen sulfide removal. The Yan model fitted the breakthrough curves better than the Thomas model under varied pH values and concentrations. The Brunauer-Emmett-Teller surface area and the total pore volume of the FARs decreased after the adsorption of hydrogen sulfide. In particular, the volume of pores with a radius of 3-5 nm decreased, while the volume of pores with a radius of 2 nm increased. Therefore, it was inferred that new adsorption sites were generated during the adsorption process. The pH of the FARs increased greatly after adsorption. Moreover, differential scanning calorimetry analysis indicated that elemental sulfur was present in the FARs, while the derivative thermal gravimetry curves indicated the presence of sulfuric acid and sulfurous acid. These results indicated that both oxidization and ligand exchange contribute to the removal of hydrogen sulfide by FARs. Under anaerobic conditions, the maximum amount of hydrogen sulfide released was approximately 0.026 mg g(-1), which was less than 0.19% of the total amount adsorbed by the FARs. The hydrogen sulfide that was released may be re-adsorbed by the FARs and transformed into more stable mineral forms. Therefore, FARs are an excellent adsorbent for hydrogen sulfide. PMID- 22520972 TI - Coexistence of transthyretin familial amyloid polyneuropathy and hereditary neuropathy with liability to pressure palsy. PMID- 22520973 TI - An analysis of B-cell epitope discontinuity. AB - Although it is widely acknowledged that most B-cell epitopes are discontinuous, the degree of discontinuity is poorly understood. For example, given that an antigen having a single epitope that has been chopped into peptides of a specific length, what is the likelihood that one of the peptides will span all the residues belonging to that epitope? Or, alternatively, what is the largest proportion of the epitope's residues that any peptide is likely to contain? These and similar questions are of direct relevance both to computational methods that aim to predict the location of epitopes from sequence (linear B-cell epitope prediction methods) and window-based experimental methods that aim to locate epitopes by assessing the strength of antibody binding to synthetic peptides on a chip. In this paper we present an analysis of the degree of B-cell epitope discontinuity, both in terms of the structural epitopes defined by a set of antigen-antibody complexes in the Protein Data Bank, and with respect to the distribution of key residues that form functional epitopes. We show that, taking a strict definition of discontinuity, all the epitopes in our data set are discontinuous. More significantly, we provide explicit guidance about the choice of peptide length when using window-based B-cell epitope prediction and mapping techniques based on a detailed analysis of the likely effectiveness of different lengths. PMID- 22520974 TI - "Monovalent" ligands that trigger TLR-4 and TCR are not necessarily truly monovalent. AB - Cell surface receptors mediate many cellular responses in health and disease. Recent progress in our understanding of how ligand binding to the extracellular domains of receptors triggers intracellular signaling has underlined the role of ligand-promoted receptor clustering following by oligomerization of the cytoplasmic signaling domains. The clustering suggests the requirement of ligand multivalency and is especially important for triggering receptors involved in innate and adaptive immune responses. However, although numerous studies have established that multivalent, but not monovalent, ligands induce receptor mediated signal transduction, considerable uncertainty still remains. Here, I hypothesize that "monovalent" ligands that have been reported to trigger immune receptors in vitro are not necessarily truly monovalent. This is illustrated by focusing on studies of signal transduction by toll-like receptor-4 and T cell receptor. By generalizing this concept to a variety of lipid and protein ligands, one would propose an alternative interpretation of apparent ligand monovalency in other receptor activation studies as well. PMID- 22520976 TI - mTOR signaling pathway and mTOR inhibitors in cancer therapy. AB - Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase. It is ubiquitously expressed in cells and is a therapeutic target for the cancer treatment arsenal. Despite the great responses obtained in tumors addicted to specific mutations or overactivation of key members of the mTOR pathway (HiF1alpha in RCC, cyclin D1 in MCL, or TSC in SEGA), mTOR inhibitors as single agents have modest activity. Dual PI3K/mTOR kinase inhibitors have been developed with the idea of overcoming resistance to the mTOR inhibition through preventing the activation of PI3K/Akt as a result of release negative feedback loops. PMID- 22520977 TI - Topoisomerase 1 inhibitors and cancer therapy. AB - Topoisomerase 1 inhibitors cure human cancer xenografts in animal models, more so than most other chemotherapy agents. However, their activity in patients with cancer is modest. Ongoing research is studying the optimal analogues that could reproduce animal data in the cancer population. This article analyzes the clinical research with topoisomerase 1 inhibitors in ovarian cancer. PMID- 22520975 TI - Therapeutic antibodies against cancer. AB - Antibody-based therapeutics against cancer are highly successful and currently enjoy unprecedented recognition of their potential; 13 monoclonal antibodies (mAbs) have been approved for clinical use in the European Union and in the United States. Bevacizumab, rituximab, and trastuzumab had sales in 2010 of more than $5 billion each. Hundreds of mAbs, including bispecific mAbs and multispecific fusion proteins, mAbs conjugated with small-molecule drugs, and mAbs with optimized pharmacokinetics, are in clinical trials. However, deeper understanding of mechanisms is needed to overcome major problems including resistance to therapy, access to targets, complexity of biological systems, and individual variations. PMID- 22520980 TI - Targeting the hedgehog pathway: role in cancer and clinical implications of its inhibition. AB - The Hedgehog (Hh) pathway is a signaling cascade that is evolutionally highly conserved and plays an important role in embryonic pattern formation and stem cell response to tissue damage. Given the pivotal role the Hh pathway plays in embryonic development in terms of proliferation and differentiation, it is not surprising that it has also been implicated in tumorigenesis and tumor growth acceleration in a vast variety of malignancies. This article summarizes the mechanism of Hh pathway signal transduction, discusses the models of pathway activation, reviews the clinical data using Hh inhibitors, and discusses challenges to the development of pathway inhibitors. PMID- 22520978 TI - Targeting the insulin growth factor receptor 1. AB - The IGF axis is a tightly controlled endocrine system that regulates cell growth and development, known to have an important function in cancer biology. IGF1 and IGF2 can promote cancer growth in a GH-independent manner both through paracrine and autocrine secretion and can also confer resistance to chemotherapy and radiation. Many alterations of this system have been found in neoplasias, including increased expression of ligands and receptors, loss of heterozygosity of the IGF2 locus and increased IGF1R gene copy number. The IGF1 network is an attractive candidate for targeted therapy, including receptor blockade with monoclonal antibodies and small molecule inhibitors of receptor downstream signaling. This article reviews the role of the IGF axis in the initiation and progression of cancer, and describes the recent advances in IGF inhibition as a therapeutic tool. PMID- 22520979 TI - Targeting angiogenesis in gynecologic cancers. AB - Gynecologic malignancies carry an estimated incidence of 83,750 cases per year and estimated mortality rate of more than 27,000 women per year. New therapies and therapeutic approaches are needed to improve the outlook for women with gynecologic cancers. Recent insights at the molecular and cellular levels are paving the way for a more directed approach to target mechanisms driving tumorigenesis. This article reviews the roles of new and emerging antiangiogenesis drugs, summarizes the data obtained from clinical trials of antiangiogenic agents, and discusses trials under way to address the role of such strategies in gynecologic cancers. PMID- 22520981 TI - Tyrosine kinase inhibitors in lung cancer. AB - Identification of driver mutations in growth related protein kinases, especially tyrosine kinases, has led to clinical development of an array of tyrosine kinase inhibitors in various malignancies, including lung cancer. Improved understanding of tyrosine kinase biology has led to faster drug development, identification of resistance mechanisms, and ways to overcome resistance. This review discusses the clinical data supporting the use and practical aspects of management of patients on epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors. PMID- 22520982 TI - Antimitotic inhibitors. AB - Of the agents available in the treatment of both solid and hematologic cancers, microtubule-targeted agents are among the most widely used and exploiting other mechanisms involving the microtubule and its role in mitosis is an area of continued interest. This review will focus on novel microtubule-targeted agents, both recently approved (eg, ixabepilone and eribulin) and in later-stage clinical trials, and kinase inhibitors that aim to directly inhibit the mitotic spindle, such as the aurora kinase, pololike kinase, and kinsein-spindle protein inhibitors. PMID- 22520984 TI - Poly(Adenosine diphosphate-ribose) polymerase inhibitors in cancer treatment. AB - Recently, the development of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors as a synthetic lethality approach has brought a major breakthrough in the treatment of breast cancer susceptibility gene (BRCA)-mutant cancers. Because sporadic cancers have also been found to commonly have other defects in DNA repair, PARP inhibitors are under active clinical investigation in combination with DNA-damaging therapeutics in a wide range of sporadic cancers. In this review, the authors discuss DNA repair mechanisms and PARP as a therapeutic target and summarize an update on clinical trials of available PARP inhibitors and predictive biomarkers for their efficacy. PMID- 22520985 TI - Role of histone deacetylase inhibitors in the treatment of lymphomas and multiple myeloma. AB - Histone deacetylase inhibitors (HDACI) have allowed pharmacologic manipulation of deregulated genes in cancer cells and have shown single-agent activity against T cell lymphomas, cutaneous T cell lymphomas, mantle cell lymphomas, and Hodgkin disease. The bigger promise of these agents is in enhancing the activity of other targeted therapies. In addition, the effects of HDACI on the immune system and cytokines indicate that HDACI can be useful in the treatment of immune dysfunction underlying tumorigenesis, autoimmune disorders, and graft-versus-host disease. There is also an effort to determine whether class specificity of HDACI has a biologic significance. PMID- 22520983 TI - The antifolates. AB - This article focuses on the cellular, biochemical, and molecular pharmacology of antifolates and how a basic understanding of the mechanism of action of methotrexate, its cytotoxic determinants, mechanisms of resistance, and transport into and out of cells has led to the development of a new generation of antifolates, a process that continues in the laboratory and in the clinics. New approaches to folate-based cancer chemotherapy are described based on the targeted delivery of drugs to malignant cells. PMID- 22520986 TI - Clinical drug development in 2012. PMID- 22520988 TI - Are thrombolytics indicated for pulmonary embolism? PMID- 22520987 TI - From comparative effectiveness research to patient-centered outcomes research: integrating emergency care goals, methods, and priorities. AB - Federal legislation placed comparative effectiveness research and patient centered outcomes research at the center of current and future national investments in health care research. The role of this research in emergency care has not been well described. This article proposes an agenda for researchers and health care providers to consider comparative effectiveness research and patient centered outcomes research methods and results to improve the care for patients who seek, use, and require emergency care. This objective will be accomplished by (1) exploring the definitions, frameworks, and nomenclature for comparative effectiveness research and patient-centered outcomes research; (2) describing a conceptual model for comparative effectiveness research in emergency care; (3) identifying specific opportunities and examples of emergency care-related comparative effectiveness research; and (4) categorizing current and planned funding for comparative effectiveness research and patient-centered outcomes research that can include emergency care delivery. PMID- 22520989 TI - Electrocardiographic differentiation of early repolarization from subtle anterior ST-segment elevation myocardial infarction. AB - STUDY OBJECTIVE: Anterior ST-segment elevation myocardial infarction (STEMI) can be difficult to differentiate from early repolarization on the ECG. We hypothesize that, in addition to ST-segment elevation, T-wave amplitude to R-wave amplitude ratio (T-wave amplitude(avg)/R-wave amplitude(avg)), and R-wave amplitude in leads V2 to V4, computerized corrected QT interval (QTc) and upward concavity would help to differentiate the 2. We seek to determine which ECG measurements best distinguish STEMI versus early repolarization. METHODS: This was a retrospective study of patients with anterior STEMI (2003 to 2009) and early repolarization (2003 to 2005) at 2 urban hospitals, one of which (Minneapolis Heart Institute) receives 500 STEMI patients per year. We compared the ECGs of nonobvious ("subtle") anterior STEMI with emergency department noncardiac chest pain patients with early repolarization. ST-segment elevation at the J point and 60 ms after the J point, T-wave amplitude, R-wave amplitude, QTc, upward concavity, J-wave notching, and T waves in V1 and V6 were measured. Multivariate logistic regression modeling was used to identify ECG measurements independently predictive of STEMI versus early repolarization in a derivation group and was subsequently validated in a separate group. RESULTS: Of 355 anterior STEMIs identified, 143 were nonobvious, or subtle, compared with 171 early repolarization ECGs. ST-segment elevation was greater, R-wave amplitude lower, and T-wave amplitude(avg)/R-wave amplitude(avg) higher in leads V2 to V4 with STEMI versus early repolarization. Computerized QTc was also significantly longer with STEMI versus early repolarization. T-wave amplitude did not differ significantly between the groups, such that the T-wave amplitude(avg)/R-wave amplitude(avg) difference was entirely due to the difference in R-wave amplitude. An ECG criterion based on 3 measurements (R-wave amplitude in lead V4, ST-segment elevation 60 ms after J-point in lead V3, and QTc) was derived and validated for differentiating STEMI versus early repolarization, such that if the value of the equation ([1.196 x ST-segment elevation 60 ms after the J point in lead V3 in mm]+[0.059 x QTc in ms]-[0.326 x R-wave amplitude in lead V4 in mm]) is greater than 23.4 predicted STEMI and if less than or equal to 23.4, it predicted early repolarization in both groups, with overall sensitivity, specificity, and accuracy of 86% (95% confidence interval [CI] 79, 91), 91% (95% CI 85, 95), and 88% (95% CI 84, 92), respectively, with positive likelihood ratio 9.2 (95% CI 8.5 to 10) and negative likelihood ratio 0.1 (95% CI 0.08 to 0.3). Upward concavity, upright T wave in V1 or T wave, in V1 greater than T wave in V6, and J-wave notching did not provide important information. CONCLUSION: R-wave amplitude is lower, ST-segment elevation greater, and QTc longer for subtle anterior STEMI versus early repolarization. In combination with other clinical data, this derived and validated ECG equation could be an important adjunct in the diagnosis of anterior STEMI. PMID- 22520990 TI - Do febrile infants aged 60 to 90 days with bronchiolitis require a septic evaluation? PMID- 22520991 TI - A is for airway: a pediatric emergency department challenge. PMID- 22520992 TI - Are there pharmacologic agents that safely and effectively treat post-lumbar puncture headache? PMID- 22520993 TI - Do decongestants, antihistamines, and nasal irrigation relieve the symptoms of sinusitis in children? PMID- 22520994 TI - Individual interactive instruction: an innovative enhancement to resident education. PMID- 22520995 TI - Body mass index is negatively correlated with the response to controlled ovarian stimulation but does not influence oocyte morphology in ICSI cycles. AB - OBJECTIVE: To investigate whether or not body mass index (BMI) is associated with oocyte dysmorphisms. STUDY DESIGN: This retrospective study enrolled 1105 patients undergoing intracytoplasmic sperm injection (ICSI). The correlation between BMI and the response to controlled ovarian stimulation (COS) and ICSI outcomes was analysed. Oocyte morphology was determined in metaphase II (MII) oocytes retrieved from all cycles. The influence of BMI on the odds of having oocyte dysmorphism was also studied. RESULTS: A negative correlation was found between BMI and the number of oocytes retrieved, MII oocytes, oocytes injected, embryos obtained, high-quality embryos and oocyte recovery rate. In addition, a trend towards a negative correlation between BMI and implantation rate was observed. However, BMI did not influence oocyte dysmorphisms. CONCLUSIONS: A negative correlation was found between BMI and the response to COS, and a trend towards a negative correlation was observed between BMI and implantation rate in the ICSI cycles. However, oocyte dysmorphisms were not influenced by BMI and, therefore, do not account for the reduced ICSI outcomes. PMID- 22520996 TI - Diagnosing vaginal infections through measurement of biogenic amines by ion mobility spectrometry. AB - OBJECTIVE: To compare diagnosis of bacterial vaginosis according to the Amsel criteria with measurement by ion mobility spectrometry (IMS) of the biogenic amines that are present in vaginal discharge fluid. STUDY DESIGN: Duplicate samples of vaginal fluid were collected from 115 unselected and consecutive patients in a vaginitis clinic in Detroit. All samples were evaluated using Amsel criteria and the results were compared with the diagnosis based on the IMS results. RESULTS: The incidence rate of vaginal infections was assessed on the basis of both tests and the frequency of BV was found to be 17.4%. The sensitivity and specificity for bacterial vaginosis diagnosis using IMS determination were 95.5% and 98.9%, respectively, with an accuracy of 94.4%. CONCLUSIONS: The results show that IMS may be used to rapidly diagnose this common vaginal infection with high accuracy. PMID- 22521001 TI - Local ointment versus cauterization in childhood recurrent epistaxis. PMID- 22521002 TI - Refractory relapsing polychondritis in a child treated with antiCD20 monoclonal antibody (rituximab): first case report. AB - To report the first case of refractory relapsing polychondritis in a child who was treated with the biological agent, rituximab, an antiCD20 monoclonal antibody. The case is reported with a review of the literature on the use of biological agents in the treatment of refractory relapsing polychondritis. A 10 year-old boy presented with relapsing polychondritis who was treated initially with prednisolone and methotrexate. As there was no response to the treatment, anti TNF antagonist infliximab was given but with a failed response. A subsequent therapy with rituximab produced significant clinical remission with no recurrence at 1 year. Relapsing polychondritis unresponsive to primary treatment modalities but treated with various biological agents in adult have been well described in adults but not reported in children age below 13 yrs. Hence we present this case report. Biological agents such as rituximab has promising role in children when primary treatment fails as reported in our case. PMID- 22521004 TI - [Intra-gastric ballon in the treatment of morbid obesity]. AB - BACKGROUND: Intragastric balloon is a temporary treatment for weight loss with proven safety and efficacy when associated with lifestyle intervention. It is indicated in the super--obese who are candidates for bariatric surgery to lose weight and to reduce their high surgical risk. Our aim was to retrospectively evaluate the results of the patients in whom this device was inserted during a three-year period from the beginning of this practice in the Hospital de Santa Maria. METHODS: Data from the medical records in what concerns bioanthropometric characteristics in the beginning and following balloon removal were reviewed and submitted to descriptive analysis. RESULTS: Fifty-seven patients underwent intragastric balloon placement, of whom 46 female and 11 male, with median age 44,2 +/- 11,77 years. Median body mass index (BMI) 51,6 +/- 9,45 kg/m(2). Five patients were lost to follow-up. The balloon was inserted for a median time of 206 +/- 62,62 days, during which there was a median weight loss of 17,2 +/- 9,46 kg, a reduction of 6,7 +/- 3,73 kg/m(2) in BMI and a mean excessive weight loss of 26,7 +/- 16,99%. There were 5 patients in whom serious complications occurred, one of which died. One half of the patients went on to bariatric surgery. The median time between balloon removal and surgery was 241,6 +/- 243,66 days in which there was a median weight variation of + 3,5 +/- 11,69 kg. The remaining patients: 15 dropped out further treatment, 5 patients are under medical therapy and have no invasive procedure scheduled, 4 patients are to be submitted to another balloon insertion and 2 patients were submitted to the insertion of a second balloon during the time this article refers to. CONCLUSIONS: Our findings are similar to some previously described. Intragastric balloon is a temporary and efficacious option in the treatment of morbid obesity. However, it is very important to strictly select the patients and to have a good coordination with the Surgical department so that results can be optimized. PMID- 22521005 TI - [Trends in prostate cancer mortality in Portugal (1980-2006)]. AB - INTRODUCTION: In the last decade prostate cancer mortality declined in several countries. We aimed to quantify the variation in prostate cancer mortality rates, in Portugal (1980-2006) and in different regions of the country (1992-2005). PATIENTS AND METHODS: Prostate cancer mortality rates and number of deaths were obtained from the World Health Organization (1980-2003), and from the publication Risco de Morrer em Portugal (2004-2006). The latter was the source of regional data (1992-2005). Joinpoint regression analyses of the standardized rates were performed to identify the years in which changes in trends have occurred, and to estimate the annual percent changes in each period, for the age groups > 44, 45 54, 55-64, 65-74 and > 74 years. At a regional level the annual variation was computed for ages above 44 years. RESULTS: Prostate cancer standardized mortality rates increased 2.8%/year (95% Confidence Interval (CI): 2.1 to 3.6) between 1986 and 1998 and changed -3.1%/year (95% CI: -4.1 to -2.2) from 1998 to 2006. At a regional level there was a significant decline in Porto since 1992, and later on in Aveiro, Lisboa, Viana do Castelo and Viseu. The regional trends were inversely associated with the standardized mortality rates in each region at the beginning of the period (r=-0.67, p=0.003). CONCLUSION: An inflection in prostate cancer mortality was observed in Portugal in the late 1990s, with an estimated annual percent change of -3%/year from 1998 to 2006, and higher declines in the regions with the highest mortality rates at the beginning of the period. PMID- 22521003 TI - Folate intake and depressive symptoms in Japanese workers considering SES and job stress factors: J-HOPE study. AB - BACKGROUND: Recently socioeconomic status (SES) and job stress index received more attention to affect mental health. Folate intake has been implicated to have negative association with depression. However, few studies were published for the evidence association together with the consideration of SES and job stress factors. The current study is a part of the Japanese study of Health, Occupation and Psychosocial factors related Equity (J-HOPE study) that focused on the association of social stratification and health and our objective was to clarify the association between folate intake and depressive symptoms in Japanese general workers. METHODS: Subjects were 2266 workers in a Japanese nationwide company. SES and job stress factors were assessed by self-administered questionnaire. Folate intake was estimated by a validated, brief, self-administered diet history questionnaire. Depressive symptoms were measured by Kessler's K6 questionnaire. "Individuals with depressive symptoms" was defined as K6>=9 (in K6 score of 0-24 scoring system). Multiple logistic regression and linear regression model were used to evaluate the association between folate and depressive symptoms. RESULTS: Several SES factors (proportion of management positions, years of continuous employment, and annual household income) and folate intake were found to be significantly lower in the subjects with depressive symptom (SES factors: p < 0.001; folate intake: P = 0.001). There was an inverse, independent linear association between K6 score and folate intake after adjusting for age, sex, job stress scores (job strains, worksite supports), and SES factors (p = 0.010). The impact of folate intake on the prevalence of depressive symptom by a multiple logistic model was (ORs[95% CI]: 0.813 [0.664-0.994]; P =0.044). CONCLUSIONS: Our cross-sectional study suggested an inverse, independent relation of energy adjusted folate intake with depression score and prevalence of depressive symptoms in Japanese workers, together with the consideration of SES and job stress factors. PMID- 22521006 TI - [Cow's milk protein allergy: a challenging diagnosis]. AB - BACKGROUND: Cow's Milk Protein Allergy (CMPA) is the most common food allergy in infants. It can manifest itself through a wide variety of symptoms depending on the type of immune response is IgE or non-IgE mediated. In most cases acquisition of tolerance to cow's milk protein (CMP) occurs until the second year of life. OBJECTIVE: To evaluate the cases of CMPA followed in our Outpatient Clinic of Pediatric Gastroenterology and compare IgE and non-IgE mediated CMPA. METHODS: CMPA patients observed between December 1992 and December 2009 were included in this prospective study and followed-up according to our CMPA protocol. RESULTS: 199 children were included in the protocol, but only 130 cases were confirmed the diagnoses of CMPA, 77 were IgE mediated (group A) and 53 non-IgE mediated (group B). Comparing the two groups, 45% vs 36% had positive family history of atopy. The median age of onset was 10 and six weeks respectively, and the interval between introduction of PLV into the diet and the onset of symptoms was four and five days. Infant formula was, in both groups, the main dairy product that triggered symptoms (71% vs 81%). In group A over half the children did the first dose of PLV in first 24 hours of life. The value of specific IgE to the major PLV was identified in 76 children and only 15.6% were positive. The most frequent symptoms in both groups were cutaneous (85.7% vs 50.6%), especially urticaria and angioedema, gastrointestinal symptoms (40% vs 38%), including vomiting and diarrhea. PMID- 22521007 TI - [Barriers in access and utilization of health services among immigrants: the perspective of health professionals]. AB - The growing international migration has reinforcing the importance of a greater adequacy of health services in order to respond effectively to immigrants' needs. Previous studies indicate that several difficulties in the access and utilization of health services persist for some immigrant groups. The objective of this study was to understand the perspective of different health professionals' groups about the barriers in access and utilization of services by immigrants. In a transversal study a questionnaire was applied to 320 primary health care professionals of Lisbon and Tagus Valley. Differences between professional groups were analysed using the Kruskal-Wallis test. To determine which groups diverged more in their perceptions, mean ranks of each group were compared. Of the total participants, 64.2% evaluated their knowledge and competencies to deal with immigrants as reasonable however, 15.2% evaluated it as bad. Around one third of professionals admitted to be unaware of the legislation which regulates migrants' access to services. The largest proportion considered that, at the individual level, the frequent change of residence, the lack of economic resources, the cultural and religious beliefs and traditions, the fear of denunciation when the immigrant is undocumented, the lack of knowledge about legislation and services, and the linguistic differences influence access and utilization of health services. Most considered as barriers at the professionals' and services' level the limited sociocultural skills, the complex bureaucratic procedures, the cost and the lack of interpreters. The divergences in the perception of these factors occurred mainly between office workers and the other professionals. The perceptions of health professionals about the barriers in access and utilization of services by immigrants highlight opportunities for intervention in the context of cultural diversity. Given the different perceptions among the professional groups, which may be reflection of the functions they perform, it is reinforced the importance of developing appropriate training to the different professional profiles. The capacity-building of health professionals to deal with cultural diversity may be an important component of human resources training, contributing to better adequate services to the needs of the immigrant. PMID- 22521008 TI - [Minimally invasive surgery in women with recurrent stress urinary incontinence]. AB - OBJECTIVES: Evaluate the efficacy and safety of minimally invasive surgical techniques as second procedure in recurrent stress urinary incontinence (SUI). STUDY DESIGN: We retrospectively analyzed data on patients submitted to this type of surgery after previous surgery failure, since September 2002 to December 2006. Several parameters were evaluated: women's age, symptoms, previous surgery, urodynamics results, procedure technique, complications at short (two months) and medium term (one year) results. RESULTS: Of the 73 analyzed cases, 57 patients had been submitted previously to classic surgery and 16 to minimally invasive surgery. In surgery for recurrent SUI using minimally invasive techniques eight complications were registered (five vaginal perforations, two bladder lacerations and one femoral vein laceration); post-op complications occurred in 13 cases (three urinary retentions, two urinary tract infections, one anaemia and seven vaginal sling erosions). Short-term cure, improvement and failure rates were 69.9%, 28.8% and 1.4%, respectively. At medium term, these rates were of 54.8%, 41.1% and 4.1%, respectively. CONCLUSIONS: Minimally invasive surgery for recurrent SUI is a valid option after previous surgery failure, given the low morbidity and reduced failure rate at short and medium term. PMID- 22521009 TI - [Analysis of handgrip strength from elderly women: a comparative study among age groups]. AB - The senior population has increasing recently and demanding greater attention due to of falling related to the reduction of muscle strength. The early falling risk identification has been prized by many countries and allows the implementation of preventive actions, such as the participation of physical activities, which have been considered a promising way to prevent the loss of muscle mass and strength. By this way, the present application intended to identify the handgrip profile, known as an important predictor of physical function, of Brazilian women of different ages. Eight-four women were divided into four age groups (20-27, 50-64, 65-74, and 75-86 years old) being made the comparison among the peak of handgrip strength. It was observed smaller values of handgrip strength (p >0.05) for age groups 50-64,65-74 and 75-86 years old when compared to age group 20-27 years old. It has been identified a negative correlation among age and the peak of handgrip strength (Spearman's Rho = -0,78, p > 0.05) which was associated to much smaller values of peak of handgrip strength between age group 75-86 years old compared to age groups 50-64, and 65-74 years old (p > 0.05). The results demonstrate a functional decline beginning at the fifth decade, which could guide preventive actions such as the incentive to a physical engagement in activity programs. It was suggested the development of other studies with a bigger sample which encloses other age groups and males. PMID- 22521010 TI - [Rehabilitation programme using neuromuscular electrical stimulation in spinal cord: epidemiological aspects]. AB - OBJECTIVE: To assess epidemiological profile of spinal cord injury outpatients which have been participating of rehabilitation programme using neuromuscular electrical stimulation, in order to implement campaigns for preventing spinal cord trauma. METHODS: From January to April 2009, 30 patients at the spinal cord injury ambulatory clinic at Hospital das Clinicas of Unicamp were analysed by some epidemiologic characteristics: age, profession, type and level of their paralysis, origin and time of injury. RESULTS: All patients had complete spinal cord injury (ASIA); 24 patients were men and six were women, the mean age was 34.6 years (range, 10-64 years), two patients were children. Twenty-one patients were paraplegic and nine were tetraplegic; causes included automobile accident (12), run over (three), diving (four), bicycle accident (one), motorcycle accident (three), gunshot wound (six), thoracic tuberculosis (one), and lumbar surgery (one). The mean lesion time was 8.2 years (range, 1-15 years). Two patients were retired. CONCLUSION: The results suggested that spinal cord injury affects mainly young active men. It is necessary to develop incisive actions to prevent accidents, specially directed to traffic security. PMID- 22521011 TI - [High dose chemotherapy with autologous stem-cell support in germ cell tumors: The Instituto Portugues de Oncologia de Lisboa Francisco Gentil Series]. AB - BACKGROUND: High dose chemotherapy with autologous stem cell transplantation (HDCT-ASCT) has been administered to patients with high-risk germ cell tumours (GCT). The role of this treatment for GCT still remains unclear, including the identification of subgroups more likely to benefit from such strategy. METHODS: A retrospective review was conducted of all male patients with gonadal and extra gonadal GCT treated with HDCT-ASCT between 1996 and 2008 at the Instituto Portugues de Oncologia de Lisboa Francisco Gentil (IPOLFG). RESULTS: Twenty patients were treated with HDCT-ASCT, 17 with primary testicular tumours, two mediastinal and one retroperitoneal GCT. According to the International Germ Cell Cancer Consensus Group (IGCCCG) classification, at diagnosis three patients had good risk, four intermediate, eight poor but for the patients left the risk group could not be ascertained. In eight patients HDCT-ASCT was used upfront, after induction with first-line conventional chemotherapy, and in the remaining 12 for relapsed GCT. One patient had platinum-resistant and another platinum-refractory disease. Only two patients had Beyer score > 2. All but one patient were treated with ICE (Ifosfamide, Carboplatin, Etoposide). Six patients underwent a second HDCT-ASCT course. The 5-year overall survival and progression free survival were respectively 53% and 44%; both patients with mediastinal GCT are long term survivors. CONCLUSION: Randomized studies to date have failed to indicate a survival advantage for HDCT-ASCT in GCT. This series is small and heterogeneous which prevents us from drawing conclusions regarding the benefit of this treatment for GCT. However, we could confirm the lack of benefit of HDCT-ASCT for platinum-resistant GCT and to question the absolute contraindication to this therapeutic modality in mediastinal GCT. HDCT-ASCT should therefore be performed exclusively in experienced centers and, preferably, in the setting of clinical trials. PMID- 22521012 TI - [Comparative study of end-of-life care in an internal medicine ward and a palliative care unit]. AB - INTRODUCTION: Dued to ageing population and growing of chronic advanced illnesses, nowadays, the majority of deaths take place in hospitals. Terminal patients with cancer and other non-malignant diseases share the same type of problems which, once correctly accessed, may have similar approach. Inappropriate terminal care can lead to unnecessary suffering of patients and their families. METHODS: A retrospective chart review was done for the first 96 patients who died in 2005 due to advanced chronic illnesses in a Internal Medicine ward (48 patients) and in a Palliative Care unit (48 patients). The main outcome was the documentation of the presence/absence of a group of symptoms, the ability of the medical staff to perceive the patients as dying and the adjustments made in the comfort care plans. RESULTS: There were no demographic differences between the two sets of populations. In the Internal medicine ward it was seen an acute pattern of treatment even though the situation was clearly chronic and advanced. In the Palliative Care Unit there was a systematic surveillance and assessment of symptoms and other problems, like psycho-spiritual needs. In both environments, pain, dyspnoea and gastrointestinal problems were the symptoms most frequently recorded in clinical charts. The number of symptom recordings entered diminished in the agonic phase. CONCLUSION: These data highlight the need for a better assessment of patients' needs in order to promote impeccable end-of-life care. PMID- 22521013 TI - [Characterization of patients with type 2 diabetes treated with vildagliptin]. AB - INTRODUCTION: Diabetes mellitus is a progressive disease and the rapid growth of this global prevalence has been a worldwide concern. About a third of Portuguese population has type 2 diabetes or pre-diabetes. 2 DM is associated with significant morbidity and mortality, although the treatment so far available it is a high percentage of patients who do not achieve the proposed objectives. Vildagliptin is an inhibitor of oral DPP-4, the most studied of this new class. Inhibiting the rapid degradation of incretins, the vildagliptin increases levels of GLP-1, getting this hormone available to modulate the function of a and beta cells. AIMS: This study aims to characterize the first patients with DM2 treated with vildagliptin in the Department of Endocrinology, Diabetes and Metabolism at the Military Hospital. METHODS: Retrospective study with the first 70 patients treated with vildagliptin, between October and December 2008. The information collected was demographic data, disease duration, associated diseases and their medication, metabolic control in the beginning of the disease (values HbA1c) and criteria for use of vildagliptin. RESULTS: Among the patients included in the study, 55, 7% were male, with the average age of 63, 3 years. These patients had a average duration of diabetes of 11, 7 years. Hypertension was the most frequent associated pathology (85.7% of patients), although dyslipidemia and obesity have a high percentage, 80% and 51% respectively. All patients were overweight (BMI =25 Kg/m(2)). More than half of the patients (55,7%) were on monotherapy until the introduction of vildagliptin, having been associated with other oral antidiabetic agents in all patients. CONCLUSIONS: Most of patients showed risk factors, for witch they were medicated. Vildagliptin has been added mostly in patients medicated with metformin. It is suggested that the therapeutic approach in type 2 diabetes is more and more early, effective and secure. PMID- 22521014 TI - [Reference values for bone strength assessed by quantitative ultrasound early after birth in term and preterm neonates]. AB - AIM: To obtain reference values for bone strength assessed early after birth for term and preterm neonates in Portugal. METHODS: Speed of sound (SOS) (m/s) was measured using the quantitative ultrasound method in a systematic sample of appropriate-for-gestationalage term and preterm neonates, within the first two and five days after birth, respectively. Homogeneity of values between genders and between gestational age groups was assessed. RESULTS: A sample of 158 neonates was enrolled, 34 full-term and 124 preterm (26-41 weeks of gestation), birth weights of 595g-4195g, 84 males (53.2%) and 20 twins (10.8%). The mean of the SOS significantly increases with gestational age. Reference values of SOS for gestational age groups are provided as 10th, 25th, 50th, 75th and 90th centiles without gender distinction. CONCLUSION: Reference values for SOS early after birth are made available for term and preterm appropriate-for-gestational age neonates, reflecting the intrauterine bone status, a baseline for follow-up studies on bone strength in Portugal. PMID- 22521015 TI - [Clinical effectiveness and economical evaluation of preventive vaccination]. AB - The value of mass vaccination as a preventive measure for infectious diseases is one of the most important advances of modern Medicine. The impact on incidence of several infectious diseases, until recently responsible for significant morbidity and mortality at world level, is well proved in a series of high quality epidemiological studies. In this scientific review we aimed firstly to briefly resume the history of mass vaccination and its scientists, responsible for synthesis and marketing of these drugs. In second place we present a group of a few disease preventable by vaccines as well as the Portuguese National Vaccination Plan and its benefits. In third place we identified groups of subjects in which a well structured vaccination plan is particularly important, as well as the correspondent diseases to be covered by vaccination. Fourthly, we discussed the ethical considerations of vaccination, and its tensions between subject autonomy and society advantages in com pulsive programs. Fifthly, we analyzed clinical effectiveness of vaccines through the concept of herd immunity, clinical evaluation of immune response to vaccines and some examples of systematic reviews on three relevant diseases (influenza, meningococcal and pneumococcal infections). In sixth place we discussed vaccine safety presenting monitoring methods of vaccination risks, as well as discussing the public myths concerning vaccines. Finally we present a economic analysis of preventive vaccination with a review of some published literature on specific diseases. We conclude that mass vaccination is a efficacious preventive measure, as well as a economic rational choice, and that this public health intervention should be a pillar of a modern preventive system. PMID- 22521016 TI - [Hepatitis B genotype distribution in Portugal and worldwide]. AB - INTRODUCTION: Infection with Hepatitis B is a public health problem worldwide. In Portugal, around 1% of the population is chronically infected. Some genotypes are only predominant in some geographical regions; however migration around the world can lead to the dissemination of the different genotypes. The heterogeneity of hepatitis B genotypes seems to be related to differences in clinical evolution of the infection and response to antiviral treatment. AIM: The present study was designed to review the worldwide geographical distribution of Hepatitis B genotypes, and to analyze the possible relationships with the distribution of genotypes in Portugal. METHODS: Studies of interest were identified by search on indexed journals. Search of Portuguese information was extended to conference proceedings in the areas of Virology and Hepatology. RESULTS: In Asia genotypes B and C were prevalent; in the North of Africa the genotype D was prevalent, and in the East Coast genotype E was predominant. In the American continent the most predominant genotypes were A, D, F, G and H. In South America, Venezuela and Argentina showed a high prevalence of genotype F, in Brazil genotype A was prevalent. In Europe, including Portugal, genotypes A and D were predominant. In Portugal genotypes C, E and F were observed in Portuguese patients and in immigrant patients. DISCUSSION: The pattern of global migration affects the pattern of genotype distribution, introducing genotypes in regions where the clinical outcome can differ from the population of origin. The genotypic distribution found in Portugal seems to be associated not just with being a European country, but also with immigration from Africa, Brazil, Eastern Europe, and Asian countries like China. The study of the hepatitis B genotypic distribution should be extended to all regions in Portugal, namely Lisbon where the immigration levels are higher, as well as to the autonomous regions of Portugal, the Azores and Madeira islands. The relationship between hepatitis B genotypes and pathogenicity remains largely unknown, however evidence suggests the clinical and public health relevance of these genotypes. Further research is needed, not only to know how genotypes affect the severity of liver disease, but also to understand if and how the response to treatments is influenced by hepatitis B virus genotype. PMID- 22521017 TI - [Forensic telepsychiatry in Portugal: a few reflections]. AB - Forensic Telepsychiatry has had growing usage in countries such as the USA and England in the last decade, due to ongoing development of technologies which allow a better access to mental health care in needed populations, and improve the outcome of technicians' work, while facing a more demanding performance of Mental Health facilities. In this article we make a revision of literature concerning applications of Forensic Telepsychiatry, analyzing its potencialities and limits in Portugal. The literature shows positive evidence about efficiency, cost and acceptance, to both patients and doctors. On the other hand, several authors rise issues related to technical, ethical and legal aspects, such as restrictions to its application in forensics; privacy, confidentiality, safety, consent, diagnostic skills and professional responsibility. Forensic Telepsychiatry has shown special utility in remote rural populations with poor access to mental health care, victims of domestic violence, victims of sexual abuse, minor inpatients in correctional facilities and convicts in prisons. It may improve exchange of information with courts and penitentiaries, and production of evidence through quick and efficacious auditing. It has also been used in court to communicate forensic reports concerning mental health patients, to clarify issues related to psychiatric evaluations and testify in criminal and civil courts. Besides the literature revision, three areas of applicability for Forensic Telepsychiatry in Portugal are discussed in this article: teleconference for experts - psychiatrists and psychologists - testifying in court sessions; psychiatric and psychological evaluations through teleconference; expert auditions through a hotline, designed to provide specialized support to courts - both for urgent guidance and clarification. The reflections and proposals included in this article aim to make way to empirical studies which could evaluate the applicability of a more widespread usage of Forensic Telepsychiatry in Portugal in the near future. PMID- 22521018 TI - [Antidepressants and suicide in adolescents]. AB - In recent years, drug regulation agencies from the US and the UK have issued warnings concerning the emergence of suicidal behavior in children and adolescents treated with antidepressants. As suicidal behavior is the most feared of the core symptoms of depression, these warnings were naturally met with great concern by mental health care technicians and afflicted patients and families. In this article we have conducted a review of the literature discussing the controversy that originated in 2003 with the reanalysis of data from clinical trials with selective serotonine reuptake inhibitors. Following our review of meta-analyses, observational studies and ecological studies, we found that SSRIs show some efficacy and are generally safe in the treatment of adolescent depressive disease, provided that the clinical decision to prescribe them is properly weighed and discussed. We make some clinical recommendations, underscoring that adolescents who are medicated with antidepressants must be carefully monitored with regard to suicidal behavior and eventual adverse effects. PMID- 22521019 TI - [Shoulder dystocia: an obstetrical emergency]. AB - Shoulder dystocia is one of the most feared obstetric emergencies due to related maternal and neonatal complications and therefore, the growing of medico-legal litigation that it entails. Although associated with risk factors such as fetal macrossomia, gestacional diabetes and instrumented delivery, the majority of cases are unpredictable. The lack of a consensus on shoulder dystocia diagnosis causes variations on its incidence and hampers a more comprehensive analysis. Management guidelines described for its resolution include several manoeuvres but the ideal sequence of procedures is not clearly defined in more severe cases. Hands-on and team training, through simulation-based techniques applied to medicine, seems to be a promising method to learn how to deal with shoulder dystocia having in mind a reduction in related maternal or neonatal morbidity and mortality. The main goal of this paper is to provide a comprehensive revision of shoulder dystocia highlighting its relevance as an obstetric emergency. A reflection on the management is presented emphasising the importance of simulation-based training. PMID- 22521020 TI - [Lithokelyphopedion]. AB - Lithopedions are extremely rare conditions. Less than 300 cases were described worldwide. We report a case occurring in a woman of 77 years of age, admitted with dehydration, urinary tract infection and infected limb pressure ulcers. She had been recently admitted in a Surgery ward for incarcerated umbilical hernia. At the time the abdominal examination revealed a mass with about 10 cm in diameter, with petrous consistency, adherent to the deep plans around the umbilical regium and the hypogastrium. This finding was interpreted as a probable left renal tumor. The abdominal X-ray revealed voluminous calcified mass and the CT-scan showed to be a lithokelyphopedion with about fifty years, of a full term pregnancy. PMID- 22521021 TI - [Acute abdomen: transverse colonic volvulus]. AB - Volvulus of the transverse colon continues to be a rare medical problem in the bibliographic medical revisions of large bowel obstructions (1%), being frequently excluded of the differential diagnosis. However it is associated with higher morbid-mortality than the commonest cecal and sigmoid volvulus, making urgent a rapid diagnostic and chirurgical intervention. The authors present a case of this entity emphasizing the imagiologic diagnostic aspects and a bibliographic revision. PMID- 22521022 TI - [Arthritis and clinical history]. AB - In front of a patient with arthritis, clinical good-sense tells that the most probable diagnosis are the most prevalent ones. Nevertheless, we have to exclude a multiplicity of other aetiologies, less frequent, but with highest implications in the therapeutic conduct. Infections by Brucella and by Borrelia are rare causes of chronic arthritis, yet are diagnosis to consider, even when the clinical manifestations aren't the most typical, as there still exist endemic areas in Portugal. Here we report two clinical cases about patients with arthritis for more than one year, subject to ineffective exams ant treatments. Only the clinical history could put on evidence clinical-epidemiological data, suggestive of Brucellosis and Lyme Disease, namely the professional contact with infected animals, and the history of probable erythema migrans, that pointed toward the correct diagnosis. So, with directed therapeutic, there was complete resolution of the inflammatory symptoms. PMID- 22521023 TI - [Heterozygous beta thalassemia with triplication of the alpha globin gene]. AB - We describe a case in which the interaction of heterozygosis for the mutation Beta IVSI - 110 G> A and the alphaalphaalpha(anti 3,7) allele was the likely cause of the clinical occurrence of thalassemia intermedia. The proposita, a 19 years old, gypsy, Portuguese woman presented with chronic mild anemia, jaundice and splenomegaly in spite of having the beta-thalassemia trait. The analysis of the alpha-globin gene revealed heterozygosis for alpha-globin gene triplication with the presence of allele alphaalphaalpha(anti -3.7). This case brings again to discussion the complexity of genetic interactions underlying a phenotype of thalassemia intermedia and stresses the importance of looking for another cause in individuals with beta-Thalassemia minor uncommom phenotype. PMID- 22521024 TI - [Sickle cell disease and cerebrovascular stroke: a preventable event]. AB - INTRODUCTION: About 75% of the children presenting with cerebrovascular stroke have an identified cause. For black children, the most common underlying condition is sickle cell disease. This case report describes a preventable natural history, with an unusual presenting feature. CASE PRESENTATION: 27th month black infant without relevant background, presented with an acute focal neurological deficit. Brain computed tomography scan showed extensive acute infarction, and magnetic resonance also revealed previous silent cerebral infarct. Blood sample showed normocytic anemia and spontaneous sickling of the red blood cells, with 87% hemoglobin S. Exchange transfusion was made. CONCLUSION: Stroke, as a sickle cell disease complication, can occur at early ages and being the presenting sign. We consider that it would be worth spread the antenatal hemoglobinopathy screening programme, and evaluating the cost effectiveness of a neonatal screening programme for sickle cell disease in Portugal. PMID- 22521025 TI - [Infant cervical spondylodiscitis and abscess]. AB - INTRODUCTION: Spondylodiscitis in childhood is rare and has non-specific clinical features, requiring a high index of suspicion. CLINICAL CASE: The authors describe a nine month-old female infant, who presented at the emergency room (ER) with a torticollis for four days, without fever or trauma. Cervical X-rays were normal, and she received symptomatic treatment. Six days after, she returned to the ER with the same torticollis and also irritability, anorexia, and cervical hyper-extension. The CT scan showed cervical spondylodiscitis (C6-C7) with pre vertebral abscess. The laboratory results only revealed a slightly elevated Sedimentation Rate. Treatment was systemic vancomycin, gentamicin and metronidazol for six weeks, followed by two weeks of oral flucloxacillin. The causative organism was not identified. The symptoms and the abscess resolved during the first week of treatment. Five days after finishing the antibiotics the magnetic resonance showed partial C6-C7 fusion, without neurologic compression or functional disability. COMMENTS: Cervical spondylodiscitis with abscess is rare, especially in this age group. This case also emphasizes the importance of investigating an acquired persistent torticollis. PMID- 22521026 TI - [Fowler's Syndrome: diagnostic and therapeutic challenge]. AB - Urinary retention in women is not a common complaint. The main causes are structural or functional, which means that urological and neurological reviews are mandatory. Fowler's Syndrome has been described in 1988 and has stablished an association between urinary retention, electromyographic abnormality of the striated urethral sphincter and polycystic ovaries pathologies. Even though its phisiopathology is not completely understood, this disorder seems to be due to a primary failure of relaxation of the striated urethral sphincter. Not only a typical clinical history, but also the evaluation of the sphincter volume, sphincter pressure profilometry and electromyography are determinant to the diagnosis. Sacral neuromodulation seems to be the only therapeutic intervention that can restore voiding. Nevertheless an important group of women still need intermittent self-catheterization. We report the case of an otherwise healthy young women with isolated urinary retention, which exemplifies the diagnostic and therapeutic challenge of Fowler's Syndrome. PMID- 22521027 TI - [Panniculitis in the setting of visceral leishmaniasis]. AB - A 38-year-old male with a past history of intravenous drug use, AIDS and Visceral Leishmaniasis in 2000, was hospitalized after presenting with fever, myalgias and arthralgias, fatigue, hepatosplenomegaly and oedema of the inferior limbs. On the tenth day of admission, the patient developed painful subcutaneous nodules of the thighs and a Dermatology consultation was requested. A clinical and histological diagnosis of Leishmania Panniculitis was made, in the setting of Visceral Leishmaniasis recurrence. Leishmania Panniculitis is rarely found simultaneously with Visceral Leishmaniasis, and it is more frequently seen in HIV co-infected patients. In this case, the skin involvement allowed for an early diagnosis and histological confirmation of Leishmaniasis recrudescence to be made. PMID- 22521028 TI - [Acute necrosis of oesophagus]. AB - Acute esophageal necrosis is a very rare pathological entity, first described in 1990 by Goldenberg. The authors report the case of a patient of 79 years of age with this disease. The etiology of this type of esophageal injury is not yet well defined and has a reported mortality between 33 and 50% . We present this case by the rarity of the disease and the exuberance of endoscopic images in demonstration of this type of injury. PMID- 22521029 TI - Infective endocarditis due to Streptococcus gallolyticus associated with colonic displasia. AB - Streptococcus gallolyticus is a microorganism belonging to the Streptococcus bovis I group isolated in humans, bovines and equines pigeons, among other animals. Streptococcus bovis is a Streptococcus strain found in the rumen, and has been isolated in the milk of animals with mastitis. The authors describe a case of an adult immunocompetent patient with underlying valvular heart disease, with bacteraemia and infective endocarditis by Streptococcus gallolyticus, in whom adenomatous colonic polyps with dysplasia were identified. PMID- 22521030 TI - [The Institute of Anatomy in the centenary of the Medical Faculty of Lisbon University]. AB - The authors join the celebrations of the Centenary of the establishment of the Faculdade de Medicina da Universidade de Lisboa, on the 22(nd) April 2011, through the historical account of one of its main pilasters, the Institute of Anatomy. It is discussed the scope of its creation at the time, the important work done, the presence and participation in major international evolutionary landmarks in Anatomy, current thinking and action, and the measures implemented to prepare the incoming medical generations. Finally it will be presented the challenges for the 21st century and the strategies to overcome them, which includes the development of the Institute of Anatomy at the Medical Faculty of Lisbon University, in order to create a major pedagogic-scientific study space, for teaching and research of human normal morphology, above all in vivo aspects more applied, the clinic and imaging pre- and post-graduate. There is a world of morphological investigations, basic and clinical, to be held, involving teachers, students, and even doctors and surgeons, with the privileged scientific and research support from the Institute of Anatomy of the Faculdade de Medicina da Universidade de Lisboa! PMID- 22521031 TI - Andres Laguna: a great medical humanist (1499-1559). AB - Andres Laguna, a Spanish humanist physician of the 16th century, occupies an important position in the history of medicine. An illustrious and brilliant mind, pioneer of anatomy and urology, Laguna proved to be a true pacifist and humanitarian with his knowledge standards and his political eloquence. He deserves to be remembered today as the perfect example of the Renaissance men, a true Homo Universalis. PMID- 22521032 TI - Modulation of Toll-like receptor ligands and Candida albicans-induced cytokine responses by specific probiotics. AB - Probiotics have been proposed as modulators of gut inflammation, especially in inflammatory bowel disease (IBD). In order to be able to use them in these clinical conditions, their capacity to modulate immune responses towards other stimuli or microorganisms has to be thoroughly understood. In the present study, three different potentially probiotic strains, Bifidobacterium breve (NumRes 204), Lactobacillus rhamnosus (NumRes1) and Lactobacillus casei (DN-114 001), have been studied for their potential to modulate responses to stimulation with pure pattern-recognition receptor (PRR) ligands or to the gut commensal fungus Candida albicans. Cytokine production induced by PRR ligands or C. albicans was assessed in conditions of simultaneous stimulation or preincubation of primary immune cells with Bifidobacterium or Lactobacillus spp. Results indicate that simultaneous stimulation leads to potentiation of IL-1beta and IL-6 production, while the TNFalpha and IFN-gamma production was inhibited. In settings of pre incubation with these potentially probiotic strains, lower production of TNFalpha was observed in the presence of B. breve. Moreover, C. albicans-induced IL-17 production was decreased after pre-incubation with both Bifidobacterium or Lactobacillus probiotic strains. Whereas C. albicans induced cytokines are dampened by the tested probiotic strains, TNFalpha and IL-6 production by pure pattern-recognition receptor ligands are potentiated. Interestingly, an important role of Toll-like receptor 9 signalling that involves JNK kinase in the modulatory effects of these probiotic strains has been identified. In conclusion, specific probiotic strains exhibit cross-tolerance effects towards other inflammatory stimuli, especially C. albicans, which might have beneficial effects on gut inflammation. PMID- 22521033 TI - HUVEC co-culture and haematopoietic growth factors modulate human proliferative monocyte activity. AB - Monocytes and macrophages are often claimed to have limited potential for proliferation in vivo and in vitro although a human monocyte subset with increased potential to proliferate in culture, termed the proliferative monocyte (PM), has previously been identified. The response of the putatively less mature PM to conditions conducive to haematopoietic stem cell culture was determined. Co culture of monocytes on a HUVEC monolayer induced up to four cell divisions in a 9 day period. The PM response to haematopoietic growth factors (Flt3L, SCF, IL-6, IL-3 and M-CSF) was determined. M-CSF induced the greatest proliferative response in PM; IL-3 and Flt3L reduced basal and M-CSF-induced proliferation. The inhibition of M-CSFR kinase activity by GW2580 indicated that the ligand(s) for this receptor was a potent inducer of proliferation of this subset; inhibitors of intracellular signalling pathways also reduced PM proliferation. PMID- 22521036 TI - Degradation in soil of precursors and by-products associated with the illicit manufacture of methylamphetamine: implications for clandestine drug laboratory investigation. AB - Key precursors and by-products in the Leuckardt, Nagai and dissolving metal reductive syntheses of methylamphetamine undergo degradation in soil as a result of biotic and abiotic processes. Furthermore, methylamphetamine is a product of the degradation of 1-(1',4'-cyclohexadienyl)-2-methylaminopropane and N formylmethylamphetamine. These findings have implications for the forensic assessment of buried residues recovered from clandestine laboratory sites because markers used to infer the synthetic methods used might be absent as a result of degradation and because methylamphetamine might be present in residues as a result of degradation rather than as a direct result of its manufacture in the laboratory. PMID- 22521037 TI - Left ventricular assist device as bridge to recovery for anthracycline-induced terminal heart failure. AB - Anthracycline treatments are hampered by dose-related cardiotoxicity, frequently leading to heart failure (HF) with a very poor prognosis. The authors report a case of a 19-year-old man developing HF after anthracycline treatment for Ewing sarcoma. Despite medical treatment, his condition deteriorated to terminal HF, leading to implantation of a mechanical left ventricular assist device (LVAD). His heart function recovered, allowing explantation of the device 14 months after implantation. Heart transplantation is often contraindicated in the first years after treatment for cancers, and LVAD as "bridge to recovery" may be warranted in similar patients. PMID- 22521034 TI - Access, acceptability and utilization of community health workers using diagnostics for case management of fever in Ugandan children: a cross-sectional study. AB - BACKGROUND: Use of diagnostics in integrated community case management (iCCM) of fever is recognized as an important step in improving rational use of drugs and quality of care for febrile under-five children. This study assessed household access, acceptability and utilization of community health workers (CHWs) trained and provided with malaria rapid diagnostic tests (RDTs) and respiratory rate timers (RRTs) to practice iCCM. METHODS: A total of 423 households with under five children were enrolled into the study in Iganga district, Uganda. Households were selected from seven villages in Namungalwe sub-county using probability proportionate to size sampling. A semi-structured questionnaire was administered to caregivers in selected households. Data were entered into Epidata statistical software, and analysed using SPSS Statistics 17.0, and STATA version 10. RESULTS: Most (86%, 365/423) households resided within a kilometre of a CHW's home, compared to 26% (111/423) residing within 1 km of a health facility (p < 0.001). The median walking time by caregivers to a CHW was 10 minutes (IQR 5-20). The first option for care for febrile children in the month preceding the survey was CHWs (40%, 242/601), followed by drug shops (33%, 196/601).Fifty-seven percent (243/423) of caregivers took their febrile children to a CHW at least once in the three month period preceding the survey. Households located 1-3 km from a health facility were 72% (AOR 1.72; 95% CI 1.11-2.68) more likely to utilize CHW services compared to households within 1 km of a health facility. Households located 1-3 km from a CHW were 81% (AOR 0.19; 95% CI 0.10-0.36) less likely to utilize CHW services compared to those households residing within 1 km of a CHW.A majority (79%, 336/423) of respondents thought CHWs services were better with RDTs, and 89% (375/423) approved CHWs' continued use of RDTs. Eighty-six percent (209/243) of respondents who visited a CHW thought RRTs were useful. CONCLUSION: ICCM with diagnostics is acceptable, increases access, and is the first choice for caregivers of febrile children. More than half of caregivers of febrile children utilized CHW services over a three-month period. However, one-third of caregivers used drug shops in spite of the presence of CHWs. PMID- 22521038 TI - A real-life study of the use, effectiveness and tolerability of rosiglitazone in France: the AVANCE study. AB - AIM: The study aimed to determine the effectiveness and tolerability of rosiglitazone, and its profile in terms of treatment adherence, treated patients and prescribing recommendations under everyday conditions of care. METHODS: This was a "real-life" observational longitudinal study including patients with type 2 diabetes mellitus (T2DM) starting treatment with rosiglitazone and followed for up to 2 years. A questionnaire was completed at the time of inclusion and during routine consultations at around 6, 12, 18 and 24 months following inclusion. Information was collected on sociodemographics, clinical history, treatments, co morbidities, laboratory data and compliance with treatment. There were three primary outcome measures: treatment response (defined as an HbA1c <= 8.0% or a decrease in HbA1c >= 0.7%); switch to insulin (as considered necessary by the physician); and occurrence of adverse events requiring a change or discontinuation of treatment. RESULTS: The evaluation included 670 patients (61.1%) treated with rosiglitazone/metformin as fixed-dose combination tablets and 427 (38.9%) with standard rosiglitazone tablets. Rates of HbA1c response, defined as an HbA1c less than or equal to 8.0% or a decrease in HbA1c greater than or equal to 0.7%, ranged from 80.6% to 92.1% depending on the follow-up time. The percentage of patients with an HbA1c less than 7% was 18.4% before rosiglitazone was prescribed, and ranged from 48.2% to 57.8% depending on the follow-up period. Sixty-two patients (6.1%, 95% CI: 4.6-7.6%) switched to insulin therapy during the follow-up period. Spontaneously reported adverse events leading to a change or discontinuation of treatment were seen in 45 patients (4.4%, 95% CI: 3.2-5.6%). CONCLUSION: Rosiglitazone showed sustained efficacy, with around 90% of patients defined as responders to the treatment in terms of reduction in HbA1c, and was relatively well tolerated. The adverse-event profile was consistent with the known effects of rosiglitazone, and no signs of increased cardiovascular ischaemic risk were observed. These results are in agreement with previous studies on rosiglitazone. PMID- 22521039 TI - Metabolic dysfunction in late-puberty adolescent girls with type 1 diabetes: relationship to physical activity and dietary intakes. AB - AIMS: At puberty, type 1 diabetes (T1D) among young girls can lead to excess body weight, insulin resistance, deterioration of glycaemic control and dyslipidaemia. Although biological factors contribute largely to such metabolic dysfunction, little is known of the role of behavioural factors such as physical activity and diet. METHODS: This study investigated the association between metabolic dysfunction measured after a 12-h overnight fast and behavioural factors, including diet (4-day diary) and physical activity (validated questionnaire), in 19 postmenarchal adolescent girls with T1D compared with 19 healthy girls. RESULTS: T1D girls displayed higher levels of fat mass, insulin resistance (higher plasma glucose, serum leptin and waist-to-hip ratios) and dyslipidaemia (higher LDL-C and apolipoprotein B levels, lower HDL-C and apolipoprotein A-1 levels). Also, contrary to what is usually observed in T1D adults, serum adiponectin, an important vessel protector, was not raised in T1D adolescent girls compared with healthy controls. Quantity and quality of dietary macronutrient intakes as well as physical activity levels were comparable in both groups, although the T1D girls with the poorest metabolic profiles reported having the healthiest diets (fewer total calories, more protein and less carbohydrates). However, in T1D girls, less physical activity and more time spent watching television were associated with poorer metabolic profiles (higher waist to-hip ratios, fat mass and leptin levels, and lower adiponectin, HDL-C and apolipoprotein A-1 levels). CONCLUSION: Collectively, these data suggest that physical inactivity is linked to metabolic dysfunction to a greater extent than unhealthy dietary habits in postmenarchal T1D adolescent girls. PMID- 22521040 TI - Management of pregnancy in women with type 1 diabetes mellitus: guidelines of the French-Speaking Diabetes Society (Societe francophone du diabete [SFD]). AB - AIM: The clinical guidelines reported by the French-Speaking Diabetes Society (Societe francophone du diabete) include updated recommendations for preconceptual planning and care in the management of pregnancy in women with type 1 diabetes mellitus (T1DM). METHODS: The working group included diabetologists, as well as an obstetrician, a nurse and a dietician. A review of the literature was performed using PubMed and Cochrane databases. Guidelines published by foreign diabetes societies were also consulted. RESULTS: In women with T1DM, pregnancy increased the risks of hypoglycaemia, diabetic ketoacidosis, pregnancy induced hypertension, infections and worsening of diabetic microvascular disease. Moreover, T1DM during pregnancy had an impact on the embryo and the fetus, and may have increased the risk of spontaneous miscarriages, malformations, premature births, and fetal and neonatal complications. However, intensive glycaemic control and preconceptual care have been shown to decrease the rate of fetal demise and malformations. Also, the use of insulin analogues during pregnancy is now regarded as safe. Tight glucose control and frequent follow-up are recommended throughout pregnancy in women with T1DM. Their obstetric management should take place in a maternity hospital with an appropriate perinatal environment and in close collaboration with diabetologists. CONCLUSION: Pregnancy planning and adequate management during pregnancy are mandatory for improving the outcomes of women with T1DM. PMID- 22521041 TI - Prevalence of diabetes and associated risk factors in a Senegalese urban (Dakar) population. AB - AIM: The aim of this study was to estimate the prevalence of diabetes in the urban population living in Dakar, Senegal, and to investigate the factors associated with diabetes. METHODS: Data from a 2009 survey of 600 individuals, aged 20 years or above and considered representative of the population of the city of Dakar, were evaluated. Socioeconomic characteristics, hypertension, capillary whole blood glucose, and weight and height measurements of these subjects were collected during face-to-face interviews. The statistical analyses used chi-square (chi2) tests and binary logistic regressions. RESULTS: The percentage of participants with fasting blood glucose levels greater than or equal to 1.10 g/L and/or currently being treated for diabetes was 17.9% (n=107, 95% CI: 14.7-20.8). Observed rates of diabetes were significantly higher among women (chi2 = 6.3; P < 0.05), in subjects aged > 40 years (chi2=33.6; P < 0.001), in those with low educational levels (chi2=11.9; P < 0.05) and in those with hypertension (chi2 = 13.9; P < 0.001), and in those who were overweight (BMI >= 25 kg/m2 and < 30 kg/m2) or obese (BMI >= 30 kg/m2; chi2=40.3; P < 0.001). After adjusting for gender, age, educational level, BMI and blood pressure, the results showed that gender, age and BMI were associated with diabetes: women, older people and those with a higher BMI had significantly greater chances of being diabetic than the rest of the population, whatever their blood pressure and educational level. CONCLUSION: Diabetes is becoming a pressing public-health problem in Senegal, and the major risk factors for the increasing diabetes prevalence in the city of Dakar are gender, age and body mass index. PMID- 22521043 TI - Different protocols of physical exercise produce different effects on synaptic and structural proteins in motor areas of the rat brain. AB - The plastic brain responses generated by the training with acrobatic exercise (AE) and with treadmill exercise (TE) may be different. We evaluated the protein expression of synapsin I (SYS), synaptophysin (SYP), microtubule-associated protein 2 (MAP2) and neurofilaments (NF) by immunohistochemistry and Western blotting in the motor cortex, striatum and cerebellum of rats subjected to TE and AE. Young adult male Wistar rats were divided into 3 groups: sedentary (Sed) (n=15), TE (n=20) and AE (n=20). The rats were trained 3 days/week for 4 weeks on a treadmill at 0.6 km/h, 40 min/day (TE), or moved through a circuit of obstacles 5 times/day (AE). The rats from the TE group exhibited a significant increase of SYS and SYP in the motor cortex, of NF68, SYS and SYP in the striatum, and of MAP2, NF and SYS in the cerebellum, whereas NF was decreased in the motor cortex and the molecular layer of the cerebellar cortex. On the other hand, the rats from the AE group showed a significant increase of MAP2 and SYP in the motor cortex, of all four proteins in the striatum, and of SYS in the cerebellum. In conclusion, AE induced changes in the expression of synaptic and structural proteins mainly in the motor cortex and striatum, which may underlie part of the learning of complex motor tasks. TE, on the other hand, promoted more robust changes of structural proteins in all three regions, especially in the cerebellum, which is involved in learned and automatic tasks. PMID- 22521042 TI - Ceftriaxone upregulates the glutamate transporter in medial prefrontal cortex and blocks reinstatement of methamphetamine seeking in a condition place preference paradigm. AB - Glutamate signaling plays an essential role in drug-seeking behavior. Using reinstatement of conditioned place preference (CPP), we determined whether ceftriaxone, a beta-lactam antibiotic known to increase the expression and activity of the glutamate transporter (EAAT2) on glial cells, blocks methamphetamine-triggered reinstatement of CPP. Rats acquired methamphetamine CPP following 7 consecutive days of conditioning, during which each animal received pairings of alternating morning methamphetamine (2.5 mg/kg, IP) and afternoon saline (IP). Animals showing CPP were successfully extinguished with repeated twice daily saline administration over a 7-day period. Ceftriaxone (200 mg/kg, IP) was administered (vs. saline) once a day for 7 days during the extinction period. Upon successful extinction, animals received a single dose of methamphetamine (2.5 mg/kg, IP) for reinstatement and were tested for CPP one day later. Using real time PCR, EAAT2 mRNA levels in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) were quantified in response to ceftriaxone. Ceftriaxone blocked methamphetamine-triggered reinstatement of CPP and significantly increased EAAT2 mRNA levels in the mPFC, with a trend towards significance in the NAc. In conclusion, Ceftriaxone modulated the expression of the glutamate transporter in a critical region of the cortico-striatal addiction circuitry and attenuated drug-seeking behavior in rats. Further research is needed to test the efficacy of compounds targeting the EAAT2 in human methamphetamine-dependent users. PMID- 22521045 TI - Liver transplantation and resective surgery lessons learned: the case for a systems approach. PMID- 22521044 TI - Serum peptidome patterns of breast cancer based on magnetic bead separation and mass spectrometry analysis. AB - BACKGROUND: Breast cancer is one of the most common cancers in the world, and the identification of biomarkers for the early detection of breast cancer is a relevant target. The present study aims to determine serum peptidome patterns for screening of breast cancer. METHODS: The present work focused on the serum proteomic analysis of 36 healthy volunteers and 37 breast cancer patients using a ClinProt Kit combined with mass spectrometry (MS). This approach allows the determination of peptidome patterns that are able to differentiate the studied populations. An independent group of sera (36 healthy volunteers and 37 breast cancer patients) was used to verify the diagnostic capabilities of the peptidome patterns blindly. An immunoassay method was used to determine the serum mucin 1 (CA15-3) of validation group samples. RESULTS: Support Vector Machine (SVM) Algorithm was used to construct the peptidome patterns for the identification of breast cancer from the healthy volunteers. Three of the identified peaks at m/z 698, 720 and 1866 were used to construct the peptidome patterns with 91.78% accuracy. Furthermore, the peptidome patterns could differentiate the validation group achieving a sensitivity of 91.89% (34/37) and a specitivity of 91.67% (33/36) (> CA 15-3, P < 0.05). CONCLUSIONS: These results suggest that the ClinProt Kit combined with MS shows great potentiality for the diagnosis of breast cancer. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1501556838687844. PMID- 22521046 TI - Dr Robert McKechnie: Vancouver's pioneer surgeon and a patron of British Columbia sports & education. AB - Robert E. McKechnie, M.D.C.M. (1861-1944), was a distinguished graduate of McGill Medical School and a pioneer in the early days of surgery in Vancouver, Canada. He was a long-standing Canadian leader in both clinical and academic surgery. In addition, he played an important role in the founding of the University of British Columbia. He also commissioned an important challenge cup for the British Columbia rugby championship team in the same time and place as the establishment of hockey's Stanley Cup. PMID- 22521047 TI - Factors influencing humanitarian care and the treatment of local patients within the deployed military medical system: casualty referral limitations. AB - BACKGROUND: Humanitarian medical care is an essential task of the deployed military health care system. The purpose of this study was to analyze referral acceptance in treating injured local national patients during Operation Enduring Freedom. METHODS: A prospective observation study of local nationals who were referred for humanitarian trauma care in Afghanistan from March through August 2009. RESULTS: Sixty-six patients were referred for evacuation for suspected non coalition-caused injuries. The bed status at the receiving hospital was defined as green (able to accept patients), amber (nearing capacity), and red (at capacity). The only factor associated with acceptance was the accepting hospital bed status (odds ratio = 1.57%, 95% confidence interval, 1.11-2.22; P = .009). Factors not significant were age, the province of origin, the type of referring facility, a prior operation before the request, patient status/affiliation, or the mechanism of injury. CONCLUSIONS: Humanitarian medical care is directly related to the capacity for high-acuity care because bed availability is the predominate reason for acceptance or rejection. PMID- 22521048 TI - An assessment of different scoring systems in cirrhotic patients undergoing nontransplant surgery. AB - BACKGROUND: Determining surgical risk in cirrhotic patients is difficult and multiple scoring systems have sought to quantify this risk. The purpose of our study was to assess the impact of Childs-Turcotte-Pugh (CTP), Model of End-Stage Liver Disease (MELD), and MELD-Sodium (MELD-Na) scores on postoperative morbidity and mortality for cirrhotic patients undergoing nontransplant surgery. METHODS: We performed a single-center retrospective review of all cirrhotic patients who underwent nontransplant surgery under general anesthesia over a 6-year period of time to analyze outcomes using the 3 scoring systems. RESULTS: Sixty-four cirrhotic patients (mean age, 57 y; 62 men) underwent nontransplant surgery under general anesthesia. A CTP score of >= 7.5 was associated with an 8.3-fold increased risk of 30-day morbidity, a MELD score of >= 14.5 was associated with a 5.4-fold increased risk of 3-month mortality, and a MELD-Na score >= 14.5 was associated with a 4.5-fold increased risk of 1-year mortality. Emergent surgery, the presence of ascites, and low serum sodium level were associated significantly with morbidity and 1-year mortality. CONCLUSIONS: The major strengths of the 3 scoring systems are for CTP in estimating 30-day morbidity, MELD for estimating 3 month mortality, and MELD-Na for estimating 1-year mortality. PMID- 22521049 TI - Incidence of deep vein thrombosis is increased with 30 mg twice daily dosing of enoxaparin compared with 40 mg daily. AB - BACKGROUND: The purpose of this study was to analyze whether 2 standard dosing regimens of enoxaparin (30 mg twice daily vs 40 mg once daily) would result in different deep vein thrombosis (DVT) rates and anti-factor Xa activity (anti-Xa) in surgical patients. METHODS: Patients who required enoxaparin for prophylaxis were followed prospectively. Demographics were recorded. Patients underwent standardized duplex screening. Peak anti-Xa levels were drawn on 4 consecutive days. RESULTS: Sixty-three patients were followed up (28 patients on 30 mg twice daily, 35 patients on 40 mg once daily). There was no significant difference in demographics between groups. Twenty-five percent of patients on 30 mg twice daily developed a DVT, whereas 2.9% of patients on 40 mg once daily developed a DVT. Patients on 30 mg twice daily had significantly lower anti-Xa levels. CONCLUSIONS: The incidence of DVT is increased in surgical patients who receive 30 mg twice daily dosing of enoxaparin compared with 40 mg daily. Dosing of 40 mg once daily results in significantly higher peak anti-Xa levels compared with 30 mg twice daily. PMID- 22521050 TI - Revisiting the "10% rule" in breast cancer sentinel lymph node biopsy: an approach to minimize the number of sentinel lymph nodes removed. AB - BACKGROUND: Sentinel lymph node (SLN) biopsy (SLNB) is an accurate and proven axillary staging procedure for early breast cancer. The aim of this study was to determine if the "10% rule" is applicable to the performance of SLNB at the investigators' institution and if the criteria used for SLNB at their institution could be refined to minimize the number of SLNs removed. METHODS: Retrospective analysis was conducted of a prospectively collected breast cancer SLNB database. Standard statistical methods were used for data analysis. RESULTS: Five hundred nine patients underwent a SLNB for breast cancer over a 5 year period. A mean of 2.5 SLNs were removed per patient. All patients with SLN metastasis were identified within the 1st 4 SLNs removed. CONCLUSIONS: The "10% rule" is best used as a guide at the investigators' institution. Strict adherence to this rule appears to result in the removal of an excessive number of lymph nodes, which may contribute to excessive health care costs and patient morbidity. PMID- 22521051 TI - Optimization of a rapid diagnostic test for detection of group B streptococcus from antepartum patients. AB - We analyzed the performance of a new rapid diagnostic test for use in determining group B streptococcus colonization in pregnancy. Vaginal-rectal specimens were compared by the rapid test, a commercial laboratory culture result, and an in house culture. Of 150 patient samples, 72 were positive by the rapid test, giving a prevalence of 48.0% versus 24.7% by traditional culture. Characterization of these results showed cross-reactivity with Enterococcus. The addition of bacitracin reduced this interference, and when reanalyzed, a colonization rate of 31.3% was found (P = 0.3961, chi-square), as well as a sensitivity of 100% (95% confidence interval [CI] 89.1-100) and a specificity of 93.6% (95% CI 86.9-97.2). The addition of bacitracin greatly improves the reliability of this diagnostic test and demonstrates a novel approach to reduce interference. An accurate determination of the test's sensitivity and specificity, however, awaits enrollment of the remaining subjects. PMID- 22521052 TI - Sensitivity of QuantiFERON-TB GOLD In-Tube for diagnosis of recent versus remote M. tuberculosis infection. AB - The sensitivity of QuantiFERON-TB GOLD In-Tube was measured in 104 subjects with recent (<=2 years) and remote Mycobacterium tuberculosis infection using tuberculin skin test conversion as the reference standard. The sensitivity was not significantly different between the 2 groups (33% versus 20%, P = 0.3). This finding suggests interferon-gamma release assays may not be more sensitive for diagnosis of recent than remote infection. Longitudinal studies are needed to validate this finding. PMID- 22521053 TI - Predominance of pHK01-like incompatibility group FII plasmids encoding CTX-M-14 among extended-spectrum beta-lactamase-producing Escherichia coli in Hong Kong, 1996-2008. AB - This study assessed the temporal changes in the molecular epidemiology of bacteremic Escherichia coli isolates producing CTX-M-14 in Hong Kong. Blood isolates from 1996 to 1998 (period 1, n = 50) and 2007 to 2008 (period 2, n = 117) were investigated by molecular methods. CTX-M-type ESBL was carried by 98.2% (164/167) of the isolates. In both periods, the CTX-M-9 group and CTX-M-14 allele were the predominant ESBL type. The major clones were found to change from ST68 and ST405 in period 1 to ST131, ST69, and ST12 in period 2. Among 65 CTX-M-14 producing plasmids investigated further, 54 had the FII replicon. Replicon sequence typing and plasmid polymerase chain reaction-restriction fragment length polymorphism showed that 79.6% (43/54) of the FII plasmid subset was similar to the completely sequenced plasmid, pHK01 (human urine, Hong Kong, 2004). These pHK01-like plasmids were found to have spread to the major clones (ST68, ST405, and ST131) and multiple singleton isolates of all 4 phylogenetic groups. PMID- 22521054 TI - Emergence of carbapenem-resistant Enterobacteriaceae isolates in the Moroccan community. PMID- 22521055 TI - End-stage kidney disease in the USA: possible solutions. PMID- 22521056 TI - New hope for sepsis. PMID- 22521057 TI - Rethinking dementia care in Australia. PMID- 22521058 TI - Insulin degludec: a new ultra-longacting insulin. PMID- 22521061 TI - Molly Stevens: material girl. PMID- 22521062 TI - Paediatric hospital-acquired bacteraemia in developing countries. PMID- 22521064 TI - Paediatric hospital-acquired bacteraemia in developing countries. PMID- 22521065 TI - CNS prophylaxis in diffuse large B-cell lymphoma. PMID- 22521067 TI - CNS prophylaxis in diffuse large B-cell lymphoma. PMID- 22521068 TI - Complementary approaches to estimation of the global burden of diabetes. PMID- 22521069 TI - Stem cells in a tissue-engineered human airway. PMID- 22521070 TI - Medicine and surgery: the yin and yang of health systems. PMID- 22521073 TI - Repeatedly red faced. PMID- 22521071 TI - Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-label, treat-to-target non inferiority trial. AB - BACKGROUND: Intensive basal-bolus insulin therapy has been shown to improve glycaemic control and reduce the risk of long-term complications that are associated with type 1 diabetes mellitus. Insulin degludec is a new, ultra longacting basal insulin. We therefore compared the efficacy and safety of insulin degludec and insulin glargine, both administered once daily with mealtime insulin aspart, in basal-bolus therapy for type 1 diabetes. METHODS: In an open label, treat-to-target, non-inferiority trial, undertaken at 79 sites (hospitals and centres) in six countries, adults (aged >=18 years) with type 1 diabetes (glycated haemoglobin [HbA(1c)] <=10% [86 mmol/mol]), who had been treated with basal-bolus insulin for at least 1 year, were randomly assigned in a 3:1 ratio, with a computer-generated blocked allocation sequence, to insulin degludec or insulin glargine without stratification by use of a central interactive response system. The primary outcome was non-inferiority of degludec to glargine, assessed as a reduction in HbA(1c) after 52 weeks, with the intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00982228. FINDINGS: Of 629 participants, 472 were randomly assigned to insulin degludec and 157 to insulin glargine; all were analysed in their respective treatment groups. At 1 year, HbA(1c) had fallen by 0.40% points (SE 0.03) and 0.39% points (0.07), respectively, with insulin degludec and insulin glargine (estimated treatment difference -0.01% points [95% CI -0.14 to 0.11]; p<0.0001 for non-inferiority testing) and 188 (40%) and 67 (43%) participants achieved a target HbA(1c) of less than 7% (<53 mmol/mol). Rates of overall confirmed hypoglycaemia (plasma glucose <3.1 mmol/L or severe) were similar in the insulin degludec and insulin glargine groups (42.54 vs 40.18 episodes per patient-year of exposure; estimated rate ratio [degludec to glargine] 1.07 [0.89 to 1.28]; p=0.48). The rate of nocturnal confirmed hypoglycaemia was 25% lower with degludec than with glargine (4.41 vs 5.86 episodes per patient-year of exposure; 0.75 [0.59 to 0.96]; p=0.021). Overall serious adverse event rates (14 vs 16 events per 100 patient years of exposure) were similar for the insulin degludec and insulin glargine groups. INTERPRETATION: Insulin degludec might be a useful basal insulin for patients with type 1 diabetes because it provides effective glycaemic control while lowering the risk of nocturnal hypoglycaemia, which is a major limitation of insulin therapy. FUNDING: Novo Nordisk. PMID- 22521074 TI - Site-directed mutagenesis and spectral studies suggest a putative role of FurA from Anabaena sp. PCC 7120 as a heme sensor protein. AB - The transcriptional repressor Fur (ferric uptake regulator) is one of the most important switches regulating prokaryotic iron metabolism. Cyanobacterial FurA binds heme in the micromolar concentration range and this interaction negatively affects its in vitro DNA binding ability in a concentration-dependent manner. Using site-directed mutagenesis along with difference absorption UV-visible, circular dichroism and electronic paramagnetic resonance spectroscopies, we further analyse the nature of heme binding in FurA. Our data point to Cys141, within a Cys-Pro motif, as an axial ligand of the Fe(III) high-spin heme. In the Fe(II) oxidation state, the heme shows low-spin form with an electronic absorption spectrum typical of six-coordinated low-spin heme proteins with a Soret absorption maximum blue-shifted by 25 nm in relation to typical low-spin thiolate-ligated Fe(II) heme proteins. Moreover, the ferrous C141S mutant shows Soret, alpha and beta bands almost identical to those observed for ferrous wild type heme-FurA, indicating that the heme in ferrous C141S is in the same six coordinated heme ligation as the ferrous native form. Therefore, Cys141 is not a ligand of the Fe(II) heme centre, suggesting a redox-dependent ligand switch undergone by this regulator. Our results indicate that the binding of heme to FurA exhibits the same physicochemical features as previously described for heme sensor proteins. PMID- 22521072 TI - Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, randomised, open-label, treat-to-target non inferiority trial. AB - BACKGROUND: Basal insulin therapy does not stop loss of beta-cell function, which is the hallmark of type 2 diabetes mellitus, and thus diabetes control inevitably deteriorates. Insulin degludec is a new, ultra-longacting basal insulin. We aimed to assess efficacy and safety of insulin degludec compared with insulin glargine in patients with type 2 diabetes mellitus. METHODS: In this 52 week, phase 3, open-label, treat-to-target, non-inferiority trial, undertaken at 123 sites in 12 countries, we enrolled adults (aged >=18 years) with type 2 diabetes mellitus and a glycated haemoglobin (HbA(1c)) of 7.0-10.0% after 3 months or more of any insulin regimen (with or without oral antidiabetic drugs). We randomly allocated eligible participants in a 3:1 ratio to receive once-daily subcutaneous insulin degludec or glargine, stratified by previous insulin regimen, via a central interactive response system. Basal insulin was titrated to a target plasma glucose concentration of 3.9-<5.0 mmol/L self-measured before breakfast. The primary outcome was non-inferiority of degludec to glargine measured by change in HbA(1c) from baseline to week 52 (non-inferiority limit of 0.4%) by ANOVA in the full analysis set. We assessed rates of hypoglycaemia in all treated patients. This study is registered with ClinicalTrials.gov, number NCT00972283. FINDINGS: 744 (99%) of 755 participants randomly allocated degludec and 248 (99%) of 251 allocated glargine were included in the full analysis set (mean age 58.9 years [SD 9.3], diabetes duration 13.5 years [7.3], HbA(1c) 8.3% [0.8], and fasting plasma glucose 9.2 mmol/L [3.1]); 618 (82%) and 211 (84%) participants completed the trial. After 1 year, HbA(1c) decreased by 1.1% in the degludec group and 1.2% in the glargine group (estimated treatment difference [degludec-glargine] 0.08%, 95% CI -0.05 to 0.21), confirming non-inferiority. Rates of overall confirmed hypoglycaemia (plasma glucose <3.1 mmol/L or severe episodes requiring assistance) were lower with degludec than glargine (11.1 vs 13.6 episodes per patient-year of exposure; estimated rate ratio 0.82, 95% CI 0.69 to 0.99; p=0.0359), as were rates of nocturnal confirmed hypoglycaemia (1.4 vs 1.8 episodes per patient-year of exposure; 0.75, 0.58 to 0.99; p=0.0399). Rates of severe hypoglycaemia seemed similar (0.06 vs 0.05 episodes per patient-year of exposure for degludec and glargine) but were too low for assessment of differences. Rates of other adverse events did not differ between groups. INTERPRETATION: A policy of suboptimum diabetes control to reduce the risk of hypoglycaemia and its consequences in advanced type 2 diabetes mellitus might be unwarranted with newer basal insulins such as degludec, which are associated with lower risks of hypoglycaemia than insulin glargine. FUNDING: Novo Nordisk. PMID- 22521075 TI - Multiple coronary artery-left ventricular fistulas causing sudden death in a young woman. AB - Multiple coronary artery fistulae arising from right and left coronary arteries were found at autopsy in a 22-year-old woman, dying suddenly while playing football. This is the fifth pathologic description of this finding with biventricular involvement. We found microscopic evidence of postischemic scars and foci of myocardial calcifications in the left ventricular wall. PMID- 22521076 TI - Anterior gradient 2 profiling in Barrett columnar epithelia and adenocarcinoma. AB - Barrett esophagus is the precancerous lesion leading to Barrett adenocarcinoma. The natural history of Barrett metaplasia and its neoplastic progression are still controversial. Anterior gradient 2 is up-regulated in both Barrett intestinal metaplasia and Barrett adenocarcinoma, but no information is available on anterior gradient 2 expression in the spectrum of the phenotypic changes occurring in the natural history of Barrett adenocarcinoma (Barrett esophagus cardiac-type metaplasia, Barrett esophagus intestinal metaplasia, low-grade intraepithelial neoplasia [formerly called low-grade dysplasia], and high-grade intraepithelial neoplasia [formerly called high-grade dysplasia]). Applying immunohistochemistry and reverse transcription and quantitative real-time polymerase chain reaction, this study addressed the role of anterior gradient 2 in Barrett carcinogenesis. Anterior gradient 2 expression was assessed semiquantitatively in 125 consecutive biopsy samples in the adenocarcinoma spectrum arising in Barrett esophagus (Barrett esophagus cardiac-type metaplasia, 25; Barrett esophagus intestinal metaplasia, 25; low-grade intraepithelial neoplasia, 25; high-grade intraepithelial neoplasia, 25; Barrett adenocarcinoma, 25). Additional biopsy samples of esophageal squamous mucosa (n=25) served as controls. Anterior gradient 2 messenger RNA expression was also tested (reverse transcription and quantitative real-time polymerase chain reaction) in a different series of 40 samples (esophageal squamous mucosa, 10; Barrett esophagus cardiac-type metaplasia, 10; Barrett esophagus intestinal metaplasia, 10; Barrett adenocarcinoma, 10). Anterior gradient 2 was never expressed in squamous esophageal epithelium but consistently overexpressed (to much the same degree) in the whole spectrum of Barrett disease (Barrett esophagus cardiac-type metaplasia, Barrett esophagus intestinal metaplasia, low-grade intraepithelial neoplasia, high-grade intraepithelial neoplasia, and Barrett adenocarcinoma). Anterior gradient 2 messenger RNA was expressed significantly more in Barrett esophagus cardiac-type metaplasia, Barrett esophagus intestinal metaplasia, and Barrett adenocarcinoma than in native squamous epithelium (P<.001), with no significant differences between the 3 groups. Anterior gradient 2 overexpression affects the whole spectrum of the metaplastic/neoplastic lesions involved in Barrett carcinogenesis. This study supports the biological similarity of the nonintestinal and intestinal types of Barrett metaplasia as precursors of Barrett adenocarcinoma. PMID- 22521077 TI - Assessment of desmosomal components (desmoglein 1-3, plakoglobin) in cardia mucosa in relation to gastroesophageal reflux disease and Helicobacter pylori infection. AB - Gastroesophageal reflux disease is associated with impaired epithelial barrier function and abnormal expression of proteins forming cell-cell contacts by tight junctions and desmosomes in distal esophageal squamous mucosa. Although gastroesophageal reflux disease and Helicobacter pylori are both associated with chronic inflammation of the adjacent cardia mucosa, it is not known whether these lead to derangements of the desmosomal complexes. Here, we assessed the expression of 4 proteins (plakoglobin and desmoglein 1, 2, and 3) forming epithelial desmosomal complexes by quantitative reverse transcription polymerase chain reaction and immunohistochemistry in biopsies from 67 patients with gastroesophageal reflux disease and 23 gastroesophageal reflux disease-negative controls. Plakoglobin and desmoglein 2 were ubiquitously expressed in all samples, whereas desmoglein 1 and 3 were not expressed in cardia mucosa. Gastroesophageal reflux disease was specifically associated with elevated transcript levels of desmoglein 2 and plakoglobin. These were significantly increased from 2.0- to 2.7-fold in patients with gastroesophageal reflux disease compared with controls (P < .01), and significantly increased immunohistochemical scores for both proteins were observed (P < .05) as well. The combined presence of gastroesophageal reflux disease and Helicobacter pylori infection had no additional effect on desmosomal gene expression. Taken together, the up regulation of plakoglobin and desmoglein 2 in cardia mucosa of patients with gastroesophageal reflux disease supports the concept that the "transition zone" between distal esophagus and proximal stomach is affected by gastroesophageal reflux disease as well, and architectural and molecular changes in the desmosomal compartment contribute to the pathogenesis of gastroesophageal reflux disease in the cardia mucosa. PMID- 22521078 TI - Adjuvant interferon therapy for patients at high risk for recurrent melanoma: an updated systematic review. PMID- 22521080 TI - rTMS in the management of allodynia from brachial plexus injuries. PMID- 22521079 TI - Transfemoral Edwards-Novaflex valve implantation in a patient with aorto-iliac endoprosthesis and severely tortuous bilateral external iliac arteries-"Railing track". AB - Transcatheter aortic valve implantation (TAVI) has nowadays been introduced as an alternative for surgical aortic valve replacement as a treatment for high risk aortic stenosis patients. This procedure is not free of complications: the SOURCE registry, indeed, showed that vascular complications are more frequent with the transfemoral approach. We present the case of an 82-year-old man with known history of severe aortic stenosis at high-risk for surgery. Pre-TAVI screening shows bilateral severely tortuous iliac arteries and aorto-bi-iliac endoprosthesis. Transapical TAVI as a first choice was rejected due to severe lung disease. The patient was then treated by Transfemoral TAVI using a dedicated interventional technique that is described in this case-report. PMID- 22521081 TI - EBUS-TBNA in patients presented with superior vena cava syndrome. AB - INTRODUCTION: Expedient pathological diagnosis is crucial in selection of appropriate treatment in patients presented with superior vena cava syndrome (SVCS). The performance and safety of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in this setting is unknown. METHODS: Over a 4-year period, patients presented with SVCS in the presence of mediastinal mass and referred for EBUS-TBNA were enrolled for the study. The procedure was performed under local anaesthesia with conscious sedation. TBNA was performed under real-time with the curvilinear probe of EBUS. Rapid on site cytological examination (ROSE) was not available. RESULTS: Eighteen procedures of EBUS-TBNA were performed in 17 patients. Malignancy was confirmed in 16 patients (diagnostic yield 94.1%). There was no major complication including significant bleeding or pneumothorax related to the procedures. CONCLUSIONS: EBUS-TBNA has high diagnostic yield and is safe in patients presented with SVCS and mediastinal mass. PMID- 22521082 TI - Assessment of macular choroidal thickness by optical coherence tomography and angiographic changes in central serous chorioretinopathy. AB - OBJECTIVE: To investigate the relationship between macular choroidal thickness measured by high-penetrating swept-source optical coherence tomography (SS-OCT) and angiographic findings in central serous chorioretinopathy (CSC). DESIGN: Prospective cross-sectional case series. PARTICIPANTS AND CONTROLS: Thirty-four patients with CSC (44 eyes) and 17 volunteer subjects (17 normal eyes). METHODS: All subjects underwent a comprehensive ophthalmologic and SS-OCT prototype examination. All patients with CSC also underwent simultaneous fluorescein angiography (FA) and indocyanine green angiography (IA). Mean regional choroidal thickness measurements on the Early Treatment Diabetic Retinopathy Study (ETDRS) layout and squared sector grids were obtained by 3-dimensional raster scanning using SS-OCT. MAIN OUTCOME MEASURES: Macular choroidal thickness and angiographic abnormalities. RESULTS: Mean whole macular choroidal thickness in eyes with CSC (total, 329.3+/-83.0 MUm; classic CSC, 326.9+/-83.1 MUm; chronic CSC, 325.4+/ 93.3 MUm; and multifocal posterior pigment epitheliopathy, 359.0+/-15.5 MUm) was greater than that in normal eyes (233.0+/-67.0 MUm) (P < 0.001). In unilateral cases, mean whole macular choroidal thickness was greater in eyes with unilateral CSC than in unaffected fellow eyes (P=0.021). There was no significant difference in choroidal thickness between active eyes and resolved eyes in any of the ETDRS sectors. Mean choroidal thickness was greater in areas with leakage on FA than in areas without leakage (P=0.001). Mean choroidal thickness was greater in areas with choroidal vascular hyperpermeability and in areas with punctate hyperfluorescent spots on IA than in unaffected areas (P<0.001 for both). CONCLUSIONS: Increased choroidal thickness was observed in the whole macular area of eyes with any of the CSC subtypes. Choroidal thickness was related to leakage from the retinal pigment epithelium, choroidal vascular hyperpermeability, and punctate hyperfluorescent lesions. These findings provide evidence that CSC may be caused by focally increased hydrostatic pressure in the choroid. PMID- 22521083 TI - Risk factors for moderate and severe microbial keratitis in daily wear contact lens users. AB - OBJECTIVE: To establish risk factors for moderate and severe microbial keratitis among daily contact lens (CL) wearers in Australia. DESIGN: A prospective, 12 month, population-based, case-control study. PARTICIPANTS: New cases of moderate and severe microbial keratitis in daily wear CL users presenting in Australia over a 12-month period were identified through surveillance of all ophthalmic practitioners. Case detection was augmented by record audits at major ophthalmic centers. Controls were users of daily wear CLs in the community identified using a national telephone survey. TESTING: Cases and controls were interviewed by telephone to determine subject demographics and CL wear history. Multiple binary logistic regression was used to determine independent risk factors and univariate population attributable risk percentage (PAR%) was estimated for each risk factor. MAIN OUTCOME MEASURES: Independent risk factors, relative risk (with 95% confidence intervals [CIs]), and PAR%. RESULTS: There were 90 eligible moderate and severe cases related to daily wear of CLs reported during the study period. We identified 1090 community controls using daily wear CLs. Independent risk factors for moderate and severe keratitis while adjusting for age, gender, and lens material type included poor storage case hygiene 6.4* (95% CI, 1.9-21.8; PAR, 49%), infrequent storage case replacement 5.4* (95% CI, 1.5-18.9; PAR, 27%), solution type 7.2* (95% CI, 2.3-22.5; PAR, 35%), occasional overnight lens use (<1 night per week) 6.5* (95% CI, 1.3-31.7; PAR, 23%), high socioeconomic status 4.1* (95% CI, 1.2-14.4; PAR, 31%), and smoking 3.7* (95% CI, 1.1-12.8; PAR, 31%). CONCLUSIONS: Moderate and severe microbial keratitis associated with daily use of CLs was independently associated with factors likely to cause contamination of CL storage cases (frequency of storage case replacement, hygiene, and solution type). Other factors included occasional overnight use of CLs, smoking, and socioeconomic class. Disease load may be considerably reduced by attention to modifiable risk factors related to CL storage case practice. PMID- 22521084 TI - Role of vascular endothelial growth factor polymorphisms in the treatment success in patients with wet age-related macular degeneration. AB - PURPOSE: Along with environmental risk factors such as smoking, hypertension, and atherosclerosis, genetic susceptibility is a primary contributor to the development and progression of exudative age-related macular degeneration (AMD). Vascular endothelial growth factor (VEGF) is a central angiogenic regulator and there has been general agreement now that it is an important trigger for the progression of exudative AMD. In the present study, we tested the hypothesis that VEGF gene polymorphisms play a role in the treatment success with VEGF inhibitors in patients with exudative AMD. DESIGN: Prospective cohort study. PARTICIPANTS: We included 185 eyes of 141 patients with exudative AMD who were scheduled for their first treatment with intravitreally administered bevacizumab in this trial. METHODS: All patients were aged >50 years and had angiographically verified exudative AMD. Blood from the finger pad was collected on blood cards for genotyping for the VEGF polymorphisms rs1413711, rs3025039, rs2010963, rs833061, rs699947, rs3024997, and rs1005230. At each follow-up visit, visual acuity was reassessed and an ophthalmic examination was carried out. Visual acuity outcome, number of retreatments, and overall time of treatment were analyzed in dependence of the VEGF polymorphisms. MAIN OUTCOME MEASURES: Mean change in visual acuity at the end of the treatment period. RESULTS: The included patients were reinjected with bevacizumab 1 to 15 times, resulting in a total treatment period of 42 to 1182 days. In univariate analysis only the G/G genotypes of rs3024997 and rs2010963 compared with all other 5 single nucleotide polymorphisms (SNPs) showed a significantly lower visual acuity at the end of treatment. In multivariate analysis including parameters such as time, baseline visual acuity, and number of reinjections, none of the SNPs showed a significant correlation. CONCLUSIONS: The current study indicates that VEGF polymorphisms are not major predictors of anti VEGF treatment success in patients with exudative AMD. PMID- 22521085 TI - Glaucoma risk alleles at CDKN2B-AS1 are associated with lower intraocular pressure, normal-tension glaucoma, and advanced glaucoma. AB - PURPOSE: Genetic variation at the 9p21 locus encompassing the CDKN2B-AS1, CDKN2A, and CDKN2B genes has been associated with primary open-angle glaucoma (POAG) in several independent studies. This study aimed to dissect the association further and to determine genotype-phenotype correlations between genetic variation at this locus and a range of glaucoma-related traits in a large cohort of POAG patients. DESIGN: Comparative case series and case-control study. PARTICIPANTS: One thousand four hundred thirty-two POAG patients and 595 unaffected controls recruited from 2 population-based and 2 cross-sectional studies. METHODS: Each patient was genotyped at 9 single nucleotide polymorphisms (SNPs) previously associated with POAG at the 9p21 locus. Each SNP was assessed for association with each outcome measure using linear regression under an additive genetic model. Associated traits were explored further including adjustment for relevant covariates. Highest recorded intraocular pressure (IOP) also was analyzed both with and without correction for central corneal thickness (CCT) and was dichotomized into high-tension glaucoma and normal-tension glaucoma (NTG). MAIN OUTCOME MEASURES: Intraocular pressure and vertical cup-to-disc ratio (VCDR). RESULTS: Glaucoma risk alleles at 9p21, particularly, rs7049105 and rs10120688, were associated with the presence of both NTG and advanced POAG. The SNP rs10120688 was associated with greater VCDR after adjustment for covariates (P = 0.003; beta = 0.016; standard error, 0.006). In addition, multiple SNPs in the region were associated with reduced IOP, before and after adjustment for CCT. The SNP most significantly associated with IOP was also rs10120688 (P = 0.001; beta = -2.135; standard error, 0.634) after adjustment for covariates under an additive model. In a comparison of high-tension versus low-tension glaucoma, this SNP was also the most significantly associated, particularly when IOP was corrected for CCT before classification of the type of glaucoma (P = 0.0009; odds ratio, 0.63; 95% confidence interval, 0.48-0.83). CONCLUSIONS: Patients with POAG carrying the glaucoma risk alleles at the 9p21 locus have larger VCDR and lower IOP than POAG patients without these alleles. Carriers of these alleles seem to be predisposed to POAG developing at lower IOP levels and exhibit stronger associations with NTG and advanced glaucoma phenotypes. This may be of relevance when setting target pressures in patients carrying these risk alleles. PMID- 22521086 TI - Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma. AB - PURPOSE: This study evaluates the prognostic performance of a 15 gene expression profiling (GEP) assay that assigns primary posterior uveal melanomas to prognostic subgroups: class 1 (low metastatic risk) and class 2 (high metastatic risk). DESIGN: Prospective, multicenter study. PARTICIPANTS: A total of 459 patients with posterior uveal melanoma were enrolled from 12 independent centers. TESTING: Tumors were classified by GEP as class 1 or class 2. The first 260 samples were also analyzed for chromosome 3 status using a single nucleotide polymorphism assay. Net reclassification improvement analysis was performed to compare the prognostic accuracy of GEP with the 7th edition clinical Tumor-Node Metastasis (TNM) classification and chromosome 3 status. MAIN OUTCOME MEASURES: Patients were managed for their primary tumor and monitored for metastasis. RESULTS: The GEP assay successfully classified 446 of 459 cases (97.2%). The GEP was class 1 in 276 cases (61.9%) and class 2 in 170 cases (38.1%). Median follow up was 17.4 months (mean, 18.0 months). Metastasis was detected in 3 class 1 cases (1.1%) and 44 class 2 cases (25.9%) (log-rank test, P<10(-14)). Although there was an association between GEP class 2 and monosomy 3 (Fisher exact test, P<0.0001), 54 of 260 tumors (20.8%) were discordant for GEP and chromosome 3 status, among which GEP demonstrated superior prognostic accuracy (log-rank test, P = 0.0001). By using multivariate Cox modeling, GEP class had a stronger independent association with metastasis than any other prognostic factor (P<0.0001). Chromosome 3 status did not contribute additional prognostic information that was independent of GEP (P = 0.2). At 3 years follow-up, the net reclassification improvement of GEP over TNM classification was 0.43 (P = 0.001) and 0.38 (P = 0.004) over chromosome 3 status. CONCLUSIONS: The GEP assay had a high technical success rate and was the most accurate prognostic marker among all of the factors analyzed. The GEP provided a highly significant improvement in prognostic accuracy over clinical TNM classification and chromosome 3 status. Chromosome 3 status did not provide prognostic information that was independent of GEP. PMID- 22521089 TI - Probiotic suppression of the H. pylori-induced responses by conjugated linoleic acids in a gastric epithelial cell line. AB - Conjugated linoleic acids (CLA) produced by Lactobacillus acidophilus was reported to decrease the activation of nuclear factor-kappa B. CLA was suggested as one of the anti-inflammatory molecular mechanisms of probiotics. In the present study, the effects of CLA on H. pylori-induced multiple responses were evaluated. IL-8, TNF-alpha and iNOS were measured in mRNA and/or protein levels in AGS cells after pretreatment with CLA or CLA-containing conditioned medium (CM) produced by Lactobacillus acidophilus or Lactobacillus plantarum. The increased expressions of IL-8 mRNA/protein and TNF-alpha mRNA were significantly suppressed by pretreatment with CM or CLA. The levels of IL-8 protein and TNF alpha mRNA were suppressed by CM pretreatment better than CLA. The expression of iNOS mRNA was also significantly inhibited by CM pretreatment. These results suggest that the suppression of multiple mediators by CLA-containing CM plays a key role in the anti-inflammatory and anti-carcinogenic effects of probiotics on H. pylori infection. PMID- 22521090 TI - Correlations between blood and tissue omega-3 LCPUFA status following dietary ALA intervention in rats. AB - The aim of this study was to assess relationships between the fatty acid contents of plasma and erythrocyte phospholipids and those in liver, heart, brain, kidney and quadriceps muscle in rats. To obtain a wide range of tissue omega-3 (n-3) long chain polyunsaturated fatty acids (LCPUFA) we subjected weanling rats to dietary treatment with the n-3 LCPUFA precursor, alpha linolenic acid (ALA, 18:3 n-3) for 3 weeks. With the exception of the brain, we found strong and consistent correlations between the total n-3 LCPUFA fatty acid content of both plasma and erythrocyte phospholipids with fatty acid levels in all tissues. The relationships between eicosapentaenoic acid (EPA, 20:5 n-3) and docosapentaenoic acid (DPA, 22:5 n-3) content in both blood fractions with levels in liver, kidney, heart and quadriceps muscle phospholipids were stronger than those for docosahexaenoic acid (DHA, 22:6 n-3). The strong correlations between the EPA+DHA (the Omega-3 Index), total n-3 LCPUFA and total n-3 PUFA contents in both plasma and erythrocyte phospholipids and tissues investigated in this study suggest that, under a wide range of n-3 LCPUFA values, plasma and erythrocyte n-3 fatty acid content reflect not only dietary PUFA intakes but also accumulation of endogenously synthesised n-3 LCPUFA, and thus can be used as a reliable surrogate for assessing n-3 status in key peripheral tissues. PMID- 22521091 TI - The trade-off between sensitivity and specificity of clinical protocols for identification of insignificant prostate cancer. PMID- 22521092 TI - To predict the future, consider the present as well as the past. PMID- 22521093 TI - Reflex ImmunoCyt testing for the diagnosis of bladder cancer in patients with atypical urine cytology. AB - BACKGROUND: ImmunoCyt/uCyt (Scimedx, Denville, NJ, USA) is a well-established urinary marker assay with high sensitivity for the diagnosis of urothelial carcinoma (UC) and can function as a second-level test to arbitrate atypical reads of urine cytology. OBJECTIVE: To determine the utility of uCyt as a reflex test for atypical cytology in patients undergoing a hematuria evaluation or surveillance with a history of UC. DESIGN, SETTING, AND PARTICIPANTS: The uCyt assay was performed as a second-level reflex test on all voided urine cytology tests read as atypical between January 2007 and June 2010 in an academic medical center. Records were retrospectively reviewed. Three hundred twenty-four patients underwent a total of 506 uCyt assays. INTERVENTION: Reflex uCyt assay on atypical urine cytology. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The uCyt test characteristics include sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV). RESULTS AND LIMITATIONS: Reflex uCyt was performed on 506 atypical voided urine samples that were followed by cystoscopy within 90 d. Reflex uCyt with a history of UC showed a sensitivity of 73%, a specificity of 49%, and an NPV of 80%. In those with a history of low grade UC, reflex uCyt had a sensitivity of 75%, a specificity of 50%, and an NPV of 82%, while in those with a history of high-grade UC, it had a sensitivity of 74%, a specificity of 44%, and an NPV of 79%. Without prior history of UC, reflex uCyt had a sensitivity of 85%, a specificity of 59%, and an NPV of 94%. This study's limitations include its retrospective design and interobserver variability inherent to cystoscopy, which was used as the reference test. CONCLUSIONS: When used as a reflex test on atypical urine cytology, negative uCyt may predict a negative cystoscopy in select patients and modulate the urgency and further work-up in those with no prior history or low-grade disease. PMID- 22521095 TI - Combined trifocal and microsurgical testicular sperm extraction is the best technique for testicular sperm retrieval in "low-chance" nonobstructive azoospermia. AB - BACKGROUND: There is no consensus for the best testicular sperm extraction (TESE) technique in patients with "low-chance" nonobstructive azoospermia (NOA). OBJECTIVE: To determine sperm retrieval rates in an intraindividual comparison using three locations of the testicle with and without the assistance of a microscope (microsurgical TESE [M-TESE]). DESIGN, SETTING, AND PARTICIPANTS: A series of 65 patients with low-chance NOA presenting with low testicular volume (<8 ml) and high serum follicle-stimulating hormone (FSH) (>12.4 IU/l) underwent trifocal-TESE plus M-TESE bilaterally (four biopsies per testis). INTERVENTION: Sperm retrieval was performed as trifocal-TESE (upper, middle, and lower testicular pole) with and without the assistance of a microscope in the middle incision. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The number of evaluated tubules, the mean spermatogenetic scores, and the sperm retrieval rates were evaluated to determine retrieval locations and the use of the microscope. The Friedman and Cochrane Q tests were applied to determine statistical differences. Receiver operating characteristic curves were used for the analysis of serum FSH and testicular volume as preoperative prognostic factors. RESULTS AND LIMITATIONS: The sperm retrieval success of 66.2% using the combined technique, meaning the percentage of patients with at least one tubule containing elongated spermatids, was the highest in the combination of trifocal- and M-TESE (p<0.01), indicating this technique as optimal for patients with low-chance NOA. M-TESE and trifocal-TESE alone were not significantly better. The mean spermatogenetic score giving the number of tubules with elongated spermatids in relation to all tubules was significantly higher in M-TESE versus conventional TESE (p<0.01), indicating the superior quality of the tissue harvested using the microscope. These results are limited by the definition of "success" using "one" spermatid/tubule. Preoperatively, high serum FSH and low testicular volumes did not exclude successful sperm retrieval. CONCLUSIONS: The combination of trifocal- and M-TESE is the best technique to reach high sperm retrieval rates in patients with low chance NOA. PMID- 22521096 TI - Neuromodulation of pelvic visceral pain: review of the literature and case series of potential novel targets for treatment. AB - Chronic pelvic pain (CPP) is complex and often resistant to treatment. While the exact pathophysiology is unknown, the pain states resultant from conditions such as interstitial cystitis and the like yield patients with a presentation that bears a striking similarity to neuropathic syndromes that are known to respond to neuromodulation. While there has been past success using the sacral region as a target for spinal cord stimulation (SCS) to treat these patients, there remains to be a consensus on the optimal location for lead placement. In this article, the authors discuss the potential etiology of CPP, examine the current literature on lead placement for SCS as a method of treatment, as well as present several cases where novel lead placement was successfully employed. PMID- 22521097 TI - Effect of coupled UV-A and UV-C LEDs on both microbiological and chemical pollution of urban wastewaters. AB - Wastewater reuse for irrigation is an interesting alternative for many Mediterranean countries suffering from water shortages. The development of new technologies for water recycling is a priority for these countries. In this study we test the efficiency of UV-LEDs (Ultraviolet-Light-Emitting Diodes) emitting UV A or UV-C radiations, used alone or coupled, on bacterial and chemical indicators. We monitored the survival of fecal bioindicators found in urban wastewaters and the oxidation of creatinine and phenol which represent either conventional organic matter or the aromatic part of pollution respectively. It appears that coupling UV-A/UV-C i) achieves microbial reduction in wastewater more efficiently than when a UV-LED is used alone, and ii) oxidizes up to 37% of creatinine and phenol, a result comparable to that commonly obtained with photoreactants such as TiO(2). PMID- 22521098 TI - Alternative ozone metrics and daily mortality in Suzhou: the China Air Pollution and Health Effects Study (CAPES). AB - Controversy remains regarding the relationship between various metrics of ozone (O(3)) and mortality. In China, the largest developing country, there have been few studies investigating the acute effect of O(3) on death. We used three exposure metrics of O(3) (1-hour maximum, maximum 8-hour average and 24-hour average) to examine its short-term association with daily mortality in Suzhou, China. We used a Generalized Additive Model (GAM) with penalized splines to analyze the mortality, O(3), and covariate data. We examined the association by season, age group, sex and educational level. We found that the current level of O(3) in Suzhou is associated with death rates from all causes and cardiovascular diseases. Among various metrics of O(3), maximum 8-hour average and 1-hour maximum concentrations seem to be more strongly associated with increased mortality rate compared to 24-hour average concentrations. Using maximum 8-hour average, an inter-quartile range increase of 2-day average O(3) (lag 01) corresponds to 2.15% (95%CI, 0.36 to 3.93), 4.47% (95%CI, 1.43 to 7.51), -1.85% (95%CI, -6.91 to 3.22) increase in all-cause, cardiovascular, and respiratory mortality, respectively. The associations between O(3) and daily mortality appeared to be more evident in the cool season than in the warm season. In conclusion, maximum 8-hour average and 1-hour maximum concentrations of O(3) are associated with daily mortality in Suzhou. Our analyses strengthen the rationale for further limiting levels of O(3) pollution in the city. PMID- 22521099 TI - The use of Bayesian networks for nanoparticle risk forecasting: model formulation and baseline evaluation. AB - We describe the use of Bayesian networks as a tool for nanomaterial risk forecasting and develop a baseline probabilistic model that incorporates nanoparticle specific characteristics and environmental parameters, along with elements of exposure potential, hazard, and risk related to nanomaterials. The baseline model, FINE (Forecasting the Impacts of Nanomaterials in the Environment), was developed using expert elicitation techniques. The Bayesian nature of FINE allows for updating as new data become available, a critical feature for forecasting risk in the context of nanomaterials. The specific case of silver nanoparticles (AgNPs) in aquatic environments is presented here (FINE(AgNP)). The results of this study show that Bayesian networks provide a robust method for formally incorporating expert judgments into a probabilistic measure of exposure and risk to nanoparticles, particularly when other knowledge bases may be lacking. The model is easily adapted and updated as additional experimental data and other information on nanoparticle behavior in the environment become available. The baseline model suggests that, within the bounds of uncertainty as currently quantified, nanosilver may pose the greatest potential risk as these particles accumulate in aquatic sediments. PMID- 22521100 TI - Distribution, behavior and fate of azole antifungals during mechanical, biological, and chemical treatments in sewage treatment plants in China. AB - Residue of azole antifungals in the environment is of concern due to the environmental risks and persistence. Distribution, behavior, and fate of frequently used azole antifungal pharmaceuticals were investigated in wastewater at two sewage treatment plants (STPs) in China. Fluconazole, clotrimazole, econazole, ketoconazole, and miconazole were constantly detected at 1-1834 ng L( 1) in the wastewater. The latter four were also ubiquitously detected in sewage sludge. Fluconazole passed through treatment in the STPs and largely remained in the final effluent. On the contrary, biotransformation and sorption to sludge occurred to the other azoles. Ketoconazole was more readily bio-transformed, whereas clotrimazole, econazole, and miconazole were more likely to be adsorbed onto and persisted in sewage sludge. Lipophilicity plays the governing role on adsorption. The highest concentrations in the raw wastewater were observed in winter for the azole pharmaceuticals except for fluconazole. The seasonal difference was smoothed out after treatment in the STPs. PMID- 22521101 TI - Methane and nitrous oxide emissions from rice seedling nurseries under flooding and moist irrigation regimes in Southeast China. AB - Measurements of methane (CH(4)) and nitrous oxide (N(2)O) fluxes have been extensively taken following rice seedlings transplanted into paddy fields, while little is known about CH(4) and N(2)O fluxes from rice seedling nurseries. Fluxes of CH(4) and N(2)O were simultaneously measured in rice seedling nurseries under the water regimes of continuous flooding and moist irrigation without waterlogging in Southeast China in 2010. Fluxes of CH(4) and N(2)O from continuously flooded nurseries averaged 10.33-14.84 mg m(-2) h(-1) and 28.64 34.35 MUg N(2)O-Nm(-2) h(-1) for the different fertilizer applied plots, respectively. Relative to continuous flooding, moist irrigation decreased total CH(4) by 14-50% but increased N(2)O by 72-186%, dependent on the fertilizer types. Compared with inorganic N fertilizer, organic manure application increased CH(4) by 44% and 148% in the continuously flooded and moist irrigation nurseries, respectively. Rice seedling growth parameters were the greatest in moist irrigation nurseries with inorganic N fertilizer application. Moist irrigation instead of continuous waterlogging and shifts from organic manure to combined organic/inorganic N fertilizer inputs have been increasingly experienced in Chinese rice seedling nurseries, which would benefit for mitigating the combined global warming potentials of CH(4) and N(2)O from rice seedling nurseries in China. PMID- 22521102 TI - Evaluation of quantitative real-time PCR workflow modifications on 16S rRNA and tetA gene quantification in environmental samples. AB - The study examined the variability in 16S ribosomal RNA (16S rRNA) and tetracycline resistance tetA gene quantification from environmental samples in relation to modifications in quantitative polymerase chain reaction (qPCR) workflow and subsequent data evaluation and analysis. We analysed three types of soil samples using two DNA extraction methods, two qPCR chemistries (SYBR green, LUXTM), and qPCR reaction kits from different manufacturers. To improve data quality, we employed a three-step amplification outlier removal approach prior to gene quantification calculations. We compared three variants of target gene enumerations and four variants of functional tetA gene normalisations against 16S rRNA genes. Results reveal that modifications in qPCR workflow steps significantly influence the gene quantification results from environmental samples. Primary factors affecting qPCR amplification efficiency included the variability of the target amplicon and the qPCR chemistry; the quality of the resulting datasets also had an impact. Although LUXTM qPCR has shown promise for environmental samples, SYBR green qPCR yielded considerably better-quality datasets and higher, more stable amplification efficiency values. Gene enumeration data of outlier-removed and unmodified sample sets showed minor differences for good-quality datasets (i.e., amplifications with SYBR green), but differed by up to 40% among lower-quality datasets. Different DNA extraction methods yielded varying amounts and purities of extracted microbial community DNA from environmental samples, with as much as an order of magnitude variation in gene copy numbers. Target gene normalisations yielded stable results on good quality data, regardless of the DNA extraction method or qPCR chemistry used. Even though qPCR is regarded as a precise method with low detection limit, technical variability in the qPCR workflow tends to overestimate or effectively mask minute changes in community. PMID- 22521103 TI - A geographical model of radio-frequency power density around mobile phone masts. AB - Public concern about possible health effects of EMF radiation from mobile phone masts has led to an increase of epidemiological studies and health risk assessments which, in turn, require adequate methods of exposure estimation. Difficulties in exposure modelling are exacerbated both by the complexity of the propagation processes, and the need to obtain estimates for large study populations in order to provide sufficient statistical power to detect or exclude the small relative risks that might exist. Use of geographical information system (GIS) techniques offers the means to make such computations efficiently. This paper describes the development and field validation of a GIS-based exposure model (Geomorf). The model uses a modified Gaussian formulation to represent spatial variations in power densities around mobile phone masts, on the basis of power output, antenna height, tilt and the surrounding propagation environment. Obstruction by topography is allowed for, through use of a visibility function. Model calibration was done using field data from 151 measurement sites (1510 antenna-specific measurements) around a group of masts in a rural location, and 50 measurement sites (658 antenna-specific measurements) in an urban area. Different parameter settings were found to be necessary in urban and rural areas to obtain optimum results. The calibrated models were then validated against independent sets of data gathered from measurement surveys in rural and urban areas, and model performance was compared with that of two commonly used path loss models (the COST-231 adaptations of the Hata and Walfisch-Ikegami models). Model performance was found to vary somewhat between the rural and urban areas, and at different measurement levels (antenna-specific power density, total power density), but overall gave good estimates (R(2)=0.641 and 0.615, RMSE=10.7 and 6.7 dB m at the antenna and site-level respectively). Performance was considerably better than that of both path loss models. PMID- 22521104 TI - Chemical fate and genotoxic risk associated with hypochlorite treatment of nicotine. AB - Nicotine, the main alkaloid of tobacco, is a non- prescription drug to which all members of a tobacco-smoking society are exposed either through direct smoke inhalation or through second-hand passive 'smoking'. Nicotine is also commercially available in some pharmaceutical products and is used worldwide as a botanical insecticide in agriculture. Nicotine dynamics in indoor and outdoor environments as well as the human excretions and the manufacturing process are responsible for its entry in the environment through municipal and industrial wastewater discharges. The presence of nicotine in surface and ground waters points out that it survives a conventional treatment process and persists in potable-water supplies. Complete removal of nicotine is instead reported when additional chlorination steps are used. In this paper a simulation of STP chlorination of nicotine and a genotoxic evaluation of its main degradation products are reported. Under laboratory conditions removal of nicotine seems not to be due to mineralization but to transformation in oxidized and chlorinated products. The by-products have been isolated after fractionation by diverse chromatographic procedures and their structures determined using mass spectrometry and (1)H and (13)C NMR spectroscopy. Preliminary genotoxic SOS Chromotests with Escherichia coli PQ37 evidence no toxicity of the products. PMID- 22521105 TI - Integrated coastal monitoring of a gas processing plant using native and caged mussels. AB - The biological effects of a coastal process water (PW) discharge on native and caged mussels (Mytilus edulis) were assessed. Chemical analyses of mussel tissues and semi permeable membrane devices, along with a suite of biomarkers of different levels of biological complexity were measured. These were lysosomal membrane stability in haemocytes and digestive cells; micronuclei formation in haemocytes; changes in cell-type composition in the digestive gland epithelium; integrity of digestive gland tissue; peroxisome proliferation; and oxidative stress. Additionally the Integrative Biological Response (IBR/n) index was calculated. This integrative biomarker approach distinguished mussels, both native and caged, exhibiting different stress conditions not identified from the contaminant exposure. Mussels exhibiting higher stress responses were found with increased proximity to the PW discharge outlet. However, the biological effects reported could not be entirely attributed to the PW discharge based on the chemicals measured, but were likely due to either other chemicals in the discharge that were not measured, the general impact of the processing plant and or other activities in the local vicinity. PMID- 22521106 TI - Mitochondrial pharmacology. AB - Mitochondria are being recognized as key factors in many unexpected areas of biomedical science. In addition to their well-known roles in oxidative phosphorylation and metabolism, it is now clear that mitochondria are also central to cell death, neoplasia, cell differentiation, the innate immune system, oxygen and hypoxia sensing, and calcium metabolism. Disruption to these processes contributes to a range of human pathologies, making mitochondria a potentially important, but currently seemingly neglected, therapeutic target. Mitochondrial dysfunction is often associated with oxidative damage, calcium dyshomeostasis, defective ATP synthesis, or induction of the permeability transition pore. Consequently, therapies designed to prevent these types of damage are beneficial and can be used to treat many diverse and apparently unrelated indications. Here we outline the biological properties that make mitochondria important determinants of health and disease, and describe the pharmacological strategies being developed to address mitochondrial dysfunction. PMID- 22521107 TI - Rapid-access, high-throughput synchrotron crystallography for drug discovery. AB - Synchrotron X-ray sources provide the highest quality crystallographic data for structure-guided drug design. In general, industrial utilization of such sources has been intermittent and occasionally limited. The Lilly Research Laboratories Collaborative Access Team (LRL-CAT) beamline provides a unique alternative to traditional synchrotron use by pharmaceutical and biotechnology companies. Crystallographic experiments at LRL-CAT and the results therefrom are integrated directly into the drug discovery process, permitting structural data, including screening of fragment libraries, to be routinely and rapidly used on a daily basis as part of pharmaceutical lead discovery and optimization. Here we describe how LRL-CAT acquires and disseminates the results from protein crystallography to maximize their impact on the development of new potential medicines. PMID- 22521108 TI - Passive toothbrushing-induced seizures: report of a severely disabled girl. AB - Toothbrushing-induced seizures are rare reflex seizures triggered by the brushing of one's own teeth. We encountered an 11-year-old girl with severe mental retardation, hypotonic cerebral palsy and epilepsy who presented with toothbrushing-induced seizures. She had had spontaneous brief tonic seizures several times a day since the age of 1 year and 2 months and started presenting with the same type of seizures induced by toothbrushing from the age of 8 years. As she could not brush her teeth by herself due to her disabilities, her mother brushed her teeth daily for her. The interictal EEG showed spike-and-wave complexes in the frontal regions bilaterally. The [Tc-99m]HMPAO-SPECT at the time of the seizure induced by toothbrushing suggested that the seizures originated from the left perisylvian cortex. This is the first report of toothbrushing induced seizures triggered by the brushing of the patient's teeth by another person ('passive toothbrushing'). PMID- 22521109 TI - 2012 update of French guidelines for the pharmacological treatment of postmenopausal osteoporosis. AB - OBJECTIVES: To update the evidence-based position statement published by the French National Authority for Health (HAS) in 2006 regarding the pharmacological treatment of postmenopausal osteoporosis, under the auspices of the French Society for Rheumatology and Groupe de Recherche et d'Information sur les Osteoporoses (GRIO), and with the participation of several learned societies (College National des Gynecologues et Obstetriciens Francais, Groupe d'Etude de la Menopause et du Vieillissement hormonal, Societe Francaise de Chirurgie Orthopedique, Societe Francaise d'Endocrinologie, and Societe Francaise de Geriatrie et de Gerontologie). METHODS: A multidisciplinary panel representing the spectrum of clinical specialties involved in managing patients with postmenopausal osteoporosis developed updated recommendations based on a systematic literature review conducted according to the method advocated by the HAS. RESULTS: The updated recommendations underline the need for osteoporosis pharmacotherapy in women with a history of severe osteoporotic fracture. In these patients, any osteoporosis medication can be used; however, zoledronic acid is the preferred first-line medication after a hip fracture. In patients with non severe fractures or no fractures, the appropriateness of osteoporosis pharmacotherapy depends on the bone mineral density and FRAX((r)) values; any osteoporosis medication can be used, but raloxifene and ibandronate should be reserved for patients at low risk for peripheral fractures. Initially, osteoporosis pharmacotherapy should be prescribed for 5 years. The results of the evaluation done at the end of the 5-year period determine whether further treatment is in order. CONCLUSIONS: These updated recommendations are intended to provide clinicians with clarifications about the pharmacological treatment of osteoporosis. PMID- 22521110 TI - Youth violence across multiple dimensions: a study of violence, absenteeism, and suspensions among middle school children. AB - OBJECTIVE: To determine how multidimensional measures of violence correlate with school absenteeism and suspensions among middle school youth. STUDY DESIGN: A cross-sectional survey was conducted in 2004 with 28 882 sixth graders from an urban school district. Data were collected on role (witness, victim, perpetrator) and mode (verbal, physical, weapons) of past-year violence exposures, and absences and suspensions over 1 academic year. Associations between violence and absenteeism and suspension were estimated using generalized linear models. RESULTS: ORs for suspension increased from witnessing to victimization to perpetration and then victimization-perpetration. Among those exposed to weapons, victims (OR(boys) = 1.45; OR(girls) = 1.38) had similar or slightly higher ORs for absenteeism than perpetrators (OR(boys) = 1.39; OR(girls) = 1.17). Boy victims and witnesses of physical violence had similar absenteeism patterns as those unexposed to physical violence. Of all exposed girls, victim-perpetrators had the highest ORs for absenteeism (OR = 1.76). CONCLUSION: Exposure to violence correlated with absenteeism and suspension. The strength of these relationships depended on mode and role in exposure. Our cross-sectional data limits our ability to establish causality. Findings have implications for prevention. PMID- 22521111 TI - Increased inspired oxygen in the first hours of life is associated with adverse outcome in newborns treated for perinatal asphyxia with therapeutic hypothermia. AB - OBJECTIVE: To assess whether increased inspired oxygen and/or hypocarbia during the first 6 hours of life are associated with adverse outcome at 18 months in term neonates treated with therapeutic hypothermia. STUDY DESIGN: Blood gas values and ventilatory settings were monitored hourly in 61 newborns for 6 hours after birth. We investigated if there was an association between increased inspired oxygen and/or hypocarbia and adverse outcome (death or disability by Bayley Scales of Newborn Development II examination at 18-20 months). RESULTS: Hypothermia was started from 3 hours 45 minutes (10 minutes-10 hours) and median lowest Pco(2) level within the first 6 hours of life was 30 mm Hg (16.5-96 mm Hg). The median highest fraction of inspiratory oxygen within the first hour of life was 0.43 (0.21-1.00). The area under the curve fraction of inspiratory oxygen and Pao(2) for hours 1-6 of life was 0.23 (0.21-1.0) and 86 mm Hg (22-197 mm Hg), respectively. We did not find any association between any measures of hypocapnia and adverse outcome (P > .05), but increased inspired oxygen correlated with adverse outcome, even when excluding newborns with initial oxygenation failure (P < .05). CONCLUSION: Increased fraction of inspired oxygen within the first 6 hours of life was significantly associated with adverse outcome in newborns treated with therapeutic hypothermia following hypoxic ischemic encephalopathy. PMID- 22521112 TI - Sleep problems, fatigue, and cognitive performance in Chinese kindergarten children. AB - OBJECTIVE: To examine sleep problems and fatigue and their associations with cognitive performance in Chinese kindergarten children. STUDY DESIGN: A cross sectional analysis of baseline data from Jintan Child Cohort Study was conducted, which includes a cohort of 1656 kindergarten children in Jintan City, Jiangsu Province, China. The sample used in the current study consisted of 1385 children (44.8% girls, mean age 5.72 [SD = 0.42] years) for whom data on sleep problems or cognitive performance were available. Child Behavior Checklist was used to measure child sleep problems and fatigue, and Wechsler Preschool and Primary Scale of Intelligence-Revised was used to assess child IQ. RESULTS: Sleep problems were prevalent, ranging from 8.9% for difficulty maintaining sleep to 70.5% for unwilling to sleep alone. Other reported sleep problems were difficulty initiating sleep (39.4%), nightmares (31.6%), sleep talking (28%), sleeping less (24.7%), and sleep resistance (23.4%). Fatigue was also prevalent, with 29.6% of children reported to be overtired and 12.6% lack of energy. Children with difficulty maintaining sleep, sleep talking, sleep resistance, or nightmares scored 2-3 points lower in full IQ than children without sleep problems. Children reported to have fatigue scored 3-6 points lower in full IQ than those children without fatigue. CONCLUSIONS: Sleep problems and fatigue are prevalent in Chinese kindergarten children. Furthermore, sleep problems and fatigue are associated with poor cognitive performance. PMID- 22521113 TI - Vulnerability, beliefs, treatments and economic burden of chronic obstructive pulmonary disease in rural areas in China: a cross-sectional study. AB - BACKGROUND: The incidence of chronic obstructive pulmonary disease (COPD) in China is very high. This study aimed to assess the vulnerability of COPD patients in rural areas outside Xuzhou City, Jiangsu province, in order to provide helpful guidance for future research and public policies. METHODS: The vulnerability of 8,217 COPD patients was evaluated using a face-to-face questionnaire to obtain information on general characteristics, awareness, beliefs, medication usage, acute exacerbation of the disease, and economic burdens. Direct economic burdens were calculated based on the questionnaire, and indirect economic burdens were estimated using local per capita income and life expectancy in 2008. The years of potential life lost were calculated using loss of life years for each age group and multiplying by the number of deaths in a given age group. RESULTS: Of the 8,217 patients, 7,921 (96.4%) had not heard of COPD, and 2,638 (32.1%) did not understand that smoking was a risk factor for COPD. No patients had used inhalers, nebulizer drugs or oxygen therapy, either regularly or sporadically. No patients had undergone pulmonary rehabilitation or surgical treatment, while 4,215 (51.3%) took theophylline to relieve dyspnea, and 3,418 (41.6%) used antibiotics to treat exacerbations. A total of 2,925 (35.6%) patients had been admitted to hospital during the past year because of respiratory symptoms. The average direct and indirect economic burdens on COPD patients were 1,090 and 20,605 yuan, respectively. CONCLUSIONS: The vulnerability of patients in rural Xuzhou to COPD was high. Their awareness of COPD was poor, their treatment during both the stable and acute exacerbation stages did not meet standards, and the economic burdens were large. Interventions are therefore needed to improve the prevention and management of COPD in this population. Further studies are required to verify these findings. PMID- 22521117 TI - Ovary structure and early oogenesis in the remipede, Godzilliognomus frondosus (Crustacea, Remipedia): phylogenetic implications. AB - Remipedia are enigmatic crustaceans of uncertain phylogenetic position with the general consensus that they are crucial for understanding the crustacean/arthropod evolution. It has been demonstrated previously that the features of the ovary organization and subcellular aspects of oogenesis are useful in resolving phylogenetic relationships in arthropods such as hexapods and onychophorans. The structure of the female gonads in Remipedia remains largely unknown; therefore, we examined the gross morphology and ultrastructural details of the ovary in a remipede, Godzilliognomus frondosus, with special emphasis on characters relevant to phylogenetic reconstructions. The ovaries of G. frondosus are located in the anterior part of the body and are composed of a single anterior proliferative zone (the germarium) and paired ovarian tubes (the vitellarium). The oocytes undergo subsequent stages of development within the lumen of the ovarian tubes, hence the remipede ovaries can be classified as endogenous. During oogenesis, each oocyte is enveloped by a set of characteristic somatic follicular cells, which results in the formation of distinct ovarian follicles. Here, we demonstrate that Remipedia share significant similarities in the ovary organization with Cephalocarida, including the anterior location of the ovary, the anterior-most position of the germarium and the endogenous type of oocyte development. Phylogenetic implications of our findings are discussed. PMID- 22521118 TI - Perspective: TGR5 (Gpbar-1) in liver physiology and disease. AB - Bile acids are signaling molecules with diverse endocrine functions. Bile acid effects are mediated through the nuclear receptor farnesoid X receptor (FXR), the G-protein coupled receptor TGR5 (Gpbar-1) and various other bile acid sensing molecules. TGR5 is almost ubiquitously expressed and has been detected in different non-parenchymal cells of human and rodent liver. Here, TGR5 has anti inflammatory, anti-apoptotic and choleretic functions. Mice with targeted deletion of TGR5 are protected from the development of cholesterol gallstones. Administration of specific TGR5 agonists lowers serum and liver triglyceride levels thereby reducing liver steatosis. Furthermore, activation of TGR5 promotes intestinal glucagon-like peptide-1 (GLP-1) release, thereby modulating glucose homeostasis and energy expenditure in brown adipose tissue and skeletal muscle. Additionally, TGR5 exerts anti-inflammatory actions resulting in decreased liver injury in animal models of sepsis. These beneficial effects make TGR5 an attractive therapeutic target for metabolic diseases, such as diabetes, obesity, atherosclerosis and steatohepatitis. PMID- 22521119 TI - Peribiliary cysts mistaken for a biliary dilatation in a cirrhosis patient. AB - Peribiliary cysts are common in patients with chronic liver disease. Ambiguous imaging features and association with cirrhosis-induced hyperbilirubinemia may lead to misdiagnose an obstructive jaundice. Magnetic resonance cholangiopancreatography (MRCP) may be a useful sequence by showing small cystic structures with a specific periportal distribution on both sides of the portal veins, which do not communicate with the biliary ducts. These abnormalities may be recognized in order to avoid unnecessary endoscopic retrograde cholangiography. PMID- 22521120 TI - Alagille syndrome: an overview. AB - Alagille syndrome is an embryofoetopathy, due to mutations in the gene JAG1. It is autosomic dominant with variable expressivity, or sporadic. Neonatal cholestasis is a main feature, due to the paucity of intrahepatic bile ducts. It can rarely develop into cirrhosis, but be responsible for a disabling pruritus and xanthomas. The other features are a peculiar facies, cardiac abnormalities, butterfly vertebrae, and ocular embryotoxon. The prognosis depends on the severity of the liver and heart diseases. Hepatocarcinoma has been reported. PMID- 22521121 TI - Single-center multidisciplinary management of patients with colorectal cancer and resectable synchronous liver metastases improves outcomes. AB - BACKGROUND: Management of patients with synchronous liver metastasis (SLM) is complex and the surgical decision process should be based on a comprehensive oncological strategy. The aim of the study was to compare outcome of single center management of patients with colorectal cancer (CRC) and resectable SLM to those of referred patients for liver resection only after removal of their primary tumor (PT). METHODS: Between 2000 and 2007, 47 patients with CRC and SLM underwent resection of both the PT and metastases under our care (unicentric) and 32 were referred after resection of their PT. RESULTS: The two groups were comparable for demographics, PT and metastatic disease data. In unicentric group, 23% received upfront chemotherapy with the PT in place, 53% had a combined CRC and SLM resection, 11% had a two-stage hepatectomy with resection of the primary during the first stage and 36% underwent delayed hepatectomy. The number of surgical interventions, the delay between diagnosis and liver resection (9 vs. 5 months, P < 0.001), the median number of cycles of chemotherapy before hepatectomy (12 vs. 6 months, P < 0.001) were significantly higher in the referred group. Postoperative morbidity was significantly higher in the referred group (75 vs. 47%, P = 0.023). The median follow-up was 43 months. OS and DFS were not significantly different between the two groups. CONCLUSION: Although the survival benefit is not proven, single-center management of patients with CRC and resectable SLM reduces the number of interventions, the number of cycles of chemotherapy and postoperative morbidity. PMID- 22521123 TI - A rare cause of bleeding esophageal varices: Alstrom syndrome. PMID- 22521122 TI - Autoimmune hepatitis: current knowledge. AB - Autoimmune hepatitis in children is of type 1, with antinuclear or anti-smooth muscle antibodies, more frequent in teenage girls, or of type 2, with anti-liver kidney microsomes 1 and/or anti-liver cytosol 1 antibodies, in younger children. Other autoimmune diseases may be present in the patient or his relatives. The diagnosis relies on autoantibodies testing and histology. The treatment with steroids and azathioprine is efficient in most cases. Cyclosporine A is also successfully used. Relapses under treatment are frequent. A long-term treatment may be necessary. Liver transplantation is rarely indicated. PMID- 22521124 TI - Metabolic liver disease. AB - Diagnosis of metabolic liver disease requires a high level of diagnostic suspicion. Diet is usually the primary treatment for metabolic liver disease. Where indicated, liver transplantation provides lifelong functional correction of liver-based metabolic defects. Liver cell therapy warrants further study for the future treatment of metabolic liver disease. All families should receive genetic advice and pre-emptive management of future affected siblings. PMID- 22521125 TI - Esophageal tuberculosis. PMID- 22521126 TI - Reduced expression of PTEN and increased PTEN phosphorylation at residue Ser380 in gastric cancer tissues: a novel mechanism of PTEN inactivation. AB - AIM: PTEN is a tumor suppressor gene in different cancers. This study was to determine the protein expression of PTEN and phosphorylation of PTEN (p-PTEN) at residue Ser380 in different histology specimens of gastric tissues. METHODS: A total of 179tissue specimens of normal gastric mucosa, chronic gastritis, intestinal metaplasia, dysplasia, and gastric cancer were recruited for immunohistochemical analysis of PTEN and p-PTEN expression. Four gastric cancer AGS, MKN-45, MKN-28, and SGC-7901 cell lines and a non-cancerous gastric GES-1 cell line were used to detect expression of PTEN and p-PTEN protein using Western blot. RESULTS: Expression level of PTEN protein was significantly decreased in gastric cancer tissues compared to normal gastric mucosa, chronic gastritis, intestinal metaplasia and dysplasia (P<0.05). In contrast, p-PTEN protein level was significantly increased in intestinal metaplasia, dysplasia and gastric cancer compared to normal gastric mucosa and chronic gastritis (P<0.05). However, there was no any association of PTEN and p-PTEN expression with clinicopathological characteristics from gastric cancer patients. Moreover, the ratio of p-PTEN and PTEN was higher in gastric cancer cell lines than that of the non-malignant cells. CONCLUSIONS: This study demonstrated that aberrant expression of PTEN and p-PTEN at residue Ser380 was early event that could contribute to gastric carcinogenesis, and that PTEN phosphorylation at residue Ser380 could be a mechanism for PTEN inactivation. PMID- 22521127 TI - Successful en bloc resection of papillary neuroendocrine tumors by duodenoscope using endoscopic submucosal dissection method. AB - Neuroendocrine tumors (NETs) of the main duodenal papilla are rare. Surgery such as pancreaticoduodenectomy is traditionally recommended as the standard treatment for papillary neuroendocrine tumors. Endoscopic resection is increasingly used for treating these lesions. However, resection of papillary NETs using endoscopic submucosal dissection (ESD) technique was scarcely reported. In this paper, we report a patient with neuroendocrine tumor of the main duodenal papilla originating from the muscularis propria on EUS underwent successful endoscopic submucosal dissection using a duodenoscope. With 6-month followed up, no stenosis of bile and pancreatic ducts or relapse of tumor occurred. PMID- 22521131 TI - Curcumin inhibits proliferation and invasion of osteosarcoma cells through inactivation of Notch-1 signaling. AB - The Notch signaling pathway plays critical roles in human cancers, including osteosarcoma, suggesting that the discovery of specific agents targeting Notch would be extremely valuable for osteosarcoma. Curcumin, a naturally occurring phenolic compound found in curcuma longa, has been shown to inhibit proliferation and induce apoptosis of osteosarcoma cells in vitro and tumor growth in xenotransplant or orthotransplant models. However, the precise molecular mechanisms by which curcumin exerts its antitumor activity remain unclear. Here we used multiple molecular approaches, such as the 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide assay, the invasion assay, gene transfection, real-time RT-PCR, western blot and gelatin zymography, to investigate whether the downregulation of Notch-1 contributes to curcumin-induced inhibition of proliferation and invasion in osteosarcoma cells. The results showed that curcumin caused marked inhibition of osteosarcoma cell growth and G2/M phase cell cycle arrest. This was associated with concomitant attenuation of Notch-1 and downregulation of its downstream genes, such as matrix metalloproteinases, resulting in the inhibition of osteosarcoma cell invasion through Matrigel. We also found that specific downregulation of Notch-1 via small-interfering RNA prior to curcumin treatment resulted in enhanced inhibition of cell growth and invasion. These results suggest that antitumor activity of curcumin is mediated through a novel mechanism involving inactivation of the Notch-1 signaling pathway. Our data provide the first evidence that the downregulation of Notch-1 by curcumin may be an effective approach for the treatment of osteosarcoma. PMID- 22521132 TI - Ginsenosidases and the pathogenicity of Pythium irregulare. AB - American ginseng (Panax quinquefolius L.) produces triterpenoid saponins, ginsenosides, that possess mild fungitoxic activity toward some common ginseng leaf pathogens. However, numerous oomycete root pathogens of ginseng, most notably Pythium irregulare Buisman, are able to partially deglycosylate 20 (S) protopanaxadiol ginsenosides Rb1, Rd and gypenoside XVII via extracellular glycosidases, leading to a common product, ginsenoside F2. Conversion of the common 20 (S)-protopanaxadiols into F2 requires both beta (1->6) and beta (1->2) glucosidase activity. In the present study, the ability of nine distinct isolates of P. irregulare, as well as a P. ultimum Trow isolate and two isolates of Trichoderma hamatum (Bonord.) Bainier, to deglycosylate 20 (S)-protopanaxadiols, in vitro was examined. The pathogenicity of each isolate was also examined by scoring the severity of disease symptoms caused by each in separate inoculations of one- and two-year old ginseng seedlings. Disease severity was scored using a disease severity index, as well as by taking F(v)/F(m) measurements of leaves during a 14-day infection period. Based on these measurements, it was concluded that (1) the use of direct F(v)/F(m) measurements correlates strongly with observations of disease severity (R(2)=0.79), and that (2) the pathogenicity of P. irregulare isolates correlates with their ability to deglycosylate ginsenosides (R(2)=0.57). These results further support the hypothesis that the pathogenicity of P. irregulare on ginseng roots is dependent, in part, on the ability of this organism to deglycosylate ginsenosides. PMID- 22521133 TI - Guanacastane-type diterpenoids from Coprinus radians. AB - Thirteen diterpenoids, named radianspenes A-M (1-13), including three lactams radianspenes J (10), K (11) and L (12) and one dimer radianspene M (13), were isolated from fermentation products of the higher fungal strain Coprinus radians M65. All these compounds possessing guanacastane skeleton were evaluated for antitumor activity using MDA-MB-435 cell line. Radianspene C exhibited inhibitory activity with IC(50) of 0.91 MUM. PMID- 22521134 TI - Effect of potassium ferrate on disintegration of waste activated sludge (WAS). AB - The activated sludge process of wastewater treatment results in the generation of a considerable amount of excess activated sludge. Increased attention has been given to minimization of waste activated sludge recently. This paper investigated the effect of potassium ferrate oxidation pretreatment on the disintegration of the waste activated sludge at various dosages of potassium ferrate. The results show that potassium ferrate pretreatment disintegrated the sludge particle, resulting in the reduction of total solid content by 31%. The solubility (SCOD/TCOD) of the sludge increased with the increase of potassium ferrate dosage. Under 0.81 g/g SS dosage of potassium ferrate, SCOD/TCOD reached 0.32. Total nitrogen (TN) and total phosphorous (TP) concentrations in the solution all increased significantly after potassium ferrate pretreatment. The sludge particles reduced from 116 to 87 MUm. The settleability of the sludge (SVI) was enhanced by 17%, which was due to the re-flocculation by the by-product, Fe(III), during potassium ferrate oxidation and the decrease of the viscosity. From the result of the present investigations, it can be concluded that potassium ferrate oxidation is a feasible method for disintegration of excess activated sludge. PMID- 22521135 TI - Toxic effect of different ZnO particles on mouse alveolar macrophages. AB - To study the toxicity mechanism of ZnO nanoparticles on mouse macrophages, the toxic effect of different ZnO nanoparticles on mouse alveolar macrophages (MH-S) was investigated in this study. The results showed that the 24h IC(50) of four ZnO particles were 48.53, 47.37, 45.43 and 26.74 MUg/ml for bulk ZnO, 100 nm, 30 nm and 10-30 nm ZnO particles, respectively. At the concentration of 10 MUg/ml and below, dissolved zinc ions induced metallothionein synthesis, enhanced cellular resistance to oxidative stress. ZnO particles mainly induced cell apoptosis. When the concentration of ZnO particles was 20 MUg/ml and above, excessive zinc destroyed mitochondrial function and cell membrane, caused cell necrosis. Dissolved zinc ions first cause toxicity in MH-S cells. However, the toxic effect of dissolved zinc ions may exist a threshold on mouse macrophages, inducing about 50% cell death. The toxic difference of different ZnO particles mainly depended on the effect of nondissolved ZnO particles. PMID- 22521136 TI - Chronic Al2O3-nanoparticle exposure causes neurotoxic effects on locomotion behaviors by inducing severe ROS production and disruption of ROS defense mechanisms in nematode Caenorhabditis elegans. AB - To date, knowledge on mechanisms regarding the chronic nanotoxicity is still largely minimal. In the present study, the effect of chronic (10-day) Al(2)O(3) nanoparticles (NPs) toxicity on locomotion behavior was investigated in the nematode Caenorhabditis elegans. Exposure to 0.01-23.1 mg/L of Al(2)O(3)-NPs induced a decrease in locomotion behavior, a severe stress response, and a severe oxidative stress; however, these effects were only detected in nematodes exposed to 23.1 mg/L of bulk Al(2)O(3). Formation of significant oxidative stress in nematodes exposed to Al(2)O(3)-NPs was due to both the increase in ROS production and the suppression of ROS defense mechanisms. More pronounced increases in ROS, decreases in SOD activity, and decrease in expression of genes encoding Mn-SODs (sod-2 and sod-3) were detected in nematodes exposed to Al(2)O(3)-NPs compared with bulk Al(2)O(3). Moreover, treatment with antioxidants or SOD-3 overexpression not only suppressed oxidative stress but also prevented adverse effects on locomotion behaviors from Al(2)O(3)-NPs exposure. Thus, chronic exposure to Al(2)O(3)-NPs may have adverse effects on locomotion behaviors by both induction of ROS production and disruption of ROS defense mechanisms. Furthermore, sod-2 and sod-3 mutants were more susceptible than the wild-type to chronic Al(2)O(3)-NPs-induced neurotoxicity inhibition. PMID- 22521137 TI - Let the four freedoms paradigm apply to ecology. PMID- 22521138 TI - Development and function of intestinal innate lymphoid cells. AB - Innate lymphoid cells (ILCs) are generated from common lymphoid precursors, like lymphocytes, but do not express an antigen receptor. ILCs include Natural Killer (NK) cells, first described 38 years ago, as well as the more recently discovered lymphoid tissue inducer (LTi) cells, NK(22) cells and ILC2s. ILCs reflect many functions of CD4(+) T helper cells by expressing IFNgamma, IL-17, IL-22 or IL-13. However, in contrast to T cells, they are not selected on the basis of antigen specificity, and expand and act shortly after stimulation. Therefore, ILCs play fundamental roles early in responses to infection and injury, in the maintenance of homeostasis, and possibly in the regulation of adaptive immunity. Here, we review the recent data on the development and role of RORgammat(+) ILCs and ILC2s in intestinal homeostasis and defense. PMID- 22521139 TI - Innate lymphoid cells: critical regulators of allergic inflammation and tissue repair in the lung. AB - Maintenance of epithelial barrier function in the skin, respiratory tract and intestine is critical to limit exposure to commensal and pathogenic microbes and to maintain tissue homeostasis. Innate lymphoid cells (ILCs) are a recently recognized innate immune cell population that plays critical roles in host defense, regulation of inflammation and promotion of wound healing and tissue repair at barrier surfaces. In this review we discuss recent advances in the understanding of how ILC populations in the respiratory tract impact allergic airway inflammation and lung epithelial repair. PMID- 22521140 TI - Adjuvants for human vaccines. AB - Rational selection of individual adjuvants can often be made on the basis of innate molecular interactions of the foreign molecules with pattern recognition receptors such as Toll-like receptors. For example, monophosphoryl lipid A, a family of endotoxic TLR4 agonist molecules from bacteria, has recently been formulated with liposomes, oil emulsions, or aluminum salts for several vaccines. Combinations of antigens and adjuvants with particulate lipid or oil components may reveal unique properties of immune potency or efficacy, but these can sometimes be exhibited differently in rodents when compared to nonhuman primates or humans. New adjuvants, formulations, microinjection devices, and skin delivery techniques for transcutaneous immunization demonstrate that adjuvant systems can include combinations of strategies and delivery mechanisms for uniquely formulated antigens and adjuvants. PMID- 22521142 TI - Exhaled nitric oxide decreases during exercise in non-asthmatic children. AB - INTRODUCTION: Exhaled nitric oxide (FENO) measurements are recommended to be performed before spirometry and exercise challenge tests because forced breathing might influence FENO values. Information on the effect of exercise on FENO is lacking in non-asthmatic children. AIM: To investigate the effect on FENO of a standardized exercise challenge test on a treadmill in non-asthmatic children with and without allergic rhinoconjunctivitis (AR) symptoms. METHODS: From the case-control study 'Asthma and allergy among school children in Nordland', 330 non-asthmatic pupils age 8-16 years were enrolled. FENO was measured at baseline and at 1 min and 30 min after exercise challenge test by the single breath technique with EcoMedics Exhalazer(r) (Eco Physics, Duernten, Switzerland). RESULTS: Pair-wise comparison of FENO from baseline demonstrated a highly significant reduction in FENO post-exercise for all children at 1 min (27.4%) and at 30 min (16.1%) (P < 0.001). The AR group had a significantly higher decline in FENO value at 1 min post-exercise compared to the non-AR group, 4.2 parts per billion (ppb) vs 2.6 ppb (P < 0.001). Decline in FENO immediately post-exercise was more significant if baseline FENO was >= 20 ppb; mean reduction 9.9 (95% CI: 8.7-11.4) ppb. CONCLUSION: FENO is reduced by 27.4% immediately after a standardized treadmill exercise test in non-asthmatic children. Pupils reporting AR symptoms demonstrate a larger decline in FENO value at 1 min post-exercise compared to pupils without AR symptoms. These findings confirm that children should refrain from physical activity before FENO measurement. PMID- 22521141 TI - Vaccines for allergy. AB - Vaccines aim to establish or strengthen immune responses but are also effective for the treatment of allergy. The latter is surprising because allergy represents a hyper-immune response based on immunoglobulin E production against harmless environmental antigens, i.e., allergens. Nevertheless, vaccination with allergens, termed allergen-specific immunotherapy is the only disease-modifying therapy of allergy with long-lasting effects. New forms of allergy diagnosis and allergy vaccines based on recombinant allergen-derivatives, peptides and allergen genes have emerged through molecular allergen characterization. The molecular allergy vaccines allow sophisticated targeting of the immune system and may eliminate side effects which so far have limited the use of traditional allergen extract-based vaccines. Successful clinical trials performed with the new vaccines indicate that broad allergy vaccination is on the horizon and may help to control the allergy pandemic. PMID- 22521143 TI - Temporally distinct translesion synthesis pathways for ultraviolet light-induced photoproducts in the mammalian genome. AB - Replicative polymerases (Pols) arrest at damaged DNA nucleotides, which induces ubiquitination of the DNA sliding clamp PCNA (PCNA-Ub) and DNA damage signaling. PCNA-Ub is associated with the recruitment or activation of translesion synthesis (TLS) DNA polymerases of the Y family that can bypass the lesions, thereby rescuing replication and preventing replication fork collapse and consequent formation of double-strand DNA breaks. Here, we have used gene-targeted mouse embryonic fibroblasts to perform a comprehensive study of the in vivo roles of PCNA-Ub and of the Y family TLS Pols eta, iota, kappa, Rev1 and the B family TLS Polzeta in TLS and in the suppression of DNA damage signaling and genome instability after exposure to UV light. Our data indicate that TLS Pols iota and kappa and the N-terminal BRCT domain of Rev1, that previously was implicated in the regulation of TLS, play minor roles in TLS of DNA photoproducts. PCNA-Ub is critical for an early TLS pathway that replicates both strongly helix-distorting (6-4) pyrimidine-pyrimidone ((6-4)PP) and mildly distorting cyclobutane pyrimidine dimer (CPD) photoproducts. The role of Poleta is mainly restricted to early TLS of CPD photoproducts, whereas Rev1 and, in particular, Polzeta are essential for the bypass of (6-4)PP photoproducts, both early and late after exposure. Thus, structurally distinct photoproducts at the mammalian genome are bypassed by different TLS Pols in temporally different, PCNA-Ub-dependent and independent fashions. PMID- 22521144 TI - The UNG2 Arg88Cys variant abrogates RPA-mediated recruitment of UNG2 to single stranded DNA. AB - In human cell nuclei, UNG2 is the major uracil-DNA glycosylase initiating DNA base excision repair of uracil. In activated B cells it has an additional role in facilitating mutagenic processing of AID-induced uracil at Ig loci and UNG deficient patients develop hyper-IgM syndrome characterized by impaired class switch recombination and disturbed somatic hypermutation. How UNG2 is recruited to either error-free or mutagenic uracil processing remains obscure, but likely involves regulated interactions with other proteins. The UNG2 N-terminal domain contains binding motifs for both proliferating cell nuclear antigen (PCNA) and replication protein A (RPA), but the relative contribution of these interactions to genomic uracil processing is not understood. Interestingly, a heterozygous germline single-nucleotide variant leading to Arg88Cys (R88C) substitution in the RPA-interaction motif of UNG2 has been observed in humans, but with unknown functional relevance. Here we demonstrate that UNG2-R88C protein is expressed from the variant allele in a lymphoblastoid cell line derived from a heterozygous germ line carrier. Enzyme activity as well as localization in replication foci of UNG2-R88C was similar to that of WT. However, binding to RPA was essentially abolished by the R88C substitution, whereas binding to PCNA was unaffected. Moreover, we show that disruption of the PCNA-binding motif impaired recruitment of UNG2 to S-phase replication foci, demonstrating that PCNA is a major factor for recruitment of UNG2 to unperturbed replication forks. Conversely, in cells treated with hydroxyurea, RPA mediated recruitment of UNG2 to stalled replication forks independently of functional PCNA binding. Modulation of PCNA- versus RPA binding may thus constitute a functional switch for UNG2 in cells subsequent to genotoxic stress and potentially also during the processing of uracil at the immunoglobulin locus in antigen-stimulated B cells. PMID- 22521145 TI - Ghrelin regulates the hypothalamic-pituitary-adrenal axis and restricts anxiety after acute stress. AB - BACKGROUND: Ghrelin plays important roles in glucose metabolism, appetite, and body weight regulation, and recent evidence suggests ghrelin prevents excessive anxiety under conditions of chronic stress. METHODS: We used ghrelin knockout (ghr-/-) mice to examine the role of endogenous ghrelin in anxious behavior and hypothalamic-pituitary-adrenal axis (HPA) responses to acute stress. RESULTS: Ghr /- mice are more anxious after acute restraint stress, compared with wild-type (WT) mice, with three independent behavioral tests. Acute restraint stress exacerbated neuronal activation in the hypothalamic paraventricular nucleus and medial nucleus of the amygdala in ghr-/- mice compared with WT, and exogenous ghrelin reversed this effect. Acute stress increased neuronal activation in the centrally projecting Edinger-Westphal nucleus in WT but not ghr-/- mice. Ghr-/- mice exhibited a lower corticosterone response after stress, suggesting dysfunctional glucocorticoid negative feedback in the absence of ghrelin. We found no differences in dexamethasone-induced Fos expression between ghr-/- and WT mice, suggesting central feedback was not impaired. Adrenocorticotropic hormone replacement elevated plasma corticosterone in ghr-/-, compared with WT mice, indicating increased adrenal sensitivity. The adrenocorticotropic hormone response to acute stress was significantly reduced in ghr-/- mice, compared with control subjects. Pro-opiomelanocortin anterior pituitary cells express significant growth hormone secretagogue receptor. CONCLUSIONS: Ghrelin reduces anxiety after acute stress by stimulating the HPA axis at the level of the anterior pituitary. A novel neuronal growth hormone secretagogue receptor circuit involving urocortin 1 neurons in the centrally projecting Edinger-Westphal nucleus promotes an appropriate stress response. Thus, ghrelin regulates acute stress and offers potential therapeutic efficacy in human mood and stress disorders. PMID- 22521146 TI - Posttraumatic stress disorder across two generations: concordance and mechanisms in a population-based sample. AB - BACKGROUND: Research conducted using small samples of persons exposed to extreme stressors has documented an association between parental and offspring posttraumatic stress disorder (PTSD), but it is unknown whether this association exists in the general population and whether trauma exposure mediates this association. We sought to determine whether mothers' posttraumatic stress symptoms were associated with PTSD in their young adult children and whether this association was mediated by higher trauma exposure in children of women with PTSD. METHODS: Using data from a cohort of mothers (n = 6924) and a cohort of their children (n = 8453), we calculated risk ratios (RR) for child's PTSD and examined mediation by trauma exposure. RESULTS: Mother's lifetime posttraumatic stress symptoms were associated with child's PTSD in dose-response fashion (mother's 1-3 symptoms, child's RR = 1.2; mother's 4-5 symptoms, RR = 1.3; mother's 6-7 symptoms, RR = 1.6, compared with children of mothers with no symptoms, p < .001 for each). Mother's lifetime symptoms were also associated with child's trauma exposure in dose-response fashion. Elevated exposure to trauma substantially mediated elevated risk for PTSD in children of women with symptoms (mediation proportion, 74%, p < .001). CONCLUSIONS: Intergenerational association of PTSD is clearly present in a large population-based sample. Children of women who had PTSD were more likely than children of women without PTSD to experience traumatic events; this suggests, in part, why the disorder is associated across generations. Health care providers who treat mothers with PTSD should be aware of the higher risk for trauma exposure and PTSD in their children. PMID- 22521147 TI - Reducing behavioral inhibition to novelty via systematic neonatal novelty exposure: the influence of maternal hypothalamic-pituitary-adrenal regulation. AB - BACKGROUND: Behavioral inhibition (BI) to novelty is thought to be a stable temperament type that appears early in life and is a major risk factor for anxiety disorders. In the rat, habituation of such inhibition can be facilitated via neonatal novelty exposure (NNE), thus reducing BI to novelty. Here, we tested the hypothesis that this early intervention effect is modulated by the context of maternal self-stress regulation. METHODS: The NNE was carried out during postnatal days 1-21, in which one half of each litter was exposed to a relatively novel nonhome environment for 3-min daily while the remaining one half stayed in the home cage. After weaning, BI to novelty was assessed in an open field with a measure of disinhibition defined as a greater increase in exploration across two brief trials. Maternal context was characterized by trait measures of hypothalamic-pituitary-adrenal (HPA) axis reactivity, including basal and stress evoked corticosterone (CORT) responses. RESULTS: Family-to-family variations in the NNE effect were associated with variations in maternal HPA function-a low basal CORT and high-evoked CORT response profile constituting the context for a novelty-induced facilitation of disinhibition (i.e., a greater increase in exploratory activity over repeated trials) and an opposite HPA profile constituting the context for a novelty-induced reduction of disinhibition. CONCLUSIONS: This result is consistent with the hypothesis that maternal self stress regulation modulates the effect of early life intervention on BI to novelty and suggests that effective interventions should include strategies to help mothers improve their self-stress regulation. PMID- 22521148 TI - Synaptic potentiation is critical for rapid antidepressant response to ketamine in treatment-resistant major depression. AB - BACKGROUND: Clinical evidence that ketamine, a nonselective N-methyl-D-aspartate receptor (NMDAR) antagonist, has therapeutic effects within hours in people suffering from depression suggests that modulating glutamatergic neurotransmission is a fundamental step in alleviating the debilitating symptoms of mood disorders. Acutely, ketamine increases extracellular glutamate levels, neuronal excitability, and spontaneous gamma oscillations, but it is unknown whether these effects are key to the mechanism of antidepressant action of ketamine. METHODS: Twenty drug-free major depressive disorder patients received a single, open-label intravenous infusion of ketamine hydrochloride (.5 mg/kg). Magnetoencephalographic recordings were made approximately 3 days before and approximately 6.5 hours after the infusion, whereas patients passively received tactile stimulation to the right and left index fingers and also while they rested (eyes-closed). Antidepressant response was assessed by percentage change in Montgomery-Asberg Depression Rating Scale scores. RESULTS: Patients with robust improvements in depressive symptoms 230 min after infusion (responders) exhibited increased cortical excitability within this antidepressant response window. Specifically, we found that stimulus-evoked somatosensory cortical responses increase after infusion, relative to pretreatment responses in responders but not in treatment nonresponders. Spontaneous somatosensory cortical gamma-band activity during rest did not change within the same timeframe after ketamine in either responders or nonresponders. CONCLUSIONS: These findings suggest NMDAR antagonism does not lead directly to increased cortical excitability hours later and thus might not be sufficient for therapeutic effects of ketamine to take hold. Rather, increased cortical excitability as depressive symptoms improve is consistent with the hypothesis that enhanced non-NMDAR mediated glutamatergic neurotransmission via synaptic potentiation is central to the antidepressant effect of ketamine. PMID- 22521150 TI - Maternal care influences hippocampal N-methyl-D-aspartate receptor function and dynamic regulation by corticosterone in adulthood. AB - BACKGROUND: Variations in maternal care in the rat associate with robust differences in hippocampal development and synaptic plasticity in the offspring. Maternal care also influences pituitary-adrenal stress responses and corticosterone (CORT) regulation of hippocampal plasticity. N-methyl-D-aspartate receptors (NMDAR) regulate synaptic plasticity, and NMDAR function is modulated by stress and CORT. We hypothesized that altered NMDAR function underlies the interaction of maternal and stress effects on hippocampal synaptic plasticity. METHODS: We used electrophysiology and western blot to examine NMDAR synaptic function/expression and NMDAR-dependent long-term potentiation (LTP) in adult offspring of mothers that varied in the frequency of pup licking/grooming (LG) (i.e., High or Low LG). RESULTS: Basal NMDAR synaptic function was enhanced in the hippocampal dentate gyrus (DG) of adult Low LG offspring. Synaptic expression of NMDAR but not alpha-amino-3-hydroxy-methyl-4-isoxazole propionic acid receptors was also increased. Stress level CORT (100 nmol/L) rapidly (< 20 min) and robustly increased NMDAR function in High LG offspring, eliminating the maternal effect. Corticosterone did not affect NMDAR function in Low LG offspring. Bovine serum albumin-conjugated CORT reproduced the CORT effect in High LG offspring, implicating a membrane-bound corticosteroid receptor. NMDAR hyperfunction might impair synaptic plasticity. Partial NMDAR antagonism by low concentration DL-2-Amino-5-phosphonopentanoic acid rescued a basal LTP deficit in Low LG offspring and inhibited LTP in High LG offspring. CONCLUSIONS: Low LG offspring exhibit basally elevated NMDAR function coupled with insensitivity to CORT modulation indicative of a chronic alteration of NMDAR function. Elevated NMDAR function in the hippocampus might underlie impaired LTP in Low LG offspring. PMID- 22521149 TI - Early-life mental disorders and adult household income in the World Mental Health Surveys. AB - BACKGROUND: Better information on the human capital costs of early-onset mental disorders could increase sensitivity of policy makers to the value of expanding initiatives for early detection and treatment. Data are presented on one important aspect of these costs: the associations of early-onset mental disorders with adult household income. METHODS: Data come from the World Health Organization (WHO) World Mental Health Surveys in 11 high-income, five upper middle income, and six low/lower-middle income countries. Information about 15 lifetime DSM-IV mental disorders as of age of completing education, retrospectively assessed with the WHO Composite International Diagnostic Interview, was used to predict current household income among respondents aged 18 to 64 (n = 37,741) controlling for level of education. Gross associations were decomposed to evaluate mediating effects through major components of household income. RESULTS: Early-onset mental disorders are associated with significantly reduced household income in high and upper-middle income countries but not low/lower-middle income countries, with associations consistently stronger among women than men. Total associations are largely due to low personal earnings (increased unemployment, decreased earnings among the employed) and spouse earnings (decreased probabilities of marriage and, if married, spouse employment and low earnings of employed spouses). Individual-level effect sizes are equivalent to 16% to 33% of median within-country household income, and population-level effect sizes are in the range 1.0% to 1.4% of gross household income. CONCLUSIONS: Early mental disorders are associated with substantial decrements in income net of education at both individual and societal levels. Policy makers should take these associations into consideration in making health care research and treatment resource allocation decisions. PMID- 22521151 TI - The importance of N = 1. PMID- 22521152 TI - Associations between ADIPOQ gene polymorphisms and coronary artery disease risk: an update. PMID- 22521154 TI - Hairless or fertile? Finasteride leads to epididymal changes and infertility in rats. PMID- 22521153 TI - Activated glucocorticoid and eicosanoid pathways in endometriosis. AB - OBJECTIVE: To define altered gene expression networks in endometriosis. DESIGN: Experiments using endometriotic tissues and primary cells. SETTING: Division of Reproductive Biology Research, Northwestern University. PATIENT(S): Premenopausal women. INTERVENTION(S): Matched samples of eutopic endometrium and ovarian endometriosis (n = 8 patients) were analyzed by microarray and verified in a separate set of tissues (n = 6 patients). Experiments to define signaling pathways were performed in primary endometriotic stromal cells (n = 12 patients). MAIN OUTCOMES MEASURE(S): Using a genome-wide in vivo approach, we identified 1,366 differentially expressed genes and a new gene network favoring increased glucocorticoid levels and action in endometriosis. RESULT(S): Transcript and protein levels of 11beta-hydroxysteroid dehydrogenase (HSD11B1), which produces cortisol, the biologically active glucocorticoid, were strikingly higher, whereas messenger RNA (mRNA) levels of the cortisol-degrading HSD11B2 enzyme were significantly lower in endometriotic tissue. Glucocorticoid receptor mRNA and protein levels were significantly higher in endometriosis. The inflammatory cytokine tumor necrosis factor robustly induced mRNA and protein levels of HSD11B1 and glucocorticoid receptor but suppressed HSD11B2 mRNA in primary endometriotic stromal cells, suggesting that tumor necrosis factor stimulates cortisol production and action. We also uncovered a subset of genes critical for prostaglandin synthesis and degradation, which favor high eicosanoid levels and activity in endometriosis. CONCLUSION(S): The proinflammatory milieu of the endometriotic lesion stimulates cortisol synthesis and action in endometriotic lesions. PMID- 22521155 TI - Nonsurgical dilation for vaginal agenesis is promising, but better research is needed. PMID- 22521156 TI - Chromosomal abnormalities in embryos from couples with a previous aneuploid miscarriage. AB - OBJECTIVE: To compare the incidence of chromosomal abnormalities in preimplantation embryos from couples undergoing preimplantation genetic screening (PGS) after previous aneuploid miscarriage after either natural conception (NC) or assisted reproductive technology (ART) versus fertile couples who underwent PGS for sex-linked diseases as a control group. DESIGN: Retrospective study. SETTING: IVF clinic. PATIENT(S): Patients with previous aneuploid conception undergoing PGS. INTERVENTION(S): Embryo biopsy, fluorescence in situ hybridization. MAIN OUTCOME MEASURE(S): Embryo aneuploidy rates and pregnancy and implantation rates in couples with a previous aneuploidy for autosomes or sex chromosomes. RESULT(S): The overall rates of chromosomal abnormalities in groups with previous autosomal aneuploidy were significantly higher compared with the control group (67.8% for those whose previous aneuploidy arose after NC and 65.8% for those previously arising after ART, vs. 34.0%). No significant differences were observed in those with previous sex chromosome abnormalities compared with control subjects. Within couples with previous aneuploidies after NC, no difference existed in the incidence of chromosomal abnormalities compared with the ART groups. Clinical outcomes were better (trend) in patients with previous autosomal aneuploidy after NC. CONCLUSION(S): In preimplantation embryos, the incidence of chromosomal abnormalities due to a previous aneuploid miscarriage after either NC or ART is significantly higher than in the control group. Furthermore, this incidence is higher when the previous aneuploidy was for autosomes; PGS is recommended in these couples. PMID- 22521157 TI - The association between fertility clinic performance and cycle volume: implications for public reporting of provider performance data. AB - OBJECTIVE: To quantitatively determine the relationship between fertility clinic performance and cycle volume, and to assess the implications for public reporting of provider performance data. DESIGN: Retrospective longitudinal analysis. SETTING: Clinic. PATIENT(S): The study population included 307 U.S. assisted reproductive technology (ART) clinics that continuously reported performance data to the Centers for Disease Control from 2003 to 2008. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Regression coefficients between pregnancy rate per cycle, live birth rate per cycle, or live birth rate per transfer and number of ART cycles performed. RESULT(S): Overall, there was no association found between a clinic's most recently reported success rate and its cycle volume. This finding was consistent across three time periods studied. Moreover, stratification analyses of clinics with greater than +/-5%, +/-10%, and +/-20% change in success rates also found no association between clinic performance and cycle volume. CONCLUSION(S): As proxied by cycle volume data, patients seeking ART treatment do not seem to be influenced by positive or negative changes in a clinic's performance despite the public availability of this data. These results suggest that current public quality reporting encompassing success rates alone will not change patient behavior and therefore is insufficient to place salient competitive pressure on health care providers. Further research is necessary to define provider performance comprehensively and to determine the metrics, if any, to which patients respond. PMID- 22521158 TI - Impact of drug price adjustments on utilization of and expenditures on angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in Taiwan. AB - BACKGROUND: A previous study has suggested that drug price adjustments allow physicians in Taiwan to gain greater profit by prescribing generic drugs. To better understand the effect of price adjustments on physician choice, this study used renin-angiotensin drugs (including angiotensin-converting enzyme inhibitors [ACEIs] and angiotensin receptor blockers [ARBs]) to examine the impact of price adjustments on utilization of and expenditures on patented and off-patent drugs with the same therapeutic indication. METHODS: Using the Taiwan's Longitudinal Health Insurance Database (2005), we identified 147,157 patients received ACEIs and/or ARBs between 1997 and 2008. The annual incident and prevalent users of ACEIs, ARBs and overall renin-angiotensin drugs were examined. Box-Tiao intervention analysis was applied to assess the impact of price adjustments on monthly utilization of and expenditures on these drugs. ACEIs were divided into patented and off-patent drugs, off-patent ACEIs were further divided into original brands and generics, and subgroup analyses were performed. RESULTS: The number of incident renin-angiotensin drug users decreased over the study period. The number of prevalent ARB users increased and exceeded the cumulative number of first-time renin-angiotensin drug users starting on ARBs, implying that some patients switched from ACEIs to ARBs. After price adjustments, long term trend increases in utilization were observed for patented ACEIs and ARBs; a long-term trend decrease was observed for off-patent ACEIs; long-term trend change was not significant for overall renin-angiotensin drugs. Significant long-term trend increases in expenditures were observed for patented ACEIs after price adjustment in 2007 (200.9%, p = 0.0088) and in ARBs after price adjustments in 2001 (173.4%, p < 0.0001) and 2007 (146.3%, p < 0.0001). A significant long-term trend decrease in expenditures was observed for off-patent ACEIs after 2004 price adjustment ( 156.9%, p < 0.0001). Expenditures on overall renin-angiotensin drugs showed long term trend increases after price adjustments in 2001 (72.2%, p < 0.0001) and 2007 (133.4%, p < 0.0001). CONCLUSIONS: Price adjustments did not achieve long-term cost savings for overall renin-angiotensin drugs. Possible switching from ACEIs to ARBs within individuals is evident. Policy makers should reconsider the appropriateness of the current adjustment strategies applied to patented and off patent drugs. PMID- 22521159 TI - [HPV testing and cervical cancer screening. Evidences, resistances and current practices]. PMID- 22521160 TI - Minimally invasive synovium harvest for potential use in meniscal tissue engineering. AB - Tissue engineering is being investigated as a means for treating avascular meniscal injury or total meniscal loss in human and veterinary patients. The purpose of this study was to determine if an arthroscopic tissue shaver can be used to collect viable synoviocytes for in vitro culture during therapeutic stifle arthroscopy, with the long term goal of producing autologous meniscal fibrocartilage for meniscal tissue engineering. Synovium was harvested arthroscopically from 13 dogs with naturally occurring cranial cruciate ligament deficiency and obtained from 5 dogs with patellar luxation via arthrotomy. Cells harvested via arthroscopy and arthrotomy were treated with a chondrogenic growth factor protocol and analyzed for meniscal-like matrix constituents including collagens type I, II, and glycosaminoglycans. Arthrotomy and Arthroscopic origin cells formed contracted tissues containing collagen I, II and small amounts of GAG. These surgical methods provide clinically relevant access to synoviocytes for potential use in meniscal tissue engineering. PMID- 22521161 TI - Brain-derived neurotrophic factor Val66Met polymorphism and obsessive-compulsive symptoms in Egyptian schizophrenia patients. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) has been advanced as a candidate gene for schizophrenia. BDNF promote the function and growth of 5-HT neurons in the brain and modulate the synaptic plasticity of DRD3-secreting neurons in the striatum, suggesting involvement of BDNF in the mediation of obsessive-compulsive disorder. OBJECTIVES: To test the hypothesis that the BDNF Val66Met polymorphism influence obsessive-compulsive symptoms (OCS) in schizophrenia, we examined the association between the BDNF Val66Met genotypes and OCS in a group of patients with schizophrenia. METHODS: 320 schizophrenia patients were assessed using the Yale-Brown Obsessive-Compulsive Scale (YBOCS). BDNF Val66Met polymorphism was genotyped using PCR-RFLP method, and severity of OCS were compared between the genotype groups. RESULTS: Out of the 320 schizophrenia patients, 120 patients (37.5%) had significant OCS. There was a significant excess of valine allele in the schizophrenia with-OCS group compared to the without-OCS group. The mean YBOCS scores were significantly different among the three genotype groups. Val/Val homozygote patients had higher mean YBOCS scores compared to Val/Met genotype (p = 0.0001) as well as to the Met/Met homozygote group (p = 0.003). CONCLUSION: Our data suggested an association between BDNF Val66Met polymorphism and OCS in Egyptian schizophrenia patients. PMID- 22521162 TI - [Has surgery of the vitreous evolved?]. AB - Three ports pars plana vitrectomy has been described 50 years ago. From indications to salvage the peripheral retina function, it has progressively shifted towards functional indications in macular pathologies, trying initially to stabilize and now to improve visual acuity. This has been achieved by improvement, not only of surgical material but also of microscopes, intraoperative rools such as perfluorocarbone liquids and more recently the use of vital dyes. PMID- 22521163 TI - A critical review on sustainability assessment of recycled water schemes. AB - Recycled water provides a viable opportunity to supplement water supplies as well as alleviate environmental loads. To further expand current schemes and explore new recycled water end uses, this study reviews several environmental assessment tools, including Life Cycle Assessment (LCA), Material Flow Analysis (MFA) and Environmental Risk Assessment (ERA) in terms of their types, characteristics and weaknesses in evaluating the sustainability of recycled water schemes. Due to the limitations in individual models, the integrated approaches are recommended in most cases, of which the outputs could be further combined with additional economic and social assessments in multi-criteria decision making framework. The study also proposes several management strategies in improving the environmental scores. The discussion and suggestions could help decision makers in making a sound judgement as well as recognising the challenges and tasks in the future. PMID- 22521164 TI - Rapid screening of aquatic toxicity of several metal-based nanoparticles using the MetPLATETM bioassay. AB - Current understanding of potential toxicity of engineered nanomaterials to aquatic microorganisms is limited for risk assessment and management. Here we evaluate if the MetPLATETM test can be used as an effective and rapid screening tool to test for potential aquatic toxicity of various metal-based nanoparticles (NPs). The MetPLATE bioassay is a heavy metal sensitive test based on beta galactosidase activity in Escherichia coli. Five different types of metal-based NPs were screened for toxicity: (1) citrate coated nAg (Citrate-nanosilver), (2) polyvinylpyrrolidone coated nAg (PVP-nAg), (3) uncoated nZnO, (4) uncoated nTiO(2) and (5) 1-Octadecylamine coated CdSe Quantum Dots (CdSe QDs); and compared with their corresponding ionic salt toxicity. Citrate-nAg was further fractionated into clean Citrate-nAg, unclean Citrate-nAg and permeate using a tangential flow filtration (TFF) system to eliminate residual ions and impurities from the stock Citrate-nAg suspension and also to differentiate between ionic- versus nano-specific toxicity. Our results showed that nAg, nZnO and CdSe QDs were less toxic than their corresponding ionic salts tested, while nano- or ionic form of TiO(2) was not toxic as high as 2.5 g L(-1) to the MetPLATETM bacteria. Although coating-dependent toxicity was noticeable between two types of Ag NPs evaluated, particle size and surface charge were not adequate to explain the observed toxicity; hence, the toxicity appeared to be material-specific. Overall, the toxicity followed the trend: CdCl(2)>AgNO(3)>PVP-nAg>unclean Citrate nAg>clean Citrate-nAg>ZnSO(4)>nZnO>CdSe QDs>nTiO(2)/TiO(2). These results indicate that an evaluation of beta-galactosidase inhibition in MetPLATETM E. coli can be an important consideration for rapid screening of metal-based NP toxicity, and should facilitate ecological risk assessment of these emerging contaminants. PMID- 22521165 TI - Decomposition of cyclohexanoic acid by the UV/H2O2 process under various conditions. AB - Naphthenic acids (NAs) are a broad range of alicyclic and aliphatic compounds that are persistent and contribute to the toxicity of oil sands process affected water (OSPW). In this investigation, cyclohexanoic acid (CHA) was selected as a model naphthenic acid, and its oxidation was investigated using advanced oxidation employing a low-pressure ultraviolet light in the presence of hydrogen peroxide (UV/H(2)O(2) process). The effects of two pHs and common OSPW constituents, such as chloride (Cl(-)) and carbonate (CO(3)(2-)) were investigated in ultrapure water. The optimal molar ratio of H(2)O(2) to CHA in the treatment process was also investigated. The pH had no significant effect on the degradation, nor on the formation and degradation of byproducts in ultrapure water. The presence of CO(3)(2-) or Cl(-) significantly decreased the CHA degradation rate. The presence of 700 mg/L CO(3)(2-) or 500 mg/L Cl(-), typical concentrations in OSPW, caused a 55% and 23% decrease in the pseudo-first order degradation rate constants for CHA, respectively. However, no change in byproducts or in the degradation trend of byproducts, in the presence of scavengers was observed. A real OSPW matrix also had a significant impact by decreasing the CHA degradation rate, such that by spiking CHA into the OSPW, the degradation rate decreased up to 82% relative to that in ultrapure water. The results of this study show that UV/H(2)O(2) AOP is capable of degrading CHA as a model NA in ultrapure water. However, in the real applications, the effect of radical scavengers should be taken into consideration for the achievement of best performance of the process. PMID- 22521166 TI - Hyperspectral determination of eutrophication for a water supply source via genetic algorithm-partial least squares (GA-PLS) modeling. AB - Morse Reservoir (MR), a major source of the water supply for the Indianapolis metropolitan region, is now experiencing nuisance cyanobacterial blooms. These blooms cause water quality degradation, as well as reducing the aesthetic quality of water by producing toxins, scums, and foul odors. Hyperspectral remote sensing data from both in situ and airborne AISA measurements were applied to GA-PLS by relating the spectral signal with measured water eutrophication parameters, e.g., chlorophyll-a (Chl-a), phycocyanin (PC), total suspended matter (TSM), and Secchi disk depth (SDD). Our results indicate that GA-PLS relating field sensor acquired spectral reflectance to the above-mentioned four parameters yielded low root mean square error between measured and estimated Chl-a (RMSE=10.4; Range (R): 1.8 215.8 MUg/L), PC (RMSE=18.6; R: 1.4-371.0 MUg/L), TSM (RMSE=3.8; R: 3.6-81.4 mg/L), SDD (RMSE=5.8; R: 25-135 cm) for MR. The GA-PLS model also yielded high performance with AISA image spectra, and the RMSEs were 12.1 MUg/L, 25.3 MUg/L, 5.9 mg/L and 5.7 cm, respectively for Chl-a, PC, TSM, and SDD. Four water quality parameters were mapped with GA-PLS using AISA hyperspectral image. Based on these results, in situ and airborne hyperspectral remote sensors can provide both quantitative and qualitative information on the distribution and concentration of cyanobacteria, suspended matter, and transparency in MR. PMID- 22521167 TI - Diversity and antibiotic resistance in Pseudomonas spp. from drinking water. AB - Pseudomonas spp. are common inhabitants of aquatic environments, including drinking water. Multi-antibiotic resistance in clinical isolates of P. aeruginosa is widely reported and deeply characterized. However, the information regarding other species and environmental isolates of this genus is scant. This study was designed based on the hypothesis that members of the genus Pseudomonas given their high prevalence, wide distribution in waters and genetic plasticity can be important reservoirs of antibiotic resistance in drinking water. With this aim, the diversity and antibiotic resistance phenotypes of Pseudomonas isolated from different drinking water sources were evaluated. The genotypic diversity analyses were based on six housekeeping genes (16S rRNA, rpoD, rpoB, gyrB, recA and ITS) and on pulsed field gel electrophoresis. Susceptibility to 21 antibiotics of eight classes was tested using the ATB PSE EU (08) and disk diffusion methods. Pseudomonas spp. were isolated from 14 of the 32 sampled sites. A total of 55 non repetitive isolates were affiliated to twenty species. Although the same species were isolated from different sampling sites, identical genotypes were never observed in distinct types of water (water treatment plant/distribution system, tap water, cup fillers, biofilm, and mineral water). In general, the prevalence of antibiotic resistance was low and often the resistance patterns were related with the species and/or the strain genotype. Resistance to ticarcillin, ticarcillin with clavulanic acid, fosfomycin and cotrimoxazol were the most prevalent (69-84%). No resistance to piperacillin, levofloxacin, ciprofloxacin, tetracycline, gentamicin, tobramycin, amikacin, imipenem or meropenem was observed. This study demonstrates that Pseudomonas spp. are not so widespread in drinking water as commonly assumed. Nevertheless, it suggests that water Pseudomonas can spread acquired antibiotic resistance, preferentially via vertical transmission. PMID- 22521168 TI - The effect of risk perception on public preferences and willingness to pay for reductions in the health risks posed by toxic cyanobacterial blooms. AB - Mass populations of toxin-producing cyanobacteria are an increasingly common occurrence in inland and coastal waters used for recreational purposes. These mass populations pose serious risks to human and animal health and impose potentially significant economic costs on society. In this study, we used contingent valuation (CV) methods to elicit public willingness to pay (WTP) for reductions in the morbidity risks posed by blooms of toxin-producing cyanobacteria in Loch Leven, Scotland. We found that 55% of respondents (68% excluding protest voters) were willing to pay for a reduction in the number of days per year (from 90, to either 45 or 0 days) that cyanobacteria pose a risk to human health at Loch Leven. The mean WTP for a risk reduction was UKL9.99 12.23/household/year estimated using a logistic spike model. In addition, using the spike model and a simultaneous equations model to control for endogeneity bias, we found the respondents' WTP was strongly dependent on socio-demographic characteristics, economic status and usage of the waterbody, but also individual specific attitudes and perceptions towards health risks. This study demonstrates that anticipated health risk reductions are an important nonmarket benefit of improving water quality in recreational waters and should be accounted for in future cost-benefit analyses such as those being undertaken under the auspices of the European Union's Water Framework Directive, but also that such values depend on subjective perceptions of water-related health risks and general attitudes towards the environment. PMID- 22521169 TI - Photochemical transformation of anionic 2-nitro-4-chlorophenol in surface waters: laboratory and model assessment of the degradation kinetics, and comparison with field data. AB - Anionic 2-nitro-4-chlorophenol (NCP) may occur in surface waters as a nitroderivative of 4-chlorophenol, which is a transformation intermediate of the herbicide dichlorprop. Here we show that NCP would undergo efficient photochemical transformation in environmental waters, mainly by direct photolysis and reaction with OH. NCP has a polychromatic photolysis quantum yield Phi(NCP)=(1.27+/-0.22).10(-5), a rate constant with OH k(NCP,)(OH)=(1.09+/ 0.09).10(10) M(-1) s(-1), a rate constant with (1)O(2)k(NCP,1O2)=(2.15+/ 0.38).10(7) M(-1) s(-1), a rate constant with the triplet state of anthraquinone 2-sulphonate k(NCP,3AQ2S*)=(5.90+/-0.43).10(8) M(-1) s(-1), and is poorly reactive toward CO(3)(-). The k(NCP,3AQ2S*) value is representative of reaction with the triplet states of chromophoric dissolved organic matter. The inclusion of photochemical reactivity data into a model of surface-water photochemistry allowed the NCP transformation kinetics to be predicted as a function of water chemical composition and column depth. Very good agreement between model predictions and field data was obtained for the shallow lagoons of the Rhone delta (Southern France). PMID- 22521170 TI - On the function of the various quinone species in Escherichia coli. AB - The respiratory chain of Escherichia coli contains three quinones. Menaquinone and demethylmenaquinone have low midpoint potentials and are involved in anaerobic respiration, while ubiquinone, which has a high midpoint potential, is involved in aerobic and nitrate respiration. Here, we report that demethylmenaquinone plays a role not only in trimethylaminooxide-, dimethylsulfoxide- and fumarate-dependent respiration, but also in aerobic respiration. Furthermore, we demonstrate that demethylmenaquinone serves as an electron acceptor for oxidation of succinate to fumarate, and that all three quinol oxidases of E. coli accept electrons from this naphtoquinone derivative. PMID- 22521178 TI - Imaging in lower urinary tract infections. AB - In epididymo-orchitis, a sonogram shows a non-homogenous and hypertrophied epididymis and testis, with increased vascularisation seen on a Doppler sonogram. Abscesses must be investigated using sonography so that a necrotic tumour is not misdiagnosed. In prostatitis, sonography is indicated to investigate urine retention and where treatment has failed (to look for a blockage, an abscess, or pyelonephritis). Endorectal sonography is the best imaging modality for analysing the parenchyma, but otherwise has limited value. Chronic prostatitis is the main differential diagnosis from prostate cancer; the two may be distinguished using diffusion MRI. In cases of cystitis, imaging is indicated when a patient has recurrent cystitis (to investigate what the causative factors might be), or an infection with a less common bacterium (to look for calcifications, emphysema, any involvement of the upper urinary tract), and in cases of cystitis with pseudotumour. PMID- 22521179 TI - Factors associated with poor nutritional status among the oldest-old. AB - BACKGROUND & AIMS: Older adults are at increased risk for malnutrition. The aim was to investigate the prevalence of and risk factors for poor nutritional status in oldest-old Chinese. METHODS: Community-living Chinese aged 90 and over were included in the study. Nutritional status was evaluated by using the Mini Nutritional Assessment short-form (MNA-SF). Demographic and socioeconomic status, health status, cognitive, behavioral, and lifestyle factors were collected via structured questionnaires during face-to-face interviews. RESULTS: 632 individuals (424 F, 208 M, 94 +/- 3 y) were included. We found that 36 (5.7%) participants were classified as being malnourished (MNA-SF < 7), 445 (70.4%) were classified as being at risk for malnutrition (8 <= MNA-SF <= 11), and 151 (23.9%) were considered as well-nourished (MNA-SF >= 12). Ordinal logistic regression showed that significant risk factors for poor nutritional status included older age, poor cognitive function, gastrointestinal (GI) system disease, poor self rated health, and lower serum albumin level. CONCLUSION: The findings suggest that the majority of the Chinese oldest-old were at risk for malnutrition. Nutritional assessment should be incorporated into regular geriatric screening among community-living oldest-old in China. Interventions targeting those at risk for malnutrition should be developed to improve health outcomes among this vulnerable population. PMID- 22521180 TI - The relationships between fat talk, body dissatisfaction, and drive for thinness: perceived stress as a moderator. AB - Although body dissatisfaction and drive for thinness are commonplace in college aged women, their relationships with fat talk and stress are understudied. This study examined (a) whether fat talk predicts body dissatisfaction and drive for thinness and (b) whether stress moderates these relationships. Results from self report questionnaires completed by 121 female college students revealed that fat talk and perceived stress were significantly positively correlated with body dissatisfaction and drive for thinness. Although fat talk was a significant independent predictor of body dissatisfaction and drive for thinness, stress moderated these relationships such that they were stronger at lower stress levels. Although contrary to predictions, these results are logical when means are considered. Results suggest that fat talk positively predicts body dissatisfaction and drive for thinness in students with relatively lower stress levels, but does not for students under high stress because mean levels of these constructs are all already high. PMID- 22521181 TI - Muscle dysmorphia in different degrees of bodybuilding activities: validation of the Italian version of Muscle Dysmorphia Disorder Inventory and Bodybuilder Image Grid. AB - The purpose of the study was to validate two measures of muscle dysmorphia (MD) into the Italian language. The sample included three participant groups: (1) competing bodybuilders, (2) non-competing bodybuilders, and (3) non-bodybuilding controls. In general the Italian versions of the scales showed psychometric utility that is consistent with the original instruments. The severity of MD was greater for competing bodybuilders than non-competing bodybuilders and controls. PMID- 22521182 TI - Screening for posttraumatic stress disorder in civilian substance use disorder patients: cross-validation of the Jellinek-PTSD screening questionnaire. AB - This study aimed to cross-validate earlier findings regarding the diagnostic efficiency of a modified version of the Primary Care Posttraumatic Stress Disorder (PC-PTSD) screening questionnaire (A. Prins, P. Ouimette, R. Kimerling, R. P. Cameron, D. S. Hugelshofer, J. Shaw-Hegwer, et al., 2004). The PC-PTSD is a four-item screening questionnaire for Posttraumatic Stress Disorder (PTSD). Based on former research, we adapted the PC-PTSD for use among civilian substance use disorder (SUD) patients (D. Van Dam, T. Ehring, E. Vedel, & P. M. G. Emmelkamp, 2010). This version will be referred to as the Jellinek-PTSD (J-PTSD) screening questionnaire. Results showed a high sensitivity (.87), specificity (.75), and overall efficiency (.77) of the J-PTSD in detecting PTSD when using a cutoff score of 2. This confirms findings in former research, and suggests that the J PTSD is a useful screening instrument for PTSD within a civilian SUD population. Both PTSD and SUD are severe and disabling disorders causing great psychological distress. An early recognition of PTSD among SUD patients makes it possible to address PTSD symptoms in time, which may ultimately lead to an improvement of symptoms in this complex patient group. PMID- 22521183 TI - Intra-luminal stent navigation for embolization of cerebral aneurysms with marked angular acuity of incorporated branch vasculature. PMID- 22521184 TI - Association of HLA-DR/DQ polymorphism with myasthenia gravis in Tunisian patients. AB - BACKGROUND AND OBJECTIVE: Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction. MG has been shown to be associated with many human leukocyte antigens (HLA) in different populations. The aim of this study was to investigate the probable association between HLA-DR/DQ alleles and MG in Tunisian patients. PATIENTS AND METHODS: HLA DR/DQ genotyping was performed using polymerase chain reaction sequence-specific primers (PCR-SSP) with 48 MG patients and 100 healthy individuals serving as the control group. RESULTS: Myasthenia gravis in Tunisian patients was found to be associated with the following alleles (p(c) denotes Bonferroni corrected probability values): HLA-DRB1*03 (p(c)<10( 3)), DRB1*04 (p(c)=0.005), DQB1*02 (p(c)=0.002) and, DQB1*03 (p(c)=0.007). CONCLUSION: Our data demonstrated a new HLA-MG predisposition with DRB1*04. The DRB1*03, DRB1*04, DQB1*02, and DQB1*03 alleles also could be predisposing genetic factors for MG in the Tunisian population. PMID- 22521185 TI - Editorial comment. PMID- 22521186 TI - Editorial comment. PMID- 22521187 TI - Coated implants and "no touch" surgical technique decreases risk of infection in inflatable penile prosthesis implantation to 0.46%. AB - OBJECTIVE: To explore whether a "no touch" enhancement to the surgical technique of inflatable penile prosthesis (IPPs) implantaion will further decrease infection rates. MATERIALS AND METHODS: A single surgeon performed 2347 IPPs between January 2002 and June 2011. Patients receiving each manufacturer's implants were stratified for age and diabetes. Since 2003, infection retardant coated IPPs were implanted through the standardized penoscrotal approach. Since 2006, the "no touch" enhancement was added to the surgical procedure. Infection rates in the noncoated IPP, coated IPP with standard technique, and coated IPP implanted with "no touch" enhancement were calculated and subjected to statistical analysis. The two company's implants were scrutinized for their individual infection rates in each group. RESULTS: Patients in all the groups were similar for age and diabetes. 132 noncoated implants had an infection rate of 5.3%. In the years 2003-2005, 704 coated devices had a statistically significant improvement in incidence of infection to 2%. In the years 2006-2010, the "no touch" technique enhanced the standard surgical procedure in 1511 patients. Only 7 infections were seen yielding an infection incidence of 0.46%. There was no difference in the two manufacturer's infection rates. Differentiation between virgin and revision operation displayed no bias in the infection rate. CONCLUSION: Infection-retardant coatings lower the risk of infection from 5.3% to 2%. The "no touch" enhancement to the surgical procedure further decreases the rate of infection to 0.46%. Neither manufacturer showed statistical superiority in survival from revision for infection. PMID- 22521189 TI - Urethroplasty after radiation therapy for prostate cancer. AB - OBJECTIVE: To report urethroplasty outcomes in men who developed urethral stricture after undergoing radiation therapy for prostate cancer. METHODS: Our urethroplasty database was reviewed for cases of urethral stricture after radiation therapy for prostate cancer between June 2004 and May 2010. Patient demographics, prostate cancer therapy type, stricture length and location, and type of urethroplasty were obtained. All patients received clinical evaluation, including imaging studies post procedure. Treatment success was defined as no need for repeat surgical intervention. RESULTS: Twenty-nine patients underwent urethroplasty for radiation-induced stricture. Previous radiation therapy included external beam radiotherapy (EBRT), radical prostatectomy (RP)/EBRT, EBRT/brachytherapy (BT) and BT alone in 11 (38%), 7 (24%), 7 (24%), and 4 (14%) patients, respectively. Mean age was 69 (+/-6.9) years. Mean stricture length was 2.6 (+/-1.6) cm. Anastomotic urethroplasty was performed in 76% patients, buccal mucosal graft in 17%, and perineal flap repair in 7%. Stricture was localized to bulbar urethra in 12 (41%), membranous in 12 (41%), vesicourethra in 3 (10%), and pan-urethral in 2 (7%) patients. Overall success rate was 90%. Median follow-up was 40 months (range 12-83). Time to recurrence ranged from 6-16 months. CONCLUSION: Multiple forms of urethroplasty appear to be viable options in treating radiation-induced urethral stricture. Future studies are needed to examine the durability of repairs. PMID- 22521191 TI - A novel approach in eight polyorchidism cases: vasoepidydimal or epididymo epididymal approximation in single vas deferens duplicated testis. AB - OBJECTIVE: To discuss the classification systems and pose a rationale for a flexible approach. We also propose our surgical approach for vasoepididymal or epidymo-epididymal approximation. Polyorchidism is a rare congenital anomaly with about 200 cases reported. METHODS: We present 8 cases of polyorchidism treated at our institute from 1992 to 2010. To our knowledge, this is the most numerous single-center experience. We performed vasoepididymal or epidymo-epididymal approximation to restore near-normal anatomy plus stabilization of the testicular and ductal system to facilitate possible future reconstructive surgery. RESULTS: In the case of contralateral anorchia or an atrophic testis, a supernumerary testis can fairly replace the contralateral counterpart. The reproductive potential of the supernumerary testis must not be ignored. Also, the malignant potential of the supernumerary testis should not be overestimated. CONCLUSION: A careful pursuit of the vessel and vasal route during surgery for an undescended testis, judicious use of laparoscopy, and a lower threshold for diagnosis both on imaging studies and during surgery might result in a greater number of cases of polyorchidism in the daily practice of pediatric urology. PMID- 22521192 TI - Short-term patient-reported quality of life after robot-assisted radical cystectomy using the Convalescence and Recovery Evaluation. AB - OBJECTIVE: To determine the short-term health status of patients after robot assisted radical cystectomy using the Convalescence and Recovery Evaluation (CARE). Radical cystectomy and urinary diversion in patients with invasive bladder cancer can have a significant effect on patients' quality of life. METHODS: A total of 91 patients completed the CARE preoperatively and postoperatively. The CARE scores were calculated from postoperative day 7 to 90. Outcome measures were calculated using the CARE difference index (CDI), defined as the difference between the baseline CARE and postoperative day 7 CARE scores. The primary outcome was the time taken to recover 90% of the CDI. RESULTS: The mean age at robot-assisted radical cystectomy was 69 years (range 42-86). Of the 91 patients, 68 (74%) were men, 38 underwent extracorporeal urinary diversion, 52 underwent intracorporeal urinary diversion, and 1 underwent no diversion. A comparison of the preoperative and postoperative day 7 scores demonstrated a 48% decline in the total CARE score. The decline in specific CARE domains was 14%, 34%, 56%, and 66% against baseline for the cognition, pain, gastrointestinal, and activity domains, respectively. The mean time to recover 90% of the CDI for the total CARE score was 63 days. The mean time to recover 90% of the CDI for the pain, cognition, and activity domains was 33, 57, and 82 days, respectively. Patients did not recover 90% of the CDI for the gastrointestinal domain within the 90-day follow-up period. CONCLUSION: Patients who underwent robot-assisted radical cystectomy approached preoperative baseline levels within 90 days using the CARE in the total CARE, pain, cognition, and activity domains but not in the gastrointestinal domain. PMID- 22521194 TI - Editorial comment. PMID- 22521193 TI - Differences in mast cell infiltration, E-cadherin, and zonula occludens-1 expression between patients with overactive bladder and interstitial cystitis/bladder pain syndrome. AB - OBJECTIVE: To investigate the difference of infiltration of mast cells and the distribution of protein involved in the urothelial barrier function between patients with overactive bladder syndrome (OAB) and interstitial cystitis/bladder pain syndrome (IC/BPS). METHODS: Bladder wall biopsies were performed in 27 patients with OAB, 18 patients with IC/BPS, and 19 controls. The expression of junction protein E-cadherin, tight junction protein zonula occludens (ZO-1), and activated mast cells in the bladder wall were evaluated quantitatively using immunofluorescence staining. RESULTS: The numbers of mast cells in the urothelium and suburothelium areas were low in the control group (mean +/- standard error 1.77 +/- 0.47). A highly significant increase in mast cell infiltration was observed in OAB (4.00 +/- 0.55, P = .002) and IC/BPS specimens (4.64 +/- 0.72, P = .000). ZO-1 expression was significantly decreased in IC/PBS (7.45 +/- 0.99) compared with OAB (13.46 +/- 1.32, P = .004) and control bladder samples (14.55 +/- 2.08, P = .004). The E-cadherin expression was also significantly decreased in IC/BPS bladder samples (59.05 +/- 9.48) compared with the controls (96.30 +/- 9.15, P = .001). No significant difference was found in E-cadherin or ZO-1 levels between the OAB and control bladders (P = .170 and P = .763, respectively). CONCLUSION: Mast cell infiltration was found in both OAB and IC/BPS bladder wall, but E-cadherin and ZO-1 expression was only decreased in IC/BPS, suggesting the urothelial barrier function was not affected in the OAB bladder. PMID- 22521195 TI - Left kidney cancer grossly extending into left-sided inferior vena cava of duplicated inferior vena cava. AB - The left radical nephrectomy with tumor thrombectomy in the presence of a duplicated inferior vena cava is of high surgical risk because the venous tumor thrombus renders the anomalous venous structures dilated and tortuous, making injury more likely. We present a case of a left kidney cancer grossly extending into the left side of a duplicated inferior vena cava. What is more important is to bring such an aberrant vascular anatomy with tumor thrombus to the attention of urologists with high-resolution pictorial illustrations. PMID- 22521196 TI - Prokaryotic selectivity and LPS-neutralizing activity of short antimicrobial peptides designed from the human antimicrobial peptide LL-37. AB - To develop novel antimicrobial peptides (AMPs) with shorter lengths, improved prokaryotic selectivity and retained lipolysaccharide (LPS)-neutralizing activity compared to human cathelicidin AMP, LL-37, a series of amino acid-substituted analogs based on IG-19 (residues 13-31 of LL-37) were synthesized. Among the IG 19 analogs, the analog a4 showed the highest prokaryotic selectivity, but much lower LPS-neutralizing activity compared to parental LL-37. The analogs, a5, a6, a7 and a8 with higher hydrophobicity displayed LPS-neutralizing activity comparable to that of LL-37, but much lesser prokaryotic selectivity. These results indicate that the proper hydrophobicity of the peptides is crucial to exert the amalgamated property of LPS-neutralizing activity and prokaryotic selectivity. Furthermore, to increase LPS-neutralizing activity of the analog a4 without a remarkable decrease in prokaryotic selectivity, we synthesized Trp substituted analogs (a4-W1 and a4-W2), in which Phe(5) or Phe(15) of a4 is replaced by Trp. Despite their same prokaryotic selectivity, a4-W2 displayed much higher LPS-neutralizing activity compared to a4-W1. When compared with parental LL-37, a4-W2 showed retained LPS-neutralizing activity and 2.8-fold enhanced prokaryotic selectivity. These results suggest that the effective site for Trp substitution when designing novel AMPs with higher LPS-neutralizing activity, without a remarkable reduction in prokaryotic selectivity, is the amphipathic interface between the end of the hydrophilic side and the start of the hydrophobic side rather than the central position of the hydrophobic side in their alpha-helical wheel projection. Taken together, the analog a4-W2 can serve as a promising template for the development of therapeutic agents for the treatment of endotoxic shock and bacterial infection. PMID- 22521197 TI - The antimicrobial peptide, epinecidin-1, mediates secretion of cytokines in the immune response to bacterial infection in mice. AB - Epinecidin-1, an antimicrobial peptide which encodes 21 amino acids, was isolated from a marine grouper (Epinephelus coioides). In this study, we investigated its immunomodulatory functions in mice co-injected with Pseudomonas aeruginosa. In vivo results showed that the synthetic epinecidin-1 peptide induced significant secretion of immunoglobulin G1 (IgG1) in mice co-injected with P. aeruginosa. Moreover, after injection of 40, 100, 200, or 500 MUg epinecidin-1/mouse, we detected IgM, IgG, IgG1, and IgG2a in mice treated for 1, 2, 3, 7, 14, 21, and 28 days. Results showed that there were no significant differences in IgM, IgG, or IgG2a between mice injected with epinecidin-1 alone. IgG1 increased to a peak at 24 h, 7 days, and 28 days after an epinecidin-1 (40 MUg/mouse) injection. Injection of 500 MUg epinecidin-1/mouse increased IgG1 to peaks at 2 and 3 days; injection of 100 MUg epinecidin-1/mouse increased IgG1 to a peak at 21 days. This supports epinecidin-1 being able to activate the Th2 cell response (enhance IgG1 production) against P. aeruginosa infection. Treatment with different concentrations of epinecidin-1 in mice elevated plasma interleukin (IL)-10 to initial peaks at 24 and 48 h, and it showed a second peak at 16 days. In RAW264.7 cells, treatment with epinecidin-1 alone did not produce significant changes in tumor necrosis factor (TNF)-alpha protein secretion at 1, 6, or 24h after treatment with 3.75, 7.5, or 15 MUg/ml epinecidin-1 compared to the lipopolysaccharide group. PMID- 22521198 TI - Role of intestinal permeability and inflammation in the biological and behavioral control of alcohol-dependent subjects. AB - BACKGROUND AND AIMS: Mood and cognition alterations play a role in the motivation for alcohol-drinking. Lipopolysaccharides are known to stimulate inflammation that was shown to induce mood and cognitive changes in rodents and humans. Enhanced intestinal permeability and elevated blood LPS characterize alcohol dependent mice. However, no data have been published in non-cirrhotic humans. Our first goal was to test whether intestinal permeability, blood LPS and cytokines are increased in non-cirrhotic alcohol-dependent subjects before withdrawal and if they recover after withdrawal. Our second goal was to test correlations between these biochemical and the behavioral variables to explore the possibility of a role for a gut-brain interaction in the development of alcohol-dependence. METHODS: Forty alcohol-dependent-subjects hospitalized for a 3-week detoxification program were tested at onset (T1) and end (T2) of withdrawal and compared for biological and behavioral markers with 16 healthy subjects. Participants were assessed for gut permeability, systemic inflammation (LPS, TNFalpha, IL-6, IL-10, hsCRP) and for depression, anxiety, alcohol-craving and selective attention. RESULTS: Intestinal permeability and LPS were largely increased in alcohol-dependent subjects at T1 but recovered completely at T2. A low-grade inflammation was observed at T1 that partially decreased during withdrawal. At T1, pro-inflammatory cytokines were positively correlated with craving. At T2 however, the anti-inflammatory cytokine IL-10 was negatively correlated with depression, anxiety and craving. CONCLUSION: Leaky gut and inflammation were observed in non-cirrhotic alcohol-dependent subjects and inflammation was correlated to depression and alcohol-craving. This suggests that the gut-brain axis may play a role in the pathogenesis of alcohol-dependence. PMID- 22521199 TI - Comparison of neonatal and maternal outcomes associated with head-pushing and head-pulling methods for impacted fetal head extraction during cesarean delivery. AB - OBJECTIVE: To compare the morbidity and mortality of 2 current techniques during cesarean delivery of an impacted fetal head. METHODS: In a comparative setting, 59 pregnant women with obstructed labor due to impacted fetal head were recruited. The patients were categorized into 2 groups according to method of extraction: the "push" group (n=30) and the "pull" group (n=29). Uterus relaxants were used before cesarean in all cases and the incision was higher and wider than routine. Maternal and neonatal morbidities were compared between the groups. RESULTS: Maternal complications in the push and pull groups were extension of the uterine incision (15 [50.0%] vs 5 [17.2%]); T or J incision (3 [10.0%] vs 4 [13.8%]); blood transfusion (3 [10.0%] vs 1 [3.4%]); wound infection (4 [13.3%] vs 1 [3.4%]); fever (16 [53.3%] vs 3 [10.3%]); and urinary tract infection (10 [33.3%] vs 0 [0.0%]). Incidences of extension of the uterine incision, fever, and urinary tract infection were significantly higher in the push group (P=0.008). CONCLUSION: Owing to a lower rate of abnormal incision and postpartum fever/infection with the pull method, this technique is preferable to the push method. PMID- 22521200 TI - Pruritic papular eruption and eosinophilic folliculitis associated with human immunodeficiency virus (HIV) infection: a histopathological and immunohistochemical comparative study. AB - BACKGROUND: Among the papular-pruriginous dermatoses related to human immunodeficiency (HIV) infection, two entities remain poorly differentiated leading to confusion in their diagnosis: HIV-related pruritic papular eruption (HIV-PPE or prurigo) and eosinophilic folliculitis (HIV-EF). OBJECTIVE: To establish histopathological and immunohistochemical parameters to differentiate between two conditions associated with HIV infection, the pruritic papular eruption (HIV-PPE) and eosinophilic folliculitis (HIV-EF). METHODS: Clinically typical HIV-PPE (18 cases) and HIV-EF (10 cases) cases were compared with each other in terms of the following topics: clinical and laboratory features (gender, age, CD4+ cell and eosinophil count), histopathological features (hematoxylin eosin and toluidine blue staining) and immunohistochemical features (anti-CD1a, anti-CD4, anti-CD7, anti-CD8, anti-CD15, anti-CD20, anti-CD30, anti CD68/macrophage and anti-S-100 reactions). RESULTS: Among the HIV-EF patients, we found an intense perivascular and diffuse inflammatory infiltration compared with those patients with HIV-PPE. The tissue mast cell count by toluidine staining was higher in the HIV-EF patients, who also presented higher expression levels of CD15 (for eosinophils), CD4 (T helper), and CD7 (pan-T lymphocytes) than the HIV PPE patients. LIMITATIONS: Only quantitative differences and not qualitative differences were found. CONCLUSIONS: These data indicate that HIV-related PPE and EF could possibly be differentiated by histopathological and immunohistochemical findings in addition to clinical characteristics. In fact, these two inflammatory manifestations could be within the spectrum of the same disease because only quantitative, and not qualitative, differences were found. PMID- 22521201 TI - Do automated text messages increase adherence to acne therapy? Results of a randomized, controlled trial. AB - BACKGROUND: Acne is a common skin condition often requiring complex therapeutic regimens. Patient nonadherence to prescribed medication regimens is a factor in treatment failure. OBJECTIVE: The goal of this study was to determine if daily automated text messages would result in increased adherence to recommended use of topical acne medication and consequently greater improvement in acne. METHODS: Forty patients with mild to moderate acne were prescribed clindamycin/benzoyl peroxide 1%/5% gel in the mornings and adapalene 0.3% gel in the evenings for 12 weeks. Each medication tube was fitted with an electronic Medication Event Monitoring System cap (MEMS, Aardex Group, Sion, Switzerland) (to record the date and time of every opening/closing of the tube). Twenty patients were randomly assigned to receive customized twice-daily text messages instructing them to apply their morning and evening medication. The remainder of patients (N = 20), who did not receive text messages, served as control subjects. RESULTS: Mean adherence rates for the correct application of both medications on a daily basis over 12 weeks was 33.9% for patients in the reminder group and 36.5% for patients in the control group (P = .75). Patients in both groups had similar clinical improvement of their acne. LIMITATIONS: The small sample size may limit the ability to detect differences between the study groups. CONCLUSIONS: Electronic reminders in the form of daily, customized text messages were not associated with significant differences in adherence to topical medications in patients with mild to moderate acne and had no significant effect on therapeutic response. PMID- 22521202 TI - Keratoacanthoma: clinical and histopathologic features of regression. AB - BACKGROUND: The clinical and histopathologic features of regressing keratoacanthomas have not been adequately described in the literature. OBJECTIVE: "True" keratoacanthomas (ie, squamous tumors with evidence of spontaneous resolution) were studied clinically and histopathologically. METHODS: Nineteen crateriform tumors with a partial biopsy histopathologically compatible with keratoacanthoma were followed over time for correlation with biologic behavior (ie, regression). Tumors displaying spontaneous resolution, arbitrarily defined as a decrease in size of at least 25%, were categorized as keratoacanthomas. RESULTS: Seven regressing keratoacanthomas tended to show flattening before a decrease in diameter. Histopathologically, there was variable epidermal hyperplasia with generally prominent hyperkeratosis, retained crateriform architecture, and dermal fibrosis. LIMITATIONS: This study has a small sample size. CONCLUSIONS: Regressing keratoacanthomas show persistent crateriform architecture, clinically and histopathologically. Lesions become flatter before decreasing in diameter, and keratinocytes appear banal and lack glassy pink cytoplasm during regression. PMID- 22521203 TI - D2-40 immunohistochemical overexpression in cutaneous squamous cell carcinomas: a marker of metastatic risk. AB - BACKGROUND: Approximately 4% of cutaneous squamous cell carcinomas (cSCCs) develop lymphatic metastases. The value of lymphatic endothelial markers to enhance the detection of lymphatic tumor invasion in cSCC has not been assessed previously. OBJECTIVE: We sought to evaluate the use of the antibody D2-40, a podoplanin immunohistochemical marker, to identify tumor lymph vessel invasion in cSCC and to assess its expression in tumor cells. METHODS: This was a retrospective case-control study. A series of 101 cSCC, including 51 cases that developed lymphatic metastatic spread (metastasizing cSCC [MSCC]) and 50 cases that resolved definitely after surgical excision (non-MSCC) were included in the study. Lymph vessel invasion using D2-40 was evaluated on all primary biopsy specimens. The percentage of tumor cells showing D2-40 positivity and intensity scoring were recorded. All the immunohistochemical findings were correlated with the clinicopathological features. RESULTS: Lymph vessel invasion was observed in 8% of non-MSCCs and in 25.5% of MSCCs (P = .031). D2-40 expression was significantly increased, both in intensity (odds ratio 4.42 for intensity ++/+++) and in area (odds ratio 2.29 for area >10%), in MSCC when compared with non-MSCC. Interestingly, almost half (49%) of the MSCC had moderate to intense D2-40 positivity compared with 16% of non-MSCC. D2-40 immunohistochemical expression was increased in tumors with an infiltrative pattern of extension. In the multivariate analysis, histologically poorly differentiated tumors, recurrent lesions, and cSCC showing D2-40 overexpression (in intensity) were significantly associated with lymphatic metastases development (odds ratios 15.67, 14.72, and 6.07, respectively). LIMITATIONS: This was a retrospective study. CONCLUSION: The expression of podoplanin associates with high metastatic risk in cSCC. PMID- 22521204 TI - Histologically challenging melanocytic tumors referred to a tertiary care pigmented lesion clinic. AB - BACKGROUND: The histopathologic diagnosis of some melanocytic tumors is extraordinarily difficult. With this in mind, melanocytic tumors from patients referred to the Massachusetts General Hospital (MGH) Pigmented Lesion Clinic (PLC) are routinely reviewed in the MGH Dermatopathology Unit. OBJECTIVE: We sought to determine the frequency of diagnostically challenging cases from patients treated at the MGH PLC, as measured by a change in the diagnosis upon review of the referral materials. METHODS: We retrospectively reviewed the MGH and referral pathology reports for 478 consecutive cutaneous melanocytic tumors: 126 from 1996-1997 and 352 from 2010-2011. Differences in diagnosis and in therapeutic impact were evaluated. RESULTS: Changes in diagnosis occurred in 168 of 478 cases (35%), more frequently when the original diagnostician was a general pathologist (P = .003). A similar fraction of diagnoses were changed from malignant to benign or vice versa, in both historic and contemporary cohorts. In 64 patients (13%), changes in diagnosis led to a change in therapy. Changes in stage or grading led to the most changes in therapy (78%; 50/64) versus changes from benign to malignant or vice versa (22%; 14/64). LIMITATIONS: This is a retrospective study with the bias of a tertiary-care referral center. CONCLUSIONS: These findings demonstrate the diagnostic difficulty of a subset of melanocytic tumors and highlight the utility of review by more than one pathologist; patient treatment is affected in more than 10% of cases. Identification of melanoma prognostic factors and melanocytic nevus grading led to clinically significant changes in diagnosis leading to a change in patient management. PMID- 22521205 TI - Characterization of 1152 lesions excised over 10 years using total-body photography and digital dermatoscopy in the surveillance of patients at high risk for melanoma. AB - BACKGROUND: The combined use of total-body photography and digital dermatoscopy, named "two-step method of digital follow-up," allowed the detection of incipient melanoma as a result of dermatoscopic or macroscopic changes during follow-up. OBJECTIVE: We sought to assess dermatoscopic features and dynamic changes leading to excision of melanocytic lesions during our 10-year experience of monitoring patients at high risk for melanoma. METHODS: We analyzed 1152 lesions excised during the surveillance of 618 patients at high risk for melanoma from 1999 to 2008. RESULTS: A total of 779 excised lesions had been previously recorded: 728 were removed because of dermatoscopic changes during follow-up and 51 were removed even though no significant change was noted. The remaining 373 excised lesions were new or undetected on previous total-body photography. A total of 98 melanomas were detected, 60 in the monitored lesions, and 38 among the "new" lesions. The most frequent dermatoscopic changes detected were asymmetric enlargement in almost 60% (n = 418), focal changes in structure in 197 (27%) and in pigmentation in 122 (17%), the latter two being more frequently seen in melanomas than in nevi (both P < .001). No significant differences were detected between dermatoscopic or histopathological characteristics of the melanomas in each group, with a considerable proportion of melanomas misclassified as benign in both groups (26.3% and 38.3%, respectively). LIMITATIONS: The dermatoscopy pattern of stable lesions and the histopathology of lesions not removed were not included in the study. CONCLUSION: The most frequent dermatoscopic features associated with melanoma were focal change in pigmentation or structure. Melanomas detected by dermatoscopic changes were remarkably similar to those detected in total-body photography. Almost 40% of melanomas diagnosed in individuals at high risk corresponded to lesions that were not under dermatoscopic surveillance. PMID- 22521206 TI - Synthesis of some 2-alkoxy glyco-[2,1-d]-2-oxazolines and evaluation of their glycosylation reactivity. AB - The synthesis of the title compounds using intramolecular nucleophilic substitution reactions in the molecules of the corresponding 2 alkoxycarbonylamino-2-deoxy glucosyl halides was studied. It was found that in contrast to the 2-alkyl (aryl) glyco-[2,1-d]-2-oxazolines, the synthesis of the target 2-alkoxy glyco-[2,1-d]-2-oxazolines was possible only in highly basic media. The synthesized 2-alkoxy oxazoline derivatives turned out to be active glycosyl donors and were used for stereoselective 1,2-trans glycosylation reactions catalyzed by weak protic acid under very mild conditions, thus preventing anomerization and other side reactions. As a result of this glycosylation, the glycoside and oligosaccharide derivatives containing urethane N-protecting groups were formed. PMID- 22521207 TI - A literature review of the disruptive effects of user fee exemption policies on health systems. AB - BACKGROUND: Several low- and middle-income countries have exempted patients from user fees in certain categories of population or of services. These exemptions are very effective in lifting part of the financial barrier to access to services, but they have been organized within unstable health systems where there are sometimes numerous dysfunctions. The objective of this article is to bring to light the disruptions triggered by exemption policies in health systems of low- and middle-income countries. METHODS: Scoping review of 23 scientific articles. The data were synthesized according to the six essential functions of health systems. RESULTS: The disruptions included specifically: 1) immediate and significant increases in service utilization; 2) perceived heavier workloads for health workers, feelings of being exploited and overworked, and decline in morale; 3) lack of information about free services provided and their reimbursement; 4) unavailability of drugs and delays in the distribution of consumables; 5) unpredictable and insufficient funding, revenue losses for health centres, reimbursement delays; 6) the multiplicity of actors and the difficulty of identifying who is responsible ('no blame' game), and deficiencies in planning and communication. CONCLUSIONS: These disruptive elements give us an idea of what is to be expected if exemption policies do not put in place all the required conditions in terms of preparation, planning and complementary measures. There is a lack of knowledge on the effects of exemptions on all the functions of health systems because so few studies have been carried out from this perspective. PMID- 22521209 TI - The role of parasites and pathogens in influencing generalised anxiety and predation-related fear in the mammalian central nervous system. AB - Behavioural and neurophysiological traits and responses associated with anxiety and predation-related fear have been well documented in rodent models. Certain parasites and pathogens which rely on predation for transmission appear able to manipulate these, often innate, traits to increase the likelihood of their life cycle being completed. This can occur through a range of mechanisms, such as alteration of hormonal and neurotransmitter communication and/or direct interference with the neurons and brain regions that mediate behavioural expression. Whilst some post-infection behavioural changes may reflect 'general sickness' or a pathological by-product of infection, others may have a specific adaptive advantage to the parasite and be indicative of active manipulation of host behaviour. Here we review the key mechanisms by which anxiety and predation related fears are controlled in mammals, before exploring evidence for how some infectious agents may manipulate these mechanisms. The protozoan Toxoplasma gondii, the causative agent of toxoplasmosis, is focused on as a prime example. Selective pressures appear to have allowed this parasite to evolve strategies to alter the behaviour in its natural intermediate rodent host. Latent infection has also been associated with a range of altered behavioural profiles, from subtle to severe, in other secondary host species including humans. In addition to enhancing our knowledge of the evolution of parasite manipulation in general, to further our understanding of how and when these potential changes to human host behaviour occur, and how we may prevent or manage them, it is imperative to elucidate the associated mechanisms involved. PMID- 22521208 TI - Cortical asymmetries in speech perception: what's wrong, what's right and what's left? AB - Over the past 30 years hemispheric asymmetries in speech perception have been construed within a domain-general framework, according to which preferential processing of speech is due to left-lateralized, non-linguistic acoustic sensitivities. A prominent version of this argument holds that the left temporal lobe selectively processes rapid/temporal information in sound. Acoustically, this is a poor characterization of speech and there has been little empirical support for a left-hemisphere selectivity for these cues. In sharp contrast, the right temporal lobe is demonstrably sensitive to specific acoustic properties. We suggest that acoustic accounts of speech sensitivities need to be informed by the nature of the speech signal and that a simple domain-general vs. domain-specific dichotomy may be incorrect. PMID- 22521210 TI - Effects of estradiol in adult neurogenesis and brain repair in zebrafish. AB - The brain of the adult teleost fish exhibits intense neurogenic activity and an outstanding capability for brain repair. Remarkably, the brain estrogen synthesizing enzyme, aromatase B, is strongly expressed, particularly in adult fishes, in radial glial cells, which act as progenitors. Using zebrafish, we tested the hypothesis that estrogens affect adult neurogenesis and brain regeneration by modulating the neurogenic activity of radial glial cells. To investigate this, the estrogenic environment was modified through inhibition of aromatase activity, blockade of nuclear estrogen receptors, or estrogenic treatments. Estrogens significantly decreased cell proliferation and migration at the olfactory bulbs/telencephalon junction and in the mediobasal hypothalamus. It also appears that cell survival is reduced at the olfactory bulbs/telencephalon junction. We also developed a model of telencephalic lesion to assess the role of aromatase and estrogens in brain repair. Proliferation increased rapidly immediately after the lesion in the parenchyma of the injured telencephalon, while proliferation at the ventricular surface appeared after 48 h and peaked at 7 days. At this time, most proliferative cells express Sox2, however, none of these Sox2 positive cells correspond to aromatase B-positive radial glial cells. Interestingly, aromatase B expression was significantly reduced 48 h and 7 days after the injury, but surprisingly, at 72 h after lesion, aromatase B expression appeared de novo expressed in parenchyma cells, suggesting a role for this ectopic expression of aromatase in brain repair mechanisms. Altogether these data suggest that estrogens modulate adult, but not reparative neurogenesis, in zebrafish. PMID- 22521211 TI - Ischemia-induced hyperglycemia: consequences, neuroendocrine regulation, and a role for RAGE. AB - Many patients that present with cerebral ischemia exhibit moderate to severe hyperglycemia. Although many hyperglycemic patients suffer from diagnosed or previously undiagnosed diabetes a further subset of individuals is hyperglycemic without diabetes. Hyperglycemia during cerebral ischemia is associated with high levels of mortality and morbidity and limits the effective treatment interventions available. Controlling hyperglycemia with insulin treatment in critical care situations improves overall outcomes, although it is not without risk. Therefore it is critically important to understand the basic mechanisms that underlie both the induction of hyperglycemia and the consequences of it for ischemic outcomes. In this manuscript, the neuroendocrine mediators, and mechanisms of hyperglycemia exacerbated inflammation, glucose dysregulation and ischemic outcomes are discussed. The possibility that the advanced glycation end product (AGE) and receptor for AGE (RAGE) axis mediates the deleterious effects of hyperglycemia on inflammation and neuronal damage is discussed. PMID- 22521212 TI - Ultrasound-assisted extraction of three bufadienolides from Chinese medicine ChanSu. AB - In this study, the application of ultrasound-assisted extraction (UAE) method was shown to be more efficient in extracting anti-tumor bufadienolides (bufalin, cinobufagin and resibufogenin) from important animal medicine of ChanSu than the maceration extraction (ME) and soxhlet extraction (SE) method. The effects of ultrasonic variables including extraction solvent, solvent concentration, solvent to solid ratio, ultrasound power, temperature, extraction time and particle size on the yields of three bufadienolides were investigated. The optimum extraction conditions found were: 70% (v/v) methanol solution, solvent to solid ratio of 10ml/g, ultrasound power of 125W, temperature of 20 degrees C, extraction time of 20min and particle size of 60-80 mesh. The extraction yields of bufalin, cinobufagin and resibufogenin were 43.17+/-0.85, 52.58+/-1.12, 137.70+/-2.65mg/g, respectively. In order to achieve a similar yield as UAE, soxhlet extraction required 6h and maceration extraction required much longer time of 18h. The results indicated that UAE is an alternative method for extracting bufadienolides from ChanSu. PMID- 22521213 TI - LC-MS/MS method for the quantitation of metabolites of eight commonly-used synthetic cannabinoids in human urine--an Australian perspective. AB - An LC-MS/MS method for the quantitation of urinary metabolites of eight JWH-type synthetic cannabinoids (SCs) has been developed and validated. Urine samples are subjected to deconjugation using beta-glucuronidase, followed by a solvent extraction procedure. Compounds are separated on a reverse-phase HPLC column within a 14 min cycle. Low assay limits are required in order to demonstrate prior exposure to SCs. Matrix effects were studied and proved to be significant for selected analytes, and were challenging to circumvent as isotope-labeled internal standards are not available. An elimination profile from a naive user following a single smoke of "Kronic" was constructed, showing urinary excretion over 2-3 days with peak concentrations of different metabolites 3-16.5 h after smoking. This method has been developed to process several hundred samples within a high-throughput drugs of abuse laboratory, with growing evidence that the use of synthetic cannabinoid blends is common within the Australian workforce. PMID- 22521214 TI - Aspirin insensitive thromboxane generation is associated with oxidative stress in type 2 diabetes mellitus. AB - INTRODUCTION: Aspirin (ASA) irreversibly inhibits platelet cyclooxygenase-1 (COX 1) leading to decreased thromboxane-mediated platelet activation. The effect of ASA ingestion on platelet activation, thromboxane generation, oxidative stress and anti-oxidant biomarkers was studied in type 2 diabetes mellitus (DM). MATERIAL AND METHODS: Baseline and post-ASA samples (100/325 mg x 7 days) were obtained from 75 DM patients and 86 healthy controls for urinary 11-dehydro thromboxane B2 (11 dhTxB2), 8-iso-prostaglandin-F2alpha (8-isoPGF2alpha) and serum sP-Selectin, nitrite (NO(2)(-)), nitrate (NO(3)(-)) and paraoxonase 1 (PON1) activity. RESULTS: Compared to baseline controls, baseline DM had higher mean levels of 11 dhTxB2 (3,665 +/- 2,465 vs 2,450 +/- 1,572 pg/mg creatinine, p=0.002), 8-isoPGF2alpha (1,457 +/- 543 vs 1,009 +/- 412 pg/mg creatinine, p<0.0001), NO(2)(-) (11.8 +/- 7.3 vs 4.8 +/- 5.3 MUM, p<0.0001), NO(3)(-) (50.4 +/- 39.3 vs 20.9 +/- 16.7 MUM, p<0.0001) and sP-Selectin (120.8 +/- 56.7 vs 93.0 +/- 26.1 ng/mL, p=0.02), and the same held for post-ASA levels (p<0.0001). ASA demonstrated no effect on 8-isoPGF2alpha, NO(2)(-), NO(3)(-), sP-Selectin or PON1 activity in either DM or controls. Post ASA inhibition of urinary 11 dhTxB2 was 71.5% in DM and 75.1% in controls. There were twice as many ASA poor responders in DM than in controls (14.8% and 8.4%) based on systemic thromboxane reduction. Urinary 8-isoPGF2alpha excretion was greater in DM ASA poor responders than good responders (p<0.009). CONCLUSIONS: This suggests that oxidative stress may maintain platelet function irrespective of COX-1 pathway inhibition and/or increase systemic generation of thromboxane from non-platelet sources. PMID- 22521215 TI - Emergence of classical ctxB genotype 1 and tetracycline resistant strains of Vibrio cholerae O1 El Tor in Assam, India. AB - Cholera epidemics with moderately high case fatality rates in Assam, northeast India were investigated in 2007, 2008 and 2010. Based on mismatch amplification mutation assay PCR for detection of ctxB allele, 40 isolates of Vibrio cholerae O1 El Tor collected from the epidemics were found to harbour the classical ctxB gene allele of cholera toxin (CT). DNA sequencing of ctxB gene confirmed the isolates to be genotype 1 of ctxB. Antimicrobial susceptibility tests reveal that 100% of the isolates were resistant to trimethoprim and 40% were resistant to tetracycline. The recent V. cholerae O1 strains circulating in Assam, India are due to the El Tor variant carrying classical type CT. Emergence of tetracycline and trimethoprim resistant strains necessitates the review of antibiotic use for severe cholera. PMID- 22521216 TI - Incidence of tuberculosis and early mortality in a large cohort of HIV infected patients receiving antiretroviral therapy in a tertiary hospital in Addis Ababa, Ethiopia. AB - Preceding studies on morbidities and mortalities associated with TB in a cohort of HIV care indicate high incidence of TB development and premature death among patients on highly active antiretroviral treatment (HAART). This study aims to measure the rate of TB, TB mortality, and associated risk factors following commencement of HAART in a cohort of patients attending HIV care in Ethiopia. Patient information was gathered from the hospital register and analysed. TB incidence peaked within six months of HAART initiation, and dropped from 3.3/100 person-years in the first year to 0.4/100 person-years in the fifth year. At baseline, risk factors associated with TB included WHO clinical stage 3 HIV infection (adjusted hazard ratio (AHR) 2.53; 95% CI 1.70-3.70), WHO clinical stage 4 HIV infection (AHR, 3.86; 95% CI 2.54-5.86), and patients who were bed ridden >50% a day (AHR, 1.52; 95% CI 1.13-2.05). The rate of mortality was 6.9% (incidence 2.8 per 100 person-years) and 57% of deaths occurred in the first six months of HAART initiation. Multivariate Cox model indicated WHO clinical stage 4 HIV infection, CD4+ cell count <50 cells/MUl, bed ridden >50% a day, and TB after HAART initiation as baseline independent predictors of mortality. Additional evidence shows that regular CD4+monitoring of patients before HAART initiation as well as earlier HAART initiation decreases death, and regular clinical staging decreases TB incidence. PMID- 22521217 TI - Yellow fever virus susceptibility of two mosquito vectors from Kenya, East Africa. AB - Yellow fever is an unpredictable disease of increasing epidemic threat in East Africa. Aedes (Stegomyia) aegypti has never been implicated as a vector in this region and recent outbreaks have involved a newly emerging virus genotype (East African). To better understand the increasing epidemic risk of yellow fever in East Africa, this study is the first to investigate the vector competence for an emerging East African virus genotype in Kenyan A. aegypti sensu latu (s.l) and A. (Stegomyia) simpsoni s.l. mosquito species. Using first filial generation mosquitoes and a low passage yellow fever virus, this study demonstrated that although A. aegypti s.l. is a competent vector, A. simpsoni s.l. is likely a more efficient vector. PMID- 22521218 TI - Propensity of Selaginella delicatula aqueous extract to offset rotenone-induced oxidative dysfunctions and neurotoxicity in Drosophila melanogaster: Implications for Parkinson's disease. AB - The primary objective of this investigation was to examine the neuroprotective efficacy of an aqueous extract of Selaginella delicatula (a pteridophyte) employing a rotenone (ROT) Drosophila model in vivo. Aqueous extract of S. delicatula (SDAE) exhibited multiple antioxidant activity in selected chemical systems. Initially, we examined the ability of SDAE-enriched diet to modulate the levels of endogenous oxidative markers and antioxidant defenses in Drosophila melanogaster. Further, employing a co-exposure paradigm, we investigated the propensity of SDAE to protect flies against ROT-induced lethality, locomotor dysfunction, oxidative stress, mitochondrial dysfunctions and neurotoxicity. Adult flies were fed SDAE-enriched diet (0.05, 0.1 and 0.2%) with or without ROT (500 MUM) for seven consecutive days. SDAE offered concentration-dependent protection against ROT-induced lethality (30-95% protection), while the survivor flies performed better in the negative geotaxis assay suggesting attenuation of ROT-induced locomotor deficits. Biochemical analysis revealed that SDAE completely restored ROT-induced elevation in the levels of ROS, protein carbonyls and hydroperoxides in both head and body regions of flies. Elevations in the activities of antioxidant enzymes (superoxide dismutase, glutathione reductase) and glutathione-S-transferase caused by ROT were also restored to normal levels by SDAE. Further, SDAE improved the activity levels of membrane bound enzymes viz., NADH-cytochrome c reductase and succinate dehydrogenase suggesting its propensity to protect mitochondrial integrity. Interestingly, SDAE normalized the activity levels of acetylcholinesterase and ROT-induced dopamine depletion. Collectively, these findings suggest the neuromodulatory potential of SDAE and our further studies are directed toward characterization of the nature of biomolecule/s and their mechanism of action employing relevant cell models. PMID- 22521219 TI - Pesticide exposure and amyotrophic lateral sclerosis. AB - Our objectives were to summarize literature on the association of amyotrophic lateral sclerosis (ALS) with pesticides as a group and to evaluate associations of ALS with specific pesticides. We conducted a meta-analysis of published studies of ALS and pesticides as a group and investigated the association of ALS with specific pesticides, using data from the Agricultural Health Study (AHS), a cohort including 84,739 private pesticide applicators and spouses. AHS participants provided information on pesticide use at enrollment in 1993-1997. In mortality data collected through February 2010, ALS was recorded on death certificates of 41 individuals whom we compared to the remaining cohort (controls), using unconditional logistic regression adjusted for age and gender to calculate odds ratios (ORs) and 95% confidence intervals. In the meta analysis, ALS was associated with use of pesticides as a group (1.9, 1.1-3.1). In the AHS, ALS was not associated with pesticides as a group, but was associated with use of organochlorine insecticides (OCs) (1.6, 0.8-3.5), pyrethroids (1.4, 0.6-3.4), herbicides (1.6, 0.7-3.7), and fumigants (1.8, 0.8-3.9). ORs were elevated forever use of the specific OCs aldrin (2.1, 0.8-5.1), dieldrin (2.6, 0.9-7.3), DDT (2.1, 0.9-5.0), and toxaphene (2.0, 0.8-4.9). None of these associations was statistically significant. Similar results were observed in an analysis restricted to men. In conclusion, the meta-analysis suggests that ALS risk is associated with use of pesticides as a group, and our analysis of AHS data points to OC use in particular. The latter results are novel but based on a small number of cases and require replication in other populations. PMID- 22521220 TI - Hydrophilic polymers enhance early functional outcomes after nerve autografting. AB - BACKGROUND: Approximately 12% of operations for traumatic neuropathy are for patients with segmental nerve loss, and less than 50% of these injuries obtain meaningful functional recovery. Polyethylene glycol (PEG) therapy has been shown to improve functional outcomes after nerve severance, and we hypothesized this therapy could also benefit nerve autografting. METHODS: We used a segmental rat sciatic nerve injury model in which we repaired a 0.5-cm defect with an autograft using microsurgery. We treated experimental animals with solutions containing methylene blue (MB) and PEG; control animals did not receive PEG. We recorded compound action potentials (CAPs) before nerve transection, after solution therapy, and at 72 h postoperatively. The animals underwent behavioral testing at 24 and 72 h postoperatively. After we euthanized the animals, we fixed the nerves, sectioned and immunostained them to allow for quantitative morphometric analysis. RESULTS: The introduction of hydrophilic polymers greatly improved morphological and functional recovery of rat sciatic axons at 1-3 d after nerve autografting. Polyethylene glycol therapy restored CAPs in all animals, and CAPs were still present 72 h postoperatively. No CAPS were detectable in control animals. Foot Fault asymmetry scores and sciatic functional index scores were significantly improved for PEG therapy group at all time points (P < 0.05 and P < 0.001; P < 0.001 and P < 0.01). Sensory and motor axon counts were increased distally in nerves treated with PEG compared with control (P = 0.019 and P = 0.003). CONCLUSIONS: Polyethylene glycol therapy improves early physiologic function, behavioral outcomes, and distal axonal density after nerve autografting. PMID- 22521221 TI - Hypothyroidism improves random-pattern skin flap survival in rats. AB - BACKGROUND: The protective effect of hypothyroidism against ischemic or toxic conditions has been shown in various tissues. We investigated the effect of propylthiouracil (PTU)/methimazole (MMI)-induced hypothyroidism and acute local effect of MMI on the outcome of lethal ischemia in random-pattern skin flaps. MATERIALS AND METHODS: Dorsal flaps with caudal pedicles were elevated at midline and flap survival was measured at the seventh day after surgery. The first group, as control, received 1 mL of 0.9% saline solution in the flap before flap elevation. In groups 2 and 3, hypothyroidism was induced by administration of either PTU 0.05% or MMI 0.04% in drinking water. The next four groups received local injections of MMI (10, 20, 50, or 100 MUg/flap) before flap elevation. Local PTU injection was ignored due to insolubility of the agent. RESULTS: Hypothyroidism was induced in chronic PTU- and MMI-treated groups, and animals in these groups showed significant increase in their flap survival, compared to control euthyroid rats (79.47% +/- 10.49% and 75.48% +/- 12.93% versus 52.26% +/- 5.75%, respectively, P < 0.01). Acute local treatment of skin flaps with MMI failed to significantly affect the flap survival. CONCLUSION: This study demonstrates for the first time that hypothyroidism improves survival of random pattern skin flaps in rats. PMID- 22521222 TI - Reconstruction of anorectal function through end-to-side neurorrhaphy by autonomic nerves and somatic nerve in rats. AB - BACKGROUND: End-to-side nerve repair is a new tool in managing certain nerve injuries. In previous studies, it was limited to somatic nerves. Herein, we evaluate the feasibility of anorectal reinnervation after end-to-side coaptation of autonomic nerve to somatic nerve. MATERIALS AND METHODS: Forty adult male Sprague-Dawley rats were randomly divided into three groups: end-to-side coaptation group (n = 16), the left L6 and S1 spinal nerves were transected, and the distal stump of L6 ventral root (L6VR) was sutured to L4VR (L4VR) through end to-side neurorrhaphy; no coaptation group (n = 12), rats received the same operation as the end-to-side coaptation group but without coaptation; and control group (n = 12), rats received the same operation as the end-to-side coaptation group but the L6VR was preserved. At 16 wk, using double retrograde tracing and histomorphological technique and anorectal manometry, morphological and functional properties of regenerated nerve were investigated. RESULTS: Retrograde tracing indicated that the new neural pathway was established and the main nerve regeneration mechanism was axon collateral sprouting. Histology showed good axonal regeneration with end-to-side neurorrhaphy. The wet weight and morphology of left tibialis anterior muscles appeared no detrimental effect on donor nerve. Anorectal manometry showed good anorectal functional recovery. CONCLUSIONS: These results suggest that the somatic motor axon ingrowth into autonomic nerve could be through collateral sprouting after end-to-side coaptation of autonomic nerve to somatic nerve. Our innovative technique of end-to-side coaptation may be of great value in anorectal reinnervation without functional impairment of the donor somatic nerve. PMID- 22521223 TI - Ventilator-associated sinusitis in adults: systematic review and meta-analysis. AB - OBJECTIVE: To review the epidemiology, risk factors for, treatment and outcome of ventilator-associated sinusitis (VAS). METHODS: We performed a systematic review and meta-analysis of available data without time restrictions. A conservative random effects model was employed to calculate pooled odds ratios (OR) and 95% confidence intervals (CIs). RESULTS: Out of 620 retrieved reports, 31 papers fulfilled our inclusion criteria. Infectious sinusitis affects 27% of mechanically ventilated patients and was found to be the cause of undetermined fever in 25% of the cases. Although radiographic VAS was higher in nasotracheally compared to orotracheally intubated patients (OR 4.66, 95% CI 1.35-16.13), clinical VAS was not (3.67, 0.80-6.81). The presence of VAS has been associated with the presence of VAP (3.66, 1.81-7.37) or bacteremia (6.85, 2.14, 21.92); however, it is unknown whether an etiologic relationship between them exists. In patients with concomitant VAS and VAP or bloodstream infections identical pathogens are isolated in 59% and 20% of the cases, respectively. The presence as opposed to absence of VAS was not associated with excess mortality (1.02, 0.35 3.01). CONCLUSION: VAS is a common infection in critically ill adults and correlates with other important infectious complications. PMID- 22521224 TI - Downregulation of lung mitochondrial prohibitin in COPD. AB - Prohibitins (PHB1 and PHB2) are versatile proteins located at the inner mitochondrial membrane, maintaining normal mitochondrial function and morphology. They interact with the NADH dehydrogenase protein complex, which is essential for oxidoreductase activity within cells. However, their expression in lung epithelium, especially in smokers and patients with inflammatory lung diseases associated with increased oxidative stress, such as COPD, is unknown. Lung tissue specimens from 45 male subjects were studied: 20 COPD patients [age: 65.7 +/- 5.8 years, smoking: 84.6 +/- 33.6 pack-years, FEV(1) (%pred.): 58.7 +/- 14.6, FEV(1)/FVC (%): 63.8 +/- 9.4], 15 non-COPD smokers [age: 59.0 +/- 12.1 years, smoking: 52.5 +/- 20.8 pack-years, FEV(1) (%pred.): 85.5 +/- 14.2, FEV(1)/FVC (%): 78.5 +/- 4.7] and 10 non-smokers. Quantitative real-time PCR experiments were carried out for PHB1 and PHB2, using beta-actin as internal control. Non COPD smokers exhibited lower PHB1 mRNA levels when compared to non-smokers (0.55 +/- 0.06 vs. 0.90 +/- 0.06, P = 0.043), while PHB1 expression was even further decreased in COPD patients (0.32 +/- 0.02), a statistically significant finding vs. both non-COPD smokers (P = 0.040) and non-smokers (P < 0.001). By contrast, PHB2 levels were similar among the three study groups. Western blot analysis for the PHB1 protein verified the qPCR results (non-smokers: 1.77 +/- 0.13; non-COPD smokers: 0.97 +/- 0.08; COPD patients: 0.59 +/- 0.10, P = 0.007). Further analysis revealed that PHB1 downregulation in COPD patients cannot be attributed solely to smoking, and that PHB1 expression levels are associated with the degree of airway obstruction [FEV(1) (P(mRNA) = 0.004, P(protein) = 0.014)]. The significant downregulation of PHB1 in COPD and non-COPD smokers in comparison to non-smokers possibly reflects a distorted mitochondrial function due to decreased mitochondrial stability, especially in the mitochondria of COPD patients. PMID- 22521225 TI - Daily step counts in a US cohort with COPD. AB - BACKGROUND: Baseline values for daily step counts in US adults with COPD and knowledge of its accurate measurement, natural change over time, and independent relationships with measures of COPD severity are limited. METHODS: 127 persons with stable COPD wore the StepWatch Activity Monitor (SAM) for 14 days, and 102 of them wore it a median 3.9 months later. SAM counts were compared to manual counts in the clinic. We assessed change over time, the effect of season, and relationships with forced expiratory volume in 1 s (FEV(1)) % predicted, 6-min walk test (6MWT) distance, the modified Medical Research Council (MMRC) dyspnea score, and the St. George's Respiratory Questionnaire Total Score (SGRQ-TS). RESULTS: 98% of subjects were males, with mean age 71 +/- 8 years and FEV(1) 1.48 +/- 0.54 L (52 +/- 19% predicted). All 4 GOLD stages were represented, with the most subjects in GOLD II (44%) and GOLD III (37%). The SAM had >90% accuracy in 99% of subjects. Average step count was 5680 steps/day, which decreased with increasing GOLD stage (p = 0.0046). Subjects walked 645 fewer steps/day at follow up, which was partly explained by season of monitoring (p = 0.013). In a multivariate model, FEV(1) % predicted, 6MWT distance and MMRC score were weakly associated with daily step counts, while SGRQ-TS was not. CONCLUSIONS: These findings will aid the design of future studies using daily step counts in COPD. Accurately measured, daily step counts decline over time partly due to season and capture unique information about COPD status. PMID- 22521227 TI - Does injury compensation lead to worse health after whiplash? A systematic review. AB - One might expect that injury compensation would leave injured parties better off than they would otherwise have been, yet many believe that compensation does more harm than good. This study systematically reviews the evidence on this "compensation hypothesis" in relation to compensable whiplash injuries. PubMed, CINAHL, EMBASE, PEDro, PsycInfo, CCTR, Lexis, and EconLit were searched from the date of their inception to April 2010 to locate longitudinal studies, published in English, comparing the health outcomes of adults exposed/not exposed to compensation-related factors. Studies concerning serious neck injuries, using claimants only, or using proxy measures of health outcomes were excluded. Eleven studies were included. These examined the effect of lawyer involvement, litigation, claim submission, or previous claims on pain and other health outcomes. Among the 16 results reported were 9 statistically significant negative associations between compensation-related factors and health outcomes. Irrespective of the compensation-related factor involved and the health outcome measured, the quality of these studies was similar to studies that did not find a significant negative association: most took some measures to address selection bias, confounding, and measurement bias, and none resolved the potential for reverse causality bias that arises in the relationship between compensation related factors and health. Unless ambiguous causal pathways are addressed, one cannot draw conclusions from statistical associations, regardless of their statistical significance and the extent of measures to address other sources of bias. Consequently, there is no clear evidence to support the idea that compensation and its related processes lead to worse health. PMID- 22521226 TI - Obstructive sleep apnea does not promote esophageal reflux in fibrosing interstitial lung disease. AB - BACKGROUND: In patients with fibrosing interstitial lung disease (fILD), gastroesophageal reflux (GER) is highly prevalent, perhaps because of the effects of lung fibrosis on altering intrathoracic pressure, diaphragm morphology and lower esophageal sphincter (LES) function. For unclear reasons, obstructive sleep apnea (OSA) is also highly prevalent among patients with fILD. We conducted this study to test our hypothesis that, in patients with fILD, OSA would exacerbate diaphragm/LES dysfunction and increase the propensity for-and severity of - GER. METHODS: We identified patients with fILD who underwent screening polysomnogram and pH or pH/impedence probe at our center during the same week. We examined the association between OSA and GER and used logistic regression to determine independent predictors of OSA or GER. RESULTS: In 54 included subjects, neither OSA (dichotomous) nor apnea hypopnea index (continuous) predicted the presence of GER. Regardless of body position (upright, recumbent), GER was no more frequent or severe among subjects with OSA vs. those without OSA. Subjects with idiopathic pulmonary fibrosis (IPF) had an odds of GER nearly seven-fold greater than subjects with other forms of fILD (odds ratio = 6.84, 95% confidence interval 1.36-34.43, p = 0.02). For the entire cohort and the subgroup with IPF, there was no correlation between pulmonary physiology and GER. CONCLUSIONS: In fILD, OSA does not appear to promote GER. Research is needed to determine if compensatory mechanisms emanating from the crural diaphragm prevent GER in fILD patients with OSA and to sort out whether GER has a role in the pathogenesis of certain forms of fILD. PMID- 22521228 TI - A measure of pediatric pain intensity across ages and clinical conditions. PMID- 22521229 TI - Chemical evolution as a concrete scheme for naturalizing the relative-state of quantum mechanics. AB - The evolutionary onset of a reaction cycle such as an autocatalytic cycle requires a reliable framework for protecting the harbinger cycle, once it appears by any chance, against the hostile environments in the neighborhood. One natural candidate for protecting the fragile nascent cycle could be available from the operation of internal measurement envisioned in the relative-state formulation of quantum mechanics. Once every chemical reactant is taken to be relative to every other reactant in the act of measuring each other internally, the relative-state formulation provides the condition for favoring and protecting those events such that the reactions mediating between the reactants and the products may eventually form a reaction cycle. PMID- 22521230 TI - Identification of two novel synaptic gamma-secretase associated proteins that affect amyloid beta-peptide levels without altering Notch processing. AB - Synaptic degeneration is one of the earliest hallmarks of Alzheimer disease (AD) and results in loss of cognitive function. One of the causative agents for the synaptic degeneration is the amyloid beta-peptide (Abeta), which is formed from its precursor protein by two sequential cleavages mediated by beta- and gamma secretase. We have earlier shown that gamma-secretase activity is enriched in synaptic compartments, suggesting that the synaptotoxic Abeta is produced locally. Proteins that interact with gamma-secretase at the synapse and regulate the production of Abeta can therefore be potential therapeutic targets. We used a recently developed affinity purification approach to identify gamma-secretase associated proteins (GSAPs) in synaptic membranes and synaptic vesicles prepared from rat brain. Liquid chromatography-tandem mass spectrometry analysis of the affinity purified samples revealed the known gamma-secretase components presenilin-1, nicastrin and Aph-1b along with a number of novel potential GSAPs. To investigate the effect of these GSAPs on APP processing, we performed siRNA experiments to knock down the expression of the GSAPs and measured the Abeta levels. Silencing of NADH dehydrogenase [ubiquinone] iron-sulfur protein 7 (NDUFS7) resulted in a decrease in Abeta levels whereas silencing of tubulin polymerization promoting protein (TPPP) resulted in an increase in Abeta levels. Treatment with gamma-secretase inhibitors often results in Notch-related side effects and therefore we also studied the effect of the siRNAs on Notch processing. Interestingly, silencing of TPPP or NDUFS7 did not affect cleavage of Notch. We also studied the expression of TPPP and NDUFS7 in control and AD brain and found NDUFS7 to be highly expressed in vulnerable neurons such as pyramidal neurons in the hippocampus, whereas TPPP was found to accumulate in intraneuronal granules and fibrous structures in hippocampus from AD cases. In summary, we here report on two proteins, TPPP and NDUFS7, which interact with gamma-secretase and alter the Abeta levels without affecting Notch cleavage. PMID- 22521231 TI - Effect of Angeli's salt on the glutamate/glutamine cycle activity and on glutamate excitotoxicity in the hamster retina. AB - Glutamate is the main excitatory neurotransmitter in the retina, but it is toxic when present in excessive amounts. It is well known that NO is involved in glutamate excitotoxicity, but information regarding the possibility that NO related species could reciprocally affect glutamate synaptic levels was not previously provided. The dependence of glutamatergic neurons upon glia via the glutamate/glutamine cycle to provide the precursor for neurotransmitter glutamate is well established. The aim of the present work was to comparatively analyze the effect of nitroxyl and NO on the retinal glutamate/glutamine cycle in vitro activity. For this purpose, Angeli's salt (AS) and diethylamine NONOate (DEA/NO) were used as nitroxyl and NO donor, respectively. AS and DEA/NO significantly decreased retinal l-glutamate uptake and glutamine synthetase activity, but only AS decreased l-glutamine influx. Dithiothreitol prevented all the effects of AS and DEA/NO. The intravitreal injection of DEA/NO (but not AS) or a supraphysiological concentration of glutamate induced retinal histological alterations. Although AS could increase glutamate synaptic concentration in vitro, the histological alterations induced by glutamate were abrogated by AS. These results suggest that nitroxyl could regulate the hamster retinal glutamatergic pathway by acting through differential mechanisms at pre- and postsynaptic level. PMID- 22521232 TI - Decision making under ambiguity but not under risk is related to problem gambling severity. AB - The aim of the present study was to examine the relationship between problem gambling severity and decision-making situations that vary in two degrees of uncertainty (probability of outcome is known: decision-making under risk; probability of outcome is unknown: decision-making under ambiguity). For this purpose, we recruited 65 gamblers differing in problem gambling severity and 35 normal controls. Decision-making under ambiguity was assessed with the Iowa Gambling Task (IGT) and the Card Playing Task (CPT). Decision-making under risk was assessed with the Coin Flipping Task (CFT) and the Cups Task. In addition, we included an examination of two working memory components (verbal storage and dual tasking). Results show that problem gamblers performed worse than normal controls on both ambiguous and risky decision-making. Higher problem gambling severity scores were associated with poorer performance on ambiguous decision-making tasks (IGT and CPT) but not decision-making under risk. Additionally, we found that dual task performance correlated positively with decision-making under risk (CFT and Cups tasks) but not with decision-making under ambiguity (IGT and CPT). These results suggest that impairments in decision-making under uncertain conditions of problem gamblers may represent an important neurocognitive mechanism in the maintenance of their problem gambling. PMID- 22521233 TI - Predictors of antipsychotic dose changes in the CATIE schizophrenia trial. AB - Data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) was used with the objective of evaluating factors associated with antipsychotic dose changes. CATIE was a randomized, comparative effectiveness trial for patients with schizophrenia in which a clinician prescribed a double-blind, flexible dose of one of five antipsychotic medications. The mean number of capsules prescribed monthly was evaluated to identify the period following up titration with the least sample attrition in which dose changes were likely in response to clinical factors. Demographic, efficacy and tolerability variables were evaluated in two regression models predicting a one capsule dose decrease or increase. The mean dose increased to 2.7 capsules over the first 3 months. The post-titration plateau was identified as between 3 and 6 months. Factors associated with dose increases included the Clinical Global Impression Scale at 6 months and change in the Positive and Negative Syndrome Scale between 3 and 6 months. Decreased dosing was associated only with lower patient rated at 6 months global impression of health. Neither tolerability measures, nor body weight was significantly associated with dose changes. In conclusion, dose changes were weakly associated with measures of current or changing clinical status and not affected by measures of side effects. PMID- 22521234 TI - Nonlinear indices of circadian changes in individuals with dementia and aggression. AB - Nonlinear analyses of actigraphy data were utilized to investigate circadian rest activity system motor control in nursing-home residents with dementia and with/without aggressive behavior (AB). Significant differences observed between groups in measures of approximate entropy (ApEn) and fractal dimension (FD). ApEn and FD are sensitive to detecting and characterizing discrete changes in central motoric control and temporality of behaviors in dementia. Findings may inform understanding of clinical heterogeneity and possible physiologic sub classifications of Alzheimer's dementia. PMID- 22521235 TI - Smoking and chronic rhinitis: effects of nasal irrigations with sulfurous arsenical-ferruginous thermal water: A prospective, randomized, double-blind study. AB - PURPOSE: Smoking is a self-destructive behavior that is known to induce remodeling of the lower airways, leading to squamous metaplasia, but little is known about its effects on the nose and paranasal sinuses. Nasal irrigations are often mentioned as measures for treating sinonasal inflammations. The purpose of our study was to compare the effects of nasal irrigations with sulfurous arsenical-ferruginous thermal water or isotonic sodium chloride solution in smokers with nonallergic chronic rhinosinusitis, based on clinical and olfactory evidence. MATERIALS AND METHODS: The present study was a prospective, randomized, double-blind study performed in a tertiary academic referral center. Seventy smokers with nonallergic chronic rhinitis were enrolled. Nasal endoscopy, rhinomanometry, nasal cytology, and odor threshold measurements were performed in subjects randomized to daily nasal irrigations with either thermal water or isotonic sodium chloride solution for 1 month. RESULTS: Immediately after the treatment, the thermal water irrigations revealed a positive pharmacologic action, judging from a tendency toward lower nasal resistances (P = .07) and larger numbers of ciliated cells in the patients treated (P = .003). Endoscopic findings in the thermal water group were still better than in the control group a further 2 months later (P = .03). CONCLUSIONS: Our results indicate that nasal irrigations with thermal water had a good effect on endoscopic objective signs, nasal resistances, and epithelial trophism. PMID- 22521236 TI - Analysis of surgical margins in cases of mandibular osteoradionecrosis that progress despite extensive mandible resection and free tissue transfer. AB - INTRODUCTION: Approximately 1 of 4 patients with osteoradionecrosis (ORN) of the mandible develop ongoing disease despite extensive mandible resection to margins determined by the presence of bleeding bone at the time of surgery. OBJECTIVE: To determine whether pathologic examination of bony margins in assessing for the presence of necrotic edges is correlated with ongoing ORN. METHODS: Resected mandible specimens from 34 patients with severe mandibular ORN were examined histologically for the presence of necrotic margins and compared with clinical outcome of ORN persistence at follow-up. RESULTS: Median follow-up was 17.4 months. Eight specimens had histologic evidence of necrotic, nonviable bone at the margins of resections; however, there was no progression of disease among patients in this group. Twenty-six specimens were clear of necrotic margins; however, 8 patients from this group developed persistent disease. CONCLUSIONS: Irradiated mandible is susceptible to ORN progression even if clinical and final histopathologic assessments confirm complete resection of necrotic bone margins. Progression of disease in ORN is not related to inadequate resection of necrotic bone. PMID- 22521237 TI - Closed tube method for rapid screening of IL28B polymorphisms involved in response to hepatitis C treatment. AB - BACKGROUND & AIM: Hepatitis C is a liver disease caused by the hepatitis C virus. Interferon and ribavirin combination therapy has been a standard treatment of chronic hepatitis C. But only about 50% of patients have positive response to treatment and achieve so called sustained virological response. Recent studies indicate association of several single nucleotide polymorphisms near IL28B gene and response of hepatitis C patients to combined interferon/ribavirin treatment. In this study, rapid, specific and cost-effective small amplicon genotyping method for the two clinically important polymorphisms, rs12979860 C > T and rs8099917 T > G, near the IL28B gene is described. METHODS: The distribution of genotypes of 181 HCV-uninfected Slovak Caucasians was analyzed using this novel method, based on a real-time melting analysis of the small amplicon. RESULTS AND CONCLUSIONS: The frequency of wild-type (TT) homozygotes for rs8099917 was 66.30%, frequency of heterozygotes (TG) was 30.94% and we found only 2.76% subjects homozygous for risk G allele (allelic frequencies: T = 81.77%, G = 18.23%) were found. The frequency of wild-type genotype (CC) for rs12979860 was 49.72%, frequencies of heterozygous (CT) and risk-allele homozygous genotypes (TT) were 39.78% and 10.50%, respectively (allele frequencies: C = 69.61%, T = 30.39%). Statistically significant differences in the distribution of the alleles between the men and the women were not found. The novel method developed in our laboratory proved to be simple and highly customizable. PMID- 22521238 TI - Surface chemistry of porous silicon and implications for drug encapsulation and delivery applications. AB - Porous silicon (pSi) has a number of unique properties that appoint it as a potential drug delivery vehicle; high loading capacity, controllable surface chemistry and structure, and controlled release properties. The native Si(y)SiH(x) terminated pSi surface is highly reactive and prone to spontaneous oxidation. Surface modification is used to stabilize the pSi surface but also to produce surfaces with desired drug delivery behavior, typically via oxidation, hydrosilylation or thermal carbonization. A number of advanced characterization techniques have been used to analyze pSi surface chemistry, including X-ray photoelectron spectroscopy and time of flight secondary ion mass spectrometry. Surface modification not only stabilizes the pSi surface but determines its charge, wettability and dissolution properties. Manipulation of these parameters can impact drug encapsulation by altering drug-pSi interactions. pSi has shown to be a successful vehicle for the delivery of poorly soluble drugs and protein therapeutics. Surface modification influences drug pore penetration, crystallinity, loading level and dissolution rate. Surface modification of pSi shows great potential for drug delivery applications by controlling pSi-drug interactions. Controlling these interactions allows specific drug release behaviors to be engineered to aid in the delivery of previously challenging therapeutics. Within this review, different pSi modification techniques will be outlined followed by a summary of how pSi surface modification has been used to improve drug encapsulation and delivery. PMID- 22521239 TI - Acoustic emission signals can discriminate between compressive bone fractures and tensile ligament injuries in the spine during dynamic loading. AB - Acoustic emission (AE) sensors are a reliable tool in detecting fracture; however they have not been used to differentiate between compressive osseous and tensile ligamentous failures in the spine. This study evaluated the effectiveness of AE data in detecting the time of injury of ligamentum flavum (LF) and vertebral body (VB) specimens tested in tension and compression, respectively, and in differentiating between these failures. AE signals were collected while LF (n=7) and VB (n=7) specimens from human cadavers were tested in tension and compression (0.4m/s), respectively. Times of injury (time of peak AE amplitude) were compared to those using traditional methods (VB: time of peak force, LF: visual evidence in high speed video). Peak AE signal amplitudes and frequencies (using Fourier and wavelet transformations) for the LF and VB specimens were compared. In each group, six specimens failed (VB, fracture; LF, periosteal stripping or attenuation) and one did not. Time of injury using AE signals for VB and LF specimens produced average absolute differences to traditional methods of 0.7 (SD=0.2) ms and 2.4 (SD=1.5) ms (representing 14% and 20% of the average loading time), respectively. AE signals from VB fractures had higher amplitudes and frequencies than those from LF failures (average peak amplitude 87.7 (SD=6.9) dB vs. 71.8 (SD=9.8)dB for the inferior sensor, p<0.05; median characteristic frequency from the inferior sensor 97 (interquartile range, IQR, 41) kHz vs. 31 (IQR 2) kHz, p<0.05). These findings demonstrate that AE signals could be used to delineate complex failures of the spine. PMID- 22521240 TI - Mechanical interaction of center of pressure and force direction in the upright human. AB - Humans maintain upright bipedal posture by producing appropriate force against the environment through the interaction of neural controlled muscle force with the mechanics of the skeletal system. Characterizing these mechanics facilitates understanding of the neural control. We used a mechanical model of an upright human to analyze how the mechanical linkage aspects of the human body affect the force between the feet and the ground (F). Key parameters of F that directly regulate upright body posture are the direction of F (theta(F)) and its point of application (x(CP), anterior-posterior position of the center of pressure). Instantaneous analysis of the equations of motion demonstrated that theta(F) varied systematically with x(CP) such that the F vectors intersected at a point called the Posture-specific force Intersection point or PI (Pi). The Pi was located above the center of mass when the hip and knee joints were modeled as rigid and was located near the knee when the hip and knee torques were held constant. Limb posture and the knee torque affected the location of Pi. This Pi behavior quantifies the purely mechanical effect of anterior-posterior center of pressure shifts on the direction of F, which has consequences for the control of whole body posture. PMID- 22521241 TI - The role of CCR7 in allergic airway inflammation induced by house dust mite exposure. AB - House dust mite (HDM), the most common allergen, activate both the IgE-associated and innate immune responses. To clarify the process of sensitization, we investigated the role of the CCL21, CCL19, and CCR7 axis in a mouse model of HDM induced allergic asthma. HDM inhalation without systemic immunization resulted in a HDM-specific IgE response. CCR7-knockout (CCR7KO) mice exhibited greater airway inflammation and IgE responses compared to wild-type mice. We examined FoxP3 expression in these mice to clarify the contribution of regulatory cells to the responses. FoxP3 expression was higher in the lungs but not in the lymph nodes of CCR7KO mice compared to wild-type mice. In CCR7KO mice, FoxP3-positive cells were found in lung, but we observed higher release of IL-13, IL-5, TGF-beta, IL-17, and HMGB1 in bronchoalveolar lavage fluid. We demonstrate here that immuno regulation through CCR7 expression in T cells plays a role in HDM-specific sensitization in the airway. PMID- 22521242 TI - Effect of antiangiogenic therapy on tumor growth, vasculature and kinase activity in basal- and luminal-like breast cancer xenografts. AB - Several clinical trials have investigated the efficacy of bevacizumab in breast cancer, and even if growth inhibiting effects have been registered when antiangiogenic treatment is given in combination with chemotherapy no gain in overall survival has been observed. One reason for the lack of overall survival benefit might be that appropriate criteria for selection of patients likely to respond to antiangiogenic therapy in combination with chemotherapy, are not available. To determine factors of importance for antiangiogenic treatment response and/or resistance, two representative human basal- and luminal-like breast cancer xenografts were treated with bevacizumab and doxorubicin alone or in combination. In vivo growth inhibition, microvessel density (MVD) and proliferating tumor vessels (pMVD = proliferative microvessel density) were analysed, while kinase activity was determined using the PamChip Tyrosine kinase microarray system. Results showed that both doxorubicin and bevacizumab inhibited basal-like tumor growth significantly, but with a superior effect when given in combination. In contrast, doxorubicin inhibited luminal-like tumor growth most effectively, and with no additional benefit of adding antiangiogenic therapy. In agreement with the growth inhibition data, vascular characterization verified a more pronounced effect of the antiangiogenic treatment in the basal-like compared to the luminal-like tumors, demonstrating total inhibition of pMVD and a significant reduction in MVD at early time points (three days after treatment) and sustained inhibitory effects until the end of the experiment (day 18). In contrast, luminal-like tumors only showed significant effect on the vasculature at day 10 in the tumors having received both doxorubicin and bevacizumab. Kinase activity profiling in both tumor models demonstrated that the most effective treatment in vivo was accompanied with increased phosphorylation of kinase substrates of growth control and angiogenesis, like EGFR, VEGFR2 and PLCgamma1. This may be a result of regulatory feedback mechanisms contributing to treatment resistance, and may suggest response markers of value for the prediction of antiangiogenic treatment efficacy. PMID- 22521244 TI - Phenocopies in families with essential tremor and restless legs syndrome challenge Mendelian laws. Epigenetics might provide answers. AB - Essential Tremor (ET) and Restless Legs Syndrome (RLS) are both highly heritable neurological disorders. The frequent occurrence of multi-incident families suggests the existence of highly penetrant alleles. However, linkage analyses and positional cloning approaches performed within the last 10 years essentially failed to identify responsible mutations. Several loci were found, but their relevance was questioned given the occurrence of suspected phenocopies in many of those families. Remarkably, in some ET and RLS families with an apparent autosomal dominant mode of transmission, the proportion of affected individuals was higher than the expected 50% and therefore suggests a non-mendelian inheritance in some cases. In fact, there is increasing evidence that epigenetic modifications, which refer to changes in gene expression without changes in DNA sequence, can be transmitted to the next generation. Moreover, epigenetic information can be transferred from one allele of a gene to the other allele of the same gene; if then inherited to the next generation, the offspring consequently presents phenotypic properties related to the untransmitted allele. This phenomenon known as paramutation is well documented in plants and has recently been shown to occur also in mammals. Here, I explore the possibility that it is the epigenetic and not only the genetic state which confers disease risk in families. Inheritance of epigenetic mutations along with paramutational events have the potential to explain the non-mendelian features in the genetics of both diseases. PMID- 22521243 TI - ALDH+ tumor-initiating cells exhibiting gain in NOTCH1 gene copy number have enhanced regrowth sensitivity to a gamma-secretase inhibitor and irinotecan in colorectal cancer. AB - The Notch signaling pathway has been shown to be upregulated in colorectal cancer (CRC) and important for the self-renewal of cancer stem cells. In this study, we evaluated the efficacy of PF-03084014, a gamma-secretase inhibitor, in combination with irinotecan to identify the effects of treatment on tumor recurrence and the tumor-initiating population in our CRC preclinical explant model. The combination of PF-03084014 and irinotecan had the greatest effect at reducing tumor growth on four CRC tumors when compared with treatment with PF 03084014 or irinotecan alone. The combination significantly reduced tumor recurrence in two CRC explants (CRC001 and CRC036) after treatment was discontinued. Both of these tumors exhibited elevated baseline levels of Notch pathway activation as well as an increase in NOTCH1 gene copy number when compared with the two CRC explants (CRC026 and CRC027) where tumors reappeared quickly after termination of treatment. Isolation and injection of aldehyde dehydrogenase (ALDH(+) and ALDH(-)) cells in an in vivo explant model demonstrated that the ALDH(+) cell population were tumorigenic. Evaluation of the ALDH(+) cells after 28 days of treatment showed that the combination reduced the ALDH(+) population in the tumors that did not regrow. Furthermore, ALDH(+) cells from CRC001 and CRC027 were injected in vivo and treated immediately for 28 days. Two months after treatment, tumors were evident in the combination treatment group for CRC027 but not for CRC036. These results indicate the combination of PF 03084014 and irinotecan may be effective in reducing tumor recurrence in CRC patients whose tumors exhibit elevated levels of the Notch pathway. PMID- 22521245 TI - Immunolocalization of beta-catenin and Lef-1 during postnatal hair follicle development in mice. AB - It is well recognized that the Wnt pathway, in which beta-catenin and Lef-1 are important factors, is associated with many physiological processes, including embryogenesis and postnatal development. The Wnt pathway also plays a critical role in the development of skin. It regulates the formation of the dorsal dermis and epidermal appendages in the skin and the activity of epithelial stem cells. In this study, we investigated the presence and localization of beta-catenin and Lef-1 in murine hair follicles through the first postnatal month, which encompasses the first hair cycle in mice, using Western blotting and immunohistochemistry. Our results show that beta-catenin and Lef-1 are expressed during all stages in a hair cycle, most strongly in the anagen and weakly in the catagen and telogen phases. The results also suggest that the beta-catenin-Lef-1 complex may regulate hair follicle cycling. This process will be of considerable interest to future studies. PMID- 22521246 TI - The public health benefits of air pollution control. PMID- 22521247 TI - Imidazoquinoline Toll-like receptor 8 agonists activate human newborn monocytes and dendritic cells through adenosine-refractory and caspase-1-dependent pathways. AB - BACKGROUND: Newborns have frequent infections and manifest impaired vaccine responses, motivating a search for neonatal vaccine adjuvants. Alum is a neonatal adjuvant but might confer a T(H)2 bias. Toll-like receptor (TLR) agonists are candidate adjuvants, but human neonatal cord blood monocytes demonstrate impaired T(H)1-polarizing responses to many TLR agonists caused by plasma adenosine acting through cyclic AMP. TLR8 agonists, including imidazoquinolines (IMQs), such as the small synthetic 3M-002, induce adult-level TNF from neonatal monocytes, but the scope and mechanisms of IMQ-induced activation of neonatal monocytes and monocyte-derived dendritic cells (MoDCs) have not been reported. OBJECTIVE: We sought to characterize IMQ-induced activation of neonatal monocytes and MoDCs. METHODS: Neonatal cord and adult peripheral blood monocytes and MoDCs were cultured in autologous plasma; levels of alum- and TLR agonist-induced cytokines and costimulatory molecules were measured. TLR8 and inflammasome function were assayed by using small interfering RNA and Western blotting/caspase-1 inhibitory peptide, respectively. The ontogeny of TLR8 agonist-induced cytokine responses was defined in rhesus macaque whole blood ex vivo. RESULTS: IMQs were more potent and effective than alum at inducing TNF and IL-1beta from monocytes. 3M-002 induced robust TLR pathway transcriptome activation and T(H)1-polarizing cytokine production in neonatal and adult monocytes and MoDCs, signaling through TLR8 in an adenosine/cyclic AMP-refractory manner. Newborn MoDCs displayed impaired LPS/ATP-induced caspase-1-mediated IL-1beta production but robust 3M-002-induced caspase-1-mediated inflammasome activation independent of exogenous ATP. TLR8 IMQs induced robust TNF and IL-1beta in whole blood of rhesus macaques at birth and infancy. CONCLUSIONS: IMQ TLR8 agonists engage adenosine-refractory TLR8 and inflammasome pathways to induce robust monocyte and MoDC activation and represent promising neonatal adjuvants. PMID- 22521248 TI - Development of atopic dermatitis according to age of onset and association with early-life exposures. AB - BACKGROUND: Environmental factors can affect the development of atopic dermatitis, and this was described to be already effective during pregnancy and in early life. An important early postnatal exposure is nutrition, although its association with allergic disease remains unclear. OBJECTIVE: We sought to determine prospectively whether early postnatal exposures, such as the introduction to complementary food in the first year of life, are associated with the development of atopic dermatitis, taking into account the reverse causality. METHODS: One thousand forty-one children who participated in the Protection Against Allergy-Study in Rural Environments birth cohort study were included in the current study. Atopic dermatitis was defined by a doctor's diagnosis reported by the parents of children up to 4 years of age, by questionnaires, and/or by positive SCORAD scores from 1 year of age and according to the age of onset within or after the first year of life. Feeding practices were reported by parents in monthly diaries between the 3rd and 12th months of life. RESULTS: The diversity of introduction of complementary food in the first year of life was associated with a reduction in the risk of having atopic dermatitis with onset after the first year of life (adjusted odds ratio for atopic dermatitis with each additional major food item introduced, 0.76; 95% CI, 0.65-0.88). The introduction of yogurt in the first year of life also reduced the risk for atopic dermatitis (adjusted odds ratio, 0.41; 95% CI, 0.23-0.73). CONCLUSION: As early-life exposure, the introduction of yogurt and the diversity of food introduced in the first year of life might have a protective effect against atopic dermatitis. PMID- 22521249 TI - TH2 cytokines increase kallikrein 7 expression and function in patients with atopic dermatitis. PMID- 22521251 TI - The cortical eye proprioceptive signal modulates neural activity in higher-order visual cortex as predicted by the variation in visual sensitivity. AB - Whereas the links between eye movements and the shifts in visual attention are well established, less is known about how eye position affects the prioritization of visual space. It was recently observed that visual sensitivity varies with the direction of gaze and the level of excitability in the eye proprioceptive representation in human left somatosensory cortex (S1(EYE)), so that after 1Hz repetitive transcranial magnetic stimulation (rTMS) over S1(EYE), targets presented nearer the center of the orbit are detected more accurately. Here we used whole-brain functional magnetic resonance imaging to map areas where S1(EYE) rTMS affects the neural response evoked by retinally identical stimuli depending on the direction of rotation of the right eye. After S1(EYE)-rTMS, a single area in the left cuneus outside Brodmann Areas 17/18 showed an increased neuronal response to a right hemifield target when the right eye was rotated leftwards as compared with when it was rotated rightwards. This effect was larger after S1(EYE)-rTMS than after rTMS of a control area in the motor cortex. The neural response to retinally identical stimuli in this area could be predicted from the changes in visual detectability observed previously, but not from the location of the visual targets relative to the body. These results strongly argue for a modulatory connection from the eye proprioceptive area in the somatosensory cortex to the higher-order visual cortex. This connection may contribute to flexibly allocate priorities for visual perception depending on the proprioceptively signaled direction of gaze. PMID- 22521250 TI - Prevalence, risk factors and awareness of albuminuria on a Canadian First Nation: a community-based screening study. AB - BACKGROUND: Both diabetic and non-diabetic end stage renal disease (ESRD) are more common among Canadian First Nations people than among the general Canadian population. The purpose of this research was to determine the prevalence of and risk factors for albuminuria in a Canadian First Nation population at high risk for ESRD and dialysis. METHODS: Data from a community-based screening study of 483 residents of a Plains Ojibway First Nation in Manitoba was used. Participants provided random urine samples. Proteinuria was defined as any dipstick positive for protein (>=1 g/L) or those with ACR in the macroalbuminuric range (>=30 mg/mmol) on at least one sample. Microalbuminuria was defined as ACR >=2 mg/mmol for males and >=2.8 mg/mmol for females. Other measures included fasting glucose, haemoglobin A1c, triglycerides, cholesterol, blood pressure, height, weight and waist and hip circumferences. RESULTS: Twenty percent of study participants had albuminuria, (5% proteinuria and 15% microalbuminuria). Of participants with diabetes, 42% (56/132) had albuminuria compared to 26% (7/27) among those with impaired fasting glucose and 10% (30/303) among those with normal glucose tolerance. Only 5.3% of those with albuminuria were aware of any degree of renal disease. In a multivariate logistic regression, independent associations with albuminuria were male gender [p = 0.002], increasing fasting glucose [p <0.0001], years diagnosed with diabetes [p = 0.03], increasing systolic blood pressure [p = 0.009], and increasing body mass index (BMI) [p = 0.04]. CONCLUSIONS: The independent association between BMI and albuminuria has not been previously reported among indigenous populations. There is a high prevalence of albuminuria in this Canadian First Nation population; the high proportion of patients with diabetes and undiagnosed kidney disease demonstrates the need for screening, education and intervention to halt the progression and development of albuminuria and ultimately ESRD and CVD. PMID- 22521252 TI - The fraction of an action is more than a movement: neural signatures of event segmentation in fMRI. AB - When we observe an action, we recognize meaningful action steps that help us to predict probable upcoming action steps. This segmentation of observed actions, or more generally events, has been proposed to rely in part on changes in motion features. However, segmentation of actions, in contrast to meaningless movements, may exploit additional information such as action knowledge. The present fMRI study sought to tear apart the neural signatures of processing two sources of information that observers may exploit at action boundaries: change in motion dynamics and action knowledge. To this end, subjects performed a segmentation task on both actions (that can be segmented based on motion and action knowledge) as well as tai chi movements (that can be segmented only based on motion) and two further control conditions that implemented point-light walker like displays of the same videos. Behavioral tests showed that motion features played a critical role in boundary detection in all conditions. Consistent with this finding, activity in area MT was enhanced during boundary detection in all conditions, but importantly, this effect was not stronger for actions. In contrast, only action boundary detection was reflected by specific activation in the superior frontal sulcus, parietal angular gyrus and the parahippocampal cortex. Based on these findings, we propose that during action observation, motion features trigger a top-down modulation of the attentional focus and the incitement of retrieving long-term memory place-action associations. While action perception entails activity common to processing of all motion stimuli, it is at the same time unique as it allows long-term memory based predictions of succeeding steps. PMID- 22521253 TI - Neural mechanisms underlying the integration of emotion and working memory. AB - The present study aimed at investigating the behavioral effects and neuronal correlates of emotional content and emotional components, i.e. valence and arousal, in the context of a verbal working memory task. Our findings in twenty healthy male subjects demonstrate that (1) word valence has no impact on performance in the verbal working memory task, and (2) that emotion leads to an increase of activation in cognition-related lateral prefrontal regions, whereas cognitive effort yields enhanced deactivation in emotion-related cortical midline regions. The stronger dorsolateral prefrontal recruitment during emotional stimuli may reflect an arousal effect or higher cognitive effort due to interference with emotion. PMID- 22521254 TI - A meta-analysis of neurofunctional imaging studies of emotion and cognition in major depression. AB - Major depressive disorder (MDD) is characterized by altered emotional and cognitive functioning. We performed a voxel-based whole-brain meta-analysis of functional neuroimaging data on altered emotion and cognition in MDD. Forty peer reviewed studies in English-language published between 1998 and 2010 were included, which used functional neuroimaging during cognitive-emotional challenge in adult individuals with MDD and healthy controls. All studies reported between groups differences for whole-brain analyses in standardized neuroanatomical space and were subjected to Activation Likelihood Estimation (ALE) of brain cluster showing altered responsivity in MDD. ALE resulted in thresholded and false discovery rate corrected hypo- and hyperactive brain regions. Against the background of a complex neural activation pattern, studies converged in predominantly hypoactive cluster in the anterior insular and rostral anterior cingulate cortex linked to affectively biased information processing and poor cognitive control. Frontal areas showed not only similar under- but also over activation during cognitive-emotional challenge. On the subcortical level, we identified activation alterations in the thalamus and striatum which were involved in biased valence processing of emotional stimuli in MDD. These results for active conditions extend findings from ALE meta-analyses of resting state and antidepressant treatment studies and emphasize the key role of the anterior insular and rostral anterior cingulate cortex for altered emotion and cognition in MDD. PMID- 22521255 TI - Trans-saccadic parafoveal preview benefits in fluent reading: a study with fixation-related brain potentials. AB - During natural reading, a parafoveal preview of the upcoming word facilitates its subsequent recognition (e.g., shorter fixation durations compared to masked preview) but nothing is known about the neural correlates of this so-called preview benefit. Furthermore, while the evidence is strong that readers preprocess orthographic features of upcoming words, it is controversial whether word meaning can also be accessed parafoveally. We investigated the timing, scope, and electrophysiological correlates of parafoveal information use in reading by simultaneously recording eye movements and fixation-related brain potentials (FRPs) while participants read word lists fluently from left to right. For one word-the target-(e.g., "blade") parafoveal information was manipulated by showing an identical ("blade"), semantically related ("knife"), or unrelated ("sugar") word as preview. In boundary trials, the preview was shown parafoveally but changed to the correct target word during the incoming saccade. Replicating classic findings, target words were fixated shorter after identical previews. In the EEG, this benefit was reflected in an occipitotemporal preview positivity between 200 and 280 ms. In contrast, there was no facilitation from related previews. In parafoveal-on-foveal trials, preview and target were embedded at neighboring list positions without a display change. Consecutive fixation of two related words produced N400 priming effects, but only shortly (160 ms) after the second word was directly fixated. Results demonstrate that neural responses to words are substantially altered by parafoveal preprocessing under normal reading conditions. We found no evidence that word meaning contributes to these effects. Saccade-contingent display manipulations can be combined with EEG recordings to study extrafoveal perception in vision. PMID- 22521257 TI - In vivo voxel based morphometry: detection of increased hippocampal volume and decreased glutamate levels in exercising mice. AB - Voluntary exercise has tremendous effects on adult hippocampal plasticity and metabolism and thus sculpts the hippocampal structure of mammals. High-field (1)H magnetic resonance (MR) investigations at 9.4 T of metabolic and structural changes can be performed non-invasively in the living rodent brain. Numerous molecular and cellular mechanisms mediating the effects of exercise on brain plasticity and behavior have been detected in vitro. However, in vivo attempts have been rare. In this work a method for voxel based morphometry (VBM) was developed with automatic tissue segmentation in mice using a 9.4 T animal scanner equipped with a (1)H-cryogenic coil. The thus increased signal to noise ratio enabled the acquisition of high resolution T2-weighted images of the mouse brain in vivo and the creation of group specific tissue class maps for the segmentation and normalization with SPM. The method was used together with hippocampal single voxel (1)H MR spectroscopy to assess the structural and metabolic differences in the mouse brain due to voluntary wheel running. A specific increase of hippocampal volume with a concomitant decrease of hippocampal glutamate levels in voluntary running mice was observed. An inverse correlation of hippocampal gray matter volume and glutamate concentration indicates a possible implication of the glutamatergic system for hippocampal volume. PMID- 22521256 TI - Multiple testing corrections, nonparametric methods, and random field theory. AB - I provide a selective review of the literature on the multiple testing problem in fMRI. By drawing connections with the older modalities, PET in particular, and how software implementations have tracked (or lagged behind) theoretical developments, my narrative aims to give the methodological researcher a historical perspective on this important aspect of fMRI data analysis. PMID- 22521258 TI - Quantitative estimates of stimulation-induced perfusion response using two-photon fluorescence microscopy of cortical microvascular networks. AB - Functional hyperemia, or the increase in focal perfusion elicited by neuronal activation, is one of the primary functions of the neurovascular unit and a hallmark of healthy brain functioning. While much is known about the hemodynamics on the millimeter to tenths of millimeter-scale accessible by MRI, there is a paucity of quantitative data on the micrometer-scale changes in perfusion in response to functional stimulation. We present a novel methodology for quantification of perfusion and intravascular flow across the 3D microvascular network in the rat somatosensory cortex using two-photon fluorescence microscopy (2PFM). For approximately 96% of responding microvessels in the forelimb representation of the primary somatosensory cortex, brief (~2s) forepaw stimulation resulted in an increase of perfusion 20+/-4% (mean+/-sem). The perfusion levels associated with the remaining 4% of the responding microvessels decreased 10+/-9% upon stimulation. Vessels irrigating regions of lower vascular density were found to exhibit higher flow (p<0.02), supporting the notion that local vascular morphology and hemodynamics reflect the metabolic needs of the surrounding parenchyma. High dispersion (~77%) in perfusion levels suggests high spatial variation in tissue susceptibility to hypoxia. The current methodology enables quantification of absolute perfusion associated with individual vessels of the cortical microvascular bed and its changes in response to functional stimulation and thereby provides an important tool for studying the cellular mechanisms of functional hyperemia, the spatial specificity of perfusion response to functional stimulation, and, broadly, the micrometer-scale relationship between vascular morphology and function in health and disease. PMID- 22521259 TI - Peroxisome proliferator-activated receptor beta/delta agonist GW0742 ameliorates cerulein- and taurocholate-induced acute pancreatitis in mice. AB - BACKGROUND: Peroxisome proliferator-activated receptors (PPARs) are ligand activated transcription factors belonging to the nuclear receptor superfamily. PPARs activation has a profound impact on the local immune response with consequences affecting the progression of chronic inflammatory diseases. Relatively little is known on the role of PPAR-beta/delta in the regulation of inflammatory responses. The aim of the present study was to evaluate the influence of PPAR-beta/delta receptor in a model of edematous pancreatitis induced in mice by administration of cerulein at supramaximal doses, as well as in necrohemorrhagic model induced by intraductal administration of sodium taurocholate (STC). MEASUREMENTS: Mice were treated with cerulein (50 MUg/kg) or STC (5%). GW0742 (0.3 mg/kg) was intraperitoneally administered 1 and 6 hours after cerulein injection or was injected 2 hours before STC infusion. The pancreas and exopancreatic organs were carefully removed for microscopic examination. Pancreatic weight, serum amylase, lipase, tumor necrosis factor alpha and interleukin-1beta levels, as well as cytokines, adhesion molecules, nitrotyrosine, poly (ADP-ribose), inducible nitric oxide, FAS ligand, Bax, Bcl-2 expression by immunohistochemistry, and myeloperoxidase activity of the pancreas were assayed. Moreover, the involvement of nuclear factor-kappaB pathway was investigated by Western blot analysis. RESULTS: Intraperitoneal injection of cerulein in mice resulted in severe, acute pancreatitis characterized by edema, neutrophil infiltration and apoptosis, and elevated serum levels of amylase and lipase. Taurocholate challenge caused a clear increase in serum amylase, neutrophil infiltration, and tissue damage in the pancreas. Tissue and inflammatory changes in the pancreata were significantly less in GW0742 group than in cerulein or STC groups. In addition, the pancreatic water content was reduced in mice treated with PPAR-beta/delta agonist. In the mild pancreatitis, GW0742 was also able to decrease the expression of proinflammatory cytokines and enzymes, as well as of proteins involved in apoptosis and nuclear factor-Kappa B pathway. CONCLUSION: GW0742 attenuated pancreatic damage in 2 different experimental models of pancreatitis in mice. PMID- 22521260 TI - Sentinel lymph node biopsy using carbon nanoparticles for Chinese patients with papillary thyroid microcarcinoma. AB - AIMS: To compare the efficacies of methylene blue (MB) and carbon nanoparticles (CNs) as tracers for sentinel lymph node biopsy (SLNB), and assess the value of SLNB in predicting the cervical LN status of patients with thyroid microcarcinoma. METHODS: This retrospective analysis comprised 200 thyroid microcarcinoma patients who underwent intraoperative SLNB. Among them, 100 patients were injected with MB dye. The other 100 patients received a CN suspension injection. Routine pathological examination was performed in all resected specimens. RESULTS: SLNs detected in the experimental and control groups were 126 and 102, respectively, of which the metastatic LNs confirmed by histopathology were 77 and 48, respectively. The staining rate of cervical level VI LNs in the experimental group was significantly higher than that in the control group (P<0.001). For the CN method, the sensitivity, specificity, accuracy rate, and false negative rate were 93.3%, 100%, 97%, and 5.2%, respectively, whereas the corresponding figures for the MB method were 80.6%, 100%, 93%, and 9.9%, respectively. The positive rate of cancer metastases for SLNs in the experimental group was 61.1%, which is significantly higher than that in the control group (47.1%; P=0.034). CONCLUSIONS: In contrast to the MB method, CNs can maintain the durability of SLN imaging and accurately forecast the LN status of patients with thyroid microcarcinoma; in addition, the CN method was found to be feasible and repeatable. The CN method better aids the screening and selection of patients who are most likely to benefit from cervical LN dissection. PMID- 22521261 TI - Oral cavity, pharyngeal and salivary gland cancer: disparities in ethnicity specific incidence among the London population. AB - OBJECTIVES: We examined the association between ethnicity and the incidence of oral and pharyngeal cancers in the London population. METHODS: Data on London residents diagnosed with oral and pharyngeal cancer (ICD-10 codes C00-C14) between 1998 and 2007 were retrieved from the Thames Cancer Registry. Age standardised incidence rate ratios (IRR) for cancers of the nasopharynx (C11), oropharynx (C09-C10), hypopharynx (C12-C13), oral cavity (C00.3-C06), salivary glands (C07-C08) and Waldeyer's ring (C02.4, C09, C11.1, C14.2) were calculated for different ethnic groups using White males and females as the baseline groups. RESULTS: Records on 5833 individuals were examined, and ethnicity information was available for 4679 (80%) of these patients. The incidence rate of oral and pharyngeal cancer combined was 9.0 and 3.9 per 100,000 for males and females, respectively. Compared with their White counterparts, the highest incidence rate ratios of nasopharyngeal cancer were seen in Chinese males (IRR: 23, 95% confidence interval (CI): 7-73) and females (IRR: 16, 95% CI: 2-107). Waldeyer's ring cancers were most common in Bangladeshi and White groups. Analysis of the oropharynx and oral cavity cancers gave rise to variable but less obvious patterns among the different ethnic groups, whereas less variation was observed between ethnic groups for cancers of the hypopharynx and salivary glands. CONCLUSION: The incidence rates of individual oral and pharyngeal cancer types are low, but seem to vary by ethnic group. The variation in incidence appears to be unique to the different cancer subtypes and may therefore reflect specific ethnicity-related risk factors. PMID- 22521262 TI - Co-expression of BMPs and BMP-inhibitors in human fractures and non-unions. AB - Bone morphogenetic proteins (BMPs) are increasingly being used clinically to enhance fracture repair and healing of non-unions. However, the potential efficacy of supraphysiological dosing for clinical results warrants further clarification of the BMP signaling pathway in human fracture healing. As BMP signaling can be fine-tuned at numerous levels, the role of BMP-inhibitors has become a major focus. The aim of the present study was to document co-expression of BMPs, pSmad 1/5/8, and BMP-inhibitors in human fracture callus and human non unions. Using human tissue of fracture callus (n=14) and non-unions (n=4) we documented expression of BMPs (BMP2, BMP3 and BMP7), pSmad 1/5/8 and the BMP inhibitors noggin, gremlin, chordin, Smad-6, Smad-7 and BAMBI. Co-expression of pSmad 1/5/8, BMPs and BMP-inhibitors was noted in the osteoblasts of fracture callus as well as of non-unions. Expression of BMP-inhibitors was generally stronger in non-unions than in fracture callus. The most pertinent differences were noted in the cartilaginous tissue components. Expression of BMP2 in chondrocytes was markedly decreased in non-unions compared to fracture callus and that of BMP7 was almost completely absent. Expression of BMP-inhibitors was almost the same in osteoblasts, chondrocytes and fibroblasts of fracture callus and well as in non-unions. Interestingly, although BMP ligands were present in the chondrocytes and fibroblasts of non-unions, they did not co-express pSmad 1/5/8 suggesting that BMP signaling may have been inhibited at some point before Smad 1/5/8 phosphorylation. These results suggest co-expression of BMP, pSmad 1/5/8 and BMP-inhibitors occurs in human fracture callus as well as non-unions but the relative expression of BMPs vs. BMP-inhibitors was different between these two tissue types. In contrast to our expectations, the expression of BMP inhibitors was comparable between fracture callus and non-unions, whereas the expression of BMPs was notably lower in the cartilaginous component of the non unions in comparison to fracture callus. Based on these results, we believe that aberrations in the BMP-signaling pathway in the cartilaginous component of fracture healing could influence clinical fracture healing. An imbalance between the local presence of BMP and BMP-inhibitors may switch the direction towards healing or non-healing of a fracture. PMID- 22521263 TI - Genetic relatedness among Japanese HAV isolates, 2010. PMID- 22521264 TI - Reading a standing wave: figure-ground-alternation masking of primes in evaluative priming. AB - We propose a new masking technique for masking word stimuli. Drawing on the phenomena of metacontrast and paracontrast, we alternately presented two prime displays of the same word with the background color in one display matching the font color in the other display and vice versa. The sequence of twenty alterations (spanning approx. 267 ms) was sandwich-masked by structure masks. Using this masking technique, we conducted evaluative priming experiments with positive and negative target and prime words. Significant priming effects were found - for primes and targets drawn from the same as well as from different word sets. Priming effects were independent of prime discrimination performance in direct tests and they were still significant after the sample was restricted to those participants who showed random responding in the direct test. PMID- 22521265 TI - Reprint of: Betaglycan: a multifunctional accessory. AB - Betaglycan is a co-receptor for the TGFbeta superfamily, particularly important in establishing the potency of its ligands on their target cells. In recent years, new insights have been gained into the structure and function of betaglycan, expanding its role from that of a simple co-receptor to include additional ligand-dependent and ligand-independent roles. This review focuses on recent advances in the betaglycan field, with a particular emphasis on its newly discovered actions in mediating the trafficking of TGFbeta superfamily receptors and as a determinant of the functional output of TGFbeta superfamily signalling. In addition, this review encompasses a discussion of the emerging roles of the betaglycan/inhibin pathway in reproductive cancers and disease. PMID- 22521266 TI - MEK/ERK pathway mediates insulin-promoted degradation of MKP-3 protein in liver cells. AB - MAP kinase phosphatase 3 (MKP-3) was recently identified as an important regulator of glucose homeostasis in the liver and its expression can be repressed by insulin at post transcriptional level. In this study, the mechanism underlying insulin promoted decrease of MKP-3 protein was investigated by studying MKP-3 protein stability via immunoblot analysis in the presence of cycloheximide using cultured liver cells. Several pathways were examined and activation of the MEK/ERK pathway was found to mediate reduction of MKP-3 protein expression in response to insulin. MEK inhibitor markedly slowed down MKP-3 protein degradation. Mutation of two ERK phosphorylation sites on MKP-3 rendered it resistant to insulin and constitutively active MEK-induced MKP-3 protein degradation. To understand the biological effect of MKP-3 protein stability on liver cell glucose output, expression level of G6Pase gene, which encodes the key enzyme controlling the last step of de novo glucose synthesis in liver cells, was examined by real time PCR analysis upon manipulation of MEK signaling. Activation of MEK pathway in Fao cells resulted in decreased expression of G6Pase gene and lowered glucose output. Consistent with this result, MEK inhibitor increased expression of G6Pase gene and glucose output in Fao cells. In conclusion, insulin likely promotes MKP-3 protein degradation through activation of MEK/ERK pathway in liver cells and MKP-3 protein level affects the capability of Fao cells to output glucose. PMID- 22521267 TI - Immunization site pain: case definition and guidelines for collection, analysis, and presentation of immunization safety data. PMID- 22521268 TI - Criminal justice outcomes for cannabis use offences in New Zealand, 1991-2008. AB - BACKGROUND: There have been no changes to the statutory penalties for cannabis use in New Zealand for over 35 years and this has attracted some criticism. However, statutory penalties often provide a poor picture of the actual criminal justice outcomes for minor drug offending. AIM: To examine criminal justice outcomes for cannabis use offences in New Zealand over the past two decades. METHOD: Rates of apprehension, prosecution, conviction and related criminal justice outcomes for the use of cannabis in New Zealand (per 100,000 population) were calculated for 1991-2008. The same measures were calculated (per 1000 last year cannabis users) for 1998, 2001, 2003 and 2006. Trends were tested for using logistic regression with year predicting each measure outcome and with chi-square tests. RESULTS: The number of police apprehensions for cannabis use per year (per 100,000 population) declined from 468 in 1994 to 247 in 2008. The number of apprehensions for cannabis use per year (per 1000 cannabis users) also declined from 36 in 1998 to 21 in 2006. There were similar declines in prosecutions and convictions for cannabis use from 1991 to 2008. Those prosecuted for cannabis use in 2000-2008 were less likely than those prosecuted in 1991-1999 to be convicted and were more likely to be diverted away from the courts, 'discharged without conviction' and 'convicted and discharged'. CONCLUSION: There has been a substantial decline in arrests for cannabis use in New Zealand over the past decade and this lead to similar declines in prosecutions and convictions for cannabis use. The decline in convictions for cannabis use was further assisted by the expansion of police diversion to include cannabis use offences. Our findings underline the importance of examining the implementation of law, as well as statutory penalties, when characterising a country's criminal justice approach to minor drug offending. PMID- 22521269 TI - Acute phase proteins in ruminants. AB - The physiological response to infections and injuries involves local inflammation and the initiation of events leading to a systemic response, also called acute phase reaction (APR). This multiplicity of changes is distant from the site of injury, and includes fever, leukocytosis and quantitative and qualitative modification of a group of non-structurally related proteins present in blood and other biological fluids, collectively named Acute Phase Proteins (APP). Proteomic investigations of serum or plasma following natural or experimental infection frequently reveal substantial alterations in the APP, several of which are high abundance proteins in these fluids. The present review will focus on the results of recent research on ruminant APP. Highlight points will include: - The structure and the functions of the main APPs in ruminants, as well as the regulatory mechanisms that trigger their systemic and local expression in both physiological and pathological conditions.- The clinical aspects of APPs in ruminants, including the current and future application to veterinary diagnosis and animal production.- The APP in small and wildlife ruminants.- Alteration in APP detected by proteomic investigations. PMID- 22521270 TI - Concentration-dependent effects of the soy phytoestrogen genistein on the proteome of cultured cardiomyocytes. AB - The soy-derived phytoestrogen genistein (GEN) has received attention for its potential benefits on the cardiovascular system by providing direct protection to cardiomyocytes against pathophysiological stresses. Here, we employed a proteomic approach to study the concentration-dependent effects of GEN treatments on cardiomyocytes. Cultured HL-1 cardiomyocytes were treated with low (1MUM) and high (50MUM) concentrations of GEN. Proteins were pre-fractionated by sequential hydrophilic/hydrophobic extraction and both protein fractions from each treatment group were separated by 2D gel electrophoresis (2DE). Overall, approximately 2,700 spots were visualized on the 2D gels. Thirty-nine and 99 spots changed in volume relative to controls (p<0.05) following the low- and high-concentration GEN treatments, respectively. From these spots, 25 and 62 protein species were identified by ESI-MS/MS and Mascot database searching, respectively. Identified proteins were further categorized according to their functions and possible links to cardioprotection were discussed. MetaCore gene ontology analysis suggested that 1MUM GEN significantly impacted the anti-apoptosis process, and that both the low and high concentrations of GEN influenced the glucose catabolic process and regulation of ATPase activity. This proteomics study provides the first global insight into the molecular events triggered by GEN treatment in cardiomyocytes. PMID- 22521271 TI - Accounting for biological variation in differential display two-dimensional electrophoresis experiments. AB - Variation of protein expression levels was investigated in the heart, lung and liver from an inbred (C57/BL6) and an outbred (CD-1) mouse line. Based on the measured inter-individual variation, optimal sample sizes for two-dimensional electrophoresis experiments were determined by means of power analysis. For both lines, the level of protein expression variation was in the range of technical variation. Thus, although the differences in protein expression variation were significant between organs and mouse lines, optimal sample sizes were very similar (between 8 for heart proteins from C57/BL6 and 10 for liver proteins of the same line). Proteins with organ expression bias (higher expression in one organ as compared to the other two organs) exhibited higher variation of expression and the proportion of these proteins in each organ explained at least partly inter-organ differences in protein expression variation. The results suggest that proteomic experiments using more heterogeneous mouse samples would not require much larger sample sizes than those using narrowly standardized samples. Experiment designs encompassing a broader genetic variation and thus affording increased relevance of the results can be accessible to proteomics researchers at still affordable sample sizes. PMID- 22521272 TI - Myotonia congenita: novel mutations in CLCN1 gene and functional characterizations in Italian patients. AB - Myotonia congenita is an autosomal dominantly or recessively inherited muscle disorder causing impaired muscle relaxation and variable degrees of permanent muscle weakness, abnormal currents linked to the chloride channel gene (CLCN1) encoding the chloride channel on skeletal muscle membrane. We describe 12 novel mutations: c.1606G>C (p.Val536Leu), c.2533G>A (p.Gly845Ser), c.2434C>T (p.Gln812X), c.1499T>G (p.E500X), c.1012C>T (p.Arg338X), c.2403+1G>A, c.2840T>A (p.Val947Glu), c.1598C>T (p.Thr533Ile), c.1110delC, c.590T>A (p.Ile197Arg), c.2276insA Fs800X, c.490T>C (p.Trp164Arg) in 22 unrelated Italian patients. To further understand the functional outcome of selected missense mutations (p.Trp164Arg, p.Ile197Arg and p.Gly845Ser, and the previously reported p.Gly190Ser) we characterized the biophysical properties of mutant ion channels in tsA cell model. In the physiological range of muscle membrane potential, all the tested mutations, except p.Gly845Ser, reduced the open probability, increased the fast and slow components of deactivation and affected pore properties. This suggests a decrease in macroscopic chloride currents impairing membrane potential repolarization and causing hyperexcitability in muscle membranes. Detailed clinical features are given of the 8 patients characterized by cell electrophysiology. These data expand the spectrum of CLCN1 mutations and may contribute to genotype-phenotype correlations. Furthermore, we provide insights into the fine protein structure of ClC-1 and its physiological role in the maintenance of membrane resting potential. PMID- 22521273 TI - Levodopa dosage determines adherence to long-acting dopamine agonists in Parkinson's disease. AB - OBJECTIVE: To test whether adherence to non-ergot, once-daily dopamine agonist (ODDA) therapy depends upon concomitant levodopa daily dose in Parkinson's disease (PD). METHODS: Consecutive levodopa-treated PD patients on ODDA therapy were invited to participate in the study. ODDA adherence was measured using subjective (Morisky-Green test, MGT) and objective (electronic monitoring of refill compliance, IANUS) methods. A combination of MGT and IANUS was used to define full (100%) adherence to ODDA therapy. Logistic regression methods were used to investigate the impact of levodopa daily dose on ODDA adherence after adjusting for relevant covariates. RESULTS: Thirty-nine patients (19 men, 20 women; age, 70.2+/-8.9 years) were enrolled in the study. Twelve (31%) participants admitted to suboptimal ODDA compliance. Only 18 (46%) were estimated to be fully compliant. As expected, adherence was inversely related to levodopa daily dose. For every 100mg increase in levodopa dose, the risk to failure to adhere increased 1.86 times (95% CI, 1.21-3.74; p=0.0020). The covariate "total daily number of drugs" (not total daily number of pills) was also associated with worse adherence (p=0.0061). In contrast, patients who were initially treated with a dopamine agonist showed better ODDA adherence than those who were initially treated with levodopa (p=0.012). Levodopa doses greater than 600 mg/day were associated with suboptimal compliance. CONCLUSIONS: In levodopa-treated PD patients, adherence to ODDA therapy is suboptimal and strongly associated with the levodopa daily dose and the total number of drugs used to treat patients' medical conditions. PMID- 22521274 TI - Low-contrast acuity measures visual improvement in phase 3 trial of natalizumab in relapsing MS. AB - OBJECTIVE: Low-contrast letter acuity has demonstrated treatment effects for sustained visual loss in trials of natalizumab for relapsing multiple sclerosis (MS). To test new therapies that may involve neuroprotection and repair, it will be essential for outcome measures to detect improvement as well as loss of visual function. We determined the effects of natalizumab on the frequency and cumulative probability of visual improvement using low-contrast letter acuity a prespecified tertiary outcome measure in AFFIRM. METHODS: AFFIRM was a randomized, double-blind, placebo-controlled, phase 3 trial that evaluated efficacy and safety of natalizumab (n=627) vs. placebo (n=315) in relapsing remitting MS. Binocular acuities were measured at low-contrast (1.25%, 2.5%) and high-contrast visual acuity (VA). Improvement was defined as 12-week sustained increases from baseline. Clinically meaningful change for primary analyses was pre-defined as 7-letter improvement for low-contrast acuity and 5-letter improvement for VA based upon previous studies. RESULTS: Compared to placebo, cumulative probabilities of sustained visual improvement were greater in the natalizumab group by 57% for 2.5% contrast (21.7% vs. 14.0%; HR=1.57; 95% CI: 1.11-2.22; P=0.012) and 39% for 1.25% contrast (32.5% vs. 25.0%; HR=1.39; 95% CI: 1.07-1.82; P=0.014). The 5- and 10-letter low-contrast assessments did not show treatment differences. High-contrast VA was insensitive to changes over time and treatment effects. CONCLUSION: Low-contrast letter acuity detected treatment effects on sustained visual improvement in patients with relapsing MS. The ability to detect visual improvement and loss makes low-contrast acuity an important measure for future trials assessing the impact of therapy on this outcome and the potential of a therapy for neuroprotection and repair. PMID- 22521276 TI - Pharmacokinetic behavior of argirein, derived from rhein, is characterized as slow release and prolonged T1/2 of rhein in rats. AB - AIM: Rhein is an effective ingredient from Rheum palmatum L., Polygonum cuspidatum Sielb.et Zucc., Polygonum multiflorum Thunb. and has anti-inflammatory activity, however, plasma levels are too high and T(1/2) is not long enough following oral medication. Therefore, a modification of the rhein moiety was encouraged to improve the pharmacokinetic behavior. Argirein was produced by connecting rhein with l-arginine through hydrogen bond, which releases both rhein and L-arginine while getting into the body. The present study was to verify if the pharmacokinetic profile of argirein by measuring the released rhein is improved against those of untreated rhein administered alone. METHODS: A reversed phase HPLC with a mobile phase of methanol mixed with acetate buffer was conducted. Rhein was monitored after arginine administration by i.g. and i.v. routes. Rhein alone was also administered and compared. RESULTS: The C(max) and AUC(0-48) of the released rhein following argirein medication were less than those following rhein administered. The bioavailability of argirein was 18.5 20.8% against 22.77-25.22% of rhein. A delayed T(max), a reduced C(max) and AUC(0 t) and an increased T(1/2) were significant in the argirein group as compared with those in the rhein group. CONCLUSION: The pharmacokinetic behavior of oral argirein presents a slow release property against those following oral rhein in rats. The released rhein following oral argirein is suitable in suppressing chronic inflammatory reactions attributed to prolonged T(1/2) and delayed T(max) due to its slow release pharmacokinetic characteristics. PMID- 22521277 TI - Rational formulation development and in vitro assessment of SMEDDS for oral delivery of poorly water soluble drugs. AB - The aims of this study were to formulate a self-microemulsifying drug delivery system (SMEDDS) by a rational formulation approach using mixture experimental design and to derive general concepts that make the development of such systems more feasible. Various types of oils and surfactants were systematically combined and the phase behaviour upon dilution with simulated gastric fluid examined by construction of phase diagrams. The systems solubilising the highest amount of simulated gastric fluid in the continuous microemulsion area were selected for investigation and optimisation of drug solubility. Simvastatin was added as a poorly water-soluble, lipophilic model drug. Two different mixture experimental designs using D-optimal design were set up and used to investigate the solubility of simvastatin in the SMEDDS before and after dilution with simulated gastric fluid respectively. The solubility in each mixture region was analysed by fitting quadratic models using partial least squares analysis. The established models revealed the influence of mixture components on phase behaviour and drug solubility and gave the rationale for formulation optimisation. This study demonstrated that the development of complex self-emulsifying formulations with sufficient solubilisation capacity for poorly water-soluble drugs upon oral administration can be more feasible when using experimental design. PMID- 22521279 TI - [Swelling of right knee in an immunologically compromised patient]. PMID- 22521278 TI - [Reliability of MALDI-TOF mass spectrometry in the identification of anaerobic bacteria]. AB - AIM OF THE STUDY: MALDI-TOF mass spectrometry (MS) is becoming a major resource in the Clinical Microbiology laboratory. Results on some groups of microorganisms are still controversial. We have studied the reliability of MALDI-TOF MS for the identification of anaerobic clinical isolates was studied compared to conventional biochemical methods, with rRNA 16S sequencing being used as a reference when discrepancies arose. MATERIAL AND METHODS: A total of 126 anaerobic bacteria clinical isolates were studied by using API20A kits (bioMerieux, Marcy l'Etoile, France) and MALDI-TOF MS (Autoflex II, Bruker Daltonics, Germany), and using the data library BioTyper 2.0 (Bruker Daltonics, Germany). When discrepancies arose, or MALDI-TOF MS was not able to identify any microorganism, rRNA 16S sequencing was used as the reference standard. RESULTS: The biochemical method and MALDI-TOF MS agreed in identifying 60.9% of isolates at species level, and 20.3% of isolates at genus level. Among the 48 discrepancies observed, rRNA 16S sequencing supported MALDI-TOF MS identification, at species level, in 32 isolates (66.7%), and in 8 isolates (16.7%) at genus level. rRNA 16S sequencing supported biochemical identification in only two isolates (4.2%) at species level, and in 26 isolates (54.2%) at genus level. The eight isolates for which MALDI-TOF MS did not manage to identify, or the identification obtained was rejected by sequencing, belonged to species that are still not added to the BioTyper II data library. CONCLUSIONS: Results obtained in this study show that, overall, MALDI-TOF MS identification of anaerobic bacteria is more reliable than identification obtained by conventional biochemical methods (24% more correct identifications at species level). The number of major errors (incorrect identification at the genus level) is also 2.5 times lower. Moreover, all the major errors obtained by MALDI-TOF MS were due to the absence of some species in the data library. Thus, when data libraries are more complete, reliability differences between both methods will probably be even higher. PMID- 22521280 TI - Development of reagents to study the turkey's immune response: cloning and characterisation of two turkey cytokines, interleukin (IL)-10 and IL-13. AB - The cDNAs of two turkey cytokines, interleukin (IL)-10 and IL-13, were cloned using oligonucleotide primers designed from their chicken orthologues. The coding regions of the chicken and turkey genes are highly conserved, with IL-10 and IL 13 exhibiting 94.1% and 90% nucleotide and 92% and 79.9% amino acid identity respectively. Both showed consistent mRNA expression in turkey lymphoid and gut tissues. Expression in non-lymphoid tissues was more variable but generally highest in the skin and trachea. Recombinant turkey IL-10 was expressed and bioactivity demonstrated by inhibition of IFN-gamma synthesis from activated splenocytes. Chicken and turkey IL-10 cross-reacted in functional assays. PMID- 22521281 TI - Comparative phenotypic and molecular characterization of porcine mesenchymal stem cells from different sources for translational studies in a large animal model. AB - Mesenchymal stem cells have demonstrated their potentiality for therapeutic use in treating diseases or repairing damaged tissues. However, in some cases, the results of clinical trials have been disappointing or have not worked out as well as hoped. These disappointing results can be attributed to an inadequate or insufficient preclinical study. For medical and surgical purposes, the similarities between the anatomy of pig and human make this animal an attractive preclinical model. In this sense, for mesenchymal stem cell-based therapy, it is strongly necessary to have well characterized animal-derived mesenchymal stem cell lines to validate preclinical effectiveness of these cells. In this work, porcine mesenchymal stem cells (pMSCs) were isolated from bone marrow, adipose tissue and peripheral blood and compared in terms of differentiation potential, cell surface markers and gene expression. Our results demonstrated that the isolation and in vitro expansion protocols were feasible and effective. The data presented in this work are relevant because they provide an extensive phenotypic characterization; genetic study and differentiation behavior of the most commonly used stem cell lines for clinical practices. These pMSCs are widely available to scientists and could be a valuable tool to evaluate the safety and efficacy of adoptively transferred cells. PMID- 22521283 TI - Protective role of antibodies induced by Brucella melitensis B115 against B. melitensis and Brucella abortus infections in mice. AB - It has been demonstrated that antibodies specific for O-PS antigen of Brucella smooth strains are involved in the protective immunity of brucellosis. Since the rough strain Brucella melitensis B115 was able to protect mice against wild Brucella strains brucellosis despite the lack of anti-OPS antibodies, in this study we evaluated the biological significance of antibodies induced by this strain, directed to antigens other than O-PS, passively tranferred to untreated mice prior to infection with Brucella abortus 2308 and B. melitensis 16M virulent strains. The protective ability of specific antisera collected from mice vaccinated with B. melitensis B115, B. abortus RB51 and B. abortus S19 strains was compared. The results indicated that antibodies induced by B115 were able to confer a satisfactory protection, especially against B. abortus 2308, similar to that conferred by the antiserum S19, while the RB51 antiserum was ineffective. These findings suggest that antibodies induced by B115 could act as opsonins as well as antibodies anti-O-PS, thus triggering more efficient internalization and degradation of bacteria within phagocytes. This is the first study assessing the efficacy of antibodies directed to antigens other than O-PS in the course of brucellosis infection. PMID- 22521284 TI - Edwardsiella tarda flagellar protein FlgD: a protective immunogen against edwardsiellosis. AB - Edwardsiella tarda is a gram-negative bacterium and a causative agent of edwardsiellosis, resulting to severe loss of the aquaculture industry. In this study, based on the reverse vaccinology, sixteen flagellar proteins were selected from highly pathogenic E. tarda EIB202 genome information and in silico analyzed as potential vaccine candidates. Among them, ten recombinant proteins were highly expressed in Escherichia coli and successfully purified. The immunoprotective potentials of these purified recombinant proteins were evaluated in zebrafish model. And recombinant FlgD and FliD were found to lead to a high relative percent survival (RPS, about 70%) against E. tarda EIB202. Furthermore, FlgD required in flagellum hook assembly brought about the similar immune protection in turbot. The immune responses of zebrafish and turbot to recombinant FlgD were also investigated, and the results indicated that its high protection was mainly involved in cellular mediated immune response, corresponding to the intracellular pathogenicity of E. tarda. PMID- 22521282 TI - Baseline kidney function as predictor of mortality and kidney disease progression in HIV-positive patients. AB - BACKGROUND: Chronic kidney disease (CKD) is associated with increased all-cause mortality and kidney disease progression. Decreased kidney function at baseline may identify human immunodeficiency virus (HIV)-positive patients at increased risk of death and kidney disease progression. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: 7 large HIV cohorts in the United Kingdom with kidney function data available for 20,132 patients. PREDICTOR: Baseline estimated glomerular filtration rate (eGFR). OUTCOMES: Death and progression to stages 4-5 CKD (eGFR <30 mL/min/1.73 m(2) for >3 months) in Cox proportional hazards and competing-risk regression models. RESULTS: Median age at baseline was 34 (25th 75th percentile, 30-40) years, median CD4 cell count was 350 (25th-75th percentile, 208-520) cells/MUL, and median eGFR was 100 (25th-75th percentile, 87 112) mL/min/1.73 m(2). Patients were followed up for a median of 5.3 (25th-75th percentile, 2.0-8.9) years, during which 1,820 died and 56 progressed to stages 4 5 CKD. A U-shaped relationship between baseline eGFR and mortality was observed. After adjustment for potential confounders, eGFRs <45 and >105 mL/min/1.73 m(2) remained associated significantly with increased risk of death. Baseline eGFR <90 mL/min/1.73 m(2) was associated with increased risk of kidney disease progression, with the highest incidence rates of stages 4-5 CKD (>3 events/100 person-years) observed in black patients with eGFR of 30-59 mL/min/1.73 m(2) and those of white/other ethnicity with eGFR of 30-44 mL/min/1.73 m(2). LIMITATIONS: The relatively small numbers of patients with decreased eGFR at baseline and low rates of progression to stages 4-5 CKD and lack of data for diabetes, hypertension, and proteinuria. CONCLUSIONS: Although stages 4-5 CKD were uncommon in this cohort, baseline eGFR allowed the identification of patients at increased risk of death and at greatest risk of kidney disease progression. PMID- 22521285 TI - The combined measles, mumps, and rubella vaccines and the total number of vaccines are not associated with development of autism spectrum disorder: the first case-control study in Asia. AB - OBJECTIVE: The aim of this study was to investigate the relationship between autism spectrum disorder (ASD) and general vaccinations, including measles-mumps rubella (MMR) vaccine, in Japanese subjects, a population with high genetic homogeneity. PATIENTS AND METHODS: A case-control study was performed. Cases (n=189) were diagnosed with ASD, while controls (n=224) were volunteers from general schools, matched by sex and birth year to cases. Vaccination history and prenatal, perinatal, and neonatal factors from the Maternal and Child Health handbook, which was part of each subject's file, were examined. To determine the relationship between potential risk factors and ASD, crude odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated, and the differences in mean values of the quantitative variables between cases and controls were analyzed using an unpaired t-test. Moreover, MMR vaccination and the effect of the number of vaccine injections were investigated using a conditional multiple regression model. RESULTS: For MMR vaccination, the OR was 1.04 (95% CI, 0.65-1.68), and no significant differences were found for the other vaccines. For all of the prenatal, perinatal and neonatal factors, there were no significant differences between cases and controls. Furthermore, regarding the presence of ASD, MMR vaccination and the number of vaccine injections had ORs of 1.10 (95% CI, 0.64 1.90) and 1.10 (95% CI, 0.95-1.26), respectively, in the conditional multiple regression model; no significant differences were found. CONCLUSIONS: In this study, there were not any convincing evidences that MMR vaccination and increasing the number of vaccine injections were associated with an increased risk of ASD in a genetically homogeneous population. Therefore, these findings indicate that there is no basis for avoiding vaccination out of concern for ASD. PMID- 22521286 TI - Construction of chimeric bovine viral diarrhea viruses containing glycoprotein E rns of heterologous pestiviruses and evaluation of the chimeras as potential marker vaccines against BVDV. AB - Bovine viral diarrhea virus (BVDV) infections are enzootic in the cattle population and continue to cause significant economic losses to the beef and dairy industries worldwide. Extent of the damages has stimulated increasing interest in control programs directed at eradicating BVDV infections. Use of a BVDV marker vaccine would facilitate eradication efforts as a negatively marked vaccine would enable differentiation of infected from vaccinated animals (DIVA). We describe here the construction of three chimeric BVDVs containing glycoprotein E(rns) of heterologous pestiviruses and the evaluation of the chimera viruses as potential marker vaccines against BVDV infections. Chimeric NADL/G-E(rns), NADL/R E(rns), and NADL/P-E(rns) were constructed by replacing the E(rns) gene of the full-length BVDV (NADL strain) genome with the E(rns) genes of giraffe (G E(rns)), reindeer (R-E(rns)), or pronghorn antelope (P-E(rns)) pestiviruses, respectively. Each chimeric NADL virus was viable and infectious in RD 420 (bovine testicular) and BK-6 (bovine kidney) cells. By immunohistochemistry assays, NADL/G-E(rns) and NADL/R-E(rns) chimeric viruses reacted to BVDV E(rns) specific monoclonal antibody (mAb) 15C5, whereas the NADL/P-E(rns) chimeric virus did not. In an animal vaccination study, inactivated vaccines made from two chimeric viruses and the wild type NADL BVDV induced similar neutralizing antibody responses. NADL/P-E(rns)-vaccinated animals were distinguished from animals vaccinated with the wild type virus by means of a companion serological DIVA assay. These results show that chimeric NADL/P-E(rns) virus containing the E(rns) gene of pronghorn antelope pestivirus could be a potential marker vaccine candidate for use in a BVDV control and eradication program. PMID- 22521287 TI - Cost-effectiveness of 13-valent pneumococcal conjugate vaccine in Switzerland. AB - The 7-valent pneumococcal conjugate vaccine (PCV7) has been shown to be highly cost-effective. The 13-valent pneumococcal conjugate vaccine (PCV13) offers seroprotection against six additional serotypes. A decision-analytic model was constructed to estimate direct medical costs and clinical effectiveness of PCV13 vaccination on invasive pneumococcal disease (IPD), pneumonia, and otitis media relative to PCV7 vaccination. The option with an one-dose catch-up vaccination in children of 15-59 months was also considered. Assuming 83% vaccination coverage and considering indirect effects, 1808 IPD, 5558 pneumonia and 74,136 otitis media cases could be eliminated from the entire population during a 10-year modelling period. The PCV13 vaccination programme would lead to additional costs (+?26.2 Mio), but saved medical costs of -?77.1 Mio due to cases averted and deaths avoided, overcompensate these costs (total cost savings -?50.9 Mio). The national immunisation programmes with PCV13 can be assumed cost saving when compared with the current vaccine PCV7 in Switzerland. PMID- 22521288 TI - Does bladder outlet obstruction alter the non-neuronal cholinergic system of the human urothelium? AB - AIMS: Alterations of the bladder sensory system are considered to contribute to detrusor overactivity (DO) when patients suffer from bladder outlet obstruction (BOO). The urothelium is one part of this sensory system and it harbors a non neuronal cholinergic system (NNCS). We aimed to investigate if BOO causes alterations in the NNCS. MAIN METHODS: Urothelial specimens were collected by endoscopy from six male controls and eight male patients suffering from BOO and DO. The samples were examined by immunofluorescence (IF) and real-time RT-PCR for high-affinity choline transporter-1 (CHT1), choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT), organic cation transporters OCT1-3, muscarinic receptor (mAChR) subtypes M1-M5 and nicotinic receptor (nAChR) subunits alpha7, alpha9 and alpha10. KEY FINDINGS: ChAT, VAChT and OCT2 are not present in the male urothelium. Real-time RT-PCR and IF detected all other investigated targets. Rank order of expression was M2?M3=M5>M4=M1 for mAChR subtypes and alpha7?alpha10>alpha9 for nAChR subunits. Statistical analysis of RT PCR results did not detect significant differences between patients and controls. Only IF detected differences between both groups: alpha9-Immunolabeling was increased in all BOO/DO patients. SIGNIFICANCE: BOO does not induce considerable alterations of the human urothelial NNCS on mRNA level. Expression of mAChRs, CHT1, OCT1 and OCT3 is not significantly affected by BOO. Thus, transport mechanisms for choline and acetylcholine (ACh) stay unaltered. BOO increases immunolabeling of alpha9-nAChR but whether this sole finding contributes to the onset of DO seems questionable. Comparing the present results with our previous work, the urothelial NNCS does not differ between men and women. PMID- 22521289 TI - Erythropoietin alleviates post-ischemic injury of rat hearts by attenuating nitrosative stress. AB - AIMS: Nitrosative stress caused by ischemia contributes to poor functional recovery in hearts. A previous study showed that recombinant human erythropoietin (EPO) activates the Janus-tyrosine kinase 2/extracellular signal-regulated kinase (Jak2/ERK) pathway to protect myocardium against ischemia/reperfusion (IR) injury. However, it is not clear how pro-survival signals triggered by EPO affect the nitric oxide (NO) system in post-ischemic myocardial tissue. MAIN METHODS: Isolated rat hearts were subjected to IR injury and changes in protein expression in the myocardium were evaluated by immunostaining. KEY FINDINGS: Compared with untreated hearts, EPO-treated IR hearts showed significant improvements in contractility and reduced myocardial injury and infarction; this was associated with attenuated caspase-3 activation. Excess formation of NO metabolites and nitrotyrosine, which cause nitrosative stress, was markedly suppressed by EPO. The mechanism underlying EPO-mediated alleviation of nitrosative stress was related to an increase in arginase II expression and to the suppression of heat shock protein 90 (HSP90)-dependent upregulation of endothelial and inducible NO synthase (NOS). Myocardial EPO content was restored after EPO treatment, which in turn recruited signal transducer and activator of transcription (STAT) 3 protein and induced ERK signaling downstream of Jak2, which increased arginase II levels and suppressed HSP90 expression, respectively. Inhibition of STAT3 and ERK specifically reversed the effects of EPO on arginase II and HSP90 expression. SIGNIFICANCE: These results indicate that EPO triggers the Jak2-STAT3/ERK pathway to restore the balance between arginase and NOS and, thus, reduces nitrosative stress. This may form the basis of myocardial protection following IR. PMID- 22521290 TI - The adipokine chemerin augments vascular reactivity to contractile stimuli via activation of the MEK-ERK1/2 pathway. AB - AIMS: Cytokines interfere with signaling pathways and mediators of vascular contraction. Endothelin-1 (ET-1) plays a major role on vascular dysfunction in conditions characterized by increased circulating levels of adipokines. In the present study we tested the hypothesis that the adipokine chemerin increases vascular contractile responses via activation of ET-1/ET-1 receptors-mediated pathways. MAIN METHODS: Male, 10-12 week-old Wistar rats were used. Endothelium intact and endothelium-denuded aortic rings were incubated with chemerin (0.5 ng/mL or 5 ng/mL, for 1 or 24h), and isometric contraction was recorded. Protein expression was determined by Western blotting. KEY FINDINGS: Constrictor responses to phenylephrine (PE) and ET-1 were increased in vessels treated for 1h with chemerin. Chemerin incubation for 24h decreased PE contractile response whereas it increased the sensitivity to ET-1. Endothelium removal significantly potentiated chemerin effects on vascular contractile responses to PE and ET-1. Incubation with either an ERK1/2 inhibitor (PD98059) or ETA antagonist (BQ123) abolished chemerin effects on PE- and ET-1-induced vasoconstriction. Phosphorylation of MEK1/2 and ERK1/2 was significantly increased in vessels treated with chemerin for 1 and 24h. Phosphorylation of these proteins was further increased in vessels incubated with ET-1 plus chemerin. ET-1 increased MEK1/2, ERK1/2 and MKP1 protein expression to values observed in vessels treated with chemerin. SIGNIFICANCE: Chemerin increases contractile responses to PE and ET-1 via ERK1/2 activation. Our study contributes to a better understanding of the mechanisms by which the adipose tissue affects vascular function and, consequently, the vascular alterations present in obesity and related diseases. PMID- 22521292 TI - Sulfuretin, a major flavonoid isolated from Rhus verniciflua, ameliorates experimental arthritis in mice. AB - AIM: Sulfuretin, a major flavonoid isolated from Rhus verniciflua, is known to have anti-inflammatory effects. However, the mechanisms underlying the anti inflammatory effect of sulfuretin on rheumatoid arthritis have not been elucidated. In this study we investigated whether sulfuretin treatment modulates the severity of arthritis in an experimental model. MAIN METHODS: We evaluated the effects of sulfuretin on tumor necrosis factor-alpha (TNF-alpha)-treated human rheumatoid fibroblast-like synoviocytes (FLS) in vitro and on collagen induced arthritis (CIA) mice in vivo. KEY FINDINGS: In vitro experiments demonstrated that sulfuretin suppressed the chemokine production, matrix metalloproteinase secretion, and cell proliferation induced by tumor necrosis factor-alpha in rheumatoid FLS. In addition, sulfuretin inhibited the osteoclast differentiation induced by macrophage colony-stimulating factor and receptor activator of NF-kappaB ligand in bone marrow macrophages. In mice with CIA, early intervention with sulfuretin prevented joint destruction, as evidenced by a lower cumulative disease incidence and an absence of diverse disease features based on hind paw thickness, radiologic and histopathologic findings, and inflammatory cytokine levels. In mice with established arthritis, sulfuretin treatment significantly reduced synovial inflammation and joint destruction. The in vitro and in vivo protective effects of sulfuretin were mediated by inhibition of the NF-kappaB signaling pathway. SIGNIFICANCE: These results suggest that using sulfuretin to block the NF-kappaB pathway in rheumatoid joints reduces both inflammatory responses and joint destruction. Therefore, sulfuretin may have therapeutic value in preventing or delaying the progression of rheumatoid arthritis. PMID- 22521291 TI - Ouabain stimulates atrial natriuretic peptide secretion via the endothelin 1/ET(B) receptor-mediated pathway in beating rabbit atria. AB - AIMS: Ouabain has been reported to increase the secretion of atrial natriuretic peptide (ANP) in vitro. However, the mechanism by which ouabain increases ANP secretion is not well known. Therefore, the purpose of the present study was to investigate the underlying mechanism of ouabain-stimulated ANP secretion. MAIN METHODS: A perfused beating rabbit atrial model was used. The ANP and ET-1 levels in the atrial perfusates were measured by radioimmunoassays. KEY FINDINGS: Ouabain (1.0, 3.0 and 6.0 MUmol/L) significantly increased atrial ANP secretion in a dose-dependent manner, while the endothelin (ET)-1 levels were increased by the higher doses (3.0 and 6.0 MUmol/L) of ouabain. Ouabain-increased atrial ET-1 release was blocked by PD98059 (30.0 MUmol/L), an inhibitor of mitogen-activated protein kinase (MAPK). Nifedipine (1.0 MUmol/L), an inhibitor of L-type Ca(2+) channels, completely abolished ouabain-increased ANP secretion without changing the ouabain-induced atrial dynamics. KB-R7943 (3.0 MUmol/L), an inhibitor of Na(+)-Ca(2+) exchangers, completely blocked the effects of ouabain-increased atrial dynamics, but did not modulate ouabain-increased ANP secretion. ET-1 significantly stimulated atrial ANP release in a dose-dependent manner. The effects of ET-1 and ouabain on ANP secretion were completely blocked by BQ788 (0.3 MUmol/L), an inhibitor of ET-1 type B (ET(B)) receptors, but not by BQ123 (0.3 MUM), an inhibitor of ET-1 type A receptors. Ouabain-increased atrial ANP secretion was blocked by PD98059 and indomethacin (30.0 MUmol/L), an inhibitor of cyclooxygenase. SIGNIFICANCE: Ouabain significantly stimulated atrial ANP secretion via an ET-1-ET(B) receptor-mediated pathway involving MAPK signaling pathway activation and prostaglandin formation. PMID- 22521293 TI - ETS-dependent p16INK4a and p21waf1/cip1 gene expression upon endothelin-1 stimulation in malignant versus and non-malignant proximal tubule cells. AB - AIM: Cellular senescence, leading to cell death through prevention of regular cell renewal, is associated with the upregulation of the tumor suppressor gene p16(INK4a). While this mechanism has been described as leading to progressive nephron loss, p16(INK4a) upregulation in renal cell carcinoma has been linked to a disease-specific improved patient survival rate. While in both conditions endothelin-1 is also upregulated, the signaling pathway connecting ET-1 to p16(INK4a) has not been characterized until this study. MAIN METHODS: Cell culture, qRT-PCR, Western Blot, immunoprecipitation (IP), proximity ligation assay (PLA), and non-radioactive electrophoretic mobility shift assay (EMSA). KEY FINDINGS: In malignant renal proximal tumor cells (Caki-1), an activation of p16(INK4a) and p21(waf1/cip1) was observed. An increased expression of E-26 transformation-specific (ETS) transcription factors was detectable. Using specific antibodies, a complex formation between ETS1 and extracellular signal regulated kinase-2 (ERK2) was shown. A further complex partner was Mxi2. EMSA with supershift analysis for ETS1 and Mxi2 indicated the involvement of both factors in the protein-DNA interaction. After specifically blocking the endothelin receptors, ETS1 expression was significantly downregulated. However, the endothelin B receptor dependent downregulation was stronger than that of the A receptor. In contrast, primary proximal tubule cells showed a nuclear decrease after ET-1 stimulation. This indicates that other ETS members may be involved in the observed p16(INK4a) upregulation (as described in the literature). SIGNIFICANCE: ETS1, ERK2 and Mxi2 are important complex partners initiating increased p16(INK4a) and p21w(af1/cip1) activation in renal tumor cells. PMID- 22521294 TI - Different kinds of bilinguals: different kinds of brains: the neural organisation of two languages in one brain. AB - The aim of this study was to determine whether the type of bilingualism affects neural organisation. We performed identification experiments and mismatch negativity (MMN) registrations in Finnish and Swedish language settings to see, whether behavioural identification and neurophysiological discrimination of vowels depend on the linguistic context, and whether there is a difference between two kinds of bilinguals. The stimuli were two vowels, which differentiate meaning in Finnish, but not in Swedish. The results indicate that Balanced Bilinguals are inconsistent in identification performance, and they have a longer MMN latency. Moreover, their MMN amplitude is context-independent, while Dominant Bilinguals show a larger MMN in the Finnish context. These results indicate that Dominant Bilinguals inhibit the preattentive discrimination of native contrast in a context where the distinction is non-phonemic, but this is not possible for Balanced Bilinguals. This implies that Dominant Bilinguals have separate systems, while Balanced Bilinguals have one inseparable system. PMID- 22521295 TI - Geographical patterns of genetic divergence in the widespread Mesoamerican bumble bee Bombus ephippiatus (Hymenoptera: Apidae). AB - Bumble bees (Bombus Latreille) are an important group of social insects, well recognized throughout northern temperate regions as important pollinators of wild and agricultural plants. Little is known about the biology of this group in southern portions of the Americas, especially in Mesoamerica, a region of geological and ecological complexity from Mexico through Central America. One ubiquitous Mesoamerican species, Bombus ephippiatus, is enigmatic. Like many other Bombus, this species is homogeneous in body structure yet exhibits striking intraspecific color pattern polymorphism across its range, leading to uncertainty about its genealogical boundaries. It has been grouped taxonomically with B. wilmattae, a species narrowly restricted to southern Mexico and northern Guatamala. Furthermore, the relationships between these two taxa and a third species, B. impatiens, found only in America north of Mexico, have been controversial. Our phylogenetic analysis of DNA sequences from mitochondrial COI and nuclear PEPCK and CAD resolves the phylogeny of these three taxa as (B. impatiens, (B. ephippiatus, B. wilmattae)). Additional data from eight nuclear microsatellite markers reveal complex patterns of genetic divergence and isolation among populations of B. ephippiatus across its extensive geographic range, providing evidence for multiple independent evolutionary lineages. These lineages correspond not only to geographic and habitat variation across their range, but also to distinct color pattern groups present in the species. Knowledge of the phylogeny and genetic divergence of the B. ephippiatus group will provide a framework for understanding evolutionary and ecological origins of color pattern polymorphism in bumble bees, as well as providing insight into geographical factors enhancing speciation in Mesoamerica. PMID- 22521296 TI - Long-term outcomes after percutaneous intervention of the internal thoracic artery anastomosis: the use of drug-eluting stents is associated with a higher need of repeat revascularization. AB - BACKGROUND: There is a lack of data and absence of clear recommendations regarding the optimal treatment of lesions located at the anastomosis of internal thoracic artery (ITA) grafts and native coronary arteries (CAs). The objective of this study was to assess the long-term outcomes of percutaneous coronary intervention (PCI) at the ITA anastomosis according to delivered treatment, namely deployment of a drug-eluting stent (DES), bare-metal stent (BMS), or balloon angioplasty only (POBA). METHODS: We used a prospective PCI registry at a large Canadian teaching hospital to identify all patients who underwent PCI at the ITA-CA anastomosis between June 2000 and June 2010. Our primary end point was repeat target lesion revascularization (TLR) at follow-up. RESULTS: Of the 53 patients included in the study (mean age 67.1 +/- 10.7; 84.9% males), 45 (84.9%) underwent a successful PCI procedure. Of these, 23 patients (51.1%) received DES, 18 (40%) BMS, and 4 (8.9%) POBA. After a median follow-up of 29.2 months (interquartile range, 11.1-77.7 months), TLR was 47.8% with DES, 7.1% with BMS, and 50% with POBA (P = 0.032). Patients who underwent repeat revascularization were more likely to have longer stents than those who did not (18.2 mm vs 14.2 mm, P = 0.043). CONCLUSIONS: Deployment of a DES for the treatment of ITA anastomotic lesions appears to be associated with a higher rate of repeat revascularization compared with BMS. Further studies will be necessary to evaluate if the present results might reflect different underlying pathophysiology in anastomotic and native coronary atherosclerotic lesions. PMID- 22521297 TI - Resistant hypertension and aldosterone: an update. AB - Resistant hypertension (RHTN) is defined as a blood pressure remaining above goal despite the concurrent use of 3 antihypertensive medications of different classes, including, ideally a diuretic. RHTN is an important health problem with a prevalence rate expected to increase as populations become older, more obese, and at higher risk of having diabetes and chronic kidney disease, all of which are important risk factors for development of RHTN. The role of aldosterone has gained increasing recognition as a significant contributor to antihypertensive treatment resistance. In prospective studies, the prevalence of primary aldosteronism (PA) has ranged from 14%-21% in patients with RHTN, which is considerably higher than in the general hypertensive population. Furthermore, marked antihypertensive effects are seen when mineralocorticoid antagonists are added to the treatment regimen of patients with RHTN, further supporting aldosterone excess as an important cause of RHTN. A close association exists between hyperaldosteronism, RHTN, and obstructive sleep apnea (OSA) based upon recent studies which indicate that OSA is worsened by aldosterone-mediated fluid retention. This interaction is supported by preliminary data which demonstrates improvement in OSA severity after treatment with spironolactone. PMID- 22521298 TI - Medium-term evaluation of an educational intervention on dietary and physical exercise habits in schoolchildren: the Avall 2 study. AB - OBJECTIVE: To assess whether the benefits seen in nutrition, physical activity. and body mass index were maintained at 2 years of completion of the educational intervention. MATERIAL AND METHODS: An experimental, longitudinal, 4-year, two arm, parallel study with cluster randomization to assess an intervention program aimed at children in their first year of primary schooling attending schools in the city of Granollers. Intervention consisted of promoting healthy dietary habits and increasing physical activity through the educational pedagogy Investigation, Vision, Action and Change (IVAC), applied over 2 school years (2006-2008). Weight and height of each child wee measured in situ, and families self-completed a physical activity survey and the Krece Plus quick test in 2006, 2008, and 2010. RESULTS: A greater increase in body mass index was seen in 2010 in children from the control group (2.84 +/- 0.22 vs 1.96 +/- 0.163 kg/m(2), <.001). Prevalence of overweight and obesity increased by 8% and 0.5% respectively in schoolchildren in the control group, while the intervention group showed a 5.3% increase in prevalence of overweight and a 3.6%decrease in prevalence of obesity. Prevalence of excess weight therefore increased by 8.5% in the control group and by 1.8% in the intervention group. Reduction in body mass indexincrease was maintained 2 years after completion of educational intervention regardless of sex, origin, maternal obesity, and educational level of parents. CONCLUSIONS: These results confirm that school-based interventions may help contain the current increase in childhood obesity. PMID- 22521299 TI - Rhinomucormycosis and type 1 diabetes mellitus. PMID- 22521300 TI - Waist circumference percentiles in children and adolescents between 6 and 14 years from Santiago, Chile. AB - OBJECTIVE: To describe the percentile distribution of waist circumference (WC) by sex and age in a representative sample of children and adolescents of lower middle and low socioeconomic status in Santiago, Chile. METHODS: A cross-section of 3022 primary-school students between the ages of 6 and 14 from middle-low and low-class schools of Santiago. Ten schools from the Primary Education Society (SIP) in Santiago, Chile, were selected at random. WC was measured under standardized procedures as instructed by the WHO (midpoint between lower costal margin and iliac crest). The population was categorized between percentiles 10 and 90 and divided by sex and age. RESULTS: WC tends to increase with age in both males and females, but no significant differences were found in the percentiles by age for boys and girls at any age range (p>0.05). In our sample, comparing Chilean children with other populations (British, Australian, European-American, African-American, Mexican - American and Colombian), Chilean children have shown a significantly greater WC (p<0.05). CONCLUSIONS: We present new WC reference values for Chilean children according to sex and age from a representative sample of Chilean population. These can be considered as a new anthropometric assessment tool for estimating cardiometabolic risk in Chilean children. PMID- 22521301 TI - Mossbauer spectroscopy with a high velocity resolution: advances in biomedical, pharmaceutical, cosmochemical and nanotechnological research. AB - The methodological principles of velocity resolution as additional characteristic of the quality of both Mossbauer spectrometer velocity driving system and Mossbauer spectrum were briefly considered. Significantly better quality of Mossbauer spectra measured with a high velocity resolution in comparison with those measured with a low velocity resolution was demonstrated. The main advances of recent studies of iron containing biomolecules, pharmaceutical products, meteorite samples and nanoparticles using Mossbauer spectroscopy with a high velocity resolution were considered and advantages of this technique were shown. PMID- 22521302 TI - MEF2C ablation in endothelial cells reduces retinal vessel loss and suppresses pathologic retinal neovascularization in oxygen-induced retinopathy. AB - Ischemic retinopathies, including retinopathy of prematurity and diabetic retinopathy, are major causes of blindness. Both have two phases, vessel loss and consequent hypoxia-driven pathologic retinal neovascularization, yet relatively little is known about the transcription factors regulating these processes. Myocyte enhancer factor 2 (MEF2) C, a member of the MEF2 family of transcription factors that plays an important role in multiple developmental programs, including the cardiovascular system, seems to have a significant functional role in the vasculature. We, therefore, generated endothelial cell (EC)-specific MEF2C deficient mice and explored the role of MEF2C in retinal vascularization during normal development and in a mouse model of oxygen-induced retinopathy. Ablation of MEF2C did not cause appreciable defects in normal retinal vascular development. However, MEF2C ablation in ECs suppressed vessel loss in oxygen induced retinopathy and strongly promoted vascular regrowth, consequently reducing retinal avascularity. This finding was associated with suppression of pathologic retinal angiogenesis and blood-retinal barrier dysfunction. MEF2C knockdown in cultured retinal ECs using small-interfering RNAs rescued ECs from death and stimulated tube formation under stress conditions, confirming the endothelial-autonomous and antiangiogenic roles of MEF2C. HO-1 was induced by MEF2C knockdown in vitro and may play a role in the proangiogenic effect of MEF2C knockdown on retinal EC tube formation. Thus, MEF2C may play an antiangiogenic role in retinal ECs under stress conditions, and modulation of MEF2C may prevent pathologic retinal neovascularization. PMID- 22521303 TI - Increased expression of P-glycoprotein and doxorubicin chemoresistance of metastatic breast cancer is regulated by miR-298. AB - MicroRNAs (miRNAs) are short, noncoding RNA molecules that regulate the expression of a number of genes involved in cancer; therefore, they offer great diagnostic and therapeutic targets. We have developed doxorubicin-resistant and sensitive metastatic human breast cancer cell lines (MDA-MB-231) to study the chemoresistant mechanisms regulated by miRNAs. We found that doxorubicin localized exclusively to the cytoplasm and was unable to reach the nuclei of resistant tumor cells because of the increased nuclear expression of MDR1/P glycoprotein (P-gp). An miRNA array between doxorubicin-sensitive and -resistant breast cancer cells showed that reduced expression of miR-298 in doxorubicin resistant human breast cancer cells was associated with increased expression of P gp. In a transient transfection experiment, miR-298 directly bound to the MDR1 3' untranslated region and regulated the expression of firefly luciferase reporter in a dose-dependent manner. Overexpression of miR-298 down-regulated P-gp expression, increasing nuclear accumulation of doxorubicin and cytotoxicity in doxorubicin-resistant breast cancer cells. Furthermore, down-regulation of miR 298 increased P-gp expression and induced doxorubicin resistance in sensitive breast cancer cells. In summary, these results suggest that miR-298 directly modulates P-gp expression and is associated with the chemoresistant mechanisms of metastatic human breast cancer. Therefore, miR-298 has diagnostic and therapeutic potential for predicting doxorubicin chemoresistance in human breast cancer. PMID- 22521304 TI - Conditioning the whole heart--not just the cardiomyocyte. AB - Conditioning, the recruitment of endogenous cytoprotective pathways that protect the myocardium against injurious ischaemia/reperfusion injury, has developed into a range of modalities that can be applied before (preconditioning), during (perconditioning) or after the injurious ischaemic insult (postconditioning), either directly to the heart or in a distal tissue (remote preconditioning). A wide range of triggers, signaling pathways and potential end-effector mechanisms have been identified, which appear common to all forms of conditioning. Interestingly, conditioning applies to not only the cardiac myocyte, but to all the constitutive cell types within the myocardium. As our understanding of conditioning mechanisms continue to develop and we start to realise some of the difficulties in translating these phenomena to clinical treatments, it may be time to take a more integrative approach to conditioning, considering the many cellular and tissue types within the heart, and how they contribute to cytoprotective adaptations. In this review, we shall look at the conditioning phenomena, how different cell types contribute to the conditioned phenotype, and where novel cardioprotective modalities may be developed. PMID- 22521305 TI - Usefulness of risk scores to estimate the risk of cardiovascular disease in patients with rheumatoid arthritis. AB - Patients with rheumatoid arthritis (RA) have an excess burden of cardiovascular (CV) disease (CVD). CV risk scores for the general population may not accurately predict CV risk for patients with RA. A population-based inception cohort of patients who fulfilled 1987 American College of Rheumatology criteria for RA from 1988 to 2007 was followed until death, migration, or December 31, 2008. CV risk factors and CVD (myocardial infarction, CV death, angina, stroke, intermittent claudication, and heart failure) were ascertained by medical record review. Ten year predicted CVD risk was calculated using the general Framingham and the Reynolds risk scores. Standardized incidence ratios were calculated to compare observed and predicted CVD risks. The study included 525 patients with RA aged >=30 years without previous CVD. The mean follow-up period was 8.4 years, during which 84 patients developed CVD. The observed CVD risk was 2-fold higher than the Framingham risk score predicted in women and 65% higher in men, and the Reynolds risk score revealed similar deficits. Patients aged >=75 years had observed CVD risk >3 times the Framingham-predicted risk. Patients with positive rheumatoid factor or persistently elevated erythrocyte sedimentation rates also experienced more CVD events than predicted. In conclusion, the Framingham and Reynolds risk scores substantially underestimated CVD risk in patients with RA of both genders, especially in older ages and in patients with positive rheumatoid factor. These data underscore the need for more accurate tools to predict CVD risk in patients with RA. PMID- 22521306 TI - Relation of systemic blood pressure to sudden cardiac death. AB - The role of systolic blood pressure (SBP) as an independent risk factor for sudden cardiac death (SCD) is not well defined in a general population. Thus, we assessed the association between BP at rest and risk of SCD. BP and other risk factors were measured in a representative population-based sample of 2,666 Finnish men (42 to 61 years of age). During an average follow-up period of 18.9 years (interquartile range 17.9 to 22.6), 213 SCDs occurred. Each increment 10-mm Hg of SBP at rest was associated with an increased risk of SCD (relative hazard 1.15, 95% confidence interval 1.07 to 1.25, p <0.001) after adjustment for age, alcohol consumption, cigarette smoking, serum low-density lipoprotein cholesterol, type 2 diabetes, body mass index, left ventricular hypertrophy, previous myocardial infarction, family history of coronary heart disease, and use of antihypertensive medications. Men with increased SBP of >145 mm Hg had a 2.04 fold (95% confidence interval 1.23 to 2.52, p = 0.003) adjusted risk for SCD compared to those with SBP <123 mm Hg. In conclusion, this study emphasizes the importance of the definition of SBP at rest because it provides a valuable prognostic measurement for SCD. PMID- 22521307 TI - Alcohol and vagal tone as triggers for paroxysmal atrial fibrillation. AB - Alcohol and vagal activity may be important triggers for paroxysmal atrial fibrillation (PAF), but it remains unknown if these associations occur more often than would be expected by chance alone because of the lack of a comparator group in previous studies. We compared self-reported frequency of these triggers in patients with PAF to those with other supraventricular tachycardias (SVTs). Consecutive consenting patients presenting for electrophysiology procedures at a single university medical center underwent a structured interview regarding arrhythmia triggers. Two hundred twenty-three patients with a documented arrhythmia (133 with PAF and 90 with SVT) completed the survey. After multivariable adjustment, patients with PAF had a 4.42 greater odds (95% confidence interval [CI] 1.35 to 14.44) of reporting alcohol consumption (p = 0.014) and a 2.02 greater odds (95% CI 1.02 to 4.00) of reporting vagal activity (p = 0.044) as an arrhythmia trigger compared to patients with SVT. In patients with PAF, drinking primarily beer was associated with alcohol as a trigger (odds ratio [OR] 4.49, 95% CI 1.41 to 14.28, p = 0.011), whereas younger age (OR 0.68, 95% CI 0.49 to 0.95, p = 0.022) and a family history of AF (OR 5.73, 95% CI 1.21 to 27.23, p = 0.028) each were independently associated with having vagal activity provoke an episode. Patients with PAF and alcohol triggers were more likely to have vagal triggers (OR 10.32, 95% CI 1.05 to 101.42, p = 0.045). In conclusion, alcohol consumption and vagal activity elicit PAF significantly more often than SVT. Alcohol and vagal triggers often were found in the same patients with PAF, raising the possibility that alcohol may precipitate AF by vagal mechanisms. PMID- 22521308 TI - Meta-analysis of randomized trials of angioedema as an adverse event of renin angiotensin system inhibitors. AB - Angioedema is a rare, potentially life-threatening adverse event of renin angiotensin system inhibitors. The objective of the present study was to determine the risk of angioedema from randomized clinical trials. A PubMed/CENTRAL/EMBASE search was made for randomized clinical trials from 1980 to October 2011 in patients on angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or direct renin inhibitor (DRI). Trials with a total number of patients >=100 and a duration of >=8 weeks were included for analysis. Incidence of angioedema was pooled by weighing the incident rate of each trial by the inverse of the variance. Twenty-six trials with 74,857 patients in the ACE inhibitor arm with 232,523 person-years of follow-up, 19 trials with 35,479 patients on ARB with 122,293 person-years of follow-up, and 2 trials with 5,141 patients on DRI with 1,735 person-years of follow-up met the inclusion criteria and were included in the analysis. In head-to-head comparison in 7 trials, risk of angioedema with ACE inhibitors was 2.2 times higher than with ARBs (95% confidence interval [CI] 1.5 to 3.3). With ACE inhibitors and ARBs, incidence of angioedema was higher in heart failure trials compared to hypertension or coronary artery disease trials without heart failure (p <0.0001). Weighted incidence of angioedema with ACE inhibitors was 0.30% (95% CI 0.28 to 0.32) compared to 0.11% (95% CI 0.09 to 0.13) with ARBs, 0.13% (95% CI 0.08 to 0.19) with DRIs, and 0.07% with placebo (95% CI 0.05 to 0.09). In conclusion, incidence of angioedema with ARBs and DRI was <1/2 than that with ACE inhibitors and not significantly different from placebo. Incidence of angioedema was higher in patients with heart failure compared to those without heart failure with ACE inhibitors and ARBs. PMID- 22521309 TI - Effect of new versus known versus no atrial fibrillation on 30-day and 10-year mortality in patients with acute coronary syndrome. AB - Coronary artery disease promotes the development of atrial fibrillation (AF). The aim of this study was to determine short- and long-term mortality in patients with acute coronary syndromes (ACS) and AF, depending on the AF presentation. A total of 2,335 consecutive patients with ACS were included. AF was classified as known persistent or permanent AF, known paroxysmal AF, new AF at admission, and new AF during hospitalization for ACS. Four hundred forty-two patients had any AF: 54 with known persistent or permanent AF, 150 with known paroxysmal AF, 54 with new AF at admission, and 184 with new AF during hospitalization. Statistically significant differences among subgroups related to previous heart failure (p <0.0001), stroke (p = 0.04), myocardial infarction (p <0.0001), angina pectoris (p <0.0001), hypercholesterolemia (p = 0.007), coronary artery bypass grafting (p <0.0001), and percutaneous coronary intervention (p = 0.03) were observed. Thirty-day mortality differed among the subgroups (p = 0.02) and was lowest in patients with known paroxysmal AF (7.3%). Ten-year mortality ranged from 53% to 78% among the subgroups. There were 5 predictors of long-term mortality across the subgroups: age (hazard ratio [HR] 1.06, 95% confidence interval [CI] 1.04 to 1.09, p <0.0001), previous myocardial infarction (HR 1.4, 95% CI 1.0 to 1.8, p = 0.04), heart failure (HR 1.8, 95% CI 1.3 to 2.4, p = 0.0002), diabetes (HR 1.7, 95% CI 1.2 to 2.2, p = 0.0005), and smoking (HR 1.7, 95% CI 1.2 to 2.3, p = 0.001). In conclusion, patient characteristics and 30-day mortality differed significantly among the subgroups, but long-term mortality did not. Any AF associated with ACS almost doubled the long-term mortality risk. AF in patients with ACS should therefore be regarded as an important risk factor irrespective of its presentation. PMID- 22521310 TI - Rem sleep brady-arrhythmias: an indication to pacemaker implantation? AB - OBJECTIVES: Important adjustments in the autonomic nervous system occur during sleep. Bradycardia, due to increased vagal tone, and hypotension, caused by reduction of sympathetic activity, may occur during non rapid eye movement (REM) sleep (NREM). Increased sympathetic activity, causing increased heart rate, is conversely a feature of phasic REM sleep. During REM sleep, sinus arrests and atrioventricular (AV) blocks unrelated to apnea or hypopnea have been described. These arrhythmias are very rare and only a few cases have been reported in the literature. PATIENTS/METHODS: Following an ECG performed for other reasons, two patients with no history of sleep complaints nor symptoms of heart failure or heart attack were referred to our center for nocturnal brady-arrhythmias. RESULTS: 24h ECG Holter recorded several episodes of brady-arrhythmia with sinus arrest in the first patients and brady-arrhythmias with complete AV block in the second patient. In both patients, episodes of brady-arrhythmia were prevalent in the second part of the night. Nocturnal polysomnography (PSG) demonstrated that episodes occurred only during REM sleep, particularly during phasic events. Treatment with pacemaker was considered only for the patient with complete AV blocks. CONCLUSIONS: These types of brady-arrhythmias are usually detected accidentally due to their lack of symptoms. It has been suggested that in some patients they may lead to sudden unexpected death. Thus, the identification of predisposing factors is mandatory in order to prevent potentially dangerous arrhythmic events. PMID- 22521311 TI - Obstructive sleep apnea and the risk of autoimmune diseases: a longitudinal population-based study. AB - BACKGROUND: Obstructive sleep apnea (OSA) has been associated with chronic inflammation. However, no data regarding the risk for autoimmune disease in patients with OSA has been reported. This study aims to investigate the longitudinal risk for the development of certain autoimmune diseases in patients with OSA. METHODS: For the study cohort, we identified 1411 patients from the Taiwan Longitudinal Health Insurance Database who had a diagnosis of OSA. For controls, 7055 subjects matched in terms of sex, age, and the index year were randomly extracted from the same database. Each patient was tracked for a five year period to identify those patients who had received a diagnosis of rheumatoid arthritis (RA), ankylosing spondylitis (AS), or systemic lupus erythematous (SLE). Stratified Cox proportional hazard regression was performed on the two cohorts to compute the risk of autoimmune diseases during follow-up period. RESULTS: Of 8466 patients, 1.76% had developed autoimmune diseases during the five-year follow-up period; 2.91% and 1.53% for the study cohort and the controls, respectively. The stratified Cox proportional analysis revealed that, after eliminating individuals who died during the follow-up period and adjusting for geographic and socioeconomic factors, the hazard for developing autoimmune disease during the five-year follow-up period was 1.91 (95% CI=1.32-2.77, p<0.001) times greater for patients with OSA than for controls. CONCLUSION: Patients with OSA have a higher risk of developing certain autoimmune diseases. Further study is advised to confirm our findings and explore the underlying pathomechanism. PMID- 22521312 TI - Involvement of postnatal apoptosis on sex difference in number of cells generated during late fetal period in the sexually dimorphic nucleus of the preoptic area in rats. AB - Postnatal apoptosis is involved in formation of the sex difference in neuron number of the sexually dimorphic nucleus of the preoptic area (SDN-POA) in rats. In this study, we examined the origin of neurons that die with apoptosis on the postnatal period to exhibit the sex difference in neuron number of the SDN-POA. First, we measured the number of cells that were labeled with 5-bromo-2' deoxyuridine (BrdU) on embryonic day (ED) 17, ED18, and ED19 in the SDN-POA of rats on postnatal day (PD) 4 and PD8. The SDN-POA had many more cells labeled with BrdU on ED17 and ED18 than those on ED19. Significantly fewer cells labeled with BrdU on ED18 in the female SDN-POA from PD4 to PD8 resulted in a significant sex difference in the number at PD8. Next, combination analyses of BrdU-labeling and immunohistochemistry for single-stranded DNA (ssDNA), an apoptotic marker, were succeeded to investigate whether SDN-POA neurons generated during ED17-18 were removed by apoptosis. Many more ssDNA-immunoreactive cells that had been labeled with BrdU during ED17-18 were found in the SDN-POA of PD8 females, but few in the SDN-POA of PD8 males and PD4 females and males. These results suggest that the sex difference in the number of SDN-POA neurons generated during the late fetal period was caused by postnatal apoptosis. PMID- 22521313 TI - Involvement of P2Y13 receptor in suppression of neuronal differentiation. AB - We examined the receptor-mediated effects of extracellular ATP on neuronal differentiation of PC12 cells, Neuro2a cells and MEB5 cells by using a series of receptor antagonists. The P2Y13 receptor antagonist MRS2211 significantly accelerated neurite outgrowth in all cases. Treatment with nerve growth factor (NGF) alone activated ERK1/2 in PC12 cells, and the activation was further increased by MRS2211. These results suggest involvement of P2Y13 receptor in suppression of neuronal differentiation. Thus, P2Y13 receptor antagonists might be candidates for treatment of neurodegenerative diseases. PMID- 22521314 TI - Chronic peripheral hyperinsulinemia has no substantial influence on tau phosphorylation in vivo. AB - Chronic peripheral hyperinsulinemia is one of the main characteristics of type 2 diabetes accompanied by impaired glucose homeostasis and obesity resulting from increased food intake and decreased physical activity. Patients with type 2 diabetes have a higher risk of cognitive decline and neurodegenerative diseases e.g. Alzheimer's disease (AD). Furthermore, obesity or hyperinsulinemia alone already increase the probability of cognitive decline possibly progressing to AD. Tau hyperphosphorylation is one of the pathological hallmarks of AD and so called tauopathies. Aim of the present study was to analyze the influence of obesity associated hyperinsulinemia on tau phosphorylation without changes in glucose homeostasis. 15% high fat diet fed over 12-16 weeks induced 2.4-fold increased plasma insulin levels without changing glucose tolerance. However, this diet did not lead to substantial differences in tau phosphorylation in the brain of C57Bl/6 mice. Additionally, chronic hyperinsulinemia did not influence downstream insulin receptor signaling and the expression of the tau kinases (e.g. ERK-1/-2, Akt, GSK-3beta, CDK5 or JNK) and tau phosphatases (e.g. PP2A) in the murine central nervous system. Thus, we successfully induced hyperinsulinemia without causing glucose intolerance in our experimental animals but this did not influence central insulin receptor signaling or tau phosphorylation. PMID- 22521315 TI - Simple technologies for on-farm composting of cattle slurry solid fraction. AB - Composting technologies and control systems have reached an advanced stage of development, but these are too complex and expensive for most agricultural practitioners for treating livestock slurries. The development of simple, but robust and cost-effective techniques for composting animal slurries is therefore required to realise the potential benefits of waste sanitation and soil improvement associated with composted livestock manures. Cattle slurry solid fraction (SF) was collected at the rates of 4m(3)h(-1) and 1m(3)h(-1) and composted in tall (1.7 m) and short (1.2m) static piles, to evaluate the physicochemical characteristics and nutrient dynamics of SF during composting without addition of bulking agent materials, and without turning or water addition. Highest maximum temperatures (62-64 degrees C) were measured in tall piles compared to short piles (52 degrees C). However, maximum rates of organic matter (OM) destruction were observed at mesophilic temperature ranges in short piles, compared to tall piles, whereas thermophilic temperatures in tall piles maximised sanitation and enhanced moisture reduction. Final OM losses were within the range of 520-660 g kg(-1) dry solids and the net loss of OM significantly (P<0.001) increased nutrient concentrations during the composting period. An advanced degree of stabilization of the SF was indicated by low final pile temperatures and C/N ratio, low concentrations of NH(4)(+) and increased concentrations of NO(3)(-) in SF composts. The results indicated that minimum intervention composting of SF in static piles over 168 days can produce agronomically effective organic soil amendments containing significant amounts of OM (772-856 g kg(-1)) and plant nutrients. The implications of a minimal intervention management approach to composting SF on compost pathogen reduction are discussed and possible measures to improve sanitation are suggested. PMID- 22521316 TI - Defective PAX4 R192H transcriptional repressor activities associated with maturity onset diabetes of the young and early onset-age of type 2 diabetes. AB - AIMS: PAX4 R192H polymorphism was reported to be associated with maturity onset diabetes of the young (MODY) and early onset-age of type 2 diabetes (T2D). This study aimed to evaluate transcriptional repression activity of PAX4 R192H polymorphism on its target promoters comparing with wild-type PAX4. METHODS: Wild type PAX4 and PAX4 R192H proteins were expressed in vitro and the cell compartmentalization of each protein was examined after transfection of the plasmid constructs into betaTC3 cells followed by Western-blot analysis. The plasmid containing wild-type PAX4 or PAX4 R192H was co-transfected into betaTC3 and alphaTC-1.9 cells with insulin or glucagon promoter-reporter construct. Transcriptional repression activities were then determined by dual-luciferase reporter assay. RESULTS: Wild-type PAX4 and PAX4 R192H, which were found to be equally expressed in vitro and transfection systems, were present in the nuclear compartment. Transcriptional repressor activities of PAX4 R192H on human insulin and glucagon promoters were reduced when they were compared with those of wild type PAX4. CONCLUSIONS: These results suggested that PAX4 R192H polymorphism generated a protein with defect in transcriptional repressor activities on its target genes, which may lead to beta-cell dysfunction associated with MODY and early onset-age of T2D as reported in our previous study. PMID- 22521317 TI - Frequent insulin dosage adjustments based on glucose readings alone are sufficient for a safe and effective therapy. AB - PROBLEM: Frequent dosage adjustments are necessary to achieve effective insulin therapy. However, a controversy surrounds the pertinent clinical parameters required to make effective and safe insulin titrations. We hypothesize that glucose readings are sufficient to adjust insulin dosage provided that it is done on a weekly basis. METHODS: In a prospective pilot study, we recruited 14 subjects with suboptimally controlled insulin-treated Type-2 and Type-1 diabetes. Subjects were treated with basal-bolus insulin therapy that was titrated weekly for 12 weeks. Dosage adjustments were made by the study Endocrinologist by reviewing subjects' glucose readings, exclusively based on logsheets and contingent upon the approval of the on-site study team. To corroborate that the glucose readings were sufficient for making dosage adjustments, we used software to process only glucose readings and recommend insulin dosage adjustments. The recommendations made by the software were retrospectively compared to the ones made by the study Endocrinologist. RESULTS: All N=568 recommendations were approved by the study team and in 99.3% of the cases the recommendations were clinically similar to the ones made by the software. No hazardous disagreements were found. The mean A1C improved from 9.8% (+/- 2.0) to 7.9% (+/- 1.3) (p=0.001) in 12 weeks and the weekly mean glucose progressively improved from 220.3 mg/dl (+/- 51.9) to 151.5 mg/dl (+/- 19.2) (p<0.0001). The frequency of minor hypoglycemia was 22.7 per patient-year in subjects with Type-2 diabetes and 42.7 in the subjects with Type-1 diabetes. No severe hypoglycemic events occurred. CONCLUSIONS: Glucose readings are sufficient to adjust insulin therapy in a safe and effective manner, when adjustments are made on a weekly basis. Thus, dedicated software may help adjust insulin dosage between clinic visits. PMID- 22521318 TI - Hyperglycemia and oxidative stress in cultured endothelial cells--a comparison of primary endothelial cells with an immortalized endothelial cell line. AB - Diabetes mellitus is a major risk factor for the development of cardiovascular disease and oxidative stress plays an important role in this process. Therefore, we investigated the effects of hyperglycemia on the formation of reactive oxygen species (ROS) and nitric oxide/cGMP signaling in two different endothelial cell cultures. Human umbilical vein endothelial cells (HUVEC) and EA.hy 926 cells showed increased oxidative stress and impaired NO-cGMP signaling in response to hyperglycemia. The major difference between the two different cell types was the dramatic decrease in viability in HUVEC whereas EA.hy cells showed rather increased growth under hyperglycemic conditions. Starvation led to an additional substantial decrease in viability and increased superoxide formation in HUVEC. Both endothelial cell types, HUVEC and EA.hy 926, may be used as models for vascular hyperglycemia. However, high growth medium should be used to avoid starvation-induced oxidative stress and cell death. PMID- 22521319 TI - The multi-faceted outcomes of conjunct diabetes and cardiovascular familial history in type 2 diabetes. AB - BACKGROUND: Familial history of early-onset CHD (EOCHD) is a major risk factor for CHD. Familial diabetes history (FDH) impacts beta-cell function. Some transmissible, accretional gradient of CHD risk may exist when diabetes and EOCHD familial histories combine. We investigated whether the impact of such combination is neutral, additive, or potentiating in T2DM descendants, as regards cardiometabolic phenotype, glucose homeostasis and micro-/macroangiopathies. METHODS: Cross-sectional retrospective cohort study of 796 T2DM divided according to presence (Diab[+]) or absence (Diab[-]) of 1st-degree diabetes familial history and/or EOCHD (CVD(+) and (-)). Four subgroups: (i) [Diab(-)CVD(-)] (n=355); (ii) [Diab(+)CVD(-)] (n=338); (iii) [Diab(-)CVD(+)] (n=47); and (iv) [Diab(+)CVD(+)] (n=56). RESULTS: No interaction on subgroup distribution between presence of both familial histories, the combination of which translated into additive detrimental outcomes and higher rates of fat mass, sarcopenia, (hs)CRP and retinopathy. FDH(+) had lower insulinemia, insulin secretion, hyperbolic product, and accelerated hyperbolic product loss. An EOCHD family history affected neither insulin secretion nor sensitivity. There were significant differences regarding macroangiopathy/CAD, more prevalent in [Diab(-)CVD(+)] and [Diab(+)CVD(+)]. Among CVD(+), the highest macroangiopathy prevalence was observed in [Diab(-)CVD(+)], who had 66% macroangiopathy, and 57% CAD, rates higher (absolute-relative) by 23%-53% (overall) and 21%-58% (CAD) than [Diab(+)CVD(+)], who inherited the direst cardiometabolic familial history (p 0.0288 and 0.0310). CONCLUSIONS: A parental history for diabetes markedly affects residual insulin secretion and secretory loss rate in T2DM offspring without worsening insulin resistance. It paradoxically translated into lower macroangiopathy with concurrent familial EOCHD. Conjunct diabetes and CV familial histories generate multi-faceted vascular outcomes in offspring, including lesser macroangiopathy/CAD. PMID- 22521320 TI - Does treatment affect the levels of serum interleukin-6, interleukin-8 and procalcitonin in diabetic foot infection? A pilot study. AB - AIMS: To investigate about serum PCT, IL-6 and IL-8 levels and how they are affected by the treatment in diabetic foot patients. METHODS: Fifty patients' blood samples were taken to study ESR and CRP, IL-6, IL-8 and PCT before and at the 14th day of the treatment. RESULTS: The pretreatment results of the 50 patients showed positive correlations between PCT and either ESH (r=0.49, p<0.001), or CRP (r=0.56, p<0.001). Similarly, there was a positive correlation between IL-6 and ESH (r=0.46, p=0.001), just like as it was between IL-6 and CRP (r=0.54, p<0.001). At the 14th day, the levels of ESR (70 +/- 30.2 and 58.4 +/- 26.2, p=0.02), CRP (63.8 +/- 73.1 and 18.1 +/- 19.7, p<0.001) and PCT (0.6 +/- 2.1 and 0.05 +/- 0.02, p=0.007) were significantly decreased while IL-6 was decreased at a close range to statistical significancy at healing patients (97.5 +/- 147.2 and 47.1 +/- 77.6; p=0.05), but they did not at nonhealing patients. IL 8 levels were not changed anyhow. CONCLUSIONS: PCT was significantly decreased such as ESR and CRP were in the early phase of healing; IL-6 and IL-8 levels were also decreased by the treatment, but not statistically significantly. IL-6 and PCT were affected in correlation with the other inflammatory parameters in the beginning, but IL-8 was not. PCT and IL-6 may be useful like CRP and ESR in the diagnosis and follow up of diabetic foot infection, but IL-8 is not. Further investigation is needed. PMID- 22521321 TI - Relationship between DDAH gene variants and serum ADMA level in individuals with type 1 diabetes. AB - Asymmetric dimethylarginine (ADMA) levels are elevated in diabetes and likely contribute to diabetic complications such as retinopathy and nephropathy. The DDAH enzymes are primarily responsible for ADMA metabolism. Polymorphisms in the dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2 genes have been previously associated with serum ADMA levels in type 2 diabetes (T2DM). We sought to determine whether they are also associated with ADMA levels in individuals with type 1 diabetes (T1DM). Serum ADMA concentrations were measured in 196 individuals with T1DM. Twenty-six tag SNPs in the DDAH1 gene and 10 in the DDAH2 gene were genotyped. One SNP in the DDAH1 gene (rs3738111) and one in the DDAH2 gene (rs805293) showed a correlation with serum ADMA levels; however, neither survived correction for multiple testing. We found limited evidence that genetic polymorphisms in DDAH genes influence serum ADMA levels in individuals with T1DM. This differs to findings in T2DM and may be due to underlying differences in the cohorts or to fundamental differences in the pathogenesis of the two types of diabetes. PMID- 22521322 TI - Vocal warm-up produces acoustic change in singers' vibrato rate. AB - Vibrato rate and vibrato extent were acoustically assessed in 12 classically trained female singers before and after 25 minutes of vocal warm-up exercises. Vocal warm-up produced three notable changes in vibrato rate: (1) more regularity in the cyclic undulations comprising the vibrato rate of a note, (2) more stability in mean vibrato rates from one sustained note to the next, and (3) a moderating of excessively fast and excessively slow mean vibrato rates. No significant change was found for vibrato extent. The findings indicate that vocal warm-up may regulate vibrato rate. Thus tone quality, which is strongly linked to vibrato characteristics, may undergo positive change as a result of vocal warm up. PMID- 22521323 TI - Perception of vocal tremor during sustained phonation compared with sentence context. AB - OBJECTIVES/HYPOTHESIS: Vocal tremor is an acoustical phenomenon characterized by relatively periodic modulations in fundamental frequency and intensity. Although vocal tremor is considered easier to perceive during sustained phonation than during connected speech, systematic comparison between these speech contexts has not been investigated. This investigation compared vocal tremor perception during sustained phonation and connected speech contexts. STUDY DESIGN: This is a prospective, controlled study with randomized conditions. METHODS: Audio recordings from five speakers diagnosed with essential vocal tremor were used for this study. Twenty-four naive adult listeners rated the overall severity (ie, aberrance) of the voice and the degree of shakiness (ie, tremor) during sustained phonation of /i/. A different group of 21 naive adult listeners rated sentence stimuli consisting of two different sentences, one loaded with voiced and the other with voiceless speech sounds. RESULTS: All speakers were rated by listeners to have similar levels of shakiness and overall severity during sustained phonation. However, significantly higher levels of shakiness and overall severity were perceived during sustained phonation than during sentence context. A nonsignificant trend was shown for higher average ratings for shakiness and overall severity on voice-loaded compared with voiceless-loaded sentences. CONCLUSIONS: This study demonstrated that vocal tremor is perceived as significantly more severe during sustained phonation than during connected speech. More importantly, individual speakers differed in their ability to reduce vocal tremor perception during connected speech. Thus, sustained phonation does not necessarily offer a valid estimation of the impact of a vocal tremor on an individual's connected speech. PMID- 22521324 TI - Ascending the nucleosome face: recognition and function of structured domains in the histone H2A-H2B dimer. AB - Research over the past decade has greatly expanded our understanding of the nucleosome's role as a dynamic hub that is specifically recognized by many regulatory proteins involved in transcription, silencing, replication, repair, and chromosome segregation. While many of these nucleosome interactions are mediated by post-translational modifications in the disordered histone tails, it is becoming increasingly apparent that structured regions of the nucleosome, including the histone fold domains, are also recognized by numerous regulatory proteins. This review will focus on the recognition of structured domains in the histone H2A-H2B dimer, including the acidic patch, the H2A docking domain, the H2B alpha3-alphaC helices, and the HAR/HBR domains, and will survey the known biological functions of histone residues within these domains. Novel post translational modifications and trans-histone regulatory pathways involving structured regions of the H2A-H2B dimer will be highlighted, along with the role of intrinsic disorder in the recognition of structured nucleosome regions. PMID- 22521325 TI - A method for stable transgenesis of radial glia lineage in rat neocortex by piggyBac mediated transposition. AB - Methods that combine lineage tracing with cellular transgenesis are needed in order to determine mechanisms that specify neural cell types. Currently available methods include viral infection and Cre-mediated recombination. In utero electroporation (IUE) has been used in multiple species to deliver multiple transgenes simultaneously into neural progenitors. In standard IUE, most plasmids remain episomal, are lost during cell division, and so transgenes are not expressed in the complete neural lineage. Here we combine IUE with a binary piggyBac transposon system (PB-IUE), and show that unlike conventional IUE, a single embryonic transfection of neocortical radial glia with a piggyBac transposon system results in stable transgene expression in the neural lineage of radial glia: cortical neurons, astrocytes, oligodendrocytes, and olfactory bulb interneurons. We also developed a modular toolkit of donor and helper plasmids with different promoters that allows for shRNA, bicistronic expression, and trangenesis in subsets of progenitors. As a demonstration of the utility of the toolkit we show that transgenesis of epidermal growth factor receptor (EGFR) expands the number of astrocytes and oligodendrocyrtes generated from progenitors. The relative ease of implementation and experimental flexibility should make the piggyBac IUE method a valuable new tool for tracking and manipulating neural lineages. PMID- 22521326 TI - A new method of quantitatively assessing the opening of the blood-brain barrier in murine animal models. AB - The blood-brain barrier (BBB) restricts the delivery of drugs into the brain. Different strategies have been developed to circumvent this obstacle. One such approach, the osmotic BBB disruption (BBBD), has been under pre-clinical study since the 70's. Typically, qualitative ex vivo assessment of the extent of BBBD has been performed using Evan's blue staining technique. In this study, we describe a simple quantitative technique based on albumin indirect immunohistochemistry to measure the extent of BBB breach. Thirty Fischer rats were assigned to one of 6 groups: a control group, and BBBD groups with escalation in IA mannitol infusion rate: 0.06, 0.08, 0.10, 0.12 and 0.15 cc/s. Fifteen minutes after the BBBD procedure, the animals were sacrificed, brain harvested and sections stained for albumin. Using an image analysis software, isolated albumin staining pixels were expressed as a fraction of the treated hemisphere. This ratio was used as a percentage value in the intensity of the BBB permeabilization. All sections studied harbored staining, averaging 0.37% for the controls (group 1), 5.69% for group 2 (0.06 cc/s), 10.44% for group 3 (0.08 cc/s), 6.99% for group 4 (0.1 cc/s), 18.50% for group 5 (0.12 cc/s) and reaching 61.70% for group 6 (0.15 cc/s). Important variations were observed between animals. A threshold effect was observed, and animals in group 6 presented a significant increase in BBB permeabilization compared to the other groups. We hereby detail a simple technique that can be applied to quantitatively measure the extent of the BBB breach notwithstanding the pathological process. PMID- 22521327 TI - Safety of uterine artery embolization in patients with preexisting hydrosalpinx. AB - PURPOSE: To determine (i) if preexisting hydrosalpinx poses a risk for development of pyosalpinx following uterine artery embolization (UAE) and (ii) the effect of UAE on fallopian tube diameter. MATERIALS AND METHODS: Between 2005 and 2011, 429 women underwent UAE for treatment of symptomatic leiomyomas. Magnetic resonance (MR) imaging before UAE revealed 16 (3.7%) premenopausal women (median age, 47 y; range, 40-52 y) with preexisting hydrosalpinx. Bilateral UAE was performed by using 500-700-MUm tris-acryl microspheres with the administration of routine prophylactic antibiotics. Pre- and post-UAE MR images were used to measure fallopian tube diameter. Fallopian tube diameters were classified as normal (1-4 mm) or mildly (< 10 mm), moderately (10-20 mm), or severely enlarged (> 20 mm). A diameter change >= 3 mm was considered significant. Resolution of hydrosalpinx was defined by the inability to identify fallopian tubes on post-UAE MR imaging or a normal fallopian tube diameter. Radiology and hospital records were reviewed to determine clinical outcomes. RESULTS: All 16 patients underwent successful bilateral UAE. Clinical follow-up ranged from 14 to 1,531 days (median, 106 d). There was no clinical evidence of pyosalpinx after UAE. Two patients experienced minor complications unrelated to fallopian tube dilation. Post-UAE MR images were available in 13 of 16 patients (81.3%). There were no MR findings to suggest pyosalpinx after UAE. Resolution or improvement was noted in four of 15 hydrosalpinges (26.7%) for patients with follow-up imaging. CONCLUSIONS: The results of the present study suggest that UAE is safe for patients with preexisting hydrosalpinx. PMID- 22521328 TI - Percutaneous device closure of a pseudoaneurysm arising from the junction of the innominate artery and the aorta. PMID- 22521330 TI - Prevalence of psychiatric disorders in patients with diabetes types 1 and 2. AB - BACKGROUND: Diabetes mellitus, classified into types 1 and 2, is a chronic disease that shows high comorbidity with psychiatric disorders. Insulin-dependent patients show a higher prevalence of psychiatric disorders than do patients with type 2 diabetes. METHODS: This research involved the participation of 200 subjects divided into 2 groups: 100 patients with diabetes type 1 and 100 patients with diabetes type 2. This study used the Mini International Neuropsychiatric Interview for the identification of psychiatric disorders. RESULTS: Of the 200 participants, 85 (42.5%) were found to have at least 1 psychiatric disorder. The most prevalent disorders were generalized anxiety disorder (21%), dysthymia (15%), social phobia (7%), current depression (5.5%), lifelong depression (3.5%), panic disorder (2.5%), and risk of suicide (2%). Other disorders with lower prevalence were also identified. The groups showed a statistically significant difference in the presence of dysthymia, current depression, and panic disorder, which were more prevalent in patients with diabetes type 1. CONCLUSION: The high prevalence of psychiatric disorders in diabetic patients points to the need for greater investment in appropriate diagnostic evaluation of patients that considers mental issues. The difference identified between the groups shows that preventive measures and therapeutic projects should consider the specific demands of each type of diabetes. PMID- 22521329 TI - Can patterns of alcohol use disorder in young adulthood help explain gender differences in depression? AB - OBJECTIVE: To test whether gender differences in the prevalence of major depressive disorder differ by longitudinal patterns of alcohol use disorder symptoms. METHOD: Data are from a prospective longitudinal study examining a broad range of mental health and substance use problems. A gender-balanced sample of 808 participants was interviewed at ages 21, 24, 27, and 30. The sample was divided into subgroups corresponding to longitudinal patterns of alcohol use disorder derived from latent class growth analysis. RESULTS: Four patterns of alcohol use disorder symptoms were identified: A "low disorder symptom" group, a "decreaser" group, an "increaser" group, and a "chronic disorder symptom" group. Rates of depression were significantly higher for females only among those with a pattern of chronic or decreasing alcohol disorder symptoms. CONCLUSIONS: Elevated rates of depression among females in young adulthood may depend on patterns of co occurring alcohol disorder symptoms. Practitioners should pay particular attention to signs of chronic alcohol use disorders and associated risks for depression among young adult women. PMID- 22521331 TI - Spatial confinement can lead to increased stability of amorphous indomethacin. AB - The aim of this study was to investigate whether the physical stability of amorphous indomethacin can be improved by separating the drug material into small units by the use of microcontainers. Crystallisation from the spatially confined amorphous indomethacin in the microcontainers was determined and compared with the crystallisation kinetics of amorphous bulk indomethacin. Amorphous indomethacin in both a bulk form and contained within microcontainers was prepared by melting of bulk or container-incorporated gamma-indomethacin, respectively, followed by quench-cooling. Microcontainers of three different sizes (diameters of 73 MUm, 174 MUm and 223 MUm) were used for the confinement of amorphous indomethacin, in order to elucidate whether the size of the microcontainer had an influence on the stability of the amorphous form. Following preparation, all samples were stored at 30 degrees C and 23% RH. A sample of 100 microcontainers of each size was selected and measured on a Raman microscope over a period of 30 days to ascertain whether the indomethacin in each container was amorphous or crystalline. Over time, a crystallisation number was obtained for the amorphous indomethacin in the microcontainers. The crystallisation numbers from the microcontainers were compared with the crystallisation kinetics of the amorphous bulk indomethacin, as determined by FT-Raman spectroscopy. Comparison of the numeric crystallisation in the microcontainers with the crystallisation kinetics of the amorphous bulk indomethacin showed that spatial confinement of indomethacin led to a significantly lower extent of crystallisation of the amorphous form. In the 174 MUm microcontainers, 29.0 +/- 2.6% of the amorphous indomethacin crystallised to the stable gamma-form over a period of 30 days, whilst 38.3 +/- 1.5% of the amorphous indomethacin crystallised in the 223 MUm microcontainers. Both these values were significantly different from that observed in the amorphous bulk indomethacin, where 51.0% crystallised to the gamma-form after 30 days. Comparing the 174 and 223 MUm microcontainers also revealed a significantly greater stabilising effect of the 174MUm microcontainers (p-value of 0.0061). Surprisingly, for microcontainers with an inner diameter of 73 MUm, no stability improvement was found when compared to amorphous bulk indomethacin. It was observed that the amorphous indomethacin within these containers converted to the alpha-form of indomethacin (a metastable polymorph) which was unexpected at the storage conditions at 30 degrees C and 23% RH. PMID- 22521332 TI - Upscaling of the hot-melt extrusion process: comparison between laboratory scale and pilot scale production of solid dispersions with miconazole and Kollicoat IR. AB - Since only limited amount of drug is available in early development stages, the extruder design has evolved towards smaller batch sizes, with a more simple design. An in dept study about the consequences of the differences in design is mandatory and little can be found in literature. Miconazole and Kollicoat IR were used as model drug and carrier for this study. Two series of solid dispersions were made with a laboratory scale (internal circulation-simple screw design) and a pilot scale extruder (continuous throughput-modular screw design). Efforts were made to match the operating parameters as close as possible (residence time, extrusion temperature and screw speed). The samples were analyzed with modulated DSC straight after production and after exact 24h and 15 days storage at -26 degrees C. The kinetic miscibility of the samples prepared with the laboratory scale extruder was slightly higher than the samples prepared with the pilot scale extruder. As the solid dispersions with high drug load were unstable over time, demixing occurred, slightly faster for the samples prepared with the laboratory scale extruder. After 15 days, the levels of molecular mixing were comparable, pointing to the predictive value of samples prepared on laboratory scale. PMID- 22521333 TI - Race, ethnicity and health: the costs and benefits of conceptualising racism and ethnicity. PMID- 22521334 TI - Sleep deprivation impairs emotional memory retrieval in mice: influence of sex. AB - The deleterious effects of paradoxical sleep deprivation on memory processes are well documented. However, non-selective sleep deprivation occurs more commonly in modern society and thus represents a better translational model. We have recently reported that acute total sleep deprivation (TSD) for 6 h immediately before testing impaired performance of male mice in the plus-maze discriminative avoidance task (PM-DAT) and in the passive avoidance task (PAT). In order to extend these findings to females, we examined the effect of (pre-test) TSD on the retrieval of different memory tasks in both male and female mice. Animals were tested using 3 distinct memory models: 1) conditioning fear context (CFC), 2) PAT and 3) PM-DAT. In all experiments, animals were totally sleep-deprived by the gentle interference method for 6h immediately before being tested. In the CFC task and the PAT, TSD induced memory impairment regardless of sex. In PM-DAT, the memory impairing effects of TSD were greater in females. Collectively, our results confirm the impairing effect of TSD on emotional memory retrieval and demonstrate that it can be higher in female mice depending on the memory task evaluated. PMID- 22521337 TI - Low molecular weight heparin therapy in pediatric otogenic sigmoid sinus thrombosis: a safe treatment option? AB - OBJECTIVE: Septic thrombosis of the sigmoid and lateral sinus is a rare complication of acute otitis media, mastoiditis and cholesteatoma. Hence, the aim of this chat review was to analyze the demographics, presenting symptoms, diagnosis, and therapeutic management of otogenic sigmoid sinus thrombosis. Especially the role of low molecular weight heparin in the therapy of septic intracranial sinus thrombosis in children should be illuminated. METHODS: A retrospective chart review was performed. RESULTS: Six patients were included in this trial. One patient was treated completely conservatively. All other patients underwent surgical treatment consisting of mastoidectomy (n=5), additional thrombectomy (n=3) and ligation of the internal jugular vein (n=2). All patients received intravenous antibiotics and anticoagulants. Unfractionated heparin was administered for three days after surgery followed by an anticoagulant therapy with low-molecular weight heparin for three months. The activated partial thromboplastin time (aPTT) and the anti-factor-Xa-plasma-levels were monitored during anticoagulation in short term intervals. There were no complications related to the anticoagulant therapy. Recanalization was found in all patients who were treated without thrombectomy or ligation of the internal jugular vein and in the case of complete conservative treatment. CONCLUSION: Simple mastoidectomy combined with broad spectrum antibiotics is the therapy of choice. Our results indicate that anticoagulants represent a safe treatment option if they are administered correctly. PMID- 22521335 TI - New insights on endocannabinoid transmission in psychomotor disorders. AB - The endocannabinoids are lipid signaling molecules that bind to cannabinoid CB(1) and CB(2) receptors and other metabotropic and ionotropic receptors. Anandamide and 2-arachidonoyl glycerol, the two best-characterized examples, are released on demand in a stimulus-dependent manner by cleavage of membrane phospholipid precursors. Together with their receptors and metabolic enzymes, the endocannabinoids play a key role in modulating neurotransmission and synaptic plasticity in the basal ganglia and other brain areas involved in the control of motor functions and motivational aspects of behavior. This mini-review provides an update on the contribution of the endocannabinoid system to the regulation of psychomotor behaviors and its possible involvement in the pathophysiology of Parkinson's disease and schizophrenia. PMID- 22521336 TI - The role of inflammation in epileptogenesis. AB - One compelling challenge in the therapy of epilepsy is to develop anti epileptogenic drugs with an impact on the disease progression. The search for novel targets has focused recently on brain inflammation since this phenomenon appears to be an integral part of the diseased hyperexcitable brain tissue from which spontaneous and recurrent seizures originate. Although the contribution of specific proinflammatory pathways to the mechanism of ictogenesis in epileptic tissue has been demonstrated in experimental models, the role of these pathways in epileptogenesis is still under evaluation. We review the evidence conceptually supporting the involvement of brain inflammation and the associated blood-brain barrier damage in epileptogenesis, and describe the available pharmacological evidence where post-injury intervention with anti-inflammatory drugs has been attempted. Our review will focus on three main inflammatory pathways, namely the IL-1 receptor/Toll-like receptor signaling, COX-2 and the TGF-beta signaling. The mechanisms underlying neuronal-glia network dysfunctions induced by brain inflammation are also discussed, highlighting novel neuromodulatory effects of classical inflammatory mediators such as cytokines and prostaglandins. The increase in knowledge about a role of inflammation in disease progression, may prompt the use of specific anti-inflammatory drugs for developing disease modifying treatments. This article is part of the Special Issue entitled 'New Targets and Approaches to the Treatment of Epilepsy'. PMID- 22521338 TI - Cardiorespiratory safety evaluation in non-human primates. AB - INTRODUCTION: This study was designed to provide a comprehensive nonclinical respiratory safety pharmacology assessment using respiratory inductance plethysmography (RIP) concomitant with a standard cardiovascular (CV) safety assessment in non-human primates (NHP) in a single cardiorespiratory study. METHODS: RIP calibration data were generated in conscious, ketamine-sedated, or propofol-anesthetized NHP to determine the most appropriate method. Calibration accuracy was assessed using a CO(2) rebreathe maneuver. Regardless of the technique, the RIP system reliably demonstrated accurate assessment of the CO(2) rebreathe response when expressed as a percent change with respect to control. Four male NHP were given single oral doses of vehicle, 1.25 and 5 mg/kg test article followed by 20 mg/kg repeatedly for 7 days. Telemetry-derived cardiovascular parameters (PR, QRS, QT, heart rate corrected QT (QTcR) intervals, blood pressure [BP], and heart rate [HR]) and RIP-derived respiratory parameters (respiration rate [RR], tidal volume [TV], and minute volume [MV]) were determined for 24 h pretest, 2 h predose and 24 h postdose. RESULTS: A single dose of the test article at 5 or 20 mg/kg was associated with slight increases in HR, BP, RR, and MV at 2 to 7 h postdose, followed by decreases in HR, RR, TV, and MV at 5-23 h postdose. Decreases in HR, RR, TV, and MV were observed following 7 days of dosing at 20 mg/kg. Slight QTcR prolongation at 1 to 11 h postdose was observed following a single dose of 20 mg/kg. CONCLUSION: These data show that the integrated assessment of cardiovascular and respiratory parameters in NHP is achievable continuously for at least 24 h postdose. The use of RIP as a method to assess the effects of a novel compound on the respiratory system complements, but does not interfere with, the cardiovascular assessment of new drugs. PMID- 22521340 TI - [Drug-induced adverse events in elderly persons presenting to the emergency department]. PMID- 22521339 TI - Muscle on a chip: in vitro contractility assays for smooth and striated muscle. AB - INTRODUCTION: To evaluate the viability of a muscle tissue, it is essential to measure the tissue's contractile performance as well as to control its structure. Accurate contractility data can aid in development of more effective and safer drugs. This can be accomplished with a robust in vitro contractility assay applicable to various types of muscle tissue. METHODS: The devices developed in this work were based on the muscular thin film (MTF) technology, in which an elastic film is manufactured with a 2D engineered muscle tissue on one side. The tissue template is made by patterning extracellular matrix with microcontact printing. When muscle cells are seeded on the film, they self-organize with respect to the geometric cues in the matrix to form a tissue. RESULTS: Several assays based on the "MTF on a chip" technology are demonstrated. One such assay incorporates the contractility assay with striated muscle into a fluidic channel. Another assay platform incorporates the MTFs in a multi-well plate, which is compatible with automated data collection and analysis. Finally, we demonstrate the possibility of analyzing contractility of both striated and smooth muscle simultaneously on the same chip. DISCUSSION: In this work, we assembled an ensemble of contractility assays for striated and smooth muscle based on muscular thin films. Our results suggest an improvement over current methods and an alternative to isolated tissue preparations. Our technology is amenable to both primary harvests cells and cell lines, as well as both human and animal tissues. PMID- 22521341 TI - [Motivations for adolescent pregnancy]. AB - OBJECTIVES: To identify the motivations (beliefs, values) for adolescent pregnancy among girls aged less than 17 years old. METHOD: We performed a phenomenological qualitative study with audio recording of in-depth interviews with 12 pregnant adolescents between March and September 2008. Purposive sampling of pregnant adolescents (14-16 years) in the high-risk obstetric unit of the Hospital of Jaen (Spain) was performed, using education, voluntariness of pregnancy, urban-rural setting of the family residence and family socioeconomic status as heterogeneity criteria. A content analysis was performed with coding, triangulation of categories, and extraction and verification of results. RESULTS: The adolescent's sociocultural context was of considerable weight in sexual and reproductive decisions. Adolescents with unplanned pregnancies felt that their responsibility was relative, showing an attitude of acceptance and resignation, which later became a tendency to rationalize the events and claim that the child was wanted or even planned. Girls with a wanted pregnancy did not have a clear idea of the consequences of having a child. Previous ideas about pregnancy were mainly related to physical changes without taking into account other changes that occur during and after pregnancy. CONCLUSIONS: The family context and socialization of girls are based on a traditional division of gender roles in which the traditional role of the female caregiver is strongly internalized. The reasons for teenage pregnancy are unclear; pregnant adolescents lacked a sense of self-determination and felt that their lives were determined by circumstances. PMID- 22521343 TI - Interferon responses and spontaneous HCV clearance: is it all a matter of fat? PMID- 22521342 TI - Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci. AB - BACKGROUND & AIMS: A limited number of genetic risk factors have been reported in primary sclerosing cholangitis (PSC). To discover further genetic susceptibility factors for PSC, we followed up on a second tier of single nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS). METHODS: We analyzed 45 SNPs in 1221 PSC cases and 3508 controls. The association results from the replication analysis and the original GWAS (715 PSC cases and 2962 controls) were combined in a meta-analysis comprising 1936 PSC cases and 6470 controls. We performed an analysis of bile microbial community composition in 39 PSC patients by 16S rRNA sequencing. RESULTS: Seventeen SNPs representing 12 distinct genetic loci achieved nominal significance (p(replication) <0.05) in the replication. The most robust novel association was detected at chromosome 1p36 (rs3748816; p(combined)=2.1 * 10(-8)) where the MMEL1 and TNFRSF14 genes represent potential disease genes. Eight additional novel loci showed suggestive evidence of association (p(repl) <0.05). FUT2 at chromosome 19q13 (rs602662; p(comb)=1.9 * 10(-6), rs281377; p(comb)=2.1 * 10(-6) and rs601338; p(comb)=2.7 * 10(-6)) is notable due to its implication in altered susceptibility to infectious agents. We found that FUT2 secretor status and genotype defined by rs601338 significantly influence biliary microbial community composition in PSC patients. CONCLUSIONS: We identify multiple new PSC risk loci by extended analysis of a PSC GWAS. FUT2 genotype needs to be taken into account when assessing the influence of microbiota on biliary pathology in PSC. PMID- 22521344 TI - Methyl donor deficiency impairs fatty acid oxidation through PGC-1alpha hypomethylation and decreased ER-alpha, ERR-alpha, and HNF-4alpha in the rat liver. AB - BACKGROUND & AIMS: Folate and cobalamin are methyl donors needed for the synthesis of methionine, which is the precursor of S-adenosylmethionine, the substrate of methylation in epigenetic, and epigenomic pathways. Methyl donor deficiency produces liver steatosis and predisposes to metabolic syndrome. Whether impaired fatty acid oxidation contributes to this steatosis remains unknown. METHODS: We evaluated the consequences of methyl donor deficient diet in liver of pups from dams subjected to deficiency during gestation and lactation. RESULTS: The deprived rats had microvesicular steatosis, with increased triglycerides, decreased methionine synthase activity, S-adenosylmethionine, and S-adenosylmethionine/S-adenosylhomocysteine ratio. We observed no change in apoptosis markers, oxidant and reticulum stresses, and carnityl-palmitoyl transferase 1 activity, and a decreased expression of SREBP-1c. Impaired beta oxidation of fatty acids and carnitine deficit were the predominant changes, with decreased free and total carnitines, increased C14:1/C16 acylcarnitine ratio, decrease of oxidation rate of palmitoyl-CoA and palmitoyl-L-carnitine and decrease of expression of novel organic cation transporter 1, acylCoA dehydrogenase and trifunctional enzyme subunit alpha and decreased activity of complexes I and II. These changes were related to lower protein expression of ER alpha, ERR-alpha and HNF-4alpha, and hypomethylation of PGC-1alpha co-activator that reduced its binding with PPAR-alpha, ERR-alpha, and HNF-4alpha. CONCLUSIONS: The liver steatosis resulted predominantly from hypomethylation of PGC1-alpha, decreased binding with its partners and subsequent impaired mitochondrial fatty acid oxidation. This link between methyl donor deficiency and epigenomic deregulations of energy metabolism opens new insights into the pathogenesis of fatty liver disease, in particular, in relation to the fetal programming hypothesis. PMID- 22521345 TI - Human pluripotent stem cell-derived hepatocytes support complete replication of hepatitis C virus. AB - BACKGROUND & AIMS: Worldwide, about 180 million people are chronically infected with the hepatitis C virus (HCV). Current in vitro culture systems for HCV depend chiefly on human hepatoma cell lines. Although primary human hepatocytes support HCV infection in vitro, and immunodeficient mice repopulated with human hepatocytes support HCV infection in vivo, these models are limited because of shortage of human livers to isolate hepatocytes. Therefore, there is significant interest in the establishment from of a HCV culture system in human stem cell derived hepatocyte-like cells. METHODS: Human embryonic stem cell (hESC)-derived hepatocytes were infected with HCV in the presence or absence of direct acting antivirals. After inoculation, replication of HCV was analyzed extensively. RESULTS: We demonstrate that hESC-derived hepatocytes can be infected with the HCV JFH1 genotype 2a, resulting in the production of viral RNA in the stem cell progeny. Viral replication is inhibited by a non-nucleoside HCV polymerase inhibitor (HCV-796), a cyclophilin binding molecule (Debio 025-Alisporivir) and the protease inhibitor VX-950 (Telaprevir). Stem cell-derived hepatocytes produced, for more than 10 days, the HCV core protein as well as virions that were capable of re-infecting hepatoma cells. CONCLUSIONS: Hepatocytes derived from hESC support the complete HCV replication cycle (including the production of infectious virus), and viral replication in these cells is efficiently inhibited by selective inhibitors of HCV replication. PMID- 22521346 TI - Alpha-fetoprotein acts as a novel signal molecule and mediates transcription of Fn14 in human hepatocellular carcinoma. AB - BACKGROUND & AIMS: The function of cytoplasmic AFP as a regulatory factor in the growth of tumor cells has been well defined. However, its precise mechanism of action and its clinical significance remain to be worked out. METHODS: Specimens from HCC patients were analyzed by using immunohistochemistry, co immunoprecipitation (CoIP), and chromatin immunoprecipitation (ChIP) assays to evaluate the role of AFP in RAR signaling-mediated carcinogenesis. Quantitative real-time reverse transcription PCR, Western blotting, confocal microscopy, CoIP, GST pull-down, siRNA, gene transfection, and ChIP assays were also used for analysis of cell lines. RESULTS: RAR is able to interact with cytoplasmic AFP and binds to the element of the regulatory region of the Fn14 gene in the neoplastic tissue of HCC patients. An assay of hepatocyte cell lines of differing AFP expression showed that cytoplasmic AFP is able to block ATRA-induced nuclear translocation of RAR and expression of the Fn14 gene. Knockdown of AFP in siRNA transfected HepG2 and Bel7402 cells led to greater binding of RAR to its response element. The expression of the Fn14 gene was therefore up regulated as reflected by increases in mRNA and protein levels. Conversely, transfection of HLE and L02 cells (AFP negative) with the afp gene resulted in apparent reduction of RAR binding to DNA and Fn14 protein. CONCLUSIONS: Demonstration of the involvement of cytoplasmic AFP in RAR-mediated expression of the Fn14 gene strongly indicates AFP plays a signal molecule-like role in the regulation of hepatocellular carcinoma growth. PMID- 22521347 TI - Liver transplantation for acute liver failure in Europe: outcomes over 20 years from the ELTR database. AB - BACKGROUND & AIMS: Liver transplantation for acute liver failure (ALF) still has a high early mortality. We evaluated changes during 20 years, and identified risk factors for poor outcome. METHODS: Donor, graft, and recipient variables from the European Liver Transplant Registry database (January 1988-June 2009), were analysed. Aetiologies and time periods were compared. Three and 12-month survival models were generated from separate training data sets, which were validated. A sub-analysis was performed for recipient older than 50 years. RESULTS: Four thousand nine hundred and three patients were evaluated. One, 5- and 10-year patient, and graft survival rates were 74%, 68%, 63%, and 63%, 57%, 50%, respectively. Survival was better in 2004-2009 compared to previous quinquennia (p<0.001), despite donors >60 years increased from 1.8% to 21%. A higher incidence of suicide or non-adherence occurred in paracetamol-related ALF (p<0.001). Death or graft loss were independently associated with male recipients (adjusted OR 1.25), recipient >50 years (1.26), incompatible ABO matching (1.93), donors >60 years (1.21), and reduced size graft (1.54). For both 3- and 12-month models, incompatible ABO matching, non-viral aetiology, reduced size graft, and non-UW preservation fluid were associated with increased mortality/graft loss, whereas male recipients and age >50 years were associated only at 12 months. Both models had reasonable discriminative ability with good calibration at 3 months. Recipients >50 years, combined with donors >60 years resulted in 57% mortality/graft loss within the first year. CONCLUSIONS: Survival after liver transplantation has improved despite increases in donor/recipient age. Recipients >50 years paired with donors >60 years had a very high mortality/graft loss within the first year. PMID- 22521348 TI - Liver transplantation for unresectable hepatocellular carcinoma in normal livers. AB - BACKGROUND & AIMS: The role of liver transplantation in the treatment of hepatocellular carcinoma in livers without fibrosis/cirrhosis (NC-HCC) is unclear. We aimed to determine selection criteria for liver transplantation in patients with NC-HCC. METHODS: Using the European Liver Transplant Registry, we identified 105 patients who underwent liver transplantation for unresectable NC HCC. Detailed information about patient, tumor characteristics, and survival was obtained from the transplant centers. Variables associated with survival were identified using univariate and multivariate statistical analyses. RESULTS: Liver transplantation was primary treatment in 62 patients and rescue therapy for intrahepatic recurrences after liver resection in 43. Median number of tumors was 3 (range 1-7) and median tumor size 8 cm (range 0.5-30). One- and 5-year overall and tumor-free survival rates were 84% and 49% and 76% and 43%, respectively. Macrovascular invasion (HR 2.55, 95% CI 1.34 to 4.86), lymph node involvement (HR 2.60, 95% CI 1.28 to 5.28), and time interval between liver resection and transplantation < 12 months (HR 2.12, 95% CI 0.96 to 4.67) were independently associated with survival. Five-year survival in patients without macrovascular invasion or lymph node involvement was 59% (95% CI 47-70%). Tumor size was not associated with survival. CONCLUSIONS: This is the largest reported series of patients transplanted for NC-HCC. Selection of patients without macrovascular invasion or lymph node involvement, or patients >= 12months after previous liver resection, can result in 5-year survival rates of 59%. In contrast to HCC in cirrhosis, tumor size is not a predictor of post-transplant survival in NC-HCC. PMID- 22521349 TI - Increased activity of serum mitochondrial isoenzyme of creatine kinase in hepatocellular carcinoma patients predominantly with recurrence. AB - BACKGROUND & AIMS: Mitochondrial isoenzyme of creatine kinase (MtCK) is reportedly highly expressed in hepatocellular carcinoma (HCC). Clinical relevance of serum MtCK activity in patients with HCC was assessed using a novel immuno inhibition method. METHODS: Among patients with cirrhosis caused by hepatitis B or C virus, 147 patients with HCC (12 with the first occurrence and 135 with recurrence) and 92 patients without HCC were enrolled. RESULTS: Serum MtCK activity was higher in cirrhotic patients with HCC than in those without HCC or healthy subjects. Elevated serum MtCK activity in HCC patients decreased after radiofrequency ablation. In case of prediction of HCC, MtCK had a sensitivity of 62.6% and a specificity of 70.7% at a cut-off point of 8.0 U/L, with an area under the receiver operating curve of 0.722 vs. 0.713 for alpha-fetoprotein (AFP) and 0.764 for des-gamma-carboxy prothrombin (DCP). Among the HCC patients, serum MtCK activity was elevated in 52.9% individuals with serum AFP level < 20 ng/ml and 63.2% individuals with serum DCP level < 40 mAu/ml. Even in patients with a single HCC <= 2 cm, the sensitivity of serum MtCK activity for the prediction of HCC was 64.4%, which was comparable to the overall sensitivity. This increased activity was due to an increase in ubiquitous MtCK, not sarcomeric MtCK, and the enhanced mRNA expression of ubiquitous MtCK was observed in cell lines originating from HCCs in contrast to healthy liver tissues. CONCLUSIONS: Serum MtCK activity merits consideration as a novel marker for HCC to be further tested as for its diagnostic and prognostic power. PMID- 22521350 TI - Visceral adiposity index is not a predictor of liver histology in patients with non-alcoholic fatty liver disease. AB - BACKGROUND & AIMS: Visceral adiposity is associated with hepatic steatosis, inflammation, and fibrosis in non-alcoholic fatty liver disease (NAFLD). The visceral adiposity index (VAI), a novel marker of visceral fat distribution and dysfunction, has been correlated with histology in hepatitis C. We assessed the ability of VAI to predict disease severity in NAFLD and hence its role as a non invasive marker of liver damage. METHODS: We examined 190 adults with biopsy proven NAFLD and 129 controls. All had anthropometric and metabolic profiling. VAI was calculated using waist circumference (WC), body mass index, triglycerides, and HDL-cholesterol. Abdominal fat was quantified by magnetic resonance imaging (MRI) in 38 patients. RESULTS: On multivariate analysis, NAFLD diagnosis and fasting glucose were independently associated with VAI (p <0.05). VAI increased across control, steatosis, and NASH groups (1.5, 2.3, and 3.2, respectively; p=0.000), however, this association was no stronger than the increase in WC across groups (r=0.452 vs. 0.540 respectively, p <0.001). VAI was not associated with steatosis, lobular inflammation or fibrosis, but WC was associated with fibrosis (p=0.01). VAI and WC correlated with an increasing number of metabolic syndrome components (r=0.623 vs. 0.614, p <0.001) and with metabolic syndrome diagnosis (r=0.559 vs. 0.509, p <0.001). VAI only modestly correlated with visceral fat on MRI (r=0.39, p <0.05) compared to WC (r=0.52, p <0.01). CONCLUSIONS: In NAFLD, VAI is not associated with steatosis, inflammation or fibrosis. VAI is no more powerful than WC in discriminating steatosis from steatohepatitis, reflecting limitations of the formula with what is known about the pathogenesis of NAFLD. PMID- 22521351 TI - Urinary neutrophil gelatinase-associated lipocalin as biomarker in the differential diagnosis of impairment of kidney function in cirrhosis. AB - BACKGROUND & AIMS: Impairment of kidney function is common in cirrhosis but differential diagnosis remains a challenge. We aimed at assessing the usefulness of neutrophil gelatinase-associated lipocalin (NGAL), a biomarker of tubular damage, in the differential diagnosis of impairment of kidney function in cirrhosis. METHODS: Two-hundred and forty-one patients with cirrhosis, 72 without ascites, 85 with ascites, and 84 with impaired kidney function, were studied. Urinary levels of NGAL were measured by ELISA. RESULTS: Patients with impaired kidney function had higher urinary NGAL levels compared to patients with and without ascites. Patients with urinary tract infection (n=25) had higher uNGAL values than non-infected patients. Patients with acute tubular necrosis (ATN) had uNGAL levels markedly higher (417MUg/g creatinine (239-2242) median and IQ range) compared to those of patients with pre-renal azotemia due to volume depletion 30 (20-59), chronic kidney disease (CKD) 82 (34-152), and hepatorenal syndrome (HRS) 76 (43-263) MUg/g creatinine (p<0.001 for all). Among HRS patients, the highest values were found in HRS-associated with infections, followed by classical (non associated with active infections) type-1 and type-2 HRS (391 (72-523), 147 (83 263), and 43 (31-74) MUg/g creatinine, respectively; p<0.001). Differences in uNGAL levels between classical type 1 HRS and ATN on the one hand and classical type 1 HRS and CKD and pre-renal azotemia on the other were statistically significant (p<0.05). CONCLUSIONS: uNGAL levels may be useful in the differential diagnosis of impairment of kidney function in cirrhosis. Urinary tract infections should be ruled out because they may increase uNGAL excretion. PMID- 22521352 TI - Excessive alcohol consumption after liver transplantation impacts on long-term survival, whatever the primary indication. AB - BACKGROUND & AIMS: Beyond 5 years, poorer survival, related to alcohol relapse, is observed in patients with liver transplant for alcohol-related liver disease (ALD). However, alcohol consumption has been significantly understudied in non ALD transplant recipients. We aimed at analyzing the impact of alcohol consumption on long-term survival irrespective of the indication for transplantation. METHODS: This observational study included consecutive adult recipients of a primary liver graft between 1991 and 2007 in our hospital, who survived >6 months. Patients without ALD as primary indication, but with a history of excessive alcohol consumption before transplantation, were classified as secondary indication ALD. We studied the impact on survival of excessive consumption of alcohol after transplantation and several other variables. RESULTS: The 441 patients had mean follow-up of 81.7 months. Among the 281 patients with excessive alcohol consumption before transplantation, 206 had ALD as primary indication. After transplantation, alcohol consumption was reported by 32.3% of the study population, 43.7% in primary indication ALD, and 24.3% in non ALD patients. Survival was 82% at 5 years and 49% at 10 years for patients with excessive alcohol relapse, compared with 86% and 75%, respectively, for patients without persistent excessive alcohol relapse. By multivariable analysis, the independent risk factors of death were: excessive alcohol relapse, age >51 years, post-transplantation diabetes mellitus, cyclosporine-based immunosuppression, and non-hepatic cancer. CONCLUSIONS: Excessive alcohol consumption has a negative impact on long-term survival after liver transplant, irrespective of the primary indication. Death is mainly due to recurrence of liver disease and non-hepatic cancer. PMID- 22521353 TI - Severe hyponatremia is a better predictor of mortality than MELDNa in patients with cirrhosis and refractory ascites. AB - BACKGROUND & AIMS: The MELDNa score was developed to improve the prognostic value of the MELD score in cirrhosis and was built for serum sodium concentrations numerically capped between 125 and 140 mmol/L. This model is not validated in a well-defined population of patients with cirrhosis and refractory ascites in whom severe hyponatremia (<= 125 mmol/L) is frequent. This study assessed the prognostic value of severe hyponatremia and the MELDNa score in these patients. METHODS: A consecutive, single-centre, observational, prospective study was performed in patients with cirrhosis and refractory ascites defined according to the International Ascites Club criteria. The prevalence of low serum sodium was assessed in this population. Predictive factors of mortality were analyzed and compared. RESULTS: One hundred seventy-four patients were included. Sixty-six (37.9%) had low serum sodium (< 130 mmol/L). Sixty-one (35.1%) had diuretic intractable ascites due to severe hyponatremia (<= 125 mmol/L). The median MELDNa score was 23 (10-33). The 1-year cumulative incidence of death was 55% (95% CI: 55-56%). The best predictive factors of mortality were the following: severe hyponatremia (<= 125 mmol/L) as an underlying cause of refractory ascites, a higher Child-Pugh score, beta-blocker therapy, and a high frequency of large volume paracentesis. The Child-Pugh score had a higher area under receiver operating curve to predict mortality than MELDNa. CONCLUSIONS: In patients with cirrhosis and refractory ascites, severe hyponatremia and Child-Pugh score are better predictors of mortality than MELDNa. PMID- 22521354 TI - A survey of patterns of practice and perception of NAFLD in a large sample of practicing gastroenterologists in France. AB - BACKGROUND & AIMS: Most studies on non-alcoholic fatty liver disease (NAFLD) originate from tertiary care centers with an academic interest. How this emerging entity is accepted and managed by a wider body of gastroenterologists is unknown, despite significant implications for the diagnosis of at-risk subjects and the utilization of healthcare resources. METHODS: We conducted a survey among 352 French, board-certified gastroenterologists from a large variety of practices to understand the clinical burden, perceived severity, and management patterns of NAFLD. RESULTS: Half of participants saw >30 new cases (equal to HCV) of NAFLD and 40% >5 new cases of NASH-cirrhosis yearly. Only 20% of patients were referred by endocrinologists; conversely, gastroenterologists overwhelmingly referred NAFLD patients for assessment of metabolic co-morbidities. In patients with metabolic risk factors, a majority of physicians considered the diagnosis of NAFLD, even if other liver diseases co-existed. The diagnosis heavily relies on aminotransferases, hence patients with normal ALT are usually not diagnosed. Liver biopsy is performed for fibrosis staging but not for the diagnosis/grading of steatohepatitis, and mainly decided based on non-invasive fibrosis procedures. Pharmacological treatment is used despite a lack of clear evidence of efficacy. Physicians monitor patients themselves, usually twice a year. CONCLUSIONS: NAFLD is recognized and accepted as a disease in itself with potentially severe outcomes. Most at-risk patients are currently missed because of non-referral by endocrinologists and no exploration of those with normal aminotransferases. The medical need for the diagnosis and treatment of NAFLD is real in the community of gastroenterologists at large. PMID- 22521355 TI - ARFI, FibroScan, ELF, and their combinations in the assessment of liver fibrosis: a prospective study. AB - BACKGROUND & AIMS: Our aim was to evaluate a serologic marker (ELF) and two ultrasound-based methods (FibroScan and ARFI), as well as their combinations, in the assessment of liver fibrosis. METHODS: One-hundred and forty-six patients (87 liver transplant recipients, 59 non-transplant patients) who underwent liver biopsy were prospectively included. We evaluated the diagnostic accuracy of FibroScan, ARFI, ELF and the combination of ELF with either ARFI or FibroScan. After analyzing in separate transplant and non-transplant patients, the whole cohort was divided into a training set and a validation set. RESULTS: ARFI imaging was successfully performed across the whole cohort, while FibroScan failed in 16 (11%) patients. The three methods showed similar AUROCs and best cut off values in transplant and non-transplant patients. In the training set, differences between the AUROCs of ARFI, FibroScan and ELF to diagnose F?2 (0.879, 0.861, and 0.764, respectively) and cirrhosis (0.936, 0.918, and 0.841) were not statistically significant, although both ultrasound-based methods showed higher accuracy than ELF. The combination of ELF with ARFI or FibroScan increased the negative and positive predictive values of single tests for the diagnosis of F >= 2 and cirrhosis. Similar results were obtained when the methods were tested in the validation set. CONCLUSIONS: ARFI is as effective as either FibroScan or ELF in the non-invasive assessment of liver fibrosis, and its inclusion in an ultrasound device could facilitate its incorporation into routine clinical practice. The combination of ARFI or FibroScan with ELF may help better identify patients with or without significant fibrosis or cirrhosis. PMID- 22521356 TI - Immediate vs. delayed treatment in patients with acute hepatitis C based on IL28B polymorphism: a model-based analysis. AB - BACKGROUND & AIMS: Timing of treatment initiation in acute hepatitis C (AHC) patients is unclear. Spontaneous viral clearance argues for a "watch-and-wait" strategy. However, early initiation of treatment could increase the sustained virological response (SVR) rate. We compared three different HCV treatment initiation strategies in patients with AHC according to presence of clinical symptoms and IL28B polymorphism: (1) within 2 months after transmission (immediate initiation), (2) at 3 months (early initiation), and (3) at 4/5 months (delayed initiation). METHODS: We calculated spontaneous HCV clearance probability based on the symptomatic (sAHC) and asymptomatic (aAHC) nature of disease and C/C or non-C/C genotype. We used different SVR probabilities according to delay between transmission and treatment. We estimated the probability of developing chronic hepatitis C (CHC). RESULTS: The probability of developing CHC was lower for immediate treatment initiation (7.1% in C/C and 7.3% in non-C/C patients with sAHC; 6.6% in C/C and 7.1% in non-C/C patients with aAHC) than for delayed initiation (13.5% in C/C and 18.0% in non-C/C patients with sAHC; 14.6% in C/C and 18.5% in non-C/C patients with aAHC) regardless of the presence of symptoms or IL28B genotype. CONCLUSIONS: In patients such as health care workers, in whom HCV is detected <= 2 months following transmission, treatment should be immediately initiated regardless of clinical symptoms and IL28B polymorphism. In those in whom HCV is detected>2 months after transmission, treatment 4/5 months after may be preferable because of a higher rate of spontaneous HCV clearance after 2 months and a poor HCV treatment efficacy's differential between months 3 and 4/5. PMID- 22521357 TI - Modest alcohol consumption is associated with decreased prevalence of steatohepatitis in patients with non-alcoholic fatty liver disease (NAFLD). AB - BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is a cardiovascular risk factor. Although modest alcohol consumption may reduce the risk for cardiovascular mortality, whether patients with NAFLD should be allowed modest alcohol consumption remains an important unaddressed issue. We aimed to evaluate the association between modest alcohol drinking and non-alcoholic steatohepatitis (NASH), among subjects with NAFLD. METHODS: In a cross-sectional analysis of adult participants in the NIH NASH Clinical Research Network, only modest or non drinkers were included: participants identified as (1) drinking >20 g/day, (2) binge drinkers, or (3) non-drinkers with previous alcohol consumption were excluded. The odds of having a histological diagnosis of NASH and other histological features of NAFLD were analyzed using multiple ordinal logistic regression. RESULTS: The analysis included 251 lifetime non-drinkers and 331 modest drinkers. Modest drinkers compared to non-drinkers had lower odds of having a diagnosis of NASH (summary odds ratio 0.56, 95% CI 0.39-0.84, p=0.002). The odds of NASH decreased as the frequency of alcohol consumption increased within the range of modest consumption. Modest drinkers also had significantly lower odds for fibrosis (OR 0.56 95% CI 0.41-0.77) and ballooning hepatocellular injury (OR 0.66 95% CI 0.48-0.92) than lifetime non-drinkers. CONCLUSIONS: In a large, well-characterized population with biopsy-proven NAFLD, modest alcohol consumption was associated with lesser degree of severity as determined by lower odds of the key features that comprise a diagnosis of steatohepatitis, as well as fibrosis. These findings demonstrate the need for prospective studies and a coordinated consensus on alcohol consumption recommendations in NAFLD. PMID- 22521358 TI - National patterns and predictors of liver biopsy use for management of hepatitis C. AB - BACKGROUND & AIMS: Liver biopsy remains the standard, recommended method for assessing liver damage associated with chronic hepatitis C (HCV) infection. However, there is considerable debate about how liver biopsy should best be used, especially with the advent of more efficacious antiviral therapies. To identify the factors that influence the use of liver biopsy for HCV patients, we describe variations in liver biopsy use at the delivery system and patient level in a national VA sample. METHODS: We analyzed VA HCV registry data for 171,893 VA patients with confirmed chronic HCV. Delivery system characteristics included geographic region and specialist time. Patient characteristics included antiviral treatment indicators, contraindications, volume of healthcare visits, and demographic variables. Logistic regression was used to explore correlates of biopsy use. RESULTS: Liver biopsy use in the VA system increased from 1997 to 2003 but began declining in 2004. Rates of liver biopsy from 2004 to 2006 varied by VA region, ranging from 5% to 18%. Treatment contraindications and laboratory tests were significantly associated with more biopsies. Demographic variables (higher age, lower BMI, race/ethnicity, and less% service connected disability) were associated with fewer biopsies. Regional variability remained significant independent of volume of care and specialist time. CONCLUSIONS: Liver biopsy rates in the VA system have variability that seems unrelated to clinical need. New antiviral therapies and non-invasive assessment techniques may create additional uncertainty for the role of liver biopsy, perhaps explaining its decline in recent years. The availability of more effective antiviral therapies may also affect biopsy rates in the future. PMID- 22521359 TI - M6P/IGF2R modulates the invasiveness of liver cells via its capacity to bind mannose 6-phosphate residues. AB - BACKGROUND & AIMS: The mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R), a multifunctional protein, plays a central role in intracellular targeting of lysosomal enzymes and control of insulin-like growth factor II (IGF II) bioactivity. Importantly, the gene encoding this receptor is frequently inactivated in a wide range of malignant tumors including hepatocellular carcinomas. Thus, M6P/IGF2R is considered a putative liver tumor suppressor. The aim of this study was to establish the impact of the receptor on the invasive properties of liver cells. METHODS: Reconstitution experiments were performed by expression of wild type and mutant M6P/IGF2R in receptor-deficient FRL14 fetal rat liver cells. RNA interference was used to induce M6P/IGF2R downregulation in receptor-positive MIM-1-4 mouse hepatocytes. RESULTS: We show that the M6P/IGF2R status exerts a strong impact on the invasiveness of tumorigenic rodent liver cells. M6P/IGF2R-deficient fetal rat liver cells hypersecrete lysosomal cathepsins and penetrate extracellular matrix barriers in a cathepsin-dependent manner. Forced expression of M6P/IGF2R restores intracellular transport of cathepsins to lysosomes and concomitantly reduces the tumorigenicity and invasive potential of these cells. Conversely, M6P/IGF2R knock-down in receptor-positive mouse hepatocytes causes increased cathepsin secretion as well as enhanced cell motility and invasiveness. We also demonstrate that functional M6P-binding sites are important for the anti-invasive properties of M6P/IGF2R, whereas the capacity to bind IGF-II is dispensable for the anti-invasive activity of the receptor in liver cells. CONCLUSIONS: M6P/IGF2R restricts liver cell invasion by preventing the pericellular action of M6P-modified proteins. PMID- 22521360 TI - An in situ molecular signature to predict early recurrence in hepatitis B virus related hepatocellular carcinoma. AB - BACKGROUND & AIMS: To develop an in situ molecular signature to predict postsurgical recurrence in hepatocellular carcinoma (HCC) patients. METHODS: Immunohistochemistry was performed using tissue microarrays containing both tumoral and peri-tumoral regions of the advancing tumor edge from 336 HCC patients (289 were positive for hepatitis B virus) who underwent curative resection. Forty-nine variables were analyzed in the training set (n=151) using support vector machine and stepwise algorithms to develop a classifier to predict recurrence within 1 year, which was mainly caused by invasion or metastasis from the primary tumors. The classifier was further validated in an independent cohort of 185 patients (71 internal and 114 external). RESULTS: The final signature was composed of eight IHC features: CD80(T), B7-DC(T), HLA-DR(P), FasL(P), Bcl-2(T), Ki-67(T), cyclin D1(T), and CK19(T). In the independent test set, this classifier reliably predicted recurrence within 1 year (sensitivity, 69.1%; specificity, 65.0%) with an odds ratio of 4.149 (95% CI, 2.189-7.864). Based on a multivariate logistic model, the in situ molecular signature provided significant predictive power independent of tumor number, tumor size, vascular invasion and BCLC classification (p=0.001). The highest potential clinical impact of the classifier was observed in early-stage (BCLC classification 0-A) patients (p<0.0001), and the classifier was also predictive of the time-to-recurrence and overall survival (both p<0.0001). CONCLUSIONS: This in situ molecular classifier could provide a novel approach to identify patients who are at greatest risk for postsurgical recurrence of HCC and may benefit from intensive clinical follow-up or chemopreventive strategies. PMID- 22521362 TI - The relationship between Bayesian motor unit number estimation and histological measurements of motor neurons in wild-type and SOD1(G93A) mice. AB - OBJECTIVE: To assess the relationship between Bayesian MUNE and histological motor neuron counts in wild-type mice and in an animal model of ALS. METHODS: We performed Bayesian MUNE paired with histological counts of motor neurons in the lumbar spinal cord of wild-type mice and transgenic SOD1(G93A) mice that show progressive weakness over time. We evaluated the number of acetylcholine endplates that were innervated by a presynaptic nerve. RESULTS: In wild-type mice, the motor unit number in the gastrocnemius muscle estimated by Bayesian MUNE was approximately half the number of motor neurons in the region of the spinal cord that contains the cell bodies of the motor neurons supplying the hindlimb crural flexor muscles. In SOD1(G93A) mice, motor neuron numbers declined over time. This was associated with motor endplate denervation at the end-stage of disease. CONCLUSION: The number of motor neurons in the spinal cord of wild type mice is proportional to the number of motor units estimated by Bayesian MUNE. In SOD1(G93A) mice, there is a lower number of estimated motor units compared to the number of spinal cord motor neurons at the end-stage of disease, and this is associated with disruption of the neuromuscular junction. SIGNIFICANCE: Our finding that the Bayesian MUNE method gives estimates of motor unit numbers that are proportional to the numbers of motor neurons in the spinal cord supports the clinical use of Bayesian MUNE in monitoring motor unit loss in ALS patients. PMID- 22521361 TI - Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. AB - Balanced chromosomal abnormalities (BCAs) represent a relatively untapped reservoir of single-gene disruptions in neurodevelopmental disorders (NDDs). We sequenced BCAs in patients with autism or related NDDs, revealing disruption of 33 loci in four general categories: (1) genes previously associated with abnormal neurodevelopment (e.g., AUTS2, FOXP1, and CDKL5), (2) single-gene contributors to microdeletion syndromes (MBD5, SATB2, EHMT1, and SNURF-SNRPN), (3) novel risk loci (e.g., CHD8, KIRREL3, and ZNF507), and (4) genes associated with later-onset psychiatric disorders (e.g., TCF4, ZNF804A, PDE10A, GRIN2B, and ANK3). We also discovered among neurodevelopmental cases a profoundly increased burden of copy number variants from these 33 loci and a significant enrichment of polygenic risk alleles from genome-wide association studies of autism and schizophrenia. Our findings suggest a polygenic risk model of autism and reveal that some neurodevelopmental genes are sensitive to perturbation by multiple mutational mechanisms, leading to variable phenotypic outcomes that manifest at different life stages. PMID- 22521363 TI - Assault related substance use as a predictor of substance use over time within a sample of recent victims of sexual assault. AB - Substance use at time of assault is reported by a significant subgroup of rape victims. This study examined: (1) prevalence of assault related marijuana or alcohol use among women seeking post-rape medical care; (2) sensitivity, specificity, positive and negative predictive power associated with reported use at time of assault in association with use in 6 weeks pre-assault, post-assault use, and post-assault abuse; and (3) trajectories of use and abuse over time as a function of use in 6 weeks pre-assault/assault time frame use, exposure to brief intervention, and interaction of pre-assault/assault time frame use with intervention. Participants were 268 women seeking post-sexual assault medical services completing one or more follow-up assessment at: (1) <3 months post assault; (2) 3 to 6 months post-assault; and (3) 6 months or longer post-assault. Use of alcohol or marijuana at time of assault was a fairly sensitive and specific indicator respectively, of reported use of specific substance in the 6 weeks preceding assault and use or abuse at follow-up. Growth modeling revealed that use of alcohol or marijuana at the time of the assault or in the 6 weeks prior to assault predicted higher Time 1 follow-up alcohol and marijuana use and abuse. Although there was relatively little change in use or abuse over time, alcohol use at time of the assault or in the 6 weeks prior also predicted a steeper decline in alcohol use over the course of follow-up. Interestingly, women who reported using marijuana at the time of the assault or in the 6 weeks prior who also received a video intervention actually had lower initial marijuana use, a pattern that remained stable over time. Implications for evaluating screening, brief intervention and referral to treatment services among sexual assault victims seeking post-assault medical care are discussed. PMID- 22521364 TI - Rash impulsiveness and reward sensitivity in relation to risky drinking by university students: potential roles of frontal systems. AB - BACKGROUND: Two forms of impulsivity, rash impulsiveness and reward sensitivity, have been proposed to reflect aspects of frontal lobe functioning and promote substance use. The present study examined these two forms of impulsivity as well as frontal lobe symptoms in relation to risky drinking by university students. METHODS: University undergraduates aged 18-26years completed the Alcohol Use Disorders Identification Test (AUDIT), Barratt Impulsiveness Scale (BIS-11), Sensitivity to Punishment and Sensitivity to Reward Questionnaire (SPSRQ), Frontal Systems Behavior Scale (FrSBe), and a demographics questionnaire assessing age, gender, and age of onset of weekly drinking (AOD). RESULTS: AUDIT defined harmful drinkers reported earlier AOD and scored higher on BIS-11, the Sensitivity to Reward (SR) scale of the SPSRQ, and the Disinhibition and Executive Dysfunction scales of the FrSBe compared to lower risk groups. Differences remained significant after controlling for duration of alcohol exposure. Path analyses indicated that the influence of SR on AUDIT was mediated by FrSBe Disinhibition, whereas the influence of BIS-11 on AUDIT was mediated by both Disinhibition and Executive Dysfunction scales of the FrSBe. CONCLUSIONS: Findings tentatively suggest that the influence of rash impulsiveness on drinking may reflect dysfunction in dorsolateral prefrontal and orbitofrontal systems, whereas the influence of reward sensitivity on drinking may primarily reflect orbitofrontal dysfunction. Irrespective of the underlying functional brain systems involved, results appear to be more consistent with a pre-drinking trait interpretation than effects of alcohol exposure. PMID- 22521366 TI - E2->E1 transition and Rb(+) release induced by Na(+) in the Na(+)/K(+)-ATPase. Vanadate as a tool to investigate the interaction between Rb(+) and E2. AB - This work presents a detailed kinetic study that shows the coupling between the E2->E1 transition and Rb(+) deocclusion stimulated by Na(+) in pig-kidney purified Na,K-ATPase. Using rapid mixing techniques, we measured in parallel experiments the decrease in concentration of occluded Rb(+) and the increase in eosin fluorescence (the formation of E1) as a function of time. The E2->E1 transition and Rb(+) deocclusion are described by the sum of two exponential functions with equal amplitudes, whose rate coefficients decreased with increasing [Rb(+)]. The rate coefficient values of the E2->E1 transition were very similar to those of Rb(+)-deocclusion, indicating that both processes are simultaneous. Our results suggest that, when ATP is absent, the mechanism of Na(+)-stimulated Rb(+) deocclusion would require the release of at least one Rb(+) ion through the extracellular access prior to the E2->E1 transition. Using vanadate to stabilize E2, we measured occluded Rb(+) in equilibrium conditions. Results show that, while Mg(2+) decreases the affinity for Rb(+), addition of vanadate offsets this effect, increasing the affinity for Rb(+). In transient experiments, we investigated the exchange of Rb(+) between the E2-vanadate complex and the medium. Results show that, in the absence of ATP, vanadate prevents the E2->E1 transition caused by Na(+) without significantly affecting the rate of Rb(+) deocclusion. On the other hand, we found the first evidence of a very low rate of Rb(+) occlusion in the enzyme-vanadate complex, suggesting that this complex would require a change to an open conformation in order to bind and occlude Rb(+). PMID- 22521365 TI - alphaB-crystallin/sHSP protects cytochrome c and mitochondrial function against oxidative stress in lens and retinal cells. AB - BACKGROUND: alphaB-crystallin/sHSP protects cells against oxidative stress damage. Here, we mechanistically examined its ability to preserve mitochondrial function in lens and retinal cells and protect cytochrome c under oxidative stress conditions. METHODS: alphaB-crystallin/sHSP was localized in human lens (HLE-B3) and retinal (ARPE-19) cells. alphaB-crystallin/sHSP was stably over expressed and its ability to preserve mitochondrial membrane potential under oxidative stress conditions was monitored. Interactions between alphaB crystallin/sHSP and cytochrome c were examined by fluorescent resonance energy transfer (FRET) and by co-immune precipitation. The ability of alphaB crystallin/sHSP to protect cytochrome c against methionine-80 oxidation was monitored. RESULTS: alphaB-crystallin/sHSP is present in the mitochondria of lens and retinal cells and is translocated to the mitochondria under oxidative conditions. alphaB-crystallin/sHSP specifically interacts with cytochrome c in vitro and in vivo and its overexpression preserves mitochondrial membrane potential under oxidative stress conditions. alphaB-crystallin/sHSP directly protects cytochrome c against oxidation. GENERAL SIGNIFICANCE: These data demonstrate that alphaB-crystallin/sHSP maintains lens and retinal cells under oxidative stress conditions at least in part by preserving mitochondrial function and by protecting cytochrome c against oxidation. Since oxidative stress and loss of mitochondrial function are associated with eye lens cataract and age-related macular degeneration, loss of these alphaB-crystallin/sHSP functions likely plays a key role in the development of these diseases. alphaB-crystallin/sHSP is expressed throughout the body and its ability to maintain mitochondrial function is likely important for the prevention of multiple degenerative diseases. PMID- 22521367 TI - A brain penetration after Taser injury: controversies regarding Taser gun safety. AB - We report the case of a 27 year old man who was injured by a Taser gun device which penetrated the frontal part of the skull and damaged the underlying frontal lobe. Cerebral penetration was revealed by a brain CT scan. A neurosurgical procedure was required to remove the dart from the skull and brain and the evolution was successful allowing discharge of the patient one week later. There were no additional lesions, particularly electrifying lesion, as only one probe had penetrated the skull. We also observed the length of a Taser dart is sufficient to allow brain penetration. Fortunately, no infection or neurological complication occurred following brain injury. This case study underlines the potential risk induced by the use of Taser stun gun. Although generally regarded as a safe alternative, serious injuries have however been reported and questions regarding the safety of the device still remains unresolved. PMID- 22521368 TI - Supine exercise echocardiographic measures of systolic and diastolic function in children. AB - BACKGROUND: Echocardiography has been used to determine ventricular function, segmental wall motion abnormality, and pulmonary artery pressure before and after peak exercise. No prior study has investigated systolic and diastolic function using echocardiography at various phases of exercise in children. The aim of this study was to determine the fractional shortening (FS), systolic-to-diastolic (S/D) ratio, heart rate-corrected velocity of circumferential fiber shortening (VCFc), circumferential wall stress (WS), ratio of mitral passive inflow to active inflow (E/A), ratio of passive inflow by pulsed-wave to tissue Doppler (E/E'), and right ventricular-to-right atrial pressure gradient from tricuspid valve regurgitation jet velocity (RVP) and time duration at various phases of exercise in children. METHODS: In an 8-month period (December 2007 to July 2008), 100 healthy children were evaluated, and 97 participants aged 8 to 17 years who performed complete cardiopulmonary exercise stress tests using supine cycle ergometry were prospectively enrolled. The participants consisted of 48 female and 49 male subjects with various body sizes, levels of exercise experience, and physical capacities. The cardiopulmonary exercise stress test consisted of baseline pulmonary function testing, continuous gas analysis and monitoring of blood pressure and heart rate responses, electrocardiographic recordings, and oxygen saturation measurement among participants who pedaled against a ramp protocol based on body weight. All participants exercised to exhaustion. Echocardiography was performed during exercise at baseline, at a heart rate of 130 beats/min, at a heart rate of 160 beats/min, at 5 min after exercise, and at 10 min after exercise. FS, S/D ratio, VCFc, WS, E/A, E', E/E', and RVP at these five phases were compared in all subjects. RESULTS: All echocardiographic parameters differed at baseline from 160 beats/min (P < .0001) except E/E', which remained at 5.4 to 5.8. Specifically, FS (from 37% to 46%), S/D ratio, VCFc (from 1.1 to 1.6), WS (from 200 to 258 g/cm(2)), E' (from 0.2 to 0.3), and RVP (from 18 to 35 mm Hg) increased from baseline to 160 beats/min and then subsequently decreased to at or near baseline, while tricuspid valve regurgitation duration decreased (from 370 to 178 msec). CONCLUSIONS: Normal values for systolic and diastolic echocardiographic measurements of function are now available. FS, VCFc, WS, and RVP increase with exercise and then return to near baseline levels. The E/E' ratio is unaltered with exercise in normal subjects. PMID- 22521369 TI - Educate one to save a few. Educate a few to save many. AB - Roughly one-third of the world's nearly 7 billion people are covered by approximately 1/20 of its neurosurgeons. Neurosurgeons in the more developed countries have a moral obligation to increase access to neurosurgical care for the rest of the world. This can be achieved most effectively through neurosurgical education. Many neurosurgeons have already contributed greatly in this regard. Because of insufficient access to neurosurgical care, most children with hydrocephalus in Africa go untreated. Possibly as many as 2000 infants per neurosurgeon per year will develop hydrocephalus in sub-Saharan Africa. We have adopted a disease-specific strategy for training and equipping centers to provide evidence-based endoscopic treatment of hydrocephalus to save lives while avoiding the danger of shunt dependence, which is magnified in this context. In Uganda, we have successfully educated one to save a relative few. Our aim is to educate a few to save many. Such a disease-specific approach may provide a useful strategy for increasing access to care for other common, treatable neurosurgical conditions in resource-poor settings. PMID- 22521370 TI - Structure-based virtual screening of novel inhibitors of the uridyltransferase activity of Xanthomonas oryzae pv. oryzae GlmU. AB - N-Acetylglucosamine-1-phosphate uridyltransferase (GlmU) catalyzes the formation of UDP-GlcNAc, a fundamental precursor in cell wall biosynthesis. GlmU represents an attractive target for new antibacterial agents. In this study, a theoretical three-dimensional (3D) structure of GlmU from Xanthomonas oryzae pv. oryzae (Xo GlmU) was generated, and the ligand-receptor interaction was investigated by molecular docking. Then a structure-based virtual screening was performed, three hit compounds were identified as specific inhibitors of the uridyltransferase activity of Xo-GlmU, with IC(50) values in the 0.81-23.21 MUM range. Subsequently, the mode-of-inhibition and K(i) values of the three inhibitors were confirmed. The minimum inhibitory concentrations (MICs) of the candidate compounds for X. oryzae pv. oryzae (Xoo) were also determined. The research provided novel chemical scaffolds for antimicrobial drug discovery. PMID- 22521371 TI - Synthesis of 4-methylcoumarin derivatives containing 4,5-dihydropyrazole moiety to scavenge radicals and to protect DNA. AB - A series of 4-methylcoumarin derivatives containing 4,5-dihydropyrazole moiety were synthesized and their antioxidant activities were evaluated in AAPH (2,2' azobis(2-amidinopropane hydrochloride))-induced oxidation of DNA, and in trapping DPPH (2,2'-diphenyl-1-picrylhydrazyl) and ABTS(+*) (2,2'-azinobis(3 ethylbenzothiazoline-6-sulfonate) cationic radical), respectively. Among coumarin derivatives, 3a-d and 4a-c exhibited the termination of radical propagation chains in AAPH-induced oxidation of DNA. The ortho dihydroxyphenyl substitution at 5 position and 1-unsubstitution of the 4,5-dihydroxylpyrazole was found enhancing the antioxidant activities of these coumarin derivatives. PMID- 22521372 TI - Self-organizing molecular field analysis of NSAIDs: assessment of pharmacokinetic and physicochemical properties using 3D-QSPkR approach. AB - Non-steroidal anti-inflammatory drug (NSAID) induced gastrointestinal toxicity has attracted greater attention over the years. The development of NSAIDs having safer therapeutic profile depends on the better understanding of their mechanisms, physicochemical and pharmacokinetic properties. The present investigation is aimed at in silico three dimensional quantitative structure pharmacokinetic relationship (3D-QSPkR) assessment of a group of NSAIDs using self-organizing molecular field analysis (SOMFA) approach. Two different statistically validated models for dissociation constant (pK(a)) and volume of distribution (V(d)) were obtained from SOMFA studies of 22 clinically active NSAIDs having diversity in structure. 3D-QSPkR models delivered useful information about the contribution of shape and electrostatic potential on pK(a) and V(d). The study illustrated the significance of structural variables in molecular architecture of NSAIDs especially etodolac for further optimization of ADMET properties with improved therapeutic profile. PMID- 22521373 TI - Assessment of leisure-time physical activity for the prediction of inflammatory status and cardiometabolic profile. AB - OBJECTIVES: Associations of leisure-time physical activity (LTPA), commuting and total physical activity with inflammatory markers, insulin resistance and metabolic profile in individuals at high cardiometabolic risk were investigated. DESIGN: This was a cross-sectional study. METHODS: A total of 193 prediabetic adults were compared according to physical activity levels measured by the international physical activity questionnaire; p for trend and logistic regression was employed. RESULTS: The most active subset showed lower BMI and abdominal circumference, reaching significance only for LTPA (p for trend=0.02). Lipid profile improved with increased physical activity levels. Interleukin-6 decreased with increased total physical activity and LTPA (p for trend=0.02 and 0.03, respectively), while adiponectin increased in more active subsets for LTPA (p for trend=0.03). Elevation in adjusted OR for hypercholesterolemia was significant for lower LTPA durations (p for trend=0.04). High apolipoprotein B/apolipoprotein A ratio was inversely associated with LTPA, commuting and total physical activity. Increase in adjusted OR for insulin resistance was found from the highest to the lowest category of LTPA (p for trend=0.04) but significance disappeared after adjustments for BMI and energy intake. No association of increased C-reactive protein with physical activity domains was observed. CONCLUSIONS: In general, the associations of LTPA, but not commuting or total physical activity, with markers of cardiometabolic risk reinforces the importance of initiatives to increase this domain in programs for the prevention of lifestyle-related diseases. PMID- 22521374 TI - Computational identification of novel histone deacetylase inhibitors by docking based QSAR. AB - Histone deacetylases (HDACs) are enzymes that modify chromatin structure and contribute to aberrant gene expression in cancer. A series compounds with well assigned HDAC inhibitory activity was used for docking based 3D-QSAR analysis. The 3D-QSAR acquired had excellent correlation coefficient value (q2=0.753) and high Fisher ratio (F=300.2). A validated pharmacophore model (AAAPR) was employed for virtual screening. After manual selection, molecular docking and further refinement, six compounds with good absorption, distribution, metabolism, and excretion (ADME) properties were selected as potential HDAC inhibitors. Further, the molecular interactions of these inhibitors with the HDAC active site residues were discussed in detail. PMID- 22521375 TI - Stressed brain, diseased heart: a review on the pathophysiologic mechanisms of neurocardiology. AB - Cardiovascular diseases are traditionally related to well known risk factors like dyslipidemia, smoking, diabetes and hypertension. More recently, stress, anxiety and depression have been proposed as risk factors for cardiovascular diseases including heart failure, ischemic disease, hypertension and arrhythmias. Interestingly, this association has been established largely on the basis of epidemiological data, due to insufficient knowledge on the underlying pathophysiologic mechanisms. This review will revisit evidence on the interaction between the cardiovascular and nervous systems, highlighting the perspective on how the central nervous system is involved in the pathogenesis of cardiovascular diseases. Such knowledge is likely to be of relevance for the development of better strategies to treat patients in a holistic perspective. PMID- 22521377 TI - Response letter to 'Adiponectin and arterial stiffness in hypertensive patients'. PMID- 22521376 TI - Iliofemoral anatomy among Asians: implications for transcatheter aortic valve implantation. AB - BACKGROUND/OBJECTIVES: This study aims to examine iliofemoral anatomy and predictors of vessel size and tortuosity in Asian patients as transfemoral transcatheter aortic valve implantation (TAVI) may be limited by the smaller Asian physique. METHODS: Characteristics and vessel dimensions of 549 patients undergoing ultrasonography were reviewed. The minimal luminal diameter (MLD) along the iliofemoral vasculature of each side was identified and the larger of the two sides was used to determine suitability for transfemoral TAVI. RESULTS: The mean age was 66 +/- 11 years (68% males). Mean iliac MLD was 7.6 +/- 1.7 mm, females smaller than males (7.2 +/- 1.7 vs 7.8 +/- 1.7, p<0.001). Mean iliac MLD decreased with age: 7.9 +/- 1.7 mm, 7.4 +/- 1.9 mm and 7.3 +/- 1.6mm for ages <70 years, 70-79 years and >= 80 years respectively (p=0.038). Mean femoral MLD was 7.0 +/- 1.7 mm, females smaller than males (6.3 +/- 1.5mm vs 7.3 +/- 1.8mm, p<0.001). Females were more likely than males to have iliac and femoral MLD <6mm (20% vs 12%, p=0.019 and 34% vs 21%, p=0.001). Independent predictors of smaller iliofemoral dimensions were female gender, lower body surface area, diabetes mellitus, dyslipidemia and smoking history. Significant iliac tortuosity was present in 11.8%, more frequent in males than females (15% vs 6%, p=0.005), and in those with logistic EuroSCORE >= 15 than <15 (27% vs 10%, p=0.001). CONCLUSIONS: This study establishes the mean iliac and femoral artery diameters in a cohort of relatively young Asian patients. Age and female gender were associated with smaller vessel dimension and several independent predictors of smaller vasculature and tortuosity were identified. These results have implications for TF TAVI in Asia. PMID- 22521378 TI - Univentricular hearts in Denmark 1977 to 2009: incidence and survival. AB - BACKGROUND: The incidence of children born with functional univentricular heart (UVH) and their prognosis presumably changed substantially in recent years. This is due to introduction of fetal echocardiography and potential termination of pregnancy (TOP) when UVH is diagnosed (UVH TOP), and to improvements in treatment. We aimed to explore changes in incidence, to estimate changes in survival, and to describe predictors of mortality in UVH patients. METHODS: Using a population-based design we identified all UVH cases in Denmark from 1977 to 2009. RESULTS: 703 UVH live births and 106 UVH TOP were identified. A dramatic decrease in birth incidence of UVH patients and a corresponding increase in UVH TOP was observed in recent years. Mean incidence rate of UVH (live births and UVH TOP) was 0.39 per 1000 births. In adjusted analysis survival improved significantly from birth era 1977-1989 to 1990-1999 (HR 2.65, 95% confidence interval (CI), 2.06-3.42) but not significantly from 1990-1999 to 2000-2009 (HR 0.77, 95% CI, 0.57-1.05). In the birth era 2000-2009, the lowest five-year survival was seen with hypoplastic left heart syndrome (HLHS) (18.8%), whereas the best survival was seen with tricuspid atresia (79.8%). Adjusted risk of death was 7.3 times higher in the HLHS group compared to the tricuspid atresia group (95% CI, 3.94-13.47). CONCLUSIONS: This study demonstrates a dramatic decrease in birth incidence of UVH patients most probably due to a corresponding increase in UVH TOP. Despite survival improved after introduction of Fontan surgery, survival has not improved significantly during the last 20years. PMID- 22521379 TI - Trends in publications on stress-induced cardiomyopathy. PMID- 22521380 TI - First reported case of Pasteurella pneumotropica tricuspid valve endocarditis. PMID- 22521381 TI - Fragmented QRS complexes predict right ventricular dysfunction and outflow tract aneurysms in patients with repaired tetralogy of Fallot. AB - BACKGROUND: Fragmented QRS complexes (fQRS) correlate with myocardial scar, and may predict arrhythmias in patients with repaired tetralogy of Fallot (TOF). We investigated the relationship between fQRS in operated TOF patients with right ventricular (RV) dysfunction and RV outflow tract (RVOT) aneurysm. METHODS: We studied 56 operated TOF patients with moderate/severe pulmonary regurgitation, referred for cardiac magnetic resonance imaging (MRI) over a 4.5 year period. The presence of fQRS (additional notches in the R/S wave in >= 2 contiguous leads on the ECG) was correlated with MRI findings. RESULTS: fQRS was observed in 44 (78.6%) patients. Patients with fQRS had significantly larger RV end diastolic volume index (RVEDVi; 162 ml vs 141 ml, p=0.028) and RV end systolic volume index (RVESVi; 88 ml vs 70 ml, p=0.031). Increasing number of leads with fragmentation was independently associated with increasingly lower RV ejection fraction (adjusted co-efficient -0.97, 95%CI -1.83 to -0.12, p=0.026), greater pulmonary regurgitation fraction (1.65, 0.28 to 3.01, p=0.019), larger RVEDVi (6.78, 2.00 to 11.56, p=0.006) and RVESVi (5.41, 1.66 to 9.15, p=0.005). Anterior fragmentation correlated most significantly with RV dysfunction (p<0.05). fQRS had no significant association with LV dysfunction. Presence of any fQRS (OR 17.5, 95%CI 2.1-147.8, p=0.009) and inferior fQRS (OR 9.0, 95%CI 2.7-30.1, p<0.001) were found to be significant predictors for RVOT aneurysm. CONCLUSIONS: The presence of fQRS on the ECG is significantly associated with RV dysfunction and RVOT aneurysms in repaired TOF patients. Increasing burden of fragmentation, especially in the anterior leads, is associated with increasing RV dysfunction. PMID- 22521382 TI - Conduction disturbances in takotsubo cardiomyopathy: a cause or a consequence? PMID- 22521383 TI - Exertional periodic breathing potentiates erythrocyte rheological dysfunction by elevating pro-inflammatory status in patients with anemic heart failure. AB - BACKGROUND: Exertional periodic breathing (EPB) or anemia is associated with an adverse prognosis in advanced heart failure (HF). The disturbed rheological properties of erythrocytes may contribute to circulatory disorders. This study investigated whether EPB with/without anemia influences rheological/hemodynamic functions in patients with HF. METHODS: According to the WHO criteria for anemia, 168 HF patients were divided into six groups: non (N)-anemic with (n=27)/without (n=56) EPB, light (L)-anemic with (n=17)/without (n=21) EPB, and moderate/several (M/S)-anemic with (n=21)/without (n=26) EPB groups. These HF patients and 30 healthy counterparts performed an incremental exercise test using a bicycle ergometer. Rheological and hemodynamic characteristics were determined by slit flow ektacytometer and bioreactance-based device/near infrared spectrometer, respectively. RESULTS: In the HF patients with EPB, both L- and M/S-anemic groups exhibited 1) higher plasma myeloperoxidase/interleukin-6 concentrations, 2) more blood senescent/spherical erythrocyte counts, 3) larger aggregability and smaller deformability of erythrocytes under shear flows, 4) higher systemic vascular resistance, which was accompanied by smaller amounts of blood distributed to cerebral/muscular tissues during exercise, 5) less VO(2peak) and ventilatory efficiency, and 6) lower Short Form-36 physical/mental component scores and higher Minnesota Living with HF questionnaire score than N-anemic group. Additionally, plasma myeloperoxidase/interleukin-6 levels were directly related to erythrocyte aggregability and inversely related to erythrocyte deformability. However, there were no significant differences in pro-inflammatory factors, rheological/hemodynamic properties, and aerobic capacity between L- and N-anemic groups in the HF patients without EPB. CONCLUSION: EPB potentiates anemia-related rheological/hemodynamic dysfunctions by elevating pro-inflammatory status, reducing physical fitness in patients with HF. PMID- 22521384 TI - Atypical thymic carcinoid associated with coronary artery spasm: incidental finding of myocardial perfusion imaging. PMID- 22521385 TI - Glenoid morphology after reaming in computer-simulated total shoulder arthroplasty. AB - BACKGROUND: The relationships between reaming parameters for glenoid-implant surface area and bone loss in total shoulder arthroplasty have not been well established. The hypotheses of this study are: (1) for large version corrections, a large reaming depth of 5 mm is not sufficient to obtain complete glenoid implant contact; (2) glenoid bone is removed in a linear proportion with reaming depth; and (3) initial reamer placement has no effect on glenoid bone removal. METHODS: Ten computer models from computed tomography scans of patients with advanced osteoarthritis were created for computer-simulated reaming as performed during total shoulder arthroplasty. Reaming variables studied included reaming depth, reamer placement, and version correction. The resulting reamed glenoid surface area available for implantation and bone volume removed were calculated for each permutation. RESULTS: Reamed surface area significantly increased with larger depths of reaming (P < .0001) and smaller version corrections (P < .0001). Bone volume removed and reaming depth had a strong quadratic relationship (r(2) = 0.999). With off-center reamer placement, volume removed when deviating in the posterior direction was significantly greater than when deviating in the anterior, superior, or inferior direction (P < .05). CONCLUSION: Performing smaller version corrections allows for greater attainable implant-bone surface contact because increasing reaming depth results in small increases in conforming surface area but large losses in glenoid bone stock. Bone volume removed was most sensitive to off-center position errors in the posterior direction. PMID- 22521386 TI - Acute surgical treatment of acromioclavicular dislocation type V with a hook plate: superiority to late reconstruction. AB - BACKGROUND: Outcomes for patients with acromioclavicular joint dislocation, Rockwood type V, treated with acute or delayed hook plate surgery were investigated. MATERIALS AND METHODS: Patients treated with a hook plate for acromioclavicular joint dislocation, Rockwood type V, were retrospectively evaluated 1 to 8 years after the injury. Of 41 patients, 37 were re-evaluated, 32 in person and 5 by telephone or letter. The acute surgery group comprised 22 patients operated on with a hook plate within 4 weeks after the injury. The delayed surgery group comprised 15 patients, with unacceptable pain or functional disability after a minimum of 4 months of conservative treatment, who were operated on with modified Weaver-Dunn procedure augmented with a hook plate. The evaluation was based on radiographs, registration of activity level, and shoulder function. RESULTS: The median Constant Score was 91 for the acute surgery group and 85 for the delayed surgery group (P = .097). The acutely treated patients had better outcomes according to the median Shoulder Pain and Disability Index (SPADI; P = .006), shortened version of the Disabilities of the Arm, Shoulder, and Hand (QuickDASH; P = .002), and Subjective Shoulder Value (P = .032). The acutely treated patients had less pain in their injured shoulder during rest (P = .014) and during movement (P = .005). There was a significant difference in subluxation between the groups in favor of the acute group, shown by weighted radiographs (P = .011), but no significant relation between subluxation on the weighted radiographs and the shoulder function according to Constant Score at follow-up (r(s) = .122, P = .619). CONCLUSIONS: Patients treated with acute surgery had a more satisfactory outcome than those with late surgery after failed conservative treatment. PMID- 22521387 TI - Early failures with single clavicular transosseous coracoclavicular ligament reconstruction. AB - INTRODUCTION: Coracoclavicular (CC) ligament reconstruction remains a challenging procedure. The ideal reconstruction is biomechanically strong, allows direct visualization of passage around the coracoid, and is minimally invasive. Few published reports have evaluated arthroscopic techniques with a single clavicular tunnel and transcoracoid reconstruction. One such report noted early excellent results, but without specific outcome measures. This study reports the clinical and radiographic results of a minimally invasive, arthroscopically assisted technique of CC ligament reconstruction using a transcoracoid and single clavicular tunnel technique. MATERIALS AND METHODS: A retrospective review was performed of 10 consecutive repairs in 9 active duty patients who underwent CC ligament reconstruction with the GraftRope (Arthrex, Naples FL, USA). All reconstructions were performed according to the manufacturer's technique by a single, fellowship-trained surgeon. Medical records and radiographs were evaluated for demographics, operative details, loss of reduction, and return to duty. RESULTS: In 8 of 10 repairs (80%) intraoperative reduction was lost at an average of 7.0 weeks (range, 3-12 weeks). Four patients (40%) required revision. Subjective patient outcomes included 5 excellent/good results, 1 fair result, and 4 poor results. Tunnel widening was universally noted, and the failure mode in most patients appeared to be at the holding suture. CONCLUSION: This transcoracoid, single clavicular tunnel technique was not a reliable approach to CC ligament reconstruction. We noted a high percentage of radiographic redisplacement and clinical failure. This technique, in its current form, cannot be recommended to treat AC joint injuries in our population. PMID- 22521388 TI - Teres minor muscle and related anatomy. AB - BACKGROUND: The purpose of this study was to describe the complex anatomy surrounding the teres minor muscle. METHODS: Thirty-one cadaveric human shoulders were dissected. Qualitative fascial and neurovascular anatomy were described. Location of motor nerves to teres minor were measured in reference to local anatomy. RESULTS: Fascial anatomy of the posterior shoulder had 2 distinct and equally common variants, 1 of which demonstrated a stout, inflexible fascial compartment enveloping the teres minor muscle. The other had a continuous fascia enveloping both the infraspinatus and teres minor muscles. In both variants, the primary nerve to teres minor traveled around a fascial sling, becoming sub fascial at an average of 44 mm (range, 25-68) medial to the teres minor's insertion. The nerve took its most angulated course as it entered the fascial sling. Smaller accessory innervation of teres minor began, on average, 30 mm (range, 15-48) medial to the muscle's lateral insertion. None of the accessory motor nerves coursed deep to the fascial sling nor to the distinct teres minor fascial compartment. CONCLUSION: A stout fascial sling may be the potential site of greatest compression and tethering of the primary motor nerve to teres minor. Additional lateral accessory motor nerves to teres minor remained extra-fascial and took a less angulated path. Half of the shoulders demonstrated a separate teres minor fascial compartment. An improved understanding of the fascial anatomy and innervation pattern of the teres minor muscle may help clinicians who treat patients with symptomatic isolated teres minor muscle atrophy. PMID- 22521389 TI - Anatomic considerations of transclavicular-transcoracoid drilling for coracoclavicular ligament reconstruction. AB - HYPOTHESIS: Acromioclavicular (AC) joint injuries vary in severity and damage to the AC and coracoclavicular (CC) ligaments. We hypothesized that transclavicular transcoracoid drilling techniques, which allow for arthroscopic passage and fixation of tendon grafts in bone sockets to replace the insufficient conoid and trapezoid ligaments, cannot restore the footprints of the conoid and trapezoid ligaments without significant risk of cortical breach and coracoid fracture. MATERIALS AND METHODS: Data from a prospective computed tomography shoulder registry were used to create 23 distinct shoulders. Three-dimensional models were constructed the shoulders in which virtual CC ligament reconstruction tunnels were superimposed using previously described anatomic distances and landmarks. RESULTS: Transclavicular-transcoracoid techniques resulted in mean remaining medial and lateral wall thicknesses before cortical breach of 7.3 +/- 1.7 and 7.0 +/- 1.6 mm, respectively. The distance from the entry point of this tunnel from the anatomic midpoint of the CC ligaments was 9.9 +/- 2.2 mm. Attempts to recapitulate the CC ligament anatomy by using anatomic distances and landmarks with transcoracoid, transclavicular techniques resulted in medial cortical breach of the coracoid in 91.3% of the shoulders. CONCLUSION: Transclavicular transcoracoid reconstructive techniques cannot restore the footprints of the conoid and trapezoid ligaments without significant risk of cortical breach and fracture. Attempts to correct this nonanatomic configuration by creating a tunnel based on the anatomic footprints results in a nearly universal medial cortical breach of the coracoid process. PMID- 22521390 TI - Arthroscopically assisted internal fixation of the symptomatic unstable os acromiale with absorbable screws. AB - BACKGROUND: Symptomatic meso- type os acromiale is a common pathology with inconsistent outcomes of treatment with various surgical techniques. We report the outcome of a new technique for arthroscopic fusion of symptomatic os acromiale with absorbable screws. MATERIALS AND METHODS: The study included 8 shoulders in 8 patients with symptomatic meso- type os acromiale who were treated with the use of a new technique for arthroscopic fusion with absorbable screws. The mean age was 54 years (range, 38-67 years), and the mean time from onset of symptoms to surgery was 18 months (range, 9-25 months). No patients reported a specific traumatic event before the onset of symptoms, and all noted the insidious onset of pain with no precipitating event. RESULTS: The average length of follow-up was 22 months (range, 12-36 month). The average Constant score improved from 49 points (range, 35-57 points) to 81 points (range, 75-86 points). The average satisfaction score improved from 4.5 of 10 (range, 2-6) to 8.5 of 10 (range 7-9). All patients made a good clinical recovery at 3 to 6 months after surgery. At the last follow-up, full radiographic union was observed in 6 patients, partial union in 1 patient, and persistent radiologic nonunion in 1 patient. Anterior bulging of the absorbable screws was noted in 2 patients, and the screws were trimmed 6 months after the first procedure. CONCLUSIONS: We have found that this new arthroscopic technique of fixation of os acromiale with absorbable screws provides promising clinical, cosmetic, and radiologic results with high patient satisfaction. PMID- 22521391 TI - The value of somatosensory evoked potential monitoring during scapulothoracic arthrodesis: case report and review of literature. PMID- 22521392 TI - Effect of radial head malunion on radiocapitellar stability. AB - BACKGROUND: Management for Mason type II radial head fractures is controversial. We hypothesized that angulation or depression of a marginal radial head fragment would affect radiocapitellar stability similarly to fragment excision. MATERIALS AND METHODS: A Mason type II radial head fracture was created in 6 cadaveric elbows by excising a segment from the anterolateral quadrant that was 30% of the diameter of the articular surface. Radiocapitellar stability was recorded under 5 sets of conditions: (1) intact radial head (intact), (2) 30% surface area fragment resected (partially excised), (3) anatomic fragment fixation with screws (fixed), (4) fragment fixation with 2 mm of depression relative to the articular surface (depressed), and (5) fragment fixation after a 30 degrees wedge resection (angulated). RESULTS: The forces required to subluxate the joint were greatly reduced after fragment excision (5 +/- 1 N; P = .0001) and restored to normal (21 +/- 1 N; P = .9) after anatomic fixation of the excised fragment. The peak forces were significantly reduced with fragment depression (4 +/- 1 N) and angulation (4 +/- 2 N; P = .0001). CONCLUSION: A radial head fracture that is depressed 2 mm or angulated 30 degrees may cause up to an 80% loss of concavity compression stability of the radiocapitellar joint. PMID- 22521393 TI - Perforation tolerance of glenoid implants to abnormal glenoid retroversion, anteversion, and medialization. AB - BACKGROUND: Loosening of the glenoid implant is a common complication of total shoulder arthroplasty. To prevent this, we need to ensure the glenoid vault is not perforated during insertion of the glenoid implant to allow for cement containment and maximum pressurization. Factors affecting perforation potential include glenoid implant design and alignment. This study looks at the perforation tolerance of 15 commercially available glenoid implants to increased retroversion, increased anteversion, and medialization. MATERIALS AND METHODS: Accurate 3-dimensional models of the 15 glenoid implants were created from exact dimensions obtained from the manufacturers and virtually implanted into 3 dimensional reconstructed models of 40 nonarthritic scapulae. Perforation tolerances of each implant to increased retroversion, increased anteversion, and medialization were determined through computer simulation to represent asymmetrical arthritic posterior wear, anterior wear, and eccentric corrective reaming, respectively. RESULTS: In all 15 glenoid implants, the overall mean increased retroversion tolerated before perforation was 19 degrees , increased anteversion was 16 degrees , and abnormal version fully corrected by eccentric reaming was 17 degrees . Each glenoid implant was evaluated individually to allow for direct comparison and, finally, size-matched and downsized glenoid implants in relation to the size of the humeral head. CONCLUSION: The results from this study help surgeons, when faced with a severely arthritic glenoid, to choose the appropriate glenoid implant to minimize perforation potential, and provide guidance on how much abnormal version and how much corrective reaming can be tolerated before perforation occurs and fixation is compromised. These results can also help with future implant designs. PMID- 22521394 TI - Tenocytes of chronic rotator cuff tendon tears can be stimulated by platelet released growth factors. AB - BACKGROUND: Bone-to-tendon healing after rotator cuff repairs is mainly impaired by poor tissue quality. The tenocytes of chronic rotator cuff tendon tears are not able to synthesize normal fibrocartilaginous extracellular matrix (ECM). We hypothesized that in the presence of platelet-released growth factors (PRGF), tenocytes from chronically retracted rotator cuff tendons proliferate and synthesize the appropriate ECM proteins. MATERIALS AND METHODS: Tenocytes from 8 patients with chronic rotator cuff tears were cultured for 4 weeks in 2 different media: standard medium (Iscove's Modified Dulbecco's Media + 10% fetal calf serum + 1% nonessential amino acids + 0.5 MUg/mL ascorbic acid) and media with an additional 10% PRGF. Cell proliferation was assessed at 7, 14, 21, and 28 days. Messenger (m)RNA levels of collagens I, II, and X, decorin, biglycan, and aggrecan were analyzed using real time reverse-transcription polymerase chain reaction. Immunocytochemistry was also performed. RESULTS: The proliferation rate of tenocytes was significantly higher at all time points when cultured with PRGF. At 21 days, the mRNA levels for collagens I, II, and X, decorin, aggrecan, and biglycan were significantly higher in the PRGF group. The mRNA data were confirmed at protein level by immunocytochemistry. CONCLUSIONS: PRGFs enhance tenocyte proliferation in vitro and promote synthesis of ECM to levels similar to those found with insertion of the normal human rotator cuffs. CLINICAL RELEVANCE: Biologic augmentation of repaired rotator cuffs with PRGF may enhance the properties of the repair tissue. However, further studies are needed to determine if application of PRGF remains safe and effective in long-term clinical studies. LEVEL OF EVIDENCE: Basic Science Study, Cell Biology. PMID- 22521395 TI - Three-dimensional analysis of acute plastic bowing deformity of ulna in radial head dislocation or radial shaft fracture using a computerized simulation system. AB - BACKGROUND: Little 3-dimensional biomechanical investigation of plastic bowing deformity of the ulna has been reported, and the purpose of this study was to conduct such an investigation to elucidate mechanisms of injury and appropriate treatments. METHODS: Ten cases of traumatic plastic deformity of the ulna in pediatric patients, 4 with chronic radial head dislocations (Monteggia equivalent) and 6 with malunited radial shaft fractures, were analyzed for rotational deformities in the axial plane and bending deformities in the sagittal and coronal planes in Euler angle space by use of a 3-dimensional computerized simulation system with a markerless registration technique. RESULTS: Deformed ulnae with radial head dislocations had 18.7 degrees +/- 17.4 degrees of external rotation in the axial plane and 10.4 degrees +/- 7.0 degrees of extension in the sagittal plane whereas those with malunited radial shaft fractures had 12.5 degrees +/- 12.7 degrees of internal rotation and 6.3 degrees +/- 5.6 degrees of flexion displacement compared with mirror images of the opposite ulnae. Absolute values of rotational deformities in both groups were larger than those of sagittal and coronal bending deformities. DISCUSSION: Most major traumatic plastic bowing deformities of the ulna involved rotation rather than bending. External rotational stress on the ulna is suspected to cause radial head dislocation, and internal rotational stress results in radial shaft fracture during falls onto outstretched arms. Therefore the correction of rotational deformities of the ulna should be considered in the treatment of chronic radial head dislocations and malunited radial shaft fractures. PMID- 22521396 TI - Association between the dopamine D2 receptor (DRD2) polymorphism and the personality traits of healthy Japanese participants. AB - BACKGROUND: Dopamine neurotransmitter systems have been associated with reward related and novelty-seeking personality traits. We investigated the possible relationship between the personality traits measured by the Temperament and Character Inventory (TCI) and the TaqI A and -141C Ins/Del polymorphisms in the dopamine D2 receptor gene (DRD2). METHODS: The sample consisted of 1084 healthy Japanese medical students and medical staff (age=29.0+/-9.7 years), each of whom completed the TCI. Their genomic DNA was isolated from whole blood and genotyped using the TaqMan allele-specific assay method. The associations between gene polymorphisms and the scores for TCI were statistically analyzed by one-way analysis of covariance (ANCOVA) adjusting age. Males and females were analyzed separately. Epstatis was assesses using two-way ANCOVA between the DRD2 and ANKK1 genes. RESULTS: Men with the Ins/Del genotype of the -141C Ins/Del polymorphism had significantly higher self-directedness scores than those with the Ins/Ins genotype (p=0.021). None of the TCI scores differed among women with regard to the three genotype groups of the -141C Ins/Del polymorphism. The DRD2/ANKK1 Taq1 A polymorphism did not affect any TCI factor for either men or women. An epistatic analysis did not reveal main effects of the two genes with regard to TCI scores, but an ANKK1*DRD2 interaction significantly predicted TCI scores. CONCLUSION: These findings suggest the possibility that the -141C Ins/Del polymorphism and the DRD2/ANKK1 Taq1 A polymorphism are not strongly linked to personality traits directly, but influences them under the interaction between the DRD2 and ANKK1 genes. PMID- 22521397 TI - Effect on blood loss and cost-effectiveness of pain cocktails, platelet-rich plasma, or fibrin sealant after total knee arthroplasty. AB - This study evaluated the effect of periarticular pain cocktail, platelet-rich plasma, or fibrin sealant injections on blood loss, transfusion rate, and hospital costs after total knee arthroplasty. A retrospective review of 400 patients undergoing primary total knee arthroplasty with one of the different periarticular treatments as stated above was performed. Postoperative blood loss, hemoglobin levels, allogenic blood transfusion rates, and per-case hospital injection cost were reported. Although platelet-rich plasma and fibrin sealant decreased blood loss compared with the control group (P < .001), there was no significant difference in blood loss in the pain-cocktail group or in postoperative hemoglobin levels or transfusion rates between all groups. Significant efficacy and cost-effectiveness for these modalities could not be identified and have, therefore, been discontinued at our practice. LEVEL OF EVIDENCE: level III. PMID- 22521398 TI - Anatomical hip range of motion after implantation during total hip arthroplasty with a large change in pelvic inclination. AB - The supine functional pelvic plane is the recommended reference pelvic plane for acetabular cup planning in navigation-assisted total hip arthroplasty. However, it is unclear whether it can be used in patients with a large preoperative positional change in pelvic inclination (PC) from the supine to the standing position because it is unknown whether these patients have a different hip range of motion (ROM). We measured the anatomical hip ROM after implantation by computed tomography-based navigation in 91 patients and found it to be similar between those with a small PC (<10 degrees ) and those with a large PC (>=10 degrees ). There was no significant correlation between ROM and preoperative PC. The supine functional pelvic plane is adequate for cup planning whether the PC is small or large. PMID- 22521399 TI - Periprosthetic femoral fracture due to biodegradable cement restrictor. AB - Biodegradable materials are gaining popularity in orthopedics. Despite finding use in different areas of orthopedic surgery, they do not come without disadvantages such as foreign body reactions, granulomatous reactions, and sterile sinus formation in bone. We report a case of a patient who sustained a periprosthetic fracture seen at the tip of a cemented femoral stem approximately 5 years postsurgery, secondary to the use of a biodegradable cement restrictor. There was no evidence of trauma or fall on the affected hip. To our knowledge, there has been no previous report describing periprosthetic fracture at the tip of cemented femoral stem secondary to the use of a biodegradable cement restrictor. We suggest abandoning use of these materials while performing cemented hip arthroplasties. PMID- 22521400 TI - The use of the posterior lesser trochanter line to estimate femoral neck version: an analysis of computed tomography measurements. AB - We hypothesized that the lesser trochanter could be a useful guide for estimating femoral component version during total hip arthroplasty. We conducted a study of 88 patients to evaluate the relationship between the posterior lesser trochanter line (PLTL) and the femoral neck axis (FNA) using computed tomographic scans. The mean angle between the PLTL and the FNA was 17.4 degrees +/- 7.1 degrees (range, -1.6 degrees to 36.5 degrees ). The PLTL angle correlated (r(2) = 0.67 0.72) with the FNA angle. Intraclass correlation coefficient values showed a high level of intraobserver and interobserver agreement in the angles between the PLTL and the FNA. We found a constant relationship between the lesser trochanter and the FNA, and femoral neck version can be estimated, using the PLTL, with reasonable reliability. PMID- 22521401 TI - Matrilin-3 switches from anti- to pro-anabolic upon integration to the extracellular matrix. AB - The extracellular matrix (ECM) has long been viewed primarily as an organized network of solid-phase ligands for integrin receptors. During degenerative processes, such as osteoarthritis, the ECM undergoes deterioration, resulting in its remodeling and in the release of some of its components. Matrilin-3 (MATN3) is an almost cartilage specific, pericellular protein acting in the assembly of the ECM of chondrocytes. In the past, MATN3 was found required for cartilage homeostasis, but also involved in osteoarthritis-related pro-catabolic functions. Here, to better understand the pathological and physiological functions of MATN3, its concentration as a circulating protein in articular fluids of human osteoarthritic patients was determined and its functions as a recombinant protein produced in human cells were investigated with particular emphasis on the physical state under which it is presented to chondrocytes. MATN3 down-regulated cartilage extracellular matrix (ECM) synthesis and up-regulated catabolism when administered as a soluble protein. When artificially immobilized, however, MATN3 induced chondrocyte adhesion via a alpha5beta1 integrin-dependent mechanism, AKT activation and favored survival and ECM synthesis. Furthermore, MATN3 bound directly to isolated alpha5beta1 integrin in vitro. TGFbeta1 stimulation of chondrocytes allowed integration of exogenous MATN3 into their ECM and ECM integrated MATN3 induced AKT phosphorylation and improved ECM synthesis and accumulation. In conclusion, the integration of MATN3 to the pericellular matrix of chondrocytes critically determines the direction toward which MATN3 regulates cartilage metabolism. These data explain how MATN3 plays either beneficial or detrimental functions in cartilage and highlight the important role played by the physical state of ECM molecules. PMID- 22521402 TI - Activation of inactivation process initiates rapid eye movement sleep. AB - Interactions among REM-ON and REM-OFF neurons form the basic scaffold for rapid eye movement sleep (REMS) regulation; however, precise mechanism of their activation and cessation, respectively, was unclear. Locus coeruleus (LC) noradrenalin (NA)-ergic neurons are REM-OFF type and receive GABA-ergic inputs among others. GABA acts postsynaptically on the NA-ergic REM-OFF neurons in the LC and presynaptically on the latter's projection terminals and modulates NA release on the REM-ON neurons. Normally during wakefulness and non-REMS continuous release of NA from the REM-OFF neurons, which however, is reduced during the latter phase, inhibits the REM-ON neurons and prevents REMS. At this stage GABA from substantia nigra pars reticulate acting presynaptically on NA ergic terminals on REM-ON neurons withdraws NA-release causing the REM-ON neurons to escape inhibition and being active, may be even momentarily. A working-model showing neurochemical-map explaining activation of inactivation process, showing contribution of GABA-ergic presynaptic inhibition in withdrawing NA-release and dis-inhibition induced activation of REM-ON neurons, which in turn activates other GABA-ergic neurons and shutting-off REM-OFF neurons for the initiation of REMS-generation has been explained. Our model satisfactorily explains yet unexplained puzzles (i) why normally REMS does not appear during waking, rather, appears following non-REMS; (ii) why cessation of LC-NA-ergic-REM-OFF neurons is essential for REMS-generation; (iii) factor(s) which does not allow cessation of REM-OFF neurons causes REMS-loss; (iv) the association of changes in levels of GABA and NA in the brain during REMS and its deprivation and associated symptoms; v) why often dreams are associated with REMS. PMID- 22521403 TI - Disinhibition is easier learned than inhibition. The effects of (dis)inhibition training on food intake. AB - Impulsivity seems to be a strong candidate when it comes to psychological factors leading to overeating and eventually to obesity (Guerrieri, Nederkoorn, & Jansen, 2008). The question is whether reversing the logic and strengthening an individual's inhibitory skills will be equally potent against overeating. In the current study the stop signal task was adjusted so that one group of female students (n=21) gradually got more trials in which they could practise inhibition (inhibition), whereas another group (n=20) gradually got more trials in which they had to react quickly, without having time to think or inhibit (impulsivity). A third group (n=20) did a neutral reading task (control). The participants in the impulsivity group had a significantly higher caloric intake during a subsequent taste test, whereas the inhibition group did not differ from the control group. Hence, the data support that impulsivity is a direct cause of overeating. However, the concept of inhibition training needs to be investigated further. Issues like the specificity of inhibition training (general vs. food specific) need to be addressed and used to optimise the training so that its effectiveness can be tested within clinical settings. PMID- 22521404 TI - Acute kidney injury after cardiac surgery: does the time interval from contrast administration to surgery matter? AB - OBJECTIVE: The authors sought to evaluate the association between the time interval from contrast administration to cardiac surgery and postoperative acute kidney injury (AKI). DESIGN: A retrospective observational study over a 1-year period. SETTING: A US academic medical institution. PARTICIPANTS: Six hundred forty-four adult patients undergoing nonemergent cardiac surgery. INTERVENTIONS: No interventions were performed as part of the study. MEASUREMENTS AND MAIN RESULTS: AKI was defined as an increase in serum creatinine by >=0.3 mg/dL or >=50% above baseline within the first 2 postoperative days or the commencement of renal replacement therapy within the same period. Using a contrast-to-surgery time interval >7 days as the baseline, multivariable logistic regression analysis determined the association between a contrast-to-surgery time interval <=1 day or 2 to 7 days and postoperative AKI adjusting for potential confounding variables. The incidence of AKI within the study cohort was 21.9%. After adjusting for other covariates, there was no association between the contrast-to-surgery time and AKI (odds ratio [OR] <=1 day = 0.93; 95% confidence interval [CI], 0.52-1.66; p = 0.81; OR = 2-7 days = 1.28; 95% CI, 0.78-2.11; p = 0.34). CONCLUSIONS: In an appropriately selected population, cardiac surgery can be performed within 1 day of cardiovascular catheterization and contrast administration without an increase in the incidence of postoperative AKI. Recommendations to delay cardiac surgery for a specified period after contrast administration to reduce the risk of postoperative AKI are premature. Additional evidence is required before making recommendations on optimal surgical timing after contrast exposure. PMID- 22521405 TI - Unusual mobile structure in the left ventricular outflow tract leading to re exploration after elective aortic valve replacement. PMID- 22521406 TI - Health promotion: healing through loss. AB - For many women, miscarriage constitutes an often sudden, unexpected physically as well as psychologically traumatic event. A large percentage of women having miscarriage must present to an outpatient setting, primarily the emergency department, for care during this time. Studies indicate that health care professionals are failing to meet the needs of women and their families during and after miscarriage and that greater emphasis should be placed on psychosocial and interpersonal skills. The problem has been identified as how to assist or prepare emergency nurses to better care for the physical and psychological needs of women having early, unanticipated loss of pregnancy. At 1 rural Midwest medical center, it was the women's health staff who took the initiative to address this problem. They recognized the need for a holistic approach to care for women experiencing pregnancy loss. This would be accomplished through bridging the gap between outpatient services and primary care. This resulted in creating a support group called Ended Beginnings, which was organized to help women convalesce through the physical, emotional, and spiritual hardships associated with pregnancy and infant loss. Positive feedback has been received from both patients and staff with regard to the extent to which collaborative services provide a positive impact for both the patient and staff assisting the patient during a time of sudden, unanticipated loss. PMID- 22521407 TI - Mass transfusion to combat trauma's lethal triad. PMID- 22521408 TI - Training nurses in a self-learning station for resuscitation: factors contributing to success or failure. PMID- 22521409 TI - Introduction to Quo Vadis behavioral neuroscience: a Festschrift for Philip Teitelbaum. PMID- 22521410 TI - Mechanisms of attention to conditioned stimuli predictive of a cigarette outcome. AB - Attention to stimuli associated with a rewarding outcome may be mediated by the incentive motivational properties that the stimulus acquires during conditioning. Other theories of attention state that the prediction error (the discrepancy between the expected and the actual outcome) during conditioning guides attention; once the outcome is fully predicted, attention should be abolished for the conditioned stimulus. The current study examined which of these mechanisms is dominant in conditioning when the outcome is highly rewarding. Allocation of attention to stimuli associated with cigarettes (the rewarding outcome) was tested in 16 smokers, who underwent a classical conditioning paradigm, where abstract visual stimuli were paired with a tobacco outcome. Stimuli were associated with 100% (stimulus A), 50% (stimulus B), or 0% (stimulus C) probability of receiving tobacco. Attention was measured using an eye-tracker device, and the appetitive value of the stimuli was measured with subjective pleasantness ratings during the conditioning process. Dwell time bias (duration of eye gaze) was greatest overall for the A stimulus, and increased over conditioning. Attention to stimulus A was dependent on the ratings of pleasantness that the stimulus evoked, and on the desire to smoke. These findings appear to support the theory that attention for conditioned stimuli is dominated by the incentive motivational qualities of the outcome they predict, and implicate a role for attention in the maintenance of addictive behaviours like smoking. PMID- 22521411 TI - Modelling the effects of calcium waves and oscillations on saliva secretion. AB - An understanding of Ca(2+) signalling in saliva-secreting acinar cells is important, as Ca(2+) is the second messenger linking stimulation of cells to production of saliva. Ca(2+) signals affect secretion via the ion channels located both apically and basolaterally in the cell. By approximating Ca(2+) waves with periodic functions on the apical and basolateral membranes, we isolate individual wave properties and investigate them for their effect on fluid secretion in a mathematical model of the acinar cell. Mean Ca(2+) concentration is found to be the most significant property in signalling secretion. Wave speed was found to encode a range of secretion rates. Ca(2+) oscillation frequency and amplitude had little effect on fluid secretion. PMID- 22521412 TI - Memory modulation in the classroom: selective enhancement of college examination performance by arousal induced after lecture. AB - Laboratory studies examining moderate physiological or emotional arousal induced after learning indicate that it enhances memory consolidation. Yet, no studies have yet examined this effect in an applied context. As such, arousal was induced after a college lecture and its selective effects were examined on later exam performance. Participants were divided into two groups who either watched a neutral video clip (n=66) or an arousing video clip (n=70) after lecture in a psychology course. The final examination occurred two weeks after the experimental manipulation. Only performance on the group of final exam items that covered material from the manipulated lecture were significantly different between groups. Other metrics, such as the midterm examination and the total final examination score, did not differ between groups. The results indicate that post-lecture arousal selectively increased the later retrieval of lecture material, despite the availability of the material for study before and after the manipulation. The results reinforce the role of post-learning arousal on memory consolidation processes, expanding the literature to include a real-world learning context. PMID- 22521413 TI - Cell population based mass spectrometry using platinum nanodots for algal and fungal studies. AB - For the first time, we applied cell-population based mass spectrometry (CP-MS) for biosensing intact eukaryotic cells of Chlamydomonas reinhardtii and Saccharomyces cerevisiae. Cell counts ranging from 1 * 10(7) to 1.28 * 10(2) were analyzed using MALDI-MS to obtain the threshold detection sensitivity. Platinum nanodots (Pt NDs) were used to enhance the detection sensitivity of CP-MS. Pt NDs were able to improve the detection sensitivity of CP-MS from 3200 cells/mL to 640 cells/mL (5-fold) for Chlamydomonas. For yeast cells, the detection sensitivity was also increased from 400,000 cells/mL to 3200 cells/mL (125-fold) when Pt NDs were used. Using the Clin Pro tool, the obtained results from MALDI-MS data were validated. Statistical analysis of the mass data was performed using MYSTAT software. PMID- 22521414 TI - Electrogenerated chemiluminescence biosensor incorporating ruthenium complex labelled Concanavalin A as a probe for the detection of Escherichia coli. AB - A novel electrogenerated chemiluminescence (ECL) biosensor for highly sensitive detection of Escherichia coli (E. coli) was first developed by employing Concanavalin A (Con A) as a biological recognition element and bis(2,2' bipyridine)-4'-methyl-4-carboxybipyridine ruthenium (II) (Ru1) complex as the detector. The ECL biosensor was fabricated by adsorbing carboxyl-functionalised single-wall carbon nanotubes (SWNTs) onto a paraffin-impregnated graphite electrode and further covalently coupling the Ru1-Con A probe onto the surface of the SWNT-modified electrode. Upon the binding of E. coli O157:H7 (as a model target), the biosensor showed a decreased ECL intensity in the presence of tri-n propylamine (TPrA), which was in logarithmically direct proportion to the concentration of E. coli over a range from 5.0 * 10(2) to 5.0 * 10(5)cells/mL. The detection limit of this sensor was 127 cells/mL. Additionally, the ECL biosensor also showed satisfactory selectivity in discriminating gram-negative E. coli from gram-positive bacteria. The strategy developed in this study may be a promising approach and could be extended to the design of ECL biosensors for highly sensitive and rapid detection of other desired bacteria. PMID- 22521415 TI - Discovery of boceprevir, a direct-acting NS3/4A protease inhibitor for treatment of chronic hepatitis C infections. AB - Hepatitis C virus (HCV) infection is the primary cause of liver cirrhosis and hepatocellular carcinoma. HCV is the leading cause of liver transplantation in the USA, and more than 200 million people worldwide are infected with HCV. Before the introduction of NS3 protease inhibitors, the standard of care was treatment with peg-interferon and ribavirin. Recent developments in virology have identified many novel targets in the HCV genome, allowing the development of direct-acting antivirals. In this article, I outline the discovery and development of boceprevir, the first HCV NS3/4A protease inhibitor approved for treatment of genotype 1 HCV infection. Boceprevir greatly improves the sustained virologic response (SVR) and provides new hope for treating genotype 1 infections. PMID- 22521416 TI - A truncating mutation of CEP135 causes primary microcephaly and disturbed centrosomal function. AB - Autosomal-recessive primary microcephaly (MCPH) is a rare congenital disorder characterized by intellectual disability, reduced brain and head size, but usually without defects in cerebral cortical architecture, and other syndromic abnormalities. MCPH is heterogeneous. The underlying genes of the seven known loci code for centrosomal proteins. We studied a family from northern Pakistan with two microcephalic children using homozygosity mapping and found suggestive linkage for regions on chromosomes 2, 4, and 9. We sequenced two positional candidate genes and identified a homozygous frameshift mutation in the gene encoding the 135 kDa centrosomal protein (CEP135), located in the linkage interval on chromosome 4, in both affected children. Post hoc whole-exome sequencing corroborated this mutation's identification as the causal variant. Fibroblasts obtained from one of the patients showed multiple and fragmented centrosomes, disorganized microtubules, and reduced growth rate. Similar effects were reported after knockdown of CEP135 through RNA interference; we could provoke them also by ectopic overexpression of the mutant protein. Our findings suggest an additional locus for MCPH at HSA 4q12 (MCPH8), further strengthen the role of centrosomes in the development of MCPH, and place CEP135 among the essential components of this important organelle in particular for a normal neurogenesis. PMID- 22521417 TI - Meconium ileus caused by mutations in GUCY2C, encoding the CFTR-activating guanylate cyclase 2C. AB - Meconium ileus, intestinal obstruction in the newborn, is caused in most cases by CFTR mutations modulated by yet-unidentified modifier genes. We now show that in two unrelated consanguineous Bedouin kindreds, an autosomal-recessive phenotype of meconium ileus that is not associated with cystic fibrosis (CF) is caused by different homozygous mutations in GUCY2C, leading to a dramatic reduction or fully abrogating the enzymatic activity of the encoded guanlyl cyclase 2C. GUCY2C is a transmembrane receptor whose extracellular domain is activated by either the endogenous ligands, guanylin and related peptide uroguanylin, or by an external ligand, Escherichia coli (E. coli) heat-stable enterotoxin STa. GUCY2C is expressed in the human intestine, and the encoded protein activates the CFTR protein through local generation of cGMP. Thus, GUCY2C is a likely candidate modifier of the meconium ileus phenotype in CF. Because GUCY2C heterozygous and homozygous mutant mice are resistant to E. coli STa enterotoxin-induced diarrhea, it is plausible that GUCY2C mutations in the desert-dwelling Bedouin kindred are of selective advantage. PMID- 22521420 TI - The expression of dopa decarboxylase and dopamine beta hydroxylase and their responding to bacterial challenge during the ontogenesis of scallop Chlamys farreri. AB - Dopa decarboxylase (DDC) and dopamine beta hydroxylase (DBH) is responsible for the synthesis of dopamine and norepinephrine, respectively. In the present study, dopa decarboxylase (CfDDC) and dopamine beta hydroxylase (CfDBH) were selected as indicator to investigate the development of catecholaminergic nervous system in the larvae of scallop Chlamys farreri. The CfDDC and CfDBH transcripts were all detectable during the whole ontogenesis expect for the CfDDC transcripts in 2 cell embryos stage. The expression level of CfDDC and CfDBH mRNA increased significantly in the veliger stage, and reached the peak in late (35.64-fold, P < 0.05) and mid-veliger (400.21-fold, P < 0.05) larvae, respectively. By immunofluorescence, two CfDDC immunoreactive areas were observed in the trochophore and D-hinged larvae, and then three CfDDC immunoreactive areas and two immunopositive fibres formed in early and late veliger larvae, respectively. Two CfDBH immunopositive fibers appeared initially in the early D-hinged stage, and another two similar fibers developed in the late D-hinged stage. The bacteria Vibrio anguillarum challenge could induce the mRNA expression of CfDDC and CfDBH in different developmental stage. The significantly increase of CfDDC mRNA was observed in the trochophore larvae at 12 h (8.61-fold, P < 0.05) and in late D hinged larvae at 24 h (1.56-fold, P < 0.05) post challenge. The expression level of CfDBH mRNA decreased significantly in late D-hinged larvae at 6 h (0.45-fold, P < 0.05), whereas it increased significantly in late veliger larvae at 12 h after bacterial challenge (14.52-fold, P < 0.05). These results concluded that the scallop catecholaminergic nervous system appeared firstly as the form of dopaminergic neurons in the trochophore larvae, and the developing catecholaminergic nervous system in the trochophore, D-hinged and veliger larvae of scallop could respond to the immune stimulation in different patterns. PMID- 22521421 TI - Effect of berberine hydrochloride on grass carp Ctenopharyngodon idella serum bactericidal activity against Edwardsiella ictaluri. AB - Bactericidal activity of grass carp (Ctenopharyngodon idella) serum was significantly enhanced when pre-treated with 15 mg l-1 or 3 mg l-1 of berberine hydrochloride, an effective component of several commonly used herbal medicines in aquaculture. The complement consumption experiment demonstrated that berberine hydrochloride can certainly activate fish complement system. The results of both experiments suggested that berberine hydrochloride could enhance the serum bactericidal activity in grass carp by activating the complement system and indicating the potential in the prevention or treatment of fish diseases. PMID- 22521418 TI - PSORS2 is due to mutations in CARD14. AB - Psoriasis is a common, immune-mediated genetic disorder of the skin and is associated with arthritis in approximately 30% of cases. Previously, we localized PSORS2 (psoriasis susceptibility locus 2) to chromosomal region 17q25.3-qter after a genome-wide linkage scan in a family of European ancestry with multiple cases of psoriasis and psoriatic arthritis. Linkage to PSORS2 was also observed in a Taiwanese family with multiple psoriasis-affected members. In caspase recruitment domain family, member 14 (CARD14), we identified unique gain-of function mutations that segregated with psoriasis by using genomic capture and DNA sequencing. The mutations c.349G>A (p.Gly117Ser) (in the family of European descent) and c.349+5G>A (in the Taiwanese family) altered splicing between CARD14 exons 3 and 4. A de novo CARD14 mutation, c.413A>C (p.Glu138Ala), was detected in a child with sporadic, early-onset, generalized pustular psoriasis. CARD14 activates nuclear factor kappa B (NF-kB), and compared with wild-type CARD14, the p.Gly117Ser and p.Glu138Ala substitutions were shown to lead to enhanced NF-kB activation and upregulation of a subset of psoriasis-associated genes in keratinocytes. These genes included chemokine (C-C motif) ligand 20 (CCL20) and interleukin 8 (IL8). CARD14 is localized mainly in the basal and suprabasal layers of healthy skin epidermis, whereas in lesional psoriatic skin, it is reduced in the basal layer and more diffusely upregulated in the suprabasal layers of the epidermis. We propose that, after a triggering event that can include epidermal injury, rare gain-of-function mutations in CARD14 initiate a process that includes inflammatory cell recruitment by keratinocytes. This perpetuates a vicious cycle of epidermal inflammation and regeneration, a cycle which is the hallmark of psoriasis. PMID- 22521419 TI - Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis. AB - Psoriasis is a common inflammatory disorder of the skin and other organs. We have determined that mutations in CARD14, encoding a nuclear factor of kappa light chain enhancer in B cells (NF-kB) activator within skin epidermis, account for PSORS2. Here, we describe fifteen additional rare missense variants in CARD14, their distribution in seven psoriasis cohorts (>6,000 cases and >4,000 controls), and their effects on NF-kB activation and the transcriptome of keratinocytes. There were more CARD14 rare variants in cases than in controls (burden test p value = 0.0015). Some variants were only seen in a single case, and these included putative pathogenic mutations (c.424G>A [p.Glu142Lys] and c.425A>G [p.Glu142Gly]) and the generalized-pustular-psoriasis mutation, c.413A>C (p.Glu138Ala); these three mutations lie within the coiled-coil domain of CARD14. The c.349G>A (p.Gly117Ser) familial-psoriasis mutation was present at a frequency of 0.0005 in cases of European ancestry. CARD14 variants led to a range of NF-kB activities; in particular, putative pathogenic variants led to levels >2.5* higher than did wild-type CARD14. Two variants (c.511C>A [p.His171Asn] and c.536G>A [p.Arg179His]) required stimulation with tumor necrosis factor alpha (TNF-alpha) to achieve significant increases in NF-kB levels. Transcriptome profiling of wild-type and variant CARD14 transfectants in keratinocytes differentiated probably pathogenic mutations from neutral variants such as polymorphisms. Over 20 CARD14 polymorphisms were also genotyped, and meta analysis revealed an association between psoriasis and rs11652075 (c.2458C>T [p.Arg820Trp]; p value = 2.1 * 10(-6)). In the two largest psoriasis cohorts, evidence for association increased when rs11652075 was conditioned on HLA-Cw*0602 (PSORS1). These studies contribute to our understanding of the genetic basis of psoriasis and illustrate the challenges faced in identifying pathogenic variants in common disease. PMID- 22521422 TI - Molecular identification and expression analysis of two distinct BPI/LBPs (bactericidal permeability-increasing protein/LPS-binding protein) from rock bream, Oplegnathus fasciatus. AB - We identified two cDNAs designated as RbBPI/LBP-1 and RbBPI/LBP2, respectively, which were identified by expressed sequence tag (EST) analysis of a lipopolysaccharide (LPS)-stimulated rock bream liver cDNA library. The two cDNA displayed 36.9% identity at the translated amino acid level. Despite the low level of identity between the two genes, high conservation was seen in the BPI/LBP/CETP N-terminal, LPS-binding, the proline-rich central and the BPI/LBP/CETP C-terminal domains. The full-length RbBPI/LBP-1 cDNA (1945 bp) contained an open reading frame (ORF) of 1431 bp encoding 476 amino acids. The full-length RbBPI/LBP-2 cDNA was 2652 bp in length and contained an ORF of 1422 bp encoding 473 amino acids. RbBPI/LBP-1 was significantly expressed in the spleen, liver, intestine and gill. On the other hand, RbBPI/LBP-2 showed significant expression in the kidney, peripheral blood leukocytes, and spleen. Real-time RT-PCR was used to examine RbBPI/LBP-1 and RbBPI/LBP-2 mRNA expression in kidney under conditions of bacterial and viral challenge. Experimental infection of rock bream with Streptococcus iniae, Edwardsiella tarda, and red sea bream iridovirus resulted in significant increases in RbBPI/LBP-1 and RbBPI/LBP-2 mRNA levels in the kidneys, however, the increases in transcription was seen at different time points. PMID- 22521423 TI - Mass spectrometric identification and characterization of new fluoxymesterone metabolites in human urine by liquid chromatography time-of-flight tandem mass spectrometry. AB - In this study fluoxymesterone urinary profiles were investigated by liquid chromatography quadrupole time-of-flight tandem mass spectrometry (LC-QTOFMS) with accurate mass measurement. Twelve metabolites including the parent drug were detected in two fluoxymesterone positive control urine samples. Three parameters were employed for evaluation of the accuracy of the chemical formulae in positive full scan experiment, which contained error between actual and calculated mass weights of prontonated and isotopic molecules together with abundance match between prontonated and isotopic molecules. The 13 analytes were determined with mass accuracy less than 1.1 ppm and isotopic abundance match more than 94 marks. Based on the ionization, CID fragmentation, the accurate mass of the product ion and comparison of the accurate mass weight and retention time with reference standard, fluoxymesterone and its 12 metabolites containing three unreported ones were detected. The chemical structures of three unreported metabolites were identified as: 9-fluro-17beta-ol-17-methyl-11-en-5alpha-androstan-3-one (F13), 9 fluro-17beta-ol-17-methyl-11-en-5beta-androstan-3-one (F8) and 9-fluro-17beta-ol 17-methyl-5-androstan-3,6,11-trione, and meanwhile a dihydroxylated metabolite (F12), 6,16-dihydroxylated fluoxymesterone, was also detected in human urine, which was previously reported to be available only in equine urine. PMID- 22521424 TI - Synthesis of ferrocene-labeled steroids via copper-catalyzed azide-alkyne cycloaddition. Reactivity difference between 2beta-, 6beta- and 16beta-azido androstanes. AB - Copper-catalyzed cycloaddition of steroidal azides and ferrocenyl-alkynes were found to be an efficient methodology for the synthesis of ferrocene-labeled steroids. At the same time, a great difference between the reactivity of 2beta- or 16beta-azido-androstanes and a sterically hindered 6beta-azido steroid toward both ferrocenyl-alkynes and simple alkynes, such as phenylacetylene, 1-octyne, propargyl acetate and methyl propiolate, was observed. PMID- 22521425 TI - An integrative test of agility, speed and skill in soccer: effects of exercise. AB - OBJECTIVES: The aim of this study was to evaluate the effect of 45 min of soccer specific exercise in the reactive motor skills test (RMST); a novel test which measures sprint, passing and reactive agility (RAT) performance. DESIGN: A repeated-measures design was used to collect performance data. METHODS: Forty-two high-level amateur male soccer players (age 18.5+/-3.5 years) were recruited. Participants were familiarised with the RMST prior to initial testing. Participants undertook 10 repetitions of the RMST before and after 45 min of soccer-specific exercise using the Loughborough Intermittent Shuttle Test. Eighteen of these participants repeated the RMST for test re-test reliability determination. Paired t-tests and effect size statistics were used to determine the effect of 45 min of intermittent exercise on RMST performance. Reliability was assessed using the standard error of measurement. RESULTS: The exercise protocol resulted in moderate decreases of sprint (3.0+/-0.9%, mean+/-SD; 1.030+/ 0.09 ES+/-90% Confidence Intervals; p<0.00001) and RAT performance (1.5+/-1.1%; 1.015+/-0.011; p<0.05), but improved passing task time (-2.7+/-1.2%; 0.973+/ 0.012; p<0.001) and passing accuracy (3.6+/-3.3%; 1.036+/-0.33). Change in total test time was trivial. The test-retest coefficient of variation for the test was 2.4+/-0.8%. CONCLUSIONS: Soccer-specific exercise decreased sprint and reactive agility performance but improved technical skill performance on a novel, integrative and reliable test of soccer skill performance. Overall RMST performance time was largely unchanged. PMID- 22521426 TI - Differential effects of swimming training on neuronal calcium sensor-1 expression in rat hippocampus/cortex and in object recognition memory tasks. AB - Physical activity has been proposed as a behavioral intervention that improves learning and memory; nevertheless, the mechanisms underlying these health benefits are still not well understood. Neuronal Calcium Sensor-1 (NCS-1) is a member of a superfamily of proteins that respond to local Ca(2+) changes shown to have an important role in learning and memory. The aim of the present study was to investigate the effects of swimming training on NCS-1 levels in the rat brain after accessing cognitive performance. Wistar rats were randomly assigned to sedentary (SG) or exercised groups (EG). The EG was subject to forced swimming activity, 30 min/day, 5 days/week, during 8 weeks. Progressive load trials were performed in the first and last week in order to access the efficiency of the training. After the 8 week training protocol, memory performance was evaluated by the novel object preference and object location tasks. NCS-1 levels were measured in the cortex and hippocampus using immunoblotting. The EG performed statistically better for the spatial short-term memory (0.73 +/- 0.01) when compared to the SG (0.63 +/- 0.02; P<0.05). No statistically significant exercise effect was observed in the novel object preference task (SG 0.65 +/- 0.02 and EG 0.68 +/- 0.02; p>0.05). In addition, chronic exercise promoted a significant increase in hippocampal NCS-1 levels (1.8 +/- 0.1) when compared to SG (1.17 +/- 0.08; P<0,05), but had no effect on cortical NCS-1 levels (SG 1.6 +/- 0.1 and EG 1.5 +/- 0.1; p>0.05). Results suggest that physical exercise would modulate the state of the neural network regarding its potential for plastic changes: physical exercise could be modulating NCS-1 in an activity dependent manner, for specific neural substrates, thus enhancing the cellular/neuronal capability for plastic changes in these areas; which, in turn, would differentially effect ORM task performance for object recognition and displacement. PMID- 22521428 TI - Circadian regulation of cellular homeostasis--implications for cell metabolism and clinical diseases. AB - The major pathways involving nutrient and energy metabolism including cellular homeostasis are profoundly impacted by the circadian clock, which orchestrates diurnal rhythms in physiology and behavior. While the links between circadian and metabolic rhythms are unclear, recent studies imply a close link between the two with one feeding back on the other. In this discussion, we present the hypothesis that circadian clocks likely contribute to cellular homeostasis, especially proteostasis, through regulation of metabolic rhythms, which in turn feed-back on circadian oscillators. The disruption of circadian clocks leads to altered metabolic rhythms and metabolic disease states as a result of altered cellular homeostasis. PMID- 22521429 TI - Mercury chronic toxicity might be associated to some cases of hydrocephalus in adult humans? AB - Mercury accumulates in nervous tissue causing neurological and psychiatric manifestations. Numerous clinical findings have been described in patients that suffered chronic mercury intoxication. Some findings, such as hydrocephalus, have been described only in experimental studies. Following, we present a case of 50 year-old man with a 3-month history of severe frontal headache episodes and vision loss together with a history of asthenia, anorexia, muscle pain, fatigue and neuropsychiatric symptoms. The magnetic resonance imaging showed hydrocephalus and stenosis of aqueduct of Sylvius. This patient reported that he worked as laboratory metallurgic auxiliary for over 30 years. During this time, he had been chronically exposed to elemental mercury. The metals whole blood test was normal, except by his blood mercury level that was 61.5 MUg/L (normal ~1 MUg/L). In our best knowledge, hydrocephalus and stenosis of aqueduct of Sylvius have been described only in animals exposed to methylmercury during their gestation. We think that this case of hydrocephalus might be associated with the chronic mercury exposure and therefore this etiology must be taken in account in a patient with hydrocephalus of unknown etiology. PMID- 22521427 TI - The immunological challenges of cell transplantation for the treatment of Parkinson's disease. AB - Dopaminergic cell transplantation is an experimental therapy for Parkinson's disease (PD). It has many potential theoretical advantages over current treatment strategies such as providing continuous local dopaminergic replenishment, eliminating motor fluctuations and medication-induced dyskinesias, slowing down disease progression or even reversing disease pathology in the host. Recent studies also show that dopaminergic cell transplants provide long-term neuromodulation in the basal ganglia that simulates the combined effects of oral dopaminergic therapy and surgical therapies like deep brain stimulation, the contemporary therapeutic approach to advanced PD. However, dopaminergic cell transplantation in PD as not been optimized and current experimental techniques have many drawbacks. In published experiments to date of attempted dopaminergic grafting in PD, the major challenges are unacceptable graft-induced dyskinesias or failure of such grafts to exceed the benefits afforded by sham surgery. A deleterious host immune response to the transplant has been implicated as a major putative cause for these adverse outcomes. This article focuses on recent advances in understanding the immunology of the transplantation in PD and possible methods to overcome adverse events such that we could translate cell replacement strategies into viable clinical treatments in the future. PMID- 22521430 TI - Circulating levels of soluble Fas ligand and left ventricular remodeling after acute myocardial infarction (from the REVE-2 study). AB - BACKGROUND: Apoptosis-related molecules may contribute to left ventricular (LV) remodeling after myocardial infarction (MI). To validate this hypothesis, we evaluated the relation between circulating plasma levels of soluble Fas ligand (sFas-L) and LV remodeling in patients post-MI. METHODS AND RESULTS: This prospective multicenter study included 246 patients with a first anterior Q-wave MI. Serial echocardiographic studies were performed at hospital discharge and 3 and 12 months after MI; quantitative analysis was performed at a core echocardiography laboratory. Clinical follow-up was performed at 3 years post-MI. Blood samples to measure sFas-L were obtained at 1 month after MI. Median sFas-L level was 50.2 pg/mL. During the 1 year follow-up, LV remodeling was documented by a significant increase in LV volumes. LV end-diastolic and end-systolic volumes at baseline, 3 months, and 12 months after MI did not differ according to sFas-L levels; changes in LV volumes were not associated with sFas-L levels. By multivariate analysis, 2 variables were independently associated with LV remodeling: B-type natriuretic peptide (BNP) (p=0.008) and baseline ejection fraction (p=0.02). sFas-L levels were not associated with cardiovascular death or rehospitalization for heart failure at 3 years; conversely, high levels of BNP were associated with worse clinical outcome. CONCLUSIONS: Soluble Fas-L levels are not associated with LV remodeling after MI. Further research is needed to identify apoptotic markers that may be associated with outcome post-MI. PMID- 22521431 TI - Prognostic impact of systolic blood pressure at admission on in-hospital outcome after primary percutaneous coronary intervention for acute myocardial infarction. AB - BACKGROUND: Data regarding the relationship between systolic blood pressure (SBP) at admission and in-hospital outcome in patients with acute myocardial infarction (AMI) undergoing primary percutaneous coronary intervention (PCI) are still lacking in Japan. METHODS AND RESULTS: A total of 1475 primary PCI-treated AMI patients were classified into quintiles based on admission SBP (<105 mmHg, n=300; 105-125 mmHg, n=294; 126-140 mmHg, n=306; 141-158 mmHg, n=286; and >=159 mmHg n=289). The patients with SBP<105 mmHg tended to have higher age, previous myocardial infarction, chronic kidney disease (CKD), Killip class>=3 at admission, right coronary artery, left main trunk (LMT), or multivessels as culprit lesions, larger number of diseased vessels, lower Thrombolysis In Myocardial Infarction (TIMI) grade in the infarct-related artery before primary PCI, and higher value of peak creatine phosphokinase concentration. Patients with SBP<105 mmHg had a significantly higher mortality, while mortality was not significantly different among the other quintiles: 24.3% (<105 mmHg), 4.8% (105 125 mmHg), 4.9% (126-140 mmHg), 2.8% (141-158 mmHg), and 5.2% (>=159 mmHg) (p<0.001). On multivariate analysis, Killip class>=3 at admission, LMT or multivessels as culprit lesions, admission SBP<105 mmHg, CKD, and age were the independent positive predictors of in-hospital mortality, whereas admission SBP 141-158 mmHg and TIMI 3 flow after PCI were the negative ones, but admission SBP 105-125 mmHg, admission SBP 126-140 mmHg, and admission SBP>=159 mmHg were not. CONCLUSIONS: These results suggest that admission SBP 141-158 mmHg might be correlated with better in-hospital prognosis, whereas admission SBP<105 mmHg was associated with in-hospital death in Japanese AMI patients undergoing primary PCI. PMID- 22521432 TI - High-mobility group box-1 protein induces mucin 8 expression through the activation of the JNK and PI3K/Akt signal pathways in human airway epithelial cells. AB - High-mobility group box-1 protein (HMGB1), which is produced by immune cells, was recently identified as a proinflammatory mediator in various inflammatory diseases. In this study, we investigated the effect of HMGB1 on the expression of mucin (MUC) genes in human airway epithelial cells. We showed that HMGB1 markedly increased MUC8 expression, and that the expression of other MUC genes was also regulated by HMGB1. HMGB1 activated the JNK and PI3K/Akt signaling pathways, and inhibitors of JNK and PI3K/Akt markedly inhibited HMGB1-induced MUC8 expression. Furthermore, HMGB1 increased the production of intracellular reactive oxygen species (ROS). However, the ROS scavengers Trolox and N-acetylcysteine (NAC) had no effect on MUC8 expression in HMGB1-treated NCI-H292 cells. Taken together, our results suggest that HMGB1 induces MUC8 expression in a JNK and PI3K/Akt signaling pathway-dependent manner but that HMGB1 acts in an ROS-independent manner. PMID- 22521433 TI - In situ fatty acid profile of femoral cancellous subchondral bone in osteoarthritic and fragility fracture females: implications for bone remodelling. AB - We report here differences in the fatty acid profile of cancellous bone matrix, including n-3, n-6, mono- and poly-unsaturated, as well as saturated fats, between femoral heads from female OA (n=8, aged 68-88years), fractured neck of femur (#NOF) (n=19, 67-88years) and autopsy controls (CTRL) (n=4, 85-97years). Femoral heads were collected from individuals undergoing orthopaedic surgery for OA or #NOF; the fatty acid profile of sub-samples from the superior principal compressive and superior principal tensile regions were determined by gas chromatography. A total of 42 individual fatty acids were detected at varying concentrations with significant differences between subchondral bone from OA subjects, subchondral bone from #NOF subjects and subchondral bone from CTRL subjects, as well as between the superior principal compressive and superior principal tensile regions (for saturated fats only). Subchondral bone from OA subjects had higher total n-6 (OA=10.89+/-3.17, #NOF=11.11+/-1.83, CTRL=8.32+/ 2.05, p=0.008) and total n-3 (OA=1.34+/-0.38, #NOF=1.19+/-0.18, CTRL=1.15+/-0.48, p=0.011) percentages than subchondral bone from #NOF subjects and subchondral bone from CTRL subjects, and there was no difference in the n-6:n-3 ratio, nor within the percentage of n-9 fatty acids. Arachidonic acid (OA=0.42+/-0.16, #NOF=0.26+/-0.06, CTRL=0.28+/-0.06, p=0.01), and gamma-linolenic acid (OA=0.11+/ 0.03, #NOF=0.05+/-0.02, CTRL=0.04+/-0.02, p<0.001) were higher in subchondral bone from OA subjects than subchondral bone from #NOF subjects and subchondral bone from CTRL subjects. In conclusion, there is a wide diversity of fatty acids in cancellous bone matrix from the femoral heads of OA and #NOF, suggesting they may have regulatory effects on inflammatory processes, and their metabolites. This article is part of a Special Issue entitled "Osteoarthritis". PMID- 22521434 TI - Hepatocyte growth factor (HGF) and 1,25-dihydroxyvitamin D together stimulate human bone marrow-derived stem cells toward the osteogenic phenotype by HGF induced up-regulation of VDR. AB - Bone formation and remodeling require generation of osteoprogenitors from bone marrow stem cells (MSC), which are regulated by growth factors and hormones, with putative roles in mesenchymal cell differentiation. Hepatocyte growth factor (HGF) is a pleiotropic growth factor, and together with its high affinity receptor cMet are widely expressed in normal tissues. 1,25-dihydroxyvitamin D (1,25OHD) is the most active metabolite of vitamin D; produced mainly in the kidney, but also by osteoblasts. We previously reported that HGF and 1,25OHD act together to increase osteogenic differentiation of human MSC (hMSC) potentially through increasing p53. Although p53 does not induce the vitamin D receptor (VDR), p63, a member of the p53 family of transcription factors has been reported to up-regulate VDR expression in some tumor cell lines, and thus might play a part in HGF-regulated VDR expression. Our hypothesis is that the combination of HGF and 1,25OHD can induce hMSC differentiation by up-regulation of 1,25OHD and/or VDR expression to increase cell response(s) to 1,25OHD. Using real-time RT qPCR, Western blots, luciferase reporter assays, and siRNAs, as well as antibodies to specific signaling molecules we showed that HGF induced VDR gene expression, as well as up-regulated p63 gene expression. p63 gene knockdown by siRNA eliminated the effects of HGF on VDR gene expression as measured by RT qPCR, Western blots and luciferase reporter assay, and downstream on osteogenic differentiation markers, including alkaline phosphatase staining. Differentiation is a coordinated process of cell cycle exit and tissue-specific gene expression. These results suggest HGF might be a good candidate to coordinate the regulation of these two processes during hMSC osteogenic differentiation. p63 could be a key connecting molecule on the pathway of HGF-induced VDR expression. Understanding the role of these factors and their actions could have important clinical implications for the use of hMSC in the development of novel stem cell therapies. PMID- 22521435 TI - Aicardi-Goutieres syndrome with systemic lupus erythematosus and hypothyroidism. AB - We report a case of Aicardi-Goutieres syndrome with systemic lupus erythematosus and hypothyroidism. A 3-year-old girl, diagnosed with Aicardi-Goutieres syndrome at 9 months, was transferred to our hospital for fever of unknown origin. Severe spasticity with dystonic posturing and flexion contracture of the limbs were noted. Interstitial pneumonia with pleural effusion was evident. Immunological investigations revealed positive antinuclear antibodies and reduced thyroid function. Prompt treatment with steroids, cyclophosphamide, and levothyroxine sodium hydrate elicited a good response. It is necessary to emphasize that its possible relationship between Aicardi-Goutieres syndrome and systemic lupus erythematosus and/or hypothyroidism. PMID- 22521436 TI - Quantitative computed tomography for enzyme replacement therapy in Pompe disease. AB - OBJECTIVE: Pompe disease is an autosomal recessive disorder caused by deficiency of the lysosomal enzyme, acid alpha-glucosidase (GAA). To the best of our knowledge, no studies have reported the results of systematic and sequential CT analyses before and during ERT. In this study we have treated three patients with late onset Pompe disease by ERT, and investigated the efficacy of treatment by computed tomography number. METHODS: We measured the serial changes in the computed tomography (CT) number of multiple organs in three patients with late onset of Pompe disease during 24 months of enzyme replacement therapy (ERT). RESULTS: Before treatment, the liver and muscle CT numbers were higher in these patients than in the controls. The liver CT number decreased after performing ERT. Furthermore, the urinary glucose tetrasaccharide levels, a biomarker of glycogen accumulation, were elevated before ERT and reduced thereafter. CONCLUSIONS: The findings in these cases suggest that the elevation of the liver CT number represents glycogen accumulation in the liver and that the analysis of the liver CT number is therefore a useful tool for assessing the efficacy of ERT. PMID- 22521438 TI - Intraoperative resident education for robotic laparoscopic gastric banding surgery: a pilot study on the safety of stepwise education. AB - BACKGROUND: Incorporation of robotic surgery into resident education poses questions regarding intraoperative teaching and patient care. This study aimed to evaluate the impact of gradually increasing resident console responsibility on resident competency and patient safety, in the presence of a proctor and bedside surgeon, for robotic laparoscopic-assisted gastric banding (R-LAGB) compared with the classical training model (CTM) of residents as first assistant. STUDY DESIGN: Eight clinical year 4 (CY4) residents completed 60 R-LAGB using a one-to-one proctored training model (PTM). R-LAGB was distilled into 7 key steps: gastroesophageal-junction dissection, gastrohepatic ligament dissection, retrogastric space creation, band placement, band closure, gastrogastric suturing, and port placement. Residents performed more complex steps after each case to gain competency in all aspects of the operation. Patient demographics, comorbidities, operative complications, operating times, and clinical outcomes were compared with a control group of 287 R-LAGB cases completed using the CTM (n = 15 CY4 residents). RESULTS: All residents using the PTM were able to successfully complete an R-LAGB as primary surgeon after a median of 8 operations (range 5 to 11); no residents in the CTM completed an R-LAGB as primary surgeon. Mean operative time was statistically greater in the PTM group (99.3 +/- 22.1 minutes) vs CTM (91.5 +/- 21.1 minutes) (p = 0.001). There were no intraoperative complications in either group; incidence of postoperative complications was similar between groups. CONCLUSIONS: All residents in the proctored setting claimed competence and have persistent console experience without significantly increasing procedure complications. PTM, otherwise known as stepwise education, is a safe, standardized method to train surgical residents in R-LAGB. PMID- 22521437 TI - [Comorbidities in patients hospitalized due to chronic obstructive pulmonary disease. A comparative analysis of the ECCO and ESMI studies]. AB - BACKGROUNDS AND OBJECTIVES: The presence of associated diseases is very frequent in patients hospitalized due to exacerbation of COPD. We have studied the comorbidities of patients admitted due to the disease in the Spanish Internal Medicine Services and we have evaluated the variations in regards to a previous study (ECCO study) performed two years earlier. PATIENTS AND METHODS: A cross sectional, multicenter and cohort study was performed. Patients hospitalized due to exacerbation of COPD in Spanish Internal Medicine Services were enrolled. All the patients were studied for the presence of comorbidity using the Charlson index and a questionnaire with relevant conditions not included in this index. Furthermore, spirometric data were collected on the duration of the disease or home treatment, among other variables. RESULTS: A total of 1004 patients (398 in the ECCO study and 606 in the ESMI study) were studied. Of these, 89.4% were males, with mean age of 73 years (SD: 9.5 years). The patients of the ESMI study obtain higher scores on the Charlson index (3.04 vs. 2.71; P<0.01), and had a greater prevalence of ischemic heart disease (17 vs. 22.0%; P<0.05), heart failure (26.9 vs. 35.5%; P<.002), peripheral vascular disease (12.6 vs. 17.4%; P<.02), arterial hypertension (54.8 vs. 65.6%; P<.001), diabetes mellitus (29.4 vs. 37%; P<.02) and renal failure (6.5 vs. 16.8%; P<.0001). CONCLUSIONS: This study confirms the elevated prevalence of associated diseases in patients with COPD who are admitted to the Spanish Internal Medicine Services and the increase of comorbidities. PMID- 22521440 TI - Routine pedicular lymphadenectomy for colorectal liver metastases. PMID- 22521439 TI - Minimally invasive component separation results in fewer wound-healing complications than open component separation for large ventral hernia repairs. AB - BACKGROUND: Minimally invasive component separation (CS) with inlay bioprosthetic mesh (MICSIB) is a recently developed technique for abdominal wall reconstruction that preserves the rectus abdominis perforators and minimizes subcutaneous dead space using limited-access tunneled incisions. We hypothesized that MICSIB would result in better surgical outcomes than conventional open CS. STUDY DESIGN: All consecutive patients who underwent CS (open or minimally invasive) with inlay bioprosthetic mesh for ventral hernia repair from 2005 to 2010 were included in a retrospective analysis of prospectively collected data. Surgical outcomes, including wound-healing complications, hernia recurrences, and abdominal bulge/laxity rates, were compared between patient groups based on the type of CS repair, either MICSIB or open. RESULTS: Fifty-seven patients who underwent MICSIB and 50 who underwent open CS were included. Mean follow-ups were 15.2 +/- 7.7 months and 20.7 +/- 14.3 months, respectively. Mean fascial defect size was significantly larger in the MICSIB group (405.4 +/- 193.6 cm(2) vs 273.8 +/- 186.8 cm(2); p = 0.002). The incidences of skin dehiscence (11% vs 28%; p = 0.011), all wound-healing complications (14% vs 32%; p = 0.026), abdominal wall laxity/bulge (4% vs 14%; p = 0.056), and hernia recurrence (4% vs 8%; p = 0.3) were lower in the MICSIB group than in the open CS group. CONCLUSIONS: MICSIB resulted in fewer wound-healing complications than did open CS used for complex abdominal wall reconstructions. These findings are likely attributable to the preservation of paramedian skin vascularity and reduction in subcutaneous dead space with MICSIB. MICSIB should be considered for complex abdominal wall reconstructions, particularly in patients at increased risk of wound-healing complications. PMID- 22521441 TI - Laparoscopic treatment for choledochal cysts with stenosis of the common hepatic duct. PMID- 22521442 TI - En bloc stapling division of the gastroesophageal vessels controlling portal hemodynamic status in living donor liver transplantation. PMID- 22521443 TI - Development and validation of a bariatric surgery mortality risk calculator. AB - BACKGROUND: While the epidemic of obesity continues to plague America, bariatric surgery is underused due to concerns for surgical risk among patients and referring physicians. A risk score estimating postoperative mortality (OS-MRS) exists, however, is limited by consideration of only 12 preoperative variables, failure to separate open and laparoscopic cases, a lack of robust statistical analyses, risk factors not being weighted, and being applicable to only gastric bypass surgery. The objective of this study was to develop a validated risk calculator for 30-day postoperative mortality after bariatric surgery. STUDY DESIGN: The National Surgical Quality Improvement Program (NSQIP) dataset (2006 to 2008) was used. Patients undergoing bariatric surgery for morbid obesity (n = 32,889) were divided into training (n = 21,891) and validation (n = 10,998) datasets. Multiple logistic regression analysis was performed on the training dataset. The model fit from the training dataset was maintained and was used to estimate mortality probabilities for all patients in the validation dataset. RESULTS: Thirty-day mortality was 0.14%. Seven independent predictors of mortality were identified: peripheral vascular disease, dyspnea, previous percutaneous coronary intervention, age, body mass index, chronic corticosteroid use, and type of bariatric surgery. This risk model was subsequently validated. The model performance was very similar between the training and the validation datasets (c-statistics, 0.80 and 0.82, respectively). The high c-statistics indicate excellent predictive performance. The risk model was used to develop an interactive risk calculator. CONCLUSIONS: This risk calculator has excellent predictive ability for mortality after bariatric procedures. It is anticipated that it will aid in surgical decision-making, informed patient consent, and in helping patients and referring physicians to assess the true bariatric surgical risk. PMID- 22521444 TI - Cervical and upper mediastinal lymph node metastasis from gastrointestinal and pancreatic neuroendocrine tumors: true incidence and management. AB - BACKGROUND: The incidence, clinical importance, and optimal management of cervical and upper mediastinal lymph node metastasis from gastrointestinal and pancreatic neuroendocrine tumors (NETS) are largely unknown. Historically, cervical nodes have been regarded as asymptomatic and ignored. We hypothesized that these lesions have clinical implications and should be removed surgically. STUDY DESIGN: Consecutive (111)In pentetreotide scans (OctreoScan) performed at our institution from May 2008 to October 2010 were reviewed to determine the incidence of cervical and upper mediastinal lymph node metastases among patients with gastrointestinal and pancreatic NETs. The charts of surgically treated patients were reviewed to evaluate the clinical importance of these metastases and the subsequent outcomes of their surgical treatment. RESULTS: A total of 161 NET patients presented with positive OctreoScans. Fourteen patients (8.7%) scanned positive for cervical and upper mediastinal lymph node metastasis. Nine patients underwent surgical exploration; 8 had successful removal of their metastatic nodes. Seven had clinical symptoms that resolved after surgery. CONCLUSIONS: Cervical and upper mediastinal lymph node metastases from gastrointestinal and pancreatic NETs were seen in up to 8.7% of patients. In the past, these metastases were assumed to be insignificant and ignored. Our study clearly demonstrates that most, if not all, such metastases are symptomatic and their clinical implications should not be overlooked. Notably, these metastases can be easily and safely resected using radioguided surgery. PMID- 22521445 TI - Chemoprevention of liver cancer by plant polyphenols. AB - Primary liver cancer or hepatocellular carcinoma (HCC) is one of the most frequent tumors representing the fifth commonest malignancy worldwide and the third cause of mortality from cancer. Currently, the treatments for HCC are not so effective and new strategies are needed for its fight. Chemoprevention, the use of natural or synthetic chemical agents to reverse, suppress or prevent carcinogenesis is considered an important way for confronting HCC. Many of the chemopreventive agents are phytochemicals, namely non-nutritive plant chemicals with protective or disease preventive properties. In this review, we focus on plant polyphenols, one of the most important classes of phytochemicals, their chemopreventive properties against HCC and discuss the molecular mechanisms accounting for this activity. PMID- 22521446 TI - Information-seeking behaviours and decision-making process of parents of children with cancer. AB - PURPOSE: This study aimed to explore the information-seeking behaviours, perceptions and decision-making experiences of parents of children with cancer by employing semi-structured interviews. METHODS AND SAMPLE: A qualitative research design was used to assess the information-seeking behaviours, perceptions and decision-making processes used by parents in Turkey whose children have cancer. Interviews were conducted with 15 parents of children with cancer using a semi structured interview schedule. The interviews were recorded and transcribed verbatim. RESULTS: Six main issues emerged. Issues were related to parents' information needs, the sources of information, difficulties that the parents encountered when seeking information, the decision-making process, the factors affecting decision-making, and expectations from the health team. Information resources for parents included medical doctors and nurses, the internet, friends and the parents of other children who were staying in the hospital. The parents mostly sought information about their child's illness, prognoses, treatment, side effects and care giving issues. The parents expressed that they were directed primarily by health care providers during their decision-making process. CONCLUSIONS: Adequate and systematic information pertaining to illness, treatment, prognosis and child care must be provided by health care professionals throughout the illness process. In addition, individual guidance and spare time are key components to helping parents make decisions about their children with cancer. PMID- 22521447 TI - Associations of antimicrobial use with antimicrobial resistance in Campylobacter coli from grow-finish pigs in Japan. AB - To determine associations between antimicrobial use and antimicrobial resistance in Campylobacter coli, 155 isolates were obtained from the feces of apparently healthy grow-finish pigs in Japan. In addition, data on the use of antibiotics collected through the national antimicrobial resistance monitoring system in Japan were used for the analysis. Logistic regression was used to identify risk factors to antimicrobial resistance in C. coli in pigs for the following antimicrobials: ampicillin, dihydrostreptomycin, erythromycin, oxytetracycline, chloramphenicol, and enrofloxacin. The data suggested the involvement of several different mechanisms of resistance selection. The statistical relationships were suggestive of co-selection; use of macrolides was associated with enrofloxacin resistance (OR=2.94; CI(95%): 0.997, 8.68) and use of tetracyclines was associated with chloramphenicol resistance (OR=2.37; CI(95%): 1.08, 5.19). The statistical relationships were suggestive of cross-resistance: use of macrolides was associated with erythromycin resistance (OR=9.36; CI(95%): 2.96, 29.62) and the use of phenicols was associated with chloramphenicol resistance (OR=11.83; CI(95%): 1.41, 99.44). These data showed that the use of antimicrobials in pigs selects for resistance in C. coli within and between classes of antimicrobials. PMID- 22521448 TI - The influence of rewarming after therapeutic hypothermia on outcome after cardiac arrest. AB - INTRODUCTION: Treatment with hypothermia has been shown to improve outcome after cardiac arrest (CA). Current consensus is to rewarm at 0.25-0.5 degrees C/h and avoid fever. The aim of this study was to investigate whether active rewarming, the rate of rewarming or development of fever after treatment with hypothermia after CA was correlated with poor outcome. METHODS: This retrospective cohort study included adult patients treated with hypothermia after CA and admitted to the intensive care unit between January 2006 and January 2009. The average rewarming rate from end of hypothermia treatment (passive rewarming) or start active rewarming until 36 degrees C was dichotomized in a high (>= 0.5 degrees C/h) or normal rate (<0.5 degrees C/h). Fever was defined as >38 degrees C within 72 h after admission. Poor outcome was defined as death, vegetative state, or severe disability after 6 months. RESULTS: From 128 included patients, 56% had a poor outcome. Actively rewarmed patients (38%) had a higher risk for poor outcome, OR 2.14 (1.01-4.57), p<0.05. However, this effect disappeared after adjustment for the confounders age and initial rhythm, OR 1.51 (0.64-3.58). A poor outcome was found in 15/21 patients (71%) with a high rewarming rate, compared to 54/103 patients (52%) with a normal rewarming rate, OR 2.61 (0.88 7.73), p = 0.08. Fever was not associated with outcome, OR 0.64 (0.31-1.30), p = 0.22. CONCLUSIONS: This study showed that patients who needed active rewarming after therapeutic hypothermia after CA did not have a higher risk for a poor outcome. In addition, neither speed of rewarming, nor development of fever had an effect on outcome. PMID- 22521449 TI - Ischemic postconditioning at the initiation of cardiopulmonary resuscitation facilitates functional cardiac and cerebral recovery after prolonged untreated ventricular fibrillation. AB - OBJECTIVES: Ischemic postconditioning (PC) with "stuttering" reintroduction of blood flow after prolonged ischemia has been shown to offer protection from ischemia reperfusion injury to the myocardium and brain. We hypothesized that four 20-s pauses during the first 3 min of standard CPR would improve post resuscitation cardiac and neurological function, in a porcine model of prolonged untreated cardiac arrest. METHODS: 18 female farm pigs, intubated and isoflurane anesthetized had 15 min of untreated ventricular fibrillation followed by standard CPR (SCPR). Nine animals were randomized to receive PC with four, controlled, 20-s pauses, during the first 3 min of CPR (SCPR+PC). Resuscitated animals had echocardiographic evaluation of their ejection fraction after 1 and 4 h and a blinded neurological assessment with a cerebral performance category (CPC) score assigned at 24 and 48 h. All animals received 12 h of post resuscitation mild therapeutic hypothermia. RESULTS: SCPR+PC animals had significant improvement in left ventricular ejection fraction at 1 and 4 h compared to SCPR (59+/-11% vs. 35+/-7% and 55+/-8% vs. 31+/-13% respectively, p<0.01). Neurological function at 24h significantly improved with SCPR+PC compared to SCPR alone (CPC: 2.7+/-0.4 vs. 3.8+/-0.4 respectively, p=0.003). Neurological function significantly improved in the SCPR+PC group at 48 h and the mean CPC score of that group decreased from 2.7+/-0.4 to 1.7+/-0.4 (p<0.00001). CONCLUSIONS: Ischemic postconditioning with four 20-s pauses during the first 3 min of SCPR improved post resuscitation cardiac function and facilitated neurological recovery after 15 min of untreated cardiac arrest in pigs. PMID- 22521450 TI - Immediate cardiac arrest resuscitation skills are acquired in 8th grade students during normal class hours with a low-cost, short-term, self-instruction video. PMID- 22521451 TI - Molecular chaperone involvement in chloroplast protein import. AB - Chloroplasts are organelles of endosymbiotic origin that perform essential functions in plants. They contain about 3000 different proteins, the vast majority of which are nucleus-encoded, synthesized in precursor form in the cytosol, and transported into the chloroplasts post-translationally. These preproteins are generally imported via envelope complexes termed TOC and TIC (Translocon at the Outer/Inner envelope membrane of Chloroplasts). They must navigate different cellular and organellar compartments (e.g., the cytosol, the outer and inner envelope membranes, the intermembrane space, and the stroma) before arriving at their final destination. It is generally considered that preproteins are imported in a largely unfolded state, and the whole process is energy-dependent. Several chaperones and cochaperones have been found to mediate different stages of chloroplast import, in similar fashion to chaperone involvement in mitochondrial import. Cytosolic factors such as Hsp90, Hsp70 and 14-3-3 may assist preproteins to reach the TOC complex at the chloroplast surface, preventing their aggregation or degradation. Chaperone involvement in the intermembrane space has also been proposed, but remains uncertain. Preprotein translocation is completed at the trans side of the inner membrane by ATP-driven motor complexes. A stromal Hsp100-type chaperone, Hsp93, cooperates with Tic110 and Tic40 in one such motor complex, while stromal Hsp70 is proposed to act in a second, parallel complex. Upon arrival in the stroma, chaperones (e.g., Hsp70, Cpn60, cpSRP43) also contribute to the folding, assembly or onward intraorganellar guidance of the proteins. In this review, we focus on chaperone involvement during preprotein translocation at the chloroplast envelope. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids. PMID- 22521453 TI - Metalloproteinases facilitate connection of wound bed vessels to pre-existing skin graft vasculature. AB - BACKGROUND: Despite advances in tissue engineering of human skin, the exact revascularization processes remain unclear. Therefore it was the aim of this study to investigate the vascular transformations during engraftment and to identify associated proteolytic factors. METHODS: The modified dorsal skinfold chamber with autologous skin grafting was prepared in C57BL/6J mice, and intravital microscopy was performed. The expression of proteases and vascular factors was quantified by immunohistochemistry. RESULTS: Reperfusion of the skin graft after 72hours was followed by a temporary angiogenic response of the graft vessels. Wound bed bud formation appeared after 24 to 48hours representing starting points for capillary sprouting. In the reperfused skin graft larger buds developed over several days without transformation into angiogenic sprouts; instead pruning took place. MT1-MMP was detected at sprout tips of in-growing vessels. MMP-2 expression was located at the wound bed/graft connection sites. Pericytes were found to withdraw from the angiogenic vessel in order to facilitate sprouting. CONCLUSIONS: Skin graft vasculature responded with temporary angiogenesis to reperfusion, which was pruned after several days and exhibited a different morphology than regular sprouting angiogenesis present within the wound bed. Furthermore we identified MT1-MMP as sprout-tip located protease indicating its potential role as sprout growth facilitator as well as potentially in lysing the existing graft capillaries in order to connect to them. The differences between the wound bed and skin graft angiogenesis may represent a relevant insight into the processes of vascular pruning and may help in the engineering of skin substitutes. PMID- 22521454 TI - Systems biology: the 'new biotechnology'. PMID- 22521452 TI - Visualizing metal ions in cells: an overview of analytical techniques, approaches, and probes. AB - Quantifying the amount and defining the location of metal ions in cells and organisms are critical steps in understanding metal homeostasis and how dyshomeostasis causes or is a consequence of disease. A number of recent advances have been made in the development and application of analytical methods to visualize metal ions in biological specimens. Here, we briefly summarize these advances before focusing in more depth on probes for examining transition metals in living cells with high spatial and temporal resolution using fluorescence microscopy. This article is part of a Special Issue entitled: Cell Biology of Metals. PMID- 22521455 TI - Recent advances in production of recombinant spider silk proteins. AB - Spider silk has been drawing much attention as a great biomaterial having many applications in biotechnology and biomedicine owing to its several desired material characteristics such as outstanding strength, toughness, and elasticity as well as biodegradability and biocompatibility. With various applications foreseeable in industry, there has been much effort to produce recombinant spider silk protein in large amounts. However, owing to the difficulties in its production using spiders, alternative host systems and engineering methods have been investigated to develop suitable production systems that can efficiently produce spider silk protein. Here, we review recent advances in production of spider silk proteins in various heterologous host systems with focus given on the development of metabolic and cellular engineering strategies. PMID- 22521456 TI - Placental pathology and long-term neurodevelopment of very preterm infants. AB - OBJECTIVE: The objective of the study was to compare neonatal morbidity and long term neurodevelopmental outcome between very preterm infants with placental underperfusion and very preterm infants with histological chorioamnionitis. STUDY DESIGN: We measured the mental and motor development at age 2 and 7 years in 51 very preterm infants with placental underperfusion and 21 very preterm infants with histological chorioamnionitis. RESULTS: At 2 years, very preterm infants with placental underperfusion had poorer mental development than very preterm infants with histological chorioamnionitis (mean [SD] 90.8 [18.3] vs 104.1 [17.2], adjusted d = 1.12, P = .001). Motor development was not different between both groups (92.8 [17.2] vs 96.8 [8.7], adjusted d = 0.52, P = .12). At 7 years, large, although nonsignificant, effects were found for better mental and motor development and fewer behavioral problems in infants with histological chorioamnionitis. CONCLUSION: Placental pathology contributes to variance in mental development at 2 years and should be taken into account when evaluating neurodevelopmental outcome of very preterm infants. PMID- 22521457 TI - Ovulation induction in women with polycystic ovarian syndrome: still steps to take. PMID- 22521459 TI - Maternal exposure to moderate ambient carbon monoxide is associated with decreased risk of preeclampsia. AB - OBJECTIVE: Carbon monoxide (CO) in cigarette smoke may be the mechanism by which tobacco use during pregnancy decreases the risk of the development of preeclampsia. We attempted to test this hypothesis by examining the effect of maternal exposure to ambient CO on preeclampsia. STUDY DESIGN: Births that occurred between 2004 and 2009 in the Canadian province of Ontario were extracted from the data. Study subjects were divided into 4 groups according to quartiles of CO concentration that were based on maternal residence. Adjusted odds ratio and 95% confidence interval were used to estimate the independent effect of CO on preeclampsia. RESULTS: Rates of preeclampsia were 2.32%, 1.97%, 1.59%, and 1.26%, respectively, in the first, second, third, and fourth quartile of CO concentration. The inverse association between CO concentration and preeclampsia risk remained the same after adjustment for several important confounding factors. CONCLUSION: Maternal exposure to moderate ambient CO is associated independently with a decreased risk of preeclampsia. PMID- 22521458 TI - Knowledge of contraceptive effectiveness. AB - OBJECTIVE: The purpose of this study was to determine women's knowledge of contraceptive effectiveness. STUDY DESIGN: We performed a cross-sectional analysis of a contraceptive knowledge questionnaire that had been completed by 4144 women who were enrolled in the Contraceptive CHOICE Project before they received comprehensive contraceptive counseling and chose their method. For each contraceptive method, women were asked "what percentage would get pregnant in a year: <1%, 1-5%, 6-10%, >10%, don't know." RESULTS: Overall, 86% of subjects knew that the annual risk of pregnancy is >10% if no contraception is used. More than 45% of women overestimate the effectiveness of depo-medroxyprogesterone acetate, pills, the patch, the ring, and condoms. After adjustment for age, education, and contraceptive history, the data showed that women who chose the intrauterine device (adjusted relative risk, 6.9; 95% confidence interval, 5.6-8.5) or implant (adjusted relative risk, 5.9; 95% confidence interval, 4.7-7.3) were significantly more likely to identify the effectiveness of their method accurately compared with women who chose either the pill, patch, or ring. CONCLUSION: This cohort demonstrated significant knowledge gaps regarding contraceptive effectiveness and over-estimated the effectiveness of pills, the patch, the ring, depo-medroxyprogesterone acetate, and condoms. PMID- 22521460 TI - Does route of delivery affect maternal and perinatal outcome in women with eclampsia? A randomized controlled pilot study. AB - OBJECTIVE: The route of delivery in eclampsia is controversial. We hypothesized that adverse maternal and perinatal outcomes may not be improved by early cesarean delivery. STUDY DESIGN: This was a randomized controlled exploratory trial carried out in a rural teaching institution. In all, 200 eclampsia cases, carrying >=34 weeks, were allocated to either cesarean or vaginal delivery. Composite maternal and perinatal event rates (death and severe morbidity) were compared by intention-to-treat principle. RESULTS: Groups were comparable at baseline with respect to age and key clinical parameters. Maternal event rate was similar: 10.89% in the cesarean arm vs 7.07% for vaginal delivery (relative risk, 1.54; 95% confidence interval, 0.62-3.81). Although the neonatal event rate was less in cesarean delivery-9.90% vs 19.19% (relative risk, 0.52; 95% confidence interval, 0.25-1.05)-the difference was not significant statistically. CONCLUSION: A policy of early cesarean delivery in eclampsia, carrying >=34 weeks, is not associated with better outcomes. PMID- 22521461 TI - AAV2 mediated retrograde transduction of corticospinal motor neurons reveals initial and selective apical dendrite degeneration in ALS. AB - Corticospinal motor neurons (CSMN) are the cortical component of motor neuron circuitry, which controls voluntary movement and degenerates in diseases such as amyotrophic lateral sclerosis, primary lateral sclerosis and hereditary spastic paraplegia. By using dual labeling combined with molecular marker analysis, we identified AAV2-2 mediated retrograde transduction as an effective approach to selectively target CSMN without affecting other neuron populations both in wild type and hSOD1(G93A) transgenic ALS mice. This approach reveals very precise details of cytoarchitectural defects within vulnerable neurons in vivo. We report that CSMN vulnerability is marked by selective degeneration of apical dendrites especially in layer II/III of the hSOD1(G93A) mouse motor cortex, where cortical input to CSMN function is vastly modulated. While our findings confirm the presence of astrogliosis and microglia activation, they do not lend support to their direct role for the initiation of CSMN vulnerability. This study enables development of targeted gene replacement strategies to CSMN in the cerebral cortex, and reveals CSMN cortical modulation defects as a potential cause of neuronal vulnerability in ALS. PMID- 22521462 TI - Mutant HSPB1 overexpression in neurons is sufficient to cause age-related motor neuronopathy in mice. AB - The small heat shock protein HSPB1 is a multifunctional, alpha-crystallin-based protein that has been shown to be neuroprotective in animal models of motor neuron disease and peripheral nerve injury. Missense mutations in HSPB1 result in axonal Charcot-Marie-Tooth disease with minimal sensory involvement (CMT2F) and distal hereditary motor neuropathy type 2 (dHMN-II). These disorders are characterized by a selective loss of motor axons in peripheral nerve resulting in distal muscle weakness and often severe disability. To investigate the pathogenic mechanisms of HSPB1 mutations in motor neurons in vivo, we have developed and characterized transgenic PrP-HSPB1 and PrP-HSPB1(R136W) mice. These mice express the human HSPB1 protein throughout the nervous system including in axons of peripheral nerve. Although both mouse strains lacked obvious motor deficits, the PrP-HSPB1(R136W) mice developed an age-dependent motor axonopathy. Mutant mice showed axonal pathology in spinal cord and peripheral nerve with evidence of impaired neurofilament cytoskeleton, associated with organelle accumulation. Accompanying these findings, increases in the number of Schmidt-Lanterman incisures, as evidence of impaired axon-Schwann cell interactions, were present. These observations suggest that overexpression of HSPB1(R136W) in neurons is sufficient to cause pathological and electrophysiological changes in mice that are seen in patients with hereditary motor neuropathy. PMID- 22521463 TI - Selective increase of two ABC drug efflux transporters at the blood-spinal cord barrier suggests induced pharmacoresistance in ALS. AB - ATP-binding cassette (ABC) drug efflux transporters in the CNS are predominantly localized to the luminal surface of endothelial cells in capillaries to impede CNS accumulation of xenobiotics. Inflammatory mediators and cellular stressors regulate their activity. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of upper and lower motor neurons characterized by extensive neuroinflammation. Here we tested the hypothesis that disease-driven changes in ABC transporter expression and function occur in ALS. Given the multitude of ABC transporters with their widespread substrate recognition, we began by examining expression levels of several ABC transporters. We found a selective increase in only two transporters: P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) both at mRNA and protein levels, in the SOD1 G93A mouse model of ALS, specifically in disease-affected CNS regions. Detailed analysis revealed a similar disease-driven increase in P-gp and BCRP levels in spinal cord microvessels, indicating that their altered expression occurs at the blood spinal cord barrier. Transport activity of P-gp and BCRP increased with disease progression in spinal cord and cerebral cortex capillaries. Finally, P-gp and BCRP protein expression also increased in spinal cords of ALS patients. Preclinical drug trials in the mouse model of ALS have failed to decisively slow or arrest disease progression; pharmacoresistance imparted by ABC transporters is one possible explanation for these failures. Our observations have large implications for ALS therapeutics in humans and suggest that the obstacle provided by these transporters to drug treatments must be overcome to develop effective ALS pharmacotherapies. PMID- 22521465 TI - Cerebellar abnormalities in purine nucleoside phosphorylase deficient mice. AB - Inherited defects in purine nucleoside phosphorylase (PNP) cause severe T cell immunodeficiency and progressive neurological dysfunction, yet little is known about the effects of PNP deficiency on the brain. PNP-KO mice display metabolic and immune anomalies similar to those observed in patients. Our objectives were to characterize brain abnormalities in PNP-KO mice and determine whether restoring PNP activity prevents these abnormalities. We analyzed structural brain defects in PNP-KO mice by magnetic resonance imaging, while assessing motor deficits using the accelerating rotarod and stationary balance beam tests. We detected morphological abnormalities and apoptosis in the cerebellum of PNP-KO mice by hematoxylin and eosin, electron microscopy, TUNEL and activated caspase 3 staining. We treated PNP-KO mice with PNP fused to the HIV-TAT protein transduction domain (TAT-PNP) from birth or from 4 weeks of age. Magnetic resonance imaging revealed a smaller than normal cerebellum in PNP-KO mice. PNP KO mice displayed motor abnormalities including rapid fall from the rotating rod and frequent slips from the balance beam. The cerebellum of PNP-KO mice contained reduced purkinje cells (PC), which were irregular in shape and had degenerated dendrites. PC from the cerebellum of PNP-KO mice, expanded ex vivo, demonstrated increased apoptosis, which could be corrected by supplementing cultures with TAT PNP. TAT-PNP injections restored PNP activity in the cerebellum of PNP-KO mice. TAT-PNP from birth, but not treatment initiated at 4 weeks of age, prevented the cerebellar PC damage and motor deficits. We conclude that PNP deficiency cause cerebellar abnormalities, including PC damage and progressive motor deficits. TAT PNP treatment from birth can prevent the neurological abnormalities in PNP-KO mice. PMID- 22521464 TI - Neural response to reward as a predictor of increases in depressive symptoms in adolescence. AB - Adolescence is a developmental period characterized by significant increases in the onset of depression, but also by increases in depressive symptoms, even among psychiatrically healthy youth. Disrupted reward function has been postulated as a critical factor in the development of depression, but it is still unclear which adolescents are particularly at risk for rising depressive symptoms. We provide a conceptual stance on gender, pubertal development, and reward type as potential moderators of the association between neural response to reward and rises in depressive symptoms. In addition, we describe preliminary findings that support claims of this conceptual stance. We propose that (1) status-related rewards may be particularly salient for eliciting neural response relevant to depressive symptoms in boys, whereas social rewards may be more salient for eliciting neural response relevant to depressive symptoms in girls and (2) the pattern of reduced striatal response and enhanced medial prefrontal response to reward may be particularly predictive of depressive symptoms in pubertal adolescents. We found that greater vmPFC activation when winning rewards predicted greater increases in depressive symptoms over 2 years, for boys only, and less striatal activation when anticipating rewards predicted greater increases in depressive symptoms over 2 years, for adolescents in mid to late pubertal stages but not those in pre to early puberty. We also propose directions for future studies, including the investigation of social vs. monetary reward directly and the longitudinal assessment of parallel changes in pubertal development, neural response to reward, and depressive symptoms. PMID- 22521467 TI - Fractal analysis of heterogeneous polymer networks formed by photopolymerization of dental dimethacrylates. AB - OBJECTIVES: In this work the influence of the dimethacrylate monomer chemical structure on structural heterogeneity and physico-mechanical properties of the resulting polymer networks was investigated. Rigid aromatic dimethacrylate (Bis GMA), triethylene glycol dimethacrylate (TEGDMA) and flexible aliphatic urethane dimethacrylate (UDMA) were chosen for room-temperature homopolymerizations and copolymerizations induced by camphorquinone/N,N-dimethylaminoethyl methacrylate photoinitiating system. METHODS: Atomic force microscopy (AFM) was used for visualizing the morphology of poly(dimethacrylate)s, which was described by: the fractal dimension (D(F)), the generalized fractal dimensions (D(q) and DeltaD) as well as the modified fractal dimension (D(beta)). Estimated fractal characteristics were correlated with polymer density, hardness and impact strength. RESULTS: AFM images of fractured surfaces revealed the highly complex morphology of dimethacrylate polymer networks. They were found to possess the fractal character. The fractal parameters were observed to be proportional to the density, hardness and impact resistance of investigated polymers. DeltaD appeared to be a good indicator of the structural heterogeneity of dimethacrylate networks. The results suggest that the fracture behavior of poly(dimethacrylate) matrix of dental materials can be controlled by the fractal morphology. SIGNIFICANCE: Correlating the morphological studies with the mechanical tests would be beneficial in defining the role of morphology in the mechanical behavior of dimethacrylate networks and consequently, lead to the development of a reliable method for identifying the cause of dental material failures under stress. Thus, fractal analysis could become one of the key elements in designing and developing dental materials. PMID- 22521466 TI - Creatine pretreatment protects cortical axons from energy depletion in vitro. AB - Creatine is a natural nitrogenous guanidino compound involved in bioenergy metabolism. Although creatine has been shown to protect neurons of the central nervous system (CNS) from experimental hypoxia/ischemia, it remains unclear if creatine may also protect CNS axons, and if the potential axonal protection depends on glial cells. To evaluate the direct impact of creatine on CNS axons, cortical axons were cultured in a separate compartment from their somas and proximal neurites using a modified two-compartment culture device. Axons in the axon compartment were subjected to acute energy depletion, an in vitro model of white matter ischemia, by exposure to 6mM sodium azide for 30 min in the absence of glucose and pyruvate. Energy depletion reduced axonal ATP by 65%, depolarized axonal resting potential, and damaged 75% of axons. Application of creatine (10 mM) to both compartments of the culture at 24h prior to energy depletion significantly reduced axonal damage by 50%. In line with the role of creatine in the bioenergy metabolism, this application also alleviated the axonal ATP loss and depolarization. Inhibition of axonal depolarization by blocking sodium influx with tetrodotoxin also effectively reduced the axonal damage caused by energy depletion. Further study revealed that the creatine effect was independent of glial cells, as axonal protection was sustained even when creatine was applied only to the axon compartment (free from somas and glial cells) for as little as 2h. In contrast, application of creatine after energy depletion did not protect axons. The data provide the first evidence that creatine pretreatment may directly protect CNS axons from energy deficiency. PMID- 22521468 TI - Effects of a customized biomechanical therapy on patients with medial compartment knee osteoarthritis. AB - OBJECTIVE: Previous studies have shown that a customized biomechanical therapy can improve symptoms of knee osteoarthritis. These studies were small and did not compare the improvements across gender, age, BMI or initial severity of knee osteoarthritis. The purpose of this study was to evaluate the effect of new biomechanical therapy on the pain, function and quality of life of patients with medial compartment knee osteoarthritis. METHODS: Six hundred and fifty-four patients with medial compartment knee osteoarthritis were examined before and after 12 weeks of a personalized biomechanical therapy (AposTherapy). Patients were evaluated using the Western Ontario and McMaster Osteoarthritis (WOMAC) Index and SF-36 Health Survey. RESULTS: After 12 weeks of treatment, the WOMAC pain and WOMAC-function subscales were significantly lower compared to baseline (both P<=0.001). All eight categories of the SF-36 health survey significantly improved after treatment (all P<=0.001). Females and younger patients showed greater improvements with therapy. CONCLUSIONS: Twelve weeks of a customized biomechanical therapy (AposTherapy) improved symptoms of patients with medial compartment knee osteoarthritis. We recommend that this therapy will be integrated in the management of knee osteoarthritis. PMID- 22521469 TI - Conjugated linoleic acid modulates immune responses in patients with mild to moderately active Crohn's disease. AB - BACKGROUND & AIMS: Conjugated linoleic acid (CLA) has demonstrated efficacy as an immune modulator and anti-inflammatory compound in mouse and pig models of colitis. We investigated the immunoregulatory efficacy of CLA in patients with mild to moderate Crohn's disease (CD). METHODS: Thirteen patients with mild to moderately active CD were enrolled in an open-label study of CLA (6 g/d orally) for 12 weeks. Peripheral blood was collected at baseline, 6 and 12 weeks after treatment initiation for isolation of peripheral blood mononuclear cells for functional analyses of lymphoproliferation and cytokine production. Disease activity was calculated using the CD activity index (CDAI) and quality of life was assessed using the Inflammatory Bowel Disease Questionnaire (IBDQ). RESULTS: CLA significantly suppressed the ability of peripheral blood CD4+ and CD8+ T cell subsets to produce IFN-gamma, TNF-alpha and IL-17 and lymphoproliferation at week 12. There was a statistically significant drop in CDAI from 245 to 187 (P = 0.013) and increase in IBDQ from 141 to 165 (P = 0.017) on week 12. CONCLUSION: Oral CLA administration was well tolerated and suppressed the ability of peripheral blood T cells to produce pro-inflammatory cytokines, decreased disease activity and increased the quality of life of patients with CD. PMID- 22521470 TI - The relationship between nutritional status of hip fracture operated elderly patients and their functioning, comorbidity and outcome. AB - BACKGROUND & AIMS: Malnutrition is common in hip fracture elderly patients. The purpose of this study was to examine the relationship between the Mini Nutrition Assessment Short Form (MNA-SF) and cognitive, functional status, comorbidity and outcome of operated patients. METHODS: Clinical data, MNA, functioning, cognition were prospectively determined. Retrospectively, the Charlson Comorbidity Index (CCI) and Cumulative Illness Rating Scale for Geriatrics (CIRS-G) were applied. RESULTS: The study consisted of 95 well-nourished (WN), 95 at risk of malnutrition (ARM) and 25 malnourished (MN) patients. More WN patients were independent vs. partially or fully dependent; more WN patients were cognitively normal vs. cognitively impaired (p < 0.001). CIRS-G was higher in MN vs. WN patients and CCI was higher in MN and ARM vs. WN patients (p < 0.001). During a 6 month period, 100 patients were readmitted, with less readmissions in the WN group (p = 0.024). During a 36 month follow-up, 79 patients died. The mortality rate was lower in the WN group (p = 0.01). Stepwise regression analysis found that the only independent variables for mortality were CCI and functioning (p < 0.01). CONCLUSIONS: Patients with higher cognitive and functional status were in superior nutritional condition. Poor nutritional status was associated with higher comorbidity indices, mortality and readmissions. However, we found that only comorbidity and low functioning can predict long-term mortality. PMID- 22521471 TI - Awareness is awareness is awareness? Decomposing different aspects of awareness and their role in operant learning of pain sensitivity. AB - Regarding awareness as a consistent concept has contributed to the controversy about implicit learning. The present study emphasized the importance of distinguishing aspects of awareness in order to determine whether learning is implicit. By decomposing awareness into awareness of contingencies, of the procedure being a learning task, and of the reinforcing stimuli, it was demonstrated that implicit operant learning modulated pain sensitivity. All of these aspects of awareness were demonstrated to not be necessary for learning. Additionally, discrimination of contingencies was not necessary on different levels of processing as demonstrated by a verbal and a behavioral method. It was demonstrated that explicit cognitive processes about one's own behavior, impaired learning, even though these cognitions were not immediately related to the learning process. The results of this study are of special interest in the context of pain, since implicit operant learning can explain the gradual development of hypersensitivity in chronic pain. PMID- 22521472 TI - Does self-efficacy mediate transfer effects in the learning of easy and difficult motor skills? AB - The effect of task difficulty on inter-task transfer is a classic issue in motor learning. We examined the relation between self-efficacy and transfer of learning after practicing different versions of a stick balancing task. Practicing the same task or an easier version led to significant pre- to post-test transfer of learning, whereas practicing a more difficult version did not. Self-efficacy increased modestly from pre- to post-test with easy practice, but decreased significantly with difficult practice. In addition, self-efficacy immediately prior to the post-test was significantly lower after difficult practice than easy or intermediate practice. Self-efficacy immediately prior to the post-test, performance at the end of practice, and pre-test performance explained 75% of the variance in post-test performance. The mediating role of self-efficacy on transfer of learning offers an alternative explanation for recent findings on the superiority of easy-to-difficult transfer and may help clarify inconsistencies in earlier research. PMID- 22521473 TI - Common and distinct mechanisms associated with view-specific and view-invariant recognition. PMID- 22521474 TI - Genuine and drug-induced synesthesia: a comparison. AB - Despite some principal similarities, there is no systematic comparison between the different types of synesthesia (genuine, acquired and drug-induced). This comprehensive review compares the three principal types of synesthesia and focuses on their phenomenological features and their relation to different etiological models. Implications of this comparison for the validity of the different etiological models are discussed. Comparison of the three forms of synesthesia show many more differences than similarities. This is in contrast to their representation in the literature, where they are discussed in many respects as being virtually similar. Noteworthy is the much broader spectrum and intensity with the typical drug-induced synesthesias compared to genuine and acquired synesthesias. A major implication of the phenomenological comparison in regard to the etiological models is that genuine and acquired synesthesias point to morphological substrates, while drug-induced synesthesia appears to be based on functional changes of brain activity. PMID- 22521475 TI - Ten ironic rules for non-statistical reviewers. AB - As an expert reviewer, it is sometimes necessary to ensure a paper is rejected. This can sometimes be achieved by highlighting improper statistical practice. This technical note provides guidance on how to critique the statistical analysis of neuroimaging studies to maximise the chance that the paper will be declined. We will review a series of critiques that can be applied universally to any neuroimaging paper and consider responses to potential rebuttals that reviewers might encounter from authors or editors. PMID- 22521476 TI - Neural processing of overt word generation in healthy individuals: the effect of age and word knowledge. AB - Verbal fluency is a classical and widely used neuropsychological instrument to assess cognitive abilities. Results of previous studies indicate an influence on verbal fluency performance of both, age and word knowledge. So far, no imaging study has investigated the neural mechanisms underlying an age and word knowledge related decline on the quantitative verbal output in a highly demanding overt and continuous semantic fluency task. Fifty healthy volunteers (age 22-56 years, verbal IQ 95-143) overtly and continuously articulated words in response to ten visually presented semantic categories while BOLD signal was measured with fMRI. Verbal responses were recorded with an MRI compatible microphone and transcribed after the scanning session. The number of produced words as well as age, word knowledge and level of education was implemented in the design matrix enabling a separate analysis of these factors on both, neural responses and behavioral differences. There was a significant correlation of level of education and number of generated words, but no significant correlations of generated words and age or word knowledge were observed. On the neural level, a widespread network was found for the word production task as contrasted with the resting condition, encompassing the bilateral superior temporal gyri, the cerebellum and the SMA. An age related positive correlation was found in the bilateral inferior and middle frontal gyri, the anterior cingulate gyrus, the left precentral gyrus and the right insula. A lower word knowledge resulted in enhanced BOLD responses in the right superior temporal gyrus and the left superior frontal gyrus. Results are interpreted in terms of compensation mechanisms countervailing potential age and word knowledge related effects. PMID- 22521477 TI - Hundreds of brain maps in one atlas: registering coordinate-independent primate neuro-anatomical data to a standard brain. AB - Non-invasive measuring methods such as EEG/MEG, fMRI and DTI are increasingly utilised to extract quantitative information on functional and anatomical connectivity in the human brain. These methods typically register their data in Euclidean space, so that one can refer to a particular activity pattern by specifying its spatial coordinates. Since each of these methods has limited resolution in either the time or spatial domain, incorporating additional data, such as those obtained from invasive animal studies, would be highly beneficial to link structure and function. Here we describe an approach to spatially register all cortical brain regions from the macaque structural connectivity database CoCoMac, which contains the combined tracing study results from 459 publications (http://cocomac.g-node.org). Brain regions from 9 different brain maps were directly mapped to a standard macaque cortex using the tool Caret (Van Essen and Dierker, 2007). The remaining regions in the CoCoMac database were semantically linked to these 9 maps using previously developed algebraic and machine-learning techniques (Bezgin et al., 2008; Stephan et al., 2000). We analysed neural connectivity using several graph-theoretical measures to capture global properties of the derived network, and found that Markov Centrality provides the most direct link between structure and function. With this registration approach, users can query the CoCoMac database by specifying spatial coordinates. Availability of deformation tools and homology evidence then allow one to directly attribute detailed anatomical animal data to human experimental results. PMID- 22521478 TI - Automatic sulcal line extraction on cortical surfaces using geodesic path density maps. AB - We present here a method that is designed to automatically extract sulcal lines on the mesh of any cortical surface. The method is based on the definition of a new function, the Geodesic Path Density Map (GPDM), within each sulcal basin (i.e. regions with a negative mean curvature). GPDM indicates at each vertex the likelihood that a shortest path between any two points of the basins boundary goes through that vertex. If the distance used to compute shortest path is anisotropic and constrained by a geometric information such as the depth, the GPDM indicates the likelihood that a vertex belongs to the sulcal line in the basin. An automatic GPDM adaptive thresholding procedure is proposed and sulcal lines are then defined. The process has been validated on a set of 25 subjects by comparing results to the manual segmentation from an expert and showed an average error below 2mm. It is also compared to our previous reference method in the context of inter-subject cortical surface registration and shows an significant improvement in performance. PMID- 22521479 TI - The cortical representation of simple mathematical expressions. AB - Written mathematical notation conveys, in a compact visual form, the nested functional relations among abstract concepts such as operators, numbers or sets. Is the comprehension of mathematical expressions derived from the human capacity for processing the recursive structure of language? Or does algebraic processing rely only on a language-independent network, jointly involving the visual system for parsing the string of mathematical symbols and the intraparietal system for representing numbers and operators? We tested these competing hypotheses by scanning mathematically trained adults while they viewed simple strings ranging from randomly arranged characters to mathematical expressions with up to three levels of nested parentheses. Syntactic effects were observed in behavior and in brain activation measured with functional magnetic resonance imaging (fMRI) and magneto-encephalography (MEG). Bilateral occipito-temporal cortices and right parietal and precentral cortices appeared as the primary nodes for mathematical syntax. MEG estimated that a mathematical expression could be parsed by posterior visual regions in less than 180 ms. Nevertheless, a small increase in activation with increasing expression complexity was observed in linguistic regions of interest, including the left inferior frontal gyrus and the posterior superior temporal sulcus. We suggest that mathematical syntax, although arising historically from language competence, becomes "compiled" into visuo-spatial areas in well-trained mathematics students. PMID- 22521480 TI - Meta-analytic clustering of the insular cortex: characterizing the meta-analytic connectivity of the insula when involved in active tasks. AB - The human insula has been parcellated on the basis of resting state functional connectivity and diffusion tensor imaging. Little is known about the organization of the insula when involved in active tasks. We explored this issue using a novel meta-analytic clustering approach. We queried the BrainMap database asking for papers involving normal subjects that recorded activations in the insular cortex, retrieving 1305 papers, involving 22,872 subjects and a total of 2957 foci. Data were analyzed with several different methodologies, some of which expressly designed for this work. We used meta-analytic connectivity modeling and meta analytic clustering of data obtained from the BrainMap database. We performed cluster analysis to subdivide the insula in areas with homogeneous connectivity, and density analysis of the activated foci using Voronoi tessellation. Our results confirm and extend previous findings obtained investigating the resting state connectivity of the anterior-posterior and left-right insulae. They indicate, for the first time, that some blocks of the anterior insula play the role of hubs between the anterior and the posterior insulae, as confirmed by their activation in several different paradigms. This finding supports the view that the network to which the anterior insula belongs is related to saliency detection. The insulae of both sides can be parcellated in two clusters, the anterior and the posterior: the anterior is characterized by an attentional pattern of connectivity with frontal, cingulate, parietal, cerebellar and anterior insular highly connected areas, whereas the posterior is characterized by a more local connectivity pattern with connections to sensorimotor, temporal and posterior cingulate areas. This antero-posterior subdivision, better characterized on the right side, results sharper with the connectivity based clusterization than with the behavioral based clusterization. The circuits belonging to the anterior insula are very homogeneous and their blocks in multidimensional scaling of MACM-based profiles are in central position, whereas those belonging to the posterior insula, especially on the left, are located at the periphery and sparse, thus suggesting that the posterior circuits bear a more heterogeneous connectivity. The anterior cluster is mostly activated by cognition, whereas the posterior is mostly activated by interoception, perception and emotion. PMID- 22521481 TI - Oxidative stress and adult neurogenesis--effects of radiation and superoxide dismutase deficiency. AB - Hippocampus plays an important role in learning and memory and in spatial navigation. Production of new neurons that are functionally integrated into the hippocampal neuronal network is important for the maintenance of functional plasticity. In adults, production of new neurons in the hippocampus takes place in the subgranular zone (SGZ) of dentate gyrus. Neural progenitor/stem cells go through processes of proliferation, differentiation, migration, and maturation. This process is exquisitely sensitive to oxidative stress, and perturbation in the redox balance in the neurogenic microenvironment can lead to reduced neurogenesis. Cranial irradiation is an effective treatment for primary and secondary brain tumors. However, even low doses of irradiation can lead to persistent elevation of oxidative stress and sustained suppression of hippocampal neurogenesis. Superoxide dismutases (SODs) are major antioxidant enzymes for the removal of superoxide radicals in different subcellular compartments. To identify the subcellular location where reactive oxygen species (ROS) are continuously generated after cranial irradiation, different SOD deficient mice have been used to determine the effects of irradiation on hippocampal neurogenesis. The study results suggest that, regardless of the subcellular location, SOD deficiency leads to a significant reduction in the production of new neurons in the SGZ of hippocampal dentate gyrus. In exchange, the generation of new glial cells was significantly increased. The SOD deficient condition, however, altered the tissue response to irradiation, and SOD deficient mice were able to maintain a similar level of neurogenesis after irradiation while wild type mice showed a significant reduction in the production of new neurons. PMID- 22521483 TI - Long-term follow-up after percutaneous treatment of the unprotected left main stenosis in high risk patients not suitable for bypass surgery. AB - INTRODUCTION AND OBJECTIVES: Percutaneous coronary intervention is recommended in patients with unprotected left main stenosis non suitable for coronary artery bypass graft. Long-term follow-up of those patients remains uncertain. METHODS: All patients with de novo unprotected left main stenosis treated with stent implantation were consecutively enrolled. Percutaneous coronary intervention was indicated according to the standards of care, taking into account clinical and anatomical conditions unfavorable for coronary artery bypass graft. The primary end point was the occurrence of major adverse cardiac events, a composite of death, nonfatal acute myocardial infarction, or target lesion revascularization. RESULTS: Of 226 consecutive patients included, 202 (89.4%) were treated with drug eluting stents. Mean age was 72.1 years, 41.1% had renal dysfunction, and mean Syntax score and EuroSCORE were 28.9 and 7.4, respectively. Angiographic and procedural success was achieved in 99.6% and 92.9% of patients. At 3 years, the rates of major adverse cardiac events, death, nonfatal acute myocardial infarction and target lesion revascularization were 36.2%, 25.2%, 8.4%, 8.0%, respectively. Target lesion revascularization was more frequently observed when >= 2 stents were implanted rather than a single stent (18.5% vs 5.8%, P=.03); and with bare metal stents rather than drug-eluting stents (13.0% vs 7.9%, P=.24). Definite stent thrombosis was observed in 2 patients (0.9%) and probable stent thrombosis in 7 (3.1%). Female sex, impaired left ventricular function, and use of bare metal stents were significantly related with all-cause mortality. CONCLUSIONS: High-risk patients with unprotected left main stenosis treated with percutaneous coronary intervention presented with a high rate of major adverse cardiac events at long-term follow-up. Female sex, impaired left ventricular function, and use of bare metal stents were predictors of poor prognosis. PMID- 22521484 TI - How to assess the nonresponder to cardiac resynchronization therapy-a comprehensive stepwise approach. PMID- 22521482 TI - Age-related decline in mitochondrial bioenergetics: does supercomplex destabilization determine lower oxidative capacity and higher superoxide production? AB - Mitochondrial decay plays a central role in the aging process. Although certainly multifactorial in nature, defective operation of the electron transport chain (ETC) constitutes a key mechanism involved in the age-associated loss of mitochondrial energy metabolism. Primarily, mitochondrial dysfunction affects the aging animal by limiting bioenergetic reserve capacity and/or increasing oxidative stress via enhanced electron leakage from the ETC. Even though the important aging characteristics of mitochondrial decay are known, the molecular events underlying inefficient electron flux that ultimately leads to higher superoxide appearance and impaired respiration are not completely understood. This review focuses on the potential role(s) that age-associated destabilization of the macromolecular organization of the ETC (i.e. supercomplexes) may be important for development of the mitochondrial aging phenotype, particularly in post-mitotic tissues. PMID- 22521485 TI - Physiological effects following administration of Citrus aurantium for 28 days in rats. AB - BACKGROUND: Since ephedra-containing dietary supplements were banned from the US market, manufacturers changed their formulations by eliminating ephedra and replacing with other botanicals, including Citrus aurantium, or bitter orange. Bitter orange contains, among other compounds, synephrine, a chemical that is chemically similar to ephedrine. Since ephedrine may have cardiovascular effects, the goal of this study was to investigate the cardiovascular effects of various doses of bitter orange extract and pure synephrine in rats. METHOD: Female Sprague-Dawley rats were dosed daily by gavage for 28 days with synephrine from two different extracts. One extract contained 6% synephrine, and the other extract contained 95% synephrine. Doses were 10 or 50mg synephrine/kg body weight from each extract. Additionally, caffeine was added to these doses, since many dietary supplements also contain caffeine. Telemetry was utilized to monitor heart rate, blood pressure, body temperature and QT interval in all rats. RESULTS AND CONCLUSION: Synephrine, either as the bitter orange extract or as pure synephrine, increased heart rate and blood pressure. Animals treated with 95% synephrine showed minimal effects on heart rate and blood pressure; more significant effects were observed with the bitter orange extract suggesting that other components in the botanical can alter these physiological parameters. The increases in heart rate and blood pressure were more pronounced when caffeine was added. None of the treatments affected uncorrected QT interval in the absence of caffeine. PMID- 22521487 TI - Gadolinium loaded nanoparticles in theranostic magnetic resonance imaging. AB - Theranostic magnetic resonance imaging (MRI) is now receiving a growing interest in imaging-guided drug delivery, monitoring the treatment and personalized administration etc. Theranostic agents are essential for the usage of theranostic MRI. Among different kinds of theranostic agents, gadolinium loaded nanoparticles (GdNPs) are one of the most promising theranostic agents which are very promising in combination of diagnostics (molecular imaging) and therapeutics (molecular therapy) functions in a single platform. In this review, we provided fully discussion on the design considerations of GdNPs as a platform for theranostic MRI. The mainly factors that affect the preparation process, such as GdNP materials, the loading of Gd/drugs in GdNPs, and the passive and active targeting strategies were discussed. Major classes of GdNPs including lipid-based nanoparticles, polymeric nanoparticles, micelles, dendrimers and Gd-silica nanoparticles were described in detail. The use of GdNPs as theranostic agents offers potential advantages that change the usual cancer therapy from separating diagnosis and treatment to theranostic approach. PMID- 22521486 TI - Rat liver mitochondrial damage under acute or chronic carbon tetrachloride induced intoxication: protection by melatonin and cranberry flavonoids. AB - In current societies, the risk of toxic liver damage has markedly increased. The aim of the present work was to carry out further research into the mechanism(s) of liver mitochondrial damage induced by acute (0.8 g/kg body weight, single injection) or chronic (1.6g/ kg body weight, 30 days, biweekly injections) carbon tetrachloride - induced intoxication and to evaluate the hepatoprotective potential of the antioxidant, melatonin, as well as succinate and cranberry flavonoids in rats. Acute intoxication resulted in considerable impairment of mitochondrial respiratory parameters in the liver. The activity of mitochondrial succinate dehydrogenase (complex II) decreased (by 25%, p<0.05). Short-term melatonin treatment (10 mg/kg, three times) of rats did not reduce the degree of toxic mitochondrial dysfunction but decreased the enhanced NO production. After 30-day chronic intoxication, no significant change in the respiratory activity of liver mitochondria was observed, despite marked changes in the redox-balance of mitochondria. The activities of the mitochondrial enzymes, succinate dehydrogenase and glutathione peroxidase, as well as that of cytoplasmic catalase in liver cells were inhibited significantly. Mitochondria isolated from the livers of the rats chronically treated with CCl4 displayed obvious irreversible impairments. Long-term melatonin administration (10 mg/kg, 30 days, daily) to chronically intoxicated rats diminished the toxic effects of CCl4, reducing elevated plasma activities of alanine aminotransferase and aspartate aminotransferase and bilirubin concentration, prevented accumulation of membrane lipid peroxidation products in rat liver and resulted in apparent preservation of the mitochondrial ultrastructure. The treatment of the animals by the complex of melatonin (10 mg/kg) plus succinate (50 mg/kg) plus cranberry flavonoids (7 mg/kg) was even more effective in prevention of toxic liver injury and liver mitochondria damage. PMID- 22521488 TI - Pharmacokinetics of a paclitaxel-loaded low molecular weight heparin-all-trans retinoid acid conjugate ternary nanoparticulate drug delivery system. AB - Amphiphilic low molecular weight heparin-all-trans-retinoid acid (LHR) conjugate, as a drug carrier for cancer therapy, was found to have markedly low toxicity and to form self-assembled nanoparticles for simultaneous delivery of paclitaxel (PTX) and all-trans-retinoid acid (ATRA) in our previous study. In the present study, PTX-loaded LHR nanoparticles were prepared and demonstrated a spherical shape with particle size of 108.9 nm. Cellular uptake analysis suggested rapid internalization and nuclear transport of LHR nanoparticles. In order to investigate the dynamic behaviors and targeting ability of LHR nanoparticles on tumor-bearing mice, near-infrared fluorescent (NIFR) dye DiR was encapsulated into the nanoparticles for ex vivo optical imaging. The results indicated that LHR nanoparticles could enhance the targeting and residence time in tumor site. Furthermore, in vivo biodistribution study also showed that the area under the plasma concentration time curve (AUC (0->inf)) values of PTX and ATRA for PTX loaded LHR nanoparticles in tumor were 1.56 and 1.62-fold higher than those for PTX plus ATRA solution. Finally, PTX-loaded LHR nanoparticles demonstrated greater tumor growth inhibition effect in vivo without unexpected side effects, compared to PTX solution and PTX plus ATRA solution. These results suggest that PTX-loaded LHR nanoparticles can be considered as promising targeted delivery system for combination cancer chemotherapy to improve therapeutic efficacy and minimize adverse effects. PMID- 22521489 TI - Engineering of fibrillar decorin matrices for a tissue-engineered trachea. AB - Decorin is a structural and functional proteoglycan (PG) residing in the complex network of extracellular matrix (ECM) proteins in many connective tissues. Depending on the protein core and the glycosaminoglycan chain, PGs support cell adhesion, migration, proliferation, differentiation, ECM assembly and growth factor binding. For applications in tissue engineering, it is crucial to develop reliable, ECM-mimicking biomaterials. Electrospinning is a suitable method for creating three-dimensional (3D), fibrillar scaffolds. While there are numerous reports on the electrospinning of proteins including collagen, to date, there are no reports on the electrospinning of PGs. In the following study, we used electrospinning to generate decorin-containing matrices for tracheal tissue engineering applications. The electrospun scaffolds were analyzed using scanning electron microscopy, atomic force microscopy, contact angle measurements and dynamic mechanical analysis. Additionally, we confirmed PG functionality with immunostaining and 1,9-dimethylmethylene blue. To determine cell-matrix interactions, tracheal cells (hPAECs) were seeded and analyzed using an FOXJ1 antibody. Moreover, interactions of the electrospun scaffolds with immune mediated mechanisms were analyzed in detail. To conclude, we demonstrated the feasibility of electrospinning of decorin to generate functional 3D scaffolds with low immunogenicity for hPAEC expansion. Our data suggest that these hybrid materials may be suitable as a substrate for tracheal tissue engineering. PMID- 22521490 TI - Polyethylene glycol-based protein nanocapsules for functional delivery of a differentiation transcription factor. AB - Transcription factors (TFs) can direct cell fate by binding to DNA and regulating gene transcription. Controlling the intracellular levels of specific TFs can therefore enable reprogramming of cellular function and differentiation. Direct delivery of recombinant TFs to target cells can thus have widespread therapeutic value, but has remained challenging due to structural fragility of TFs and inefficient membrane transduction. Here we describe the functional delivery of TFs using degradable polymeric nanocapsules to drive cellular differentiation. The nanocapsules were synthesized with poly(ethylene) glycol (PEG)-based monomers and intracellularly-degradable crosslinkers. Physical properties and release kinetics of the nanocapsules were optimized through tuning of monomer and crosslinker ratios to achieve enhanced delivery of cargo destined for the nuclei. The nanocapsules did not display cytotoxicity in primary cell lines up to concentrations of 5 MUm. A recombinant myogenic transcription factor, MyoD, was delivered to the nuclei of myoblast cells using degradable nanocapsules to induce myogenic differentiation. MyoD was confirmed to be delivered to the nuclei of myoblasts using confocal microscopy and was demonstrated to be active in transcription through a luciferase-based reporter assay. More importantly, delivered MyoD was able to drive myoblast differentiation as evidenced by the hallmark elongated and multinuclear morphology of myotubes. The activation of downstream cascade was also confirmed through immunostaining of late myogenic markers myogenin and My-HC. The efficiency of differentiation achieved via nanocapsule delivery is significantly higher than that of native MyoD, and is comparable to that of plasmid transfection. The encapsulated MyoD can also withstand prolonged protease treatment and remain functional. The ease of preparation, biocompatibility and effective cargo delivery make the polymeric nanocapsule a useful tool to deliver a variety of recombinant TFs for therapeutic uses. PMID- 22521493 TI - Hypokalemic paralysis in a young obese female. AB - BACKGROUND: Profound hypokalemia with paralysis usually poses a diagnostic and therapeutic challenge. METHODS: We report on a 28-y-old obese Chinese female presenting with sudden onset of flaccid quadriparesis upon awaking in the morning. There is no family history of hyperthyroidism. She experienced body weight loss of 7 kg in 2 months. RESULTS: The most conspicuous blood biochemistry is marked hypokalemia (1.8 mmol/l) and hypophosphatemia (0.5 mmol/l) associated with low urine K(+) and phosphate excretion. Surreptitious laxatives and/or diuretics abuse-related hypokalemic paralysis were tentatively made. However, her relatively normal blood acid-base status and the absence of low urine Na(+) and/or Cl(-) excretion made these diagnoses unlikely. Furthermore, she developed rebound hyperkalemia (5.7 mmol/l) after only 80 mmol K(+) supplementation. Thyroid function test confirmed hyperthyroidism due to Graves' disease. Control of the hyperthyroidism completely abolished her periodic paralysis. CONCLUSIONS: Thyrotoxic periodic paralysis (TPP) should be kept in mind as a cause of paralysis in female, even with obesity, despite its predominance in adult males. PMID- 22521492 TI - Evaluation of a novel, commercially available mass spectrometry kit for newborn screening including succinylacetone without hydrazine. AB - Newborn screening for tyrosinemia type I (Tyr-I) is mandatory to identify infants at risk before life-threatening symptoms occur. The analysis of tyrosine alone is limited, and might lead to false-negative results. Consequently, the analysis of succinylacetone (SUAC) is needed. Current protocols are time-consuming, and above all, include hazardous reagents such hydrazine. We evaluated a novel, commercial kit to analyze amino acids, acylcarnitines and SUAC with a significantly less harmful hydrazine derivative in a newborn screening laboratory. Dried blood spot specimens from 4683 newborns and samples from known patients with inborn errors of metabolism (IEM) were analyzed by a novel protocol and compared to an in-house screening assay. All samples were derivatized with butanol-HCl after extraction from 1/8-inch DBS punches. For the novel protocol, the residual blood spots were extracted separately for SUAC, converted into hydrazone, combined with amino acids and acylcarnitines, and subsequently analyzed by mass spectrometry using internal isotope-labeled standards. All newborns were successfully tested, and 74 patients with IEMs including three with Tyr-I (SUAC 1.50, 4.80 and 6.49; tyrosine levels 93.10, 172.40 and 317.73, respectively) were detected accurately. The mean SUAC level in non-affected newborns was 0.68 MUmol/l (cut-off 1.29 MUmol/l). The novel assay was demonstrated to be accurate in the detection of newborns with IEM, robust, and above all, without the risk of the exposure to highly toxic reagents and requirement of additional equipment for toxic fume evacuation. PMID- 22521494 TI - Psychosis and suicide risk by ethnic origin and history of migration in the Netherlands. AB - BACKGROUND: There is an increased incidence of non-affective psychotic disorders (NAPD) among first- and second-generation migrants in Europe. The purpose of this population-based study was to compare the risk of suicide in Dutch natives and immigrants with or without NAPD. METHODS: Cases of NAPD (n=12 580) from three Dutch psychiatric registers were linked to the cause of death register of Statistics Netherlands and were compared to matched controls (n=244 792) from the population register, who had no such diagnosis. Hazard ratios (HRs) of suicide were estimated and adjusted for age and gender by Cox regression analysis. RESULTS: The presence of NAPD was strongly associated with suicide risk in each ethnic group. However, for all ethnic minority groups the HRs were somewhat lower than among Dutch natives, for whom the HR was 23.4 (95%-CI; 18.5-29.7). A closer examination revealed that suicide risk was influenced by the history of migration. While the risk for immigrants of the first generation, diagnosed with NAPD, was significantly lower than that for native Dutch patients (HR=0.45; 95% CI: 0.28-0.73), the risk for those of the second generation was more similar to that for the Dutch (HR=0.85; 95%-CI: 0.51-1.40) (P value of history of migration=0.005). CONCLUSION: Immigrants diagnosed with NAPD of the first generation appear to be protected against suicide, whereas this protection is waning among those of the second generation. This is the first study worldwide on suicide in migrants with NAPD and the first study of suicide in patients with NAPD in the Netherlands. PMID- 22521491 TI - Engineering microscale topographies to control the cell-substrate interface. AB - Cells in their in vivo microenvironment constantly encounter and respond to a multitude of signals. While the role of biochemical signals has long been appreciated, the importance of biophysical signals has only recently been investigated. Biophysical cues are presented in different forms including topography and mechanical stiffness imparted by the extracellular matrix and adjoining cells. Microfabrication technologies have allowed for the generation of biomaterials with microscale topographies to study the effect of biophysical cues on cellular function at the cell-substrate interface. Topographies of different geometries and with varying microscale dimensions have been used to better understand cell adhesion, migration, and differentiation at the cellular and sub cellular scales. Furthermore, quantification of cell-generated forces has been illustrated with micropillar topographies to shed light on the process of mechanotransduction. In this review, we highlight recent advances made in these areas and how they have been utilized for neural, cardiac, and musculoskeletal tissue engineering application. PMID- 22521495 TI - Analysis of OPCRIT results indicate the presence of a novel 'social functioning' domain and complex structure of other dimensions in the Wielkopolska (Poland) population. AB - OBJECTIVE: The main goal of our study was to examine factor structure of schizophrenia and bipolar affective disorder in the Wielkopolska population, using dimension reduction techniques. METHODS: Schizophrenia (n=443) and bipolar affective disorder (n=499) patients were assessed using Operational Criteria Checklist (OPCRIT). Principal component analysis and Maximum Likelihood Factor analysis were carried out to obtain factor structure with significance level for the factor loadings exceeding 0.4. Varimax and promax rotations were used to identify the meaningful factors. RESULTS: Rotated solution indicated multidimensional structure for depression and excitement as well as positive domains in the schizophrenia sample. Negative and disorganized dimensions existed as single factors, with item composition similar to that already described. Additionally, a new "social functioning" dimension was identified. In bipolar affective disorder sample, the interpretable dimensions included: depression, psychotic, atypical depression, negative, substance use, excitement and "social functioning". Factor structure of the combined sample consisted of depression, excitement, disorganization, delusions, substance use, negative and social functioning factors. CONCLUSIONS: Our results indicated multidimensional and hierarchical structures for some of the previously described dimensions. Additional use of items not exactly related to disease symptoms lead to discovery of "substance use" and "social functioning" dimensions. PMID- 22521496 TI - Myocardial viability imaging: does it still have a role in patient selection prior to coronary revascularisation? AB - Patients with severe left ventricular (LV) dysfunction and multi-vessel coronary artery disease (CAD) are at high risk during revascularisation, however they are also likely to derive the most benefit. Historically, the detection of dysfunctional but potentially viable myocardium ('stunned or hibernating myocardium') has been central to the decision-making regarding revascularisation. A number of recent studies have challenged this paradigm, questioning the role of viability testing in this population. In this review, we will examine the position of viability testing and how it is best incorporated in the modern era of coronary revascularisation. We will outline the role of currently available imaging modalities in viability assessment. Myocardial viability testing will continue to play a role in revascularisation decisions, although larger randomised trials with clinical outcome end-points are needed to further define its role. PMID- 22521497 TI - The effect of the internet on teen and young adult tobacco use: a literature review. AB - Research has shown that a positive association exists between exposure to smoking imagery, such as that found in movies and print advertising, and the subsequent uptake of cigarette smoking. Children appear to be especially vulnerable to advertising messaging and other positive portrayals of smoking, given that most adult smokers develop the habit before age 18 years. Although many traditional types of media have been studied, the current generation of youth is growing up as digital natives, with young people increasingly using the Internet for entertainment and to obtain information. Currently the Internet is an essentially unregulated marketplace of ideas and images. However, the effect of the Internet on teen smoking initiation has received little attention in studies. In this literature review, we summarize and critique the existing work, identify current knowledge gaps, and offer suggestions to health care providers about how to address this issue. PMID- 22521498 TI - [Early-onset leg ulcers: superficial venous insufficiency may not be enough]. PMID- 22521500 TI - The effects of diazepam on the behavioral structure of the rat's response to pain in the hot-plate test: anxiolysis vs. pain modulation. AB - The aim of the present study was to evaluate, by means of quantitative and multivariate analyses, the effects of diazepam on the behavioral structure of the rat's response to pain in the hot-plate test as well as whether such changes are associated with drug-induced effects on anxiety and/or nociception. To this purpose, ten groups of male Wistar rats were intraperitoneally injected with saline, diazepam (0.25, 0.5 and 2 mg/kg), FG-7142 (1, 4 and 8 mg/kg) or morphine (3, 6 and 12 mg/kg). The mean number and mean latency to first appearance were calculated for each behavioral component. In addition, multivariate cluster and adjusted residual analyses based on the elaboration of transition matrices were performed. Three main behavioral categories were identified: exploratory (walking, sniffing), primary noxious-evoked (hind paw licking, front paw licking, shaking/stamping) and escape (climbing, jumping). Although no significant modifications in the latencies of the primary noxious-evoked components were induced by treatment with diazepam or FG-7142, significant effects were provoked by morphine treatment. Multivariate analyses showed that diazepam-induced anxiolysis redirected the rat's behavior toward a more purposeful and effective escape strategy. In contrast, the high level of anxiety induced by FG-7142 caused the behavioral structure to become disorganized and not purposefully oriented. Changes in the organization of behavioral components were observed in morphine treated animals and mainly consisted of modifications in the primary noxious evoked and escape components. The findings suggest that the effects of diazepam on the structure of the rat's response to pain in the hot-plate test are more likely attributable to anxiolysis than pain modulation. PMID- 22521501 TI - A review of phytotherapy of acne vulgaris: perspective of new pharmacological treatments. AB - AIM: This review focuses on plants currently used and those with a high potency for the future development of anti-acne products. METHODS: All relevant literature databases were searched up to 25 March 2011. The search terms were plant, herb, herbal therapy, phytotherapy, and acne, acne vulgaris and anti-acne. All of the human, animal, and in vitro studies, and reviews were included. Anti bacterial, anti-inflammatory, anti-oxidant, and anti-androgen effects were the key outcomes. RESULTS: Studies on cell lines revealed that flavonoid, alkaloid, essential oil, phenol and phenolic compound, tannin, xanthone and xanthone derivative, and the bisnaphthquione derivative are effective in treatment of acne. Animal studies showed that diterpene acid, phenylpropanoid glycosides, acteoside and flavonoids have anti-inflammatory activity. Eleven human studies revealed that Camellia sinensis has 5alpha-reductase inhibitory and anti inflammatory activities. Also anti-bacterial effect was shown by oleoresin of Commiphora mukul. CONCLUSION: In addition to the standardization of these herbs, screening herbs as anti-acne agents may help to find new sources of therapy for acne. PMID- 22521502 TI - Clinical target volumes in anal cancer: calculating what dose was likely to have been delivered in the UK ACT II trial protocol. AB - PURPOSE: Preliminary results of the UK Anal Cancer Trial (ACT) II trial in squamous cell carcinoma of the anus (SCCA) are promising, but 2-D planning with parallel-opposed fields provoked significant toxicity. We calculated likely doses delivered in the ACT II protocol to the planning target volume (PTV), nodal clinical target volumes (n-CTV) and organs at risk (OARs). METHODS AND MATERIALS: Original planning CT datasets of 33 consecutive patients with SCCA, included in the ACT II trial or treated to an identical protocol, enabled dose to the primary tumour, involved nodal PTV's, uninvolved nodal CTVs (inguino-femoral and pelvic lymph nodes) and femoral heads to be retrospectively calculated. RESULTS: The mean dose delivered to primary PTV was 51.37+/-1.68 Gy (95% CI), with a maximum dose (D(max)) of 54.63+/-2.68 Gy (95% CI). Involved inguinal nodes received a mean 51.41+/-3.08 Gy, D(max) 54.17+/-2.84 Gy (95% CI). Clinically uninvolved nCTVs received a mean 36.53+/-3.38 Gy (inguinal nodes) and 34.15+/-5.59 Gy (external/internal iliac nodes). Femoral heads received a D(max) of 47.32+/-3.45 (95% CI). CONCLUSION: Calculating the likely doses delivered in ACT II from chemoradiation to PTV, n-CTV and OARs facilitates specification of nodal doses and constraints for 3D-conformal/IMRT planning and allows rational dose escalation for T3/T4 tumours, and potential dose-reduction for T1/T2 tumours. PMID- 22521499 TI - Modulation of pyramidal cell output in the medial prefrontal cortex by mGluR5 interacting with CB1. AB - The medial prefrontal cortex (mPFC) serves executive cognitive functions such as decision-making that are impaired in neuropsychiatric disorders and pain. We showed previously that amygdala-driven abnormal inhibition and decreased output of mPFC pyramidal cells contribute to pain-related impaired decision-making (Ji et al., 2010). Therefore, modulating pyramidal output is desirable therapeutic goal. Targeting metabotropic glutamate receptor subtype mGluR5 has emerged as a cognitive-enhancing strategy in neuropsychiatric disorders, but synaptic and cellular actions of mGluR5 in the mPFC remain to be determined. The present study determined synaptic and cellular actions of mGluR5 to test the hypothesis that increasing mGluR5 function can enhance pyramidal cell output. Whole-cell voltage- and current-clamp recordings were made from visually identified pyramidal neurons in layer V of the mPFC in rat brain slices. Both the prototypical mGluR5 agonist CHPG and a positive allosteric modulator (PAM) for mGluR5 (VU0360172) increased synaptically evoked spiking (E-S coupling) in mPFC pyramidal cells. The facilitatory effects of CHPG and VU0360172 were inhibited by an mGluR5 antagonist (MTEP). CHPG, but not VU0360172, increased neuronal excitability (frequency current [F-I] function). VU0360172, but not CHPG, increased evoked excitatory synaptic currents (EPSCs) and amplitude, but not frequency, of miniature EPSCs, indicating a postsynaptic action. VU0360172, but not CHPG, decreased evoked inhibitory synaptic currents (IPSCs) through an action that involved cannabinoid receptor CB1, because a CB1 receptor antagonist (AM281) blocked the inhibitory effect of VU0360172 on synaptic inhibition. VU0360172 also increased and prolonged CB1-mediated depolarization-induced suppression of synaptic inhibition (DSI). Activation of CB1 with ACEA decreased inhibitory transmission through a presynaptic mechanism. The results show that increasing mGluR5 function enhances mPFC output. This effect can be accomplished by increasing excitability with an orthosteric agonist (CHPG) or by increasing excitatory synaptic drive and CB1 mediated presynaptic suppression of synaptic inhibition ("dis-inhibition") with a PAM (VU0360172). Therefore, mGluR5 may be a useful target in conditions of impaired mPFC output. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. PMID- 22521503 TI - The role of microRNAs in synaptic plasticity, major affective disorders and suicidal behavior. AB - Major affective disorders are common widespread conditions associated with multiple psychosocial impairments and suicidal risk in the general population. At least 3-4% of all depressive individuals die by suicide. At a molecular level, affective disorders and suicidal behavior are recently associated with disturbances in structural and synaptic plasticity. A recent hypothesis suggested that small non-coding RNAs (ncRNAs), in particular microRNAs (miRNAs), play a critical role in the translational regulation at the synapse. We performed a selective overview of the current literature on miRNAs putative subcellular localization and sites of action in mature neurons analyzing their role in neurogenesis, synaptic plasticity, pathological stress changes, major affective disorders and suicidal behavior. miRNAs have played a fundamental role in the evolution of brain functions. The perturbation of some intracellular mechanisms as well as impaired assembly, localization, and translational regulation of specific RNA binding proteins may affect learning and memory, presumably contributing to the pathogenesis of major affective disorders and perhaps suicidal behavior. Also, miRNA dys-regulation has also been linked to several neuropsychiatric diseases. However, further evidence are needed in order to directly clarify the role of miRNAs in major affective disorders and suicidal behavior. PMID- 22521504 TI - Pilot study of denileukin diftitox alternate dosing regimen in patients with cutaneous peripheral T-cell lymphomas. AB - Better treatment and survival outcomes are needed for the rare primary cutaneous peripheral T-cell lymphomas.Five (62.5%) of 8 patients with peripheral T-cell lymphomas enrolled in a pilot study of denileukin diftitoxat 18 MUg/kg per day for 5 days followed by once weekly for 24 weeks responded, including 2 complete responses, one of which is ongoing at 8 years. PURPOSE: To evaluate the safety and efficacy of an alternate dosing regimen in rare primary cutaneous peripheral T-cell lymphoma variants. METHODS: This is a prospective, single center, pilot study of denileukin diftitox (Dd) in patients with persistent or recurrent cutaneous peripheral T-cell lymphomas and mycosis fungoides (MF) variants, excluding Sezary syndrome (SS). Dd was administered at 18 MUg/kg per day for 5 days and once weekly for 24 weeks, with response by modified skin weighed assessment tool. RESULTS: Eight patients, with a median age of 76 years (range, 44-88 years), were treated between December 2003 and July 2008. Five (62.5%) of 8 patients responded, including 3 patients with CD30(+) anaplastic large-cell lymphoma (ALCL) with 2 complete responses, one ongoing at 8 years. One patient with CD8(+) and 1 patient with natural killer T cell lymphoma (NK-T) had partial responses. Progressive disease occurred in 1 patient positive for human T-cell lymphotropic virus and 1 patient with ALCL. Vascular leak syndrome (VLS) occurred in 6 (75%) of 8 patients during or just after cycle 1. Three were grade 3, and 2 of these resulted in study withdrawal. Other adverse effects included nausea or vomiting (n = 3), fatigue (n = 1), back pain (n = 1), transaminase elevations (n = 3), and elevated creatinine (n = 1). CONCLUSIONS: Dd with an alternate dosing schedule was active in this small study of primary cutaneous T-cell lymphomas. PMID- 22521505 TI - Dual effects of ATP on isolated arteries of the bovine eye. AB - Although the presence of purinoreceptors has been shown in many human and animal arteries, there is few data yet about their role in the arteries of the eye. The purpose of the present study was to evaluate the effects of several agonists of purinoreceptors on isolated arteries of the bovine eye. Responses of isolated preparations of bovine ophthalmic (OA) and posterior ciliary arteries (PCA) to agonists of purinoreceptors (ATP, alpha,beta-methylene-ATP-alpha,beta-meATP, 2 methylthioATP-2meSATP, uridine-5'-triphosphate-UTP) as well as agonists of adreno , cholino-, adenosine and histamine receptors were recorded by a standard organ bath method. ATP induced contractions of the intact vessels but caused relaxation of alpha,beta-meATP-pretreated arteries. Contractile responses of PCA to high concentrations of ATP and alpha,beta-meATP were significantly stronger than responses of OA, as well as relaxative responses to ATP and adenosine were significantly stronger in PCA than in OA. We suggest that there are several subtypes of functionally active purinoreceptors in both OA and PCA, although the potency of agonists of purinoreceptors to produce mechanical responses is higher in PCA than in OA. Purinoreceptors can be potential targets for new drugs, treating vascular pathology of the eye. PMID- 22521506 TI - Similar but different: ligand-induced activation of the insulin and epidermal growth factor receptor families. AB - The insulin and epidermal growth factor receptor families are among the most intensively studied proteins in biology. They are closely related members of the receptor tyrosine kinase superfamily and deregulated signaling by members of either receptor family has been implicated in the progression of a variety of cancers. These receptors have thus emerged as validated therapeutic targets for the development of anti-tumour agents. Recent studies have revealed detail of the ligand-binding sites in the insulin receptor family, as well as detail of conformational change upon ligand binding in the epidermal growth factor receptor family. Taken together, these findings and further data relating to kinase activation highlight the fact that while the receptor families share common structural elements, the structural detail of their functioning is remarkably different. PMID- 22521507 TI - Cytokine receptor activation at the cell surface. AB - Cytokines are well recognized for the pleiotropic nature of their signaling and biological activities on many cell types and their role in health and disease. Recent years have seen a steady stream of new cytokine receptor crystal structures including those that are activated by GM-CSF, type I interferon, and a variety of interleukins. Highlights include the observation of a dodecameric signaling complex for the GM-CSF receptor, electron microscopy imaging of an intact gp130/IL-6/IL-6Ralpha ternary receptor complex bound to its signal transducing Janus kinase and visualization of novel cytokine recognition mechanisms in the interleukin-17 and type I interferon families. This increasing knowledge in cytokine structural biology is driving new opportunities for developing novel therapies to modulate cytokine function in a diverse range of diseases including malignancies and chronic inflammation. PMID- 22521508 TI - The P2Y2/Src/p38/COX-2 pathway is involved in the resistance to ursolic acid induced apoptosis in colorectal and prostate cancer cells. AB - One of the hallmarks of cancer is resistance to apoptosis. Elucidating the mechanisms of how cancer cells evade or delay apoptosis should lead to novel therapeutic strategies. Previously, we showed that HT-29 colorectal cancer cells undergoing apoptosis overexpressed cyclooxygenase-2 (COX-2), in a p38 dependent pathway, to delay ursolic acid-induced apoptosis. Here, we focused on elucidating the upstream signaling pathways regulating this resistance mechanism. The role of ATP as an extracellular signaling molecule took a long time to be accepted. In recent years, ATP and its analogs, via the activation of specific purinergic receptors, have been implicated in many biological processes including cell proliferation, differentiation and apoptosis. In the present report, we have demonstrated a novel role involving purinergic receptors and particularly the P2Y(2) receptor in resistance to ursolic acid-induced apoptosis in both colorectal HT-29 and prostate DU145 cancer cells. We found that ursolic acid induced an increase in intracellular ATP and P2Y(2) transcript levels. Upon activation, P2Y(2) activated Src which in turn phosphorylated p38 leading to COX 2 overexpression which induced resistance to apoptosis in both HT-29 and DU145 cells. Furthermore, Ca(2+)-independent PLA(2) (iPLA(2)) and Ca(2+)-dependent secretory PLA(2) (sPLA(2)) were responsible for arachidonic acid release, the substrate of COX-2. Our findings document that apoptosis triggering was dependent on protein kinase C (PKC) activation in both cell lines after ursolic acid treatment. PMID- 22521510 TI - The temporal course of recovery from brief (sub-second) adaptations to spatial contrast. AB - Visual adaptation is a critical and ubiquitous mechanism that occurs for any stimulus feature and involves a continuous adjustment of the neuronal contrast gain. These adjustments prevent our visual system from dropping in sensitivity for the prevailing ranges of stimulus features that are processed at a given time. In addition to the classical adaptation, which arises over several seconds to minutes, a number of psychophysical, electrophysiological and interference studies have documented a much faster form of adaptation occurring with motion stimuli. This faster adaptation operates on a sub-second scale. In the present study, we investigated whether a fast form of adaptation also exists for spatial contrast and whether its characteristics (e.g., dependence on the duration of adaptation, time course of recovery) are similar to the classical, slower contrast adaptation. We found that a fast form of adaptation does exist and is maximal at intervals of 16-50 ms after the offset of the adapting stimulus. Similar to what previous studies have found regarding the classical contrast adaptation, the initial threshold elevation of this study did not depend on the duration of the adapting stimulus, but only on its contrast. Our results showed that the function which best describes the decay of brief adaptations to high contrast stimuli was a double exponential decay function, whereas the best function for describing adaptation to low-contrast stimuli was a single exponential decay function with a very fast recovery rate. Thus, adapting contrast influences both the threshold elevation, which rises with increasing adapting contrast, and the time course of recovery from adaptation. Overall, our data suggest the presence of a mechanism that is similar to the classical contrast adaptation involved in longer adaptations, but it operates over much shorter timescales. PMID- 22521512 TI - Environmental variations and toxicological responses. PMID- 22521509 TI - Toll-like receptor (TLR) and inflammasome actions in the central nervous system. AB - During the past 10 years, much attention has been focused towards elucidating the impact of Toll-like receptors (TLRs) in central nervous system (CNS) innate immunity. TLR signaling triggers the transcriptional activation of pro interleukin-1beta (pro-IL-1beta) and pro-IL-18 that are processed into their active forms by the inflammasome. Recent studies have demonstrated inflammasome involvement during CNS infection, autoimmune disease, and injury. This review will address inflammasome actions within the CNS and how cooperation between TLR and inflammasome signaling may influence disease outcome. In addition, the concept of alternative inflammasome functions independent of IL-1 and IL-18 processing are considered in the context of CNS disease. PMID- 22521513 TI - DCC mediated axon guidance of spinal interneurons is essential for normal locomotor central pattern generator function. AB - Coordinated limb rhythmic movements take place through organized signaling in local spinal cord neuronal networks. The establishment of these circuitries during development is dependent on the correct guidance of axons to their targets. It has previously been shown that the well-known axon guidance molecule netrin-1 is required for configuring the circuitry that provides left-right alternating coordination in fictive locomotion. The attraction of commissural axons to the midline in response to netrin-1 has been shown to involve the netrin 1 receptor DCC (deleted in Colorectal Cancer). However, the role of DCC for the establishment of CPG coordination has not yet been resolved. We show that mice carrying a null mutation of DCC displayed an uncoordinated left-right activity during fictive locomotion accompanied by a loss of interneuronal subpopulations originating from commissural progenitors. Thus, DCC plays a crucial role in the formation of spinal neuronal circuitry coordinating left-right activities. Together with the previously published results from netrin-1 deficient mice, the data presented in this study suggest a role for the most ventral originating V3 interneurons in synchronous activities over the midline. Further, it provides evidence that axon crossing in the spinal cord is more intricately controlled than in previously suggested models of DCC-netrin-1 interaction. PMID- 22521511 TI - Inhibition of return in a visual foraging task in non-human subjects. AB - Inhibition of return is thought to help guide visual search by inhibiting the orienting of attention to previously attended locations. We have previously shown that, in a foraging visual search task, the neural responses to objects in parietal cortex are reduced after they have been examined. Here we ask whether the animals' reaction times (RTs) in the same task show a psychophysical correlate of inhibition of return: a slowing of reaction time in response to a probe placed at a previously fixated location. We trained three animals to perform an RT version of the visual foraging task. In the foraging task, subjects visually searched through an array of five identical distractors and five identical potential targets; one of which had a reward linked to it. In the RT variant of the task, subjects had to rapidly respond to a probe if it appeared. We found that RTs were slower for probes presented at locations that contained previously fixated objects, faster to potential targets and between the two for behaviorally irrelevant distractors that had not been fixated. These data show behavioral inhibitory tagging of previously fixated objects and suggest that the suppression of activity seen previously in the same task in parietal cortex could be a neural correlate of this mechanism. PMID- 22521514 TI - Dominance hierarchies and social status ascent opportunity: anticipatory behavioral and physiological adjustments in a Neotropical cichlid fish. AB - In this work we characterized the social hierarchy of non-reproductive individuals of Cichlasoma dimerus (Heckel, 1840), independently for both sexes, and its relationship to the opportunity for social status ascent. Female and male individuals who were located on the top rank of the social hierarchy, ascended in social status when the opportunity arose, therefore indicating that dominance is directly correlated with social ascent likelihood. Dominance was positively correlated with size in males but not in females, suggesting for the latter a relationship with intrinsic features such as aggressiveness or personality rather than to body and/or ovarian size. Physiological and morphometrical variables related to reproduction, stress and body color were measured in non-reproductive fish and correlated with dominance and social ascent likelihood. Dominance was negatively correlated with plasma cortisol levels for both sexes. No correlation with dominance was found for androgen plasma levels (testosterone and 11 ketotestosterone). No correlation was detected between dominance and the selected morphological and physiological variables measured in females, suggesting no reproductive inhibition in this sex at a physiological level and that all females seem to be ready for reproduction. In contrast, social hierarchy of non reproductive males was found to be positively correlated with follicle stimulating hormone (FSH) pituitary content levels and gonadosomatic indexes. This suggests an adaptive mechanism of non reproductive males, adjusting their reproductive investment in relation to their likelihood for social status ascent, as perceived by their position in the social hierarchy. This likelihood is translated into a physiological signal through plasma cortisol levels that inhibit gonad investment through pituitary inhibition of FSH, representing an anticipatory response to the opportunity for social status ascent. PMID- 22521515 TI - Why we eat what we eat. The Eating Motivation Survey (TEMS). AB - Understanding why people select certain food items in everyday life is crucial for the creation of interventions to promote normal eating and to prevent the development of obesity and eating disorders. The Eating Motivation Survey (TEMS) was developed within a frame of three different studies. In Study 1, a total of 331 motives for eating behavior were generated on the basis of different data sources (previous research, nutritionist interviews, and expert discussions). In Study 2, 1250 respondents were provided with a set of motives from Study 1 and the Eating Motivation Survey was finalized. In Study 3, a sample of 1040 participants filled in the Eating Motivation Survey. Confirmatory factor analysis with fifteen factors for food choice yielded a satisfactory model fit for a full (78 items) and brief survey version (45 items) with RMSEA .048 and .037, 90% CI .047-.049 and .035-.039, respectively. Factor structure was generally invariant across random selected groups, gender, and BMI, which indicates a high stability for the Eating Motivation Survey. On the mean level, however, significant differences in motivation for food choice associated with gender, age, and BMI emerged. Implications of the fifteen distinct motivations to choose foods in everyday life are discussed. PMID- 22521516 TI - It tastes better because ... consumer understandings of UK farmers' market food. AB - In the social sciences there has been much exciting and informative work on farmers' markets and this paper contributes to this literature by considering how the place of farmers' markets affects the way consumers understand the taste of food. I draw on the difficulty faced by many consumers in articulating the taste of food, especially when food is perceived to taste good. I explore how consumers demonstrate their evaluations of taste, whether through descriptions of taste that are metaphor-laden or through beliefs and values emboldened by food knowledges and opinions. I argue these are how farmers' market consumers understand and perform taste in relation to market food. The findings that inform the paper are taken from interviews with farmers' market consumers in the UK. PMID- 22521517 TI - Higher food intake and appreciation with a new food delivery system in a Belgian hospital. Meals on Wheels, a bedside meal approach: a prospective cohort trial. AB - AIM: A new system of meal distribution called Meals on Wheels, allowing food ordering at mealtime and providing guidance by trained nutritional assistants, might show benefit in offering nutritional support. This study investigates whether Meals on Wheels improves total food intake per day and yielded improved appreciation of food quality and increased access to food and mealtimes. METHODS: In a prospective cohort trial where control and intervention groups were taken from all patients hospitalized at the respiratory disease department, age, sex, BMI, admission weight, height, reason for admission and discharge weight were noted, as was food intake, supplements, waste per meal and daily total. For food appreciation the questionnaire developed by Naithani et al. was used. The study included 83 patients in the control group and 106 patients in the Meals on Wheels group. RESULTS: Mean total daily food intake was 236 g higher in patients in the Meals on Wheels than in controls. There was higher intake of oral nutritional supplements in the Meals on Wheels group compared to controls, resulting in significantly less oral nutritional supplements wasted. There was also significantly less waste in the Meals on Wheels group. For food access and appreciation, patients appreciated Meals on Wheels more than the old system in terms of choice, hunger, food quality and organization. CONCLUSIONS: Meals on Wheels resulted in higher food intake during each meal, less waste and better use of oral nutritional supplements. Patients appreciated Meals on Wheels more than the old system in terms of choice, hunger, food quality and organization. PMID- 22521518 TI - Non-communicable diseases in prisons. PMID- 22521519 TI - Emma Plugge: time for outrage. PMID- 22521520 TI - Prevalence of risk factors for non-communicable diseases in prison populations worldwide: a systematic review. AB - BACKGROUND: The burden of non-communicable diseases (NCDs) is disproportionately carried by low-income and middle-income countries and disadvantaged sectors of society such as prisoners. No systematic analysis has been done to assess the prevalence of poor diet, inadequate physical activity, and overweight and obesity in prisoners. We aim to synthesise current evidence and to highlight areas for action and further research. METHODS: We systematically searched online databases for reports published between 1948 and May, 2011. Studies were screened against eligibility criteria; two authors then independently extracted data with previously agreed proformas. The risk of bias was assessed for each study with a domain-based assessment. Data on body-mass index and physical activity were presented in forest plots; no overall estimates were calculated on account of data heterogeneity. Available data from the population subgroup most similar in terms of age and sex were used to calculate age-adjusted and sex-adjusted prevalence ratios, which estimate the likelihood of insufficient activity and obesity prevalence in prisoners compared with the national population. FINDINGS: 31 eligible studies were reported in 29 publications, including more than 60,000 prisoners in 884 institutions in 15 countries. Male prisoners were less likely to be obese than males in the general population (prevalence ratios ranged from 0.33 to 0.87) in all but one study (1.02, 0.92-1.07), whereas female prisoners were more likely to be obese than non-imprisoned women in the USA (1.18, 1.08-1.30) and Australia (prevalence ratios ranged from 1.15 to 1.20). Australian prisoners were more likely to achieve sufficient activity levels than the general population compared with prisoners in the UK (prevalence ratio 1.19, 95% CI 1.04 1.37, for women in Australia in 2009 vs 0.32, 0.21-0.47, for women in the UK; prevalence ratios ranged from 1.37 to 1.59 for men in Australia vs 0.71, 0.34 0.78, for men in the UK). Female mean energy intake exceeded recommended levels and sodium intake was about two to three times the recommended intake for all prisoners. INTERPRETATION: Contact with the criminal justice system is a public health opportunity to promote health in this vulnerable population; the costs to the individual and to society of failing to do so are likely to be substantial. Improved monitoring and further research is essential to inform appropriate targeting of public health interventions. FUNDING: Oxford University Department of Public Health, Oxford University Hospitals NHS Trust. PMID- 22521521 TI - Biliary ileus. PMID- 22521522 TI - iPSCs from cancer cells: challenges and opportunities. AB - Reprogramming and oncogenic transformation are stepwise processes that share many similarities, and induced pluripotent stem cells (iPSCs) generated from cancer cells could illuminate molecular mechanisms underlying the pathogenesis of human cancer. Deciphering the barriers underlying the reprogramming process of primary cancer cells could reveal information on the links between pluripotency and oncogenic transformation that would be instrumental for therapy development. PMID- 22521523 TI - Nitric oxide-dependent killing of aerobic, anaerobic and persistent Burkholderia pseudomallei. AB - Burkholderia pseudomallei infections are fastidious to treat with conventional antibiotic therapy, often involving a combination of drugs and long-term regimes. Bacterial genetic determinants contribute to the resistance of B. pseudomallei to many classes of antibiotics. In addition, anaerobiosis and hypoxia in abscesses typical of melioidosis select for persistent populations of B. pseudomallei refractory to a broad spectrum of antibacterials. We tested the susceptibility of B. pseudomallei to the drugs hydroxyurea, spermine NONOate and DETA NONOate that release nitric oxide (NO). Our investigations indicate that B. pseudomallei are killed by NO in a concentration and time-dependent fashion. The cytoxicity of this diatomic radical against B. pseudomallei depends on both the culture medium and growth phase of the bacteria. Rapidly growing, but not stationary phase, B. pseudomallei are readily killed upon exposure to the NO donor spermine NONOate. NO also has excellent antimicrobial activity against anaerobic B. pseudomallei. In addition, persistent bacteria highly resistant to most conventional antibiotics are remarkably susceptible to NO. Sublethal concentrations of NO inhibited the enzymatic activity of [4Fe-4S]-cofactored aconitase of aerobic and anaerobic B. pseudomallei. The strong anti-B. pseudomallei activity of NO described herein merits further studies on the application of NO-based antibiotics for the treatment of melioidosis. PMID- 22521524 TI - Bactericidal activity against meticillin-resistant Staphylococcus aureus of a novel eukaryotic therapeutic recombinant antimicrobial peptide. AB - Antimicrobial peptides (AMPs) are one of several potential antibacterial agents in the current era of antibiotics facing severe challenges. In this study, the bactericidal activity and stability of two eukaryotic AMPs were determined. Both AMPs showed specific antibacterial activity in a HEK293T cell model infected with meticillin-resistant Staphylococcus aureus. The recombinant eukaryotic AMP pVAX1/hBD3-CBD showed better bactericidal activity and stability than the eukaryotic AMP pVAX1/hBD3. These results illustrate that this peptide, designed and used with eukaryotic expression and recombinant methods, should be studied and applied in further AMP research and trials. PMID- 22521525 TI - Nosocomial occurrence of OXA-48-producing enterobacterial isolates in a Moroccan hospital. PMID- 22521526 TI - Plasmid-mediated quinolone resistance genes in enteroaggregative Escherichia coli from infants in Lima, Peru. PMID- 22521527 TI - Dietary fish oil replacement with canola oil up-regulates glutathione peroxidase 1 gene expression in yellowtail kingfish (Seriola lalandi). AB - The marine carnivore yellowtail kingfish (YTK, Seriola lalandi) was fed diets containing 5% residual fish oil (from the dietary fish meal) plus either 20% fish oil (FO), 20% canola oil (CO), 20% poultry oil (PO), 10% fish oil plus 10% canola oil (FO/CO) or 10% fish oil plus 10% poultry oil (FO/PO) and the effects on fish growth and hepatic expression of two glutathione peroxidase (GPx 1 and GPx 4) and two peroxiredoxin (Prx 1 and Prx 4) antioxidant genes were investigated. Partial (50%) replacement of the added dietary fish oil with poultry oil significantly improved fish growth whereas 100% replacement with canola oil significantly depressed fish growth. The fatty acid profiles of the fish fillets generally reflected those of the dietary oils except that there was apparent selective utilization of palmitic acid (16:0) and oleic acid (18:1n-9) and apparent selective retention of eicospentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3). The Prx 1 and 4 genes were expressed at 10- and 100-fold the level of the GPx 4 and 1 genes, respectively, and at one-tenth the level of the highly expressed beta-actin reference gene. Dietary fish oil replacement with canola oil significantly up-regulated GPx 1 gene expression and there was a non significant tendency towards down-regulation of Prx 1 and Prx 4. The results are discussed in terms of the effects of fish oil replacement on the peroxidation index of the diets and the resulting effects on the target antioxidant enzymes. PMID- 22521528 TI - PET/CT scanning guided intensity-modulated radiotherapy in treatment of recurrent ovarian cancer. AB - OBJECTIVE: This study was undertaken to evaluate the clinical contribution of positron emission tomography using (18)F-fluorodeoxyglucose and integrated computer tomography (FDG-PET/CT) guided intensity-modulated radiotherapy (IMRT) for treatment of recurrent ovarian cancer. MATERIALS AND METHODS: Fifty-eight patients with recurrent ovarian cancer from 2003 to 2008 were retrospectively studied. In these patients, 28 received PET/CT guided IMRT (PET/CT-IMRT group), and 30 received CT guided IMRT (CT-IMRT group). Treatment plans, tumor response, toxicities and survival were evaluated. RESULTS: Changes in GTV delineation were found in 10 (35.7%) patients based on PET-CT information compared with CT data, due to the incorporation of additional lymph node metastases and extension of the metastasis tumor. PET/CT guided IMRT improved tumor response compared to CT-IMRT group (CR: 64.3% vs. 46.7%, P=0.021; PR: 25.0% vs. 13.3%, P=0.036). The 3-year overall survival was significantly higher in the PET-CT/IMRT group than control (34.1% vs. 13.2%, P=0.014). CONCLUSIONS: PET/CT guided IMRT in recurrent ovarian cancer patients improved the delineation of GTV and reduce the likelihood of geographic misses and therefore improve the clinical outcome. PMID- 22521530 TI - Comparison of efficacy, safety, and cost-effectiveness of in-office cup forcep biopsies versus operating room biopsies for laryngopharyngeal tumors. AB - OBJECTIVE: To compare the diagnostic yield, safety, and cost of biopsies of laryngopharyngeal tumor performed in an office setting with those performed in the operating room (OR) under general anesthesia. STUDY DESIGN: This was a retrospective review of patients' records at Boston Medical Center from 2006 to 2008. METHODS: In-office biopsies were performed using flexible digital videolaryngoscopy with cup forcep biopsies taken via the working channel in patients in whom cancer was strongly suspected. Patients whose in-office biopsies were nondiagnostic or suspected to be falsely negative were taken to the OR for biopsy under general anesthesia and served as the control group. RESULTS: Twelve patients fit the selection criteria and had in-office biopsies attempted. One patient could not tolerate the in-office biopsy. Seven of the 11 in-office biopsies performed were diagnostic for squamous cell carcinoma. The average cost (facility and professional otolaryngology charges) for an in-office biopsy was $2053.91. Five of these patients required further biopsy in the OR at an average cost (charges for surgeon, OR, anesthesia, and recovery room) of $9024.47. There were no significant complications reported for any of the procedures. CONCLUSIONS: In patients with strongly suspected laryngopharyngeal cancer, in office cup forcep biopsies were 64% diagnostic. When compared with the OR, in office cup biopsies of laryngopharyngeal tumor are safe and considerably more cost-effective. Although 36% of patients required operative biopsies, the cost would have been considerably higher in this cohort if all patients had gone to the OR for biopsies. PMID- 22521531 TI - Letter to the Editor: Re: Misun V, Svancara P, Martin V. Experimental analysis of the characteristics of artificial vocal folds. J Voice. 2011;25:308-318. PMID- 22521532 TI - Evaluation of vocal fold vibration with an assessment form for high-speed digital imaging: comparative study between healthy young and elderly subjects. AB - OBJECTIVES/STUDY DESIGN: We conducted a prospective study with a subjective assessment form for high-speed digital imaging (HSDI) to elucidate the features of vocal fold vibrations in vocally healthy subjects and to clarify gender- and age-related differences. METHODS: Healthy adult volunteers participated in this study. They were divided into young (aged 35 and younger) and elderly (aged 65 and older) groups, and the scores of an assessment form for HSDI characteristics elaborated at our institution were statistically analyzed. RESULTS: Twenty-six young subjects (males: 9, females: 17; mean age: 27 years) and 20 elderly subjects (males: 8, females: 12; mean age: 72 years) were assigned to our study. Posterior gap and posterior-to-anterior longitudinal phase difference were characteristic to young females, whereas in young males, mucosal wave, anterior to-posterior longitudinal phase difference, and supraglottic hyperactivity were frequent. In elderly males, axis shift, asymmetry, supraglottic hyperactivity, increased mucosal wave, lateral phase difference, and anterior-to-posterior longitudinal phase difference were frequent; and in elderly females, high incidence of lateral phase difference, atrophic change, anterior gap, and asymmetry were observed. CONCLUSIONS: The results show that the behaviors of vocal fold vibrations were diverse even in healthy subjects with no vocal complaints or history of laryngeal diseases, and hence, the diversity of vocal fold vibrations in normal subjects must be taken into account in evaluating vocal fold vibrations. PMID- 22521533 TI - The effect of voice amplification on occupational vocal dose in elementary school teachers. AB - Two elementary school teachers, one with and one without a history of vocal complaints, wore a vocal dosimeter all day at school for a 3-week period. In the second week, each teacher wore a portable voice amplifier. Each teacher showed a reduction in vocal intensity during the week of amplification, with a larger effect for the teacher with vocal difficulties. This teacher also showed a decrease in hourly vocal fold distance dose as measured by the dosimeter despite incurring longer phonation times. Fundamental frequency and vocal fold cycle dose did not appear to be affected by the use of amplification during the teaching day. Both teachers showed evidence of a possible moderate effect of adjusting vocal intensity in the week after amplification, possibly as a means to recalibrate their perceived vocal loudness. This study demonstrates the usefulness of both vocal dosimetry and amplification in monitoring and modifying vocal dose in an occupational setting and reinforces previous data suggesting the effectiveness of amplification in reducing the vocal load in schoolteachers. Implications of the data for future research regarding prevention and treatment of occupational voice disorders are discussed. PMID- 22521534 TI - Noninvasive monitoring of vocal fold vertical vibration using the acoustic Doppler effect. AB - OBJECTIVES/HYPOTHESIS: To validate a proposed method of noninvasively monitoring vocal fold vertical vibration through utilization of the acoustic Doppler effect and the waveguide property of the vocal tract. STUDY DESIGN: Validation case control study. METHODS: In this device, an ultrasound beam is generated and directed into the mouth. The vocal tract, acting as a natural waveguide, guides the ultrasound beam toward the vibrating vocal folds. The vertical velocity of vocal fold vibration is then recovered from the Doppler frequency of the reflected ultrasound. One subject (age 32, male) was studied and measurements were taken under three modes of vocal fold vibration: breathing (no vibration), whispering (irregular vibration), and normal phonation (regular vibration). RESULTS: The peak-to-peak amplitude of the measured velocity of vocal fold vertical vibration was about 0.16 m/s, and the fundamental frequency was 172 Hz; the extracted velocity information showed a reasonable waveform and value in comparison with the previous studies. In all three modes of phonation, the Doppler frequencies derived from the reflected ultrasound corresponded with the vertical velocity of vocal fold vibration as expected. CONCLUSIONS: The proposed method can accurately represent the characteristics of different phonation modes such as no phonation, whisper and normal phonation. The proposed device could be used in daily monitoring and assessment of vocal function and vocal fold vibration. PMID- 22521535 TI - Clinical implications of pathologic diagnosis and classification for diabetic nephropathy. AB - AIM: The usefulness of renal pathologic diagnosis in type II DM (diabetes mellitus) remains debate. METHODS: We grouped the pathologic diagnoses as pure DN (diabetic nephropathy), NDRD (non-diabetic renal disease), and NDRD mixed with DN (Mixed). We classified pure DN as the criteria suggested by Tervaert. We compared the accuracy of clinical parameters to predict DN and usefulness of pathology to predict renal prognosis. RESULTS: Among 126 enrolled patients, there were 50 pure DN, 65 NDRN, and 11 Mixed. The sensitivity and specificity for predicting DN with the presence of retinopathy were 77.8-73.6% and, with a cut-off value of 7.5 years of diabetic duration, the sensitivity and specificity were 64.5-67.2%. ESRD (end stage renal disease) occurred in 44.0% of DN, 18.2% of Mixed, and 12.3% of NDRD (p<0.001). Among pure DN, Class IV showed the lowest estimated glomerular filtration rate (eGFR). We estimated the 5-year renal survival rate as 100.0% in Classes I and IIa, 75.0% in Class IIb, 66.7% in Class III, and 38.1% in Class IV (p=0.002). CONCLUSIONS: Nephropathy of type II DM was diverse and could not be completely predicted by clinical parameters. The renal pathologic diagnosis was a good predictor for renal prognosis in type II DM. PMID- 22521537 TI - Role of B12 and homocysteine status in determining BMD and bone turnover in young Indians. AB - Vitamin B(12) (B(12)) deficiency and hyperhomocysteinemia (HHcy) are independent risk factors for low bone mineral density (BMD) and fracture risk. We studied the role of HHcy and B(12) deficiency in determining the peak bone mass in Indians. Randomly selected 151 healthy young adult subjects (females 100, mean age: 26 yr) underwent evaluation of dietary intake of calcium and B(12); sun exposure; estimation of BMD by dual-energy X-ray absorptiometry at total hip, forearm, and lumbar spine; serum 25(OH)D(3); intact parathyroid hormone; B(12); homocysteine (Hcy); and bone turnover markers (BTMs) serum crosslaps, N-mid osteocalcin, and bone-specific alkaline phosphatase. Hypovitaminosis D (serum 25OHD(3)<20 ng/mL) and serum ALP level >150 IU/L were seen in 83% and 27%, respectively. Median serum B(12) and Hcy levels were 140 pg/mL (interquartile range [IQR]: 72-230 pg/mL) and 18 MUmol/L (IQR 14-32 MUmol/L); B(12) deficiency (serum B(12)<200 pg/mL) and HHcy (serum Hcy>30 MUmol/L) were present in 71% and 68%, respectively. Low BMD (Z-score <-2.0) was present in 17% of subjects. There was no significant correlation between serum Hcy, folate, B(12), BTM, and BMD. BMD was predicted by height, weight, and body mass index. Young Indian healthy adults have high prevalence of hypovitaminosis D, B(12) deficiency, and HHcy. There is no correlation of serum B(12), folate, and Hcy status with BTMs and BMD in young, healthy, vegetarian Indian adults. Anthropometric variables predict BMD in young Indians. PMID- 22521536 TI - Protein kinase Calpha and integrin-linked kinase mediate the negative axon guidance effects of Sonic hedgehog. AB - In addition to its role as a morphogen, Sonic hedgehog (Shh) has also been shown to function as a guidance factor that directly acts on the growth cones of various types of axons. However, the noncanonical signaling pathways that mediate the guidance effects of Shh protein remain poorly understood. We demonstrate that a novel signaling pathway consisting of protein kinase Calpha (PKCalpha) and integrin-linked kinase (ILK) mediates the negative guidance effects of high concentration of Shh on retinal ganglion cell (RGC) axons. Shh rapidly increased Ca(2+) level and activated PKCalpha and ILK in the growth cones of RGC axons. By in vitro kinase assay, PKCalpha was found to directly phosphorylate ILK on threonine-173 and -181. Inhibition of PKCalpha or expression of a mutant ILK with the PKCalpha phosphorylation sites mutated (ILK-DM), abolished the Shh-induced macropinocytosis, growth cone collapse and repulsive axon turning. In vivo, expression of a dominant negative PKCalpha or ILK-DM disrupted RGC axon pathfinding at the optic chiasm but not the projection toward the optic disk, supporting that this signaling pathway plays a specific role in Shh-mediated negative guidance effects. PMID- 22521538 TI - X-ray knee as a screening tool for osteoporosis. AB - Cortical thickness (Cor-Th) of tibia varies considerably on X-ray knees. It was hypothesized that Cor-Th can be used for preliminary prediction of BMD. Ninety nine patients underwent a digital X-ray left knee fixed flexion PA view with an external calibration scale attached to X-ray plate and BMD by DXA using GE lunar machine (Madison, Wisconsin.). Cor-Th was measured at 5 selected levels (A,B,C,D, and E) ranging from 5-7 cm below the tibial plateau on its medial aspect. T scores were recorded for BMD at AP spine, left forearm and left femur. Cor-Th of tibia at each level significantly correlated with each site of BMD measurement namely AP spine, left femur and left forearm. This correlation varied in the range from 0.241 to 0.426. For AP spine, it was maximum at level C (r=0.347, p<0.001) whereas for left femur and forearm sites, it was maximum at level B (r=0.426 &r=0.373 respectively, p<0.001). The correlation of Cor-Th with BMD varied with age. Above 56 years of age, Cor-Th at each level significantly correlated to BMD at each site. Medial tibial cortical thickness, 6 cm (level C) below tibial plateau can be used as preliminary predictor of patients who need a DXA scan. PMID- 22521539 TI - The importance of absolute bone mineral density in the assessment of antiresorptive agents used for the prevention of osteoporotic fractures. AB - The usefulness of bone mineral density (BMD) monitoring during antiresorptive treatment is still controversial. This study aimed to determine which factors of change (absolute value or the percent change from the baseline) in BMD are associated with the risk of future fractures. A total of 565 postmenopausal osteoporosis who were treated antiresorptive drugs were included in this prospective observational study. Lumbar BMD (LBMD) was measured at baseline and 1 yr after the initial and subsequent incident fracture was observed. The percent changes in LBMD at 1 yr were 5.4 +/- 6.4% and 118 (20.9%) achieved increased LBMD with change of classification to >-2.5 standard deviation (SD). After the initial 1-yr examination, incident fractures developed in 152 (26.9%). The incident fracture risk was significantly associated with the absolute value in LBMD, but not with the percent change. A Cox proportional hazard model demonstrated that increased LBMD with change of classification to >-2.5 SD was a significant predictor for a reduction in incident fractures (hazard ratio: 0.41, 95% confidence interval: 0.21-0.71). In conclusion, these results suggest that monitoring of the antifracture efficacy of antiresorptive treatments should be based on the absolute value of BMD. In particular, increased change to >-2.5 SD is important for reducing the future fracture risk. PMID- 22521540 TI - Radiograph-based study of gender-specific vertebral area gain in healthy children and adolescents as a function of age, height, and weight. AB - This study reports gender-specific vertebral area gain data from children and adolescents. Vertebral area was measured on lateral and anteroposterior thoracic and lumbar spine radiographs from 100 female and 100 male subjects aged 7-28 yr. T9, T11, T12, L1, and L2 X-ray area calculation was based on calculation of the area of the geometric figure of a trapezoid whose 2 nonparallel sides were equal in length, taking account of the waisted shape of the vertebrae. Both the boys and girls of our study population showed statistically significant dependence (p<0.001) of vertebral area gain on chronologic age, height, and weight right through the end of puberty, and especially so up to age 15 yr. However, height and weight were clearly better predictors of lateral and anteroposterior vertebral area gain than was chronologic age. Once vertebral growth is complete by age 18 yr or so, the lateral vertebral areas of the male subjects-regardless of body weight and height-are, on average, 25% larger, and the anteroposterior areas up to 30% larger than those of their female counterparts. After adjusting for chronologic age, height, and weight however we did not find significant differences, between gender, in vertebral area of male and female subjects, neither among children younger than 11 yr nor adolescents ages of 12-14 yr and young adults older than 18 yr. PMID- 22521541 TI - Lean mass predicts hip geometry and bone mineral density in chinese men and women and age comparisons of body composition. AB - Previous studies have suggested that changes in hip geometry increase the risk of hip fracture. The aim of this study was to identify whether body composition were associated with hip geometry or bone mineral density (BMD) in a large sample of Chinese people. A total of 2072 subjects aged 20-79 yr (including 700 males and 1372 females) were selected. The following measurements were taken: lumbar spine (L1-4); proximal femur BMD; lean mass (LM); fat mass (FM); and hip geometric parameters, including hip axis length (HAL), cross-sectional moment of inertia (CSMI), cross-sectional area (CSA), neck-shaft angle, and femur strength index (SI) by dual-energy X-ray absorptiometry. FM and LM were positively correlated with HAL, CSMI, and CSA, and negatively correlated with SI in both men and women. Multiple regression analysis showed that leg LM contributions to HAL, CSMI, and CSA variance were 12.6-37.6%. Compared with FM, LM was generally more strongly related to hip geometry and BMD in young and old men and women. Body composition was a good predictor for hip geometry parameter variation and BMD variation. PMID- 22521542 TI - Fat and muscle indices assessed by pQCT: relationships with physical activity and type 2 diabetes risk. AB - The aim of this study was to compare and determine the repeatability of foreleg and forearm muscle and fat indices evaluated by the peripheral quantitative computed tomography (pQCT). Effects of habitual physical activity and associated health risk of type 2 diabetes were examined within the interrelations of intermuscular adipose tissue (IMAT) and muscle density. Eighty-two premenopausal women (mean age +/- standard deviation: 38.6 +/- 4.7 yr) underwent dual-energy X ray absorptiometry scans and pQCT of foreleg and forearm scans to assess muscle and fat parameters. Physical activity status was based on 4-d self-reported log and pedometer step counts. Fat and muscle distribution between the foreleg and forearm were similar and highly correlated to total body adiposity. The pQCT device reliably measured muscle density in the foreleg and forearm; coefficients of variation were 0.8% and 2.1%, which was therefore used to reflect IMAT status. Muscle density was positively related to physical activity and negatively associated with markers of fat distribution and risk for type 2 diabetes. The pQCT is a novel, noninvasive tool to assess IMAT and muscle density in the foreleg and forearm. Additional research is necessary to understand the biology of IMAT and its relations with physical activity and potentially, with risks for cardiometabolic disease. PMID- 22521543 TI - Denosumab significantly increases DXA BMD at both trabecular and cortical sites: results from the FREEDOM study. AB - Denosumab is an approved therapy for postmenopausal women with osteoporosis at high or increased risk for fracture. In the FREEDOM study, denosumab reduced fracture risk and increased bone mineral density (BMD). We report the spine and hip dual-energy X-ray absorptiometry (DXA) BMD responses from the overall study of 7808 women and from a substudy of 441 participants in which more extensive spine and hip assessments as well as additional skeletal sites were evaluated. Significant BMD improvements were observed as early as 1 mo at the lumbar spine, total hip, and trochanter (all p<0.005 vs placebo and baseline). BMD increased progressively at the lumbar spine, total hip, femoral neck, trochanter, 1/3 radius, and total body from baseline to months 12, 24, and 36 (all p<0.005 vs placebo and baseline). BMD gains above the least significant change of more than 3% at 36 months were observed in 90% of denosumab-treated subjects at the lumbar spine and 74% at the total hip, and gains more than 6% occurred in 77% and 38%, respectively. In conclusion, denosumab treatment resulted in significant, early, and continued BMD increases at both trabecular and cortical sites throughout the skeleton over 36 mo with important gains observed in most subjects. PMID- 22521544 TI - Characterization of sphere-forming cells with stem-like properties from the small cell lung cancer cell line H446. AB - A relatively novel paradigm in tumor biology hypothesizes that cancer growth is driven by tumor cells with stem-like properties. However, direct proof of a population of stem cells in small cell lung cancer (SCLC) remains elusive. In this study, we enriched for stem-like cells from the SCLC cell line H446 by growing them as spheres in a defined serum-free medium. Sphere-derived cells have increased in vitro clonogenic and in vivo tumorigenic potentials as well as drug resistant properties. After enrichment for stem-like cells, we used multiple candidate stem cell markers to examine the expression profile and found that the sphere-derived cells contained a higher proportion of cells expressing the stem cell surface markers uPAR and CD133 when compared with parental cells. To identify a selectable marker for the sphere-forming cells, we evaluated the sphere-forming abilities of uPAR(+) and uPAR(-) cells as well as the sphere forming abilities of CD133(+) and CD133(-) cells. Both CD133(+) and CD133(-) cell fractions were capable of forming spheres, and no statistically significant difference was observed in the sphere-forming efficiency between these two populations. In contrast, cells derived from the uPAR(+) fraction were capable of forming spheres, whereas cells derived from the uPAR(-) fraction remained as single cells. Moreover, uPAR(+) cells efficiently formed transplantable tumors, whereas uPAR(-) cells were unable to initiate tumors when transplanted at equivalent cell numbers. In addition, uPAR(+) cells could differentiate into CD56(+)cells, CK(+) cells, and uPAR(-) cells. These data support the existence of a population of tumor sphere-forming cells with stem cell properties in the H446 SCLC cell line. Furthermore, the stem cell population may be enriched in cells expressing the uPAR cell surface marker. PMID- 22521545 TI - Breast cancer, side population cells and ABCG2 expression. AB - Recurrent metastatic breast cancer may arise in part due to the presence of drug resistant adult stem cells such as Side Population (SP) cells, whose phenotype has been demonstrated to be due to the expression of ABCG2. We hypothesised that SP may be identified in Fine Needle Aspirates (FNAs) and their presence may be determined by expression of ABCG2 in breast tumours. SP and non-side population cells (NSP) were isolated using dual wavelength flow cytometry combined with Hoechst 33342 dye efflux and analysed for expression of ABCG2 and chemoresistance. FNA samples used in SP analysis were matched with paraffin embedded tissue which was used in immunohistochemical analysis to assess ABCG2 expression. Results were correlated to the pathobiology of the tumour. MCF7 and MDA-MB-231 cell lines contain SP cells. MCF7 SP have increased expression of ABCG2 and increased resistance to mitoxantrone compared to NSP cells. The presence of SP in FNAs were significantly associated with ER-negative (p=0.008) and with triple negative breast cancers (p=0.011) which were also found to have a significant increase in ABCG2 protein expression. ABCG2 transcript was detected in some but not all SP cell populations isolated from FNA samples. PMID- 22521547 TI - DNA damage induces the IL-6/STAT3 signaling pathway, which has anti-senescence and growth-promoting functions in human tumors. AB - IL-6 is a multifunctional cytokine that is important for immune responses, cell survival, apoptosis, and proliferation. However, little is known about the correlation between the IL-6 signaling pathway and DNA damage in human tumors. The present study demonstrates the role of the IL-6/STAT3 signaling pathway in human tumor cells exposed to DNA damage. Tumor cells exposed to DNA damage increase the expression and secretion of IL-6 and the phosphorylation of JAK1 and STAT3. The activation of the JAK1-STAT3 signaling pathway is inhibited by knockdown of gp130 or neutralization of soluble IL-6, implying that DNA damage induces the phosphorylation of JAK1 and STAT3 by autocrine IL-6. Interestingly, inhibition of the IL-6/STAT3 signaling pathway impairs the growth of tumor cells exposed to DNA damage and results in the induction of senescence. Therefore, the present study suggests that IL-6 inhibits senescence but promotes the survival and proliferation of tumor cells exposed to DNA damage through the activation of the JAK1-STAT3 signaling pathway. PMID- 22521548 TI - Incretins and thiazolidinediones in glucose homeostasis and cancer: role of common polymorphisms. AB - With growing epidemiologic and molecular evidence linking the pathogenesis of diabetes mellitus and oncogenesis, the role of anti-diabetic drugs as antineoplastic agents becomes a subject of intense investigation. Several trials are underway assessing the effect of adding metformin to the existing chemotherapy regimen in the treatment of cancers. This review has a focus on other commonly used drugs classified into two broad groups, incretins and thiazolidinediones. The aim of this review is to discuss the common genetic polymorphisms implicated in the pathogenesis of type 2 diabetes mellitus (type 2 DM) and how they are linked to molecular pathways involved in carcinogenesis. PMID- 22521546 TI - Bone-targeting radiopharmaceuticals for the treatment of prostate cancer with bone metastases. AB - Patients with castration-resistant prostate cancer (CRPC) frequently have metastases to the bone, which may cause pain and lead to a deterioration in quality-of-life. Bone-seeking radiopharmaceuticals are agents which, when administered systemically, localize to the site of bone metastases and deliver focal radiation there. In this review, we will summarize the current literature on bone-targeting radiopharmaceuticals for CRPC, focusing on strontium-89, samarium-153, rhenium-186 and radium-223. We will discuss their indications, clinical efficacy, and toxicities and highlight some of the challenges in optimizing treatment with these agents. Historically, clinical trials with these drugs have failed to demonstrate survival improvements, restricting their use for palliative purposes only. Radium-223 is the first agent in this class to show an overall survival advantage in CRPC patients with bone metastases. This landmark finding will likely have a considerable impact on the treatment paradigm of bone metastatic CRPC, and will pave the way for further developments in the future. PMID- 22521549 TI - The extinction context enables extinction performance after a change in context. AB - One experiment with human participants determined the extent to which recovery of extinguished responding with a context switch was due to a failure to retrieve contextually controlled learning, or some other process such as participants learning that context changes signal reversals in the meaning of stimulus-outcome relationships. In a video game, participants learned to suppress mouse clicking in the presence of a stimulus that predicted an attack. Then, that stimulus underwent extinction in a different context (environment within the game). Following extinction, suppression was recovered and then extinguished again during testing in the conditioning context. In a final test, participants that were tested in the context where extinction first took place showed less of a recovery than those tested in a neutral context, but they showed a recovery of suppression nevertheless. A change in context tended to cause a change in the meaning of the stimulus, leading to recovery in both the neutral and extinction contexts. The extinction context attenuated that recovery, perhaps by enabling retrieval of the learning that took place in extinction. Recovery outside an extinction context is due to a failure of the context to enable the learning acquired during extinction, but only in part. PMID- 22521550 TI - Assessing signaling pathways associated with in vitro resistance to cytotoxic agents in AML. AB - This study uses single cell network profiling (SCNP) to characterize biological pathways associated with in vitro resistance or sensitivity to chemotherapeutics commonly used in acute myeloid leukemia (AML) (i.e. cytarabine/daunorubicin, gemtuzumab ozogamicin (GO), decitabine, azacitidine, clofarabine). Simultaneous measurements at the single cell level of changes in DNA damage, apoptosis and signaling pathway responses in AML blasts incubated in vitro with the above drugs showed distinct profiles for each sample and mechanistically different profiles between distinct classes of agents. Studies are ongoing to assess the clinical predictive value of these findings. PMID- 22521551 TI - Additional aberrations of the ETV6 and RUNX1 genes have no prognostic impact in 229 t(12;21)(p13;q22)-positive B-cell precursor acute lymphoblastic leukaemias treated according to the NOPHO-ALL-2000 protocol. PMID- 22521553 TI - Evaluation of the genetic diversity of Plum pox virus in a single plum tree. AB - Genetic diversity of Plum pox virus (PPV) and its distribution within a single perennial woody host (plum, Prunus domestica) has been evaluated. A plum tree was triply infected by chip-budding with PPV-M, PPV-D and PPV-Rec isolates in 2003 and left to develop untreated under open field conditions. In September 2010 leaf and fruit samples were collected from different parts of the tree canopy. A 745 bp NIb-CP fragment of PPV genome, containing the hypervariable region encoding the CP N-terminal end was amplified by RT-PCR from each sample and directly sequenced to determine the dominant sequence. In parallel, the PCR products were cloned and a total of 105 individual clones were sequenced. Sequence analysis revealed that after 7 years of infection, only PPV-M was still detectable in the tree and that the two other isolates (PPV-Rec and PPV-D) had been displaced. Despite the fact that the analysis targeted a relatively short portion of the genome, a substantial amount of intra-isolate variability was observed for PPV-M. A total of 51 different haplotypes could be identified from the 105 individual sequences, two of which were largely dominant. However, no clear-cut structuration of the viral population by the tree architecture could be highlighted although the results obtained suggest the possibility of intra leaf/fruit differentiation of the viral population. Comparison of the consensus sequence with the original source isolate showed no difference, suggesting within plant stability of this original isolate under open field conditions. PMID- 22521552 TI - Differences in the characteristics of tolerance to MU-opioid receptor agonists in the colon from wild type and beta-arrestin2 knockout mice. AB - Drawbacks to opioid use include development of analgesic tolerance and persistent constipation. We previously reported that tolerance to morphine develops upon repeated exposure in the isolated ileum but not the isolated colon. The cellular mechanisms of antinociceptive tolerance vary among MU-opioid receptor agonists. In this study, we assess beta-arrestin2 deletion on the development of tolerance to different opioids in ileum and colon circular muscle. Tolerance was determined by assessing the ability of repeated in-vitro opioid exposure to induce contraction of the circular muscle from C57BL/6 wild type (WT) and beta-arrestin2 knockout (KO) mice. Repeated exposure every 30 min with in-between washes resulted in tolerance to all agonists in the ileum of both WT and KO mice. However, in the colon of WT mice, comparison of the contractions between the 4th exposure and 1st response was similar to DAMGO (100 +/- 10%; N=5) but reduced to fentanyl (62 +/- 13%; N=8) and etorphine (38 +/- 4%; N=7) indicative of tolerance to fentanyl and etorphine but not DAMGO. In contrast, all agonists produced tolerance in the colon of KO: DAMGO response at the 4th exposure decreased to 52 +/- 10% (N=5), fentanyl to 20 +/- 5% (N=6) and etorphine 33 +/- 7% (N=6). Differences in tolerance among opioid agonists in the colon suggest ligand bias. The deletion of beta-arrestin2 in colon appears to be necessary for tolerance to DAMGO but not fentanyl or etorphine. beta-arrestin2 potentially represents an important target for treating opioid-induced bowel dysfunction and warrants further exploration of its ligand bias. PMID- 22521554 TI - Portal hypertension in children. AB - The main causes of intrahepatic portal hypertension in children are cirrhosis and congenital hepatic fibrosis. Non cirrhotic portal hypertension in children is mostly due to extrahepatic portal vein obstruction. In half of cases, no underlying disorder is found. The meso-Rex bypass is the preferred treatment, when it is possible. The closest to the portal vein the obstruction, the highest the risk of esophagogastric varices. PMID- 22521555 TI - Acute liver failure in children and adolescents. AB - Acute liver failure is a severe and sudden onset of hepatocyte dysfunction, leading on to synthetic and detoxification failure, which could progress to multi organ failure and death. Common causes vary with age and geographical location. Metabolic liver diseases are frequent in the young child, sometimes amenable to a specific treatment or prenatal diagnosis. In older children, viruses, toxics, metabolic diseases (especially Wilson), autoimmune hepatitis are the main causes. Management should be initiated in conjunction with investigations, as soon as liver failure is diagnosed. The patients should be early transferred to an expert centre, where complications can be prevented and liver transplantation is possible. Improved intensive care management and availability of donor organs (split livers or living-related donors) has made it possible to transplant young children, and improved their survival chances. PMID- 22521556 TI - Complications of chronic liver disease. AB - Children with chronic liver disease (CLD) need a head to toe approach and an early suspicion of multi organ involvement. Nutritional assessment and management is the cornerstone of management. Consider immune dysfunction in everyday treatment decisions. Consider early heart-lung-brain involvement in transplant evaluation. PMID- 22521557 TI - Hepatitis B virus infection in children. AB - Hepatitis B can develop in less than 5% of neonates of infected mothers, despite neonatal serovaccination. Most children will develop a chronic hepatitis. Most children are in an immune-tolerant or in an inactive phase. Interferon is the treatment of choice, in the rare cases where it is necessary. PMID- 22521558 TI - Non-alcoholic fatty liver disease in children. AB - Non-alcoholic fatty liver disease is increasingly prevalent in children, together with obesity. Transaminases, tests for insulin resistance, ultrasonography and MRI are variably used as surrogates markers of steatosis. Other liver diseases, such as Wilson disease, should be excluded. A liver biopsy is performed in selected cases: young children, familial history of severe disease, inconclusive tests for other pathologies, suspected advanced fibrosis, hypertransaminasemia despite weight loss and in clinical trials. Weight reduction, and changes in lifestyle, are the front-line treatment. Drug therapy is under evaluation. PMID- 22521559 TI - Hepatitis C infection in childhood. AB - Hepatitis C infection in children has a different course than in adults, with higher rates of spontaneous clearance. Prenatal (vertical) transmission is the most common route of transmission in childhood. Only a high maternal viral load and HIV co-infection have been proven to increase the risk of infection in the offspring. There is thus no evidence to recommend abstinence from breastfeeding, or elective C-section to prevent transmission. Standard interferon, pegylated interferon and ribavirin are the only approved therapies in children. Severe liver disease is extremely rare in childhood, and described mainly in patients contaminated through blood transfusion. PMID- 22521560 TI - Dendritic cell therapy in advanced gastric cancer: a promising new hope? AB - Advanced gastric cancer carries a very poor prognosis when the tumor becomes unresectable. Even with the best currently available chemotherapy regimens the survival rate remains dismal. A recent breakthrough in the treatment paradigm has been the approval of trastuzumab, a monoclonal antibody, in HER2-positive metastatic gastric cancer. A large number of trials are underway using dendritic cells (DCs) in a number of human malignancies and do show a ray of hope in management of these patients. This review attempts to summarize tumor immunology and the current data regarding use of DCs in gastric cancer therapy. PMID- 22521561 TI - Increase in breast cancer incidence among older women in Mumbai: 30-year trends and predictions to 2025. AB - BACKGROUND: Increasing trends in the incidence of breast cancer have been observed in India, including Mumbai. These have likely stemmed from an increasing adoption of lifestyle factors more akin to those commonly observed in westernized countries. Analyses of breast cancer trends and corresponding estimation of the future burden are necessary to better plan rationale cancer control programmes within the country. METHODS: We used data from the population-based Mumbai Cancer Registry to study time trends in breast cancer incidence rates 1976-2005 and stratified them according to younger (25-49) and older age group (50-74). Age period-cohort models were fitted and the net drift used as a measure of the estimated annual percentage change (EAPC). Age-period-cohort models and population projections were used to predict the age-adjusted rates and number of breast cancer cases circa 2025. RESULTS: Breast cancer incidence increased significantly among older women over three decades (EAPC = 1.6%; 95% CI 1.1-2.0), while lesser but significant 1% increase in incidence among younger women was observed (EAPC = 1.0; 95% CI 0.2-1.8). Non-linear period and cohort effects were observed; a trends-based model predicted a close-to-doubling of incident cases by 2025 from 1300 mean cases per annum in 2001-2005 to over 2500 cases in 2021-2025. CONCLUSIONS: The incidence of breast cancer has increased in Mumbai during last two to three decades, with increases greater among older women. The number of breast cancer cases is predicted to double to over 2500 cases, the vast majority affecting older women. PMID- 22521562 TI - CHEK2 1100delC, IVS2+1G>A and I157T mutations are not present in colorectal cancer cases from Turkish population. AB - BACKGROUND: The cell cycle checkpoint kinase 2 (CHEK2) protein participates in the DNA damage response in many cell types. Germline mutations in CHEK2 (1100delC, IVS2+1G>A and I157T) have been impaired serine/threonine kinase activity and associated with a range of cancer types. This hospital-based case control study aimed to investigate whether CHEK2 1100delC, IVS2+1G>A and I157T mutations play an important role in the development of colorectal cancer (CRC) in Turkish population. METHODS: A total of 210 CRC cases and 446 cancer-free controls were genotyped for CHEK2 mutations by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and allele specific polymerase chain reaction (AS-PCR) methods. RESULTS: We did not find the CHEK2 1100delC, IVS2+1G>A and I157T mutations in any of the Turkish subjects. CONCLUSION: Our result demonstrate for the first time that CHEK2 1100delC, IVS2+1G>A and I157T mutations have not been agenetic susceptibility factor for CRC in the Turkish population. Overall, our data suggest that genotyping of CHEK2 mutations in clinical settings in the Turkish population should not be recommended. However, independent studies are need to validate our findings in a larger series, as well as in patients of different ethnic origins. PMID- 22521564 TI - Position paper: The membrane estrogen receptor GPER--Clues and questions. AB - Rapid signaling of estrogen involves membrane estrogen receptors (ERs), including membrane subpopulations of ERalpha and ERbeta. In the mid-1990s, several laboratories independently reported the cloning of an orphan G protein-coupled receptor from vascular and cancer cells that was named GPR30. Research published between 2000 and 2005 provided evidence that GPR30 binds and signals via estrogen indicating that this intracellular receptor is involved in rapid, non-genomic estrogen signaling. The receptor has since been designated as the G protein coupled estrogen receptor (GPER) by the International Union of Pharmacology. The availability of genetic tools such as different lines of GPER knock-out mice, as well as GPER-selective agonists and antagonists has advanced our understanding, but also added some confusion about the new function of this receptor. GPER not only binds estrogens but also other substances, including SERMs, SERDs, and environmental ER activators (endocrine disruptors; xenoestrogens) and also interacts with other proteins. This article represents a summary of a lecture given at the 7(th) International Meeting on Rapid Responses to Steroid Hormones in September 2011 in Axos, Crete, and reviews the current knowledge and questions about GPER-dependent signaling and function. Controversies that have complicated our understanding of GPER, including interactions with human ERalpha-36 and aldosterone as a potential ligand, will also be discussed. PMID- 22521563 TI - Methionine sulfoxide reductase contributes to meeting dietary methionine requirements. AB - Methionine sulfoxide reductases are present in all aerobic organisms. They contribute to antioxidant defenses by reducing methionine sulfoxide in proteins back to methionine. However, the actual in vivo roles of these reductases are not well defined. Since methionine is an essential amino acid in mammals, we hypothesized that methionine sulfoxide reductases may provide a portion of the dietary methionine requirement by recycling methionine sulfoxide. We used a classical bioassay, the growth of weanling mice fed diets varying in methionine, and applied it to mice genetically engineered to alter the levels of methionine sulfoxide reductase A or B1. Mice of all genotypes were growth retarded when raised on chow containing 0.10% methionine instead of the standard 0.45% methionine. Retardation was significantly greater in knockout mice lacking both reductases. We conclude that the methionine sulfoxide reductases can provide methionine for growth in mice with limited intake of methionine, such as may occur in the wild. PMID- 22521565 TI - Metabolic regulatory effects of licorice: a bile acid metabonomic study by liquid chromatography coupled with tandem mass spectrometry. AB - Licorice is one of the most popular herbal medicines worldwide, and is mainly used to moderate the characteristics of other herbs in Traditional Chinese Medicine. It is hypothesized that licorice exerts this role by regulating systemic metabolism. Bile acids play a critical role in lipid digestion and cholesterol metabolism, and are sensitive biomarkers for hepatic function. In this study, the regulatory effects of licorice on bile acid metabonome in rats were investigated using liquid chromatography coupled with tandem mass spectrometry. After oral administration of a clinical dosage of licorice water extract, the levels of 21 fully identified and 41 tentatively characterized bile acid analogs in rat plasma were determined by a fully validated method. Following partial least squares discriminant analysis, the results showed that licorice treatment led to dose-dependent up-regulation of free and glycine-conjugated bile acids excretion. Particularly, the plasma levels of cholic acid (1465.33+/-915.93 7156.46+/-3490.49 ng/mL, p=0.0027) and beta-muricholic acid (228.19+/-163.95 1284.40+/-775.62 ng/mL, p=0.0045) increased significantly 48 h after administration. As licorice is widely used as a detoxifying drug, the regulation of plasma bile acids may be an important evidence to interpret its mechanism. PMID- 22521566 TI - Evidence for a rationale use of frozen plasma for the treatment and prevention of bleeding. AB - Frozen plasma is a commonly used blood product. The primary indication for frozen plasma is the treatment and prevention of bleeding in patients with prolonged coagulation tests. Unfortunately, there is a lack of well conducted clinical trials to determine the appropriate indications for frozen plasma and, as a result, a large proportion of frozen plasma transfusions are inappropriate according to current guidelines. As an alternative approach to foster improved transfusion practice, we outline a recently described paradigm for the use of frozen plasma to prevent and treat bleeding: (1) prolonged coagulation tests increase the risk of bleeding, (2) frozen plasma will correct abnormal coagulations and (3) correcting abnormal coagulation with frozen plasma transfusions will reduce bleeding. However, the evidence does not support either of the first two tenets, which suggests that transfusing frozen plasma will not reduce bleeding in some situations. Targeting these situations may allow an opportunity to improve current utilization of frozen plasma. PMID- 22521567 TI - The impact of donor selection on blood safety in Iran. AB - INTRODUCTION: Donor selection is a critical process to identify high risk volunteers and defer them from donating blood. Despite viral screening test on all donated blood, one cannot rely on screening tests alone to ensure a safe blood supply. Monitoring and assessment of the deferral procedure is of utmost importance to balance blood availability and safety. This study compares the prevalence of HIV, HCV, and HBV markers between deferred donors and accepted blood donors in order to evaluate the effectiveness of the current donor selection process in Iran. MATERIALS AND METHODS: This study was carried out on deferred blood donors throughout the country. A blood sample was collected from participants and tested for three viral markers: HbsAg, anti-HCV, and anti-HIV. Repeatedly reactive samples were retested with a confirmatory screening assay. The prevalence of viral markers among deferred donors was compared with national statistical data on blood donors. RESULTS: The prevalence of HIV, Hepatitis B, and Hepatitis C was 120 (CI 95%; 90-150), 1280 (CI 95%; 1170-1390), and 580 (CI 95%; 510-650) in 100,000 deferred donors respectively. A significant increase exists in the prevalence of HBV (1.7 times), HIV (24 times) and HCV (15 times) in deferred donors as compared to accepted blood donors. DISCUSSION: The effectiveness of donor selection in identifying high risk individuals is obvious upon comparing the prevalence of selected viral infections in deferred donors with those accepted for blood donation. This study showed the role and necessity of donor selection criteria. PMID- 22521568 TI - Low rates of synonymous mutations in sequences of Mycobacterium tuberculosis GyrA and KatG genes. AB - Partial sequences of KatG and GyrA genes have been obtained from multi and extensively drug-resistant (MDR and XDR) clinical isolates of Mycobacterium tuberculosis. Nonsynonymous (DN) and synonymous (DS) distances between those sequences have been calculated by Kumar method. Results revealed that DN is significantly higher than DS between some pairs of partial GyrA sequences. We found out that DN is higher than DS in many other partial and complete sequences of KatG and GyrA coding regions deposited in GenBank. The cause of the DN > DS situation is in several nonsynonymous substitutions occurrence (which may be associated with drug-resistance or not) in the absence of synonymous substitutions. Low rates of synonymous mutations occurrence is a consequence of the strong mutational GC-pressure. Due to the high saturation of third codon positions by guanine and cytosine (78.81 +/- 0.17% for all the genes from M. tuberculosis H37Rv genome), the probability to be synonymous for the nucleotide mutation of preferable (AT to GC) direction is low. Fixation of a single nonsynonymous mutation leading to drug-resistance is a consequence of Darwinian selection. This clear example of Darwinian selection on the molecular level can be confirmed by selection test (DN > DS) only in case of DN and DS calculation in pairs of sequences possessing at least two additional nonsynonymous mutations which may be neutral or excessive. PMID- 22521569 TI - Sialylation of Streptococcus suis serotype 2 is essential for capsule expression but is not responsible for the main capsular epitope. AB - The capsular polysaccharide is a critical virulence factor of the swine and zoonotic pathogen Streptococcus suis serotype 2. The capsule of this bacterium is composed of five different sugars, including terminal sialic acid. To evaluate the role of sialic acid in the pathogenesis of the infection, the neuC gene, encoding for an enzyme essential for sialic acid biosynthesis, was inactivated in a highly virulent S. suis serotype 2 strain. Using transmission electron microscopy, it was shown that inactivation of neuC resulted in loss of expression of the whole capsule. Compared to the parent strain, the DeltaneuC mutant strain was more phagocytosed by macrophages and was also severely impaired in virulence in a mouse infection model. Both native and desialylated S. suis serotype 2 purified capsular polysaccharides were recognized by a polyclonal anti-whole cell S. suis serotype 2 serum and a monospecific polyclonal anti-capsule serotype 2 serum. In contrast, only the native capsular polysaccharide was recognized by a monoclonal antibody specific for the sialic acid moiety of the serotype 2 capsule. Together, our results infer that sialylation of S. suis serotype 2 may be essential for capsule expression, but that this sugar is not the main epitope of this serotype. PMID- 22521571 TI - The TBX21 transcription factor T-1993C polymorphism is associated with decreased IFN-gamma and IL-4 production by primary human lymphocytes. AB - T-bet is a transcription factor that drives the Th1 immune response primarily through promoting expression of the IFN-gamma gene. Polymorphisms in the T-bet gene, TBX21, have been associated with immune-mediated diseases such as asthma and systemic sclerosis. We found that the TBX21 promoter polymorphism T-1993C is associated with a significant decrease in IL-4 and IFN-gamma production by stimulated primary human lymphocytes from healthy participants. PMID- 22521572 TI - Spatio-temporal biodiversity of soft bottom macrofaunal assemblages in shallow coastal waters exposed to episodic hypoxic events. AB - The Humboldt Current System (HCS) has one of the three most important oxygen minimum zones (OMZ) of the global ocean. Several studies have looked at the macrofaunal benthic assemblages inhabiting the continental shelf and shallow bays off central-southern Chile associated with low oxygen areas, but little is known about open coast macrofaunal communities within this zone, which are frequently subjected to the low oxygen conditions of Equatorial Subsurface Waters (ESSW). In order to assess local and mesoscale coastal macrofauna dynamics, the sampling area (ca. 40 linear km) was divided into seven local zones (Cobquecura, southern Cobquecura, northern Itata, Itata River mouth, external, southern Itata, and Coliumo). Eight oceanographic cruises were carried out between May 2006 and February 2008 covering 16 coastal sampling sites, between 36 degrees 07'S and 36 degrees 30'S. The macrofaunal assemblage was dominated by polychaetes, crustaceans, and mollusks. Our results suggest a high degree of temporal faunal stability on the mesoscale in soft bottom communities along the open coast, given the persistence of a faunal assemblage dominated by organisms tolerant of low oxygen conditions. While there is some local variability in community attributes, the main structuring factor for soft bottom communities in the shallow coastal area off central-southern Chile is the seasonal intrusion of low oxygen ESSW. PMID- 22521573 TI - CLASI-FISH: principles of combinatorial labeling and spectral imaging. AB - Although the number of phylotypes present in a microbial community may number in the hundreds or more, until recently, fluorescence in situ hybridization has been used to label, at most, only a handful of different phylotypes in a single sample. We recently developed a technique, CLASI-FISH for combinatorial labeling and spectral imaging - fluorescence in situ hybridization, to greatly expand the number of distinguishable taxa in a single FISH experiment. The CLASI technique involves labeling microbes of interest with combinations of probes coupled with spectral imaging to allow the use of fluorophores with highly overlapping excitation and emission spectra. Here, we present the basic principles and theory of CLASI-FISH along with some guidelines for performing CLASI-FISH experiments. We further include a protocol for creating fluorescence spectral reference standards, a vital component of successful CLASI-FISH. PMID- 22521570 TI - Bacterial endophthalmitis in the age of outpatient intravitreal therapies and cataract surgeries: host-microbe interactions in intraocular infection. AB - Bacterial endophthalmitis is a sight threatening infection of the interior structures of the eye. Incidence in the US has increased in recent years, which appears to be related to procedures being performed on an aging population. The advent of outpatient intravitreal therapy for management of age-related macular degeneration raises yet additional risks. Compounding the problem is the continuing progression of antibiotic resistance. Visual prognosis for endophthalmitis depends on the virulence of the causative organism, the severity of intraocular inflammation, and the timeliness of effective therapy. We review the current understanding of the pathogenesis of bacterial endophthalmitis, highlighting opportunities for the development of improved therapeutics and preventive strategies. PMID- 22521574 TI - MLSA barcoding of Marichromatium spp. and reclassification of Marichromatium fluminis (Sucharita et al., 2010) as Phaeochromatium fluminis gen. nov. comb. nov. AB - Thirty-one members of the genus Marichromatium were analysed based on multilocus sequence analysis (MLSA) of four concatenated protein-coding genes (fusA, pufM, dnaK, recA) along with the internal transcribed spacer (ITS; 16S-23S rRNA) region and 16S rRNA gene. The restriction patterns obtained from the in silico analysis of the concatenated sequences were good barcodes for the identification of Marichromatium spp. Distinct phenotypic, chemotaxonomic and molecular differences allowed the separation of Marichromatium fluminis JA418(T) into a new genus in the family Chromatiaceae, for which we propose the name Phaeochromatium fluminis gen. nov. comb. nov. PMID- 22521575 TI - Classification and codification of rare diseases. PMID- 22521577 TI - Ensuring relevance for Cochrane reviews: evaluating processes and methods for prioritizing topics for Cochrane reviews. AB - OBJECTIVE: The purpose of this study was to assess the presence and effectiveness of existing systems of prioritization for Cochrane review topics and to explore methods of improving those systems. STUDY DESIGN AND SETTING: We surveyed groups of Cochrane review authors and recorded any evidence of their use of priority setting processes or policies. To evaluate the effectiveness of the policies we encountered, we assessed them using two frameworks from the literature: "Accountability for Reasonableness" (1) and Sibbald's 2009 framework (2) for successful priority setting. We then held two workshops with the subject groups to discuss our findings and their implications. RESULTS: Of the 66 groups surveyed, 29 had a system in place to inform the selection or prioritization of topics for Cochrane reviews. Fifteen groups used a more comprehensive structured approach that eventually resulted in a list of ranked priority titles for authoring, updating, or disseminating Cochrane reviews. Most groups involved researchers, practitioners, and patients in their prioritization processes. CONCLUSION: Groups within The Cochrane Collaboration currently use a range of different priority-setting systems, some of which are more detailed than others. These differences often reflect the nature of The Cochrane Collaboration itself: given the topic breadth, history, and variety of international contexts present in the organization, a single unified system would not always be appropriate. All Cochrane entities, however, should have or develop strategic plans to improve the inclusiveness and transparency of their own prioritization processes, increase the number of finished prioritized reviews, and make more effective use of feedback from end users to increase the likelihood of producing reviews that have positive effects on health outcomes. PMID- 22521578 TI - Risk factors for tuberculosis among health care workers in South India: a nested case-control study. AB - OBJECTIVE: The epidemiology of tuberculosis (TB) among health care workers (HCWs) in India remains under-researched. This study is a nested case-control design assessing the risk factors for acquiring TB among HCWs in India. STUDY DESIGN AND SETTINGS: It is a nested case-control study conducted at a tertiary teaching hospital in India. Cases (n = 101) were HCWs with active TB. Controls (n = 101) were HCWs who did not have TB, randomly selected from the 6,003 subjects employed at the facility. Cases and controls were compared with respect to clinical and demographic variables. RESULTS: The cases and controls were of similar age. Logistic regression analysis showed that body mass index (BMI) <19 kg/m(2) (odds ratio [OR]: 2.96, 95% confidence interval [CI]: 1.49-5.87), having frequent contact with patients (OR: 2.83, 95% CI: 1.47-5.45) and being employed in medical wards (OR: 12.37, 95% CI: 1.38-110.17) or microbiology laboratories (OR: 5.65, 95% CI: 1.74-18.36) were independently associated with increased risk of acquiring TB. CONCLUSION: HCWs with frequent patient contact and those with BMI <19 kg/m(2) were at high risk of acquiring active TB. Nosocomial transmission of TB was pronounced in locations, such as medical wards and microbiology laboratories. Surveillance of high-risk HCWs and appropriate infrastructure modifications may be important to prevent interpersonal TB transmission in health care facilities. PMID- 22521576 TI - Hearing, mobility, and pain predict mortality: a longitudinal population-based study. AB - OBJECTIVE: Measures of health-related quality of life (HRQL), including the Health Utilities Index Mark 3 (HUI3) are predictive of mortality. HUI3 includes eight attributes, vision, hearing, speech, ambulation, dexterity, cognition, emotion, and pain and discomfort, with five or six levels per attribute that vary from no to severe disability. This study examined associations between individual HUI3 attributes and mortality. STUDY DESIGN AND SETTING: Baseline data and 12 years of follow-up data from a closed longitudinal cohort study, the 1994/95 Canadian National Population Health Survey, consisting of 12,375 women and men aged 18 and older. A priori hypotheses were that ambulation, cognition, emotion, and pain would predict mortality. Cox proportional hazards regression models were applied controlling for standard determinants of health and risk factors. RESULTS: Single-attribute utility scores for ambulation (hazard ratio [HR]=0.10; 0.04-0.22), hearing (HR=0.18; 0.06-0.57), and pain (HR=0.53; 0.29-0.96) were statistically significantly associated with an increased risk of mortality; ambulation and hearing were predictive for the 60+ cohort. CONCLUSION: Few studies have identified hearing or pain as risk factors for mortality. This study is innovative because it identifies specific components of HRQL that predict mortality. Further research is needed to understand better the mechanisms through which deficits in hearing and pain affect mortality risks. PMID- 22521579 TI - Directed acyclic graphs can help understand bias in indirect and mixed treatment comparisons. AB - OBJECTIVE: To introduce and advocate directed acyclic graphs (DAGs) as a useful tool to understand when indirect and mixed treatment comparisons are invalid and guide strategies that limit bias. STUDY DESIGN AND SETTING: By means of DAGs, it is heuristically explained when indirect and mixed treatment comparisons are biased, and whether statistical adjustment of imbalances in study and patient characteristics across different comparisons in the network of RCTs is appropriate. RESULTS: A major threat to the validity of indirect and mixed treatment comparisons is a difference in modifiers of the relative treatment effect across comparisons, and statistically adjusting for these differences can improve comparability and remove bias. However, adjustment for differences in covariates across comparisons that are not effect modifiers is not necessary and can even introduce bias. As a special case, we outline that adjustment for the baseline risk might be useful to improve similarity and consistency, but may also bias findings. CONCLUSION: DAGs are useful to evaluate conceptually the assumptions underlying indirect and mixed treatment comparison, to identify sources of bias and guide the implementation of analytical methods used for network meta-analysis of RCTs. PMID- 22521580 TI - Ten years of structural reforms in Danish healthcare. AB - A major structural reform of the Danish public sector took place in 2007 when the number of administrative units at the regional and municipal levels was reduced. The larger administrative units allowed for a new hospital structure with a reduced number of acute hospitals covering a population of between 200,000 and 400,000 inhabitants. The restructuring involves creation of acute hospitals with a 24-h acute service by a range of specialists. The idea was to weight quality higher than geographical closeness to the nearest hospital. Concurrently, the pre hospital service will be expanded. The National Board of Health was given authority to approve regional plans for specialties rather than provide guidelines. The use of private hospitals was increased as a means to fulfil a waiting time guarantee of between 2 and 1 month. Increased use of private insurance also increased use of private hospitals. A new way of financing health care was intended to give municipalities incentives to invest in health prevention and health promotion. Concurrent reforms included economic incentives to increase hospital production as measured by DRGs; quality programmes to secure high quality and patient safety; and electronic patient records and increased use of IT systems. PMID- 22521581 TI - Glutamatergic projection from the nucleus incertus to the septohippocampal system. AB - Recent findings support a relevant role of the nucleus incertus in the control of the hippocampal activity through the modulation of theta rhythm. Previous studies from our group have shown that this nucleus is a critical relay between reticularis pontis oralis and the medial septum/diagonal band, regarded as the main activator and the pacemaker of the hippocampal oscillations, respectively. Besides, the nucleus incertus is highly linked to activated states related to the arousal response. The neurotransmission of the nucleus incertus, however, remains uncertain. Only GABA and the neuromodulator relaxin 3 are usually considered to be involved in its contribution to the septohippocampal system. In this work, we have analyzed the existence of an excitatory projection from the nucleus incertus to the medial septum. We have found a group of glutamatergic neurons in the nucleus incertus projecting to the medial septum. Moreover, we were able to describe a segregated distribution of calbindin and calretinin neurons. While calretinin expression was restricted to the nucleus incertus pars compacta, calbindin positive neurons where observed both in the pars dissipata and the pars compacta of the nucleus. The present work provides innovative data supporting an excitatory component in the pontoseptal pathway. PMID- 22521582 TI - PBN fails to suppress in delayed neuronal death of hippocampal CA1 injury following transient forebrain ischemia in gerbils. AB - Free radicals have been suggested to be involved in the genesis of ischemic brain damage, as shown by the protective effects of alpha-phenyl-N-tert-butyl nitrone (PBN), a spin trapping agent, in ischemic cerebral injury. However, the involvement of free radicals in transient ischemic-induced delayed neuronal death is not fully understood. To clarify this, in the present study, we evaluated the effect of PBN on delayed neuronal death and on the levels of free radicals in hippocampal CA1 region in the gerbil. The administration of PBN (10 mg/kg, i.v.) failed to show any preventive effect on the delayed neuronal death, examined by hematoxylin and eosin staining and the TUNEL method. Furthermore, we observed no free radical formation in delayed neuronal death, determined immunohistochemically using a specific 8-OHdG antibody, after transient ischemic insult. These results suggest that free radical formation may not contribute to the formation of delayed neuronal death. PMID- 22521583 TI - Chronic nicotine exposure inhibits estrogen-mediated synaptic functions in hippocampus of female rats. AB - Nicotine, the addictive agent in cigarettes, reduces circulating estradiol-17beta (E2) and inhibits E2-mediated intracellular signaling in hippocampus of female rats. In hippocampus, E2-signaling regulates synaptic plasticity by phosphorylation of the N-methyl-D-aspartic acid receptor subunit NR2B and cyclic AMP response element binding protein (pCREB). Therefore, we hypothesized that chronic nicotine exposure induces synaptic dysfunction in hippocampus of female rats. Female rats were exposed to nicotine or saline for 16 days followed by electrophysiological analysis of hippocampus. Briefly, population measurements of excitatory post-synaptic field potentials (fEPSPs) were recorded from stratum radiatum of the CA1 hippocampal slice subfield. A strict software-controlled protocol was used which recorded 30 min of baseline data (stimulation rate of 1/min), a paired-pulse stimulation sequence followed by tetanic stimulation, and 1h of post-tetanus recording. EPSP amplitude and the initial EPSP slope were measured off-line. We then investigated by Western blot analysis the effects of nicotine on hippocampal estrogen receptor-beta (ER-beta), NR2B and pCREB. The results demonstrated significantly decreased post-tetanic potentiation and paired pulse facilitation at the 40, and 80 ms interval in nicotine-exposed rats compared to the saline group. Western blot analysis revealed that nicotine decreased protein levels of ER-beta, NR2B, and pCREB. We also confirmed the role of E2 in regulating NR2B and pCREB phosphorylation by performing Western blots in hippocapmal tissue obtained from E2-treated ovariectomized rats. In conclusion, chronic nicotine exposure attenuates short-term synaptic plasticity, and the observed synaptic defects might be a consequence of loss of estradiol-17beta signaling. However, determining the exact molecular mechanisms of chronic nicotine exposure on synaptic plasticity specific to the female brain require further investigation. PMID- 22521584 TI - Elevated cerebrospinal fluid sphingomyelin levels in prodromal Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common neurodegenerative disorder, but still without known disease mechanism, proper treatment and efficient diagnostic tools for an early stage diagnosis. There is increasing evidence that lipids, especially cholesterol and sphingolipids, may play a role in pathological processes that occur in the AD brain even in very early stages of the disease. However, lipid changes in cerebrospinal fluid (CSF) of individuals with AD have not been well studied. In previous work, we developed a reproducible and sensitive nano-HPLC-MS method for CSF phospholipids screening and conducted a pilot study to find potential phospholipid changes in CSF from individuals with AD dementia. We observed a slight increase (24%) of sphingomyelin (SM) in CSF samples from patients with probable AD compared to non-demented controls. The goal of this work was to validate our findings and to analyze how SM CSF levels change in different stages of AD from prodromal to mild and moderate AD. We found significantly increased SM levels (50.4+/-11.2%, p=0.003) in the CSF from individuals with prodromal AD compared to cognitively normal controls, but no change in CSF SM levels between mild and moderate AD groups and cognitively normal controls. These results suggest that alterations in the SM metabolism may contribute to early pathological processes leading to AD. PMID- 22521585 TI - Reduced protein O-glycosylation in the nervous system of the mutant SOD1 transgenic mouse model of amyotrophic lateral sclerosis. AB - In the neurodegenerative disease amyotrophic lateral sclerosis (ALS), a number of proteins have been found to be hyperphosphorylated, including neurofilament proteins (NFs). In addition to protein phosphorylation, another important post translational modification is O-glycosylation with beta-N-acetylglucosamine residues (O-GlcNAc) and it has been found that O-GlcNAc can modify proteins competitively with protein phosphorylation, so that increased O-GlcNAc can reduce phosphorylation at specific sites. We evaluated a transgenic mouse model of ALS that overexpresses mutant superoxide dismutase (mSOD) and found that O-GlcNAc immunoreactivity levels are decreased in spinal cord tissue from mSOD mice, compared to controls. This reduction in O-GlcNAc levels is prominent in the motor neurons of spinal cord. We find that inhibition of O-GlcNAcase (OGA), the enzyme catalyzing removal of O-GlcNAc, using the inhibitor NButGT for 3 days, resulted in increased O-GlcNAc levels in spinal cord, both in mSOD and control mice. Furthermore, NButGT increased levels of O-GlcNAc modified NF-medium in spinal cords of control mice, but not in mSOD mice. These observations suggest that the neurodegeneration found in mSOD mice is associated with a reduction of O-GlcNAc levels in neurons, including motor neurons. PMID- 22521587 TI - Microdialysis: characterisation of haematomas in myocutaneous flaps by use of biochemical agents. AB - Metabolic markers are measured by microdialysis to detect postoperative ischaemia after reconstructive surgery with myocutaneous flaps. If a haematoma develops around the microdialysis catheter, it can result in misinterpretation of the measurements. The aim of the present study was to investigate whether a haematoma in a flap can be identified and dissociated from ischaemia, or a well-perfused flap, by a characteristic chemical profile. In 7 pigs, the pedicled rectus abdominal muscle flap was mobilised on both sides. A haematoma was made in each flap and two microdialysis catheters were placed, one in the haematoma, and the other in normal tissue. One flap was made ischaemic by ligation of the pedicle. For 6 hours, the metabolism was monitored by measurement every half-an-hour of the concentrations of glucose, lactate, pyruvate, and glycerol from all 4 catheters. After 3 hours of monitoring, intravenous glucose was given as a challenge test to identify ischaemia. The non-ischaemic flap could be differentiated from the ischaemic flap by low glucose, and high lactate, concentrations. It was possible to identify a catheter surrounded by a haematoma in ischaemic as well as non-ischaemic muscle from a low or decreasing concentration of glucose together with a low concentration of lactate. All four sites could be completely dissociated when the concentrations of glucose and lactate were evaluated and combined with the lactate:glucose ratio and a flow chart. The challenge test was useful for differentiating between haematomas in ischaemic and non-ischaemic tissue. PMID- 22521586 TI - Neuronal D-serine regulates dendritic architecture in the somatosensory cortex. AB - D-Serine, which is synthesized by the enzyme serine racemase (SR), is a co agonist at the N-methyl-D-aspartate receptor (NMDAR). In an animal model of NMDAR hypofunction, the constitutive SR knockout (SR-/-) mouse, pyramidal neurons in primary somatosensory cortex (S1) have reductions in the complexity, total length, and spine density of apical and basal dendrites. We wondered whether the dendritic pathology required deprivation of D-serine throughout development or reflected the loss of D-serine only in adulthood. To address this question, we used mice homozygous for floxed SR in which we bred CaMKIICre2834, which is expressed in forebrain glutamatergic neurons starting at 3-4 weeks post-partum (nSR-/-). Our prior studies demonstrated that the majority of cortical SR is expressed in glutamatergic neurons. We found that similar to SR-/- mice, pyramidal neurons in S1 of nSR-/- also had significantly reduced dendritic arborization and spine density, albeit to a lesser degree. S1 neurons of nSR-/- mice had reduced total basal dendritic length that was accompanied by less complex arborization. These characteristics were unaltered in the apical dendritic compartment. In contrast, spine density on S1 neurons was significantly reduced on apical, but not basal dendrites of nSR-/- mice. These results demonstrate that in adulthood neuronally derived D-serine, which is required for optimal activation of post-synaptic NMDAR activity, regulates pyramidal neuron dendritic arborization and spine density. Moreover, they highlight the glycine modulatory site (GMS) of the NMDAR as a potential target for therapeutic intervention in diseases characterized by synaptic deficits, like schizophrenia. PMID- 22521588 TI - miR-32 and its target SLC45A3 regulate the lipid metabolism of oligodendrocytes and myelin. AB - Oligodendrocytes generate large amounts of myelin by extension of their cell membranes. Though lipid is the major component of myelin, detailed lipid metabolism in the maintenance of myelin is not understood. We reported previously that miR-32 might be involved in myelin maintenance (Shin et al., 2009). Here we demonstrate a novel role for miR-32 in oligodendrocyte function and development through the regulation of SLC45A3 (solute carrier family 45, member 3) and other downstream targets such as CLDN-11. miR-32 is highly expressed in the myelin enriched regions of the brain and mature oligodendrocytes, and it promotes myelin protein expression. We found that miR-32 directly regulates the expression of SLC45A3 by binding to the complementary sequence on the 3'UTR of cldn11 and slc45a3. As a myelin-enriched putative sugar transporter, SLC45A3 enhances intracellular glucose levels and the synthesis of long-chain fatty acids. Therefore, overexpression of SLC45A3 triggers neutral lipid accumulation. Interestingly, both overexpression and suppression of SLC45A3 reduces myelin protein expression in mature oligodendrocytes and alters oligodendrocyte morphology, indicating that tight regulation of SLC45A3 expression is necessary for the proper maintenance of myelin proteins and structure. Taken together, our data suggest that miR-32 and its downstream target SLC45A3 play important roles in myelin maintenance by modulating glucose and lipid metabolism and myelin protein expression in oligodendrocytes. PMID- 22521589 TI - Photoperiod and stress regulation of corticosteroid receptor, brain-derived neurotrophic factor, and glucose transporter GLUT3 mRNA in the hippocampus of male Siberian hamsters (Phodopus sungorus). AB - In response to changing day lengths, small photoperiodic rodents have evolved a suite of adaptations to survive the energetic bottlenecks of winter. Among these adaptations are changes in metabolism, adiposity, and energy balance. Whereas hypothalamic and neuroendocrine regulation of these adaptations has been extensively studied, the impact of day length, and interaction of day length and stress, on the energy balance of neurons within the central nervous system remains unspecified. Thus, we exposed male Siberian hamsters (Phodopus sungorus) to either short or long day lengths for 14 weeks to induce the full suite of adaptive responses, exposed them to 4h of restraint, and then measured relative mRNA expression in the hippocampus for low- and high-affinity glucocorticoid receptors (glucocorticoid receptor (GR), mineralocorticoid receptor (MR)), brain derived neurotrophic factor (BDNF), and the neuron-specific glucose transporter GLUT3. Independent of photoperiod, restraint elevated plasma cortisol (CORT) concentrations and reduced expression of GR, MR, and BDNF. Neither restraint nor photoperiod significantly altered GLUT3 expression. Among all groups, plasma cortisol concentrations were negatively correlated with GR and MR expression. MR, BDNF, and GLUT3 levels were positively correlated with one another, even when controlling for photoperiod and CORT. Taken together, these results suggest that, as peripheral energy balance changes across day length in this photoperiodic species, the neurons of the hippocampus do not alter relative gene expression levels of three proteins involved in monitoring neuronal glucose regulation and morphology. PMID- 22521590 TI - Sex differences in social interaction behaviors in rats are mediated by extracellular signal-regulated kinase 2 expression in the medial prefrontal cortex. AB - Considerable sex differences occur in the incidence and prevalence of anxiety disorders where women are more anxious than men, particularly in situations where social interaction is required. In preclinical studies, the social interaction test represents a valid animal model to study sex differences in social anxiety. Indeed, female rats engage less in conspecific interactions than their male counterparts, which are behaviors indicative of higher social anxiety in female rats. In this work, we implicated extracellular signal-regulated kinase 2 (ERK2) in the medial prefrontal cortex (mPFC) in mediating social interaction. Indeed, female rats' had lower ERK2 expression compared to male rats, and overexpression of ERK2 in the mPFC increases their social interaction to the level seen in their male counterparts. These data indicate that the sexually dimorphic expression of ERK2 mediates social anxiety-like behaviors. PMID- 22521591 TI - Immune changes of Schistosoma japonicum infections in various rodent disease models. AB - Rodent models for Schistosoma japonicum infections have demonstrated that these animals possess a degree of resistance to schistosome infections that may be both T and B lymphocyte-mediated. However, their exact role is not well-defined and other immune mechanisms are likely to also play a role in protecting against infection. Immunosuppressed and immunocompetent reed voles (Microtus fortis, Mf), rats and mice (n=24/group) were infected with S. japonicum, and animals were sacrificed 42 days later under anesthesia. Neither worms nor eggs were observed in infected immunosuppressed Mf or rats, with the exception of one rat that presented with few eggs. In immunosuppressed mice, changes in the number and size of the worms were not significantly different compared to immunocompetent mice, but worm fecundity was affected. The size and number of granulomas in immunosuppressed animals was also reduced. Analysis of serum antibodies specific to schistosome adult worm antigen at 3 weeks post-infection demonstrated that the levels of antibodies in the sera of rats were significantly higher than in Mf and mice. In addition, Mf serum levels of IL-4 and IL-12 were significantly higher than levels observed in rats and mice. Antibodies and cytokines in the sera of Mf peaked 3 weeks post-infection and then began to decrease, while antibody responses in rats and mice increased gradually between weeks 3-7 post-infection. It is possible that T and B cells have a dual role in both mediating protection and exacerbating disease outcomes. PMID- 22521592 TI - A systematic, functional genomics, and reverse vaccinology approach to the identification of vaccine candidates in the cattle tick, Rhipicephalus microplus. AB - In the post-genomic era, reverse vaccinology is proving promising in the development of vaccines against bacterial and viral diseases, with limited application in ectoparasite vaccine design. In this study, we present a systematic approach using a combination of functional genomics (DNA microarrays) techniques and a pipeline incorporating in silico prediction of subcellular localization and protective antigenicity using VaxiJen for the identification of novel anti-tick vaccine candidates. A total of 791 candidates were identified using this approach, of which 176 are membrane-associated and 86 secreted soluble proteins. A preliminary analysis on the antigenicity of selected membrane proteins using anti-gut antisera yielded candidates with an IgG binding capacity greater than previously identified epitopes of Bm86. Subsequent vaccination trials using recombinant proteins will not only validate this approach, but will also improve subsequent reverse vaccinology approaches for the identification of novel anti-tick vaccine candidates. PMID- 22521593 TI - Intramyocardial bridges: a real indication for cross-sectional cardiac imaging. PMID- 22521594 TI - Paraoxonase 1 polymorphisms L55M and Q192R were not risk factors for Parkinson's disease: a HuGE review and meta-analysis. AB - PURPOSE: The Paraoxonase 1 (PON1) has been studied as a potential candidate gene for Parkinson's disease risk, but direct evidence from genetic association studies remains inconclusive. We performed a meta-analysis pooling data from all relevant studies in order to determine the effects of two PON 1 polymorphisms (L55M and Q192R) on Parkinson's disease. METHODS: We applied a random effects to combine odds ratio (OR) and 95% confidence intervals. Q statistic was used to evaluate the homogeneity, and Egger's test and Funnel plot were used to assess publication bias. In secondary analyses, we examined dominant and recessive models as well. RESULTS: Concerning the PON1 L55M polymorphism, we identified 9 eligible studies (a total of 2582 cases and 3997 controls). The random effects pooled OR was OR=1.29, (0.90, 1.84). Concerning the Q192R polymorphism, we identified 7 eligible studies (a total of 2582 cases and 3997 controls). The random effects pooled OR was OR=1.08(0.81, 1.43). Analysis with dominant and recessive genetic models yielded the same inferences as genotype-based comparisons for both of the two polymorphisms. CONCLUSION: The results of this meta-analysis suggested that both PON1 L55M and Q192R were not responsible for PD. PMID- 22521595 TI - Effect of molecular weight of PGG-paclitaxel conjugates on in vitro and in vivo efficacy. AB - Polymeric prodrugs are one of the most promising chemotherapeutic agent delivery approaches, displaying unique drug release profiles, serum stability, formulation flexibility, and reduced drug resistance. One of the most important aspects of a polymeric prodrug, albeit a less-extensively studied one, is the polymer's molecular weight, which affects particle formation, drug release and PK/PD profiles, drug stability, and cell uptake; these factors in turn affect the prodrug's maximum tolerated dose and anticancer efficacy. Poly(L-gamma glutamylglutamine) (PGG) is a linear polymer designed to improve the therapeutic index of attached drugs. In this study we selected poly(L-gamma glutamylglutamine)-paclitaxel (PGG-PTX), as a model system for the methodical investigation into the effects of the poly(L-gamma-glutamylglutamine) backbone molecular weight on its pharmacological performance. The polymeric prodrug was characterized by NMR, DLS and GPC-MALS, and its anticancer activity in vitro and in vivo was assessed. Herein we present data which provide valuable insight into improving anticancer polymer-based prodrug design and development. PMID- 22521596 TI - Photosystem II and the unique role of bicarbonate: a historical perspective. AB - In photosynthesis, cyanobacteria, algae and plants fix carbon dioxide (CO(2)) into carbohydrates; this is necessary to support life on Earth. Over 50 years ago, Otto Heinrich Warburg discovered a unique stimulatory role of CO(2) in the Hill reaction (i.e., O(2) evolution accompanied by reduction of an artificial electron acceptor), which, obviously, does not include any carbon fixation pathway; Warburg used this discovery to support his idea that O(2) in photosynthesis originates in CO(2). During the 1960s, a large number of researchers attempted to decipher this unique phenomenon, with limited success. In the 1970s, Alan Stemler, in Govindjee's lab, perfected methods to get highly reproducible results, and observed, among other things, that the turnover of Photosystem II (PSII) was stimulated by bicarbonate ions (hydrogen carbonate): the effect would be on the donor or the acceptor, or both sides of PSII. In 1975, Thomas Wydrzynski, also in Govindjee's lab, discovered that there was a definite bicarbonate effect on the electron acceptor (the plastoquinone) side of PSII. The most recent 1.9A crystal structure of PSII, unequivocally shows HCO(3)(-) bound to the non-heme iron that sits in-between the bound primary quinone electron acceptor, Q(A), and the secondary quinone electron acceptor Q(B). In this review, we focus on the historical development of our understanding of this unique bicarbonate effect on the electron acceptor side of PSII, and its mechanism as obtained by biochemical, biophysical and molecular biological approaches in many laboratories around the World. We suggest an atomic level model in which HCO(3)( )/CO(3)(2-) plays a key role in the protonation of the reduced Q(B). In addition, we make comments on the role of bicarbonate on the donor side of PSII, as has been extensively studied in the labs of Alan Stemler (USA) and Vyacheslav Klimov (Russia). We end this review by discussing the uniqueness of bicarbonate's role in oxygenic photosynthesis and its role in the evolutionary development of O(2) evolving PSII. This article is part of a Special Issue entitled: Photosynthesis Research for Sustainability: from Natural to Artificial. PMID- 22521597 TI - Enhancement of validamycin A production by addition of ethanol in fermentation of Streptomyces hygroscopicus 5008. AB - The effect of ethanol on the production of the important agro-antibiotic validamycin A (Val-A) in medium containing agricultural by-products was investigated. Under the optimal condition of ethanol addition, the maximal Val-A production titer reached 18 g/L, which increased by 60% compared to the control. To provide an insight into cell response to ethanol, the intracellular reactive oxygen species (ROS), gene transcription and enzyme activity were determined. Intracellular ROS as the molecular signal was increased in the ethanol condition. Global regulators afsR and glnR were involved in regulation of Val-A biosynthesis, and the transcription of eight Val-A structural genes was enhanced. The activity of glucose-6-phosphate dehydrogenase (G6PD) was enhanced while glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was inhibited. A signal transduction cascade from cell signal response to activated transcription of Val A biosynthetic genes and enhanced antibiotic production is proposed. The information can be helpful for the improvement of large-scale fermentation. PMID- 22521598 TI - Continuous removal of ore floatation reagents by an anaerobic-aerobic biological filter. AB - A laboratory scale up-flow anaerobic-aerobic biological filter was constructed to treat synthetic ore floatation wastewater. Volcanic stone was applied as packing media for aerobic section. Biodegradation of some common ore floatation reagents as potassium ethyl xanthate dithiophosphate and turpentine were evaluated. An average COD reduction rate of 88.7% for potassium ethyl xanthate by the biofilter was obtained at HRT of 6h, air water flow ratio of 10:1 and pH of 7. Its effluent COD concentration varied between 17 and 43 mg/L. Xanthates and dithiophosphate were found to be easily biodegradable, whereas turpentine was not favorable for microorganism to digest. The performance of the reactor fluctuated slightly within the temperature range of 10-35 degrees C. Operation of the biofilter was sensitive to influent pH values. A neutral to weak basic influent was preferred for biofilter to maintain an efficient operation. Anaerobic treatment was able to enhance the biodegradability of influents significantly. PMID- 22521599 TI - Non-cardiogenic mechanisms for the pulmonary edema induced by scorpion venom. PMID- 22521600 TI - Paediatric international travellers from Greece: characteristics and pre-travel recommendations. AB - The aim of this study was to describe the children who seek pre-travel advice in Greece. During 2008-2010, 4065 persons sought pre-travel services in the 57 Prefectures, including 128 (3.15%) children <15 years. Main travel destinations were sub-Saharan Africa (54 children; 42.2%), South America (18; 14.1%), the Middle East (16; 12.5%), the Indian subcontinent (12; 9.4%), and South East Asia (7; 5.5%). Seventy-six children (59.4%) stayed for <1 month, 34 (26.6%) for 1-6 months, and 10 (7.8%) for >6 months. Recreation was the main purpose of travel (81 children; 63.3%), followed by work (24; 18.8%), and to visit friends and relatives (VFRs) (14; 10.9%). Paediatric travellers VFRs stayed more frequently in local residences compared to non-VFR paediatric travellers (85.7% and 20.2%). Children stayed more frequently in local residences and travelled more frequently for recreational purposes or to VFRs (27.3%, 63.3%, and 10.9%, respectively), compared to older travellers (11.9%, 58.8%, and 4%, respectively). Malaria chemoprophylaxis was prescribed for 64.8% of children travelling to sub-Saharan Africa. This study demonstrated clearly that only a very small number of international paediatric travellers seek pre-travel services in Greece. Communication strategies to access paediatric travellers should be developed in order to improve travel medicine services for children in Greece. PMID- 22521601 TI - Microbiological findings from the Haiti disaster. AB - There are few data regarding microbiological findings from the disaster situation in Haiti. A rapid and accurate diagnosis of infection is necessary for the optimal efficacy of antimicrobial therapy, considering the antimicrobial spectrum and the duration of treatment. Furthermore, understanding the microorganisms and their susceptibility profiles is necessary to implement appropriate infection control policies and to contain the emergence and dissemination of Gram-negative multidrug-resistant pathogens. PMID- 22521602 TI - Space representation in the prefrontal cortex. AB - The representation of space and its function in the prefrontal cortex have been examined using a variety of behavioral tasks. Among them, since the delayed response task requires the temporary maintenance of spatial information, this task has been used to examine the mechanisms of spatial representation. In addition, the concept of working memory to explain prefrontal functions has helped us to understand the nature and functions of space representation in the prefrontal cortex. The detailed analysis of delay-period activity observed in spatial working memory tasks has provided important information for understanding space representation in the prefrontal cortex. Directional delay-period activity has been shown to be a neural correlate of the mechanism for temporarily maintaining information and represent spatial information for the visual cue and the saccade. In addition, many task-related prefrontal neurons exhibit spatially selective activities. These neurons are also important components of spatial information processing. In fact, information flow from sensory-related neurons to motor-related neurons has been demonstrated, along with a change in spatial representation as the trial progresses. The dynamic functional interactions among neurons exhibiting different task-related activities and representing different aspects of information could play an essential role in information processing. In addition, information provided from other cortical or subcortical areas might also be necessary for the representation of space in the prefrontal cortex. To better understand the representation of space and its function in the prefrontal cortex, we need to understand the nature of functional interactions between the prefrontal cortex and other cortical and subcortical areas. PMID- 22521603 TI - VirtualToxLab - a platform for estimating the toxic potential of drugs, chemicals and natural products. AB - The VirtualToxLab is an in silico technology for estimating the toxic potential (endocrine and metabolic disruption, some aspects of carcinogenicity and cardiotoxicity) of drugs, chemicals and natural products. The technology is based on an automated protocol that simulates and quantifies the binding of small molecules towards a series of proteins, known or suspected to trigger adverse effects. The toxic potential, a non-linear function ranging from 0.0 (none) to 1.0 (extreme), is derived from the individual binding affinities of a compound towards currently 16 target proteins: 10 nuclear receptors (androgen, estrogen alpha, estrogen beta, glucocorticoid, liver X, mineralocorticoid, peroxisome proliferator-activated receptor gamma, progesterone, thyroid alpha, and thyroid beta), four members of the cytochrome P450 enzyme family (1A2, 2C9, 2D6, and 3A4), a cytosolic transcription factor (aryl hydrocarbon receptor) and a potassium ion channel (hERG). The interface to the technology allows building and uploading molecular structures, viewing and downloading results and, most importantly, rationalizing any prediction at the atomic level by interactively analyzing the binding mode of a compound with its target protein(s) in real-time 3D. The VirtualToxLab has been used to predict the toxic potential for over 2500 compounds: the results are posted on http://www.virtualtoxlab.org. The free platform - the OpenVirtualToxLab - is accessible (in client-server mode) over the Internet. It is free of charge for universities, governmental agencies, regulatory bodies and non-profit organizations. PMID- 22521604 TI - Prenatal cadmium exposure alters postnatal immune cell development and function. AB - Cadmium (Cd) is generally found in low concentrations in the environment due to its widespread and continual use, however, its concentration in some foods and cigarette smoke is high. Although evidence demonstrates that adult exposure to Cd causes changes in the immune system, there are limited reports of immunomodulatory effects of prenatal exposure to Cd. This study was designed to investigate the effects of prenatal exposure to Cd on the immune system of the offspring. Pregnant C57Bl/6 mice were exposed to an environmentally relevant dose of CdCl(2) (10ppm) and the effects on the immune system of the offspring were assessed at two time points following birth (2 and 7weeks of age). Thymocyte and splenocyte phenotypes were analyzed by flow cytometry. Prenatal Cd exposure did not affect thymocyte populations at 2 and 7weeks of age. In the spleen, the only significant effect on phenotype was a decrease in the number of macrophages in male offspring at both time points. Analysis of cytokine production by stimulated splenocytes demonstrated that prenatal Cd exposure decreased IL-2 and IL-4 production by cells from female offspring at 2weeks of age. At 7weeks of age, splenocyte IL-2 production was decreased in Cd-exposed males while IFN-gamma production was decreased from both male and female Cd-exposed offspring. The ability of the Cd-exposed offspring to respond to immunization with a S. pneumoniae vaccine expressing T-dependent and T-independent streptococcal antigens showed marked increases in the levels of both T-dependent and T independent serum antibody levels compared to control animals. CD4(+)FoxP3(+)CD25(+) (nTreg) cell percentages were increased in the spleen and thymus in all Cd-exposed offspring except in the female spleen where a decrease was seen. CD8(+)CD223(+) T cells were markedly decreased in the spleens in all offspring at 7weeks of age. These findings suggest that even very low levels of Cd exposure during gestation can result in long term detrimental effects on the immune system of the offspring and these effects are to some extent sex-specific. PMID- 22521606 TI - Systemic inflammatory changes and increased oxidative stress in rural Indian women cooking with biomass fuels. AB - The study was undertaken to investigate whether regular cooking with biomass aggravates systemic inflammation and oxidative stress that might result in increase in the risk of developing cardiovascular disease (CVD) in rural Indian women compared to cooking with a cleaner fuel like liquefied petroleum gas (LPG). A total of 635 women (median age 36 years) who cooked with biomass and 452 age matched control women who cooked with LPG were enrolled. Serum interleukin-6 (IL 6), C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha) and interleukin-8 (IL-8) were measured by ELISA. Generation of reactive oxygen species (ROS) by leukocytes was measured by flow cytometry, and erythrocytic superoxide dismutase (SOD) was measured by spectrophotometry. Hypertension was diagnosed following the Seventh Report of the Joint Committee. Tachycardia was determined as pulse rate >100 beats per minute. Particulate matter of diameter less than 10 and 2.5 MUm (PM10 and PM2.5, respectively) in cooking areas was measured using real-time aerosol monitor. Compared with control, biomass users had more particulate pollution in indoor air, their serum contained significantly elevated levels of IL-6, IL-8, TNF-alpha and CRP, and ROS generation was increased by 37% while SOD was depleted by 41.5%, greater prevalence of hypertension and tachycardia compared to their LPG-using neighbors. PM10 and PM2.5 levels were positively associated with markers of inflammation, oxidative stress and hypertension. Inflammatory markers correlated with raised blood pressure. Cooking with biomass exacerbates systemic inflammation, oxidative stress, hypertension and tachycardia in poor women cooking with biomass fuel and hence, predisposes them to increased risk of CVD development compared to the controls. Systemic inflammation and oxidative stress may be the mechanistic factors involved in the development of CVD. PMID- 22521605 TI - Arsenite activates NFkappaB through induction of C-reactive protein. AB - C-reactive protein (CRP) is an acute phase protein in humans. Elevated levels of CRP are produced in response to inflammatory cytokines and are associated with atherosclerosis, hypertension, cardiovascular disease and insulin resistance. Exposure to inorganic arsenic, a common environmental toxicant, also produces cardiovascular disorders, namely atherosclerosis and is associated with insulin resistance. Inorganic arsenic has been shown to contribute to cardiac toxicities through production of reactive oxygen species (ROS) that result in the activation of NFkappaB. In this study we show that exposure of the hepatic cell line, HepG2, to environmentally relevant levels of arsenite (0.13 to 2 MUM) results in elevated CRP expression and secretion. ROS analysis of the samples showed that a minimal amount of ROS are produced by HepG2 cells in response to these concentrations of arsenic. In addition, treatment of FvB mice with 100 ppb sodium arsenite in the drinking water for 6 months starting at weaning age resulted in dramatically higher levels of CRP in both the liver and inner medullary region of the kidney. Further, mouse Inner Medullary Collecting Duct cells (mIMCD-4), a mouse kidney cell line, were stimulated with 10 ng/ml CRP which resulted in activation of NFkappaB. Pretreatment with 10 nM Y27632, a known Rho-kinase inhibitor, prior to CRP exposure attenuated NFkappaB activation. These data suggest that arsenic causes the expression and secretion of CRP and that CRP activates NFkappaB through activation of the Rho-kinase pathway, thereby providing a novel pathway by which arsenic can contribute to metabolic syndrome and cardiovascular disease. PMID- 22521607 TI - CYP3A-mediated apoptosis of dauricine in cultured human bronchial epithelial cells and in lungs of CD-1 mice. AB - Dauricine is the major bioactive component isolated from the root of Menispermum dauricum DC and has shown promising pharmacologic activities with a great potential for clinical use. Recently, we found that intraperitoneal exposure of dauricine produced selective pulmonary injury in mice. A quinone methide metabolite of dauricine was identified and is suggested to be associated with the pulmonary toxicity of dauricine. The present study evaluated the apoptotic effect of dauricine in cultured cells and mice, determined the change in cellular glutathione (GSH) contents after exposure to dauricine, investigated the role of GSH depletion in dauricine-induced cytotoxicity and apoptosis, and examined the role of CYP3A in dauricine-induced GSH depletion and apoptosis. Dauricine was found to induce apoptosis in NL-20 cells. Additionally, intraperitoneal administration of dauricine caused GSH depletion and apoptosis in lungs of mice. Treatment with ketoconazole, an inhibitor of CYP3A, reversed cellular GSH depletion in lungs of mice given dauricine and showed protective effect on dauricine-induced apoptosis in lungs of mice. This indicates that metabolic activation is involved in dauricine-induced GSH-depletion, cytotoxicity and apoptosis. The glutathione depletor L-buthionine sulfoximine showed potentiating effect on cytotoxicity and apoptosis induced by dauricine. We propose that dauricine is metabolized to a quinone methide intermediate which depletes cellular GSH, and the depletion of GSH may trigger and/or intensify the cytotoxicity and apoptosis induced by dauricine. PMID- 22521608 TI - Cyclosporine A and palmitic acid treatment synergistically induce cytotoxicity in HepG2 cells. AB - Immunosuppressant cyclosporine A (CsA) treatment can cause severe side effects. Patients taking immunosuppressant after organ transplantation often display hyperlipidemia and obesity. Elevated levels of free fatty acids have been linked to the etiology of metabolic syndromes, nonalcoholic fatty liver and steatohepatitis. The contribution of free fatty acids to CsA-induced toxicity is not known. In this study we explored the effect of palmitic acid on CsA-induced toxicity in HepG2 cells. CsA by itself at therapeutic exposure levels did not induce detectible cytotoxicity in HepG2 cells. Co-treatment of palmitic acid and CsA resulted in a dose dependent increase in cytotoxicity, suggesting that fatty acid could sensitize cells to CsA-induced cytotoxicity at the therapeutic doses of CsA. A synergized induction of caspase-3/7 activity was also observed, indicating that apoptosis may contribute to the cytotoxicity. We demonstrated that CsA reduced cellular oxygen consumption which was further exacerbated by palmitic acid, implicating that impaired mitochondrial respiration might be an underlying mechanism for the enhanced toxicity. Inhibition of c-Jun N-terminal kinase (JNK) attenuated palmitic acid and CsA induced toxicity, suggesting that JNK activation plays an important role in mediating the enhanced palmitic acid/CsA-induced toxicity. Our data suggest that elevated FFA levels, especially saturated FFA such as palmitic acid, may be predisposing factors for CsA toxicity, and patients with underlying diseases that would elevate free fatty acids may be susceptible to CsA-induced toxicity. Furthermore, hyperlipidemia/obesity resulting from immunosuppressive therapy may aggravate CsA induced toxicity and worsen the outcome in transplant patients. PMID- 22521609 TI - EGCG protects endothelial cells against PCB 126-induced inflammation through inhibition of AhR and induction of Nrf2-regulated genes. AB - Tea flavonoids such as epigallocatechin gallate (EGCG) protect against vascular diseases such as atherosclerosis via their antioxidant and anti-inflammatory functions. Persistent and widespread environmental pollutants, including polychlorinated biphenyls (PCB), can induce oxidative stress and inflammation in vascular endothelial cells. Even though PCBs are no longer produced, they are still detected in human blood and tissues and thus considered a risk for vascular dysfunction. We hypothesized that EGCG can protect endothelial cells against PCB induced cell damage via its antioxidant and anti-inflammatory properties. To test this hypothesis, primary vascular endothelial cells were pretreated with EGCG, followed by exposure to the coplanar PCB 126. Exposure to PCB 126 significantly increased cytochrome P450 1A1 (Cyp1A1) mRNA and protein expression and superoxide production, events which were significantly attenuated following pretreatment with EGCG. Similarly, EGCG also reduced DNA binding of NF-kappaB and downstream expression of inflammatory markers such as monocyte chemotactic protein-1 (MCP-1) and vascular cell adhesion protein-1 (VCAM-1) after PCB exposure. Furthermore, EGCG decreased endogenous or base-line levels of Cyp1A1, MCP-1 and VCAM-1 in endothelial cells. Most of all, treatment of EGCG upregulated expression of NF-E2 related factor 2 (Nrf2)-controlled antioxidant genes, including glutathione S transferase (GST) and NAD(P)H:quinone oxidoreductase 1 (NQO1), in a dose dependent manner. In contrast, silencing of Nrf2 increased Cyp1A1, MCP-1 and VCAM 1 and decreased GST and NQO1 expression, respectively. These data suggest that EGCG can inhibit AhR regulated genes and induce Nrf2-regulated antioxidant enzymes, thus providing protection against PCB-induced inflammatory responses in endothelial cells. PMID- 22521610 TI - Gender-specific reduction of hepatic Mrp2 expression by high-fat diet protects female mice from ANIT toxicity. AB - Emerging evidence suggests that feeding a high-fat diet (HFD) to rodents affects the expression of genes involved in drug transport. However, gender-specific effects of HFD on drug transport are not known. The multidrug resistance associated protein 2 (Mrp2, Abcc2) is a transporter highly expressed in the hepatocyte canalicular membrane and is important for biliary excretion of glutathione-conjugated chemicals. The current study showed that hepatic Mrp2 expression was reduced by HFD feeding only in female, but not male, C57BL/6J mice. In order to determine whether down-regulation of Mrp2 in female mice altered chemical disposition and toxicity, the biliary excretion and hepatotoxicity of the Mrp2 substrate, alpha-naphthylisothiocyanate (ANIT), were assessed in male and female mice fed control diet or HFD for 4weeks. ANIT-induced biliary injury is a commonly used model of experimental cholestasis and has been shown to be dependent upon Mrp2-mediated efflux of an ANIT glutathione conjugate that selectively injures biliary epithelial cells. Interestingly, HFD feeding significantly reduced early-phase biliary ANIT excretion in female mice and largely protected against ANIT-induced liver injury. In summary, the current study showed that, at least in mice, HFD feeding can differentially regulate Mrp2 expression and function and depending upon the chemical exposure may enhance or reduce susceptibility to toxicity. Taken together, these data provide a novel interaction between diet and gender in regulating hepatobiliary excretion and susceptibility to injury. PMID- 22521611 TI - New developments in the second heart field. AB - During cardiac looping the heart tube elongates by addition of progenitor cells from adjacent pharyngeal mesoderm to the arterial and venous poles. This cell population, termed the second heart field, was first identified ten years ago and many studies in the intervening decade have refined our understanding of how heart tube elongation takes place and identified signaling pathways that regulate proliferation and differentiation during progressive contribution of second heart field cells to the embryonic heart. It has also become apparent that defective second heart field development results in common congenital heart anomalies affecting both the conotruncal region and venous pole of the heart, including atrial and atrioventricular septal defects. In this review we focus on a series of recent papers that have identified new regulators of second heart field development, in particular the retinoic acid signaling pathway and HOX, SIX and EYA transcription factors. We also discuss new findings concerning the regulation of fibroblast growth factor signaling during second heart field deployment and studies that have implicated FGF10 and FGF3 in outflow tract development in addition to FGF8. Second heart field derived parts of the heart share common progenitor cells in pharyngeal mesoderm with craniofacial skeletal muscles and recent findings from xenopus, zebrafish and the protochordate Ciona intestinalis provide insights into the evolution of the second heart field during vertebrate radiation. PMID- 22521612 TI - Cell-specific transmembrane injection of molecular cargo with gold nanoparticle generated transient plasmonic nanobubbles. AB - Optimal cell therapies require efficient, selective and rapid delivery of molecular cargo into target cells without compromising their viability. Achieving these goals ex vivo in bulk heterogeneous multi-cell systems such as human grafts is impeded by low selectivity and speed of cargo delivery and by significant damage to target and non-target cells. We have developed a cell level approach for selective and guided transmembrane injection of extracellular cargo into specific target cells using transient plasmonic nanobubbles (PNB) as cell specific nano-injectors. As a technical platform for this method we developed a laser flow cell processing system. The PNB injection method and flow system were tested in heterogeneous cell suspensions of target and non-target cells for delivery of Dextran-FITC dye into squamous cell carcinoma HN31 cells and transfection of human T-cells with a green fluorescent protein-encoding plasmid. In both models the method demonstrated single cell type selectivity, high efficacy of delivery (96% both for HN31 cells T-cells), speed of delivery (nanoseconds) and viability of treated target cells (96% for HN31 cells and 75% for T-cells). The PNB injection method may therefore be beneficial for real time processing of human grafts without removal of physiologically important cells. PMID- 22521613 TI - Licorice isoliquiritigenin suppresses RANKL-induced osteoclastogenesis in vitro and prevents inflammatory bone loss in vivo. AB - Osteoclasts, bone-specialized multinucleated cells, are responsible for bone destructive diseases such as osteoporosis, periodontitis, and rheumatoid arthritis. Natural plant-derived products have received substantial attention given their potential therapeutic and preventive activities against human diseases. In the present study, we investigated the effects of isoliquiritigenin (ISL), a natural flavonoid isolated from licorice, on receptor activator of nuclear factor-kappaB ligand (RANKL)-induced in vitro osteoclastogenesis and inflammation-mediated bone destruction in vivo. We observed that ISL dose dependently inhibited RANKL-induced osteoclast formation from RAW 264.7 and primary mouse bone marrow-derived macrophages (BMMs), as well as decreased the extent of lacunar resorption. Specifically, ISL targeted RANKL-induced osteoclastogenesis and F-actin rings formation at an early stage. The RANKL stimulated mRNA expression of osteoclast-related genes and transcription factors were also diminished by ISL. Mechanistically, ISL blocked the RANKL-triggered RANK-TRAF6 association, phosphorylation of mitogen-activated protein kinases (MAPKs), inhibitor of kappaBalpha (IkappaBalpha) phosphorylation and degradation, nuclear factor-kappaB (NF-kappaB) p65 nuclear translocation, as well as activator protein (AP)-1 activation. ISL almost abrogated the nuclear factor of activated T cells (NFATc1) expression and inhibited its nuclear translocation specifically in pre-osteoclasts. Furthermore, the ectopic introduction of NFATc1 into osteoclast precursors almost reversed the ISL-elicited anti-osteoclastogenic effects. Consistent with the in vitro results, administration of ISL prevented inflammatory bone loss in mice by attenuating osteoclast activity. Taken together, our results demonstrated that ISL suppresses RANKL-induced osteoclastogenesis and inflammatory bone loss via RANK-TRAF6, MAPK, IkappaBalpha/NF-kappaB, and AP-1 signaling pathways. Therefore, ISL may be considered as a novel therapeutic and/or preventive strategy against lytic bone diseases. PMID- 22521614 TI - Subcellular localization of RNA and proteins in prokaryotes. AB - The field of bacterial cell biology has been revolutionized in the last decade by improvements in imaging capabilities which have revealed that bacterial cells, previously thought to be non-compartmentalized, possess an intricate higher-order organization. Many bacterial proteins localize to specific subcellular domains and regulate the spatial deployment of other proteins, DNA and lipids. Recently, the surprising discovery was made that bacterial RNA molecules are also specifically localized. However, the mechanisms that underlie bacterial cell architecture are just starting to be unraveled. The limited number of distribution patterns observed thus far for bacterial proteins and RNAs, and the similarity between the patterns exhibited by these macromolecules, suggest that the processes that underlie their localization are inextricably linked. We discuss these spatial arrangements and the insights that they provide on processes, such as localized translation, protein complex formation, and crosstalk between bacterial machineries. PMID- 22521615 TI - Cardiomyopathy and angiogenesis defects of Wistar rat fetuses of diabetic and hypercholesterolemic mothers. AB - OBJECTIVE: We aimed to illustrate the histogenesis, lactic dehydrogenase isoenzymes electrophoresis, and DNA damage of cardiac muscles and blood vessels during prenatal life of maternal diabetic or hypercholesterolemic mother. METHODS: Eighty fertile male and virgin female Wistar rats (1 male/3 females), weighing approximately 130 g, were mated and zero date of gestation was determined. Diabetes was induced at the fifth day of gestation by intraperitoneal injection of a single dose of 60 mg streptozotocin/kg body weight in citrate buffer, pH 4.6. At the same time, hypercholesterolemia was carried out by feeding virgin rats a diet containing 3% cholesterol for 6 wk before the onset of conception. Pregnant rats were arranged into three groups: control, diabetic, and hypercholesterolemic (n = 20). The animals were sacrificed and embryos were separated at 7-, 13-, 15-, 17-, and 19 d old, respectively, and subjected to light and transmission electron microscopy, lactic dehydrogenases isoenzymes electrophoresis, DNA fragmentation, and comet assay. The sera of the mothers were examined for fasting glucose level, total cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein, and creatine phosphokinase levels. RESULTS: Diabetic and hypercholesterolemic mothers exhibited a significant increase of sera cholesterol level, low-density lipoprotein, and creatine phosphokinase activity. Histologic findings of embryos of diabetic and hypercholesterolemic mothers revealed cardiomyopathy and malformation of blood vessels with an apparent degeneration of their endothelium. Transmission electron microscopy possessed massive necrosis of muscle fibers, disorganization of Z and I bands, and mitochondrial damage. Lactic dehydrogenase isoenzyme electrophoresis was altered and genomic DNA fragmentation was markedly increased. CONCLUSION: Maternal diabetes or hypercholesterolemia led to marked alterations in blood vessel differentiation as well as to cardiomyopathy during prenatal growth as assessed by the disruption of fine structures, abnormal lactic dehydrogenase isoenzymes electrophoresis, and an increase of DNA damage. These may be attributed to the marked oxidative stress and liberation of free oxygen radicals, which interrupted the myocardium structure and function during organogenesis. PMID- 22521616 TI - Is multiple sclerosis a proresolution deficiency disorder? AB - The inflammatory process seen in multiple sclerosis is due to an excess production of proinflammatory cytokines interleukin-1 (IL-1), IL-6, tumor necrosis factor-alpha, interferons, macrophage migration inhibitory factor, HMGB1 (high mobility group B1), and, possibly, a reduction in antiinflammatory cytokines IL-10, IL-4, and transforming growth factor-beta that leads to increased secretion of reactive oxygen species, including nitric oxide, resulting in neuronal damage. It is suggested that failure of production of adequate amounts of resolution-inducing molecules lipoxins, resolvins, and protectins that suppress inflammation and reactive oxygen species production, enhance wound healing, and have neuroprotective properties results in inappropriate inflammation and delay in the healing/repair process, and so neuronal damage continues, as seen in multiple sclerosis. Hence, methods designed to enhance the production and/or administration of lipoxins, resolvins, and protectins may form a new approach in the prevention and treatment of multiple sclerosis and other similar autoimmune diseases. PMID- 22521617 TI - Fabrication of gelatin/calcium phosphate composite nanofibrous membranes by biomimetic mineralization. AB - Based on the principles of biomimetic mineralization, biocomposite nanofibrous membranes were fabricated by the growth of CaP crystals on electrospun gelatin nanofibers to mimic both the physical architecture and chemical composition of natural bone ECM. Plenty more CaP crystals formed on the nanofibrous membrane containing Ca(2+) ion precursors, in which these crystals were also observed on the inner side of membrane. The release rate of Ca(2+) ion precursors from the nanofibrous membrane was slower than that of PO(4)(3-) ion precursors, suggesting the existence of more strong intermolecular interaction between gelatin and Ca(2+) ions. ATR-FTIR and XRD results clearly revealed the formation of CaP crystals mixed with apatite and CaCO(3), or apatite and TCP on the membranes. The Ca/P molar ratio of crystals obtained from the XPS data was 2.03 and 1.60, which depended on the mineralization conditions. Higher amount of CaP crystals significantly accelerated the deposit rate of bone-like apatite on the surface of composite membrane, meaning to the improved in vivo bone bioactivity. PMID- 22521618 TI - In vitro antioxidant effects and cytotoxicity of polysaccharides extracted from Laminaria japonica. AB - A water-soluble crude polysaccharide (WPS) was obtained from Laminaria japonica by hot water extraction. Three major polysaccharide fractions (WPS-1, WPS-2 and WPS-3) were purified from WPS by anion-exchange chromatography. Monosaccharide components analysis indicated that galactose was the predominant monosaccharide in WPS and WPS-3, accounting for 56.25% and 54.11%, respectively. And fucose was the predominant monosaccharide in WPS-1 and WPS-2, accounting for 46.91% and 45.1%, respectively. Antioxidant activity tests revealed that WPS-2 showed significant function of scavenging hydroxyl free radical and WPS-1 exhibited the highest inhibitory effects on superoxide radical. Cytotoxicity of all polysaccharide fractions was evaluated by MTT assay and Hoechst 33258 staining. Results showed that WPS-1 and WPS-2 significantly inhibited the growth of A375 cells and low anti-proliferative effects of WPS-2 on vascular smooth muscle cells (VSMCs) were observed. These results suggested that the polysaccharide fraction of WPS-2 might be explored as a potential safe antioxidant and antitumor agent. PMID- 22521619 TI - Electrospun core-shell nanofibers from homogeneous solution of poly(vinyl alcohol)/bovine serum albumin. AB - We report on the preparation and characterization of core-shell structure of bovine serum albumin (BSA) blended poly(vinyl alcohol) (PVA) composite nanofibers by using electrospinning process. The core-shell structure nanofibers have been electrospun from the homogeneous solution of BSA (as shell) and PVA (as core). The morphology, chemical compositions, structure and thermal properties of the resultant products were characterized by scanning electron microscopy (SEM), energy dispersive X-ray spectrometer (EDX), high-resolution transmission electron microscopy (HR-TEM), Fourier transform infrared (FT-IR) spectroscopy, differential scanning calorimetry, thermogravimetric analysis (TGA) and X-ray photoelectron spectroscopy (XPS) techniques. The blending ratio of PVA and BSA, molecular weight of BSA and the applied voltage of electrospinning process were observed to be the key influence factors on the formation of core-shell nanofibers structure. Based on the experimental findings, we proposed a possible physical mechanism for the formation of core-shell nanofibers structure of PVA blended BSA composite. PMID- 22521620 TI - Studies on the UV spectrum of poly(gamma-glutamic acid) based on development of a simple quantitative method. AB - A simple and valid ultraviolet (UV) spectrophotometric method for the determination of poly(gamma-glutamic acid) is developed. The method is based on the UV absorption spectrum of gamma-PGA in aqueous solution, which exhibits a maximum absorption wavelength at 216 nm. The results obtained were comparable to those obtained with the reported high-performance liquid chromatography (HPLC) method according to ICH guidelines. Under the proposed procedure, the calibration graph is linear over the range of 20-200 MUg/ml with regression correlation coefficient of 0.9997. Precision (%R.S.D.<1.50) and recovery (%R.>99.29%) are good. The limit of detection (LOD) and limit of quantitation (LOQ) are 0.39 and 1.19 MUg/ml, respectively. These results agree well with those of HPLC method. Its spectrum properties studies showed that the spectrum of gamma-PGA remarkably changed with an increase in temperature due to gamma-PGA was digested into glutamate monomer. In spite of this, the determining procedure could carried out in a wide temperature range (25-50 degrees C). In addition, the method is not influenced by the molecular weight, but the measurement system need to control in pH 3.0-10.0 and ionic strength not more than 0.5M. The proposed method is applied successfully for high-throughput quantification of poly(gamma-glutamic acid) in biological samples. The advantages of the UV method are simplicity of operation, rapidity, sensitive, low-cost and high-throughput. PMID- 22521621 TI - Structure, fluorescence quenching and antioxidant activity of a carbohydrate polymer from Eugenia jambolana. AB - Natural products provide an excellent source for novel antioxidants. Herein, we have studied the water-extracted carbohydrate polymer (WE) of Eugenia jambolana using chemical, chromatographic, and spectroscopic methods. A 116 kDa arabinogalactan containing p-coumaric and ferulic acids in monomeric and dimeric forms has been isolated. Cellulase generated oligomeric fragments containing ester linked phenolic acids were also characterized. The antioxidant capacity of this carbohydrate polymer is comparable to butylated hydroxy anisole and butylated hydroxy toluene. Interaction of WE with bovine serum albumin (BSA) was studied by fluorescence quenching measurement. Conformational change of BSA at high carbohydrate polymer concentration was indicated. PMID- 22521622 TI - Adults with myelomeningocele: an interview study about life situation and bladder and bowel management. AB - AIM: To assess life situation, and bladder and bowel management in individuals with myelomeningocele (MMC) after transferal to adult medical care. MATERIALS AND METHODS: All individuals (134) with myelomeningocele from western Sweden, born before 1981, and assessed on at least two occasions by a pediatric urologist, were invited to participate in a telephone interview according to a structured protocol. Sixty-nine individuals (32 males, 37 females) with a median age of 34 years (range 27-50) agreed to participate. RESULTS: Sixty-two individuals (90%) passed high school or had university education and 46 (67%) were employed. Fifty three (77%) had their own apartment and 27 (39%) lived with a partner. Clean intermittent catheterization was used by 49 (71%), more commonly in females (p < 0.05). Pads were used by 60 (87%) individuals. Ten (14%) had urotherapy support. Of those operated on, 16 (53%) had a consultation with a urologist every 3 years; the corresponding number for the non-operated was 12 (31%). Eight individuals were treated with anticholinergic drugs. None had support for improvement of the fecal emptying regimen. CONCLUSIONS: Of the participants in the study, one third had no or rare contact with a urologist, few had urotherapy support and none had support for bowel regimen. PMID- 22521623 TI - Small heat shock proteins HSP27 (HspB1), alphaB-crystallin (HspB5) and HSP22 (HspB8) as regulators of cell death. AB - Hsp27, alphaB-crystallin and HSP22 are ubiquitous small heat shock proteins (sHsp) whose expression is induced in response to a wide variety of unfavorable physiological and environmental conditions. These sHsp protect cells from otherwise lethal conditions mainly by their involvement in cell death pathways such as necrosis, apoptosis or autophagy. At a molecular level, the mechanisms accounting for sHsp functions in cell death are (1) prevention of denatured proteins aggregation, (2) regulation of caspase activity, (3) regulation of the intracellular redox state, (4) function in actin polymerization and cytoskeleton integrity and (5) proteasome-mediated degradation of selected proteins. In cancer cells, these sHsp are often overexpressed and associated with increased tumorigenicity, cancer cells metastatic potential and resistance to chemotherapy. Altogether, these properties suggest that Hsp27, alphaB-crystallin and Hsp22 are appropriate targets for modulating cell death pathways. In the present, we briefly review recent reports showing molecular evidence of cell death regulation by these sHsp and co-chaperones. This article is part of a Directed Issue entitled: Small HSPs in physiology and pathology. PMID- 22521625 TI - Dietary exposure to trace elements and health risk assessment in the 2nd French Total Diet Study. AB - Dietary exposure of the French population to trace elements has been assessed in the second national Total Diet Study (TDS). Food samples (n = 1319) were collected between 2007 and 2009 to be representative of the whole diet of the population, prepared as consumed, and analyzed. Occurrence data were combined with national individual consumption data to estimate dietary exposure for adults and children mean and high consumers. Compared to the 1st French TDS performed in 2000-2004, exposure is higher for cadmium, aluminium, antimony, nickel, cobalt and lower for lead, mercury and arsenic. For aluminium, methylmercury, cadmium, lead and inorganic arsenic risk cannot be ruled out for certain consumer groups. It still appears necessary to continue undertaking efforts to reduce exposure to these elements. Due to the lack of robust toxicological data and/or speciation analysis in food on chromium, tin, silver and vanadium to perform a risk assessment, data on occurrence and dietary exposure are provided as Supplementary material. In order to minimize nutritional and chemical risks, the French Agency for Food, Environmental and Occupational Health & Safety (ANSES) reiterates its recommendation for a diversified diet (food items and origins). PMID- 22521626 TI - Severe methylenetetrahydrofolate reductase deficiency in mice results in behavioral anomalies with morphological and biochemical changes in hippocampus. AB - The brain is particularly sensitive to folate metabolic disturbances, since methyl groups are critical for its functions. Methylenetetrahydrofolate reductase (MTHFR) generates the primary circulatory form of folate required for homocysteine remethylation to methionine. Neurological disturbances have been described in homocystinuria caused by severe MTHFR deficiency. The goal of this study was to determine if behavioral anomalies are present in severe Mthfr deficient (Mthfr(-/-)) mice and to identify neurobiological changes that could contribute to these anomalies. Adult male mice of 3 Mthfr genotypes (+/+, +/-, -/ ) were tested on motor, anxiety, exploratory and cognitive tasks. Volumes (whole brain and hippocampus) and morphology, global DNA methylation, apoptosis, expression of choline acetyltransferase (ChAT) and glucocorticoid receptor (GR), and concentrations of choline metabolites were assessed in hippocampus. Mthfr(-/ ) mice had impairments in motor function and in short- and long-term memory, increased exploratory behavior and decreased anxiety. They showed decreased whole brain and hippocampal volumes, reduced thickness of the pyramidal cell layer of CA1 and CA3, and increased apoptosis in hippocampus. There was a disturbance in choline metabolism as manifested by differences in acetylcholine, betaine or glycerophosphocholine concentrations, and by increased ChAT levels. Mthfr(-/-) mice also had increased GR mRNA and protein. Our study has revealed significant anomalies in affective behavior and impairments in memory of Mthfr(-/-) mice. We identified structural changes, increased apoptosis, altered choline metabolism and GR dysregulation in hippocampus. These findings, as well as some similar observations in cerebellum, could contribute to the behavioral changes and suggest that choline is a critical metabolite in homocystinuria. PMID- 22521624 TI - Blood pressure measurement: clinic, home, ambulatory, and beyond. AB - Blood pressure traditionally has been measured in the clinic setting using the auscultatory method and a mercury sphygmomanometer. Technologic advances have led to improvements in measuring clinic blood pressure and allowed for measuring blood pressures outside the clinic. This review outlines various methods for evaluating blood pressure and the clinical utility of each type of measurement. Home blood pressures and 24-hour ambulatory blood pressures have improved our ability to evaluate the risk of target-organ damage and hypertension-related morbidity and mortality. Measuring home blood pressures may lead to more active participation in health care by patients and has the potential to improve blood pressure control. Ambulatory blood pressure monitoring enables measuring nighttime blood pressures and diurnal changes, which may be the most accurate predictors of risk associated with elevated blood pressure. Additionally, reducing nighttime blood pressure is feasible and may be an important component of effective antihypertensive therapy. Finally, estimating central aortic pressures and pulse wave velocity are 2 of the newer methods for assessing blood pressure and hypertension-related target-organ damage. PMID- 22521627 TI - Immune activation is inversely related to, but does not cause variation in androgen levels in a cichlid fish species. AB - Studies on birds and mammals indicate that sexual traits may signal superior health because active immunity, like inflammatory responses to infections, is suppressive to the production of androgens that facilitate the expression of these traits. Here we test this possible pathway for honest signaling in a teleost species, Sarotherodon galilaeus, by activating the immune system with sheep red blood cells (SRBC), which is a non-pathogenic T- and B-cell stimulating antigen. Two weeks after the start of treatment adult males injected with SRBC showed a significant increase in antibody production in comparison with control males. The variation in specific antibody production was negatively related with variation in both testosterone and 11-ketotestosterone levels. This suggests that investment in immune protection is incompatible with increased activity of the hypothalamic-pituitary-gonadal axis. However, opposite to our expectation no difference in androgen levels was found between placebo and SRBC treatment suggesting that immune activation did not cause androgen suppression in our studied species. PMID- 22521628 TI - Oral immunization of rainbow trout to infectious pancreatic necrosis virus (Ipnv) induces different immune gene expression profiles in head kidney and pyloric ceca. AB - Induction of neutralizing antibodies and protection by oral vaccination with DNA alginates of rainbow trout Oncorhynchus mykiss against infectious pancreatic necrosis virus (IPNV) was recently reported. Because orally induced immune response transcript gene profiles had not been described yet neither in fish, nor after IPNV vaccination, we studied them in head kidney (an immune response internal organ) and a vaccine entry tissue (pyloric ceca). By using an oligo microarray enriched in immune-related genes validated by RTqPCR, the number of increased transcripts in head kidney was higher than in pyloric ceca while the number of decreased transcripts was higher in pyloric ceca than in head kidney. Confirming previous reports on intramuscular DNA vaccination or viral infection, mx genes increased their transcription in head kidney. Other transcript responses such as those corresponding to interferons, their receptors and induced proteins (n=91 genes), VHSV-induced genes (n=25), macrophage-related genes (n=125), complement component genes (n=176), toll-like receptors (n=31), tumor necrosis factors (n=32), chemokines and their receptors (n=121), interleukines and their receptors (n=119), antimicrobial peptides (n=59), and cluster differentiation antigens (n=58) showed a contrasting and often complementary behavior when head kidney and pyloric ceca were compared. For instance, classical complement component transcripts increased in head kidney while only alternative pathway transcripts increased in pyloric ceca, different beta-defensins increased in head kidney but remained constant in pyloric ceca. The identification of new gene markers on head kidney/pyloric ceca could be used to follow up and/or to improve immunity during fish oral vaccination. PMID- 22521629 TI - Process evaluation to explore internal and external validity of the "Act in Case of Depression" care program in nursing homes. AB - BACKGROUND: A multidisciplinary, evidence-based care program to improve the management of depression in nursing home residents was implemented and tested using a stepped-wedge design in 23 nursing homes (NHs): "Act in case of Depression" (AiD). OBJECTIVE: Before effect analyses, to evaluate AiD process data on sampling quality (recruitment and randomization, reach) and intervention quality (relevance and feasibility, extent to which AiD was performed), which can be used for understanding internal and external validity. In this article, a model is presented that divides process evaluation data into first- and second order process data. METHODS: Qualitative and quantitative data based on personal files of residents, interviews of nursing home professionals, and a research database were analyzed according to the following process evaluation components: sampling quality and intervention quality. SETTING: Nursing home. RESULTS: The pattern of residents' informed consent rates differed for dementia special care units and somatic units during the study. The nursing home staff was satisfied with the AiD program and reported that the program was feasible and relevant. With the exception of the first screening step (nursing staff members using a short observer-based depression scale), AiD components were not performed fully by NH staff as prescribed in the AiD protocol. CONCLUSION: Although NH staff found the program relevant and feasible and was satisfied with the program content, individual AiD components may have different feasibility. The results on sampling quality implied that statistical analyses of AiD effectiveness should account for the type of unit, whereas the findings on intervention quality implied that, next to the type of unit, analyses should account for the extent to which individual AiD program components were performed. In general, our first order process data evaluation confirmed internal and external validity of the AiD trial, and this evaluation enabled further statistical fine tuning. The importance of evaluating the first-order process data before executing statistical effect analyses is thus underlined. PMID- 22521630 TI - Can botulinum toxin decrease carer burden in long term care residents with upper limb spasticity? A randomized controlled study. AB - OBJECTIVE: To evaluate whether botulinum toxin can decrease the burden for caregivers of long term care patients with severe upper limb spasticity. METHOD: This was a double-blind placebo-controlled trial with a 24-week follow-up period. SETTING: A 250-bed long term care hospital, the infirmary units of 3 regional hospitals, and 5 care and attention homes. PARTICIPANTS: Participants included 55 long term care patients with significant upper limb spasticity and difficulty in basic upper limb care. INTERVENTIONS: Patients were randomized into 2 groups that received either intramuscular botulinum toxin A or saline. MAIN OUTCOME MEASURES: The primary outcome measure was provided by the carer burden scale. Secondary outcomes included goal attainment scale, measure of spasticity by modified Ashworth score, passive range of movement for shoulder abduction, and elbow extension and finger extension. Pain was assessed using the Pain Assessment in Advanced Dementia Scale. RESULTS: A total of 55 patients (21 men; mean age = 69, SD =18) were recruited. At week 6 post-injection, 18 (60%) of 30 patients in the treatment group versus 2 (8%) of 25 patients in the control group had a significant 4-point reduction of carer burden scale (P < .001). There was also significant improvement in the goal attainment scale, as well as the modified Ashworth score, resting angle, and passive range of movement of the 3 regions (shoulder, elbow, and fingers) in the treatment group which persisted until week 24. There were also fewer spontaneous bone fractures after botulinum toxin injection, although this did not reach statistical significance. No significant difference in Pain Assessment in Advanced Dementia scale was found between the 2 groups. No serious botulinum toxin type A-related adverse effects were reported. CONCLUSION: Long term care patients who were treated for upper limb spasticity with intramuscular injections of botulinum toxin A had a significant decrease in the caregiver burden. The treatment was also associated with improved scores on patient-centered outcome measures. PMID- 22521631 TI - Regional cortical thinning in patients with major depressive disorder: a surface based morphometry study. AB - This study uses surfaced-based morphometry to investigate cortical thinning and its functional correlates in patients with major depressive disorder (MDD). Subjects with MDD (N=36) and healthy control subjects (N=36) were enrolled in the study. Each subject received T1 structural magnetic resonance imaging (MRI), clinical evaluations, and neuropsychological examinations of executive functions with the Color Trail Test (CTT) and the Wisconsin Card Sorting Test (WCST). This study used an automated surface-based method (FreeSurfer) to measure cortical thickness and to generate the thickness maps for each subject. Statistical comparisons were performed using a general linear model. Compared with healthy controls, subjects with MDD showed the largest area of cortical thinning in the prefrontal cortex. This study also noted smaller areas of cortical thinning in the bilateral inferior parietal cortex, left middle temporal gyrus, left entorhinal cortex, left lingual cortex, and right postcentral gyrus. Regression analysis demonstrated cortical thinning in several frontoparietal regions, predicting worse executive performance measured by CTT 2, though the patterns of cortical thickness/executive performance correlation differed in healthy controls and MDD subjects. In conclusion, the results provide further evidence for the significant role of a prefrontal structural deficit and an aberrant structural/functional relationship in patients with MDD. PMID- 22521632 TI - European Journal of Pharmaceutical Sciences. Preface. PMID- 22521633 TI - A critical review on the use of modern sophisticated hyphenated tools in the characterization of impurities and degradation products. AB - With ever increasing regulatory and compendial stringency on the control of impurities (IMPs) and degradation products (DPs) (including genotoxic impurities) in drug substances and finished pharmaceutical formulations, a profound emphasis is being paid on their characterization and analysis at trace levels. Fortunately, there have been parallel tremendous advancements in the instrumental techniques that allow rapid characterization of IMPs and/or DPs at the prescribed levels of ~0.1%. With this, there is perceptible shift from conventional protocol of isolation and spectral analysis to on-line analysis using modern sophisticated hyphenated tools, like GC-MS, LC-MS, CE-MS, SFC-MS, LC-NMR, CE-NMR, LC-FTIR, etc. These are already being extensively used by industry and also there is tremendous increase in publications in the literature involving their use. This write-up critically reviews the literature for application of hyphenated tools in impurity and degradation product profiling of small molecules. A brief mention is made on possible pitfalls in the experimentation and data interpretation. Appropriate strategies are proposed, following which one can obtain unambiguous characterization of the unidentified IMPs and/or DPs. PMID- 22521635 TI - A novel approach to signal normalisation in atmospheric pressure ionisation mass spectrometry. AB - The aim of our study was to test an alternative principle of signal normalisation in LC-MS/MS. During analyses, post column infusion of the target analyte is done via a T-piece, generating an "area under the analyte peak" (AUP). The ratio of peak area to AUP is assessed as assay response. Acceptable analytical performance of this principle was found for an exemplary analyte. Post-column infusion may allow normalisation of ion suppression not requiring any additional standard compound. This approach can be useful in situations where no appropriate compound is available for classical internal standardisation. PMID- 22521634 TI - Inhibition of myeloperoxidase and antioxidative activity of Gentiana lutea extracts. AB - The aim of this study was to investigate the inhibitory activity of Gentiana lutea extracts on the enzyme myeloperoxidase (MPO), as well as the antioxidant activity of these extracts and their correlation with the total polyphenol content. Extracts were prepared using methanol (100%), water and ethanol aqueous solutions (96, 75, 50 and 25%v/v) as solvents for extraction. Also, isovitexin, amarogentin and gentiopicroside, pharmacologically active constituents of G. lutea were tested as potential inhibitors of MPO. Antioxidant activity of extracts was determined using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging test and also using cyclic voltammetry (CV). Among all extracts, the antioxidant capacity of 50% ethanol aqueous extract was the highest, both when measured using the DPPH test, with IC(50)=20.6 MUg/ml, and when using CV. Also, 50% ethanol extract, showed the best inhibition of MPO activity in comparison with other extracts. In the group of the selected G. lutea constituents, gentiopicroside has proved to be the strongest inhibitor of MPO, with IC(50)=0.8 MUg/ml. Also, the concentration of G. lutea constituents were determined in all extracts, using Ultra Performance Liquid Chromatography (UPLC). PMID- 22521636 TI - UPLC-MS/MS determination of paeoniflorin, naringin, naringenin and glycyrrhetinic acid in rat plasma and its application to a pharmacokinetic study after oral administration of Si-Ni-San decoction. AB - A UPLC-MS/MS method was developed for the simultaneous determination of paeoniflorin, naringin, naringenin and glycyrrhetinic acid in rat plasma. A Waters BEH C(18) column was used with a gradient mobile phase system of methanol water containing 2 mM ammonium acetate. The analysis was performed on a positive ionization electrospray mass spectrometer via multiple reaction monitoring (MRM). One-step protein precipitation with acetonitrile was used to extract the analytes from plasma. The limits of quantification were 9.800 ng/ml for paeoniflorin, 5.100 ng/ml for naringin, 5.200 ng/ml for naringenin and 10.60 ng/ml for glycyrrhetinic acid, respectively. The intra- and inter-day precision (relative standard deviation, RSD) ranged 4.9-12% and 2.8-13%, respectively. The accuracy (relative error, RE) was from -7.3% to 7.5% at all quality control (QC) levels. The validated method was applied to a pharmacokinetic study in rats after oral administration of Si-Ni-San decoction. PMID- 22521637 TI - Zearalenone exposure modulates the expression of ABC transporters and nuclear receptors in pregnant rats and fetal liver. AB - The mycotoxin zearalenone (ZEN) is produced by a variety of Fusarium fungi and contaminates numerous cereals, fruits and vegetables. Interacting with the estrogen receptors, ZEN and reduced metabolites zearalenols cause hormonal effects in animals. Few data are available on the effects of repeated exposure to ZEN, particularly during pregnancy. The aim of our work was to assess the impact of this toxin on the expression of ABC transporters and nuclear receptors in fetal liver and pregnant rats that were exposed daily (gestation day 7-20) to 1 mg/kg ZEN. Significant variations were observed, depending on the tissue type, the tissue origin (maternal or fetal), and the time of analysis after the last exposure to ZEN (4 h or 24 h). The modulations of expression were independent of the magnitude of tissue impregnation by ZEN and its metabolites. The maternal uterus was the most sensitive tissue: Abcb1a, Abcb1b and Abcg2 mRNA and protein expressions were induced at both times, while Abcc1, Abcc3 and Esr1 mRNA and protein expressions were inhibited then induced 4 h and 24 h after exposure, respectively. In the fetal liver, Abcb1a and Esr1 protein expression was inhibited at both times, while mRNA expression was induced 24 h after the last exposure to ZEN. These results suggested that ZEN exposure could impact maternal and fetal exposure to ABC transporters substrates, and influence fetus development through nuclear receptor modulation. PMID- 22521638 TI - Stroma and pancreatic ductal adenocarcinoma: an interaction loop. AB - Pancreatic ductal adenocarcinoma (PDA) has two exceptional features. First, it is a highly lethal disease, with a median survival of less than 6 months and a 5 year survival rate less than 5%. Second, PDA tumor cells are surrounded by an extensive stroma, which accounts for up to 90% of the tumor volume. It is well recognized that stromal microenvironment can accelerate malignant transformation, tumor growth and progression. More importantly, the interaction loop between PDA and its stroma greatly contributes to tumor growth and progression. We propose that the extensive stroma of PDA is closely linked to its poor prognosis. An improved understanding of the mechanisms that contribute to pancreatic tumor growth and progression is therefore urgently needed. Targeting the stroma may thus provide novel prevention, earlier detection and therapeutic options to this deadly malignancy. Accordingly, in this review, we will summarize the mechanism of PDA stroma formation, the role of the stroma in tumor progression and therapy resistance and the potential of stroma-targeted therapeutics strategies. PMID- 22521639 TI - The role of protein tyrosine phosphatases in colorectal cancer. AB - Colorectal cancer is one of the most common oncogenic diseases in the Western world. Several cancer associated cellular pathways have been identified, in which protein phosphorylation and dephosphorylation, especially on tyrosine residues, are one of most abundant regulatory mechanisms. The balance between these processes is under tight control by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Aberrant activity of oncogenic PTKs is present in a large portion of human cancers. Because of the counteracting role of PTPs on phosphorylation-based activation of signal pathways, it has long been thought that PTPs must act as tumor suppressors. This dogma is now being challenged, with recent evidence showing that dephosphorylation events induced by some PTPs may actually stimulate tumor formation. As such, PTPs might form a novel attractive target for anticancer therapy. In this review, we summarize the action of different PTPs, the consequences of their altered expression in colorectal cancer, and their potential as target for the treatment of this deadly disease. PMID- 22521640 TI - WITHDRAWN: Hexavalent chromium induces premature senescence through reactive oxygen species-mediated p53 pathway in L-02 hepatocytes. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 22521641 TI - An expanded view of the protein folding landscape of PDZ domains. AB - Most protein domains fold in an apparently co-operative and two-state manner with only the native and denatured states significantly populated at any experimental condition. However, the protein folding energy landscape is often rugged and different transition states may be rate limiting for the folding reaction under different conditions, as seen for the PDZ protein domain family. We have here analyzed the folding kinetics of two PDZ domains and found that a previously undetected third transition state is rate limiting under conditions that stabilize the native state relative to the denatured state. In light of these results, we have re-analyzed previous folding data on PDZ domains and present a unified folding mechanism with three distinct transition states separated by two high-energy intermediates. Our data show that sequence composition tunes the relative stabilities of folding transition states within the PDZ family, while the overall mechanism is determined by topology. This model captures the kinetic folding mechanism of all PDZ domains studied to date. PMID- 22521642 TI - KNK437, abrogates hypoxia-induced radioresistance by dual targeting of the AKT and HIF-1alpha survival pathways. AB - KNK437 is a benzylidene lactam compound known to inhibit stress-induced synthesis of heat shock proteins (HSPs). HSPs promote radioresistance and play a major role in stabilizing hypoxia inducible factor-1alpha (HIF-1alpha). HIF-1alpha is widely responsible for tumor resistance to radiation under hypoxic conditions. We hypothesized that KNK437 sensitizes cancer cells to radiation and overrides hypoxia-induced radioresistance via destabilizing HIF-1alpha. Treatment of human cancer cells MDA-MB-231 and T98G with KNK437 sensitized them to ionizing radiation (IR). Surprisingly, IR did not induce HSPs in these cell lines. As hypothesized, KNK437 abrogated the accumulation of HIF-1alpha in hypoxic cells. However, there was no induction of HSPs under hypoxic conditions. Moreover, the proteosome inhibitor MG132 did not restore HIF-1alpha levels in KNK437-treated cells. This suggested that the absence of HIF-1alpha in hypoxic cells was not due to the enhanced protein degradation. HIF-1alpha is mainly regulated at the level of post-transcription and AKT is known to modulate the translation of HIF-1alpha mRNA. Interestingly, pre-treatment of cells with KNK437 inhibited AKT signaling. Furthermore, down regulation of AKT by siRNA abrogated HIF-1alpha levels under hypoxia. Interestingly, KNK437 reduced cell survival in hypoxic conditions and inhibited hypoxia-induced resistance to radiation. Taken together, these data suggest that KNK437 is an effective radiosensitizer that targets multiple pro survival stress response pathways. PMID- 22521643 TI - The functional analysis of the CHMP2B missense mutation associated with neurodegenerative diseases in the endo-lysosomal pathway. AB - Endosomal sorting complexes required for transport (ESCRTs) regulate a key sorting step of protein trafficking between endosomal compartments in lysosomal degradation. Interestingly, mutations in charged multivesicular body protein 2B (CHMP2B), which is a core subunit of ESCRT-III, have been identified in some neurodegenerative diseases. However, the cellular pathogenesis resulting from CHMP2B missense mutations is unclear. Furthermore, little is known about their functional analysis in post-mitotic neurons. In order to examine their cellular pathogenesis, we analyzed their effects in the endo-lysosomal pathway in post mitotic neurons. Interestingly, of the missense mutant proteins, CHMP2B(T104N) mostly accumulated in the Rab5- and Rab7-positive endosomes and caused delayed degradation of EGFR as compared to CHMP2B(WT). Furthermore, CHMP2B(T104N) showed less association with Vps4 ATPase and was avidly associated with Snf7-2, a core component of ESCRT-III, suggesting that it may cause defects in the process of dissociation from ESCRT. Of the missense variants, CHMP2B(T104N) caused prominent accumulation of autophagosomes. However, neuronal cell survival was not dramatically affected by expression of CHMP2B(T104N). These findings suggested that, from among the various missense mutants, CHMP2B(T104N) was associated with relatively mild cellular pathogenesis in post-mitotic neurons. This study provided a better understanding of the cellular pathogenesis of neurodegenerative diseases associated with various missense mutations of CHMP2B as well as endocytic defects. PMID- 22521644 TI - Suppression of estrogen receptor-alpha transactivation by thyroid transcription factor-2 in breast cancer cells. AB - Estrogen receptors (ERs), which mediate estrogen actions, regulate cell growth and differentiation of a variety of normal tissues and hormone-responsive tumors through interaction with cellular factors. In this study, we show that thyroid transcription factor-2 (TTF-2) is expressed in mammary gland and acts as ERalpha co-repressor. TTF-2 inhibited ERalpha transactivation in a dose-dependent manner in MCF-7 breast cancer cells. In addition, TTF-2 directly bound to and formed a complex with ERalpha, colocalizing with ERalpha in the nucleus. In MCF-7/TTF-2 stable cell lines, TTF-2 repressed the expression of endogenous ERalpha target genes such as pS2 and cyclin D1 by interrupting ERalpha binding to target promoters and also significantly decreased cell proliferation. Taken together, these data suggest that TTF-2 may modulate the function of ERalpha as a corepressor and play a role in ER-dependent proliferation of mammary cells. PMID- 22521645 TI - Synthesis and characterization of folic acid modified water-soluble chitosan derivatives for folate-receptor-mediated targeting. AB - Three chemical modification methods of carboxymethylation, quaternization and hydroxypropylation were used to synthesize water-soluble chitosan derivatives. In order to study the feasibility of these chitosan derivatives as backbones of nuclear imaging agents, folic acid (FA) and Technetium-99m were introduced onto the water-soluble chitosan chains. The bifunctional chelating agent 1,4,7,10 tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was conjugated to the folate grafted chitosan derivatives for chelating with radionuclides such as (64)Cu and (68)Ga. The structures of these new ligands were characterized with multiple methods. The solubility and stability of the (99m)Tc-complexes were both favorable. Further study of their radiochemical and biological properties will be performed to evaluate the usefulness of these water-soluble chitosan derivatives for nuclear imaging agent design. PMID- 22521646 TI - Novel triazolopyridylbenzamides as potent and selective p38alpha inhibitors. AB - A new class of p38alpha inhibitors based on a biaryl-triazolopyridine scaffold was investigated. X-ray crystallographic data of the initial lead compound cocrystallised with p38alpha was crucial in order to uncover a unique binding mode of the inhibitor to the hinge region via a pair of water molecules. Synthesis and SAR was directed towards the improvement of binding affinity, as well as ADME properties for this new class of p38alpha inhibitors and ultimately afforded compounds showing good in vivo efficacy. PMID- 22521647 TI - Conjugates of 5-isoquinolinesulfonylamides and oligo-D-arginine possess high affinity and selectivity towards Rho kinase (ROCK). AB - In the present work, conjugates of 5-isoquinolinesulfonylamides and D-arginine rich peptides were developed into highly potent inhibitors for basophilic protein kinases. Based on Hidaka's inhibitor H9, a generic fluorescent probe ARC-1083 was constructed possessing subnanomolar dissociation constant towards several kinases of the AGC-group. Thereafter, Hidaka's inhibitor HA1077 or Fasudil was conjugated with oligo-D-arginine resulting in the compound ARC-3002 revealing high affinity towards ROCK-II (K(d)=20 pM) and over 160-fold selectivity compared to PKAc. PMID- 22521648 TI - In vivo phage display to identify new human antibody fragments homing to atherosclerotic endothelial and subendothelial tissues [corrected]. AB - In vivo phage display selection is a powerful strategy for directly identifying agents that target the vasculature of normal or diseased tissues in living animals. We describe here a new in vivo biopanning strategy in which a human phage single-chain antibody (scFv) library was injected into high-fat diet-fed ApoE(-/-) mice. Extracellular and internalized phage scFvs were selectively recovered from atherosclerotic vascular endothelium and subjacent tissues. After three successive biopanning rounds, a panel of six clones with distinct gene sequences was isolated. Four scFvs produced and purified in soluble form were shown to interact in vitro with a rabbit atheromatous protein extract by time resolved fluorescence resonance energy transfer and to target the endothelial cell surface and inflamed intima-related regions of rabbit and human tissue sections ex vivo. These new scFvs selected in a mouse model recognized both rabbit and human tissue, underlying the interspecies similarities of the recognized epitopes. By combining immunoprecipitation and mass spectrometry, one of the selected scFvs was shown to recognize carbonic anhydrase II, an up regulated enzyme involved in resorption of ectopic calcification. These results show that in vivo biopanning selection in hypercholesterolemic animals makes it possible to identify both scFvs homing to atherosclerotic endothelial and subendothelial tissues, and lesion-associated biomarkers. Such scFvs offer promising opportunities in the field of molecular targeting for the treatment of atherosclerosis. PMID- 22521649 TI - EGFR mutations as a predictive marker of cytotoxic chemotherapy. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) are important predictive markers for the response to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Whether EGFR mutations can also predict the clinical outcomes in NSCLC patients receiving chemotherapy has not yet been established. METHODS: We included 217 locally advanced/metastatic NSCLC cases in our study cohort. Each patient had received platinum doublet chemotherapy as a first line treatment, and had been screened for an EGFR mutation. RESULTS: The subject cohort comprised 80 EGFR wild type and 137 EGFR-mutated lung cancer patients. Gemcitabine-based and taxane-based regimens were administered in 131 (60.4%) and 86 (39.6%) cases, respectively. Among the patients with a wild type EGFR, there was no significant difference in the response rate (RR), disease control rate (DCR), or progression-free survival (PFS) between gemcitabine-based and taxane-based therapies. Among the patients with EGFR mutations, no difference in RR was observed between gemcitabine-based and taxane-based treatments. On the other hand, the DCR and PFS associated with taxane-based therapy were superior when compared with the gemcitabine-based treatments. When we analyzed patients with an EGFR exon 19 deletion, the PFS of the taxane treated cases was better than that of the gemcitabine treated cases (5.3 months vs 3.7 months, P=0.012). CONCLUSIONS: Our current data indicate that lung cancer patients with EGFR mutations had longer PFS with taxane than gemcitabine when receiving a platinum based doublet regimen. The predictive meaning of EGFR mutations for cytotoxic chemotherapy should be further investigated. PMID- 22521650 TI - Re: Alexander Kutikov, Boris Rozenfeld, Brian L. Egleston, et al. Academic ranking score: a publication-based reproducible metric of thought leadership in urology. Eur Urol 2012;61:435-9. PMID- 22521654 TI - 5alpha-reductase inhibitors: preventing the treatable. PMID- 22521655 TI - Classification of complications: is the Clavien-Dindo classification the gold standard? PMID- 22521656 TI - Robotic transrectal ultrasonography during robot-assisted radical prostatectomy. AB - We evaluate the use of robotically manipulated transrectal ultrasound (TRUS) for real-time monitoring of prostate and periprostatic anatomy during robot-assisted prostatectomy (RAP). Ten patients with clinically organ-confined prostate cancer undergoing RAP underwent preoperative and real-time intraoperative biplanar TRUS evaluation using a robotically manipulated TRUS device (ViKY System; EndoControl Medical, Grenoble, France). Median patient age was 66 yr (range: 54-88), baseline prostate-specific antigen (PSA) was 5.3 (range: 1.3-17.9), and four patients (40%) had clinical high-grade and high-stage disease. Bilateral or unilateral nerve sparing was performed in nine patients (90%). Median time for ViKY System setup to insertion of the TRUS probe was 7 min (range: 4-12). Complete robotic TRUS evaluation was successful in all patients. Five patients (50%) had TRUS visible hypoechoic lesions, confirmed cancerous on preoperative biopsy. Relevant intraoperative TRUS findings were relayed in real time to the robotic surgeon, particularly during dissection of the bladder neck and prostatic apex, during neurovascular bundle preservation, and when hypoechoic prostate lesions approximated nerve-preserving dissection. Negative margins were achieved in nine patients (90%), including cases where significant intraprostatic lesions abutted or extended through the prostate capsule. No complications occurred. We concluded that real-time robotic TRUS guidance during RAP is feasible and safe. Robotic TRUS can provide the console surgeon with valuable anatomic information, thus maximizing functional preservation and oncologic success. PMID- 22521657 TI - Using electroretinograms to assess flicker fusion frequency in domestic hens Gallus gallus domesticus. AB - The assessment of flicker fusion frequency (FFF), the stimulus frequency at which a flickering light stimulus can no longer be resolved and appears continuous, and critical flicker fusion frequency (CFF; the highest frequency at any light intensity that an observer can resolve flicker) are useful methods for comparing temporal resolution capabilities between animals. Behavioural experiments have found that average CFFs in domestic chickens (Gallus gallus domesticus) are in the range of ca. 75-87 Hz, measured in response to full spectrum (i.e. white light plus UV) stimuli. In order to examine whether the chicken retina is able to detect flicker at higher frequencies, we used electroretinograms (ERGs) to assess FFF/CFF in adult hens from two commercial genotypes, Lohmann Selected Leghorns (LSLs) and Lohmann Browns (LBs). ERGs were recorded in response to flickering light at ten full spectrum light intensities ranging from 0.7 to 2740 cd m(-2). Two methods were used to determine FFF/CFF from the ERG recordings and these methods yielded very similar results, with average FFF ranging from ca. 20Hz at 0.7 cd m(-2) to an average CFF of ca. 105 Hz at 2740 cd m(-2). In some individuals, CFFs of 118-119 Hz were recorded. The Intensity/FFF (I/FFF) curves are double-branched with a break point representing the rod-cone transition occurring between 2.5 and 5.9 cd m(-2). No significant differences in the I/FFF curves were found between the two genotypes. At stimulus light intensities >250 cd m(-2), the ERG-derived FFF and CFF values are all higher than those from behavioural studies using the same stimuli. Although hens do not appear to be able to consciously perceive flicker above approximately 90 Hz, the finding that the ERG responses are able to remain in phase with light flickering at frequencies >100 Hz means that the retinae of domestic poultry housed in artificial light conditions may be able to resolve flicker from fluorescent lamps. As range of detrimental effects have been reported in humans as a result of exposure to such "invisible flicker", the possibility exists that flicker from fluorescent lamps also acts as stressor in domesticated birds. PMID- 22521658 TI - Averaging is not everything: the saccade global effect weakens with increasing stimulus size. AB - When two elements are presented closely aligned, the average saccade endpoint will generally be located in between these two elements. This 'global effect' has been explained in terms of the center of gravity account which states that the saccade endpoint is based on the relative saliency of the different elements in the visual display. In the current study, we tested one of the implications of the center of gravity account: when two elements are presented closely aligned with the same size and the same distance from central fixation, the saccade should land on the intermediate location, irrespective of the stimulus size. To this end, two equally-sized elements were presented simultaneously and participants were required to execute an eye movement to the visual information presented on the display. Results showed that the strongest global effect was observed in the condition with smaller stimuli, whereas the saccade averaging was weaker when larger stimuli were presented. In a second experiment, in which only one element was presented, we observed that the width of the distribution of saccade endpoints is influenced by stimulus size in that the distribution is broader with smaller stimuli. We conclude that perfect saccade averaging is not always the default response by the oculomotor system. There appears to be a tendency to initiate an eye movement towards one of the visual elements, which becomes stronger with increasing stimulus size. This effect might be explained by an increased uncertainty in target localization for smaller stimuli, resulting in a higher probability of the merging of two stimulus representations into one representation. PMID- 22521659 TI - Spatial-frequency requirements for reading revisited. AB - Blur is one of many visual factors that can limit reading in both normal and low vision. Legge et al. [Legge, G. E., Pelli, D. G., Rubin, G. S., & Schleske, M. M. (1985). Psychophysics of reading. I. Normal vision. Vision Research, 25, 239 252.] measured reading speed for text that was low-pass filtered with a range of cutoff spatial frequencies. Above 2cycles per letter (CPL) reading speed was constant at its maximum level, but decreased rapidly for lower cutoff frequencies. It remains unknown why the critical cutoff for reading speed is near 2 CPL. The goal of the current study was to ask whether the spatial-frequency requirement for rapid reading is related to the effects of cutoff frequency on letter recognition and the size of the visual span. Visual span profiles were measured by asking subjects to recognize letters in trigrams (random strings of three letters) flashed for 150ms at varying letter positions left and right of the fixation point. Reading speed was measured with Rapid Serial Visual Presentation (RSVP). The size of the visual span and reading speed were measured for low-pass filtered stimuli with cutoff frequencies from 0.8 to 8 CPL. Low-pass letter recognition data, obtained under similar testing conditions, were available from our previous study (Kwon & Legge, 2011). We found that the spatial frequency requirement for reading is very similar to the spatial-frequency requirements for the size of the visual span and single letter recognition. The critical cutoff frequencies for reading speed, the size of the visual span and a contrast-invariant measure of letter recognition were all near 1.4 CPL, which is lower than the previous estimate of 2 CPL for reading speed. Although correlational in nature, these results are consistent with the hypothesis that the size of the visual span is closely linked to reading speed. PMID- 22521661 TI - The virtuous technology cycle concept and its application in next-generation sequencing. AB - External access to scientific technology plays an increasingly important part in pharmaceutical R&D. One advantage of accessing technology externally is the avoidance of costs associated with purchase and the reduced time required for developing new methods; in addition, access to external scientific expertise can be beneficial. However, few conceptual frameworks exist for achieving an optimal mix of internal and external technology access. In this review, we describe the virtuous technology cycle (VTC) concept and exemplify its application to next generation sequencing (NGS). Based on selected examples, we show that the VTC concept can greatly enhance the number of technologies accessed and thus significantly increase flexibility and efficiency in drug discovery. We also discuss the challenges of externally accessing NGS technologies. PMID- 22521660 TI - The effect of dot speed and density on the development of global motion perception. AB - The purpose of this study was to investigate the effect of dot speed and dot density on the development of global motion perception by comparing the performance of adults and children (5-6years old) on a direction-discrimination task. Motion coherence thresholds were measured at two dot speeds (1 and 4deg/s) and three dot densities (1, 15, 30dots/deg(2)). Adult coherence thresholds were constant at approximately 9%, regardless of speed or density. Child coherence thresholds were significantly higher across conditions, and were most immature at the slow speed and at the sparse density. Thus, the development of global motion perception depends heavily on stimulus parameters. This finding can account for some of the discrepancy in the current developmental literature. Our results, however, caution against making general claims about motion deficits in clinical populations based on only a single measurement at a specific combination of speed and density. PMID- 22521662 TI - Demineralized bone matrix as a vehicle for delivering endogenous and exogenous therapeutics in bone repair. AB - As a unique human bone extract approved for implant use, demineralized bone matrix (DBM) retains substantial amounts of endogenous osteoconductive and osteoinductive proteins. Commercial preparations of DBM represent a clinically accessible, familiar, widely used and degradable bone-filling device, available in composite solid, strip/piece, and semi-solid paste forms. Surgically placed and/or injected, DBM releases its constituent compounds to bone sites with some evidence for inducing new bone formation and accelerating healing. Significantly, DBM also has preclinical history as a drug carrier by direct loading and delivery of several important classes of therapeutics. Exogenous bioactive agents, including small molecule drugs, protein and peptide drugs, nucleic acid drugs and transgenes and therapeutic cells have been formulated within DBM and released to bone sites to enhance DBM's intrinsic biological activity. Local release of these agents from DBM directly to surgical sites in bone provides improved control of dosing and targeting of both endogenous and exogenous bioactivity in the context of bone healing using a clinically familiar product. Given DBM's long clinical track record and commercial accessibility in standard forms and sources, opportunities to formulate DBM as a versatile matrix to deliver therapeutic agents locally to bone sites in orthopedic repair and regenerative medicine contexts are attractive. PMID- 22521663 TI - NMDA alters rotenone toxicity in rat substantia nigra zona compacta and ventral tegmental area dopamine neurons. AB - Previous patch-clamp studies by our laboratory showed that acute exposure to the pesticide rotenone augments inward currents evoked by N-methyl-d-aspartate (NMDA) in substantia nigra zona compacta (SNC) dopamine neurons in slices of rat brain. The present experiments were done to search for histological evidence of increased neurotoxicity produced by combined rotenone and NMDA treatments. In horizontal slices of rat midbrain, we found that a 30 min superfusion with 100 nM rotenone caused significant injury to tyrosine hydroxylase (TH)-positive proximal dendrites in dorsal and ventral regions of the SNC and ventral tegmental area (VTA). Moreover, treatment with 100 MUM NMDA potentiated rotenone toxicity. In contrast, treatment with 30 MUM NMDA protected against rotenone-induced injury to dendrites in the ventral SNC and ventral VTA. Interestingly, treatment with 30 MUM NMDA-alone produced an apparent increase in proximal dendrite scores in ventral SNC and dorsal VTA. We conclude that NMDA has concentration-dependent actions on rotenone toxicity that differ according to regional subtype of dopamine neuron. PMID- 22521664 TI - An overview of natural polymers for oral insulin delivery. AB - Current therapy for diabetes mellitus through oral anti-diabetic drugs and subcutaneous administration of insulin suffers from serious disadvantages, such as patient noncompliance and occasional hypoglycemia. Moreover, these approaches doesn't mimic the normal physiological pattern of insulin release. Oral route would be the most convenient and preferred route if it is available. Polymeric nano and/or microparticles, either natural or synthetic have been used as matrices for oral insulin delivery. Natural polymers are of particular interest due to their nontoxic, biocompatible, biodegradable and hydrophilic nature. Among the natural polymers used for oral insulin delivery, chitosan (CS) is widely explored owing to its ease of chemical modification and favorable biological properties. In addition, many advantages such as safety, biodegradability, widespread availability and low cost justify the continuing development of promising insulin delivery system based on CS. PMID- 22521665 TI - Promoting drug discovery by collaborative innovation: a novel risk- and reward sharing partnership between the German Cancer Research Center and Bayer HealthCare. AB - As a result of the increasing cost pressure on healthcare systems, the depletion of easily addressable and well-validated target groups in drug development and the requirement of public research to contribute to innovative treatment paradigms, broad partnerships between industry and academia are becoming increasingly important. However, owing to different goals and drivers, hurdles have to be overcome to exploit the full potential of such alliances. The factors that need to be taken into account during set-up and management of such alliances and the result and impact all of this has on drug discovery have not been analyzed in a systematic manner until now. This will be the focus of this review, using the strategic alliance between the German Cancer Research Center and Bayer HealthCare as an example. PMID- 22521667 TI - Neurotransmitter release mechanisms studied in Caenorhabditis elegans. AB - The process of regulated exocytosis has received considerable interest as a key component of synaptic transmission. Fusion of presynaptic vesicles and the subsequent release of their neurotransmitter contents is driven by a series of interactions between evolutionarily conserved proteins. Key insights into the molecular mechanisms of vesicle fusion have come from research using genetic model systems such as the nematode worm Caenorhabditis elegans. We review here the current knowledge regarding regulated exocytosis at the C. elegans synapse and future research directions involving this model organism. PMID- 22521669 TI - Age does not affect outcomes of nonoperative management of blunt splenic trauma. AB - BACKGROUND: The purpose of this study was to examine the effect of age on the outcomes of nonoperative management (NOM) of blunt splenic trauma (BST). STUDY DESIGN: The records of patients with BST, from July 2000 to December 2010 at a level I trauma center, were retrospectively reviewed using NTRACS (National Trauma Registry of the American College of Surgeons). Patients were divided into 2 age groups: 17 to 55 years and greater than 55 years. Stepwise logistic regression analysis was used to identify risk factors associated with failure of nonoperative management (FNOM). RESULTS: There were 539 hemodynamically stable patients with BST who underwent NOM. Of these, 459 were age 55 or less, and 80 were greater than 55. Overall, there was no significant difference in FNOM rate for patients age 55 or less vs greater than 55 (4% vs 5%, p = 0.73). This also held true when FNOM was analyzed by each grade: I (1% vs 3%, p = 0.38), II (2% vs 0%, p = 1.0), III (4% vs 0%, p = 1.0), IV (8% vs 20%, p = 0.33), and V (21% vs 50%, p = 0.47). The addition of angioembolization (AE) to high grade IV to V injuries significantly lowered the FNOM rate: age 55 or less (6% AE vs 28% NO-AE, p = 0.02); with a trend toward significance for age greater than 55 (0% AE vs 60% NO-AE, p = 0.2). Age was not a statistically significant independent risk factor for FNOM (p = 0.37). CONCLUSIONS: Age does not affect outcomes of NOM of BST. High grade (IV to V) injuries are not a contraindication to NOM for patients older than 55. As experience with AE grows in patients with high grade injury and age greater than 55, it may prove to be a valuable adjunct to NOM in this group of patients. PMID- 22521670 TI - Effect of repetitive loading on the mechanical properties of biological scaffold materials. AB - BACKGROUND: Coughing, bending, and lifting raise the pressure inside the abdomen, repetitively increasing stresses on the abdominal wall and the associated scaffold. The purpose of this study was to evaluate the effect of repetitive loading on biological scaffolds. It was hypothesized that exposure to repetitive loading would result in decreased tensile strength and that crosslinked scaffolds would resist these effects more effectively than non-crosslinked scaffolds. STUDY DESIGN: Nine materials were evaluated (porcine dermis: Permacol, CollaMend, Strattice, XenMatrix; human dermis: AlloMax, FlexHD; bovine pericardium: Veritas, PeriGuard; and porcine small intestine submucosa: Surgisis; in addition, Permacol, CollaMend, and PeriGuard are crosslinked). Ten specimens were hydrated and subjected to uniaxial tension to establish baseline properties. Thirty specimens were hydrated and subjected to 10, 100, or 1,000 loading cycles (n = 10 each). RESULTS: Tensile strength remained unchanged for CollaMend, XenMatrix, Veritas, and Surgisis during all cycles (p > 0.05). However, Strattice and AlloMax exhibited reduced tensile strength, and Permacol, FlexHD, and PeriGuard exhibited a slight increase in tensile strength with increasing number of cycles. Crosslinked bovine pericardium (PeriGuard) displayed greater tensile strength than non-crosslinked bovine pericardium (Veritas) and crosslinked porcine dermis (Permacol) exhibited greater tensile strength than non-crosslinked porcine dermis (Strattice, XenMatrix) during all cycles (p < 0.0001). CONCLUSIONS: Materials that rapidly lose strength after repetitive loading might not be appropriate in clinical scenarios involving elevated stresses, such as in patients with high body mass index or when replacing large areas of the abdominal wall without tissue reinforcement, although scaffolds that maintain initial tensile strength can be particularly advantageous. PMID- 22521666 TI - Function and regulation of large conductance Ca(2+)-activated K+ channel in vascular smooth muscle cells. AB - Large conductance Ca(2+)-activated K(+) (BK(Ca)) channels are abundantly expressed in vascular smooth muscle cells. Activation of BK(Ca) channels leads to hyperpolarization of cell membrane, which in turn counteracts vasoconstriction. Therefore, BK(Ca) channels have an important role in regulation of vascular tone and blood pressure. The activity of BK(Ca) channels is subject to modulation by various factors. Furthermore, the function of BK(Ca) channels are altered in both physiological and pathophysiological conditions, such as pregnancy, hypertension and diabetes, which has dramatic impacts on vascular tone and hemodynamics. Consequently, compounds and genetic manipulation that alter activity and expression of the channel might be of therapeutic interest. PMID- 22521668 TI - Racial disparities and sex-based outcomes differences after severe injury. AB - BACKGROUND: Controversy exists about the mechanisms responsible for sex-based outcomes differences post-injury. X-chromosome-linked immune response pathway polymorphisms represent a potential mechanism resulting in sex-based outcomes differences post-injury. The prevalence of these variants is known to differ across race. We sought to characterize racial differences and the strength of any sex-based dimorphism post-injury. STUDY DESIGN: A retrospective analysis was performed using data derived from the National Trauma Data Bank 7.1 (2002-2006). Blunt-injured adult (older than 15 years) patients, surviving >24 hours and with an Injury Severity Score >16 were analyzed (n = 244,371). Patients were stratified by race (Caucasian, black, Hispanic, Asian) and multivariable regression analysis was used to characterize the risk of mortality and the strength of protection associated with sex (female vs male). RESULTS: When stratified by race, multivariable models demonstrated Caucasian females had an 8.5% lower adjusted risk of mortality (odds ratio [OR] = 0.91; 95% CI, 0.88-0.95; p < 0.001) relative to Caucasian males, with no significant association found for Hispanics or blacks. An exaggerated survival benefit was afforded to Asian females relative to Asian males, having a >40% lower adjusted risk of mortality (OR = 0.59; 95% CI, 0.44-78; p < 0.001). Asian males had a >75% higher adjusted risk of mortality relative to non-Asian males (OR = 1.77; 95% CI, 1.5-2.0; p < 0.001), and no significant difference in the mortality risk was found for Asian females relative to non-Asian females. CONCLUSIONS: These results suggest that Asian race is associated with sex-based outcomes differences that are exaggerated, resulting from worse outcomes for Asian males. These racial disparities suggest a negative male X-chromosome-linked effect as the mechanism responsible for these sex-based outcomes differences. PMID- 22521671 TI - Effect of preoperative ibuprofen on pain and swelling after lower third molar removal: a randomized controlled trial. AB - The aim of this study was to compare the analgesic and anti-inflammatory effects of preoperative and postoperative administration of ibuprofen after the surgical removal of impacted lower third molars. A triple-blind, randomized, placebo controlled clinical trial of 120 patients requiring the surgical removal of lower third molars was performed. The subjects were randomized into the experimental group (patients were administered 600 mg of ibuprofen (p.o.) 1h before the surgical procedure, followed by placebo just after the end of the operation) or into the control group (subjects received the same medication but the administration sequence was reversed). Pain was assessed using visual analogue scales, and consumption of rescue analgesic. The facial swelling and trismus were evaluated by measuring facial reference distances and maximum mouth opening. There were no significant differences between the two study groups regarding postoperative pain, rescue analgesics consumption, facial swelling and trismus. There was a slightly higher need for rescue analgesics in the experimental group. The preoperative intake of ibuprofen does not seem to reduce pain, facial swelling and trismus after impacted lower third molar removal when compared to the postoperative administration of the same drug. PMID- 22521673 TI - The impact of discography on the surgical decision in patients with chronic low back pain. AB - BACKGROUND CONTEXT: A reduced frequency of discographies might be the result of increasing concern with long-term effects of discography such as disc degeneration. More knowledge is needed in what patient discography is most likely to influence the surgical decision. PURPOSE: This study was aimed at highlighting how discography affects surgical decisions when performed on one of four different indications in a complicated subgroup of patients with chronic low back pain assumed to be associated with degenerative disc disease (DDD). STUDY DESIGN: Prospective before-after study to analyze how frequently a prediscography preliminary decision was changed and in what direction by adding information from discography in a subgroup of patients with DDD. PATIENT SAMPLE: One hundred thirty-eight patients admitted to a spine clinic more than 4 years with the DDD diagnosis (15% of all) were referred for discography because it was considered that medical history, clinical findings, and magnetic resonance imaging (MRI) were insufficient to make a final assessment on whether to propose surgery/recommend against surgery or what segments to operate on. OUTCOME MEASURES: These were the recorded changes to prediscography preliminary decisions after information was added from discography. METHODS: Before these patients were referred to provocative discography, the surgeon had to select one of four alternative questions/indications being the reason for the discography and choose what decision would have been made if discography would not have been available. The questions/indications were as follows: surgery decided discography to establish whether to treat adjacent segment as well (n=17); several segments degenerated on MRI, pain likely to be discogenic, discography to evaluate what segments to treat (n=56); uncertainty whether pain is discogenic but one suspected segment on MRI (n=38); uncertainty whether pain is discogenic and several segments degenerated in MRI (n=27); the decision after discography was then compared with the prediscography decision and the changes affected by the result of the discography were analyzed. RESULTS: Changes were made to the prediscography decision in 71% of the patients in total. When the surgeon was assured that the pain was discogenic, one segment was added or subtracted in 58% of the patients compared with original prediscography decision. When the surgeon was uncertain if pain was discogenic, the final decision changed from surgery to no surgery in 8%, from no surgery to surgery in 42%, and in cases that were planned for surgery prediscography, one segment was added or subtracted in 17% of the patients. The more certain the surgeon was before discography that the patient's pain was indeed discogenic, the fewer changes between surgical treatment and no surgical treatment took place. The more uncertain the surgeon was before discography that the patient's pain was discogenic, the fewer changes in segments to treat took place in patients who went on to surgery. Changes of involved segments were made to all the 27 patients with a preliminary decision for surgical treatment of the L5-S1 segment solely. The corresponding figure for L4-L5 and L4-L5-S1 was 70% and 53%, respectively. CONCLUSIONS: A high frequency of decisions was altered in this group of surgeons when using discography as an additional examination in patients where uncertainty remains in how to treat after clinical examination, questioning, and MRI. PMID- 22521672 TI - Obstructive sleep apnoea in Treacher Collins syndrome: prevalence, severity and cause. AB - This cohort study in 35 patients (13 children) evaluates the prevalence, severity and anatomical cause of obstructive sleep apnoea syndrome (OSAS) in patients with Treacher Collins syndrome. Ambulatory polysomnography was performed cross sectionally to determine OSAS prevalence and severity. All upper airway related surgical interventions were evaluated retrospectively. In 11 patients, sleep endoscopy, and flexible and rigid endoscopy were applied to determine the level of anatomical obstruction of the upper airway. The overall prevalence of OSAS in Treacher Collins patients was 46% (54% in children; 41% in adults). Thirty-eight upper airway related surgical interventions were performed in 17 patients. Examination of the upper airway revealed various anatomical levels of obstruction, from the nasal septum to the trachea. Most significant obstruction was found at the level of the oro/hypopharynx. OSAS in Treacher Collins patients is an important problem so all patients should be screened for OSAS by polysomnography. Endoscopy of the upper airways was helpful in determining the level of obstruction. Surgical treatment at one level will not resolve OSAS in most patients because OSAS in Treacher Collins has a multilevel origin. Non invasive ventilation (continuous positive airway pressure or bilevel positive airway pressure) or tracheotomy should be considered as a treatment modality. PMID- 22521674 TI - Spinal cord compression by hematoma in the cervical ligamentum flavum: a case report. AB - BACKGROUND CONTEXT: There have been some reports describing hematoma in the thoracic and lumbar ligamentum flavum, but there have been only three reports of hematoma in the cervical ligamentum flavum. PURPOSE: We describe another case of the ligamentum flavum hematoma in the cervical spine with a different feature of occurrence that required surgical treatment. STUDY DESIGN: Case report. PATIENT SAMPLE: Patient with ligamentum flavum hematoma in the cervical spine. OUTCOME MEASURES: Preoperative magnetic resonance imaging and pathologic finding from operative specimen confirmed the diagnosis. METHODS: A 69-year-old man insidiously presented with pain in his left upper arm and difficulty in left shoulder abduction. Neurologic examination demonstrated a cervical myelopathy with diffuse muscle weakness of left upper extremity and sensory disturbance. Imaging studies revealed a mass of high intense on T1-weighted images and isointense on T2-weighted images posterior to the dura at C4 lower end level. The patient underwent C4-C5 hemilaminectomy and the removal of the mass. The mass existed within the ligamentum flavum and was connected toward the pedicle like the beads of a rosary. RESULTS: Histopathologic examination of the surgical specimen showed that the hematoma was present within the ligamentum flavum and contained macrophages that had phagocytosed red blood cells and hemosiderin. After surgery, the patients' symptoms immediately improved, and no recurrence was observed at 2 years postoperatively. CONCLUSIONS: We reported a very rare case of hematoma in the ligamentum flavum of the cervical spine that required surgery. Because the patient was without the history of trauma, it was suggested that the use of antiplatelet drugs was responsible for the occurrence of the disease. PMID- 22521675 TI - Primary malignant peripheral nerve sheath tumor of the cauda equina with metastasis to the brain in a child: case report and literature review. AB - BACKGROUND CONTEXT: Primary intradural malignant peripheral nerve sheath tumors (MPNSTs) are extremely rare; only 23 cases have been reported in the English language literature till now. No gold standard for treating primary intradural MPNSTs has yet been established. PURPOSE: To report a rare case of primary intradural MPNSTs in a child and review the literature pertaining to this rare disease. STUDY DESIGN/SETTING: Case report and literature review. METHODS: We report our experience with one new case. An 8-year-old boy diagnosed with primary intradural MPNSTs underwent three surgical excisions and two rounds of radiotherapy; however, metastasis to the brain was found, and the boy died 16 months after the first surgery. We also review the literature pertaining to both MPNSTs in general and primary intradural MPNSTs. RESULTS: Surgery is currently the mainstay of MPNST treatment. Radiotherapy and chemotherapy are of limited value in these tumors. Based on the review of the 24 cases described in the literature, including the present case, primary intradural MPNST is a very aggressive tumor with a very high recurrence rate even after gross total resection and with significant potential for leptomeningeal and systemic metastasis. The overall prognosis is very poor and seems to be worse than that of MPNSTs in general. CONCLUSIONS: Primary intradural MPNST is a very rare entity with a poor prognosis. Surgical tumor removal combined with postoperative high dose radiation may be recommended. Chemotherapy is usually reserved for patients with disseminated metastases or tumors that are unresectable at the time of diagnosis. PMID- 22521676 TI - Quality of life in epilepsy (QOLIE): insights about epilepsy and support groups from people with epilepsy (San Francisco Bay Area, USA). AB - INTRODUCTION: This study evaluated quality of life (QOL) in people with epilepsy (PWE) in the San Francisco Bay Area. METHODS: This was a qualitative study examining QOL through the use of focus groups and of the QOLIE-31-P survey instrument. Six focus groups were conducted to examine self-reported challenges due to epilepsy. Focus groups were conducted for individuals who did and did not attend support groups. RESULTS: Individuals with epilepsy reported substantial difficulties with finances, physical and psychosocial functioning. Also, limited knowledge about services and relatively negative feelings toward self were common among newly diagnosed participants. CONCLUSION: Many of the issues surrounding QOL and challenges were shared across groups. Epilepsy-related social services appeared to be useful in helping PWE cope and in increasing PWE's awareness of key enabling services. Although many individuals with epilepsy reported poor QOL and other challenges, epilepsy-related services may be under-utilized due to a lack of awareness. PMID- 22521677 TI - Pharmacovigilance in Europe and North America: divergent approaches. AB - Although international medicines regulators adopt a common system to assess the safety and efficacy of new drugs, pre-market evaluation is recognized as incomplete given the much larger post-market experience to follow. Adverse drug reactions contribute to more than 100,000 deaths in the United States annually and are among the top 10 leading causes of death. Regulators are developing active surveillance approaches to assess the risks of medicines in the post market phase to enhance passive adverse drug reaction reporting systems that capture only one to ten percent of ADRs. The objective of this study is to compare international approaches to active surveillance and the manner in which regulatory agencies access and use post-market evidence in their decisions. A conceptual framework is used to guide the comparative analysis of pharmacovigilance governance and policy in the United Kingdom, France, the European Union, the United States and Canada using data gathered from key informant interviews and document review. While research networks are emerging internationally, we found a greater reliance on industry funding and oversight of post-market research in Europe compared to an emphasis on publicly funded programs in North America. PMID- 22521678 TI - Use of the Yitzhaki Index as a test of relative deprivation for health outcomes: a review of recent literature. AB - We reviewed the empirical studies published between 2000 and 2010 that test the relative deprivation (RD) hypothesis in relation to population health. Our review focuses primarily on 14 studies using the Yitzhaki Index and related relative income measures. We summarize their main findings by health outcome, address methodological challenges in measuring RD, and identify several gaps in the literature as well as future directions for research in this area. Gaps in the evidence include the need for longitudinal studies with stronger causal designs - for example, examining changes in RD in relation to changes in health outcomes, with careful control for confounding by individual income and other indicators of socioeconomic position. Defining the appropriate reference group (from which people make social comparisons) poses a major empirical challenge, as evidenced by the fact that the measurement of RD has not materially advanced since Yitzhaki's original formulation in 1979. More innovative approaches to operationalizing RD are needed - including the measurement of RD in dimensions other than income, incorporating inter-generational comparisons; and attempting exogenous manipulation of RD, e.g. through laboratory-based experiments. PMID- 22521679 TI - Macro-level gender equality and alcohol consumption: a multi-level analysis across U.S. States. AB - Higher levels of women's alcohol consumption have long been attributed to increases in gender equality. However, only limited research examines the relationship between gender equality and alcohol consumption. This study examined associations between five measures of state-level gender equality and five alcohol consumption measures in the United States. Survey data regarding men's and women's alcohol consumption from the 2005 Behavioral Risk Factor Surveillance System were linked to state-level indicators of gender equality. Gender equality indicators included state-level women's socioeconomic status, gender equality in socioeconomic status, reproductive rights, policies relating to violence against women, and women's political participation. Alcohol consumption measures included past 30-day drinker status, drinking frequency, binge drinking, volume, and risky drinking. Other than drinker status, consumption is measured for drinkers only. Multi-level linear and logistic regression models adjusted for individual demographics as well as state-level income inequality, median income, and % Evangelical Protestant/Mormon. All gender equality indicators were positively associated with both women's and men's drinker status in models adjusting only for individual-level covariates; associations were not significant in models adjusting for other state-level characteristics. All other associations between gender equality and alcohol consumption were either negative or non-significant for both women and men in models adjusting for other state-level factors. Findings do not support the hypothesis that higher levels of gender equality are associated with higher levels of alcohol consumption by women or by men. In fact, most significant findings suggest that higher levels of equality are associated with less alcohol consumption overall. PMID- 22521680 TI - Preliminary study on the effects of ageing cold oxygen plasma treated PET/PP with respect to protein adsorption. AB - Surfaces of polyethylene terephthalate (PET) and polypropylene (PP) have been modified by oxygen plasma. The surface hydrophilicity and changes in topography during up to 90 days storage in water and in dry air in a desiccator were analysed by dynamic contact angle test and atomic force microscopy (AFM). Clear ageing effects on the plasma treated surface were observed as increases in contact angle and changes in roughness as functions of increasing storage time. However, the effect of oxygen plasma treatment to increase the hydrophilicity of surface was still evident on the treated surfaces even after 90 days storage either in dry air or in water. In protein adsorption experiments, human serum albumin (HSA) and fibrinogen (Fg) were adsorbed on untreated and oxygen plasma treated PET and PP surfaces. The quantified ATR-FTIR results showed that both HSA and Fg adsorption on PET and PP surfaces decreased after oxygen plasma treatment, with the effect most evident for HSA. Although for both proteins adsorption increased with ageing, the amount of adsorbed proteins was still lower than untreated surface at 30 days. This suggests the shelf life of oxygen plasma treated samples could be as long as 30 days. PMID- 22521681 TI - In vitro application of paclitaxel loaded magnetoliposomes for combined chemotherapy and hyperthermia. AB - Paclitaxel loaded thermosensitive magnetoliposomes containing 1,2-dipalmitoyl-sn glycero-3-phosphocholine (DPPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-rac glycerol (PG) were prepared by thin film hydration method. Encapsulation efficiencies of paclitaxel and citric acid coated Fe(3)O(4) nanoparticles were 83+/-3% and 74.6+/-5%, respectively. Based on the release study, DPPC/PG in 9:1 (w/w) liposomes (PCPG) formulation was found to be thermosensitive and showed 46 fold higher drug release at 43 degrees C than at 37 degrees C. Drug release was done under an alternating magnetic field of intensity 10 kA/m and a fixed frequency of 423 kHz. In-vitro cytotoxicity and hyperthermia studies were carried out using a human cervical cancer cell line (HeLa). IC(50) value of the magnetoliposomes formulation was 100 nM. When the magnetoliposomes with 100 nM drug was used to treat HeLa cells in combination with hyperthermia under AC magnetic field, 89% cells were killed and were found to be more effective than either hyperthermia or chemotherapy alone. So, PCPG liposomes which co encapsulate both Fe(3)O(4) nanoparticles and paclitaxel may be useful for combined chemotherapy and hyperthermia. PMID- 22521682 TI - A novel study of antibacterial activity of copper iodide nanoparticle mediated by DNA and membrane damage. AB - In this article potential activity of nanoparticles (NPs) of copper iodide (CuI) as an antibacterial agent has been presented. The nano particles are synthesized by co-precipitation method with an average size of 8 nm as determined by Transmission Electron Microscope (TEM). The average charge of the NPs is -21.5 mV at pH 7 as obtained by zeta potential measurement and purity is determined by XRD. These NPs are able to kill both gram positive and gram negative bacteria. Among the bacteria tested, DH5alpha is more sensitive but Bacillus subtilis is more resistant to NPs of CuI. Consequently, the MIC and MBC values of DH5alpha is least (0.066 mg/ml and 0.083 mg/ml respectively) and B. subtilis is highest (0.15 mg/ml and 0.18 mg/ml respectively) among the tested bacterial strains. From our studies it is inferred that CuI NPs produce reactive oxygen species (ROS) in both gram negative and gram positive bacteria and it also causes ROS mediated DNA damage for the suppression of transcription as revealed by reporter gene assay. Probably ROS is formed on the surface of NPs of CuI in presence of amine functional groups of various biological molecules. Furthermore they induce membrane damage as determined by atomic force microscopy (AFM). Thus production of ROS and membrane damage are major mechanisms of the bactericidal activity of these NPs of CuI. PMID- 22521683 TI - Biosynthesis of silver nanoparticles from Tribulus terrestris and its antimicrobial activity: a novel biological approach. AB - In the recent decades, increased development of green synthesis of nanoparticles is inevitable because of its incredible applications in all fields of science. There were numerous work have been produced based on the plant and its extract mediated synthesis of nanoparticles, in this present study to explore that the novel approaches for the biosynthesis of silver nanoparticles using plant fruit bodies. The plant, Tribulus terrestris L. fruit bodies are used in this study, where the dried fruit body extract was mixed with silver nitrate in order to synthesis of silver nanoparticles. The active phytochemicals present in the plant were responsible for the quick reduction of silver ion (Ag(+)) to metallic silver nanoparticles (Ag(0)). The reduced silver nanoparticles were characterized by Transmission Electron Microscope (TEM), Atomic Force Microscope (AFM), XRD, FTIR, UV-vis spectroscopy. The spherical shaped silver nanoparticles were observed and it was found to be 16-28 nm range of sizes. The diffraction pattern also confirmed that the higher percentage of silver with fine particles size. The antibacterial property of synthesized nanoparticles was observed by Kirby-Bauer method with clinically isolated multi-drug resistant bacteria such as Streptococcus pyogens, Pseudomonas aeruginosa, Escherichia coli, Bacillus subtilis and Staphylococcus aureus. The plant materials mediated synthesis of silver nanoparticles have comparatively rapid and less expensive and wide application to antibacterial therapy in modern medicine. PMID- 22521684 TI - Hearing handicap, rather than measured hearing impairment, predicts poorer quality of life over 10 years in older adults. AB - BACKGROUND: We aimed to determine the prospective association between measured hearing impairment, self-reported hearing handicap and hearing aid use with quality of life. STUDY DESIGN: 829 Blue Mountains Hearing Study participants (>= 55 years) were examined between 1997-1999 and 2007-2009. The shortened version of the hearing handicap inventory was administered. Hearing levels were measured using pure-tone audiometry. Quality of life was assessed using the 36-Item Short Form Survey (SF-36); higher scores reflect better quality of life. RESULTS: Hearing impairment at baseline compared with no impairment was associated with lower mean SF-36 mental composite score 10 years later (multivariable-adjusted p=0.03). Physical composite score and mean scores for seven of the eight SF-36 domains after 10-year follow-up were significantly lower among participants who self-reported hearing handicap at baseline. Differences in the adjusted means between participants with and without hearing handicap ranged from 2.7 (physical composite score) to 10.4 units ('role limitations due to physical problems' domain). Individuals who developed incident hearing impairment compared to those who did not, had adjusted mean scores 9.5- and 7.7-units lower in the 'role limitation due to physical problems', and 'bodily pain' domains, respectively, at the 10-year follow-up. Hearing aid users versus non-users at baseline showed a 1.82-point (p=0.03) and 3.32-point (p=0.01) increase in SF-36 mental composite score and mental health domain over the 10-year follow-up, respectively. CONCLUSION: Older adults with self-perceived hearing handicap constitute a potential risk group for overall deterioration in quality of life, while hearing aid use could help improve the well-being of hearing impaired adults. PMID- 22521685 TI - Should questionnaires of female sexual dysfunction be used in routine clinical practice? AB - AIMS: The aim of this paper is to explore the potential value of questionnaires in routine clinical practice to assess female sexual dysfunction (FSD), and to identify if this could increase the competence of a physician in the initial management of women with these problems. The rationale to encourage Health Care Professionals (HCPs) to engage women in dialogue about their sexual health is that it may enhance a woman's quality of life (which may lead to improved general health) and might lead to timely interventions and possible preventative measures for certain diseases. METHOD: A short literature review of the most relevant publications was undertaken evaluating current practice. RESULTS: FSD can have a negative impact on women's well-being and can also be an early symptom of underlying disease. Many HCPs do not broach the subject, consequently women do not get the opportunity either to voice their sexual concerns or access appropriate services. Review of currently available FSD questionnaires suggests that many but not all are generally inappropriate for use in routine clinical practice. Kriston et al.'s STEFFI-2 may be an appropriate starting point. Evidence suggests that this would facilitate discussion of sexual matters between the HCP and the women, and increase the likelihood of FSD being diagnosed. CONCLUSIONS: Following this review of the literature, the authors strongly recommend that HCPs include FSD questionnaires as part of their routine engagement with women. However, the questionnaire would need to be used as part of the overall assessment and cannot replace a detailed case history and examination, which should lead to effective treatment and management of FSD. The authors recommend further research in the following areas: * Effective training for HCPs. * FSD as an early presentation of sub-clinical disease. * The cost benefit of early treatment of FSD. * A standardised, validated FSD screening tool. * Benefits of using FSD screener in routine clinical practice. PMID- 22521687 TI - Development of a harpacticoid copepod bioassay: selection of species and relative sensitivity to zinc, atrazine and phenanthrene. AB - Worldwide, estuaries are under increasing pressure from numerous contaminants. This study aimed to identify a suitable marine harpacticoid copepod species for toxicity testing of New Zealand estuaries. Multiple aspects were considered for species selection and included: a broad regional distribution, ease of culture, reproductive rate under laboratory conditions, sexual dimorphism, and sensitivity to contaminants. Five species were evaluated and two (Robertsonia propinqua and Quinquelaophonte sp.) were able to be cultured. The relative sensitivity of these copepods to three reference toxicants was assessed by determining the medial lethal values following a 96 h exposure (96 h LC(50)) to these toxicants in the aquatic phase. LC(50) values for zinc, phenanthrene, and atrazine respectively were 2.0, 0.89, and 7.58 mg/L in R. propinqua and 0.64, 0.75, and 20.8 mg/L in Quinquelaophonte sp. After evaluating all factors involved in choosing a bioassay species for New Zealand, Quinquelaophonte sp. was selected as the most suitable bioassay species. PMID- 22521686 TI - Cortical and subcortical mapping of language areas: correlation of functional MRI and tractography in a 3T scanner with intraoperative cortical and subcortical stimulation in patients with brain tumors located in eloquent areas. AB - OBJECTIVE: To describe the detection of cortical areas and subcortical pathways involved in language observed in MRI activation studies and tractography in a 3T MRI scanner and to correlate the findings of these functional studies with direct intraoperative cortical and subcortical stimulation. MATERIAL AND METHODS: We present a series of 14 patients with focal brain tumors adjacent to eloquent brain areas. All patients underwent neuropsychological evaluation before and after surgery. All patients underwent MRI examination including structural sequences, perfusion imaging, spectroscopy, functional imaging to determine activation of motor and language areas, and 3D tractography. All patients underwent cortical mapping through cortical and subcortical stimulation during the operation to resect the tumor. Postoperative follow-up studies were done 24 hours after surgery. RESULTS: The correlation of motor function and of the corticospinal tract determined by functional MRI and tractography with intraoperative mapping of cortical and subcortical motor areas was complete. The eloquent brain areas of language expression and reception were strongly correlated with intraoperative cortical mapping in all but two cases (a high grade infiltrating glioma and a low grade glioma located in the frontal lobe). 3D tractography identified the arcuate fasciculus, the lateral part of the superior longitudinal fasciculus, the subcallosal fasciculus, the inferior fronto occipital fasciculus, and the optic radiations, which made it possible to mark the limits of the resection. The correlation with the subcortical mapping of the anatomic arrangement of the fasciculi with respect to the lesions was complete. CONCLUSION: The best treatment for brain tumors is maximum resection without associated deficits, so high quality functional studies are necessary for preoperative planning. PMID- 22521688 TI - Cumulative ecological impacts of two successive annual treatments of imidacloprid and fipronil on aquatic communities of paddy mesocosms. AB - Agricultural landscapes, including paddies, play an important role in maintaining biodiversity, but this biodiversity has been under the threat of toxic agro chemicals. Our knowledge about how aquatic communities react to, and recover from, pesticides, particularly in relation to their residues, is deficient, despite the importance of such information for realistic environmental impact assessment of pesticides. The cumulative ecological impacts on aquatic paddy communities and their recovery processes after two successive annual applications of two systemic insecticides, imidacloprid and fipronil, were monitored between mid-May and mid-September each year. The abundance of benthic organisms during both years was significantly lower in both insecticide-treated fields than in the controls. Large-impacts of fipronil on aquatic arthropods were found after the two years. Growth of medaka fish, both adults and their juveniles, was affected by the application of the two insecticides. A Principal Response Curve analysis (PRC) showed the escalation and prolongation of changes in aquatic community composition by the successive annual treatments of each insecticide over two years. Residues of fipronil in soil, which are more persistent than those of imidacloprid, had a high level of impact on aquatic communities over time. For some taxonomic groups, particularly for water surface-dwelling and water-borne arthropods, the second annual treatment had far greater impacts than the initial treatment, indicating that impacts of these insecticides under normal use patterns cannot be accurately assessed during short-term monitoring studies, i.e., lasting less than one year. It is concluded that realistic prediction and assessment of pesticide effects at the community level should also include the long-term ecological risks of their residues whenever these persist in paddies over a year. PMID- 22521689 TI - CRISPR immunity relies on the consecutive binding and degradation of negatively supercoiled invader DNA by Cascade and Cas3. AB - The prokaryotic CRISPR/Cas immune system is based on genomic loci that contain incorporated sequence tags from viruses and plasmids. Using small guide RNA molecules, these sequences act as a memory to reject returning invaders. Both the Cascade ribonucleoprotein complex and the Cas3 nuclease/helicase are required for CRISPR interference in Escherichia coli, but it is unknown how natural target DNA molecules are recognized and neutralized by their combined action. Here we show that Cascade efficiently locates target sequences in negatively supercoiled DNA, but only if these are flanked by a protospacer-adjacent motif (PAM). PAM recognition by Cascade exclusively involves the crRNA-complementary DNA strand. After Cascade-mediated R loop formation, the Cse1 subunit recruits Cas3, which catalyzes nicking of target DNA through its HD-nuclease domain. The target is then progressively unwound and cleaved by the joint ATP-dependent helicase activity and Mg(2+)-dependent HD-nuclease activity of Cas3, leading to complete target DNA degradation and invader neutralization. PMID- 22521691 TI - Integrative genomics identifies the corepressor SMRT as a gatekeeper of adipogenesis through the transcription factors C/EBPbeta and KAISO. AB - The molecular role of corepressors is poorly understood. Here, we studied the transcriptional function of the corepressor SMRT during terminal adipogenesis. Genome-wide DNA-binding profiling revealed that this corepressor is predominantly located in active chromatin regions and that most distal SMRT binding events are lost after differentiation induction. Promoter-proximal tethering of SMRT in preadipocytes is primarily mediated by KAISO through the conserved TCTCGCGAGA motif. Further characterization revealed that KAISO, similar to SMRT, accelerates the cell cycle and increases fat accumulation upon knockdown, identifying KAISO as an adipogenic repressor that likely modulates the mitotic clonal expansion phase of this process. SMRT-bound promoter-distal sites tend to overlap with C/EBPbeta-bound regions, which become occupied by proadipogenic transcription factors after SMRT clearance. This reveals a role for SMRT in masking enhancers from proadipogenic factors in preadipocytes. Finally, we identified SMRT as an adipogenic gatekeeper as it directly fine-tunes transcription of pro- and antiadipogenic genes. PMID- 22521690 TI - Mechanism of foreign DNA selection in a bacterial adaptive immune system. AB - In bacterial and archaeal CRISPR immune pathways, DNA sequences from invading bacteriophage or plasmids are integrated into CRISPR loci within the host genome, conferring immunity against subsequent infections. The ribonucleoprotein complex Cascade utilizes RNAs generated from these loci to target complementary "nonself" DNA sequences for destruction, while avoiding binding to "self" sequences within the CRISPR locus. Here we show that CasA, the largest protein subunit of Cascade, is required for nonself target recognition and binding. Combining a 2.3 A crystal structure of CasA with cryo-EM structures of Cascade, we have identified a loop that is required for viral defense. This loop contacts a conserved three base pair motif that is required for nonself target selection. Our data suggest a model in which the CasA loop scans DNA for this short motif prior to target destabilization and binding, maximizing the efficiency of DNA surveillance by Cascade. PMID- 22521693 TI - Antimicrobial resistance trends among 5608 clinical Gram-positive isolates in China: results from the Gram-Positive Cocci Resistance Surveillance program (2005 2010). AB - A total of 5608 clinical isolates of Gram-positive bacteria were collected from 12 teaching hospitals across China from 2005 to 2010. The minimum inhibitory concentrations (MICs) of 19 antimicrobial agents were determined by the agar dilution method at the central laboratory. Overall, the prevalence of methicillin resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase negative staphylococci (MRSCoN) were 46.8% and 81.5%, respectively. Isolates from inpatients exhibited a higher rate of MRSA than that from outpatients (52.3% versus 26.2%, P < 0.001). The prevalence of MRSA in respiratory infections (67.5%) was higher than in other sources of infections (P < 0.001). A shift in vancomycin MICs from <0.5 to 1.0 MUg/mL was observed during the 6-year period. In 2005, 70.5% of S. aureus isolates were inhibited at the vancomycin MIC of 0.5 MUg/mL, while in 2010, 89% of the isolates were inhibited at the vancomycin MIC of 1 MUg/mL. With the use of penicillin oral breakpoints, penicillin-resistant Streptococcus pneumoniae (PRSP) increased from 28.6% in 2005 to 59.5% in 2010 and varied among different age groups, with an average rate of 70.6% for children under 5 years old. Importantly, an obvious penicillin MIC right shift was observed from 0.032 to 4 MUg/mL during the study period. Serotyping for the isolates from 2005 and 2010 indicated that the high rate of PRSP could be due to the increased prevalence of serogroup 19. The prevalence of vancomycin-resistant enterococci (VRE) increased from 0 in 2005 to 4.9% in 2010. Of the 27 VRE isolates, vanA gene was the most prevalent gene. During the study period, 97.9 100% of different species tested were susceptible to teicoplanin. Linezolid and tigecycline showed potent activities, and no resistant isolate was identified. In conclusion, although the prevalence of MRSA and MRSCoN remained stable over the 6 years, a sharp increase in the prevalence of PRSP was identified. In addition, MIC shifts, including the MICs of penicillin against S. pneumoniae and vancomycin against S. aureus, were observed. Continuous surveillance is warranted to evaluate the resistance trend of clinically important Gram-positive organisms in the future. PMID- 22521692 TI - In vitro activity of cefditoren and other comparators against Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis causing community acquired respiratory tract infections in China. AB - The aim of this study was to evaluate the in vitro activity of cefditoren and comparators against Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis causing community-acquired respiratory tract infections (CARTIs). A total of 391 Streptococcus pneumoniae, 266 H. influenzae, and 76 M. catarrhalis were isolated from 10 centers located at 6 cities in China from January 2009 to May 2010. The microdilution method was used to determine minimum inhibitory concentrations (MICs). The pneumococci comprised 189 (48.3%) penicillin susceptible, 129 (33.0%) penicillin intermediate, and 73 (18.7%) penicillin resistant. Moxifloxacin and levofloxacin showed the highest activity (99.2% and 97.7%, respectively) against Streptococcus pneumoniae, followed by parenteral penicillin G (95.7%), cefditoren (83.1%) and amoxicillin-clavulanic acid (79.3%). Among the 266 H. influenzae isolates, 26 (9.8%) were ampicillin resistant beta-lactamase-producing strains and 24 (9.0%) were ampicillin resistant beta-lactamase-nonproducing strains (BLNAR). Most of antimicrobial agents demonstrated good activity (>97% susceptibility) against H. influenzae except ampicillin, cefuroxime, and cefaclor, which showed relatively lower activity (81.2%, 88.7%, and 88%, respectively). Cefditoren showed excellent activity with the lowest MIC(50) and MIC(90) (<=0.016/0.064 MUg/mL) among all tested drugs, which is independent of beta-lactamase production or ampicillin resistance. Cefditoren at a concentration of 0.5 MUg/mL inhibited all BLNAR strains. Seventy of 76 isolates of M. catarrhalis produced beta-lactamase. Cefditoren also showed excellent activity with MIC(90) of 0.064 MUg/mL against beta-lactamase-nonproducing strains and 0.5 MUg/mL against beta-lactamase producing strains. In conclusion, the excellent intrinsic activity of cefditoren suggests that it may be a good choice for the treatment of CARTIs caused by Streptococcus pneumoniae, H. influenzae, and M. catarrhalis in China, while the activity should be closely monitored. PMID- 22521694 TI - The role of the peritoneal cavity in adhesion formation. PMID- 22521695 TI - Running interference. PMID- 22521696 TI - Effect of laparoscopic excision of endometriomas on ovarian reserve: serial changes in the serum antimullerian hormone levels. AB - OBJECTIVE: To investigate the effect of laparoscopic endometrioma stripping on serum antimullerian hormone (AMH) and the correlation between the clinicopathologic factors. DESIGN: Prospective study. SETTING: University hospital. PATIENT(S): Sixty-five women with endometriomas. INTERVENTION(S): All patients underwent laparoscopic cystectomy. Serum AMH, FSH, LH, E(2), and antral follicle count (AFC) were measured preoperatively, at 6 weeks, and at 6 months postoperatively. Specimens were analyzed histopathologically. MAIN OUTCOME MEASURE(S): The primary end point was to assess the ovarian reserve damage based on alterations of AMH and the secondary end point was to detect the changes in FSH, LH, E(2), and AFC. RESULT(S): Serum AMH decreased significantly at the sixth month (61%) postoperatively. The FSH level increased significantly at the sixth week, but returned to normal at the sixth month. The AFC increased significantly at the sixth week and at the sixth month. The AMH level decrease was more evident in patients with the cyst <5 cm (65.7% vs. 41.3%). The AMH decrease was more in bilateral compared with unilateral endometriomas (67% versus 57%, respectively). No correlation was detected between the histopathologic analyses and tAMH level. Initially the AMH level was the only independent factor affecting the AMH decrease (odds ratio, 3.68; 95% confidence interval 1.66-8.14). CONCLUSION(S): Laparoscopic cystectomy of ovarian endometriomas causes a significant and progressive decline in serum AMH levels. PMID- 22521697 TI - Spontaneous pregnancies among couples previously treated by in vitro fertilization. AB - OBJECTIVE: To determine the frequency of live births following spontaneous pregnancy (BSP) and to examine their associated factors among couples who have unsuccessfully or successfully experienced fertility treatments. DESIGN: Retrospective cohort. SETTING: Eight IVF centers. PATIENT(S): A total of 2,134 couples who began IVF treatment in the centers in 2000-2002 and were followed up by a postal questionnaire sent 7-9 years after they started treatment in the inclusion center. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Rates of BSP and factors associated with BSP. Univariate and multivariate analyses were conducted using logistic regression. RESULT(S): The BSP rate was 17% (218/1,320) among couples who had previously had a child through medical treatment and 24% (193/814) among couples who had remained childless after treatment. In both groups, the probability of BSP was higher among younger women and increased with a smaller number of IVF attempts. Probability was also higher when the cause of infertility was unexplained. CONCLUSION(S): Our results should give hope to couples who have been unsuccessfully treated by IVF, especially young couples with unexplained infertility. Nonetheless, it should be remembered that the BSP rates are cumulative rates observed over a long period of time and that these couples have a very low monthly probability of conceiving. PMID- 22521698 TI - Role of routine monitoring of liver and renal function during treatment of ectopic pregnancies with single-dose methotrexate protocol. AB - OBJECTIVE: To assess whether or not baseline serum transaminases and creatinine measurements, before administration of methotrexate, identified significant liver or kidney disease, which have the potential to alter the management plan for the treatment of ectopic pregnancies. DESIGN: This is a retrospective study of patients treated for ectopic pregnancy. SETTING: Women's emergency room and reproductive endocrinology office at a teaching hospital over a 3-year period. PATIENT(S): Women presenting for treatment of ectopic pregnancy. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Assessment of baseline serum transaminases and creatinine measurements before administration of methotrexate to identify significant liver or kidney disease. RESULT(S): A total of 383 patients were managed for ectopic pregnancy from January 2006 to December 2008. Of these, 320 patients received methotrexate as part of their treatment. No patient was denied treatment with methotrexate secondary to concerns regarding liver or renal function. No complication related to methotrexate administration was documented. A subgroup of 81 patients had pre- and postadministration labs, and no significant difference was noted upon comparing the values. CONCLUSION(S): Routine measurement of serum aspartate aminotransferase and creatinine levels may not be necessary before instituting a single-dose methotrexate treatment regimen for the management of ectopic pregnancy. PMID- 22521699 TI - Morphometric-stereological and functional epididymal alterations and a decrease in fertility in rats treated with finasteride and after a 30-day post-treatment recovery period. AB - OBJECTIVE: To evaluate morphometric-stereological changes in the epididymal caput, sperm quality, and fertility parameters in rats treated with finasteride and after a 30-day post-treatment recovery period. DESIGN: Experimental study in a research laboratory. SETTING: Reproductive biology research laboratory. ANIMAL(S): Male and female Sprague Dawley rats. INTERVENTION(S): Treatment with finasteride (5 mg/kg/day) for 56 days followed by 30 days without treatment. MAIN OUTCOME MEASURE(S): Serum hormone analyses, morphometric-stereological and ultrastructural evaluation of the epididymal caput, sperm transit time, natural mating, in utero insemination, sperm membrane integrity, and fertility parameters. RESULT(S): Serum dihydrotestosterone levels in the finasteride group decreased by ~40% compared with that of control rats. Ultrastructural analysis revealed significant reductions in several morphometric-stereological parameters of the epididymal caput. All parameters recovered significantly in the post treatment period. There was no alteration in daily sperm production in the finasteride group. However, significant reductions in sperm transit time, motility, sperm membrane integrity, and fertility parameters were observed in rats treated with finasteride. CONCLUSION(S): Treatment with finasteride caused morphometric-stereological and functional changes in the epididymis and in sperm function that led to a reduction in fertility parameters. A 30-day post-treatment recovery period was insufficient to restore normal sperm motility, sperm transit time, and some fertility parameters. PMID- 22521700 TI - The antifungal properties of chlorhexidine digluconate and cetylpyrinidinium chloride on oral Candida. AB - INTRODUCTION: C. tropicalis and C. krusei have emerged as virulent species causing oral infections. Both have developed resistance to commonly prescribed azole antifungal agents. OBJECTIVE: The study aimed to determine the effect of mouth rinses containing chlorhexidine digluconate (CHX), cetylpyridinium chloride (CPC) and their combination (CHX-CPC) on the growth of these strains. METHODS: The minimal inhibition concentrations (MIC) of the mouth rinses were determined. The growth curves of the strains produced under the mouth rinse-treated and untreated conditions, as well as alterations to the morphology of the growth colonies and cells following the treatments were compared and analysed. RESULTS: The MICs of CPC compared to CHX mouth rinses were found to be lower for both Candida sp. In the mixed formulation, CPC doubled the inhibitory effect of CHX towards both Candida sp., while CHX quadrupled the activity of CPC towards C. tropicalis. The growth colonies also appeared coarse, wrinkled and dried. CONCLUSION: The profound effects shown may suggest the fungicidal activities of the mouth rinses incorporated with CHX, CPC or their combination on both C. tropicalis and C. krusei. Gargling using mouth rinses with such fungicidal activity would enhance a rapid reduction in the candidal population of patients with fungal infection. PMID- 22521701 TI - Shear bond strength of porcelain laminate veneers to enamel, dentine and enamel dentine complex bonded with different adhesive luting systems. AB - OBJECTIVES: The aim of this study was to evaluate the shear bond strength of porcelain laminate veneers to 3 different surfaces by means of enamel, dentine, and enamel-dentine complex. METHODS: One hundred thirty-five extracted human maxillary central teeth were used, and the teeth were randomly divided into 9 groups (n=15). The teeth were prepared with 3 different levels for bonding surfaces of enamel (E), dentine (D), and enamel-dentine complex (E-D). Porcelain discs (IPS e.max Press, Ivoclar Vivadent) of 2mm in thickness and 4mm in diameter were luted to the tooth surfaces by using 2 light-curing (RelyX Veneer [RV], 3M ESPE; Variolink Veneer [VV], Ivoclar Vivadent) and a dual-curing (Variolink II [V2], Ivoclar Vivadent) adhesive systems according to the manufacturers' instructions. Shear bond strength test was performed in a universal testing machine at 0.5mm/min until bonding failure. Failure modes were determined under a stereomicroscope, and fracture surfaces were evaluated with a scanning electron microscope. The data were statistically analysed (SPSS 17.0) (p=0.05). RESULTS: Group RV-D exhibited the lowest bond strength value (5.42+/-6.6MPa). There was statistically no difference among RV-D, V2-D (13.78+/-8.8MPa) and VV-D (13.84+/ 6.2MPa) groups (p>0.05). Group VV-E exhibited the highest bond strength value (24.76+/-8.8MPa). CONCLUSIONS: The type of tooth structure affected the shear bond strength of the porcelain laminate veneers to the 3 different types of tooth structures (enamel, dentine, and enamel-dentine complex). CLINICAL SIGNIFICANCE: When dentine exposure is necessary during preparation, enough sound enamel must be protected as much as possible to maintain a good bonding; to obtain maximum bond strength, preparation margins should be on sound enamel. PMID- 22521702 TI - Hereditary dentine diseases resulting from mutations in DSPP gene. AB - OBJECTIVES: This review groups the newest results of molecular analyses of DSPP gene for patients diagnosed either with dentinogenesis imperfecta type II/III or dentine dysplasia and tries to link the phenotypes with specific mutations in the DSPP gene. DATA: The review includes biochemical data introducing a specificity of DSPP protein which justifies it as a critical factor for dentine mineralization and maturation. The majority of the review analyzes mutations in the DSPP gene which result in phenotypes of dentinogenesis imperfecta types II or/and III or dentine dysplasia. SOURCES: An electronic search was conducted in the databases of Pub Med and supplemented by manual study of relevant references. STUDY SELECTION: 52 out of 108 references were finally selected for the review based on the novelty and/or originality of data. CONCLUSION: Hereditary dentine disorders dentinogenesis imperfecta type II/III and dentine dysplasia are currently proposed to be one disease with distinct clinical manifestations reflecting various mutations in the same DSPP gene. For years both disorders were linked exclusively to mutations in the DSP code but a growing number of papers describe mutations which manifest a similar phenotype but are localized in the strongly repetitive sequence of the 3' terminus of the DSPP which codes DPP protein. Our search suggests that the localization of mutation in the sequence of the DSPP gene might result in a different phenotype due to the diverse cellular fate of the mutated protein. Thus comprehensive research on the cellular fate and processing of both normal and mutated DSPP is still required. PMID- 22521703 TI - Swallowing threshold parameters of subjects with shortened dental arches. AB - OBJECTIVES: To quantify swallowing threshold parameters of subjects with a moderate shortened dental arch dentition (SDA: missing molar teeth, but premolar teeth in occluding position and uninterrupted anterior regions) compared to subjects with a complete dental arch dentition (CDA). METHODS: Fourteen females with SDA (3-4 occlusal premolar units) and 14 females with CDA were instructed to chew silicone test 'food' (cubic particles with a total volume of 3 cm(3)). They spit it out the moment they felt the urge to swallow and the pulverized particles were collected. Swallowing threshold parameters were number of chewing cycles, time until 'swallowing', and median particle size of the pulverized particles as determined by sieving the food. Chewing tests were performed twice and outcomes were averaged. RESULTS: The number of chewing cycles until 'swallowing' of subjects with SDA was approximately 1.7 times (p<0.005) that of the controls and this took approximately 1.6 times more time (p<0.01). The median particle size until 'swallowing' did not differ significantly between the groups, but demonstrated large individual differences. Regression analyses indicated that the ratio of median particle size until 'swallowing' of SDA and CDA becomes progressively unfavourable for SDA with increasing numbers of chewing cycles. CONCLUSIONS: Subjects with SDA pulverized test 'food' particles to sizes comparable to subjects with CDA, but chewed longer with more chewing cycles until 'swallowing'. Higher numbers of chewing cycles were associated with increasing difference between SDA and CDA regarding the median particle size until 'swallowing'. CLINICAL SIGNIFICANCE: Compared to subjects with CDA, subjects with moderate SDA pulverize test food particles to comparable size by chewing longer before "swallowing". Therefore, overloading the digestive system by swallowing courser food particles is unlikely in SDA. Consequently, replacement of absent molars just to optimize chewing function is not advised. PMID- 22521704 TI - Effect of fluoride sustained slow-releasing device on fluoride, phosphate and calcium levels in plaque biofilms over time measured using ion chromatography. AB - OBJECTIVES: To determine whether there are any differences in fluoride (F), calcium (Ca) or phosphate (PO(4)) concentrations in natural plaque biofilms between the upper right and left quadrants using a fluoride sustained slow releasing device (FSSRD) placed in the upper right quadrant after 7 and 21 days. To report and validate a new methodology in measuring very low concentrations of F in dental plaque and saliva using ion chromatography. METHODS: Twenty-one participants were divided into two groups with 11 participants in group one and 10 in group two. Each participant had a FSSRD attached to the upper right second permanent molar and two plaque generating devices (PGDs) attached to the upper right and left first permanent molars. The PGDs were recovered after 7 days in group one and 21 days in group two. RESULTS: At both 7 and 21 days (right, left), F (1.081+/-1.517 ppm, 0.736+/-0.840 ppm) and (0.459+/-0.888 ppm, 0.203+/-0.139 ppm), PO(4) (1053+/-533 ppm, 654+/-246 ppm) and (865+/-1099 ppm, 474+/-304 ppm) and Ca (136+/-132 ppm, 74+/-36 ppm) and (130+/-109 ppm, 77+/-24 ppm), were higher in the quadrant containing the FSSRD but not significantly so (p>0.05). Fluoride and PO(4) fell in both quadrants between 7 and 21 days, though not significantly. CONCLUSIONS: Intriguingly while not statistically significant, 21 day plaque contained less fluoride than those investigated after 7 days. While the data was not statistically significant, it seems possible that F, Ca and PO(4) accumulated around the device to a limited extent but were washed away fairly quickly and distributed around the oral cavity. CLINICAL IMPORTANCE: The FSSRD was found to reduce dmfs/DMFS by 76% and raise salivary F levels by ~10 folds. This device is very helpful in reducing dental decay where compliance is impaired such as in patients with special needs. This study further investigates the anti-cariogenic effect of this device. PMID- 22521705 TI - Assessment of laminate technique using glass ionomer and resin composite for restoration of root filled teeth. AB - OBJECTIVE: To evaluate the open laminate technique using glass ionomer cements (GIC) in association with a low shrink composite for restoring root filled premolars. METHODS: Extensive MOD cavities plus endodontic access and root filling were performed in intact extracted maxillary premolars. Three restoration types were evaluated: (1) resin composite alone; (2) resin-modified GIC (RM-GIC) open laminate plus resin composite; (3) conventional GIC open laminate plus resin composite (n=8 for all groups and tests). Three tests were conducted to assess restorations: (A) inward cusp deflection during light curing, using DCDTs; (B) fracture strength using a ramped oblique load at 45 degrees to the long axis in a servohydraulic testing machine in comparison with intact and unrestored teeth; (C) proximal marginal leakage using methylene blue dye and the effect of thermocycling. Data were analysed using 1-way ANOVA for cuspal deflection and fracture strength and Fisher's exact test for leakage. RESULTS: Laminate restorations resulted in significantly less cuspal deflection compared with resin composite (4.2+/-1.2 MUm for RM-GIC and 5.1+/-2.3 MUm for conventional GIC vs. 12.2+/-2.6 MUm for composite, P<0.001). Fracture strength was not significantly different among all groups. Failure with all restorations was predominantly adhesive at the tooth-restoration interface. The two laminate groups showed significantly better marginal seal than composite alone, but sealing ability of conventional GIC deteriorated after thermocycling. CONCLUSIONS: Laminate restoration of root filled teeth had beneficial effects in terms of reducing cuspal deflection and marginal seal, with acceptable fracture strength. PMID- 22521706 TI - Effects of epigallocatechin-3-gallate on pentylenetetrazole-induced kindling, cognitive impairment and oxidative stress in rats. AB - Cognitive dysfunction is commonly observed in epileptic patients. It has been shown that not only epilepsy but also antiepileptic drugs could induce cognitive impairment. Thus, there is an urgent need for drugs that can suppress seizures without causing cognitive deficit. Recent studies have shown that oxidative stress is involved in the pathophysiology of epilepsy, and many antioxidants have an antiepileptic property. Epigallocatechin-3-gallate (EGCG), a catechin polyphenols component, is found to be an effective antioxidant. The purpose of this study was to assess the effect of EGCG against seizures, seizure-induced oxidative stress and cognitive impairment in pentylenetetrazole-induced kindling. Male Sprague-Dawley rats were injected intraperitoneally with a dose of 35 mg/kg of pentylenetetrazole (PTZ) once every alternate day for 13 injections. EGCG was administered daily in two doses (25mg/kg and 50mg/kg) intraperitoneally along with alternate-day PTZ. Morris water maze test was carried out 24h after the last injection of PTZ, and the oxidative stress parameters (malondialdehyde and glutathione) were assessed after the completion of the behavioral test. The results showed that EGCG dose-dependently suppressed the progression of kindling. EGCG also ameliorated the cognitive impairment and oxidative stress induced by PTZ kindling. These observations suggest that EGCG may be a potential agent for the treatment of epilepsy as well as a preventive agent against cognitive impairment induced by seizure. PMID- 22521707 TI - Electrocortical reactivity to emotional images and faces in middle childhood to early adolescence. AB - The late positive potential (LPP) is an event-related potential (ERP) component that indexes sustained attention toward motivationally salient information. The LPP has been observed in children and adults, however little is known about its development from childhood into adolescence. In addition, whereas LPP studies examine responses to images from the International Affective Picture System (IAPS; Lang et al., 2008) or emotional faces, no previous studies have compared responses in youth across stimuli. To examine how emotion interacts with attention across development, the current study used an emotional-interrupt task to measure LPP and behavioral responses in 8- to 13-year-olds using unpleasant, pleasant, and neutral IAPS images, as well as sad, happy, and neutral faces. Compared to older youth, younger children exhibited enhanced LPPs over occipital sites. In addition, sad but not happy faces elicited a larger LPP than neutral faces; behavioral measures did not vary across facial expressions. Both unpleasant and pleasant IAPS images were associated with increased LPPs and behavioral interference compared to neutral images. Results suggest that there may be developmental differences in the scalp distribution of the LPP, and compared to faces, IAPS elicit more robust behavioral and electrocortical measures of attention to emotional stimuli. PMID- 22521708 TI - Recognition memory in tree shrew (Tupaia belangeri) after repeated familiarization sessions. AB - Recognition memories are formed during perceptual experience and allow subsequent recognition of previously encountered objects as well as their distinction from novel objects. As a consequence, novel objects are generally explored longer than familiar objects by many species. This novelty preference has been documented in rodents using the novel object recognition (NOR) test, as well is in primates including humans using preferential looking time paradigms. Here, we examine novelty preference using the NOR task in tree shrew, a small animal species that is considered to be an intermediary between rodents and primates. Our paradigm consisted of three phases: arena familiarization, object familiarization sessions with two identical objects in the arena and finally a test session following a 24 h retention period with a familiar and a novel object in the arena. We employed two different object familiarization durations: one and three sessions on consecutive days. After three object familiarization sessions, tree shrews exhibited robust preference for novel objects on the test day. This was accompanied by significant reduction in familiar object exploration time, occurring largely between the first and second day of object familiarization. By contrast, tree shrews did not show a significant preference for the novel object after a one-session object familiarization. Nonetheless, they spent significantly less time exploring the familiar object on the test day compared to the object familiarization day, indicating that they did maintain a memory trace for the familiar object. Our study revealed different time courses for familiar object habituation and emergence of novelty preference, suggesting that novelty preference is dependent on well-consolidated memory of the competing familiar object. Taken together, our results demonstrate robust novelty preference of tree shrews, in general similarity to previous findings in rodents and primates. PMID- 22521709 TI - Competition with a host nestling for parental provisioning imposes recoverable costs on parasitic cuckoo chick's growth. AB - Chicks of the brood parasitic common cuckoo (Cuculus canorus) typically monopolize host parental care by evicting all eggs and nestmates from the nest. To assess the benefits of parasitic eviction behaviour throughout the full nestling period, we generated mixed broods of one cuckoo and one great reed warbler (Acrocephalus arundinaceus) to study how hosts divide care between own and parasitic young. We also recorded parental provisioning behaviour at nests of singleton host nestlings or singleton cuckoo chicks. Host parents fed the three types of broods with similar-sized food items. The mass of the cuckoo chicks was significantly reduced in mixed broods relative to singleton cuckoos. Yet, after the host chick fledged from mixed broods, at about 10-12 days, cuckoo chicks in mixed broods grew faster and appeared to have compensated for the growth costs of prior cohabitation by fledging at similar weights and ages compared to singleton cuckoo chicks. These results are contrary to suggestions that chick competition in mixed broods of cuckoos and hosts causes an irrecoverable cost for the developing brood parasite. Flexibility in cuckoos' growth dynamics may provide a general benefit to ecological uncertainty regarding the realized successes, failures, and costs of nestmate eviction strategies of brood parasites. PMID- 22521710 TI - Prediction of drug-packaging interactions via molecular dynamics (MD) simulations. AB - The interaction between packaging materials and drug products is an important issue for the pharmaceutical industry, since during manufacturing, processing and storage a drug product is continuously exposed to various packaging materials. The experimental investigation of a great variety of different packaging material drug product combinations in terms of efficacy and safety can be a costly and time-consuming task. In our work we used molecular dynamics (MD) simulations in order to evaluate the applicability of such methods to pre-screening of the packaging material-solute compatibility. The solvation free energy and the free energy of adsorption of diverse solute/solvent/solid systems were estimated. The results of our simulations agree with experimental values previously published in the literature, which indicates that the methods in question can be used to semi quantitatively reproduce the solid-liquid interactions of the investigated systems. PMID- 22521711 TI - Chitosan-g-PEG nanoparticles ionically crosslinked with poly(glutamic acid) and tripolyphosphate as protein delivery systems. AB - In the present study chitosan grafted copolymers with poly(ethylene glycol) (CS-g PEG) were prepared and studied using PEG with molecular weights 2000 and 5000g/mol. The materials were characterized using (1)H NMR, FTIR and WAXD techniques. These polyelectrolytes were ionically crosslinked with tripolyphosphate (TPP) and poly(glutamic acid) (PGA) at different polymer/crosslinking agent ratios (1:1, 2:1, 3:1 and 4:1, w/w) for the nanoencapsulation of bovine serum albumin (BSA). Prepared nanoparticles are spherical in shape with a mean diameter ranging from 150 to 600 nm. The size depends mainly to the molecular weight of the PEG and the crosslinking agent used. The PEG molecular weight also seems to affect the release rate of BSA especially the first burst effect which appears to be high in copolymers containing PEG5000, compared with copolymer prepared with PEG2000, and it is also higher when PGA was used as crosslinking agent, instead of TPP. PMID- 22521712 TI - Expression without boundaries: cell-free protein synthesis in pharmaceutical research. AB - Proteins are an increasingly important class of new drugs. Pharmaceutical proteins are usually expressed in cell based systems in the development phase and in production, and although cell free methods have recently emerged they have not been used widely for therapeutic protein development or production. Cell free expression methodology is well suited for pharmaceutical protein expression and engineering and will probably become more commonly used in the future. Cell free expression allows protein engineering in high throughput format, flexible strategies for glycosylation and chemical conjugation, and allows easy use of unnatural amino acids as building blocks of proteins. Thus, cell free expression can be used to modify protein solubility, stability, and pharmacokinetics of therapeutic proteins. Likewise, it is potentially useful in protein development for biomaterial matrices, nanoparticles, and vaccines. This review illustrates the potential of cell free expression in pharmaceutical protein research and development while highlighting both advantages and limitations of the method. PMID- 22521713 TI - Dysequilibrium of neuronal proliferation and apoptosis in a pharmacological animal model of psychosis. AB - Growing evidence implicates that abnormal stem cell proliferation and neurodegenerative mechanisms may be involved in the pathogenesis of neuropsychiatric disorders including schizophrenia. Here, we studied the underlying pathomechanisms of psychosis. We are employing a translational approach combining in vivo data with supplementary data from an adult neuronal stem cell-derived cell culture model by generating a large number of analytes in our specimens following a multiplexing strategy. In the animal model the NMDA receptor was chronically antagonized by MK-801 at ultralow doses. As a result of this, we were able to demonstrate a roughly twofold increased density of PCNA positive cells in the germinal zone of the dentate gyrus indicating enhanced neuroproliferative activity. In vitro stem cell experiments additionally pointed to this direction showing an increase both in proliferation and neuronal differentiation after MK-801 treatment. These alterations were partially prevented by coapplication of the dopamine receptor antagonist haloperidol. In addition, apoptotic activity assessed by immunohistochemical demonstration of cleaved caspase-3 stainings was unaffected by MK-801 treatment. These observations were largely supported by microarray gene expression analysis, which permits high-throughput multiplexed assessment of expression data from a comprehensive set of genes and showed parallels with data from human post mortem studies. In conclusion, our data support the notion, that abnormal proliferation due to anti-apoptotic mechanisms may represent a factor in the pathogenesis of psychosis. Thus, research on the exact interplay between glutamatergic neurotransmission and neuronal proliferation deserves more attention. This dual in vivo and in vitro strategy described here may prove as a suitable model for addressing complex neuropsychiatric diseases especially when taking advantage of the potential of multiplex technologies not only in diagnostics but also in basic research. PMID- 22521714 TI - New phenotype and pathology features in MYH7-related distal myopathy. AB - Laing distal myopathy is an autosomal dominant disease due to mutations in the gene encoding for the human slow-beta myosin heavy chain, MYH7. Most reports describe it as a mild, early onset myopathy with involvement usually restricted to foot extensors, hand finger extensors and neck flexors, and unspecific findings on muscle biopsy. We identified the first two Italian families with Laing distal myopathy, harboring two novel mutations in the MYH7 gene and performed clinical, neurophysiological, pathological, muscle MRI and cardiological investigations on affected members from the two families. Subjects from one family presented a moderate-severe phenotype, with proximal together with distal involvement and even loss of ambulation at advanced age. One patient displayed atypical muscle biopsy findings including cytoplasmic bodies and myofibrillar myopathy-like features. Affected members from the second family shared a very mild phenotype, with weakness largely limited to long toe and foot extensors and/or late onset. No patient showed any sign of heart involvement. Our study significantly broadens the clinical and pathological spectrum of Laing distal myopathy. We suggest that MYH7 screening should be considered in undiagnosed late-onset distal myopathy or cytoplasmic body myopathy patients. PMID- 22521716 TI - Precision genetic engineering in large mammals. AB - Precision genetic engineering based on stable chromosomal insertion of exogenous DNA in the genomes of large mammals is immensely important for the development of improved biomedical models, pharmaceutical research and an accelerated breeding progress. Precision genetic engineering requires (i) a known locus of genomic integration, (ii) a defined status of foreign DNA, (iii) that transgene expression is unaffected by neighbouring chromosomal sequences, (iv) endogenous genes are not mutated and (v) no unwanted DNA sequences are present. Recently, advanced molecular techniques exploiting exogenous enzymes have opened the possibilities for more sophisticated genetic engineering. Here, we critically review current developments of enzyme-catalysed approaches for targeted transgenesis in large mammals. PMID- 22521715 TI - Interactions of organophosphates with keratins in the cornified epithelium of human skin. AB - Methods to unequivocally assess and quantify exposure to organophosphate anti cholinesterase agents are highly valuable, either from a biomonitoring or a forensic perspective. Since for both OP pesticides and various nerve agents the skin is a predominant route of entry, we hypothesized that proteins in the skin might represent an ideal source of unequivocal and persistent biomarkers for exposure to these compounds. In this exploratory study we show that keratin proteins in human skin are relevant binding sites for organophosphates. The thick cornified epithelium of human plantar skin (callus) was exposed to a selection of relevant organophosphorus compounds and keratin proteins were subsequently extracted. After carboxymethylation of cysteine residues, enzymatic digestion of the keratins with pronase and trypsin was performed and the resulting amino acid and peptides were analyzed to assess whether covalent adducts had formed. LC tandem MS analysis of the pronase digests demonstrated that tyrosine and to a lesser extent serine residues were selectively modified by organophosphate pesticides (both phosphorothioates and the corresponding oxon forms) under physiological conditions. In addition, modification of tyrosine with the nerve agent VX was unequivocally assessed. In order to elucidate specific binding sites, LC-tandem MS analysis of trypsin digests showed two separate tryptic keratin fragments, i.e. LASY*LDK and SLY*GLGGSK, with Y* the modified tyrosine residues, originating from keratin 1/6 and keratin 10, respectively. These preliminary findings, revealing novel binding targets for anti-cholinesterase organophosphates, will form a firm basis for the development of novel (non invasive) methods for assessment of exposure to organophosphates. Whether this binding will also have biological implications remains an issue for further investigations. PMID- 22521717 TI - Purification of a recombinant baculovirus of Autographa californica M nucleopolyhedrovirus by ion exchange membrane chromatography. AB - Significant progress in the application of viral vectors for gene delivery into mammalian cells and the use of viruses as biopesticides requires downstream processing that can satisfy application-specific demands on performance. In the present work the stability and ion exchange membrane chromatography of a recombinant of Autographa californica M nucleopolyhedrovirus is studied. To adjust the degree of purification the effect of ionic conductivity or pH on the viral infectivity was assessed (0.77-78.00mS/cm, pH 3-8). Infectivity decreased rapidly by several orders of magnitude at below 5mS/cm (i.e., 0.49MPa osmotic pressure change) or at below pH 5.5 (rationalized with particle aggregation). The virus was concentrated and purified via adsorption (0.2-1.1*10(16)pfu/m(3) chromatographic bed volume, 0.6-1.1*10(12)pfu/m(2) membrane area facing the incident fluid flow) and elution at pH 6.1 and 6.35mS/cm from three strong anion exchange membranes. Virus recovery and concentration in accord with the volume reduction were obtained using a polyether sulfone-based membrane with quaternary ammonium ligands. The level of host cell protein (down to below the detection limit) and suspended DNA (below 93pg DNA per 10(6)pfu) are reported for each membrane employed, for the purpose of comparability, under equal adsorption or elution conditions respectively. PMID- 22521718 TI - Usability of a novel clinician interface for genetic results. AB - The complexity and rapid growth of genetic data demand investment in information technology to support effective use of this information. Creating infrastructure to communicate genetic information to healthcare providers and enable them to manage that data can positively affect a patient's care in many ways. However, genetic data are complex and present many challenges. We report on the usability of a novel application designed to assist providers in receiving and managing a patient's genetic profile, including ongoing updated interpretations of the genetic variants in those patients. Because these interpretations are constantly evolving, managing them represents a challenge. We conducted usability tests with potential users of this application and reported findings to the application development team, many of which were addressed in subsequent versions. Clinicians were excited about the value this tool provides in pushing out variant updates to providers and overall gave the application high usability ratings, but had some difficulty interpreting elements of the interface. Many issues identified required relatively little development effort to fix suggesting that consistently incorporating this type of analysis in the development process can be highly beneficial. For genetic decision support applications, our findings suggest the importance of designing a system that can deliver the most current knowledge and highlight the significance of new genetic information for clinical care. Our results demonstrate that using a development and design process that is user focused helped optimize the value of this application for personalized medicine. PMID- 22521720 TI - Bilateral fornix injury due to cerebral infarct and traumatic intraventricular hemorrhage: a case study. PMID- 22521719 TI - Health literacy screening instruments for eHealth applications: a systematic review. AB - OBJECTIVE: To systematically review current health literacy (HL) instruments for use in consumer-facing and mobile health information technology screening and evaluation tools. DESIGN: The databases, PubMed, OVID, Google Scholar, Cochrane Library and Science Citation Index, were searched for health literacy assessment instruments using the terms "health", "literacy", "computer-based," and "psychometrics". All instruments identified by this method were critically appraised according to their reported psychometric properties and clinical feasibility. RESULTS: Eleven different health literacy instruments were found. Screening questions, such as asking a patient about his/her need for assistance in navigating health information, were evaluated in seven different studies and are promising for use as a valid, reliable, and feasible computer-based approach to identify patients that struggle with low health literacy. However, there was a lack of consistency in the types of screening questions proposed. There is also a lack of information regarding the psychometric properties of computer-based health literacy instruments. LIMITATIONS: Only English language health literacy assessment instruments were reviewed and analyzed. CONCLUSIONS: Current health literacy screening tools demonstrate varying benefits depending on the context of their use. In many cases, it seems that a single screening question may be a reliable, valid, and feasible means for establishing health literacy. A combination of screening questions that assess health literacy and technological literacy may enable tailoring eHealth applications to user needs. Further research should determine the best screening question(s) and the best synthesis of various instruments' content and methodologies for computer-based health literacy screening and assessment. PMID- 22521721 TI - Thrombin receptor regulates hematopoiesis and endothelial-to-hematopoietic transition. AB - Hematopoietic development and vascular development are closely related physiological processes during vertebrate embryogenesis. Recently, endothelial-to hematopoietic transition (EHT) was demonstrated to be critical for hematopoietic stem and progenitor cell induction, but its underlying regulatory mechanisms remain poorly understood. Here we show that thrombin receptor (F2r), a protease activated G protein-coupled receptor required for vascular development, functions as a negative regulator during hematopoietic development. F2r is significantly upregulated during hematopoietic differentiation of mouse embryonic stem cells (mESCs) and zebrafish hematopoietic development. Pharmacological or genetic inhibition of F2r promotes hematopoietic differentiation, whereas F2r overexpression shows opposite effects. Further mechanistic studies reveal that F2r-RhoA/ROCK pathway inhibits EHT in vitro and negatively regulates zebrafish EHT and hematopoietic stem cell induction in vivo. Taken together, this study demonstrates a fundamental role of F2r-RhoA/ROCK pathway in vertebrate hematopoiesis and EHT, as well as an important molecular mechanism coordinating hematopoietic and vascular development. PMID- 22521722 TI - Structural basis of the intracellular sorting of the SNARE VAMP7 by the AP3 adaptor complex. AB - VAMP7 is involved in the fusion of late endocytic compartments with other membranes. One possible mechanism of VAMP7 delivery to these late compartments is via the AP3 trafficking adaptor. We show that the linker of the delta-adaptin subunit of AP3 binds the VAMP7 longin domain and determines the structure of their complex. Mutation of residues on both partners abolishes the interaction in vitro and in vivo. The binding of VAMP7 to delta-adaptin requires the VAMP7 SNARE motif to be engaged in SNARE complex formation and hence AP3 must transport VAMP7 when VAMP7 is part of a cis-SNARE complex. The absence of delta-adaptin causes destabilization of the AP3 complex in mouse mocha fibroblasts and mislocalization of VAMP7. The mislocalization can be rescued by transfection with wild-type delta adaptin but not by delta-adaptin containing mutations that abolish VAMP7 binding, despite in all cases intact AP3 being present and LAMP1 trafficking being rescued. PMID- 22521723 TI - Radio-modulatory effects of green tea catechin EGCG on pBR322 plasmid DNA and murine splenocytes against gamma-radiation induced damage. AB - Green tea is rich in polyphenols, like catechins, which are thought to contribute to the health benefits of tea. The aim of this study was to evaluate the radioprotective effect of EGCG (epigallocatechin-3-gallate), a green tea catechin on gamma-radiation induced cell damage. Under acellular condition of radiation exposure, pBR322 plasmid DNA was protected by EGCG in a concentration dependent manner. Treatment of murine splenocytes with EGCG 2h prior to radiation (3Gy), protected the cellular DNA against radiation-induced strand breaks. EGCG also inhibited gamma-radiation induced cell death in splenocytes. EGCG pretreatment to the cells decreased the radiation induced lipid peroxidation and membrane damage. The levels of phase II enzymes, glutathione and lactate dehydrogenase were restored with EGCG treatment prior to radiation. Our results show that pretreatment with EGCG offers protection to pBR322 DNA under acellular condition and normal splenocytes under cellular condition, against gamma-radiation induced damage and is better radioprotector in comparison to quercetin and vitamin C. PMID- 22521724 TI - Utility of the World Health Organization Disability Assessment Schedule II in schizophrenia. AB - AIM: The World Health Organization Disability Assessment Schedule II (WHODAS II) was developed for assessing disability. This study provides data on the validity and utility of the Spanish version of the WHODAS II in a large sample of patients with schizophrenia. METHODS: The sample included 352 patients with a schizophrenia spectrum disorder. They completed a comprehensive assessment battery including measures of psychopathology, functionality and quality-of-life. A sub-sample of 36 patients was retested after six months to assess its temporal stability. RESULTS: Participation in society (6.3%) and Life activities (4.0%) were the domains with the highest percentage of missing data. The internal consistency (Cronbach's alpha) of the total scale was 0.94, and the test-retest stability reached an intraclass correlation coefficient of 0.92. It became apparent that the six primary factor models represent a better fit with reality than other competing models. Relationships between the WHODAS and measures of symptomatology, social and work-related functionality, and quality-of-life were in the expected direction and the scale was ultimately found to be able to differentiate among patients with different degrees of disease severity and different work status. CONCLUSIONS: Assessment of disability using appropriate tools is a crucial aspect in the context of mental health and, in this regard, the Spanish version of the WHODAS II shows ample evidence of validity in patients with schizophrenia. The most important contribution of this study is that it is the first analyzing the Spanish version of the WHODAS II (36-item version) in a large sample of patients with schizophrenia. PMID- 22521725 TI - Near-infrared spectroscopy in post-cardiac arrest patients undergoing therapeutic hypothermia. AB - AIMS: To investigate the relationship between tissue oxygen saturation during a vascular occlusion test with systemic hemodynamics, central and peripheral skin temperature in patients resuscitated from cardiac arrest. METHODS: This prospective, observational study included a convenience sample of 30 patients hospitalized in a multidisciplinary intensive care unit in a university hospital and treated with therapeutic hypothermia. Near infrared spectroscopy (NIRS) was used to measure thenar tissue oxygen saturation, desaturation rate and saturation recovery rate after the vascular occlusion test, conducted within 24h of hospital admission and within 12h of initiating re-warming. Measurements included heart rate (HR), mean arterial blood pressure (MAP), oxygen saturation, use of vasopressors and sedatives, core body (esophageal) and peripheral skin temperature and sequential organ failure assessment (SOFA) score. RESULTS: Peripheral skin temperature was found to have a significant effect on StO(2) deoxygenation and recovery slopes, resulting in lower rates at colder temperatures. This effect was independent of MAP, HR, and core temperature. NIRS derived variables were not associated with SOFA score or use of vasopressors and did not predict mortality. DISCUSSION: Colder peripheral skin temperatures resulting in lower StO(2) desaturation rates may be explained by slower aerobic metabolism, thus lower extraction rate of oxygen, in the tissue beds. Lower recovery slopes at colder local temperatures may result from peripheral vasoconstriction during reactive hyperemia. CONCLUSION: We found that peripheral skin temperature in post-arrest critically ill patients undergoing TH strongly influences tissue oxygen desaturation and reoxygenation rates. In additional, changes in NIRS derived variables were independent of measures of shock, vasopressor use or illness severity. PMID- 22521726 TI - Gadd45a transcriptional induction elicited by the Aurora kinase inhibitor MK-0457 in Bcr-Abl-expressing cells is driven by Oct-1 transcription factor. AB - The advantage of Aurora kinase (AK) inhibitors in chronic myeloid leukemia (CML) therapy mostly arises from "off-target" effects on tyrosine kinase (TK) activity of wild type (wt) or mutated Bcr-Abl proteins which drive the disease resistance to imatinib (IM). We proved that the AK inhibitor MK-0457 induces the growth arrest DNA damage-inducible (Gadd) 45a through recruitment of octamer-binding (Oct)-1 transcription factor at a critical promoter region for gene transcription and covalent modifications of histone H3 (lysine 14 acetylation, lysine 9 de methylation). Such epigenetic chromatin modifications may depict a general mechanism promoting the re-activation of tumor suppressor genes silenced by Bcr Abl. PMID- 22521727 TI - Evaluation of peripheral blood lymphocyte subsets in family-owned dogs naturally infected by Ehrlichia canis. AB - Previous research suggested that clinical manifestations, histopathological lesions, and even infection maintenance in the course of canine monocytic ehrlichiosis (CME) are directly related to the immune response developed by the host. In the present study, blood lymphocyte subsets were analyzed by multiparametric flow cytometry in 37 dogs with naturally occurring CME and 47 healthy dogs used as controls. T, T helper (Th), T cytotoxic (Tc), B, non-T, non B lymphocytes and those that express MHC class II were characterized in every dog. Animals with CME showed higher relative values of T and Tc cells and a higher absolute number of Tc cells in peripheral blood. The percentage of Th cells and the absolute and relative values of B cells were higher in healthy animals than in CME-affected dogs. The significance of these changes on the pathogenesis of natural Ehrlichia canis infection in dogs needs further evaluation. PMID- 22521728 TI - Awareness and level of knowledge of interventional radiology among medical students at a Canadian institution. AB - PURPOSE: To assess the awareness and level of exposure of interventional radiology (IR) among medical students at a Canadian medical school. To understand how IR can be better described and introduced to medical students. MATERIALS AND METHODS: Electronic anonymous surveys were sent to 542 medical students in their first, second, and third years at a Canadian 3-year medical school. A total of 103 students (19%) responded. Each survey contained 17 questions assessing knowledge, interest, and perception of IR. RESULTS: Fifty-three percent (55/103) of respondents reported "poor" knowledge of IR and only 18% (19/103) said they would consider a career in IR. Respondents cited lack of knowledge (48%, 37/77) or lack of interest (43%, 33/77) as the main reasons why they would not consider IR as a career. Although 92% (95/103) of respondents could name at least one IR procedure, many (54%, 56/103) were unclear as to the duties of an interventional radiologist within the hospital. Seventy-four percent (76/103) of students stated that a mandatory 2-week rotation in radiology during clerkship would be beneficial, whereas 71% (73/103) stated that they would be interested in a 2-week IR selective during their mandatory core surgery rotation. CONCLUSIONS: The knowledge and exposure to IR in medical school is limited. Students were eager to learn more about IR and expressed a desire for more exposure. Early exposure of medical students to IR should be introduced to attract future interventional radiologists as well as increase awareness among future referring physicians. PMID- 22521729 TI - Computed tomography scans in the evaluation of fatty liver disease in a population based study: the multi-ethnic study of atherosclerosis. AB - RATIONALE AND OBJECTIVES: Fatty liver disease is a common clinical entity in hepatology practice. This study evaluates the prevalence and reproducibility of computed tomography (CT) measures for diagnosis of fatty liver and compares commonly used CT criteria for the diagnosis of liver fat. MATERIALS AND METHODS: The study includes 6814 asymptomatic participants from a population-based sample. The ratio of liver-to-spleen (L/S) Hounsfield units (HU) <1.0 and liver attenuation <40 HU were used for diagnosing and assessing the severity of liver fat content. Participants with heavy alcohol intake (>7 drinks/week for women and >14 drinks/week for men) were excluded. Final analysis was performed on participants where images of both liver and spleen were available on the scans. RESULTS: The overall prevalence of fatty liver (4175 subjects included in final analysis) was 17.2% (using L/S ratio <1.0), with 6.3% (with <40 HU cutoff) of the population having moderate to severe steatosis (>30% liver fat content). The prevalence was high in participants with dyslipidemia (70.4%), hypertension (56.8%), and obesity (53%). Diabetic patients had 24.1% prevalence of fatty liver. The prevalence provided by L/S ratio <1.0 (17.2%) was comparable to prevalence provided by <51 HU (17.3%), whereas prevalence obtained by <40 HU (6.3%) cutoff corresponded to L/S ratio of <0.8 (6.5%). The measurements of liver and spleen HU attenuations were highly reproducible (0.96, 0.99 and 0.99, 0.99 for intra- and inter-reader variability, respectively) in a sample of 100 scans. CONCLUSION: Fatty liver can be reliably diagnosed using nonenhanced CT scans. PMID- 22521730 TI - Primary malignant fibrous histiocytoma of the breast: a case report and review of 38 chinese cases. PMID- 22521731 TI - Synergistic antidiabetic activity of Vernonia amygdalina and Azadirachta indica: biochemical effects and possible mechanism. AB - ETHNOPHARMACOLOGICAL RELEVANCE: A decoction from a combination of herbs is commonly used in Traditional African Medicine for the management of chronic ailments. In Nigeria, the leaves of Vernonia amygdalina Del. (VA) and Azadirachta indica A. Juss (AI) are used traditionally as a remedy against diabetes mellitus for which empirical evidence attests to its efficacy. AIM OF THE STUDY: To evaluate the synergistic antidiabetic action of VA and AI, the biochemical effects and possible mechanism in streptozotocin-induced diabetic rat (SDR) models. MATERIALS AND METHODS: Ethanolic extracts of VA and AI were co administered (200 mg/kg, 50:50) to non-diabetic rats (NDRs) and SDRs for 28 days. Blood glucose and body weight were monitored during this period, and at end of treatment, serum glucose, insulin, triiodothyronine (T3), tetraiodothyronine (T4) and alpha-amylase activity were studied. Glucose and activities of antioxidant enzymes, e.g., catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD), were estimated in hepatocytes, along with the impact on the histology of the liver and pancreas. Medium acting insulin, HU (5 IU/kg, s.c.) was used as a positive control. RESULTS: The study reveals that compared with single extracts, the combined extract (VA/AI) promptly lowered blood glucose and maintained a relatively steady level over the study period, in tandem with HU. During this period, body weight gain successively increased. In SDRs, fasting blood glucose at days 0 and 28 was raised by 4.33 and 3.16 fold, respectively, and the serum glucose was raised by 7.70 fold vs. normal control (P<0.05). The discrepancies in the individual effects of VA and AI on hepatic glucose and alpha amylase activity were also restored. In NDRs, VA/AI lowered blood and serum glucose (1.14 and 1.94 fold, respectively), although to a lesser extent when compared with HU. Furthermore, VA/AI was found to lower serum insulin, T3 and T4 by 1.66, 1.57 and 2.16 fold, respectively, in SDR (P<0.05). This was similar to HU, which demonstrated 1.79 and 1.68 fold reduction of insulin and T3, respectively (P<0.05), but had no effect on T4. Conversely, in NDRs, VA/AI caused 1.32, 4.93 and 1.04 fold increase in insulin, T3 and T4, respectively, reciprocal to its effect on blood and serum glucose. Oxidative stress in SDR, characterised by decreased GPx and CAT activities, was ameliorated, as the activities of the enzymes and SOD increased following a 28-day treatment with VA/AI (P<0.05). The features of diabetic pathology, indicated in the histology of the liver and pancreas, were reversed. However, the extent of recovery was partial with VA, better with AI, and distinct and total with VA/AI, compared with a null effect by HU. CONCLUSION: Taken together, our results contribute towards validation of enhanced antidiabetic efficacy of VA and AI when combined. This synergy may be exerted by oxidative stress attenuation, insulin mimetic action and beta-cell regeneration. PMID- 22521732 TI - Topical application of Acalypha indica accelerates rat cutaneous wound healing by up-regulating the expression of Type I and III collagen. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Acalypha indica Linn. (Acalypha indica) vernacularly called Kuppaimeni in Tamil, has been used as a folklore medicine since ages for the treatment of wounds by tribal people of Tamil Nadu, Southern India. The present study investigates the biochemical and molecular rationale behind the healing potential of Acalypha indica on dermal wounds in rats. MATERIAL AND METHODS: Acalypha indica extract (40 mg/kg body weight) was applied topically once a day on full-thickness excision wounds created on rats. The wound tissue was removed and used for estimation of various biochemical and biophysical analyses and to observe histopathological changes with and with-out extract treatment. The serum levels of pro-inflammatory cytokine tumor necrosis factor (TNF-alpha) was measured at 12 h, 24 h, 48 h and 72 h post-wounding using ELISA. Reverse transcription-polymerase chain reaction (RT-PCR) analysis was performed to study the expression pattern of transforming growth factor [TGF-beta1], collagen 1 alpha (I) [Col 1 alpha (I)] and collagen 3 alpha (I) [Col 3 alpha (I)]. Likewise, linear incision wounds were created and treated with the extract and used for tensile strength measurements. RESULTS: Wound healing in control rats was characterized by less inflammatory cell infiltration, lack of granulation tissue formation, deficit of collagen and significant decrease in biomechanical strength of wounds. Acalypha indica treatment mitigated the oxidative stress and decreased lipid peroxidation with concomitant increase in ascorbic acid levels. It also improved cellular proliferation, increased TNF alpha levels during early stages of wound healing, up-regulated TGF-beta1 and elevated collagen synthesis by markedly increasing the expression of Col 1 alpha (I) and Col 3 alpha (I). Increased rates of wound contraction, epithelialization, enhanced shrinkage temperature and high tensile strength were observed in the extract treated rats. CONCLUSION: Acalypha indica extract was shown to augment the process of dermal wound healing by its ability to increase collagen synthesis through up-regulation of key players in different phases of wound healing and by its antioxidative potential. PMID- 22521733 TI - Efficacy of Daphne oleoides subsp. kurdica used for wound healing: identification of active compounds through bioassay guided isolation technique. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In Turkish traditional medicine, the aerial parts of Daphne oleoides Schreber subsp. kurdica (DOK) have been used to treat malaria, rheumatism and for wound healing. The aim was to evaluate the ethnopharmacological usage of the plant using in vivo and in vitro pharmacological experimental models, and to perform bioassay-guided fractionation of the 85% methanolic extract of DOK for the isolation and identification of active wound-healing component(s) and to elucidate possible mechanism of the wound-healing activity. MATERIALS AND METHODS: In vivo wound-healing activity was evaluated by the linear incision and the circular excision wound models. Anti inflammatory and antioxidant activities, which are known to support the wound healing process, were also assessed by the Whittle method and the DPPH (2,2 diphenyl-1-picrylhydrazyl) radical-scavenging assays, respectively. The total phenolic content of the extract and subextracts was estimated to establish any correlation between the phenolic content and the antioxidant activity. The methanolic extract of DOK was subjected to various chromatographic separation techniques leading to the isolation and identification of the active component(s). Furthermore, in vitro hyaluronidase, collagenase and elastase enzymes inhibitory activity assays were conducted on the active components to explore the activity pathways of the remedy. RESULTS: After confirmation of the wound-healing activity, the methanolic extract was subjected to successive solvent partitioning using solvents of increasing polarity creating five subextracts. Each subextract was tested on the same biological activity model and the ethyl acetate (EtOAc) subextract had the highest activity. The EtOAc subextract was subjected to further chromatographic separation for the isolation of components 1, 2 and 3. The structures of these compounds were elucidated as daphnetin (1), demethyldaphnoretin 7-O-glucoside (2) and luteolin-7-O-glucoside (3). Further in vivo testing revealed that luteolin-7-O-glucoside was responsible for the wound-healing activity of the aerial parts. It was also found to exert significant anti-inflammatory, antioxidant, anti-hyaluronidase and anti collagenase activities. CONCLUSION: The present study explored the wound-healing potential of Daphne oleoides subsp. kurdica. Through bioassay-guided fractionation and isolation techniques, luteolin-7-O-glucoside was determined as the main active component of the aerial parts. This compound exerts its activity through inhibition of hyaluronidase and collagenase enzymes activity as well as interfering with the inflammatory stage. PMID- 22521735 TI - Optimization of treatment planning parameters used in tomotherapy for prostate cancer patients. AB - BACKGROUND AND PURPOSE: Tomotherapy treatment planning depends on parameters that are not used conventionally such as: field width (FW), pitch factor (PF) and modulation factor (MF). The aim of this study is to analyze the relationship between these parameters and their influence on the quality of treatment plans and beam-on time. MATERIAL AND METHODS: Ten prostate cancer patients were included in the study. For each patient, two cases of irradiation were considered depending on the target volume: PTV1 included the prostate gland, seminal vesicles, pelvic lymph nodes and a 1 cm margin, whereas PTV2 included only the prostate gland with a 1 cm margin. For each patient and each case of irradiation (PTV1 and PTV2) 8 treatment plans were created - all consisted of a different combination of planning parameters (FW = 1.05, 2.5, 5 cm; PF = 0.107, 0.215, 0.43; MF = 1.5, 2.5, 3.5). Default values used in this study were FW = 2.5 cm, PF = 0.215 and MF = 2.5. Hence, for plans with different FWs, parameters of PF and MF were 0.215 and 2.5, respectively; for different PFs, FW and MF were 2.5 and 2.5, respectively; finally for different MFs, FW and PF were 2.5 and 0.215, respectively. The reference plan was optimized for FW = 1.05 cm, PF = 0.107 and MF = 3.5, which was assumed to result in the best dose distribution and the longest treatment time. As a result, 160 plans were created. Each plan was analyzed for dose distribution and execution time. RESULTS AND CONCLUSION: : Treatment plans with FW of 5 cm resulted in the shortest execution time compromising the dose distribution. Moreover, the dose fall off in the longitudinal direction was not sharp. FW of 1.05 cm and PF of 0.107 were not recommended for routine prostate plans due to long execution time, which was 3 times longer than for plans with FW = 5 cm. There was no substantial decrease of irradiation time when PF was increased from 0.215 to 0.43 for both cases (PTV1 and PTV2); however, the dose distribution was slightly compromised. Finally, decreasing MF from 2.5 to 1.5 was useless because it did not change the beam-on time; however, it did remarkably decrease the dose distribution. Nevertheless, increasing MF up to 3.5 could be considered. The lowest EUD for the rectum and intestines, could be observed for PF = 0.107. For the other plans the differences were rather small (the EUD was almost the same). By reducing PF from 0.43 to 0.107 or FW from 5 to 1.05 the EUD for bladder (in PTV1 case) decreased by 3.13% and 2.60%. When PTV2 was a target volume, the EUD for bladder decreased by 4.54% and 3.43% when FW was changed from 5 to 1.05 and MF from 1.5 to 3.5, respectively. For optimal balance between beam-on time and dose distribution in OARs for routine patients, the authors would suggest to use: FW = 2.5, PF = 0.215 and MF = 2.5. PMID- 22521734 TI - Effect of JBP485 on obstructive jaundice is related to regulation of renal Oat1, Oat3 and Mrp2 expression in ANIT-treated rats. AB - The objective was to determine whether protective effects of JBP485 on biliary obstruction induced by alpha-naphthylisothiocyanate (ANIT) are mediated by the organic anion transporters Oat1, Oat3 and the multidrug resistance-associated protein Mrp2. The ANIT-induced increases in bilirubin (BIL), alanine aminotransferase (ALT) and aspartate transaminase (AST) in rat serum were inhibited significantly by oral administration of JBP485. The plasma concentration of JBP485 which is the substrate of Oat1 and Oat3 determined by LC MS/MS was markedly increased after intravenous administration in ANIT-treated rats, whereas cumulative urinary excretion of JBP485 in vivo and the uptake of JBP485 in kidney slices were decreased remarkably. RT-PCR and Western blot showed the decreased expression of Oat1 and Oat3, increased expression of Mrp2 in ANIT induced rats, meanwhile, the expression levels of Mrp2 and Oat1 were up-regulated after administration of JBP485. The up-regulation of Mrp2 and Oat1 was associated with a concomitant increase in urinary BIL after treatment with JBP485 in ANIT treated rats. The mechanism for JBP485 to restore liver function might be related to improvement of the expression and function for Oat1 and Mrp2 as well as facilitation of urinary excretion for hepatoxic substance. PMID- 22521736 TI - Supporting role of lysine 13 and glutamate 16 in the acid-base mechanism of saccharopine dehydrogenase from Saccharomyces cerevisiae. AB - Saccharopine dehydrogenase (SDH) catalyzes the NAD+ dependent oxidative deamination of saccharopine to form lysine (Lys) and alpha-ketoglutarate (alpha kg). The active site of SDH has a number of conserved residues that are believed important to the overall reaction. Lysine 13, positioned near the active site base (K77), forms a hydrogen bond to E78 neutralizing it, and contributing to setting the pKa of the catalytic residues to near neutral pH. Glutamate 16 is within hydrogen bond distance to the Nepsilon atom of R18, which has strong H bonding interactions with the alpha-carboxylate and alpha-oxo groups of alpha-kg. Mutation of K13 to M and E16 to Q decreased kcat by about 15-fold, and primary and solvent deuterium kinetic isotope effects measured with the mutant enzymes indicate hydride transfer is rate limiting for the overall reaction. The pH-rate profiles for K13M exhibited no pH dependence, consistent with an increase in negative charge in the active site resulting in the perturbation in the pKas of catalytic groups. Elimination of E16 affects optimal positioning of R18, which is involved in binding and holding alpha-kg in the correct conformation for optimum catalysis. In agreement, a DeltaDeltaG degrees ' of 2.60 kcal/mol is estimated from the change in Kalpha-kg for replacing E16 with Q. PMID- 22521737 TI - Genistein regulates the IL-1 beta induced activation of MAPKs in human periodontal ligament cells through G protein-coupled receptor 30. AB - Periodontal ligament (PDL) cells are fibroblasts that play key roles in tissue integrity, periodontal inflammation and tissue regeneration in the periodontium. The periodontal tissue destruction in periodontitis is mediated by host tissue produced inflammatory cytokines, including interleukin-1beta (IL-1beta). Here, we report the expression of G protein-coupled receptor 30 (GPR30, also known as G protein-coupled estrogen receptor 1 GPER) in human PDL cells and its regulation by IL-1beta. IL-1beta-induced GPR30 expression in human PDL cells leads to the activation of multiple signaling pathways, including MAPK, NF-kappaB and PI3K. In contrast, genistein, an estrogen receptor ligand, postpones the activation of MAPKs induced by IL-1beta. Moreover, the inhibition of GPR30 by G15, a GPR30 specific antagonist, eliminates this delay. Thus, genistein plays a role in the regulation of MAPK activation via GPR30, and GPR30 represents a novel target regulated by steroid hormones in PDL cells. PMID- 22521738 TI - Challenges in the clinical utility of the serum test for HER2 ECD. AB - Approximately 15-30% of breast cancers over-express the HER2/neu receptor. Historically, over-expression of HER2/neu has been identified using IHC or FISH, both of which are invasive approaches requiring tissue samples. Recent evidence has shown that some tumors identified as "negative" using these methods can respond to HER2/neu targeted therapy. Shedding of the extracellular domain (ECD) of the receptor into the circulation has led to the development of a serum test of HER2 ECD as an additional approach to probe HER2/neu overexpression. The serum test will be able to monitor the dynamic changes of HER2 status over the course of disease progression. Some studies further suggest that the serum HER2 ECD level and its change may serve as a biomarker to reflect patients' response to therapy. Yet more than 10years after the first serum HER2 ECD test was approved by the FDA, serum HER2 testing has yet to be widely used in clinical practice. In this article we will review the progress of the serum HER2 ECD test and discuss some obstacles impeding its incorporation into broad clinical practice. We will also discuss recent improvements in the sensitivity and specificity of the assay that offer some hope for the future of serum HER2 test. PMID- 22521739 TI - Prevalence of Bartonella species, hemoplasmas, and Rickettsia felis DNA in blood and fleas of cats in Bangkok, Thailand. AB - Flea infestations are common in Thailand, but little is known about the flea borne infections. Fifty flea pools and 153 blood samples were collected from client-owned cats between June and August 2009 from veterinary hospitals in Bangkok, Thailand. Total DNA was extracted from all samples, and then assessed by conventional PCR assays. The prevalence rates of Bartonella spp. in blood and flea samples were 17% and 32%, respectively, with DNA of Bartonella henselae and Bartonella clarridgeiae being amplified most commonly. Bartonella koehlerae DNA was amplified for the first time in Thailand. Hemoplasma DNA was amplified from 23% and 34% of blood samples and flea pools, respectively, with 'Candidatus Mycoplasma haemominutum' and Mycoplasma haemofelis being detected most frequently. All samples were negative for Rickettsia felis. Prevalence rate of B. henselae DNA was increased 6.9 times in cats with flea infestation. Cats administered flea control products were 4.2 times less likely to be Bartonella infected. PMID- 22521740 TI - [Which abnormalities can be detected in myopic peripheral retina?]. AB - Vitreoretinal periphery in myopic eyes may present abnormalities whose frequency and severity are correlated with axial elongation of the eye: white-without pressure, lattice degeneration, pigmentary degeneration, and paving stone degeneration. Sometimes one can find atrophic round holes, retinal breaks, or retinoschisis whose differential diagnosis with slow progressive retinal detachment can be made on the presence of an absolute field defect. The presence of peripheral vitreous strands, pigmentary migrations, holes, associated with extensive liquefaction of the central vitreous body and facial dysmorphy are symptomatic of Stickler syndrome often complicated with bilateral retinal detachments. Congenital hereditary retinoschisis should be raised in the presence of temporal and inferior bullous detachment of a thin inner layer of the retina associated with large multiple holes in a boy with poor vision and cystic macular changes. Examination of peripheral retina should be systematic after the age of 40 in myopic patients to specify the presence of abnormalities predisposing to retinal detachment. It is more important to inform the patient of posterior vitreous detachment or retinal detachment symptoms, a true emergency situation, rather than to suggest regular and repeated consultations in the nonsymptomatic eye. PMID- 22521741 TI - Mesenchymal stem cell therapy for heart disease. AB - Mesenchymal stem cells (MSC) are adult stem cells with capacity for self-renewal and multi-lineage differentiation. Initially described in the bone marrow, MSC are also present in other organs and tissues. From a therapeutic perspective, because of their easy preparation and immunologic privilege, MSC are emerging as an extremely promising therapeutic agent for tissue regeneration and repair. Studies in animal models of myocardial infarction have demonstrated the ability of transplanted MSC to engraft and differentiate into cardiomyocytes and vascular cells. Most importantly, engrafted MSC secrete a wide array of soluble factors that mediate beneficial paracrine effects and may greatly contribute to cardiac repair. Together, these properties can be harnessed to both prevent and reverse remodeling in the ischemically injured ventricle. In proof-of-concept and phase I clinical trials, MSC therapy improved left ventricular function, induced reverse remodeling, and decreased scar size. In this review we will focus on the current understanding of MSC biology and MSC mechanism of action in cardiac repair. PMID- 22521742 TI - Long-term ethanol consumption initiates atherosclerosis in rat aorta through inflammatory stress and endothelial dysfunction. AB - Controversy exists on whether alcohol has a direct cardioprotective effect or it provokes atherosclerosis, so the present study sought to assess the effect of chronic consumption of ethanol on the markers of endothelial function, vessel rigidity, and atherosclerosis in the aorta of rat. Male Wistar rats were selected randomly and exposed to ethanol (4.5g/kg of 20% w/v solution in saline) once per day for 6weeks. Blood pressure, hemodynamic parameters, foam cell formation, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, endothelial leukocyte adhesion molecule-1, and high-sensitivity C-reactive protein (CRP) were assessed in ethanol treated rats and compared with either sham or control rats. The results revealed a concurrent significant increase of adhesion molecules, CRP levels, systolic, diastolic, pulse, and dicrotic pressures as well as enhanced formation of foam cell in ethanol-treated rats. These findings implicate that long-term ethanol exposure provokes atherogenic and hemodynamic changes via significant induction of proinflammatory response, augmenting of cell adhesion molecules, stiffness in rat aorta wall and induction of foam cell formation. PMID- 22521744 TI - Amylase gene expression patterns in Helicoverpa armigera upon feeding on a range of host plants. AB - Expression of two amylase genes (HaAmy1 and HaAmy2) was studied in Helicoverpa armigera (Hubner; Lepidoptera: Noctuidae) feeding on different host plants and during larval development. Alignment of HaAmy1 and HaAmy2 with other insect amylases shows similarities with known Lepidopteran amylase transcripts. H. armigera amylase gene expression is influenced by the availability of reducing sugars, sucrose and starch content of host plants and further correlates to the pool of reducing sugars in the gut and haemolymph of larvae. HaAmy1 and HaAmy2 during larval development on two host plants viz., maize (cereal) and marigold (ornamental) showed their relative difference. Results support the view that when host plants differ in their macronutrients, relationships of enzymes and substrates are flexible. The present work highlights the distribution of HaAmy1 and HaAmy2 (i) during various stages of insect development (second, fourth and sixth instar, pupa, adult and egg), (ii) in various tissues viz., head, haemolymph, fat body, integument and whole larval body of H. armigera feeding on artificial diet and (iii) in three gut regions of larvae fed on various diets. Complexity in expression of amylase genes suggests existence of mechanisms involved to detect nutrient balance required for avoiding fitness costs and focus their importance in insect nutrition. PMID- 22521745 TI - Evolutionary conservation and disease gene association of the human genes composing pseudogenes. AB - Pseudogenes, the 'genomic fossils' present portrayal of evolutionary history of human genome. The human genes configuring pseudogenes are also now coming forth as important resources in the study of human protein evolution. In this communication, we explored evolutionary conservation of the genes forming pseudogenes over the genes lacking any pseudogene and delving deeper, we probed an evolutionary rate difference between the disease genes in the two groups. We illustrated this differential evolutionary pattern by gene expressivity, number of regulatory miRNA targeting per gene, abundance of protein complex forming genes and lesser percentage of protein intrinsic disorderness. Furthermore, pseudogenes are observed to harbor sequence variations, over their entirety, those become degenerative disease-causing mutations though the disease involvement of their progenitors is still unexplored. Here, we unveiled an immense association of disease genes in the genes casting pseudogenes in human. We interpreted the issue by disease associated miRNA targeting, genes containing polymorphisms in miRNA target sites, abundance of genes having disease causing non-synonymous mutations, disease gene specific network properties, presence of genes having repeat regions, affluence of dosage sensitive genes and the presence of intrinsically unstructured protein regions. PMID- 22521743 TI - Molecular characterization of a catalase from Hydra vulgaris. AB - Catalase, an antioxidant and hydroperoxidase enzyme protects the cellular environment from harmful effects of hydrogen peroxide by facilitating its degradation to oxygen and water. Molecular information on a cnidarian catalase and/or peroxidase is, however, limited. In this work an apparent full length cDNA sequence coding for a catalase (HvCatalase) was isolated from Hydra vulgaris using 3'- and 5'- (RLM) RACE approaches. The 1859 bp HvCatalase cDNA included an open reading frame of 1518 bp encoding a putative protein of 505 amino acids with a predicted molecular mass of 57.44 kDa. The deduced amino acid sequence of HvCatalase contained several highly conserved motifs including the heme-ligand signature sequence RLFSYGDTH and the active site signature FXRERIPERVVHAKGXGA. A comparative analysis showed the presence of conserved catalytic amino acids [His(71), Asn(145), and Tyr(354)] in HvCatalase as well. Homology modeling indicated the presence of the conserved features of mammalian catalase fold. Hydrae exposed to thermal, starvation, metal and oxidative stress responded by regulating its catalase mRNA transcription. These results indicated that the HvCatalase gene is involved in the cellular stress response and (anti)oxidative processes triggered by stressor and contaminant exposure. PMID- 22521746 TI - Computational exploration of polymorphisms in 5-hydoxytryptamine 5-HT1A and 5 HT2A receptors associated with psychiatric disease. AB - The huge polymorphic data have been prioritized towards a specific disease based on sequence and structure homology tools to a large extent. In this study, we have explored the potential non-synonymous Single Nucleotide Polymorphism (nsSNP) in serotonin (5-HT) receptors involved in psychotic syndromes and their response pathway. The most damaging point mutations were screened from 12 classes of serotonin receptors comprising 7743 variants. In 5HT(1A) receptor, two alleles were found to be highly deleterious located at ligand binding extracellular-2 and one at intracellular loop-3 domains. Similarly, we found two alleles predicted to be highly damaging in 5HT(2A) residing at N and C-Terminal domains. The above alleles were further confirmed based on their flexibility and stability difference using the molecular dynamic simulation analysis. Integrating these results appeared promising for being able to filter out potential non-synonymous Single Nucleotide Polymorphisms for neuropsychiatric disorders. PMID- 22521747 TI - Increasing the risk of late rectal bleeding after high-dose radiotherapy for prostate cancer: the case of previous abdominal surgery. Results from a prospective trial. AB - PURPOSE: To evaluate and discuss the role of specific types of abdominal surgery (SURG) before radical radiation therapy as a risk factor for late rectal toxicity in prostate cancer patients. METHODS: Results concerning questionnaire-based scored late bleeding and faecal incontinence in 718 patients with a complete follow-up of 36 months were analysed, focusing on the impact of specific pre radiotherapy abdominal/pelvic surgery procedures. Patients were accrued in the prospective study AIROPROS 0102. Different types of surgery (rectum-sigma resection, kidney resection, cholecystectomy or appendectomy) were considered as covariates together with a number of different parameters previously found to be predictive of late toxicity and including clinical as well as dosimetric parameters. Univariate (UVA) and multivariate (MVA) logistic analyses were carried out. RESULTS: In total 69/718 patients were previously submitted to one or more surgical procedures, mostly cholecystectomy (n=21) and appendectomy (n=27). Actuarial incidences of G2-G3 and G3 bleeding were 52 (7.2%) and 24 (3.3%) respectively; 19 (2.6%) chronic incontinence events were registered. Cholecystectomy was found to be highly correlated with late rectal bleeding at UVA: OR=4.3 and p=0.006 for G2-G3 and OR=5.4 and p=0.01 for G3. Considering MVA (including dosimetric and clinical factors), G2-G3 bleeding was significantly correlated to cholecystectomy (OR=6.5, p=0.002), V75 Gy (OR=1.074, p=0.003) and secondarily with appendectomy (OR=2.7, p=0.10), presence of acute radioinduced rectal bleeding (OR=1.70, p=0.21) and androgen deprivation (OR=0.67, p=0.25). Appendectomy (OR=5.9, p=0.004) and cholecystectomy (OR=5.5, p=0.016) were very strong predictors of G3 bleeding with V75 Gy playing a less significant role (OR=1.037, p=0.26). Conversely, no specific surgery was correlated with actuarial or chronic incontinence. CONCLUSIONS: This analysis highlights previous SURG as the best predictor of late rectal bleeding. Among the different types of abdominal surgery, cholecystectomy and appendectomy play the major role, especially for severe late bleeding. PMID- 22521748 TI - How does imaging frequency and soft tissue motion affect the PTV margin size in partial breast and boost radiotherapy? AB - PURPOSE: This study investigates (i) the effect of verification protocols on treatment accuracy and PTV margins for partial breast and boost breast radiotherapy with short fractionation schema (15 fractions), (ii) the effect of deformation of the excision cavity (EC) on PTV margin size, (iii) the imaging dose required to achieve specific PTV margins. METHODS AND MATERIALS: Verification images using implanted EC markers were studied in 36 patients. Target motion was estimated for a 15 fraction partial breast regimen using imaging protocols based on on-line and off-line motion correction strategies (No Action Level (NAL) and the extended NAL (eNAL) protocols). Target motion was used to estimate a PTV margin for each protocol. To evaluate treatment errors due to deformation of the excision cavity, individual marker positions were obtained from 11 patients. The mean clip displacement and daily variation in clip position during radiotherapy were determined and the contribution of these errors to PTV margin calculated. Published imaging dose data were used to estimate total dose for each protocol. Finally the number of images required to obtain a specific PTV margin was evaluated and hence, the relationship between PTV margins and imaging dose was investigated. RESULTS: The PTV margin required to account for excision cavity motion, varied between 10.2 and 2.4mm depending on the correction strategy used. Average clip movement was 0.8mm and average variation in clip position during treatment was 0.4mm. The contribution to PTV margin from deformation was estimated to be small, less than 0.2mm for both off-line and on-line correction protocols. CONCLUSION: A boost or partial breast PTV margin of ~10 mm, is possible with zero imaging dose and workload, however, patients receiving boost radiotherapy may benefit from a margin reduction of ~4 mm with imaging doses from 0.4cGy to 25cGy using an eNAL protocol. PTV margin contributions from deformation errors are likely to be small in comparison to other sources of error, i.e., set up or delineation. PMID- 22521749 TI - Phase II trial of 3D-conformal accelerated partial breast irradiation: lessons learned from patients and physicians' evaluation. AB - INTRODUCTION: The present study prospectively reported both physicians' and patients' assessment for toxicities, cosmetic assessment and patients' satisfaction after 3D-conformal accelerated partial breast irradiation (APBI). MATERIALS AND METHODS: From October 2007 to September 2009, 30 early breast cancer patients were enrolled in a 3D-conformal APBI Phase II trial (40 Gy/10 fractions/5 days). Treatment related toxicities and cosmetic results were assessed by both patients and physicians at each visit (at 1, 2, 6 months, and then every 6 months). Patient satisfaction was also scored. RESULTS: After a median follow-up of 27.7 months, all patients were satisfied with APBI treatment, regardless of cosmetic results or late adverse events. Good/excellent cosmetic results were noticed by 80% of patients versus 92% of cases by radiation oncologists. Breast pain was systematically underestimated by physicians (8-20% vs. 16.6-26.2%; Kappa coefficient KC=0.16-0.44). Grade 1 and 2 fibrosis and/or breast retraction occurred in 7-12% of patients and were overestimated by patients (KC=0.14-0.27). CONCLUSIONS: Present results have shown discrepancies between patient and physician assessments. In addition to the assessment of efficacy and toxicity after 3D-conformal APBI, patients' cosmetic results consideration and satisfaction should be also evaluated. PMID- 22521750 TI - Evaluation of the respiratory prostate motion with four-dimensional computed tomography scan acquisitions using three implanted markers. AB - BACKGROUND AND PURPOSE: During the irradiation of the prostate cancer, it is crucial to take into account the possible displacements in defining the planning target volume. The objective of this study was to specifically analyze the respiratory-induced prostate motion using a four-dimensional CT scan (4DCT). MATERIALS AND METHODS: Ten patients have been treated for prostate cancer in the supine position and with three implanted gold markers; they underwent a 4DCT using a GE LightSpeed16 CT scan (slice thickness 2.5mm). This acquisition was divided into 10 phases over the respiratory cycle using the Advantage4D software. For each phase, digitally-reconstructed radiographs (DRRs) were created at 0 degrees and 90 degrees with the view of the markers. The coordinates of each marker center were generated from the scan isocenter. The motion amplitude was: visually analyzed on the dynamic 4DCT sequences and then more precisely calculated by comparing the marker coordinates on the 10 scans. RESULTS: There was not any difficulty in defining the coordinates of the markers on each series. No prostate motion was observed on a simple visual analysis of the dynamic 4DCT sequences. After a more specific analysis, using the coordinates of the fiducials on the 10 phases, the prostate motion remained below 1mm in all directions, except for the cranio-caudal, where it was undetectable (thereby below the slice thickness of 2.5mm). CONCLUSIONS: To our knowledge, this is the first study that evaluates the respiratory-induced prostate motion, using a 4DCT scan. Even if important prostate displacement can occur during the prostate treatment, because of the bladder or rectum filling, in the present study no respiratory-induced prostate motion was observed. PMID- 22521751 TI - Interleukin-1 (IL-1) family of cytokines: role in type 2 diabetes. AB - Cytokines are small cell signaling protein molecules which encompass a large and diverse family. They consist of immunomodulating agents such as interleukins and inteferons. Virtually all nucleated cells, especially endo/epithelial cells and macrophages are potent producers of IL-1, IL-6 and TNF-alpha. IL-1 family is a group of cytokines which play a central role in the regulation of immune and inflammatory responses. Type 2 diabetes (T2D) has been recognized as an immune mediated disease leading to impaired insulin signaling and selective destruction of insulin producing beta-cells in which cytokines play an important role. Disturbance of anti-inflammatory response could be a critical component of the chronic inflammation resulting in T2D. IL-1 family of cytokines has important roles in endocrinology and in the regulation of responses associated with inflammatory stress. The IL-1 family consists of two pro-inflammatory cytokines, IL-1alpha and IL-1beta, and a naturally occurring anti-inflammatory agent, the IL 1 receptor antagonist (IL-1Ra or IL-1RN). This review is an insight into the different types of cytokines belonging to IL-1 family, their modes of action and association with Type 2 diabetes. PMID- 22521752 TI - Multiplex primer extension reaction and capillary electrophoresis to study the frequency of thrombophilia-related mutations in a spanish population. AB - BACKGROUND: Thrombophilia is defined as an inherited or acquired abnormality of hemostasis predisposing to thrombosis. While the most common thrombophilia has a genetic origin and is manifested by elevated circulating antiphospholipid antibodies, about 40% of cases presenting with thrombosis are acquired. Factor V Leiden G1691A, prothrombin G20210A, MTHFR C677T, and Factor XII C46T mutations are associated with the risk of developing thrombophilia. METHODS: In this study, a method using single base extension assay coupled with fluorescent detection and capillary electrophoresis was applied to simultaneously detect G1691A, G20210A, C677T and C46T mutations in 1499 patients from Spain with suspicion of thrombotic disease. RESULTS: Out of these individuals, 5.4% were heterozygous for G20210A mutation, 9.21% were heterozygous and 0.20% homozygous for G1691A mutation, 46.36% were heterozygous and 20.71% homozygous for MTHFR mutation, and 30.41% were heterozygous and 3.4% homozygous for C46T mutation. CONCLUSION: We applied an accurate, simple, semi-automatic, and cost-effective method to simultaneously detect the main thrombophilia-related mutations, allowing us to determine the frequency of these mutations in a Spanish population. PMID- 22521753 TI - In vitro anti-influenza virus and anti-inflammatory activities of theaflavin derivatives. AB - The theaflavins fraction (TF80%, with a purity of 80%) and three theaflavin (TF) derivatives from black tea have been found to exhibit potent inhibitory effects against influenza virus in vitro. They were evaluated with a neuraminidase (NA) activity assay, a hemagglutination (HA) inhibition assay, a real-time quantitative PCR (qPCR) assay for gene expression of hemagglutinin (HA) and a cytopathic effect (CPE) reduction assay. The experimental results showed that they all exerted significant inhibitory effects on the NA of three different subtypes of influenza virus strains [A/PR/8/34(H1N1), A/Sydney/5/97(H3N2) and B/Jiangsu/10/2003] with 50% inhibitory concentration (IC(50)) values ranging from 9.27 to 36.55 MUg/mL, and they also displayed an inhibitory effect on HA; these inhibitory effects might constitute two major mechanisms of their antiviral activity. Time-of-addition studies demonstrated that TF derivatives might have a direct effect on viral particle infectivity, which was consistent with the inhibitory effect on HA. Subsequently, the inhibitory effect of TF derivatives on the replication of the viral HA gene as assayed by qPCR and on the nuclear localization of the influenza virus vRNP further demonstrated that they may primarily act during the early stage of infection. Interestingly, besides the activity against functional viral proteins, TF derivatives also decreased the expression level of the inflammatory cytokine IL-6 during viral infection, expression of which may result in serious tissue injury and apoptosis. Our results indicated that TF derivatives are potential compounds with anti-influenza viral replication and anti-inflammatory properties. These findings will provide important information for new drug design and development for the treatment of influenza virus infection. PMID- 22521754 TI - Increased mean corpuscular volume of erythrocytes predicts the response to metronomic cyclophosphamide, capecitabine and bevacizumab treatment: is it true for capecitabine treatment or more? PMID- 22521755 TI - A randomised controlled trial of a pilot intervention to encourage early presentation of oral cancer in high risk groups. AB - OBJECTIVE: Prognosis for oral cancer is substantially improved when diagnosed early. This research aimed to evaluate an intervention to promote early presentation of oral cancer. METHODS: Participants were randomly assigned to a leaflet group (n = 42), a one-to-one group (n = 46) or a control group (n = 24). Participants in the leaflet group read a theory-based (Extended Self-Regulatory Model; Social Cognitive Theory) leaflet on how to spot oral cancer early. Those in the one-to-one group received a brief, interactional discussion on early presentation of oral cancer and were then asked to read the leaflet. Participants in the control group received no information about oral cancer. RESULTS: The leaflet and the one-to-one instruction led to more accurate knowledge of oral cancer, decreased anticipated delay, and increased understanding, likelihood and confidence to perform self-examination. Neither intervention raised participants' anxiety. There were minimal differences between the two interventions, yet both were superior to the control group. CONCLUSION: This piloting indicates the initial effectiveness of an brief intervention purposefully designed for people at risk of developing oral cancer. PRACTICE IMPLICATION: A low cost intervention may be a useful tool to encourage early detection of oral cancer. This could be embedded into routine consultations or an early detection programme. PMID- 22521756 TI - Genotype 3f predominance in symptomatic acute autochthonous hepatitis E: a short case series in south-eastern France. PMID- 22521757 TI - Symptomatic and chondroprotective treatment with collagen derivatives in osteoarthritis: a systematic review. AB - OBJECTIVE: Osteoarthritis (OA) is one of the most prevalent musculoskeletal diseases. Collagen derivatives are candidates for disease-modifying OA drugs. This group of derivatives can be divided into undenatured collagen (UC), gelatine and collagen hydrolysate (CH). Collagen derivatives are marketed as having direct chondroprotective action and reducing complaints of OA. This review summarizes the evidence for the effectiveness of symptomatic and chondroprotective treatment with collagen derivatives in patients with OA. METHODS: Eligible randomised controlled trials (RCTs) and quasi-RCTs were identified by searching PubMed, Embase and the Cochrane Central Register of Controlled Trials until November 2011. Methodological quality was assessed using methods of the Cochrane Back Review Group. RESULTS: Eight studies were identified: six on CH, two on gelatine, and one on UC. The pooled mean difference based on three studies for pain reduction measured with the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index comparing CH with placebo was -0.49 (95% CI -1.10 0.12). However, some studies report significant between-group differences in pain when measured with a visual analogical scale (VAS) or other instruments, or when CH is compared with glucosamine sulphate. For disability no significant between group mean differences were found when comparing CH with placebo. Gelatine compared with placebo and with alternative therapies was superior for the outcome pain. UC compared with glucosamine+chondroitin showed no significant between group differences for pain and disability. The most reported adverse events of collagen derivatives were mild to moderate gastro-intestinal complaints. The overall quality of evidence was moderate to very low. CONCLUSIONS: There is insufficient evidence to recommend the generalized use of CHs in daily practice for the treatment of patients with OA. More independent high-quality studies are needed to confirm the therapeutic effects of collagen derivatives on OA complaints. PMID- 22521758 TI - Equivalence and precision of knee cartilage morphometry between different segmentation teams, cartilage regions, and MR acquisitions. AB - OBJECTIVE: To compare precision and evaluate equivalence of femorotibial cartilage volume (VC) and mean cartilage thickness over total area of bone (ThCtAB.Me) from independent segmentation teams using identical Magnetic Resonance (MR) images from three series: sagittal 3D Dual Echo in the Steady State (DESS), coronal multi-planar reformat (DESS-MPR) of DESS and coronal 3D Fast Low Angle SHot (FLASH). DESIGN: Nineteen subjects underwent test-retest MR imaging at 3 T. Four teams segmented the cartilage using prospectively defined plate regions and rules. Mixed models analysis of the pooled data were used to evaluate the effect of acquisition, team and plate on precision and Pearson correlations and mixed models were used to evaluate equivalence. RESULTS: Segmentation team differences dominated measurement variability in most cartilage regions for all image series. Precision of VC and ThCtAB.Me differed significantly by team and cartilage plate, but not between FLASH and DESS. Mean values of VC and ThCtAB.Me differed by team (P < 0.05) for DESS, FLASH and DESS MPR. FLASH VC was 4-6% larger than DESS in the medial tibia and lateral central femur, and FLASH ThCtAB.Me was 5-6% larger in the medial tibia, but 4-8% smaller in the medial central femur. Correlations between DESS and FLASH for VC and ThCtAB.Me were high (r = 0.90-0.97), except for DESS vs FLASH medial central femur ThCtAB.Me (r = 0.81-0.83). CONCLUSIONS: Cartilage morphology metrics from different image contrasts had similar precision, were generally equivalent, and may be combined for cross-sectional analyses if potential systematic offsets are accounted for. Data from different teams should not be pooled unless equivalence is demonstrated for cartilage metrics of interest. PMID- 22521759 TI - Muscle sarcomas and alopecia in A/J mice chronically treated with nicotine. AB - AIMS: To evaluate the pathobiologic effects of long-term treatment with nicotine of A/J mice susceptible to tobacco-induced lung carcinogenesis. MAIN METHODS: Experimental group of mice received subcutaneous injections of the LD(50) dose of (-)nicotine hydrogen tartrate of 3 mg/kg/day, 5 days per week for 24 months, and control group received the vehicle phosphate-buffered saline. KEY FINDINGS: Nicotine treated mice, 78.6%, but none of control of mice, developed neoplasms originating from the uterus or skeletal muscle. Examination of the uterine neoplasms revealed leiomyosarcomas, composed of whorled bundles of smooth-muscle like cells with large and hyperchromatic nuclei. Sections of the thigh neoplasms revealed densely cellular tumors composed of plump spindle cells, with occasional formation of 'strap' cells, containing distorted striations. Both neoplasms were positive for desmin staining. A solitary pulmonary adenoma with papillary architecture also occurred in one nicotine treated mouse. Experimental mice also developed transient balding starting as small patches of alopecia that progressed to distinct circumscribed areas of complete hair loss or large areas of diffuse hair loss. SIGNIFICANCE: We demonstrate for the first time that chronic nicotine treatment can induce the development of muscle sarcomas as well as transient hair loss. These findings may help explain the association of childhood rhabdomyosarcoma with parental smoking and earlier onset of balding in smokers. It remains to be determined whether the pathobiologic effects of nicotine result from its receptor-mediated action and/or its tissue metabolites cotinine and N' nitrosonornicotine, or toxic effects of reactive oxygen species activated due to possible intracellular accumulation of nicotine. PMID- 22521761 TI - Analysis of how an aspiration catheter is included in the bronchial suture during lung resection surgery. PMID- 22521760 TI - Maternal high-sodium intake alters the responsiveness of the renin-angiotensin system in adult offspring. AB - AIMS: The goal of the current study was to evaluate the impact of maternal sodium intake during gestation on the systemic and renal renin-angiotensin-aldosterone system (RAAS) of the adult offspring. MAIN METHODS: Female Wistar rats were fed high- (HSD-8.0% NaCl) or normal-sodium diets (NSD-1.3% NaCl) from 8 weeks of age until the delivery of their first litter. After birth, the offspring received NSD. Tail-cuff blood pressure (TcBP) was measured in the offspring between 6 and 12 weeks of age. At 12 weeks of age, the offspring were subjected to either one week of HSD or low sodium diet (LSD-0.16% NaCl) feeding to evaluate RAAS responsiveness or to acute saline overload to examine sodium excretory function. Plasma (PRA) and renal renin content (RRC), serum aldosterone (ALDO) levels, and renal cortical and medullary renin mRNA expression levels were evaluated at the end of the study. KEY FINDINGS: TcBP was higher among dams fed HSD, but no TcBP differences were observed among the offspring. Male offspring, however, exhibited increased TcBP after one week of HSD feeding, and this effect was independent of maternal diet. Increased RAAS responsiveness to the HSD and LSD was also observed in male offspring. The baseline levels of PRA, ALDO, and cortical and medullary renin gene expression were lower but the RRC levels were higher among HSD-fed male offspring (HSDoff). Conversely, female HSDoff showed reduced sodium excretion 4 h after saline overload compared with female NSDoff. SIGNIFICANCE: High maternal sodium intake is associated with gender-specific changes in RAAS responsiveness among adult offspring. PMID- 22521762 TI - Neuroprotective effect of early and short-time applying sophoridine in pMCAO rat brain: down-regulated TRAF6 and up-regulated p-ERK1/2 expression, ameliorated brain infaction and edema. AB - BACKGROUND: Matrine has been proven to protect ischemic injury in brain and sophoridine (SOP) is an isomeride of matrine. It is unknown whether SOP has this protective effect on ischemic injury in brain. We therefore investigated the potential neuroprotective role of SOP and the underlying mechanism. METHODS: Male, Sprague-Dawley rats were randomly assigned into five groups: Vehicle (pMCAO+saline), High dose (pMCAO+SOP 10 mg/kg), Middle dose (pMCAO+SOP 5 mg/kg), Low dose (pMCAO+SOP 2.5 mg/kg) and Sham operated group. Permanent middle cerebral artery occlusion (pMCAO) model was used and SOP was administered intraperitoneally immediately after cerebral ischemia and once daily in the following days. Neurological deficit was evaluated using a modified six point scale; brain water content and infarct volume were measured. The expression of TRAF6 and ERK1/2 were measured by immunohistochemistry, Western blotting. RESULTS: Compared with Vehicle group, the cerebral edema was alleviated in High dose group (P<0.05), and the infarct volume was decreased in Low dose group (P<0.05). Consistent with these results, immunohistochemistry and Western blot analysis indicated that TRAF6 expression was significantly decreased in SOP administrated groups at 24 h, and the expression of phosphorylated ERK1/2 increased in Low dose at 72 h. CONCLUSIONS: SOP protected the brain from damage caused by pMCAO, and this effect may be through down-regulation of TRAF6 expression and up-regulation of ERK1/2 phosphorylation expression. PMID- 22521763 TI - Jacaric acid, a linolenic acid isomer with a conjugated triene system, has a strong antitumor effect in vitro and in vivo. AB - In this study, we compared the cytotoxic effects of natural conjugated linolenic acids (CLnAs) on human adenocarcinoma cells (DLD-1) in vitro, with the goal of finding CLnA isomers with strong cytotoxic effects. The antitumor effect of the CLnA with the strongest cytotoxic effect was then examined in mice. The results showed that all CLnA isomers have strong cytotoxic effects on DLD-1 cells, with jacaric acid (JA) having the strongest effect. Examination of the mechanism of cell death showed that CLnAs induce apoptosis in DLD-1 cells via lipid peroxidation. The intracellular levels of incorporated CLnAs were measured to examine the reason for differences in cytotoxic effects. These results showed that JA was taken into cells efficiently. Collectively, these results suggest that the cytotoxic effect of CLnAs is dependent on intracellular incorporation and induction of apoptosis via lipid peroxidation. JA also had a strong preventive antitumor effect in vivo in nude mice into which DLD-1 cells were transplanted. These results suggest that JA can be used as a dietary constituent for prevention of cancer. PMID- 22521764 TI - Insight into NSAID-induced membrane alterations, pathogenesis and therapeutics: characterization of interaction of NSAIDs with phosphatidylcholine. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most widely consumed pharmaceuticals, yet both the mechanisms involved in their therapeutic actions and side-effects, notably gastrointestinal (GI) ulceration/bleeding, have not been clearly defined. In this study, we have used a number of biochemical, structural, computational and biological systems including; Fourier Transform InfraRed (FTIR). Nuclear Magnetic Resonance (NMR) and Surface Plasmon Resonance (SPR) spectroscopy, and cell culture using a specific fluorescent membrane probe, to demonstrate that NSAIDs have a strong affinity to form ionic and hydrophobic associations with zwitterionic phospholipids, and specifically phosphatidylcholine (PC), that are reversible and non-covalent in nature. We propose that the pH-dependent partition of these potent anti-inflammatory drugs into the phospholipid bilayer, and possibly extracellular mono/multilayers present on the luminal interface of the mucus gel layer, may result in profound changes in the hydrophobicity, fluidity, permeability, biomechanical properties and stability of these membranes and barriers. These changes may not only provide an explanation of how NSAIDs induce surface injury to the GI mucosa as a component in the pathogenic mechanism leading to peptic ulceration and bleeding, but potentially an explanation for a number of (COX-independent) biological actions of this family of pharmaceuticals. This insight also has proven useful in the design and development of a novel class of PC-associated NSAIDs that have reduced GI toxicity while maintaining their essential therapeutic efficacy to inhibit pain and inflammation. PMID- 22521765 TI - First report of a Pseudomonas aeruginosa clinical isolate co-harbouring KPC-2 and IMP-18 carbapenemases. PMID- 22521766 TI - Anti-anaerobic activity of a new beta-lactamase inhibitor NXL104 in combination with beta-lactams and metronidazole. AB - NXL104 is a new beta-lactamase inhibitor (BLI) that inhibits class A and class C beta-lactamase enzymes. In this study, the activity of NXL104 in combination with the third-generation cephalosporins ceftazidime (CAZ) and ceftriaxone (CRO) or with piperacillin (PIP) was evaluated against 316 anaerobic bacteria. Minimum inhibitory concentrations (MICs) were determined using an agar dilution method. The BLIs NXL104 or tazobactam (TAZ) were added to the beta-lactams at a fixed concentration of 4 mg/L. A triple combination of NXL104 with an 8:1 ratio of CAZ and metronidazole (MTZ) was also tested. The activities of CAZ, CRO and PIP in combination with NXL104 were enhanced against many of the bacteria. MIC(50) values (MIC for 50% of the organisms) for CAZ+NXL104 were 8-16-fold lower than those of CAZ against Gram-negative anaerobes. Antibiotic resistance rates against all anaerobic strains were: CAZ, 37.7%; CRO, 31%; CAZ+NXL104, 15.2%; CRO+NXL104, 5.4%; and MTZ, 4.1%. No resistant strains could be observed with PIP+TAZ, PIP+NXL104 or the triple combination MTZ+CAZ+NXL104. In conclusion, the triple combination of MTZ+CAZ+NXL104 demonstrated potent antibacterial activity against anaerobes representing most clinical species. It appears appropriate for the treatment of polymicrobial infections, since CAZ+NXL104 also exhibits potent activity against beta-lactamase-producing Enterobacteriaceae and Pseudomonas aeruginosa. It is currently being tested in phase 2 clinical trials for the treatment of complicated intra-abdominal infections. PMID- 22521767 TI - Characterisation and clonal dissemination of OXA-23-producing Acinetobacter baumannii in Tabriz, northwest Iran. AB - The characteristics and molecular epidemiology of carbapenemase genes amongst 68 imipenem-resistant Acinetobacter baumannii isolated from Imam Reza Hospital (Tabriz, Iran) during a 17-month period were studied. All 68 isolates were typed using sequence group-based multiplex polymerase chain reaction (PCR) to compare the clonal relationship of isolates with known international clonal lineages. Repetitive sequence-based PCR was further performed with representative isolates of each clone. PCR and sequencing were performed to detect OXA-type carbapenemases and class 1, 2 and 3 integron genes as well as to confirm the presence of insertion sequence ISAba1 upstream of bla(OXA-23) and bla(OXA-51 like) genes. Sixty-four isolates (94%) belonged to international clone (IC) II, two isolates (3%) belonged to IC I and two isolates (3%) did not belong to known international clones. All isolates carried bla(OXA-51-like), bla(OXA-23) and class 1 integron genes. No other acquired bla(OXA) genes or class 2 or 3 integron genes were detected. Sequence analysis confirmed the presence of bla(OXA-23) as well as the bla(OXA-51-like) variants bla(OXA-66), bla(OXA-69) and bla(OXA-88). ISAba1 was present upstream of the bla(OXA-23) gene in all of the isolates. Clonal spread of OXA-23-producing A. baumannii emphasises the need for appropriate infection control measures to prevent further spread of these multidrug-resistant organisms. PMID- 22521768 TI - Drug-interaction studies evaluating T-cell proliferation reveal distinct activity of dasatinib and imatinib in combination with cyclosporine A. AB - Development of small molecule tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia has been astonishingly successful; however, their off target effects have generated both challenges and opportunities for extending their clinical application. Dasatinib and imatinib are two of the most commonly used tyrosine kinase inhibitors and both have been shown to impact T-cell function. Due to this activity, their use as potential immune suppressants has been proposed. In this report, we investigated drug interactions with cyclosporine A in suppressing T-cell proliferation. Dasatinib and imatinib were titrated against varying concentrations of cyclosporine in the cultures and T cell proliferation assessed by 5-6-carboxyfluorescein diacetate, succinimidyl ester dye dilution. These proliferation data were then used to determine the combination index to evaluate additive, synergistic, or antagonistic interactions between the drugs. This analysis uncovered a number of different drug interactions affecting T-cell proliferation. Cyclosporine had an additive or synergistic effect on T-cell proliferation when combined with dasatinib and imatinib for 3 of the 4 methods of stimulating T-cell proliferation. However, when T cells were stimulated with anti-CD3 and anti-CD28 antibodies, this interaction was found to be strongly antagonistic at low dasatinib concentrations. In contrast, this strong antagonism was not observed when imatinib was used in combination with cyclosporine A. This study suggests drug interactions affecting T cells may need to be carefully taken into account when using tyrosine kinase inhibitors. Furthermore, the technique to evaluate drug interactions is novel, and applicable to study any interaction affecting proliferation. PMID- 22521769 TI - Activation of adjuvant core response genes by the novel adjuvant PCEP. AB - Adjuvants are critical components of many vaccines but their mechanisms of action are often poorly understood. Understanding the mechanisms of adjuvant activity is critical in defining how innate immunity influenced adaptive immunity. We investigated the capacity of a novel adjuvant, poly[di(sodiumcarboxylatoethylphenoxy)phosphazene] (PCEP), to induce innate immune responses at the site of injection. PCEP induced time-dependent changes in the gene expression of many "adjuvant core response genes" including cytokines, chemokines, innate immune receptors, interferon-induced genes, adhesion molecules and antigen-presentation genes. In addition, PCEP triggered local production of cytokines and the chemokine CCL-2 as indicated by ELISA. Interestingly, PCEP up regulated the gene expression of the inflammasome receptor, Nlrp3, and induced the production of pro-inflammatory cytokines IL-1beta, and IL-18 at the site of injection. Secretion of these cytokines is predominantly a result of activation of the inflammasome, a multi-protein complex that activates caspase-1, leading to the processing and secretion of proinflammatory cytokines. These results suggest that PCEP may modulate antigen-specific immune responses by strongly activating early innate immune responses and promoting a strong immuno-stimulatory environment at the site of injection. PMID- 22521770 TI - Thermal ablation of the small renal mass: case selection using the R.E.N.A.L. Nephrometry Score. AB - OBJECTIVES: Treatment decision-making for localized renal lesions remains overly subjective. While the AUA Guidelines list thermal ablation (TA) as a treatment option for the clinical T1 renal mass, few data exist regarding the relationship between TA and tumor complexity. The R.E.N.A.L.-Nephrometry Scoring System (NS) was introduced to objectify salient renal mass anatomy and standardize academic reporting. Here we correlate the salient anatomical attributes of renal masses undergoing TA with technical and oncologic outcomes. MATERIALS AND METHODS: We queried our prospectively maintained kidney cancer database of 2,312 patients and identified 39 patients who underwent TA with available nephrometry scores. Patient clinical, technical, functional, and oncologic characteristics were reviewed. RESULTS: Median patient age, serum creatinine, estimated glomerular filtration rate, and Charlson Comorbidity Index were 71 (range = 57-86) years, 1.37 (range = 0.7-3.5) mg/dl, 57.1 (range = 23.3-93.8) ml/min, and 2 (range = 0 5), respectively. Median Nephrometry Score for patients undergoing tumor ablation was 6 (4-10). Low (NS = 4-6), moderate (NS = 7-9), and high (NS = 10-12) complexity tumors were identified in 20 (51.3%), 17 (43.6%), and 2 (5.1%) patients. Six (15%) patients experienced a tumor recurrence. Of those with a recurrence, 5/6 (83.3%) had moderate complexity tumors with the remaining tumor being low complexity. Minor and major Clavien complications occurred in 4 (10%) and 1 (3%) patients, all of whom had moderate complexity tumors. CONCLUSIONS: At our institution, 95% of tumors undergoing TA were anatomically low or moderate complexity lesions as measured by the R.E.N.A.L.-Nephrometry Scoring System. Nephrometry may help predict disease recurrence and peri-procedural complications, yet multi-institutional analysis is needed to further validate these findings. PMID- 22521771 TI - Prognostic significance of non-muscle-invasive bladder tumor history in patients with upper urinary tract urothelial carcinoma. AB - OBJECTIVE: To evaluate the prognostic factors for survival and disease recurrence in patients treated surgically for upper tract urothelial carcinoma (UTUC), focusing especially on the impact of history of non-muscle-invasive bladder cancer. PATIENTS AND METHODS: A single-center series of 221 consecutive patients who were treated surgically for UTUC between January 1999 and December 2010 was evaluated. Patients who had a history of bladder tumor at a higher stage than the upper tract disease, preoperative chemotherapy, or previous contralateral UTUC were excluded. None of the patients included in this study had distant metastasis at diagnosis of UTUC. In total, 183 patients (mean age 66 years, range 36-88) were then available for evaluation. Tumor multifocality was defined as the synchronous presence of 2 or more pathologically confirmed tumors in any upper urinary tract location (renal pelvis or ureter). All patients were treated with either open radical nephroureterectomy (RNU) or open conservative surgery. Recurrence-free probabilities and cancer-specific survival were estimated using the Kaplan-Meier method and Cox regression analyses. RESULTS: Fifty-one patients (28%) had previous carcinoma not invading bladder muscle. Previous history of non muscle-invasive bladder cancer was significantly associated with tumor multifocality (P < 0.001), concomitant bladder cancer (P < 0.001), higher tumor stage (P = 0.020), and lymphovascular invasion (P = 0.026). Using univariate analyses, history of non-muscle-invasive bladder cancer was significantly associated with an increased risk of both any recurrence (HR = 2.17; P = 0.003) and bladder-only recurrence (HR = 3.17; P = 0.001). Previous carcinoma not invading bladder muscle (HR = 2.58; P = 0.042) was an independent predictor of bladder-only recurrence. Overall 5-year disease recurrence-free (any recurrence and bladder-only recurrence) survival rates were 66.7% and 77%, respectively. Previous history of non-muscle-invasive bladder cancer was not associated with cancer-specific survival. Our results are subject to the inherent biases associated with high-volume tertiary care centers. CONCLUSIONS: Patients with previous history of non-muscle-invasive bladder cancer had a higher risk of having multifocal and UTUC with higher tumor stages (pT3 or greater). History of bladder tumor was an independent predictor of bladder cancer recurrence but had no effect on non-bladder recurrence, and cancer-specific survival in patients who underwent surgical treatment of UTUC. PMID- 22521772 TI - Bcl-2 increases stroke-induced striatal neurogenesis in adult brains by inhibiting BMP-4 function via activation of beta-catenin signaling. AB - Our previous experiments suggest that treatment with Bcl-2 increases proliferation and differentiation of neuronal progenitors induced by ischemic injury and ameliorates neurological functional deficits after stroke. However, in addition to its traditional anti-apoptotic effect, little is known about the concrete molecular modulation mechanism. In this study, Bcl-2-expressing plasmids were injected into the lateral ventricle of rat brains immediately following a 30 min occlusion of the middle cerebral artery to determine the role of Bcl-2 in adult neurogenesis. Bcl-2 overexpression reduced ischemic infarct and astrogenesis, and enhanced ischemia-induced striatal neurogenesis. We further found that Bcl-2 increased beta-catenin, a key mediator of canonical Wnt/beta catenin signaling pathway, and reduced bone morphogenetic proteins-4 (BMP-4) expression in the ipsilateral striatum following ischemia. Treatment of stroke with beta-catenin siRNA (i.c.v.) showed that beta-catenin siRNA antagonized Bcl-2 neuroprotection against ischemic brain injury. More interestingly, beta-catenin siRNA simultaneously abolished Bcl-2-mediated reduction of BMP-4 expression and enhancement of neurogenesis in the ipsilateral striatum. This effect is independent of Noggin, the known BMP antagonist. These findings highlight a new regulatory mechanism that Bcl-2 elevates ischemia-induced striatal neurogenesis by down-regulating expression of BMP-4 via activation of the Wnt/beta-catenin signaling pathway in adult rat brains. PMID- 22521773 TI - Daidzein has neuroprotective effects through ligand-binding-independent PPARgamma activation. AB - Phytoestrogens are a group of plant-derived compounds that include mainly isoflavones like daidzein. Phytoestrogens prevent neuronal damage and improve outcome in experimental stroke; however, the mechanisms of this neuroprotective action have not been fully elucidated. In this context, it has been postulated that phytoestrogens might activate the peroxisome proliferator-activated receptor gamma (PPARgamma), which exerts neuroprotective effects in several settings. The aim of this study was to determine whether the phytoestrogen daidzein elicits beneficial actions in neuronal cells by mechanisms involving activation of PPARgamma. Our results show that daidzein (0.05-5 MUM) decreases cell death induced by exposure to oxygen-glucose deprivation (OGD) from rat cortical neurons and that improves synaptic function, in terms of increased synaptic vesicle recycling at nerve terminals, being both effects inhibited by the PPARgamma antagonist T0070907 (1 MUM). In addition, this phytoestrogen activated PPARgamma in neuronal cultures, as shown by an increase in PPARgamma transcriptional activity. Interestingly, these effects were not due to binding to the receptor ligand site, as shown by a TR-FRET PPARgamma competitive binding assay. Conversely, daidzein increased PPARgamma nuclear protein levels and decreased cytosolic ones, suggesting nuclear translocation. We have used the receptor antagonist (RE) fulvestrant to study the neuroprotective participation of daidzein via estrogen receptor and at least in our model, we have discarded this pathway. These results demonstrate that the phytoestrogen daidzein has cytoprotective properties in neurons, which are due to an increase in PPARgamma activity not mediated by direct binding to the receptor ligand-binding domain but likely due to post-translational modifications affecting its subcellular location and not depending to the RE and it is not additive with the agonist rosiglitazone. PMID- 22521775 TI - Differential effects of chronic hyperammonemia on modulation of the glutamate nitric oxide-cGMP pathway by metabotropic glutamate receptor 5 and low and high affinity AMPA receptors in cerebellum in vivo. AB - Previous studies show that chronic hyperammonemia impairs learning ability of rats by impairing the glutamate-nitric oxide (NO)-cyclic guanosine mono-phosphate (cGMP) pathway in cerebellum. Three types of glutamate receptors cooperate in modulating the NO-cGMP pathway: metabotropic glutamate receptor 5 (mGluR5), (RS) alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d aspartic acid (NMDA) receptors. The aim of this work was to assess whether hyperammonemia alters the modulation of this pathway by mGluR5 and AMPA receptors in cerebellum in vivo. The results support that in control rats: (1) low AMPA concentrations (0.1mM) activate nearly completely Ca(2+)-permeable (glutamate receptor subunit 2 (GluR2)-lacking) AMPA receptors and the NO-cGMP pathway; (2) higher AMPA concentrations (0.3 mM) also activate Ca(2+)-impermeable (GluR2 containing) AMPA receptors, leading to activation of NMDA receptors and of NO cGMP pathway. Moreover, the data support that chronic hyperammonemia: (1) reduces glutamate release and activation of the glutamate-NO-cGMP pathway by activation of mGluR5; (2) strongly reduces the direct activation by AMPA receptors of the NO cGMP pathway, likely due to reduced entry of Ca(2+) through GluR2-lacking, high affinity AMPA receptors; (3) strongly increases the indirect activation of the NO cGMP pathway by high affinity AMPA receptors, likely due to increased entry of Na(+) through GluR2-lacking AMPA receptors and NMDA receptors activation; (4) reduces the indirect activation of the NO-cGMP pathway by low affinity AMPA receptors, likely due to reduced activation of NMDA receptors. PMID- 22521774 TI - Ethyl pyruvate-mediated Nrf2 activation and hemeoxygenase 1 induction in astrocytes confer protective effects via autocrine and paracrine mechanisms. AB - Ethyl pyruvate (EP), a simple ester of pyruvic acid, has been shown to act as an anti-inflammatory molecule under various pathological conditions, such as, during cerebral ischemia and sepsis in animal models. Here, the authors investigated the novel molecular mechanism underlying the anti-oxidative effect of EP in primary astrocyte cultures, particularly with respect to nuclear factor E2-related factor 2 (Nrf2) activation and hemeoxygenase 1 (HO-1) induction. EP was found to induce Nrf2 translocation and the inductions of various genes downstream of Nrf2 and these resulted in the amelioration of the oxidative damage of H(2)O(2). Furthermore, EP dose-dependently suppressed H(2)O(2)-induced astrocyte cell death (12h preincubation with 5mM EP increased cell survival after 1h exposure to 100 MUM H(2)O(2) from 32.6+/-0.7% to 63+/-1.8%). HO-1 was markedly induced (4.9-fold) in EP-treated primary astrocyte cultures and Nrf2 was found to translocate from the cytosol to the nucleus and bind to the antioxidant response element (ARE) located on HO-1 promoter after EP treatment. siRNA-mediated HO-1 or Nrf2 knockdown and zinc protoporphyrin (ZnPP)-mediated inhibition of HO-1 activity showed that Nrf2 activation and HO-1 induction were responsible for the observed cytoprotective effect of EP, which was found to involve the ERK and Akt signaling pathways. Furthermore, EP-conditioned astrocyte culture media was found to have neuroprotective effects on primary neuronal cultures exposed to oxidative or excitotoxic stress, and this seemed to be mediated by glial cell line-derived neurotrophic factor (GDNF) and glutathione (GSH), which accumulated in EP-treated astrocyte culture media. Interestingly, we also found that in addition to HO-1, EP-induced Nrf2 activation increased the expressions of various anti-oxidant genes, including GST, NQO1, and GCLM. The study shows that EP-mediated Nrf2 activation and HO-1 induction in astrocytes act via autocrine and paracrine mechanisms to confer protective effects. PMID- 22521776 TI - Imaging in infections of the left iliac fossa. AB - The main organs in the left iliac fossa are the descending colon, sigmoid colon and, in women, internal reproductive organs. An infection of the left iliac fossa must lead the clinician firstly to suspect diverticulitis of the sigmoid colon in older patients and salpingitis in women of childbearing age. Other less common aetiologies are possible (inflammatory or infectious colitis, epiploic appendagitis, abscess of the psoas, pyelonephritis, renal abscess, etc.). Sonography as a first-line investigation may lead to diagnosis (especially in gynaecological disease), but a CT scan with intravenous injection of an iodine containing contrast medium will allow for a full assessment of disease spread, and complications of sigmoid colitis or its differential diagnoses (abscess, fistula, perforation) to be investigated. It can also be used to guide percutaneous drainage or fine-needle aspiration for microbiology investigations. PMID- 22521777 TI - Imaging orthopedic implant infections. AB - The diagnosis of infections associated with orthopedic implants is based on a combination of clinical signs, laboratory findings and imaging studies. There is no gold standard imaging technique: conventional radiography is indispensable, although 50% of the time the radiograph is normal. Computed tomography (CT), magnetic resonance imaging (MRI) and ultrasonography are valuable to detect soft tissue abnormalities. Bone scintigraphy (BS) rules out active infection. For infections involving the peripheral skeleton, labeled white blood cell (WBC) scintigraphy coupled with colloid scintigraphy is the reference technique, whereas a gallium scan is always necessary for imaging the spine or pelvis. To confirm or rule out infection, needle aspiration with analysis of aspirated fluid is the cornerstone of the diagnostic algorithm. PMID- 22521778 TI - Repeated dengue shock syndrome and 'dengue myocarditis' responding dramatically to a single dose of methyl prednisolone. AB - The place of steroids in the management of severe forms of dengue is unclear. A retrospective observational study showed the benefits of a single dose of intravenous methyl prednisolone in a highly selected group of patients who developed severe dengue during the febrile phase of infection. We report the case of a 14-year-old boy with dengue who developed three episodes of severe hemodynamic compromise while having high fever, 'myocarditis', third space fluid accumulation, progressive reduction in urine output, and altered mentation, who made a dramatic recovery following a single dose of intravenous methyl prednisolone. Results justify a well powered randomized controlled trial to evaluate the efficacy of this treatment in severe dengue. PMID- 22521779 TI - Clinical characteristics of influenza A H1N1 versus other influenza-like illnesses amongst outpatients attending a university health center in Oman. AB - OBJECTIVES: To identify the clinical characteristics of outpatients with flu-like illnesses stratified by influenza A H1N1 status. METHODS: The study was conducted at the H1N1 staff clinic of Sultan Qaboos University Hospital in Muscat, Oman. The population consisted of university students and university/hospital staff and their family members. All adult patients who presented to the H1N1 clinic with an influenza-like illness over a 4-month period (from August until the end of November 2009) were included. Real-time reverse transcriptase (rRT) PCR was used for the diagnosis of H1N1 influenza. Demographic data, clinical signs and symptoms, history of exposure to H1N1, history of recent travel, and co-morbid conditions were documented. Analyses were conducted using univariate and multivariate statistical techniques. RESULTS: Out of the 2318 patients identified, 27% (n=616) were positive for H1N1 influenza. The mean temperature in the H1N1-positive group was significantly higher than in the negative group (38.3 degrees C vs. 37.2 degrees C; p<0.001). Proportions of patients who reported cough, sore throat, headache, myalgia, gastrointestinal symptoms, exposure to a confirmed case of H1N1, and a history of travel were significantly higher in the H1N1-positive group as compared to the swab-negative group. However, the multivariable logistic model identified only the following significant predictor variables of H1N1 infection: younger age, fever (>= 37.8 degrees C), sore throat, myalgia, diarrhea, and exposure to a confirmed H1N1 case within the last 7 days. CONCLUSIONS: This study provides useful data on the clinical characteristics of H1N1 influenza in a large outpatient population from the Middle East. Patients who tested positive for H1N1 were more likely to have fever, sore throat, diarrhea, and myalgia compared to those with other influenza like illnesses. PMID- 22521780 TI - Empower U: effectiveness of an adolescent outreach and prevention program with sixth-grade boys and girls: a pilot study. AB - Sixth graders are at a prime age to modify behaviors and beliefs regarding exercise, nutrition, body image, and smoking. Empower U was created to change knowledge, beliefs, and behaviors regarding these topics. This pilot study utilized pre/post assessments of 58 sixth graders from a private middle school in the midsouth. Results showed a significant increase in self-esteem as well as in exercise and nutrition knowledge and beliefs at posttest and a significant increase in body image as well as in self-reported exercise and nutrition behaviors at the 1-month follow-up. Empower U provides nurses with an effective educational program that may be useful in positively impacting health behaviors. PMID- 22521781 TI - World Health Organization-European Organization for Research and Treatment of Cancer classification of cutaneous lymphoma in Korea: a retrospective study at a single tertiary institution. AB - BACKGROUND: The relative frequency and the clinicopathological characteristics of lymphoma may vary according to geography and ethnicity. Data are limited regarding the features of cutaneous lymphoma (CL) presented according to the World Health Organization (WHO) and the European Organization for Research and Treatment of Cancer (EORTC) classification (2005) in Korea. OBJECTIVE: The study determined the relative frequency of CL in Korea and presented the clinical relevance of CL based on the WHO-EORTC classification. METHODS: We reclassified the cases of CL collected over a 16-year period in a tertiary institution-based dermatologic setting in Korea. RESULTS: In all, 164 cases were divided into 96 primary and 68 secondary CL. The group of primary CL consisted of T- and natural killer-cell lymphomas (84.3%), B-cell lymphomas (13.5%), and immature hematopoietic malignancies (2%). The Korean population presented with a higher rate of T-cell and natural killer-/T-cell CL and a lower rate of cutaneous B-cell lymphoma than Western countries. Compared with 2003 Korean data, the rate of mycosis fungoides was lower and the rate of nasal and nasal-type natural killer /T-cell lymphomas was higher. LIMITATIONS: This study was retrospective and based on a single-center experience. CONCLUSION: As the relative frequency of lymphomas differs widely with geography and ethnicity, there is a need to collect more data to describe the epidemiologic characteristics in the Far East. PMID- 22521782 TI - Effect of hormone implantation on cryopreservation of Atlantic halibut (Hippoglossus hippoglossus L.) sperm. AB - Hormone implantation is widely applied in halibut (Hippoglossus hippoglossus L.) aquaculture to extend the sperm production season of broodstock males. The ability to combine this technique with cryopreservation would increase sperm availability, thereby improving reproduction success and facilitating gene management. In this paper, the cryopreservation ability of sperm from hormone treated males was examined at three times post-implantation and compared with that of sperm from males that were not hormone-treated. All sperm samples were cryopreserved using the same method. The effectiveness of these techniques was assessed by examining the fertilization rate and motility of thawed sperm. The spermotocrit and concentration of fresh sperm samples were measured to reveal the effect of hormone implantation on sperm characteristics. The reported results indicate that hormone implantation did not affect cryopreservation efficiency. The fertilization rate resulting from thawed sperm of hormone-treated males showed no significant difference from that of untreated males or from fresh sperm. A significant positive relationship was demonstrated between the spermatocrit and concentration of sperm; and a significant decrease of spermatocrit was found in sperm collected from hormone-treated males 14days post implantation. No significant linear relationship between spermotocrit and fertilization rate of thawed sperm was shown. PMID- 22521783 TI - Effect of transcatheter renal arterial embolization combined with cryoablation on regulatory CD4+CD25+ T lymphocytes in the peripheral blood of patients with advanced renal carcinoma. AB - OBJECTIVE: To analyze the effect of Argon-Helium cryosurgery (AHCS) combined with transcatheter renal arterial embolization (TRAE) on the differentiation of regulatory CD4+ CD25+ T cell (Treg) and its implication in patients with renal carcinoma. METHODS: Seventy seven patients are included in the study, and divided into two groups: TRAE group (n=45, receiving TRAE only) and TRAE+cryoablation group (n=32, receiving cryoablation 2-3 weeks after TRAE). The percentage of Treg cells and T lymphocyte subsets (CD4+T, CD8+T, and CD4+T/CD8+T) in the peripheral blood is measured by flow cytometry previous to the therapy and 3 months after therapy. Meanwhile, the extent of tumor necrosis is measured by MRI or CT 1 month after therapy. RESULTS: The percentages of Treg cells of patients in TRAE + cryoablation group decrease from (6.65+/-1.22)% to (3.93+/-1.16)%, (t=42.768, P<0.01), and the percentages of CD4+T and CD4+T/CD8+T increase significantly (P<0.01). However, the results of patients in TRAE group show that the percentages of Treg, CD4+T, CD8+T and CD4+T/CD8+T increase slightly although the differences had no statistical significance (P>0.05). The tumor necrosis rate of TRAE+cryoablation group is 57.5%, significantly higher than those of TRAE group, which shows 31.6% (t=6.784, P<0.01). The median survival duration of the TRAE+cryoablation group is 20 months, significantly longer than that of the TRAE group (chi2 = 7.368, P<0.01). The decreasing extent of Treg cells is correlated with tumor necrosis rates (r=0.90, P<0.01) and life time (r=0.67, P<0.01). CONCLUSION: The therapy of TRAE combined with cryoablation contributes to reduce the percentage of Treg cells and improve the immune situation of patients with renal cell carcinoma, which consequently increase tumor necrosis rate and prolong the patients' survival duration. PMID- 22521784 TI - Spatiotemporal regulation of Ipl1/Aurora activity by direct Cdk1 phosphorylation. AB - Oscillating cyclin-dependent kinase 1 (Cdk1) activity is the major regulator of cell-cycle progression, whereas the Aurora B kinase, as part of the chromosome passenger complex (CPC), controls critical aspects of mitosis such as chromosome condensation and biorientation on the spindle. How these kinases mechanistically coordinate their important functions is only partially understood. Here, using budding yeast, we identify a regulatory mechanism by which the Cdk1 kinase Cdc28 directly controls the Aurora kinase Ipl1. We show that Cdk1 phosphorylates Ipl1 on two serine residues in the N-terminal domain, thereby suppressing its association with the microtubule plus-end tracking protein Bim1 until the onset of anaphase. Failure to phosphorylate Ipl1 leads to its premature targeting to the metaphase spindle and results in constitutive Bim1 phosphorylation, which is normally restricted to anaphase. Cells expressing an Ipl1-Sli15 complex that cannot be phosphorylated by Cdk1 display a severe growth defect. Our work shows that Ipl1/Aurora is not only the catalytic subunit of the CPC but also an important regulatory target that allows Cdk1 to coordinate chromosome biorientation with spindle morphogenesis. PMID- 22521785 TI - How navigational guidance systems are combined in a desert ant. AB - Animals use information from multiple sources in order to navigate between goals. Ants such as Cataglyphis fortis use an odometer and a sun-based compass to provide input for path integration (PI). They also use configurations of visual features to learn both goal locations and habitual routes to the goals. Information is not combined into a unified representation but appears to be exploited by separate expert guidance systems. Visual and PI goal memories are acquired rapidly and provide the consistency for route memories to be formed. Do established route memories then suppress the guidance from PI? A series of manipulations putting PI and route memories into varying levels of conflict found that ants follow compromise trajectories. The guidance systems are therefore active together and share the control of behavior. Route memories do not suppress the other guidance systems. A simple model shows that observed patterns of control could arise from a superposition of the output commands from the guidance systems, potentially approximating Bayesian inference. These results help show how an insect's relatively simple decision-making can produce navigation that is reliable and efficient and that also adapts to changing demands. PMID- 22521786 TI - Phosphodependent recruitment of Bub1 and Bub3 to Spc7/KNL1 by Mph1 kinase maintains the spindle checkpoint. AB - The spindle assembly checkpoint (SAC) is the major surveillance system that ensures that sister chromatids do not separate until all chromosomes are correctly bioriented during mitosis. Components of the checkpoint include Mad1, Mad2, Mad3 (BubR1), Bub3, and the kinases Bub1, Mph1 (Mps1), and Aurora B. Checkpoint proteins are recruited to kinetochores when individual kinetochores are not bound to spindle microtubules or not under tension. Kinetochore association of Mad2 causes it to undergo a conformational change, which promotes its association to Mad3 and Cdc20 to form the mitotic checkpoint complex (MCC). The MCC inhibits the anaphase-promoting complex/cyclosome (APC/C) until the checkpoint is satisfied. SAC silencing derepresses Cdc20-APC/C activity. This triggers the polyubiquitination of securin and cyclin, which promotes the dissolution of sister chromatid cohesion and mitotic progression. We, and others, recently showed that association of PP1 to the Spc7/Spc105/KNL1 family of kinetochore proteins is necessary to stabilize microtubule-kinetochore attachments and silence the SAC. We now report that phosphorylation of the conserved MELT motifs in Spc7 by Mph1 (Mps1) recruits Bub1 and Bub3 to the kinetochore and that this is required to maintain the SAC signal. PMID- 22521788 TI - Long-term memory for affiliates in ravens. AB - Complex social life requires individuals to recognize and remember group members and, within those, to distinguish affiliates from nonaffiliates. Whereas long term individual recognition has been demonstrated in some nonhuman animals, memory for the relationship valence to former group members has received little attention. Here we show that adult, pair-housed ravens not only respond differently to the playback of calls from previous group members and unfamiliar conspecifics but also discriminate between familiar birds according to the relationship valence they had to those subjects up to three years ago as subadult nonbreeders. The birds' distinction between familiar and unfamiliar individuals is reflected mainly in the number of calls, whereas their differentiation according to relationship valence is reflected in call modulation only. As compared to their response to affiliates, ravens responded to nonaffiliates by increasing chaotic parts of the vocalization and lowering formant spacing, potentially exaggerating the perceived impression of body size. Our findings indicate that ravens remember relationship qualities to former group members even after long periods of separation, confirming that their sophisticated social knowledge as nonbreeders is maintained into the territorial breeding stage. PMID- 22521787 TI - Phosphoregulation of Spc105 by Mps1 and PP1 regulates Bub1 localization to kinetochores. AB - Kinetochores are the macromolecular complexes that interact with microtubules to mediate chromosome segregation. Accurate segregation requires that kinetochores make bioriented attachments to microtubules from opposite poles. Attachments between kinetochores and microtubules are monitored by the spindle checkpoint, a surveillance system that prevents anaphase until every pair of chromosomes makes proper bioriented attachments. Checkpoint activity is correlated with the recruitment of checkpoint proteins to the kinetochore. Mps1 is a conserved protein kinase that regulates segregation and the spindle checkpoint, but few of the targets that mediate its functions have been identified. Here, we show that Mps1 is the major kinase activity that copurifies with budding yeast kinetochore particles and identify the conserved Spc105/KNL-1/blinkin kinetochore protein as a substrate. Phosphorylation of conserved MELT motifs within Spc105 recruits the Bub1 protein to kinetochores, and this is reversed by protein phosphatase I (PP1). Spc105 mutants lacking Mps1 phosphorylation sites are defective in the spindle checkpoint and exhibit growth defects. Together, these data identify Spc105 as a key target of the Mps1 kinase and show that the opposing activities of Mps1 and PP1 regulate the kinetochore localization of the Bub1 protein. PMID- 22521789 TI - A novel mode of colony formation in a hydrozoan through fusion of sexually generated individuals. AB - Coloniality, as displayed by most hydrozoans, is thought to confer a size advantage in substrate-limited benthic marine environments and affects nearly every aspect of a species' ecology and evolution. Hydrozoan colonies normally develop through asexual budding of polyps that remain interconnected by continuous epithelia. The clade Aplanulata is unique in that it comprises mostly solitary species, including the model organism Hydra, with only a few colonial species. We reconstruct a multigene phylogeny to trace the evolution of coloniality in Aplanulata, revealing that the ancestor of Aplanulata was solitary and that coloniality was regained in the genus Ectopleura. Examination of Ectopleura larynx development reveals a unique type of colony formation never before described in Hydrozoa, in that colonies form through sexual reproduction followed by epithelial fusion of offspring polyps to adults. We characterize the expression of manacle, a gene involved in foot development in Hydra, to determine polyp-colony boundaries. Our results suggest that stalks beneath the neck do not have polyp identity and instead are specialized structures that interconnect polyps. Epithelial fusion, brooding behavior, and the presence of a skeleton were all key factors behind the evolution of this novel pathway to coloniality in Ectopleura. PMID- 22521790 TI - Ca2+ pulses control local cycles of lamellipodia retraction and adhesion along the front of migrating cells. AB - Ca(2+) signals regulate polarization, speed, and turning of migrating cells. However, the molecular mechanism by which Ca(2+) acts on moving cells is not understood. Here we show that local Ca(2+) pulses along the front of migrating human endothelial cells trigger cycles of retraction of local lamellipodia and, concomitantly, strengthen local adhesion to the extracellular matrix. These Ca(2+) release pulses had small amplitudes and diameters and were triggered repetitively near the leading plasma membrane with only little coordination between different regions. We show that each Ca(2+) pulse triggers contraction of actin filaments by activating myosin light-chain kinase and myosin II behind the leading edge. The cyclic force generated by myosin II operates locally, causing a partial retraction of the nearby protruding lamellipodia membrane and a strengthening of paxillin-based focal adhesion within the same lamellipodia. Photo release of Ca(2+) demonstrated a direct role of Ca(2+) in triggering local retraction and adhesion. Together, our study suggests that spatial sensing, forward movement, turning, and chemotaxis are in part controlled by confined Ca(2+) pulses that promote local lamellipodia retraction and adhesion cycles along the leading edge of moving cells. PMID- 22521792 TI - Sex determination from os sacrum by postmortem CT. AB - Sex determination in forensic practice is performed mostly on sexually dimorphic bones, including pelvic bones such as the os sacrum. Postmortem CT scan provides an easy and fast method for depicting and measuring bone structures prior to elaborate autopsy preparations. To develop a simple and objective method for sex determination in postmortem CT, metric data were evaluated from CT images of the pelvic-associated os sacrum of 95 corpses (49 men and 46 women) from the Canton of Bern, Switzerland. Discriminant function analysis of the data showed that the best accuracy in determining sex was 76.8% and 78.9% with two different observers. It is concluded that measuring the os sacrumin postmortem CT for sex determination has moderate accuracy and should only be applied in combination with other methods. PMID- 22521791 TI - Enhanced nitrite reductase activity associated with the haptoglobin complexed hemoglobin dimer: functional and antioxidative implications. AB - The presence of acellular hemoglobin (Hb) within the circulation is generally viewed as a pathological state that can result in toxic consequences. Haptoglobin (Hp), a globular protein found in the plasma, binds with high avidity the alphabeta dimers derived from the dissociation of Hb tetramer and thus helps clear free Hb. More recently there have been compelling indications that the redox properties of the Hp bound dimer (Hb-Hp) may play a more active role in controlling toxicity by limiting the potential tissue damage caused by propagation of the free-radicals generated within the heme containing globin chains. The present study further examines the potential protective effect of Hp through its impact on the production of nitric oxide (NO) from nitrite through nitrite reductase activity of the Hp bound alphabeta Hb dimer. The presented results show that the Hb dimer in the Hb-Hp complex has oxygen binding, CO recombination and spectroscopic properties consistent with an Hb species having properties similar to but not exactly the same as the R quaternary state of the Hb tetramer. Consistent with these observations is the finding that the initial nitrite reductase rate for Hb-Hp is approximately ten times that of HbA under the same conditions. These results in conjunction with the earlier redox properties of the Hb-Hp are discussed in terms of limiting the pathophysiological consequences of acellular Hb in the circulation. PMID- 22521793 TI - Review on Labisia pumila (Kacip Fatimah): bioactive phytochemicals and skin collagen synthesis promoting herb. AB - Labisia pumila is a traditional herb widely used as post-partum medication for centuries. Recently, extensive researches have been carried out on the phytochemical identification, biological and toxicological studies for the herb. Phytochemicals found in the herbal extract showed high antioxidant properties, which were essential for various pharmacological activities. The significant findings are anti-estrogenic deficiency and -immunodeficiency diseases. Another finding that has considerable impact on natural product research is the contribution of L. pumila in promoting skin collagen synthesis. The performance of the herb as anti-aging agent due to natural aging process and accelerated by UV radiation was reviewed critically. PMID- 22521795 TI - Modeling volatilization of residual VOCs in unsaturated zones: a moving boundary problem. AB - It is of practical interest to investigate the natural evaporation of volatile organic compounds (VOCs) after the removal of a leaking tank situated on the top of the soil. This study aims to develop a mathematical model to predict mole fraction distributions and migration of evaporation front for two VOCs emanating from residual non-aqueous phase liquid (NAPL) due to the leak from the tank in a homogeneous soil. Considering the location of the front and the regions above and below the front, a numerical model for the diffusive transport of VOCs in unsaturated soils was developed using the finite difference method with a moving grid approach. The model was further simplified to the case of single VOC and solved analytically by Boltzmann's transformation with a moving boundary. Analytical expressions for the depth and moving speed of the front for a single VOC were then obtained for practical use. Finally, the developed model was used to predict the concentration distributions of VOCs below the land surface and examine the factors affecting the location and moving speed of the evaporation front. PMID- 22521796 TI - Mechanism of the reduction of hexavalent chromium by organo-montmorillonite supported iron nanoparticles. AB - Iron nanoparticles exhibit greater reactivity than micro-sized Fe(0), and they impart advantages for groundwater remediation. In this paper, supported iron nanoparticles were synthesized to further enhance the speed and efficiency of remediation. Natural montmorillonite and organo-montmorillonite were chosen as supporting materials. The capacity of supported iron nanoparticles was evaluated, compared to unsupported iron nanoparticles, for the reduction of aqueous Cr(VI). The reduction of Cr(VI) was much greater with organo-montmorillonite supported iron nanoparticles and fitted the pseudo-second order equation better. With a dose at 0.47 g/L, a total removal capacity of 106 mg Cr/g Fe(0) was obtained. Other factors that affect the efficiency of Cr(VI) removal, such as pH values, the initial Cr(VI) concentration and storage time of nanoparticles were investigated. X-ray photoelectron spectrometry (XPS) and X-ray absorption near edge structure (XANES) were used to figure out the mechanism of the removal of Cr(VI). XPS indicated that the Cr(VI) bound to the particle surface was completely reduced to Cr(III) under a range of conditions. XANES confirmed that the Cr(VI) reacted with iron nanoparticles was completely reduced to Cr(III). PMID- 22521797 TI - Hexavalent chromium reduction in a sulfur reducing packed-bed bioreactor. AB - The most commonly used approach for the detoxification of hazardous industrial effluents and wastewaters containing Cr(VI) is its reduction to the much less toxic and immobile form of Cr(III). This study investigates the cleanup of Cr(VI) containing wastewaters using elemental sulfur as electron acceptor, for the production of hydrogen sulfide that induces Cr(VI) reduction. An elemental sulfur reducing packed-bed bioreactor was operated at 28-30 degrees C for more than 250 days under varying influent Cr(VI) concentrations (5.0-50.0 mg/L) and hydraulic retention times (HRTs, 0.36-1.0 day). Ethanol or acetate (1000 mg/L COD) was used as carbon source and electron donor. The degree of COD oxidation varied between 30% and 85%, depending on the operating conditions and the type of organic carbon source. The oxidation of organic matter was coupled with the production of hydrogen sulfide, which reached a maximum concentration of 750 mg/L. The biologically produced hydrogen sulfide reduced Cr(VI) chemically to Cr(III) that precipitated in the reactor. Reduction of Cr(VI) and removal efficiency of total chromium always exceeded 97% and 85%, respectively, implying that the reduced chromium was retained in the bioreactor. This study showed that sulfur can be used as an electron acceptor to produce hydrogen sulfide that induces efficient reduction and immobilization of Cr(VI), thus enabling decontamination of Cr(VI) polluted wastewaters. PMID- 22521798 TI - Neonatal hippocampal lesion alters the functional maturation of the prefrontal cortex and the early cognitive development in pre-juvenile rats. AB - Mnemonic and executive performance is encoded into activity patterns of complex neuronal networks. Lesion studies revealed that adult recognition memory critically depends on the activation of the prefrontal cortex (PFC) and hippocampus (HP). However, its developmental profile remains poorly elucidated. We previously showed the rat PFC and HP are functionally coupled in theta- and gamma-band oscillations during neonatal [postnatal day (P) 5-8] and pre-juvenile (P10-15) stages of development. Here, we assess the behavioral readout of this early prefrontal-hippocampal activation by investigating the ontogeny and the mechanisms of novelty detection and recognition memory in relationship to the functional integrity of the PFC and HP. Excitotoxic lesion of the HP at birth led to abnormal oscillatory entrainment of the PFC throughout neonatal and pre juvenile development. Although the onset of novelty detection correlated rather with the maturation of sensory perception and motor skills than with hippocampal integrity, the pre-juvenile performance in item, spatial and temporal order recognition memory significantly decreased after HP lesion at birth. This poorer performance does result neither from abnormal developmental milestones and locomotion nor from increased anxiety. Thus, novelty recognition in rat emerges during the second postnatal week and requires functional integrity of communication within neuronal networks including the PFC and HP. PMID- 22521794 TI - Roles for the ubiquitin-proteasome pathway in protein quality control and signaling in the retina: implications in the pathogenesis of age-related macular degeneration. AB - The accumulation of damaged or postsynthetically modified proteins and dysregulation of inflammatory responses and angiogenesis in the retina/RPE are thought be etiologically related to formation of drusen and choroidal neovascularization (CNV), hallmarks of age-related macular degeneration (AMD). The ubiquitin-proteasome pathway (UPP) plays crucial roles in protein quality control, cell cycle control and signal transduction. Selective degradation of aberrant proteins by the UPP is essential for timely removal of potentially cytotoxic damaged or otherwise abnormal proteins. Proper function of the UPP is thought to be required for cellular function. In contrast, age--or stress induced -impairment the UPP or insufficient UPP capacity may contribute to the accumulation of abnormal proteins, cytotoxicity in the retina, and AMD. Crucial roles for the UPP in eye development, regulation of signal transduction, and antioxidant responses are also established. Insufficient UPP capacity in retina and RPE can result in dysregulation of signal transduction, abnormal inflammatory responses and CNV. There are also interactions between the UPP and lysosomal proteolytic pathways (LPPs). Means that modulate the proteolytic capacity are making their way into new generation of pharmacotherapies for delaying age related diseases and may augment the benefits of adequate nutrition, with regard to diminishing the burden of AMD. PMID- 22521801 TI - Quality and readability of online patient information for abdominal aortic aneurysms. AB - OBJECTIVE: We assessed the quality and readability of patient information for abdominal aortic aneurysms (AAAs) on the World Wide Web, as accessed from the United Kingdom. METHODS: Web sites returned by a simple Web search using the three largest search engines by market share were objectively and subjectively assessed for quality and readability. The Internet search engines Google, Yahoo!, and Bing were interrogated for the term "abdominal aortic aneurysm" and the first 50 hits screened. Organization type and Health on the Net status were recorded. Each unique site containing AAA information was scored for quality using the University of Michigan Consumer Health Web site Evaluation Checklist by two authors, and readability was calculated using the Flesch Reading Ease (FRE) score. Subjective content assessment was also undertaken. RESULTS: Of 150 hits, 112 were relevant, with 55 unique sites for assessment. Overall, the FRE score was 39 (range, 29-47) and the Michigan score was 36 (range, 25-56), with good interobserver agreement (r(s) = 0.83; P = .01). Michigan and FRE scores were poorly correlated (r(s) = 0.064; P = .6). Sites containing discussion on the merits of endovascular/open repair and the concept of an intervention threshold had the highest Michigan scores (58.5 [50-59.75] vs 28 [13-36.5]; P < .001). Search engine ranking, Health on the Net status, country of origin, and organization type did not affect quality or readability. CONCLUSIONS: The current quality and readability of online patient information for AAAs is poor and requires significant improvement. Clinicians treating patients with AAAs should be aware of the limitations of the online "lay literature." PMID- 22521800 TI - Molecular studies to identify the Fusarium species responsible for HT-2 and T-2 mycotoxins in UK oats. AB - High levels of Fusarium mycotoxins HT-2 and T-2 have been detected in UK oats since surveys started in 2002. Fusarium langsethiae and the closely related species F. sporotrichioides have previously been associated with the contamination of cereals with type A trichothecenes HT-2 and T-2 in Nordic countries. Preliminary microbiological analysis of UK oat samples with high concentrations of HT-2 and T-2 detected and isolated F. langsethiae and F. poae but not the other type A trichothecene producing species F. sporotrichioides, F. sibiricum and F. armeniacum. Two hundred and forty oat flour samples with a known mycotoxin profile were selected from a previous four year study (2002-2005) to cover the full concentration range from below the limit of quantification (<20 MUg/kg) to 9,990 MUg/kg HT-2+T-2 combined. All samples were analysed for the DNA of F. langsethiae, F. poae and F. sporotrichioides based on previously published PCR assays. F. langsethiae was detectable in nearly all samples; F. poae was detected in 90% of samples whereas F. sporotrichioides was not detected in any sample. A real-time PCR assay was developed to quantify F. langsethiae DNA in plant material. The assay could quantify as low as 10(-4)ngF. langsethiae DNA/MUl. Based on this assay and a previously published assay for F. poae, both species were quantified in the oat flour samples with known HT-2+T-2 content. Results showed a good regression (P<0.001, r(2)=0.60) between F. langsethiae DNA and HT-2+T-2 concentration. F. poae DNA concentration was not correlated to HT2+T2 concentration (P=0.448) but was weakly correlated to nivalenol concentration (P<0.001, r(2)=0.09). Multiple regression with F. langsethiae and F. poae DNA as explanatory variates identified that both F. langsethiae and F. poae DNA were highly significant (P<0.001) but F. poae DNA only accounted for an additional 4% of the variance and the estimate was negative, indicating that higher concentrations of F. poae DNA were correlated with slightly lower concentrations of HT2+T2 detected. A stronger regression (P<0.001, r(2)=0.77) between F. langsethiae DNA and HT-2+T-2 was obtained after extraction and quantification of DNA and mycotoxins from individual oat grains. The results from this study provide strong evidence that F. langsethiae is the primary, if not sole, fungus responsible for high HT-2 and T-2 in UK oats. PMID- 22521799 TI - Developmental effects of acute, chronic, and withdrawal from chronic nicotine on fear conditioning. AB - Pre-adolescence and adolescence are developmental periods associated with increased vulnerability for tobacco addiction, and exposure to tobacco during these periods may lead to long-lasting changes in behavioral and neuronal plasticity. The present study examined the short- and long-term effects of nicotine and nicotine withdrawal on fear conditioning in pre-adolescent, adolescent, and adult mice, and potential underlying substrates that may mediate the developmental effects of nicotine, such as changes in nicotinic acetylcholine receptor (nAChR) binding, CREB expression, and nicotine metabolism. Age-related differences existed in sensitivity to the effects of acute nicotine, chronic nicotine and nicotine withdrawal on contextual fear conditioning (no changes in cued fear conditioning were seen); younger mice were more sensitive to the acute effects and less sensitive to the effects of nicotine withdrawal 24 h post treatment cessation. Developmental differences in nAChR binding were associated with the effects of nicotine withdrawal on contextual learning. Developmental differences in nicotine metabolism and CREB expression were also observed, but were not related to the effects of nicotine withdrawal on contextual learning 24 h post treatment. Chronic nicotine exposure during pre-adolescence or adolescence, however, produced long-lasting impairments in contextual learning that were observed during adulthood, whereas adult chronic nicotine exposure did not. These developmental effects could be related to changes in CREB. Overall, there is a developmental shift in the effects of nicotine on hippocampus dependent learning and developmental exposure to nicotine results in adult cognitive deficits; these changes in cognition may play an important role in the development and maintenance of nicotine addiction. PMID- 22521803 TI - Durability of saphenous vein grafts: 44-year follow-up of a saphenous vein interposition graft in a pediatric patient. AB - We report the 44-year follow-up of a 9-year-old girl who underwent a saphenous vein interposition graft in 1964 after suffering extensive pelvic trauma with complete disruption of the right common femoral artery. The patient recovered from this injury and experienced no disability or pain until 2008, when she suddenly developed numbness in the right leg. Evaluation at that time showed a new occlusion of the saphenous vein graft, and she underwent uneventful repeat revascularization with autogenous vein. To our knowledge, this 44-year patency is the longest reported for a saphenous vein graft. PMID- 22521802 TI - Transforming growth factor-beta increases vascular smooth muscle cell proliferation through the Smad3 and extracellular signal-regulated kinase mitogen activated protein kinases pathways. AB - INTRODUCTION: We have previously demonstrated that transforming growth factor beta (TGF-beta) in the presence of elevated levels of Smad3, its primary signaling protein, stimulates rat vascular smooth muscle cell (VSMC) proliferation and intimal hyperplasia. The mechanism is partly through the nuclear exportation of phosphorylated cyclin-dependent kinase inhibitor p27. The objective of this study is to clarify the downstream pathways through which Smad3 produces its proliferative effect. Specifically, we evaluated the role of extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) in TGF-beta-induced VSMC proliferation. METHODS: Cultured rat aortic VSMCs were incubated with TGF-beta at varying concentrations and times, and phosphorylated ERK was measured by Western blotting. Smad3 was enhanced in VSMCs using an adenovirus expressing Smad3 or inhibited with small interfering RNA (siRNA). For in vivo experiments, male Sprague-Dawley rats underwent carotid balloon injury, followed by intraluminal infection with an adenovirus expressing Smad3. Arteries were harvested at 3 days and subjected to immunohistochemistry for Smad3, phospho-ERK MAPK, and proliferating cell nuclear antigen. RESULTS: In cultured VSMCs, TGF-beta induced activation and phosphorylation of ERK MAPK in a time-dependent and concentration-dependent manner. Overexpression of the signaling protein Smad3 enhanced TGF-beta-induced activation of ERK MAPK, whereas inhibition of Smad3 with a siRNA blocked ERK MAPK phosphorylation in response to TGF-beta. These data suggest that Smad3 acts as a signaling intermediate between TGF-beta and ERK MAPK. Inhibition of ERK MAPK activation with PD98059 completely blocked the ability of TGF-beta/Smad3 to stimulate VSMC proliferation, demonstrating the importance of ERK MAPK in this pathway. Immunoprecipitation of phospho-ERK MAPK and blotting with Smad3 revealed a physical association, suggesting that activation of ERK MAPK by Smad3 requires a direct interaction. In an in vivo rat carotid injury model, overexpression of Smad3 resulted in an increase in phosphorylated ERK MAPK as well as increased VSMC proliferation as measured by proliferating cell nuclear antigen. CONCLUSIONS: Our findings demonstrate a mechanism through which TGF-beta stimulates VSMC proliferation. Although TGF-beta has been traditionally identified as an inhibitor of proliferation, our data suggest that TGF-beta enhances VSMC proliferation through a Smad3/ERK MAPK signaling pathway. These findings at least partly explain the mechanism by which TGF-beta enhances intimal hyperplasia. Knowledge of this pathway provides potential novel targets that may be used to prevent restenosis. PMID- 22521804 TI - Assessment of cerebral venous return by a novel plethysmography method. AB - BACKGROUND: Magnetic resonance imaging and echo color Doppler (ECD) scan techniques do not accurately assess the cerebral venous return. This generated considerable scientific controversy linked with the diagnosis of a vascular syndrome known as chronic cerebrospinal venous insufficiency (CCSVI) characterized by restricted venous outflow from the brain. The purpose of this study was to assess the cerebral venous return in relation to the change in position by means of a novel cervical plethysmography method. METHODS: This was a single-center, cross-sectional, blinded case-control study conducted at the Vascular Diseases Center, University of Ferrara, Italy. The study involved 40 healthy controls (HCs; 18 women and 22 men) with a mean age of 41.5 +/- 14.4 years, and 44 patients with multiple sclerosis (MS; 25 women and 19 men) with a mean age of 41.0 +/- 12.1 years. All participants were previously scanned using ECD sonography, and further subset in HC (CCSVI negative at ECD) and CCSVI groups. Subjects blindly underwent cervical plethysmography, tipping them from the upright (90 degrees ) to supine position (0 degrees ) in a chair. Once the blood volume stabilized, they were returned to the upright position, allowing blood to drain from the neck. We measured venous volume (VV), filling time (FT), filling gradient (FG) required to achieve 90% of VV, residual volume (RV), emptying time (ET), and emptying gradient (EG) required to achieve 90% of emptying volume (EV) where EV = VV - RV, also analyzing the considered parameters by receiver operating characteristic (ROC) curves and principal component mathematical analysis. RESULTS: The rate at which venous blood discharged in the vertical position (EG) was significantly faster in the controls (2.73 mL/second +/- 1.63) compared with the patients with CCSVI (1.73 mL/second +/- 0.94; P = .001). In addition, respectively, in controls and in patients with CCSVI, the following parameters were highly significantly different: FT 5.81 +/- 1.99 seconds vs 4.45 +/- 2.16 seconds (P = .003); FG 0.92 +/- 0.45 mL/second vs 1.50 +/- 0.85 mL/second (P < .001); RV 0.54 +/- 1.31 mL vs 1.37 +/- 1.34 mL (P = .005); ET 1.84 +/- 0.54 seconds vs 2.66 +/- 0.95 seconds (P < .001). Mathematical analysis demonstrated a higher variability of the dynamic process of cerebral venous return in CCSVI. Finally, ROC analysis demonstrated a good sensitivity of the proposed test with a percent concordant 83.8, discordant 16.0, tied 0.2 (C = 0.839). CONCLUSIONS: Cerebral venous return characteristics of the patients with CCSVI were markedly different from those of the controls. In addition, our results suggest that cervical plethysmography has great potential as an inexpensive screening device and as a postoperative monitoring tool. PMID- 22521805 TI - Adherence to medication in adults with attention deficit hyperactivity disorder and pro re nata dosing of psychostimulants: a systematic review. AB - Adherence to a regular medication regimen may be challenging for adults with attention deficit hyperactivity disorder (ADHD). Some report taking psychostimulants on a pro re nata (PRN) basis. This review aims to establish the rate of adherence, and reasons for and consequences of non-adherence to medication for ADHD in adults, and to review literature on PRN dosing of psychostimulants in these patients. A systematic literature search was conducted. Four primary research studies have investigated the rate of adherence to medication in adults with ADHD. Mean adherence rate in two studies ranged from 52% to 87%. A number of possible reasons for poor adherence have been suggested. Prospective studies are needed to further define the rate of adherence and causes of poor adherence. Evidence examining whether differences in adherence affect clinical outcomes is equivocal. Therefore, caution should be applied to the assumption that maximising adherence to regular medication regimens will improve clinical outcomes. Two articles acknowledge that patients take medication on a PRN basis. Studies comparing the effectiveness of a regular and PRN regimen of psychostimulants are needed. If PRN dosing is as effective as a regular regimen, advantages might include enhanced doctor-patient communication, reduced side effects and cost savings. PMID- 22521806 TI - Do benzodiazepines still deserve a major role in the treatment of psychiatric disorders? A critical reappraisal. AB - Discovered in the late 1950s by Leo Sternbach, the first benzodiazepine (BZD) chlordiazepoxide was followed by several congeners, which rapidly constituted one of the largest and most widely prescribed classes of psychotropic compounds. After 50 years, BZDs are still routinely utilized not only in psychiatry but, more generally, in the whole of medicine. Despite their high therapeutic index which makes BZDs safer than other compounds like barbiturates, as well as their rapidity of onset, psychiatrists and family physicians are well aware about the controversy that surrounds the wide use - often not adequately based on scientific evidence - of BZDs in many psychiatric disorders. In this overview of international treatment guidelines, systematic reviews and randomized clinical trials, the aim was to provide a critical appraisal of the current use and role of BZDs in psychiatric disorders and their disadvantages, with specific emphasis on anxiety and affective disorders, sleep disorders, alcohol withdrawal, violent and aggressive behaviours in psychoses, and neuroleptic-induced disorders. In addition, specific emphasis has been given to the extent of usage of BZDs and its appropriateness through the assessment of available international surveys. Finally, the entire spectrum of BZD-related adverse effects including psychomotor effects, use in the elderly, paradoxical reactions, tolerance and rebound, teratologic risk, dependence, withdrawal and abuse issues was examined in detail. PMID- 22521807 TI - Early exposure to ethanol differentially affects ethanol preference at adult age in two inbred mouse strains. AB - Although the acute effects of ethanol exposure on brain development have been extensively studied, the long term consequences of juvenile ethanol intake on behavior at adult age, regarding especially ethanol consumption, are still poorly known. The aim of this study was to analyze the consequences of ethanol ingestion in juvenile C57BL/6J and DBA/2J mice on ethanol intake and neurobiological regulations at adulthood. Mice were given intragastric ethanol at 4 weeks of age under different protocols and their spontaneous ethanol consumption was assessed in a free choice paradigm at adulthood. Both serotonin 5-HT(1A) and cannabinoid CB1 receptors were investigated using [(35)S]GTP-gamma-S binding assay for the juvenile ethanol regimens which modified adult ethanol consumption. In DBA/2J mice, juvenile ethanol ingestion dose-dependently promoted adult spontaneous ethanol consumption. This early ethanol exposure enhanced 5-HT(1A) autoreceptor mediated [(35)S]GTP-gamma-S binding in the dorsal raphe nucleus and reduced CB1 receptor-mediated G protein coupling in both the striatum and the globus pallidus at adult age. In contrast, early ethanol ingestion by C57BL/6J mice transiently lowered spontaneous ethanol consumption and increased G protein coupling of postsynaptic 5-HT(1A) receptors in the hippocampus but had no effect on CB1 receptors at adulthood. These results show that a brief and early exposure to ethanol can induce strain-dependent long-lasting changes in both behavior toward ethanol and key receptors of central 5-HT and CB systems in mice. PMID- 22521808 TI - Association of chronic obstructive pulmonary disease maintenance medication adherence with all-cause hospitalization and spending in a Medicare population. AB - BACKGROUND: Although maintenance medications are a cornerstone of chronic obstructive pulmonary disease (COPD) management, adherence remains suboptimal. Poor medication adherence is implicated in poor outcomes with other chronic conditions; however, little is understood regarding links between adherence and outcomes in COPD patients. OBJECTIVE: This study investigates the association of COPD maintenance medication adherence with hospitalization and health care spending. METHODS: Using the 2006 to 2007 Chronic Condition Warehouse administrative data, this retrospective cross-sectional study included 33,816 Medicare beneficiaries diagnosed with COPD who received at least 2 prescriptions for >=1 COPD maintenance medications. After a 6-month baseline period (January 1, 2006 to June 30, 2006), beneficiaries were followed through to December 31, 2007 or death. Two medication adherence measures were assessed: medication continuity and proportion of days covered (PDC). PDC values ranged from 0 to 1 and were calculated as the number of days with any COPD maintenance medication divided by duration of therapy with these agents. The association of adherence with all cause hospital events and Medicare spending were estimated using negative binomial and gamma generalized linear models, respectively, adjusting for sociodemographics, Social Security disability insurance status, low-income subsidy status, comorbidities, and proxy measures of disease severity. RESULTS: Improved adherence using both measures was significantly associated with reduced rate of all-cause hospitalization and lower Medicare spending. Patients who continued with their medications had lower hospitalization rates (relative rate [RR] = 0.88) and lower Medicare spending (-$3764), compared with patients who discontinued medications. Similarly, patients with PDC >=0.80 exhibited lower hospitalization rates (RR = 0.90) and decreased spending (-$2185), compared with patients with PDC <0.80. CONCLUSIONS: COPD patients with higher adherence to prescribed regimens experienced fewer hospitalizations and lower Medicare costs than those who exhibited lower adherence behaviors. Findings suggested the clinical and economic importance of medication adherence in the management of COPD patients in the Medicare population. PMID- 22521810 TI - Age differential response of Hyalella curvispina to a cadmium pulse: influence of sediment particle size. AB - In Argentina periurban streams frequently receive agricultural, livestock and industrial discharges. Heavy metals have been found in the water column and sediments of numerous water bodies of the pampean region, at levels above the limits established for aquatic life protection. This study aimed to evaluate the effect of a contaminant pulse of cadmium discharged into a water-sediment system of different particle sizes, by means of laboratory tests using juveniles and adults of Hyalella curvispina, a native amphipod. We found that the substrate particle size was a determining factor in the toxicity of cadmium and that the adults of H. curvispina were more sensitive than juveniles. We also observed a temporal difference between the two ages for the same type of sediment. Given the nature of the sediments of regional water bodies, it is expected that a discharge of cadmium, even at concentrations as low as those tested here, will affect the survival of native amphipods. PMID- 22521811 TI - Metal and metalloid levels and bio-accumulation characteristics in soil, sediment, land plants and hippopotami (Hippopotamus amphibius L) from the South Luangwa National Park, Zambia. AB - Hippopotami (Hippopotamus amphibius L) are large semi-aquatic mammals that can be exposed to metals and metalloid from both terrestrial and aquatic environments. Therefore, knowledge of metal and metalloid accumulation characteristics in hippopotami living in the national park is important from ecotoxicological point of view. Levels of toxic metals (Cd, Pb and Hg) and metalloid (As) in hippopotami liver from the South Luangwa National Park in Zambia were far lower compared to the established values of toxic levels in cattle. No temporal variations of metal levels in hippopotami were observed, probably because of good management condition and the lack of anthropogenic activities around the national park. However, hippopotami liver accumulated significantly higher concentrations of Hg compared to soil, sediment and their food (plants), most likely due to a process of biomagnification throughout a trophic chain. Moreover, hippopotami liver and land plants showed significantly higher Cd levels than those of soil. These results strongly suggest that hippopotami liver accumulate higher levels of these metals if surrounding environment is contaminated. Levels of Cr and Ni in hippopotami liver were higher compared to other toxic metals. Since this is the first report to show the Cr and Ni levels and bio-accumulation characteristics of Hg and Cd in hippopotami, we concluded that continuous monitoring and evaluation of toxic effects of these metals on hippopotami should be conducted. PMID- 22521809 TI - Binding of the three-repeat domain of tau to phospholipid membranes induces an aggregated-like state of the protein. AB - In patients with Alzheimer's disease, the microtubule-associated protein tau is found aggregated into paired helical filaments (PHFs) in neurofibrillary deposits. In solution, tau is intrinsically unstructured. However, the tubulin binding domain consisting of three or four 31-32 amino acid repeat regions exhibits both helical and beta-structure propensity and makes up the proteolysis resistant core of PHFs. Here, we studied the structure and dynamics of the three repeat domain of tau (i.e. K19) when bound to membranes consisting of a phosphatidylcholine and phosphatidylserine mixture or phosphatidylserine alone. Tau K19 binds to phospholipid vesicles with submicromolar affinity as measured by fluorescence spectroscopy. The interaction is driven by electrostatic forces between the positively charged protein and the phospholipid head groups. The structure of the membrane-bound state of K19 was studied using CD spectroscopy and solid-state magic-angle spinning NMR spectroscopy. To this end, the protein was selectively (13)C-labeled at all valine and leucine residues. Isotropic chemical shift values of tau K19 were consistent with a beta-structure. In addition, motionally averaged (1)H-(13)C dipolar couplings indicated a high rigidity of the protein backbone. The structure formation of K19 was also shown to depend on the charge density of the membrane. Phosphatidylserine membranes induced a gain in the alpha-helix structure along with an immersion of K19 into the phospholipid bilayer as indicated by a reduction of the lipid chain (2)H NMR order parameter. Our results provide structural insights into the membrane-bound state of tau K19 and support a potential role of phospholipid membranes in mediating the physiological and pathological functions of tau. PMID- 22521812 TI - Predicting multiple ecotoxicological profiles in agrochemical fungicides: a multi species chemoinformatic approach. AB - Agriculture is needed to deal with crop losses caused by biotic stresses like pests. The use of pesticides has played a vital role, contributing to improve crop production and harvest productivity, providing a better crop quality and supply, and consequently contributing with the improvement of the human health. An important group of these pesticides is fungicides. However, the use of these agrochemical fungicides is an important source of contamination, damaging the ecosystems. Several studies have been realized for the assessment of the toxicity in agrochemical fungicides, but the principal limitation is the use of structurally related compounds against usually one indicator species. In order to overcome this problem, we explore the quantitative structure-toxicity relationships (QSTR) in agrochemical fungicides. Here, we developed the first multi-species (ms) chemoinformatic approach for the prediction multiple ecotoxicological profiles of fungicides against 20 indicators species and their classifications in toxic or nontoxic. The ms-QSTR discriminant model was based on substructural descriptors and a heterogeneous database of compounds. The percentages of correct classification were higher than 90% for both, training and prediction series. Also, substructural alerts responsible for the toxicity/no toxicity in fungicides respect all ecotoxicological profiles, were extracted and analyzed. PMID- 22521813 TI - Estrogenic potential of benzotriazole on marine medaka (Oryzias melastigma). AB - This study, for the first time, assessed the reproductive effects of benzotriazoles, widely used industrial chemicals, on marine fish. Marine medakas (Oryzias melastigma) were exposed to 0.01, 0.1, and 1mg/L benzotriazole for periods of four and 35 days. The results that are obtained showed that the expression levels of CYP1A1 were down-regulated in the liver, gills and intestines of both males and females. Vitellogenin (VTG) was highly induced in the liver, gills and intestine of both male and female marine medaka, and CYP19a was up-regulated in the ovaries especially after being exposed for 35 days. Most importantly, the results of the present study suggest that even at environmentally relevant concentrations detected in the aquatic environment, 0.01 mg/L, benzotriazole also caused notable changes in expression levels of VTG, CYP1A1 and CYP19a. More concerns about the toxicity of benzotriazoles on marine animals should be raised. PMID- 22521814 TI - Revisiting the hippocampal-amygdala pathway in primates: association with immature-appearing neurons. AB - Elucidation of the 'fear circuit' has opened exciting avenues for understanding and treating human anxiety disorders. However, the translation of rodent to human studies, and vice versa, depends on understanding the homology in relevant circuits across species. Although abundant evidence indicates that the hippocampal-amygdala circuit mediates contextual fear learning, previous studies indicate that this pathway is more restricted in primates than in rodents. Moreover, cellular components of the amygdala differ across species. The paralaminar nucleus (PL) of the amygdala, a structure that is closely associated with the basal nucleus, is one example, having no clear homologue in rodents. In both human and nonhuman primates, the PL contains a subpopulation of immature appearing neurons, which merge into the corticoamygdaloid transition area (CTA). To understand whether immature-appearing neurons are positioned to participate in fear circuitry, we first mapped the hippocampal-amygdala projection in the monkey. We then determined whether immature-appearing neurons were targets of this path. Retrograde results show that the hippocampal inputs to the amygdala originate in uncal region (CA1') and the rostral prosubiculum, consistent with earlier studies. The amygdalohippocampal area, ventral basal nucleus, the medial paralaminar nucleus, and its confluence with the CTA are the main targets of this projection. Immature neurons are prominent in the PL and CTA, and are overlapped by anterogradely labeled fibers from CA1', particularly in the medial PL and CTA. Hippocampal inputs to the amygdala are more focused in higher primates compared to rodents, supporting previous anatomic studies and recent data from human functional imaging studies of contextual fear. At the cellular level, a hippocampal interaction with immature neurons in the amygdala suggests a novel substrate for cellular plasticity, with implications for mechanisms underlying contextual learning and emotional memory processes. PMID- 22521815 TI - Antidepressant-like effects of low ketamine dose is associated with increased hippocampal AMPA/NMDA receptor density ratio in female Wistar-Kyoto rats. AB - Preclinical as well as limited clinical studies indicate that ketamine, a non competitive glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, may exert a quick and prolonged antidepressant effect. It has been postulated that ketamine action is due to inhibition of NMDA and stimulation of alpha-amino-3-hydroxy-5 methyl-4-isoxazole propionic acid (AMPA) receptors. Here, we sought to determine whether ketamine would exert antidepressant effects in Wistar-Kyoto (WKY) rats, a putative animal model of depression and whether this effect would be associated with changes in AMPA/NMDA receptor densities in the hippocampus. Adult female WKY rats and their control Wistar rats were subjected to acute and chronic ketamine doses and their locomotor activity (LMA) and immobility in the forced swim test (FST) were evaluated. Hippocampal AMPA and NMDA receptor densities were also measured following a chronic ketamine dose. Ketamine, both acutely (0.5-5.0 mg/kg i.p.) and chronically (0.5-2.5 mg/kg daily for 10 days) resulted in a dose dependent and prolonged decrease in immobility in FST in WKY rats only, suggesting an antidepressant-like effect in this model. Chronic treatment with an effective dose of ketamine also resulted in an increase in AMPA/NMDA receptor density ratio in the hippocampus of WKY rats. LMA was not affected by any ketamine treatment in either strain. These results indicate a rapid and lasting antidepressant-like effect of a low ketamine dose in WKY rat model of depression. Moreover, the increase in AMPA/NMDA receptor density in the hippocampus could be a contributory factor to behavioral effects of ketamine. These findings suggest potential therapeutic benefit in simultaneous reduction of central NMDA and elevation of AMPA receptor function in treatment of depression. PMID- 22521817 TI - Relationship between the distribution of the paired-like homeobox gene (Phox2b) expressing cells and blood vessels in the parafacial region of the ventral medulla of neonatal rats. AB - It has been reported that central chemoreceptor cells in the medulla are distributed in close apposition to capillary blood vessels in the medulla. Phox2b expressing neurons in the retrotrapezoid nucleus (RTN) respond to high CO(2)/H(+) stimulation and have been suggested to play an important role in central chemoreception. In newborn rats, the RTN overlaps at least partially with the parafacial respiratory group (pFRG), which consists predominantly of preinspiratory neurons. In the present study, we visualized the blood vessels in the ventral medulla of newborn rats using a neurobiotin method and examined the relationship between the blood vessels and the location of Phox2b-immunoreactive (-ir) neurons. We showed that Phox2b-ir neurons in the parafacial region of the rostral ventral medulla tended to assemble around capillary blood vessels. We also confirmed that pFRG/preinspiratory neurons that were sensitive to hypercapnic stimulation in the presence of tetrodotoxin were Phox2b-ir neurons and were tightly apposed to the blood vessels along the longitudinal axis. Our findings suggested that the location of Phox2b-ir neurons, including preinspiratory neurons of the pFRG, matched their role as sensors of blood CO(2) concentration. PMID- 22521818 TI - Coordination of the head with respect to the trunk and pelvis in the roll and pitch planes during quiet stance. AB - This study examined the relationship between head and trunk sway during quiet stance and compared this relationship with that of the pelvis to the trunk. Sixteen younger and 14 elderly subjects participated, performing four different sensory tasks: standing quietly on a firm or foam support surface, with eyes open or closed. Roll and pitch angular velocities were recorded with six body-worn gyroscopes; a set of two mounted at the upper trunk, an identical set at the hips, and another set on a head band. Angle correlation analysis was performed in three frequency bands: below 0.7 Hz (LP), above 3 Hz (HP) and in between (BP) using the integrated angle velocity signals. Angular velocities were spectrally analysed. Greater head than trunk motion was observed in angle correlations, power spectral density (PSD) ratios, and transfer functions (TFs). Head on trunk motion could be divided for all sensory conditions into a low-frequency (<0.7 Hz) "head locked to trunk" inverted pendulum mode, a mid-frequency (ca. 3 Hz), resonant mode, and a slightly anti-phasic head motion on stabilised trunk, high frequency (>3 Hz) mode. There was coherent motion between head and trunk but not between head and pelvis. Trunk and pelvis data were consistent with previously reported in-phase and anti-phase movements between these segments. Significant age differences were not found. These data indicate that during quiet stance body motion increases in the order of pelvis, trunk, head and quiet stance involves control of at least two separate links: trunk on pelvis and head on trunk dominated by head resonance. The head is locked to the trunk for low-frequency motion possibly because motion is just supra-vestibular threshold. The head is not stabilised in space during stance, rather the pelvis is. PMID- 22521816 TI - Intermittent social defeat stress enhances mesocorticolimbic DeltaFosB/BDNF co expression and persistently activates corticotegmental neurons: implication for vulnerability to psychostimulants. AB - Intermittent social defeat stress exposure augments behavioral response to psychostimulants in a process termed cross-sensitization. Brain-derived neurotrophic factor (BDNF) mediates synaptic plasticity and cellular responses to stress and drugs of abuse. We previously showed that repeated social defeat stress persistently alters BDNF and activates DeltaFosB expression in mesocorticolimbic regions. Here, we hypothesized that social defeat stress would increase DeltaFosB expression in BDNF-containing mesocorticolimbic neurons at a time when cross-sensitization is evident. Because the ventral tegmental area (VTA) is critical for cross-sensitization, we similarly hypothesized that repeated social defeat stress would induce DeltaFosB in neurons of mesocorticolimbic terminal regions that innervate the VTA. We induced social defeat stress in rats by short confrontations with an aggressive resident rat every third day for 10 days. Control rats were handled according to the same schedule. Defeated rats exhibited sensitized locomotor response to amphetamine (1.0mg/kg, i.p.) 10 days after termination of stress exposure. Separate rats, which underwent stress procedures without amphetamine challenge, were used for histological assessments. Rats received intra-VTA infusion of the retrograde tracer, Fluorogold (FG), and brain tissue was collected 10 days after stress or handling for immunohistochemistry. Stress exposure increased BDNF immunoreactivity in anterior cingulate, prelimbic and infralimbic regions of the prefrontal cortex (PFC), medial amygdala (AMY), nucleus accumbens (NAc) and VTA; DeltaFosB labeling in anterior cingulate cortex (ACG) and nucleus accumbens; and DeltaFosB/BDNF co-expression in prelimbic cortex (PL), nucleus accumbens and medial amygdala. Infralimbic DeltaFosB-labeling was enhanced by stress in neurons innervating the VTA. Increased DeltaFosB/BDNF co-expression and persistent functional activation of corticolimbic neurons after stress may contribute to mechanisms underlying cross-sensitization to psychostimulants. PMID- 22521819 TI - Autophagy activation is associated with neuroprotection against apoptosis via a mitochondrial pathway in a rat model of subarachnoid hemorrhage. AB - Autophagy, the bulk intracellular degradation of cytoplasmic constituents, can be a pro-survival or a pro-death mechanism depending on the context. A recent study showed that autophagy was activated in the phase of early brain injury following subarachnoid hemorrhage (SAH). However, whether autophagy activation after SAH is protective or harmful is still elusive. This study was undertaken to determine the potential role of autophagy pathway activation in early brain injury following SAH. The rats were pretreated with intracerebral ventricular infusion of either the autophagy inducer rapamycin (RAP) or inhibitor 3-methyladenine (3 MA) before SAH onset. The results from electron microscopic examinations showed that RAP administration caused the formation of autophagosomal vacuoles, and 3-MA induced neuronal apoptosis. RAP treatment significantly increased the expression of autophagic proteins Atg5 and Beclin 1, the ratio of microtubule-associated protein 1 light chain 3 (LC3)-II to LC3-I and reduced caspase-3 activity, the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL)-positive cells, brain edema and neurological deficits after SAH. Conversely, 3-MA treatment exacerbated early brain injury. RAP treatment significantly increased the expression of the autophagic proteins Atg5 and Beclin 1, the ratio of LC3-II to LC3-I and reduced caspase-3 activity, the number of TUNEL-positive cells, brain edema and neurological deficits after SAH. Conversely, 3-MA treatment reversed these changes and exacerbated early brain injury. To further clarify the mechanism of autophagy protection, we investigated the expression levels of key apoptosis related molecules. The results showed that RAP administration decreased Bax translocation to the mitochondria and downstream cytochrome c release from the mitochondria to the cytosol. Taken together, our study indicates that activation of autophagic pathways reduces early brain injury after SAH. This neuroprotective effect is likely exerted by anti-apoptotic mechanisms. PMID- 22521820 TI - Working memory and the homeostatic control of brain adenosine by adenosine kinase. AB - The neuromodulator adenosine maintains brain homeostasis and regulates complex behaviour via activation of inhibitory and excitatory adenosine receptors (ARs) in a brain region-specific manner. AR antagonists such as caffeine have been shown to ameliorate cognitive impairments in animal disease models but their effects on learning and memory in normal animals are equivocal. An alternative approach to reduce AR activation is to lower the extracellular tone of adenosine, which can be achieved by up-regulating adenosine kinase (ADK), the key enzyme of metabolic adenosine clearance. However, mice that globally over-express an Adk transgene ('Adk-tg' mice) were devoid of a caffeine-like pro-cognitive profile; they instead exhibited severe spatial memory deficits. This may be mechanistically linked to cortical/hippocampal N-methyl-d-aspartate receptor (NMDAR) hypofunction because the motor response to acute MK-801 was also potentiated in Adk-tg mice. Here, we evaluated the extent to which the behavioural phenotypes of Adk-tg mice might be modifiable by up-regulating adenosine levels in the cortex/hippocampus. To this end, we investigated mutant 'fb-Adk-def' mice in which ADK expression was specifically reduced in the telencephalon leading to a selective increase in cortical/hippocampal adenosine, while the rest of the brain remained as adenosine-deficient as in Adk-tg mice. The fb-Adk-def mice showed an even greater impairment in spatial working memory and a more pronounced motor response to NMDAR blockade than Adk-tg mice. These outcomes suggest that maintenance of cortical/hippocampal adenosine homeostasis is essential for effective spatial memory and deviation in either direction is detrimental with increased expression seemingly more disruptive than decreased expression. PMID- 22521821 TI - Matrix metalloproteinase-2 or -9 deletions protect against hemorrhagic transformation during early stage of cerebral ischemia and reperfusion. AB - MMP-9 deficiency protected against photochemical thrombosis-induced brain hemorrhagic transformation (HT), but it did not protect against tissue plasminogen activator-induced brain hemorrhage. The roles of MMP-2 and/or MMP-9 knockout (KO) in mechanical reperfusion induced HT after ischemia have not been investigated. Here we assessed the effects of MMP-2 KO, MMP-9 KO and MMP-2/9 double KO (dKO) in protecting against mechanical reperfusion induced HT and other brain injuries after the early stages of cerebral ischemia in mice of the same genetic background. Middle cerebral artery occlusion (MCAO) was performed in mice. Reperfusion was started at 1 or 1.5h after onset of MCAO. All mice were sacrificed 8h after MCAO. We found that both pro- and active MMP-2 and MMP-9 levels were significantly elevated in the early ischemic brain. After the early stages of ischemia and reperfusion, the hemorrhagic incidence was reduced in the cortex of MMP-2 KO mice (p<0.05 vs. WT). The hemorrhagic volume was significantly decreased in the cortexes of MMP-2 and/or -9 knockout mice (MMP-9 KO vs. WT: p<0.01, MMP-2 KO and dKO vs. WT: p<0.001). In the basal ganglia, MMP-2 KO and MMP 2/9 dKO mice displayed a remarkable decrease in hemorrhagic volume (p<0.01 or 0.05 vs. WT), but MMP-9 KOs did not protect against hemorrhage. MMP-2 and/or -9 knockout mice displayed significantly decreased infarction volume in both the cortex and striatum, in addition to improved neurological function (p<0.001 vs. WT). The results suggested that MMP-2 deficiency and MMP-2 and MMP-9 double deficiency were more protective than MMP-9 deficiency against HT after the early stages of ischemia and reperfusion. These studies increase our understanding of MMP-2 and MMP-9 in HT development and will help to selectively target MMPs to protect the post-ischemic brain from injury and HT. PMID- 22521822 TI - Changes in hippocampal theta rhythm and their correlations with speed during different phases of voluntary wheel running in rats. AB - Hippocampal theta rhythm (4-12 Hz) can be observed during locomotor behavior, but findings on the relationship between locomotion speed and theta frequency are inconsistent if not contradictory. The inconsistency may be because of the difficulties that previous analyses and protocols have had excluding the effects of behavior training. We recorded the first or second voluntary wheel running each day, and assumed that theta frequency and activity are correlated with speed in different running phases. By simultaneously recording electroencephalography, physical activity, and wheel running speed, this experiment explored the theta oscillations during spontaneous running of the 12-h dark period. The recording was completely wireless and allowed the animal to run freely while being recorded in the wheel. Theta frequency and theta power of middle frequency were elevated before running and theta frequency, theta power of middle frequency, physical activity, and running speed maintained persistently high levels during running. The slopes of the theta frequency and theta activity (4-9.5 Hz) during the initial running were different compared to the same values during subsequent running. During the initial running, the running speed was positively correlated with theta frequency and with theta power of middle frequency. Over the 12-h dark period, the running speed did not positively correlate with theta frequency but was significantly correlated with theta power of middle frequency. Thus, theta frequency was associated with running speed only at the initiation of running. Furthermore, theta power of middle frequency was associated with speed and with physical activity during running when chronological order was not taken into consideration. PMID- 22521824 TI - Suppression of Frizzled-2-mediated Wnt/Ca2+ signaling significantly attenuates intracellular calcium accumulation in vitro and in a rat model of traumatic brain injury. AB - Traumatic brain injury (TBI) can dramatically increase levels of intracellular calcium (Ca2+). The association between Wnt5a/Frizzled-2 (wingless-type mouse mammary tumor virus integration site family member 5a/Fzd2) signaling and Ca2+ cellular homeostasis in lower vertebrates has been well documented. However, little is known about Wnt5a/Fzd2 signaling in mammalian nerve cells, or whether Ca2+ accumulation after TBI is mediated through this pathway. We hypothesized that an activated Wnt5a/Fzd2 pathway following TBI may play a role in Ca2+ overloading. To elucidate the influence of Fzd2 and the Wnt5a signal transduction pathway on an increase in intracellular Ca2+, we assessed the expression of Wnt5a/Fzd2 in rat hippocampal cells both in vitro and in vivo. We found that transfection of the rat Fzd2 gene in rat neonatal hippocampal astrocytes significantly increased gene expressions of both Wnt5a and Fzd2 by fourfold when compared to non-transfected cells (P<0.01 in both cases). Expressions of the proteins Wnt5a and Fzd2 were significantly increased approximately two- and threefold, respectively, when compared to non-transfected control cells (P<0.01 in both cases). Moreover, intracellular Ca2+, as manifested by the fluorescent intensity of the intracellular Ca2+ indicator Fluo-3/AM, was significantly increased by 1.75-fold (P<0.01). The blocking of Fzd2 signaling using Stealth RNAi markedly inhibited the elevated gene and protein expression of Wnt5a in the transfected cells by two- and fourfold, respectively (P<0.01), and suppressed intracellular Ca2+ by 1.5-fold (P<0.01). Furthermore, in vivo, we demonstrated that TBI-induced dramatic upregulation of gene and protein expression of Wnt5a/Fzd2 by two- and fivefold (P<0.01) in injured hippocampi, and intracellular Ca2+ increased in isolated injured hippocampal cells. Whereas, the in vivo blocking of Fzd2 signaling by hippocampal delivery of Stealth RNAi and Invivofectamine significantly suppressed the increased gene and protein expression of Wnt5a and Fzd2 induced by TBI by 1- to 3.5-fold (P<0.01) and also inhibited Ca2+ accumulation by 1.5-fold (P<0.01). These findings demonstrated that the Wnt5a/Fzd2 signaling pathway contributed to increasing intracellular Ca2+ in nerve cells under physiological and pathological conditions. Furthermore, our findings provide evidence that specifically expressed components of this signal pathway, such as Wnt5a and Fzd2, are potential therapeutic targets following brain trauma. PMID- 22521823 TI - Developmental shift of short-term synaptic plasticity in cortical organotypic slices. AB - Although short-term synaptic plasticity (STP) is ubiquitous in neocortical synapses its functional role in neural computations is not well understood. Critical to elucidating the function of STP will be to understand how STP itself changes with development and experience. Previous studies have reported developmental changes in STP using acute slices. It is not clear, however, to what extent the changes in STP are a function of local ontogenetic programs or the result of the many different sensory and experience-dependent changes that accompany development in vivo. To address this question we examined the in vitro development of STP in organotypic slices cultured for up to 4 weeks. Paired recordings were performed in L5 pyramidal neurons at different stages of in vitro development. We observed a shift in STP in the form of a decrease in the paired pulse ratio (PPR) (less depression) from the second to fourth week in vitro. This shift in STP was not accompanied by a change in initial excitatory postsynaptic potential (EPSP) amplitude. Fitting STP to a quantitative model indicated that the developmental shift is consistent with presynaptic changes. Importantly, despite the change in the PPR we did not observe changes in the time constant governing STP. Since these experiments were conducted in vitro our results indicate that the shift in STP does not depend on in vivo sensory experience. Although sensory experience may shape STP, we suggest that developmental shifts in STP are at least in part ontogenetically determined. PMID- 22521825 TI - Visual object processing as a function of stimulus energy, retinal eccentricity and Gestalt configuration: a high-density electrical mapping study. AB - To reveal the fundamental processes underlying the different stages of visual object perception, most studies have manipulated relatively complex images, such as photographs, line drawings of natural objects, or perceptual illusions. Here, rather than starting from complex images and working backward to infer simpler processes, we investigated how the visual system parses and integrates information contained in stimuli of the most basic variety. Simple scatterings of a few points of light were manipulated in terms of their numerosity, spatial extent, and organization, and high-density electrophysiological recordings were made from healthy adults engaged in an unrelated task. We reasoned that this approach permitted an uncontaminated view of the spatio-temporal dynamics of the related neural processes. We were guided in our predictions by the "frame-and fill" model for object perception, whereby fast inputs to the dorsal stream of the visual "where" system first frame the spatial extent of visual objects, which are subsequently "filled-in" by the slower activation of the ventral stream of the visual "what" system. Our findings were consistent with this view, showing a rapidly-onsetting effect of spatial extent in dorsal stream sources, and later onsetting effects due to dot number and symmetry, which were deemed to be more closely tied to the details of object identity, from ventral stream sources. This collection of observations provides an important baseline from which to understand the spatio-temporal properties of basic visual object perception, and from which to test dysfunction of this system in clinical populations. PMID- 22521826 TI - Functional recovery and neuronal regeneration of a rat model of epilepsy by transplantation of Hes1-down regulated bone marrow stromal cells. AB - Gamma-amino butyric acid (GABA)ergic cells play an important inhibitory role in epilepsy. Until now, there are no reports on promoting transplanted bone marrow stromal cells (BMSCs) to differentiate into GABAergic cells for treatment of epilepsy. In this study, hairy and enhancer of split 1 (Hes1)-down regulated BMSCs (H-BMSCs) were transplanted into an epileptic rat model to induce GABAergic cells differentiation to improve the function recovery and neuronal regeneration. First, Hes1 expression in isolated BMSCs was down regulated by Hes1 siRNA. Then, the H-BMSCs were labeled with 5-bromo-2'-deoxyuridine (BrdU) and transplanted into the lateral ventricle of pilocarpine-induced epileptic rats. To evaluate the therapeutic effects, behavior and electroencephalography (EEG) of the recipient rats were monitored in the following 4 weeks, followed by histological confirmation. The results showed that the rate of mortality, frequency of spontaneous recurrent seizures (SRS) and incidence of epileptiform waves presented a tendency to decrease after H-BMSCs transplantation. The histology results showed that (1) the transplanted H-BMSCs which migrated to the adjacent parahippocampal cortical areas expressed glutamate decarboxylase (GAD) 67, neuron specific enolase (NSE) and some glial fibrillary acidic protein (GFAP), and (2) the neuronal density of corresponding cortical areas was significantly increased (P<0.01 VS. experimental group I or positive control group). Given these results and other advantages of BMSCs, such as easy harvest and minimal immunogenicity, transplantation of H-BMSCs could be a promising approach to improve the functional recovery and neuronal regeneration of epileptic model in the early stage. PMID- 22521827 TI - Pontomedullary and hypothalamic distribution of Fos-like immunoreactive neurons after acute exercise in rats. AB - During exercise, intense brain activity orchestrates an increase in muscle tension. Additionally, there is an increase in cardiac output and ventilation to compensate the increased metabolic demand of muscle activity and to facilitate the removal of CO(2) from and the delivery of O(2) to tissues. Here we tested the hypothesis that a subset of pontomedullary and hypothalamic neurons could be activated during dynamic acute exercise. Male Wistar rats (250-350 g) were divided into an exercise group (n=12) that ran on a treadmill and a no-exercise group (n=7). Immunohistochemistry of pontomedullary and hypothalamic sections to identify activation (c-Fos expression) of cardiorespiratory areas showed that the no-exercise rats exhibited minimal Fos expression. In contrast, there was intense activation of the nucleus of the solitary tract, the ventrolateral medulla (including the presumed central chemoreceptor neurons in the retrotrapezoid/parafacial region), the lateral parabrachial nucleus, the Kolliker Fuse region, the perifornical region, which includes the perifornical area and the lateral hypothalamus, the dorsal medial hypothalamus, and the paraventricular nucleus of the hypothalamus after running exercise. Additionally, we observed Fos immunoreactivity in catecholaminergic neurons within the ventrolateral medulla (C1 region) without Fos expression in the A2, A5 and A7 neurons. In summary, we show for the first time that after acute exercise there is an intense activation of brain areas crucial for cardiorespiratory control. Possible involvement of the central command mechanism should be considered. Our results suggest whole brain specific mobilization to correct and compensate the homeostatic changes produced by acute exercise. PMID- 22521828 TI - Functional effect of short-term immobilization: kinematic changes and recovery on reaching-to-grasp. AB - Although previous investigations agree in showing significant cortical modifications related to short-term limb immobilization, little is known about the functional changes induced by non-use. To address this issue, we studied the kinematic effect of 10h of hand immobilization. In order to prevent any movement, right handed healthy participants wore on their dominant hand a soft bandage. They were requested to perform the same reaching-to-grasping task immediately after immobilization, 1 day before (baseline 1) and in other two following days without non-use (baseline 2 and baseline 3). While no differences were found among baseline conditions, an increase of the total duration of reaching movement together with an anticipation of the time to peak velocity were observed in the first trial after immobilization. Interestingly, these initial effects decreased quickly trial-by-trial, following an exponential function till reaching values equal to those observed in the control conditions. The present findings show firstly that the transport phase of the reaching-to-grasp task was affected by a temporary reduction of sensory and motor information. Secondly, a trial-by-trial recovery of the immobilization-related changes, likely driven by the sensory inputs and motor outputs associated to the repetition of the movement has been observed. All together these results confirm a fundamental role of a continuous stream of sensorimotor signals in maintaining motor efficiency and in driving recovery process. PMID- 22521829 TI - Reduced GABA(A) receptor alpha6 expression in the trigeminal ganglion alters inflammatory TMJ hypersensitivity. AB - Trigeminal ganglia neurons express the GABA(A) receptor subunit alpha 6 (Gabralpha6) but the role of this particular subunit in orofacial hypersensitivity is unknown. In this report the function of Gabralpha6 was tested by reducing its expression in the trigeminal ganglia and measuring the effect of this reduction on inflammatory temporomandibular joint (TMJ) hypersensitivity. Gabralpha6 expression was reduced by infusing the trigeminal ganglia of male Sprague Dawley rats with small interfering RNA (siRNA) having homology to either the Gabralpha6 gene (Gabralpha6 siRNA) or no known gene (control siRNA). Sixty hours after siRNA infusion the rats received a bilateral TMJ injection of complete Freund's adjuvant to induce an inflammatory response. Hypersensitivity was then quantitated by measuring meal duration, which lengthens when hypersensitivity increases. Neuronal activity in the trigeminal ganglia was also measured by quantitating the amount of phosphorylated ERK. Rats in a different group that did not have TMJ inflammation had an electrode placed in the spinal cord at the level of C1 sixty hours after siRNA infusion to record extracellular electrical activity of neurons that responded to TMJ stimulation. Our results show that Gabralpha6 was expressed in both neurons and satellite glia of the trigeminal ganglia and that Gabralpha6 positive neurons within the trigeminal ganglia have afferents in the TMJ. Gabralpha6 siRNA infusion reduced Gabralpha6 gene expression by 30% and significantly lengthened meal duration in rats with TMJ inflammation. Gabralpha6 siRNA infusion also significantly increased p-ERK expression in the trigeminal ganglia of rats with TMJ inflammation and increased electrical activity in the spinal cord of rats without TMJ inflammation. These results suggest that maintaining Gabralpha6 expression was necessary to inhibit primary sensory afferents in the trigeminal pathway and reduce inflammatory orofacial nociception. PMID- 22521830 TI - Distribution of CB1 cannabinoid receptors and their relationship with mu-opioid receptors in the rat periaqueductal gray. AB - The periaqueductal gray (PAG) is part of a descending pain modulatory system that, when activated, produces widespread and profound antinociception. Microinjection of either opioids or cannabinoids into the PAG elicits antinociception. Moreover, microinjection of the cannabinoid 1 (CB1) receptor agonist HU-210 into the PAG enhances the antinociceptive effect of subsequent morphine injections, indicating a direct relationship between these two systems. The objective of this study was to characterize the distribution of CB1 receptors in the dorsolateral and ventrolateral PAG in relationship to mu-opioid peptide (MOP) receptors. Immunocytochemical analysis revealed extensive and diffuse CB1 receptor labeling in the PAG, 60% of which was found in somatodendritic profiles. CB1 and MOP receptor immunolabeling were co-localized in 32% of fluorescent Nissl stained cells that were analyzed. Eight percent (8%) of PAG neurons that were MOP receptor-immunoreactive (-ir) received CB1 receptor-ir appositions. Ultrastructural analysis confirmed the presence of CB1 receptor-ir somata, dendrites and axon terminals in the PAG. These results indicate that behavioral interactions between cannabinoids and opioids may be the result of cellular adaptations within PAG neurons co-expressing CB1 and MOP receptors. PMID- 22521831 TI - Positron emission tomograghy with [13N]ammonia evidences long-term cerebral hyperperfusion after 2h-transient focal ischemia. AB - BACKGROUND AND PURPOSE: It is well known that after cerebral ischemia, brain suffers blood flow changes over time that have been correlated with inflammation, angiogenesis and functional recovery processes. Nevertheless, post-ischemic spatiotemporal changes of brain perfusion have not been fully investigated to date. Here we tested whether PET with [13N]ammonia would evidence the perfusion changes presented by different brain regions in an experimental model of brain ischemia. EXPERIMENTAL PROCEDURES: Seven rats were subjected to a 2-h transient middle cerebral artery occlusion with reperfusion. PET studies were performed longitudinally using [13N]ammonia at 1, 3, 7, 14, 21 and 28 days after cerebral ischemia. RESULTS: In vivo PET imaging showed a significant increase in [13N]ammonia uptake at 7 days after cerebral ischemia with respect to one day after the occlusion in the cerebral territory irrigated by the MCA in both the ischemic and contralateral hemispheres. This increase was followed by a return to control values at day 28 after ischemia onset. Brain regions located both inside and outside the primary infarct areas showed similar perfusion changes after cerebral ischemia. CONCLUSIONS: [13N]ammonia shows hemodynamic changes after stroke involving hyperperfusion that might be related to angiogenesis and functional recovery. Long-term blood hyperperfusion is found both in ischemic and remote areas to infarction. These results may contribute to a better understanding of the evolution of cerebral ischemic lesion in animal models. PMID- 22521832 TI - Evidence of oxidative stress in very long chain fatty acid--treated oligodendrocytes and potentialization of ROS production using RNA interference directed knockdown of ABCD1 and ACOX1 peroxisomal proteins. AB - X-linked adrenoleukodystrophy (X-ALD) and pseudo neonatal adrenoleukodystrophy (P NALD) are neurodegenerative demyelinating diseases resulting from the functional loss of the peroxisomal ATP-binding cassette transporter D (ABCD1) and from single peroxisomal enzyme deficiency (Acyl-CoA oxidase1: ACOX1), respectively. As these proteins are involved in the catabolism of very long chain fatty acids (VLCFA: C24:0, C26:0), X-ALD and P-NALD patients are characterized by the accumulation of VLCFA in plasma and tissues. Since peroxisomes are involved in the metabolism of reactive oxygen species (ROS) and nitrogen species (RNS), we examined the impact of VLCFA on the oxidative status of 158N murine oligodendrocytes expressing or not Abcd1 or Acox1. VLCFA triggers an oxidative stress characterized by an overproduction of ROS and RNS associated with lipid peroxidation, protein carbonylation, increased superoxide dismutase (SOD) activity, decreased catalase activity and glutathione level. SiRNA knockdown of Abcd1 or Acox1 increased ROS and RNS production even in the absence of VLCFA, and especially potentialized VLCFA-induced ROS overproduction. Moreover, mainly in cells with reduced Acox1 level, the levels of VLCFA and neutral lipids were strongly enhanced both in untreated and VLCFA - treated cells. Our data obtained on 158N murine oligodendrocytes highlight that VLCFA induce an oxidative stress, and demonstrate that Abcd1 or Acox1 knockdown contributes to disrupt RedOx equilibrium supporting a link between oxidative stress and the deficiency of Abcd1 or Acox1 peroxisomal proteins. PMID- 22521833 TI - Possible aryl hydrocarbon receptor-independent pathway of 2,3,7,8 tetrachlorodibenzo-p-dioxin-induced antiproliferative response in human breast cancer cells. AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a ligand with high affinity for the aryl hydrocarbon receptor (AhR). It suppresses 17beta-estradiol (E2)-induced cell proliferation in human breast cancer cells. Although it has been theorized that the AhR is involved in TCDD-induced antiestrogenic activity and antiproliferation in human breast cancer cells, some evidence suggests that these activities of chlorinated aromatic compounds also occur by AhR-independent pathways. Here, we investigated the possibility of TCDD-induced antiproliferative responses in human breast cancer cells through AhR-independent pathways. Compared with that in vehicle-treated controls, DNA synthesis was significantly suppressed in MCF-7 cells and ZR75-1 cells treated with TCDD at a very low concentration (0.01 nM), whereas that in human ovarian carcinoma OVCAR3 cells, human cervical carcinoma HeLa cells and human choriocarcinoma JEG-3 cells was unaffected, even by exposure to 10 nM TCDD. The suppression induced by TCDD was not associated with the estrogen receptor alpha-signaling pathway. Another AhR agonist, 3,3',4,4',5 pentachlorobiphenyl, had no effect on DNA synthesis in MCF-7 cells at concentrations high enough to induce the transactivation function of the AhR. Furthermore, in MCF-7 cells, knockdown of the AhR by RNA interference had no effect on TCDD-induced antiproliferation. These findings suggest that the principal pathways of TCDD-induced antiproliferation in breast cancer cells are not AhR dependent. PMID- 22521834 TI - Genetic variations of CYP2B6 gene were associated with plasma BPDE-Alb adducts and DNA damage levels in coke oven workers. AB - Polycyclic aromatic hydrocarbons (PAHs), the main components of coke oven emissions, can induce activation of cytochrome P450 (CYP) enzymes, which metabolize PAHs and result in DNA damage by forming adducts. This study was designed to know whether genetic variants of CYP genes are associated with plasma benzo[a]pyrene-7,8-diol-9,10-epoxide-albumin (BPDE-Alb) adducts and DNA damage in coke oven workers. In this study, 298 workers were divided into four groups according to the environmental PAHs exposure levels. The concentrations of plasma BPDE-Alb adducts were detected by reverse-phase high-performance liquid chromatography and the DNA damage levels were measured using comet assay. Twelve tag single nucleotide polymorphisms (tagSNPs) of 4 CYP genes were selected and genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. In the top group, workers with CYP2B6 rs3760657GA genotype have lower BPDE-Alb adducts and DNA damage levels than those with rs3760657GG genotype (P<0.05). In the control group, the DNA damage levels of subjects with CYP1A1 rs4646421AA or GA+AA genotypes were lower than those with GG genotype (P<0.05). However, no such effects were shown for the other tagSNPs. These results suggested that genetic variations of CYP2B6 might be associated with low BPDE-Alb adducts and DNA damage levels in worker with high exposure to PAHs. PMID- 22521835 TI - Impact of prenatal ischemia on behavior, cognitive abilities and neuroanatomy in adult rats with white matter damage. AB - Early brain damage, such as white matter damage (WMD), resulting from perinatal hypoxia-ischemia in preterm and low birth weight infants represents a high risk factor for mortality and chronic disabilities, including sensory, motor, behavioral and cognitive disorders. In previous studies, we developed a model of WMD based on prenatal ischemia (PI), induced by unilateral ligation of uterine artery at E17 in pregnant rats. We have shown that PI reproduced some of the main deficits observed in preterm infants, such as white and gray matter damage, myelination deficits, locomotor, sensorimotor, and short-term memory impairments, as well as related musculoskeletal and neuroanatomical histopathologies [1-3]. Here, we determined the deleterious impact of PI on several behavioral and cognitive abilities in adult rats, as well as on the neuroanatomical substratum in various related brain areas. Adult PI rats exhibited spontaneous exploratory and motor hyperactivity, deficits in information encoding, and deficits in short- and long-term object memory tasks, but no impairments in spatial learning or working memory in watermaze tasks. These results were in accordance with white matter injury and damage in the medial and lateral entorhinal cortices, as detected by axonal degeneration, astrogliosis and neuronal density. Although there was astrogliosis and axonal degeneration in the fornix, hippocampus and cingulate cortex, neuronal density in the hippocampus and cingulate cortex was not affected by PI. Levels of spontaneous hyperactivity, deficits in object memory tasks, neuronal density in the medial and lateral entorhinal cortices, and astrogliosis in the fornix correlated with birth weight in PI rats. Thus, this rodent model of WMD based on PI appears to recapitulate the main neurobehavioral and neuroanatomical human deficits often observed in preterm children with a perinatal history of ischemia. PMID- 22521836 TI - Vestibular stimulation enhances hippocampal long-term potentiation via activation of cholinergic septohippocampal cells. AB - Vestibular stimulation induced acetylcholine release in the hippocampus, and acetylcholine is known to facilitate long-term potentiation (LTP) in the hippocampus. Thus, we hypothesize that vestibular stimulation enhances LTP in CA1 in freely behaving rats, and this enhancement depends on the activation of septohippocampal cholinergic neurons. Field excitatory postsynaptic potentials were recorded in CA1 area of behaving rats following stimulation of the basal dendritic afferents. LTP was induced by a single stimulation train (100 pulses at 200 Hz) during passive whole-body rotation or during awake-immobility. LTP induced during rotation was significantly larger than that induced during immobility. Pretreatment with cholinergic antagonist atropine sulfate (50mg/kg i.p.) abolished the facilitation of LTP during rotation as compared to immobility. Selective lesion of cholinergic cells in the medial septum (MS) with 192 IgG-saporin (0.49 MUg in 1.4 MUl) also abolished the difference in LTP induced during rotation and immobility, which was found in sham-lesion rats. 192 IgG-saporin lesioned rats, as compared to sham-lesion rats, revealed a depletion of MS cells immunopositive to choline acetyltransferase and paling of acetylcholinesterase staining in the hippocampus, without significant change in the number of parvalbumin-immunopositive cells. We conclude that enhancement of LTP during vestibular stimulation is mediated by the activation of cholinergic septohippocampal cells. This is the first direct evidence that vestibular stimulation facilitates hippocampal synaptic plasticity via a cholinergic input. PMID- 22521837 TI - Event-related potential variations in the encoding and retrieval of different amounts of contextual information. AB - Episodic memory events occur within multidimensional contexts; however, the electrophysiological manifestations associated with processing of more than one context have been rarely investigated. The effect of the amount of context on the ERPs was studied using two single and one double source memory tasks and by comparing full and partial context retrieval within a double source task. The single source tasks elicited waveforms with a larger amplitude during successful encoding and retrieval than the double source task. Compared with the waveforms elicited with a full source response, a partial source response elicited waveforms with a smaller amplitude, probably because the retrieval success for one context was combined with the retrieval attempt processes for the missing source. Comparing the tasks revealed that the larger the amount of contextual information processed, the smaller the amplitude of the ERPs, indicating that greater effort or further control processes were required during double source retrieval. PMID- 22521838 TI - Consumption of an acute dose of caffeine reduces acquisition but not memory in the honey bee. AB - Caffeine affects several molecules that are also involved in the processes underlying learning and memory such as cAMP and calcium. However, studies of caffeine's influence on learning and memory in mammals are often contradictory. Invertebrate model systems have provided valuable insight into the actions of many neuroactive compounds including ethanol and cocaine. We use the honey bee (Apis mellifera) to investigate how the ingestion of acute doses of caffeine before, during, and after conditioning influences performance in an appetitive olfactory learning and memory task. Consumption of caffeine doses of 0.01 M or greater during or prior to conditioning causes a significant reduction in response levels during acquisition. Although bees find the taste of caffeine to be aversive at high concentrations, the bitter taste does not explain the reduction in acquisition observed for bees fed caffeine before conditioning. While high doses of caffeine reduced performance during acquisition, the response levels of bees given caffeine were the same as those of the sucrose only control group in a recall test 24h after conditioning. In addition, caffeine administered after conditioning had no affect on recall. These results suggest that caffeine specifically affects performance during acquisition and not the processes involved in the formation of early long term memory. PMID- 22521839 TI - A systematic review of the role of cardiopulmonary exercise testing in vascular surgery. AB - OBJECTIVE: To perform a systematic review of cardiopulmonary exercise testing (CPET) in the pre-operative evaluation of patients with abdominal aortic aneurysm or peripheral vascular disease requiring surgery. METHODS: Review methods and reporting were according to the PRISMA guidelines. Studies were eligible if they reported CPET-derived physiological parameters in patients undergoing abdominal aortic aneurysm repair or lower extremity arterial bypass. Data were extracted regarding patient populations and correlation between CPET and surgical outcomes including mortality, morbidity, critical care bed usage and length of hospital stay. RESULTS: The searches identified 1301 articles. Although 53 abstracts referred to the index vascular procedures, only seven articles met inclusion criteria. There were no data from randomised controlled trials. Data from prospective studies did not comprehensively correlate CPET and surgical outcomes in patients with abdominal aortic aneurysms. There were no studies reporting CPET in patients undergoing lower extremity arterial bypass. Major limitations included small sample sizes, lack of blinding, and an absence of reporting standards. CONCLUSION: The paucity of robust data precludes routine adoption of CPET in risk stratifying patients undergoing major vascular surgery. The use of CPET should be restricted to clinical trials and experimental registries, reporting to consensus-defined standards. PMID- 22521840 TI - Risk stratification scores in elective open abdominal aortic aneurysm repair: are they suitable for preoperative decision making? AB - OBJECTIVES: Risk indices help quantify the risk of cardiovascular events and death prior to making decisions about prophylactic AAA repair. This paper aims to study the predictive capabilities of 5 validated indices. DESIGN AND METHODS: A prospective observational multi-centre cohort study from August 2005 to September 2007 in Glasgow recruited 106 consecutive patients undergoing elective open AAA repair. The Glasgow Aneurysm Score (GAS), Vascular physiology only Physiological and Operative Severity Score for enUmeration of Mortality (V(p)-POSSUM), Vascular Biochemical and Haematological Outcome Model (VBHOM), Revised Cardiac Risk Index (RCRI) and Preoperative Risk Score of the Estimation of Physiological Ability and Surgical Stress Score (PRS of E-PASS) were calculated. Indices were compared using receiver operating characteristic (ROC) analysis and area under the curve (AUC) estimates. End points were all-cause mortality, Major Adverse Cardiac Events (MACE) and cardiac death. RESULTS: GAS, VBHOM and RCRI did not predict outcome. V(p)-POSSUM predicted MACE (AUC = 0.681), cardiac death (AUC = 0.762) and all-cause mortality (AUC = 0.780), as did E-PASS (AUC = 0.682, 0.821, 0.703 for MACE, cardiac death and all-cause mortality respectively). CONCLUSION: Whilst V(p)-POSSUM and E-PASS predicted outcome, the less complex RCRI and GAS performed poorly which questions the utility of decision making based on these surgical risk indices. PMID- 22521841 TI - Current issues with the immunization program in Japan: can we fill the "vaccine gap"? AB - The "vaccine gap" is a term which has been used in Japan to indicate that the current immunization program is behind compared to the programs in other developed countries. The current national immunization program (NIP) which was established under the Japanese Immunization Law includes only six vaccines (eight targeted diseases), and the rest of available vaccines have been categorized as voluntary vaccines, which require out-of-pocket expense in order for the patients to receive them. This has led the vaccination rates for the voluntary vaccines remaining low, and the incidence of the target diseases remaining high. In addition, there are a few domestic rules that exist for immunizations including (1) subcutaneous injection is the standard method of vaccination, (2) the thigh is not considered to be the common site of vaccination in infants, and (3) the intervals of administration of inactivated and live vaccines are strictly determined by law. Along with the "vaccine gap" and the domestic rules, some movements to improve our current NIP are underway; including increased calls to change the NIP from civilians and professionals, the establishment of a group by the representatives from 13 medical professional societies asking the government to consider the immunization policy a "national policy" and seeking the establishment of a new and reorganized national immunization technical advisory group (NITAG). In addition, the Vaccination Subcommittee of Health Sciences Council was formed in the government to reform the current Immunization Law and NIP, which established a new national program for three voluntary vaccines funded by a temporary budget. We hope these new movements will fill the "vaccine gap" and that the NITAG will help ensure that vaccine policy becomes a national policy, and will provide necessary vaccinations without out-of-pocket expense to protect children in Japan from vaccine preventable diseases. PMID- 22521843 TI - Nosocomial transmission of measles: an updated review. AB - Despite a decrease in global incidence, measles outbreaks continue to occur in developed countries as a result of suboptimal vaccine coverage. Currently, an important mode of measles transmission appears to be nosocomial, especially in countries where measles is largely under control. We therefore conducted a review of the literature by searching PubMed for the term "measles" plus either "nosocomial" or "hospital acquired" between 1997 (the date of the last review in the field) and 2011. The reports indicate that measles is being transmitted from patients to health care workers (HCWs) and from HCWs to patients and colleagues. Here, we explain how outbreaks of measles occurring in healthcare settings differ in some ways from cases of community transmission. We also highlight the need for all HCWs to be immunized against measles. PMID- 22521842 TI - Influenza vaccination uptake amongst pregnant women and maternal care providers is suboptimal. AB - OBJECTIVE: To assess the uptake of influenza vaccination by pregnant women and maternity care providers and explore their attitudes towards influenza vaccination. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional survey administered in a Victorian tertiary level public hospital to 337 pregnant women and 96 maternity care providers. RESULTS: 31.3% of patients planned to or had received influenza vaccination this year, but only a quarter had received education about influenza. Women were more likely to receive influenza vaccination if they had been vaccinated in the last two years (RR 4.5, 95% CI: 3.1-6.4, p<0.001), received education about influenza (RR 2.3, 95% CI: 1.6-3.2, p<0.001) or believed that they were at high risk of influenza-related complications while pregnant (RR 2.0, 95% CI: 1.4-2.7, p<0.001). While only 56.8% of maternity care providers believed pregnant women were at high risk of influenza-related complications, 72.9% would recommend influenza vaccination to all pregnant women. Of the maternity care providers studied, 69% planned to or had been vaccinated in 2011, with this group more likely to recommend vaccination to their patients (RR 2.0, 95% CI: 1.3-3.0, p<0.001). Significantly more maternity care providers indicated that they would routinely recommend influenza vaccination than the proportion of patients who reported receiving education. CONCLUSIONS: Influenza vaccination rates in pregnant women are low, reflecting inadequate patient education despite most maternity care providers indicating that they would routinely recommend influenza vaccination. Increasing influenza vaccination uptake by women in pregnancy will require better education of both women and maternity care providers. PMID- 22521844 TI - Changes in the composition of the pneumococcal population and in IPD incidence in The Netherlands after the implementation of the 7-valent pneumococcal conjugate vaccine. AB - The implementation of nationwide pneumococcal vaccination may lead to alterations in the pneumococcal population due to selective pressure induced by the vaccine. To monitor such changes, pneumococcal isolates causing invasive pneumococcal disease (IPD) before (2004-2005, n=1154) and after (2008-2009, n=1190) the implementation of the 7-valent pneumococcal vaccine (PCV7) in 2006 in the national immunization program (NIP) of The Netherlands were characterized by molecular typing using multiple-locus variable number tandem repeat analysis (MLVA) and capsular sequence typing (CST). The IPD incidence after the implementation of PCV7 in children <5 years of age declined, mainly due to an impressive reduction of cases caused by vaccine serotypes. In the age group of patients >=5 years of age, the overall IPD incidence remained constant, but the IPD incidence due to vaccine serotypes declined in this age cohort as well, indicating herd immunity. IPD incidence of non-vaccine serotypes 1 and 22F isolates increased significantly and a shift in genetic background of the isolates belonging to these serotypes was observed. In general the composition of the pneumococcal population remained similar after the introduction of PCV7. Both before and after introduction of the vaccine several possible capsular switch events were noticed. We found 4 isolates from the pre-vaccination period in which the serotype 19F capsular locus had been horizontally transferred to a different genetic background. Remarkably, none of the 5 post-vaccination isolates in which we observed possible capsule switch belonged to the 19F serotype, possibly due to vaccine induced pressure. In the post-vaccine implementation period we found no evidence for capsular switch of a vaccine serotype to a non-vaccine serotype, indicating that capsular switch is not the main driving force for replacement. This study provides insights into the effects of nationwide vaccination on the pneumococcal population causing IPD. PMID- 22521845 TI - Monitoring of progress in the establishment and strengthening of national immunization technical advisory groups. AB - The majority of industrialized and some developing countries have established technical advisory bodies to guide and formulate national immunization policies and strategies. These are referred to as National Immunization Technical Advisory Groups (NITAGs), WHO and its partners have placed a high priority on assisting in the establishment or strengthening of functional, sustainable, and independent NITAGs. To enable systematic global monitoring of the existence and functionality of NITAGs, in 2010, WHO and UNICEF included related questions in the WHO-UNICEF Joint Reporting Form (JRF) that provides an official means for WHO and UNICEF to collect indicators of immunization programme performance. This paper presents the status of NITAGs based on the analysis of the 2010 JRF. Although 115 countries (64% of responders) reported having a NITAG in 2010, only 50% of countries reported the existence of a NITAG with a formal administrative or legislative basis. Despite limitations in the ability to compare 2010 JRF data with that from a 2008 global survey, it appears that substantial progress has been achieved globally over with 43 committees reporting affirmatively about six NITAG process indicators, compared with 23 in the 2008 survey. Impressive progress has been observed in the proportion of countries reporting NITAGs with formal terms of reference (24% increase), a legislative or administrative basis (10% increase), and a requirement for members to disclose their interests (14% increase). Some of the poorest developing countries now enjoy support from a NITAG which meet all six process indicators. These may serve as examples for other countries. PMID- 22521846 TI - Streptococcus pneumoniae serotypes isolated from the middle ear fluid of Costa Rican children following introduction of the heptavalent pneumococcal conjugate vaccine into a limited population. AB - BACKGROUND: The heptavalent pneumococcal conjugate vaccine (PCV-7) was introduced in high risk children and into the private market in Costa Rica in 2004 (<5% annual birth cohort). The aim of this study was to compare the Streptococcus pneumoniae serotype (ST) distribution, antibiotic resistance patterns and potential coverage before and after partial introduction of PCV-7. METHODS: A comparison between the S. pneumoniae isolates obtained and serotyped from the middle ear fluid (MEF) of Costa Rican children with otitis media between years 1999 and 2003 (before PCV-7 usage) and those isolates obtained from 2004 to 2008. RESULTS: A total of 145 and 218 MEF S. pneumoniae were serotyped between years 1999 and 2003 and 2004 and 2008, respectively. Considering a 19F outbreak observed between years 1999 and 2003, the following statistically significant changes in serotype distribution were detected between 1999 and 2003 and 2004 and 2008: ST 3: 4.8-12.8% (P=0.01); ST 11A: 0-4.1% (P=0.01); ST 14: 3.5-21.1% (P<0.001) and ST 19F: 52.4-18.3% (P<0.05). Comparison of the two study periods demonstrated that during 2004 and 2008 a statistically significant decrease in penicillin non-susceptible serotypes (36.2-20.4% [P=0.003]) and a statistically significant increase in trimethoprim-sulfametoxazole resistant serotypes (54.9 68.5%, respectively [P=0.03]) was observed. Potential pneumococcal vaccines coverage between 1999 and 2003 and between 2004 and 2008 were: for PCV-7: 77.2 60.5%, respectively (P=0.001); for the 10-valent conjugated vaccine (PCV-10): 78.6-61.4%, respectively (P=0.0008) and for the 13-valent conjugated vaccine (PCV 13): 84.8-79.3%, respectively (P=0.2). CONCLUSIONS: Changes in the serotype distribution and antimicrobial susceptibility of MEF S. pneumoniae have been observed in Costa Rican children with OM. Because of the limited use of PCV-7 during the study period, these changes probably cannot be attributed to PCV-7 use. Between 2004 and 2008, PCV-13 offered the highest potential vaccine coverage. PMID- 22521847 TI - Antibody responses following vaccination versus infection in a porcine circovirus type 2 (PCV2) disease model show distinct differences in virus neutralization and epitope recognition. AB - Porcine circovirus associated disease (PCVAD) encompasses a group of syndromes linked to infection with porcine circovirus type 2 (PCV2). Based on the hypothesis that the immune responses to vaccination versus infection are quantitatively and qualitatively different, the objective of this study was to evaluate immunity, virus replication and disease protection in pigs vaccinated with PCV2 capsid protein (CP) and during infection. The disease model included dual infection with PCV2 and porcine reproductive and respiratory syndrome virus (PRRSV), a virus known to enhance disease progression and severity. The principal effect of PRRSV infection was to increase peak PCV2 viremia by almost 40-fold; however, PCV2 failed to show a reciprocal effect on PRRSV. In vaccinated pigs, there was no evidence of disease or PCV2 replication following dual virus challenge. Immunity following vaccination favored PCV2 neutralizing activity; whereas, PCV2 infection and disease produced high levels of non-neutralizing antibody, primarily directed against a polypeptide in the C-terminal region of CP. These results support the notion that the magnitude of the total antibody response cannot be used as a measure of protective immunity. Furthermore, protection versus disease lies in the immunodominance of specific epitopes. Epitope specificity should be taken into consideration when designing PCV2 vaccines. PMID- 22521848 TI - Estimation of immunization providers' activities cost, medication cost, and immunization dose errors cost in Iraq. AB - The immunization status of children is improved by interventions that increase community demand for compulsory and non-compulsory vaccines, one of the most important interventions related to immunization providers. The aim of this study is to evaluate the activities of immunization providers in terms of activities time and cost, to calculate the immunization doses cost, and to determine the immunization dose errors cost. Time-motion and cost analysis study design was used. Five public health clinics in Mosul-Iraq participated in the study. Fifty (50) vaccine doses were required to estimate activities time and cost. Micro costing method was used; time and cost data were collected for each immunization related activity performed by the clinic staff. A stopwatch was used to measure the duration of activity interactions between the parents and clinic staff. The immunization service cost was calculated by multiplying the average salary/min by activity time per minute. 528 immunization cards of Iraqi children were scanned to determine the number and the cost of immunization doses errors (extraimmunization doses and invalid doses). The average time for child registration was 6.7 min per each immunization dose, and the physician spent more than 10 min per dose. Nurses needed more than 5 min to complete child vaccination. The total cost of immunization activities was 1.67 US$ per each immunization dose. Measles vaccine (fifth dose) has a lower price (0.42 US$) than all other immunization doses. The cost of a total of 288 invalid doses was 744.55 US$ and the cost of a total of 195 extra immunization doses was 503.85 US$. The time spent on physicians' activities was longer than that spent on registrars' and nurses' activities. Physician total cost was higher than registrar cost and nurse cost. The total immunization cost will increase by about 13.3% owing to dose errors. PMID- 22521849 TI - Heterologous prime-boost regimen adenovector 35-circumsporozoite protein vaccine/recombinant Bacillus Calmette-Guerin expressing the Plasmodium falciparum circumsporozoite induces enhanced long-term memory immunity in BALB/c mice. AB - BACKGROUND: Sustained antibody levels are a hallmark of immunity against many pathogens, and induction of long-term durable antibody titers is an essential feature of effective vaccines. Heterologous prime-boost approaches with vectors are optimal strategies to improve a broad and prolonged immunogenicity of malaria vaccines. RESULTS: In this study, we demonstrate that the heterologous prime boost regimen Ad35-CS/BCG-CS induces stronger immune responses by enhancing type 1 cellular producing-cells with high levels of CSp-specific IFN-gamma and cytophilic IgG2a antibodies as compared to a homologous BCG-CS and a heterologous BCG-CS/CSp prime-boost regimen. Moreover, the heterologous prime-boost regimen elicits the highest level of LLPC-mediated immune responses. CONCLUSION: The increased IFN-gamma-producing cell responses induced by the combination of Ad35 CS/BCG-CS and sustained type 1 antibody profile together with high levels of LLPCs may be essential for the development of long-term protective immunity against liver-stage parasites. PMID- 22521851 TI - One dose of an MF59-adjuvanted pandemic A/H1N1 vaccine recruits pre-existing immune memory and induces the rapid rise of neutralizing antibodies. AB - Protective antibody responses to a single dose of 2009 pandemic vaccines have been observed in the majority of healthy subjects aged more than 3 years. These findings suggest that immune memory lymphocytes primed by previous exposure to seasonal influenza antigens are recruited in the response to A/H1N1 pandemic vaccines and allow rapid seroconversion. However, a clear dissection of the immune memory components favoring a fast response to pandemic vaccination is still lacking. Here we report the results from a clinical study where antibody, CD4+ T cell, plasmablast and memory B cell responses to one dose of an MF59 adjuvanted A/H1N1 pandemic vaccine were analyzed in healthy adults. While confirming the rapid appearance of antibodies neutralizing the A/H1N1 pandemic virus, we show here that the response is dominated by IgG-switched antibodies already in the first week after vaccination. In addition, we found that vaccination induces the rapid expansion of pre-existing CD4+ T cells and IgG memory B lymphocytes cross-reactive to seasonal and pandemic A/H1N1 antigens. These data shed light on the different components of the immune response to the 2009 H1N1 pandemic influenza vaccination and may have implications in the design of vaccination strategies against future influenza pandemics. PMID- 22521850 TI - Protection of pigs against Taenia solium cysticercosis by immunization with novel recombinant antigens. AB - Recombinant antigens from the oncosphere stage of the parasite Taenia solium were expressed in Escherichia coli. The TSOL16, TSOL45-1A and TSOL45-1B recombinant antigens, each consisting of fibronectin type III (FnIII) domain S, were produced as fusion proteins with glutathione S-transferase (GST) and maltose binding protein (MBP). Groups of pigs were immunized twice with the GST fusions of the antigens and boosted a third time with the MBP fusions prior to receiving a challenge infection with T. solium eggs. The TSOL16 antigen was found to be capable of inducing high levels of immunity in pigs against a challenge infection with T. solium. Immunological investigations identified differences in immune responses in the pigs vaccinated with the various antigens. The results demonstrate that the TSOL16 antigen could be a valuable adjunct to current porcine vaccination approaches and may allow the further development of new vaccination strategies against T. solium cysticercosis. PMID- 22521852 TI - The safety of early versus late ambulation in the management of patients after percutaneous coronary interventions: a meta-analysis. AB - OBJECTIVE: Early ambulation after percutaneous coronary intervention (PCI) could increase patient comfort, decrease length of hospital stay, and reduce the costs. However, this approach may increase the risk of vascular complications and has not been well assessed. This study was conducted to assess the safety of early ambulation versus late ambulation by combining the study results on safety in patients undergoing PCI. MATERIALS AND METHODS: Studies were identified via five electronic databases, hand search and grey literature databases up to December 2011. We performed a meta-analysis of five randomized controlled trials to compare the safety of early versus late ambulation in the treatment of cardiac patients undergoing PCI. Of 1854 patients, 1083 were assigned to an early ambulation (range: 2-4 h of bed rest time) and 771 were assigned to late ambulation (range: 6-10 h of bed rest time). RESULTS: There was no evidence that early ambulation was more harmful than late ambulation in terms of haematoma or bleeding event. The pooled relative risk (RR) of haematoma was 0.82 (95% CI, 0.53 1.28) and bleeding, 1.77 (95% CI, 0.87-3.59). A funnel plot showed minimal evidence of publication bias for haematoma event. CONCLUSIONS: The results of this first meta-analysis indicated that early ambulation after PCI was not associated with an increased risk of haematoma or bleeding. This study also confirmed the findings of the included studies recommending reducing the bed rest time from 6-10 h to 2-4 h after removal of the arterial sheath, and supporting early mobilization. PMID- 22521853 TI - Hospital and unit characteristics associated with nursing turnover include skill mix but not staffing level: an observational cross-sectional study. AB - BACKGROUND: Nursing turnover is expensive and may have adverse effects on patient care. Little is known about turnover's association with most hospital and nursing unit characteristics, including nurse staffing level and registered nurse skill mix. OBJECTIVE: To explore associations between nursing unit turnover rates and several hospital- and unit-level variables, including staffing level and skill mix. DESIGN: Observational cross-sectional study of longitudinal data. SETTINGS: 1884 nursing units in 306 U.S. acute care hospitals. METHODS: During a 2-year period units reported monthly data on staffing and turnover. Total nursing staff turnover and registered nurse turnover rates were modeled as dependent variables in hierarchical Poisson regression models. The following hospital characteristics were considered as predictors: Magnet((r)) status, ownership (government or non government), teaching status, locale (metropolitan, micropolitan, or rural), and size (average daily census). The U.S. state in which the hospital was located was included as a covariate. Unit-level variables included total nursing hours per patient day, size of nursing staff, registered nurse skill mix, population age group (neonatal, pediatric, or adult), and service line (critical care, step down, medical, surgical, medical/surgical, psychiatric, or rehabilitation). RESULTS: Government ownership, Magnet designation, and higher skill mix were associated with lower total turnover and registered nurse turnover. Neonatal units had lower total and registered nurse turnover than pediatric units, which had lower total and registered nurse turnover than adult units. Unit service line was associated only with total turnover. Psychiatric, critical care, and rehabilitation units had the lowest mean turnover rates, but most differences between service lines were not significant. The other explanatory variables considered were not significant. CONCLUSIONS: Several hospital and unit characteristic variables have significant associations with nursing turnover; these associations should be taken into account in nursing turnover research and need to be explored further. Controlling for hospital ownership, Magnet status, unit service line, and unit population age group, registered nurse skill mix is apparently more important than total nurse staffing level in predicting nursing turnover. PMID- 22521854 TI - Mood-state effects on amygdala volume in bipolar disorder. AB - BACKGROUND: Prior structural neuroimaging studies of the amygdala in patients with bipolar disorder have reported higher or lower volumes, or no difference relative to healthy controls. These inconsistent findings may have resulted from combining subjects in different mood states. The prefrontal cortex has recently been reported to have a lower volume in depressed versus euthymic bipolar patients. Here we examined whether similar mood state-dependent volumetric differences are detectable in the amygdala. METHODS: Forty subjects, including 28 with bipolar disorder type I (12 depressed and 16 euthymic), and 12 healthy comparison subjects were scanned on a 3T magnetic resonance image (MRI) scanner. Amygdala volumes were manually traced and compared across subject groups, adjusting for sex and total brain volume. RESULTS: Statistical analyses found a significant effect of mood state and hemisphere on amygdala volume. Subsequent comparisons revealed that amygdala volumes were significantly lower in the depressed bipolar group compared to both the euthymic bipolar (p=0.005) and healthy control (p=0.043) groups. LIMITATIONS: Our study was cross-sectional and some patients were medicated. CONCLUSIONS: Our results suggest that mood state influences amygdala volume in subjects with bipolar disorder. Future studies that replicate these findings in unmedicated patient samples scanned longitudinally are needed. PMID- 22521855 TI - A pilot study of acupuncture monotherapy in patients with major depressive disorder. AB - BACKGROUND: We have previously shown that a standardized acupuncture augmentation was effective for antidepressant partial responders with major depressive disorder (MDD). This pilot study examines the efficacy and safety of this protocol as monotherapy for MDD. METHODS: Thirty outpatients (73% female, mean age 47+/-12 yrs) with SCID-diagnosed MDD were recruited and received 8 weeks of standardized 30-minute open acupuncture treatment using 5 specific body points on the arms and legs bilaterally, with manual stimulation every 10 min, and concurrent electroacupuncture (2Hz current) at two points along the midline of the head. Subjects were assigned to once-weekly (n=21) or twice-weekly (n=9) treatment, depending on preference. Change in Hamilton-D-17 score was the primary outcome measure, and positive response to treatment (defined as >=50% improvement in HAM-D-17 scores compared to baseline) was the secondary outcome measure. RESULTS: HAM-D-17 scores decreased from 19.1+/-4.4 to 9.9+/-6.3 (p<0.001) in the once-weekly acupuncture group, and from 21.9+/-5.3 to 14.3+/-6.1 (p=0.012) in the twice-weekly acupuncture group. Improvement did not differ significantly between treatment arms. Response rates were 62% for the once-weekly acupuncture group and 22% for the twice-weekly acupuncture group (NS). Twenty patients (14 in weekly treatment group and 6 in twice-weekly treatment group) completed the study. The most common side effects included mild soreness/pain (n=13), and mild bleeding (n=16) at the needle site. LIMITATIONS: Open design and small sample. CONCLUSIONS: Standardized acupuncture treatment was safe, well-tolerated and effective, suggesting good feasibility in outpatient settings. Replication in controlled trials is warranted. PMID- 22521856 TI - Genetic causes of combined pituitary hormone deficiencies in humans. AB - Congenital hypopituitarism is a rare disease, usually induced by mutations of genes coding for transcription factors involved in pituitary development. PROP1 mutations represent the first cause of identified congenital hypopituitarism. Current techniques only identify 10-20% of congenital hypopituitarism etiologies, suggesting that new techniques are needed to improve this ratio. This should lead to a better management and follow-up of patients presenting with combined pituitary hormone deficiencies. PMID- 22521857 TI - [Treatment of acromegaly: a critical analysis of the last ten years]. AB - The ten previous years in terms of acromegaly treatment were essentially characterized by the experience accumulated with new formulations of somatostatin analogues or new drugs such GH-receptor antagonists recently available. Surgery remains the first-line treatment and its results did not change despite the generalization of endoscopy, which mainly seems to decrease local side-effects. The setting of radiotherapy was essentially modified by the increasing use of gamma-knife or stereotactic radiotherapy; however, their results are essentially the same as the classic fractionated, conventional radiotherapy and nobody knows if it will decrease the side-effects of this therapeutic modality. Nevertheless, thanks to a multistep therapeutic strategy, combining the different therapeutic modalities, it has become very rare for acromegaly not to be controlled in a patient. PMID- 22521858 TI - Rhodium and iridium salts inhibit proliferation and induce DNA damage in rat fibroblasts in vitro. AB - Environmental concentration of the platinum group elements is increased in the last years due to their use in automobile catalytic converters. Limited data are available on the effects of such elements at a cellular level and on their toxicity, especially for rhodium and iridium which have been more recently introduced in use. The toxic effects of rhodium and iridium salts were analyzed on a normal diploid rat fibroblast cell line in vitro. Both salts halted cell growth in a dose- and time-dependent fashion by inhibiting cell cycle progression, inducing apoptosis and modulating the expression of cell cycle regulatory proteins. In fact, they both caused an accumulation of cells in the G2/M phase of the cell cycle and affected the expression levels of pRb, cyclins D1 and E, p21(Waf1) and p27(Kip1). DNA strand breaks, as assessed by comet test, and an increase in the intracellular levels of reactive oxygen species also occurred in exposed cell cultures. These findings suggest a potential toxicity of both iridium and rhodium salts and emphasize the need for further studies to understand their effects at a cellular level to enable a better assessment of their toxic effects and to identify ways for their modulation and/or prevention. PMID- 22521859 TI - Role of bovine adrenal medulla 22 (BAM22) in the pathogenesis of neuropathic pain in rats with spinal nerve ligation. AB - The opioid peptide bovine adrenal medulla 22 (BAM22) is a cleavage product of proenkephalin and has been shown to be involved in inflammatory pain and morphine tolerance. This study was designed to investigate a role of BAM22 in neuropathic pain. L5 spinal nerve ligation (SNL) significantly reduced BAM22-immunoreactivity in small-sized neurons and depleted IB4 binding in injured L5 dorsal root ganglia (DRG) compared to sham rats. Double labeling study showed that the expression of BAM22-immunoreactivity was decreased mainly in IB4 neurons in the neighboring intact L4 and L6 DRGs following SNL. The nerve injury dramatically increased sensitivity of hindpaw to mechanical stimulation. Intrathecal (i.t.) administration of BAM22 on day 10 post-SNL attenuated mechanical allodynia in a dose-dependent manner (3-30 nmol) and the effect lasted for up to 90 min. Similar treatment with morphine at a dose of 30 nmol produced a mild and brief inhibition on pain hypersensitivity. Furthermore, i.t. administration of 30 nmol of BAM22 suppressed SNL-induced upregulation of interleukin-1beta (IL-1beta) in the spinal dorsal horn. The present study suggests that the reduction of BAM22 expression in small-sized neurons in both injured and the adjacent DRGs may contribute to pain hypersensitivity in peripheral nerve injury as a result of loss of inhibition of IL-1beta upregulation in the spinal dorsal horn. Our results support the hypothesis that a reduction of antinociceptive activity loses the counteraction against activity of pronociceptive mediators, enhancing pain hypersensitivity following peripheral nerve injury. PMID- 22521860 TI - Sleep disturbances and sedation practices in the intensive care unit--a postal survey in the Netherlands. AB - BACKGROUND: Sleep disturbances are common in critically ill patients treated in the intensive care unit (ICU) with possible serious consequences. OBJECTIVE: The aim of this study was to get insight into sleeping and sedation practices in the adult ICUs in the Netherlands and survey which factors are important with respect to sleep in critically ill patients in the ICU. METHOD: A multi-centre, exploratory survey sent via mail to nurse managers of all adult ICUs in the Netherlands. RESULTS: Interventions without medication to improve the sleep of the critically ill patients were mostly defined as keeping patients awake during the day (94.2%), reducing noise of the ICU staff (89.7%) and reducing nursing interventions at night (86.8%). None of the ICUs used a sleep questionnaire. Nursing autonomy regarding sleep and sedation practices for patients (rated on a 10-point numerical scale) was judged as moderate (median 5, interquartile range (IQR) 3-7). How often nursing observations influence sleeping practices in the ICU was judged as good (median 8, IQR 7-8). How the average ICU patient was sleeping was judged as moderately well (median 6, IQR 5-7). Most intensive care units (83.8%) did not have a sleeping protocol, but 67.6% of these intensive care units suggested they should implement a sleeping protocol. CONCLUSIONS: The average critically ill patient has sleep disturbances, that is, is sleeping moderately well according to nurses' views and opinions, mostly due to a disturbed sleep-awake cycle, delirium and nursing interventions. Intensive care nurses perceive only a moderate feeling of autonomy and influence regarding the management of sleeping practices. PMID- 22521861 TI - Persistent hyperammonemia is associated with complications and poor outcomes in patients with acute liver failure. AB - BACKGROUND & AIMS: Patients admitted to the hospital with acute liver failure (ALF) and high arterial levels of ammonia are more likely to have complications and poor outcomes than patients with lower levels of ammonia. ALF is a dynamic process; ammonia levels can change over time. We investigated whether early changes (first 3 days after admission) in arterial levels of ammonia were associated with complications and outcomes and identified factors associated with persistent hyperammonemia. METHODS: We performed a prospective observational study that measured arterial ammonia levels each day for 5 days in 295 consecutive patients with ALF. We analyzed associations of changes in ammonia levels during the first 3 days with complications and outcomes. RESULTS: Patients with persistent arterial hyperammonemia (>=122 MUmol/L for 3 consecutive days), compared with those with decreasing levels, had lower rates of survival (23% vs 72%; P < .001) and higher percentages of cerebral edema (71% vs 37%; P < .001), infection (67% vs 28%; P = .003), and seizures (41% vs 7.7%; P < .001). Patients with persistent hyperammonemia had greater mortality, with an odds ratio (OR) of 10.7, compared with patients with baseline levels of ammonia >=122 MUmol/L (OR, 2.4). Patients with persistent hyperammonemia were more likely to progress to and maintain advanced hepatic encephalopathy than those with decreasing levels. Patients with persistent, mild hyperammonemia (>=85 MUmol/L for 3 days) were also more likely to have complications or die (P < .001) than patients with serial ammonia levels <85 MUmol/L. Infections (OR, 4.17), renal failure (OR, 2.20), and decreased arterial pH (OR, 0.003) were independent predictors of persistent hyperammonemia. CONCLUSIONS: Patients with ALF and persistent arterial hyperammonemia for 3 days after admission are more likely to develop complications and have greater mortality than patients with decreasing levels or high baseline levels. Infection, renal failure, and decreased arterial pH are independent predictors of persistent hyperammonemia. PMID- 22521862 TI - Inhibitory effect of 5,8,11-eicosatrienoic acid on angiogenesis. AB - INTRODUCTION: Cartilage contains high levels of n-9 eicosatrienoic acid (20:3n-9) but no blood vessels. 20:3n-9 might inhibit angiogenesis. MATERIALS AND METHODS: Angiogenesis was measured in human umbilical vein endothelial cells and diploid fibroblasts. Co-culture was performed with vascular endothelial growth factor-A (VEGF-A, 10 ng/mL) and fatty acids (0.1-10 MUmol/L). After 10 days of incubation and immunostaining for endothelial cells, vessel areas were calculated with image analyser software. RESULTS: Addition of 20:3n-9 and n-3 eicosatrienoic acid (20:3n-3) dose dependently inhibited VEGF-A-stimulated angiogenesis (more than the positive control suramin). Arachidonic, eicosapentaenoic, dihomo-gamma linolenic (20:3n-6) and oleic acids did not affect VEGF-A-stimulated angiogenesis even at 10 MUmol/L. Arachidonic and dihomo-gamma-linolenic acids enhanced angiogenesis without VEGF-A. DISCUSSION AND CONCLUSIONS: We suggest that the presence of 20:3n-9 in cartilage may be related to its vessel-free status and that 20:3n-9 may be useful for the treatment of disorders with excessive vasculature. ACKNOWLEDGEMENTS: This work was partly supported by Polyene Project, Inc. PMID- 22521864 TI - Eicosanoids in skin inflammation. AB - Eicosanoids play an integral part in homeostatic mechanisms related to skin health and structural integrity. They also mediate inflammatory events developed in response to environmental factors, such as exposure to ultraviolet radiation, and inflammatory and allergic disorders, including psoriasis and atopic dermatitis. This review article discusses biochemical aspects related to cutaneous eicosanoid metabolism, the contribution of these potent autacoids to skin inflammation and related conditions, and considers the importance of nutritional supplementation with bioactives such as omega-3 and omega-6 polyunsaturated fatty acids and plant-derived antioxidants as means of addressing skin health issues. PMID- 22521865 TI - Novel dual-binding function of a poly (C)-binding protein 3, transcriptional factor which binds the double-strand and single-stranded DNA sequence. AB - Poly(C)-binding proteins (PCBPs) are generally known as RNA-binding proteins that interact in a sequence-specific manner with single-stranded poly(C) sequences. These proteins are mainly involved in various posttranscriptional regulations (e.g., mRNA stabilization or translational activation/silencing). This study reports a novel dual-binding function for PCBP3, a member of the PCBP family. Recombinant PCBP3 was purified using affinity column chromatography and its identity confirmed by MALDI-TOF mass spectrometry. The protein folding conditions of the purified and renatured PCBP3 were optimized. Electrophoretic mobility shift assays demonstrated that the recombinant PCBP3 is capable of binding to both double- and single-strand poly(C) sequences. Furthermore, plasmids expressing PCBP3 repressed the expression of luciferase reporters when cotransfected with single-strand (pGL-SS) and double-strand (pGL-DS) constructs containing poly(C) sequences in their promoters. This study demonstrates for the first time that PCBP3 can function as a repressor dependent on binding to single strand and double-stranded poly(C) sequences. PMID- 22521866 TI - Cloning and expression of a zebrafish 5-HT(2C) receptor gene. AB - The 5-HT(2C) receptor is one of 14 different serotonin (5-HT) receptors that control neural function and behavior. Here, we present the entire sequence of a zebrafish 5-HT(2C) receptor cDNA including the 3' untranslated region and the previously unknown 5' untranslated region. The cloned 5-HT(2C) receptor gene is located on chromosome 7, is approximately 202 kbp long, and contains six exons. The coding region of the gene is 1557 bp long and flanked by a 504 bp 5' UTR and a 1474 bp 3' UTR. The deduced protein sequence of 518 amino acids aligns with orthologs of other vertebrates and is 54% identical to the human and mouse 5 HT(2C) receptor protein sequences. The region of the cDNA that encodes the 2nd cytoplasmic loop of the protein shows a 66% identity with vertebrate orthologs and clearly identifies the gene as a 5-HT(2C) receptor gene. Coupling sites for beta-arrestin and calmodulin are conserved in zebrafish. In-situ hybridization shows that the receptor is expressed in the brain and spinal cord including areas such as the olfactory bulb, the dorsal thalamus, the posterior tuberculum, the hypothalamus and the medulla oblongata. Reverse Transcriptase-PCR experiments indicate that the receptor gene can also be active in other tissues such as skin, ovaries, and axial muscle of adult zebrafish. Expression of the 5-HT(2C) receptor during ontogeny was found as early as 2.5 hpf. Five edited adenines in the region of the human, rat and mouse mRNA that encodes the 2nd cytoplasmic loop are conserved in the zebrafish transcript. However, RNA editing was not detected in the zebrafish. The results characterize the zebrafish 5-HT(2C) receptor gene and gene expression pattern for the first time. The similarities to mammalian 5 HT(2C) receptor genes suggest the use of zebrafish for the study of 5-HT(2C) receptor function in behavior, development and drug discovery. PMID- 22521867 TI - Identification of conserved and novel microRNAs in Aquilaria sinensis based on small RNA sequencing and transcriptome sequence data. AB - Agarwood is in great demand for its high value in medicine, incense, and perfume across Asia, Middle East, and Europe. As agarwood is formed only when the Aquilaria trees are wounded or infected by some microbes, overharvesting and habitat loss are threatening some populations of agarwood-producing species. Aquilaria sinensis is such a significant economic tree species. To promote the production efficiency and protect the resource of A. sinensis, it would be critical to reveal the regulation mechanisms of stress-induced agarwood formation. MicroRNAs (miRNAs), a key gene expression regulator involved in various plant stress response and metabolic processes, might function in agarwood formation, but no report concerning miRNAs in Aquilaria is available. In this study, the small RNA high-throughput sequencing and 454 transcriptome data were adopted to identify both conserved and novel miRNAs in A. sinensis. Deep sequencing showed that the small RNA (sRNA) population of A. sinensis was complex and the length of sRNAs varied. By in silico analysis of the small RNA deep sequencing data and transcriptome data, we discovered 27 novel miRNAs in A. sinensis. Based on the mature miRNA sequence conservation, we identified 74 putative conserved miRNAs from A. sinensis and 10 of them were confirmed with hairpin forming precursor. Interestingly, a novel miRNA sequence was determined to be the miRNA of asi-miR408, but with accumulation much higher than asi-miR408. The expression levels of ten stress-responsive miRNAs were examined during the time-course after wound treatment. Eight were shown to be wound-responsive. This not only shows the existence of miRNAs in this Asian economically significant tree species but also indicated its critical role in stress-induced agarwood formation. The highly accumulated miRNA of asi-miR408 implied miRNAs would be functional as well as miRNAs in plants. PMID- 22521863 TI - Deciphering the role of docosahexaenoic acid in brain maturation and pathology with magnetic resonance imaging. AB - Animal studies have found that deficits in brain docosahexaenoic acid (DHA, 22:6n 3) accrual during perinatal development leads to transient and enduring abnormalities in brain development and function. Determining the relevance of this evidence to brain disorders in humans has been hampered by an inability to determine antimortem brain DHA levels and limitations associated with a postmortem approach. Accordingly, there is a need for alternate or complementary approaches to better understand the role of DHA in cortical function and pathology, and conventional magnetic resonance imaging (MRI) techniques may be ideally suited for this application. A major advantage of neuroimaging is that it permits prospective evaluation of the effects of manipulating DHA status on both clinical and neuroimaging variables. Emerging evidence from MRI studies suggest that greater DHA status is associated with cortical structural and functional integrity, and suggest that reduced DHA status and abnormalities in cortical function observed in psychiatric disorders may be interrelated phenomenon. Preliminary evidence from animal MRI studies support a critical role of DHA in normal brain development. Neuroimaging research in both human and animals therefore holds tremendous promise for developing a better understanding of the role of DHA status in cortical function, as well as for elucidating the impact of DHA deficiency on neuropathological processes implicated in the etiology and progression of neurodevelopmental and psychiatric disorders. PMID- 22521868 TI - A novel method for whole blood PCR without pretreatment. AB - PCR is usually performed on purified DNA. However, the extraction of DNA from whole blood is time consuming and involves the risk of contamination at every step. Hence, it is desirable to amplify DNA directly from whole blood. Earlier, investigators tried to achieve this target by either pretreatment of whole blood samples with different agents or by altering the conventional thermal cyclic conditions. This would make the technique cumbersome and time consuming. Here, we describe a simple protocol to amplify DNA directly from whole blood without the need of pretreatment. PCR buffer system was optimized in the laboratory and Apolipoprotein B gene was used as a model for this experiment. 480 bp was the target site for amplification. Fresh whole blood samples were used both from healthy and diseased individuals (coronary artery disease patients). Successful amplification was achieved with 1 MUl volume of whole blood and it was comparable to that of genomic DNA. No pretreatment of whole blood samples was required with the optimized buffer system. 3mM concentration of MgCl(2) was observed to be optimal and hence used in the reaction mixture. Amplification was relatively better with this buffer system as compared to that of commercially available PCR buffer. With the present technique, amplicon detection did not require the centrifugation/dilution of the PCR products which further saves time. Successful amplification was achieved in both the healthy and diseased blood samples, indicating the robustness of the technique as changed blood composition and presence of increased inhibitory molecules in the diseased state did not seem to affect the efficacy of the present technique. In conclusion, as compared to the existing protocols for whole blood PCR, the present technique is relatively novel, simple, requires minimal steps and eliminates the need for additional standardizations. PMID- 22521869 TI - On the formation of envelope solitons with tube ended by spherical beads. AB - In this paper it is suggested the possibility of using a simple device to explore the propagation of short transverse perturbations in specimens of three linearly aligned elements (bead, tube and bead). By using time signal analysis and frequency spectroscopy some properties of the transmitted wave packets are experimentally analyzed in the acoustic domain. It is clearly demonstrated that the shape and the velocity of propagation of the waves do not change with distance. The amplitude may vary depending on the dissipation effect. These properties allow us to identify the wave packets as "envelope solitons". The influence of the elasticity of these materials composing the beads and the tube on the generation of envelope solitons is also investigated. PMID- 22521870 TI - Hepatic artery reconstruction following ablative surgery for hepatobiliary and pancreatic malignancies. AB - OBJECTIVE: Hepatic artery (HA) reconstruction is an important part of resective surgery for advanced hepatobiliary and pancreatic malignancies, but few reports have been published. To identify indications for HA reconstruction, we retrospectively analyzed our surgical procedures and outcomes. METHODS: En-bloc resection of advanced hepatobiliary and pancreatic malignancies followed by HA reconstruction was performed in 35 patients. Patients ranged in age from 27 to 81 years and included 18 men and 17 women. The primary site of cancer included the bile duct in 22 patients, the pancreas in 7, and others in 6. Reconstruction of the HA was necessitated by HA resection due to direct cancer invasion in 29 patients and by accidental arterial injury during surgical procedure in 6 patients. RESULTS: The HA was reconstructed with end-to-end anastomosis between hepatic arteries in 17 patients. Transposition of an intra-abdominal artery, such as the gastroepiploic artery, was required in 14 patients, and arterial grafting was required in 4 patients. Although the HA patency was achieved in 30 patients, 4 cases of arterial thrombosis and 1 case of arterial rupture developed postoperatively. The overall RFS time was analyzed in all patients, and mean and median RFS times were 18 and 9 months, respectively. CONCLUSION: Although oncologic outcomes remain poor, HA resection and reconstruction can be performed in selected patients. We believe that the method of first choice for HA reconstruction is end-to-end anastomosis between HAs. A vascular autograft should be used only in selected cases. PMID- 22521871 TI - Serum levels of selenium in patients with brain metastases from non-small cell lung cancer before and after radiotherapy. AB - PURPOSE: This study was to evaluate the influence of radiotherapy on the selenium serum levels of non-small cell cancer patients with brain metastases. PATIENTS AND METHODS: This prospective study included 95 non-small cell cancer patients with brain metastases treated by radiotherapy from December 2007 until November 2010. Plasma selenium levels were determined before and at the end of the radiotherapy. Age, body mass index (BMI), prior chemotherapy, pathological type and personal habits (smoking and alcoholism) were recorded for each patient. RESULTS: The mean age was 63 years; the mean BMI was 27.6. Seventy-six patients (80%) were non-smokers. Sixty-two patients (65.3%) showed no drinking habits and 8 (8.4%) have no prior chemotherapy. Thirty-nine patients (41.1%) were adenocarcinoma, 51 (53.7%) were squamous cell carcinoma and five (5.3%) were large cell carcinoma. At the beginning of radiotherapy, the mean selenium level for all patients was 90.4 MUg/l and after radiation this value dropped to 56.3 MUg/l. Multivariate analysis showed statistically significant difference in the plasma selenium concentration before and after radiotherapy for age (P<0.001), BMI (P<0.001), smoking (P<0.001), alcoholism (P<0.001), prior chemotherapy (P<0.001) and pathological type (P<0.001). CONCLUSION: Significant reduction in plasma levels of selenium was recorded in patients undergoing radiotherapy, suggesting attention to the nutritional status of this micronutrient and other antioxidant agents. PMID- 22521872 TI - [Ethical reflection on multidisciplinarity and confidentiality of information in medical imaging through new information and communication technologies]. AB - Technological advances in medical imaging has resulted in the exponential increase of the number of images per examination, caused the irreversible decline of the silver film and imposed digital imaging. This digitization is a concept whose levels of development are multiple, reflecting the complexity of this process of technological change. Under these conditions, the use of medical information via new information and communication technologies is at the crossroads of several scientific approaches and several disciplines (medicine, ethics, law, economics, psychology, etc.) surrounding the information systems in health, doctor-patient relationship and concepts that are associated. Each day, these new information and communication technologies open up new horizons and the space of possibilities, spectacularly developing access to information and knowledge. In this perspective of digital technology emergence impacting the multidisciplinary use of health information systems, the ethical questions are numerous, especially on the preservation of privacy, confidentiality and security of medical data, and their accessibility and integrity. PMID- 22521873 TI - Crowd perception in prosopagnosia. AB - Prosopagnosics, individuals who are impaired at recognizing single faces, often report increased difficulty when confronted with crowds. However, the discrimination of crowds has never been fully tested in the prosopagnosic population. Here we investigate whether developmental prosopagnosics can extract ensemble characteristics from groups of faces. DP and control participants viewed sets of faces varying in either identity or emotion, and were asked to estimate the average identity or emotion of each set. Face sets were displayed in two orientations (upright and inverted) to control for low-level visual features during ensemble encoding. Control participants made more accurate estimates of the mean identity and emotion when faces were upright than inverted. In all conditions, DPs performed equivalently to controls. This finding demonstrates that integration across different faces in a crowd is possible in the prosopagnosic population and appears to be intact despite their face recognition deficits. Results also demonstrate that ensemble representations are derived differently for upright and inverted faces, and the effects are not due to low level visual information. PMID- 22521874 TI - Individual differences in premotor and motor recruitment during speech perception. AB - Although activity in premotor and motor cortices is commonly observed in neuroimaging studies of spoken language processing, the degree to which this activity is an obligatory part of everyday speech comprehension remains unclear. We hypothesised that rather than being a unitary phenomenon, the neural response to speech perception in motor regions would differ across listeners as a function of individual cognitive ability. To examine this possibility, we used functional magnetic resonance imaging (fMRI) to investigate the neural processes supporting speech perception by comparing active listening to pseudowords with matched tasks that involved reading aloud or repetition, all compared to acoustically matched control stimuli and matched baseline tasks. At a whole-brain level there was no evidence for recruitment of regions in premotor or motor cortex during speech perception. A focused region of interest analysis similarly failed to identify significant effects, although a subset of regions approached significance, with notable variability across participants. We then used performance on a battery of behavioural tests that assessed meta-phonological and verbal short-term memory abilities to investigate the reasons for this variability, and found that individual differences in particular in low phonotactic probability pseudoword repetition predicted participants' neural activation within regions in premotor and motor cortices during speech perception. We conclude that normal listeners vary in the degree to which they recruit premotor and motor cortex as a function of short-term memory ability. This is consistent with a resource-allocation approach in which recruitment of the dorsal speech processing pathway depends on both individual abilities and specific task demands. PMID- 22521875 TI - Detection of the acute effects of hydrocortisone in the hippocampus using pharmacological fMRI. AB - Impaired hippocampal function is believed to be important in the pathogenesis of depression. The hippocampus contains a high concentration of both mineralocorticoid (MR) and glucocorticoid receptors (GR), and the experimental administration of corticosteroids has been reported to mimic memory impairments seen in depression. Using pharmacological functional magnetic resonance imaging (phMRI) we investigated whether hippocampal function is altered after acute administration of hydrocortisone. Changes in BOLD signal following infusion of 100mg hydrocortisone given as a rapid intravenous bolus were measured in 14 healthy volunteers in a within-subject placebo-controlled crossover design. Subsequently, subjects completed an n-back task during an fMRI scan. Hydrocortisone infusion caused a significant, time-dependent increase in fMRI BOLD signal in hippocampus reaching a maximal effect at 11-19min. The n-back task increased BOLD signal in prefrontal and parietal cortical areas and decreased it in the hippocampus. After hydrocortisone the left hippocampal decrease in BOLD signal was attenuated with the magnitude of attenuation correlating with the increase seen after hydrocortisone infusion. No difference in behavioural task performance was observed. The results suggest acute hydrocortisone has rapid direct and modulatory influences on hippocampal function, probably acting through non-genomic GR or MR signalling. Hydrocortisone infusion phMRI may be a useful tool to investigate hippocampal corticosteroid receptor function in depression. PMID- 22521876 TI - Transcriptome analysis of enriched Golovinomyces orontii haustoria by deep 454 pyrosequencing. AB - Powdery mildews are phytopathogenic ascomycetes that have an obligate biotrophic lifestyle and establish intimate relationships with their plant hosts. A crucial aspect of this plant-fungus interaction is the formation of specialized fungal infection structures termed haustoria. Although located within the cell boundaries of plant epidermal cells, haustoria remain separated from the plant cytoplasm by a host plasma membrane derivative, the extrahaustorial membrane. Haustoria are thought to represent pivotal sites of nutrient uptake and effector protein delivery. We enriched haustorial complexes from Arabidopsis thaliana plants infected with the powdery mildew fungus Golovinomyces orontii and performed in-depth transcriptome analysis by 454-based pyrosequencing of haustorial cDNAs. We assembled 7077 expressed sequence tag (EST) contigs with greater than 5-fold average coverage and analyzed these with regard to the respective predicted protein functions. We found that transcripts coding for gene products with roles in protein turnover, detoxification of reactive oxygen species and fungal pathogenesis are abundant in the haustorial EST contigs, while surprisingly transcripts encoding presumptive nutrient transporters were not highly represented in the haustorial cDNA library. A substantial proportion (~38%) of transcripts coding for predicted secreted proteins comprises effector candidates. Our data provide valuable insights into the transcriptome of the key infection structure of a model obligate biotrophic phytopathogen. PMID- 22521877 TI - Cap-independent Nrf2 translation is part of a lipoic acid-stimulated detoxification stress response. AB - Little is known about either the basal or stimulated homeostatic mechanisms regulating nuclear tenure of Nf-e2-related factor 2 (Nrf2), a transcription factor that mediates expression of over 200 detoxification genes. Our data show that stress-induced nuclear Nrf2 accumulation is largely from de novo protein synthesis, rather than translocation from a pre-existing cytoplasmic pool. HepG2 cells were used to monitor nuclear Nrf2 24h following treatment with the dithiol micronutrient (R)-alpha-lipoic acid (LA; 50MUM), or vehicle. LA caused a >=2.5 fold increase in nuclear Nrf2 within 1h. However, pretreating cells with cycloheximide (50MUg/ml) inhibited LA-induced Nrf2 nuclear accumulation by 94%. Providing cells with the mTOR inhibitor, rapamycin, decreased basal Nrf2 levels by 84% after 4h, but LA overcame this inhibition. LA-mediated de novo protein translation was confirmed using HepG2 cells transfected with a bicistronic construct containing an internal ribosome entry sequence (IRES) for Nrf2, with significant (P<0.05) increase in IRES use under LA treatment. These results suggest that a dithiol stimulus mediates Nrf2 nuclear tenure via cap-independent protein translation. Thus, translational control of Nrf2 synthesis, rather than reliance solely on pre-existing protein, may mediate the rapid burst of Nrf2 nuclear accumulation following stress stimuli. PMID- 22521879 TI - The human nail--barrier characterisation and permeation enhancement. AB - The human nail remains one of the most challenging membranes for formulation scientists to target and for clinicians to heal. Its formidable barrier properties are the primary reason that oral therapy remains the primary approach to manage ungual infections. This article considers the major structural properties underlying the excellent barrier function of the nail, with particular emphasis on the role of biophysical methods in advancing our knowledge of this appendage. Formulations currently available for management of ungual disease are discussed and their therapeutic efficacy is assessed. Finally, experimental strategies to enhance ungual permeation are reviewed and prospects for future developments in the field are considered. PMID- 22521878 TI - Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c. AB - Mammalian target of rapamycin complex 2 (mTORC2) phosphorylates and activates AGC kinase family members, including Akt, SGK1, and PKC, in response to insulin/IGF1. The liver is a key organ in insulin-mediated regulation of metabolism. To assess the role of hepatic mTORC2, we generated liver-specific rictor knockout (LiRiKO) mice. Fed LiRiKO mice displayed loss of Akt Ser473 phosphorylation and reduced glucokinase and SREBP1c activity in the liver, leading to constitutive gluconeogenesis, and impaired glycolysis and lipogenesis, suggesting that the mTORC2-deficient liver is unable to sense satiety. These liver-specific defects resulted in systemic hyperglycemia, hyperinsulinemia, and hypolipidemia. Expression of constitutively active Akt2 in mTORC2-deficient hepatocytes restored both glucose flux and lipogenesis, whereas glucokinase overexpression rescued glucose flux but not lipogenesis. Thus, mTORC2 regulates hepatic glucose and lipid metabolism via insulin-induced Akt signaling to control whole-body metabolic homeostasis. These findings have implications for emerging drug therapies that target mTORC2. PMID- 22521880 TI - Sustainable release of vancomycin, gentamicin and lidocaine from novel electrospun sandwich-structured PLGA/collagen nanofibrous membranes. AB - This study investigated the in vitro release of vancomycin, gentamicin, and lidocaine from novel electrospun sandwich-structured polylactide-polyglycolide (PLGA)/collagen nanofibrous membranes. For the electrospinning of biodegradable membranes, PLGA/collagen and PLGA/vancomycin/gentamicin/lidocaine were separately dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP). They were then electrospun into sandwich structured membranes, with PLGA/collagen for the surface layers and PLGA/drugs for the core layer. After electrospinning, an elution method and HPLC assay were employed to characterize the in vitro release rates of the pharmaceutics over a 30-day period. The experiment showed that biodegradable nanofibrous membranes released high concentrations of vancomycin and gentamicin (well above the minimum inhibition concentration) for 4 and 3 weeks, respectively, and lidocaine for 2 weeks. A bacterial inhibition test was carried out to determine the relative activity of the released antibiotics. The bioactivity of vancomycin and gentamicin ranged from 30% to 100% and 37% to 100%, respectively. In addition, results indicated that the nanofibrous membranes were functionally active in responses in human fibroblasts. By adopting the electrospinning technique, we will be able to manufacture biodegradable biomimetic nanofibrous extracellular membranes for long-term drug delivery of various pharmaceuticals. PMID- 22521881 TI - Ticagrelor: oral reversible P2Y(12) receptor antagonist for the management of acute coronary syndromes. AB - BACKGROUND: The clinical benefits of dual antiplatelet treatment (aspirin + clopidogrel) in the management of acute coronary syndromes (ACS) are well established. However, clopidogrel is a prodrug that requires hepatic activation. Concerns regarding its delayed onset of action, variability in antiplatelet effects, and prolonged recovery of platelet function after discontinuation have prompted the development of P2Y(12) receptor antagonists. Ticagrelor is the most recently developed P2Y(12) receptor antagonist available in the United States. Ticagrelor is a nonthienopyridine antiplatelet agent and is the first reversible oral antagonist of the P2Y(12) receptors. OBJECTIVE: This article reviews the pharmacology, clinical efficacy, and tolerability of ticagrelor use in management of ACS. METHODS: Peer-reviewed clinical trials, review articles, and relevant treatment guidelines published from 1966 to March 15, 2012, were identified from the MEDLINE and Current Content databases using the search terms ticagrelor, ACS, pharmacokinetics, pharmacodynamics, pharmacoeconomics, and cost-effectiveness. Citations from available articles were also reviewed for additional references. RESULTS: Nine pharmacokinetics/pharmacodynamics studies in humans and 1 clinical study were identified. In addition, the findings from 6 subanalyses based on the clinical study were included. Compared with clopidogrel, ticagrelor was associated with a significantly reduced composite rate of death from cardiovascular causes, myocardial infarction, or stroke (ticagrelor, 9.8%; clopidogrel, 11.7%; hazard ratio [HR] = 0.84; 95% CI, 0.77-0.92; P < 0.001). The difference in the rates of major bleeding was not significant (ticagrelor, 11.6%; clopidogrel, 11.2%). Ticagrelor was associated with a higher rate of non-coronary artery bypass graft surgery related major bleeding (4.5% vs 3.8%; P = 0.03), including fatal intracranial bleeding (0.1% vs 0.01%; P = 0.02), and fewer cases of other types of fatal bleeding (0.1% vs 0.3%; P = 0.03). Other adverse events reported with ticagrelor use included dyspnea (13.8%), headache (6.5%), and bradyarrhythmia (5.8%). The effects of ticagrelor have not been compared to those of other antiplatelet agents, including prasugrel. CONCLUSIONS: Based on the findings from the present review, ticagrelor provides reversible inhibition of adenosine diphosphate-induced platelet aggregation, with a faster onset of action than clopidogrel, and is effective in the treatment of patients with ACS. More data are required to definitively position ticagrelor with respect to other antiplatelet agents, including prasugrel. PMID- 22521882 TI - Global tyrosine kinome profiling of human thyroid tumors identifies Src as a promising target for invasive cancers. AB - BACKGROUND: Novel therapies are needed for the treatment of invasive thyroid cancers. Aberrant activation of tyrosine kinases plays an important role in thyroid oncogenesis. Because current targeted therapies are biased toward a small subset of tyrosine kinases, we conducted a study to reveal novel therapeutic targets for thyroid cancer using a bead-based, high-throughput system. METHODS: Thyroid tumors and matched normal tissues were harvested from twenty-six patients in the operating room. Protein lysates were analyzed using the Luminex immunosandwich, a bead-based kinase phosphorylation assay. Data was analyzed using GenePattern 3.0 software and clustered according to histology, demographic factors, and tumor status regarding capsular invasion, size, lymphovascular invasion, and extrathyroidal extension. Survival and invasion assays were performed to determine the effect of Src inhibition in papillary thyroid cancer (PTC) cells. RESULTS: Tyrosine kinome profiling demonstrated upregulation of nine tyrosine kinases in tumors relative to matched normal thyroid tissue: EGFR, PTK6, BTK, HCK, ABL1, TNK1, GRB2, ERK, and SRC. Supervised clustering of well differentiated tumors by histology, gender, age, or size did not reveal significant differences in tyrosine kinase activity. However, supervised clustering by the presence of invasive disease showed increased Src activity in invasive tumors relative to non-invasive tumors (60% v. 0%, p<0.05). In vitro, we found that Src inhibition in PTC cells decreased cell invasion and proliferation. CONCLUSION: Global kinome analysis enables the discovery of novel targets for thyroid cancer therapy. Further investigation of Src targeted therapy for advanced thyroid cancer is warranted. PMID- 22521883 TI - Human carbamoyl phosphate synthetase I (CPSI): insights on the structural role of the unknown function domains. AB - Carbamoyl phosphate synthetase (CPS) is an ancient protein. In mammals it intervenes in the urea cycle. This enzyme is organized into six domains, three of which have no established role in the mammalian enzyme. Taking advantage of the high degree of conservation between the human and the Escherichia coli homologue a comparative study was carried out in order to infer about the biological role of these less characterized domains. We show that among the residues involved in the maintenance of quaternary structure of the E. coli enzyme, several are highly conserved between human and bacterial enzyme and match the homologous positions of the "unknown function" domains in human enzyme, suggesting they are involved in the structural stability of the human enzyme as they are in bacteria. PMID- 22521884 TI - Cadmium activates extracellular signal-regulated kinase 5 in HK-2 human renal proximal tubular cells. AB - We examined the effects of cadmium chloride (CdCl(2)) exposure on the phosphorylation and functionality of extracellular signal-regulated kinase 5 (ERK5), a recently identified member of the mitogen-activated protein kinase (MAPK) family, in HK-2 human renal proximal tubular cells. Following exposure to CdCl(2), ERK5 phosphorylation increased markedly, but the level of total ERK5 was unchanged. ERK5 phosphorylation following CdCl(2) exposure was rapid and transient, similar to the time course of ERK1/2 phosphorylation. Treatment of HK 2 cells with the MAPK/ERK kinase 5 inhibitor, BIX02189, suppressed CdCl(2) induced ERK5 but not ERK1/2 phosphorylation. The CdCl(2)-induced increase of phosphorylated cAMP response element-binding protein (CREB) and activating transcription factor-1 (ATF-1), as well as the accumulation of mobility-shifted c Fos protein, were suppressed by BIX02189 treatment. Furthermore, BIX02189 treatment enhanced cleavage of poly(ADP-ribose) polymerase and increased the level of cytoplasmic nucleosomes in HK-2 cells exposed to CdCl(2). These findings suggest that ERK5 pathway activation by CdCl(2) exposure might induce the phosphorylation of cell survival-transcription factors, such as CREB, ATF-1, and c-Fos, and may exert a partial anti-apoptotic role in HK-2 cells. PMID- 22521885 TI - Nitric oxide regulated two-component signaling in Pseudoalteromonas atlantica. AB - Bacteria employ two-component signaling to detect and respond to environmental stimuli. In essence, two-component signaling relies on a protein called a response regulator that can elicit a change in gene expression or protein function in response to phosphoryl transfer from a histidine kinase. Phosphorylation of the associated histidine kinase is regulated by detection of an environmental signal, thus linking sensing to cellular response. Recently, it has been suggested that H-NOX (Heme-nitric oxide/oxygen binding) proteins may act as nitric oxide (NO) sensors in two-component signaling systems. NO/H-NOX regulated histidine kinases have been reported, but their cognate response regulators have yet to be identified. In this work we provide biochemical characterization of a complete NO/H-NOX-regulated two-component signaling pathway in the biofilm-dwelling marine bacterium, Pseudoalteromonas atlantica. In P. atlantica, as is typical for bacteria that code for H-NOX, an hnoX gene is found in the same operon as a gene coding for a two-component signaling histidine kinase (H-NOX-associated histidine kinase; HahK). We find that HahK is capable of autophosphorylation in vitro and that NO-bound H-NOX inhibits HahK activity, implicating H-NOX as a selective NO sensor. The cognate response regulator, a protein annotated as a cyclic-di-GMP processing enzyme that we have named HarR (H NOX-associated response regulator), was identified using bioinformatics tools. Phosphoryl transfer from HahK to HarR has been established. This report reveals the first biochemical characterization of an H-NOX-associated response regulator and contributes to a deeper understanding of NO/H-NOX signaling in bacteria. PMID- 22521886 TI - Altered nucleotide cofactor-dependent properties of the mutant [S240K]RecA protein. AB - Two mutant Escherichia coli RecA proteins were prepared in which the ATP active site residue, Ser240, was replaced with asparagine and lysine (these amino acids are found in the corresponding positions in other bacterial RecA proteins). The S240N mutation had no discernible effect on the ATP-dependent activities of the RecA protein, indicating that serine and asparagine are functionally interchangeable at position 240. The S240K mutation, in contrast, essentially eliminated the ability of the RecA protein to utilize ATP as a nucleotide cofactor. The [S240K]RecA protein was able to catalyze the hydrolysis of dATP, however, suggesting that the absence of the 2'-hydroxyl group reduced an inhibitory interaction with the Lys240 side chain. Interestingly, the [S240K]RecA protein was able to promote an efficient LexA cleavage reaction but exhibited no strand exchange activity when dATP was provided as the nucleotide cofactor. This apparent separation of function may be attributable to the elevated S(0.5) value for dATP for the [S240K]RecA protein (490 MUM, compared to 20-30 MUM for the wild type and [S240N]RecA proteins), and may reflect a differential dependence of the LexA co-protease and DNA strand exchange activities on the nucleotide cofactor mediated stabilization of the functionally-active state of the RecA-ssDNA complex. PMID- 22521888 TI - Overexpression of Robo2 causes defects in the recruitment of metanephric mesenchymal cells and ureteric bud branching morphogenesis. AB - Roundabout 2 (Robo2) is a member of the membrane protein receptor family. The chemorepulsive effect of Slit2-Robo2 signaling plays vital roles in nervous system development and neuron migration. Slit2-Robo2 signaling is also important for maintaining the normal morphogenesis of the kidney and urinary collecting system, especially for the branching of the ureteric bud (UB) at the proper site. Slit2 or Robo2 mouse mutants exhibit multilobular kidneys, multiple ureters, and dilatation of the ureter, renal pelvis, and collecting duct system, which lead to vesicoureteral reflux. To understand the effect of Robo2 on kidney development, we used microinjection and electroporation to overexpress GFP-Robo2 in an in vitro embryonic kidney model. Our results show reduced UB branching and decreased glomerular number after in vitro Robo2 overexpression in the embryonic kidneys. We found fewer metanephric mesenchymal (MM) cells surrounding the UB but no abnormal morphology in the branching epithelial UB. Meanwhile, no significant change in MM proliferation or apoptosis was observed. These findings indicate that Robo2 is involved in the development of embryonic kidneys and that the normal expression of Robo2 can help maintain proper UB branching and glomerular morphogenesis. Overexpression of Robo2 leads to reduced UB branching caused by fewer surrounding MM cells, but MM cell apoptosis is not involved in this effect. Our study demonstrates that overexpression of Robo2 by microinjection in embryonic kidneys is an effective approach to study the function of Robo2. PMID- 22521887 TI - Injury-induced insulin resistance in adipose tissue. AB - Hyperglycemia and insulin resistance are common findings in critical illness. Patients in the surgical ICU are frequently treated for this 'critical illness diabetes' with intensive insulin therapy, resulting in a substantial reduction in morbidity and mortality. Adipose tissue is an important insulin target tissue, but it is not known whether adipose tissue is affected by critical illness diabetes. In the present study, a rodent model of critical illness diabetes was used to determine whether adipose tissue becomes acutely insulin resistant and how insulin signaling pathways are being affected. There was a reduction in insulin-induced phosphorylation of IR, IRS-1, Akt and GSK-3beta. Since insulin resistance occurs rapidly in adipose tissue, but before the insulin resistance in skeletal muscle, it may play a role in the initial development of critical illness diabetes. PMID- 22521889 TI - Down-regulation of spinal D-amino acid oxidase expression blocks formalin-induced tonic pain. AB - A series of inhibitors of d-amino acid oxidase (DAAO) are specific in blocking chronic pain, including formalin-induced tonic pain, neuropathic pain and bone cancer pain. This study used RNA interference technology to further validate the notion that spinal DAAO mediates formalin-induced pain. To target DAAO, a siRNA/DAAO formulated in polyetherimide (PEI) complexation and a shRNA/DAAO (shDAAO, with the same sequence as siRNA/DAAO after intracellular processing) expressed in recombinant adenoviral vectors were designed. The siRNA/DAAO was effective in blocking DAAO expression in NRK-52E rat kidney tubule epithelial cells, compared to the nonspecific oligonucleotides. Furthermore, multiple-daily intrathecal injections of both siRNA/DAAO and Ad-shDAAO for 7 days significantly inhibited spinal DAAO expression by 50-80% as measured by real-time quantitative PCR and Western blot, and blocked spinal DAAO enzymatic activity by approximately 60%. Meanwhile, both siRNA/DAAO and Ad-shDAAO prevented formalin-induced tonic phase pain by approximately 60%. Multiple-daily intrathecal injections of siRNA/DAAO and Ad-shDAAO also blocked more than 30% spinal expression of GFAP, a biomarker for the activation of astrocytes. These results further suggest that down-regulation of spinal DAAO expression and enzymatic activity leads to analgesia with its mechanism potentially related to activation of astrocytes in the spinal cord. PMID- 22521890 TI - Short-hairpin RNA-mediated Heat shock protein 90 gene silencing inhibits human breast cancer cell growth in vitro and in vivo. AB - Hsp90 interacts with proteins that mediate signaling pathways involved in the regulation of essential processes such as proliferation, cell cycle control, angiogenesis and apoptosis. Hsp90 inhibition is therefore an attractive strategy for blocking abnormal pathways that are crucial for cancer cell growth. In the present study, the role of Hsp90 in human breast cancer MCF-7 cells was examined by stably silencing Hsp90 gene expression with an Hsp90-silencing vector (Hsp90 shRNA). RT-PCR and Western blot analyses showed that Hsp90-shRNA specifically and markedly down-regulated Hsp90 mRNA and protein expression. NF-kB and Akt protein levels were down-regulated in Hsp90-shRNA transfected cells, indicating that Hsp90 knockout caused a reduction of survival factors and induced apoptosis. Treatment with Hsp90-shRNA significantly increased apoptotic cell death and caused cell cycle arrest in the G1/S phase in MCF-7 cells, as shown by flow cytometry. Silencing of Hsp90 also reduced cell viability, as determined by MTT assay. In vivo experiments showed that MCF-7 cells stably transfected with Hsp90 shRNA grew slowly in nude mice as compared with control groups. In summary, the Hsp90-shRNA specifically silenced the Hsp90 gene, and inhibited MCF-7 cell growth in vitro and in vivo. Possible molecular mechanisms underlying the effects of Hsp90-shRNA include the degradation of Hsp90 breast cancer-related client proteins, the inhibition of survival signals and the upregulation of apoptotic pathways. shRNA-mediated interference may have potential therapeutic utility in human breast cancer. PMID- 22521891 TI - Crystal structure of receiver domain of putative NarL family response regulator spr1814 from Streptococcus pneumoniae in the absence and presence of the phosphoryl analog beryllofluoride. AB - Spr1814 of Streptococcus pneumoniae is a putative response regulator (RR) that has four-helix helix-turn-helix DNA-binding domain and belongs to the NarL family. The prototypical RR contains two domains, an N-terminal receiver domain linked to a variable effector domain. The receiver domain functions as a phosphorylation-activated switch and contains the typical doubly wound five stranded alpha/beta fold. Here, we report the crystal structure of the receiver domain of spr1814 (spr1814(R)) determined in the absence and presence of beryllofluoride as a phosphoryl analog. Based on the overall structure, spr1814(R) was shown to contain the typical fold similar with other structures of the receiver domain; however, an additional linker region connecting the receiver and DNA-binding domain was inserted into the dimer interface of spr1814(R), resulting in the formation of unique dimer interface. Upon phosphorylation, the conformational change of the linker region was observed and this suggests that domain rearrangement between the receiver domain and effector domain could occur in full-length spr1814. PMID- 22521892 TI - Structural and enzymatic properties of an in vivo proteolytic form of PD-S2, type 1 ribosome-inactivating protein from seeds of Phytolacca dioica L. AB - PD-S2, type 1 ribosome-inactivating protein from Phytolacca dioica L. seeds, is an N-beta-glycosidase likely involved in plant defence. In this work, we purified and characterized an in vivo proteolytic form of PD-S2, named cutPD-S2. Spectroscopic characterization of cutPD-S2 showed that the proteolytic cleavage between Asn195 and Arg196 does not alter the protein fold, but significantly affects its thermal stability. Most importantly, the proteolytic cleavage induces a 370-fold decrease of PD-S2 capacity of inhibiting in vitro protein biosynthesis. Our data catch the turning point from a typical role of PD-S2 as a defence protein to that of supplier of essential amino acids during seedling development. PMID- 22521893 TI - Salivary antioxidants and oral health in children with autism. AB - Individuals with autism vary widely in abilities, intelligence, and behaviours. Autistic children have preferences for soft and sweetened food making them susceptible to caries. A wide spectrum of medical and behavioural symptoms is exhibited by children with autism, which makes routine dental care very difficult in them. Mental retardation is evident in approximately 70% of individuals with autism and most psychiatric disorders including autism are associated with increased oxidative stress. OBJECTIVES: To evaluate the oral health status of children with autism and to determine the salivary pH and total salivary antioxidant concentration (TAC). MATERIALS AND METHODS: 101 subjects with autism between age group of 6 and 12 year were part of the study and 50 normal healthy siblings of same age group were taken as control group. Oral health status was analysed using oral hygiene index-simplified and dentition status index. The salivary total anti-oxidant level was estimated using phosphomolybdic acid using spectrophotometric method and the salivary pH using the pH indicating paper. The results were statistically analyzed using Mann-Whitney U test. RESULTS: A statistically very highly significant difference was seen in the mean oral hygiene index scores (autistic group--1.2 and control group--1, P<0.001) and the mean salivary total antioxidant concentration (autistic group--5.7 MUg/ml and control group--38 MUg/ml, P<0.001). No statistical significant difference was observed in the dental caries status and the salivary pH of autistic group and the control group. CONCLUSIONS: Similar dental caries status was observed in children with autism and their healthy normal siblings. Oral hygiene was poor in children with autism whereas the Salivary TAC was significantly reduced in autistic children. PMID- 22521894 TI - TLR2 may influence the behavior of the malignant clone in B-CLL. AB - B-cell receptor (BCR) and Toll-like receptor (TLR) stimulation and integration with signals from the pathogen or immune cells and their products determine the B cell antibody response. Low expression of BCR is the hallmark of B lymphocytes in CLL, however little is known about the expression and function of TLR in B-CLL. We studied TLR2, TLR4, IL-6 and mIL-6Ralpha expression on mRNA and protein level in CD19(+) subpopulation of normal lymphocytes and the CD19(+)CD5(+) subpopulation from B-CLL. Experiments were performed on unstimulated and stimulated lymphocytes [Staphylococcus aureus Cowan I (SAC) and lipopolysaccharide (LPS) from Escherichia coli - TLR2- and TLR4-specific agonists, respectively]. We showed undetectable or low IL-6 expression, which seems to be specific for B-CLL lymphocytes. Induction of TLR4 mRNA upon LPS stimulation affected the expression of IL-6, but not of mIL-6Ralpha. Increased expression of TLR2 (MFI) after LPS and SAC stimulation did not correlate with mIL 6Ralpha receptor expression. B-CLL CD19(+)CD5(+) lymphocytes showed a significant increase in TLR2 expression at the protein level after stimulation with SAC and LPS compared to normal CD19(+) lymphocytes. TLR2 may influence the behaviour of the malignant clone in B-CLL. PMID- 22521895 TI - Myalgic Encephalomyelitis (ME), Chronic Fatigue Syndrome (CFS), and Chronic Fatigue (CF) are distinguished accurately: results of supervised learning techniques applied on clinical and inflammatory data. AB - There is much debate on the diagnostic classification of Myalgic Encephalomyelitis (ME), Chronic Fatigue Syndrome (CFS) and chronic fatigue (CF). Post-exertional malaise (PEM) is stressed as a key feature. This study examines whether CF and CFS, with and without PEM, are distinct diagnostic categories. Fukuda's criteria were used to diagnose 144 patients with chronic fatigue and identify patients with CFS and CF, i.e. those not fulfilling the Fukuda's criteria. PEM was rated by means of a scale with defined scale steps between 0 and 6. CFS patients were divided into those with PEM lasting more than 24h (labeled: ME) and without PEM (labeled: CFS). The 12-item Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale was used to measure severity of illness. Plasma interleukin-1 (IL-1), tumor necrosis factor (TNF)alpha, and lysozyme, and serum neopterin were employed as external validating criteria. Using fatigue, a subjective feeling of infection and PEM we found that ME, CFS, and CF were distinct categories. Patients with ME had significantly higher scores on concentration difficulties and a subjective experience of infection, and higher levels of IL-1, TNFalpha, and neopterin than patients with CFS. These biomarkers were significantly higher in ME and CFS than in CF patients. PEM loaded highly on the first two factors subtracted from the data set, i.e. "malaise-sickness" and "malaise-hyperalgesia". Fukuda's criteria are adequate to make a distinction between ME/CFS and CF, but ME/CFS patients should be subdivided into ME (with PEM) and CFS (without PEM). PMID- 22521896 TI - The duration of untreated psychosis is associated with social support and temperament. AB - The duration of untreated psychosis (DUP) has been suggested to be a modifiable factor influencing psychosis outcome. There are many studies on the factors that predict DUP, although with contradictory findings. Although temperament has been associated with seeking help in other pathologies, studies about how temperament influences DUP are lacking. This study explored the role of temperament (measured by the Eysenck Personality Inventory Questionnaire) on DUP and tested the hypothesis that social support modifies the effects of neuroticism and extraversion on DUP. We evaluated 97 first-episode psychosis patients. The effect of temperament, affective diagnosis and social support (measured by the Social Support Index) on DUP was explored through a multivariate analysis using Cox regression model. Once psychotic symptoms had started, a patient with affective psychosis was 76% more likely to start antipsychotic medications than a patient with non-affective psychosis of comparable time without treatment (adjusted hazard ratio, HR, 1.76; 95% CI, (1.07, 2.9)). There was a significant interaction between diffuse social support and neuroticism (p=0.04). Among patients who had a good diffuse social support, a patient with a high neuroticism score was 45% less likely to start antipsychotic medication than a time-comparable patient with a low neuroticism (HR, 0.55 (0.32, 0.95)). Among patients who had a low neuroticism score, a patient with poor diffuse social support was 56% less likely to start antipsychotic medication than a comparable patient with good support (HR, 0.44 (0.23, 0.86)). In conclusion, patients with affective psychosis had significantly shorter DUPs. In patients with a good diffuse social support, low neuroticism scores were significantly associated with decreased DUP. In patients with low neuroticism scores, a poor diffuse social support was associated with a significant increase in DUP. PMID- 22521898 TI - Schizotypal people stick longer to their first choices. AB - Many studies have reported that schizophrenic patients show a Bias Against Disconfirmatory Evidence (BADE). This cognitive bias has been related to the formation and maintenance of delusion. The aim of this paper was to study whether BADE was present in healthy people displaying psychometric schizotypy, and to compare a closure task, which has been used for schizophrenia, with a new chronometric paradigm. Results with the new paradigm showed that the high schizotypy group maintained their initial hypotheses longer than the low schizotypy group. This finding corroborated the similarities between schizophrenic disorder and schizotypal traits, in this case with respect to the BADE. Research of this kind could facilitate the study of cognition in the schizophrenic spectrum without the difficulties of working with schizophrenic patients for some tasks and the assessment and early intervention in at-risk populations. PMID- 22521897 TI - Exploring the relationship between posttraumatic stress disorder and deliberate self-harm: the moderating roles of borderline and avoidant personality disorders. AB - Despite increasing evidence for an association between posttraumatic stress disorder (PTSD) and deliberate self-harm (DSH), few studies have examined the factors that moderate this association or the impact of co-occurring personality disorders among individuals with PTSD on DSH frequency. Given the high rates of co-occurrence between PTSD and two personality disorders of particular relevance to DSH, borderline personality disorder (BPD) and avoidant personality disorder (AVPD), this study examined the moderating role of these personality disorders in the association between PTSD and DSH frequency among a sample of substance use disorder patients (N=61). Patients completed structured clinical interviews assessing PTSD, BPD, and AVPD and a questionnaire assessing DSH. Results revealed more frequent DSH among patients with (vs. without) PTSD and provided evidence for the moderating role of AVPD in this association. Specifically, results revealed heightened levels of DSH only among PTSD patients with co-occurring AVPD. Findings are consistent with past research demonstrating that the presence of co-occurring AVPD among patients with other Axis I and II disorders is associated with worse outcomes, and highlight the importance of continuing to examine the moderating role of AVPD in the association between PTSD and a variety of health-risk behaviors. PMID- 22521899 TI - Medical, psychiatric and demographic factors associated with suicidal behavior in homeless veterans. AB - This study assessed potential for suicidal behaviors associated with sociodemographic, predisposing physical and mental health factors and self reported psychological problems among homeless veterans in a large northeastern region. Data were obtained from a demographic and clinical history interview conducted with 3595 homeless veterans. Odds-ratio (OR) statistics were used to assess potential for suicidal behavior. Statistically significant ratios were similar for ideation and attempts. The highest ratios were for self-report of depression and difficulty controlling violence, but statistically significant ratios were found for reporting sleeping in a treatment facility the night before the interview, receiving VA support for a psychiatric condition, and the diagnoses of Alcoholism, Mood Disorder and Post Traumatic Stress Disorder (PTSD). Low but statistically significant odds-ratios were obtained for most of the physical health items. A negative odds-ratio was obtained for African-American ethnicity. Logistic regression results indicated that for ideation and attempts items entered first involved subjective report of trouble controlling violent behavior and experiencing depression. High odds ratios for the interview items concerning experiencing serious depression and having difficulties controlling violence may have strong implications for treatment and management of homeless veterans. There may be up to 14-1 odds that an individual who reports being seriously depressed or having difficulty inhibiting aggression may have a serious potential for suicidal behaviors. PMID- 22521900 TI - Reduced metal ion concentrations in atherosclerotic plaques from subjects with type 2 diabetes mellitus. AB - AIMS: Transition metal ions have been implicated in atherosclerosis. The goal of this study was to investigate whether metal ion levels were higher in people with diabetes, in view of their increased risk of aggravated atherosclerosis. METHODS AND RESULTS: Absolute concentrations of iron, copper, zinc and calcium, and products of protein and lipid oxidation were quantified in atherosclerotic lesions from subjects with (T2DM, n=27), without Type 2 diabetes (nonDM, n=22), or hyperglycaemia (HG, n=17). Iron (P<0.05), zinc (P<0.01) and calcium (P=0.01) were lower in T2DM compared to nonDM subjects. Copper levels were comparable. A strong correlation (r=0.618; P<0.001) between EPR-detectable and total iron in nonDM patients was not seen in T2DM. X-ray fluorescence microscopy revealed "hot spots" of iron in both T2DM and nonDM. Calcium and zinc co-localised and levels correlated strongly. F(2)-isoprostanes (P<0.05) and di-Tyr/Tyr ratio (P<0.025), oxidative damage markers were decreased in T2DM compared to nonDM, or HG. CONCLUSION: Advanced atherosclerotic lesions from T2DM subjects unexpectedly contained lower levels of transition metal ions, and protein and lipid oxidation products, compared to nonDM and HG. These data do not support the hypothesis that elevated metal ion levels may be a major causative factor in the aggravated atherosclerosis observed in T2DM patients. PMID- 22521901 TI - Assessment of the value of a genetic risk score in improving the estimation of coronary risk. AB - BACKGROUND: The American Heart Association has established criteria for the evaluation of novel markers of cardiovascular risk. In accordance with these criteria, we assessed the association between a multi-locus genetic risk score (GRS) and incident coronary heart disease (CHD), and evaluated whether this GRS improves the predictive capacity of the Framingham risk function. METHODS AND RESULTS: Using eight genetic variants associated with CHD but not with classical cardiovascular risk factors (CVRFs), we generated a multi-locus GRS, and found it to be linearly associated with CHD in two population based cohorts: The REGICOR Study (n=2351) and The Framingham Heart Study (n=3537) (meta-analyzed HR [95%CI]: ~1.13 [1.01-1.27], per unit). Inclusion of the GRS in the Framingham risk function improved its discriminative capacity in the Framingham sample (c statistic: 72.81 vs.72.37, p=0.042) but not in the REGICOR sample. According to both the net reclassification improvement (NRI) index and the integrated discrimination index (IDI), the GRS improved re-classification among individuals with intermediate coronary risk (meta-analysis NRI [95%CI]: 17.44 [8.04; 26.83]), but not overall. CONCLUSIONS: A multi-locus GRS based on genetic variants unrelated to CVRFs was associated with a linear increase in risk of CHD events in two distinct populations. This GRS improves risk reclassification particularly in the population at intermediate coronary risk. These results indicate the potential value of the inclusion of genetic information in classical functions for risk assessment in the intermediate risk population group. PMID- 22521903 TI - Malignant migrating partial seizures of infancy controlled by stiripentol and clonazepam. AB - The syndrome of malignant migrating partial seizures of infancy (MMPSI) is characterized by early onset of multiple seizure types and overall poor prognosis. Seizures are markedly drug resistant and few reports have suggested the efficacy of some antiepileptic drugs. We report one case of MMPSI in which prolonged seizure control is obtained with an association of clonazepam, levetiracetam and stiripentol, confirming thus the possibility of complete sustained seizure control in this epileptic syndrome. Of more than 60 cases reported to date, ours is the forth in which sustained complete control of seizures was obtained. PMID- 22521902 TI - Reduced circulating oxidized LDL is associated with hypocholesterolemia and enhanced thiol status in Gilbert syndrome. AB - A protective association between bilirubin and atherosclerosis/ischemic heart disease clearly exists in vivo. However, the relationship between bilirubin and in vivo oxidative stress parameters in a clinical population remains poorly described. The aim of this study was to assess whether persons expressing Gilbert syndrome (GS; i.e., unconjugated hyperbilirubinemia) are protected from thiol oxidation and to determine if this, in addition to their improved lipoprotein profile, could explain reduced oxidized low-density lipoprotein (oxLDL) status in them. Forty-four matched GS and control subjects were recruited and blood was prepared for the analysis of lipid profile and multiple plasma antioxidants and measures of oxidative stress. GS subjects possessed elevated plasma reduced thiol (8.03+/-1.09 versus 6.75+/-1.39 nmol/mg protein; P<0.01) and glutathione concentrations (12.7+/-2.39 versus 9.44+/-2.45 MUM; P<0.001). Oxidative stress status (reduced:oxidized glutathione; GSH:GSSG) was significantly improved in GS (0.49+/-0.16 versus 0.32+/-0.12; P<0.001). Protein carbonyl concentrations were negatively associated with bilirubin concentrations and were significantly lower in persons with >40 MUM bilirubin versus controls (<17.1 MUmol/L; P<0.05). Furthermore, absolute oxLDL concentrations were significantly lower in GS subjects (P<0.05). Forward stepwise regression analysis revealed that bilirubin was associated with increased GSH:GSSG ratio and reduced thiol concentrations, which, in addition to reduced circulating LDL, probably decreased oxLDL concentrations within the cohort. In addition, a marked reduction in total cholesterol concentrations in hyperbilirubinemic Gunn rats is presented (Gunn 0.57+/-0.09 versus control 1.69+/-0.40 mmol/L; P<0.001), arguing for a novel role for bilirubin in modulating lipid status in vivo. These findings implicate the physiological importance of bilirubin in protecting from atherosclerosis by reducing thiol and subsequent lipoprotein oxidation, in addition to reducing circulating LDL concentrations. PMID- 22521904 TI - Effects of lamotrigine on cognition and behavior compared to carbamazepine as monotherapy for children with partial epilepsy. AB - To compare the cognitive and behavioral effects of lamotrigine (LTG) to carbamazepine (CBZ) as monotherapy for pediatric epilepsy. A multicenter, randomized, open-label, parallel-group clinical trial was conducted in children with partial-onset seizures. LTG or CBZ was prescribed as monotherapy for previously untreated children and titrated over 8 weeks, followed by maintenance for 24 weeks. Outcome measures were change in cognition and behavior in a combined analysis of standardized measures from screening to the end of the maintenance phase, as well as antiepileptic efficacy and tolerability. A total of 67 children completed the study, including 32 of 43 (74.4%) treated with LTG and 35 of 41 (85.4%) treated with CBZ. Seizure-free outcomes did not differ between the intent-to-treat populations (53.5% LTG, 56.1% CBZ; p=0.81). There were no statistically significant differences in the intelligence of the two groups after treatment. Externalizing behavior problems improved in the CBZ group (p<0.05). However, there were no significant differences between the two groups in terms of externalizing behavior. The parents' report on the Conner scale showed an improvement in the CBZ group compared to the LTG group (p<0.05). LTG and CBZ showed similar efficacy and cognitive effects in treating childhood partial epilepsy. However, CBZ showed more benefits in improving externalizing behaviors. PMID- 22521906 TI - Malaria vaccine development: persistent challenges. AB - There is no licensed vaccine against any human parasitic disease and apicomplexan parasites cause enormous human suffering; the malaria parasite alone kills approximately one million people annually and is the cause of the majority of infection-related deaths in the young. A malaria vaccine is essential if the goal of malaria eradication is to be achieved. Decades ago it was shown that attenuated malaria parasites could induce sterile immunity to infection but progress towards efficacious vaccines for malaria has been slow. However, recent studies have begun to tease out the immune correlates of vaccine-induced sterile protection and essential research on animal models of disease continues to guide vaccine design. Whole parasite approaches to vaccine design through attenuation as well as subunit vaccine development continue to move forward to clinical trials and are showing promising results. PMID- 22521905 TI - Comparison and contrast of noise-induced hyperactivity in the dorsal cochlear nucleus and inferior colliculus. AB - Induction of hyperactivity in the central auditory system is one of the major physiological hallmarks of animal models of noise-induced tinnitus. Although hyperactivity occurs at various levels of the auditory system, it is not clear to what extent hyperactivity originating in one nucleus contributes to hyperactivity at higher levels of the auditory system. In this study we compared the time courses and tonotopic distribution patterns of hyperactivity in the dorsal cochlear nucleus (DCN) and inferior colliculus (IC). A model of acquisition of hyperactivity in the IC by passive relay from the DCN would predict that the two nuclei show similar time courses and tonotopic profiles of hyperactivity. A model of acquisition of hyperactivity in the IC by compensatory plasticity mechanisms would predict that the IC and DCN would show differences in these features, since each adjusts to changes of spontaneous activity of opposite polarity. To test the role of these two mechanisms, animals were exposed to an intense hyperactivity inducing tone (10 kHz, 115 dB SPL, 4 h) then studied electrophysiologically at three different post-exposure recovery times (from 1 to 6 weeks after exposure). For each time frame, multiunit spontaneous activity was mapped as a function of location along the tonotopic gradient in the DCN and IC. Comparison of activity profiles from the two nuclei showed a similar progression toward increased activity over time and culminated in the development of a central peak of hyperactivity at a similar tonotopic location. These similarities suggest that the shape of the activity profile is determined primarily by passive relay from the cochlear nucleus. However, the absolute levels of activity were generally much lower in the IC than in the DCN, suggesting that the magnitude of hyperactivity is greatly attenuated by inhibition. PMID- 22521907 TI - Assessment of renal involvement by cystatin C: a forgotten biomarker. PMID- 22521908 TI - Preparation and use of Xenopus egg extracts to study DNA replication and chromatin associated proteins. AB - The use of cell-free extracts prepared from eggs of the South African clawed toad, Xenopus laevis, has led to many important discoveries in cell cycle research. These egg extracts recapitulate the key nuclear transitions of the eukaryotic cell cycle in vitro under apparently the same controls that exist in vivo. DNA added to the extract is first assembled into a nucleus and is then efficiently replicated. Progression of the extract into mitosis then allows the separation of paired sister chromatids. The Xenopus cell-free system is therefore uniquely suited to the study of the mechanisms, dynamics and integration of cell cycle regulated processes at a biochemical level. In this article we describe methods currently in use in our laboratory for the preparation of Xenopus egg extracts and demembranated sperm nuclei for the study of DNA replication in vitro. We also detail how DNA replication can be quantified in this system. In addition, we describe methods for isolating chromatin and chromatin-bound protein complexes from egg extracts. These recently developed and revised techniques provide a practical starting point for investigating the function of proteins involved in DNA replication. PMID- 22521909 TI - Evaluation of the efficacy of a recombinant Entamoeba histolytica cysteine proteinase (EhCP112) antigen in minipig. AB - Cysteine proteinases 112 (EhCP112) of Entamoeba histolytica are considered important for ameba pathogenicity. The recombinant gene was obtained by cloning and expression of the EhCP112 gene in heterologous host Escherichia coli BL-21 (DE3), were used to evaluate their ability to induce immune protective responses in minipig against challenge infection in a minipig-E. histolytica model. There was a 46.29% reduction (P<0.001) in the group of recovery of challenged E. histolytica compared with that in the control group. Specific anti-EhCP112 antibodies from immune protected minipig had significantly higher levels of immunoglobulin G (IgG) (P<0.001). This is a first report demonstrating that a recombinant form of EhCP112 generated in E. coli, to immunize a minipig model of E. histolytica, and there is significant protection. This study may help to understand the EhCP112 for human in the future. PMID- 22521910 TI - The examination of fatty acid taste with edible strips. AB - The objective of this study was to determine whether humans could detect long chain fatty acids when these lipid molecules are delivered to the oral cavity by edible taste strips. For suprathreshold studies, up to 1.7 MUmol of stearic acid or linoleic acid was incorporated into 0.03 mm thick, one-inch square taste strips. Normalized taste intensity values for stearic acid were in the barely detectable range, with values equal to, or slightly above control strips. One third of test subjects described the taste quality as oily/fatty/waxy. Approximately 75% of test subjects could detect the presence of linoleic acid when this fatty acid was incorporated into dissolvable strips. Normalized taste intensity values for linoleic acid were in the weak to moderate range. The most commonly reported taste quality responses for linoleic acid were fatty/oily/waxy, or bitter. When nasal airflow was obstructed, the perceived taste intensity of linoleic acid decreased by approximately 40%. Taste intensity values and taste quality responses for linoleic acid were then compared among tasters and non tasters of 6-n-propylthiouracil (PROP). Individuals who could detect the bitter taste of PROP reported higher taste intensity values for linoleic acid compared with PROP non-tasters. However, taste quality responses for linoleic acid were similar among both PROP tasters and PROP non-tasters. These results indicate that humans can detect long-chain fatty acids by both olfactory and non-olfactory pathways when these hydrophobic molecules are delivered to the oral cavity by means of edible taste strips. These studies further show that genetic variation in taste sensitivity to PROP affects chemosensory responses to the cis unsaturated fatty acid (linoleic acid) in the oral cavity. PMID- 22521911 TI - Determining the period, phase and anticipatory component of activity and temperature patterns in newborn rabbits that were maintained under a daily nursing schedule and fasting conditions. AB - During the last decade, lagomorphs have gained relevance as valuable models for the study of the development of circadian rhythmicity. This relevance is due to both the peculiar behavior of the lactating doe, in which maternal care is limited from 3 to 5 min per day, and the temporal organization that newborn rabbits exhibit during the early stages of development. In this study, we characterized the development of the temporal pattern of core body temperature and locomotor activity of newborn rabbits. This activity was recorded simultaneously for individual newborn rabbits and was maintained under constant light conditions, a 24-h nursing schedule and without access to the lactating doe. In addition, different mathematical algorithms were designed to determine the period, phase and anticipatory component of the time series obtained for the newborn rabbits. During the first two weeks of life, the average gross locomotor activity decreased as age increased; conversely however, the core body temperature exhibited a significant increment during the early stages of postnatal development. The newborn rabbits' circadian patterns of activity and temperature were consolidated as early as the first week of life. Similarly, the acrophase and nadir of both rhythms were settled by postnatal day 5, and the maximum activity consistently occurred approximately 2 h before the animals' maximum body temperature. The anticipation of nursing was evident from postnatal day 2 for both parameters, and the duration and intensity showed changes associated with the stage of development. In addition, the anticipatory component persisted with the same duration and intensity, even when nursing was omitted. The mathematical methods used in this study are suitable for producing unbiased analyses of the time series that are obtained from developing animals in situations during which biological signals generally show variability in frequencies and trends. By using these methods, it was possible to establish that circadian rhythmicity at the behavioral and physiological levels was evident during the first week of age in newborn rabbits. This circadian rhythmicity represents an endogenous rhythm because it persists throughout constant conditions. PMID- 22521913 TI - Breadth of cellular and humoral immune responses elicited in rhesus monkeys by multi-valent mosaic and consensus immunogens. AB - To create an HIV-1 vaccine that generates sufficient breadth of immune recognition to protect against the genetically diverse forms of the circulating virus, we have been exploring vaccines based on consensus and mosaic protein designs. Increasing the valency of a mosaic immunogen cocktail increases epitope coverage but with diminishing returns, as increasingly rare epitopes are incorporated into the mosaic proteins. In this study we compared the immunogenicity of 2-valent and 3-valent HIV-1 envelope mosaic immunogens in rhesus monkeys. Immunizations with the 3-valent mosaic immunogens resulted in a modest increase in the breadth of vaccine-elicited T lymphocyte responses compared to the 2-valent mosaic immunogens. However, the 3-valent mosaic immunogens elicited significantly higher neutralizing responses to Tier 1 viruses than the 2-valent mosaic immunogens. These findings underscore the potential utility of polyvalent mosaic immunogens for eliciting both cellular and humoral immune responses to HIV-1. PMID- 22521912 TI - Modulation of taste responsiveness and food preference by obesity and weight loss. AB - Palatable foods lead to overeating, and it is almost a forgone conclusion that it is also an important contributor to the current obesity epidemic - there is even talk about food addiction. However, the cause-effect relationship between taste and obesity is far from clear. As discussed here, there is substantial evidence for altered taste sensitivity, taste-guided liking and wanting, and neural reward processing in the obese, but it is not clear whether such traits cause obesity or whether obesity secondarily alters these functions. Studies with calorie restriction-induced weight loss and bariatric surgery in humans and animal models suggest that at least some of the obesity-induced alterations are reversible and consequently represent secondary effects of the obese state. Thus, both genetic and non-genetic predisposition and acquired alterations in taste and reward functions appear to work in concert to aggravate palatability-induced hyperphagia. In addition, palatability is typically associated with high energy content, further challenging energy balance regulation. The mechanisms responsible for these alterations induced by the obese state, weight loss, and bariatric surgery, remain largely unexplored. Better understanding would be helpful in designing strategies to promote healthier eating and prevention of obesity and the accompanying chronic disease risks. PMID- 22521914 TI - The adenovirus E1A N-terminal repression domain represses transcription from a chromatin template in vitro. AB - The adenovirus repression domain of E1A 243R at the E1A N-terminus (E1A 1-80) transcriptionally represses genes involved in differentiation and cell cycle progression. E1A 1-80 represses transcription in vitro from naked DNA templates through its interaction with p300 and TFIID. E1A 1-80 can also interact with several chromatin remodeling factors and associates with chromatin in vivo. We show here that E1A 243R and E1A 1-80 can repress transcription from a reconstituted chromatin template in vitro. Temporal analysis reveals strong repression by E1A 1-80 when added at pre-activation, activation and early transcription stages. Interestingly, E1A 1-80 can greatly enhance transcription from chromatin templates, but not from naked DNA, when added at pre-initiation complex (PIC) formation and transcription-initiation stages. These data reveal a new dimension for E1A 1-80's interface with chromatin and may reflect its interaction with key players in PIC formation, p300 and TFIID, and/or possibly a role in chromatin remodeling. PMID- 22521916 TI - Midterm results of combined acromioclavicular and coracoclavicular reconstruction using nylon tape. AB - PURPOSE: The purpose of this study was to evaluate the radiologic and functional outcomes of an anatomic reconstruction of both acromioclavicular (AC) and coracoclavicular (CC) ligaments in types III to V AC injuries using nylon tape and no metal hardware. METHODS: A prospective case-series study was performed on 17 cases with types III to V AC injuries treated by anatomic reconstruction of the AC ligaments (anterior and superior) and CC ligaments (conoid and trapezoid) using nylon tape and no metal hardware. Clinical assessments, radiologic findings, and visual analog scale, American Shoulder and Elbow Surgeons, and Constant scores were recorded for all patients. After a minimum postoperative period of 2 years, all cases were re-evaluated and rescored. RESULTS: The case series study comprised 17 cases with types III to V AC injuries. After a mean follow-up period of 28 months (minimum, 24 months), the patients had a significantly improved mean visual analog scale score (from 6.4 to 2.4 points), American Shoulder and Elbow Surgeons score (from 25 to 81.7 points), and Constant score (from 21 to 85 points), with overall 88.2% satisfaction. Radiographic superior displacement showed reduction from 13 to 2 mm whereas posterior displacement showed reduction from 5 to 2 mm, and both were statistically significant (P < .05). The rate of return to the patients' preinjury jobs was 82.4%, and there was 1 case of recurrent subluxation. CONCLUSIONS: Combined anatomic reconstruction of both AC and CC ligaments using nylon tape by the described technique provides overall 88.2% satisfaction, 94% radiologic reduction, and a low complication rate. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 22521915 TI - The KSHV viral IL-6 homolog is sufficient to induce blood to lymphatic endothelial cell differentiation. AB - The predominant tumor cell of Kaposi's Sarcoma (KS) is the spindle cell, a cell of endothelial origin that expresses markers of lymphatic endothelium. In culture, Kaposi's Sarcoma-associated herpesvirus (KSHV) infection of blood endothelial cells drives expression of lymphatic endothelial cell specific markers, in a process that requires activation of the gp130 receptor and the JAK2/STAT3 and PI3K/AKT signaling pathways. While expression of each of the KSHV major latent genes in endothelial cells failed to increase expression of lymphatic markers, the viral homolog of human IL-6 (vIL-6) was sufficient for induction and requires the JAK2/STAT3 and PI3K/AKT pathways. Therefore, activation of gp130 and downstream signaling by vIL-6 is sufficient to drive blood to lymphatic endothelial cell differentiation. While sufficient, vIL-6 is not necessary for lymphatic reprogramming in the context of viral infection. This indicates that multiple viral genes are involved and suggests a central importance of this pathway to KSHV pathogenesis. PMID- 22521917 TI - Consequences of the ablation of nonpeptidergic afferents in an animal model of trigeminal neuropathic pain. AB - Damage to peripheral nerves causes significant remodeling of peripheral innervation and can lead to neuropathic pain. Most nociceptive primary afferents are unmyelinated (C fibers) and subdivided into peptidergic and nonpeptidergic fibers. Previous studies have found nerve injury in the trigeminal system to induce changes in small-diameter primary afferent innervation and cause significant autonomic sprouting into the upper dermis of the lower-lip skin of the rat. In this study, we used the ribosomal toxin, saporin, conjugated to the lectin IB4 to specifically ablate the nonpeptidergic nociceptive C fibers, to see if loss of these fibers was enough to induce autonomic fiber sprouting. IB4 saporin treatment led to specific and permanent ablation of the IB4-positive, P2X(3)-immunoreactive fibers and led to sprouting of parasympathetic fibers into the upper dermis, but not of sympathetic fibers. These changes were associated with significant increase in glial-derived nerve growth factor levels in the lower-lip skin. While IB4-saporin treatment had no effect on evoked mechanical thresholds when von Frey hairs were applied to the lower-lip skin, ablation of nonpeptidergic fibers in a chronic constriction injury model caused significant sympathetic and parasympathetic fiber sprouting, and led to an exacerbated pain response. This was an unexpected finding, as it has been suggested that nonpeptidergic fibers play a major role in mechanical pain, and suggests that these fibers play a complex role in the development of neuropathic pain. PMID- 22521918 TI - [European Association of Urology guidelines on vasectomy]. AB - CONTEXT: The European Association of Urology presents its guidelines for vasectomy. Vasectomy is highly effective, but problems can arise that are related to insufficient preoperative patient information, the surgical procedure, and postoperative follow-up. OBJECTIVE: These guidelines aim to provide information and recommendations for physicians who perform vasectomies and to promote the provision of adequate information to the patient before the operation to prevent unrealistic expectations and legal procedures. EVIDENCE ACQUISITION: An extensive review of the literature was carried out using Medline, Embase, and the Cochrane Database of Systematic Reviews from 1980 to 2010. The focus was on randomised controlled trials (RCTs) and meta-analyses of RCTs (level 1 evidence) and on well designed studies without randomisation (level 2 and 3 evidence). A total of 113 unique records were identified for consideration. Non-English language publications were excluded as well as studies published as abstracts only or reports from meetings. EVIDENCE SYNTHESIS: The guidelines discuss indications and contraindications for vasectomy, preoperative patient information and counselling, surgical techniques, postoperative care and subsequent semen analysis, and complications and late consequences. CONCLUSIONS: Vasectomy is intended to be a permanent form of contraception. There are no absolute contraindications for vasectomy. Relative contraindications may be the absence of children, age <30 yr, severe illness, no current relationship, and scrotal pain. Preoperative counselling should include alternative methods of contraception, complication and failure rates, and the need for postoperative semen analysis. Informed consent should be obtained before the operation. Although the use of mucosal cautery and fascial interposition have been shown to reduce early failure compared to simple ligation and excision of a small vas segment, no robust data show that a particular vasectomy technique is superior in terms of prevention of late recanalisation and spontaneous pregnancy after vasectomy. After semen analysis, clearance can be given in case of documented azoospermia and in case of rare nonmotile spermatozoa in the ejaculate at least 3 mo after the procedure. PMID- 22521919 TI - [Variability of the urological clinical practice in prostate cancer in Spain]. AB - OBJECTIVES: Study the opinion of the Spanish urologists regarding the main points in the diagnosis, prevention, quality of life and treatment of prostate cancer. MATERIAL AND METHODS: An anonymous questionnaire was administered to 290 specialists who represented the urological professional group involved in the management of prostate cancer in Spain. The following were considered in their definition: grade of professional experience, work setting, contractual relation with patient and academic character of the center. The statistical analysis was based on the study of relative frequencies for qualitative variables. The results were interpreted in 2009-10 and the final report of them was done in 2011. RESULTS: Response rate collected and correctly transcribed from the forms was 96.9% (n=281). This accounts for 10-15% of the national group. Median age was 47.7 (29-69) years and 92% were men. Mean years of professional experience were 19.1 (1-43). Responses collected regarding 153 questions were analyzed. These dealt with: a) How the diagnosis of the disease was carried out in the setting of the surveyed; b) The opinions given on the disease prevention; c) Treatment of the localized treatment; d) Treatment of the advanced disease; and e) The definition of the fields of interest for the professional. CONCLUSION: This survey showed important variability in some points of clinical practice in regards to the recommendations of the experts. It also shows the principal concerns of the professional, defines opportunities for training improvements and detects needs in the national urological group. PMID- 22521920 TI - Baseline functional capacity and the benefit of cardiac resynchronization therapy in patients with mildly symptomatic heart failure enrolled in MADIT-CRT. AB - BACKGROUND: Mildly symptomatic heart failure (HF) patients were shown to derive substantial clinical benefit from cardiac resynchronization therapy with defibrillator (CRT-D) in Multicenter Automatic Defibrillator Implantation Trial in Cardiac Resynchronization Therapy. However, the relationship between functional capacity (FC) and CRT-D benefit in the trial was not assessed. OBJECTIVE: To evaluate the association between FC and response to CRT-D in Multicenter Automatic Defibrillator Implantation Trial in Cardiac Resynchronization Therapy. METHODS: We evaluated the association between preimplantation FC and the benefit of CRT-D in reducing the risk of HF or death in Multicenter Automatic Defibrillator Implantation Trial in Cardiac Resynchronization Therapy. Functional status was assessed by a 6-minute walk test (6MWT), dichotomized at the median value as poor (<350 m) or good (>=350 m). RESULTS: Implantable cardioverter-defibrillator-only patients with a poor FC had an adjusted 73% increased risk for HF or death (P <.001) and a 2.4-fold (P = .001) increased risk for all-cause mortality. CRT-D therapy was associated with 63% (P <.001) and 44% (P <.001) reductions in the risk of HF or death among left bundle branch block patients with a poor FC and a good FC, respectively (P for interaction = .10). Among left bundle branch block patients with a poor FC, CRT-D was also associated with a significant reduction in the risk of all-cause mortality (hazard ratio 0.52; P = .015) whereas the survival benefit of CRT-D was not observed among those who had a higher FC at enrollment (hazard ratio 1.01; P = .98; P for interaction = .10). CONCLUSIONS: Poor FC is a strong independent predictor for mortality and HF events in patients with mildly symptomatic HF. Left bundle branch block patients with poor baseline FC derive a pronounced benefit from CRT-D, manifest by a significant reduction in mortality. PMID- 22521921 TI - Designed formulation based on alpha-tocopherol anchored on chitosan microspheres for pH-controlled gastrointestinal controlled release. AB - Chitosan microspheres were prepared and vitamin E (alpha-tocopherol) was anchored onto the polymer. The amount of alpha-tocopherol entrapped onto a gram of the microspheres based system was 13.4+/-0.4 mg. The microspheres modified with alpha tocopherol were applied to vitamin E controlled release in a simulated gastrointestinal system. Characterizations were carried out by optical microscopy, FTIR and HPLC-UV techniques. For chitosan microspheres based system there was a 4.10% release, while for pure alpha-tocopherol the release was 25.53%. The percentage of alpha-tocopherol released at pH 6.8 was 13.10% for chitosan microspheres and 60.00% for free alpha-tocopherol. At pH 7.4, alpha tocopherol release reached 51.30% and 92.88% for chitosan microspheres and pure alpha-tocopherol, respectively. alpha-tocopherol immobilized onto chitosan presented three distinct landings at each studied pH, whereas pure alpha tocopherol presented only two established solubilization regions, one at pH 1.2, while between pH 6.8 and 7.4 it did not present any difference, establishing after 3.5h. Thus, the immobilization of alpha-tocopherol onto chitosan microspheres figures it as an efficient controlled release system. PMID- 22521923 TI - Enhancement of BODIPY505/515 lipid fluorescence method for applications in biofuel-directed microalgae production. AB - This paper describes a microalgal cell lipid fluorescence enhancement method using BODIPY(505/515), which can be used to screen for lipids in wild-type microalgae and to monitor lipid content within microalgae production processes to determine optimal harvesting time. The study was based on four microalgae species (Dunaliella teteriolecta, Tetraselmis suecica, Nannochloropsis oculata, and Nannochloris atomus) selected because of their inherent high lipid content. An extended analysis was carried out with N. oculata due to the depressed fluorescence observed when compared with the other experimental strains. BODIPY(505/515) lipid fluorescence was determined for two solvent pre-treatment methods (DMSO and glycerol) and four staining condition parameters (analysis time, staining temperature, dye concentration, and algal cell concentration). It was found that lipid fluorescence of thick cell-walled microalgae, such as N. oculata, is significantly enhanced by both the pre-treatment methods and staining condition parameters, thereby significantly enhancing lipid fluorescence by ca. 800 times the base autofluorescence. The lipid fluorescence enhancement method provides a quick and simple index for in vivo Flow Cytometry quantification of total lipid contents for purposes of species screening or whole culture monitoring in biofuel-directed microalgae production. PMID- 22521922 TI - DNA binding site analysis of Burkholderia thailandensis response regulators. AB - Bacterial response regulators (RR) that function as transcription factors in two component signaling pathways are crucial for ensuring tight regulation and coordinated expression of the genome. Currently, consensus DNA binding sites in the promoter for very few bacterial RRs have been identified. A systematic method to characterize these DNA binding sites for RRs would enable prediction of specific gene expression patterns in response to extracellular stimuli. To identify RR DNA binding sites, we functionally activated RRs using beryllofluoride and applied them to a protein-binding microarray (PBM) to discover DNA binding motifs for RRs expressed in Burkholderia, a Gram-negative bacterial genus. We identified DNA binding motifs for conserved RRs in Burkholderia thailandensis, including KdpE, RisA, and NarL, as well as for a previously uncharacterized RR at locus BTH_II2335 and its ortholog in the human pathogen Burkholderia pseudomallei at locus BPSS2315. We further demonstrate RR binding of predicted genomic targets for the two orthologs using gel shift assays and reveal a pattern of RR regulation of expression of self and other two component systems. Our studies illustrate the use of PBMs to identify DNA binding specificities for bacterial RRs and enable prediction of gene regulatory networks in response to two component signaling. PMID- 22521924 TI - [Multicentric giant cell tumor in the upper extremity]. AB - Multicentric giant cell tumors of bone are rare; they represent less than 1% of all giant cell tumors. We report the case of a 24-year-old right-handed man, who presented in 1985 with a giant cell tumor of the upper end of the right humerus. After failure of conservative treatment (curettage and bone grafting), resection arthrodesis of the shoulder with a free vascularised fibular autograft was performed. Three years later, the patient developed an osteolytic lesion of the lower end of the ipsilateral radius, involving the soft tissues and the wrist joint. He was treated with resection-arthrodesis of the wrist with a free vascularised fibular graft. View after 24 years for a new localization of the lower extremity of the humerus, which treated by curettage and bone grafting with a favorable postoperative (follow-up). The histologic study confirmed again the same diagnosis. After review of the literature, we report the uniqueness of this case report. PMID- 22521925 TI - High expression of XYL2 coding for xylitol dehydrogenase is necessary for efficient xylose fermentation by engineered Saccharomyces cerevisiae. AB - The traditional ethanologenic yeast Saccharomyces cerevisiae cannot metabolize xylose, which is an abundant sugar in non-crop plants. Engineering this yeast for a practicable fermentation of xylose will therefore improve the economics of bioconversion for the production of fuels and chemicals such as ethanol. One of the most widely employed strategies is to express XYL1, XYL2, and XYL3 genes derived from Scheffersomyces stipitis (formerly Pichia stiptis) in S. cerevisiae. However, the resulting engineered strains have been reported to exhibit large variations in xylitol accumulation and ethanol yields, generating many hypotheses and arguments for elucidating these phenomena. Here we demonstrate that low expression levels of the XYL2 gene, coding for xylitol dehydrogenase (XDH), is a major bottleneck in efficient xylose fermentation. Through an inverse metabolic engineering approach using a genomic library of S. cerevisiae, XYL2 was identified as an overexpression target for improving xylose metabolism. Specifically, we performed serial subculture experiments after transforming a genomic library of wild type S. cerevisiae into an engineered strain harboring integrated copies of XYL1, XYL2 and XYL3. Interestingly, the isolated plasmids from efficient xylose-fermenting transformants contained XYL2. This suggests that the integrated XYL2 migrated into a multi-copy plasmid through homologous recombination. It was also found that additional overexpression of XYL2 under the control of strong constitutive promoters in a xylose-fermenting strain not only reduced xylitol accumulation, but also increased ethanol yields. As the expression levels of XYL2 increased, the ethanol yields gradually improved from 0.1 to 0.3g ethanol/g xylose, while the xylitol yields significantly decreased from 0.4 to 0.1g xylitol/g xylose. These results suggest that strong expression of XYL2 is a necessary condition for developing efficient xylose-fermenting strains. PMID- 22521926 TI - Is the Berg Balance Scale an internally valid and reliable measure of balance across different etiologies in neurorehabilitation? A revisited Rasch analysis study. AB - OBJECTIVES: To assess, within the context of Rasch analysis, (1) the internal validity and reliability of the Berg Balance Scale (BBS) in a sample of rehabilitation patients with varied balance abilities; and (2) the comparability of the BBS measures across different neurologic diseases. DESIGN: Observational prospective study. SETTING: Rehabilitation ward of an Italian district hospital. PARTICIPANTS: Consecutively admitted inpatients and outpatients (N=217); for 85 participants, data were collected both on admission and discharge, giving a total sample of 302 observations. INTERVENTION: Not applicable. MAIN OUTCOME MEASURE: BBS. RESULTS: Most of the BBS items had to be rescored, and 2 items (static sitting and standing balance) had to be deleted, to attain adequate internal construct validity (chi(2)(24)=35.68; P=.059). The reliability of the Rasch modified BBS (BBS-12) (total score, 0-35) was high (.957), indicating precision of measurement at the individual level. The analysis of differential item functioning (DIF) showed invariance of the item calibrations across patients' sex, age, and etiology. After adjusting for the possible effect of repeated measurements on person estimates, the analysis of DIF by timing of assessment confirmed the stability of the item hierarchy across time. A practical ruler was provided to convert item raw scores into Rasch estimates of balance ability. CONCLUSIONS: This study supports the internal validity and reliability of the BBS 12 as a measurement tool independent of the etiology of the neurologic disease causing the balance impairment. In view of some sample-related issues and that not all possible etiologies encountered in the neurorehabilitation settings were tested, a larger multicenter study is warranted to confirm these findings. PMID- 22521927 TI - PWC 75%/kg, a fitness index not linked to resting heart rate: testing procedure and reference values. AB - OBJECTIVES: To develop a fitness index unlinked to resting heart rate and suitable for clinical use, and to obtain reference values of this new index for healthy subjects. DESIGN: Cross-sectional study. SETTING: Research laboratory. PARTICIPANTS: A volunteer sample of healthy subjects (N=100; 50 men; age range, 20-70y) randomly recruited from the general community. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Participants performed a submaximal, multistage cycle ergometer test. A new fitness index, the physical working capacity at 75% of the predicted maximal heart rate per kilogram of body weight (PWC(75%)/kg), was calculated. Its concordance with a previously described fitness index and its relationship with age were examined, as well as differences attributable to sex and lifestyle. Reference values of the PWC(75%)/kg (mean +/- SD and 95% confidence interval) were calculated and categorized by age classes of 10 years and by sex. RESULTS: The intraclass correlation coefficient (ICC) between PWC(75%)/kg and the working capacity index at 65% of the heart rate reserve per kilogram of body weight (WCI(65%HRreserve)/kg) was very high (ICC=.96, P<.001), indicating that the fitness index can be estimated without measuring the resting heart rate. PWC(75%)/kg decreased as age increased. The average PWC(75%)/kg was significantly higher in men than in women (P<.001), and in active than in inactive subjects (P<.01). CONCLUSIONS: This study presents a new fitness index, the PWC(75%)/kg, which is suitable for measuring fitness in active and sedentary people aged 20 to 70 years. It may also be a suitable fitness index for selected chronically ill individuals. This study also provides reference values of the PWC(75%)/kg obtained from healthy men and women. PMID- 22521929 TI - Multispecialty approach: the need for heart failure disease management for refining cardiac resynchronization therapy. AB - Cardiac resynchronization therapy (CRT) has been proven in clinical trials to be a very effective therapy in appropriate patients. However, although the literature has primarily focused on appropriate implanting techniques and inclusion criteria for CRT devices by electrophysiologists, most patients who receive CRT are managed by their primary care providers with the help of general cardiologists and/or heart failure (HF) specialists. As CRT has been more broadly applied over the past decade, the fragmentation and specialization of care in the current health care system have created challenges in optimizing this otherwise invasive but potentially beneficial intervention in the complex HF patient. Furthermore, cost considerations as well as appropriate follow-up care continue to challenge the optimal application of these devices, particularly when evidence to support multidisciplinary approaches is lacking. The challenge begins with identification of appropriate candidates for CRT, which is an evolving concept due to data emerging from new studies with a wide range of inclusion and exclusion criteria coupled with increasing oversight from providers or even logistical hurdles from patients. Postimplant management practices and procedures are still evolving. The important and so-far unresolved concept of the "nonresponder" to CRT remains largely subjective and is variably defined in the literature, and the lack of understanding of the underlying mechanisms of "nonresponse" continues to challenge long-term management of CRT, even given the recent developments in advanced sensor technologies. Therefore, further investigations into HF disease management with a multispecialty approach, pre-CRT and post-CRT, are warranted. PMID- 22521928 TI - The quest for rotors in atrial fibrillation: different nets catch different fishes. PMID- 22521930 TI - Cause for concern. PMID- 22521931 TI - Managing atrial fibrillation in the CRT patient: controversy or consensus? AB - The cumulative incidence of new onset atrial fibrillation (AF) in patients undergoing cardiac resynchronization therapy (CRT) is substantial, exceeding 25% in multiple recent studies. Although AF patients undergoing CRT show improved echocardiographic parameters, functional status, and quality of life in, they benefit to a lesser degree than do patients in normal sinus rhythm. They also exhibit a trend toward increased mortality. Understanding the barriers to response from CRT among AF patients is critical to addressing the needs of growing populations of patients with AF and HF. Foremost among these are suboptimal biventricular pacing, often characterized by fusion or pseudo-fusion complexes, leading to inefficient CRT delivery. Furthermore, AF increases the risk of inappropriate shocks, which lead to substantial psychiatric morbidity, increased risk of heart failure hospitalization, and may also increase mortality. Assiduous rate control is reasonable for all AF patients receiving CRT, but there is a paucity of data regarding specific antiarrhythmic drug therapy recommendations. For patients with permanent AF and severe symptoms, atrioventricular junction ablation appears effective in improving response by ensuring biventricular capture and reducing implantable cardioverter defibrillator shock burden in selected patients. Catheter-based techniques such as pulmonary vein isolation appear more attractive and in the future may offer further advantages and lower risks, particularly for patients with paroxysmal AF. PMID- 22521932 TI - Thinking beyond resynchronization therapy in the failing heart. PMID- 22521933 TI - The challenge of nonresponders to cardiac resynchronization therapy: lessons learned from oncology. PMID- 22521934 TI - Cardiac resynchronization therapy (CRT): clinical trials, guidelines, and target populations. AB - Over the last 10 years, several large, well-designed clinical trials have firmly established the role of cardiac resynchronization therapy (CRT) as a recommended treatment strategy for moderate-to-severe heart failure (HF). A review of the relevant results from the MUSTIC, MIRACLE, CONAK-CD, and MIRACLE ICD trials reveals that in patients with New York Heart Association (NYHA) class III-IV HF, CRT produces consistent improvements in quality of life, functional status, and exercise capacity while also providing strong evidence for reverse remodeling and diminished functional mitral regurgitation, resulting in reductions in both HF hospitalizations and all-cause morbidity and mortality. In patients with earlier NYHA class I-II HF, the benefit of CRT has been more controversial. The principal ongoing challenges addressed in this article include the substantial 30% of patients who receive a CRT device but fail to respond, the wide variations in how to define "response" vs "nonresponse," and how to identify patients who will benefit from CRT, especially narrow QRS (<120 ms), those with right bundle branch block, and those with mild-to-moderate (NYHA class I-II) HF. An important result of this uncertainty is the lack of a good sense of the optimal rate of CRT implantation, making consideration of the data reviewed in this article crucial for identifying important gaps of knowledge and mechanisms of action that need to be studied in the near future. PMID- 22521935 TI - To the Editor-Jailing of cardiac leads with endovascular stents in hemodialysis patients. PMID- 22521936 TI - Understanding the cardiac substrate and the underlying physiology: Implications for individualized treatment algorithm. PMID- 22521937 TI - Biological pacemaker created by percutaneous gene delivery via venous catheters in a porcine model of complete heart block. AB - BACKGROUND: Pacemaker-dependent patients with device infection require temporary pacing while the infection is treated. External transthoracic pacing is painful and variably effective, while temporary pacing leads are susceptible to superinfection. OBJECTIVE: To create a biological pacemaker delivered via venous catheters in a porcine model of complete heart block, providing a temporary alternative/adjunct to external pacing devices without additional indwelling hardware. METHODS: Complete atrioventricular (AV) nodal block was induced in pigs by radiofrequency ablation after the implantation of a single-chamber electronic pacemaker to maintain a ventricular backup rate of 50 beats/min. An adenoviral vector cocktail (K(AAA) + H2), expressing dominant-negative inward rectifier potassium channel (Kir2.1AAA) and hyperpolarization-activated cation channel (HCN2) genes, was injected into the AV junctional region via a NOGA Myostar catheter advanced through the femoral vein. RESULTS: Animals injected with K(AAA) + H2 maintained a physiologically relevant ventricular rate of 93.5 +/- 7 beats/min (n = 4) compared with control animals (average rate, 59.4 +/- 4 beats/min; n = 6 at day 7 postinjection; P <.05). Backup electronic pacemaker utilization decreased by almost 4-fold in the K(AAA) + H2 group compared with the control (P <.05), an effect maintained for the entire 14-day window. In contrast to the efficacy of gene delivery into the AV junctional region, open-chest, direct injection of K(AAA) + H2 (or its individual vectors) into the ventricular myocardium failed to elicit significant pacemaker activity. CONCLUSIONS: The right-sided delivery of K(AAA) + H2 to the AV junctional region provided physiologically relevant biological pacing over a 14-day period. Our approach may provide temporary, bridge-to-device pacing for the effective clearance of infection prior to the reimplantation of a definitive electronic pacemaker. PMID- 22521938 TI - Atrioventricular node functional remodeling induced by atrial fibrillation. AB - BACKGROUND: The atrioventricular node (AVN) plays a vital role in determining the ventricular rate during atrial fibrillation (AF). AF results in profound electrophysiological and structural remodeling in the atria as well as the sinus node. However, it is unknown whether AVN undergoes remodeling during AF. OBJECTIVE: To determine whether AVN undergoes functional remodeling during AF. METHODS: AVN conduction properties were studied in vitro in 9 rabbits with AF and 10 normal controls. A previously validated index of AVN dual-pathway electrophysiology, His-electrogram alternans, was used to monitor fast-pathway or slow-pathway (SP) AVN conduction in these experiments. AVN conduction properties were further studied in vivo in 7 dogs with chronic AF and 8 controls. RESULTS: Compared with the control rabbits, the rabbits with AF had a longer AVN conduction time (83 +/- 16 ms vs 68 +/- 7 ms; P <.01), longer AVN effective refractory period (141 +/- 27 ms vs 100 +/- 9 ms; P <.01), an earlier transition from fast-pathway to SP conduction (at a longer prematurity, 249 +/- 60 ms vs 171 +/- 24 ms; P <.01), and a slower ventricular rate during simulated AF (RR interval 249 +/- 42 ms vs 202 +/- 12 ms; P <.01). Notably, a larger proportion of conducted beats utilized the SP in AF preparations (92% +/- 12% vs 63% +/- 32%; P <.05). Long-term AF in dogs resulted in a longer atrioventricular conduction time and AVN effective refractory period and a slower ventricular rate during AF compared with the controls. CONCLUSIONS: Pronounced AVN functional electrophysiological remodeling occurs after long-term AF, which could lead to a spontaneous slowing of the ventricular rate. Furthermore, the SP dominance during AF underscores the effectiveness of its modification by ablation for ventricular rate control during AF. PMID- 22521939 TI - Contemporary and future trends in cardiac resynchronization therapy to enhance response. AB - The rationale for cardiac resynchronization therapy (CRT), expectations in terms of patient benefit, patient selection for CRT, selection of a CRT pacemaker (CRT P) vs CRT plus implantable cardioverter-defibrillator (CRT-D) platform, and studies evaluating device programming to enhance benefit from CRT are reviewed. The notion of an "optimal" left ventricular (LV) pacing site, the rationale for identifying and avoiding LV pacing in regions of scar, the use of anatomic, hemodynamic, and electrical parameters to identify an optimal LV pacing site, and the potential utility of multisite LV pacing to enhance benefit from CRT are discussed. Finally, the advantages and disadvantages of the various methods for LV lead delivery are reviewed. PMID- 22521940 TI - Advances in electrical therapy for heart failure: papers from the International ADVANCE CRT Summit. PMID- 22521941 TI - Markers associated with testosterone enhancement of methamphetamine-induced striatal dopaminergic neurotoxicity. AB - Intact male CD-1 mice received an injection of testosterone propionate (TP--5 ug), progesterone (P--5 mg), the oil vehicle or remained untreated (control). At 24 hours after hormonal treatments the mice received an injection of methamphetamine (MA--40 mg/kg) and rectal temperatures were measured. At 5 days post-MA, assays were performed to assess effects of these treatments. Maximal increases in body temperatures, that were significantly greater than oil-treated controls, were obtained in TP-treated mice. At 5 days post-MA, maximal weight reductions were obtained with TP-treated mice, while P-treated mice showed no significant decrease between the pre- versus post-MA determinations. Striatal dopamine concentrations showed maximal reductions and heat-shock protein-70 maximal increases in the TP group, with both differing significantly as compared with all other groups. Protein levels of dopamine transporters were significantly decreased in P-treated mice, while vesicular monoamine transporter-2 was significantly decreased in TP-treated mice. Taken together, these results suggest that testosterone exacerbates the deleterious effects of MA within male mice as indicated by a number of markers related to neurotoxicity. The changes in markers as associated with this enhanced neurotoxicity suggest that TP may increase thermal/energy responses and/or oxidative stress to produce this effect. PMID- 22521942 TI - Deep oxidation of glucose in enzymatic fuel cells through a synthetic enzymatic pathway containing a cascade of two thermostable dehydrogenases. AB - A synthetic enzymatic pathway was designed for the deep oxidation of glucose in enzymatic fuel cells (EFCs). Polyphosphate glucokinase converts glucose to glucose-6-phosphate using low-cost, stable polyphosphate rather than costly ATP. Two NAD-dependent dehydrogenases (glucose-6-phosphate dehydrogenase and 6 phosphogluconate dehydrogenase) that were immobilized on the bioanode were responsible for generating two NADH per glucose-6-phosphate (i.e., four electrons were generated per glucose via a diaphorase-vitamin K(3) electron shuttle system at the anode). Additionally, to prolong the enzyme lifetime and increase the power output, all of the recombinant enzymes that originated from thermophiles were expressed in Escherichia coli and purified to homogeneity. The maximum power density of the EFC with two dehydrogenases was 0.0203 mW cm(-2) in 10 mM glucose at room temperature, which was 32% higher than that of an EFC with one dehydrogenase, suggesting that the deep oxidation of glucose had occurred. When the temperature was increased to 50 degrees C, the maximum power density increased to 0.322 mW cm(-2), which was approximately eight times higher than that based on mesophilic enzymes at the same temperature. Our results suggest that the deep oxidation of glucose could be achieved by using multiple dehydrogenases in synthetic cascade pathways and that high power output could be achieved by using thermostable enzymes at elevated temperatures. PMID- 22521944 TI - MR neurography of the median nerve at 3.0T: optimization of diffusion tensor imaging and fiber tractography. AB - OBJECTIVES: The purpose of this study was to systematically assess the optimal b value and reconstruction parameters for DTI and fiber tractography of the median nerve at 3.0T. METHODS: Local ethical board approved study with 45 healthy volunteers (15 men, 30 women; mean age, 41 +/- 3.4 years) who underwent DTI of the right wrist at 3.0T. A single-shot echo-planar-imaging sequence (TR/TE 10123/40 ms) was acquired at four different b-values (800, 1000, 1200, and 1400 s/mm(2)). Two independent readers performed post processing and fiber tractography. Fractional anisotropy (FA) maps were calculated. Fiber tracts of the median nerve were generated using four different algorithms containing different FA thresholds and different angulation tolerances. Data were evaluated quantitatively and qualitatively. RESULTS: Tracking algorithms using a minimum FA threshold of 0.2 and a maximum angulation of 10 degrees were significantly better than other algorithms. Fiber tractography generated significantly longer fibers in DTI acquisitions with higher b-values (1200 and 1400 s/mm(2) versus 800 s/mm(2); p<0.001). The overall quality of fiber tractography was best at a b value of 1200 s/mm(2) (p<0.001). CONCLUSIONS: In conclusion, our results indicate use of b-values between 1000 and 1400 s/mm(2) for DTI of the median nerve at 3.0T. Optimal reconstruction parameters for fiber tractography should encompass a minimum FA threshold of 0.2 and a maximum angulation tolerance of 10. PMID- 22521943 TI - Determination of trace copper ions with ultrahigh sensitivity and selectivity utilizing CdTe quantum dots coupled with enzyme inhibition. AB - A fluorescent transducer with the combination of the unique property of CdTe quantum dots (QDs) and enzymatic inhibition assays was successfully constructed for the purpose of ultrasensitive determination of Cu(2+) ions. Alcohol oxidase (AO) catalyzed the oxidation of methanol to produce hydrogen peroxide (H(2)O(2)), inducing the quenching of QDs fluorescence. In the presence of Cu(2+) ions, the activity of AO was inhibited and therefore, the quenching of QDs fluorescence was decreased. Other metal ions showed no intensive inhibition to the AO activity even at 10 or 100 times Cu(2+) ions concentration, presenting a high selectivity of this fluorescent sensor. Using this QDs-enzyme hybrid system, the detection limit for Cu(2+) ions was found to be as low as 0.176 ng/mL (2.75 nM) due to the superior fluorescence property of QDs. Practical application of the QDs-enzyme hybrid system has been demonstrated by domestic waste water, agricultural irrigation water and lake water analysis. Results of Cu(2+) determinations were in good agreement with those obtained by inductively coupled plasma analytical method. The coupling of efficient quenching of QDs photoluminescence by H(2)O(2) generated from oxidase-catalyzed reaction and the effective enzymatic inhibition make this a simple and sensitive method for heavy metal ions detection. PMID- 22521945 TI - Transcript profiling of pattern recognition receptors in a semi domesticated breed of buffalo, Toda, of India. AB - The primary objective of this study was to assess the expression profile and levels of toll-like receptor (TLR) mRNAs in the spleen, lung, mediastinal lymph node (MLN), jejunum, rectum, skin and peripheral blood mononuclear cells (PBMC) of Toda and Murrah buffalos. Spleen and PBMC had increased expression of TLR mRNAs 2, 4, 5, 6, 8, 9 and 10; lung had increased expression of TLR mRNAs 2, 4, 5, 6 and 8, MLN TLR mRNA 6, 9, 10 and decrease in TLR 3 and 7 mRNAs in skin. No significant differences were observed in the expression levels of any of the TLR mRNA in jejunum and rectum. Toda buffaloes showed significantly higher expression levels of TLR 9 mRNA in MLN, TLR mRNAs 1, 5, 6, 9 and 10 in skin and TLR mRNAs 2, 4, 7 and 9 in PBMC than Murrah buffaloes living in the vicinity. Toda and Murrah buffaloes were inoculated with TLR5 (flagellin) and TLR9 (CpG ODN) ligands in vivo and expression levels of the respective TLRs analyzed 12h later. Following CpG inoculation, Toda buffaloes had significantly higher levels of TLR 9 mRNA expression but not in Murrah. However, flagellin induction did not increase TLR 5 mRNA expression in both these breeds. Histological sections of the skin were made and infiltrating cell clusters were graded and quantified. Following CpG inoculation, Toda buffaloes showed higher numbers of infiltrating grade 1 and grade 3 cell clusters while Murrah showed lower numbers of infiltrating grade 1 cells as compared to mock-inoculated skin sections. Flagellin treatment revealed no significant differences in infiltrating cell clusters in both the breeds. The results have shown differential expression of TLR mRNAs in various tissues between two divergent buffalo breeds with the highest difference in TLR expression profile seen in the skin, the largest portal of entry of pathogens, of Toda. PMID- 22521946 TI - A nano switch mechanism for the redox-responsive sulfotransferase. AB - Cellular redox signaling is important in diverse physiological and pathological processes. The activity of rat phenol sulfotransferase (rSULT1A1), which is important for the metabolism of hormone and drug, is subjected to redox regulation. Two cysteines, Cys232 and Cys66, nanometer away from each other and from the enzyme active site were proposed to form disulfide bond to regulate the activity of rSULT1A1. A nano switch, composed of a flexible loop from amino acid residues 59-70, explained how this long distance interaction between two cysteines can be achieved. The enzyme properties were investigated through site directed muatagnesis, circular dichroism, enzyme kinetics and homologous modeling of the rSULT1A1 structures. We proposed that the formation of disulfide bond between Cys232 and Cys66 induced conformational changes of sulfotransferase, then in turn affected its nucleotide binding and enzyme activity. This discovery was extended to understand the possible redox regulation of other sulfotransferases from different organisms. The redox switch can be created in other redox insensitive sulfotransferases, such as human phenol sulfotransferase (hSULT1A1) and human alcohol sulfotransferase (hSULT2A1), to produce mutant enzymes with redox regulation capacity. This study strongly suggested that redox regulation of drug and hormone metabolism can be significantly varied even though the sequence and structure of SULT1A1 of human and rat have a high degree of homology. PMID- 22521947 TI - Exploring the association between lifetime physical activity and pelvic floor disorders: study and design challenges. AB - BACKGROUND: One in four women has moderate to severe symptoms of at least one pelvic floor disorder. Lifetime physical activity, a modifiable risk factor, may theoretically predispose women to, or protect them from, developing pelvic floor disorders. It is neither feasible nor ethical to test this association using the most rigorous (level I) study design. PURPOSE: The aim of this manuscript is to describe the methods for the PHysical ACtivity Study (PHACTS), which encompasses two case-control studies and the development of a registry, and to describe challenges and solutions to study progress to date. For each of the case-control studies, the primary aims are to determine, compared to controls with neither pelvic organ prolapse nor urinary incontinence, whether 1) pelvic organ prolapse or 2) stress urinary incontinence is associated with a) increased or decreased current leisure activity or b) increased or decreased overall lifetime activity (including leisure, household, outdoor, and occupational) measured in MET-hours per week, as well as in strenuous hours per week. METHODS: To obtain 175 pelvic organ prolapse cases, 175 stress urinary incontinence cases, and an equal number of age, body mass index and recruitment site matched controls, we plan to enroll 1500 women from about 20 primary care level clinics. RESULTS: We have encountered various challenges leading to lessons learned about minimizing bias, recruitment from community clinics, the lifetime physical activity instrument used, and data management. CONCLUSIONS: Our experiences can help guide future investigators studying risk factors, particularly physical activity, and pelvic floor disorders. PMID- 22521948 TI - Secondary production of a zoobenthic community under metal stress. AB - Little is known about the influence of toxicants on the function of freshwater sediments. To better understand these effects, a long-term microcosm experiment was carried out with cadmium (Cd) as the model pollutant (50 and 400 mg Cd kg(-1) dw). In a seven-month study the effect of Cd was examined on secondary production of the zoobenthos (higher taxonomic level) and specifically of the nematode community (species level). Production of almost all taxa decreased under low Cd stress, with rotifers as the only taxon that was able to thrive under this condition. High Cd stress resulted in a decrease in secondary production of all groups with strong differences between taxa. Nematode production likewise decreased, with strongest effects in the higher Cd concentration. Interestingly, at the end of the study, several bacteria-feeding species had benefited from the low Cd stress, probably due to their rapid development in relation to other species and/or the high bacterial density under this condition. Taken together, the results of this study provide insight into secondary production of sediment communities and the important effects of a toxicant thereon. PMID- 22521949 TI - Emergency water supply: a review of potential technologies and selection criteria. AB - Access to safe drinking water is one of the first priorities following a disaster. However, providing drinking water to the affected population (AP) is challenging due to severe contamination and lack of access to infrastructure. An onsite treatment system for the AP is a more sustainable solution than transporting bottled water. Emergency water technologies (WTs) that are modular, mobile or portable are suitable for emergency relief. This paper reviews WTs including membrane technologies that are suitable for use in emergencies. Physical, chemical, thermal- and light-based treatment methods, and membrane technologies driven by different driving forces such as pressure, temperature and osmotic gradients are reviewed. Each WT is evaluated by ten mutually independent criteria: costs, ease of deployment, ease of use, maintenance, performance, potential acceptance, energy requirements, supply chain requirements, throughput and environmental impact. A scoring system based on these criteria is presented. A methodology for emergency WT selection based on compensatory multi-criteria analysis is developed and discussed. Finally, critical research needs are identified. PMID- 22521950 TI - Modelling city-scale facade leaching of biocide by rainfall. AB - A methodology is presented for estimating, at the city scale, the amount of biocide released from facades during rain events. The methodology consists of two elements. First, leaching of a single facade is simulated using a two-region model, one region for the biocide in the facade and the other for that in the flow over the facade surface. In the latter region, water advection moves the biocide to the base of the facade, and so into the environment. Rates of detachment and deposition define the exchange process between the two regions. The two-region model was calibrated on laboratory data, and afterward applied at city scale to Lausanne, Switzerland (200,000 inhabitants). The city-scale application uses the second element of the methodology, which consists of an estimate of the exposure of the city's facades to rainfall, and relating that rainfall to the over-facade flow in the calibrated single-facade model. This results in a straightforward translation of over-facade flow volume to facade paint age, a necessary connection since facade leaching is dependent on paint age. For Lausanne, it was estimated that approximately 30% of the mass of biocides applied annually is released into the environment. PMID- 22521951 TI - Adaptation and evaluation of the Canadian Council of Ministers of the Environment Water Quality Index (CCME WQI) for use as an effective tool to characterize drinking source water quality. AB - Protecting drinking source water quality is a critical step in ensuring a safe supply of drinking water. Increasingly, drinking source water protection programs rely on the active participation of various stakeholders with differing degrees of water science knowledge. A drinking source water quality index presents a potential communication and analysis tool to facilitate cooperation between diverse interest groups as well as represent composite water quality. We tested the effectiveness of the Canadian Council of Ministers of the Environment Water Quality Index (CCME WQI) in capturing expert assessments of drinking water quality. In cooperation with a panel of drinking water quality experts we identified a core set of parameters to reflect common source water concerns. Drinking source water target values were drafted for use in the index corresponding to two basic treatment levels. Index scores calculated using the core parameter set and associated source water target values were strongly correlated with expert assessments of water quality. We recommend a modified index calculation procedure to accommodate parameters measured at different frequencies within any particular study period. The resulting drinking source water CCME WQI provides a valuable means of monitoring, communicating, and understanding surface source water quality. PMID- 22521952 TI - Osteoarthritis and the metabolic syndrome: more evidence that the etiology of OA is different in men and women. PMID- 22521954 TI - Dose-finding designs in pediatric phase I clinical trials: comparison by simulations in a realistic timeline framework. AB - OBJECTIVE: Usual dose-finding methods in oncology are sequential. Accrual is suspended after each group of patients to assess toxicity before increasing the dose. An adapted Continual Reassessment Method (CRM) and Rolling 6 (R6) method, designed to avoid this suspension of accrual in pediatric oncology, are compared with the traditional 3+3 design. STUDY DESIGN AND SETTING: The competing performances were evaluated in a simulation study integrating the temporal dimension, and a phase I trial was reanalyzed. We compared methods for various interpatient arrival times and dose-toxicity relations, in terms of distribution of final recommendations, number of skipped children and duration of trials. RESULTS: R6 and CRM can be safely implemented to limit trial suspensions, especially when mean interpatient arrival time is short. CRM was found to be more efficient than algorithm-based methods (44% of good recommendations vs. 38%) but moderately increased the risk of overtreatment. The R6 design included more patients at suboptimal doses. The design with the shortest study duration depended on the number of dose to escalate before the target. CONCLUSION: These new methods can reduce the number of skipped patients, but only provide limited gain in terms of ability to select the right dose. New designs are needed. PMID- 22521953 TI - Sex dimorphism in the association of cardiometabolic characteristics and osteophytes-defined radiographic knee osteoarthritis among obese and non-obese adults: NHANES III. AB - OBJECTIVE: To examine the relationship of knee osteoarthritis (OA) with cardiovascular and metabolic risk factors by obesity status and gender. METHODS: Data from 1,066 National Health and Nutrition Examination Survey III participants (>=60 years of age) was used to examine relationships of osteophytes-defined radiographic knee OA and cardiovascular and metabolic measures. Analyses were considered among obese [body mass index (BMI)>=30 kg/m(2)] and non-obese (BMI<30 kg/m(2)) men and women. RESULTS: The prevalence of osteophytes-defined radiographic knee OA was 34%. Leptin levels and homeostatic model assessment insulin resistance (HOMA-IR), a proxy measure of insulin resistance, were significantly associated with knee OA; those with knee OA had 35% higher HOMA-IR values and 52% higher leptin levels compared to those without knee OA. The magnitude of the association between HOMA-IR and knee OA was strongest among men, regardless of obesity status; odds ratios (ORs) for HOMA-IR were 34% greater among non-obese men (OR=1.18) vs obese women (OR=0.88). Among obese women, a 5 MUg/L higher leptin was associated with nearly 30% higher odds of having knee OA (OR=1.28). Among men, ORs for the association of leptin and knee OA were in the opposite direction. CONCLUSIONS: Cardiometabolic dysfunction is related to osteophytes-defined radiographic knee OA prevalence and persists within subgroups defined by obesity status and gender. A sex dimorphism in the direction and magnitude of cardiometabolic risk factors with respect to knee OA was described including HOMA-IR being associated with OA prevalence among men while leptin levels were most important among women. PMID- 22521955 TI - Molecular analysis of mucopolysaccharidosis IVA (Morquio A) in Spain. AB - Mucopolysaccharidosis type IVA (Morquio A) is an inherited metabolic disease with autosomal recessive inheritance. The pathology is due to a deficient activity of N-acetylgalactosamine-6-sulfate-sulfatase, which is involved in the degradation of keratan sulfate and chondroitin-6-sulfate. To date more than 150 mutations have been described in the GALNS gene in different populations. The aim of this study was to analyze the mutations and polymorphisms in Spain in order to know the epidemiology of our population and also to offer genetic counseling to affected families. We found 30 mutant alleles in the 15 families analyzed completing all the genotypes. Most of the mutations that we found were missense mutations, six of which were novel: p.S74F, p.E121D, p.Y254C, p.E260K, p.T394P and p.N495Y; we also found a small deletion (c.1142delC) and a probable deep intronic mutation that causes the loss of exon 5 (c.423_566del) found in cDNA. Both mutations are described in this study for the first time. We also identified 20 polymorphisms previously reported and 2 novel ones: (c.633+222T/C and c.898+25C>G). In conclusion, we have identified the mutations responsible for Mucopolysaccharidosis IV A in Spain. We found great allelic heterogeneity, as occurs in other populations, which hinders the establishment of genotype phenotype correlations in Spain. This study has been very useful for genetic counseling to the affected families. PMID- 22521956 TI - Pressure, temperature and density drops along supercritical fluid chromatography columns. I. Experimental results for neat carbon dioxide and columns packed with 3- and 5-micron particles. AB - The pressure drop and temperature drop on columns packed with 3- and 5-micron particles were measured using neat CO(2) at a flow rate of 5 mL/min, at temperatures from 20 degrees C to 100 degrees C, and outlet pressures from 80 to 300 bar. The density drop was calculated based on the temperature and pressure at the column inlet and outlet. The columns were suspended in a circulating air bath either bare or covered with foam insulation. The results show that the pressure drop depends on the outlet pressure, the operating temperature, and the thermal environment. A temperature drop was observed for all conditions studied. The temperature drop was relatively small (less than 3 degrees C) for combinations of low temperature and high pressure. Larger temperature drops and density drops occurred at higher temperatures and low to moderate pressures. Covering the column with thermal insulation resulted in larger temperature drops and corresponding smaller density drops. At 20 degrees C the temperature drop was never more than a few degrees. The largest temperature drops occurred for both columns when insulated at 80 degrees C and 80 bar, reaching a maximum value of 21 degrees C for the 5-micron column, and 26 degrees C for the 3-micron column. For an adiabatic column, the temperature drop depends on the pressure drop, the thermal expansion coefficient, and the density and the heat capacity of the mobile phase fluid, and can be described by a simple mathematical relationship. For a fixed operating temperature and outlet pressure, the temperature drop increases monotonically with the pressure drop. PMID- 22521958 TI - Implementing image-guided prostate radiotherapy: use of the ACCULOC(r) system to optimise the planning target volume margins and to assess the potential clinical benefit. PMID- 22521959 TI - Primary lymphoma of the ocular adnexa (orbital lymphoma) and primary intraocular lymphoma. AB - Lymphomas of the orbit and eye are rare conditions that should be treated as separate entities due to the differences in presumed aetiology, investigations, management and outcomes. Orbital lymphoma is most often of low-grade histology; thyroid eye disease may predispose and chlamydial infection has been suggested as a trigger. Commonly, stage IE, in most cases, can be managed with radiotherapy alone using either a kilovoltage portal for conjunctival disease or a wedged pair of megavoltage beams for more infiltrative disease to a dose of 30 Gy in 15 fractions over 3 weeks. However, medical therapy is being investigated, including a rituximab-only approach for conjunctival-only presentations. The cure rate for stage IE disease is very high. In contrast, primary ocular lymphoma is often of high-grade histology, in particular diffuse large B-cell lymphoma, and can be regarded as one end of primary central nervous system lymphoma - both eyes and brain being at risk. Immunosuppression predisposes to the disease. Management consists of an initial high-dose chemotherapy regimen with methotrexate. In most cases, this should be followed by radiotherapy to the whole brain and globes to a dose of 30-36 Gy with a boost to bulk/presenting disease. Cure rates are rarely above 50%. PMID- 22521957 TI - Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. AB - Chronic arsenic exposure remains a human health risk; however a clear mode of action to understand gene signaling-driven arsenic carcinogenesis is currently lacking. This study chronically exposed human lung epithelial BEAS-2B cells to low-dose arsenic trioxide to elucidate cancer promoting gene signaling networks associated with arsenic-transformed (B-As) cells. Following a 6month exposure, exposed cells were assessed for enhanced cell proliferation, colony formation, invasion ability and in vivo tumor formation compared to control cell lines. Collected mRNA was subjected to whole genome expression microarray profiling followed by in silico Ingenuity Pathway Analysis (IPA) to identify lung carcinogenesis modes of action. B-As cells displayed significant increases in proliferation, colony formation and invasion ability compared to BEAS-2B cells. B As injections into nude mice resulted in development of primary and secondary metastatic tumors. Arsenic exposure resulted in widespread up-regulation of genes associated with mitochondrial metabolism and increased reactive oxygen species protection suggesting mitochondrial dysfunction. Carcinogenic initiation via reactive oxygen species and epigenetic mechanisms was further supported by altered DNA repair, histone, and ROS-sensitive signaling. NF-kappaB, MAPK and NCOR1 signaling disrupted PPARalpha/delta-mediated lipid homeostasis. A 'pro cancer' gene signaling network identified increased survival, proliferation, inflammation, metabolism, anti-apoptosis and mobility signaling. IPA-ranked signaling networks identified altered p21, EF1alpha, Akt, MAPK, and NF-kappaB signaling networks promoting genetic disorder, altered cell cycle, cancer and changes in nucleic acid and energy metabolism. In conclusion, transformed B-As cells with their whole genome expression profile provide an in vitro arsenic model for future lung cancer signaling research and data for chronic arsenic exposure risk assessment. PMID- 22521960 TI - Influenza A (H1N1) complicated by invasive aspergillosis in non-severely immunocompromised patients. PMID- 22521961 TI - Fever of intermediate duration in an 8-year-old boy: is this a condition worth investigating in childhood? PMID- 22521962 TI - Advantages of intermediate X-ray energies in Zernike phase contrast X-ray microscopy. AB - Understanding the hierarchical organizations of molecules and organelles within the interior of large eukaryotic cells is a challenge of fundamental interest in cell biology. Light microscopy is a powerful tool for observations of the dynamics of live cells, its resolution attainable is limited and insufficient. While electron microscopy can produce images with astonishing resolution and clarity of ultra-thin (<1 MUm thick) sections of biological specimens, many questions involve the three-dimensional organization of a cell or the interconnectivity of cells. X-ray microscopy offers superior imaging resolution compared to light microscopy, and unique capability of nondestructive three dimensional imaging of hydrated unstained biological cells, complementary to existing light and electron microscopy. Until now, X-ray microscopes operating in the "water window" energy range between carbon and oxygen k-shell absorption edges have produced outstanding 3D images of cryo-preserved cells. The relatively low X-ray energy (<540 eV) of the water window imposes two important limitations: limited penetration (<10 MUm) not suitable for imaging larger cells or tissues, and small depth of focus (DoF) for high resolution 3D imaging (e.g., ~1 MUm DoF for 20 nm resolution). An X-ray microscope operating at intermediate energy around 2.5 keV using Zernike phase contrast can overcome the above limitations and reduces radiation dose to the specimen. Using a hydrated model cell with an average chemical composition reported in literature, we calculated the image contrast and the radiation dose for absorption and Zernike phase contrast, respectively. The results show that an X-ray microscope operating at ~2.5 keV using Zernike phase contrast offers substantial advantages in terms of specimen size, radiation dose and depth-of-focus. PMID- 22521964 TI - High molecular weight polysaccharides are key immunomodulators in North American ginseng extracts: characterization of the ginseng genetic signature in primary human immune cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ginseng (GS) has played a pivotal role in traditional Chinese medicine for thousands of years. Its use has become increasingly popular in North America, in part due to the many claims of its immune-enhancing properties. The immunopharmacology of the North American variety of GS and its extracts is needed to substantiate these claims. MATERIALS AND METHODS: Human peripheral blood mononuclear cells were exposed to different North American GS extracts and microarray analysis was performed. The profile of cytokine response to GS extracts was established by ELISA, and Ingenuity Pathway Analysis was used to identify potential signaling pathways responsible for the transcriptional profile induced by GS. Fractionation of the aqueous and polysaccharide extracts was done to determine the molecular weight of the active immune modulatory ingredient(s). RESULTS: We found that GS induced a transcriptional profile of immunomodulation characterized by a net T(h)1 immune response, with up-regulation of multiple pro-inflammatory cytokines (e.g., IFN gamma, IL-23A and IL-6) and down-regulation of TGF-beta, IL-13 and the LPS co receptor CD14. Ingenuity Pathway Analysis (IPA) revealed that the MAPK (ERK-1/2), PI3K, p38 and NF-kappaB cascades were key signaling pathways through which GS may trigger its immunomodulatory action. Furthermore, induction of such an immunomodulatory signature was recapitulated with the high molecular weight polysaccharides found in aqueous and polysaccharide GS extracts. CONCLUSIONS: Based on our results, we conclude that high molecular weight polysaccharides in North American GS aqueous and polysaccharide extracts likely trigger the MAPK (ERK-1/2), PI3K, p38 and NF-kappaB signaling pathways in PBMC resulting in the induction of a T(h)1 transcriptional profile. Our results may assist in optimizing GS-mediated immunomodulation and focus the search for compounds in GS extracts with specific immunomodulatory activities. PMID- 22521963 TI - Simultaneous analysis of dendritic spine density, morphology and excitatory glutamate receptors during neuron maturation in vitro by quantitative immunocytochemistry. AB - Alterations in the density and morphology of dendritic spines are characteristic of multiple cognitive disorders. Elucidating the molecular mechanisms underlying spine alterations are facilitated by the use of experimental and analytical methods that permit concurrent evaluation of changes in spine density, morphology and composition. Here, an automated and quantitative immunocytochemical method for the simultaneous analysis of changes in the density and morphology of spines and excitatory glutamate receptors was established to analyze neuron maturation, in vitro. In neurons of long-term neuron-glia co-cultures, spine density as measured by drebrin cluster fluorescence, increased from DIV (days in vitro)10 to DIV18 (formation phase), remained stable from DIV18 to DIV21 (maintenance phase), and decreased from DIV21 to DIV26 (loss phase). The densities of spine-localized NMDAR and AMPAR clusters followed a similar trend. Spine head sizes as measured by the fluorescence intensities of drebrin clusters increased from DIV10 to DIV21 and decreased from DIV21 to DIV26. Changes in the densities of NR1-only, GluR2 only, and NR1+GluR2 spines were measured by the colocalizations of NR1 and GluR2 clusters with drebrin clusters. The densities of NR1-only spines remained stable from the maintenance to the loss phases, while GluR2-only and NR1+GluR2 spines decreased during the loss phase, thus suggesting GluR2 loss as a proximal molecular event that may underlie spine alterations during neuron maturation. This study demonstrates a sensitive and quantitative immunocytochemical method for the concurrent analysis of changes in spine density, morphology and composition, a valuable tool for determining molecular events involved in dendritic spine alterations. PMID- 22521965 TI - Biomechanical strategies to accommodate expected slips in different directions during walking. AB - The aim of the study was to verify whether heel kinematics, ground reaction forces and electromyography (EMG) during walking are affected when anticipating slips in anterior-posterior (AP) and medial-lateral directions (ML). Eight healthy men walked through a 7-m walkway, stepping on a robotic force platform. Initially, baseline (BASE) gait mechanics were assessed with the platform at rest. Subsequently, two sets of randomized perturbations (10-cm translations with at different platform movement velocities) in the AP and ML direction were applied. Perturbations were interspersed with unperturbed walking (i.e., catch trials C-AP and C-ML). Heel accelerations, ground reaction forces and activities from the perturbed leg and trunk muscles were analyzed. EMG was analysed in four epochs: PRE (-100 ms to heel strike [HS]), EARLY (HS to 150 ms after HS), MID (150-300 ms after HS) and LATE (300 ms to toe-off). Comparisons were made between BASE, C-AP and C-ML. The first peak of the vertical force component (Fz) was decreased for C-AP and C-ML (p<0.05) but no changes were found for braking and propulsion impulses. EMG showed effects of expected slips on tibialis anterior, gastrocnemius lateralis, soleus and peroneus longus, especially for EARLY and MID epochs, with direction-specific increases in activity. In conclusion, expected slips in different directions determine only marginal changes in terms of kinetics and heel kinematics, but selective activation after HS indicates that direction-dependent strategies are adopted when anticipating perturbations. PMID- 22521966 TI - Retrospective lifetime estimation of failed and explanted diamond-like carbon coated hip joint balls. AB - Diamond-like carbon (DLC) coatings are known to have extremely low wear in many technical applications. The application of DLC as a coating has aimed at lowering wear and to preventing wear particle-induced osteolysis in artificial hip joints. In a medical study femoral heads coated with diamond-like amorphous carbon, a subgroup of DLC, articulating against polyethylene cups were implanted between 1993 and 1995. Within 8.5 years about half of the hip joints had to be revised due to aseptic loosening. The explanted femoral heads showed many spots of local coating delamination. Several of these explanted coated TiAlV femoral heads have been analyzed to investigate the reason for this failure. Raman analysis and X ray photoelectron spectroscopy (XPS) depth profiling showed that the coating consists of diamond-like amorphous carbon, several Si-doped layers and an adhesion-promoting Si interlayer. Focused ion beam (FIB) transverse cuts revealed that the delamination of the coatings is caused by in vivo corrosion of the Si interlayer. Using a delamination test set-up dissolution of the silicon adhesion promoting interlayer at a speed of more than 100 MUm year(-1) was measured in vitro in solutions containing proteins. Although proteins are not directly involved in the corrosion reactions, they can block existing small cracks and crevices under the coating, hindering the exchange of liquid. This results in a build-up of crevice corrosion conditions in the crack, causing a slow dissolution of the Si interlayer. PMID- 22521967 TI - [Adipokines: some players of inflammation in inflammatory rheumatic diseases and systemic autoimmune diseases?]. AB - Adipocytokines or adipokines are a group of molecules (such as leptin, adiponectin, visfatine and resistine) mainly produced by adipose tissue. The adipokines are involved in different physiological processes but their participation to inflammatory and immune responses have been recently described. Their contribution to inflammatory diseases such as chronic inflammatory joint diseases and autoimmune diseases, and osteoarthritis as well, is currently growing, suggesting new pathophysiological schema and treatments. Leptin, visfatin and resistin have pro-inflammatory properties while adiponectin is anti inflammatory, especially for the vascular wall. Adiponectin is considered to be protective for cardiovascular risk. The influence of the treatments given in inflammatory rheumatic diseases and autoimmune diseases (traditional drugs and biologics) on adipokines requires to be studied. PMID- 22521968 TI - [The cardiologist and immunosuppressive therapy]. AB - The monitoring of immunosuppressive therapy may involve the cardiologist in various settings. TNF inhibitors are contra-indicated in patients with NYHA III IV cardiac failure. This contra-indication is not absolute for etanercept. In patients with milder forms of cardiac failure, TNF inhibitors can be prescribed in the absence of alternative therapy. A cardiac follow-up is necessary in this situation. Cyclosporine and tacrolimus are both nephrotoxic and hypertensive drugs. For the treatment of arterial hypertension induced by the immunosuppressive therapy, first-line recommended drugs are calcium-blockers and renin-angiotensin inhibitors. Other antihypertensive classes may also be used in these patients. Calcium-blockers may cause frequent oedema and plasma calcineurin inhibitor concentration elevations. Moreover, cyclosporine+calcium-blocker association may induce gingival hypertrophy and gynecomastia. PMID- 22521969 TI - [Syncope, what should not be missed]. AB - Syncope is a common medical problem with a precise definition of which one must know the words but also their justification. This is the condition that the diagnostic approach can be effective. Although usually benign, syncope can sometimes be a warning sign of a sudden cardiac death. If the search for the specific cause of syncope remains an important objective to optimize the treatment, the basic purpose of the diagnostic approach is first to reduce sudden death. It therefore requires a good risk stratification of major cardiovascular events and sudden cardiac death. Clearly identify signs that indicate potential "dangerousness" of syncope is crucial because if present, the management strategy should be "aggressive" to promptly determine the cause and treat it immediately. PMID- 22521970 TI - Antihypertensive drug use and the risk of dementia in patients with diabetes mellitus. AB - BACKGROUND: Diabetes and hypertension are independent risk factors for dementia, and hypertension may increase this risk in patients with diabetes. It is unclear whether antihypertensive drugs are associated with risk of dementia in these patients. METHODS: A retrospective study using a national cohort of beneficiaries of the Department of Veterans Affairs who have diabetes examined incidence of dementia over a 2-year follow-up period. Multivariate Cox proportional hazards regression model was used to estimate the unique effects of comorbid hypertension and antihypertensive medications on risk of dementia, after adjusting for several potential confounders. RESULTS: In all, 377,838 patients were studied (mean age: 75.53 +/- 6.07 years). After adjustments were made for sociodemographic factors, duration of diabetes, comorbidity, and comedications, hypertension was associated with increased risk of developing dementia (hazard ratio [HR] = 1.08; 95% confidence interval [CI] = 1.03, 1.14). Antihypertensive medications decreased risk, ranging from 24% for angiotensin receptor blockers (ARBs) to 4% for beta blockers. In a stratified analysis of patients without hypertension, angiotensin converting enzyme inhibitors (HR = 0.81; 95% CI = 0.69, 0.94) and ARBs (HR = 0.55; 95% CI = 0.34, 0.88) continued to show protective effects. CONCLUSIONS: Comorbid hypertension was associated with increased risk of dementia, whereas antihypertensive medications, especially angiotensin-converting enzyme inhibitors and ARBs, were associated with reduced risk, even among patients without hypertension. Consequently, these agents may have potential therapeutic roles in delaying the onset of dementia in patients with diabetes. PMID- 22521971 TI - Leishmanicidal activity in vitro of Musa paradisiaca L. and Spondias mombin L. fractions. AB - Visceral leishmaniasis (VL) is a zoonotic disease characterized by infection of mononuclear phagocytes by Leishmania chagasi. The primary vector is Lutzomyia longipalpis and the dog is the main domestic reservoir. The control and current treatment of dogs using synthetic drugs have not shown effectiveness in reducing the incidence of disease in man. In attempt to find new compounds with leishmanicidal action, plant secondary metabolites have been studied in search of treatments of VL. This study aimed to evaluate the leishmanicidal activity of Musa paradisiaca (banana tree) and Spondias mombin (cajazeira) chemical constituents on promastigotes and amastigotes of L. chagasi. Phytochemical analysis by column chromatography was performed on ethanol extracts of two plants and fractions were isolated. Thin layer chromatography was used to compare the fractions and for isolation the substances to be used in vitro tests. The in vitro tests on promastigotes of L. chagasi used the MTT colorimetric method and the method of ELISA in situ was used against amastigotes besides the cytotoxicity in RAW 264.7 cells. Of the eight fractions tested, Sm1 and Sm2 from S. mombin had no action against promastigotes, but had good activity against amastigotes. The fractions Mp1 e Mp4 of M. paradisiaca were very cytotoxic to RAW 264.7 cells. The best result was obtained with the fraction Sm3 from S. mombin with IC(50) of 11.26 MUg/ml against promastigotes and amastigotes of 0.27 MUg/ml. The fraction Sm3 characterized as tannic acid showed the best results against both forms of Leishmania being a good candidate for evaluation in in vivo tests. PMID- 22521972 TI - Environmental factors influencing the transmission of Haemonchus contortus. AB - Infection with the gastrointestinal nematode Haemonchus contortus causes considerable losses in the sheep industry. In this study, we evaluated the effect that climate has on third-stage larvae (L3) of H. contortus in terms of their migration from sheep feces to Brachiaria decumbens grass, as well as their distribution among the forage plants. Fecal samples containing H. contortus L3 was deposited on the soil among the herbage at an initial height of 30 cm. Sample collection began 24h after contamination and was performed on alternate days over 13 days. The L3 were recovered and quantified in three strata (heights) of grass (0-10 cm, 10-20 cm and >20 cm) as well as in the remaining feces and a superficial layer of soil, collected from beneath the feces. In order to obtain results under different environmental conditions, fecal samples containing H. contortus L3 were deposited on pasture in January (summer), in April (autumn), and July (winter). In all of the periods, the L3 were able to migrate from the feces to the herbage. However, rains, accompanied by high relative humidity and high temperatures, apparently favored migration. The highest L3 recovery rate in the pasture was in the summer observation period, which had the highest number of days with measurable precipitation, high relative humidity (>68.2%), and the highest temperatures at the soil level (minimum and maximum means of 19 degrees C and 42 degrees C, respectively). Under those conditions, larvae began to reach the upper stratum of the grass (>20 cm) by 24h after the deposition of fecal matter, the number of larvae having reached that stratum peaking at seven days after deposition. In the autumn observation period, there was no rainfall in the first five days post-contamination. During that period, high numbers of larvae were found in the fecal samples demonstrating that feces can act as a reservoir of larvae in the absence of rain. Except for two days in the summer observation period, when most of the L3 were recovered from the tops of blades of grass, L3 where located predominantly at the base of the herbage. In conclusion, rainfall favors the migration of L3 from feces to herbage. In addition, larval migration up and along blades of grass can occur relatively rapidly when the temperature is high. PMID- 22521973 TI - Update on trematode infections in sheep. AB - Trematode parasites live in the liver, fore stomachs or blood vessels of a wide range of animals and humans. Most of them have a special economic and veterinary significance. Liver fluke disease of sheep and other animal species is caused by the common liver fluke Fasciola hepatica. Hepatic fasciolosis occurs throughout the world, where climatic conditions are suitable for the survival of aquatic intermediate host snails. Also of importance for ruminants, in some parts of the world, are Fasciola gigantica and Fascioloides magna. Other trematodes infecting ruminants include Dicrocoelium dendriticum; Eurytrema pancreaticum and Eurytrema coelomaticum. Among the Paramphistomidae, some species can infect sheep and other ruminants. Finally, Schistosoma spp. are found in the blood vessels of ruminants and are of minor importance in temperate regions. The manuscript concentrates on trematode species of veterinary importance for domestic sheep. PMID- 22521974 TI - Epidemiological survey of Neospora caninum infection in dogs from Romania. AB - The aim of this study was to evaluate the seroprevalence of Neospora caninum infection in dogs from Romania at a national level and to detect possible correlations between the value of seroprevalence and a series of factors like sex, age, breed category and area. The prevalence of anti-N. caninum antibodies was determined in sera samples from 1114 dogs located in different regions of Romania using the IFAT method. Antibodies to N. caninum were found in 364 dogs (32.7%). The titers of anti-N. caninum antibodies varied from 1:50 to 1:800. PMID- 22521975 TI - The contribution of simple random sampling to observed variations in faecal egg counts. AB - It has been over 100 years since the classical paper published by Gosset in 1907, under the pseudonym "Student", demonstrated that yeast cells suspended in a fluid and measured by a haemocytometer conformed to a Poisson process. Similarly parasite eggs in a faecal suspension also conform to a Poisson process. Despite this there are common misconceptions how to analyse or interpret observations from the McMaster or similar quantitative parasitic diagnostic techniques, widely used for evaluating parasite eggs in faeces. The McMaster technique can easily be shown from a theoretical perspective to give variable results that inevitably arise from the random distribution of parasite eggs in a well mixed faecal sample. The Poisson processes that lead to this variability are described and illustrative examples of the potentially large confidence intervals that can arise from observed faecal eggs counts that are calculated from the observations on a McMaster slide. Attempts to modify the McMaster technique, or indeed other quantitative techniques, to ensure uniform egg counts are doomed to failure and belie ignorance of Poisson processes. A simple method to immediately identify excess variation/poor sampling from replicate counts is provided. PMID- 22521976 TI - Host social rank and parasites: plains zebra (Equus quagga) and intestinal helminths in Uganda. AB - The main aim of this study was to evaluate the relationship between the social hierarchy of plain zebra, Equus quagga, and the level of parasitism. For the study 141 fecal samples from the same number of animals were collected within the two major populations of E. quagga of Uganda (Lake Mburo Conservation Area and Kidepo Valley National Park). Quantitative (eggs per gram of feces) and qualitative parasite assessment were performed with standard methods. The relationship between parasite burden and individual host features was analyzed using Generalized Linear Models. Strongyles, cestodes, Strongyloides sp. and oxiurids where present in the examined samples. Social rank and age class significantly affect all parasites' abundance with dominant individuals being less parasitized than subordinate individuals, regardless of the parasite groups excluding oxiurids. Sex could not been shown to be related with any of the found parasites. Age was positively related with strongyles and oxiurids abundance and negatively related with cestodes and Strongyloides sp. The main result of the present study was the evidence that social status influences parasite level with dominant zebras shedding less parasite eggs than subordinate ones. Social rank appears, therefore, as an important factor giving rise to parasite aggregation in plain zebras. PMID- 22521977 TI - Differential feeding success of two paralysis-inducing ticks, Rhipicephalus warburtoni and Ixodes rubicundus on sympatric small mammal species, Elephantulus myurus and Micaelamys namaquensis. AB - Rodents are recognised as important hosts of ixodid ticks and as reservoirs of tick-borne pathogens across the world. Sympatric insectivores are usually inconspicuous and often overlooked as hosts of ticks and reservoirs of disease. Elephant shrews or sengis of the order Macroscelidea are small insectivores that often occur in sympatry with rodents in southern Africa. Sengis are invariably parasitised by large numbers of immature ticks while sympatric rodents are infested with very few. The reason for the difference in tick parasitism rates between these hosts is unknown. While a number of mechanisms are possible, we hypothesised that certain tick species exhibit "true host specificity" and as such would only attach and feed successfully on their preferred host or a very closely related host species. To investigate this, we conducted feeding experiments using two economically important tick species, the brown paralysis tick, Rhipicephalus warburtoni and the Karoo paralysis tick, Ixodes rubicundus and two sympatric small mammal species as potential hosts, the eastern rock sengi, Elephantulus myurus and the Namaqua rock mouse, Micaelamys namaquensis. Ticks attached and fed readily on E. myurus, but did not attach or feed successfully on M. namaquensis suggesting that these ticks exhibit true host specificity. We suggest that a kairomonal cue originating from the odour of E. myurus may stimulate the attachment and feeding of these ticks and that they further possess immunosuppressive mechanisms specific to E. myurus, allowing them to feed on this host species but not on M. namaquensis. This study highlights the importance of small mammalian insectivores as potential hosts of ixodid tick species and hence their potential as reservoirs of tick-borne pathogens. PMID- 22521978 TI - Therapy and prevention of cryptosporidiosis in animals. AB - Cryptosporidiosis is a common gastro-intestinal illness in animals and man worldwide. The disease is devastating in immune-suppressed individuals but self limiting in competent hosts. The infectious stages of the organism (oocysts) are shed in the faeces of affected individuals, survive in adverse environmental conditions and spread by direct contact or through contaminants (food, water). Due to the robustness of the oocysts, their tenacity, tiny size, and resistance to common disinfectants, the parasite is difficult to eradicate from contaminated environments. To obtain sufficient control both treatment of infected hosts and inactivation of oocysts are necessary. Several drugs are commonly used to treat cryptosporidiosis in man and very few in animals but none of them are completely effective in terms of both clinical and parasitological response. Only a few chemical agents are able to inactivate oocysts in the environment including water treatment plants but their application has certain limitations. Therefore, control of cryptosporidiosis remains a global challenge in both veterinary and human medicine. Extensive research has been performed on suitable drugs and disinfectants. Thousands of agents have been tested both in vivo and in vitro. Some are excitingly active in vitro but exhibit poor or no response in clinical trials. Currently, no single or combined drug therapy has proven to be completely effective against this disease. This article will focus on therapy and prevention of cryptosporidiosis in animals including perspectives for new drugs. PMID- 22521979 TI - Novel insights in the faecal egg count reduction test for monitoring drug efficacy against gastrointestinal nematodes of veterinary importance. AB - The faecal egg count reduction test (FECRT) is the method of choice to monitor anthelmintic efficacy against gastro-intestinal nematodes in livestock. Guidelines on how to conduct a FECRT are made available by the World Association for the Advancement of Veterinary Parasitology (WAAVP). Since the publication of these guidelines in the early 1990 s, some limitations have been noted, including (i) the ignorance of host-parasite interactions that depend on animal and parasite species, (ii) their feasibility under field conditions, (iii) appropriateness of study design, and (iv) the high detection limit of the recommended faecal egg count (FEC) method. Therefore, the objective of the present study was to empirically assess the impact of the level of excretion and aggregation of FEC, sample size and detection limit of the FEC method on the sensitivity and specificity of the FECRT to detect reduced efficacy (<90% or <95%) and to develop recommendations for surveys on anthelmintic resistance. A simulation study was performed in which the FECRT (based on the arithmetic mean of grouped FEC of the same animals before and after drug administration) was conducted under varying conditions of mean FEC, aggregation of FEC (inversely correlated with k), sample size, detection limit and 'true' drug efficacies. Classification trees were built to explore the impact of the above factors on the sensitivity and specificity of detecting a truly reduced efficacy. For a reduced efficacy threshold of 90%, most combinations resulted in a reliable detection of reduced and normal efficacy. For the reduced-efficacy threshold of 95% however, unreliable FECRT results were found when sample sizes <15 were combined with highly aggregated FEC (k=0.25) and detection limits >= 5 EPG or when combined with detection limits >= 15 EPG. Overall, an increase in sample size and mean preDA FEC, and a decrease in detection limit improved the diagnostic accuracy. FECRT remained inconclusive under any evaluated condition for drug efficacies ranging from 87.5% to 92.5% for a reduced-efficacy-threshold of 90% and from 92.5% to 97.5% for a threshold of 95%. The results highlight that (i) the interpretation of this FECRT is affected by a complex interplay of factors, including the level of excretion and aggregation of FEC and (ii) the diagnostic value of FECRT to detect small reductions in efficacy is limited. This study, therefore, provides a framework allowing researchers to adapt their study design according to a wide range of field conditions, while ensuring a good diagnostic performance of the FECRT. PMID- 22521980 TI - [A new low-cost webcam-based laparoscopic training model]. AB - OBJECTIVES: To validate a new laparoscopy home training model (GYN Trainer(r)) in order to practise and learn basic laparoscopic surgery. PATIENTS AND METHOD: Ten junior surgical residents and six experienced operators were timed and assessed during six laparoscopic exercises performed on the home training model. RESULTS: Acquisition of skill was 35%. All the novices significantly improved performance in surgical skills despite an 8% partial loss of acquisition between two training sessions. Qualitative evaluation of the system was good (3.8/5). DISCUSSION AND CONCLUSION: This low-cost personal laparoscopic model seems to be a useful tool to assist surgical novices in learning basic laparoscopic skills. PMID- 22521981 TI - [Predictive value of combined fibronectin and ultrasound cervical assessment in twin pregnancies]. AB - OBJECTIVE: To test a sequential test with fetal fibronectin detection after ultrasound measurement of cervical length to predict preterm delivery in twin pregnancies with preterm labor. PATIENTS AND METHODS: Descriptive retrospective study on 50 women with twin pregnancy hospitalised for preterm labor between 24 and 34 weeks and 6 days of gestation. The primary outcomes were preterm delivery before 34 or 37 weeks of gestation or within 7 or 14 days. Selective use of fibronectin after cervical length measurement has been tested, with a sequential test considered positive if cervical length was less than or equal to 15mm or if cervical length was between 16 and 30mm with fetal fibronectin positive. RESULTS: The sensitivity/specificity/and positive and negative predictive values of fetal fibronectin positive were 71%, 64%, 26%, et 93% for delivery within 7 days; those of cervical length less than or equal to 20mm were 89%, 51%, 31%, et 95% for delivery before 34 weeks and 6 days. The efficiency of the sequential test seemed better than each test and than for singleton pregnancies keeping an excellent negative predictive value: sensitivity of 75%, specificity of 63%, positive predictive value of 26% and negative predictive value of 93.5% for prediction of preterm delivery within 14 days. The use of this sequential test could have decreased half of fibronectin tests. DISCUSSION AND CONCLUSION: A sequential test with selective use of fetal fibronectin detection in twin pregnancies selected by ultrasound measurement of cervical length appears to be effective for predicting preterm birth if preterm labor, avoiding half of fibronectin tests. PMID- 22521982 TI - [General practitioners and the challenge of endometriosis screening and care: results of a survey]. AB - OBJECTIVE: To evaluate the knowledge of general practitioners concerning the endometriosis diagnostic and care. POPULATION AND METHODS: Survey enrolling 100 general practitioners of the 76th Seine Maritime French department (region of Upper Normandy) who usually perform gynaecological follow up, asked to answer an irreversible 36 item step-by-step questionnaire. RESULTS: Among them, 44% perform more than one gynaecological consultation each week. They were 63% to feel ill at ease in the diagnosis and follow up of women presenting with endometriosis. One half of physicians could not cite three main symptoms of the disease out of dysmenorrhea, dyspareunia, chronic pelvic pain and infertility. Only 38% of general practitioners perform a clinical gynaecological examination when they suspect the endometriosis, and 28% of them recommended MRI to confirm the diagnosis. They are 24% to refer the patient without delay, but only 52% to the universitary hospital, which is the tertiary regional referral center, while 68% of them refer to a fellow practicing in a private facility. They were 64% to believe that therapeutic amenorrhea is on the bottom of the medical therapy. General practitioners were more likely to accurately answer the questionnaire when they attended gynaecological advanced courses during previous 5 years and when they followed up more than three patients previously managed for endometriosis. DISCUSSION AND CONCLUSION: General practitioners' knowledge about endometriosis is limited, with possible direct consequences on the delay of the diagnosis. The attendance of gynaecological advanced courses and the exchange of information between gynaecologic surgeons and general practitioners who follow up the patients appear to be two-way to improve the accuracy of the answers to the questionnaire. PMID- 22521983 TI - [Clues for paraaortic lymphadenectomy in patients older than 70 years with ovarian cancer]. PMID- 22521984 TI - [Materno-fetal morbidity of instrumental deliveries: forceps versus spatulas. About a series of 77 cases]. AB - OBJECTIVE: To compare the early feto-maternal morbidity after assisted vaginal delivery using forceps versus spatulas. PATIENTS AND METHODS: It is a retrospective comparative study conducted in a third level maternity carrying on cephalic instrumental non premature deliveries by forceps or spatulas, on singleton pregnancies. Forty assisted vaginal deliveries using forceps and 40 others using spatulas were registered, over a period of 4.5 months. Feto-maternal lesions were analyzed. RESULTS: Characteristics of the population of forceps and spatulas groups were alike (Body Mass Index: 25.9 versus 26.7kg/m(2), P=0.79; parity: 0.6 versus 0.4, P=0.20; fetal weight: 3306g versus 3295g, P=0.91). The characteristics of labor were also similar, except for the left transverse fetal position more important in spatulas group (10.8% - 4/37 - versus 0%; P=0.03). More fetus had no lesion in the spatulas group (85.7% - 30/35 - versus 60.5% - 23/38), P=0.02). The episiotomy rate was higher in the forceps group: 32/40 (80.0%) versus 13/37 (35.1%); P=0.0001. DISCUSSION AND CONCLUSION: These results are similar to those from the literature, which evoke a fetal protection by spatulas. However, this is biased by the fact that the two instruments are not always used in the same conditions. Besides, spatulas do not appear to be more deleterious to maternal perinea. Therefore, perpetuation and teaching the use of these two instruments seem essential. PMID- 22521985 TI - [A more and more painful intrauterine device... where it is not enough to see the wires to exclude malposition!]. AB - We report a case of a 30-year-old woman with an intrauterine device (IUD) improperly inserted deep within the myometrium, with a muscularis layer injury of the recto-sigmoid colon resulting of a uterine perforation and presented as abdomino-pelvic pain and dyspareunia. The ultrasonographic control of the IUD after the insertion (performed seven months before) was not checked. Cervical examination showed the strings of the IUD. The ultrasonographic exploration identified an intra-myometrial IUD with fundus perforation of the uterus. A laparoscopic exploration permitting the removal of the IUD revealed an insertion through the bowel wall. The lessons to draw of about this case report are discussed through a brief review of the literature. PMID- 22521986 TI - [Low circulating anti-Mullerian hormone and normal follicle stimulating hormone levels: which prognosis in an IVF program?]. AB - OBJECTIVE: To evaluate the results of controlled ovarian hyperstimulation (COH) for IVF in patients with low anti-Mullerian hormone (AMH) and normal basal follicle stimulating hormone (FSH) and Estradiol levels (<=50 pg/mL). PATIENTS AND METHODS: A retrospective cohort study including 704 patients for whom AMH and FSH levels (measured between days 3 and 5 of the menstrual cycle) were available, is performed in the IVF center at the Sevres Hospital (France). Three groups are designed and analyzed: group 1 with AMH less or equal to 2 ng/mL and FSH less or equal to 10 mUI/mL (study group), Group 2 with AMH greater than 2 ng/mL and FSH less or equal to 10 mUI/mL (control group) and Group 3 with AMH less or equal to 2 ng/mL and FSH greater than 10 mUI/mL (group with decreased ovarian reserve). RESULTS: IVF outcome for patients from the study group is significantly worse than that of the second but not than that of the third group. In the first group, the number of retrieved oocytes, the number of total obtained embryos, the clinical pregnancy rate and the live birth rate are significantly lower than in the second group; moreover, there are more cancelled cycles because of poor response in the first group. There is no difference with the third group. DISCUSSION AND CONCLUSIONS: This study shows that women with a low baseline AMH have a similar response to COH to the poor responders patients with a decreased ovarian reserve revealed by an elevated FSH level. Thus, when a woman undergoing IVF cycle presents a low AMH, she might be considered as a poor responder patient regardless of the FSH level and, although the clinical pregnancy rate is not so disappointing (18%), the couple should be informed of a higher risk of cycle cancellation. PMID- 22521987 TI - [Breast cancer in young patient in Morocco]. AB - OBJECTIVE: Breast cancer occurring in young women is rare with epidemiological, diagnostic and prognostic characteristics of their own. It is more often linked to genetic predisposition and especially correlated with a lower survival and higher rates of recidivism. The aim of the study was to analyze epidemiological, clinicopathological, biological and evolutionary characteristics. PATIENTS AND METHODS: It is a retrospective study concerning 74 patients aged 35 and younger, in whom a diagnosis of invasive breast cancer was made between September 2004 and December 2009. RESULTS: Incidence of breast cancer in women aged under 35 in our series was 18.6%, mean age was 30.62years and five patients (6.75%) had a family history of breast cancer. The mean tumor size was 3.9+/-2.6cm; 45.4% of tumors were locally advanced. It was an infiltrating ductal carcinoma of grade III of Scarff-Bloom and Richardson (SBR) in 45.7% cases and half the time it was accompanied by an axillary lymph node involvement. Negative hormone receptor (HR ) was found in only 28.7% of cases and 13 cases overexpressed Her2. Eighteen percent of the tumors were classified as triple negative. The overall survival at 3years was 87.8%. DISCUSSION AND CONCLUSION: The incidence of breast cancer in young Moroccan patients is high. In our context, it is distinguished by a delayed diagnosis explaining the advanced stage at diagnosis. Biological characteristics are often more aggressive, including high histological grade, lack of hormone receptors and the higher rate of triple negative tumours significantly reducing treatment options. PMID- 22521988 TI - [Medical treatment of endometriosis: an obligation rather than a mere option!]. AB - The aim of this article is to argue the usefulness of the systematic administration of medical treatment in women managed for endometriosis, either alone or associated with the surgery. The authors dispute seven frequent objections against the medical treatment: the lack of curative effect, the lack of primary prevention and the risk of delaying the diagnostic, the contraceptive effect in women wishing to conceive, the adverse effects, the risk of occurrence of new lesions following the arrest of the treatment, the lack of proof favourable to the efficient prevention of recurrences and the cost of the treatment. The authors conclude that to date the therapeutic amenorrhea represents an indispensable tool in the management of the endometriosis, in women both benefiting or not from surgical procedures. PMID- 22521989 TI - [Robot-assisted coelioscopic proximal tubal reanastomosis]. AB - We report two cases of robot-assisted coelioscopic proximal tubal reanastomosis after proximal tubal ligature. Patients were aged 43 and 34 years respectively and had previously undergone proximal tubal ligation by coagulation section at 37 years of age for the first patient, and by Filshie clip at 24 years for the second one. Both had regular menstrual cycles and their ovarian reserve was good. Their partners were presenting with normal sperm criteria. Proximal tubal reanastomosis was carried out in September 2010 by robotic coelioscopy with five extramucous vicryl 5-0 stitches on each tube and positive blue testing. Total durations of the interventions were 200 and 220minutes respectively. Postoperative outcomes were simple and patients had spontaneous pregnancy at 4 and 2.5 months respectively. Both pregnancies show normal progress currently. This is a contribution to literature data meant to determine the role of robotics in proximal tubal reanastomosis. PMID- 22521990 TI - [Living birth after partial hysterectomy for chemorefractory gestational choriocarcinoma]. AB - Chemotherapy is the reference treatment for gestational trophoblastic neoplasia. In case of chemoresistance, hysterectomy has to be considered even in women wishing to conceive. A 31-year-old nulliparous patient presented a recurrent invasive mole, despite two regimens of chemotherapy. She underwent a partial uterine resection of an intramyometrial choriocarcinoma followed by a third-line regimen. Two years later she gave birth by cesarean section at 32 weeks of amenorrhea to a healthy child after a spontaneous pregnancy. In order to preserve patient's fertility, conservative uterine surgery is an alternative to hysterectomy for selected chemoresistant gestational trophoblastic neoplasia. PMID- 22521991 TI - Gadofosveset-enhanced magnetic resonance angiography as a means of evaluating pulmonary arteriovenous malformation: a case report. AB - This case report is a unique presentation of a new potential indication for Gadofosvest (Ablavar), a blood pool contrast agent for magnetic resonance angiography (MRA). Ablavar is an excellent MRA contrast agent because it provides optimal contrast opacification of both the arterial and venous system, unlike the conventional extracellular agents that are used for arterial imaging only. The present case report demonstrates the ability of Ablavar to demonstrate pulmonary arteriovenous malformation (AVM), showing both its arterial feeders as well as its venous drainage tract. PMID- 22521992 TI - Combined renal MRA and perfusion with a single dose of contrast. AB - Both anatomical and functional scans are often performed when diagnosing renovascular diseases, which in many cases require two separate contrast injections. With nephrogenic systemic fibrosis being associated with gadolinium, minimizing contrast injection dosage is desirable. In this study, a technique which performs time-resolved renal magnetic resonance angiography (MRA) and perfusion with a single scan and single dose of contrast has been evaluated in six healthy volunteers. A previously developed three-dimensional MRA technique called Contrast-enhanced Angiography with Multi-Echo and Radial k-space (CAMERA) has been used to acquire images, and perfusion analysis was performed using deconvolution methods. Time-resolved MRA, as well as renal blood flow, renal volume of distribution and mean transit time maps, were acquired. PMID- 22521993 TI - An approach for computer-aided detection of brain metastases in post-Gd T1-W MRI. AB - PURPOSE: To develop an approach for computer-aided detection (CAD) of small brain metastases in post-Gd T1-weighted magnetic resonance imaging (MRI). METHOD: A set of unevenly spaced 3D spherical shell templates was optimized to localize brain metastatic lesions by cross-correlation analysis with MRI. Theoretical and simulation analyses of effects of lesion size and shape heterogeneity were performed to optimize the number and size of the templates and the cross correlation thresholds. Also, effects of image factors of noise and intensity variation on the performance of the CAD system were investigated. A nodule enhancement strategy to improve sensitivity of the system and a set of criteria based upon the size, shape and brightness of lesions were used to reduce false positives. An optimal set of parameters from the FROC curves was selected from a training dataset, and then the system was evaluated on a testing dataset including 186 lesions from 2753 MRI slices. Reading results from two radiologists are also included. RESULTS: Overall, a 93.5% sensitivity with 0.024 of intra cranial false positive rate (IC-FPR) was achieved in the testing dataset. Our investigation indicated that nodule enhancement was very effective in improving both sensitivity and specificity. The size and shape criteria reduced the IC-FPR from 0.075 to 0.021, and the brightness criterion decreases the extra-cranial FPR from 0.477 to 0.083 in the training dataset. Readings from the two radiologists had sensitivities of 60% and 67% in the training dataset and 70% and 80% in the testing dataset for the metastatic lesions <5 mm in diameter. CONCLUSION: Our proposed CAD system has high sensitivity and fairly low FPR for detection of the small brain metastatic lesions in MRI compared to the previous work and readings of neuroradiologists. The potential of this method for assisting clinical decision- making warrants further evaluation and improvements. PMID- 22521995 TI - Modeling the photo-oxidation of dissolved organic matter by ultraviolet radiation in freshwater lakes: implications for mercury bioavailability. AB - Uncertainties in projected ultraviolet (UV) radiation may lead to future increases in UV irradiation of freshwater lakes. Because dissolved organic carbon (DOC) is the main binding phase for mercury (Hg) in freshwater lakes, an increase in DOC photo-oxidation may affect Hg speciation and bioavailability. We quantified the effect of DOC concentration on the rate of abiotic DOC photo oxidation for five lakes (DOC=3.27-12.3 mg L(-1)) in Kejimkujik National Park, Canada. Samples were irradiated with UV-A or UV-B radiation over a 72-h period. UV-B radiation was found to be 2.36 times more efficient at photo-oxidizing DOC than UV-A, with energy-normalized rates of dissolved inorganic carbon (DIC) production ranging from 3.8*10(-5) to 1.1*10(-4) mg L(-1)J(-1) for UV-A, and from 6.0*10(-5) to 3.1*10(-4) mg L(-1)J(-1) for UV-B. Energy normalized rates of DIC production were positively correlated with DOC concentrations. Diffuse integrated attenuation coefficients were quantified in situ (UV-A K(d)=0.056-0.180 J cm(-1); UV-B K(d)=0.015-0.165 J cm(-1)) and a quantitative depth-integrated model for yearly DIC photo-production in each lake was developed. The model predicts that, UV-A produces between 3.2 and 100 times more DIC (1521-2851 mg m(-2) year(-1)) than UV-B radiation (29.17-746.7 mg m(-2) year(-1)). Future increases in UV radiation may increase DIC production and increase Hg bioavailability in low DOC lakes to a greater extent than in high DOC lakes. PMID- 22521994 TI - Noncontrast dynamic MRA in intracranial arteriovenous malformation (AVM), comparison with time of flight (TOF) and digital subtraction angiography (DSA). AB - Digital subtraction angiography (DSA) remains the gold standard to diagnose intracranial arteriovenous malformations (AVMs) but is invasive. Existing magnetic resonance angiography (MRA) is suboptimal for assessing the hemodynamics of AVMs. The objective of this study was to evaluate the clinical utility of a novel noncontrast four-dimensional (4D) dynamic MRA (dMRA) in the evaluation of intracranial AVMs through comparison with DSA and time-of-flight (TOF) MRA. Nineteen patients (12 women, mean age 26.2+/-10.7 years) with intracranial AVMs were examined with 4D dMRA, TOF and DSA. Spetzler-Martin grading scale was evaluated using each of the above three methods independently by two raters. Diagnostic confidence scores for three components of AVMs (feeding artery, nidus and draining vein) were also rated. Kendall's coefficient of concordance was calculated to evaluate the reliability between two raters within each modality (dMRA, TOF, TOF plus dMRA). The Wilcoxon signed-rank test was applied to compare the diagnostic confidence scores between each pair of the three modalities. dMRA was able to detect 16 out of 19 AVMs, and the ratings of AVM size and location matched those of DSA. The diagnostic confidence scores by dMRA were adequate for nidus (3.5/5), moderate for feeding arteries (2.5/5) and poor for draining veins (1.5/5). The hemodynamic information provided by dMRA improved diagnostic confidence scores by TOF MRA. As a completely noninvasive method, 4D dMRA offers hemodynamic information with a temporal resolution of 50-100 ms for the evaluation of AVMs and can complement existing methods such as DSA and TOF MRA. PMID- 22521996 TI - A comparison of prevalence estimates for selected health indicators and chronic diseases or conditions from the Behavioral Risk Factor Surveillance System, the National Health Interview Survey, and the National Health and Nutrition Examination Survey, 2007-2008. AB - OBJECTIVE: To compare the prevalence estimates of selected health indicators and chronic diseases or conditions among three national health surveys in the United States. METHODS: Data from adults aged 18 years or older who participated in the Behavioral Risk Factor Surveillance System (BRFSS) in 2007 and 2008 (n=807,524), the National Health Interview Survey (NHIS) in 2007 and 2008 (n=44,262), and the National Health and Nutrition Examination Survey (NHANES) during 2007 and 2008 (n=5871) were analyzed. RESULTS: The prevalence estimates of current smoking, obesity, hypertension, and no health insurance were similar across the three surveys, with absolute differences ranging from 0.7% to 3.9% (relative differences: 2.3% to 20.2%). The prevalence estimate of poor or fair health from BRFSS was similar to that from NHANES, but higher than that from NHIS. The prevalence estimates of diabetes, coronary heart disease, and stroke were similar across the three surveys, with absolute differences ranging from 0.0% to 0.8% (relative differences: 0.2% to 17.1%). CONCLUSION: While the BRFSS continues to provide invaluable health information at state and local level, it is reassuring to observe consistency in the prevalence estimates of key health indicators of similar caliber between BRFSS and other national surveys. PMID- 22521997 TI - The effectiveness of physical activity interventions in socio-economically disadvantaged communities: a systematic review. AB - OBJECTIVE: Interventions to increase levels of physical activity (PA) in socio economically disadvantaged communities are needed but little is known about their effectiveness. This review examines the effectiveness of interventions designed to increase PA in these communities and the theoretical frameworks and components used. METHODS: Five databases were searched for papers published in English between January 2000 and December 2010 that reported outcomes of PA interventions in socio-economically disadvantaged communities. Studies targeting individuals with pre-existing disease and not reporting a measure of free-living PA were excluded. Two reviewers independently extracted data and evaluated quality of evidence against pre-defined criteria. RESULTS: Of 478 publications identified, 27 were included. We found that group-based interventions were effective for adults but not for children; evidence for the effectiveness of interventions targeting individuals was insufficient; limited evidence suggested that community wide interventions produced small changes in PA. Interventions underpinned by any theoretical framework, compared to none, were more likely to be effective. Several effective interventions included education, PA and social support components. CONCLUSION: Compared to other approaches, multi-component adult group based interventions with theoretical frameworks are most effective in increasing PA in socio-economically disadvantaged communities. More robust evaluations of interventions targeting individuals in these 'hard-to-reach' communities are required. PMID- 22521998 TI - Time spent traveling in motor vehicles and its association with overweight and abdominal obesity in Colombian adults who do not own a car. AB - OBJECTIVE: This study examined associations between time spent traveling in motor vehicles per week (TSTMV) and BMI and abdominal obesity (AO) among Colombian adults residing in urban areas who do not own car. METHOD: Secondary data analysis of the 2005 National Nutrition Survey of Colombia was conducted. TSTMV was assessed using the long International Physical Activity Questionnaire. Body composition was measured in 7900 adults. Polytomous and binary logistic regressions were conducted, stratified by gender and adjusted for confounders, including physical activity (PA). RESULTS: Forty-two percent of participants were either overweight or obese according to their BMI, and 22.4% had AO. Males in the middle (10 to 149 min) and highest (>150 min) TSTMV tertiles were more likely to be overweight (POR=1.58, 95% CI=1.13-2.21 and POR=1.55, 95% CI=1.12-2.15 respectively, p-trend=0.012), obese (POR=2.39, 95% CI=1.43-3.99 and POR=1.93, 95% CI=1.22-3.08 respectively, p trend=0.019) and to have AO (POR=1.81, 95% CI=1.18 2.78 and POR=1.73, 95% CI=1.18-2.54 respectively, p-trend=0.009). Associations were not significant in females. CONCLUSIONS: TSTMV was positively associated with overweight and AO in adult Colombian males even after adjusting for PA. These findings highlight the potential deleterious health effects of sedentary behaviors such as prolonged traveling time, independently of having met PA recommendations. PMID- 22521999 TI - Methyl and ethyl ketone analogs of salicylaldehyde isonicotinoyl hydrazone: novel iron chelators with selective antiproliferative action. AB - Salicylaldehyde isonicotinoyl hydrazone (SIH) is a lipophilic, orally-active tridentate iron chelator providing both effective protection against various types of oxidative stress-induced cellular injury and anticancer action. However, the major limitation of SIH is represented by its labile hydrazone bond that makes it prone to plasma hydrolysis. Recently, nine new SIH analogues derived from aromatic ketones with improved hydrolytic stability were developed. Here we analyzed their antiproliferative potential in MCF-7 breast adenocarcinoma and HL 60 promyelocytic leukemia cell lines. Seven of the tested substances showed greater selectivity than the parent agent SIH towards the latter cancer cell lines compared to non-cancerous H9c2 cardiomyoblast-derived cells. The tested chelators induced a dose-dependent dissipation of the inner mitochondrial membrane potential, an induction of apoptosis as evidenced by Annexin V positivity or significant increases of activities of caspases 3, 7, 8 and 9 and cell cycle arrest. With the exception of nitro group-bearing NHAPI, the studies of iron complexes of the chelators confirmed the crucial role of iron in the mechanism of their antiproliferative action. Finally, all the assayed chelators inhibited the oxidation of ascorbate by iron ions indicating lack of redox activity of the chelator-iron complexes. In conclusion, this study identified several important design criteria for improvement of the antiproliferative selectivity of the aroylhydrazone iron chelators. Several of the novel compounds- in particular the ethylketone-derived HPPI, NHAPI and acetyl-substituted A2,4DHAPI--merit deeper investigation as promising potent and selective anticancer agents. PMID- 22522001 TI - Polymorphisms in SP110 are not associated with pulmonary tuberculosis in Indonesians. AB - Despite being high transmissible, Mycobacterium tuberculosis (M. tuberculosis) infection causes active disease in only 5-10% of disease-susceptible individuals. This has instigated interest in studying potentially underlying genetic host factors and mechanisms in tuberculosis (TB). The recent identification of the Intracellular pathogen resistance 1 (Ipr1) gene, which plays a major role in controlling M. tuberculosis susceptibility and infection severity in mice (Pan et al., 2005), has prompted studies on its human homolog; SP110 in humans. Association of SP110 SNPs with pulmonary TB were first reported in a study on West African families (Tosh et al., 2006). Subsequent attempts to replicate these findings in other populations, including another West African (Ghanaian) cohort (Thye et al., 2006), however, were unsuccessful. Here we have genotyped 20 SNPs located in the SP110 gene, including the previously TB associated variants; rs2114592 and rs3948464, for the first time in a South East Asian cohort from Indonesia. Our study did not reveal any statistically significant associations between SP110 SNPs and pulmonary TB. In addition, a meta-analysis of the two previously TB associated SNPs revealed that these are not associated with TB, further confirming the lack of convincing evidence for SP110 to be implicated in TB susceptibility, as yet in humans. PMID- 22522000 TI - Comparative genome analysis of two Cryptosporidium parvum isolates with different host range. AB - Parasites of the genus Cryptosporidium infect the intestinal and gastric epithelium of different vertebrate species. Some of the many Cryptosporidium species described to date differ with respect to host range; whereas some species' host range appears to be narrow, others have been isolated from taxonomically unrelated vertebrates. To begin to investigate the genetic basis of Cryptosporidium host specificity, the genome of a Cryptosporidium parvum isolate belonging to a sub-specific group found exclusively in humans was sequenced and compared to the reference C. parvum genome representative of the zoonotic group. Over 12,000 single-nucleotide polymorphisms (SNPs), or 1.4 SNP per kilobase, were identified. The genome distribution of SNPs was highly heterogeneous, but non synonymous and silent SNPs were similarly distributed. On many chromosomes, the most highly divergent regions were located near the ends. Genes in the most diverged regions were almost twice as large as the genome-wide average. Transporters, and ABC transporters in particular, were over-represented among these genes, as were proteins with predicted signal peptide. Possibly reflecting the presence of regulatory sequences, the distribution of intergenic SNPs differed according to the function of the downstream open reading frame. A 3-way comparison of the newly sequenced anthroponotic C. parvum, the reference zoonotic C. parvum and the human parasite Cryptosporidium hominis identified genetic loci where the anthroponotic C. parvum sequence is more similar to C. hominis than to the zoonotic C. parvum reference. Because C. hominis and anthroponotic C. parvum share a similar host range, this unexpected observation suggests that proteins encoded by these genes may influence the host range. PMID- 22522002 TI - The association between hepatitis C virus infection, genetic polymorphisms of oxidative stress genes and B-cell non-Hodgkin's lymphoma risk in Egypt. AB - Hepatitis C virus (HCV) has been postulated to be an etiological agent for lymphoid malignancies. Polymorphisms in oxidative stress genes as; superoxide dismutase (SOD2), glutathione peroxidase (GPX1), catalase (CAT), myeloperoxidase (MPO) and nitric oxide synthase (NOS2) may influence non-Hodgkin's lymphoma (NHL) risk. HCV screening and polymorphisms in these five genes coding for antioxidant enzymes were studied in 100 Egyptian patients with B cell-NHL and 100 controls to clarify the association between HCV infection, oxidative stress genes polymorphisms and B cell-NHL risk. A significantly higher prevalence of HCV infection was detected among NHL patients relative to controls and this carried a 14-fold increased NHL risk (odds ratio (OR)=14.3, 95% confidence interval (CI)=5.4-38.3, p<0.0001). GPX1 and MPO genetic polymorphisms conveyed increase in B-NHL risk (OR=3.3, 95% CI=1.4-7.4, p=0.004 and OR=4.4, 95% CI=1.3-14.2, p=0.009 respectively). Further analyses stratified by HCV infection revealed that concomitant HCV infection and GPX1 gene polymorphism had a synergetic effect on NHL risk with an OR of 15 (95%CI=2.2-69.6, p<0.0001). In addition, combined HCV infection and MPO gene polymorphisms had a pronounced NHL risk (OR=9.2, 95%CI=2.5 33.9, p<0.0001). SOD2, CAT and NOS2 genetic polymorphisms were not found to confer increased NHL risk. This study revealed that HCV infection is a risk factor for NHL in Egypt. Polymorphisms in GPX1 and MPO genes may influence NHL risk in HCV infected Egyptian patients. Larger scale studies are warranted to establish this genetic susceptibility for NHL. PMID- 22522003 TI - Genes of the bovine lungworm Dictyocaulus viviparus associated with transition from pasture to parasitism. AB - Genes necessary to enable nematode parasitic life after free-living larval life are of substantial interest to understand parasitism. We investigated transcriptional changes during transition to parasitism in the bovine lungworm Dictyocaulus viviparus, one of the most important parasites in cattle farming due to substantial economic losses. Upregulated transcripts in either free-living, developmentally arrested L3 or parasitic immature L5 were identified by suppression subtractive hybridization (SSH) followed by differential screening and subsequent virtual Northern blot verification. From 400 sequenced clones of parasitic L5, 372 (93.0%) upregulated high quality ESTs were obtained clustering into 30 contigs and 38 singletons. Most conceptual translated peptides were SCP/TAPS "family" members also known as pathogenesis-related protein (PRP) superfamily (28.5% of total ESTs), cysteine proteases (24.5%), and H-gal-GP orthologues (9.9%). These proteins are predicted to play key roles in fundamental biological processes such as nutrition and development but also parasite-host interactions and immune defense mechanisms. Increased energy requirement of the rapidly developing L5 lungworm stage was obvious in a proportion of 12.2% upregulated ESTs being components of the respiratory chain. From the developmentally arrested L3 stage sequencing of 200 clones resulted in 195 high quality ESTs (97.0%) clustering into 7 contigs and 3 singletons only. Besides a hypothetical protein (70.1% of total ESTs) most transcripts encoded the cleavage stimulation factor subunit 2 (17.5%), which is a component of the poly(A(+)) machinery and found to be involved in gene silencing. Obtained data provide the basis for future fundamental research into genes associated with parasitic lifestyle but also applied research like vaccine and/or drug development. PMID- 22522004 TI - Wing geometry of Anopheles darlingi Root (Diptera: Culicidae) in five major Brazilian ecoregions. AB - We undertook geometric morphometric analysis of wing venation to assess this character's ability to distinguish Anopheles darlingi Root populations and to test the hypothesis that populations from coastal areas of the Brazilian Atlantic Forest differ from those of the interior Atlantic Forest, Cerrado, and the regions South and North of the Amazon River. Results suggest that populations from the coastal and interior Atlantic Forest are more similar to each other than to any of the other regional populations. Notably, the Cerrado population was more similar to that from north of the Amazon River than to that collected of south of the River, thus showing no correlation with geographical distances. We hypothesize that environmental and ecological factors may affect wing evolution in An. darlingi. Although it is premature to associate environmental and ecological determinants with wing features and evolution of the species, investigations on this field are promising. PMID- 22522005 TI - The opportunity cost of exercise: do higher-earning Australians exercise longer, harder, or both? AB - Despite the widely documented benefits of exercise, very little is known about how individuals make the decision on exercise. In particular, the decision on the intensity of exercise has attracted only one US study to date, which tests the hypothesis that individuals shift toward less time-intensive but more physically intensive forms of exercise as their wages increase. In this article, we revisit this hypothesis by employing a more credible empirical framework. Studying Australian data we confirm that higher-income Australians tend to exercise more frequently with a longer duration and a higher intensity of exercise. Exercise regimens individualised based on the behavioural patterns of exercise across socio-economic groups will contribute to the efficiency and efficacy of the exercise promotion. PMID- 22522006 TI - Priority setting and policy advocacy by nursing associations: a scoping review and implications using a socio-ecological whole systems lens. AB - OBJECTIVE: We undertook an interpretative scoping review to examine organizational priority setting and policy advocacy and the factors that influence nursing associations' cross-sector public policy choices and actions. METHOD: Evidence was drawn from research, narrative, and theoretical sources that described priority setting and policy advocacy undertaken by non-governmental, non-profit, and nursing associations. Text was extracted from selected papers, imported into NVivo 8, coded, and analyzed using a descriptive-analytical narrative method. RESULTS: Many internal and external factors are shown to shape organizations' policy choices and actions including governance and governance structures, membership arrangements, legislative, professional, and jurisdictional mandates, perceived credibility, and external system disruptions. CONCLUSIONS: Internal and external factors are identified in the literature as critical to how organizations succeed or fail to set achievable priorities and advance their advocacy goals. Case comparisons and longitudinal research are needed to understand nursing associations' policy choices and actions for cross sector public policy given their complex organizational structures and dynamic professional-legal-social-economic-political-ecological environments. A socio ecological systems perspective can inform the development of theoretical frameworks and research to understand leverage points and blockages to guide nursing associations' public policy choices and actions at varying points in time. PMID- 22522009 TI - Hemolytic properties of synthetic nano- and porous silica particles: the effect of surface properties and the protection by the plasma corona. AB - Novel silica materials incorporating nanotechnology are promising materials for biomedical applications, but their novel properties may also bring unforeseen behavior in biological systems. Micro-size silica is well documented to induce hemolysis, but little is known about the hemolytic activities of nanostructured silica materials. In this study, the hemolytic properties of synthetic amorphous silica nanoparticles with primary sizes of 7-14 nm (hydrophilic vs. hydrophobic), 5-15 nm, 20 nm and 50 nm, and model meso/macroporous silica particles with pore diameters of 40 nm and 170 nm are investigated. A crystalline silica sample (0.5 10 MUm) is included for benchmarking purposes. Special emphasis is given to investigations of how the temperature and solution complexity (solvent, plasma), as well as the physicochemical properties (such as size, surface charge, hydrophobicity and other surface properties), link to the hemolytic activities of these particles. Results suggests the potential importance of small size and large external surface area, as well as surface charge/structure, in the hemolysis of silica particles. Furthermore, a significant correlation is observed between the hemolytic profile of red blood cells and the cytotoxicity profile of human promyelocytic leukemia cells (HL-60) induced by nano- and porous silica particles, suggesting a potential universal mechanism of action. Importantly, the results generated suggest that the protective effect of plasma towards silica nanoparticle-induced hemolysis as well as cytotoxicity is primarily due to the protein/lipid layer shielding the silica particle surface. These results will assist the rational design of hemocompatible silica particles for biomedical applications. PMID- 22522007 TI - Screening a library of 1600 adamantyl ureas for anti-Mycobacterium tuberculosis activity in vitro and for better physical chemical properties for bioavailability. AB - Adamantyl ureas were previously identified as a group of compounds active against Mycobacterium tuberculosis in culture with minimum inhibitor concentrations (MICs) below 0.1 MUg/ml. These compounds have been shown to target MmpL3, a protein involved in secretion of trehalose mono-mycolate. They also inhibit both human soluble epoxide hydrolase (hsEH) and M. tuberculosis epoxide hydrolases. However, active compounds to date have high cLogP's and are poorly soluble, leading to low bioavailability and thus limiting any therapeutic application. In this study, a library of 1600 ureas (mostly adamantyl ureas), which were synthesized for the purpose of increasing the bioavailability of inhibitors of hsEH, was screened for activity against M. tuberculosis. 1-Adamantyl-3-phenyl ureas with a polar para substituent were found to retain moderate activity against M. tuberculosis and one of these compounds was shown to be present in serum after oral administration to mice. However, neither it, nor a closely related analog, reduced M. tuberculosis infection in mice. No correlation between in vitro potency against M. tuberculosis and the hsEH inhibition were found supporting the concept that activity against hsEH and M. tuberculosis can be separated. Also there was a lack of correlation with cLogP and inhibition of the growth of M. tuberculosis. Finally, members of two classes of adamantyl ureas that contained polar components to increase their bioavailability, but lacked efficacy against growing M. tuberculosis, were found to taken up by the bacterium as effectively as a highly active apolar urea suggesting that these modifications to increase bioavailability affected the interaction of the urea against its target rather than making them unable to enter the bacterium. PMID- 22522008 TI - COMPARE analysis of the toxicity of an iminoquinone derivative of the imidazo[5,4 f]benzimidazoles with NAD(P)H:quinone oxidoreductase 1 (NQO1) activity and computational docking of quinones as NQO1 substrates. AB - Synthesis and cytotoxicity of imidazo[5,4-f]benzimidazolequinones and iminoquinone derivatives is described, enabling structure-activity relationships to be obtained. The most promising compound (an iminoquinone derivative) has undergone National Cancer Institute (NCI) 60 cell line (single and five dose) screening, and using the NCI COMPARE program, has shown correlation to NQO1 activity and to other NQO1 substrates. Common structural features suggest that the iminoquinone moiety is significant with regard to NQO1 specificity. Computational docking into the active site of NQO1 was performed, and the first comprehensive mitomycin C (MMC)-NQO1 docking study is presented. Small distances for hydride reduction and high binding affinities are characteristic of MMC and of iminoquinones showing correlations with NQO1 via COMPARE analysis. Docking also indicated that the presence of a substituent capable of hydrogen bonding to the His194 residue is important in influencing the orientation of the substrate in the NQO1 active site, leading to more efficient reduction. PMID- 22522010 TI - The effect of autoclaving on the physical and biological properties of dicalcium phosphate dihydrate bioceramics: brushite vs. monetite. AB - Dicalcium phosphate dihydrate (brushite) is an osteoconductive biomaterial with great potential as a bioresorbable cement for bone regeneration. Preset brushite cement can be dehydrated into dicalcium phosphate anhydrous (monetite) bioceramics by autoclaving. This heat treatment results in changes in the physical characteristics of the material, improving in vivo bioresorption. This property is a great advantage in bone regeneration; however, it is not known how autoclaving brushite preset cement might improve its capacity to regenerate bone. This study was designed to compare brushite bioceramics with monetite bioceramics in terms of physical characteristics in vitro, and in vivo performance upon bone implantation. In this study we observed that monetite bioceramics prepared by autoclaving preset brushite cements had higher porosity, interconnected porosity and specific surface area than their brushite precursors. In vitro cell culture experiments revealed that bone marrow cells expressed higher levels of osteogenic genes Runx2, Opn, and Alp when the cells were cultured on monetite ceramics rather than on brushite ones. In vivo experiments revealed that monetite bioceramics resorbed faster than brushite ones and were more infiltrated with newly formed bone. In summary, autoclaving preset brushite cements results in a material with improved properties for bone regeneration procedures. PMID- 22522011 TI - Synthesis of elastic biodegradable polyesters of ethylene glycol and butylene glycol from sebacic acid. AB - High molecular weight biodegradable polyesters were prepared from sebacic acid, ethylene glycol and butylene glycol through a simple non-solvent polycondensation with a low toxicity catalyst. The successful synthesis of the polyesters was confirmed by gel permeation chromatography, (1)H-nuclear magnetic resonance and Fourier transform-infrared spectroscopies and differential scanning calorimetry. The degradation tests were performed at 37 degrees C in phosphate buffer solution (pH 7.4) and showed a mass loss of ~5% over 12 weeks compared with only 2% for polycaprolactone (PCL). Reverse transcription polymerase chain reaction results following culture of osteoblasts on the polymer surface showed that poly(ethylene sebacate) and poly(butylene sebacate) films were optimal for osteoblast formation in terms of Runx 2 and osteocalcin gene expression. PMID- 22522013 TI - Hydrolysis of cellulose over functionalized glucose-derived carbon catalyst in ionic liquid. AB - A sulfonated carbon material was prepared by incomplete hydrothermal carbonization of glucose followed by sulfonation. The carbon material contained SO(3)H, -COOH, and phenolic -OH groups, and exhibited high catalytic performance for the hydrolysis of cellulose. A total reducing sugar (TRS) yield of 72.7% was obtained in ionic liquid 1-butyl-3-methyl imidazolium chloride at 110 degrees C in 240 min reaction time. The effect of water on the hydrolysis of cellulose in the catalytic system was studied. A water content of less than 2% in the ionic liquid promoted the formation of TRS, whereas a water content of greater than 2% lead to a decrease in TRS. The sulfonated carbon material catalyst was demonstrated to be stable for five cycles with minimal loss in catalytic activity. The use of an ionic liquid with functionalized carbon catalyst derived from glucose provides a green and efficient process for cellulose conversion. PMID- 22522012 TI - Polyvalent display of RGD motifs on turnip yellow mosaic virus for enhanced stem cell adhesion and spreading. AB - Turnip yellow mosaic virus (TYMV) is a stable 28 nm icosahedral plant virus that can be isolated in gram quantities. In order to study the polyvalent effect of Arg-Gly-Asp (RGD) clustering on the response of bone marrow stem cells (BMSCs), an RGD motif was genetically displayed on the coat protein of the TYMV capsid. Composite films composed of either wild-type TYMV or TYMV-RGD44, in combination with poly(allylamine hydrochloride) (PAH), were fabricated by a layer-by-layer adsorption of virus and PAH. The deposition process was studied by quartz crystal microbalance, UV-visible spectroscopy and atomic force microscopy. BMSC adhesion assays showed enhanced cell adhesion and spreading on TYMV-RGD44 coated substrates compared to native TYMV. These results demonstrate the potential of TYMV as a viable scaffold for bioactive peptide display and cell culturing studies. PMID- 22522014 TI - Potential of Phragmites australis for the removal of veterinary pharmaceuticals from aquatic media. AB - The potential of Phragmites australis was evaluated for the removal of three veterinary drugs, enrofloxacin (ENR), ceftiofur (CEF) and tetracycline (TET), from aquatic mediums. Results showed that the plant promoted the removal of 94% and 75% of ENR and TET, respectively, from wastewater. Microbial abundance estimation revealed that microorganisms were not a major participant. Occurrence of drugs adsorption to plant roots was observed in small extension. Therefore, main mechanisms occurring were drug removal by plant uptake and/or degradation. Present results demonstrated the potential of P. australis-planted beds to be used for removal of pharmaceuticals from livestock and slaughterhouse industries wastewater. PMID- 22522015 TI - Excess sludge reduction using pilot-scale lysis-cryptic growth system integrated ultrasonic/alkaline disintegration and hydrolysis/acidogenesis pretreatment. AB - A pilot-scale lysis-cryptic growth system was built and operated continuously for excess sludge reduction. Combined ultrasonic/alkaline disintegration and hydrolysis/acidogenesis were integrated into its sludge pretreatment system. Continuous operation showed that the observed biomass yield and the sludge reduction efficiency of the lysis-cryptic growth system were 0.27 kg VSS/kg COD consumed and 56.5%, respectively. The water quality of its effluent was satisfactory. The sludge pretreatment system performed well and its TCOD removal efficiency was 7.9% which contributed a sludge reduction efficiency of 2.1%. The SCOD, VFA, TN, NH(4)(+)-N, TP and pH in the supernatant of pretreated sludge were 1790 mg/L, 1530 mg COD/L, 261.1mg/L, 114.0mg/L, 93.1mg/L and 8.69, respectively. The total operation cost of the lysis-cryptic growth system was $ 0.186/m(3) wastewater, which was 11.4% less than that of conventional activated sludge (CAS) system without excess sludge pretreatment. PMID- 22522016 TI - Interaction of uranium with a filamentous, heterocystous, nitrogen-fixing cyanobacterium, Anabaena torulosa. AB - The filamentous, heterocystous, diazotrophic cyanobacterium, Anabaena torulosa was found to bind uranium from aqueous solutions containing 100 MUM uranyl carbonate at pH 7.8. The uranyl sequestration kinetics exhibited (a) an initial rapid phase, binding 48% uranium within 30 min resulting in a loading of 56 mg U g(-1) of dry wt, followed by (b) a slower phase, binding 65% uranium with resultant loading of 77.35 mg U g(-1) in 24h. Energy Dispersive X-ray fluorescence spectroscopy of uranium loaded biomass revealed all components of UL X-rays (UL(l), UL(alpha), UL(beta1) and UL(beta2)). Heat killed cells or extracellular polysaccharides derived from live cells exhibited limited uranyl binding (~26%) highlighting the importance of cell viability for optimum uranyl binding. The present study revealed the involvement of acid soluble polyphosphates in uranium accumulation by this brackish water cyanobacterium. PMID- 22522017 TI - Behaviors of glucose decomposition during acid-catalyzed hydrothermal hydrolysis of pretreated Gelidium amansii. AB - Acid-catalyzed hydrothermal hydrolysis is one path to cellulosic glucose and subsequently to its dehydration end products such as hydroxymethyl furfural (HMF), formic acid and levulinic acid. The effect of sugar decomposition not only lowers the yield of fermentable sugars but also forms decomposition products that inhibit subsequent fermentation. The present experiments were conducted with four different acid catalysts (H(2)SO(4), HNO(3), HCl, and H(3)PO(4)) at various acid normalities (0.5-2.1N) in batch reactors at 180-210 degrees C. From the results, H(2)SO(4) was the most suitable catalyst for glucose production, but glucose decomposition occurred during the hydrolysis. The glucose production was maximized at 160.7 degrees C, 2.0% (w/v) H(2)SO(4), and 40 min, but resulted in a low glucan yield of 33.05% due to the decomposition reactions, which generated formic acid and levulinic acid. The highest concentration of levulinic acid, 7.82 g/L, was obtained at 181.2 degrees C, 2.0% (w/v) H(2)SO(4), and 40 min. PMID- 22522018 TI - High-level exogenous glutamic acid-independent production of poly-(gamma-glutamic acid) with organic acid addition in a new isolated Bacillus subtilis C10. AB - A new exogenous glutamic acid-independent gamma-PGA producing strain was isolated and characterized as Bacillus subtilis C10. The factors influencing the endogenous glutamic acid supply and the biosynthesis of gamma-PGA in this strain were investigated. The results indicated that citric acid and oxalic acid showed the significant capability to support the overproduction of gamma-PGA. This stimulated increase of gamma-PGA biosynthesis by citric acid or oxalic acid was further proved in the 10 L fermentor. To understand the possible mechanism contributing to the improved gamma-PGA production, the activities of four key intracellular enzymes were measured, and the possible carbon fluxes were proposed. The result indicated that the enhanced level of pyruvate dehydrogenase (PDH) activity caused by oxalic acid was important for glutamic acid synthesized de novo from glucose. Moreover, isocitrate dehydrogenase (ICDH) and glutamate dehydrogenase (GDH) were the positive regulators of glutamic acid biosynthesis, while 2-oxoglutarate dehydrogenase complex (ODHC) was the negative one. PMID- 22522019 TI - Feedstock mixture effects on sugar monomer recovery following dilute acid pretreatment and enzymatic hydrolysis. AB - This study seeks to investigate the effects of biomass mixtures on overall sugar recovery from the combined processes of dilute acid pretreatment and enzymatic hydrolysis. Aspen, a hardwood species well suited to biochemical processing, was chosen as the model species for this study. Balsam, a high-lignin softwood species, and switchgrass, an herbaceous energy crop with high ash content, were chosen as adjuncts. A matrix of three different dilute acid pretreatment severities and three different enzyme loading levels was used to characterize interactions between pretreatment and enzymatic hydrolysis. No synergism or antagonism was observed for any of the feedstock mixtures. Maximum glucose yield was 70% of theoretical for switchgrass and maximum xylose yield was 99.7% of theoretical for aspen. Supplemental beta-glucosidase increased glucose yield from enzymatic hydrolysis by an average of 15%. Total sugar recoveries for mixtures could be predicted to within 4% by linear interpolation of the pure species results. PMID- 22522020 TI - A novel process for enhancing oil production in algae biorefineries through bioconversion of solid by-products. AB - This paper focuses on a novel process for adding value to algae residue. In current processes oleaginous microalgae are grown and harvested for lipid production leaving a lipid-free algae residue. The process described here includes conversion of the carbohydrate fraction into glucose prior to lipid extraction. This can be fermented to produce up to 15% additional lipids using another oleaginous microorganism. It was found that in situ enzymes can hydrolyze storage carbohydrates in the algae into glucose and that a temperature of 55 degrees C for about 20 h gave the best glucose yield. Up to 75% of available carbohydrates were converted to a generic fermentation feedstock containing 73 g/L glucose. The bioconversion step was found to increase the free water content by 60% and it was found that when the bioconversion was carried out prior to the extraction step, it improved the solvent extractability of lipids from the algae. PMID- 22522021 TI - Effects of biofilm geometry on deammonification biofilm performance: a simulation study. AB - Three geometrically different biofilms were investigated for the start-up of deammonification reactor. The planar biofilm with 4 g/L biomass could achieve 0.47 kg N/(m(3)day) nitrogen removal, compared to only 3 and 2g/L biomass needed for cylindrical and granular biofilms, respectively. Planar biofilm was significantly affected by Dissolved Oxygen (DO) changes, whereas granular biofilm could effectively work in a wide range of DO. The maximum performance of 0.49, 0.83 and 1.27 kg N/(m(3)day) were obtained in planar, cylindrical and granular biofilms, respectively, reflecting that granular biofilm was the most capable due to its large surface area for mass transfer. Cylindrical biofilm was also effective as denitrifiers growth was intimately related to a large anaerobic zone. In addition, DO should be increased abruptly for each biofilm as the shortened HRT. This investigation indicates profound influence of biofilm geometry on deammonification process, which might serve as input for further experimental progress. PMID- 22522022 TI - Quo Vadis behavioral neuroscience: a Festschrift for Philip Teitelbaum. Preface. PMID- 22522023 TI - The change in muscarinic receptor subtypes in different brain regions of rats treated with fluoxetine or propranolol in a model of post-traumatic stress disorder. AB - This study shows the possible contribution of muscarinic receptors in the pathophysiology of post-traumatic stress disorder. Sprague-Dawley rats of both sexes were exposed to dirty cat litter (trauma) for 10 min and the protocol was repeated 1 week later with a trauma reminder (clean litter). The rats also received intraperitoneal fluoxetine (2.5, 5 or 10 mg/kg/day), propranolol (10 mg/kg/day) or saline for 7 days between two exposure sessions. Functional behavioral experiments were performed using elevated plus maze, following exposure to trauma reminder. Western blot analyses for M(1), M(2), M(3), M(4) and M(5) receptor proteins were employed in the homogenates of the hippocampus, the frontal cortex and the amygdaloid complex. The anxiety indices increased from 0.63+/-0.02 to 0.89+/-0.04 in rats exposed to the trauma reminder. The freezing times were also recorded as 47+/-6 and 133+/-12 s, in control and test animals respectively. Fluoxetine or propranolol treatments restored the increases in the anxiety indices and the freezing times. Female rats had higher anxiety indices compared to males. Western blot data showed increases in M(2) and M(5) expression in the frontal cortex. Expression of M(1) receptors increased and M(4) subtype decreased in the hippocampus. In the amygdaloid complex of rats, we also detected a down-regulation of M(4) receptors. Fluoxetine and propranolol only corrected the changes occurred in the frontal cortex. These results may imply that muscarinic receptors are involved in this experimental model of post-traumatic stress disorder. PMID- 22522025 TI - The pitfalls of the "sniff test". PMID- 22522026 TI - In reply. PMID- 22522024 TI - Middle-aged female rats retain sensitivity to the anorexigenic effect of exogenous estradiol. AB - It is well established that estradiol (E2) decreases food intake and body weight in young female rats. However, it is not clear if female rats retain responsiveness to the anorexigenic effect of E2 during middle age. Because middle aged females exhibit reduced responsiveness to E2, manifesting as a delayed and attenuated luteinizing hormone surge, it is plausible that middle-aged rats are less responsive to the anorexigenic effect of E2. To test this we monitored food intake in ovariohysterectomized young and middle-aged rats following E2 treatment. E2 decreased food intake and body weight to a similar degree in both young and middle-aged rats. Next, we investigated whether genes that mediate the estrogenic inhibition of food intake are similarly responsive to E2 by measuring gene expression of the anorexigenic genes corticotropin-releasing hormone (CRH), proopiomelanocortin (POMC), the long form of the leptin receptor (Lepr) and serotonin 2C receptors (5HT2CR) and the orexigenic genes agouti-related peptide (AgRP), neuropeptide Y (NPY), prepromelanin-concentrating hormone (pMCH) and orexin in the hypothalamus of young and middle-aged OVX rats treated with E2. As expected, E2 increased expression of all anorexigenic genes while decreasing expression of all orexigenic genes in young rats. Although CRH, 5HT2CR, Lepr, AgRP, NPY and orexin were also sensitive to E2 treatment in middle-aged rats, POMC and pMCH expression were not influenced by E2 in middle-aged rats. These data demonstrate that young and middle-aged rats are similarly sensitive to the anorexigenic effect of E2 and that most, but not all feeding-related genes retain sensitivity to E2. PMID- 22522027 TI - American Society of Blood and Marrow Transplantation Guidelines for Training in Hematopoietic Progenitor Cell Transplantation. AB - Advances in hematopoietic progenitor cell transplantation (HCT) have led to an increasing number of transplantations and a concomitant requirement for physicians skilled in transplantation care. Guidelines for training HCT physicians were published in 2001; however, the past decade has seen a rapid expansion of the medical knowledge and skill set that these physicians need to deliver the highest quality of care. Recognizing the importance of education for transplantation programs, the American Society of Blood and Marrow Transplantation established a Committee on Education in 2010. The Committee's updated guidelines presented here provide an extensive and detailed framework for use by HCT educators and directors in developing HCT training programs and evaluating and mentoring their trainees. PMID- 22522028 TI - Single-shot NMR measurement of protein unfolding landscapes. AB - The transient unfolding events from the native state of a protein towards higher energy states can be closely investigated by studying the process of hydrogen exchange. Here, we present BLUU-Tramp (Biophysics Laboratory University of Udine Temperature ramp), a new method to measure the rates for the exchange process and the underlying equilibrium thermodynamic parameters, using just a single sample preparation, in a single experiment that lasts some 20 to 60h depending on the protein thermal stability, to record hundreds of points over a virtually continuous temperature window. The method is suitable also in presence of other proteins in the sample, if only the target protein is (15)N-labelled. This allows the complete thermodynamic description of the unfolding landscape at an atomic level in the presence of small or macromolecular ligands or cosolutes, or in physiological environments. The method was successfully tested with human ubiquitin. Then the unfolding thermodynamic parameters were satisfactorily determined for the amyloidogenic protein beta(2)-microglobulin, in aqueous buffer and in synovial liquid, that is the natural medium of amyloid deposition in joints. PMID- 22522029 TI - Inhibitory effects of beta-tricalciumphosphate wear particles on osteocytes via apoptotic response and Akt inactivation. AB - Wear debris-induced osteolysis, a major contributing factor of orthopedic implant aseptic loosening, affects long-term survival of orthopedic prostheses following joint replacement and revision surgery. Pathogenic effects of wear debris on various cell types including macrophages/monocytes, osteoblasts, and osteoclasts have been well studied. However, the interactions between wear debris particles and osteocytes, which make up over 90% of all bone cells, have not been clearly illustrated. Here, we explored the biological effects of endotoxin-free beta tricalciumphosphate (beta-TCP) wear particles with the average diameter of 1.997 MUm (range 1.3-3.2 MUm) on osteocytes in vitro. Our results showed that 24 h or 48 h incubation of beta-TCP particles dose-dependently inhibited cell viability of osteocytes MLO-Y4. Alternatively, beta-TCP particles treatment for 24 h significantly increased the osteocytic marker SOST/sclerostin mRNA expression and the release of inflammatory cytokines including TNF-alpha and IL-1beta into the culture media, but decreased the mRNA expression of another osteocytic marker dentin matrix protein-1 (DMP-1). Furthermore, these osteocytes dysfunctions were accompanied by F-actin disassembly, cell apoptosis, sustained enhancement of intracellular reactive oxygen species (ROS) and mitochondrial injury upon beta TCP particles stimulation. In addition, beta-TCP particles also caused Akt inactivation at Ser473 resides with a dose- and time-dependent pattern. Taken together, beta-TCP wear particles could cause osteocytes dysfunctions, which may be mediated by apoptotic death and Akt inactivation in MLO-Y4 cells. These findings strongly suggest that osteocytes may play an important role in the beta TCP wear particles-induced osteolysis, and provide valuable insights for understanding the molecular mechanisms of osteocytes death involved in tissue damage during bone cement and intolerance of cemented prostheses. PMID- 22522030 TI - Interaction of gentamicin polycation with model and cell membranes. AB - The interaction of positively-charged antibiotic gentamicin with cell membranes was studied to determine if any changes in membrane organization were induced by the drug. Opossum kidney epithelia (OK) cells were used as models of eukaryotic cells. Two methods were used: laurdan fluorescence spectroscopy and fluorescence anisotropy recordings on 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene p-toluenesulfonate (TMA-DPH) labeled cell suspensions. Both methods showed an altered membrane hydration and fluidity of gentamicin treated cells. Liposomes prepared from dimyristoyl-phosphatidylcholine (DMPC) mixed with cardiolipin, which mimics the heterogeneous charge composition of the natural cell membrane, were used to determine the effect of gentamicin on artificial bilayers. The membrane lipid packing as revealed by generalized polarization (GP) and fluorescence anizotropy variation with increasing temperature was studied. It was found that the generalized polarization of liposomal membranes containing a negatively charged lipid (cardiolipin) is higher in the presence of gentamicin; in the membrane of living cell (OK), gentamicin induces, on the contrary, a decrease of general polarization. Considering the role of membrane organization in the function of transmembrane channels and receptors, our findings suggest hypotheses that may explain the permeation of gentamicin through the living cell membrane by using these channels. PMID- 22522031 TI - Nonenzymatic amperometric determination of glucose by CuO nanocubes-graphene nanocomposite modified electrode. AB - Here, we report a nonenzymatic amperometric glucose sensor based on copper oxide (CuO) nanocubes-graphene nanocomposite modified glassy carbon electrode (CuO-G GCE). In this case, the graphene sheets were cast on the GCE directly. CuO nanocubes were obtained by oxidizing electrochemically deposited Cu on the graphene. The morphology of CuO-G nanocomposite was characterized by scanning electron microscopy. The CuO-G-GCE-based sensor exhibited excellent electrocatalytic activity and high stability for glucose oxidation. Under optimized conditions, the linearity between the current response and the glucose concentration was obtained in the range of 2MUM to 4mM with a detection limit of 0.7MUM (S/N=3), and a high sensitivity of 1360MUAmM(-1)cm(-2). The proposed electrode showed a fast response time (less than 5s) and a good reproducibility. The as-made sensor was applied to determine the glucose levels in clinic human serum samples with satisfactory results. In addition, the effects of common interfering species, including ascorbic acid, uric acid, dopamine and other carbohydrates, on the amperometric response of the sensor were investigated and discussed in detail. PMID- 22522032 TI - [Cancer screening practices and associated lifestyles in population controls of the Spanish multi-case control study]. AB - OBJECTIVES: To estimate the prevalence of screening practices in the population controls of the multi-case control study (MCC-Spain) study and to evaluate its association with lifestyles. METHODS: We carried out a cross-sectional analysis of 1505 population controls of the MCC-Spain study, aged 20-85, enrolled from 2008-2010 in five areas of Spain. The prevalence of screening tests in the last 5 years was estimated and its association with lifestyles was assessed using logistic regression models. RESULTS: The most prevalent tests were mammography (98.2%, age 50-69 years) and cytology (94.5%, age 25-65 years) in women and prostate-specific antigen in men (71.5%, age 50 or over). Participation in fecal occult blood testing was lower (11.2% and 16.2% in women and men aged 50-74, respectively). Eating at least three pieces of fruit and vegetables per day was associated with higher participation in mammography (ORa: 5.24, 95% CI: 1.96 14.07). In men, overweight-obesity was linked to higher participation in prostate specific antigen testing (ORa: 1.88; 95% CI: 1.15-3.08). In general, the presence of comorbidities was associated with utilization of cancer screening tests. CONCLUSIONS: The prevalence of screening practices was high for breast, cervical and prostate cancer and was low for colorectal cancer. No common lifestyle patterns were associated with participation, although differences were found by sex and type of screening test. These results may be useful to guide further studies on screening practices and review possible inefficiencies. PMID- 22522034 TI - Continuing professional development systems for medical physicists: a global survey and analysis. AB - Continuing professional development (CPD) and continuing professional education (CPE) are seen as being necessary for medical physicists to ensure that they are up-to-date with current clinical practice. CPD is more than just continuing professional education, but can include research publication, working group contribution, thesis examination and many other activities. A systematic way of assessing and recording such activities that a medical physicist undertakes is used in a number of countries. This can be used for certification and licensing renewal purposes. Such systems are used in 27 countries, but they should be implemented in all countries where clinical medical physicists are employed. A survey of the CPD systems that are currently operated around the world is presented. In general they are quite similar although there are a few countries that have CPD systems that differ significantly from the others in many respects. Generally they ensure that medical physicists are kept up-to-date, although there are some that clearly will fail to achieve that. An analysis of what is required to construct a useful medical physics CPD system is made. Finally, the need for medical physicist professional organizations to cooperate and share in the production and distribution of CPD and CPE materials is emphasized. PMID- 22522033 TI - Suicidal ideation and drinking to cope among college binge drinkers. AB - Suicidality among college students is associated with binge drinking and alcohol related problems. Consistent with motivational models of alcohol use, drinking to cope (DTC) is a significant intervening variable in the association between suicidal ideation and alcohol use and problems among students. This study examined whether several factors shown to be associated with both suicidal ideation and DTC (i.e., impulsivity, mood regulation expectancies, and coping skills) account for the relationship between these variables, as well as the associations of depression and hopelessness with DTC. Participants were 109 emerging adult (18- to 25-year-old) college students who reported at least one episode of binge drinking during a typical month in the past year. Hierarchical regression analyses revealed that while greater negative urgency and low negative mood regulation expectancies were significantly associated with DTC, suicidal ideation remained significantly associated with DTC, even when controlling for depression. Suicidal ideation showed a stronger association with DTC than either depression or hopelessness both before and after accounting for other variables. These findings suggest that suicidal ideation has a direct association with DTC, and that negative urgency and mood regulation expectancies may be useful treatments targets for reducing alcohol misuse among emerging adult students who experience suicidal ideation. PMID- 22522035 TI - The expression of prophenoloxidase mRNA in red swamp crayfish, Procambarus clarkii, when it was challenged. AB - The expression of the prophenoloxidase (proPO) gene was investigated in nine tissues of red swamp crayfish Procambarus clarkii, by real-time PCR after challenges by CpG oligodeoxynucleotide (ODN), Aeromonas hydrophila and white spot syndrome virus (WSSV). The results can be summarized as follows: (i) the expression level of the proPO gene in haemocytes was highest among nine studied tissues before the challenge; (ii) the expression of proPO increased in all studied tissues after stimulation by CpG ODN and WSSV, and also increased in all tissues, except the ovary, after the A. hydrophila challenge; (iii) the whole expression profiles were different, suggesting that different immune mechanisms may exist for crayfish that are resistant to WSSV and A. hydrophila, although the expression in haemocytes was similar before and after the WSSV and A. hydrophila challenges. PMID- 22522036 TI - Characterization of semi-solid Self-Emulsifying Drug Delivery Systems (SEDDS) of atorvastatin calcium by Raman image spectroscopy and chemometrics. AB - A methodology based on Raman image spectroscopy and chemometrics for homogeneity evaluation of formulations containing atorvastatin calcium in Gelucire((r)) 44/14 is presented. In the first part of the work, formulations with high amounts of Gelucire((r)) 44/14 (80%) and solvents of different polarities (diethylene glycol monoethyl ether, propyleneglycol, propylene glycol monocaprylate and glyceryl mono/dicaprylate/caprate) were prepared for miscibility screening evaluation by classical least squares (CLS). It was observed that Gelucire((r)) 44/14 presented higher affinity for the lipophilic solvents glyceryl mono/dicaprylate/caprate and propylene glycol monocaprylate, whose samples were observed to be homogeneous, and lower affinity for the hydrophilic solvents diethylene glycol monoethyl ether and propyleneglycol, whose samples were heterogeneous. In the second part of the work, the ratio of glyceryl mono/dicaprylate/caprate and Gelucire((r)) 44/14 was determined based on studies in water and allowed the selection of the proportions of these two excipients in the preconcentrate that provided supersaturation of atorvastatin upon dilution. The preconcentrate was then evaluated for homogeneity by partial least squares (PLS) and an excellent miscibility was observed in this proportion as well. Therefore, it was possible to select a formulation that presented simultaneously homogeneous preconcentrate and solubility enhancement in water by Raman image spectroscopy and chemometrics. PMID- 22522038 TI - Determination of total and unbound sufentanil in human plasma by ultrafiltration and LC-MS/MS: application to clinical pharmacokinetic study. AB - A sensitive and specific liquid chromatography-tandem mass spectrometry (LC MS/MS) method was developed and validated for the quantification of sufentanil total and unbound drug concentrations. Unbound drug was separated by an ultrafiltration step before sample preparation. Both the ultrafiltrate and plasma samples were extracted with solid-phase extraction and substituted with deuterated sufentanil used as an internal standard. Separation was performed by gradient elution using UPLC-like system and analysed by MS/MS consisting of an electrospray ionization source. Calibration curves showed linearity in the concentration range of 5-2500 pg/ml for analysis of both total and unbound concentrations of sufentanil. The lower limit of quantification was 5 pg/ml for both total and unbound sufentanil plasma drug concentrations. Intra- and interassay precision and accuracy did not exceed 15%. Method was applied to pharmacokinetic study in patients undergoing coronary artery bypass grafting. PMID- 22522037 TI - Metabolite profiles of icariin in rat plasma by ultra-fast liquid chromatography coupled to triple-quadrupole/time-of-flight mass spectrometry. AB - In this work, the metabolite profiles of icariin in rat plasma were qualitatively investigated, and the possible metabolic pathways of icariin were subsequently proposed. After oral administration of icariin, rat plasma samples were collected and pretreated by protein precipitation. Then these pretreated samples were injected into a Venusil ASB-C18 column with mobile phase consisted of 0.1% formic acid water and 0.1% formic acid acetonitrile and detected by Ultra fast liquid chromatography coupled to time-of-flight mass spectrometry (UFLC-TOF/MS). A total of 19 metabolites, namely, icariside I (M1), icaritin (M2), desmethylicaritin and its isomer (M3-M6), icaritin-3-O-gluA (M7), icaritin-7-O-gluA (M8), icariside II and its isomer (M9 and M10), icaritin-3,7-di-O-gluA (M11), 1,3-isoprene alcohol icaritin and its isomer (M12, M13 and M18), 1,3-isoprene alcohol icariside II (M14), allylic alcohol icaritin and its isomer (M15 and M16), 1,3-isoprene icariside II (M17) and icaritin-3-O-rha-7-O-gluA (M19) were detected and tentatively identified, and 9 of them, including M7 and M8 and M12-M18 were reported for the first time. The metabolites profiles in plasma revealed that glucuronide conjugates of isoflavonoids and flavonoid aglycones were the major circulating forms of icariin. PMID- 22522039 TI - Validation of a dried blood spot LC-MS/MS approach for cyclosporin A in cat blood: comparison with a classical sample preparation. AB - A rapid, selective and sensitive bioanalytical method was developed and validated for cyclosporin A (CsA) in cat blood samples using dried blood spot (DBS) coupled with high pressure liquid chromatography hyphenated to positive electrospray tandem mass spectrometry (HPLC-ESI-MS/MS). CsA was quantified using a structural analog cyclosporin D (CsD) as internal standard in multiple reaction monitoring mode (MRM) using the transitions 1220->1203 for CsA and 1234->1217 for CsD. A 5 MUL blood aliquot was spotted onto a DBS card, then after a drying step, blood spots were punched out from the cards and extracted with MeOH before injection into a LC-MS/MS system. The linear range of the method was 5-2000 ng/mL, with accuracy and precision within the FDA acceptance criteria (i.e., +/-15% and +/ 20% for the lowest level). In the study presented herein a comparison was made between this new methodology, based on the use of DBS, and a previously developed solid phase extraction (SPE) procedure, applied to blood samples from a cat pharmacokinetic study. Good correlation (r(2)=0.97) was demonstrated between the data obtained with the two methods. The DBS methodology revealed to be cheaper, faster, less solvent-consuming and requiring less blood volume from animals than the previous SPE method. Thus, the proposed HPLC-ESI-MS/MS method, based on DBS, has demonstrated to be a suitable and advantageous approach for the analysis of CsA in cat blood. PMID- 22522040 TI - A distinctive translocation carcinoma of the kidney; "rosette forming," t(6;11), HMB45-positive renal tumor: a histomorphologic, immunohistochemical, ultrastructural, and molecular genetic study of 4 cases. PMID- 22522041 TI - Suicidal ideation among students of a medical college in Western Nepal: a cross sectional study. AB - Many studies have been conducted in the developed countries to know the magnitude and factors influencing suicidal ideation among medical students, but such data are sparse in developing countries. This cross-sectional study was therefore conducted to find out the prevalence of suicidal ideation and factors influencing such ideation among students of a medical college in Western Nepal. A total of 206 students were selected using random sampling and questioned about their socio demographic factors, other risk factors and suicidal ideation using a preformed validated questionnaire. The data were analyzed using SPSS for Windows Version 16.0 and the EPI Info 3.5.1 Windows Version. Descriptive statistics and testing of hypothesis were applied for the statistical methodology. The univariate and multivariate logistic regression methods were used to examine the association between different variables. Suicidal ideation in the last one year was present in nearly one tenth of the study population and in almost one fifth of them life time suicidal ideation was present. Factors that were associated with suicidal ideation were primarily dissatisfaction with academic performance, being in the clinical semesters, having history of drug abuse and feeling neglected by parents. Most common reason reported for suicidal ideation was family related followed by self-related. Recognition of suicidal ideation among students and their associated factors can help in detecting it on time, making the right interventions and controlling the problem. Understanding the magnitude of the problem and their epidemiology via scientific study like this would be the first step in this process. PMID- 22522042 TI - [Multiple bilateral pulmonary nodules revealing a congenital cystic adenomatoid malformation]. AB - Congenital cystic adenomatoid malformation (CCAM) of the lung is a rare congenital developmental abnormality, representing about 25% of all congenital lung lesions. It is very rare that presentation is delayed until adulthood. We report a case of 63-year-old woman without notable pathological antecedents in whom a systematic chest X-ray revealed multiple bilateral pulmonary nodules. The patient was asymptomatic and her physical examination was normal. CT scan showed bilateral liquid rounded thin-walled densities of various size, with a homogeneous non calcified content. The diagnosis was based on radiological findings and surgery. The result of histopathological examination obtained by thoracic surgery confirmed CCAM without malignancy. The postoperative follow up showed an excellent recovery. PMID- 22522043 TI - Monolayers of an amphiphilic para-carboxy-calix[4]arene act as templates for the crystallization of acetaminophen. AB - The title compound, 5,11,17,23-tetra-carboxy-25,26,27,28-tetradodecyloxy calix[4]arene, 1, has been studied at the air-water interface, self-assembled as Langmuir monolayers, for its ability to interact with an active pharmaceutical ingredient (API), acetaminophen (APAP), and to initiate its crystallization. The Pi/A isotherm study shows that there is a clear interaction between 1 and APAP causing an expansion of the monolayer. In addition to the known phase transition occurring at a surface tension of 38 mN m(-1), an additional kink is observed in the compression isotherm for concentrations of APAP above 40 mM suggesting that this API is causing an additional phase transition of the monolayer. Interface initiated crystallization studies show that the presence of a monolayer spread on a supersaturated solution of APAP (26 g L(-1)) triggers this API crystal growth from the interface. The transfer of 1-based monolayers on glass surfaces has been carried out using the Langmuir-Blodgett technique. The so-produced monolayers have been shown to template the crystallization of APAP. LB films of 1 have characterized using imaging and spectroscopic ellipsometry. The results suggest that each monolayer has an average thickness of 18 A, which is consistent with the molecular structure of 1 self-organized parallel to the interface with the alkyl chains pointing out parallel to the axis of the macrocycle and without interdigitation of the alkyl chains. The presence of APAP in the subphase during the LB transfer causes a limited but relevant increase in the layer thickness. The study of the capabilities of the LB films to initiate crystallization of APAP is also demonstrated showing the influence of the monolayer packing on the quantity of formed crystals. PMID- 22522044 TI - Regulation of inducible heme oxygenase and cyclooxygenase isozymes in a mouse model of spotted fever group rickettsiosis. AB - Vascular endothelial cells (ECs) lining the blood vessels are the preferred primary targets of pathogenic Rickettsia species in the host. In response to oxidative stress triggered by infection, ECs launch defense mechanisms such as expression of heme oxygenase-1 (HO-1). Previous evidence from an established animal model of Rocky Mountain spotted fever also suggests selective modulation of anti-oxidant enzyme activities in the target host tissues. In this study, we have examined the expression profiles of HO-1 and COX-2 in different tissues during Rickettsia conorii infection of susceptible C3H/HeN mice. RNA hybridization with murine HO-1 and COX-2-specific complementary DNA probes revealed increased HO-1 expression in the liver and brain of mice infected with three different doses of R. conorii ranging from 2.25*10(3) to 2.25*10(5) pfu, relatively non-remarkable changes in the lungs, and a trend for down-regulation in the spleen. The most prominent HO-1 response was evident in the liver with ~4 fold increase on day 4 post-infection, followed by a decline on day 7. HO-1 expression in the brain, however, peaked with significantly higher levels on day 7. Following infection with both sub-lethal as well as lethal doses of infection, the transcript encoding COX-2 also displayed a pattern of increased expression in the liver and brain. Although immunohistochemical staining revealed increased abundance of HO-1 protein in the liver of infected mice, adjoining serial sections did not exhibit positive staining for COX-2 in infected tissues. The levels of monocyte chemoattractant protein-1 (MCP-1) and keratinocyte-derived cytokine (KC) were significantly higher in the sera of infected mice and corresponded with the onset and severity of the disease. Treatment of infected animals with anti-oxidants alpha-lipoic acid and N-acetylcysteine and HO inhibitor stannous protoporphyrin (SnPPIX) showed only selective beneficial effects on HO-1 and COX-2 expression in the liver and spleen and serum levels of KC and MCP-1. R. conorii infection of susceptible mice, therefore, results in selective regulation of the expression of HO-1 and COX-2 in a manner dependent on the target host tissue's cellular environment and the propensity of infection with rickettsiae. PMID- 22522045 TI - Potential of lower-limb muscles to accelerate the body during cerebral palsy gait. AB - Two of the most common gait patterns in children with spastic diplegic cerebral palsy (CP) are termed 'crouch gait' and 'jump gait'. While outcomes of surgical interventions designed to improve functional mobility are generally positive, many children displaying these gait patterns show minimal or no improvement post surgery. A poor response to treatment may be partially attributable to incorrect interpretations of muscle function. Computational techniques that assess muscle function may help address this issue, but before studying specific surgeries, the gait patterns themselves must be better understood. The aim of this study was to identify differences in lower-limb muscle function when comparing crouch, jump and able-bodied gait patterns by quantifying the potential of lower-limb muscles to accelerate the body's center of mass. A muscle's potential acceleration was defined as the acceleration induced by a unit of muscle force. Dynamic simulations of walking using musculoskeletal models were developed for eight children with crouch gait, ten with jump gait, and ten controls. There were significant differences (p<0.05) in muscle potential accelerations between crouch and able-bodied gait patterns, and between jump and able-bodied gait patterns, for most of the major muscles of the hip, knee, and ankle. One important outcome was the identification of the significantly reduced potential of gluteus medius to extend the hip in both crouch gait and jump gait. Potential acceleration analyses appear to be suitable for evaluating differences between common gait patterns and may also be applied to study the effects of surgical treatments. The results of such studies may lead to improved treatment outcomes for individuals with impaired mobility. PMID- 22522046 TI - Arm training in standing also improves postural control in participants with chronic stroke. AB - PURPOSE: To prove the concept that postural control will improve without specific balance control training during arm training in standing with individuals with chronic stroke. METHODS: Nine participants (mean age 64+/-7) received training involving hand orthotic assisted grasp, reach and release in standing 1 h, 3*'s/week for 6 weeks. Training focused on task completion with no explicit instructions provided for postural alignment, weight shift or balance strategy. Testing consisted of quantified measures using NeuroComTM Balance Master, Berg Balance Scale (BBS) and Activities-specific Balance Confidence Scale (ABC). RESULTS: Post training participants demonstrate increased (p<.05) composite stability scores for sensory organization testing (mean 71.55+/-12.7-75.55+/-11). Velocity and directional control of COP weight shift improved for all 9 subjects with 6/9 achieving 100% target acquisition. Directional control improved (p<.05) for medial/lateral movements for all speeds and composite score. Anterior/posterior rhythmic weight shifting increased significantly in COP velocity control at moderate and fast velocities and composite score. Increases in mean BBS (p<.01) from 41.33+/-10.1-46.88+/-8.03 exceeded the clinically important cutoff for the scale. Balance confidence improved with ABC mean scores 70.22+/-14.5-79.55+/-12.86 (p<.05). Seven participants demonstrated changes above the minimally important difference for this scale. CONCLUSIONS: Postural control improved following task oriented arm training in standing without explicit postural control goals, instruction or feedback challenging current training paradigms of isolated postural control training with conscious attention directed to center of pressure location and movement. PMID- 22522047 TI - Slow-tight binding inhibition of pepsin by an aspartic protease inhibitor from Streptomyces sp. MBR04. AB - The present article reports a low molecular weight aspartic protease inhibitor from a Streptomyces sp. MBR04 exhibiting a two-step inhibition mechanism against pepsin. The kinetic interactions revealed a reversible, competitive, slow-tight binding inhibition with an IC(50) and K(i) values of 4.5 nM and 4 nM respectively. The conformational changes induced upon inhibitor binding to pepsin was monitored by far and near UV analysis, demonstrated that the inhibitor binds to the active site and causes inactivation. Chemical modification of the inhibitor with WRK and TNBS abolished the antiproteolytic activity of the inhibitor. PMID- 22522048 TI - Extraction of chitosan from shrimp shells waste and application in antibacterial finishing of bamboo rayon. AB - Chitosan can be best utilized as safe antibacterial agent for textiles but there is always a limitation of its durability. The chitin containing shellfish waste is available in huge quantities, but very low quantities are utilized for extraction of high value products like chitosan. In the current work chitosan was extracted from shrimp shells and then used as antibacterial exhaust finishing agent for grafted bamboo rayon. Chitosan bound bamboo rayon was then evaluated for antibacterial activity against both gram positive and gram negative bacteria. The product showed antibacterial activity against both types of bacterias which was durable till 30 washes. PMID- 22522049 TI - Variation in the gonadotrophin-releasing hormone-1 and the song control system in the tropical breeding rufous-collared sparrow (Zonotrichia capensis) is dependent on sex and reproductive state. AB - Seasonal breeding in temperate zone vertebrates is characterised by pronounced variation in both central and peripheral reproductive physiology as well as behaviour. In contrast, many tropical species have a comparatively longer and less of a seasonal pattern of breeding than their temperate zone counterparts. These extended, more "flexible" reproductive periods may be associate with a lesser degree of annual variation in reproductive physiology. Here we investigated variation in the neuroendocrine control of reproduction in relation to the changes in the neural song control system in a tropical breeding songbird the rufous-collared sparrows (Zonotrichia capensis). Using in situ hybridization, we show that the optical density of GnRH1 mRNA expression is relatively constant across pre-breeding and breeding states. However, males were found to have significantly greater expression compared to females regardless of breeding state. Both males and females showed marked variation in measures of peripheral reproductive physiology with greater gonadal volumes and concentrations of sex steroids in the blood (i.e. testosterone in males; estrogen in females) during the breeding season as compared to the pre-breeding season. These findings suggest that the environmental cues regulating breeding in a tropical breeding bird ultimately exert their effects on physiology at the level of the median eminence and regulate the release of GnRH1. In addition, histological analysis of the song control system HVC, RA and Area X revealed that breeding males had significantly larger volumes of these brain nuclei as compared to non-breeding males, breeding females, and non-breeding females. Females did not exhibit a significant difference in the size of song control regions across breeding states. Together, these data show a marked sex difference in the extent to which there is breeding-associated variation in reproductive physiology and brain plasticity that is dependent on the reproductive state in a tropical breeding songbird. PMID- 22522050 TI - Steroidogenic response of carp ovaries to piscine FSH and LH depends on the reproductive phase. AB - The gonadotropins (GTHs) follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are the key regulators of reproduction. We determined the competence of heterologous recombinant GTHs at eliciting steroid secretion from carp ovaries at different reproductive stages. We collected carp ovaries at: early, mid and end vitellogenesis, when most of the oocytes still contained a germinal vesicle (GV) at a central stage, and mature ovaries with a migrating GV. Plasma estradiol (E2) levels at early vitellogenesis were high and decreased thereafter. Basal secretion levels of E2 increased with oocyte diameter and GSI value, whereas 17alpha,20beta-dihydroxy-4-pregnen-3-one (DHP) was detected only in females with mature follicles. Carp ovary fragments were exposed to recombinant fish GTHs belonging to different teleost orders: Japanese eel (Anguilla japonica, Anguilliformes), Manchurian trout (Brachymystax lenok, Salmoniformes), and Nile tilapia (Oreochromis niloticus); to mammalian GTHs (pFSH and hCG), or to carp and tilapia pituitary extract (CPE and TPE, respectively). All of the recombinant GTHs tested stimulated steroid secretion. However, the steroid secretion differed according to the type of GTH and the developmental state of the ovary. CPE increased the secretion of both E2 and DHP at almost all stages of ovarian maturity. In mature ovarian fragments, DHP secretion was higher in response to recombinant LHs (eel and tilapia) than to recombinant FSH. Early- and mid vitellogenic ovaries showed no secretion of DHP and high secretion of E2 in response to all recombinant GTHs tested. This is in line with the hypothesis that LH regulates the final stages of maturation, when the involvement of FSH is marginal. These results may contribute to understanding the mechanisms that determine differential activation of steroid secretion and specificity in fish. PMID- 22522051 TI - How well do aliskiren's purported mechanisms track its effects on cardiovascular and renal disorders? AB - The overactivation of the renin-angiotensin-aldosterone system (RAAS) is associated with cardiovascular and renal abnormalities, which can be mitigated by angiotensin converting enzyme inhibitors (ACEIs) and angiotensin-II (Ang-II) AT(1) receptor blockers (ARBs). Both prorenin and renin bind to the (pro)renin receptor (PRR) to activate Ang-II-dependent and -independent signaling cascades. Renin cleaves angiotensinogen to Ang-I, which is subsequently converted into Ang II leading to cardiovascular and renal compensatory responses and eventually dysfunction. This initial step is blocked by renin inhibitor aliskiren, thus explaining its anti-hypertensive effect. Aliskiren is approved for the treatment of hypertension either as monotherapy or in combination with amlodipine, hydrochlorothiazide, or valsartan. Several clinical trials have suggested an organoprotective potential of aliskiren beyond its anti-hypertensive action, but the mechanism by which this might occur is less clear. Like ACEIs and ARBs, aliskiren increases plasma renin concentration; however, aliskiren reduces plasma renin activity. Intriguingly, aliskiren has additional abilities to downregulate the expression of the PRR and the AT(1) receptor, adding novel mechanistic insights to our current knowledge. Importantly, a few questions remain unresolved, such as the potential effects of aliskiren on (i) prorenin and its receptor-mediated Ang-II-independent pathways, and (ii) the signal network that comprises of PRR-associated vacuolar-H(+)-ATPase-linked Wnt/Frizzled signal transduction, including canonical-beta-catenin and non-canonical Wnt-JNK-Ca(2+) signals. Discrepant outcomes in ALTITUDE study make more complex understanding aliskiren's therapeutic potential in treating cardio-renal disorders. This review attempts to address some of the remaining questions regarding aliskiren's action in cardiovascular and renal disorders. PMID- 22522052 TI - Characterization of dual agonists for kinin B1 and B2 receptors and their biased activation of B2 receptors. AB - Kinin B1 and B2 receptors (kB1R and kB2R) play important roles in many physiological and pathological processes. In some cases, kB1R or kB2R activation can have overlapping or complementary beneficial effects, thus an activator of both receptors might be advantageous. We found that replacement of the C-terminal Arg in the natural kB2R activators bradykinin (BK) or kallidin (KD) with Lys (K(9)-BK or K(10)-KD) resulted in agonists that effectively stimulate the downstream signaling of both the kB1R and kB2R as measured by increased inositol turnover, intracellular calcium, ERK1/2 phosphorylation, arachidonic acid release and NO production. However, K(9)-BK and K(10)-KD displayed some characteristics of biased agonism for kB2Rs as indicated by the rapid kinetics of ERK1/2 phosphorylation induced by K(9)-BK or K(10)-KD compared with the prolonged response mediated by BK or KD. In contrast, kinetics of ERK phosphorylation stimulated by K(10)-KD activation of the kB1R was the same as that induced by known kB1R agonist des-Arg(10)-KD. Furthermore, the endocytosis of kB2Rs mediated by K(9)-BK and K(10)-KD was remarkably less than that induced by BK and KD respectively. K(10)-KD stimulated kB1R and kB2R-dependent calcium responses and ERK1/2 phosphorylation in bovine endothelial cells. In cytokine-treated human endothelial cells, K(10)-KD stimulated ERK1/2 phosphorylation and a transient peak of NO production that was primarily kB2R-dependent. K(10)-KD also stimulated prolonged NO production that was both kB1R and kB2R-dependent. These data provide the first examples of dual agonists of kB1R and kB2R, and a biased agonist of kB2R and may provide useful clues for developing dual modulators of kB1Rs and kB2Rs for potential therapeutic use. PMID- 22522053 TI - Curcumin induces cell apoptosis in human chondrosarcoma through extrinsic death receptor pathway. AB - Chondrosarcoma is a soft tissue sarcoma with a poor prognosis that is unresponsive to conventional chemotherapy. Surgical treatment leads to severe disability with high rates of local recurrence and life threat. Curcumin, an active compound in turmeric and curry, has been proven to induce tumor apoptosis and inhibit tumor proliferation, invasion, angiogenesis, and metastasis of cancer cells. In this study, we investigated the anticancer effects of curcumin in human chondrosarcoma cells. Curcumin induced apoptosis in human chondrosarcoma cell lines (JJ012 and SW1353) but not in primary chondrocytes. Curcumin induced upregulation of Fas, FasL, and DR5 expression in chondrosarcoma cells. Transfection of cells with Fas, FasL, or DR5 siRNA reduced curcumin-induced cell death. In addition, p53 involved in curcumin-mediated Fas, FasL, and DR5 expression and cell apoptosis in chondrosarcoma cells. Most importantly, animal studies revealed a dramatic 60% reduction in tumor volume after 21 days of treatment. Thus, curcumin may be a novel anticancer agent for the treatment of chondrosarcoma. PMID- 22522054 TI - Monocyte-derived interferon-alpha primed dendritic cells in the pathogenesis of psoriasis: new pieces in the puzzle. AB - Psoriasis is a common chronic inflammatory skin disorder with serious clinical, psychosocial, and economic consequences. There is much evidence that different dendritic cell (DC) subsets, various proinflammatory cytokines and Toll-like receptors (TLRs) have a central role in the pathogenesis of the disease. One of the early events in psoriatic inflammation is the secretion of interferon (IFN) alpha by activated plasmacytoid DCs, a special DC subset present in symptomless psoriatic skin. Secreted IFN-alpha along with other proinflammatory cytokines can lead to monocyte-derived DC (moDC) development, which might contribute to T helper (Th)1 and Th17 lymphocyte differentiation/activation and to keratinocyte proliferation. Recently it was proven that interleukin (IL)-12 and IL-23 play a critical role in this process. Additionally in psoriatic lesions, Th1 and Th17 lympocytes can interact with monocytes and instruct these cells to differentiate into Th1- and Th17-promoting moDCs, further governing the formation and function of specialized moDC subsets. The concept we present here focuses on the initial and central role of IFN-alpha, on the importance of other proinflammatory cytokines, on TLR stimulation and on the effect of T lymphocytes in priming moDCs, which may play an important role in initiating and maintaining psoriasis. PMID- 22522055 TI - Nutritional and immunological characteristics of fresh and refrigerated stored human milk in Hong Kong: a pilot study. AB - BACKGROUND: The nutritional and immunological qualities of human milk from Hong Kong mothers were profiled. METHODS: A total of 25 colostrum (<= 3 days postpartum) and 11 mature (30-45 days postpartum) milk specimens were collected from healthy Chinese women in Hong Kong. Parameters including total protein, whey, casein, triglycerides, lactose, lysozyme, secretory immunoglobulin A, lactoferrin and antibacterial activity of human milk were quantified. RESULT: Breast milk of Hong Kong Chinese mothers is nutritionally comparable to that of western mothers for colostrum and mature milk, with protein (25.0+/-11.3 g/l vs 10.1+/-1.4 g/l) and lactose (44.2+/-7.5 g/l vs 66.6+/-5.5 g/l) for growth and energy supply in infants, respectively. The milk of Hong Kong mothers is however characterized by its exceptionally high levels of sIgA (806.3+/-792.6 mg/dl and 1545.9+/-334.6 mg/dl) and low levels of triglycerides (10.8+/-9.3 mmol/l and 11.1+/-7.7 mmol/l). The human milk in Hong Kong was also shown to be superior to bovine formula milk, particularly in terms of lower total protein level, the high whey to casein protein ratio, rich immunological active contents, and significant antibacterial activity against 2 common Escherichia coli strains. CONCLUSIONS: Preliminary data also indicated that mature milk could be refrigerated for at least 3 days in order to maintain the major nutritional constituents and antibacterial activity. PMID- 22522056 TI - Evaluation of factors influencing accuracy in the analysis of succinylacetone in dried blood spots. AB - BACKGROUND: Dried blood spots offer specific advantages over conventional blood collection methods, but with certain limitations. This article aims to evaluate factors which affect succinylacetone test in dried blood spots. METHODS: Whole blood with defined hematocrit and blood volume spiked with succinylacetone was spotted on filter paper, and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Four hematocrit levels (30%, 40%, 50%, and 60%) and five blood volume levels (10, 30, 50, 70, and 100 MUl) were tested. RESULTS: Succinylacetone concentration increased with increasing hematocrit, large bias from added concentration was found to be - 45% when hematocrit was 30%, as the difference of hematocrit level between the calibrator and QC sample increased, the bias from nominal value was increased. Blood volume also has effect on succinylacetone concentration level, but the accuracy was <15% when blood volume was 10 to 50 MUl, and >20% as the blood volume went to >=70 MUl. CONCLUSIONS: Both hematocrit and blood volume have effect on analysis of succinylacetone in dried blood spots, the effect of hematocrit is more significant, due to hematocrit level of majority Type I tyrosinemia patients is low, diagnoses may be missed by using dried blood spots to analysis. PMID- 22522057 TI - Rotational atherectomy: a "survivor" in the drug-eluting stent era. AB - Mechanical debulking of coronary plaques with rotational atherectomy (RA) has been used for more than 20 years during percutaneous coronary interventions (PCI). Modification of plaque characteristics may be accomplished with selective ablation of inelastic fibrocalcific tissue. The use of RA, though reduced with the development of bare-metal stents (BMS) and even more with drug-eluting stents (DES), has never been completely abandoned. The present review will analyze reasons for conflicting results obtained in large series and randomized trials on this topic in the past, and will identify criteria for an appropriate use in current times. PMID- 22522058 TI - Percutaneous mitral balloon valvotomy in a case of situs inversus dextrocardia with severe rheumatic mitral stenosis. AB - The efficacy, safety and applicability of Inoue balloon technique for BMV are clearly established worldwide in selected subset of patients with rheumatic mitral stenosis (MS). However, in altered cardiac anatomy it offers technical challenges. Distorted cardiac anatomy and cardiac malpositions considerably increase the complications involved in interatrial septal puncture and left ventricular entry during BMV. There are only a few reports worldwide on successful BMV in altered cardiac anatomy using the standard Inoue technique. Here we describe a case of a 27-year-old female with situs inversus and dextrocardia, where BMV was successfully performed with a few modifications of the standard Inoue technique previously described in similar patients. PMID- 22522059 TI - Vitamin C in mouse and human red blood cells: an HPLC assay. AB - Although vitamin C (ascorbate) is present in whole blood, measurements in red blood cells (RBCs) are problematic because of interference, instability, limited sensitivity, and sample volume requirements. We describe a new technique using HPLC with coulometric electrochemical detection for ascorbate measurement in RBCs of humans, wild-type mice, and mice unable to synthesize ascorbate. Exogenously added ascorbate was fully recovered even when endogenous RBC ascorbate was below the detection threshold (25 nM). Twenty microliters of whole blood or 10 MUl of packed RBCs was sufficient for assay. RBC ascorbate was stable for 24h from whole blood samples at 4 degrees C. Processed, stored samples were stable for >1 month at -80 degrees C. Unlike other tissues, ascorbate concentrations in human and mouse RBCs were linear in relation to plasma concentrations (R=0.8 and 0.9, respectively). In healthy humans, RBC ascorbate concentrations were 9-57 MUM, corresponding to ascorbate plasma concentrations of 15-90 MUM. Mouse data were similar. In human blood stored as if for transfusion, initial RBC ascorbate concentrations varied approximately sevenfold and decreased 50% after 6 weeks of storage under clinical conditions. With this assay, it becomes possible for the first time to characterize ascorbate function in relation to endogenous concentrations in RBCs. PMID- 22522060 TI - Comparison of mechanical properties of normal and malignant thyroid cells. AB - Cancer is a disease of uncontrolled cell proliferation causing approximately 13% of deaths worldwide. Cancer cell mechanics is currently an important topic of investigation in cancer diagnostics as a possible tool to distinguish malignant cells from normal cells in addition to increasing our understanding of pathophysiology of the disease. Our study, based on Atomic Force Microscopy (AFM) measurements on cells, shows that malignant thyroid cells are 3- to 5-fold softer in comparison to primary normal thyroid cells depending on duration between cell seeding and AFM experiments. These results reveal cultivation period as an important factor that influences cell mechanics and which must be considered when comparing cells. Investigation of actin cytoskeleton by fluorescent labelling revealed differences in organization of actin between malignant and normal thyroid cells, which may be directly contributing to alteration of cell mechanics in cancer cells. PMID- 22522062 TI - Comparison of checking behavior in adults with or without checking symptom of obsessive-compulsive disorder using a novel computer-based measure. AB - Easy to administer behavioral measures of checking are needed to improve the assessment of this hallmark feature of OCD. We recently developed a new computer based behavioral assessment of OCD in a previous study. As a follow-up experiment for this method, the goal of this study was to examine whether the new computer based behavioral assessment would be capable of differentiating behaviors in adults with OCD characterized by checking behavior from those without checking behavior. We compared 22 OCD patients with compulsive checking behaviors (OCD checkers), 17 OCD controls without checking behavior (OCD controls), and 31 healthy controls (HCs) on a novel computer-based behavioral measure of checking behavior. Despite similar levels of successfully completed tasks, OCD checkers demonstrated longer duration of checking behaviors than OCD controls or HCs. Interestingly, no differences were found between OCD controls and HCs in any of the dependent variables. Our new behavioral measure offers a novel, objective, and ecologically valid measure of checking behaviors in a sample of adults with OCD. PMID- 22522061 TI - Ubiquitination and phosphorylation in the regulation of NOD2 signaling and NOD2 mediated disease. AB - The immune system is exquisitely balanced. It has the ability to effectively respond to and control infections while at the same time preventing inappropriate responses to self and environmental antigens. When this response goes awry, either through a failure to activate the immune response, or failure to terminate it, inflammatory pathology results. Posttranslational modifications (PTMs) such as ubiquitination and phosphorylation help ensure that the delicate balance underlying immune signal transduction is maintained. Ubiquitination and phosphorylation affect localization, activity, stability, and interactions of various components of the immune signal transduction machinery. Moreover, ubiquitination and phosphorylation are tightly linked, with one PTM affecting the other. Therefore, in order to find potential therapies for many immune-related pathologies, it is necessary to understand not only how the immune response is activated by ubiquitination and phosphorylation, but also how it is regulated by these PTMs at different stages of the response. An excellent system to study such activation and regulation is the NOD2 pathway. Dysregulation of NOD2 signaling is involved in the pathogenesis of a variety of inflammatory disorders including Crohn's disease, early onset sarcoidosis, and Blau syndrome. More recently NOD2 has been implicated in the development of autoimmune disease, allergy and asthma. This review will focus on what is currently known about how ubiquitination and phosphorylation regulate NOD2 signaling with particular emphasis on novel in vitro substrates which may serve as potential in vivo therapeutic targets for hyperactive NOD2 states. This article is part of a Special Issue entitled: Ubiquitin Drug Discovery and Diagnostics. PMID- 22522063 TI - Validating a postural evaluation method developed using a Digital Image-based Postural Assessment (DIPA) software. AB - OBJECTIVE: To investigate (1) the accuracy of the palpatory method to identify anatomical points by comparison with the X-ray exams, (2) the validity of classifying spinal posture in the frontal plane using Digital Image-Based Postural Assessment (DIPA) software by comparison with the X-ray exams and (3) the intra and inter-evaluator reproducibility of the DIPA software. MATERIALS AND METHODS: The postural assessment and X-ray examination of the spine, both in the frontal plane and standing position, were performed consecutively in 24 subjects. The postural assessment protocol consisted of: (1) palpation and the use of reflective markers containing lead to mark the spinous processes (SP) of the C7, T2, T4, T6, T8, T10, T12, L2, L4 and S2 vertebrae and; (2) acquisition of photographic records. First, the X-ray examinations were used to check the correlation between the palpated and marked SP and the true location of the SP of the vertebra in question, by assessing the distance between them. The spinal posture was classified based on the calculation of the scoliosis arrows in the DIPA (DIPA-SA). The X-ray examinations provided the scoliosis arrows (X-SA), the Cobb angles and the classification of spinal posture based on the Cobb angle. The results from the DIPA protocol were compared to those from the X-ray examination based protocol. The statistical tests used were: (1) Kruskal-Wallis--differences in terms of the numerical distance between the markers and the anatomical landmarks, (2) Pearson's Correlation--DIPA-SA and Cobb angles, (3) Pearson's Correlation--X-SA and DIPA-SA; (4) Bland and Altman's graphic representation--X SA and DIPA-SA, (5) Spearman's Correlation--classification of spinal posture obtained using the X-ray and DIPA protocols, (6) the intraclass correlation test (ICC) for the relationship between the DIPA-SA made by each evaluator (inter evaluator), and (7) independent t-test to compare the data from the two evaluation days (intra-evaluator), alpha=0.05. RESULTS: There were no significant differences between the location of the anatomical points located using palpation and identified with reflective markers and the respective location of the SP as identified using X-ray exams (chi2=9.366, p=0.404). Significant correlations were found between the DIPA-SA and the Cobb angles in the dorsal (r=0.75, p<0.001) and lumbar (r=0.76, p=0.007) regions; between the DIPA-SA and the X-SA in the dorsal (r=0.79, p<0.001) and lumbar (r=0.92, p<0.001) regions and; between the classifications of posture obtained with the DIPA and X-ray protocols (r=0.804, p<0.001). Bland and Altman's representation showed agreement between DIPA-SA and X-SA for both curvatures. Significant correlations were found for the intra evaluator test in the thoracic (r=0.99, p<0.001) and lumbar (r=0.98, p<0.001) regions; for the inter-evaluator test in the thoracic (r=0.99, p<0.001) and lumbar (r=0.88, p<0.001) regions. CONCLUSION: The results suggest that the DIPA protocol constitutes a valid simple, practical and low-cost non-invasive tool for the evaluation of the spine in the frontal plane which can be used to obtain reproducible measurements (inter and intra-evaluators). PMID- 22522064 TI - A parallel solution for high resolution histological image analysis. AB - This paper describes a general methodology for developing parallel image processing algorithms based on message passing for high resolution images (on the order of several Gigabytes). These algorithms have been applied to histological images and must be executed on massively parallel processing architectures. Advances in new technologies for complete slide digitalization in pathology have been combined with developments in biomedical informatics. However, the efficient use of these digital slide systems is still a challenge. The image processing that these slides are subject to is still limited both in terms of data processed and processing methods. The work presented here focuses on the need to design and develop parallel image processing tools capable of obtaining and analyzing the entire gamut of information included in digital slides. Tools have been developed to assist pathologists in image analysis and diagnosis, and they cover low and high-level image processing methods applied to histological images. Code portability, reusability and scalability have been tested by using the following parallel computing architectures: distributed memory with massive parallel processors and two networks, INFINIBAND and Myrinet, composed of 17 and 1024 nodes respectively. The parallel framework proposed is flexible, high performance solution and it shows that the efficient processing of digital microscopic images is possible and may offer important benefits to pathology laboratories. PMID- 22522065 TI - [Places of interest, human, key for the dawn of time...]. PMID- 22522066 TI - The mode of death in implantable cardioverter-defibrillator and cardiac resynchronization therapy with defibrillator patients: results from routine clinical practice. AB - BACKGROUND: Although data on the mode of death of implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy with defibrillator (CRT D) patients have been examined in randomized clinical trials, in routine clinical practice data are scarce. To provide reasonable expectations and prognosis for patients and physicians, this study assessed the mode of death in routine clinical practice. OBJECTIVE: To assess the mode of death in ICD/CRT-D recipients in routine clinical practice. METHODS: All patients who underwent an ICD or CRT-D implantation at the Leiden University Medical Center, the Netherlands, between 1996 and 2010 were included. Patients were divided into primary prevention ICD, secondary prevention ICD, and CRT-D patients. For patients who died during follow up, the mode of death was retrieved from hospital and general practitioner records and categorized according to a predetermined classification: heart failure death, other cardiac death, sudden death, noncardiac death, and unknown death. RESULTS: A total of 2859 patients were included in the analysis. During a median follow-up of 3.4 years (interquartile range 1.7-5.7 years), 107 (14%) primary prevention ICD, 253 (28%) secondary prevention ICD, and 302 (25%) CRT-D recipients died. The 8-year cumulative incidence of all-cause mortality was 39.9% (95% confidence interval 37.0%-42.9%). Heart failure death and noncardiac death were the most common modes of death for all groups. Sudden death accounted for approximately 7%-8% of all deaths. CONCLUSION: For all patients, heart failure and noncardiac death are the most common modes of death. The proportion of patients who died suddenly was low and comparable for primary and secondary ICD and CRT-D patients. PMID- 22522067 TI - Prolongation of prion disease-associated symptomatic phase relates to CD3+ T cell recruitment into the CNS in murine scrapie-infected mice. AB - Prion diseases are caused by the transconformation of the host cellular prion protein PrP(c) into an infectious neurotoxic isoform called PrP(Sc). While vaccine-induced PrP-specific CD4(+) T cells and antibodies partially protect scrapie-infected mice from disease, the potential autoreactivity of CD8(+) cytotoxic T lymphocytes (CTLs) received little attention. Beneficial or pathogenic influence of PrP(c)-specific CTL was evaluated by stimulating a CD8(+) T-cell-only response against PrP in scrapie-infected C57BL/6 mice. To circumvent immune tolerance to PrP, five PrP-derived nonamer peptides identified using prediction algorithms were anchored-optimized to improve binding affinity for H 2D(b) and immunogenicity (NP-peptides). All of the NP-peptides elicited a significant number of IFNgamma secreting CD8(+) T cells that better recognized the NP-peptides than the natives; three of them induced T cells that were lytic in vivo for NP-peptide-loaded target cells. Peptides 168 and 192 were naturally processed and presented by the 1C11 neuronal cell line. Minigenes encoding immunogenic NP-peptides inserted into adenovirus (rAds) vectors enhanced the specific CD8(+) T-cell responses. Immunization with rAd encoding 168NP before scrapie inoculation significantly prolonged the survival of infected mice. This effect was attributable to a significant lengthening of the symptomatic phase and was associated with enhanced CD3(+) T cell recruitment to the CNS. However, immunization with Ad168NP in scrapie-incubating mice induced IFNgamma-secreting CD8(+) T cells that were not cytolytic in vivo and did not influence disease progression nor infiltrated the brain. In conclusion, the data suggest that vaccine-induced PrP-specific CD8(+) T cells interact with prions into the CNS during the clinical phase of the disease. PMID- 22522068 TI - American Association of Clinical Endocrinologists' Guidelines for Management of Dyslipidemia and Prevention of Atherosclerosis. PMID- 22522069 TI - Association between the risk of congenital toxoplasmosis and the classification of toxoplasmosis in pregnant women and prenatal treatment in Brazil, 1994-2009. AB - OBJECTIVES: The objectives of this study were to analyze the association between the classification of toxoplasmosis in the pregnant woman (TP) according to the classification of Lebech et al. and the incidence of congenital toxoplasmosis (CT), also taking into consideration prenatal treatment. METHODS: A clinical cohort study of 524 children followed-up until 1 year of age was conducted. Adjusted odds ratios (OR) were estimated by logistic regression. RESULTS: Of 519 pregnant women, 61.3% were not classified due to the incompleteness of hospital records. Among the pregnant women classified as confirmed cases of TP (n=19), the CT risk was six times greater than in the probable/possible group. No case of CT was identified in the group of pregnant women classified as unlikely to have TP. The children with no prenatal treatment (46.2% n=242/524) presented a risk almost three times greater of CT than the treated children (OR 2.77, 95% confidence interval (CI) 1.54-4.97; p=0.001). Complete prenatal treatment was identified as a protecting factor for CT (OR 0.35, 95% CI 0.19-0.65; p=0.001). CONCLUSIONS: A lack or incomplete prenatal treatment was identified as an important risk factor for CT in this study. The proportions of non-classified mothers and children with no prenatal treatment reflect the need to improve prenatal care in Brazil. PMID- 22522070 TI - Control of phonatory onset and offset in Parkinson patients following deep brain stimulation of the subthalamic nucleus and caudal zona incerta. AB - Laryngeal hypokinesia is a common symptom in Parkinson's disease (PD) that affects quality of life. Deep brain stimulation (DBS) is well recognized as a complementary method for treatment of motor symptoms in PD but the outcomes on patients' control over phonatory alternation have yet not been clearly elucidated. The present study examined the effect of subthalamic nucleus STN-DBS (n = 8, aged 51-72 yrs; median = 63 yrs) and caudal Zona incerta cZi-DBS (n = 8, aged 49-71 yrs; median = 61 yrs) on control of onset and offset of phonation in connected speech. The patients were evaluated in a preoperatively (Med ON, 1.5 times the ordinary Levodopa dose) and 12 months post-operatively (Med ON, ordinary Levodopa dose). The results provided evidence of a progressive reduction in the ability to manifest alternations between voicing and voiceless states in a reading task. Mean proportion produced with inappropriate voicing increased from 47.6% to 55.3% and from 62.9% to 68.6% of the total duration for the two groups of patients between Pre-op and Post-op, Stim OFF evaluations. The medial and final parts of the fricative were more affected than the initial part, indicating an increased voicing lead into the following vowel. We propose that this reduction in phonatory control is be due to either progression of the disease, an effect of reduced Levodopa dosage or a microlesional effect. Patients' proficiency in alternating between voiced and voiceless states in connected speech remained unaffected by both STN-DBS and cZi-DBS. PMID- 22522071 TI - Hardware complications in deep brain stimulation: electrode impedance and loss of clinical benefit. AB - BACKGROUND: Deep brain stimulation (DBS) is an effective treatment in patients with movement disorders. Successful outcomes are correlated with patient selection, accurate placement of the electrodes in their surgical target and optimal programming of patients. The loss of clinical efficacy after successful treatment may be related to hardware complications. OBJECTIVES: We studied the causes of loss of stimulation efficacy in patients with stable antiparkinsonian benefit after DBS. RESULTS: Seven out of 110 (6.3%) patients surgically treated with DBS showed a loss of clinical efficacy, and were included in the study. Five cases had subacute clinical worsening and two sudden deterioration. All of them had an impedance increment (>4000 Omega) with the active contacts. Further reprogramming was attempted in all the cases using the undamaged contacts. However, five patients had incomplete clinical control and were reoperated with an electrode replacement. X-rays provided information in all cases except one showing the disruption or rupture of electrode. CONCLUSIONS: It is important to identify this hardware problem in view of the growing number of patients receiving this therapy. A protocol for patients with loss of stimulation efficacy and electrode impedance increment needs to be created in clinical visits in order to detect the failed stimulation mechanism. PMID- 22522072 TI - Self perceived weakness in Parkinson's disease. AB - BACKGROUND: Parkinson's disease (PD) has been known as "the shaking palsy" as well as "paralysis agitans", yet clinically apparent weakness is not a feature of the disorder. Relative weakness, and early muscle fatigue may be demonstrated on testing but frank weakness should not be apparent on routine clinical examination. AIM: To determine the prevalence of self perceived weakness (SPW) and whether this feeling was associated with the sense of fatigue. METHODS: We asked 113 consecutive PD patients, who had no demonstrable weakness on routine neurological exam and were able to provide reliable answers, whether they perceived themselves to be weak, and whether they felt fatigued. We did not use a fatigue questionnaire or measure strength. The motor scale of the unified Parkinson's disease rating scale was also used to evaluate every subject. RESULTS: Self perceived weakness was reported by 43.8%. Self perceived weakness was associated with fatigue but not with bradykinesia, tremor or total motor score (motor severity). SPW is common in PD but affects less than half the studied population. SPW appears to be related to fatigue, a major determinant of quality of life in PD, and therefore is an important symptom to understand. PMID- 22522073 TI - Antihypertensive medication use, adherence, stops, and starts in Canadians with hypertension. AB - BACKGROUND: Some of the greatest barriers to achieving blood pressure control are perceived to be failure to prescribe antihypertensive medication and lack of adherence to medication prescriptions. METHODS: Self-reported data from 6017 Canadians with diagnosed hypertension who responded to the 2008 Canadian Community Health Survey and the 2009 Survey on Living with Chronic Diseases in Canada were examined. RESULTS: The majority (82%) of individuals with diagnosed hypertension reported using antihypertensive medications. The main reasons for not taking medications were either that they were not prescribed (42%) or that blood pressure had been controlled without medications (45%). Of those not taking antihypertensive medications in 2008 (n = 963), 18% had started antihypertensive medications by 2009, and of those initially taking medications (n = 5058), 5% had stopped. Of those taking medications in 2009, 89% indicated they took the medication as prescribed, and 10% indicated they occasionally missed a dose. Participants who were recently diagnosed, not measuring blood pressure at home, not having a plan to control blood pressure, or not receiving instructions on how to take medications were less likely to be taking antihypertensive medications; similar factors tended to be associated with stopping antihypertensive medication use. CONCLUSIONS: Compatible with high rates of hypertension control, most Canadians diagnosed with hypertension take antihypertensive medications and report adherence. Widespread implementation of self-management strategies for blood pressure control and standardized instructions on antihypertensive medication may further optimize drug treatment. PMID- 22522074 TI - Increase of chondrogenic potentials in adipose-derived stromal cells by co delivery of type I and type II TGFbeta receptors encoding bicistronic vector system. AB - Stem cell therapy has been developing rapidly as a potential cure for repairing or regenerating the functions of diseased organs and tissues. Adipose-derived stromal cells (ASCs) are an attractive cell source for stem cell therapy because they can be isolated easily from fat tissue in significant numbers and exhibit multiple differentiation potential under appropriate in vitro culture conditions. However, ASCs derived from individual donors can show wide variations in differentiation potential. In addition, the regulatory mechanisms underlying stem cell differentiation remain unclear. Transforming growth factor beta (TGFbeta) is a well-known ASC chondrogenic differentiation factor that stimulates ASC signaling pathways by activating transmembrane type I and type II receptors. We hypothesized that the chondrogenic differentiation potential of ASCs is dependent upon the expression of TGFbeta receptors and could be improved by the co-delivery of type I (TGFbetaRI) and type II (TGFbetaRII) TGFbeta receptors. To prove this, heterogeneity within the chondrogenic potential of ASCs isolated from 10 donors was examined and their susceptibility to TGFbeta during the process of chondrogenic differentiation investigated. In addition, the results showed that co-delivery of the TGFbetaRI and TGFbetaRII genes increased the expression of TGFbeta receptor signaling in ASCs with low chondrogenic potential, resulting in increased chondrogenic differentiation. Monitoring and delivering TGFbetaRI and TGFbetaRII may, therefore, be a powerful tool for predicting the differentiation potential of stem cells and for enhancing their differentiation capacity prior to stem cell transplantation. PMID- 22522075 TI - Evidence for co-infection of ovine prion strains in classical scrapie isolates. AB - The diversity of strains of ovine prions within classical scrapie isolates was investigated by transmission studies in wild type mice. To determine the maximum diversity of prion strains present in each ovine scrapie isolate examined, isolates from mice having the shortest and longest incubation times for terminal disease after primary inoculation were passaged serially. Serial passage of ARQ/ARQ scrapie isolates in RIII mice revealed the ME7 prion strain in mice with short incubation times for terminal prion disease and the 87A strain in those mice with long incubation times. Serial passage of VRQ/VRQ scrapie isolates in RIII mice led to emergence of the 221C prion strain in mice with short incubation times and a variant of the 221C strain in those mice with long incubation times. RIII mice with short incubation times had higher levels of total and proteinase K resistant PrP(Sc) compared with those RIII mice with long incubation times, while mice with long incubation times had large aggregates and plaques of PrP(Sc). ME7 PrP(Sc) differed in stability compared with the 87A prion strain, while PrP(Sc) associated with 221C had similar stability to that of the 221C variant. Serial passage in VM mice led to identification of ME7 and 87V in the same scrapie isolate. The data show that different prion strains can emerge from the same ovine scrapie isolate following serial passage in wild type mice and that the transmission properties of these strains correlate with distinct patterns of PrP(Sc) deposition. PMID- 22522076 TI - Simultaneous porcine circovirus type 2 and Mycoplasma hyopneumoniae co inoculation does not potentiate disease in conventional pigs. AB - The aim of this study was to assess the effect of simultaneous experimental inoculation of porcine circovirus type 2 (PCV2; intranasal delivery) and Mycoplasma hyopneumoniae (Mhyo; transtracheal delivery) into conventional, seropositive 6-week-old piglets. Thirty-six male piglets were assigned randomly to four groups: control (n=6), PCV2 (n=6), Mhyo (n=12) and PCV2+Mhyo (n=12). Blood samples and faecal and nasal swabs were collected at 0, 7, 14 and 21 days post inoculation (dpi). No significant clinical signs attributable to PCV2 infection were observed during the experiment. Coughing was recorded in three pigs from the Mhyo group and six from the PCV2+Mhyo group. No significant differences in mean body weight and rectal temperature were observed between the groups. Mild microscopical lesions similar to those reported for post-weaning multisystemic wasting syndrome were observed in two PCV2 pigs and in one PCV2+Mhyo animal. Mhyo-compatible lung lesions were observed in 21/24 pigs inoculated with Mhyo (10 from the Mhyo group and 11 from the PCV2+Mhyo group). PCV2 was detected by in-situ hybridization in 3/12 PCV2 and in 4/12 PCV2+Mhyo animals. No significant differences in PCV2 load (serum and nasal and faecal swabs), duration of viraemia or antibody titre were detected between PCV2 inoculated groups. No significant differences in Mhyo load in nasal swabs, percentage of Mhyo-seropositive pigs and mean lung score was detected between Mhyo-inoculated groups. Under the conditions of the present study, concurrent inoculation of PCV2 and Mhyo did not result in potentiation of clinical signs and lesions attributed to either infection. PMID- 22522077 TI - An application of ARIMA model to predict submicron particle concentrations from meteorological factors at a busy roadside in Hangzhou, China. AB - In order to investigate the effect of meteorological factors on submicron particle (ultrafine particle (UFP) and particulate matter 1.0 (PM(1.0))) concentrations under busy traffic conditions, a model study was conducted in Hangzhou, a city with a rapid increase of on-road vehicle fleet in China. A statistical model, Autoregressive Integrated Moving Average (ARIMA), was used for this purpose. ARIMA results indicated that barometric pressure and wind velocity were anti-correlated and temperature and relative humidity were positively correlated with UFP number concentrations and PM(1.0) mass concentrations (p<0.05). These data suggest that meteorological factors are significant predictors in forecasting roadside atmospheric concentrations of submicron particles. The findings provide baseline information on the potential effect of meteorological factors on UFP and PM(1.0) levels on a busy viaduct with heavy traffic most of the day. This study also provides a framework that may be applied in future studies, with large scale time series data, to predict the impact of meteorological factors on submicron particle concentrations in fast-developing cities, in China. PMID- 22522078 TI - Maternal and developmental immune challenges alter behavior and learning ability of offspring. AB - Stimulation of the offspring immune response during development is known to influence growth and behavioral phenotype. However, the potential for maternal antibodies to block the behavioral effects of immune activation during the neonatal period has not been assessed. We challenged female zebra finches (Taeniopygia guttata) prior to egg laying and then challenged offspring during the nestling and juvenile periods with one of two antigens (keyhole limpet hemocyanin (KLH) or lipopolysaccharide (LPS)). We then tested the effects of maternal and neonatal immune challenges on offspring growth rates and neophobia and learning ability of offspring during adulthood. Neonatal immune challenge depressed growth rates. Neophobia of adult offspring was influenced by a combination of maternal treatment, offspring treatment, and offspring sex. Males challenged with LPS during the nestling and juvenile periods had reduced learning performance in a novel foraging task; however, female learning was not impacted. Offspring challenged with the same antigen as mothers exhibited similar growth suppression and behavioral changes as offspring challenged with a novel antigen. Thus, developmental immune challenges have long-term effects on the growth and behavioral phenotype of offspring. We found limited evidence that matching of maternal and offspring challenges reduces the effects of immune challenge in the altricial zebra finch. This may be a result of rapid catabolism of maternal antibodies in altricial birds. Our results emphasize the need to address sex differences in the long-term effects of developmental immune challenge and suggest that neonatal immune activation may be one proximate mechanism underlying differences in adult behavior. PMID- 22522079 TI - Continuous estrone treatment impairs spatial memory and does not impact number of basal forebrain cholinergic neurons in the surgically menopausal middle-aged rat. AB - CEE (conjugated equine estrogens) is the most widely prescribed estrogen-only menopausal hormone therapy in the United States, and is comprised of over 50% estrone (E1) sulfate. Following CEE administration, E1 is the principal circulating estrogen. However, the cognitive and neurobiological effects of E1 in a middle-aged rodent model have not yet been evaluated. We assessed cognitive effects of continuous E1 treatment in middle-aged surgically menopausal rats using a maze battery. We also quantified number of choline acetyltransferase immunoreactive (ChAT-IR) neurons in distinct basal forebrain regions known in earlier studies in to be impacted by the most potent naturally-circulating estrogen in rodents and women, 17beta-estradiol (17beta-E2), as well as CEE. On the spatial working memory delayed-match-to-sample water maze, the highest E1 dose impaired memory performance during acquisition and after delay challenge. E1 did not impact ChAT-IR neuron number in the medial septum (MS) or horizontal/vertical diagonal bands. In a comparison study, 17beta-E2 increased MS ChAT-IR neuron number. Findings indicate that E1 negatively impacts spatial working memory and memory retention, and does not increase ChAT-IR neuron number in basal forebrain, as does 17beta-E2. Thus, data from prior studies suggest that 17beta-E2 and CEE can enhance cognition and increase number of ChAT-IR basal forebrain neurons, while here we show that E1 does not induce these effects. Findings from preclinical basic science studies can inform the design of specific combinations of estrogens that could be beneficial to the brain and cognition. Accumulating data suggest that E1 is not likely to be among these key beneficial estrogens. PMID- 22522080 TI - SOX2 hypomorphism disrupts development of the prechordal floor and optic cup. AB - Haploinsufficiency for the HMG-box transcription factor SOX2 results in abnormalities of the human ventral forebrain and its derivative structures. These defects include anophthalmia (absence of eye), microphthalmia (small eye) and hypothalamic hamartoma (HH), an overgrowth of the ventral hypothalamus. To determine how Sox2 deficiency affects the morphogenesis of the ventral diencephalon and eye, we generated a Sox2 allelic series (Sox2(IR), Sox2(LP), and Sox2(EGFP)), allowing for the generation of mice that express germline hypomorphic levels (<40%) of SOX2 protein and that faithfully recapitulate SOX2 haploinsufficient human phenotypes. We find that Sox2 hypomorphism significantly disrupts the development of the posterior hypothalamus, resulting in an ectopic protuberance of the prechordal floor, an upregulation of Shh signaling, and abnormal hypothalamic patterning. In the anterior diencephalon, both the optic stalks and optic cups (OC) of Sox2 hypomorphic (Sox2(HYP)) embryos are malformed. Furthermore, Sox2(HYP) eyes exhibit a loss of neural potential and coloboma, a common phenotype in SOX2 haploinsufficient humans that has not been described in a mouse model of SOX2 deficiency. These results establish for the first time that germline Sox2 hypomorphism disrupts the morphogenesis and patterning of the hypothalamus, optic stalk, and the early OC, establishing a model of the development of the abnormalities that are observed in SOX2 haploinsufficient humans. PMID- 22522081 TI - Heterogeneity across the dorso-ventral axis in zebrafish EVL is regulated by a novel module consisting of sox, snail1a and max genes. AB - In vertebrates, the dorso-ventral (DV) axis is defined by the combinatorial action of localised Wnt, FGF and Nodal signalling along with the antagonizing activities of Chordin and BMP pathways. Our knowledge of the factors that may act in concert with these core pathways to regulate early embryonic patterning is far from complete. Furthermore, while all three germ layers respond to these patterning cues, it is not clear whether in zebrafish the outermost protective epithelium, the enveloping layer (EVL), is also patterned along the DV axis. Here, we have identified a transgenic line driving GFP under a crestin promoter, which specifically labels the dorsal domain of the EVL suggesting heterogeneity in the EVL across the DV axis. Our attempts to understand how the expression from this promoter fragment is regulated specifically in the dorsal domain, have unravelled potential novel players involved in early EVL and embryonic patterning. We show that along with Nodal signalling components, four proteins Sox11b, Sox19b, Snail1a and Max are involved in regulating the size of this EVL domain. However, Chordin-BMP signalling might be dispensable for the dorso ventral patterning of the EVL. For the first time, this transgenic line unravels the heterogeneity in the EVL and will serve as an important tool in understanding the molecular basis of the DV patterning of the EVL. PMID- 22522082 TI - One-stage procedure for total knee arthroplasty in post-traumatic osteoarthritis of the knee with wound defect. Usefulness of navigation and flap surgery. AB - Total knee arthroplasty in post-traumatic arthritis of the knee joint is a challenging situation. Difficulties are linked to malalignment, joint stiffness, or wound complications. The authors report on a case of post-traumatic intra articular knee arthritis with tibial malalignment and a skin defect. Using computer-assisted surgery for implant positioning, and simultaneous pedicled flap surgery for wound coverage, IKS score at 2 years follow-up was 85 and 75 for clinical and function respectively. The results of total knee replacement in post traumatic knee arthritis are not as satisfactory as in degenerative situations. In severe malalignment due to bone landmark changes following malunions, computer assisted surgery gives immediate correct references for final positioning of implants and restoration of limb alignment. Implant selection must allow use of normal and revision components to fit the local anatomy. Commonly-used pedicle flaps such as the gastrocnemius flap are valuable to cover wound defects after prosthesis implantation. All these procedures can be used successfully in a one stage surgical procedure. PMID- 22522083 TI - Vitamin D: methods of 25 hydroxyvitamin D analysis, targeting at risk populations and selecting thresholds of treatment. AB - Interest in vitamin D has intensified with the association of vitamin D deficiency (VDD) with many diseases. This review will outline the limitations of current 25 hydroxyvitamin D (25OHD) methods, the target treatment threshold, and review the classical (endocrine/bone) and non-classical (paracrine/non-bone) actions of vitamin D. Recent standardisation by the National Institutes of Standards and Technology and use of LC tandem mass methodology has reduced inter method bias but insensitivity and imprecision of automated methods have challenged assay performance. Many diseases are associated with VDD but randomised clinical trial data demonstrating the benefit of un-activated sterol supplementation only exists for the prevention of falls and fractures. Consequently, 25OHD measurement should be restricted to high falls or fracture risk patients. Controversy regarding the 25OHD target of therapy requires consensus. Until resolved, widespread adoption of screening programmes and measurement of 25OHD in patients at risk of non-musculoskeletal disease is premature, costly and not supported by evidence. PMID- 22522084 TI - Serum and hair zinc levels of infants and their mothers. AB - OBJECTIVES: This cross-sectional study aimed to investigate the zinc status of mothers and their infants attending a well-child clinic. METHODS: Blood and hair samples were collected from infants and their mothers at 2nd, 6th,12th month after delivery. Information on infant and their mothers' dietary habits was gathered. RESULTS: Of all infants and their mothers, 54.6% and 12.6% had low hair zinc levels; 17% and 4.6% low serum zinc levels respectively. There was a positive relationship between mother's hair zinc level and her meat consumption at 2 and 6 months after delivery. CONCLUSION: A significant number of infants and mothers had low hair zinc levels. Hair zinc concentrations of infants decreased significantly towards the end of first year. This may be due to low zinc intake of mothers. The main contribution of our study to the literature was the positive relationship between the red meat intake and maternal hair zinc levels. PMID- 22522085 TI - Epileptic encephalopathy and amelogenesis imperfecta: Kohlschutter-Tonz syndrome. AB - Kohlschutter-Tonz syndrome is a rare genetic disorder with epilepsy, psychomotor regression, and a severe enamel defect with yellow or brownish discoloration of the teeth. The first affected family was described in 1974, and 25 patients in 11 families have been reported until now. Inheritance is autosomal recessive. Epilepsy usually starts within the first or second year of life. All affected individuals show a psychomotor regression after onset of epilepsy or a developmental delay from birth on. Clinical course and disease severity are variable even within families. There are no known biochemical or other diagnostic markers of the condition. Very recently it has been shown that the condition is caused by mutations in the gene ROGDI but molecular data have only been reported for three families. It remains to be seen whether Kohlschutter-Tonz syndrome has the same molecular basis in all affected individuals. PMID- 22522086 TI - Klippel-Feil syndrome associated with situs inversus: description of a new case and exclusion of GDF1, GDF3 and GDF6 as causal genes. AB - OBJECTIVE: Klippel-Feil syndrome is characterized by faulty segmentation of two or more cervical vertebrae and, in its most severe form, consists of massive cervical vertebral fusion, short neck, low posterior hairline, and limitation of head movement. Several cases associating Klippel-Feil syndrome with situs inversus totalis have been reported. In the present study, we describe the clinical features of a novel case of Klippel-Feil syndrome associated with situs inversus totalis and searched for mutations in GDF1, GDF3 and GDF6 genes, which were recently implicated in the development of skeletal and visceral anomalies. METHODS: A case of Klippel-Feil syndrome associated with situs inversus totalis underwent a full clinical examination including X-ray of cervical spine and thorax, abdominal ultrasound, and computerized tomography scanning of thorax and abdomen. PCR amplification and automated nucleotide sequencing of coding exons and intron-exon junctions of GDF1, GDF3, and GDF6 genes were performed in genomic DNA. RESULTS: No molecular alterations were found in GDF1, GDF3 and GDF6 genes in this patient. CONCLUSION: An additional patient associating Klippel-Feil syndrome and situs inversus totalis is reported. Mutations in GDF1, GDF3, and GDF6 genes were excluded as the cause of this unusual clinical association. PMID- 22522087 TI - The perioperative use of biologic agents in patients with rheumatoid arthritis. AB - Biologic drugs have gained an important place in the treatment of rheumatic diseases. These medications may, however, pose a higher risk of infections in rheumatic patients who a priori are prone to infections. The potential consequences of the immunosuppressive effects of the biologics raise concern about their safety in the perioperative setting. This article reviews the scientific literature that examines the influence of biologic drugs on post surgical complications. According to these studies, it is apparently safe to use tumor necrosis factor-alpha blockers and the IL-6 receptor blocker, although a few study limitations, such as small sample size, retrospective design and differences in the comparison groups weaken the conclusions. In addition, the recommendations for some of the biologic drugs are based solely on pharmacological parameters due to the absence of trials, and larger randomized controlled studies are needed to establish the safety of their use by patients with rheumatic diseases. PMID- 22522088 TI - Study of the photodegradation of 2-bromophenol under UV and sunlight by spectroscopic, chromatographic and chemometric techniques. AB - This work is focused on the study of the photodegradation of 2-bromophenol under the action of UV light and sunlight. The photodegradation process has been monitored using UV-Vis spectroscopy and High Performance Liquid Chromatography coupled to diode array and mass spectrometry detectors in tandem (HPLC-DAD-MS). Multivariate resolution methods, such as Multivariate Curve Resolution Alternating Least Squares (MCR-ALS) and hybrid soft- and hard-modeling Multivariate Curve Resolution (HS-MCR), have been applied to the experimental data to obtain the information about the kinetic evolution and identification of the compounds involved in the photodegradation process. From the analysis of HPLC DAD results, the complexity of the photodegradation process has been confirmed. Ten components were found to be involved in parallel, second- or higher-order reactions, which could not be ascertained from the spectroscopic results. The HPLC-MS results allowed postulating the identity of some of the compounds (such as hydroxyderivatives and bromophenol homologs) which resulted from the reactions of photohydrolysis, debromination and bromine transfer to different position of the phenol ring. The effect of the UV light and sunlight on the photodegradation process was found to affect mainly the rate of the reaction, but not the identity of the photoproducts formed. The advantages and limitations of the spectroscopic and chromatographic analysis were also discussed. The potential of combining spectroscopic and chromatographic data in a single multiset structure was also shown. This strategy, uses the advantage of the good definition of the process time axis from the spectroscopic experiment and the capability to distinguish among compounds, linked to the use of chromatographic information. PMID- 22522089 TI - Investigating the language needs of culturally and linguistically diverse nursing students to assist their completion of the bachelor of nursing programme to become safe and effective practitioners. AB - BACKGROUND: Australia has an increasing number of nursing students from culturally and linguistically diverse backgrounds however problems communicating in the clinical setting, difficulty with academic writing and a tendency to achieve lower grades have been reported. OBJECTIVES: To identify the language needs of culturally and linguistically diverse students, and evaluate the English language support programme to develop appropriate strategies and assist academic progression and clinical communication skills. DESIGN AND METHODS: An action research approach was adopted and this paper reports findings from the first round of semi-structured individual interviews. The strategies suggested by the participants will subsequently be implemented and evaluated during the first cycle of action research. SETTING: An Australian Bachelor of Nursing programme which has students from culturally and linguistically diverse backgrounds. PARTICIPANTS: Eight second and third year students who have a primary language other than English. RESULTS: Four strategies emerged from initial student interviews. The English language support programme to be conducted during semester breaks, ongoing focus on reading and writing but also to include some International English Language Testing System exam strategies and practice, increase the use of nursing specific language and context in the English language support programme, and informing or reminding lecturers of the impact of their lecture delivery style on learning for students from diverse backgrounds. CONCLUSION: Themes emerging from the initial round of interviews inform both the implementation of the English language support programme and teacher delivery. It is hoped that implementing these strategies will support the English language development of nurses from diverse backgrounds. Proficient communication will more likely contribute to providing safe and effective culturally sensitive care in a culturally diverse health care environment. Additional cycles of action research may be conducted to further improve the programme. PMID- 22522090 TI - Decreasing risk of colorectal cancer in patients with inflammatory bowel disease over 30 years. AB - BACKGROUND & AIMS: The risk for colorectal cancer (CRC) in patients with inflammatory bowel disease (IBD) could have changed over time, with changes in treatment options. We studied CRC risk in a nationwide cohort of 47,374 Danish patients with IBD over a 30-year period. METHODS: We determined relative risk (RR) values using Poisson regression-derived incidence rate ratios of CRC from 1 year after IBD diagnosis, adjusted for age, sex, and calendar time. We compared incidence of CRC among patients with IBD vs individuals without IBD. RESULTS: During 178 million person-years of follow-up evaluation, 268 patients with ulcerative colitis (UC) and 70 patients with Crohn's disease (CD) developed CRC. The overall risk of CRC among patients with UC was comparable with that of the general population (RR, 1.07; 95% confidence interval [CI], 0.95-1.21). However, patients diagnosed with UC in childhood or as adolescents, those with long duration of disease, and those with concomitant primary sclerosing cholangitis were at increased risk. For patients with UC, the overall RR for CRC decreased from 1.34 (95% CI, 1.13-1.58) in 1979-1988 to 0.57 (95% CI, 0.41-0.80) in 1999 2008. Among patients with CD, the overall RR for CRC was 0.85 (95% CI, 0.67 1.07), which did not change over time. CONCLUSIONS: A diagnosis of UC or CD no longer seems to increase patients' risk of CRC, although subgroups of patients with UC remain at increased risk. The decreasing risk for CRC from 1979 to 2008 might result from improved therapies for patients with IBD. PMID- 22522091 TI - Persistence of HCV in quiescent hepatic cells under conditions of an interferon induced antiviral response. AB - BACKGROUND & AIMS: Hepatitis C virus (HCV) is a common cause of chronic liver disease. Many patients do not clear the viral infection; little is known about the mechanisms of HCV persistence or the frequent failure of interferon (IFN) to eliminate it. Better culture systems are needed to study viral replication in quiescent liver cells. METHODS: We used human hepatoma (Huh7.5) cells and those that had undergone proliferation arrest and differentiation (Huh7.5(dif)) to study the persistence of HCV infection following exposure of the cells to IFN alpha and to compare the antiviral effects of IFN-alpha and IFN-lambda. We validated these results with primary human hepatocytes and Huh7 cells that expressed an IFN-inducible fluorophore. RESULTS: Following infection of Huh7.5(dif) cells, HCV replicated persistently and released infectious particles. Long-term exposure of the cells to IFN-alpha reduced HCV replication ~1000-fold but did not eliminate the virus; viral replication rebounded after withdrawal of IFN, as it does in patients with chronic HCV infection. HCV replicated at higher levels, but not exclusively, in cells that had a low level of response to IFN alpha. Following incubation of cells with equipotent concentrations of IFN-alpha or IFN-lambda, Huh7.5(dif) cells expressed a wider pattern of IFN-stimulated genes than undifferentiated Huh7.5 cells or primary human hepatocytes, indicating that the antiviral response depends on the differentiation status of the cells. CONCLUSIONS: We developed a cell culture system using hepatoma cells to study persistent HCV infection during the type I or type III IFN-induced antiviral response. The level and range of the antiviral responses were associated with the differentiation status of the cells. We propose that HCV exploits the stochastic nature of the response of hepatocytes to IFN to sustain persistence. PMID- 22522092 TI - Intestinal microbes affect phenotypes and functions of invariant natural killer T cells in mice. AB - BACKGROUND & AIMS: Invariant natural killer T (iNKT) cells undergo canonical, Valpha14-Jalpha18 rearrangement of the T-cell receptor (TCR) in mice; this form of the TCR recognizes glycolipids presented by CD1d. iNKT cells mediate many different immune reactions. Their constitutive activated and memory phenotype and rapid initiation of effector functions after stimulation indicate previous antigen-specific stimulation. However, little is known about this process. We investigated whether symbiotic microbes can determine the activated phenotype and function of iNKT cells. METHODS: We analyzed the numbers, phenotypes, and functions of iNKT cells in germ-free mice, germ-free mice reconstituted with specified bacteria, and mice housed in specific pathogen-free environments. RESULTS: Specific pathogen-free mice, obtained from different vendors, have different intestinal microbiota. iNKT cells isolated from these mice differed in TCR Vbeta7 frequency and cytokine response to antigen, which depended on the environment. iNKT cells isolated from germ-free mice had a less mature phenotype and were hyporesponsive to activation with the antigen alpha-galactosylceramide. Intragastric exposure of germ-free mice to Sphingomonas bacteria, which carry iNKT cell antigens, fully established phenotypic maturity of iNKT cells. In contrast, reconstitution with Escherichia coli, which lack specific antigens for iNKT cells, did not affect the phenotype of iNKT cells. The effects of intestinal microbes on iNKT cell responsiveness did not require Toll-like receptor signals, which can activate iNKT cells independently of TCR stimulation. CONCLUSIONS: Intestinal microbes can affect iNKT cell phenotypes and functions in mice. PMID- 22522093 TI - Tyrosyl-DNA phosphodiesterase 1 initiates repair of apurinic/apyrimidinic sites. AB - Tyrosyl-DNA phosphodiesterase 1 (Tdp1) catalyzes the hydrolysis of the phosphodiester linkage between the DNA 3' phosphate and a tyrosine residue as well as a variety of other DNA 3' damaged termini. Recently we have shown that Tdp1 can liberate the 3' DNA phosphate termini from apurinic/apyrimidinic (AP) sites. Here, we found that Tdp1 is more active in the cleavage of the AP sites inside bubble-DNA structure in comparison to ssDNA containing AP site. Furthermore, Tdp1 hydrolyzes AP sites opposite to bulky fluorescein adduct faster than AP sites located in dsDNA. Whilst the Tdp1 H493R (SCAN1) and H263A mutants retain the ability to bind an AP site-containing DNA, both mutants do not reveal endonuclease activity, further suggesting the specificity of the AP cleavage activity. We suggest that this Tdp1 activity can contribute to the repair of AP sites particularly in DNA structures containing ssDNA region or AP sites in the context of clustered DNA lesions. PMID- 22522094 TI - Glucose oxidase induces insulin resistance via influencing multiple targets in vitro and in vivo: The central role of oxidative stress. AB - It is well known that reactive oxygen species (ROS) plays a role in the pathogenesis of insulin resistance which is the hallmark of type 2 diabetes. However, it is still needed to clarify the mechanism underlying insulin resistance. Glucose oxidase (GOD) is an oxi-reductase catalyzing the conversion of glucose to glucolactone, which is further converted to glucuronic acid and H(2)O(2). The present study was designed to establish a rat model of insulin resistance using GOD and to investigate possible mechanisms. The results showed that three days administration of GOD could significantly increase fasting blood glucose, resulting in impaired glucose and insulin tolerance. Moreover, GOD disrupted insulin signaling both in rats and in hepatocytes, as evidenced by decreased phosphorylation of insulin-stimulated Akt, GSK3 and FOXO1alpha. Furthermore, GOD administration decreased the expression of PPARgamma, alterated the phosphorylation of MAPKs, including p38, ERK and JNK, increased the expression of GRP78 and reduced the expression of PGC-1alpha and decreased the activities of ATPase and respiratory complexes, all of which have been reported to contribute to insulin resistance. Redox balance was evaluated by detecting the expression of antioxidant defenses and ROS generation. After the treatment with GOD, nuclear factorerythroid 2 p45-related factor 2 (Nrf2)-regulated antioxidant enzymes were damaged and ROS production increased significantly. N-acetyl-L cysteine (NAC), a potent antioxidant, could notably inhibit these effects of GOD. Although further studies are needed to investigate the clear mechanism, these data also support the conclusion that, if not the most early event, ROS generation is the most important event that plays a central role in the pathogenesis of insulin resistance. Overall, our study established an insulin resistant animal model induced by GOD, elucidated the importance of ROS in pathogenesis of insulin resistance and provided the clue for further studies on the underlying mechanisms. PMID- 22522095 TI - Impact of recombination on polymorphism of genes encoding Kunitz-type protease inhibitors in the genus Solanum. AB - BACKGROUND: The group of Kunitz-type protease inhibitors (KPI) from potato is encoded by a polymorphic family of multiple allelic and non-allelic genes. The previous explanations of the KPI variability were based on the hypothesis of random mutagenesis as a key factor of KPI polymorphism. RESULTS: KPI-A genes from the genomes of Solanum tuberosum cv. Istrinskii and the wild species Solanum palustre were amplified by PCR with subsequent cloning in plasmids. True KPI sequences were derived from comparison of the cloned copies. "Hot spots" of recombination in KPI genes were independently identified by DnaSP 4.0 and TOPALi v2.5 software. The KPI-A sequence from potato cv. Istrinskii was found to be 100% identical to the gene from Solanum nigrum. This fact illustrates a high degree of similarity of KPI genes in the genus Solanum. Pairwise comparison of KPI A and B genes unambiguously showed a non-uniform extent of polymorphism at different nt positions. Moreover, the occurrence of substitutions was not random along the strand. Taken together, these facts contradict the traditional hypothesis of random mutagenesis as a principal source of KPI gene polymorphism. The experimentally found mosaic structure of KPI genes in both plants studied is consistent with the hypothesis suggesting recombination of ancestral genes. The same mechanism was proposed earlier for other resistance-conferring genes in the nightshade family (Solanaceae). Based on the data obtained, we searched for potential motifs of site-specific binding with plant DNA recombinases. During this work, we analyzed the sequencing data reported by the Potato Genome Sequencing Consortium (PGSC), 2011 and found considerable inconsistence of their data concerning the number, location, and orientation of KPI genes of groups A and B. CONCLUSIONS: The key role of recombination rather than random point mutagenesis in KPI polymorphism was demonstrated for the first time. PMID- 22522096 TI - Development of two mobile laboratories for a routine and accident monitoring of internal contamination. AB - To provide medical surveillance of workers exposed to risk of internal contamination, IRSN (French Institute for Radiological Protection and Nuclear Safety) has developed two mobile laboratories for on-site monitoring. The laboratories are unique in Europe. They meet the new radiation protection requirements for nuclear medicine departments and radiological emergency response. Details of the design, calibration procedures and performance characteristics of these systems in measurements of various types of organs (thyroid, lung and whole body) are described. The sensitivity of the measurements is very close to that achieved in a heavily shielded stationary laboratory. PMID- 22522097 TI - The gamma ray response of alanine film dosimeters at low temperatures. AB - The response of alanine film EPR dosimeters was studied for low temperature gamma irradiation conditions (77-293 K) in the dose interval from 6.3 to 80 kGy. It was found that the response of the dosimeter decreases with decreased irradiation temperature and saturates at lower doses for lower irradiation temperatures. The analysis of the EPR signal suggests that the radical species formed at low temperature are the same as those used for dosimetry at room temperature, but with different concentrations. Their concentrations evolve as the temperature of the sample increases until the usual EPR signal used at room temperature is obtained. PMID- 22522098 TI - In vivo and in vitro estrogenic activity of the antidepressant fluoxetine. AB - Recent years have seen an increase in the use of antidepressant drugs, especially fluoxetine (FLX), in sensitive populations, such as pregnant and lactating women. Although some evidence suggests a possible endocrine action of FLX, no specific studies have been performed to investigate this hypothesis. In the present study, we investigated the possible (anti)androgenic and (anti)estrogenic actions of FLX using Hershberger, uterotrophic (0.4, 1.7, and 17mg/kg), and reporter gene (7.6 129MUM) assays. In the Hershberger assay, no differences were observed in androgen-dependent organ weights. However, the uterotrophic and gene reporter assays indicated a possible estrogenic action of FLX. Uterine weight increased in the 1.7 and 17mg/kg/day groups in the 3-day uterotrophic assay in immature rats. Additionally, noncytotoxic concentrations of FLX induced estrogenic responses and increased the estrogenic response of estradiol in MCF-7 breast cancer cells transfected with luciferase. PMID- 22522099 TI - Area variations in health: a spatial multilevel modeling approach. AB - Both space and membership in geographically-embedded administrative units can produce variations in health, resulting in geographic clusters of good and poor health. Despite important differences between these two types of dependence, one is easily mistaken for the other, and the possibility that both are at work is commonly ignored. We fit a series of hierarchical and spatially-explicit multilevel models to a U.S. county-level life dataset of life expectancy in 1999 to demonstrate approaches for data analysis and interpretation when multiple sources of area-clustering are present. We demonstrate the methods to detect, interpret, and differentiate evidence of spatial and geographic membership effects and discuss key considerations for analyzing data with spatial or/and membership dimensions. We find evidence that life expectancy is driven by both within-state geographic process, and by spatial processes. We argue that considering spatial and membership processes simultaneously yields valuable insights into the patterning of area variations in health. PMID- 22522100 TI - Variation in geographic access to specialist inpatient hospices in England and Wales. AB - We seek to map and describe variation in geographic access to the set of 189 specialist adult inpatient hospices in England and Wales. Using almost 35,000 small Census areas (Local Super Output Areas: LSOAs) as our units of analysis, the locations of hospices, and estimated drive times from LSOAs to hospices we construct an accessibility 'score' for each LSOA, for England and Wales as a whole. Data on cancer mortality are used as a proxy for the 'demand' for hospice care and we then identify that subset of small areas in which accessibility (service supply) is relatively poor yet the potential 'demand' for hospice services is above average. That subset is then filtered according to the deprivation score for each LSOA, in order to identify those LSOAs which are also above average in terms of deprivation. While urban areas are relatively well served, large parts of England and Wales have poor access to hospices, and there is a risk that the needs of those living in relatively deprived areas may be unmet. PMID- 22522103 TI - Genetic structure and phylogeography of Aedes aegypti, the dengue and yellow fever mosquito vector in Bolivia. AB - Between the 16th and 18th centuries, Aedes aegypti (Diptera: Culicidae), a mosquito native to Africa, invaded the Americas, where it was successively responsible for the emergence of yellow fever (YF) and dengue (DEN). The species was eradicated from numerous American countries in the mid-20th century, but re invaded them in the 1970s and 1980s. Little is known about the precise identities of Ae. aegypti populations which successively thrived in South America, or their relation with the epidemiological changes in patterns of YF and DEN. We examined these questions in Bolivia, where Ae. aegypti, eradicated in 1943, re-appeared in the 1980s. We assessed the genetic variability and population genetics of Ae. aegypti samples in order to deduce their genetic structure and likely geographic origin. Using a 21-population set covering Bolivia, we analyzed the polymorphism at nine microsatellite loci and in two mitochondrial DNA regions (COI and ND4). Microsatellite markers revealed a significant genetic structure among geographic populations (F(ST)=0.0627, P<0.0001) in relation with the recent re-expansion of Ae. aegypti in Bolivia. Analysis of mtDNA sequences revealed the existence of two genetic lineages, one dominant lineage recovered throughout Bolivia, and the second restricted to rural localities in South Bolivia. Phylogenic analysis indicated that this minority lineage was related to West African Ae. aegypti specimens. In conclusion, our results suggested a temporal succession of Ae. aegypti populations in Bolivia, that potentially impacted the epidemiology of dengue and yellow fever. PMID- 22522104 TI - Applicability of large databases in outcomes research. AB - Outcomes research serves as a mechanism to assess the quality of care, cost effectiveness of treatment, and other aspects of health care. The use of administrative databases in outcomes research is increasing in all medical specialties, including hand surgery. However, the real value of databases can be maximized with a thorough understanding of their contents, advantages, and limitations. We performed a literature review pertaining to databases in medical, surgical, and epidemiologic research, with special emphasis on orthopedic and hand surgery. This article provides an overview of the available database resources for outcomes research, their potential value to hand surgeons, and suggestions to improve their effective use. PMID- 22522105 TI - Predictors of diagnosis of ulnar neuropathy after surgically treated distal humerus fractures. AB - PURPOSE: Ulnar nerve dysfunction is a common sequela of surgical treatment of distal humerus fractures. This study addresses the null hypothesis that different types of distal humerus injuries have comparable rates of diagnosis of ulnar neuropathy. METHODS: We assessed diagnosis of ulnar neuropathy in 107 consecutive adults who had a surgically treated fracture of the distal humerus followed up at least 6 months after injury. Diagnosis of ulnar neuropathy was defined as documentation of sensory and motor dysfunction of the ulnar nerve in the medical record. Fractures were categorized as either columnar fractures or fractures of the capitellum and trochlea. The explanatory (independent) variables included age, sex, fracture type, AO type, associated wound, associated elbow dislocation, mechanism of trauma, ipsilateral skeletal injury, olecranon osteotomy, implant over or below the medial epicondyle, infection, time from injury to surgery, the number of surgeries within 4 weeks and 6 months of injury, the total number of surgeries, and whether the nerve was transposed. RESULTS: Postoperative ulnar neuropathy was diagnosed in 17 of 107 patients (16%), including 16 of 59 columnar fractures (21%). The only risk factor for ulnar neuropathy was columnar fracture. CONCLUSIONS: Patients with columnar fractures might be at higher risk for the development of postoperative ulnar neuropathy than patients with capitellum and trochlea fractures, regardless of whether the ulnar nerve was transposed. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV. PMID- 22522106 TI - Trapezoid fractures: report of 11 cases. AB - PURPOSE: Trapezoid fractures are rare. Mostly single cases reports appear in the literature. The purpose of this study was to review 11 patients treated for trapezoid fractures at our center. METHODS: We reviewed all trapezoid fractures that presented over the past 10 years at our institution. We reviewed case notes regarding mechanism of injury, fracture pattern, mode of diagnosis, and time to diagnosis and treatment. RESULTS: We treated 11 patients for trapezoid fractures over the 10-year period. A correct diagnosis was made in 5 cases on initial evaluation. Most trapezoid fractures were diagnosed on computed tomographic scan. The fracture plane was predominantly sagittal. Coronal fractures could not be diagnosed on plain radiographs. CONCLUSIONS: Fractures of the trapezoid should be suspected from the mechanism of injury, in particular, axial force, and from local tenderness. These fractures may be underdiagnosed. We recommend computed tomography rather than plain radiography alone in case of clinical suspicion. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic IV. PMID- 22522107 TI - Juvenile arthritis patients report favorable subjective outcomes of hip arthroplasty despite poor standard outcome scores. AB - We evaluated midterm patient-reported outcomes and satisfaction with total hip arthroplasty in patients who had severe juvenile idiopathic arthritis. Thirty-one patients (49 hips), with a mean age of 29 years (range, 16-43 years), reported low hip pain and stiffness at follow-up (mean, 7 years; range, 3-17 years). Up to 92% were satisfied with their ability to perform various activities; 96% were satisfied with pain relief. A mean postoperative flexion arc of 96 degrees was observed. Final 36-Item Short Form Health Survey, EuroQol in 5 dimensions, Western Ontario and McMaster Universities Arthritis Index, and Harris Hip scores were lower than reference populations, particularly for mobility, physical functioning, and social functioning subscores. Young adults with end-stage hip involvement and severe longstanding juvenile idiopathic arthritis expressed high satisfaction with total hip arthroplasty, which improved range of motion, pain, and stiffness, despite poor performance on widely used outcome measures. PMID- 22522108 TI - The distribution of vascular foramina at the femoral head/neck junction: implications for resurfacing arthroplasty. AB - Reaming for resurfacing arthroplasty may endanger the blood supply at the head neck junction, possibly predisposing to osteonecrosis and femoral neck fracture. The current study hypothesizes that reaming endangers femoral head vasculature. Vascular foramina were identified on 16 cadaveric femora and registered on computed tomographic models. Virtual reaming was performed after templating of resurfacing components. Almost half (41.8%) of foramina was located in the anterosuperior quadrant. Loss of foramina after reaming averaged 28% (P = .03), with up to 34.6% and 33.1% loss in the anterosuperior and posterosuperior quadrants, respectively. Reaming for resurfacing arthroplasty endangers a substantial number of vascular foramina. Notching or malpositioning of components may worsen injury to the vascular supply and could subsequently increase the risk of implant failure. PMID- 22522109 TI - Pseudogout in the early postoperative period after total knee arthroplasty. AB - Postoperative pseudogout after total knee arthroplasty is rare. If pseudogout attacks are misdiagnosed as periprosthetic sepsis, patients may undergo unnecessary surgical procedures. We report a case of pseudogout in the early postoperative period. The attack ensued shortly after a nonsteroidal antiinflammatory drug was discontinued. The diagnosis was confirmed by aspiration, and the patient improved after readministration of the nonsteroidal antiinflammatory drug. Although rare, pseudogout should be considered in the differential when approaching a suspected infection after total knee arthroplasty. PMID- 22522110 TI - Salt-inducible kinase 1 regulates E-cadherin expression and intercellular junction stability. AB - The protein kinase liver kinase B1 (LKB1) regulates cell polarity and intercellular junction stability. Also, LKB1 controls the activity of salt inducible kinase 1 (SIK1). The role and relevance of SIK1 and its downstream effectors in linking the LKB1 signals within these processes are partially understood. We hypothesize that SIK1 may link LKB1 signals to the maintenance of epithelial junction stability by regulating E-cadherin expression. Results from our studies using a mouse lung alveolar epithelial (MLE-12) cell line or human renal proximal tubule (HK2) cell line transiently or stably lacking the expression of SIK1 (using SIK1 siRNAs or shRNAs), or with its expression abrogated (sik1(+/+) vs. sik1(-/-) mice), indicate that suppression of SIK1 (~40%) increases the expression of the transcriptional repressors Snail2 (~12 fold), Zeb1 (~100%), Zeb2 (~50%), and TWIST (~20-fold) by activating cAMP response element binding protein. The lack of SIK1 and activation of transcriptional repressors decreases the availability of E-cadherin (mRNA and protein expression by ~100 and 80%, respectively) and the stability of intercellular junctions in epithelia (decreases in transepithelial resistance). Furthermore, LKB1-mediated increases in E-cadherin expression are impaired in cells where SIK1 has been disabled. We conclude that SIK1 is a key regulator of E cadherin expression, and thereby contributes to the stability of intercellular junctions. PMID- 22522111 TI - The broad spectrum of urate crystal deposition: unusual presentations of gouty tophi. AB - OBJECTIVES: Gout is typically described as an inflammatory arthropathy that affects the peripheral joints. Our aim was to describe atypical and rare clinical presentations of gouty tophi to help increase physician awareness and aid in patient care. METHODS: The relevant English literature of unusual gout manifestations was searched using the keywords gout, toph*, monosodium urate, uric acid, unusual, and rare. Well-described case reports, case series, and review articles were evaluated and included, if relevant, in the literature review. RESULTS: Review of the literature revealed many unusual manifestations of gouty tophi involving the head and neck, skin, viscera, bones, tendons, ligaments, nerves, and axial skeleton. Transplant recipients, women, and elderly people are particularly susceptible to developing tophi. Furthermore, gout can cause diagnostic dilemmas, as it can be a great mimicker of and can coexist with infection, malignancy, and other connective tissue diseases. Imaging modalities can help detect tophi in atypical locations. CONCLUSIONS: Tophi can present in unexpected locations, even as the first sign of gout, and vigilance is required when unusual symptoms or signs occur in a patient with gout. PMID- 22522112 TI - Using smartphone technology to monitor physical activity in the 10,000 Steps program: a matched case-control trial. AB - BACKGROUND: Website-delivered physical activity interventions are successful in producing short-term behavior change. However, problems with engagement and retention of participants in these programs prevent long-term behavior change. New ways of accessing online content (eg, via smartphones) may enhance engagement in these interventions, which in turn may improve the effectiveness of the programs. OBJECTIVE: To measure the potential of a newly developed smartphone application to improve health behaviors in existing members of a website delivered physical activity program (10,000 Steps, Australia). The aims of the study were to (1) examine the effect of the smartphone application on self monitoring and self-reported physical activity levels, (2) measure the perceived usefulness and usability of the application, and (3) examine the relationship between the perceived usefulness and usability of the application and its actual use. METHODS: All participants were existing members of the 10,000 Steps program. We recruited the intervention group (n = 50) via email and instructed them to install the application on their smartphone and use it for 3 months. Participants in this group were able to log their steps by using either the smartphone application or the 10,000 Steps website. Following the study, the intervention group completed an online questionnaire assessing perceived usability and usefulness of the smartphone application. We selected control group participants (n = 150), matched for age, gender, level of self-monitoring, preintervention physical activity level, and length of membership in the 10,000 Steps program, after the intervention was completed. We collected website and smartphone usage statistics during the entire intervention period. RESULTS: Over the study period (90 days), the intervention group logged steps on an average of 62 days, compared with 41 days in the matched group. Intervention participants used the application 71.22% (2210/3103) of the time to log their steps. Logistic regression analyses revealed that use of the application was associated with an increased likelihood to log steps daily during the intervention period compared with those not using the application (odds ratio 3.56, 95% confidence interval 1.72-7.39). Additionally, use of the application was associated with an increased likelihood to log greater than 10,000 steps on each entry (odds ratio 20.64, 95% confidence interval 9.19-46.39). Linear regression analysis revealed a nonsignificant relationship between perceived usability (r = .216, P = .21) and usefulness (r = .229, P = .17) of the application and frequency of logging steps in the intervention group. CONCLUSION: Using a smartphone application as an additional delivery method to a website-delivered physical activity intervention may assist in maintaining participant engagement and behavior change. However, due to study design limitations, these outcomes should be interpreted with caution. More research, using larger samples and longer follow-up periods, is needed to replicate the findings of this study. PMID- 22522113 TI - Genetic damage induced by organic extract of coke oven emissions on human bronchial epithelial cells. AB - Coke oven emissions are known as human carcinogen, which is a complex mixture of polycyclic aromatic hydrocarbon. In this study, we aimed to clarify the mechanism of action of coke oven emissions induced carcinogenesis and to identify biomarkers of early biological effects in a human bronchial epithelial cell line with CYP1A1 activity (HBE-CYP1A1). Particulate matter was collected in the oven area on glass filter, extracted and analyzed by GC/MS. DNA breaks and oxidative damage were evaluated by alkaline and endonucleases (FPG, hOGG1 and ENDO III) modified comet assays. Cytotoxicity and chromosomal damage were assessed by the cytokinesis-block micronucleus cytome (CBMN-Cyt) assay. The cells were treated with organic extract of coke oven emissions (OE-COE) representing 5, 10, 20, 40MUg/mL extract for 24h. We found that there was a dose-effect relationship between the OE-COE and the direct DNA damage presented by tail length, tail intensity and Olive tail moment in the comet assay. The presence of lesion specific endonucleases in the assays increased DNA migration after OE-COE treatment when compared to those without enzymes, which indicated that OE-COE produced oxidative damage at the level of pyrimidine and purine bases. The dose dependent increase of micronuclei, nucleoplasmic bridges and nuclear buds in exposed cells was significant, indicating chromosomal and genomic damage induced by OE-COE. Based on the cytotoxic biomarkers in CBMN-Cyt assay, OE-COE may inhibit nuclear division, interfere with apoptosis, or induce cell necrosis. This study indicates that OE-COE exposure can induce DNA breaks/oxidative damage and genomic instability in HBE-CYP1A1 cells. The FPG-comet assay appears more specific for detecting oxidative DNA damage induced by complex mixtures of genotoxic substances. PMID- 22522114 TI - Myeloid-derived suppressor cell measurements in fresh and cryopreserved blood samples. AB - Myeloid-derived suppressor cells (MDSC) present in the human peripheral blood, represent a heterogeneous population of cells with monocytic and granulocytic features. To provide guidelines for reliable assessments of the frequency and function of MDSC, we compared fresh vs. cryopreserved peripheral blood mononuclear cell (PBMC) samples obtained from normal controls and patients with cancer. PBMC were obtained from 4 healthy donors and 21 patients with cancer. They were stained with labeled antibodies, and the frequency of DR-/LIN-/CD11b+, DR-/LIN-/CD15+, DR-/LIN-/CD33+ and DR(-/low)/CD14+ cells was determined by flow cytometry before and after cryopreservation. CFSE-based suppressor assays were used to test inhibitory functions of MDSC. Arginase I expression and reactive oxygen species (ROS) upregulation in MDSC subsets were evaluated by flow cytometry. The DR(-/low)/CD14+ and DR-/LIN-/CD11b+ subsets of MDSC were found to be more resistant to the cryopreservation/thawing procedure compared to the DR /LIN-/CD15+ and DR-/LIN-/CD33+ subsets. The frequency of the latter two MDSC subsets was significantly reduced after cryopreservation. All but DR-/LIN-/CD15+ cells inhibited proliferation of autologous CSFE-labeled CD4+ cells but lost suppressor activity after cryopreservation. Only DR-/LIN-/CD15+ cells were positive for Arginase I, but lost its expression after cryopreservation. Only fresh DR-/LIN-/CD11b+ and DR-/LIN-/CD15+ cells produced ROS after in vitro stimulation. Studies of human MDSC should be performed in fresh blood samples. If samples have to be cryopreserved, monitoring of CD11b+ and CD14+ MDSC subsets provides the most reliable results. Arginase I expression or stimulated ROS production assessed by flow cytometry are useful markers for MDSC subsets only in fresh samples. PMID- 22522115 TI - Blood storage affects the detection of cellular prion protein on peripheral blood leukocytes and circulating dendritic cells in part by promoting platelet satellitism. AB - BACKGROUND: Flow cytometry represents an attractive approach for developing currently unavailable screening tests for prion diseases. Several studies have reported significant differences in the binding of antibodies directed against cellular prion protein (PrP(C)) to blood cells of prion-infected subjects compared with healthy controls. However, flow cytometry data usually show large individual variations in detected PrP(C) levels in both infected and control groups, rendering the interpretation of individual patient data difficult. OBJECTIVES: To determine how pre-analytical variables, such as the choice of anticoagulant, whether or not the blood was stored, and the storage temperature, affect the detection of PrP(C) in blood cells. METHODS: Blood from healthy donors was collected in EDTA or citrate anticoagulant and processed either immediately or after storage overnight at room temperature or at 4 degrees C. The expression of PrP(C) by T cells, B cells, NK cells, monocytes and circulating dendritic cells was evaluated using quantitative flow cytometry with the PrP(C) monoclonal antibodies AG4 and AH6. RESULTS: The anticoagulation of blood with citrate resulted in decreased levels of PrP(C) on monocytes but not the other cell types. The storage of blood prior to analysis led to a significant decrease in the levels of PrP(C) on the cells studied, although there were substantial differences between the cell populations. This decrease was more pronounced when using mAb AG4, which targets the N-terminal portion of the PrP(C) molecule, or following storage at room temperature. Moreover, we identified platelet satellitism on leukocytes, especially on monocytes and granulocytes, as an additional factor contributing to the heterogeneity of PrP(C) detection in stored blood. CONCLUSIONS: Our study demonstrates that the storage of blood prior to analysis greatly affects the detection of PrP(C) by flow cytometry. To limit the inclusion of storage-generated artifacts, we recommend the processing of blood samples immediately after their collection. PMID- 22522116 TI - A novel delivery system of doxorubicin with high load and pH-responsive release from the nanoparticles of poly (alpha,beta-aspartic acid) derivative. AB - A poly (amino acid)-based amphiphilic copolymer was utilized to fabricate a better micellar drug delivery system (DDS) with improved compatibility and sustained release of doxorubicin (DOX). First, poly (ethylene glycol) monomethyl ether (mPEG) and DOX were conjugated onto polyasparihyazide (PAHy), prepared by hydrazinolysis of the poly (succinimide) (PSI), to afford an amphiphilic polymer [PEG-hyd-P (AHy-hyd-DOX)] with acid-liable hydrazone bonds. The DOX, chemically conjugated to the PAHy, was designed to supply hydrophobic segments. PEGs were also grafted to the polymer via hydrazone bonds to supply hydrophiphilic segments and prolong its lifetime in blood circulation. Free DOX molecules could be entrapped into the nanoparticles fabricated by such an amphiphilic polymer (PEG hyd-P (AHy-hyd-DOX)), via hydrophobic interaction and pi-pi stacking between the conjugated and free DOX molecules to obtain a pH responsive drug delivery system with high DOX loaded. The drug loading capacity, drug release behavior, and morphology of the micelles were investigated. The biological activity of micelles was evaluated in vitro. The drug loading capacity was intensively augmented by adjusting the feed ratio, and the maximum loading capacity was as high as 38%. Besides, the DOX-loaded system exhibited pH-dependent drug release profiles in vitro. The cumulative release of DOX was much faster at pH 5.0 than that at pH 7.4. The DOX-loaded system kept highly antitumor activity for a long time, compared with free DOX. This easy-prepared DDS, with features of biocompatibility, biodegradability, high drug loading capacity and pH responsiveness, was a promising controlled release delivery system for DOX. PMID- 22522117 TI - Improved oral bioavailability of alendronate via the mucoadhesive liposomal delivery system. AB - This study aimed to design the chitosan coated liposomes of alendronate and optimize their in vitro/in vivo characteristics to improve the bioavailability as well as potentially to reduce the mucosal irritation of alendronate. Liposomes of alendronate were prepared with DSPC/DSPG by using thin layer film hydration method and then the surface of anionic liposomes was coated by chitosan. In vitro characteristics of liposomes (e.g., stability in various biological media, mucoadhesiveness and cellular uptake profiles) were evaluated along with the pharmacokinetic studies in rats. Lipid vesicles of 200 nm size were obtained with narrow size distribution (PI<0.1) and subsequently coated with chitosan. Chitosan coated liposomes were stable for 24 h without either size change or drug leakage in various biological fluids including simulated gastric fluids and intestinal fluids. Furthermore, it exhibited strong mucoadhesive properties. Compared to the untreated drug (non-liposome), the chitosan coated liposomes indicated significantly (p<0.05) increased cellular uptake of alendronate in Caco-2 cells and also 2.6-fold enhancement in oral bioavailability of alendronate in rats. Taken all together, the mucoadhesive liposomes for the oral delivery of alendronate was prepared by using DSPC and DSPG with narrow size distribution and appeared to be effective to enhance the bioavailability of alendronate in rats. PMID- 22522118 TI - A one-step process in preparation of cationic nanoparticles with poly(lactide-co glycolide)-containing polyethylenimine gives efficient gene delivery. AB - A one-step preparation of nanoparticles with poly(lactide-co-glycolide) (PLGA) pre-modified with polyethylenimine (PEI) is better in requirements for DNA delivery compared to those prepared in a two-step process (preformed PLGA nanoparticles and subsequently coated with PEI). The particles were prepared by emulsification of PLGA/ethyl acetate in an aqueous solution of PVA and PEI. DLS, AFM and SEM were used for the size characteristics. The cytotoxicity of PLGA/PEI nanoparticles was detected by MTT assay. The transfection activity of the particles was measured using pEGFP and pbeta-gal plasmid DNA. Results showed that the PLGA/PEI nanoparticles were spherical and non-porous with a size of about 0.2 MUm and a small size distribution. These particles had a positive zeta potential demonstrating that PEI was attached. Interestingly, the zeta potential of the particles (from one-step procedure) was substantially higher than that of two step process and is ascribed to the conjugation of PEI to PLGA via aminolysis. The PLGA/PEI nanoparticles were able to bind DNA and the formed complexes had a substantially lower cytotoxicity and a higher transfection activity than PEI polyplexes. In conclusion, given their small size, stability, low cytotoxicity and good transfection activity, PLGA/PEI-DNA complexes are attractive gene delivery systems. PMID- 22522119 TI - Antennal morphology and sensillar ultrastructure of Dastarcus helophoroides (Fairmaire) (Coleoptera: Bothrideridae). AB - The parasitoid beetle Dastarcus helophoroides (Fairmaire) (Coleoptera: Bothrideridae) is an important parasite of longicorn beetles (Cerambycidae), and has been used in China for the biological control of the Asian longicorn beetle and the Japanese pine sawyer. In this study the antennal morphology and sensillar ultrastructure of D. helophoroides were observed using scanning electron microscopy and transmission electron microscopy. Two types of sensilla trichodea (Tr. 1 and Tr. 2), two types of sensilla basiconica (Ba. 1 and Ba. 2), three types of sensilla chaetica (Ch. 1, Ch. 2 and Ch. 3), and Bohm's bristles were identified according to the morphology and fine structure of each type of sensilla in both sexes. Ultrastructural studies revealed porous structures on the cuticle wall and dendritic branches in the inner lumen of Tr. 1, Tr. 2, Ba. 1, and Ba. 2, thereby suggesting chemoreceptor functions. No difference in shape, structure, sensilla distribution and typology was observed between the sexes. These structures likely have roles in the host locating and habitat searching behavior of adult D. helophoroides, and suggest future studies on the olfaction and host location behavior of D. helophoroides and other coleopteran parasitoids. PMID- 22522120 TI - Posterior capsular opacification and intraocular lens surface micro-roughness characteristics: an atomic force microscopy study. AB - OBJECTIVE: Surface roughness parameters of various intraocular lenses (IOLs) biomaterials using atomic force microscopy (AFM) are compared. Variation, if any, in the micro-roughness properties of different IOLs made up of the same biomaterial is also explored. Retrospective analysis of posterior capsular opacification (PCO) incidence has been followed up for a period of four years post IOL implantation to evaluate the correlation of PCO formation with surface roughness of IOLs. DESIGN: Experimental materials study. MATERIALS AND PARTICIPANTS: Surface characteristics of 20 different IOL models were assessed using AFM. These IOL models were made up of PMMA or HEMA or acrylic hydrophobic or acrylic hydrophilic or silicone. Retrospective analysis of PCO incidence in 3629 eyes of 2656 patients implanted with the same IOL models was performed. METHODS: Topological characteristics of 20 different IOLs made up of 5 different biomaterials including (i) PMMA, (ii) HEMA, (iii) acrylic hydrophobic, (iv) acrylic hydrophilic and (v) silicone were evaluated using AFM in the tapping mode. Images were acquired with a resolution of 256 * 256 data points per scan at a scan rate of 0.5 Hz per line and a scan size of 10 * 10MUm. Rate of PCO formation in 3629 eyes of 2656 patients implanted with the five different IOL biomaterials was retrospectively analyzed. RESULTS: AFM images of IOL optic surfaces showed a collection of pores, grooves, ridges and surface irregularities. Surface roughness parameters of the IOL optics were significantly different on comparing lenses of different materials. Acrylic hydrophobic IOLs had minimum surface roughness while acrylic hydrophilic IOLs showed the highest surface roughness. Different IOL models of the same biomaterial showed varied topological roughness characteristics. Retrospective analyses of PCO formation rate after IOL implantation was carried out, which revealed that rate of PCO incidence, was directly proportional to the increase in surface micro-roughness of IOLs. CONCLUSIONS: AFM is a powerful technique for the topological characterization of IOLs. Acrylic hydrophobic IOLs showed minimum surface roughness properties as well as minimum PCO incidence over a period of four years post implantation. It is, therefore, tempting to consider acrylic hydrophobic IOLs over other IOL biomaterials as the ideal biocompatible material for lowering PCO incidence. These results suggest an urgent need for manufacturers to optimize the various steps involved in the fabrication of IOLs. PMID- 22522121 TI - Limitations of respiratory muscle and vastus lateralis blood flow during continuous exercise. AB - Measurement of regional blood flow to the respiratory muscles has traditionally been invasive. The blood flow index (BFI), a minimally invasive method using indocyanine green dye (ICG) and near infrared spectroscopy, allows assessment of within subject changes in regional blood flow. This study assessed regional BFI to the vastus lateralis muscle (QBFI) and the superficial respiratory muscles in the seventh intercostal space (RMBFI). Eight healthy subjects cycled continuously at incrementally more difficulty stages to exhaustion. In our subjects, QBFI declined between 83% and 100% of maximal exertion (p=0.002) and no statistically significant changes in RMBFI were seen despite steadily increasing ventilatory workloads. Post hoc pairwise comparisons demonstrated that QBFI at 83% work (0.015MUmoless(-1)+/-0.005) was significantly higher than at maximum work output (0.011MUmoless(-1)+/-0.004, p=0.007). There were no other significant differences of QBFI between maximum work output and different levels of work. The current study suggests that respiratory and locomotor muscle blood flow during sub maximal and maximal exertion is unable to match increasing workloads. PMID- 22522122 TI - Diet-derived polyphenols inhibit angiogenesis by modulating the interleukin 6/STAT3 pathway. AB - Several epidemiological studies have indicated that abundant consumption of foods from plant origin is associated with a reduced risk of developing several types of cancers. This chemopreventive effect is related to the high content of these foods in phytochemicals, such as polyphenols, that interfere with several processes involved in cancer progression including tumor cell growth, survival and angiogenesis. In addition to the low intake of plant-based foods, increased body mass and physical inactivity have recently emerged as other important lifestyle factors influencing cancer risk, leading to the generation of low-grade chronic inflammatory conditions which are a key process involved in tumor progression. The objectives of the current study are to investigate the inhibitory effects of these polyphenols on angiogenesis triggered by an inflammatory cytokine (IL-6) and to determine the mechanisms underlying this action. We found that, among the tested polyphenols, apigenin and luteolin were the most potent angiogenesis inhibitors through their inhibitory effect on the inflammatory cytokine IL-6/STAT3 pathway. These effects resulted in modulation of the activation of extracellular signal-regulated kinase-1/2 signaling triggered by IL-6, as well as in a marked reduction in the proliferation, migration and morphogenic differentiation of endothelial cells. Interestingly, these polyphenols also modulated the expression of IL-6 signal transducing receptor (IL 6Ralpha) and the secretion of the extracellular matrix degrading enzyme MMP-2 as well as the expression of suppressor of cytokine signaling (SOCS3) protein. Overall, these results may provide important new information on the role of diet in cancer prevention. PMID- 22522123 TI - Proteomic and redox-proteomic analysis of berberine-induced cytotoxicity in breast cancer cells. AB - Berberine is a natural product isolated from herbal plants such as Rhizoma coptidis which has been shown to have anti-neoplastic properties. However, the effects of berberine on the behavior of breast cancers are largely unknown. To determine if berberine might be useful in the treatment of breast cancer and its cytotoxic mechanism, we analyzed the impact of berberine treatment on differential protein expression and redox regulation in human breast cancer cell line MCF-7 using lysine- and cysteine-labeling two-dimensional difference gel electrophoresis (2D-DIGE) combined with mass spectrometry (MS). This study demonstrated that 96 and 22 protein features were significantly changed in protein expression and thiol reactivity, respectively and revealed that berberine induced cytotoxicity in breast cancer cells involves dysregulation of protein folding, proteolysis, redox regulation, protein trafficking, cell signaling, electron transport, metabolism and centrosomal structure. Our work shows that this combined proteomic strategy provides a rapid method to study the molecular mechanisms of berberine-induced cytotoxicity in breast cancer cells. The identified targets may be useful for further evaluation as potential targets in breast cancer therapy. PMID- 22522124 TI - Acromegaly and type 1 neurofibromatosis. Is association of both conditions due to chance? PMID- 22522125 TI - Adult neuropsychological performance following prenatal and early postnatal exposure to tetrachloroethylene (PCE)-contaminated drinking water. AB - This population-based retrospective cohort study examined adult performance on a battery of neuropsychological tests in relation to prenatal and early postnatal exposure to tetrachloroethylene (PCE)-contaminated drinking water on Cape Cod, Massachusetts. Subjects were identified through birth records from 1969 through 1983. Exposure was modeled using pipe network information from town water departments, a PCE leaching and transport algorithm, EPANet water flow modeling software, and a Geographic Information System (GIS). Results of crude and multivariate analyses among 35 exposed and 28 unexposed subjects showed no association between prenatal and early postnatal exposure and decrements on tests that assess abilities in the domains of omnibus intelligence, academic achievement or language. The results were suggestive of an association between prenatal and early postnatal PCE exposure and diminished performance on tests that assessed abilities in the domains of visuospatial functioning, learning and memory, motor, attention and mood. Because the sample size was small, most findings were not statistically significant. Future studies with larger sample sizes should be conducted to further define the neuropsychological consequences of early developmental PCE exposure. PMID- 22522127 TI - Structural insights into the dehydroascorbate reductase activity of human omega class glutathione transferases. AB - The reduction of dehydroascorbate (DHA) to ascorbic acid (AA) is a vital cellular function. The omega-class glutathione transferases (GSTs) catalyze several reductive reactions in cellular biochemistry, including DHA reduction. In humans, two isozymes (GSTO1-1 and GSTO2-2) with significant DHA reductase (DHAR) activity are found, sharing 64% sequence identity. While the activity of GSTO2-2 is higher, it is significantly more unstable in vitro. We report the first crystal structures of human GSTO2-2, stabilized through site-directed mutagenesis and determined at 1.9 A resolution in the presence and absence of glutathione (GSH). The structure of a human GSTO1-1 has been determined at 1.7 A resolution in complex with the reaction product AA, which unexpectedly binds in the G-site, where the glutamyl moiety of GSH binds. The structure suggests a similar mode of ascorbate binding in GSTO2-2. This is the first time that a non-GSH-based reaction product has been observed in the G-site of any GST. AA stacks against a conserved aromatic residue, F34 (equivalent to Y34 in GSTO2-2). Mutation of Y34 to alanine in GSTO2-2 eliminates DHAR activity. From these structures and other biochemical data, we propose a mechanism of substrate binding and catalysis of DHAR activity. PMID- 22522126 TI - The folding transition state of protein L is extensive with nonnative interactions (and not small and polarized). AB - Progress in understanding protein folding relies heavily upon an interplay between experiment and theory. In particular, readily interpretable experimental data that can be meaningfully compared to simulations are required. According to standard mutational phi analysis, the transition state for Protein L contains only a single hairpin. However, we demonstrate here using psi analysis with engineered metal ion binding sites that the transition state is extensive, containing the entire four-stranded beta sheet. Underreporting of the structural content of the transition state by phi analysis also occurs for acyl phosphatase [Pandit, A. D., Jha, A., Freed, K. F. & Sosnick, T. R., (2006). Small proteins fold through transition states with native-like topologies. J. Mol. Biol.361, 755 770], ubiquitin [Sosnick, T. R., Dothager, R. S. & Krantz, B. A., (2004). Differences in the folding transition state of ubiquitin indicated by phi and psi analyses. Proc. Natl Acad. Sci. USA 101, 17377-17382] and BdpA [Baxa, M., Freed, K. F. & Sosnick, T. R., (2008). Quantifying the structural requirements of the folding transition state of protein A and other systems. J. Mol. Biol.381, 1362 1381]. The carboxy-terminal hairpin in the transition state of Protein L is found to be nonnative, a significant result that agrees with our Protein Data Bank based backbone sampling and all-atom simulations. The nonnative character partially explains the failure of accepted experimental and native-centric computational approaches to adequately describe the transition state. Hence, caution is required even when an apparent agreement exists between experiment and theory, thus highlighting the importance of having alternative methods for characterizing transition states. PMID- 22522128 TI - Femtosecond laser ablation enhances cell infiltration into three-dimensional electrospun scaffolds. AB - Electrospun scaffolds are used extensively in tissue-engineering applications as they offer a cell-friendly microenvironment. However, one major limitation is the dense fibers, small pore size and consequently poor cell infiltration. Here, we employ a femtosecond (FS) laser system to ablate and create microscale features on electrospun poly(L-lactide) (PLLA) nanofibrous scaffolds. Upon determining the ablation parameters, we pattern structured holes with diameters of 50, 100 and 200 MUm and spacings of 50 and 200 MUm between adjacent holes on the scaffolds. The elastic moduli of ablated scaffolds decrease with the decrease in spacing and the increase in hole size. Cells seeded on the laser-ablated scaffolds exhibit different morphology but similar proliferation rate when compared with control (non-ablated) scaffold. Furthermore, animal studies indicate that ablated scaffolds facilitate endothelial cell ingrowth as well as drastically increase M2 macrophage and overall cell infiltration. These findings demonstrate that FS laser ablation can be used to increase cell infiltration into nanofibrous scaffolds. Laser ablation not only can create desired features in micrometer length scale but also presents a new approach in the fabrication of three dimensional porous constructs for tissue engineering. PMID- 22522129 TI - Micromechanical finite-element modeling and experimental characterization of the compressive mechanical properties of polycaprolactone-hydroxyapatite composite scaffolds prepared by selective laser sintering for bone tissue engineering. AB - Bioresorbable scaffolds with mechanical properties suitable for bone tissue engineering were fabricated from polycaprolactone (PCL) and hydroxyapatite (HA) by selective laser sintering (SLS) and modeled by finite-element analysis (FEA). Both solid gage parts and scaffolds having 1-D, 2-D and 3-D orthogonal, periodic porous architectures were made with 0, 10, 20 and 30 vol.% HA. PCL:HA scaffolds manufactured by SLS had nearly full density (99%) in the designed solid regions and had excellent geometric and dimensional control. Through optimization of the SLS process, the compressive moduli for our solid gage parts and scaffolds are the highest reported in the literature for additive manufacturing. The compressive moduli of solid gage parts were 299.3, 311.2, 415.5 and 498.3 MPa for PCL:HA loading at 100:0, 90:10, 80:20 and 70:30, respectively. The compressive effective stiffness tended to increase as the loading of HA was increased and the designed porosity was lowered. In the case of the most 3-D porous scaffold, the compressive modulus more than doubled from 14.9 to 36.2 MPa when changing the material from 100:0 to 70:30 PCL:HA. A micromechanical FEA model was developed to investigate the reinforcement effect of HA loading on the compressive modulus of the bulk material. Using a first-principles based approach, the random distribution of HA particles in a solidified PCL matrix was modeled for any HA loading to predict the bulk mechanical properties of the composites. The bulk mechanical properties were also used for FEA of the scaffold geometries. The results of the FEA were found to be in good agreement with experimental mechanical testing. The development of patient- and site-specific composite tissue-engineering constructs with tailored properties can be seen as a direct extension of this work on computational design, a priori modeling of mechanical properties and direct digital manufacturing. PMID- 22522130 TI - Surface modifications by gas plasma control osteogenic differentiation of MC3T3 E1 cells. AB - Numerous studies have shown that the physicochemical properties of biomaterials can control cell activity. Cell adhesion, proliferation, differentiation as well as tissue formation in vivo can be tuned by properties such as the porosity, surface micro- and nanoscale topography and chemical composition of biomaterials. This concept is very appealing for tissue engineering since instructive properties in bioactive materials can be more economical and time efficient than traditional strategies of cell pre-differentiation in vitro prior to implantation. The biomaterial surface, which is easy to modify due to its accessibility, may provide the necessary signals to elicit a certain cellular behavior. Here, we used gas plasma technology at atmospheric pressure to modify the physicochemical properties of polylactic acid and analyzed how this influenced pre-osteoblast proliferation and differentiation. Tetramethylsilane and 3-aminopropyl-trimethoxysilane with helium as a carrier gas or a mixture of nitrogen and hydrogen were discharged to polylactic acid discs to create different surface chemical compositions, hydrophobicity and microscale topographies. Such modifications influenced protein adsorption and pre-osteoblast cell adhesion, proliferation and osteogenic differentiation. Furthermore polylactic acid treated with tetramethylsilane enhanced osteogenic differentiation compared to the other surfaces. This promising surface modification could be further explored for potential development of bone graft substitutes. PMID- 22522131 TI - Functional reconstruction of corneal endothelium using nanotopography for tissue engineering applications. AB - Dysfunction in the corneal endothelium, which controls the hydration and transparency of the cornea, is one of the common reasons for transplantation. A tissue-engineered corneal endothelium is of interest for corneal regeneration and for in vitro testing of ocular drugs. In the native environment, corneal endothelial cells interact with the nanotopography of the underlying Descemet's membrane. This study showed that nanotopography enhanced bovine corneal endothelial cell (BCEC) responses, creating a monolayer which resembled the healthy corneal endothelium. Topographies of different geometries were first tested to identify those that would elicit the most significant responses. A BCEC monolayer was then generated on both micro- and nanoscale pillars and wells. The BCEC monolayer cultured on topographies exhibited polygonal geometries with well developed tight junction proteins. Scanning electron microscopy revealed that cells on pillars showed a higher density of microvilli, which was similar to native corneal endothelium. BCECs on nanopillars displayed a lower coefficient of variation of area (0.31) that was within the range of healthy corneal endothelium. More importantly, a BCEC monolayer cultured on nanopillars also had an enhanced Na(+)/K(+)-ATPase immunofluorescence expression, mRNA upregulation and a higher Na(+)/K(+)-ATPase activity. These results suggest that nanopillar substrate topography may provide relevant topographical cues, which could significantly enhance the formation and function of corneal endothelium. PMID- 22522132 TI - Electromechanical properties of dried tendon and isoelectrically focused collagen hydrogels. AB - Assembling artificial collagenous tissues with structural, functional, and mechanical properties which mimic natural tissues is of vital importance for many tissue engineering applications. While the electro-mechanical properties of collagen are thought to play a role in, for example, bone formation and remodeling, this functional property has not been adequately addressed in engineered tissues. Here the electro-mechanical properties of rat tail tendon are compared with those of dried isoelectrically focused collagen hydrogels using piezoresponse force microscopy under ambient conditions. In both the natural tissue and the engineered hydrogel D-periodic type I collagen fibrils are observed, which exhibit shear piezoelectricity. While both tissues also exhibit fibrils with parallel orientations, Fourier transform analysis has revealed that the degree of parallel alignment of the fibrils in the tendon is three times that of the dried hydrogel. The results obtained demonstrate that isoelectrically focused collagen has similar structural and electro-mechanical properties to that of tendon, which is relevant for tissue engineering applications. PMID- 22522133 TI - Nanopatterned polymer substrates promote endothelial proliferation by initiation of beta-catenin transcriptional signaling. AB - Control of endothelial phenotype involves a variety of signaling pathways and transcriptional regulators, including the junctional protein beta-catenin. This multifunctional signaling molecule is part of adhesion contacts in the endothelium and is able to translocate into the nucleus to activate genetic programs and control proliferation and the fate of the cells. We investigated the influence of laser-generated nanopatterns on polymeric cell culture substrates on endothelial tissue architecture, proliferation and beta-catenin signaling. For our experiments human microvascular endothelial cells or CD34(+) endothelial progenitor cells, isolated from human adipose tissue, were cultured on polyethylene terephthalate (PET) substrates with oriented nanostructures with lateral periodicities of 1.5 MUm and 300 nm, respectively. The surface topography and chemistry of the PET substrates were characterized by electron microscopy, atomic force microscopy, water contact angle measurement and X-ray photoelectron spectroscopy. Analysis of cell phenotype markers as well as beta-catenin signaling revealed that short-term culture of endothelial cells on nanostructured substrates generates a proliferative cell phenotype associated with nuclear accumulation of beta-catenin and activation of specific beta-catenin target genes. The effects of the nanostructures were not directly correlated with nanostructure-induced alignment of cells and were also clearly distinguishable from the effects of altered PET surface chemistry due to photomodification. In summary, we present a novel mechanism of surface topology-dependent control of transcriptional programs in mature endothelium and endothelial progenitor cells. PMID- 22522134 TI - Improving GO semantic similarity measures by exploring the ontology beneath the terms and modelling uncertainty. AB - MOTIVATION: Several measures have been recently proposed for quantifying the functional similarity between gene products according to well-structured controlled vocabularies where biological terms are organized in a tree or in a directed acyclic graph (DAG) structure. However, existing semantic similarity measures ignore two important facts. First, when calculating the similarity between two terms, they disregard the descendants of these terms. While this makes no difference when the ontology is a tree, we shall show that it has important consequences when the ontology is a DAG-this is the case, for example, with the Gene Ontology (GO). Second, existing similarity measures do not model the inherent uncertainty which comes from the fact that our current knowledge of the gene annotation and of the ontology structure is incomplete. Here, we propose a novel approach based on downward random walks that can be used to improve any of the existing similarity measures to exhibit these two properties. The approach is computationally efficient-random walks do not need to be simulated as we provide formulas to calculate their stationary distributions. RESULTS: To show that our approach can potentially improve any semantic similarity measure, we test it on six different semantic similarity measures: three commonly used measures by Resnik (1999), Lin (1998), and Jiang and Conrath (1997); and three recently proposed measures: simUI, simGIC by Pesquita et al. (2008); GraSM by Couto et al. (2007); and Couto and Silva (2011). We applied these improved measures to the GO annotations of the yeast Saccharomyces cerevisiae, and tested how they correlate with sequence similarity, mRNA co-expression and protein protein interaction data. Our results consistently show that the use of downward random walks leads to more reliable similarity measures. PMID- 22522135 TI - GLOGS: a fast and powerful method for GWAS of binary traits with risk covariates in related populations. AB - SUMMARY: Mixed model-based approaches to genome-wide association studies (GWAS) of binary traits in related individuals can account for non-genetic risk factors in an integrated manner. However, they are technically challenging. GLOGS (Genome wide LOGistic mixed model/Score test) addresses such challenges with efficient statistical procedures and a parallel implementation. GLOGS has high power relative to alternative approaches as risk covariate effects increase, and can complete a GWAS in minutes. AVAILABILITY: Source code and documentation are provided at http://www.bioinformatics.org/~stanhope/GLOGS. PMID- 22522136 TI - A hybrid approach to protein differential expression in mass spectrometry-based proteomics. AB - MOTIVATION: Quantitative mass spectrometry-based proteomics involves statistical inference on protein abundance, based on the intensities of each protein's associated spectral peaks. However, typical MS-based proteomics datasets have substantial proportions of missing observations, due at least in part to censoring of low intensities. This complicates intensity-based differential expression analysis. RESULTS: We outline a statistical method for protein differential expression, based on a simple Binomial likelihood. By modeling peak intensities as binary, in terms of 'presence/absence,' we enable the selection of proteins not typically amenable to quantitative analysis; e.g. 'one-state' proteins that are present in one condition but absent in another. In addition, we present an analysis protocol that combines quantitative and presence/absence analysis of a given dataset in a principled way, resulting in a single list of selected proteins with a single-associated false discovery rate. AVAILABILITY: All R code available here: http://www.stat.tamu.edu/~adabney/share/xuan_code.zip. PMID- 22522137 TI - Probabilistic suffix array: efficient modeling and prediction of protein families. AB - MOTIVATION: Markov models are very popular for analyzing complex sequences such as protein sequences, whose sources are unknown, or whose underlying statistical characteristics are not well understood. A major problem is the computational complexity involved with using Markov models, especially the exponential growth of their size with the order of the model. The probabilistic suffix tree (PST) and its improved variant sparse probabilistic suffix tree (SPST) have been proposed to address some of the key problems with Markov models. The use of the suffix tree, however, implies that the space requirement for the PST/SPST could still be high. RESULTS: We present the probabilistic suffix array (PSA), a data structure for representing information in variable length Markov chains. The PSA essentially encodes information in a Markov model by providing a time and space efficient alternative to the PST/SPST. Given a sequence of length N, construction and learning in the PSA is done in O(N) time and space, independent of the Markov order. Prediction using the PSA is performed in O(mlog{N is divided by /Sigma/}) time, where m is the pattern length, and Sigma is the symbol alphabet. In terms of modeling and prediction accuracy, using protein families from Pfam 25.0, SPST and PSA produced similar results (SPST 89.82%, PSA 89.56%), but slightly lower than HMMER3 (92.55%). A modified algorithm for PSA prediction improved the performance to 91.7%, or just 0.79% from HMMER3 results. The average (maximum) practical construction space for the protein families tested was 21.58+/-6.32N (41.11N) bytes using the PSA, 27.55+/-13.16N (63.01N) bytes using SPST and 47+/ 24.95N (140.3N) bytes for HMMER3. The PSA was 255 times faster to construct than the SPST, and 11 times faster than HMMER3. PMID- 22522138 TI - Therapeutic strategies for controlling the metastasis and recurrence of cancers: contribution of drug delivery technologies. PMID- 22522140 TI - The sedation increases the acceptance of repeat colonoscopies. AB - AIM: The aim of this research was to assess how the use of sedation during colonoscopy influences patient anxiety, fear, satisfaction, and acceptance of repeat examinations. MATERIALS AND METHODS: A prospective case-control study quantifying the anxiety and fears of patients appointed for colonoscopy, comparing patients who had undergone previous colonoscopies with sedation (cases) with patients who had undergone previous colonoscopies without sedation and patients who had never had a colonoscopy before (controls). Following the examination, patients answered a satisfaction survey and were asked whether they would be willing to undergo future colonoscopies. RESULTS: The study included 2016 patients (average age 50.05 +/- 14.44 years; 47% men). Of these, 1270 patients (63%) were undergoing colonoscopy for the first time and 746 (37%) had undergone the procedure before; in the latter group, 313 patients (42%) had been provided sedation, whereas 433 (58%) had not. Patients who had been sedated for prior colonoscopies assigned significantly lower scores than patients who had undergone previous colonoscopies without sedation and those undergoing the procedure for the first time both in the anxiety survey (3.3 +/- 2.5 vs. 7.5 +/- 2.8 vs. 10.3 +/- 3.5; P<0.01) and in the fears survey (7.1 +/- 3.0 vs. 14 +/- 2.8 vs. 20.3 +/- 4.5; P<0.01). Satisfaction survey scores were significantly higher among sedated patients than among nonsedated patients (22.8 +/- 2.7 vs. 18.6 +/- 2.3). The percentage of sedated patients who would be willing to undergo colonoscopy again was significantly higher than that of nonsedated patients (70 vs. 25%; P<0.001). CONCLUSION: Sedation reduces the anxiety and fear of undergoing a repeat colonoscopy and improves both patient satisfaction and the acceptability of future procedures. PMID- 22522141 TI - Addition of probiotics to norfloxacin does not improve efficacy in the prevention of spontaneous bacterial peritonitis: a double-blind placebo-controlled randomized-controlled trial. AB - BACKGROUND: Spontaneous bacterial peritonitis (SBP) may occur despite antibiotic prophylaxis. We investigated whether the addition of probiotics to norfloxacin enhances its efficacy in the prevention of SBP. METHODS: A double-blind, randomized-controlled trial was conducted among consecutive cirrhotic patients who had either recovered from SBP (secondary prophylaxis) or who were at a high risk for the development of SBP (low ascitic fluid protein or serum bilirubin >= 2.5 mg/dl; primary prophylaxis). Norfloxacin 400 mg/day with probiotics capsules (Enterococcus faecalis JPC 30 million, Clostridium butyricum 2 million, Bacillus mesentericus JPC 1 million, Bacillus coagulans 50 million spores) at a dose of two capsules three times daily (group 1) or norfloxacin with a placebo (group 2) was given and the occurrence of SBP within a period of 6 months (primary endpoint) or side-effects of therapy and mortality (secondary endpoints) were recorded. RESULTS: From April 2005 through August 2007, 110 patients were randomized to group 1 (n=55) or group 2 (n=55) and 45 (82%) and 43 (78%) of them completed the trial, respectively. The baseline characteristics were comparable. On intention-to-treat analysis, the cumulative probability of treatment failures was similar in both the groups [19/55 (34%) in group 1 vs. 20/55 (36%) in group 2, P=0.840]. The cumulative probability of mortality was also similar [13/45 (29%) in group 1 vs. 14/43 (32%) in group 2, P=0.834]. The frequency of side effects was also comparable. In subgroup analyses, the frequencies of SBP and deaths were similar in the two groups in the subgroups of primary and secondary prophylaxes. The presence of encephalopathy and serum bilirubin of greater than 3.65 mg/dl were found to predict mortality independently. CONCLUSION: The addition of probiotics to norfloxacin does not improve its efficacy in primary or secondary prophylaxis of SBP or in reducing the mortality in cirrhotic patients with ascites. PMID- 22522139 TI - Silk constructs for delivery of musculoskeletal therapeutics. AB - Silk fibroin (SF) is a biopolymer with distinguishing features from many other bio- as well as synthetic polymers. From a biomechanical and drug delivery perspective, SF combines remarkable versatility for scaffolding (solid implants, hydrogels, threads, solutions), with advanced mechanical properties and good stabilization and controlled delivery of entrapped protein and small molecule drugs, respectively. It is this combination of mechanical and pharmaceutical features which renders SF so exciting for biomedical applications. This pattern along with the versatility of this biopolymer has been translated into progress for musculoskeletal applications. We review the use and potential of silk fibroin for systemic and localized delivery of therapeutics in diseases affecting the musculoskeletal system. We also present future directions for this biopolymer as well as the necessary research and development steps for their achievement. PMID- 22522142 TI - Oral intake throughout the patients' lives after palliative metallic stent placement for malignant gastroduodenal obstruction: a retrospective multicentre study. AB - OBJECTIVES: Patients with inoperable malignant gastric outlet obstruction (GOO) have been managed with self-expandable metal stents to improve oral intake. Recent studies have shown conflicting results on the capacity of self-expandable metal stents to restore food intake in the long term. This study evaluated the clinical effectiveness of enteral stent placement for GOO throughout the patients' lives. METHODS: This was a multicentre, retrospective study with a long term follow-up of 74 patients who underwent enteral stenting for symptomatic GOO. Data were collected to analyse improvements in oral intake for the patients' entire lives as assessed by the GOO scoring system (GOOSS), technical success, stent patency, complications, the need for reintervention, survival and the prognostic factors associated with stent patency. RESULTS: Technical and clinical success was achieved in 100 and 97.2% of the patients, respectively. A total of 71/74 patients (95.9%) continued oral intake for the rest of their lives and 58/74 patients (78.4%) needed no further intervention until death. Solid food intake (GOOSS 2-3) continued until death in 47/74 patients (63.5%). The GOOSS score improved (P<0.001) during the follow-up compared with the baseline. The median survival and the mean stent patency were 8 and 76.6 weeks, respectively. The complication rate was 18.9%. Malignant stent reobstruction was observed in 7/74 patients (9.5%). A Cox multivariate analysis showed that duodenal location of the obstruction was the only independent factor associated with stent patency (hazard ratio=5.28; 95% confidence interval=1.14-24.45; P=0.033). CONCLUSION: Enteral stenting in patients with unresectable GOO is safe and clinically effective. Ninety-five per cent of patients are able to resume oral intake for the rest of their lives, and the great majority remain free from further intervention. In approximately two-thirds of patients, solid food intake continues until death. PMID- 22522143 TI - Homelessness outcome reporting normative framework: systems-level evaluation of progress in ending homelessness. AB - Homelessness is a serious and growing issue. Evaluations of systemic-level changes are needed to determine progress in reducing or ending homelessness. The report card methodology is one means of systems-level assessment. Rather than solely establishing an enumeration, homelessness report cards can capture pertinent information about structural determinants of homelessness. This information can inform the development of evidence-based strategies aimed at ending (rather than managing) homelessness. To aid in the development of homelessness report card creation, a systems-level Homelessness Outcome Reporting Normative Framework (the HORN Framework) was developed. This article provides an overview of the framework and its application. PMID- 22522144 TI - [Vascular Ehlers-Danlos syndrome and pregnancy: an obstetrical specific support]. AB - The Ehlers-Danlos syndrome (EDS) is a rare inheritable disease, characterised by a defect in collagen synthesis. Various types have been described and the type IV or vascular type is the most severe characterised by vascular, gastrointestinal and gynaecologic complications. We describe in a case report the specific obstetrical support we applied to avoid the most frequent complications such as early spontaneous abortions, pre-term delivery, tearing of perineum, uterine and vascular rupture and hard healing. Pregnancy is very risky in women with vascular EDS. Combination of multidisciplinary support and advice of the rare vascular disease national reference centre may reduce the morbi-mortality rate, including celiprolol long-term treatment. PMID- 22522145 TI - Contribution of TNF receptor 1 to retinal neural cell death induced by elevated glucose. AB - Diabetic retinopathy (DR), a leading cause of vision loss and blindness among working-age adults, holds several hallmarks of an inflammatory disease. The increase in cell death in neural retina is an early event in the diabetic retina, preceding the loss of microvascular cells. Since tumor necrosis factor-alpha (TNF alpha) has been shown to trigger the death of perycites and endothelial cells as well as the breakdown of the blood-retinal barrier, we set out to investigate whether TNF-alpha acting through tumor necrosis factor receptor 1 (TNFR1), the major receptor responsible for mediating TNF-induced cell death, could also be responsible for the early neuronal cell death observed in DR. We used retinal neural cell cultures exposed to high glucose conditions, to mimic hyperglycaemia, and evaluated the contribution of TNFR1 in neural cell death. TNFR1 was found to be present to a great extent in retinal neurons and the levels of this receptor were found to be altered in cells cultured in high glucose conditions. High glucose induced an early decrease in cell viability, an increase in apoptosis and a higher immunoreactivity for the cleaved caspase-3, indicating a high glucose induced caspase-dependent cell death. These observations were correlated with an increase in TNF-alpha expression. Nonetheless, inhibiting the activation of TNFR1 was sufficient to prevent the decrease in cell viability and the increase in retinal cell death by apoptosis. In conclusion, our data indicate that TNF-alpha acting through TNFR1 is responsible for the high glucose-induced cell death and that blocking the activity of this receptor is an adequate strategy to avoid cell loss in such conditions. PMID- 22522147 TI - Enhancing informed consent best practices: gaining patient, family and provider perspectives using reverse simulation. AB - BACKGROUND: Obtaining informed consent in the clinical setting is an important yet challenging aspect of providing safe and collaborative care to patients. While the medical profession has defined best practices for obtaining informed consent, it is unclear whether these standards meet the expressed needs of patients, their families as well as healthcare providers. The authors sought to address this gap by comparing the responses of these three groups with a standardised informed consent paradigm. METHODS: Piloting a web-based 'reverse' simulation paradigm, participants viewed a video showing a standardised doctor engaging in an informed consent discussion. The scenario depicted a simulated patient with psychotic symptoms who is prescribed an atypical antipsychotic medication. 107 participants accessed the simulation online and completed a web based debriefing survey. RESULTS: Survey responses from patients, family members and healthcare providers indicated disparities in information retention, perception of the doctor's performance and priorities for required elements of the consent process. CONCLUSIONS: To enhance existing informed consent best practices, steps should be taken to improve patient retention of critical information. Adverse events should be described in the short-term and long-term along with preventative measures, and alternative psychosocial and pharmacological treatment options should be reviewed. Information about treatment should include when the medication takes therapeutic effect and how to safely maintain the treatment. The reverse simulation design is a model that can discern gaps in clinical practice, which can be used to improve patient care. PMID- 22522146 TI - Lysophosphatidic acid differentially regulates axonal mRNA translation through 5'UTR elements. AB - Sensory neurons transport a complex population of mRNAs into their axons, including many encoding ER chaperone proteins. Transport of the mRNA encoding the ER chaperone protein calreticulin is regulated through 3'UTR elements. In other cellular systems, translation of chaperone protein mRNAs can be regulated by ER stress. Here, we have asked if the translation of axonal calreticulin mRNA is regulated in a different manner than its transport into axons. Treatment with lysophosphatidic acid, which is known to trigger axon retraction and stimulate ER Ca(2+) release, caused a translation-dependent increase in axonal calreticulin protein levels. RNA sequences in the 5'UTR of calreticulin confer this translational control through a mechanism that requires an inactivating phosphorylation of eIF2alpha. In contrast to calreticulin, these signaling events do not activate axonal translation through beta-actin's 5'UTR. Together, these data indicate that stimulation of ER stress can regulate specificity of localized mRNA translation through 5'UTR elements. PMID- 22522148 TI - Terminating pregnancy after prenatal diagnosis--with a little help of professional ethics? AB - Termination of pregnancy after a certain gestational age and following prenatal diagnosis, in many nations seem to be granted with a special status to the extent that they by law have to be discussed within a predominantly medical context and have physicians as third parties involved in the decision-making process ('indication-based' approach). The existing legal frameworks for indication-based approaches, however, do frequently fail to provide clear guidance for the involved physicians. Critics, therefore, asked for professional ethics and professional institutions in order to provide normative guidance for the physicians in termination of pregnancy on medical grounds. After outlining the clinical pathway in an indication-based approach and the involved types of (clinical) judgements, this paper draws upon different understandings of professional ethics in order to explore their potential to provide normative guidance in termination of pregnancy on medical grounds. The analysis reveals that professional ethics will not suffice-neither as a set of established norms nor as internal morality-in order to determine the normative framework of indication-based approaches on termination of pregnancy. In addition, there seem to be considerable inconsistencies regarding the target and outcome between prenatal testing on the one hand and following termination of pregnancy on the other hand. A source of morality external to medicine has to be the basis of evaluation if a consistent and workable normative framework for termination of pregnancy and prenatal testing should be established. PMID- 22522150 TI - Use of seasonal influenza virus titer and respiratory symptom score to estimate effective human contact rates. AB - BACKGROUND: We linked viral titers and respiratory symptom scores for seasonal influenza to estimate the effective contact rate among schoolchildren. METHODS: We analyzed 274 diary-based questionnaires. In addition, 2 sets of influenza data from published studies were used to investigate the relationship between viral titer, total symptom score, and normalized contact rate in children. RESULTS: The mean number (SD) of contacts for children in grades 7 to 9 ranged from 9.44 +/- 8.68 to 11.18 +/- 7.98 person-1 day-1; contact behavior was similar across school grades. The mean number of contacts was 5.66 +/- 6.23 person-1 day-1 (range, 0 to 44 person-1 day-1) for the age group of 13 to 19 years. Estimated contact age, household size, contact duration, and contact frequency were the variables most strongly associated with total number of contacts. We also found that a reduction in total respiratory symptom scores among infected individuals had a positive correlation with an increase in the normalized contact rate. CONCLUSIONS: The relationship between daily virus titer and respiratory symptom score can be used to estimate the effective contact rate in explaining the spread of an airborne transmissible disease. The present findings can be incorporated into population dynamic models of influenza transmission among schoolchildren. PMID- 22522149 TI - Parity and risk of death from lung cancer among a cohort of premenopausal parous women in Taiwan. AB - BACKGROUND: We examined the association between parity and risk of lung cancer. METHODS: The study cohort consisted of all women with a record of a first singleton birth in the Taiwanese Birth Register between 1978 and 1987. We tracked each woman from the time of their first childbirth to 31 December 2009. Follow-up was terminated when the mother died, when she reached age 50 years, or on 31 December 2009, whichever occurred first. The vital status of mothers was ascertained by linking records with the computerized mortality database. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) for death from lung cancer associated with parity. RESULTS: There were 1375 lung cancer deaths during 32 243 637.08 person-years of follow-up. The mortality rate of lung cancer was 4.26 cases per 100,000 person-years. As compared with women who had given birth to only 1 child, the adjusted HR was 1.13 (95% CI, 0.94-1.35) for women who had 2 children, 1.10 (0.91-1.33) for those who had 3 children, and 1.22 (0.96-1.54) for those who had 4 or more children. CONCLUSIONS: The findings suggest that premenopausal women of higher parity tended to have an increased risk of lung cancer, although the trend was not statistically significant. PMID- 22522152 TI - [Casual finding of an osteochondritis after an injury]. PMID- 22522153 TI - [Recommendations from the Spanish Society of Paediatric Infectious Diseases on the diagnosis and treatment of non-tuberculous mycobacterial cervical lymphadenitis]. AB - Non-tuberculous mycobacteria (NTM) have been increasingly isolated over the last 20 years in Spain. However, as NTM disease is not a notifiable condition, there is no national registry, thus the true prevalence and incidence of these infections in children are difficult to estimate. Cervical adenitis is the most common clinical manifestation of NTM infection in immunocompetent children. The clinical course can be sub-acute or chronic, and is often associated with fluctuation, fistulisation, and scarring at a later stage. Although much less common, it is important to consider Mycobacterium tuberculosis in the differential diagnosis, as the management and the epidemiological implications of tuberculous lymphadenitis are completely different. Diagnosis of NTM cervical lymphadenitis is based on a high level of clinical suspicion, supported by results of the tuberculin skin test and interferon-gamma release assays (IGRA). Fine needle aspiration or excisional biopsy is usually required for histological and microbiological confirmation. Complete surgical excision of the affected nodes is the treatment of choice. Incision and drainage is not recommended, due to the high risk of chronic fistulisation and recurrence rate. Antibiotic treatment or conservative wait-and-see therapy may be indicated in certain circumstances. PMID- 22522154 TI - [Recent research progress of biogenesis and functions of miRNA*]. AB - MicroRNA*s are about 22nt noncoding RNAs, which are processed from precursors with a characteristic hairpin secondary structure in the biogenesis of microRNAs. Recently, miRNA* strands were shown to mediate post-transcriptional regulatory networks, rather than serve merely as non-functional by-product in general view. Unlike miRNAs bound to AGO1, miRNA* strands are bound to AGO2 to form RISC duplex to mediate RNAi, which is similar to siRNA. This paper mainly reviewed the recent research progresses on miRNA*, such as the biosynthesis, biological characteristics, and functions. PMID- 22522151 TI - Effectiveness of the combined approach for assessing social gradients in stroke risk among married women in Japan. AB - BACKGROUND: Analysis of the effects of social gradients on women's health requires a suitable means of assessing social standing. METHODS: We compared social gradients in stroke risk among 9317 married Japanese women from the Japan Public Health Center-based Prospective Study over a 16-year period. Social gradient was estimated by 3 methods of indicating social position: education level derived by using the individual approach (woman's own educational level), the conventional approach (using her partner's educational level), and the combined approach (combining the woman's and her partner's educational levels). RESULTS: As compared with the lowest educational group, stroke risk was similar among women in the highest educational group using the individual approach and lower, but not significantly so, with the conventional approach. With the combined approach, however, the age- and area-adjusted hazard ratio (HR) was significantly lower among the highest education group as compared with the lowest group (HR = 0.52, 95% CI: 0.36, 0.76), and the relative index of inequality was significant (RII = 0.48, 95% CI: 0.32, 0.72). Using the combined approach, the results were similar irrespective of employment status. In the combined highest educational group, stroke risk among unemployed women was significantly reduced by 54%, while stroke risk for employed women was significantly reduced by 46%, as compared with the lowest educational group, with RIIs of 0.42 (95% CI: 0.21, 0.85) and 0.49 (0.30, 0.80), respectively. CONCLUSIONS: The results suggest that a combined approach better reflects social standing among married women in Japan. PMID- 22522155 TI - [Function of SM protein in vesicle transport]. AB - Most cells contain various transport vesicles that target to different destinations. The underlying molecular mechanisms are highly conserved in evolution. Sec1/Munc-18 (SM) proteins play an important role on regulating vesicle transport by interacting with soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) at each vesicle fusion sites. SM proteins interact with syntaxin, an important component in SNARE complex, to regulate the assembly of SNARE complex, and promote overall membrane fusion process together with SNARE complex. This review summaries new research progresses of structure and function of SM protein. PMID- 22522156 TI - [Progress on breeding for best-hybridized crossing of meat rabbits]. AB - Best-hybridized crossing should ideally result in optimal exploitation of heterosis of lines and capitalize on expressed heterosis. Rabbit breeding is heading in the direction of breeding for best-hybridized crossing of meat rabbits. Most special sire lines are selected for post-weaning average daily gain and marketing weight. Post-weaning growth has a negative and favorable genetic correlation with the feed conversion ratio, which is used in indirect selection for feed conversion ratio. The most common selection criteria for special maternal lines are related to litter size at birth or at weaning. Since the heritability of most reproductive traits is low, we must collect as many individual and relative records as possible in the genetic evaluation of rabbits. The BLUP procedure under an animal repeatability model is the most common procedure used for evaluation of animals in selection programs for special lines of meat rabbits. Direct selection for litter size is less efficient than selection for post-weaning growth, but the estimation of heterosis is generally higher for litter size than that for the post-weaning growth. Evaluation of heterosis could be performed by estimating crossbreeding parameters in the cross or comparing contemporary productivity among purebreds and crossbreds. Here, we reviewed breeding of special lines, exploitation of heterosis of crossbreds, and establishment of crossbreeding system of hybrid meat rabbits and summarized the methodologies of breeding special lines, criteria in selection programs, and the result of heterosis estimates. PMID- 22522157 TI - [Mechanism of avian sex determination and differentiation]. AB - Avian sex is determined by genes on the sex chromosomes (ZZ for male and ZW for female). In avian embryo stage, genes on one or two chromosomes control the sex differentiation. Gonad develops to testis in ZZ male and to ovary in ZW female. To date, DMRT1 (Doublesex and mab-3 related transcription factor 1) is considered to be the best candidate gene in controlling the avian gonad differentiation. However, recent study showed that avian sex might be determined by cell autonomous independent of sex hormone signal. Therefore, sex determination gene does not only control the gonadal differentiation, but also control body cells. From this sense, DMRT1 is not the switch gene of avian sex determination. What is the switch factor of avian sex determination, and what is the mechanism of avian sex determination? This review discussed the current progresses on avian sex determination and differentiation from three aspects: W chromosome and ovary development, Z chromosome and testis development, and avian sex determination and cell autonomous. PMID- 22522158 TI - [Research progress on banana functional genomics involved in fruit quality]. AB - Banana is one of the most important tropical fruits and main economical resource for tropical people. Banana quality is always becoming a focus for people to follow with interest. Here, we reviewed recent research progresses on isolation and identification of banana genes involved in fruit quality such as ripening, softening, glycometabolism, and scent, which will help us explore their functions and facilitate banana quality improvement. PMID- 22522159 TI - [Current status of theoretical studies on essential genes in microbes]. AB - Essential genes are indispensable for the survival of an organism in optimal conditions. Recently, study on essential gene is becoming a hot topic of microbiology, genomics, and bioinformatics. This paper described the experiments that determined essential genes in some microbes and the theoretical researches on essential genes were reviewed. The major content contained comparison of essential genes and non-essential genes based on information on evolutionary conservation and sequence composition, and in silico prediction of essential genes, and analysis of the chromosomal distributions of essential genes. Finally, related progresses were concluded and the open problems were pointed out. PMID- 22522160 TI - [Haplotype analysis for mucocutaneous venous malformations in a Chinese Han ethnic family]. AB - A Chinese Han ethnic family with mucocutaneous venous malformations (VMCM) was investigated. This family has autosomal dominantly inherited VMCM in five generations, and the offspring has a 50% risk of this inherited disorder. Affected individuals have small, spongy, and multiple vascular lesions, which often locate in the skin, oral mucosa, and upper and lower extremities. None of the family members had gastrointestinal bleeding, central nervous system involvement and cardiac defects. Pathological analysis showed that the veins have irregular vascular space and walls with variable thickness. All phenotypes of the patients displayed the basic characters of VMCM. To analyze the genetic locus and haplotype, genomic DNA of 26 family members was obtained from peripheral leukocytes, and the linkage analysis and haplotypes analysis were performed using microsatellites markers. The results of two-point linkage analysis and haplotype analysis showed that the disease-causing gene located within a 7 cM region between D9S1121 and D9S161 on the short arm of chromosome 9. The study firstly reported the Chinese family with VMCM, which disease-causing gene is located in 9p, consistent with western VMCM families reported. Four flanking markers, D9S1121, D9S169, D9S16 and D9S248, were used to define the linkage haplotypes in the family, which can provide useful informaion for researchers to study VMCM in different racial background. PMID- 22522161 TI - [Comparative analysis on content and distribution of CpG sites in milk production traits and mastitis-related genes in dairy cattle]. AB - DNA methylation is a major part of epigenetics. DNA methylation on the CpG sites in gene promoter and the first exon often represses gene expression, but demethylation activates gene expression. Previous research has shown that a negative correlation was found between mastitis index (somatic cell count, SCC) and milk production traits in Holsteins. The content and distribution of CpG dinucleotide sites in different regions of the candidate genes related to milk production traits and mastitis were studied in the present study. The regions contained promoter (2000 bp upstream of transcriptional start site), exon 1, and 2000 bp downstream of transcriptional end site. The CpG number of promoter and exon 1 in the mastitis-related genes was significantly less than that of the milk production-associated genes. However, the CpG number of 2000 bp downstream of the genes for the two traits was not significantly different. Two new index quantified CpG characterizations were proposed. One is the CpG distance, which can measure the distribution of CpG. The other is the conditional probability p(G|C), which is used to quantify the probability of CpG in a nucleotide sequence along with C. The two indexes of promoter and exon 1 in the two types of genes and their statistic analysis were carried out. This study sets the basis for DNA methylation regulation of milk production traits- and mastitis-related genes. PMID- 22522162 TI - [Cloning and functional verification of U6 and 7SK promoter of small RNA from Bama mini-pig in Guangxi]. AB - To investigate the functions of U6 and 7SK of Bama mini-pig and produce Bama mini pig with silenced GGTA1 gene, the siRNA promoters U6 and 7SK were cloned, ligated into pMD18-shEGFP, and co-transfected with PEGFP- N1 into PK-15 kidney cells of pigs to be used in RNAi experiments. The functions of the two promoters in pig cells were verified using pMD18-hU6-shEGFP as the positive control, pMD18-shEGFP vector without promoter as the negative control, PEGFP-N1 as the first blank control, ddH2O in replacement of the plasmid as the second blank control. The results showed that the lengths of U6 and 7SK in Bama mini-pig were 553 bp and 437 bp, respectively. Vectors pMD18-pU6- shEGFP and pMD18-p7SK-shEGFP were constructed and transfected into PK-15 cells from pigs. Promoters pU6 and p7SK proved to express high levels of siRNA activity and can be used in the experiment of silencing alpha-1,3galactosyltransferase gene. PMID- 22522163 TI - [Characterization of chicken PPARgamma expression and its impact on adipocyte proliferation and differentiation]. AB - To characterize the chicken PPARgamma gene expression and its impact on chicken adipocyte proliferation and differentiation, western blotting approach was conducted to investigate the expression of PPARgamma in various chicken tissues and the difference of expression level in abdominal adipose tissues between the NEAU broiler lines divergently selected for abdominal fat content. The expression of PPARgamma gene was suppressed in chicken adipocytes using RNAi technology, and the roles of PPARgamma gene in the adipocytes proliferation and differentiation were investigated by MTT assay and Oil Red O staining extraction assay, respectively. After PPARgamma gene was downregulated, the expression level of other transcript factors and marker genes related to the adipocyte differentiation was detected by Real-time PCR and Western blotting analyses. The results showed that PPARgamma highly expressed in abdominal adipose tissue, gizzard, spleen, kidney, lowly expressed in heart, and not expressed in liver, breast muscle, leg muscle, and duodenum. Meanwhile, PPARgamma expressed much higher in fat birds than in lean ones in abdominal adipose tissue at 5 and 7 weeks of age (P<0.05). RNAi analysis showed that knockdown of PPARgamma gene increased chicken adipocyte proliferation and decreased cell differentiation and significantly decreased the expression levels of C/EBPalpha, SREBP1, A-FABP, Perilipin1, LPL, and IGFBP-2 (P<0.05). In summary, PPARgamma gene may be related to the broiler abdominal fat deposition, and be probably a key regulator of chicken adipocyte proliferation and differentiation. PMID- 22522164 TI - [Cloning and expression of VLRB of Lampetra japonica and generation of the corresponding monoclonal antibodies]. AB - The agnathans (lampreys and hagfishes) are representatives of the jawless vertebrates. The receptor molecules of adaptive immune system in lampreys are different from the antigen receptors in mammal vertebrates. The unique receptor molecules of lampreys are known as variable lymphocyte receptors (VLR). There are three types of VLRs in lampreys, VLRA, VLRB, and VLRC. Multimeric antigen specific VLRB antibodies are secreted by VLRB+ lymphocytes and constitute the major components of the humoral arm of the lamprey adaptive immune system. Oligomeric VLRB antibodies are composed of four or five disulfide-linked dimeric subunits, which are similar to IgM antibodies in structure and function. In this study, the conservative c-terminal of Lampetra japonica VLRB was cloned and expressed in BL21 E. coli. The recombinant VLRB protein was purified by Ni2+ affinity chromatography column. After Balb/c mice immunity, cell fusion, the positive clones were screened by indirect enzyme-linked immunosorbent assay (ELISA). Finally, the hybridoma cells that produced specific anti-VLRB monoclonal antibodies were obtained. In order to get a large number of antibodies against VLRB, the hybridoma cells were injected into the abdominal cavity of Balb/c mice and the antibodies were purified by protein G sepharose. The results of ELISA indicated that the valence of anti-VLRB antibodies was 1:40000. Western blotting assay showed that the antibodies were able to detect both recombinant VLRB and secreted VLRB in lamprey sera. Flow cytometry analysis also revealed the existence of VLRB on the surface of lymphocytes. In summary, the anti-VLRB monoclonal antibodies provided a major tool for studying lamprey adaptive immune system. PMID- 22522165 TI - [Cloning and expression analysis of differentially expressed genes in Chinese fir stems treated by different concentrations of exogenous IAA]. AB - To reveal the potential genetic mechanisms of indole-3-acetic acid (IAA) that regulate Chinese fir wood formation, cloned the differentially expressed genes via suppress subtractive hybridization (SSH) using the truncated stems treated by 0 and 3 mg IAA/g lanolin as the driver and tester, respectively. A total of 332 unigenes that were involved in cell organization and biosynthesis, developmental processes control, electron transport, stress response, and signal transduction. To further test the results from SSH, we selected those unigenes, whose putative encoding proteins showed significantly homologous with HIRA, PGY1, SMP1, TCT, TRN2, and ARF4, and analyzed their expressed specificity in the wood formative tissues and their response to the secondary developmental changes of vascular cambium stimulated by 0, 1, and 3 mg.IAA/g.lanolin treatment. The results showed that ClHIRA, ClPGY1, and ClARF4, which were specifically expressed in the adaxial zone of stem, were positively response to the activities of cell division and tracheid differentiation stimulated by exogenous IAA treatment. However, ClSMP1, ClTCTP1, and ClTRN2, which were mainly expressed in the abaxial zones of stems, showed negative correlation with the treated levels of exogenous IAA and activities of vascular cambium secondary development at the transcriptional level. This result showed that the differential response of developmental regulatory genes located in different vascular tissues to the level changes of edogenous IAA in stems is likely to be an important molecular mechanism of auxin regulating wood formation. PMID- 22522166 TI - [Nucleotide polymorphism and molecular evolution of the LRR region in potato late blight resistance gene Rpi-blb2]. AB - Rpi-blb2, which is originally derived from Solanum bulbocastanum, is a broad spectrum potato late blight resistance gene and belongs to the NBS-LRR family. Here, the LRR homologues of Rpi-blb2 were cloned with PCR method from 40 potato cultivars (including 20 resistant potato cultivars and 20 susceptible ones) and 7 wild potato populations. Then, the similarities of the sequences, polymorphic (segregating) sites, and nucleotide diversities were estimated by bioinformatic methods. The results showed that high nucleotide polymorphism and some hot-spot mutations existed in the LRR region of Rpi-blb2. The test of Ka/Ks ratio showed that the function of LRR was conserved because of the purifying selection, although different positions of the Rpi-blb2 LRR region were under different selection pressures. Moreover, the LRR region of Rpi-blb2 had no clear differentiation between the cultivated and wild potatoes. PMID- 22522167 TI - [Cloning and function identification of gene 'admA' and up-stream regulatory sequence related to antagonistic activity of Enterobacter cloacae B8]. AB - To reveal the antagonistic mechanism of B8 strain to Xanthomonas oryzae pv. oryzae, transposon tagging method and chromosome walking were deployed to clone antagonistic related fragments around Tn5 insertion site in the mutant strain B8B. The function of up-stream regulatory sequence of gene 'admA' involved in the antagonistic activity was further identified by gene knocking out technique. An antagonistic related left fragment of Tn5 insertion site, 2 608 bp in length, was obtained by tagging with Kan resistance gene of Tn5. A 2 354 bp right fragment of Tn5 insertion site was amplified with 2 rounds of chromosome walking. The length of the B contig around the Tn5 insertion site was 4 611 bp, containing 7 open reading frames (ORFs). Bioinformatic analysis revealed that these ORFs corresponded to the partial coding regions of glyceraldehyde-3-phosphate dehydrogenase, two LysR family transcriptional regulators, hypothetical protein VSWAT3-20465 of Vibrionales and admA, admB, and partial sequence of admC gene of Pantoea agglomerans biosynthetic gene cluster, respectively. Tn5 was inserted in the up-stream of 200 bp or 894 bp of the sequence corresponding to anrP ORF or admA gene on B8B, respectively. The B-1 and B-2 mutants that lost antagonistic activity were selected by homeologuous recombination technology in association with knocking out plasmid pMB-BG. These results suggested that the transcription and expression of anrP gene might be disrupted as a result of the knocking out of up-stream regulatory sequence by Tn5 in B8B strain, further causing biosythesis regulation of the antagonistic related gene cluster. Thus, the antagonistic related genes in B8 strain is a gene family similar as andrimid biosynthetic gene cluster, and the upstream regulatory region appears to be critical for the antibiotics biosynthesis. PMID- 22522168 TI - [Application of the Barr body case in teaching practice of genetics]. AB - There are three classical problems at the chromosome level in cytogenetics, namely the formation mechanisms and effects of Barr body, polytenic chromosome, and lampbrush chromosome. Teachers and researchers keep sustaining attention to the Barr body because of the relationships between Barr body and the X chromosome dosage compensation effect in mammals, the human sex identification, and some human diseases. In our genetics teaching practice, we tried the case-based teaching method. We introduced the classical problems and research progress of the Barr body, as a line, into partial sections of our genetics teaching contents such as sex-linked genetic analysis, eukaryotic gene expression regulation, cancer genetic analysis, and genetic experiments. Finally, it will form a comprehensive summary of related knowledge of genetics through class discussion on the Barr body. We found that this teaching method can not only optimize the teaching contents of genetics, consolidate and widen students' basic knowledge, and help student to form the systemic and developmental views of a classical genetics problem, but also inspire students' interest in life sciences. Good teaching results have been achieved. PMID- 22522169 TI - Effects of triclosan in the freshwater mussel Dreissena polymorpha: a proteomic investigation. AB - Triclosan (TCS, 5-chloro-2-(2,4-dichlorophenoxy)phenol) is commonly used in several personal care products, textiles, and children's toys. Because the removal of TCS by wastewater treatment plants is incomplete, its environmental fate is to be discharged into freshwater ecosystems, where its ecotoxicological impact is still largely unexplored. Previously, we began a structured multi tiered approach in order to evaluate TCS toxicity in the freshwater mussel Dreissena polymorpha. The results of our previous studies, based on in vitro and in vivo experiments, highlighted a pronounced cytogenotoxic effect exerted by TCS, and showed that an increase in oxidative stress was likely to be one of its main toxic mechanisms. In this work, in order to investigate TCS toxicity mechanisms in aquatic non-target species in greater depth, we decided to use a proteomic approach, analysing changes in protein expression profiles in gills of D. polymorpha exposed for seven days to TCS. Moreover, thiobarbituric acid reactive substances (TBARS) were measured to investigate further the role played by TCS in inducing oxidative stress. Finally, TCS bioaccumulation in mussel tissues was also assessed, to ensure an effective accumulation of the toxicant. Our results not only confirmed the role played by TCS in inducing oxidative stress, but furthered knowledge about the mechanism exerted by TCS in inducing toxicity in an aquatic non-target organisms. TCS induced significant alterations in protein expression profiles in gills of D. polymorpha. The wide range of proteins affected suggested that this chemical has marked effects on various biological processes, especially those involved in calcium binding or stress response. We also confirmed that the proteomic analysis, using 2-DE and de novo sequencing, is a reliable and powerful approach to investigate cellular responses to pollutants in a non-model organism with few genomic sequences available in databases. PMID- 22522170 TI - Accumulation and toxicity of copper oxide nanoparticles in the digestive gland of Mytilus galloprovincialis. AB - Given the wide use of CuO nanoparticles in various industrial and commercial applications they will inevitably end up in the aquatic environment. However, little information exists on their biological effects in bivalve species. Accordingly, mussels Mytilus galloprovincialis were exposed to 10 MUg Cu L(-1) as CuO nanoparticles and Cu(2+) for 15 days, and biomarkers of oxidative stress (superoxide dismutase, catalase and glutathione peroxidase), damage (lipid peroxidation) and metal exposure (metallothionein) were determined along with Cu accumulation in the digestive glands of mussels. Cu was linearly accumulated with time of exposure in mussels exposed to CuO nanoparticles, while in those exposed to Cu(2+) elimination was significant by day 15. Both forms of Cu cause oxidative stress with distinct modes of action. Exposure to CuO nanoparticles induces lower SOD activity in digestive glands compared to those exposed to Cu(2+), while CAT was only activated after 7 days of exposure to nano and ionic Cu, with contradictory effects after 15 days of exposure and GPX activities were similar. Lipid peroxidation levels increased in both Cu forms despite different antioxidant efficiency. Moreover, a linear induction of metallothionein was detected with time in mussels exposed to CuO nanoparticles, directly related to Cu accumulation, whereas in those exposed to Cu(2+) metallothionein was only induced after 15 days of exposure. Since only a small fraction of soluble Cu fraction was released from CuO nanoparticles, the observed effects seem to be related to the nano form of Cu, with aggregation as a key factor. Overall, our results show that the digestive gland is susceptible to CuO nanoparticles related oxidative stress, and is also the main tissue for their accumulation. PMID- 22522171 TI - Id proteins synchronize stemness and anchorage to the niche of neural stem cells. AB - Stem-cell functions require activation of stem-cell-intrinsic transcriptional programs and extracellular interaction with a niche microenvironment. How the transcriptional machinery controls residency of stem cells in the niche is unknown. Here we show that Id proteins coordinate stem-cell activities with anchorage of neural stem cells (NSCs) to the niche. Conditional inactivation of three Id genes in NSCs triggered detachment of embryonic and postnatal NSCs from the ventricular and vascular niche, respectively. The interrogation of the gene modules directly targeted by Id deletion in NSCs revealed that Id proteins repress bHLH-mediated activation of Rap1GAP, thus serving to maintain the GTPase activity of RAP1, a key mediator of cell adhesion. Preventing the elevation of the Rap1GAP level countered the consequences of Id loss on NSC-niche interaction and stem-cell identity. Thus, by preserving anchorage of NSCs to the extracellular environment, Id activity synchronizes NSC functions to residency in the specialized niche. PMID- 22522172 TI - Reconstitution of clathrin-coated bud and vesicle formation with minimal components. AB - During the process of clathrin-mediated endocytosis an essentially planar area of membrane has to undergo a gross deformation to form a spherical bud. Three ways have been recognized by which membranes can be induced to transform themselves locally from a planar state to one of high curvature: a change in lipid distribution between the leaflets, insertion of a protein into one leaflet and formation of a protein scaffold over the surface. Such a scaffold is spontaneously generated by clathrin. Conjectures that the attachment of clathrin was the cause of the change in curvature were challenged on theoretical grounds, and also by the discovery of a number of clathrin-associated proteins with the capacity to induce membrane curvature. We have now developed a cell-free system that has enabled us to demonstrate that clathrin polymerization alone is sufficient to generate spherical buds in a membrane. This process is reversible, as shown by the reassimilation of the buds into the planar membrane when the intra-clathrin contacts are dissociated by the chaperone Hsc70. We further show that the final step in the formation of coated vesicles ensues when clathrin coated buds are released through the action of dynamin. PMID- 22522173 TI - Kdm2b promotes induced pluripotent stem cell generation by facilitating gene activation early in reprogramming. AB - Transcription-factor-directed reprogramming from somatic cells to induced pluripotent stem cells (iPSCs) is by nature an epigenetic process of cell fate change. Previous studies have demonstrated that this inefficient process can be facilitated by the inclusion of additional factors. To gain insight into the reprogramming mechanism, we aimed to identify epigenetic enzymes capable of promoting iPSC generation. Here we show that Kdm2b, a histone H3 Lys 36 dimethyl (H3K36me2)-specific demethylase, has the capacity to promote iPSC generation. This capacity depends on its demethylase and DNA-binding activities, but is largely independent of its role in antagonizing senescence. Kdm2b functions at the beginning of the reprogramming process and enhances activation of early responsive genes in reprogramming. Kdm2b contributes to gene activation by binding to and demethylating the gene promoters. Our studies not only identify an important epigenetic factor for iPSC generation, but also reveal the molecular mechanism underlying how Kdm2b contributes to reprogramming. PMID- 22522174 TI - Mosaicism in Stickler syndrome. AB - Stickler syndrome is a heterogeneous condition due to mutations in COL2A1, COL11A1, COL11A2, and COL9A1. To our knowledge, neither non-penetrance nor mosaicism for COL2A1 mutations has been reported for Stickler syndrome. We report on a family with two clinically affected sibs with Stickler syndrome who have clinically unaffected parents. Both sibs have a novel heterozygous mutation in exon 26 of COL2A1 (c.1525delT); this results in a premature termination codon downstream of the mutation site. One parent was found to have low level mosaicism in DNA extracted from whole blood. This scenario encourages consideration of molecular testing in seemingly unaffected parents for recurrence risks and potential screening for mild age-related manifestations. PMID- 22522175 TI - Oral manifestations of patients with Kenny-Caffey Syndrome. AB - Kenny-Caffey syndrome (KCS) is a rare osteosclerotic bone dysplasia characterized by hypocalcemia, short stature, ophthalmological features, and teeth anomalies. The TBCE gene coding for a tubulin-specific chaperone E, is located at chromosome 1q42-q43, and is responsible for the recessive form. After reviewing the literature, we found around 60 cases, however with limited dental data. In this article 5 new individuals with KCS, are described focusing on oral findings. All cases had short roots and showed dental anomalies as hypo/oligodontia, microdontia. Dental anomalies are a constant feature in KCS, further study is required to better delineate the syndrome. PMID- 22522177 TI - Natural radioactivity measurements of building materials in Baotou, China. AB - Natural radioactivity due to (226)Ra, (232)Th and (40)K in the common building materials collected from Baotou city of Inner Mongolia, China was measured using gamma-ray spectrometry. The radiation hazard of the studied building materials was estimated by the radium equivalent activity (Ra(eq)), internal hazard index (H(in)) and annual effective dose (AED). The concentrations of the natural radionuclides and Ra(eq) in the studied samples were compared with the corresponding results of other countries. The Ra(eq) values of the building materials are below the internationally accepted values (370 Bq kg(-1)). The values of H(in) in all studied building materials are less than unity. The AEDs of all measured building materials are at an acceptable level. PMID- 22522176 TI - Xq28 duplications including MECP2 in five females: Expanding the phenotype to severe mental retardation. AB - Duplications leading to functional disomy of chromosome Xq28, including MECP2 as the critical dosage-sensitive gene, are associated with a distinct clinical phenotype in males, characterized by severe mental retardation, infantile hypotonia, progressive neurologic impairment, recurrent infections, bladder dysfunction, and absent speech. Female patients with Xq duplications including MECP2 are rare. Only recently submicroscopic duplications of this region on Xq28 have been recognized in four females, and a triplication in a fifth, all in combination with random X-chromosome inactivation (XCI). Based on this small series, it was concluded that in females with MECP2 duplication and random XCI, the typical symptoms of affected boys are not present. We present clinical and molecular data on a series of five females with an Xq28 duplication including the MECP2 gene, both isolated and as the result of a translocation, and compare them with the previously reported cases of small duplications in females. The collected data indicate that the associated phenotype in females is distinct from males with similar duplications, but the clinical effects may be as severe as seen in males. PMID- 22522178 TI - Calculation of dose rate conversion factors for (238)U, (232)TH and (40)K in concrete structures of various dimensions, with application to Nis, Serbia. AB - The absorbed gamma dose rate in indoor air due to natural radionuclides in concrete as a building material was determined in this work. The dose rate conversion factors for (238)U, (232)Th and (40)K, for standard rooms as well as rooms with different sets of dimensions, were evaluated by the point kernel technique, using Harima (geometric progression) build-up factors. The values of the conversion factors, in units (nGy h(-1) (Bq kg(-1))(-1)) calculated for the standard room are: 0.76, 0.91 and 0.070, respectively for (238)U, (232)Th and (40)K. The fitting formula was obtained for dose rate conversion factors, enabling them to be conveniently calculated for a room with arbitrary dimensions. For concrete block samples collected in the area of Nis, Serbia, the measurement of the radionuclide activity concentrations was also carried out. The evaluated absorbed dose rate conversion factors were then applied in the assessment of corresponding indoor gamma dose rates, finding that all the concrete samples fulfilled the usage requirement. PMID- 22522179 TI - Identification of quantitative trait loci and candidate genes for cadmium tolerance in Populus. AB - Understanding genetic variation for the response of Populus to heavy metals like cadmium (Cd) is an important step in elucidating the underlying mechanisms of tolerance. In this study, a pseudo-backcross pedigree of Populus trichocarpa Torr. & Gray and Populus deltoides Bart. was characterized for growth and performance traits after Cd exposure. A total of 16 quantitative trait loci (QTL) at logarithm of odds (LOD) ratio >= 2.5 were detected for total dry weight, its components and root volume. Major QTL for Cd responses were mapped to two different linkage groups and the relative allelic effects were in opposing directions on the two chromosomes, suggesting differential mechanisms at these two loci. The phenotypic variance explained by Cd QTL ranged from 5.9 to 11.6% and averaged 8.2% across all QTL. A whole-genome microarray study led to the identification of nine Cd-responsive genes from these QTL. Promising candidates for Cd tolerance include an NHL repeat membrane-spanning protein, a metal transporter and a putative transcription factor. Additional candidates in the QTL intervals include a putative homolog of a glutamate cysteine ligase, and a glutathione-S-transferase. Functional characterization of these candidate genes should enhance our understanding of Cd metabolism and transport and phytoremediation capabilities of Populus. PMID- 22522180 TI - WITHDRAWN: Use of a recombinant Entamoeba histolytica cysteine proteinase antigen to evaluation of the efficacy of immune protective responses in miniature pigs. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 22522181 TI - HERG potassium channel regulation by the N-terminal eag domain. AB - Human ether-a-go-go related gene (hERG, K(v)11.1) potassium channels play a significant role in cardiac excitability. Like other K(v) channels, hERG is activated by membrane voltage; however, distinct from other K(v) channels, hERG channels have unusually slow kinetics of closing (deactivation). The mechanism for slow deactivation involves an N-terminal "eag domain" which comprises a PAS (Per-Arnt-Sim) domain and a short Cap domain. Here we review recent advances in understanding how the eag domain regulates deactivation, including several new Nuclear Magnetic Resonance (NMR) solution structures of the eag domain, and evidence showing that the eag domain makes a direct interaction with the C terminal C-linker and Cyclic Nucleotide-Binding Homology Domain. PMID- 22522182 TI - Molecular mechanisms of feedback inhibition of protein kinase A on intracellular cAMP accumulation. AB - The cAMP-protein kinase A (PKA) pathway is a major signalling pathway in the yeast Saccharomyces cerevisiae, but also in many other eukaryotic cell types, including mammalian cells. Since cAMP plays a crucial role as second messenger in the regulation of this pathway, its levels are strictly controlled, both in the basal condition and after induction by agonists. A major factor in the down regulation of the cAMP level after stimulation is PKA itself. Activation of PKA triggers feedback down-regulation of the increased cAMP level, stimulating its return to the basal concentration. This is accomplished at different levels. The best documented mechanisms are: inhibition of cAMP synthesis by down-regulation of adenylate cyclase and/or its regulatory proteins, stimulation of cAMP breakdown by phosphodiesterases and spatial regulation of cAMP levels in the cell by A-Kinase Anchoring Proteins (AKAPs). In this review we describe these processes in detail for S. cerevisiae, for cells of mammals and selected other organisms, and we hint at other possible targets for feedback regulation of intracellular cAMP levels. PMID- 22522183 TI - Cell cycle control by anchorage signaling. AB - Virtually all the cells constituting solid organs in adult animals require anchorage to the extracellular matrix for their proliferation and survival. When deprived of anchorage, those cells arrest in G(1) phase of the cell cycle and die of apoptosis known as anoikis. However, if malignantly transformed, cells no longer require such an anchorage to proliferate and survive, and it is generally thought that the acquirement of this ability underlies the tumorigenic and metastatic capability of malignant cells. Therefore, for the past two decades, great efforts have been devoted to uncovering the nature of the anchorage signal and the mechanism by which this signal controls the G(1)-S transition in the cell cycle with little progress. However, several critical findings were recently made on anchorage signaling and the control of the cell cycle and cell death by this signaling. This review focuses on the newly emerging understanding and perspective of this highly important cell cycle and cell death regulation. PMID- 22522185 TI - Embodying approach motivation: body posture influences startle eyeblink and event related potential responses to appetitive stimuli. AB - Past research suggested that the motivational significance of images influences reflexive and electrocortical responses to those images (Briggs and Martin, 2009; Gard et al., 2007; Schupp et al., 2004), with erotica often exerting the largest effects for appetitive pictures (Grillon and Baas, 2003; Weinberg and Hajcak, 2010). This research paradigm, however, compares responses to different types of images (e.g., erotica vs. exciting sports scenes). This past motivational interpretation, therefore, would be further supported by experiments wherein appetitive picture content is held constant and motivational states are manipulated with a different method. In the present experiment, we tested the hypothesis that changes in physical postures associated with approach motivation influences reflexive and electrocortical responses to appetitive stimuli. Past research has suggested that bodily manipulations (e.g., facial expressions) play a role in emotion- and motivation-related physiology (Ekman and Davidson, 1993; Levenson et al., 1990). Extending these results, leaning forward (associated with a heightened urge to approach stimuli) relative to reclining (associated with less of an urge to approach stimuli) caused participants to have smaller startle eyeblink responses during appetitive, but not neutral, picture viewing. Leaning relative to reclining also caused participants to have larger LPPs to appetitive but not neutral pictures, and influenced ERPs as early as 100ms into stimulus viewing. This evidence suggests that body postures associated with approach motivation causally influence basic reflexive and electrocortical reactions to appetitive emotive stimuli. PMID- 22522184 TI - Clinical nutrition, body composition and oncology: a critical literature review of the synergies. AB - PURPOSE OF THE RESEARCH: Review the oncology and clinical nutrition literature to highlight the synergies between those two subjects. This review focuses on diagnostic of lean body wasting and the recent improvements in measuring body composition to monitor the response to nutrition during optimal oncology treatment. PRINCIPAL RESULTS: Nutrition support in cancer patients has made major progresses. A variety of advanced tools allow monitoring and explaining weight loss, body composition changes and metabolic alterations. Body composition is more accurate than body surface area to determine chemotherapeutic drug dosing. As with any therapeutic approach, clinical nutrition has a better risk-benefit ratio if implemented when indicated rather than used routinely. Body composition measurements are helpful for a better understanding of the host-tumor interactions during cancer treatment and nutrition support. MAJOR CONCLUSIONS: Nutrition support based on body composition analysis may significantly contribute to optimize current oncology treatment and clinical outcomes. PMID- 22522187 TI - A chip-based method for studying the effects of exogenous proteins on neuronal axons. AB - Axons are long, slender processes of neurons that have various functions at different stages of development. Here, we report the use of a chip device to study the effects of various exogenous proteins on the growth and presynaptic differentiation of axons in a high-throughput manner. The device consists of a glass chip whose surface contains a protein-coated micropattern. When neurons are maintained on the chip, a specific region of the chip surface will be occupied exclusively by axons. The axons and clusters of release-competent synaptic vesicles, a presynapse-like specialization in the axon, can be quantified as the proportions of this specific region's area occupied respectively by these subcellular structures. By using chips with this specific region coated with different proteins, these proteins' effects on the growth and presynaptic differentiation of the axon were investigated by comparing the amounts of axons and clusters of release-competent synaptic vesicles in this region of the chip. We also demonstrate another application of this chip device by investigating the effective range of the signal produced by the interaction between neurons and neuroligin 1 in neurons. These results indicate the diverse applications of the chip device in exploring various issues pertaining to axonal functions. PMID- 22522186 TI - Developing peptide-based multivalent antagonists of proliferating cell nuclear antigen and a fluorescence-based PCNA binding assay. AB - Proliferating cell nuclear antigen (PCNA) is a critical player in cell proliferation. It interacts with a myriad of cellular proteins in genomic DNA replication and cell cycle control. This makes PCNA an attractive target for developing antiproliferative therapeutics. Indeed, the binding of a human tumor suppressor protein, p21, to PCNA contributes to its antiproliferative effect in cells. In this work, we report a fluorescence polarization-based binding assay for determining the affinity between the p21 peptide and human PCNA. To improve the potency of the p21-based PCNA antagonist, we exploited the homotrimeric structure of PCNA and developed multivalent peptide-based PCNA antagonists. The di- and trivalent p21-based antagonists bind to PCNA with low nanomolar dissociation constant. Moreover, we show that the multivalent PCNA antagonists inhibited PCNA-dependent DNA synthesis in a human cell extract with improved avidity when compared with the monovalent p21 peptide. The fluorescence polarization assay holds promise for the discovery of potent small-molecule PCNA inhibitors given its ready adaptability to a high-throughput screening format. PMID- 22522188 TI - [Management and outcomes of pregnancies complicated by preterm premature rupture of membranes before 26 weeks of gestation]. AB - OBJECTIVE: To evaluate short-term outcomes of pregnancies complicated by preterm premature rupture of membranes (PPROM) before 26 weeks of gestation (wg). PATIENTS AND METHODS: Forty patients were included in a retrospective study from 1998 to 2008. RESULTS: Fifty percent of PPROM occurred before 23 wg. Survival rate was 21.4% when PPROM occurred before 22 wg versus 54.5% when it occurred between 22 and 23+6 wg and reached 80% after 24 wg (P=0.006). Perinatal mortality affected more frequently primigravida women (OR=5.16; IC9 5% [0.99-36.59]). Invasive procedures before PPROM did not affect survival rates. Smoking induced shorter latency (19.1+/-13.8 vs. 40.3+/-2.3j; P=0.01). Chorioamnionitis complicated all pregnancies terminated before 26 wg versus 50% of pregnancies terminated after 26 wg (P=0.02). In case of chorioamnionitis, 70% of the germs were identified prenatally. Patients whose CRP was higher than 6 mg/L at the time of PPROM had a higher fetal mortality rate (63.6% vs. 27.8%; P=0.02; OR=4.3; IC95% [0,99-22,1]). No significant difference was found in the occurrence of chorioamnionitis based on gestational age at PPROM, result of the vaginal swab on admission or the amount of amniotic fluid. DISCUSSION AND CONCLUSION: The gestational age of PPROM and the one of delivery are the major prognostic factors. Primigravida women are more exposed to perinatal mortality. CRP appears to be a predictive factor of perinatal mortality. PMID- 22522189 TI - Surgical management of a suspicious adnexal mass: a systematic review. AB - OBJECTIVE: To systematically review the existing literature in order to determine the optimal recommended protocols for the surgical management of adnexal masses suspicious for apparent early stage malignancy. METHODS: A review of all systematic reviews and guidelines published between 1999 and 2009 was conducted as a first step. After the identification of two systematic reviews on the topic, searches of MEDLINE for studies published since 2004 were also conducted to update and supplement the evidentiary base. RESULTS: The updated literature search identified 31 studies that met the inclusion criteria. A bivariate random effects analysis of 15 frozen section diagnosis studies yielded an overall sensitivity of 89.2% (95% CI, 86.3 to 91.5%) and specificity of 97.9% (95% CI, 96.6 to 98.7%). The surgical evidence suggests that systematic lymphadenectomy and proper surgical staging improve survival. Conservative fertility-preserving surgical approaches are an acceptable option in women with low malignant potential tumours. The accuracy and the adequacy of surgical staging by laparotomy or laparoscopic approaches appear to be comparable, with neither approach conferring a survival advantage. Intraoperative tumour rupture was indeed reported to occur more frequently in patients undergoing laparoscopy versus laparotomy in two retrospective cohort studies. CONCLUSIONS: The best available evidence was collected and included in this rigorous systematic review. The abundant evidentiary base provided the context and direction for the surgical management of adnexal masses suspicious for apparent early stage malignancy. PMID- 22522190 TI - Frailty: an outcome predictor for elderly gynecologic oncology patients. AB - OBJECTIVES: The objective of this pilot study was to determine if frailty predicts surgical complications among elderly women undergoing gynecologic oncology procedures. METHODS: A cohort of gynecologic oncology patients age >= 65, undergoing surgery between March and December 2011 was identified. Frailty was evaluated using a validated assessment tool. The primary outcome measure was 30 day postoperative complication rate. RESULTS: Forty women were approached for study entry and 37 (92%) enrolled. The mean age was 73 years (range 65-95). The majority of women had a malignancy and underwent a major abdominal surgical procedure. Twenty-one women (57%) were not frail, 10 (27%) were intermediately frail and 6 (16%) were frail. There was no difference in age or prevalence of medical comorbidities between groups. Frail women had a significantly higher BMI compared to intermediately frail and not frail women, (36.0, 31.5 and 26.1 kg/m(2), p=0.02). The rate of 30-day surgical complications increased with frailty score and was 24%, versus 67% for women who were not frail as compared to the frail (p=0.04). CONCLUSIONS: Pre-operative frailty assessment is well accepted by gynecologic oncology patients and feasible in a clinic setting. Frail women had a higher BMI, indicating that low body weight is not a marker for frailty, and had a significantly higher rate of 30-day postoperative complications in this pilot study. Initial findings support the concept of measuring frailty as a possible predictor for postoperative morbidity that will allow for improved patient counseling and decision making. PMID- 22522191 TI - Characteristics of children and adolescents in the Dutch national in- and outpatient mental health service for deaf and hard of hearing youth over a period of 15 years. AB - In this study socio-demographic, deafness-related and diagnostic characteristics of hearing impaired children and adolescents referred to a national mental health service for deaf and hard of hearing children and adolescents were examined. Socio-demographic and diagnostic characteristics were compared to corresponding characteristics of hearing referred peers with identified mental health problems. The difference in characteristics between them and hearing referred peers with identified mental health problems was analyzed. A total of 389 deaf and hard of hearing and 3361 hearing children and adolescents was extracted from a database, all first referrals of patients of a center for child and adolescent psychiatry over a 15-year period. With deaf and hard of hearing patients we found higher rates of environmental stress, as indicated by conditions such as more one parent families (38.6% versus 25.8%), and more parents with a low educational level (44.2% versus 31.1%). Moreover, deaf and hard of hearing patients were older at their first referral (10.8 versus 9.4 years) and had higher rates of pervasive developmental disorders (23.7% versus 12.3%) and mental retardation (20.3% versus 3.9%). Within the target group of deaf and hard of hearing patients, most patients were deaf (68.9%; 22.3% was severely hard of hearing), relatively few (13.7%) had a non-syndromal hereditary hearing impairment, and more (21.3%) had a disabling physical health condition, especially those with a pervasive developmental disorder (42.6%). These findings illustrate both the complexity of the problems of deaf and hard of hearing children and adolescents referred to specialist mental health services, and the need for preventive interventions aimed at early recognition. PMID- 22522192 TI - Agreement among physical educators, teachers and parents on children's behaviors: a multitrait-multimethod design approach. AB - The study examines the agreement among raters on children's problematic behaviors. A multitrait-multimethod (MTMM) matrix was applied to a normative sample of elementary school-aged children (N = 841). The participants were rated by their physical educators, using the Motor Behavior Checklist for children (MBC; Efstratopoulou, Janssen, & Simons, 2012). Teachers and parents rated the same students using the Teacher Report Form (TRF; Achenbach, 1991b), the Child Behavior Checklist (CBCL; Achenbach, 1991a) and the ADHD Rating Scale-IV (DuPaul, Power, Anastopoulos, & Reid, 1998). The resulting matrix revealed significant correlations for the Rules Breaking, Lack of Attention, Hyperactivity/Impulsivity, Lack of Social interaction problem scale and for the Internalizing, Externalizing and Total scores. Convergent validity of the specific MBC subscales was supported by significant correlations with the corresponding subscales of TRF, CBCL and ADHD Rating Scale-IV. Findings underscore the importance of taking child's settings and observer influences into account and suggest that MBC is a new promising instrument that can provide valid ratings on externalizing behavior and social problems in children when used by physical educators in school settings. PMID- 22522193 TI - Factor structure of the Serbian version of the Children's Communication Checklist 2. AB - Keeping in mind that traditional tests were largely insensitive to pragmatic impairment, Bishop (2003) created a second version of the Children's Communication Checklist (CCC-2) in order to identify pragmatic deficits in children with communication problems. Unfortunately, it was revealed that certain subscales of the Serbian version of the CCC-2 have unacceptably low internal consistency. Because dividing the test into original subscales did not apply for the Serbian population, the aim of this paper was to determine the factor structure of the CCC-2. The sample consisted of 1344 typically developing, monolingual participants of both sexes, aged from 4 to 17 (M = 9.52; SD = 2.72). Participants were recruited from three statistical regions in Serbia. All participants attended regular kindergarten, elementary or secondary schools. CCC 2 factor analysis was determined by using the principal component method, with Varimax rotation of principal axes. A factor analysis showed that the CCC-2 had three factors (General Communication Ability, Pragmatics and Structural Language Aspects), which accounted for 29.39% of the total variance. A three-factor solution should be further confirmed in the course of a clinical validation of the CCC-2. PMID- 22522194 TI - A finger-pressing position detector for assisting people with developmental disabilities to control their environmental stimulation through fine motor activities with a standard keyboard. AB - This study used a standard keyboard with a newly developed finger-pressing position detection program (FPPDP), i.e. a new software program, which turns a standard keyboard into a finger-pressing position detector, to evaluate whether two people with developmental disabilities would be able to actively perform fine motor activities to control their preferred environmental stimulation. An ABAB design was adopted in this study. The data showed that both participants' target responses (i.e. fine motor activities) significantly increased (i.e. they performed more fine motor activities to activate the environmental stimulation) during the intervention phases. The practical and developmental implications of the findings are discussed. PMID- 22522195 TI - Probing the perceptual and cognitive underpinnings of braille reading. An Estonian population study. AB - Similar to many sighted children who struggle with learning to read, a proportion of blind children have specific difficulties related to reading braille which cannot be easily explained. A lot of research has been conducted to investigate the perceptual and cognitive processes behind (impairments in) print reading. Very few studies, however, have aimed for a deeper insight into the relevant perceptual and cognitive processes involved in braille reading. In the present study we investigate the relations between reading achievement and auditory, speech, phonological and tactile processing in a population of Estonian braille reading children and youngsters and matched sighted print readers. Findings revealed that the sequential nature of braille imposes constant decoding and effective recruitment of phonological skills throughout the reading process. Sighted print readers, on the other hand, seem to switch between the use of phonological and lexical processing modes depending on the familiarity, length and structure of the word. PMID- 22522196 TI - Theory of mind and irony comprehension in children with cerebral palsy. AB - The main goal of the present study was to characterise the pragmatic abilities of French children with cerebral palsy through their understanding of irony and other people's mental states. We predicted that children with cerebral palsy would have difficulty understanding false-belief and ironic remarks, due to the executive dysfunction that accompanies the motor disorders of cerebral palsy. We conducted an experiment in which children with cerebral palsy and typically developing matched controls performed theory-of-mind and executive function tasks. They then listened to ironic stories and answered questions about the speakers' beliefs and attitudes. The groups differed significantly on second order theory of mind, irony comprehension and working memory, indicating pragmatic difficulties in children with cerebral palsy. PMID- 22522197 TI - Examining factors associated with pre-admission to discharge of stroke patients. AB - Stroke is the second leading cause of death and a major cause of adult disability in Taiwan. This research established correlations between pre-admission and discharge data in stroke patients to promote education of the general public, prevention, treatment and high standards of chronic care. A total of 790 stroke patients at Chung Shan Medical University Hospital from 2007 to 2009 contained in the Taiwan Stroke Registry were included in this study. The patients were classified into two major categories: ischemic and hemorrhagic. Thirteen variables, including time series variables, were explored. Our results showed that age, education, hours from symptom onset to the emergency department (ED) arrival, and length of stay in hospital were significantly associated with stroke incidence. These findings show the present situation and medical quality of medical care for stroke patients in Taiwan. The factors association model may assist in developing a set of improvement plans for the coming year. PMID- 22522198 TI - Narrative competence and internal state language of children with Asperger Syndrome and ADHD. AB - The central question of the present study was whether there are differences between children with Asperger Syndrome (AS), children with attention deficit hyperactivity disorder (ADHD) and healthy controls (HC) with respect to the organization of narratives and their verbalization of internal states. Oral narrations of a wordless picture book produced by 31 children (11 with AS, 9 with ADHD, 11 HC, aged 8-12) were analyzed regarding the following linguistic variables: story length, sentence structure and sentence complexity, coherence and cohesion of the stories, verbalization of the narrator's perspective, as well as internal state language (verbal reference to mental states). Considerable similarities were noted between the two clinical groups, which deviate from HC children. Narratives of the children with AS and ADHD were shorter than the narratives produced by the HC children. The children of both clinical groups failed to point out the main aspects of the story. In particular, children with AS did not refer to cognitive states as often as the other groups. With respect to narrative coherence, they produced fewer pronominal references than HC children and children with ADHD. In conclusion, the two clinical groups differed from the HC group on a number of features, and a less frequent reference to cognitive states was identified for the children with AS. PMID- 22522199 TI - Sleep disruption as a correlate to cognitive and adaptive behavior problems in autism spectrum disorders. AB - Sleep problems associated with autism spectrum disorders (ASD) have been well documented, but less is known about the effects of sleep problems on day-time cognitive and adaptive performance in this population. Children diagnosed with autism or pervasive developmental disorder-not otherwise specified (PDD-NOS) (N = 335) from 1 to 10 years of age (M = 5.5 years) were evaluated for the relationships of Behavioral Evaluation of Disorders of Sleep (BEDS; Schreck, 1998) scores to measures of intelligence and adaptive behavior. Results suggested that children who slept fewer hours per night had lower overall intelligence, verbal skills, overall adaptive functioning, daily living skills, socialization skills, and motor development. Children who slept fewer hours at night with waking during the night had more communication problems. Breathing related sleep problems and fewer hours of sleep related most often to problems with perceptual tasks. The results indicate that quality of sleep--especially sleep duration--may be related to problems with day-time cognitive and adaptive functioning in children with autism and PDD-NOS. However, future research must be conducted to further understand these relationships. PMID- 22522200 TI - Is interlimb coordination during walking preserved in children with cerebral palsy? AB - Arm movements during gait in children with cerebral palsy (CP) are altered compared to typically developing children (TD). We investigated whether these changes in arm movements alter interlimb coordination in CP gait. 3D gait analysis was performed in CP (diplegia [DI]: N = 15 and hemiplegia [HE]: N = 11) and TD (N = 24) children at preferred and fast walking speeds. Mean Relative Phase (MRP, i.e. mean over the gait cycle of the Continuous Relative Phase or CRP) was calculated as a measure of coordination, standard deviation of CRP was used as a measure of coordinative stability, and the sign of MRP indicated which limb was leading (for all pair combinations of the four limbs). In HE, coordination was significantly altered, less stable and a different leading limb was found compared to TD whenever the most affected arm was included in the studied limb pair. In DI, coordination deteriorated significantly when any of the two legs was included in the studied limb pair, and coordinative stability was significantly affected when any of the two arms was included. In almost all limb pair combinations, a different limb was leading in DI compared to TD. Increasing walking speed significantly improved coordination and coordinative stability of several limb pairs in DI. Coordination and limb-leading deficits were mostly linked to the affected limb. The compensating (non-affected) arm primarily affected coordinative stability, which underlines the importance of active arm movements in HE. Increasing walking speed may be used to improve interlimb coordination in DI. PMID- 22522201 TI - Comparison of outpatient services between elderly people with intellectual disabilities and the general elderly population in Taiwan. AB - This study aims to analyze the ambulatory visit frequency and medical expenditures of the general elderly population versus the elderly with intellectual disabilities in Taiwan, while examining the effects of age, gender, urbanization and copayment status on ambulatory utilization. A cross-sectional study was conducted to analyze data from 103,183 national health insurance claimants aged 65 or older. A total of 1469 had a principal diagnosis of mental retardation (intellectual disability) and claimed medical outpatient services in 2007. The average number of ambulatory visits was 30.1 +/- 23.1, which is much higher than in the United States and other developed countries, and the mean annual visits of the elderly with intellectual disabilities was significantly higher than the general population in Taiwan (35.2 +/- 28.7 vs. 30.0 +/- 23.1). Age and copayment status affected outpatient visit frequency. The mean medical expenditure per visit and the mean annual outpatient cost were 1146.5 +/- 4497.7 NT$ and 34,533.7 +/- 115,891.7 NT$, respectively. Male beneficiaries tended to have higher average annual medical expenses and mean medical expenses per visit than female beneficiaries. The three most frequent principal diagnoses at ambulatory visits were circulatory system diseases, musculoskeletal system and connective tissue diseases and digestive system diseases. We conclude that the elderly with intellectual disabilities had higher demand than the general population for healthcare services, and the NHI program lowers the barrier to care for populations with special needs. PMID- 22522202 TI - Gait strategy in patients with Ehlers-Danlos syndrome hypermobility type and Down syndrome. AB - People suffering from Ehlers-Danlos syndrome (EDS) hypermobility type present a severe ligament laxity that results in difficulties in muscle force transmission. The same condition is present in people suffering from Down syndrome (DS) even if their clumsy movements are due to cerebral and cognitive impairments. The aim of this study was to quantify the gait patterns of subjects with EDS and with DS using Gait Analysis (GA). We quantified the gait strategy in 12 EDS individuals and in 16 participants with DS. Both pathological groups were compared to 20 age matched healthy controls in terms of kinematics and kinetics. Results showed that DS individuals are characterized by a more compromised gait pattern than EDS participants, even if both groups are characterized by joint hypermobility. All the patients showed significant decreased of ankle stiffness probably due to congenital hypotonia and ligament laxity, while different values of hip stiffness. These findings help to elucidate the complex biomechanical changes due to joint hypermobility and may have a major role in the multidimensional evaluation and tailored management of these patients. PMID- 22522204 TI - Cognitive inhibition in students with and without dyslexia and dyscalculia. AB - The present study presents a comparison of the cognitive inhibition abilities of dyslexic, dyscalculic, and control students. The participants were 45 dyslexic students, 45 dyscalculic students, and 45 age-, gender-, and IQ-matched control students. The major evaluation tools included six cognitive inhibition tasks which were restructured during principal component analysis into three categories: graph inhibition, number inhibition, and word inhibition. Comparisons of the 3 groups of students revealed that in graph inhibition, dyscalculic students performed worst of the 3 groups, with dyslexic students also performing worse than control students in this category. For number inhibition, the control students' performances were equal to those of dyslexic students, with both groups performing better than dyscalculic students. For word inhibition, control students' performances were equal to those of dyscalculic students; both groups had shorter response times and lower incorrect rates than dyslexic students. These results suggest the complexity of the different cognitive inhibition abilities displayed by dyslexic, dyscalculic, and control students. However, some regular patterns occurred. PMID- 22522203 TI - Use of the Medical Research Council Framework to develop a complex intervention in pediatric occupational therapy: Assessing feasibility. AB - The United Kingdom Medical Research Council recommends use of a conceptual framework for designing and testing complex therapeutic interventions. Partnering for Change (P4C) is an innovative school-based intervention for children with Developmental Coordination Disorder (DCD) that was developed by an interdisciplinary team who were guided by this framework. The goals of P4C are to facilitate earlier identification, build capacity of educators and parents to manage DCD, and improve children's participation in school and at home. Eight occupational therapists worked in school settings during the 2009-2010 school year. Their mandate was to build capacity through collaboration and coaching with the school becoming the "client", rather than any individual student. Over 2600 students and 160 teachers in 11 elementary schools received service during the project. Results from questionnaires and individual interviews indicated that this model was highly successful in increasing knowledge and capacity. P4C intervention holds promise for transforming service delivery in schools. PMID- 22522205 TI - Allophonic mode of speech perception in Dutch children at risk for dyslexia: a longitudinal study. AB - There is ample evidence that individuals with dyslexia have a phonological deficit. A growing body of research also suggests that individuals with dyslexia have problems with categorical perception, as evidenced by weaker discrimination of between-category differences and better discrimination of within-category differences compared to average readers. Whether the categorical perception problems of individuals with dyslexia are a result of their reading problems or a cause has yet to be determined. Whether the observed perception deficit relates to a more general auditory deficit or is specific to speech also has yet to be determined. To shed more light on these issues, the categorical perception abilities of children at risk for dyslexia and chronological age controls were investigated before and after the onset of formal reading instruction in a longitudinal study. Both identification and discrimination data were collected using identical paradigms for speech and non-speech stimuli. Results showed the children at risk for dyslexia to shift from an allophonic mode of perception in kindergarten to a phonemic mode of perception in first grade, while the control group showed a phonemic mode already in kindergarten. The children at risk for dyslexia thus showed an allophonic perception deficit in kindergarten, which was later suppressed by phonemic perception as a result of formal reading instruction in first grade; allophonic perception in kindergarten can thus be treated as a clinical marker for the possibility of later reading problems. PMID- 22522206 TI - The relationship among attributions, emotions, and interpersonal styles of staff working with clients with intellectual disabilities and challenging behavior. AB - Several studies have tested Weiner's model, which suggests a relationship among causal attributions regarding challenging behavior (CB), emotions, and helping behavior of staff. No studies have focused on interpersonal styles. The goals of this study were to investigate the influence of type of CB on attributions, emotions and interpersonal style of staff, the relationships among staff attributions, emotions, and interpersonal style, and the mediating function of emotions in the relation between attributions and interpersonal style. Participants were 99 staff members. CB aimed at the environment was related to higher levels of negative emotions, attributions and certain interpersonal styles such as controlling behavior. In addition, a relationship between emotions, attributions, and interpersonal style was found. However, there was no mediating function of emotions in the relationships between attributions and interpersonal style. Future research should take a more dynamic view of staff behavior and staff-client interaction into account. PMID- 22522207 TI - Relationship between reaction time, fine motor control, and visual-spatial perception on vigilance and visual-motor tasks in 22q11.2 Deletion Syndrome. AB - 22q11.2 Deletion Syndrome (22q11DS) is a common microdeletion disorder associated with mild to moderate intellectual disability and specific neurocognitive deficits, particularly in visual-motor and attentional abilities. Currently there is evidence that the visual-motor profile of 22q11DS is not entirely mediated by intellectual disability and that these individuals have specific deficits in visual-motor integration. However, the extent to which attentional deficits, such as vigilance, influence impairments on visual motor tasks in 22q11DS is unclear. This study examines visual-motor abilities and reaction time using a range of standardised tests in 35 children with 22q11DS, 26 age-matched typically developing (TD) sibling controls and 17 low-IQ community controls. Statistically significant deficits were observed in the 22q11DS group compared to both low-IQ and TD control groups on a timed fine motor control and accuracy task. The 22q11DS group performed significantly better than the low-IQ control group on an untimed drawing task and were equivalent to the TD control group on point accuracy and simple reaction time tests. Results suggest that visual motor deficits in 22q11DS are primarily attributable to deficits in psychomotor speed which becomes apparent when tasks are timed versus untimed. Moreover, the integration of visual and motor information may be intact and, indeed, represent a relative strength in 22q11DS when there are no time constraints imposed. While this may have significant implications for cognitive remediation strategies for children with 22q11DS, the relationship between reaction time, visual reasoning, cognitive complexity, fine motor speed and accuracy, and graphomotor ability on visual-motor tasks is still unclear. PMID- 22522208 TI - Does intellectual disability affect the development of dental caries in patients with cerebral palsy? AB - The aim of this study was to evaluate if the severity of intellectual disability is a factor that affects the development of dental cavities in patients with cerebral palsy. This cross-sectional study was conducted on 165 individuals who were selected from a physical rehabilitation center, a special public school and a regular public school. Of these, 76 individuals had been diagnosed with spastic cerebral palsy and 89 had no neurological impairment. The subjects were matched based on age and gender and selected randomly by lottery. All patients were examined to determine the number of dental cavities, and tested for their intellectual functioning (Raven Test) and motor abilities. The study showed that children with CP who presented with intellectual disabilities had a larger number of dental cavities than children with CP without intellectual disabilities. Considering intellectual functioning and motor impairment in the multivariate logistic regression, only intellectual functioning was found to have a significant effect on the development of dental cavities. These results suggest that intellectual disability can be considered a contributing factor for the development of dental caries in patients with cerebral palsy. PMID- 22522210 TI - Deficits in the covert orienting of attention in children with Developmental Coordination Disorder: does severity of DCD count? AB - Children with Developmental Coordination Disorder (DCD) show deficits in the covert orienting of visuospatial attention, suggesting an underlying issue in attentional disengagement and/or inhibitory control. However, an important theoretical issue that remains unclear is whether the pattern of deficits varies with DCD severity. Fifty-one children with moderate DCD (MDCD), 24 children with severe DCD (SDCD), and 38 typically developing (TD) children participated in the study. Their performance was compared on the covert orienting of visuospatial attention task (COVAT), specifically the voluntary control mode. Results showed that the pattern of performance differed between groups. At a short stimulus response asynchrony (350 ms), the difference in response times for validly and invalidly cued trials was similar for all three groups. However, at the longer SOA (800 ms), both DCD groups continued to show a relative disadvantage for responses that followed invalid cues. This suggests that a deficit in response inhibition and/or attentional disengagement is manifest in children with both moderate and severe DCD. The implications of these findings for theory and treatment are discussed. PMID- 22522209 TI - High blood pressure in adults with disabilities: influence of gender, body weight and health behaviors. AB - The aims of this study were to explore the mean and distribution of systolic and diastolic blood pressure, and to examine the influence of gender, body weight and health behaviors on hypertension in adults with disabilities. We analyzed the 2010 annual community health examination chart of adults with disabilities in east Taiwan. The study samples included 833 adults with disabilities whose age 30 years and over participated in the analyses. The mean value of diastolic and systolic blood pressure (mmHg) of the study participants was 76.51 +/- 12.65 (range = 40-155) and 127.39 +/- 20.32 (range = 77-221). Fifteen percent and 23.4% of the participants have high diastolic (>/=90 mmHg) and systolic (>/= 140 mmHg) blood pressure. There were 27.4% of the participants who had hypertension, high diastolic or/and systolic blood pressure. Finally, we found that the factors of older age (OR = 2.45, 95% CI = 1.22-4.93), overweight or obese in BMI (OR = 6.72, 95% CI = 1.90-23.78; OR = 6.76, 95% CI = 1.84-24.84), waist circumference (OR = 1.64, 95% CI = 1.03-2.61) and vegetable/fruit intake (OR = 0.61, 95% CI = 0.39 0.94) were variables that could significantly predict the hypertension condition of the subjects after controlling factors of marital status, type and level of disability. To improve the healthcare for people who suffer with and prevention for hypertension, the study highlights the health authorities should pay much attention to blood pressure condition and their determinants for people with disabilities in the communities. PMID- 22522211 TI - Measuring staff behavior towards clients with ID and challenging behavior: further psychometric evaluation of the Staff-Client Interactive Behavior Inventory (SCIBI). AB - Recently, the Staff-Client Interactive Behavior Inventory (SCIBI) was developed, measuring both interpersonal and intrapersonal staff behavior in response to challenging behavior in clients with ID. The aim of the two studies presented here was first to confirm the factor structure and internal consistency of the SCIBI and second to demonstrate its convergent validity. In the first study, a total of 265 support staff members, employed in residential and community services, completed the SCIBI for 62 clients with ID and challenging behavior. In the second study, 158 staff members completed the SCIBI for 158 clients, as well as the SASB-Intrex, the NIAS and the Bar-On Emotional Quotient Inventory (EQI). Replication of a confirmatory factor analysis resulted in a consistent seven factor solution of the SCIBI with high levels of internal consistency. Also, mostly good convergent validity with the SASB-Intrex and sufficient to good convergent validity with the NIAS and EQI were found, except for the self reflective intrapersonal staff behavior scale. By replicating and extending earlier results on the SCIBI, it proves to be a reliable and sufficient valid measure of interpersonal and intrapersonal behavior of staff working with people with intellectual disabilities. PMID- 22522213 TI - Vitamin D and autism: clinical review. AB - BACKGROUND: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with multiple genetic and environmental risk factors. The interplay between genetic and environmental factors has become the subject of intensified research in the last several years. Vitamin D deficiency has recently been proposed as a possible environmental risk factor for ASD. OBJECTIVE: The aim of the current paper is to systematically review the research regarding the possible connection between ASD and vitamin D, and to provide a narrative review of the literature regarding the role of vitamin D in various biological processes in order to generate hypotheses for future research. RESULTS: Systematic data obtained by different research groups provide some, albeit very limited, support for the possible role of vitamin D deficiency in the pathogenesis of ASD. There are two main areas of involvement of vitamin D in the human body that could potentially have direct impact on the development of ASD: (1) the brain (its homeostasis, immune system and neurodevelopment) and (2) gene regulation. CONCLUSION: Vitamin D deficiency--either during pregnancy or early childhood--may be an environmental trigger for ASD in individuals genetically predisposed for the broad phenotype of autism. On the basis of the results of the present review, we argue for the recognition of this possibly important role of vitamin D in ASD, and for urgent research in the field. PMID- 22522212 TI - The WNT2 gene polymorphism associated with speech delay inherent to autism. AB - Previous evidence suggests that language function is modulated by genetic variants on chromosome 7q31-36. However, it is unclear whether this region harbors loci that contribute to speech delay in autism. We previously reported that the WNT2 gene located on 7q31 was associated with the risk of autism. Additionally, two other genes on 7q31-36, FOXP2 and the EN2 genes are also found to play a role in language impairment. Therefore, we hypothesize that the WNT2 gene, FOXP2 gene, and EN2 gene, may act in concert to influence language development in the same population. A total of 373 individuals diagnosed with autistic disorder were recruited in the current study. We selected 6 tag single nucleotide polymorphisms (SNPs) within the WNT2 gene, 3 tag SNPs in the FOXP2, and 3 tag SNPs in the EN2 genes, to study the effect of these genes on language development. Age of first phrase was treated as a quantitative trait. We used general linear model to assess the association between speech delay and these variants. The results show that rs2896218 in the WNT2 gene was moderately significantly associated with age of first phrase (permutation p = 0.0045). A three-locus haplotype in the WNT2 gene was significantly associated with age of first phrase (permutation p = 2 * 10(-4)). Furthermore, we detected an interaction effect on age of first phrase between a SNP rs2228946 in the WNT2 gene and another SNP rs6460013 in the EN2 gene (p = 0.0012). Therefore, the WNT2 gene may play a suggestive role in language development in autistic disorder. Additionally, the WNT2 gene and EN2 gene may act in concert to influence the language development in autism. PMID- 22522214 TI - Development of an instrument for diagnosing significant limitations in adaptive behavior in early childhood. AB - Although adaptive behavior became a diagnostic criterion in the 5th edition of the American Association on Intellectual and Developmental Disabilities, AAIDD (Heber, 1959, 1961), there are no measures with adequate psychometric properties for diagnosing significant limitations in adaptive behavior according to the current conception of the construct. This fact has led to an excessive reliance on intellectual functioning measures. The goal of the present paper consists of presenting the development of the AAIDD's forthcoming Diagnostic Adaptive Behavior Scale (DABS) in Spain, and, specifically, it will be focused on one of its three forms: DABS Form 4-8 years old. The sample consisted of 388 people, aged 4-8 years old, with and without intellectual disabilities. The functioning of an initial pool of 168 items was analyzed under the assumptions of Item Response Theory models (IRT) with the aim to select those items around the cut off point for determining significant limitations in adaptive behavior. A set of 72 items was selected (96 items were removed due to misfit, unsatisfying response category functioning, or low precision of measurement). The final version seems to be essentially unidimensional, shows good fit to the model, and represents an accurate precision of measurement around the cutoff point for diagnosing significant limitations in conceptual, social or practical skills. PMID- 22522215 TI - Neurodevelopmental problems in maltreated children referred with indiscriminate friendliness. AB - We aimed to explore the extent of neurodevelopmental difficulties in severely maltreated adopted children. We recruited 34 adopted children, referred with symptoms of indiscriminate friendliness and a history of severe maltreatment in their early childhood and 32 typically developing comparison children without such a history, living in biological families. All 66 children, aged 5-12 years, underwent a detailed neuropsychiatric assessment. The overwhelming majority of the adopted/indiscriminately friendly group had a range of psychiatric diagnoses, including Attention Deficit Hyperactivity Disorder (ADHD), Post-Traumatic Stress Disorder (PTSD) and Reactive Attachment Disorder (RAD) and one third exhibited the disorganised pattern of attachment. The mean IQ was 15 points lower than the comparison group and the majority of the adopted group had suspected language disorder and/or delay. Our findings show that school-aged adopted children with a history of severe maltreatment can have very complex and sometimes disabling neuropsychiatric problems. PMID- 22522216 TI - Developmental Coordination Disorder, gender, and body weight: examining the impact of participation in active play. AB - BACKGROUND: To examine whether differences in participation in active play (PAP) can account for gender differences in the relationship between Developmental Coordination Disorder (DCD) and body weight/fat (BMI and percentage fat) in youth. METHODS: A cross-sectional investigation of students in grades four through eight (n = 590). Height, weight (BMI), and percentage body fat using bioelectrical impedance analysis (BIA; RJL Systems, MI) were collected. Motor proficiency and physical activity levels were also evaluated. RESULTS: We found gender specific patterns in the relationship between PAP, DCD, and BMI and body fat. Among boys with DCD, greater participation in active play is associated with higher BMI and percentage body fat. For girls with the disorder, the opposite relationship is observed. CONCLUSIONS: Participation in active play moderates the association between DCD, gender and body weight. Three possible explanations for why PAP is associated with higher BMI and percentage body fat in boys with DCD are provided. PMID- 22522217 TI - Activity and energy expenditure in older people playing active video games. AB - Tayl OBJECTIVES: To quantify energy expenditure in older adults playing interactive video games while standing and seated, and secondarily to determine whether participants' balance status influenced the energy cost associated with active video game play. DESIGN: Cross-sectional study. SETTING: University research center. PARTICIPANTS: Community-dwelling adults (N=19) aged 70.7+/-6.4 years. INTERVENTION: Participants played 9 active video games, each for 5 minutes, in random order. Two games (boxing and bowling) were played in both seated and standing positions. MAIN OUTCOME MEASURES: Energy expenditure was assessed using indirect calorimetry while at rest and during game play. Energy expenditure was expressed in kilojoules per minute and metabolic equivalents (METs). Balance was assessed using the mini-BESTest, the Activities-specific Balance Confidence Scale, and the Timed Up and Go (TUG). RESULTS: Mean +/- SD energy expenditure was significantly greater for all game conditions compared with rest (all P<=.01) and ranged from 1.46+/-.41 METs to 2.97+/-1.16 METs. There was no significant difference in energy expenditure, activity counts, or perceived exertion between equivalent games played while standing and seated. No significant correlations were observed between energy expenditure or activity counts and balance status. CONCLUSIONS: Active video games provide light intensity exercise in community-dwelling older people, whether played while seated or standing. People who are unable to stand may derive equivalent benefits from active video games played while seated. Further research is required to determine whether sustained use of active video games alters physical activity levels in community settings for this population. PMID- 22522218 TI - Changes in balance and walking from stroke rehabilitation to the community: a follow-up observational study. AB - OBJECTIVES: To investigate (1) whether clinical test scores at discharge predict falls or limited community mobility after discharge from inpatient stroke rehabilitation; and (2) how walking and dynamic standing balance change after discharge. DESIGN: Follow-up observational study between 6 and 36 months after discharge. SETTING: Rehabilitation setting. PARTICIPANTS: Community-dwelling stroke survivors (N=30) who could walk unassisted when discharged from inpatient rehabilitation. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Six-minute walk test (6MWT), Four Square Step Test (FSST), Step Test (ST), Environmental Analysis of Mobility Questionnaire (EAMQ), Falls Efficacy Scale-International (FES-I), and self-reported falls. RESULTS: Follow-up occurred at a median of 14.5 months postdischarge. Significant improvements occurred between discharge and follow-up for the 6MWT (mean difference [MD]=110.1m; 95% confidence interval [CI], 70.8-149.4; P<.001), ST (MD=1.8 steps; 95% CI, 0.3-3.4; P=.03), and FSST (MD=4.3s; 95% CI, -10.3 to 1.6; P=.05). Despite this, 40% of participants reported falling. The group who fell had lower clinical test scores at discharge and follow-up than nonfallers. Specific cutoff scores for the clinical tests accurately classified falls history in 70% to 78% of participants. The cutoff scores were <250m for the 6MWT, <10 steps on the ST, and a failure or >=15 seconds to complete the FSST. Participants performing under the cutoff scores reported lower levels of community mobility (EAMQ, P<.04). Concern about falling was only higher for those classified at risk by the FSST (FES-I, P=.008). CONCLUSIONS: The FSST, ST, and 6MWT scores at discharge had good falls prediction. People classified at risk of falls avoided more tasks in their home and community than those not classified at risk. PMID- 22522219 TI - Effects of chronic chromium(vi) exposure on blood element homeostasis: an epidemiological study. AB - One hundred chromate production workers chronically exposed to low-level of hexavalent chromium [Cr(vi)] and eighty healthy individuals free from Cr exposure were recruited to the study. Personal sampling of airborne Cr was conducted and Cr content was quantified by Flame Atomic Absorption Spectrometry (FAAS). At the end of the sampling shift, blood samples were collected and element concentrations were measured by inductively coupled plasma mass spectrometry (ICP MS) for Cr, Cd, Cu, Mo and Se and inductively coupled plasma atomic emission spectrometry (ICP-AES) for Ca, Fe, Mg and Zn. According to our results, 90% of the chromate production workers were exposed to airborne Cr in a concentration lower than 50 MUg m(-3), which is the threshold limit value recommended by the American Conference of Governmental Industrial Hygienists and Chinese Ministry of Health. After Cr(vi) exposure, a significant increase in blood Cr, Cd, Fe, Mg, Mo, Se and Zn concentrations was observed, as well as a significant decrease in Ca concentration. A decrease in blood Cu was only observed among female workers. Blood Cr concentrations of the exposed workers (median = 15.68 ng mL(-1)) was four times higher than that of the controls (median = 3.03 ng mL(-1)), and significantly correlated with airborne Cr (r = 0.568, P<0.001). In addition, the inter-element correlations exhibited significant differences between the two groups. Our findings of the related health effects suggested that the underlying mechanisms of chronic Cr(vi) exposure on blood element homeostasis might be partly explained by oxidative stress in the body, dysfunction of Fe metabolism and renal injury. PMID- 22522220 TI - The defecation pattern of healthy term infants up to the age of 3 months. AB - BACKGROUND: Defecation problems occur frequently in infants. A clearer insight into the normal defecation pattern is required to gain a better understanding of abnormal defecation. AIM: To describe the defecation pattern of healthy infants in The Netherlands. METHODS: From a research population of 1175 healthy Dutch infants, 600 infants without any complaints were selected. The parents recorded details of feeding and defecation at the age of 1, 2 and 3 months using a standardised questionnaire and bowel diary. RESULTS: In breastfed infants, average daily defecation frequency decreased significantly during the first 3 months (from 3.65 to 1.88 times per day), whereas no significant changes were observed in infants fed standard formula or mixed feeding. At every age both the average and the range of defecation frequency of breastfed infants were higher than those of infants receiving formula feeding. Breastfed infants had softer faeces than formula-fed infants and the colour more often was yellow. At the age of 3 months, 50% of stools of formula-fed infants were green coloured. There was no significant difference in quantity between the three types of feeding, but there existed a negative correlation between defecation frequency and quantity. CONCLUSION: This study gives insight into the defecation patterns of the largest cohort of healthy infants published so far. In the first 3 months of life, breastfed infants have more frequent, softer and more yellow-coloured stools than standard formula-fed infants. Green-coloured stools in standard formula-fed infants should be considered normal. PMID- 22522221 TI - Structural dependence of microwave dielectric properties of ixiolite structured ZnTiNb2O8 materials: crystal structure refinement and Raman spectra study. AB - Structural and property relationships of ixiolite structured ZnTiNb(2)O(8) microwave dielectric materials were studied by structure refinement and Raman spectra analysis. The vibration modes which have Raman activities of the ixiolite structure were assigned for the first time. The bands with wavenumbers greater than 450 cm(-1) can be associated with several modes (A(g(2)), B(3g(1)), B(3g(2)), A(g(1)), B(1g(2)), A(g(3)), B(2g(2))) involving the stretching of the cation-O bonds. For wavenumbers between 250 and 450 cm(-1), the bands are due, principally, to the bending of O-cation-O (B(1g(1)), B(2g(1)), B(1g(3))). The origin of the bands with wavenumbers below 250 cm(-1) would be lattice vibrations (B(1g(4)), A(g(4)), B(3g(4)), B(2g(4))), mainly associated with cation ions. The correlation between bond strength and packing fraction, Raman shift, full width at half maximum (FWHM) of Raman spectra were discussed. With increase of bond strength, the oxygen octahedron became rigid, the Raman shift increased, and the damping behavior became weaker. With increase of Raman shift, the dielectric constant decreased. With increase of packing fraction and decrease of FWHM, the Q(f) (quality factor * resonance frequency) value increased. The tau(f) (temperature coefficient of resonance frequency) decreased with increase of bond strength. And there was no direct relationship between oxygen octahedron distortion and tau(f). The excellent microwave dielectric properties of ZnTiNb(2)O(8) in this work were: dielectric constant (epsilon) = 34.4, Q(f) = 56,900 GHz, tau(f) = -47.94 * 10(-6)/ degrees C. PMID- 22522222 TI - Elementary, my dear Doctor Watson. PMID- 22522223 TI - Is early detection of cancer with circulating biomarkers feasible? PMID- 22522224 TI - Genome structure determination via 3C-based data integration by the Integrative Modeling Platform. AB - The three-dimensional (3D) architecture of a genome determines the spatial localization of regulatory elements and the genes they regulate. Thus, elucidating the 3D structure of a genome may result in significant insights about how genes are regulated. The current state-of-the art in experimental methods, including light microscopy and cell/molecular biology, are now able to provide detailed information on the position of genes and their interacting partners. However, such methods by themselves are not able to determine the high-resolution 3D structure of genomes or genomic domains. Here we describe a computational module of the Integrative Modeling Platform (IMP, http://www.integrativemodeling.org) that uses chromosome conformation capture data to determine the 3D architecture of genomic domains and entire genomes at unprecedented resolutions. This approach, through the visualization of looping interactions between distal regulatory elements, allows characterizing global chromatin features and their relation to gene expression. We illustrate our work by outlining the determination of the 3D architecture of the alpha-globin domain in the human genome. PMID- 22522225 TI - Impact of food administration on lopinavir-ritonavir bioequivalence studies. AB - A bioequivalence study in 16 Caucasian healthy volunteers (eight male, eight female), comparing plasma drug concentrations after a single oral dose of lopinavir and ritonavir (400 and 100mg, respectively), was carried out following a two-period, two-sequence, two-treatment, randomized crossover design. Formulations were given 15 min after a moderate-fat breakfast in order to diminish both the intrinsic highly-variable performance and the sex differences observed in bioequivalence trials under fasting conditions. Ninety percent confidence intervals for the Test/Reference (T/R) ratio of geometric means for area under concentration-time curve (AUC) and maximum concentration (C(MAX)), either for lopinavir or ritonavir, were within the range of 0.80-1.25. Coprandial administration of formulations not only reduced the number of subjects required for bioequivalence assessment, reducing both ethical and economic cost of the trial, but also the sex differences in the T/R ratio of means. PMID- 22522226 TI - Regional, temporal, and species patterns of mercury in Alaskan seabird eggs: mercury sources and cycling or food web effects? AB - Mercury concentration ([Hg]), delta(15)N, and delta(13)C values were measured in eggs from common murres (Uria aalge), thick-billed murres (U. lomvia), glaucous gulls (Larus hyperboreus), and glaucous-winged gulls (L. glaucescens) collected in Alaska from 1999 to 2005. [Hg] was normalized to a common trophic level using egg delta(15)N values and published Hg trophic magnification factors. Egg [Hg] was higher in murres from Gulf of Alaska, Cook Inlet, and Norton Sound regions compared to Bering Sea and Bering Strait regions, independent of trophic level. We believe the Yukon River outflow and terrestrial Hg sources on the southern Seward Peninsula are responsible for the elevated [Hg] in Norton Sound eggs. Normalizing for trophic level generally diminished or eliminated differences in [Hg] among taxa, but temporal variability was unrelated to trophic level. Normalizing murre egg [Hg] by trophic level improves the confidence in regional comparisons of Hg sources and biogeochemical cycling in Alaska. PMID- 22522227 TI - Sperm penetration assay as an indicator of bull fertility. AB - To predict the fertility of frozen-thawed bull spermatozoa, a sperm penetration assay (SPA) using zona-free hamster oocytes was optimized, and the assay results were compared with data from field fertility expressed as the non-return rate (NRR). To increase sperm penetration, the spermatozoa were pre-incubated and coincubated with oocytes in media containing various concentrations of heparin (0 to 50 MUg/ml). Coincubation with 10 MUg/ml heparin showed the highest sperm penetration (P<0.05); it is considered to be the optimized SPA method. Sperm fertility index values obtained from WSPA were significantly correlated with the historic average NRR of 46 bulls (P<0.01). To determine the normal range for SPA, we established the lower limits of the sperm fertility index and set the cut-off value at 2.55, at which point the NRR was more than 70%, using the receiver operating characteristic curve. The overall accuracy for the 46 bulls was 95.7% (44/46) for both the low and high NRR, with a sensitivity of 95.5% (21/22) and a specificity of 95.8%. This protocol would make it easier to discriminate bulls according to their sperm fertilizing ability. PMID- 22522228 TI - Embryonic development and implantation related gene expression of oocyte reconstructed with bovine trophoblast cells. AB - The temporal progressive increase of interferon tau (IFNtau) secretion from the bovine trophoblast is a major embryonic signal of establishing pregnancy. Here, we cultured and isolated bovine trophoblast cells (BTs) from IVM/IVF oocytes and in vitro produced blastocysts, used them, for the first time, as donor cells for nuclear transfer and compared them with adult fibroblasts (AFs) as donor cells. BTs were reprogrammed in enucleated oocytes to blastocysts with similar efficiency to AFs (14.5% and 15.6% respectively, P<=0.05). The levels of IFNtau, CDX2 and OCT4 expression in IVF-, BT- and AF-derived blastocysts were analyzed using reverse transcription polymerase chain reaction and reverse transcription quantitative polymerase chain reaction (RT-PCR and RT-qPCR). IVF-produced embryos were used as reference to analyze the linear progressive expression of IFNtau through mid, expanded and hatching blastocysts. RT-PCR and RT-qPCR studies showed that IFNtau expression was higher in BT-derived blastocysts than IVF- and AF derived blastocysts. Both IVF- and BT-derived blastocysts showed a progressive increase in IFNtau expression as blastocyst development advanced when it compared with AF-derived blastocysts. OCT4 was inversely related with IFNtau expression, while CDX2 was found to be directly related with IFNtau temporal expression. Persistence of high expression of IFNtau and CDX2 was found to be higher in BT derived embryos than in IVF- or AF-derived embryos. In conclusion, using BTs expressing IFNtau as donor cells for bovine NT could be a useful tool for understanding the IFNtau genetics and epigenetics. PMID- 22522229 TI - Somatic reactivation of expression of the silent maternal Mest allele and acquisition of normal reproductive behaviour in a colony of Peg1/Mest mutant mice. AB - Genomic imprinting confers allele-specific expression in less than 1% of genes, in a parent-of-origin specific fashion. In humans and mice the Peg1/Mest gene (Mest) is maternally repressed, and paternally expressed. Mest is expressed in embryogenic mesoderm-derived tissues and in adult brain, and paternal mutations in Mest lead to growth retardation and defective maternal behaviour. Despite our current understanding of mechanisms associated with the establishment of imprinting of Mest and other imprinted genes, it is unclear to what extent Mest imprinting needs to be maintained in adult tissues. Aberrations of imprinting are known to occur in certain rare syndromes, and involve either inherited mutations, or constitutive epigenetic alterations occurring soon after fertilization. Imprinting abnormalities may also occur in the aging somatic tissues of adult individuals. Here we report an occurrence of post-embryonic somatic variability of Mest allelic expression in a colony of mice where heterozygotes at the imprinted Mest locus for a mutation inherited from the father spontaneously expressed the normally silenced allele from the mother. In addition, a newly acquired ability to overcome the deficit in maternal reproductive behaviour had occurred in the mutant mice, but this appeared not to be directly linked to the Mest mutation. Our results suggest that at least one allele of Mest expression is required in the somatic tissues of adult individuals and that under certain conditions (such as in the presence of a Mest insertional mutation or in an altered genetic background), somatically acquired alterations of allelic expression at the Mest locus may occur. PMID- 22522230 TI - Does 2-hydroxyflutamide inhibit apoptosis in porcine granulosa cells? - An in vitro study. AB - In mammalian ovaries, the majority of follicles are lost before ovulation by atresia. This degenerative process is initiated or caused by granulosa cell apoptosis. To reveal the androgen-dependent mechanism of selective follicular atresia, the culture model system for agonism and antagonism of the androgen receptor has been established. We examined the influence of an androgen receptor antagonist, 2-hydroxyflutamide (2-Hf), on the incidence of apoptosis in cultured porcine granulosa cells. They were incubated (6 and 12-h) in the presence of testosterone (T, 10-7M), 2-Hf (1.7*10-4 M) or both T and 2-Hf (T+2-Hf), and then analyzed by flow cytometry with fluorescein labelled annexin V. To better imitate in vivo conditions, the intact porcine follicles (6-8 mm in diameter) have been incubated in an organ culture system with the addition of the same factors. Sections obtained from follicles fixed after culture were stained with hematoxylin and eosin, and the presence of apoptosis-related DNA strand breaks was evaluated by the TUNEL method. Estradiol and progesterone concentrations in the culture media were measured by radioimmunoassays. The addition of T or 2-Hf to the culture media caused an increase in the number of apoptotic granulosa cells, while treatment with T+2-Hf decreased it in both in vitro and organotypic models. Follicles cultured with the addition of T or 2-Hf exhibited morphological changes indicating follicular atresia. Granulosal estradiol secretion was considerably stimulated by T+2-Hf. The highest increase in follicular estradiol secretion was observed after the anti-androgen addition. In both granulosal and follicular cultures, the production of progesterone declined in the presence of T or 2-Hf but increased after their simultaneous addition. In conclusion, androgen receptor antagonist 2-Hf attenuates induction of granulosa cell apoptosis in the presence of a high T level. The nature of this protective mechanism as yet is unknown and requires further research. PMID- 22522231 TI - Gene expressions in the persistent corpus luteum of postpartum dairy cows: distinct profiles from the corpora lutea of the estrous cycle and pregnancy. AB - Persistence of the corpus luteum (CL) in cattle usually occurs during the puerperium and is associated with interference of prostaglandin (PG) F(2alpha) release from the uterus. The objective of the present study was to determine for the first time the gene expressions in the persistent CL compared with the CL of pregnancy and cyclic CL. Three types of CL biopsy samples were collected from 32 lactating Holstein cows: (1) CL persisting for 29 to 33 days after the first ovulation postpartum (persistent CL, n=9), (2) CL between days 29 and 33 of early pregnancy (CL of pregnancy, n=8) and (3) CL between days 10 and 13 of the estrous cycle (cyclic CL, n=27). mRNA expression of 2',5'-oligoadenylate synthetase-1 was upregulated only in the CL of pregnancy, confirming exposure to interferon-tau (IFNT) produced by trophoblasts in pregnant cows. mRNA expressions of immune tolerance-related factors (PGES and forkhead/winged helix transcription factor 3) were upregulated in the CL of pregnancy but not in the persistent CL, suggesting that IFNT controls upregulation of these genes. mRNA expression relating to some of the major systems such as lymphangiogenesis, inflammation and apoptosis were similarly upregulated in the persistent CL and the CL of pregnancy but not in the cyclic CL. The results suggest that the persistent CL may survive for a long period without changes in local immune tolerance but develops several major systems required for CL maintenance similar to the CL of pregnancy. PMID- 22522233 TI - Transoral robotic surgery total laryngectomy. PMID- 22522232 TI - Interleukin-6 enhances porcine parthenote development in vitro, through the IL 6/Stat3 signaling pathway. AB - Signal transducer and activator of transcription-3 (Stat3) plays a central role in interleukin-6 (IL-6)-mediated cell proliferation by inhibiting apoptosis in a variety of cell types. The Stat3 pathway is essential for embryonic development. The aim of this study was to determine the effects of recombinant IL-6 on the viability and development of porcine diploid parthenotes cultured in vitro. Four cell parthenotes, derived in vitro, were cultured to the blastocyst stage, with or without recombinant IL-6. The addition of 10 or 100 ng/ml of recombinant swine IL-6 into PZM3 medium increased the development rate of parthenotes to the blastocyst stage (P<0.05). When supplemented with 10 ng/ml of recombinant swine IL-6, the number of parthenotes at the blastocyst stage increased (P<0.05) and apoptosis decreased (P<0.05). Real-time RT-PCR experiments revealed that the addition of recombinant swine IL-6 decreased the mRNA expression of the pro apoptotic gene Caspase3 (P<0.01) but increased the expression levels of the anti apoptotic genes Bcl2l1 and Survivin. IL-6 receptors and Stat3 mRNA expression were upregulated after treatment with 10 ng/ml recombinant swine IL-6. Immunoblots and fluorescence labeling experiments showed that the levels of phosphorylated Stat3 were upregulated. These results suggest that recombinant swine IL-6 prevents apoptosis of porcine parthenotes and enhances porcine embryo viability through the IL-6/Stat3 signaling pathway in vitro. PMID- 22522234 TI - Effect of thermal sterilization on ferulic, coumaric and cinnamic acids: dimerization and antioxidant activity. AB - BACKGROUND: Some phenolic compounds, such as ferulic acid and p-coumaric acid, exist in the form of free acids, in fruits, rice, corn and other grains. Thermal treatment (121 degrees C at 15-17 psi) for different times on ferulic, p coumaric and cinnamic acids as well as equimolar mixtures of these acids was investigated. RESULTS: Ferulic and p-coumaric acids underwent decarboxylation, yielding dimeric products formed through their corresponding radical intermediates, while cinnamic acid was recovered unreacted. High-performance liquid chromatography analysis showed no cross-dimerization when equimolar mixtures of pairs of hydroxycinnamic acids were treated under the same conditions. Dimers were characterized as (E)-4',4"-(but-1-ene-1,3-diyl)bis(2' methoxyphenol)) (dimer of 4-vinylguaiacol) and (E)-4,4'-(but-1-ene-1,3 diyl)diphenol) (dimer of 4-vinylphenol) by nuclear magnetic resonance and mass spectrometry. CONCLUSION: Sterilization by thermal processing produced dimers of ferulic and coumaric acid. The antioxidant activity of these dimers was greater than that of the respective hydroxycinnamic acids. These results may be relevant for fruits and grains that contain hydroxycinnamic acids and undergo sterilization processes such as canning. PMID- 22522235 TI - Pseudo semiparametric maximum likelihood estimation exploiting gene environment independence for population-based case-control studies with complex samples. AB - Advances in human genetics have led to epidemiological investigations not only of the effects of genes alone but also of gene-environment (G-E) interaction. A widely accepted design strategy in the study of how G-E relate to disease risks is the population-based case-control study (PBCCS). For simple random samples, semiparametric methods for testing G-E have been developed by Chatterjee and Carroll in 2005. The use of complex sampling in PBCCS that involve differential probabilities of sample selection of cases and controls and possibly cluster sampling is becoming more common. Two complexities, weighting for selection probabilities and intracluster correlation of observations, are induced by the complex sampling. We develop pseudo-semiparametric maximum likelihood estimators (pseudo-SPMLE) that apply to PBCCS with complex sampling. We study the finite sample performance of the pseudo-SPMLE using simulations and illustrate the pseudo-SPMLE with a US case-control study of kidney cancer. PMID- 22522236 TI - Non-exponential tolerance to infection in epidemic systems--modeling, inference, and assessment. AB - The transmission dynamics of infectious diseases have been traditionally described through a time-inhomogeneous Poisson process, thus assuming exponentially distributed levels of disease tolerance following the Sellke construction. Here we focus on a generalization using Weibull individual tolerance thresholds under the susceptible-exposed-infectious-removed class of models which is widely employed in epidemics. Applications with experimental foot and-mouth disease and historical smallpox data are discussed, and simulation results are presented. Inference is carried out using Markov chain Monte Carlo methods following a Bayesian approach. Model evaluation is performed, where the adequacy of the models is assessed using methodology based on the properties of Bayesian latent residuals, and comparison between 2 candidate models is also considered using a latent likelihood ratio-type test that avoids problems encountered with relevant methods based on Bayes factors. PMID- 22522237 TI - A comparison of sexual behavior patterns among men who have sex with men and heterosexual men and women. AB - OBJECTIVE: Men who have sex with men (MSM) have higher rates of HIV and other sexually transmitted infections than women and heterosexual men. This elevated risk persists across age groups and reflects biological and behavioral factors; yet, there have been few direct comparisons of sexual behavior patterns between these populations. METHODS: We compared sexual behavior patterns of MSM and male and female heterosexuals aged 18-39 using 4 population-based random digit dialing surveys. A 1996-1998 survey in 4 US cities and 2 Seattle surveys (2003 and 2006) provided estimates for MSM; a 2003-2004 Seattle survey provided data about heterosexual men and women. RESULTS: Sexual debut occurred earlier among MSM than heterosexuals. MSM reported longer cumulative lifetime periods of new partner acquisition than heterosexuals and a more gradual decline in new partnership formation with age. Among MSM, 86% of 18- to 24-year-olds and 72% of 35- to 39 year-olds formed a new partnership during the previous year, compared with 56% of heterosexual men and 34% of women at 18-24 years, and 21% and 10%, respectively, at 35-39 years. MSM were also more likely to choose partners >5 years older and were 2-3 times as likely as heterosexuals to report recent concurrent partnerships. MSM reported more consistent condom use during anal sex than heterosexuals reported during vaginal sex. CONCLUSIONS: MSM have longer periods of partnership acquisition, a higher prevalence of partnership concurrency, and more age disassortative mixing than heterosexuals. These factors likely help to explain higher HIV/sexually transmitted infections rates among MSM, despite higher levels of condom use. PMID- 22522238 TI - Synthesis of cholic acid based calixpyrroles and porphyrins. AB - New cholic acid based calix[4]pyrroles and porphyrins were prepared and their properties were studied. It was confirmed by spectral measurements that the superassembly of 5,15-bis(3alpha,7alpha,12alpha-trihydroxy-5beta-cholan-24-yl) 10,20-diphenylporphyrin, the best candidate for this study from the conjugates prepared, may be influenced not only by the solvent mixture composition (polar/non-polar component ratio) but by time as well. PMID- 22522246 TI - Custom labware: Chemical creativity with 3D printing. PMID- 22522247 TI - Infrared spectroscopy: Mapping protein-protein contacts. PMID- 22522248 TI - Total synthesis: Welwitindolinone is well worth it. PMID- 22522249 TI - Main group chemistry: A heavier-element ketone at last. PMID- 22522250 TI - Asymmetric catalysis: Correlating sterics in catalysis. PMID- 22522251 TI - Self-assembly: Proteins on parade. PMID- 22522252 TI - Magnetic anisotropy: The orientation is in the details. PMID- 22522253 TI - Integrated 3D-printed reactionware for chemical synthesis and analysis. AB - Three-dimensional (3D) printing has the potential to transform science and technology by creating bespoke, low-cost appliances that previously required dedicated facilities to make. An attractive, but unexplored, application is to use a 3D printer to initiate chemical reactions by printing the reagents directly into a 3D reactionware matrix, and so put reactionware design, construction and operation under digital control. Here, using a low-cost 3D printer and open source design software we produced reactionware for organic and inorganic synthesis, which included printed-in catalysts and other architectures with printed-in components for electrochemical and spectroscopic analysis. This enabled reactions to be monitored in situ so that different reactionware architectures could be screened for their efficacy for a given process, with a digital feedback mechanism for device optimization. Furthermore, solely by modifying reactionware architecture, reaction outcomes can be altered. Taken together, this approach constitutes a relatively cheap, automated and reconfigurable chemical discovery platform that makes techniques from chemical engineering accessible to typical synthetic laboratories. PMID- 22522254 TI - Two-dimensional infrared spectroscopy reveals the complex behaviour of an amyloid fibril inhibitor. AB - Amyloid formation has been implicated in the pathology of over 20 human diseases, but the rational design of amyloid inhibitors is hampered by a lack of structural information about amyloid-inhibitor complexes. We use isotope labelling and two dimensional infrared spectroscopy to obtain a residue-specific structure for the complex of human amylin (the peptide responsible for islet amyloid formation in type 2 diabetes) with a known inhibitor (rat amylin). Based on its sequence, rat amylin should block formation of the C-terminal beta-sheet, but at 8 h after mixing, rat amylin blocks the N-terminal beta-sheet instead. At 24 h after mixing, rat amylin blocks neither beta-sheet and forms its own beta-sheet, most probably on the outside of the human fibrils. This is striking, because rat amylin is natively disordered and not previously known to form amyloid beta sheets. The results show that even seemingly intuitive inhibitors may function by unforeseen and complex structural processes. PMID- 22522255 TI - A stable germanone as the first isolated heavy ketone with a terminal oxygen atom. AB - The carbon-oxygen double bond of ketones (R(2)C=O) makes them among the most important organic compounds, but their homologues, heavy ketones with an E=O double bond (E = Si, Ge, Sn or Pb), had not been isolated as stable compounds. Their unavailability as monomeric molecules is ascribed to their high tendency for intermolecular oligomerization or polymerization via opening of the E=O double bond. Can such an intermolecular process be inhibited by bulky protecting groups? We now report that it can, with the first isolation of a monomeric germanium ketone analogue (Eind)(2)Ge=O (Eind = 1,1,3,3,5,5,7,7-octaethyl-s hydrindacen-4-yl), stabilized by appropriately designed bulky Eind groups, with a planar tricoordinate germanium atom. Computational studies and chemical reactions suggest the Ge=O double bond is highly polarized with a contribution of a charge separated form (Eind)(2)Ge(+)-O(-). The germanone thus exhibits unique reactivities that are not observed with ordinary ketones, including the spontaneous trapping of CO(2) gas to provide a cyclic addition product. PMID- 22522256 TI - Multidimensional steric parameters in the analysis of asymmetric catalytic reactions. AB - Although asymmetric catalysis is universally dependent on spatial interactions to impart specific chirality on a given substrate, examination of steric effects in these catalytic systems remains empirical. Previous efforts by our group and others have seen correlation between steric parameters developed by Charton and simple substituents in both substrate and ligand; however, more complex substituents were not found to be correlative. Here, we review and compare the steric parameters common in quantitative structure activity relationships (QSAR), a common method for pharmaceutical function optimization, and how they might be applied in asymmetric catalysis, as the two fields are undeniably similar. We re evaluate steric/enantioselection relationships, which we previously analysed with Charton steric parameters, using the more sophisticated Sterimol parameters developed by Verloop and co-workers in a QSAR context. Use of these Sterimol parameters led to strong correlations in numerous processes where Charton parameters had previously failed. Sterimol parameterization also allows for greater mechanistic insight into the key elements of asymmetric induction within these systems. PMID- 22522257 TI - Metal-directed, chemically tunable assembly of one-, two- and three-dimensional crystalline protein arrays. AB - Proteins represent the most sophisticated building blocks available to an organism and to the laboratory chemist. Yet, in contrast to nearly all other types of molecular building blocks, the designed self-assembly of proteins has largely been inaccessible because of the chemical and structural heterogeneity of protein surfaces. To circumvent the challenge of programming extensive non covalent interactions to control protein self-assembly, we have previously exploited the directionality and strength of metal coordination interactions to guide the formation of closed, homoligomeric protein assemblies. Here, we extend this strategy to the generation of periodic protein arrays. We show that a monomeric protein with properly oriented coordination motifs on its surface can arrange, on metal binding, into one-dimensional nanotubes and two- or three dimensional crystalline arrays with dimensions that collectively span nearly the entire nano- and micrometre scale. The assembly of these arrays is tuned predictably by external stimuli, such as metal concentration and pH. PMID- 22522258 TI - Reversible hydrogen storage using CO2 and a proton-switchable iridium catalyst in aqueous media under mild temperatures and pressures. AB - Green plants convert CO(2) to sugar for energy storage via photosynthesis. We report a novel catalyst that uses CO(2) and hydrogen to store energy in formic acid. Using a homogeneous iridium catalyst with a proton-responsive ligand, we show the first reversible and recyclable hydrogen storage system that operates under mild conditions using CO(2), formate and formic acid. This system is energy efficient and green because it operates near ambient conditions, uses water as a solvent, produces high-pressure CO-free hydrogen, and uses pH to control hydrogen production or consumption. The extraordinary and switchable catalytic activity is attributed to the multifunctional ligand, which acts as a proton-relay and strong pi-donor, and is rationalized by theoretical and experimental studies. PMID- 22522259 TI - Elucidation of the timescales and origins of quantum electronic coherence in LHCII. AB - Photosynthetic organisms harvest sunlight with near unity quantum efficiency. The complexity of the electronic structure and energy transfer pathways within networks of photosynthetic pigment-protein complexes often obscures the mechanisms behind the efficient light-absorption-to-charge conversion process. Recent experiments, particularly using two-dimensional spectroscopy, have detected long-lived quantum coherence, which theory suggests may contribute to the effectiveness of photosynthetic energy transfer. Here, we present a new, direct method to access coherence signals: a coherence-specific polarization sequence, which isolates the excitonic coherence features from the population signals that usually dominate two-dimensional spectra. With this polarization sequence, we elucidate coherent dynamics and determine the overall measurable lifetime of excitonic coherence in the major light-harvesting complex of photosystem II. Coherence decays on two distinct timescales of 47 fs and ~800 fs. We present theoretical calculations to show that these two timescales are from weakly and moderately strongly coupled pigments, respectively. PMID- 22522260 TI - Electronic coherence lineshapes reveal hidden excitonic correlations in photosynthetic light harvesting. AB - The effective absorption cross-section of a molecule (acceptor) can be greatly increased by associating it with a cluster of molecules that absorb light and transfer the excitation energy to the acceptor molecule. The basic mechanism of such light harvesting by Forster resonance energy transfer (FRET) is well established, but recent experiments have revealed a new feature whereby excitation is coherently shared among donor and acceptor molecules during FRET. In the present study, two-dimensional electronic spectroscopy was used to examine energy transfer at ambient temperature in a naturally occurring light-harvesting protein (PE545 of the marine cryptophyte alga Rhodomonas sp. strain CS24). Quantum beating was observed across a range of excitation frequencies. The shapes of those features in the two-dimensional spectra were examined. Through simulations, we show that two-dimensional electronic spectroscopy provides a probe of the adiabaticity of the free energy landscape underlying light harvesting. PMID- 22522261 TI - A gold-catalysed enantioselective Cope rearrangement of achiral 1,5-dienes. AB - Since the discovery of the Cope rearrangement in the 1940s, no asymmetric variant of the rearrangement of achiral 1,5-dienes has emerged, despite the successes that have been achieved with its heteroatom variants (Claisen, aza-Cope, and so on). This article reports the first example of an enantioselective Cope reaction that starts from an achiral diene. The new gold(I) catalyst derived from double Cl(-)-abstraction of ((S)-3,5-xylyl-PHANEPHOS(AuCl)(2)), has been developed for the sigmatropic rearrangement of alkenyl-methylenecyclopropanes. The reaction proceeds at low temperature and the synthetically useful vinylcyclopropane products are obtained in high yield and enantioselectivity. Density functional theory calculations predict that: (1) the reaction proceeds via a cyclic carbenium ion intermediate, (2) the relief of strain in the methylenecyclopropane moiety provides the thermodynamic driving force for the rearrangement and (3) metal complexation of the transition-state structure lowers the rearrangement barriers. PMID- 22522262 TI - Protein fold determined by paramagnetic magic-angle spinning solid-state NMR spectroscopy. AB - Biomacromolecules that are challenging for the usual structural techniques can be studied with atomic resolution by solid-state NMR spectroscopy. However, the paucity of distance restraints >5 A, traditionally derived from measurements of magnetic dipole-dipole couplings between protein nuclei, is a major bottleneck that hampers such structure elucidation efforts. Here, we describe a general approach that enables the rapid determination of global protein fold in the solid phase via measurements of nuclear paramagnetic relaxation enhancements (PREs) in several analogues of the protein of interest containing covalently attached paramagnetic tags, without the use of conventional internuclear distance restraints. The method is demonstrated using six cysteine-EDTA-Cu(2+) mutants of the 56-residue B1 immunoglobulin-binding domain of protein G, for which ~230 longitudinal backbone (15)N PREs corresponding to distances of ~10-20 A were obtained. The mean protein fold determined in this manner agrees with the X-ray structure with a backbone atom root-mean-square deviation of 1.8 A. PMID- 22522265 TI - The four worlds of carbon. PMID- 22522263 TI - A molecular ruthenium catalyst with water-oxidation activity comparable to that of photosystem II. AB - Across chemical disciplines, an interest in developing artificial water splitting to O(2) and H(2), driven by sunlight, has been motivated by the need for practical and environmentally friendly power generation without the consumption of fossil fuels. The central issue in light-driven water splitting is the efficiency of the water oxidation, which in the best-known catalysts falls short of the desired level by approximately two orders of magnitude. Here, we show that it is possible to close that 'two orders of magnitude' gap with a rationally designed molecular catalyst [Ru(bda)(isoq)(2)] (H(2)bda = 2,2'-bipyridine-6,6' dicarboxylic acid; isoq = isoquinoline). This speeds up the water oxidation to an unprecedentedly high reaction rate with a turnover frequency of >300 s(-1). This value is, for the first time, moderately comparable with the reaction rate of 100 400 s(-1) of the oxygen-evolving complex of photosystem II in vivo. PMID- 22522266 TI - Detecting and treating prostate cancer: a surgeon's perspective. PMID- 22522267 TI - Great expectations: use of molecular tests and computerised prognostic tools in New Zealand cancer care. AB - BACKGROUND: Use of molecular tests and computerised prognostic tools designed to individualise cancer care appears to be rapidly increasing in New Zealand. These tests have important clinical and health economic implications, but their impact on cancer care has not been fully assessed. AIM: To determine cancer clinicians' use of and expectations for molecular tests and computerised prognostic tools. METHOD: Online survey of clinicians managing cancer in New Zealand. RESULTS: 137 clinicians participated, 31% used molecular tests and 57% used computerised prognostic tools. These technologies affected clinical decisions made by a quarter of participants. Over 85% of participants believed that the impact of molecular tests and computerised prognostic tools would increase over the next decade and that a stronger evidence base would support their use. CONCLUSIONS: Molecular tests and computerised prognostic tools already influence treatment provided to many New Zealand cancer patients. Clinicians who participated in this survey overwhelmingly expect the use of these tests to increase, which has important clinical implications since there is little high quality prospective data assessing the ability of these tests to improve patient outcomes. Expanded use of these often-expensive tests also has economic implications. The role of these technologies needs to be considered in the context of a wide-ranging cancer control strategy. PMID- 22522268 TI - Clinical trials in New Zealand--an update. AB - AIMS: To describe clinical trial activity in New Zealand for the period 2005-2009 and estimate the number of trials that were listed on World Health Organization compliant trials registers. METHODS: Clinical trials were identified from the annual reports (2005-2009) of the six Health and Disability Ethics Committees. To be included, trials must have been referred to as phase I, II, III or IV trials; or included key descriptors in the title; or have been known to the authors as randomised controlled trials. Key trial characteristics were obtained from searching trials registers or through contact with the investigators. RESULTS: 900 clinical trials were approved in the period 2005-2009 (average 180 per year). The Multi Region ethics committee received most of the applications (379, 42%) followed by the Northern X (190, 21%) and Northern Y (151, 17%). 621 (69%) trials were late phase trials (average 124 per year) and 279 (31%) were early phase trials (average 56 per year). Most trials involved a drug (651, 72%). Trials that recruited infants, children or adolescents accounted for just 68 trials (8%). The most frequent conditions targeted were cancer (163, 18%), cardiovascular disease (125, 14%) and respiratory disease (83, 9%). 532 (59%) trials were commercially sponsored and 335 (37%) were non-commercial. Merck Sharp and Dohme were the single most frequent commercial sponsor (50, 9% of commercial trials) and the Health Research Council the single most frequent non-commercial sponsor (70, 21% of non-commercial trials). 758 (84%) trials could be identified as being listed on a WHO-compliant trials registry. Non-commercially sponsored trials had lower rates of registration (278, 83%) than commercially sponsored trials (480, 90%). CONCLUSIONS: Clinical trial activity in New Zealand has increased compared with the period 1998-2003 and early phase activity accounted for most of the increase. There has been a dramatic rise in trials registration and the commercial sector has been more compliant with the International Committee of Medical Journal Editors' statement on trials registration than the non-commercial sector. PMID- 22522269 TI - Short and long term outcomes of oesophagectomy in a provincial New Zealand hospital. AB - BACKGROUND: Oesophagectomy is a complex procedure associated with a significant morbidity and mortality rate. There is very little published data from New Zealand, with no published data from a non-Tertiary New Zealand hospital. We aimed to evaluate the outcomes of oesophagectomy at a single provincial hospital in New Zealand. METHOD: Retrospective review of clinical records of all patients who underwent oesophagectomy at Palmerston North Hospital (a level II provincial New Zealand public hospital) between 1993 and 2010 was performed. Demographic data, operative details, postoperative recovery parameters, survival data, pathological data, and details of adjuvant treatment were collected. RESULTS: Data from all 68 patients who underwent oesophagectomy were included. Mean age was 63.6 plus or minus 10.9 years, and 69% of patients were male. Mean operating time was 438.37 plus or minus 101.8 min, and mean intraoperative blood loss was 934.5 plus or minus 790.2 ml. Median intensive care unit stay was 7 (1-29) days, and total day stay was 17.5 (4-60) days. Tracheostomy was performed in 20 patients (29.4%). Anastomotic leak occurred in 7 patients (10.3%), chylothorax in 6 patients (8.8%) and cardiopulmonary complications in 34 patients (50.0%). The all cause in-hospital mortality rate was 4.4%. Overall survival at 30 days was 98.5%, at 1 year was 78.3% and at 5 years was 30.3%. CONCLUSION: Survival outcomes of oesophagectomy in this provincial New Zealand hospital are comparable to published series from national and international tertiary centres. PMID- 22522270 TI - Arcobacter species in diarrhoeal faeces from humans in New Zealand. AB - AIM: To determine the prevalence, genetic diversity and antimicrobial susceptibility of Arcobacter spp in faecal samples from humans with diarrhoea in New Zealand. METHODS: An enrichment method was used to isolate Arcobacter spp from diarrhoeal human faeces submitted to a community laboratory in Hawke's Bay. The identity of isolates was confirmed by PCR and their diversity was determined by pulsed field gel electrophoresis (PFGE). Antibiotic susceptibility was established with E test strips. RESULTS: Arcobacter spp were isolated from 12 of 1380 diarrhoeal faecal samples examined (0.9%), including 7 A. butzleri and 5 A. cryaerophilus. Additional enteric pathogens were detected in four of these diarrhoeal faecal samples. All the Arcobacter isolates were genetically distinct and susceptible to ciprofloxacin. Most were also susceptible to erythromycin (92%) but fewer to tetracycline (67%) and ampicillin(50%). CONCLUSION: A. butzleri and A. cryaerophilus cause a small proportion of cases of diarrhoea in humans resident in New Zealand. PMID- 22522271 TI - Is late-night salivary cortisol a better screening test for possible cortisol excess than standard screening tests in obese patients with Type 2 diabetes? AB - AIM: To compare the performance, in terms of specificity for cortisol excess, of late-night salivary cortisol with 24-hour urine-free cortisol (24hr UFC) and overnight 1mg dexamethasone suppression test (1mg DST) in a group of obese T2DM patients. METHODS: Forty obese patients with T2DM without clinical features of Cushing's syndrome were recruited. Plasma, urinary and salivary cortisol were measured directly by an enzyme-linked immunosorbent assay using monoclonal antibodies. The specificities of the three tests using various cutoffs were calculated and compared, employing the assumption that none of the patients had hypercortisolism. RESULTS: The patients had a mean age and BMI of 56 years (range 31-75) and 37 kg/m2 (31-56) respectively. All 40 provided late-night salivary cortisol samples. Thirty-eight patients completed all three tests. Two patients only completed two screening tests. The specificities of late-night salivary cortisol (cutoff 10 nmol/L), 24hr UFC (400 nmol) and 1mg DST (50 nmol/L) were 70% (95% CI 53-83%), 90% (76-97%) and 72% (55-85%) respectively. The specificity of late-night salivary cortisol was significantly less than 24 hr UFC (P=0.039) but not 1mg DST (P>0.99). CONCLUSION: Late-night salivary cortisol has a poor specificity for cortisol excess in obese patients with T2DM with 24 hr UFC showing significantly better specificity in our population. PMID- 22522272 TI - Beyond PSA: are new prostate cancer biomarkers of potential value to New Zealand doctors? AB - The widespread introduction of prostate-specific antigen (PSA) screening has enhanced the early detection of prostate cancer within New Zealand. However, uncertainties associated with the test make it difficult to confidently differentiate low-risk patients from those that require a definitive diagnostic biopsy. In consequence, the decisions surrounding prostate cancer treatment become extremely difficult. A number of new tests have become available which might have the potential to complement the current PSA screens. We review a number of the best validated of these which provide data that, although currently not available in clinical practice, some of these might have considerable potential to aid diagnosis, prognosis and therapeutic decisions for men with prostate cancer in New Zealand. PMID- 22522273 TI - Reporting of adverse effects in randomised clinical trials of chiropractic manipulations: a systematic review. AB - OBJECTIVE: To systematically review the reporting of adverse effects in clinical trials of chiropractic manipulation. DATA SOURCES: Six databases were searched from 2000 to July 2011. Randomised clinical trials (RCTs) were considered, if they tested chiropractic manipulations against any control intervention in human patients suffering from any type of clinical condition. The selection of studies, data extraction, and validation were performed independently by two reviewers. RESULTS: Sixty RCTs had been published. Twenty-nine RCTs did not mention adverse effects at all. Sixteen RCTs reported that no adverse effects had occurred. Complete information on incidence, severity, duration, frequency and method of reporting of adverse effects was included in only one RCT. Conflicts of interests were not mentioned by the majority of authors. CONCLUSIONS: Adverse effects are poorly reported in recent RCTs of chiropractic manipulations. PMID- 22522274 TI - Hepatocellular carcinoma during pregnancy: case report and review of the literature. AB - Hepatocellular carcinoma (HCC) during pregnancy is very rare with poor prognosis. We report a case of a HCC in a 33-year-old, pregnant female with an otherwise normal liver and no risk factors, diagnosed by routine prenatal ultrasound scan and elevated alpha-feto protein levels. She underwent a synchronous caesarean section and liver resection at 30 weeks of gestation with good perioperative outcome and no recurrent disease at 1-year follow-up. This case report discusses the clinical presentations, diagnostic and therapeutic strategies and literature review of this rare presentation. PMID- 22522275 TI - "Valve in valve" percutaneous aortic valve implantation for severe mixed bioprosthetic aortic valve disease. AB - Transcatheter aortic valve implantation (TAVI) is an effective treatment for patients with severe aortic stenosis at high risk for surgical valve replacement. We present a case of successful, off-label transfemoral valve-in-valve implantation of the self-expandable Medtronic-CoreValve prosthesis in an inoperable elderly patient with structural deterioration of an existing bioprosthesis in the aortic position. This case illustrates that TAVI for a deteriorated aortic bioprosthesis is feasible in a patient who was not suitable for reoperation. PMID- 22522276 TI - Medical image. Septic cavernous sinus thrombosis. PMID- 22522277 TI - Medical image. Septicaemia with acute renal failure. PMID- 22522278 TI - Comparing Finland with New Zealand: lessons from Finland for controlling infectious diseases. PMID- 22522279 TI - Crimes Amendment Act (3) 2011. PMID- 22522281 TI - Consensus statement from the Health of the Health Professional Conference, November 2011. AB - This article presents a consensus statement that arose from the views of participants that attended the multidisciplinary conference "The Health of the Health Professional", in Auckland in November 2011. A healthy workforce is the key to improving the health of all New Zealanders. Yet health practitioners' health is of concern, and despite the evidence of real problems little has been done to constructively and systematically address these issues. This consensus statement provides some potential ways to move forward. PMID- 22522280 TI - Chronic arthropathy management in haemophilia: assessing the impact of a new model of care. PMID- 22522282 TI - Pubertal development predicts eating behaviors in adolescence. AB - OBJECTIVE: Early maturing girls are at increased risk for disordered eating. However, it is unclear if the association between puberty and disordered eating continues throughout pubertal development and if a similar association is exhibited in boys. METHOD: Participants included 1340 same- and 624 opposite-sex twins from the Swedish Twin Study of Child and Adolescent Development. Pubertal development was assessed at age 13-14 with the pubertal development scale. General disordered eating, measured with the eating disorder inventory-2 (EDI) was assessed at age 16-17, and dieting and purging behaviors were assessed at both ages 16-17 and 19-20. We applied analysis of variance and logistic regression analyses to determine whether pubertal development in early-to-mid adolescence predicted eating disorder-related behaviors in late adolescence and young adulthood. RESULTS: Pubertal development in early-to-mid adolescence was significantly associated with EDI scores and dieting in late adolescence. No significant association was observed between pubertal development and dieting and purging in young adulthood. DISCUSSION: Complex combinations of cultural and biological influences likely converge during pubertal development increasing vulnerability to disordered eating. The impact of pubertal development on disordered eating appears to be limited to the adolescent period. PMID- 22522283 TI - Design, characterisation and in vivo testing of a new, adjustable stiffness, external fixator for the rat femur. AB - Very little is known about the influence of the mechanical environment on the healing of large segmental defects. This partly reflects the lack of standardised, well characterised technologies to enable such studies. Here we report the design, construction and characterisation of a novel external fixator for use in conjunction with rat femoral defects. This device not only imposes a predetermined axial stiffness on the lesion, but also enables the stiffness to be changed during the healing process. The main frame of the fixator consists of polyethylethylketone with titanium alloy mounting pins. The stiffness of the fixator is determined by interchangeable connection elements of different thicknesses. Fixators were shown to stabilise 5 mm femoral defects in rats in vivo for at least 8 weeks during unrestricted cage activity. No distortion or infections, including pin infections, were noted. The healing process was simulated in vitro by inserting into a 5 mm femoral defect, materials whose Young's moduli approximated those of the different tissues present in regenerating bone. These studies confirmed that, although the external fixator is the major determinant of axial stiffness during the early phase of healing, the regenerate within the lesion subsequently dominates this property. There is much clinical interest in altering the mechanics of the defect to enhance bone healing. Our data suggest that, if alteration of the mechanical environment is to be used to modulate the healing of large segmental defects, this needs to be performed before the tissue properties become dominant. PMID- 22522284 TI - Identification of trabecular excrescences, novel microanatomical structures, present in bone in osteoarthropathies. AB - It is widely held that bone architecture is finely regulated in accordance with homeostatic requirements. Aberrant remodelling (hyperdensification and/or cyst formation in the immediately subchondral region) has previously been described in bone underlying cartilage in arthropathies. The present study examined the trabecular architecture of samples of bone, initially in the severe osteoarthropathy of alkaptonuria, but subsequently in osteoarthritis using a combination of light microscopy, 3D scanning electron microscopy and quantitative backscattered electron scanning electron microscopy. We report an extraordinary and previously unrecognised bone phenotype in both disorders, including novel microanatomical structures. The underlying subchondral trabecular bone contained idiosyncratic architecture. Trabecular surfaces had numerous outgrowths that we have termed "trabecular excrescences", of which three distinct types were recognised. The first type arose from incomplete resorption of branching secondary trabeculae arising from the deposition of immature (woven) bone in prior marrow space. These were characterised by very deeply scalloped surfaces and rugged edges. The second type had arisen in a similar way but been smoothed over by new bone deposition. The third type, which resembled coarse stucco, probably arises from resting surfaces that had been focally reactivated. These were poorly integrated with the prior trabecular wall. We propose that these distinctive microanatomical structures are indicative of abnormal osteoclast/osteoblast modelling in osteoarthropathies, possibly secondary to altered mechanical loading or other aberrant signalling. Identification of the mechanisms underlying the formation of trabecular excrescences will contribute to a better understanding of the role of aberrant bone remodelling in arthropathies and development of new therapeutic strategies. PMID- 22522285 TI - Strategies for improved targeting of therapeutic cells: implications for tissue repair. AB - Multipotent mesenchymal stem cells (MSCs) have been suggested as a suitable cell source for cell-based treatments for diseases such as osteoarthritis due to their ability to differentiate towards chondrogenic and osteogenic lineages. MSCs can be obtained from a variety of tissue sources, are scalable for mass-production and immuno-privileged enabling their use for allogeneic cell therapy. However, recent pre-clinical studies and clinical trials point to the necessity of increasing engraftment and efficacy of MSCs. This review explores how cell surface modification of the cells can improve homing of MSCs and summarises the use of nanoparticles to enable gene delivery by stem cells as well as facilitate in vivo imaging. The use of advanced biomaterials and how they can be applied to reduce the overall dose of MSCs during therapeutic interventions while achieving optimal targeting efficiency of cells to the diseased sites are addressed. Particular attention is paid to methods that improve engraftment of MSCs to cartilage and research describing combinatorial approaches of particle-based cell therapies for improved regeneration of this tissue is reviewed. The use of such approaches will add to the array of potential regenerative therapeutics for treatment of osteoarthritis. PMID- 22522286 TI - Immune gene expression in trout cell lines infected with the fish pathogenic oomycete Saprolegnia parasitica. AB - The oomycete Saprolegnia parasitica causes significant losses in the aquaculture industry, mainly affecting salmon, trout and catfish. Since the ban of malachite green, effective control measures are currently not available prompting a re evaluation of the potential for immunological intervention. In this study, the immune response of salmonid cells is investigated at the transcript level, by analysis of a large set of immune response genes in four different rainbow trout cell lines (RTG-2, RTGill, RTL and RTS11) upon infection with S. parasitica. Proinflammatory cytokine transcripts were induced in all four cell lines, including IL-1beta1, IL-8, IL-11, TNF-alpha2, as well as other components of the innate defences, including COX-2, the acute phase protein serum amyloid A and C type lectin CD209a and CD209b. However, differences between the four cell lines were found. For example, the fold change of induction was much higher in the epithelial RTL and macrophage-like RTS11 cell lines compared to the fibroblast cell lines RTG-2 and RTGill. Several antimicrobial peptides (AMPs) were also up regulated in response to Saprolegnia infection, including hepcidin and cathelicidin 1 (rtCATH1) and 2 (rtCATH2). An rtCATH2 peptide was synthesised and tested for activity and whilst it showed no killing activity for zoospores, it was able to delay sporulation of S. parasitica. These results demonstrate that particular immune genes are up-regulated in response to S. parasitica infection and that AMPs may play a crucial role in the first line of defence against oomycetes in fish. PMID- 22522287 TI - A computer-aided diagnosis approach for emphysema recognition in chest radiography. AB - The purpose of this work is twofold: (i) to develop a CAD system for the assessment of emphysema by digital chest radiography and (ii) to test it against CT imaging. The system is based on the analysis of the shape of lung silhouette as imaged in standard chest examination. Postero-anterior and lateral views are processed to extract the contours of the lung fields automatically. Subsequently, the shape of lung silhouettes is described by polyline approximation and the computed feature-set processed by a neural network to estimate the probability of emphysema. Images of radiographic studies from 225 patients were collected and properly annotated to build an experimental dataset named EMPH. Each patient had undergone a standard two-views chest radiography and CT for diagnostic purposes. In addition, the images (247) from JSRT dataset were used to evaluate lung segmentation in postero-anterior view. System performances were assessed by: (i) analyzing the quality of the automatic segmentation of the lung silhouette against manual tracing and (ii) measuring the capabilities of emphysema recognition. As to step i, on JSRT dataset, we obtained overlap percentage (Omega) 92.7+/-3.3%, Dice Similarity Coefficient (DSC) 95.5+/-3.7% and average contour distance (ACD) 1.73+/-0.87 mm. On EMPH dataset we had Omega=93.1+/-2.9%, DSC=96.1+/-3.5% and ACD=1.62+/-0.92 mm, for the postero-anterior view, while we had Omega=94.5+/-4.6%, DSC=91.0+/-6.3% and ACD=2.22+/-0.86 mm, for the lateral view. As to step ii, accuracy of emphysema recognition was 95.4%, with sensitivity and specificity 94.5% and 96.1% respectively. According to experimental results our system allows reliable and inexpensive recognition of emphysema on digital chest radiography. PMID- 22522288 TI - Medial-frontal cortex hypometabolism in chronic phencyclidine exposed rats assessed by high resolution magic angle spin 11.7 T proton magnetic resonance spectroscopy. AB - BACKGROUND: Proton magnetic resonance spectroscopy ((1)H-MRS) clinical studies of patients with schizophrenia document prefrontal N-acetylaspartate (NAA) reductions, suggesting an effect of the disease or of antipsychotic medications. We studied in the rat the effect of prolonged exposure to a low-dose of the NMDA glutamate receptor antagonist phencyclidine (PCP) on levels of NAA, glutamate and glutamine in several brain regions where metabolite reductions have been reported in chronically medicated patients with schizophrenia. METHODS: Two groups of ten rats each were treated with PCP (2.58 mg/kg/day) or vehicle and were sacrificed after 1 month treatment. Concentrations of neurochemicals were determined with high resolution magic angle (HR-MAS) (1)H-MRS at 11.7 T in ex vivo punch biopsies from the medial frontal and cingulate cortex, striatum, nucleus accumbens, amygdala and ventral hippocampus. RESULTS: PCP treatment reduced NAA, glutamate, glycine, aspartate, creatine, lactate and GABA in medial frontal cortex. In the nucleus accumbens, PCP reduced levels of NAA, aspartate and glycine; similarly aspartate and glycine were reduced in the striatum. Finally the amygdala and hippocampus had elevations in glutamine and choline, respectively. CONCLUSIONS: Low-dose PCP in rats models prefrontal NAA and glutamate reductions documented in chronically-ill schizophrenia patients. Chronic glutamate NMDA receptor blockade in rats replicates an endophenotype in schizophrenia and may contribute to the prefrontal hypometabolic state in schizophrenia. PMID- 22522289 TI - Factors associated with cerebrospinal fluid HIV RNA in HIV infected subjects undergoing lumbar puncture examination in a clinical setting. AB - BACKGROUND: Cerebrospinal fluid (CSF) HIV RNA load may be associated with central nervous system (CNS) disease in HIV infected subjects. We investigated parameters associated with CSF HIV RNA within a large clinical cohort. METHODS: All HIV infected subjects undergoing CSF examination including assessment of CSF HIV RNA at St. Mary's Hospital, London, UK between January 2008 and October 2010 were included. Parameters associated with a detectable CSF HIV RNA load were assessed using linear regression modelling. CSF viral escape was defined as CSF RNA >0.5 log(10) copies/mL greater than plasma HIV RNA and >200 copies/mL where plasma HIV RNA <50 copies/mL. RESULTS: Of 142 subjects, 99 were receiving antiretroviral therapy (ART). Plasma HIV RNA was <50 copies/mL in 69 subjects. CSF examination was performed for investigation of presumed HIV encephalopathy (IxHE, n = 57), other CNS diseases considered HIV related (n = 39), syphilis (n = 20) and CNS presentations not considered HIV related (n = 26). CSF viral escape was present in 30/142 (21%) subjects overall and in 9/69 (13%) of those on ART with undetectable plasma HIV RNA. Overall, plasma HIV RNA load was significantly associated with detectable CSF HIV RNA (p <= 0.001). In subjects with plasma HIV RNA <50 copies/mL, only CNS penetration effectiveness (CPE, 2008) score of <2 was significantly associated with detectable CSF HIV RNA (p = 0.044). In patients undergoing LP for IxHE both plasma HIV RNA and CPE scores were independently associated with detectable CSF HIV RNA (p = 0.019 & 0.003 respectively) which was not observed in subjects undergoing CSF examination for other medical reasons. CONCLUSIONS: In a clinical setting, CSF viral escape is observed frequently in 21% of subjects and is associated with different parameters depending on the clinical scenario. PMID- 22522290 TI - The impact of A(H1N1)pdm09 infection on renal transplant recipients: a multicenter cohort study. PMID- 22522291 TI - Rapid diagnosis of influenza: an evaluation of two commercially available RT-PCR assays. AB - OBJECTIVE: To evaluate the sensitivity and specificity of influenza virus detection by two commercial reverse transcriptase PCR methods compared with a reference real-time PCR. METHODS: 122 clinical specimens were tested on Xpert((r)) Flu and RealStar((r)) Influenza Screen & Type. A reference real-time RT-PCR, at a specialist laboratory was chosen as the gold standard for comparison. RESULTS: RealStar((r)) Influenza Screen & Type had higher sensitivity for influenza A and influenza B respectively (92.3% and 88.2%) when compared to Xpert((r)) Flu (78.8% and 76.5%). Both tests had excellent specificity. CONCLUSIONS: The simplicity and speed of the Xpert((r)) Flu system could allow it to be used in the near-patient setting; however in circumstances where excluding a diagnosis of influenza may be critical, negative specimens may need to be repeated using a more sensitive assay. PMID- 22522293 TI - A rapid biosynthesis route for the preparation of gold nanoparticles by aqueous extract of cypress leaves at room temperature. AB - In the present study, green synthesis of gold nanoparticles was reported using the aqueous extract of cypress leaves. The reduction of gold salt with the extract of cypress leaves resulted in the formation of gold nanoparticles. Effects of extract concentration and extract pH were investigated on the size of the nanoparticles. It was found that the average particle size of synthesized gold nanoparticles depends strongly on extract concentration and extract pH. FT IR spectroscopy showed that bioorganic capping molecules were bound to the surface of particles. X-ray techniques confirmed the formation of gold nanoparticles and their crystalline structure. The inductively coupled plasma atomic emission spectroscopy analysis displayed that the reaction progress is higher than 90% at room temperature. Gold nanoparticles were mostly spherical in shape along with some irregular shapes. Cypress is an evergreen plant and its leaves are easily available in all four seasons. Also, the rate of the reaction was high and it was completed in only 10min. For these reasons, this method is cost-effective and environmentally friendly. Thus, it can be used in the synthesis of gold nanoparticles instead of chemical methods and other biosynthesis approaches. PMID- 22522292 TI - Long-term chikungunya infection clinical manifestations after an outbreak in Italy: a prognostic cohort study. AB - OBJECTIVES: Following a Chikungunya (CHIKV) outbreak in Italy, a cohort study was conducted to describe the infection long-term clinical course and outcome. METHODS: Persons identified through active and passive surveillance as confirmed or possible CHIKV cases during the outbreak were enrolled and interviewed by trained public health nurses, between 4-5 and 12-13 months following the acute stage. Patients reporting persistent clinical symptoms were evaluated by rheumatologists. Serum samples were obtained and anti-CHIKV specific IgG and IgM immune responses detected. Only confirmed cases who completed the follow-up were analysed. RESULTS: Out of 250 patients, 66.5% still reported myalgia, asthenia or arthralgia (most frequent sign) after 12 months. Functional ability, measured by the ROAD index, was more impaired for lower extremities (3.75; Inter Quartile Range - IQR 4.4), and the activities of daily living (average 4.2; IQR 5). Variables independently associated with the presence of joint pain at 12-13 months were increasing age, and history of rheumatologic diseases). Elderly, females, and persons with history of rheumatologic diseases had higher anti-CHIKV IgG titres at 12-13 months. CONCLUSIONS: This study confirms, in an unselected population, that the long-lasting burden of CHIKV infection is significant. PMID- 22522294 TI - Fluorescence characteristics of 5-amino salicylic acid: An iodide recognition study. AB - In this paper we report the effect of iodide on the fluorescence of 5-amino salicylic acid (5-ASA). In the absence of iodide, prominent blue green (BG) emission band at ~465nm (broad) is observed in aprotic solvents whereas violet (V) emission at ~408nm, blue green (BG) at ~480nm and green (G) at ~500nm are observed in case of protic solvents. On the addition of iodide ion (I(-)), the intensity of BG fluorescence is enhanced in case of aprotic solvents. On the other hand the G band is enhanced in protic solvents and decrease in the intensity of the V band is observed. The effect of hydrogen bonding as well as the interplay of neutral and ionic species is invoked to explain the observed results. The study projects the application of this system in iodide recognition in protic/aprotic environments. PMID- 22522295 TI - Synthesis, FT-IR, FT-Raman, dispersive Raman and NMR spectroscopic study of a host molecule which potential applications in sensor devices. AB - The solid phase FT-IR, FT-Raman and dispersive Raman spectra of the host molecule which potential applications in sensor devices have been recorded in the region 400-4000 and 50-3500cm(-1), respectively. The spectra were interpreted in terms of fundamentals modes, combination and overtone bands. The structure of the molecule was optimized and the structural characteristics were determined by density functional theory (DFT) using B3LYP method with 6-31G(d) basis set. The vibrational frequencies were calculated for the studied molecule by DFT method, and compared with the experimental frequencies, which yield good agreement between observed and calculated frequencies. Finally the calculation results were applied to simulate infrared and Raman spectra of the compound. Obtained these spectra also showed good agreement with observed spectra. The dipole moment, linear polarizability and first hyperpolarizability values were also computed. The linear polarizability and first hyperpolarizability of the studied molecule indicate that the compound is a good candidate of nonlinear optical materials. PMID- 22522296 TI - Synthesis, characterization and biological activity of transition metal complexes with Schiff bases derived from 2-nitrobenzaldehyde with glycine and methionine. AB - Schiff bases derived from 2-nitrobenzaldehyde with amino acids (glycine, methionine) and their Co(II), Ni(II) and Cu(II) complexes have been synthesized and characterized by various physico-chemical techniques. From spectral studies, it has been concluded that the ligands acts as bidentate molecule, coordinates metal through azomethine nitrogen and carboxylate oxygen. Mass spectrum explains the successive degradation of the molecular species in solution and justifies ML(2) complexes. X-ray powder diffraction helps to determine the cell parameters of the complexes. Molecular structure of the complexes has been optimized by MM2 calculations and suggests a square planar geometry. The ligands and their metal complexes have been tested in vitro against Streptococcus, Staph, Staphylococcus aureus and Escherchia coli bacteria in order to assess their antibacterial potential. The results indicate that the biological activity increases on complexation. PMID- 22522297 TI - Studies on synthesis, characterization, DNA interaction and cytotoxicity of ruthenium(II) Schiff base complexes. AB - The synthesis and characterization of three hexa-coordinated ruthenium(II) Schiff base complexes of the type [RuCl(CO)(B)L] (B=PPh(3)/AsPh(3)/py and L=monobasic tridentate Schiff base ligand derived by the condensation of salicylaldehyde with 4-aminoantipyrine) are reported. IR, electronic, NMR and mass spectral data of the complexes are discussed. An octahedral geometry has been tentatively proposed for all the complexes. DNA binding properties of the ligand and its ruthenium(II) complexes have been investigated by electronic absorption spectroscopy. Two of the complexes were tested for DNA cleavage property. Finally, in vitro study of the cytotoxicity of the ligand and the complex [RuCl(CO)(PPh(3))L] on HeLa were tested. The IC(50) value for the ligand and the complex were 52.3 and 31.6MUm respectively. PMID- 22522298 TI - Two tridentate Schiff base ligands and their mononuclear cobalt (III) complexes: Synthesis, characterization, antibacterial and antifungal activities. AB - Two Schiff base ligands (HL1, HL2) and their Co(III) complexes, [Co(HL1)(L1)] (1) and [Co(HL2)(L2)] (2) [where HL1=2-((E)-(2-hydroxyethylimino)methyl)-4 chlorophenol and HL2=2-((E)-(2-hydroxyethylimino)methyl)-4-bromophenol] were synthesized and characterized using spectroscopic methods. The crystal structures of 1 and 2 have been re-determined by single crystal diffraction at 100K. The ligands and their Co(III) complexes were screened for antibacterial and antifungal activities by the disc diffusion, microdilution broth and single spore culture techniques. The antimicrobial activity of the Co(III) complexes and the free ligands exhibit antimicrobial properties and the Co(III) complexes show enhanced inhibitory activity compared with their parent ligand. PMID- 22522299 TI - Photophysical properties of a hydrazone-based switch: A TDDFT study and comparison. AB - The photophysical properties of a hydrazone-based switch, which can be induced using pH to yield three stable configurations (QPH-E, QPH-Z-H(+) and QPH-Z H(2)(2+)) and another unstable configuration (QPH-Z). The three stable configuration have been investigated by means of density functional theory (DFT) and time-dependent density functional theory (TDDFT). A generalized gradient approximation (GGA) functional (PBE) and two hybrid-type functional (B3LYP and BH&HLYP) as well as four popular basis sets (6-31G(d,p), SVP, TZVP and DZP) have been selected to calculate the photophysical properties. The solvent effects were in view with the Conductor-like Polarizable Continuum Model (CPCM). Besides, the charge distribution of this switch had been investigated by the pop at the level of the B3YLP/6-31G(d,p) in gas. Results show that the B3LYP functional is more accurate in all simulations. PMID- 22522300 TI - Spectroscopic analyses on sonocatalytic damage to bovine serum albumin (BSA) induced by ZnO/hydroxylapatite (ZnO/HA) composite under ultrasonic irradiation. AB - ZnO/hydroxylapatite (ZnO/HA) composite with HA molar content of 6.0% was prepared by the method of precipitation and heat-treated at 500 degrees C for 40min and was characterized by powder X-ray diffraction (XRD). The sonocatalytic activities of ZnO/HA composite was carried out through the damage of bovine serum albumin (BSA) in aqueous solution. Furthermore, the effects of several factors on the damage of BSA molecules were evaluated by means of UV-vis and fluorescence spectra. Experimental results indicated that the damage degree of BSA aggravated with the increase of ultrasonic irradiation time, irradiation power and ZnO/HA addition amount, but weakened with the increase of solution acidity and ionic strength. In addition, the damage site to BSA was also studied by synchronous fluorescence technology and the damage site was mainly at tryptophan (Trp) residue. This paper provides a valuable reference for driving sonocatalytic method to treat tumor in clinic application. PMID- 22522301 TI - Uniaxial growth of <100> zinc (tris) thiourea sulphate (ZTS) single crystal by Sankaranarayanan-Ramasamy (SR) method and its characterizations. AB - <100> directed single crystals of zinc (tris) thiourea sulphate, a semi-organic compound, have been grown at an average growth rate of 2mm per day by Sankaranarayanan-Ramasamy (SR) method. Transparent ZTS crystal of size 70mm length and 15mm diameter was grown. The growth conditions have been optimized. Chemical etching, Vickers microhardness, UV-Vis NIR, dielectric constant and dielectric loss analysis were made on conventional and SR method grown ZTS crystals. Thermo gravimetric and differential thermal analysis was carried out to determine the thermal properties of the grown crystal. The NLO efficiency of the crystal has been confirmed using the Kurtz powder technique. The comparative study indicates that the crystal quality of unidirectional grown ZTS crystal is better compared to conventional slow evaporation method grown crystal. PMID- 22522302 TI - Determination of total flavonoids content in fresh Ginkgo biloba leaf with different colors using near infrared spectroscopy. AB - Total flavonoids content is often considered an important quality index of Ginkgo biloba leaf. The feasibility of using near infrared (NIR) spectra at the wavelength range of 10,000-4000cm(-1) for rapid and nondestructive determination of total flavonoids content in G. biloba leaf was investigated. 120 fresh G. biloba leaves in different colors (green, green-yellowish and yellow) were used to spectra acquisition and total flavonoids determination. Partial least squares (PLS), interval partial least squares (iPLS) and synergy interval partial least squares (SiPLS) were used to develop calibration models for total flavonoids content in two colors leaves (green-yellowish and yellow) and three colors leaves (green, green-yellowish and yellow), respectively. The level of total flavonoids content for green, green-yellowish and yellow leaves was in an increasing order. Two characteristic wavelength regions (5840-6090cm(-1) and 6620-6880cm(-1)), which corresponded to the absorptions of two aromatic rings in basic flavonoid structure, were selected by SiPLS. The optimal SiPLS model for total flavonoids content in the two colors leaves (r(2)=0.82, RMSEP=2.62mg g(-1)) had better performance than PLS and iPLS models. It could be concluded that NIR spectroscopy has significant potential in the nondestructive determination of total flavonoids content in fresh G. biloba leaf. PMID- 22522303 TI - Temperature-modulated quenching and photoregulated optical switching of poly(N isopropylacrylamide)/spironaphthoxazine/Rhodamine B hybrid in water. AB - Temperature and photo-responsive poly(N-isopropylacrylamide) (PNIPAM)/spironaphthoxazine (WSPO)/Rhodamine B (RhoB) hybrid was studied in this paper. Aqueous PNIPAM/WSPO/RhoB hybrid showed phase transition and fluorescent decrease by rising temperature. And also color and fluorescent change of aqueous PNIPAM/WSPO/RhoB hybrid were showed upon UV/vis light. PMID- 22522304 TI - New hexadentate macrocyclic ligand and their copper(II) and nickel(II) complexes: Spectral, magnetic, electrochemical, thermal, molecular modeling and antimicrobial studies. AB - Ni(II) and Cu(II) complexes were synthesized with a hexadentate macrocyclic ligand [3,4,8,9tetraoxo-2,5,7,10tetraaza-1,6dithio-(3,4,8,9) dipyridinedodecane(L)] and characterized by elemental analysis, molar conductance measurements, mass, NMR, IR, electronic, EPR spectral, thermal and molecular modeling studies. All the complexes are 1:2 electrolytes in nature and may be formulated as [M(L)]X(2) [where, M=Ni(II) and Cu(II) and X=Cl(-), NO(3)(-), 1/2SO(4)(2-), CH(3)COO(-)]. On the basis of IR, electronic and EPR spectral studies an octahedral geometry has been assigned for Ni(II) complexes and tetragonal geometry for Cu(II) complexes. The antimicrobial activities and LD(50) values of the ligand and its complexes, as growth inhibiting agents, have been screened in vitro against two different species of bacteria and plant pathogenic fungi. PMID- 22522305 TI - Tissue penetration of bipolar electrosurgical currents: Joule overheating beyond the surface layer. AB - BACKGROUND: There is extensive evidence that electrosurgical current application increases hemorrhage when compared with "cold" dissection and hemostasis. The way that the "hot" technique is used may influence the outcome decisively. METHODS: Temperature-time functions were measured in distances of 3 to 12 mm underneath the surface at which bipolar electrosurgical current was applied. Measurements were made in human cadaver, excised pig tissues, and pig animal models. RESULTS: Bipolar current causes Joule heating in distances of several millimeters. A single maximum power pulse of 1 second increased the temperature in the muscle in 3 and 6 mm distance to 90 degrees and 65 degrees C, respectively; similar accumulated thermal effects were detected for a series of low- and medium-power pulses, too. CONCLUSION: Joule heating is primarily responsible for unintended thermal damages. Severe damages can easily occur even in several millimeters distance from the forceps tips. Utmost caution is also advised at low power setting when current is applied repetitively. PMID- 22522306 TI - Antioxidant capacity and mineral contents of edible wild Australian mushrooms. AB - Five selected edible wild Australian mushrooms, Morchella elata, Suillus luteus, Pleurotus eryngii, Cyttaria gunnii, and Flammulina velutipes, were evaluated for their antioxidant capacity and mineral contents. The antioxidant capacities of the methanolic extracts of the dried caps of the mushrooms were determined using a number of different chemical reactions in evaluating multi-mechanistic antioxidant activities. These included the Trolox equivalent antioxidant capacity, ferric ion reducing antioxidant power, and ferrous ion chelating activity. Mineral contents of the dried caps of the mushrooms were also determined by inductively coupled plasma-optical emission spectroscopy. The results indicated that these edible wild mushrooms have a high antioxidant capacity and all, except C. gunnii, have a high level of several essential micro nutrients such as copper, magnesium, and zinc. It can be concluded that these edible wild mushrooms are good sources of nutritional antioxidants and a number of mineral elements. PMID- 22522307 TI - Effects of hot air and freeze drying methods on antioxidant activity, colour and some nutritional characteristics of strawberry tree (Arbutus unedo L) fruit. AB - Antioxidant activity, colour and some nutritional properties of hot air and freeze-dried strawberry tree (Arbutus unedo L.) fruits were investigated. Additionally, the effects of two pre-treatments, namely ethyl oleate and water blanching, were compared in terms of drying characteristics. For determination of antioxidant activities in ethanol extracts, two different analytical methods were used: 1,1-diphenyl-2-picrylhydrazyl scavenging activity and beta-carotene bleaching activity. As a result, the ethyl oleate pre-treatment shortened the drying time by hot air method and gave a higher 1,1-diphenyl-2-picrylhydrazyl scavenging activity (82.16 +/- 0.34%), total phenolic content (7.62 +/- 1.09 ug GAE/g extract), ascorbic acid content (236.93 +/- 20.14 mg/100 g), besides hydromethylfurfural was not observed. Freeze-dried fruits exhibited higher ascorbic acid content (368.63 +/- 17.16 mg/100 g) than those fresh fruits (231.33 +/- 19.51 mg/100 g) and nearly 1,1-diphenyl-2-picrylhydrazyl activity (93.52 +/- 0.41 %) to fresh fruits (94.03 +/- 1.18%). Colour characteristics, sugar content and mineral contents of fruits were significantly affected by pre-treatments and drying methods (p < 0.05). It is concluded that the drying of strawberry tree fruits should bring a valuable and attractive foodstuff to food industry due to the rich nutritional components, antioxidant activity and colour. Another conclusion from this study is that the freeze-drying is the best drying method to keep the nutritional value, antioxidant activity and sensory properties of fruits. PMID- 22522308 TI - A universal method for the study of CR1 retroposons in nonmodel bird genomes. AB - Presence/absence patterns of retroposon insertions at orthologous genomic loci constitute straightforward markers for phylogenetic or population genetic studies. In birds, the convenient identification and utility of these markers has so far been mainly restricted to the lineages leading to model birds (i.e., chicken and zebra finch). We present an easy-to-use, rapid, and cost-effective method for the experimental isolation of chicken repeat 1 (CR1) insertions from virtually any bird genome and potentially nonavian genomes. The application of our method to the little grebe genome yielded insertions belonging to new CR1 subfamilies that are scattered all across the phylogenetic tree of avian CR1s. Furthermore, presence/absence analysis of these insertions provides the first retroposon evidence grouping flamingos + grebes as Mirandornithes and several markers for all subsequent branching events within grebes (Podicipediformes). Five markers appear to be species-specific insertions, including the hitherto first evidence in birds for biallelic CR1 insertions that could be useful in future population genetic studies. PMID- 22522309 TI - Non conservation of function for the evolutionarily conserved prdm1 protein in the control of the slow twitch myogenic program in the mouse embryo. AB - Muscles are composed of multinucleated muscle fibers with different contractile and physiological properties, which result from specific slow or fast gene expression programs in the differentiated muscle cells. In the zebra fish embryo, the slow program is under the control of Hedgehog signaling from the notochord and floor plate. This pathway activates the expression of the conserved transcriptional repressor, Prdm1 (Blimp1), which in turn represses the fast program and promotes the slow program in adaxial cells of the somite and their descendants. In the mouse embryo, myogenesis is also initiated in the myotomal compartment of the somite, but the slow muscle program is not confined to a specific subset of cells. We now show that Prdm1 is expressed in the first differentiated myocytes of the early myotome from embryonic day (E)9.5-E11.5. During this period, muscle formation depends on the myogenic regulatory factors, Myf5 and Mrf4. In their absence, Prdm1 is not activated, in apparent contrast to zebra fish where Prdm1 is expressed in the absence of Myf5 and MyoD that drive myogenesis in adaxial cells. However, as in zebra fish, Prdm1 expression in the mouse myotome does not occur in the absence of Hedgehog signaling. Analysis of the muscle phenotype of Prdm1 mutant embryos shows that myogenesis appears to proceed normally. Notably, there is no requirement for Prdm1 activation of the slow muscle program in the mouse myotome. Furthermore, the gene for the transcriptional repressor, Sox6, which is repressed by Prdm1 to permit slow muscle differentiation in zebra fish, is not expressed in the mouse myotome. We propose that the lack of functional conservation for mouse Prdm1, that can nevertheless partially rescue the adaxial cells of zebra fish Prdm1 mutants, reflects differences in the evolution of the role of key regulators such as Prdm1 or Sox6, in initiating the onset of the slow muscle program, between teleosts and mammals. PMID- 22522310 TI - Endogenous lentiviral elements in the weasel family (Mustelidae). AB - Endogenous retroviruses provide molecular fossils for studying the ancient evolutionary history of retroviruses. Here, we report our independent discovery and analysis of endogenous lentiviral insertions (Mustelidae endogenous lentivirus [MELV]) within the genomes of weasel family (Mustelidae). Genome-scale screening identified MELV elements in the domestic ferret (Mustela putorius furo) genome (MELVmpf). MELVmpf exhibits a typical lentiviral genomic organization. Phylogenetic analyses position MELVmpf basal to either primate lentiviruses or feline immunodeficiency virus. Moreover, we verified the presence of MELV insertions in the genomes of several species of the Lutrinae and Mustelinae subfamilies but not the Martinae subfamily, suggesting that the invasion of MELV into the Mustelidae genomes likely took place between 8.8 and 11.8 Ma. The discovery of MELV in weasel genomes extends the host range of lentiviruses to the Caniformia (order Carnivora) and provides important insights into the prehistoric diversity of lentiviruses. PMID- 22522311 TI - Interaction structure of the complex between neuroprotective factor humanin and Alzheimer's beta-amyloid peptide revealed by affinity mass spectrometry and molecular modeling. AB - Humanin (HN) is a linear 24-aa peptide recently detected in human Alzheimer's disease (AD) brain. HN specifically inhibits neuronal cell death in vitro induced by beta-amyloid (Abeta) peptides and by amyloid precursor protein and its gene mutations in familial AD, thereby representing a potential therapeutic lead structure for AD; however, its molecular mechanism of action is not well understood. We report here the identification of the binding epitopes between HN and Abeta(1-40) and characterization of the interaction structure through a molecular modeling study. Wild-type HN and HN-sequence mutations were synthesized by SPPS and the HPLC-purified peptides characterized by MALDI-MS. The interaction epitopes between HN and Abeta(1-40) were identified by affinity-MS using proteolytic epitope excision and extraction, followed by elution and mass spectrometric characterization of the affinity-bound peptides. The affinity-MS analyses revealed HN(5-15) as the epitope sequence of HN, whereas Abeta(17-28) was identified as the Abeta interaction epitope. The epitopes and binding sites were ascertained by ELISA of the complex of HN peptides with immobilized Abeta(1 40) and by ELISA with Abeta(1-40) and Abeta-partial sequences as ligands to immobilized HN. The specificity and affinity of the HN-Abeta interaction were characterized by direct ESI-MS of the HN-Abeta(1-40) complex and by bioaffinity analysis using a surface acoustic wave biosensor, providing a K(D) of the complex of 610 nm. A molecular dynamics simulation of the HN-Abeta(1-40) complex was consistent with the binding specificity and shielding effects of the HN and Abeta interaction epitopes. These results indicate a specific strong association of HN and Abeta(1-40) polypeptide and provide a molecular basis for understanding the neuroprotective function of HN. PMID- 22522312 TI - The interaction rainfall vs. weight as determinant of total mercury concentration in fish from a tropical estuary. AB - Mercury loads in tropical estuaries are largely controlled by the rainfall regime that may cause biodilution due to increased amounts of organic matter (both live and non-living) in the system. Top predators, as Trichiurus lepturus, reflect the changing mercury bioavailability situations in their muscle tissues. In this work two variables [fish weight (g) and monthly total rainfall (mm)] are presented as being important predictors of total mercury concentration (T-Hg) in fish muscle. These important explanatory variables were identified by a Weibull Regression model, which best fit the dataset. A predictive model using readily available variables as rainfall is important, and can be applied for human and ecological health assessments and decisions. The main contribution will be to further protect vulnerable groups as pregnant women and children. Nature conservation directives could also improve by considering monitoring sample designs that include this hypothesis, helping to establish complete and detailed mercury contamination scenarios. PMID- 22522313 TI - The use of levoglucosan for tracing biomass burning in PM2.5 samples in Tuscany (Italy). AB - Levoglucosan was present in all samples and its concentrations showed a pronounced annual cycle with maximum levels in the cold season. The annual percentage of ratios of levoglucosan to OC ranged from 0.04 to 9.75% evidencing a major contribution of biomass burning to the aerosol OC during the winter. In the urban-background site, OC was strongly correlated with EC in winter, suggesting that the major fraction of OC was generated as primary particles along with EC. A background levoglucosan component showed that biomass burning was continuously taking place in all the investigated sites. The biomass burning contribution to the Tuscany aerosol was made up of a background component and an additional component during winter probably due to wood burning for domestic heating. PMID- 22522314 TI - Remediation of copper in vineyards--a mini review. AB - Viticulturists use copper fungicide to combat Downy Mildew. Copper, a non degradable heavy metal, can accumulate in soil or leach into water sources. Its accumulation in topsoil has impacted micro and macro organisms, spurring scientists to research in situ copper removal methods. Recent publications suggest that microorganism assisted phytoextraction, using plants and bacteria to actively extract copper, is most promising. As vineyards represent moderately polluted sites this technique has great potential. Active plant extraction and chelate assisted remediation extract too little copper or risk leaching, respectively. However, despite interesting pot experiment results using microorganism assisted phytoextraction, it remains a challenge to find plants that primarily accumulate copper in their shoots, a necessity in vineyards where whole plant removal would be time consuming and financially cumbersome. Vineyard remediation requires a holistic approach including sustainable soil management, proper plant selection, increasing biodiversity and microorganisms. PMID- 22522315 TI - Cell-wall-dependent effect of carboxyl-CdSe/ZnS quantum dots on lead and copper availability to green microalgae. AB - The present study examines the effect of carboxyl-CdSe/ZnS quantum dots (QDs) on Cu and Pb availability to microalgae with different cell wall characteristics: Chlorella kesslerii possessing a cellulosic cell wall and two strains of Chlamydomonas reinhardtii, a wall-less and a walled strain containing glycoproteins as the main cell wall component. Results demonstrated that QDs decreased Pb and Cu intracellular contents ({Cu}(int) and {Pb}(int)) in walled strains by a factor of 2.5 and 2, respectively, as expected by the decrease of about 70% and 40% in the dissolved Cu and Pb concentrations. QDs increased {Cu}(int) and {Pb}(int) in wall-less strain by a factor of 4 and 3.5. These observations were consistent with the observed association of QDs to the wall less C. reinhardtii, and lack of association to walled algal strains. Suwannee River humic acid did not influence metal association to QDs, but decreased {Cu}(int) and {Pb}(int) in all microalgae. PMID- 22522316 TI - Using disposable solid-phase microextraction (SPME) to determine the freely dissolved concentration of polybrominated diphenyl ethers (PBDEs) in sediments. AB - Polybrominated diphenyl ethers (PBDEs) are brominated flame retardants (BFRs). The ubiquity and persistence of PBDEs in sediment have raised concerns over their environmental fate and ecological risks. Due to strong affinity for sediment organic matter, environmental fate and bioavailability of PBDEs closely depend on their phase distribution. In this study, disposable polydimethylsiloxane (PDMS) fiber was used to derive the freely dissolved concentration (C(free)) of PBDEs in sediment porewater as a measurement of bioavailability. The PDMS-to-water partition coefficient (log K(PDMS)) was 5.46-5.83 for BDE 47, 99, and 153. In sediments, PBDEs were predominantly sorbed to the sediment phase, with C(free) accounting for <0.012% of the total chemical mass. The C(free) of PBDEs decreased as their bromination or sediment organic carbon content increased. The strong association with dissolved organic matter (DOM) implies a potential for facilitated offsite transport and dispersion in the environment that depends closely on the stability of sediment aggregates. PMID- 22522317 TI - Thiacloprid affects trophic interaction between gammarids and mayflies. AB - Neonicotinoid insecticides like thiacloprid enter agricultural surface waters, where they may affect predator-prey-interactions, which are of central importance for ecosystems as well as the functions these systems provide. The effects of field relevant thiacloprid concentrations on the leaf consumption of Gammarus fossarum (Amphipoda) were assessed over 96 h (n = 13-17) in conjunction with its predation on Baetis rhodani (Ephemeroptera) nymphs. The predation by Gammarus increased significantly at 0.50-1.00 MUg/L. Simultaneously, its leaf consumption decreased with increasing thiacloprid concentration. As a consequence of the increased predation at 1.00 MUg/L, gammarids' dry weight rose significantly by 15% compared to the control. At 4.00 MUg/L, the reduced leaf consumption was not compensated by an increase in predation causing a significantly reduced dry weight of Gammarus (~20%). These results may finally suggest that thiacloprid adversely affects trophic interactions, potentially translating into alterations in ecosystem functions, like leaf litter breakdown and aquatic-terrestrial subsidies. PMID- 22522318 TI - Probing the local strain-mediated magnetoelectric coupling in multiferroic nanocomposites by magnetic field-assisted piezoresponse force microscopy. AB - The magnetoelectric effect that occurs in multiferroic materials is fully described by the magnetoelectric coupling coefficient induced either electrically or magnetically. This is rather well understood in bulk multiferroics, but it is not known whether the magnetoelectric coupling properties are retained at nanometre length scales in nanostructured multiferroics. The main challenges are related to measurement difficulties of the coupling at nanoscale, as well as the fabrication of suitable nano-multiferroic samples. Addressing these issues is an important prerequisite for the implementation of multiferroics in future nanoscale devices and sensors. In this paper we report on the local measurement of the magnetoelectric coefficient in bilayered ceramic nanocomposites from the variation in the longitudinal piezoelectric coefficient of the electrostrictive layer in the presence of a magnetic field. The experimental data were analyzed using a theoretical relationship linking the piezoelectric coefficient to the magneto-electric coupling coefficient. Our results confirm the presence of a measurable magnetoelectric coupling in bilayered nanocomposites constructed by a perovskite as the electrostrictive phase and two different ferrites (cubic spinel and hexagonal) as the magnetic phases. The reported experimental values as well as our theoretical approach are both in good agreement with previously published data for bulk and nanostructure magnetoelectric multiferroics. PMID- 22522319 TI - Ultrasensitive regulation of anapleurosis via allosteric activation of PEP carboxylase. AB - Anapleurosis is the filling of the tricarboxylic acid cycle with four-carbon units. The common substrate for both anapleurosis and glucose phosphorylation in bacteria is the terminal glycolytic metabolite phosphoenolpyruvate (PEP). Here we show that Escherichia coli quickly and almost completely turns off PEP consumption upon glucose removal. The resulting buildup of PEP is used to quickly import glucose if it becomes available again. The switch-like termination of anapleurosis results from depletion of fructose-1,6-bisphosphate (FBP), an ultrasensitive allosteric activator of PEP carboxylase. E. coli expressing an FBP insensitive point mutant of PEP carboxylase grow normally when glucose is steadily available. However, they fail to build up PEP upon glucose removal, grow poorly when glucose availability oscillates and suffer from futile cycling at the PEP node on gluconeogenic substrates. Thus, bacterial central carbon metabolism is intrinsically programmed with ultrasensitive allosteric regulation to enable rapid adaptation to changing environmental conditions. PMID- 22522320 TI - YcaO domains use ATP to activate amide backbones during peptide cyclodehydrations. AB - Thiazole/oxazole-modified microcins (TOMMs) encompass a recently defined class of ribosomally synthesized natural products with a diverse set of biological activities. Although TOMM biosynthesis has been investigated for over a decade, the mechanism of heterocycle formation by the synthetase enzymes remains poorly understood. Using substrate analogs and isotopic labeling, we demonstrate that ATP is used to directly phosphorylate the peptide amide backbone during TOMM heterocycle formation. Moreover, we present what is to our knowledge the first experimental evidence that the D-protein component of the heterocycle-forming synthetase (YcaO/domain of unknown function 181 family member), formerly annotated as a docking protein involved in complex formation and regulation, is able to perform the ATP-dependent cyclodehydration reaction in the absence of the other TOMM biosynthetic proteins. Together, these data reveal the role of ATP in the biosynthesis of azole and azoline heterocycles in ribosomal natural products and prompt a reclassification of the enzymes involved in their installation. PMID- 22522321 TI - Copper(II) complexes of bis(amino amide) ligands: effect of changes in the amino acid residue. AB - A family of ligands derived from bis(amino amides) containing aliphatic spacers has been prepared, and their protonation and stability constants for the formation of Cu(2+) complexes have been determined potentiometrically. Important differences are associated to both the length of the aliphatic spacer and the nature of the side chains derived from the amino acid. In general, ligands containing aliphatic side chains display higher basicities as well as stability constants with Cu(2+). In the same way, basicities and stability constants tend to increase when decreasing the steric hindrance caused by the corresponding side chain. FT-IR, UV-vis and ESI-MS were used for analyzing the complex species detected in the speciation diagram. UV-vis studies showed the presence of different coordination environments for the copper(II) complexes. Complexes with different stoichiometries can be formed in some instances. This was clearly highlighted with the help of ESI-MS experiments. PMID- 22522322 TI - Boost Your High: Cigarette Smoking to Enhance Alcohol and Drug Effects among Southeast Asian American Youth. AB - The current study examined: 1) whether using cigarettes to enhance the effects of other drugs (here referred to as "boosting") is a unique practice related to blunts (i.e., small cheap cigars hollowed out and filled with cannabis) or marijuana use only; 2) the prevalence of boosting among drug-using young people; and 3) the relationship between boosting and other drug-related risk behaviors. We present data collected from 89 Southeast Asian American youth and young adults in Northern California (35 females). 72% respondents reported any lifetime boosting. Controlling for gender, results of linear regression analyses show a significant positive relationship between frequency of boosting to enhance alcohol high and number of drinks per occasion. Boosting was also found to be associated with use of blunts but not other forms of marijuana and with the number of blunts on a typical day. The findings indicate that boosting may be common among drug-using Southeast Asian youths. These findings also indicate a need for further research on boosting as an aspect of cigarette uptake and maintenance among drug- and alcohol-involved youths. PMID- 22522326 TI - Medical care for chronic-phase stroke in Japan. AB - Stroke leaves serious neurological sequelae, which require long-term medical and social care, imposing financial and mental burdens on the patients and their families, and causing enormous losses to society. It is currently required that medical resources be used efficiently and the cost-effectiveness of treatment be analyzed carefully. We conducted a follow-up survey of stroke patients admitted to the hospital attached to our university in order to build a picture of the current status of chronic-phase stroke medical treatment. In total, 330 patients were analyzed in this study. We evaluated utility and medical cost at one year after onset. To investigate the relationship between activities of daily living (ADL) classified according to the modified Rankin scale (mRS) and quality of life (QOL), utility was calculated for each ADL level. Utility at 1 year post-onset for each mRS level was: ADL0, 0.89; ADL1, 0.79; ADL2, 0.65; ADL3, 0.58; ADL4, 0.36; and ADL5, 0.09. A significant correlation was seen between utility and mRS. Direct monthly medical costs at 1 year post-onset were 61,536 yen in the ADL0 group and 383,444 yen in the ADL5 group, indicating that a worse ADL score required higher medical costs. Direct monthly costs were significantly different between ADL levels. This present study has clarified the QOL and medical costs of chronic-phase stroke patients, and many cost-utility analyses will be based on our data in the future in Japan. PMID- 22522327 TI - Intracerebral hemorrhage in patients with chronic liver disease. AB - The characteristics of intracerebral hemorrhage (ICH) accompanying chronic liver disease (CLD) were investigated in ICH patients hospitalized between 1998 and 2008 divided into the CLD group (55 ICHs in 49 patients) and the idiopathic group without CLD (668 ICHs in 648 patients). The CLD group included a subgroup with liver cirrhosis (LC). Age, sex, history of hypertension, Glasgow Coma Scale (GCS) score on admission, and hematoma locations were reviewed. Outcomes on discharge and causes of in-hospital death were also studied. Factors associated with life prognosis in CLD patients were investigated using uni- and multivariate analyses. History of hypertension and deep cerebral hemorrhage were less frequent in the LC subgroup compared to the idiopathic group. Distributions of GCS scores on admission were not significantly different, but incidence of in-hospital death was significantly higher in the CLD group than in the idiopathic group. LC was an independent prognostic factor for CLD patients, but hematoma enlargement was not. Death primarily due to ICH was less frequent in the CLD group than in the idiopathic group. In conclusion, hemostatic disorders seemed to be related to site of hemorrhage, but not to life prognosis in the CLD group. Prognosis was mainly worsened by non-neurological complications. PMID- 22522323 TI - Alphaviruses: population genetics and determinants of emergence. AB - Alphaviruses are responsible for several medically important emerging diseases and are also significant veterinary pathogens. Due to the aerosol infectivity of some alphaviruses and their ability to cause severe, sometimes fatal neurologic diseases, they are also of biodefense importance. This review discusses the ecology, epidemiology and molecular virology of the alphaviruses, then focuses on three of the most important members of the genus: Venezuelan and eastern equine encephalitis and chikungunya viruses, with emphasis on their genetics and emergence mechanisms, and how current knowledge as well as gaps influence our ability to detect and determine the source of both natural outbreaks and potential use for bioterrorism. This article is one of a series in Antiviral Research on the genetic diversity of emerging viruses. PMID- 22522328 TI - Valproic acid inhibits angiogenesis in vitro and glioma angiogenesis in vivo in the brain. AB - Antiangiogenic strategy is promising for malignant glioma. Histone deacetylase inhibitors (HDACIs) are unique anticancer agents that exhibit antiangiogenic effects. The in vitro and in vivo antiangiogenic effects of HDACIs, valproic acid (VPA), were investigated in malignant glioma in the brain. In vitro, VPA preferentially inhibited endothelial cell proliferation compared to glioma cell proliferation at the optimum concentration in a dose-dependent manner. VPA reduced vascular endothelial growth factor (VEGF) secretion of glioma cells in a dose-dependent manner under both normoxic and hypoxic conditions. VPA was also found to inhibit tube formation in the angiogenesis assay. In vivo, treatment with VPA combined with irinotecan reduced the number of vessels expressing factor VIII in the brain tumor model. VPA inhibits glioma angiogenesis by direct (inhibition of endothelial cell proliferation and tube formation) and indirect (decreased secretion of VEGF by glioma cells) mechanisms. These data suggest a potential role for VPA as an adjuvant therapy for patients with malignant glioma. PMID- 22522329 TI - Glioma immunotherapy with combined autologous tumor cell and endothelial cell vaccine in vivo. AB - Combined vaccines containing GL261 murine glioma cells and F-2 murine endothelial cells fixed with glutaraldehyde-phosphate buffered saline were injected into the intradermal tissue of the tail base of C57BL/6 mice. After the vaccination, GL261 cells were injected subcutaneously into the left flank of the mice. Vaccination with fixed F-2 cells induced the development of relatively high amounts of interferon-gamma-releasing cells after in vitro re-stimulation with vascular endothelial growth factor-receptor 2 peptide. Tumor growth was inhibited after preventive use of the combined vaccine, prepared from GL261 and F-2 cells. Tumor specimens obtained from the combined vaccine group in a therapeutic experiment showed significantly decreased vessel count. Glioma immunotherapy with a combined vaccine prepared from tumor cells and endothelial cells might represent a new clinical strategy, as such combinations may theoretically affect both high-grade glioma cells and their environment. PMID- 22522330 TI - Pupil-sparing oculomotor nerve palsy caused by upward compression of a large posterior communicating artery aneurysm. Case report. AB - A 69-year-old woman without diabetes or hypertension presented with a large posterior communicating artery aneurysm projecting beneath the oculomotor nerve manifesting as a 2-week history of progressive diplopia. Neurological examination revealed external ophthalmoplegia and blepharoptosis without pupil involvement. Neuroimaging showed a large aneurysm in the left internal carotid artery projecting postero-inferiorly. Craniotomy and neck clipping of the aneurysm revealed the origin at the junction of the internal carotid artery and posterior communicating artery, and elevation of the oculomotor nerve. Pupil-sparing oculomotor nerve palsy is often assumed to be caused by ischemic injury such as hypertension and diabetes mellitus. Sometimes compressive lesion can cause pupil sparing oculomotor nerve palsy with a short interval from the onset of symptoms to diagnosis. Despite the 2-week interval from the onset of symptoms, this patient presented with pupil-sparing oculomotor nerve palsy caused by compressive lesion. Involvement or sparing of the pupil is often considered to be the most important criterion in the diagnosis of isolated oculomotor nerve palsy. This unique case demonstrated that unusual compressive lesions must be taken into consideration in the diagnosis of pupil-sparing oculomotor nerve palsy. PMID- 22522331 TI - Shrinkage of a vertebral dissecting aneurysm after stent-assisted coil embolization demonstrated by the three-dimensional driven equilibrium sequence. Case report. AB - A 61-year-old man with a history of cerebellar infarction was transferred to our hospital for the treatment of vertebral artery (VA) stenosis. The VA dissection was treated with endovascular stent placement followed by coil embolization in which shrinkage of the dissecting aneurysm was confirmed by the three-dimensional driven equilibrium (3D DRIVE) sequence. Using 3D DRIVE, the outer contour of the aneurysm was well visualized, free from the influence of the metallic devices. 3D DRIVE may be useful in the follow-up assessment of the vertebrobasilar artery after stent-assisted coil embolization. PMID- 22522332 TI - Technical options for the surgical management of extracranial carotid artery aneurysms. Three case reports. AB - Three cases of extracranial carotid artery (ECA) aneurysm were treated with various surgical options. Two female patients (74 and 37-year-old women) presented with pulsatile masses in their necks, which were confirmed as ECA aneurysms. Another 65-year-old woman presented with a calcified mass in her neck caused by an ECA aneurysm. The first case was treated with aneurysmorrhaphy with primary closure, the second with replacement of the involved site with vascular prosthesis, and the third with a high flow bypass with proximal ligation of the internal carotid artery. All three different surgical techniques were successful. ECA aneurysms are rare and require careful selection of the surgical method according to etiology, shape, and location of the ECA aneurysm. Proficiency in various vascular reconstruction techniques is a desirable prerequisite for the surgeon in-charge. PMID- 22522333 TI - Tailored flow alteration treatment for intracranial internal carotid artery aneurysms: strategy beyond parent artery occlusion with bypass. Case report. AB - A 58-year-old woman with multiple right internal carotid artery (ICA) aneurysms detected incidentally was referred to us. Three-dimensional computed tomography (CT) angiography revealed a broad-necked paraclinoid aneurysm and an aneurysm on the C(1) segment. Aneurysm clipping with preservation of the anterior choroidal artery and posterior communicating artery was not possible because these vessels could not be adequately identified. Intraoperative digital subtraction angiography during obliteration of the cervical portion of the ICA confirmed retrograde flow from the extracranial-intracranial (EC-IC) bypass to the right ophthalmic artery and stagnation of flow in the aneurysms. The cervical portion of the ICA was ligated. Postoperative three-dimensional CT angiography confirmed complete occlusion of both aneurysms and absence of ischemic lesions involving branches of the ICA. Reversal of the blood flow in the ICA via the EC-IC bypass primarily into the ophthalmic artery as the flow outlet by obliterating the cervical portion of the ICA was successful. To prevent ischemia in the territory fed by the perforating arteries of the ICA, tailored flow alteration treatment may be superior to simple parent artery occlusion of the ICA with/without bypass. The pattern of flow alteration should be deliberately based on individual anatomic variations, especially the preservation of flow outlets. PMID- 22522334 TI - Treatment of an unruptured fusiform aneurysm of the internal carotid artery associated with Wegener's granulomatosis by endovascular balloon occlusion. Case report. AB - A 22-year-old woman developed an unruptured fusiform aneurysm of the internal carotid artery 7 months after being diagnosed with Wagener's granulomatosis. Intracranial aneurysmal formation is an extremely rare complication of Wegener's granulomatosis. This rare case of intracranial aneurysm was treated by endovascular balloon occlusion. PMID- 22522335 TI - Single stage multiple stenting in Takayasu's arteritis. Case report. AB - A 32-year-old Filipino female presented with Takayasu's arteritis manifesting as an abrupt onset of syncope. Physical examination revealed diminished consciousness, right hemiparesis, and a large discrepancy in blood pressure between the upper and lower extremities. Magnetic resonance imaging revealed cerebral infarcts in the left basal ganglia and the left temporal lobe. Angiography revealed complete occlusion of the left common carotid artery and severe stenosis of the brachiocephalic artery, the right common carotid artery, and the left subclavian artery. Based on the clinical examination and studies, the diagnosis was Takayasu's arteritis, type I. The patient's condition stabilized after 2 months of prednisone and anti-platelet therapy. Single stage multiple stenting in the brachiocephalic artery, the right common carotid artery, and the left subclavian artery was then performed using high pressure inflation to dilate the arteries due to the remarkably rigid lesions that resulted from extensive and diffuse fibrosis throughout the vessel walls. Although a small intimal flap occurred during inflation of the left subclavian artery, re-dilation was possible with the stent. Even with evidence of notable recovery in blood pressure and cerebral blood flow, no further neurological improvement was observed. In view of the favorable short- and intermediate-term results, single stage multiple stenting may be the optimum treatment option for first-line stent supported angioplasty in patients with Takayasu's arteritis. PMID- 22522336 TI - Radiation-induced World Health Organization grade II meningiomas in young patients following prophylactic cranial irradiation for acute lymphoblastic leukemia in childhood. Three case reports. AB - Current chemotherapeutic regimens have been used to successfully treat many children with acute lymphoblastic leukemia (ALL), but have resulted in an increased risk of late central nervous system tumors, most commonly meningioma, particularly in patients who have received cranial irradiation. We treated 3 young patients with World Health Organization grade II meningiomas who had previously received cranial irradiation for the treatment of childhood ALL: a cerebellopontine angle tumor in a 19-year-old woman, a petroclival tumor in a 28 year-old man, and a frontal parasagittal tumor in a 19-year-old woman. These cases were difficult to treat due to the aggressive and invasive biology of the tumors. Therefore, we recommend systematic cranial imaging and long follow-up periods for leukemia survivors to detect brain tumors before progression. PMID- 22522337 TI - Difficulty of pinching behind the back: an atypical symptom of carpal tunnel syndrome related to a specific wrist position. Two case reports. AB - Carpal tunnel syndrome (CTS) may be overlooked in the absence of typical sensory symptoms. Two patients with CTS lacked the attendant sensory symptoms but experienced difficulties performing a pinching action behind the back (manipulation of the buckle of a baby sling or the hook of a brassiere), a mode of pinching that required wrist flexion. The causative mechanism was probably exacerbation of a latent weakness of the intrinsic muscles of the thumb by wrist flexion, in which the strength of the extrinsic flexors of the thumb and index finger were decreased due to loosening of the tendons. Such symptoms, induced by a specific wrist position, may be help to diagnose a latent weakness in the intrinsic muscles of the thumb, present in patients with CTS. PMID- 22522338 TI - Disproportionately large communicating fourth ventricle associated with syringomyelia and intradural arachnoid cyst in the spinal cord successfully treated with additional shunting. Case report. AB - A 44-year-old woman presented with a rare case of disproportionately large communicating fourth ventricle (DLCFV) associated with syringomyelia and intradural arachnoid cyst in the spinal cord. Ventriculoperitoneal shunt operation was performed for hydrocephalus after subarachnoid hemorrhage. She developed DLCFV, which was then associated with syringomyelia and spinal intradural arachnoid cyst. Shunting of the fourth ventricle improved DLCFV, and then the syringomyelia and arachnoid cyst. Although the aqueduct was patent, independent pressure control of the fourth ventricle and the other ventricles was necessary to improve the symptoms. Shunting of the fourth ventricle should be considered for patients with DLCFV when the symptoms persist despite adequate pressure control of the other ventricles. PMID- 22522339 TI - Intradural invasion of lumbar synovial cyst. Case report. AB - A 63-year-old female presented with a rare case of synovial cyst invading the dura mater and mimicking an intradural extramedullary tumor in the lumbar spine. She underwent posterior lumbar fusion with laminar wire fixation from L3 to S1 levels. She complained of severe pain along the anterolateral thigh in both legs for 1 year. Radiological examinations, including magnetic resonance imaging and computed tomography revealed an intradural extramedullary lesion at the L2-3 level that was compressing the thecal sac. Histological examination confirmed a synovial cyst. Synovial cyst should be considered in the differential diagnosis of an intradural extramedullary mass causing lumbar radiculopathy. PMID- 22522340 TI - Surgical technique for idiopathic spinal cord herniation: the Hammock method. Technical note. AB - Idiopathic spinal cord herniation is a rare disease, and surgical treatment is recommended for patients with motor deficits or progressive neurological symptoms. Surgery is performed to release and reposition the tethered spinal cord. In terms of repositioning and prevention of reherniation, various procedures have been proposed; enlargement of the ventral dural defect, primary closure of the defect with sutures, and insertion of a ventral patch for duraplasty. We treated 3 patients with idiopathic spinal cord herniation, using a ventral patch for duraplasty with an expanded polytetrafluoroethylene pericardial membrane (the Hammock method), and all 3 cases had good clinical outcome. The specific important technical aspects are described and illustrated. If this procedure is performed meticulously under the microscope by following the specific techniques, the Hammock method is safer and more effective for prevention of reherniation than simple enlargement of the dural defect. PMID- 22522342 TI - ScreenTroll: a searchable database to compare genome-wide yeast screens. AB - Systematic biological screens typically identify many genes or proteins that are implicated in a specific phenotype. However, deriving mechanistic insight from these screens typically involves focusing upon one or a few genes within the set in order to elucidate their precise role in producing the phenotype. To find these critical genes, researchers use a variety of tools to query the set of genes to uncover underlying common genetic or physical interactions or common functional annotations (e.g. gene ontology terms). Not only it is necessary to find previous screens containing genes in common with the new set, but also useful to easily access the individual manuscript or study that classified those genes. Unfortunately, no tool currently exists to facilitate this task. We have developed a web-based tool (ScreenTroll) that queries one or more genes against a database of systematic yeast screens. The software determines which genome-wide yeast screens also identified the queried gene(s) and the resulting screens are listed in an order based on the extent of the overlap between the queried gene(s) and the open reading frames (ORFs) characterized in each individual yeast screen. In a separate list, the corresponding ORFs that are found in both the queried set of genes and each individual genome-wide screen are displayed along with links to the relevant manuscript via NIH's PubMed database. ScreenTroll is useful for comparing a list of ORFs with genes identified in a wide array of published genome-wide screens. This comparison informs users whether any of their queried ORFs overlaps a previous study in the ScreenTroll database. By listing the manuscript of the published screen, users can read more about the phenotype associated with that study. Together, this information provides insight into the function of the queried genes and helps the user focus on a subset of them. PMID- 22522341 TI - Intravenous tolerance effectively overcomes enhanced pro-inflammatory responses and experimental autoimmune encephalomyelitis severity in the absence of IL-12 receptor signaling. AB - Intravenous (i.v.) administration of autoantigen effectively induces Ag-specific tolerance against experimental autoimmune encephalomyelitis (EAE). We and others have shown enhanced EAE severity in mice lacking IL-12 or its receptor, strongly suggesting an immunoregulatory effect of IL-12 signaling. To examine the role of IL-12 responsiveness in autoantigen-induced tolerance in EAE, we administered autoantigen i.v. in two distinct treatment regimes to wildtype and IL-12Rbeta2(-/ ) mice, immunized to develop EAE. Administration at the induction phase suppressed EAE in wildtype and IL-12Rbeta2(-/-) mice however the effect was somewhat less potent in the absence of IL-12Rbeta2. Expression of pro inflammatory cytokines such as IFN-gamma, IL-17 and IL-2, was inhibited in wild type tolerized mice but less so in IL-12Rbeta2(-/-) mice. I.v. antigen was also effective in suppressing disease in both genotypes when given during the clinical phase of disease with similar CNS inflammation, demyelination and peripheral inflammatory cytokine profiles observed in both genotypes. There was however a mild impact of a lack of IL-12 signaling on Treg induction during tolerance induction compared to WT mice in this treatment regime. These findings show that the enhanced severity of EAE that occurs in the absence of IL-12 signaling can be effectively overcome by i.v. autoantigen, indicating that this therapeutic effect is not primarily mediated by IL-12 and that i.v. tolerance could be a powerful approach in suppressing severe and aggressive MS. PMID- 22522343 TI - Hypothyroidism modulates renal antioxidant gene expression during postnatal development and maturation in rat. AB - In the present study effects of 6-n-propyl thiouracil (PTU)-induced hypothyroidism on renal antioxidant defence system during postnatal development (from birth to 7, 15 and 30days old) and on adult rats were reported. Hypothyroidism in rats was induced by feeding the lactating mothers (from the day of parturition till weaning, 25days old) or directly to the pups with 0.05% PTU in drinking water. The activities of Cu/Zn-superoxide dismutase (SOD1) and glutathione peroxidase (GPx) were increased in 30days old hypothyroid rats with respect to their respective controls, on the other hand, levels of translated products and activities of Mn-superoxide dismutase (SOD2) and catalase (CAT) were decreased in hypothyroid rats of all age groups as compared to their respective control rats. SOD1 activity remained unchanged in persistent (PTU-treatment from birth to 90days old) hypothyroid rats as compared to euthyroid. However, a decreased activity of SOD1 was recorded in transient (PTU-treatment from birth to 30days then withdrawal till 90days old) hypothyroid rats with respect to control rats. The mRNA level, protein expression and activity of SOD2 and CAT were significantly decreased in persistent hypothyroid rats as compared to euthyroid rats. The activity of GPx was significantly increased in both persistent and transient hypothyroid rats with respect to euthyroid rats. The present study indicates modulation of antioxidant defence status of rat kidney during postnatal development and maturation by hypothyroidism. PMID- 22522344 TI - A novel polypeptide from Meretrix meretrix Linnaeus inhibits the growth of human lung adenocarcinoma. AB - A novel polypeptide (Mere15) was purified from Meretrix meretrix Linnaeus by ammonium sulfate fractionation, ion exchange, gel filtration and reversed phase chromatography. Mere15 exhibited selective cytotoxicity to several human cancer cells. In vivo study showed that Mere15 significantly suppressed the growth of human lung adenocarcinoma A549 xenograft in nude mice. The mechanism was associated with a G(2)/M phase arrest followed by apoptosis, including membrane blebbing, loss of mitochondrial membrane potential, externalization of phosphatidylserine, chromosome condensation and DNA fragmentation. Western blot analysis showed that the intrinsic pathway was involved in Mere15-induced apoptosis. These results suggest that Mere15 may have therapeutic potential for the treatment of non-small-cell lung carcinoma. PMID- 22522345 TI - Chromatin immunoprecipitation-promoter microarray identification of genes regulated by PRDM16 in murine embryonic palate mesenchymal cells. AB - The transcription factor PRDM16 regulates differentiation of brown adipocyte tissue in mice. Recently, however, it has been demonstrated that genetic knockout of Prdm16 in mice leads to a complete cleft of the secondary palate in offspring. To identify genes whose promoters bind PRDM16 in mouse embryonic palate/maxillary mesenchymal cells, we have conducted a chromatin immunoprecipitation-promoter microarray analysis (ChIP-Chip). One hundred and twenty-two gene promoters were identified as capable of binding PRDM16. These could be functionally grouped to include those on genes linked to muscle development, chondrogenesis and osteogenesis, in addition to many transcription factors. These results suggest that PRDM16 may play a role in differentiation of mesenchymal cells in the embryonic secondary palate that contribute to the anterior, bony palate and posterior, muscular palate. PMID- 22522346 TI - Mucosal permeability is an intrinsic factor in susceptibility to dextran sulfate sodium-induced colitis in rats. AB - We investigated differences in the pathogenesis of dextran sulfate sodium (DSS) induced colitis between two inbred rat strains, Wistar King A Hokkaido (WKAH) and Dark Agouti (DA) rats, to determine the intrinsic factors responsible for the development of colitis. DSS exposure exacerbated the clinical symptoms such as body weight loss, stool consistency and rectal bleeding in DA rats rather than that in WKAH rats. Additionally, the average survival was shorter in DA rats than in WKAH rats. The expression levels of tumor necrosis factor-alpha, interleukin (IL)-12 p35 and IL-23 p19 increased prominently in the DA rats that were administered DSS, accompanied by severe infiltration of leukocytes into the colon. We also found that colonic permeability was greater in the DA rats than in the WKAH rats. In Ussing chambers, exposure of the isolated colon tissue to DSS enhanced the colonic permeability of both strains. Immunoblot analysis revealed that the expression levels of tight junction (TJ) proteins were modulated during DSS administration. Higher expression levels of claudin-4 and junctional adhesion molecule-A proteins were observed in DA rats than in WKAH rats, even in intact conditions. These results indicated that the expression pattern of TJ proteins determines the colonic permeability of the rats. In conclusion, the intrinsic colonic permeability is one of critical factors responsible for the susceptibility of rats to colitis. PMID- 22522347 TI - The CTIS Womb to Classroom Screening Program for the detection of agents with adverse effects on neuropsychological development. AB - Over the last several decades, federal agencies engaged in the screening of environmental or pharmaceutical agents have recognized the need to conduct research in animal models to identify agents that have classic teratogenic effects as well as effects on neural and behavioral development. Many questions typically addressed in rodent models can be further addressed using real-world, everyday human exposures. Although some postmarketing surveillance programs have been put in place to examine the influences on birth characteristics, it is now urgent that programs be launched to examine the long-term risks associated with exposure to the many medications, drugs, and environmental chemicals for which data are currently unavailable and unexplored. The California Teratogen Information Service (CTIS), established in 1983, and its corresponding Clinical Research Program represent the oldest national program directed at identifying pregnancy risk factors and exposures associated with adverse pregnancy outcome, including behavioral dysfunction. In recognition of the rising rates of developmental disorders involving compromised mental ability, in 2007, CTIS committed to the development of a more comprehensive screening program designed to detect relationships between adverse prenatal exposures and compromised human neurobehavioral development. The "CTIS Womb to Classroom Screening Program for the Detection of Agents with Adverse Effects on Neuropsychological Development" is the first program designed to identify agents not yet known to be of concern. PMID- 22522348 TI - Systolic blood pressure reactions to acute stress are associated with future hypertension status in the Dutch Famine Birth Cohort Study. AB - These analyses examined the association between blood pressure reactions to acute psychological stress and subsequent hypertension status in a substantial Dutch cohort. Blood pressure was recorded during a resting baseline and during three acute stress tasks, Stroop colour word, mirror tracing and speech. Five years later, diagnosed hypertension status was determined by questionnaire. Participants were 453 (237 women) members of the Dutch Famine Birth Cohort. In analysis adjusting for a number of potential confounders, systolic blood pressure reactivity was positively related to future hypertension. This was the case irrespective of whether reactivity was calculated as the peak or the average response to the stress tasks. The association was strongest for reactions to the speech and Stroop tasks. Diastolic blood pressure reactivity was not significantly associated with hypertension. The results provide support for the reactivity hypothesis. PMID- 22522349 TI - How will academic health centers define success in 2025? PMID- 22522350 TI - Endoscopic view of the ostium of the posterior ethmoid sinus. PMID- 22522351 TI - Third branchial anomaly: endoscopic management revisited. PMID- 22522352 TI - Palatoglossal flap: a novel approach to cover herniated fat during tonsillectomy. PMID- 22522353 TI - The burden of hearing loss in Kaduna, Nigeria: a 4-year study at the National Ear Care Centre. AB - Hearing loss among people in developing countries has been recognized as a major source of disability. Many of its causes are preventable, and others are curable. We reviewed the records of 5,485 patients who had presented during a 4-year period to the National Ear Care Centre in Kaduna, Nigeria. Of these, we identified 1,435 patients-812 males and 623 females, aged 9 months to 90 years (mean: 29.2 yr)-who had been diagnosed with hearing loss (26.2%). In addition to demographic data, we compiled information on each patient's type and degree of hearing loss, the affected side, and the predisposing factors. Sex and age cross tabulations revealed that the greatest proportion of hearing loss according to sex occurred between the ages of 11 and 20 years for males and 21 and 30 years for females. The most common type of hearing loss was sensorineural, which was seen in 78.9% of patients; conductive hearing loss was seen in 17.7% and mixed in 3.4%. More than three-quarters of hearing losses were either moderate, moderately severe, or severe. Bilateral losses were far more common than unilateral losses; among the latter, the left side was affected slightly more often than the right. Predisposing factors were not documented in the vast majority of cases (87.6%), but when they were, the most common were chronic suppurative otitis media, meningitis, febrile convulsion, measles, and trauma. We present these findings to highlight the burden of hearing loss in our part of the world. PMID- 22522354 TI - Congenital os vomer agenesis: case report and literature review. AB - Defects of the nasal septum occur as a result of a variety of causes, including tuberculosis, irritation, neoplasia, trauma, infection, and chronic inflammatory diseases. Congenital os vomer agenesis as a cause is very rare. We report the case of a 28-year-old man with a defect in the posteroinferior part of the nasal septum that was discovered incidentally during a routine endoscopic examination. The patient was diagnosed with congenital os vomer agenesis, and the diagnosis was confirmed by computed tomography. We discuss the features of this case and review the literature on this rare anomaly. PMID- 22522355 TI - The effect of asthma on phonation: a controlled study of 34 patients. AB - The effect of upper respiratory tract diseases on phonation has been reviewed, but little is known about the influence of lower respiratory tract diseases. In particular, the effect of asthma as a reversible obstructive small-airway disease on phonatory variables is not yet clear. We conducted a cross-sectional controlled study to evaluate the quality of phonation in a group of 34 adults with untreated mild to severe persistent asthma who were seen at the Ghaem Hospital in Mashhad, Iran. Patients with sinusitis, gastroesophageal reflux disease, or primary laryngeal disease were ineligible for study participation. For comparison purposes, we identified a group of nonasthmatic, age- and sex matched healthy controls. We evaluated eight voice parameters: basal voice frequency at the glottic level (F0), jitter, shimmer, breathiness, harshness, hoarseness, normalized noise energy (NNE), and S/Z ratio. These parameters were measured by a voice meter with Dr. Speech statistical software. We found that values for F0, jitter, and shimmer were very similar in the two groups, but there were statistically significant differences in values for harshness, hoarseness, NNE, S/Z ratio (all p < 0.01), and breathiness (p = 0.015). Our findings suggest that lower airway diseases such as asthma can impair phonation, and we recommend future studies with larger populations to further explore this issue. PMID- 22522356 TI - Germ cell tumor metastatic to the oral cavity. AB - Neoplasms metastatic to the oral cavity are rare, accounting for less than 1% of all malignancies found there. When they do occur, they are usually found in the soft tissue or mandible. Metastatic malignancies involving the gingival, alveolar, or buccal mucosa are very rare. We present a case of what appeared to be a benign epulis in a 25-year-old man. Biopsy revealed that the lesion represented metastatic testicular cancer. PMID- 22522357 TI - Topical measles-mumps-rubella vaccine in the treatment of recurrent respiratory papillomatosis: results of a preliminary randomized, controlled trial. AB - We conducted a study to test the hypothesis that the measles-mumps-rubella (MMR) vaccine can either prevent further recurrences of recurrent respiratory papillomatosis (RRP) or prolong its remission. Our study population was made up of 26 children with RRP. All patients underwent surgical excision of their lesions. After the lesions were removed, half of these patients were prospectively randomized to receive a topical coating of the MMR vaccine on the site of their excised lesion (intervention group); the other half were treated with excision alone (control group). The patients in the intervention group experienced a longer period of recurrence-free remission than did those in the control group (median: 160 and 133 days, respectively), but the difference was not statistically significant. Therefore, it appears that topical MMR vaccine as an adjunct to routine surgical management may not be beneficial in preventing or slowing the return of RRP. However, we believe that further studies with larger patient populations are warranted. PMID- 22522358 TI - Idiopathic bilateral auricular petrification. AB - Auricular petrification is a rare diagnosis and presents an interesting therapeutic challenge. Fewer than 160 cases have been reported in the literature since the first description by Bochdalek in 1866. The most common etiology is ectopic calcification. It may also result from injurious processes including frostbite, physical trauma, inflammatory conditions, and various endocrinopathies. We report an incidental finding of idiopathic bilateral auricular petrification in a 40-year-old man presenting with idiopathic unilateral sensorineural deafness. PMID- 22522359 TI - Poorly differentiated small-cell neuroendocrine carcinoma of the submandibular gland: a case report. AB - Neuroendocrine carcinoma (NEC) is uncommon in the head and neck and rare in the salivary glands. In the latter location, it may manifest as pain or a palpable mass. These tumors can be quite aggressive, with a tendency toward recurrence and regional and distant metastasis. Because of the limited number of reported cases in the literature, no reliable treatment has been established. We describe the case of a 79-year-old man who presented with a persistent submandibular mass that was suspicious for a malignancy on imaging. Following surgical resection and histopathologic analysis, a diagnosis of poorly differentiated small-cell NEC was made. The patient was further treated with postoperative chemotherapy, and he exhibited no evidence of recurrence or metastasis on follow-up. PMID- 22522360 TI - Lateral ectopic thyroid: a case diagnosed preoperatively. AB - Ectopic thyroid is an uncommon condition defined as the presence of thyroid tissue at a site other than the pretracheal area. When the process of embryologic migration is disturbed, aberrant thyroid tissue may appear. In most cases, ectopic thyroid is located along the embryologic descent path of migration as either a lingual thyroid or a thyroglossal duct cyst. In rare cases, aberrant migration can result in lateral ectopic thyroid tissue. Approximately 1 to 3% of all ectopic thyroids are located in the lateral neck. Ectopic tissue frequently represents the only presence of thyroid tissue; a second site of orthotopic or ectopic thyroid tissue is found in other cases. The presentation of ectopic thyroid as a lateral mass should be differentiated from metastatic thyroid cancer; other differential diagnoses include a submandibular tumor, branchial cleft cyst, carotid body tumor, and lymphadenopathy of various etiologies. In addition to the history and physical examination, the workup for a patient with a submandibular mass suspicious for ectopic thyroid should include (1) technetium 99m or iodine-131 scintigraphy, (2) ultrasonography and either computed tomography or magnetic resonance imaging, (3) fine-needle aspiration biopsy, and (4) thyroid function testing. No treatment is required for asymptomatic patients with normal thyroid function and cytology, but hypothyroid patients should be placed on thyroid hormone replacement therapy. Most cases are diagnosed postoperatively. Surgical treatment of ectopic thyroid should be considered when a malignancy is suspected or diagnosed, when the patient is symptomatic, or when thyroid suppression therapy fails. PMID- 22522361 TI - Microbial colonization of Blom-Singer indwelling voice prostheses in laryngectomized patients: a perspective from India. AB - We analyzed a series of adults with an implanted voice prosthesis that had malfunctioned and required removal as a result of the attachment and growth of microorganisms. Our goal was to determine the characteristics of these colonizing microbes. We swabbed the esophageal side of each prosthesis to obtain microbial flora for analysis with standard culture media. In all, we studied 22 prostheses in 18 patients (3 patients had received multiple prostheses). We found mixed contamination (both yeast and bacteria) in 19 of the 22 cultures (86.4%); the other 3 cultures yielded bacteria only, and there was no instance of yeast only. The most common yeast isolated was Candida albicans (68.2% of cultures), and the most common bacterium was Pseudomonas aeruginosa (63.6%). The average lifetime of the prostheses was 201 days (~6 mo, 3 wk). This study, which was the first of its kind in India, revealed that the microbial picture here was different from that found in previously reported studies of European populations. We presume the differences are attributable to different lifestyles and dietary habits. PMID- 22522362 TI - Recurrent meningitis in an adult secondary to an inner ear malformation: imaging demonstration. AB - Congenital labyrinthine dysplasia with a translabyrinthine cerebrospinal fluid (CSF) fistula may be an anatomic cause for recurrent meningitis. This condition is usually seen in children aged 5 to 10 years who present with sensorineural hearing loss (SNHL) and CSF discharge through the nose or ear, with or without recurrent meningitis. Multidetector-row computed tomography (MDCT) and high resolution T2-weighted magnetic resonance imaging (MRI) of the petrous portion of the temporal bone can help to diagnose this abnormality. We report a case of translabyrinthine CSF fistula in an adult-a 30-year-old man-who presented with recurrent pneumococcal meningitis, a long history of a clear nasal discharge, and evidence of SNHL. MDCT and MRI of the temporal bone demonstrated a cystic appearing cochleovestibular malformation (an incomplete partition type I) in the right inner ear. Imaging also showed an absence of the basal turn of the cochlea and the cribriform membrane at the lateral end of the right internal auditory canal, which was shorter and narrower than normal. Evidence of fluid in the right middle ear suggested a CSF fistula. PMID- 22522363 TI - Intracranial sarcoid granuloma as an extension of severe sinonasal sarcoidosis. AB - Sarcoidosis is a chronic, multisystem, granulomatous disease of unknown etiology. It manifests with a wide range of symptoms and clinical findings, including some that occur in the head and neck. Sinonasal sarcoidosis, in particular, frequently demonstrates a rather recalcitrant course and a potential for severe complications if left untreated. We present the case of a 46-year-old woman with extensive sinonasal sarcoidosis that progressed to involve the skull base and olfactory tract and ultimately led to the formation of a granuloma within the frontal lobe that required craniotomy and excision. Although surgery is not considered the primary treatment modality for sarcoidosis, it may have a role in managing this highly variable disease in certain patients. PMID- 22522364 TI - Myxoid malignant fibrous histiocytoma presenting as a midline nasal mass. AB - Myxoid malignant fibrous histiocytoma is a rare type of pediatric non rhabdomyosarcoma soft-tissue sarcoma. The case of a 5-year-old girl is presented, highlighting the potential for multiple pitfalls and aberrant differential diagnoses that need to be identified for successful treatment of pediatric myxofibrosarcomas. An awareness of these tumors and a call for standardized postsurgical treatment protocols is necessary in order to successfully treat children with this disease. PMID- 22522365 TI - Otoscopic findings in otosclerosis. PMID- 22522366 TI - Extraorbital pseudotumor of the petrous apex: biopsy via a transnasal endoscopic approach. AB - Extraorbital idiopathic pseudotumors of the skull base are very uncommon. We report the case of a 50-year-old woman who presented with left ophthalmoplegia and vision loss. Imaging studies revealed an enhancing lesion involving the left petrous apex and cavernous sinus. A transnasal endoscopic approach was used to obtain a biopsy of the left petrous apex. Pathology identified the lesion as an idiopathic pseudotumor. The patient was treated with high-dose steroids and steroid-sparing immunomodulators, and she experienced a significant improvement. To the best of our knowledge, this is the first reported case of a transnasal endoscopic approach to a biopsy of a pseudotumor involving the petrous apex. We discuss the features of this case, and we review the literature on this condition. PMID- 22522367 TI - Diabetic CVI figures for England and Wales (2007-2009). PMID- 22522368 TI - Three-dimensional graphene nanosheet encrusted carbon micropillar arrays for electrochemical sensing. AB - Integrating graphene onto three-dimensional (3D) microelectrodes is a plausible technique to significantly improve the sensitivity of electrochemical devices. However, the construction of graphene coated 3D microstructures has been a considerable challenge. In this paper, we present a simple methodology using electrostatic spray deposition (ESD) to conformally coat graphene onto 3D carbon micropillars that are fabricated by pyrolyzing finely patterned photoresist. During the ESD, changes in the critical parameters such as substrate temperature, deposition time, and nozzle to substrate distance have shown a significant effect on the morphology of the deposited graphene film. The amperometric response of graphene/carbon micropillar electrode arrays exhibited higher electrochemical activity, improved charge transfer and a linear response towards H(2)O(2) detection between 250 MUM and 5.5 mM. The ESD technique, with the flexibility of integrating a wide variety of functional nanomaterials onto complex 3D microstructures, is attractive in the field of electrochemistry and biotechnology. PMID- 22522369 TI - Synthesis, structures of (aminopyridine)nickel complexes and their use for catalytic ethylene polymerization. AB - A series of alpha-aminopyridines in the form of (2,6 C(6)H(3)N)(R(1))(CHR(2)NR(3)R(4)) (R(1) = R(2) = H R(3) = H R(4) = (i)Pr (L1a), R(4) = (t)Bu (L1b), R(4) = Ph (L1c), R(4) = 2,6-Me(2)C(6)H(3) (L1d), R(4) = 2,6 (i)Pr(2)C(6)H(3) (L1e), R(1) = R(2) = H R(3) = R(4) = Et (L1f), R(1) = H R(2) = Me R(3) = H R(4) = (i)Pr (L2a), R(4) = Ph (L2c), R(4) = 2,6-Me(2)C(6)H(3) (L2d), R(4) = 2,6-(i)Pr(2)C(6)H(3) (L2e), R(1) = Me R(2) = H R(3) = H R(4) = 2,6 (i)Pr(2)C(6)H(3) (L3e)) and beta-aminopyridines in the form of (2 C(6)H(4)N)(CH(2)CH(2)NR(1)R(2)) (R(1) = H R(2) = (i)Pr (4a), R(2) = (t)Bu (L4b), R(1) = R(2) = Et (L4f)) have been prepared. Their corresponding halonickel complexes 1a-4f are synthesized by ligand substitution from (DME)NiBr(2) and the molecular structures are characterized. Four types of coordination modes include four-coordinate mononuclear species with one ligand, five-coordinate mononuclear species with two ligands, five-coordinate dinuclear species with two ligands, and a six-coordinate polymeric framework were determined by X-ray crystallography. Using methylaluminoxanes (MAO) as the activator, the nickel complexes can catalyze ethylene polymerization under moderate pressure and ambient temperature. The activity reaches 10(5) g PE mol(-1) Ni h. The PE products with high branching and high crystallinity have M(n) ~ 10(3) with PDI < 2. PMID- 22522370 TI - Mu suppression as an index of sensorimotor contributions to speech processing: evidence from continuous EEG signals. AB - Mu rhythm suppression is an index of sensorimotor activity during the processing of sensory stimuli. Two present studies investigate the extent to which this measure is sensitive to differences in acoustic processing. In both studies, participants were required to listen to 90second acoustic stimuli clips with their eyes closed and identify predetermined targets. Experimental conditions were designed to vary the acoustic processing demands. Mu suppression was measured continuously across central electrodes (C3, Cz, and C4). Ten adult females participated in the first study in which the target was a pseudoword presented in three conditions (identification, discrimination, discrimination in noise). Mu suppression was strongest and reached significance relative to baseline only in the discrimination in noise task at C3 (indicative of left hemisphere sensorimotor activity) when measured in a 10-12Hz bandwidth. Thirteen adult females participated in the second study, which measured mu suppression to acoustic stimuli with 'segmentation' (i.e., separating a parsed stimulus into individual components) versus non-segmentation requirements in both speech and tone discrimination conditions. Significantly greater overall suppression to speech relative to tone tasks was found in the 10-12Hz bandwidth. Further, suppression relative to baseline was significant only at C3 during the speech discrimination with segmentation task. Taken together, findings indicate that mu rhythm suppression in acoustic processing is sensitive to dorsal stream processing. More specifically, it is sensitive to (1) increases in overall processing demands and (2) processing linguistic versus non-linguistic information. PMID- 22522372 TI - Surgical site infections in paediatric otolaryngology operative procedures. AB - OBJECTIVE: An assessment of the rate of surgical site infections associated with elective paediatric otolaryngology surgical procedures. METHODS: Prospective data was collected for a 3-week period for all children undergoing surgery where either mucosa or skin was breached. The parents of the children were requested to complete a questionnaire at 30 days after the operation. RESULTS: Data was collected on 80 consecutive cases. The majority of cases were admitted on the day of the procedure. The procedures included adenotonsillectomy (24), grommets (12), cochlear implantation (6), bone-anchored hearing aid (2), submandibular gland excision (1), branchial sinus excision (1), cystic hygroma excision (3), nasal glioma excision (1), microlaryngobronchoscopy (13), tracheostomy (3) and other procedures (14). Nearly half the cases had more than one operation done at the same time. 26/80 (32.5%) patients had a temporary or permanent implant inserted at the time of operation (grommet, bone-anchored hearing aid, cochlear implant). 25/80 (31%) operative fields were classed as clean and 55/80 (68.7%) as clean contaminated operations. The duration of the operation varied from 6 min to 142 min. Hospital antibiotic protocol was adhered to in 69/80 (86.3%) cases but not in 11/80 cases. In our series, 3/80 (3.7%) patients had an infection in the postoperative period. CONCLUSIONS: Surgical site infections do occur at an appreciable rate in paediatric otolaryngology. With the potential for serious consequences, reduction in the risk of surgical site infections is important. PMID- 22522371 TI - Tongue adiposity and strength in healthy older adults. AB - OBJECTIVES/HYPOTHESIS: To identify treatable risk factors for aspiration in older adults, particularly those associated with sarcopenia, we examined tongue composition. We hypothesized that isometric and swallowing posterior tongue strength would positively correlate with posterior tongue adiposity, and healthy older adults who aspirate would have greater tongue adiposity than healthy older adults who did not aspirate. STUDY DESIGN: Prospective. METHODS: Participants were 40 healthy adults, comprised of 20 aspirators (mean age, 78 years) and 20 nonaspirators (mean age, 81 years), as identified via flexible endoscopic evaluation of swallowing. Measures of maximal isometric posterior tongue strength and posterior swallowing tongue strength were acquired via tongue manometry. An index of posterior tongue adiposity was acquired via computed tomography for a 1 cm region of interest. RESULTS: Posterior tongue adiposity was correlated with posterior tongue isometric (r = 0.32, P = .05) but not swallowing pressures (P > .05) as examined with separate partial correlation analyses. Tongue adiposity did not significantly differ as a function of age, gender, or aspiration status (P > .05). CONCLUSIONS: Lower posterior isometric tongue strength was associated with greater posterior tongue adiposity. However, aspiration in healthy older adults was not affected by posterior tongue adiposity. This finding offers insight into the roles of tongue composition and strength in healthy older adults. PMID- 22522376 TI - Testing Markovianity in the three-state progressive model via future-past association. AB - The three-state progressive model is a special multi-state model with important applications in Survival Analysis. It provides a suitable representation of the individual's history when an intermediate event (with a possible influence on the survival prognosis) is experienced before the main event of interest. Estimation of transition probabilities in this and other multi-state models is usually performed through the Aalen-Johansen estimator. However, Aalen-Johansen may be biased when the underlying process is not Markov. In this paper, we provide a new approach for testing Markovianity in the three-state progressive model. The new method is based on measuring the future-past association along time. This results in a deep inspection of the process that often reveals a non-Markovian behaviour with different trends in the association measure. A test of significance for zero future-past association at each time point is introduced, and a significance trace is proposed accordingly. The finite sample performance of the test is investigated through simulations. We illustrate the new method through real data analysis. PMID- 22522378 TI - Competing regression models for longitudinal data. AB - The choice of an appropriate family of linear models for the analysis of longitudinal data is often a matter of concern for practitioners. To attenuate such difficulties, we discuss some issues that emerge when analyzing this type of data via a practical example involving pretest-posttest longitudinal data. In particular, we consider log-normal linear mixed models (LNLMM), generalized linear mixed models (GLMM), and models based on generalized estimating equations (GEE). We show how some special features of the data, like a nonconstant coefficient of variation, may be handled in the three approaches and evaluate their performance with respect to the magnitude of standard errors of interpretable and comparable parameters. We also show how different diagnostic tools may be employed to identify outliers and comment on available software. We conclude by noting that the results are similar, but that GEE-based models may be preferable when the goal is to compare the marginal expected responses. PMID- 22522377 TI - Incorporating temporal features of repeatedly measured covariates into tree structured survival models. AB - Tree-structured survival methods empirically identify a series of covariate-based binary split points, resulting in an algorithm that can be used to classify new patients into risk groups and subsequently guide clinical treatment decisions. Traditionally, only fixed-time (e.g. baseline) values are used in tree-structured models. However, this manuscript considers the scenario where temporal features of a repeated measures polynomial model, such as the slope and/or curvature, are useful for distinguishing risk groups to predict future outcomes. Both fixed- and random-effects methods for estimating individual temporal features are discussed, and methods for including these features in a tree model and classifying new cases are proposed. A simulation study is performed to empirically compare the predictive accuracies of the proposed methods in a wide variety of model settings. For illustration, a tree-structured survival model incorporating the linear rate of change of depressive symptomatology during the first four weeks of treatment for late-life depression is used to identify subgroups of older adults who may benefit from an early change in treatment strategy. PMID- 22522379 TI - Hierarchical Bayesian modeling of heterogeneous cluster- and subject-level associations between continuous and binary outcomes in dairy production. AB - The augmentation of categorical outcomes with underlying Gaussian variables in bivariate generalized mixed effects models has facilitated the joint modeling of continuous and binary response variables. These models typically assume that random effects and residual effects (co)variances are homogeneous across all clusters and subjects, respectively. Motivated by conflicting evidence about the association between performance outcomes in dairy production systems, we consider the situation where these (co)variance parameters may themselves be functions of systematic and/or random effects. We present a hierarchical Bayesian extension of bivariate generalized linear models whereby functions of the (co)variance matrices are specified as linear combinations of fixed and random effects following a square-root-free Cholesky reparameterization that ensures necessary positive semidefinite constraints. We test the proposed model by simulation and apply it to the analysis of a dairy cattle data set in which the random herd level and residual cow-level effects (co)variances between a continuous production trait and binary reproduction trait are modeled as functions of fixed management effects and random cluster effects. PMID- 22522380 TI - Joint generalized models for multidimensional outcomes: a case study of neuroscience data from multimodalities. AB - This paper is motivated from the analysis of neuroscience data in a study of neural and muscular mechanisms of muscle fatigue. Multidimensional outcomes of different natures were obtained simultaneously from multiple modalities, including handgrip force, electromyography (EMG), and functional magnetic resonance imaging (fMRI). We first study individual modeling of the univariate response depending on its nature. A mixed-effects beta model and a mixed-effects simplex model are compared for modeling the force/EMG percentages. A mixed effects negative-binomial model is proposed for modeling the fMRI counts. Then, I present a joint modeling approach to model the multidimensional outcomes together, which allows us to not only estimate the covariate effects but also to evaluate the strength of association among the multiple responses from different modalities. A simulation study is conducted to quantify the possible benefits by the new approaches in finite sample situations. Finally, the analysis of the fatigue data is illustrated with the use of the proposed methods. PMID- 22522381 TI - Accurate mean comparisons for paired samples with missing data: an application to a smoking-cessation trial. AB - In this paper, we consider mean comparisons for paired samples in which a certain portion of the observations are missing. This type of data commonly arises in medical researches where the outcomes are assessed at two time points after the application of treatments. New methods for statistical inference are proposed by making finiteness correction based on asymptotic expansions of some intuitive statistics. The comparison methods naturally extend to the two-group case after some suitable manipulations. Simulation study is carried out to demonstrate the numerical accuracy of the proposed methods. Data from a smoking-cessation trial are used to illustrate the application of the methods. PMID- 22522382 TI - Regulatory T cells and autoimmune hepatitis: defective cells or a hostile environment? PMID- 22522383 TI - Focus. Metchnikoff, macrophages and the metabolic syndrome. PMID- 22522384 TI - Influence of lithium cations on prolyl peptide bonds. AB - The influence of lithium cations on the cis/trans isomerization of prolyl peptide bonds was investigated in a quantitative manner in trifluoroethanol (TFE) and acetonitrile, employing NMR techniques. The focus was on various environmental and structural aspects, such as lithium cation and water concentrations, the type of the partner amino acid in the prolyl peptide bond, and the peptide sequence length. Comparison of the thermodynamic parameters of the isomerization in LiCl/TFE and TFE shows a lithium cation concentration dependence of the cis/trans ratio, which saturates at cation concentrations >200 mM. A pronounced increase in the cis isomer content in the presence of lithium cations occurs with the exception of peptides with Gly-Pro and Asp-Pro moieties. The cation effect appears already at the dipeptide level. The salt concentration can considerably be reduced in solvents with a lower number of nucleophilic centers like acetonitrile. The lithium cation effect decreases with small amounts of water and disappears at a water concentration of about 5%. The isomerization kinetics under the influence of lithium cations suggests a weak cation interaction with the carbonyl oxygen of the peptide bond. PMID- 22522385 TI - Relationships of 137Cs inventory with magnetic measures of calcareous soils of hilly region in Iran. AB - Erosion is a natural process, but it has been dramatically increased by human activities; and this adversely influences soil productivity and environmental quality. For quantification of soil erosion, several techniques including the use of Cs-137 have been employed. This study was conducted to explore the relationships of Cs-137 inventory with magnetic properties in calcareous soils in western Iran. Ten transects were selected in the hilly region in Chelgerd district of Iran. Soil samples from 0 to 30 and 30-50 cm depths were collected from fifty points to determine Cs-137 inventory, magnetic measures and selected physico-chemical properties (in total there were 100 soil samples). The results showed that simple mass balance model (SMBM) estimated a gross erosion rate of 29.6 t ha(-1) yr(-1) and a net soil deposition of 21.8 t ha(-1) yr(-1); hence, a net soil loss of 9.6 t ha(-1) yr(-1) and a sediment delivery ratio of 31.4%. Simple linear regression and non-linear regression analysis showed that mass magnetic susceptibility (chi(lf)) explained only 33.64% and 45% of variability in Cs-137 in the transects studied. The results of multiple linear regression analysis of (137)Cs with magnetic parameters and physico-chemical properties indicated that extractable potassium and chi(lf) explained approximately 61% of the total variability in (137)Cs in the area studied. Overall, the results suggest that further research is needed for the use of magnetic characteristics as an alternative technique in place Cs-137 methodology for calcareous soils. PMID- 22522386 TI - Assessment of plant biomass and nitrogen nutrition with plant height in early-to mid-season corn. AB - BACKGROUND: The physiological basis for using non-destructive high-resolution measurements of plant height through plant height sensing to guide variable-rate nitrogen (N) applications on corn (Zea mays L.) during early (six-leaf growth stage, V6) to mid (V12) season is largely unknown. This study was conducted to assess the relationships of plant biomass and leaf N with plant height in early- to mid-season corn under six different N rate treatments. RESULTS: Corn plant biomass was significantly and positively related to plant height under an exponential model when both were measured at V6. This relationship explained 62 78% of the variations in corn biomass production. Leaf N concentration was, in general, significantly and positively related to plant height when both were measured at V6, V8, V10 and V12. This relationship became stronger as the growing season progressed from V6 to V12. The relationship of leaf N with plant height in early- to mid-season corn was affected by initial soil N fertility and abnormal weather conditions. CONCLUSION: The relationship of leaf N concentration with plant height may provide a physiological basis for using plant height sensing to guide variable-rate N applications on corn. PMID- 22522387 TI - Association between single-nucleotide polymorphisms on chromosome 1p22 and 20q12 and nonsyndromic cleft lip with or without cleft palate: new data in Han Chinese and meta-analysis. AB - BACKGROUND: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a common congenital malformation associated with genetic and environmental risk factors. A recent genome-wide association study identified two novel susceptibility loci on chromosomes 1p22 and 20q12; however, conflicting results, especially for 1p22, have been reported in Han Chinese population. The aims of this study were to replicate this association with risk of NSCL/P in the southern Han Chinese population and to discern the effect of these loci by a meta analysis. METHODS: To this end, 305 patients with NSCL/P, 356 phenotypically normal controls, and an additional 176 case-parent trios were recruited. Four of the previously associated single nucleotide polymorphisms (SNPs) were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Furthermore, two published datasets were combined with the present results to determine the precise roles of the loci. RESULTS: SNPs (rs6072081, rs13041247, and rs6102085) on 20q12 were found to be strongly associated with NSCL/P (Bonferroni-corrected and chi(2) test; p values < 0.05). Subsequent analysis of the case-parent trio provided similar results. However, neither the association study nor the trio analysis supported a causative role for SNP rs560426 on 1p22 in NSCL/P susceptibility. Stratified meta- analysis combining Chinese samples supported our findings. CONCLUSIONS: This cross-validation study confirmed the previous findings that SNPs in 20q12 are associated with NSCL/P in Han Chinese population. We further conclude that rs560426 on 1p22 might not have a major influence on susceptibility to NSCL/P in southern Han Chinese, but future studies with other Han Chinese populations are needed. PMID- 22522388 TI - Distinct clinical features in nontuberculous mycobacterial disease with or without latent tuberculosis infection. AB - Nontuberculous mycobacteria (NTM) diseases are in the face of a progressive increase even in immune-competent subjects, and the clinical features of NTM diseases are heterogenous. The decision to institute treatment of the patients should be made after a period of follow up, because therapy is often prolonged, and frequently ineffective. The reasons why some patients develop severe NTM diseases are not clear. Here we observed the involvement of latent tuberculosis infection (LTBI) in clinical and laboratory features of NTM diseases. We evaluated various tuberculosis-related inflammatory markers including osteopontin (OPN), pentraxin-3 (PTX-3), and soluble IL-2 receptor (sIL-2R) in NTM infected patients with or without LTBI. Eight NTM and 5 tuberculosis (TB) patients, and 5 healthy subjects were enrolled. Polymerase Chain Reaction (PCR) analysis confirmed the absence of tuberculosis specific gene (RD1 region), among clinical isolates from NTM patients. Interferon-gamma (IFN-gamma) release assay (IGRA) using Early Secreted Antigenic Target-6 (ESAT-6) and CFP-10, the RD1-encoded protein, was employed for determining LTBI. IGRA was positive in 4/8 NTM (NTM with LTBI, 50%) and 5/5 TB patients. Only 2 of 4 NTM with LTBI were under chemotherapy among all NTM patients, and others were followed up. The plasma levels of OPN, PTX3 and sIL-2R were significantly higher in NTM patients with LTBI than in those without LTBI (P < 0.05). The two patients under therapy showed the highest OPN levels that persisted after treatment. The increased inflammatory levels in NTM patients with LTBI indicate enhanced inflammatory reaction. Extensive therapy may be necessary in such patients. PMID- 22522389 TI - Posterior tibial artery cross-leg perforator flap: a case report. AB - Lower extremity traumatic injuries with exposed vessels mandate prompt repair. Here the authors present a traumatic case in which a contralateral "septocutaneous tibialis posterior artery perforator"-based cross-leg flap was used to cover an open wound. PMID- 22522390 TI - lobSTR: A short tandem repeat profiler for personal genomes. AB - Short tandem repeats (STRs) have a wide range of applications, including medical genetics, forensics, and genetic genealogy. High-throughput sequencing (HTS) has the potential to profile hundreds of thousands of STR loci. However, mainstream bioinformatics pipelines are inadequate for the task. These pipelines treat STR mapping as gapped alignment, which results in cumbersome processing times and a biased sampling of STR alleles. Here, we present lobSTR, a novel method for profiling STRs in personal genomes. lobSTR harnesses concepts from signal processing and statistical learning to avoid gapped alignment and to address the specific noise patterns in STR calling. The speed and reliability of lobSTR exceed the performance of current mainstream algorithms for STR profiling. We validated lobSTR's accuracy by measuring its consistency in calling STRs from whole-genome sequencing of two biological replicates from the same individual, by tracing Mendelian inheritance patterns in STR alleles in whole-genome sequencing of a HapMap trio, and by comparing lobSTR results to traditional molecular techniques. Encouraged by the speed and accuracy of lobSTR, we used the algorithm to conduct a comprehensive survey of STR variations in a deeply sequenced personal genome. We traced the mutation dynamics of close to 100,000 STR loci and observed more than 50,000 STR variations in a single genome. lobSTR's implementation is an end-to-end solution. The package accepts raw sequencing reads and provides the user with the genotyping results. It is written in C/C++, includes multi-threading capabilities, and is compatible with the BAM format. PMID- 22522391 TI - Precision genome engineering with programmable DNA-nicking enzymes. AB - Zinc finger nucleases (ZFNs) are powerful tools of genome engineering but are limited by their inevitable reliance on error-prone nonhomologous end-joining (NHEJ) repair of DNA double-strand breaks (DSBs), which gives rise to randomly generated, unwanted small insertions or deletions (indels) at both on-target and off-target sites. Here, we present programmable DNA-nicking enzymes (nickases) that produce single-strand breaks (SSBs) or nicks, instead of DSBs, which are repaired by error-free homologous recombination (HR) rather than mutagenic NHEJ. Unlike their corresponding nucleases, zinc finger nickases allow site-specific genome modifications only at the on-target site, without the induction of unwanted indels. We propose that programmable nickases will be of broad utility in research, medicine, and biotechnology, enabling precision genome engineering in any cell or organism. PMID- 22522392 TI - The use of a supplemental sulcus fixated IOL (HumanOptics Add-On IOL) to correct pseudophakic refractive errors. AB - PURPOSE: To evaluate the safety and efficacy of piggybacking with the HumanOptics Add-On intraocular lens (IOL) to correct pseudophakic refractive errors. MATERIALS AND METHODS: Ten eyes of 10 patients with pseudophakic refractive errors were included in this study. All patients were targeted for a range of refraction -0.50 to +0.50 D. Uncorrected and corrected distance visual acuities (UDVA and CDVA, respectively), endothelial cell count (ECC), anterior chamber depth (ACD), the distance between intraocular lenses, and contrast sensitivity measurements under mesopic, scotopic, and scotopic with glare conditions were evaluated preoperatively and postoperatively. RESULTS: The mean age of the patients was 54+/-27 years (range 4-78). Mean follow-up time was 10.5+/-1.36 months (range 6-15 months). Mean diopters of implanted Add-On IOLs were -1.4+/ 6.9 (range -12 to +9 D). Mean preoperative and postoperative UDVA was 0.133+/ 0.12 and 0.73+/-0.27, respectively (p=0.0001); mean preoperative and postoperative CDVA were 0.77+/-0.26 and 0.79+/-0.27, respectively (p=0.066). Mean preoperative and postoperative ACD were 3.87+/-0.91 mm vs 3.58+/-1.05 mm, respectively (p=0.343); mean inter-IOL distance was 0.53+/-0.08 mm. Mean preoperative and postoperative ECC were 2455+/-302 and 2426+/-294, respectively (p=0.55). All patients were within the targeted refractive range of -0.50 D to +0.50 D. No complications were observed during the operations or postoperative follow-up period. CONCLUSIONS: Piggybacking with the Add-On IOL is a safe, efficient, and reliable technique to correct pseudophakic refractive errors. PMID- 22522393 TI - An improved synthesis of pentacene: rapid access to a benchmark organic semiconductor. AB - Pentacene is an organic semiconductor used in a variety of thin-film organic electronic devices. Although at least six separate syntheses of pentacene are known (two from dihydropentacenes, two from 6,13-pentacenedione and two from 6,13 dihydro-6,13-dihydroxypentacene), none is ideal and several utilize elevated temperatures that may facilitate the oxidation of pentacene as it is produced. Here, we present a fast (-2 min of reaction time), simple, high-yielding (>= 90%), low temperature synthesis of pentacene from readily available 6,13-dihydro 6,13-dihydroxypentacene. Further, we discuss the mechanism of this highly efficient reaction. With this improved synthesis, researchers gain rapid, affordable access to high purity pentacene in excellent yield and without the need for a time consuming sublimation. PMID- 22522394 TI - Synthesis and antibacterial evaluation of New N-acylhydrazone derivatives from dehydroabietic acid. AB - A series of new N-acylhydrazone derivatives were synthesized in good yields through the reactions of dehydroabietic acid hydrazide with a variety of substituted arylaldehydes. The structures of the synthesized compounds were confirmed by IR, 1H- and 13C-NMR, ESI-MS, elemental analysis and single crystal X ray diffraction. From the crystal structure of compound 4l, the C=N double bonds of these N-acylhydrazones showed (E)-configuration, while the NMR data of compounds 4a-q indicated the existence of two rotamers for each compound in solution. The target compounds were evaluated for their antibacterial activities against four microbial strains. The result suggested that several compounds exhibited pronounced antibacterial activities. Particularly, compound 4p exhibited good antibacterial activity against Staphylococcus aureus and Bacillus subtilis comparable to positive control. The possible antibacterial metabolism and the strategy for further optimization of this compound were also discussed. PMID- 22522395 TI - Anti-tumour promoting activity and antioxidant properties of girinimbine isolated from the stem bark of Murraya koenigii S. AB - Girinimbine, a carbazole alkaloid isolated from the stem bark of Murraya koenigii was tested for the in vitro anti-tumour promoting and antioxidant activities. Anti-tumour promoting activity was determined by assaying the capability of this compound to inhibit the expression of early antigen of Epstein-Barr virus (EA EBV) in Raji cells that was induced by the tumour promoter, phorbol 12-myristate 13-acetate. The concentration of this compound that gave an inhibition rate at fifty percent was 6.0 ug/mL and was not cytotoxic to the cells. Immunoblotting analysis of the expression of EA-EBV showed that girinimbine was able to suppress restricted early antigen (EA-R). However, diffused early antigen (EA-D) was partially suppressed when used at 32.0 ug/mL. Girinimbine exhibited a very strong antioxidant activity as compared to a-tocopherol and was able to inhibit superoxide generation in the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced differentiated premyelocytic HL-60 cells more than 95%, when treated with the compound at 5.3 and 26.3 ug/mL, respectively. However girinimbine failed to scavenge the stable diphenyl picryl hydrazyl (DPPH)-free radical. PMID- 22522396 TI - The rotational barrier in ethane: a molecular orbital study. AB - The energy change on each Occupied Molecular Orbital as a function of rotation about the C-C bond in ethane was studied using the B3LYP, mPWB95 functional and MP2 methods with different basis sets. Also, the effect of the ZPE on rotational barrier was analyzed. We have found that sigma and pi energies contribution stabilize a staggered conformation. The sigma(s) molecular orbital stabilizes the staggered conformation while the stabilizes the eclipsed conformation and destabilize the staggered conformation. The pi(z) and molecular orbitals stabilize both the eclipsed and staggered conformations, which are destabilized by the pi(v) and molecular orbitals. The results show that the method of calculation has the effect of changing the behavior of the energy change in each Occupied Molecular Orbital energy as a function of the angle of rotation about the C-C bond in ethane. Finally, we found that if the molecular orbital energy contribution is deleted from the rotational energy, an inversion in conformational preference occurs. PMID- 22522397 TI - Effect of paeonol on antioxidant and immune regulatory activity in hepatocellular carcinoma rats. AB - The study investigated the immunity and antioxidant potential of paeonol by employing a hepatocellular carcinoma (HCC) rat model. Three doses of paeonol (20, 40, 60 mg/kg b.w. orally) were administrated to diethylnitrosamine (DEN)-induced HCC rats. Results showed that paeonol significantly reduced the serum AST, ALT, ALP, GGT, AFU and liver MDA levels, increased serum WBC, TP, ALB, A/G, TNF-alpha and IFN-gamma and liver antioxidant enzymes activities (SOD, CAT, GSH-Px, GR) in HCC rats. Altogether, these results suggest that the paeonol could effectively decrease oxidative injury and improve immunity function in HCC rats. PMID- 22522398 TI - Self-organizing maps of molecular descriptors for sesquiterpene lactones and their application to the chemotaxonomy of the Asteraceae family. AB - The Asteraceae, one of the largest families among angiosperms, is chemically characterised by the production of sesquiterpene lactones (SLs). A total of 1,111 SLs, which were extracted from 658 species, 161 genera, 63 subtribes and 15 tribes of Asteraceae, were represented and registered in two dimensions in the SISTEMATX, an in-house software system, and were associated with their botanical sources. The respective 11 block of descriptors: Constitutional, Functional groups, BCUT, Atom-centred, 2D autocorrelations, Topological, Geometrical, RDF, 3D-MoRSE, GETAWAY and WHIM were used as input data to separate the botanical occurrences through self-organising maps. Maps that were generated with each descriptor divided the Asteraceae tribes, with total index values between 66.7% and 83.6%. The analysis of the results shows evident similarities among the Heliantheae, Helenieae and Eupatorieae tribes as well as between the Anthemideae and Inuleae tribes. Those observations are in agreement with systematic classifications that were proposed by Bremer, which use mainly morphological and molecular data, therefore chemical markers partially corroborate with these classifications. The results demonstrate that the atom-centred and RDF descriptors can be used as a tool for taxonomic classification in low hierarchical levels, such as tribes. Descriptors obtained through fragments or by the two-dimensional representation of the SL structures were sufficient to obtain significant results, and better results were not achieved by using descriptors derived from three-dimensional representations of SLs. Such models based on physico-chemical properties can project new design SLs, similar structures from literature or even unreported structures in two-dimensional chemical space. Therefore, the generated SOMs can predict the most probable tribe where a biologically active molecule can be found according Bremer classification. PMID- 22522399 TI - Cationic Ti(IV) and neutral Ti(III) titanocene-phosphinoaryloxide frustrated Lewis pairs: hydrogen activation and catalytic amine-borane dehydrogenation. AB - Titanium-phosphorus frustrated Lewis pairs (FLPs) based on titanocene phosphinoaryloxide complexes have been synthesised. The cationic titanium(IV) complex [Cp(2)TiOC(6)H(4)P((t)Bu)(2)][B(C(6)F(5))(4)] 2 reacts with hydrogen to yield the reduced titanium(III) complex [Cp(2)TiOC(6)H(4)PH((t)Bu)(2)][B(C(6)F(5))(4)] 5. The titanium(III)-phosphorus FLP [Cp(2)TiOC(6)H(4)P((t)Bu)(2)] 6 has been synthesised either by chemical reduction of [Cp(2)Ti(Cl)OC(6)H(4)P((t)Bu)(2)] 1 with [CoCp*(2)] or by reaction of [Cp(2)Ti{N(SiMe(3))(2)}] with 2-C(6)H(4)(OH){P((t)Bu)(2)}. Both 2 and 6 catalyse the dehydrogenation of Me(2)HN.BH(3). PMID- 22522400 TI - Rac1 is essential in cocaine-induced structural plasticity of nucleus accumbens neurons. AB - Repeated cocaine administration increases the dendritic arborization of nucleus accumbens neurons, but the underlying signaling events remain unknown. Here we show that repeated exposure to cocaine negatively regulates the active form of Rac1, a small GTPase that controls actin remodeling in other systems. Further, we show, using viral-mediated gene transfer, that overexpression of a dominant negative mutant of Rac1 or local knockout of Rac1 is sufficient to increase the density of immature dendritic spines on nucleus accumbens neurons, whereas overexpression of a constitutively active Rac1 or light activation of a photoactivatable form of Rac1 blocks the ability of repeated cocaine exposure to produce this effect. Downregulation of Rac1 activity likewise promotes behavioral responses to cocaine exposure, with activation of Rac1 producing the opposite effect. These findings establish that Rac1 signaling mediates structural and behavioral plasticity in response to cocaine exposure. PMID- 22522401 TI - Neurogenesis requires TopBP1 to prevent catastrophic replicative DNA damage in early progenitors. AB - The rapid proliferation of progenitors during neurogenesis requires a stringent genomic maintenance program to ensure transmission of genetic fidelity. However the essential factors that govern neural progenitor genome integrity are unknown. Here we report that conditional inactivation of mouse TopBP1, a protein linked to DNA replication, and a key activator of the DNA damage response kinase ATR (ataxia telangiectasia and rad3-related) is critical for maintenance of early born neural progenitors. During cortical development TopBP1 prevented replication associated DNA damage in Emx1-progenitors which otherwise resulted in profound tissue ablation. Notably, disrupted neurogenesis in TopBP1-depleted tissues was substantially rescued by inactivation of p53 but not of ATM. Our data establish that TopBP1 is essential for preventing replication-associated DNA strand breaks, but is not essential per se for DNA replication. Thus, TopBP1 is crucial for maintaining genome integrity in the early progenitors that drive neurogenesis. PMID- 22522403 TI - Effect of telmisartan on paroxysmal atrial fibrillation recurrence in hypertensive patients with normal or increased left atrial size. AB - BACKGROUND: Hypertension is the most prevalent and potentially modifiable risk factor for atrial fibrillation (AF). In a previous secondary prevention study, the authors observed that the angiotensin II receptor blocker telmisartan was more effective than the calcium channel blocker amlodipine in preventing AF relapse in hypertensive patients with normal atrial size. HYPOTHESIS: Telmisartan may be more effective than amlodipine in preventing AF recurrence in hypertensive patients with paroxysmal AF and normal or increased left atrial dimension (LAD). METHODS: The authors assigned 378 mild hypertensive outpatients in sinus rhythm, but with >=2 episodes of AF in the previous 6 months, to 1 of 2 groups. Group 1 comprised patients with LAD <40 mm in females and <45 mm in males. Group 2 comprised patients with LAD >40 mm and <45 mm in females and >45 mm and <50 mm in males. In both groups, patients were randomly treated with telmisartan or amlodipine for 1 year. RESULTS: Systolic and diastolic blood pressure were similarly reduced by telmisartan and amlodipine in both groups. The AF recurrence rate was significantly lower in the telmisartan-treated patients than in the amlodipine-treated patients in both group 1 (12 vs 39, P < 0.01) and group 2 (40 vs 59, P < 0.05). Under telmisartan, the AF recurrence rate was significantly lower in group 1 than in group 2 (12.9% vs 42.1%, P < 0.05). Time to a first AF relapse was significantly longer with telmisartan than with amlodipine in both group 1 (176 +/- 94 days vs 74 +/- 61 days, P < 0.05) and group 2 (119 +/- 65 days vs 38 +/- 35 days, P < 0.05). CONCLUSIONS: Telmisartan was more effective than amlodipine in preventing AF recurrences in hypertensive patients with paroxysmal AF. PMID- 22522406 TI - Au25(SG)18 as a fluorescent iodide sensor. AB - The recently emerging gold nanoclusters (GNC) are of major importance for both basic science studies and practical applications. Based on its surface-induced fluorescence properties, we investigated the potential use of Au(25)(SG)(18) (GSH: glutathione) as a fluorescent iodide sensor. The current detection limit of 400 nM, which can possibly be further enhanced by optimizing the conditions, and excellent selectivity among 12 types of anion (F(-), Cl(-), Br(-), I(-), NO(3)( ), ClO(4)(-), HCO(3)(-), IO(3)(-), SO(4)(2-), SO(3)(2-), CH(3)COO(-) and C(6)H(5)O(7)(3-)) make Au(25)(SG)(18) a good candidate for iodide sensing. Furthermore, our work has revealed the particular sensing mechanism, which was found to be affinity-induced ratiometric and enhanced fluorescence (abbreviated to AIREF), which has rarely been reported previously and may provide an alternative strategy for devising nanoparticle-based sensors. PMID- 22522402 TI - SUMOylation and phosphorylation of GluK2 regulate kainate receptor trafficking and synaptic plasticity. AB - Phosphorylation or SUMOylation of the kainate receptor (KAR) subunit GluK2 have both individually been shown to regulate KAR surface expression. However, it is unknown whether phosphorylation and SUMOylation of GluK2 are important for activity-dependent KAR synaptic plasticity. We found that protein kinase C mediated phosphorylation of GluK2 at serine 868 promotes GluK2 SUMOylation at lysine 886 and that both of these events are necessary for the internalization of GluK2-containing KARs that occurs during long-term depression of KAR-mediated synaptic transmission at rat hippocampal mossy fiber synapses. Conversely, phosphorylation of GluK2 at serine 868 in the absence of SUMOylation led to an increase in KAR surface expression by facilitating receptor recycling between endosomal compartments and the plasma membrane. Our results suggest a role for the dynamic control of synaptic SUMOylation in the regulation of KAR synaptic transmission and plasticity. PMID- 22522407 TI - Health-related quality of life in sickle cell disease: past, present, and future. AB - Health-related quality of life (HRQL) is defined as the patient's appraisal of how his/her well being and level of functioning, compared to the perceived ideal, are affected by individual health. The study of HRQL in children and adults with sickle cell disease (SCD) has begun to flourish. Given the devastating complications of the disease and other co-morbid factors patients experience that influence HRQL, it is increasingly important to understand HRQL. The focus of this critical review was to examine past and current research in HRQL in SCD where a validated instrument was used. In addition, future directions for HRQL in SCD are explored. PMID- 22522409 TI - Verbal communication for the ventilator-dependent patient requiring an inflated tracheotomy tube cuff: A prospective, multicenter study on the Blom tracheotomy tube with speech inner cannula. AB - BACKGROUND: The purpose of this study was to present our findings on the impact of the Blom tracheotomy tube with speech inner cannula on voice production abilities and speech intelligibility scores of ventilator-dependent patients requiring a fully inflated tracheotomy tube cuff. METHODS: Prospective single group case-series design permitted consecutive accrual of 23 adult inpatients from acute care and rehabilitation settings. Maximum ambient room noise, voice intensity, phonation duration of vowel /a/, and speech intelligibility scores were determined over 3 sessions. RESULTS: All participants achieved audible voicing with the Blom tracheotomy tube. Voice intensity was significantly greater than ambient room noise by >10 dB SPL (p = .003). Speech intelligibility scores improved significantly from 80% to 85% (p = .03). Phonation duration averaged from 3.30 to 3.45 seconds. There were no significant changes in oxygen saturation (p > .05), and no significant complications occurred. CONCLUSION: The Blom tracheotomy tube with speech inner cannula permitted individuals requiring mechanical ventilation with a fully inflated tracheotomy tube cuff to produce excellent speech intelligibility for verbal communication. (c) 2012 Wiley Periodicals, Inc. Head Neck, 2013. PMID- 22522408 TI - Identification of biomarkers of meat tenderisation and its use for early classification of Asturian beef into fast and late tenderising meat. AB - BACKGROUND: The objective of this work was to study the post-mortem evolution of potential biomarkers (u-calpain activity and proteolytic profile) of meat tenderisation in bovine longissimus dorsi (LD) muscle from several biotypes coming from two beef breeds ('Asturiana de los Valles' and 'Asturiana de la Montana') and showing different levels of muscular hypertrophy (mh/mh, mh/+, + /+). RESULTS: LD samples were taken at 2, 12, 24 and 48 h and 3, 7, 14 and 21 days post-mortem. The presence of muscular hypertrophy produced a faster rate of pH decline, faster exhaustion of u-calpain activity and earlier occurrence of proteolytic changes. Changes in the electrophoretic pattern of some peptides from sarcoplasmic (glyceraldehyde-3-phosphate dehydrogenase) and myofibrillar (troponin T and troponin I) muscle extracts within the first 24 h significantly correlated with meat toughness and allowed accurate discrimination of meat products into two groups: (1) fast tenderising meat, coming from mh-biotypes, and (2) late tenderising meat, from normal (+/+) biotypes. CONCLUSION: Early monitoring (within 24 h after slaughter) of selected biomarkers in LD muscle allowed accurate prediction of ultimate meat toughness and could be used in the meat industry as a tool for early classification of beef into fast and late tenderising meat. PMID- 22522411 TI - Tuning the electronic structure of Mo-Mo quadruple bonds by N for O for S substitution. AB - A series of quadruply bonded dimolybdenum compounds of form Mo(2)(EE'CC=CPh)(4) (EE' = {NPh}(2), Mo(2)NN; {NPh}O, Mo(2)NO;{NPh}S, Mo(2)NS; OO, Mo(2)OO) have been synthesised by ligand exchange reactions of Mo(2)(O(2)CCH(3))(4) with the acid or alkali metal salt of {PhC=CCEE'}(-). The compounds Mo(2)NO, Mo(2)NS and Mo(2)OO were structurally characterised by single crystal X-ray crystallography. The structures show that Mo(2)NO adopts a cis-2,2 arrangement of the ligands about the Mo(2)(4+) core, whereas Mo(2)NS adopts the trans-2,2 arrangement. The influence of heteroatom substitution on the electronic structure of the compounds was investigated using cyclic voltammetry and UV-Vis spectroscopy. Simple N for O for S substitution in the bridging ligands significantly alters the electronic structure, lowering the energy of the Mo(2)-delta HOMO and reducing the Mo(2)(4+/5+) oxidation potential by up to 0.9 V. A different trend is found in the optoelectronic properties, with the energy of the Mo(2)-delta-to-ligand-pi* transition following the order Mo(2)OO > Mo(2)NO > Mo(2)NN > Mo(2)NS. Electronic structure calculations employing density functional theory were used to rationalise these observations. PMID- 22522410 TI - Bypass to the ankle and foot in the era of endovascular therapy of tibial disease. Results and factors influencing the outcome. AB - AIM: Endovascular therapy (ET) is the treatment of choice for critical limb ischemia (CLI) and tibial arteries disease (TAD) in focal lesions with restorable run-off; ankle and foot bypass (BPG) is indicated in patients unfit for ET with foot or ankle arteries suitable for surgery. The aim of this study was to evaluate limb salvage (LS), primary patency (PP) and survival (S) of patients underwent BPG in the era of ET for TAD and to define the correlated prognostic factors. METHODS: Between February 2000 and November 2008, patients with CLI and TAD were collected prospectively in a data-base (demographics, Fontaine's stage, Texas University Wound Classification [TUC]of ulcers, risk-factors, TAD, techniques of foot revascularization and surgical factors). BPG was performed in tibial arteries occlusion longer than 4 cm or focal occlusion without line-flow to pedal arteries. Clinical and Duplex-ultrasound follow-up was performed at discharge, 1, 3, 6 months and every 6 months. LS, PP, and S rates were assessed with Kaplan-Meier method; factors influencing outcomes were sought by multivariate Cox proportional hazards model analysis. RESULTS: A total of 410 revascularizations were performed in patients with CLI and TAD; BPG in 153 patients (mean age: 69.3+/-10.6, male/female=117/36, diabetes mellitus=75.2% hyperlypidemia=54.9%, hypertension=87.6%, renal disease=32.7%, coronary arteries disease=51.6%, Fontaine stage IV=96.1%, TUC grade-III=65.4%, TUC stage-D=51%). All autologous grafts in 96.7% (non-reversed saphenous vein=74.5%, reversed=7.2%, composite vein graft=12.4%, arm's veins=2.6%). LS and S after 1 month were 88.2% and 97.1%, respectively. Mean follow-up was 23 months. At 12 and 36 months: LS 76.7% and 70.9%, PP 62.3% and 52.9%, S 91.5% and 74.6%. LS was negatively associated with age (HR=1.041 [95%CI=1.005-1.079]), infected ulcers (HR=3.377 [95%CI=1.571-7.258]), run-off arteries diameter <1.8 mm (HR=5.854[95% CI=2.274 15.070]). PP was negatively associated with hyperlipidemia (HR=2.555 [95% CI=1.418-4.603]), female gender (HR=2.125[95% CI=1.182-3.823]), run-off arteries diameter <1.8 mm (HR=6.165 [95% CI=2.774-13.699]), reversed saphenous graft (HR=3.105 [95% CI=1.166-8.272]), composite vein graft (HR=2.930 [95% CI=1.406 6.107]) and homograft (HR=2.762 [95% CI=1.040-7.333]); instead it is positively related with hypertension (HR=4.229 [95% CI=2.089-8.563]). S was negatively correlated with renal disease (HR=3.035 [95% CI=1.363-6.756]). CONCLUSION: BPG may be a reasonable first treatment for CLI patients with TAD unfit for ET; female gender, hyperlipidemia, use of reversed saphenous, composite vein or alternative grafts, foot infection and renal disease are associated with worse outcome. PMID- 22522412 TI - Water conservation behavior in Australia. AB - Ensuring a nation's long term water supply requires the use of both supply-sided approaches such as water augmentation through water recycling, and demand-sided approaches such as water conservation. Conservation behavior can only be increased if the key drivers of such behavior are understood. The aim of this study is to reveal the main drivers from a comprehensive pool of hypothesized factors. An empirical study was conducted with 3094 Australians. Data was analyzed using multivariate linear regression analysis and decision trees to determine which factors best predict self-reported water conservation behavior. Two key factors emerge: high level of pro-environmental behavior; and pro actively seeking out information about water. A number of less influential factors are also revealed. Public communication strategy implications are derived. PMID- 22522413 TI - Endovascular salvage of a right brachial artery-right atrium hemodialysis graft using a covered endoprosthesis. AB - Creation of a functional hemodialysis access in patients with exhausted peripheral access sites and concomitant central venous occlusive disease (CVOD) is a multifaceted challenge; often requiring complex, innovative solutions, not without their own complications. We present a 57-year-old hemodialysis patient with a history of hypercoagulable disorder and multiple failed arteriovenous accesses. Because of inadequate peripheral access sites and chronic occlusions in superior vena cava, brachiocephalic veins and inferior vena cava, in addition to multiple transhepatic catheter related issues; we decided to perform a right brachial artery to right atrium (RA) hemodialysis graft. The access was used without complications for 18 months at which point he had his first episode of thrombosis; open thrombectomy and percutaneous balloon angioplasty (PTA) at the atrial anastomosis were done with success. The following three months, he endured two more thrombectomies and PTAs. During the last intervention we performed an intravascular Ultrasound (IVUS) through the atrial anastomosis, which demonstrated stenosis; and the decision was made to extend the outflow anastomosis with a covered stent into the atrium. Therefore a 10 cm x 10 mm Viabahn stent-graft (W. L. Gore and Associates, Flagstaff, Ariz.) was deployed and post dilated with 8 mm balloon within the graft component. Repeat injection and Intravascular Ultrasound (IVUS) demonstrated significant improvement and free outflow. The brachial-RA hemodialysis graft could be use immediately and at 5 months has remained fully functional and no reinterventions have been necessary. PMID- 22522415 TI - Isoflurane but not halothane minimum alveolar concentration-sparing response of dexmedetomidine is enhanced in rats chronically treated with selective alpha2 adrenoceptor agonist. AB - Halothane minimum alveolar concentration (MAC)-sparing response is preserved in rats rendered tolerant to the action of dexmedetomidine. It has been shown that halothane and isoflurane act at different sites to produce immobility. The authors studied whether there was any difference between halothane and isoflurane MAC-sparing effects of dexmedetomidine in rats after chronic administration of a low dose of this drug. Twenty-four female Wistar rats were randomly allocated into four groups of six animals: two groups received 10 MUg/kg intraperitoneal dexmedetomidine for five days (treated groups) and the other two groups received intraperitoneal saline solution for five days (naive groups) prior to halothane or isoflurane MAC determination (one treated and one naive group of halothane and one treated and one naive group of isoflurane). Halothane or isoflurane MAC determination was performed before (basal) and 30 min after an intraperitoneal dose of 30 MUg/kg of dexmedetomidine (post-dex) from alveolar gas samples at the time of tail clamp. Administration of an acute dose of dexmedetomidine to animals that had chronically received dexmedetomidine resulted in a MAC-sparing effect that was similar to that seen in naive animals for halothane; however, the same treatment increased the MAC-sparing response of dexmedetomidine for isoflurane. Isoflurane but not halothane MAC-sparing response of acutely administered dexmedetomidine is enhanced in rats chronically treated with this drug. PMID- 22522414 TI - Measuring patient-based outcomes: is treatment satisfaction associated with oral health-related quality of life? AB - OBJECTIVES: To evaluate the level of association between patients' denture satisfaction and oral health-related quality of life (OHRQoL) in edentate patients, and to identify the determinants of satisfaction that best predict OHRQoL. The effects of time and treatment type were also assessed. METHODS: Data from 255 edentate elders who participated in a randomised clinical trial were used. OHRQoL ratings were gathered using the Oral Health Impact Profile (OHIP-20) questionnaire. The McGill Denture Satisfaction Instrument was used to assess satisfaction with treatment (mandibular conventional denture or implant overdenture). Outcomes were measured prior to treatment, then 6 and 12 months after delivery of the new prostheses. Simple linear and multiple linear regression analyses were performed to statistically analyse the relationship. RESULTS: When the combined effect of all factors was assessed, only two variables of denture satisfaction ratings were significantly associated with OHRQoL: chewing ability (P=.005) and oral condition (P=.002). These two variables explained 46.4% of the variance in the OHIP change scores. This association varied with time, but the variables of importance remained the same. Type of treatment, gender, age and other socio-demographic variables were not significantly associated with improvement in OHRQoL once their effects were combined with denture satisfaction ratings. CONCLUSIONS: Within the limitations of this study, a highly positive association exists between oral health-related quality of life and denture satisfaction. Chewing ability and oral condition are the determinants of denture satisfaction best associated with OHRQoL, predicting 46.4% of its improvement following a treatment. PMID- 22522416 TI - The impact of commercial rodent diets on the induction of tumours and flat aberrant crypt foci in the intestine of multiple intestinal neoplasia mice. AB - A large variation in spontaneous tumour development in the multiple intestinal neoplasia (Min) mouse model between laboratories has been reported. The composition of the diet might be an important factor. We examined the impact of five commercial rodent diets: the natural ingredient breeding diet Harlan Teklad 2018 (HT), the purified breeding diet AIN93G, the natural ingredient maintenance diet RM1, and the purified maintenance diets AIN93M and AIN76A, on the spontaneous intestinal tumorigenesis in the Min mouse model. The Min mice were fed one of two breeding diets during gestation and until four weeks of age, thereafter one of the three maintenance diets. Min mice bred on the breeding diet HT had significantly higher numbers and incidences of tumours in the colon, but fewer tumours in the small intestine than the breeding diet AIN93G. The maintenance diet RM1 gave a significantly higher number of small intestinal and colonic tumours and precancerous lesions called flat aberrant crypt foci (ACF) compared with the maintenance diets AIN93M and AIN76A. These findings show the importance of defining the type of diet used in experimental intestinal carcinogenesis studies, and that the diet should be taken into consideration when comparing results from different studies with Min mice. PMID- 22522417 TI - Evaluation of the spontaneous reversibility of carbon tetrachloride-induced liver cirrhosis in rabbits. AB - There is a general consensus that liver fibrosis in humans is potentially reversible, while scepticism prevails on the concept that cirrhosis can be truly reversed. The availability of suitable experimental models is fundamental for disease research. The experimental murine model of liver cirrhosis induced by carbon tetrachloride (CCl(4)) reproduces both the histological picture of the postnecrotic cirrhosis and its biochemical and clinical parameters. Normal hepatic structure is modified by formation of regeneration nodules. Fibrosis represents a morphological element of disease and an effect of hepatocyte necrosis. However, the relevance for research of this well-established model of liver cirrhosis is hampered by some spontaneous cirrhosis regression reported in mice and rats. It has been reported that CCl(4) also induces experimental liver cirrhosis in rabbits, but it is not known whether the process is reversible in this species. The aim of our study was to investigate this question. Male New Zealand White rabbits were treated intragastrically with CCl(4) or the vehicle only for 19 weeks and groups were sacrificed three and five months after treatment interruption. Cirrhotic and control livers were processed for routine light microscopy and for morphometric study of fibrosis by semiquantitative evaluation. The degree of fibrosis was based on the Knodell's scoring system. PMID- 22522418 TI - A surgical technique for a terminal intracranial hypertension model in pigs. AB - The life-threatening effects of intracranial hypertension on brain perfusion and cerebral metabolism are the subject of current research in different animal models. The purpose of this study was to describe an efficient, reliable and inexpensive surgical method for temporary elevation of intracranial pressure (ICP) in acutely instrumented pigs in a research setting. Therefore, a balloon catheter was inserted into the left lateral ventricle and an ICP sensor was placed in the parenchyma of the right cerebral hemisphere. Ten acutely instrumented pigs were studied while under deep terminal general anaesthesia. The step-by-step inflation of the intraventricular balloon allows one to achieve the desired ICP up to 46 mmHg and maintain it at this level. ICP values ranged from a median of 2 (1-2) mmHg to 43 (29-45) mmHg. To the authors' knowledge, this is the first detailed description of a minimally invasive surgical technique for temporary ICP elevation in pigs via stepwise inflation of an intraventricular balloon. PMID- 22522419 TI - Anaphylactic reaction to etoposide phosphate. PMID- 22522422 TI - Polymerization on stepped surfaces: alignment of polymers and identification of catalytic sites. PMID- 22522420 TI - ISPD loss-of-function mutations disrupt dystroglycan O-mannosylation and cause Walker-Warburg syndrome. AB - Walker-Warburg syndrome (WWS) is clinically defined as congenital muscular dystrophy that is accompanied by a variety of brain and eye malformations. It represents the most severe clinical phenotype in a spectrum of diseases associated with abnormal post-translational processing of a-dystroglycan that share a defect in laminin-binding glycan synthesis1. Although mutations in six genes have been identified as causes of WWS, only half of all individuals with the disease can currently be diagnosed on this basis2. A cell fusion complementation assay in fibroblasts from undiagnosed individuals with WWS was used to identify five new complementation groups. Further evaluation of one group by linkage analysis and targeted sequencing identified recessive mutations in the ISPD gene (encoding isoprenoid synthase domain containing). The pathogenicity of the identified ISPD mutations was shown by complementation of fibroblasts with wild-type ISPD. Finally, we show that recessive mutations in ISPD abolish the initial step in laminin-binding glycan synthesis by disrupting dystroglycan O mannosylation. This establishes a new mechanism for WWS pathophysiology. PMID- 22522423 TI - Quality and safety assessment of food and agricultural products by hyperspectral fluorescence imaging. AB - Hyperspectral fluorescence imaging (HSFI) is potentially useful for assessing food and agricultural products, because it combines the merits of both hyperspectral imaging and fluorescence spectroscopy. This paper provides an introduction to HSFI: the principle and components of HSFI, calibration and image processing are described. In addition, recent advances in the application of HSFI to food and agricultural product assessment are reviewed, such as contaminant detection, constituent analysis and quality evaluation. Finally, current limitations and likely future development trends are discussed. PMID- 22522424 TI - A step further toward glyphosate-induced epidermal cell death: involvement of mitochondrial and oxidative mechanisms. AB - A deregulation of programmed cell death mechanisms in human epidermis leads to skin pathologies. We previously showed that glyphosate, an extensively used herbicide, provoked cytotoxic effects on cultured human keratinocytes, affecting their antioxidant capacities and impairing morphological and functional cell characteristics. The aim of the present study, carried out on the human epidermal cell line HaCaT, was to examine the part of apoptosis plays in the cytotoxic effects of glyphosate and the intracellular mechanisms involved in the apoptotic events. We have conducted different incubation periods to reveal the specific events in glyphosate-induced cell death. We observed an increase in the number of early apoptotic cells at a low cytotoxicity level (15%), and then, a decrease, in favor of late apoptotic and necrotic cell rates for more severe cytotoxicity conditions. At the same time, we showed that the glyphosate-induced mitochondrial membrane potential disruption could be a cause of apoptosis in keratinocyte cultures. PMID- 22522421 TI - Mutations in ISPD cause Walker-Warburg syndrome and defective glycosylation of alpha-dystroglycan. AB - Walker-Warburg syndrome (WWS) is an autosomal recessive multisystem disorder characterized by complex eye and brain abnormalities with congenital muscular dystrophy (CMD) and aberrant a-dystroglycan glycosylation. Here we report mutations in the ISPD gene (encoding isoprenoid synthase domain containing) as the second most common cause of WWS. Bacterial IspD is a nucleotidyl transferase belonging to a large glycosyltransferase family, but the role of the orthologous protein in chordates is obscure to date, as this phylum does not have the corresponding non-mevalonate isoprenoid biosynthesis pathway. Knockdown of ispd in zebrafish recapitulates the human WWS phenotype with hydrocephalus, reduced eye size, muscle degeneration and hypoglycosylated a-dystroglycan. These results implicate ISPD in a-dystroglycan glycosylation in maintaining sarcolemma integrity in vertebrates. PMID- 22522425 TI - Combination of opium smoking and hypercholesterolemia augments susceptibility for lethal cardiac arrhythmia and atherogenesis in rabbit. AB - Opium consumption is increasing in some eastern societies, where it is grown. We investigated the effect of opium smoking on plasma atherogenic index and incidence of lethal cardiac arrhythmia, i.e. ventricular tachycardia (VT) and ventricular fibrillation (VF) in rabbits. Animals were divided into two-, normo- and hyper-cholesterolemic main groups fed with normal or high cholesterol diet prior and during short-term and long-term exposure to opium smoke. Then, isoproterenol (3mg/kg, i.p.) was injected to induce cardiac ischemia and animals were followed for 3h for counting of lethal arrhythmia incidence. Long-term opium smoking significantly increased the plasma atherogenic index. In ischemic hearts, opium smoking along with hypercholesterolemia significantly enhanced the incidence of fatal arrhythmia. This vulnerability was not mediated by changes in QT interval. These data suggest that opium smoking, especially in hypercholesterolemic conditions, can be a predisposing factor for atherogenesis and lethal arrhythmia. PMID- 22522426 TI - Trace elements in scalp hair of children living in differing environmental contexts in Sicily (Italy). AB - We present here data about trace elements in human scalp hair samples to test whether they are valuable to reflect environmental exposure and contamination by trace elements. The study compares contents of trace elements in scalp hair from a total of 336 children, aged 11-13 years old, living in various geographical areas of Sicily (southern Italy) characterized by differing environmental conditions. Nineteen elements (Al, As, Ba, Cd, Co, Cr, Cu, Li, Mn, Mo, Ni, Pb, Rb, Sb, Se, Sr, U, V and Zn) were determined by inductively coupled plasma mass spectrometry (ICP-MS). Coverage intervals (CI) formulated by the elemental composition of hair samples from the Palermo subjects were compared with the median content of hair from children living in the other study areas. Statistical analysis showed that Al, Ba, Sr and Zn concentrations differed significantly between gender, higher concentrations being observed in girls' hair. Children living close to the volcanic area had higher concentrations of As, Cr, Mn, Ni, Rb, Sb, U, V and Zn. Those living in an area with several old quarries had higher levels of Al, As, Pb, Rb and U. The hair of children living near the Pace del Mela industrial area contained higher levels of As, Ba, Mn, Pb, Rb, Sr and U. Linear discriminant analysis (LDA) between Palermo and the other sites allowed to better assess which variables contribute towards differentiating the groups. Our observations suggest that human hair can be used to monitor exposure to several metals, provided that sampling and analytical procedures, together with statistical treatment of data, are carried out according to standardized protocols. PMID- 22522427 TI - Ecotoxicological risks associated with tannery effluent wastewater. AB - The problem of water pollution acquires greater relevance in the context of a developing agrarian economy like Pakistan. Even though, the leather industry is a leading economic sector in Pakistan, there is an increasing environmental concern regarding tanneries because they produce large amounts of potentially toxic wastewater containing both trivalent and hexavalent chromium, which are equally hazardous for human population, aquaculture and agricultural activities in the area. Therefore, we defined the scope of the present study as to employ different bioassays to determine the eco-toxic potential of tannery effluent wastewater (TW) and its chromium based components, i.e., potassium dichromate (K(2)Cr(2)O(7)) and chromium sulfate Cr(2)(SO(4))(3). Particle-induced X-ray emission (PIXE) analysis of TW was carried out to determine the concentration of chromium in TW and then equal concentrations of hexavalent (K(2)Cr(2)O(7)) and trivalent chromium Cr(2)(SO(4))(3) were obtained for this study. Cytotoxicity assay, artemia bioassay and phytotoxicity assay was utilized to investigate the eco-toxicological potential of different concentrations of TW, K(2)Cr(2)O(7) and Cr(2)(SO(4))(3). All the dilutions of TW, K(2)Cr(2)O(7) and Cr(2)(SO(4))(3) presented concentration dependent cytotoxic effects in these assays. The data clearly represents that among all three tested materials, different dilutions of K(2)Cr(2)O(7) caused significantly more damage (P<0.001) to vero cell, brine shrimp and germination of maize seeds. Interestingly, the overall toxicity effects of TW treated groups were subsequent to K(2)Cr(2)O(7) treated group. Based on biological evidences presented in this article, it is concluded that hexavalent chromium (K(2)Cr(2)O(7)) and TW has got significant eco-damaging potential clearly elaborating that environmental burden in district Kasur is numerous and high levels of chromium is posing a considerable risk to the human population, aquaculture and agricultural industry that can obliterate ecosystem surrounding the tanneries. PMID- 22522428 TI - Aerobic fitness enhances relational memory in preadolescent children: the FITKids randomized control trial. AB - It is widely accepted that aerobic exercise enhances hippocampal plasticity. Often, this plasticity co-occurs with gains in hippocampal-dependent memory. Cross-sectional work investigating this relationship in preadolescent children has found behavioral differences in higher versus lower aerobically fit participants for tasks measuring relational memory, which is known to be critically tied to hippocampal structure and function. The present study tested whether similar differences would arise in a clinical intervention setting where a group of preadolescent children were randomly assigned to a 9-month after school aerobic exercise intervention versus a wait-list control group. Performance measures included eye-movements as a measure of memory, based on recent work linking eye-movement indices of relational memory to the hippocampus. Results indicated that only children in the intervention increased their aerobic fitness. Compared to the control group, those who entered the aerobic exercise program displayed eye-movement patterns indicative of superior memory for face scene relations, with no differences observed in memory for individual faces. The results of this intervention study provide clear support for the proposed linkage among the hippocampus, relational memory, and aerobic fitness, as well as illustrating the sensitivity of eye-movement measures as a means of assessing memory. PMID- 22522430 TI - Down-regulation of NLRP3 inflammasome in gingival fibroblasts by subgingival biofilms: involvement of Porphyromonas gingivalis. AB - Recognition of pathogen-associated molecular patterns that activate IL-1beta is regulated by inflammasomes, predominantly of the nucleotide-binding oligomerization domain-like receptor (NLR) family. NLRP3 inflammasome is involved in the innate immune responses in periodontal disease. This is an inflammatory condition that destroys the tooth-supporting (periodontal) tissues, initiated by the subgingival formation of multi-species biofilms, frequently including the Gram-negative species Porphyromonas gingivalis. The aim of this study was to investigate the relative effect of P. gingivalis as part of subgingival biofilm, on the expressions of NLRP3 inflammasome, absent in melanoma (AIM)2 (a non-NLR inflammsome) and IL-1beta by human gingival fibroblasts. The 10-species subgingival biofilm model, or its 9-species variant excluding P. gingivalis, were used to challenge the cells for 6 h. Gene expression analysis for various inflammasome components and IL-1beta was performed by TaqMan real-time PCR. The 10-species subgingival biofilm reduced NLRP3 and IL-1beta, but did not affect AIM2 expression. Exclusion of P. gingivalis from the biofilm partially rescued NLRP3 and IL-1beta expressions. In conclusion, subgingival biofilms down-regulate NLRP3 and IL-1beta expression, partly because of P. gingivalis. These dampened host innate immune responses may favour the survival and persistence of the associated biofilm species in the periodontal tissues. PMID- 22522429 TI - The role of microRNAs miR-200b and miR-200c in TLR4 signaling and NF-kappaB activation. AB - Recognition of microbial products by members of the Toll-like receptor (TLR) family initiates intracellular signaling cascades that result in NF-kappaB activation and subsequent production of inflammatory cytokines. We explored the potential roles of microRNAs (miRNAs) in regulating TLR pathways. A target analysis approach to the TLR4 pathway adaptor molecules identified several putative targets of miR-200a, miR-200b and miR-200c. miRNA mimics were co transfected with a NF-kappaB activity reporter plasmid into HEK293 cells stably expressing TLR4 (HEK293-TLR4). Mimics of both miR-200b and miR-200c, but not miR 200a, decreased NF-kappaB reporter activity in either untreated cells or in cells treated with endotoxin:MD2 as a TLR4 agonist. Transfection of HEK293-TLR4 cells with miR-200b or miR-200c significantly decreased expression of MyD88, whereas TLR4, IRAK-1 and TRAF-6 mRNAs were unaffected. When miR-200b or miR-200c mimics were transfected into the differentiated monocytic THP-1 cell line, the abundance of MyD88 transcripts, as well as LPS-induced expression of the pro-inflammatory molecules IL-6, CXCL9 and TNF-alpha were diminished. These data define miRNAs miR 200b and miR-200c as factors that modify the efficiency of TLR4 signaling through the MyD88-dependent pathway and can thus affect host innate defenses against microbial pathogens. PMID- 22522431 TI - Choosing the best rehabilitation treatment for Bell's palsy. AB - BACKGROUND: It is useful to perform neurophysiologic electromyography and electroneurography (EMG/ENG) on patients with peripheral facial palsy during the acute phase of paralysis in order to assess the severity of their nerve lesion and thus plan rehabilitation treatment and evaluate its results. AIM: To evaluate the motor recovery of patients with Bell's palsy with respect to the severity of their neurological lesion and to compare the results of two different rehabilitation treatments, with electromyographic biofeedback (EMG-BFB) and mirror visual biofeedback (mirror-BFB), in patients with Bell's palsy and neurophysiologic pattern of axonotmesis. STUDY DESIGN: Cohort study on retrospective clinical records. POPULATION: 102 patients with Bell's facial palsy were clinically assessed according to the House scale both during the acute phase of paralysis and 12 months after onset. METHODS: All patients underwent EMG/ENG examination 3-4 weeks after the onset of paralysis; 29 patients had an EMG pattern of neurapraxia and were not given rehabilitation treatment; 73 patients who presented with signs of denervation had an EMG pattern of axonotmesis. The group, which was homogenous in terms of lesion severity, was divided into two parts: 38 patients were treated with electromyographic biofeedback (EMG-BFB) and 35 were treated with mirror visual feedback (mirror-BFB). RESULTS: All 29 patients with neurapraxia made a full spontaneous recovery; Although the 73 patients with axonotmesis received different types of rehabilitation treatment, they obtained similar results regarding quality of recovery, development of synkinesis, rehabilitation timing and resources used. CONCLUSION AND CLINICAL REHABILITATION IMPACT: Rehabilitation treatment is not necessary for patients with neurapraxia. The two biofeedback methods used to treat patients with axonotmesis resulted in similar rehabilitation outcomes. PMID- 22522432 TI - Action observation and mirror neuron network: a tool for motor stroke rehabilitation. AB - Mirror neurons are a specific class of neurons that are activated and discharge both during observation of the same or similar motor act performed by another individual and during the execution of a motor act. Different studies based on non invasive neuroelectrophysiological assessment or functional brain imaging techniques have demonstrated the presence of the mirror neuron and their mechanism in humans. Various authors have demonstrated that in the human these networks are activated when individuals learn motor actions via execution (as in traditional motor learning), imitation, observation (as in observational learning) and motor imagery. Activation of these brain areas (inferior parietal lobe and the ventral premotor cortex, as well as the caudal part of the inferior frontal gyrus [IFG]) following observation or motor imagery may thereby facilitate subsequent movement execution by directly matching the observed or imagined action to the internal simulation of that action. It is therefore believed that this multi-sensory action-observation system enables individuals to (re) learn impaired motor functions through the activation of these internal action-related representations. In humans, the mirror mechanism is also located in various brain segment: in Broca's area, which is involved in language processing and speech production and not only in centres that mediate voluntary movement, but also in cortical areas that mediate visceromotor emotion-related behaviours. On basis of this finding, during the last 10 years various studies were carry out regarding the clinical use of action observation for motor rehabilitation of sub-acute and chronic stroke patients. PMID- 22522434 TI - Pediatric rehabilitation of severe acquired brain injury: a multicenter survey. AB - BACKGROUND: Epidemiological and descriptive data concerning the clinical and socio-demographic characteristics of severe acquired brain injuries (ABI) in pediatric age are meager. In particular, in Italy we only find data concerning traumatic brain injury (TBI) in adults. Earlier data show that the most prevalent etiology in ABI is traumatic and that greater clinical impairments are reported for patients with non-traumatic etiologies. AIM: The main aims of the GISCAR (Gruppo Italiano per lo Studio delle Gravi Cerebrolesioni Acquisite e Riabilitazione) study are: 1) to define the clinical features of pediatric patients with severe neurological disabilities; 2) to determine the etiology and onset modality of the cerebral lesions; and 3) to analyse the characteristics of the rehabilitation processes and patient outcome in terms of disability, strategies for treatment and clinical picture. DESIGN: Quasi-epidemiologic. SETTING: In-patient. POPULATION: 184 pediatric patients with severe ABI were recruited. METHODS: Data collection was done by means of an assessment protocol created and used by a group of Italian neurorehabilitation centers. Traumatic and non traumatic aetiologies (NTBI) have been treated separately. RESULTS: Traumatic etiology of ABI is the most prevalent (51.6%, N. 95) and about twice as many males as females are involved. Of these cases, 70.5% (N. 67) are the result of a car accident, either as a pedestrian or as a passenger, representing a crucial area for preventive action by the public health services. Eighty-six (46.7%) patients were in the acute state, 19 (10.3%) in subacute state and 76 (42.9%) in chronic condition. The results show that the positive trend for the TBI group was steeper than for NTBIs. Neuropsychological data are also discussed. CONCLUSIONS AND CLINICAL REHABILITATION IMPACT: We report the first Italian descriptive study on pediatric patients affected by ABI of traumatic or non traumatic etiology. The main points concerning rehabilitation are that major differences between aetiologies must be taken into account and that ABI of any severity in the acute phase may lead to long term disability, confirming the high social and economic impact of this pathology. Our study demonstrates the great importance of providing specialised rehabilitation centers for pediatric patients, and increases awareness of the importance of ABI prevention. PMID- 22522435 TI - Impact of participation on rehabilitation results: a multivariate study. AB - BACKGROUND: Participation in inpatients is commonly considered as a relevant factor influencing rehabilitation results, but its effects are still not exhaustively investigated. AIM: To clarify and quantify the impact of level of participation in rehabilitation on functional outcome in inpatients. DESIGN: Prospective, observational multivariate study. SETTINGS: Rehabilitation hospital. POPULATION: Three hundred and sixty-two patients (mean age 59.41+/-12.85 years) with stroke or orthopedic diseases consecutively admitted to rehabilitation hospital. METHODS: Rehabilitation program participation was assessed by means of Pittsburgh Rehabilitation Participation Scale (PRPS). Patients who scored below 4 in 25% of the physical and occupational therapy treatment were classified as "low" participants. Multiple and logistic regressions were performed to identify variables associated not only with participation but also with rehabilitation results. RESULTS: Nearly one third of patients (33.88%, primarily stroke) showed low participation. Low early participation (within the first two weeks) was associated with disability and depressive symptoms at admission, and late participation with early participation, age and years of schooling. Both early and late participation were associated with effectiveness of treatment on both ADL and mobility, even if there was much unexplained variance in both models. Patients with low early participation had a greater risk (OR=2.45, 95% CI 1.27 4.71) of a low response to treatment on mobility than the patients who had participated more. Among other prognostic factors, early start of rehabilitation treatment and the presence of cognitive and neuropsychological impairments have significant roles. CONCLUSIONS: Our results confirm the importance of participation in rehabilitation programs, which should be encouraged. Further studies are needed to improve knowledge about the overall effects of participation. CLINICAL REHABILITATION IMPACT: Early participation should be considered a treatment target as well as a prognostic factor. PMID- 22522437 TI - Misfiring in multiple sclerosis: cerebellar channelopathy, a potential novel target? PMID- 22522438 TI - Brain death in children: why does it have to be so complicated? PMID- 22522436 TI - The pituitary tumor transforming gene in thyroid cancer. AB - The pituitary tumor transforming gene (PTTG) is a multifunctional proto-oncogene that is over-expressed in various tumors including thyroid carcinomas, where it is a prognostic indicator of tumor recurrence. PTTG has potent transforming capabilities in vitro and in vivo, and many studies have investigated the potential mechanisms by which PTTG contributes to tumorigenesis. As the human securin, PTTG is involved in critical mechanisms of cell cycle regulation, whereby aberrant expression induces aneuploidy. PTTG may further contribute to tumorigenesis through its role in DNA damage response pathways and via complex interactions with hormones and growth factors. Furthermore, PTTG over-expression negatively impacts upon the efficacy of radioiodine therapy in thyroid cancer, through repression of expression and function of the sodium iodide symporter. Given its various roles at all disease stages, PTTG appears to be an important oncogene in thyroid cancer. This review discusses the current knowledge of PTTG with particular focus on its role in thyroid cancer. PMID- 22522439 TI - COL4A1 mutations in patients with sporadic late-onset intracerebral hemorrhage. AB - OBJECTIVE: Mutations in the type IV collagen alpha 1 gene (COL4A1) cause dominantly inherited cerebrovascular disease. We seek to determine the extent to which COL4A1 mutations contribute to sporadic, nonfamilial, intracerebral hemorrhages (ICHs). METHODS: We sequenced COL4A1 in 96 patients with sporadic ICH. The presence of putative mutations was tested in 145 ICH-free controls. The effects of rare coding variants on COL4A1 biosynthesis were compared to previously validated mutations that cause porencephaly, small vessel disease, and hereditary angiopathy, nephropathy, aneurysms, and cramps (HANAC) syndrome. RESULTS: We identified 2 rare nonsynonymous variants in ICH patients that were not detected in controls, 2 rare nonsynonymous variants in controls that were not detected in patients, and 2 common nonsynonymous variants that were detected in patients and controls. No variant found in controls affected COL4A1 biosynthesis. Both variants (COL4A1(P352L) and COL4A1(R538G)) found only in patients changed conserved amino acids and impaired COL4A1 secretion much like mutations that cause familial cerebrovascular disease. INTERPRETATION: This is the first assessment of the broader role for COL4A1 mutations in the etiology of ICH beyond a contribution to rare and severe familial cases and the first functional evaluation of the biosynthetic consequences of an allelic series of COL4A1 mutations that cause cerebrovascular disease. We identified 2 putative mutations in 96 patients with sporadic ICH and showed that these and other previously validated mutations inhibit secretion of COL4A1. Our data support the hypothesis that increased intracellular accumulation of COL4A1, decreased extracellular COL4A1, or both, contribute to sporadic cerebrovascular disease and ICH. PMID- 22522440 TI - Adipocytokines and the risk of ischemic stroke: the PRIME Study. AB - OBJECTIVE: Adipocytokines are hormones secreted from adipose tissue that possibly link adiposity and the risk of cardiovascular disease, but limited prospective data exist on plasma adipocytokines and ischemic stroke risk. We investigated associations and predictive properties of 4 plasma adipocytokines, namely resistin, adipsin, leptin, and total adiponectin, with regard to incident ischemic stroke in the PRIME Study. METHODS: A cohort of 9,771 healthy men 50 to 59 years of age at baseline was followed up over a period of 10 years. In a nested case-control study, 95 ischemic stroke cases were matched with 190 controls on age, study center, and date of examination. Hazard ratios (HRs) per standard deviation increase in plasma adipocytokine levels were estimated using conditional logistic regression analysis. The additive value of adipocytokines in stroke risk prediction was evaluated by discrimination and reclassification metrics. RESULTS: Resistin (HR, 1.88; 95% confidence interval [CI], 1.16-3.03), adipsin (HR, 2.01; 95% CI, 1.33-3.04), and total adiponectin (HR, 1.53; 95% CI, 1.01-2.34), but not leptin, were independent predictors of ischemic stroke. The performance of a traditional risk factor model predicting ischemic stroke was significantly improved by the simultaneous inclusion of resistin, adipsin, and total adiponectin (c-statistic: 0.673 [95% CI, 0.631-0.766] vs 0.826 [95% CI, 0.792-0.892], p < 0.001; net reclassification improvement: 38.1%, p < 0.001). INTERPRETATION: Higher plasma levels of resistin, adipsin, and total adiponectin were associated with an increased 10-year risk of ischemic stroke among healthy middle-aged men. Resistin, adipsin, and total adiponectin provided incremental value over traditional risk factors for the prediction of ischemic stroke risk. PMID- 22522441 TI - FXN methylation predicts expression and clinical outcome in Friedreich ataxia. AB - OBJECTIVE: Friedreich ataxia (FA) is the most common ataxia and results from an expanded GAA repeat in the first intron of FXN. This leads to epigenetic modifications and reduced frataxin. We investigated the relationships between genetic, epigenetic, and clinical parameters in a large case-control study of FA. METHODS: Clinical data and samples were obtained from individuals with FA during annual visits to our dedicated FA clinic. GAA expansions were evaluated by polymerase chain reaction (PCR) and restriction endonuclease digest. DNA methylation was measured using bisulfite-based EpiTYPER MassARRAY (Sequenom, San Diego, CA). FXN expression was determined using real-time reverse transcriptase PCR. Significant correlations between the different parameters were examined using the nonparametric Spearman rank correlation coefficient, as well as univariate and multivariate regression modeling. RESULTS: Characteristic DNA methylation was identified upstream and downstream of the expansion, and validated in an independent FA cohort. Univariate and multivariate analyses showed significant inverse correlations between upstream methylation and FXN expression, and variation in downstream methylation and age of onset. FXN expression also inversely correlated with the Friedreich Ataxia Rating Scale score, an indicator of disease severity. INTERPRETATION: These novel findings provide compelling evidence for the link between the GAA expansion, the DNA methylation profile, FXN expression, and clinical outcome in FA. Epigenetic profiling of FXN could be used to gain greater insight into disease onset and progression, but also as a biomarker to learn more about specific treatment responses and pharmacological mechanism(s). This work also highlights the potential for developing therapies aimed at increasing frataxin levels to treat this debilitating disease. PMID- 22522442 TI - A rare recessive distal hereditary motor neuropathy with HSJ1 chaperone mutation. AB - OBJECTIVE: Distal hereditary motor neuropathies (dHMN) form a clinically and genetically heterogeneous group of disorders, characterized by muscle weakness and atrophy predominating at the distal part of the limbs, due to the progressive degeneration of motor neurons in the spinal cord. We report here a novel rare variant of dHMN with autosomal recessive inheritance in a large Jewish family originating from Morocco. The disease is characterized by a predominance of paralysis at the lower limbs and an early adulthood onset. We performed a genetic study in this family to identify and characterized the causing mutation. METHODS: Homozygosity mapping strategy and sequencing of the candidate genes were performed. Expression studies were made on patient fibroblasts. Functional experiments were performed on a cellular model of motor neuron disease. RESULTS: We mapped the disease to the 2q34-q36.1 chromosomal region and identified a homozygous splice mutation in the gene HSJ1 (DNAJB2) decreasing the expression of the 2 main isoforms HSJ1a and HSJ1b. Overexpression of both HSJ1a and HSJ1b reduced inclusion formation induced by the mutated SOD1-A4V in a neuronal cellular model. INTERPRETATION: HSJ1 is a neuronal enriched member of the HSP40/DNAJ co-chaperone family. Previous studies have shown that HSP40 proteins play a crucial role in protein aggregation and neurodegeneration in several neuronal types, in animal models and human diseases. Interestingly, this mutation causing a loss-of-function of HSJ1 is linked to a pure lower motor neuron disease, strongly suggesting that HSJ1 also plays an important and specific role in motor neurons. PMID- 22522443 TI - Sepiapterin reductase deficiency: a treatable mimic of cerebral palsy. AB - OBJECTIVE: Sepiapterin reductase deficiency (SRD) is an under-recognized levodopa responsive disorder. We describe clinical, biochemical, and molecular findings in a cohort of patients with this treatable condition. We aim to improve awareness of the phenotype and available diagnostic and therapeutic strategies to reduce delayed diagnosis or misdiagnosis, optimize management, and improve understanding of pathophysiologic mechanisms. METHODS: Forty-three individuals with SRD were identified from 23 international medical centers. The phenotype and treatment response were assessed by chart review using a detailed standardized instrument and by literature review for cases for which records were unavailable. RESULTS: In most cases, motor and language delays, axial hypotonia, dystonia, weakness, oculogyric crises, and diurnal fluctuation of symptoms with sleep benefit become evident in infancy or childhood. Average age of onset is 7 months, with delay to diagnosis of 9.1 years. Misdiagnoses of cerebral palsy (CP) are common. Most patients benefit dramatically from levodopa/carbidopa, often with further improvement with the addition of 5-hydroxytryptophan. Cerebrospinal fluid findings are distinctive. Diagnosis is confirmed by mutation analysis and/or enzyme activity measurement in cultured fibroblasts. INTERPRETATION: Common, clinical findings of SRD, aside from oculogyric crises and diurnal fluctuation, are nonspecific and mimic CP with hypotonia or dystonia. Patients usually improve dramatically with treatment. Consequently, we recommend consideration of SRD not only in patients with levodopa-responsive motor disorders, but also in patients with developmental delays with axial hypotonia, and patients with unexplained or atypical presumed CP. Biochemical investigation of cerebrospinal fluid is the preferred method of initial investigation. Early diagnosis and treatment are recommended to prevent ongoing brain dysfunction. PMID- 22522444 TI - Risk of intraparenchymal hemorrhage with magnetic resonance imaging-defined leukoaraiosis and brain infarcts. AB - OBJECTIVE: To determine whether the burden of leukoaraiosis and the number of brain infarcts, defined by magnetic resonance imaging (MRI), are prospectively and independently associated with intraparenchymal hemorrhage (IPH) incidence in a pooled population-based study. METHODS: Among 4,872 participants initially free of clinical stroke in the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study, we assessed white matter grade (range, 0-9), reflecting increasing leukoaraiosis, and brain infarcts using MRI. Over a median of 13 years of follow-up, 71 incident, spontaneous IPH events occurred. RESULTS: After adjustment for other IPH risk factors, the hazard ratios (95% confidence intervals) across white matter grades 0 to 1, 2, 3, and 4 to 9 were 1.00, 1.68 (0.86-3.30), 3.52 (1.80-6.89), and 3.96 (1.90-8.27), respectively (p for trend <0.0001). These hazard ratios were weakened only modestly (p for trend = 0.0003) with adjustment for MRI-defined brain infarcts. The IPH hazard ratios for 0, 1, 2, or >=3 MRI-defined brain infarcts were 1.00, 1.97 (1.10-3.54), 2.00 (0.83 4.78), and 3.12 (1.31-7.43) (p for trend = 0.002), but these were substantially attenuated when adjusted for white matter grade (p for trend = 0.049). INTERPRETATION: Greater MRI-defined burden of leukoaraiosis is a risk factor for spontaneous IPH. Spontaneous IPH should be added to the growing list of potential poor outcomes in people with leukoaraiosis. PMID- 22522446 TI - Hereditary sensory autonomic neuropathy caused by a mutation in dystonin. AB - In 4 infants with a new lethal autonomic sensory neuropathy with clinical features similar to familial dysautonomia as well as contractures, we identified a deleterious mutation in the DST gene, using homozygosity mapping followed by exome sequencing. DST encodes dystonin, a cytoskeleton linker protein, and the mutation results in an unstable transcript. Interestingly, dystonin is significantly more abundant in cells of familial dysautonomia patients with IKBKAP (I-kappa-B kinase complex-associated protein) mutation compared to fibroblasts of controls, suggesting that upregulation of dystonin is responsible for the milder course in familial dysautonomia. Homozygosity mapping followed by exome sequencing is a successful approach to identify mutated genes in rare monogenic disorders. PMID- 22522445 TI - Symptoms of rapid eye movement sleep behavior disorder are associated with cholinergic denervation in Parkinson disease. AB - OBJECTIVE: Rapid eye movement sleep behavior disorder (RBD) is common in Parkinson disease (PD), but its relationship to the varied neurotransmitter deficits of PD and prognostic significance remain incompletely understood. RBD and cholinergic system degeneration are identified independently as risk factors for cognitive impairment in PD. We aimed to assess the association between cholinergic denervation and symptoms of RBD in PD patients without dementia. METHODS: Eighty subjects with PD without dementia (age, 64.6 +/- 7.0 years; range, 50-82 years; 60 males, 20 females; mean Montreal Cognitive Assessment Test [MoCA] score, 26.2 +/- 2.1; range 21-30) underwent clinical assessment, neuropsychological testing, and [(11)C]methylpiperidyl propionate acetylcholinesterase and [(11)C]dihydrotetrabenazine (DTBZ) vesicular monoamine transporter type 2 positron emission tomography (PET) imaging. (11)C3-Amino-4-(2 dimethylaminomethyl-phenylsulfaryl)-benzonitrile (DASB) serotonin transporter PET imaging was performed in a subset of 35 subjects. The presence of RBD symptoms was determined using the Mayo Sleep Questionnaire. RESULTS: Twenty-seven of 80 subjects (33.8%) indicated a history of RBD symptoms. Subjects with and without RBD symptoms showed no significant differences in age, motor disease duration, MoCA, Unified Parkinson Disease Rating Scale motor scores, or striatal DTBZ binding. Subjects with RBD symptoms, in comparison to those without, exhibited decreased neocortical, limbic cortical, and thalamic cholinergic innervation (0.0213 +/- 0.0018 vs 0.0236 +/- 0.0022, t = 4.55, p < 0.0001; 0.0388 +/- 0.0029 vs 0.0423 +/- 0.0058, t = 2.85, p = 0.0056; 0.0388 +/- 0.0025 vs 0.0427 +/- 0.0042, t = 4.49, p < 0.0001, respectively). Brainstem and striatal DASB binding showed no significant differences between groups. INTERPRETATION: The presence of RBD symptoms in PD is associated with relative neocortical, limbic cortical, and thalamic cholinergic denervation although not with differential serotoninergic or nigrostriatal dopaminergic denervation. The presence of RBD symptoms may signal cholinergic system degeneration. PMID- 22522447 TI - Guidelines for the determination of brain death in infants and children: an update of the 1987 task force recommendations-executive summary. AB - OBJECTIVE: To review and revise the 1987 pediatric brain death guidelines. METHODS: Relevant literature was reviewed. Recommendations were developed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) system. CONCLUSIONS AND RECOMMENDATIONS: (1) Determination of brain death in term newborns, infants, and children is a clinical diagnosis based on the absence of neurologic function with a known irreversible cause of coma. Because of insufficient data in the literature, recommendations for preterm infants <37 weeks gestational age are not included in these guidelines. (2) Hypotension, hypothermia, and metabolic disturbances should be treated and corrected, and medications that can interfere with the neurologic examination and apnea testing should be discontinued allowing for adequate clearance before proceeding with these evaluations. (3) Two examinations including apnea testing with each examination separated by an observation period are required. Examinations should be performed by different attending physicians. Apnea testing may be performed by the same physician. An observation period of 24 hours for term newborns (37 weeks gestational age) to 30 days of age and 12 hours for infants and children (>30 days to 18 years) is recommended. The first examination determines the child has met the accepted neurologic examination criteria for brain death. The second examination confirms brain death based on an unchanged and irreversible condition. Assessment of neurologic function after cardiopulmonary resuscitation or other severe acute brain injuries should be deferred for 24 hours or longer if there are concerns or inconsistencies in the examination. (4) Apnea testing to support the diagnosis of brain death must be performed safely and requires documentation of an arterial PaCO(2) 20mmHg above the baseline and >=60mmHg with no respiratory effort during the testing period. If the apnea test cannot be safely completed, an ancillary study should be performed. (5) Ancillary studies (electroencephalogram and radionuclide cerebral blood flow) are not required to establish brain death and are not a substitute for the neurologic examination. Ancillary studies may be used to assist the clinician in making the diagnosis of brain death (a) when components of the examination or apnea testing cannot be completed safely due to the underlying medical condition of the patient; (b) if there is uncertainty about the results of the neurologic examination; (c) if a medication effect may be present; or (d) to reduce the interexamination observation period. When ancillary studies are used, a second clinical examination and apnea test should be performed, and components that can be completed must remain consistent with brain death. In this instance, the observation interval may be shortened, and the second neurologic examination and apnea test (or all components that are able to be completed safely) can be performed at any time thereafter. (6) Death is declared when these above criteria are fulfilled. PMID- 22522448 TI - Cerebral amyloid angiopathy in the elderly. PMID- 22522453 TI - The Proto-oncogene PKCiota regulates the alternative splicing of Bcl-x pre-mRNA. AB - Two splice variants derived from the Bcl-x gene via alternative 5' splice site selection (5'SS) are proapoptotic Bcl-x(s) and antiapoptotic Bcl-x(L). Previously, our laboratory showed that apoptotic signaling pathways regulated the alternative 5'SS selection via protein phosphatase-1 and de novo ceramide. In this study, we examined the elusive prosurvival signaling pathways that regulate the 5'SS selection of Bcl-x pre-mRNA in cancer cells. Taking a broad-based approach by using a number of small-molecule inhibitors of various mitogenic/survival pathways, we found that only treatment of non-small cell lung cancer (NSCLC) cell lines with the phosphoinositide 3-kinase (PI3K) inhibitor LY294002 (50 MUmol/L) or the pan-protein kinase C (PKC) inhibitor Go6983 (25 MUmol/L) decreased the Bcl-x(L)/(s) mRNA ratio. Pan-PKC inhibitors that did not target the atypical PKCs, PKCiota and PKCzeta, had no effect on the Bcl-x(L)/(s) mRNA ratio. Additional studies showed that downregulation of the proto-oncogene, PKCiota, in contrast to PKCzeta, also resulted in a decrease in the Bcl-x(L)/(s) mRNA ratio. Furthermore, downregulation of PKCiota correlated with a dramatic decrease in the expression of SAP155, an RNA trans-acting factor that regulates the 5'SS selection of Bcl-x pre-mRNA. Inhibition of the PI3K or atypical PKC pathway induced a dramatic loss of SAP155 complex formation at ceramide responsive RNA cis-element 1. Finally, forced expression of Bcl-x(L) "rescued" the loss of cell survival induced by PKCiota siRNA. In summary, the PI3K/PKCiota regulates the alternative splicing of Bcl-x pre-mRNA with implications in the cell survival of NSCLC cells. PMID- 22522455 TI - Overexpression of Aurora-A enhances invasion and matrix metalloproteinase-2 expression in esophageal squamous cell carcinoma cells. AB - Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers, and metastasis is the principal cause of death in ESCC patients. It has been shown that amplification and overexpression of mitotic serine/threonine kinase Aurora-A occur in several types of human tumors, including ESCC. Moreover, increase in expression levels of Aurora-A has been predicted to correlate with the grades of tumor differentiation and invasive capability. However, the mechanisms by which Aurora-A mediates its invasive effects still remain elusive. In this article, we showed that Aurora-A overexpression significantly increased cell migration and invasion as well as secretion and expression of matrix metalloproteinase-2 (MMP-2). Conversely, siRNA-mediated knockdown of Aurora-A expression in human ESCC cells led to inhibition of cell invasiveness as well as secretion and expression of MMP-2. In addition, Aurora-A overexpression increased phosphorylation levels of p38 mitogen-activated protein kinase (MAPK) and Akt, and the knockdown of Aurora-A by siRNA decreased the activity of p38 MAPK and Akt. Moreover, the blocking of the activity of above kinases using chemical inhibitors suppressed the ability of Aurora-A to induce MMP-2 secretion and expression as well as cell invasion. These data show that overexpression of Aurora-A contributes to the malignancy development of ESCC by enhancing tumor cell invasion as well as MMP-2 activity and expression, which can occur through signaling pathways involving p38 MAPK and Akt protein kinases. Taken together, these studies provide a molecular basis for promoting the role of Aurora-A in malignancy development of ESCC. PMID- 22522456 TI - STEAP proteins: from structure to applications in cancer therapy. AB - The human 6-transmembrane epithelial antigen of prostate (STEAP) family comprises STEAP1, STEAP2, STEAP3, and STEAP4. All of these proteins are unique to mammals and share an innate activity as metalloreductases, indicating their importance in metal metabolism. Overall, they participate in a wide range of biologic processes, such as molecular trafficking in the endocytic and exocytic pathways and control of cell proliferation and apoptosis. STEAP1 and STEAP2 are overexpressed in several types of human cancers, namely prostate, bladder, colon, pancreas, ovary, testis, breast, cervix, and Ewing sarcoma, but their clinical significance and role in cancer cells are not clear. Still, their localization in the cell membrane and differential expression in normal and cancer tissues make STEAP proteins potential candidates as biomarkers of several cancers, as well as potential targets for new immunotherapeutic strategies for disease attenuation or treatment. This review brings together the current knowledge about each STEAP protein, giving an overview of the roles of this family of proteins in human physiology and disease, and analyzes their potential as immunotherapeutic agents in cancer research. PMID- 22522454 TI - TGF-beta1 induces endothelial cell apoptosis by shifting VEGF activation of p38(MAPK) from the prosurvival p38beta to proapoptotic p38alpha. AB - TGF-beta1 and VEGF, both angiogenesis inducers, have opposing effects on vascular endothelial cells. TGF-beta1 induces apoptosis; VEGF induces survival. We have previously shown that TGF-beta1 induces endothelial cell expression of VEGF, which mediates TGF-beta1 induction of apoptosis through activation of p38 mitogen activated protein kinase (MAPK). Because VEGF activates p38(MAPK) but protects the cells from apoptosis, this finding suggested that TGF-beta1 converts p38(MAPK) signaling from prosurvival to proapoptotic. Four isoforms of p38(MAPK) alpha, beta, gamma, and delta-have been identified. Therefore, we hypothesized that different p38(MAPK) isoforms control endothelial cell apoptosis or survival, and that TGF-beta1 directs VEGF activation of p38(MAPK) from a prosurvival to a proapoptotic isoform. Here, we report that cultured endothelial cells express p38alpha, beta, and gamma. VEGF activates p38beta, whereas TGF-beta1 activates p38alpha. TGF-beta1 treatment rapidly induces p38alpha activation and apoptosis. Subsequently, p38alpha activation is downregulated, p38beta is activated, and the surviving cells become refractory to TGF-beta1 induction of apoptosis and proliferate. Gene silencing of p38alpha blocks TGF-beta1 induction of apoptosis, whereas downregulation of p38beta or p38gamma expression results in massive apoptosis. Thus, in endothelial cells p38alpha mediates apoptotic signaling, whereas p38beta and p38gamma transduce survival signaling. TGF-beta1 activation of p38alpha is mediated by VEGF, which in the absence of TGF-beta1 activates p38beta. Therefore, these results show that TGF-beta1 induces endothelial cell apoptosis by shifting VEGF signaling from the prosurvival p38beta to the proapoptotic p38alpha. PMID- 22522457 TI - Inhibition of Eg5 acts synergistically with checkpoint abrogation in promoting mitotic catastrophe. AB - The G(2) DNA damage checkpoint is activated by genotoxic agents and is particularly important for cancer therapies. Overriding the checkpoint can trigger precocious entry into mitosis, causing cells to undergo mitotic catastrophe. But some checkpoint-abrogated cells can remain viable and progress into G(1) phase, which may contribute to further genome instability. Our previous studies reveal that the effectiveness of the spindle assembly checkpoint and the duration of mitosis are pivotal determinants of mitotic catastrophe after checkpoint abrogation. In this study, we tested the hypothesis whether mitotic catastrophe could be enhanced by combining genotoxic stress, checkpoint abrogation, and the inhibition of the mitotic kinesin protein Eg5. We found that mitotic catastrophe induced by ionizing radiation and a CHK1 inhibitor (UCN-01) was exacerbated after Eg5 was inhibited with either siRNAs or monastrol. The combination of DNA damage, UCN-01, and monastrol sensitized cancer cells that were normally resistant to checkpoint abrogation. Importantly, a relatively low concentration of monastrol, alone not sufficient in causing mitotic arrest, was already effective in promoting mitotic catastrophe. These experiments suggest that it is possible to use sublethal concentrations of Eg5 inhibitors in combination with G(2) DNA damage checkpoint abrogation as an effective therapeutic approach. PMID- 22522459 TI - Lithium phenolates with a hexagonal-prismatic Li6O6 core isolated via a cage shaped tripodal ligands system: crystal structures and their behavior in solution. AB - Stable hexanuclear lithium phenolate bearing a cage-shaped tripodal ligand was isolated, which had a hexagonal-prismatic Li(6)O(6) core at room temperature, because of the hard mobility of the ligand and its reduction of the problematic steric repulsion. The properties of the lithium phenolates were analyzed by X-ray crystallography and NMR spectroscopy. PMID- 22522458 TI - Heparin-like polysaccharides reduce osteolytic bone destruction and tumor growth in a mouse model of breast cancer bone metastasis. AB - TGF-beta regulates several steps in cancer metastasis, including the establishment of bone metastatic lesions. TGF-beta is released from bone during osteoclastic bone resorption and it stimulates breast cancer cells to produce osteolytic factors such as interleukin 11 (IL-11). We conducted a cell-based siRNA screen and identified heparan sulfate 6-O-sulfotransferase 2 (HS6ST2) as a critical gene for TGF-beta-induced IL-11 production in highly bone metastatic MDA MB-231(SA) breast cancer cells. HS6ST2 attaches sulfate groups to glucosamine residues in heparan sulfate glycosaminoglycans. We subsequently showed how heparin and a high-molecular-weight Escherichia coli K5-derived heparin-like polysaccharide (K5-NSOS) inhibited TGF-beta-induced IL-11 production in MDA-MB 231(SA) cells. In addition, K5-NSOS inhibited bone resorption activity of human osteoclasts in vitro. We evaluated the therapeutic potential of K5-NSOS and fragmin in a mouse model of breast cancer bone metastasis. MDA-MB-231(SA) cells were inoculated into the left cardiac ventricle of athymic nude mice which were treated with fragmin, K5-NSOS, or vehicle once a day for four weeks. Both heparin like glycosaminoglycans inhibited weight reduction, decreased osteolytic lesion area, and reduced tumor burden in bone. In conclusion, our data imply novel mechanisms involved in TGF-beta induction and support the critical role of heparan sulfate glycosaminoglycans in cancer metastasis as well as indicate that K5-NSOS is a potential antimetastatic and antiresorptive agent for cancer therapy. This study illustrates the potential to translate in vitro siRNA screening results toward in vivo therapeutic concepts. PMID- 22522460 TI - Printed silver nanowire antennas with low signal loss at high-frequency radio. AB - Silver nanowires are printable and conductive, and are believed to be promising materials in the field of printed electronics. However, the resistivity of silver nanowire printed lines is higher than that of metallic particles or flakes even when sintered at high temperatures of 100-400 degrees C. Therefore, their applications have been limited to the replacement of transparent electrodes made from high-resistivity materials, such as doped metallic oxides, conductive polymers, carbon nanotubes, or graphenes. Here we report that using printed silver nanowire lines, signal losses obtained in the high-frequency radio were lower than those obtained using etched copper foil antennas, because their surfaces were much smoother than those of etched copper foil antennas. This was the case even though the resistivity of silver nanowire lines was 43-71 MUOmega cm, which is much higher than that of etched copper foil (2 MUOmega cm). When printed silver nanowire antennas were heated at 100 degrees C, they achieved signal losses that were much lower than those of silver paste antennas comprising microparticles, nanoparticles, and flakes. Furthermore, using a low temperature process, we succeeded in remotely controlling a commercialized radio-controlled car by transmitting a 2.45 GHz signal via a silver nanowire antenna printed on a polyethylene terephthalate film. PMID- 22522461 TI - [Trans-scrotal penile degloving, a new procedure for corporoplasties]. AB - INTRODUCTION: The subcoronal approach is the most widely used skin degloving procedure for corporoplasty. Although it is relatively easy and it fully exposes the corpora cavernosa, it is not free from several complications (subcoronal lymphedema, decrease of glans sensitivity, paraphimosis, distal skin necrosis), which sometimes require a postoperative circumcision, or a preoperative prophylactic circumcision. AIM: To describe our own degloving approach, the "Trans-scrotal Penile Degloving (TPD)", that is suitable for most corporoplasties, and to present the outcomes. METHODS: This is a retrospective analysis conducted on 89 patients (pts) presenting with different penile diseases, and submitted to the TPD during Corporoplasty, from February 2008 to July 2010: Congenital curvature (26 pts); Peyronie's Disease (PD) with penile curvature (18 pts); PD with erectile dysfunction and curvature (25 pts); Redo surgery with complex tunica albuginea remodeling and prosthesis implant (20 pts). The TPD approach calls for a 5 cm incision to be placed ventrally on the scrotal raphe at the penile base: penile degloving is then easily carried out up to the coronal line. Subsequently, the dorsal neurovascular bundle is normally isolated and all types of different corporoplasties can be carried out. RESULTS: Any complication occurring during or after surgery has been registered. Patient follow-up controls were performed on day 7, month 1 and month 3 post-surgery: -No pre- or post-operative circumcision procedures were required; -There was no evidence of post-operative preputial edema or penile skin necrosis or loss of glans sensitivity; -In 6 patients, we noted a mild scrotal sub-dartos hematoma, which reabsorbed spontaneously. CONCLUSIONS: TPD, which represents an evolution of our previous combined subcoronal-trans-scrotal approach, may be advantageously performed in most corporoplasties with optimal aesthetic and functional outcomes, and may replace in many cases the subcoronal approach without its associated complications. PMID- 22522462 TI - [Therapy for non-muscle invasive bladder cancer: HP-NAP]. AB - PURPOSE: Patients with non-muscle invasive bladder cancer recurrence after 2 induction courses of BCG are eligible for radical cystectomy. So, in the last years research to discover new drugs for the management of non-muscle invasive bladder cancer recurrence after failure of first and second line therapy is ongoing. In accordance to the results obtained with BCG, whose mechanism depends on the induction of the T helper 1 (TH1) immune response, we investigated the activity of a Toll-like receptor (TLR) 2 ligand, named Helicobacter Pylori Neutrophil Activating Protein (HP-NAP), that we recently demonstrated being able of enhancing the differentiation of Th1 cells, both in vitro and in vivo, because of its ability to create an IL-12 enriched milieu. MATERIALS AND METHODS: We show here, in a mouse model of bladder neoplasm implants, that local administration of HP-NAP decreases tumor growth by inducing tumor necrosis. RESULTS: The result is joined up with a massive cluster of both CD4+ and CD8+ IFN-gamma+ cells, within neoplasm and regional lymph nodes. It is of note that HP-NAP-treated tumors show also a reduced vascularization due to the anti-angiogenic activity of IFN-gamma induced by HP-NAP. CONCLUSIONS: The present study suggests that the activity of HP-NAP against urothelial tumor burden warrants subsequent in vivo studies. PMID- 22522463 TI - [Accuracy of endorectal Magnetic Resonance Imaging (MRI) and Dynamic Contrast Enhanced-MRI (DCE-MRI) in the preoperative local staging of prostate cancer]. AB - BACKGROUND: The proper management of newly diagnosed prostate cancer (PCa) requires the choice of the appropriate treatment plan. A crucial factor is the accurate evaluation of the tumor local extension. The Magnetic Resonance Imaging (MRI) plays an important role in the local staging of prostate cancer, although its use in clinical practice is widely debated. Therefore, the purpose of our study was to evaluate the diagnostic accuracy of T2-weighted MR imaging in association with DCE-MRI, performed using an endorectal coil, in preoperative local staging of patients with prostate cancer, by using the histopathologic findings as the reference standard. MATERIALS AND METHODS: From April 2010 to May 2011, 65 patients (mean age, 65 years; range, 51-77 years) with clinical localized PCa, underwent radical prostatectomy at our institution, performed by 2 experienced surgeons. All patients were prospectively evaluated with eMRI in association with DCE-MRI prior to radical prostatectomy. In all patients MRI was performed at least 6 weeks after biopsy and within 2 weeks before Radical Prostatectomy (RP). Histologic analysis was our diagnostic "gold standard". To ensure that the histopathological findings matched with MR images, the assessment of radiological images and the RP specimens were performed dividing the prostate in 14 regions. RESULTS: First, we performed a "per-patient" analysis, considering the entire prostate as a single region. Then, we performed a "per-emigland" analysis, finally a "per-region" analysis. The sensitivity, specificity, PPV, NPV and AUC in predicting ECE in the analysis "per-emigland" were respectively 66.7, 95.7, 66.7, 95.7, 0.824. The evaluation of SVI reported similar results: 62.5, 97.5, 62.5, 97.5, 0.797. DCE-MRI did not improve the diagnostic accuracy of T1-T2 weighted MR images in the evaluation of ECE or SVI. CONCLUSIONS: T1-, T2-weighted MRI adds important information regarding the preoperative local staging of PCa. DCE-MRI does not improve the diagnostic accuracy of MRI in the local staging of PCa. PMID- 22522464 TI - [The relationship between oxidative stress and obesity in prostate disease]. AB - Recent data suggest that chronic increment of reactive oxygen species (ROS) may be involved in the development and progression of chronic prostatic disease, such as BPH and PCa; adipose tissue produces bioactive substances called adipokines, also involved in the production of ROS. Our study aims to evaluate the relationship between obesity and oxidative stress in prostate disease. PMID- 22522465 TI - Spatial summation of neurometabolic coupling in the central visual pathway. AB - Noninvasive neural imaging has become an important tool in both applied and theoretical applications. The hemodynamic properties that are measured in functional magnetic resonance imaging (fMRI), for example, are generally used to infer neuronal characteristics. In an attempt to provide empirical data to connect the hemodynamic measurements with neural function, we have conducted previous studies in which neural activity and tissue oxygen metabolic functions are determined together in co-localized regions of the central visual pathway. A basic question in this procedure is whether oxygen responses are coupled linearly in space and time with neural activity. We have previously examined temporal factors, and in the current study, spatial characteristics are addressed. We have recorded from neurons in the lateral geniculate nucleus (LGN) and striate cortex in anesthetized cats. In both structures, there is a classical receptive field (CRF) within which a neuron can be activated. There is also a region outside the CRF from which stimulation cannot activate the cell directly but can influence the response elicited from the CRF. In this investigation we have used several specific spatial stimulus patterns presented to either the CRF or the surrounding region or to both areas together in order to determine spatial response patterns. Within the CRF, we find that neural and metabolic responses sum in a nonlinear fashion but changes in these two measurements are closely coupled. For stimuli that extend beyond the CRF, neural activity is generally reduced while oxygen response exhibits uncoupled changes. PMID- 22522466 TI - Hypothalamic vasopressin system regulation by maternal separation: its impact on anxiety in rats. AB - Maternal separation (MS) has been used to model the causal relationship between early life stress and the later stress-over-reactivity and affective disorders. Arginine vasopressin (AVP) is among several factors reported to be abnormal. The role of AVP on anxiety is still unclear. In order to further investigate this causal relationship and its possible role in anxiogenesis, male rat pups were separated from their dams for 3h daily (3 hMS) from post-natal day (PND) 2 to PND15. Fos expression in AVP+ neurons in the hypothalamic paraventricular (PVN) and supraoptic nuclei (SON) triggered by 3 hMS, and AVP-mRNA expression, were examined at PND10 and PND21 respectively, whereas AVP-mRNA expression, PVN and SON volumes and plasma AVP concentration were assessed in adulthood. Elevated plus maze test (EPM) and Vogel conflict test (VCT) were also performed to evaluate unconditioned and conditioned anxious states at PND70-75. At PND10, a single 3hMS event increased Fos expression in AVP+ neurons fourfold in PVN and six to twelvefold in SON. AVP-mRNA was over-expressed in whole hypothalamus, PVN and SON between 122% and 147% at PND21 and PND63. Volumes of AVP-PVN and AVP-SON measured at PND75 had marked increases as well as AVP plasma concentration at 12h of water deprivation (WD). MS rats demonstrated a high conditioned anxious state under VCT paradigm whereas no difference was found under EPM. These data demonstrate direct relationships between enhanced AVP neuronal activation and a potentiated vasopressin system, and this latter one with high conditioned anxiety in MS male rats. PMID- 22522467 TI - Neuropeptide Y receptor-expressing dorsal horn neurons: role in nocifensive reflex and operant responses to aversive cold after CFA inflammation. AB - The spinal Neuropeptide Y (NPY) system is a potential target for development of new pain therapeutics. NPY and two of its receptors (Y1 and Y2) are found in the superficial dorsal horn of the spinal cord, a key area of nociceptive gating and modulation. Lumbar intrathecal injection of (NPY) is antinociceptive, reducing hyper-reflexia to thermal and mechanical stimulation, particularly after nerve injury and inflammation. We have also shown that intrathecal injection of the targeted cytotoxin, Neuropeptide Y-sap (NPY-sap), is also antinociceptive, reducing nocifensive reflex responses to noxious heat and formalin. In the present study, we sought to determine the role of dorsal horn Y1R-expressing neurons in pain by destroying them with NPY-sap and testing the rats on three operant tasks. Lumbar intrathecal NPY-sap (1) reduced Complete Freund's Adjuvant (CFA)-induced hyper-reflexia on the 10 degrees C cold plate, (2) reduced cold aversion on the thermal preference and escape tasks, (3) was analgesic to noxious heat on the escape task, (4) reduced the CFA-induced allodynia to cold temperatures experienced on the thermal preference, feeding interference, and escape tasks, and (5) did not inhibit or interfere with morphine analgesia. PMID- 22522469 TI - Dendritic spine pathology in epilepsy: cause or consequence? AB - Abnormalities in dendritic spines have commonly been observed in brain specimens from epilepsy patients and animal models of epilepsy. However, the functional implications and clinical consequences of this dendritic pathology for epilepsy are uncertain. Dendritic spine abnormalities may promote hyperexcitable circuits and seizures in some types of epilepsy, especially in specific genetic syndromes with documented dendritic pathology, but in these cases it is difficult to differentiate their effects on seizures versus other comorbidities, such as cognitive deficits and autism. In other situations, seizures themselves may cause damage to dendrites and dendritic spines and this seizure-induced brain injury may then contribute to progressive epileptogenesis, memory problems and other neurological deficits in epilepsy patients. The mechanistic basis of dendritic spine abnormalities in epilepsy has begun to be elucidated and suggests novel therapeutic strategies for treating epilepsy and its complications. PMID- 22522468 TI - Methods of dendritic spine detection: from Golgi to high-resolution optical imaging. AB - Dendritic spines, the bulbous protrusions that form the postsynaptic half of excitatory synapses, are one of the most prominent features of neurons and have been imaged and studied for over a century. In that time, changes in the number and morphology of dendritic spines have been correlated to the developmental process as well as the pathophysiology of a number of neurodegenerative diseases. Due to the sheer scale of synaptic connectivity in the brain, work to date has merely scratched the surface in the study of normal spine function and pathology. This review will highlight traditional approaches to the imaging of dendritic spines and newer approaches made possible by advances in microscopy, protein engineering, and image analysis. The review will also describe recent work that is leading researchers toward the possibility of a systematic and comprehensive study of spine anatomy throughout the brain. PMID- 22522470 TI - Stress, anxiety, and dendritic spines: what are the connections? AB - Stressful life events, especially those that induce fear, can produce a state of anxiety that is useful for avoiding similar fearful and potentially dangerous situations in the future. However, they can also lead to exaggerated states, which over time can produce mental illness. These changing states of readiness versus illness are thought to be regulated, at least in part, by alterations in dendritic and synaptic structure within brain regions known to be involved in anxiety. These regions include the amygdala, hippocampus, and prefrontal cortex. In this article, we review the reciprocal relationships between the expression of stress- and anxiety-related behaviors and stress-induced morphological plasticity as detected by changes in dendrites and spines in these three brain regions. We begin by highlighting the acute and chronic effects of stress on synaptic morphology in each area and describe some of the putative mechanisms that have been implicated in these effects. We then discuss the functional consequences of stress-induced structural plasticity focusing on synaptic plasticity as well as cognitive and emotional behaviors. Finally, we consider how these structural changes may contribute to adaptive behaviors as well as maladaptive responses associated with anxiety. PMID- 22522471 TI - Rapamycin attenuates aggressive behavior in a rat model of pilocarpine-induced epilepsy. AB - Psychiatric disorders are fairly common comorbidities of epilepsy in humans. Following pilocarpine-induced status epilepticus (SE), experimental animals not only developed spontaneous recurrent seizures, but also exhibited significantly elevated levels of aggressive behavior. The cellular and molecular mechanism triggering these behavioral alterations remains unclear. In the present study, we found that aggression is positively correlated with development of spontaneous seizures. Treatment with rapamycin, a potent mTOR (mammalian target of rapamycin pathway)-pathway inhibitor, markedly diminished aggressive behavior. Therefore, the mTOR pathway may have significance in the underlying molecular mechanism leading to aggression associated with epilepsy. PMID- 22522473 TI - Auditory perception of natural sound categories--an fMRI study. AB - Despite an extremely rich and complex auditory environment, human beings categorize sounds effortlessly. While it is now well-known that this ability is a result of complex interaction of bottom-up processing of low-level acoustic features and top-down influences like evolutionary relevance, it is yet unclear how these processes drive categorization. The objective of the current study was to use functional neuroimaging to investigate the contribution of these two processes for category selectivity in the cortex. We used a set of ecologically valid sounds that belonged to three different categories: animal vocalizations, environmental sounds and human non-speech sounds, all matched on acoustic structure attributes like harmonic-to-noise ratio to minimize differences in bottom-up processing as well as matched for familiarity to rule out other top down influences. Participants performed a loudness judgment task in the scanner and data were acquired using a sparse-temporal sampling paradigm. Our functional imaging results show that there is category selectivity in the cortex only for species-specific vocalizations and this is revealed in six clusters in the right and left STG/STS. Category selectivity was not observed for any other category of sounds. Our findings suggest a potential role of evolutionary relevance for cortical processing of sounds. While this seems to be an appealing proposition, further studies are required to explore the role of top-down mechanisms arising from such features to drive category selectivity in the brain. PMID- 22522472 TI - The trouble with spines in fragile X syndrome: density, maturity and plasticity. AB - Dendritic spines are the principal recipients of excitatory synaptic inputs and the basic units of neural computation in the mammalian brain. Alterations in the density, size, shape, and turnover of mature spines, or defects in how spines are generated and establish synapses during brain development, could all result in neuronal dysfunction and lead to cognitive and/or behavioral impairments. That spines are abnormal in fragile X syndrome (FXS) and in the best-studied animal model of this disorder, the Fmr1 knockout mouse, is an undeniable fact. But the trouble with spines in FXS is that the exact nature of their defect is still controversial. Here, we argue that the most consistent abnormality of spines in FXS may be a subtle defect in activity-dependent spine plasticity and maturation. We also propose some future directions for research into spine plasticity in FXS at the cellular and ultrastructural levels that could help solve a two-decade long riddle about the integrity of synapses in this prototypical neurodevelopmental disorder. PMID- 22522474 TI - Does the United States economy affect heart failure readmissions? A single metropolitan center analysis. AB - BACKGROUND: To determine the effects of the US economy on heart failure hospitalization rates. HYPOTHESIS: The recession was associated with worsening unemployment, loss of private insurance and prescription medication benefits, medication nonadherence, and ultimately increased rates of hospitalization for heart failure. METHODS: We compared hospitalization rates at a large, single, academic medical center from July 1, 2006 to February 28, 2007, a time of economic stability, and July 1, 2008 to February 28, 2009, a time of economic recession in the United States. RESULTS: Significantly fewer patients had private medical insurance during the economic recession than during the control period (36.5% vs 46%; P = 0.04). Despite this, there were no differences in the heart failure hospitalization or readmission rates, length of hospitalization, need for admission to an intensive care unit, in-hospital mortality, or use of guideline recommended heart failure medications between the 2 study periods. CONCLUSIONS: We conclude that despite significant effects on medical insurance coverage, rates of heart failure hospitalization at our institution were not significantly affected by the recession. Additional large-scale population-based research is needed to better understand the effects of fluctuations in the US economy on heart failure hospitalization rates. PMID- 22522475 TI - Cerebrospinal fluid proteomics: a new window for understanding human demyelinating disorders? PMID- 22522476 TI - Cell therapy for neonatal hypoxia-ischemia and cerebral palsy. AB - Perinatal hypoxic-ischemic brain injury remains a major cause of cerebral palsy. Although therapeutic hypothermia is now established to improve recovery from hypoxia-ischemia (HI) at term, many infants continue to survive with disability, and hypothermia has not yet been tested in preterm infants. There is increasing evidence from in vitro and in vivo preclinical studies that stem/progenitor cells may have multiple beneficial effects on outcome after hypoxic-ischemic injury. Stem/progenitor cells have shown great promise in animal studies in decreasing neurological impairment; however, the mechanisms of action of stem cells, and the optimal type, dose, and method of administration remain surprisingly unclear, and some studies have found no benefit. Although cell-based interventions after completion of the majority of secondary cell death appear to have potential to improve functional outcome for neonates after HI, further rigorous testing in translational animal models is required before randomized controlled trials should be considered. PMID- 22522477 TI - Proteomic pattern analysis discriminates among multiple sclerosis-related disorders. AB - OBJECTIVE: To use a new, unbiased biomarker discovery strategy to obtain and assess proteomic data from cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS)-related disorders. METHODS: CSF protein profiles were analyzed from 107 patients with either MS-related disorders (including relapsing remitting MS [RRMS], primary progressive MS [PPMS], anti-aquaporin4 antibody seropositive neuromyelitis optica spectrum disorder [SP-NMOSD], and seronegative-NMOSD with long cord lesions on spinal magnetic resonance imaging [SN-NMOSD]), amyotrophic lateral sclerosis (ALS), or other inflammatory neurological diseases (used as controls). CSF peptides/proteins were purified with magnetic beads, and directly measured by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The obtained spectra were analyzed with multivariate statistics and pattern matching algorithms. These analyses were replicated in an independent sample set of 84 patients composed of those with MS-related disorders or with other neurological diseases (the second cohort). RESULTS: MS-related disorders differed considerably in terms of CSF protein profiles. SP-NMOSD and SN-NMOSD, both of which fit within the NMO spectrum, were distinguishable from RRMS with high cross-validation accuracy on a support vector machine classifier, especially in relapse phases. Some peaks derived from samples of relapsed SP-NMOSD can discriminate RRMS with high area under curve scores (>0.95) and this was reproduced on the second cohort. The similarity of proteomic patterns between selected neurological diseases were demonstrated by pattern matching analysis. To our surprise, the spectral differences between RRMS and PPMS were much larger than those of PPMS and ALS. INTERPRETATION: Our findings suggest that CSF proteomic pattern analysis can increase the accuracy of disease diagnosis of MS related disorders and will aid physicians in appropriate therapeutic decision making. PMID- 22522478 TI - Symptomatic intracranial hemorrhage after stroke thrombolysis: the SEDAN score. AB - OBJECTIVE: A study was undertaken to develop a score for assessing risk for symptomatic intracranial hemorrhage (sICH) in ischemic stroke patients treated with intravenous (IV) thrombolysis. METHODS: The derivation cohort comprised 974 ischemic stroke patients treated (1995-2008) with IV thrombolysis at the Helsinki University Central Hospital. The predictive value of parameters associated with sICH (European Cooperative Acute Stroke Study II) was evaluated, and we developed our score according to the magnitude of logistic regression coefficients. We calculated absolute risks and likelihood ratios of sICH per increasing score points. The score was validated in 828 patients from 3 Swiss cohorts (Lausanne, Basel, and Geneva). Performance of the score was tested with area under a receiver operating characteristic curve (AUC-ROC). RESULTS: Our SEDAN score (0 to 6 points) comprises baseline blood Sugar (glucose; 8.1-12.0 mmol/l [145-216 mg/dl] = 1; >12.0 mmol/l [>216 mg/dl] = 2), Early infarct signs (yes = 1) and (hyper)Dense cerebral artery sign (yes = 1) on admission computed tomography scan, Age (>75 years = 1), and NIH Stroke Scale on admission (>=10 = 1). Absolute risk for sICH in the derivation cohort was: 1.4%, 2.9%, 8.5%, 12.2%, 21.7%, and 33.3% for 0, 1, 2, 3, 4, and 5 score points, respectively. In the validation cohort, absolute risks were similar (1.0%, 3.5%, 5.1%, 9.2%, 16.9%, and 27.8%, respectively). AUC-ROC was 0.77 (0.71-0.83; p < 0.001). INTERPRETATION: Our SEDAN score reliably assessed risk for sICH in IV thrombolysis-treated patients with anterior- and posterior circulation ischemic stroke, and it can support clinical decision making in high-risk patients. External validation of the score supports its generalization. PMID- 22522479 TI - Validation of the Charcot-Marie-Tooth disease pediatric scale as an outcome measure of disability. AB - OBJECTIVE: Charcot-Marie-Tooth disease (CMT) is a common heritable peripheral neuropathy. There is no treatment for any form of CMT, although clinical trials are increasingly occurring. Patients usually develop symptoms during the first 2 decades of life, but there are no established outcome measures of disease severity or response to treatment. We identified a set of items that represent a range of impairment levels and conducted a series of validation studies to build a patient-centered multi-item rating scale of disability for children with CMT. METHODS: As part of the Inherited Neuropathies Consortium, patients aged 3 to 20 years with a variety of CMT types were recruited from the USA, United Kingdom, Italy, and Australia. Initial development stages involved definition of the construct, item pool generation, peer review, and pilot testing. Based on data from 172 patients, a series of validation studies were conducted, including item and factor analysis, reliability testing, Rasch modeling, and sensitivity analysis. RESULTS: Seven areas for measurement were identified (strength, dexterity, sensation, gait, balance, power, endurance), and a psychometrically robust 11-item scale was constructed (CMT Pediatric Scale [CMTPedS]). Rasch analysis supported the viability of the CMTPedS as a unidimensional measure of disability in children with CMT. It showed good overall model fit, no evidence of misfitting items, and no person misfit, and it was well targeted for children with CMT. INTERPRETATION: The CMTPedS is a well-tolerated outcome measure that can be completed in 25 minutes. It is a reliable, valid, and sensitive global measure of disability for children with CMT from the age of 3 years. PMID- 22522480 TI - Childhood socioeconomic status and adult brain size: childhood socioeconomic status influences adult hippocampal size. AB - OBJECTIVE: To investigate in older adults without dementia the relationships between socioeconomic status (SES) in childhood and magnetic resonance imaging (MRI)-derived brain volume measures typical of brain aging and Alzheimer's disease (AD). METHODS: Using a cross-sectional and longitudinal observation approach, we invited volunteers without dementia, all born in 1936, and who were participants in the 1947 Scottish Mental Survey, for MR brain imaging; 249 of 320 (77%) agreed. We measured whole brain and hippocampal volumes and recorded childhood SES history, the number of years of education undertaken, and adult SES history. Mental ability at age 11 years was recorded in 1947 and was also available. RESULTS: Analysis shows a significant association between childhood SES and hippocampal volume after adjusting for mental ability at age 11 years, adult SES, gender, and education. INTERPRETATION: A significant association between childhood SES and hippocampal volumes in late life is consistent with the established neurodevelopmental findings that early life conditions have an effect on structural brain development. This remains detectable more than 50 years later. PMID- 22522482 TI - Losartan, a therapeutic candidate in congenital muscular dystrophy: studies in the dy(2J) /dy(2J) mouse. AB - OBJECTIVE: Lamininalpha2-deficient congenital muscular dystrophy type 1A (MDC1A) is a cureless disease associated with severe disability and shortened lifespan. Previous studies have shown reduced fibrosis and restored skeletal muscle remodeling following treatment with losartan, an angiotensin II type I receptor blocker. We therefore evaluated the effect of losartan treatment in the dy(2J) /dy(2J) mouse model of MDC1A. METHODS: Homozygous dy(2J) /dy(2J) and control mice were treated with losartan or placebo for 12 weeks from 6 weeks of age. Outcome measures included hindlimb and forelimb muscle strength by Grip Strength Meter and quantitative muscle fibrosis parameters. Losartan's effects on transforming growth factor beta (TGF-beta) and mitogen-activated protein kinase (MAPK) signaling pathways were evaluated with Western blotting, immunofluorescence, and cytokine measurements. RESULTS: Losartan treatment was associated with significant impressive improvement in muscle strength and amelioration of fibrosis. Administration of losartan inhibited TGF-beta signaling pathway, resulting in decreased serum TGF-beta1 level and reduced downstream phosphorylated (P) Smad2/3 proteins. Moreover, losartan activated Smad7 protein, a key negative regulator of TGF-beta signaling. In addition, losartan treatment inhibited the MAPK cascade as shown by decreased expression of P-p38 MAPK, P-c jun-N-terminal kinase, and P-extracellular signal-regulated kinases 1 and 2 in the treated mice. INTERPRETATION: Losartan, a commonly prescribed US Food and Drug Administration-approved medication for hypertension, demonstrated clinical improvement and amelioration of fibrosis in the dy(2J) /dy(2J) mouse model of MDC1A via TGF-beta and MAPK signaling pathways. The results of this study support pursuing a clinical trial of losartan treatment in children with MDC1A. PMID- 22522481 TI - Dynamics of hemispheric dominance for language assessed by magnetoencephalographic imaging. AB - OBJECTIVE: The goal of the current study was to examine the dynamics of language lateralization using magnetoencephalographic (MEG) imaging, to determine the sensitivity and specificity of MEG imaging, and to determine whether MEG imaging can become a viable alternative to the intracarotid amobarbital procedure (IAP), the current gold standard for preoperative language lateralization in neurosurgical candidates. METHODS: MEG was recorded during an auditory verb generation task and imaging analysis of oscillatory activity was initially performed in 21 subjects with epilepsy, brain tumor, or arteriovenous malformation who had undergone IAP and MEG. Time windows and brain regions of interest that best discriminated between IAP-determined left or right dominance for language were identified. Parameters derived in the retrospective analysis were applied to a prospective cohort of 14 patients and healthy controls. RESULTS: Power decreases in the beta frequency band were consistently observed following auditory stimulation in inferior frontal, superior temporal, and parietal cortices; similar power decreases were also seen in inferior frontal cortex prior to and during overt verb generation. Language lateralization was clearly observed to be a dynamic process that is bilateral for several hundred milliseconds during periods of auditory perception and overt speech production. Correlation with the IAP was seen in 13 of 14 (93%) prospective patients, with the test demonstrating a sensitivity of 100% and specificity of 92%. INTERPRETATION: Our results demonstrate excellent correlation between MEG imaging findings and the IAP for language lateralization, and provide new insights into the spatiotemporal dynamics of cortical speech processing. PMID- 22522483 TI - Homozygous deletion of an EGR2 enhancer in congenital amyelinating neuropathy. AB - The transcription factor EGR2 is expressed in Schwann cells, where it controls peripheral nerve myelination. Mutations of EGR2 have been found in patients with congenital hypomyelinating neuropathy or Charcot-Marie-Tooth disease type 1D. In a patient with congenital amyelinating neuropathy, we observed pathological abnormalities recapitulating the peripheral nervous system phenotype of homozygous Egr2-null mice. This patient, born from consanguineous parents, showed no EGR2 immunoreactivity in Schwann cells and harbored a homozygous 10.7-kilobase long deletion encompassing a myelin-specific enhancer of EGR2. This regulatory mutation is the first genetic abnormality associated with congenital amyelinating neuropathy in humans. PMID- 22522488 TI - Multiple sclerosis drugs: sticker shock. PMID- 22522484 TI - Angiogenin variation and Parkinson disease. PMID- 22522489 TI - Genomic testing update: whole genome sequencing may be worth the money. PMID- 22522490 TI - Near infrared reflectance imaging spectroscopy to map paint binders in situ on illuminated manuscripts. PMID- 22522491 TI - Constitutive MHC class I molecules negatively regulate TLR-triggered inflammatory responses via the Fps-SHP-2 pathway. AB - The molecular mechanisms that fine-tune Toll-like receptor (TLR)-triggered innate inflammatory responses remain to be fully elucidated. Major histocompatibility complex (MHC) molecules can mediate reverse signaling and have nonclassical functions. Here we found that constitutively expressed membrane MHC class I molecules attenuated TLR-triggered innate inflammatory responses via reverse signaling, which protected mice from sepsis. The intracellular domain of MHC class I molecules was phosphorylated by the kinase Src after TLR activation, then the tyrosine kinase Fps was recruited via its Src homology 2 domain to phosphorylated MHC class I molecules. This led to enhanced Fps activity and recruitment of the phosphatase SHP-2, which interfered with TLR signaling mediated by the signaling molecule TRAF6. Thus, constitutive MHC class I molecules engage in crosstalk with TLR signaling via the Fps-SHP-2 pathway and control TLR-triggered innate inflammatory responses. PMID- 22522492 TI - Nonclassical MHC class Ib-restricted cytotoxic T cells monitor antigen processing in the endoplasmic reticulum. AB - The aminopeptidase ERAAP is essential for trimming peptides presented by major histocompatibility complex (MHC) class I molecules. Inhibition of ERAAP by cytomegalovirus results in evasion of the immune response by this virus, and polymorphisms in ERAAP are associated with autoimmune disorders. How normal ERAAP function is monitored is unknown. We found that inhibition of ERAAP rapidly induced presentation of the peptide FYAEATPML (FL9) by the MHC class Ib molecule Qa-1(b). Antigen-experienced T cells specific for the Qa-1(b)-FL9 complex were frequent in naive mice. Wild-type mice immunized with ERAAP-deficient cells mounted a potent CD8(+) T cell response specific for Qa-1(b)-FL9. MHC class Ib restricted cytolytic effector cells specifically eliminated ERAAP-deficient cells in vitro and in vivo. Thus, nonclassical Qa-1(b)-peptide complexes direct cytotoxic T cells to targets with defective antigen processing in the endoplasmic reticulum. PMID- 22522493 TI - Nutrient content, in vitro ruminal fermentation characteristics and methane reduction potential of tropical tannin-containing leaves. AB - BACKGROUND: Plant tannins as rumen modifiers are better than chemicals or antibiotic-based modifiers since these compounds are natural products which are environmentally friendly and therefore have a better acceptance with regard to feed safety issues. Tropical plants containing phenols such as tannins were found to suppress or eliminate protozoa from the rumen and reduce methane and ammonia production. The screening of these plants is an important step in the identification of new compounds and feed additives which might contribute to mitigate rumen methanogenesis. The present study was carried out to determine the efficacy of tannins from tropical tree leaves for their methane reduction properties. RESULTS: Activity of tannins, as represented by the increase in gas volume with the addition of polyethylene glycol (PEG)-6000 as a tannin binder (tannin bioassay) was highest in Ficus bengalensis (555%), followed by Azardirachta indica (78.5%). PEG addition did not alter (P > 0.05) methane percentage in Ficus racemosa, Glyricidia maculata, Leucena leucocephala, Morus alba and Semaroba glauca, confirming that tannins in these samples did not affect methanogenesis. The increase (P < 0.05) in protozoa population with PEG was maximal in Ficus religiosa (50), followed by Moringa oleifera (31.2), Azardirachta indica (29.9) and Semaroba glauca (27.5). There was no change (P > 0.05) in the protozoa population in Autocarpus integrifolia, Ficus bengalensis, Jatropha curcus, Morus alba and Sesbania grandiflora, demonstrating that methane reduction observed in these samples per se was not due to defaunation effect of the tannin. The increase in total volatile fatty acid concentration in samples with PEG ranged from 0.6% to > 70%. The highest increase (%) in NH(3)-N was recorded in Azardirachta indica (67.4), followed by Ficus mysoriensis (35.7) and Semaroba glauca (32.6) leaves, reflecting strong protein binding properties of tannin. CONCLUSION: The results of our study established that in vitro methanogenesis was not essentially related to the density of protozoa population. Tropical tree leaves containing tannins such as Autocarpus integrifolia, Jatropha curcus and Sesbania grandiflora have the potential to suppress methanogenesis. Therefore tannins contained in these plants could be of interest in the development of new additives in ruminant nutrition. PMID- 22522494 TI - Medial temporal lobe projections to the retrosplenial cortex of the macaque monkey. AB - The projections to the retrosplenial cortex (areas 29 and 30) from the hippocampal formation, the entorhinal cortex, perirhinal cortex, and amygdala were examined in two species of macaque monkey by tracking the anterograde transport of amino acids. Hippocampal projections arose from the subiculum and presubiculum to terminate principally in area 29. Label was found in layer I and layer III(IV), the former seemingly reflecting both fibers of passage and termination. While the rostral subiculum mainly projects to the ventral retrosplenial cortex, mid and caudal levels of the subiculum have denser projections to both the caudal and dorsal retrosplenial cortex. Appreciable projections to dorsal area 30 [layer III(IV)] were only seen following an extensive injection involving both the caudal subiculum and presubiculum. This same case provided the only example of a light projection from the hippocampal formation to posterior cingulate area 23 (layer III). Anterograde label from the entorhinal cortex injections was typically concentrated in layer I of 29a-c, though the very caudal entorhinal cortex appeared to provide more widespread retrosplenial projections. In this study, neither the amygdala nor the perirhinal cortex were found to have appreciable projections to the retrosplenial cortex, although injections in either medial temporal region revealed efferent fibers that pass very close or even within this cortical area. Finally, light projections to area 30V, which is adjacent to the calcarine sulcus, were seen in those cases with rostral subiculum and entorhinal injections. The results reveal a particular affinity between the hippocampal formation and the retrosplenial cortex, and so distinguish areas 29 and 30 from area 23 within the posterior cingulate region. The findings also suggest further functional differences within retrosplenial subregions as area 29 received the large majority of efferents from the subiculum. PMID- 22522495 TI - Regional muscle glucose uptake remains elevated one week after cessation of resistance training independent of altered insulin sensitivity response in older adults with type 2 diabetes. AB - BACKGROUND: Aging is associated with a decline in skeletal muscle size.Muscle is critical both for mobility and glucose disposal. While resistance exercise (RE) increases muscle mass and function in the elderly, its role in improving glucose utilization is less clear. AIMS: To investigate whether muscle size was linked with insulin sensitivity (IS) in elders with diabetes following RE and if regional muscle glucose uptake differed from systemic glucose utilization. METHODS: Seven (68.4 +/- 5.9 yr) adults with diabetes participated. After 16 weeks of RE, within 24 h (post 1) and after 1 week of no exercise (post 2), lean tissue cross-sectional area (CSA) and IS via glucose infusion rate (GIR) were assessed along with a standardized 18-F fluorodeoxyglucose (FDG)-positron emission tomography uptake value (SUV). RESULTS: CSA increased between pre-test (108.5 +/- 35.3 cm2) and post 1 (116.8 +/- 40.9 cm2), p=0.02 and did not differ at post 2 (116.0 +/- 39.3 cm2). GIR during the 40 mU/m2/min insulin clamp differed between pretest (22.0 +/- 15.8 mg/kg/min) and post 1 (67.9 +/- 72.8 mg/kg/min), and post 1 and post 2 (25.0 +/- 27.2 mg/kg/min) but not between pre test and post 2. GIR results during the 200 mU/m2/min insulin clamps also differed between pre-test and post 1, and post 1 and post 2 but not between pre test and post 2. FDG-SUV increased between pre-test (1.1 +/- 0.2) and post 1 (1.4 +/- 0.3), and remained stable between post 1 and post 2 (1.4 +/- 0.4). CONCLUSION: RE that increased muscle size and FDG-SUV improved IS 24 h but not 1 week after exercise training. PMID- 22522496 TI - The medical home experience among children with sickle cell disease. AB - BACKGROUND: While a large body of research documents acute care services for children with sickle cell disease (SCD), little is known about the primary care experiences of this population. The goal of this study was to determine to what extent children with SCD experienced care consistent with a patient-centered medical home (PCMH). PROCEDURE: We collected and analyzed data from 150 children, ages 1-17 years, who received care within a large children's hospital. The primary dependent variable was access to a PCMH or its four individual components (regular provider, comprehensive care, family-centered care, and coordinated care) as determined by parental report. Multivariate logistic regression was conducted to investigate associations between socio-demographic variables and having access to a PCMH. RESULTS: Only 11% (16/150) of children qualified as having a PCMH, achieving the required thresholds in all four components. Approximately half of children had access to two or fewer components. Over 90% of children were reported to have a personal provider. Two-thirds of children had access to comprehensive care. Almost 60% of children were reported to receive family-centered care. Only 20% of children had access to coordinated care. No consistent associations were found between socio-demographic variables and having access to a PCMH or its individual components. CONCLUSIONS: Within our study sample, children with SCD experienced multiple deficiencies in having access to a PCMH, particularly with respect to care coordination. However, further studies with larger samples are needed to determine associations between socio demographic variables and having a PCMH. PMID- 22522498 TI - Common stock solutions, buffers, and media. AB - This collection of recipes describes the preparation of buffers and reagents used in Current Protocols in Pharmacology for cell culture, manipulation of neural tissue, molecular biological methods, and neurophysiological/neurochemical measurements. RECIPES: Acid, concentrated stock solutions Ammonium hydroxide, concentrated stock solution EDTA (ethylenediaminetetraacetic acid), 0.5 M (pH 8.0) Ethidium bromide staining solution Fetal bovine serum (FBS) Gel loading buffer, 6* LB medium (Luria broth) and LB plates Potassium phosphate buffer, 0.1 M Sodium phosphate buffer, 0.1 M TE (Tris/EDTA) buffer Tris?Cl, 1 M. PMID- 22522497 TI - Peptides that anneal to natural collagen in vitro and ex vivo. AB - Collagen comprises 1/4 of the protein in humans and 3/4 of the dry weight of human skin. Here, we implement recent discoveries about the structure and stability of the collagen triple helix to design new chemical modalities that anchor to natural collagen. The key components are collagen mimetic peptides (CMPs) that are incapable of self-assembly into homotrimeric triple helices, but are able to anneal spontaneously to natural collagen. We show that such CMPs containing 4-fluoroproline residues, in particular, bind tightly to mammalian collagen in vitro and to a mouse wound ex vivo. These synthetic peptides, coupled to dyes or growth factors, could herald a new era in assessing or treating wounds. PMID- 22522499 TI - Helping to address the over treatment of prostate cancer: tools to differentiate lethal and non-lethal phenotype in prostate cancer. PMID- 22522500 TI - Experimental therapeutics in prostate cancer: where are we now and where do we need to go. PMID- 22522501 TI - The role of BRCA1 and BRCA2 in prostate cancer. AB - One of the strongest risk factors for prostate cancer is a family history of the disease. Germline mutations in the breast cancer predisposition gene 2 (BRCA2) are the genetic events known to date that confer the highest risk of prostate cancer (8.6-fold in men <=65 years). Although the role of BRCA2 and BRCA1 in prostate tumorigenesis remains unrevealed, deleterious mutations in both genes have been associated with more aggressive disease and poor clinical outcomes. The increasing incidence of prostate cancer worldwide supports the need for new methods to predict outcome and identify patients with potentially lethal forms of the disease. As we present here, BRCA germline mutations, mainly in the BRCA2 gene, are one of those predictive factors. We will also discuss the implications of these mutations in the management of prostate cancer and hypothesize on the potential for the development of strategies for sporadic cases with similar characteristics. PMID- 22522503 TI - Decline of semen quality among 10 932 males consulting for couple infertility over a 20-year period in Marseille, France. AB - Semen from 10 932 male partners of infertile couples was analysed and sperm parameter trends were evaluated at the Reproduction Biology Laboratory of the University Hospital of Marseille (France) between 1988 and 2007. After 3-6 days of abstinence, semen samples were collected. Measurements of seminal fluid volume, pH, sperm concentration, total sperm count, motility and detailed morphology of spermatozoa were performed. Sperm parameters were analysed on the entire population and in men with normal total numeration (>=40 million per ejaculate). The whole population demonstrated declining trends in sperm concentration (1.5% per year), total sperm count (1.6% per year), total motility (0.4% per year), rapid motility (5.5% per year) and normal morphology (2.2% per year). In the group of selected samples with total normal sperm count, the same trends of sperm quality deterioration with time were observed. Our results clearly indicate that the quality of semen decreased in this population over the study period. PMID- 22522502 TI - Why are epididymal tumours so rare? AB - Epididymal tumour incidence is at most 0.03% of all male cancers. It is an enigma why the human epididymis does not often succumb to cancer, when it expresses markers of stem and cancer cells, and constitutively expresses oncogenes, pro proliferative and pro-angiogenic factors that allow tumour cells to escape immunosurveillance in cancer-prone tissues. The privileged position of the human epididymis in evading tumourigenicity is reflected in transgenic mouse models in which induction of tumours in other organs is not accompanied by epididymal neoplasia. The epididymis appears to: (i) prevent tumour initiation (it probably lacks stem cells and has strong anti-oxidative mechanisms, active tumour suppressors and inactive oncogene products); (ii) foster tumour monitoring and destruction (by strong immuno-surveillance and -eradication, and cellular senescence); (iii) avert proliferation and angiogenesis (with persistent tight junctions, the presence of anti-angiogenic factors and misplaced pro-angiogenic factors), which together (iv) promote dormancy and restrict dividing cells to hyperplasia. Epididymal cells may be rendered non-responsive to oncogenic stimuli by the constitutive expression of factors generally inducible in tumours, and resistant to the normal epididymal environment, which mimics that of a tumour niche promoting tumour growth. The threshold for tumour initiation may thus be higher in the epididymis than in other organs. Several anti-tumour mechanisms are those that maintain spermatozoa quiescent and immunologically silent, so the low incidence of cancer in the epididymis may be a consequence of its role in sperm maturation and storage. Understanding these mechanisms may throw light on cancer prevention and therapy in general. PMID- 22522505 TI - Inverse relationship between bioavailable testosterone and subclinical coronary artery calcification in non-obese Korean men. AB - Although low testosterone levels in men have been associated with high risk for cardiovascular disease, little is known about the association between male sex hormones and subclinical coronary disease in men with apparently low cardiometabolic risk. This study was performed to investigate the association between male sex hormones and subclinical coronary artery calcification measured as coronary calcium score in non-obese Korean men. We examined the relationship of total testosterone, sex hormone-binding globulin, bioavailable testosterone and free testosterone with coronary calcium score in 291 non-obese Korean men (mean age: 52.8+/-9.3 years) not having a history of cardiovascular disease. Using multiple linear regression, we evaluated associations between log (sex hormone) levels and log (coronary calcium score) after adjusting for confounding variables in 105 men with some degree of coronary calcification defined as coronary calcium score >= 1. In multiple linear regression analysis, bioavailable testosterone was inversely associated with coronary calcium score (P=0.046) after adjusting for age, body mass index, smoking status, alcohol consumption, regular exercise, mean blood pressure, resting heart rate, C-reactive protein, fasting plasma glucose, total cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol, hypertension medication and hyperlipidemia medication, whereas total testosterone, sex hormone-binding globulin and free testosterone were not (P=0.674, P=0.121 and P=0.102, respectively). Our findings indicate that bioavailable testosterone is inversely associated with the degree of subclinical coronary artery calcification in non-obese men. PMID- 22522504 TI - Testosterone and cardiovascular disease in men. AB - Despite regional variations in the prevalence of coronary artery disease (CAD), men are consistently more at risk of developing and dying from CAD than women, and the gender-specific effects of sex hormones are implicated in this inequality. This 'Perspectives' article reviews the current evidence regarding the cardiovascular effects of testosterone in men including an examination of the age-related decline in testosterone, the relationship between testosterone levels and coronary disease, coronary risk factors and mortality. We also review the vaso-active effects of testosterone, and discuss how these have been used in men with heart failure and angina. We discuss the 'cause' versus 'effect' controversy, regarding low testosterone levels in men with coronary heart disease, as well as concerns over the use of testosterone replacement therapy in middle aged and elderly men. The article concludes with a discussion regarding the future direction for work in this interesting area, including the relative merits of screening for, and treating hypogonadism with testosterone replacement therapy in men with heart disease. PMID- 22522507 TI - Pum 1 sequesters apoptosis during spermatogenesis. PMID- 22522506 TI - Objective non-intrusive markers of sperm production and sexual activity. AB - Objective studies of men's reproductive function are hindered by their reliance on: (i) self-reporting to quantify sexual activity and (ii) masturbation to quantify sperm output rendering both types of estimate vulnerable to unverifiable subjective factors. We therefore examined whether detection of spermatozoa and measurement of prostate-specific antigen (PSA) in urine could provide objective semiquantitative estimates of sperm output and recent ejaculation, respectively, using widely available laboratory techniques. Of 11 healthy volunteers who provided urine samples before and at intervals for 5 days after ejaculation, sperm was present in 2/11 men before, and in all 11/11 samples immediately after ejaculation, but by the second and subsequent void, spermatozoa were present in ~10%. PSA was detectable at high levels in all urine samples, peaking at the first post-ejaculatory sample but returning to baseline levels by the second post ejaculatory void. We conclude that urinary spermatozoa and PSA are objective biomarkers for sperm production and sexual activity, but only for a short-time window until the first post-ejaculatory urine void. Hence, for a single urine specimen, the presence of spermatozoa and PSA are valid biomarkers, reflecting sperm production and recent ejaculation only until the next micturition, so their measurement should be restricted to the first morning urine void. PMID- 22522508 TI - Relationship of flow-mediated arterial dilation and exercise capacity in older patients with heart failure and preserved ejection fraction. AB - BACKGROUND: Older heart failure patients with preserved ejection fraction (HFpEF) have severely reduced exercise capacity and quality of life. Both brachial artery flow-mediated dilation (FMD) and peak exercise oxygen uptake (peak VO(2)) decline with normal aging. However, uncertainty remains regarding whether FMD is reduced beyond the degree associated with normal aging and if this contributes to reduced peak VO(2) in elderly HFpEF patients. METHODS: Sixty-six older (70 +/- 7 years) HFpEF patients and 47 healthy participants (16 young, 25 +/- 3 years, and 31 older, 70 +/- 6 years) were studied. Brachial artery diameter was measured before and after cuff occlusion using high-resolution ultrasound. Peak VO(2) was measured using expired gas analysis during upright cycle exercise. RESULTS: Peak VO(2) was severely reduced in older HFpEF patients compared with age-matched healthy participants (15.2 +/- 0.5 vs 19.6 +/- 0.6 mL/kg/min, p < .0001), and in both groups, peak VO(2) was reduced compared with young healthy controls (28.5 +/ 0.8 mL/kg/min; both p < .0001). Compared with healthy young participants, brachial artery FMD (healthy young, 6.13% +/- 0.53%) was significantly reduced in healthy older participants (4.0 +/- 0.38; p < .0002) and in HFpEF patients (3.64% +/- 0.28%; p < .0001). However, FMD was not different in HFpEF patients compared with healthy older participants (p = .86). Although brachial artery FMD was modestly related to peak VO(2) in univariate analyses (r = .19; p = .048), it was not related in multivariate analyses that accounted for age, gender, and body size. CONCLUSION: These results suggest that endothelial dysfunction may not be a significant independent contributor to the severely reduced exercise capacity in elderly HFpEF patients. PMID- 22522509 TI - Mechanisms of age-related cognitive change and targets for intervention: epigenetics. AB - Epigenetic regulation of gene expression plays an important role in learning and memory, mediating the influence of experience on critical mechanisms of plasticity. Speakers in the opening session of the Summit reviewed research on epigenetic contributions to age-related cognitive decline and discussed strategies for the development of interventions targeting epigenetic mechanisms. The presentations focused on experience-dependent DNA methylation, the regulatory role of microRNAs, histone deacetylases as potential therapeutic targets, and strategies for exploring epigenetic contributions to the aging of brain and cognition. This session established useful mileposts for gaging progress in this rapidly advancing area of research. PMID- 22522511 TI - Two new Co(II) coordination polymers based on carboxylate-bridged di- and trinuclear clusters with a pyridinedicarboxylate ligand: synthesis, structures and magnetism. AB - Two new Co(II) coordination polymers with a pyridinedicarboxylate ligand, {[Co(L)(H(2)O)].H(2)O}(n) (1) and [Co(3)(HCOO)(2)(L)(2)(H(2)O)(2)](n) (2) (H(2)L = 5-(pyridin-4-yl)isophthalic acid), have been synthesized and structurally characterized by elemental analysis, IR, XRPD, and single-crystal X-ray diffraction. Structure analyses show that complex 1 has a two-dimensional (2D) double-layered structure with a (3,6)-connected kgd topology based on [Co(2)O(2)] units, while complex 2 takes a three-dimensional (3D) structure with (3,6) connected rtl topology network based on linear [Co(3)(HCOO)(2)(CO(2))(4)] clusters with triple carboxylate bridges. Magnetic investigation indicates that besides strong spin-orbit coupling of Co(II) ions, ferromagnetic and weak ferromagnetic exchange interactions between Co(II) ions in the Co(2) and Co(3) clusters exist in 1 and 2, respectively. The FC/ZFC magnetization behaviors for both of them suggest the absence of any long-range magnetic ordering. PMID- 22522512 TI - Transcriptional activation and production of tryptophan-derived secondary metabolites in arabidopsis roots contributes to the defense against the fungal vascular pathogen Verticillium longisporum. AB - The soil-borne fungal pathogen Verticillium longisporum causes vascular disease on Brassicaceae host plants such as oilseed rape. The fungus colonizes the root xylem and moves upwards to the foliage where disease symptoms become visible. Using Arabidopsis as a model for early gene induction, we performed root transcriptome analyses in response to hyphal growth immediately after spore germination and during penetration of the root cortex, respectively. Infected roots showed a rapid reprogramming of gene expression such as activation of transcription factors, stress-, and defense-related genes. Here, we focused on the highly coordinated gene induction resulting in the production of tryptophan derived secondary metabolites. Previous studies in leaves showed that enzymes encoded by CYP81F2 and PEN2 (PENETRATION2) execute the formation of antifungal indole glucosinolate (IGS) metabolites. In Verticillium-infected roots, we found transcriptional activation of CYP81F2 and the PEN2 homolog PEL1 (PEN2-LIKE1), but no increase in antifungal IGS breakdown products. In contrast, indole-3 carboxylic acid (I3CA) and the phytoalexin camalexin accumulated in infected roots but only camalexin inhibited Verticillium growth in vitro. Whereas genetic disruption of the individual metabolic pathways leading to either camalexin or CYP81F2-dependent IGS metabolites did not alter Verticillium-induced disease symptoms, a cyp79b2 cyp79b3 mutant impaired in both branches resulted in significantly enhanced susceptibility. Hence, our data provide an insight into root-specific early defenses and suggest tryptophan-derived metabolites as active antifungal compounds against a vascular pathogen. PMID- 22522514 TI - The problem with graduate medical education. PMID- 22522515 TI - Successful implementation of new osteopathic graduate medical education programs in a community hospital: challenges and lessons learned. AB - Development of new osteopathic graduate medical education (OGME) programs has emerged as a priority for the osteopathic medical profession. As colleges of osteopathic medicine (COMs) expand class sizes and branch campuses, and as new COMs are launched, availability of sufficient internship, residency, and fellowship positions for future COM graduates will become a challenge. Because of constraints in graduate medical education reimbursement, growth of existing training programs is limited. For hospitals that did not sponsor internship and residency programs before January 1, 1995, the Centers for Medicare and Medicaid Services offers an exception to funding restraints on expansion of training programs. However, successful development and implementation of new OGME programs remains a formidable undertaking. Moreover, because of idiosyncrasies of medical education reimbursement, successful recruitment of COM graduates into new training positions is paramount to ensure program viability. The authors describe lessons learned from the successful implementation of new OGME programs in a community hospital, and they offer recommendations for other hospitals considering such an endeavor. PMID- 22522510 TI - Diverse roles of growth hormone and insulin-like growth factor-1 in mammalian aging: progress and controversies. AB - Because the initial reports demonstrating that circulating growth hormone and insulin-like growth factor-1 decrease with age in laboratory animals and humans, there have been numerous studies related to the importance of these hormones for healthy aging. Nevertheless, the role of these potent anabolic hormones in the genesis of the aging phenotype remains controversial. In this chapter, we review the studies demonstrating the beneficial and deleterious effects of growth hormone and insulin-like growth factor-1 deficiency and explore their effects on specific tissues and pathology as well as their potentially unique effects early during development. Based on this review, we conclude that the perceived contradictory roles of growth hormone and insulin-like growth factor-1 in the genesis of the aging phenotype should not be interpreted as a controversy on whether growth hormone or insulin-like growth factor-1 increases or decreases life span but rather as an opportunity to explore the complex roles of these hormones during specific stages of the life span. PMID- 22522516 TI - Prediction of Osteopathic Medical School Performance on the basis of MCAT score, GPA, sex, undergraduate major, and undergraduate institution. AB - CONTEXT: The relationships of students' preadmission academic variables, sex, undergraduate major, and undergraduate institution to academic performance in medical school have not been thoroughly examined. OBJECTIVES: To determine the ability of students' preadmission academic variables to predict osteopathic medical school performance and whether students' sex, undergraduate major, or undergraduate institution influence osteopathic medical school performance. METHODS: The study followed students who graduated from New York College of Osteopathic Medicine of New York Institute of Technology in Old Westbury between 2003 and 2006. Student preadmission data were Medical College Admission Test (MCAT) scores, undergraduate grade point averages (GPAs), sex, undergraduate major, and undergraduate institutional selectivity. Medical school performance variables were GPAs, clinical performance (ie, clinical subject examinations and clerkship evaluations), and scores on the Comprehensive Osteopathic Medical Licensing Examination-USA (COMLEX-USA) Level 1 and Level 2-Clinical Evaluation (CE). Data were analyzed with Pearson product moment correlation coefficients and multivariate linear regression analyses. Differences between student groups were compared with the independent-samples, 2-tailed t test. RESULTS: A total of 737 students were included. All preadmission academic variables, except nonscience undergraduate GPA, were statistically significant predictors of performance on COMLEX-USA Level 1, and all preadmission academic variables were statistically significant predictors of performance on COMLEX-USA Level 2-CE. The MCAT score for biological sciences had the highest correlation among all variables with COMLEX-USA Level 1 performance (Pearson r=0.304; P<.001) and Level 2-CE performance (Pearson r=0.272; P<.001). All preadmission variables were moderately correlated with the mean clinical subject examination scores. The mean clerkship evaluation score was moderately correlated with mean clinical examination results (Pearson r=0.267; P<.001) and COMLEX-USA Level 2-CE performance (Pearson r=0.301; P<.001). Clinical subject examination scores were highly correlated with COMLEX USA Level 2-CE scores (Pearson r=0.817; P<.001). No statistically significant difference in medical school performance was found between students with science and nonscience undergraduate majors, nor was undergraduate institutional selectivity a factor influencing performance. CONCLUSION: Students' preadmission academic variables were predictive of osteopathic medical school performance, including GPAs, clinical performance, and COMLEX-USA Level 1 and Level 2-CE results. Clinical performance was predictive of COMLEX-USA Level 2-CE performance. PMID- 22522517 TI - Trainer-to-student ratios for teaching psychomotor skills in health care fields, as applied to osteopathic manipulative medicine. AB - The hallmark of osteopathic medical education is the inclusion of hands-on instruction in osteopathic manipulative medicine (OMM), which includes palpatory diagnosis and osteopathic manipulative treatment (OMT). This OMM training typically involves a primary instructor presenting theory and techniques with step-by-step demonstrations to a large group of first- and second-year osteopathic medical students. Additional instructors, referred to as table trainers, assist the primary instructor by supervising the students as they practice the presented techniques. To the authors' knowledge, there is no currently accepted standard for a table trainer-to-student ratio in OMM skills laboratories within osteopathic medical schools in the United States. However, through a Google Web search and PubMed literature review, the authors identified published trainer-to-student ratios used in other health care skills training curricula. Psychomotor skills training courses in health care fields typically have a table trainer-to-student ratio of 1 trainer to 8 or fewer students. On the basis of these findings and psychomotor skills learning theory, the authors conclude that this ratio is likely sufficient for OMM skills training. PMID- 22522525 TI - Ecthyma gangrenosum caused by Pseudomonas aeruginosa [corrected]. PMID- 22522530 TI - Mixing of non-Newtonian fluids in wavy serpentine microchannel using electrokinetically driven flow. AB - A numerical investigation is performed into the mixing performance of electrokinetically driven non-Newtonian fluids in a wavy serpentine microchannel. The flow behavior of the non-Newtonian fluids is described using a power-law model. The simulations examine the effects of the flow behavior index, the wave amplitude, the wavy-wall section length, and the applied electric field strength on the mixing performance. The results show that the volumetric flow rate of shear-thinning fluids is higher than that of shear-thickening fluids, and therefore results in a poorer mixing performance. It is shown that for both types of fluid, the mixing performance can be enhanced by increasing the wave amplitude, extending the length of the wavy-wall section, and reducing the strength of the electric field. Thus, although the mixing efficiency of shear thinning fluids is lower than that of shear-thickening fluids, the mixing performance can be improved through an appropriate specification of the flow and geometry parameters. For example, given a shear-thinning fluid with a flow behavior index of 0.8, a mixing efficiency of 87% can be obtained by specifying the wave amplitude as 0.7, the wavy-wall section length as five times the characteristic length, the nondimensional Debye-Huckel parameter as 100, and the applied electric field strength as 43.5 V/cm. PMID- 22522531 TI - Effects of microchannel geometry on preconcentration intensity in microfluidic chips with straight or convergent-divergent microchannels. AB - Preconcentration microfluidic devices are fabricated incorporating straight or convergent-divergent microchannels and hydrogel or Nafion membranes. Sample preconcentration is achieved utilizing concentration-polarization effects. The effects of the microchannel geometry on the preconcentration intensity are systematically examined. It is shown that for the preconcentrator with the straight microchannel, the time required to achieve a satisfactory preconcentration intensity increases with an increasing channel depth. For the convergent-divergent microchannel, the preconcentration intensity increases with a reducing convergent channel width. Comparing the preconcentration performance of the two different microchannel configurations, it is found that for an equivalent width of the main microchannel, the concentration effect in the convergent-divergent microchannel is faster than that in the straight microchannel. PMID- 22522532 TI - Ion concentration polarization near microchannel-nanochannel interfaces: effect of pH value. AB - This study investigates the effect of the pH value on the ion concentration polarization phenomenon and the nonlinear current-voltage characteristics of a hybrid soda-lime glass micro/nanochannel for a constant KCl salt concentration of about 1 mM. The experimental results show that the electrical conductance of the nanochannel in the Ohmic regime and the critical threshold voltage of the limiting current are both dependent on the pH value of the salt solution when the electrical double layer thickness is considerable in the nanochannel. Specifically, the nanochannel conductance increases and the critical threshold voltage for the limiting current decreases as the pH value is increased. It also suggests that a higher pH value induces a higher surface charge density on the nanochannel walls, and therefore increases both the ionic conductance and the counter-ion flux within the nanochannel. PMID- 22522533 TI - Microchip electrophoresis-SDS methods with high-resolution and silver stain sensitivity for quality screening and quantitation of protein products. AB - Two microchip electrophoresis (ME)-SDS methods have been developed for high throughput quantitation and quality screening of protein products. Both methods utilize a commercial microchip instrument to separate dodecyl sulfate-coated proteins within 1 min. In the high-resolution ME-SDS method, improved separation selectivity is achieved using a mixture of sieving polymers. Proteins of similar sizes, such as different fragment antigen-binding (Fab) assemblies can be readily resolved and individually quantified. A high-sensitivity ME-SDS method was also developed with sensitivity comparable to that of SDS-PAGE with silver staining. In this method, protein molecules are derivatized with a fluorescence reagent prior to analysis. LIF detection of the covalently attached fluorophore enables accurate quantitation of low-expressing proteins and detection of minor species at 0.04% level (1 ng/mL loading concentration). Both the high-resolution and the high-sensitivity ME-SDS methods can be applied to crude fermentation samples. The utilities of these methods in process development and formulation stability study are presented. PMID- 22522534 TI - Evaluating cell migration in vitro by the method based on cell patterning within microfluidic channels. AB - Cell migration is an early-stage and critical step for cancer metastasis. The most common approach to monitor this process is wound-healing assay. However, this traditional method has some unavoidable limitations. We observed that simply scratching the monolayer of cultured cells might cause local cell damage around the injury line. The cells along the scratched border seemed to be irritated and exhibited abnormal distribution of cytoskeleton reassembly with protruding "cell islands" and "pseudopodia" during wound healing, which might potentially affect the assessment of cell migration behavior. Herein, we applied a microfluidic device that mechanically constrained cells seeded in a designed pattern inside microchannels, and monitored cell movement in a way of mimicking the natural microenvironment of cancerous tissues. We illustrated the capacity of this simple method to probe cellular migration behaviors and to screen some biological active agents that reflected in their influence on cellular motility. PMID- 22522535 TI - A microfluidic device for separating erythrocytes polluted by lead (II) from a continuous bloodstream flow. AB - To sort and separate erythrocytes contaminated by lead (II) from whole bloodstream flow, the first step is to use a microchannel to transport the blood cells into a microdevice. Within the device, polluted erythrocytes can be separated from the bloodstream by applying local dielectrophoretic (DEP) forces. Exploiting the fact that Pb(2+) ions attach to the membranes of the erythrocytes, we utilize the microfluidic DEP device to perform property-based fractionation of the blood samples and to separate the polluted erythrocytes from the continuous bloodstream flow. Atomic absorption spectrometer analysis reveals that, to remove lead-polluted erythrocytes, the most effective driving velocity was less than 0.1 cm/s through our microfluidic DEP device, based on an applied power of 10 V(peak-peak) and a frequency of 15.5 MHz AC field. We were able to remove 80% of the polluted erythrocytes. Using gentle DEP manipulating techniques to efficiently sort unique cells within a complex biological sample may potentially allow biological sorting to be performed outside of hospitals, in facilities without biological analyzing equipment. PMID- 22522537 TI - Capillary zone electrophoresis-based cytotoxicity analysis of Caco-2 cells. AB - A capillary zone electrophoresis-based method to evaluate the cytotoxicity of substances to Caco-2 cells was established. The estimation of the injected cell number (500-5000) and the minor effect of injection condition on cytotoxicity determination were investigated. Caco-2 cells the best model of the intestinal absorptive epithelium, were treated with substances and then stained with Trypan Blue and fixed with paraformaldehyde. The treated Caco-2 cells were detected simultaneously at 590 nm and 214 nm, and the absorbance ratio of the two wavelengths (R(590/214)) can reflect simultaneously the loss of cell membrane integrity and the degradation/leak of intracellular components and indicate the cytotoxicity of substances. The cytotoxicity of the four substances sodium sulfite (Na(2)SO(3)), methyl mercury (MeHg), paclitaxel (PTX), and cadmium chloride (CdCl(2)) were determined and compared. There was no obvious cytotoxicity caused by 20 MUM Na(2)SO(3) for 24 h treatment, and the toxicity of the other three toxicants was sequenced as: CdCl(2) > MeHg > PTX. The results are in good agreement with the references and the conventional Trypan Blue exclusion counting assay. PMID- 22522538 TI - Exploring of tri-allelic SNPs using pyrosequencing and the SNaPshot methods for forensic application. AB - Tri-allelic single nucleotide polymorphisms (SNPs) are potential forensic markers for DNA analysis. Currently, only a limited number of tri-allelic SNP loci have been proved to be fit for forensic application. In this study, we aimed to develop an effective method to select and genotype tri-allelic SNPs based on both Pyrosequencing (PSQ) and the SNaPshot methods. 50 candidate SNPs were chosen from NCBI's dbSNP database and were analyzed by PSQ. The results revealed that 20 SNPs were tri-allelic and were located on 16 autosomal chromosomes. Then 20 SNP loci were combined in one multiplex polymerase chain reaction to develop a single base extension (SBE)-based SNP-typing assay. A total of 100 unrelated Chinese individuals were genotyped by this assay and allele frequencies were estimated. The total discrimination power was 0.999999999975 and the cumulative probability of exclusion was 0.9937. These data demonstrated that the strategy is a rapid and effective method for seeking and typing tri-allelic SNPs. In addition, the 20 tri allelic SNP multiplex typing assay may be used to supplement paternity testing and human identification. PMID- 22522539 TI - Separation and identification of four distinct serine-phosphorylation states of ovalbumin by Phos-tag affinity electrophoresis. AB - Ovalbumin (OVA) derived from egg white contains two residues that can be phosphorylated: Ser-68 and Ser-344. Native polyacrylamide gel electrophoresis(PAGE) shows the presence of three distinct migration bands corresponding to phosphorylation states with two, one, or no phosphate groups, respectively. Phosphate-affinity sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE; Zn(2+)-Phos-tag SDS-PAGE), on the other hand, showed the presence of four distinct phosphorylated states in intact OVA. In addition to the diphosphorylated and nonphosphorylated forms, two distinct species, one with a phosphate group at Ser-68 and one with a phosphate group at Ser-344, were separately visualized. The content of the OVA monophosphorylated at Ser-68 was greater than that of OVA monophosphorylated at Ser-344. Zn(2+)-Phos-tag SDS-PAGE is therefore a useful method for the quantitative analysis of the detailed phosphorylation status of food proteins. PMID- 22522536 TI - Harnessing glycomics technologies: integrating structure with function for glycan characterization. AB - Glycans, or complex carbohydrates, are a ubiquitous class of biological molecule which impinge on a variety of physiological processes ranging from signal transduction to tissue development and microbial pathogenesis. In comparison to DNA and proteins, glycans present unique challenges to the study of their structure and function owing to their complex and heterogeneous structures and the dominant role played by multivalency in their sequence-specific biological interactions. Arising from these challenges, there is a need to integrate information from multiple complementary methods to decode structure-function relationships. Focusing on acidic glycans, we describe here key glycomics technologies for characterizing their structural attributes, including linkage, modifications, and topology, as well as for elucidating their role in biological processes. Two cases studies, one involving sialylated branched glycans and the other sulfated glycosaminoglycans, are used to highlight how integration of orthogonal information from diverse datasets enables rapid convergence of glycan characterization for development of robust structure-function relationships. PMID- 22522540 TI - Enhancing separation of histidine from amino acids via free-flow affinity electrophoresis with gravity-induced uniform hydrodynamic flow. AB - In this paper, a novel mode of free-flow affinity electrophoresis (FFAE) was developed to indirectly enhance the separation of free-flow electrophoresis (FFE). In the mode of FFAE, a Ni(II) with high electric charge density and histidine (His) is chosen as a model ligand and target solute, respectively. Through the controlling of experimental conditions (10 mM pH 6.0 Na(2)HPO(4) NaH(2)PO(4) with 2.0 mM NiCl(2).6H(2)O background buffer), Ni(II) can combine with His and the combination leads to the high electric charge density of affinity complex of His-Ni(II) in contrast to the low density of free His molecule. But the ligand has weak interaction with uninterested amino acids. Thus, the mobility of His existing as His-Ni(II) is greatly increased from 14.5*10(-8) m(2) V(-1) s(-1) to 30.2 * 10(-8) m(2) V(-1) s(-1), while those mobilities of uninterested amino acids are almost constant. By virtue of the mode, we developed the FFAE procedure and conducted the relevant experiments. The experiments demonstrated the following merits of the FFAE technique: (i) clear enhancement of separation between the target solute of His and uninterested amino acids; (ii) simplicity, and (iii) low cost. Furthermore, the technique was used for the continuous separation of His from its complex sample, and the purity of His was near to 100%. All of the results demonstrate the feasibility of affinity separation in FFE. The developed FFAE may be used in the separation and pretreatment of some biological molecules (e.g. peptides). PMID- 22522541 TI - Assessment of aptamer-steroid binding using stacking-enhanced capillary electrophoresis. AB - The binding affinity of 17beta-estradiol with an immobilized DNA aptamer was measured using capillary electrophoresis. Estradiol captured by the immobilized DNA was injected into the separation capillary using pH-mediated sample stacking. Stacked 17beta-estradiol was then separated using micellar electrokinetic capillary chromatography and detected with UV-visible absorbance. Standard addition was used to quantify the concentration of estradiol bound to the aptamer. Following incubation with immobilized DNA, analysis of free and bound estradiol yielded a dissociation constant of 70 +/- 10 MUM. The method was also used to screen binding affinity of the aptamer for estrone and testosterone. This study demonstrates the effectiveness of capillary electrophoresis to assess the binding affinity of DNA aptamers. PMID- 22522542 TI - Induced-charge electrophoresis of uncharged dielectric spherical Janus particles. AB - We derive the equations governing the dipolophoretic motion of an electrically inhomogeneous Janus particle composed of two hemispheres with differing permittivities. The general formulation is valid for any electric forcing, including alternating current (AC) and makes no assumptions regarding the size of the electric double layer (EDL). The solution is thus valid even for nanoparticles where the particle radius can be of the same order as the EDL thickness. Semi-analytic and numerical solutions for the linear phoretic velocity and angular rotation of a single Janus particle suspended in an infinite medium are given in the limit of uniform direct current (DC) electric forcing. It is determined that particle mobility is a function of the permittivity in each hemisphere and the contrast between them as well as the EDL length. For a particle in which both hemispheres are characterized by a finite permittivity, we discover that maximum mobility and rotation is not obtained in the Helmholtz Smoluchowski thin EDL limit but is rather a function of the permittivity and EDL properties. PMID- 22522543 TI - One-dimensional simulation of lanthanide isotachophoresis using COMSOL. AB - Electrokinetic separations can be used to quickly separate rare earth metals to determine their forensic signature. In this work, we simulate the concentration and separation of trivalent lanthanide cations by isotachophoresis. A one dimensional simulation is developed using COMSOL v4.0a, a commercial finite element simulator, to represent the isotachophoretic separation of three lanthanides: lanthanum, terbium, and lutetium. The binding ligand chosen for complexation with the lanthanides is alpha-hydroxyisobutyric acid (HIBA) and the buffer system includes acetate, which also complexes with the lanthanides. The complexes formed between the three lanthanides, HIBA, and acetate are all considered in the simulation. We observe that the presence of only lanthanide:HIBA complexes in a buffer system with 10 mM HIBA causes the slowest lanthanide peak (lutetium) to split from the other analytes. The addition of lanthanide:acetate complexes into the simulation of the same buffer system eliminates this splitting. Decreasing the concentration of HIBA in the buffer to 7 mM causes the analyte stack to migrate faster through the capillary. PMID- 22522546 TI - Smoke without fire? PMID- 22522547 TI - Optical coherence tomography (OCT) evaluation after coronary stenting: the "black hole" and other low OCT signal-intensity areas. PMID- 22522548 TI - The new European Society of Cardiology eLearning Platform. PMID- 22522549 TI - Systemic endothelin receptor blockade in ST-segment elevation acute coronary syndrome protects the microvasculature: a randomised pilot study. AB - AIMS: ST-elevation acute coronary syndrome (STE-ACS) is characterised by compromised blood flow at the epicardial and microvascular levels. Endothelin-1 (ET-1) is a mediator of microvascular dysfunction and adverse cardiac remodelling. We hypothesised that administration of an endothelin type A (ETA) receptor antagonist (BQ-123; Clinalfa, Laufelfingen, Switzerland) may protect microvascular function. METHODS AND RESULTS: In this proof-of-concept, randomised, double-blind, placebo-controlled trial, patients with posterior-wall STE-ACS (n=57) were randomly assigned to receive intravenous BQ-123 at 400 nmol/minute or placebo over 60 minutes, starting at the onset of primary percutaneous coronary intervention (PCI). Time to myocardial contrast wash-in of the infarcted segment assessed by first-pass perfusion cardiac magnetic resonance imaging was the primary efficacy endpoint. Secondary endpoints included enzymatic infarct size and left ventricular ejection fraction (LVEF). In patients randomised to BQ-123 we observed shorter microvessel perfusion delays six days after PCI (1.8 sec [0.7-3.4] versus 3.3 sec [2.3-5.4] in placebo-treated patients, p=0.005). The treatment group demonstrated smaller enzymatic infarct sizes (p=0.014). All patients were alive at six months, with an LVEF of 63% (58 69) in patients randomised to BQ-123 and 59% (51-66) in placebo-treated patients (p=0.047). CONCLUSIONS: Administration of an ETA receptor blocker during primary PCI in patients with STE-ACS is safe and may improve tissue-level perfusion and LVEF. PMID- 22522550 TI - Pre-infarction angina predicts thrombus burden in patients admitted for ST segment elevation myocardial infarction. AB - AIMS: In patients with ST-elevation myocardial infarction (STEMI), high thrombotic burden, subsequent distal embolisation and myocardial no-reflow remain a large obstacle that may negate the benefits of urgent coronary revascularisation. We aimed at assessing the predictors of: 1) thrombus grade in patients undergoing primary percutaneous coronary intervention (PPCI) and 2) infarct size, in order to optimise therapy to reduce thrombus burden. METHODS AND RESULTS: One-hundred and fifty-three consecutive patients presenting with STEMI and undergoing PPCI were included. Thrombus was evaluated by angiography and scored according to the TIMI study group score. Next, patients were categorised into two groups that had either high thrombus grade (HTG; score 4-5) or low thrombus grade (LTG; score 1-3). We evaluated predictors of angiographic thrombus grade among a number of clinical, angiographic and laboratory data. We also assessed infarct size and scintigraphic left ventricular ejection fraction (LVEF) at three months in both patient groups. Ninety-four patients (58+/-11 years; 75% males) presented with HTG, whereas 59 patients (58+/-12 years; 78% males) presented with LTG. Pre-infarction angina (PIA) was more frequently encountered in the LTG group than in the HTG group (25% vs. 10%, p=0.009). Pre-procedural TIMI flow was significantly lower in the HTG group (p<0.001), and thrombosuction was more frequently applied in the HTG group (p<0.001). Absence of PIA (OR=0.29, 95% CI=0.11-0.75, p=0.01) and proximal culprit lesion (OR=2.10, 95% CI=1.02-4.36, p=0.04) were the only independent predictors of HTG. HTG proved an independent predictor of higher peak levels of creatine kinase (CK) (p<0.001) and troponin T (p<0.001), as well as lower LVEF (p=0.05) along with male gender and absence of prior statin therapy. CONCLUSIONS: Absence of PIA and proximal culprit lesions are associated with higher thrombus grade. Higher thrombus grade is associated with larger infarct size and slightly worse LV function. This may have clinical implications in planning strategies, particularly regarding pharmacotherapy, that aim to decrease thrombus burden prior to stent implantation. PMID- 22522551 TI - A new electrocardiographic marker of myocardial reperfusion in patients with acute ST-segment elevation myocardial infarction treated with primary percutaneous intervention: the value of QRS duration. AB - AIMS: Although ischaemia-induced QRS complex changes have been described previously, their relation with reperfusion status is not clear. We aimed to investigate the relation of QRS duration with reperfusion at tissue level compared to myocardial blush in patients with acute myocardial infarction who underwent successful primary percutaneous coronary angioplasty. METHODS AND RESULTS: One hundred and forty-eight patients were enrolled. Based on the post angioplasty myocardial blush grade (MBG), patients were divided into reperfusion (grades 2 and 3) and impaired reperfusion (grades 0 and 1) groups. Although the two groups did not differ in terms of admission QRS duration (81+/-17 vs. 79+/-15 msec, p=0.473), the patients in the impaired reperfusion group had a significantly longer QRS duration both at immediate post-angioplasty (78+/-18 vs. 68+/-17 msec, p=0.001) and at the 60th minute ECG (77+/-17 vs. 60+/-17 msec, p<0.001). Patients in the impaired reperfusion group revealed significantly less narrowing of QRS duration in the post-angioplasty 60th minute ECG (6+/-5 vs. 20+/ 5 msec, p<0.001) when compared to the patients in the reperfusion group. After adjusting all variables, QRS narrowing in the 60th minute ECG was determined as an independent electrocardiographic predictor of reperfusion (OR:1.39, 95% CI: 1.25-1.54, p<0.001). CONCLUSIONS: We demonstrated that QRS duration is a strong indicator of myocardial reperfusion status. PMID- 22522552 TI - Dual antiplatelet therapy after myocardial infarction and percutaneous coronary intervention: analysis of patient adherence using a French health insurance reimbursement database. AB - AIMS: Current guidelines recommend the use of dual antiplatelet therapy (DAT) (aspirin+clopidogrel) for patients after acute myocardial infarction (MI). In relation to this, we sought to examine the adherence to this recommended treatment regimen in a population of patients admitted with MI and subsequent percutaneous coronary intervention (PCI). METHODS AND RESULTS: A cohort study was conducted using data from the main health insurance reimbursement database of South West France. Patients hospitalised for MI in 2008 were identified, and then their reimbursement form of DAT for the subsequent 12 months was reviewed. Adherence was assessed by using the proportion of days covered by the treatment and persistence. Among the 634 patients included in the study, 34 had no reimbursement for DAT immediately after discharge. For the remaining patients, the probability of stopping DAT at least for one month was 18.6% (95% CI [15.4;21.8]) during the first three months and 49.1% (95% CI [44.9;53.2]) at 12 months, although the medication availability was 90%. CONCLUSIONS: These results suggest that while this medication is available to patients, the treatment is often stopped before one year. This may account for what has been reported as "resistance" to antiplatelet therapy described in a subset of patients. PMID- 22522553 TI - Long-term outcome after statin treatment in routine clinical practice: results from a prospective PCI cohort study. AB - AIMS: We aim to investigate the association between different types of statins, in particular simvastatin and atorvastatin, and long-term mortality after percutaneous coronary intervention (PCI). METHODS AND RESULTS: Between 2000 and 2005, a prospective cohort was constituted of 5,647 patients who underwent PCI. Type and doses of statin use were collected after the PCI procedure. Survival status was obtained from municipal civil registries. The primary endpoint was all cause mortality. Secondary endpoints were cardiac and cancer mortality. Median follow-up was 5.0 years (range three to nine years). During follow-up 738 patients (13.1%) died. In total, 4,970 patients (88%) were on statin therapy four weeks after PCI of whom the majority used either atorvastatin (34%) or simvastatin (29%). Cumulative survival rates at eight years in the atorvastatin group were 83%, and 79% in the simvastatin group (log-rank, p=0.004). After adjustment, statin use was associated with a 50% mortality reduction (HR 0.49, 95% CI 0.40-0.59) and atorvastatin use was associated with lower total mortality than simvastatin use (adjusted HR 0.77, 95% CI 0.61-0.97). This was largely driven by cancer mortality (adjusted HR 0.59, 95% CI 0.38-0.91). CONCLUSIONS: In patients undergoing PCI the use of statins is associated with reduced mortality during prolonged follow-up. Patients using atorvastatin had a 23% lower mortality than those using simvastatin. PMID- 22522554 TI - Characterisation of a novel porcine coronary artery CTO model. AB - AIMS: To create a large animal coronary chronic total occlusion (CTO) model. Presence of microvessels within the CTO lumen facilitates guidewire crossing. The patterns and time profiles of matrix changes and microvessel formation during coronary CTO maturation are unknown. METHODS AND RESULTS: CTO were created in 15 swine by percutaneous deployment of a collagen plug. Matrix changes were assessed by histology. Intraluminal neovascularisation was assessed by histology and several imaging modalities, including conventional and 3D spin angiography, micro computed tomography (micro-CT) imaging, and contrast-enhanced magnetic resonance imaging (MRI), at six and 12 weeks following CTO creation. Matrix changes included an intense inflammatory reaction at six weeks which had partially abated by 12 weeks. A proteoglycan-rich matrix at six weeks was partially replaced with collagen by 12 weeks. Similar changes were noted in the proximal cap which was acellular. Three patterns of microvessel formation were identified and defined based on the presence and extent of a "lead" neovessel. No major differences in pattern or extent of neovascularisation were noted between six and 12 weeks. CONCLUSIONS: Heterogeneity in neovascularisation patterns occurs during coronary CTO development in a porcine model. Non-invasive imaging to determine the predominant type of neovascularisation prior to and during CTO revascularisation may improve guidewire crossing success rates. This model may be useful for further exploration of CTO pathophysiology, and may aid in further refinements of in vivo imaging of CTO and development of novel therapeutic approaches to revascularisation of CTO, such as manipulations of the proximal cap, matrix composition, neovessel induction, and device testing. PMID- 22522555 TI - Use of the Impella 2.5 system alone, after and in combination with an intra aortic balloon pump in patients with cardiogenic shock: case description and review of the literature. AB - Cardiogenic shock remains a serious complication of acute myocardial infarction as it is associated with very poor prognosis. Despite the historical clinical benefits of the intra-aortic balloon pump (IABP), in some patients additional mechanical cardiac support is necessary. The recent introduction of the percutaneous Impella(r) 2.5 mechanical circulatory support system (Abiomed Inc., Danvers, MA, USA) represents a major advancement and has been used in these circumstances. Nevertheless, the data supporting the use of this technology alone, after, or in combination with the IABP in patients with cardiogenic shock is limited and the clinical benefits remain unproven. We herein provide an updated comprehensive overview of the literature supporting the use of the Impella 2.5 system compared to the use of IABP in patients with cardiogenic shock. We also discuss the potential role for combination therapy for a patient with refractory shock. We describe a case in which an IABP was used as a bail-out strategy to provide additional haemodynamic support in a patient with refractory cardiogenic shock after the Impella 2.5 system was in place. In selected cases of refractory cardiogenic shock, the use of combined therapy with both the the Impella 2.5 and IABP can provide enhanced circulatory support and could be considered an option to maintain haemodynamic support in these patients. PMID- 22522556 TI - The 3mensio ValvesTM multimodality workstation. PMID- 22522557 TI - How should I treat a "swinging" left main thrombosis complicating coronary angioplasty in an obese, diabetic, elderly woman treated with fondaparinux? PMID- 22522558 TI - Tools and techniques: edge-to-edge percutaneous MitraClip(r) implantation. PMID- 22522559 TI - Atypical "black hole" phenomenon after treatment of sirolimus stent restenosis with a paclitaxel-coated balloon. PMID- 22522560 TI - Serial optical coherence tomography imaging of the "black-hole" phenomenon by intravascular ultrasound following sirolimus-eluting stent implantation. PMID- 22522561 TI - MRSA epidemic linked to a quickly spreading colonization and virulence determinant. AB - The molecular processes underlying epidemic waves of methicillin-resistant Staphylococcus aureus (MRSA) infection are poorly understood(1). Although a major role has been attributed to the acquisition of virulence determinants by horizontal gene transfer(2), there are insufficient epidemiological and functional data supporting that concept. We here report the spread of clones containing a previously extremely rare(3,4) mobile genetic element-encoded gene, sasX. We demonstrate that sasX has a key role in MRSA colonization and pathogenesis, substantially enhancing nasal colonization, lung disease and abscess formation and promoting mechanisms of immune evasion. Moreover, we observed the recent spread of sasX from sequence type 239 (ST239) to invasive clones belonging to other sequence types. Our study identifies sasX as a quickly spreading crucial determinant of MRSA pathogenic success and a promising target for therapeutic interference. Our results provide proof of principle that horizontal gene transfer of key virulence determinants drives MRSA epidemic waves. PMID- 22522562 TI - Lethal inflammasome activation by a multidrug-resistant pathobiont upon antibiotic disruption of the microbiota. AB - The mammalian intestine harbors a complex microbial community that provides numerous benefits to its host. However, the microbiota can also include potentially virulent species, termed pathobiont, which can cause disease when intestinal homeostasis is disrupted. The molecular mechanisms by which pathobionts cause disease remain poorly understood. Here we describe a sepsis like disease that occurs upon gut injury in antibiotic-treated mice. Sepsis was associated with the systemic spread of a specific multidrug-resistant Escherichia coli pathobiont that expanded markedly in the microbiota of antibiotic-treated mice. Rapid sepsis-like death required a component of the innate immune system, the Naip5-Nlrc4 inflammasome. In accordance with Koch's postulates, we found the E. coli pathobiont was sufficient to activate Naip5-Nlrc4 and cause disease when injected intravenously into unmanipulated mice. These findings reveal how sepsis like disease can result from recognition of pathobionts by the innate immune system. PMID- 22522563 TI - Leptin action through hypothalamic nitric oxide synthase-1-expressing neurons controls energy balance. AB - Few effective measures exist to combat the worldwide obesity epidemic(1), and the identification of potential therapeutic targets requires a deeper understanding of the mechanisms that control energy balance. Leptin, an adipocyte-derived hormone that signals the long-term status of bodily energy stores, acts through multiple types of leptin receptor long isoform (LepRb)-expressing neurons (called here LepRb neurons) in the brain to control feeding, energy expenditure and endocrine function(2-4). The modest contributions to energy balance that are attributable to leptin action in many LepRb populations(5-9) suggest that other previously unidentified hypothalamic LepRb neurons have key roles in energy balance. Here we examine the role of LepRb in neuronal nitric oxide synthase (NOS1)-expressing LebRb (LepRb(NOS1)) neurons that comprise approximately 20% of the total hypothalamic LepRb neurons. Nos1(cre)-mediated genetic ablation of LepRb (Lepr(Nos1KO)) in mice produces hyperphagic obesity, decreased energy expenditure and hyperglycemia approaching that seen in whole-body LepRb-null mice. In contrast, the endocrine functions in Lepr(Nos1KO) mice are only modestly affected by the genetic ablation of LepRb in these neurons. Thus, hypothalamic LepRb(NOS1) neurons are a key site of action of the leptin-mediated control of systemic energy balance. PMID- 22522564 TI - Electrophysiological and morphological properties of neurons in layer 5 of the rat postrhinal cortex. AB - The postrhinal (POR) cortex of the rat is homologous to the parahippocampal cortex of the primate based on connections and other criteria. POR provides the major visual and visuospatial input to the hippocampal formation, both directly to CA1 and indirectly through connections with the medial entorhinal cortex. Although the cortical and hippocampal connections of the POR cortex are well described, the physiology of POR neurons has not been studied. Here, we examined the electrical and morphological characteristics of layer 5 neurons from POR cortex of 14- to 16-day-old rats using an in vitro slice preparation. Neurons were subjectively classified as regular-spiking (RS), fast-spiking (FS), or low threshold spiking (LTS) based on their electrophysiological properties and similarities with neurons in other regions of neocortex. Cells stained with biocytin included pyramidal cells and interneurons with bitufted or multipolar dendritic patterns. Similarity analysis using only physiological data yielded three clusters that corresponded to FS, LTS, and RS classes. The cluster corresponding to the FS class was composed entirely of multipolar nonpyramidal cells, and the cluster corresponding to the RS class was composed entirely of pyramidal cells. The third cluster, corresponding to the LTS class, was heterogeneous and included both multipolar and bitufted dendritic arbors as well as one pyramidal cell. We did not observe any intrinsically bursting pyramidal cells, which is similar to entorhinal cortex but unlike perirhinal cortex. We conclude that POR includes at least two major classes of neocortical inhibitory interneurons, but has a functionally restricted cohort of pyramidal cells. PMID- 22522565 TI - Enhancing the polyphenol content of a red-fleshed Japanese plum (Prunus salicina Lindl.) nectar by incorporating a polyphenol-rich extract from the skins. AB - BACKGROUND: Plum skins are a waste product generated during production of plum juice or pulp. Polyphenols, shown to have various health-promoting properties, can be recovered from this waste product. Red-fleshed plum nectar formulations containing plum skin extract in varying amounts were characterised in terms of intensity of sensory attributes, consumer acceptability, colour, polyphenol content and antioxidant activity. Commercial beverages containing red fruits were used as benchmarks. RESULTS: The polyphenolic profile of the plum skin extract was similar to that of the pulp, including anthocyanins, flavonols, flavan-3-ols and a phenolic acid. Addition of the extract to plum nectar, which enhanced the colour, polyphenol content and antioxidant capacity, was limited by its negative sensory impact. The formulations were deemed acceptable by consumers, although a decrease in positive sensory attributes (plum flavour, plum aroma and sweetness) and an increase in negative sensory attributes (plant-like flavour, plant-like aroma, acidity and astringency) were observed with increasing skin extract content. The formulations compared favourably with commercial beverages in terms of colour total polyphenol content and antioxidant activity. CONCLUSION: Plum skins were successfully used to enhance the functional status of plum nectar. Use of a functional ingredient from plum skins is, therefore, a feasible value addition strategy. PMID- 22522566 TI - Neurologic indications for therapeutic plasma exchange: 2011 update. AB - Neurologists commonly use therapeutic plasma exchange (TPE) to treat a number of conditions. This concise review examines the most common neurologic indications for TPE. It focuses on Guillain-Barre' syndrome and myasthenia gravis and also the role of TPE in chronic inflammatory demyelinating polyneuropathy, Lambert Eaton syndrome, multiple sclerosis, neuromyelitis optica, paraproteinemic polyneuropathy, Sydenham's chorea, and natalizumab-associated progressive multifocal leukoencephalopathy (PML). As with any treatment, the proven efficacy, cost, side effects, and availability must be considered before initiation of therapy. PMID- 22522567 TI - Zinc-catalyzed amide cleavage and esterification of beta-hydroxyethylamides. PMID- 22522568 TI - Ultra-short course sirolimus contributes to effective GVHD prophylaxis after reduced-intensity allogeneic hematopoietic cell transplantation. AB - Reduced-intensity conditioning (RIC) allo-SCT is a potentially curative treatment approach for patients with relapsed Hodgkin's or non-Hodgkin's lymphoma. In the present study, 37 patients underwent RIC allo-SCT after induction treatment with EPOCH-F(R) using a novel form of dual-agent immunosuppression for GVHD prophylaxis with CsA and sirolimus. With a median follow-up of 28 months among survivors, the probability for OS at 3 and 5 years was 56%. Treatment-related mortality was 16% at day +100 and 30% after 1 year of transplant. Acute GVHD grades II-IV developed in 38% of patients, suggesting that the regimen consisting of CsA and an ultra-short course of sirolimus is effective in the prevention of acute GVHD. PMID- 22522569 TI - Autologous platelet lysate for treatment of refractory ocular GVHD. AB - Current treatment of ocular GVHD (oGVHD), represented by systemic immunosuppressive regimens and local therapies (mainly artificial tears and corticosteroids), gives unsatisfactory results. We investigated the safety and efficacy of autologous plasma rich in PDGFs to treat oGVHD unresponsive to standard medications. A total of 23 patients with refractory oGVHD (grade II-IV) unresponsive to standard therapy were treated with autologous plasma rich in PDGFs eye drops (PRGD) four times/day for 6 months. Symptoms and signs (best visual acuity, Schirmer's test and tear break up time (TBUT), evaluation of the anterior segment and fluorescein and lissamine staining) were always assessed by the same ophthalmologist. Patients were defined as 'responders' when showing improvement for total complaints and at least one sign. At 30 days of treatment, 17 patients (73.9%) were classified as responders. The symptom that improved most was photophobia (improved in 19 patients, 82.6%). TBUT improved in 20 patients (86.9%) and anterior segment score in 19 patients (82.6%). Response was maintained over time. No serious adverse events occurred. PRGD proved to be safe and effective in treating oGVHD and may be a valid treatment option from the early stages of the disease to avoid irreversible ocular damage. PMID- 22522570 TI - Auto-HSCT induces sustained responses in severe systemic sclerosis patients failing pulse cyclophosphamide. PMID- 22522571 TI - Complete resolution of guttate psoriasis following autologous SCT for Ewing's sarcoma in a pediatric patient. PMID- 22522572 TI - Metronomic chemotherapy may be active in heavily pre-treated patients with metastatic adreno-cortical carcinoma. AB - OBJECTIVE: The potential benefit of further chemotherapy approaches in patients with adrenocortical carcinoma (ACC) showing progressive disease after 2 chemotherapy lines is actually unknown. This study provides explorative information on the activity of metronomic chemotherapy in heavily pre-treated ACC patients. DESIGN AND METHODS: We tested the activity of cytotoxic treatments administered on a metronomic schedule in metastatic ACC patients showing disease progression after treatment with gemcitabine and capecitabine scheme. RESULTS: Eight patients out of 28 consecutively enrolled in that trial were treated with several metronomic cytotoxic regimens. Six of them showed disease progression, but 2 patients obtained a clear benefit. The first patient was treated with oral etoposide (50 mg daily) as the 6th-line therapy and obtained a partial response lasting 24 months, while the second patient obtained a partial response lasting 10 months with metronomic oral cyclophosphamide (50 mg daily) as the 5th chemotherapy line. Both patients had sex hormone secreting tumors and were bearing a rather indolent ACC. CONCLUSIONS: The administration of several chemotherapy lines in advanced ACC patients cannot be routinely recommended outside prospective clinical trials. Few patients with indolent tumors, however, may benefit from this approach. According to our experience, oral cyclophosphamide and oral etoposide may be used in this setting. PMID- 22522573 TI - A national epidemiological study of offending and its relationship with ADHD symptoms and associated risk factors. AB - OBJECTIVE: The objective was to disentangle the relationship between offending, ADHD, and comorbid risk factors. METHOD: A total of 11,388 students in further education completed a questionnaire, which measured nonviolent and violent delinquency, current ADHD symptoms, conduct disorder, substance use, association with delinquent peers, emotional lability, anger problems, violent attitudes, and low self-esteem. RESULTS: The nonviolent and violent delinquency measures correlated significantly with all the predictor measures, with small to large effect sizes. Multiple regressions showed that after controlling for age and gender, ADHD contributed 8.2% and 8.8% to the variance in nonviolent and violent delinquency, respectively, but these effects were largely mediated by the comorbid measures, particularly substance use, association with delinquent peers, and conduct disorder. CONCLUSION: The relationship between ADHD symptoms and offending among young people is largely explained indirectly by comorbid factors. A key prevention is to address substance use problems and association with delinquent peers. PMID- 22522574 TI - No beneficial effects of adding parent training to methylphenidate treatment for ADHD + ODD/CD children: a 1-year prospective follow-up study. AB - OBJECTIVE: The aim of this study was to compare the effect of methylphenidate (MPH) versus MPH + parent training in children with ADHD and oppositional defiant disorder/conduct disorder (ODD/CD) over a 12-month period. METHOD: After careful screening, 120 children diagnosed with ADHD + ODD/CD were included in the study. Treatment consisted of ongoing medication management for 12 months, with or without participation in a parent-training program beginning after the 1st month. Participants were not randomly assigned to treatment groups because of ethical, practical, and methodological reasons. RESULTS: Data analyses revealed that mother-child relationship improvements and symptom severity did not benefit from parent training. CONCLUSION: The results of this study highlighted the positive role of MPH in ADHD. No significant effects were observed after the addition of parent training to MPH treatment. Clinicians should carefully follow patients' improvements and titrate the MPH dosage during long-term treatment. PMID- 22522575 TI - Hg(OTf)(2)-catalyzed direct vinylation of tryptamines and versatile applications for tandem reactions. AB - We have developed a unique catalytic protocol for direct gem-vinylation of tryptamine derivatives employing Hg(OTf)(2) as the optimum catalyst. The intermolecular vinylations with a series of aromatic acetylenes proceeded under ambient temperature at the C2 positions of indoles with high functional group tolerance. Based on the mechanistic insights, we further developed the tandem reactions successfully constructing a quaternary center. PMID- 22522576 TI - Rapid reduction of central line infections in hospitalized pediatric oncology patients through simple quality improvement methods. AB - BACKGROUND: Pediatric hematology-oncology (PHO) patients are at significant risk for developing central line-associated bloodstream infections (CLA-BSIs) due to their prolonged dependence on such catheters. Effective strategies to eliminate these preventable infections are urgently needed. In this study, we investigated the implementation of bundled central line maintenance practices and their effect on hospital-acquired CLA-BSIs. MATERIALS AND METHODS: CLA-BSI rates were analyzed within a single-institution's PHO unit between January 2005 and June 2011. In May 2008, a multidisciplinary quality improvement team developed techniques to improve the PHO unit's safety culture and implemented the use of catheter maintenance practices tailored to PHO patients. Data analysis was performed using time-series methods to evaluate the pre- and post-intervention effect of the practice changes. RESULTS: The pre-intervention CLA-BSI incidence was 2.92 per 1,000-patient days (PD) and coagulase-negative Staphylococcus was the most prevalent pathogen (29%). In the post-intervention period, the CLA-BSI rate decreased substantially (45%) to 1.61 per 1,000-PD (P < 0.004). Early on, blood and marrow transplant (BMT) patients had a threefold higher CLA-BSI rate compared to non-BMT patients (P < 0.033). With additional infection control countermeasures added to the bundled practices, BMT patients experienced a larger CLA-BSI rate reduction such that BMT and non-BMT CLA-BSI rates were not significantly different post-intervention. CONCLUSIONS: By adopting and effectively implementing uniform maintenance catheter care practices, learning multidisciplinary teamwork, and promoting a culture of patient safety, the CLA BSI incidence in our study population was significantly reduced and maintained. PMID- 22522577 TI - Mercury-induced biochemical and proteomic changes in rice roots. AB - Mercury (Hg) is a serious environmental pollution threats to the planet. Accumulation of Hg in plants disrupts many cellular-level functions and inhibits growth and development, but the mechanism is not fully understood. We investigated cellular, biochemical and proteomic changes in rice roots under Hg stress. Root growth rate was decreased and Hg, reactive oxygen species (ROS), and malondialdehyde (MDA) content and lipoxygenase activity were increased significantly with increasing Hg concentration in roots. We revealed a time dependent alteration in total glutathione content and enzymatic activity of superoxide dismutase (SOD), ascorbate peroxidase (APX), catalase (CAT) and peroxidase (POD) during Hg stress. 2-D electrophoresis revealed differential expression of 25 spots with Hg treatment of roots: 14 spots were upregulated and 11 spots downregulated. These differentially expressed proteins were identified by ESI-MS/MS to be involved in cellular functions including redox and hormone homeostasis, chaperone activity, metabolism, and transcription regulation. These results may provide new insights into the molecular basis of the Hg stress response in plants. PMID- 22522578 TI - Molecular cloning and characterization of the genes encoding an auxin efflux carrier and the auxin influx carriers associated with the adventitious root formation in mango (Mangifera indica L.) cotyledon segments. AB - Polar auxin transport (PAT) plays an important role in the adventitious root formation of mango cotyledon segments, but the molecular mechanism remains unclear. In this study, we cloned a gene encoding an auxin efflux carrier (designated as MiPIN1), and we cloned four genes encoding auxin influx carriers (designated as MiAUX1, MiAUX2, MiAUX3 and MiAUX4). The results of a phylogenetic tree analysis indicated that MiPIN1 and the MiAUXs belong to plant PIN and AUXs/LAXs groups. Quantitative real-time PCR indicated that the expression of MiPIN1 and the MiAUXs was lowest at 0 days but sharply increased on and after day 4. During the root formation in the mango cotyledon segments, the MiPIN1 expression in the distal cut surface (DCS) was always higher than the expression in the proximal cut surface (PCS) whereas the expression of the MiAUXs in the PCS was usually higher than in the DCS. This expression pattern might be result in the PAT from the DCS to the PCS, which is essential for the adventitious root formation in the PCS. Our previous study indicated that a pre-treatment of embryos with indole-3-butyric acid (IBA) significantly promoted adventitious rooting in PCS whereas a pre-treatment with 2,3,5-triiodobenzoic acid (TIBA) completely inhibited this rooting. In this study, however, IBA and TIBA pre treatments slightly changed the expression of MiPIN1. In contrast, while the MiAUX3 and MiAUX4 expression levels were significantly up-regulated by the IBA pre-treatment, the expression levels were down-regulated by the TIBA pre treatment. These findings imply that MiAUX3 and MiAUX4 are more sensitive to the IBA and TIBA treatments and that they might play important roles during adventitious root formation in mango cotyledon segments. PMID- 22522580 TI - A comparative study of the topology of the experimental electron density within 2 and 4e- donor alkyne complexes. AB - A comparison of the topology of the experimental electron density, as revealed by high resolution X-ray diffraction, is provided for two prototypal transition metal alkyne complexes where the alkyne formally behaves as a 2 or 4e(-) donor. A higher value of the electron density rho(r)(bcp) at the M(T)...C bond critical point (bcp), a lower value of rho(r)(bcp) at the coordinated C=C bcp, outwardly bent MC bond paths and a close to zero ellipticity for the C[triple bond, length as m-dash]C bond constitute the topological signature of a 4e(-) donor alkyne ligand. PMID- 22522579 TI - The influence of EDDS on the metabolic and transcriptional responses induced by copper in hydroponically grown Brassica carinata seedlings. AB - To improve the knowledge about the use of plants for the removal of toxic metals from contaminated soils, metabolic and transcriptional responses of Brassica carinata to different forms of copper (Cu) were studied. Two-week-old hydroponically grown seedlings were exposed for 24 h to 30 MUM CuSO4 or CuEDDS. CuSO4 appeared to be more toxic than CuEDDS as roots showed higher levels of thiobarbituric acid reactive substances (TBARS) and increased relative leakage ratios (RLR), although the superoxide dismutase (SOD, EC 1.15.1.1) activity increased following both exposures. In CuSO4-exposed seedlings the higher toxicity was underlined by increased transcription of lipoxygenases (EC 1.13.11.12) and NADPH oxidases (EC 1.6.99.6) and by the higher Cu accumulation in both tissues compared to CuEDDS exposure. The presence of EDDS increased Cu translocation, which resulted 5-times higher than when exposed to CuSO4. Decreases in catalase (CAT, EC 1.11.1.6), ascorbate peroxidase (APX, EC 1.11.1.11) and glutathione reductase (GR, EC 1.6.4.2) activities together with increases of reduced glutathione (GSH) and tocopherols and a reduction of lipoic acid (LA) were observed in roots of CuSO4-exposed seedlings. On the contrary, CuEDDS exposure induced a general increase in enzyme activities and decreases in ascorbate (AsA) and tocopherol levels. In the primary leaves, in both exposures Cu differently affected the oxidative stress responses indicating that the cellular redox balance was anyway maintained. EDDS plays a crucial role in B. carinata tolerance to oxidative stress induced by Cu and might be proposed to improve the efficiency of Cu phytoextraction. PMID- 22522581 TI - The use of fish-derived cell lines for investigation of environmental contaminants. AB - This unit describes protocols for growing salmonid cell lines and using them in in vitro toxicology studies. Cell viability of cultures is assessed with three indicator dyes: alamar blue for metabolic activity, CFDA-AM for membrane integrity, and neutral red for lysosomal activity. These protocols are essential tools for investigating environmental toxicity at the cellular level. PMID- 22522582 TI - [Strategy in advanced castration-resistant prostate cancer]. AB - If androgen deprivation, chemical with LH-RH analogs or surgical with bilateral orchiectomy, still remains the stone edge of treatment of prostate cancer, in the metastatic setting, this hormonosensitivity, most of the time long, finally move on in hormonal-failure. If rare changes in the therapeutic strategy have been achieved in this setting since 2004 and the arrival of docetaxel, it is the global perception of the disease that has been modified and the definition of one specific entity: the castrate-resistant prostate cancer. This new definition and the changes of design and end-points of clinical trials testing new agents with strong recruitment during the past years have conducted to a real revolution in the management of castrate-refractory prostate cancer. The place of secondary hormonal manipulations, such as withdrawal of the anti-androgen, oestrogen or ketoconazole, still exists for a selected group of patients. In case of aggressive disease and symptoms, chemotherapy should be selected, docetaxel, in a three weeks schedule, and may be combined with Estracyt. It is time to consider the revolution of the post-chemotherapy setting with the arrival of two new drugs ; a cytotoxic one, the cabazitaxel and hormonal for the second one, the abiraterone acetate. The place of the immunotherapy with the sipuleucel-T may be more difficult to precise, especially in Europe, even if it has been finally indicated in the United States in the metastatic setting. Concerning bone metastasis, zoledronic acid was during a long time the only bone-targeted agent, effective in reducing the incidence of skeletal related events, and was recently exceeded by the denosumab, an anti-RANK ligand. Finally, let us hope that other changes will be achieved in the near future, with the cabazitaxel-docetaxel confrontation in the first-line setting, and the introduction of the abiraterone acetate before chemotherapy with docetaxel, already tested in ongoing trials. PMID- 22522583 TI - Efficient treatment of solvation shells in 3D molecular theory of solvation. AB - We developed a technique to decrease memory requirements when solving the integral equations of three-dimensional (3D) molecular theory of solvation, a.k.a. 3D reference interaction site model (3D-RISM), using the modified direct inversion in the iterative subspace (MDIIS) numerical method of generalized minimal residual type. The latter provides robust convergence, in particular, for charged systems and electrolyte solutions with strong associative effects for which damped iterations do not converge. The MDIIS solver (typically, with 2 * 10 iterative vectors of argument and residual for fast convergence) treats the solute excluded volume (core), while handling the solvation shells in the 3D box with two vectors coupled with MDIIS iteratively and incorporating the electrostatic asymptotics outside the box analytically. For solvated systems from small to large macromolecules and solid-liquid interfaces, this results in 6- to 16-fold memory reduction and corresponding CPU load decrease in MDIIS. We illustrated the new technique on solvated systems of chemical and biomolecular relevance with different dimensionality, both in ambient water and aqueous electrolyte solution, by solving the 3D-RISM equations with the Kovalenko-Hirata (KH) closure, and the hypernetted chain (HNC) closure where convergent. This core shell-asymptotics technique coupling MDIIS for the excluded volume core with iteration of the solvation shells converges as efficiently as MDIIS for the whole 3D box and yields the solvation structure and thermodynamics without loss of accuracy. Although being of benefit for solutes of any size, this memory reduction becomes critical in 3D-RISM calculations for large solvated systems, such as macromolecules in solution with ions, ligands, and other cofactors. PMID- 22522584 TI - Can a single question provide an accurate measure of physical activity? AB - OBJECTIVE: The 'single-item measure' was developed as a short self-report tool for assessing physical activity. The aim of this study was to test the criterion validity of the single-item measure against accelerometry. DESIGN: Participants (n=66, 65% female, age: 39+/-11 years) wore an accelerometer (ActiGraph GT3X) over a 7-day period and on day 8, completed the single-item measure. The number of days of >=30 min of accelerometer-determined moderate to vigorous intensity physical activity (MVPA) were calculated using two approaches; first by including all minutes of MVPA and second by including only MVPA accumulated in bouts of >=10 min (counts/min >=1952). Associations between the single-item measure and accelerometer were examined using Spearman correlations and 95% limits of agreement. Percent agreement and kappa statistic were used to assess agreement between the tools in classifying participants as sufficiently/insufficiently active. RESULTS: Correlations between the number of days of >=30 min MVPA recorded by the single-item and accelerometer ranged from 0.46 to 0.57. Participants underreported their activity on the single-item measure (-1.59 days) when compared with all objectively measured MVPA, but stronger congruence was observed when compared with MVPA accumulated in bouts of >=10 min (0.38 days). Overall agreement between the single-item and accelerometry in classifying participants as sufficiently/insufficiently active was 58% (k=0.23, 95% CI 0.05 to 0.41) when including all MVPA and 76% (k=0.39, 95% CI 0.14 to 0.64) when including activity undertaken in bouts of >=10 min. CONCLUSIONS: The single-item measure is a valid screening tool to determine whether respondents are sufficiently active to benefit their health. PMID- 22522585 TI - Respiratory health of elite athletes - preventing airway injury: a critical review. AB - Elite athletes, particularly those engaged in endurance sports and those exposed chronically to airborne pollutants/irritants or allergens, are at increased risk for upper and lower airway dysfunction. Airway epithelial injury may be caused by dehydration and physical stress applied to the airways during severe exercise hyperpnoea and/or by inhalation of noxious agents. This is thought to initiate an inflammatory cascade/repair process that, ultimately, could lead to airway hyperresponsiveness (AHR) and asthma in susceptible athletes. The authors review the evidence relating to prevention or reduction of the risk of AHR/asthma development. Appropriate measures should be implemented when athletes exercise strenuously in an attempt to attenuate the dehydration stress and reduce the exposure to noxious airborne agents. Environmental interventions are the most important. Non-pharmacological strategies can assist, but currently, pharmacological measures have not been demonstrated to be effective. Whether early prevention of airway injury in elite athletes can prevent or reduce progression to AHR/asthma remains to be established. PMID- 22522586 TI - Diagnosis, treatment and prevention of ankle sprains: an evidence-based clinical guideline. AB - Ankle injuries are a huge medical and socioeconomic problem. Many people have a traumatic injury of the ankle, most of which are a result of sports. Total costs of treatment and work absenteeism due to ankle injuries are high. The prevention of recurrences can result in large savings on medical costs. A multidisciplinary clinical practice guideline was developed with the aim to prevent further health impairment of patients with acute lateral ankle ligament injuries by giving recommendations with respect to improved diagnostic and therapeutic opportunities. The recommendations are based on evidence from published scientific research, which was extensively discussed by the guideline committee. This clinical guideline is helpful for healthcare providers who are involved in the management of patients with ankle injuries. PMID- 22522587 TI - Fitness levels and physical activity among class A drug users entering prison. AB - BACKGROUND: Physical activity could benefit drug users' physiological and mental health. Previous research has suggested that physical activity levels change when drug users enter prison. METHODS: Twenty-five class A drug users who were new to prison answered physical activity and drug use cross-sectional questionnaires, took a submaximal fitness test and wore a pedometer for 1 week. RESULTS: Participants' mean aerobic capacity was estimated as 49 mls O2/kg/min (+/-12 SD). Their mean self-reported walking distance outside of prison was 4.67 miles on an average day (+/-4.14 SD). Pedometer data suggest they walked a mean of 1.8 miles/day in prison. CONCLUSION: Many class A drug users entering prison had high levels of fitness and physical activity before admission, often gained from walking. Walking activity reduced when they entered prison, posing a challenge to maintaining healthy activity levels. PMID- 22522588 TI - Determination of future prevention strategies in elite track and field: analysis of Daegu 2011 IAAF Championships injuries and illnesses surveillance. AB - OBJECTIVE: To determine the incidence and characteristics of newly incurred injuries and illnesses during international Athletics Championships, by improving the medical surveillance coverage, in order to determine future prevention strategies. DESIGN: Prospective recording of newly occurred injuries and illnesses. SETTING: 13th International Association of Athletics Federations World Championships in Athletics 2011 in Daegu, Korea. PARTICIPANTS: National team and Local Organising Committee physicians; and 1851 registered athletes. MAIN OUTCOME MEASURES: Incidence and characteristics of newly incurred injuries and illnesses. RESULTS: 82% of athletes were covered by medical teams participating with a response rate of 94%. A total of 249 injuries were reported, representing an incidence of 134.5 injuries per 1000 registered athletes, and 119 (48%) resulted in time loss from sport. A total of 185 injuries affected the lower limb (74%). Hamstring strain was the main diagnosis and 67% resulted in absence from sport. Overuse (n=148; 59%) was the predominant cause. A total of 126 illnesses were reported, signifying an incidence of 68.1 per 1000 registered athletes. Upper respiratory tract infection was the most common reported diagnosis (18%), followed by exercise-induced dehydration (12%), and gastroenteritis/diarrhoea (10%). The highest incidences of injuries were found in combined events and middle and long-distance events, and of illness in race walking events. CONCLUSION: During elite Athletics World Championships, 135 injuries, 60 time loss injuries and 68 illnesses per 1000 registered athletes were reported. Higher risks of injuries were found in combined events and long-distance runs. Preventive interventions should focus on overuse injuries and hamstring strains, decreasing the risk of transmission of infectious diseases, appropriate event scheduling and heat acclimatisation. PMID- 22522589 TI - Emerging concept: 'central benefit model' of exercise in falls prevention. AB - Falls are a common geriatric syndrome and are the third leading cause of chonic disability worldwide. Falls are not random events and occur, at least in part, due to impaired physiological function, such as impaired balance, and cognitive impairment. The clinical syndrome of falls is important for Sports and Exercise Medicine Clinicians as there is Level 1 evidence that targeted exercise prescription is an effective intervention strategy. The widely accepted dogma is that improved physical function, balance and muscle strength, underlies the effectiveness of the exercise in reducing falls. However, findings from randomised controlled trials suggest that exercise reduce falls via mechanisms other than improved physiological function. The authors propose that improved cognitive function - specifically, executive functions - and associated functional plasticity may be an important yet underappreciated mechanism by which the exercise reduces falls in older adults. PMID- 22522590 TI - The effects of eccentric training on lower limb flexibility: a systematic review. AB - BACKGROUND: Reduced flexibility has been documented in athletes with lower limb injury, however, stretching has limited evidence of effectiveness in preventing injury or reducing the risk of recurrence. In contrast, it has been proposed that eccentric training can improve strength and reduce the risk of injury, and facilitate increased muscle flexibility via sarcomerogenesis. OBJECTIVES: This systematic review was undertaken to examine the evidence that eccentric training has demonstrated effectiveness as a means of improving lower limb flexibility. STUDY APPRAISAL AND SYNTHESIS METHODS: Six electronic databases were systematically searched by two independent reviewers to identify randomised clinical trials comparing the effectiveness of eccentric training to either a different intervention, or a no-intervention control group. Studies evaluating flexibility using both joint range of motion (ROM) and muscle fascicle length (FL) were included. Six studies met the inclusion/exclusion criteria, and were appraised using the PEDro scale. Differences in the muscles studied, and the outcome measures used, did not allow for pooled analysis. RESULTS: There was consistent, strong evidence from all six trials in three different muscle groups that eccentric training can improve lower limb flexibility, as assessed using either joint ROM or muscle FL. CONCLUSION: The results support the hypothesis that eccentric training is an effective method of increasing lower limb flexibility. Further research is required to compare the increased flexibility obtained after eccentric training to that obtained with static stretching and other exercise interventions. PMID- 22522591 TI - Genetic variations in bile acid homeostasis are not overrepresented in alcoholic cirrhosis compared to patients with heavy alcohol abuse and absent liver disease. AB - Increased serum bile salt levels have been associated to a single-nucleotide polymorphism in the bile salt export pump (BSEP; ABCB11) in several acquired cholestatic liver diseases but there is little evidence in alcoholic liver disease (ALD). Furthermore, a crosstalk between vitamin D and bile acid synthesis has recently been discovered. Whether this crosstalk has an influence on the course of ALD is unclear to date. Our aim was to analyse the role of genetic polymorphisms in BSEP and the vitamin D receptor gene (NR1I1) on the emergence of cirrhosis in patients with ALD. Therefore, 511 alcoholic patients (131 with cirrhosis and 380 without cirrhosis) underwent ABCB11 genotyping (rs2287622). Of these, 321 (131 with cirrhosis and 190 without cirrhosis) were also tested for NR1I1 polymorphisms (bat-haplotype: BsmI rs1544410, ApaI rs7975232 and TaqI rs731236). Frequencies of ABCB11 and NR1I1 genotypes and haplotypes were compared between alcoholic patients with and without cirrhosis and correlated to serum bile salt, bilirubin and aspartate aminotransferase levels in those with cirrhosis. Frequencies of ABCB11 and NR1I1 genotypes and haplotypes did not differ between the two subgroups and no significant association between genotypes/haplotypes and liver function tests could be determined for neither polymorphism. We conclude that ABCB11 and NR1I1 polymorphisms are obviously not associated with development of cirrhosis in patients with ALD. PMID- 22522592 TI - Effects of high hydrostatic pressure on structure and colour of red ginseng (Panax ginseng). AB - BACKGROUND: The conventional method of processing ginseng (Panax ginseng) roots into red ginseng involves mainly heating and drying processes. In the present study, this method was modified by using high hydrostatic pressure (HHP) to improve the physicochemical characteristics of red ginseng. RESULTS: The HHP process (600 MPa for 1 min) significantly improved the histological properties of red ginseng by increasing cellular disruption and release of cell contents. The total reducing sugar content was significantly (P < 0.05) higher (increased from 10.67 to 15.25 mg g(-1)) in red ginseng processed at 600 MPa for 1 min. Similarly, the total free amino acid content also increased significantly (from 2.81 to 7.77 mg g(-1)). The HHP process resulted in superior and more even colouration and gave an attractive visual appearance to red ginseng. The optical density at 420 nm and Hunter's colour a value (redness) of extracts prepared from red ginseng increased significantly (P < 0.05) with the application of HHP. CONCLUSION: HHP-processed red ginseng has significantly higher reducing sugar and free amino acid contents together with a more compact cell structure and superior visual quality (brighter red colour). Hence the application of HHP in red ginseng processing can result in ginseng products of improved quality compared with those obtained by the conventional method. PMID- 22522593 TI - Effects of chemical bonding on heat transport across interfaces. AB - Interfaces often dictate heat flow in micro- and nanostructured systems. However, despite the growing importance of thermal management in micro- and nanoscale devices, a unified understanding of the atomic-scale structural features contributing to interfacial heat transport does not exist. Herein, we experimentally demonstrate a link between interfacial bonding character and thermal conductance at the atomic level. Our experimental system consists of a gold film transfer-printed to a self-assembled monolayer (SAM) with systematically varied termination chemistries. Using a combination of ultrafast pump-probe techniques (time-domain thermoreflectance, TDTR, and picosecond acoustics) and laser spallation experiments, we independently measure and correlate changes in bonding strength and heat flow at the gold-SAM interface. For example, we experimentally demonstrate that varying the density of covalent bonds within this single bonding layer modulates both interfacial stiffness and interfacial thermal conductance. We believe that this experimental system will enable future quantification of other interfacial phenomena and will be a critical tool to stimulate and validate new theories describing the mechanisms of interfacial heat transport. Ultimately, these findings will impact applications, including thermoelectric energy harvesting, microelectronics cooling, and spatial targeting for hyperthermal therapeutics. PMID- 22522594 TI - Exchange biasing of magnetoelectric composites. AB - Magnetoelectric composite materials are promising candidates for highly sensitive magnetic-field sensors. However, the composites showing the highest reported magnetoelectric coefficients require the presence of external d.c. magnetic bias fields, which is detrimental to their use as sensitive high-resolution magnetic field sensors. Here, we report magnetoelectric composite materials that instead rely on intrinsic magnetic fields arising from exchange bias in the device. Thin film magnetoelectric two-two composites were fabricated by magnetron sputtering on silicon-cantilever substrates. The composites consist of piezoelectric AlN and multilayers with the sequence Ta/Cu/Mn(70)Ir(30)/Fe(50)Co(50) or Ta/Cu/Mn(70)Ir(30)/Fe(70.2)Co(7.8)Si(12)B(10) serving as the magnetostrictive component. The thickness of the ferromagnetic layers and angle dependency of the exchange bias field are used to adjust the shift of the magnetostriction curve in such a way that the maximum piezomagnetic coefficient occurs at zero magnetic bias field. These self-biased composites show high sensitivity to a.c. magnetic fields with a maximum magnetoelectric coefficient of 96 V cm(-1) Oe(-1) at mechanical resonance. PMID- 22522595 TI - Effects of plant flavonoids on Manduca sexta (tobacco hornworm) fifth larval instar midgut and fat body mitochondrial transhydrogenase. AB - The reversible, membrane-associated transhydrogenase that catalyzes hydride-ion transfer between NADP(H) and NAD(H) was evaluated and compared to the corresponding NADH oxidase and succinate dehydrogenase activities in midgut and fat body mitochondria from fifth larval instar Manduca sexta. The developmentally significant NADPH-forming transhydrogenation occurs as a nonenergy- or energy linked activity with energy for the latter derived from either electron transport dependent NADH or succinate utilization, or ATP hydrolysis by Mg++-dependent ATPase. In general, the plant flavonoids examined (chyrsin, juglone, morine, quercetin, and myricetin) affected all reactions in a dose-dependent fashion. Differences in the responses to the flavonoids were apparent, with the most notable being inhibition of midgut, but stimulation of fat body transhydrogenase by morin, and myricetin as also noted for NADH oxidase and succinate dehydrogenase. Although quercetin inhibited or stimulated transhydrogenase activity depending on the origin of mitochondria, it was without effect on either midgut or fat body NADH oxidase or succinate dehydrogenase. Observed sonication dependent increases in flavonoid inhibition may well reflect an alteration in membrane configuration, resulting in increased exposure of the enzyme systems to the flavonoids. The effects of flavonoids on the transhydrogenation, NADH oxidase, and succinate dehydrogenase reactions suggest that compounds of this nature may prove valuable in the control of insect populations by affecting these mitochondrial enzyme components. PMID- 22522596 TI - MKP-1 antagonizes C/EBPbeta activity and lowers the apoptotic threshold after ischemic injury. AB - The dual specificity phosphatase MAPK phosphatase-1 (MKP-1) feeds back on MAP kinase signaling to regulate metabolic, inflammatory and survival responses. MKP 1 is widely expressed in the central nervous system (CNS) and induced after ischemic stress, although its function in these contexts remains unclear. Here we report that MKP-1 activated several cell death factors, including BCL2 and adenovirus E1B 19 kDa interacting protein 3, and caspases 3 and 12 culminating in apoptotic cell death in vitro. MKP-1 also exerted inhibitory effects on the bZIP transcription factor CCAAT/enhancer-binding protein (C/EBPbeta), previously shown to have neuroprotective properties. These effects included reduced expression of the full-length C/EBPbeta variant and hypo-phosphorylation at the MEK-ERK1/2 sensitive Thr(188) site. Notably, enforced expression C/EBPbeta rescued cells from MKP-1-induced toxicity. Studies performed in knock-out mice indicate that the MKP-1 activity is required to exclude C/EBPbeta from the nucleus basally, and that MKP-1 antagonizes C/EBPbeta expression after global forebrain ischemia, particularly within the vulnerable CA1 sector of the hippocampus. Overall, MKP-1 appears to lower the cellular apoptotic threshold by inhibiting C/EBPbeta and enhancing both BH3 protein expression and cellular caspase activity. Thus, although manipulation of the MKP-1-C/EBPbeta axis could have therapeutic value in ischemic disorders, our observations using MKP-1 catalytic mutants suggest that approaches geared towards inhibiting MKP-1's phosphatase activity alone may be ineffective. PMID- 22522597 TI - Nucleolar protein GLTSCR2 stabilizes p53 in response to ribosomal stresses. AB - p53 is a key regulator of cell growth and death by controlling cell cycle progression and apoptosis under conditions of stress such as DNA damage or oncogenic stimulation. As these processes are critical for cell function and inhibition of tumor development, p53 regulatory pathways are strictly monitored in cells. Recently, it was recognized that nucleolar proteins, including nucleophosmin/B23, ribosomal protein L11, and alternate reading frame (ARF), form the nucleolus-ARF-murine double minute 2 (MDM2) axis in p53 regulatory pathways, which increases p53 stability by suppressing the activity of MDM2. In this work, we show that nucleolar protein glioma tumor-suppressor candidate region gene 2 (GLTSCR2) translocates to the nucleoplasm under ribosomal stress, where it interacts with and stabilizes p53 and inhibits cell cycle progression without the involvement of the major upstream p53 regulator, ARF. Furthermore, ectopic expression of GLTSCR2 significantly suppressed growth of cancer cells in a xenograft animal model via p53-dependent pathway. Our data identify GLTSCR2 as a new member of the nucleolus-nucleoplasmic axis for p53 regulation. ARF independent direct regulation of p53 by GLTSCR2 may be a key mechanism and therapeutic target for cell death or growth inhibition when nucleolus-ARF-p53 pathways are inactivated by genetic or epigenetic modifications of ARF, which are the second most common types of genetic change observed in human cancers. PMID- 22522598 TI - Bid protects the mouse hematopoietic system following hydroxyurea-induced replicative stress. AB - Hematopoietic stem cells (HSCs) possess long-term self-renewal capacity and multipotent differentiative capacity, to maintain the hematopoietic system. Long term hematopoietic homeostasis requires effective control of genotoxic damage to maintain HSC function and prevent propagation of deleterious mutations. Here we investigate the role of the BH3-only Bcl-2 family member Bid in the response of murine hematopoietic cells to long-term replicative stress induced by hydroxyurea (HU). The PI3-like serine/threonine kinase, ATR, initiates the DNA damage response (DDR) to replicative stress. The pro-apoptotic Bcl-2 family member, Bid, facilitates this response to replicative stress in hematopoietic cells, but the in vivo role of this DDR function of Bid has not been defined. Surprisingly, we demonstrate that long-term HU treatment expands wild-type myeloid progenitor cells (MPCs) and HSC-enriched Lin(-)Sca1(+)Kit(+) (LSK) cells to maintain bone marrow function as measured by long-term competitive repopulating ability. Bid-/- MPCs demonstrate increased sensitivity to HU and are depleted. Bid-/- LSK cells demonstrate increased mobilization manifest by increased Bromodeoxyuridine (BrdU) incorporation. Bid-/- MPCs and LSK cells are relatively depleted, however, and bone marrow from Bid-/- mice demonstrates decreased long-term competitive repopulating ability in both primary and secondary transplants. We thus describe a survival function of Bid in hematopoiesis in the setting of chronic replicative stress. PMID- 22522599 TI - Almost all human gastric mucin O-glycans harbor blood group A, B or H antigens and are potential binding sites for Helicobacter pylori. AB - Helicobacter pylori infects more than half of the world's population. Although most patients are asymptomatic, persistent infection may cause chronic gastritis and gastric cancer. Adhesion of the bacteria to the gastric mucosa is a necessary prerequisite for the pathogenesis of H. pylori-related diseases and is mediated by mucin O-glycans. In order to define which glycans may be implicated in the binding of the bacteria to the gastric mucosa in humans, we have characterized the exact pattern of glycosylation of gastric mucins. We have identified that the major component was always a core 2-based glycan carrying two blood group H antigens, whatever was the blood group of individuals. We have also demonstrated that around 80% of O-glycans carried blood group A, B or H antigens, suggesting that the variation of gastric mucin glycosylation between individuals is partly due to the blood group status. This study will help better understanding the role of O-glycans in the physiology and homeostasis of gastric mucosa. Overall, the results reported here give us the necessary background information to begin studies to determine whether individuals who express certain carbohydrate epitopes on specific mucins are predisposed to certain gastric diseases. PMID- 22522600 TI - A Siglec-like sialic-acid-binding motif revealed in an adenovirus capsid protein. AB - Sialic-acid-binding immunoglobulin-like lectins (Siglecs) are a family of transmembrane receptors that are well documented to play roles in regulation of innate and adaptive immune responses. To see whether the features that define the molecular recognition of sialic acid were found in other sialic-acid-binding proteins, we analyzed 127 structures with bound sialic acids found in the Protein Data Bank database. Of these, the canine adenovirus 2-fiber knob protein showed close local structural relationship to Siglecs despite low sequence similarity. The fiber knob harbors a noncanonical sialic-acid recognition site, which was then explored for detailed specificity using a custom glycan microarray comprising 58 diverse sialosides. It was found that the adenoviral protein preferentially recognizes the epitope Neu5Acalpha2-3[6S]Galbeta1-4GlcNAc, a structure previously identified as the preferred ligand for Siglec-8 in humans and Siglec-F in mice. Comparison of the Siglec and fiber knob sialic-acid-binding sites reveal conserved structural elements that are not clearly identifiable from the primary amino acid sequence, suggesting a Siglec-like sialic-acid-binding motif that comprises the consensus features of these proteins in complex with sialic acid. PMID- 22522601 TI - Many pathways in laboratory evolution can lead to improved enzymes: how to escape from local minima. AB - Directed evolution is a method to tune the properties of enzymes for use in organic chemistry and biotechnology, to study enzyme mechanisms, and to shed light on darwinian evolution in nature. In order to enhance its efficacy, iterative saturation mutagenesis (ISM) was implemented. This involves: 1) randomized mutation of appropriate sites of one or more residues; 2) screening of the initial mutant libraries for properties such as enzymatic rate, stereoselectivity, or thermal robustness; 3) use of the best hit in a given library as a template for saturation mutagenesis at the other sites; and 4) continuation of the process until the desired degree of enzyme improvement has been reached. Despite the success of a number of ISM-based studies, the question of the optimal choice of the many different possible pathways remains unanswered. Here we considered a complete 4-site ISM scheme. All 24 pathways were systematically explored, with the epoxide hydrolase from Aspergillus niger as the catalyst in the stereoselective hydrolytic kinetic resolution of a chiral epoxide. All 24 pathways were found to provide improved mutants with notably enhanced stereoselectivity. When a library failed to contain any hits, non improved or even inferior mutants were used as templates in the continuation of the evolutionary pathway, thereby escaping from the local minimum. These observations have ramifications for directed evolution in general and for evolutionary biological studies in which protein engineering techniques are applied. PMID- 22522602 TI - Salivary glands ultrasound examination after radioiodine-131 treatment for differentiated thyroid cancer. AB - BACKGROUND: The most important side effect of radioiodine ((131)I) therapy is sialoadenitis and xerostomy. AIM: To evaluate by ultrasound (US) parotid and submandibular glands after (131)I therapy for differentiated thyroid cancer (DTC). PATIENTS: Seventy-six subjects thyroidectomized for DTC submitted to salivary glands US examination. Forty-three of them had been previously treated with (131)I: 22 with 1.11 GBq (30 mCi) for remnant ablation, and 21 with higher doses [up to 44.4 GBq (1200 mCi)] for metastases. Thirty-three subjects studied before (131)I therapy served as controls. Parotid and submandibular volume, homogeneity, and echogenicity were determined. (131)I-treated patients filled a questionnaire about sialoadenitis symptoms. RESULTS: Parotid gland volume was significantly higher in treated patients (28.3+/-16.2 ml) than in untreated patients (20.7+/-10.4 ml, p=0.0154) and related to the time from last (131)I therapy. Three had parotid volume <1.5 ml and complained severe xerostomy. Submandibular gland volume was similar in treated (11.2+/-7.6 ml) and untreated patients (8.6+/-4.2 ml, p=0.0602). Homogeneity and echogenicity were similar in treated and untreated patients. Sialoadenitis symptoms were reported in 26% and were related to the (131)I cumulative dose. Symptoms were not related to gland volume. Hypoechogenicity and inhomogeneity of the parotids were more frequent in patients with salivary stickiness. CONCLUSION: Parotid, but not submandibular, volume is increased after (131)I treatment depending on the received activity and the time from irradiation but not on sialoadenitis symptoms. Xerostomy is associated to gland atrophy at US. PMID- 22522603 TI - Salvage therapy of refractory hemophagocytic lymphohistiocytosis with alemtuzumab. AB - BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that remains difficult to treat. Even with current standard HLH therapy, only approximately half of patients will experience complete resolution of disease, and early mortality remains a significant problem. Salvage therapies have been described only in limited case reports, and there are no large studies of second-line therapies. PROCEDURE: We reviewed the charts of 22 pediatric and adult patients who received alemtuzumab for the treatment of refractory HLH at our center or in consultation with our group. RESULTS: Patients had received conventional therapies for a median of 8 weeks (range: 2-70) prior to alemtuzumab, and treatment immediately prior to alemtuzumab included dexamethasone (100%), etoposide (77%), cyclosporine (36%), intrathecal hydrocortisone +/- methotrexate (23%), methylprednisolone (9%), and rituximab (14%). Patients received a median dose of 1 mg/kg alemtuzumab (range: 0.1-8.9 mg/kg) divided over a median of 4 days (range: 2-10). Fourteen patients experienced an overall partial response, defined as at least a 25% improvement in two or more quantifiable symptoms or laboratory markers of HLH 2 weeks following alemtuzumab (64%). Five additional patients had a 25% or greater improvement in a single quantifiable symptom or laboratory marker of HLH (23%). Seventy-seven percent of patients survived to undergo allogeneic hematopoietic cell transplantation. Patients experienced an acceptable spectrum of complications, including CMV and adenovirus viremia. CONCLUSION: Alemtuzumab appears to be an effective salvage agent for refractory HLH, leading to improvement and survival to HCT in many patients. Prospective trials to define optimal dosing levels, schedules, and responses are needed. PMID- 22522604 TI - Ca3Pt(4+x)Ge(13-y) and Yb3Pt4Ge13: new derivatives of the Pr3Rh4Sn13 structure type. AB - The new phases Ca(3)Pt(4+x)Ge(13-y) (x = 0.1; y = 0.4; space group I2(1)3; a = 18.0578(1) A; R(I) = 0.063; R(P) = 0.083) and Yb(3)Pt(4)Ge(13) (space group P4(2)cm; a = 12.7479(1) A; c = 9.0009(1) A; R(I) = 0.061, R(P) = 0.117) are obtained by high-pressure, high-temperature synthesis and crystallize in new distortion variants of the Pr(3)Rh(4)Sn(13) type. Yb(3)Pt(4)Ge(13) features Yb in a temperature-independent non-magnetic 4f(14) (Yb(2+)) configuration validated by X-ray absorption spectra and resonant inelastic X-ray scattering data. Ca(3)Pt(4+x)Ge(13-y) is diamagnetic (chi(0) = -5.05 * 10(-6) emu mol(-1)). The Sommerfeld coefficient gamma = 4.4 mJ mol(-1) K(-2) for Ca(3)Pt(4+x)Ge(13-y), indicates metallic properties with a low density of states at the Fermi level in good agreement with electronic structure calculation (N(E(F)) = 3.3 eV( 1)/f.u.)); the Debye temperature (theta(D)) is 398 K. PMID- 22522605 TI - Highly selective colorimetric sensing of cyanide based on formation of dipyrrin adducts. AB - Cyanide sensing has attracted increasing interest due to its toxicity and wide use in industrial activities. Herein, we developed three colorimetric cyanide sensors by the modification of the alpha-position of a dipyrrin chromophore with various carbonyl groups, namely, C(6)F(5)CO, C(6)H(5)CO and CHO for 1, 2 and 3, respectively. In dichloromethane, these sensors respond to both CN(-) and F(-) with distinct colour changes. UV-Vis, (1)H NMR and HRMS measurements imply a two process interaction between the sensors and CN(-). Initially, CN(-) forms a hydrogen bond with the NH moiety, and then it attacks the carbonyl group of the sensors via a nucleophilic addition reaction. In contrast, in aqueous systems, only cyanide induced vivid solution colour changes from light yellow to pink via nucleophilic addition reactions. The CN(-) detection limits reach a micromolar level of 3.6 * 10(-6) M, 4.2 * 10(-6) M and 7.1 * 10(-6) M for 1, 2 and 3, respectively. In view of the easy synthesis and the highly selective recognition of CN(-) with vivid colour changes, 1-3 may be developed as a novel and promising prototype of selective and sensitive colorimetric cyanide sensors. PMID- 22522606 TI - Lipoteichoic acid of Bifidobacterium in combination with 5-fluorouracil inhibit tumor growth and relieve the immunosuppression. AB - To investigate the therapeutic efficacy of lipoteichoic acid of Bifidobacterium (BLTA) in combination with 5-fluorouracil (5-FU) treatment on the mice bearing inoculated hepatoma-22 (H(22)) cells and the effects of BLTA on immunological regulation of organism, and explore its mechanisms. METHODS: Tumor-bearing mice were treated with 5-FU alone, BLTA alone or BLTA in combination with 5-FU. The tumor size were observed and measured regularly. The growth inhibiting rate (IR) of tumor was detected. MTT assay was used to evaluate the proliferation of T lymphocytes and splenic NK cell and CTL activity. Enzyme linked immunosorbent assay (ELISA) was used to detect the change of IFN-gamma. FCM was used to detect T subgroup ratio of spleen cells of tumor-bearing mice. Expression change of mRNA and proteins of Foxp3 and TIM-3 were detected by Real-Time-PCR and Western blot in tumor-bearing mice tumor tissue. RESULTS: Both 5-FU and BLTA had inhibition effect on tumor-growth. While in the 5-FU + BLTA group, the inhibition of tumor growth was more significant, with increased T lymphocyte proliferation and IFN gammaproduction of spleen cells. Spleen cells of tumor-bearing mice had high CD4(+)CD25(+)regulatory T cell (CD4(+)CD25(+)T(reg)) ratio and high mRNA and proteins expression of Foxp3 and TIM-3, but in the BLTA and 5-FU group, CD4(+)CD25(+)T(reg) ratio degraded, with down regulation mRNA and proteins expression of Foxp3 and TIM-3. But CD4(+) T cells also decreased in spleen cells of tumor-bearing mice by alone 5-FU treated, splenic NK cell and CTL activity also degraded, while CD4(+) T cells and splenic NK cell and CTL activity significantly increased by BLTA treated. BLTA in combination with 5-FU could also enhance the ratio of CD4(+) T cells and splenic NK cell and CTL activity. CONCLUSION: The present study suggested that BLTA in combination with 5-FU could enhance antitumor effect, with inhibiting TIM-3/TIM-3L pathway, cutting down immunosuppressive activity of CD4(+)CD25(+) T(reg) and enhancing cell-mediated immunity. PMID- 22522607 TI - Localization of molecular orbitals on fragments. AB - A non-iterative algorithm for the localization of molecular orbitals (MOs) from complete active space self consistent field (CASSCF) and for single-determinantal wave functions on predefined moieties is given. The localized fragment orbitals can be used to analyze chemical reactions between fragments and also the binding of fragments in the product molecule with a fragments-in-molecules approach by using a valence bond expansion of the CASSCF wave function. The algorithm is an example of the orthogonal Procrustes problem, which is a matrix optimization problem using the singular value decomposition. It is based on the similarity of the set of MOs for the moieties to the localized MOs of the molecule; the similarity is expressed by overlap matrices between the original fragment MOs and the localized MOs. For CASSCF wave functions, localization is done independently in the space of occupied orbitals and active orbitals, whereas, the space of virtual orbitals is mostly uninteresting. Localization of Hartree-Fock or Kohn Sham density functional theory orbitals is not straightforward; rather, it needs careful consideration, because in this case some virtual orbitals are needed but the space of virtual orbitals depends on the basis sets used and causes considerable problems due to the diffuse character of most virtual orbitals. PMID- 22522608 TI - Draft screening guidelines spark debate: possible drawbacks and long-term effects of new draft guidelines for prostate cancer screening. PMID- 22522609 TI - Other methods for improved prostate cancer detection? PMID- 22522610 TI - Overexpression of monocarboxylate transporter-1 (SLC16A1) in mouse pancreatic beta-cells leads to relative hyperinsulinism during exercise. AB - Exercise-induced hyperinsulinism (EIHI) is an autosomal dominant disorder characterized by inappropriate insulin secretion in response to vigorous physical exercise or pyruvate injection. Activating mutations in the monocarboxylate transporter-1 (MCT1, SLC16A1) promoter have been linked to EIHI. Expression of this pyruvate transporter is specifically repressed (disallowed) in pancreatic beta-cells, despite nearly universal expression across other tissues. It has been impossible to determine, however, whether EIHI mutations cause MCT1 expression in patient beta-cells. The hypothesis that MCT1 expression in beta-cells is sufficient to cause EIHI by allowing entry of pyruvate and triggering insulin secretion thus remains unproven. Therefore, we generated a transgenic mouse capable of doxycycline-induced, beta-cell-specific overexpression of MCT1 to test this model directly. MCT1 expression caused isolated islets to secrete insulin in response to pyruvate, without affecting glucose-stimulated insulin secretion. In vivo, transgene induction lowered fasting blood glucose, mimicking EIHI. Pyruvate challenge stimulated increased plasma insulin and smaller excursions in blood glucose in transgenic mice. Finally, in response to exercise, transgene induction prevented the normal inhibition of insulin secretion. Forced overexpression of MCT1 in beta-cells thus replicates the key features of EIHI and highlights the importance of this transporter's absence from these cells for the normal control of insulin secretion. PMID- 22522611 TI - Adipose tissue overexpression of vascular endothelial growth factor protects against diet-induced obesity and insulin resistance. AB - During the expansion of fat mass in obesity, vascularization of adipose tissue is insufficient to maintain tissue normoxia. Local hypoxia develops and may result in altered adipokine expression, proinflammatory macrophage recruitment, and insulin resistance. We investigated whether an increase in adipose tissue angiogenesis could protect against obesity-induced hypoxia and, consequently, insulin resistance. Transgenic mice overexpressing vascular endothelial growth factor (VEGF) in brown adipose tissue (BAT) and white adipose tissue (WAT) were generated. Vessel formation, metabolism, and inflammation were studied in VEGF transgenic mice and wild-type littermates fed chow or a high-fat diet. Overexpression of VEGF resulted in increased blood vessel number and size in both WAT and BAT and protection against high-fat diet-induced hypoxia and obesity, with no differences in food intake. This was associated with increased thermogenesis and energy expenditure. Moreover, whole-body insulin sensitivity and glucose tolerance were improved. Transgenic mice presented increased macrophage infiltration, with a higher number of M2 anti-inflammatory and fewer M1 proinflammatory macrophages than wild-type littermates, thus maintaining an anti-inflammatory milieu that could avoid insulin resistance. These studies suggest that overexpression of VEGF in adipose tissue is a potential therapeutic strategy for the prevention of obesity and insulin resistance. PMID- 22522612 TI - Opioid receptor blockade prevents exercise-associated autonomic failure in humans. AB - Hypoglycemia and exercise both induce the release of beta-endorphin, which plays an important role in the modulation of the autonomic response during subsequent events. Because opioid receptor (OR) blockade during antecedent hypoglycemia has been shown to prevent hypoglycemia-associated autonomic failure, we hypothesized that OR blockade during exercise would prevent exercise-associated autonomic failure (EAAF). We studied 8 healthy subjects on 2 consecutive days, each of whom participated in three different studies in random order. The protocol on day 1 involved one of the following: 1) two 90-min hyperinsulinemic-euglycemic clamps plus naloxone infusion (control); 2) two 90-min hyperinsulinemic-euglycemic clamps with exercise at 60% Vo(2max), plus naloxone infusion (N+); or 3) same protocol as in the N+ group, but with saline infusion only (N-). On day 2, all were studied with stepped hyperinsulinemic-hypoglycemic clamps, using hormone concentrations and glucose turnover as indicators of hypoglycemia counterregulation. Compared with control, N- studies resulted in significantly blunted epinephrine and norepinephrine responses to subsequent hypoglycemia. Conversely, the N+ group exhibited unimpaired hypoglycemia counterregulation, characterized by appropriate increases in epinephrine, norepinephrine, and endogenous glucose production. Thus, OR blockade with naloxone during antecedent exercise prevents the development of acute EAAF by improving the catecholamine responses and by restoring endogenous glucose production. PMID- 22522613 TI - Amyloid-beta induces hepatic insulin resistance by activating JAK2/STAT3/SOCS-1 signaling pathway. AB - Epidemiological studies indicate that patients with Alzheimer's disease (AD) have an increased risk of developing type 2 diabetes mellitus (T2DM), and experimental studies suggest that AD exacerbates T2DM, but the underlying mechanism is still largely unknown. This study aims to investigate whether amyloid-beta (Abeta), a key player in AD pathogenesis, contributes to the development of insulin resistance, as well as the underlying mechanism. We find that plasma Abeta40/42 levels are increased in patients with hyperglycemia. APPswe/PSEN1dE9 transgenic AD model mice with increased plasma Abeta40/42 levels show impaired glucose and insulin tolerance and hyperinsulinemia. Furthermore, Abeta impairs insulin signaling in mouse liver and cultured hepatocytes. Abeta can upregulate suppressors of cytokine signaling (SOCS)-1, a well-known insulin signaling inhibitor. Knockdown of SOCS-1 alleviates Abeta-induced impairment of insulin signaling. Moreover, JAK2/STAT3 is activated by Abeta, and inhibition of JAK2/STAT3 signaling attenuates Abeta-induced upregulation of SOCS-1 and insulin resistance in hepatocytes. Our results demonstrate that Abeta induces hepatic insulin resistance by activating JAK2/STAT3/SOCS-1 signaling pathway and have implications toward resolving insulin resistance and T2DM. PMID- 22522614 TI - Inhibition of hypothalamic inflammation reverses diet-induced insulin resistance in the liver. AB - Defective liver gluconeogenesis is the main mechanism leading to fasting hyperglycemia in type 2 diabetes, and, in concert with steatosis, it is the hallmark of hepatic insulin resistance. Experimental obesity results, at least in part, from hypothalamic inflammation, which leads to leptin resistance and defective regulation of energy homeostasis. Pharmacological or genetic disruption of hypothalamic inflammation restores leptin sensitivity and reduces adiposity. Here, we evaluate the effect of a hypothalamic anti-inflammatory approach to regulating hepatic responsiveness to insulin. Obese rodents were treated by intracerebroventricular injections, with immunoneutralizing antibodies against Toll-like receptor (TLR)4 or tumor necrosis factor (TNF)alpha, and insulin signal transduction, hepatic steatosis, and gluconeogenesis were evaluated. The inhibition of either TLR4 or TNFalpha reduced hypothalamic inflammation, which was accompanied by the reduction of hypothalamic resistance to leptin and improved insulin signal transduction in the liver. This was accompanied by reduced liver steatosis and reduced hepatic expression of markers of steatosis. Furthermore, the inhibition of hypothalamic inflammation restored defective liver glucose production. All these beneficial effects were abrogated by vagotomy. Thus, the inhibition of hypothalamic inflammation in obesity results in improved hepatic insulin signal transduction, leading to reduced steatosis and reduced gluconeogenesis. All these effects are mediated by parasympathetic signals delivered by the vagus nerve. PMID- 22522615 TI - Progressive axonal dysfunction precedes development of neuropathy in type 2 diabetes. AB - To evaluate the development of diabetic neuropathy, the current study examined changes in peripheral axonal function. Nerve excitability techniques were undertaken in 108 type 2 diabetic patients with nerve conduction studies (NCS), HbA(1c) levels, and total neuropathy score (TNS). Patients were categorized into two cohorts: patients with diabetes without neuropathy (DWN group [n = 56]) and patients with diabetes with neuropathy (DN group [n = 52]) and further into severity grade 0 (TNS 0-1 [n = 35]), grade 1 (TNS 2-8 [n = 42]), and grade 2/3 (TNS 9-24 [n = 31]). Results revealed that the DWN group had a significantly increased threshold, prolonged latency, and changes in excitability parameters compared with age-matched control subjects. Patients with neuropathy demonstrated significant alteration in recovery cycle parameters and depolarizing threshold electrotonus. Within the DWN cohort, there were significant correlations between HbA(1c) level and latency and subexcitability, whereas the estimated glomerular filtration rate correlated with superexcitability in patients with neuropathy. Furthermore, excitability parameters became progressively more abnormal with increasing clinical severity. These results suggest a spectrum of excitability abnormalities in patients with diabetes and that early axonal dysfunction may be detected prior to the development of neuropathy. As progressive changes in excitability parameters correlated to neuropathy severity, excitability testing may provide a biomarker of the early development and severity of diabetic neuropathy, providing insights into the pathophysiological mechanisms producing axonal dysfunction. PMID- 22522616 TI - Insulin rescues impaired spermatogenesis via the hypothalamic-pituitary-gonadal axis in Akita diabetic mice and restores male fertility. AB - The mechanism responsible for poor reproductive outcomes in type 1 diabetic males is not well understood. In light of new evidence that the Sertoli cells of the testis secrete insulin, it is currently unclear whether diabetic subfertility is the result of deficiency of pancreatic insulin, testicular insulin, or both. In this study, the Akita mouse diabetic model, which expresses a mutant, nonfunctional form of ins2 in testes and pancreas, was used to distinguish between systemic and local effects of insulin deficiency on the process of spermatogenesis and fertility. We determined that Akita homozygous male mice are infertile and have reduced testis size and abnormal morphology. Spermatogonial germ cells are still present but are unable to mature into spermatocytes and spermatids. Exogenous insulin treatment regenerates testes and restores fertility, but this plasma insulin cannot pass through the blood-testis barrier. We conclude that insulin does not rescue fertility through direct interaction with the testis; instead, it restores function of the hypothalamic-pituitary gonadal axis and, thus, normalizes hormone levels of luteinizing hormone and testosterone. Although we show that the Sertoli cells of the testis secrete insulin protein, this insulin does not appear to be critical for fertility. PMID- 22522617 TI - Xenin-25 amplifies GIP-mediated insulin secretion in humans with normal and impaired glucose tolerance but not type 2 diabetes. AB - Glucose-dependent insulinotropic polypeptide (GIP) potentiates glucose-stimulated insulin secretion (GSIS). This response is blunted in type 2 diabetes (T2DM). Xenin-25 is a 25-amino acid neurotensin-related peptide that amplifies GIP mediated GSIS in hyperglycemic mice. This study determines if xenin-25 amplifies GIP-mediated GSIS in humans with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or T2DM. Each fasting subject received graded glucose infusions to progressively raise plasma glucose concentrations, along with vehicle alone, GIP, xenin-25, or GIP plus xenin-25. Plasma glucose, insulin, C-peptide, and glucagon levels and insulin secretion rates (ISRs) were determined. GIP amplified GSIS in all groups. Initially, this response was rapid, profound, transient, and essentially glucose independent. Thereafter, ISRs increased as a function of plasma glucose. Although magnitudes of insulin secretory responses to GIP were similar in all groups, ISRs were not restored to normal in subjects with IGT and T2DM. Xenin-25 alone had no effect on ISRs or plasma glucagon levels, but the combination of GIP plus xenin-25 transiently increased ISR and plasma glucagon levels in subjects with NGT and IGT but not T2DM. Since xenin-25 signaling to islets is mediated by a cholinergic relay, impaired islet responses in T2DM may reflect defective neuronal, rather than GIP, signaling. PMID- 22522618 TI - Circulating preproinsulin signal peptide-specific CD8 T cells restricted by the susceptibility molecule HLA-A24 are expanded at onset of type 1 diabetes and kill beta-cells. AB - Type 1 diabetes results from T cell-mediated beta-cell destruction. The HLA-A*24 class I gene confers significant risk of disease and early onset. We tested the hypothesis that HLA-A24 molecules on islet cells present preproinsulin (PPI) peptide epitopes to CD8 cytotoxic T cells (CTLs). Surrogate beta-cell lines secreting proinsulin and expressing HLA-A24 were generated and their peptide ligandome examined by mass spectrometry to discover naturally processed and HLA A24-presented PPI epitopes. A novel PPI epitope was identified and used to generate HLA-A24 tetramers and examine the frequency of PPI-specific T cells in new-onset HLA-A*24(+) patients and control subjects. We identified a novel naturally processed and HLA-A24-presented PPI signal peptide epitope (PPI(3-11); LWMRLLPLL). HLA-A24 tetramer analysis reveals a significant expansion of PPI(3 11)-specific CD8 T cells in the blood of HLA-A*24(+) recent-onset patients compared with HLA-matched control subjects. Moreover, a patient-derived PPI(3-11) specific CD8 T-cell clone shows a proinflammatory phenotype and kills surrogate beta-cells and human HLA-A*24(+) islet cells in vitro. These results indicate that the type 1 diabetes susceptibility molecule HLA-A24 presents a naturally processed PPI signal peptide epitope. PPI-specific, HLA-A24-restricted CD8 T cells are expanded in patients with recent-onset disease. Human islet cells process and present PPI(3-11), rendering themselves targets for CTL-mediated killing. PMID- 22522619 TI - PTGS-2-PTGER2/4 signaling pathway partially protects from diabetogenic toxicity of streptozotocin in mice. AB - Prostanoids are suggested to participate in diabetes pathology, but their roles are controversially discussed. The purpose of the current study was to examine the role of cyclooxygenase (prostaglandin synthase [PTGS]) enzymes and prostaglandin (PG) E(2) signaling pathways in streptozotocin (STZ)-induced type 1 diabetes. Blood glucose, insulin, and survival rate were studied in mice with targeted disruption of the genes for PTGS and PGE receptors (PTGERs). PGE(2) was found as the main prostanoid formed by the pancreas. Contrarily to PTGS-1, deficiency of PTGS-2 activity significantly amplified STZ effect, causing dramatic loss of insulin production and rise in blood glucose and death rate. STZ metabolism was unaffected by PTGS deficiency. Diabetogenicity of STZ in PTGER1(-/ ), PTGER2(-/-), PTGER3(-/-), and PTGER4(-/-) mice was comparable to control mice. In striking contrast, combined knockout of PTGER2 and PTGER4 by blocking PTGER4 in PTGER2(-/-) mice strongly enhanced STZ pathology. Treatment of PTGS-2(-/-) and wild-type mice with PTGER2/PTGER4 agonists partially protected against STZ induced diabetes and restored beta-cell function. Our data uncover a previously unrecognized protective role of PTGS-2-derived PGE(2) in STZ-induced diabetes mediated by the receptor types PTGER2 and PTGER4. These findings offer the possibility to intervene in early progression of type 1 diabetes by using PTGER selective agonists. PMID- 22522621 TI - A nomenclature paradigm for benign midmembranous vocal fold lesions. AB - OBJECTIVES/HYPOTHESIS: There is a significant lack of uniform agreement regarding nomenclature for benign vocal fold lesions (BVFLs). This confusion results in difficulty for clinicians communicating with their patients and with each other. In addition, BVFL research and comparison of treatment methods are hampered by the lack of a detailed and uniform BVFL nomenclature. STUDY DESIGN: Clinical consensus conferences were held to develop an initial BVFL nomenclature paradigm. Perceptual video analysis was performed to validate the stroboscopy component of the paradigm. METHODS: The culmination of the consensus conferences and the video perceptual analysis was used to evaluate the BVFL nomenclature paradigm using a retrospective review of patients with BVFL. RESULTS: An initial BVFL nomenclature paradigm was proposed utilizing detailed definitions relating to vocal fold lesion morphology, stroboscopy, response to voice therapy and intraoperative findings. Video-perceptual analysis of stroboscopy demonstrated that the proposed binary stroboscopy system used in the BVFL nomenclature paradigm was valid and widely applicable. Retrospective review of 45 patients with BVFL followed to the conclusion of treatment demonstrated that slight modifications of the initial BVFL nomenclature paradigm were required. With the modified BVFL nomenclature paradigm, 96% of the patients fit into the predicted pattern and definitions of the BVFL nomenclature system. CONCLUSIONS: This study has validated a multidimensional BVFL nomenclature paradigm. This vocal fold nomenclature paradigm includes nine distinct vocal fold lesions: vocal fold nodules, vocal fold polyp, pseudocyst, vocal fold cyst (subepithelial or ligament), nonspecific vocal fold lesion, vocal fold fibrous mass (subepithelial or ligament), and reactive lesion. PMID- 22522622 TI - Increasing scientific standards, independence and transparency in post authorisation studies: the role of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance. AB - PURPOSE: The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP), an initiative coordinated by the European Medicines Agency, aims to build capacity for and increase trust in post-authorisation studies to further support medicine decision making. METHODS: ENCePP seeks to promote and support high standards throughout the post-authorisation research process based on robust methodologies, transparency and scientific independence. RESULTS: ENCePP provides a point of access to researchers for industry, academia and regulatory authorities seeking collaboration for the conduct of post authorisation studies. As of 30 November 2011, the network consisted of 98 research centres, 13 networks and 18 data sources, mostly academic and publicly funded institutions but also data source providers and contract research organisations with expertise in the conduct of post-authorisation studies. All are listed in the free, public and fully searchable electronic Database of Research Resources. A guide and a checklist on methodological standards have been published; the concept of an 'ENCePP study', including a Code of Conduct, introduced; and an electronic register of studies have been launched. CONCLUSION: It is envisaged that application of the ENCePP study concept will result in an increase in trust in post-authorisation studies of medicines. The register of studies will allow for ready access to study protocols and results, thereby enhancing transparency and facilitating review. Through the network, standards, transparency and clarity of relationships, ENCePP is expected to add to the European Union capacity to conduct robust post-authorisation studies, thereby benefiting public health. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 22522620 TI - Xenografted islet cell clusters from INSLEA29Y transgenic pigs rescue diabetes and prevent immune rejection in humanized mice. AB - Islet transplantation is a potential treatment for type 1 diabetes, but the shortage of donor organs limits its routine application. As potential donor animals, we generated transgenic pigs expressing LEA29Y, a high-affinity variant of the T-cell costimulation inhibitor CTLA-4Ig, under the control of the porcine insulin gene promoter. Neonatal islet cell clusters (ICCs) from INSLEA29Y transgenic (LEA-tg) pigs and wild-type controls were transplanted into streptozotocin-induced hyperglycemic NOD-scid IL2Rgamma(null) mice. Cloned LEA-tg pigs are healthy and exhibit a strong beta-cell-specific transgene expression. LEA-tg ICCs displayed the same potential to normalize glucose homeostasis as wild type ICCs after transplantation. After adoptive transfer of human peripheral blood mononuclear cells, transplanted LEA-tg ICCs were completely protected from rejection, whereas reoccurrence of hyperglycemia was observed in 80% of mice transplanted with wild-type ICCs. In the current study, we provide the first proof-of-principle report on transgenic pigs with beta-cell-specific expression of LEA29Y and their successful application as donors in a xenotransplantation model. This approach may represent a major step toward the development of a novel strategy for pig-to-human islet transplantation without side effects of systemic immunosuppression. PMID- 22522623 TI - Potent systemic therapy of multiple myeloma utilizing oncolytic vesicular stomatitis virus coding for interferon-beta. AB - Multiple myeloma (MM) is an incurable malignancy of plasma secreting B cells disseminated in the bone marrow. Successful utilization of oncolytic virotherapy for myeloma treatment requires a systemically administered virus that selectively destroys disseminated myeloma cells in an immune-competent host. Vesicular stomatitis virus (VSV)-expressing interferon-beta (IFNbeta) is a promising new oncolytic agent that exploits tumor-associated defects in innate immune signaling pathways to destroy cancer cells specifically. We demonstrate here that a single, intravenous dose of VSV coding for IFNbeta (VSV-IFNbeta) specifically destroys subcutaneous and disseminated 5TGM1 myeloma in an immune-competent myeloma model. VSV-IFN treatment significantly prolonged survival in mice bearing orthotopic myeloma. Viral murine IFNbeta expression further delayed myeloma progression and significantly enhanced survival compared with VSV-expressing human IFNbeta. Evaluation of VSV-IFNbeta oncolytic activity in human myeloma cell lines and primary patient samples confirmed myeloma-specific oncolytic activity, but revealed variable susceptibility to VSV-IFNbeta oncolysis. The results indicate that VSV-IFNbeta is a potent, safe oncolytic agent that can be systemically administered to target and destroy disseminated myeloma effectively in immune competent mice. IFNbeta expression improves cancer specificity and enhances VSV therapeutic efficacy against disseminated myeloma. These data show VSV-IFNbeta to be a promising vector for further development as a potential therapy for the treatment of MM. PMID- 22522624 TI - Open access. PMID- 22522625 TI - Nanoferronics is a winning combination. PMID- 22522631 TI - Dendritic polymers: Universal glue for cells. PMID- 22522632 TI - Ferromagnetic semicondutors: Battle of the bands. PMID- 22522633 TI - Supercooled liquids: Clearing the water. PMID- 22522634 TI - Material witness: Material computation. PMID- 22522635 TI - Spintronics. PMID- 22522636 TI - New moves of the spintronics tango. PMID- 22522637 TI - Current-induced torques in magnetic materials. AB - The magnetization of a magnetic material can be reversed by using electric currents that transport spin angular momentum. In the reciprocal process a changing magnetization orientation produces currents that transport spin angular momentum. Understanding how these processes occur reveals the intricate connection between magnetization and spin transport, and can transform technologies that generate, store or process information via the magnetization direction. Here we explain how currents can generate torques that affect the magnetic orientation and the reciprocal effect in a wide variety of magnetic materials and structures. We also discuss recent state-of-the-art demonstrations of current-induced torque devices that show great promise for enhancing the functionality of semiconductor devices. PMID- 22522638 TI - Spin Hall effect devices. AB - The spin Hall effect is a relativistic spin-orbit coupling phenomenon that can be used to electrically generate or detect spin currents in non-magnetic systems. Here we review the experimental results that, since the first experimental observation of the spin Hall effect less than 10 years ago, have established the basic physical understanding of the phenomenon, and the role that several of the spin Hall devices have had in the demonstration of spintronic functionalities and physical phenomena. We have attempted to organize the experiments in a chronological order, while simultaneously dividing the Review into sections on semiconductor or metal spin Hall devices, and on optical or electrical spin Hall experiments. The spin Hall device studies are placed in a broader context of the field of spin injection, manipulation, and detection in non-magnetic conductors. PMID- 22522639 TI - Spin caloritronics. AB - Spintronics is about the coupled electron spin and charge transport in condensed matter structures and devices. The recently invigorated field of spin caloritronics focuses on the interaction of spins with heat currents, motivated by newly discovered physical effects and strategies to improve existing thermoelectric devices. Here we give an overview of our understanding and the experimental state-of-the-art concerning the coupling of spin, charge and heat currents in magnetic thin films and nanostructures. Known phenomena are classified either as independent electron (such as spin-dependent Seebeck) effects in metals that can be understood by a model of two parallel spin transport channels with different thermoelectric properties, or as collective (such as spin Seebeck) effects, caused by spin waves, that also exist in insulating ferromagnets. The search to find applications--for example heat sensors and waste heat recyclers--is on. PMID- 22522640 TI - Silicon spintronics. AB - Worldwide efforts are underway to integrate semiconductors and magnetic materials, aiming to create a revolutionary and energy-efficient information technology in which digital data are encoded in the spin of electrons. Implementing spin functionality in silicon, the mainstream semiconductor, is vital to establish a spin-based electronics with potential to change information technology beyond imagination. Can silicon spintronics live up to the expectation? Remarkable advances in the creation and control of spin polarization in silicon suggest so. Here, I review the key developments and achievements, and describe the building blocks of silicon spintronics. Unexpected and puzzling results are discussed, and open issues and challenges identified. More surprises lie ahead as silicon spintronics comes of age. PMID- 22522641 TI - Spintronics and pseudospintronics in graphene and topological insulators. AB - The two-dimensional electron systems in graphene and in topological insulators are described by massless Dirac equations. Although the two systems have similar Hamiltonians, they are polar opposites in terms of spin-orbit coupling strength. We briefly review the status of efforts to achieve long spin-relaxation times in graphene with its weak spin-orbit coupling, and to achieve large current-induced spin polarizations in topological-insulator surface states that have strong spin orbit coupling. We also comment on differences between the magnetic responses and dilute-moment coupling properties of the two systems, and on the pseudospin analogue of giant magnetoresistance in bilayer graphene. PMID- 22522642 TI - Incidence of cancer in patients with schizophrenia and their first-degree relatives: a population-based study in Sweden. AB - CONTEXT: Previous studies of the association between schizophrenia and cancer have produced conflicting results, probably because of the failure to control for confounding factors. OBJECTIVE: To test if the possible association between schizophrenia and cancer is genetic by investigating the incidence of cancer in patients with schizophrenia and their relatives. DESIGN: Retrospective cohort study with follow-up between 1965 and 2008. Estimated smoking rates were used to adjust the incidence rates of smoking-related cancers. PARTICIPANTS: The entire Swedish population. MAIN OUTCOME MEASURES: Risk of overall cancer and 34 site /type-specific cancers. RESULTS: A total of 59,233 patients in Sweden with schizophrenia were identified, of whom 6137 developed cancer during the study period, giving a decreased standardized incidence ratio (SIR) of 0.79 (95% CI 0.77-0.81). The decrease was more pronounced (SIR 0.40, 95% CI 0.38-0.43) before the first diagnosis of schizophrenia. The overall risk was significantly reduced among their unaffected parents (SIR 0.96, 95% CI 0.94-0.98) and siblings (SIR 0.92, 95% CI 0.89-0.96). Sex-stratified analyses indicated different incidence rates between males and females, with female patients having higher cancer risks than the general population. CONCLUSIONS: The significantly decreased incidences of cancers in patients diagnosed with schizophrenia and their unaffected relatives suggest that familiar/genetic factors contributing to schizophrenia may protect against the development of cancer, especially for those cancer sites observed in both settings. The increased risk of breast, cervical, and endometrial cancers after the first diagnosis of schizophrenia could be attributed to nongenetic factors such as antipsychotics administration, which may justify preventive medical screening. PMID- 22522643 TI - Biosynthesis of piperazic acid via N5-hydroxy-ornithine in Kutzneria spp. 744. AB - Which came first? We have investigated the biosynthesis of the piperazic acid (Piz) building blocks in the kutzneride family of metabolites. The flavin dependent oxygenase KtzI was shown to convert ornithine to N(5)-OH-Orn. LC-MS/MS showed (13)C(5)-labeled versions of these two amino acids to be direct precursors of piperazic acid in vivo. PMID- 22522644 TI - Eu(III) emission band changes caused by peripheral C-H/O hydrogen bonding. AB - We synthesized Eu(III) and Sm(III) complexes with tridentate phosphine oxide ligands, Eu(hfa)(3)(TPPM) and Sm(hfa)(3)(TPPM) (hfa: hexafluoroacetylacetonato, TPPM: tris(diphenylphosphinyl)methane), and we then examined their luminescent properties. In the complexes the Eu(III) and Sm(III) centres were fully surrounded by low-vibrational frequency ligands, which led to relatively high emission quantum yields (Phi(Eu) = 30%, Phi(Sm) = 4.7%). The X-ray single crystal structures of the Eu(hfa)(3)(TPPM) revealed nona-coordinated Eu(III) complexes and C-H/O hydrogen bonding formations between the acidic hydrogen atom of the TPPM ligand and oxygen atoms of solvent molecules. The C-H/O hydrogen bonding slightly affected the coordination structure around the Eu(III) ion. Despite the seemingly small effect on the structural change, because the emission band profile of the (5)D(0)->(7)F(2) transition is sensitive to changes in the coordination environment of the Eu(III) complex, we observed a red shift in the emission spectral line. PMID- 22522645 TI - A novel intronic mutation and a missense mutation of MEN1 identified in two Chinese families with multiple endocrine neoplasia type 1. AB - BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) caused by MEN1 mutation is widely recognized. To date, 14 novel mutations were reported in Chinese and intronic mutations are getting more attention. AIM: To explore clinical features and MEN1 mutations in two Chinese families suffering from MEN1. METHODS: Nineteen individuals (10 males and 9 females) from two unrelated families with MEN1 were studied. Mutations of MEN1 were analyzed by direct sequencing of PCR products. In vitro splicing analysis was also performed with minigenes containing both wildtype and novel mutant fragments. Through the RNAstructure program, we analyzed the secondary structure of the wild type MEN1 pre-mRNA and then introduced T>G mutation at +2 donor splice site of intron 7. RESULTS: Clinical features of 3 patients in two families were described, and 5 individuals were proven to be carriers of MEN1 mutation without apparent symptoms. A novel splicing site mutation of the intron 7 (IVS7+2 T->G) was identified in the first family. In vitro analysis also verified this mutation caused the aberrant splicing of MEN1 mRNA. With the RNAstructure program, we could figure out that the global secondary structure as well as the number of stems and loops of pre mRNA greatly changed after this mutation. The mutation c. 1227 C>A (C409X) was identified in another family, which also caused the truncation of menin. CONCLUSION: We reported a novel intronic mutation and a missense mutations in two Chinese families suffering from MEN1. PMID- 22522646 TI - [The place of general practitioners in cancer care in Champagne-Ardenne]. AB - INTRODUCTION: In France, general practitioners (GPs) are playing a key role in cancer care since the HPST law and the second national cancer plan. METHOD: A postal questionnaire survey was conducted in Champagne-Ardenne Area to evaluate GPs' satisfaction and needs in cancer management. A questionnaire was sent by mail in March and April 2011 to 1231 GPs. Statistical analysis of the results was done using Sphinx software (France). RESULTS: Participation rate was 33% (n = 405/1231). Most of the participants were male (n = 296; 73%), and the mean age was 51.8 years (s.d.: 9 years). Participants described as acceptable their communication with oncologists (n = 343; 85%), the delay of receiving the multidisciplinary team meeting report (n = 353; 88%) and the patient personalised care plan (n = 319; 81%). However, 69% (n = 269) stated that the communication between GPs and oncologists should improve and 64% (n = 243) were not satisfied with their level of oncology knowledge. CONCLUSION: This study identified important key points that need to be improved in order to strengthen the place of GPs in cancer management. PMID- 22522647 TI - Shared medical decision-making: considering what options to present based on an ethical analysis of the treatment of brain tumors in very young children. AB - The treatment of brain tumors in very young children poses both a therapeutic challenge and a bioethical quandary. The administration of craniospinal radiation after surgery offers the greatest chance for cure but causes severe neurocognitive damage. As a result, current practice does not offer parents the option of full-dose postoperative craniospinal radiation. Some may regard this approach as inappropriate medical paternalism, while others may consider it an example of responsible therapeutics. Evaluation of this dilemma reveals principles which can guide clinicians in determining which treatment options to present to their patients or surrogates, in the context of shared medical decision-making. PMID- 22522648 TI - An Escherichia coli cell membrane chromatography-offline LC-TOF-MS method for screening and identifying antimicrobial peptides from Jatropha curcas meal protein isolate hydrolysates. AB - A novel, simple, and rapid method, named cell membrane affinity extraction (CMAE) offline liquid chromatography time-of-flight mass spectrometry (LC-TOF-MS) was developed for screening and identifying antimicrobial peptides from Jatropha curcas meal protein isolate hydrolysates (JCMPIH) obtained by proteolytic enzyme (pepsin, trypsin, protamex, neutrase, flavourzyme, papain, alcalase, and acid protease) hydrolysis. A cationic antimicrobial peptide (CAILTHKR, JCpep8) was successfully isolated and identified by this method. Antimicrobial assay indicated that JCpep8 was active against the tested microorganisms (Escherichia coli ATCC 25922, Shigella dysenteriae ATCC 51302, Pseudomonas aeruginosa ATCC 27553, Staphylococcus aureus ATCC 25923, Bacillus subtilis ATCC 23631, Streptococcus pneumoniae ATCC 49619) with minimal inhibitory concentration values ranging from 29 to 68 ug/mL. JCpep8 induced significant morphological alterations of the tested microbe surfaces, as shown by transmission electron microscopy, indicating strong membrane disruption. The results showed that CMAE-offline LC TOF-MS could be a promising method for discovering high-throughput screening antimicrobial peptides from JCMPIH. PMID- 22522649 TI - Development of a novel ectonucleotidase assay suitable for high-throughput screening. AB - 5'-Ectonucleotidase (NT5E) catalyzes the conversion of adenosine monophosphate to adenosine and free phosphate. The role of this ectonucleotidase and its production of adenosine are linked with immune function, angiogenesis, and cancer. NT5E activity is typically assayed either by chromatographic quantification of substrates and products using high-performance liquid chromatography (HPLC) or by quantification of free phosphate using malachite green. These methods are not suitable for robust screening assays of NT5E activity. HPLC is not readily suitable for the rapid and efficient assay of multiple samples and malachite green is highly sensitive to the phosphate containing buffers common in various media and sample buffers. Here the development and validation of a novel high-throughput ectonucleotidase screening assay are described, which makes use of a luciferase-based assay reagent, the Promega CellTiter-Glo kit, to measure the catabolism of AMP by NT5E. This multiwell plate-based assay facilitates the screening of potential ectonucleotidase antagonists and is unaffected by the presence of contaminating phosphate molecules present in screening samples. PMID- 22522650 TI - Synthesis of the anti-influenza agent (-)-oseltamivir free base and (-)-methyl 3 epi-shikimate. AB - A new enantioselective synthesis of the anti-influenza agent (-)-oseltamivir free base (7.1% overall yield; 98% ee) and (-)-methyl 3-epi-shikimate (16% overall yield; 98% ee) has been described from readily available raw materials. Sharpless asymmetric epoxidation and diastereoselective Barbier allylation of an aldehyde are the key reactions employed in the incorporation of chirality, while the cyclohexene carboxylic ester core was constructed through a ring closing metathesis reaction. PMID- 22522651 TI - Interaction between alkyl radicals and single wall carbon nanotubes. AB - The addition of primary, secondary, and tertiary alkyl radicals to single wall carbon nanotubes (SWCNTs) was studied by means of dispersion corrected density functional theory. The PBE, B97-D, M06-L, and M06-2X functionals were used. Consideration of Van der Waals interactions is essential to obtain accurate addition energies. In effect, the enthalpy changes at 298 K, for the addition of methyl, ethyl, isopropyl, and tert-butyl radicals onto a (5,5) SWCNT are: -25.7, 25.1, -22.4, and -16.6 kcal/mol, at the M06-2X level, respectively, whereas at PBE/6-31G* level they are significantly lower: -25.0, -19.0, -16.7, and -5.0 kcal/mol respectively. Although the binding energies are small, the attached alkyl radicals are expected to be stable because of the large desorption barriers. The importance of nonbonded interactions was more noticeable as we moved from primary to tertiary alkyl radicals. Indeed, for the tert-butyl radical, physisorption onto the (11,0) SWCNT is preferred rather than chemisorption. The bond dissociation energies determined for alkyl radicals and SWCNT follow the trend suggested by the consideration of radical stabilization energies. However, they are in disagreement with some degrees of functionalization observed in recent experiments. This discrepancy would stem from the fact that for some HiPco nanotubes, nonbonded interactions with alkyl radicals are stronger than covalent bonds. PMID- 22522652 TI - Transnasal tracheoscopy. AB - OBJECTIVES/HYPOTHESIS: Unsedated transnasal tracheoscopy (TNT) has emerged as a technique in otolaryngology-head and neck surgery for an awake airway examination in the office setting. This study investigates the safety, procedural success rate, indications, and findings of TNTs performed over a 3-year period at an academic medical center. STUDY DESIGN: Retrospective chart review. METHODS: After institutional review board approval, billing records were reviewed for patients who underwent TNT from 2007-2009 in the University of Wisconsin-Madison Department of Otolaryngology-Head and Neck Surgery. Hospital charts for these patients were obtained, and data regarding patient demographics, complications, procedural success rate, indications, and findings were recorded. RESULTS: Sixty eight TNTs were performed on 44 patients over the last 3 years (25 males, 19 females; age range, 16-91 years). No complications were noted. Ninety-one percent of procedures were able to be completed. Indications for TNT were to: 1) detect airway stenosis or pathology, 2) evaluate the larynx and trachea prior to airway surgery, 3) monitor postoperative results of airway interventions, and 4) evaluate the airway prior to tracheotomy tube decannulation. CONCLUSIONS: TNT is a safe procedure that can be performed on the unsedated patient using only topical anesthesia and is an attractive alternative to rigid bronchoscopy. The procedural success rate was high, indicating good patient tolerance. The indications for TNT, including its use as a tool for surgical planning, have become better defined. TNT has become a standard tool in the management of patients with airway pathology in our practices. PMID- 22522653 TI - CD28 ligation increases macrophage suppression of T-cell proliferation. AB - When compared to spleen or lymph node cells, resident peritoneal cavity cells respond poorly to T-cell activation in vitro. The greater proportional representation of macrophages in this cell source has been shown to actively suppress the T-cell response. Peritoneal macrophages exhibit an immature phenotype (MHC class II(lo), B7(lo)) that reduces their efficacy as antigen presenting cells. Furthermore, these cells readily express inducible nitric oxide synthase (iNOS), an enzyme that promotes T-cell tolerance by catabolism of the limiting amino acid arginine. Here, we investigate the ability of exogenous T cell costimulation to recover the peritoneal T-cell response. We show that CD28 ligation failed to recover the peritoneal T-cell response and actually suppressed responses that had been recovered by inhibiting iNOS. As indicated by cytokine ELISpot and neutralizing monoclonal antibody (mAb) treatment, this 'cosuppression' response was due to CD28 ligation increasing the number of interferon (IFN)-gamma-secreting cells. Our results illustrate that cellular composition and cytokine milieu influence T-cell costimulation biology.Cellular & Molecular Immunology advance online publication, 23 April 2012; doi:10.1038/cmi.2012.13. PMID- 22522655 TI - Systematic evaluation of factors influencing ChIP-seq fidelity. AB - We evaluated how variations in sequencing depth and other parameters influence interpretation of chromatin immunoprecipitation-sequencing (ChIP-seq) experiments. Using Drosophila melanogaster S2 cells, we generated ChIP-seq data sets for a site-specific transcription factor (Suppressor of Hairy-wing) and a histone modification (H3K36me3). We detected a chromatin-state bias: open chromatin regions yielded higher coverage, which led to false positives if not corrected. This bias had a greater effect on detection specificity than any base composition bias. Paired-end sequencing revealed that single-end data underestimated ChIP-library complexity at high coverage. Removal of reads originating at the same base reduced false-positives but had little effect on detection sensitivity. Even at mappable-genome coverage depth of ~1 read per base pair, ~1% of the narrow peaks detected on a tiling array were missed by ChIP-seq. Evaluation of widely used ChIP-seq analysis tools suggests that adjustments or algorithm improvements are required to handle data sets with deep coverage. PMID- 22522656 TI - An image analysis toolbox for high-throughput C. elegans assays. AB - We present a toolbox for high-throughput screening of image-based Caenorhabditis elegans phenotypes. The image analysis algorithms measure morphological phenotypes in individual worms and are effective for a variety of assays and imaging systems. This WormToolbox is available through the open-source CellProfiler project and enables objective scoring of whole-worm high-throughput image-based assays of C. elegans for the study of diverse biological pathways that are relevant to human disease. PMID- 22522657 TI - Faster STORM using compressed sensing. AB - In super-resolution microscopy methods based on single-molecule switching, the rate of accumulating single-molecule activation events often limits the time resolution. Here we developed a sparse-signal recovery technique using compressed sensing to analyze images with highly overlapping fluorescent spots. This method allows an activated fluorophore density an order of magnitude higher than what conventional single-molecule fitting methods can handle. Using this method, we demonstrated imaging microtubule dynamics in living cells with a time resolution of 3 s. PMID- 22522654 TI - Highlights of the advances in basic immunology in 2011. AB - In this review, we summarize the major fundamental advances in immunological research reported in 2011. The highlights focus on the improved understanding of key questions in basic immunology, including the initiation and activation of innate responses as well as mechanisms for the development and function of various T-cell subsets. The research includes the identification of novel cytosolic RNA and DNA sensors as well as the identification of the novel regulators of the Toll-like receptor (TLR) and retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling pathway. Moreover, remarkable advances have been made in the developmental and functional properties of innate lymphoid cells (ILCs). Helper T cells and regulatory T (Treg) cells play indispensable roles in orchestrating adaptive immunity. There have been exciting discoveries regarding the regulatory mechanisms of the development of distinct T-cell subsets, particularly Th17 cells and Treg cells. The emerging roles of microRNAs (miRNAs) in T cell immunity are discussed, as is the recent identification of a novel T cell subset referred to as follicular regulatory T (TFR) cells. PMID- 22522658 TI - Ultrastructural features of the myotendinous junction of the sternomastoid muscle in Wistar rats: from newborn to aging. AB - The myotendinous junction (MTJ) is a major area for transmitting force from the skeletal muscle system and acts in joint position and stabilization. This study aimed to use transmission electron microscopy to describe the ultrastructural features of the MTJ of the sternomastoid muscle in Wistar rats from newborn to formation during adulthood and possible changes with aging. Ultrastructural features of the MTJ from the newborn group revealed pattern during development with interactions between muscle cells and extracellular matrix elements with thin folds in the sarcolemma and high cellular activity evidenced through numerous oval mitochondria groupings. The adult group had classical morphological features of the MTJ, with folds in the sarcolemma forming long projections called "finger-like processes" and sarcoplasmic invaginations. Sarcomeres were aligned in series, showing mitochondria near the Z line in groupings between collagen fiber bundles. The old group had altered "finger-like processes," thickened in both levels of sarcoplasmic invaginations and in central connections with the lateral junctions. We conclude that the MTJ undergoes intense activity from newborn to its formation during adulthood. With increasing age, changes to the MTJ were observed in the shapes of the invaginations and "finger-like processes" due to hypoactivity, potentially compromising force transmission and joint stability. PMID- 22522659 TI - Flow injection chemiluminescence determination of 2-methoxyestradiol based on inhibition of luminol-potassium ferricyanide reaction. AB - A novel flow-injection chemiluminescence (FI-CL) method is described for the determination of 2-methoxyestradiol (2-ME). The method is based on the inhibitory effect of 2-ME on the CL reaction of luminol and potassium ferricyanide in alkaline solution. Under optimal conditions, net CL intensity was proportional to 2-ME concentration in synthetic and mouse plasma samples. Corresponding linear regression equations were 8.0 x 10(-9) -1.0 x 10(-7) g/mL for synthetic samples and 2.0 x 10(-9) -1.0 x 10(-7) g/mL for plasma samples. Detection limit for synthetic samples and limits for quantification of plasma samples were 8.4 x 10( 10) g/mL (3sigma) for synthetic samples and 4.0 x 10(-9) g/mL for mouse samples. A complete analysis was performed for 60 s, including washing and sampling, resulting in a throughput of ~ 60/h. The proposed method was applied for the determination of 2-ME in synthetic and mouse plasma samples. Percentage recoveries were 101.0-102.8% and 98.0-105.0%, respectively. A possible mechanism responsible for CL reaction is proposed. PMID- 22522660 TI - Effects of the microbial metabolite destruxin A on ion transport by the gut and renal epithelia of Drosophila melanogaster. AB - Destruxins have been implicated in the infection process by entomopathogenic fungi and have been also found to be highly toxic when applied topically or ingested by different insect species. To gain insight into the mechanism of action of this toxin on insect internal organs, we have evaluated the effects of destruxin A on Drosophila melanogaster Malpighian tubules and gut tissues. Destruxin A was toxic when injected into adults; the calculated EC(50) was 0.11 mM. Destruxin A significantly inhibited fluid secretion rate by Malpighian tubules as well; the calculated IC(50) was 0.25 MUM. The Na(+) concentration in the secreted fluid increased significantly when tubules were exposed to 0.25 MUM destruxin A, whereas pH and the concentrations of Ca(2+) and K(+) did not change. In gut, there was no effect of destruxin on H(+) flux, but there was a significant decrease in K(+) and Ca(2+) absorption. The concentration of Ca(2+) and K(+) in the hemolymph of destruxin A-injected flies was not significantly different from those of control flies after 3 h. Taken together, these results show that destruxin A produces differential effects on ion transport by renal and gut tissues. (c) 2012 Wiley Periodicals, Inc. PMID- 22522661 TI - What is it about STI research that is unappealing? An experience of conducting sexual health research in general practice in England. PMID- 22522662 TI - Insulin vs GLP-1 analogues in poorly controlled Type 2 diabetic subjects on oral therapy: a meta-analysis. AB - AIM: To compare insulin and GLP-1 analogues therapy on glycemic control in poorly controlled Type 2 diabetes (T2DM) subjects failing on oral therapy. METHODS: The electronic database PubMed was systematically searched for randomized controlled trial (RCT) with duration >16 weeks comparing the addition of insulin therapy vs glucagon-like peptide (GLP-1) analogues in poorly controlled T2DM subjects on oral therapy. RESULTS: We identified 7 RCT with 2199 patients of whom 1119 were assigned to insulin therapy and 1080 received a GLP-1 analogue. Both insulin and GLP-1 analogues were effective in lowering glycated hemoglobin (HbA(1c)) with no statistically significant difference between the mean decreases in HbA(1c). However, insulin was more effective than GLP-1 analogues in lowering the fasting plasma glucose concentration, while GLP-1 agonists were more effective in lowering the postprandial glucose concentration. Insulin therapy was associated with weight gain while GLP-1 analogues consistently caused weight loss and the difference between the mean change in body weight between the two therapies was highly statistically significant. Despite a similar decrease in HbA(1c), the risk of hypoglycemia was 35% lower (p=0.001) with GLP-1 therapy compared to insulin. Compared to insulin, GLP-1 analogues caused a significant decrease in systolic blood pressure and were associated with greater rate of gastrointestinal adverse events. CONCLUSION/INTERPRETATION: In poorly controlled T2DM subjects on oral therapy, GLP-1 analogues and insulin are equally effective in lowering the HbA(1c). However, GLP-1 analogues have additional non-glycemic benefits and lower risk of hypoglycemia. Thus, GLP-1 analogues should be considered as a treatment option in this group of diabetic individuals. PMID- 22522663 TI - Recovery of sulfate saturated soils in the Plynlimon catchments, mid-Wales following reductions in atmospheric S inputs from the 1980s to 2011. AB - Sulfate adsorption capacity of B-horizons of base-poor, predominantly stagnopodzol, soils from the Plynlimon catchments, mid-Wales was determined by combination of laboratory adsorption and desorption isotherms. Results show that sulfate adsorption capacity of a range of stagnopodzol (Histic-stagno-podzol (Leptic), WRB), brown podzolic soil (Histic-umbrisol (Leptic), WRB) and stagnohumic gley (Histic-stagno-gleysol, WRB) B-horizons was positively related to the amounts of extractable (pyrophosphate and oxalate) Fe + Al, with the stagnopodzol and brown podzolic soil Bs horizon having the largest adsorption capacity and stagnohumic gley Bg horizon the smallest adsorption capacity. Results show that dissolved organic carbon (DOC) has a negative but limited effect on sulfate adsorption in these soils. Results obtained from a set of historical soil samples revealed that the grassland brown podzolic soil Bs horizon and afforested stagnopodzol Bs horizon were highly saturated with sulfate in the 1980s, at 63% and 89% respectively, whereas data from some recently sampled soil from two sites revisited in 2010-11 indicates that percentage sulfate adsorption saturation has since fallen substantially, to 41% and 50% respectively. Between 1984 and 2009 the annual rainfall-weighted mean excess SO(4)-S concentration in bulk precipitation declined linearly from 0.37 mg S l( 1) to 0.17 mg S l(-1). Over the same period, flow weighted annual mean stream water SO(4)-S concentrations decreased approximately linearly from 1.47 mg S l( 1) to 0.97 mg S l(-1) in the plantation afforested Hafren catchment compared to a drop from 1.25 to 0.69 mg S l(-1) in the adjacent moorland catchment of the Afon Gwy. In flux terms, the mean decrease in annual stream water SO(4)-S flux has been approximately 0.4 kg S ha(-1) yr(-1), whilst the recovery in stream water quality in the Afon Cyff grassland catchment has been partly offset by loss of SO(4)-S by desorption from the soil sulfur pool of approximately 0.2 kg S ha(-1) yr(-1). PMID- 22522664 TI - Access to health care and control of ABCs of diabetes. AB - OBJECTIVE: To examine the relationship between access to health care and diabetes control. RESEARCH DESIGN AND METHODS: Using data from the National Health and Nutrition Examination Survey, 1999-2008, we identified 1,221 U.S. adults (age 18 64 years) with self-reported diabetes. Access was measured by current health insurance coverage, number of times health care was received over the past year, and routine place to go for health care. Diabetes control measures included the proportion of people with A1C >9%, blood pressure >=140/90 mmHg, and non-HDL cholesterol >=130 mg/dL. RESULTS: An estimated 16.0% of known diabetic adults were uninsured. Diabetes control profiles were worse among uninsured than among insured persons (A1C >9% [34.1 vs. 16.5%, P = 0.002], blood pressure >=140/90 mmHg [31.8 vs. 22.8%, P < 0.05], and non-HDL cholesterol >=130 mg/dL [67.1 vs. 65.4%, P = 0.7]). Compared with insured persons, uninsured persons were more likely to have A1C >9% (multivariate-adjusted odds ratio 2.4 [95% CI 1.2-4.7]). Compared with those who reported four or more health care visits in the past year, those who reported no health care visits were more likely to have A1C >9% (5.5 [1.2-26.3]) and blood pressure >=140/90 mmHg (1.9 [1.1-3.4]). CONCLUSIONS: In people with diabetes, lack of health care coverage is associated with poor glycemic control. In addition, low use of health care service is associated with poor glucose and blood pressure control. PMID- 22522666 TI - [Insomnias in oncology: screening and management]. AB - Sleep disorders and more particularly insomnias are very frequently found in cancer patients. We notice a growing interest for this subject in the current literature. However, they still remain under diagnosed and thus mostly not taken into account. Nevertheless, these insomnias represent a real discomfort for these patients, with not insignificant repercussions on their quality of life. It is important to be able to screen these disorders with a detailed and precised interview allowing a global patient care including pharmacologic and non pharmacologic treatment. PMID- 22522665 TI - Placevent: an algorithm for prediction of explicit solvent atom distribution application to HIV-1 protease and F-ATP synthase. AB - We have created a simple algorithm for automatically predicting the explicit solvent atom distribution of biomolecules. The explicit distribution is coerced from the three-dimensional (3D) continuous distribution resulting from a 3D reference interaction site model (3D-RISM) calculation. This procedure predicts optimal location of solvent molecules and ions given a rigid biomolecular structure and the solvent composition. We show examples of predicting water molecules near the KNI-272 bound form of HIV-1 protease and predicting both sodium ions and water molecules near the rotor ring of F-adenosine triphosphate (ATP) synthase. Our results give excellent agreement with experimental structure with an average prediction error of 0.39-0.65 A. Further, unlike experimental methods, this method does not suffer from the partial occupancy limit. Our method can be performed directly on 3D-RISM output within minutes. It is extremely useful for examining multiple specific solvent-solute interactions, as a convenient method for generating initial solvent structures for molecular dynamics calculations, and may assist in refinement of experimental structures. (c) 2012 Wiley Periodicals, Inc. PMID- 22522667 TI - Water coordinated zinc dioxo-chlorin and porphyrin self-assemblies as chlorosomal mimics: variability of supramolecular interactions. AB - Semisynthetic zinc chlorins are shown for the first time to self-assemble in the absence of an intrinsic hydroxy group, which is always present in the chlorosomal bacteriochlorophylls (BChl's) c, d and e. Instead, the presently studied compounds have carbonyl groups. These cannot function as hydrogen bond donating groups. However due to interspacing water molecules bound to the zinc ion, double hydrogen bonding can occur to adjacent tetrapyrrolic macrocycles equipped with carbonyl recognition groups. Solution studies comprising UV-Vis absorption, electronic circular dichroism (ECD) and FT-IR show that different aggregates are formed in hydrated solvents in comparison to dry nonpolar solvents. Single crystal X-ray studies show variable supramolecular interactions either with interspacing water molecules coordinating the Zn ion within a porphyrin or with the 17(2) carbonyl group of a chlorin ligating the Zn ion. Our findings have implications for a minimalistic design of self-assembling chromophores, which can act as efficient light-harvesting units. PMID- 22522668 TI - Tunable infrared plasmonic devices using graphene/insulator stacks. AB - The collective oscillation of carriers--the plasmon--in graphene has many desirable properties, including tunability and low loss. However, in single-layer graphene, the dependence on carrier concentration of both the plasmonic resonance frequency and magnitude is relatively weak, limiting its applications in photonics. Here, we demonstrate transparent photonic devices based on graphene/insulator stacks, which are formed by depositing alternating wafer-scale graphene sheets and thin insulating layers, then patterning them together into photonic-crystal-like structures. We show experimentally that the plasmon in such stacks is unambiguously non-classical. Compared with doping in single-layer graphene, distributing carriers into multiple graphene layers effectively enhances the plasmonic resonance frequency and magnitude, which is different from the effect in a conventional semiconductor superlattice and is a direct consequence of the unique carrier density scaling law of the plasmonic resonance of Dirac fermions. Using patterned graphene/insulator stacks, we demonstrate widely tunable far-infrared notch filters with 8.2 dB rejection ratios and terahertz linear polarizers with 9.5 dB extinction ratios. An unpatterned stack consisting of five graphene layers shields 97.5% of electromagnetic radiation at frequencies below 1.2 THz. This work could lead to the development of transparent mid- and far-infrared photonic devices such as detectors, modulators and three dimensional metamaterial systems. PMID- 22522669 TI - The ongoing proliferation of nano journals. PMID- 22522670 TI - Sirenomelia and caudal malformations in two families. AB - We report on two families with co-occurrence of sirenomelia and caudal malformations. In the first family, the mother had undergone surgery for a short form of imperforate anus. Her first pregnancy was terminated because of bilateral renal agenesis with oligohydramnios. Her second pregnancy was interrupted because of sirenomelia. The second family was referred to us because of caudal malformation in their two children. The parents' spinal radiographs were normal. The first pregnancy resulted in a girl with imperforate anus, absence of S3-S5 and coccyx, abnormal pelvic floor, and an almost bifid anteriorly located bladder. The second pregnancy resulted in a baby girl with sirenomelia. No diabetes was present during the pregnancies in either of these two families. These families confirm the hypothesis that major genes are responsible for the embryogenesis of the caudal part of the embryo, with variable expression, as has been already described in sirenomelia mouse models (CYP26A1, BMP7/tsg). Molecular studies are underway in these families and in sporadic cases in our laboratory to explore the genetic basis of sirenomelia in humans. PMID- 22522671 TI - Macroporous silicon chips for laterally resolved, multi-parametric analysis of epithelial barrier function. AB - This study describes a novel assay to visualize the macromolecular permeability of epithelial and endothelial cell layers with subcellular lateral resolution. Defects within the cell layer and details about the permeation route of the migrating solute are revealed. The assay is based on silicon chips with densely packed, highly ordered, dead-ended pores of MUm-diameters on one side. The cells under study are grown on the porous side of the chip such that the pores in the growth surface serve as an array of femtolitre-sized cuvettes in which the permeating probe accumulates at the site of permeation. The pattern of pore filling reveals the permeability characteristics of the cell layer with a lateral resolution in the MUm range. Coating of the chip surface with a thin layer of gold allows for impedance analysis of the adherent cells in order to measure their tightness for inorganic ions at the same time. The new assay provides an unprecedented look on epithelial and endothelial barrier function. PMID- 22522672 TI - Effect of vardenafil on semen parameters in infertile men: a pilot study evaluating short-term treatment. AB - BACKGROUND: Severeal in vivo and in vitro studies have been carried out in order to evaluate the efficacy of long-term treatment with phosphodiesterase type-5 (PDE5) inhibitors (PDE5i) on spermatogenesis, but the results are still controversial. AIM: To evaluate the effects of vardenafil on seminal parameters of infertile men after a short-term treatment. MATERIALS/SUBJECTS AND METHODS: A total of 205 male subjects were randomized to receive a single dose of vardenafil 10 mg (73 men, group B), a single dose of vardenafil 10 mg every other day for 15 days (67 men, group C), and no treatment (65 men, group A). Semen parameters were evaluated before and after the end of the treatment in each of group A, B, and C, respectively. Additionally, an IIEF- 5 questionnaire was administered to all patients with erectile dysfunction (ED) before and after each treatment period. RESULTS: The semen parameters in groups B and C has shown a significant increase in percentage forward motility after vardenafil administration as compared with baseline (p<0.001). In group C, we observed an increase in the mean semen volume and an improvement in the mean total sperm concentration (p<0.001) as compared with baseline. CONCLUSIONS: We showed the efficacy of vardenafil in the treatment of ED and, on a large series of infertile patients, the positive effect on sperm motility after a single-dose administration. It also showed that after 15 days of treatment on alternate days is also achieved an improvement in sperm concentration. PMID- 22522673 TI - Merkel cell carcinoma: identification of prognostic factors unique to tumors located in the head and neck based on analysis of SEER data. AB - OBJECTIVES/HYPOTHESIS: Merkel cell carcinoma (MCC) is an aggressive cutaneous neoplasm that occurs most frequently in the head and neck region. Because of its rarity, prognostic factors are poorly characterized. Head and neck MCC (HN-MCC) may require separate consideration from MCC that occurs in other anatomic regions. Our objective was to determine the relevance of clinicopathologic parameters as prognostic factors in a large series of patients with HN-MCC and to compare these to a series of patients with non-head and neck MCC (NHN-MCC). STUDY DESIGN: Retrospective analysis of large population database. METHODS: Patients with MCC were identified using the Surveillance, Epidemiology, and End Results database and categorized according to tumor location either 1) within or 2) outside of the head and neck region. Clinicopathologic data were compared between groups. Retrospective univariable and multivariable analyses of factors associated with disease-specific survival (DSS) were performed. RESULTS: We identified 2,104 patients with HN-MCC and 2,272 with NHN-MCC. DSS was similar between groups. Independent prognostic factors in HN-MCC are male sex (P < .001), lip primary site (P = .005), tumor extension beyond the dermis (P = .03), histologically confirmed nodal disease (P < .001), absence of histologic lymph node evaluation (P = .01), and distant metastasis (P = .001). Male sex and tumor extension limited to the subcutis are prognostic factors that are unique to HN MCC. CONCLUSIONS: Because independent markers of aggressive disease appear to be unique in HN-MCC, it is important that future studies provide separate consideration for HN-MCC to allow for the most accurate identification of prognostic indicators and assessment of treatment outcomes accordingly. PMID- 22522674 TI - Biochemical and histological characterization of tomato mutants. AB - Biochemical responses inherent to antioxidant systems as well morphological and anatomical properties of photomorphogenic, hormonal and developmental tomato mutants were investigated. Compared to the non-mutant Micro-Tom (MT), we observed that the malondialdehyde (MDA) content was enhanced in the diageotropica (dgt) and lutescent (l) mutants, whilst the highest levels of hydrogen peroxide (H(2)O(2)) were observed in high pigment 1 (hp1) and aurea (au) mutants. The analyses of antioxidant enzymes revealed that all mutants exhibited reduced catalase (CAT) activity when compared to MT. Guaiacol peroxidase (GPOX) was enhanced in both sitiens (sit) and notabilis (not) mutants, whereas in not mutant there was an increase in ascorbate peroxidase (APX). Based on PAGE analysis, the activities of glutathione reductase (GR) isoforms III, IV, V and VI were increased in l leaves, while the activity of superoxide dismutase (SOD) isoform III was reduced in leaves of sit, epi, Never ripe (Nr) and green flesh (gf) mutants. Microscopic analyses revealed that hp1 and au showed an increase in leaf intercellular spaces, whereas sit exhibited a decrease. The au and hp1 mutants also exhibited a decreased in the number of leaf trichomes. The characterization of these mutants is essential for their future use in plant development and ecophysiology studies, such as abiotic and biotic stresses on the oxidative metabolism. PMID- 22522675 TI - Does evolution matter?: a case study in Brazil of the effects of an evolutionary thinking academic atmosphere in postgraduate students' belief in God/religious belief. AB - Although the theory of evolution is more than 150 years old, a substantial proportion of the world population does not mention it when explaining the origin of human beings. The usual alternative conception is offered by creationism, one of the main obstacles to full acceptance of evolution in many countries. National polls have demonstrated that schooling and religiosity are negatively correlated, with scientists being one of the least religious professionals. Herein we analyzed both (1) the profile of 1st semester undergraduate students and (2), thesis and dissertations, concerning religious and evolutionary thoughts from Biology and Veterinary Schools at the largest university of South America. We have shown that students of Biology are biased towards evolution before they enter university and also that the presence of an evolutionary-thinking academic atmosphere influences the deism/religiosity beliefs of postgraduate students. PMID- 22522676 TI - Identification of Encephalitozoon and Enterocytozoon (microsporidia) spores in stool and urine samples obtained from free-living South American Coatis (Nasua nasua). AB - This study emphasizes the importance of free-living coatis as a potential source of microsporidian infection for humans living in large cities. We found 19 (31.7%) positive results among 60 fecal samples analyzed by PCR-based analysis and the Gram-Chromotrope staining technique (11.7% were positive for Encephalitozoon cuniculi, 6.7% for E. intestinalis, 6.7% for E. hellem, and 6.7% for Enterocytozoon bieneusi). Only 5 (8.4%) urine samples tested positive for E. cuniculi as assessed by the two techniques. PMID- 22522677 TI - In vitro reconstitution of the complete Clostridium thermocellum cellulosome and synergistic activity on crystalline cellulose. AB - Artificial cellulase complexes active on crystalline cellulose were reconstituted in vitro from a native mix of cellulosomal enzymes and CipA scaffoldin. Enzymes containing dockerin modules for binding to the corresponding cohesin modules were prepared from culture supernatants of a C. thermocellum cipA mutant. They were reassociated to cellulosomes via dockerin-cohesin interaction. Recombinantly produced mini-CipA proteins with one to three cohesins either with or without the carbohydrate-binding module (CBM) and the complete CipA protein were used as the cellulosomal backbone. The binding between cohesins and dockerins occurred spontaneously. The hydrolytic activity against soluble and crystalline cellulosic compounds showed that the composition of the complex does not seem to be dependent on which CipA-derived cohesin was used for reconstitution. Binding did not seem to have an obvious local preference (equal binding to Coh1 and Coh6). The synergism on crystalline cellulose increased with an increasing number of cohesins in the scaffoldin. The in vitro-formed complex showed a 12-fold synergism on the crystalline substrate (compared to the uncomplexed components). The activity of reconstituted cellulosomes with full-size CipA reached 80% of that of native cellulosomes. Complexation on the surface of nanoparticles retained the activity of protein complexes and enhanced their stability. Partial supplementation of the native cellulosome components with three selected recombinant cellulases enhanced the activity on crystalline cellulose and reached that of the native cellulosome. This opens possibilities for in vitro complex reconstitution, which is an important step toward the creation of highly efficient engineered cellulases. PMID- 22522678 TI - Temporal orchestration of glycogen synthase (GlgA) gene expression and glycogen accumulation in the oceanic picoplanktonic cyanobacterium Synechococcus sp. strain WH8103. AB - Glycogen is accumulated during the latter half of the diel cycle in Synechococcus sp. strain WH8103 following a midday maximum in glgA (encoding glycogen synthase) mRNA abundance. This temporal pattern is quite distinct from that of Prochlorococcus and may highlight divergent regulatory control of carbon/nitrogen metabolism in these closely related picocyanobacteria. PMID- 22522679 TI - Influence of salinity on the bacterial community composition in Lake Bosten, a large oligosaline lake in arid northwestern China. AB - Salinity was found to be the dominating contributor controlling bacterial community composition (BCC) and the abundance of Betaproteobacteria in the oligosaline Lake Bosten. The high percentage of unclassified bacteria inhabiting this unique habitat highlights the potential ecological importance of BCC in the early stage of lake salinization and eutrophication. PMID- 22522680 TI - Precise manipulation of the Clostridium difficile chromosome reveals a lack of association between the tcdC genotype and toxin production. AB - Clostridium difficile causes a potentially fatal diarrheal disease through the production of its principal virulence factors, toxin A and toxin B. The tcdC gene is thought to encode a negative regulator of toxin production. Therefore, increased toxin production, and hence increased virulence, is often inferred in strains with an aberrant tcdC genotype. This report describes the first allele exchange system for precise genetic manipulation of C. difficile, using the codA gene of Escherichia coli as a heterologous counterselection marker. It was used to systematically restore the Delta117 frameshift mutation and the 18-nucleotide deletion that occur naturally in the tcdC gene of C. difficile R20291 (PCR ribotype 027). In addition, the naturally intact tcdC gene of C. difficile 630 (PCR ribotype 012) was deleted and then subsequently restored with a silent nucleotide substitution, or "watermark," so the resulting strain was distinguishable from the wild type. Intriguingly, there was no association between the tcdC genotype and toxin production in either C. difficile R20291 or C. difficile 630. Therefore, an aberrant tcdC genotype does not provide a broadly applicable rationale for the perceived notion that PCR ribotype 027 strains are "high-level" toxin producers. This may well explain why several studies have reported that an aberrant tcdC gene does not predict increased toxin production or, indeed, increased virulence. PMID- 22522681 TI - Biotransformation strategy to reduce allergens in propolis. AB - Propolis (bee glue) is a resinous, sticky, dark-colored material produced by honeybees. Propolis today, due to its medicinal properties, is increasingly popular and is extensively used in food, beverages, and cosmetic products. Besides its numerous positive properties, propolis may also have adverse effects, such as, principally, allergic eczematous contact dermatitis in apiarists and in consumers with an allergic predisposition. In this study, we found appropriate conditions for removing caffeate esters, which are the main allergenic components, from raw propolis. The proposed method consists of the resuspension of propolis in a food grade solvent, followed by a biotransformation based on the cinnamoyl esterase activity of Lactobacillus helveticus. We showed that the reduction of caffeate esters by L. helveticus did not affect the content of flavonoids, which are the main bioactive molecules of propolis. Furthermore, we verified that the biotransformation of propolis did not cause a loss of antimicrobial activity. Finally, we demonstrated that the ability of L. helveticus to hydrolyze caffeate esters in propolis is strain specific. In conclusion, the proposed strategy is simple, employs food grade materials, and is effective in selectively removing allergenic molecules without affecting the bioactive fraction of propolis. This is the first study demonstrating that the allergenic caffeate esters of propolis can be eliminated by means of a bacterial biotransformation procedure. PMID- 22522682 TI - Heterologous expression in Pichia pastoris and characterization of an endogenous thermostable and high-glucose-tolerant beta-glucosidase from the termite Nasutitermes takasagoensis. AB - Termites are well-known cellulose decomposers and can give researchers insights into how to utilize lignocellulosic biomass in the actual scenario of energy consumption. In this work, an endogenous beta-glucosidase from the midgut of the higher termite Nasutitermes takasagoensis was purified to homogeneity by Ni(2+) affinity chromatography and its properties were characterized. This beta glucosidase (G1mgNtBG1), which belongs to glycoside hydrolase family 1, is a homotrimer in its native form, with a molecular mass of 169.5 kDa, as demonstrated by gel filtration chromatography. The enzyme displayed maximum activity at pH 5.5 and had broad substrate specificities toward several saccharides, including cellobiose. G1mgNtBG1 showed a relatively high temperature optimum of 65 degrees C and one of the highest levels of glucose tolerance among several beta-glucosidases already characterized, with a K(i) of 600 mM glucose. To examine the applicability of G1mgNtBG1 in biomass conversion, we compared the thermostability and glucose tolerance of G1mgNtBG1 with those of Novozym 188. We found that G1mgNtBG1 was more thermostable after 5 h of incubation at 60 degrees C and more resistant to glucose inhibition than Novozym 188. Furthermore, our result suggests that G1mgNtBG1 acts synergistically with Celluclast 1.5 L in releasing reducing sugars from Avicel. Thus, G1mgNtBG1 seems to be a potential candidate for use as a supplement in the hydrolysis of biomass. PMID- 22522683 TI - Requirement of siderophore biosynthesis for plant colonization by Salmonella enterica. AB - Contaminated fresh produce has become the number one vector of nontyphoidal salmonellosis to humans. However, Salmonella enterica genes essential for the life cycle of the organism outside the mammalian host are for the most part unknown. Screening deletion mutants led to the discovery that an aroA mutant had a significant root colonization defect due to a failure to replicate. AroA is part of the chorismic acid biosynthesis pathway, a central metabolic node involved in aromatic amino acid and siderophore production. Addition of tryptophan or phenylalanine to alfalfa root exudates did not restore aroA mutant replication. However, addition of ferrous sulfate restored replication of the aroA mutant, as well as alfalfa colonization. Tryptophan and phenylalanine auxotrophs had minor plant colonization defects, suggesting that suboptimal concentrations of these amino acids in root exudates were not major limiting factors for Salmonella replication. An entB mutant defective in siderophore biosynthesis had colonization and growth defects similar to those of the aroA mutant, and the defective phenotype was complemented by the addition of ferrous sulfate. Biosynthetic genes of each Salmonella siderophore, enterobactin and salmochelin, were upregulated in alfalfa root exudates, yet only enterobactin was sufficient for plant survival and persistence. Similar results in lettuce leaves indicate that siderophore biosynthesis is a widespread or perhaps universal plant colonization fitness factor for Salmonella, unlike phytobacterial pathogens, such as Pseudomonas and Xanthomonas. PMID- 22522684 TI - Squid-derived chitin oligosaccharides are a chemotactic signal during colonization by Vibrio fischeri. AB - Chitin, a polymer of N-acetylglucosamine (GlcNAc), is noted as the second most abundant biopolymer in nature. Chitin serves many functions for marine bacteria in the family Vibrionaceae ("vibrios"), in some instances providing a physical attachment site, inducing natural genetic competence, and serving as an attractant for chemotaxis. The marine luminous bacterium Vibrio fischeri is the specific symbiont in the light-emitting organ of the Hawaiian bobtail squid, Euprymna scolopes. The bacterium provides the squid with luminescence that the animal uses in an antipredatory defense, while the squid supports the symbiont's nutritional requirements. V. fischeri cells are harvested from seawater during each host generation, and V. fischeri is the only species that can complete this process in nature. Furthermore, chitin is located in squid hemocytes and plays a nutritional role in the symbiosis. We demonstrate here that chitin oligosaccharides produced by the squid host serve as a chemotactic signal for colonizing bacteria. V. fischeri uses the gradient of host chitin to enter the squid light organ duct and colonize the animal. We provide evidence that chitin serves a novel function in an animal-bacterial mutualism, as an animal-produced bacterium-attracting synomone. PMID- 22522685 TI - Emergence of atypical Mycoplasma agalactiae strains harboring a new prophage and associated with an alpine wild ungulate mortality episode. AB - The bacterium Mycoplasma agalactiae is responsible for contagious agalactia (CA) in small domestic ruminants, a syndrome listed by the World Organization for Animal Health and responsible for severe damage to the dairy industry. Recently, we frequently isolated this pathogen from lung lesions of ibexes during a mortality episode in the French Alps. This situation was unusual in terms of host specificity and tissue tropism, raising the question of M. agalactiae emergence in wildlife. To address this issue, the ibex isolates were characterized using a combination of approaches that included antigenic profiles, molecular typing, optical mapping, and whole-genome sequencing. Genome analyses showed the presence of a new, large prophage containing 35 coding sequences (CDS) that was detected in most but not all ibex strains and has a homolog in Mycoplasma conjunctivae, a species causing keratoconjunctivitis in wild ungulates. This and the presence in all strains of large integrated conjugative elements suggested highly dynamic genomes. Nevertheless, M. agalactiae strains circulating in the ibex population were shown to be highly related, most likely originating from a single parental clone that has also spread to another wild ungulate species of the same geographical area, the chamois. These strains clearly differ from strains described in Europe so far, including those found nearby, before CA eradication a few years ago. While M. agalactiae pathogenicity in ibexes remains unclear, our data showed the emergence of atypical strains in Alpine wild ungulates, raising the question of a role for the wild fauna as a potential reservoir of pathogenic mycoplasmas. PMID- 22522686 TI - Multilocus sequence typing scheme for the characterization of 936-like phages infecting Lactococcus lactis. AB - Lactococcus lactis phage infections are costly for the dairy industry because they can slow down the fermentation process and adversely impact product safety and quality. Although many strategies have been developed to better control phage populations, new virulent phages continue to emerge. Thus, it is beneficial to develop an efficient method for the routine identification of new phages within a dairy plant to rapidly adapt antiphage tactics. Here, we present a multilocus sequence typing (MLST) scheme for the characterization of the 936-like phages, the most prevalent phage group infecting L. lactis strains worldwide. The proposed MLST system targets the internal portion of five highly conserved genomic sequences belonging to the packaging, morphogenesis, and lysis modules. Our MLST scheme was used to analyze 100 phages with different restriction fragment length polymorphism (RFLP) patterns isolated from 11 different countries between 1971 and 2010. PCR products were obtained for all the phages analyzed, and sequence analysis highlighted the high discriminatory power of the MLST system, detecting 93 different sequence types. A conserved locus within the lys gene (coding for endolysin) was the most discriminative, with 65 distinct alleles. The locus within the mcp gene (major capsid protein) was the most conserved (54 distinct alleles). Phylogenetic analyses of the concatenated sequences exhibited a strong concordance of the clusters with the phage host range, indicating the clonal evolution of these phages. A public database has been set up for the proposed MLST system, and it can be accessed at http://pubmlst.org/bacteriophages/. PMID- 22522687 TI - Two systems for targeted gene deletion in Coxiella burnetii. AB - Coxiella burnetii is a ubiquitous zoonotic bacterial pathogen and the cause of human acute Q fever, a disabling influenza-like illness. C. burnetii's former obligate intracellular nature significantly impeded the genetic characterization of putative virulence factors. However, recent host cell-free (axenic) growth of the organism has enabled development of shuttle vector, transposon, and inducible gene expression technologies, with targeted gene inactivation remaining an important challenge. In the present study, we describe two methods for generating targeted gene deletions in C. burnetii that exploit pUC/ColE1 ori-based suicide plasmids encoding sacB for positive selection of mutants. As proof of concept, C. burnetii dotA and dotB, encoding structural components of the type IVB secretion system (T4BSS), were selected for deletion. The first method exploited Cre-lox mediated recombination. Two suicide plasmids carrying different antibiotic resistance markers and a loxP site were integrated into 5' and 3' flanking regions of dotA. Transformation of this strain with a third suicide plasmid encoding Cre recombinase resulted in the deletion of dotA under sucrose counterselection. The second method utilized a loop-in/loop-out strategy to delete dotA and dotB. A single suicide plasmid was first integrated into 5' or 3' target gene flanking regions. Resolution of the plasmid cointegrant by a second crossover event under sucrose counterselection resulted in gene deletion that was confirmed by PCR and Southern blot. DeltadotA and DeltadotB mutants failed to secrete T4BSS substrates and to productively infect host cells. The repertoire of C. burnetii genetic tools now allows ready fulfillment of molecular Koch's postulates for suspected virulence genes. PMID- 22522688 TI - Infections and coinfections of questing Ixodes ricinus ticks by emerging zoonotic pathogens in Western Switzerland. AB - In Europe, Ixodes ricinus is the vector of many pathogens of medical and veterinary relevance, among them Borrelia burgdorferi sensu lato and tick-borne encephalitis virus, which have been the subject of numerous investigations. Less is known about the occurrence of emerging tick-borne pathogens like Rickettsia spp., Babesia spp., "Candidatus Neoehrlichia mikurensis," and Anaplasma phagocytophilum in questing ticks. In this study, questing nymph and adult I. ricinus ticks were collected at 11 sites located in Western Switzerland. A total of 1,476 ticks were analyzed individually for the simultaneous presence of B. burgdorferi sensu lato, Rickettsia spp., Babesia spp., "Candidatus Neoehrlichia mikurensis," and A. phagocytophilum. B. burgdorferi sensu lato, Rickettsia spp., and "Candidatus Neoehrlichia mikurensis" were detected in ticks at all sites with global prevalences of 22.5%, 10.2%, and 6.4%, respectively. Babesia- and A. phagocytophilum-infected ticks showed a more restricted geographic distribution, and their prevalences were lower (1.9% and 1.5%, respectively). Species rarely reported in Switzerland, like Borrelia spielmanii, Borrelia lusitaniae, and Rickettsia monacensis, were identified. Infections with more than one pathogenic species, involving mostly Borrelia spp. and Rickettsia helvetica, were detected in 19.6% of infected ticks. Globally, 34.2% of ticks were infected with at least one pathogen. The diversity of tick-borne pathogens detected in I. ricinus in this study and the frequency of coinfections underline the need to take them seriously into consideration when evaluating the risks of infection following a tick bite. PMID- 22522689 TI - Identification and mechanism of evolution of new alleles coding for the AIDA-I autotransporter of porcine pathogenic Escherichia coli. AB - Autotransporters are a large family of virulence factors of Gram-negative bacterial pathogens. The autotransporter adhesin involved in diffuse adherence (AIDA-I) is an outer membrane protein of Escherichia coli, which allows binding to epithelial cells as well as the autoaggregation of bacteria. AIDA-I is glycosylated by a specific heptosyltransferase encoded by the aah gene that forms an operon with the aidA gene. aidA is highly prevalent in strains that cause disease in pigs. Nevertheless, there are only two published whole-length sequences for this gene. In this study, we sequenced the aah and aidA genes of 24 aidA-positive porcine strains harboring distinct virulence factor profiles. We compared the obtained sequences and performed phylogenetic and pulsed-field electrophoresis analyses. Our results suggest that there are at least 3 different alleles for aidA, which are associated with distinct virulence factor profiles. The genes are found on high-molecular-weight plasmids and seem to evolve via shuffling mechanisms, with one of the sequences showing evidence of genetic recombination. Our work suggests that genetic plasticity allows the evolution of aah-aidA alleles that are selected during pathogenesis. PMID- 22522690 TI - Shifts in identity and activity of methanotrophs in arctic lake sediments in response to temperature changes. AB - Methane (CH(4)) flux to the atmosphere is mitigated via microbial CH(4) oxidation in sediments and water. As arctic temperatures increase, understanding the effects of temperature on the activity and identity of methanotrophs in arctic lake sediments is important to predicting future CH(4) emissions. We used DNA based stable-isotope probing (SIP), quantitative PCR (Q-PCR), and pyrosequencing analyses to identify and characterize methanotrophic communities active at a range of temperatures (4 degrees C, 10 degrees C, and 21 degrees C) in sediments (to a depth of 25 cm) sampled from Lake Qalluuraq on the North Slope of Alaska. CH(4) oxidation activity was measured in microcosm incubations containing sediments at all temperatures, with the highest CH(4) oxidation potential of 37.5 MUmol g(-1) day(-1) in the uppermost (depth, 0 to 1 cm) sediment at 21 degrees C after 2 to 5 days of incubation. Q-PCR of pmoA and of the 16S rRNA genes of type I and type II methanotrophs, and pyrosequencing of 16S rRNA genes in (13)C labeled DNA obtained by SIP demonstrated that the type I methanotrophs Methylobacter, Methylomonas, and Methylosoma dominated carbon acquisition from CH(4) in the sediments. The identity and relative abundance of active methanotrophs differed with the incubation temperature. Methylotrophs were also abundant in the microbial community that derived carbon from CH(4), especially in the deeper sediments (depth, 15 to 20 cm) at low temperatures (4 degrees C and 10 degrees C), and showed a good linear relationship (R = 0.82) with the relative abundances of methanotrophs in pyrosequencing reads. This study describes for the first time how methanotrophic communities in arctic lake sediments respond to temperature variations. PMID- 22522691 TI - High-throughput PCR assays to monitor Wolbachia infection in the dengue mosquito (Aedes aegypti) and Drosophila simulans. AB - We have developed and validated two new fluorescence-based PCR assays to detect the Wolbachia wMel strain in Aedes aegypti and the wRi and wAu strains in Drosophila simulans. The new assays are accurate, informative, and cost-efficient for large-scale Wolbachia screening. PMID- 22522692 TI - Phylogenetic grouping and virulence potential of extended-spectrum-beta-lactamase producing Escherichia coli strains in cattle. AB - In line with recent reports of extended-spectrum beta-lactamases (ESBLs) in Escherichia coli isolates of highly virulent serotypes, such as O104:H4, we investigated the distribution of phylogroups (A, B1, B2, D) and virulence factor (VF)-encoding genes in 204 ESBL-producing E. coli isolates from diarrheic cattle. ESBL genes, VFs, and phylogroups were identified by PCR and a commercial DNA array (Alere, France). ESBL genes belonged mostly to the CTX-M-1 (65.7%) and CTX M-9 (27.0%) groups, whereas those of the CTX-M-2 and TEM groups were much less represented (3.9% and 3.4%, respectively). One ESBL isolate was stx(1) and eae positive and belonged to a major enterohemorrhagic E. coli (EHEC) serotype (O111:H8). Two other isolates were eae positive but stx negative; one of these had serotype O26:H11. ESBL isolates belonged mainly to phylogroup A (55.4%) and, to lesser extents, to phylogroups D (25.5%) and B1 (15.6%), whereas B2 strains were quasi-absent (1/204). The number of VFs was significantly higher in phylogroup B1 than in phylogroups A (P = 0.04) and D (P = 0.02). Almost all of the VFs detected were found in CTX-M-1 isolates, whereas only 64.3% and 33.3% of them were found in CTX-M-9 and CTX-M-2 isolates, respectively. These results indicated that the widespread dissemination of the bla(CTX-M) genes within the E. coli population from cattle still spared the subpopulation of EHEC/Shiga toxigenic E. coli (STEC) isolates. In contrast to other reports on non-ESBL producing isolates from domestic animals, B1 was not the main phylogroup identified. However, B1 was found to be the most virulent phylogroup, suggesting host-specific distribution of virulence determinants among phylogenetic groups. PMID- 22522693 TI - Systematic mapping of fragile X granules in the mouse brain reveals a potential role for presynaptic FMRP in sensorimotor functions. AB - Loss of Fragile X mental retardation protein (FMRP) leads to Fragile X syndrome (FXS), the most common form of inherited intellectual disability and autism. Although the functions of FMRP and its homologs FXR1P and FXR2P are well studied in the somatodendritic domain, recent evidence suggests that this family of RNA binding proteins also plays a role in the axonal and presynaptic compartments. Fragile X granules (FXGs) are morphologically and genetically defined structures containing Fragile X proteins that are expressed axonally and presynaptically in a subset of circuits. To further understand the role of presynaptic Fragile X proteins in the brain, we systematically mapped the FXG distribution in the mouse central nervous system. This analysis revealed both the circuits and the neuronal types that express FXGs. FXGs are enriched in circuits that mediate sensory processing and motor planning-functions that are particularly perturbed in FXS patients. Analysis of FXG expression in the hippocampus suggests that CA3 pyramidal neurons use presynaptic Fragile X proteins to modulate recurrent but not feedforward processing. Neuron-specific FMRP mutants revealed a requirement for neuronal FMRP in the regulation of FXGs. Finally, conditional FMRP ablation demonstrated that FXGs are expressed in axons of thalamic relay nuclei that innervate cortex, but not in axons of thalamic reticular nuclei, striatal nuclei, or cortical neurons that innervate thalamus. Together, these findings support the proposal that dysregulation of axonal and presynaptic Fragile X proteins contribute to the neurological symptoms of FXS. PMID- 22522694 TI - beta-Tubulins in Gibberella zeae: their characterization and contribution to carbendazim resistance. AB - BACKGROUND: Fusarium head blight caused by Gibberella zeae is an important disease of wheat and barley because it reduces grain yield and quality and results in the contamination of grain with mycotoxins. Recent studies have shown that carbendazim resistance in field strains of G. zeae is not caused by mutation of the beta-tubulin gene (beta1 tub), which is the case with other filamentous fungi, but that fungicide resistance is greatly increased by deletion of beta1 tub. The aim of the present study was to clarify the function of beta1 tub and its role in carbendazim resistance in G. zeae by artificial gene operation. RESULTS: Deletion of beta1 tub reduced vegetative growth and pathogenicity but increased asexual reproduction in G. zeae. All the mutants were more resistant to carbendazim than parent strains. A three-dimensional model of beta1 tub was constructed, and the possible carbendazim binding site was analysed. CONCLUSION: beta1 tub is not an essential gene in G. zeae, but it affects the sensitivity of the fungus to carbendazim. PMID- 22522695 TI - [Biologic modulation of ionizing radiation by Toll-like receptors agonists: towards an increase in the therapeutic index of radiotherapy?]. AB - Toll-like receptors are ubiquitous and very well conserved throughout evolution, with important functions mediating innate and adaptative immunological mechanisms. The importance of these receptors and their agonists has been recently pointed out in immunology and cancerology, although the accurate underlying mechanisms are still under investigation. The association of agonists of these receptors with ionizing radiation has been studied in preclinical experiments with promising results. Part of these compounds is flagellin, which seems to be able to modulate the radiosensitivity of both tumors and healthy tissues. PMID- 22522697 TI - Deletion of filamin A in two female patients with periventricular nodular heterotopia. PMID- 22522696 TI - A new size-independent score for pairwise protein structure alignment and its application to structure classification and nucleic-acid binding prediction. AB - A structure alignment program aligns two structures by optimizing a scoring function that measures structural similarity. It is highly desirable that such scoring function is independent of the sizes of proteins in comparison so that the significance of alignment across different sizes of the protein regions aligned is comparable. Here, we developed a new score called SP-score that fixes the cutoff distance at 4 A and removed the size dependence using a normalization prefactor. We further built a program called SPalign that optimizes SP-score for structure alignment. SPalign was applied to recognize proteins within the same structure fold and having the same function of DNA or RNA binding. For fold discrimination, SPalign improves sensitivity over TMalign for the chain-level comparison by 12% and over DALI for the domain-level comparison by 13% at the same specificity of 99.6%. The difference between TMalign and SPalign at the chain level is due to the inability of TMalign to detect single domain similarity between multidomain proteins. For recognizing nucleic acid binding proteins, SPalign consistently improves over TMalign by 12% and DALI by 31% in average value of Mathews correlation coefficients for four datasets. SPalign with default setting is 14% faster than TMalign. SPalign is expected to be useful for function prediction and comparing structures with or without domains defined. The source code for SPalign and the server are available at http://sparks.informatics.iupui.edu. PMID- 22522698 TI - Morphology of immature stages of Megaselia spiracularis Schmitz (Diptera: Phoridae). AB - In addition to causing myiasis in humans, Megaselia spiracularis Schmitz has also been reported as a forensically important fly. In this study, we presented the morphology of all larval instars and puparium of M. spiracularis using scanning electron microscopy. The first instar larva was composed of 12 segments. Antennae and maxillary palp complex were visible. Two spiracular slits could be seen at the posterior spiracle. The branch of posterior spiracular hairs was approximately equal to the palm-formed base in length. Second and third larval instars were very similar to first instar, except for the presence of anterior spiracle. The labium of the second instar larva was triangular and ventrally curved, whereas it was a bilobed structure and the tip forked in the first instar. The bubble membrance comprised of ~40 globules presented at the third instar larvae. Puparia showed a retracted cephalic region and a pair of pupal respiratory horns on the dorsum. A comparison of the morphological features between immature stages of M. spiracularis and M. scalaris, a forensically important fly indoors in Germany, Malaysia, and China, was discussed. PMID- 22522699 TI - Drosophila midgut homeostasis involves neutral competition between symmetrically dividing intestinal stem cells. AB - The Drosophila adult posterior midgut has been identified as a powerful system in which to study mechanisms that control intestinal maintenance, in normal conditions as well as during injury or infection. Early work on this system has established a model of tissue turnover based on the asymmetric division of intestinal stem cells. From the quantitative analysis of clonal fate data, we show that tissue turnover involves the neutral competition of symmetrically dividing stem cells. This competition leads to stem-cell loss and replacement, resulting in neutral drift dynamics of the clonal population. As well as providing new insight into the mechanisms regulating tissue self-renewal, these findings establish intriguing parallels with the mammalian system, and confirm Drosophila as a useful model for studying adult intestinal maintenance. PMID- 22522700 TI - Direct conversion in the heart: a simple twist of fate. PMID- 22522701 TI - Epigenetic reprogramming: Prdm14 hits the accelerator. PMID- 22522702 TI - Structural basis for Arf6-MKLP1 complex formation on the Flemming body responsible for cytokinesis. AB - A small GTPase, Arf6, is involved in cytokinesis by localizing to the Flemming body (the midbody). However, it remains unknown how Arf6 contributes to cytokinesis. Here, we demonstrate that Arf6 directly interacts with mitotic kinesin-like protein 1 (MKLP1), a Flemming body-localizing protein essential for cytokinesis. The crystal structure of the Arf6-MKLP1 complex reveals that MKLP1 forms a homodimer flanked by two Arf6 molecules, forming a 2:2 heterotetramer containing an extended beta-sheet composed of 22 beta-strands that spans the entire heterotetramer, suitable for interaction with a concave membrane surface at the cleavage furrow. We show that, during cytokinesis, Arf6 is first accumulated around the cleavage furrow and, prior to abscission, recruited onto the Flemming body via interaction with MKLP1. We also show by structure-based mutagenesis and siRNA-mediated knockdowns that the complex formation is required for completion of cytokinesis. A model based on these results suggests that the Arf6-MKLP1 complex plays a crucial role in cytokinesis by connecting the microtubule bundle and membranes at the cleavage plane. PMID- 22522703 TI - Csy4 relies on an unusual catalytic dyad to position and cleave CRISPR RNA. AB - CRISPR-Cas adaptive immune systems protect prokaryotes against foreign genetic elements. crRNAs derived from CRISPR loci base pair with complementary nucleic acids, leading to their destruction. In Pseudomonas aeruginosa, crRNA biogenesis requires the endoribonuclease Csy4, which binds and cleaves the repetitive sequence of the CRISPR transcript. Biochemical assays and three co-crystal structures of wild-type and mutant Csy4/RNA complexes reveal a substrate positioning and cleavage mechanism in which a histidine deprotonates the ribosyl 2'-hydroxyl pinned in place by a serine, leading to nucleophilic attack on the scissile phosphate. The active site catalytic dyad lacks a general acid to protonate the leaving group and positively charged residues to stabilize the transition state, explaining why the observed catalytic rate constant is ~10(4) fold slower than that of RNase A. We show that this RNA cleavage step is essential for assembly of the Csy protein-crRNA complex that facilitates target recognition. Considering that Csy4 recognizes a single cellular substrate and sequesters the cleavage product, evolutionary pressure has likely selected for substrate specificity and high-affinity crRNA interactions at the expense of rapid cleavage kinetics. PMID- 22522704 TI - Not lost in translation: stepwise regulation of microRNA targets. AB - MicroRNAs (miRNAs) are endogenous, ~22-nucleotide-long, noncoding RNAs that play critical roles in physiology and disease via mechanisms that remain obscure. Although numerous studies implicate miRNAs in repression of translation, more recent reports suggest that the major role of miRNAs is in reduction of target mRNA stability. Because mRNA translation and stability are intimately connected, it has been a challenge to establish whether miRNAs induce translational repression, mRNA decay, or both. If miRNAs reduce both mRNA translation and stability, the timing and contribution of each process to overall repression is unclear. Indeed, it has been debated whether mRNA decay is a cause or consequence of miRNA-mediated translational repression. On the other hand, if these events are mutually exclusive, what determines which mechanism is used? In a recent issue of Science, Bazzini et al (2012) use genome-wide ribosome footprinting and RNA sequencing (RNA-Seq) to demonstrate that in developing zebrafish embryos, miR 430 naturally represses translation initiation of target mRNAs, followed by their deadenylation and decay. PMID- 22522705 TI - Mmi1 RNA surveillance machinery directs RNAi complex RITS to specific meiotic genes in fission yeast. AB - RNA interference (RNAi) silences gene expression by acting both at the transcriptional and post-transcriptional levels in a broad range of eukaryotes. In the fission yeast Schizosaccharomyces pombe the RNA-Induced Transcriptional Silencing (RITS) RNAi complex mediates heterochromatin formation at non-coding and repetitive DNA. However, the targeting and role of RITS at other genomic regions, including protein-coding genes, remain unknown. Here we show that RITS localizes to specific meiotic genes and mRNAs. Remarkably, RITS is guided to these meiotic targets by the RNA-binding protein Mmi1 and its associated RNA surveillance machinery that together degrade selective meiotic mRNAs during vegetative growth. Upon sexual differentiation, RITS localization to the meiotic genes and mRNAs is lost. Large-scale identification of Mmi1 RNA targets reveals that RITS subunit Chp1 associates with the vast majority of them. In addition, loss of RNAi affects the effective repression of sexual differentiation mediated by the Mmi1 RNA surveillance machinery. These findings uncover a new mechanism for recruiting RNAi to specific meiotic genes and suggest that RNAi participates in the control of sexual differentiation in fission yeast. PMID- 22522707 TI - Consequences. PMID- 22522706 TI - Co-transcriptional degradation of aberrant pre-mRNA by Xrn2. AB - Eukaryotic protein-coding genes are transcribed as pre-mRNAs that are matured by capping, splicing and cleavage and polyadenylation. Although human pre-mRNAs can be long and complex, containing multiple introns and many alternative processing sites, they are usually processed co-transcriptionally. Mistakes during nuclear mRNA maturation could lead to potentially harmful transcripts that are important to eliminate. However, the processes of human pre-mRNA degradation are not well characterised in the human nucleus. We have studied how aberrantly processed pre mRNAs are degraded and find a role for the 5'->3' exonuclease, Xrn2. Xrn2 associates with and co-transcriptionally degrades nascent beta-globin transcripts, mutated to inhibit splicing or 3' end processing. Importantly, we provide evidence that many endogenous pre-mRNAs are also co-transcriptionally degraded by Xrn2 when their processing is inhibited by Spliceostatin A. Our data therefore establish a previously unknown function for Xrn2 and an important further aspect of pre-mRNA metabolism that occurs co-transcriptionally. PMID- 22522708 TI - Patients in England waited 6% longer for elective operations in 2011, says report. PMID- 22522709 TI - Austerity measures will lead to rise in unemployment and suicides, says Marmot. PMID- 22522710 TI - Current recommendations for levothyroxine treatment of differentiated thyroid cancer patients are not properly implemented in clinical practice. AB - BACKGROUND: Levothyroxine (L-T4) treatment aims to minimize the risk of differentiated thyroid cancer (DTC) recurrence and should be tailored to patient risk stratification and potential morbidity from adverse effects. AIM: To evaluate the effectiveness of current recommendations on L-T4 treatment of DTC patients in clinical practice. MATERIAL AND METHODS: We submitted to in-person interviews and revised the charts of 139 low-risk (LR) and 57 not-low-risk (NLR) DTC patients. A second evaluation made 24-60 months after surgery reclassified 131 patients who maintained (thyroglobulin) Tg<=2 ng/dl with no evidence of relapse/recurrence as LR, whereas the remaining 65 cases were considered NLR. RESULTS: Only 27% LR patients were appropriately controlled; 18% were kept suppressed; 49% maintained serum TSH levels between 0.11-0.4 mU/l; 21% had TSH=2.5- 4.5 mU/l; and 12% TSH>4.5 mU/l. Among the NLR patients, 24 (37%) of the patients presented serum TSH levels above goal, including 13 (20%) patients with TSH>4.5 mU/l. There were 4 NLR elders whose TSH levels were kept between 0.41 and 4.5 for medical reasons; likewise, 28 NLR patients maintained with low but not undetectable serum TSH levels had cardiovascular and/or bone risk factors, but all the remaining 24 NLR patients were not adequately controlled because of poor treatment compliance. On the other hand, 45% of 152 inappropriately controlled patients presented risks for bone fractures, including 33 patients kept with low serum TSH levels without medical indication. CONCLUSION: We concluded that guidelines are not adequately applied and alternative strategies aiming to increase adherence are urgently needed for DTC patients. PMID- 22522711 TI - Capacitance-based assay for real-time monitoring of endocytosis and cell viability. AB - Label-free cell-based assays have emerged as a promising means for high throughput screening. Most label-free sensors are based on impedance measurements that reflect the passive electrical properties of cells. Here we introduce a capacitance-based assay that measures the dielectric constant (capacitance) of biological cells, and demonstrate the feasibility of analyzing endocytosis and screening chemotherapeutic agents with this assay. Endocytosis induces a change in the zeta potential, leading to a change in the dielectric constant which enables real-time endocytosis monitoring using the capacitance sensor. Additionally, since the dielectric constant is proportional to cell radius and cell volume, cell viability can be estimated from the change in capacitance. Therefore, the capacitance sensor array can also be used for cytotoxicity testing for large-scale chemotherapeutic screening. PMID- 22522712 TI - Ab initio study of the positronation of the CaO and SrO molecules including calculation of annihilation rates. AB - Ab initio multireference single- and double-excitation configuration interaction calculations have been performed to compute potential curves for ground and excited states of the CaO and SrO molecules and their positronic complexes, e(+)CaO, and e(+)SrO. The adiabatic dissociation limit for the (2)Sigma(+) lowest states of the latter systems consists of the positive metal ion ground state (M(+)) and the OPs complex (e(+)O(-)), although the lowest energy limit is thought to be e(+)M + O. Good agreement is found between the calculated and experimental spectroscopic constants for the neutral diatomics wherever available. The positron affinity of the closed-shell X (1)Sigma(+) ground states of both systems is found to lie in the 0.16-0.19 eV range, less than half the corresponding values for the lighter members of the alkaline earth monoxide series, BeO and MgO. Annihilation rates (ARs) have been calculated for all four positronated systems for the first time. The variation with bond distance is generally similar to what has been found earlier for the alkali monoxide series of positronic complexes, falling off gradually from the OPs AR value at their respective dissociation limits. The e(+)SrO system shows some exceptional behavior, however, with its AR value reaching a minimum at a relatively large bond distance and then rising to more than twice the OPs value close to its equilibrium distance. PMID- 22522713 TI - Stop refilling (Ca(2+) stores). PMID- 22522714 TI - Holding tight onto the niche. PMID- 22522715 TI - Musical chairs at the epithelium. PMID- 22522721 TI - Distance from home to exercise site did not influence the adherence of 796 participants. AB - BACKGROUND: One of the difficulties in maintaining long-term adherence to exercise is the distance from home to the place of exercise. OBJECTIVE: To determine, for a private supervised exercise program (PSEP), the influence of the home-PSEP distance on adherence. METHODS: We identified 976 individuals and selected 796 who met the inclusion criteria. The home-PSEP distance was obtained by the Google Maps. Adherence was determined by quartiles (months): 1-4, 5-12, 13 36 and more than 36. The clinical conditions were stratified as healthy, obese and/or hypertensive and/or dyslipidemic and/or diabetic patients without coronary disease; coronary artery disease patients and other health problems like cancer, respiratory disease and panic. The home-PSEP distance was divided into (km): up to 1, 1 to 3, 3 to 10 and more than 10. For the statistical analysis, we used the Kruskal-Wallis ANOVA and the chi-square test. RESULTS: Of respondents, 46% lived up to 3 km, 39% lived between 3 and 10 km and about 15% lived more than 10 kilometers from the place of the PSEP. No differences were found between the medians of the months of participation in the PSEP as a function of home-PSEP distance (p = 0.11). CONCLUSION: For a given PSEP in the city of Rio de Janeiro, open from Monday through Saturday with free choice of time, the home-PSEP distance did not influence the adherence of participants. This was probably due to the quality of the service and/or lack of places closer to the participants' home. PMID- 22522720 TI - Effect of penicillin G every three weeks on oral microflora by penicillin resistant Viridans Streptococci. AB - BACKGROUND: Benzathine penicillin G every 3 weeks is the standard protocol for secondary prophylaxis for recurrent rheumatic fever. OBJECTIVE: Assess the effect of Benzathine penicillin G on Streptococcus sanguinis and Streptococcus oralis in patients with cardiac valvular disease due to rheumatic fever receiving secondary prophylaxis. METHODS: Oral streptococci were evaluated before (baseline) and after 7 days (day 7) with Benzathine penicillin G in 100 patients receiving routine secondary rheumatic fever prophylaxis. Saliva samples were evaluated for colony count and presence of S. sanguinis and S. oralis. Chewing-stimulated saliva samples were serially diluted and plated onto both nonselective and selective 5% sheep blood agar containing penicillin G. The species were identified using conventional biochemical tests. Minimal inhibitory concentrations were determined with the Etest. RESULTS: No statistical differences were found in the presence of S. sanguinis comparing baseline and day 7 (p = 0.62). However, the existing number of positive cultures of S. oralis on day 7 after Benzathine penicillin G presented a significant increase compared to baseline (p = 0.04). No statistical difference was found between baseline and day 7 concerning the number of S. sanguinis or S. oralis CFU/mL and median minimal inhibitory concentrations. CONCLUSION: This study showed that Benzathine penicillin G every 3 weeks did not change the colonization by S. sanguinis, but increased colonization of S. oralis on day 7 of administration. Therefore, susceptibility of Streptococcus sanguinis and Streptococcus oralis to penicillin G was not modified during the penicillin G routine secondary rheumatic fever prophylaxis. PMID- 22522719 TI - Bittersweet memories: linking metabolism to epigenetics through O-GlcNAcylation. AB - O-GlcNAcylation, which is a nutrient-sensitive sugar modification, participates in the epigenetic regulation of gene expression. The enzymes involved in O-linked beta-D-N-acetylglucosamine (O-GlcNAc) cycling - O-GlcNAc transferase (OGT) and O GlcNAcase (OGA) - target key transcriptional and epigenetic regulators including RNA polymerase II, histones, histone deacetylase complexes and members of the Polycomb and Trithorax groups. Thus, O-GlcNAc cycling may serve as a homeostatic mechanism linking nutrient availability to higher-order chromatin organization. In response to nutrient availability, O-GlcNAcylation is poised to influence X chromosome inactivation and genetic imprinting, as well as embryonic development. The wide range of physiological functions regulated by O-GlcNAc cycling suggests an unexplored nexus between epigenetic regulation in disease and nutrient availability. PMID- 22522722 TI - Absence of cutaneous symptoms of pseudoxanthoma elasticum at the immobile joint of a stroke patient. PMID- 22522723 TI - A nurse-led ocular oncology clinic in Liverpool: results of a 6-month trial. AB - PURPOSE: To describe the design and implementation of a nurse-led clinic in a tertiary adult ocular oncology service and to assess its feasibility and patient satisfaction. METHODS: Patients with a melanocytic uveal tumour attending for review during an initial 6-month trial period were assessed in a dedicated ocular oncology clinic by an ophthalmic nurse practitioner. These were: (1) patients who would have been discharged back to the referring hospital but whose ophthalmologist refused to continue their follow-up; (2) patients who preferred to be reviewed in our clinic; and (3) patients with a risk of metastatic disease that was increased but not enough for them to be referred to our medical oncologist. Quality assurance mechanisms were established to ensure safe practice. Patient satisfaction was assessed by means of anonymised questionnaires. RESULTS: A total of 65 patients were seen between 1 November 2011 and 31 May 2011. The mean age was 58 years (range 16-82 years). Most lesions seen were choroidal suspicious naevi (54%) and treated choroidal malignant melanomas (20%). Nine (14%) patients with an increased risk of metastatic disease attended the clinic. Nine patients (14%) were referred back to the ophthalmologist's ocular oncology clinic, because of tumour growth in two patients, macular oedema in one, cataract in five, and conjunctival melanosis at the plaque site in one. Questionnaires showed high levels of satisfaction with the service. CONCLUSION: A nurse-led adult ocular oncology clinic is feasible, thanks to developments in ocular photography. It is well accepted by patients. PMID- 22522724 TI - Differential expression of components of the retinoic acid signaling pathway in the adult mouse olfactory epithelium. AB - Position within a tissue often correlates with cellular phenotype, for example, differential expression of odorant receptors and cell adhesion molecules across the olfactory mucosa (OM). The association between position and phenotype is often paralleled by gradations in the concentration of retinoic acid (RA), caused by differential expression of the RA synthetic enzymes, the retinaldehyde dehydrogenases (RALDH). We show here that RALDH-1, -2, and -3 are enriched in the sustentacular cells, deep fibroblasts of the lamina propria, and the superficial fibroblasts, respectively, of the ventral and lateral OM as compared to the dorsomedial OM. The shift from high to low expression of the RALDHs matches the boundary defined by the differential expression of OCAM/mamFasII. Further, we found that RA-binding proteins are expressed in the epithelium overlying the RALDH-3 expressing fibroblasts of the lamina propria. Both findings suggest that local alterations in RA concentration may be more important than a gradient of RA across the epithelial plane, per se. In addition, RALDH-3 is found in a small population of basal cells in the ventral and lateral epithelium, which expand and contribute to the neuronal lineage following MeBr lesion. Indeed, transduction with a retrovirus expressing a dominant negative form of retinoic acid receptor type alpha blocks the reappearance of mature, olfactory marker protein (OMP) (+) olfactory neurons as compared to empty vector. These results support the notion of a potential role for RA, both in maintaining the spatial organization of the normal olfactory epithelium and in reestablishing the neuronal population during regeneration after injury. PMID- 22522725 TI - Stepped early psychological intervention for posttraumatic stress disorder, other anxiety disorders, and depression following serious injury. AB - The best approach for implementing early psychological intervention for anxiety and depressive disorders after a traumatic event has not been established. This study aimed to test the effectiveness of a stepped model of early psychological intervention following traumatic injury. A sample of 683 consecutively admitted injury patients were screened during hospitalization. High-risk patients were followed up at 4-weeks postinjury and assessed for anxiety and depression symptom levels. Patients with elevated symptoms were randomly assigned to receive 4-10 sessions of cognitive-behavioral therapy (n = 24) or usual care (n = 22). Screening in the hospital identified 89% of those who went on to develop any anxiety or affective disorder at 12 months. Relative to usual care, patients receiving early intervention had significantly improved mental health at 12 months. A stepped model can effectively identify and treat injury patients with high psychiatric symptoms within 3 months of the initial trauma. PMID- 22522726 TI - Guidelines for peer support in high-risk organizations: an international consensus study using the Delphi method. AB - Despite widespread adoption of peer-support programs in organizations around the world whose employees are at high risk of exposure to potentially traumatic incidents, little consensus exists regarding even the most basic concepts and procedures for these programs. In this article, consensus refers to a group decision-making process that seeks not only agreement from most participants, but also resolution of minority objections. The aim of the current study was to develop evidence-informed peer-support guidelines for use in high-risk organizations, designed to enhance consistency around goals and procedures and provide the foundation for a systematic approach to evaluation. From 17 countries, 92 clinicians, researchers, and peer-support practitioners took part in a 3-round web-based Delphi process rating the importance of statements generated from the existing literature. Consensus was achieved for 62 of 77 (81%) statements. Based upon these, 8 key recommendations were developed covering the following areas: (a) goals of peer support, (b) selection of peer supporters, (c) training and accreditation, (d) role of mental health professionals, (e) role of peer supporters, (f) access to peer supporters, (g) looking after peer supporters, and (h) program evaluation. This international consensus may be used as a starting point for the design and implementation of future peer-support programs in high-risk organizations. PMID- 22522727 TI - Finding meaning in a traumatic loss: a families approach. AB - Meaning-making, like much of coping research, has been conceptualized and assessed as an individual-centered phenomenon. On the premise that most traumas affect families as a whole, we assessed the extent to which meanings following a traumatic loss were congruent within families. Qualitative and quantitative data from family members coping with the loss of a family member in a mine explosion indicated moderate family congruence in meanings and global well-being. Furthermore, greater family similarity in meaning was associated with less depressive affect in individuals (pseudo R(2) = .063), but was not associated with individual differences in well-being. The research highlights the important role that families play in coping with trauma. PMID- 22522728 TI - A pilot study of a 12-week model of group-based exposure therapy for veterans with PTSD. AB - Group-based exposure therapy (GBET) is an intensive group treatment that targets posttraumatic stress disorder (PTSD) symptoms through repeated imaginal and in vivo exposure. The purpose of the present study was to assess the feasibility and acceptability of a modified 12-week course of GBET (modified from the standard 16 weeks) and to examine its effectiveness in reducing veterans' PTSD symptoms. Participants were 10 male Operation Iraqi Freedom and Vietnam-era veterans recruited from a PTSD specialty clinic at a large Veterans Affairs Medical Center. All participants were retained and demonstrated clinically significant reductions in PTSD symptoms (eta(2) = .84-.87) comparable to the standard protocol. The findings from this small sample indicate that the abbreviated 12 week GBET protocol is a potentially effective treatment for PTSD. PMID- 22522729 TI - Behavioral markers of coping and psychiatric symptoms among sexually abused children. AB - The current study examined coping and psychiatric symptoms in a longitudinal sample of sexually abused children. Coping was behaviorally coded from children's forensic interviews in the aftermath of sexual abuse. Using principal components analysis, coping behaviors were found to cluster into 3 categories: avoidant, expressive, and positive affective coping. Avoidant coping had predictive utility for a range of psychiatric symptoms, including depressive, posttraumatic stress, anxiety, and dissociative symptoms as well as aggression and attention problems measured 8-36 months following the forensic interview. Specific behaviors, namely fidgetiness and distractibility, were also found to be associated with future symptoms. These findings suggest the predictive utility of avoidant behaviors in general, and fidgetiness and distractibility in particular, among sexually abused children. PMID- 22522730 TI - Risk factors for PTSD, anxiety, and depression among adolescents in Gaza. AB - The present study examined among adolescents in Gaza the relationship between exposure to war stressors and psychological distress as well as the effects of age, gender, and socioeconomic status. Data were collected from a sample of 139 adolescents 12 to 17 years old. Results showed that adolescents reported elevated levels of intrusion, avoidance, and depression compared to levels in communities not affected by war in the recent past. The proportion scoring within the clinical range of posttraumatic stress disorder (PTSD) was 56.8% compared to 6.3% in peacetime populations, reflecting a Hedges's g of 1.29 (p < .001). Significant risk factors for PTSD were exposure (beta = .377, p < .001), female gender (beta = -.257, p < .001), older age (beta = .280, p < .01), and an unemployed father (beta = -.280, p < .01). Risk factors for anxiety were exposure (beta = .304, p < .001), female gender (beta = -.125, p < .01), and older age (beta = 272, p < .01), whereas female gender (beta = <.238, p < .001) was the only significant risk factor for depression. The present study suggests large individual differences in how adolescents are affected by war stressors. PMID- 22522731 TI - Identification of trauma exposure and PTSD in adolescent psychiatric inpatients: an exploratory study. AB - Trauma exposure and posttraumatic stress disorder (PTSD), though prevalent among adolescent psychiatric inpatients, are underidentified in standard clinical practice. In a retrospective chart review of 140 adolescents admitted to a psychiatric inpatient unit, we examined associations between probable PTSD identified through the Child PTSD Symptom Scale and adolescents' service use and clinical characteristics. Results suggest a large discrepancy between rates of probable PTSD identified through standardized assessment and during the emergency room psychiatric evaluation (28.6% vs. 2.2%). Adolescents with probable PTSD had greater clinical severity and service utilization, an increased likelihood of being diagnosed with bipolar disorder (27.5% vs. 9.2%) and being prescribed antipsychotic medications (47.5% vs. 27.6%), and were prescribed more psychotropic medications. Upon discharge, those with probable PTSD were more than those without to be assigned a diagnosis of PTSD (45% vs. 7.1%), a comorbid diagnosis of major depressive disorder (30% vs. 14.3%), to be prescribed an antidepressant medication (52.5% vs. 33.7%), and to be prescribed more medications. The underidentification of trauma exposure and PTSD has important implications for the care of adolescents given that accurate diagnosis is a prerequisite for providing effective care. Improved methods for identifying trauma-related problems in standard clinical practice are needed. PMID- 22522732 TI - PTSD symptoms as risk factors for intimate partner violence revictimization and the mediating role of victims' violent behavior. AB - Apart from being a consequence of intimate partner violence (IPV), posttraumatic stress disorder (PTSD) can also be a risk factor for IPV revictimization. The current study examined how each of 4 PTSD symptom clusters (reexperiencing, arousal, avoidance, and numbing) related to revictimization in a sample of 156 female help-seeking victims of IPV, recruited from various victim support services in the Netherlands. In addition, we hypothesized that victim-perpetrated IPV would mediate the relation between PTSD symptomatology and IPV revictimization. Our results show that victims' PTSD reexperiencing symptoms predict revictimization of partner violence (d = .45 for physical IPV revictimization; d = .35 for psychological IPV revictimization); the other 3 PTSD symptom clusters were not related to IPV revictimization. Furthermore, victim perpetrated psychological IPV was found to partially mediate the relation between victims' PTSD reexperiencing symptoms and IPV revictimization (Z = 2.339, SE = 0.044, p = .019 for physical IPV revictimization, and Z = 2.197, SE = 0.038, p = .028 for psychological IPV revictimization). Findings indicate that IPV victims with higher levels of PTSD reexperiencing symptoms may be more likely to perpetrate psychological IPV themselves, which may put them at greater risk for receiving IPV in return. Based on these results, a focus on individual PTSD symptom clusters and victim behaviors seems relevant for practice and may contribute to a decrease in victims' risk for future IPV. PMID- 22522733 TI - An examination of PTSD symptoms and relationship functioning in U.S. soldiers of the Iraq war over time. AB - We examined associations between overall posttraumatic stress disorder (PTSD) symptoms, symptom clusters of PTSD (reexperiencing, avoidance, dysphoria, and arousal), and relationship adjustment cross sectionally and longitudinally using self-report measures from a dyadic sample of U.S. National Guard soldiers from the Iraq war and their intimate partners (N = 49 couples). Results of multilevel modeling revealed that Time 1 PTSD symptom severity significantly predicted lower relationship adjustment as rated by partners at Time 2 after controlling for baseline relationship adjustment (beta = -.20, p = .025). Total PTSD symptoms did not significantly predict soldiers' ratings of relationship adjustment at Time 2. For soldiers, the PTSD symptom cluster of dysphoria was uniquely and significantly related to relationship adjustment ratings both at Time 1 and at Time 2, controlling for Time 1 adjustment. For partners, none of the soldiers' PTSD symptoms clusters was uniquely associated with Time 1 relationship adjustment or with change in adjustment over time. In contrast, findings regarding the effect of relationship adjustment on changes in PTSD over time found that Time 1 relationship adjustment was not associated with changes in PTSD symptoms at Time 2. PMID- 22522734 TI - The role of shame in distinguishing perpetrators of intimate partner violence in U.S. veterans. AB - Increasing attention is being paid to the fact that exposure to traumatic stressors in military combat may lead to perpetration of intimate partner violence (IPV). Because shame has been identified as a factor in posttraumatic stress disorder (PTSD), the current cross-sectional study examined the relationship in U.S. veterans between IPV and PTSD, depression, guilt, and shame. We hypothesized that shame would be the strongest correlate of perpetration of IPV and that shame would mediate the relationship between PTSD and IPV. Participants were 264 primarily male and Caucasian mixed-era veterans presenting for psychological treatment at a Veterans Affairs hospital. They completed standard measures of depression, PTSD symptoms, shame, and guilt and a local checklist was used to dichotomize the sample regarding IPV. Discriminant analysis indicated that shame contributed most (standardized canonical discriminant function coefficient = .44) to distinguishing perpetrators of IPV. In addition, the results were consistent with shame as a mediator of the relationship between PTSD and IPV. These results are in line with studies indicating that shame is linked to IPV perpetration in nonveteran samples (Harmon, 2002; Rand, 2004; Schibik, 2002) and suggests that shame may be an important aspect of the relationship between PTSD and IPV. PMID- 22522735 TI - Neural substrates for processing task-irrelevant emotional distracters in maltreated adolescents with depressive disorders: a pilot study. AB - In this pilot study, neural systems related to cognitive and emotional processing were examined using event-related functional magnetic resonance imaging in 5 maltreated youth with depressive disorders and 11 nonmaltreated healthy participants. Subjects underwent an emotional oddball task, where they detected infrequent ovals (targets) within a continual stream of phase-scrambled images (standards). Sad and neutral images were intermittently presented as task irrelevant distracters. The maltreated youth revealed significantly decreased activation in the left middle frontal gyrus and right precentral gyrus to target stimuli and significantly increased activation to sad stimuli in bilateral amygdala, left subgenual cingulate, left inferior frontal gyrus, and right middle temporal cortex compared to nonmaltreated subjects. Additionally, the maltreated youth showed significantly decreased activation to both attentional targets and sad distracters in the left posterior middle frontal gyrus compared to nonmaltreated subjects. In this exploratory study of dorsal control and ventral emotional circuits, we found that maltreated youth with distress disorders demonstrated dysfunction of neural systems related to cognitive control and emotional processing. PMID- 22522736 TI - Remission of PTSD after victims of intimate partner violence leave a shelter. AB - Intimate partner violence (IPV) is a significant public health problem associated with high rates of posttraumatic stress disorder (PTSD). Few longitudinal studies have investigated IPV-related PTSD and we know of only 1 longitudinal study to date that has explored IPV-related PTSD in residents of battered women's shelters. The current report describes a prospective study of IPV-related PTSD in an initial sample of 147 residents of battered women's shelters. Baseline correlates of remission of IPV-related PTSD (i.e., PTSD and IPV severity, loss of personal and social resources, cessation of abuse, reunion with abuser, and length of shelter stay) over a 6-month follow-up period were investigated. Although findings are consistent with prior research suggesting a natural recovery of PTSD in IPV-victims, they also show that a significant number (46.8%) of women exhibit chronic PTSD. Participants whose PTSD remitted over follow-up had at baseline less severe IPV-related PTSD (partial eta(2) = .104) and fewer loss of personal and social resources (partial eta(2) = .095), and were less likely to reunite with their abuser after leaving the shelter than participants with chronic PTSD (3.3% and 22.4%, respectively). Clinical implications and limitations of findings are discussed. PMID- 22522737 TI - Trauma-related guilt and posttraumatic stress among journalists. AB - This study explored the psychological impact of exposure to work-related trauma among journalists. It was hypothesised that positive associations would exist between (a) exposure and PTSD symptoms, (b) exposure and guilt cognitions, and (c) guilt cognitions and PTSD symptoms, and that the relationship between exposure and PTSD symptoms would be mediated by guilt cognitions. The sample consisted of 50 journalists (response rate = 15%), who had recently been exposed to work-related trauma. They were predominantly male, aged 40 years or older, well-educated, and most had worked in journalism for at least 15 years. Participants completed an online questionnaire that explored their work-related experiences of trauma, PTSD symptoms, and trauma-related guilt cognitions. The findings showed that higher levels of exposure to work-related trauma were significantly associated with higher levels of PTSD symptoms (r = .36) and trauma related guilt cognitions (r = .29). Guilt cognitions were significantly and positively independently associated with PTSD symptoms (r = .12) and were consistent with partial mediation of relationship between exposure to work related trauma and PTSD symptoms. This study provides greater insight into the psychological processing of work-related traumatic events among journalists and emphasizes the importance of posttrauma appraisals of guilt regarding their experiences. PMID- 22522738 TI - The influence of combat and interpersonal trauma on PTSD, depression, and alcohol misuse in U.S. Gulf War and OEF/OIF women veterans. AB - The present study evaluated the impact of combat and interpersonal trauma exposure in a sample of 115 U.S. women veterans from Gulf War I and the Iraq and Afghanistan wars on 3 postdeployment trauma-related mental health outcomes: posttraumatic stress disorder symptoms (PSS), depressive symptom severity (DSS), and alcohol misuse. Patients presenting for healthcare services at a Veterans Affairs postdeployment health specialty clinic completed screening questionnaires that assessed combat exposure, lifetime interpersonal trauma history of childhood neglect, physical, or sexual abuse, and adult sexual and physical assault. In a regression model, combat exposure was the only significant independent variable associated with PSS, DSS, and alcohol misuse (beta = .42, .27 and B = 1.58, respectively) even after adding lifetime interpersonal assault exposure to the model. Results highlight the negative effects of combat exposure on treatment seeking women veterans' postdeployment mental health. Incorporating combat exposure into routine screening procedures for Gulf War and Iraq and Afghanistan war women veterans can aid in mental health treatment planning. PMID- 22522740 TI - PTSD symptom structure among West African war trauma survivors living in African refugee camps: a factor-analytic investigation. AB - We examined the factor structure of measured posttraumatic stress disorder (PTSD) symptoms in a sample of West African civilian refugees who had fled the civil war in Sierra Leone between 2001 and 2006. Given that such war-affected populations are common but understudied in trauma research, our objective was to examine the similarities and differences in this factor structure compared to prevailing models of PTSD symptom structure. As part of treatment services provided in refugee camps, refugees (2,140 women, 1,662 men, 1 unknown) from Sierra Leone, Liberia, and Guinea completed the 17 symptoms portion of the Posttraumatic Stress Diagnostic Scale (PDS). We used exploratory and confirmatory factor analyses to investigate whether there was a factor structure unique to this population, and made comparisons with the numbing, dysphoria, and aroused intrusion models. Results from the confirmatory analyses showed that the dysphoria model best fit the data (root mean square error of approximation [RMSEA] = .062); however, exploratory analyses revealed that 3 items loaded differently than theoretically expected. Psychological distress cross-loaded on reexperiencing and avoidance factors and physiological reactivity loaded on the avoidance factor instead of the reexperiencing factor. The sleep difficulties item was not well explained, generally; the highest loading (lambda = .22) was on the dysphoria factor. PMID- 22522739 TI - Posttraumatic stress disorder, substance use disorders, and medical comorbidity among returning U.S. veterans. AB - Evidence suggests that posttraumatic stress disorder (PTSD) and substance use disorders (SUD) are associated with poorer physical health among U.S. veterans who served in Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF). No research of which we are aware has examined the independent and interactive effects of PTSD and SUD on medical comorbidity among OEF/OIF veterans. This cross sectional study examined medical record data of female and male OEF/OIF veterans with >= 2 Veterans Affairs primary care visits (N = 73,720). Gender-stratified logistic regression analyses, adjusted for sociodemographic factors, were used to examine the association of PTSD, SUD, and their interaction on the odds of medical diagnoses. PTSD was associated with increased odds of medical diagnoses in 9 of the 11 medical categories among both women and men, range of odds ratios (ORs) ranged from 1.07 to 2.29. Substance use disorders were associated with increased odds of 2 of the 11 medical categories among women and 3 of the 11 medical categories among men; ORs ranged from 1.20 to 1.74. No significant interactions between PTSD and SUD were detected for women or men. Overall, findings suggest that PTSD had a stronger association with medical comorbidity (in total and across various medical condition categories) than SUD among female and male OEF/OIF veterans. PMID- 22522741 TI - The functional duality of HoxB4 in hematopoietic reconstituting cells. AB - Transplantation of CD34+ hematopoietic reconstituting cells (HRC) is an important treatment modality. The cells needed for clinical hematopoietic reconstitution after myeloablation most commonly derive from bone marrow which have been mobilized into the peripheral blood. The number of CD34+ cells in mobilized blood samples is used to indicate the appropriateness of transplantation although it does not evaluate the two necessary functions for successful transplantation: long-term reconstitution mediated by cells with self-renewing proliferation and short-term hematopoietic differentiation mediated by progenitor cells. Using a novel high-resolution immunophenotyping technology on a flow cytometric platform, we have assessed uniformly mobilized CD34+ cells for expression levels of 16 molecules previously associated with HRC function and sought correlations of these expression data with functional short-term assays for colony formation that do predict successful transplantation. We found that colony-forming units were significantly correlated with HoxB4 expression, which was explained by the number of CD34+ cells in the samples. However, analysis of colony-forming units normalized to the CD34+ cell count revealed a significant negative correlation with HoxB4 expression. Thus, increased levels of HoxB4 enhance CD34+ cell number via self-renewing expansion but concomitantly depreciate the capacity for short term differentiation per cell. Our findings demonstrate the translation of experimental findings into a clinical setting and suggest that the expression level of HoxB4 in CD34+ cells can be used as a measure of a sample's appropriateness for transplantation. PMID- 22522742 TI - Methods to array photonic crystal microcavities for high throughput high sensitivity biosensing on a silicon-chip based platform. AB - We experimentally demonstrate a method to create large-scale chip-integrated photonic crystal sensor microarrays by combining the optical power splitting characteristics of multi-mode interference (MMI) power splitters and transmission drop resonance characteristics of multiple photonic crystal microcavities arrayed along the length of the same photonic crystal waveguide. L13 photonic crystal microcavities are employed which show high Q values (~9300) in the bio-ambient phosphate buffered saline (PBS) as well as high sensitivity, experimentally demonstrated to ~98 atto-grams. Two different probe antibodies were specifically detected simultaneously with a control sample, in the same experiment. PMID- 22522743 TI - A rare cause of small bowel obstruction: Abdominal cocoon. AB - INTRODUCTION: The clinical manifestations of abdominal 'cocoon' are non-specific and hence its diagnosis is rarely made preoperatively and the management is often delayed. Surgery remains the main stay of treatment with satisfactory outcome and comprises excision of the fibrous membrane, meticulous adhesionolysis and release of the entrapped small bowel. PRESENTATION OF CASE: A 45-year-old male patient presented with 6-month history of progressive subacute small bowel obstruction. After initial radiological investigations, he underwent diagnostic laparoscopy and was misdiagnosed as abdominal tuberculosis. He was started on anti tuberculous therapy, but exploratory laparotomy was carried out after failure to respond to anti-tuberculous therapy. At laparotomy, the abdominal 'cocoon' which was encapsulating the entire small bowel was excised, and the adhesions were carefully lysed. The patient remained well and without recurrence at 1-year follow-up. DISCUSSION: Abdominal 'cocoon' is a rare cause of subacute, acute and chronic small bowel obstruction. Its diagnosis is rarely made preoperatively. CONCLUSION: Abdominal 'cocoon' should be thought of as a rare cause of small bowel obstruction. It may be mistaken with abdominal tuberculosis. Surgery remains the mainstay of curative treatment. PMID- 22522744 TI - Relationship of EEG sources of neonatal seizures to acute perinatal brain lesions seen on MRI: a pilot study. AB - Even though it is known that neonatal seizures are associated with acute brain lesions, the relationship of electroencephalographic (EEG) seizures to acute perinatal brain lesions visible on magnetic resonance imaging (MRI) has not been objectively studied. EEG source localization is successfully used for this purpose in adults, but it has not been sufficiently explored in neonates. Therefore, we developed an integrated method for ictal EEG dipole source localization based on a realistic head model to investigate the utility of EEG source imaging in neonates with postasphyxial seizures. We describe here our method and compare the dipole seizure localization results with acute perinatal lesions seen on brain MRI in 10 full-term infants with neonatal encephalopathy. Through experimental studies, we also explore the sensitivity of our method to the electrode positioning errors and the variations in neonatal skull geometry and conductivity. The localization results of 45 focal seizures from 10 neonates are compared with the visual analysis of EEG and MRI data, scored by expert physicians. In 9 of 10 neonates, dipole locations showed good relationship with MRI lesions and clinical data. Our experimental results also suggest that the variations in the used values for skull conductivity or thickness have little effect on the dipole localization, whereas inaccurate electrode positioning can reduce the accuracy of source estimates. The performance of our fused method indicates that ictal EEG source imaging is feasible in neonates and with further validation studies, this technique can become a useful diagnostic tool. PMID- 22522745 TI - Association of breast cancer and obesity in a homogeneous population from Spain. AB - OBJECTIVE: To evaluate for the first time in Spain if the association between obesity and breast cancer prognosis is similar to that reported in other countries with non Mediterranean dietary patterns. METHODS: Weight and height and other variables of interest, tumor characteristics and current clinical status 3 yr after diagnosis were retrieved from medical files of breast cancer women diagnosed during 2006. A total of 159 cases with complete information were studied and categorized according to the World Health Organization criteria in normal-/under-weight, overweight, and obese. RESULTS: Among breast cancer patients, 70.4% were classified as overweight/ obese and 29.6% as normal weight. Prevalence of obesity was high (38.4%) in comparison with information reported for healthy women of the same region (27.11%) and was higher among post menopausal patients and in women with low level of alcohol and tobacco consumption. Moreover, overweight/ obese cases (79.5%) tended to have more often human epidermal growth factor receptor 2 status negative when compared with those with normal weight (70.2%; p=0.097) and the survival curves tended to be influenced by body mass index although without statistical significance. CONCLUSIONS: Overweight/obesity in a Mediterranean country is highly prevalent among breast cancer patients. Our results support a putative influence of obesity per se and not the alimentary patterns as a prognostic factor in breast cancer patients justifying the need to perform larger prospective studies. PMID- 22522746 TI - Bacterial physiology: Setting the speed of translation. PMID- 22522747 TI - Reevaluation of a quantitative structure pharmacokinetic model for biliary excretion in rats. AB - Quantitative structure pharmacokinetic relationship (QSPKR) modeling can be used to predict the biliary clearance and percentage of dose eliminated in bile (PD(b)) in humans before clinical studies. Recently, a QSPKR model based on in house compounds was derived using simple physicochemical descriptors to predict the PD(b) in rats (Drug Metab Dispos 38:422-430, 2010). Our objective was to evaluate the QSPKR model derived for the prediction of PD(b) for our larger dataset of 164 compounds in the rat and for the 97 compounds in our human dataset (AAPS J 11:511-525, 2009). Re-analysis of the published QSPKR model revealed the model to be statistically insignificant (Drug Metab Dispos 38:422-430, 2010). Thus, a new statistically significant QSPKR model, consisting of one less descriptor than the published model, was derived from the published data. The newly derived model performed as well as the published model in predicting the PD(b) for the training and test sets (Drug Metab Dispos 38:422-430, 2010). In contrast, the new model performed poorly in predicting the PD(b) for our larger rat (r(2) = 0.253) and human dataset (r(2) = 0.013). The poor predictions for our datasets may be due, in part, to the quality and diversity of the data used to derive and test the model. Our reevaluation suggests that hepatobiliary excretion is a process that cannot truly be captured by simple physicochemical descriptors when examining chemically dissimilar compounds. A simple approach involving a limited number of physicochemical predictors may be useful when examining a structurally similar series of compounds. PMID- 22522748 TI - Hydralazine as a selective probe inactivator of aldehyde oxidase in human hepatocytes: estimation of the contribution of aldehyde oxidase to metabolic clearance. AB - Aldehyde oxidase (AO) metabolism could lead to significant underestimation of clearance in prediction of human pharmacokinetics as well as unanticipated exposure to AO-generated metabolites, if not accounted for early in drug research. We report a method using cryopreserved human hepatocytes and the time dependent AO inhibitor hydralazine (K(I) = 83 +/- 27 MUM, k(inact) = 0.063 +/- 0.007 min(-1)), which estimates the contribution of AO metabolism relative to total hepatic clearance. Using zaleplon as a probe substrate and simultaneously monitoring the AO-catalyzed formation of oxozaleplon and the CYP3A-catalyzed formation of desethyzaleplon in the presence of a range of hydralazine concentrations, it was determined that >90% inhibition of the AO activity with minimal effect on the CYP3A activity could be achieved with 25 to 50 MUM hydralazine. This method was used to estimate the fraction metabolized due to AO [f(m(AO))] for six compounds with clearance attributed to AO along with four other drugs not metabolized by AO. The f(m(AO)) values for the AO substrates ranged between 0.49 and 0.83. Differences in estimated f(m(AO)) between two batches of pooled human hepatocytes suggest that sensitivity to hydralazine varies slightly with hepatocyte preparations. Substrates with a CYP2D6 contribution to clearance were affected by hydralazine to a minor extent, because of weak inhibition of this enzyme. Overall, these findings demonstrate that hydralazine, at a concentration of 25 to 50 MUM, can be used in human hepatocyte incubations to estimate the contribution of AO to the hepatic clearance of drugs and other compounds. PMID- 22522749 TI - Density functional theory study of 1,2-dioxetanone decomposition in condensed phase. AB - The decomposition of 1,2-dioxetanone into a CO(2) molecule and into an excited state formaldehyde molecule was studied in condensed phase, using a density functional theory approach. Singlet and triplet ground and excited states were all included in the calculations. The calculations revealed a novel mechanism for the chemiluminescence of this compound. The triplet excitation can be explained by two intersystem crossings (ISCs) with the ground state, while the singlet excitation can be accounted by an ISC with the triplet state. The experimentally verified small excitation yield can then be explained by the presence of an energy barrier present in the potential energy surface of the triplet excited state, which will govern both triplet and singlet excitation. It was also found that the triplet ground state interacts with both the triplet excited and singlet ground states. A MPWB1K/mPWKCIS approach provided results in agreement with the existent literature. PMID- 22522750 TI - Watch peripheral arterial tonometry in the diagnosis of obstructive sleep apnea: influence of aging. AB - OBJECTIVES/HYPOTHESIS: To investigate the consequences of aging and associated peripheral vascular tone impairment on peripheral arterial tonometry (Watch PAT) based sleep and respiratory disturbance analysis in obstructive sleep apnea (OSA) diagnosis. STUDY DESIGN: Prospective, nonrandomized, clinical trial. METHODS: A total of 56 subjects with age ranges of 20 to 35 years (group I, n = 27) and 50 to 65 years (group II, n = 29) referred to the sleep laboratory for overnight polysomnography (PSG) with suspected OSA were enrolled. All patients underwent simultaneous overnight PSG and Watch PAT monitoring. The data derived from PSG and Watch PAT records, including apnea-hypopnea index (AHI), rapid eye movement (REM) AHI, non-rapid eye movement (NREM) AHI, oxygen desaturation index (ODI), mean O(2) saturation (mean O(2) sat), minimum O(2) saturation (min O(2) sat), sleep duration, and the percentages of NREM sleep stages 1-2 and 3 and of REM sleep were used for comparisons. The calculated DeltaPSG-Watch PAT of the two groups were compared statistically. The correlations between the PSG-Watch PAT measurements in each group were assessed. RESULTS: The comparison of AHI, REM AHI, NREM AHI, ODI, mean O(2) sat, min O(2) sat, NREM sleep stage 1-2, and REM sleep DeltaPSG-Watch PAT between the two groups did not reveal statistical significance. The difference between the two groups in terms of DeltaPSG-Watch PAT of sleep duration and sleep stage 3 was statistically significant. CONCLUSIONS: In addition to the good agreement confirmed between PSG and Watch PAT data in each group, aging did not negatively impact Watch PAT recorded data in terms of included parameters, except the difference in DeltaPSG-Watch PAT of sleep stage 3, which may be attributable to aging and impaired vascular tone. PMID- 22522751 TI - Human papillomavirus vaccine practices in the USA: do primary care providers use sexual history and cervical cancer screening results to make HPV vaccine recommendations? AB - OBJECTIVES: Guidelines recommend against the use of Papanicolaou (Pap) or human papillomavirus (HPV) testing when determining eligibility for the HPV vaccine. Optimally, the HPV vaccine should be administered before sexual initiation. Guidelines recommend that age-eligible women with past exposure to HPV should still be vaccinated. Little is known about how primary care providers (PCPs) use sexual history and HPV and Pap tests in their HPV vaccine recommendations. METHODS: Data from the 2007 Cervical Cancer Screening Supplement (CCSS) administered with the National Ambulatory Medical Care Survey (NAMCS) and the National Hospital Ambulatory Medical Care Survey (NHAMCS) were used to assess HPV vaccination recommendations. The CCSS investigates cervical cancer screening practices, HPV testing and HPV vaccine recommendations among PCPs. A summary measure of compliance with guidelines was defined as rarely or never using the number of sexual partners and HPV tests and Pap tests to determine vaccine receipt. A total of 421 PCPs completed the CCSS in 2007. RESULTS: Among NAMCS and NHAMCS providers who recommend the HPV vaccine, only 53% (95% CI 42% to 63%) reported making guideline-consistent recommendations. The majority reported sometimes to always recommending the HPV vaccine to women with a history of an abnormal Pap result (85%; 95% CI 75% to 91%) and a positive HPV test (79%; 95% CI 70% to 86%). CONCLUSIONS: A large proportion of providers report practices that are inconsistent with guidelines. Providers may also be recommending the vaccine to women who may receive little benefit from the vaccine. Provider and system level efforts to improve guideline-consistent practices are needed. PMID- 22522752 TI - Medical care for sexual assault victims. PMID- 22522753 TI - Stomachs: does the size matter? Aspects of intestinal satiety, gastric satiety, hunger and gluttony. PMID- 22522754 TI - Predictors of the risk of falls among elderly with chronic atrial fibrillation. AB - OBJECTIVES: Though elderly persons with chronic atrial fibrillation have more comorbidities that could limit indications for the chronic use of anticoagulants, few studies have focused on the risk of falls within this particular group. To evaluate the predictors of the risk of falls among elderly with chronic atrial fibrillation, a cross-sectional, observational study was performed. METHODS: From 295 consecutive patients aged 60 years or older with a history of atrial fibrillation who were enrolled within the last 2 years in the cardiogeriatrics outpatient clinic of the Instituto do Coracao do Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, 107 took part in this study. Their age was 77.9+/-6.4 years, and 62 were female. They were divided into two groups: a) no history of falls in the previous year and b) a history of one or more falls in the previous year. Data regarding the history of falls and social, demographic, anthropometric, and clinical information were collected. Multidimensional assessment instruments and questionnaires were applied. RESULTS: At least one fall was reported in 55 patients (51.4%). Among them, 27 (49.1%) presented recurrent falls, with body lesions in 90.4% and fractures in 9.1% of the cases. Multivariate logistic regression showed that self-reported difficulty maintaining balance, use of amiodarone, and diabetes were independent variables associated with the risk of falls, with a sensitivity of 92.9% and a specificity of 44.9%. CONCLUSION: In a group of elderly patients with chronic atrial fibrillation who were relatively independent and able to attend an outpatient clinic, the occurrence of falls with recurrence and clinical consequences was high. Difficulty maintaining balance, the use of amiodarone and a diagnosis of diabetes mellitus were independent predictors of the risk for falls. Thus, simple clinical data predicted falls better than objective functional tests. PMID- 22522755 TI - Chest computed tomography findings in severe influenza pneumonia occurring in neutropenic cancer patients. AB - OBJECTIVE: To describe the chest computed tomography findings for severe influenza H1N1 infection in a series of hospitalized neutropenic cancer patients. METHODS: We performed a retrospective systematic analysis of chest computed tomography scans for eight hospitalized patients with fever, neutropenia, and confirmed diagnoses of influenza H1N1. The clinical data had been prospectively collected. RESULTS: Six of eight patients (75%) developed respiratory failure and required intensive care. Prolonged H1N1 shedding was observed in the three mechanically ventilated patients, and overall hospital mortality in our series was 25%. The most frequent computed tomography findings were ground-glass opacity (all patients), consolidation (7/8 cases), and airspace nodules (6/8 cases) that were frequently moderate or severe. Other parenchymal findings were not common. Five patients had features of pneumonia, two had computed tomography findings compatible with bronchitis and/or bronchiolitis, and one had tomographic signs of chronicity. CONCLUSION: In this series of neutropenic patients with severe influenza H1N1 infection, chest computed tomography demonstrated mainly moderate or severe parenchymatous disease, but bronchiolitis was not a common feature. These findings associated with febrile neutropenia should elicit a diagnosis of severe viral infection. PMID- 22522756 TI - Daily activities are sufficient to induce dynamic pulmonary hyperinflation and dyspnea in chronic obstructive pulmonary disease patients. AB - OBJECTIVE: The aim of this study was to measure dynamic lung hyperinflation and its influence on dyspnea perception in moderate and severe chronic obstructive pulmonary disease patients after performing activities of daily living. METHODS: We measured inspiratory capacity, sensation of dyspnea, peripheral oxygen saturation, heart rate and respiratory rate in 19 chronic obstructive pulmonary disease patients. These measurements were taken at rest and after performing activities of daily living (e.g., going up and down a set of stairs, going up and down a ramp and sweeping and mopping a room). RESULT: The inspiratory capacity of patients at rest was significantly decreased compared to the capacity of patients after performing activities. The change in inspiratory capacity was -0.67 L after going up and down a ramp, -0.46 L after sweeping and mopping a room, and -0.55 L after climbing up and down a set of stairs. Dyspnea perception increased significantly between rest, sweeping and mopping, and going up and down a set of stairs. Dyspnea perception correlated positively with inspiratory capacity variation (r = 0.85) and respiratory rate (r = 0.37) and negatively with peripheral oxygen saturation (r = -0.28). CONCLUSION: Chronic obstructive pulmonary disease patients exhibited reductions in inspiratory capacity and increases in dyspnea perception during commonly performed activities of daily living, which may limit physical performance in these patients. PMID- 22522757 TI - The behavior and diagnostic utility of procalcitonin and five other inflammatory molecules in critically ill patients with respiratory distress and suspected 2009 influenza a H1N1 infection. AB - OBJECTIVES: During the 2009 influenza A H1N1 pandemic, it became difficult to differentiate viral infections from other conditions in patients admitted to the intensive care unit. We sought to evaluate the behavior and diagnostic utility of procalcitonin, C-reactive protein and four other molecules in patients with suspected 2009 Influenza A H1N1 infection. METHODS: The serum levels of procalcitonin, C-reactive protein, tumor necrosis factor alpha, interferon gamma, interleukin 1beta, and interleukin 10 were tested on admission and on days 3, 5, and 7 in 35 patients with suspected 2009 H1N1 infection who were admitted to two ICUs. RESULTS: Twelve patients had confirmed 2009 influenza A H1N1 infections, 6 had seasonal influenza infections, and 17 patients had negative swabs. The procalcitonin levels at inclusion and on day 3, and the C-reactive protein levels on day 3 were higher among subjects with 2009 influenza A H1N1 infections. The baseline levels of interleukin 1b were higher among the 2009 influenza A H1N1 patients compared with the other groups. The C-reactive protein levels on days 3, 5, and 7 and procalcitonin on days 5 and 7 were greater in non-surviving patients. CONCLUSION: Higher levels of procalcitonin, C-reactive protein and interleukin-1beta might occur in critically ill patients who had a 2009 H1N1 infection. Neither procalcitonin nor CRP were useful in discriminating severe 2009 H1N1 pneumonia. Higher levels of CRP and procalcitonin appeared to identify patients with worse outcomes. PMID- 22522758 TI - Endophenotypes and serotonergic polymorphisms associated with treatment response in obsessive-compulsive disorder. AB - OBJECTIVES: Approximately 40-60% of obsessive-compulsive disorder patients are nonresponsive to serotonin reuptake inhibitors. Genetic markers associated with treatment response remain largely unknown. We aimed (1) to investigate a possible association of serotonergic polymorphisms in obsessive-compulsive disorder patients and therapeutic response to selective serotonin reuptake inhibitors and (2) to examine the relationship between these polymorphisms and endocrine response to intravenous citalopram challenge in responders and non-responders to serotonin reuptake inhibitors and in healthy volunteers. METHODS: Patients with obsessive-compulsive disorder were classified as either responders or non responders after long-term treatment with serotonin reuptake inhibitors, and both groups were compared with a control group of healthy volunteers. The investigated genetic markers were the G861C polymorphism of the serotonin receptor 1Dbeta gene and the T102C and C516T polymorphisms of the serotonin receptor subtype 2A gene. RESULTS: The T allele of the serotonin receptor subtype 2A T102C polymorphism was more frequent among obsessive-compulsive disorder patients (responders and non responders) than in the controls (p<0.01). The CC genotype of the serotonin receptor subtype 2A C516T polymorphism was more frequent among the non-responders than in the responders (p<0.01). The CC genotype of the serotonin receptor subtype 1Dbeta G681C polymorphism was associated with higher cortisol and prolactin responses to citalopram (p<0.01 and p<0.001, respectively) and with a higher platelet-rich plasma serotonin concentration among the controls (p<0.05). However, this pattern was not observed in the non-responders with the same CC genotype after chronic treatment with serotonin reuptake inhibitors. This CC homozygosity was not observed in the responders. PMID- 22522759 TI - Psychological crisis intervention for the family members of patients in a vegetative state. AB - OBJECTIVES: Family members of patients in a vegetative state have relatively high rates of anxiety and distress. It is important to recognize the problems faced by this population and apply psychological interventions to help them. This exploratory study describes the psychological stress experienced by family members of patients in a vegetative state. We discuss the effectiveness of a psychological crisis intervention directed at this population and offer suggestions for future clinical work. METHODS: A total of 107 family members of patients in a vegetative state were included in the study. The intervention included four steps: acquisition of facts about each family, sharing their first thoughts concerning the event, assessment of their emotional reactions and developing their coping abilities. The Symptom Check List-90 was used to evaluate the psychological distress of the participants at baseline and one month after the psychological intervention. Differences between the Symptom Check List-90 scores at the baseline and follow-up evaluations were analyzed. RESULTS: All participants in the study had significantly higher Symptom Check List-90 factor scores than the national norms at baseline. There were no significant differences between the intervention group and the control group at baseline. Most of the Symptom Check List-90 factor scores at the one-month follow-up evaluation were significantly lower than those at baseline for both groups; however, the intervention group improved significantly more than the control group on most subscales, including somatization, obsessive-compulsive behavior, depression, and anxiety. CONCLUSION: The results of this study indicate that the four-step intervention method effectively improves the mental health of the family members who received this treatment and lessens the psychological symptoms of somatization, obsessive-compulsive behavior, depression and anxiety. PMID- 22522760 TI - Plasma kinetics of an LDL-like nanoemulsion and lipid transfer to HDL in subjects with glucose intolerance. AB - OBJECTIVE: Glucose intolerance is frequently associated with an altered plasma lipid profile and increased cardiovascular disease risk. Nonetheless, lipid metabolism is scarcely studied in normolipidemic glucose-intolerant patients. The aim of this study was to investigate whether important lipid metabolic parameters, such as the kinetics of LDL free and esterified cholesterol and the transfer of lipids to HDL, are altered in glucose-intolerant patients with normal plasma lipids. METHODS: Fourteen glucose-intolerant patients and 15 control patients were studied; none of the patients had cardiovascular disease manifestations, and they were paired for age, sex, race and co-morbidities. A nanoemulsion resembling a LDL lipid composition (LDE) labeled with 14C cholesteryl ester and 3H-free cholesterol was intravenously injected, and blood samples were collected over a 24-h period to determine the fractional clearance rate of the labels by compartmental analysis. The transfer of free and esterified cholesterol, triglycerides and phospholipids from the LDE to HDL was measured by the incubation of the LDE with plasma and radioactivity counting of the supernatant after chemical precipitation of non-HDL fractions. RESULTS: The levels of LDL, non-HDL and HDL cholesterol, triglycerides, apo A1 and apo B were equal in both groups. The 14C-esterified cholesterol fractional clearance rate was not different between glucose-intolerant and control patients, but the 3H free-cholesterol fractional clearance rate was greater in glucose-intolerant patients than in control patients. The lipid transfer to HDL was equal in both groups. CONCLUSION: In these glucose-intolerant patients with normal plasma lipids, a faster removal of LDE free cholesterol was the only lipid metabolic alteration detected in our study. This finding suggests that the dissociation of free cholesterol from lipoprotein particles occurs in normolipidemic glucose intolerance and may participate in atherogenic signaling. PMID- 22522761 TI - The impact of pretransplant donor-specific antibodies on graft outcome in renal transplantation: a six-year follow-up study. AB - OBJECTIVE: The significance of pretransplant, donor-specific antibodies on long term patient outcomes is a subject of debate. This study evaluated the impact and the presence or absence of donor-specific antibodies after kidney transplantation on short- and long-term graft outcomes. METHODS: We analyzed the frequency and dynamics of pretransplant donor-specific antibodies following renal transplantation from a randomized trial that was conducted from 2002 to 2004 and correlated these findings with patient outcomes through 2009. Transplants were performed against a complement-dependent T- and B-negative crossmatch. Pre- and posttransplant sera were available from 94 of the 118 patients (80%). Antibodies were detected using a solid-phase (Luminex(r)), single-bead assay, and all tests were performed simultaneously. RESULTS: Sixteen patients exhibited pretransplant donor-specific antibodies, but only 3 of these patients (19%) developed antibody mediated rejection and 2 of them experienced early graft losses. Excluding these 2 losses, 6 of 14 patients exhibited donor-specific antibodies at the final follow-up exam, whereas 8 of these patients (57%) exhibited complete clearance of the donor-specific antibodies. Five other patients developed ''de novo'' posttransplant donor-specific antibodies. Death-censored graft survival was similar in patients with pretransplant donor-specific and non-donor-specific antibodies after a mean follow-up period of 70 months. CONCLUSION: Pretransplant donor-specific antibodies with a negative complement-dependent cytotoxicity crossmatch are associated with a risk for the development of antibody-mediated rejection, although survival rates are similar when patients transpose the first months after receiving the graft. Our data also suggest that early posttransplant donor-specific antibody monitoring should increase knowledge of antibody dynamics and their impact on long-term graft outcome. PMID- 22522762 TI - A proton nuclear magnetic resonance-based metabonomics study of metabolic profiling in immunoglobulin a nephropathy. AB - OBJECTIVES: Immunoglobulin A nephropathy is the most common cause of chronic renal failure among primary glomerulonephritis patients. The ability to diagnose immunoglobulin A nephropathy remains poor. However, renal biopsy is an inconvenient, invasive, and painful examination, and no reliable biomarkers have been developed for use in routine patient evaluations. The aims of the present study were to identify immunoglobulin A nephropathy patients, to identify useful biomarkers of immunoglobulin A nephropathy and to establish a human immunoglobulin A nephropathy metabolic profile. METHODS: Serum samples were collected from immunoglobulin A nephropathy patients who were not using immunosuppressants. A pilot study was undertaken to determine disease-specific metabolite biomarker profiles in three groups: healthy controls (N = 23), low risk patients in whom immunoglobulin A nephropathy was confirmed as grades I-II by renal biopsy (N = 23), and high-risk patients with nephropathies of grades IV V (N = 12). Serum samples were analyzed using proton nuclear magnetic resonance spectroscopy and by applying multivariate pattern recognition analysis for disease classification. RESULTS: Compared with the healthy controls, both the low risk and high-risk patients had higher levels of phenylalanine, myo-Inositol, lactate, L6 lipids ( = CH-CH2-CH = O), L5 lipids (-CH2-C = O), and L3 lipids ( CH2-CH2-C = O) as well as lower levels of beta -glucose, alpha-glucose, valine, tyrosine, phosphocholine, lysine, isoleucine, glycerolphosphocholine, glycine, glutamine, glutamate, alanine, acetate, 3-hydroxybutyrate, and 1-methylhistidine. CONCLUSIONS: These metabolites investigated in this study may serve as potential biomarkers of immunoglobulin A nephropathy. Point scoring of pattern recognition analysis was able to distinguish immunoglobulin A nephropathy patients from healthy controls. However, there were no obvious differences between the low-risk and high-risk groups in our research. These results offer new, sensitive and specific, noninvasive approaches that may be of great benefit to immunoglobulin A nephropathy patients by enabling earlier diagnosis. PMID- 22522763 TI - Influence of food restriction on lipid profile and spontaneous glucose levels in male rats subjected to paradoxical sleep deprivation. AB - OBJECTIVES: The purpose of this study was to determine the paired consequences of food restriction and paradoxical sleep deprivation on lipid profile and spontaneous glucose levels in male rats. METHOD: Food restriction began at weaning, with 6 g of food being provided per day, which was subsequently increased by 1 g per week until reaching 15 g per day by the eighth week. At adulthood, both rats subjected to food restriction and those fed ad libitum were exposed to paradoxical sleep deprivation for 96 h or were maintained in their home-cage groups. RESULTS: Animals subjected to food restriction exhibited a significant increase in high-density lipoprotein levels compared to animals that were given free access to food. After the paradoxical sleep deprivation period, the food-restricted animals demonstrated reduced concentrations of high-density lipoprotein relative to their respective controls, although the values for the food-restricted animals after sleep deprivation were still higher than those for the ad libitum group. The concentration of low-density lipoproteins was significantly increased in sleep-deprived animals fed the ad libitum diet. The levels of triglycerides, very low-density lipoproteins, and glucose in food restricted animals were each decreased compared to both ad libitum groups. CONCLUSION: These results may help to illustrate the mechanisms underlying the relationship between sleep curtailment and metabolism and may suggest that, regardless of sleep deprivation, dietary restriction can minimize alterations in parameters related to cardiovascular risk. PMID- 22522764 TI - Anesthesia-related mortality in pediatric patients: a systematic review. AB - This systematic review of the Brazilian and worldwide literature aimed to evaluate the incidence and causes of perioperative and anesthesia-related mortality in pediatric patients. Studies were identified by searching EMBASE (1951-2011), PubMed (1966-2011), LILACS (1986-2011), and SciElo (1995-2011). Each paper was revised to identify the author(s), the data source, the time period, the number of patients, the time of death, and the perioperative and anesthesia related mortality rates. Twenty trials were assessed. Studies from Brazil and developed countries worldwide documented similar total anesthesia-related mortality rates (<1 death per 10,000 anesthetics) and declines in anesthesia related mortality rates in the past decade. Higher anesthesia-related mortality rates (2.4-3.3 per 10,000 anesthetics) were found in studies from developing countries over the same time period. Interestingly, pediatric perioperative mortality rates have increased over the past decade, and the rates are higher in Brazil (9.8 per 10,000 anesthetics) and other developing countries (10.7-15.9 per 10,000 anesthetics) compared with developed countries (0.41-6.8 per 10,000 anesthetics), with the exception of Australia (13.4 per 10,000 anesthetics). The major risk factors are being newborn or less than 1 year old, ASA III or worse physical status, and undergoing emergency surgery, general anesthesia, or cardiac surgery. The main causes of mortality were problems with airway management and cardiocirculatory events. Our systematic review of the literature shows that the pediatric anesthesia-related mortality rates in Brazil and in developed countries are similar, whereas the pediatric perioperative mortality rates are higher in Brazil compared with developed countries. Most cases of anesthesia-related mortality are associated with airway and cardiocirculatory events. The data regarding anesthesia-related and perioperative mortality rates may be useful in developing prevention strategies. PMID- 22522765 TI - Castration-resistant prostate cancer: systemic therapy in 2012. AB - Prostate cancer is the most common non-cutaneous neoplasm in the male population worldwide. It is typically diagnosed in its early stages, and the disease exhibits a relatively indolent course in most patients. Despite the curability of localized disease with prostatectomy and radiation therapy, some patients develop metastatic disease and die. Although androgen deprivation is present in the majority of patients with metastatic prostate cancer, a state of androgen resistance eventually develops. Castration-resistant prostate cancer, defined when there is progression of disease despite low levels of testosterone, requires specialized care, and improved communication between medical and urologic oncologists has been identified as a key component in delivering effective therapy. Despite being considered a chemoresistant tumor in the past, the use of a prostate-specific antigen has paved the way for a new generation of trials for castration-resistant prostate cancer. Docetaxel is a life-prolonging chemotherapy that has been established as the standard first-line agent in two phase III clinical trials. Cabazitaxel, a novel taxane with activity in cancer models resistant to paclitaxel and docetaxel, is the only agent that has been compared to a chemotherapy control in a phase III clinical trial as a second-line therapy; it was found to prolong the overall survival of patients with castration resistant prostate cancer previously treated with docetaxel when compared to mitoxantrone. Other agents used in this setting include abiraterone and sipuleucel-T, and novel therapies are continually being investigated in an attempt to improve the outcome for patients with castration-resistant prostate cancer. PMID- 22522766 TI - DEFB1 gene 5' untranslated region (UTR) polymorphisms in inflammatory bowel diseases. PMID- 22522767 TI - Assessment of organ transplants from donors with markers of hepatitis B. PMID- 22522768 TI - Scurvy in an alcoholic malnourished cirrhotic man with spontaneous bacterial peritonitis. PMID- 22522769 TI - Emergencies in dermatology outpatient clinics: our experience in Spain. PMID- 22522771 TI - The effect of women's decision-making power on maternal health services uptake: evidence from Pakistan. AB - A large body of research has explored the links between women's decision making and their uptake of maternal health services, but the evidence so far is inconclusive. This study uses the Pakistan Social and Living Standards Measurement Survey to examine the influence of household decision making on women's uptake of maternal health services. We find that women's decision-making power has a significant positive correlation with maternal health services uptake and that influential males' decision-making power has the opposite effect, after controlling for socio-economic indicators and supply-side conditions. Our findings suggest that empowering women and increasing their ability to make decisions may increase their uptake of maternal health services. They also suggest that policies directed toward improving women's utilization of maternal health services in Pakistan must target men as well as women. PMID- 22522770 TI - Provider payment in community-based health insurance schemes in developing countries: a systematic review. AB - OBJECTIVES: Community-based health insurance (CBI) is a common mechanism to generate financial resources for health care in developing countries. We review for the first time provider payment methods used in CBI in developing countries and their impact on CBI performance. METHODS: We conducted a systematic review of the literature on provider payment methods used by CBI in developing countries published up to January 2010. RESULTS: Information on provider payment was available for a total of 32 CBI schemes in 34 reviewed publications: 17 schemes in South Asia, 10 in sub-Saharan Africa, 4 in East Asia and 1 in Latin America. Various types of provider payment were applied by the CBI schemes: 17 used fee for-service, 12 used salaries, 9 applied a coverage ceiling, 7 used capitation and 6 applied a co-insurance. The evidence suggests that provider payment impacts CBI performance through provider participation and support for CBI, population enrolment and patient satisfaction with CBI, quantity and quality of services provided and provider and patient retention. Lack of provider participation in designing and choosing a CBI payment method can lead to reduced provider support for the scheme. CONCLUSION: CBI schemes in developing countries have used a wide range of provider payment methods. The existing evidence suggests that payment methods are a key determinant of CBI performance and sustainability, but the strength of this evidence is limited since it is largely based on observational studies rather than on trials or on quasi-experimental research. According to the evidence, provider payment can affect provider participation, satisfaction and retention in CBI; the quantity and quality of services provided to CBI patients; patient demand of CBI services; and population enrollment, risk pooling and financial sustainability of CBI. CBI schemes should carefully consider how their current payment methods influence their performance, how changes in the methods could improve performance, and how such effects could be assessed with scientific rigour to increase the strength of evidence on this topic. PMID- 22522772 TI - The presence of IL-17+/FOXP3+ double-positive cells in periodontitis. AB - Increasing evidence suggests that distinct inflammatory cytokines convert forkhead box protein P3 (FOXP3(+)) regulatory T-cells (Tregs) into IL-17 producing cells (Th17 cells) in vitro. However, this functional plasticity has not been examined in the pathogenesis of periodontal disease. In this study, we analyzed the IL-17A(+)FOXP3(+) cells present in periodontitis lesions to determine the association between Treg conversion and the pathogenesis of periodontitis. The immunohistochemical analysis of gingival tissues demonstrated that the numbers of Th17 cells (IL-17A(+)FOXP3(-)) and Tregs (IL-17A(-)FOXP3(+)) were greater in periodontitis lesions than in gingivitis lesions. We further identified a small number of IL-17A(+)FOXP3(+) cells in periodontitis lesions but not in gingivitis lesions. The flow cytometry analysis of CD4(+) T-cell lines established from gingival tissues and the peripheral blood of periodontitis patients showed that the proportion of Tregs was reduced and the proportion of IL 17A(+)FOXP3(+) cells among all FOXP3(+) cells was elevated in gingival tissue T cell lines relative to the proportions in peripheral blood T-cell lines. Our findings indicate that Treg-Th17 conversion may occur in periodontitis lesions. Further studies addressing the role of Treg conversion during inflammatory responses against periodontopathic bacteria are needed. PMID- 22522773 TI - DNA demethylating agent decitabine increases AQP5 expression and restores salivary function. AB - Xerostomia is the symptom of oral dryness resulting most frequently, but not exclusively, from salivary gland hypofunction. Because the prevalence of xerostomia may increase with age, it has multiple oral health consequences in aging populations. In the present study, we demonstrate that the in vivo administration of 5-aza-2'-deoxycytidine (5-Aza-CdR; decitabine), a DNA demethylating agent, to the murine aging model C57BL/6CrSlc mice (24 wks old) increased the volumes of salivary flow compared with those of control mice. Western blot analysis and immunohistochemical staining demonstrated the augmented expression of AQP5 protein in the salivary glands of 5-Aza-CdR-treated mice compared with those of control mice. In addition, AQP5 protein expression levels in 5-Aza-CdR-treated old mice (27 wks old) were much higher than those in untreated and young mice (6 wks old). Global methylation levels in the salivary glands were significantly lower in the 5-Aza-CdR-treated mice than in the untreated mice. Moreover, the induction of demethylation in the AQP5 promoter of 5-Aza-CdR-treated mice was stronger than in the control mice. Analysis of our data therefore suggests that a DNA demethylating agent may be a useful drug for restoring hyposalivation in elderly individuals, thereby leading to the resolution of xerostomia. PMID- 22522774 TI - Muscle organization in individuals with and without pain and joint dysfunction. AB - Central nervous system organization of masticatory muscles determines the magnitude of joint and muscle forces. Validated computer-assisted models of neuromuscular organization during biting were used to determine organization in individuals with and without temporomandibular disorders (TMD). Ninety-one individuals (47 women, 44 men) were assigned to one of four diagnostic groups based on the presence (+) or absence (-) of pain (P) and bilateral temporomandibular joint disc displacement (DD). Electromyography and bite-forces were measured during right and left incisor and molar biting. Two three dimensional models employing neuromuscular objectives of minimization of joint loads (MJL) or muscle effort (MME) simulated biting tasks. Evaluations of diagnostic group and gender effects on choice of best-fit model were by analysis of variance (ANOVA) and Tukey-Kramer post hoc tests, evaluations of right-left symmetry were by Chi-square and Fisher's exact statistics, and evaluations of model accuracy were by within-subject linear regressions. MME was the best-fit during left molar biting in +DD individuals and incisor biting in men (all p < 0.03). Incisor biting symmetry in muscle organization was significantly higher (p < 0.03) in healthy individuals compared with those with TMD. Within-subject regressions showed that best-fit model errors were similar among groups: 8 to 15% (0.68 <= R(2) <= 0.74). These computer-assisted models predicted muscle organization during static biting in humans with and without TMDs. PMID- 22522776 TI - Dyspnoea and mortality in older people in the community: a 10-year follow-up. AB - BACKGROUND: examine baseline dyspnoea and subsequent 10-year mortality adjusting for age and gender and determine whether dyspnoea is related to early or late mortality or both. Examine the relationship between dyspnoea and mortality adjusting for confounding effects of underlying diseases. METHODS: we sent modified Medical Research Council (MRC) dyspnoea questionnaire to identify breathlessness in 1,404 randomly selected subjects from general practitioner lists of 5,002 subjects aged 70 years and over living in the community. A further random sample of 500 subjects underwent clinical assessment including pulmonary function tests, electrocardiography and echocardiography. Subjects were followed up for 10 years and all deaths were recorded, using general practitioner records and the local death registry. RESULTS: prevalence of dyspnoea was 32.3%. Breathlessness was associated with early mortality and late mortality. At 2 years 10.1% breathless subjects died compared with 3.4% non-breathless (P=0.02). At 10 years 63.3% breathless had died compared with 40.5% non-breathless (P=0.0001). Increasing grade of MRC dyspnoea was associated with 10 mortality. Advancing age (OR: 2.27), male gender (OR: 1.95), breathlessness (OR: 2.53), left ventricular dysfunction (OR: 5.01) and chronic airways disease (OR: 3.04) were all significantly associated with 10-year mortality. After adjustment of age, gender and underlying diseases breathlessness was associated with 10-year mortality (P=0.02). CONCLUSION: dyspnoea is a predictor of early and late mortality and increasing grade of dyspnoea is associated with a higher rate of mortality. Dyspnoea is an independent risk factor for mortality after adjustment for age, gender and underlying diseases. PMID- 22522775 TI - The frailty index in Europeans: association with age and mortality. AB - BACKGROUND: the frailty index (FI) is an approach to the operationalisation of frailty based on accumulation of deficits. It has been less studied in Europeans. OBJECTIVE: to construct sex-specific FIs from a large sample of Europeans and study their associations with age and mortality. DESIGN: longitudinal population based survey. SETTING: the Survey of Health, Ageing and Retirement in Europe (SHARE, http://share-dev.mpisoc.mpg.de/). SUBJECTS: a total of 16,217 females and 13,688 males aged >=50 from wave 1 (2004-05). Mortality data were collected between 2005 and 2006 (mean follow-up: 2.4 years). METHODS: regression curve estimations between age and an FI constructed as per the standard procedure. Logistic regressions were used to assess the relative effects of age and the FI towards mortality. RESULTS: in both sexes, there was a significant non-linear association between age and the FI (females: quadratic R(2) = 0.20, P < 0.001; males: quadratic R(2) = 0.14, P < 0.001). Overall, the FI was a much stronger predictor of mortality than age, even after adjusting for the latter (females: age-adjusted OR 100.5, 95% confidence interval (CI): 46.3-218.2, P < 0.001; males: age-adjusted OR 221.1, 95% CI: 106.7-458.4, P < 0.001). CONCLUSION: the FI had the expected properties in this large sample of Europeans. PMID- 22522777 TI - Isolation and characterization of melanopsin photoreceptors of Atlantic salmon (Salmo salar). AB - Melanopsins constitute a recently described group of vertebrate opsin photoreceptors that are involved in nonvisual photoreception. Here we describe the identification of six melanopsin genes of Atlantic salmon (Salmo salar), a valuable teleost model for studying nonvisual photoreception and the basis of photoperiodism. The results show that genes belonging to two different groups, the mammalian-like (Opn4m) and the Xenopus-like (Opn4x) melanopsins have been duplicated in teleosts. In addition, two pairs of salmon duplicates were identified, presumably originating from the salmon lineage whole genome duplication event. The expression pattern of melanopsins was studied by in situ hybridization. The results show that Opn4m and Opn4x melanopsins are differentially expressed in the brain and retina, indicating a functional divergence. In the retina, Opn4m and Opn4x melanopsin are differentially expressed in ganglion, amacrine, and horizontal cells. In the brain, Opn4m is expressed in the dorsal thalamus and in the nucleus lateralis tuberis of the hypothalamus, which is closely connected to and involved in the regulation of pituitary function. Opn4x melanopsins are expressed in the dopaminergic, hypophysiotrophic cell population of the suporaoptic/chiasmatic nucleus and in the serotonergic cell population of the left habenula. The results suggest that melanopsin photoreceptors can be involved in signaling of photoperiodic information through multiple pathways, involving both the retina and possibly as deep-brain photoreceptors directly transmitting photoperiodic information to the hypothalamus-pituitary axis. PMID- 22522779 TI - Allogeneic bone marrow grafts with high levels of CD4(+) CD25(+) FoxP3(+) T cells can lead to engraftment failure. AB - Regulatory CD4(+) CD25(+) FoxP3(+) T cells (T(regs) ) suppress immunological reactions. However, the effect of adding T(regs) to hematopoietic stem cell grafts on recovery and graft versus host disease (GvHD) is unknown. T(regs) from splenocytes of C57Bl/6 and Balb/c wild-type mice were isolated by MACS separation and analyzed by flow cytometry. Using a murine syngeneic transplantation model that clearly distinguishes between donor and host hematopoiesis, we showed that co-transplantation of bone marrow cells (BMCs) with high levels of T(regs) leads to a 100% survival of the mice and accelerates the hematopoietic recovery significantly (full donor chimerism). In allogeneic transplantation, bone marrow and T(regs) co-transplantation were compared to allogeneic bone marrow transplantation with or without the addition of splenocytes. Survival, leukocyte recovery, chimerism at days -2, 19, 33, and 61 for murine CD4, human CD4, HLA DR3, murine CD3, murine CD8, murine Balb/c-H2K(d) , murine C57Bl/6-H2K(b) , and GvHD appearance were analyzed. Allogeneic bone marrow transplantation requires the addition of splenocytes to reach engraftment. Mice receiving grafts with bone marrow, splenocytes and high levels of allogeneic T(regs) died within 28 days (hematopoietic failure). Here, we show also detailed flow cytometric data reagarding analysis of chimerism after transplantation in unique murine hematopoietic stem cell transplantation models. Our findings showed that the syngeneic co-transplantation of CD4(+) , CD25(+) , FoxP3(+) T-cells and BMCs induced a stimulating effect on reconstitution of hematopoiesis after irradiation. However, in the allogeneic setting the co-transplantation of T(regs) aggravates the engraftment of transplanted cells. PMID- 22522778 TI - Effects of metformin plus rosuvastatin on hyperandrogenism in polycystic ovary syndrome patients with hyperlipidemia and impaired glucose tolerance. AB - AIM: We aimed to compare the effects of metformin and metformin-rosuvastatin combination therapies on hyperandrogenism in patients with polycystic ovary syndrome (PCOS). PATIENTS AND METHODS: Thirty-eight PCOS patients with hyperlipidemia and impaired glucose tolerance, who were followed at Department of Endocrinology and Metabolism out-patient clinic of Cerrahpasa Medical School were included in the study. Twenty patients had lifestyle changes and metformin (2000 mg/day) therapy (M group) and 18 had statin (rosuvastatin 10 mg/day) in addition to this therapy (MR group). Total and free testosterone, DHEAS, FSH, LH, estrodiol, fasting glucose, insulin, and high-sensitivity C-reactive protein (hs CRP) levels, lipid parameters and homeostasis model assesment index (HOMAIR) were evaluated for each patient before and 12 weeks after the treatment. RESULTS: After 12 weeks of treatment body mass index (BMI), insulin and glucose levels, HOMA-IR had similar decreaments in both groups, whereas there was a greater decline of the total and free testosterone levels in MR group (p<0.001, p=0.004, respectively). DHEAS levels did not change in M group, however, significantly decreased in MR group after treatment (p=0.8, p=0.002, respectively). As expected hsCRP, triglyceride, total and LDL-cholesterol levels decreased more in MR group. CONCLUSION: Metformin and rosuvastatin combination therapy could lead to a better reduction on hyperandrogenism and on atherosclerosis-related factors in PCOS, in addition to improving lipid parameters. PMID- 22522780 TI - From cosmic chirality to protein structure: Lord Kelvin's legacy. AB - A selection of my work on chirality is sketched in two distinct parts of this lecture. Symmetry and Chirality explains how the discrete symmetries of parity P, time reversal T, and charge conjugation C may be used to characterize the properties of chiral systems. The concepts of true chirality (time-invariant enantiomorphism) and false chirality (time-noninvariant enantiomorphism) that emerge provide an extension of Lord Kelvin's original definition of chirality to situations where motion is an essential ingredient thereby clarifying, inter alia, the nature of physical influences able to induce absolute enantioselection. Consideration of symmetry violations reveals that strict enantiomers (exactly degenerate) are interconverted by the combined CP operation. Raman optical activity surveys work, from first observation to current applications, on a new chiroptical spectroscopy that measures vibrational optical activity via Raman scattering of circularly polarized light. Raman optical activity provides incisive information ranging from absolute configuration and complete solution structure of smaller chiral molecules and oligomers to protein and nucleic acid structure of intact viruses. PMID- 22522781 TI - On-chip continuous monitoring of motile microorganisms on an ePetri platform. AB - Self-imaging Petri dish platforms with microscopy resolution, which we term 'ePetri', can significantly streamline cell cultures and/or other longitudinal biological studies. In this paper, we demonstrate high-resolution imaging and long-term culture of motile microorganisms in a specialized ePetri platform by taking advantage of the inherent motion. By applying a super-resolution algorithm to a set of low-resolution images of the microorganisms as they move across the sensing area of a complementary metal oxide semiconductor (CMOS) image sensor chip, we can render an improved-resolution image of the microorganisms. We perform a longitudinal study of Euglena gracilis cultured in an ePetri platform, and image-based analysis on the motion and morphology of the cells. As a miniaturized and automated culture monitoring platform, this ePetri technology can greatly improve studies and experiments with motile microorganisms. PMID- 22522782 TI - The interplay between thiol-compounds against chromium (VI) in the freshwater green alga Monoraphidium convolutum: toxicology, photosynthesis, and oxidative stress at a glance. AB - In this paper, the multifaceted Cr(VI) toxicity over the freshwater green alga Monoraphidium convolutum was assessed by concomitantly monitoring thiol-dependent redox balances, photosynthesis activity and growth-survival scores. Control group showed exponential growth rate at (5.78+/-0.29) division/day until 8th day with linear increasing chlorophyll a/protein ratios (CHLa/PROT) throughout the period. Cultures of M. convolutum were exposed for 5 days to Cr(VI) concentrations from 0 up to 100mg/L showing that CHLa/PROT ratios were sensibly affected, in agreement to the calculated LC(50,48 h) (5.38+/-0.72) mg/L from the concentration-response curve of cell mortality after 48 h. Regarding photosynthesis effects, Cr(VI) concentrations >1.0 mg/L showed significant increases in short-term (after 2 h) electron transfer rates (ETR) and quantum yields of photosystem II (Phi(PSII)), followed by subsequent decline of both parameters after 48 and 72 h. Biochemical analyses showed that maximal GSH concentrations in algal cultures were observed upon 1mg Cr(VI)/L and higher dichromate concentrations dramatically increased the activity of antioxidant GSH-dependent enzymes ascorbate peroxidase and glutathione reductase. However, no variation was observed in the cellular GSH levels, whereas GSSG and lipid peroxidation indexes abruptly increased upon 10 mg Cr(VI)/L exposure. Altogether, plant physiology, photosynthesis and biochemical data suggest that the GSH-dependent antioxidant system is capable to sustain M. convolutum viability through efficient photosynthesis activity and adequate antioxidant responses up to Cr(VI) concentrations of 1.0mg/L, when redox unbalances were first evidenced. PMID- 22522783 TI - Evidence for a left-over-right inhibitory mechanism during figural creative thinking in healthy nonartists. AB - As a complex mental process, creativity requires the coordination of multiple brain regions. Previous pathological research on figural creativity has indicated that there is a mechanism by which the left side of the brain inhibits the activities of the right side of the brain during figural creative thinking, but this mechanism has not been directly demonstrated. In this study, we used functional magnetic resonance imaging (fMRI) to demonstrate the existence of this inhibitory mechanism in young adults (15 women, 11 men, mean age: 22 years) that were not artists. By making comparisons between brain activity during creative and uncreative tasks, we found increased activity in the left middle and inferior frontal lobe and strong decreases in activity in the right middle frontal lobe and the left inferior parietal lobe. As such, these data suggest that the left frontal lobe may inhibit the right hemisphere during figural creative thinking in normal people. Moreover, removal of this inhibition by practicing artistry or through specific damage to the left frontal lobe may facilitate the emergence of artistic creativity. PMID- 22522784 TI - Identification and expression profiles of nine glutathione S-transferase genes from the important rice phloem sap-sucker and virus vector Laodelphax striatellus (Fallen) (Hemiptera: Delphacidae). AB - BACKGROUND: Glutathione S-transferases (GSTs) have received considerable attention in insects for their roles in insecticide resistance. Laodelphax striatellus (Fallen) is a serious rice pest. L. striatellus outbreaks occur frequently throughout eastern Asia. A key problem in controlling this pest is its rapid adaptation to numerous insecticides. In this research, nine cDNAs encoding GSTs in L. striatellus were cloned and characterised. RESULTS: The cloned GSTs of L. striatellus belonged to six cytosolic classes and a microsomal subgroup. Exposure to sublethal concentrations of each of the six insecticides, DDT, chlorpyrifos, fipronil, imidacloprid, buprofezin and beta-cypermethrin, quickly induced (6 h) up-expression of LsGSTe1. The expression of LsGSTs2 was increased by chlorpyrifos, fipronil and beta-cypermethrin. Furthermore, exposure of L. striatellus to fipronil, imidacloprid, buprofezin and beta-cypermethrin increased the expression of the LsGSTm gene after 24 or 48 h. CONCLUSION: This work is the first identification of GST genes from different GST groups in Auchenorrhyncha species and their induction characteristics with insecticide types and time. The elevated expression of GST genes induced by insecticides might be related to the enhanced tolerance of this insect to insecticides and xenobiotics. PMID- 22522785 TI - Effects of an educational back care program on Brazilian schoolchildren's knowledge regarding back pain prevention. AB - BACKGROUND: Children are often exposed to ergonomic risk factors at school. Thus, the school is a potential environment for developing musculoskeletal disorders and implementing back care programs. OBJECTIVES: To evaluate the effect of an educational program on schoolchildren's knowledge regarding back pain prevention. METHODS: 392 students from 4th to 8th grade from a Brazilian state school took part in the study; 114 students (30%) were evaluated at follow-up. The back care program included pre- and post-intervention assessments and a follow-up assessment, as well as theoretical and practical lessons. The time interval between the pre- and post-intervention assessments was 9 weeks, and between the post-intervention and follow-up assessments, it was 2 years. Statistical analysis included non-parametric ANOVA tests. Significance level was set at 5% (p<0.05). RESULTS: There was a significant increase (p<0.001) between pre- (3.6+/-2.9) and postintervention (7.5+/-2.2) scores and a significant decrease in the follow-up score (5.1+/-2.5). However, the follow-up score was still significantly higher (p<0.001) than the pre-intervention score. The rate of correct answers in the post-intervention assessment increased for all questions, and some of them were still high at follow-up. Significant differences were identified for the comparison between grades, with the 8th grade being significantly different from the other grades. CONCLUSION: The back care program showed an increase in the level of knowledge of Brazilian schoolchildren. Two years after the intervention, students still retained ergonomic concepts. Although the program has limitations, theoretical knowledge acquisition is the first step towards adopting healthy postural habits to prevent back pain. PMID- 22522786 TI - Do muscle strengthening exercises improve performance in the 6-minute walk test in postmenopausal women? AB - BACKGROUND: Walking speed seems to be related to aerobic capacity, lower limb strength, and functional mobility, however it is not clear whether there is a direct relationship between improvement in muscle strength and gait performance in early postmenopausal women. OBJECTIVE: To evaluate the effect of muscle strengthening exercises on the performance of the 6-minute walk test in women within 5 years of menopause. METHODS: The women were randomized into control group (n=31), which performed no exercise, and exercise group (n=27), which performed muscle strengthening exercises. The exercises were performed twice a week for 3 months. The exercise protocol consisted of warm-up, stretching, and strengthening of the quadriceps, hamstring, calf, tibialis anterior, gluteus maximus, and abdominal muscles, followed by relaxation. Muscular strength training started with 60% of 1MR (2 series of 10-15 repetitions), reaching 85% until the end of the 3-month period (4 series of 6 repetitions each). RESULTS: The between-group comparisons pre- and post-intervention did not show any difference in distance walked, heart rate or blood pressure (p>0.05), but showed differences in muscle strength post-intervention, with the exercise group showing greater strength (p CONCLUSION: The results suggest that muscle strengthening of the lower limbs did not improve performance in the 6-minute walk test in this population of postmenopausal women. PMID- 22522788 TI - Stewart-Treves syndrome arising in patients with lymphaticovenular anastomosis for chronic lymphedema of the leg. PMID- 22522787 TI - LOSS of Mrp1 alters detoxification enzyme expression in a tissue- and hormonal status-specific manner. AB - The multidrug resistance-associated protein1 (MRP1/ABCC1) is a member of the ABCC transporter subfamily that mediates the efflux of pharmaceuticals, xenobiotics and steroid hormones, typically as glutathione, glucuronide or sulfate conjugates. Since loss of one transporter can be compensated by increasing the expression of other transporters and conjugation enzymes, we sought to examine compensatory changes in phase I, II and III enzyme expression in extrahepatic tissues, including the kidney, lungs and small intestine of intact or castrated Mrp1(-/-) male mice. In the kidney, the expression of several P450s, sulfotransferase 1a1 (Sult), glucuronosyltransferases (Ugt) and Mrps2-4, were significantly changed owing to castration alone. The only time genotype mattered was between the castrated FVB and Mrp1 knockout mice. In contrast, expression of the Ugts, Sult 1a1 and Mrp3 in the lungs was significantly downregulated in the Mrp1 knockout mice, so based exclusively on genotype. In the small intestine, there were interactions between steroid hormone levels and genotype, as the expression differences were only found in mice lacking Mrp1, and were changed between intact and castrated animals. The mechanism behind this pattern of expression may be to due to Nrf2 regulation, as its expression mirrors that of the phase II and phase III enzymes. These results indicate that compensatory responses owing to the loss of Mrp1 vary dramatically, depending on the particular tissue. This information will aid in the understanding of how drug uptake, disposition and elimination can be influenced by both hormone status and the presence and magnitude of transporter expression. PMID- 22522789 TI - Multiple myeloma induces the immunosuppressive capacity of distinct myeloid derived suppressor cell subpopulations in the bone marrow. PMID- 22522790 TI - Systemic microRNA-34a delivery induces apoptosis and abrogates growth of diffuse large B-cell lymphoma in vivo. PMID- 22522791 TI - Evidence for a protective role of the STAT5 transcription factor against oxidative stress in human leukemic pre-B cells. AB - STAT5 transcription factors are involved in normal B lymphocyte development and in leukemogenesis. We show that the inhibition of STAT5A expression or activity in the NALM6, 697 and Reh leukemic pre-B cell lines, results in a higher spontaneous apoptosis and an increased FAS-induced cell death. However, the molecular mechanisms underlying the altered pre-B cell survival are unclear. We used a proteomic approach to identify proteins that are differentially regulated in cells expressing (NALM6Delta5A) or not a dominant negative form of STAT5A. Among the 14 proteins identified, six were involved in the control of the oxidative stress like glutathione (GSH) synthetase and DJ-1. Accordingly, we showed increased levels of reactive oxygen species (ROS) in NALM6Delta5A cells and suppression of the increased sensitivity to Fas-mediated apoptosis by the GSH tripeptide. Similar results were observed when NALM6 cells were treated with TAT STAT5Delta5A fusion proteins or STAT5A shRNA. In addition, the 697 and Reh pre-B cells were found to share number of molecular changes observed in NALM6Delta5A cells including ROS generation, following inhibition of STAT5 expression or function. Our results point out to a hitherto undescribed link between STAT5 and oxidative stress and provide new insights into STAT5 functions and their roles in leukemogenesis. PMID- 22522792 TI - Specific small nucleolar RNA expression profiles in acute leukemia. AB - Apart from microRNAs, little is known about the regulation of expression of non coding RNAs in cancer. We investigated whether small nucleolar RNAs (snoRNAs) accumulation displayed specific signatures in acute myeloblastic and acute lymphoblastic leukemias. Using microarrays and high-throughput quantitative PCR (qPCR), we demonstrate here that snoRNA expression patterns are negatively altered in leukemic cells compared with controls. Interestingly, a specific signature was found in acute promyelocytic leukemia (APL) with ectopic expression of SNORD112-114 snoRNAs located at the DLK1-DIO3 locus. In vitro experiments carried out on APL blasts demonstrate that transcription of these snoRNAs was lost under all-trans retinoic acid-mediated differentiation and induced by enforced expression of the PML-RARalpha fusion protein in negative leukemic cell lines. Further experiments revealed that the SNORD114-1 (14q(II-1)) variant promoted cell growth through cell cycle modulation; its expression was implicated in the G0/G1 to S phase transition mediated by the Rb/p16 pathways. This study thus reports three important observations: (1) snoRNA regulation is different in normal cells compared with cancer cells; (2) a relationship exists between a chromosomal translocation and expression of snoRNA loci; and (3) snoRNA expression can affect Rb/p16 cell cycle regulation. Taken together, these data strongly suggest that snoRNAs have a role in cancer development. PMID- 22522793 TI - Thiazolidinediones for plaque psoriasis: a systematic review and meta-analysis. AB - BACKGROUND: There is some evidence for the role of inflammation and insulin resistance in the pathophysiology of plaque psoriasis. Thiazolidinediones are antidiabetic drugs that act by improving insulin sensitivity and also possess anti-inflammatory effects. Evidence from in vitro, animal and human studies has accumulated suggesting that these drugs may be of use in psoriasis. OBJECTIVE: This systematic review and meta-analysis was performed to assess the efficacy of thiazolidinediones on psoriasis severity. STUDY SELECTION: Randomised, open-label or single blind or double blind, published as well as unpublished, studies of thiazolidinedione administration compared with placebo, given to patients with plaque psoriasis for at least 8 weeks were considered for inclusion in this review. The primary outcomes were as follows: mean or mean percent change in Psoriasis Area and Severity Index (PASI) from baseline to end of treatment with pioglitazone, proportion of patients showing >75% improvement in PASI score, and proportion of patients showing >50% improvement in PASI score. Data analysis was done using Revman 5. FINDINGS: Twenty-seven relevant citations were identified. Two studies each for pioglitazone and rosiglitazone were included in the meta analysis. There was a significantly greater mean decrease in PASI scores from baseline to end of treatment (-4.24 (95% CI -5.35 to -3.12)) in the pioglitazone group as compared to placebo. There was a non-significant improvement in PASI50/70 in the pooled analysis of rosiglitazone trials. CONCLUSION: Pioglitazone appears to have efficacy for the treatment of psoriasis. The clinical significance of the effect and role in management of psoriasis deserve further study. PMID- 22522798 TI - A proteomics performance standard to support measurement quality in proteomics. AB - The emergence of MS-based proteomic platforms as a prominent technology utilized in biochemical and biomedical research has increased the need for high-quality MS measurements. To address this need, National Institute of Standards and Technology (NIST) reference material (RM) 8323 yeast protein extract is introduced as a proteomics quality control material for benchmarking the preanalytical and analytical performance of proteomics-based experimental workflows. RM 8323 yeast protein extract is based upon the well-characterized eukaryote Saccharomyces cerevisiae and can be utilized in the design and optimization of proteomics-based methodologies from sample preparation to data analysis. To demonstrate its utility as a proteomics quality control material, we coupled LC-MS/MS measurements of RM 8323 with the NIST MS Quality Control (MSQC) performance metrics to quantitatively assess the LC-MS/MS instrumentation parameters that influence measurement accuracy, repeatability, and reproducibility. Due to the complexity of the yeast proteome, we also demonstrate how NIST RM 8323, along with the NIST MSQC performance metrics, can be used in the evaluation and optimization of proteomics-based sample preparation methods. PMID- 22522799 TI - Highly sensitive detection of protein phosphorylation by using improved Phos-tag Biotin. AB - We have previously shown that the dinuclear zinc(II) complex Phos-tag and its derivatives act as phosphate-capture molecules in aqueous solution under conditions of neutral pH. In this study, our aim was to develop more-advanced applications for the detection of phosphopeptides and phosphoproteins by using several newly synthesized Phos-tag derivatives, including a bisbiotinylated Phos tag (BTL-108), a tetrakisbiotinylated Phos-tag (BTL-109), and a monobiotinylated Phos-tag with a dodeca(ethylene glycol) spacer (BTL-111), as well as the commercially available product BTL-104. Among these complexes, BTL-111 showed the best performance in Western blotting by an ECL system using HRP conjugated streptavidin. In addition, in a quartz-crystal microbalance analysis of a phosphoprotein, the presence of the long hydrophilic dodeca(ethylene glycol) spacer in a novel Phos-tag sensor chip coated with BTL-111 resulted in a greater sensitivity than was achieved with a similar chip coated with BTL-104. Moreover, a peptide microarray technique using the ECL system and BTL-111 permitted high throughput assays for the specific and highly sensitive detection of protein kinase activities in cell lysates. PMID- 22522800 TI - Improving gel-based proteome analysis of soluble protein extracts by heat prefractionation. AB - The presence of high-abundance proteins in complex protein mixtures often masks low-abundance proteins and causes loss of resolution of 2DE. Protein fractionation steps conducted prior to 2DE can enhance the detection of low abundance proteins and improve the resolution of 2DE. Here, we report a method to prefractionate soluble protein extracts based on protein thermal denaturation. Soluble proteins were extracted from maize embryos and leaves and Escherichia coli cells. Through heating at 95 degrees C for 5 min, soluble protein extracts were prefractionated as heat stable protein fraction (the supernatant) and heat labile protein fraction (the precipitate). Our results showed that heat prefractionation enhanced the separation of proteins in both fractions by 2DE, thereby increasing the chance of detecting low-abundance proteins, many of which were nonvisible in unfractionated extract. In maize embryo, 330 spots were detected in soluble protein extract, while 577 spots were detected after prefractionation. Furthermore, this prefractionation method facilitated the enrichment, detection, and identification of de novo synthesized stress proteins. Because of its simplicity, the one-step heat prefractionation minimizes protein loss. Finally, heat prefractionation requires no expensive special hardware or reagents, and provides an alternative prefractionation for increasing the resolving power of 2DE. PMID- 22522802 TI - Methylation of translation-associated proteins in Saccharomyces cerevisiae: Identification of methylated lysines and their methyltransferases. AB - This study aimed to identify sites of lysine methylation in Saccharomyces cerevisiae and the associated methyltransferases. Hexapeptide ligand affinity chromatography was used to normalize the abundance levels of proteins in whole cell lysate. MS/MS, in association with antibody-based detection, was then used to identify lysine methylated proteins and the precise sites of modification. Lysine methylation was found on the proteins elongation factor (EF) 1-alpha, 2, and 3A, as well as ribosomal proteins 40S S18-A/B, 60S L11-A/B, L18-A/B, and L42 A/B. Precise sites were mapped in all cases. Single-gene knockouts of known and putative methyltransferase(s), in association with MS/MS, showed that EF1-alpha is monomethylated by Efm1 at lysin 30 and dimethylated by See1 at lysine 316. Methyltransferase Rkm1 was found to monomethylate 40S ribosomal protein S18-A/B at lysine 48. Knockout analysis also revealed that putative methyltransferase YBR271W affects the methylation of proteins EF2 and 3A; this was detected by Western blotting and immunodetection. This methyltransferase shows strong interspecies conservation and a tryptophan-containing motif associated with its active site. We suggest that enzyme YBR271W is named EF methyltransferase 2 (Efm2), in line with the recent naming of YHL039W as Efm1. PMID- 22522801 TI - Multiple phosphorylations of cytochrome c oxidase and their functions. AB - Cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial electron transport chain, is regulated by isozyme expression, allosteric effectors such as the ATP/ADP ratio, and reversible phosphorylation. Of particular interest is the "allosteric ATP-inhibition," which has been hypothesized to keep the mitochondrial membrane potential at low healthy values (<140 mV), thus preventing the formation of superoxide radical anions, which have been implicated in multiple degenerative diseases. It has been proposed that the "allosteric ATP inhibition" is switched on by the protein kinase A-dependent phosphorylation of COX. The goal of this study was to identify the phosphorylation site(s) involved in the "allosteric ATP-inhibition" of COX. We report the mass spectrometric identification of four new phosphorylation sites in bovine heart COX. The identified phosphorylation sites include Tyr-218 in subunit II, Ser-1 in subunit Va, Ser-2 in subunit Vb, and Ser-1 in subunit VIIc. With the exception of Ser-2 in subunit Vb, the identified phosphorylation sites were found in enzyme samples with and without "allosteric ATP inhibition," making Ser-2 of subunit Vb a candidate site enabling allosteric regulation. We therefore hypothesize that additional phosphorylation(s) may be required for the "allosteric ATP inhibition," and that these sites may be easily dephosphorylated or difficult to identify by mass spectrometry. PMID- 22522803 TI - Dephosphorylation of cardiac proteins in vitro - a matter of phosphatase specificity. AB - Protein phosphorylation is reversibly regulated by the interplay between kinases and phosphatases. Recent developments within the field of proteomics have revealed the extent of this modification in nature. To date there is still a lack of information about phosphatase specificity for different proteomes and their conditions to achieve maximum enzyme activity. This information is important per se, and in addition often requested in functional and biochemical in vitro studies, where a dephosphorylated sample is needed as a negative control to define baseline conditions. In this study, we have addressed the effectiveness of two phosphatases endogenously present in the heart (protein phosphatases 1 and 2A) and two generic phosphatases (alkaline phosphatase and lambda protein phosphatase) on three cardiac subproteomes known to be regulated by phosphorylation. We optimized the dephoshorylating conditions on a cardiac tissue fraction comprising cytosolic and myofilament proteins using 2DE and MS. The two most efficient conditions were further investigated on a mitochondrial-enriched fraction. Dephosphorylation of specific proteins depends on the phosphatase, its concentration, as well as sample preparation including buffer composition. Finally, we analyzed the efficiency of alkaline phosphatase, the phosphatase with the broadest substrate specificity, using TiO(2) peptide enrichment and 2DLC MS/MS. Under these conditions, 95% of the detected cardiac cytoplasmic-enriched phospho-proteome was dephosphorylated. In summary, targeting dephosphorylation of the cardiac muscle subproteomes or a specific protein will drive the selection of the specific phosphatase, and each requires different conditions for optimal performance. PMID- 22522804 TI - Deciphering the proteome of the in vivo diagnostic reagent "purified protein derivative" from Mycobacterium tuberculosis. AB - Purified protein derivative (PPD) has served as a safe and effective diagnostic reagent for 60 years and is the only broadly available material to diagnose latent tuberculosis infections. This reagent is also used as a standard control for a number of in vitro immunological assays. Nevertheless, the molecular composition and specific products that contribute to the extraordinary immunological reactivity of PPD are poorly defined. Here, a proteomic approach was applied to elucidate the gene products in the U.S. Food and Drug Administration (FDA) standard PPD-S2. Many known Mycobacterium tuberculosis T cell antigens were detected. Of significance, four heat shock proteins (HSPs) (GroES, GroEL2, HspX, and DnaK) dominated the composition of PPD. The chaperone activities and capacity of these proteins to influence immunological responses may explain the exquisite solubility and immunological potency of PPD. Spectral counting analysis of three separate PPD reagents revealed significant quantitative variances. Gross delayed-type hypersensitivity (DTH) responses in M. tuberculosis infected guinea pigs were comparable among these PPD preparations; however, detailed histopathology of the DTH lesions exposed unique differences, which may be explained by the variability observed in the presence and abundance of early secretory system (Esx) proteins. Variability in PPD reagents may explain differences in DTH responses reported among populations. PMID- 22522806 TI - Phosphoproteome profile of Fusarium graminearum grown in vitro under nonlimiting conditions. AB - This study presents a high-throughput proteomic analysis of phosphopeptides from Fusarium graminearum strain DAOM 233423 grown in vitro without nutritional limitation. Using a combination of strong cation exchange (SCX) and immobilized metal affinity chromatography (IMAC) followed by LC-MS, we identified 2902 putative phosphopeptides with homologous matches to 1496 different proteins. Functional classification of the annotated protein set revealed that phosphopeptides from nuclear proteins with ATP-binding function were the most abundant. There are indications that phosphorylation sites from well characterized phosphoproteins representing diverse biological processes are conserved in F. graminearum: sequences of three phosphopeptides from known phosphoproteins (transcription elongation factor 1beta, acidic ribosomal proteins, and glycogen synthase) revealed phosphorylation site conservation. PMID- 22522805 TI - Deep metaproteomic analysis of human salivary supernatant. AB - The human salivary proteome is extremely complex, including proteins from salivary glands, serum, and oral microbes. Much has been learned about the host component, but little is known about the microbial component. Here we report a metaproteomic analysis of salivary supernatant pooled from six healthy subjects. For deep interrogation of the salivary proteome, we combined protein dynamic range compression (DRC), multidimensional peptide fractionation, and high-mass accuracy MS/MS with a novel two-step peptide identification method using a database of human proteins plus those translated from oral microbe genomes. Peptides were identified from 124 microbial species as well as uncultured phylotypes such as TM7. Streptococcus, Rothia, Actinomyces, Prevotella, Neisseria, Veilonella, Lactobacillus, Selenomonas, Pseudomonas, Staphylococcus, and Campylobacter were abundant among the 65 genera from 12 phyla represented. Taxonomic diversity in our study was broadly consistent with metagenomic studies of saliva. Proteins mapped to 20 KEGG pathways, with carbohydrate metabolism, amino acid metabolism, energy metabolism, translation, membrane transport, and signal transduction most represented. The communities sampled appear to be actively engaged in glycolysis and protein synthesis. This first deep metaproteomic catalog from human salivary supernatant provides a baseline for future studies of shifts in microbial diversity and protein activities potentially associated with oral disease. PMID- 22522807 TI - Two-dimensional gel-based alkaline proteome of the probiotic bacterium Lactobacillus acidophilus NCFM. AB - Lactobacillus acidophilus NCFM (NCFM) is a well-documented probiotic bacterium isolated from human gut. Detailed 2D gel-based NCFM proteomics addressed the so called alkaline range, i.e., pH 6-11. Proteins were identified in 150 of the 202 spots picked from the Coomassie Brilliant Blue stained 2D gel using MALDI-TOF-MS. The 102 unique gene products among the 150 protein identifications were assigned to different functional categories, and evaluated by considering a calculated distribution of abundance as well as grand average of hydrophobicity values. None of the very few available lactic acid bacteria proteome reference maps included the range of pI >7.0. The present report of such data on the proteome of NCFM fundamentally complements current knowledge on protein profiles limited to the acid and neutral pH range. PMID- 22522808 TI - An interactome map of the nucleocapsid protein from a highly pathogenic North American porcine reproductive and respiratory syndrome virus strain generated using SILAC-based quantitative proteomics. AB - Positive strand RNA viruses replicate in the cytoplasm of an infected cell and encode nucleocapsid proteins. These proteins function to promote encapsidation of the RNA genome and virus particle assembly as well as playing potential roles in viral RNA synthesis. Nucleocapsid proteins can also associate with cellular proteins and signaling cascades. The arterivirus nucleocapsid (N) protein is no exception and localizes to both the cytoplasm and the nucleolus in virus-infected cells. This study generated an interactome map of the N protein from a highly virulent North American strain of porcine reproductive and respiratory syndrome virus (PRRSV). This is a major pathogen of swine resulting in significant morbidity and mortality. Crucial to the study was the use of SILAC coupled to affinity purification using GFP-traps and LC-MS/MS. This approach has not been applied before to the investigation of host/viral protein interactomes and this study revealed that the PRRSV N protein interacts with the host cell protein synthesis machinery especially at the level of translation initiation as well as with the RNA post-transcriptional modification machinery. Applications of the dataset can include studies of virus/host interactions and the design of live attenuated recombinant vaccines. PMID- 22522809 TI - Dynamic protein composition of Arabidopsis thaliana cytosolic ribosomes in response to sucrose feeding as revealed by label free MSE proteomics. AB - Cytosolic ribosomes are among the largest multisubunit cellular complexes. Arabidopsis thaliana ribosomes consist of 79 different ribosomal proteins (r proteins) that each are encoded by two to six (paralogous) genes. It is unknown whether the paralogs are incorporated into the ribosome and whether the relative incorporation of r-protein paralogs varies in response to environmental cues. Immunopurified ribosomes were isolated from A. thaliana rosette leaves fed with sucrose. Trypsin digested samples were analyzed by qTOF-LC-MS using both MS(E) and classical MS/MS. Peptide features obtained by using these two methods were identified using MASCOT and Proteinlynx Global Server searching the theoretical sequences of A. thaliana proteins. The A. thaliana genome encodes 237 r-proteins and 69% of these were identified with proteotypic peptides for most of the identified proteins. These r-proteins were identified with average protein sequence coverage of 32% observed by MS(E) . Interestingly, the analysis shows that the abundance of r-protein paralogs in the ribosome changes in response to sucrose feeding. This is particularly evident for paralogous RPS3aA, RPS5A, RPL8B, and RACK1 proteins. These results show that protein synthesis in the A. thaliana cytosol involves a heterogeneous ribosomal population. The implications of these findings in the regulation of translation are discussed. PMID- 22522810 TI - Proteomic profiling of Tectona grandis L. leaf. AB - Tectona grandis L. (teak) is one of the premier hardwood timbers in the world, ranking at present in the top five tropical hardwood species in terms of worldwide plantation area. Characterization of the proteins present in teak leaves will provide a basis for the development of new tools aimed at assisting tree selection, the monitoring of plant propagation, and the certification of clonal and phenotypic identities. In this paper, we describe the extraction, separation, and identification of leaf proteins from T. grandis using a TCA/acetone protocol, 2DE, and MALDI-TOF. After TCA/acetone protein extraction of leaves, 998 well-resolved spots were detected in Coomassie-stained gels within the 10-114 kDa relative molecular mass (Mr) range at a pH ranging from 3 to 11. A total of 120 spots were digested and subjected to MS. Of these, 100 nonredundant protein species were successfully identified. Functional classification of the identified proteins revealed that proteins involved in photosynthesis, protein translation, and energy production were the most abundant. This work is the first high-throughput attempt to study the T. grandis leaf proteome and represents a stepping stone for further differential expression proteomic studies related to growth, development, biomass production, and culture-associated physiological responses. PMID- 22522811 TI - A stable panel comprising 18 urinary proteins in the human healthy population. AB - Just as biomarkers specific for diseases, biomarkers indicative of healthy conditions are valuable for the early diagnosis, monitoring, and prognosis of diseases. Our study focused on discovering via proteomics a stable panel of urinary proteins in the human healthy population. Urine samples were collected three times during 4 months from 100 male and 100 female healthy donors and analyzed through four different fractionation techniques (i.e. in-gel, 2D-LC, OFFGEL, and mRP) coupled with HPLC-Chip-MS/MS. Thus, 1641 urinary proteins were identified with a high confidence, among which 70 exhibiting an intergender/day variation <0.25 were selected and matched with the previously published five largest urinary proteomes to get 56 candidate proteins. Next, a panel comprising 18 intact urinary proteins was constructed by comparing the urinary proteomes via SDS-PAGE and 2DE. Finally, such 18 urinary proteins were validated via enzyme linked immunosorbent assay in eight healthy individuals. Most of these proteins had been related to multiple rather than to single diseases. Therefore, we surmise that this protein set could be used as a biomarker to assess the human health status. Further determinations of the normal fluctuations of the single urinary proteins in this series using samples from large numbers of healthy individuals are required prior to any application in clinical settings. PMID- 22522812 TI - Measuring acoustic energy density in microchannel acoustophoresis using a simple and rapid light-intensity method. AB - We present a simple and rapid method for measuring the acoustic energy density in microchannel acoustophoresis based on light-intensity measurements of a suspension of particles. The method relies on the assumption that each particle in the suspension undergoes single-particle acoustophoresis. It is validated by the single-particle tracking method, and we show by proper re-scaling that the re scaled light intensity plotted versus re-scaled time falls on a universal curve. The method allows for analysis of moderate-resolution images in the concentration range encountered in typical experiments, and it is an attractive alternative to particle tracking and particle image velocimetry for quantifying acoustophoretic performance in microchannels. PMID- 22522813 TI - Forest land cover continues to exacerbate freshwater acidification despite decline in sulphate emissions. AB - Evidence from a multi-date regional-scale analysis of both high-flow and annual average water quality data from Galloway, south-west Scotland, demonstrates that forest land cover continues to exacerbate freshwater acidification. This is in spite of significant reductions in airborne pollutants. The relationship between freshwater sulphate and forest cover has decreased from 1996 to 2006 indicating a decrease in pollutant scavenging. The relationship between forest cover and freshwater acidity (pH) is, however, still present over the same period, and does not show conclusive signs of having declined. Furthermore, evidence for forest cover contributing to a chlorine bias in marine ion capture suggests that forest scavenging of sea-salts may mean that the forest acidification effect may continue in the absence of anthropogenic pollutant inputs, particularly in coastal areas. PMID- 22522814 TI - Angular versus spatial resolution trade-offs for diffusion imaging under time constraints. AB - Diffusion weighted magnetic resonance imaging (DW-MRI) are now widely used to assess brain integrity in clinical populations. The growing interest in mapping brain connectivity has made it vital to consider what scanning parameters affect the accuracy, stability, and signal-to-noise of diffusion measures. Trade-offs between scan parameters can only be optimized if their effects on various commonly-derived measures are better understood. To explore angular versus spatial resolution trade-offs in standard tensor-derived measures, and in measures that use the full angular information in diffusion signal, we scanned eight subjects twice, 2 weeks apart, using three protocols that took the same amount of time (7 min). Scans with 3.0, 2.7, 2.5 mm isotropic voxels were collected using 48, 41, and 37 diffusion-sensitized gradients to equalize scan times. A specially designed DTI phantom was also scanned with the same protocols, and different b-values. We assessed how several diffusion measures including fractional anisotropy (FA), mean diffusivity (MD), and the full 3D orientation distribution function (ODF) depended on the spatial/angular resolution and the SNR. We also created maps of stability over time in the FA, MD, ODF, skeleton FA of 14 TBSS-derived ROIs, and an information uncertainty index derived from the tensor distribution function, which models the signal using a continuous mixture of tensors. In scans of the same duration, higher angular resolution and larger voxels boosted SNR and improved stability over time. The increased partial voluming in large voxels also led to bias in estimating FA, but this was partially addressed by using "beyond-tensor" models of diffusion. PMID- 22522815 TI - Evaluation of dazomet as fumigant for the control of brown root rot disease. AB - BACKGROUND: Brown root rot disease caused by Phellinus noxius is widespread in approximately 216 tree and plant species in tropical and subtropical countries. No direct means of protection against P. noxius infection have thus far been developed. Therefore, in this field survey, a method was developed for preventing and controlling brown root rot disease using fumigation with dazomet. RESULTS: Tracers were used to monitor the effect of dazomet fumigation. The results from field surveys and phytotoxicity tests showed that dazomet is able to kill P. noxius without any side effects on plants. CONCLUSION: The use of an environmentally friendly agent to control brown root rot disease is needed, and prevention of the disease is more important than treatment. Hence, chemical fumigation with 60 g m(-2) of 98% dazomet may be a possible means of preventing P. noxius incursion in agriculture, gardening and agroforestry. PMID- 22522816 TI - The molecularly controlled synthesis of ordered bi-dimensional C60 arrays. AB - Much of the research effort concerning the nanoscopic properties of clays has focused on its mechanical applications, for example, as nanofillers for polymer reinforcement. To broaden the horizon of what is possible by exploiting the richness of clays in nanoscience, herein we report a bottom-up approach for the production of hybrid materials in which clays act as the structure-directing interface and reaction media. This new method, which combines self-assembly with the Langmuir-Schaefer technique, uses the clay nanosheets as a template for the grafting of C(60) into a bi-dimensional array, and allows for perfect layer-by layer growth with control at the molecular level. In contrast to the more-common growth of C(60) arrays through nanopatterning, our approach can be performed under atmospheric conditions, can be upscaled to areas of tenths of cm(2), and can be applied to almost any hydrophobic substrate. Herein, we report a detailed study of this approach by using temperature-dependent X-ray diffraction, spectroscopic measurements, and STM. PMID- 22522817 TI - Signs of shock and raised jugular venous pressure. PMID- 22522818 TI - US bill proposes speeding up free online access to federally funded research. PMID- 22522819 TI - Consultation process on closing children's cardiac surgery services at Brompton Hospital was fair, judges rule. PMID- 22522820 TI - Survey of Dutch doctors finds evidence of widespread research misconduct. PMID- 22522821 TI - Organization of the histaminergic system in adult zebrafish (Danio rerio) brain: neuron number, location, and cotransmitters. AB - Histamine is an essential factor in the ascending arousal system (AAS) during motivated behaviors. Histamine and hypocretin/orexin (hcrt) are proposed to be responsible for different aspects of arousal and wakefulness, histamine mainly for cognitive and motivated behaviors. In this study we visualized the entire histaminergic neuron population in adult male and female zebrafish brain and quantified the histaminergic neuron numbers. There were 40-45 histaminergic neurons in both male and female zebrafish brain. Further, we identified cotransmitters of histaminergic neurons in the ventrocaudal hypothalamus, i.e., around the posterior recess (PR) in adult zebrafish. Galanin, gamma-aminobutyric acid (GABA), and thyrotropin-releasing hormone (TRH) were colocalized with histamine in some but not all neurons, a result that was verified by intracerebroventricular injections of colchicine into adult zebrafish. Fibers immunoreactive (ir) for galanin, GABA, TRH, or methionine-enkephalin (mENK) were dense in the ventrocaudal hypothalamus around the histaminergic neurons. In histamine-ir fibers TRH and galanin immunoreactivities were also detected in the ventral telencephalon. All these neurotransmitters are involved in maintaining the equilibrium of the sleep-wake state. Our results are in accordance with results from rats, further supporting the use of zebrafish as a tool to study molecular mechanisms underlying complex behaviors. PMID- 22522822 TI - Rapid oligomer formation of human muscle acylphosphatase induced by heparan sulfate. AB - Many human diseases are caused by the conversion of proteins from their native state into amyloid fibrils that deposit in the extracellular space. Heparan sulfate, a component of the extracellular matrix, is universally associated with amyloid deposits and promotes fibril formation. The formation of cytotoxic prefibrillar oligomers is challenging to study because of its rapidity, transient appearance and the heterogeneity of species generated. The process is even more complex with agents such as heparan sulfate. Here we have used a stopped-flow device coupled to turbidometry detection to monitor the rapid conversion of human muscle acylphosphatase into oligomers with varying heparan sulfate and protein concentrations. We also analyzed mutants of the 15 basic amino acids of acylphosphatase, identifying the residues primarily involved in heparan sulfate induced oligomerization of this protein and tracing the process with unprecedented molecular detail. PMID- 22522824 TI - The influence of visual search efficiency on the time-course of identity-based SR compatibility. AB - Three experiments were conducted to investigate the impact of stimulus-driven control on the time-course of stimulus-response (SR) compatibility. Participants responded to the presence or absence of a singleton arrow that was presented among multiple nontargets. When the singleton arrow was present, observers pressed a button with their right index finger, when it was absent they pressed with their left-index finger. SR-compatibility depended on the relation between the identity of the target and the present response: Even though the identity of the target singleton arrow (whether it was pointing to the right or left) was irrelevant to the task, the direction could be corresponding (right arrow) or noncorresponding (left arrow) with a target present response (the right hand). To examine the time-course of performance target-distractor similarity was varied to increase or decrease visual search efficiency and accordingly response latency. There were three main findings. First, the results of Experiment 1 showed that observers were no faster to respond 'present' when the singleton arrow pointed to the right (corresponding to the right hand) than when it pointed left (noncorresponding to the right hand) in a simple present-absent detection task. Second, only when observers were encouraged to process the identity of the arrow singleton, an effect of an SR-compatibility effect was found which developed over time. Third, the time-course of SR-compatibility was not influenced by visual search efficiency. The results of the present work suggest that visual selection and response selection occur in different stages. PMID- 22522823 TI - The cryo-EM structure of the UPF-EJC complex shows UPF1 poised toward the RNA 3' end. AB - Nonsense-mediated mRNA decay (NMD) is a eukaryotic surveillance pathway that degrades aberrant mRNAs containing premature termination codons (PTCs). NMD is triggered upon the assembly of the UPF surveillance complex near a PTC. In humans, UPF assembly is prompted by the exon junction complex (EJC). We investigated the molecular architecture of the human UPF complex bound to the EJC by cryo-EM and using positional restraints from additional EM, MS and biochemical interaction data. The heptameric assembly is built around UPF2, a scaffold protein with a ring structure that closes around the CH domain of UPF1, keeping the helicase region in an accessible and unwinding-competent state. UPF2 also positions UPF3 to interact with the EJC. The geometry is such that this transient complex poises UPF1 to elicit helicase activity toward the 3' end of the mRNP. PMID- 22522825 TI - Macroautophagy is deregulated in murine and human lupus T lymphocytes. AB - Macroautophagy was recently shown to regulate both lymphocyte biology and innate immunity. In this study we sought to determine whether a deregulation of autophagy was linked to the development of autoimmunity. Genome-wide association studies have pointed out nucleotide polymorphisms that can be associated with systemic lupus erythematosus, but the potential role of autophagy in the initiation and/or development of this syndrome is still unknown. Here, we provide first clues of macroautophagy deregulation in lupus. By the use of LC3 conversion assays and electron microscopy experiments, we observed that T cells from two distinct lupus-prone mouse models, i.e., MRL (lpr/lpr) and (NZB/NZW)F1, exhibit high loads of autophagic compartments compared with nonpathologic control CBA/J and BALB/c mice. Unlike normal mice, autophagy increases with age in murine lupus. In vivo lipopolysaccharide stimulation in CBA/J control mice efficiently activates T lymphocytes but fails to upregulate formation of autophagic compartments in these cells. This argues against a deregulation of autophagy in lupus T cells solely resulting from an acute inflammation injury. Autophagic vacuoles quantified by electron microscopy are also found to be significantly more frequent in T cells from lupus patients compared with healthy controls and patients with non-lupus autoimmune diseases. This elevated number of autophagic structures is not distributed homogeneously and appears to be more pronounced in certain T cells. These results suggest that autophagy could regulate the survival of autoreactive T cell during lupus, and could thus lead to design new therapeutic options for lupus. PMID- 22522827 TI - New codes of professional conduct come into effect. PMID- 22522826 TI - Synthesis of atrial natriuretic peptide in the rabbit inner ear. AB - OBJECTIVES/HYPOTHESIS: Atrial natriuretic peptide (ANP) exhibits natriuretic, diuretic, and vasorelaxant activity, maintaining fluid and electrolyte homeostasis. Although ANP is mainly synthesized and secreted in/from atrium, ANP has been found in various tissues including the rat inner ear. The aim of this study was to identify the synthesis of ANP in lateral cochlear wall tissues and the presence of ANP in perilymph using rabbits. STUDY DESIGN: In vivo study using a rabbit model. METHODS: Expression of ANP in the rabbit inner ear tissue and the presence of perilymph were examined by radioimmunoassay and polymerase chain reaction using an ANP polyclonal antibody and rat ANP primers, respectively. Characteristics of ANP and pro-ANP present in the inner ear were also evaluated by high-performance liquid chromatography (HPLC), comparing to rat cardiac ANP and pro-ANP. RESULTS: Immunoreactive ANP (ir-ANP) was found in the perilymph and lateral cochlear wall tissue of rabbits. The levels of ir-ANP in the perilymph were 5 to 16 ng/mL. Elusion profiles of HPLC showed two main peaks that were exactly matched with rat cardiac ANP and pro-ANP. Expression of ANP mRNA was also detected. CONCLUSIONS: Our findings suggest that ANP and its precursor protein are synthesized in the ear tissues and secreted to perilymph. This hormone may play a role in control of water and/or ion homeostasis of the fluids in the ear that are responsible for normal hearing. PMID- 22522828 TI - Review group sets out principles for delivery of surveillance. PMID- 22522829 TI - US FDA takes steps to reduce use of antibiotic growth promoters. PMID- 22522830 TI - Reprimand for vet who continued to practise after not paying his fees. PMID- 22522831 TI - BVA responds to LRO consultation. PMID- 22522833 TI - Helping hand for puppy buyers. PMID- 22522834 TI - Pet care: an aid to teaching responsibility. PMID- 22522835 TI - One health high on the agenda at world congress. PMID- 22522836 TI - Eliminating rabies at its source. PMID- 22522837 TI - Displaced abomasum in cattle: evaluation beyond the ping. PMID- 22522838 TI - RCVS overspend review group. PMID- 22522839 TI - Investigating badger bites. PMID- 22522842 TI - A contemporary European experience with surgical septal myectomy in hypertrophic cardiomyopathy. AB - AIMS: The recent American College of Cardiology and American Heart Association Guidelines on hypertrophic cardiomyopathy (HCM) have confirmed surgical myectomy as the gold standard for non-pharmacological treatment of obstructive HCM. However, during the last 15 years, an extensive use of alcohol septal ablation has led to the virtual extinction of myectomy programmes in several European countries. Therefore, many HCM candidates for myectomy in Europe cannot be offered the option of this procedure. The purpose of our study is to report the difficulties and results in developing a myectomy programme for HCM in a centre without previous experience with this procedure. METHODS AND RESULTS: The clinical course is reported of 124 consecutive patients with obstructive HCM and heart failure symptoms who underwent myectomy at a single European centre between 1996 and 2010. The median follow-up was 20.3 months (inter-quartile range: 3.9 40.6 months). No patients were lost to follow-up. A cumulative incidence of HCM related death after myectomy was 0.8, 3.3, and 11.2% at 1, 5, and 10 years, respectively, including one operative death (procedural mortality 0.8%). The left ventricular (LV) outflow gradient decreased from 95 +/- 36 mmHg before surgery to 12 +/- 6 mmHg at most recent evaluation (P < 0.001), with none of the patients having a significant residual LV outflow gradient. Of the 97 patients in New York Heart Association functional class III-IV before surgery, 93 (96%) were in class I-II at most recent evaluation (P < 0.001). CONCLUSION: Our results show that the development of a myectomy programme at a centre without previous experience with this procedure is feasible and can lead to highly favourable clinical results. PMID- 22522843 TI - A rapid method for profiling samples of illicit heroin. AB - The aim of this investigation was to profile samples of illicit heroin. It involved derivatization and gas chromatographic separation followed by a fully automated data analysis. Six major constituents (acetylcodeine, 6 monoacetylmorphine, papaverine, noscapine, codeine, and morphine) were tested and analyzed. The square cosine function was used to evaluate correlation values. The method proved to be efficient and reliable providing information on links between illicit heroin samples. PMID- 22522844 TI - Superelastic metal microsprings as fluidic sensors and actuators. AB - Superelastic metal microsprings fabricated by deterministic rolling of nanomembranes have been anisotropic-strain-engineered via glancing angle deposition. The advantageous applications of metal microsprings in liquid flow rate sensors and chemical-stimulated actuators due to their reliable superelasticity are demonstrated. Theoretical calculation of microspring elongation as a function of flow rate agrees with our experimental observation and reveals that the sensitivity can be well tuned by the geometrical design of the microsprings. Such outstanding mechanical properties of rolled-up metal microsprings should find important applications in future fluidic micro-/nano devices. PMID- 22522845 TI - Loss of heterozygosity, aberrant methylation, BRAF mutation and KRAS mutation in colorectal signet ring cell carcinoma. AB - The relationship of molecular abnormalities with clinicopathologic features and survival in colorectal signet ring cell carcinoma, and its comparison with mucinous and conventional adenocarcinomas, has not been well studied. High-level microsatellite instability, loss of heterozygosity (LOH) at four loci, CpG island methylation phenotype based on seven loci, BRAF V600E mutation and KRAS mutation in signet ring cell carcinoma were compared with mucinous and conventional adenocarcinomas. The relationship of these molecular features in signet ring cell carcinoma with clinicopathologic features and survival was examined. LOH was observed in 93% of signet ring cell carcinomas compared with 62 and 70% of mucinous and conventional adenocarcinomas. Also, 80% of signet ring cell carcinomas with high-level microsatellite instability showed LOH compared with 14% each of mucinous and conventional adenocarcinomas. High-level microsatellite instability, CpG island methylation phenotype-positive status and BRAF V600E mutation were more often seen in signet ring cell carcinoma and mucinous adenocarcinoma compared with conventional adenocarcinoma. BRAF V600E mutation was significantly associated with CpG island methylation phenotype-positive status. Stage and BRAF V600E mutation in microsatellite-stable cases were the only variables with an affect on survival. In conclusion, chromosomal instability manifested by LOH is nearly a universal finding in signet ring cell carcinoma, including cases with high-level microsatellite instability. This may explain the aggressive behavior of signet ring cell carcinoma irrespective of high-level microsatellite-instability status. BRAF V600E mutation and CpG island methylation phenotype-positive status are similar in signet ring cell carcinoma and mucinous adenocarcinoma but more frequent when compared with conventional adenocarcinoma. In signet ring cell carcinoma, BRAF V600E mutation adversely affects survival in microsatellite-stable tumors, but not in high-level microsatellite-unstable tumors. The high frequency of methylation and BRAF V600E mutation suggests that many signet ring cell carcinomas may be related to the serrated pathway of carcinogenesis. PMID- 22522846 TI - Gene discovery in familial cancer syndromes by exome sequencing: prospects for the elucidation of familial colorectal cancer type X. AB - Recent advances in genotyping and sequencing technologies have provided powerful tools with which to explore the genetic basis of both Mendelian (monogenic) and sporadic (polygenic) diseases. Several hundred genome-wide association studies have so far been performed to explore the genetics of various polygenic or complex diseases including those cancers with a genetic predisposition. Exome sequencing has also proven very successful in elucidating the etiology of a range of hitherto poorly understood Mendelian disorders caused by high-penetrance mutations. Despite such progress, the genetic etiology of several familial cancers, such as familial colorectal cancer type X, has remained elusive. Familial colorectal cancer type X and Lynch syndrome are similar in terms of their fulfilling certain clinical criteria, but the former group is not characterized by germline mutations in DNA mismatch-repair genes. On the other hand, the genetics of sporadic colorectal cancer have been investigated by genome wide association studies, leading to the identification of multiple new susceptibility loci. In addition, there is increasing evidence to suggest that familial and sporadic cancers exhibit similarities in terms of their genetic etiologies. In this review, we have summarized our current knowledge of familial colorectal cancer type X, discussed current approaches to probing its genetic etiology through the application of new sequencing technologies and the recruitment of the results of colorectal cancer genome-wide association studies, and explore the challenges that remain to be overcome given the uncertainty of the current genetic model (ie, monogenic vs polygenic) of familial colorectal cancer type X. PMID- 22522847 TI - Correlation of DLC1 gene methylation with oncogenic PIK3CA mutations in extramammary Paget's disease. AB - Extramammary Paget's disease is a rare cutaneous malignant neoplasm. The genetic and epigenetic mechanisms underlying its pathology remain unknown. In this study, we investigated the expression levels, and mutation and methylation status of a common tumor suppressor gene, deleted in liver cancer 1 (DLC1), and an oncogene, PIK3CA, in tumor (n=132) and normal tissues (n=20) from unrelated patients. The presence of epigenetic and genetic lesions was then correlated to the patient pathology data to determine the potential role of these genes in extramammary Paget's disease etiology and progression. The DLC1 gene was found to be downregulated in 43 (33%) tumors, as compared with immunohistochemistry results from normal tissues. Methylation-sensitive, high-resolution melting analysis indicated that the DLC1 promoter was hypermethylated in 51 (39%) extramammary Paget's disease tumors. This hypermethylation was associated with significantly decreased DLC1 levels (P=0.011), and had a strong positive correlation with advanced age (P=0.002). PIK3CA mutations were detected by direct sequencing in 32 (24%) tumors, the majority of which were invasive. Furthermore, PIK3CA mutations significantly correlated with DLC1 hypermethylation. Thus, aberrant DLC1 methylation and PIK3CA mutations may have important roles in extramammary Paget's disease pathogenesis, and may represent potential molecular targets for therapy. PMID- 22522848 TI - [Study of diaphragmatic muscle function during abdominal weight in normal subjects]. AB - The effects of the abdominal weight with the intention of producing training of the diaphragm, have not been sufficiently evaluated. We studied the function of the diaphragm during the abdominal weight training and during associated changes in the respiratory pattern. Six normal volunteers were studied. Flow at the mouth at functional residual capacity (FRC) was obtained as well as gastric pressure (Pga), esophageal pressure (Pes), thoracic and abdominal movements, maximal inspiratory pressure and mean and maximal transdiaphragmatic pressure (Pdi and Pdi max). Pdi/Pdimax and the diaphragm tension-time index (TTdi) were calculated. Studied steps: normal pattern (NP), abdominal pattern (AP) and weight of 1, 2, 4 and 6 kg with NP and AP as well. We found 1) The AP was facilitated by the abdominal weight, 2) Only with 6 kg (NP and AP) the Pga at FRC increased significantly (p 0.001), 3) the Pdi followed the variations of the Pga and increased with all the AP (p < 0.001), 4) The index TTdi load reached a value of 0.05 +/- 0.02 (p < 0.001). The charges did not increase this rate more than did the AP alone. Our findings suggest abdominal weight increases propioception related to the respiratory movements and descent of the diaphragm. The loads on the abdomen produce minor changes in mechanics of the diaphragm (1/3 of the load required to develop fatigue in normal subjects). Al least in normal subjects these changes appear to be insufficient to produce respiratory muscle training. PMID- 22522849 TI - [Systemic treatment of ocular cicatricial pemphigoid]. AB - Ocular cicatricial pemphigoid (OCP) is a blistering autoimmune disease that can produce severe conjunctival damage. Its response to immunosuppressive treatment is poorly known. We describe a group of 76 patients, 62 women and 14 men. Mean age at diagnosis was 67+/-14 years old, with a delay to diagnosis of 7.5+/-10 years. Sixty patients continued their follow up in our services for 19+/-21 months. Nineteen out of 51 had mild disease, 19 moderate, 5 severe and 8 very severe at onset of treatment. The more frequently prescribed drugs were dapsone, in 35 (23 discontinued it because of adverse effects), and methotrexate in 42 patients, nine of them stopped it. Other patients received azathioprine, cyclophosphamide and ciclosporine. Seventeen received oral steroids in addition to immunosuppressive drugs. Four patients combined two immunosuppressive drugs to control their disease. In three refractory cases IV immunoglobulin (Ig) was administered with good response. From 48 evaluated patients, 39 improved with treatment, eight remained stable and one progressed. In our experience, methotrexate and azathioprine were effective drugs, with low toxicity. Dapsone was useful in mild cases, with frequent adverse effects. IVIg was effective for refractory cases. PMID- 22522850 TI - [Active infective endocarditis: 152 cases]. AB - Active infective endocarditis (IE) is a disease of low incidence that has showed changes in presentation, diagnosis and treatment options during the past decades. Despite these advances, mortality remains very high. Our goal was to analyze the characteristics of patients with active IE and their relationship with in hospital mortality over 16 years. Between 1994 and 2010 we performed a prospective registry of 152 consecutive patients (64.5% male, age 45 +/- 16 years) admitted with IE. Clinical characteristics, treatment and inpatient outcomes were analyzed. The most common causes of underlying heart disease were: congenital (21%) and rheumatic fever (13.2%). The reasons for hospitalization were fever (76.3%) and heart failure (40.1%). The infectious agent was identified in 69.7% of cases, and the most frequent was Streptococcus viridans. The echocardiogram showed vegetations in 80.9% of patients and 57.8% of them presented complications (the most frequent was heart failure) during hospitalization. Surgical treatment was indicated in 63.2% of cases, mainly due to heart failure. The overall hospital mortality was 30.2%. The presence of complications, requirement of surgical treatment and refractory heart failure were independent predictors of mortality whereas the single presence of vegetation showed better survival rate. The identification of these predictors could help to improve the outcomes in IE. PMID- 22522851 TI - [Oral administration of intravenous preparation of Vitamin K for excessive anticoagulation due to warfarin]. AB - Anticoagulation therapy with warfarin, a common clinical practice, needs to be monitored using protombine time expressed as the International Normalized Ratio (INR); when safety range is exceeded, Vitamin K (Vit-K) could be administered with preference orally. In Venezuela the specific oral preparation for Vit-K is not available. This is a double blinded, randomized, placebo controlled, clinical trial; 20 patients, age 18-60 year with initial INR >= 6, <= 10, were randomized to oral Vit-K 1.25mg (prepared from intravenous presentation) or placebo plus withholding warfarin. INR < 3.5 at 24 hours of treatment (the primary end point) was achieved by 70% among Vit-K, and 20% among placebo patients; given an absolute risk reduction (ARR), of 50% (CI95%: 14.4-85.6) p = 0.028, NNT 2 (CI95%: 1.3 - 6.9). No adverse events were recorded including INR < 2 at 24 hours of treatment administration. Our results are consistent with studies where specific oral presentation of Vit-K was used. The results indicate that oral administration of Vit-K, prepared from an intravenous Vit-K preparation, is safe and more effective to revert excessive anticoagulation than simply withholding warfarin, in places where specific preparation of oral Vit-K is not available or too expensive. PMID- 22522852 TI - [Hereditary angioedema. A therapeutic guide]. AB - Hereditary angioedema (HAE) is a rare autosomal dominant disease, characterized by episodes of edema involving the skin, gastrointestinal tract and larynx. HAE has a historical asphyxia mortality of 15% to 50%. It is the consequence of functional C1 inhibitor deficiency. The identification of bradykinin as the principal mediator of the disease has lead to the development of new drugs for its treatment. HAE management and treatment are agreed by international consensus decision. A therapeutic guide for the treatment of the disease is important to improve diagnosis and treatment. We here describe the pharmacology of drugs available for the treatment of HAE in Argentina: plasma derived C1 Inhibitor, the bradykinin antagonist: icatibant, the attenuated androgen danazol and the anti fibrinolytic agents epsilonaminocaproic acid and tranexamic acid. Furthermore, we describe drug use and adverse effects control, as well as the last international consensus document recommendations applicable to Argentina to conform a first guide to HAE treatment in our country. PMID- 22522853 TI - [Neuromyelitis optica with high aquaporin-4 expression and positive serum aquaporin-4 autoantibodies]. AB - Disease-specific aquaporin-4 antibodies (NMO-IgG) are the main effector of lesions in neuromyelitis optica (NMO) patients. Brain MRI lesions are detected in 60% of them, with 8% (almost infants) at sites of high aquaporin-4 expression. Patient 1: A fifty-year-old male with loss of vision in the right eye. Empiric treatment with metilprednisolone 1g/d for 3 days was indicated. After 30 days he complained of generalized pain, and a right hemiparesis was evident. The patient received bolus of metilprednisolone 1g/d for 5 days plus IgG 400 mg/kg/d IV for 5 days. He recovered ambulation but persisted with pain and paroxysmal phenomena (Lhermitte). Visual Evoked Potentials (VEP): P100 left eye 123 ms, right eye without response. Brain MRI (FLAIR) showed hyperintensity in the right optic nerve, hypothalamus and anterior white commissure. Cervical MRI showed extensive spinal cord lesion to an extension of 5 vertebral bodies. Patient 2: A fifty three-year-old female who referred decreased visual acuity in both eyes and paresthesia in lower limbs which subsided spontaneously. One month later the patient evolved with cuadriparesis and sphincter incontinence. No improvement was observed with bolus of metilprednisolone 1g/d for 5 day. VEP: P100 left eye 124 ms, right eye 128 ms. Brain MRI (FLAIR) disclosed hypothalamic and periaqueductal hyperintensity. Cervical MRI showed extensive spinal cord lesion to an extension of 7 vertebral bodies. NMO-IgG antibodies were positive in both patients (indirect immunofluorescence assay). NMO brain lesions at sites of high aquaporin 4 expression, once considered atypical for their topography and infrequency in adults, should be borne in mind when considering differential diagnosis. PMID- 22522854 TI - [High-risk massive pulmonary thromboembolism associated with patent foramen ovale]. AB - High mortality rate associated with massive pulmonary embolism requires an aggressive invasive approach including surgical pulmonary embolectomy when thrombolytic therapy has failed or is contraindicated. We describe a case of high risk massive pulmonary embolism who underwent surgical treatment due to the presence of a mobile intracardiac clot in a patent foramen ovale, and the possible risk of paradoxical arterial embolism. PMID- 22522855 TI - [Magnetic resonance images in Wilson's disease]. PMID- 22522856 TI - [Cutis verticis gyrata]. PMID- 22522857 TI - [Hyperglycemia in acute coronary syndrome: multidisciplinary scientific report]. AB - Hyperglycemia with or without pre-existing diabetes mellitus, occurs frequently in the setting of acute coronary syndrome. Previous studies have demonstrated that hyperglycemia is highly prevalent and is associated with an increased risk of hospital complications and death. The underlying pathophysiology related an adverse clinical outcome to hyperglycemia is unclear, and it is uncertain whether increased serum glucose is simply a marker of adverse outcomes or their cause. Detrimental effects of hyperglycemia on the cardiovascular system are multiple. Glycemia control with insulin would prevent adverse outcomes. Numerous glucose control protocols have been developed and tested proving to be safe and effective. In an initiative from the Emergency Council of the Argentine Society of Cardiology, local experts analyzed the management of hyperglycemia in acute coronary syndrome. The main objective of the prevent statement is to summarize the current state of knowledge on glycemic control, and to offer general recommendations regarding glucose management in the coronary care unit. PMID- 22522858 TI - [Vitamin D and cancer: antineoplastic effects of 1alpha,25(OH)2-vitamin D3]. AB - The hormonal form of vitamin D, 1alpha,25(OH)2-vitamin D3 (1alpha,25(OH)2D3), in addition of playing a central role in the control of calcium homeostasis in the body, regulates the growth and differentiation of different cell types, including cancer cells. At present several epidemiologic and clinical studies investigate the effect of the hormone in these cells due to the interest in the therapeutic use of 1alpha,25(OH)2D3 and analogues with less calcemic activity for prevention or treatment of cancer. This review describes vitamin D endocrine system, its mechanism of action, its antineoplastic activity and provides information about the latest advances in the study of new hormone analogues with less calcemic activity for cancer treatment. PMID- 22522859 TI - [Pulmonary hypertension and lung edema at high altitude. Role of endothelial dysfunction and fetal programming]. AB - High altitude constitutes an exciting natural laboratory for medical research. While initially, the aim of high-altitude research was to understand the adaptation of the organism to hypoxia and find treatments for altitude-related diseases, over the past decade or so, the scope of this research has broadened considerably. Two important observations led to the foundation for the broadening of the scientific scope of high-altitude research. First, high-altitude pulmonary edema (HAPE) represents a unique model which allows studying fundamental mechanisms of pulmonary hypertension and lung edema in humans. Secondly, the ambient hypoxia associated with high-altitude exposure facilitates the detection of pulmonary and systemic vascular dysfunction at an early stage. Here, we review studies that, by capitalizing on these observations, have led to the description of novel mechanisms underpinning lung edema and pulmonary hypertension and to the first direct demonstration of fetal programming of vascular dysfunction in humans. PMID- 22522860 TI - [Glucocorticoids: examples of translational medicine; from molecular aspects to bedside]. AB - Glucocorticoids are anti-inflammatory, immunosuppressant and anti-allergic drugs derived from hydrocortisone. Their widespread use was originated from Hench's observations in patients with rheumatoid arthritis. These drugs are examples of translational medicine and they can be envisaged as one of the most prescribed and feared drugs. The objective of this review is to highlight their pharmacological properties and thus, allow a more suitable prescription. PMID- 22522861 TI - [Lithium and its relation with the epithelial sodium channel and aquaporin-2]. AB - For more than 40 years lithium has been used to treat bipolar disorder and recent trials suggest a potential efficacy also in the treatment of the amnestic mild cognitive impairment. Lithium is filtered by the glomerulus and 65% - 75% of the filtered amount is reabsorbed along the proximal tubule and in the thick ascending limb of Henle's loop by the Na+, K+, 2Cl- transporter and via paracellular. A small fraction of lithium is reabsorbed in the collecting duct's principal cells through the epithelial Na channel (ENaC) located on the apical side of the cells. Polyuria, renal tubular acidosis and chronic renal failure are the most frequent adverse effects of lithium after 10-20 years of treatment and these alterations can reach to a vasopressin nonresponding form of diabetes insipidus entity called nephrogenic diabetes insipidus. It is believed that the molecular mechanisms of these renal changes are related to a reduction in the number of aquaporin-2 inserted in the apical membrane of the cells. The causes of this are complex. Lithium is a powerful inhibitor of the enzyme glycogen synthase kinase 3beta and this is associated with a lower activity of adenylate cyclase with a reduction in the cAMP levels inside of the cells. The latter may interfere with the synthesis of aquaporin-2 and also with the traffic of these molecules from the subapical site to membrane promoting the impairment of water reabsorption in the distal part of the kidney. PMID- 22522862 TI - [The price of progress. The rise of all-administrative university]. PMID- 22522863 TI - [Predicting the future. The death of paper books]. PMID- 22522864 TI - [False positives in medicine]. PMID- 22522866 TI - [It's the patient, stupid!]. PMID- 22522867 TI - [Clinical judicial syndrome]. PMID- 22522869 TI - [Remembering Eugenia Sacerdote de Lustig (1910-2011)]. PMID- 22522870 TI - [Frequency of medication errors by patients]. AB - OBJECTIVE: Analyze the frequency of medication errors committed and reported by patients. METHODS: Descriptive study based on a telephone survey of a random sample of adult patients from the primary care level of the Spanish public health care system. A total of 1 247 patients responded (75% response rate); 63% were women and 29% were older than 70 years. RESULTS: While 37 patients (3%, 95% CI: 2 4) experienced complications associated with medication in the course of treatment, 241 (19.4%, 95% CI: 17-21) reported having made some mistake with their medication. A shorter consultation time (P < 0.01) and a worse assessment of the information provided by the physician (P < 0.01) were associated with the fact that during pharmacy dispensing the patient was told that the prescribed treatment was not appropriate. CONCLUSIONS: In addition to the known risks of an adverse event due to a health intervention resulting from a system or practitioner error, there are risks associated with patient errors in the self administration of medication. Patients who were unsatisfied with the information provided by the physician reported a greater number of errors. PMID- 22522871 TI - Population study of depressive symptoms and risk factors in pregnant and parenting Mexican adolescents. AB - OBJECTIVE: To study the prevalence of, severity of, and risk factors for depressive symptoms in a probabilistic sample of Mexican adolescent mothers. METHODS: A sample of adolescents aged 13-19 years, drawn from a national survey, was interviewed in relation to severity of depressive symptoms [Center for Epidemiological Studies Depression Scale (CES-D) 16-23 and CES-D > 24] and pregnancy or parenting status. RESULTS: Depressive symptoms (CES-D 16-23) ranged from 2.3% in the first postpartum semester to 32.5% in the second trimester of pregnancy; high depressive symptoms (CES-D > 24) ranged from 3.0% in the second postpartum semester to 24.7% in mothers of an infant more than 1 year old. Significant differences between groups were in mothers in the second gestation trimester, who had significantly more symptoms than those who had never been pregnant and those in the first postpartum semester. In those with high symptomatology, no significant differences were observed between groups. A multinomial logistic regression model used to estimate the likelihood of depression found increased risk of depressive symptoms (CES-D 16-23) in those without a partner in the first, second, or third trimester of pregnancy; in the second postpartum semester; and with a child over the age of 1 year. Increased risk of high symptomatology (CES-D > 24) was found in those not in school or with a child over the age of 1 year. CONCLUSIONS: Depressive symptoms entail an enormous burden of disease for the mother and mental health risks to the infant; mothers should therefore be targeted in prevention and intervention actions. PMID- 22522872 TI - Registration of work-related diseases, injuries, and complaints in Aruba, Bonaire, and Curacao. AB - OBJECTIVE: To estimate the incidence of work-related diseases, injuries, and complaints in Aruba, Bonaire, and Curacao and to identify some next steps in the prevention process. METHODS: All of the three countries' 18 occupational health specialists were asked to participate; 100% agreed to report all work-related diseases, injuries, and complaints in 2004-2008. A standard online notification form was used to register cases in a database maintained by the Netherlands Center for Occupational Diseases (NCOD). The public health service of Curacao analyzed the data and presented the results to the participating physicians during educational and feedback meetings. RESULTS: During the study period, 1 519 cases were reported: 720 (47.0%) work-related diseases; 515 (34.0%) injuries; and 284 (19.0%) complaints. The mean patient age was 42.4 years (range 16-70 years); 924 (60.8%) were males and 571 (37.6%), females. Most frequently reported were musculoskeletal diseases, injuries, and complaints; mental health disorders; and skin injuries. Analysis showed incidence rates of work-related diseases, injuries, and complaints in Aruba to be 157 new cases per 100 000 employee years; in Bonaire, 53/100 000; and in Curacao, 437/100 000. CONCLUSIONS: These results suggest that labor protection laws need improvement and that preventive action should be fostered. Further study is needed on working conditions, preventive policy, and the quality of occupational health and safety practices in Aruba, Bonaire, and Curacao. Funding is imperative for collecting and publishing accurate data, which will keep this problem on the social-political agenda. PMID- 22522873 TI - [Health promotion education in the context of primary care]. AB - OBJECTIVE: To investigate whether the educational initiatives carried out in basic health units in Belo Horizonte, Minas Gerais, Brazil, follows the principles of health promotion. METHODS: This descriptive study examined 33 educational health promotion initiatives to determine whether they were guided by five principles, used as categories of analysis: multicausality of the health disease process, intersectoriality, social engagement, sustainability, and use of dialogic teaching methods (active participation of subjects in the learning process, planning the activity to generate new knowledge, and use of various teaching strategies). Structured observation was used for data collection. The frequency of each category was evaluated in each initiative. RESULTS: Multicausality was the most frequent category observed (73.0%), and intersectoriality the least frequent (9.0%). Regarding the use of dialogic methods, 38.0% of the initiatives promoted the active engagement of subjects, 6.0% promoted knowledge generation, and 40.0% employed a variety of teaching strategies. CONCLUSIONS: Most educational initiatives were not actively oriented toward health promotion, understood as the strengthening of autonomy and self management of health processes, social engagement, and employment of dialogic teaching approaches. However, some progress has been made moving away from hegemonic models of education in primary health care. PMID- 22522874 TI - Predictive factors for repetition of the tuberculin test after a nonreactive test in patients with HIV/AIDS. AB - OBJECTIVE: The outcome of interest was repetition of the tuberculin skin test (TST) and the objectives were to estimate the rate of TST repetition, the probability of no TST repetition after 1 year, and the probability of no TST repetition at the end of the follow-up period in patients whose initial test was nonreactive. The study also set out to analyze factors associated with the time until TST repetition at two HIV/AIDS referral services that carry out the TST on a routine basis in Recife, Pernambuco, Brazil. METHODS: A cohort of HIV-positive patients who initially tested nonreactive on the TST were followed from November 2007 to February 2010. The Kaplan-Meier method was used to estimate the probability of not repeating the TST, and Cox's regression analysis was used to analyze the factors associated with time until repeating the TST. Cox's multivariate analysis was stratified according to each hospital where patients were followed, because this variable did not respect the principle of proportionality of risk. RESULTS: The probability of not repeating the TST for 1 year was 80.0% and at the end of the follow-up period it was 42.0%. The variables that remained associated with TST repetition in the final Cox multivariate model were an age of 40 years or older, body mass index between 18.0 and 24.9, being female, and years of schooling. CONCLUSIONS: This study encountered a very low TST repetition rate after 1 year of follow-up and identified groups of individuals who should be the target of interventions aimed at repeating the TST. PMID- 22522875 TI - Preliminary reliability and validity of the Spanish Generalized Expectancies for Negative Mood Regulation Scale. AB - OBJECTIVE: This article introduces a Spanish version of the Generalized Expectancies for Negative Mood Regulation Scale (NMR-S) and tests the reliability and the validity of the new questionnaire. METHODS: A sample of 360 students from Chile completed the NMR-S along with instruments measuring depressive symptoms, social desirability, coping, and emotion regulation. RESULTS: A factor analysis indicated that the NMR-S has a one-dimensional structure. The reliability of the new instrument was alpha = 0.89. The concurrent validity of the NMR-S was supported by correlations with measures of coping, emotion regulation, and depressive symptoms. Furthermore, the NMR-S predicted depressive symptoms when controlling for emotion regulation and coping. CONCLUSIONS: The findings are the first evidence to support the reliability and validity of the NMR-S. PMID- 22522876 TI - [Racial inequity in oral health in Brazil]. AB - OBJECTIVE: To identify racial inequities in oral health between groups of adults selfdeclared as white, black, or mixed in Brazil. METHODS: Secondary data were obtained from the national oral health survey of the Brazilian population (SB Brasil 2002-2003) database. Initially, a cross-sectional study was conducted to compare the following outcome variables: caries, tooth loss, pain of dental origin, and need for prostheses according to race/color in a sample of 12 811 adults of both sexes, aged 35 to 44 years. In the second stage, an ecologic study was carried out with data aggregated by Brazilian state to contextualize racial inequity in a population of 6 918 black individuals (black and mixed). For that, the oral health outcomes studied in the first stage were correlated with human development and income distribution indicators. RESULTS: Significant differences were observed between the race/color groups for all oral health outcomes examined (P < 0.01). Correlations were found between oral health outcomes and indicators related to the human development profile, average family income, and income inequality by state for the group of Brazilian blacks. CONCLUSIONS: The results show racial inequity in oral health in Brazil for all the indicators analyzed (caries, tooth loss, pain, and need for prostheses), with greater vulnerability among the black population compared to whites. Contextual factors related to the human development profile, income distribution, and access to health care policies appear to play a key role in describing the vulnerability of populations to oral health problems. PMID- 22522877 TI - [Diarrheal disease caused by rotavirus in epidemic outbreaks]. AB - OBJECTIVE: Determine the epidemiological profile of outbreaks of acute diarrheal disease caused by rotavirus (RV) occurring in pediatric patients, based on a critical review of the literature published between 2000 and 2010. METHODS: A search was carried out for articles published from January 2000 to April 2010, collected by the Artemisa, EBSCO, Embase, Imbiomed, Lilacs, Ovid, PubMed, and Science Direct databases. In the studies that met the inclusion criteria, possible confounding factors were identified and risks of bias were attributed based on the number of items considered inadequate in each case. The epidemiological and microbiological characteristics of the outbreaks were described. RESULTS: The sample was comprised of only 14 (10.8%) of the 129 titles identified, which accounted for 91 092 reported cases of acute diarrhea. In 5 250 of these cases, a search for rotavirus was conducted, yielding 1 711 (32.5%) positive isolations. It was observed that the RV from Group A was the causative agent in 100% of the outbreaks, while genotype G9 was documented in 50% of the articles. CONCLUSIONS: Rotavirus, mainly serotype G9, was one of the principal agents responsible for outbreaks of acute diarrheal disease over the past decade. A careful outbreak study can contribute valuable information for RV disease control and prevention. PMID- 22522878 TI - [Atraumatic restorative treatment: a dental alternative well-received by children]. AB - The purpose of this study is to compare atraumatic restorative treatment (ART) with the conventional rotational restorative method (CM) to determine in both cases the total time required for the procedure, the cost, the presence of pain, and the behavior of pediatric patients in Peru. Of the 30 children selected for the study, half received ART and restoration with glass ionomer cement and the other half, CM and restoration with amalgam. The study parameters were the times required to remove the decayed tissue and to complete the entire procedure, the total cost of the procedure, the presence of pain, and the patient's behavior during treatment. Significant differences were found between the two techniques in all parameters, except for the patient's behavior. Although removing the decayed tissue was faster with the CM, the entire procedure was faster with ART, which, moreover, was significantly less expensive and less painful than the CM. The results indicated that ART is a very good alternative due to its low cost and acceptance by the children. PMID- 22522879 TI - [Share of health care activities in the Brazilian economy: information on Health Accounts from 2000 to 2007]. AB - OBJECTIVE: To describe the share of health care activities in the Brazilian economy between 2000 and 2007 in terms of economic value added and creation of jobs. METHODS: Secondary data from the Brazilian Institute of Geography and Statistics (IBGE) for the years 2000 to 2007 were employed. The following health care activities were analyzed: public health, production of private health services and private social services, health insurance, the pharmaceutical industry, medical equipment manufacturing, and medical and pharmaceutical product sales. The share of each activity in the total economy and in the health care sector was calculated, as well as the percentage share of value-added components from the perspective of income for health care activities and the real growth in value added by health care activity. To complement the analysis, the average income of workers and the number of jobs per activity were established. RESULTS: The participation of the health care sector in the economy ranged from 5.2% to 5.8%. The share of public health increased from 1.7% to 2.0%, and that of private healthcare services fell from 2.4% to 2.2%. The average annual growth of 3.5% for the sector was close to the 3.4% annual growth recorded for the economy. The share of medical and pharmaceutical product commerce in the sector increased from 9.1% to 13.2%. The activities with the highest accumulated growth were: manufacture of medical/hospital devices (42.7%), public health (39.4%), and health insurance (35.8%). Health care represented 4.1% of jobs in the economy in 2000 vs. 4.4% in 2007, with 1 million new jobs. Income from labor represented 6.7% of the total economy in 2000 and 7.5% in 2007. CONCLUSIONS: The health care sector has an important stake in the Brazilian economy, although this share is still lower than that observed in high-income countries. The rising share of public services in the sector's added value, the relative growth of medical and pharmaceutical product sales margins, and a real growth below the average for the pharmaceutical industry should be monitored. PMID- 22522880 TI - [Health: an adaptive complex system]. AB - This article points out the enormous gap that exists between complex thinking of an intellectual nature currently present in our environment, and complex experimental thinking that has facilitated the scientific and technological advances that have radically changed the world. The article suggests that life, human beings, global society, and all that constitutes health be considered as adaptive complex systems. This idea, in turn, prioritizes the adoption of a different approach that seeks to expand understanding. When this rationale is recognized, the principal characteristics and emerging properties of health as an adaptive complex system are sustained, following a care and services delivery model. Finally, some pertinent questions from this perspective are put forward in terms of research, and a series of appraisals are expressed that will hopefully serve to help us understand all that we have become as individuals and as a species. The article proposes that the delivery of health care services be regarded as an adaptive complex system. PMID- 22522881 TI - [Social class and health in Latin America]. AB - This paper reviews the principal concepts of social class, occupation, and social stratification, and their contribution to the analysis of the social determinants of health (SDH), and reviews empirical studies conducted in Latin America that use employment relations as an SDH. The review focuses on studies of the relationship between health and social class based on neo-Weberian or neo-Marxist perspectives. A search of the BIREME Virtual Health Library and the SciELO database found 28 articles meeting these characteristics. This relative dearth contrasts with the profusion of papers that use these approaches written in Europe and in the United States, with a long tradition in the analysis of SDH. In this regard, the political and programmatic implications of research on social class and employment relations are different from and complementary to studies of health gradients associated with income and education. Globalization of employment relations requires the development of new concepts to explain and measure the mechanisms of action of the SDH going beyond what is strictly labor related; in particular, the importance in the current Latin American reality of the impact of informal work on health. PMID- 22522882 TI - [Hospitals safe from disasters: a reflection on architecture and biosafety]. AB - One of the biggest challenges in today's society is facing adversity caused by disasters. Health facilities, especially hospitals, are considered essential in these situations. This article discusses the principles of architectural design of hospitals safe from disasters, as proposed by the World Health Organization and the Pan American Health Organization. Designing a safe hospital requires multidisciplinary efforts, involving administrators, architects, engineers, physicians, and nurses. The planning of each hospital demands the analysis of specific risks and safety concerns. The concept of biosafety should also be addressed in planning safe hospitals. The balance between architectural aspects and biosafety provides an understanding of work-associated risks, facilitating the adequate planning of spaces to support response actions to emergencies. In short, the planning of a safe hospital requires the synthesis of various types of expertise, including those relating to biosafety and architecture. These principles should support the appraisal of safe hospitals and architectural planning with a focus on preparing facilities to function at full capacity even in the face of adverse situations. PMID- 22522883 TI - The effects of overfeeding on spontaneous physical activity in obesity prone and obesity resistant humans. AB - Despite living in an environment that promotes weight gain in many individuals, some individuals maintain a thin phenotype while self-reporting expending little or no effort to control their weight. When compared with obesity prone (OP) individuals, we wondered if obesity resistant (OR) individuals would have higher levels of spontaneous physical activity (SPA) or respond to short-term overfeeding by increasing their level of SPA in a manner that could potentially limit future weight gain. SPA was measured in 55 subjects (23 OP and 32 OR) using a novel physical activity monitoring system (PAMS) that measured body position and movement while subjects were awake for 6 days, either in a controlled eucaloric condition or during 3 days of overfeeding (1.4 * basal energy) and for the subsequent 3 days (ad libitum recovery period). Pedometers were also used before and during use of the PAMS to provide an independent measure of SPA. SPA was quantified by the PAMS as fraction of recording time spent lying, sitting, or in an upright posture. Accelerometry, measured while subjects were in an upright posture, was used to categorize time spent in different levels of movement (standing, walking slowly, quickly, etc.). There were no differences in SPA between groups when examined across all study periods (P > 0.05). However, 3 days following overfeeding, OP subjects significantly decreased the amount of time they spent walking (-2.0% of time, P = 0.03), whereas OR subjects maintained their walking (+0.2%, P > 0.05). The principle findings of this study are that increased levels of SPA either during eucaloric feeding or following short term overfeeding likely do not significantly contribute to obesity resistance although a decrease in SPA following overfeeding may contribute to future weight gain in individuals prone to obesity. PMID- 22522884 TI - Upregulation of plasma insulin-like growth factor binding protein 2 levels after biliopancreatic diversion in humans. AB - The biliopancreatic diversion surgery with duodenal switch (BPD-DS) is a surgical procedure that not only induces significant weight loss, but also promotes remission of diabetes. However, the mechanism responsible for this insulin potentiating effect (both on sensitivity and production) is not yet clearly understood. The insulin-like growth factor (IGF) binding protein 2 (IGFBP-2) is a 36 kDa circulating protein that has been recently suggested to modulate insulin sensitization and fat accumulation. In humans, a low-circulating concentration of IGFBP-2 has been associated with obesity and insulin resistance. We thus tested the hypothesis that BPD-DS would trigger an increase in IGFBP-2 levels. Plasma IGFBP-2 was quantified by enzyme-linked immunosorbent assay in 77 severely obese men and women before and up to 1 year after BPD-DS surgery. Baseline IGFBP-2 levels were 159 +/- 17 ng/ml. Plasma IGFBP-2 levels increased significantly as soon as 24 h after BPD-DS surgery and were further augmented at both 6 months and 1 year after the surgery, reaching 748 +/- 65 ng/ml. Changes in IGFBP-2 concentrations were significantly and negatively associated with blood glucose, insulin, triglycerides, and total cholesterol levels. The present findings suggest that the rise in IGFBP-2 levels is associated with the improvements in glucose and lipid metabolism in the short- and long-term after BPD-DS. The mechanisms for the augmentation in IGFBP-2 after BPD-DS and its contribution to insulin sensitization remain to be elucidated. PMID- 22522885 TI - Body composition at 6 months of life: comparison of air displacement plethysmography and dual-energy X-ray absorptiometry. AB - Body composition assessment during infancy is important because it is a critical period for obesity risk development, thus valid tools are needed to accurately, precisely, and quickly determine both fat and fat-free mass. The purpose of this study was to compare body composition estimates using dual-energy x-ray absorptiometry (DXA) and air displacement plethysmography (ADP) at 6 months old. We assessed the agreement between whole body composition using DXA and ADP in 84 full-term average-for-gestational-age boys and girls using DXA (Lunar iDXA v11 30.062; Infant whole body analysis enCore 2007 software, GE, Fairfield, CT) and ADP (Infant Body Composition System v3.1.0, COSMED USA, Concord, CA). Although the correlations between DXA and ADP for %fat (r = 0.925), absolute fat mass (r = 0.969), and absolute fat-free mass (r = 0.945) were all significant, body composition estimates by DXA were greater for both %fat (31.1 +/- 3.6% vs. 26.7 +/- 4.7%; P < 0.001) and absolute fat mass (2,284 +/- 449 vs. 1,921 +/- 492 g; P < 0.001), and lower for fat-free mass (5,022 +/- 532 vs. 5,188 +/- 508 g; P < 0.001) vs. ADP. Inter-method differences in %fat decreased with increasing adiposity and differences in fat-free mass decreased with increasing infant age. Estimates of body composition determined by DXA and ADP at 6 months of age were highly correlated, but did differ significantly. Additional work is required to identify the technical basis for these rather large inter-method differences in infant body composition. PMID- 22522886 TI - Short-term lenalidomide (Revlimid) administration ameliorates cardiomyocyte contractile dysfunction in ob/ob obese mice. AB - Lenalidomide is a potent immunomodulatory agent capable of downregulating proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and upregulating anti-inflammatory cytokines. Lenalidomide has been shown to elicit cardiovascular effects, although its impact on cardiac function remains obscure. This study was designed to examine the effect of lenalidomide on cardiac contractile function in ob/ob obese mice. C57BL lean and ob/ob obese mice were given lenalidomide (50 mg/kg/day, p.o.) for 3 days. Body fat composition was assessed by dual-energy X-ray absorptiometry. Cardiomyocyte contractile and intracellular Ca(2+) properties were evaluated. Expression of TNF-alpha, interleukin-6 (IL-6), Fas, Fas ligand (FasL), the short-chain fatty acid receptor GPR41, the NFkappaB regulator IkappaB, endoplasmic reticulum (ER) stress, the apoptotic protein markers Bax, Bcl-2, caspase-8, tBid, cytosolic cytochrome C, and caspase-12; and the stress signaling molecules p38 and extracellular signal regulated kinase (ERK) were evaluated by western blot. ob/ob mice displayed elevated serum TNF-alpha and IL-6 levels, fat composition and glucose intolerance, the effects of which except glucose intolerance and fat composition were attenuated by lenalidomide. Cardiomyocytes from ob/ob mice exhibited depressed peak shortening (PS) and maximal velocity of shortening/relengthening, prolonged time-to-PS and time-to-90% relengthening as well as intracellular Ca(2+) mishandling, which were ablated by lenalidomide. Western blot analysis revealed elevated levels of TNF-alpha, IL-6, Fas, Bip, Bax, caspase-8, tBid, cleaved caspase-3 caspase-12, cytochrome C, phosphorylation of p38, and ERK in ob/ob mouse hearts, the effects of which with the exception of Bip, Bax, and caspase-12 were alleviated by lenalidomide. Taken together, these data suggest that lenalidomide is protective against obesity-induced cardiomyopathy possibly through antagonism of cytokine/Fas-induced activation of stress signaling and apoptosis. PMID- 22522887 TI - Sexual functioning and obesity: a review. AB - We review the literature on the relationship between obesity and sexual functioning. Eleven population-based studies, 20 cross-sectional non-population based studies, and 16 weight loss studies are reviewed. The consistency of findings suggests that the relationship between obesity and reduced sexual functioning is robust, despite diverse methods, instruments, and settings. In most population-based studies, erectile dysfunction (ED) is more common among obese men than among men of recommended weight. Studies of patients in clinical settings often include individuals with higher degrees of obesity, with most studies showing a relationship between obesity and lower levels of sexual functioning, especially ED. The few studies that include both genders generally report more problems among women. Most studies of patients with comorbidities associated with obesity also find an association between obesity and reduced sexual functioning. Most weight loss studies demonstrate improvement in sexual functioning concurrent with weight reduction despite varying study designs, weight loss methods, and follow-up periods. We recommend that future studies (i) investigate differences and similarities between men and women with respect to obesity and sexual functioning, (ii) use instruments that go beyond the assessment of sexual dysfunction to include additional concepts such as sexual satisfaction, interest, and arousal and, (iii) assess how and the degree to which obese individuals are affected by sexual difficulties. Given the high prevalence of obesity and the inverse association between body mass and sexual functioning, we also recommend that sexual functioning should be more fully addressed by clinicians, both in general practice and in weight loss programs. PMID- 22522888 TI - A novel transgenic line using the Cre-lox system to allow permanent lineage labeling of the zebrafish neural crest. AB - Accurate lineage tracing is crucial to understanding of developmental and stem cell biology, but is particularly challenging for transient and highly dispersive cell-types like the neural crest (NC). The authors report in this article a new zebrafish transgenic line Tg(-4725sox10:Cre)(ba74). This line expresses Cre under the control of a well-characterized portion of the sox10 promoter and, by crossing to a floxed-reporter line, the authors show in this article that expression in this line is consistent with those described for GFP reporter lines using the same promoter. Reporter expression is readily detected in patterns consistent with the early expression domains. Thus, the authors see all major groups (pigment, neural, and skeletal) of NC-derived cell-types, as well as cell types derived from the known non-NC sites of sox10 expression, including otic epithelium and oligodendrocytes. This line provides an invaluable tool for the further study of zebrafish NC development and NC-derived stem cells as well as that of the otic vesicle and oligodendrocytes. PMID- 22522890 TI - Direct crystallographic observation of catalytic reactions inside the pores of a flexible coordination polymer. AB - A new flexible porous coordination polymer (PCP), {[Gd(2)(L)(3)(dmf)(4)].4DMF.3H(2)O}(n) (1), was synthesized under solvothermal condition by reacting [Gd(NO(3))(3)].6H(2)O with the ligand 2,6,2',6'-tetranitro biphenyl-4,4'-dicarboxylic acid (H(2)L). Compound 1 had a 3D coordination polymeric structure with two types of 1D channels (A and B) that were occupied by DMF and water molecules. When crystals of 1 were separately exposed to vapors of various aromatic aldehydes, either the lattice or both the lattice and metal bound solvent molecules were replaced by aldehyde molecules. The aldehyde molecules inside the pores spontaneously underwent cyanosilylation and Knoevenagel condensation reactions upon exposure to vapors of trimethylsilyl cyanide and malononitrile, respectively. These reactions took place at ambient temperature and pressure. Moreover, both the reactants and the products translocated from one cavity to another. The products that occupied the cavity were expunged upon exposure to the vapors of an aldehyde. Because crystallinity was maintained during these chemical transformations, direct crystallographic observation was possible. Herein, we showed that confinement of the reactants inside the void spaces of the PCP led to the products; we also assessed catalytic activities of this PCP in bulk quantities. PMID- 22522889 TI - Expression of GABAergic and glutamatergic phenotypic markers in hypothalamic proopiomelanocortin neurons. AB - Hypothalamic proopiomelanocortin (POMC) neurons have traditionally been defined by their peptide transmitters, which are important regulators of energy balance and reward. Recent work shows that POMC neurons can also release the amino acid transmitters gamma-aminobutyric acid (GABA) and glutamate, although studying GABAergic and glutamatergic populations of POMC neurons has been hindered by the difficulty in reliably identifying amino acid (AA) transmitter phenotypes. In the present study, fluorescent in situ hybridization and immunohistochemistry were used to identify POMC neurons and to detect the presence of mRNA for the transporters responsible for packaging either GABA (vesicular GABA transporter [vGAT]) or glutamate (vesicular glutamate transporter [vGLUT]) into vesicles, as well as the enzymes responsible for GABA synthesis, glutamic acid decarboxylase (GAD)65 and GAD67. Approximately 7% of POMC neurons expressed vGlut2 and the highest percentage of vGlut2-positive POMC cells were located in the rostral arcuate nucleus. Despite the reports of GABA release from POMC neurons, vGat was not detected in POMC neurons, although Gad65 and Gad67 were present in ~40% of POMC neurons. Approximately half of the vGlut2-expressing POMC cells also expressed Gad65. Markers of neurotransmitter phenotype were better detected by using in situ hybridization techniques rather than transgenic expression of fluorophores under the control of the vGat or Gad67 promoters. It is now clear that the expression of markers of AA phenotype provides a useful means to identify distinct subpopulations of POMC neurons. Additionally, the method described will be useful to explore the possibility that plasticity of AA phenotype is an important aspect of POMC neuron function. PMID- 22522891 TI - Computational analysis of cysteine and methionine metabolism and its regulation in dairy starter and related bacteria. AB - Sulfuric volatile compounds derived from cysteine and methionine provide many dairy products with a characteristic odor and taste. To better understand and control the environmental dependencies of sulfuric volatile compound formation by the dairy starter bacteria, we have used the available genome sequence and experimental information to systematically evaluate the presence of the key enzymes and to reconstruct the general modes of transcription regulation for the corresponding genes. The genomic organization of the key genes is suggestive of a subdivision of the reaction network into five modules, where we observed distinct differences in the modular composition between the families Lactobacillaceae, Enterococcaceae, and Leuconostocaceae, on the one hand, and the family Streptococcaceae, on the other. These differences are mirrored by the way in which transcription regulation of the genes is structured in these families. In the Lactobacillaceae, Enterococcaceae, and Leuconostocaceae, the main shared mode of transcription regulation is methionine (Met) T-box-mediated regulation. In addition, the gene metK, encoding S-adenosylmethionine (SAM) synthetase, is controlled via the S(MK) box (SAM). The S(MK) box is also found upstream of metK in species of the family Streptococcaceae. However, the transcription control of the other modules is mediated via three different LysR-family regulators, MetR/MtaR (methionine), CmbR (O-acetyl[homo]serine), and HomR (O acetylhomoserine). Redefinition of the associated DNA-binding motifs helped to identify/disentangle the related regulons, which appeared to perfectly match the proposed subdivision of the reaction network. PMID- 22522892 TI - Iron regulates expression of Bacillus cereus hemolysin II via global regulator Fur. AB - The capacity of pathogens to respond to environmental signals, such as iron concentration, is key to bacterial survival and establishment of a successful infection. Bacillus cereus is a widely distributed bacterium with distinct pathogenic properties. Hemolysin II (HlyII) is one of its pore-forming cytotoxins and has been shown to be involved in bacterial pathogenicity in a number of cell and animal models. Unlike many other B. cereus pathogenicity factors, HlyII is not regulated by pleiotropic transcriptional regulator PlcR but is controlled by its own regulator, HlyIIR. Using a combination of in vivo and in vitro techniques, we show that hlyII expression is also negatively regulated by iron by the global regulator Fur via direct interaction with the hlyII promoter. DNase I footprinting and in vitro transcription experiments indicate that Fur prevents RNA polymerase binding to the hlyII promoter. HlyII expression profiles demonstrate that both HlyIIR and Fur regulate HlyII expression in a concerted fashion, with the effect of Fur being maximal in the early stages of bacterial growth. In sum, these results show that Fur serves as a transcriptional repressor for hlyII expression. PMID- 22522893 TI - Natural transformation of an engineered Helicobacter pylori strain deficient in type II restriction endonucleases. AB - Restriction-modification (RM) systems are important for bacteria to limit foreign DNA invasion. The naturally competent bacterium Helicobacter pylori has highly diverse strain-specific type II systems. To evaluate the roles of strain-specific restriction in H. pylori natural transformation, a markerless type II restriction endonuclease-deficient (REd) mutant was constructed. We deleted the genes encoding all four active type II restriction endonucleases in H. pylori strain 26695 using sacB-mediated counterselection. Transformation by donor DNA with exogenous cassettes methylated by Escherichia coli was substantially (1.7 and 2.0 log(10) for cat and aphA, respectively) increased in the REd strain. There also was significantly increased transformation of the REd strain by donor DNA from other H. pylori strains, to an extent corresponding to their shared type II R-M system strain specificity with 26695. Comparison of the REd and wild-type strains indicates that restriction did not affect the length of DNA fragment integration during natural transformation. There also were no differentials in cell growth or susceptibility to DNA damage. In total, the data indicate that the type II REd mutant has enhanced competence with no loss of growth or repair facility compared to the wild type, facilitating H. pylori mutant construction and other genetic engineering. PMID- 22522895 TI - Effects of the SpoVT regulatory protein on the germination and germination protein levels of spores of Bacillus subtilis. AB - Bacillus subtilis isolates lacking the SpoVT protein, which regulates gene expression in developing forespores, gave spores that released their dipicolinic acid (DPA) via germinant receptor (GR)-dependent germination more rapidly than wild-type spores. Non-GR-dependent germination via dodecylamine was more rapid with spoVT spores, but germination via Ca-DPA was slower. The effects of a spoVT mutation on spore germination were seen with spores made in rich and poor media, and levels of SpoVT-LacZ were elevated 2-fold in poor-medium spores; however, elevated SpoVT levels were not the only cause of the slower GR-dependent germination of poor-medium spores. The spoVT spores had >=5-fold higher GerA GR levels, ~2-fold elevated GerB GR levels, wild-type levels of a GerK GR subunit and the GerD protein required for normal GR-dependent germination, ~2.5-fold lower levels of the SpoVAD protein involved in DPA release in spore germination, and 30% lower levels of DNA protective alpha/beta-type small, acid-soluble spore proteins. With one exception, the effects on protein levels in spoVT spores are consistent with the effects of SpoVT on forespore transcription. The spoVT spores were also more sensitive to UV radiation and outgrew slowly. While spoVT spores' elevated GR levels were consistent with their more rapid GR-dependent germination, detailed analysis of the results suggested that there is another gene product crucial for GR-dependent spore germination that is upregulated in the absence of SpoVT. Overall, these results indicate that SpoVT levels during spore formation have a major impact on the germination and the resistance of the resultant spores. PMID- 22522896 TI - The Azospirillum brasilense Che1 chemotaxis pathway controls swimming velocity, which affects transient cell-to-cell clumping. AB - The Che1 chemotaxis-like pathway of Azospirillum brasilense contributes to chemotaxis and aerotaxis, and it has also been found to contribute to regulating changes in cell surface adhesive properties that affect the propensity of cells to clump and to flocculate. The exact contribution of Che1 to the control of chemotaxis and flocculation in A. brasilense remains poorly understood. Here, we show that Che1 affects reversible cell-to-cell clumping, a cellular behavior in which motile cells transiently interact by adhering to one another at their nonflagellated poles before swimming apart. Clumping precedes and is required for flocculation, and both processes appear to be independently regulated. The phenotypes of a DeltaaerC receptor mutant and of mutant strains lacking cheA1, cheY1, cheB1, or cheR1 (alone or in combination) or with che1 deleted show that Che1 directly mediates changes in the flagellar swimming velocity and that this behavior directly modulates the transient nature of clumping. Our results also suggest that an additional receptor(s) and signaling pathway(s) are implicated in mediating other Che1-independent changes in clumping identified in the present study. Transient clumping precedes the transition to stable clump formation, which involves the production of specific extracellular polysaccharides (EPS); however, production of these clumping-specific EPS is not directly controlled by Che1 activity. Che1-dependent clumping may antagonize motility and prevent chemotaxis, thereby maintaining cells in a metabolically favorable niche. PMID- 22522894 TI - Cyclic diguanylate inversely regulates motility and aggregation in Clostridium difficile. AB - Clostridium difficile-associated disease is increasing in incidence and is costly to treat. Our understanding of how this organism senses its entry into the host and adapts for growth in the large bowel is limited. The small-molecule second messenger cyclic diguanylate (c-di-GMP) has been extensively studied in gram negative bacteria and has been shown to modulate motility, biofilm formation, and other processes in response to environmental signals, yet little is known about the functions of this signaling molecule in gram-positive bacteria or in C. difficile specifically. In the current study, we investigated the function of the second messenger c-di-GMP in C. difficile. To determine the role of c-di-GMP in C. difficile, we ectopically expressed genes encoding a diguanylate cyclase enzyme, which synthesizes c-di-GMP, or a phosphodiesterase enzyme, which degrades c-di-GMP. This strategy allowed us to artificially elevate or deplete intracellular c-di-GMP, respectively, and determine that c-di-GMP represses motility in C. difficile, consistent with previous studies in gram-negative bacteria, in which c-di-GMP has a negative effect on myriad modes of bacterial motility. Elevated c-di-GMP levels also induced clumping of C. difficile cells, which may signify that C. difficile is capable of forming biofilms in the host. In addition, we directly quantified, for the first time, c-di-GMP production in a gram-positive bacterium. This work demonstrates the effect of c-di-GMP on the motility of a gram-positive bacterium and on aggregation of C. difficile, which may be relevant to the function of this signaling molecule during infection. PMID- 22522897 TI - Complete DNA sequence analysis of enterohemorrhagic Escherichia coli plasmid pO157_2 in beta-glucuronidase-positive E. coli O157:H7 reveals a novel evolutionary path. AB - Strains of enterohemorragic Escherichia coli (EHEC) O157:H7 that are non-sorbitol fermenting (NSF) and beta-glucuronidase negative (GUD(-)) carry a large virulence plasmid, pO157 (>90,000 bp), whereas closely related sorbitol-fermenting (SF) E. coli O157:H(-) strains carry plasmid pSFO157 (>120,000 bp). GUD(+) NSF O157:H7 strains are presumed to be precursors of GUD(-) NSF O157:H7 strains that also carry pO157. In this study, we report the complete sequence of a novel virulence plasmid, pO157-2 (89,762 bp), isolated from GUD(+) NSF O157:H7 strain G5101. PCR analysis confirmed the presence of pO157-2 in six other strains of GUD(+) NSF O157:H7. pO157-2 carries genes associated with virulence (e.g., hemolysin genes) and conjugation (tra and trb genes) but lacks katP and espP present in pO157. Comparative analysis of the three EHEC plasmids shows that pO157-2 is highly related to pO157 and pSFO157 but not ancestral to pO157. These results indicated that GUD(+) NSF O157:H7 strains might not be direct precursors to GUD(-) NSF O157:H7 as previously proposed but rather have evolved independently from a common ancestor. PMID- 22522898 TI - Flagellar hook flexibility is essential for bundle formation in swimming Escherichia coli cells. AB - Swimming Escherichia coli cells are propelled by the rotary motion of their flagellar filaments. In the normal swimming pattern, filaments positioned randomly over the cell form a bundle at the posterior pole. It has long been assumed that the hook functions as a universal joint, transmitting rotation on the motor axis through up to ~90 degrees to the filament in the bundle. Structural models of the hook have revealed how its flexibility is expected to arise from dynamic changes in the distance between monomers in the helical lattice. In particular, each of the 11 protofilaments that comprise the hook is predicted to cycle between short and long forms, corresponding to the inside and outside of the curved hook, once each revolution of the motor when the hook is acting as a universal joint. To test this, we genetically modified the hook so that it could be stiffened by binding streptavidin to biotinylated monomers, impeding their motion relative to each other. We found that impeding the action of the universal joint resulted in atypical swimming behavior as a consequence of disrupted bundle formation, in agreement with the universal joint model. PMID- 22522899 TI - Centromere binding and evolution of chromosomal partition systems in the Burkholderiales. AB - How split genomes arise and evolve in bacteria is poorly understood. Since each replicon of such genomes encodes a specific partition (Par) system, the evolution of Par systems could shed light on their evolution. The cystic fibrosis pathogen Burkholderia cenocepacia has three chromosomes (c1, c2, and c3) and one plasmid (pBC), whose compatibility depends on strictly specific interactions of the centromere sequences (parS) with their cognate binding proteins (ParB). However, the Par systems of B. cenocepacia c2, c3, and pBC share many features, suggesting that they arose within an extended family. Database searching revealed seven subfamilies of Par systems like those of B. cenocepacia. All are from plasmids and secondary chromosomes of the Burkholderiales, which reinforces the proposal of an extended family. The subfamily of the Par system of B. cenocepacia c3 includes plasmid variants with parS sequences divergent from that of c3. Using electrophoretic mobility shift assay (EMSA), we found that ParB-c3 binds specifically to centromeres of these variants, despite high DNA sequence divergence. We suggest that the Par system of B. cenocepacia c3 has preserved the features of an ancestral system. In contrast, these features have diverged variably in the plasmid descendants. One such descendant is found both in Ralstonia pickettii 12D, on a free plasmid, and in Ralstonia pickettii 12J, on a plasmid integrated into the main chromosome. These observations suggest that we are witnessing a plasmid-chromosome interaction from which a third chromosome will emerge in a two-chromosome species. PMID- 22522900 TI - Mechanism for regulation of the putrescine utilization pathway by the transcription factor PuuR in Escherichia coli K-12. AB - In Escherichia coli, putrescine is metabolized to succinate for use as a carbon and nitrogen source by the putrescine utilization pathway (Puu pathway). One gene in the puu gene cluster encodes a transcription factor, PuuR, which has a helix turn-helix DNA-binding motif. DNA microarray analysis of an E. coli puuR mutant, in which three amino acid residues in the helix-turn-helix DNA binding motif of PuuR were mutated to alanine to eliminate DNA binding of PuuR, suggested that PuuR is a negative regulator of puu genes. Results of gel shift and DNase I footprint analyses suggested that PuuR binds to the promoter regions of puuA and puuD. The binding of wild-type PuuR to a DNA probe containing PuuR recognition sites was diminished with increasing putrescine concentrations in vitro. These results suggest that PuuR regulates the intracellular putrescine concentration by the transcriptional regulation of genes in the Puu pathway, including puuR itself. The puu gene cluster is found in E. coli and closely related enterobacteria, but this gene cluster is uncommon in other bacterial groups. E. coli and related enterobacteria may have gained the Puu pathway as an adaptation for survival in the mammalian intestine, an environment in which polyamines exist at relatively high concentrations. PMID- 22522902 TI - Characterization of an O-demethylase of Desulfitobacterium hafniense DCB-2. AB - Besides acetogenic bacteria, only Desulfitobacterium has been described to utilize and cleave phenyl methyl ethers under anoxic conditions; however, no ether-cleaving O-demethylases from the latter organisms have been identified and investigated so far. In this study, genes of an operon encoding O-demethylase components of Desulfitobacterium hafniense strain DCB-2 were cloned and heterologously expressed in Escherichia coli. Methyltransferases I and II were characterized. Methyltransferase I mediated the ether cleavage and the transfer of the methyl group to the superreduced corrinoid of a corrinoid protein. Desulfitobacterium methyltransferase I had 66% identity (80% similarity) to that of the vanillate-demethylating methyltransferase I (OdmB) of Acetobacterium dehalogenans. The substrate spectrum was also similar to that of the latter enzyme; however, Desulfitobacterium methyltransferase I showed a higher level of activity for guaiacol and used methyl chloride as a substrate. Methyltransferase II catalyzed the transfer of the methyl group from the methylated corrinoid protein to tetrahydrofolate. It also showed a high identity (~70%) to methyltransferases II of A. dehalogenans. The corrinoid protein was produced in E. coli as cofactor-free apoprotein that could be reconstituted with hydroxocobalamin or methylcobalamin to function in the methyltransferase I and II assays. Six COG3894 proteins, which were assumed to function as activating enzymes mediating the reduction of the corrinoid protein after an inadvertent oxidation of the corrinoid cofactor, were studied with respect to their abilities to reduce the recombinant reconstituted corrinoid protein. Of these six proteins, only one was found to catalyze the reduction of the corrinoid protein. PMID- 22522901 TI - The response regulator RcsB activates expression of Mat fimbriae in meningitic Escherichia coli. AB - The common colonization factor of Escherichia coli, the Mat (also termed ECP) fimbria, functions to advance biofilm formation on inert surfaces as well as bacterial adherence to epithelial cells and subsequent colonization. We used global mini-Tn5 transposon mutagenesis to identify novel regulators of biofilm formation by the meningitic E. coli isolate IHE 3034. Of the 4,418 transformants, we found 17 that were impaired in biofilm formation. Most of these mutants were affected in lipopolysaccharide synthesis and were reduced in growth but not in Mat fimbria expression. In contrast, two mutants grew well but did not express Mat fimbria. The insertions in these two mutants were located at different sites of the rcsB gene, which encodes a DNA-binding response regulator of the Rcs response regulon. The mutations abrogated temperature-dependent biofilm formation by IHE 3034, and the phenotype correlated with loss of mat expression. The defect in biofilm formation in the rcsB mutant was reversed upon complementation with rcsB as well as by overexpression of structural mat genes but not by overexpression of the fimbria-specific activator gene matA. Monitoring of the mat operon promoter activity with chromosomal reporter fusions showed that the RcsB protein and an RcsAB box in the mat regulatory region, but not RcsC, RcsD, AckA, and Pta, are essential for initiation of mat transcription. Gel retardation assays showed that RcsB specifically binds to the mat promoter DNA, which enables its function in promoting biofilm formation by E. coli. PMID- 22522903 TI - Effects of lipopolysaccharide biosynthesis mutations on K1 polysaccharide association with the Escherichia coli cell surface. AB - The presence of cell-bound K1 capsule and K1 polysaccharide in culture supernatants was determined in a series of in-frame nonpolar core biosynthetic mutants from Escherichia coli KT1094 (K1, R1 core lipopolysaccharide [LPS] type) for which the major core oligosaccharide structures were determined. Cell-bound K1 capsule was absent from mutants devoid of phosphoryl modifications on L glycero-D-manno-heptose residues (HepI and HepII) of the inner-core LPS and reduced in mutants devoid of phosphoryl modification on HepII or devoid of HepIII. In contrast, in all of the mutants, K1 polysaccharide was found in culture supernatants. These results were confirmed by using a mutant with a deletion spanning from the hldD to waaQ genes of the waa gene cluster to which individual genes were reintroduced. A nuclear magnetic resonance (NMR) analysis of core LPS from HepIII-deficient mutants showed an alteration in the pattern of phosphoryl modifications. A cell extract containing both K1 capsule polysaccharide and LPS obtained from an O-antigen-deficient mutant could be resolved into K1 polysaccharide and core LPS by column chromatography only when EDTA and deoxycholate (DOC) buffer were used. These results suggest that the K1 polysaccharide remains cell associated by ionically interacting with the phosphate-negative charges of the core LPS. PMID- 22522904 TI - Social Organization in Bars: Implications for Tobacco Control Policy. AB - This paper considers social roles and relationships of the patrons, staff and owners of bars as critical factors determining adherence to public health policies, and specifically California's smokefree workplace law. Specific elements of social organization in bars affecting health policy include the community within which the bar is set, the unique identity the bar creates, the bar staff and patrons who enact this identity, and their bar society. These elements were found to contribute to the development of power relations within the bar and solidarity against the outside world, resulting in either resistance to or compliance with smokefree workplace policy. PMID- 22522905 TI - Comprehensive assessment of potential multiple myeloma immunoglobulin heavy chain V-D-J intraclonal variation using massively parallel pyrosequencing. AB - Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells (PCs) in the bone marrow (BM). MM is viewed as a clonal disorder due to lack of verified intraclonal sequence diversity in the immunoglobulin heavy chain variable region gene (IGHV). However, this conclusion is based on analysis of a very limited number of IGHV subclones and the methodology employed did not permit simultaneous analysis of the IGHV repertoire of non-malignant PCs in the same samples. Here we generated genomic DNA and cDNA libraries from purified MM BMPCs and performed massively parallel pyrosequencing to determine the frequency of cells expressing identical IGHV sequences. This method provided an unprecedented opportunity to interrogate the presence of clonally related MM cells and evaluate the IGHV repertoire of non-MM PCs. Within the MM sample, 37 IGHV genes were expressed, with 98.9% of all immunoglobulin sequences using the same IGHV gene as the MM clone and 83.0% exhibiting exact nucleotide sequence identity in the IGHV and heavy chain complementarity determining region 3 (HCDR3). Of interest, we observed in both genomic DNA and cDNA libraries 48 sets of identical sequences with single point mutations in the MM clonal IGHV or HCDR3 regions. These nucleotide changes were suggestive of putative subclones and therefore were subjected to detailed analysis to interpret: 1) their legitimacy as true subclones; and 2) their significance in the context of MM. Finally, we report for the first time the IGHV repertoire of normal human BMPCs and our data demonstrate the extent of IGHV repertoire diversity as well as the frequency of clonally related normal BMPCs. This study demonstrates the power and potential weaknesses of in-depth sequencing as a tool to thoroughly investigate the phylogeny of malignant PCs in MM and the IGHV repertoire of normal BMPCs. PMID- 22522906 TI - Acute toxic effects and gender-related biokinetics of silver nanoparticles following an intravenous injection in mice. AB - This study evaluated the acute toxicity and biokinetics of intravenously administered silver nanoparticles (AgNPs) in mice. Mice were exposed to different dosages of AgNPs (7.5, 30 or 120 mg kg(-1) ). Toxic effects were assessed via general behavior, serum biochemical parameters and histopathological observation of the mice. Biokinetics and tissue distribution of AgNPs were evaluated at a dose of 120 mg kg(-1) in both male and female mice. Inductively coupled plasma mass spectrometry (ICP-MS) was used to determine silver concentrations in blood and tissue samples collected at predetermined time intervals. After 2 weeks, AgNPs exerted no obvious acute toxicity in the mice. However, inflammatory reactions in lung and liver cells were induced in mice treated at the 120 mg kg( 1) dose level. The highest silver levels were observed in the spleen, followed by liver, lungs and kidneys. The elimination half-lives and clearance of AgNPs were 15.6 h and 1.0 ml h(-1) g(-1) for male mice and 29.9 h and 0.8 ml h(-1) g(-1) for female mice. These results indicated that AgNPs could be distributed extensively to various tissues in the body, but primarily in the spleen and liver. Furthermore, there appears to be gender-related differences in the biokinetic profiles in blood and distribution in lungs and kidneys following an intravenous injection of AgNPs. The data from this study provides information on toxicity and biodistribution of AgNPs following intravenous administration in mice, which represents the worst case scenario of toxicity among all the different administration routes, and may shed light in the future use of products containing AgNPs in humans. PMID- 22522907 TI - The detection of the urinary metabolites of 1-[(5-fluoropentyl)-1H-indol-3-yl]-(2 iodophenyl)methanone (AM-694), a high affinity cannabimimetic, by gas chromatography - mass spectrometry. AB - AM-694 (1-[(5-fluoropentyl)-1H-indol-3-yl]-(2-iodophenyl)methanone), a synthetic indole-based cannabimimetic, was first reported to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) via the Early Warning System (EWS) by Irish authorities in 2010. Using gas chromatography-mass spectrometry (GC-MS), we have identified six AM-694 metabolites in post-ingestion samples. The metabolites were tentatively identified as products of (1) hydrolytic defluorination, (2) carboxylation, (3) monohydroxylation of N-alkyl chain, and (4) hydrolytic defluorination combined with monohydroxylation of N-alkyl chain. The parent compound was not detected. The excretion of major metabolites was observed up to 117 h following administration. One metabolite (a product of hydrolytic defluorination) was also identified in urine samples from two individuals admitted to hospital suffering from suspected drug overdoses. PMID- 22522908 TI - Electrode calibration with a microfluidic flow cell for fast-scan cyclic voltammetry. AB - Fast-scan cyclic voltammetry (FSCV) is a common analytical electrochemistry tool used to measure chemical species. It has recently been adapted for measurement of neurotransmitters such as dopamine in awake and behaving animals (in vivo). Electrode calibration is an essential step in FSCV to relate observed current to concentration of a chemical species. However, existing methods require multiple components, which reduce the ease of calibrations. To this end, a microfluidic flow cell (MUFC) was developed as a simple device to switch between buffer and buffer with a known concentration of the analyte of interest--in this case dopamine--in a microfluidic Y-channel. The ability to quickly switch solutions yielded electrode calibrations with faster rise times and that were more stable at peak current values. The MUFC reduced the number of external electrical components and produced linear calibrations over a range of concentrations. To demonstrate this, an electrode calibrated with the MUFC was used in FSCV recordings from a rat during the delivery of food reward--a stimulus that reliably evokes a brief increase in current due to the oxidation of dopamine. Using the linear calibration, dopamine concentrations were determined from the current responses evoked during the behavioral task. The MUFC is able to easily and quickly calibrate FSCV electrode responses to chemical species for both in vitro and in vivo experiments. PMID- 22522909 TI - Key epigenetic changes associated with lung cancer development: results from dense methylation array profiling. AB - Epigenetic alterations are a common event in lung cancer and their identification can serve to inform on the carcinogenic process and provide clinically relevant biomarkers. Using paired tumor and non-tumor lung tissues from 146 individuals from three independent populations we sought to identify common changes in DNA methylation associated with the development of non-small cell lung cancer. Pathologically normal lung tissue taken at the time of cancer resection was matched to tumorous lung tissue and together were probed for methylation using Illumina GoldenGate arrays in the discovery set (n = 47 pairs) followed by bisulfite pyrosequencing for validation sets (n = 99 pairs). For each matched pair the change in methylation at each CpG was calculated (the odds ratio), and these ratios were averaged across individuals and ranked by magnitude to identify the CpGs with the greatest change in methylation associated with tumor development. We identified the top gene-loci representing an increase in methylation (HOXA9, 10.3-fold and SOX1, 5.9-fold) and decrease in methylation (DDR1, 8.1-fold). In replication testing sets, methylation was higher in tumors for HOXA9 (p < 2.2 * 10 (-16) ) and SOX1 (p < 2.2 * 10 (-16) ) and lower for DDR1 (p < 2.2 * 10 (-16) ). The magnitude and strength of these changes were consistent across squamous cell and adenocarcinoma tumors. Our data indicate that the identified genes consistently have altered methylation in lung tumors. Our identified genes should be included in translational studies that aim to develop screening for early disease detection. PMID- 22522910 TI - Individual variation and longitudinal pattern of genome-wide DNA methylation from birth to the first two years of life. AB - Prenatal development and early childhood are critical periods for establishing the tissue-specific epigenome, and may have a profound impact on health and disease in later life. However, epigenomic profiles at birth and in early childhood remain largely unexplored. The focus of this report is to examine the individual variation and longitudinal pattern of genome-wide DNA methylation levels from birth through the first two years of life in 105 Black children (59 males and 46 females) enrolled at the Boston Medical Center. We performed epigenomic mapping of cord blood at birth and venous blood samples from the same set of children within the first two years of life using Illumina Infinium Humanmethylation27 BeadChip. We observed a wide range of inter-individual variations in genome-wide methylation at each time point including lower levels at CpG islands, TSS200, 5'UTR and 1st Exon locations, but significantly higher levels in CpG shores, shelves, TSS1500, gene body and 3'UTR. We identified CpG sites with significant intra-individual longitudinal changes in the first two years of life throughout the genome. Specifically, we identified 159 CpG sites in males and 149 CpG sites in females with significant longitudinal changes defined by both statistical significance and magnitude of changes. These significant CpG sites appeared to be located within genes with important biological functions including immunity and inflammation. Further studies are needed to replicate our findings, including analysis by specific cell types, and link those individual variations and longitudinal changes with specific health outcomes in early childhood and later life. PMID- 22522911 TI - Silencing of Wnt5a during colon cancer metastasis involves histone modifications. AB - Colorectal cancer (CRC) is the third most common cancer in the United States. Approximately 90% of colon cancer deaths arise from the metastasis of primary tumors. Aberrant expression of Wnt5a, one of the WNT signaling factors, has been reported during colon cancer development and progression. We found that both mRNA and protein expression of Wnt5a were decreased in the highly metastatic human colon cancer cell line SW620 compared with the non-metastatic human colon cancer cell SW480. This study tested the hypothesis that the silencing of Wnt5a in metastatic human colon cancer cells is related to altered epigenetic modifications. Wnt5a expression was not responsive to DNA methyltransferase inhibitor 5-aza-cytidine treatment. However, histone deacetylase (HDAC) inhibitors trichostatin A (TSA) and sodium butyrate (NaBt) significantly increased Wnt5a mRNA expression in SW620. Importantly, lower transcription of Wnt5a in SW620 than SW480 corresponded to multiple histone modifications, including lower levels of acetylated histone H3, H4 and H3K4me2 and higher levels of H3K27me3 in the promoter region. The increase of H3Ac, H4Ac and H3K4me2 after NaBt treatment in SW620 confirmed the involvement of histone modifications in the transcriptional regulation of Wnt5a. Additionally, NaBt treatment increased beta catenin signaling and diminished the difference in cell adhesion ability between non-metastatic SW480 and metastatic SW620, suggesting that the HDAC inhibitor plays critical roles in the WNT signaling pathway and cell physiology that relate to metastasis. In conclusion, our study suggests the importance of Wnt5a in colon cancer metastasis and also indicates that Wnt5a silencing in the highly invasive human colon cancer cell line might result from transcriptional regulation of the gene by histone modifications. PMID- 22522912 TI - Correlation analysis of clinical parameters with epigenetic modifications in the DUX4 promoter in FSHD. AB - The aim of our study was to identify relationships between epigenetic parameters correlating with a relaxed chromatin state of the DUX4 promoter region and clinical severity as measured by a clinical severity score or muscle pathologic changes in D4Z4 contraction-dependent (FSHD1) and -independent (FSHD2) facioscapulohumeral muscular dystrophy patients. Twenty primary fibroblast (5 control, 10 FSHD1 and 5 FSHD2) and 26 primary myoblast (9 control, 12 FSHD1 and 5 FSHD2) cultures originating from patients with FSHD and controls were analyzed. Histone modification levels were determined by chromatin immunoprecipitation. We examined correlations between the chromatin compaction score (ChCS) defined by the H3K9me3:H3K4me2 ratio and an age corrected clinical severity score (CSS) or muscle pathology score (MPS). Possible relationships were investigated using linear regression analysis and significance was tested by Pearson's product moment coefficient. We found a significant difference of the ChCS between controls and patients with FSHD1 and between controls and patients with FSHD2. Tissue specific differences in ChCS were also observed. We also found a near significant relationship between ChCS and the age corrected CSS in fibroblasts but not in myoblasts. Surprisingly, we found a strong correlation between the MPS of the vastus lateralis and the CSS. Our results confirm the D4Z4 chromatin relaxation previously shown to be associated with FSHD in a small number of samples. A possible relationship between clinical and epigenetic parameters could be established in patient fibroblasts, but not in myoblasts. The strong correlation between the MPS of the vastus lateralis and the CSS suggests that this muscle can be used to study for surrogate markers of overall disease severity. PMID- 22522914 TI - Prolonged rock climbing activity induces structural changes in cerebellum and parietal lobe. AB - This article analyzes whether climbing, a motor activity featured by upward movements by using both feet and hands, generation of new strategies of motor control, maintenance of not stable equilibrium and adoption of long-lasting quadrupedal posture, is able to modify specific brain areas. MRI data of 10 word class mountain climbers (MC) and 10 age-matched controls, with no climbing experience were acquired. Combining region-of-interest analyses and voxel-based morphometry we investigated cerebellar volumes and correlation between cerebellum and whole cerebral gray matter. In comparison to controls, world-class MC showed significantly larger vermian lobules I-V volumes, with no significant difference in other cerebellar vermian lobules or hemispheres. The cerebellar enlargement was associated with an enlargement of right medial posterior parietal area. The specific features of the motor climbing skills perfectly fit with the plastic anatomical changes we found. The enlargement of the vermian lobules I-V seems to be related to highly dexterous hand movements and to eye-hand coordination in the detection of and correction of visuomotor errors. The concomitant enlargement of the parietal area is related to parallel work in predicting sensory consequences of action to make movement corrections. Motor control and sensory-motor prediction of actions make the difference between survive or not at extreme altitude. PMID- 22522915 TI - Versatile switching in substrate topicity: supramolecular chirality induction in di- and trinuclear host complexes. AB - Supramolecular chirality effects have been achieved both for ditopic and monotopic substrates by using a programmable bis-salphen scaffold that incorporates either two or three Zn nuclei. The dinuclear host shows preferential chirogenesis in the presence of ditopic systems, whereas effective chirality transfer to the trinuclear complex is realized through monotopic binding. The mode of binding in the trinuclear host has been investigated through X-ray crystallography, CD measurements, UV/Vis spectroscopy, and DFT analysis. The bis salphen scaffold holds promise for the development of substrate-specific host systems useful for determination of the absolute configuration of various types of organic molecules. PMID- 22522916 TI - Making ideas "stick": the 15-minute family interview. PMID- 22522917 TI - Analysis of a Jup hypomorphic allele reveals a critical threshold for postnatal viability. AB - Mutations in the human Jup gene cause arrhythmogenic right ventricular cardiomyopathy (ARVC), a heart muscle disease that often leads to sudden cardiac death. Inactivation of the murine Jup gene (also known as plakoglobin) results in embryonic lethality due to cardiac rupture. In an effort to generate a conditional knockout allele, a neomycin cassette was introduced into the murine plakoglobin (PG) gene. This allele (PG F(N)) functions as a hypomorph when combined with a null allele (PG Delta). About half of the PG F(N)/Delta animals were smaller than their littermates and died before weaning age, whereas the remaining PG F(N)/Delta animals survived. Despite the reduced levels of PG in the heart, there were no signs of cardiomyopathy or cardiac dysfunction as determined by echocardiography. Importantly, the PG homolog, beta-catenin (CTNNB1), was increased in the PG F(N)/Delta hearts. In addition to its structural role as part of the N-cadherin/catenin adhesion complex, beta-catenin is a downstream effector of Wnt signaling. However, no change in beta-catenin/TCF reporter activity was observed in PG F(N)/Delta embryos suggesting that excess beta-catenin was not likely causing increased transcription of Wnt/beta-catenin target genes. These data suggest novel function(s) for PG beyond the heart and define a critical threshold of PG expression that is necessary for postnatal survival. PMID- 22522918 TI - A novel experience of antiviral therapy for chronic hepatitis B in renal transplant recipients. AB - BACKGROUND: Entecavir (ETV) is a potent inhibitor of viral replication in chronic hepatitis B. There is no published data concerning ETV therapy in nucleoside analogue (NUC)-naive hepatitis B surface antigen (HBsAg)-positive renal transplant recipients (RTRs). METHODS: We prospectively treated 27 HBsAg-positive RTRs with ETV since 2007. Serial HBV DNA was assessed at baseline and weeks 12, 24, 52 and 104 after treatment. A cohort of 19 patients who received 2-year lamivudine (3TC) therapy during 2004-2007 was used as a historical control. RESULTS: Of the 27 RTRs, 18 (67%) were NUC-naive patients and 9 (33%) were 3TC experienced without YMDD mutations. HBV DNA levels became undetectable in 70%, 74%, 96% and 100% of patients after 12, 24, 52 and 104 weeks, respectively, of ETV treatment without viral resistance. There was no change of glomerular filtration rate, and no lactic acidosis or myopathy during treatment. By comparison with the 19 3TC-treated patients, ETV-treated RTRs presented higher rates of undetectable HBV DNA than 3TC-treated RTRs (32%, 37%, 63% and 63% at 12, 24, 52 and 104 weeks; P<0.005). In an analysis excluding 9 patients from the ETV group who were also 3TC-experienced, the remaining 18 ETV-naive RTRs exhibited a better virological response at 52 and 104 weeks than 19 3TC-treated RTRs (P<0.05). Even in the 9 patients who overlapped in two cohorts, ETV exhibited a more rapid virological response than 3TC did, especially at 12 and 24 weeks (P=0.009). CONCLUSIONS: ETV is effective in treating chronic hepatitis B in RTRs. ETV is safe with regards to renal graft function, lactic acidosis, myopathy and virological resistance. PMID- 22522919 TI - Insecticide imidacloprid induces morphological and DNA damage through oxidative toxicity on the reproductive organs of developing male rats. AB - We investigated whether treatment with imidacloprid would induce morphological changes, DNA fragmentation, antioxidant imbalance and apoptosis in the reproductive system of developing male rats. Twenty-four male rats were included in this 90-day study, starting at 7 days of age. The rats were divided into four groups. The first group was used as control. The second, third and fourth groups received oral 0.5-, 2- and 8-mg/kg imidacloprid, respectively. Serum, sperm and testis samples were collected from all groups at the end of the experimental period. The weights of the epididymis, vesicula seminalis, epididymal sperm concentration, body weight gain, testosterone and reduced glutathione values were lower in the imidacloprid-treated groups than that in the controls. All treated groups had increased lipid peroxidation, fatty acid concentrations and higher rates of abnormal sperm. Apoptosis and fragmentation of seminal DNA were higher in rats treated at the two higher doses of imidacloprid. These results show that this compound has a negative effect on sperm and testis of rats. PMID- 22522921 TI - Developmental dynamics of PAFAH1B subunits during mouse brain development. AB - Platelet-activating factor (PAF) mediates an array of biological processes in the mammalian central nervous system as a bioactive lipid messenger in synaptic function and dysfunction (plasticity, memory, and neurodegeneration). The intracellular enzyme that deacetylates the PAF (PAFAH1B) is composed of a tetramer of two catalytic subunits, ALPHA1 (PAFAH1B3) and ALPHA2 (PAFAH1B2), and a regulatory dimer of LIS1 (PAFAH1B1). We have investigated the mouse PAFAH1B subunit genes during brain development in normal mice and in mice with a hypomorphic allele for Lis1 (Lis1/sLis1; Cahana et al. [2001] Proc Natl Acad Sci U S A 98:6429-6434). We have analyzed quantitatively (by means of real-time polymerase chain reaction) and qualitatively (by in situ hybridization techniques) the amounts and expression patterns of their transcription in developing and postnatal brain, focusing mainly on differences in two laminated encephalic regions, the forebrain (telencephalon) and hindbrain (cerebellum) separately. The results revealed significant differences in cDNA content between these two brain subdivisions but, more importantly, between the LIS1 complex subunits. In addition, we found significant spatial differences in gene expression patterns. Comparison of results obtained with Lis1/sLis1 analysis also revealed significant temporal and spatial differences in Alpha1 and Lis1 expression levels. Thus, small changes in the amount of the Lis1 gene may differentially regulate expression of Alpha1 and Alpha2, depending on the brain region, which suggests different roles for each LIS1 complex subunit during neural differentiation and neural migration. PMID- 22522920 TI - Cystic fibrosis transmembrane conductance regulator modulation by the tobacco smoke toxin acrolein. AB - OBJECTIVES/HYPOTHESIS: Evidence indicates that decreased mucociliary clearance (MCC) is a major contributing feature to chronic rhinosinusitis. Tobacco-smoke exposure is thought to inhibit transepithelial Cl(-) secretion, a major determinant of airway surface liquid hydration and MCC. The objective of the current study was to evaluate the effects of acrolein exposure (a prominent tobacco smoke toxin) on vectorial Cl(-) transport through the major apical anion channel cystic fibrosis transmembrane conductance regulator (CFTR) in sinonasal epithelium. STUDY DESIGN: In vitro investigation. METHODS: Primary murine nasal septal epithelia (MNSE; wild-type and transgenic CFTR(-/-)) cultures were exposed to acrolein in Ussing chambers and the effects on Cl(-) secretion investigated using pharmacologic manipulation. Cellular cyclic adenosine monophosphate (cAMP) signaling and cytotoxicity were also investigated. RESULTS: Acrolein stimulated Cl(-) secretion (DeltaI(SC) - change in short-circuit current in MUA/cm(2)) at concentrations similar to smoker's airways (100 MUM, 15.8 +/- 2.2 vs. 2.4 +/- 0.8 [control]; P < .0001), suppressed forskolin-stimulated C- transport at 300 MUM (13.3 +/- 1.2 vs. 19.9 +/- 1.0; P < .01), and completely abolished all transport at 500 MUM (-1.1 +/- 1.6). Stimulated Cl(-) secretion was solely reliant upon the presence of CFTR (confirmed in transgenic CFTR(-/-) MNSE), but independent of cAMP signaling. Inhibition at higher concentrations was not secondary to cellular cytotoxicity. CONCLUSIONS: The present study demonstrates that acrolein has complex but pronounced interaction with the major apical Cl(-) transport mechanism that uses CFTR. Further investigations are required to determine acrolein's impact as a tobacco smoke constituent on mucociliary transport. PMID- 22522922 TI - Prevalence of new psychoactive substances: A retrospective study in hair. AB - New psychoactive substances are conquering the drug scene. Police seize different colourful packages with exceptional names. They are declared as 'bath salts', 'plant food', or 'research chemical powders'. Little is known about the actual prevalence of these drugs. Reanalysis of hair samples from routine cases concerning the presence of new psychoactive substances or 'smart drugs' should provide insight into changing patterns of designer drugs. All hair samples from 2009 and 2010 that originally tested positive for amphetamines or MDMA (N = 325) were reanalyzed for new or smart drugs such as 4-fluoroamphetamine, piperazines (BZP, mCPP and TFMPP), cathinones (4-MMC (mephedrone), methylone, butylone, ethylone, MDPV, methcathinone and cathinone), methylphenidate and ketamine. Hair snippets were extracted using a two-step extraction procedure. The analytes were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) (electrospray ionization; multiple-reaction-monitoring mode - information dependent acquisition - enhanced product ion scan). New psychoactive substances were found in 120 cases (37%). Concerning the piperazine drugs, mCPP was positive in 34 (10.5%) cases and TFMPP in one case. Five mCPP cases were also positive for trazodone, an antidepressant which is metabolized to mCPP. In 11 (3%) cases, 4 MMC was detected. Concerning the smart drugs, methylphenidate was found in 16 (5%). Ketamine was found in 45 (14%) cases. 4-Fluoroamphetamine was identified in 12 (4%) cases and methylone in one case.In conclusion, there is a high prevalence of these drugs. Consequently, at least the most common ones (e.g. mCPP, KET, 4 MMC and 4-FA) should be included in screening procedures in clinical and forensic toxicology. PMID- 22522923 TI - Sensitivity of cloned muscle, heart and neuronal voltage-gated sodium channels to block by polyamines: a possible basis for modulation of excitability in vivo. AB - Spermidine and spermine, are endogenous polyamines (PAs) that regulate cell growth and modulate the activity of numerous ion channel proteins. In particular, intracellular PAs are potent blockers of many different cation channels and are responsible for strong suppression of outward K (+) current, a phenomenon known as inward rectification characteristic of a major class of KIR K (+) channels. We previously described block of heterologously expressed voltage-gated Na (+) channels (NaV) of rat muscle by intracellular PAs and PAs have recently been found to modulate excitability of brain neocortical neurons by blocking neuronal NaV channels. In this study, we compared the sensitivity of four different cloned mammalian NaV isoforms to PAs to investigate whether PA block is a common feature of NaV channel pharmacology. We find that outward Na (+) current of muscle (NaV 1.4), heart (NaV 1.5), and neuronal (NaV 1.2, NaV 1.7) NaV isoforms is blocked by PAs, suggesting that PA metabolism may be linked to modulation of action potential firing in numerous excitable tissues. Interestingly, the cardiac NaV 1.5 channel is more sensitive to PA block than other isoforms. Our results also indicate that rapid binding of PAs to blocking sites in the NaV 1.4 channel is restricted to access from the cytoplasmic side of the channel, but plasma membrane transport pathways for PA uptake may contribute to long-term NaV channel modulation. PAs may also play a role in drug interactions since spermine attenuates the use-dependent effect of the lidocaine, a typical local anesthetic and anti-arrhythmic drug. PMID- 22522924 TI - Human adipose stem cells maintain proliferative, synthetic and multipotential properties when suspension cultured as self-assembling spheroids. AB - Adipose-derived stromal/stem cells (ASCs) have been gaining recognition as an extremely versatile cell source for tissue engineering. The usefulness of ASCs in biofabrication is further enhanced by our demonstration of the unique properties of these cells when they are cultured as three-dimensional cellular aggregates or spheroids. As described herein, three-dimensional formulations, or self assembling ASC spheroids develop their own extracellular matrix that serves to increase the robustness of the cells to mechanical stresses. The composition of the extracellular matrix can be altered based on the external environment of the spheroids and these constructs can be grown in a reproducible manner and to a consistent size. The spheroid formulation helps preserve the viability and developmental plasticity of ASCs even under defined, serum-free media conditions. For the first time, we show that multiple generations of adherent ASCs produced from these spheroids retain their ability to differentiate into multiple cell/tissue types. These demonstrated properties support the idea that culture expanded ASCs are an excellent candidate cellular material for 'organ printing' the approach of developing complex tissue structures from a standardized cell 'ink' or cell formulation. PMID- 22522925 TI - The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. AB - The elucidation of breast cancer subgroups and their molecular drivers requires integrated views of the genome and transcriptome from representative numbers of patients. We present an integrated analysis of copy number and gene expression in a discovery and validation set of 997 and 995 primary breast tumours, respectively, with long-term clinical follow-up. Inherited variants (copy number variants and single nucleotide polymorphisms) and acquired somatic copy number aberrations (CNAs) were associated with expression in ~40% of genes, with the landscape dominated by cis- and trans-acting CNAs. By delineating expression outlier genes driven in cis by CNAs, we identified putative cancer genes, including deletions in PPP2R2A, MTAP and MAP2K4. Unsupervised analysis of paired DNA-RNA profiles revealed novel subgroups with distinct clinical outcomes, which reproduced in the validation cohort. These include a high-risk, oestrogen receptor-positive 11q13/14 cis-acting subgroup and a favourable prognosis subgroup devoid of CNAs. Trans-acting aberration hotspots were found to modulate subgroup-specific gene networks, including a TCR deletion-mediated adaptive immune response in the 'CNA-devoid' subgroup and a basal-specific chromosome 5 deletion-associated mitotic network. Our results provide a novel molecular stratification of the breast cancer population, derived from the impact of somatic CNAs on the transcriptome. PMID- 22522926 TI - A PPARgamma-FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis. AB - Although feast and famine cycles illustrate that remodelling of adipose tissue in response to fluctuations in nutrient availability is essential for maintaining metabolic homeostasis, the underlying mechanisms remain poorly understood. Here we identify fibroblast growth factor 1 (FGF1) as a critical transducer in this process in mice, and link its regulation to the nuclear receptor PPARgamma (peroxisome proliferator activated receptor gamma), which is the adipocyte master regulator and the target of the thiazolidinedione class of insulin sensitizing drugs. FGF1 is the prototype of the 22-member FGF family of proteins and has been implicated in a range of physiological processes, including development, wound healing and cardiovascular changes. Surprisingly, FGF1 knockout mice display no significant phenotype under standard laboratory conditions. We show that FGF1 is highly induced in adipose tissue in response to a high-fat diet and that mice lacking FGF1 develop an aggressive diabetic phenotype coupled to aberrant adipose expansion when challenged with a high-fat diet. Further analysis of adipose depots in FGF1-deficient mice revealed multiple histopathologies in the vasculature network, an accentuated inflammatory response, aberrant adipocyte size distribution and ectopic expression of pancreatic lipases. On withdrawal of the high-fat diet, this inflamed adipose tissue fails to properly resolve, resulting in extensive fat necrosis. In terms of mechanisms, we show that adipose induction of FGF1 in the fed state is regulated by PPARgamma acting through an evolutionarily conserved promoter proximal PPAR response element within the FGF1 gene. The discovery of a phenotype for the FGF1 knockout mouse establishes the PPARgamma-FGF1 axis as critical for maintaining metabolic homeostasis and insulin sensitization. PMID- 22522927 TI - Selective cortical representation of attended speaker in multi-talker speech perception. AB - Humans possess a remarkable ability to attend to a single speaker's voice in a multi-talker background. How the auditory system manages to extract intelligible speech under such acoustically complex and adverse listening conditions is not known, and, indeed, it is not clear how attended speech is internally represented. Here, using multi-electrode surface recordings from the cortex of subjects engaged in a listening task with two simultaneous speakers, we demonstrate that population responses in non-primary human auditory cortex encode critical features of attended speech: speech spectrograms reconstructed based on cortical responses to the mixture of speakers reveal the salient spectral and temporal features of the attended speaker, as if subjects were listening to that speaker alone. A simple classifier trained solely on examples of single speakers can decode both attended words and speaker identity. We find that task performance is well predicted by a rapid increase in attention-modulated neural selectivity across both single-electrode and population-level cortical responses. These findings demonstrate that the cortical representation of speech does not merely reflect the external acoustic environment, but instead gives rise to the perceptual aspects relevant for the listener's intended goal. PMID- 22522928 TI - Restoration of grasp following paralysis through brain-controlled stimulation of muscles. AB - Patients with spinal cord injury lack the connections between brain and spinal cord circuits that are essential for voluntary movement. Clinical systems that achieve muscle contraction through functional electrical stimulation (FES) have proven to be effective in allowing patients with tetraplegia to regain control of hand movements and to achieve a greater measure of independence in daily activities. In existing clinical systems, the patient uses residual proximal limb movements to trigger pre-programmed stimulation that causes the paralysed muscles to contract, allowing use of one or two basic grasps. Instead, we have developed an FES system in primates that is controlled by recordings made from microelectrodes permanently implanted in the brain. We simulated some of the effects of the paralysis caused by C5 or C6 spinal cord injury by injecting rhesus monkeys with a local anaesthetic to block the median and ulnar nerves at the elbow. Then, using recordings from approximately 100 neurons in the motor cortex, we predicted the intended activity of several of the paralysed muscles, and used these predictions to control the intensity of stimulation of the same muscles. This process essentially bypassed the spinal cord, restoring to the monkeys voluntary control of their paralysed muscles. This achievement is a major advance towards similar restoration of hand function in human patients through brain-controlled FES. We anticipate that in human patients, this neuroprosthesis would allow much more flexible and dexterous use of the hand than is possible with existing FES systems. PMID- 22522929 TI - In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. AB - The reprogramming of adult cells into pluripotent cells or directly into alternative adult cell types holds great promise for regenerative medicine. We reported previously that cardiac fibroblasts,which represent 50%of the cells in the mammalian heart, can be directly reprogrammed to adult cardiomyocyte-like cells in vitro by the addition of Gata4, Mef2c and Tbx5 (GMT). Here we use genetic lineage tracing to show that resident non-myocytes in the murine heart can be reprogrammed into cardiomyocyte-like cells in vivo by local delivery of GMT after coronary ligation. Induced cardiomyocytes became binucleate, assembled sarcomeres and had cardiomyocyte-like gene expression. Analysis of single cells revealed ventricular cardiomyocyte-like action potentials, beating upon electrical stimulation, and evidence of electrical coupling. In vivo delivery of GMT decreased infarct size and modestly attenuated cardiac dysfunction up to 3 months after coronary ligation. Delivery of the pro-angiogenic and fibroblast activating peptide, thymosin b4, along with GMT, resulted in further improvements in scar area and cardiac function. These findings demonstrate that cardiac fibroblasts can be reprogrammed into cardiomyocyte-like cells in their native environment for potential regenerative purposes. PMID- 22522930 TI - Osteoprotection by semaphorin 3A. AB - The bony skeleton is maintained by local factors that regulate bone-forming osteoblasts and bone-resorbing osteoclasts, in addition to hormonal activity. Osteoprotegerin protects bone by inhibiting osteoclastic bone resorption, but no factor has yet been identified as a local determinant of bone mass that regulates both osteoclasts and osteoblasts. Here we show that semaphorin 3A (Sema3A) exerts an osteoprotective effect by both suppressing osteoclastic bone resorption and increasing osteoblastic bone formation. The binding of Sema3A to neuropilin-1 (Nrp1) inhibited receptor activator of nuclear factor-kappaB ligand (RANKL) induced osteoclast differentiation by inhibiting the immunoreceptor tyrosine based activation motif (ITAM) and RhoA signalling pathways. In addition, Sema3A and Nrp1 binding stimulated osteoblast and inhibited adipocyte differentiation through the canonical Wnt/beta-catenin signalling pathway. The osteopenic phenotype in Sema3a-/- mice was recapitulated by mice in which the Sema3A-binding site of Nrp1 had been genetically disrupted. Intravenous Sema3A administration in mice increased bone volume and expedited bone regeneration. Thus, Sema3A is a promising new therapeutic agent in bone and joint diseases. PMID- 22522931 TI - Stereospecific binding of a disordered peptide segment mediates BK channel inactivation. AB - A number of functionally important actions of proteins are mediated by short, intrinsically disordered peptide segments, but the molecular interactions that allow disordered domains to mediate their effects remain a topic of active investigation. Many K+ channel proteins, after initial channel opening, show a time-dependent reduction in current flux, termed 'inactivation', which involves movement of mobile cytosolic peptide segments (approximately 20-30 residues) into a position that physically occludes ion permeation. Peptide segments that produce inactivation show little amino-acid identity and tolerate appreciable mutational substitutions without disrupting the inactivation process. Solution nuclear magnetic resonance of several isolated inactivation domains reveals substantial conformational heterogeneity with only minimal tendency to ordered structures. Channel inactivation mechanisms may therefore help us to decipher how intrinsically disordered regions mediate functional effects. Whereas many aspects of inactivation of voltage-dependent K+ channels (Kv) can be described by a simple one-step occlusion mechanism, inactivation of the voltage-dependent large conductance Ca2+-gated K+ (BK) channel mediated by peptide segments of auxiliary beta-subunits involves two distinguishable kinetic steps. Here we show that two step inactivation mediated by an intrinsically disordered BK beta-subunit peptide involves a stereospecific binding interaction that precedes blockade. In contrast, blocking mediated by a Shaker Kv inactivation peptide is consistent with direct, simple occlusion by a hydrophobic segment without substantial steric requirement. The results indicate that two distinct types of molecular interaction between disordered peptide segments and their binding sites produce qualitatively similar functions. PMID- 22522932 TI - Evidence of non-random mutation rates suggests an evolutionary risk management strategy. AB - A central tenet in evolutionary theory is that mutations occur randomly with respect to their value to an organism; selection then governs whether they are fixed in a population. This principle has been challenged by long-standing theoretical models predicting that selection could modulate the rate of mutation itself. However, our understanding of how the mutation rate varies between different sites within a genome has been hindered by technical difficulties in measuring it. Here we present a study that overcomes previous limitations by combining phylogenetic and population genetic techniques. Upon comparing 34 Escherichia coli genomes, we observe that the neutral mutation rate varies by more than an order of magnitude across 2,659 genes, with mutational hot and cold spots spanning several kilobases. Importantly, the variation is not random: we detect a lower rate in highly expressed genes and in those undergoing stronger purifying selection. Our observations suggest that the mutation rate has been evolutionarily optimized to reduce the risk of deleterious mutations. Current knowledge of factors influencing the mutation rate-including transcription coupled repair and context-dependent mutagenesis-do not explain these observations, indicating that additional mechanisms must be involved. The findings have important implications for our understanding of evolution and the control of mutations. PMID- 22522933 TI - Spin-orbital separation in the quasi-one-dimensional Mott insulator Sr2CuO3. AB - When viewed as an elementary particle, the electron has spin and charge. When binding to the atomic nucleus, it also acquires an angular momentum quantum number corresponding to the quantized atomic orbital it occupies. Even if electrons in solids form bands and delocalize from the nuclei, in Mott insulators they retain their three fundamental quantum numbers: spin, charge and orbital. The hallmark of one-dimensional physics is a breaking up of the elementary electron into its separate degrees of freedom. The separation of the electron into independent quasi-particles that carry either spin (spinons) or charge (holons) was first observed fifteen years ago. Here we report observation of the separation of the orbital degree of freedom (orbiton) using resonant inelastic X ray scattering on the one-dimensional Mott insulator Sr2CuO3. We resolve an orbiton separating itself from spinons and propagating through the lattice as a distinct quasi-particle with a substantial dispersion in energy over momentum, of about 0.2 electronvolts, over nearly one Brillouin zone. PMID- 22522934 TI - Restoration of vision after transplantation of photoreceptors. AB - Cell transplantation is a potential strategy for treating blindness caused by the loss of photoreceptors. Although transplanted rod-precursor cells are able to migrate into the adult retina and differentiate to acquire the specialized morphological features of mature photoreceptor cells, the fundamental question remains whether transplantation of photoreceptor cells can actually improve vision. Here we provide evidence of functional rod-mediated vision after photoreceptor transplantation in adult Gnat1-/- mice, which lack rod function and are a model of congenital stationary night blindness. We show that transplanted rod precursors form classic triad synaptic connections with second-order bipolar and horizontal cells in the recipient retina. The newly integrated photoreceptor cells are light-responsive with dim-flash kinetics similar to adult wild-type photoreceptors. By using intrinsic imaging under scotopic conditions we demonstrate that visual signals generated by transplanted rods are projected to higher visual areas, including V1. Moreover, these cells are capable of driving optokinetic head tracking and visually guided behaviour in the Gnat1-/- mouse under scotopic conditions. Together, these results demonstrate the feasibility of photoreceptor transplantation as a therapeutic strategy for restoring vision after retinal degeneration. PMID- 22522935 TI - Postoperative hemorrhage following adenoidectomy. AB - OBJECTIVES/HYPOTHESIS: To examine postoperative hemorrhage following adenoidectomy. STUDY DESIGN: Prospective multicenter observational study. METHODS: The Surgical Instrument Surveillance Programme (SISP) was established in 2003 to monitor tonsil and adenoid surgery in all hospitals in Wales. Data were examined between April 1, 2003 and June 30, 2008, for risk factors that may contribute to primary (R1) or secondary (R2) postoperative hemorrhage from the adenoid bed, of a severity sufficient to require a return to the operating room. RESULTS: There were 5,588 procedures included, of which 4,225 included simultaneous tonsillectomy. The study included 2,903 (52%) males with a median age of 5.8 years (interquartile range [IQR], 4.5-7.7 years) and 2,685 (48%) females with a median age of 6.5 years (IQR, 5.0-9.1 years). There were 22 patients (0.4%; confidence interval [CI], 0.2-0.6) who returned to the operating room with a postoperative hemorrhage arising from the adenoid bed. These were exclusively R1 hemorrhage; there were no instances of R2 hemorrhage (0.0%; CI, 0.0-0.1). No specific risk factors for R1 hemorrhage could be identified. There were 38 patients in the adenotonsillectomy group who returned to operating room with a postoperative hemorrhage arising from the tonsil bed (0.5%; CI, 0.3-0.8). R1 was seen in 22 patients (0.5%; CI, 0.3-0.8) and R2 in 16 patients (0.4%; CI, 0.2-0.6). CONCLUSIONS: Adenoidectomy appears to be primarily a procedure performed in childhood. The rate of R1 hemorrhage following adenoidectomy is one in 200 (0.5%) and is similar to the R1 hemorrhage rate for tonsillectomy. R2 hemorrhage following an adenoidectomy appears to be extremely rare. In children, the risk of a serious primary hemorrhage following an adenotonsillectomy is double that of either procedure when performed alone. PMID- 22522936 TI - Intrapartum fetal surveillance: review of three national guidelines. AB - Evidence-based guidelines regarding intrapartum fetal surveillance from three countries (United States, Canada, and Australia/New Zealand) were reviewed. The similarities in the three national guidelines (purported etiology, management of periodic changes, and intermittent auscultation for low-risk women) are understandable. Differences in recommendations (role of fetal admission test, amnioinfusion for variable decelerations, scalp pH, umbilical arterial acid-base status, and education in interpretation of fetal heart tracing) are not explained. The likelihood of recommendations being categorized as level A differed for the countries: United States, 41% (7/17); Canada, 18% (3/17); and Australia and New Zealand, 17% (2/12). Only one publication was cited by all three guidelines. To avoid confusion and possibly enhance their quality, national guidelines should acknowledge the presence of others on the same topic, and if there are differences then provide explanations for dissimilarities. PMID- 22522937 TI - Damage to left anterior temporal cortex predicts impairment of complex syntactic processing: a lesion-symptom mapping study. AB - Sentence processing problems form a common consequence of left-hemisphere brain injury, in some patients to such an extent that their pattern of language performance is characterized as "agrammatic". However, the location of left hemisphere damage that causes such problems remains controversial. It has been suggested that the critical site for syntactic processing is Broca's area of the frontal cortex or, alternatively, that a more widely distributed network is responsible for syntactic processing. The aim of this study was to identify brain regions that are required for successful sentence processing. Voxel-based lesion symptom mapping (VLSM) was used to identify brain regions where injury predicted impaired sentence processing in 50 native speakers of Icelandic with left hemisphere stroke. Sentence processing was assessed by having individuals identify which picture corresponded to a verbally presented sentence. The VLSM analysis revealed that impaired sentence processing was best predicted by damage to a large left-hemisphere temporo-parieto-occipital area. This is likely due to the multimodal nature of the sentence processing task, which involves auditory and visual analysis, as well as lexical and syntactic processing. Specifically impaired processing of noncanonical sentence types, when compared with canonical sentence processing, was associated with damage to the left-hemisphere anterior superior and middle temporal gyri and the temporal pole. Anterior temporal cortex, therefore, appears to play a crucial role in syntactic processing, and patients with brain damage to this area are more likely to present with receptive agrammatism than patients in which anterior temporal cortex is spared. PMID- 22522939 TI - Auditory function in children with Charcot-Marie-Tooth disease. AB - The peripheral manifestations of the inherited neuropathies are increasingly well characterized, but their effects upon cranial nerve function are not well understood. Hearing loss is recognized in a minority of children with this condition, but has not previously been systemically studied. A clear understanding of the prevalence and degree of auditory difficulties in this population is important as hearing impairment can impact upon speech/language development, social interaction ability and educational progress. The aim of this study was to investigate auditory pathway function, speech perception ability and everyday listening and communication in a group of school-aged children with inherited neuropathies. Twenty-six children with Charcot-Marie-Tooth disease confirmed by genetic testing and physical examination participated. Eighteen had demyelinating neuropathies (Charcot-Marie-Tooth type 1) and eight had the axonal form (Charcot-Marie-Tooth type 2). While each subject had normal or near-normal sound detection, individuals in both disease groups showed electrophysiological evidence of auditory neuropathy with delayed or low amplitude auditory brainstem responses. Auditory perception was also affected, with >60% of subjects with Charcot-Marie-Tooth type 1 and >85% of Charcot-Marie-Tooth type 2 suffering impaired processing of auditory temporal (timing) cues and/or abnormal speech understanding in everyday listening conditions. PMID- 22522938 TI - Clinically concordant variations of Alzheimer pathology in aphasic versus amnestic dementia. AB - Primary progressive aphasia is a neurodegenerative syndrome characterized by gradual dissolution of language but relative sparing of other cognitive domains, especially memory. It is associated with asymmetric atrophy in the language dominant hemisphere (usually left), and differs from typical Alzheimer-type dementia where amnesia is the primary deficit. Various pathologies have been reported, including the tangles and plaques of Alzheimer's disease. Identification of Alzheimer pathology in these aphasic patients is puzzling since tangles and related neuronal loss in Alzheimer's disease typically emerge in memory-related structures such as entorhinal cortex and spread to language related neocortex later in the disease. Furthermore, Alzheimer pathology is typically symmetric. How can a predominantly limbic and symmetric pathology cause the primary progressive aphasia phenotype, characterized by relative preservation of memory and asymmetric predilection for the language-dominant hemisphere? Initial investigations into the possibility that Alzheimer pathology displays an atypical distribution in primary progressive aphasia yielded inconclusive results. The current study was based on larger groups of patients with either primary progressive aphasia or a typical amnestic dementia. Alzheimer pathology was the principal diagnosis in all cases. The goal was to determine whether Alzheimer pathology had clinically-concordant, and hence different distributions in these two phenotypes. Stereological counts of tangles and plaques revealed greater leftward asymmetry for tangles in primary progressive aphasia but not in the amnestic Alzheimer-type dementia (P < 0.05). Five of seven aphasics had more leftward tangle asymmetry in all four neocortical regions analysed, whereas this pattern was not seen in any of the predominantly amnestic cases. One aphasic case displayed higher right-hemisphere tangle density despite greater left-hemisphere hypoperfusion and atrophy during life. Although there were more tangles in the memory-related entorhinal cortex than in language-related neocortical areas in both phenotypes (P < 0.0001), the ratio of neocortical-to-entorhinal tangles was significantly higher in the aphasic cases (P = 0.034). Additionally, overall numbers of tangles and plaques were greater in the aphasic than amnestic cases (P < 0.05), especially in neocortical areas. No significant hemispheric asymmetry was found in plaque distribution, reinforcing the conclusion that tangles have greater clinical concordance than plaques in the spectrum of Alzheimer pathologies. The presence of left-sided tangle predominance and higher neocortical-to-entorhinal tangle ratio in primary progressive aphasia establishes clinical concordance of Alzheimer pathology with the aphasic phenotype. The one case with reversed asymmetry, however, suggests that these concordant clinicopathological relationships are not universal and that individual primary progressive aphasia cases with Alzheimer pathology exist where distributions of plaques and tangles do not account for the observed phenotype. PMID- 22522940 TI - Subthalamic deep brain stimulation can improve gastric emptying in Parkinson's disease. AB - It is established that deep brain stimulation of the subthalamic nucleus improves motor function in advanced Parkinson's disease, but its effects on autonomic function remain to be elucidated. The present study was undertaken to investigate the effects of subthalamic deep brain stimulation on gastric emptying. A total of 16 patients with Parkinson's disease who underwent bilateral subthalamic deep brain stimulation were enrolled. Gastric emptying was expressed as the peak time of (13)CO(2) excretion (T(max)) in the (13)C-acetate breath test and was assessed in patients with and without administration of 100-150 mg levodopa/decarboxylase inhibitor before surgery, and with and without subthalamic deep brain stimulation at 3 months post-surgery. The pattern of (13)CO(2) excretion curve was analysed. To evaluate potential factors related to the effect of subthalamic deep brain stimulation on gastric emptying, we also examined the association between gastric emptying, clinical characteristics, the equivalent dose of levodopa and serum ghrelin levels. The peak time of (13)CO(2) excretion (T(max)) values for gastric emptying in patients without and with levodopa/decarboxylase inhibitor treatment were 45.6 +/- 22.7 min and 42.5 +/- 13.6 min, respectively (P = not significant), thus demonstrating levodopa resistance. The peak time of (13)CO(2) excretion (T(max)) values without and with subthalamic deep brain stimulation after surgery were 44.0 +/- 17.5 min and 30.0 +/- 12.5 min (P < 0.001), respectively, which showed that subthalamic deep brain stimulation was effective. Simultaneously, the pattern of the (13)CO(2) excretion curve was also significantly improved relative to surgery with no stimulation (P = 0.002), although the difference with and without levodopa/decarboxylase inhibitor was not significant. The difference in peak time of (13)CO(2) excretion (T(max)) values without levodopa/decarboxylase inhibitor before surgery and without levodopa/decarboxylase inhibitor and subthalamic deep brain stimulation after surgery was not significant, although motor dysfunction improved and the levodopa equivalent dose decreased after surgery. There was little association between changes in ghrelin levels (Deltaghrelin) and changes in T(max) values (DeltaT(max)) in the subthalamic deep brain stimulation trial after surgery (r = -0.20), and no association between changes in other characteristics and DeltaT(max) post-surgery in the subthalamic deep brain stimulation trial. These results showed that levodopa/decarboxylase inhibitor did not influence gastric emptying and that subthalamic deep brain stimulation can improve the dysfunction in patients with Parkinson's disease possibly by altering the neural system that controls gastrointestinal function after subthalamic deep brain stimulation. This is the first report to show the effectiveness of subthalamic deep brain stimulation on gastrointestinal dysfunction as a non-motor symptom in Parkinson's disease. PMID- 22522941 TI - Identification of the metabolites after oral administration of extract of ziziphi spinosae semen to rats or dogs by high-performance liquid chromatography/linear ion trap FTICR hybrid mass spectrometry. AB - Ziziphi spinosae semen (ZSS) is a traditional Chinese medicine that has been widely used to treat insomnia and anxiety. Modern pharmacological studies have demonstrated that flavonoids are the main active compounds in ZSS. However, the metabolites and the metabolic pathways of flavonoids in ZSS have not been investigated thoroughly. In this study, a method based on high-performance liquid chromatography coupled with Fourier transform ion cyclotron resonance mass spectrometry (HPLC/FTICR-MS) was established to identify the metabolites of flavonoids after oral administration of extract of ZSS to rats or dogs, using parent mass list-triggered data-dependent multiple-stage mass analysis at a resolving power of 50,000 in the external calibration mode. The mass accuracies obtained for all full-scan analyses were less than 4 ppm (<2 ppm in most cases). A total of 15 compounds were detected in biological samples of rats and dogs, and nine compounds were identified. The metabolic pathways of flavonoids of ZSS in rats and dogs were proposed. The results may help better understand the material basis and pharmacological mechanism of ZSS. PMID- 22522942 TI - An organocatalytic cascade strategy for the enantioselective construction of spirocyclopentane bioxindoles containing three contiguous stereocenters and two spiro quaternary centers. PMID- 22522943 TI - A Cre knock-in mouse line on the Sickle tail locus induces recombination in the notochord and intervertebral disks. AB - Sickle tail (Skt) was originally identified by gene trap mutagenesis in mice, and the trapped gene is highly expressed in the notochord, intervertebral discs (IVD), and mesonephros. Here, we report the generation of Skt(cre) mice expressing Cre recombinase in the IVD due to target insertion of the cre gene into the Skt locus by recombinase-mediated cassette exchange. Crossing a conditional lacZ Reporter (R26R), Cre expression from the Skt(cre) allele specifically activates beta-galactosidase expression in the whole notochord from E9.5 onwards. In E15.5 Skt(cre);R26R embryos, reporter activity was detected in the nucleus pulposus and in a portion of the annulus fibrosus, resulting in expansion of Cre-expressing cells in the adult IVD. Reporter activity was also seen in the Skt(cre);R26R mesonephros at E15.5. These results suggest that Skt(cre) mice are useful for exploring the fate specification of notochordal cells and creating models for IVD-related skeletal diseases. PMID- 22522944 TI - Photo-induced DNA scission by Cu(ii)-meso-tetrakis(n-N methylpyridiniumyl)porphyrins (n = 2, 3, 4) and their binding modes to supercoiled DNA. AB - The photo-induced cleavage of pGEM-7zf-NIS super-coiled DNA by Cu(ii)-meso tetrakis(n-N-methylpyridiniumyl)porphyrins (n = 2, 3, 4 referred to as o-, m- and p-CuTMPyP, respectively) and their binding mode were investigated in this study. m-CuTMPyP was most efficient in cleavage than o- and p-CuTMPyP isomers. Cleavage was suppressed by N(2) bubbling, suggesting that the cleavage occurred by an oxidative cleavage mechanism. Sodium azide, an (1)O(2) quencher, and DMSO, a hydroxyl radical scavenger, inhibited cleavage, indicating that hydroxyl radicals and singlet oxygen were likely reactive species responsible for the cleavage. Reduced linear dichroism spectroscopy showed angles of o-CuTMPyP's electric transition moments, in which the periphery pyridinium ring was prevented from free rotation, of 59 degrees and 61 degrees with respect to the local DNA helix axis. The spectra of m- and p-CuTMPyP complexed with pGEM-7zf-NIS DNA were characterized by large signals in the Soret band, coincident with those of known intercalated porphyrins. PMID- 22522945 TI - Selective distribution of GABA(A) receptor subtypes in mouse spinal dorsal horn neurons and primary afferents. AB - In the spinal cord dorsal horn, presynaptic GABA(A) receptors (GABA(A)Rs) in the terminals of nociceptors as well as postsynaptic receptors in spinal neurons regulate the transmission of nociceptive and somatosensory signals from the periphery. GABA(A)Rs are heterogeneous and distinguished functionally and pharmacologically by the type of alpha subunit variant they contain. This heterogeneity raises the possibility that GABA(A)R subtypes differentially regulate specific pain modalities. Here, we characterized the subcellular distribution of GABA(A)R subtypes in nociceptive circuits by using immunohistochemistry with subunit-specific antibodies combined with markers of primary afferents and dorsal horn neurons. Confocal laser scanning microscopy analysis revealed a distinct, partially overlapping laminar distribution of alpha1-3 and alpha5 subunit immunoreactivity in laminae I-V. Likewise, a layer specific pattern was evident for their distribution among glutamatergic, gamma aminobutyric acid (GABA)ergic, and glycinergic neurons (detected in transgenic mice expressing vesicular glutamate transporter 2-enhanced green fluorescent protein [vGluT2-eGFP], glutamic acid decarboxylase [GAD]67-eGFP, and glycine transporter 2 (GlyT2)-eGFP, respectively). Finally, all four subunits could be detected within primary afferent terminals. C-fibers predominantly contained either alpha2 or alpha3 subunit immunoreactivity; terminals from myelinated (Abeta/Adelta) fibers were colabeled in roughly equal proportion with each subunit. The presence of axoaxonic GABAergic synapses was determined by costaining with gephyrin and vesicular inhibitory amino acid transporter to label GABAergic postsynaptic densities and terminals, respectively. Colocalization of the alpha2 or alpha3 subunit with these markers was observed in a subset of C fiber synapses. Furthermore, gephyrin mRNA and protein expression was detected in dorsal root ganglia. Collectively, these results show that differential GABA(A)R distribution in primary afferent terminals and dorsal horn neurons allows for multiple, circuit-specific modes of regulation of nociceptive circuits. PMID- 22522947 TI - Research and its pitfalls. PMID- 22522948 TI - Oral piercings and their dental implications: a mini review. AB - Oral piercing has become common in young adults in recent years. Adolescents are characterized by a compulsive tendency to distinguish themselves from the rest; differences in clothes, hairstyle, or "decorative" details are used to this effect, based on highly-diverse criteria. Dental health-care professionals need to be aware of the procedures and risks involved with oral piercings and the social and psychological reasons that lead people to engage in this practice, regardless of the risks. The present article addresses oral mutilation practices, specifically from the oral health perspective, as it is of concern to dental professionals due to the health risks and oral complications associated with such practices. The various oral ornaments, piercing sites, and their implications, orally, as well as systemically, have been discussed. PMID- 22522946 TI - Bimolecular fluorescence complementation and targeted biotinylation provide insight into the topology of the skeletal muscle Ca ( 2+) channel beta1a subunit. AB - In skeletal muscle, L-type calcium channels (DHPRs), localized to plasma membrane sarcoplasmic reticulum junctions, are tightly packed into groups of four termed tetrads. Here, we have used bimolecular fluorescence complementation (BiFC) and targeted biotinylation to probe the structure and organization of beta1a subunits associated with native CaV 1.1 in DHPRs of myotubes. The construct YN-beta1a-YC, in which the non-fluorescent fragments of YFP ("YN" corresponding to YFP residues 1-158, and "YC" corresponding to YFP residues 159-238) were fused, respectively, to the N- and C-termini of beta1a, was fully functional and displayed yellow fluorescence within DHPR tetrads after expression in beta1-knockout (beta1KO) myotubes; this yellow fluorescence demonstrated the occurrence of BiFC of YN and YC on the beta1a N- and C-termini. In these experiments, we avoided overexpression because control experiments in non-muscle cells indicated that this could result in non-specific BiFC. BiFC of YN-beta1a-YC in DHPR tetrads appeared to be intramolecular between N- and C-termini of individual beta1a subunits rather than between adjacent DHPRs because BiFC (1) was observed for YN beta1a-YC co-expressed with CaV 1.2 (which does not form tetrads) and (2) was not observed after co-expression of YN-beta1a-YN plus YC-beta1a-YC in beta1KO myotubes. Thus, beta1a function is compatible with N- and C-termini being close enough together to allow BiFC. However, both termini appeared to have positional freedom and not to be closely opposed by other junctional proteins since both were accessible to gold-streptavidin conjugates. Based on these results, a model is proposed for the arrangement of beta1a subunits in DHPR tetrads. PMID- 22522949 TI - Idiopathic bone cavity: case series involving children and adolescents. AB - AIM: This study aimed at reviewing a series of clinical cases of children and adolescents treated for idiopathic bone cavity (IBC). METHODS: Ten lesions diagnosed as IBC in nine patients treated between February 2000 and December 2008 were reviewed, focusing on clinical and radiographic aspects, as well the therapeutic approach. RESULTS: Most of the patients were Caucasian with no sex predilection (55.5% males and 45.5% females), and all were in the second decade of life at the time of IBC diagnosis. The lesions were asymptomatic and detected during routine radiographic examinations. All the lesions were located in the mandible, and the anterior region was the most affected. The most adopted therapeutic approach was simple curettage of the bone cavity, and all surgically treated patients presented complete bone healing after 6 months, postoperatively. CONCLUSIONS: Clinical and radiographic diagnoses associated with surgical exploration are the most important treatment options in order to avoid radical surgery or unnecessary endodontic treatment, mainly when idiopathic bone cavities are detected in children and adolescents. Further studies aimed at elucidating the etiopathogenesis of this condition and defining the most appropriate treatment should be conducted. PMID- 22522950 TI - Association between cigarette smoking and the intraoral distribution of periodontal disease in Thai men over 50 years of age. AB - AIM: This study aimed to investigate the effects of cigarette smoking on periodontal conditions in specific tooth regions of older Thai men. METHODS: There were 272 current smokers, 714 former smokers, and 477 non-smokers enrolled in the present study. Differences between groups in the mean probing depth or attachment loss were compared using ancova. The relationship between smoking exposure or cessation duration and periodontal conditions was examined using linear trend analysis. RESULTS: Smokers had deeper pockets and attachment loss than non-smokers. The greatest differences between smokers and non-smokers were observed in the maxillary posterior palatal region, where current smokers had 0.88 mm greater attachment loss than non-smokers, compared to 0.36-0.60 mm observed in other tooth regions. Among the current smokers, there was a trend towards an increase in attachment loss with increasing smoking exposure in the maxillary posterior regions. However, it was not statistically significant. Among the former smokers, a better periodontal condition was observed, depending on the length of time since smoking cessation; this was most pronounced in the maxillary posterior palatal region. CONCLUSIONS: The palatal site of maxillary posterior teeth was the area most affected by cigarette smoke. The results suggest a possible local effect of smoking in addition to its systemic effects. PMID- 22522951 TI - Bonding quality of contemporary dental cements to sandblasted esthetic crown copings. AB - AIM: To evaluate the shear bond strength of current luting cements to sandblasted crown-coping substrates. METHODS: Specimens of nickel-chromium, pressable glass ceramic, and zirconia crown-coping substrates were sandblasted in three groups (n = 30 each) with 50 (group 1), 110 (group 2), and 250 MUm (group 3) alumina particles at a pressure of 250 kPa. Cylinders of glass ionomer, universal resin, and self-adhesive resin cements were then built up on the sandblasted substrate surfaces of each group (n = 10). All bonded specimens were stressed to evaluate the cement-substrate shear bond strength. Both the mode and incidence of bond failure were also considered. RESULTS: No difference was noticed between all test groups in terms of cement-substrate bond strength. In comparison to self-adhesive type, the universal resin cement provided lower bond strengths to both metal and glass-ceramic substrates in group 1. The self-adhesive resin cement provided the highest bond strengths to the zirconia substrates in groups 2 and 3. The adhesive type of bond failure was common in the metal and zirconia substrates in all groups. CONCLUSIONS: Cement-substrate bonding quality is not affected by the size of sandblasting particles. Resin cements bond better to different coping substrates. Self-adhesive resin cement is the best choice to bond zirconia-based substrates. PMID- 22522952 TI - Peripheral ivory osteoma of the mandible in a young female patient. AB - Osteoma is an uncommon benign neoplasm composed of mature bone. Growth is slow and continuous and located principally in the cranio-maxillo-facial region, and can be central (endosteal) or peripheral (periosteal). Osteomas can be solitary or multiple masses, and they are generally asymptomatic. We discuss a case of ivory osteoma of the mandible in a 35-year-old female, which was present at the left body of the mandible since she was 10 years old, and was gradually increasing in size. The osteoma was removed surgically through an intraoral approach, and no recurrence was observed. PMID- 22522953 TI - Cystic variant of calcifying epithelial odontogenic tumor. AB - The calcifying epithelial odontogenic tumor is a rare benign odontogenic neoplasm of the jaw. Clinically, calcifying epithelial odontogenic tumor manifests as an intraosseous lesion (central type) in the majority of cases (95%). Extraosseous or peripheral lesions account for less than 5% of cases. Calcifying epithelial odontogenic tumor can be associated with an impacted tooth and give a radiographic simulation of dentigerous cyst. Most calcifying epithelial odontogenic tumors are solid in nature, histopathologically, and might have few cyst-like spaces within them. However, a true cystic calcifying epithelial odontogenic tumor is a rare possibility. We describe a case of a true cystic variant of calcifying epithelial odontogenic tumor in a 30-year-old male, which to our knowledge, is only the second reported case. PMID- 22522954 TI - Cocaine-related oronasal communication and hard palate destruction. AB - Four cases of midpalatal perforation in cocaine abusers are presented. Other potential etiological processes are discussed to establish an adequate differential diagnosis. These patients were treated at our department, due to the drawback promoted by the establishment of oronasal communication that was provided after an accurate diagnosis. Histopathological evaluation of the lesion margins were conducted in two of the four cases, and yielded no evidence of vasculitis or active cocaine abuse. Therapeutic approach consisted of reconstructive surgeries and/or sealing prostheses. Histological assessment of oronasal communication margins could be useful in establishing the persistence of active addiction, and also as a complementary tool for planning possible treatment. PMID- 22522956 TI - Organodiphosphonate-functionalized lanthanopolyoxomolybdate cages. PMID- 22522955 TI - Performance comparison of benchtop high-throughput sequencing platforms. AB - Three benchtop high-throughput sequencing instruments are now available. The 454 GS Junior (Roche), MiSeq (Illumina) and Ion Torrent PGM (Life Technologies) are laser-printer sized and offer modest set-up and running costs. Each instrument can generate data required for a draft bacterial genome sequence in days, making them attractive for identifying and characterizing pathogens in the clinical setting. We compared the performance of these instruments by sequencing an isolate of Escherichia coli O104:H4, which caused an outbreak of food poisoning in Germany in 2011. The MiSeq had the highest throughput per run (1.6 Gb/run, 60 Mb/h) and lowest error rates. The 454 GS Junior generated the longest reads (up to 600 bases) and most contiguous assemblies but had the lowest throughput (70 Mb/run, 9 Mb/h). Run in 100-bp mode, the Ion Torrent PGM had the highest throughput (80-100 Mb/h). Unlike the MiSeq, the Ion Torrent PGM and 454 GS Junior both produced homopolymer-associated indel errors (1.5 and 0.38 errors per 100 bases, respectively). PMID- 22522957 TI - Two-photon polymerization-generated and micromolding-replicated 3D scaffolds for peripheral neural tissue engineering applications. AB - In this study, we explore the production of well-defined macroscopic scaffolds with two-photon polymerization (2PP) and their use as neural tissue engineering scaffolds. We also demonstrate that these 3D scaffolds can be replicated via soft lithography, which increases production efficiency. Photopolymerizable polylactic acid (PLA) was used to produce scaffolds by 2PP and soft lithography. We assessed the biocompatibility of these scaffolds using an SH-SY5Y human neuronal cell line and primary cultured rat Schwann cells (of direct relevance to the repair of nerve injuries). A Comet assay with SH-SY5Y human neuronal cells revealed minimal DNA damage after washing the photocured material for 7 days in ethanol. Additionally, thin films and 3D scaffolds of the photocured PLA sustained a high degree of Schwann cell purity (99%), enabled proliferation over 7 days and provided a suitable substrate for supporting Schwann cell adhesion such that bi polar and tri-polar morphologies were observed. Evidence of orthogonally aligned and organized actin thin filaments and the formation of focal contacts were observed for the majority of Schwann cells. In summary, this work supports the use of PLA as a suitable material for supporting Schwann cell growth and in turn use of 3D soft lithography for the synthesis of neural scaffolds in nerve repair. PMID- 22522958 TI - Contrast-enhanced ultrasound for monitoring effects of extracorporeal shock wave sialolithotripsy in sialolithiasis. AB - OBJECTIVES/HYPOTHESIS: Contrast-enhanced ultrasound (CE-US) can be used for noninvasive analysis of functional vascularization. Chronically recurrent sialadenitis due to sialolithiasis of the submandibular gland is associated with increased vascularity. The aim of this investigator-initiated clinical trial was the evaluation of CE-US as a quantitative monitoring technique during gland preserving extracorporeal shock wave sialolithotripsy (ESWL). STUDY DESIGN: In this prospective clinical evidence level 2c study, perfusion in patients (n = 10) with unilateral sialolithiasis of the submandibular gland was quantitatively analyzed using CE-US before and after ESWL, comparing with the respective contralateral gland. METHODS: Before CE-US measurements, a subjective clinical score of complaints (range, 1-10) was documented. The contrast agent SonoVue was injected into a cubital vein. The intensity-time curve gradients (ITGs) were calculated from CE-US data. RESULTS: The ITGs derived from CE-US measurements revealed higher perfusion in the affected submandibular gland compared to the contralateral side. In parallel to clinical complaints, parametric CE-US data were significantly reduced after ESWL in chronic sialolithiasis-associated sialadenitis. CONCLUSIONS: CE-US-derived ITGs appear to be an independent and quantitative marker for treatment effects of ESWL. Clinical experience and further studies will have to validate this method as a diagnostic tool to decide especially whether to proceed to sialoadenectomy in therapy-refractory cases. PMID- 22522959 TI - Psychiatric comorbidity of full and partial posttraumatic stress disorder among older adults in the United States: results from wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions. AB - OBJECTIVES: To present findings on the prevalence, correlates, and psychiatric comorbidity of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition posttraumatic stress disorder (PTSD) and partial PTSD in a nationally representative sample of U.S. older adults. DESIGN, SETTING, AND PARTICIPANTS: Face-to-face interviews with 9,463 adults age 60 years and older in the Wave 2 National Epidemiologic Survey on Alcohol and Related Conditions. MEASUREMENTS: Sociodemographic correlates; worst stressful experiences; comorbid lifetime mood, anxiety, substance use, and personality disorders; psychosocial functioning; and suicide attempts. RESULTS: Lifetime prevalences +/- standard errors of PTSD and partial PTSD were 4.5% +/- 0.25 and 5.5% +/- 0.27, respectively. Rates were higher in women (5.7% +/- 0.37 and 6.5% +/- 0.39) than in men (3.1% +/- 0.31 and 4.3% +/- 0.37). Older adults with PTSD most frequently identified unexpected death of someone close, serious illness or injury to someone close, and their own serious or life-threatening illness as their worst stressful events. Older adults exposed to trauma but without full or partial PTSD and respondents with partial PTSD most often identified unexpected death of someone close, serious illness or injury to someone close, and indirect experience of 9/11 as their worst events. PTSD was associated with elevated odds of lifetime mood, anxiety, drug use, and borderline and narcissistic personality disorders and decreased psychosocial functioning. Partial PTSD was associated with elevated odds of mood, anxiety, and narcissistic and schizotypal personality disorders and poorer psychosocial functioning relative to older adults exposed to trauma but without full or partial PTSD. CONCLUSIONS: PTSD among older adults in the United States is slightly more prevalent than previously reported and is associated with considerable psychiatric comorbidity and psychosocial dysfunction. Partial PTSD is associated with significant psychiatric comorbidity, particularly with mood and other anxiety disorders. PMID- 22522960 TI - Prevalence of neuropsychiatric symptoms in CIND and its subtypes: the Cache County Study. AB - OBJECTIVES: 1) To report rates of neuropsychiatric symptoms (NPS) in cognitive impairment, no dementia (CIND). 2) To compare the 30-day prevalence of NPS in CIND with that in dementia and cognitively normal individuals. 3) To compare the prevalence of NPS in amnestic MCI (aMCI) with other predementia syndromes. DESIGN: Comparison of prevalence proportions among several defined groups. SETTING: Population-based study. PARTICIPANTS: A subsample of the permanent residents of Cache County, Utah, aged 65 years or older in January 1995 (N = 5092) and who had completed clinical assessments and had an informant-completed Neuropsychiatric Inventory. MEASUREMENTS: Chi-square statistics, tests for trend, and logistic regression models were used to analyze the three objectives listed earlier. RESULTS: The most prevalent NPS in those with CIND were depression (16.9%), irritability (9.8%), nighttime behaviors (7.6%), apathy (6.9%), and anxiety (5.4%). Trend analyses confirmed that the CIND group had NPS prevalence rates that fell between the normal and dementia groups for most NPS. Logistic regression models showed no significant difference between aMCI and other CIND participants in the prevalence of any NPS (lowest p: 0.316). CONCLUSIONS: These data confirm the relatively high prevalence of NPS in CIND reported by other studies, especially for affective symptoms. No differences in NPS prevalence were found between aMCI and other types of CIND. PMID- 22522961 TI - Mental healthcare need and service utilization in older adults living in public housing. AB - OBJECTIVES: Anxiety and depression in socioeconomically disadvantaged older adults frequently go unrecognized and untreated. This study aims to characterize mental illness and its treatment in older adult public housing residents who have many risk factors for anxiety and depression. DESIGN: Cross-sectional study. SETTING: Public housing high-rises in Rochester, New York. PARTICIPANTS: One hundred ninety residents aged 60 years and older. MEASUREMENTS: Anxiety and depression were assessed using the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, GAD-7, and Patient Health Questionnaire. We obtained information on mental healthcare from medication review and self-report. RESULTS: Participants had a median age of 66 years, 58% were women, 80% were black, and 92% lived alone. Many participants (31%) were in need of mental healthcare: 21% had syndromal and 11% had subsyndromal anxiety or depression. Mental healthcare need was associated with younger age; intact cognitive functioning; impairments in instrumental activities of daily living (IADL); more medical illness; decreased mobility; smaller social network size; more severe life events; and increased utilization of medical, human, and informal services. Of those with mental healthcare need, most were not receiving it. Compared with residents receiving mental healthcare, residents with untreated need were more likely to be men and have less IADL impairment, medical illness, severe life events, onsite social worker use, and human services utilization. CONCLUSIONS: Mental illness was common and largely untreated in public housing residents. Increasing collaboration between medical, mental, and human services is needed to improve identification, treatment, and ultimately prevention of late-life mental illness in this community setting. PMID- 22522962 TI - [Restless legs syndrome: pathophysiology still unknown]. PMID- 22522963 TI - Alterations of the salience network in obesity: a resting-state fMRI study. AB - Obesity is a major health problem in modern societies. It has been related to abnormal functional organization of brain networks believed to process homeostatic (internal) and/or salience (external) information. This study used resting-state functional magnetic resonance imaging analysis to delineate possible functional changes in brain networks related to obesity. A group of 18 healthy adult participants with obesity were compared with a group of 16 lean participants while performing a resting-state task, with the data being evaluated by independent component analysis. Participants also completed a neuropsychological assessment. Results showed that the functional connectivity strength of the putamen nucleus in the salience network was increased in the obese group. We speculate that this abnormal activation may contribute to overeating through an imbalance between autonomic processing and reward processing of food stimuli. A correlation was also observed in obesity between activation of the putamen nucleus in the salience network and mental slowness, which is consistent with the notion that basal ganglia circuits modulate rapid processing of information. PMID- 22522964 TI - Development and validation of a sensitive LC/MS/MS method for the determination of gamma-tocotrienol in rat plasma: application to pharmacokinetic studies. AB - gamma-Tocotrienol has attracted much attention owing to its multiple health benefits. This study developed and validated a simple, specific, sensitive and reliable LC/MS/MS method to analyze gamma-tocotrienol in rat plasma. Plasma samples (50 MUL) were extracted with internal standard solution (25 ng/mL of itraconazole) in acetonitrile (200 MUL) with an average recovery of 44.7% and an average matrix effect of -2.9%. The separation of gamma-tocotrienol and internal standard from the plasma components was achieved with a Waters XTerra(r) MS C(18) column with acetonitrile-water as mobile phase. Analysis was performed under positive ionization electrospray mass spectrometer via the multiple reaction monitoring. The standard curve was linear over a concentration range of 10-1000 ng/mL with correlation coefficient values >0.997. The method was validated with intra- and inter-day accuracy (relative error) ranging from 1.79 to 9.17% and from 2.16 to 9.66%, respectively, and precision (coefficient of variation) ranged from 1.94 to 9.25% and from 2.37 to 10.08%, respectively. Short-term stability, freeze-thaw stability and the processed sample stability tests were performed. This method was further applied to analyze gamma-tocotrienol plasma concentrations in rats at various time points after administration of a 2 mg/kg single intravenous dose, and a pharmacokinetic profile was successfully obtained. PMID- 22522965 TI - Generation of conditional alleles for Foxc1 and Foxc2 in mice. AB - The Forkhead box transcription factors, Foxc1 and Foxc2, are crucial for development of the eye, cardiovascular network, and other physiological systems, but their cell-type specific and postdevelopmental functions are unknown, in part because conventional (i.e., whole-organism) homozygous-null mutations of either factor result in perinatal death. Here, we describe the generation of mice with conditional-null Foxc1(flox) and Foxc2(flox) mutations that are induced via Cre mediated recombination. Mice homozygous for the unrecombined alleles are viable and fertile, indicating that the conditional alleles retain their wild-type function. The embryos of Foxc1(flox) or Foxc2(flox) mice crossed with Cre-deleter mice that are homozygous for the recombined allele (i.e., Foxc1(Delta/Delta) or Foxc2(Delta/Delta) embryos) lack expression of the corresponding gene and show the same developmental defects observed in conventional homozygous mutant embryos. We expect these conditional mutations to enable characterization of the cell-type specific functions of Foxc1 and Foxc2 in development, disease, and adult animals. PMID- 22522967 TI - A metal-binding site in the RTN1-C protein: new perspectives on the physiological role of a neuronal protein. AB - Reticulon 1-C (RTN1-C) is an ER-associated neuronal protein characterized by horse-shoe-like topology with two transmembrane helices and the N- and C-terminal regions which are supposed in the cytosolic side of ER. The physiological role of this protein is not completely clarified, but several studies have suggested its involvement in the neuronal differentiation, membrane vesicle trafficking and induction of apoptosis. The C-terminal region of RTN1-C is characterized by the presence of a H4 histone consensus sequence that makes it able to interact with nucleic acids and HDAC enzymes both in vitro and in vivo. In the present study a potential metal ion binding motif (HxE/D) at the C-terminal of the RTN1-C has been identified and its capability to bind metals investigated by UV-vis, CD, multidimensional NMR spectroscopy and biological assays. The results suggest a possible implication of the metal ions in the mechanisms of formation of the recently observed RTNs multiprotein complexes contributing to understand the structure and function of this neuronal membrane protein, suggesting a possible effect of the metal binding property on its biological function. PMID- 22522966 TI - Expression of EAAT2 in neurons and protoplasmic astrocytes during human cortical development. AB - The major regulators of synaptic glutamate in the cerebral cortex are the excitatory amino acid transporters 1-3 (EAAT1-3). In this study, we determined the cellular and temporal expression of EAAT1-3 in the developing human cerebral cortex. We applied single- and double-label immunocytochemistry to normative frontal or parietal (associative) cortex samples from 14 cases ranging in age from 23 gestational weeks to 2.5 postnatal years. The most striking finding was the transient expression of EAAT2 in layer V pyramidal neuronal cell bodies up until 8 postnatal months prior to its expression in protoplasmic astrocytes at 41 postconceptional weeks onward. EAAT2 was also expressed in neurons in layer I (presumed Cajal-Retzius cells), and white matter (interstitial) neurons. This expression in neurons in the developing human cortex contrasts with findings by others of transient expression exclusively in axon tracts in the developing sheep and rodent brain. With western blotting, we found that EAAT2 was expressed as a single band until 2 postnatal months, after which it was expressed as two bands. The expression of EAAT2 in pyramidal neurons during human brain development may contribute to cortical vulnerability to excitotoxicity during the critical period for perinatal hypoxic-ischemic encephalopathy. In addition, by studying the expression of EAAT1 and EAAT2 glutamate transporters, it was possible to document the development of protoplasmic astrocytes. PMID- 22522968 TI - Methodological aspects of exhaled breath condensate collection and analysis. AB - The collection and analysis of exhaled breath condensate (EBC) may be useful for the management of patients with chronic respiratory disease at all ages. It is a promising technique due to its apparent simplicity and non-invasiveness. EBC does not disturb an ongoing respiratory inflammation. However, the methodology remains controversial, as it is not yet standardized. The current diversity of the methods used to collect and preserve EBC, the analytical pitfalls and the high degree of within-subject variability are the main issues that hamper further development into a clinical useful technique. In order to facilitate the process of standardization, a simplified schematic approach is proposed. An update of available data identified open issues on EBC methodology. These issues were then classified into three separate conditions related to their influence before, during or after the condensation process: (1) pre-condenser conditions related to subject and/or environment; (2) condenser conditions related to condenser equipment; and (3) post-condenser conditions related to preservation and/or analysis. This simplified methodological approach highlights the potential influence of the many techniques used before, during and after condensation of exhaled breath. It may also serve as a methodological checklist for a more systematical approach of EBC research and development. PMID- 22522969 TI - Improving BPH symptoms and sexual dysfunctions with a saw palmetto preparation? Results from a pilot trial. AB - In elderly men, benign prostatic hyperplasia (BPH) is a major risk factor for sexual dysfunctions (SDys). Additionally, the standard treatments for BPH symptoms, alpha blockers and 5-alpha-reductase inhibitors, cause SDys themselves. Preparations from saw palmetto berries are an efficacious and well-tolerated symptomatic treatment for mild to moderate BPH and have traditionally been used to treat SDys. We conducted an open multicentric clinical pilot trial to investigate whether the saw palmetto berry preparation Prostasan(r) influenced BPH symptoms and SDys. Eighty-two patients participated in the 8-week trial, taking one capsule of 320 mg saw palmetto extract daily. At the end of the treatment, the International Prostate Symptom Score was reduced from 14.4 +/- 4.7 to 6.9 +/- 5.2 (p < 0.0001); SDys measured with the brief Sexual Function Inventory improved from 22.4 +/- 7.2 to 31.4 +/- 9.2 (p < 0.0001), and the Urolife BPH QoL-9 sex total improved from 137.3 +/- 47.9 to 195.0 +/- 56.3 (p < 0.0001). Investigators' and patients' assessments confirmed the good efficacy, and treatment was very well tolerated and accepted by the patients. Correlation analyses confirmed the relationship between improved BPH symptoms and reduced SDys. This was the first trial with saw palmetto to show improvement in BPH symptoms and SDys as well. [Corrections made here after initial online publication.] PMID- 22522970 TI - Mini-scale bioprocessing systems for highly parallel animal cell cultures. AB - Animal cells have been used extensively in therapeutic protein production. The growth of animal cells and the expression of therapeutic proteins are highly dependent on the culturing environments. A large number of experimental permutations need to be explored to identify the optimal culturing conditions. Miniaturized bioreactors are well suited for such tasks as they offer high throughput parallel operation and reduce cost of reagents. They can also be automated and be coupled to downstream analytical units for online measurements of culture products. This review summarizes the current status of miniaturized bioreactors for animal cell cultivation based on the design categories: microtiter plates, flasks, stirred tank reactors, novel designs with active mixing, and microfluidic cell culture devices. We compare cell density and product titer, for batch or fed-batch modes for each system. Monitoring/controlling devices for engineering parameters such as pH, dissolved oxygen, and dissolved carbon dioxide, which could be applied to such systems, are summarized. Finally, mini-scale tools for process performance evaluation for animal cell cultures are discussed: total cell density, cell viability, product titer and quality, substrates, and metabolites profiles. PMID- 22522971 TI - Nasoseptal flap repair after endoscopic transsellar versus expanded endonasal approaches: is there an increased risk of postoperative cerebrospinal fluid leak? AB - OBJECTIVES/HYPOTHESIS: The development of expanded endoscopic endonasal approaches (EEAs) has allowed resection of cranial-base lesions beyond the sella. One major criticism is an increased risk of postoperative cerebrospinal fluid (CSF) leakage because of the larger skull base defect. We evaluated our experience with vascularized pedicled nasoseptal flap (PNSF) reconstruction and compared the postoperative CSF leak rates between patients undergoing endoscopic transsphenoidal (transsellar) approaches versus expanded EEA (transplanum transtuberculum, transcribriform, transclival). STUDY DESIGN: Retrospective analysis at a tertiary care medical center. METHODS: A retrospective review of a prospective database was performed on patients who underwent PNSF reconstruction for intraoperative high-flow CSF leaks after EEA between December 2008 and August 2011. Demographic data, repair materials, surgical approach, and incidence of postoperative CSF leaks were collected. RESULTS: Thirty-seven transsellar defects (group I) were repaired with a PNSF, and 32 expanded EEA defects (19 transplanum transtuberculum, 10 transcribriform, three transclival) (group II) were repaired with a PNSF. No postoperative CSF leaks occurred in group I. One delayed postoperative CSF leak was encountered in group II leading to a 3.1% leak rate in that group. The incidence of postoperative CSF leakage was not significantly different between the two groups (P > .05). Our overall success rate in this series using a PNSF was 98.6%. CONCLUSIONS: Based on our data, there is no significant increased risk of postoperative CSF leak between transsellar and expanded EEA defects when a PNSF is used. The potential risk of postoperative CSF leaks associated with larger defects created through expanded EEA can be minimized by multilayered closure with a PNSF and meticulous surgical technique. PMID- 22522972 TI - Stratified medicine in psychiatry: a worrying example or new opportunity in the treatment of anxiety? AB - Stratified medicine is a new term that figures highly in current MRC and NHS strategy. It has developed from the earlier terms individualised or personalised medicine and refers to the use of genetic and/or endophenotypic measures to allow better targeting of treatments. The best exemplar is HER2 positivity in breast cancer to determine the efficacy of Herceptin. Clinical trials of this anti cancer drug were initially unpromising, but once the HER2 positive subgroup was identified it was found, in this subgroup only, to be highly effective. It is presumed that similar subgroups will be found for many common disorders not just cancers, and that these will lead to much better targeted treatments. Such an advance may be necessary to develop new treatments in certain fields where the development of broad-spectrum/blockbuster treatments appears to have reached the end of the road; a particular example of this is in psychiatry. In this paper we discuss this issue in relation to psychiatry using a new and interesting example of how genotyping might help rescue an apparently failed novel treatment in anxiety disorders. PMID- 22522973 TI - Morphine alters the locomotor responses to a D2/D3 dopamine receptor agonist differentially in adolescent and adult mice. AB - The D2-like dopamine receptors mediate the emotional/aversive state during morphine withdrawal. Given age-dependent differences in the affective responses to withdrawal, this study examined whether the response to dopamine receptor agonists is altered differentially across ages following morphine administration. Adolescent and adult mice were injected with morphine (twice daily, 10-40 mg/kg, s.c.) or saline for 6 days. Subsequently, they were examined for their locomotor response to quinpirole, a D2/D3 receptor agonist, and SKF 38393, a D1 receptor agonist. Quinpirole dose-dependently reduced locomotion in drug-naive animals. Initial suppression was also observed in morphine-treated animals, but was followed by enhanced locomotion. Notably, this enhanced locomotion was markedly greater in adolescents than adults. Quinpirole-induced hypo-locomotion is thought to be mediated by the presynaptic D2Short receptors, whereas its activating effect is mediated by postsynaptic D2Long/D3 receptors. This suggests that following morphine administration, the postsynaptic, but not the presynaptic, dopaminergic signaling is differentially modulated across ages. This locomotor supersensitivity was not observed for SKF 38393, a D1 dopamine receptor agonist. The D2/D3 receptors are involved in the pathophysiology of many mental illnesses. Thus, this study offers a potential explanation for the increased psychiatric disorder co-morbidities when drug use begins during adolescence. PMID- 22522974 TI - Forehead reconstruction with microvascular flaps: utility of aesthetic subunits. AB - BACKGROUND: Current literature describes the forehead as one aesthetic subunit of the face. We argue for the usefulness of aesthetic forehead subunits when microvascular flap reconstruction is required. Key to utilization of microvascular flaps for restoration of forehead subunits is an understanding of the patient population and defect characteristics most amiable to treatment. METHODS: We conducted an International Review Board-approved retrospective chart review of nine consecutive patients who had undergone free flap reconstruction for large forehead defects. RESULTS: The patients' foreheads included one paramedian defect; one central and paramedian defect; four central, paramedian, and lateral defects; and three lateral defects. Seven patients had ulnar forearm flaps and two had anterolateral thigh flaps. The success rate was 100%. CONCLUSION: A forehead subunit classification system has been devised that provides a suitable option for cases that benefit from distant tissue replacement in a single stage, while preserving the principles of aesthetic replacement. PMID- 22522975 TI - fMRI evidence of degeneration-induced neuropathic pain in diabetes: enhanced limbic and striatal activations. AB - Persistent neuropathic pain due to peripheral nerve degeneration in diabetes is a stressful symptom; however, the underlying neural substrates remain elusive. This study attempted to explore neuroanatomical substrates of thermal hyperalgesia and burning pain in a diabetic cohort due to pathologically proven cutaneous nerve degeneration (the painful group). By applying noxious 44 degrees C heat stimuli to the right foot to provoke neuropathic pain symptoms, brain activation patterns were compared with those of healthy control subjects and patients with a similar degree of cutaneous nerve degeneration but without pain (the painless group). Psychophysical results showed enhanced affective pain ratings in the painful group. After eliminating the influence of different pain intensity ratings on cerebral responses, the painful group displayed augmented responses in the limbic and striatal structures, including the perigenual anterior cingulate cortex (ACC), superior frontal gyrus, medial thalamus, anterior insular cortex, lentiform nucleus (LN), and premotor area. Among these regions, blood oxygen level-dependent (BOLD) signals in the ACC and LN were correlated with pain ratings to thermal stimulations in the painful group. Furthermore, activation maps of a simple regression analysis as well as a region of interest analysis revealed that responses in these limbic and striatal circuits paralleled the duration of neuropathic pain. However, in the painless group, BOLD signals in the primary somatosensory cortex and ACC were reduced. These results suggest that enhanced limbic and striatal activations underlie maladaptive responses after cutaneous nerve degeneration, which contributed to the development and maintenance of burning pain and thermal hyperalgesia in diabetes. PMID- 22522976 TI - In vivo metabolism study of vaccarin in rat using HPLC-LTQ-MSn. AB - In order to illustrate the main biotransformation pathways of vaccarin in vivo, metabolites of vaccarin in rats were identified using a specific and sensitive high-performance liquid chromatography-electrospray ionization linear ion trap mass spectrometry (LTQ XLTM) method. The rats were administered a single dose (200 mg/kg) of vaccarin by oral gavage. By comparing their changes in molecular masses (DeltaM), retention times and spectral patterns with those of the parent drug, the parent compound and six metabolites were found in rat urine after oral administration of vaccarin. The parent compound and five metabolites were detected in rat plasma. In heart, liver and kidney samples, respectively, one, four and three metabolites were identified, in addition to the parent compound. Three metabolites, but no trace of parent drug, were found in the rat feces. This is the first systematic metabolism study of vaccarin in vivo. The biotransformation pathways of vaccarin involved methylation, hydroxylation, glycosylation and deglycosylation. PMID- 22522977 TI - Galanin gene expression and effects of its knock-down on the development of the nervous system in larval zebrafish. AB - Despite the known importance of galanin in the nervous system of vertebrates, the galanin gene structure and expression and the consequences of galanin deficiency in developing zebrafish are unknown. We cloned the galanin gene and analyzed its expression by using in situ hybridization, PCR, and immunocytochemistry throughout the early development of zebrafish until the end of the first week of life. The single zebrafish galanin gene encoded for a single amidated galanin peptide and a galanin message-associated peptide. Two forms resulting from alternative processing were identified. Galanin mRNA was maternally expressed and found in developing fish throughout early development. In situ hybridization showed the first positive neurons in three groups in the brain at 28 hours postfertilization. At 2 days postfertilization, three prosencephalic neuron groups were seen in the preoptic area and in rostral and caudal periventricular hypothalamus. In addition, two other groups of weakly stained neurons were visible, one in the midbrain and another in the hindbrain. Translation inhibition of galanin mRNA with morpholino oligonucleotides caused complete disappearance of galanin immunoreactivity in the brain until 7 dpf and did not induce known cascades of nonspecific pathways or morphological abnormalities. A minor disturbance of sensory ganglia was found. Galanin knockdown did not alter the expression of tyrosine hydroxylases 1 and 2, choline acetyltransferase, histidine decarboxylase, or orexin mRNA. The results suggest that galanin does not regulate the development of these key markers of specific neurons, although galanin expressing fibers were in a close spatial proximity to several neurons of these neuronal populations. PMID- 22522978 TI - New insights into bicuspid aortic valve disease: the elongated anterior mitral leaflet. AB - OBJECTIVES: The bicuspid aortic valve (BAV) is associated with various cardiovascular malformations, most predominantly with dilatation of the aortic root and ascending aorta. After sporadic observations of various BAV-associated mitral valve pathologies, we sought to systematically examine the mitral valve morphology in patients with a BAV. METHODS: Forty-four operated patients with a BAV (type I L/R) and 40 operated patients with a tricuspid aortic valve (TAV) as well as 20 healthy subjects (Normal) were examined by means of transthoracic echocardiography. In all patients, the primary operative indication was aortic valve pathology (stenosis/regurgitation), and no patients with degenerative mitral valve pathology were included. RESULTS: In patients with a BAV, the anterior mitral leaflet (AML) was significantly elongated in comparison with patients with a TAV and Normal subjects (33.2 +/- 6.6 vs 27.7 +/- 3.2 vs 27.0 +/- 1.9 mm; P < 0.001). Regression analysis revealed that patients with a BAV had significantly elongated AML (P < 0.001) even after correcting for the mitral annulus (MA) diameter and somatometric characteristics (weight, height, body surface area, age). Furthermore, patients with a BAV and concomitant aortic valve insufficiency had significantly elongated AML in comparison with the other groups (35.2 +/- 7.6 vs 28.4 +/- 3.7 mm; P < 0.001). This difference persisted even after correcting for MA diameter and somatometric differences (P < 0.001). AML heights >32 mm in patients undergoing aortic root/valve procedures were highly predictive of the presence of a BAV [specificity: 90%, positive predictive value: 82%, area under curve: 0.80 (95% CI: 0.71-0.88)]. CONCLUSIONS: We provide evidence that the cardiovascular alterations observed in the BAV are not limited to the aortic valve or ascending aorta but also involve the AML, and seem to be more pronounced in patients with a BAV with concomitant, clinically significant aortic regurgitation. PMID- 22522979 TI - Natural and modified history of single-ventricle physiology in adult patients. PMID- 22522981 TI - Persistent post-surgical pain following anterior thoracotomy for lung cancer: a cross-sectional study of prevalence, characteristics and interference with functioning. AB - OBJECTIVES: Most studies of persistent post-surgical pain following thoracic surgery have focused on classic posterolateral thoracotomy in mixed surgical populations without systematic assessment of disease recurrence and other potential sources of pain. The purpose of this study was to examine patterns in the prevalence of persistent post-surgical pain following lung cancer surgery and to quantitatively assess the characteristics of persistent post-surgical pain and associated sensory changes. METHODS: In May 2010, a sample of 702 patients undergoing lung cancer surgery from 1 January 2000 to 31 December 2009 was asked to complete a mail distributed questionnaire. The questionnaire included the Brief Pain Inventory and questions on pain-associated characteristics, symptoms and sensory changes. Patients were enrolled according to the following criteria: (1) no additional surgical procedures performed in the thoracic region 10 years prior to and up until the cross section; (2) no explorative surgery; (3) no resection of the thoracic wall and (4) no clinical or radiological signs of disease recurrence. Patients undergoing video-assisted thoracoscopic surgery were excluded. RESULTS: The response rate was 89%. The final study population consisted of 414 patients with a median age of 69 years and a median follow-up time of 45 months. The overall prevalence of persistent post-surgical pain following anterior thoracotomy was estimated to 19% (95% CI: 15-23%). Clinically relevant pain defined as >=4 on a 0-10 numerical rating scale was prevalent in 9% of the study participants (95% CI: 6-12%); pain with neuropathic characteristics was present in 36% (95% CI: 25-48%). A total of 62% of the participants with persistent post-surgical pain reported an increased or decreased sense of touch in the painful area. CONCLUSIONS: Persistent post-surgical pain following anterior thoracotomy was prevalent in 19% (95% CI: 15-23%) of lung cancer patients for up to 10 years postoperatively. Future preventive strategies should focus on the role of intraoperative nerve damage, including the potentially protective role of anterior thoracotomy. PMID- 22522982 TI - Worldwide experience with the 29-mm Edwards SAPIEN XTTM transcatheter heart valve in patients with large aortic annulus. AB - OBJECTIVES: The feasibility of transcatheter aortic valve implantation is limited by the diameter of the aortic annulus. Patients with an annulus of >25 mm were previously unsuitable for transcatheter valve implantation using the Edwards SAPIENTM bioprosthesis. The 29-mm Edwards SAPIEN XTTM bioprosthesis is a new device suitable for transapical aortic valve implantation in patients with a large aortic annulus. We report the worldwide experience in using this device. METHODS: A total of 120 patients (age 80.3 +/- 5.7 years, 2.5% female) underwent transapical aortic valve implantation using a 29-mm Edwards SAPIEN XTTM bioprosthesis between the period of December 2009 and February 2011. The mean values of the logistic EuroSCORE and the STS score were 23.4 +/- 7.7 and 6.8 +/- 4.0, respectively. A total of 20 centres participated in this study and all patients gave written informed consent. RESULTS: There were two conversions to open heart surgery (1.7%) and four patients (3.3%) required a temporary cardiopulmonary bypass support. A mean of 131 +/- 68.0-ml contrast dye was used. The procedural success, defined as one valve implanted, no aortic regurgitation (AR) >2+ and a transcatheter valve in the appropriate position, was achieved in 95.8% of patients. Early postoperative complications at <= 30 days included renal failure requiring temporary dialysis (n = 7, 5.8%), reopening for bleeding (n = 5, 4.2%), stroke (n = 2, 1.7%), respiratory complications requiring prolonged mechanical ventilation (n = 11, 9.2%) and postoperative pacemaker implantation (n = 15/12.5%). The Kaplan-Meier survival estimates were 95.8% at 30-day, 88.9% at 6 month and 79.8% at the 1-year follow-up. The controlled echocardiography data at 30 days (n = 95) revealed no/trivial AR in 79 (84.1%), mild AR in 12 (12.8%) and moderate in two (2.2%) patients. The univariable analysis of baseline characteristics revealed no predictor for 30-day mortality. CONCLUSIONS: The 29 mm Edwards SAPIEN XTTM bioprosthesis provides an excellent outcome in patients with a large aortic annulus undergoing transapical aortic valve implantation. Using this larger transcatheter heart valve, a broader population of high-risk elderly patients with aortic stenosis can be treated by minimally invasive transapical implantation techniques. PMID- 22522983 TI - Differences in sensitivity to rocuronium among orbicularis oris muscles innervated by normal or damaged facial nerves and gastrocnemius muscle innervated by somatic nerve in rats: combined morphological and functional analyses. AB - OBJECTIVES/HYPOTHESIS: To evaluate mechanisms of discrepant responses to the nondepolarizing muscle relaxant rocuronium among normal and injured facial nerve innervated orbicularis oris and tibial nerve-innervated gastrocnemius, and to provide information for the proper use of muscle relaxants to balance evoked electromyography (EEMG) monitoring and immobility in general anesthesia. STUDY DESIGN: Randomized controlled study. METHODS: Right-sided facial nerve injury was induced by crush axotomy in 18 Sprague-Dawley rats. At different rocuronium concentrations, muscular tension amplitude (MTA) was determined in vitro for normal and injured facial nerve-innervated orbicularis oris and gastrocnemius; the number of unsaturated acetylcholine receptors (AChRs) at end plates was determined by (125) I-alpha-bungarotoxin staining followed with gamma spectroscopy. The morphological composition of muscle fibers was determined by histological examination. RESULTS: Following rocuronium incubation, the percentage of MTA inhibition (MTAI%) of gastrocnemius was significantly higher than the corresponding values of orbicularis oris (P < .05), and the degree of saturation of AChR in gastrocnemius was significantly greater than that in orbicularis oris (P < .05). The baseline MTA and AChR density of injured-side orbicularis oris was significantly smaller than those of the normal side, whereas no significant difference was found regarding MTAI% and the degree of AChR saturation between the normal and injured side. CONCLUSIONS: The affinity of AChR at end plates and different number of AChR per unit fiber cross-sectional area may be the mechanisms for differential sensitivities to neuromuscular blockers between facial nerve-innervated muscles and somatic nerve-innervated muscles. The lower EEMG responses in the impaired facial nerve-innervated muscles may result from the lower AChR density at end plates compared with the normal facial nerve innervated muscles. PMID- 22522984 TI - Targeted therapeutics in treatment of children and young adults with solid tumors: an expert survey and review of the literature. AB - Although prognosis of children with solid tumors is steadily improving, long-term survival is not achievable in all patients, especially in patients with recurrent or refractory disease. Despite the increasing number of targeted therapeutics (TT), only very few TT have been introduced into clinical protocols. Accordingly, clinical experience concerning the efficacy and safety of these drugs is limited. This may possibly discourage oncologists from administering TT to children.We performed a comprehensive review of the literature to identify TT that may be considered for treatment of children and young adults with solid tumors. Moreover, we interviewed an expert panel of the Society for Pediatric Oncology and Hematology (GPOH) using questionnaires in a modified Delphi process in order to describe the experts' experiences in the use of these TT.Among 30 TT identified to be possibly useful in children and young adults, imatinib, bevacizumab and rapamycin were most widely used. These drugs were reported as having mostly little to no severe adverse events and seem to induce at least partial responses in a subset of patients. In addition, our study confirms and expands the present knowledge about adverse events and the potential efficacy of 5 other commonly used TT in this population.This information may be useful for oncologists when administering these TT to children and young adults with solid tumors. Controlled clinical trials are urgently needed to test their safety and efficacy. PMID- 22522985 TI - Cancer in Croatia; where do we stand and how to move forward? PMID- 22522986 TI - Trends in lung cancer incidence and mortality in Croatia, 1988-2008. AB - AIM: To describe and interpret lung cancer incidence and mortality trends in Croatia between 1988 and 2008. METHODS: Incidence data on lung cancer for the period 1988-2008 were obtained from the Croatian National Cancer Registry, while mortality data were obtained from the World Health Organization mortality database. Population estimates for Croatia were obtained from the Population Division of the Department of Economic and Social Affairs of the United Nations. We also calculated and analyzed age-standardized incidence and mortality rates. To describe time incidence and mortality trends, we used joinpoint regression analysis. RESULTS: Lung cancer incidence and mortality rates in men decreased significantly in all age groups younger than 70 years. Age-standardized incidence rates in men decreased significantly by -1.3% annually. Joinpoint analysis of mortality in men identified three trends, and average annual percent change (AAPC) decreased significantly by -1.1%. Lung cancer incidence and mortality rates in women increased significantly in all age groups older than 40 years and decreased in younger women (30-39- years). Age-standardized incidence rates increased significantly by 1.7% annually. Joinpoint analysis of age-standardized mortality rates in women identified two trends, and AAPC increased significantly by 1.9%. CONCLUSION: Despite the overall decreasing trend, Croatia is still among the European countries with the highest male lung cancer incidence and mortality. Although the incidence trend in women is increasing, their age standardized incidence rates are still 5-fold lower than in men. These trends follow the observed decrease and increase in the prevalence of male and female smokers, respectively. These findings indicate the need for further introduction of smoking prevention and cessation policies targeting younger population, particularly women. PMID- 22522987 TI - Breast and gynecological cancers in Croatia, 1988-2008. AB - AIM: To analyze and interpret incidence and mortality trends of breast and ovarian cancers and incidence trends of cervical and endometrial cancers in Croatia for the period 1988-2008. METHODS: Incidence data were obtained from the Croatian National Cancer Registry. Themortality data were obtained from the World Health Organization (WHO) mortality database. Trends of incidence and mortality were analysed by joinpoint regression analysis. RESULTS: Joinpoint analysis showed an increase in the incidence of breast cancer with estimated annual percent of change (EAPC) of 2.6% (95% confidence interval [CI], 1.9 to 3.4). The mortality rate was stable, with the EAPC of 0.3%. Endometrial cancer showed an increasing incidence trend, with EAPC of 0.8% (95% CI, 0.2 to 1.4), while cervical cancer showed a decreasing incidence trend, with EAPC of -1.0 (95% CI, 1.6 to -0.4). Ovarian cancer incidence showed three trends, but the average annual percent change (AAPC) for the overall period was not significant, with a stable trend of 0.1%. Ovarian cancer mortality was increasing since 1992, with EAPC of 1.2% (95% CI, 0.4 to 1.9), while the trend for overall period was stable with AAPC 0.1%. CONCLUSION: Incidence trends of breast, endometrial, and ovarian cancers in Croatia 1988-2008 are similar to the trends observed in most of the European countries, while the modest decline in cervical cancer incidence and lack of decline in breast cancer mortality suggest suboptimal cancer prevention and control. PMID- 22522988 TI - Trends in prostate cancer incidence and mortality in Croatia, 1988-2008. AB - AIM: To describe and interpret prostate cancer incidence and mortality trends in Croatia between 1988 and 2008. METHODS: Incidence data for the period 1988-2008 were obtained from the Croatian National Cancer Registry. The number of prostate cancer deaths was obtained from the World Health Organization mortality database. We also used population estimates for Croatia from the Population Division of the Department of Economic and Social Affairs of the United Nations. Age standardized incidence and mortality rates were calculated by the direct standardization method. To describe time trends of incidence and mortality, joinpoint regression analysis was used. RESULTS: Average age-standardized incidence rate between the first and last five-year period doubled, from 19.0/100,000 in 1988-1992 to 39.1 per 100,000 in 2004-2008. Age-standardized mortality rate increased by 6.9%, from 14.5 to 15.5 per 100,000. Joinpoint analysis of incidence identified two joinpoints. The increasing incidence trend started from 1997, with the estimated annual percent of change (EAPC) of 12.9% from 1997-2002 and of 4.1% from 2002 2008. Joinpoint analyses of mortality identified one joinpoint. Mortality trend first decreased, with EAPC of -3.0% from 1988-1995 to increase later with EAPC of 2.0% from 1995-2008. CONCLUSION: The incidence of prostate cancer in Croatia has been on the increase since 1997. Trend in mortality is increasing, contrary to the trends in some higher-income countries. An improvement in the availability of different treatment modalities as well as establishing prostate cancer units could have a positive impact on prostate cancer mortality in Croatia. PMID- 22522989 TI - Incidence and mortality trends of leukemia and lymphoma in Croatia, 1988-2009. AB - AIM: To investigate the time trends of leukemia and lymphoma in Croatia from 1988 2009, compare them with trends in other populations, and identify possible changes. METHODS: The data sources were the Croatian National Cancer Registry for incidence data, Croatian Bureau of Statistics for the numbers of deaths, and United Nations population estimates. Joinpoint regression analysis using the age standardized rates was used to analyze incidence and mortality trends. RESULTS: Acute lymphoblastic leukemia and chronic lymphocytic leukemia incidence did not significantly change. Acute myeloid leukemia incidence significantly increased in women, with estimated annual percentage change (EAPC) of 2.6% during the whole period, and in men since 1998, with EAPC of 3.2%. Chronic myeloid leukemia incidence significantly decreased in women (EAPC -3.7%) and remained stable in men. Mortality rates were stable for both lymphoid and myeloid leukemia in both sexes. Hodgkin lymphoma non-significantly increased in incidence and significantly decreased in mortality (EAPCs of -5.6% in men and -3.7% in women). Non-Hodgkin lymphoma significantly increased in incidence in women (EAPC 3.2%) and non-significantly in men and in mortality in both men (EAPC 1.6%) and women (EAPC 1.8%). CONCLUSION: While Croatia had similar leukemia and lymphoma incidence trends as the other countries, the mortality trends were less favorable than in Western Europe. The lack of declines of leukemia incidence and non Hodgkin lymphoma mortality could be attributed to late introduction of optimal therapies. As currently the most up-to-date diagnostics and treatments are available and covered by health insurance, we expect more favorable trends in the future. PMID- 22522990 TI - Incidence and mortality trends of gastric and colorectal cancers in Croatia, 1988 2008. AB - AIM: To estimate the incidence and mortality trends of gastric and colorectal cancers in Croatia between 1988 and 2008. METHODS: Incidence data for the period 1988-2008 were obtained from the Croatian National Cancer Registry. The number of deaths from gastric and colorectal cancers were obtained from the World Health Organization mortality database. Joinpoint regression analysis was used to describe changes in trends by sex. RESULTS: Gastric cancer incidence rates declined steadily during the study period, with estimated annual percent change (EAPC) of -3.2% for men and -2.8% for women. Mortality rates in men decreased, with EAPC of -5.0% from 1988-1995 and -2.5% from 1995-2008. Mortality rates in women decreased, with EAPC of -3.2% throughout the study period. For colorectal cancer in men, joinpoint analysis revealed increasing trends of both incidence (EAPC 2.9%) and mortality (EAPC 2.1%). In women, the increase in incidence was not significant, but mortality rates in the last 15 years showed a significant increase (EAPC 1.1%). CONCLUSION: The incidence and mortality trends of gastric cancer in Croatia are similar to other European countries, while the still increasing colorectal cancer mortality calls for more efficient prevention and treatment. PMID- 22522991 TI - Incidence and mortality trends of melanoma in Croatia. AB - AIM: To analyze melanoma incidence and mortality trends in Croatia 1988-2008, compare them with the trends in other populations, and identify possible changes in the trends. METHODS: Incidence data were obtained from the Croatian National Cancer Registry and the mortality data from the Croatian Bureau of Statistics. United Nations population estimates were used for calculating the age-specific rates. Age-standardized rates were calculated by the direct standardization method, using the world standard population as a reference. To estimate incidence and mortality trends, we performed joinpoint regression analysis. RESULTS: A significantly increasing incidence trend, with estimated annual percent change (EAPC) of 5.9% for men and 5.6% for women, was observed over the whole 21-year period and no additional joinpoints were identified. The overall incidence increase between the first and the last five-year period was 149% for men and 130% for women. Significant increase in the mortality trend was observed, with EAPC of 3.0% for men and 2.4% for women. No joinpoints were identified. The overall increase in mortality between the first and the last five-year period was 45% for men and 50% for women. CONCLUSION: Melanoma rates in Croatia are steadily and markedly rising, with similar trends to those in the countries with lower/intermediate incidence. It is important to further investigate the more specific causes of the increasing trends, as well as to implement effective public policies targeting the melanoma burden. PMID- 22522992 TI - Regional differences in incidence and clinical presentation of type 1 diabetes in children aged under 15 years in Croatia. AB - AIM: To determine regional differences in the incidence, incidence trends, and clinical presentation of type 1 diabetes in children under the age of 15 years in Croatia in a 9-year period (1995-2003). METHODS: We included the patients who had been diagnosed with the disease and had started the insulin treatment before they were 15 years old. Regional differences between eastern, central, and southern Croatia were observed. The gross incidence was expressed by the number of newly diagnosed type 1 diabetes patients in 100000 children of the same age and sex per year, ie, for the 0-14 age group, and for the 0-4, 5-9, and 10-14 subgroups. RESULTS: The highest incidence was observed in southern Croatia (10.91 per 100000/y) and the lowest in central Croatia (8.64 per 100000/y), and in eastern Croatia the incidence was 8.93 per 100000/y. All three regions showed a growing incidence trend, which was significant only in eastern and southern Croatia. There was 35.9% of patients with diabetic ketoacidosis in eastern Croatia, 41.7% in central Croatia, and 31.28% in southern Croatia. CONCLUSION: Croatian regions show differences in the incidence, incidence trends, and disease presentation of type 1 diabetes. A further follow-up is needed to establish whether the regional differences are a consequence of the population dynamics in the observed period or they will continue to exist, pointing to differences in environmental risk factors. PMID- 22522993 TI - Prevalence of the American College of Rheumatology classification criteria in a group of 162 systemic lupus erythematosus patients from Croatia. AB - AIM: To identify systemic lupus erythematosus (SLE) patients diagnosed and treated at the outpatient clinic of our Division fulfilling at least four American College of Rheumatology (ACR) classification criteria at the time of the study, to determine the prevalence of each of the criteria at three different time points, and to compare the data with similar studies. METHODS: We performed retrospective and descriptive analysis of medical records of 162 patients fulfilling at least 4 ACR criteria. Classification criteria were counted and the frequency of each criterion was identified at three different time points: disease onset, time of diagnosis, and the time when the study was conducted. RESULTS: At diagnosis and at the time when the study was conducted there were 3.8 and 5.4 fulfilled classification criteria, respectively. The most common criterion at the time of the disease onset was arthritis (52.6%); at the time of diagnosis it was positive antinuclear antibody (ANA) titer (88.0%); and at the time when the study was conducted it was positive ANA titer (95.7%), immunologic disorder (89.5%), arthritis (71.0%), hematologic disorder (70.4%), malar rash (61.7%), and photosensitivity (51.9%). CONCLUSION: The prevalence of ACR criteria in our patients is similar to that in other studies, especially those involving Caucasian patients. Our results confirm the value of the ACR criteria in patients with an already established diagnosis. This is the first study on the prevalence of disease manifestations among Croatian patients with SLE. PMID- 22522994 TI - Comparison of peritonsillar infiltration effects of ketamine and tramadol on post tonsillectomy pain: a double-blinded randomized placebo-controlled clinical trial. AB - AIM: To assess the effect of peritonsillar infiltration of ketamine and tramadol on post tonsillectomy pain and compare the side effects. METHODS: The double blind randomized clinical trial was performed on 126 patients aged 5-12 years who had been scheduled for elective tonsillectomy. The patients were randomly divided into 3 groups to receive either ketamine, tramadol, or placebo. They had American Society of Anesthesiologists physical status class I and II. All patients underwent the same method of anesthesia and surgical procedure. The three groups did not differ according to their age, sex, and duration of anesthesia and surgery. Post operative pain was evaluated using CHEOPS score. Other parameters such as the time to the first request for analgesic, hemodynamic elements, sedation score, nausea, vomiting, and hallucination were also assessed during 12 hours after surgery. RESULTS: Tramadol group had significantly lower pain scores (P=0.005), significantly longer time to the first request for analgesic (P=0.001), significantly shorter time to the beginning of liquid regimen (P=0.001), and lower hemodynamic parameters such as blood pressure (P=0.001) and heart rate (P=0.001) than other two groups. Ketamine group had significantly greater presence of hallucinations and negative behavior than tramadol and placebo groups. The groups did not differ significantly in the presence of nausea and vomiting. CONCLUSION: Preoperative peritonsillar infiltration of tramadol can decrease post-tonsillectomy pain, analgesic consumption, and the time to recovery without significant side effects. PMID- 22522995 TI - On-admission serum uric acid predicts outcomes after acute myocardial infarction: systematic review and meta-analysis of prognostic studies. AB - AIM: To evaluate the prognostic value of serum uric acid (SUA) in acute myocardial infarction (AMI) patients. METHODS: Systematic review and random effects meta-analysis of prognostic studies assessing AMI outcomes (death, major adverse cardiac events, MACE) in relation to on-admission SUA. RESULTS: Nine studies (7655 patients) were identified, 6 in the ST-segment elevation AMI patients treated with invasive revascularization and three in mixed AMI type cohorts with variable reperfusion strategies. "High" SUA (vs "low," different cut offs) was univariately associated with higher short-term mortality (8 studies/6805 patients; odds ratio [OR], 3.24; 95% confidence interval [CI], 2.47 4.27) and incidence of MACE (7/6467; OR, 2.46; 95% CI, 1.84-3.27, moderate heterogeneity, mild bias), and with higher medium-term mortality (5/5194; OR, 2.69; 95% CI, 2.00-3.62, moderate heterogeneity, mild bias) and MACE (4/4299; OR, 1.93; 95% CI, 1.36-2.74, high heterogeneity, mild bias). It was independently associated with a higher short-term (4/3625; OR, 2.26, 95% CI, 1.85-2.77) and medium/long-term (3/2683; hazard ratio [HR], 1.30; 95% CI 1.01-1.68, moderate heterogeneity, mild bias) occurrence of poor outcomes (death/MACE). As a continuous variable (by 50 MUmol/L), higher SUA was also independently associated with poorer medium/long-term outcomes (4/3533; HR, 1.19; 95% CI, 1.03-1.37, high heterogeneity, mild bias). All individual study effects (unadjusted or adjusted) were in the same direction, but differed in size. Heterogeneity was mainly due to the included AMI type and/or definition of MACE. All bias-corrected pooled effects remained significant. CONCLUSION: Based on the available data, high(er) on-admission SUA independently predicts worse short-term and medium/long-term outcomes after AMI. However, the number of data are modest and additional prospective studies are warranted. PMID- 22522996 TI - Diffusion of counterfeit drugs in developing countries and stability of galenics stored for months under different conditions of temperature and relative humidity. AB - AIM: To investigate the diffusion of counterfeit medicines in developing countries and to verify the stability of galenic dosage forms to determine the stability of galenics prepared and stored in developing countries. METHODS: We purchased 221 pharmaceutical samples belonging to different therapeutic classes both in authorized and illegal pharmacies and subjected them to European Pharmacopoeia, 7th ed. quality tests. An UV-visible spectrophotometric assay was used to determine the galenics stability under different conditions of temperature (T) and relative humidity (RH). RESULTS: A substantial percentage of samples was substandard (52%) and thus had to be considered as counterfeit. Stability tests for galenics showed that the tested dosage forms were stable for 24 months under "standard" (t=25+/-2 degrees C, RH=50+/-5%) conditions. Under "accelerated" (t=40+/-2 degrees C, RH=50+/-5%) conditions, samples were stable for 3 months provided that they were stored in glass containers. Stability results of samples stored in "accelerated" conditions were similar to those obtained by on site in tropical countries and could so supply precious information on the expected stability of galenics in tropical countries. CONCLUSION: This study gives useful information about the presence of counterfeit medicinal products in the pharmacies of many developing countries. This should serve as an alarm bell and an input for the production of galenics. We recommend setting up of galenic laboratories in developing countries around the globe. PMID- 22522997 TI - Prostitutes and criminals: beginnings of eugenics in Croatia in the works of Fran Gundrum from Oriovac (1856-1919). AB - Fran Gundrum (1856-1919) was a Croatian physician, encyclopedist, and an advocate of medical enlightenment and healthy lifestyle. In order to identify and analyze Gundrum's ideas about the problems of prostitution and criminality, we studied all of his books, booklets, and articles published between 1905 and 1914. We showed that Gundrum's theories of heredity, morality, and sexual hygiene incorporated many of the important discussions of his time, especially those related to the Darwinian paradigm. Gundrum's project of collecting statistics on prostitutes was the first such study published on the territory of today's Croatia. Although he rejected the notions of born prostitutes and born criminals, defended by Italian criminal anthropologist Cesare Lombroso, he still regarded eugenics as a convenient method of dealing with the ills of society. He believed that criminals were degenerate individuals representing a violent threat to the society and that it was legitimate to use radical means, such as sterilization and deportation, to deal with this problem. Organicistic view of the society prevented him from seeing the individual rights as important as that of the society to protect itself. Nevertheless, this view led to many humanistic ideas, such as the binomial illness/poverty in case of prostitution, which influenced many prominent works of social medicine movement. PMID- 22522998 TI - Bio-objects and generative relations. PMID- 22522999 TI - Are therapeutic human mesenchymal stromal cells compatible with human blood? AB - Multipotent mesenchymal stromal cells (MSCs) are tested in numerous clinical trials. Questions have been raised concerning fate and function of these therapeutic cells after systemic infusion. We therefore asked whether culture expanded human MSCs elicit an innate immune attack, termed instant blood-mediated inflammatory reaction (IBMIR), which has previously been shown to compromise the survival and function of systemically infused islet cells and hepatocytes. We found that MSCs expressed hemostatic regulators similar to those produced by endothelial cells but displayed higher amounts of prothrombotic tissue/stromal factors on their surface, which triggered the IBMIR after blood exposure, as characterized by formation of blood activation markers. This process was dependent on the cell dose, the choice of MSC donor, and particularly the cell passage number. Short-term expanded MSCs triggered only weak blood responses in vitro, whereas extended culture and coculture with activated lymphocytes increased their prothrombotic properties. After systemic infusion to patients, we found increased formation of blood activation markers, but no formation of hyperfibrinolysis marker D-dimer or acute-phase reactants with the currently applied dose of 1.0-3.0 * 10(6) cells per kilogram. Culture-expanded MSCs trigger the IBMIR in vitro and in vivo. Induction of IBMIR is dose-dependent and increases after prolonged ex vivo expansion. Currently applied doses of low passage clinical-grade MSCs elicit only minor systemic effects, but higher cell doses and particularly higher passage cells should be handled with care. This deleterious reaction can compromise the survival, engraftment, and function of these therapeutic cells. PMID- 22523000 TI - Exhaled nitric oxide in pediatrics: what is new for practice purposes and clinical research in children? AB - Fractional exhaled NO (FeNO) is universally considered an indirect marker of eosinophilic airways inflammation, playing an important role in the physiopathology of childhood asthma. Advances in technology and standardization have allowed a wider use of FeNO in clinical practice in children from the age of four years. FeNO measurements add a new dimension to the traditional clinical tools (symptoms scores, lung function tests) in the assessment of asthma. To date a number of studies have suggested a possible use of FeNO in early identification of exacerbation risk and in inhaled corticosteroids titration. The aim of this paper is to address practical issues of interest to paediatric clinicians who are attempting to use FeNO measurements as an adjunctive tool in the diagnosis and management of childhood airway diseases. PMID- 22523001 TI - Postnatal development of the amygdala: a stereological study in rats. AB - The amygdala is the central component of a functional brain system regulating fear and emotional behaviors. Studies of the ontogeny of fear behaviors reveal the emergence of distinct fear responses at different postnatal ages. Here, we performed a stereological analysis of the rat amygdala to characterize the cellular changes underlying its normal structural development. Distinct amygdala nuclei exhibited different patterns of postnatal development, which were largely similar to those we have previously shown in monkeys. The combined volume of the lateral, basal, and accessory basal nuclei increased by 113% from 1 to 3 weeks of age and by an additional 33% by 7 months of age. The volume of the central nucleus increased only 37% from 1 to 2 weeks of age and 38% from 2 weeks to 7 months. At 1 week of age, the medial nucleus was 77% of the 7-month-old's volume and exhibited a constant, marginal increase until 7 months. Neuron number did not differ in the amygdala from 1 week to 7 months of age. In contrast, astrocyte number decreased from 3 weeks to 2 months of age in the whole amygdala. Oligodendrocyte number increased in all amygdala nuclei from 3 weeks to 7 months of age. Our findings revealed that distinct amygdala nuclei exhibit different developmental profiles and that the rat amygdala is not fully mature for an extended period postnatally. We identified different periods of postnatal development of distinct amygdala nuclei and cellular components, which are concomitant with the ontogeny of different fear and emotional behaviors. PMID- 22523002 TI - Abstracts of the ILTS (International Liver Transplantation Society) 18th Annual International Congress. May 15-19, 2012. San Francisco, California, USA. PMID- 22523003 TI - Elf5 regulates mammary gland stem/progenitor cell fate by influencing notch signaling. AB - The transcription factor E74-like factor 5 (Elf5) functions downstream of the prolactin receptor signaling pathway and plays an important role in mammary gland development. Using conditional mouse knockouts, we have previously shown that Elf5-null mammary glands exhibit a complete failure of alveologenesis during pregnancy. The Elf5-null developmental phenotype is mediated through alteration in the expression of several critical genes involved in alveologenesis, particularly those belonging to the JAK/STAT pathway. Here, we demonstrate that in addition to regulating terminal differentiation of alveolar cells, Elf5 also plays a critical role in determining cell fate and in regulating the stem/progenitor function of the mammary epithelium. Targeted deletion of Elf5 in the mammary glands leads to accumulation of cell types with dual luminal/basal properties such as coexpression of K8 and K14 and an increase in CD61(+) luminal progenitor population during pregnancy. Further interrogation suggests that the abnormal increase in K14(+) K8(+) cells may represent the CD61(+) luminal progenitors blocked in differentiation. Remarkably, Elf5 deficiency in mammary epithelium also triggers an increase of adult mammary stem activity as evidenced by the accumulation of mammary stem cell (MaSC)-enriched cell population in both pregnant and virgin mice and further confirmed by mammosphere and transplantation assays. Additional support for this phenotype comes from the enriched MaSC gene signature based on transcriptomic analysis of the Elf5-null mammary gland. Finally, our biochemical studies suggest that Elf5 loss leads to hyperactivation of the Notch signaling pathway, which might constitute in part, the underlying molecular mechanism for the altered cell lineage decisions in Elf5-null mammary epithelial cells. PMID- 22523005 TI - Minimizing data transfer with sustained performance in wireless brain-machine interfaces. AB - Brain-machine interfaces (BMIs) may be used to investigate neural mechanisms or to treat the symptoms of neurological disease and are hence powerful tools in research and clinical practice. Wireless BMIs add flexibility to both types of applications by reducing movement restrictions and risks associated with transcutaneous leads. However, since wireless implementations are typically limited in terms of transmission capacity and energy resources, the major challenge faced by their designers is to combine high performance with adaptations to limited resources. Here, we have identified three key steps in dealing with this challenge: (1) the purpose of the BMI should be clearly specified with regard to the type of information to be processed; (2) the amount of raw input data needed to fulfill the purpose should be determined, in order to avoid over- or under-dimensioning of the design; and (3) processing tasks should be allocated among the system parts such that all of them are utilized optimally with respect to computational power, wireless link capacity and raw input data requirements. We have focused on step (2) under the assumption that the purpose of the BMI (step 1) is to assess single- or multi-unit neuronal activity in the central nervous system with single-channel extracellular recordings. The reliability of this assessment depends on performance in detection and sorting of spikes. We have therefore performed absolute threshold spike detection and spike sorting with the principal component analysis and fuzzy c-means on a set of synthetic extracellular recordings, while varying the sampling rate and resolution, noise level and number of target units, and used the known ground truth to quantitatively estimate the performance. From the calculated performance curves, we have identified the sampling rate and resolution breakpoints, beyond which performance is not expected to increase by more than 1-5%. We have then estimated the performance of alternative algorithms for spike detection and spike sorting in order to examine the generalizability of our results to other algorithms. Our findings indicate that the minimization of recording noise is the primary factor to consider in the design process. In most cases, there are breakpoints for sampling rates and resolution that provide guidelines for BMI designers in terms of minimum amount raw input data that guarantees sustained performance. Such guidelines are essential during system dimensioning. Based on these findings we conclude by presenting a quantitative task-allocation scheme that can be followed to achieve optimal utilization of available resources. PMID- 22523004 TI - Phenolic-linked biochemical rationale for the anti-diabetic properties of Swertia chirayita (Roxb. ex Flem.) Karst. AB - The crude extract of Swertia chirayita, an important medicinal plant of Nepal, is locally used for many diseases including type 2 diabetes. In this study, crude aqueous and 12% ethanol solution extracts of S. chirayita collected from nine districts of Nepal were analyzed for anti-diabetic-linked anti-hyperglycemia potential using in vitro biochemical assays. There was moderate-to-high positive correlation between antioxidant activity and total phenolic content of both extracts and moderate-to-high alpha-glucosidase inhibitory activity. Although the anti-diabetic property of S. chirayita is mainly attributed to the phytochemical swerchirin present in its hexane fraction, we propose that the crude extract of this plant used in local healing also has anti-hyperglycemia potential. The crude extracts indicated the presence of three main phytochemicals mainly mangiferin, swertiamarin, and amarogentin and their derivatives. Among the standard compounds (mangiferin, swertiamarin, and amarogentin), mangiferin showed alpha-glucosidase and 2,2-diphenyl-1-picrylhydrazyl radical inhibitory activity indicating anti hyperglycemia potential. PMID- 22523006 TI - Effects of seeding rate, nitrogen rate and cultivar on barley malt quality. AB - BACKGROUND: Crop management tools have been shown to affect barley kernel size and grain protein content, but the direct effect on malt quality is not well understood. The present study investigated the effect of seeding rate, nitrogen fertilisation and cultivar on malt quality. RESULTS: Higher seeding rates produced barley with less grain protein and smaller, more uniformly sized kernels. The small, uniformly sized kernels modified more completely, leading to malt with higher extract and lower wort beta-glucan than malt from low-seeding rate barley. Increasing rates of nitrogen fertilisation caused grain protein levels to increase, which limited endosperm modification and reduced malt extract levels. AC Metcalfe showed better modification and higher malt extract than CDC Copeland, but CDC Copeland had better protein modification at higher fertilisation rates, which resulted in less reduction of malt extract as nitrogen rate increased. CONCLUSION: Higher seeding rates reduced kernel size and grain protein levels without compromising malt extract owing to better endosperm modification of the more uniformly sized kernels. Negative effects of higher nitrogen rates on malt quality can be reduced through development of cultivars with improved ability to modify protein during malting. PMID- 22523007 TI - Role of regulatory T cells in the promotion of transplant tolerance. AB - Liver transplantation is now recognized as the most effective therapy for patients with end-stage acute and chronic liver failure. Despite outstanding short-term graft and patient survival, liver transplantation continues to face several major challenges, including poor long-term graft survival due to chronic rejection and major side effects of long-term immunosuppressive therapy (which is required for the prevention of rejection). The ability to produce a state of tolerance after transplantation would potentially obviate long-term immunosuppression. Self-tolerance and immune homeostasis involve both central and peripheral immunoregulatory mechanisms. To date, studies have shown that many subsets of regulatory T cells (Tregs) control immune responses to foreign and alloantigens. The identification of Tregs that are positive for CD4, CD25, and the transcription factor forkhead box (Foxp3) has resulted in major advances in our understanding of the immunology of rejection and the development of transplant tolerance. In this article, we focus on the importance of Tregs in tolerance induction in experimental models of liver transplantation. Furthermore, we discuss the therapeutic potential of Tregs for the promotion of tolerance in transplant patients and highlight recent clinical trials of Treg-based therapies. PMID- 22523008 TI - Coronary computed tomography: current role and future perspectives for cardiovascular risk stratification. AB - Coronary artery disease (CAD) is the major cause of morbidity and mortality worldwide. More than 50% of CAD deaths occur in previously asymptomatic individuals at intermediate cardiovascular risk, highlighting the need of more accurate individual risk assessment to decrease cardiovascular events. Cardiac computed tomography (CCT) has emerged as a valuable technique for risk stratification in asymptomatic subjects and in symptomatic patients without known CAD. The absence of coronary artery calcium (CAC) identifies asymptomatic subjects at very low cardiac risk and is reasonable in intermediate risk individuals, in whom CAC measurement reclassifies a substantial number of subjects to different risk categories. In symptomatic patients with suspected CAD, detection of non-obstructive or obstructive CAD by CCT angiography is associated with increased all-cause mortality, and provides incremental risk stratification to CAC. Further studies are needed to assess the impact of CCT on clinical outcomes and its cost-effectiveness in different clinical settings. PMID- 22523009 TI - Community based rehabilitation after neurologic injury. PMID- 22523010 TI - Behavioral strategies for assessing and promoting community readiness in brain injury rehabilitation. AB - Individuals with acquired brain injuries often display problematic behaviors, such as impulsivity, disinhibition, lack of initiation, isolation, and aggression, that impact their readiness to return to home and/or the community. The occurrence and treatment of these behaviors is often complicated by impairments in cognition and self-awareness, as well as by co-occurring issues including substance abuse. Community reintegration for these individuals is a goal that can be both hazardous and difficult to attain. This article briefly reviews the literature and describes a treatment philosophy and methodology by which an interdisciplinary team can employ evidence-based behavioral principles and procedures to assess and promote behavioral stability toward the goal of community readiness within a residential rehabilitation setting. Assessment includes a comprehensive evaluation of individual strengths and barriers across all disciplines as well as an analysis of the function of problematic behaviors. Based upon these assessments and analyses, integrated interdisciplinary treatment efforts then support the development and implementation of specific strategies and tools to promote community readiness and ultimately reentry. These strategies and tools are intended to provide direction and support to the client and include prompts and cues to self-manage, as well as ways to assist clients and staff to collect and reflect upon relevant data. Additionally, other methods of data collection, techniques to develop self-management skills, and the use of contingencies as part of a community reentry plan are discussed. PMID- 22523011 TI - Remediation of information processing following traumatic brain injury: a community-based rehabilitation approach. AB - Traumatic brain injury (TBI) results in disruption of information processing via damage to primary, secondary, and tertiary cortical regions, as well as, subcortical pathways supporting information flow within and between cortical structures. TBI predominantly affects the anterior frontal poles, anterior temporal poles, white matter tracts and medial temporal structures. Fundamental information processing skills such as attention, perceptual processing, categorization and cognitive distance are concentrated within these same regions and are frequently disrupted following injury. Information processing skills improve in accordance with the extent to which residual frontal and temporal neurons can be encouraged to recruit and bias neuronal networks or the degree to which the functional connectivity of neural networks can be re-established and result in re-emergence or regeneration of specific cognitive skills. Higher-order cognitive processes, i.e., memory, reasoning, problem solving and other executive functions, are dependent upon the integrity of attention, perceptual processing, categorization, and cognitive distance. A therapeutic construct for treatment of attention, perceptual processing, categorization and cognitive distance deficits is presented along with an interventional model for encouragement of re-emergence or regeneration of these fundamental information processing skills. PMID- 22523012 TI - Functional improvements following the use of the NVT Vision Rehabilitation program for patients with hemianopia following stroke. AB - The incidence of visual deficits following stroke ranges from 20%-68% and has significant impact on activities of daily living. The NVT system is a compensatory visual scanning training program that consists of combined static and mobility training and transfer to activities of daily living. The study aims to evaluate functional changes following the NVT program for people who have homonymous hemianopia (HH) following stroke. METHOD: Interventional case series of 13 consecutive participants with HH undergoing NVT vision rehabilitation. The primary outcome measure was the number of targets missed on a standardized Mobility Assessment Course (MAC). Other outcome measures included assessment of visual scanning, vision specific Quality of Life questionnaires and reading performance. RESULTS: The average number of targets (sd) missed on the MAC course was 39.6 +/- 20.9% before intervention, 27.5 +/- 16.3% immediately post intervention and 20.8 +/- 15.5% at 3 months post rehabilitation. The study showed a statistically significant trend in improvement in mobility related subscales of National Eye Institute Visual Function Questionnaire-NEI VFQ-25 (p=0.003) and the Veteran Affairs Low Vision Visual Function Questionnaire-VA LVFQ-48 (p=0.036) at 3 months post rehabilitation. DISCUSSION: The NVT intervention resulted in functional improvements in mobility post rehabilitation. The NVT training showed improvement in vision specific quality of life. There is a need for standardised vision therapy intervention, in conjunction with existing rehabilitation services, for patients with stroke and traumatic brain injury. PMID- 22523013 TI - Vocational rehabilitation after traumatic brain injury: models and services. AB - BACKGROUND: A recent systematic review suggests that around 40% of people with traumatic brain injury (TBI) return to work (RTW). Yet in the U.K. currently only a small minority of people with TBI receive vocational rehabilitation (VR) to enable a RTW. Agencies with an interest in developing such services are likely to favour different models of VR. OBJECTIVE: The primary objective of this paper was to review models of specialist VR after TBI and their outcomes to inform service development across relevant agencies. METHOD: A literature review on VR after TBI was undertaken in MEDLINE, EMBASE and PsychINFO (from 1967 to date). Papers reporting models of VR were selected for more detailed consideration. RESULTS: Illustrative examples of VR models are outlined: brain injury rehabilitation programmes with added VR elements, VR models adapted for TBI, case coordination/resource facilitation models, and consumer-directed models. Models differ, both within and across these four broad categories, in provision of core TBI rehabilitation, work preparation, work trials and supported placements. Methodological variation limits direct comparison of outcomes across models with few comparative or controlled studies. CONCLUSIONS: There is evidence to support the benefits of a wide range of models of specialist VR after TBI. However, there remains a need for controlled studies to inform service development and more evidence on cost-effectiveness to inform funding decisions. PMID- 22523014 TI - Community based rehabilitation: special issues. AB - The primary goal in the developing field of community based rehabilitation (CBR) for individuals with TBI / ABI is community participation and integration. At present, CBR is less than clearly defined and is represented by a set of interventions with varied types, degrees of clinical support and models of intervention that are conducted for a diverse and complex set of individuals, situations, deficits and settings. Nonetheless, holistic neurorehabilitation programs should be considered both evidence based and a practice standard. This paper attempts to address some of the significant issues relevant to optimizing long term adaptation for persons receiving CBR. The article also addresses the current need for definitions, models, program classifications and comparisons, as well as programmatic methodologies by attempting to integrate some of the best scientifically supported methodologies within an eclectic holistic rehabilitation model that is easily understood and teachable to persons with TBI, families and rehabilitation professionals. This model and associated methodologies are intended to inform best practices while offering a framework for hypothesis generation, clinical decision-making, evaluation of treatment outcomes and direction of future research. PMID- 22523015 TI - Removing barriers to rehabilitation: Theory-based family intervention in community settings after brain injury. AB - Rehabilitation professionals have become increasingly aware that family members play a critical role in the recovery process of individuals after brain injury. In addition, researchers have begun to identify a relationship between family member caregivers' well-being and survivors' outcomes. The idea of a continuum of care or following survivors from inpatient care to community reintegration has become an important model of treatment across many hospital and community-based settings. In concert with the continuum of care, present research literature indicates that family intervention may be a key component to successful rehabilitation after brain injury. Yet, clinicians interacting with family members and survivors often feel confounded about how exactly to intervene with the broader family system beyond the individual survivor. Drawing on the systemic nature of the field of marriage and family therapy (MFT), this article provides information to assist clinicians in effectively intervening with families using theory-based interventions in community settings. First, a rationale for the utilization of systems-based, as opposed to individual-based, therapies will be uncovered. Second, historically relevant publications focusing on family psychotherapy and intervention after brain injury are reviewed and their implications discussed. Recommendations for the utilization of systemic theory based principles and strategies, specifically cognitive behavioral therapy (CBT), narrative therapy (NT), and solution-focused therapy (SFT) will be examined. Descriptions of common challenges families and couples face will be presented along with case examples to illustrate how these theoretical frameworks might be applied to these special concerns postinjury. Finally, the article concludes with an overview of the ideas presented in this manuscript to assist practitioners and systems of care in community-based settings to more effectively intervene with the family system as a whole after brain injury. PMID- 22523016 TI - Long-term health implications of individuals with TBI: a rehabilitation perspective. AB - Individuals with acquired brain injuries often present with lifelong health challenges. Trauma to the body directly related to the injury, physical and medical sequelae resulting from the brain injury itself, and an increase in the observed onset of physical aging are among the problems which require consideration throughout their lives. For many rehabilitation professionals, issues related to medical stability and health maintenance are unfamiliar and intimidating. As both hospital stays shorten and an existing population of individuals with brain injuries' survival and life expectancy rates increase, rehabilitation professionals have been increasingly challenged by medical issues. Rehabilitation nurses are positioned to best navigate these issues and facilitate needed care coordination, early intervention, and ongoing education for individuals, their families, and other caregivers. This article describes common medical complications related to the initial and related disability and aging in individuals with brain injury including chronic and late emerging complications involving all body systems including spasticity and changing mobility, aspiration and dysphagia, incontinence, diabetes, and acute and chronic pain. Strategies for successful management of these issues in a home or community setting are also discussed. Special attention is paid to falls and fall prevention, issues specific to aging women, and nutrition and weight control. Ways to promote positive health behaviors to preserve function are also explored. Additionally, patient and family education as part of a lifetime management plan is discussed. PMID- 22523017 TI - An effective community-based mentoring program for return to work and school after brain and spinal cord injury. AB - Information is presented on a community-based mentoring program, developed to work with existing community agencies and provide structure to the frequently confusing network of services for young adults, ages 16 to 26 years, with a recently acquired disability including TBI, SCI, and other neurological disorders. The over-arching goal of the Mentoring Program was to improve the ability of individuals with disabilities to access and maximally utilize the services and programs that are available in the community. The two objectives of this study were: (1) to demonstrate continuing increases in standardized measures of community integration from the time of enrollment in the program to the time of exit from the program, and (2) to improve the percentage of youth and young adults with disabilities who successfully access post-secondary education or employment opportunities. 53 participants had post-secondary education as a goal. 12 participants had an employment goal. 12 participants had both education and employment as a combined goal. It was not uncommon for participants to change goals. Of those with education goals, 23/53 achieved educational goals and 7/53 achieved employment goals. Of those with vocational goals, 5/12 achieved vocational goals and 1/12 achieved educational goals. Of those with both goals, 5/12 achieved educational goals and 1/12 achieved vocational goals. Significant community integration and independence improvements were noted for program participants (CHART Mobility and Cognitive Independence, M2PI, DRS, and SRS). Overall, findings suggest that mentoring can be beneficial toward achieving the goals of post-secondary education, employment and community independence for individuals with disabilities; specifically those with traumatic brain injury, spinal cord injury and other neurological disorders. PMID- 22523018 TI - 100-point scale evaluating job satisfaction and the results of the 12-item General Health Questionnaire in occupational workers. AB - OBJECTIVE: Job satisfaction is an important factor in the occupational lives of workers. In this study, the relationship between one-dimensional scale of job satisfaction and psychological wellbeing was evaluated. PARTICIPANTS: A total of 1,742 workers (1,191 men and 551 women) participated. METHODS: 100-point scale evaluating job satisfaction (0 [extremely dissatisfied] to 100 [extremely satisfied]) and the General Health Questionnaire, 12-item version (GHQ-12) evaluating psychological wellbeing were used. A multiple regression analysis was then used, controlling for gender and age. The change in the GHQ-12 and job satisfaction scores after a two-year interval was also evaluated. RESULTS: The mean age for the subjects was 42.2 years for the men and 36.2 years for the women. The GHQ-12 and job satisfaction scores were significantly correlated in each generation. The partial correlation coefficients between the changes in the two variables, controlling for age, were -0.395 for men and -0.435 for women (p< 0.001). A multiple regression analysis revealed that the 100-point job satisfaction score was associated with the GHQ-12 results (p< 0.001). The adjusted multiple correlation coefficient was 0.275. CONCLUSIONS: The 100-point scale, which is a simple and easy tool for evaluating job satisfaction, was significantly associated with psychological wellbeing as judged using the GHQ-12. PMID- 22523019 TI - Exploring workplace related health resources from a salutogenic perspective. Results from a focus group study among healthcare workers in Sweden. AB - OBJECTIVE: The aim of this study was to explore healthcare workers' opinions on workplace related health resources relevant to promotion of their health. PARTICIPANTS: 16 registered nurses and 19 assistant nurses, from a medical emergency ward at a medium sized hospital in the south of Sweden, participated in the study. METHODS: Eight focus group interviews were conducted, the material was condensed and conventional qualitative content analysis was used to elicit and identify patterns in the expressed opinions of the participants. RESULTS: The analysis yielded four themes that were labelled the reward, the team, the mission and the context. An explanatory model was constructed consisting of concentric circles, with the reward at the core. The qualitative analysis also revealed two divergent patterns; some of the participants associated positive health with stability while others referred to flexibility. CONCLUSIONS: The results from this study have contributed to the body of knowledge regarding salutogenic health indicators in the field of work and health research in particular as well as in health promotion in general. The findings show that individuals can have diverse responses to any given work situation, and this should be taken into account before implementation of salutogenic health promotion programs. PMID- 22523020 TI - Exploring the relationship between managers' leadership and their health. AB - OBJECTIVE: To explore the relationship between managers' leadership and their health, by investigating what psychosocial conditions in the workplace managers experience as being important to their health, and how their health influences their leadership. PARTICIPANTS AND METHODS: Semi-structured interviews with forty two managers at different managerial levels in a large Swedish industrial production company. RESULTS: Most managers felt their health was good, but many perceived their work as stressful. They said it was important to their health that they did a good job and achieved results as expected, that conditions in the workplace enabled this achievement, and that their performance was acknowledged. In comparison to the other managerial levels, the first-line managers' work and health were especially dependent on such enabling conditions. The results also showed that the managers' health influenced their leadership, the quality of their work and the quality of their relationship with subordinates. CONCLUSION: Managers' leadership, health and their work conditions are reciprocally related to each other. A productive and healthy workplace is facilitated by focusing on managers' conditions for leadership, their health and their work conditions. PMID- 22523021 TI - Effects of training intervention on non-ergonomic positions among video display terminals (VDT) users. AB - OBJECTIVE: Substantial evidence shows an association between musculoskeletal disorders (MSDs) and certain work-related physical factors. One of the jobs with known ergonomic hazards is working with video display terminals (VDTs). Redesign, ergonomic improvements, and education have generally been recommended as solutions for the prevention of musculoskeletal disorders. We designed this study to assess the effects of ergonomic training on the working postures of VDT users. METHODS: In an intervention study, we assessed the impact of ergonomic training on the ergonomic hazards and work postures in employees working with VDTs. Participants and their workstations were assessed by Rapid Upper Limb Assessment (RULA) method before and after training. PARTICIPANTS: 70 employees of an office, working with a VDT more than four hours per day entered the study. RESULTS: The greatest compliance with OSHA workstation recommendations was seen with the monitor (21.4% of cases) and the least compliance with the one was the chair (10.0%). Mean RULA score before and after intervention were 5.90, and 5.07, respectively, and the difference was statistically significant (p < 0.001). CONCLUSIONS: It can be concluded from this study that training office ergonomics to the VDT users, even without changing work place components can significantly improve VDT users' behavior and ability to properly fit a workstation to him/herself. PMID- 22523022 TI - Effects of protective respiratory devices and physical workloads in harsh weather conditions on individuals' physiological measures and exertion ratings. AB - OBJECTIVE: Although respiratory device is an essential item to protect the wearer from hazardous gases and dust, it tends to increase heat load on the workers. The goal of this paper was to select the appropriate respiratory devices that can be used in a harsh weather under different work-loads. METHODS: Sixteen young male participants participated in this study. Participants exercised on an ergometer bike in a laboratory at 30% and 50% of their physical workloads, in temperature and humidity controlled environments (30 degrees C and 40 degrees C dry bulb temperatures with 50% and 90% Relative Humidity), while wearing six different respiratory devices. The effects on the participant's body functions (e.g., heart rate, aural canal temperature and blood pressure), and their subjective exertion ratings were measured. RESULTS: Results proved that when wearing protective devices in hot environments, all physiological measures as well as exertion ratings were significantly increased. However, wearing half-face masks with two inlets exerted less stresses on the worker's physiological measures and subjective rating. CONCLUSIONS: This study recommended wearing half-face masks with two inlets to be used when performing tasks at hot environmental conditions. PMID- 22523023 TI - The Work Environment Impact Scale - Self-Rating (WEIS-SR) evaluated in primary health care in Sweden. AB - OBJECTIVE: To develop a self-report alternative to the Work Environment Impact Scale (WEIS). PARTICIPANTS: First the novel instrument was used and evaluated by ten occupational therapists and 45~clients in primary health care. Then the instrument was used by 26~clients who participated in a rehabilitation programme in another primary health care district. METHODS: The instrument was investigated in two steps. First content validity and utility were investigated through a questionnaire addressed to occupational therapists and their clients respectively. The response distribution was calculated by frequencies. Internal consistency was investigated. In the second step, a revised version of the instrument was investigated for test-retest reliability and internal consistency. The test-retest reliability was calculated by weighted kappa. The internal consistency of the WEIS-SR was calculated by means of Cronbach's alpha. RESULTS: In step one the content validity was good to moderately good, the utility was good, and the internal consistency was satisfactory (0.72). In step two the internal consistency was good (0.88/0.89) and the test-retest reliability was mostly good to moderate (0.35-0.78, median 0.61). CONCLUSIONS: The instrument will be further investigated in other populations and take into consideration additional psychometric properties such as sensitivity to change, predictive validity, and concurrent validity. PMID- 22523024 TI - Health factors in the everyday life and work of public sector employees in Sweden. AB - OBJECTIVE: The aim was to explore aspects of everyday life in addition to established risk factors and their relationship to subjective health and well being among public sector employees in Sweden. Gainful employment impact on employees' health and well-being, but work is only one part of everyday life and a broader perspective is essential in order to identify health-related factors. PARTICIPANTS: Data were obtained from employees at six Social Insurance Offices in Sweden, 250 women and 50 men. METHOD: A questionnaire based on established instruments and questions specifically designed for this study was used. Relationships between five factors of everyday life, subjective health and well being were investigated by means of multivariate logistic regression analysis. RESULTS: The final model revealed a limited importance of certain work-related factors. A general satisfaction with everyday activities, a stress-free environment and general control in addition to not having monotonous movements at work were found to be factors explaining 46.3% of subjective good health and well being. CONCLUSIONS: A person's entire activity pattern, including work, is important, and strategies for promoting health should take into account the person's situation as a whole. The interplay between risk and health factors is not clear and further research is warranted. PMID- 22523026 TI - The use of a vertical arm support device to reduce upper extremity muscle firing in sonographers. AB - Work-related musculoskeletal disorders (WRMSD) in sonographers have increased over the past 20 years with shoulder injuries being the most prevalent. Advancing ultrasound technologies have reduced a sonographer's need to move when performing exams and increased prolonged arm abduction, resulting in static work postures and decreased joint perfusion. Work modifications in other industries have demonstrated that reducing arm abduction to 30 degrees reduces muscle firing and fatigue. Although this is the ideal work posture for sonographers, there are many instances in which excessive arm abduction and static postures cannot be avoided. These positions are further complicated by the fact that the scanning arm is also supporting the weight of the ultrasound transducer. This observational case study evaluated the use of a moveable arm support system as a means to provide support for the scanning arm and reduce muscle firing during ultrasound exams in the scanning lab of a university diagnostic ultrasound educational program. PMID- 22523027 TI - Caring for self and others: Increasing health care students' healthy behaviors. AB - OBJECTIVE: Living a healthy lifestyle in order to manage stress encountered in the health care system is important for health care professionals. The purpose of this study was to increase healthy behaviors of undergraduate students in professional health care majors by introducing a health promotion intervention in a required course. PARTICIPANTS: The sample consisted of 201 undergraduate health professional students from nursing (NUR) (n=82, 40.8%), occupational therapy (OT) (n=72, 35.8%), and speech- language pathology (SLP) (n=47, 23.4%). METHODS: A pretest-posttest comparison group design was used. The NUR and OT students received a health promotion intervention to encourage a healthy lifestyle in a required course. SLP students served as a comparison group and did not receive content on self health promotion. RESULTS: The comparison group (SLP) had significantly lower scores on the overall Health Promoting Lifestyle Profile II (HPLPII), physical activity and nutrition scales at posttest when compared to pretest. In contrast, students in the intervention group (NUR & OT) significantly increased in their health responsibility as measured on the HPLPII survey at the end of the semester. CONCLUSIONS: Infusing content on healthy behaviors in undergraduate curricula may better prepare professionals for living a healthy lifestyle. PMID- 22523028 TI - An analysis of occupational factors related to shoulder discomfort in diagnostic medical sonographers and vascular technologists. AB - OBJECTIVE: Three-fourths of diagnostic medical sonographers (DMS) and vascular technologists (VT) experiencing discomfort due to job demands indicate having discomfort in the shoulder region. An analysis of factors related to shoulder discomfort highlighted salient factors requiring further investigation and intervention. PARTICIPANTS: The respondents were a convenient sample of DMS and VT that answered a survey, hosted on a secure website. METHODS: The responses of 2,163 DMS and VT from a survey of a representative sample were analyzed to determine personal factors, work demands, and workstation design characteristics of those experiencing discomfort in the shoulder region. Frequencies and response distributions were calculated and cross tabulation with chi-square analysis was completed. RESULTS: A majority of respondents with shoulder discomfort have co morbid reports of discomfort in other locations. While overall sonographer discomfort is linked to age and years of experience, shoulder discomfort was also noted to be linked to specific workstation characteristics. A lack of adjustability in equipment, picture archiving and communication system (PACS) workstations, and positions required to complete bedside exams contributes to discomfort due to sustained and repetitive shoulder abduction and twisting of the neck and trunk. CONCLUSIONS: There is a need for studies investigating redesign of equipment and workstations or interventions with DMS and VT specifically focused on improving adjustability and improved positioning of sonographers in order to reduce shoulder discomfort while performing job demands. PMID- 22523029 TI - A wrist tendon travel assessment of hand movements associated with industrial repetitive activities. AB - OBJECTIVE: To investigate slow and fast paced industrial activity hand repetitive movements associated with carpal tunnel syndrome where movements are evaluated based on finger and wrist tendon travel measurements. METHODS: Nine healthy subjects were recruited for the study aged between 23 and 33 years. Participants mimicked an industrial repetitive task by performing the following activities: wrist flexion and extension task, palm open and close task; and pinch task. Each task was performed for a period of 5 minutes at a slow (0.33 Hz) and fast (1 Hz) pace for a duration of 3 minutes and 2 minutes respectively. RESULTS: Tendon displacement produced higher flexor digitorum superficialis (FDS) tendon travel when compared to the flexor digitorum profundus (FDP) tendons. The left hand mean (SD) tendon travel for the FDS tendon and FDP tendon were 11108 (5188) mm and 9244 (4328) mm while the right hand mean tendon travel (SD) for the FDS tendon and FDP tendon were 9225 (3441) mm and 7670 (2856) mm respectively. Of the three tasks mimicking an industrial repetitive activity, the wrist flexion and extension task produced the most tendon travel. CONCLUSION: The findings may be useful to researchers in classifying the level of strenuous activity in relation to tendon travel. PMID- 22523030 TI - Estimated energy expenditure of nursing assistants in long term care. AB - Ergonomic research on nursing work has focused primarily on the biomechanical analysis of patient handling tasks. Few studies have addressed the intensity of a full day of nursing work as measured by changes in heart rate and energy expenditure. OBJECTIVE: A pilot study was conducted between August 2009 and May 2010 to examine the intensity of performing nursing assistant work in long term care settings and to assess the usefulness of heart rate monitoring as a measure of work intensity. The residents of the facilities were physically dependent adults. The settings had floor-based mechanical lifting devices available and no lift policies that restricted workers from lifting. PARTICIPANTS: Eight women between the ages of 19 and 54 from two facilities participated in this study. METHODS: A wearable recorder allowed unobtrusive heart rate monitoring while nursing assistants worked their usual shift. Continuous heart rate monitoring for a full shift provided an estimation of energy expenditure. RESULTS: The data suggest that the nursing assistants worked at a moderate level yet were within the safe work intensity level recommended by NIOSH [32]. CONCLUSIONS: The information provides preliminary baseline data for nursing assistants who work with physically dependent adults using floor-based lifts in a no-lift environment. PMID- 22523032 TI - Ergonomic and safety risk factors in home health care: Exploration and assessment of alternative interventions. AB - OBJECTIVE: The goals of this project were to improve the understanding of risk factors that may lead to injury and increased turnover in home health aides, discover unexplored opportunities for intervention, and test those intervention ideas for potential effects, feasibility, and acceptance by home health aides and their employers. METHODS: Analysis of injury data, extensive direct observation and analysis of aide-patient interactions, participatory intervention ideation focus group discussions, and intervention pilot testing was conducted. RESULTS: A method of categorizing each patient's level of skill in transfer and bathing activities, and their mobility assistance requirements was developed from information collected during the study as well as a review of the literature. In a pilot test, the new categorization scheme was used to control the aides' daily exposure to higher needs patients. The percentage of time that aides worked with patients in higher needs categories was found to be related to the aides' self reports of end-of-shift fatigue and pain. CONCLUSION: Home health care companies may find that developing a scheduling system that manages the exposure of their aides to higher needs patients may be a feasible and effective method for reducing the aides' exposure to risk factors for musculoskeletal injuries. PMID- 22523031 TI - Work-related activities associated with injury in occupational and physical therapists. AB - OBJECTIVE: The purpose of this study was to examine work activities associated with work-related injury (WRI) in occupational and physical therapy. PARTICIPANTS: 1,158 occupational and physical therapists in Wisconsin responded to a mailed survey, from a total of 3,297 OTs and PTs randomly selected from the State licensure list. METHODS: The study used a cross-sectional, survey design. Participants reported information about WRI they sustained between 2004 and 2006, including the activities they were performing when injured. Investigators analyzed 248 injury incidents using qualitative and quantitative analysis. RESULTS: Data were examined across OT and PT practice in general, and also by practice area. Manual therapy and transfers/lifts were associated with 54% of all injuries. Other activities associated with injury were distinct to practice area, for example: floor work in pediatrics; functional activities in acute care; patient falls in skilled nursing facilities; and motor vehicle activities in home care. CONCLUSIONS: Injury prevention activities must address transfers and manual therapy, but also must examine setting-specific activities influenced by environment and patient population. PMID- 22523033 TI - Small-bore pigtail catheters for the treatment of primary spontaneous pneumothorax in young adolescents. AB - OBJECTIVE: Small-bore pigtail catheters have been found to be effective in the treatment of primary spontaneous pneumothorax (PSP) in adults. The aim of this study was to compare the effectiveness of small-bore pigtail and large-bore catheters in the treatment of PSP in young adolescents. MATERIALS AND METHODS: Young adolescents (<18 years) with initial PSP were treated with aspiration (control group), small-bore pigtail catheters or large-bore catheters. Treatment was determined on a case-by-case basis with parental consultation. Success rate, recurrence rate (within 12 months), duration of hospital stay, duration of catheter insertion, and complications were analysed. MAIN RESULTS: There were 41 patients treated: aspiration, n=8; small-bore pigtail catheters, n=10; large-bore catheters, n=23. Demographic and baseline clinical characteristics were similar between groups. The success rates were 50.0% and 65.2% in the small-bore pigtail and large-bore catheter groups, respectively. Corresponding recurrence rates were 20.0% and 56.5%. There was no difference between the small-bore pigtail and large bore catheter groups in the duration of hospital stay in patients for whom treatment was successful; however, the duration of catheter insertion was significantly shorter in the small-bore pigtail catheter group compared with the large-bore catheter group in patients for whom treatment was successful (p<0.05). There were no major complications in either catheter treatment group and few minor complications (small-bore pigtail catheter, n=2; large-bore catheter, n=4). CONCLUSIONS: The findings suggest that small-bore pigtail catheters may be as effective as large-bore catheters for the initial treatment of PSP in young adolescents. PMID- 22523034 TI - Genetic ablation of SOX18 function suppresses tumor lymphangiogenesis and metastasis of melanoma in mice. AB - The lymphatic vasculature provides a major route for tumor metastasis and inhibiting neolymphangiogenesis induced by tumors can reduce metastasis in animal models. Developmental biology studies have identified the transcription factor SOX18 as a critical switch for lymphangiogenesis in the mouse embryo. Here, we show that SOX18 is also critical for tumor-induced lymphangiogenesis, and we show that suppressing SOX18 function is sufficient to impede tumor metastasis. Immunofluorescence analysis of murine tumor xenografts showed that SOX18 is reexpressed during tumor-induced neolymphangiogenesis. Tumors generated by implantation of firefly luciferase-expressing B16-F10 melanoma cells exhibited a reduced rate of metastasis to the regional draining lymph node in Sox18-deficient mice, as assessed by live bioluminescence imaging. Lower metastatic rates correlated with reduced tumoral lymphatic vessel density and diameter and with impaired drainage of peritumoral injected liposomes specific for lymph vessels from the sentinel lymph nodes. Overall, our findings suggested that SOX18 induction is a key step in mediating tumor lymphangiogenesis and metastasis, and they identify SOX18 as a potential therapeutic target for metastatic blockade. PMID- 22523035 TI - Novel TOPK inhibitor HI-TOPK-032 effectively suppresses colon cancer growth. AB - The serine-threonine mitogen-activated protein kinase kinase family member T-LAK cell-originated protein kinase (TOPK/PBK) is heavily involved in tumor development, cancer growth, apoptosis, and inflammation. Despite the identification of TOPK as a promising novel therapeutic target, no inhibitor of TOPK has yet been reported. In this study, we screened 36 drug candidates using an in vitro kinase assay and identified the novel TOPK inhibitor HI-TOPK-032. In vitro, HI-TOPK-032 strongly suppressed TOPK kinase activity but had little effect on extracellular signal-regulated kinase 1 (ERK1), c-jun-NH2-kinase 1, or p38 kinase activities. HI-TOPK-032 also inhibited anchorage-dependent and independent colon cancer cell growth by reducing ERK-RSK phosphorylation as well as increasing colon cancer cell apoptosis through regulation of the abundance of p53, cleaved caspase-7, and cleaved PARP. In vivo, administration of HI-TOPK-032 suppressed tumor growth in a colon cancer xenograft model. Our findings therefore show that HI-TOPK-032 is a specific inhibitor of TOPK both in vitro and in vivo that may be further developed as a potential therapeutic against colorectal cancer. PMID- 22523036 TI - Stromal estrogen receptor-alpha promotes tumor growth by normalizing an increased angiogenesis. AB - Estrogens directly promote the growth of breast cancers that express the estrogen receptor alpha (ERalpha). However, the contribution of stromal expression of ERalpha in the tumor microenvironment to the protumoral effects of estrogen has never been explored. In this study, we evaluated the molecular and cellular mechanisms by which 17beta-estradiol (E2) impacts the microenvironment and modulates tumor development of ERalpha-negative tumors. Using different mouse models of ER-negative cancer cells grafted subcutaneously into syngeneic ovariectomized immunocompetent mice, we found that E2 potentiates tumor growth, increases intratumoral vessel density, and modifies tumor vasculature into a more regularly organized structure, thereby improving vessel stabilization to prevent tumor hypoxia and necrosis. These E2-induced effects were completely abrogated in ERalpha-deficient mice, showing a critical role of host ERalpha. Notably, E2 did not accelerate tumor growth when ERalpha was deficient in Tie2-positive cells, even in mice grafted with wild-type bone marrow. These results were extended by clinical evidence of ERalpha-positive stromal cell labeling in the microenvironment of human breast cancers. Together, our findings therefore show that E2 promotes the growth of ERalpha-negative cancer cells through the activation of stromal ERalpha (extra-hematopoietic Tie-2 positive cells), which normalizes tumor angiogenesis and allows an adaptation of blood supply to tumors, thereby preventing hypoxia and necrosis. These findings significantly deepen mechanistic insights into the impact of E2 on tumor development with potential consequences for cancer treatment. PMID- 22523037 TI - School furniture and work surface lighting impacts on the body posture of Paraiba's public school students. AB - OBJECTIVE: The main objective of this study is to evaluate the impact of school furniture and work surface lighting on the body posture of public Middle School students from Paraiba (Brazil). PARTICIPANTS AND METHODS: The survey was carried out in two public schools and the target population for the study included 8th grade groups involving a total of 31 students. Brazilian standards for lighting levels, the CEBRACE standards for furniture measurements and the Postural Assessment Software (SAPO) for the postural misalignment assay were adopted for the measurements comparison. The statistic analysis includes analyses of parametric and non-parametric correlations. RESULTS: The results show that the students' most affected parts of the body were the spine, the regions of the knees and head and neck, with 90% of the total number of students presenting postural misalignment. The lighting levels were usually found below 300 lux, below recommended levels. The statistic analysis show that the more adequate the furniture seems to be to the user, the less the user will complain of pain. CONCLUSIONS: Such results indicate the need of investments in more suitable school furniture and structural reforms aimed at improving the lighting in the classrooms, which could fulfill the students' profile and reduce their complaints. PMID- 22523038 TI - Effect of assistive reading software on high school students with learning disabilities: a pilot study. AB - OBJECTIVE: This research project was designed to test the immediate effect of using assistive reading software - Kurzweil 3000 (K-3000) for high school students with learning disabilities (LD) to improve their English reading and other school performances. PARTICIPANTS: 29 Taiwanese high school students with LD were randomly assigned to one of two groups: (1) use of the K-3000 or (2) control group (using a pen and paper). METHODS: Both groups were asked to complete the standardized measurements using pen and paper a pre-test. Students in experiment group used the K-3000 to do the post-test after they were familiarized with the K-3000, while the students in the control group used pen and paper for the post-test. The differences between the pre-test and post-test of two groups were analyzed. RESULTS: The results suggested that the K-3000 had an immediate impact on students' English word recognition and pronunciation. However, the use of K-3000 did not have a significant influence on the students' general English proficiency, learning adjustment, and academic self-perception. CONCLUSIONS: The use of K-3000 had a positive effect on students' English word recognition. The reason why there was no significant change in students' other performances could be due to the length of the intervention. PMID- 22523039 TI - Vocational rehabilitation, interagency collaboration and social representations. AB - OBJECTIVE: The aim of this study is to describe and analyse two important dimensions of vocational rehabilitation for disadvantaged groups and persons with disabilities: interagency collaboration and social representations. PARTICIPANTS: Four focus group discussions were conducted. The participants were 20 officials of various agencies who had taken part in collaboration projects in vocational rehabilitation. METHODS: Qualitative content analysis was used for the analysis. The material was categorised and central themes identified. RESULTS: Three themes emerged: 'Collaboration Process', 'Other Agencies' and 'Object for Collaboration'. The results indicate that interagency collaboration is very important in vocational rehabilitation, but that there are a number of obstacles to smooth collaboration. The professionals of the different agencies shared social representations to a great extent. Working with people with psychiatric disorders is especially challenging, and conflicts tended to arise between the projects and the home organisations. CONCLUSIONS: Recognition of others' knowledge and respectfulness toward other professions facilitated vocational rehabilitation and the interagency collaboration process. The agencies' lack of flexibility increased the risk of conflicts as attempts were made to integrate the new working methods developed within the projects into the ordinary activities of the agencies. PMID- 22523040 TI - Supporting workers with mental health problems to retain employment: users' experiences of a UK job retention project. AB - OBJECTIVES: To understand experiences and perspectives of job retention project users in relation to challenges faced and support received; to develop explanatory insight into effective interventions. PARTICIPANTS: 14 employed users of a United Kingdom job retention project, with a range of mental health problems. METHODS: Semi-structured individual interviews which were collaboratively designed with service users. Data analysis involved deductive & inductive thematic analysis, constant comparative analysis, and service user collaboration. RESULTS: Participants' feelings of guilt and self blame were a major obstacle to job retention. The project helped them address these by supporting a reappraisal of their situation. This assisted identification of job accommodations and adjustments and confidence in self advocacy. Thus an important basis for improved dialogue with their employer was established. A peer support group provided an important adjunct to individual project worker interventions. 10 participants retained employment; three of those who did not were helped to retain work aspirations. CONCLUSIONS: The project effectively used a multi faceted approach involving a person - environment-occupation focus on the worker, their work, and workplace. Such complex interventions may offer more promise than those interventions (such as cognitive behavioural therapy) which have a primary focus on the individual worker. PMID- 22523041 TI - Backpacks. Several factors likely to influence design and usage: a systematic literature review. AB - OBJECTIVE: The purpose of this study was to systematically review the literature to answer three questions: 1) what is the best backpack positioning on the spine; 2) what are the human effects of front packs and double packs compared to backpacks; and 3) what is best shoulder strap design. METHODS: A systematic review of the literature using eight databases was carried out. Studies relevant to backpack design were retrieved. Two independent reviewers assessed the papers; a third party was used for consensus decisions. Descriptive characteristics, type of research design and level of evidence of papers were evaluated with a view to pooling data. The trials were also quality appraised using a modified Crombie tool. RESULTS: Thirty papers met the inclusion criteria. There were similarities in methods of measurement between some papers but subject's age group, tasks performed and backpack usages were so different between studies that it prevented data pooling and made it difficult to draw firm generic conclusions. Subsequent qualitative analysis shows that there are conflicting results on best backpack placement and shoulder strap design but front packs and double packs provide better posture than backpacks. CONCLUSIONS: Some recommendations for best practice design are made for children and adults based on elements of design and correct spinal placement. PMID- 22523042 TI - Validation of the programme impact theory for a work rehabilitation programme. AB - OBJECTIVE: The Therapeutic Return to Work (TRW) is a comprehensive rehabilitation process that is centralised in the workplace and consists of a worker's progressive return to his or her regular work. A programme impact theory for the TRW and three mechanism hypotheses were developed [12]. The objective of this study was to validate the mechanism hypotheses. participants: Construction workers who received compensation for low back pain. METHODS: A multiple-case study was carried out. Data on the programme activities were collected on a repeated basis using validated measurement instruments and semi-structured interviews of the 20 participants and the clinicians responsible for them. Analyses were carried out using the pattern matching technique. RESULTS: The results supported two of the three hypotheses proposed in the impact theory, specifically, that the development of competent work behaviours is a key factor in promoting return to work and appears to be associated with a reduction in work environment constraints, an improvement in work capacities and the presence of concerted action. CONCLUSION: This study revealed that rehabilitation interventions carried out in the workplace and involving workers with low back pain are both complex and embedded in the social environment, and that the actions taken must be coordinated in collaboration with various stakeholders. PMID- 22523043 TI - Postural analysis of eight university student wheelchair users when performing written exercises in their classroom: a case study in Santiago de Cali, Colombia. AB - In students with physical disabilities, the more energy and time required and invested into finding a good posture, the longer the learning process takes. For this reason, the objective of this study was to characterize the posture in the act of writing of wheelchair users in a classroom. Eight students, (three women) aged 18-40, of some of the main universities of the city of Santiago de Cali participated. An observational field study filming of approximately 10 minutes was done while they took notes in their classes. Posture of the head, trunk, and upper extremities was analyzed with respect to its axis and the type of movement in each joint. The postures were classified depending on the location of support surface finding five different postures in the eight students. In these five postures some biomechanical risk factors, usually present in wheelchair users, are increased when they are associated with those postures. Those associated risk factors are: possible disc spine deformation, muscular stress and causing of pressure ulcer. In conclusion, in four of these five postures a poor interaction among person, task and work desk was observed. Therefore, seven of the eight students in this study were found to have a posture that could be considered risky. PMID- 22523044 TI - Prevalence and risk factors for musculoskeletal symptoms with computer based work across occupations. AB - OBJECTIVES: The purpose of this study was to compare the 12-month prevalence of musculoskeletal symptoms and risk factors associated with computer based work between occupations in a sample of Australian public sector employees. METHOD: A cross-sectional study was completed with employees of 6 government departments. An online survey was electronically distributed to over 8,000 employees characterised by a range of occupational groups and levels of employment. Data collected included individual and employment characteristics, estimation of hours worked with a computer per day and self-reported musculoskeletal symptoms in the upper extremity and spinal areas using the Nordic Musculoskeletal Questionnaire. RESULTS: Responses from 934 completed surveys could be used. There was no significant difference in the prevalence of reported musculoskeletal symptoms between occupational groups except for the wrist/hand and elbow areas. Estimated duration of computer work per day was significantly associated with increased musculoskeletal symptoms in the neck (OR 1.41, 95%CI: 1.09 to 1.83), wrist/hand/s (OR 1.46, 95%CI: 1.17 to 1.83) and elbow/s (OR 1.41, 95%CI: 1.07 to 1.85) areas, with the finding of a linear relationship between hours worked and prevalence of symptoms. A greater proportion of employees in higher level management and professional occupational groups were found to be working with a computer in excess of 6 to 8 hours per day compared with those in non-professional (administration and secretarial) groups. CONCLUSION: Hours worked with a computer per day was a significant risk factor for reported musculoskeletal symptoms amongst all occupational groups working in Australian public sector offices. No significant difference in the level of risk was found between occupations. PMID- 22523045 TI - Background music: effects on attention performance. AB - OBJECTIVE: Previous studies indicate that noise may affect worker attention. However, some background music in the work environment can increase worker satisfaction and productivity. This study compared how music with, and without, lyrics affects human attention. PARTICIPANTS: One hundred and two participants, aged 20-24 years, were recruited into this study. Fifty-six males and 46 females participated in this study. METHODS: Background music with, and without lyrics, was tested for effects on listener concentration in attention testing using a randomized controlled trial (RCT) study. RESULTS: The comparison results revealed that background music with lyrics had significant negative effects on concentration and attention. CONCLUSIONS: The findings suggest that, if background music is played in the work environment, music without lyrics is preferable because songs with lyrics are likely to reduce worker attention and performance. PMID- 22523046 TI - Young worker safety in construction: do family ties and workgroup size affect hazard exposures and safety practices? AB - OBJECTIVE: Little is known about how social aspects of the work environment influence exposures or safety practices affecting young construction workers. Our objective was to investigate whether working on a construction site with a small number of workers (<=10 vs. 11-50) or having a family-firm connection (working in a family-owned firm or one in which a family member also works) impacts hazard exposures and safety practices. PARTICIPANTS: Participants included 187 North Carolina construction workers 14 to 17 years old who were surveyed about their jobs. METHODS: We conducted stratified analyses using cross-tabulations and chi square statistics to measure associations between workgroup size (i.e., the total number of workers on a jobsite) and family-firm connections (yes/no) and hazard exposures (e.g., saws) and safety practices (e.g., supervision). RESULTS: Having a family-firm connection was associated with fewer hazard exposures and greater safety practices. Youth who worked on jobsites with a larger workgroup (11-50 workers) reported more hazards but also more safety practices. CONCLUSIONS: Family-firm connections, in particular, may have a protective effect for youth in construction. Even though the statistical significance of our findings on workgroup size was limited in places, the pattern of differences found suggest that further research in this area is warranted. PMID- 22523047 TI - Disability on campus: a perspective from faculty and staff. AB - OBJECTIVE: To identify employee perceptions regarding disability-related workplace issues in Institutions of Higher Education (IHE). PARTICIPANTS: Faculty and staff (N=1,144) at a large, Midwestern university. METHODS: A voluntary on line survey of disability-related employment issues was developed by the university's Chancellor's Committee of Persons with Disabilities. Item responses were analyzed using descriptive and Pearson chi-square statistical methods. RESULTS: Fifteen percent of faculty and staff respondents were found to have disabilities, with 26% reporting experience of job discrimination, and 20% reporting harassment because of their disability. Results indicated significant differences on gender, employment standing (i.e., faculty or staff) and disability status (i.e., with or without a disability), in regard to perceptions of disability acceptance, campus accessibility, disability awareness, ADA policy, and knowledge of work accommodation procedures. CONCLUSIONS: Recommendations for IHEs are provided to promote a welcoming and inclusive campus that ultimately supports work success for persons with a disability. PMID- 22523048 TI - Individuals with traumatic brain injuries perceptions and experiences of returning to work in South Africa. AB - OBJECTIVE: The aim of this study was to identify the central concepts of a model that would facilitate the return to work process of individuals with brain injury. However for the purpose of this paper there will be a focus only on the barriers and facilitators that influence the return to work process. PARTICIPANTS: Ten individuals who were diagnosed with a mild to moderate brain injury participated in this study. METHODS: Qualitative research methods were used in order to explore the research question. The participants were selected by means of purposive sampling and the data was collected by means of in depth interviews. RESULTS: The results of the study revealed that the participants experienced a sense of loss of function after the brain injury, a fear of the future and loss of confidence in their worker roles. The participants also indicated that by means of adapting occupational routines an actively engaging in rehabilitation they developed confidence in their worker roles. CONCLUSION: Occupational therapists have to use a client centred holistic work integrative approach in order to successfully rehabilitate as well as facilitate the return to work process with people who have suffered a traumatic brain injury. PMID- 22523049 TI - Trade unionism in the information technology (IT) industry: an employee's perspective. AB - OBJECTIVES: This research aimed to understand the information technology (IT) employees' perception and approach towards union formation in the Indian IT Industry. PARTICIPANTS: Fifty IT professionals from three different organizations participated in this study who were dispersed throughout the organizational hierarchy and were selected via randomized quota sampling to reflect a mix of age, experience, gender and position they held with the organization. METHODS: Qualitative methods were used in order to collect the data, through phenomenological principles. RESULTS: Discussion with the participants led to the emergence of four themes which influence the employees' perception of trade union formation the Indian IT industry. These were: (a) feeling of a blue collar, (b) collective to individual bargaining, (c) changing role of HR and (d) other reasons. CONCLUSIONS: This study provided a tentative starting point towards the greater understanding of the employee's perceived notion of organizational life that influences employee's outlook towards trade unionism. Based on the study findings, there is an imperative that the human resource department, organizational forerunners and trade union philosophers continue to use research findings to understand employees' views about union formation in the IT industry. PMID- 22523051 TI - Prior anti-thrombotic drugs and stroke mortality. PMID- 22523052 TI - Short thromboelastography and the identification of high platelet reactivity while on and off therapy. PMID- 22523053 TI - Brain natriuretic peptide, survival and response to targeting therapy: another piece in the complex puzzle of Eisenmenger syndrome. PMID- 22523054 TI - French Registry on Acute ST-elevation and non ST-elevation Myocardial Infarction 2010. FAST-MI 2010. AB - AIM OF FAST-MI 2010: To gather data on characteristics, management and outcomes of patients hospitalised for acute myocardial infarction (AMI) at the end of 2010 in France. INTERVENTIONS: To provide cardiologists and health authorities national and regional data on AMI management every 5 years. SETTING: Metropolitan France. 213 academic (n=38), community (n=110), army hospitals (n=2), private clinics (n=63), representing 76% of centres treating AMI patients. Inclusion from 1 October 2010. POPULATION: Consecutive patients included during 1 month, with a possible extension of recruitment up to one additional month (132 centres); 4169 patients included over the entire recruitment period, 3079 during the first 31 days; 249 additional patients declining participation (5.6%). STARTPOINTS: Consecutive adults with ST-elevation and non-ST-elevation AMI with symptom onset <=48 h. Patients with AMI following cardiovascular procedures excluded. DATA CAPTURE: Web-based collection of 385 items (demographic, medical, biologic, management data) recorded online from source files by external research technicians; case-record forms with automatic quality checks. Centralised biology in voluntary centres to collect DNA samples and serum. Long-term follow-up organised centrally with interrogation of municipal registry offices, patients' physicians, and direct contact with the patients. DATA QUALITY: Data management in Toulouse University. STATISTICAL ANALYSES: Universite Paris Descartes, Universite de Toulouse, Universite Pierre et Marie Curie-Paris 06, Paris. ENDPOINTS AND LINKAGES TO OTHER DATA: In-hospital events; cardiovascular events, hospital admissions and mortality during follow-up. Linkage with Institute for National Statistics. ACCESS TO DATA: Available for research to any participating clinician upon request to executive committee (fastmi2010@yahoo.fr). PMID- 22523055 TI - Personalised antiplatelet therapy in stent thrombosis: observations from the Clopidogrel Resistance in Stent Thrombosis (CREST) registry. AB - OBJECTIVE: Previous studies have demonstrated significant heterogeneity in responses to antiplatelet therapy (APT), and high residual platelet reactivity is associated with the risk of ischaemic events, including stent thrombosis (ST). The prevalence of APT hyporesponsiveness in a 'real world' registry of ST patients and the feasibility of personalising APT are reported. PATIENTS AND SETTING: 39 consecutive patients admitted to a single regional cardiothoracic centre with definite ST were prospectively evaluated. INTERVENTIONS: Response to aspirin and clopidogrel was measured following discharge using short thrombelastography (TEG), a rapid, well validated near patient platelet function test. Treatment modification in hyporesponders comprised an increase in aspirin dose and/or changing clopidogrel to prasugrel or ticagrelor. Short TEG was repeated following treatment modification to ensure an adequate response had been achieved. RESULTS: 12 (31%) patients had an adequate response to both aspirin and clopidogrel, 16 (41%) were hyporesponsive to clopidogrel alone, one (3%) was hyporesponsive to aspirin alone and 10 (26%) were hyporesponsive to both aspirin and clopidogrel. Following treatment modification, an adequate response to aspirin and P2Y12 agent was achieved in 10 (91%) and 22 (85%) patients, respectively. None has presented with a further ST episode. CONCLUSIONS: There is a high prevalence of hyporesponsiveness to APT in patients with ST. Improved APT efficacy can be achieved by tailored therapy. Short TEG is a plausible platelet function test that can be used to deliver point of care personalised APT. PMID- 22523056 TI - Lower GI bleeding is more common than upper among patients on dual antiplatelet therapy: long-term follow-up of a cohort of patients commonly using PPI co therapy. AB - OBJECTIVE: Patients undergoing percutaneous coronary intervention require dual antiplatelet therapy. Proton-pump inhibitor (PPI) therapy is recommended for the prevention of upper GI complications. No study has determined the rate and type of GI bleeding events in such patients in routine clinical practice. DESIGN: Observational study with a prospective follow-up to confirm medication use and occurrence of events, which were validated. PATIENTS AND SETTING: We have followed up a cohort of 1219 consecutive patients admitted for percutaneous coronary intervention in Zaragoza (Spain). MAIN OUTCOME MEASURES: Major GI bleeding and cardiovascular events. RESULTS: At discharge, 96.7% of patients were on dual antiplatelet therapy and 76.6% on PPI therapy, which increased up to 87.9% during follow-up of 2107.6 patient (pt) s-years (1.72+/-1.07 years/patient). There were eight patients who developed GI bleeding during hospitalisation and 27 patients during follow-up, (1.52 bleeds per 100 pt-years). Most GI bleeding events (81.4%) occurred during the first year (mean time to bleeding event: 7.03+/-7.65 months) and 84.6% of patients were on long-term PPI at the time of the bleed. Lower GI bleeding occurred more frequently than upper GI bleeding (74% lower vs. 26% upper). Peptic ulcer history and concomitant warfarin therapy were the only risk factors identified for upper or lower GI bleeding respectively. CONCLUSIONS: Among patients on dual antiplatelet therapy and PPI co-therapy, gastrointestinal bleeding episodes are more frequent in the lower GI tract. This changing pattern of bleeding may reflect the success of gastroprotection and focuses attention on research to address lower GI bleeding in this population. PMID- 22523057 TI - Long-term outcomes following infection of cardiac implantable electronic devices: a prospective matched cohort study. AB - OBJECTIVE: To assess long-term outcomes and predictors of mortality in patients treated according to current recommendations for cardiac implantable electronic device (CIED) infection. DESIGN: Two-group matched cohort study. SETTING: Tertiary-care institution. PATIENTS: Consecutive patients admitted for CIED infection between 2004 and 2008 were prospectively enrolled. Study subjects were matched to a cohort of uninfected CIED patients by age, sex and type of device. INTERVENTIONS: In all infected patients, the therapeutic approach consisted of complete hardware removal whenever possible, antimicrobial therapy, and implantation of a new device, if indicated. Patients were systematically followed, with standardised outcomes assessment. MAIN OUTCOME MEASURES: All-cause mortality and predictors of long-term mortality. RESULTS: 197 patients were included and matched 1:1 to controls. Pocket infections were present in 41.1% and definite or suspected infective endocarditis in 58.9%. Total or subtotal hardware removal was achieved in 98.5% of cases. Median follow up was 25 months (12-70). Mortality rates in the study group and controls were 14.3% vs 11.0% (NS) at 1 year and 35.4% vs 27.0% (p=NS) at 5 years. Independent predictors of long-term mortality were older age (HR=1.09, p<0.001), cardiac resynchronisation therapy (HR=3.70, p=0.001), thrombocytopenia (HR=5.10, p=0.003) and renal insufficiency (HR=2.66, p=0.006). In patients with reimplanted devices, epicardial right ventricular pacemakers were associated with higher mortality (HR=2.85, p=0.034). CONCLUSION: In patients with CIED infection managed by recommended therapy, long term mortality rates are similar to comparable controls. Independent predictors include patient and disease-related factors, in addition to implantation of right ventricular epicardial pacemakers. PMID- 22523058 TI - Timing of troponin I measurement in pulmonary embolism. AB - BACKGROUND: Troponin I (TnI) is an important prognostic marker and risk stratification tool in patients with pulmonary embolism (PE). However, the best timing for this biomarker measurement is still unclear. OBJECTIVE: To analyse the kinetics of TnI in patients hospitalised for PE in order to better ascertain the evolution of the biomarker in this disease. In particular, we attempted to determine which measurement is the most appropriate to assess the PE risk according to this biomarker's status. DESIGN, SETTING, PATIENTS AND MAIN OUTCOME MEASURES: This was a prospective, single center, cohort study. TnI (Beckman Access method) was measured on admission, then every 8 h for 72 h in 200 stable patients hospitalised for PE in our cardiology department. Patients were classified into two groups: TnI-(negative) or TnI +. RESULTS: Mean TnI peak occurred at H8: 0.67+/-0.55 ng/ml. TnI values then decreased quickly, but remained positive (>0.06 ng/ml) beyond the 72-h surveillance period. The TnI biological profile varied widely after admission. Of the patients TnI- on the first assessment, 15% were positive at the second measurement. Among patients hospitalised less than 24 h after the onset of symptoms, 30% were misclassified on admission. In all cases, the second assessment, eight hours after admission, gave the biomarker's true status. CONCLUSION: Our study clarifies the kinetics of TnI in PE and highlights the situations in which an early TnI can be false negative. Many misclassifications could be avoided by taking into account the value of this biomarker obtained at H8. PMID- 22523059 TI - Transcatheter aortic valve implantation: implications of multimodality imaging in patient selection, procedural guidance, and outcomes. PMID- 22523060 TI - Enhancing immune responses to limit chronic immune activation during SIV. AB - The persistent immune activation that is typical of HIV-1 and SIV infection results in exhaustion and dysfunction of T and B cells; in T cells, this is marked by increased expression and signaling through the inhibitory receptor programmed death-1 (PD-1). Targeting this exhaustion pathway could result in improved antiviral immune responses, but there have been concerns that it would also lead to increased inflammation and immunopathology. In this issue of the JCI, Dyavar Shetty et al. demonstrate that blocking PD-1 actually reduced proinflammatory responses and improved immunity in the gut of SIV-infected rhesus macaques, suggesting that this might have therapeutic potential to prevent opportunistic infections in HIV-infected patients. PMID- 22523061 TI - Epidermal Langerhans cells tune skin reactivity to contact allergens. AB - Allergic contact dermatitis is a common disorder that has fascinated dermatologists and immunologists for decades. Extensive studies of contact sensitivity reactions in mice established a mechanistic paradigm that has been revisited in recent years, and the involvement of Langerhans cells (LCs), a population of epidermal dendritic cells, in immune responses to epicutaneously applied antigens has been questioned. In this issue of the JCI, Gomez de Aguero et al. describe an elegant series of experiments that implicate LCs in tolerance induction, positioning these cells as key regulators of immunologic barrier function. PMID- 22523062 TI - NADPH oxidase regulates efficacy of vaccination in aspergillosis. AB - Invasive aspergillosis is often a consequence of immune suppression, and accumulating evidence points to a role for adaptive immunity. Hence, it may be possible to manipulate the adaptive immune system to enhance protective immunity in at-risk individuals. In this issue of the JCI, De Luca and colleagues describe the ontogeny of adaptive immune responses to murine aspergillosis infection in relation to vaccination. Their thought-provoking findings reveal the complexities of vaccine-induced immunity and could be used to improve vaccine efficacy. PMID- 22523063 TI - Gene therapy: too much splice can spoil the dish. AB - The use of integrating vectors for gene therapy - required for stable correction of gene expression - carries the risk of insertional mutagenesis, which can lead to activation of a tumorigenic program. In this issue of the JCI, Moiani et al. and Cesana et al. investigate how viral vectors can induce aberrant splicing, resulting in chimeric cellular-viral transcripts. The finding that this is a general phenomenon is concerning, but some of their results do suggest approaches for the development of safeguards in gene therapy vector design. PMID- 22523064 TI - Whole transcriptome characterization of aberrant splicing events induced by lentiviral vector integrations. AB - Gamma-retroviral/lentiviral vectors (gammaRV/LV) with self-inactivating (SIN) long terminal repeats (LTRs) and internal moderate cellular promoters pose a reduced risk of insertional mutagenesis when compared with vectors with active LTRs. Yet, in a recent LV-based clinical trial for beta-thalassemia, vector integration within the HMGA2 gene induced the formation of an aberrantly spliced mRNA form that appeared to cause clonal dominance. Using a method that we developed, cDNA linear amplification-mediated PCR, in combination with high throughput sequencing, we conducted a whole transcriptome analysis of chimeric LV cellular fusion transcripts in transduced human lymphoblastoid cells and primary hematopoietic stem/progenitor cells. We observed a surprising abundance of read through transcription originating outside and inside the provirus and identified the vector sequences contributing to the aberrant splicing process. We found that SIN LV has a sharply reduced propensity to engage in aberrant splicing compared with that of vectors carrying active LTRs. Moreover, by recoding the identified vector splice sites, we reduced residual read-through transcription and demonstrated an effective strategy for improving vectors. Characterization of the mechanisms and genetic features underlying vector-induced aberrant splicing will enable the generation of safer vectors, with low impact on the cellular transcriptome. PMID- 22523065 TI - PD-1 blockade during chronic SIV infection reduces hyperimmune activation and microbial translocation in rhesus macaques. AB - Hyperimmune activation is a strong predictor of disease progression during pathogenic immunodeficiency virus infections and is mediated in part by sustained type I IFN signaling in response to adventitious microbial infection. The immune inhibitory receptor programmed death-1 (PD-1) regulates functional exhaustion of virus-specific CD8(+) T cells during chronic infections, and in vivo PD-1 blockade has been shown to improve viral control of SIV. Here, we show that PD-1 blockade during chronic SIV infection markedly reduced the expression of transcripts associated with type I IFN signaling in the blood and colorectal tissue of rhesus macaques (RMs). The effect of PD-1 blockade on type I IFN signaling was durable and persisted even under conditions of high viremia. Reduced type I IFN signaling was associated with enhanced expression of some of the junction-associated genes in colorectal tissue and with a profound decrease in plasma LPS levels, suggesting a possible repair of gut-associated junctions and decreased microbial translocation into the blood. PD-1 blockade enhanced immunity to gut-resident pathogenic bacteria, control of gut-associated opportunistic infections, and survival of SIV-infected RMs. Our results suggest PD-1 blockade as a potential novel therapeutic approach to enhance combination antiretroviral therapy by suppressing hyperimmune activation in HIV-infected individuals. PMID- 22523066 TI - CD4(+) T cell vaccination overcomes defective cross-presentation of fungal antigens in a mouse model of chronic granulomatous disease. AB - Aspergillus fumigatus is a model fungal pathogen and a common cause of infection in individuals with the primary immunodeficiency chronic granulomatous disease (CGD). Although primarily considered a deficiency of innate immunity, CGD is also linked to dysfunctional T cell reactivity. Both CD4(+) and CD8(+) T cells mediate vaccine-induced protection from experimental aspergillosis, but the molecular mechanisms leading to the generation of protective immunity and whether these mechanisms are dysregulated in individuals with CGD have not been determined. Here, we show that activation of either T cell subset in a mouse model of CGD is contingent upon the nature of the fungal vaccine, the involvement of distinct innate receptor signaling pathways, and the mode of antigen routing and presentation in DCs. Aspergillus conidia activated CD8(+) T cells upon sorting to the Rab14(+) endosomal compartment required for alternative MHC class I presentation. Cross-priming of CD8(+) T cells failed to occur in mice with CGD due to defective DC endosomal alkalinization and autophagy. However, long-lasting antifungal protection and disease control were successfully achieved upon vaccination with purified fungal antigens that activated CD4(+) T cells through the endosome/lysosome pathway. Our study thus indicates that distinct intracellular pathways are exploited for the priming of CD4(+) and CD8(+) T cells to A. fumigatus and suggests that CD4(+) T cell vaccination may be able to overcome defective antifungal CD8(+) T cell memory in individuals with CGD. PMID- 22523067 TI - Langerhans cells protect from allergic contact dermatitis in mice by tolerizing CD8(+) T cells and activating Foxp3(+) regulatory T cells. AB - Allergic contact dermatitis is the most frequent occupational disease in industrialized countries. It is caused by CD8(+) T cell-mediated contact hypersensitivity (CHS) reactions triggered at the site of contact by a variety of chemicals, also known as weak haptens, present in fragrances, dyes, metals, preservatives, and drugs. Despite the myriad of potentially allergenic substances that can penetrate the skin, sensitization is relatively rare and immune tolerance to the substance is often induced by as yet poorly understood mechanisms. Here we show, using the innocuous chemical 2,4 dinitrothiocyanobenzene (DNTB), that cutaneous immune tolerance in mice critically depends on epidermal Langerhans cells (LCs), which capture DNTB and migrate to lymph nodes for direct presentation to CD8(+) T cells. Depletion and adoptive transfer experiments revealed that LCs conferred protection from development of CHS by a mechanism involving both anergy and deletion of allergen specific CD8(+) T cells and activation of a population of T cells identified as ICOS(+)CD4(+)Foxp3(+) Tregs. Our findings highlight the critical role of LCs in tolerance induction in mice to the prototype innocuous hapten DNTB and suggest that strategies targeting LCs might be valuable for prevention of cutaneous allergy. PMID- 22523068 TI - Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization. AB - Serum calcium levels are tightly controlled by an integrated hormone-controlled system that involves active vitamin D [1,25(OH)(2)D], which can elicit calcium mobilization from bone when intestinal calcium absorption is decreased. The skeletal adaptations, however, are still poorly characterized. To gain insight into these issues, we analyzed the consequences of specific vitamin D receptor (Vdr) inactivation in the intestine and in mature osteoblasts on calcium and bone homeostasis. We report here that decreased intestinal calcium absorption in intestine-specific Vdr knockout mice resulted in severely reduced skeletal calcium levels so as to ensure normal levels of calcium in the serum. Furthermore, increased 1,25(OH)(2)D levels not only stimulated bone turnover, leading to osteopenia, but also suppressed bone matrix mineralization. This resulted in extensive hyperosteoidosis, also surrounding the osteocytes, and hypomineralization of the entire bone cortex, which may have contributed to the increase in bone fractures. Mechanistically, osteoblastic VDR signaling suppressed calcium incorporation in bone by directly stimulating the transcription of genes encoding mineralization inhibitors. Ablation of skeletal Vdr signaling precluded this calcium transfer from bone to serum, leading to better preservation of bone mass and mineralization. These findings indicate that in mice, maintaining normocalcemia has priority over skeletal integrity, and that to minimize skeletal calcium storage, 1,25(OH)(2)D not only increases calcium release from bone, but also inhibits calcium incorporation in bone. PMID- 22523069 TI - Lentiviral vector integration in the human genome induces alternative splicing and generates aberrant transcripts. AB - Retroviral vectors integrate in genes and regulatory elements and may cause transcriptional deregulation of gene expression in target cells. Integration into transcribed genes also has the potential to deregulate gene expression at the posttranscriptional level by interfering with splicing and polyadenylation of primary transcripts. To examine the impact of retroviral vector integration on transcript splicing, we transduced primary human cells or cultured cells with HIV derived vectors carrying a reporter gene or a human beta-globin gene under the control of a reduced-size locus-control region (LCR). Cells were randomly cloned and integration sites were determined in individual clones. We identified aberrantly spliced, chimeric transcripts in more than half of the targeted genes in all cell types. Chimeric transcripts were generated through the use of constitutive and cryptic splice sites in the HIV 5iota long terminal repeat and gag gene as well as in the beta-globin gene and LCR. Compared with constitutively spliced transcripts, most aberrant transcripts accumulated at a low level, at least in part as a consequence of nonsense-mediated mRNA degradation. A limited set of cryptic splice sites caused the majority of aberrant splicing events, providing a strategy for recoding lentiviral vector backbones and transgenes to reduce their potential posttranscriptional genotoxicity. PMID- 22523070 TI - Selective targeting of proteins within secretory pathway for endoplasmic reticulum-associated degradation. AB - The endoplasmic reticulum-associated degradation (ERAD) is a cellular quality control mechanism to dispose of misfolded proteins of the secretory pathway via proteasomal degradation. SEL1L is an ER-resident protein that participates in identification of misfolded molecules as ERAD substrates, therefore inducing their ER-to-cytosol retrotranslocation and degradation. We have developed a novel class of fusion proteins, termed degradins, composed of a fragment of SEL1L fused to a target-specific binding moiety located on the luminal side of the ER. The target-binding moiety can be a ligand of the target or derived from specific mAbs. Here, we describe the ability of degradins with two different recognition moieties to promote degradation of a model target. Degradins recognize the target protein within the ER both in secretory and membrane-bound forms, inducing their degradation following retrotranslocation to the cytosol. Thus, degradins represent an effective technique to knock-out proteins within the secretory pathway with high specificity. PMID- 22523071 TI - HBx protein of hepatitis B virus promotes reinitiation of DNA replication by regulating expression and intracellular stability of replication licensing factor CDC6. AB - Prevention of re-replication via negative regulation of replication initiator proteins, such as CDC6, is key to maintenance of genomic integrity, whereas their up-regulation is generally associated with perturbation in cell cycle, genomic instability, and potentially, tumorigenesis. The HBx oncoprotein of hepatitis B virus is well known to deregulate cell cycle and has been intricately linked to development of hepatocellular carcinoma. Despite a clear understanding of the proliferative effects of HBx on cell cycle, a mechanistic link between HBx mediated hepatocarcinogenesis and host cell DNA replication remains poorly perused. Here we show that HBx overexpression in both the cellular as well as the transgenic environment resulted in the accumulation of CDC6 through transcriptional and post-translational up-regulation. The HBx-mediated increase in CDK2 activity altered the E2F1-Rb (retinoblastoma) balance, which favored CDC6 gene expression by E2F1. Besides, HBx impaired the APC(Cdh1)-dependent protein degradation pathway and conferred intracellular stability to CDC6 protein. Increase in CDC6 levels correlated with increase in CDC6 occupancy on the beta globin origin of replication, suggesting increment in origin licensing and re replication. In conclusion, our findings strongly suggest a novel role for CDC6 in abetting the oncogenic sabotage carried out by HBx and support the paradigm that pre-replicative complex proteins have a role in oncogenic transformation. PMID- 22523072 TI - Asymmetry in the homodimeric ABC transporter MsbA recognized by a DARPin. AB - ABC transporters harness the energy from ATP binding and hydrolysis to translocate substrates across the membrane. Binding of two ATP molecules at the nucleotide binding domains (NBDs) leads to the formation of an outward-facing state. The conformational changes required to reset the transporter to the inward facing state are initiated by sequential hydrolysis of the bound nucleotides. In a homodimeric ABC exporter such as MsbA responsible for lipid A transport in Escherichia coli, sequential ATP hydrolysis implies the existence of an asymmetric conformation. Here we report the in vitro selection of a designed ankyrin repeat protein (DARPin) specifically binding to detergent-solubilized MsbA. Only one DARPin binds to the homodimeric transporter in the absence as well as in the presence of nucleotides, suggesting that it recognizes asymmetries in MsbA. DARPin binding increases the rate of ATP hydrolysis by a factor of two independent of the substrate-induced ATPase stimulation. Electron paramagnetic resonance (EPR) measurements are found to be in good agreement with the available crystal structures and reveal that DARPin binding does not affect the large nucleotide-driven conformational changes of MsbA. The binding epitope was mapped by cross-linking and EPR to the membrane-spanning part of the transmembrane domain (TMD). Using cross-linked DARPin-MsbA complexes, 8-azido-ATP was found to preferentially photolabel one chain of the homodimer, suggesting that the asymmetries captured by DARPin binding at the TMDs are propagated to the NBDs. This work demonstrates that in vitro selected binders are useful tools to study the mechanism of membrane proteins. PMID- 22523073 TI - Toll-like receptor 2 is required for LPS-induced Toll-like receptor 4 signaling and inhibition of ion transport in renal thick ascending limb. AB - Previously we demonstrated that basolateral LPS inhibits HCO(3)(-) absorption in the renal medullary thick ascending limb (MTAL) through TLR4-dependent ERK activation. Here we report that the response of the MTAL to basolateral LPS requires TLR2 in addition to TLR4. The basolateral addition of LPS (ultrapure Escherichia coli K12) decreased HCO(3)(-) absorption in isolated, perfused MTALs from wild-type mice but had no effect in MTALs from TLR2(-/-) mice. In contrast, inhibition of HCO(3)(-) absorption by lumen LPS was preserved in TLR2(-/-) MTALs, indicating that TLR2 is involved specifically in mediating the basolateral LPS response. LPS also did not increase ERK phosphorylation in MTALs from TLR2(-/-) mice. TLR2 deficiency had no effect on expression of TLR4, MD-2, or MyD88. However, LPS-induced recruitment of MyD88 to the basolateral membrane was impaired in TLR2(-/-) MTALs. Inhibition of HCO(3)(-) absorption by LPS did not require CD14. Co-immunoprecipitation studies demonstrated an association between TLR4 and TLR2. Inhibition of HCO(3)(-) absorption by TLR2-specific ligands was preserved in MTALs from TLR4(-/-) mice. These results indicate that the effect of basolateral LPS to inhibit HCO(3)(-) absorption in the MTAL through MyD88 dependent ERK activation depends on a novel interaction between TLR4 and TLR2. TLR2 plays a dual role in the induction of intracellular signals that impair MTAL function, both through cooperation with TLR4 to mediate ERK signaling by LPS and through a TLR4-independent signaling pathway activated by Gram-positive bacterial ligands. Regulation of TLR2 expression and its interaction with TLR4 may provide new mechanisms for controlling and therapeutic targeting of TLR4-mediated LPS responses. PMID- 22523074 TI - ARF6 activated by the LHCG receptor through the cytohesin family of guanine nucleotide exchange factors mediates the receptor internalization and signaling. AB - The luteinizing hormone chorionic gonadotropin receptor (LHCGR) is a G(s)-coupled GPCR that is essential for the maturation and function of the ovary and testis. LHCGR is internalized following its activation, which regulates the biological responsiveness of the receptor. Previous studies indicated that ADP-ribosylation factor (ARF)6 and its GTP-exchange factor (GEF) cytohesin 2 regulate LHCGR internalization in follicular membranes. However, the mechanisms by which ARF6 and cytohesin 2 regulate LHCGR internalization remain incompletely understood. Here we investigated the role of the ARF6 signaling pathway in the internalization of heterologously expressed human LHCGR (HLHCGR) in intact cells using a combination of pharmacological inhibitors, siRNA and the expression of mutant proteins. We found that human CG (HCG)-induced HLHCGR internalization, cAMP accumulation and ARF6 activation were inhibited by Gallein (betagamma inhibitor), Wortmannin (PI 3-kinase inhibitor), SecinH3 (cytohesin ARF GEF inhibitor), QS11 (an ARF GAP inhibitor), an ARF6 inhibitory peptide and ARF6 siRNA. However, Dynasore (dynamin inhibitor), the dominant negative mutants of NM23-H1 (dynamin activator) and clathrin, and PBP10 (PtdIns 4,5-P2-binding peptide) inhibited agonist-induced HLHCGR and cAMP accumulation but not ARF6 activation. These results indicate that heterotrimeric G-protein, phosphatidylinositol (PI) 3-kinase (PI3K), cytohesin ARF GEF and ARF GAP function upstream of ARF6 whereas dynamin and clathrin act downstream of ARF6 in the regulation of HCG-induced HLHCGR internalization and signaling. In conclusion, we have identified the components and molecular details of the ARF6 signaling pathway required for agonist-induced HLHCGR internalization. PMID- 22523075 TI - Allosteric regulation of GRASP protein-dependent Golgi membrane tethering by mitotic phosphorylation. AB - Mitotic phosphorylation of the conserved GRASP domain of GRASP65 disrupts its self-association, leading to a loss of Golgi membrane tethering, cisternal unlinking, and Golgi breakdown. Recently, the structural basis of the GRASP self interaction was determined, yet the mechanism by which phosphorylation disrupts this activity is unknown. Here, we present the crystal structure of a GRASP phosphomimic containing an aspartic acid substitution for a serine residue (Ser 189) that in GRASP65 is phosphorylated by PLK1, causing a block in membrane tethering and Golgi ribbon formation. The structure revealed a conformational change in the GRASP internal ligand that prevented its insertion into the PDZ binding pocket, and gel filtration assays showed that this phosphomimic mutant exhibited a significant reduction in dimer formation. Interestingly, the structure also revealed an apparent propagation of conformational change from the site of phosphorylation to the shifted ligand, and alanine substitution of two residues (Glu-145 and Ser-146) at penultimate positions in this chain rescued dimer formation by the phosphomimic. These data reveal the structural basis of the phosphoinhibition of GRASP-mediated membrane tethering and provide a mechanism for its allosteric regulation. PMID- 22523076 TI - Cysteine scanning mutagenesis and disulfide mapping analysis of arrangement of GspC and GspD protomers within the type 2 secretion system. AB - The type II secretion system (T2SS) secretes enzymes and toxins across the outer membrane of Gram-negative bacteria. The precise assembly of T2SS, which consists of at least 12 core-components called Gsp, remains unclear. The outer membrane secretin, GspD, forms the channels, through which folded proteins are secreted, and interacts with the inner membrane component, GspC. The periplasmic regions of GspC and GspD consist of several structural domains, HR(GspC) and PDZ(GspC), and N0(GspD) to N3(GspD), respectively, and recent structural and functional studies have proposed several interaction sites between these domains. We used cysteine mutagenesis and disulfide bonding analysis to investigate the organization of GspC and GspD protomers and to map their interaction sites within the secretion machinery of the plant pathogen Dickeya dadantii. At least three distinct GspC GspD interactions were detected, and they involve two sites in HR(GspC), two in N0(GspD), and one in N2(GspD). None of these interactions occurs through static interfaces because the same sites are also involved in self-interactions with equivalent neighboring domains. Disulfide self-bonding of critical interaction sites halts secretion, indicating the transient nature of these interactions. The secretion substrate diminishes certain interactions and provokes an important rearrangement of the HR(GspC) structure. The T2SS components OutE/L/M affect various interaction sites differently, reinforcing some but diminishing the others, suggesting a possible switching mechanism of these interactions during secretion. Disulfide mapping shows that the organization of GspD and GspC subunits within the T2SS could be compatible with a hexamer of dimers arrangement rather than an organization with 12-fold rotational symmetry. PMID- 22523077 TI - Silent scaffolds: inhibition OF c-Jun N-terminal kinase 3 activity in cell by dominant-negative arrestin-3 mutant. AB - We established a new in vivo arrestin-3-JNK3 interaction assay based on bioluminescence resonance energy transfer (BRET) between JNK3-luciferase and Venus-arrestins. We tested the ability of WT arrestin-3 and its 3A mutant that readily binds beta2-adrenergic receptors as well as two mutants impaired in receptor binding, Delta7 and KNC, to directly bind JNK3 and to promote JNK3 phosphorylation in cells. Both receptor binding-deficient mutants interact with JNK3 significantly better than WT and 3A arrestin-3. WT arrestin-3 and Delta7 mutant robustly promoted JNK3 activation, whereas 3A and KNC mutants did not. Thus, receptor binding, JNK3 interaction, and JNK3 activation are three distinct arrestin functions. We found that the KNC mutant, which tightly binds ASK1, MKK4, and JNK3 without facilitating JNK3 phosphorylation, has a dominant-negative effect, competitively decreasing JNK activation by WT arrestin-3. Thus, KNC is a silent scaffold, a novel type of molecular tool for the suppression of MAPK signaling in living cells. PMID- 22523079 TI - The FKBP38 catalytic domain binds to Bcl-2 via a charge-sensitive loop. AB - FKBP38 is a regulator of the prosurvival protein Bcl-2, but in the absence of detailed structural insights, the molecular mechanism of the underlying interaction has remained unknown. Here, we report the contact regions between Bcl 2 and the catalytic domain of FKBP38 derived by heteronuclear NMR spectroscopy. The data reveal that a previously identified charge-sensitive loop near the putative active site of FKBP38 is mainly responsible for Bcl-2 binding. The corresponding binding epitope of Bcl-2 could be identified via a peptide library based membrane assay. Site-directed mutagenesis of the key residues verified the contact sites of this electrostatic protein/protein interaction. The derived structure model of the complex between Bcl-2 and the FKBP38 catalytic domain features both electrostatic and hydrophobic intermolecular contacts and provides a rationale for the regulation of the FKBP38/Bcl-2 interaction by Ca(2+). PMID- 22523078 TI - Microphthalmia-associated transcription factor (MITF) promotes differentiation of human retinal pigment epithelium (RPE) by regulating microRNAs-204/211 expression. AB - The retinal pigment epithelium (RPE) plays a fundamental role in maintaining visual function and dedifferentiation of RPE contributes to the pathophysiology of several ocular diseases. To identify microRNAs (miRNAs) that may be involved in RPE differentiation, we compared the miRNA expression profiles of differentiated primary human fetal RPE (hfRPE) cells to dedifferentiated hfRPE cells. We found that miR-204/211, the two most highly expressed miRNAs in the RPE, were significantly down-regulated in dedifferentiated hfRPE cells. Importantly, transfection of pre-miR-204/211 into hfRPE cells promoted differentiation whereas adding miR-204/211 inhibitors led to their dedifferentiation. Microphthalmia-associated transcription factor (MITF) is a key regulator of RPE differentiation that was also down-regulated in dedifferentiated hfRPE cells. MITF knockdown decreased miR-204/211 expression and caused hfRPE dedifferentiation. Significantly, co-transfection of MITF siRNA with pre-miR 204/211 rescued RPE phenotype. Collectively, our data show that miR-204/211 promote RPE differentiation, suggesting that miR-204/211-based therapeutics may be effective treatments for diseases that involve RPE dedifferentiation such as proliferative vitreoretinopathy. PMID- 22523080 TI - Dynamics and Distribution of Klothobeta (KLB) and fibroblast growth factor receptor-1 (FGFR1) in living cells reveal the fibroblast growth factor-21 (FGF21) induced receptor complex. AB - FGF21 stimulates FGFR1c activity in cells that co-express Klothobeta (KLB); however, relatively little is known about the interaction of these receptors at the plasma membrane. We measured the dynamics and distribution of fluorescent protein-tagged KLB and FGFR1c in living cells using fluorescence recovery after photobleaching and number and brightness analysis. We confirmed that fluorescent protein-tagged KLB translocates to the plasma membrane and is active when co expressed with FGFR1c. FGF21-induced signaling was enhanced in cells treated with lactose, a competitive inhibitor of the galectin lattice, suggesting that lattice binding modulates KLB and/or FGFR1c activity. Fluorescence recovery after photobleaching analysis consistently revealed that lactose treatment increased KLB mobility at the plasma membrane, but did not affect the mobility of FGFR1c. The association of endogenous KLB with the galectin lattice was also confirmed by co-immunoprecipitation with galectin-3. KLB mobility increased when co-expressed with FGFR1c, suggesting that the two receptors form a heterocomplex independent of the galectin lattice. Number and brightness analysis revealed that KLB and FGFR1c behave as monomers and dimers at the plasma membrane, respectively. Co expression resulted in monomeric expression of KLB and FGFR1c consistent with formation of a 1:1 heterocomplex. Subsequent addition of FGF21 induced FGFR1 dimerization without changing KLB aggregate size, suggesting formation of a 1:2 KLB-FGFR1c signaling complex. Overall, these data suggest that KLB and FGFR1 form a 1:1 heterocomplex independent of the galectin lattice that transitions to a 1:2 complex upon the addition of FGF21. PMID- 22523081 TI - Quadriceps activation failure after anterior cruciate ligament rupture is not mediated by knee joint effusion. AB - STUDY DESIGN: Descriptive prospective cohort study. OBJECTIVES: To investigate the relationships between knee joint effusion, quadriceps activation, and quadriceps strength. These relationships may help clinicians better identify impaired quadriceps activation. BACKGROUND: After anterior cruciate ligament (ACL) injury, the involved quadriceps may demonstrate weakness. Experimental data have shown that quadriceps activation and strength may be directly mediated by intracapsular joint pressure created by saline injection. An inverse relationship between quadriceps activation and the amount of saline injected has been reported. This association has not been demonstrated for traumatic effusion. We hypothesized that traumatic joint effusion due to ACL rupture and postinjury quadriceps strength would correlate well with quadriceps activation, allowing clinicians to use effusion and strength measurement as a surrogate for electrophysiological assessment of quadriceps activation. METHODS: Prospective data were collected on 188 patients within 100 days of ACL injury (average, 27 days) referred from a single surgeon. A complete clinical evaluation of the knee was performed, including ligamentous assessment and assessment of range of motion and effusion. Quadriceps function was electrophysiologically assessed using maximal volitional isometric contraction and burst superimposition techniques to quantify both strength and activation. RESULTS: Effusion grade did not correlate with quadriceps central activation ratio (CAR) (zero effusion: mean +/- SD CAR, 93.5% +/- 5.8%; trace effusion: CAR, 93.8% +/- 9.5%; 1+ effusion: CAR, 94.0% +/- 7.5%; 2+/3+ effusion: CAR, 90.6% +/- 11.1%). These values are lower than normative data from healthy subjects (CAR, 98% +/- 3%). CONCLUSION: Joint effusion after ACL injury does not directly mediate quadriceps activation failure seen after injury. Therefore, it should not be used as a clinical substitute for electrophysiological assessment of quadriceps activation. Patients presenting to physical therapy after ACL injury should be treated with high-intensity neuromuscular electrical stimulation to help normalize this activation. PMID- 22523083 TI - DNA origami as biocompatible surface to match single-molecule and ensemble experiments. AB - Single-molecule experiments on immobilized molecules allow unique insights into the dynamics of molecular machines and enzymes as well as their interactions. The immobilization, however, can invoke perturbation to the activity of biomolecules causing incongruities between single molecule and ensemble measurements. Here we introduce the recently developed DNA origami as a platform to transfer ensemble assays to the immobilized single molecule level without changing the nano environment of the biomolecules. The idea is a stepwise transfer of common functional assays first to the surface of a DNA origami, which can be checked at the ensemble level, and then to the microscope glass slide for single-molecule inquiry using the DNA origami as a transfer platform. We studied the structural flexibility of a DNA Holliday junction and the TATA-binding protein (TBP)-induced bending of DNA both on freely diffusing molecules and attached to the origami structure by fluorescence resonance energy transfer. This resulted in highly congruent data sets demonstrating that the DNA origami does not influence the functionality of the biomolecule. Single-molecule data collected from surface immobilized biomolecule-loaded DNA origami are in very good agreement with data from solution measurements supporting the fact that the DNA origami can be used as biocompatible surface in many fluorescence-based measurements. PMID- 22523082 TI - Retargeting transposon insertions by the adeno-associated virus Rep protein. AB - The Sleeping Beauty (SB), piggyBac (PB) and Tol2 transposons are promising instruments for genome engineering. Integration site profiling of SB, PB and Tol2 in human cells showed that PB and Tol2 insertions were enriched in genes, whereas SB insertions were randomly distributed. We aimed to introduce a bias into the target site selection properties of the transposon systems by taking advantage of the locus-specific integration system of adeno-associated virus (AAV). The AAV Rep protein binds to Rep recognition sequences (RRSs) in the human genome, and mediates viral integration into nearby sites. A series of fusion constructs consisting of the N-terminal DNA-binding domain of Rep and the transposases or the N57 domain of SB were generated. A plasmid-based transposition assay showed that Rep/SB yielded a 15-fold enrichment of transposition at a particular site near a targeted RRS. Genome-wide insertion site analysis indicated that an approach based on interactions between the SB transposase and Rep/N57 enriched transgene insertions at RRSs. We also provide evidence of biased insertion of the PB and Tol2 transposons. This study provides a comparative insight into target site selection properties of transposons, as well as proof-of-principle for targeted chromosomal transposition by composite protein-protein and protein-DNA interactions. PMID- 22523084 TI - Dissociation from DNA of Type III Restriction-Modification enzymes during helicase-dependent motion and following endonuclease activity. AB - DNA cleavage by the Type III Restriction-Modification (RM) enzymes requires the binding of a pair of RM enzymes at two distant, inversely orientated recognition sequences followed by helicase-catalysed ATP hydrolysis and long-range communication. Here we addressed the dissociation from DNA of these enzymes at two stages: during long-range communication and following DNA cleavage. First, we demonstrated that a communicating species can be trapped in a DNA domain without a recognition site, with a non-specific DNA association lifetime of ~ 200 s. If free DNA ends were present the lifetime became too short to measure, confirming that ends accelerate dissociation. Secondly, we observed that Type III RM enzymes can dissociate upon DNA cleavage and go on to cleave further DNA molecules (they can 'turnover', albeit inefficiently). The relationship between the observed cleavage rate and enzyme concentration indicated independent binding of each site and a requirement for simultaneous interaction of at least two enzymes per DNA to achieve cleavage. In light of various mechanisms for helicase-driven motion on DNA, we suggest these results are most consistent with a thermally driven random 1D search model (i.e. 'DNA sliding'). PMID- 22523085 TI - PocketQuery: protein-protein interaction inhibitor starting points from protein protein interaction structure. AB - PocketQuery (http://pocketquery.csb.pitt.edu) is a web interface for exploring the properties of protein-protein interaction (PPI) interfaces with a focus on the discovery of promising starting points for small-molecule design. PocketQuery rapidly focuses attention on the key interacting residues of an interaction using a 'druggability' score that provides an estimate of how likely the chemical mimicry of a cluster of interface residues would result in a small-molecule inhibitor of an interaction. These residue clusters are chemical starting points that can be seamlessly exported to a pharmacophore-based drug discovery workflow. PocketQuery is updated on a weekly basis to contain all applicable PPI structures deposited in the Protein Data Bank and allows users to upload their own custom structures for analysis. PMID- 22523088 TI - Diagnosis of primary task-specific lower extremity dystonia in a runner. AB - STUDY DESIGN: Resident's case problem. BACKGROUND: A 56-year-old man was referred to physical therapy for analysis of unusual gait, first noticed 3 years previously when running. Prior to this evaluation, the patient had seen multiple orthopaedic, sports medicine, and neurological specialists while undergoing repeated and extensive testing. Ten months of testing and treatment, including conservative and surgical management, did not provide an explanation for the gait abnormality or result in improvement of the patient's condition. DIAGNOSIS: The patient's physical examination was relatively unremarkable, considering the severity of the gait abnormality. Distinct abnormalities were apparent with computerized gait analysis and dynamic electromyography, and, when combined with the physical examination findings, led to a suspicion of the task-specific disorder of runner's dystonia. The patient was referred to a neurologist specializing in movement-related disorders, with a final confirmed diagnosis of primary task-specific dystonia with first onset during running (ie, runner's dystonia). DISCUSSION: Idiopathic, task-specific dystonia of the lower extremity is documented as a very rare occurrence, yet increasing trends in running participation may result in a higher incidence of this condition. Improved awareness of runner's dystonia in the present case might have enhanced the clinical decision-making process and resulted in more timely and effective treatment solutions. Clinical examination findings, including computerized gait analysis and electromyography, in conjunction with imaging, blood, and genetic testing, can aid in the diagnosis of runner's dystonia. LEVEL OF EVIDENCE: Differential diagnosis, level 4. PMID- 22523086 TI - Gene variants in the angiogenesis pathway and prostate cancer. AB - Although the causes of prostate cancer are still unknown, numerous studies support the role of genetic factors in the development and progression of this disease. Single nucleotide polymorphisms (SNPs) in key angiogenesis genes have been studied in prostate cancer. In this review, we provide an overview of the current knowledge of the role of genetic variants in the angiogenesis pathway in prostate cancer risk and progression. Of the 17 prostate cancer genome-wide association studies (GWAS) conducted to date, only one identified disease associated SNPs in a region of an angiogenesis pathway gene. An association was observed between aggressive disease and three intergenic SNPs (rs11199874, rs10749408 and rs10788165) in a region on chromosome 10q26 that encompasses FGFR2. The majority (27/32, 84.4%) of primary candidate gene studies reviewed had a small (n < 800, 20/32, 62.5%) to medium sample size (n = 800-2000, 7/32, 21.9%), whereas only five (15.6%) had a large sample size (n >= 2000). Results from the large studies revealed associations with risk and aggressive disease for SNPs in NOS2A, NOS3 and MMP-2 and risk for HIF1-alpha. Meta-analyses have so far been conducted on FGFR2, TGF-beta, TNF-alpha, HIF1-alpha and IL10 and the results reveal an association with risk for SNPs in FGFR2 and TGF-beta and aggressive disease for SNPs in IL-10. Thus, existing evidence from GWAS and large candidate gene studies indicates that SNPs from a limited number of angiogenesis pathway genes are associated with prostate cancer risk and progression. PMID- 22523089 TI - Spontaneous dimerization of titin protein Z1Z2 domains induces strong nanomechanical anchoring. AB - Muscle elasticity strongly relies on the mechanical anchoring of the giant protein titin to both the sarcomere M-band and the Z-disk. Such strong attachment ensures the reversible dynamics of the stretching-relaxing cycles determining the muscle passive elasticity. Similarly, the design of biomaterials with enhanced elastic function requires experimental strategies able to secure the constituent molecules to avoid mechanical failure. Here we show that an engineered titin mimicking protein is able to spontaneously dimerize in solution. Our observations reveal that the titin Z1Z2 domains are key to induce dimerization over a long range distance in proteins that would otherwise remain in their monomeric form. Using single molecule force spectroscopy, we measure the threshold force that triggers the noncovalent transition from protein dimer to monomer, occurring at ~700 piconewtons. Such extremely high mechanical stability is likely to be a natural protective mechanism that guarantees muscle integrity. We propose a simple molecular model to understand the force-induced dimer-to-monomer transition based on the geometric distribution of forces occurring within a dimeric protein under mechanical tension. PMID- 22523090 TI - Short-term effects of kinesio taping versus cervical thrust manipulation in patients with mechanical neck pain: a randomized clinical trial. AB - STUDY DESIGN: Randomized clinical trial. OBJECTIVE: To compare the effectiveness of cervical spine thrust manipulation to that of Kinesio Taping applied to the neck in individuals with mechanical neck pain, using self-reported pain and disability and cervical range of motion as measures. BACKGROUND: The effectiveness of cervical manipulation has received considerable attention in the literature. However, because some patients cannot tolerate cervical thrust manipulation, alternative therapeutic options should be investigated. METHODS: Eighty patients (36 women) were randomly assigned to 1 of 2 groups: the manipulation group, which received 2 cervical thrust manipulations, and the tape group, which received Kinesio Taping applied to the neck. Neck pain (11-point numeric pain rating scale), disability (Neck Disability Index), and cervical range-of-motion data were collected at baseline and 1 week after the intervention by an assessor blinded to the treatment allocation of the patients. Mixed-model analyses of variance were used to examine the effects of the treatment on each outcome variable, with group as the between-subjects variable and time as the within-subjects variable. The primary analysis was the group-by-time interaction. RESULTS: No significant group-by-time interactions were found for pain (F = 1.892, P = .447) or disability (F = 0.115, P = .736). The group-by-time interaction was statistically significant for right (F = 7.317, P = .008) and left (F = 9.525, P = .003) cervical rotation range of motion, with the patients who received the cervical thrust manipulation having experienced greater improvement in cervical rotation than those treated with Kinesio Tape (P<.01). No significant group-by-time interactions were found for cervical spine range of motion for flexion (F = 0.944, P = .334), extension (F = 0.122, P = .728), and right (F = 0.220, P = .650) and left (F = 0.389, P = .535) lateral flexion. CONCLUSION: Patients with mechanical neck pain who received cervical thrust manipulation or Kinesio Taping exhibited similar reductions in neck pain intensity and disability and similar changes in active cervical range of motion, except for rotation. Changes in neck pain surpassed the minimal clinically important difference, whereas changes in disability did not. Changes in cervical range of motion were small and not clinically meaningful. Because we did not include a control or placebo group in this study, we cannot rule out a placebo effect or natural changes over time as potential reasons for the improvements measured in both groups. LEVEL OF EVIDENCE: Therapy, level 1b. PMID- 22523087 TI - Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer. AB - Four loci have been associated with pancreatic cancer through genome-wide association studies (GWAS). Pathway-based analysis of GWAS data is a complementary approach to identify groups of genes or biological pathways enriched with disease-associated single-nucleotide polymorphisms (SNPs) whose individual effect sizes may be too small to be detected by standard single-locus methods. We used the adaptive rank truncated product method in a pathway-based analysis of GWAS data from 3851 pancreatic cancer cases and 3934 control participants pooled from 12 cohort studies and 8 case-control studies (PanScan). We compiled 23 biological pathways hypothesized to be relevant to pancreatic cancer and observed a nominal association between pancreatic cancer and five pathways (P < 0.05), i.e. pancreatic development, Helicobacter pylori lacto/neolacto, hedgehog, Th1/Th2 immune response and apoptosis (P = 2.0 * 10( 6), 1.6 * 10(-5), 0.0019, 0.019 and 0.023, respectively). After excluding previously identified genes from the original GWAS in three pathways (NR5A2, ABO and SHH), the pancreatic development pathway remained significant (P = 8.3 * 10( 5)), whereas the others did not. The most significant genes (P < 0.01) in the five pathways were NR5A2, HNF1A, HNF4G and PDX1 for pancreatic development; ABO for H.pylori lacto/neolacto; SHH for hedgehog; TGFBR2 and CCL18 for Th1/Th2 immune response and MAPK8 and BCL2L11 for apoptosis. Our results provide a link between inherited variation in genes important for pancreatic development and cancer and show that pathway-based approaches to analysis of GWAS data can yield important insights into the collective role of genetic risk variants in cancer. PMID- 22523091 TI - Evidence for FHL1 as a novel disease gene for isolated hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric left ventricular hypertrophy, diastolic dysfunction and myocardial disarray. HCM is caused by mutations in sarcomeric genes, but in >40% of patients, the mutation is not yet identified. We hypothesized that FHL1, encoding four-and-a-half-LIM domains 1, could be another disease gene since it has been shown to cause distinct myopathies, sometimes associated with cardiomyopathy. We evaluated 121 HCM patients, devoid of a mutation in known disease genes. We identified three novel variants in FHL1 (c.134delA/K45Sfs, c.459C>A/C153X and c.827G>C/C276S). Whereas the c.459C>A variant was associated with muscle weakness in some patients, the c.134delA and c.827G>C variants were associated with isolated HCM. Gene transfer of the latter variants in C2C12 myoblasts and cardiac myocytes revealed reduced levels of FHL1 mutant proteins, which could be rescued by proteasome inhibition. Contractility measurements after adeno-associated virus transduction in rat engineered heart tissue (EHT) showed: (i) higher and lower forces of contraction with K45Sfs and C276S, respectively, and (ii) prolonged contraction and relaxation with both mutants. All mutants except one activated the fetal hypertrophic gene program in EHT. In conclusion, this study provides evidence for FHL1 to be a novel gene for isolated HCM. These data, together with previous findings of proteasome impairment in HCM, suggest that FHL1 mutant proteins may act as poison peptides, leading to hypertrophy, diastolic dysfunction and/or altered contractility, all features of HCM. PMID- 22523093 TI - Human DJ-1 and its homologs are novel glyoxalases. AB - Human DJ-1 is a genetic cause of early-onset Parkinson's disease (PD), although its biochemical function is unknown. We report here that human DJ-1 and its homologs of the mouse and Caenorhabditis elegans are novel types of glyoxalase, converting glyoxal or methylglyoxal to glycolic or lactic acid, respectively, in the absence of glutathione. Purified DJ-1 proteins exhibit typical Michaelis Menten kinetics, which were abolished completely in the mutants of essential catalytic residues, consisting of cysteine and glutamic acid. The presence of DJ 1 protected mouse embryonic fibroblast and dopaminergically derived SH-SY5Y cells from treatments of glyoxals. Likewise, C. elegans lacking cDJR-1.1, a DJ-1 homolog expressed primarily in the intestine, protected worms from glyoxal induced death. Sub-lethal doses of glyoxals caused significant degeneration of the dopaminergic neurons in C. elegans lacking cDJR-1.2, another DJ-1 homolog expressed primarily in the head region, including neurons. Our findings that DJ-1 serves as scavengers for reactive carbonyl species may provide a new insight into the causation of PD. PMID- 22523092 TI - Calpain and STriatal-Enriched protein tyrosine phosphatase (STEP) activation contribute to extrasynaptic NMDA receptor localization in a Huntington's disease mouse model. AB - In Huntington's disease (HD), the mutant huntingtin (mhtt) protein is associated with striatal dysfunction and degeneration. Excitotoxicity and early synaptic defects are attributed, in part, to altered NMDA receptor (NMDAR) trafficking and function. Deleterious extrasynaptic NMDAR localization and signalling are increased early in yeast artificial chromosome mice expressing full-length mhtt with 128 polyglutamine repeats (YAC128 mice). NMDAR trafficking at the plasma membrane is regulated by dephosphorylation of the NMDAR subunit GluN2B tyrosine 1472 (Y1472) residue by STriatal-Enriched protein tyrosine Phosphatase (STEP). NMDAR function is also regulated by calpain cleavage of the GluN2B C-terminus. Activation of both STEP and calpain is calcium-dependent, and disruption of calcium homeostasis occurs early in the HD striatum. Here, we show increased calpain cleavage of GluN2B at both synaptic and extrasynaptic sites, and elevated extrasynaptic total GluN2B expression in the YAC128 striatum. Calpain inhibition significantly reduced extrasynaptic GluN2B expression in the YAC128 but not wild type striatum. Furthermore, calpain inhibition reduced whole-cell NMDAR current and the surface/internal GluN2B ratio in co-cultured striatal neurons, without affecting synaptic GluN2B localization. Synaptic STEP activity was also significantly higher in the YAC128 striatum, correlating with decreased GluN2B Y1472 phosphorylation. A substrate-trapping STEP protein (TAT-STEP C-S) significantly increased VGLUT1-GluN2B colocalization, as well as increasing synaptic GluN2B expression and Y1472 phosphorylation. Moreover, combined calpain inhibition and STEP inactivation reduced extrasynaptic, while increasing synaptic GluN2B expression in the YAC128 striatum. These results indicate that increased STEP and calpain activation contribute to altered NMDAR localization in an HD mouse model, suggesting new therapeutic targets for HD. PMID- 22523094 TI - Clinical and radiological investigation of thoracic spine extension motion during bilateral arm elevation. AB - STUDY DESIGN: Single-cohort laboratory-based study. OBJECTIVES: To measure thoracic spine extension motion during bilateral arm elevation using functional radiography and photographic image analysis. BACKGROUND: Impairment of thoracic spine extension motion may impact shoulder girdle function. Motion of the thoracic spine during arm movement has not been directly measured using functional radiographic analysis. METHODS: In 21 asymptomatic men, thoracic kyphosis was measured in neutral standing and in end-range bilateral arm elevation, using lateral radiographs and photographic image analysis. Using both measurement techniques, the difference in thoracic kyphosis between the 2 body positions was used to quantify the range of extension motion of the thoracic spine. Bland-Altman plots were used to examine the agreement between measurement techniques. The relationship between the amount of thoracic kyphosis in neutral standing and kyphosis in full bilateral arm elevation was also examined. RESULTS: The mean +/- SD increase in thoracic extension with bilateral arm elevation was 12.8 degrees +/- 7.6 degrees and 10.5 degrees +/- 4.4 degrees , when measured from the radiographs and photographs, respectively. There was a significant correlation between the radiographic and photographic measurements of the amount of thoracic kyphosis measured in neutral posture (r = 0.71, P<.01) and for the kyphosis measured in full bilateral arm elevation (r = 0.79, P<.001). The mean difference between the 2 measurement techniques was 2.1 degrees for kyphosis measured in neutral posture and 0.5 degrees when measured in full bilateral arm elevation. The thoracic kyphosis angle measured in neutral posture was strongly correlated with the thoracic kyphosis angle measured in full bilateral arm elevation when measured with both radiographic (r = 0.80, P<.001) and photographic (r = 0.84, P<.001) techniques. CONCLUSION: In asymptomatic men, bilateral arm elevation is associated with movement of the thoracic spine toward extension, but the amount of movement is variable among individuals. PMID- 22523095 TI - Tbx3: a new trick for an 'old' myocyte? PMID- 22523096 TI - Tear trough deformity: review of anatomy and treatment options. AB - The lower eyelid can be a challenging area in facial rejuvenation. While lower eyelid bags are commonly the reason that patients present for lower eyelid rejuvenation, a separate entity known as a tear trough deformity may occur in conjunction with lower eyelid bags or alone. In this article, the authors outline the current understanding of the tear trough anatomy; describe multiple classification systems, which provide an objective means of evaluating the deformity and aid the surgeon in choosing appropriate treatment options; and review surgical and nonsurgical techniques for correcting the tear trough deformity. Treatment options include hyaluronic acid filler, fat grafting, skeletal implants, and fat transposition. Each procedure is associated with advantages and disadvantages, and each should be considered more complex than traditional lower blepharoplasty alone. While lower blepharoplasty removes excess fat and may tighten the anterior lamella, tear trough procedures require the addition of volume to the underlying depression. These procedures requiring release of the ligamentous structures and orbicularis (of which the tear trough is composed), as well as fat transposition or fat grafting, are associated with additional complications, which are also reviewed. PMID- 22523097 TI - Blepharoplasty in senile blepharoptosis: preoperative measurements and design for skin excision. AB - BACKGROUND: For patients with senile ptosis, aesthetic blepharoplasty can be combined with ptosis surgery. However, the amount of skin excision necessary in blepharoplasty is not clearly defined by measurements of the upper eyelids. OBJECTIVES: The authors preoperatively evaluate the amount of skin to be excised in blepharoplasty. METHODS: Fifty patients with bilateral senile ptosis were included in this study. The amount of skin to be excised from the upper eyelids was selected based on preoperative measurements of redundant skin, equivalent to the maximum lid height (MLH) while manually stretching the eyelid upwards minus resting lid height (RLH) with the eyes closed passively. Ptosis surgery (such as plication of the aponeurosis) followed blepharoplasty. RESULTS: Preoperatively, mean MLH was 35 mm on the right and 36 mm on the left. Mean RLH was 25 mm bilaterally. The mean amount (height) of excised skin was 10 mm on the right and 11 mm on the left. At six months postoperatively, mean MLH and RLH were 29 and 23 mm on both sides, respectively. Significant differences between pre- and postoperative MLH and RDH were seen on both sides (P<.001). No complications due to overexcision were observed, but revision was performed for two patients with asymmetry of the lid folds and five patients with recurrence of drooping. CONCLUSIONS: Preoperative measurements of upper eyelid heights (stretched and at rest) appear useful in determining the amount of skin excision required in blepharoplasty for senile ptosis. LEVEL OF EVIDENCE: 4. PMID- 22523098 TI - Anatomic and anthropometric analysis of 72 lower lateral nasal cartilages from fresh Persian (Iranian) cadavers. AB - BACKGROUND: Understanding the anatomy of nasal cartilage, which varies by ethnic group, is important for surgical correction of nasal tip deformities. OBJECTIVES: The authors measure the size and shape of the lower lateral cartilages (LLC) in Persian cadavers to provide summary guidelines. METHODS: A total of 72 cartilage dissections were performed on 36 fresh Persian cadavers. All soft tissue was removed from the lateral crura cartilages. The lateral, middle, and medial distances from the caudal edge of the lateral crus to the alar rim were measured at the junction of the middle and lateral crura. Measurements were obtained for alar cartilage, alar flaring, divergence angle, and other parameters. Comparisons were made between sexes and select ethnic groups. RESULTS: Significant gender differences were observed for the middle (P=.03) and medial crura (P=.02), but not the lateral crura (P=.05). Approximately 87% of lateral crura were convex, and 86% of middle crura were flat. The medial crus was convex in 58.3% of the cadavers, with no significant gender difference. We noted occasional asymmetry between the middle and medial crura. Measurements for Persians differed from those of Asians and African Americans, but were similar to those of Caucasians. The shape of Persian alar cartilage is distinct from other ethnicities. CONCLUSIONS: Alar cartilage anatomy varies across ethnic groups, and attention to the differences is recommended during preoperative planning and intraoperative technique when treating the nasal tip. PMID- 22523099 TI - Commentary on: Anatomic and anthropometric analysis of 72 lower lateral nasal cartilages from fresh Persian (Iranian) cadavers. PMID- 22523100 TI - Effect of incision choice on outcomes in primary breast augmentation. AB - BACKGROUND: Capsular contracture (CC) is the most common complication following primary breast augmentation and one of the most common causes of reoperation. Various studies have suggested certain risk factors, including incision choice. OBJECTIVES: The authors investigate a possible association between the three most common breast augmentation incisions (inframammary, periareolar, and transaxillary) and CC. METHODS: The authors conducted a retrospective chart review of 197 primary breast augmentation patients treated between 2003 and 2009. Significant CC was determined to have occurred if the patient required reoperation for her CC. Patients were excluded if they underwent an augmentation/mastopexy, had previously undergone breast surgery, or received shaped silicone gel implants. CC rates were analyzed on a per-patient basis with Fisher's exact test and on a per-breast basis with the Rao-Scott chi-squared test. RESULTS: One hundred eighty-three patients (336 augmented breasts) were included. Average patient age was 36.5 years. Mean follow-up was 392.6 days. Surgical complications included six breasts with CC (1.8%), three with hematoma (0.9%), and one with an infection (0.3%). Transaxillary incisions produced the highest incidence of contracture (6.4%), followed by periareolar (2.4%) and inframammary (0.5%). There was a statistically-significant difference in the incidence of CC among the three incision sites (P=.03). The increased rate seen with transaxillary incisions versus inframammary incisions was also statistically significant. No significant association between implant fill material and contracture was found (P=.27). CONCLUSIONS: The risk of CC is significantly higher with transaxillary incisions than with periareolar or inframammary incisions. LEVEL OF EVIDENCE: 4. PMID- 22523101 TI - Commentary on: Effect of incision choice on outcomes in primary breast augmentation. PMID- 22523102 TI - Secondary augmentation mammaplasties and periprosthetic infection: a three-year retrospective review. AB - BACKGROUND: Secondary or revision surgery following primary augmentation mammaplasty is common. There are several published studies on the incidence and prevention of infection after primary augmentation mammaplasty, but there is a paucity of information on the incidence of periprosthetic infection after secondary or revision augmentation mammaplasty procedures. OBJECTIVES: The author evaluates the incidence of periprosthetic infection in a series of revision and secondary mammaplasty patients from his practice. METHODS: A retrospective review was performed of the charts for 92 consecutive patients who underwent bilateral secondary mammaplasty with the author between July 2008 and April 2011. Each breast was taken as a single unit, for a total of 184 breasts. The data were compiled and compared with previous studies related to periprosthetic infection following primary augmentation mammaplasty. RESULTS: The average age of the patients was 35.8+/-7.9 years (range, 19-54 years). One patient developed unilateral periprosthetic infection in her left breast. This incidence of 0.54% was comparable to infection incidence of 0.5% for primary augmentation mammaplasty previously reported by the author. CONCLUSIONS: In this series, there was no higher incidence of infection seen in secondary augmentation mammaplasty than was seen in previous studies on primary mammaplasty. LEVEL OF EVIDENCE: 4. PMID- 22523103 TI - Commentary on: Outpatient-based massive weight loss body contouring: a review of 260 consecutive cases. PMID- 22523104 TI - Commentary on: Outpatient-based massive weight loss body contouring: a review of 260 consecutive cases. PMID- 22523105 TI - A Snapshot of ASJ Reader Opinions. PMID- 22523106 TI - The table tilt: preventing traction on the brachial plexus during facelift surgery. PMID- 22523107 TI - Recent progress in positron emission tomography concerning diagnosis and treatment of lung cancer. PMID- 22523108 TI - Alzheimer's disease: is pacemaker implantation safe? AB - AIM: To evaluate the safety of pacemaker implantation in patients with Alzheimer's disease (AD). METHODS: We reviewed all cases admitted to our institution between January 2008 and June 2009, with symptomatic bradyarrhythmia for whom a permanent pacemaker was implanted. Beginning in June 2009, we prospectively collected data from all patients with the same diagnosis and procedure. Patients with a diagnosis of AD were included in the study. The risks and frequency of complications due to the pacemaker implantation were evaluated. Because of the older age of patients, they were divided into 2 groups to define the effect of age on complication rate. Group 1 consisted of patients aged <75 years, and group 2 consisted of those who are >=75 years. RESULTS: Among the 574 patients with permanent pacemaker, 20 patients (3.4%) had a diagnosis of AD. Three patients with an AD experienced a complication and all were in group 2. However, the rate of complication was not significant within groups (P = 1.000). Reoperation was needed for all of them, and it was significantly higher in patients with AD than in patients without a concomitant disease (P = .006). Patients in group 2 had 3 times higher rate of complication (21.4%) than those without an AD and aged >=75 years (7.1%; P = .125). CONCLUSION: Pacemaker implantation may be of risk in patients with AD, especially in those aged >=75 years. PMID- 22523110 TI - The role of molecular chaperones in spermatogenesis and the post-testicular maturation of mammalian spermatozoa. AB - BACKGROUND: Spermatogenesis culminates in production of one of the most highly differentiated cells in biology, the spermatozoon. The gametes that emerge from the testes are, however, functionally immature and only acquire full functionality once they have completed a process of post-testicular maturation in the epididymis and female reproductive tract. Remarkably, this acquisition of sperm function occurs while these cells are transcriptionally and translationally silent and is therefore highly dependent on post-translational modifications to their existing protein complement. In this review, we consider the emerging roles of several prominent molecular chaperone families in orchestrating both the morphological differentiation of male germ cells during spermatogenesis and their functional transformation during sperm maturation. METHODS: Journal databases were searched using key words, including chaperone, heat shock protein, testes, spermatogenesis, spermatozoa, epididymal maturation, capacitation and fertilization. RESULTS: In the past two decades, molecular chaperones have been acknowledged to play key roles in controlling both the morphological transformation of germ cells during spermatogenesis and the post-testicular maturation of these cells as they transit the male and female reproductive tracts. Furthermore, there is mounting evidence that aberrant chaperone expression may be a major contributing factor to the defective sperm function seen in many cases of male infertility. CONCLUSIONS: Molecular chaperones are critically involved in all phases of sperm development. Targeted disruption of these proteins has the ability to arrest spermatogenesis, compromise sperm maturation and inhibit fertilization. These proteins therefore hold considerable promise as targets for novel contraceptive strategies and as diagnostic biomarkers for male infertility. PMID- 22523111 TI - First trimester prenatal screening among women pregnant after IVF/ICSI. AB - BACKGROUND: Prenatal screening and diagnosis of chromosomal abnormalities especially Down's syndrome in IVF pregnancies are complicated by higher maternal age, a high multiple pregnancy rate, a high risk of a vanishing twin and an increased risk of chromosomal abnormalities, particularly in pregnancies after ICSI. The aim of the present systematic review was to evaluate the findings of first trimester screening for chromosomal abnormalities in IVF/ICSI singleton and twin pregnancies. METHODS: A systematic MESH-term search in MEDLINE using PubMed and the Cochrane Library was performed until May 2011, with no earlier date limit. RESULTS: The electronic search retrieved 562 citations, 96 of which were evaluated in detail and 57 were then excluded for not meeting the selection criteria. A total of 61 articles were finally selected for review. Our analysis of the data shows that, for IVF/ICSI singletons, combined first trimester prenatal screening based on maternal age, nuchal translucency scan and biomarkers is appropriate. However, biomarkers seem to be altered, causing a higher false positive rate, in IVF/ICSI singleton gestations. Correction factors have been developed and should be used when screening for Down's syndrome in singleton pregnancies. With regard to IVF/ICSI twin pregnancies, biomarker values seem to be dependent on chorionicity as well as gestational age. Whether the use of a correction factor for mode of conception in the risk calculations for Down's syndrome in twin pregnancies is valid has not been fully elucidated. In vanishing twin pregnancies with a second gestational sac with a dead fetus, first trimester screening should be based solely on the maternal age and the nuchal translucency scan as biomarkers are significantly altered in these cases. CONCLUSIONS: First trimester prenatal screening after IVF/ICSI treatment requires specific precautions in both singleton and twin pregnancies. PMID- 22523112 TI - Association of IRS-1 and IRS-2 genes polymorphisms with polycystic ovary syndrome: a meta-analysis. AB - Insulin resistance (IR) plays an important role in the pathogenesis of polycystic ovary syndrome (PCOS) which is a common disorder in premenopausal women. The association between the single nucleotide polymorphisms (SNPs) of insulin receptor substrate (IRS) gene and PCOS in several populations has been studied, but the results are conflicting. The aim of this study was undertaken to investigate association of IRS-1 and IRS-2 genes polymorphisms with PCOS by conducting a meta-analysis. Literature search was conducted through PubMed and EMBASE databases (up to July 31, 2011). Fifteen articles with 1,358 cases and 1,561 controls were enrolled in the meta-analysis of the association between Gly972Arg variant and PCOS, and five articles with 519 cases and 883 controls were enrolled in the meta-analysis of Gly1057Asp variant. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using fixed and random effects models. The Q-statistic test was used to assess heterogeneity, and Begg's test and Egger's test were used to evaluate publication bias. Sensitivity analysis was also performed. Our results indicated that A allele of Gly972Arg conferred a significantly increased risk of PCOS compared with G allele (OR = 1.91, 95% CI: 1.36-2.68). However, in Gly1057Asp polymorphism the OR of allele A vs. G is 0.92 (95% CI: 0.72, 1.18). Our meta-analysis suggested that IRS-1 Gly972Arg polymorphism might be considered a significant risk for PCOS. Otherwise, no significant associations were observed in IRS-2 Gly1057Asp polymorphism which needs to be further confirmed by further studies. PMID- 22523109 TI - Extravillous trophoblast and decidual natural killer cells: a remodelling partnership. AB - BACKGROUND: During pregnancy, maternal uterine spiral arteries (SAs) are remodelled from minimal-flow, high-resistance vessels into larger diameter vessels with low resistance and high flow. Fetal extravillous trophoblasts (EVT) have important roles in this process. Decidual natural killer cells (dNK cells) are the major maternal immune component of the decidua and accumulate around SAs before trophoblast invasion. A role for dNK cells in vessel remodelling is beginning to be elucidated. This review examines the overlapping and dissimilar mechanisms used by EVT and dNK cells in this process and how this may mirror another example of tissue remodelling, namely cancer development. METHODS: The published literature was searched using Pubmed focusing on EVT, dNK cells and SA remodelling. Additional papers discussing cancer development are also included. RESULTS: Similarities exist between actions carried out by dNK cells and EVT. Both interact with vascular cells lining the SA, as well as with each other, to promote transformation of the SA. EVT differentiation has previously been likened to the epithelial-mesenchymal transition in cancer cells, and we discuss how dNK EVT interactions at the maternal-fetal interface can also be compared with the roles of immune cells in cancer. CONCLUSIONS: The combined role that dNK cells and EVT play in SA remodelling suggests that these interactions could be described as a partnership. The investigation of pregnancy as a multicellular system involving both fetal and maternal components, as well as comparisons to similar examples of tissue remodelling, will further identify the key mechanisms in SA remodelling that are required for a successful pregnancy. PMID- 22523113 TI - FGF-23 and vitamin D: don't shoot the messenger? AB - The discovery of fibroblast growth factor-23 (FGF-23) as a key regulator of phosphate and vitamin D metabolism has forced a rethink about the mineral and bone disorder of chronic kidney disease (CKD). FGF-23 powerfully predicts adverse cardiovascular outcomes in patients with CKD and an important question is whether treatment regimens should now be tailored to address FGF-23 levels in addition to those of calcium, phosphate, parathyroid hormone and vitamin D. Nevertheless, despite the known action of active vitamin D therapies to increase FGF-23, this should probably still form an important part of the management of patients with hyperparathyroidism and perhaps at low doses of essentially all patients with advanced renal disease. PMID- 22523114 TI - Probing 'dry weight' in haemodialysis patients: 'back to the future'. PMID- 22523115 TI - Copeptin, a surrogate marker for vasopressin, is associated with kidney function decline in subjects with autosomal dominant polycystic kidney disease. AB - BACKGROUND: Experimental studies have suggested that vasopressin plays a detrimental role in autosomal dominant polycystic kidney disease (ADPKD). It is, however, unknown whether endogenous vasopressin concentration is associated with kidney function decline in subjects with ADPKD. METHODS: We measured plasma copeptin (a marker of vasopressin) in 79 ADPKD subjects with renal function assessed during short-term follow-up by inulin clearance measured glomerular filtration rate (mGFR) and during long-term follow-up by Modification of Diet in Renal Disease (MDRD) equation estimated GFR (eGFR). RESULTS: In these subjects (43% male, age 36.8 +/- 10.1 years, GFR 96.8 +/- 18.2 mL/min/1.73 m(2)), median copeptin concentration at baseline was 2.71 [interquartile ranges (IQR) 1.63 5.46] pmol/L. Baseline copeptin concentration was inversely associated both with change in mGFR during follow-up for 3.3 (3.1-3.5) years, (R = -0.300, P = 0.01), as well as with change in eGFR during follow-up for 11.2 (4.5-14.3) years, (R = 0.302, P < 0.01). These associations were independent of age, gender and baseline GFR. Nine subjects started renal replacement therapy during follow-up of which eight had at baseline a copeptin concentration above the median in this population. CONCLUSION: In ADPKD subjects, a higher copeptin concentration is associated with kidney function decline during follow-up, suggesting that copeptin may be a new marker to predict kidney outcome in ADPKD. PMID- 22523116 TI - Survival analysis and causes of mortality in patients with lupus nephritis. AB - BACKGROUND: This study aimed to define the causes and associated risks of death compared with the local general population in Chinese patients with lupus nephritis in the recent era. METHODS: The records of all lupus nephritis patients followed in a single centre during 1968-2008 were reviewed. The causes of death were identified, the survival curves constructed and the standardized mortality ratios (SMRs) of potential risk factors were calculated with reference to the local general population. RESULTS: Two hundred and thirty systemic lupus erythematosus patients with history of renal involvement (predominantly Class III/IV lupus nephritis with or without membranous features) were included. The follow-up was 4076.6 person-years (mean 17.7 +/- 8.9 years). Twenty-four patients (10.4%) died, and 85% of the deaths occurred after 10 years of follow-up. The 5-, 10-, and 20-year survival rates were 98.6, 98.2 and 90.5%, respectively. The leading causes of death were infection (50.0%), cardiovascular disease (20.8%) and malignancy (12.5%). The renal survival rates at 5, 10 and 20 years were 99.5, 98.0 and 89.7%, respectively. The SMR in patients with renal involvement, end stage renal disease (ESRD), malignancy or cardiovascular disease was 5.9, 26.1, 12.9 and 13.6, respectively. CONCLUSIONS: Lupus nephritis is associated with a 6 fold increase in mortality compared with the general population. Lupus patients who develop ESRD have a 26-fold excess in the risk of death, which is more than twice the risk associated with malignancy or cardiovascular disease in these patients. PMID- 22523117 TI - Mass spectrometry as a novel method for detection of podocyturia in pre eclampsia. AB - BACKGROUND: Podocyturia, i.e. urinary loss of viable podocytes, may serve as a diagnostic tool for pre-eclampsia and as a marker of active renal disease. The current method to detect podocyturia is technically complex, lengthy and requires a high level of expertise for interpretation. The aim of this study was to develop a new technique for the identification of urinary podocytes, based on the detection of podocyte-specific tryptic peptides by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), which will provide an operator independent and highly reproducible method. METHODS AND RESULTS: The diagnosis of pre-eclampsia was confirmed in the presence of hypertension (>140/90 mmHg) and proteinuria >0.3 g/24 h urine. The diagnosis of HELLP was confirmed based on the accepted clinical criteria of hemolysis, elevated liver enzymes and low platelet count. Random urine samples within 24 h prior to delivery were collected and centrifuged. One half of the sediment was cultured for 24 h to select for viable cells and then stained with a podocin antibody, followed by a secondary fluorescein isothiocyanate-labeled antibody to identify podocytes. The second half of the pellet was solubilized, digested and analyzed by LC-MS/MS using an internal standard. We have recruited 13 patients with pre-eclampsia and 6 patients with pre-eclampsia/HELLP syndrome. The presence of podocytes was confirmed in all patients by the podocyte culture method. In the respective samples, the presence of a podocin-specific tryptic peptide was confirmed with LC MS/MS technology. CONCLUSION: The LC-MS/MS method is a reliable technology for the identification of urinary podocytes, based on the presence of podocyte specific proteins in the urine. PMID- 22523118 TI - Estimated glomerular filtration rate at reinitiation of dialysis and mortality in failed kidney transplant recipients. AB - BACKGROUND: Recent observational studies and a controlled trial suggest more favorable outcomes upon later dialysis initiation in chronic kidney disease. The role of estimated glomerular filtration rate (eGFR) in predicting outcome at reinitiation of dialysis in failed kidney transplant recipients is unclear. METHODS: Five-year data in a large dialysis organization was linked to the 'Scientific Registry of Transplant Recipients' to identify 747 failed kidney transplant patients with CKD Stage 5, who had restarted dialysis therapy. A propensity score for early (eGFR>10.5 mL/min/1.73 m2) versus late reinitiation of dialysis was fit by logistic regression. The mortality hazard ratio (HR) was estimated across tertiles of the fitted score. RESULTS: Patients were 44+/-14 years old and included 42% women. Male gender {odds ratio (OR), [95% confidence interval (CI)]: 1.82 (1.22-2.73)}, diabetes mellitus [OR: 1.75 (1.14-2.68)] and peripheral vascular disease [OR: 3.55 (1.17-10.77)] were associated with higher odds of early dialysis reinitiation. Each mL/min/1.73 m2 higher eGFR was associated with 6% higher death risk in unadjusted model [HR: 1.06 (1.01-1.11)], and although not significant in fully adjusted models [HR: 1.02 (0.96-1.07)], it was significant in some subgroups including women and younger patients. The death HR of higher eGFR across lowest to highest tertiles of propensity score of early dialysis initiation (corresponding healthiest to sickest patients) were 1.10 (0.98-1.24), 1.00 (0.91-1.10) and 0.99 (0.92-1.07), respectively (P for trend<0.05), indicating a trend toward higher mortality risk with earlier dialysis initiation in the healthiest patients. CONCLUSIONS: Earlier return to dialysis therapy in failed kidney transplant patients tends to correlate with worse dialysis survival especially among healthiest and younger patients and women. Additional studies need to verify these findings. PMID- 22523119 TI - VDRA therapy is associated with improved survival in dialysis patients with serum intact PTH <= 150 pg/mL: results of the Italian FARO Survey. AB - BACKGROUND: Chronic kidney disease (CKD) patients affected by mineral bone disorders (MBD) have higher rates of all-cause and cardiovascular-related mortality. Approximately, one-third of dialysis patients have low serum parathyroid hormone (PTH) levels (<= 150 pg/mL). However, the reason why these patients have higher mortality compared to patients with normal PTH levels has not yet been fully elucidated. METHODS: The FARO study was performed on 2453 Italian patients followed prospectively from 28 dialysis centres over a 2-year period. Data were collected every 6 months and end points included time-to-death cumulative probability in patients with serum intact PTH (iPTH) <= 150 pg/mL and the effect of vitamin D receptor activation (VDRA) therapy. Kaplan-Meier curves and proportional hazards regression models stratified by PTH levels (i.e. <= 150 and >150 pg/mL) were used to determine cumulative probability of time-to-death and adjusted hazard ratios (HRs) for demographic, clinical and CKD-MBD treatment characteristics. RESULTS: The cumulative probability of death was higher (P < 0.01) for patients with serum iPTH levels <= 150 pg/mL [25.1%, 95% confidence interval (CI): 22.1-28.5 at 18 months] versus those with serum iPTH levels within the normal range (18.0%, 95% CI: 16.1-20.1). In a model with time-dependent covariates restricted to time periods when patients had iPTH levels <= 150 pg/mL, lower mortality was observed in patients treated with VDRA [i.e. HR = 0.62, 95% CI: 0.42-0.92 for oral or intravenous (IV) calcitriol; HR = 0.18, 95% CI: 0.04 0.8 for IV paricalcitol] versus those not receiving any VDRA (P < 0.01) independently of other variables. Patients who received IV paricalcitol, compared with either oral or IV calcitriol, showed reduced mortality, but this was not statistically significant (HR = 0.3, 95% CI: 0.07-1.31, P = 0.11). CONCLUSION: Results from this observational study suggest that VDRA therapy was associated with improved survival in dialysis patients, even with low serum iPTH levels. PMID- 22523120 TI - Preventing smoking relapse using text messages: analysis of data from the txt2stop trial. AB - INTRODUCTION: Interactive text message-based technologies which operate in real time have the potential to be especially effective for delivery of relapse prevention interventions. We examined predictors of use of a text message system for providing support for lapses and cravings, describe the natural history of requests for support, and predictors of time to requests for support. METHODS: Data were collected prospectively from participants in the intervention arm of txt2stop, a large randomized controlled trial of an automated, text message-based smoking cessation intervention. Txt2stop included 2,915 men and women aged 16-78, recruited from London, United Kingdom from 2009 to 2010. Participants could text "crave" or "lapse" when they experienced either; an automated system registered the time of the text message to the nearest second. RESULTS: One thousand one hundred and twenty one (38.5%) participants sent a lapse or crave message to request support. Women were more likely to lapse at some point during the trial. Of those who lapsed, being female, younger age, and setting a Saturday quit date were predictors of sending a lapse text requesting support. Half of all crave texts arrived within 106 hr of quitting. Half of all lapse texts arrived between 4 and 17 days after the quit date. Sending a crave text, being female, younger, and setting a quit date on a Saturday were associated with shorter time to sending a first lapse text. CONCLUSIONS: Text-based lapse support should be developed and evaluated, especially for women. Smokers may benefit from additional support to prevent lapses on days 4-17 postquit attempt. PMID- 22523121 TI - Trends in services among pediatric hospice providers during 2002 to 2008. AB - The medical complexities involved in caring for children at end of life have increased during the past few decades. This study sought to understand what hospice services were offered for these children and to examine service trends among pediatric hospice providers over a 7-year (2002-2008) timeframe. The number of core hospice services diminished in 2003 (IRR = 0.873, 95% CI [0.795,0.971]) and 2004 (IRR = 0.889, 95% CI [0.793, 0.995]); however, by 2008 there was an increase in offering core (IRR = 1.130, 95% CI [1.038,1.230]), noncore (IRR = 1.117, 95% CI [1.013,1.231]), and other hospice (IRR = 1.117, 95% CI [1.005,1.583]) services among pediatric providers. These findings highlight the importance of family-clinician communication about needed services prior to admitting children to hospice care. PMID- 22523122 TI - Variation in the incidence of agitated delirium during the day in a palliative care unit: a preliminary report. AB - In the literature regarding delirium and agitation in palliative care, there are references of their worsening as the hours of the day flows from afternoon on, with an inversion of the awake-sleep cycle. We studied the frequency of the use of our protocol for the control of agitation. From June 18, 2007, to January 4, 2010, 27 (5.3%) patients from the 509 admitted were sedated intermittently 86 times, in strict compliance with the protocol, because of episodes of agitation. We verified that from 8 pm until 6 am, the number of observed cases clearly exceeds the expected cases, if the distribution was uniform. The reverse situation occurs in all other hours of the day. The chi-square goodness of fit test proves that the differences are statistically significant (P < .001). PMID- 22523123 TI - Examining an outlier: molecular diversity in the cirripedia. AB - Despite the typical assumption in studies of mitochondrial diversity that such data are useful for approximating population size and demography, studies of sequence diversity in mitochondrial DNA across the Metazoa have shown a surprising excess of rare alleles, a pattern associated either with strong selection or population growth. Previous work has shown that this bias toward an excess of rare alleles is typical across the Crustacea, and in particular, in the Cirripedia (barnacles). Here, we directly evaluate sequence data from studies of barnacle populations to ensure that inclusion of cryptic species is not the cause of this pattern. The results shown here reinforce previous studies that suggest caution in interpreting such patterns of allele frequencies, as they are likely to be influenced both by demographic changes and selection. PMID- 22523124 TI - Adaptive transgenerational plasticity in an annual plant: grandparental and parental drought stress enhance performance of seedlings in dry soil. AB - Stressful parental (usually maternal) environments can dramatically influence expression of traits in offspring, in some cases resulting in phenotypes that are adaptive to the inducing stress. The ecological and evolutionary impact of such transgenerational plasticity depends on both its persistence across generations and its adaptive value. Few studies have examined both aspects of transgenerational plasticity within a given system. Here we report the results of a growth-chamber study of adaptive transgenerational plasticity across two generations, using the widespread annual plant Polygonum persicaria as a naturally evolved model system. We grew five inbred Polygonum genetic lines in controlled dry vs. moist soil environments for two generations in a fully factorial design, producing replicate individuals of each genetic line with all permutations of grandparental and parental environment. We then measured the effects of these two-generational stress histories on traits critical for functioning in dry soil, in a third (grandchild) generation of seedling offspring raised in the dry treatment. Both grandparental and parental moisture environment significantly influenced seedling development: seedlings of drought-stressed grandparents or parents produced longer root systems that extended deeper and faster into dry soil compared with seedlings of the same genetic lines whose grandparents and/or parents had been amply watered. Offspring of stressed individuals also grew to a greater biomass than offspring of nonstressed parents and grandparents. Importantly, the effects of drought were cumulative over the course of two generations: when both grandparents and parents were drought stressed, offspring had the greatest provisioning, germinated earliest, and developed into the largest seedlings with the most extensive root systems. Along with these functionally appropriate developmental effects, seedlings produced after two previous drought-stressed generations had significantly greater survivorship in very dry soil than did seedlings with no history of drought. These findings show that plastic responses to naturalistic resource stresses experienced by grandparents and parents can "preadapt" offspring for functioning under the same stresses in ways that measurably influence realized fitness. Possible implications of these environmentally-induced, inherited adaptations are discussed with respect to ecological distribution, persistence under novel stresses, and evolution in natural populations. PMID- 22523125 TI - Nurse eggs form through an active process of apoptosis in the spionid Polydora cornuta (Annelida). AB - The production of nurse eggs is fundamental to poecilogony in some species of spionid annelids. In species such as Polydora cornuta, nurse-egg production varies among females and ingestion of nurse eggs varies among young, resulting in a form of poecilogony with divergent phenotypes for females (e.g., fecundity and per-offspring investment) as well as for larvae (e.g., trophic mode, size, and stage at hatching). We tested the hypothesis that nurse eggs of P. cornuta form through an active developmental process and specifically, through apoptosis. Results of a TUNEL assay indicate nuclear fragmentation occurs in a process that is characteristic of apoptosis. Cellular indicators of apoptosis in nurse eggs include activation of caspase-3, a positive Annexin V reaction indicating exposure of phosphatidylserine on the outer cell membrane, and invagination of the membrane to form yolk vesicles. These results indicate that formation of nurse eggs in this population of P. cornuta occurs through an active, adaptive process. Furthermore, while apoptosis also occurs in some cells of P. cornuta embryos, it was not detected until later in development. This suggests that nurse eggs originate through heterochrony in a developmental process (apoptosis) that is common to all young of P. cornuta. PMID- 22523126 TI - The effects of salinity on acute toxicity of zinc to two euryhaline species of fish, Fundulus heteroclitus and Kryptolebias marmoratus. AB - It is well known that the toxicity of zinc (Zn) varies with water chemistry and that its bioavailability is controlled by ligand interactions and competing ions. Zn toxicity in freshwaters with varying water chemistry has been well characterized; however, far less attention has been paid to the toxicity of Zn in estuarine and marine systems. We performed experiments using two euryhaline species of killifish, Fundulus heteroclitus and Kryptolebias marmoratus, to investigate the effects of changing salinity on acute toxicity of Zn. Larvae (7- to 8-days old) of each species were exposed to various concentrations of Zn for 96 h at salinities ranging from 0 to 36 ppt and survival was monitored. As salinity increased, Zn toxicity decreased in both fish species, and at salinities above 10 ppt, K. marmoratus larvae were generally more sensitive to Zn than were those of F. heteroclitus. The protection of salinity against Zn toxicity in F. heteroclitus was further investigated to determine the role of Ca(2+). Increased Ca(2+) in freshwater protected against Zn toxicity to the same extent as did saline waters with an equal Ca(2+) concentration up to ~200 mg/L Ca for F. heteroclitus and ~400 mg/L Ca for K. marmoratus. These results suggest that these two species may have differing Ca(2+) requirements and/or rates of Ca(2+) uptake in water of intermediate to full-strength salinity (~200-400 mg/L Ca(2+)) and thus differ in their sensitivity to Zn. The overall goal of this study was to better understand Zn toxicity in waters of different salinity and to generate data on acute Zn toxicity from multiple species over a range of salinities, ultimately for use in development of estuarine and marine biotic ligand models. PMID- 22523127 TI - Genetic and morphological differentiation of the Indo-West Pacific intertidal barnacle Chthamalus malayensis. AB - Chthamalus malayensis is a common intertidal acorn barnacle widely distributed in the Indo-West Pacific. Analysis of sequences of mitochondrial cytochrome c oxidase subunit I reveals four genetically differentiated clades with almost allopatric distribution in this region. The four clades exhibit morphological differences in arthropodal characters, including the number of conical spines and number of setules of the basal guard setae on the cirri. These characters are, however, highly variable within each clade; such that the absolute range of the number of conical spines and setules overlaps between clades, and therefore, these are not diagnostic characters for taxonomic identification. The geographic distribution of the four clades displays a strong relationship between surface temperatures of the sea and ocean-current realms. The Indo-Malay (IM) clade is widespread in the tropical, equatorial region, including the Indian Ocean, Malay Peninsula, and North Borneo. The South China (SC) and Taiwan (TW) clades are found in tropical to subtropical regions, with the former distributed along the coasts of southern China, Vietnam, Thailand, and the western Philippines under the influence of the South China Warm Current. The TW clade is endemic to Taiwan, while the Christmas Island (CI) clade is confined to CI. There was weak or no population subdivision observed within these clades, suggesting high gene flow within the range of the clades. The clades demonstrate clear signatures of recent demographic expansion that predated the Last Glacial Maximum (LGM), but they have maintained a relatively stable effective population in the past 100,000 years. The persistence of intertidal fauna through the LGM may, therefore, be a common biogeographic pattern. The lack of genetic subdivision in the IM clade across the Indian and Pacific Oceans may be attributed to recent expansion of ranges and the fact that a mutation-drift equilibrium has not been reached, or the relaxed habitat requirements of C. malayensis that facilitates high concurrent gene flow. Further studies are needed to determine between these alternative hypotheses. PMID- 22523128 TI - Sexual systems and life history of barnacles: a theoretical perspective. AB - Thoracican barnacles show one of the most diverse sexual systems in animals: hermaphroditism, dioecy (males and females), and androdioecy (males and hermaphrodites). In addition, when present, male barnacles are very small and are called "dwarf males". The diverse sexual systems and male dwarfism in this taxon have attracted both theoretical and empirical biologists. In this article, we review the theoretical studies on barnacles' sexual systems in the context of sex allocation and life history theories. We first introduce the sex allocation models by Charnov, especially in relation to the mating group size, and a new expansion of his models is also proposed. We then explain three studies by Yamaguchi et al., who have studied the interaction between sex allocation and life history in barnacles. These studies consistently showed that limited mating opportunity favors androdioecy and dioecy over hermaphroditism. In addition, other factors, such as rates of survival and availability of food, are also important. We discuss the importance of empirical studies testing these predictions and how empirical studies interact with theoretical constructs. PMID- 22523129 TI - Surgical left ventricular radius enlargement by patch insertion on the beating heart: a new experimental aneurysm model. AB - We presented a novel experimental aneurysm model for studies in left ventricular (LV) reconstruction techniques and assessed LV function. In eight pigs, the LV radius and geometry were enlarged surgically on the beating heart by inserting an aortic allograft construct. Haemodynamics and LV dimensions were assessed by echocardiography at baseline and under dobutamine stress. Surgery was successfully performed without lethal blood loss or arrhythmias. LV end-diastolic and end-systolic short-axis areas increased from 13.0 +/- 1.7 to 17.0 +/- 4.3 cm(2) (P = 0.001) and from 4.0 +/- 0.9 to 13.0 +/- 2.6 cm(2) (P = 0.001), respectively. Stroke volume decreased from 56 +/- 11 to 33 +/- 16 ml (P = 0.001). Incremental dobutamine infusion concurred with a biphasic response on fractional area shortening. Mitral valve insufficiency ranging from grades 2 to 4 was observed. In the pig, a novel, reproducible aneurysm model for acute cardiac dysfunction was created on the beating heart. Innovative (surgical) strategies for (staged) reconfiguration of the ventricle, e.g. adjustable Dor procedures and stepwise volume restraining cardiac support devices, can be tested for efficacy using this acute model. PMID- 22523131 TI - Recovery of endothelial function after sirolimus-eluting stent implantation: a pilot study. AB - Whether endothelial dysfunction after sirolimus-eluting stent (SES) implantation is persistent has not been fully evaluated. Endothelial function was evaluated in 152 lesions that underwent follow-up coronary angiography after SES implantation. Lesions were classified into 2 groups according to the duration between SES implantation and follow-up: <=12 months (n = 95) and >12 months (n = 57). Changes in coronary diameter in response to 10(-8) mol/L (-2.4% +/- 6.3% vs -4.9% +/- 3.8%, P < .01) and 10(-7) mol/L acetylcholine (Ach; -4.6% +/- 7.6% vs -10.7% +/- 9.1%, P < .001) in segment proximal to SES were significantly attenuated in the >12-month group than in the <=12-month group. There were less changes in coronary diameter in response to 10(-8) mol/L (-2.3% +/- 4.6% vs -6.9% +/- 5.0%, P < .001) and 10(-7) mol/L Ach (-6.5% +/- 11.4% vs -16.8% +/- 10.5%, P < .001) in segment distal to SES in the >12-month group. Endothelial dysfunction may diminish long after SES implantation. PMID- 22523133 TI - The convergent and concurrent validity of trait-based prototype assessment of personality disorder categories in homeless persons. AB - The DSM-5 proposal indicates that personality disorders (PDs) be defined as collections of maladaptive traits but does not provide a specific diagnostic method. However, researchers have previously suggested that PD constructs can be assessed by comparing individuals' trait profiles with those prototypic of PDs and evidence from the five-factor model (FFM) suggests that these prototype matching scores converge moderately with traditional PD instruments. The current study investigates the convergence of FFM PD prototypes with interview-assigned PD diagnoses in a sample of 99 homeless individuals. This sample had very high rates of PDs, which extends previous research on samples with more modest prevalence rates. Results indicated that diagnostic agreement between these methods was generally low but consistent with the agreement previously observed between explicit PD measures. Furthermore, trait-based and diagnostic interview scores evinced similar relationships with clinically important indicators such as abuse history and past suicide attempts. These findings demonstrate the validity of prototype methods and suggest their consideration for assessing trait-defined PD types within DSM-5. PMID- 22523134 TI - Coefficient alpha and interculture test selection. AB - The internal consistency reliability of a measure can be a focal point in an evaluation of the potential adequacy of an instrument for adaptation to another cultural setting. Cronbach's alpha (alpha) coefficient is often used as the statistical index for such a determination. However, alpha presumes a tau equivalent test and may constitute an inaccurate population estimate for multidimensional tests. These notions are expanded and examined with a Japanese version of a questionnaire on nursing attitudes toward suicidal patients, originally constructed in Sweden using the English language. The English measure was reported to have acceptable internal consistency (alpha) albeit the dimensionality of the questionnaire was not addressed. The Japanese scale was found to lack tau-equivalence. An alternative to alpha, "composite reliability," was computed and found to be below acceptable standards in magnitude and precision. Implications for research application of the Japanese instrument are discussed. PMID- 22523135 TI - Stroke prevention in cardiac surgery. AB - This article addresses the main risk factors for stroke in cardiac surgery and discusses the role of carotid artery intervention and peri-operative epi-aortic scanning in the prevention of stroke. In great Britain and Northern Ireland, there were ~2789 new strokes following the 105,558 cases of cardiac surgery from 2004 to 2008 (an annual stroke rate of 2.6% complicating heart surgery in the UK). We argue that The National Health Service in the UK is set to spend L187,682 preventing each stroke in some 30 cardiac surgical patients while ignoring the remaining 528 strokes that complicate cardiac surgery in the UK each year. Caution must be taken in pricing the prevention of perioperative stroke as we must question our use of finite resources. Aortic atheroma has been demonstrated as the foremost cause of post-coronary artery bypass graft strokes. Epi-aortic scanning is effective in identifying aortic atheroma encouraging measures to reduce perioperative stroke with heart surgery, and it is cheap. Several studies have confirmed epi-aortic scanning at the time of heart surgery to be effective in reducing the incidence of perioperative brain damage. We suggest that it is time to adopt epi-aortic scanning in our routine cardiac surgical practice if only to confirm or refute its cost-effectiveness in brain protection during this surgery. PMID- 22523136 TI - Magnesium and diltiazem relaxes phenylephrine-precontracted rat aortic rings. AB - Perioperative vasospasm during cardiovascular surgery is a challenging problem. Several vasodilator agents are frequently utilized for its prevention in surgical practice. Magnesium and diltiazem both have known potential vasorelaxant effects. We planned to compare the efficacy of diltiazem and magnesium in relieving phenylephrine-precontracted rat aortic rings. Ten young adult female Wistar albino rats weighing 230-260 g were used in this study. The aortic rings in the organ bath equilibrated and reached their baseline tension. Precontraction was induced by 0.001 mmol/l phenylephrine and cumulative concentration-relaxation curves were obtained by consecutively increasing the addition of either diltiazem (10(-6)-0.1 mmol/l) or magnesium (0.1-10 mmol/l). The mean maximal relaxation responses observed by diltiazem and magnesium on separate aortic rings were 90 +/ 3 and 53 +/- 2%, respectively. The calculated EC50 of diltiazem was 0.01035 mmol/l, whereas the EC50 of magnesium was 4.064 mmol/l (P < 0.05). Both magnesium and diltiazem produced vasorelaxation on phenylephrine-precontracted rat aortic rings in this study, but the potency of diltiazem regarding the EC50 value was significantly higher than that of magnesium. Magnesium could be a candidate together with diltiazem to inhibit vasospasm on arterial grafts during coronary bypass surgery. PMID- 22523137 TI - Recognising and responding to adolescent depression in general practice: developing and implementing the Therapeutic Identification of Depression in Young people (TIDY) programme. AB - Rates of depressive disorder in adolescents attending primary care are increasing. Most presentations are for physical complaints and concurrent depressive symptoms go unrecognised and untreated. Primary care practitioners describe reluctance to intervene due to lack of confidence and skills. This paper describes the development and implementation of TIDY (Therapeutic Identification of Depression in Young people), a programme designed by child psychiatrists and general practitioners to improve detection and intervention for depression within ordinary consultations. The paper describes the integration of educational principles and current evidence into the development of the training programme and the intervention package. The content of the intervention is described. For cases of mild to moderate depressive disorder, where patients do not require referral for specialist treatment, practitioners are trained to deliver self-help and coping strategies within a single consultation. PMID- 22523138 TI - Bioterrorism: toxins as weapons. AB - The potential for biological weapons to be used in terrorism is a real possibility. Biological weapons include infectious agents and toxins. Toxins are poisons produced by living organisms. Toxins relevant to bioterrorism include ricin, botulinum, Clostridium perfrigens epsilson toxin, conotoxins, shigatoxins, saxitoxins, tetrodotoxins, mycotoxins, and nicotine. Toxins have properties of biological and chemical weapons. Unlike pathogens, toxins do not produce an infection. Ricin causes multiorgan toxicity by blocking protein synthesis. Botulinum blocks acetylcholine in the peripheral nervous system leading to muscle paralysis. Epsilon toxin damages cell membranes. Conotoxins block potassium and sodium channels in neurons. Shigatoxins inhibit protein synthesis and induce apoptosis. Saxitoxin and tetrodotoxin inhibit sodium channels in neurons. Mycotoxins include aflatoxins and trichothecenes. Aflatoxins are carcinogens. Trichothecenes inhibit protein and nucleic acid synthesis. Nicotine produces numerous nicotinic effects in the nervous system. PMID- 22523141 TI - Do clinical psychologists extend the bereavement exclusion for major depression to other stressful life events? AB - BACKGROUND: In assessing potential cases of major depressive disorder (MDD), to what extent do clinicians interpret symptoms within the explanatory context of major life stressors? Past research suggests that when clinicians know a plausible life event cause for a person's disordered symptoms, they generally judge that person to be less abnormal than if the cause was unknown. However, the current, fourth edition of the Diagnostic and Statistical Manual of Mental Disorders specifies that only bereavement-related life events exclude a client from a diagnosis of MDD, and the upcoming fifth edition of the manual (DSM-V) is currently slated to eliminate this bereavement clause altogether. OBJECTIVE: To systematically examine whether clinicians' judgments reflect agreement with either of these formal DSM specifications. METHOD: In a controlled experiment, 72 practicing, licensed clinical psychologists made judgments about realistic MDD vignettes that included a bereavement event, stressful non-bereavement event, neutral event, or no event. RESULTS: Bonferroni-corrected paired comparisons revealed that both bereavement and non-bereavement life events led MDD symptoms to be rated as significantly less indicative of a depression diagnosis, less abnormal, less rare, and less culturally unacceptable (all P <= 0.001) relative to control conditions. LIMITATIONS: Clinicians made judgments of realistic, controlled vignettes rather than patients. CONCLUSIONS: The results suggest that practicing clinical psychologists assess symptoms within the explanatory context of bereavement and non-bereavement life stressors, indicating a departure from the DSM's recommendations, both current and proposed. IMPLICATIONS: for diagnostic decision making and the clinical utility of the DSM's recommendations are discussed. PMID- 22523142 TI - A quarterly report. PMID- 22523144 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 1: is abdominal pain when asked to hop suggestive of appendicitis in children? AB - A short-cut review was carried out to establish whether abdominal pain on hopping/jumping can assist in the initial diagnosis of appendicitis in children. Four studies were directly relevant to the question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. The clinical bottom line is that the presence of abdominal pain when asked to hop seems to be both reasonably sensitive and specific to a diagnosis of appendicitis in children. PMID- 22523145 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 2: C-reactive protein in the diagnosis of bacteraemia. AB - A short-cut review was carried out to establish the sensitivity and specificity of CRP as a tool for diagnosing bacteraemia. Three studies were directly relevant to the question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. The clinical bottom line suggests that CRP is not a useful tool in the initial diagnosis of severe bacterial infection. PMID- 22523146 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 3: thromboprophylaxis significantly reduces venous thromboembolism rate in ambulatory patients immobilised in below-knee plaster cast. AB - A short-cut review was carried out to establish whether ambulatory patients immobilized in a below knee plaster of paris cast and administered with a prophylactic dose anticoagulation with low molecular weight heparin; LMWH can benefit from a reduced risk of venous thromboembolism within the next 90 days One Cochrane Review was relevant to the question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. The clinical bottom line is that the use of LMWH thromboprophylaxis is effective at reducing the incidence of VTE in these patients. PMID- 22523147 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 4: thromboprophylaxis reduces venous thromboembolism rate in ambulatory patients immobilised in above-knee plaster cast. AB - A short-cut review was carried out to establish whether ambulatory patients immobilized in an above knee plaster of paris cast and administered with a prophylactic dose anticoagulation with low molecular weight heparin; LMWH can benefit from a reduced risk of venous thromboembolism within the next 90 days. One randomised controlled trial was relevant to the question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of this paper are tabulated. The clinical bottom line is that despite limited data the use of LMWH thromboprophylaxis appears to be effective at reducing the incidence of VTE in these patients. PMID- 22523149 TI - Palm oil and LDL cholesterol. PMID- 22523150 TI - Oral folic acid and vitamin B-12 supplementation to prevent cognitive decline. PMID- 22523151 TI - Are nonsignificant differences between SFAs and oleic acid truly indicative of equality or masked by methodologic errors? PMID- 22523152 TI - Intakes of copper in nutrition surveys are falsely high. PMID- 22523153 TI - Conclusions of the Optimal Lean Diet Study go beyond the data. PMID- 22523155 TI - Critical role of types 2 and 3 deiodinases in the negative regulation of gene expression by T3in the mouse cerebral cortex. AB - Thyroid hormones regulate brain development and function through the control of gene expression, mediated by binding of T(3) to nuclear receptors. Brain T(3) concentration is tightly controlled by homeostatic mechanisms regulating transport and metabolism of T(4) and T(3). We have examined the role of the inactivating enzyme type 3 deiodinase (D3) in the regulation of 43 thyroid hormone-dependent genes in the cerebral cortex of 30-d-old mice. D3 inactivation increased slightly the expression of two of 22 positively regulated genes and significantly decreased the expression of seven of 21 negatively regulated genes. Administration of high doses of T(3) led to significant changes in the expression of 12 positive genes and three negative genes in wild-type mice. The response to T(3) treatment was enhanced in D3-deficient mice, both in the number of genes and in the amplitude of the response, demonstrating the role of D3 in modulating T(3) action. Comparison of the effects on gene expression observed in D3 deficiency with those in hypothyroidism, hyperthyroidism, and type 2 deiodinase (D2) deficiency revealed that the negative genes are more sensitive to D2 and D3 deficiencies than the positive genes. This observation indicates that, in normal physiological conditions, D2 and D3 play critical roles in maintaining local T(3) concentrations within a very narrow range. It also suggests that negatively and positively regulated genes do not have the same physiological significance or that their regulation by thyroid hormone obeys different paradigms at the molecular or cellular levels. PMID- 22523156 TI - Primary progressive multiple sclerosis developing in the context of young onset Parkinson's disease. AB - We report a patient with young onset Parkinson's disease (PD) and a heterozygous point mutation in parkin (c.1000C>T; p.Arg334Cys). After 8 years he developed pyramidal signs and reinvestigation demonstrated MRI and laboratory findings supportive of a diagnosis of multiple sclerosis (MS) with a primary progressive (PP) clinical course. This is a previously un-described association of young onset PD with PPMS. Imaging clearly dates the occurrence of each disease as chronologically separate phenomena. There is not currently evidence for shared causation or pathogenesis between the two neurological disorders but we will follow with interest the emerging genetic characterization of parkin in both PD and MS. PMID- 22523157 TI - Acute demyelinating lesions with restricted diffusion in multiple sclerosis. AB - BACKGROUND AND OBJECTIVES: It is widely accepted that typical acute demyelinating lesions in relapsing-remitting multiple sclerosis (RRMS) exhibit vasogenic edema with increased diffusion, as demonstrated by an increased apparent diffusion coefficient on MRI. In contrast, acute ischemic lesions demonstrate cytotoxic edema with restricted diffusion. Recent reports have documented selected cases of acute demyelinating lesions exhibiting restricted diffusion (ADLRD) in MS. We aimed to assess the morphologies, distributions, signal characteristics and changes over time of nine ADLRD. An additional goal was to obtain clinical correlations and relate our findings to all previously published case reports describing ADLRD. METHODS: A retrospective case series study was performed at two academic centers. MRI characteristics of nine ADLRD found in six RRMS patients were compared with typical active symptomatic contrast-enhancing lesions with increased or normal diffusion in control RRMS patients. RESULTS: The average size of ADLRD was not significantly different from typical lesions. A periventricular location and faint signal on T2-weighted images were significantly more common for ADLRD compared with typical lesions. Two patients with ADLRD on initial MRI exhibited new ADLRD on their follow up scans. CONCLUSION: Our results and review of prior published cases suggest that ADLRD represent a new variant of MS lesion. The restricted diffusion that is a characteristic of ADLRD on MRI is a new challenge in the differential diagnosis of stroke in young adults. The pathogenesis of ADLRD remains to be understood. PMID- 22523158 TI - Nutrition assessment, care, and considerations of ventricular assist device patients. AB - A ventricular assist device (VAD) is an implantable mechanical device that is used to partially or completely replace the circulatory function of a failing heart. VADs may serve as a bridge to heart transplantation or as permanent circulatory assistance, also referred to as destination therapy. There is a paucity of information regarding the nutrition complications in VAD patients, and as such, little is presently known of the optimal means of nutrition assessment and management of these complex and often critically ill patients. In this review, a general overview of the VAD, comparisons of nutrition assessment measures, and strategies to meet the nutrition needs of these patients are provided using evidence-based information wherever possible. Because there is a lack of nutrition studies and assessment guidelines specifically for VAD patients, many of the guidelines for care of these patients are currently based on the information available for the care of patients with heart failure. Although the optimal measure to assess nutrition status remains poorly studied, a systematic, thorough nutrition assessment of patients with heart failure and heart transplant candidates prior to VAD placement appears to be important to identify those at nutrition risk and, with appropriate nutrition therapy, decrease their risk for morbidity and mortality. VAD patients with inadequate oral intake may require nutrition support to meet their nutrition needs; however, feeding the hemodynamically compromised patient provides additional challenges. PMID- 22523159 TI - A glycerin hydrogel-based wound dressing prevents peristomal infections after percutaneous endoscopic gastrostomy (PEG): a prospective, randomized study. AB - BACKGROUND: Despite the use of prophylactic antibiotics, peristomal infection is the most common complication of percutaneous endoscopic gastrostomy (PEG). A new glycerin hydrogel (GHG) wound dressing has been proposed to possess more effective antimicrobial properties but has not been tested in a larger trial. The aim of the study was therefore to assess the superiority of GHG regarding the incidence of peristomal wound infections during a 30-day postprocedure follow-up. METHODS: Sixty-eight patients with cancer undergoing PEG were recruited from 1 university and 2 general hospitals between January 2007 and December 2008. Patients were randomized to group 1 (34 patients), which received GHG, or group 2 (34 patients), which received a traditional wound dressing. Dressing changes were done at day 1 and weeks 1, 2, and 4 (group 1) vs daily changes during week 1 and at weeks 2 and 4 (group 2). The PEG site was assessed by using 2 different infection scores. RESULTS: At the end of the first and second weeks, a statistically significant reduction of the mean infection scores was seen in patients with GHG wound dressings (first week: 1.64 +/- 1.6 vs 3.12 +/- 2.69, P < .008; second week: 1.37 +/- 1.11 vs 2.53 +/- 2.37, P < .02). After 7 days, wound reactions occurred in 14.7% in the GHG group vs 47.05% in the traditional group (p <0.005). The GHG wound dressing required 5 times less frequent dressing changes. CONCLUSION: The GHG wound dressing significantly reduces peristomal wound infections and is a convenient, cost-effective alternative for wound management following PEG. PMID- 22523160 TI - Enterococcus ureilyticus sp. nov. and Enterococcus rotai sp. nov., two urease producing enterococci from the environment. AB - A set of 25 urease-producing, yellow-pigmented enterococci was isolated from environmental sources. Phenotypic classification divided the isolates into two phena. Both phena were characterized using 16S rRNA gene sequence analysis, DNA base composition, rep-PCR fingerprinting and automated ribotyping. The obtained data distinguished the isolates from all members of the genus Enterococcus with validly published names and placed them in the Enterococcus faecalis species group. DNA-DNA hybridization experiments, pheS and rpoA sequencing and whole-cell protein electrophoresis provided conclusive evidence for the classification of each phenon as a novel species of the genus Enterococcus, for which the names Enterococcus ureilyticus sp. nov. (type strain CCM 4629(T) = LMG 26676(T) = CCUG 48799(T)), inhabiting water and plants, and Enterococcus rotai sp. nov. (type strain CCM 4630(T) = LMG 26678(T) = CCUG 61593(T)), inhabiting water, insects (mosquitoes) and plants, are proposed. PMID- 22523161 TI - Castellaniella hirudinis sp. nov., isolated from the skin of Hirudo verbana. AB - A Gram-staining-negative, rod-shaped, non-spore-forming bacterium, designated strain E103(T), was isolated from the skin of the medical leech Hirudo verbana. 16S rRNA gene sequence analysis showed that the isolate was closely related to species of the genus Castellaniella. Castellaniella ginsengisoli DCY36(T) was shown to be the most closely related (98.4 % 16S rRNA gene sequence similarity), followed by Castellaniella denitrificans NKNTAU(T) and Castellaniella daejeonensis MJ06(T) (both 97.8 %), then Castellaniella caeni Ho-11(T) (97.5 %). Chemotaxonomic data (major ubiquinone, Q-8; major polar lipids, phosphatidylethanolamine, phosphatidylglycerol and phosphatidylserine; predominant polyamine, putrescine with a moderate amount of 2-hydroxyputrescine; and major fatty acids, C(17 : 0) cyclo, C(16 : 0) and summed feature 4 comprising C(16 : 1)omega7c and/or iso-C(15 : 0) 2-OH) supported the affiliation of the isolate to the genus Castellaniella. DNA-DNA hybridization values with the type strains of all species of the genus Castellaniella were 23 % (reciprocal, 18 %) with C. ginsengisoli KCTC 22398(T), 20 % (26 %) with C. daejeonensis KCTC 22454(T), 11 % (58 %) with C. denitrificans DSM 11046(T) and 13 % (12 %) with C. caeni KCTC 12197(T)(.) Phenotypic differentiation of strain E103(T) from its closest neighbours was possible. Strain E103(T) therefore represents a novel species of the genus Castellaniella, for which the name Castellaniella hirudinis sp. nov. is proposed, with the type strain E103(T) ( = CCUG 62394(T) = LMG 26910(T)). PMID- 22523162 TI - Brevibacterium yomogidense sp. nov., isolated from a soil conditioner made from poultry manure. AB - A novel Gram-stain-positive rod-shaped actinobacterium was isolated from a soil conditioner made from poultry manure. The isolate, designated strain MN-6-a(T), contained anteiso-C(15 : 0) and anteiso-C(17 : 0) as the major fatty acids, and MK-7(H(2)) and MK-8(H(2)) as the major menaquinones. Phosphatidylglycerol was a major polar lipid. The G+C content of the genomic DNA was 67.4 mol%. Phylogenetic analysis showed that strain MN-6-a(T) was closely related to Brevibacterium salitolerans TRM 415(T) with 97.1 % 16S rRNA gene sequence similarity. DNA-DNA hybridization showed that strain MN-6-a(T) had 10.2 % genomic relatedness with B. salitolerans TRM 415(T). On the basis of phenotypic, phylogenetic and chemotaxonomic data obtained in this study, strain MN-6-a(T) represents a novel species of the genus Brevibacterium, for which the name Brevibacterium yomogidense sp. nov. is proposed. The type strain is MN-6-a(T) ( = JCM 17779(T) = DSM 24850(T)). PMID- 22523163 TI - Brevibacterium siliguriense sp. nov., a facultatively oligotrophic bacterium isolated from river water. AB - A Gram-positive-staining, rod-shaped, facultatively oligotrophic bacterial strain, designated MB18(T), was isolated from a water sample collected from the River Mahananda at Siliguri (26 degrees 44' 23.20' N, 88 degrees 25' 22.89' E), West-Bengal, India. On the basis of 16S rRNA gene sequence similarity, the closest relative of this strain was Brevibacterium epidermidis NCDO 2286(T) (96 % similarity). The DNA G+C content of strain MB18(T) was 64.6 mol%. Chemotaxonomic data [MK-8(H(2)) as the major menaquinone, galactose as the sole cell-wall sugar, meso-diaminopimelic acid as the diagnostic cell-wall diamino acid, phosphatidylglycerol and diphosphatidylglycerol as constituents of the polar lipids, anteiso-C(15 : 0), anteiso-C(17 : 0) and iso-C(15 : 0) as the major fatty acids] supported the affiliation of strain MB18(T) to the genus Brevibacterium. The results of DNA G+C content, 16S rRNA gene sequence analysis and biochemical and physiological analyses allowed genotypic and phenotypic differentiation of strain MB18(T) from its nearest neighbour B. epidermidis. The isolate therefore represents a novel species, for which the name Brevibacterium siliguriense sp. nov. is proposed; the type strain is MB18(T) ( = DSM 23676(T) = LMG 25772(T)). PMID- 22523164 TI - Listeria fleischmannii sp. nov., isolated from cheese. AB - A study was performed on three isolates (LU2006-1(T), LU2006-2 and LU2006-3), which were sampled independently from cheese in western Switzerland in 2006, as well as a fourth isolate (A11-3426), which was detected in 2011, using a polyphasic approach. The isolates could all be assigned to the genus Listeria but not to any known species. Phenotypic and chemotaxonomic data were compatible with the genus Listeria and phylogenetic analysis based on 16S rRNA gene sequences confirmed that the closest relationships were with members of this genus. However, DNA-DNA hybridization demonstrated that the isolates did not belong to any currently described species. Cell-wall-binding domains of Listeria monocytogenes bacteriophage endolysins were able to attach to the isolates, confirming their tight relatedness to the genus Listeria. Although PCR targeting the central portion of the flagellin gene flaA was positive, motility was not observed. The four isolates could not be discriminated by Fourier transform infrared spectroscopy or pulsed-field gel electrophoresis. This suggests that they represent a single species, which seems to be adapted to the environment in a cheese-ripening cellar as it was re-isolated from the same type of Swiss cheese after more than 5 years. Conjugation experiments demonstrated that the isolates harbour a transferable resistance to clindamycin. The isolates did not exhibit haemolysis or show any indication of human pathogenicity or virulence. The four isolates are affiliated with the genus Listeria but can be differentiated from all described members of the genus Listeria and therefore they merit being classified as representatives of a novel species, for which we propose the name Listeria fleischmannii sp. nov.; the type strain is LU2006-1(T) ( = DSM 24998(T) = LMG 26584(T)). PMID- 22523165 TI - 'Candidatus Phytoplasma malaysianum', a novel taxon associated with virescence and phyllody of Madagascar periwinkle (Catharanthus roseus). AB - This study addressed the taxonomic position and group classification of a phytoplasma responsible for virescence and phyllody symptoms in naturally diseased Madagascar periwinkle plants in western Malaysia. Unique regions in the 16S rRNA gene from the Malaysian periwinkle virescence (MaPV) phytoplasma distinguished the phytoplasma from all previously described 'Candidatus Phytoplasma' species. Pairwise sequence similarity scores, calculated through alignment of full-length 16S rRNA gene sequences, revealed that the MaPV phytoplasma 16S rRNA gene shared 96.5 % or less sequence similarity with that of previously described 'Ca. Phytoplasma' species, justifying the recognition of the MaPV phytoplasma as a reference strain of a novel taxon, 'Candidatus Phytoplasma malaysianum'. The 16S rRNA gene F2nR2 fragment from the MaPV phytoplasma exhibited a distinct restriction fragment length polymorphism (RFLP) profile and the pattern similarity coefficient values were lower than 0.85 with representative phytoplasmas classified in any of the 31 previously delineated 16Sr groups; therefore, the MaPV phytoplasma was designated a member of a new 16Sr group, 16SrXXXII. Phytoplasmas affiliated with this novel taxon and the new group included diverse strains infecting periwinkle, coconut palm and oil palm in Malaysia. Three phytoplasmas were characterized as representatives of three distinct subgroups, 16SrXXXII-A, 16SrXXXII-B and 16SrXXXII-C, respectively. PMID- 22523166 TI - Oligosphaera ethanolica gen. nov., sp. nov., an anaerobic, carbohydrate fermenting bacterium isolated from methanogenic sludge, and description of Oligosphaeria classis nov. in the phylum Lentisphaerae. AB - A mesophilic, obligately anaerobic, carbohydrate-fermenting bacterium, designated 8KG-4(T), was isolated from an upflow anaerobic sludge blanket reactor treating high-strength organic wastewater from salted vegetable production processes. Cells of strain 8KG-4(T) were non-motile, spherical and 0.7-1.5 um in diameter (mean, 1.0 um). Spore formation was not observed under any culture conditions tested. The strain grew optimally at 37 degrees C (range for growth 25-40 degrees C) and pH 7.0 (range, pH 6.5-7.5), and could grow fermentatively on glucose, ribose, xylose, galactose and sucrose. The main end products of glucose fermentation were acetate, ethanol and hydrogen. Organic acids, alcohols and amino acids were not utilized for growth. Yeast extract was not required for growth. Nitrate, sulfate, thiosulfate, elemental sulfur, sulfite and Fe(III) nitrilotriacetate were not used as terminal electron acceptors. The G+C content of the genomic DNA was 61.1 mol%. 16S rRNA gene sequence analysis revealed that the isolate represented a previously uncultured lineage at the subphylum level within the phylum Lentisphaerae known as 'WWE2 subgroup I'. The major cellular fatty acids were anteiso-C(15 : 0), iso-C(16 : 0), C(16 : 0) and anteiso-C(17 : 0). Respiratory quinones were not detected. The most abundant polar lipid of strain 8KG-4(T) was phosphatidylethanolamine. A novel genus and species, Oligosphaera ethanolica gen. nov., sp. nov., is proposed to accommodate strain 8KG-4(T) ( = JCM 17152(T) = DSM 24202(T) = CGMCC 1.5160(T)). In addition, we formally propose Oligosphaeria classis nov. and the subordinate taxa Oligosphaerales order nov. and Oligosphaeraceae fam. nov. PMID- 22523167 TI - Stakelama sediminis sp. nov., isolated from tidal flat sediment. AB - A novel bacterial strain designated CJ70(T) was isolated from tidal flat sediment in Korea. A polyphasic approach was used to identify this strain taxonomically. The isolate was Gram-stain-negative, strictly aerobic, yellow-pigmented, rod shaped and non-motile. Phylogenetic analysis of the 16S rRNA gene sequence revealed that strain CJ70(T) was related most closely to Stakelama pacifica JLT832(T) with 95.7 % similarity and formed an independent phyletic line from recognized species of the genus Sphingomonas, comprising a clade with Stakelama pacifica, which is the only recognized species of the genus Stakelama. The predominant cellular fatty acids of strain CJ70(T) were C(18 : 1)omega7c (60.0 %), C(16 : 0) (21.2 %) and C(14 : 0) 2-OH (5.8 %). The major isoprenoid quinone was ubiquinone-10. The G+C content of the genomic DNA was 61.4 mol%. The results obtained from this study suggested that strain CJ70(T) represents a novel species of the genus Stakelama, for which the name Stakelama sediminis sp. nov. is proposed. The type strain is CJ70(T) ( = KACC 16559(T) = JCM 18079(T)). PMID- 22523168 TI - Pontibacter saemangeumensis sp. nov., isolated from seawater. AB - A gram-negative, rod-shaped, non-motile and pink bacterial strain, designated strain GCM0142(T), was isolated from the confined seawater in the Saemangeum Tide Embankment of South Korea, and characterized using a polyphasic approach. 16S rRNA gene sequence analysis of strain GCM0142(T) indicated that the isolate belonged to the phylum Bacteroidetes and exhibited similarity levels of 94.0-96.4 % to the type strains of recognized Pontibacter species. Strain GCM0142(T) was oxidase- and catalase-positive. The major cellular fatty acids of the novel strain were summed feature 4 (comprising iso-C(17 : 1)I and/or anteiso-C(17 : 1)B, 36.8 %), iso-C(15 : 0) (22.3 %) and summed feature 3 (comprising C(16 : 1)omega7c and/or C(16 : 1)omega6c, 6.2 %). The DNA G+C content of strain GCM0142(T) was 48.9 mol% and the major quinone was MK-7. The polar lipid profile consisted of phosphatidylethanolamine, two unknown aminolipids (AL1-2), an unknown aminophospholipid, five unknown lipids (L1-5) and an unknown glycolipid. On the basis of the evidence presented, strain GCM0142(T) is considered to represent a novel species of the genus Pontibacter, for which the name Pontibacter saemangeumensis sp. nov. is proposed. The type strain is GCM0142(T) ( = KACC 16448(T) = JCM 17926(T)). PMID- 22523169 TI - Saccharothrix hoggarensis sp. nov., an actinomycete isolated from Saharan soil. AB - An actinomycete, designated SA181(T), was isolated from Saharan soil in the Hoggar region (south Algeria) and was characterized taxonomically by using a polyphasic approach. The morphological and chemotaxonomic characteristics of the isolate were consistent with the genus Saccharothrix, and 16S rRNA gene sequence analysis confirmed that strain SA181(T) was a novel member of the genus Saccharothrix. DNA-DNA hybridization values between strain SA181(T) and its closest phylogenetic neighbours, the type strains of Saccharothrix longispora, Saccharothrix texasensis and Saccharothrix xinjiangensis, were clearly below the 70 % threshold. The genotypic and phenotypic data showed that the isolate represents a novel species of the genus Saccharothrix, for which the name Saccharothrix hoggarensis sp. nov. is proposed, with the type strain SA181(T) ( = DSM 45457(T) = CCUG 60214(T)). PMID- 22523170 TI - Micromonospora sediminicola sp. nov., isolated from marine sediment. AB - An actinomycete strain, designated strain SH2-13(T), was isolated from a marine sediment sample collected from the Andaman Sea of Thailand. Applying a polyphasic approach, the isolate was identified as a member of the genus Micromonospora using morphological and chemotaxonomic characteristics, including the presence of meso-diaminopimelic acid in the peptidoglycan. Whole-cell sugars were arabinose, galactose, glucose, rhamnose, ribose and xylose. Diagnostic polar lipids were phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylinositol, phosphatidylinositol mannosides and phosphoglycolipids. The major menaquinones were MK-10(H(2)), MK-10(H(4)) and MK-10(H(6)). 16S rRNA gene sequence analysis revealed similarity to Micromonospora marina JSM1-1(T) (99.1 %), Micromonospora coxensis 2-30-b(28)(T) (99.1 %), Micromonospora aurantiaca DSM 43813(T) (98.8 %) and Micromonospora chalcea DSM 43026(T) (98.7 %). However, a combination of DNA-DNA hybridization results and phenotypic properties indicated that strain SH2-13(T) ( = NBRC 107934(T) = BCC 45601(T)) should be classified as the type strain of a novel species, with the proposed name Micromonospora sediminicola sp. nov. PMID- 22523171 TI - Micromonospora maritima sp. nov., isolated from mangrove soil. AB - Strain D10-9-5(T) was isolated from mangrove soil in Samut Sakhon province, Thailand. A polyphasic approach was used to determine the taxonomic position of the strain. The strain presented single rough spores on substrate mycelium and no aerial mycelium. Chemotaxonomic data supported the assignment of strain D10-9 5(T) to the genus Micromonospora based on the presence of meso-diaminopimelic acid and glycolyl muramic acid in the peptidoglycan, ribose, mannose, galactose, xylose and glucose as whole-cell sugars, MK-10(H(4)) (14.8 %), MK-10(H(6)) (46.7 %) and MK-10(H(8)) (27.5 %) as the predominant isoprenoid quinones, iso-C(15 : 0) (17.9 %), anteiso-C(17 : 0) (14.6 %), iso-C(17 : 0) (9.6 %), C(17 : 0) (8.0 %), iso-C(16 : 0) (7.7 %) and C(17 : 1)omega8c (7.0 %) as the major cellular fatty acids, and diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, phosphatidylinositol mannosides and phosphatidylethanolamine as the predominant phospholipids in the cell wall. The 16S rRNA gene sequence and phylogenetic analysis showed that strain D10-9-5 was closely related to Micromonospora marina JCM 12870(T) (99.6 %), Micromonospora coxensis JCM 13248 (T) (99.4 %), Micromonospora aurantiaca JCM 10878(T) (99.3 %), Micromonospora humi JCM15292(T) (99.3 %), Micromonospora halophytica JCM 3125(T) (99.1%) and Micromonospora chalcea JCM 3031(T) (99.1 %). Strain D10-9-5(T) could be clearly distinguished from related members of the genus Micromonospora by its physiological and biochemical characteristics as well as its phylogenetic position and level of DNA DNA relatedness. Therefore, the strain represents a novel species for which the name Micromonospora maritima sp. nov. is proposed; the type strain is D10-9-5(T) ( = JCM 17013(T) = NBRC 108767(T) = PCU 322(T) = TISTR 2000(T)). PMID- 22523172 TI - Actinomadura xylanilytica sp. nov., an actinomycete isolated from soil. AB - The taxonomic position of a soil isolate, strain BK147(T), was established using data from a polyphasic study. The organism showed a combination of chemotaxonomic and morphological characteristics consistent with its classification in the genus Actinomadura. It formed a distinct phyletic line in the phylogenetic tree based on 16S rRNA gene sequences of members of the genus Actinomadura and was most closely, albeit loosely, related to Actinomadura bangladeshensis DSM 45347(T), Actinomadura meyerae DSM 44715(T) and Actinomadura napierensis NRRL B-24319(T) but was readily distinguished from these strains using a range of phenotypic properties. Based on the combined genotypic and phenotypic data it is proposed that isolate BK147(T) ( = KACC 20919(T) = NCIMB 14771(T) = NRRL B-24852(T)) be classified as the type strain of a novel species of the genus Actinomadura, for which the name Actinomadura xylanilytica sp. nov. is proposed. PMID- 22523173 TI - Impact of adenotonsillectomy on high-sensitivity C-reactive protein levels in obese children with obstructive sleep apnea. AB - OBJECTIVE: To evaluate the effect of adenotonsillectomy (T&A) in obese children with obstructive sleep apnea (OSA) and to compare changes in high-sensitivity C reactive protein (hs-CRP) levels before and 6 months after T&A in obese children with OSA. STUDY DESIGN: Before and after study with planned data collection. SETTING: Tertiary care, university-based pediatric hospital. SUBJECTS AND METHODS: Seventy-five obese children with OSA were included. Clinical information such as the apnea-hypopnea index (AHI), nadir oxyhemoglobin saturation (SaO(2)), and body mass index (BMI) were recorded. The hs-CRP level was determined before T&A and at the 6-month follow-up examination. RESULTS: Reductions in AHI (21.96 +/- 9.277 before T&A vs 8.64 +/- 5.997 after 6 months of T&A) and higher levels of nadir SaO(2) (74.08 +/- 7.860 before T&A vs 86.87 +/- 5.586 after 6 months of T&A) were observed. The hs-CRP levels were obviously correlated with BMI (r = 0.7948, P < .001). Other than AHI (r = 0.0579, P = .6217) in obese children, however, hs-CRP levels showed no changes 6 months after T&A therapy. CONCLUSION: T&A treatment improves clinical signs and symptoms in obese children but does not reduce chronic inflammation as reflected by hs-CRP. To lower the risks of cardiovascular disease and diabetes mellitus morbidity, other treatments should be taken into account. PMID- 22523174 TI - Home is where we start from. PMID- 22523175 TI - Are you sitting too comfortably? Using the praxis of positioning to move between the activities of therapy-supervision and the identities of therapist-supervisor. AB - Practitioners extending their repertoire to include supervising the practice of others may see it as an additional professional activity which may be accommodated within their current identities. For some, it may also become a turning point that requires/promotes a second order development across personal and professional identities. Positioning theory (Harre and Langhove 1999) offers a framework which practitioners can use in making the intellectual and linguistic distinctions between different activities/identities, including the supervisory relationship. This paper further explores how a reflexive awareness of physical position, and an ability/willingness to move and re-position can facilitate the elaboration of both the activity of supervision and the identity of supervisor at the levels of approach, method and technique (Burnham 1992, 1993). PMID- 22523176 TI - Systemic supervision practices compared: a closer look at 'reflection' and 'self' in Multisystemic Therapy and Family Therapy supervision. AB - Family and systemic therapists are becoming increasingly interested in evidence based practice. By implication, clinical supervision practices that support therapists need to keep step with this trend. Supervision practices within Multisystemic Therapy as a more outcome-focussed treatment model that works with families are compared with the supervision of family therapists working a mental health clinic. This paper looks at some of the more prominent supervisory practices in MST and Family Therapy and explores their similarities and differences. The various challenges that are present when working in clients' homes are explored and implications for supervision discussed. Therapists who frequent clients' homes may need a different skill-set and their supervisors in turn require taking a different approach. The clinical supervisor to a therapist working out in the community tends to (be able to) be more proactive. Systemic supervisors to more clinical based family therapist put emphasis on the explorative aspects of the therapeutic encounter including self-reflective practices, whereas MST supervisors' primary focus remains on the clinical outcomes for the clients. The place of self-reflexivity in both approaches to supervision is explored. Case examples drawn from the authors' own supervisory practice will be presented to illustrate the different practices presented. PMID- 22523178 TI - Relationship of vitamin D deficiency to clinical outcomes in critically ill patients. AB - BACKGROUND: Despite the numerous disease conditions associated with vitamin D deficiency in the general population, the relationship of this deficiency to outcome in critically ill patients remains unclear. The objective of this study is to determine the burden of vitamin D deficiency in intensive care unit (ICU) patients and determine if it is associated with poor patient outcomes. METHODS: The authors conducted an analysis of samples collected from a prospective study of 196 patients admitted to a medical/surgical ICU in a tertiary care hospital. They measured serum 25-hydroxyvitamin D at admission and up to 10 days following admission and followed patients prospectively for 28-day outcomes. RESULTS: Of analyzable patients, 50 (26%) were deficient (<=30 nmol/L) and 109 (56%) were insufficient (>30 and <=60 nmol/L). Baseline 25(OH)D levels decreased significantly in all patients after 3 days in the ICU and remained significantly lower through 10 days (P < .001). 25(OH)D status was not significantly associated with 28-day all-cause mortality (hazard ratio [HR], 0.89; 95% confidence interval, [CI] 0.37-2.24). Higher levels of 25(OH)D were associated with a shorter time-to-alive ICU discharge (HR, 2.11; 95% CI, 1.27-3.51). 25(OH)D deficient patients showed a nonstatistically significant trend toward a higher infection rate (odds ratio [OR], 3.20; 95% CI, 0.784-13.07; P = .11) compared with patients with sufficient levels of 25(OH)D. CONCLUSIONS: This study demonstrates significant decreases in vitamin D status over the duration of the patient's ICU stay. Low levels of vitamin D are associated with longer time to ICU discharge alive and a trend toward increased risk of ICU-acquired infection. PMID- 22523179 TI - Characteristics and current practice of parenteral nutrition in hospitalized patients. AB - BACKGROUND: For 40 years, parenteral nutrition (PN) has provided therapeutic benefits to patients unable to receive oral/enteral nutrition. Very limited published evidence exists to describe modern PN practices or characteristics of patients receiving PN. The aim of this article was to describe the characteristics of hospitalized patients receiving PN in 196 U.S. hospitals to define patient groups at risk for PN-related complications. This will provide researchers a baseline understanding about who is receiving hospital-based PN to maximize generalizability and validity of future research. METHODS: Claims data from the Premier Perspective database, the largest inpatient clinical database in the United States, were used to evaluate hospital-based PN practices. Data gathered between January 2005 and December 2007 included a total of 106,374 patients receiving PN. A total of 68,984 adults (age >= 18 years), 34,307 infants (age <1 year), and 3083 pediatric patients (age 1-17 years) were evaluated. Key variables such as admitting diagnosis, infection rates, in-hospital mortality, and costs were extracted. RESULTS: Hospitalized patients requiring PN in the United States are older and more often white than the overall hospitalized population. Hospitalized PN patients are more likely to be admitted emergently and have a higher severity of illness. Bloodstream infection rates in adult PN patients (25.5%) were considerably higher than in pediatric (14.7%) or neonatal patients (1.7%) receiving PN. CONCLUSIONS: These findings are the first large scale description of "real-world" hospital-based PN practices in the United States, helping set a baseline for future PN research. PMID- 22523180 TI - EGFR somatic mutations in lung tumors: radon exposure and passive smoking in former- and never-smoking U.S. women. AB - BACKGROUND: Patients with lung cancer with mutations in EGF receptor (EGFR) tyrosine kinase have improved prognosis when treated with EGFR inhibitors. We hypothesized that EGFR mutations may be related to residential radon or passive tobacco smoke. METHODS: This hypothesis was investigated by analyzing EGFR mutations in 70 lung tumors from a population of never and long-term former female smokers from Missouri with detailed exposure assessments. The relationship with passive smoking was also examined in never-smoking female lung cancer cases from the Mayo clinic. RESULTS: Overall, the frequency of EGFR mutation was 41% [95% confidence interval (CI), 32%-49%]. Neither radon nor passive-smoking exposure was consistently associated with EGFR mutations in lung tumors. CONCLUSIONS: The results suggest that EGFR mutations are common in female, never smoking lung cancer cases from the United States, and EGFR mutations are unlikely due to exposure to radon or passive smoking. PMID- 22523181 TI - A randomized trial of aerobic exercise and sleep quality in lymphoma patients receiving chemotherapy or no treatments. AB - BACKGROUND: Patients with lymphoma experience sleep problems that may be managed with aerobic exercise but no previous study has examined this issue. METHODS: We randomized 122 patients with lymphoma to usual care (n = 62) or 12 weeks of supervised aerobic exercise training (AET; n = 60). Our primary sleep endpoint was global sleep quality assessed by the Pittsburgh Sleep Quality Index (PSQI). Secondary endpoints were the PSQI component scores. Planned subgroup analyses were also conducted. RESULTS: Intention-to-treat analyses indicated that AET resulted in a nonsignificant (P = 0.16) improvement in global sleep quality compared with usual care [mean group difference = -0.64; 95% confidence interval (CI), -1.56 to +0.27]. In planned subgroup analyses, statistically significant or borderline significant interactions were identified for type of lymphoma (P(interaction) = 0.006), current treatment status (P(interaction) = 0.036), time since diagnosis (P(interaction) = 0.010), body mass index (P(interaction) = 0.075), and baseline sleep quality (P(interaction) = 0.041). Specifically, AET improved global sleep quality in patients with lymphoma who had indolent non Hodgkin lymphoma (P = 0.001), were receiving chemotherapy (P = 0.013), were <2 years post-diagnosis (P = 0.005), were obese (P = 0.025), and were poor sleepers at baseline (P = 0.007). CONCLUSIONS: AET did not significantly improve sleep quality in this heterogeneous sample of patients with lymphoma; however, clinically identifiable subgroups appeared to benefit. Future exercise trials targeting these responsive subgroups are needed to confirm these findings. IMPACT: If replicated in larger and more focused trials, aerobic exercise may be an attractive option to manage sleep dysfunction in patients with cancer because of its favorable safety profile and other documented health benefits. PMID- 22523182 TI - Intraindividual variation in plasma 25-hydroxyvitamin D measures 5 years apart among postmenopausal women. AB - BACKGROUND: Current literature examining associations between vitamin D and chronic disease generally use a single assessment of 25-hydroxyvitamin D [25(OH)D], assuming the 25(OH)D concentration of an individual is consistent over time. METHODS: We investigated the intraindividual variability between two measures of plasma 25(OH)D concentrations collected approximately five years apart (1997-2000 to 2002-2005) in 672 postmenopausal women participating in the Women's Health Initiative. Plasma 25(OH)D was assessed using the DiaSorin LIAISON(r) chemiluminescence immunoassay. The within-pair coefficient of variation (CV) was 4.9% using blinded quality control samples. Mean and SDs of 25(OH)D at the two time points were compared using a paired t test. An intraindividual CV and intraclass correlation coefficient (ICC) were used to assess intraindividual variability. A Spearman correlation coefficient (r) assessed the strength of the association between the two measures, and concordance in vitamin D status at two time points was compared. RESULTS: Mean 25(OH)D concentrations (nmol/L) significantly increased over time from 60.0 (SD = 22.2) to 67.8 (SD = 22.2; P < 0.05). The CV was 24.6%, the ICC [95% confidence interval (CI)] was 0.59 (0.54-0.64), and the Spearman r was 0.61 (95% CI = 0.56 0.66). Greater concordance over five years was observed in participants with sufficient compared with deficient or inadequate baseline 25(OH)D concentrations (weighted kappa = 0.39). Reliability measures were moderately influenced by season of blood draw and vitamin D supplement use. CONCLUSION: There is moderate intraindividual variation in 25(OH)D concentrations over approximately five years. IMPACT: These data support the use of a one-time measure of blood 25(OH)D in prospective studies with <= five years of follow-up. PMID- 22523184 TI - Dropout in crossover and longitudinal studies: is complete case so bad? AB - We discuss inference for longitudinal clinical trials subject to possibly informative dropout. A selection of available methods is reviewed for the simple case of trials with two timepoints. Using data from two such clinical trials, each with two treatments, we demonstrate that different analysis methods can at times lead to quite different conclusions from the same data. We investigate properties of complete-case estimators for the type of trials considered, with emphasis on interpretation and meaning of parameters. We contrast longitudinal and crossover designs and argue that for crossover studies there are often good reasons to prefer a complete case analysis. More generally, we suggest that there is merit in an approach in which no untestable assumptions are made. Such an approach would combine a dropout analysis, an analysis of complete-case data only, and a careful statement of justified conclusions. PMID- 22523183 TI - High-resolution mapping of anatomical connections in marmoset extrastriate cortex reveals a complete representation of the visual field bordering dorsal V2. AB - The primate visual cortex consists of many areas. The posterior areas (V1, V2, V3, and middle temporal) are thought to be common to all primate species. However, the organization of cortex immediately anterior to area V2 (the "third tier" cortex) remains controversial, particularly in New World primates. The main point of contention has been whether the third tier cortex consists of a single area V3, representing lower and upper visual quadrants in dorsal and ventral cortex, respectively, or of 2 distinct areas (the dorsomedial [DM] area and a V3 like area). Resolving this controversy is crucial to understand the function and evolution of the third tier cortex. We have addressed this issue in marmosets, by performing high-precision mapping of corticocortical connections in cortex bordering dorsal V2. Multiple closely spaced neuroanatomical tracer injections were placed across the full width of dorsal V2 or adjacent anterior cortex, and the location of resulting labeled cells mapped throughout whole flattened visual cortex. The resulting topographic patterns of labeled connections allowed us to define areas and their boundaries. We found that a complete representation of the visual field borders dorsal V2 and that the third tier cortex consists of 2 distinct areas. These results unequivocally support the DM model. PMID- 22523185 TI - The analysis of multivariate longitudinal data: a review. AB - Longitudinal experiments often involve multiple outcomes measured repeatedly within a set of study participants. While many questions can be answered by modeling the various outcomes separately, some questions can only be answered in a joint analysis of all of them. In this article, we will present a review of the many approaches proposed in the statistical literature. Four main model families will be presented, discussed and compared. Focus will be on presenting advantages and disadvantages of the different models rather than on the mathematical or computational details. PMID- 22523186 TI - Suppressive effect of chronic peroral topiramate on potassium-induced cortical spreading depression in rats. AB - OBJECTIVE: To evaluate the chronic effect of topiramate (TPM) on cortical spreading depression (CSD), which is thought to be related to migraine aura. METHODS: Male rats (n = 30) were randomized to once-daily peroral treatment with TPM (50, 100, 200 or 600 mg/kg) or vehicle for 6 weeks. We evaluated the characteristics of CSD induced by topical application of KCl under isoflurane anesthesia and the changes in plasma level of TPM in each group. The effect of single administration of TPM on CSD was also evaluated. RESULTS: After the final administration of TPM, when the plasma level of TPM was high, KCl-induced CSD frequency and CSD propagation velocity were dose-dependently reduced and the interval between CSD episodes was elongated, compared with the vehicle control. However, before the final administration of TPM, when the plasma level was very low, the KCl-induced CSD profile was the same as that in the vehicle control. Single administration of TPM did not alter the CSD profile. Local cerebral blood flow was not significantly altered by chronic administration of TPM. CONCLUSION: TPM suppressed the frequency and propagation of CSD along the cerebral cortex, and might be a candidate for relief of migraine. PMID- 22523187 TI - Peripheral endothelial function and arterial stiffness in women with migraine with aura: a case-control study. AB - BACKGROUND: Vascular dysfunction may be involved in migraine pathophysiology and contribute to the increased risk of ischemic stroke in migraine, particularly in women with migraine with aura (MA). However, data on endothelial function in MA are controversial. Here, we investigated whether systemic endothelial function and arterial stiffness are altered in women with MA, using a novel peripheral arterial tonometry device for the first time. METHODS: Twenty-nine female MA patients without comorbidities and 30 healthy women were included, and carotid intima-media thickness was assessed by a standardized procedure. Endothelial function was assessed using peripheral arterial tonometry. Reactive hyperaemic response of digital pulse amplitude was measured following 5 minutes of forearm occlusion of the brachial artery. Arterial stiffness was assessed by fingertip tonometry derived and heart-rate-adjusted augmentation index. RESULTS: No differences were found in peripheral arterial tonometry ratio (2.3 +/- 0.6 vs 2.2 +/- 0.8; p = 0.58) and left carotid intima-media thickness (in um: 484 +/- 119 vs 508 +/- 60; p = 0.37). Women with MA had higher heart-rate-averaged augmentation index [median (interquartile range, IQR) of 5 (IQR 0.5 to 18) vs -5 (IQR -16.8 to 8.3), p = 0.005] and heart-rate-adjusted augmentation index [1 (IQR -6 to 12.5) vs -8 (IQR -20.3 to 2.5), p = 0.008] than healthy controls. CONCLUSION: Peripheral endothelial function is not impaired in women with MA, but they have greater arterial stiffness. This may contribute to the increased stroke risk in women with MA. PMID- 22523188 TI - Posterior circulation embolism as a potential mechanism for migraine with aura. AB - BACKGROUND: Although the mechanism of migraine is regarded as a functional disorder of the brain, numerous studies have reported that migraine is closely associated with vascular system abnormalities. CASE REPORTS: We describe a 19 year-old female with recurrent migraine attacks and typical aura for 7 years. MRI showed multiple stroke lesions in the posterior circulation. Moreover, a pseudoaneurysm (1.9 * 1.4 cm) originating from the left vertebral artery was observed on four-vessel angiography. Multiple microembolic signals (MES) were repeatedly observed in the basilar artery using 30-minute transcranial Doppler monitoring. Interestingly, MES and her typical migrainous symptoms disappeared simultaneously with removal of the pseudoaneurysm. DISCUSSION: This case supports the fact that microemboli play a pivotal role in the development of migraine attacks. PMID- 22523189 TI - Preparation and chiral separation of a novel immobilized cellulose-based chiral stationary phase in high-performance liquid chromatography. AB - The chiral selector 6-azido-2, 3-di(p-chlorophenylcarbamoylated) cellulose was synthesized and further chemically immobilized onto 5-MUm amino functionalized spherical porous silica gel. It was used as chiral stationary phase in high performance liquid chromatography. Thirty racemates were successfully separated into enantiomers in either normal phase mode or reversed-phase mode. Good reproducibility and stability of the chiral stationary phase have been demonstrated. PMID- 22523190 TI - Pharmacists' impact on improving outcomes in patients with type 2 diabetes mellitus. AB - PURPOSE: The purpose of this study was to evaluate a diabetes education program that includes a pharmacist as a member of the diabetes management team by assessing the change in hemoglobin A1c (A1C), cholesterol, and blood pressure for patients with type 2 diabetes in outpatient clinics. METHODS: This was a retrospective study in outpatient clinics at Shands Jacksonville Medical Center. The patients were assigned into either the pharmacist group or the nonpharmacist group, according to the presence or the absence of a pharmacist in the clinic. The primary end point was the absolute change in A1C versus baseline. Secondary end points included change in cholesterol and blood pressure and the number of patients to attain American Diabetes Association goals. End points were recorded to correlate within 3 months of the initial visit and final visit with a provider. RESULTS: Compared to the nonpharmacist group, patients in the pharmacist group had more advanced and uncontrolled diabetes at baseline. The pharmacist group showed a greater percent change in A1C and improvement between the initial and final clinic visits, after adjusting for baseline confounders. Despite the statistically significant improvement in A1C in the pharmacist group, there was no difference found between the 2 groups for the end points of cholesterol and blood pressure. CONCLUSION: Including a pharmacist as a part of the diabetes management team may result in lower A1C in patients with more advanced and uncontrolled type 2 diabetes mellitus versus a health care team without a pharmacist. PMID- 22523192 TI - Overexpressing the ANR1 MADS-box gene in transgenic plants provides new insights into its role in the nitrate regulation of root development. AB - The expression of the ANR1 MADS-box gene was manipulated in transgenic plants to investigate its role in the NO(3)(-)-dependent regulation of root development in Arabidopsis thaliana. Constitutive overexpression of ANR1 in roots, achieved using GAL4 enhancer trap lines, resulted in more rapid early seedling development, increased lengths and numbers of lateral roots and increased shoot fresh weight. Based on results obtained with five different enhancer trap lines, the overexpression of ANR1 in the lateral root tips appears to be more important for this phenotype than its level of expression in the developing lateral root primordia. Dexamethasone-mediated induction of ANR1 in lines expressing an ANR1 GR (glucocorticoid receptor) fusion protein stimulated lateral root growth but not primary root growth. Short-term (24 h) dexamethasone treatments led to prolonged stimulation of lateral root growth, whether the lateral roots were already mature or still unemerged at the time of treatment. In split-root experiments, localized application of dexamethasone to half of the root system of an ANR1-GR line elicited a localized increase in both the length and numbers of lateral roots, mimicking the effect of a localized NO(3)(-) treatment. In both types of transgenic line, the root phenotype was strongly dependent on the presence of NO(3)(-), indicating that there are additional components involved in ANR1 function that are NO(3)(-) regulated. The implications of these results for our understanding of ANR1's mode of action in the root response to localized NO(3)(-) are discussed. PMID- 22523197 TI - Can intensive longitudinal monitoring of individuals advance cancer research? PMID- 22523198 TI - Prognostic role of serum parathyroid hormone levels in advanced prostate cancer patients undergoing zoledronic acid administration. AB - BACKGROUND: Secondary hyperparathyroidism is frequent in prostate cancer patients with bone metastases, and this condition is worsened by the administration of potent bisphosphonates. Serum parathyroid hormone (PTH) elevation can impair the efficacy of these drugs in terms of survival. METHODS: The prognostic role of elevated serum PTH levels at baseline and after 3 months of zoledronic acid administration was assessed prospectively in 643 bone metastatic prostate cancer patients enrolled in a prospective randomized, placebo-controlled study. RESULTS: On multivariate analysis, after adjusting for major prognostic factors and bone turnover markers, elevated baseline serum PTH level was negatively associated with overall survival (hazard ratio [HR], 1.448; 95% confidence interval [CI], 1.045-2.006; p < .03) in zoledronic acid-treated patients but not in placebo treated patients. In patients with normal baseline PTH levels, there was a trend but insignificant association between zoledronic acid administration and a better survival outcome than with placebo (HR, 0.81; 95% CI, 0.65-1.01; p = .065), whereas a trend in the opposite direction was observed in patients with elevated PTH levels (HR, 1.45; 95% CI, 0.87-2.39; p = .151); interaction test, p = .040. Elevated serum PTH level after 3 months of zoledronic acid treatment was not significantly associated with survival outcome. CONCLUSIONS: Secondary hyperparathyroidism has a negative prognostic impact in metastatic prostate cancer patients undergoing zoledronic acid administration. Counteracting elevated PTH levels by adequate doses of vitamin D may improve the efficacy of this drug. PMID- 22523200 TI - Commentary: a step towards understanding asthma in low- and middle-income countries. PMID- 22523199 TI - Advances in first-line treatment for patients with HER-2+ metastatic breast cancer. AB - BACKGROUND: The prognosis for breast cancer patients overexpressing human epidermal growth factor receptor (HER)-2 has changed with anti-HER-2-targeted therapy. Although anti-HER-2 therapy with trastuzumab and chemotherapy is the standard first-line treatment, the best therapeutic regimen has yet to be defined, and new strategies are evolving. METHODS: A literature review of well established and recently published trials, reviews, and ongoing clinical trials addressing first-line treatment for HER-2(+) metastatic breast cancer patients was performed. RESULTS: Taxanes are the agents most commonly used in combination with trastuzumab, but other chemotherapy drugs, such as anthracyclines, vinorelbine, and gemcitabine and triple-combination therapies including platinum compounds, capecitabine, and taxanes have been studied. The combination of aromatase inhibitors with anti-HER-2 therapies is a new therapeutic option for some patients who coexpress HER-2 and hormone receptors, although its activity observed in randomized clinical trials seems to be inferior to that of chemotherapy plus anti-HER-2 therapies. In addition, new anti-HER-2 therapies have shown activity in HER-2(+) tumors, both alone and in combination with trastuzumab. CONCLUSIONS: Trastuzumab plus chemotherapy is the current standard of care for the upfront treatment of HER-2(+) breast cancer patients, though other anti-HER-2-targeting agents may appear as new standards in the upcoming years. PMID- 22523201 TI - CNS infections, sepsis and risk of Parkinson's disease. AB - BACKGROUND: Neuroinflammation may play an important role in the aetiology of Parkinson's disease (PD); however, little is known about infections in relation to future PD risk. METHODS: We conducted a register-based nested case-control study in Sweden to examine infections of the central nervous system (CNS) and sepsis in relation to PD with 18,648 patients and 93,240 matched controls. We defined the index date as the date of first recorded PD diagnosis in the Swedish Patient Register. RESULTS: Overall, PD patients were more likely to have a previous hospitalization for CNS infections [odds ratio (OR) = 1.5, 95% confidence interval (CI): 1.2-1.9] or sepsis (OR = 1.6, 95% CI: 1.4-1.7) than controls, largely due to hospitalizations in the year before PD identification (CNS infections: OR = 3.0, 95% CI: 1.6-5.7; sepsis: OR = 3.5, 95% CI: 3.0-4.0). However, we found that subjects with multiple CNS infections at least 5 years before the index date had higher PD occurrence than those without CNS infections (OR = 3.3, 95% CI: 1.4-8.2), whereas the corresponding OR for sepsis was 1.4 (95% CI: 0.8-2.4). After the index date, PD patients were more likely to be hospitalized for CNS infections [hazard ratio (HR) =1.8, 95% CI: 1.2-2.7] or sepsis (HR = 2.2, 95% CI: 2.1-2.4) than controls. CONCLUSIONS: This study provides preliminary evidence for an association between CNS infections, but not sepsis, and a higher future risk of PD. It also shows that PD patients were more prone to CNS infections and sepsis than controls. PMID- 22523202 TI - Secretory pathway research: the more experimental systems the better. AB - Transient gene expression, in plant protoplasts or specific plant tissues, is a key technique in plant molecular cell biology, aimed at exploring gene products and their modifications to examine functional subdomains, their interactions with other biomolecules, and their subcellular localization. Here, we highlight some of the major advantages and potential pitfalls of the most commonly used transient gene expression models and illustrate how ectopic expression and the use of dominant mutants can provide insights into protein function. PMID- 22523203 TI - Emergent decarboxylase activity and attenuation of alpha/beta-hydrolase activity during the evolution of methylketone biosynthesis in tomato. AB - Specialized methylketone-containing metabolites accumulate in certain plants, in particular wild tomatoes in which they serve as toxic compounds against chewing insects. In Solanum habrochaites f. glabratum, methylketone biosynthesis occurs in the plastids of glandular trichomes and begins with intermediates of de novo fatty acid synthesis. These fatty-acyl intermediates are converted via sequential reactions catalyzed by Methylketone Synthase2 (MKS2) and MKS1 to produce the n-1 methylketone. We report crystal structures of S. habrochaites MKS1, an atypical member of the alpha/beta-hydrolase superfamily. Sequence comparisons revealed the MKS1 catalytic triad, Ala-His-Asn, as divergent to the traditional alpha/beta hydrolase triad, Ser-His-Asp. Determination of the MKS1 structure points to a novel enzymatic mechanism dependent upon residues Thr-18 and His-243, confirmed by biochemical assays. Structural analysis further reveals a tunnel leading from the active site consisting mostly of hydrophobic residues, an environment well suited for fatty-acyl chain binding. We confirmed the importance of this substrate binding mode by substituting several amino acids leading to an alteration in the acyl-chain length preference of MKS1. Furthermore, we employ structure-guided mutagenesis and functional assays to demonstrate that MKS1, unlike enzymes from this hydrolase superfamily, is not an efficient hydrolase but instead catalyzes the decarboxylation of 3-keto acids. PMID- 22523204 TI - Disruption of OPR7 and OPR8 reveals the versatile functions of jasmonic acid in maize development and defense. AB - Here, multiple functions of jasmonic acid (JA) in maize (Zea mays) are revealed by comprehensive analyses of JA-deficient mutants of the two oxo-phytodienoate reductase genes, OPR7 and OPR8. Single mutants produce wild-type levels of JA in most tissues, but the double mutant opr7 opr8 has dramatically reduced JA in all organs tested. opr7 opr8 displayed strong developmental defects, including formation of a feminized tassel, initiation of female reproductive buds at each node, and extreme elongation of ear shanks; these defects were rescued by exogenous JA. These data provide evidence that JA is required for male sex determination and suppression of female reproductive organ biogenesis. Moreover, opr7 opr8 exhibited delayed leaf senescence accompanied by reduced ethylene and abscisic acid levels and lack of anthocyanin pigmentation of brace roots. Remarkably, opr7 opr8 is nonviable in nonsterile soil and under field conditions due to extreme susceptibility to a root-rotting oomycete (Pythium spp), demonstrating that these genes are necessary for maize survival in nature. Supporting the importance of JA in insect defense, opr7 opr8 is susceptible to beet armyworm. Overall, this study provides strong genetic evidence for the global roles of JA in maize development and immunity to pathogens and insects. PMID- 22523207 TI - IgG4-related systemic sclerosing disease of the ocular adnexa: a potential mimic of ocular lymphoma. AB - IgG4-related sclerosing disease has been described in the orbit and ocular adnexa. Of 164 biopsies of the ocular region for suspected lymphoma, we identified 6 cases of IgG4 disease, 4 of which were previously unrecognized. All 6 cases demonstrated increased plasma cells in a background of sclerosis and increased absolute numbers of IgG4-expressing cells. Our results confirm the difficulty in diagnosing IgG4-related sclerosing disease in the ocular region. Based on the findings, we suggest that specimens from biopsies of the eye and ocular adnexa for which a definitive diagnosis of lymphoma is not established undergo further workup for IgG and IgG4, particularly if increased plasma cells and sclerosis are present. When IgG4-expressing plasma cells account for greater than 50% of IgG-expressing plasma cells, a diagnosis of IgG4 disease should be considered. Timely recognition would benefit patients by allowing appropriate management with corticosteroid therapy and avoiding more aggressive or unnecessary therapeutic options. PMID- 22523206 TI - The effect of 96-hour formalin fixation on the immunohistochemical evaluation of estrogen receptor, progesterone receptor, and HER2 expression in invasive breast carcinoma. AB - We studied the impact of 96 hours of formalin fixation on estrogen receptor (ER), progesterone receptor (PR), and HER2 testing by comparing immunohistochemical results from core biopsy specimens fixed under current American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines with results for corresponding resection samples fixed for 96 hours. Samples enriched with cases showing weak to moderate receptor expression on core biopsy were included in the study. Cases were scored using ASCO/CAP guidelines. Of the 47 cases, only 1 case (2%) showed a qualitative change in result. However, this change was a positive ER result (H score, 1) on the 96-hour fixed resected sample compared with a negative ER result (H score, 0) for the core biopsy. Minimal changes in semiquantitative H scoring were noted for ER and PR that were likely due to tumor heterogeneity and/or intraobserver variability as the variation occurred in both directions. ER, PR, and HER2 immunohistochemical results should be considered valid for cases fixed up to 96 hours. PMID- 22523205 TI - Arabidopsis annexin1 mediates the radical-activated plasma membrane Ca2+- and K+ permeable conductance in root cells. AB - Plant cell growth and stress signaling require Ca2+ influx through plasma membrane transport proteins that are regulated by reactive oxygen species. In root cell growth, adaptation to salinity stress, and stomatal closure, such proteins operate downstream of the plasma membrane NADPH oxidases that produce extracellular superoxide anion, a reactive oxygen species that is readily converted to extracellular hydrogen peroxide and hydroxyl radicals, OH*. In root cells, extracellular OH* activates a plasma membrane Ca2+-permeable conductance that permits Ca2+ influx. In Arabidopsis thaliana, distribution of this conductance resembles that of annexin1 (ANN1). Annexins are membrane binding proteins that can form Ca2+-permeable conductances in vitro. Here, the Arabidopsis loss-of-function mutant for annexin1 (Atann1) was found to lack the root hair and epidermal OH*-activated Ca2+- and K+-permeable conductance. This manifests in both impaired root cell growth and ability to elevate root cell cytosolic free Ca2+ in response to OH*. An OH*-activated Ca2+ conductance is reconstituted by recombinant ANN1 in planar lipid bilayers. ANN1 therefore presents as a novel Ca2+-permeable transporter providing a molecular link between reactive oxygen species and cytosolic Ca2+ in plants. PMID- 22523208 TI - Exocrine and endocrine modulation in common gastric carcinoma. AB - Diagnostic and prognostic implications of endocrine differentiation were evaluated in 103 common gastric adenocarcinomas and undifferentiated carcinomas. Maturely differentiated exocrine and endocrine phenotypes were evaluated by using gastric exocrine and endocrine markers along with intestinal exocrine and endocrine markers. Immunohistochemical analysis revealed that 66 tumors (64%) were positive for generic endocrine markers such as chromogranin A and/or synaptophysin. The 14 patients with more than 20% tumor cells positive for at least 1 endocrine marker experienced a poorer prognosis than patients with no (n = 37) or 1% to 20% (n = 52) positivity. The 16 carcinomas expressing the maturely differentiated exocrine gastric phenotype significantly correlated with poorer outcome compared with carcinomas with mature exocrine intestinal (n = 22) or mixed/gastrointestinal (n = 64) phenotypes. Among tumors expressing chromogranin A and/or synaptophysin, the maturely differentiated endocrine gastric phenotype (n = 26) was a negative prognostic factor compared with mature endocrine intestinal (n = 21) and mixed/gastrointestinal (n = 5) phenotypes. Endocrine differentiation and maturely exocrine/endocrine gastric phenotypes are associated with an unfavorable prognosis and may identify subsets of patients for tailored therapy. PMID- 22523209 TI - CDX2 expression in columnar cell variant of papillary thyroid carcinoma. AB - The columnar cell variant of papillary thyroid carcinoma (CCV-PTC) is a rare subtype of PTC that exhibits morphologic features often described as reminiscent of secretory endometrium or colonic adenomas/adenocarcinomas. CDX2, a nuclear transcription factor, is important for intestinal development. It is normally expressed in intestinal epithelium and is also detected in adenoma and adenocarcinomas of the gastrointestinal tract; however, it has also been reported in tumors of other sites with intestinal-type morphologic features. We evaluated CDX2 expression in CCV-PTC and in a thyroid tissue microarray composed of various benign and malignant thyroid lesions. CDX2 expression was identified in 6 (55%) of 11 cases of CCV-PTC, but not in any other benign and malignant thyroid lesions. We conclude that CDX2 is selectively expressed in CCV-PTC and can be used in distinguishing it from other variants of PTC with overlapping morphologic features. PMID- 22523210 TI - Lesions indefinite for intraepithelial neoplasia and OLGA staging for gastric atrophy. AB - Gastric intraepithelial neoplasia (IEN; formerly dysplasia) is an advanced precancerous lesion. Lesions indefinite for IEN mimic the IEN phenotype but lack some morphologic attributes of IEN. Indefinite for IEN lesions may arise in native foveolae (atypical foveolar hyperproliferation [aFH]) or intestinalized glands (hyperproliferative intestinal metaplasia [HIM]). The clinicopathologic outcome of such lesions is debated. We retrospectively studied the clinicopathologic behavior of 129 consecutive indefinite for IEN lesions (HIM, 98; aFH, 31; median follow-up, 31 months) and correlated outcome with the extent and topography of mucosal atrophy (assessed by OLGA staging) at the initial endoscopy/biopsy. At enrollment, aFH never coexisted with severe/extensive atrophy (all cases were in low-risk OLGA stages [0-II]), whereas HIM was associated with low- and high-risk OLGA stages (0-II, 73; III-IV, 25). At follow up, IEN was never documented among cases enrolled as aFH, while follow-up endoscopy/biopsy documented 6 neoplastic intraepithelial lesions among 98 cases of HIM (6%, all had high-risk OLGA stages at initial biopsy). OLGA staging can stratify indefinite for IEN lesions into different risk classes, potentially contributing to decisions for a patient-specific follow-up strategy. PMID- 22523211 TI - Helicobacter pylori: to stain or not to stain? AB - We performed a retrospective study to investigate the usefulness of immunohistochemical stains for the diagnosis of Helicobacter pylori (HP). We reviewed 200 consecutive gastric biopsy specimens, as well as immunohistochemical stains for HP. Of the biopsy specimens, 32 were positive for HP by immunohistochemical staining; of those, HP was seen on H&E stains in 29 cases (91%). The number of high-power fields required to detect HP on H&E-stained slides ranged from 1 to 25 (mean, 5.75). Combined significant (2+ or 3+) acute and chronic inflammation had a specificity of 98% and a negative predictive value of 97%. Our results show that, in our institution, HP can be seen relatively easily with H&E staining in the majority of cases; however, a small number of cases with significant inflammation can be missed if stains are not used. PMID- 22523212 TI - Findings in 12-core transrectal ultrasound-guided prostate needle biopsy that predict more advanced cancer at prostatectomy: analysis of 388 biopsy prostatectomy pairs. AB - We analyzed 5 features on 12-core transrectal ultrasound-guided prostate needle biopsy (TRUS) to predict the extent of cancer at radical prostatectomy (RP). In 388 TRUS-RP pairs, number of positive cores (NPC), percentage of each core involved (%PC), perineural invasion (PNI), Gleason score (GS), distribution of positive cores (DPC), and preoperative prostate-specific antigen (PSA) were correlated with extraprostatic extension (EPE), seminal vesicle invasion (SVI), positive surgical margin (R1), positive lymph nodes (N1), and tumor volume. All features predicted EPE and SVI. NPC, GS, %PC, and PNI strongly predicted R1 status. RP tumor volume was directly proportional to the NPC and %PC. PSA alone and with selected biopsy findings correlated with tumor volume, stage, SVI, and N1 (P < .0001). Contiguous DPC was a significant risk for EPE and SVI (P < .0001) compared with isolated positive cores. Findings at 12-core TRUS along with preoperative PSA reliably predict advanced local disease and have practical value as guides to effective planning for surgical resections. PMID- 22523213 TI - Metaplastic and medullary mammary carcinomas do not express mammaglobin. AB - Mammaglobin A (MG-A) is purportedly useful for detecting metastatic carcinomas suspected to be of breast origin and has been advocated as a useful marker of micrometastasis in sentinel lymph nodes and minimal residual tumor in bone marrow. Little is known about its expression frequency in histologic subtypes of breast cancer. Excisional biopsy specimens from 1,079 untreated invasive mammary carcinomas were evaluated for immunohistochemical expression of MG-A. In addition to estrogen (ER) and progesterone receptors (PR) and HER2, staining for p63 and HLA-DR was used to further characterize histologic subtypes. Of the carcinomas, 36 were classified as metaplastic (based on morphologic features, ER-/PR-/HER2-, p63+), 38 as medullary (ER-/PR-/HER2-, HLA-DR+), and 1,005 as ductal, no special type (NST). All metaplastic and medullary carcinomas were negative for MG-A. Of 1,005 ductal carcinomas, NST, 492 (49.0%) were MG-A+, 62.0% with a reaction in fewer than 25% of the cells. MG-A immunohistochemical studies failed to detect all medullary and metaplastic cancers and more than 50% of ductal carcinomas, NST. In two thirds of MG-A+ ductal carcinomas, the reaction was only focal and usually in a minority of cells. These findings suggest that MG-A has limited value in identifying the mammary origin of carcinomas, particularly in small biopsy specimens used to detect metastasis or minimal residual disease. PMID- 22523214 TI - The clinical significance of "squamous intraepithelial lesion of indeterminate grade" as a distinct cytologic category. AB - The histologic and/or cytologic follow-up of 127 cases of cervical lesions termed "squamous intraepithelial lesion of indeterminate grade" (SIL) on Papanicolaou (Pap) smears by the 2001 Bethesda System was compared with 150 control cases of low-grade SIL (LSIL), high-grade SIL (HSIL), and atypical squamous cells, cannot exclude HSIL (ASC-H). A follow-up diagnosis of cervical intraepithelial neoplasia (CIN) 2 or higher was identified in 22.8% of SIL cases, which was 2.6 times higher than LSIL, 3 times lower than HSIL, and 1.5 times lower than ASC-H. A follow-up diagnosis of CIN 1 was identified in 31.5% of SIL cases, which was 2 times lower than the LSIL group, 1.5 times higher than the ASC-H cases, and 1.8 times higher than the HSIL group. We found that 22.0% of cases diagnosed as SIL were followed up by Pap smears rather than colposcopy and biopsy, compared with about 1% of LSIL and HSIL cases. Because SIL cases have a significant risk of harboring CIN 2 or greater, we recommend follow-up by colposcopy and biopsy. PMID- 22523215 TI - Renal cell carcinoma associated with transcription factor E3 expression and Xp11.2 translocation: incidence, characteristics, and prognosis. AB - We studied the characteristics and prognosis of renal cell carcinoma (RCC) associated with Xp11.2 translocation and transcription factor E3 (TFE3) expression and determined the need for genetic analysis in routine diagnostics. Of 848 consecutive cases, 75 showed microscopic features suggestive of Xp11.2 translocation RCC or occurred in patients 40 years or younger. Of these cases, 17 (23%) showed strong nuclear TFE3 immunostaining, which was associated with more advanced tumors and inverse prognosis in univariate (P = .032) but not multivariate (P = .404) analysis. With fluorescence in situ hybridization and polymerase chain reaction, only 2 cases showed alterations of the X chromosome and the ASPL-TFE3 gene fusion, respectively. In our laboratory, the predictive value of TFE3 expression for the Xp11.2 translocation was 12%. Strong nuclear TFE3 expression is associated with metastatic spread and a poor prognosis. In our laboratory, TFE3 is not diagnostic for Xp11.2 translocation RCC. Diagnosis of Xp11.2 translocation RCC may be made only genetically. PMID- 22523216 TI - Performance evaluation of new automated hepatitis B viral markers in the clinical laboratory: two quantitative hepatitis B surface antigen assays and an HBV core related antigen assay. AB - We evaluated quantitative hepatitis B surface antigen (qHBsAg) assays and a hepatitis B virus (HBV) core-related antigen (HBcrAg) assay. A total of 529 serum samples from patients with hepatitis B were tested. HBsAg levels were determined by using the Elecsys (Roche Diagnostics, Indianapolis, IN) and Architect (Abbott Laboratories, Abbott Park, IL) qHBsAg assays. HBcrAg was measured by using Lumipulse HBcrAg assay (Fujirebio, Tokyo, Japan). Serum aminotransferases and HBV DNA were respectively quantified by using the Hitachi 7600 analyzer (Hitachi High Technologies, Tokyo, Japan) and the Cobas AmpliPrep/Cobas TaqMan test (Roche). Precision of the qHBsAg and HBcrAg assays was assessed, and linearity of the qHBsAg assays was verified. All assays showed good precision performance with coefficients of variation between 4.5% and 5.3% except for some levels. Both qHBsAg assays showed linearity from 0.1 to 12,000.0 IU/mL and correlated well (r = 0.9934). HBsAg levels correlated with HBV DNA (r = 0.3373) and with HBcrAg (r = 0.5164), and HBcrAg also correlated with HBV DNA (r = 0.5198; P < .0001). This observation could provide impetus for further research to elucidate the clinical usefulness of the qHBsAg and HBcrAg assays. PMID- 22523217 TI - Impact of laboratory-reported urine culture colony counts on the diagnosis and treatment of urinary tract infection for hospitalized patients. AB - Reducing health care-associated urinary tract infection (UTI) is a National Patient Safety Goal. The purpose of this investigation was to establish a colony count threshold to predict clinically significant UTIs that develop in hospitalized patients. A total of 185 cases were reviewed sequentially by 2 physicians. The information extracted included subjective complaints, presence of an indwelling urinary catheter, clinical signs and symptoms, WBC count, urinalysis, and urine culture results. The first reviewer recorded whether the patient was diagnosed and treated for a UTI by the clinician. The second reviewer determined if the patient met National Healthcare Safety Network guidelines for nosocomial UTI. Compared with patients with colony counts less than 100,000 colony-forming units per milliliter (CFU/mL), patients with colony counts 100,000 CFU/mL or more were 73.86 times more likely to have a clinically significant UTI (odds ratio, 73.86; 95% confidence interval, 24.23 ~ 225.15; P < .0001; c statistic, 0.859). Reporting positive results only for patients with 100,000 CFU/mL or more would have reduced the number of positive cultures by 38%. These data suggest that reporting colony counts less than 100,000 CFU/mL encourages treatment of non-clinically significant UTIs in hospitalized patients, causing inappropriate antibiotic use. PMID- 22523218 TI - Flow cytometric findings in hemophagocytic lymphohistiocytosis. AB - Hemophagocytic lymphohistiocytosis (HLH) is an often fatal hyperinflammatory syndrome. HLH may be inherited, but it more commonly arises secondary to Epstein Barr virus (EBV) or other infections, hematologic malignancies, or rheumatologic diseases. We identified 17 patients diagnosed with HLH who had flow cytometric analysis of peripheral blood or bone marrow performed at the time of diagnosis. Two patients had primary HLH, and the others had HLH secondary to EBV infection, hematologic malignancies, rheumatologic conditions, or tuberculosis. The marrow typically showed a reactive lymphocytosis and a marked left shift in myelopoiesis regardless of the etiology. Qualitative abnormalities were also found in several cases, including T-cell abnormalities in the majority of the EBV-associated HLH cases. While not specific, flow cytometric findings in HLH are different from the findings in uninvolved marrow samples, and care should be taken not to overinterpret immunophenotypic findings in these cases as indicative of a primary marrow disorder or lymphoma. PMID- 22523219 TI - Detection of leukemic lymphoblasts in CSF is instrument-dependent. AB - Staging and monitoring of pediatric acute lymphoblastic leukemia (ALL) includes examination of the cerebrospinal fluid (CSF). At our institution, we noted an increased incidence of low-level leukemic blasts in CSF samples from patients with ALL. This increase coincided with a conversion from the Shandon CytoSpin 4 (Thermo Fisher Scientific, Waltham, MA) to the Wescor Cytopro Rotor AC-060 (Wescor, Logan, UT). This study directly compared these 2 machines using patient samples and known concentrations of cultured leukemia cells. With patient samples, the Wescor Cytopro led to a 5- to 9-fold increase in the number of cells on a slide compared with the Shandon CytoSpin; furthermore, leukemic blasts were detected only with the Wescor Cytopro in 2 cases. Similar findings were observed using cultured leukemia cells. Thus, the detection of blasts in CSF is highly instrument-dependent. The newer, more sensitive cytocentrifuge machines identify blasts that were previously missed by older machines, but the clinical significance remains under investigation. PMID- 22523220 TI - A dissection of the CD45/side scatter "blast gate". AB - CD45/side scatter (SS) gating is widely used for isolating blasts by flow cytometry (FC). However, other cells contaminate the "blast gate" (BG); CD45/SS gating is thus imprecise, particularly when there are few blasts. We studied the BG contents in 21 myelodysplastic syndromes (MDSs), 14 myeloproliferative neoplasms (MPNs), 7 chronic myelomonocytic leukemias (CMMLs), and 40 nonneoplastic control samples using 4-color FC with cluster analysis. There were no significant differences across groups in the median percentage of BG events represented by blasts (14.7%-22%), granulocytes (23.3%-33.2%), lymphocytes (2.1% 3.2%), and erythroids (1.0%-9.8%). Monocytes were a larger percentage of BG events in CMML (24.2%). Basophils averaged 35.4% of the BG in MPNs. The percentage of blasts within the BG averaged 94.2% in control samples vs 88.2% in MDSs and 80.7% in CMMLs. Blasts averaged about 20% of events in the BG. About 10% to 20% of blasts fell outside the BG in CMMLs and MDSs. Our data highlight pitfalls in using a traditional BG for blast analysis in nonacute myeloid disorders. PMID- 22523222 TI - Analysis of urine sediment for cytology and antigen expression in acute renal allograft rejection: an alternative to renal biopsy. AB - Acute rejection in renal transplant recipients is diagnosed by renal biopsy at an advanced disease stage. There is no modality for sequential monitoring of graft status. We studied the role of urine cytology in predicting acute cellular rejection (ACR) and its ability to correctly diagnose ACR and differentiate it from drug toxicity (DT). Urine samples from 203 renal transplant recipients were studied to determine the cellular composition using cytology and immunocytochemistry for HLA-DR, intercellular adhesion molecule (ICAM)-1, and interleukin (IL)-2R. In a 3-month follow-up period, there were 36 episodes of graft dysfunction, of which 28 occurred due to ACR and 8 due to DT. The cytology results showed a significantly increased percentage of lymphocytes and polymorphonuclear cells in samples obtained before and during the clinical manifestations of ACR. A greater level of expression of antigens was observed before and during ACR. The use of IL2-R-, ICAM-1-, and HLA class II-specific monoclonal antibodies gave very high specificity, sensitivity, and positive predictive values in diagnosing rejection through urine cytology, suggesting that routine cytology along with immunocytochemistry of urine sediment has clinical potential for early diagnosis and management of ACR and DT. PMID- 22523221 TI - B cells with high side scatter parameter by flow cytometry correlate with inferior survival in diffuse large B-cell lymphoma. AB - Despite advances in the understanding of diffuse large B-cell lymphoma (DLBCL) biology, only the clinically based International Prognostic Index (IPI) is used routinely for risk stratification at diagnosis. To find novel prognostic markers, we analyzed flow cytometric data from 229 diagnostic DLBCL samples using an automated multiparameter data analysis approach developed in our laboratory. By using the developed automated data analysis pipeline, we identified 71 of 229 cases as having more than 35% B cells with a high side scatter (SSC) profile, a parameter reflecting internal cellular complexity. This high SSC B-cell feature was associated with inferior overall and progression-free survival (P = .001 and P = .01, respectively) and remained a significant predictor of overall survival in multivariate Cox regression analysis (IPI, P = .001; high SSC, P = .004; rituximab, P = .53). This study suggests that high SSC among B cells may serve as a useful biomarker to identify patients with DLBCL at high risk for relapse. This is of particular interest because this biomarker is readily available in most clinical laboratories without significant alteration to existing routine diagnostic strategies or incurring additional costs. PMID- 22523223 TI - Screening for IgG antinuclear autoantibodies by HEp-2 indirect fluorescent antibody assays and the need for standardization. AB - We evaluated 5 commercially available HEp-2 antinuclear antibody (ANA) indirect fluorescent antibody (IFA) assays using patient serum samples from 45 patients with rheumatoid arthritis, 50 with systemic lupus erythematosus (SLE), 35 with scleroderma, 20 with Sjogren syndrome, 10 with polymyositis, and 100 healthy control subjects. In addition, 12 defined serum samples from the Centers for Disease Control and Prevention and 100 patient serum samples sent to ARUP Laboratories (Salt Lake City, UT) for ANA IFA testing were also examined (n = 372). Standardization among the HEp-2 IFA assays occurred when they exhibited the same titer +/- 1 doubling dilution. Agreement of the 5 assays was 78%. Within the specific groups of serum samples, agreement ranged from 44% in scleroderma serum samples to 93% in healthy control subjects, with 72% agreement in the SLE group. Variations in slide and substrate quality were also noted (ie, clarity, consistency of fluorescence, cell size, number and quality of mitotic cells). Along with subjectivity of interpretation, HEp-2 IFA assays are also vulnerable to standardization issues similar to other methods for ANA screening. PMID- 22523224 TI - The measurement of vitamin D3requires maintaining quality control. PMID- 22523225 TI - Interobserver reproducibility of thyroid fine-needle aspiration using the UK Royal College of Pathologists' classification system. PMID- 22523227 TI - Neurotoxicity of anhydroecgonine methyl ester, a crack cocaine pyrolysis product. AB - Smoking crack cocaine involves the inhalation of cocaine and its pyrolysis product, anhydroecgonine methyl ester (AEME). Although there is evidence that cocaine is neurotoxic, the neurotoxicity of AEME has never been evaluated. AEME seems to have cholinergic agonist properties in the cardiovascular system; however, there are no reports on its effects in the central nervous system. The aim of this study was to investigate the neurotoxicity of AEME and its possible cholinergic effects in rat primary hippocampal cell cultures that were exposed to different concentrations of AEME, cocaine, and a cocaine-AEME combination. We also evaluated the involvement of muscarinic cholinergic receptors in the neuronal death induced by these treatments using concomitant incubation of the cells with atropine. Neuronal injury was assessed using 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. The results of the viability assays showed that AEME is a neurotoxic agent that has greater neurotoxic potential than cocaine after 24 and 48 h of exposure. We also showed that incubation for 48 h with a combination of both compounds in equipotent concentrations had an additive neurotoxic effect. Although both substances decreased cell viability in the MTT assay, only cocaine increased LDH release. Caspase-3 activity was increased after 3 and 6 h of incubation with 1mM cocaine and after 6 h of 0.1 and 1.0mM AEME exposure. Atropine prevented the AEME induced neurotoxicity, which suggests that muscarinic cholinergic receptors are involved in AEME's effects. In addition, binding experiments confirmed that AEME has an affinity for muscarinic cholinergic receptors. Nevertheless, atropine was not able to prevent the neurotoxicity produced by cocaine and the cocaine-AEME combination, suggesting that these treatments activated other neuronal death pathways. Our results suggest a higher risk for neurotoxicity after smoking crack cocaine than after cocaine use alone. PMID- 22523226 TI - Atypical thioredoxins in poplar: the glutathione-dependent thioredoxin-like 2.1 supports the activity of target enzymes possessing a single redox active cysteine. AB - Plant thioredoxins (Trxs) constitute a complex family of thiol oxidoreductases generally sharing a WCGPC active site sequence. Some recently identified plant Trxs (Clot, Trx-like1 and -2, Trx-lilium1, -2, and -3) display atypical active site sequences with altered residues between the two conserved cysteines. The transcript expression patterns, subcellular localizations, and biochemical properties of some representative poplar (Populus spp.) isoforms were investigated. Measurements of transcript levels for the 10 members in poplar organs indicate that most genes are constitutively expressed. Using transient expression of green fluorescent protein fusions, Clot and Trx-like1 were found to be mainly cytosolic, whereas Trx-like2.1 was located in plastids. All soluble recombinant proteins, except Clot, exhibited insulin reductase activity, although with variable efficiencies. Whereas Trx-like2.1 and Trx-lilium2.2 were efficiently regenerated both by NADPH-Trx reductase and glutathione, none of the proteins were reduced by the ferredoxin-Trx reductase. Only Trx-like2.1 supports the activity of plastidial thiol peroxidases and methionine sulfoxide reductases employing a single cysteine residue for catalysis and using a glutathione recycling system. The second active site cysteine of Trx-like2.1 is dispensable for this reaction, indicating that the protein possesses a glutaredoxin-like activity. Interestingly, the Trx-like2.1 active site replacement, from WCRKC to WCGPC, suppresses its capacity to use glutathione as a reductant but is sufficient to allow the regeneration of target proteins employing two cysteines for catalysis, indicating that the nature of the residues composing the active site sequence is crucial for substrate selectivity/recognition. This study provides another example of the cross talk existing between the glutathione/glutaredoxin and Trx-dependent pathways. PMID- 22523228 TI - Microcystin-LR induces ceramide to regulate PP2A and destabilize cytoskeleton in HEK293 cells. AB - Microcystin-LR (MCLR) is one of the most common and most toxic members of the microcystins, which cause serious environmental disasters worldwide. Although the major toxicity of MCLR has been ascribed to its potent ability to inhibit protein phosphatase 1 and protein phosphatase 2A (PP2A), recent studies have suggested that MCLR may also perturb other important cellular processes, such as generation of ceramide. Ceramide is an essential second messenger in cells and regulates various cellular mechanisms, including PP2A activation and cytoskeleton destabilization. However, whether and how ceramide may mediate MCLR-induced cellular effects is unclear. We have previously reported that low concentrations of MCLR upregulate, rather than inhibit, PP2A activity in human embryonic kidney 293 (HEK293) cells. In this study, we provide evidence that MCLR induces ceramide generation in HEK293 cells and in mouse kidney. Furthermore, ceramide may mediate the MCLR-induced upregulation of PP2A activity and protein level of PP2A regulatory subunits in HEK293 cells. MCLR intoxication also causes the PP2A/B55alpha subunit to localize to the Golgi apparatus, and this process may also be mediated by ceramide. Importantly, ceramide may mediate cytoskeleton destabilization, cell detachment, and apoptosis induced by MCLR in HEK293 cells, whereas a ceramide synthase inhibitor, desipramine, protects cells from these changes. Our results suggest that ceramide may mediate MCLR-induced PP2A regulation and cytoskeleton destabilization. PMID- 22523230 TI - Accurate risk-based chemical screening relies on robust exposure estimates. PMID- 22523229 TI - A dual role for poly(ADP-ribose) polymerase-1 during caspase-dependent apoptosis. AB - 2,3,5-Tris(glutathion-S-yl)hydroquinone (TGHQ), a metabolite of benzene, catalyzes the generation of reactive oxygen species (ROS) and caspase-dependent apoptosis in human promyelocytic leukemia (HL-60) cells. We now report that TGHQ induces severe DNA damage, as evidenced by DNA ladder formation and H2AX phosphorylation. The subsequent activation of the DNA nick sensor enzyme, poly(ADP-ribose) polymerase-1 (PARP-1), leads to the rapid depletion of ATP and NAD and the concomitant formation of poly(ADP-ribosylated) proteins (PARs). PJ-34 (a PARP-1 inhibitor) completely prevented the formation of PARs, partially attenuated TGHQ-mediated ATP depletion, but had little effect on NAD depletion. Intriguingly, although z-vad-fmk (a pan-caspase inhibitor) attenuated TGHQ induced apoptosis, cotreatment with PJ-34 led to a further decrease in apoptosis, suggesting that PARP-1 participates in caspase-dependent apoptosis. Indeed, PARP 1 inhibition reduced TGHQ-induced caspase-3, -7, and -9 activation, at least partially by attenuating cytochrome c translocation from mitochondria to the cytoplasm. In contrast, PJ-34 potentiated TGHQ-induced caspase-8 activation, suggesting that PARP-1 plays a dual role in regulating TGHQ-induced apoptosis via opposing effects on the intrinsic (mitochondrial) and extrinsic (death-receptor) pathways. PARP-1 knockdown in HL-60 cells confirmed that PARP-1 participates in effector caspase activation. Finally, PJ-34 also inhibited TGHQ-induced apoptosis inducing factor (AIF) nuclear translocation, but neither c-jun NH(2)-terminal kinase nor p38 MAPK (p38 mitogen-activated protein kinase) activation was required for AIF translocation. In summary, TGHQ-induced apoptosis of HL-60 cells is accompanied by PARP-1, caspase activation, and AIF nuclear translocation. TGHQ induced apoptosis appears to primarily occur via engagement of the mitochondrial mediated pathway in a process amenable to PARP inhibition. Residual cell death in the presence of PJ-34 is likely mediated via the extrinsic apoptotic pathway. PMID- 22523232 TI - Oxoguanine glycosylase 1 (OGG1) protects cells from DNA double-strand break damage following methylmercury (MeHg) exposure. AB - Methylmercury (MeHg) is a potent neurotoxin, teratogen, and probable carcinogen, but the underlying mechanisms of its actions remain unclear. Although MeHg causes several types of DNA damage, the toxicological consequences of this macromolecular damage are unknown. MeHg enhances oxidative stress, which can cause various oxidative DNA lesions that are primarily repaired by oxoguanine glycosylase 1 (OGG1). Herein, we compared the response of wild-type and OGG1 null (Ogg1(-/-)) murine embryonic fibroblasts to environmentally relevant, low micromolar concentrations of MeHg by measuring clonogenic efficiency, cell cycle arrest, DNA double-strand breaks (DSBs), and activation of the DNA damage response pathway.Ogg1(-/-) cells exhibited greater sensitivity to MeHg than wild type controls, as measured by the clonogenic assay, and showed a greater propensity for MeHg-initiated apoptosis. Both wild-type and Ogg1(-/-) cells underwent cell cycle arrest when exposed to micromolar concentrations of MeHg; however, the extent of DSBs was exacerbated in Ogg1(-/-) cells compared with that in wild-type controls. Pretreatment with the antioxidative enzyme catalase reduced levels of DSBs in both wild-type and Ogg1(-/-) cells but failed to block MeHg-initiated apoptosis at micromolar concentrations. Our findings implicate reactive oxygen species mediated DNA damage in the mechanism of MeHg toxicity; and demonstrate for the first time that impaired DNA repair capacity enhances cellular sensitivity to MeHg. Accordingly, the genotoxic properties of MeHg may contribute to its neurotoxic and teratogenic effects, and an individual's response to oxidative stress and DNA damage may constitute an important determinant of risk. PMID- 22523233 TI - The scientific basis of migraine. PMID- 22523234 TI - Vascular changes have a primary role in migraine. PMID- 22523235 TI - Migraine is not primarily a vascular disorder. PMID- 22523238 TI - Flat tori in three-dimensional space and convex integration. AB - It is well-known that the curvature tensor is an isometric invariant of C(2) Riemannian manifolds. This invariant is at the origin of the rigidity observed in Riemannian geometry. In the mid 1950s, Nash amazed the world mathematical community by showing that this rigidity breaks down in regularity C(1). This unexpected flexibility has many paradoxical consequences, one of them is the existence of C(1) isometric embeddings of flat tori into Euclidean three dimensional space. In the 1970s and 1980s, M. Gromov, revisiting Nash's results introduced convex integration theory offering a general framework to solve this type of geometric problems. In this research, we convert convex integration theory into an algorithm that produces isometric maps of flat tori. We provide an implementation of a convex integration process leading to images of an embedding of a flat torus. The resulting surface reveals a C(1) fractal structure: Although the tangent plane is defined everywhere, the normal vector exhibits a fractal behavior. Isometric embeddings of flat tori may thus appear as a geometric occurrence of a structure that is simultaneously C(1) and fractal. Beyond these results, our implementation demonstrates that convex integration, a theory still confined to specialists, can produce computationally tractable solutions of partial differential relations. PMID- 22523237 TI - Mechanical impulses can control metaphase progression in a mammalian cell. AB - Chromosome segregation machinery is controlled by mechanochemical regulation. Tension in a mitotic spindle, which is balanced by molecular motors and polymerization-depolymerization dynamics of microtubules, is thought to be essential for determining the timing of chromosome segregation after the establishment of the kinetochore-microtubule attachments. It is not known, however, whether and how applied mechanical forces modulate the tension balance and chemically affect the molecular processes involved in chromosome segregation. Here we found that a mechanical impulse externally applied to mitotic HeLa cells alters the balance of forces within the mitotic spindle. We identified two distinct mitotic responses to the applied mechanical force that either facilitate or delay anaphase onset, depending on the direction of force and the extent of cell compression. An external mechanical impulse that physically increases tension within the mitotic spindle accelerates anaphase onset, and this is attributed to the facilitation of physical cleavage of sister chromatid cohesion. On the other hand, a decrease in tension activates the spindle assembly checkpoint, which impedes the degradation of mitotic proteins and delays the timing of chromosome segregation. Thus, the external mechanical force acts as a crucial regulator for metaphase progression, modulating the internal force balance and thereby triggering specific mechanochemical cellular reactions. PMID- 22523239 TI - Genomic landscape of human allele-specific DNA methylation. AB - DNA methylation mediates imprinted gene expression by passing an epigenomic state across generations and differentially marking specific regulatory regions on maternal and paternal alleles. Imprinting has been tied to the evolution of the placenta in mammals and defects of imprinting have been associated with human diseases. Although recent advances in genome sequencing have revolutionized the study of DNA methylation, existing methylome data remain largely untapped in the study of imprinting. We present a statistical model to describe allele-specific methylation (ASM) in data from high-throughput short-read bisulfite sequencing. Simulation results indicate technical specifications of existing methylome data, such as read length and coverage, are sufficient for full-genome ASM profiling based on our model. We used our model to analyze methylomes for a diverse set of human cell types, including cultured and uncultured differentiated cells, embryonic stem cells and induced pluripotent stem cells. Regions of ASM identified most consistently across methylomes are tightly connected with known imprinted genes and precisely delineate the boundaries of several known imprinting control regions. Predicted regions of ASM common to multiple cell types frequently mark noncoding RNA promoters and represent promising starting points for targeted validation. More generally, our model provides the analytical complement to cutting-edge experimental technologies for surveying ASM in specific cell types and across species. PMID- 22523240 TI - Mathematical modeling elucidates the role of transcriptional feedback in gibberellin signaling. AB - The hormone gibberellin (GA) is a key regulator of plant growth. Many of the components of the gibberellin signal transduction [e.g., GIBBERELLIN INSENSITIVE DWARF 1 (GID1) and DELLA], biosynthesis [e.g., GA 20-oxidase (GA20ox) and GA3ox], and deactivation pathways have been identified. Gibberellin binds its receptor, GID1, to form a complex that mediates the degradation of DELLA proteins. In this way, gibberellin relieves DELLA-dependent growth repression. However, gibberellin regulates expression of GID1, GA20ox, and GA3ox, and there is also evidence that it regulates DELLA expression. In this paper, we use integrated mathematical modeling and experiments to understand how these feedback loops interact to control gibberellin signaling. Model simulations are in good agreement with in vitro data on the signal transduction and biosynthesis pathways and in vivo data on the expression levels of gibberellin-responsive genes. We find that GA-GID1 interactions are characterized by two timescales (because of a lid on GID1 that can open and close slowly relative to GA-GID1 binding and dissociation). Furthermore, the model accurately predicts the response to exogenous gibberellin after a number of chemical and genetic perturbations. Finally, we investigate the role of the various feedback loops in gibberellin signaling. We find that regulation of GA20ox transcription plays a significant role in both modulating the level of endogenous gibberellin and generating overshoots after the removal of exogenous gibberellin. Moreover, although the contribution of other individual feedback loops seems relatively small, GID1 and DELLA transcriptional regulation acts synergistically with GA20ox feedback. PMID- 22523241 TI - Committed carbon emissions, deforestation, and community land conversion from oil palm plantation expansion in West Kalimantan, Indonesia. AB - Industrial agricultural plantations are a rapidly increasing yet largely unmeasured source of tropical land cover change. Here, we evaluate impacts of oil palm plantation development on land cover, carbon flux, and agrarian community lands in West Kalimantan, Indonesian Borneo. With a spatially explicit land change/carbon bookkeeping model, parameterized using high-resolution satellite time series and informed by socioeconomic surveys, we assess previous and project future plantation expansion under five scenarios. Although fire was the primary proximate cause of 1989-2008 deforestation (93%) and net carbon emissions (69%), by 2007-2008, oil palm directly caused 27% of total and 40% of peatland deforestation. Plantation land sources exhibited distinctive temporal dynamics, comprising 81% forests on mineral soils (1994-2001), shifting to 69% peatlands (2008-2011). Plantation leases reveal vast development potential. In 2008, leases spanned ~65% of the region, including 62% on peatlands and 59% of community managed lands, yet <10% of lease area was planted. Projecting business as usual (BAU), by 2020 ~40% of regional and 35% of community lands are cleared for oil palm, generating 26% of net carbon emissions. Intact forest cover declines to 4%, and the proportion of emissions sourced from peatlands increases 38%. Prohibiting intact and logged forest and peatland conversion to oil palm reduces emissions only 4% below BAU, because of continued uncontrolled fire. Protecting logged forests achieves greater carbon emissions reductions (21%) than protecting intact forests alone (9%) and is critical for mitigating carbon emissions. Extensive allocated leases constrain land management options, requiring trade-offs among oil palm production, carbon emissions mitigation, and maintaining community landholdings. PMID- 22523242 TI - Intramembrane proteolysis of Toxoplasma apical membrane antigen 1 facilitates host-cell invasion but is dispensable for replication. AB - Apical membrane antigen 1 (AMA1) is a conserved transmembrane adhesin of apicomplexan parasites that plays an important role in host-cell invasion. Toxoplasma gondii AMA1 (TgAMA1) is secreted onto the parasite surface and subsequently released by proteolytic cleavage within its transmembrane domain. To elucidate the function of TgAMA1 intramembrane proteolysis, we used a heterologous cleavage assay to characterize the determinants within the TgAMA1 transmembrane domain (ALIAGLAVGGVLLLALLGGGCYFA) that govern its processing. Quantitative analysis revealed that the TgAMA1(L/G) mutation enhanced cleavage by 13-fold compared with wild type. In contrast, the TgAMA1(AG/FF) mutation reduced cleavage by 30-fold, whereas the TgAMA1(GG/FF) mutation had a minor effect on proteolysis; mutating both motifs in a quadruple mutant blocked cleavage completely. We then complemented a TgAMA1 conditional knockout parasite line with plasmids expressing these TgAMA1 variants. Contrary to expectation, variants that increased or decreased TgAMA1 processing by >10-fold had no phenotypic consequences, revealing that the levels of rhomboid proteolysis in parasites are not delicately balanced. Only parasites transgenically expressing or carrying a true knock-in allele of the uncleavable TgAMA1(AG/FF+GG/FF) mutant showed a growth defect, which resulted from inhibiting invasion without perturbing intracellular replication. These data demonstrate that TgAMA1 cleavage plays a role in invasion, but refute a recently proposed model in which parasite replication within the host cell is regulated by intramembrane proteolysis of TgAMA1. PMID- 22523245 TI - Development and psychometric testing of the nursing culture assessment tool. AB - A valid and reliable nursing culture assessment tool aimed at capturing general aspects of nursing culture is needed for use in health care settings to assess and then reshape indicated troubled areas of the nursing culture. This article summarizes the Nursing Culture Assessment Tool's (NCAT) development and reports on a cross-sectional, exploratory investigation of its psychometric properties. The research aims were to test the tool's psychometric properties; discover its dimensionality; and refine the item structure to best represent the construct of nursing culture, an occupational subset of organizational culture. Empirical construct validity was tested using a sample of licensed nurses and nursing assistants (n = 340). Exploratory and confirmatory factor analysis (CFA) and logistical regression yielded a 6-factor, 19-item solution. Evidence supports the tool's validity for assessing nursing culture as a basis for shaping the culture into one that supports change, thereby accelerating, improving, and advancing nursing best practices and care outcomes. PMID- 22523243 TI - Gene delivery to mitochondria by targeting modified adenoassociated virus suppresses Leber's hereditary optic neuropathy in a mouse model. AB - To introduce DNA into mitochondria efficiently, we fused adenoassociated virus capsid VP2 with a mitochondrial targeting sequence to carry the mitochondrial gene encoding the human NADH ubiquinone oxidoreductase subunit 4 (ND4). Expression of WT ND4 in cells with the G11778A mutation in ND4 led to restoration of defective ATP synthesis. Furthermore, with injection into the rodent eye, human ND4 DNA levels in mitochondria reached 80% of its mouse homolog. The construct expressed in most inner retinal neurons, and it also suppressed visual loss and optic atrophy induced by a mutant ND4 homolog. The adenoassociated virus cassette accommodates genes of up to ~5 kb in length, thus providing a platform for introduction of almost any mitochondrial gene and perhaps even allowing insertion of DNA encompassing large deletions of mtDNA, some associated with aging, into the organelle of adults. PMID- 22523244 TI - Growth-induced hormone dilution can explain the dynamics of plant root cell elongation. AB - In the elongation zone of the Arabidopsis thaliana plant root, cells undergo rapid elongation, increasing their length by ~10-fold over 5 h while maintaining a constant radius. Although progress is being made in understanding how this growth is regulated, little consideration has been given as to how cell elongation affects the distribution of the key regulating hormones. Using a multiscale mathematical model and measurements of growth dynamics, we investigate the distribution of the hormone gibberellin in the root elongation zone. The model quantifies how rapid cell expansion causes gibberellin to dilute, creating a significant gradient in gibberellin levels. By incorporating the gibberellin signaling network, we simulate how gibberellin dilution affects the downstream components, including the growth-repressing DELLA proteins. We predict a gradient in DELLA that provides an explanation of the reduction in growth exhibited as cells move toward the end of the elongation zone. These results are validated at the molecular level by comparing predicted mRNA levels with transcriptomic data. To explore the dynamics further, we simulate perturbed systems in which gibberellin levels are reduced, considering both genetically modified and chemically treated roots. By modeling these cases, we predict how these perturbations affect gibberellin and DELLA levels and thereby provide insight into their altered growth dynamics. PMID- 22523246 TI - Activation of HIF-1 by metallothionein contributes to cardiac protection in the diabetic heart. AB - Metallothionein (MT) protects against heavy metal-induced cellular damage and may participate in other fundamental physiological and pathological processes, such as antioxidation, proliferation, and cell survival. Previously, we have shown that elevation of MT by transgene or by induction with zinc protects the heart against diabetic cardiomyopathy by mechanisms such as antidiabetes-induced oxidative stress and inactivation of glycogen synthase kinase-3, which mediates glucose metabolism. We also reported that MT overexpression rescued the diabetic induced reduction of hypoxia-inducible factor (HIF)-1alpha, which plays an important role in glucose utilization and angiogenesis. Here, we showed that overexpression of MT increased hexokinase (HK)-II expression under control conditions and attenuated diabetes-decreased HK-II expression. Glycolytic flux assay demonstrated that MT increased glycolysis output in high glucose-containing media-cultured H9c2 cells. The diabetes-induced reduction in cardiac capillaries was also attenuated by MT overexpression. Furthermore, MT induction significantly increased HIF-1 expression under both control and diabetic conditions. Moreover, in the present study, we demonstrated that MT-enhanced HIF-1alpha activity is likely through a mechanism of protein nuclear translocation. These results suggest that MT induces HIF-1alpha expression, leading to increased HK-II in the diabetic heart. PMID- 22523247 TI - Angiotensin II type 2 receptor-stimulated activation of plasma prekallikrein and bradykinin release: role of SHP-1. AB - ANG II type 2 receptors (AT(2)R) elicit cardioprotective effects in part by stimulating the release of kinins; however, the mechanism(s) responsible have not been fully explored. We demonstrated previously that overexpression of AT(2)R increased expression of prolylcarboxypeptidase (PRCP; a plasma prekallikrein activator) and release of bradykinin by mouse coronary artery endothelial cells (ECs). In the present study we hypothesized that the AT(2)R-stimulated increase in PRCP is mediated by the tyrosine phosphatase SHP-1, which in turn activates the PRCP-dependent prekallikrein-kallikrein pathway and releases bradykinin. We found that activation of AT(2)R using the specific agonist CGP42112A increased SHP-1 activity in ECs, which was blocked by the AT(2)R antagonist PD123319. Activation of AT(2)R also enhanced conversion of plasma prekallikrein to kallikrein, and this effect was blunted by a small interfering RNA (siRNA) to SHP 1 and abolished by the tyrosine phosphatase inhibitor sodium orthovanadate. Treating cells with a siRNA to PRCP also blunted AT(2)R-stimulated prekallikrein activation and bradykinin release. Furthermore, blocking plasma kallikrein with soybean trypsin inhibitor (SBTI) abolished AT(2)R-stimulated bradykinin release. These findings support our hypothesis that stimulation of AT(2)R activates a PRCP dependent plasma prekallikrein pathway, releasing bradykinin. Activation of SHP-1 may also play an important role in AT(2)R-induced PRCP activation. PMID- 22523248 TI - Pulmonary artery pressure and cardiac function in children and adolescents after rapid ascent to 3,450 m. AB - High-altitude destinations are visited by increasing numbers of children and adolescents. High-altitude hypoxia triggers pulmonary hypertension that in turn may have adverse effects on cardiac function and may induce life-threatening high altitude pulmonary edema (HAPE), but there are limited data in this young population. We, therefore, assessed in 118 nonacclimatized healthy children and adolescents (mean +/- SD; age: 11 +/- 2 yr) the effects of rapid ascent to high altitude on pulmonary artery pressure and right and left ventricular function by echocardiography. Pulmonary artery pressure was estimated by measuring the systolic right ventricular to right atrial pressure gradient. The echocardiography was performed at low altitude and 40 h after rapid ascent to 3,450 m. Pulmonary artery pressure was more than twofold higher at high than at low altitude (35 +/- 11 vs. 16 +/- 3 mmHg; P < 0.0001), and there existed a wide variability of pulmonary artery pressure at high altitude with an estimated upper 95% limit of 52 mmHg. Moreover, pulmonary artery pressure and its altitude induced increase were inversely related to age, resulting in an almost twofold larger increase in the 6- to 9- than in the 14- to 16-yr-old participants (24 +/- 12 vs. 13 +/- 8 mmHg; P = 0.004). Even in children with the most severe altitude induced pulmonary hypertension, right ventricular systolic function did not decrease, but increased, and none of the children developed HAPE. HAPE appears to be a rare event in this young population after rapid ascent to this altitude at which major tourist destinations are located. PMID- 22523249 TI - Cardiac resynchronization therapy modulation of exercise left ventricular function and pulmonary O2 uptake in heart failure. AB - To better understand the mechanisms contributing to improved exercise capacity with cardiac resynchronization therapy (CRT), we studied the effects of 6 mo of CRT on pulmonary O(2) uptake (Vo(2)) kinetics, exercise left ventricular (LV) function, and peak Vo(2) in 12 subjects (age: 56 +/- 15 yr, peak Vo(2): 12.9 +/- 3.2 ml.kg(-1).min(-1), ejection fraction: 18 +/- 3%) with heart failure. We hypothesized that CRT would speed Vo(2) kinetics due to an increase in stroke volume secondary to a reduction in LV end-systolic volume (ESV) and that the increase in peak Vo(2) would be related to an increase in cardiac output reserve. We found that Vo(2) kinetics were faster during the transition to moderate intensity exercise after CRT (pre-CRT: 69 +/- 21 s vs. post-CRT: 54 +/- 17 s, P < 0.05). During moderate-intensity exercise, LV ESV reserve (exercise - resting) increased 9 +/- 7 ml (vs. a 3 +/- 9-ml decrease pre-CRT, P < 0.05), and steady state stroke volume increased (pre-CRT: 42 +/- 8 ml vs. post-CRT: 61 +/- 12 ml, P < 0.05). LV end-diastolic volume did not change from rest to steady-state exercise post-CRT (P > 0.05). CRT improved heart rate, measured as a lower resting and steady-state exercise heart rate and as faster heart rate kinetics after CRT (pre-CRT: 89 +/- 12 s vs. post-CRT: 69 +/- 21 s, P < 0.05). For peak exercise, cardiac output reserve increased significantly post-CRT and was 22% higher at peak exercise post-CRT (both P < 0.05). The increase in cardiac output was due to both a significant increase in peak and reserve stroke volume and to a nonsignificant increase in heart rate reserve. Similar patterns in LV volumes as moderate-intensity exercise were observed at peak exercise. Cardiac output reserve was related to peak Vo(2) (r = 0.48, P < 0.05). These findings demonstrate the chronic CRT-mediated cardiac factors that contribute, in part, to the speeding in Vo(2) kinetics and increase in peak Vo(2) in clinically stable heart failure patients. PMID- 22523250 TI - A model of preeclampsia in rats: the reduced uterine perfusion pressure (RUPP) model. AB - Preeclampsia is defined as new-onset hypertension with proteinuria after 20 wk gestation and is hypothesized to be due to shallow trophoblast invasion in the spiral arteries thus resulting in progressive placental ischemia as the fetus grows. Many animal models have been developed that mimic changes in maternal circulation or immune function associated with preeclampsia. The model of reduced uterine perfusion pressure in pregnant rats closely mimics the hypertension, immune system abnormalities, systemic and renal vasoconstriction, and oxidative stress in the mother, and intrauterine growth restriction found in the offspring. The model has been successfully used in many species; however, rat and primate are the most consistent in comparison of characteristics with human preeclampsia. The model suffers, however, from lack of the ability to study the mechanisms responsible for abnormal placentation that ultimately leads to placental ischemia. Despite this limitation, the model is excellent for studying the consequences of reduced uterine blood flow as it mimics many of the salient features of preeclampsia during the last weeks of gestation in humans. This review discusses these features. PMID- 22523251 TI - Post-translational modification of cardiac proteasomes: functional delineation enabled by proteomics. AB - Proteasomes are ubiquitously expressed multicatalytic complexes that serve as key regulators of protein homeostasis. There are several lines of evidence indicating that proteasomes exist in heterogeneous subpopulations in cardiac muscle, differentiated, in part, by post-translational modifications (PTMs). PTMs regulate numerous facets of proteasome function, including catalytic activities, complex assembly, interactions with associating partners, subcellular localization, substrate preference, and complex turnover. Classical technologies used to identify PTMs on proteasomes have lacked the ability to determine site specificity, quantify stoichiometry, and perform large-scale, multi-PTM analysis. Recent advancements in proteomic technologies have largely overcome these limitations. We present here a discussion on the importance of PTMs in modulating proteasome function in cardiac physiology and pathophysiology, followed by the presentation of a state-of-the-art proteomic workflow for identifying and quantifying PTMs of cardiac proteasomes. PMID- 22523252 TI - Atrial septostomy benefits severe pulmonary hypertension patients by increase of left ventricular preload reserve. AB - At present, it is unknown why patients suffering from severe pulmonary hypertension (PH) benefit from atrial septostomy (AS). Suggested mechanisms include enhanced filling of the left ventricle, reduction of right ventricular preload, increased oxygen availability in the peripheral tissue, or a combination. A multiscale computational model of the cardiovascular system was used to assess the effects of AS in PH. Our model simulates beat-to-beat dynamics of the four cardiac chambers with valves and the systemic and pulmonary circulations, including an atrial septal defect (ASD). Oxygen saturation was computed for each model compartment. The acute effect of AS on systemic flow and oxygen delivery in PH was assessed by a series of simulations with combinations of different ASD diameters, pulmonary flows, and degrees of PH. In addition, blood pressures at rest and during exercise were compared between circulations with PH before and after AS. If PH did not result in a right atrial pressure exceeding the left one, AS caused a left-to-right shunt flow that resulted in decreased oxygenation and a further increase of right ventricular pump load. Only in the case of severe PH a right-to-left shunt flow occurred during exercise, which improved left ventricular preload reserve and maintained blood pressure but did not improve oxygenation. AS only improves symptoms of right heart failure in patients with severe PH if net right-to-left shunt flow occurs during exercise. This flow enhances left ventricular filling, allows blood pressure maintenance, but does not increase oxygen availability in the peripheral tissue. PMID- 22523253 TI - Histone acetyl transferases CBP and p300 are necessary for maintenance of renin cell identity and transformation of smooth muscle cells to the renin phenotype. AB - In response to a homeostatic threat circulating renin increases by increasing the number of cells expressing renin by dedifferentiation and re-expression of renin in arteriolar smooth muscle cells (aSMCs) that descended from cells that expressed renin in early life. However, the mechanisms that govern the maintenance and reacquisition of the renin phenotype are not well understood. The cAMP pathway is important for renin synthesis and release: the transcriptional effects are mediated by binding of cAMP responsive element binding protein with its co-activators, CBP and p300, to the cAMP response element in the renin promoter. We have shown previously that mice with conditional deletion of CBP and p300 (cKO) in renin cells had severely reduced renin expression in adult life. In this study we investigated when the loss of renin-expressing cells in the cKO occurred and found that the loss of renin expression becomes evident after differentiation of the kidney is completed during postnatal life. To determine whether CBP/p300 is necessary for re-expression of renin we subjected cKO mice to low sodium diet + captopril to induce retransformation of aSMCs to the renin phenotype. The cKO mice did not increase circulating renin, their renin mRNA and protein expression were greatly diminished compared with controls, and only a few aSMCs re-expressed renin. These studies underline the crucial importance of the CREB/CBP/p300 complex for the ability of renin cells to retain their cellular memory and regain renin expression, a fundamental survival mechanism, in response to a threat to homeostasis. PMID- 22523254 TI - Oxygen dependence of respiration in rat spinotrapezius muscle in situ. AB - The oxygen dependence of respiration in striated muscle in situ was studied by measuring the rate of decrease of interstitial Po(2) [oxygen disappearance curve (ODC)] following rapid arrest of blood flow by pneumatic tissue compression, which ejected red blood cells from the muscle vessels and made the ODC independent from oxygen bound to hemoglobin. After the contribution of photo consumption of oxygen by the method was evaluated and accounted for, the corrected ODCs were converted into the Po(2) dependence of oxygen consumption, Vo(2), proportional to the rate of Po(2) decrease. Fitting equations obtained from a model of heterogeneous intracellular Po(2) were applied to recover the parameters describing respiration in muscle fibers, with a predicted sigmoidal shape for the dependence of Vo(2) on Po(2). This curve consists of two regions connected by the point for critical Po(2) of the cell (i.e., Po(2) at the sarcolemma when the center of the cell becomes anoxic). The critical Po(2) was below the Po(2) for half-maximal respiratory rate (P(50)) for the cells. In six muscles at rest, the rate of oxygen consumption was 139 +/- 6 nl O(2)/cm(3).s and mitochondrial P(50) was k = 10.5 +/- 0.8 mmHg. The range of Po(2) values inside the muscle fibers was found to be 4-5 mmHg at the critical Po(2). The oxygen dependence of respiration can be studied in thin muscles under different experimental conditions. In resting muscle, the critical Po(2) was substantially lower than the interstitial Po(2) of 53 +/- 2 mmHg, a finding that indicates that Vo(2) under this circumstance is independent of oxygen supply and is discordant with the conventional hypothesis of metabolic regulation of the oxygen supply to tissue. PMID- 22523255 TI - Left ventricular outflow tract obstruction in Tako-Tsubo cardiomyopathy. PMID- 22523256 TI - Fluconazole effectiveness against Leishmania (Viannia) braziliensis: is the evidence enough? PMID- 22523257 TI - Pneumococcal pyomyositis: report of 2 cases and review of the literature. AB - Streptococcus pneumoniae is an uncommon cause of pyomyositis. It is unclear whether the clinical presentation and outcome of pneumococcal pyomyositis differ depending on the host's underlying immune status. We describe 2 patients with pneumococcal pyomyositis, review all published cases, and compare characteristics between apparently healthy hosts and at-risk hosts. A total of 35 cases of pneumococcal pyomyositis were identified, 11 in apparently healthy hosts and 24 in at-risk hosts. Two-thirds of the patients had an antecedent respiratory illness or meningitis. At-risk hosts tended to have a longer interval between the development of symptomatic muscle infection and the diagnosis of pyomyositis and a significantly higher risk of disseminated disease at presentation, as manifested by involvement of multiple noncontiguous muscles or presence of meningitis. Overall, other than 1 death, all patients recovered with antibiotics and surgical drainage, but as might be expected there was a significantly higher rate of complications among at-risk hosts. PMID- 22523258 TI - Association between circulating DNA, serum (1->3)-beta-D-glucan, and pulmonary fungal burden in Pneumocystis pneumonia. AB - Circulating Pneumocystis jirovecii DNA and (1->3)-beta-d-glucan determined in 70 serum samples from immunocompromised patients were compared to fungal load in bronchoalveolar lavage fluids assessed using quantitative polymerase chain reaction. Both serum biomarkers are influenced by pulmonary fungal load, which should be taken into account when diagnosing Pneumocystis infection. PMID- 22523259 TI - Clinical Sindbis alphavirus infection is associated with HLA-DRB1*01 allele and production of autoantibodies. AB - BACKGROUND: Sindbis virus (SINV) is a mosquito-borne alphavirus found in Eurasia, Africa, and Oceania. Clinical SINV infection, characterized by arthropathic disease that may persist for years, is primarily reported in Northern Europe where the disease has considerable public health importance in endemic areas. The aim of this study was to investigate the role of genetic factors in the susceptibility and outcome of SINV infection and to elucidate the association between SINV infection and autoimmunity. METHODS: The study included 49 patients with serologically confirmed symptomatic SINV infection who were followed for 3 years after acute infection. Human leukocyte antigen (HLA) genes known to be associated with rheumatic and infectious diseases and complement C4 genes were determined in 35 patients. Furthermore, a set of autoantibodies was measured at the acute phase and 3 years after infection in 44 patients. RESULTS: The frequency of DRB1*01 was significantly higher among patients with SINV infection than in the reference population (odds ratio, 3.3; 95% confidence interval, 1.7 6.5; P = .003). The DRB1*01 allele was particularly frequent in patients who at 3 years postinfection experienced joint manifestations. The frequency of rheumatoid factor at 3 years postinfection was 29.5% and had increased significantly (P = .02) during the 3-year period. In addition, antinuclear and antimitochondrial antibodies were present in serum 3 years postinfection with frequencies of 15.9% and 6.8%, respectively. CONCLUSIONS: Our data show that symptomatic SINV infection is associated with the HLA system and that autoantibody titers are elevated in patients 3 years postinfection. These findings indicate that SINV induced arthritis shares features with autoimmune diseases. PMID- 22523260 TI - Treatment of erythema migrans with doxycycline for 10 days versus 15 days. AB - BACKGROUND: The efficacy of 10-day doxycycline treatment in patients with erythema migrans has been assessed in the United States but not in Europe. Experts disagree on the significance of post-Lyme borreliosis symptoms. METHODS: In a noninferiority trial, the efficacies of 10 days and 15 days of oral doxycycline therapy were evaluated in adult European patients with erythema migrans. The prevalence of nonspecific symptoms was compared between patients with erythema migrans and 81 control subjects without a history of Lyme borreliosis. The efficacy of treatment, determined on the basis of clinical observations and microbiologic tests, was assessed at 14 days and at 2, 6, and 12 months. Nonspecific symptoms in patients and controls were compared at 6 months after enrollment. RESULTS: A total of 117 patients (52%) were treated with doxycycline for 15 days, and 108 (48%) received doxycycline for 10 days. Twelve months after enrollment, 85 of 91 patients (93.4%) in the 15-day group and 79 of 86 (91.9%) in the 10-day group had complete response (difference, 1.6 percentage points; upper limit of the 95% confidence interval, 9.1 percentage points). At 6 months, the frequency of nonspecific symptoms in the patients was similar to that among controls. CONCLUSIONS: The 10-day regimen of oral doxycycline was not inferior to the 15-day regimen among adult European patients with solitary erythema migrans. Six months after treatment, the frequency of nonspecific symptoms among erythema migrans patients was similar to that among control subjects. CLINICAL TRIALS REGISTRATION: NCT00910715. PMID- 22523262 TI - Variation in reported neonatal group B streptococcal disease incidence in developing countries. AB - Group B Streptococcus (GBS) is a leading cause of neonatal sepsis in developed countries. Its burden in the developing world is less clear. Studies reporting neonatal GBS disease incidence from developing countries were identified from 5 literature databases. Studies were assessed with respect to case finding and culture methods. Only 20 studies were identified. The GBS incidence ranged 0-3.06 per 1000 live births with variation within and between geographic regions. All but 1 study identified GBS cases within a hospital setting, despite the potential for births in the community. Possible case under-ascertainment was only discussed in 2 studies. A higher GBS incidence was reported when using automated culture methods. Prospective, population-based surveillance is urgently needed in developing countries to provide an accurate assessment of the neonatal GBS disease burden. This will be crucial for the design of interventions, including novel vaccines, and the understanding of their potential to impact mortality from neonatal sepsis. PMID- 22523263 TI - Fool's gold: Why imperfect reference tests are undermining the evaluation of novel diagnostics: a reevaluation of 5 diagnostic tests for leptospirosis. AB - BACKGROUND: We observed that some patients with clinical leptospirosis supported by positive results of rapid tests were negative for leptospirosis on the basis of our diagnostic gold standard, which involves isolation of Leptospira species from blood culture and/or a positive result of a microscopic agglutination test (MAT). We hypothesized that our reference standard was imperfect and used statistical modeling to investigate this hypothesis. METHODS: Data for 1652 patients with suspected leptospirosis recruited during three observational studies and one randomized control trial that described the application of culture, MAT, immunofluorescence assay (IFA), lateral flow (LF) and/or PCR targeting the 16S rRNA gene were reevaluated using Bayesian latent class models and random-effects meta-analysis. RESULTS: The estimated sensitivities of culture alone, MAT alone, and culture plus MAT (for which the result was considered positive if one or both tests had a positive result) were 10.5% (95% credible interval [CrI], 2.7%-27.5%), 49.8% (95% CrI, 37.6%-60.8%), and 55.5% (95% CrI, 42.9%-67.7%), respectively. These low sensitivities were present across all 4 studies. The estimated specificity of MAT alone (and of culture plus MAT) was 98.8% (95% CrI, 92.8%-100.0%). The estimated sensitivities and specificities of PCR (52.7% [95% CrI, 45.2%-60.6%] and 97.2% [95% CrI, 92.0%-99.8%], respectively), lateral flow test (85.6% [95% CrI, 77.5%-93.2%] and 96.2% [95% CrI, 87.7%-99.8%], respectively), and immunofluorescence assay (45.5% [95% CrI, 33.3%-60.9%] and 96.8% [95% CrI, 92.8%-99.8%], respectively) were considerably different from estimates in which culture plus MAT was considered a perfect gold standard test. CONCLUSIONS: Our findings show that culture plus MAT is an imperfect gold standard against which to compare alterative tests for the diagnosis of leptospirosis. Rapid point-of-care tests for this infection would bring an important improvement in patient care, but their future evaluation will require careful consideration of the reference test(s) used and the inclusion of appropriate statistical models. PMID- 22523264 TI - Impact of USA300 methicillin-resistant Staphylococcus aureus on clinical outcomes of patients with pneumonia or central line-associated bloodstream infections. AB - BACKGROUND: The USA300 methicillin-resistant Staphylococcus aureus (MRSA) strain, which initially emerged as a cause of community-associated infections, has recently become an important pathogen in healthcare-associated infections (HAIs). However, its impact on patient outcomes has not been well studied. We evaluated patients with invasive MRSA infections to assess differences in outcomes between infections caused by USA100 and those caused by USA300. METHODS: Population-based data for invasive MRSA infections were used to identify 2 cohorts: (1) nondialysis patients with central line-associated bloodstream infections (CLABSIs) and (2) patients with community-onset pneumonia (PNEUMO) during 2005 2007 from 6 US metropolitan areas. Medical records of patients with confirmed MRSA USA100 or USA300 infection were reviewed. Logistic regression and, when appropriate, survival analysis was performed to evaluate mortality, early and late complications, and length of stay. RESULTS: A total of 236 and 100 patients were included in the CLABSI and PNEUMO cohorts, respectively. USA300 was the only independent predictor of early complications for PNEUMO patients (odds ratio [OR], 2.6; P = .02). Independent predictors of CLABSI late complications included intensive care unit (ICU) admission before MRSA culture (adjusted OR [AOR], 2.1; P= .01) and Charlson comorbidity index (AOR, 2.6; P = .003), but not strain type. PNEUMO patients were significantly more likely to die if they were older (P = .02), black (P < .001), or infected with USA100 strain (P = .02), whereas those with CLABSI were more likely to die if they were older (P < .001), had comorbidities (P < .001), or had an ICU admission before MRSA culture (P = .001). CONCLUSIONS: USA300 was associated with early complications in PNEUMO patients. However, it was not associated with mortality for either PNEUMO or CLABSI patients. Concerns regarding higher mortality from HAIs caused by USA300 may not be warranted. PMID- 22523266 TI - The power of policy change, federal collaboration, and state coordination in healthcare-associated infection prevention. AB - Policymakers have prioritized the prevention of healthcare-associated infections (HAIs) as a double-win that can both improve health outcomes and reduce healthcare costs. In the past few years, state and federal policymakers have developed policies to improve coordination and promote transparency and prevention. At the federal level, congressional oversight, policy directives, and targeted funding have helped focus national HAI prevention efforts through the Department of Health and Human Services Action Plan to Prevent Healthcare Associated Infections. The development of this action plan and the collaboration of its implementing agencies-the Centers for Disease Control and Prevention, the Centers for Medicare and Medicaid Services, and the Agency for Healthcare Research and Quality-have heightened nationwide awareness of HAIs and their preventability, and provided an infrastructure and tools to reduce HAIs. State policymakers have also acted to promote local transparency and tailor prevention efforts to local needs. The collaboration and action generated by these state and federal efforts have helped accelerate HAI prevention across the United States. PMID- 22523265 TI - Evaluation of real-time polymerase chain reaction for detection of the 16S ribosomal RNA gene of Mycobacterium tuberculosis and the diagnosis of cervical tuberculous lymphadenitis in a country with a high tuberculosis incidence. AB - BACKGROUND: Tuberculous lymphadenitis (TBL) is the most common form of extrapulmonary tuberculosis. Currently, the standard diagnostic test for TBL is culture, which takes more than several weeks to yield results. We studied a real time polymerase chain reaction (PCR) for rapid detection of Mycobacterium tuberculosis in cervical lymph node specimens obtained from patients in a country where the tuberculosis incidence is high. METHODS: Patients with cervical lymphadenopathy were prospectively enrolled between April 2009 and March 2010. Clinical specimens obtained through fine-needle aspiration (FNA) and excisional biopsy were tested for M. tuberculosis by the COBAS TaqMan MTB Test, a real-time PCR assay for detecting the 16S ribosomal RNA gene of M. tuberculosis. Mycobacterial culture and histopathological findings from tissue biopsy specimens were used as a reference standard for sensitivity and specificity calculations. RESULTS: Of 73 patients, 41 received a diagnosis of TBL. For biopsy specimens, the sensitivity of real-time PCR was 63.4%, and the specificity was 96.9%. For FNA specimens, the sensitivity was 17.1%, and the specificity was 100%. The sensitivity of real-time PCR of biopsy specimens was comparable to that of tissue culture but significant lower than that of histopathological examination (P < .01). CONCLUSIONS: Real-time PCR did not increase the yield for rapid diagnosis of TBL. PMID- 22523267 TI - Postflood pseudofungemia due to Penicillium species. AB - We report an outbreak investigation of fungemia due to Penicillium species after prolonged flooding of a Thai hospital. Contaminated rubber diaphragms of blood culture bottles were identified, and the pseudo-outbreak was resolved after environmental cleaning, use of high-efficiency particulate air filtration, and strict compliance with basic infection control practices for blood culture procurement. PMID- 22523268 TI - Rates of acquisition of pneumococcal colonization and transmission probabilities, by serotype, among newborn infants in Kilifi District, Kenya. AB - BACKGROUND: Herd protection and serotype replacement disease following introduction of pneumococcal conjugate vaccine (PCV) are attributable to the vaccine's impact on colonization. Prior to vaccine introduction in Kenya, we did an epidemiological study to estimate the rate of pneumococcal acquisition, by serotype, in an uncolonized population. METHODS: Nasopharyngeal swab specimens were taken from newborns aged <= 7 days and weekly thereafter for 13 weeks. Parents, and siblings aged <10 years, were swabbed at monthly intervals. Swabs were transported in skim milk-tryptone-glucose-glycerin and cultured on gentamicin blood agar. Pneumococci were serotyped by the Quellung reaction. We used survival analysis and Cox regression analysis to examine serotype-specific acquisition rates and risk factors and calculated transmission probabilities from the pattern of acquisitions within the family. RESULTS: Of 1404 infants recruited, 887 were colonized by 3 months of age, with the earliest acquisition detected on the first day of life. The median time to acquisition was 38.5 days. The pneumococcal acquisition rate was 0.0189 acquisitions/day (95% confidence interval, .0177-.0202 acquisitions/day). Serotype-specific acquisition rates varied from 0.00002-0.0025 acquisitions/day among 49 different serotypes. Season, coryza, and exposure to cigarettes, cooking fumes, and other children in the home were each significant risk factors for acquisition. The transmission probability per 30-day duration of contact with a carrier was 0.23 (95% CI, .20-.26). CONCLUSIONS: Newborn infants in Kilifi have high rates of nasopharyngeal acquisition of pneumococci. Half of these acquisitions involve serotypes not included in any current vaccine. Several risk factors are modifiable through intervention. Newborns represent a consistent population of pneumococcus-naive individuals in which to estimate the impact of PCV on transmission. PMID- 22523269 TI - Comparative risk of liver-related mortality from chronic hepatitis B versus chronic hepatitis C virus infection. AB - BACKGROUND: It is not known whether chronic hepatitis B (CH-B) or chronic hepatitis C (CH-C) carries a greater risk of liver-related mortality. This study compared rates of liver-related mortality between these 2 groups in the Multicenter AIDS Cohort Study (MACS). METHODS: Six hundred eighty men with CH-B (n = 337) or CH-C (n = 343) at study entry into the MACS were prospectively followed to death, last follow-up visit, or 30 March 2010, whichever came first. Four hundred seventy-two (69.4%) of these men were infected with human immunodeficiency virus type 1 (HIV-1). Causes of death were obtained from death registry matching and death certificates. Liver-related and all-cause mortality rates (MRs) were compared between groups using Poisson regression and adjusted for potential confounders and competing risks. RESULTS: In 6728 person-years (PYs) of follow-up, there were 293 deaths from all causes (43.5 per 1000 PYs), of which 51 were liver-related (7.6 per 1000 PYs). The all-cause MR was similar between those with CH-B and CH-C; however, the liver-related MR was significantly higher in those with CH-B (9.6 per 1000 PYs; 95% confidence interval [CI], 6.9 13.2) than those with CH-C (5.0 per 1000 PYs; 95% CI, 3.0-8.4). In the HIV infected subgroup, which had 46 (90.2%) of the liver-related deaths, the liver related MR remained higher from CH-B after adjusting for potential confounders (incidence rate ratio, 2.2; P = .03) and competing risks (subhazard rate ratio, 2.4; P = .02). Furthermore, among HIV-infected subjects, CD4 cell counts <200 cells/mm(3) were associated with a 16.2-fold (95% CI, 6.1-42.8) increased risk of liver-related death compared with CD4 cell counts >350 cell/mm(3). CONCLUSIONS: Chronic hepatitis B carries a higher risk of death from liver disease than does CH-C, especially in HIV-infected men with greater immunosuppression. PMID- 22523270 TI - Uncertainty in the application of contact precautions. PMID- 22523271 TI - Decreased cure and increased recurrence rates for Clostridium difficile infection caused by the epidemic C. difficile BI strain. AB - BACKGROUND: An epidemic strain of Clostridium difficile designated by restriction endonuclease analysis (REA) as group BI has caused multiple outbreaks of severe C. difficile infection (CDI). The treatment response of patients infected with this strain is uncertain. METHODS: Clostridium difficile isolates were collected from 2 phase 3 clinical trials comparing fidaxomicin to vancomycin and typed using REA. Clinical cure and recurrence outcomes were analyzed by strain type of the infecting organism, BI and non-BI, using both univariate and multivariate analyses. RESULTS: From 999 patients, 719 isolates were available for typing (356 fidaxomicin treated and 363 vancomycin treated). BI was the most common REA group (34% of isolates). Patients infected with BI had lower cure rates (86.6%; 214 of 247) than those infected with non-BI strains (94.3%; 445 of 472) (P < .001). The cure rate difference between the BI and non-BI patients was significant for both vancomycin (P = .02) and fidaxomicin (P = .007). BI patients had a recurrence rate of 27.4% (51 of 186), compared with a recurrence rate of 16.6% (66 of 397) in non-BI patients (P = .002). By multivariate analysis, BI infection was statistically significant as a risk factor for reduced cure (odds ratio [OR], 0.48; 95% confidence interval [CI], .27-.85; P = .030) and for increased recurrence (OR, 1.57; 95% CI, 1.01-2.45; P = .046). CONCLUSIONS: The clinical cure rate of patients infected with the epidemic BI C. difficile strain is lower than the cure rate of those infected with non-BI strains whether treated with fidaxomicin or vancomycin. Similarly, the CDI recurrence rate is increased in patients with the BI strain compared with patients with other C. difficile strains. PMID- 22523273 TI - Reminder: how with little effort the vaccination of children can be made less painful. PMID- 22523272 TI - Genetic modifiers predisposing to congenital heart disease in the sensitized Down syndrome population. AB - BACKGROUND: About half of people with Down syndrome (DS) exhibit some form of congenital heart disease (CHD); however, trisomy for human chromosome 21 (Hsa21) alone is insufficient to cause CHD, as half of all people with DS have a normal heart, suggesting that genetic modifiers interact with dosage-sensitive gene(s) on Hsa21 to result in CHD. We hypothesize that a threshold exists in both DS and euploid populations for the number of genetic perturbations that can be tolerated before CHD results. METHODS AND RESULTS: We ascertained a group of individuals with DS and complete atrioventricular septal defect and sequenced 2 candidate genes for CHD: CRELD1, which is associated with atrioventricular septal defect in people with or without DS, and HEY2, whose mouse ortholog (Hey2) produces septal defects when mutated. Several deleterious variants were identified, but the frequency of these potential modifiers was low. We crossed mice with mutant forms of these potential modifiers to the Ts65Dn mouse model of DS. Crossing loss-of function alleles of either Creld1 or Hey2 onto the trisomic background caused a significant increase in the frequency of CHD, demonstrating an interaction between the modifiers and trisomic genes. We showed further that, although each of these mutant modifiers is benign by itself, they interact to affect heart development when inherited together. CONCLUSIONS: Using mouse models of Down syndrome and of genes associated with congenital heart disease, we demonstrate a biological basis for an interaction that supports a threshold hypothesis for additive effects of genetic modifiers in the sensitized trisomic population. PMID- 22523274 TI - Obesity prevalence in low-income preschool children in Oklahoma. AB - OBJECTIVE: To determine the prevalence of overweight and obesity in low-income preschool children in Oklahoma and to identify potential race/ethnic disparities. METHODS: Subjects included 39,151 children aged 2 to 4 years who participated in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) in 2009. Body mass index percentiles were calculated from the child's height, weight, sex, and age. RESULTS: In 2009, 30.7% of Oklahoma's children in WIC were overweight, including 13.7% obese. Disparities by race/ethnicity were greatest for obese children: prevalence was 18.8% for American Indians (odds ratio [OR] = 1.8, confidence interval [CI] = 1.54-2.03) and 17.2% for Hispanics (OR = 1.6, CI = 1.52-1.73) compared with 11.8% for non-Hispanic whites, whereas African Americans were less obese (OR = 0.9, CI = 0.79-0.98). CONCLUSION: Obesity rates in low-income Oklahoma children are highest among American Indians and Hispanic children. Interventions aimed at these high-risk groups need to be explored. PMID- 22523275 TI - Screening for depression in urban Latino adolescents. AB - PURPOSE: Investigations were conducted on whether screening for adolescent depression was feasible and acceptable to patients in low-income, urban, predominantly Latino clinics. Further investigations were undertaken for provider acceptance of such screening. METHODS: Adolescents aged between 13 and 20 years presenting to 3 pediatric and adolescent primary care practices affiliated with an academic medical center in New York City were screened for depressive symptoms using the Columbia Depression Scale. Providers were surveyed pre- and postimplementation of the screening regarding their attitudes and practices. RESULTS: The vast majority (92%) of those approached accepted the screening. Twelve percent of those screened were referred for mental health treatment. Providers reported satisfaction with the screening tool and a desire to continue to use it. Screening was limited to 24% of eligible participants, and only 10% of screens were at sick visits. CONCLUSIONS: The Columbia Depression Scale seems acceptable to adolescent providers and patients in the mostly Latino study population. It may prove to be a helpful tool in evaluating adolescents presenting to primary care for depression. Further study will be required in other Spanish-speaking and minority populations. New methods will also be required to reach a greater proportion of patients, particularly those presenting for sick visits. PMID- 22523276 TI - Establishing a telepsychiatry consultation practice in rural Georgia for primary care physicians: a feasibility report. AB - OBJECTIVE: One approach to solving mental health care disparity issues in rural areas is by establishing a telepsychiatry consultation practice for children, in which a psychiatrist sees a child via videoconferencing for a limited number of sessions and then provides a treatment plan to that child's primary care physician and family. METHOD: The present study offered a 2-session telepsychiatry consultation clinic, consisting of a psychiatric evaluation session and a recommendation session, with patients located remotely in rural Georgia. RESULTS: Fifteen consultations with children aged 4 to 18 years (M = 9.73, SD = 3.39) with varying diagnoses were completed. Parental satisfaction with the telepsychiatry consultation model was high, overall mean of 4.58 (SD = 0.63) on a 5-point scale (n = 11). CONCLUSION: Establishing a child telepsychiatry consultation practice is feasible in rural areas. This report describes the benefits and challenges of our telepsychiatry consultation clinic with rural pediatric patients. PMID- 22523277 TI - Nephronophthisis cannot be detected by urinary screening program. PMID- 22523278 TI - Factors associated with low moderate-to-vigorous physical activity levels in pediatric patients with Kawasaki disease. AB - BACKGROUND/METHODS: We sought to determine functional health status and physical activity determinants in 27 patients with Kawasaki disease (KD; 20 males, 11 +/- 3 years old). Patient physical activity data were compared with a population based study of healthy children (Canadian Health Measures Survey). RESULTS: KD patients performed less moderate-to-vigorous physical activity (MVPA) than healthy children (males, 27 vs 61 min/d, P < .001; females, 10 vs 47 min/d, P < .001). Male KD patients performed more MVPA than female KD patients (median = 27; quartiles [Q1 15, Q3 26] min/d vs 10 [Q1 7, Q3 11] min/day, P = .009). Lower MVPA in KD patients was significantly associated with female gender; lower child self efficacy score; lower Child Health Questionnaire (CHQ-PF50) scores for role functioning behavioral issues, physical functioning, and family cohesion; and higher CHQ-PF50 scores for self-esteem and family activity limitations. CONCLUSION: Physical activity counseling should be a focus of management for children with a history of KD. PMID- 22523279 TI - Does oxygen tune cellular mechanotransduction? PMID- 22523280 TI - Serotonylated fibronectin is elevated in pulmonary hypertension. AB - Serotonin (5-HT) and fibronectin (FN) have been associated with pulmonary hypertension (PH). We previously reported that FN is posttranslationally modified by tissue transglutaminase (TGase) to form serotonylated FN (s-FN) in pulmonary artery smooth muscle cells and that serotonylation stimulates their proliferation and migration, hallmarks of PH. We hypothesized that s-FN and its binding to TGase are elevated in human and experimental PH. To assess this hypothesis, FN isolation and electrophoretic, immunoblotting, and densitometric techniques were used. Mean ratio of serum s-FN to total FN level (s-FN/FN) was elevated in 19 consecutive pulmonary arterial hypertension (PAH) patients compared with 25 controls (0.3 +/- 0.18 vs. 0.05 +/- 0.07, P < 0.001). s-FN/FN also was increased in lungs of mice and rats with hypoxia-induced PH and in rats with monocrotaline induced PH. In mice, the increase was detected at 1 wk of hypoxia, preceding the development of PH. Hypoxic rats had elevated serum s-FN/FN. Enhanced binding of TGase to its substrate FN occurred in serum from patients with PAH (mean 0.50 +/- 0.51 vs. 0.063 +/- 0.11, P = 0.002) and s-FN/FN and TGase-bound FN were highly correlated (R(2) = 0.77). TGase-bound FN also was increased in experimental PH. We conclude that increased serotonylation of FN occurs in human and experimental PH and may provide a biomarker for the disease. PMID- 22523281 TI - The presence of LPS in OVA inhalations affects airway inflammation and AHR but not remodeling in a rodent model of asthma. AB - Ovalbumin (OVA) is the most frequently used allergen in animal models of asthma. Lipopolysaccharide (LPS) contaminating commercial OVA may modulate the evoked airway inflammatory response to OVA. However, the effect of LPS in OVA on airway remodeling, especially airway smooth muscle (ASM) has not been evaluated. We hypothesized that LPS in commercial OVA may enhance allergen-induced airway inflammation and remodeling. Brown Norway rats were sensitized with OVA on day 0. PBS, OVA, or endotoxin-free OVA (Ef-OVA) was instilled intratracheally on days 14, 19, 24. Bronchoalveolar lavage (BAL) fluid, lung, and intrathoracic lymph node tissues were collected 48 h after the last challenge. Immunohistochemistry for alpha-smooth muscle actin, Periodic-Acid-Schiff staining, and real-time qPCR were performed. Airway hyperresponsiveness (AHR) was also measured. BAL fluid macrophages, eosinophils, neutrophils, and lymphocytes were increased in OVA challenged animals, and macrophages and neutrophils were significantly lower in Ef-OVA-challenged animals. The ASM area in larger airways was significantly increased in both OVA and Ef-OVA compared with PBS-challenged animals. The mRNA expression of IFN-gamma and IL-13 in lung tissues and IL-4 in lymph nodes was significantly increased by both OVA and Ef-OVA compared with PBS and were not significantly different between OVA and Ef-OVA. Monocyte chemoattractant protein (MCP)-1 in BAL fluid and AHR were significantly increased in OVA but not in Ef OVA. LPS contamination in OVA contributes to the influx of macrophages and MCP-1 increase in the airways and to AHR after OVA challenges but does not affect OVA induced Th1 and Th2 cytokine expression, goblet cell hyperplasia, and ASM remodeling. PMID- 22523282 TI - Role for TAK1 in cigarette smoke-induced proinflammatory signaling and IL-8 release by human airway smooth muscle cells. AB - Chronic obstructive pulmonary disease (COPD) is an inflammatory disease, characterized by a progressive decline in lung function. Airway smooth muscle (ASM) mass may be increased in COPD, contributing to airflow limitation and proinflammatory cytokine production. Cigarette smoke (CS), the major risk factor of COPD, causes ASM cell proliferation, as well as interleukin-8 (IL-8)-induced neutrophilia. In various cell types, transforming growth factor-beta-activated kinase 1 (TAK1) plays a crucial role in MAP kinase and NF-kappaB activation, as well as IL-8 release induced by IL-1beta, TNF-alpha, and lipopolysaccharide. The role of TAK1 in CS-induced IL-8 release is not known. The aim of this study was to investigate the role of TAK1 in CS-induced NF-kappaB and MAP kinase signaling and IL-8 release by human ASM cells. Stimulation of these cells with CS extract (CSE) increased IL-8 release and ERK-1/2 phosphorylation, as well as Ikappa Balpha degradation and p65 NF-kappaB subunit phosphorylation. CSE-induced ERK-1/2 phosphorylation and Ikappa-Balpha degradation were both inhibited by pretreatment with the specific TAK1 inhibitor LL-Z-1640-2 (5Z-7-oxozeaenol; 100 nM). Similarly, expression of dominant-negative TAK1 inhibited CSE-induced ERK-1/2 phosphorylation. In addition, inhibitors of TAK1 and the NF-kappaB (SC-514; 50 MUM) and ERK-1/2 (U-0126; 3 MUM) signaling inhibited the CSE-induced IL-8 release by ASM cells. These data indicate that TAK1 plays a major role in CSE-induced ERK 1/2 and NF-kappaB signaling and in IL-8 release by human ASM cells. Furthermore, they identify TAK1 as a novel target for the inhibition of CS-induced inflammatory responses involved in the development and progression of COPD. PMID- 22523283 TI - Mechanisms of attenuation of abdominal sepsis induced acute lung injury by ascorbic acid. AB - Bacterial infections of the lungs and abdomen are among the most common causes of sepsis. Abdominal peritonitis often results in acute lung injury (ALI). Recent reports demonstrate a potential benefit of parenteral vitamin C [ascorbic acid (AscA)] in the pathogenesis of sepsis. Therefore we examined the mechanisms of vitamin C supplementation in the setting of abdominal peritonitis-mediated ALI. We hypothesized that vitamin C supplementation would protect lungs by restoring alveolar epithelial barrier integrity and preventing sepsis-associated coagulopathy. Male C57BL/6 mice were intraperitoneally injected with a fecal stem solution to induce abdominal peritonitis (FIP) 30 min prior to receiving either AscA (200 mg/kg) or dehydroascorbic acid (200 mg/kg). Variables examined included survival, extent of ALI, pulmonary inflammatory markers (myeloperoxidase, chemokines), bronchoalveolar epithelial permeability, alveolar fluid clearance, epithelial ion channel, and pump expression (aquaporin 5, cystic fibrosis transmembrane conductance regulator, epithelial sodium channel, and Na(+)-K(+) ATPase), tight junction protein expression (claudins, occludins, zona occludens), cytoskeletal rearrangements (F-actin polymerization), and coagulation parameters (thromboelastography, pro- and anticoagulants, fibrinolysis mediators) of septic blood. FIP-mediated ALI was characterized by compromised lung epithelial permeability, reduced alveolar fluid clearance, pulmonary inflammation and neutrophil sequestration, coagulation abnormalities, and increased mortality. Parenteral vitamin C infusion protected mice from the deleterious consequences of sepsis by multiple mechanisms, including attenuation of the proinflammatory response, enhancement of epithelial barrier function, increasing alveolar fluid clearance, and prevention of sepsis-associated coagulation abnormalities. Parenteral vitamin C may potentially have a role in the management of sepsis and ALI associated with sepsis. PMID- 22523284 TI - A critical role for increased labile zinc in reducing sensitivity of cultured sheep pulmonary artery endothelial cells to LPS-induced apoptosis. AB - We previously noted an important signaling role for decreased labile intracellular zinc ([ Zn ] (i)) in LPS-induced apoptosis in cultured sheep pulmonary artery endothelial cells (SPAEC) (Tang ZL, Wasserloos KJ, Liu X, Stitt MS, Reynolds IJ, Pitt BR, St Croix CM. Mol Cell Biochem 234-235: 211-217, 2002; Thambiayya K, Wasserloos KJ, Huang Z, Kagan VE, St Croix CM, Pitt BR. Am J Physiol Lung Cell Mol Physiol 300: L624-632, 2011). In the present study, we used small interfering RNA (siRNA) to important contributors of zinc homeostasis [ SLC39A14 or Zrt/Irt-like protein 14 (ZIP14), a zinc importer; metallothionein (MT), a zinc binding protein ] to define molecular pathways by which extracellular zinc or nitric oxide (NO) increase labile [ Zn ] (i) [ e.g., zinc sensitive fluorophore (FluoZin-3) detectable and/or chelatable by N,N,N',N' tetrakis(2-pyridylmethyl)ethylenediamine ] and reduce the sensitivity of SPAEC to LPS. Addition of 10 MUM zinc to serum-free medium of SPAEC increased [ Zn ] (i) and abolished LPS-induced apoptosis (e.g., increased annexin V binding). The increase in [ Zn ] (i) and the protective effect of extracellular zinc were sensitive to reduction in ZIP14 expression (by siRNA), but not affected by collectively knocking down major isoforms of sheep MT (sMT-Ia, -Ib, -Ic, and II). Pretreatment of wild-type SPAEC with 250 MUM of the NO donor S-nitroso-N acetylpenicillamine (SNAP) increased labile zinc in a relatively similar fashion to addition of extracellular zinc and reduced sensitivity of SPAEC to LPS-induced apoptosis (e.g., caspase-3/7 activation) in a N,N,N',N'-tetrakis(2 pyridylmethyl)ethylenediamine-sensitive fashion. The antiapoptotic effects of SNAP were insensitive to siRNA knockdown of ZIP14, but were abolished (along with SNAP-induced increase in [ Zn ] (i)) when SPAEC were pretreated with siRNA to sheep MT. Zinc was able to directly inhibit recombinant caspase-3 activity in an in vitro assay. Collectively, these data show that increases in labile [ Zn ] (i) are an important component of ZIP14- or NO-mediated resistance to LPS-induced apoptosis. Cytoprotection via ZIP14 appeared to be secondary to transcellular movement of extracellular zinc, whereas NO-mediated protection was secondary to S nitrosation of MT and redistribution of [ Zn ] (i). PMID- 22523286 TI - Effects of culture supernatant from Lactobacillus pentosus strain S-PT84 on autonomic nerve activity in rats. AB - Intestinal administration of various lactobacilli has been reported to affect autonomic neurotransmission, blood pressure, blood glucose, and body weight in rats, however, the mechanisms of action of the lactobacilli remain to be clarified. Therefore, the effect of the culture supernatant of Lactobacillus pentosus strain S-PT84 on the autonomic nerve activity in urethane-anesthetized rats was investigated. Intraduodenal injection of the low-molecular-weight (LMW) fraction (molecules less than 10,000 Da) of the S-PT84 culture supernatant elevated the brown adipose tissue sympathetic nerve activity and reduced the gastric vagal nerve activity. Moreover, intraoral administration of this LMW fraction increased the body temperature of rats above the interscapular brown adipose tissue. These results suggest that the LMW fraction of the S-PT84 culture supernatant affects the autonomic nerve activity and thermogenesis, and that the change in thermogenesis may be caused by the change in the sympathetic nerve activity of brown adipose tissue. PMID- 22523285 TI - Ionizing irradiation protection and mitigation of murine cells by carbamazepine is p53 and autophagy independent. AB - BACKGROUND: Carbamazepine, a sodium channel blocker and pro-autophagy agent used in the treatment of epilepsy and trigeminal neuralgia, is also an ionizing radiation mitigator and protector. MATERIALS AND METHODS: We measured the effect of carbamazepine, compared to other pro-autophagy drugs (i.e. lithium and valproic acid), on irradiation of autophagy incompetent (Atg5(-/-)) and competent (Atg5(+/+)) mouse embryonic fibroblasts, p53(-/-) and p53(+/+) bone marrow stromal cells, and human IB3, KM101, HeLa, and umbilical cord blood cell and in total body-irradiated or orthotopic tumor-bearing mice. RESULTS: Carbamazepine, but not other pro-autophagy drugs, was a radiation protector and mitigator for mouse cell lines, independent of apoptosis, autophagy, p53, antioxidant store depletion, and class I phosphatidylinositol 3-kinase, but was ineffective with human cells. Carbamazepine was effective when delivered 24 hours before or 12 hours after total body irradiation of C57BL/6HNsd mice and did not protect orthotopic Lewis lung tumors. CONCLUSION: Carbamazepine is a murine radiation protector and mitigator. PMID- 22523287 TI - Human chorionic gonadotropin inhibits N-Methyl-N-nitrosourea-induced mammary carcinoma growth in female Lewis rats. AB - Human chorionic gonadotropin (hCG), a hormone produced by the placenta, is essential for maintaining pregnancy. The tumor-suppressive property of hCG against palpable N-methyl-N-nitrosourea (MNU)-induced rat mammary carcinomas was examined. A single intraperitoneal injection of 60 mg/kg MNU was administered to female Lewis rats. When the MNU-induced mammary tumors reached a palpable size (>= 1 cm in diameter), 0, 100, or 300 IU hCG were intraperitoneally injected 5 times per week for 4 weeks (a total of 20 injections). At the end of the treatment period, the 300 IU hCG treatment had significantly suppressed the growth of MNU-induced mammary carcinomas as compared to the sham treatment. The lower dose of hCG (100 IU) did not exert a significant effect. Final tumor volume and tumor wet weight, respectively, were as follows: sham-treated, 8151.3 +/- 1367.1 mm(3) and 6011.3 +/- 1042.2 mg; 100 IU hCG, 7480.6 +/- 2011.2 mm(3) and 5613.5 +/- 1142.0 mg; and 300 IU hCG, 3925.0 +/- 875.3 mm(3) and 3482.4 +/- 817.3 mg. Serum estrogen and progesterone levels were markedly elevated to pregnancy levels in 300 IU hCG-treated animals, while serum hCG levels remained low, resulting in significantly increased ovarian and uterine weights with multiple corpora lutea in the ovary and cystically dilated endometrial glands. Immunohistochemical studies revealed that almost all hCG-treated mammary carcinoma cells expressed estrogen and progesterone receptors, whereas luteinizing hormone/chorionic gonadotropin receptor was barely detectable. In conclusion, 300 IU hCG treatment for a short duration (4 weeks) suppressed the growth of overt and palpable MNU-induced mammary carcinomas. The mechanism of action may be through accelerated ovarian steroid secretion with the elevation of estrogen and progesterone levels to those in pregnancy. PMID- 22523288 TI - In vitro effects of doxycycline on inflammatory cytokines and gelatinases in chronic rhinosinusitis. AB - BACKGROUND/AIM: The pathophysiology of chronic rhinosinusitis (CRS) is unknown, but the majority of patients suffer from eosinophilic infiltration. We hypothesised that doxycycline might alter the eosinophil-associated expression of interleukin-5 (IL-5) and eotaxin-3 in CRS and also the expression of matrix metalloproteinase 9 (MMP-9), being involved in the tissue-remodelling in CRS. MATERIALS AND METHODS: After obtaining samples from 10 CRS patients with and without nasal-polyposis undergoing functional endoscopic sinus surgery and two healthy individuals, the expression of IL-5, eotaxin-3 and MMP-9 were evaluated by an ELISA technique. The tested agent was doxycycline at 0.1 or 1 mg/ml. RESULTS: IL-5 levels remained unchanged, but eotaxin-3 levels actually increased under doxycycline treatment. The only marker showing a slight drop was MMP-9, albeit not significant. CONCLUSION: As first clinical trials with doxycycline in the treatment of CRS produced reasonable results we could demonstrate that the underlying pathology is more complex, and doxycycline affects only a part of the factors believed to support the chronic infection of the respiratory mucosa. PMID- 22523289 TI - Canine malignant mammary gland neoplasms with advanced clinical staging treated with carboplatin and cyclooxygenase inhibitors. AB - Surgery remains the treatment of choice for female dogs with mammary gland tumors. Chemotherapy is not commonly used as an adjuvant therapy. Cyclooxygenase 2 (COX-2) has been related to angiogenesis development in tumors, disease progression and worse prognosis. The aim of this prospective study was to compare overall survival periods of female dogs diagnosed with advanced mammary tumors submitted to different treatment protocols, including surgery, chemotherapy and cyclooxygenase inhibitors. Twenty-nine female dogs were evaluated and treated with four different protocols. The overall survival of patients with low COX-2 scores was longer when compared to patients with high COX-2 scores. Different proposed adjuvant treatments associated with surgery led to a statistically significant longer overall survival when compared to surgical treatment alone. Canine patients presenting malignant mammary gland neoplasms with advanced clinical staging should be submitted to complementary therapeutic medication based on clinical staging and immunophenotypical characteristics of the disease. PMID- 22523290 TI - The role of nonsteroidal antiinflammatory drugs and cyclooxygenase-2 inhibitors on experimental colitis. AB - The nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely used in the management of pain and inflammation. Unfortunately, they are associated with dose dependent gastrointestinal (GI) adverse events ranging from dyspepsia to symptomatic and complicated ulcers. The mechanism of NSAID action is attributed to the cyclooxygenase (COX) inhibition. New anti-inflammatory drugs have been synthesized, such as selective COX-2 inhibitors, however, these drugs may present side effects, such as modification of the epithelial barrier. Inflammatory bowel disease (IBD) is a common chronic gastrointestinal disorder characterized by alternating periods of remission and active intestinal inflammation. A possible association between the use of NSAIDs and the relapse of IBD has been repeatedly suggested. For this reason, many studies are conducted with the use of COX-2 in experimental models. The objective of this review is to describe the role of NSAIDs and COX-2 inhibitors in different experimental models of colitis. We reviewed controlled trials, original articles, case reports and reviews. The role of selective inhibition of COX-2 in the inflammatory process and the course of experimental and human colitis is controversially discussed. In conclusion, the relative role of COX-2 selective inhibitors on human and experimental colitis remains to be explored. Thus, the use of COX-2 inhibitors in IBD should be considered with caution. PMID- 22523291 TI - Oxidative stress-mediated biomolecular damage and inflammation in tumorigenesis. AB - At the cellular level, free radicals are tightly controlled by an inducible antioxidant program, since at low non-hazardous amounts they contribute to physiological signalling and homeostasis. However, high levels of oxidative stress promote the accumulation of damaged biomolecules, the impairment of cell signalling pathways and the increase of oncogenic hits. As the intracellular and extracellular levels of oxidative stress increase during ageing or in various diseases, so does the amount of damaged biomolecules, since the repair mechanisms are also targets of oxidative damage and thus become gradually ineffective over time. Depending on the severity of the biomolecular damage, the responses of normal human cells to oxidants may range from transient growth arrest to premature senescence, and even to cell death. Although some responses are clearly tumour suppressing (apoptosis), others may be potentially oncogenic as they combine damage accumulation with a retained ability for proliferation (transient growth arrest) or with inflammation (senescence, necrosis). This array of events significantly increases the likelihood of the appearance of tumour-initiating cells, which may then give rise to pre-neoplastic focal lesions and eventually to neoplasia. In the present manuscript, we will focus on the role of free radical mediated biomolecular damage and inflammation in tumorigenesis. PMID- 22523292 TI - The cytotoxic protein can induce autophagocytosis in addition to apoptosis in MCF 7 human breast cancer cells. AB - Phagocytic clearance of dying cells is found in many phagocytes. It has been shown that dying cells can be phagocytosed by other phagocytic cells through autophagic or apoptotic cellular death. To date, whether cancer cells have such phagocytic activity has not been studied. In this study, our data shows that RC RNase can trigger cell death in human breast cancer MCF-7 cells through the apoptotic pathway. Interestingly, when treated with cytotoxic protein, the remaining MCF-7 cells can phagocytose the dying MCF-7 cells via autophagocytic activity, demonstrated directly by real-time image observation and electron microscopy analysis. To sum up, this study demonstrates for the first time that RC-RNase can trigger apoptosis and autophagocytosis in MCF-7 cancer cells. PMID- 22523293 TI - Biological activity of SE-10, granulated powder of Sasa senanensis Rehder leaf extract. AB - BACKGROUND: We have previously reported that alkaline extract of Sasa senanensis leaves (SE) showed potent anti-HIV, anti-UV and radical scavenging activity. In the present study, we investigated the biological activities of SE-10, a granulated powder of SE supplemented with lactose, lactitol, trehalose and tea extract. MATERIALS AND METHODS: Cell viability of mock-infected, HIV-infected, and UV-irradiated cells was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) method. Scavenging activity of superoxide anion and hydroxyl radicals was determined by electron-spin resonance spectroscopy. Cytochrome P-450 (CYP)3A4 activity was measured by beta-hydroxylation of testosterone in human recombinant CYP3A4. RESULTS: SE-10 had slightly higher anti HIV and anti-UV activities, but slightly lower radical-scavenging and CYP3A4 inhibitory activities, as compared with SE. CONCLUSION: The present study demonstrates that the biological activities of SE were well preserved during the manufacturing process of SE-10. PMID- 22523295 TI - Retinal and renal vascular permeability changes caused by stem cell stimulation in alloxan-induced diabetic rats, measured by extravasation of fluorescein. AB - AIM: To determine whether treatment with the stem cell stimulator Olimpiq(r) Stem*Cell prevents increase of retinal and renal vascular permeability in alloxan induced diabetic rats. MATERIALS AND METHODS: Two groups of Wistar rats were made diabetic by single intraperitoneal injection of Alloxan. The third, the control group, received vehicle alone. One diabetic group received Olimpiq(r) Stem*Cell treatment for 4 weeks. The permeability of the blood-retinal barrier (BRB) and renal vessels were measured by the extravasation of fluorescein-labeled bovine serum albumin. RESULTS: Six weeks subsequently to Alloxan injection, significantly elevated the tissue fluorescence, the renal vascular leakage and BRB breakdown was demonstrated in the diabetic group, compared to the nondiabetic group. Olimpiq(r) Stem*Cell treatment significantly reduced the BRB breakdown, tissue fluorescence, and vascular leakage. CONCLUSION: Olimpiq(r) Stem*Cell would be a useful choice of treatment for complications associated with increased vascular permeability of diabetes, such as retinopathy or nephropathy. PMID- 22523296 TI - Evaluation of genotoxicity and subclinical toxicity of Agaricus blazei Murrill in the Ames test and in histopathological and biochemical analysis. AB - This study was conducted in order to assess the safety and tolerability of Agaricus blazei Murrill (ABM) in general toxicological studies by Ames tests in vitro and in 28-day feeding toxicity experiments. There were no dose-dependent increases or decreases in the number of revertant colonies both with and without metabolic activation in Ames tests. Doses of 10, 5 and 0.1 mg/per mouse of ABM daily were administered by oral gavage to mice (n=10) for 28 days. The effects on clinical observations, clinical pathology, and histopathology were evaluated. There were no significant changes in the brain, heart, kidney, liver, spleen, adrenal gland, testes or ovaries visually. With increasing doses, male and female treated mice did not show any gradual elevation of serum concentration in any of the nine items we examined, except for aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in females. The AST levels of the treatment by medium or high dose and the ALT levels of the treatment by high dose in females were abnormal in comparison to those of the baseline control group, with significant differences. On studying the histological changes in mice, tissue sections of negative control and experimental groups exhibited no apparent pathological alterations. In summary, the Ames test, pathology determinations, biochemical analysis and routine blood parameters were all normal, except for AST and ALT in females. Results showed that the statistical differences observed in one sex were not observed in the other and were not dose dependent. PMID- 22523294 TI - Efficacy of a proapoptotic peptide towards cancer cells. AB - BACKGROUND: Conventional cancer therapies are associated with severe side-effects and the development of drug resistance. Therefore, new strategies to specifically target tumor cells leaving healthy tissue unaffected are of great interest. MATERIALS AND METHODS: On this respect, we tested the antimicrobial peptide (KLAKLAK)(2). RESULTS: This peptide exhibits cytotoxicity against human breast cancer and other tumor cells, while healthy cells remain unaffected. Moreover, treatment with this cationic amphipathic peptide results in slower tumor growth and longer overall survival in vivo. CONCLUSION: Our data suggest a potential use of (KLAKLAK)(2) peptide for patients with breast and other types of cancer. PMID- 22523297 TI - Venous graft for reconstruction of neoplastic and post-traumatic eyelid defects. AB - AIM: The repair of an eyelid-wide full-thickness defect is a challenging procedure, mostly for the tarso-conjunctival layer reconstruction. The Authors illustrate their own experience in reconstructing eyelid-wide defects with a composite venous wall and skin graft to repair both neoplastic and post-traumatic injuries, aiming to reach both functionally and cosmetically satisfactory results. PATIENTS AND METHODS: Eight patients were treated with this procedure; six of them were affected by a local invasive tumor, two had a wide defect following a trauma. RESULTS: Most of the patients had good functional and cosmetic results after a median follow-up of 51 months; only one had a minor complication. CONCLUSION: Eyelid reconstruction with a venous wall and skin graft is a recently introduced technique that represents a reliable alternative to traditional procedures, granting esthetically and functionally good results. PMID- 22523298 TI - Nasolabial cyst: case report with respect to immunohistochemical findings. AB - The nasolabial cyst is a rare, usually unilateral lesion arising in the soft tissues adjacent to the alveolar process of the anterior maxilla, above the apices of frontal teeth and below the alar base. The typical clinical features of nasolabial cysts are: swelling between the upper lip and nasal aperture caused by a smooth and fluctuant, well defined space-occupying lesion, elevation of the nasal ala and obliteration of the nasolabial fold. This report describes some clinical, radiological and morphological findings in a nasolabial cyst. The cyst was lined up with bilayered epithelium showing scattered goblet cells. The immunohistochemical analysis revealed that the basaloid epithelial cells exhibited nuclear positive reactions for p63. The proliferative activity of the epithelial cells was low (<5%). Reaction for podoplanin was only discretely positive in basal cells within the non-inflamed portions but was enhanced in areas with inflammatory changes of the cyst wall. Cytokeratin subtyping showed a distinct expression of intermediate filaments in the nasolabial cyst. Nasolabial cysts are developmental cysts that can be cured by adequate surgical techniques. The expression pattern of podoplanin in this entity points to an association of this protein expression with inflammatory reactions to the cyst. PMID- 22523299 TI - Angiomyolipomatous hamartoma of the inguinal lymph node--report of two cases and literature review. AB - Angiomyolipomatous hamartoma is a variant of angiomyomatous hamartoma (AMH), a rare nodal smooth muscle proliferation, first identified as a distinct entity by Chan et al. in 1992. To date, several cases have been described, mostly involving inguinal lymph nodes. We present two cases of angiomyolipomatous hamartoma, in a 52-year-old male and 67-year-old female patient. Both patients were surgically treated. Microscopically, in the affected nodes, the parenchyma was mostly replaced with bundles of smooth muscle cells, fibrous tissue and lobules of mature adipocytes. Only a few atrophic lymphatic follicles were maintained in the subcapsular area. The presence of smooth muscle cells and endothelial cells was confirmed immunohistochemically by staining for smooth muscle actin, desmin and CD31. The hilus contained numerous thick-walled vessels extending to the medulla. Pleomorphism, mitoses and necrosis were absent. Considering there are no reported recurrences of AMH, it probably has benign behaviour; thus extensive resection may not be needed. Nevertheless, we believe that recognition of AMH is important in the differential diagnosis of other pathological conditions that may affect lymph nodes. PMID- 22523300 TI - Local tolerance of a sublingual nicotine tablet, an open single-centre study. AB - Nicotine replacement therapy (NRT) is now widely used in various forms of administration to aid cessation of tobacco use. In this smoking cessation programme, a new tablet formulation has been compared to and found bioequivalent to the existing one. The present trial was performed in order to investigate the local tolerance of the new sublingual tablet. The study was performed as a prospective follow-up study of 16 weeks' duration on smokers using the new tablet, Nicorette(r) Microtab, over a period of 12 weeks. Fifty smokers were included in the study and the oral mucosa was inspected and photographed at each visit. At 12 weeks, participants were asked for their consent to take a biopsy from the site of application. Compliance with tablet use was high, with participants using an average of 12 tablets/day throughout the 12 week treatment period. Adverse events related to treatment were mild and tolerable. The changes observed were classified as being induced by frictional stimuli, with no changes to the deeper layers of the epithelium, and no thickening of the basal layers of the epithelium. The new tablet was considered well tolerated during the course of this study, with a benign local effect on the mucous membrane that was consistent with lesions that are reversible in nature. PMID- 22523301 TI - An antibiotic care bundle approach based on results of rapid molecular screening for nasal carriage of methicillin-resistant Staphylococcus aureus in the intensive care unit. AB - The potential role of active methicillin-resistant Staphylococcus aureus (MRSA) surveillance in the intensive care unit (ICU), has been recently proposed as a guide for antibiotic treatment in patients suspected of being infected with MRSA by using an antibiotic care bundle (ACB) approach. A group of 376 consecutive ICU patients were prospectively screened for nasal carriage of MRSA using a real-time polymerase chain reaction test. The study group consisted of 244 (64.9%) males and (35.1%) females, with a median age of 64 (range 17-95 years). Overall, 26 (6.9%) patients were positive for MRSA, while 350 (93.1%) were MRSA-negative. No difference was observed in gender and age between groups. During ICU stay, 9 (2.4%) patients developed generalized MRSA infection, of whom 8 out of 26 (30.8%) were MRSA-carriers and one out of the 350 (0.3%) was MRSA-negative. Thus, a strong relationship between MRSA infection and MRSA carriage (relative risk=107.7, 95% confidence interval=14.0-828.5, p<0.0001) was found. Subsequently, in our ICU, we developed and introduced a new ACB approach based on rapid nasal screening results for improving the management of critically ill patients. The use of anti-MRSA agents should be re-evaluated daily on the basis of clinical and laboratory features, with positive cultures from sterile site or signs of active infection supporting prolongation of empirical treatment. On the contrary, MRSA-negative clinical cultures support a de-escalation strategy. In conclusion, the early identification of MRSA-carriers using a rapid molecular screening is safe and accurate, allowing MRSA-positive patients, who will more likely develop MRSA infections, to be detected. PMID- 22523302 TI - heterogeneity of dna ploidy in endometrial carcinoma: comparison of different tissue samples obtained during diagnosis and treatment. AB - AIM: Comparison of DNA ploidy status of different tumour tissue samples (fresh/frozen vs. paraffin-embedded; curettage vs. hysterectomy samples) obtained during diagnosis and treatment of patients with endometrial carcinoma. PATIENTS AND METHODS: DNA ploidy status and conventional prognostic parameters were recorded for 74 patients with endometrial carcinoma prospectively. RESULTS: In 59 (79.7%) patients the DNA status was described as diploid in all analyzed tissue samples. The remaining 15 (20.3%) cases were described as DNA aneuploid in at least one of the corresponding tissue samples. The concordance between DNA ploidy status in fresh vs. paraffin-embedded hysterectomy samples as well as curettage vs. hysterectomy paraffin-embedded samples was high (kappa coefficient kappa=0.6348, 95% confidence interval CI=0.3673-0.9023, and p=0.6408, 95% CI=0.3977-0.8838), however, the methods are not interchangeable. CONCLUSION: The DNA ploidy discordance observed in our study group seems to document intratumoral heterogeneity that should be expected when applying DNA ploidy status in the clinical management of endometrial carcinoma. PMID- 22523303 TI - Influence of gender on mortality and need for extracorporeal membrane oxygenation in neonates with congenital diaphragmatic hernia. AB - AIM: To evaluate the influence of gender in neonates with congenital diaphragmatic hernia (CDH) on survival and to assess the necessity of extracorporeal membrane oxygenation (ECMO) therapy. PATIENTS AND METHODS: All parturients with newborns suffering from CDH were included. A total of 425 infants with CDH were analyzed. The primary outcome parameters evaluated were the necessity of ECMO and the survival. Secondary outcome parameters were the mode of delivery, the arterial umbilical cord pH value, the Apgar score, and the postpartum day of death. Cases with incomplete data were excluded. RESULTS: An analysis of the gender distribution of neonates in our study revealed that more males (n=248) than females (n=177) suffered from CDH. This represented a male versus female gender ratio of 58.4% to 41.6%, a significantly different ratio from that for neonates without CDH (p=0.003). Comparing both groups, statistical analysis showed no significant differences in mode of delivery, arterial umbilical cord blood pH, Apgar score, or CDH-relevant parameters of postpartum survival, including the need for ECMO therapy. CONCLUSION: CDH occurred significantly more frequently in male newborns. However, there were no significant differences in postnatal survival nor in the necessity of ECMO therapy. PMID- 22523304 TI - A Bayesian approach for unplanned sample sizes in phase II cancer clinical trials. AB - BACKGROUND: Phase II cancer clinical trials commonly employ two-stage designs that incorporate a single interim analysis for lack of efficacy and are designed to achieve specified frequentist properties. The requirement to examine the outcome at a prespecified sample size (SS) can be problematic, because the attained SS often differs from the planned SS. PURPOSE: We propose to address unplanned SSs achieved at either stage by means of a Bayesian approach that approximately preserves the original design's properties. METHODS: Our approach translates the rejection rule of the original frequentist design into equivalent statements about the posterior distribution of the response rate and applies this Bayesian criterion to the analysis with any realized SS. RESULTS: The results demonstrate that our approach approximately maintains operating characteristics of the original frequentist design including type I and type II error rates, probability of early termination, and expected SS under the null hypothesis. LIMITATIONS: Designs attained under this approach may not satisfy target limits for type I error rate and power. CONCLUSIONS: Our method offers a coherent analysis plan when the attained SS at either stage deviates from that specified in the original design. The price of its flexibility, in terms of erosion of the desired frequentist properties, is modest. PMID- 22523305 TI - On-pump versus off-pump coronary artery bypass surgery in elderly patients: results from the Danish on-pump versus off-pump randomization study. AB - BACKGROUND: Conventional coronary artery bypass grafting performed with the use of cardiopulmonary bypass is a well-validated treatment for patients with ischemic heart disease. Off-pump coronary artery bypass grafting (OPCAB) has been suggested to reduce the number of perioperative complications, especially in elderly patients. METHODS AND RESULTS: In a multicenter, randomized trial, we assigned 900 patients >70 years of age to conventional coronary artery bypass grafting or OPCAB surgery. After 30 days, a blinded end-point committee assessed whether a combined end point of death, stroke, or myocardial infarction had occurred. At baseline and 6 months postoperatively, self-assessed quality of life was measured with the Medical Outcomes Study Short Form-36 and EuroQol-5D questionnaires. A 6-month follow-up of mortality was performed through the Danish National Registry. The proportion of patients experiencing the combined end point within 30 days was 10.2% for conventional coronary artery bypass grafting and 10.7% for OPCAB. Implied risk difference of 0.4% (with a 95% confidence interval, -3.6 to 4.4) showed nonsignificance in a standard test for equality (P=0.83) and for noninferiority with an inferiority margin of 0.5% (P=0.49). At the 6-month follow-up, mortality was 4.7% compared with 4.2% (P=0.75). Both groups showed significant improvement in self-assessed health-related quality of life. CONCLUSIONS: Both conventional coronary artery bypass grafting and OPCAB are safe procedures that improved the quality of life when performed in elderly patients. No major differences in intermediate-term outcomes were found. However, the noninferiority of OPCAB with the prespecified margin could not be confirmed. PMID- 22523307 TI - Severe malaria, artesunate and haemolysis. PMID- 22523306 TI - Cell therapy in Chagas cardiomyopathy (Chagas arm of the multicenter randomized trial of cell therapy in cardiopathies study): a multicenter randomized trial. AB - BACKGROUND: Previous studies suggested that transplantation of autologous bone marrow-derived mononuclear cells (BMNCs) improves heart function in chronic chagasic cardiomyopathy. We report the results of the first randomized trial of BMNC therapy in chronic chagasic cardiomyopathy. METHODS AND RESULTS: Patients 18 to 75 years of age with chronic chagasic cardiomyopathy, New York Heart Association class II to IV heart failure, left ventricular ejection fraction (LVEF) <35, and optimized therapy were randomized to intracoronary injection of autologous BMNCs or placebo. The primary end point was the difference in LVEF from baseline to 6 and 12 months after treatment between groups. Analysis was by intention to treat and powered to detect an absolute between-group difference of 5. Between July 2005 and October 2009, 234 patients were enrolled. Two patients abandoned the study and 49 were excluded because of protocol violation. The remaining 183 patients, 93 in the placebo group and 90 in the BMNC group, had a trimmed mean age of 52.4 years (range, 50.8-54.0 years) and LVEF of 26.1 (range, 25.1-27.1) at baseline. Median number of injected BMNCs was 2.20*10(8) (range, 1.40-3.50*10(8)). Change in LVEF did not differ significantly between treatment groups: trimmed mean change in LVEF at 6 months, 3.0 (1.3-4.8) for BMNCs and 2.5 (0.6-4.5) for placebo (P=0.519); change in LVEF at 12 months, 3.5 (1.5-5.5) for BMNCs and 3.7 (1.5-6.0) for placebo (P=0.850). Left ventricular systolic and diastolic volumes, New York Heart Association functional class, Minnesota quality of-life questionnaire, brain natriuretic peptide concentrations, and 6-minute walking test did also not differ between groups. CONCLUSION: Intracoronary injection of autologous BMNCs does not improve left ventricular function or quality of life in patients with chronic chagasic cardiomyopathy. PMID- 22523308 TI - Tailoring evidence-based interventions for new populations: a method for program adaptation through community engagement. AB - Evidence-based interventions (EBIs) are an important tool for community health practitioners, but there is often a mismatch between the population in which the EBI was validated and the target population in which it will be used. Methods of planned adaptation identify differences in the new target population and attempt to make changes to the EBI that accommodate these differences without diluting the program's effectiveness. This article outlines an innovative method for eliciting ideas for program modifications and deciding on program changes. The Method for Program Adaptation through Community Engagement (M-PACE) uses systematic and detailed feedback from program participants to guide adaptation. The authors describe procedures for obtaining high-quality participant feedback and adjudicating recommendations to decide on program changes. M-PACE was developed as part of the adaptation of an evidence-based, arthritis self management program for older adults. The application and results of the M-PACE method are presented using this case as an example. PMID- 22523309 TI - Republished editorial: Improving teamwork in healthcare: current approaches and the path forward. PMID- 22523310 TI - Republished original research: Understanding how rapid response systems may improve safety for the acutely ill patient: learning from the frontline. AB - INTRODUCTION: Rapid response systems (RRSs) have been introduced to facilitate effective 'rescue' of seriously ill patients on hospital wards. While research has demonstrated some benefit, uncertainty remains regarding impact on patient outcomes. Little is known about the relationship between social contexts and the application of the RRS. DESIGN: This comparative case study of the RRS within the medical services of two UK hospitals used ethnographic methods over a 12-month period in 2009, including observation (ward work and shadowing medical staff = 150 h), interviews with doctors, ward and critical care nurses, healthcare assistants, safety leads and managers (n=35), documentary review and analysis of routine data. Data were analysed using NVivo software. RESULTS: The RRS reduced variability in recording, recognition and response behaviour. The RRS formalised understandings of deterioration and provided a mandate for escalating care across professional and hierarchical boundaries. However, markers of deterioration not assimilated into risk scores were marginalised and it was harder for staff to escalate care without the 'objective evidence' provided by the score. Contextual features (eg, leadership, organisational culture and training) shaped implementation, utilisation and impact of the RRS. Reporting and feedback of audit data enabled learning about 'selected' escalation work on the wards. Difficulties with referral upwards and across medical boundaries were reported by junior medical staff. CONCLUSION: Locating a RRS within a pathway of care for the acutely ill patient illustrates the role of these safety strategies within the social organisation of clinical work. There is a need to broaden the focus of inquiry from detection and initiation of escalation (where the strategies are principally directed) towards team response behaviour and towards those medical response practices which to date have escaped scrutiny and monitoring. PMID- 22523311 TI - Republished review: Autoantibody testing in encephalopathies. PMID- 22523312 TI - Republished Education in Heart: Cardiac involvement in muscular dystrophy: advances in diagnosis and therapy. PMID- 22523313 TI - Right or left ventricular pacing in young minipigs with chronic atrioventricular block: long-term in vivo cardiac performance, morphology, electrophysiology, and cellular biology. AB - BACKGROUND: Left ventricular (LV) dyssynchrony may occur as a result of right ventricular (RV) pacing and is a known risk factor for the development of heart failure. In children with complete atrioventricular block, pacing-induced dyssynchrony lasting for decades might be especially deleterious for LV function. To determine the hemodynamic and ultrastructural remodeling after either RV free wall or LV apical pacing, we used a chronic minipig model. METHODS AND RESULTS: Fourteen piglets 8 weeks of age underwent atrioventricular node ablation and were paced from either the RV free wall or the LV apex at 120 bpm for 1 year (7 age matched minipigs served as controls with spontaneous heart rates of 104 +/- 5 bpm). Echocardiographic examinations, pressure-volume loops, patch-clamp investigations, and examinations of connexin43, calcium-handling proteins, and histomorphology were carried out. RV free wall-paced minipigs exhibited significantly more LV dyssynchrony than LV apex-paced animals, which was accompanied by worsening of LV function (maximum LV mechanical delay/LV ejection fraction: RV free wall pacing, 154 +/- 36 ms/28 +/- 3%, LV apical pacing, 52 +/- 19 ms/45 +/- 2%, control 47 +/- 14 ms/62 +/- 1%; P=0.0001). At the cellular level, both pacemaker groups exhibited a significant reduction in L-type calcium and peak sodium current, shortening of action potential duration and amplitude, increased cell capacity, and alterations in the calcium-handling proteins that were similar for RV free wall- and LV apex-paced animals. CONCLUSIONS: The observed molecular remodeling seemed to be more dependent on heart rate than on dyssynchrony. LV apical pacing is associated with less dyssynchrony, a more physiological LV contraction pattern, and preserved LV function as opposed to RV free wall pacing. PMID- 22523314 TI - Does initial shunt type for the Norwood procedure affect echocardiographic measures of cardiac size and function during infancy?: the Single Vventricle Reconstruction trial. AB - BACKGROUND: The Pediatric Heart Network trial comparing outcomes in 549 infants with single right ventricle undergoing a Norwood procedure randomized to modified Blalock-Taussig shunt or right ventricle-pulmonary artery shunt (RVPAS) found better 1-year transplant-free survival in those who received RVPAS. We sought to compare the impact of shunt type on echocardiographic indices of cardiac size and function up to 14 months of age. METHODS AND RESULTS: A core laboratory measured indices of cardiac size and function from protocol exams: early after Norwood procedure (age 22.5 +/- 13.4 days), before stage II procedure (age 4.8 +/- 1.8 months), and at 14 months (age 14.3 +/- 1.2 months). Mean right ventricular ejection fraction was <50% at all intervals for both groups and was higher in the RVPAS group after Norwood procedure (49 +/- 7% versus 44 +/- 8%; P<0.001) but was similar by 14 months. Tricuspid and neoaortic regurgitation, diastolic function, and pulmonary artery and arch dimensions were similar in the 2 groups at all intervals. Neoaortic annulus area (4.2 +/- 1.2 versus 4.9 +/- 1.2 cm(2)/m(2)), systolic ejection times (214.0 +/- 29.4 versus 231.3 +/- 28.6 ms), neoaortic flow (6.2 +/- 2.4 versus 9.4 +/- 3.4 L/min per square meter), and peak arch velocity (1.9 +/- 0.7 versus 2.2 +/- 0.7 m/s) were lower at both interstage examinations in the RVPAS compared with the modified Blalock-Taussig shunt group (P<0.001 for all), but all were similar at 14 months. CONCLUSIONS: Indices of cardiac size and function after the Norwood procedure are similar for modified Blalock-Taussig shunt and RVPAS by 14 months of age. Interstage differences between shunt types can likely be explained by the physiology created when the shunts are in place rather than by intrinsic differences in cardiac function. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00115934. PMID- 22523315 TI - Nosocomial transmission of community-associated methicillin-resistant Staphylococcus aureus in Danish Hospitals. AB - OBJECTIVES: The emergence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has changed the epidemiology of MRSA infections worldwide. In contrast to hospital-associated MRSA (HA-MRSA), CA-MRSA more frequently affects healthy individuals, both with and without recent healthcare exposure. Despite obvious epidemiological differences, it is unknown whether differences in nosocomial transmissibility exist. We have, therefore, quantified the transmissibility, expressed by the single admission reproduction number (R(A)), of CA-MRSA and HA-MRSA in hospital settings in Denmark. METHODS: MRSA index cases and secondary cases were investigated in four hospitals in the Copenhagen area. Index cases were defined as non-isolated, non-screened patients with MRSA, and secondary cases were defined as persons carrying MRSA isolates identical to that of the corresponding index-as identified through contact screening. CA-MRSA and HA-MRSA were categorized upon genotyping [CA-MRSA: t008 ST8, PVL+; t019-ST30, PVL+; t127-ST1, PVL+; t044-ST80, PVL+; and their related spa types; and HA-MRSA: all other (where ST stands for sequence type and PVL stands for Panton-Valentine leucocidin)]. A mathematical model was applied to determine the genotype-specific transmission rate (i.e. R(A)) of CA-MRSA and HA MRSA strains. RESULTS: During the 7 year study period there were 117 MRSA index cases with subsequent post-contact screening (of 1108 patients and healthcare workers), revealing 22 outbreaks with a total of 52 secondary patients. R(A) values were 0.07 (95% CI 0.00-0.28) and 0.65 (95% CI 0.48-0.84) for CA-MRSA and HA-MRSA, respectively. CONCLUSIONS: In four Danish hospitals the nosocomial transmission rate of CA-MRSA was 9.3 times lower than that of HA-MRSA. PMID- 22523316 TI - Multicentre Etest evaluation of in vitro activity of conventional antifungal drugs against European bovine mastitis Prototheca spp. isolates. AB - OBJECTIVES: Bovine mammary protothecosis is a serious pathology that entails high economic losses in the dairy industry. The disease, the frequency of which has recently been increasing worldwide, is caused by unicellular, achlorophyllous, yeast-like algae of two species: Prototheca zopfii and Prototheca blaschkeae. The objective of this study was to investigate the in vitro activity of a panel of conventional antifungal drugs against Prototheca spp. isolates. METHODS: A total of 144 P. zopfii genotype 2 and P. blaschkeae strains isolated from milk of mastitic cows were subjected to drug susceptibility testing by Etest methodology. RESULTS: Five out of ten antifungal drugs tested exhibited no activity against Prototheca spp. isolates. The best activity against Prototheca spp. was demonstrated by amphotericin B (MIC90 of 1.5 mg/L). The MICs differed significantly (P < 0.01) between P. zopfii genotype 2 and P. blaschkeae, with the latter species being more susceptible to amphotericin B and azoles. Marked differences (P < 0.05) in azole and amphotericin B activities were noted among Prototheca spp. isolates originating from different European countries. Based on the correlation coefficients, a considerable cross-interaction was found among MICs of azoles and between MICs of azoles and amphotericin B for Prototheca spp. (P < 0.03). CONCLUSIONS: This study represents the largest, cross-European evaluation of antifungal activity against Prototheca spp. to date. The activity of amphotericin B against Prototheca spp. validates its potential use as a therapeutic agent against bovine protothecosis. For laboratory testing of drug activity against Prototheca spp., the Etest method is encouraged, due to its technical simplicity, rapidity and high intra- and inter-laboratory reproducibility. PMID- 22523317 TI - Characterization of CTX-M-14- and CTX-M-15-producing Escherichia coli of porcine origin. PMID- 22523318 TI - Associations between Internet-based patient ratings and conventional surveys of patient experience in the English NHS: an observational study. AB - OBJECTIVE: Unsolicited web-based comments by patients regarding their healthcare are increasing, but controversial. The relationship between such online patient reports and conventional measures of patient experience (obtained via survey) is not known. The authors examined hospital level associations between web-based patient ratings on the National Health Service (NHS) Choices website, introduced in England during 2008, and paper-based survey measures of patient experience. The authors also aimed to compare these two methods of measuring patient experience. DESIGN: The authors performed a cross-sectional observational study of all (n=146) acute general NHS hospital trusts in England using data from 9997 patient web-based ratings posted on the NHS Choices website during 2009/2010. Hospital trust level indicators of patient experience from a paper-based survey (five measures) were compared with web-based patient ratings using Spearman's rank correlation coefficient. The authors compared the strength of associations among clinical outcomes, patient experience survey results and NHS Choices ratings. RESULTS: Web-based ratings of patient experience were associated with ratings derived from a national paper-based patient survey (Spearman rho=0.31 0.49, p<0.001 for all). Associations with clinical outcomes were at least as strong for online ratings as for traditional survey measures of patient experience. CONCLUSIONS: Unsolicited web-based patient ratings of their care, though potentially prone to many biases, are correlated with survey measures of patient experience. They may be useful tools for patients when choosing healthcare providers and for clinicians to improve the quality of their services. PMID- 22523319 TI - Comparative economic analyses of patient safety improvement strategies in acute care: a systematic review. AB - BACKGROUND: The objective was to systematically review comparative economic analyses of patient safety improvements in the acute care setting. METHODS: A systematic review of 15 patient safety target conditions and six improvement strategies was conducted. The authors searched the published literature through Medline (2000-November 2011) using the following search terms for costs: 'costs and cost analysis', 'cost-effectiveness', 'cost' and 'financial management, hospital'. The methodological quality of potentially relevant studies was appraised using Cochrane rules of evidence for clinical effectiveness in quality improvement, and standard economic methods. RESULTS: The authors screened 2151 abstracts, reviewed 212 potentially eligible studies, and identified five comparative economic analyses that reported a total of seven comparisons based on at least one clinical effectiveness study of adequate methodological quality. Pharmacist-led medication reconciliation to prevent potential adverse drug events dominated (lower costs, better safety) a strategy of no reconciliation. Chlorhexidine for vascular catheter site care to prevent catheter-related bloodstream infections dominated a strategy of povidone-iodine for catheter site care. The Keystone ICU initiative to prevent central line-associated bloodstream infections was economically dominant over usual care. Detecting surgical foreign bodies using standard counting compared with a strategy of no counting had an incremental cost of US$1500 (CAN$1676) for each surgical foreign body detected. Several safety improvement strategies were less economically attractive, such as bar-coded sponges for reducing retained surgical sponges compared with standard surgical counting, and giving erythropoietin to reduce transfusion requirements in critically ill patients to avoid one transfusion-related adverse event. CONCLUSIONS: Five comparative economic analyses were found that reported a total of seven comparisons based on at least one effectiveness study of adequate methodological quality. On the basis of these limited studies, pharmacist-led medication reconciliation, the Keystone ICU intervention for central line associated bloodstream infections, chlorhexidine for vascular catheter site care, and standard surgical sponge counts were economically attractive strategies for improving patient safety. More comparative economic analyses of such strategies are needed. PMID- 22523320 TI - Constitutively active mutant gp130 receptor protein from inflammatory hepatocellular adenoma is inhibited by an anti-gp130 antibody that specifically neutralizes interleukin 11 signaling. AB - Ligand-independent constitutively active gp130 mutants were described to be responsible for the development of inflammatory hepatocellular adenomas (IHCAs). These variants had gain-of-function somatic mutations within the extracellular domain 2 (D2) of the gp130 receptor chain. Cytokine-dependent Ba/F3 cells were transduced with the constitutively active variant of gp130 featuring a deletion in the domain 2 from Tyr-186 to Tyr-190 (gp130DeltaYY). These cells showed constitutive phosphorylation of signal transducer and activator of transcription 3 (STAT3) and cytokine-independent proliferation. Deletion of the Ig-like domain 1 (D1) of gp130, but not anti-gp130 mAbs directed against D1, abolished constitutive activation of gp130DeltaYY, highlighting that this domain is involved in ligand-independent activation of gp130DeltaYY. Moreover, soluble variants of gp130 were not able to inhibit the constitutive activation of gp130DeltaYY. However, the inhibition of constitutive activation of gp130DeltaYY was achieved by the anti-gp130 mAb B-P4, which specifically inhibits gp130 signaling by IL-11 but not by other IL-6 type cytokines. IL-11 but not IL-6 levels were found previously to be up-regulated in IHCAs, suggesting that mutations in gp130 are leading to IL-11-like signaling. The mAb B-P4 might be a valuable tool to inhibit the constitutive activation of naturally occurring gp130 mutants in IHCAs and rare cases of gp130-associated hepatocellular carcinoma. PMID- 22523321 TI - Adipose tissue macrophages: MR tracking to monitor obesity-associated inflammation. AB - PURPOSE: To investigate whether cellular imaging by using ultrasmall superparamagnetic iron oxide (USPIO)-enhanced magnetic resonance (MR) imaging can allow detection and quantification of adipose tissue macrophage-related inflammation within adipose tissue in a mouse model. MATERIALS AND METHODS: Experimental protocols were conducted in accordance with French government policies. Adipose tissue macrophages were detected and quantified with a 4.7-T MR imager in ob/ob obese mice on the basis of the signal variance of adipose tissue triggered by injection of P904 iron oxide nanoparticles (USPIO). Mice were either intravenously injected with 1000 MUmol of iron per kilogram of body weight of P904 (10 ob/ob and 11 ob/+) or used as noninjected control animals (seven ob/ob and six ob/+). Three-dimensional T2*-weighted gradient-echo MR images were acquired 10 days after intravenous injection. MR imaging signal variance in mice was correlated to adipose tissue macrophage quantification by using monoclonal antibody to F4/80 immunostaining, to proinflammatory marker quantification by using reverse transcription polymerase chain reaction (CCl2, Tnfalpha, Emr1), and to P904 quantification by using electron paramagnetic resonance imaging. Quantitative data were compared by using the Mann-Whitney or Student t test, and correlations were performed by using the Pearson correlation test. RESULTS: MR imaging measurements showed a significant increase in adipose tissue signal variance in ob/ob mice compared with ob/+ controls or noninjected animals (P < .0001), which was consistent with increased P904 uptake by adipose tissue in ob/ob mice. There was a significant and positive correlation between adipose tissue macrophage quantification at MR imaging and P904 iron oxide content (r = 0.87, P < .0001), adipose tissue macrophage-related inflammation at immunohistochemistry (r = 0.60, P < .01), and adipose tissue proinflammatory marker expression (r = 0.55, 0.56, and 0.58 for CCl2, Tnfalpha, and Emr1, respectively; P < .01). CONCLUSION: P904 USPIO-enhanced MR imaging is potentially a tool for noninvasive assessment of adipose tissue inflammation during experimental obesity. These results provide the basis for translation of MR imaging into clinical practice as a marker of patients at risk for metabolic syndrome. PMID- 22523322 TI - Invasive breast cancer: relationship between shear-wave elastographic findings and histologic prognostic factors. AB - PURPOSE: To compare the histologic prognostic feature of invasive breast cancer with mean stiffness as measured with shear-wave elastography. MATERIALS AND METHODS: This retrospective study was exempted from ethical committee review. Patient consent for use of images for research was obtained. The study group comprised 101 consecutive women (age range, 38-91 years) with solid lesions identified during routine breast ultrasonography (US) performed between April 2010 and March 2011 and subsequently confirmed at histologic examination to be invasive cancers. Four elastographic images in two orthogonal planes were obtained of each lesion, and mean stiffness values were obtained from each image. Histologic findings following surgery were used for comparison, namely histologic grade, tumor type, invasive size, vascular invasion status, and lymph node status. Relationship between mean stiffness and histologic parameters was investigated by using a general linear model and multiple regression analysis. RESULTS: High histologic grade (P < .0001), large invasive size (P < .0001), lymph node involvement (P < .0001), tumor type (P < .0001), and vascular invasion (P = .0077) all showed statistically significant positive association with high mean stiffness values. Multiple linear regression indicated that invasive size is the strongest pathologic determinant of mean stiffness (P < .0001), with histologic grade also having significant influence (P = .022). CONCLUSION: In this study, breast cancers with higher mean stiffness values at shear-wave elastography had poorer prognostic features. PMID- 22523323 TI - High-resolution 3D MR microangiography of the rat ocular circulation. AB - PURPOSE: To develop high-spatial-resolution magnetic resonance (MR) microangiography techniques to image the rat ocular circulation. MATERIALS AND METHODS: Animal experiments were performed with institutional Animal Care Committee approval. MR microangiography (resolution, 84*84*84 MUm or 42*42*84 MUm) of the rat eye (eight rats) was performed by using a custom-made small circular surface coil with an 11.7-T MR unit before and after monocrystalline iron oxide nanoparticle (MION) injection. MR microangiography measurements were made during air, oxygen, and carbogen inhalation. From three-dimensional MR microangiography, the retina was virtually flattened to enable en face views of various retinal depths, including the retinal and choroidal vascular layers. Signal intensity changes within the retinal or choroidal arteries and veins associated with gas challenges were analyzed. Statistical analysis was performed by using paired t tests, with P<.05 considered to indicate a significant difference. Bonferroni correction was used to adjust for multiple comparisons. RESULTS: The central retinal artery, long posterior ciliary arteries, and choroidal vasculature could be distinguished on MR microangiograms of the eye. With MR microangiography, retinal arteries and veins could be distinguished on the basis of blood oxygen level-dependent contrast. Carbogen inhalation-enhanced MR microangiography signal intensity in both the retina (P=.001) and choroid (P=.027) compared with oxygen inhalation. Carbogen inhalation showed significantly higher signal intensity changes in the retinal arteries (P=.001, compared with oxygen inhalation), but not in the veins (P=.549). With MION administration, MR microangiography depicted retinal arterial vasoconstriction when the animals were breathing oxygen (P=.02, compared with animals breathing air). CONCLUSION: MR microangiography of the eye allows depth-resolved imaging of small angiographic details of the ocular circulation. This approach may prove useful in studying microvascular pathologic findings and neurovascular dysfunction in the eye and retina. PMID- 22523324 TI - Undiagnosed breast cancer at MR imaging: analysis of causes. AB - PURPOSE: To retrospectively review the causes of false-negative results on prior magnetic resonance (MR) imaging studies in patients who developed breast cancer as revealed on a follow-up MR imaging study and to determine the presumptive causes of these false-negative findings. MATERIALS AND METHODS: Fifty-eight pairs of MR imaging studies from one institution were assessed, consisting of a prior study without a diagnosis of cancer and a diagnostic study with subsequent findings of 60 cancers in 58 women at MR imaging (mean interval between prior and diagnostic MR examinations, 13.8 months). Two radiologists reviewed in consensus, in a nonblinded fashion, each pair of MR studies, comparing the diagnostic and the prior MR imaging studies to evaluate the rate of false-negative findings. The prospective reports were then analyzed to classify false-negatives findings in breast enhancement of breast cancers not identified at the time of imaging, potentially misinterpreted, and mismanaged. False-negative results on prior MR studies were retrospectively reassessed to identify possibly reasons why cancers had been not recognized, potentially misinterpreted, or mismanaged. RESULTS: Twenty-eight (47% [95% confidence interval {CI}: 34%, 59%]) of the 60 cancers were retrospectively diagnosed as Breast Imaging Reporting and Data System grade 3, 4, or 5 lesions. Analysis of the prospective reports showed that six lesions (10% [95% CI: 2%, 18%]) had been not identified at the time of diagnosis, 15 lesions (25% [95% CI: 14%, 36%]) were potentially misinterpreted, and seven lesions (12% [95% CI: 3%, 20%]) were mismanaged. The main causes of misinterpretation were smooth margins of a mass (n=4), stability in size (n=3), and location of a nonmass in a postsurgical area (n=5). Mismanagement was mainly due to inadequate correlations between MR imaging and ultrasonographic (US) features, with inaccurate sampling with US guidance in five cases. CONCLUSION: In patients with breast cancer seen at MR imaging, retrospective evaluation of the prior MR imaging studies showed potential observer error in 47% of cases, resulting more from misinterpretation than from nonrecognition or mismanagement of cancers. PMID- 22523325 TI - MR lymphangiography at 3.0 T: correlation with lymphoscintigraphy. AB - PURPOSE: To prospectively compare findings of magnetic resonance (MR) lymphangiography with those of lymphoscintigraphy, evaluate the pattern and delay of lymphatic drainage, compare typical findings, and investigate discrepancies between the techniques. MATERIALS AND METHODS: This prospective study was performed according to the Declaration of Helsinki and was approved by the local ethics committee. Thirty consecutive patients with uni- or bilateral lymphedema and lymph vessel transplants of the lower extremities were examined with 3.0-T fat-saturated three-dimensional gradient-echo MR after gadopentetate dimeglumine injection. Results of all examinations were correlated with corresponding results of lymphoscintigraphy examinations. Results of both techniques were separately reviewed in consensus by a radiologist and a nuclear physician, who rated delay and pattern of drainage, number of enhancing levels, and quality of conspicuity of the depiction of lymph nodes and lymph vessels. Sensitivity and specificity were calculated by using combined results of both techniques and clinical presentation findings as reference standard. Correlation was calculated with weighted k coefficients. RESULTS: Weak lymphatic drainage at lymphoscintigraphy correlated with lymphangiectasia at MR lymphangiography (13 of 33 affected extremities). Lymph vessels were clearly visualized with MR lymphangiography (five of 24 affected extremities), while they were not detectable with lymphoscintigraphy. Depiction of inguinal lymph nodes was clearer with lymphoscintigraphy (five of 60 extremities). Correlation of both techniques was excellent for delay (kappa=0.93) and pattern (kappa=0.84) of drainage, good for depiction of lymph nodes (kappa=0.67) and number of enhancing levels (kappa=0.77), and moderate for depiction of lymph vessels (kappa=0.50). Sensitivity and specificity for delay and pattern of drainage were concordant, whereas MR lymphangiography showed a higher sensitivity for lymph vessel abnormalities (100% vs 79%) and lower specificity for lymph node abnormalities (78% vs 100%). CONCLUSION: Imaging findings of MR lymphangiography and lymphoscintigraphy show a clear concordance. With lymphoscintigraphy, better visualization of inguinal lymph nodes was achieved, whereas with MR lymphangiography, better depiction of lymph vessels and morphologic features of lymph vessel abnormalities were achieved. PMID- 22523326 TI - Liver and spleen stiffness in patients with extrahepatic portal vein obstruction. AB - PURPOSE: To evaluate liver stiffness (LS) and spleen stiffness (SS) in patients with extrahepatic portal vein obstruction (EHPVO). MATERIALS AND METHODS: Institutional research board approval and informed consent were obtained. LS and SS were measured in 65 consecutive patients with EHPVO. Patients underwent endoscopy, liver biopsy, liver function tests, abdominal ultrasonography, a detailed history, and examination. LS and SS measurements were also obtained in 50 age-matched healthy control subjects. Comparisons were made by using the Student t test, Mann-Whitney test for quantitative data, and chi(2) or Fisher exact test for qualitative data. RESULTS: Sixty-five patients with EHPVO (with a bleed, n = 45; without a bleed, n = 20; mean age, 25.4 years +/- 10.7 [standard deviation]; 29 men, 36 women) were enrolled. Twenty-two (34%) had hypersplenism. LS (P = .001) and SS (P = .01) were higher in patients with EHPVO (6.7 kPa +/- 2.3 and 51.7 kPa +/- 21.5, respectively) than in control subjects (4.6 kPa +/- 0.7 and 16.0 kPa +/- 3.0, respectively). Patients who had a bleed had higher SS than did those without a bleed (60.4 kPa +/- 5.4 vs 30.3 kPa +/- 14.2, P = .01). There was no significant difference in age (26.7 years +/- 10.4 vs 22.5 years +/- 9.8, P = .8) and median duration of disease (4.5 years [range, 1-26 years] vs 6.0 years [range, 1-22 years], P = .23) in patients with a bleed versus those without. With a cutoff of 5.9 kPa for LS, sensitivity and specificity for detection of a variceal bleed were 67% and 75%, respectively. An SS cutoff of 42.8 kPa yielded sensitivity and specificity of 88% and 94%, respectively. CONCLUSION: LS and SS were higher in patients with EHPVO than in control subjects, and patients with a history of a bleed had a higher SS than did those without a bleed. PMID- 22523327 TI - Intravoxel incoherent motion and diffusion-tensor imaging in renal tissue under hydration and furosemide flow challenges. AB - PURPOSE: To assess the reproducibility and the distribution of intravoxel incoherent motion (IVIM) and diffusion-tensor (DT) imaging parameters in healthy renal cortex and medulla at baseline and after hydration or furosemide challenges. MATERIALS AND METHODS: Using an institutional review board-approved HIPAA-compliant protocol with written informed consent, IVIM and DT imaging were performed at 3 T in 10 volunteers before and after water loading or furosemide administration. IVIM (apparent diffusion coefficient [ADC], tissue diffusivity [D(t)], perfusion fraction [f(p)], pseudodiffusivity [D(p)]) and DT (mean diffusivity [MD], fractional anisotropy [FA], eigenvalues [lambda(i)]) imaging parameters and urine output from serial bladder volumes were calculated. (a)Reproducibility was quantified with coefficient of variation, intraclass correlation coefficient, and Bland-Altman limits of agreement; (b) contrast and challenge response were quantified with analysis of variance; and (c) Pearson correlations were quantified with urine output. RESULTS: Good reproducibility was found for ADC, D(t), MD, FA, and lambda(i) (average coefficient of variation, 3.7% [cortex] and 5.0% [medulla]), and moderate reproducibility was found for D(p), f(p), and f(p) . D(p) (average coefficient of variation, 18.7% [cortex] and 25.9% [medulla]). Baseline cortical diffusivities significantly exceeded medullary values except D(p), for which medullary values significantly exceeded cortical values, and lambda(1,) which showed no contrast. ADC, D(t), MD, and lambda(i) increased significantly for both challenges. Medullary diffusivity increases were dominated by transverse diffusion (1.72 +/- 0.09 [baseline] to 1.79 +/- 0.10 [hydration] MUm(2)/msec, P = .0059; or 1.86 +/- 0.07 [furosemide] MUm(2)/msec, P = .0094). Urine output correlated with cortical ADC with furosemide (r = 0.7, P = .034) and with medullary lambda(1) (r = 0.83, P = .0418), lambda(2) (r = 0.85, P = .0301), and MD (r = 0.82, P = .045) with hydration. CONCLUSION: Diffusion MR metrics are sensitive to flow changes in kidney induced by diuretic challenges. The results of this study suggest that vascular flow, tubular dilation, water reabsorption, and intratubular flow all play important roles in diffusion-weighted imaging contrast. PMID- 22523329 TI - Extending the reach of Exendin-4: new pathways in the control of body weight and glucose homeostasis. PMID- 22523330 TI - The insulin receptor isoform A: a mitogenic proinsulin receptor? PMID- 22523331 TI - GABA: a cotransmitter linking leptin to obesity prevention. PMID- 22523332 TI - Synapsins I and II are not required for beta-cell insulin secretion: granules must pool their own weight. PMID- 22523334 TI - Metformin for liver cancer prevention in patients with type 2 diabetes: a systematic review and meta-analysis. AB - CONTEXT: Data on the potential effect of metformin on the risk of liver cancer are limited and inconsistent. OBJECTIVE: The objective of this study was to review the evidence currently available to examine the potential role of metformin in chemoprevention for liver cancer in patients with type 2 diabetes. DATA SOURCES: The data sources of the study included the PubMed and SciVerse Scopus databases. STUDY SELECTION: Selection included studies that assessed the effect of metformin therapy on the risk of liver cancer in patients with type 2 diabetes. DATA EXTRACTION: Summary effect estimates were derived using a random effects meta-analysis model. DATA SYNTHESIS: A database was developed on the basis of five studies consisting of approximately 105,495 patients with type 2 diabetes. In meta-analyses, metformin was associated with an estimated 62% reduction in the risk of liver cancer among patients with type 2 diabetes (odds ratio 0.38, 95% confidence interval 0.24, 0.59; P < 0.001). The effect estimates were heterogeneous across the five included studies (P for heterogeneity = 0.001; I(2) = 78%). When restricting the analysis to the four studies related to hepatocellular carcinoma, metformin was again associated with a significantly lower cancer risk (odds ratio 0.30, 95% confidence interval 0.17, 0.52; P < 0.001), and there was evidence of significant heterogeneity between these four studies (P for heterogeneity = 0.03; I(2) = 67%). CONCLUSIONS: Metformin appears to be associated with a lower risk of liver cancer in patients with type 2 diabetes. Further investigation, including mechanistic studies, well-designed cohort studies, and possibly controlled trials, is needed. PMID- 22523335 TI - The interaction of blood flow, insulin, and bradykinin in regulating glucose uptake in lower-body adipose tissue in lean and obese subjects. AB - CONTEXT: Impaired adipose tissue (AT) blood flow has been implicated in the pathogenesis of insulin resistance in obesity. Insulin and bradykinin are meal stimulated promoters of AT blood flow and glucose metabolism. OBJECTIVE: We tested whether blood flow regulates glucose metabolism in AT, insulin and bradykinin exert additive effects on AT blood flow and metabolism, and any of these actions explains the insulin resistance observed in obese individuals. DESIGN: Perfusion and glucose metabolism in the AT of the thighs were studied by positron emission tomography and H(2)(15)O (flow tracer) and (18)F-2-fluoro-2 deoxyglucose. Study I included five subjects in whom positron emission tomography imaging was performed in the fasting state during intraarterial infusion of bradykinin in the left leg; the right leg served as a control. Study II included seven lean and eight obese subjects in whom the imaging protocol was performed during euglycemic hyperinsulinemia. RESULTS: Bradykinin alone doubled fasting AT blood flow without modifying glucose uptake. Hyperinsulinemia increased AT blood flow (P <= 0.05) similarly in lean and obese individuals. In the lean group, bradykinin increased insulin-mediated AT glucose uptake from 8.6 +/- 1.6 to 12.3 +/- 2.4 MUmol/min . kg (P = 0.038). In the obese group, AT glucose uptake was impaired (5.0 +/- 1.0 MUmol/min . kg, P = 0.05 vs. the lean group), and bradykinin did not exert any metabolic action (6.0 +/- 0.8 MUmol/min . kg, P = 0.01 vs. the lean group). CONCLUSION: AT blood flow is not an independent regulator of AT glucose metabolism. Insulin is a potent stimulator of AT blood flow, and bradykinin potentiates the hemodynamic and metabolic actions of insulin in lean but not in obese individuals. PMID- 22523336 TI - Sex steroid-induced changes in circulating monocyte chemoattractant protein-1 levels may contribute to metabolic dysfunction in obese men. AB - CONTEXT: Low testosterone accompanied by elevated estradiol associates with the development of metabolic dysfunction in men. OBJECTIVE: The aim of the study was to explore the hypothesis that alterations in sex steroid levels induce metabolic dysfunction through adipokines. DESIGN: Circulating levels of sex steroids and 28 adipokines were determined in a cross-sectional study of morbidly obese men and aged-matched controls, as well as in a randomized clinical trial with healthy young men in which obesity-related alterations in sex steroid levels were mimicked by treatment with an aromatase inhibitor plus estradiol patches. RESULTS: Morbidly obese men had lower testosterone levels than normal-weight controls. Estradiol levels were increased in morbidly obese men (without DM2) as compared to normal-weight controls. Circulating levels of multiple proinflammatory cytokines, including IL-1Ra, IL-5, IL-6, IL-10, leptin, monocyte chemoattractant protein 1 (MCP1), and macrophage inflammatory protein 1alpha, positively associated with estradiol and negatively with testosterone. The associations with estradiol, but not with testosterone, remained significant after adjusting for adipocyte cell size. In a separate clinical trial, the direct adverse effects of lowering testosterone and raising estradiol on MCP1 were substantiated in vivo. CONCLUSIONS: Initial alterations in sex steroid levels may contribute to metabolic dysfunction through adverse effects on adipokine levels in obese men. The direct adverse effects on MCP1, a chemokine highly linked to the development of metabolic dysfunction, were substantiated in a trial mimicking obesity-related alterations of sex steroid levels in healthy young males. PMID- 22523337 TI - Benefits and risks of bisphosphonate therapy for osteoporosis. AB - CONTEXT: There has been considerable concern recently in the scientific and lay media regarding the benefits vs. the risks of bisphosphonates for the treatment of osteoporosis. Risks include possible associations with osteonecrosis of the jaw (ONJ) and atypical femur fractures. In this perspective, we review the use of bisphosphonates for the treatment of osteoporosis, including an objective assessment of the risks vs. the benefits of these drugs. EVIDENCE ACQUISITION: Authors' knowledge of the field and results of focused literature searches are presented. EVIDENCE SYNTHESIS: Bisphosphonates have proven efficacy in the prevention of bone loss and in the reduction of fractures in postmenopausal women and men with established osteoporosis. Although bisphosphonates, at doses used to treat osteoporosis, may be associated with an increased risk of ONJ and atypical femur fractures, many more fractures are prevented by the use of these drugs compared to the relatively low risk of these complications. Although oral bisphosphonates are associated with upper gastrointestinal side effects and iv bisphosphonates with acute phase reactions, the association of bisphosphonate use with esophageal cancer and atrial fibrillation is not well supported by current data. CONCLUSIONS: Bisphosphonates have been proven to prevent fractures in patients with established osteoporosis or those who are at high risk of fracture. In contrast, the incidence of major complications associated with bisphosphonate use, such as ONJ and atypical femur fractures, is very low. PMID- 22523338 TI - Proteasome subunit beta5t expression in cervical ectopic thymoma. PMID- 22523339 TI - The molecular characterisation of unusual subcutaneous spindle cell lesion of breast. AB - BACKGROUND: Spindle cell lesions of the breast represent an interesting diagnostic challenge as they comprise a wide range of tumours that are rare. Differentiating dermatofibrosarcoma protuberans (DFSP) from other dermatofibromas using CD34 immunohistochemistry alone is difficult; therefore, fluorescence in situ hybridisation (FISH) analysis is often employed to identify typical COL1A1 PDGFB fusion or gene rearrangement. Although molecular confirmation of diagnosis is unnecessary in the majority of DFSP cases, the detection of chromosomal rearrangement is valuable in tumours that show unusual clinicopathological features as in this study the authors report a case of DFSP of breast that did not show any typical known molecular features. METHODS AND RESULTS: Morphological and immunohistochemical study was highly suggestive of the diagnosis of DFSP. To further investigate this case, DNA copy number alterations were investigated by the 250 K Affymetrix SNP Mapping array. DNA analysis did not show any of the known translocations reported in DFSP or any known solid tumour category. However, in addition to copy number changes on chromosome 1, amplification of chromosome 7p which contains the epidermal growth factor receptor (EGFR) gene was observed. Results from EGFR FISH showed an increase in EGFR gene to chromosome 7 ratio (3:1) suggesting amplification of the EGFR gene. CONCLUSION: This case of an unusual DFSP demonstrates that genomic interrogation provides additional potential targets such as a therapeutic avenue with anti-EGFR therapies and shows the power of molecular characterisation of unusual tumours for a personalised medicine approach. PMID- 22523340 TI - The prognostic significance of early stage lymph node positivity in operable invasive breast carcinoma: number or stage. AB - AIM: The earlier detection of breast cancer through mammographic screening has resulted in a shift in stage distribution with patients who are node-positive tending to present with a lower number of positive lymph nodes (LN). This study aims to assess the prognostic value of absolute number of positive nodes in the pN1 TNM stage (1-3 positive LN) and whether the prognostic value of the number of nodes in this clinically important stage justifies its consideration in management decisions. METHODS: This study is based on a large and well characterised consecutive series of operable breast cancer (3491 cases), treated according to standard protocols in a single institution, with a long-term follow up. RESULTS: LN stages and the absolute number of LN are associated with both breast cancer specific survival (BCSS) and distant metastasis free survival (DMFS). In the pN1 stage, patients with three positive LN (14% of pN1) show shorter BCSS (HR=1.9, (95% CI 1.3 to 2.6)) and shorter DMFS (HR=2.2, (95% CI 1.6 to 2.9)) when compared with one and/or two positive nodes. This effect is noted in the whole series as well as in different subgroups based on tumour size (pT1c and pT2), histological grade (grade 2 and 3), vascular invasion and oestrogen receptor status (both positive and negative). Multivariable analyses showed that three positive LN, compared with one and two positive LN, are an independent predictor of shorter BCSS and DMFS. CONCLUSION: The number of LN in the pN1 stage yielded potentially informative risk assignments with three positive LN providing an independent predictor of poorer outcome. PMID- 22523341 TI - Past and present socioeconomic circumstances and psychotropic medication: a register-linkage study. AB - BACKGROUND: Various domains of socioeconomic circumstances are associated with self-reported mental health, but we lack evidence from studies using medically confirmed mental health outcomes. This longitudinal study aimed to examine the associations of multiple domains of socioeconomic circumstances with subsequent prescribed psychotropic medication among Finnish public sector employees. METHODS: Baseline survey data among 40-60-year-old employees of City of Helsinki were linked with Social Insurance Institution of Finland register data on psychotropic medication purchases (n=5563). HRs were calculated using Cox regression to examine associations of parental and own education, childhood and current economic difficulties, occupational class, household income and housing tenure with antidepressants, sleeping pills and sedatives and any psychotropic medication during a 5-year follow-up. RESULTS: In age and previous psychotropic medication adjusted models, the risk of antidepressant medication was higher in those with childhood (women: HR=1.29, men: HR=1.64) and current economic difficulties (women: HR=1.30-1.54), rented housing (women: HR=1.20, men: HR=1.45) and the second lowest income group (men: HR=1.71). Gradual adjustments had little effect on the associations. For sleeping pills and sedatives, similar associations were found in women for current economic difficulties, and in men for housing tenure. Results for any psychotropic medication reflected those observed for antidepressants. CONCLUSIONS: Past and present economic difficulties and housing tenure were more important determinants of subsequent psychotropic medication among employees than the conventional socioeconomic determinants. The associations were somewhat inconsistent between the medication groups and the sexes. The results support the importance of examining multiple domains of socioeconomic circumstances simultaneously. PMID- 22523342 TI - Changes in suicide rates following media reports on celebrity suicide: a meta analysis. AB - BACKGROUND: A growing number of studies indicate that sensationalist reporting of suicide is associated with increases in suicide rates, but in the light of some negative findings, the issue has remained controversial. The aim of this study was to evaluate the best current evidence on the association between celebrity suicide stories and subsequent suicides. METHODS: Literature searches of six data sources (Medline, Psychlit, Communication Abstracts, Education Resources Information Center, Dissertation Abstracts and Australian Public Affairs Database (APAIS)) were conducted. Studies were included if they (1) adopted an ecological design, (2) focused on celebrity suicide, (3) had completed suicide as outcome variable, (4) analysed suicide rates across all suicide methods, (5) used data from after World War II and (6) satisfied basic quality criteria. RESULTS: 10 studies with totally 98 suicides by celebrities met the criteria. The pooled estimate indicated a change in suicide rates (suicides per 100 000 population) of 0.26 (95% CI 0.09 to 0.43) in the month after a celebrity suicide. There was substantial heterogeneity between studies, which was explained by the type of celebrity (entertainment elite vs others) and the region of study, as indicated by mixed-effects meta-regression. The region-of-study-specific effect of reporting a suicide by an entertainment celebrity was 0.64 (95% CI 0.55 to 0.73) in North America, 0.58 (95% CI 0.47 to 0.68) in Asia, 0.36 (95% CI -0.10 to 0.61) in Australia and 0.68 (95% CI 0.51 to 0.85) in Europe. There was no indication of publication bias. CONCLUSIONS: Reports on celebrity suicide are associated with increases in suicides. Study region and celebrity type appear to have an impact on the effect size. PMID- 22523343 TI - Brachypodium distachyon promoters as efficient building blocks for transgenic research in maize. AB - The biotechnological approach to improve performance or yield of crops or for engineering metabolic pathways requires the expression of a number of transgenes, each with a specific promoter to avoid induction of silencing mechanisms. In maize (Zea mays), used as a model for cereals, an efficient Agrobacterium tumefaciens-mediated transformation system has been established that is applied for translational research. In the current transformation vectors, the promoters of the 35S gene of the cauliflower mosaic virus and of the ubiquitin gene of maize are often used to drive the bialaphos-selectable marker and the transgene, respectively. To expand the number of promoters, genes with either constitutive or seed-specific expression were selected in Brachypodium distachyon, a model grass distantly related to maize. After the corresponding Brachypodium promoters had been fused to the beta-glucuronidase reporter gene, their activity was followed throughout maize development and quantified in a fluorimetric assay with the 4-methylumbelliferyl beta-D-glucuronide substrate. The promoters pBdEF1alpha and pBdUBI10 were constitutively and highly active in maize, whereas pBdGLU1 was clearly endosperm-specific, hence, expanding the toolbox for transgene analysis in maize. The data indicate that Brachypodium is an excellent resource for promoters for transgenic research in heterologous cereal species. PMID- 22523345 TI - A clinical data warehouse-based process for refining medication orders alerts. AB - The objective of this case report is to evaluate the use of a clinical data warehouse coupled with a clinical information system to test and refine alerts for medication orders control before they were fully implemented. A clinical decision rule refinement process was used to assess alerts. The criteria assessed were the frequencies of alerts for initial prescriptions of 10 medications whose dosage levels depend on renal function thresholds. In the first iteration of the process, the frequency of the 'exceeds maximum daily dose' alerts was 7.10% (617/8692), while that of the 'under dose' alerts was 3.14% (273/8692). Indicators were presented to the experts. During the different iterations of the process, 45 (16.07%) decision rules were removed, 105 (37.5%) were changed and 136 new rules were introduced. Extensive retrospective analysis of physicians' medication orders stored in a clinical data warehouse facilitates alert optimization toward the goal of maximizing the safety of the patient and minimizing overridden alerts. PMID- 22523346 TI - Isolation and characterization of 10 SSR markers of Momordica charantia (Cucurbitaceae). AB - PREMISE OF THE STUDY: Microsatellite markers were isolated and characterized from the genome of Momordica charantia (bitter melon) to be applied in studies of genetic diversity and population structure. METHODS AND RESULTS: Twenty-five microsatellite loci were isolated from the genome of bitter melon using the Fast Isolation by AFLP of Sequences COntaining Repeats (FIASCO) method. Ten loci were polymorphic, and the number of alleles per locus ranged from three to seven, with the observed heterozygosity ranging from 0.46 to 0.65. The markers also amplified successfully in the related species M. cochinchinensis and Cucurbita pepo. CONCLUSIONS: These markers will have potential utility for applications in genetic diversity evaluation, molecular fingerprinting, identification, comparative genomics analysis, and genetic mapping in Momordica species, as well as in C. pepo. PMID- 22523347 TI - Intraspecific cytotypic variation and complicated genetic structure in the Phlox amabilis-P. woodhousei (Polemoniaceae) complex. AB - PREMISE OF THE STUDY: Polyploidy is widely recognized as an important process in the evolution of plants, but less attention has been paid to the study of intraspecific polyploidy, including its prevalence, formation, taxonomic implications, and effect on genetic diversity, structure, and gene flow within and among individuals and populations. Here we studied intraspecific ploidy level variation in the Phlox amabilis-P. woodhousei complex to determine the amount and distribution of cytotypic and genetic variation present and measure the extent of gene flow among species, cytotypes, and populations. METHODS: Flow cytometry and microsatellite analyses were used to ascertain cytotypic variation, genetic diversity, and population structure within and among eight populations of P. amabilis and 10 populations of P. woodhousei from Arizona and New Mexico. KEY RESULTS: Our analyses support the recognition of P. amabilis and P. woodhousei as two distinct species. Both species exhibit cytotypic variation with geographically structured diploid, tetraploid, and hexaploid populations, and genetic analyses suggest a combination of auto- and allopolyploidy in their formation. Diploid, tetraploid, and most hexaploid populations within species share much of their genetic variation, while some hexaploid populations are genetically distinct. All populations maintain moderately high genetic diversity and connectivity, and genetic structure is strongly influenced by geography. CONCLUSIONS: This study highlights the potential for complicated patterns of genetic variation relative to cytotypic variation and provides evidence for the role of cytotypic variation and geographic isolation in shaping diversity, differentiation, and potentially speciation in the P. amabilis-P. woodhousei complex. PMID- 22523344 TI - Clinical research informatics: a conceptual perspective. AB - Clinical research informatics is the rapidly evolving sub-discipline within biomedical informatics that focuses on developing new informatics theories, tools, and solutions to accelerate the full translational continuum: basic research to clinical trials (T1), clinical trials to academic health center practice (T2), diffusion and implementation to community practice (T3), and 'real world' outcomes (T4). We present a conceptual model based on an informatics enabled clinical research workflow, integration across heterogeneous data sources, and core informatics tools and platforms. We use this conceptual model to highlight 18 new articles in the JAMIA special issue on clinical research informatics. PMID- 22523348 TI - Variation in intra-annual wood formation, and foliage and shoot development of three major Canadian boreal tree species. AB - PREMISE OF THE STUDY: In a warming climate, boreal trees may have adjusted their growth strategy (e.g., onset and coordination of growth among different organs such as stem, shoot, and foliage, within and among species) to cope with the extended growing seasons. A detailed investigation into growth of different organs during a growing season may help us assess the potential effects of climate change on tree growth in the boreal forest. METHODS: The intra-annual growth of stem xylem, shoot tips, and foliage area of Pinus banksiana, Populus tremuloides, and Betula papyrifera was monitored in a boreal forest in Quebec, Canada during the growing season of 2007. Xylem formation was measured at weekly intervals, and shoot elongation and foliage expansion were measured three times per week from May to September. Growth indices for stem, shoot, and foliage were calculated and used to identify any climate-growth dependence. KEY RESULTS: The time periods required for stem growth, branch extension, and foliage expansion differed among species. Of the three species, P. banksiana had the earliest budburst (20 May) yet the latest completion date of the foliage growth (2 August); P. tremuloides had the latest budburst (27 May) yet the earliest completion date of the foliage growth (10 July). Air temperature positively affected shoot extension growth of all three species. Precipitation positively influenced stem growth of the two broadleaf species, whereas growing season temperature positively impacted stem growth of P. banksiana. CONCLUSION: The results show that both the timing of growth processes and environmental dependences differ among co-occurring species, thereby leading to different adaptive capability of these boreal tree species to climate change. PMID- 22523349 TI - Functional regeneration and spectral reflectance of trees during succession in a highly diverse tropical dry forest ecosystem. AB - PREMISE OF THE STUDY: The function of most ecosystems has been altered by human activities. To asses the recovery of plant communities, we must evaluate the recovery of plant functional traits. The seasonally dry tropical forest (SDTF), a highly threatened ecosystem, is assumed to recover relatively quickly from disturbance, but an integrated evaluation of recovery in floristic, structural, and functional terms has not been performed. In this study we aimed to (a) compare SDTF plant functional, floristic, and structural change along succession; (b) identify tree functional groups; and (c) explore the spectral properties of different successional stages. METHODS: Across a SDTF successional gradient, we evaluated the change of species composition, vegetation structure, and leaf spectral reflectance and functional traits (related to water use, light acquisition, nutrient conservation, and CO(2) acquisition) of 25 abundant tree species. KEY RESULTS: A complete recovery of SDTF takes longer than the time period inferred from floristic or structural data. Plant functional traits changed along succession from those that maximize photoprotection and heat dissipation in early succession, where temperature is an environmental constraint, to those that enhance light acquisition in late succession, where light may be limiting. A spectral indicator of plant photosynthetic performance (photochemical reflectance index) discriminated between early and late succession. This constitutes a foundation for further exploration of remote sensing technologies for studying tropical succession. CONCLUSIONS: A functional approach should be incorporated as a regular descriptor of forest succession because it provides a richer understanding of vegetation dynamics than is offered by either the floristic or structural approach alone. PMID- 22523350 TI - Drag reduction in wave-swept macroalgae: alternative strategies and new predictions. AB - PREMISE OF THE STUDY: Intertidal macroalgae must resist extreme hydrodynamic forces imposed by crashing waves. How does frond flexibility mitigate drag, and how does flexibility affect predictions of drag and dislodgement in the field? METHODS: We characterized flexible reconfiguration of six seaweed species in a recirculating water flume, documenting both shape change and area reduction as fronds reorient. We then used a high-speed gravity-accelerated water flume to test our ability to predict drag under waves based on extrapolations of drag recorded at slower speeds. We compared dislodgement forces to drag forces predicted from slow- and high-speed data to generate new predictions of survivorship and maximum sustainable frond size along wave-swept shores. KEY RESULTS: Bladed algae were generally "shape changers", limiting drag by reducing drag coefficients, whereas the branched alga Calliarthron was an "area reducer", limiting drag by reducing projected area in flow. Drag predictions often underestimated actual drag measurements at high speeds, suggesting that slow speed data may not reflect the performance of flexible seaweeds under breaking waves. Several seaweeds were predicted to dislodge at similar combinations of velocity and frond size, suggesting common scaling factors of dislodgement strength and drag. CONCLUSIONS: Changing shape and reducing projected area in flow are two distinct strategies employed by flexible seaweeds to resist drag. Flexible reconfiguration contributes to the uncertainty of drag extrapolation, and researchers should use caution when predicting drag and dislodgement of seaweeds in the field. PMID- 22523351 TI - Frequent EGFR mutations in nonsmall cell lung cancer presenting with miliary intrapulmonary carcinomatosis. AB - Nonsmall cell lung cancer (NSCLC) presenting with miliary intrapulmonary carcinomatosis (MIPC) is rare. We investigated the clinical characteristics and epidermal growth factor receptor (EGFR) mutation rate of NSCLC patients with MIPC at initial diagnosis. From June 2004 to December 2008, we screened newly diagnosed NSCLC patients for MIPC using image-based criteria. We recorded clinical data and analysed EGFR mutation status. For comparison, we collected specimens from stage IV NSCLC patients without MIPC tested for EGFR mutations from April 2001 to November 2008. From 3,612 NSCLC patients, 85 patients with MIPC at initial diagnosis were identified; 81 had adenocarcinoma. Of the 85 patients, 60 had specimen sequencing to detect EGFR mutation; 42 (70%) were positive. Compared with 673 stage IV patients without MIPC, patients with MIPC had higher EGFR mutation rate (p=0.036); even male smokers had a high EGFR mutation rate (91%). Multivariate analysis of prognostic factors for overall survival of the 85 patients with MIPC revealed that adenocarcinoma, absence of extrapulmonary metastasis and having EGFR mutation were associated with longer overall survival. NSCLC patients with MIPC at initial diagnosis had higher rates of adenocarcinoma and EGFR mutation. EGFR tyrosine kinase inhibition may be the treatment of choice for NSCLC patients with MIPC at initial diagnosis among Asians. PMID- 22523352 TI - Sputum purulence-guided antibiotic use in hospitalised patients with exacerbations of COPD. AB - In patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) needing hospitalisation, sputum purulence is associated with bacteria in the lower respiratory tract. We performed a prospective non-randomised interventional pilot study applying a sputum purulence-guided strategy of antibiotic treatment and investigating the relationship between sputum purulence and biomarkers. In hospitalised patients with acute exacerbation of COPD antibiotics were restricted to those with purulent sputum. The primary end-point was rate of therapeutic failure during hospitalisation. Secondary end-points were parameters reflecting short- and long-term outcomes. We included 73 patients, 34 with non-purulent sputum. No differences were observed on therapeutic failure criteria (9% non-purulent versus 10% purulent (p=0.51)). Serum C-reactive protein (CRP) was significantly increased in the purulent group at admission (11.6 versus 5.3, p=0.006) and at day 3 (2.7 versus 1.2, p=0.01). Serum procalcitonin (PCT) was similar between the groups. No differences were found in short-term outcomes. The exacerbation rate at 180 days was higher in the purulent group. These results support the hypothesis of performing a randomised trial using a sputum purulence guided antibiotic treatment strategy in patients with acute exacerbations of COPD. CRP, but not PCT, may be a useful parameter to increase confidence of the absence of bacterial bronchial infection. PMID- 22523353 TI - Acetazolamide and chronic hypoxia: effects on haemorheology and pulmonary haemodynamics. AB - We tested the effect of acetazolamide on blood mechanical properties and pulmonary vascular resistance (PVR) during chronic hypoxia. Six groups of rats were either treated or not treated with acetazolamide (curative: treated after 10 days of hypoxic exposure; preventive: treated before hypoxic exposure with 40 mg . kg(-1) . day(-1)) and either exposed or not exposed to 3 weeks of hypoxia (at altitude >5,500 m). They were then used to assess the role of acetazolamide on pulmonary artery pressure, cardiac output, blood volume, haematological and haemorheological parameters. Chronic hypoxia increased haematocrit, blood viscosity and PVR, and decreased cardiac output. Acetazolamide treatment in hypoxic rats decreased haematocrit (curative by -10% and preventive by -11%), PVR (curative by -36% and preventive by -49%) and right ventricular hypertrophy (preventive -20%), and increased cardiac output (curative by +60% and preventive by +115%). Blood viscosity was significantly decreased after curative acetazolamide treatment (-16%) and was correlated with PVR (r=0.87, p<0.05), suggesting that blood viscosity could influence pulmonary haemodynamics. The fall in pulmonary vascular hindrance (curative by -27% and preventive by -45%) after treatment suggests that acetazolamide could decrease pulmonary vessels remodelling under chronic hypoxia. The effect of acetazolamide is multifactorial by acting on erythropoiesis, pulmonary circulation, haemorheological properties and cardiac output, and could represent a pertinent treatment of chronic mountain sickness. PMID- 22523354 TI - Clinical and inflammatory determinants of bronchial hyperresponsiveness in COPD. AB - Bronchial hyperresponsiveness (BHR) is regarded as a hallmark of asthma, yet it is also present in a considerable number of chronic obstructive pulmonary disease (COPD) patients. Epidemiological studies have shown that BHR provides complementary information to forced expiratory volume in 1 s (FEV(1)) for development and progression of COPD. We hypothesised that the severity of BHR and its longitudinal changes associate with both clinical and airway inflammation measures in COPD. Our hypothesis was tested in 114 COPD patients (median age 62.9 years, smoking exposure 45.9 pack-yrs) participating in the GLUCOLD (Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease) study, which previously showed an improvement in BHR with fluticasone and fluticasone/salmeterol. At baseline, and 6 and 30 months after treatment, we investigated lung function, including body plethysmography, provocative concentration of methacholine causing a 20% fall in FEV(1), sputum induction, and bronchial biopsies. By performing both cross-sectional and longitudinal analyses, we show that BHR in COPD is predominantly associated with residual volume/total lung capacity (a measure of air trapping) and airway inflammation reflected by the number of neutrophils, macrophages and lymphocytes in sputum and bronchial biopsies. Our findings indicate that BHR is an independent trait in COPD and provides important information on phenotype heterogeneity and disease activity. PMID- 22523355 TI - Src tyrosine kinase is crucial for potassium channel function in human pulmonary arteries. AB - The potassium channel TWIK-related acid sensitive potassium (TASK)-1 channel, together with other potassium channels, controls the low resting tone of pulmonary arteries. The Src family tyrosine kinase (SrcTK) may control potassium channel function in human pulmonary artery smooth muscle cells (hPASMCs) in response to changes in oxygen tension and the clinical use of a SrcTK inhibitor has resulted in partly reversible pulmonary hypertension. This study aimed to determine the role of SrcTK in hypoxia-induced inhibition of potassium channels in hPASMCs. We show that SrcTK is co-localised with the TASK-1 channel. Inhibition of SrcTK decreases potassium current density and results in considerable depolarisation, while activation of SrcTK increases potassium current in patch-clamp recordings. Moderate hypoxia and the SrcTK inhibitor decrease the tyrosine phosphorylation state of the TASK-1 channel. Hypoxia also decreases the level of phospho-SrcTK (tyr419) and reduces the co-localisation of the TASK-1 channel and phospho-SrcTK. Corresponding to this, hypoxia reduces TASK 1 currents before but not after SrcTK inhibition and, in the isolated perfused mouse lung, SrcTK inhibitors increase pulmonary arterial pressure. We propose that the SrcTK is a crucial factor controlling potassium channels, acting as a cofactor for setting a negative resting membrane potential in hPASMCs and a low resting pulmonary vascular tone. PMID- 22523356 TI - Altitude illness is related to low hypoxic chemoresponse and low oxygenation during sleep. AB - Altitude illness remains a major cause of mortality. Reduced chemosensitivity, irregular breathing leading to central apnoeas/hypopnoeas, and exaggerated pulmonary vasoconstriction may compromise oxygenation. All factors could enhance susceptibility to acute mountain sickness (AMS). We compared 12 AMS-susceptible individuals with recurrent and severe symptoms (AMS+) with 12 "AMS nonsusceptible" subjects (AMS-), assessing sleep-breathing disorders in simulated altitude as well as chemoresponsive and pulmonary vasoconstrictive responses to hypoxia. During exposure to simulated altitude, mean blood oxygen saturation during sleep was lower in AMS+ subjects (81.6 +/- 2.6 versus 86.0 +/- 2.4%, p<0.01), associated with a lower central apnoea/hypopnoea index (18.2 +/- 18.1 versus 33.4 +/- 24.8 events . h(-1) in AMS+ and AMS- subjects, respectively; p=0.038). A lower hypoxic (isocapnic) chemoresponsiveness was observed in AMS+ subjects (0.40 +/- 0.49 versus 0.97 +/- 0.46 L . min(-1).%; p<0.001). This represented the only significant and independent predictive factor for altitude intolerance, despite a higher increase in pulmonary artery systolic pressure in response to hypoxia, a lower lung diffusing capacity and a higher endothelin-1 level at baseline in AMS+ subjects (p<0.05). AMS+ subjects were more hypoxaemic whilst exhibiting fewer respiratory events during sleep owing to lower hypoxic (isocapnic) chemoresponsiveness. In conclusion, the reduction in peripheral hypoxic chemosensitivity appears to be a major causative factor for altitude intolerance. PMID- 22523357 TI - Dehydroepiandrosterone reverses chronic hypoxia/reoxygenation-induced right ventricular dysfunction in rats. AB - Dehydroepiandrosterone (DHEA) prevents chronic hypoxia-induced pulmonary hypertension and associated right ventricle dysfunction in rats. In this animal model, reoxygenation following hypoxia reverses pulmonary hypertension but not right ventricle dysfunction. We thus studied the effect of DHEA on the right ventricle after reoxygenation, i.e. after a normoxic recovery phase secondary to chronic hypoxia in rats. Right ventricle function was assessed in vivo by Doppler echocardiography and in vitro by the isolated perfused heart technique in three groups of animals: control, recovery (21 days of hypoxia followed by 21 days of normoxia) and recovery DHEA (30 mg . kg(-1) every 2 days during the recovery phase). Right ventricle tissue was assessed by optical and electron microscopy. DHEA abolished right ventricle diastolic dysfunction, as the echographic E wave remained close to that of controls (mean +/- SD 76.5 +/- 2.4 and 79.7 +/- 1.7 cm . s(-1), respectively), whereas it was diminished to 40.3 +/- 3.7 in the recovery group. DHEA also abolished right ventricle systolic dysfunction, as shown by the inhibition of the increase in the slope of the pressure-volume curve in isolated heart. The DHEA effect was related to cardiac myocytes proliferation. In conclusion, DHEA prevents right ventricle dysfunction in this animal model by preventing cardiomyocyte alteration. PMID- 22523358 TI - Persistent disruption of ciliated epithelium following paediatric lung transplantation. AB - It is unclear whether ciliary function following lung transplantation is normal or not. Our aim was to study the ciliary function and ultrastructure of epithelium above and below the airway anastomosis and the peripheral airway of children following lung transplantation. We studied the ciliary beat frequency (CBF) and beat pattern, using high speed digital video imaging and ultrastructure by transmission electron microscopy, of bronchial epithelium from above and below the airway anastomosis and the peripheral airway of 10 cystic fibrosis (CF) and 10 non-suppurative lung disease (NSLD) paediatric lung transplant recipients. Compared to epithelium below the anastomosis, the epithelium above the anastomosis in the CF group showed reduced CBF (median (interquartile range): 10.5 (9.0-11.4) Hz versus 7.4 (6.4-9.2) Hz; p<0.01) and increased dyskinesia (median (IQR): 16.5 (12.9-28.2)% versus 42.2 (32.6-56.4)%; p<0.01). In both CF and NSLD groups, compared with epithelium above the anastomosis, the epithelium below the anastomosis showed marked ultrastructural abnormalities (median duration post-transplant 7-12 months). Ciliary dysfunction is a feature of native airway epithelium in paediatric CF lung transplant recipients. The epithelium below the airway anastomosis shows profound ultrastructural abnormalities in both CF and NSLD lung transplant recipients, many months after transplantation. PMID- 22523359 TI - Aalpha-Val360: a marker of neutrophil elastase and COPD disease activity. AB - Forced expiratory volume in 1 s is currently the most widely used marker of chronic obstructive pulmonary disease (COPD) severity; however, it is a poor surrogate of the emphysematous component and the underlying pathophysiological mechanism, and therefore new markers are urgently needed. Neutrophil elastase (NE) is likely to play a key pathophysiological role in COPD and the current study explores a marker of NE activity as a potential indicator of COPD disease activity. Aalpha-Val(360) was measured in 81 subjects with a clinical diagnosis of COPD, both in the stable state and at presentation with an acute exacerbation, and comparisons were made using lung function tests and computed tomography imaging. The relationship of Aalpha-Val(360) with disease progression was also assessed in 40 of the subjects over a 4-yr period. Baseline Aalpha-Val(360) related to physiological and radiological markers of disease severity, was higher at presentation with an acute exacerbation than in the stable state and (at least partly) related to disease progression over the subsequent 4 yrs. We demonstrate that Aalpha-Val(360) is a marker of cross-sectional COPD disease severity and possibly disease progression, and represents a new concept of specific biomarkers. This study therefore reports the first in vivo data to support the pathophysiological role of NE in COPD. PMID- 22523360 TI - Pulse transit time as a measure of respiratory effort under noninvasive ventilation. AB - Among the respiratory events that may occur during nocturnal noninvasive ventilation (NIV), differentiating between central and obstructive events requires appropriate indicators of respiratory effort. The aim of the present study was to assess pulse transit time (PTT) as an indicator of respiratory effort under NIV in comparison with oesophageal pressure (P(oes)). During wakefulness, PTT was compared to P(oes) during spontaneous breathing and under NIV with or without induced leaks in 11 healthy individuals. In addition, the contribution of PTT versus P(oes) to differentiation of central from obstructive respiratory events occurring under NIV during sleep was evaluated in 10 patients with obesity hypoventilation syndrome (OHS). From spontaneous breathing to NIV without leaks, respiratory effort decreased significantly whereas, with increasing level of leaks, there was a significant increase in respiratory effort. Changes in PTT accurately reflected changes in P(oes). In OHS patients during nocturnal NIV, intraclass correlation coefficients between P(oes) and PTT were 0.970 for total number of events and 0.970 for percentage of central events. PTT accurately reflects the unloading of respiratory muscles induced by NIV and the increase in respiratory effort during leaks. PTT during sleep is also useful to differentiate central from obstructive respiratory events occurring under NIV. PMID- 22523361 TI - Expressed wishes and incidence of euthanasia in advanced lung cancer patients. AB - This study explores expressed wishes and requests for euthanasia (i.e. administration of lethal drugs at the explicit request of the patient), and incidence of end-of-life decisions with possible life-shortening effects (ELDs) in advanced lung cancer patients in Flanders, Belgium. We performed a prospective, longitudinal, observational study of a consecutive sample of advanced lung cancer patients and selected those who died within 18 months of diagnosis. Immediately after death, the pulmonologist/oncologist and general practitioner (GP) of the patient filled in a questionnaire. Information was available for 105 out of 115 deaths. According to the specialist or GP, one in five patients had expressed a wish for euthanasia; and three in four of these had made an explicit and repeated request. One in two of these received euthanasia. Of the patients who had expressed a wish for euthanasia but had not made an explicit and repeated request, none received euthanasia. Patients with a palliative treatment goal at inclusion were more likely to receive euthanasia. Death was preceded by an ELD in 62.9% of patients. To conclude, advanced lung cancer patients who expressed a euthanasia wish were often determined. Euthanasia was performed significantly more among patients whose treatment goal after diagnosis was exclusively palliative. PMID- 22523362 TI - The role of mannose-binding lectin in pneumococcal infection. AB - The role of mannose-binding lectin (MBL) deficiency (MBL2; XA/O and O/O genotypes) in host defences remains controversial. The surfactant proteins (SP) A1, -A2 and -D, other collectins whose genes are located near MBL2, are part of the first-line lung defence against infection. We analysed the role of MBL on susceptibility to pneumococcal infection and the existence of linkage disequilibrium (LD) among the four genes. We studied 348 patients with pneumococcal community-acquired pneumonia (P-CAP) and 2,110 controls. A meta analysis of MBL2 genotypes in susceptibility to P-CAP and to invasive pneumococcal disease (IPD) was also performed. The extent of LD of MBL2 with SFTPA1, SFTPA2 and SFTPD was analysed. MBL2 genotypes did not associate with either P-CAP or bacteraemic P-CAP in the case-control study. The MBL-deficient O/O genotype was significantly associated with higher risk of IPD in a meta analysis, whereas the other MBL-deficient genotype (XA/O) showed a trend towards a protective role. We showed the existence of LD between MBL2 and SP genes. The data do not support a role of MBL deficiency on susceptibility to P-CAP or to IPD. LD among MBL2 and SP genes must be considered in studies on the role of MBL in infectious diseases. PMID- 22523363 TI - At 68 years, unrecognised sleep apnoea is associated with elevated ambulatory blood pressure. AB - After the age of 65 yrs the specific impact of unrecognised sleep-related breathing disorders (SRBD) on 24-h blood pressure (BP) levels remains under debate. We tested the cross-sectional relationship between the severity of obstructive sleep apnoea/hypopnoea (OSAH) and the increase of BP using ambulatory BP monitoring (ABPM) in the PROOF (PROgnostic indicator OF cardiovascular and cerebrovascular events study)-SYNAPSE (Autonomic Nervous System Activity, Aging and Sleep Apnea/Hypopnea study) cohort. 470 subjects (aged 68 yrs) neither treated for hypertension nor diagnosed for SRBD were included. All subjects underwent ABPM, and unattended at-home polygraphic studies. OSAH was defined by an apnoea/hypopnoea index (AHI) >15 . h(-1). The severity of the sleep apnoea was also quantified as the index of dips in oxyhaemoglobin saturation >3% (ODI). Results are expressed in per protocol analysis. Severe OSAH (AHI >30 . h(-1), 17% of subjects) was associated with a significant 5 mmHg increase in both diurnal and nocturnal systolic BP (SBP), and with a nocturnal 3 mmHg increase in diastolic BP (DBP). Systolic (mean SBP >135 mmHg) or diastolic (mean DBP >80 mmHg) hypertension were more frequently encountered in subjects suffering from moderate (AHI 15-30) or severe OSAH. After adjustment, the independent association between severe OSAH and 24-h systolic hypertension remained significant (OR 2.42, 95% CI 1.1-5.4). The relationship was further reinforced when SRBD severity was expressed using ODI >10 . h(-1). The impact of unrecognised SRBD on BP levels also exists at the age of 68 yrs. The hypoxaemic load appears to be the pathophysiological cornerstone for such a relationship. PMID- 22523364 TI - Matrix metalloproteinases and their inhibitors in pulmonary hypertension. AB - Pulmonary hypertension (PH) is a severe and progressive disease characterised by high pulmonary artery pressure, usually culminating in right heart failure. Current therapeutic approaches in PH largely provide symptomatic relief while the prognosis rate is lower due to the lack of specific molecular targets and the involvement of several factors in the development of PH. Numerous studies have suggested a crucial role of matrix metalloproteinase (MMP) axis during development and disease states, specifically with regard to extracellular matrix remodelling and vascular homeostasis. Increased MMP activity has been demonstrated in experimental animal models of PH, and MMP inhibition has been shown to either attenuate or enhance vascular remodelling. Moreover, several studies emphasise that restoration of deregulated MMPs to physiological MMP/tissue inhibitor of MMPs ratios would potentiate reverse remodelling in PH. This article will highlight the pathophysiological role of MMPs in vascular remodelling and the establishment of PH. In particular, we will focus on the MMP expression and regulation in pulmonary vasculature and pulmonary vascular remodelling. We will also provide an overview of recent clinical and experimental findings and their impact on achieving maximum reversal of PH, as well as current issues and future perspectives. PMID- 22523365 TI - PM10, and children's respiratory symptoms and lung function in the PATY study. AB - Studies of the impact of long-term exposure to outdoor air pollution on the prevalence of respiratory symptoms and lung function in children have yielded mixed results, partly related to differences in study design, exposure assessment, confounder selection and data analysis. We assembled respiratory health and exposure data for >45,000 children from comparable cross-sectional studies in 12 countries. 11 respiratory symptoms were selected, for which comparable questions were asked. Spirometry was performed in about half of the children. Exposure to air pollution was mainly characterised by annual average concentrations of particulate matter with a 50% cut-off aerodynamic diameter of 10 MUm (PM(10)) measured at fixed sites within the study areas. Positive associations were found between the average PM(10) concentration and the prevalence of phlegm (OR per 10 MUg . m(-3) 1.15, 95% CI 1.02-1.30), hay fever (OR 1.20, 95% CI 0.99-1.46), bronchitis (OR 1.08, 95% CI 0.98-1.19), morning cough (OR 1.15, 95% CI 1.02-1.29) and nocturnal cough (OR 1.13, 95% CI 0.98 1.29). There were no associations with diagnosed asthma or asthma symptoms. PM(10) was not associated with lung function across all studies combined. Our study adds to the evidence that long-term exposure to outdoor air pollution, characterised by the concentration of PM(10), is associated with increased respiratory symptoms. PMID- 22523366 TI - Effectiveness of an inspiratory pressure-limited approach to mechanical ventilation in septic patients. AB - Severe sepsis is one of the most common causes of acute lung injury (ALI) and is associated with high mortality. The aim of the study was to see whether a protective strategy based approach with a plateau pressure <30 cmH(2)O was associated with lower mortality in septic patients with ALI in the Surviving Sepsis Campaign international database. A retrospective analysis of an international multicentric database of 15,022 septic patients from 165 intensive care units was used. Septic patients with ALI and mechanical ventilation (n=1,738) had more accompanying organ dysfunction and a higher mortality rate (48.3% versus 33.0%, p<0.001) than septic patients without ALI (n=13,284). In patients with ALI and mechanical ventilation, the use of inspiratory plateau pressures maintained at <30 cmH(2)O was associated with lower mortality by Chi squared test (46.4% versus 55.1%, p<0.001) and by Kaplan-Meier and log-rank test (p<0.001). In a multivariable random-effects Cox regression, plateau pressure <30 cmH(2)O was significantly associated with lower mortality (hazard ratio 0.84, 95% CI 0.72-0.99; p=0.038). ALI in sepsis was associated with higher mortality, especially when an inspiratory pressure-limited mechanical ventilation approach was not implemented. PMID- 22523367 TI - Pulmonary hypertension associated with benfluorex exposure. AB - Benfluorex was marketed in France until 2009, despite its similar pharmacological properties with fenfluramine and its derivatives known to be a cause of pulmonary arterial hypertension (PAH). The aim of this study is to report clinical and haemodynamic characteristics for patients suffering from pulmonary hypertension (PH) associated with benfluorex exposure that had been identified by the French PAH Network. 85 cases of PH associated with benfluorex exposure were identified by the French PAH Network from June 1999 to March 2011. Of these, 70 patients had confirmed pre-capillary PH. The median duration of exposure was 30 months, with a median of 108 months between start of exposure and diagnosis of the pulmonary vascular disease. 33% of all patients also had prior exposure to fenfluramine or dexfenfluramine, and an additional risk factor for PH was identified in 20 (30%) out of 70 patients with pre-capillary PH. A quarter of patients in this current series showed coexisting PH and mild-to-moderate cardiac valve involvement. The results of our study, together with the accumulated data regarding the known toxic effects of fenfluramine and dexfenfluramine, strongly suggest that benfluorex exposure is a potent trigger for PAH. PMID- 22523368 TI - The monothiol glutaredoxin Grx4 exerts an iron-dependent inhibitory effect on Php4 function. AB - When iron is scarce, Schizosaccharomyces pombe cells repress transcription of several genes that encode iron-using proteins. Php4 mediates this transcriptional control by specifically interacting with the CCAAT-binding core complex that is composed of Php2, Php3, and Php5. In contrast, when there is sufficient iron, Php4 is inactivated, thus allowing the transcription of many genes that encode iron-requiring proteins. Analysis by bimolecular fluorescence complementation and two-hybrid assays showed that Php4 and the monothiol glutaredoxin Grx4 physically interact with each other. Deletion mapping analysis revealed that the glutaredoxin (GRX) domain of Grx4 associates with Php4 in an iron-dependent manner. Site-directed mutagenesis identified the Cys172 of Grx4 as being required for this iron-dependent association. Subsequent analysis showed that, although the thioredoxin (TRX) domain of Grx4 interacts strongly with Php4, this interaction is insensitive to iron. Fine mapping analysis revealed that the Cys35 of Grx4 is necessary for the association between the TRX domain and Php4. Taken together, the results revealed that whereas the TRX domain interacts constitutively with Php4, the GRX domain-Php4 association is both modulated by iron and required for the inhibition of Php4 activity in response to iron repletion. PMID- 22523370 TI - Anatomic femoral tunnel drilling in anterior cruciate ligament reconstruction: use of an accessory medial portal versus traditional transtibial drilling. AB - BACKGROUND: During anatomic anterior cruciate ligament (ACL) reconstruction, we have found that the femoral footprint can best be visualized from the anteromedial portal. Independent femoral tunnel drilling can then be performed through an accessory medial portal, medial and inferior to the standard anteromedial portal. PURPOSE: To compare the accuracy of independent femoral tunnel placement relative to the ACL footprint using an accessory medial portal versus tunnel placement with a traditional transtibial technique. STUDY DESIGN: Controlled laboratory study. METHODS: Ten matched pairs of cadaveric knees were randomized such that within each pair, one knee underwent arthroscopic transtibial (TT) drilling, and the other underwent drilling through an accessory medial portal (AM). All knees underwent computed tomography (CT) both preoperatively and postoperatively with a technique optimized for ligament evaluation (80 keV with maximum mAs). Computed tomography was performed with a dual-energy scanner. Commercially available third-party software was used to fuse the preoperative and postoperative CT scans, allowing anatomic comparison of the ACL footprint to the drilled tunnel. The ACL footprint was marked in consensus by an orthopaedic surgeon and a musculoskeletal radiologist and then compared with the tunnel aperture after drilling. The percentage of tunnel aperture contained within the native footprint as well as the distance from the center of the tunnel aperture to the center of the footprint was measured. RESULTS: The AM technique placed 97.7% +/- 5% of the tunnel within the native femoral footprint, significantly more than 61.2% +/- 24% for the TT technique (P = .001). The AM technique placed the center of the femoral tunnel 3.6 +/- 1.2 mm from the center of the native footprint, significantly closer than 6.0 +/- 1.9 mm for the TT technique (P = .003). CONCLUSION: This study demonstrates that use of an accessory medial portal will facilitate more accurate placement of the femoral tunnel in the native ACL femoral footprint. CLINICAL RELEVANCE: More accurate placement of the femoral tunnel in the native ACL femoral footprint should improve the ability to achieve more anatomic positioning of the ACL graft. PMID- 22523369 TI - Investigating the function of Ddr48p in Candida albicans. AB - Candidiasis now represents the fourth most frequent nosocomial infection both in the United States and worldwide. Candida albicans is an increasingly common threat to human health as a consequence of AIDS, steroid therapy, organ and tissue transplantation, cancer therapy, broad-spectrum antibiotics, and other immune defects. The pathogenic potential of C. albicans is intimately related to certain key processes, including biofilm formation and filamentation. Ddr48p is a damage response protein that is significantly upregulated during both biofilm formation and filamentation, but its actual function is unknown. Previous studies have indicated that this protein may be essential in C. albicans but not Saccharomyces cerevisiae. Here we examined the function of Ddr48p and investigated the role of this protein in biofilm formation and filamentation. We demonstrated that this protein is not essential in C. albicans and appears to be dispensable for filamentation. However, DDR48 is required for the flocculation response stimulated by 3-aminotriazole-induced amino acid starvation. Furthermore, we examined the response of this deletion strain to a wide variety of environmental stressors and antifungal compounds. We observed several mild sensitivity or resistance phenotypes and also found that Ddr48p contributes to the DNA damage response of C. albicans. The results of this study reveal that the role of this highly expressed protein goes beyond a general stress response and impinges on a key facet of pathogenesis, namely, the ability to sense and respond to changes in the host environment. PMID- 22523371 TI - Bone replacement of fast-absorbing biocomposite anchors in arthroscopic shoulder labral repairs. AB - BACKGROUND: Newer generation biocomposite anchors are hypothesized to resorb more reliably and faster, while allowing for bone ingrowth and replacement. PURPOSE: The purposes of this study were to (1) assess anchor resorption and bone ingrowth over time, (2) identify tunnel widening or potential reactions to the implants, (3) compare imaging findings for different sites of labral repair, and (4) determine patient subjective outcomes with the use of biocomposite anchors in glenoid labral repair. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: We enrolled 22 patients to participate in a 24-month outcomes study that included subjective and objective outcome assessments after glenoid labrum repair surgery. Magnetic resonance imaging (MRI) was performed at 6 and 12 months to identify any potential reactions to implants. Computed tomography (CT) scans were performed at 12 and 24 months to determine anchor resorption and bone ingrowth. Sixteen patients and 47 anchors were available for follow-up at 24 months. An independent, fellowship-trained musculoskeletal radiologist read the scans. Subjective outcome scores measured at 24 months postoperatively included Simple Shoulder Test, Tegner activity scale, American Shoulder and Elbow Surgeons (ASES), and University of California, Los Angeles (UCLA) shoulder scores. RESULTS: No adverse events were reported with the use of biocomposite anchors at the end of the study period. At 12 and 24 months, respectively, CT scans demonstrated that an estimated 68% and 98% of combined anchor material had been absorbed, 56% and 78% of the anchor material had been replaced by soft tissue of variable density, and 9% and 20% of total anchor volume was replaced by bone. No obvious mechanical failure of the labral repairs was detected on nonarthrogram MRI. Three of the 47 anchors showed bone cyst formation. Tunnel widening (expansion beyond tunnel diameter of 3 mm; 2.9-mm drill hole utilized) was seen in 55% of the anchors but decreased between 12 and 24 months, consistent with bone replacement. Tunnel widening was seen more in anteroinferior and posterior glenoid anchor locations (84% and 57%, respectively) than in superior labral anchors (13%). Subjective outcome scores at 24 months for ASES and UCLA shoulder scores averaged 88 and 30, respectively. All but one patient were satisfied with their outcome at 24 months. CONCLUSION: Our imaging evaluation indicates resorption of newer generation biocomposite anchors with progressive bone replacement at 12 and 24 months while maintaining acceptable subjective outcomes. PMID- 22523372 TI - The effects of chlorhexidine graft decontamination on tendon graft collagen and cell viability. AB - BACKGROUND: Chlorhexidine (CLX) has been reported as a popular and effective disinfectant of contaminated tendon grafts with no biomechanical sequelae; however, its biochemical effects on tendon collagen and fibroblasts remain unknown. PURPOSE: To determine whether CLX disinfection of contaminated tendon grafts has deleterious effects on tendon collagen or a toxic effect on fibroblast function. STUDY DESIGN: Controlled laboratory study. METHODS: Collagen fibrils prepared from purified bovine collagen type I were treated with various CLX concentrations (0.5%-4%) and incubation times (10-40 minutes), and the effects on fibril degradation and solubility were then examined using gel electrophoresis. Fresh bovine tendons were treated with sterile water or 2% CLX; then, fibroblast mobility and metabolic activity were evaluated using light microscopy and Alamar Blue assay, respectively. RESULTS: No effect on collagen fibrils was observed when they were exposed to 0%, 0.5%, or 2% CLX at any exposure time. However, 4% CLX dissolved the fibrils even after short incubation times. Fibroblasts migrated out from the control tendon explants but not from explants treated with 2% CLX, and a 5-fold reduction in metabolic activity was observed throughout the tendon in explants exposed to 2% CLX, suggesting that CLX penetrated and killed cells throughout the tissue. CONCLUSION: Four-percent CLX caused collagen fibrils to dissolve in vitro, and tendon graft disinfection with 2% CLX was cytotoxic to the cells. CLINICAL RELEVANCE: Because of its chemical effect on tendon collagen and cytotoxic effect on tendon fibroblasts, 4% CLX should not be used as a disinfectant. Two-percent CLX can be used to disinfect contaminated ACL grafts, but such treatment will drastically reduce the metabolic activity of the cells within the graft, making it similar to an acellular allograft tendon. PMID- 22523373 TI - Recruitment and activity of the pectineus and piriformis muscles during hip rehabilitation exercises: an electromyography study. AB - BACKGROUND: The pectineus muscle has been reported to function primarily as a hip flexor and secondarily as a hip internal rotator; the piriformis muscle has been reported to function as an abductor and external rotator of the hip. The recruitment and activations of these muscles during hip rehabilitation exercises have not been detailed. HYPOTHESIS: The authors hypothesized that they would measure the highest pectineus activation during exercises involving hip flexion, with moderate pectineus activation during exercises with hip internal rotation. They also hypothesized that they would measure the highest piriformis activation during exercises involving hip abduction and/or external rotation. STUDY DESIGN: Descriptive laboratory study. METHODS: Ten healthy volunteers completed 13 hip rehabilitation exercises with electromyography (EMG) electrodes inserted under ultrasound guidance into the pectineus and piriformis muscle bellies. The EMG signals were recorded and exercise activation levels were reported as a percentage of a maximum voluntary contraction (MVC). RESULTS: Both the highest peak pectineus activation (62.8% +/- 26.6% MVC) and the highest mean pectineus activation (33.1% +/- 17.4% MVC) were measured during the supine hip flexion exercise. Moderate activation was found during the single- and double-legged bridge and both phases of the stool hip rotation exercise. The highest peak piriformis activation was observed in the single-legged bridge (MVC, 35.7% +/- 25.7%), and the highest mean piriformis activation was observed in the prone heel squeeze (MVC, 24.3% +/- 8.2%). Similar moderate activation levels were found for single-legged hip abduction and resisted hip extension. CONCLUSION: The pectineus was highly activated during hip flexion exercises and moderately activated during exercises requiring rotational hip stabilization in either direction, rather than with internal hip rotation only. The piriformis was most activated during static external rotation and abduction while the participants' hips were in slight extension. These observations indicate that the pectineus and piriformis are both muscles that contribute to hip stabilization. CLINICAL RELEVANCE: The findings indicate that the pectineus and piriformis function as hip-stabilizing muscles and can be used to specifically address pectineus and piriformis muscle rehabilitation. The authors believe that strengthening and conditioning of these muscles should aid in the restoration of hip function and stability after injury or arthroscopic surgery. PMID- 22523374 TI - Impact of heart failure and changes to volume status on liver stiffness: non invasive assessment using transient elastography. AB - AIM: The impact of cardiac dysfunction on the liver is known as cardiac hepatopathy. In certain instances this can result in significant hepatic fibrosis or cirrhosis. The validity of non-invasive tools to assess hepatic fibrosis, such as FibroScan((r)) which measures liver stiffness (LSM), has not been established in this setting. We examined the impact of cardiac dysfunction on LSM using FibroScan((r)) and the influence of volume changes on LSM. METHODS AND RESULTS: A prospective, cross-sectional study examined the use of FibroScan((r)) in subjects with left-sided heart failure (LHF, n = 32), right-sided heart failure (RHF, n = 9), and acute decompensated heart failure (ADHF, n = 8). The impact of volume changes upon LSM was further examined in the ADHF group (pre- and post-diuresis) and in a haemodialysis group (HD, n = 12), pre- and post-ultrafiltration on dialysis. Compared with healthy controls [n = 55, LSM = median 4.4 (25th percentile 3.6, 75th percentile 5.1) kPa], LSM was increased in all the cardiac dysfunction subgroups [LHF, 4.7 (4.0, 8.7) kPa, P = 0.04; RHF, 9.7 (5.0, 10.8) kPa, P < 0.001; ADHF, 11.2 (6.7, 14.3) kPa, P < 0.001]. Alteration in volume status via diuresis did not change the baseline LSM in ADHF [11.2 (6.7, 14.3) to 9.5 (7.3, 21.6) kPa, P > 0.05] with mean diuresis 5051 +/- 1585 mL, or ultrafiltration in HD [6.0 (3.6, 5.1) vs. 5.7 (4.8, 7.0) kPa, P > 0.05] with mean diuresis 1962 +/- 233 mL. CONCLUSION: Our findings support the concept of increased LSM in the cardiac failure population. LSM was not altered to a statistically significant level with acute volume changes. PMID- 22523375 TI - Beyond the cardiorenal anaemia syndrome: recognizing the role of iron deficiency. AB - Growing awareness that heart failure, renal impairment, and anaemia are frequent co-morbidities which can exacerbate one another in a vicious circle of clinical deterioration has led to the concept of the cardiorenal anaemia syndrome (CRAS). The role of iron deficiency within this complex interplay has been less well examined. Scrutiny of data from the recent FAIR-HF trial raises a new hypothesis: is it time for 'CRAS' to be supplemented with new acronyms such as CRIDS (cardiorenal-iron deficiency syndrome) or even CRAIDS (cardiorenal-anaemia-iron deficiency syndrome)? Iron deficiency occurs frequently in heart failure patients with or without anaemia. It not only impairs oxygen transport through reduced erythropoiesis, but adversely affects oxidative metabolism, cellular energetics, and immune mechanisms, and the synthesis and degradation of complex molecules such as DNA. One large observational study in patients with heart failure found iron deficiency to be an independent predictor of death or urgent heart transplantation (hazard ratio 1.58, 95% confidence interval 1.14-2.17, P = 0.005). In the FAIR-HF trial, i.v. iron therapy was associated with significant improvements in physical functioning in iron-deficient patients with heart failure, even in non-anaemic patients in whom haemoglobin levels did not change following i.v. iron administration. Key questions regarding the use of i.v. iron supplementation in the setting of heart failure merit exploration and could readily be answered by appropriately designed clinical trials. It is to be hoped that these important clinical trials are conducted, to permit a more subtle characterization of the patient's pathological condition and interventional requirements. PMID- 22523376 TI - Supraventricular arrhythmias late after orthotopic cardiac transplantation: electrocardiographic and electrophysiological characterization and radiofrequency ablation. AB - AIMS: Cardiac transplantation (CTX) is an effective treatment for end-stage heart disease. Cardiac arrhythmias are increasingly recognized and associated with significant morbidity and mortality. We aim to describe the clinical and electrophysiological characteristics of patients with atrial arrhythmias occurring late after CTX. METHODS AND RESULTS: Sixteen patients with prior CTX who presented with late atrial arrhythmias for electrophysiological studies (EPS) were identified at two cardiac transplant centres. Among 859 patients, 16 (mean age 52 +/- 14 years, 11 of 16 were men) patients underwent EPS for atrial arrhythmias presenting 8.6 +/- 5.7 years following CTX. Among 16 patients, 14 underwent cardiac alone and 2 included lung transplantation. There were no cases of cardiac rejection. Arrhythmias were due to counterclockwise cavotricuspid dependent atrial flutter (AFL) in 10 of 16, atrial tachycardia (AT) in 6 (1 patient had AFL and AT), and 1 due to atrioventricular nodal re-entrant tachycardia. Recipient-donor atrial electrical connection was seen in two of six AT and in no cases of AFL. In two cases, a focal AT was mapped to the remnant atrium conducting 2 : 1 or at variable block to the donor atrium. In four cases a focal/micro re-entrant AT originated within the vicinity of the interatrial suture scar. All cases were successfully ablated with radiofrequency energy; however, one case of AFL required a repeat ablation. Patients remained free of arrhythmia at 34 +/- 15 months post-ablation. CONCLUSION: Typical AFL and AT are the most frequent supraventricular arrhythmias occurring late following CTX. Focal ATs may originate in low-voltage or border zones immediately adjacent to the atrio-atrial anastomosis. Radiofrequency ablation is an effective treatment strategy with high long-term success. PMID- 22523378 TI - The frontal plane QRS-T angle. PMID- 22523379 TI - Mesh ablator vs. cryoballoon pulmonary vein ablation of symptomatic paroxysmal atrial fibrillation: results of the MACPAF study. AB - AIMS: Catheter ablation of the pulmonary veins (PVs) is a promising therapeutic approach for symptomatic atrial fibrillation (AF). The prospective randomized single-centre study 'Mesh Ablator versus Cryoballoon Pulmonary Vein Ablation of Symptomatic Paroxysmal Atrial Fibrillation' (MACPAF; clinicaltrials.gov NCT01061931) compared the efficacy and safety of two balloon-based PV ablation systems. METHODS AND RESULTS: Thirty-two patients underwent PV ablation for symptomatic paroxysmal AF using the Arctic Front(r) or the HD Mesh Ablator(r) catheter according to study protocol. The primary endpoint was complete PV isolation (PVI) at the end of the ablation procedure, determined by exit block after achieving entrance block. Long-term follow-up data are not included in this publication. Patients' mean age was 61.7 +/- 8.9 years, 43.2% were female, and median CHA2DS2-VASc score was 2.0. In the intention-to-treat analysis, the rate of the primary endpoint was 56.5% in patients randomized to the Arctic Front(r) and 9.5% in patients randomized to the HD Mesh Ablator(r) catheter (P = 0.001). In the per-protocol analysis, complete PVI was achieved in 13 (76.5%) of 17 Arctic Front(r) patients but in none of the 15 HD Mesh Ablator(r) patients (P < 0.0001). There were one major and two minor complications in each study arm but no clinically evident stroke. Post-procedural AF recurrence was detected within hospital stay in two (11.8%) Arctic Front(r) patients and in seven (46.7%) HD Mesh Ablator(r) patients (P = 0.049). CONCLUSION: The MACPAF study revealed a superiority of the Arctic Front(r) catheter concerning complete PVI. Owing to the insufficient efficacy of the HD Mesh Ablator(r) catheter, the safety board decided to stop MACPAF prematurely. PMID- 22523380 TI - Increased central and peripheral inflammation and inflammatory hyperalgesia in Zucker rat model of leptin receptor deficiency and genetic obesity. AB - This study investigated whether sensitivity to nociceptive stimuli is altered in obese rats using established models of inflammatory pain, and using real-time PCR, profiled alterations in expression of key adipokine and inflammatory mediator mRNA (adiponectin, tumor necrosis factor-alpha, interleukin-1beta, cyclooxygenase-2, inducible nitric oxide synthase (iNOS)) in spinal cord with obesity. Responses to thermal and mechanical stimulation of the hindpaw and paw oedema were assessed in adult male Zucker fatty rats (fa/fa) and their lean littermates (fa/-; n = 6-9 per group) in the absence of inflammation (acute nociception), then in response to intradermal hindpaw injection of carrageenan (3%; 50 MUl) or capsaicin (10 MUg; 50 MUl) or hindpaw incision. The analgesic potency of morphine (1, 2.5 or 5 mg kg(-1) or vehicle; s.c.) was also assessed. Acute nociception was unaltered in obese animals, but following carrageenan induced inflammation the obese rats were significantly more sensitive to mechanical and thermal stimulation of the inflamed paw, and displayed greater paw oedema. No difference in the capsaicin- or paw-incision-induced pain sensitivity or in the analgesic potency of morphine was observed between groups. Levels of adiponectin and inducible nitric oxide synthase mRNA were downregulated in spinal cord from obese rats, whereas tumour necrosis factor-alpha mRNA was upregulated; interleukin-1beta and cyclo-oxygenase were unchanged. The increased pain sensitivity and inflammatory response together with changes in spinal adipokine expression in obese rats fit well with the hypothesis that obesity is a chronic low-grade inflammatory disorder, producing a state where responses to subsequent inflammatory challenge are potentiated. PMID- 22523382 TI - Interleukin-6 mediates exercise-induced increase in insulin sensitivity in mice. AB - Interleukin-6 (IL-6) is released from working skeletal muscle during exercise. We investigated the acute and the long-term beneficial effects of IL-6 on exercise induced glucose uptake in skeletal muscle and insulin sensitivity. The acute effect on exercise-induced glucose uptake was measured in IL-6-deficient (IL-6(-/ )) mice and wild-type control animals using a tracer technique. There was no difference in serum disappearance of (3)[H]2-deoxyglucose after a single bout of exercise between IL-6(-/-) and wild-type mice (13565 +/- 426 versus 14343 +/- 1309 d.p.m. min ml(-1), P = 0.5). The glucose uptake rate in the extensor digitorum longus muscle was, however, lower in IL-6(-/-) compared with wild-type mice (398 +/- 44 versus 657 +/- 41 nmol g(-1) min(-1), P < 0.01). In a long-term study, we monitored insulin sensitivity, serum retinol-binding protein-4 (RBP-4) levels, running activity, food intake, body weight and body composition in IL-6( /-) and wild-type mice on a high-fat diet (HFD), with or without access to running wheels. In sedentary IL-6(-/-) and wild-type mice, the HFD decreased insulin sensitivity (glucose area under the concentration-time curve increased about 20% during an insulin tolerance test, P < 0.05 for both genotypes versus baseline) and led to a 30% increase in serum RBP-4 levels (P < 0.01 for both genotypes versus baseline). Wild-type mice with access to running wheels were protected against these effects of the HFD and maintained their baseline insulin sensitivity and serum RBP-4 levels. In contrast, IL-6(-/-) mice did not benefit from running to the same extent as wild-type animals. The IL-6(-/-) mice with access to running wheels had a similar decrease in insulin sensitivity to their sedentary littermates (glucose area under the concentration-time curve during an insulin tolerance test in runners versus sedentary IL-6(-/-) HFD mice, 312 +/- 14 versus 340 +/- 22 mmol min l(-1), P = 0.4) and displayed a 14% increase in serum RBP-4 compared with baseline levels (P < 0.01). Our results indicate that endogenous IL-6 contributes to the exercise-induced increase in insulin sensitivity, but plays only a minor role for glucose uptake into skeletal muscle during exercise. PMID- 22523381 TI - Muscle cyclo-oxygenase-2 pathway contributes to the exaggerated muscle mechanoreflex in rats with congestive heart failure. AB - Cyclo-oxygenase (COX) enzymes are responsible for the formation from arachidonic acid of prostaglandins, among other metabolites. Prior studies have suggested that inhibition of the COX pathway attenuates the responses of sympathetic nerve activity and blood pressure during static muscle contraction. Static muscle contraction activates the exercise pressor reflex, which in turn increases sympathetic nerve activity and blood pressure. Also, COX products contribute to exaggeration of the exercise pressor reflex in heart failure (HF). This dysfunction of the exercise pressor reflex has previously been shown to be mediated primarily by muscle mechanoreflex overactivity. It is well known that COX-1 and COX-2 are two isoforms of the enzyme that lead to formation of these important biological mediators involved in the muscle reflex. Thus, in the present study, we determined whether the COX-1 and/or COX-2 pathway contribute(s) to the augmented mechanoreflex activity in HF. First, Western blot analysis was employed to examine protein expression of COX-1 and COX-2 in skeletal muscle tissue of control rats and rats with HF induced by myocardial infarction. Our data show that there is no significant difference in COX-1 expression in both experimental groups. However, COX-2 displays significant overexpression in rats with HF compared with control rats (optical density 1.06 +/- 0.05 in control and 1.6 +/- 0.05 in HF, P < 0.05 versus control). Second, the mechanoreflex was evoked by passive tendon stretch, and the reflex sympathetic and pressor responses to muscle stretch were examined after COX-1 and COX-2 inhibitors (FR 122047 and SC-236) were individually injected into the arterial blood supply of the hindlimb muscles. The results demonstrate that the stretch-evoked reflex responses in rats with HF were significantly attenuated by administration of SC 236, but not by FR-122047, i.e. renal sympathetic nerve activity and mean arterial pressure responses evoked by 0.5 kg of muscle tension were 52.3 +/- 8.9% and 19 +/- 1.4 mmHg, respectively, in control conditions and 26.4 +/- 5.6% and 5.7 +/- 1.6 mmHg (P < 0.05 versus control group) after 0.25 mg kg(-1) of SC-236. Muscle stretch-evoked renal sympathetic nerve activity and mean arterial pressure responses were 51.8 +/- 8.2% and 18.7 +/- 1.2 mmHg, respectively, in control conditions and 48.3 +/- 5.3% and 17.5 +/- 1.9 mmHg (P > 0.05 versus control group) after 1.0 mg kg(-1) of FR-122047. Accordingly, the results obtained from this study support our hypothesis that heightened COX-2 expression within the hindlimb muscles contributes to the exaggerated muscle mechanoreflex in congestive HF. PMID- 22523383 TI - beta1-Adrenoceptor antibody-induced increase in soluble CD40 ligand release in chronic periodontitis patients: role of prostaglandin E(2). AB - In this paper, we demonstrate that circulating antibodies from chronic periodontitis patients reacting with atrial beta(1)-adrenoceptors (beta(1)-ARs) act as an inducer of soluble CD40 ligand (sCD40L) release and prostaglandin E(2) (PGE(2)) generation. By enzyme-linked immunosorbent assay using beta(1) synthetic peptide (with an amino acid sequence identical to the second loop of human myocardial beta(1)-ARs) as a coating antigen, we demonstrated reactivity against the second extracellular loop on human myocardial beta(1)-ARs. This autoantibody present in the serum of chronic periodontitis patients was significantly correlated with the release of sCD40L and PGE(2). The release of sCD40L was blunted by atenolol, SP600125 and beta(1) synthetic peptide, and PGE(2) generation was inhibited by DuP 697 and slightly by FR122049. The effects of the antibody incubated with isolated rat atria upregulated sCD40L release with an increase of PGE(2) production and c-Jun N-terminal kinase phosphorylation. These results indicate that in chronic periodontitis patients, there is a positive association between sCD40L release and PGE(2) generation via the action of beta(1)-AR antibodies. PMID- 22523384 TI - Alternative splicing controlled by heterogeneous nuclear ribonucleoprotein L regulates development, proliferation, and migration of thymic pre-T cells. AB - The regulation of posttranscriptional modifications of pre-mRNA by alternative splicing is important for cellular function, development, and immunity. The receptor tyrosine phosphatase CD45, which is expressed on all hematopoietic cells, is known for its role in the development and activation of T cells. CD45 is known to be alternatively spliced, a process that is partially regulated by heterogeneous nuclear ribonucleoprotein (hnRNP) L. To investigate the role of hnRNP L further, we have generated conditional hnRNP L knockout mice and found that LckCre-mediated deletion of hnRNP L results in a decreased thymic cellularity caused by a partial block at the transition stage between double negative 4 and double-positive cells. In addition, hnRNP L(-/-) thymocytes express aberrant levels of the CD45RA splice isoforms and show high levels of phosphorylated Lck at the activator tyrosine Y394, but lack phosphorylation of the inhibitory tyrosine Y505. This indicated an increased basal Lck activity and correlated with higher proliferation rates of double-negative 4 cells in hnRNP L( /-) mice. Deletion of hnRNP L also blocked the migration and egress of single positive thymocytes to peripheral lymphoid organs in response to sphingosine-1 phosphate and the chemokines CCL21 and CXCL12 very likely as a result of aberrant splicing of genes encoding GTPase regulators and proteins affecting cytoskeletal organization. Our results indicate that hnRNP L regulates T cell differentiation and migration by regulating pre-TCR and chemokine receptor signaling. PMID- 22523385 TI - The human lactoferrin-derived peptide hLF1-11 exerts immunomodulatory effects by specific inhibition of myeloperoxidase activity. AB - Because of their ability to eliminate pathogens and to modulate various host immune responses, antimicrobial peptides are considered as candidate agents to fight infections by (antibiotic-resistant) pathogens. We recently reported that hLF1-11 (GRRRRSVQWCA), an antimicrobial peptide derived from the N terminus of human lactoferrin, displays diverse modulatory activities on monocytes, thereby enhancing their actions in innate immune responses. The aim of this study was to identify the cellular target of hLF1-11 that mediates these effects. Results revealed that hLF1-11 binds and subsequently penetrates human monocytes, after which it inhibits the enzymatic activities of myeloperoxidase (MPO). Moreover, a chemical inhibitor of MPO (aminobenzoic acid hydrazide) mimicked the effects of hLF1-11 on the inflammatory response by monocytes and on monocyte-macrophage differentiation. Computer-assisted molecular modeling predicted that hLF1-11 can bind to the edge of and within the crevice of the active site of MPO. Experiments with a set of hLF1-11 peptides with amino acid substitutions identified the stretch of arginines and the cysteine at position 10 as pivotal in these immunomodulatory properties of hLF1-11. We conclude that hLF1-11 may exert its modulatory effects on human monocytes by specific inhibition of MPO activity. PMID- 22523386 TI - Complement protein C1q directs macrophage polarization and limits inflammasome activity during the uptake of apoptotic cells. AB - Deficiency in C1q, the recognition component of the classical complement cascade and a pattern recognition receptor involved in apoptotic cell clearance, leads to lupus-like autoimmune diseases characterized by auto-antibodies to self proteins and aberrant innate immune cell activation likely due to impaired clearance of apoptotic cells. In this study, we developed an autologous system using primary human lymphocytes and human monocyte-derived macrophages (HMDMs) to characterize the effect of C1q on macrophage gene expression profiles during the uptake of apoptotic cells. C1q bound to autologous apoptotic lymphocytes modulated expression of genes associated with JAK/STAT signaling, chemotaxis, immunoregulation, and NLRP3 inflammasome activation in LPS-stimulated HMDMs. Specifically, C1q sequentially induced type I IFNs, IL-27, and IL-10 in LPS stimulated HMDMs and IL-27 in HMDMs when incubated with apoptotic lymphocyte conditioned media. Coincubation with C1q tails prevented the induction of type I IFNs and IL-27 in a dose-dependent manner, and neutralization of type I IFNs partially prevented IL-27 induction by C1q. Finally, C1q decreased procaspase-1 cleavage and caspase-1-dependent cleavage of IL-1beta suggesting a potent inhibitory effect of C1q on inflammasome activation. These results identify specific molecular pathways induced by C1q to suppress macrophage inflammation and provide potential therapeutic targets to control macrophage polarization and thus inflammation and autoimmunity. PMID- 22523387 TI - Antibodies to pathogenic epitopes on type XVII collagen cause skin fragility in a complement-dependent and -independent manner. AB - In bullous pemphigoid (BP), the most prevalent autoimmune blistering disease, type XVII collagen (COL17) is targeted by circulating autoantibodies. BP is thought to be an autoantibody-mediated complement-fixing blistering disease, and a juxtamembranous noncollagenous 16A (NC16A) domain spanning Glu(490) to Arg(566) was proved to be the main pathogenic region on COL17, although precise pathogenic epitopes within NC16A have not been elucidated. In this study, we showed that injection of rabbit IgG Abs targeting Asp(522) to Gln(545) induced skin fragility associated with in vivo deposition of IgG and complement in neonatal COL17 humanized mice. Notably, immunoadsorption of rabbit anti-NC16A IgG Ab with this epitope (Asp(522) to Gln(545)) or the anti-NC16A IgG administered together with the peptides of this epitope as a decoy ameliorated skin fragility in the injected neonatal COL17-humanized mice compared with the anti-NC16A IgG alone even though all of the mice showed both IgG and complement deposition. These results led us to investigate an additional, complement-independent mechanism of skin fragility in the mice injected with anti-COL17 Abs. The rabbit anti-NC16A IgG depleted the expression of COL17 in cultured normal human keratinocytes, whereas immunoadsorption of the same IgG with this epitope significantly suppressed the depletion effect. Moreover, passive transfer of F(ab')(2) fragments of the human BP or rabbit IgG Abs against COL17 demonstrated skin fragility in neonatal COL17-humanized mice. In summary, this study reveals the importance of Abs directed against distinct epitopes on COL17, which induce skin fragility in complement-dependent as well as complement-independent ways. PMID- 22523388 TI - Chronic spinal cord injury impairs primary antibody responses but spares existing humoral immunity in mice. AB - Spinal cord injury (SCI) results in immune depression. To better understand how injury inhibits humoral immunity, the effects of chronic thoracic SCI on B cell development and immune responses to thymus-independent type 2 and thymus dependent Ags were determined. Mice received complete crush injury or control laminectomy at either thoracic level 3, which disrupts descending autonomic control of the spleen, or at thoracic level 9, which conserves most splenic sympathetic activity. Although mature B cell numbers were only mildly reduced, bone marrow B cell production was transiently but profoundly depressed immediately after injury. Despite the return of normal B cell production 4 wk after SCI, mice receiving thoracic level 3 injury showed a significant reduction in their ability to mount primary thymus-independent type 2 or thymus-dependent immune responses. The latter were marked by decreases in germinal center B cells as well as class-switched high-affinity Ab-secreting cells. Importantly, injury did not affect affinity maturation per se, pre-existing B cell memory, or secondary humoral immune responses. Taken together, these findings show that chronic high thoracic SCI impairs the ability to mount optimal Ab responses to new antigenic challenges, but spares previously established humoral immunity. PMID- 22523390 TI - Incidence, patient characteristics and treatment initiated for GP-diagnosed depression in general practice: results of a 1-year nationwide surveillance study. AB - BACKGROUND: Despite its public health significance, data about depression in general practice are often unavailable. OBJECTIVE: To study (i) the incidence of GP-diagnosed depression during 2008, (ii) associations between patient characteristics, appraised severity and initiated treatment, (iii) GPs' usual care compared to diagnostic criteria from Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition guidelines and the newly developed practice guideline of the Society of Flemish GPs (2008) and (iv) GPs' initiated treatments compared to the Flemish Guideline. METHODS: General practice-based data were collected on all patients of >=18 years who were diagnosed by their GP with a new episode of depression in Belgian sentinel general practices (SGP) during 2008. RESULTS: Data on 1739 persons were recorded by 172 sentinel general practices. Incidence rates for GP-diagnosed depression were estimated at 719/100 000 men and 1440/100 000 women. Thirty-one per cent of patients had mild, 50% had moderate and 19% had severe GP-diagnosed depression. Although only 43% of the patients at risk for suicide were considered to have severe depression, having thoughts of death or suicide was the main factor associated with increased severity of depression. Seventy-five per cent of patients received a prescription for an antidepressive agent; 29% received a prescription for another psychoactive agent; in 36%, non-pharmaceutical support was initiated by the GP and 25% received a referral. In contrast with the Flemish GP guideline criteria: (i) 69% of patients with a new episode of mild or a first episode of moderate depression were prescribed an antidepressive agent and (ii) only 39% of the patients with severe depression were both prescribed an antidepressive agent and referred to a mental health service. CONCLUSIONS: This study has yielded original data on the incidence and management of depression in Belgian general practice. Our findings show that efforts are needed to improve depression management in Belgian general practice. PMID- 22523391 TI - Primary care research--an international responsibility. PMID- 22523389 TI - Structurally identical capsular polysaccharide expressed by intact group B streptococcus versus Streptococcus pneumoniae elicits distinct murine polysaccharide-specific IgG responses in vivo. AB - We previously reported distinct differences in the murine in vivo Ig polysaccharide (PS)-specific responses to intact Streptococcus pneumoniae compared with responses to Neisseria meningitidis and that in each case, the bacterial subcapsular domain markedly influences the Ig response to the associated PS. In light of potentially unique contributions of biochemically distinct capsular PS and/or their characteristic attachments to the underlying bacterium, it remains unresolved whether different bacterial subcapsular domains can exert differential effects on PS-specific Ig responses to distinct bacterial pathogens. In this report, we used a mutant strain of group B Streptococcus (Streptococcus agalactiae) type III (GBS-III) that expresses desialylated capsular polysaccharide of GBS-III, biochemically identical to capsular pneumococcal polysaccharide type 14 (PPS14) of Streptococcus pneumoniae (intact inactivated Streptococcus pneumoniae, capsular type 14, Pn14), directly to compare the in vivo PPS14-specific IgG responses to two distinct gram-positive bacteria. Although both GBS-III and Pn14 elicited relatively rapid primary PPS14 specific IgG responses dependent on CD4(+) T cells, B7-dependent costimulation, and CD40-CD40L interactions, only GBS-III induced a highly boosted ICOS-dependent PPS14-specific IgG response after secondary immunization. Of note, priming with Pn14 and boosting with GBS-III, although not isolated PPS14, elicited a similar boosted PPS14-specific IgG response that was dependent on CD4(+) T cells during secondary immunization, indicating that Pn14 primes for memory but, unlike GBS III, fails to elicit it. The inability of Pn14 to elicit a boosted PPS14-specific IgG response was overcome by coimmunization with unencapsulated GBS-III. Collectively, these data establish that structurally identical capsular PS expressed by two distinct gram-positive extracellular bacteria can indeed elicit distinct PS-specific IgG responses in vivo. PMID- 22523392 TI - Short-term follow-up of patients diagnosed by their GP with mild depression or first-time moderate depression. Results of a 1-year nationwide surveillance study. AB - BACKGROUND: Despite its public health significance, data about depression in general practice are often unavailable or incomplete. OBJECTIVE: To study half year follow-up data on patients diagnosed by their GP with a new episode of mild or a first episode of moderate depression, specifically: (i) treatment continuation, (ii) remission and, in ongoing episodes, suicidal behaviour and inability to work and (iii) the match between treatments initiated and delivered as well as the determinants of actual delivery of non-pharmacological support initiated by the GP for patients with ongoing depression. METHODS: General practice-based data were collected on all patients aged >=18 years who were diagnosed by their GP with a new episode of depression in Belgian sentinel general practices during 2008. RESULTS: Follow-up data were available for 900 of 1048 patients. Complete treatment dropout was found in 9%, treatment discontinuation in 40% and a GP visit <=8 weeks preceding the follow-up in 51%. Of the latter 457 patients, 60% were still depressed. Among these, one suicide attempt was reported and 24% were unable to work for >=1 month. While 91% of the patients who received psychoactive agents at diagnosis had actually taken them, and 62% of the referred patients actually received treatment from another caregiver, non-pharmacological support by the GP was delivered in only 43% of patients for whom it was initiated. CONCLUSIONS: Half a year after diagnosis, half of patients continue to visit their GP and 60% of those patients remain depressed. The delivery of non-pharmacological GP support takes place for less than half of the patients for whom that intervention is initiated. Our follow-up findings reinforce the policy recommendations made by stakeholders, i.e. the introduction and reimbursement of a mental health consultation in family practice and integration of primary care psychologists. Quality improvement interventions may be a strategy to overcome premature discontinuation of non-pharmacological support by GPs. PMID- 22523393 TI - Prospective observational study of imatinib therapy in Japanese patients with advanced gastrointestinal stromal tumors: long-term follow-up and second malignancy. AB - OBJECTIVE: Limited data are available concerning long-term results of imatinib therapy in patients with advanced gastrointestinal stromal tumors. We aimed to clarify the long-term outcomes of imatinib therapy in Japanese patients with advanced gastrointestinal stromal tumors. METHODS: A prospective, observational study of imatinib therapy for unresectable and metastatic gastrointestinal stromal tumors was conducted in our institution. Imatinib was initiated at a dose of 400 mg daily and continued until disease progression. Safety, efficacy and long-term tolerability and survival were evaluated in an intent-to-treat population. The median follow-up period in this study was 68 months. RESULTS: Seventy patients were enrolled between December 2001 and December 2009. Treatment related Grade 3/4 adverse events occurred in 49 patients (70.0%). Although 14 patients required adverse effect management with hospitalization, only 5 patients (7.1%) withdrew from the treatment owing to imatinib intolerance. The tumor response and clinical benefit rates were 61.4 and 85.7%, respectively. Thirty seven patients (52.9%) maintained the treatment at 400 mg daily imatinib, whereas 33 patients (47.1%) had their dose reduced to 300 mg daily or less. The overall survival rate at 5 years was 60.9% and the median survival time was 70 months. The median progression-free survival time of all the 70 enrolled patients was 30 months. Seven patients (10.0%) suffered from second malignancies, including three patients with genitourinary carcinomas. CONCLUSIONS: Despite the need for dose reduction, the long-term results of imatinib therapy for advanced gastrointestinal stromal tumors were good in Japanese patients. Physicians should pay attention to the occurrence of second malignancies during imatinib therapy for gastrointestinal stromal tumor patients. PMID- 22523394 TI - Blockade of cholesterol absorption by ezetimibe reveals a complex homeostatic network in enterocytes. AB - Enterocyte cholesterol homeostasis reflects aggregated rates of sterol synthesis, efflux, and uptake from plasma and gut lumen. Cholesterol synthesis and LDL uptake are coordinately regulated by sterol regulatory element-binding proteins (SREBP), whereas sterol efflux is regulated by liver X receptors (LXR). How these processes are coordinately regulated in enterocytes, the site of cholesterol absorption, is not well understood. Here, we treat mice with ezetimibe to investigate the effect of blocking cholesterol absorption on intestinal SREBPs, LXRs, and their effectors. Ezetimibe increased nuclear SREBP-2 8-fold. HMG-CoA reductase (HMGR) and LDL receptor (LDLR) mRNA levels increased less than 3-fold, whereas their protein levels increased 30- and 10-fold, respectively. Expression of inducible degrader of LDLR (IDOL), an LXR-regulated gene that degrades LDLRs, was reduced 50% by ezetimibe. Coadministration of ezetimibe with the LXR agonist T0901317 abolished the reduction in IDOL and prevented the increase in LDLR protein. Ezetimibe-stimulated LDLR expression was independent of proprotein convertase subtilisin/kexin type 9 (PSCK9), a protein that degrades LDLRs. To maintain cholesterol homeostasis in the face of ezetimibe, enterocytes boost LDL uptake by increasing LDLR number, and they boost sterol synthesis by increasing HMGR and other cholesterologenic genes. These studies reveal a hitherto undescribed homeostatic network in enterocytes triggered by blockade of cholesterol absorption. PMID- 22523395 TI - Regulatory role of beta-arrestin-2 in cholesterol processing in cystic fibrosis epithelial cells. AB - Cystic fibrosis (CF) cells exhibit an increase in the protein expression of beta arrestin-2 (betaarr2) coincident with perinuclear accumulation of free cholesterol. Arrestins are proteins that both serve as broad signaling regulators and contribute to G-protein coupled receptor internalization after agonist stimulation. The hypothesis of this study is that betaarr2 is an important component in the mechanisms leading to cholesterol accumulation characteristic of CF cells. To test this hypothesis, epithelial cells stably expressing GFP-tagged betaarr2 (betaarr2-GFP) and respective GFP-expressing control cells (cont-GFP) were analyzed by filipin staining. The betaarr2-GFP cells show a late endosomal/lysosomal cholesterol accumulation that is identical to that seen in CF cells. This betaarr2-mediated accumulation is sensitive to Rp-cAMPS treatment, and depleting betaarr2 expression in CF-model cells by shRNA alleviates cholesterol accumulation compared with controls. Cftr/betaarr2 double knockout mice also exhibit wild-type (WT) levels of cholesterol synthesis, and WT profiles of signaling protein expression have previously been shown to be altered in CF due to cholesterol-related pathways. These data indicate a significant regulatory role for betaarr2 in the development of CF-like cholesterol accumulation and give further insight into cholesterol processing mechanisms. An impact of betaarr2 expression on Niemann-Pick type C-1 (NPC1)-containing organelle movement is proposed as the mechanism of betaarr2-mediated alterations on cholesterol processing. It is concluded that betaarr2 expression contributes to altered cholesterol trafficking observed in CF cells. PMID- 22523396 TI - Hypoxia and miscoupling between reduced energy efficiency and signaling to cell proliferation drive cancer to grow increasingly faster. PMID- 22523398 TI - Harlequin syndrome: does a cranial autonomic neuropathy influence headache? PMID- 22523397 TI - Telomerase reverse transcriptase locus polymorphisms and cancer risk: a field synopsis and meta-analysis. AB - BACKGROUND: Several recent studies have provided evidence that polymorphisms in the telomerase reverse transcriptase (TERT) gene sequence are associated with cancer development, but a comprehensive synopsis is not available. We conducted a systematic review and meta-analysis of the available molecular epidemiology data regarding the association between TERT locus polymorphisms and predisposition to cancer. METHODS: A systematic review of the English literature was conducted by searching PubMed, Embase, Cancerlit, Google Scholar, and ISI Web of Knowledge databases for studies on associations between TERT locus polymorphisms and cancer risk. Random-effects meta-analysis was performed to pool per-allele odds ratios for TERT locus polymorphisms and risk of cancer, and between-study heterogeneity and potential bias sources (eg, publication and chasing bias) were assessed. Because the TERT locus includes the cleft lip and palate transmembrane 1-like (CLPTM1L) gene, which is in linkage disequilibrium with TERT, CLPTM1L polymorphisms were also analyzed. Cumulative evidence for polymorphisms with statistically significant associations was graded as "strong," "moderate," and "weak" according to the Venice criteria. The joint population attributable risk was calculated for polymorphisms with strong evidence of association. RESULTS: Eighty-five studies enrolling 490 901 subjects and reporting on 494 allelic contrasts were retrieved. Data were available on 67 TERT locus polymorphisms and 24 tumor types, for a total of 221 unique combinations of polymorphisms and cancer types. Upon meta-analysis, a statistically significant association with the risk of any cancer type was found for 22 polymorphisms. Strong, moderate, and weak cumulative evidence for association with at least one tumor type was demonstrated for 11, 9, and 14 polymorphisms, respectively. For lung cancer, which was the most studied tumor type, the estimated joint population attributable risk for three polymorphisms (TERT rs2736100, intergenic rs4635969, and CLPTM1L rs402710) was 41%. Strong evidence for lack of association was identified for five polymorphisms in three tumor types. CONCLUSIONS: To our knowledge, this is the largest collection of data for associations between TERT locus polymorphisms and cancer risk. Our findings support the hypothesis that genetic variability in this genomic region can modulate cancer susceptibility in humans. PMID- 22523399 TI - Competition increases binding errors in visual working memory. AB - When faced with maintaining multiple objects in visual working memory, item information must be bound to the correct object in order to be correctly recalled. Sometimes, however, binding errors occur, and participants report the feature (e.g., color) of an unprobed, non-target item. In the present study, we examine whether the configuration of sample stimuli affects the proportion of these binding errors. The results demonstrate that participants mistakenly report the identity of the unprobed item (i.e., they make a non-target response) when sample items are presented close together in space, suggesting that binding errors can increase independent of increases in memory load. Moreover, the proportion of these non-target responses is linearly related to the distance between sample items, suggesting that these errors are spatially specific. Finally, presenting sample items sequentially decreases non-target responses, suggesting that reducing competition between sample stimuli reduces the number of binding errors. Importantly, these effects all occurred without increases in the amount of error in the memory representation. These results suggest that competition during encoding can account for some of the binding errors made during VWM recall. PMID- 22523400 TI - Ocular following in humans: spatial properties. AB - Ocular following responses (OFRs) are tracking eye movements elicited at ultrashort latency by the sudden movement of a textured pattern. Here we report the results of our study of their dependency on the spatial arrangement of the motion stimulus. Unlike previous studies that looked at the effect of stimulus size, we investigated the impact of stimulus location and how two distinct stimuli, presented together, collectively determine the OFR. We used as stimuli vertical gratings that moved in the horizontal direction and that were confined to either one or two 0.58 degrees high strips, spanning the width of the screen. We found that the response to individual strips varied as a function of the location and spatial frequency (SF) of the stimulus. The response decreased as the stimulus eccentricity increased, but this relationship was more accentuated at high than at low spatial frequencies. We also found that when pairs of stimuli were presented, nearby stimuli interacted strongly, so that the response to the pair was barely larger than the response to a single strip in the pair. This suppressive effect faded away as the separation between the strips increased. The variation of the suppressive interaction with strip separation, paired with the dependency on eccentricity of the responses to single strips, caused the peak response for strip pairs to be achieved at a specific separation, which varied as a function of SF. PMID- 22523401 TI - A summary statistic representation in peripheral vision explains visual search. AB - Vision is an active process: We repeatedly move our eyes to seek out objects of interest and explore our environment. Visual search experiments capture aspects of this process, by having subjects look for a target within a background of distractors. Search speed often correlates with target-distractor discriminability; search is faster when the target and distractors look quite different. However, there are notable exceptions. A given discriminability can yield efficient searches (where the target seems to "pop-out") as well as inefficient ones (where additional distractors make search significantly slower and more difficult). Search is often more difficult when finding the target requires distinguishing a particular configuration or conjunction of features. Search asymmetries abound. These puzzling results have fueled three decades of theoretical and experimental studies. We argue that the key issue in search is the processing of image patches in the periphery, where visual representation is characterized by summary statistics computed over a sizable pooling region. By quantifying these statistics, we predict a set of classic search results, as well as peripheral discriminability of crowded patches such as those found in search displays. PMID- 22523403 TI - Application of dyadic data analysis in pediatric psychology: cystic fibrosis health-related quality of life and anxiety in child-caregiver dyads. AB - OBJECTIVE: To demonstrate the use of the actor-partner interdependence model (APIM) of dyadic relationships in a sample of children with cystic fibrosis (CF) and their caregivers. METHODS: Multilevel modeling evaluated relations between health-related quality of life (HRQOL) and anxiety in 29 child-caregiver dyads. The following effects were evaluated: actor and partner, and the respondent (i.e., child or caregiver) * HRQOL interaction. RESULTS: This study demonstrated a practical application of the APIM. Significant actor effects were found (i.e., lower child HRQOL was associated with increased child anxiety, caregiver anxiety increased as caregiver perceptions of their child's HRQOL decreased), but not partner effects. The significant interaction indicated that the effects were different for children and caregivers. CONCLUSIONS: The APIM has the potential to increase pediatric researchers' understanding of how social relationships and environments impact health outcomes. Future research should consider using dyadic data analysis when youth and caregiver data are available. PMID- 22523404 TI - Emotional processing and self-control in adolescents with type 1 diabetes. AB - OBJECTIVE: This study examined whether emotional processing (understanding emotions), self-control (regulation of thoughts, emotions, and behavior), and their interaction predicted HbA1c for adolescents with type 1 diabetes over and above diabetes-specific constructs. METHODS: Self-report measures of self control, emotional processing, self-efficacy for diabetes management, diabetes specific negative affect, and adherence, and HbA1c from medical records were obtained from 137 adolescents with type 1 diabetes (M age = 13.48 years). RESULTS: Emotional processing interacted with self-control to predict HbA1c, such that when adolescents had both low emotional processing and low self-control, HbA1c was poorest. Also, both high emotional processing and self-control buffered negative effects of low capacity in the other in relation to HbA1c. The interaction of emotional processing * self-control predicted HbA1c over diabetes specific self-efficacy, negative affect, and adherence. CONCLUSIONS: These findings suggest the importance of emotional processing and self-control for health outcomes in adolescents with diabetes. PMID- 22523405 TI - Sustainable anesthesia. PMID- 22523406 TI - Can't intubate, can't ventilate: is "rescue reversal" a pipe-dream? PMID- 22523407 TI - Waiting to exhale! PMID- 22523408 TI - Ultrasound-guided nerve blocks: the real position of the needle should be defined. PMID- 22523409 TI - Publication bias, retrospective bias, and reproducibility of significant results in observational studies. PMID- 22523410 TI - The role of carbon dioxide in facilitating emergence from inhalation anesthesia: then & now. PMID- 22523411 TI - Workplace sustainability: the "cradle to grave" view of what we do. PMID- 22523412 TI - Evoked motor response of the sartorius muscle and femoral nerve blockade. PMID- 22523413 TI - Cardiac output measured with both esophageal Doppler device and Vigileo-FloTrac device. PMID- 22523414 TI - Peripheral nerve stimulator response triggered by proximity to electrosurgical unit. PMID- 22523415 TI - Role of the dorsal hippocampus in object memory load. AB - The dorsal hippocampus is crucial for mammalian spatial memory, but its exact role in item memory is still hotly debated. Recent evidence in humans suggested that the hippocampus might be selectively involved in item short-term memory to deal with an increasing memory load. In this study, we sought to test this hypothesis. To this aim we developed a novel behavioral procedure to study object memory load in mice by progressively increasing the stimulus set size in the spontaneous object recognition task. Using this procedure, we demonstrated that naive mice have a memory span, which is the number of elements they can remember for a short-time interval, of about six objects. Then, we showed that excitotoxic selective lesions of the dorsal hippocampus did not impair novel object discrimination in the condition of low memory load. In contrast, the same lesion impaired novel object discrimination in the high memory load condition, and reduced the object memory span to four objects. These results have important heuristic and clinical implications because they open new perspective toward the understanding of the role of the hippocampus in item memory and in memory span deficits occurring in human pathologies, such as Alzheimer's disease and schizophrenia. PMID- 22523416 TI - Prophylactic epidural blood patch after unintentional dural puncture for the prevention of postdural puncture headache in parturients. AB - Unintentional dural puncture is a source of significant morbidity in obstetric patients undergoing neuraxial anesthesia. In this focused review, we discuss the use of a prophylactic epidural blood patch to prevent postdural puncture headache, particularly as it relates to the obstetric population. Although epidural blood patch is thought to be an effective treatment for postdural puncture headache, there is insufficient evidence to support its use as a prophylactic procedure. PMID- 22523417 TI - Perioperative management of face transplantation: a survey. AB - BACKGROUND: Since the first facial allograft transplantation was reported in France in 2005, 18 cases have been performed in 4 countries and the rate is increasing. METHODS: We have devised a survey to assess anesthesia-related management and rationale of facial allograft transplantation. It was sent to the lead anesthesiologists of the first 14 face transplants performed worldwide. RESULTS: Responses were received corresponding to 13 face transplants. The median duration of surgery and anesthesia was 19 hours (95% confidence interval 15-23 hours). The surgical preparation and dissection of multiple small anatomical structures of the recipient was time-consuming for 11 cases. Blood loss was considerable. All patients received packed red blood cells (median 20 U, 95% confidence interval 5-28 U). A median of 13 L of crystalloid was administered (95% confidence interval 10-18 L). CONCLUSIONS: During facial allograft transplantation, the anesthesiologist must be prepared for a long anesthetic with rapid blood loss after reperfusion of the graft. PMID- 22523418 TI - Antihyperalgesic effects of myrsinoic acid B in pain-like behavior induced by inflammatory and neuropathic pain models in mice. AB - BACKGROUND: Myrsinoic acid B (MAB) is a diprenylated benzoic acid widely found in the vegetal kingdom. Recent studies demonstrate that MAB has important antinociceptive effects in models of chemically or thermally induced nociception in mice. METHODS: In the present study we evaluated the effect of MAB in different models of inflammatory and neuropathic hypersensitivity in mice. RESULTS: This study demonstrates that the pretreatment with MAB, given orally (8.4 to 83.8 MUmol/kg), inhibited carrageenan- and complete Freund adjuvant induced mechanical hypersensitivity. When administered after the induction of hypersensitivity, MAB also reduced the mechanical hypersensitivity in the ipsilateral and in the contralateral hindpaws of mice injected with complete Freund adjuvant, interfering with a signaling cascade already established. MAB reversed the hypersensitivity (mechanical and thermal) of operated animals, with similar results to those observed with gabapentin. MAB activity was evident when administered either systemically (PO or IV) or intrathecally, suggesting interference in the central pathways of pain control. Furthermore, MAB seems to present an antiinflammatory effect evidenced by the interference in both the neutrophil migration and in the increase of interleukin-1beta levels after carrageenan injection. Of note, MAB treatment did not interfere with mechanical or thermal sensitivity in healthy mice, a frequent characteristic of commonly used analgesics, such as morphine or gabapentin. Side effects including interference in locomotor activity, motor performance, and body temperature in animals treated with MAB were absent. CONCLUSIONS: MAB reduced mechanical and thermal hypersensitivity in mice submitted to models of inflammatory and neuropathic pain, showing excellent potential for treating persistent pain in humans. PMID- 22523419 TI - The effects of gabapentin on acute opioid tolerance to remifentanil under sevoflurane anesthesia in rats. AB - BACKGROUND: Tolerance to remifentanil during sevoflurane anesthesia may blunt the ability of this drug to reduce anesthetic requirements. Gabapentin has been shown to be effective in reducing postoperative narcotic usage, a reduction that may be associated with a reduction in opioid-induced tolerance and hyperalgesia. We sought to determine whether gabapentin might prevent the observed acute opioid tolerance (AOT) produced by remifentanil in sevoflurane minimum alveolar concentration (MAC). METHODS: Wistar rats were anesthetized with sevoflurane and the effects of gabapentin alone on sevoflurane MAC were determined at doses of 150 and 300 mg . kg(-1). In a second experiment, gabapentin 300 mg . kg(-1) was administered before remifentanil (120 and 240 MUg . kg(-1) . h(-1)). The MAC was determined before gabapentin administration and 3 more times at 1.5-hour intervals after drug administration to assess AOT. MAC was determined from intratracheal gas samples using a sidestream gas analyzer; tail clamping was used as a supramaximal stimulus. Statistical analysis was performed with the 1-way analysis of variance test. RESULTS: Remifentanil reduced MAC (2.5 +/- 0.2%) by 16% +/- 5% and 36% +/- 6% (120 and 240 MUg . kg(-1) . h(-1), respectively, P < 0.01) with a further reduction produced by coadministration with gabapentin 300 mg . kg(-1) to 39% +/- 12% and 62% +/- 14%, respectively (P < 0.01 versus remifentanil alone). Gabapentin given alone at 150 and 300 mg . kg(-1) reduced MAC by 26% (both doses, P < 0.01). AOT was observed with remifentanil and characterized by a lower degree of MAC reduction, approximately 1.5 hours later (P < 0.05). However, when remifentanil was administered with gabapentin, the AOT to remifentanil was not observed (P > 0.05). CONCLUSIONS: Gabapentin reduced the sevoflurane MAC and enhanced the MAC reduction produced by remifentanil. This enhancement may limit AOT in rats. PMID- 22523420 TI - The frequency and magnitude of cerebrospinal fluid pulsations influence intrathecal drug distribution: key factors for interpatient variability. AB - BACKGROUND: Intrathecal drug delivery is an efficient method to administer therapeutic molecules to the central nervous system. However, even with identical drug dosage and administration mode, the extent of drug distribution in vivo is highly variable and difficult to control. Different cerebrospinal fluid (CSF) pulsatility from patient to patient may lead to different drug distribution. Medical image-based computational fluid dynamics (miCFD) is used to construct a patient-specific model to quantify drug transport as a function of a spectrum of physiological CSF pulsations. METHODS: Magnetic resonance imaging (MRI) and CINE MRI were performed to capture the patient's central nervous system anatomy and CSF pulsatile flow velocities. An miCFD model was reconstructed from these MRIs and the patient's CSF flow velocities were computed. The effect of CSF pulsatility (frequency and stroke volume) was investigated for a bolus injection of a model drug at the L2 vertebral level. Drug distribution profiles along the entire spine were computed for different heart rates: 43, 60, and 120 bpm, and varied CSF stroke volumes: 1, 2, and 3 mL. To assess toxicity risk for patients with different physiological variables, therapeutic and toxic concentration thresholds for a common anesthetic were derived from experimental studies. Toxicity risk analysis was performed for an injection of a spinal anesthetic for patients with different heart rates and CSF stroke volumes. RESULTS: Both heart rate and CSF stroke volume of the patient strongly influence drug distribution administered intrathecally. Doubling the heart rate (from 60 to 120 bpm) caused a 26.4% decrease in peak concentration in CSF after injection. Doubling the CSF stroke volume diminished the peak concentration after injection by 38.1%. Computations show that potentially toxic peak concentrations due to injection can be avoided by changing the infusion rate. Using slower infusion rates could avoid high peak concentrations in CSF while maintaining drug concentrations above the therapeutic threshold. CONCLUSIONS: Our computations identify key variables for patient to patient variability in drug distribution in the spine observed clinically. The speed of drug transport is strongly affected by the frequency and magnitude of CSF pulsations. Toxicity risks associated with an injection can be reduced for a particular patient by adjusting the infusion variables with our rigorous miCFD model. PMID- 22523421 TI - The incidence of bite injuries associated with transcranial motor-evoked potential monitoring. AB - BACKGROUND: Bite injuries are a disturbing complication of transcranial motor evoked potential (TcMEP) monitoring. We sought to determine the incidence, type, and severity of bite injuries, and to analyze possible related factors to determine methods of minimizing injury during TcMEP monitoring. METHODS: We reviewed the incident reports of TcMEP-associated bite injuries from 17,273 consecutive surgical procedures. Cases were reviewed for type and number of bite blocks, positioning, anesthesia, and stimulus variables. RESULTS: There were 111 bite injuries in 109 patients for a total incidence of 0.63% including 88 (79.3%) tongue injuries, 22 (19.8%) lip injuries, and 1 (0.9%) broken incisor. One patient had both tongue and lip injured; another had a lip injury and a broken tooth. Severity of bite injuries ranged from minor bruising to deep lacerations requiring suture repair. The total incidence of injury severe enough to require sutures was 25 patients (0.14%). All but 2 patients had some form of bite block used. Anterior approaches were more prevalent than posterior in the injured group although not significantly. The incidence of bite injuries was higher when the Axon NIM-Eclipse system was used (1.37%) compared with the Xltek Protektor (0.6%). Stimulus intensity was maximized in 77 cases (70.6%). In 22 cases, displacement of bite block or of the tongue was documented. CONCLUSIONS: Bite injuries associated with transcranial electric stimulation are an uncommon but disturbing complication of TcMEP monitoring occurring with an incidence of 0.63% (95% confidence interval: 0.52%-0.76%), the most severe of which requiring sutures at an incidence of 0.14% (95% confidence interval: 0.09%-0.21%). Injuries of the tongue occur approximately 4 times as frequently as injuries of the lip. Despite placement of bite blocks, shifting of the bite block during stimulation or positioning is a possible cause of failure. High-intensity transcranial stimulation may increase the risk of bite injuries. We suggest consistent use of properly sized and secured bite blocks with periodic inspection to minimize risk of bite injuries. Future study is needed to determine optimal bite block configuration. PMID- 22523422 TI - The presence of transverse cervical and dorsal scapular arteries at three ultrasound probe positions commonly used in supraclavicular brachial plexus blockade. AB - BACKGROUND: Ultrasound-guided supraclavicular brachial plexus block carries a risk for puncture of vascular structures. In this study, we determined the frequency with which the transverse cervical artery (TCA) and the dorsal scapular artery (DSA) are detected by ultrasound evaluation at 3 probe positions during supraclavicular block. METHODS: Ultrasound examinations of the supraclavicular region were performed in 53 healthy adult volunteers. Ultrasound images of the supraclavicular region were acquired at 3 probe positions: position A (the brachial plexus and the subclavian artery both lying on the first rib); position B (the brachial plexus on the first rib; the artery on the pleura); and position C (the brachial plexus between the anterior and middle scalene muscles). The primary outcome variables were the frequencies with which TCA and DSA were detected by 2-dimensional and color Doppler imaging at 3 specified probe positions. RESULTS: One hundred six supraclavicular regions were examined in 53 subjects. The subclavian artery was detected in all subjects. TCA was more often detected than DSA, 94 (88.7%, 95% confidence interval [CI] 80.7%-93.8%) and 36 (34%, 95% CI 25.3%-43.9%) of 106 scans, respectively (McNemar P value <0.001). TCA was detected in 2 (1.9%, 95% CI 0.3%-7.3%), 31 (29.2%, 95% CI 20.9%-38.9%), and 61 (57.5%, 95% CI 47.5%-66.9%) of scans at probe positions A, B, and C, respectively, whereas DSA was detected in 3 (2.8%, 95% CI 0.7%-8.6%), 23 (21.7%, 95% CI 14.5%-30.9%), and 10 (9.4%, 95% CI 4.8%-17.0%) of scans at probe positions A, B, and C, respectively. Thus, the TCA and DSA were less likely to be present with probe position A (all P < 0.001). CONCLUSION: TCA was more often detected than DSA in the vicinity of the brachial plexus in the supraclavicular region. Both TCA and DSA were least likely to be present in probe position A. Color Doppler, particularly for probe position A, may help to reduce the risk for inadvertent vascular puncture during ultrasound-guided supraclavicular block. PMID- 22523423 TI - Complementarity in root architecture for nutrient uptake in ancient maize/bean and maize/bean/squash polycultures. AB - BACKGROUND AND AIMS: During their domestication, maize, bean and squash evolved in polycultures grown by small-scale farmers in the Americas. Polycultures often overyield on low-fertility soils, which are a primary production constraint in low-input agriculture. We hypothesized that root architectural differences among these crops causes niche complementarity and thereby greater nutrient acquisition than corresponding monocultures. METHODS: A functional-structural plant model, SimRoot, was used to simulate the first 40 d of growth of these crops in monoculture and polyculture and to determine the effects of root competition on nutrient uptake and biomass production of each plant on low-nitrogen, -phosphorus and -potassium soils. KEY RESULTS: Squash, the earliest domesticated crop, was most sensitive to low soil fertility, while bean, the most recently domesticated crop, was least sensitive to low soil fertility. Nitrate uptake and biomass production were up to 7 % greater in the polycultures than in the monocultures, but only when root architecture was taken into account. Enhanced nitrogen capture in polycultures was independent of nitrogen fixation by bean. Root competition had negligible effects on phosphorus or potassium uptake or biomass production. CONCLUSIONS: We conclude that spatial niche differentiation caused by differences in root architecture allows polycultures to overyield when plants are competing for mobile soil resources. However, direct competition for immobile resources might be negligible in agricultural systems. Interspecies root spacing may also be too large to allow maize to benefit from root exudates of bean or squash. Above-ground competition for light, however, may have strong feedbacks on root foraging for immobile nutrients, which may increase cereal growth more than it will decrease the growth of the other crops. We note that the order of domestication of crops correlates with increasing nutrient efficiency, rather than production potential. PMID- 22523425 TI - Pregnancy unbosoms the heart of breast cancer survivors. PMID- 22523424 TI - Water status and associated processes mark critical stages in pollen development and functioning. AB - BACKGROUND: The male gametophyte developmental programme can be divided into five phases which differ in relation to the environment and pollen hydration state: (1) pollen develops inside the anther immersed in locular fluid, which conveys substances from the mother plant--the microsporogenesis phase; (2) locular fluid disappears by reabsorption and/or evaporation before the anther opens and the maturing pollen grains undergo dehydration--the dehydration phase; (3) the anther opens and pollen may be dispersed immediately, or be held by, for example, pollenkitt (as occurs in almost all entomophilous species) for later dispersion- the presentation phase; (4) pollen is dispersed by different agents, remaining exposed to the environment for different periods--the dispersal phase; and (5) pollen lands on a stigma and, in the case of a compatible stigma and suitable conditions, undergoes rehydration and starts germination--the pollen-stigma interaction phase. SCOPE: This review highlights the issue of pollen water status and indicates the various mechanisms used by pollen grains during their five developmental phases to adjust to changes in water content and maintain internal stability. CONCLUSIONS: Pollen water status is co-ordinated through structural, physiological and molecular mechanisms. The structural components participating in regulation of the pollen water level, during both dehydration and rehydration, include the exine (the outer wall of the pollen grain) and the vacuole. Recent data suggest the involvement of water channels in pollen water transport and the existence of several molecular mechanisms for pollen osmoregulation and to protect cellular components (proteins and membranes) under water stress. It is suggested that pollen grains will use these mechanisms, which have a developmental role, to cope with environmental stress conditions. PMID- 22523426 TI - SNAPIN: an endogenous Toll-like receptor ligand in rheumatoid arthritis. AB - OBJECTIVE: The mechanisms contributing to the persistent activation of macrophages in rheumatoid arthritis (RA) are not fully understood. Some studies suggest that endogenous toll-like receptor (TLR) ligands promote the chronic inflammation observed in RA. The objective of this study was to identify endogenous TLR ligands expressed in RA synovial tissue (ST) based on their ability to bind the extracellular domains of TLR2 or TLR4. METHODS: A yeast two hybrid cDNA library was constructed from ST obtained by arthroscopy from patients with RA and screened using the extracellular domains of TLR2 and TLR4 as the bait. Interactions between TLRs and Snapin were demonstrated by reciprocal co immunoprecipitation. ST was examined by histology, and single- and two-colour immunohistochemistry and quantitative reverse transcriptase PCR. Snapin (SNAP - associated protein) expression in macrophages was examined by Western Blot analysis and confocal microscopy. The ability of Snapin to activate through TLR2 was examined. RESULTS: Employing a yeast two-hybrid system, Snapin was the most frequently identified molecule that interacted with TLR2. These results were confirmed by pull-down of in vitro-expressed Snapin together with TLR2. By immunohistochemistry and quantitative reverse transcriptase PCR, Snapin was highly expressed in RA ST, and it was readily detected in macrophages, where it co-localised in the late endosomes. ST Snapin expression correlated with inflammation and was not disease specific. Finally, Snapin was capable of activating through TLR2. CONCLUSION: These observations identify Snapin as a novel endogenous TLR2 ligand in RA, and thus support a role for persistent TLR2 signalling in the pathogenesis of RA. PMID- 22523427 TI - Ultrasonographic assessment of osteophytes in 127 patients with hand osteoarthritis: exploring reliability and associations with MRI, radiographs and clinical joint findings. AB - OBJECTIVE: To investigate the reliability of ultrasonographic assessment of osteophytes and explore the concordance of osteophytes detected by ultrasound, MRI, conventional radiography (CR) and clinical joint examination in patients with hand osteoarthritis (HOA). METHODS: The study included 127 HOA patients (116 women, mean age 68.6 years (SD 5.8)) with ultrasound, CR and clinical examination of both hands and MRI of dominant hand. Osteophytes were assessed by all imaging modalities on 0-3 scales, whereas clinical bony enlargement was assessed as absent/present. An ultrasound atlas of ostephytes was developed, and the intra and inter-reader reliability of scoring ultrasound osteophytes on still images using the atlas as reference was examined. The reliability for ultrasound readings was examined with kappa and percentage exact agreement (PEA) and percentage close agreement (PCA), and the sensitivity, specificity and PEA/PCA of ultrasound was calculated in comparison with MRI, CR and clinical examination. RESULTS: Ultrasound had high sensitivity (0.83) and specificity (0.75) in detecting osteophytes compared with MRI, with excellent PCA (96.1%). Moderate/large osteophytes (grade 2-3) were demonstrated more often by ultrasound (n=401) than by MRI (n=288) in 851 interphalangeal joints. Ultrasound detected more osteophytes (53.2%) than CR (30.0%) and clinical examination (36.9%). Intra and inter-reader reliability of ultrasound was excellent (PEA >88%, PCA 100% and weighted kappa >0.91). CONCLUSION: Ultrasound can reliably assess osteophytes in patients with HOA. Good agreement was found between osteophytes detected by ultrasound and MRI, while ultrasound was more sensitive than CR and clinical examination, which could be due to a multiplanar joint demonstration by ultrasound. PMID- 22523429 TI - Mycobacterial diseases and antitumour necrosis factor therapy in USA. AB - OBJECTIVE: In North America, tuberculosis and nontuberculous mycobacterial (NTM) disease rates associated with antitumour necrosis factor alpha (anti-TNFalpha) therapy are unknown. METHODS: At Kaiser Permanente Northern California, the authors searched automated pharmacy records to identify inflammatory disease patients who received anti-TNF therapy during 2000-2008 and used validated electronic search algorithms to identify NTM and tuberculosis cases occurring during anti-TNF drug exposure. RESULTS: Of 8418 anti-TNF users identified, 60% had rheumatoid arthritis (RA). Among anti-TNF users, 18 developed NTM and 16 tuberculosis after drug start. Anti-TNF associated rates of NTM and tuberculosis were 74 (95% CI: 37 to 111) and 49 (95% CI: 18 to 79) per 100 000 person-years, respectively. Rates (per 100, 000 person-years) for NTM and tuberculosis respectively for etanercept were 35 (95% CI: 1 to 69) and 17 (95% CI: 0 to 41); infliximab, 116 (95% CI: 30 to 203) and 83 (95% CI: 10 to 156); and adalimumab, 122 (95% CI: 3 to 241) and 91 (95% CI: 19 to 267). Background rates for NTM and tuberculosis in unexposed RA-patients were 19.2 (14.2 to 25.0) and 8.7 (5.3 to 13.2), and in the general population were 4.1 (95% CI 3.9 to 4.4) and 2.8 (95% CI 2.6 to 3.0) per 100, 000 person-years. Among anti-TNF users, compared with uninfected individuals, NTM case-patients were older (median age 68 vs 50 years, p<0.01) and more likely to have RA (100% vs 60%, p<0.01); whereas, tuberculosis case-patients were more likely to have diabetes (37% vs 16%, p=0.02) or chronic renal disease (25% vs 6%, p=0.02). CONCLUSIONS: Among anti-TNF users in USA, mycobacterial disease rates are elevated, and NTM is associated with RA. PMID- 22523430 TI - The degree of spinal inflammation is similar in patients with axial spondyloarthritis who report high or low levels of disease activity: a cohort study. AB - BACKGROUND: The threshold for disease activity required to start antitumour necrosis factor (TNF) therapy has been arbitrarily set in patients with axial spondyloarthritis (axSpA) at Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) >= 4. How this relates to spinal inflammation is unknown. OBJECTIVE: To systematically compare the clinical, laboratory and imaging data of patients with axSpA with respect to their BASDAI level. METHODS: A total of 100 consecutive patients with axSpA who had never been treated with TNF blockers were included. Laboratory parameters, spinal MRI and x-rays were quantified. Data were stratified according to BASDAI >= 4. RESULTS: 44 patients were diagnosed as non radiographic axSpA (nraxSpA) and 56 patients as ankylosing spondylitis (AS): median age 40.3 +/- 10.4 years; 57% male, mean disease duration since diagnosis 6.4 +/- 8.4 years, 88% HLA-B27+, mean modified Stokes Ankylosing Spondylitis Spinal Score 8.3 +/- 16.4. 60% of patients had spinal inflammation by MRI. The stratification based on BASDAI >= 4 disclosed significant differences in most clinical parameters but not for inflammation: patients with nraxSpA and BASDAI < 4 versus >= 4 had 0.9 +/- 1.4 and 0.5 +/- 0.6 inflammatory lesions/patient, respectively (p=0.6), while patients with AS had 3.6 +/- 3.7 and 2.7 +/- 3.0 inflammatory lesions/patient, respectively (p=0.4). CONCLUSION: The burden of inflammation is quite comparable in patients with axSpA-regardless of disease activity. These data clearly challenge the concept of the recommended cut-off point of BASDAI >= 4. PMID- 22523428 TI - Variation in the ICAM1-ICAM4-ICAM5 locus is associated with systemic lupus erythematosus susceptibility in multiple ancestries. AB - OBJECTIVE: Systemic lupus erythematosus (SLE; OMIM 152700) is a chronic autoimmune disease for which the aetiology includes genetic and environmental factors. ITGAM, integrin alpha(M) (complement component 3 receptor 3 subunit) encoding a ligand for intracellular adhesion molecule (ICAM) proteins, is an established SLE susceptibility locus. This study aimed to evaluate the independent and joint effects of genetic variations in the genes that encode ITGAM and ICAM. METHODS: The authors examined several markers in the ICAM1-ICAM4 ICAM5 locus on chromosome 19p13 and the single ITGAM polymorphism (rs1143679) using a large-scale case-control study of 17 481 unrelated participants from four ancestry populations. The single-marker association and gene-gene interaction were analysed for each ancestry, and a meta-analysis across the four ancestries was performed. RESULTS: The A-allele of ICAM1-ICAM4-ICAM5 rs3093030, associated with elevated plasma levels of soluble ICAM1, and the A-allele of ITGAM rs1143679 showed the strongest association with increased SLE susceptibility in each of the ancestry populations and the trans-ancestry meta-analysis (OR(meta)=1.16, 95% CI 1.11 to 1.22; p=4.88*10(-10) and OR(meta)=1.67, 95% CI 1.55 to 1.79; p=3.32*10( 46), respectively). The effect of the ICAM single-nucleotide polymorphisms (SNPs) was independent of the effect of the ITGAM SNP rs1143679, and carriers of both ICAM rs3093030-AA and ITGAM rs1143679-AA had an OR of 4.08 compared with those with no risk allele in either SNP (95% CI 2.09 to 7.98; p=3.91*10(-5)). CONCLUSION: These findings are the first to suggest that an ICAM-integrin mediated pathway contributes to susceptibility to SLE. PMID- 22523431 TI - Fra-2 transgenic mice as a novel model of pulmonary hypertension associated with systemic sclerosis. AB - OBJECTIVE: Systemic sclerosis-associated pulmonary arterial hypertension differs from idiopathic pulmonary arterial hypertension with respect to histopathology, treatment responses and survival. Medical progress on PAH is hampered by the lack of human biosamples and suitable animal models. In this study, the authors evaluated fos-related antigen 2 (Fra-2) transgenic mice as a novel model for systemic sclerosis-associated pulmonary arterial hypertension. METHODS: Lung sections of Fra-2 transgenic (n=12) and wild-type mice (n=6) were analysed at 16 weeks by histology using Dana Point criteria. Cellular and molecular key players were assessed by immunohistochemistry. To test the model's sensitivity to change over treatment, a subgroup of Fra-2 transgenic mice (n=6) was treated with the tyrosine kinase inhibitor nilotinib twice daily 37.5 mg orally from 8 weeks of age. RESULTS: Fra-2 transgenic mice developed severe vascular remodelling of pulmonary arteries and non-specific interstitial pneumonia-like interstitial lung disease resembling human systemic sclerosis-associated pulmonary hypertension. Histological features typical for systemic sclerosis-associated pulmonary arterial hypertension, such as intimal thickening with concentric laminar lesions, medial hypertrophy, perivascular inflammatory infiltrates, adventitial fibrosis, but not pulmonary occlusive venopathy were frequently detected. Platelet-derived growth factor signalling pathways were activated in pulmonary vessels of Fra-2 transgenic compared with wild-type mice. Since treatment with nilotinib strongly prevented the development of proliferative vasculopathy and lung fibrosis, the model proved to be sensitive to treatment. CONCLUSIONS: This study suggests that Fra-2 transgenic mice as an animal model of systemic sclerosis-associated pulmonary arterial hypertension display main characteristic features of the human disease. It therefore allows studying pathophysiological aspects and might serve as a preclinical model for interventional proof-of concept studies. PMID- 22523432 TI - Postexposure chickenpox prophylaxis in children with leukaemia: a reply to the recent PEPtalk study and report of a service evaluation in a tertiary paediatric haematology centre in the UK. PMID- 22523433 TI - Iterative Cross-Couplng with MIDA Boronates: Towards a General Platform for Small Molecule Synthesis. PMID- 22523435 TI - Studies Culminating in the Total Synthesis and Determination of the Absolute Configuration of (-)-Saudin. AB - A full account of studies that culminated in the total synthesis of both antipodes and the assignment of its absolute configuration of Saudin, a hypoglycemic natural product. Two approaches are described, the first proceeding though bicyclic lactone intermediates and related second monocyclic esters. The former was obtained via asymmetric Diels-Alder cycloaddition and the latter by an asymmetric annulation protocol. Both approaches employ a Lewis acid promoted Claisen rearrangement, with the successful approach taking advantage of bidentate chelation to control the facial selectivity of the key Claisen rearrangement. PMID- 22523436 TI - Homophily and Contagion Are Generically Confounded in Observational Social Network Studies. AB - The authors consider processes on social networks that can potentially involve three factors: homophily, or the formation of social ties due to matching individual traits; social contagion, also known as social influence; and the causal effect of an individual's covariates on his or her behavior or other measurable responses. The authors show that generically, all of these are confounded with each other. Distinguishing them from one another requires strong assumptions on the parametrization of the social process or on the adequacy of the covariates used (or both). In particular the authors demonstrate, with simple examples, that asymmetries in regression coefficients cannot identify causal effects and that very simple models of imitation (a form of social contagion) can produce substantial correlations between an individual's enduring traits and his or her choices, even when there is no intrinsic affinity between them. The authors also suggest some possible constructive responses to these results. PMID- 22523437 TI - Bayesian Kernel Mixtures for Counts. AB - Although Bayesian nonparametric mixture models for continuous data are well developed, there is a limited literature on related approaches for count data. A common strategy is to use a mixture of Poissons, which unfortunately is quite restrictive in not accounting for distributions having variance less than the mean. Other approaches include mixing multinomials, which requires finite support, and using a Dirichlet process prior with a Poisson base measure, which does not allow smooth deviations from the Poisson. As a broad class of alternative models, we propose to use nonparametric mixtures of rounded continuous kernels. An efficient Gibbs sampler is developed for posterior computation, and a simulation study is performed to assess performance. Focusing on the rounded Gaussian case, we generalize the modeling framework to account for multivariate count data, joint modeling with continuous and categorical variables, and other complications. The methods are illustrated through applications to a developmental toxicity study and marketing data. This article has supplementary material online. PMID- 22523438 TI - Population thinking and natural selection in dual-inheritance theory. AB - A deflationary perspective on theories of cultural evolution, in particular dual inheritance theory, has recently been proposed by Lewens. On this 'pop-culture' analysis, dual-inheritance theorists apply population thinking to cultural phenomena, without claiming that cultural items evolve by natural selection. This paper argues against this pop-culture analysis of dual-inheritance theory. First, it focuses on recent dual-inheritance models of specific patterns of cultural change. These models exemplify population thinking without a commitment to natural selection of cultural items. There are grounds, however, for doubting the added explanatory value of the models in their disciplinary context-and thus grounds for engaging in other potentially explanatory projects based on dual inheritance theory. One such project is suggested by advocates of the theory. Some of the motivational narratives that they offer can be interpreted as setting up an adaptationist project with regard to cumulative change in cultural items. We develop this interpretation here. On it, dual-inheritance theory features two interrelated selection processes, one on the level of genetically inherited learning mechanisms, another on the level of the cultural items transmitted through these mechanisms. This interpretation identifies a need for further modelling efforts, but also offers scope for enhancing the explanatory power of dual-inheritance theory. PMID- 22523434 TI - Mechanism of Nitric Oxide Synthase Regulation: Electron Transfer and Interdomain Interactions. AB - Nitric oxide synthase (NOS), a flavo-hemoprotein, tightly regulates nitric oxide (NO) synthesis and thereby its dual biological activities as a key signaling molecule for vasodilatation and neurotransmission at low concentrations, and also as a defensive cytotoxin at higher concentrations. Three NOS isoforms, iNOS, eNOS and nNOS (inducible, endothelial, and neuronal NOS), achieve their key biological functions by tight regulation of interdomain electron transfer (IET) process via interdomain interactions. In particular, the FMN-heme IET is essential in coupling electron transfer in the reductase domain with NO synthesis in the heme domain by delivery of electrons required for O(2) activation at the catalytic heme site. Compelling evidence indicates that calmodulin (CaM) activates NO synthesis in eNOS and nNOS through a conformational change of the FMN domain from its shielded electron-accepting (input) state to a new electron-donating (output) state, and that CaM is also required for proper alignment of the domains. Another exciting recent development in NOS enzymology is the discovery of importance of the the FMN domain motions in modulating reactivity and structure of the catalytic heme active site (in addition to the primary role of controlling the IET processes). In the absence of a structure of full-length NOS, an integrated approach of spectroscopic (e.g. pulsed EPR, MCD, resonance Raman), rapid kinetics (laser flash photolysis and stopped flow) and mutagenesis methods is critical to unravel the molecular details of the interdomain FMN/heme interactions. This is to investigate the roles of dynamic conformational changes of the FMN domain and the docking between the primary functional FMN and heme domains in regulating NOS activity. The recent developments in understanding of mechanisms of the NOS regulation that are driven by the combined approach are the focuses of this review. An improved understanding of the role of interdomain FMN/heme interaction and CaM binding may serve as the basis for the design of new selective inhibitors of NOS isoforms. PMID- 22523439 TI - Homelessness and Children's Use of Mental Health Services: A Population-Based Study. AB - This study examined whether children who become homeless differ from other low income children in their mental health service use before and after their first homeless episode, and to what extent homelessness is associated with an increased likelihood of mental health service use. Differences between children with and without new onset of sheltered homelessness in the use of mental health services emerged following homelessness and widened over time. Sheltered homelessness and foster care placement history were associated with increased odds of receiving inpatient and ambulatory mental health services. Findings underscore the importance of collaborations between homeless assistance, foster care, and mental healthcare in efforts to mitigate family homelessness and collateral needs among homeless children. PMID- 22523440 TI - Imaged based estimation of food volume using circular referents in dietary assessment. AB - Measuring food volume (portion size) is a critical component in both clinical and research dietary studies. With the wide availability of cell phones and other camera-ready mobile devices, food pictures can be taken, stored or transmitted easily to form an image based dietary record. Although this record enables a more accurate dietary recall, a digital image of food usually cannot be used to estimate portion size directly due to the lack of information about the scale and orientation of the food within the image. The objective of this study is to investigate two novel approaches to provide the missing information, enabling food volume estimation from a single image. Both approaches are based on an elliptical reference pattern, such as the image of a circular pattern (e.g., circular plate) or a projected elliptical spotlight. Using this reference pattern and image processing techniques, the location and orientation of food objects and their volumes are calculated. Experiments were performed to validate our methods using a variety of objects, including regularly shaped objects and food samples. PMID- 22523441 TI - A sequential conditional probability ratio test procedure for comparing diagnostic tests. AB - In this paper, we derive sequential conditional probability ratio tests to compare diagnostic tests without distributional assumptions on test results. The test statistics in our method are nonparametric weighted areas under the receiver operating characteristic curves. By using the new method, the decision of stopping the diagnostic trial early is unlikely to be reversed should the trials continue to the planned end. The conservatism reflected in this approach to have more conservative stopping boundaries during the course of the trial is especially appealing for diagnostic trials since the end point is not death. In addition, the maximum sample size of our method is not greater than a fixed sample test with similar power functions. Simulation studies are performed to evaluate the properties of the proposed sequential procedure. We illustrate the method using data from a thoracic aorta imaging study. PMID- 22523442 TI - Confidence intervals and bands for the binormal ROC curve revisited. AB - Two types of confidence intervals (CIs) and confidence bands (CBs) for the receiver operating characteristic (ROC) curve are studied: pointwise CIs and simultaneous CBs. An optimized version of the pointwise CI with the shortest width is developed. A new ellipse-envelope simultaneous CB for the ROC curve is suggested as an adaptation of the Working-Hotelling-type CB implemented in a paper by Ma and Hall (1993). Statistical simulations show that our ellipse envelope CB covers the true ROC curve with a probability close to nominal while the coverage probability of the Ma and Hall CB is significantly smaller. Simulations also show that our CI for the area under the ROC curve is close to nominal while the coverage probability of the CI suggested by Hanley and McNail (1982) uniformly overestimates the nominal value. Two examples illustrate our simultaneous ROC bands: radiation dose estimation from time to vomiting and discrimination of breast cancer from benign abnormalities using electrical impedance measurements. PMID- 22523443 TI - Two-stage hierarchical modeling for analysis of subpopulations in conditional distributions. AB - In this work, we develop modeling and estimation approach for the analysis of cross-sectional clustered data with multimodal conditional distributions where the main interest is in analysis of subpopulations. It is proposed to model such data in a hierarchical model with conditional distributions viewed as finite mixtures of normal components. With a large number of observations in the lowest level clusters, a two-stage estimation approach is used. In the first stage, the normal mixture parameters in each lowest level cluster are estimated using robust methods. Robust alternatives to the maximum likelihood estimation are used to provide stable results even for data with conditional distributions such that their components may not quite meet normality assumptions. Then the lowest level cluster-specific means and standard deviations are modeled in a mixed effects model in the second stage. A small simulation study was conducted to compare performance of finite normal mixture population parameter estimates based on robust and maximum likelihood estimation in stage 1. The proposed modeling approach is illustrated through the analysis of mice tendon fibril diameters data. Analyses results address genotype differences between corresponding components in the mixtures and demonstrate advantages of robust estimation in stage 1. PMID- 22523444 TI - The Prospects for Payment for Ecosystem Services (PES) in Vietnam: A Look at Three Payment Schemes. AB - Global conservation discourses and practices increasingly rely on market-based solutions to fulfill the dual objective of forest conservation and economic development. Although varied, these interventions are premised on the assumption that natural resources are most effectively managed and preserved while benefiting livelihoods if the market-incentives of a liberalised economy are correctly in place. By examining three nationally supported payment for ecosystem service (PES) schemes in Vietnam we show how insecure land tenure, high transaction costs and high opportunity costs can undermine the long-term benefits of PES programmes for local households and, hence, potentially threaten their livelihood viability. In many cases, the income from PES programmes does not reach the poor because of political and economic constraints. Local elite capture of PES benefits through the monopolization of access to forestland and existing state forestry management are identified as key problems. We argue that as PES schemes create a market for ecosystem services, such markets must be understood not simply as bald economic exchanges between 'rational actors' but rather as exchanges embedded in particular socio-political and historical contexts to support the sustainable use of forest resources and local livelihoods in Vietnam. PMID- 22523445 TI - A fluorescence approach to investigate repartitioning of coalescing agents in acrylic polymer emulsions. AB - Repartitioning of co-solvents between particles of latex emulsions was investigated by means of a fluorescence method based on the detection of the amount of co-solvent via the solvatochromic shift of the emission maximum of a fluorescent probe, copolymerized at a low concentration. Complete repartitioning of co-solvents between particles of latex materials with a low T(g) (ca. 25 degrees C) occurred within minutes. For a hydrophilic latex with a T(g) of 68 degrees C, equilibration was achieved within an hour. Repartitioning was faster for more hydrophobic co-solvents. For a hydrophobic latex of similar T(g), co solvent repartitioning took place on the same time scale, but complete equilibration was not reached. Possibly, there is an additional slow component in the repartitioning, or the prolonged presence of co-solvent causes a structural change in the latex particles that affects the outcome of the experiment. PMID- 22523446 TI - Measuring the Return on Household Enterprise: What Matters Most for Whom? AB - Return on assets (ROA) from household enterprise is crucial for understanding the well-being and productivity of households in developing economies. Yet the definition and measurement of household enterprise ROA remain inconsistent or unclear. We illustrate potential measurement problems with examples from various actual surveys. We then take advantage of a detailed integrated household survey to perform a robustness analysis, acting as if we had gathered less data than was actually the case, to see what matters and for whom. The three issues that matter most for accurate measurement of household enterprise ROA are the choice of accrual versus cash basis of income, the treatment of household's own labor in enterprise income, and the treatment of non-factor income. Also, this sensitivity matters most for a relatively poor region dominated by crop cultivation relative to a richer region with non-farm enterprises. Though the choice between accrued income and cash income matters less when the frequency of the data declines, there remains high sensitivity in longer-term and annualized data. We conclude the paper by providing recommendations on how to improve the survey questionnaires for more accurate measurement in field research. PMID- 22523447 TI - DROUGHT AND POPULATION MOBILITY IN RURAL ETHIOPIA. AB - Significant attention has focused on the possibility that climate change will displace large populations in the developing world, but few multivariate studies have investigated climate-induced migration. We use event history methods and a unique longitudinal dataset from the rural Ethiopian highlands to investigate the effects of drought on population mobility over a ten-year period. The results indicate that men's labor migration increases with drought and that land-poor households are most vulnerable. However, marriage-related moves by women also decrease with drought. These findings suggest a hybrid narrative of environmentally-induced migration that recognizes multiple dimensions of adaptation to environmental change. PMID- 22523448 TI - Occurrence of Didymella ascospores in western and southern Poland in 2004-2006. AB - The concentration of airborne Didymella spores has been investigated at two monitoring sites situated along the west-south transect in Poland (Szczecin, Krakow), i.e. from a height of 100 to 219 m, respectively, above sea level. The aerobiological monitoring of fungal spores was performed by means of two Lanzoni volumetric spore traps. The high Didymella spore numbers were observed at both cities in June, July and August. Statistically significant correlations have been found mainly between the Didymella spore concentrations in the air and the minimum air temperature and relative air humidity. The spore count of Didymella is determined by the diversity of local flora and weather conditions, especially by the relative air humidity. The identification of factors that influence and shape spore concentrations may significantly improve the current methods of allergy prevention. PMID- 22523449 TI - Comparison of aerosol and bioaerosol collection on air filters. AB - Air filters efficiency is usually determined by non-biological test aerosols, such as potassium chloride particles, Arizona dust or di-ethyl-hexyl-sebacate (DEHS) oily liquid. This research was undertaken to asses, if application of non biological aerosols reflects air filters capacity to collect particles of biological origin. The collection efficiency for non-biological aerosol was tested with the PALAS set and ISO Fine Test Dust. Flow rate during the filtration process was 720 l/h, and particles size ranged 0.246-17.165 MUm. The upstream and downstream concentration of the aerosol was measured with a laser particle counter PCS-2010. Tested bioaerosol contained 4 bacterial strains of different shape and size: Micrococcus luteus,Micrococcus varians, Pseudomonas putida and Bacillus subtilis. Number of the biological particles was estimated with a culture-based method. Results obtained with bioaerosol did not confirmed 100% filters efficiency noted for the mineral test dust of the same aerodynamic diameter. Maximum efficiency tested with bacterial cells was 99.8%. Additionally, cells reemission from filters into air was also studied. Bioaerosol contained 3 bacterial strains: Micrococcus varians, Pseudomonas putida and Bacillus subtilis. It was proved that the highest intensity of the reemission process was during the first 5 min. and reached maximum 0.63% of total number of bacteria retained in filters. Spherical cells adhered stronger to the filter fibres than cylindrical ones. It was concluded that non-biological aerosol containing particles of the same shape and surface characteristics (like DEHS spherical particles) can not give representative results for all particles present in the filtered air. PMID- 22523450 TI - Name-writing proficiency, not length of name, is associated with preschool children's emergent literacy skills. AB - The goals of this study were twofold: first, to examine whether preschool children's name-writing proficiency differentiated them on other emergent reading and writing tasks, and second, to examine the effect of name length on preschool children's emergent literacy skills including alphabet knowledge and spelling. In study 1, a range of emergent literacy tasks was administered to 296 preschool children aged 4-5 years. The more advanced name writers outperformed the less advanced name writers on all emergent literacy measures. Furthermore, children with longer names did not show superior performance compared to children with shorter names. In study 2, four measures of alphabet knowledge and spelling were administered to 104 preschool children. Once again, the more advanced name writers outperformed the less advanced name writers on the alphabet knowledge and spelling measures. Results indicated that having longer names did not translate into an advantage on the alphabet knowledge and spelling tasks. Name writing proficiency, not length of name appears to be associated with preschool children's developing emergent literacy skills. Name writing reflects knowledge of some letters rather than a broader knowledge of letters that may be needed to support early spelling. PMID- 22523451 TI - Immunophenotyping of posttraumatic neutrophils on a routine haematology analyser. AB - INTRODUCTION: Flow cytometry markers have been proposed as useful predictors for the occurrence of posttraumatic inflammatory complications. However, currently the need for a dedicated laboratory and the labour-intensive analytical procedures make these markers less suitable for clinical practice. We tested an approach to overcome these limitations. MATERIAL AND METHODS: Neutrophils of healthy donors were incubated with antibodies commonly used in trauma research: CD11b (MAC-1), L-selectin (CD62L), FcgammaRIII (CD16), and FcgammaRII (CD32) in active form (MoPhab A27). Flow cytometric analysis was performed both on a FACSCalibur, a standard flow cytometer, and on a Cell-Dyn Sapphire, a routine haematology analyser. RESULTS: There was a high level of agreement between the two types of analysers, with 41% for FcgammaRIII, 80% for L-selectin, 98% for CD11b, and even a 100% agreement for active FcgammaRII. Moreover, analysis on the routine haematology analyser was possible in less than a quarter of the time in comparison to the flow cytometer. CONCLUSION: Analysis of neutrophil phenotype on the Cell-Dyn Sapphire leads to the same conclusion compared to a standard flow cytometer. The markedly reduced time necessary for analysis and reduced labour intensity constitutes a step forward in implementation of this type of analysis in clinical diagnostics in trauma research. PMID- 22523452 TI - Introduction of APCs in j. Young pharm. PMID- 22523453 TI - Formulation and Evaluation of Cephalexin Extended-release Matrix Tablets Using Hydroxy Propyl Methyl Cellulose as Rate-controlling Polymer. AB - The present investigation reports the design and evaluation of six-hour extended release film-coated matrix tablets of cephalexin using different grades of hydrophilic polymer hydroxypropylmethylcellulose (HPMC) employing direct compression method. The preformulation studies performed included the physical compatibility studies, Differential Scanning Calorimetry analysis, drug characterization using Fourier Transform Infra Red spectroscopic analysis and particle size analysis using sieve method. The tablets were evaluated for weight variation, hardness, thickness and friability. Results of the studies indicate that the polymers used have significant release-retarding effect on the formulation. The dissolution profile comparison of the prepared batches P1 to P8 and market preparation (Sporidex AF 375) was done by using Food and Drug Administration-recommended similarity factor (f(2)) determination. The formulation P8 (10% HPMC K4M, 15% HPMC 15cps) with a similarity factor (f(2)) of 77.75 was selected as the optimized formulae for scale-up batches. The dissolution data of the best formulation P8 was fitted into zero order, first order, Higuchi and Korsemeyer-Peppas models to identify the pharmacokinetics and mechanism of drug release. The results of the accelerated stability study of best formulation P8 for three months revealed that storage conditions were not found to have made any significant changes in final formulation F3. The release of cephalexin was prolonged for 6 h by using polymer combinations of HPMC and a twice daily matrix tablet was formulated. PMID- 22523454 TI - Formulation development and evaluation of alginate microspheres of Ibuprofen. AB - The present study was designed to investigate the effects of different variables on the release profile of ibuprofen microspheres formulated using modified emulsification method. Eight batches of microspheres (F1-F8) were prepared by applying 2(3) factorial design. The amount of sodium alginate, amount of calcium chloride, and amount of magnesium stearate were selected as formulation variables. All the batches were evaluated in terms of percentage yield, percentage encapsulation efficiency and in vitro release characteristics. The batch F7 was found to be optimum batch and was further characterized via scanning electron microscopy (SEM) and particle size analysis. Multiple linear regression was applied to confirm significant effect of each variable on release characteristics. The model developed in the present study can be effectively utilized to achieve the formulation with desired release characteristics. PMID- 22523455 TI - Assessment of In vitro Sun Protection Factor of Calendula Officinalis L. (Asteraceae) Essential Oil Formulation. AB - The present study was undertaken to study the sunscreen activity of herbal formulation. There is no evidence of the sun protection factor (SPF) studies on essential oil of Calendula flowers (Calendula officinalis L., Asteraceae). The study investigates the in vitro SPF by ultraviolet specrtophotometry method of Calendula flower oil in a cream formulation. Calendula oil was isolated by Clavenger's apparatus, compositions were identified by GC-MS and the cream of calendula flower oil was prepared by homogenization method followed by evaluation for physical parameters. The sun protection factor of cream was evaluated by in vitro method employing UV-visible spectrophotometer (Shimazdu-1600). The SPF of Calendula oil in cream formulation exhibited good activity (SPF = 14.84 +/- 0.16). Finding of this study suggested that calendula oil cream can be used to protect the skin from UV radiations in form of sunscreen cream and to maintain the natural pigmentation of the skin. PMID- 22523456 TI - Evaluation and quantification of angiogenesis activity of terminalia bellirica roxb, by mice sponge implantation method. AB - Angiogenesis represents an excellent therapeutic target for the treatment of cardiovascular diseases. It is a potent physiological process that underlies the natural manner in which our bodies respond to a diminution of blood supply to vital organs, namely the production of new collateral vessels to overcome the ischemic state. This present study is aimed to evaluate and quantify the Angiogenic potential of Terminalia bellirica Roxb, by in vivo mice sponge implantation assay. Here, gelatin sponge with or without Ethanolic extract of Terminalia bellirica leaf (EETB - 0.3 mg and 0.5 mg, respectively) were subcutaneously injected into Swiss albino mice, and 14 days later, the implanted sponges was excised and histologically examined. The stained section showed that sponge containing EETB had produced more vessels in gels than sponges alone. The new vessels were abundantly filled with intact Red blood corpuscles (RBCs), which indicate the formation of a functional vasculature inside the sponges and blood circulation in newly formed vessels by angiogenesis which is induced by EETB. It also measured that the hemoglobin content inside the sponges: Whereas, hemoglobin in control was nearly 0.3 MUg, EETB cases the hemoglobin quantity was markedly enhanced to about 17 MUg. Taken together, it demonstrated that Ethanolic extract of Terminalia bellirica leaf exhibited a profound angiogenic activity in vivo. The phytochemical screening and qualitative instrumental analysis of EETB reveals the presence of proteins and Phytosterols. The promising angiogenic potential may be due to the presence of the above chemical constituents. Further study is required to define more precisely the molecular mechanisms by which Ethanolic extract of Terminalia bellirica leaf modulates endothelial cell function and gene expression, as well as the pathological relevance of these findings. PMID- 22523457 TI - Investigation of the mechanisms underlying the gastroprotective effect of cymbopogon citratus essential oil. AB - Cymbopogon citratus is a medicinal plant popularly used in Brazil for the treatment of various diseases, and the research interest in this plant is justifiable because of its potential medicinal value in stomachache and gastric ulcer. This study was aimed to test the validity of this practice by using experimental models of gastric ulcer and to clarify the mechanisms of gastroprotection by C. citratus leaves essential oil (EOCC). EOCC was evaluated for the ability to protect the gastric mucosa against injuries caused by necrotizing agents (absolute ethanol and aspirin) in rodents. The results of this study revealed that EOCC posses a dose-independent anti-ulcer effect against the different experimental models. EOCC pretreatment depicted a higher preventive index in ethanol-(88%) and aspirin-induced (76%) acute ulceration. On pretreatment of mice with indomethacin, the cyclooxygenase inhibitor slightly suppressed the gastroprotective effect of EOCC (48.5%). Furthermore, EOCC gastroprotection was not attenuated in mice pretreated with L-NAME (85.2%), glibenclamide (100%), or yohimbine (79.7%), the respective inhibitors of nitric oxide synthase, K(+) (ATP) channel activation, and alpha(2) receptors. These results confirmed the traditional use of C. citratus for the treatment of gastric ulcer. Thus, we provide the first evidence that EOCC reduces gastric damage induced by ethanol, at least in part, by mechanisms that involve endogenous prostaglandins. PMID- 22523458 TI - Design and Microwave-assisted Synthesis of 1,3,4-Oxadiazole Derivatives for Analgesic and Anti-inflammatory Activity. AB - 1,3,4-Oxadizoles form a biologically important group of compounds having activities like analgesic, anti-inflammatory, bactericidal, antifungal, anticonvulsant, psychotropic, plant growth regulating and mono amino oxidase inhibition. This research has focused on the incorporation of the oxadiazole moiety into isoniazid because of their versatile biological action, to get 2-aryl 5-(4-pyridyl)-1,3,4-oxadiazole to explore the possibilities of some altered biological action. 1,3,4-Oxadiazole derivatives were synthesized by microwave assisted synthesis and screened for their analgesic, anti-inflammatory activities. The synthesized compounds were characterized by Melting point, Thin layer chromatographyInfra red, Nuclear magnetic resonance spectroscopy, etc. Almost all the synthesized compounds possessed good activity as compared to the standard. PMID- 22523459 TI - Synthesis of Some New Isoxazoline Derivatives of Chalconised Indoline 2-one as a Potential Analgesic, Antibacterial and Anthelmimtic Agents. AB - A series of novel 1[5"-(2"'-substituted phenyl)-4",5"'-dihydro isoxazole-3"-yl]-3 [(4 substituted phenyl)imino]1-3-dihydro-2H-indole-2-one were synthesized from different substituted chalconised indole-2,3-dione was prepared from the different chalconised Isatin. The structures of the compounds were elucidated by elemental and spectral (IR, (1)H NMR, and MS) analysis. The synthesized compounds were screened for their analgesic activity by the acetic acid induced Writhing method and in vitro antimicrobial activity against the Gram-positive bacteria Staphylococcus aureus and the Gram-negative bacteria-Pseudomonas auroginosa, Pseudomonas mirabilis, and E. coli by the cup plate agar diffusion method. Compounds 6a(1), 6a(3), 6b(3), and 6b(2) were found to be active against bacteria. The compounds 6a(1), 6b(3), and 6a(3) show a significant analgesic activity. Synthesized compounds also screened for anthelmintic activity against Pheretima posthuma. Compounds 6a(1), 6b(1), and 6b(3) show significant anthelmintic activity. PMID- 22523460 TI - Extractive spectrophotometric method for the determination of tropicamide. AB - Two simple, rapid, and extractive spectrophotometric methods were developed for the determination of tropicamide (TPC). These methods are based on the formation of ionpair complexes between the basic nitrogen of the drug with bromocresol purple (BCP) and methyl orange (MO) in acidic buffer solution. The formed complexes were extracted with chloroform and measured at 408 and 427 nm using BCP and MO, respectively. Beer's law was obeyed in the range 1.0-16 MUg ml(-1) with correlation coefficient (n=6) >=0.9991. The molar absorpitivity, Sandell sensitivity, detection, and quantification limits were also calculated. The composition of the ion pairs was found 1:1 by Job's method. The proposed methods have been applied successfully for the analysis of TPC in pure and in its eye drops. PMID- 22523461 TI - Occurrence and treatment of common health problems in a nigerian community. AB - Medicines are cost-effective interventions for the treatment and management of health problems. This research was carried out to determine the common health problems and medicine-use practices in treating health problems in Lamingo, Jos, Nigeria. A total of 109 households covering 676 individuals were recruited and followed up for a period of one month between 6 November 2010 and 11 December 2010. A structured interview was conducted on weekly visits to households to identify illnesses suffered by household members and treatment given. The results showed that 146 common health problems representing 1.3 cases per household per month were found. The cost of treatment per household per month was found to be $14.7. Infectious and parasitic diseases (44.6%), diseases of the digestive (11.0%) and respiratory system (9.6%) were common in the community. Self medication was common (34.6%) and the patent medicine stores were the most common sources of medicines. Common classes of medicines used by community members were analgesics (23.6%), antimalarials (17.9%) and antibiotics (14.2%). Factors that influenced choice of treatment were previous knowledge and experience of family members with service provider and treatment (44.4%), cost (18.9%) and severity of condition (16.7%). There is, therefore, high occurrence of health problems and self-medication practices in the Lamingo community. PMID- 22523462 TI - Health-related Quality of Life Measurement. PMID- 22523463 TI - Evolutionarily conserved essential genes from arctic bacteria: a tool for vaccination. PMID- 22523464 TI - Assessing the Prayer Lives of Older Whites, Older Blacks and Older Mexican Americans: A Descriptive Analysis. AB - The purpose of this study was to see whether differences emerge between older whites, older blacks, and older Mexican Americans in 12 measures of prayer. These measures assess four dimensions of prayer: The social context of prayer, interpersonal aspects of prayer, beliefs about how prayer operates, and the content or focus of prayers. Data from two nationwide surveys of older adults suggest that with respect to all four dimensions, the prayer lives of older whites appear be less developed than the prayer lives of older blacks and older Mexican Americans. In contrast, relatively few differences were found in the prayer lives of older African Americans and older Mexican Americans. The theoretical implications of these findings are discussed. PMID- 22523465 TI - Clothing Matching for Visually Impaired Persons. AB - Matching clothes is a challenging task for many blind people. In this paper, we present a proof of concept system to solve this problem. The system consists of 1) a camera connected to a computer to perform pattern and color matching process; 2) speech commands for system control and configuration; and 3) audio feedback to provide matching results for both color and patterns of clothes. This system can handle clothes in deficient color without any pattern, as well as clothing with multiple colors and complex patterns to aid both blind and color deficient people. Furthermore, our method is robust to variations of illumination, clothing rotation and wrinkling. To evaluate the proposed prototype, we collect two challenging databases including clothes without any pattern, or with multiple colors and different patterns under different conditions of lighting and rotation. Results reported here demonstrate the robustness and effectiveness of the proposed clothing matching system. PMID- 22523466 TI - Do Jurors Get What They Expect? Traditional versus Alternative Forms of Children's Testimony. AB - This study examined prospective jurors' expectancies for the verbal and nonverbal behavior of a child testifying in a sexual abuse case. Community members (N = 261) reporting for jury duty completed a survey in which they described their expectancies for how a child alleging sexual abuse would appear when testifying and their beliefs about discerning children's truthfulness, testimony stress, and fairness to trial parties. Within this survey, we varied the child's age (5, 10, or 15 years old), type of abuse alleged (vaginal fondling or penetration), and whether the abuse actually occurred (yes, no) between participants across five different testimony conditions (traditional live in-court, support person present, closed-circuit television, preparation, and videotape) within each participant. Participants expected a child providing traditional testimony to be more nervous, tearful, and fidgety; less confident, cooperative, and fluent; and to maintain less eye contact and provide shorter responses than when the child provided alternative forms of testimony. Participants believed it was easiest to determine a child's truthfulness and fairest to the defendant when the child testified live in court, but that this form of testimony was the most stressful and unfair to the child. Expectancies and beliefs differed within the alternative forms of testimony as well. Negative evaluations of children's alternative testimony may be the result of expectancy violation; namely, jurors expect differences in children's verbal and nonverbal behavior as a result of accommodation, but those differences actually do not occur. PMID- 22523467 TI - Culture environment-induced pluripotency of SACK-expanded tissue stem cells. AB - Previous efforts to improve the efficiency of cellular reprogramming for the generation of induced pluripotent stem cells (iPSCs) have focused mainly on transcription factors and small molecule combinations. Here, we report the results of our focus instead on the phenotype of the cells targeted for reprogramming. We find that adult mouse pancreatic tissue stem cells derived by the method of suppression of asymmetric cell kinetics (SACK) acquire increased potency simply by culture under conditions for the production and maintenance of pluripotent stem cells. Moreover, supplementation with the SACK agent xanthine, which promotes symmetric self-renewal, significantly increases the efficiency and degree of acquisition of pluripotency properties. In transplantation analyses, clonal reprogrammed pancreatic stem cells produce slow-growing tumors with tissue derivative of all three embryonic germ layers. This acquisition of pluripotency, without transduction with exogenous transcription factors, supports the concept that tissue stem cells are predisposed to cellular reprogramming, particularly when symmetrically self-renewing. PMID- 22523468 TI - Mouse ficolin B has an ability to form complexes with mannose-binding lectin associated serine proteases and activate complement through the lectin pathway. AB - Ficolins are thought to be pathogen-associated-molecular-pattern-(PAMP-) recognition molecules that function to support innate immunity. Like mannose binding lectins (MBLs), most mammalian ficolins form complexes with MBL associated serine proteases (MASPs), leading to complement activation via the lectin pathway. However, the ability of murine ficolin B, a homologue of human M ficolin, to perform this function is still controversial. The results of the present study show that ficolin B in mouse bone marrow is an oligomeric protein. Ficolin B, pulled down using GlcNAc-agarose, contained very low, but detectable, amounts of MASP-2 and small MBL-associated protein (sMAP) and showed detectable C4-deposition activity on immobilized N-acetylglucosamine. These biochemical features of ficolin B were confirmed using recombinant mouse ficolin B produced in CHO cells. Taken together, these results suggest that like other mammalian homologues, murine ficolin B has an ability to exert its function via the lectin pathway. PMID- 22523469 TI - Metabolomics analysis of Cistus monspeliensis leaf extract on energy metabolism activation in human intestinal cells. AB - Energy metabolism is a very important process to improve and maintain health from the point of view of physiology. It is well known that the intracellular ATP production is contributed to energy metabolism in cells. Cistus monspeliensis is widely used as tea, spices, and medical herb; however, it has not been focusing on the activation of energy metabolism. In this study, C. monspeliensis was investigated as the food resources by activation of energy metabolism in human intestinal epithelial cells. C. monspeliensis extract showed high antioxidant ability. In addition, the promotion of metabolites of glycolysis and TCA cycle was induced by C. monspeliensis treatment. These results suggest that C. monspeliensis extract has an ability to enhance the energy metabolism in human intestinal cells. PMID- 22523470 TI - Enzymatic synthesis of ampicillin: nonlinear modeling, kinetics estimation, and adaptive control. AB - Nowadays, the use of advanced control strategies in biotechnology is quite low. A main reason is the lack of quality of the data, and the fact that more sophisticated control strategies must be based on a model of the dynamics of bioprocesses. The nonlinearity of the bioprocesses and the absence of cheap and reliable instrumentation require an enhanced modeling effort and identification strategies for the kinetics. The present work approaches modeling and control strategies for the enzymatic synthesis of ampicillin that is carried out inside a fed-batch bioreactor. First, a nonlinear dynamical model of this bioprocess is obtained by using a novel modeling procedure for biotechnology: the bond graph methodology. Second, a high gain observer is designed for the estimation of the imprecisely known kinetics of the synthesis process. Third, by combining an exact linearizing control law with the on-line estimation kinetics algorithm, a nonlinear adaptive control law is designed. The case study discussed shows that a nonlinear feedback control strategy applied to the ampicillin synthesis bioprocess can cope with disturbances, noisy measurements, and parametric uncertainties. Numerical simulations performed with MATLAB environment are included in order to test the behavior and the performances of the proposed estimation and control strategies. PMID- 22523472 TI - Resveratrol Targeting of Carcinogen-Induced Brain Endothelial Cell Inflammation Biomarkers MMP-9 and COX-2 is Sirt1-Independent. AB - The occurrence of a functional relationship between the release of metalloproteinases (MMPs) and the expression of cyclooxygenase (COX)-2, two inducible pro-inflammatory biomarkers with important pro-angiogenic effects, has recently been inferred. While brain endothelial cells play an essential role as structural and functional components of the blood-brain barrier (BBB), increased BBB breakdown is thought to be linked to neuroinflammation. Chemopreventive mechanisms targeting both MMPs and COX-2 however remain poorly investigated. In this study, we evaluated the pharmacological targeting of Sirt1 by the diet derived and antiinflammatory polyphenol resveratrol. Total RNA, cell lysates, and conditioned culture media from human brain microvascular endothelial cells (HBMEC) were analyzed using qRT-PCR, immunoblotting, and zymography respectively. Tissue scan microarray analysis of grade I-IV brain tumours cDNA revealed increased gene expression of Sirt-1 from grade I-III but surprisingly not in grade IV brain tumours. HBMEC were treated with a combination of resveratrol and phorbol 12-myristate 13-acetate (PMA), a carcinogen known to increase MMP-9 and COX-2 through NF-kappaB. We found that resveratrol efficiently reversed the PMA induced MMP-9 secretion and COX-2 expression. Gene silencing of Sirt1, a critical modulator of angiogenesis and putative target of resveratrol, did not lead to significant reversal of MMP-9 and COX-2 inhibition. Decreased resveratrol inhibitory potential of carcinogen-induced IkappaB phosphorylation in siSirt1 transfected HBMEC was however observed. Our results suggest that resveratrol may prevent BBB disruption during neuroinflammation by inhibiting MMP-9 and COX-2 and act as a pharmacological NF-kappaB signal transduction inhibitor independent of Sirt1. PMID- 22523473 TI - Invasive leaf resources alleviate density dependence in the invasive mosquito, Aedes albopictus. AB - Interactions between invasive species can have important consequences for the speed and impact of biological invasions. Containers occupied by the invasive mosquito, Aedes albopictus Skuse, may be sensitive to invasive plants whose leaves fall into this larval habitat. To examine the potential for interactions between invasive leaf species and larval A. albopictus, we conducted a field survey of leaf material found with A. albopictus in containers in Palm Beach County, Florida and measured density dependent responses of A. albopictus larvae to two invasive and one native leaf species in laboratory experiments. We found increased diversity of leaf species, particularly invasive species, in areas further from the urbanized coast, and a significant positive association between the presence of Schinus terebinthifolious (Brazilian pepper) and the abundance of A. albopictus. In laboratory experiments, we determined that larval growth and survivorship were significantly affected by both larval density and leaf species which, in turn, resulted in higher population performance on the most abundant invasive species (Brazilian pepper) relative to the most abundant native species, Quercus virginiana (live oak). These results suggest invasive leaf species can alleviate density dependent reductions in population performance in A. albopictus, and may contribute to its invasion success and potential to spread infectious disease. PMID- 22523471 TI - Engineering airway epithelium. AB - Airway epithelium is constantly presented with injurious signals, yet under healthy circumstances, the epithelium maintains its innate immune barrier and mucociliary elevator function. This suggests that airway epithelium has regenerative potential (I. R. Telford and C. F. Bridgman, 1990). In practice, however, airway regeneration is problematic because of slow turnover and dedifferentiation of epithelium thereby hindering regeneration and increasing time necessary for full maturation and function. Based on the anatomy and biology of the airway epithelium, a variety of tissue engineering tools available could be utilized to overcome the barriers currently seen in airway epithelial generation. This paper describes the structure, function, and repair mechanisms in native epithelium and highlights specific and manipulatable tissue engineering signals that could be of great use in the creation of artificial airway epithelium. PMID- 22523474 TI - Differential Characterization and Classification of Tissue Specific Glycosaminoglycans by Tandem Mass Spectrometry and Statistical Methods. AB - The biological functions of glycoconjugate glycans arise in the context of structural heterogeneity resulting from non-template driven biosynthetic reactions. Such heterogeneity is particularly apparent for the glycosaminoglycan (GAG) classes, of which heparan sulfate (HS) is of particular interest for its properties in binding to many classes of growth factors and growth factor receptors. The structures of HS chains vary according to spatial and temporal factors in biological systems as a mechanism where by the functions of the relatively limited number of associated proteoglycan core proteins is elaborated. Thus, there is a strong driver for the development of methods to discover functionally relevant structures in HS preparations for different sources. In the present work, a set of targeted tandem mass spectra were acquired in automated mode on HS oligosaccharides deriving from two different tissue sources. Statistical methods were used to determine the precursor and product ions, the abundances of which differentiate between the tissue sources. The results demonstrate considerable potential for using this approach to constrain the number of positional glycoform isomers present in different biological preparations toward the end of discovery of functionally relevant structures. PMID- 22523476 TI - 'Are You Interested, Baby?' Young Infants Exhibit Stable Patterns of Attention during Interaction. AB - The degree to which infants' current actions are influenced by previous action is fundamental to our understanding of early social and cognitive competence. In this study, we found that infant gazing manifested notable temporal dependencies during interaction with mother even when controlling for mother behaviors. The durations of infant gazes at mother's face were positively predicted by the durations of the two previous gazes at mother's face. Similarly, the durations of gazes away from mother's face were positively predicted by the durations of the two previous gazes of the same type. The durations of gazes at and away from mother's face, however, were not predicted by one another. This pattern suggests that infants exhibit distinct and temporally stable levels of interest in social and nonsocial features of the environment. We discuss the implications of these results for parents, for experimental research using looking time measures, and for our understanding of infants' developing communicative abilities. PMID- 22523475 TI - Shame, Guilt and Remorse: Implications for Offender Populations. AB - The emotions shame and guilt may represent a critical stepping stone in the rehabilitation process. Often referred to as "moral" emotions owing to their presumed role in promoting altruistic behavior and inhibiting antisocial behaviors, shame and guilt provide potentially exciting points of intervention with offenders. In this article, we describe current psychological theory and research that underscores important differences between shame and guilt. We note parallels between psychologists' conceptions of guilt and shame, and criminologists' conceptions of reintegrative and disintegrative shaming. We summarize recent research investigating the implications of these moral emotions for criminal and risky behavior, with special emphasis on the handful of studies conducted with actual offenders. We conclude with a discussion of implications for treatment in criminal justice settings. PMID- 22523477 TI - Visual Sequence Learning in Infancy: Domain-General and Domain-Specific Associations with Language. AB - Research suggests that non-linguistic sequence learning abilities are an important contributor to language development (Conway, Bauernschmidt, Huang, & Pisoni, 2010). The current study investigated visual sequence learning as a possible predictor of vocabulary development in infants. Fifty-eight 8.5-month old infants were presented with a three-location spatiotemporal sequence of multi colored geometric shapes. Early language skills were assessed using the MacArthur Bates CDI. Analyses of children's reaction times to the stimuli suggest that the extent to which infants demonstrated learning was significantly correlated with their vocabulary comprehension at the time of test and with their gestural comprehension abilities 5 months later. These findings suggest that visual sequence learning may have both domain-general and domain-specific associations with language learning. PMID- 22523478 TI - Contributions of attentional style and previous experience to 4-month-old infants' categorization. AB - We examined how infants' categorization is jointly influenced by previous experience and how much they shift their gaze back-and-forth between stimuli. Extending previous findings reported by Kovack-Lesh, Horst, and Oakes (2008), we found that 4-month-old infants' (N = 122) learning of the exclusive category of cats was related to whether they had cats at home and how much they shifted attention between two available stimuli during familiarization. Individual differences in attention assessed in an unrelated task were not related to their categorization. Thus, infants' learning is multiply influenced by past experience and on-line attentional style. PMID- 22523479 TI - Parenting Control in Contexts of Political Violence: Testing Bi-directional Relations between Violence Exposure and Control in Post-Accord Belfast. AB - OBJECTIVE: The goal of the present study is to examine bi-directional relations between youth exposure to sectarian and nonsectarian antisocial behavior and mothers' efforts to control youth's exposure to community violence in Belfast, Northern Ireland. DESIGN: Mother-child dyads (N=773) were interviewed in their homes twice over 2 years regarding youth's exposure to sectarian (SAB) and nonsectarian (NAB) community antisocial behavior and mothers' use of control strategies, including behavioral and psychological control. RESULTS: Youth's exposure to NAB was related to increases in mothers' use of both behavioral and psychological control strategies over time, controlling for earlier levels of these constructs. Reflecting bi-directional relations, mothers' behavioral control strategies were associated with youth's reduced exposure to both NAB and SAB over time, whereas psychological control was not related to reduced exposure. CONCLUSION: Only nonsectarian community violence was associated longitudinally with mothers' increased use of control strategies, and only behavioral control strategies were effective in reducing youth's exposure to community antisocial behavior, including both sectarian and nonsectarian antisocial behavior. PMID- 22523480 TI - A Social-Ecological Perspective on Vulnerable Youth: Toward an Understanding of Sexual Development Among Urban African American Adolescents. AB - The authors employ a social-ecological framework to aid our understanding of the complex array of factors in the immediate and broader environment that influence adolescent sexual development. Further, sexual development is viewed as normative and critical to positive growth. The authors provide an overview of the Two Cities Study, a multi-stage qualitative investigation that aims to contribute to an understanding of sexual development and to illuminate gender differences in sexuality. The current studies focus on urban African American youth living in low-income neighborhoods, offering new data on sexual development among these youth. PMID- 22523481 TI - African American Adolescent Females' Perceptions of Neighborhood Safety, Familial Strategies, and Sexual Debut. AB - Sexual debut represents a developmental transition that holds possibility for growth and for risk. Family and neighborhood may impact timing of debut. This qualitative study examined family strategies (e.g., moving, parental monitoring), perceptions of neighborhood, and attitudes about sex and sexual debut among sexually experienced and inexperienced African American adolescent females living in disadvantaged urban neighborhoods. Findings show that more familial strategies were reported by sexually inexperienced females, suggesting that strategies may delay sexual debut. Furthermore, experiences with neighborhood violence related to attitudes about sex and sexual debut, suggesting a linkage between death anxiety and sexual debut among female youth. PMID- 22523482 TI - Using the R Package crlmm for Genotyping and Copy Number Estimation. AB - Genotyping platforms such as Affymetrix can be used to assess genotype-phenotype as well as copy number-phenotype associations at millions of markers. While genotyping algorithms are largely concordant when assessed on HapMap samples, tools to assess copy number changes are more variable and often discordant. One explanation for the discordance is that copy number estimates are susceptible to systematic differences between groups of samples that were processed at different times or by different labs. Analysis algorithms that do not adjust for batch effects are prone to spurious measures of association. The R package crlmm implements a multilevel model that adjusts for batch effects and provides allele specific estimates of copy number. This paper illustrates a workflow for the estimation of allele-specific copy number and integration of the marker-level estimates with complimentary Bioconductor software for inferring regions of copy number gain or loss. All analyses are performed in the statistical environment R. PMID- 22523483 TI - Behavioral Responses of Patients in AIDS Treatment Programs: Sexual Behavior in Kenya. AB - We estimate changes in sexual behavior for HIV-positive individuals enrolled in an AIDS treatment program using longitudinal household survey data collected in western Kenya. We find that sexual activity is lowest at the time that treatment is initiated and increases significantly in the subsequent six months, consistent with the health improvements that result from ART treatment. More importantly, we find large and significant increases of 10 to 30 percentage points in the reported use of condoms during last sexual intercourse. The increases in condom use appear to be driven primarily by a program effect, applying to all HIV clinic patients regardless of treatment status. PMID- 22523484 TI - The Association between Chronic Arsenic Exposure and Hypertension: A Meta Analysis. AB - Background. There is inconclusive evidence from cross-sectional and cohort studies that arsenic exposure is a risk factor involved in the development of hypertension. Methods. A database search, using several keywords, was conducted to identify relevant studies. Separate odds ratio estimates for arsenic exposure with concentration only and arsenic exposure with duration, including biomarker, were extracted from studies that met all inclusion criteria. The extracted odds ratios (OR) comparing the highest exposure categories with the lowest in each study were pooled using the random effects methods of meta-analysis. Heterogeneity of odds ratios in the included studies were analyzed using I(2) statistics. Results. Eight studies were analyzed. Using the exposure as arsenic concentration in the drinking water, the OR estimate was 1.9 (95% CI: 1.2-3.0), with the I(2) = 92%, while using the exposure as concentration and duration, the OR estimate was 1.4 (95% CI: 0.95-2.0) with the I(2) = 80%. Meta-regression was done and the quality of exposure measurement was found to be significantly associated with the effect measure. For a one unit increase in the score from exposure assessment, the odds ratio decreased by 6%. No publication bias was evident. The only major weaknesses of this study were heterogeneity across studies and small sample size. Conclusions. The study findings provide limited evidence for a relationship between arsenic and hypertension. In summary, the relationship between arsenic exposure and hypertension is still inconclusive and needs further validation through prospective cohort studies. PMID- 22523485 TI - Toxicity of Organometal(loids). PMID- 22523486 TI - Occurrence of toxic cyanobacterial blooms in rio de la plata estuary, Argentina: field study and data analysis. AB - Water samples were collected during 3 years (2004-2007) at three sampling sites in the Rio de la Plata estuary. Thirteen biological, physical, and chemical parameters were determined on the water samples. The presence of microcystin-LR in the reservoir samples, and also in domestic water samples, was confirmed and quantified. Microcystin-LR concentration ranged between 0.02 and 8.6 MUg.L(-1). Principal components analysis was used to identify the factors promoting cyanobacteria growth. The proliferation of cyanobacteria was accompanied by the presence of high total and fecal coliforms bacteria (>1500 MNP/100 mL), temperature >=25 degrees C, and total phosphorus content >=1.24 mg.L(-1). The observed fluctuating patterns of Microcystis aeruginosa, total coliforms, and Microcystin-LR were also described by probabilistic models based on the log normal and extreme value distributions. The sampling sites were compared in terms of the distribution parameters and the probability of observing high concentrations for Microcystis aeruginosa, total coliforms, and microcystin-LR concentration. PMID- 22523487 TI - Modeling the Human Kinetic Adjustment Factor for Inhaled Volatile Organic Chemicals: Whole Population Approach versus Distinct Subpopulation Approach. AB - The objective of this study was to evaluate the impact of whole- and sub population-related variabilities on the determination of the human kinetic adjustment factor (HKAF) used in risk assessment of inhaled volatile organic chemicals (VOCs). Monte Carlo simulations were applied to a steady-state algorithm to generate population distributions for blood concentrations (CAss) and rates of metabolism (RAMs) for inhalation exposures to benzene (BZ) and 1,4 dioxane (1,4-D). The simulated population consisted of various proportions of adults, elderly, children, neonates and pregnant women as per the Canadian demography. Subgroup-specific input parameters were obtained from the literature and P3M software. Under the "whole population" approach, the HKAF was computed as the ratio of the entire population's upper percentile value (99th, 95th) of dose metrics to the median value in either the entire population or the adult population. Under the "distinct subpopulation" approach, the upper percentile values in each subpopulation were considered, and the greatest resulting HKAF was retained. CAss-based HKAFs that considered the Canadian demography varied between 1.2 (BZ) and 2.8 (1,4-D). The "distinct subpopulation" CAss-based HKAF varied between 1.6 (BZ) and 8.5 (1,4-D). RAM-based HKAFs always remained below 1.6. Overall, this study evaluated for the first time the impact of underlying assumptions with respect to the interindividual variability considered (whole population or each subpopulation taken separately) when determining the HKAF. PMID- 22523488 TI - Nanoaerosols including radon decay products in outdoor and indoor air at a suburban site. AB - Nanoaerosols have been monitored inside a kitchen and in the courtyard of a suburban farmhouse. Total number concentration and number size distribution (5 1000 nm) of general aerosol particles, as measured with a Grimm Aerosol SMPS+C 5.400 instrument outdoors, were mainly influenced by solar radiation and use of farming equipment, while, indoors, they were drastically changed by human activity in the kitchen. In contrast, activity concentrations of the short-lived radon decay products (218)Po, (214)Pb, and (214)Bi, both those attached to aerosol particles and those not attached, measured with a Sarad EQF3020-2 device, did not appear to be dependent on these activities, except on opening and closing of the kitchen window. Neither did a large increase in concentration of aerosol particles smaller than 10 or 20 nm, with which the unattached radon products are associated, augment the fraction of the unattached decay products significantly. PMID- 22523489 TI - Nutritional manipulation of one-carbon metabolism: effects on arsenic methylation and toxicity. AB - Exposure to arsenic (As) through drinking water is a substantial problem worldwide. The methylation of As, a reactive metalloid, generates monomethyl- (MMA) and dimethyl-arsenical (DMA) species. The biochemical pathway that catalyzes these reactions, one-carbon metabolism, is regulated by folate and other micronutrients. Arsenic methylation exerts a critical influence on both its urinary elimination and chemical reactivity. Mice having the As methyltransferase null genotype show reduced urinary As excretion, increased As retention, and severe systemic toxicity. The most toxic As metabolite in vitro is MMA(III), an intermediate in the generation of DMA(V), a much less toxic metabolite. These findings have raised the question of whether As methylation is a detoxification or bioactivation pathway. Results of population-based studies suggest that complete methylation of inorganic As to DMA is associated with reduced risk for As-induced health outcomes, and that nutrients involved in one-carbon metabolism, such as folate, can facilitate As methylation and elimination. PMID- 22523491 TI - Measured Copper Toxicity to Cnesterodon decemmaculatus (Pisces: Poeciliidae) and Predicted by Biotic Ligand Model in Pilcomayo River Water: A Step for a Cross Fish-Species Extrapolation. AB - In order to determine copper toxicity (LC50) to a local species (Cnesterodon decemmaculatus) in the South American Pilcomayo River water and evaluate a cross fish-species extrapolation of Biotic Ligand Model, a 96 h acute copper toxicity test was performed. The dissolved copper concentrations tested were 0.05, 0.19, 0.39, 0.61, 0.73, 1.01, and 1.42 mg Cu L(-1). The 96 h Cu LC50 calculated was 0.655 mg L(-1) (0.823 - 0.488). 96-h Cu LC50 predicted by BLM for Pimephales promelas was 0.722 mg L(-1). Analysis of the inter-seasonal variation of the main water quality parameters indicates that a higher protective effect of calcium, magnesium, sodium, sulphate, and chloride is expected during the dry season. The very high load of total suspended solids in this river might be a key factor in determining copper distribution between solid and solution phases. A cross-fish species extrapolation of copper BLM is valid within the water quality parameters and experimental conditions of this toxicity test. PMID- 22523490 TI - The adverse effects of air pollution on the nervous system. AB - Exposure to ambient air pollution is a serious and common public health concern associated with growing morbidity and mortality worldwide. In the last decades, the adverse effects of air pollution on the pulmonary and cardiovascular systems have been well established in a series of major epidemiological and observational studies. In the recent past, air pollution has also been associated with diseases of the central nervous system (CNS), including stroke, Alzheimer's disease, Parkinson's disease, and neurodevelopmental disorders. It has been demonstrated that various components of air pollution, such as nanosized particles, can easily translocate to the CNS where they can activate innate immune responses. Furthermore, systemic inflammation arising from the pulmonary or cardiovascular system can affect CNS health. Despite intense studies on the health effects of ambient air pollution, the underlying molecular mechanisms of susceptibility and disease remain largely elusive. However, emerging evidence suggests that air pollution-induced neuroinflammation, oxidative stress, microglial activation, cerebrovascular dysfunction, and alterations in the blood-brain barrier contribute to CNS pathology. A better understanding of the mediators and mechanisms will enable the development of new strategies to protect individuals at risk and to reduce detrimental effects of air pollution on the nervous system and mental health. PMID- 22523494 TI - Dissection and exposure of the whole course of deep nerves in human head specimens after decalcification. AB - The whole course of the chorda tympani nerve, nerve of pterygoid canal, and facial nerves and their relationships with surrounding structures are complex. After reviewing the literature, it was found that details of the whole course of these deep nerves are rarely reported and specimens displaying these nerves are rarely seen in the dissecting room, anatomical museum, or atlases. Dissections were performed on 16 decalcified human head specimens, exposing the chorda tympani and the nerve connection between the geniculate and pterygopalatine ganglia. Measurements of nerve lengths, branching distances, and ganglia size were taken. The chorda tympani is a very fine nerve (0.44 mm in diameter within the tympanic cavity) and approximately 54 mm in length. The mean length of the facial nerve from opening of internal acoustic meatus to stylomastoid foramen was 52.5 mm. The mean length of the greater petrosal nerve was 26.1 mm and nerve of the pterygoid canal was 15.1 mm. PMID- 22523493 TI - Application of physiologically based pharmacokinetic models in chemical risk assessment. AB - Post-exposure risk assessment of chemical and environmental stressors is a public health challenge. Linking exposure to health outcomes is a 4-step process: exposure assessment, hazard identification, dose response assessment, and risk characterization. This process is increasingly adopting "in silico" tools such as physiologically based pharmacokinetic (PBPK) models to fine-tune exposure assessments and determine internal doses in target organs/tissues. Many excellent PBPK models have been developed. But most, because of their scientific sophistication, have found limited field application-health assessors rarely use them. Over the years, government agencies, stakeholders/partners, and the scientific community have attempted to use these models or their underlying principles in combination with other practical procedures. During the past two decades, through cooperative agreements and contracts at several research and higher education institutions, ATSDR funded translational research has encouraged the use of various types of models. Such collaborative efforts have led to the development and use of transparent and user-friendly models. The "human PBPK model toolkit" is one such project. While not necessarily state of the art, this toolkit is sufficiently accurate for screening purposes. Highlighted in this paper are some selected examples of environmental and occupational exposure assessments of chemicals and their mixtures. PMID- 22523492 TI - MicroRNAs in Neurotoxicity. AB - MicroRNAs are gaining importance as regulators of gene expression with the capability to fine-tune and modulate cellular events. The complex network with their selective targets (mRNAs/genes) pave way for regulation of many physiological processes. Dysregulation of normal neuronal activities could result in accumulation of substances that are detrimental to neuronal functions and subsequently result in neurotoxicity. Neurotoxicity-mediated pathophysiological conditions could then manifest as diseases or disabilities like Parkinson's and Alzheimer's which have debilitating implications. Such toxicity can be a result of individuals predisposed due to genetic inheritance or from other sources such as brain tumours. Neurotoxicity can also be brought about by external agents like drugs and alcohol as well as brain injury with miRNAs playing a pivotal role in diseases. It is therefore vital to understand the expression of these microRNAs and their impact on neuronal activities. In this paper, we discuss some of the neuronal pathophysiological conditions that could be caused by dysregulated microRNAs. PMID- 22523495 TI - Nasopharyngeal development in patients with cleft lip and palate: a retrospective case-control study. AB - Introduction. The aim of this paper was to evaluate cephalometrically the nasopharyngeal development of patients with complete unilateral cleft lip and palate. Influencing factors were evaluated and cleft to noncleft subjects were compared to each other. Material and Methods. The lateral cephalograms of 66 patients with complete cleft lip and palate were measured and compared retrospectively to the cephalograms of 123 healthy probands. Measurements were derived from a standardized analysis of 56 landmarks. Results. We observed significant differences between cleft and control group: the cleft patients showed amaxillary retroposition and a reduced maxillary length; the inclination of the maxilla was significantly more posterior and cranial; the anterior nasopharyngeal height was reduced; the nasopharyngeal growth followed a vertical tendency with reduced sagittal dimensions concerning hard and soft tissue. The velum length was reduced. In the cleft group, an accumulation of mandibular retrognathia and an anterior position of the hyoid were observed. Skeletal configuration and type of growth were predominantly vertical. Conclusions. Our data provides a fundamental radiological analysis of the nasopharyngeal development in cleft patients. It confirms the lateral cephalogram as a basic diagnostic device in the analysis of nasopharyngeal and skeletal growth in cleft patients. PMID- 22523496 TI - IgG4-Related Perineural Disease. AB - Aims. To elucidate characteristics of IgG4-related disease involving the peripheral nervous system. Methods. Retrospective review of 106 patients with IgG4-related disease identified 21 peripheral nerve lesions in 7 patients. Clinicopathological and radiological features were examined. Results. Peripheral nerve lesions were commonly identified in orbital or paravertebral area, involving orbital (n = 9), optic (n = 4), spinal (n = 7), and great auricular nerves (n = 1). The predominant radiological feature was a distinct perineural soft tissue mass, ranging 8 to 30 mm in diameter. Histologically, the epineurium was preferentially involved by massive lymphoplasmacytic infiltration rich in IgG4(+) plasma cells. All lesions were neurologically asymptomatic and steroid responsive at the first presentation, but one recurrent lesion around the optic nerve caused failing vision. Conclusion. IgG4-related disease of the peripheral nervous system is characterized by orbital or paravertebral localization, perineural mass formation, and rare neurologic symptoms. The term "IgG4-related perineural disease" seems appropriate to describe this entity. PMID- 22523497 TI - A predictive spatial model to quantify the risk of air-travel-associated dengue importation into the United States and europe. AB - The number of travel-acquired dengue infections has been on a constant rise in the United States and Europe over the past decade. An increased volume of international passenger air traffic originating from regions with endemic dengue contributes to the increasing number of dengue cases. This paper reports results from a network-based regression model which uses international passenger travel volumes, travel distances, predictive species distribution models (for the vector species), and infection data to quantify the relative risk of importing travel acquired dengue infections into the US and Europe from dengue-endemic regions. Given the necessary data, this model can be used to identify optimal locations (origin cities, destination airports, etc.) for dengue surveillance. The model can be extended to other geographical regions and vector-borne diseases, as well as other network-based processes. PMID- 22523498 TI - Investigation of Association between Susceptibility to Leprosy and SNPs inside and near the BCHE Gene of Butyrylcholinesterase. AB - Leprosy is a chronic disease caused by Mycobacterium leprae and affects the skin and the peripheral nervous system. Butyrylcholinesterase is coded by the BCHE gene, and the atypical allele (70G; rs1799807) has been investigated as a leprosy risk factor, with conflicting results. The present study estimated the frequencies of variants of rs1799807 and of five additional SNPs at the BCHE gene or near it: rs1126680, rs1803274, rs2863381, rs4440084, and rs4387996. A total of 167 patients and 150 healthy controls were genotyped by TaqMan PCR. Significantly higher allelic (70G) and genotypic (70DG) frequencies in rs1799807 were found in the patient group, with odds ratio (OR) of 6.33 (1.40 to 28.53) for the heterozygote. This finding was replicated in a comparison of the cases against a control group of 361 blood donors. The present data suggest that the atypical BChE variant may predispose to leprosy per se. PMID- 22523499 TI - Therapy of chagas disease: implications for levels of prevention. AB - This paper reviews the evidence supporting the use of etiological treatment for Chagas disease that has changed the standard of care for patients with Trypanosoma cruzi infection in the last decades. Implications of this evidence on different levels of prevention as well as gaps in current knowledge are also discussed. In this regard, etiological treatment has shown to be beneficial as an intervention for secondary prevention to successfully cure the infection or to delay, reduce, or prevent the progression to disease, and as primary disease prevention by breaking the chain of transmission. Timely diagnosis during initial stages would allow for the prescription of appropriate therapies mainly in the primary health care system thus improving chances for a better quality of life. Based on current evidence, etiological treatment has to be considered as an essential public health strategy useful to reduce disease burden and to eliminate Chagas disease altogether. PMID- 22523500 TI - Geographic distribution of chagas disease vectors in Brazil based on ecological niche modeling. AB - Although Brazil was declared free from Chagas disease transmission by the domestic vector Triatoma infestans, human acute cases are still being registered based on transmission by native triatomine species. For a better understanding of transmission risk, the geographic distribution of Brazilian triatomines was analyzed. Sixteen out of 62 Brazilian species that both occur in >20 municipalities and present synanthropic tendencies were modeled based on their ecological niches. Panstrongylus geniculatus and P. megistus showed broad ecological ranges, but most of the species sort out by the biome in which they are distributed: Rhodnius pictipes and R. robustus in the Amazon; R. neglectus, Triatoma sordida, and T. costalimai in the Cerrado; R. nasutus, P. lutzi, T. brasiliensis, T. pseudomaculata, T. melanocephala, and T. petrocchiae in the Caatinga; T. rubrovaria in the southern pampas; T. tibiamaculata and T. vitticeps in the Atlantic Forest. Although most occurrences were recorded in open areas (Cerrado and Caatinga), our results show that all environmental conditions in the country are favorable to one or more of the species analyzed, such that almost nowhere is Chagas transmission risk negligible. PMID- 22523501 TI - Immunolocalization of NLRP3 Inflammasome in Normal Murine Airway Epithelium and Changes following Induction of Ovalbumin-Induced Airway Inflammation. AB - Little is known about innate immunity and components of inflammasomes in airway epithelium. This study evaluated immunohistological evidence for NLRP3 inflammasomes in normal and inflamed murine (Balb/c) airway epithelium in a model of ovalbumin (OVA) induced allergic airway inflammation. The airway epithelium of control mice exhibited strong cytoplasmic staining for total caspase-1, ASC, and NLRP3, whereas the OVA mice exhibited strong staining for active caspase-1, with redistribution of caspase-1, IL-1beta and IL-18, indicating possible activation of the NLRP3 inflammasome. Active caspase-1, NLRP3, and other inflammasome components were also detected in tissue eosinophils from OVA mice, and may potentially contribute to IL-1beta and IL-18 production. In whole lung, inRNA expression of NAIP and procaspase-1 was increased in OVA mice, whereas NLRP3, IL 1beta and IL-18 decreased. Some OVA-treated mice also had significantly elevated and tightly correlated serum levels of IL-1beta and TNFalpha. In cultured normal human bronchial epithelial cells, LPS priming resulted in a significant increase in NLRP3 and II-lp protein expression. This study is the first to demonstrate NLRP3 inflammasome components in normal airway epithelium and changes with inflammation. We propose activation and/or luminal release of the inflammasome is a feature of allergic airway inflammation which may contribute to disease pathogenesis. PMID- 22523502 TI - Role of Allergen Source-Derived Proteases in Sensitization via Airway Epithelial Cells. AB - Protease activity is a characteristic common to many allergens. Allergen source derived proteases interact with lung epithelial cells, which are now thought to play vital roles in both innate and adaptive immune responses. Allergen source derived proteases act on airway epithelial cells to induce disruption of the tight junctions between epithelial cells, activation of protease-activated receptor-2, and the production of thymic stromal lymphopoietin. These facilitate allergen delivery across epithelial layers and enhance allergenicity or directly activate the immune system through a nonallergic mechanism. Furthermore, they cleave regulatory cell surface molecules involved in allergic reactions. Thus, allergen source-derived proteases are a potentially critical factor in the development of allergic sensitization and appear to be strongly associated with heightened allergenicity. PMID- 22523503 TI - Associations between safety from crime, cycling, and obesity in a Dutch elderly population: results from the Longitudinal Aging Study Amsterdam. AB - The objective of this cross-sectional study was to investigate differences in associations between crime rates, cycling, and weight status between people living in low and high socioeconomic status (SES) neighbourhoods. In total, 470 participants in the Longitudinal Aging Study Amsterdam were included (age: 63-70 y). Body height and weight were measured using a stadiometer and calibrated weight scale, respectively. Cycling behaviour was assessed in a face-to-face interview, and neighbourhood crime rates were assessed using data from police reports. Men residing in high SES neighbourhoods cycled more than males residing in low SES neighbourhoods. Cycling was negatively related to crime rates among both men and women living in low SES neighbourhoods. Among men living in low SES neighbourhoods, more cycling was associated with lower BMI. Interventions aiming to prevent obesity in older people may consider aiming at increasing bicycle use in lower SES neighbourhoods, but neighbourhood safety issues should be considered. PMID- 22523504 TI - Air pollution, oxidative stress, and Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common form of dementia affecting millions of people worldwide and will continue to affect millions more with population aging on the rise. AD causality is multifactorial. Known causal factors include genetic predisposition, age, and sex. Environmental toxins such as air pollution (AP) have also been implicated in AD causation. Exposure to AP can lead to chronic oxidative stress (OS), which is involved in the pathogenesis of AD. Whereas AP plays a role in AD pathology, the epidemiological evidence for this association is limited. Given the significant prevalence of AP exposure combined with increased population aging, epidemiological evidence for this link is important to consider. In this paper, we examine the existing evidence supporting the relationship between AP, OS, and AD and provide recommendations for future research on the population level, which will provide evidence in support of public health interventions. PMID- 22523505 TI - Efficacy of sublingual immunotherapy versus subcutaneous injection immunotherapy in allergic patients. AB - While it is generally accepted that Subcutaneous Injection Immunotherapy (SCIT) and Sublingual Immunotherapy (SLIT) are both efficacious, there is not yet a significant amount of information regarding their comparative efficacy. In this paper, we performed a retrospective chart review and compared treatment results in two groups of patients (both with nasal allergies with or without asthma) that were treated either with SCIT or SLIT. Both treatment modalities were found to be of similar efficacy. PMID- 22523506 TI - Comparison of size and geography of airborne tungsten particles in Fallon, Nevada, and Sweet Home, Oregon, with implications for public health. AB - To improve understanding of possible connections between airborne tungsten and public health, size and geography of airborne tungsten particles collected in Fallon, Nevada, and Sweet Home, Oregon, were compared. Both towns have industrial tungsten facilities, but only Fallon has experienced a cluster of childhood leukemia. Fallon and Sweet Home are similar to one another by their particles of airborne tungsten being generally small in size. Meteorologically, much, if not most, of residential Fallon is downwind of its hard metal facility for at least some fraction of time at the annual scale, whereas little of residential Sweet Home is downwind of its tungsten facility. Geographically, most Fallon residents potentially spend time daily within an environment containing elevated levels of airborne tungsten. In contrast, few Sweet Home residents potentially spend time daily within an airborne environment with elevated levels of airborne tungsten. Although it cannot be concluded from environmental data alone that elevated airborne tungsten causes childhood leukemia, the lack of excessive cancer in Sweet Home cannot logically be used to dismiss the possibility of airborne tungsten as a factor in the cluster of childhood leukemia in Fallon. Detailed modeling of all variables affecting airborne loadings of heavy metals would be needed to legitimately compare human exposures to airborne tungsten in Fallon and Sweet Home. PMID- 22523507 TI - Solar radiation and vitamin D: mitigating environmental factors in autoimmune disease. AB - This paper looks at the environmental role of vitamin D and solar radiation as risk reduction factors in autoimmune disease. Five diseases are considered: multiple sclerosis, type 1 diabetes, rheumatoid arthritis, autoimmune disease of the thyroid, and inflammatory bowel disease. Clinical relevant studies and factors that may indicate evidence that autoimmune disease is a vitamin D sensitive disease are presented. Studies that have resulted in prevention or amelioration of some autoimmune disease are discussed. An example of the utility of supplementing vitamin D in an unusual autoimmune disease, idiopathic thrombocytic purpura, is presented. PMID- 22523508 TI - Pitfalls in using electrophysiological studies to diagnose neuromuscular disorders. AB - Electrodiagnostic testing is used widely for the full characterization of neuromuscular disorders and for providing unique information on the processes underlying the pathology of peripheral nerves and muscles. However, such testing should be considered as an extension of anamnesis and physical examination, not as pathognomonic of a specific disease entity. There are many pitfalls that could lead to erroneous interpretation of electrophysiological study results when the studies are not performed properly or if they are performed in the presence of anatomical aberrations. The diagnostic reliability of electrodiagnostic studies can be improved and the associated pitfalls overcome if the physician is familiar with all of those possible pitfalls. In this article we discuss the most common and important pitfalls associated with electrodiagnostic medicine. PMID- 22523509 TI - Drug-induced parkinsonism. AB - Drug-induced parkinsonism (DIP) is the second-most-common etiology of parkinsonism in the elderly after Parkinson's disease (PD). Many patients with DIP may be misdiagnosed with PD because the clinical features of these two conditions are indistinguishable. Moreover, neurological deficits in patients with DIP may be severe enough to affect daily activities and may persist for long periods of time after the cessation of drug taking. In addition to typical antipsychotics, DIP may be caused by gastrointestinal prokinetics, calcium channel blockers, atypical antipsychotics, and antiepileptic drugs. The clinical manifestations of DIP are classically described as bilateral and symmetric parkinsonism without tremor at rest. However, about half of DIP patients show asymmetrical parkinsonism and tremor at rest, making it difficult to differentiate DIP from PD. The pathophysiology of DIP is related to drug-induced changes in the basal ganglia motor circuit secondary to dopaminergic receptor blockade. Since these effects are limited to postsynaptic dopaminergic receptors, it is expected that presynaptic dopaminergic neurons in the striatum will be intact. Dopamine transporter (DAT) imaging is useful for diagnosing presynaptic parkinsonism. DAT uptake in the striatum is significantly decreased even in the early stage of PD, and this characteristic may help in differentiating PD from DIP. DIP may have a significant and longstanding effect on patients' daily lives, and so physicians should be cautious when prescribing dopaminergic receptor blockers and should monitor patients' neurological signs, especially for parkinsonism and other movement disorders. PMID- 22523510 TI - Clinical utility of interictal high-frequency oscillations recorded with subdural macroelectrodes in partial epilepsy. AB - BACKGROUND AND PURPOSE: There is growing interest in high-frequency oscillations (HFO) as electrophysiological biomarkers of the epileptic brain. We evaluated the clinical utility of interictal HFO events, especially their occurrence rates, by comparing the spatial distribution with a clinically determined epileptogenic zone by using subdural macroelectrodes. METHODS: We obtained intracranial electroencephalogram data with a high temporal resolution (2000 Hz sampling rate, 0.05-500 Hz band-pass filter) from seven patients with medically refractory epilepsy. Three epochs of 5-minute, artifact-free data were selected randomly from the interictal period. HFO candidates were first detected by an automated algorithm and subsequently screened to discard false detections. Validated events were further categorized as fast ripple (FR) and ripple (R) according to their spectral profiles. The occurrence rate of HFOs was calculated for each electrode contact. An HFO events distribution map (EDM) was constructed for each patient to allow visualization of the spatial distribution of their HFO events. RESULTS: The subdural macroelectrodes were capable of detecting both R and FR events from the epileptic neocortex. The occurrence rate of HFO events, both FR and R, was significantly higher in the seizure onset zone (SOZ) than in other brain regions. Patient-specific HFO EDMs can facilitate the identification of the location of HFO-generating tissue, and comparison with findings from ictal recordings can provide additional useful information regarding the epileptogenic zone. CONCLUSIONS: The distribution of interictal HFOs was reasonably consistent with the SOZ. The detection of HFO events and construction of spatial distribution maps appears to be useful for the presurgical mapping of the epileptogenic zone. PMID- 22523511 TI - Theta oscillation related to the auditory discrimination process in mismatch negativity: oddball versus control paradigm. AB - BACKGROUND AND PURPOSE: The aim of this study was to identify the mechanism underlying the auditory discriminatory process reflected in mismatch negativity (MMN), using time-frequency analysis of single-trial event-related potentials (ERPs). METHODS: Two auditory tones of different probabilities (oddball paradigm) and the same probability (control paradigm) were used. The average dynamic changes in amplitude were evaluated, and the in-phase consistency of the EEG spectrum at each frequency and time window across trials, event-related spectral perturbations (ERSPs), and inter-trial phase coherence (ITC) were computed. RESULTS: Subtraction of the ERPs of standard stimuli from the ERPs of deviant stimuli revealed a clear MMN component in the oddball paradigm. However, no discernible MMN component was observed in the control paradigm. Statistical tests showed that in the oddball paradigm, deviant tones produced significant increases of theta ERSPs and ITC at around 250 ms as compared with the standard tone, while no significant difference between the two stimuli was observed in the control paradigm. CONCLUSIONS: Our results confirm that the auditory discriminatory process reflected in MMN is accompanied by phase resetting and power modulation at the theta frequency. PMID- 22523512 TI - Medial temporal atrophy and memory dysfunction in poststroke cognitive impairment no dementia. AB - BACKGROUND AND PURPOSE: It was recently reported that the prevalence of poststroke memory dysfunction might be higher than previously thought. Stroke may exist concomitantly with underlying Alzheimer's disease (AD), and so we determined whether post-stroke memory dysfunction indicates manifestation of underlying subclinical AD. METHODS: Of 1201 patients in a prospective cognitive assessment database, we enrolled subjects with poststroke amnestic vascular cognitive impairment-no dementia (aVCIND; n=48), poststroke nonamnestic vascular cognitive impairment-no dementia (naVCIND; n=50), and nonstroke amnestic mild cognitive impairment (aMCI; n=65). All subjects had cognitive deficits, but did not meet the criteria for dementia. A standardized neuropsychological test battery and magnetic resonance imaging were performed at least 90 days after the index stroke (mean, 473 days). Visual assessment of medial temporal atrophy (MTA) was used as a measure of underlying AD pathology. RESULTS: The MTA score was significantly lower in the naVCIND group (0.64+/-0.85, mean+/-SD) than in the aVCIND (1.10+/-1.08) and aMCI (1.45+/-1.13; p<0.01) groups. Multivariable ordinal logistic regression analysis revealed that compared with naVCIND, aVCIND [odds ratio (OR)=2.69; 95% confidence interval (CI)=1.21-5.99] and aMCI (OR=5.20; 95% CI=2.41-11.23) were significantly associated with increasing severity of MTA. CONCLUSIONS: Our findings show that compared with poststroke naVCIND, the odds of having more-severe MTA were increased for poststroke aVCIND and nonstroke aMCI. PMID- 22523513 TI - Sleep-related falling out of bed in Parkinson's disease. AB - BACKGROUND AND PURPOSE: Sleep-related falling out of bed (SFOB), with its potential for significant injury, has not been a strong focus of investigation in Parkinson's disease (PD) to date. We describe the demographic and clinical characteristics of PD patients with and without SFOB. METHODS: We performed a retrospective analysis of 50 consecutive PD patients, who completed an REM sleep behavior disorder screening questionnaire (RBDSQ), questionnaires to assess for RBD clinical mimickers and questions about SFOB and resulting injuries. Determination of high risk for RBD was based on an RBDSQ score of 5 or greater. RESULTS: Thirteen patients reported history of SFOB (26%). Visual hallucinations, sleep-related injury, quetiapine and amantadine use were more common in those patients reporting SFOB. Twenty-two patients (44%) fulfilled criteria for high risk for RBD, 12 of which (55%) reported SFOB. Five patients reported injuries related to SFOB. SFOB patients had higher RBDSQ scores than non-SFOB patients (8.2+/-3.0 vs. 3.3+/-2.0, p<0.01). For every one unit increase in RBDSQ score, the likelihood of SFOB increased two-fold (OR 2.4, 95% CI 1.3-4.2, p<0.003). CONCLUSIONS: SFOB may be a clinical marker of RBD in PD and should prompt confirmatory polysomnography and pharmacologic treatment to avoid imminent injury. Larger prospective studies are needed to identify risk factors for initial and recurrent SFOB in PD. PMID- 22523514 TI - Itemized hospital charges for acute cerebral infarction patients influenced by severity in an academic medical center in Korea. AB - BACKGROUND AND PURPOSE: Stroke imposes a major burden on patients, their families, and the national healthcare system. The purpose of this study was to determine the itemized hospital charges in acute ischemic stroke patients according to their severity by partitioning the charges in detail and then examining whether stroke severity was a significant contributor to these charges. METHODS: This study analyzed data of first-time acute ischemic stroke patients who had been admitted to an academic medical center between September 2003 and April 2009. The patients' demographic and clinical characteristics were analyzed descriptively, and then eight categorized hospital charges as well as the total charge were compared among patients grouped according to stroke severity, using analysis of variance. Multiple regression analyses were conducted to test the influence of stroke severity on itemized hospital charges as well as the total charge, while controlling for other related factors. RESULTS: More-severe strokes were associated with a higher total charge. Significantly higher charges were associated with patients with more-severe strokes regarding all charged items except imaging studies. The charges for imaging studies were similar across all severities of stroke. While controlling for other factors, a significant impact of stroke severity was found in both the total hospital charge and most itemized charges. CONCLUSIONS: Itemized hospital charges for inpatients with acute ischemic stroke varied according to stroke severity. Stroke severity was a significant factor influencing the itemized charges of acute hospitalization of ischemic stroke patients. PMID- 22523515 TI - May long term oxcarbazepine treatment be lead to secondary hyperparathyroidism? AB - BACKGROUND AND PURPOSE: The adverse effects of newer antiepileptic drugs are not well-known. This study assessed the impact of oxcarbazepine (OXC) treatment on bone turnover. METHODS: Forty-four children with idiopathic focal (and/or secondarily generalized) epilepsy who had been treated with OXC for more than 1 year were compared with 33 healthy, age- and sex-matched children. Serum calcium, phosphorus, alkaline phosphatase, parathyroid hormone, osteocalcin, calcitonin, and 25-hydroxyvitamin D, and bone mineral density were measured to evaluate and compare bone mineralization between the two groups. RESULTS: The serum levels of calcium, osteocalcin, 25-hydroxyvitamin D, and bone mineral density did not differ significantly between the study and control groups. However, serum levels of parathyroid hormone, alkaline phosphatase, phosphorus, and calcitonin differed significantly between the two groups. CONCLUSIONS: These findings suggest that OXC treatment leads to secondary hyperparathyroidism with high-turnover bone disease and/or impaired intestinal calcium absorption. PMID- 22523516 TI - Personality characteristics of male sufferers of chronic tension-type and cervicogenic headache. AB - BACKGROUND AND PURPOSE: Chronic tension-type headache (a primary headache disorder) and cervicogenic headache (a secondary headache disorder that is attributable to upper cervical spine pathology) share similar clinical manifestations, but their associated personality traits may differ. We evaluated the personality differences between sufferers of chronic tension-type headache and cervicogenic headache. METHODS: We administered the Zuckerman-Kuhlman Personality Questionnaire (ZKPQ) and the Zuckerman Sensation-Seeking Scale (SSS) to 18 patients suffering from chronic tension-type headache, 19 suffering from cervicogenic headache, and 26 healthy volunteers. Depressive trends were measured with the Plutchik-van-Praag Depression Inventory (PVP). RESULTS: Compared to healthy controls, the chronic tension-type headache group scored significantly higher on ZKPQ Neuroticism-Anxiety and on the PVP, while the cervicogenic headache group scored significantly lower on SSS Thrill and Adventure Seeking. In addition, the total SSS score was significantly lower in the cervicogenic headache group than in both the chronic tension-type headache group and the healthy controls. CONCLUSIONS: The results of this study indicate that higher scores for neuroticism-anxiety and depression were associated with chronic tension-type headache, while lower sensation-seeking scores were associated with cervicogenic headache. PMID- 22523517 TI - Malignant nerve sheath tumor of the spinal accessory nerve: a unique presentation of a rare tumor. AB - BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs), sarcomas originating from tissues of mesenchymal origin, are rare in patients without a history of neurofibromatosis. CASE REPORT: We report a case of an MPNST of the spinal accessory nerve, unassociated with neurofibromatosis, which metastasized to the brain. The tumor, originating in the intrasternomastoid segment of the spinal accessory nerve, was removed. Two years later, the patient presented with focal neurological deficits. Radiographic findings revealed a well-defined 2.2*2.2*2.2 cm, homogeneously enhancing mass in the left parieto-occipital region of the brain surrounded by significant vasogenic edema and mass effect, culminating in a 1-cm midline shift to the right. The mass was surgically removed. The patient had nearly complete recovery of vision, speech, and memory. CONCLUSIONS: To our knowledge, this is the first documented case of an MPNST arising from an extracranial segment of the spinal accessory nerve and metastasizing to the brain. PMID- 22523518 TI - Meningitis caused by Streptococcus suis: case report and review of the literature. AB - BACKGROUND: Human infection with Streptococcus suis (S. suis), a zoonotic pathogen, has been reported mainly in pig-rearing and pork-consuming countries. Meningitis is the most-common clinical manifestation and is often associated with deafness and vestibular dysfunction. CASE REPORT: A 57-year-old man was referred to the hospital with headaches, fevers, chills, and hearing impairment. Meningitis was confirmed and S. suis was isolated from the cerebrospinal fluid. Spondylodiscitis occurred after 2 weeks of antibiotic treatment, and was successfully treated with a prolonged course of antibiotics for another 4 weeks. His hearing loss was irreversible despite the improvement of other symptoms. CONCLUSIONS: We report the first human case of S. suis infection in Korea. In patients presenting with meningitis, S. suis should be considered if the characteristic features of prominent and early hearing loss are present. PMID- 22523519 TI - A case of cluster headache accompanied by myoclonus and hemiparesis. AB - BACKGROUND: Cluster headache is a primary headache disorder characterized by periodic episodes of intense headache accompanied by autonomic symptoms. We report an unusual clinical presentation of cluster headache that was preceded by myoclonus and accompanied by hemiparesis. CASE REPORT: A 26-year-old man visited hospital due to recurrent jerky movements on the left side of his face and neck area lasting 3 days. These jerky movements had disappeared spontaneously without specific treatment. On the 10th day after onset of the jerky movements, the patient developed a series of unilateral severe headaches that were accompanied by autonomic symptoms lasting 1-2 hours. According to the second edition of The International Classification of Headache Disorders, he was diagnosed as having cluster headache. Two of the 16 severe headache attacks this patient suffered were accompanied by dysarthria and hemiparesis. Electroencephalography performed during hemiparesis revealed diffuse lateralized slow activity on the ipsilateral hemisphere of the headache side. The headache and accompanying hemiparesis disappeared after medical treatment for cluster headache. CONCLUSIONS: We describe a case of cluster headache accompanied by hemiparesis, which was preceded by myoclonus. We also outline the possible mechanisms underlying this case. PMID- 22523521 TI - Modeling nuclear blebs in a nucleoskeleton of independent filament networks. AB - Correlations between altered nuclear shape and disease are empirically observed, but the causes of nuclear dysmorphisms are poorly understood. The nucleoskeleton, which provides the majority of the mechanical stability of the nucleus, is composed primarily of intermediate filaments of lamin proteins. The nucleoskeleton forms a mostly-planar network between the inner nuclear membrane and chromatin. It is unclear if blebs and larger scale changes in nuclear morphology are consequences of reorganization of the nucleoskeleton alone or of other cellular processes. To test this, we computationally recapitulate the lamina network using a mechanical network model created as a network of Hookean springs. A- and B-type lamin filaments were distributed over a spherical surface into distinct networks linked to one another by lamin-associated proteins. Iterative force-based adjustment of the network structure, together with a stochastically modified Bell model of bond breakage and formation, simulates nucleoskeleton reorganization with blebs. The rate of bleb retraction into the nucleus depends on both initial size of the bleb and number of networks being deformed. Our results show that induced blebs are more stable when only one filament component is deformed or when the networks have no interconnections. Also, the kinetics of retraction is influenced by the composition of the bleb. These results match with our experiments and others. PMID- 22523522 TI - Computational knee ligament modeling using experimentally determined zero-load lengths. AB - This study presents a subject-specific method of determining the zero-load lengths of the cruciate and collateral ligaments in computational knee modeling. Three cadaver knees were tested in a dynamic knee simulator. The cadaver knees also underwent manual envelope of motion testing to find their passive range of motion in order to determine the zero-load lengths for each ligament bundle. Computational multibody knee models were created for each knee and model kinematics were compared to experimental kinematics for a simulated walk cycle. One-dimensional non-linear spring damper elements were used to represent cruciate and collateral ligament bundles in the knee models. This study found that knee kinematics were highly sensitive to altering of the zero-load length. The results also suggest optimal methods for defining each of the ligament bundle zero-load lengths, regardless of the subject. These results verify the importance of the zero-load length when modeling the knee joint and verify that manual envelope of motion measurements can be used to determine the passive range of motion of the knee joint. It is also believed that the method described here for determining zero-load length can be used for in vitro or in vivo subject-specific computational models. PMID- 22523523 TI - North-South Gradients in Adverse Birth Outcomes for First Nations and Others in Manitoba, Canada. AB - OBJECTIVE: to determine the relationship of north-south place of residence to adverse birth outcomes among First Nations and non-First Nations in Manitoba, Canada, a setting with universal health insurance. STUDY DESIGN: Live birth records (n=151,472) for the province of Manitoba, Canada 1991-2000 were analyzed, including 25,743 First Nations and 125,729 non-First Nations infants. North-south and rural-urban residence was determined for each birth through geocoding. RESULTS: Comparing First Nations to non-First Nations, crude rates in North (and South) were: 7.0% versus 8.4% (9.3% versus 7.5%) for preterm birth; 6.1% versus 8.4% (8.7% versus 10.0%) for small-for-gestational-age birth, 4.2% versus 6.5% (6.2% versus 5.7%) for low birth weight, and 20.6% versus 13.7% (17.0% versus 11.0%) for large-for-gestational-age birth; and mortality per 1000 - neonatal 3.2 versus 6.2 (3.8 versus 3.3), post-neonatal 6.4 versus 6.4 (5.8 versus 1.5), and infant 9.5 versus 12.6 (9.6 versus 4.8). Adjusting for observed maternal and infant characteristics and rural versus urban residence, the North was high risk for large-for-gestational-age birth for both First Nations and non-First Nations. First Nations' risk of preterm, small-for-gestational-age and low birth weight was lowest in the North, but for non-First Nations, the North was lower only for small-for-gestational-age. First Nations mortality indicators were similar North to South, but for non-First Nations, the North was high risk. CONCLUSION: North South place of residence does matter for adverse birth outcomes, but the effects may differ by ethnicity and could require different intervention strategies. PMID- 22523524 TI - The choice of the best surgery after single level anterior cervical spine discectomy: a systematic review. AB - BACKGROUND: The anterior cervical discectomy (ACD) is often used to treat spinal cord and nerve root compressions and the frequent use of interbody fusion (ACDF) has popularized it as a common practice associated or not with cages or plates for maintaining the intervertebral disc height. OBJECTIVE: The aim of this study is to clarify the effectiveness of ACD compared with ACDF, with or without the use of anterior cervical spacer (Cage) or instrumentation with plate fixation (ACDFI). METHODS: randomized controlled trials or quasi-randomized trials were selected for analysis in one segmental level. The comparison criteria were the rates of success and failure with surgery (Odom's' criteria), fusion rates and kyphosis rates. Electronic search was made in the MEDLINE database (Pubmed), in the Central Registry of randomized trials of Cochrane database and EMBASE. RESULTS: Seven studies were selected for analysis. CONCLUSION: IMPLICATIONS FOR PRACTICE: There is moderate evidence that clinical results of ACD and ACDF are not significant different. There is moderate evidence that addition of intervertebral cage enhance clinical results.There is moderate evidence that anterior cervical plate does not change the clinical results of ACD. There is moderate evidence that ACD produce more segmental kyphosis than ACDF and ACDFI, with use of cage or plate.There is moderate evidence that ACD produce lower rate of fusion than ACDF and than the cages. There is limited evidence of the lower capacity of PMMA to produce fusion. There is limited evidence that fused patients have better outcome than non fused patients. PMID- 22523525 TI - Essential Nutrients for Bone Health and a Review of their Availability in the Average North American Diet. AB - Osteoporosis and low bone mineral density affect millions of Americans. The majority of adults in North America have insufficient intake of vitamin D and calcium along with inadequate exercise. Physicians are aware that vitamin D, calcium and exercise are essential for maintenance of bone health. Physicians are less likely to be aware that dietary insufficiencies of magnesium, silicon, Vitamin K, and boron are also widely prevalent, and each of these essential nutrients is an important contributor to bone health. In addition, specific nutritional factors may improve calcium metabolism and bone formation. It is the authors' opinion that nutritional supplements should attempt to provide ample, but not excessive, amounts of factors that are frequently insufficient in the typical American diet.In contrast to dietary insufficiencies, several nutrients that support bone health are readily available in the average American diet. These include zinc, manganese, and copper which may have adverse effects at higher levels of intake. Some multivitamins and bone support products provide additional quantities of nutrients that may be unnecessary or potentially harmful.The purpose of this paper is to identify specific nutritional components of bone health, the effects on bone, the level of availability in the average American diet, and the implications of supplementation for each nutritional component. A summary of recommended dietary supplementation is included. PMID- 22523526 TI - Cryopreservation effect on proliferative and chondrogenic potential of human chondrocytes isolated from superficial and deep cartilage. AB - OBJECTIVES: To compare the proliferative and chondrogenic potential of fresh and frozen chondrocytes isolated from superficial and deep articular cartilage biopsies. MATERIALS AND METHODOLOGY: The study included 12 samples of fresh and frozen healthy human knee articular cartilage. Cell proliferation was tested at 3, 6 and 9 days. Studies of mRNA quantification, protein expression and immunofluorescence for proliferation and chondrogenic markers were performed. RESULTS: Stimulation of fresh and frozen chondrocytes from both superficial and deep cartilage with fetal bovine serum produced an increase in the proliferative capacity compared to the non-stimulated control group. In the stimulated fresh cells group, the proliferative capacity of cells from the deep biopsy was greater than that from cells from the superficial biopsy (0.046 vs 0.028, respectively, p<0.05). There was also a significant difference between the proliferative capacity of superficial zone fresh (0.028) and frozen (0.051) chondrocytes (p<0.05). CCND1 mRNA and protein expression levels, and immunopositivity for Ki67 revealed a higher proliferative capacity for fresh articular chondrocytes from deep cartilage. Regarding the chondrogenic potential, stimulated fresh cells showed higher SOX9 and Col II expression in chondrocytes from deep than from superficial zone (p<0.05, T student test). CONCLUSIONS: The highest rate of cell proliferation and chondrogenic potential of fresh chondrocytes was found in cells obtained from deep cartilage biopsies, whereas there were no statistically significant differences in proliferative and chondrogenic capacity between biopsy origins with frozen chondrocytes. These results indicate that both origin and cryopreservation affect the proliferative and chondrogenic potential of chondrocytes. PMID- 22523527 TI - The organ transplant symptom and well-being instrument - psychometric evaluation. AB - BACKGROUND: There is a need for instruments combining measurements of symptom distress and well-being in the organ transplant population. OBJECTIVES: The aim of this study was to describe the development and initial psychometric evaluation of a measure of symptoms and well-being in organ transplant recipients labelled the Organ Transplant Symptom and Well-being instrument (OTSWI) and to provide descriptive data on these matters. METHOD: In this cross sectional survey, the study sample (n=185) completed several measures including demographic information, the Short form- 36 items (SF-36), and the OTSWI to assess concurrent validity by exploring relationships between OTSWI and measures of health related quality of life (HRQOL). The expected scale dimensionality of the OTSWI questionnaire was examined both by the confirmatory multi-trait analysis program and by explorative principal component analysis (with oblique, varimax rotation). Scale reliability was further estimated using the Cronbach's alpha. RESULTS: There were eight factors built up from twenty of the initial fifty one items and were labelled fatigue, joint and muscle pain, cognitive functioning, basic activities in daily life, sleeping problems, mood, foot pain and economy. For the remaining twenty-one items no consistent and meaningful factors could be found leading to relevant symptoms acting as single items. All eight factors had satisfying internal convergent validity as well as good item-scale discriminatory validity or 'success rate'. DISCUSSION: Results support the internal consistency, reliability and concurrent validity of the OTSWI as an instrument to measure symptom distress and well-being in relation to organ transplantation. (Word count 244). PMID- 22523528 TI - Towards an Ecology of Collective Innovation: Human Variome Project (HVP), Rare Disease Consortium for Autosomal Loci (RaDiCAL) and Data-Enabled Life Sciences Alliance (DELSA). PMID- 22523529 TI - ENCODING AND DECODING V1 FMRI RESPONSES TO NATURAL IMAGES WITH SPARSE NONPARAMETRIC MODELS. AB - Functional MRI (fMRI) has become the most common method for investigating the human brain. However, fMRI data present some complications for statistical analysis and modeling. One recently developed approach to these data focuses on estimation of computational encoding models that describe how stimuli are transformed into brain activity measured in individual voxels. Here we aim at building encoding models for fMRI signals recorded in the primary visual cortex of the human brain. We use residual analyses to reveal systematic nonlinearity across voxels not taken into account by previous models. We then show how a sparse nonparametric method [bJ. Roy. Statist. Soc. Ser. B71 (2009b) 1009-1030] can be used together with correlation screening to estimate nonlinear encoding models effectively. Our approach produces encoding models that predict about 25% more accurately than models estimated using other methods [Nature452 (2008a) 352 355]. The estimated nonlinearity impacts the inferred properties of individual voxels, and it has a plausible biological interpretation. One benefit of quantitative encoding models is that estimated models can be used to decode brain activity, in order to identify which specific image was seen by an observer. Encoding models estimated by our approach also improve such image identification by about 12% when the correct image is one of 11,500 possible images. PMID- 22523531 TI - Correction: Sensory coding by cerebellar mossy fibres through inhibition-driven phase resetting and synchronisation. AB - [This corrects the article on p. e26503 in vol. 6.]. PMID- 22523530 TI - Glutaredoxin-1 overexpression enhances neovascularization and diminishes ventricular remodeling in chronic myocardial infarction. AB - Oxidative stress plays a critical role in the pathophysiology of cardiac failure, including the modulation of neovascularization following myocardial infarction (MI). Redox molecules thioredoxin (Trx) and glutaredoxin (Grx) superfamilies actively maintain intracellular thiol-redox homeostasis by scavenging reactive oxygen species. Among these two superfamilies, the pro-angiogenic function of Trx 1 has been reported in chronic MI model whereas similar role of Grx-1 remains uncertain. The present study attempts to establish the role of Grx-1 in neovascularization and ventricular remodeling following MI. Wild-type (WT) and Grx-1 transgenic (Grx-1(Tg/+)) mice were randomized into wild-type sham (WTS), Grx-1(Tg/+) Sham (Grx-1(Tg/+)S), WTMI, Grx-1(Tg/+)MI. MI was induced by permanent occlusion of the LAD coronary artery. Sham groups underwent identical time matched surgical procedures without LAD ligation. Significant increase in arteriolar density was observed 7 days (d) after surgical intervention in the Grx 1(Tg/+)MI group as compared to the WTMI animals. Further, improvement in myocardial functional parameters 30 d after MI was observed including decreased LVIDs, LVIDd, increased ejection fraction and, fractional shortening was also observed in the Grx-1(Tg/+)MI group as compared to the WTMI animals. Moreover, attenuation of oxidative stress and apoptotic cardiomyocytes was observed in the Grx-1(Tg/+)MI group as compared to the WTMI animals. Increased expression of p Akt, VEGF, Ang-1, Bcl-2, survivin and DNA binding activity of NF-kappaB were observed in the Grx-1(Tg/+)MI group when compared to WTMI animals as revealed by Western blot analysis and Gel-shift analysis, respectively. These results are the first to demonstrate that Grx-1 induces angiogenesis and diminishes ventricular remodeling apparently through neovascularization mediated by Akt, VEGF, Ang-1 and NF-kappaB as well as Bcl-2 and survivin-mediated anti-apoptotic pathway in the infarcted myocardium. PMID- 22523532 TI - Caloric restriction alters the metabolic response to a mixed-meal: results from a randomized, controlled trial. AB - OBJECTIVES: To determine if caloric restriction (CR) would cause changes in plasma metabolic intermediates in response to a mixed meal, suggestive of changes in the capacity to adapt fuel oxidation to fuel availability or metabolic flexibility, and to determine how any such changes relate to insulin sensitivity (S(I)). METHODS: Forty-six volunteers were randomized to a weight maintenance diet (Control), 25% CR, or 12.5% CR plus 12.5% energy deficit from structured aerobic exercise (CR+EX), or a liquid calorie diet (890 kcal/d until 15% reduction in body weight)for six months. Fasting and postprandial plasma samples were obtained at baseline, three, and six months. A targeted mass spectrometry based platform was used to measure concentrations of individual free fatty acids (FFA), amino acids (AA), and acylcarnitines (AC). S(I) was measured with an intravenous glucose tolerance test. RESULTS: Over three and six months, there were significantly larger differences in fasting-to-postprandial (FPP) concentrations of medium and long chain AC (byproducts of FA oxidation) in the CR relative to Control and a tendency for the same in CR+EX (CR-3 month P = 0.02; CR 6 month P = 0.002; CR+EX-3 month P = 0.09; CR+EX-6 month P = 0.08). After three months of CR, there was a trend towards a larger difference in FPP FFA concentrations (P = 0.07; CR-3 month P = 0.08). Time-varying differences in FPP concentrations of AC and AA were independently related to time-varying S(I) (P<0.05 for both). CONCLUSIONS: Based on changes in intermediates of FA oxidation following a food challenge, CR imparted improvements in metabolic flexibility that correlated with improvements in S(I). TRIAL REGISTRATION: ClinicalTrials.gov NCT00099151. PMID- 22523533 TI - A cortical attractor network with Martinotti cells driven by facilitating synapses. AB - The population of pyramidal cells significantly outnumbers the inhibitory interneurons in the neocortex, while at the same time the diversity of interneuron types is much more pronounced. One acknowledged key role of inhibition is to control the rate and patterning of pyramidal cell firing via negative feedback, but most likely the diversity of inhibitory pathways is matched by a corresponding diversity of functional roles. An important distinguishing feature of cortical interneurons is the variability of the short term plasticity properties of synapses received from pyramidal cells. The Martinotti cell type has recently come under scrutiny due to the distinctly facilitating nature of the synapses they receive from pyramidal cells. This distinguishes these neurons from basket cells and other inhibitory interneurons typically targeted by depressing synapses. A key aspect of the work reported here has been to pinpoint the role of this variability. We first set out to reproduce quantitatively based on in vitro data the di-synaptic inhibitory microcircuit connecting two pyramidal cells via one or a few Martinotti cells. In a second step, we embedded this microcircuit in a previously developed attractor memory network model of neocortical layers 2/3. This model network demonstrated that basket cells with their characteristic depressing synapses are the first to discharge when the network enters an attractor state and that Martinotti cells respond with a delay, thereby shifting the excitation-inhibition balance and acting to terminate the attractor state. A parameter sensitivity analysis suggested that Martinotti cells might, in fact, play a dominant role in setting the attractor dwell time and thus cortical speed of processing, with cellular adaptation and synaptic depression having a less prominent role than previously thought. PMID- 22523534 TI - Impairment of the bacterial biofilm stability by triclosan. AB - The accumulation of the widely-used antibacterial and antifungal compound triclosan (TCS) in freshwaters raises concerns about the impact of this harmful chemical on the biofilms that are the dominant life style of microorganisms in aquatic systems. However, investigations to-date rarely go beyond effects at the cellular, physiological or morphological level. The present paper focuses on bacterial biofilms addressing the possible chemical impairment of their functionality, while also examining their substratum stabilization potential as one example of an important ecosystem service. The development of a bacterial assemblage of natural composition--isolated from sediments of the Eden Estuary (Scotland, UK)--on non-cohesive glass beads (<63 um) and exposed to a range of triclosan concentrations (control, 2-100 ug L(-1)) was monitored over time by Magnetic Particle Induction (MagPI). In parallel, bacterial cell numbers, division rate, community composition (DGGE) and EPS (extracellular polymeric substances: carbohydrates and proteins) secretion were determined. While the triclosan exposure did not prevent bacterial settlement, biofilm development was increasingly inhibited by increasing TCS levels. The surface binding capacity (MagPI) of the assemblages was positively correlated to the microbial secreted EPS matrix. The EPS concentrations and composition (quantity and quality) were closely linked to bacterial growth, which was affected by enhanced TCS exposure. Furthermore, TCS induced significant changes in bacterial community composition as well as a significant decrease in bacterial diversity. The impairment of the stabilization potential of bacterial biofilm under even low, environmentally relevant TCS levels is of concern since the resistance of sediments to erosive forces has large implications for the dynamics of sediments and associated pollutant dispersal. In addition, the surface adhesive capacity of the biofilm acts as a sensitive measure of ecosystem effects. PMID- 22523536 TI - Housekeeping mutualisms: do more symbionts facilitate host performance? AB - Mutualisms often involve one host supporting multiple symbionts, whose identity, density and intraguild interactions can influence the nature of the mutualism and performance of the host. However, the implications of multiple co-occurring symbionts on services to a host have rarely been quantified. In this study, we quantified effects of decapod symbionts on removal of sediment from their coral host. Our field survey showed that all common symbionts typically occur as pairs and never at greater abundances. Two species, the crab Trapezia serenei and the shrimp Alpheus lottini, were most common and co-occurred more often than expected by chance. We conducted a mesocosm experiment to test for effects of decapod identity and density on sediment removal. Alone, corals removed 10% of sediment, but removal increased to 30% and 48% with the presence of two and four symbionts, respectively. Per-capita effects of symbionts were independent of density and identity. Our results suggest that symbiont density is restricted by intraspecific competition. Thus, increased sediment removal from a coral host can only be achieved by increasing the number of species of symbionts on that coral, even though these species are functionally equivalent. Symbiont diversity plays a key role, not through added functionality but by overcoming density limitation likely imposed by intraspecific mating systems. PMID- 22523535 TI - Binding properties and stability of the Ras-association domain of Rap1-GTP interacting adapter molecule (RIAM). AB - The Rap1-GTP interacting adapter protein (RIAM) is an important protein in Rap1 mediated integrin activation. By binding to both Rap1 GTPase and talin, RIAM recruits talin to the cell membrane, thus facilitating talin-dependent integrin activation. In this article, we studied the role of the RIAM Ras-association (RA) and pleckstrin-homology (PH) domains in the interaction with Rap1. We found that the RA domain was sufficient for GTP-dependent interaction with Rap1B, and the addition of the PH domain did not change the binding affinity. We also detected GTP-independent interaction of Rap1B with the N-terminus of RIAM. In addition, we found that the PH domain stabilized the RA domain both in vitro and in cells. PMID- 22523537 TI - The impact of errors in copy number variation detection algorithms on association results. AB - The inaccuracy of copy number variation (CNV) detection on single nucleotide polymorphism (SNP) arrays has recently been brought to attention. Such high error rates will undoubtedly have ramifications on downstream association testing. We examined this effect for a wide range of scenarios and found a noticeable decrease in power for error rates typical of CNV calling algorithms. We compared power using CNV calls to the log relative ratio and found the latter to be superior when error rates are moderate to large or when the CNV size is small. It is our recommendation that CNV researchers use intensity measurements as an alternative to CNV calls in these scenarios. PMID- 22523538 TI - Nemitin, a novel Map8/Map1s interacting protein with Wd40 repeats. AB - In neurons, a highly regulated microtubule cytoskeleton is essential for many cellular functions. These include axonal transport, regional specialization and synaptic function. Given the critical roles of microtubule-associated proteins (MAPs) in maintaining and regulating microtubule stability and dynamics, we sought to understand how this regulation is achieved. Here, we identify a novel LisH/WD40 repeat protein, tentatively named nemitin (neuronal enriched MAP interacting protein), as a potential regulator of MAP8-associated microtubule function. Based on expression at both the mRNA and protein levels, nemitin is enriched in the nervous system. Its protein expression is detected as early as embryonic day 11 and continues through adulthood. Interestingly, when expressed in non-neuronal cells, nemitin displays a diffuse pattern with puncta, although at the ultrastructural level it localizes along the microtubule network in vivo in sciatic nerves. These results suggest that the association of nemitin to microtubules may require an intermediary protein. Indeed, co-expression of nemitin with microtubule-associated protein 8 (MAP8) results in nemitin losing its diffuse pattern, instead decorating microtubules uniformly along with MAP8. Together, these results imply that nemitin may play an important role in regulating the neuronal cytoskeleton through an interaction with MAP8. PMID- 22523539 TI - Classification and lateralization of temporal lobe epilepsies with and without hippocampal atrophy based on whole-brain automatic MRI segmentation. AB - Brain images contain information suitable for automatically sorting subjects into categories such as healthy controls and patients. We sought to identify morphometric criteria for distinguishing controls (n = 28) from patients with unilateral temporal lobe epilepsy (TLE), 60 with and 20 without hippocampal atrophy (TLE-HA and TLE-N, respectively), and for determining the presumed side of seizure onset. The framework employs multi-atlas segmentation to estimate the volumes of 83 brain structures. A kernel-based separability criterion was then used to identify structures whose volumes discriminate between the groups. Next, we applied support vector machines (SVM) to the selected set for classification on the basis of volumes. We also computed pairwise similarities between all subjects and used spectral analysis to convert these into per-subject features. SVM was again applied to these feature data. After training on a subgroup, all TLE-HA patients were correctly distinguished from controls, achieving an accuracy of 96 +/- 2% in both classification schemes. For TLE-N patients, the accuracy was 86 +/- 2% based on structural volumes and 91 +/- 3% using spectral analysis. Structures discriminating between patients and controls were mainly localized ipsilaterally to the presumed seizure focus. For the TLE-HA group, they were mainly in the temporal lobe; for the TLE-N group they included orbitofrontal regions, as well as the ipsilateral substantia nigra. Correct lateralization of the presumed seizure onset zone was achieved using hippocampi and parahippocampal gyri in all TLE-HA patients using either classification scheme; in the TLE-N patients, lateralization was accurate based on structural volumes in 86 +/- 4%, and in 94 +/- 4% with the spectral analysis approach. Unilateral TLE has imaging features that can be identified automatically, even when they are invisible to human experts. Such morphometric image features may serve as classification and lateralization criteria. The technique also detects unsuspected distinguishing features like the substantia nigra, warranting further study. PMID- 22523540 TI - Polysaccharides from wolfberry prevents corticosterone-induced inhibition of sexual behavior and increases neurogenesis. AB - Lycium barbarum, commonly known as wolfberry, has been used as a traditional Chinese medicine for the treatment of infertility and sexual dysfunction. However, there is still a scarcity of experimental evidence to support the pro sexual effect of wolfberry. The aim of this study is to determine the effect of Lycium barbarum polysaccharides (LBP) on male sexual behavior of rats. Here we report that oral feeding of LBP for 21 days significantly improved the male copulatory performance including increase of copulatory efficiency, increase of ejaculation frequency and shortening of ejaculation latency. Furthermore, sexual inhibition caused by chronic corticosterone was prevented by LBP. Simultaneously, corticosterone suppressed neurogenesis in subventricular zone and hippocampus in adult rats, which could be reversed by LBP. The neurogenic effect of LBP was also shown in vitro. Significant correlation was found between neurogenesis and sexual performance, suggesting that the newborn neurons are associated with reproductive successfulness. Blocking neurogenesis in male rats abolished the pro-sexual effect of LBP. Taken together, these results demonstrate the pro-sexual effect of LBP on normal and sexually-inhibited rats, and LBP may modulate sexual behavior by regulating neurogenesis. PMID- 22523541 TI - The nanostructure of myoendothelial junctions contributes to signal rectification between endothelial and vascular smooth muscle cells. AB - Micro-anatomical structures in tissues have potential physiological effects. In arteries and arterioles smooth muscle cells and endothelial cells are separated by the internal elastic lamina, but the two cell layers often make contact through micro protrusions called myoendothelial junctions. Cross talk between the two cell layers is important in regulating blood pressure and flow. We have used a spatiotemporal mathematical model to investigate how the myoendothelial junctions affect the information flow between the two cell layers. The geometry of the model mimics the structure of the two cell types and the myoendothelial junction. The model is implemented as a 2D axi-symmetrical model and solved using the finite element method. We have simulated diffusion of Ca(2+) and IP(3) between the two cell types and we show that the micro-anatomical structure of the myoendothelial junction in itself may rectify a signal between the two cell layers. The rectification is caused by the asymmetrical structure of the myoendothelial junction. Because the head of the myoendothelial junction is separated from the cell it is attached to by a narrow neck region, a signal generated in the neighboring cell can easily drive a concentration change in the head of the myoendothelial protrusion. Subsequently the signal can be amplified in the head, and activate the entire cell. In contrast, a signal in the cell from which the myoendothelial junction originates will be attenuated and delayed in the neck region as it travels into the head of the myoendothelial junction and the neighboring cell. PMID- 22523542 TI - Panax ginseng modulates cytokines in bone marrow toxicity and myelopoiesis: ginsenoside Rg1 partially supports myelopoiesis. AB - In this study, we have demonstrated that Korean Panax ginseng (KG) significantly enhances myelopoiesis in vitro and reconstitutes bone marrow after 5-flurouracil induced (5FU) myelosuppression in mice. KG promoted total white blood cell, lymphocyte, neutrophil and platelet counts and improved body weight, spleen weight, and thymus weight. The number of CFU-GM in bone marrow cells of mice and serum levels of IL-3 and GM-CSF were significantly improved after KG treatment. KG induced significant c-Kit, SCF and IL-1 mRNA expression in spleen. Moreover, treatment with KG led to marked improvements in 5FU-induced histopathological changes in bone marrow and spleen, and partial suppression of thymus damage. The levels of IL-3 and GM-CSF in cultured bone marrow cells after 24 h stimulation with KG were considerably increased. The mechanism underlying promotion of myelopoiesis by KG was assessed by monitoring gene expression at two time-points of 4 and 8 h. Treatment with Rg1 (0.5, 1 and 1.5 umol) specifically enhanced c Kit, IL-6 and TNF-alpha mRNA expression in cultured bone marrow cells. Our results collectively suggest that the anti-myelotoxicity activity and promotion of myelopoiesis by KG are mediated through cytokines. Moreover, the ginsenoside, Rg1, supports the role of KG in myelopoiesis to some extent. PMID- 22523543 TI - Cost analysis of various low pathogenic avian influenza surveillance systems in the Dutch egg layer sector. AB - BACKGROUND: As low pathogenic avian influenza viruses can mutate into high pathogenic viruses the Dutch poultry sector implemented a surveillance system for low pathogenic avian influenza (LPAI) based on blood samples. It has been suggested that egg yolk samples could be sampled instead of blood samples to survey egg layer farms. To support future decision making about AI surveillance economic criteria are important. Therefore a cost analysis is performed on systems that use either blood or eggs as sampled material. METHODOLOGY/PRINCIPAL FINDINGS: The effectiveness of surveillance using egg or blood samples was evaluated using scenario tree models. Then an economic model was developed that calculates the total costs for eight surveillance systems that have equal effectiveness. The model considers costs for sampling, sample preparation, sample transport, testing, communication of test results and for the confirmation test on false positive results. The surveillance systems varied in sampled material (eggs or blood), sampling location (farm or packing station) and location of sample preparation (laboratory or packing station). It is shown that a hypothetical system in which eggs are sampled at the packing station and samples prepared in a laboratory had the lowest total costs (i.e. ? 273,393) a year. Compared to this a hypothetical system in which eggs are sampled at the farm and samples prepared at a laboratory, and the currently implemented system in which blood is sampled at the farm and samples prepared at a laboratory have 6% and 39% higher costs respectively. CONCLUSIONS/SIGNIFICANCE: This study shows that surveillance for avian influenza on egg yolk samples can be done at lower costs than surveillance based on blood samples. The model can be used in future comparison of surveillance systems for different pathogens and hazards. PMID- 22523544 TI - Characterization and evolution of microRNA genes derived from repetitive elements and duplication events in plants. AB - MicroRNAs (miRNAs) are a major class of small non-coding RNAs that act as negative regulators at the post-transcriptional level in animals and plants. In this study, all known miRNAs in four plant species (Arabidopsis thaliana, Populus trichocarpa, Oryza sativa and Sorghum bicolor) have been analyzed, using a combination of computational and comparative genomic approaches, to systematically identify and characterize the miRNAs that were derived from repetitive elements and duplication events. The study provides a complete mapping, at the genome scale, of all the miRNAs found on repetitive elements in the four test plant species. Significant differences between repetitive element related miRNAs and non-repeat-derived miRNAs were observed for many characteristics, including their location in protein-coding and intergenic regions in genomes, their conservation in plant species, sequence length of their hairpin precursors, base composition of their hairpin precursors and the minimum free energy of their hairpin structures. Further analysis showed that a considerable number of miRNA families in the four test plant species arose from either tandem duplication events, segmental duplication events or a combination of the two. However, comparative analysis suggested that the contribution made by these two duplication events differed greatly between the perennial tree species tested and the other three annual species. The expansion of miRNA families in A. thaliana, O. sativa and S. bicolor are more likely to occur as a result of tandem duplication events than from segmental duplications. In contrast, genomic segmental duplications contributed significantly more to the expansion of miRNA families in P. trichocarpa than did tandem duplication events. Taken together, this study has successfully characterized miRNAs derived from repetitive elements and duplication events at the genome scale and provides comprehensive knowledge and deeper insight into the origins and evolution of miRNAs in plants. PMID- 22523545 TI - CNF1 improves astrocytic ability to support neuronal growth and differentiation in vitro. AB - Modulation of cerebral Rho GTPases activity in mice brain by intracerebral administration of Cytotoxic Necrotizing Factor 1 (CNF1) leads to enhanced neurotransmission and synaptic plasticity and improves learning and memory. To gain more insight into the interactions between CNF1 and neuronal cells, we used primary neuronal and astrocytic cultures from rat embryonic brain to study CNF1 effects on neuronal differentiation, focusing on dendritic tree growth and synapse formation, which are strictly modulated by Rho GTPases. CNF1 profoundly remodeled the cytoskeleton of hippocampal and cortical neurons, which showed philopodia-like, actin-positive projections, thickened and poorly branched dendrites, and a decrease in synapse number. CNF1 removal, however, restored dendritic tree development and synapse formation, suggesting that the toxin can reversibly block neuronal differentiation. On differentiated neurons, CNF1 had a similar effacing effect on synapses. Therefore, a direct interaction with CNF1 is apparently deleterious for neurons. Since astrocytes play a pivotal role in neuronal differentiation and synaptic regulation, we wondered if the beneficial in vivo effect could be mediated by astrocytes. Primary astrocytes from embryonic cortex were treated with CNF1 for 48 hours and used as a substrate for growing hippocampal neurons. Such neurons showed an increased development of neurites, in respect to age-matched controls, with a wider dendritic tree and a richer content in synapses. In CNF1-exposed astrocytes, the production of interleukin 1beta, known to reduce dendrite development and complexity in neuronal cultures, was decreased. These results demonstrate that astrocytes, under the influence of CNF1, increase their supporting activity on neuronal growth and differentiation, possibly related to the diminished levels of interleukin 1beta. These observations suggest that the enhanced synaptic plasticity and improved learning and memory described in CNF1-injected mice are probably mediated by astrocytes. PMID- 22523546 TI - Circulating MiR-125b as a marker predicting chemoresistance in breast cancer. AB - BACKGROUND: Chemotherapy is an important component in the treatment paradigm for breast cancers. However, the resistance of cancer cells to chemotherapeutic agents frequently results in the subsequent recurrence and metastasis. Identification of molecular markers to predict treatment outcome is therefore warranted. The aim of the present study was to evaluate whether expression of circulating microRNAs (miRNAs) can predict clinical outcome in breast cancer patients treated with adjuvant chemotherapy. METHODOLOGY/PRINCIPAL FINDINGS: Circulating miRNAs in blood serum prior to treatment were determined by quantitative Real-Time PCR in 56 breast cancer patients with invasive ductal carcinoma and pre-operative neoadjuvant chemotherapy. Proliferating cell nuclear antigen (PCNA) immunostaining and TUNEL were performed in surgical samples to determine the effects of chemotherapy on cancer cell proliferation and apoptosis, respectively. Among the miRNAs tested, only miR-125b was significantly associated with therapeutic response, exhibiting higher expression level in non-responsive patients (n = 26, 46%; p = 0.008). In addition, breast cancers with high miR-125b expression had higher percentage of proliferating cells and lower percentage of apoptotic cells in the corresponding surgical specimens obtained after neoadjuvant chemotherapy. Increased resistance to anticancer drug was observed in vitro in breast cancer cells with ectopic miR-125b expression; conversely, reducing miR-125b level sensitized breast cancer cells to chemotherapy. Moreover, we demonstrated that the E2F3 was a direct target of miR-125b in breast cancer cells. CONCLUSIONS/SIGNIFICANCE: These data suggest that circulating miR-125b expression is associated with chemotherapeutic resistance of breast cancer. This finding has important implications in the development of targeted therapeutics for overcoming chemotherapeutic resistance in novel anti-cancer strategies. PMID- 22523547 TI - Synergistic effect of SRY and its direct target, WDR5, on Sox9 expression. AB - SRY is a sex-determining gene that encodes a transcription factor, which triggers male development in most mammals. The molecular mechanism of SRY action in testis determination is, however, poorly understood. In this study, we demonstrate that WDR5, which encodes a WD-40 repeat protein, is a direct target of SRY. EMSA experiments and ChIP assays showed that SRY could bind to the WDR5 gene promoter directly. Overexpression of SRY in LNCaP cells significantly increased WDR5 expression concurrent with histone H3K4 methylation on the WDR5 promoter. To specifically address whether SRY contributes to WDR5 regulation, we introduced a 4-hydroxy-tamoxifen-inducible SRY allele into LNCaP cells. Conditional SRY expression triggered enrichment of SRY on the WDR5 promoter resulting in induction of WDR5 transcription. We found that WDR5 was self regulating through a positive feedback loop. WDR5 and SRY interacted and were colocalized in cells. In addition, the interaction of WDR5 with SRY resulted in activation of Sox9 while repressing the expression of beta-catenin. These results suggest that, in conjunction with SRY, WDR5 plays an important role in sex determination. PMID- 22523548 TI - A systems biology approach to drug targets in Pseudomonas aeruginosa biofilm. AB - Antibiotic resistance is an increasing problem in the health care system and we are in a constant race with evolving bacteria. Biofilm-associated growth is thought to play a key role in bacterial adaptability and antibiotic resistance. We employed a systems biology approach to identify candidate drug targets for biofilm-associated bacteria by imitating specific microenvironments found in microbial communities associated with biofilm formation. A previously reconstructed metabolic model of Pseudomonas aeruginosa (PA) was used to study the effect of gene deletion on bacterial growth in planktonic and biofilm-like environmental conditions. A set of 26 genes essential in both conditions was identified. Moreover, these genes have no homology with any human gene. While none of these genes were essential in only one of the conditions, we found condition-dependent genes, which could be used to slow growth specifically in biofilm-associated PA. Furthermore, we performed a double gene deletion study and obtained 17 combinations consisting of 21 different genes, which were conditionally essential. While most of the difference in double essential gene sets could be explained by different medium composition found in biofilm-like and planktonic conditions, we observed a clear effect of changes in oxygen availability on the growth performance. Eight gene pairs were found to be synthetic lethal in oxygen-limited conditions. These gene sets may serve as novel metabolic drug targets to combat particularly biofilm-associated PA. Taken together, this study demonstrates that metabolic modeling of human pathogens can be used to identify oxygen-sensitive drug targets and thus, that this systems biology approach represents a powerful tool to identify novel candidate antibiotic targets. PMID- 22523549 TI - Reactive oxygen species regulate the levels of dual oxidase (Duox1-2) in human neuroblastoma cells. AB - Dual Oxidases (DUOX) 1 and 2 are efficiently expressed in thyroid, gut, lung and immune system. The function and the regulation of these enzymes in mammals are still largely unknown. We report here that DUOX 1 and 2 are expressed in human neuroblastoma SK-N-BE cells as well as in a human oligodendrocyte cell line (MO3 13) and in rat brain and they are induced by platelet derived growth factor (PDGF). The levels of DUOX 1 and 2 proteins and mRNAs are induced by reactive oxygen species (ROS) produced by the membrane NADPH oxidase. As to the mechanism, we find that PDGF stimulates membrane NADPH oxidase to produce ROS, which stabilize DUOX1 and 2 mRNAs and increases the levels of the proteins. Silencing of gp91(phox) (NOX2), or of the other membrane subunit of NADPH oxidase, p22(phox), blocks PDGF induction of DUOX1 and 2. These data unravel a novel mechanism of regulation of DUOX enzymes by ROS and identify a circuitry linking NADPH oxidase activity to DUOX1 and 2 levels in neuroblastoma cells. PMID- 22523550 TI - Proteins from Avastin(r) (bevacizumab) show tyrosine nitrations for which the consequences are completely unclear. AB - Avastin(r) (bevacizumab) is a protein drug widely used for cancer treatment although its further use is questionable due to serious side effects reported. As no systematic proteomic study on posttranslational modifications (PTMs) was reported so far, it was the aim of the current study to use a gel-based proteomics method for determination of Avastin(r)-protein(s). Avastin(r) was run on two-dimensional gel electrophoresis (2-DE), spots were picked, followed by multi-enzyme in-gel digestion. Subsequently, the resulting peptides and posttranslational modifications were identified by mass spectrometry (nano-LC-ESI MS/MS; HCT and LTQ Orbitrap MS). Heavy and light chains were observed and the 9 spots that were picked from 2DE-gels were identified as bevacizumab with high sequence coverage. MS/MS results showed multiple tyrosine nitrations on the Avastin(r) light and heavy chains that were either represented as nitrotyrosine or as aminotyrosine, which was shown to be generated from nitrotyrosine under reducing conditions. Protein nitration is known to significantly change protein functions and interactions and it may well be that some of the adverse effects of the protein drug Avastin(r) may be due to this PTM, which may have been generated during production--thus, nitration of Avastin(r) is a challenge for the pharmaceutical industry. PMID- 22523551 TI - Effects of mechanical over-loading on the properties of soleus muscle fibers, with or without damage, in wild type and mdx mice. AB - Effects of mechanical over-loading on the characteristics of regenerating or normal soleus muscle fibers were studied in dystrophin-deficient (mdx) and wild type (WT) mice. Damage was also induced in WT mice by injection of cardiotoxin (CTX) into soleus muscle. Over-loading was applied for 14 days to the left soleus muscle in mdx and intact and CTX-injected WT mouse muscles by ablation of the distal tendons of plantaris and gastrocnemius muscles. All of the myonuclei in normal muscle of WT mice were distributed at the peripheral region. But, central myonuclei were noted in all fibers of WT mice regenerating from CTX-injection related injury. Further, many fibers of mdx mice possessed central myonuclei and the distribution of such fibers was increased in response to over-loading, suggesting a shift of myonuclei from peripheral to central region. Approximately 1.4% branched fibers were seen in the intact muscle of mdx mice, although these fibers were not detected in WT mice. The percentage of these fibers in mdx, not in WT, mice was increased by over-loading (~51.2%). The fiber CSA in normal WT mice was increased by over-loading (p<0.05), but not in mdx and CTX-injected WT mice. It was suggested that compensatory hypertrophy is induced in normal muscle fibers of WT mice following functional over-loading. But, it was also indicated that muscle fibers in mdx mice are susceptible to mechanical over-loading and fiber splitting and shift of myonuclei from peripheral to central region are induced. PMID- 22523552 TI - Membranes with the same ion channel populations but different excitabilities. AB - Electrical signaling allows communication within and between different tissues and is necessary for the survival of multicellular organisms. The ionic transport that underlies transmembrane currents in cells is mediated by transporters and channels. Fast ionic transport through channels is typically modeled with a conductance-based formulation that describes current in terms of electrical drift without diffusion. In contrast, currents written in terms of drift and diffusion are not as widely used in the literature in spite of being more realistic and capable of displaying experimentally observable phenomena that conductance-based models cannot reproduce (e.g. rectification). The two formulations are mathematically related: conductance-based currents are linear approximations of drift-diffusion currents. However, conductance-based models of membrane potential are not first-order approximations of drift-diffusion models. Bifurcation analysis and numerical simulations show that the two approaches predict qualitatively and quantitatively different behaviors in the dynamics of membrane potential. For instance, two neuronal membrane models with identical populations of ion channels, one written with conductance-based currents, the other with drift-diffusion currents, undergo transitions into and out of repetitive oscillations through different mechanisms and for different levels of stimulation. These differences in excitability are observed in response to excitatory synaptic input, and across different levels of ion channel expression. In general, the electrophysiological profiles of membranes modeled with drift diffusion and conductance-based models having identical ion channel populations are different, potentially causing the input-output and computational properties of networks constructed with these models to be different as well. The drift diffusion formulation is thus proposed as a theoretical improvement over conductance-based models that may lead to more accurate predictions and interpretations of experimental data at the single cell and network levels. PMID- 22523553 TI - Salmonella fecal shedding and immune responses are dose- and serotype- dependent in pigs. AB - Despite the public health importance of Salmonella infection in pigs, little is known about the associated dynamics of fecal shedding and immunity. In this study, we investigated the transitions of pigs through the states of Salmonella fecal shedding and immune response post-Salmonella inoculation as affected by the challenge dose and serotype. Continuous-time multistate Markov models were developed using published experimental data. The model for shedding had four transient states, of which two were shedding (continuous and intermittent shedding) and two non-shedding (latency and intermittent non-shedding), and one absorbing state representing permanent cessation of shedding. The immune response model had two transient states representing responses below and above the seroconversion level. The effects of two doses [low (0.65*10(6) CFU/pig) and high (0.65*10(9) CFU/pig)] and four serotypes (Salmonella Yoruba, Salmonella Cubana, Salmonella Typhimurium, and Salmonella Derby) on the models' transition intensities were evaluated using a proportional intensities model. Results indicated statistically significant effects of the challenge dose and serotype on the dynamics of shedding and immune response. The time spent in the specific states was also estimated. Continuous shedding was on average 10-26 days longer, while intermittent non-shedding was 2-4 days shorter, in pigs challenged with the high compared to low dose. Interestingly, among pigs challenged with the high dose, the continuous and intermittent shedding states were on average up to 10-17 and 3-4 days longer, respectively, in pigs infected with S. Cubana compared to the other three serotypes. Pigs challenged with the high dose of S. Typhimurium or S. Derby seroconverted on average up to 8-11 days faster compared to the low dose. These findings highlight that Salmonella fecal shedding and immune response following Salmonella challenge are dose- and serotype-dependent and that the detection of specific Salmonella strains and immune responses in pigs are time sensitive. PMID- 22523554 TI - Growth and asymmetry of soil microfungal colonies from "Evolution Canyon," Lower Nahal Oren, Mount Carmel, Israel. AB - BACKGROUND: Fluctuating asymmetry is a contentious indicator of stress in populations of animals and plants. Nevertheless, it is a measure of developmental noise, typically obtained by measuring asymmetry across an individual organism's left-right axis of symmetry. These individual, signed asymmetries are symmetrically distributed around a mean of zero. Fluctuating asymmetry, however, has rarely been studied in microorganisms, and never in fungi. OBJECTIVE AND METHODS: We examined colony growth and random phenotypic variation of five soil microfungal species isolated from the opposing slopes of "Evolution Canyon," Mount Carmel, Israel. This canyon provides an opportunity to study diverse taxa inhabiting a single microsite, under different kinds and intensities of abiotic and biotic stress. The south-facing "African" slope of "Evolution Canyon" is xeric, warm, and tropical. It is only 200 m, on average, from the north-facing "European" slope, which is mesic, cool, and temperate. Five fungal species inhabiting both the south-facing "African" slope, and the north-facing "European" slope of the canyon were grown under controlled laboratory conditions, where we measured the fluctuating radial asymmetry and sizes of their colonies. RESULTS: Different species displayed different amounts of radial asymmetry (and colony size). Moreover, there were highly significant slope by species interactions for size, and marginally significant ones for fluctuating asymmetry. There were no universal differences (i.e., across all species) in radial asymmetry and colony size between strains from "African" and "European" slopes, but colonies of Clonostachys rosea from the "African" slope were more asymmetric than those from the "European" slope. CONCLUSIONS AND SIGNIFICANCE: Our study suggests that fluctuating radial asymmetry has potential as an indicator of random phenotypic variation and stress in soil microfungi. Interaction of slope and species for both growth rate and asymmetry of microfungi in a common environment is evidence of genetic differences between the "African" and "European" slopes of "Evolution Canyon." PMID- 22523555 TI - Impact of tail loss on the behaviour and locomotor performance of two sympatric Lampropholis skink species. AB - Caudal autotomy is an anti-predator behaviour that is used by many lizard species. Although there is an immediate survival benefit, the subsequent absence of the tail may inhibit locomotor performance, alter activity and habitat use, and increase the individuals' susceptibility to future predation attempts. We used laboratory experiments to examine the impact of tail autotomy on locomotor performance, activity and basking site selection in two lizard species, the delicate skink (Lampropholis delicata) and garden skink (L. guichenoti), that occur sympatrically throughout southeastern Australia and are exposed to an identical suite of potential predators. Post-autotomy tail movement did not differ between the two Lampropholis species, although a positive relationship between the shed tail length and distance moved, but not the duration of movement, was observed. Tail autotomy resulted in a substantial decrease in sprint speed in both species (28-39%), although this impact was limited to the optimal performance temperature (30 degrees C). Although L. delicata was more active than L. guichenoti, tail autotomy resulted in decreased activity in both species. Sheltered basking sites were preferred over open sites by both Lampropholis species, although this preference was stronger in L. delicata. Caudal autotomy did not alter the basking site preferences of either species. Thus, both Lampropholis species had similar behavioural responses to autotomy. Our study also indicates that the impact of tail loss on locomotor performance may be temperature-dependent and highlights that future studies should be conducted over a broad thermal range. PMID- 22523556 TI - Angiotensin converting enzyme (ACE) and ACE2 bind integrins and ACE2 regulates integrin signalling. AB - The angiotensin converting enzymes (ACEs) are the key catalytic components of the renin-angiotensin system, mediating precise regulation of blood pressure by counterbalancing the effects of each other. Inhibition of ACE has been shown to improve pathology in cardiovascular disease, whilst ACE2 is cardioprotective in the failing heart. However, the mechanisms by which ACE2 mediates its cardioprotective functions have yet to be fully elucidated. Here we demonstrate that both ACE and ACE2 bind integrin subunits, in an RGD-independent manner, and that they can act as cell adhesion substrates. We show that cellular expression of ACE2 enhanced cell adhesion. Furthermore, we present evidence that soluble ACE2 (sACE2) is capable of suppressing integrin signalling mediated by FAK. In addition, sACE2 increases the expression of Akt, thereby lowering the proportion of the signalling molecule phosphorylated Akt. These results suggest that ACE2 plays a role in cell-cell interactions, possibly acting to fine-tune integrin signalling. Hence the expression and cleavage of ACE2 at the plasma membrane may influence cell-extracellular matrix interactions and the signalling that mediates cell survival and proliferation. As such, ectodomain shedding of ACE2 may play a role in the process of pathological cardiac remodelling. PMID- 22523557 TI - Composition and structure of a large online social network in The Netherlands. AB - Limitations in data collection have long been an obstacle in research on friendship networks. Most earlier studies use either a sample of ego-networks, or complete network data on a relatively small group (e.g., a single organization). The rise of online social networking services such as Friendster and Facebook, however, provides researchers with opportunities to study friendship networks on a much larger scale. This study uses complete network data from Hyves, a popular online social networking service in The Netherlands, comprising over eight million members and over 400 million online friendship relations. In the first study of its kind for The Netherlands, I examine the structure of this network in terms of the degree distribution, characteristic path length, clustering, and degree assortativity. Results indicate that this network shares features of other large complex networks, but also deviates in other respects. In addition, a comparison with other online social networks shows that these networks show remarkable similarities. PMID- 22523558 TI - The Escherichia coli SOS gene dinF protects against oxidative stress and bile salts. AB - DNA is constantly damaged by physical and chemical factors, including reactive oxygen species (ROS), such as superoxide radical (O(2)(-)), hydrogen peroxide (H(2)O(2)) and hydroxyl radical (*OH). Specific mechanisms to protect and repair DNA lesions produced by ROS have been developed in living beings. In Escherichia coli the SOS system, an inducible response activated to rescue cells from severe DNA damage, is a network that regulates the expression of more than 40 genes in response to this damage, many of them playing important roles in DNA damage tolerance mechanisms. Although the function of most of these genes has been elucidated, the activity of some others, such as dinF, remains unknown. The DinF deduced polypeptide sequence shows a high homology with membrane proteins of the multidrug and toxic compound extrusion (MATE) family. We describe here that expression of dinF protects against bile salts, probably by decreasing the effects of ROS, which is consistent with the observed decrease in H(2)O(2) killing and protein carbonylation. These results, together with its ability to decrease the level of intracellular ROS, suggests that DinF can detoxify, either direct or indirectly, oxidizing molecules that can damage DNA and proteins from both the bacterial metabolism and the environment. Although the exact mechanism of DinF activity remains to be identified, we describe for the first time a role for dinF. PMID- 22523559 TI - Neuropathology of 16p13.11 deletion in epilepsy. AB - 16p13.11 genomic copy number variants are implicated in several neuropsychiatric disorders, such as schizophrenia, autism, mental retardation, ADHD and epilepsy. The mechanisms leading to the diverse clinical manifestations of deletions and duplications at this locus are unknown. Most studies favour NDE1 as the leading disease-causing candidate gene at 16p13.11. In epilepsy at least, the deletion does not appear to unmask recessive-acting mutations in NDE1, with haploinsufficiency and genetic modifiers being prime candidate disease mechanisms. NDE1 encodes a protein critical to cell positioning during cortical development. As a first step, it is important to determine whether 16p13.11 copy number change translates to detectable brain structural alteration. We undertook detailed neuropathology on surgically resected brain tissue of two patients with intractable mesial temporal lobe epilepsy (MTLE), who had the same heterozygous NDE1-containing 800 kb 16p13.11 deletion, using routine histological stains and immunohistochemical markers against a range of layer-specific, white matter, neural precursor and migratory cell proteins, and NDE1 itself. Surgical temporal lobectomy samples from a MTLE case known not to have a deletion in NDE1 and three non-epilepsy cases were included as disease controls. We found that apart from a 3 mm hamartia in the temporal cortex of one MTLE case with NDE1 deletion and known hippocampal sclerosis in the other case, cortical lamination and cytoarchitecture were normal, with no differences between cases with deletion and disease controls. How 16p13.11 copy changes lead to a variety of brain diseases remains unclear, but at least in epilepsy, it would not seem to be through structural abnormality or dyslamination as judged by microscopy or immunohistochemistry. The need to integrate additional data with genetic findings to determine their significance will become more pressing as genetic technologies generate increasingly rich datasets. Detailed examination of brain tissue, where available, will be an important part of this process in neurogenetic disease specifically. PMID- 22523560 TI - Intrauterine growth retardation increases the susceptibility of pigs to high-fat diet-induced mitochondrial dysfunction in skeletal muscle. AB - It has been recognized that there is a relationship between prenatal growth restriction and the development of metabolic-related diseases in later life, a process involved in mitochondrial dysfunction. In addition, intrauterine growth retardation (IUGR) increases the susceptibility of offspring to high-fat (HF) diet-induced metabolic syndrome. Recent findings suggested that HF feeding decreased mitochondrial oxidative capacity and impaired mitochondrial function in skeletal muscle. Therefore, we hypothesized that the long-term consequences of IUGR on mitochondrial biogenesis and function make the offspring more susceptible to HF diet-induced mitochondrial dysfunction. Normal birth weight (NBW), and IUGR pigs were allotted to control or HF diet in a completely randomized design, individually. After 4 weeks of feeding, growth performance and molecular pathways related to mitochondrial function were determined. The results showed that IUGR decreased growth performance and plasma insulin concentrations. In offspring fed a HF diet, IUGR was associated with enhanced plasma leptin levels, increased concentrations of triglyceride and malondialdehyde (MDA), and reduced glycogen and ATP contents in skeletal muscle. High fat diet-fed IUGR offspring exhibited decreased activities of lactate dehydrogenase (LDH) and glucose-6-phosphate dehydrogenase (G6PD). These alterations in metabolic traits of IUGR pigs were accompanied by impaired mitochondrial respiration function, reduced mitochondrial DNA (mtDNA) contents, and down-regulated mRNA expression levels of genes responsible for mitochondrial biogenesis and function. In conclusion, our results suggest that IUGR make the offspring more susceptible to HF diet-induced mitochondrial dysfunction. PMID- 22523561 TI - Maternal perception of reduced fetal movements is associated with altered placental structure and function. AB - BACKGROUND: Maternal perception of reduced fetal movement (RFM) is associated with increased risk of stillbirth and fetal growth restriction (FGR). DFM is thought to represent fetal compensation to conserve energy due to insufficient oxygen and nutrient transfer resulting from placental insufficiency. To date there have been no studies of placental structure in cases of DFM. OBJECTIVE: To determine whether maternal perception of reduced fetal movements (RFM) is associated with abnormalities in placental structure and function. DESIGN: Placentas were collected from women with RFM after 28 weeks gestation if delivery occurred within 1 week. Women with normal movements served as a control group. Placentas were weighed and photographs taken. Microscopic structure was evaluated by immunohistochemical staining and image analysis. System A amino acid transporter activity was measured as a marker of placental function. Placentas from all pregnancies with RFM (irrespective of outcome) had greater area with signs of infarction (3.5% vs. 0.6%; p<0.01), a higher density of syncytial knots (p<0.001) and greater proliferation index (p<0.01). Villous vascularity (p<0.001), trophoblast area (p<0.01) and system A activity (p<0.01) were decreased in placentas from RFM compared to controls irrespective of outcome of pregnancy. CONCLUSIONS: This study provides evidence of abnormal placental morphology and function in women with RFM and supports the proposition of a causal association between placental insufficiency and RFM. This suggests that women presenting with RFM require further investigation to identify those with placental insufficiency. PMID- 22523562 TI - The interaction properties of the human Rab GTPase family--comparative analysis reveals determinants of molecular binding selectivity. AB - BACKGROUND: Rab GTPases constitute the largest subfamily of the Ras protein superfamily. Rab proteins regulate organelle biogenesis and transport, and display distinct binding preferences for effector and activator proteins, many of which have not been elucidated yet. The underlying molecular recognition motifs, binding partner preferences and selectivities are not well understood. METHODOLOGY/PRINCIPAL FINDINGS: Comparative analysis of the amino acid sequences and the three-dimensional electrostatic and hydrophobic molecular interaction fields of 62 human Rab proteins revealed a wide range of binding properties with large differences between some Rab proteins. This analysis assists the functional annotation of Rab proteins 12, 14, 26, 37 and 41 and provided an explanation for the shared function of Rab3 and 27. Rab7a and 7b have very different electrostatic potentials, indicating that they may bind to different effector proteins and thus, exert different functions. The subfamily V Rab GTPases which are associated with endosome differ subtly in the interaction properties of their switch regions, and this may explain exchange factor specificity and exchange kinetics. CONCLUSIONS/SIGNIFICANCE: We have analysed conservation of sequence and of molecular interaction fields to cluster and annotate the human Rab proteins. The analysis of three dimensional molecular interaction fields provides detailed insight that is not available from a sequence-based approach alone. Based on our results, we predict novel functions for some Rab proteins and provide insights into their divergent functions and the determinants of their binding partner selectivity. PMID- 22523563 TI - Seroprevalence and risk factors associated to Mycobacterium bovis in wild artiodactyl species from southern Spain, 2006-2010. AB - The control of bovine tuberculosis (bTB) is at a critical point in the last stage of eradication in livestock. Wildlife species recently have emerged infected with TB in Europe, particularly ungulates in the Iberian Peninsula. Epidemiological information regarding TB in wild ungulates including affected species, prevalence, associated risk factors and appropriate diagnostic methods need to be obtained in these countries. A cross-sectional study was carried out on wild artiodactyl species, including Eurasian wild boar (Sus scrofa) red deer (Cervus elaphus), roe deer (Capraelus capraelus), fallow deer (Dama dama), Spanish ibex (Capra pyrenaica hispanica) and mouflon (Ovis musimon), in Spain to assess the seroprevalence against Mycobacterium bovis or cross-reacting members of the Mycobcaterium tuberculosis complex (MTBC), and to provide information on associated risk factors. Previously, two in-house indirect enzyme linked immunosorbent assays (bPPD-ELISA and MPB83-ELISA) were developed using known TB status sera. Positive reference sera were selected from infected animals confirmed by culture. The M. bovis isolates belonged to spoligotypes SB0121, SB0120, SB0295, SB0265 and SB0134. Two hundred and two out of 1367 (7.5%; 95% CI: 6.1-8.9) animals presented antibodies against M. bovis by both bPPD-ELISA and MPB83-ELISA. Significantly higher TB seroprevalence was observed in wild boar compared to the other species analyzed. Interestingly, seropositivity against M. bovis was not found in any out of 460 Spanish ibex analyzed. The logistic regression model for wild boar indicated that the seropositivity to M. bovis was associated with age, location and year of sampling, while the only risk factor associated with M. bovis seroprevalence in red deer and fallow deer was the age. The seroprevalence observed indicates a widespread exposure to MTBC in several wild artiodactyl species in southern Spain, which may have important implications not only for conservation but also for animal and public health. PMID- 22523564 TI - Identification of JAK2 as a mediator of FIP1L1-PDGFRA-induced eosinophil growth and function in CEL. AB - The Fip1-like1 (FIP1L1)-platelet-derived growth factor receptor alpha fusion gene (F/P) arising in the pluripotent hematopoietic stem cell (HSC),causes 14% to 60% of patients with hypereosinophilia syndrome (HES). These patients, classified as having F/P (+) chronic eosinophilic leukemia (CEL), present with clonal eosinophilia and display a more aggressive disease phenotype than patients with F/P (-) HES patients. The mechanisms underlying predominant eosinophil lineage targeting and the cytotoxicity of eosinophils in this leukemia remain unclear. Given that the Janus tyrosine kinase (JAK)/signal transducers and activators of transcription (Stat) signaling pathway is key to cytokine receptor-mediated eosinophil development and activated Stat3 and Stat5 regulate the expression of genes involved in F/P malignant transformation, we investigated whether and how JAK proteins were involved in the pathogenesis of F/P-induced CEL. F/P activation of JAK2, Stat3 and Stat5, were confirmed in all the 11 F/P (+) CEL patients examined. In vitro inhibition of JAK2 in EOL-1, primary F/P(+) CEL cells (PC) and T674I F/P Imatinib resistant cells(IR) by either JAK2-specific short interfering RNA (siRNA) or the tryphostin derivative AG490(AG490), significantly reduced cellular proliferation and induced cellular apoptosis. The F/P can enhance the IL 5-induced JAK2 activation, and further results indicated that JAK2 inhibition blocked IL-5-induced cellular migration and activation of the EOL-1 and PC cells in vitro. F/P-stimulation of the JAK2 suppressed cells led to a significantly reduction in Stat3 activation, but relatively normal induction of Stat5 activation. Interestingly, JAK2 inhibition also reduced PI3K, Akt and NF-kappaB activity in a dose-dependent manner, and suppressed expression levels of c-Myc and Survivin. These results strongly suggest that JAK2 is activated by F/P and is required for F/P stimulation of cellular proliferation and infiltration, possibly through induction of c-Myc and Survivin expression via activation of multiple signaling pathways, including NF-kappaB, Stat3, and PI3K/Akt. PMID- 22523566 TI - Genetic structure of the tree peony (Paeonia rockii) and the Qinling Mountains as a geographic barrier driving the fragmentation of a large population. AB - BACKGROUND: Tree peonies are great ornamental plants associated with a rich ethnobotanical history in Chinese culture and have recently been used as an evolutionary model. The Qinling Mountains represent a significant geographic barrier in Asia, dividing mainland China into northern (temperate) and southern (semi-tropical) regions; however, their flora has not been well analyzed. In this study, the genetic differentiation and genetic structure of Paeonia rockii and the role of the Qinling Mountains as a barrier that has driven intraspecific fragmentation were evaluated using 14 microsatellite markers. METHODOLOGY/PRINCIPAL FINDINGS: Twenty wild populations were sampled from the distributional range of P. rockii. Significant population differentiation was suggested (F(ST) value of 0.302). Moderate genetic diversity at the population level (H(S) of 0.516) and high population diversity at the species level (H(T) of 0.749) were detected. Significant excess homozygosity (F(IS) of 0.076) and recent population bottlenecks were detected in three populations. Bayesian clusters, population genetic trees and principal coordinate analysis all classified the P. rockii populations into three genetic groups and one admixed Wenxian population. An isolation-by-distance model for P. rockii was suggested by Mantel tests (r = 0.6074, P<0.001) and supported by AMOVA (P<0.001), revealing a significant molecular variance among the groups (11.32%) and their populations (21.22%). These data support the five geographic boundaries surrounding the Qinling Mountains and adjacent areas that were detected with Monmonier's maximum difference algorithm. CONCLUSIONS/SIGNIFICANCE: Our data suggest that the current genetic structure of P. rockii has resulted from the fragmentation of a formerly continuously distributed large population following the restriction of gene flow between populations of this species by the Qinling Mountains. This study provides a fundamental genetic profile for the conservation and responsible exploitation of the extant germplasm of this species and for improving the genetic basis for breeding its cultivars. PMID- 22523565 TI - Ablation of proliferating cells in the CNS exacerbates motor neuron disease caused by mutant superoxide dismutase. AB - Proliferation of glia and immune cells is a common pathological feature of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Here, to investigate the role of proliferating cells in motor neuron disease, SOD1(G93A) transgenic mice were treated intracerebroventicularly (i.c.v.) with the anti-mitotic drug cytosine arabinoside (Ara-C). I.c.v. delivery of Ara-C accelerated disease progression in SOD1(G93A) mouse model of ALS. Ara-C treatment caused substantial decreases in the number of microglia, NG2+ progenitors, Olig2+ cells and CD3+ T cells in the lumbar spinal cord of symptomatic SOD1(G93A) transgenic mice. Exacerbation of disease was also associated with significant alterations in the expression inflammatory molecules IL-1beta, IL-6, TGF-beta and the growth factor IGF-1. PMID- 22523567 TI - Promoting life skills and preventing tobacco use among low-income Mumbai youth: effects of Salaam Bombay Foundation intervention. AB - BACKGROUND: In response to India's growing tobacco epidemic, strategies are needed to decrease tobacco use among Indian youth, particularly among those who are economically disadvantaged. The objective of this study was to assess the effectiveness of a school-based life-skills tobacco control program for youth of low socio-economic status in Mumbai and the surrounding state of Maharashtra. We hypothesized that compared to youth in control schools, youth exposed to the program would have greater knowledge of effects of tobacco use; be more likely to take action to prevent others from using tobacco; demonstrate more positive life skills and attitudes; and be less likely to report tobacco use. METHODS/FINDINGS: Using a quasi-experimental design, we assessed program effectiveness by comparing 8(th) and 9(th) grade students in intervention schools to 8(th) grade students in comparable schools that did not receive the program. Across all schools, 1851 students completed a survey that assessed core program components in early 2010. The program consisted of activities focused on building awareness about the hazards of tobacco, developing life skills, and advocacy development. The primary outcome measure was self-reported tobacco use in the last 30 days. Findings indicate that 4.1% of 8(th) grade intervention students (OR = 0.51) and 3.6% of 9(th) grade intervention students (OR = 0.33) reported using tobacco at least once in the last 30 days, compared to 8.7% of students in the control schools. Intervention group students were also significantly more knowledgeable about tobacco and related legislation, reported more efforts to prevent tobacco use among others, and reported stronger life skills and self-efficacy than students in control schools. Limitations to the study include schools not being randomly assigned to condition and tobacco use being measured by self-report. CONCLUSIONS: This program represents an effective model of school-based tobacco use prevention that low-income schools in India and other low- and middle-income countries can replicate. PMID- 22523568 TI - RACK1 is a ribosome scaffold protein for beta-actin mRNA/ZBP1 complex. AB - In neurons, specific mRNAs are transported in a translationally repressed manner along dendrites or axons by transport ribonucleic-protein complexes called RNA granules. ZBP1 is one RNA binding protein present in transport RNPs, where it transports and represses the translation of cotransported mRNAs, including beta actin mRNA. The release of beta-actin mRNA from ZBP1 and its subsequent translation depends on the phosphorylation of ZBP1 by Src kinase, but little is known about how this process is regulated. Here we demonstrate that the ribosomal associated protein RACK1, another substrate of Src, binds the beta-actin mRNA/ZBP1 complex on ribosomes and contributes to the release of beta-actin mRNA from ZBP1 and to its translation. We identify the Src binding and phosphorylation site Y246 on RACK1 as the critical site for the binding to the beta-actin mRNA/ZBP1 complex. Based on these results we propose RACK1 as a ribosomal scaffold protein for specific mRNA-RBP complexes to tightly regulate the translation of specific mRNAs. PMID- 22523569 TI - Dynamics of hepatitis B virus quasispecies in association with nucleos(t)ide analogue treatment determined by ultra-deep sequencing. AB - BACKGROUND AND AIMS: Although the advent of ultra-deep sequencing technology allows for the analysis of heretofore-undetectable minor viral mutants, a limited amount of information is currently available regarding the clinical implications of hepatitis B virus (HBV) genomic heterogeneity. METHODS: To characterize the HBV genetic heterogeneity in association with anti-viral therapy, we performed ultra-deep sequencing of full-genome HBV in the liver and serum of 19 patients with chronic viral infection, including 14 therapy-naive and 5 nucleos(t)ide analogue(NA)-treated cases. RESULTS: Most genomic changes observed in viral variants were single base substitutions and were widely distributed throughout the HBV genome. Four of eight (50%) chronic therapy-naive HBeAg-negative patients showed a relatively low prevalence of the G1896A pre-core (pre-C) mutant in the liver tissues, suggesting that other mutations were involved in their HBeAg seroconversion. Interestingly, liver tissues in 4 of 5 (80%) of the chronic NA treated anti-HBe-positive cases had extremely low levels of the G1896A pre-C mutant (0.0%, 0.0%, 0.1%, and 1.1%), suggesting the high sensitivity of the G1896A pre-C mutant to NA. Moreover, various abundances of clones resistant to NA were common in both the liver and serum of treatment-naive patients, and the proportion of M204VI mutants resistant to lamivudine and entecavir expanded in response to entecavir treatment in the serum of 35.7% (5/14) of patients, suggesting the putative risk of developing drug resistance to NA. CONCLUSION: Our findings illustrate the strong advantage of deep sequencing on viral genome as a tool for dissecting the pathophysiology of HBV infection. PMID- 22523570 TI - Regulation of MntH by a dual Mn(II)- and Fe(II)-dependent transcriptional repressor (DR2539) in Deinococcus radiodurans. AB - The high intracellular Mn/Fe ratio observed within the bacteria Deinococcus radiodurans may contribute to its remarkable resistance to environmental stresses. We isolated DR2539, a novel regulator of intracellular Mn/Fe homeostasis in D. radiodurans. Electrophoretic gel mobility shift assays (EMSAs) revealed that DR2539 binds specifically to the promoter of the manganese acquisition transporter (MntH) gene, and that DR0865, the only Fur homologue in D. radiodurans, cannot bind to the promoter of mntH, but it can bind to the promoter of another manganese acquisition transporter, MntABC. beta-galactosidase expression analysis indicated that DR2539 acts as a manganese- and iron-dependent transcriptional repressor. Further sequence alignment analysis revealed that DR2539 has evolved some special characteristics. Site-directed mutagenesis suggested that His98 plays an important role in the activities of DR2539, and further protein-DNA binding activity assays showed that the activity of H98Y mutants decreased dramatically relative to wild type DR2539. Our study suggests that D. radiodurans has evolved a very efficient manganese regulation mechanism that involves its high intracellular Mn/Fe ratio and permits resistance to extreme conditions. PMID- 22523571 TI - A cross-species analysis of microRNAs in the developing avian face. AB - Higher vertebrates use similar genetic tools to derive very different facial features. This diversity is believed to occur through temporal, spatial and species-specific changes in gene expression within cranial neural crest (NC) cells. These contribute to the facial skeleton and contain species-specific information that drives morphological variation. A few signaling molecules and transcription factors are known to play important roles in these processes, but little is known regarding the role of micro-RNAs (miRNAs). We have identified and compared all miRNAs expressed in cranial NC cells from three avian species (chicken, duck, and quail) before and after species-specific facial distinctions occur. We identified 170 differentially expressed miRNAs. These include thirty five novel chicken orthologs of previously described miRNAs, and six avian specific miRNAs. Five of these avian-specific miRNAs are conserved over 120 million years of avian evolution, from ratites to galliforms, and their predicted target mRNAs include many components of Wnt signaling. Previous work indicates that mRNA gene expression in NC cells is relatively static during stages when the beak acquires species-specific morphologies. However, miRNA expression is remarkably dynamic within this timeframe, suggesting that the timing of specific developmental transitions is altered in birds with different beak shapes. We evaluated one miRNA:mRNA target pair and found that the cell cycle regulator p27(KIP1) is a likely target of miR-222 in frontonasal NC cells, and that the timing of this interaction correlates with the onset of phenotypic variation. Our comparative genomic approach is the first comprehensive analysis of miRNAs in the developing facial primordial, and in species-specific facial development. PMID- 22523572 TI - Stroke correlates in chagasic and non-chagasic cardiomyopathies. AB - BACKGROUND: Aging and migration have brought changes to the epidemiology and stroke has been shown to be independently associated with Chagas disease. We studied stroke correlates in cardiomyopathy patients with focus on the chagasic etiology. METHODOLOGY/PRINCIPAL FINDINGS: We performed a cross-sectional review of medical records of 790 patients with a cardiomyopathy. Patients with chagasic (329) and non-chagasic (461) cardiomyopathies were compared. There were 108 stroke cases, significantly more frequent in the Chagas group (17.3% versus 11.1%; p<0.01). Chagasic etiology (odds ratio [OR], 1.79), pacemaker (OR, 2.49), atrial fibrillation (OR, 3.03) and coronary artery disease (OR, 1.92) were stroke predictors in a multivariable analysis of the entire cohort. In a second step, the population was split into those with or without a Chagas-related cardiomyopathy. Univariable post-stratification stroke predictors in the Chagas cohort were pacemaker (OR, 2.73), and coronary artery disease (CAD) (OR, 2.58); while atrial fibrillation (OR, 2.98), age over 55 (OR, 2.92), hypertension (OR, 2.62) and coronary artery disease (OR, 1.94) did so in the non-Chagas cohort. Chagasic stroke patients presented a very high frequency of individuals without any vascular risk factors (40.4%; OR, 4.8). In a post-stratification logistic regression model, stroke remained associated with pacemaker (OR, 2.72) and coronary artery disease (OR, 2.60) in 322 chagasic patients, and with age over 55 (OR, 2.38), atrial fibrillation (OR 3.25) and hypertension (OR 2.12; p = 0.052) in 444 non-chagasic patients. CONCLUSIONS/SIGNIFICANCE: Chagas cardiomyopathy presented both a higher frequency of stroke and an independent association with it. There was a high frequency of strokes without any vascular risk factors in the Chagas as opposed to the non-Chagas cohort. Pacemaker rhythm and CAD were independently associated with stroke in the Chagas group while age over 55 years, hypertension and atrial fibrillation did so in the non-Chagas cardiomyopathies. PMID- 22523573 TI - OXPHOS supercomplexes as a hallmark of the mitochondrial phenotype of adipogenic differentiated human MSCs. AB - Mitochondria are essential organelles with multiple functions, especially in energy metabolism. Recently, an increasing number of data has highlighted the role of mitochondria for cellular differentiation processes. Metabolic differences between stem cells and mature derivatives require an adaptation of mitochondrial function during differentiation. In this study we investigated alterations of the mitochondrial phenotype of human mesenchymal stem cells undergoing adipogenic differentiation. Maturation of adipocytes is accompanied by mitochondrial biogenesis and an increase of oxidative metabolism. Adaptation of the mt phenotype during differentiation is reflected by changes in the distribution of the mitochondrial network as well as marked alterations of gene expression and organization of the oxidative phosphorylation system (OXPHOS). Distinct differences in the supramolecular organization forms of cytochrome c oxidase (COX) were detected using 2D blue native (BN)-PAGE analysis. Most remarkably we observed a significant increase in the abundance of OXPHOS supercomplexes in mitochondria, emphasizing the change of the mitochondrial phenotype during adipogenic differentiation. PMID- 22523574 TI - Serial section scanning electron microscopy (S3EM) on silicon wafers for ultra structural volume imaging of cells and tissues. AB - High resolution, three-dimensional (3D) representations of cellular ultrastructure are essential for structure function studies in all areas of cell biology. While limited subcellular volumes have been routinely examined using serial section transmission electron microscopy (ssTEM), complete ultrastructural reconstructions of large volumes, entire cells or even tissue are difficult to achieve using ssTEM. Here, we introduce a novel approach combining serial sectioning of tissue with scanning electron microscopy (SEM) using a conductive silicon wafer as a support. Ribbons containing hundreds of 35 nm thick sections can be generated and imaged on the wafer at a lateral pixel resolution of 3.7 nm by recording the backscattered electrons with the in-lens detector of the SEM. The resulting electron micrographs are qualitatively comparable to those obtained by conventional TEM. S(3)EM images of the same region of interest in consecutive sections can be used for 3D reconstructions of large structures. We demonstrate the potential of this approach by reconstructing a 31.7 um(3) volume of a calyx of Held presynaptic terminal. The approach introduced here, Serial Section SEM (S(3)EM), for the first time provides the possibility to obtain 3D ultrastructure of large volumes with high resolution and to selectively and repetitively home in on structures of interest. S(3)EM accelerates process duration, is amenable to full automation and can be implemented with standard instrumentation. PMID- 22523575 TI - TumorHoPe: a database of tumor homing peptides. AB - BACKGROUND: Cancer is responsible for millions of immature deaths every year and is an economical burden on developing countries. One of the major challenges in the present era is to design drugs that can specifically target tumor cells not normal cells. In this context, tumor homing peptides have drawn much attention. These peptides are playing a vital role in delivering drugs in tumor tissues with high specificity. In order to provide service to scientific community, we have developed a database of tumor homing peptides called TumorHoPe. DESCRIPTION: TumorHoPe is a manually curated database of experimentally validated tumor homing peptides that specifically recognize tumor cells and tumor associated microenvironment, i.e., angiogenesis. These peptides were collected and compiled from published papers, patents and databases. Current release of TumorHoPe contains 744 peptides. Each entry provides comprehensive information of a peptide that includes its sequence, target tumor, target cell, techniques of identification, peptide receptor, etc. In addition, we have derived various types of information from these peptide sequences that include secondary/tertiary structure, amino acid composition, and physicochemical properties of peptides. Peptides in this database have been found to target different types of tumors that include breast, lung, prostate, melanoma, colon, etc. These peptides have some common motifs including RGD (Arg-Gly-Asp) and NGR (Asn-Gly-Arg) motifs, which specifically recognize tumor angiogenic markers. TumorHoPe has been integrated with many web-based tools like simple/complex search, database browsing and peptide mapping. These tools allow a user to search tumor homing peptides based on their amino acid composition, charge, polarity, hydrophobicity, etc. CONCLUSION: TumorHoPe is a unique database of its kind, which provides comprehensive information about experimentally validated tumor homing peptides and their target cells. This database will be very useful in designing peptide based drugs and drug-delivery system. It is freely available at http://crdd.osdd.net/raghava/tumorhope/. PMID- 22523576 TI - Recruiting a new substrate for triacylglycerol synthesis in plants: the monoacylglycerol acyltransferase pathway. AB - BACKGROUND: Monoacylglycerol acyltransferases (MGATs) are predominantly associated with lipid absorption and resynthesis in the animal intestine where they catalyse the first step in the monoacylglycerol (MAG) pathway by acylating MAG to form diacylglycerol (DAG). Typical plant triacylglycerol (TAG) biosynthesis routes such as the Kennedy pathway do not include an MGAT step. Rather, DAG and TAG are synthesised de novo from glycerol-3-phosphate (G-3-P) by a series of three subsequent acylation reactions although a complex interplay with membrane lipids exists. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrate that heterologous expression of a mouse MGAT acyltransferase in Nicotiana benthamiana significantly increases TAG accumulation in vegetative tissues despite the low levels of endogenous MAG substrate available. In addition, DAG produced by this acyltransferase can serve as a substrate for both native and coexpressed diacylglycerol acyltransferases (DGAT). Finally, we show that the Arabidopsis thaliana GPAT4 acyltransferase can produce MAG in Saccharomyces cerevisiae using oleoyl-CoA as the acyl-donor. CONCLUSIONS/SIGNIFICANCE: This study demonstrates the concept of a new method of increasing oil content in vegetative tissues by using MAG as a substrate for TAG biosynthesis. Based on in vitro yeast assays and expression results in N. benthamiana, we propose that co-expression of a MAG synthesising enzyme such as A. thaliana GPAT4 and a MGAT or bifunctional M/DGAT can result in DAG and TAG synthesis from G-3-P via a route that is independent and complementary to the endogenous Kennedy pathway and other TAG synthesis routes. PMID- 22523577 TI - Plasma BDNF is associated with age-related white matter atrophy but not with cognitive function in older, non-demented adults. AB - Brain derived neurotrophic factor (BDNF) seems to be involved in regulation of synaptic plasticity and neurogenesis. BDNF plasma and serum levels have been associated with depression, Alzheimer's disease, and other psychiatric and neurodegenerative disorders. In a community sample, drawn from the Baltimore Longitudinal Study of Aging (BLSA), we examined whether BDNF plasma concentration was associated with rates of age-related change in cognitive performance (n = 429) and regional brain volume (n = 59). Plasma BDNF levels, which were significantly higher in females (p<0.05), were not associated with either concurrent cognitive performance or rates of age-related change in performance across cognitive domains (p's>0.05). Sex differences in the relationship between BDNF and the trajectories of regional brain volume changes were observed for the whole brain and frontal white matter volumes (p<0.05), whereby lower plasma BDNF was associated with steeper volume decline in females but not males. Together, our findings contribute to furthering the understanding of the relationships between plasma BDNF, structural brain integrity and cognition. Potential mechanisms mediating these relationships merit further investigation. PMID- 22523578 TI - Novel expression patterns of metabotropic glutamate receptor 6 in the zebrafish nervous system. AB - The metabotropic glutamate receptor 6 (mGluR6 or GRM6) belongs to the class III of the metabotropic glutamate receptor family. It is the only known mGluR that mediates direct synaptic transmission in the nervous system and is thought to mediate the ON-response in the ON-pathway of the vertebrate retina. Phylogenetic and gene structure analysis indicated that the zebrafish genome harbours two mglur6 paralogs, mglur6a and mglur6b. Besides expression in the inner nuclear layer and distinct regions in the brain, both mglur6 paralogs are expressed in ganglion cells of the retina, an expression pattern which can also be observed in the downstream effector molecules gnaoa and gnaob. This unexpected expression pattern is consistent with immunohistological labeling using a peptide antibody specific for the mGluR6b paralog. These expression patterns contradict the existing view that mGluR6 is solely located on ON-bipolar cells where it functions in signal transmission. Consistent with expression in ON-bipolar cells, we report a decreased b-wave amplitude in the electroretinogram after morpholino based downregulation of mGluR6b, showing a function in the ON response. Our data suggest more widespread functions of mGluR6 mediated signaling in the central nervous system, possibly including sign reversing synapses in the inner retina. PMID- 22523579 TI - Large-scale changes in community composition: determining land use and climate change signals. AB - Human land use and climate change are regarded as the main driving forces of present-day and future species extinction. They may potentially lead to a profound reorganisation of the composition and structure of natural communities throughout the world. However, studies that explicitly investigate both forms of impact--land use and climate change--are uncommon. Here, we quantify community change of Dutch breeding bird communities over the past 25 years using time lag analysis. We evaluate the chronological sequence of the community temperature index (CTI) which reflects community response to temperature increase (increasing CTI indicates an increase in relative abundance of more southerly species), and the temporal trend of the community specialisation index (CSI) which reflects community response to land use change (declining CSI indicates an increase of generalist species). We show that the breeding bird fauna underwent distinct directional change accompanied by significant changes both in CTI and CSI which suggests a causal connection between climate and land use change and bird community change. The assemblages of particular breeding habitats neither changed at the same speed and nor were they equally affected by climate versus land use changes. In the rapidly changing farmland community, CTI and CSI both declined slightly. In contrast, CTI increased in the more slowly changing forest and heath communities, while CSI remained stable. Coastal assemblages experienced both an increase in CTI and a decline in CSI. Wetland birds experienced the fastest community change of all breeding habitat assemblages but neither CTI nor CSI showed a significant trend. Overall, our results suggest that the interaction between climate and land use changes differs between habitats, and that comparing trends in CSI and CTI may be useful in tracking the impact of each determinant. PMID- 22523580 TI - Dynamics, patterns and causes of fires in Northwestern Amazonia. AB - According to recent studies, two widespread droughts occurred in the Amazon basin, one during 2005 and one during 2010. The drought increased the prevalence of climate-driven fires over most of the basin. Given the importance of human atmosphere-vegetation interactions in tropical rainforests, these events have generated concerns over the vulnerability of this area to climate change. This paper focuses on one of the wettest areas of the basin, Northwestern Amazonia, where the interactions between the climate and fires are much weaker and where little is known about the anthropogenic drivers of fires. We have assessed the response of fires to climate over a ten-year period, and analysed the socio economic and demographic determinants of fire occurrence. The patterns of fires and climate and their linkages in Northwestern Amazonia differ from the enhanced fire response to climate variation observed in the rest of Amazonia. The highest number of recorded fires in Northwestern Amazonia occurred in 2004 and 2007, and this did not coincide with the periods of extreme drought experienced in Amazonia in 2005 and 2010. Rather, during those years, Northwestern Amazonia experienced a relatively small numbers of fire hotspots. We have shown that fire occurrence correlated well with deforestation and was determined by anthropogenic drivers, mainly small-scale agriculture, cattle ranching (i.e., pastures) and active agricultural frontiers (including illegal crops). Thus, the particular climatic conditions for air convergence and rainfall created by proximity to the Andes, coupled with the presence of one of the most active colonisation fronts in the region, make this region differently affected by the general drought-induced fire patterns experienced by the rest of the Amazon. Moreover, the results suggest that, even in this wet region, humans are able to modify the frequency of fires and impact these historically well preserved forests. PMID- 22523581 TI - Peripheral T cell cytokine responses for diagnosis of active tuberculosis. AB - BACKGROUND: A test for diagnosis of active Tuberculosis (TB) from peripheral blood could tremendously improve clinical management of patients. METHODS: Of 178 prospectively enrolled patients with possible TB, 60 patients were diagnosed with pulmonary and 27 patients with extrapulmonary TB. The frequencies of Mycobacterium tuberculosis (MTB) specific CD4(+) T cells and CD8(+) T cells producing cytokines were assessed using overnight stimulation with purified protein derivate (PPD) or early secretory antigenic target (ESAT)-6, respectively. RESULTS: Among patients with active TB, an increased type 1 cytokine profile consisting of mainly CD4(+) T cell derived interferon (IFN) gamma was detectable. Despite contributing to the cytokine profile as a whole, the independent diagnostic performance of one cytokine producing T cells as well as polyfunctional T cells was poor. IFN-gamma/Interleukin(IL)-2 cytokine ratios discriminated best between active TB and other diseases. CONCLUSION: T cells producing one cytokine and polyfunctional T cells have a limited role in diagnosis of active TB. The significant shift from a "memory type" to an "effector type" cytokine profile may be useful for further development of a rapid immune-diagnostic tool for active TB. PMID- 22523582 TI - Cardiovascular events in patients received combined fibrate/statin treatment versus statin monotherapy: Acute Coronary Syndrome Israeli Surveys data. AB - BACKGROUND: The effect of combination of fibrate with statin on major adverse cardiovascular events (MACE) following acute coronary syndrome (ACS) hospitalization is unclear. The main aim of this study was to investigate the 30 day rate of MACE in patients who participated in the nationwide ACS Israeli Surveys (ACSIS) and were treated on discharge with a fibrate (mainly bezafibrate) and statin combination vs. statin alone. METHODS: The study population comprised 8,982 patients from the ACSIS 2000, 2002, 2004, 2006, 2008 and 2010 enrollment waves who were alive on discharge and received statin. Of these, 8,545 (95%) received statin alone and 437 (5%) received fibrate/statin combination. MACE was defined as a composite measure of death, recurrent MI, recurrent ischemia, stent thrombosis, ischemic stroke and urgent revascularization. RESULTS: Patients from the combination group were younger (58.1+/-11.9 vs. 62.9+/-12.6 years). However, they had significantly more co-morbidities (hypertension, diabetes), current smokers and unfavorable cardio-metabolic profiles (with respect to glucose, total cholesterol, triglyceride and HDL-cholesterol). Development of MACE was recorded in 513 (6.0%) patients from the statin monotherapy group vs. 13 (3.2%) from the combination group, p = 0.01. 30-day re-hospitalization rate was significantly lower in the combination group: 68 (15.6%) vs. 1691 (19.8%) of patients, respectively; p = 0.03. Multivariable analysis identified the fibrate/statin combination as an independent predictor of reduced risk of MACE with odds ratio of 0.54, 95% confidence interval 0.32-0.94. CONCLUSION: A significantly lower risk of 30-day MACE rate was observed in patients receiving combined fibrate/statin treatment following ACS compared with statin monotherapy. However, caution should be exercised in interpreting these findings taking into consideration baseline differences between our observational study groups. PMID- 22523583 TI - Effect of a dual task on postural control in dyslexic children. AB - Several studies have examined postural control in dyslexic children; however, their results were inconclusive. This study investigated the effect of a dual task on postural stability in dyslexic children. Eighteen dyslexic children (mean age 10.3+/-1.2 years) were compared with eighteen non-dyslexic children of similar age. Postural stability was recorded with a platform (TechnoConcept(r)) while the child, in separate sessions, made reflex horizontal and vertical saccades of 10 degrees of amplitude, and read a text silently. We measured the surface and the mean speed of the center of pressure (CoP). Reading performance was assessed by counting the number of words read during postural measures. Both groups of children were more stable while performing saccades than while reading a text. Furthermore, dyslexic children were significantly more unstable than non dyslexic children, especially during the reading task. Finally, the number of words read by dyslexic children was significantly lower than that of non-dyslexic children and, in contrast to the non-dyslexic children. In line with the U-shaped non-linear interaction model, we suggest that the attention consumed by the reading task could be responsible for the loss of postural control in both groups of children. The postural instability observed in dyslexic children supports the hypothesis that such children have a lack of integration of multiple sensorimotor inputs. PMID- 22523584 TI - Is self-rated health an independent index for mortality among older people in Indonesia? AB - BACKGROUND: Empirical studies on the association between self-rated health (SRH) and subsequent mortality are generally lacking in low- and middle-income countries. The evidence on whether socio-economic status and education modify this association is inconsistent. This study aims to fill these gaps using longitudinal data from a Health and Demographic Surveillance System (HDSS) site in Indonesia. METHODS: In 2010, we assessed the mortality status of 11,753 men and women aged 50+ who lived in Purworejo HDSS and participated in the INDEPTH WHO SAGE baseline in 2007. Information on self-rated health, socio-demographic indicators, disability and chronic disease were collected through face-to-face interview at baseline. We used Cox-proportional hazards regression for mortality and included all variables measured at baseline, including interaction terms between SRH and both education and socio-economic status (SES). RESULTS: During an average of 36 months follow-up, 11% of men and 9.5% of women died, resulting in death rates of 3.1 and 2.6 per 1,000 person-months, respectively. The age adjusted Hazard Ratio (HR) for mortality was 17% higher in men than women (HR = 1.17; 95% CI = 1.04-1.31). After adjustment for covariates, the hazard ratios for mortality in men and women reporting bad health were 3.0 (95% CI = 2.0-4.4) and 4.9 (95% CI = 3.2-7.4), respectively. Education and SES did not modify this association for either sex. CONCLUSIONS: This study supports the predictive power of bad self-rated health for subsequent mortality in rural Indonesian men and women 50 years old and over. In these analyses, education and household socio economic status do not modify the relationship between SRH and mortality. This means that older people who rate their own health poorly should be an important target group for health service interventions. PMID- 22523585 TI - Corneal transduction by intra-stromal injection of AAV vectors in vivo in the mouse and ex vivo in human explants. AB - The cornea is a transparent, avascular tissue that acts as the major refractive surface of the eye. Corneal transparency, assured by the inner stroma, is vital for this role. Disruption in stromal transparency can occur in some inherited or acquired diseases. As a consequence, light entering the eye is blocked or distorted, leading to decreased visual acuity. Possible treatment for restoring transparency could be via viral-based gene therapy. The stroma is particularly amenable to this strategy due to its immunoprivileged nature and low turnover rate. We assayed the potential of AAV vectors to transduce keratocytes following intra-stromal injection in vivo in the mouse cornea and ex vivo in human explants. In murine and human corneas, we transduced the entire stroma using a single injection, preferentially targeted keratocytes and achieved long-term gene transfer (up to 17 months in vivo in mice). Of the serotypes tested, AAV2/8 was the most promising for gene transfer in both mouse and man. Furthermore, transgene expression could be transiently increased following aggression to the cornea. PMID- 22523586 TI - Destabilization of the outer and inner mitochondrial membranes by core and linker histones. AB - BACKGROUND: Extensive DNA damage leads to apoptosis. Histones play a central role in DNA damage sensing and may mediate signals of genotoxic damage to cytosolic effectors including mitochondria. METHODOLOGY/PRINCIPAL FINDINGS: We have investigated the effects of histones on mitochondrial function and membrane integrity. We demonstrate that both linker histone H1 and core histones H2A, H2B, H3, and H4 bind strongly to isolated mitochondria. All histones caused a rapid and massive release of the pro-apoptotic intermembrane space proteins cytochrome c and Smac/Diablo, indicating that they permeabilize the outer mitochondrial membrane. In addition, linker histone H1, but not core histones, permeabilized the inner membrane with a collapse of the membrane potential, release of pyridine nucleotides, and mitochondrial fragmentation. CONCLUSIONS: We conclude that histones destabilize the mitochondrial membranes, a mechanism that may convey genotoxic signals to mitochondria and promote apoptosis following DNA damage. PMID- 22523587 TI - Curcumin attenuates beta-catenin signaling in prostate cancer cells through activation of protein kinase D1. AB - Prostate cancer is the most commonly diagnosed cancer affecting 1 in 6 males in the US. Understanding the molecular basis of prostate cancer progression can serve as a tool for early diagnosis and development of novel treatment strategies for this disease. Protein Kinase D1 (PKD1) is a multifunctional kinase that is highly expressed in normal prostate. The decreased expression of PKD1 has been associated with the progression of prostate cancer. Therefore, synthetic or natural products that regulate this signaling pathway can serve as novel therapeutic modalities for prostate cancer prevention and treatment. Curcumin, the active ingredient of turmeric, has shown anti-cancer properties via modulation of a number of different molecular pathways. Herein, we have demonstrated that curcumin activates PKD1, resulting in changes in beta-catenin signaling by inhibiting nuclear beta-catenin transcription activity and enhancing the levels of membrane beta-catenin in prostate cancer cells. Modulation of these cellular events by curcumin correlated with decreased cell proliferation, colony formation and cell motility and enhanced cell-cell aggregation in prostate cancer cells. In addition, we have also revealed that inhibition of cell motility by curcumin is mediated by decreasing the levels of active cofilin, a downstream target of PKD1. The potent anti-cancer effects of curcumin in vitro were also reflected in a prostate cancer xenograft mouse model. The in vivo inhibition of tumor growth also correlated with enhanced membrane localization of beta-catenin. Overall, our findings herein have revealed a novel molecular mechanism of curcumin action via the activation of PKD1 in prostate cancer cells. PMID- 22523588 TI - No evidence for immune priming in ants exposed to a fungal pathogen. AB - There is accumulating evidence that invertebrates can acquire long-term protection against pathogens through immune priming. However, the range of pathogens eliciting immune priming and the specificity of the response remain unclear. Here, we tested if the exposure to a natural fungal pathogen elicited immune priming in ants. We found no evidence for immune priming in Formica selysi workers exposed to Beauveria bassiana. The initial exposure of ants to the fungus did not alter their resistance in a subsequent challenge with the same fungus. There was no sign of priming when using homologous and heterologous combinations of fungal strains for exposure and subsequent challenges at two time intervals. Hence, within the range of conditions tested, the immune response of this social insect to the fungal pathogen appears to lack memory and strain-specificity. These results show that immune priming is not ubiquitous across pathogens, hosts and conditions, possibly because of immune evasion by the pathogen or efficient social defences by the host. PMID- 22523589 TI - Daily rhythmic behaviors and thermoregulatory patterns are disrupted in adult female MeCP2-deficient mice. AB - Mutations in the X-linked gene encoding Methyl-CpG-binding protein 2 (MECP2) have been associated with neurodevelopmental and neuropsychiatric disorders including Rett Syndrome, X-linked mental retardation syndrome, severe neonatal encephalopathy, and Angelman syndrome. Although alterations in the performance of MeCP2-deficient mice in specific behavioral tasks have been documented, it remains unclear whether or not MeCP2 dysfunction affects patterns of periodic behavioral and electroencephalographic (EEG) activity. The aim of the current study was therefore to determine whether a deficiency in MeCP2 is sufficient to alter the normal daily rhythmic patterns of core body temperature, gross motor activity and cortical delta power. To address this, we monitored individual wild type and MeCP2-deficient mice in their home cage environment via telemetric recording over 24 hour cycles. Our results show that the normal daily rhythmic behavioral patterning of cortical delta wave activity, core body temperature and mobility are disrupted in one-year old female MeCP2-deficient mice. Moreover, female MeCP2-deficient mice display diminished overall motor activity, lower average core body temperature, and significantly greater body temperature fluctuation than wild-type mice in their home-cage environment. Finally, we show that the epileptiform discharge activity in female MeCP2-deficient mice is more predominant during times of behavioral activity compared to inactivity. Collectively, these results indicate that MeCP2 deficiency is sufficient to disrupt the normal patterning of daily biological rhythmic activities. PMID- 22523590 TI - The degree of leukocytosis and urine GATA-3 mRNA levels are risk factors for severe acute kidney injury in Puumala virus nephropathia epidemica. AB - Puumala hantavirus (PUUV) infection, also known as nephropathia epidemica, is the most common cause of hemorrhagic fever with renal syndrome (HFRS) in Europe. The pathogenesis of PUUV nephropathia epidemica is complex and multifactorial, and the risk factors for severe acute kidney injury (AKI) during acute PUUV infection are not well defined. We conducted a prospective study of hospitalized patients with PUUV infection in Tampere, Finland to identify acute illness risk factors for HFRS severity. Serial daily blood and urine samples were collected throughout acute illness and at 2 week and 6 month convalescent visits. By univariate analyses, the maximum white blood cell count during acute illness was a risk factor for severe AKI. There were no significant associations between PUUV induced AKI severity and platelet counts, C-reactive protein, or alanine aminotransferase levels. Maximum plasma interleukin (IL)-6, urine IL-6, and urine IL-8 concentrations were positively associated with PUUV-induced AKI. Finally, the maximum urinary sediment GATA-3 mRNA level was positively correlated with the peak fold-change in serum creatinine, regardless of AKI severity classification. By multivariate analyses, we found that the maximum levels of leukocytes and urinary sediment GATA-3 mRNA during acute illness were independent risk factors for severe PUUV-induced AKI. We have identified novel acute illness risk factors for severe PUUV-induced AKI. PMID- 22523591 TI - Risk factors and characterization of Plasmodium vivax-associated admissions to pediatric intensive care units in the Brazilian Amazon. AB - BACKGROUND: Plasmodium vivax is responsible for a significant proportion of malaria cases worldwide and is increasingly reported as a cause of severe disease. The objective of this study was to characterize severe vivax disease among children hospitalized in intensive care units (ICUs) in the Western Brazilian Amazon, and to identify risk factors associated with disease severity. METHODS AND FINDINGS: In this retrospective study, clinical records of 34 children, 0-14 years of age hospitalized in the 11 public pediatric and neonatal ICUs of the Manaus area, were reviewed. P. falciparum monoinfection or P. falciparum/P. vivax mixed infection was diagnosed by microscopy in 10 cases, while P. vivax monoinfection was confirmed in the remaining 24 cases. Two of the 24 patients with P. vivax monoinfection died. Respiratory distress, shock and severe anemia were the most frequent complications associated with P. vivax infection. Ninety-one children hospitalized with P. vivax monoinfections but not requiring ICU were consecutively recruited in a tertiary care hospital for infectious diseases to serve as a reference population (comparators). Male sex (p = 0.039), age less than five years (p = 0.028), parasitemia greater than 500/mm(3) (p = 0.018), and the presence of any acute (p = 0.023) or chronic (p = 0.017) co-morbidity were independently associated with ICU admission. At least one of the WHO severity criteria for malaria (formerly validated for P. falciparum) was present in 23/24 (95.8%) of the patients admitted to the ICU and in 17/91 (18.7%) of controls, making these criteria a good predictor of ICU admission (p = 0.001). The only investigated criterion not associated with ICU admission was hyperbilirubinemia (p = 0.513)]. CONCLUSIONS: Our study points to the importance of P. vivax-associated severe disease in children, causing 72.5% of the malaria admissions to pediatric ICUs. WHO severity criteria demonstrated good sensitivity in predicting severe P. vivax infection in this small case series. PMID- 22523592 TI - Bim links ER stress and apoptosis in cells expressing mutant SOD1 associated with amyotrophic lateral sclerosis. AB - Endoplasmic reticulum (ER) stress is an important pathway to cell death in amyotrophic lateral sclerosis (ALS). We previously demonstrated that ER stress is linked to neurotoxicity associated with formation of inclusions of mutant Cu,Zn superoxide dismutase 1 (SOD1). Cells bearing mutant inclusions undergo mitochondrial apoptotic signalling. Here, we demonstrate that the BH3-only protein, Bim, is a direct link between ER stress and mitochondrial apoptosis. In the murine neuroblastoma cell line, Neuro2a, bearing mutant SOD1 inclusions, indicators of both ER stress and apoptosis are expressed. Bim knockdown by siRNA significantly reduced nuclear apoptotic features in these inclusion-bearing cells (but did not affect the proportion of cells overall that bear inclusions). Further, both Bax recruitment to mitochondria and cytochrome c redistribution were also decreased under Bim-depletion conditions. However, upregulation of CHOP, a marker of ER stress, was not reduced by Bim knockdown. Significantly, knockdown of CHOP by siRNA reduced the extent of apoptosis in cells bearing mutant SOD1 inclusions. These sequential links between ER stress, CHOP upregulation, and Bim activation of mitochondrial apoptotic signalling indicate a clear pathway to cell death mediated by mutant SOD1. PMID- 22523593 TI - 1,2-Octanediol, a novel surfactant, for treating head louse infestation: identification of activity, formulation, and randomised, controlled trials. AB - BACKGROUND: Interest in developing physically active pediculicides has identified new active substances. The objective was to evaluate a new treatment for clinical efficacy. METHODS AND FINDINGS: We describe the selection of 1,2-octanediol as a potential pediculicide. Clinical studies were community based. The main outcome measure was no live lice, after two treatments, with follow up visits over 14 days. Study 1 was a proof of concept with 18/20 (90%) participants cured. Study 2 was a multicentre, parallel, randomised, observer-blind study (520 participants) that compared 0.5% malathion liquid with 1,2-octanediol lotion (20% alcohol) applied 2-2.5 hours or 8 hours/overnight. 1,2-octanediol lotion was significantly (p<0.0005) more effective with success for 124/175 (70.9%) RR = 1.50 (97.5% CI, 1.22 to 1.85) for 2-2.5 hours, and 153/174 (87.9%) RR = 1.86 (97.5% CI, 1.54 to 2.26) for 8 hours/overnight compared with 81/171 (47.4%) for malathion. Study 3, a two centre, parallel, randomised, observer-blind study (121 participants), compared 1,2-octanediol lotion, 2-2.5 hours with 1,2-octanediol alcohol free mousse applied for 2-2.5 hours or 8 hours/overnight. The mousse applied for 8 hours/overnight cured 31/40 (77.5%), compared with 24/40 (60.0%) for lotion (RR = 1.29, 95% CI, 0.95 to 1.75; NNT = 5.7) but mousse applied for 2-2.5 hours 17/41 (41.5%) was less effective than lotion (RR = 0.69, 95% CI, 0.44 to 1.08). Adverse events were more common using 1,2-octanediol lotion at both 2-2.5 hours (12.0%, p = 0.001) and 8 hours/overnight (14.9%, p<0.0005), compared with 0.5% malathion (2.3%). Similar reactions were more frequent (p<0.045) using lotion compared with mousse. CONCLUSIONS: 1,2-octanediol was found to eliminate head louse infestation. It is believed to disrupt the insect's cuticular lipid, resulting in dehydration. The alcohol free mousse is more acceptable exhibiting significantly fewer adverse reactions. TRIAL REGISTRATIONS: Controlled-Trials.com ISRCTN66611560, ISRCTN91870666, ISRCTN28722846. PMID- 22523594 TI - Endothelial differentiation of human stem cells seeded onto electrospun polyhydroxybutyrate/polyhydroxybutyrate-co-hydroxyvalerate fiber mesh. AB - Tissue engineering is based on the association of cultured cells with structural matrices and the incorporation of signaling molecules for inducing tissue regeneration. Despite its enormous potential, tissue engineering faces a major challenge concerning the maintenance of cell viability after the implantation of the constructs. The lack of a functional vasculature within the implant compromises the delivery of nutrients to and removal of metabolites from the cells, which can lead to implant failure. In this sense, our investigation aims to develop a new strategy for enhancing vascularization in tissue engineering constructs. This study's aim was to establish a culture of human adipose tissue derived stem cells (hASCs) to evaluate the biocompatibility of electrospun fiber mesh made of polyhydroxybutyrate (PHB) and its copolymer poly-3-hydroxybutyrate co-3-hydroxyvalerate (PHB-HV) and to promote the differentiation of hASCs into the endothelial lineage. Fiber mesh was produced by blending 30% PHB with 70% PHB HV and its physical characterization was conducted using scanning electron microscopy analysis (SEM). Using electrospinning, fiber mesh was obtained with diameters ranging 300 nm to 1.3 um. To assess the biological performance, hASCs were extracted, cultured, characterized by flow cytometry, expanded and seeded onto electrospun PHB/PHB-HV fiber mesh. Various aspects of the cells were analyzed in vitro using SEM, MTT assay and Calcein-AM staining. The in vitro evaluation demonstrated good adhesion and a normal morphology of the hASCs. After 7, 14 and 21 days of seeding hASCs onto electrospun PHB/PHB-HV fiber mesh, the cells remained viable and proliferative. Moreover, when cultured with endothelial differentiation medium (i.e., medium containing VEGF and bFGF), the hASCs expressed endothelial markers such as VE-Cadherin and the vWF factor. Therefore, the electrospun PHB/PHB-HV fiber mesh appears to be a suitable material that can be used in combination with endothelial-differentiated cells to improve vascularization in engineered bone tissues. PMID- 22523595 TI - A systems biology approach to characterize the regulatory networks leading to trabectedin resistance in an in vitro model of myxoid liposarcoma. AB - Trabectedin, a new antitumor compound originally derived from a marine tunicate, is clinically effective in soft tissue sarcoma. The drug has shown a high selectivity for myxoid liposarcoma, characterized by the translocation t(12;16)(q13; p11) leading to the expression of FUS-CHOP fusion gene. Trabectedin appears to act interfering with mechanisms of transcription regulation. In particular, the transactivating activity of FUS-CHOP was found to be impaired by trabectedin treatment. Even after prolonged response resistance occurs and thus it is important to elucidate the mechanisms of resistance to trabectedin. To this end we developed and characterized a myxoid liposarcoma cell line resistant to trabectedin (402-91/ET), obtained by exposing the parental 402-91 cell line to stepwise increases in drug concentration. The aim of this study was to compare mRNAs, miRNAs and proteins profiles of 402-91 and 402-91/ET cells through a systems biology approach. We identified 3,083 genes, 47 miRNAs and 336 proteins differentially expressed between 402-91 and 402-91/ET cell lines. Interestingly three miRNAs among those differentially expressed, miR-130a, miR-21 and miR-7, harbored CHOP binding sites in their promoter region. We used computational approaches to integrate the three regulatory layers and to generate a molecular map describing the altered circuits in sensitive and resistant cell lines. By combining transcriptomic and proteomic data, we reconstructed two different networks, i.e. apoptosis and cell cycle regulation, that could play a key role in modulating trabectedin resistance. This approach highlights the central role of genes such as CCDN1, RB1, E2F4, TNF, CDKN1C and ABL1 in both pre- and post transcriptional regulatory network. The validation of these results in in vivo models might be clinically relevant to stratify myxoid liposarcoma patients with different sensitivity to trabectedin treatment. PMID- 22523596 TI - Investigating the host-range of the rust fungus Puccinia psidii sensu lato across tribes of the family Myrtaceae present in Australia. AB - The exotic rust fungus Puccinia psidii sensu lato was first detected in Australia in April 2010. This study aimed to determine the host-range potential of this accession of the rust by testing its pathogenicity on plants of 122 taxa, representative of the 15 tribes of the subfamily Myrtoideae in the family Myrtaceae. Each taxon was tested in two separate trials (unless indicated otherwise) that comprised up to five replicates per taxon and six replicates of a positive control (Syzygium jambos). No visible symptoms were observed on the following four taxa in either trial: Eucalyptus grandis*camaldulensis, E. moluccana, Lophostemon confertus and Sannantha angusta. Only small chlorotic or necrotic flecks without any uredinia (rust fruiting bodies) were observed on inoculated leaves of seven other taxa (Acca sellowiana, Corymbia calophylla 'Rosea', Lophostemon suaveolens, Psidium cattleyanum, P. guajava 'Hawaiian' and 'Indian', Syzygium unipunctatum). Fully-developed uredinia were observed on all replicates across both trials of 28 taxa from 8 tribes belonging to the following 17 genera: Agonis, Austromyrtus, Beaufortia, Callistemon, Calothamnus, Chamelaucium, Darwinia, Eucalyptus, Gossia, Kunzea, Leptospermum, Melaleuca, Metrosideros, Syzygium, Thryptomene, Tristania, Verticordia. In contrast, the remaining 83 taxa inoculated, including the majority of Corymbia and Eucalyptus species, developed a broad range of symptoms, often across the full spectrum, from fully-developed uredinia to no visible symptoms. These results were encouraging as they indicate that some levels of genetic resistance to the rust possibly exist in these taxa. Overall, our results indicated no apparent association between the presence or absence of disease symptoms and the phylogenetic relatedness of taxa. It is most likely that the majority of the thousands of Myrtaceae species found in Australia have the potential to become infected to some degree by the rust, although this wide host range may not be fully realized in the field. PMID- 22523597 TI - The HSP90 inhibitor NVP-AUY922 radiosensitizes by abrogation of homologous recombination resulting in mitotic entry with unresolved DNA damage. AB - BACKGROUND: Heat shock protein 90 (HSP90) is a molecular chaperone responsible for the conformational maintenance of a number of client proteins that play key roles in cell cycle arrest, DNA damage repair and apoptosis following radiation. HSP90 inhibitors exhibit antitumor activity by modulating the stabilisation and activation of HSP90 client proteins. We sought to evaluate NVP-AUY922, the most potent HSP90 inhibitor yet reported, in preclinical radiosensitization studies. PRINCIPAL FINDINGS: NVP-AUY922 potently radiosensitized cells in vitro at low nanomolar concentrations with a concurrent depletion of radioresistance-linked client proteins. Radiosensitization by NVP-AUY922 was verified for the first time in vivo in a human head and neck squamous cell carcinoma xenograft model in athymic mice, as measured by delayed tumor growth and increased surrogate end point survival (p = <0.0001). NVP-AUY922 was shown to ubiquitously inhibit resolution of dsDNA damage repair correlating to delayed Rad51 foci formation in all cell lines tested. Additionally, NVP-AUY922 induced a stalled mitotic phenotype, in a cell line-dependent manner, in HeLa and HN5 cell lines irrespective of radiation exposure. Cell cycle analysis indicated that NVP-AUY922 induced aberrant mitotic entry in all cell lines tested in the presence of radiation-induced DNA damage due to ubiquitous CHK1 depletion, but resultant downstream cell cycle effects were cell line dependent. CONCLUSIONS: These results identify NVP-AUY922 as the most potent HSP90-mediated radiosensitizer yet reported in vitro, and for the first time validate it in a clinically relevant in vivo model. Mechanistic analysis at clinically achievable concentrations demonstrated that radiosensitization is mediated by the combinatorial inhibition of cell growth and survival pathways, ubiquitous delay in Rad51-mediated homologous recombination and CHK1-mediated G(2)/M arrest, but that the contribution of cell cycle perturbation to radiosensitization may be cell line specific. PMID- 22523598 TI - Structural and functional characterization of mature forms of metalloprotease E495 from Arctic sea-ice bacterium Pseudoalteromonas sp. SM495. AB - E495 is the most abundant protease secreted by the Arctic sea-ice bacterium Pseudoalteromonas sp. SM495. As a thermolysin family metalloprotease, E495 was found to have multiple active forms in the culture of strain SM495. E495-M (containing only the catalytic domain) and E495-M-C1 (containing the catalytic domain and one PPC domain) were two stable mature forms, and E495-M-C1-C2 (containing the catalytic domain and two PPC domains) might be an intermediate. Compared to E495-M, E495-M-C1 had similar affinity and catalytic efficiency to oligopeptides, but higher affinity and catalytic efficiency to proteins. The PPC domains from E495 were expressed as GST-fused proteins. Both of the recombinant PPC domains were shown to have binding ability to proteins C-phycocyanin and casein, and domain PPC1 had higher affinity to C-phycocyanin than domain PPC2. These results indicated that the domain PPC1 in E495-M-C1 could be helpful in binding protein substrate, and therefore, improving the catalytic efficiency. Site-directed mutagenesis on the PPC domains showed that the conserved polar and aromatic residues, D26, D28, Y30, Y/W65, in the PPC domains played key roles in protein binding. Our study may shed light on the mechanism of organic nitrogen degradation in the Arctic sea ice. PMID- 22523599 TI - Bmcc1s, a novel brain-isoform of Bmcc1, affects cell morphology by regulating MAP6/STOP functions. AB - The BCH (BNIP2 and Cdc42GAP Homology) domain-containing protein Bmcc1/Prune2 is highly enriched in the brain and is involved in the regulation of cytoskeleton dynamics and cell survival. However, the molecular mechanisms accounting for these functions are poorly defined. Here, we have identified Bmcc1s, a novel isoform of Bmcc1 predominantly expressed in the mouse brain. In primary cultures of astrocytes and neurons, Bmcc1s localized on intermediate filaments and microtubules and interacted directly with MAP6/STOP, a microtubule-binding protein responsible for microtubule cold stability. Bmcc1s overexpression inhibited MAP6-induced microtubule cold stability by displacing MAP6 away from microtubules. It also resulted in the formation of membrane protrusions for which MAP6 was a necessary cofactor of Bmcc1s. This study identifies Bmcc1s as a new MAP6 interacting protein able to modulate MAP6-induced microtubule cold stability. Moreover, it illustrates a novel mechanism by which Bmcc1 regulates cell morphology. PMID- 22523600 TI - Association of combined p73 and p53 genetic variants with tumor HPV16-positive oropharyngeal cancer. AB - p53 and p73 interact with human papillomavirus (HPV) E6 and E7 oncoproteins. The interplay between p53 and p73 and HPV16 may lead to deregulation of cell cycle and apoptosis, through which inflammation/immune responses control the HPV clearance and escape of immune surveillance, and subsequently contribute to tumor HPV16 status. In this case-case comparison study, HPV16 status in tumor specimens was analyzed and p53 codon 72 and p73 G4C14-to-A4T14 polymorphisms were genotyped using genomic DNA from blood of 309 oropharyngeal cancer patients. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated in univariate and multivariable logistic regression models to examine the association. The results from this study showed both p53 variant genotypes (Arg/Pro+Pro/Pro) and p73 variant genotypes (GC/AT+AT/AT) were significantly associated with HPV16-positive tumor in oropharyngeal cancer patients (OR, 1.9, 95% CI, 1.1-3.3 and OR, 2.1, 95% CI, 1.2-3.8, respectively), while the combined variant genotypes (p53 Pro carriers and p73 AT carriers) exhibited a significantly greater association with HPV16-positive tumor (OR, 3.2, 95% CI, 1.4-7.4), compared with combined wild-type genotypes (p53 Arg/Arg and p73 GC/GC), and the association was in a statistically significant dose-effect relationship (p = 0.001). Moreover, such association was more pronounced among several subgroups. These findings suggest that variant genotypes of p53 and p73 genes may be individually, or more likely jointly, associated with tumor HPV16-positive oropharyngeal cancer patients, particularly in never smokers. Identification of such susceptible biomarkers would greatly influence on individualized treatment for an improved prognosis. PMID- 22523601 TI - Deep RNA sequencing reveals novel cardiac transcriptomic signatures for physiological and pathological hypertrophy. AB - Although both physiological hypertrophy (PHH) and pathological hypertrophy (PAH) of the heart have similar morphological appearances, only PAH leads to fatal heart failure. In the present study, we used RNA sequencing (RNA-Seq) to determine the transcriptomic signatures for both PHH and PAH. Approximately 13-20 million reads were obtained for both models, among which PAH showed more differentially expressed genes (DEGs) (2,041) than PHH (245). The expression of 417 genes was barely detectable in the normal heart but was suddenly activated in PAH. Among them, Foxm1 and Plk1 are of particular interest, since Ingenuity Pathway Analysis (IPA) using DEGs and upstream motif analysis showed that they are essential hub proteins that regulate the expression of downstream proteins associated with PAH. Meanwhile, 52 genes related to collagen, chemokines, and actin showed opposite expression patterns between PHH and PAH. MAZ-binding motifs were enriched in the upstream region of the participating genes. Alternative splicing (AS) of exon variants was also examined using RNA-Seq data for PAH and PHH. We found 317 and 196 exon inclusions and exon exclusions, respectively, for PAH, and 242 and 172 exon inclusions and exclusions, respectively for PHH. The AS pattern was mostly related to gains or losses of domains, changes in activity, and localization of the encoded proteins. The splicing variants of 8 genes (i.e., Fhl1, Rcan1, Ndrg2, Synpo, Ttll1, Cxxc5, Egfl7, and Tmpo) were experimentally confirmed. Multilateral pathway analysis showed that the patterns of quantitative (DEG) and qualitative (AS) changes differ depending on the type of pathway in PAH and PHH. One of the most significant changes in PHH is the severe downregulation of autoimmune pathways accompanied by significant AS. These findings revealed the unique transcriptomic signatures of PAH and PHH and also provided a more comprehensive understanding at both the quantitative and qualitative levels. PMID- 22523602 TI - The adult human brain harbors multipotent perivascular mesenchymal stem cells. AB - Blood vessels and adjacent cells form perivascular stem cell niches in adult tissues. In this perivascular niche, a stem cell with mesenchymal characteristics was recently identified in some adult somatic tissues. These cells are pericytes that line the microvasculature, express mesenchymal markers and differentiate into mesodermal lineages but might even have the capacity to generate tissue specific cell types. Here, we isolated, purified and characterized a previously unrecognized progenitor population from two different regions in the adult human brain, the ventricular wall and the neocortex. We show that these cells co express markers for mesenchymal stem cells and pericytes in vivo and in vitro, but do not express glial, neuronal progenitor, hematopoietic, endothelial or microglial markers in their native state. Furthermore, we demonstrate at a clonal level that these progenitors have true multilineage potential towards both, the mesodermal and neuroectodermal phenotype. They can be epigenetically induced in vitro into adipocytes, chondroblasts and osteoblasts but also into glial cells and immature neurons. This progenitor population exhibits long-term proliferation, karyotype stability and retention of phenotype and multipotency following extensive propagation. Thus, we provide evidence that the vascular niche in the adult human brain harbors a novel progenitor with multilineage capacity that appears to represent mesenchymal stem cells and is different from any previously described human neural stem cell. Future studies will elucidate whether these cells may play a role for disease or may represent a reservoir that can be exploited in efforts to repair the diseased human brain. PMID- 22523603 TI - Genetic screening of new genes responsible for cellular adaptation to hypoxia using a genome-wide shRNA library. AB - Oxygen is a vital requirement for multi-cellular organisms to generate energy and cells have developed multiple compensatory mechanisms to adapt to stressful hypoxic conditions. Such adaptive mechanisms are intricately interconnected with other signaling pathways that regulate cellular functions such as cell growth. However, our understanding of the overall system governing the cellular response to the availability of oxygen remains limited. To identify new genes involved in the response to hypoxic stress, we have performed a genome-wide gene knockdown analysis in human lung carcinoma PC8 cells using an shRNA library carried by a lentiviral vector. The knockdown analysis was performed under both normoxic and hypoxic conditions to identify shRNA sequences enriched or lost in the resulting selected cell populations. Consequently, we identified 56 candidate genes that might contribute to the cellular response to hypoxia. Subsequent individual knockdown of each gene demonstrated that 13 of these have a significant effect upon oxygen-sensitive cell growth. The identification of BCL2L1, which encodes a Bcl-2 family protein that plays a role in cell survival by preventing apoptosis, validates the successful design of our screen. The other selected genes have not previously been directly implicated in the cellular response to hypoxia. Interestingly, hypoxia did not directly enhance the expression of any of the identified genes, suggesting that we have identified a new class of genes that have been missed by conventional gene expression analyses to identify hypoxia response genes. Thus, our genetic screening method using a genome-wide shRNA library and the newly-identified genes represent useful tools to analyze the cellular systems that respond to hypoxic stress. PMID- 22523604 TI - Cell cycle dependent association of EBP50 with protein phosphatase 2A in endothelial cells. AB - Ezrin-radixin-moesin (ERM)-binding phosphoprotein 50 (EBP50) is a phosphorylatable PDZ domain-containing adaptor protein that is abundantly expressed in epithelium but was not yet studied in the endothelium. We report unusual nuclear localization of EBP50 in bovine pulmonary artery endothelial cells (BPAEC). Immunofluorescent staining and cellular fractionation demonstrated that EBP50 is present in the nuclear and perinuclear region in interphase cells. In the prophase of mitosis EBP50 redistributes to the cytoplasmic region in a phosphorylation dependent manner and during mitosis EBP50 co-localizes with protein phosphatase 2A (PP2A). Furthermore, in vitro wound healing of BPAEC expressing phospho-mimic mutant of EBP50 was accelerated indicating that EBP50 is involved in the regulation of the cell division. Cell cycle dependent specific interactions were detected between EBP50 and the subunits of PP2A (A, C, and Balpha) with immunoprecipitation and pull-down experiments. The interaction of EBP50 with the Balpha containing form of PP2A suggests that this holoenzyme of PP2A can be responsible for the dephosphorylation of EBP50 in cytokinesis. Moreover, the results underline the significance of EBP50 in cell division via reversible phosphorylation of the protein with cyclin dependent kinase and PP2A in normal cells. PMID- 22523605 TI - Reversible Control of Third-Order Optical Nonlinearity of DNA Decorated Carbon Nanotube Hybrids. AB - Positive and negative third-order optical nonlinearities have been investigated in single-stranded DNA wrapped semiconducting single-walled carbon nanotubes. It is found that the redox reactions of hydrogen peroxide can reverse the sign of the third-order nonlinearity. The observation proves that the lowest unoccupied molecular orbital has a lower density of electronic states than that of the highest occupied molecular orbital. A three-energy-level model is used to explain the effect of the redox reactions. Raman spectroscopy has also been used to investigate the interaction between single-walled carbon nanotubes and single stranded DNA. PMID- 22523606 TI - The Cassava Genome: Current Progress, Future Directions. AB - The starchy swollen roots of cassava provide an essential food source for nearly a billion people, as well as possibilities for bioenergy, yet improvements to nutritional content and resistance to threatening diseases are currently impeded. A 454-based whole genome shotgun sequence has been assembled, which covers 69% of the predicted genome size and 96% of protein-coding gene space, with genome finishing underway. The predicted 30,666 genes and 3,485 alternate splice forms are supported by 1.4 M expressed sequence tags (ESTs). Maps based on simple sequence repeat (SSR)-, and EST-derived single nucleotide polymorphisms (SNPs) already exist. Thanks to the genome sequence, a high-density linkage map is currently being developed from a cross between two diverse cassava cultivars: one susceptible to cassava brown streak disease; the other resistant. An efficient genotyping-by-sequencing (GBS) approach is being developed to catalog SNPs both within the mapping population and among diverse African farmer-preferred varieties of cassava. These resources will accelerate marker-assisted breeding programs, allowing improvements in disease-resistance and nutrition, and will help us understand the genetic basis for disease resistance. PMID- 22523607 TI - Congenital adrenal hyperplasia. AB - Congenital adrenal hyperplasia consists of a heterogenous group of inherited disorders due to enzymatic defects in the biosynthetic pathway of cortisol and/or aldosterone. This results in glucocorticoid deficiency, mineralocorticoid deficiency, and androgen excess. 95% of CAH cases are due to 21-hydroxylase deficiency. Clinical forms range from the severe, classical CAH associated with complete loss of enzyme function, to milder, non-classical forms (NCAH). Androgen excess affects the pilosebaceous unit, causing cutaneous manifestations such as acne, androgenetic alopecia and hirsutism. Clinical differential diagnosis between NCAH and polycystic ovary syndrome may be difficult. In this review, the evaluation of patients with suspected CAH, the clinical presentation of CAH forms, with emphasis on the cutaneous manifestations of the disease, and available treatment options, will be discussed. PMID- 22523608 TI - The use of classification trees for bioinformatics. AB - Classification trees are non-parametric statistical learning methods that incorporate feature selection and interactions, possess intuitive interpretability, are efficient, and have high prediction accuracy when used in ensembles. This paper provides a brief introduction to the classification tree based methods, a review of the recent developments, and a survey of the applications in bioinformatics and statistical genetics. PMID- 22523609 TI - CBT Specific Process in Exposure-Based Treatments: Initial Examination in a Pediatric OCD Sample. AB - Cognitive-Behavioral theory and empirical support suggest that optimal activation of fear is a critical component for successful exposure treatment. Using this theory, we developed coding methodology for measuring CBT-specific process during exposure. We piloted this methodology in a sample of young children (N = 18) who previously received CBT as part of a randomized controlled trial. Results supported the preliminary reliability and predictive validity of coding variables with 12 week and 3 month treatment outcome data, generally showing results consistent with CBT theory. However, given our limited and restricted sample, additional testing is warranted. Measurement of CBT-specific process using this methodology may have implications for understanding mechanism of change in exposure-based treatments and for improving dissemination efforts through identification of therapist behaviors associated with improved outcome. PMID- 22523610 TI - Colon capsule endoscopy: Advantages, limitations and expectations. Which novelties? AB - Since the first reports almost ten years ago, wireless capsule endoscopy has gained new fields of application. Colon capsule endoscopy represents a new diagnostic technology for colonic exploration. Clinical trials have shown that colon capsule endoscopy is feasible, accurate and safe in patients suffering from colonic diseases and might be a valid alternative to conventional colonoscopy in selected cases such as patients refusing conventional colonoscopy or with contraindications to colonoscopy or when colonoscopy is incomplete. Despite the enthusiasm surrounding this new technique, few clinical and randomized controlled trials are to be found in the current literature, leading to heterogeneous or controversial results. Upcoming studies are needed to prove the substantial utility of colon capsule endoscopy for colon cancer screening, especially in a low prevalence of disease population, and for other indications such as inflammatory bowel disease. Possible perspectives are critically analysed and reported in this paper. PMID- 22523611 TI - Colorectal cancer surveillance in patients with inflammatory bowel disease: What is new? AB - Several studies assessing the incidence of colorectal cancer (CRC) in inflammatory bowel disease (IBD) patients have found an increased risk globally estimated to be 2 to 5 times higher than for the general population of the same age group. The real magnitude of this risk, however, is still open to debate. Research is currently being carried out on several risk and protective factors for CRC that have recently been identified in IBD patients. A deeper understanding of these factors could help stratify patient risk and aid specialists in choosing which surveillance program is most efficient. There are several guidelines for choosing the correct surveillance program for IBD patients; many present common characteristics with various distinctions. Current recommendations are far from perfect and have important limitations such as the fact that their efficiency has not been demonstrated through randomized controlled trials, the limited number of biopsies performed in daily endoscopic practice, and the difficulty in establishing the correct time to begin a given surveillance program and maintain a schedule of surveillance. That being said, new endoscopic technologies should help by replacing random biopsy protocols with targeted biopsies in IBD patients, thereby improving the efficiency of surveillance programs. However, further studies are needed to evaluate the cost effectiveness of introducing these techniques into daily endoscopic practice. PMID- 22523612 TI - Update on endoscopic diagnosis, management and surveillance strategies of esophageal diseases. AB - In the last few decades, upper gastrointestinal endoscopy has become the most complementary test for investigation of esophageal diseases. Its accessibility and safety guarantee wide clinical utilization in patients with suspected benign and malignant diseases of the esophagus. Recent technological advances in endoscopic imaging and tissue analysis obtained from the esophagus have been useful to better understand and manage highly relevant diseases such as gastroesophageal reflux disease, eosinophilic esophagitis and esophageal cancer. Using endoscopy to elucidate esophageal disorders in children has been another field of intensive and challenging research. This editorial highlights the latest advances in the endoscopic management of esophageal diseases, and focuses on Barrett's esophagus, esophageal cancer, eosinophilic esophagitis, as well as esophageal disorders in the pediatric population. PMID- 22523613 TI - Endoscopic submucosal dissection for removal of superficial gastrointestinal neoplasms: A technical review. AB - Endoscopic submucosal dissection (ESD) is now the most common endoscopic treatment in Japan for intramucosal gastrointestinal neoplasms (non-metastatic). ESD is an invasive endoscopic surgical procedure, requiring extensive knowledge, skill, and specialized equipment. ESD starts with evaluation of the lesion, as accurate assessment of the depth and margin of the lesion is essential. The devices and strategies used in ESD vary, depending on the nature of the lesion. Prior to the procedure, the operator must be knowledgeable about the treatment strategy(ies), the device(s) to use, the electrocautery machine settings, the substances to inject, and other aspects. In addition, the operator must be able to manage complications, should they arise, including immediate recognition of the complication(s) and its treatment. Finally, in case the ESD treatment is not successful, the operator should be prepared to apply alternative treatments. Thus, adequate knowledge and training are essential to successfully perform ESD. PMID- 22523614 TI - Unsedated colonoscopy: A neverending story. AB - Although sedation and analgesia for patients undergoing colonoscopy is the standard practice in Western countries, unsedated colonoscopy is still routinely provided in Europe and the Far East. This variation in sedation practice relies on the different cultural attitudes of both patients and endoscopists across these countries. Data from the literature consistently report that, in unsedated patients, the use of alternative techniques, such as warm water irrigation or carbon dioxide insufflation, can allow a high quality and well tolerated examination. PMID- 22523615 TI - Use of fully covered self-expanding metal stents in benign biliary diseases. AB - Biliary fully covered self-expanding metal stents (FCSEMS) are now being used to treat several benign biliary conditions. Advantages include small predeployment and large postexpansion diameters in addition to an easy insertion technique. Lack of imbedding of the metal into the bile duct wall enables removability. In benign biliary strictures that usually require multiple procedures, despite the substantially higher cost of FCSEMS compared with plastic stents, the use of FCSEMS is offset by the reduced number of endoscopic retrograde cholangiopancreatography interventions required to achieve stricture resolution. In the same way, FCSEMS have also been employed to treat complex bile leaks, perforation and bleeding after endoscopic biliary sphincterotomy and as an aid to maintain permanent drainage tracts obtained by means of Endoscopic Ultrasound guided biliary drainage. Good success rates have been achieved in all these conditions with an acceptable number of complications. FCSEMS were successfully removed in all patients. Comparative studies of FCSEMS and plastic stents are needed to demonstrate efficacy and cost-effectiveness. PMID- 22523616 TI - Covered self expandable metallic stent with flared plastic one inside for pancreatic pseudocyst avoiding stent dislodgement. AB - Endoscopic ultrasound-guided drainage has recently been recommended for increasing the drainage rate of endoscopically managed pancreatic fluid collections and decreasing the morbidity associated with conventional endoscopic trans-mural drainage. The type of stent used for endoscopic drainage is currently a major area of interest. A covered self expandable metallic stent (CSEMS) is an alternative to conventional drainage with plastic stents because it offers the option of providing a larger-diameter access fistula for drainage, and may increase the final success rate. One problem with CSEMS is dislodgement, so a metallic stent with flared or looped ends at both extremities may be the best option. An 85-year-old woman with severe co-morbidity was treated with percutaneous approach for a large (20 cm) pancreatic pseudocyst with corpuscolated material inside. This approach failed. The patient was transferred to our institute for EUS-guided transmural drainage. EUS confirmed a large, anechoic cyst with hyperechoic material inside. Because the cyst was large and contained mixed and corpusculated fluid, we used a metallic stent for drainage. To avoid migration of the stent and potential mucosal growth above the stent, a plastic prosthesis (7 cm, 10 Fr) with flaps at the tips was inserted inside the CSEMS. Two months later an esophagogastroduodenoscopy was done, and showed patency of the SEMS and plastic stents, which were then removed with a polypectomy snare. The patient experienced no further problems. PMID- 22523617 TI - A case of gastric mucosa-associated lymphoid tissue lymphoma in which magnified endoscopy with narrow band imaging was useful in the diagnosis. AB - Recently, we reported a case of gastric mucosa-associated lymphoid tissue (MALT) lymphoma presenting with unique vascular features. In the report, we defined the tree-like appearance (TLA) on the images of abnormal blood vessels which resembled branches from the trunk of a tree in the shiny mucosa, in which the glandular structure was lost. The 67-year-old female was diagnosed with gastric MALT lymphoma. The patient received eradication therapy for H. pylori. Conventional endoscopy revealed multiple ill-delineated brownish depressions in the stomach and cobblestone-like mucosa was observed at the greater curvature to the posterior wall of the upper gastric body 7 mo after successful eradication. Unsuccessful treatment of gastric MALT lymphoma was suspected on conventional endoscopy. Conventional endoscopic observations found focal depressions and cobblestone-like appearance, and these lesions were subsequently observed using magnified endoscopy combined with narrow band imaging to identify abnormal vessels presenting with a TLA within the lesions. Ten biopsies were taken from the area where abnormal vessels were present within these lesions. Ten biopsies were also taken from the lesions without abnormal vessels as a control. A total of 20 biopsy samples were evaluated to determine whether the diagnosis of MALT lymphoma could be obtained histologically from each sample. A positive diagnosis was obtained in 8/10 TLA (+) sites and in 2/10 TLA(-) sites. Target biopsies of the site with abnormal blood vessels can potentially improve diagnostic accuracy of gastric MALT lymphoma. PMID- 22523618 TI - Synthesis and Evaluation of Metabotropic Glutamate Receptor Subtype 5 Antagonists Based on Fenobam(). AB - In an effort to discover potent and selective metabotropic glutamate receptor subtype 5 (mGluR5) antagonists, 15 tetrahydropyrimidinone analogues of 1-(3 chlorophenyl)-3-(1-methyl-4-oxo-4,5-dihydro-1H-imidazol-2-yl)-urea (fenobam) were synthesized. These compounds were evaluated for antagonism of glutamate-mediated mobilization of internal calcium in an mGluR5 in vitro efficacy assay. The IC(50) value for 1-(3-chlorophenyl)-3-(1-methyl-4-oxo-1,4,5,6-tetrahydropyridine)urea (4g) was essentially identical to that of fenobam. PMID- 22523621 TI - How to make the best strategy to manage thromboembolism in ovarian cancer? PMID- 22523620 TI - Three ongoing intraperitoneal chemotherapy trials in ovarian cancer. PMID- 22523619 TI - Computer Simulations of Voltage-Gated Cation Channels. AB - The relentless growth in computational power has seen increasing applications of molecular dynamics (MD) simulation to the study of membrane proteins in realistic membrane environments, which include explicit membrane lipids, water and ions. The concomitant increasing availability of membrane protein structures for ion channels, and transporters -- to name just two examples -- has stimulated many of these MD studies. In the case of voltage-gated cation channels (VGCCs) recent computational works have focused on ion-conduction and gating mechanisms, along with their regulation by agonist/antagonist ligands. The information garnered from these computational studies is largely inaccessible to experiment and is crucial for understanding the interplay between the structure and function as well as providing new directions for experiments. This article highlights recent advances in probing the structure and function of potassium channels and offers a perspective on the challenges likely to arise in making analogous progress in characterizing sodium channels. PMID- 22523622 TI - Indications for endoscopy according to the revised FIGO staging for cervical cancer after MRI and CT scanning. AB - OBJECTIVE: A recent revision of the FIGO staging system does not recommend the mandatory use of cystoscopy and sigmoidoscopy. The objective of this study was to assess the clinical utility of CT or MRI scans for ruling out bladder or rectal invasion and determine the indication for endoscopy in patients with cervical cancer. METHODS: We retrospectively reviewed 769 patients with cervical cancer, who underwent imaging and endoscopic work-up between January 1997 and December 2010. Using endoscopy as the standard reference for comparison, we calculated the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of the imaging modality for bladder or rectal invasion. RESULTS: The CT scan showed 68.2% and 85.7% for sensitivity and 96.4% and 98.9% for specificity in detecting bladder and rectal invasion, respectively. CT scan provided a low PPV (51.7%, 54.5%) and a high NPV (98.2%, 99.8%). MRI scan showed 88.0% and 75.0% for sensitivity and 93.1% and 98.9% for specificity in detecting bladder and rectal invasion, respectively. MRI scan provided a low PPV (35.6%, 42.9%) and a high NPV (99.4%, 99.7%). The accuracies of CT and MRI scans in identifying bladder invasion were 94.9% and 92.8%, respectively. The accuracies of CT and MRI in identifying rectal invasion were 98.7% and 98.6%, respectively. CONCLUSION: The results of this study demonstrate that additional invasive endoscopy is not necessary for patients who present with no invasion on imaging work-up, and therefore, endoscopy should be considered a tool for confirming cases that are positive for invasion based on imaging work-up. PMID- 22523623 TI - Thrombopoietin: a novel candidate tumor marker for the diagnosis of ovarian cancer. AB - OBJECTIVE: To investigate the decisive role of preoperative serum thrombopoietin levels in the discrimination of benign and malignant ovarian pathologies and its value in the evaluation of treatment response. METHODS: Fifty patients with diagnoses of adnexal masses (25 benign, 25 malignant) were included in the study. Blood samples were collected from all cases preoperatively. Age, menopausal status, adnexal mass size, preoperative CA-125 level, platelet count, the stage of the disease (FIGO stage), tumor grade, histologic subgroup, the residual tumor mass, ascites cytology, surgical procedures, and postoperative treatments were recorded for the malignant group. Response to treatment was evaluated based on the revised RECIST guideline. RESULTS: The preoperative serum thrombopoietin levels of the malignant cases (median, 98; range, 7 to 768) were significantly higher when compared with those of benign cases (median, 27; range, 13 to 131; p=0.004). The positive predictive value of CA-125 was found to be 79%, when it was used as a single marker; however it had risen to 85% when both CA-125 and thrombopoietin levels were used. There was no significant relationship between preoperative serum thrombopoietin levels and tumor grade, ascites cytology, presence of residual mass, and response to treatment. The preoperative serum thrombopoietin levels were significantly higher in stage III-IV cases and cases with serous histology. The post-treatment serum thrombopoietin levels in the malignant group were significantly lower as compared with the preoperative thrombopoietin levels. CONCLUSION: Thrombopoietin can play an additive role for prediction of ovarian cancer. PMID- 22523624 TI - Intraoperative intraperitoneal chemotherapy with cisplatin in epithelial ovarian cancer. AB - OBJECTIVE: To assess retrospectively the feasibility of intraoperative intraperitoneal (IP) chemotherapy with cisplatin in epithelial ovarian cancer. METHODS: IP chemotherapy during optimal staging surgery was performed in 10 patients who were diagnosed with primary epithelial ovarian cancers between April 2008 and February 2011. Cisplatin (70 mg/m(2) in 1 L normal saline solution) was administered in the abdominal cavity for 24 hours postoperatively and then adjuvant chemotherapy was started 2-4 weeks after surgery. Perioperative toxicity of the combined treatment was evaluated until the initiation of postoperative adjuvant chemotherapy. RESULTS: A total of 23 adverse events were observed in 9 of 10 patients (grade 1, 7; grade 2, 13; grade 3, 3; grade 4, 0). In descending order of frequency, adverse events affected the gastrointestinal system (n=14), hematologic system (n=6), pulmonary system (n=2), and genito-urinary system (n=1). The adverse events did not affect adjuvant systemic chemotherapy schedules. One patient experienced disease recurrence in the liver 16 months after surgery. The remaining 9 patients have been well controlled by chemotherapy and/or observation during the follow-up period of 4 to 39 months after surgery. CONCLUSION: Intraoperative IP chemotherapy with cisplatin during surgical procedures is considered feasible for the treatment of primary epithelial ovarian cancer. Further studies, including long-term, prospective and comparative trials, are needed to validate the efficacy of this combined therapy. PMID- 22523625 TI - Cut-off value of D-dimer for prediction of deep venous thrombosis before treatment in ovarian cancer. AB - OBJECTIVE: The purpose of the present study was to elucidate the incidence of deep venous thrombosis (DVT) before treatment in ovarian cancer and the appropriate cut-off value of D-dimer (DD) for the diagnosis of DVT. METHODS: Between July 2007 and October 2008, eighty seven patients with presumed ovarian cancer (final diagnosis: ovarian cancer, n=59; borderline malignancy, n=28) were enrolled. Measurement of DD levels and subsequent venous ultrasonography were performed before treatment. RESULTS: The mean DD level was 4.1 ug/mL. Subsequent venous ultrasonography revealed DVT in 14 of 87 (16.1%) patients (ovarian cancer, 12 cases; borderline malignancy, 2 cases). None were found to have developed DVT if they had a DD level of <1.5 ug/mL. If 1.5 ug/mL was used as a cut-off value for DD levels to diagnose DVT, sensitivity, specificity, positive predictive value, and negative predictive value were 100%, 61.6%, 33.3%, and 100%. There was noclinical onset of postoperative pulmonary thromboembolism. CONCLUSION: Our data suggest that presumed ovarian cancer patients with at least more than 1.5 ug/mL should be examined using venous ultrasonogaphy to detect DVT. PMID- 22523626 TI - Changes in biologic markers of oxidative stress and plasma endotoxin levels in gynecologic cancer patients treated with pelvic radiotherapy: a pilot study. AB - OBJECTIVE: We conducted a pilot study to evaluate the effects of pelvic radiotherapy on biologic markers of oxidative stress and plasma endotoxin levels, and to assess the relationship between the changes of such factors and radiotherapy-related complications. METHODS: Twelve gynecologic cancer patients who were treated via pelvic radiotherapy with or without concurrent chemotherapy were enrolled in this study. Biologic markers of oxidative stress, such as glutathione (GSH) and oxidized glutathione (GSSG), as well as endotoxin levels, were measured weekly during treatment. Subjective symptoms were assessed using the Korean version of the EORTC QLQ-C30 at the baseline and on the 5th week of radiotherapy. RESULTS: No changes were noted in the level of GSH in whole blood, but the GSH/GSSG ratio was reduced dramatically after the initiation of radiotherapy. The mean plasma endotoxin for all patients tended to increase and persisted during radiotherapy, and the number of patients who evidenced clinically significant endotoxin levels (defined as >0.005 EU/mL) also increased. Nausea/vomiting and diarrhea were significantly changed (p=0.019 and p<0.001, respectively). A significant relationship was noted to exist between the changes in the endotoxin level and nausea/vomiting (p=0.001). However, such symptoms did not correlate with the changes of oxidative stress markers. CONCLUSION: Pelvic radiotherapy oxidized the GSH redox system and increased plasma endotoxin. Further investigations containing interventional and longitudinal studies will be required to assess the effects of the changes in oxidative stress markers and endotoxin on radiotherapy-related adverse events. PMID- 22523627 TI - Does ductal lavage assert its role as a noninvasive diagnostic modality to identify women at low risk of breast cancer development? AB - OBJECTIVE: Ductal lavage (DL) involves evaluation of the ductal system of the breast for detection of intra-ductal carcinomas and precursor lesions by collecting breast epithelial cells using a small-gauge catheter inserted into a ductal orifice on the nipple. The aim of this survey was to analyze cytologic features of samples obtained from low-risk women with DL and to elucidate the efficacy of this diagnostic modality in evaluating fluid production, cannulating and determining atypical breast epithelial cells. METHODS: Into this prospective study were consecutively registered 80 women between ages 28 to 67. Nipple aspiration was performed to identify all fluid-yielding ducts. According to the grading of specific features the interpretation of the sample included: normal/benign (category, 0), mild atypical (category, I), markedly atypical (category, II) or malignant (category, III) disorders. RESULTS: Ninety five percent (316/334) of the nipple aspirate fluid samples were classified as category 0, 4.8% (16/334) as category I and 0.2% (2/334) as category II changes. Category III disorders were not detected. Therefore, in 80% of the women examined results were within normal limits while 17.5% of the participants presented mild atypical and 2.5% markedly atypical rates. CONCLUSION: DL collection procedure proved to be rapid as well as acceptable by the women studied. It retains the advantage over other methods of nipple aspirate fluid in that it is easy to perform, thereby removing most clinician variability. It also helped low risk women to discriminate those with breast disorders that require additional investigation, further follow-up or administration of preventive medication. PMID- 22523628 TI - Photodynamic therapy for breast cancer in a BALB/c mouse model. AB - OBJECTIVE: Photodynamic therapy (PDT) has been used for superficial neoplasms and its usage has been recently extended to deeper lesions. The purpose of this study was to observe whether or not PDT can cure breast cancer in the solid tumor model, and to define the critical point of laser amount for killing the cancer cells. METHODS: Twenty four BALB/c mouse models with subcutaneous EMT6 mammary carcinomas were prepared. Mice were divided into eight groups depending on the amount of illumination, and the tumor size was between 8 mm and 10 mm. We began by peritoneal infiltration with a photosensitizer 48 hours prior to applying the laser light, and then we applied a non-thermal laser light. The energy was from 350 J/cm(2) to 30 J/cm(2) to the cancer. RESULTS: Regardless of the tumor size from 8 mm to 10 mm, all mice apparently showed positive results via PDT. We also did not find any recurrence over 90 J/cm(2). In all models, the color of the breast cancer lesions began to vary to dark on 2 days post PDT and the tumor regression began simultaneously. Also, we confirmed the complete regression of the breast cancer 21 days after PDT. CONCLUSION: We confirmed that PDT may treat breast cancers that are sized less 10 mm in mouse models. The moderate energy to destruct the breast cancer cells may be 90 J/cm(2). Therefore, we can expcect that PDT may be utilized to treat breast cancer, but we need more experience, skills and processing for clinical trials. PMID- 22523629 TI - Fertility-sparing treatment of endometrial cancer: options, outcomes and pitfalls. AB - Endometrial cancer is the most common gynecologic malignancy in the United States, with over 40,000 cases diagnosed each year. While a majority of cases are diagnosed in post-menopausal women, up to 14% of cases will be in pre-menopausal women, including 4% diagnosed in women less than 40 years of age. While hysterectomy with bilateral salpingo-oophorectomy with assessment of the retroperitoneal lymph nodes is standard initial treatment for endometrial cancer, younger women may desire fertility sparing options. The decision to proceed with conservative management in this younger patient population is associated with multiple complexities, including the inherent oncologic risks of an inadequately staged and treated endometrial cancer, the risk of a synchronous or meta synchronous cancer, the increased risk of an inherited genetic predisposition to malignancy and the lack of uniformity in the medical management and surveillance. In this review we will discuss the conservative management of endometrial cancer, specifically the role of progestin hormonal therapy, including the risks associated with non-standard care, appropriate candidate selection and work up, expected outcomes, various progestin agents and recommended follow-up. PMID- 22523630 TI - Early diagnosis of malignant-transformed ovarian mature cystic teratoma: fat suppressed MRI findings. AB - The most common form of malignant transformation developing from a mature cystic teratoma is squamous cell carcinoma, representing 80% of malignant transformations, while adenocarcinoma accounts for approximately 5%. Because of this rarity, few reports exist of preoperative diagnosis of this tumor by magnetic resonance imaging, in particular with fat suppression techniques. Here, we report magnetic resonance imaging findings and clinical features of a 79-year old woman with mucinous adenocarcinoma arising from a mature cystic teratoma (measuring 5*6 cm), classified as surgical stage IA. Because of the poor prognosis of malignant transformation, when mature cystic teratomas are detected (even smaller than 5 cm tumor size) in postmenopausal women, serum tumor marker carcinoembryonic antigen levels and fat-suppressed magnetic resonance imaging may be potential indicators of malignant transformation. PMID- 22523631 TI - Successful pregnancy following transfer of frozen-thawed embryos in a patient with pseudomyxoma peritonei who underwent peritonectomy and bilateral oophorectomy. AB - Pseudomyxoma peritonei is a rare, chronic relapsing disease in which tumor cells in the abdomen produce excessive mucin with a significant mortality rate. We describe a young unmarried nulligrava who underwent fertility preservation by in vitro fertilisation and embryo cryopreservation prior to radical surgery and adjuvant chemotherapy. Pregnancy was achieved, although complicated by obstructive uropathy. She delivered a healthy infant at 32 weeks' gestation. The few descriptions of fertility and pregnancy outcome in pseudomyxoma peritonei that appear in the literature are reviewed. PMID- 22523632 TI - HE4, CA-125, and cystic ovarian mass. PMID- 22523633 TI - Telesurgery is promising but still need proof through prospective comparative studies. PMID- 22523634 TI - Competing activation mechanisms in epidemics on networks. AB - In contrast to previous common wisdom that epidemic activity in heterogeneous networks is dominated by the hubs with the largest number of connections, recent research has pointed out the role that the innermost, dense core of the network plays in sustaining epidemic processes. Here we show that the mechanism responsible of spreading depends on the nature of the process. Epidemics with a transient state are boosted by the innermost core. Contrarily, epidemics allowing a steady state present a dual scenario, where either the hub independently sustains activity and propagates it to the rest of the system, or, alternatively, the innermost network core collectively turns into the active state, maintaining it globally. In uncorrelated networks the former mechanism dominates if the degree distribution decays with an exponent larger than 5/2, and the latter otherwise. Topological correlations, rife in real networks, may perturb this picture, mixing the role of both mechanisms. PMID- 22523635 TI - Large amplitude fluxional behaviour of elemental calcium under high pressure. AB - Experimental evidences are presented showing unusually large and highly anisotropic vibrations in the "simple cubic" (SC) unit cell adopted by calcium over a broad pressure ranging from 30-90 GPa and at temperature as low as 40 K. X ray diffraction patterns show a preferential broadening of the (110) Bragg reflection indicating that the atomic displacements are not isotropic but restricted to the [110] plane. The unusual observation can be rationalized invoking a simple chemical perspective. As the result of pressure-induced s -> d transition, Ca atoms situated in the octahedral environment of the simple cubic structure are subjected to Jahn-Teller distortions. First-principles molecular dynamics calculations confirm this suggestion and show that the distortion is of dynamical nature as the cubic unit cell undergoes large amplitude tetragonal fluctuations. The present results show that, even under extreme compression, the atomic configuration is highly fluxional as it constantly changes. PMID- 22523636 TI - Multiple tyrosine metabolites are GPR35 agonists. AB - Both kynurenic acid and 2-acyl lysophosphatidic acid have been postulated to be the endogenous agonists of GPR35. However, controversy remains whether alternative endogenous agonists exist. The molecular targets accounted for many nongenomic actions of thyroid hormones are mostly unknown. Here we report the agonist activity of multiple tyrosine metabolites at the GPR35. Tyrosine metabolism intermediates that contain carboxylic acid and/or catechol functional groups were first selected. Whole cell dynamic mass redistribution (DMR) assays enabled by label-free optical biosensor were then used to characterize their agonist activity in native HT-29. Molecular assays including beta-arrestin translocation, ERK phosphorylation and receptor internalization confirmed that GPR35 functions as a receptor for 5,6-dihydroxyindole-2-carboxylic acid, 3,3',5' triiodothyronine, 3,3',5-triiodothyronine, gentisate, rosmarinate, and 3 nitrotyrosine. These results suggest that multiple tyrosine metabolites are alternative endogenous ligands of GPR35, and GPR35 may represent a druggable target for treating certain diseases associated with abnormality of tyrosine metabolism. PMID- 22523637 TI - The potential use of N-myristoyltransferase as a biomarker in the early diagnosis of colon cancer. AB - Colon cancer is one of the most common malignant diseases and a major cause of mortality in the Western world. Metastasis to lymph nodes and other gastrointestinal organs, especially to the liver and lungs, is most common and occurs in up to 25% of cancer patients when initially diagnosed. The majority of colon cancers develop from noncancerous adenomatous polyps on the lining of the colon which grow over the years to become cancerous. If detected early, the surgical resections of the growth, often in combination with chemotherapy, significantly increases life expectancy. We have shown that the enzyme N myristoyltransferase (NMT) which carries out lipid modification of several proteins (including many of those involved in oncogenesis) is expressed at higher levels in cancerous tissues from the colon. We have also shown that in peripheral blood mononuclear cells (PBMC) and bone marrow (BM) cells collected from colon cancer patients and from azoxymethane-induced rats the expression and localization of NMT is altered. We have observed strong positivity for NMT in immunohistochemical analysis for PBMC from colon cancer patients as compared to control groups. Furthermore, in the bone marrow (BM) mononuclear cells, NMT was found to be confined to the nuclei whereas in control groups it was observed to be located in the cytoplasm. In conclusion, this strikingly differential localization offers the basis of a potential investigational tool for screening or diagnosis of individuals at risk for or suspected of having colon cancer. PMID- 22523639 TI - Association between Micronutrients (Vitamin A, D, Iron) and Schistosome-Specific Cytokine Responses in Zimbabweans Exposed to Schistosoma haematobium. AB - Micronutrients play an important role in the development of effective immune responses. This study characterised a populations exposed to schistosome infections in terms of the relationship between micronutrients and immune responses. Levels of retinol binding protein (RBP; vitamin A marker), vitamin D, ferritin and soluble transferrin receptor (sTfR), and C reactive protein (CRP) were related to levels of schistosome specific cytokines (IFN-gamma, IL-4/5/10) in 40 Zimbabweans (7-54 years) exposed to Schistosoma haematobium infection. 67.2% of the participants were deficient in vitamin D. RBP levels were within normal ranges but declined with age. The two indicators of iron levels suggested that although levels of stored iron were within normal levels (normal ferritin levels), levels of functional iron (sTfR levels) were reduced in 28.6% of the population. Schistosome infection alone was not associated with levels of any of the micronutrients, but altered the relationship between parasite-specific IL-4 and IL-5 and levels of ferritin and sTfR. PMID- 22523638 TI - Above genetics: lessons from cerebral development in autism. AB - While a distinct minicolumnar phenotype seems to be an underlying factor in a significant portion of cases of autism, great attention is being paid not only to genetics but to epigenetic factors which may lead to development of the conditions. Here we discuss the indivisible role the molecular environment plays in cellular function, particularly the pivotal position which the transcription factor and adhesion molecule, beta-catenin, occupies in cellular growth. In addition, the learning environment is not only integral to postnatal plasticity, but the prenatal environment plays a vital role during corticogenesis, neuritogenesis, and synaptogenesis as well. To illustrate these points in the case of autism, we review important findings in genetics studies (e.g., PTEN, TSC1/2, FMRP, MeCP2, Neurexin-Neuroligin) and known epigenetic factors (e.g., valproic acid, estrogen, immune system, ultrasound) which may predispose towards the minicolumnar and connectivity patterns seen in the conditions, showing how one-gene mutational syndromes and exposure to certain CNS teratogens may ultimately lead to comparable phenotypes. This in turn may shed greater light on how environment and complex genetics combinatorially give rise to a heterogenetic group of conditions such as autism. PMID- 22523641 TI - Short Communication: Some Observations on the Role of Bradykinin in Immunity to Teladorsagia circumcincta in Sheep. AB - Bradykinin is a physiologically active peptide involved in vasodilation and smooth muscle contraction and is previously shown to be increased in gastrointestinal mucus during nematode challenge in sheep. Here, it is shown that bradykinin in the abomasum is positively correlated with both mast cells and globule leukocytes in the abomasum, and that all three of these parameters are negatively associated with numbers of adult Teladorsagia circumcincta during the challenge of immune sheep. It is suggested that bradykinin either stimulates the degranulation of mast cells, or is released during this degranulation process, or both. Multiple regression showed that almost 60% of the variation of in adult T. circumcincta could be explained by two variables, bradykinin and T. circumcincta specific IgG(1) in plasma. This provides further evidence that bradykinin may be a mechanism of protective immunity in sheep, although its involvement in asthma and other allergic disorders raises questions about its role in unwanted immunopathology. PMID- 22523642 TI - Evidence for T Cell Help in the IgG Response against Tandemly Repetitive Trypanosoma cruzi B13 Protein in Chronic Chagas Disease Patients. AB - The tandemly repetitive Trypanosoma cruzi B13 protein is an immunodominant antigen among Chagas disease patients. Such repetitive domains may behave as T independent antigens. However, T cells can recognize B13 epitopes in an HLA class II-restricted fashion and could potentially provide cognate T cell help and boost antibody titers. We assessed whether the presence of HLA class II molecules able to present B13 epitopes to T cells could affect anti-B13 IgG levels in a cognate fashion, in both major clinical forms of chronic Chagas disease. We found no difference between anti-B13 IgG antibody levels between patients carrying HLA class II molecules associated to T cell responses or other alleles. The predominant anti-B13 IgG subclass was IgG1, with negligible IgG2, suggesting a T dependent, noncognate help for antibody production. In addition, the finding of increased anti-B13 IgG levels in sera from CCC patients indicates that clinical presentation is associated with increased anti-B13 antibody levels. PMID- 22523640 TI - Innate immune activation and subversion of Mammalian functions by leishmania lipophosphoglycan. AB - Leishmania promastigotes express several prominent glycoconjugates, either secreted or anchored to the parasite surface. Of these lipophosphoglycan (LPG) is the most abundant, and along with other phosphoglycan-bearing molecules, plays important roles in parasite infectivity and pathogenesis in both the sand fly and the mammalian host. Besides its contribution for parasite survival in the sand fly vector, LPG is important for modulation the host immune responses to favor the establishment of mammalian infection. This review will summarize the current knowledge regarding the role of LPG in Leishmania infectivity, focusing on the interaction of LPG and innate immune cells and in the subversion of mammalian functions by this molecule. PMID- 22523643 TI - Comparison and Optimization of Different Methods for the In Vitro Production of Plasmodium falciparum Gametocytes. AB - The generation of sexually committed parasites (gametocytogenesis) is poorly understood in malaria. If the mechanisms regulating this process were elucidated, new opportunities for blocking malaria transmission could be revealed. Here we compare several methods described previously for the in vitro production of Plasmodium falciparum gametocytes. Our approach relies on the combination of several factors that we demonstrated as impacting on or being critical to gametocytogenesis. An improved method has been developed for the in vitro production of P. falciparum gametocytes as the first step toward obtaining adequate numbers of pure gametocytes for in vitro studies, such as, for example, the identification of transmission blocking drugs. PMID- 22523645 TI - Cross-Reaction between the Crude Hydatid Cyst Fluid Antigens of Human and Animals Origin in Response to Human IgG Class and Subclasses. AB - The current work aimed to evaluate the cross-reactivity of human immune sera against crude hydatid fluid antigens of sheep, human, mouse, cattle, as well as B fraction of cystic fluid antigen. 30 balb/c mice were infected with sheep hydatid cyct fluid antigen containing protoscolex after the viability of these protoscolices was assessed. ANOVA was used to test the difference of themean of optical density (OD) values among case and control groups. The highest human IgG class antibody was against antigen B (0.93) and the lowest against cattle HCF antigen (0.32). The differences between responses to these antigens were statistically significant (P < 0.001). The sensitivity and specificity of ELISA test used for evaluating the responses of human total IgG to different hydatid cyst fluid (HCF) antigens among the case and control groups were 100 and 95.8%, respectively. Cross-reaction of human IgG class and subclasses responses was found almost for all the antigens with the best reaction against human and cattle (HCF) antigens and antigen B using a ratio of mean OD value to each antigen divided by the cut-off point value for the same antigen. Human sera showed a considerable cross-reactivity against all antigens by using ELISA. PMID- 22523644 TI - Toll-like receptors in leishmania infections: guardians or promoters? AB - Protozoa of the genus Leishmania cause a wide variety of pathologies ranging from self-healing skin lesions to visceral damage, depending on the parasite species. The outcome of infection depends on the quality of the adaptive immune response, which is determined by parasite factors and the host genetic background. Innate responses, resulting in the generation of mediators with anti-leishmanial activity, contribute to parasite control and help the development of efficient adaptive responses. Among those, the potential contribution of members of the Toll-like receptors (TLRs) family in the control of Leishmania infections started to be investigated about a decade ago. Although most studies appoint a protective role for TLRs, there is growing evidence that in some cases, TLRs facilitate infection. This review highlights recent advances in TLR function during Leishmania infections and discusses their potential role in restraining parasite growth versus yielding disease. PMID- 22523646 TI - Feasibility and Complications between Phacoemulsification and Manual Small Incision Surgery in Subluxated Cataract. AB - Purpose. To compare the feasibility of cataract surgery with implantation of endocapsular supporting devices and intraocular lens (IOL) in subluxated cataract in phacoemulsification and manual small incision cataract surgery (MSICS). Design. Prospective randomized intervention case series consisting of 60 eyes with visually significant subluxated cataract. Method. The patients were randomly distributed between the two groups equally. The main outcome measure was implantation of in-the-bag IOL, requirement of additional procedure and complications, if any. Results. Capsular bag retention in subluxated lenses is possible in 90% cases in phacoemulsification versus 76.67% cases in MSICS (P = 0.16). Both groups, achieved similar best corrected visual acuity (P = 0.73), although additional procedures, intraoperative, and postoperative complications were more common in MSICS. Conclusions. Achieving intact capsulorhexis and nuclear rotation in MSICS may be difficult in cases with large nucleus size and severe subluxation, but subluxated cataracts can be effectively managed by both phacoemuslification and MSICS. PMID- 22523647 TI - Case control analyses of acute endophthalmitis after cataract surgery in South India associated with technique, patient care, and socioeconomic status. AB - Purpose. We investigated acute endophthalmitis incidence following cataract surgery vis-a-vis the current technological and postoperative care changes in higher and lower socioeconomic categories of patients in South India. Methods. In a retrospective case control study, we analyzed 62 cases of acute endophthalmitis and 5 controls for each endophthalmitis case from 46,095 cataract surgeries done between years 1993 and 1998. The time period covered the transition of surgical technique and after care. In addition, we analyzed systemic diseases, surgeon factor, habitat, and socioeconomic status. Results. Clinical and culture positive endophthalmitis incidence were 0.13% and 0.07%, respectively. Differential incidence of 0.10% and 0.17% for in- and ambulatory care surgeries, respectively, was close to statistical significance (P = 0.054). Lower economy category ambulatory patients had higher risk of infection. Conclusion. Ambulatory cataract surgery carried additional risk for post-operative infection in lower socioeconomic group. Improved health education could ensure greater safety. PMID- 22523648 TI - Combination therapy for diabetic macular edema. AB - Diabetic macular edema is a main reason for visual loss in diabetic patients. Until recent years, macular laser photocoagulation was the only available therapy. The awareness that inflammation is an important factor in the pathogenetic process of DME gave reason for intravitreal treatment with corticosteroids. The introduction of anti-VEGF drugs brought a revolutionary change in the treatment of DME. This paper will review the important clinical trials with an emphasis on combination therapies. PMID- 22523649 TI - Keratoconus and keratoectasia: advancements in diagnosis and treatment. PMID- 22523650 TI - Combined Idiopathic Macular Hole Vitrectomy with Phacoemulsification without Face Down Positioning. AB - Purpose. To evaluate the outcome of combined vitrectomy with phacoemulsification without postoperative face-down positioning for idiopathic macular holes (MHs). Design. Retrospective, observational case series. Participants. Forty-two eyes of 42 patients with MH. Methods. We studied 42 eyes of 42 cases followed up for 6 months postoperatively. MH closure rate and preoperative and postoperative visual acuity (VA) were evaluated. Main Outcome Measures. MH closure rate and VA were evaluated after combined vitrectomy with phacoemulsification without postoperative face-down positioning. Results. Of the 42 holes, 40 (95.2%) were initially closed, and the final closure rate was 100%. Compared with preoperative VA, the mean VA was significantly improved at 1 month and the improvement was maintained for at least 6 months postoperatively. Conclusions. Combined vitrectomy with phacoemulsification without postoperative face-down positioning produced favorable anatomic and functional results for MH repair. Improvement in VA can be expected for up to at least 6 months postoperatively. PMID- 22523651 TI - Adverse effects of systemic immunosuppression in keratolimbal allograft. AB - Purpose. Keratolimbal allograft (KLAL) is a treatment for limbal stem cell deficiency. One disadvantage is systemic immunosuppression to avoid rejection. Our purpose was to examine the adverse effects of systemic immunosuppression in KLAL. Methods. A retrospective case review of 16 patients with KLAL who received systemic immunosuppression consisting of a corticosteroid, an antimetabolite, and/or a calcineurin inhibitor was performed. Patients were monitored for signs, symptoms, or laboratory evidence of toxicity. Results. Eleven of 16 patients (68%) experienced an adverse effect. The average age of those with adverse effects was 43.5 years and without was 31.4 years. Ten of 11 patients (91%) had resolution during mean followup of 16.4 months. No serious adverse effects occurred. The most common included anemia, hyperglycemia, elevated creatinine, and elevated liver function tests. Prednisone and tacrolimus were responsible for the most adverse effects. Patients with comorbidities were more likely to experience an adverse effect (82% versus 20%, P = 0.036). Conclusions. KLAL requires prolonged systemic immunosuppression. Our data demonstrated that systemic immunosuppression did not result in serious adverse effects in our population and is relatively safe with monitoring for toxicity. In addition, we demonstrated that adverse effects are more likely in older patients with comorbidities. PMID- 22523654 TI - Predictive Factors in OCT Analysis for Visual Outcome in Exudative AMD. AB - Background. Reliable predictive factors for therapy outcome may enable treating physicians to counsel their patients more efficiently concerning probability of improvement or time point of discontinuation of a certain therapy. Methods. This is a retrospective analysis of 87 patients with exudative age-related macular degeneration who received three monthly intravitreal ranibizumab injections. Visual acuity before initiation of intravitreal therapy and 4-6 weeks after last intravitreal injection was compared and related to the preoperative visualisation of continuity of the outer retinal layers as assessed by OCT: external limiting membrane (ELM), inner photoreceptor segments (IPS), junction between inner and outer segments (IS/OS), and outer photoreceptor segments (OPS). Results. Visual acuity increased in 40 of 87 (46.0%) patients, it remained stable in 25 (28.7%), and 22 (25.3%) patients had decreased visual acuity four to six weeks after triple intravitreal ranibizumab injections. No statistically significant predictive value could be demonstrated for grade of continuity of outer retinal layers concerning visual acuity development. Conclusions. In our series of AMD patients, grade of continuity of outer retinal layers was not a significant predictive value for visual acuity development after triple ranibizumab injections. PMID- 22523652 TI - Lymphatics and lymphangiogenesis in the eye. AB - Lymphatic is a prerequisite for the maintenance of tissue fluid balance and immunity in the body. A body of evidence also shows that lymphangiogenesis plays important roles in the pathogenesis of diseases such as tumor metastasis and inflammation. The eye was thought to lack lymphatic vessels except for the conjunctiva; however, advances in the field, including the identification of lymphatic endothelial markers (e.g., LYVE-1 or podoplanin) and lymphangiogenic factors (e.g., VEGF-C), have revealed the exsitence and possible roles of lymphatics and lymphangiogenesis in the eye. Recent studies have shown that corneal limbus, ciliary body, lacrimal gland, orbital meninges, and extraocular muscles contain lymphatic vessels and that the choroid might have a lymphatic like system. There is no known lymphatic outflow from the eye. However, several lymphatic channels including uveolymphatic pathway might serve the ocular fluid homeostasis. Furthermore, lymphangiogenesis plays important roles in pathological conditions in the eye including corneal transplant rejection and ocular tumor progression. Yet, the role of lymphangiogenesis in most eye diseases, especially inflammatory disease or edema, remains unknown. A better understanding of lymphatic and lymphangiogenesis in the eye will open new therapeutic opportunities to prevent vision loss in ocular diseases. PMID- 22523653 TI - Anti-VEGF Treatment Strategies for Wet AMD. AB - Over the past few years, antivascular endothelial growth factor (VEGF) therapy has become a standard treatment for neovascular age-related macular degeneration (AMD). During this time, treatment strategies have evolved from a monthly dosing schedule to individualized regimens. This paper will review the currently available anti-VEGF agents and evidence-based treatment strategies. PMID- 22523655 TI - Anti-vascular endothelial growth factor agents for ocular angiogenesis and vascular permeability. PMID- 22523656 TI - Conjunctival lymphatic response to corneal inflammation in mice. AB - Due to its unique characteristics, the cornea has been widely used for vascular research. However, it has never been studied whether lymphatic vessels in the conjunctiva, its neighboring tissue, are affected by corneal lymphangiogenesis (LG). The purpose of this study was to investigate whether the distribution pattern of conjunctival lymphatic vessels changes during LG using a standardized two-suture placement model. Our data from immunofluorescent microscopic studies demonstrate, for the first time, that conjunctival lymphatic vessels were more distributed in the nasal side under both normal and inflamed conditions. Additionally, under the inflamed condition, conjunctival lymphatic vessels showed a higher density and more branching points, indicating that LG occurs in the conjunctiva in response to corneal inflammation. This study not only provides novel insights into lymphatic events in the ocular surface but also offers new guidelines for developing therapeutic strategies to treat lymphatic diseases at related sites. PMID- 22523657 TI - Environmental factors preceding abeta40 monomer to oligomers and the detection of oligomers in Alzheimer's disease patient serum. AB - We present here environmental factors including pH shifts, temperature, and metal ions surrounding Abeta40 monomer to precede the oligomers. We also suggest a new idea to detect Abeta40 oligomers with anti-Abeta40 monoclonal antibody using enzyme-linked immunosorbent assay. This method involves the different sensitivity of the thermal shifts between Abeta40 monomer and the oligomers. The idea is useful for the diagnostics of Alzheimer's disease to detect Abeta40 oligomers in the serum from the patients. PMID- 22523658 TI - MsDpo4-a DinB Homolog from Mycobacterium smegmatis-Is an Error-Prone DNA Polymerase That Can Promote G:T and T:G Mismatches. AB - Error-prone DNA synthesis in prokaryotes imparts plasticity to the genome to allow for evolution in unfavorable environmental conditions, and this phenomenon is termed adaptive mutagenesis. At a molecular level, adaptive mutagenesis is mediated by upregulating the expression of specialized error-prone DNA polymerases that generally belong to the Y-family, such as the polypeptide product of the dinB gene in case of E. coli. However, unlike E. coli, it has been seen that expression of the homologs of dinB in Mycobacterium tuberculosis are not upregulated under conditions of stress. These studies suggest that DinB homologs in Mycobacteria might not be able to promote mismatches and participate in adaptive mutagenesis. We show that a representative homolog from Mycobacterium smegmatis (MsDpo4) can carry out template-dependent nucleotide incorporation and therefore is a DNA polymerase. In addition, it is seen that MsDpo4 is also capable of misincorporation with a significant ability to promote G:T and T:G mismatches. The frequency of misincorporation for these two mismatches is similar to that exhibited by archaeal and prokaryotic homologs. Overall, our data show that MsDpo4 has the capacity to facilitate transition mutations and can potentially impart plasticity to the genome. PMID- 22523659 TI - Metabolic effects of bariatric surgery. PMID- 22523660 TI - Prevalence of Anemia and Related Deficiencies in the First Year following Laparoscopic Gastric Bypass for Morbid Obesity. AB - Background. Anemia associated with deficiencies in iron, folic acid, and vitamin B12 are very common after Laparoscopic Roux-en-Y Gastric Bypass (LRYGB) surgery for morbid obesity. This study was conducted to evaluate the prevalence of anemia after LRYGB. Patients and Methods. A total of 377 morbid obese patients were included in our study. All patients underwent a LRYGB. Hematologic parameters were obtained prior to and after surgery on standardized time intervals. Results. Anemia was present in 21 (P = 0.02) patients after surgery. Iron, folic acid, and vitamin B12 deficiencies were diagnosed in 66%, 15%, and 50% of patients, respectively. In 86% of patients, anemia was accompanied by one of these deficiencies. Conclusion. These results show that anemia and deficiencies for iron, folic acid deficiency, and vitamin B12 are very common within the first year after LRYGB. We advise a minimal daily intake of 65 mg of iron in male and 100 mg in female patients, 350 MUg of vitamin B12, and 400 MUg of folic acid. Patients undergoing LRYGB must be closely monitored for deficiencies pre- and postoperative and supplemented when deficiencies occur. PMID- 22523662 TI - What behaviors are important for successful weight maintenance? AB - Purpose. To examine behavioral factors related to successful weight maintenance. Methods. Subjects were 90 middle-aged participants who attended a weight loss program and were followed for one year. The subjects were classified into either successful weight maintainers (maintained a weight loss of 5% or more from their initial weight for one year) (SWM) or unsuccessful weight maintainers (USWM), and weight control practice, stress, obstacles, support, and self-efficacy during the program and follow-up period were compared. Results. SWM had mean loss of 12% from their initial weight during the program. They showed a greater improvement in their regularity of eating, walked more, and felt less stress regarding their increased physical activity than the USWM. During the follow-up period, significantly more SWM participants had self-efficacy (for measuring weight, practicing dietary objective, and assessing the practice and keeping records), actually kept records and measured weight more than the USWM participants. In contrast, more USWM participants felt stress about measuring weight. Conclusion. In addition to a substantial initial weight loss due to an increased amount of physical activity, having a higher self-efficacy and consistently keeping records of one's activities, as well as regularly weighing themselves, may be important for successful weight maintenance. PMID- 22523663 TI - Overweight and Obesity among Palestinian Adults: Analyses of the Anthropometric Data from the First National Health and Nutrition Survey (1999-2000). AB - Background. A cross-sectional survey was designed to provide a baseline data on the prevalence and distribution of overweight and obesity and their associations among adults in Palestine. Methods. A random representative sample of 3617 adults aged 18-64 years was collected between October 1999 and October 2000. Results. The prevalence of overweight was 35.5% in women and 40.3% in men, obesity was 31.5% in women and 17.5% in men. Adults aged 45-54 years old were significantly more likely to be obese (29.2% in men and 50.2% in women) or overweight (48.1% in men and 37.2% in women). When compared with women, men showed significantly more normal BMI level (40.5% versus 31.6%; P < 0.05). Cut-off points for a high waist circumference and high waist-to-hip ratio identified 57.8% and 47.2% of the population, respectively, to be at an increased and high risk for cardiovascular disease. Sociodemographic factors (age, sex, educational level, and marital status) were also found to be significantly related to BMI. Conclusion. Obesity and overweight are enormous public health problems in Palestine. Population-based research at the national level to investigate the social and cultural factors associated with high prevalence of overweight and obesity among Palestinian adults should be implemented. PMID- 22523661 TI - Excessive Leucine-mTORC1-Signalling of Cow Milk-Based Infant Formula: The Missing Link to Understand Early Childhood Obesity. AB - Increased protein supply by feeding cow-milk-based infant formula in comparison to lower protein content of human milk is a well-recognized major risk factor of childhood obesity. However, there is yet no conclusive biochemical concept explaining the mechanisms of formula-induced childhood obesity. It is the intention of this article to provide the biochemical link between leucine mediated signalling of mammalian milk proteins and adipogenesis as well as early adipogenic programming. Leucine has been identified as the predominant signal transducer of mammalian milk, which stimulates the nutrient-sensitive kinase mammalian target of rapamycin complex 1 (mTORC1). Leucine thus functions as a maternal-neonatal relay for mTORC1-dependent neonatal beta-cell proliferation and insulin secretion. The mTORC1 target S6K1 plays a pivotal role in stimulation of mesenchymal stem cells to differentiate into adipocytes and to induce insulin resistance. It is of most critical concern that infant formulas provide higher amounts of leucine in comparison to human milk. Exaggerated leucine-mediated mTORC1-S6K1 signalling induced by infant formulas may thus explain increased adipogenesis and generation of lifelong elevated adipocyte numbers. Attenuation of mTORC1 signalling of infant formula by leucine restriction to physiologic lower levels of human milk offers a great chance for the prevention of childhood obesity and obesity-related metabolic diseases. PMID- 22523664 TI - The impact of an intervention taught by trained teachers on childhood fruit and vegetable intake: a randomized trial. AB - Our study aimed to assess the impact of a six-months nutrition program, taught by trained teachers, on fruit and vegetable consumption among children in grades 1 to 4. Four hundred and sixty-four children (239 female), 6 to 12 years old, from seven elementary schools were assigned to this randomized trial. Teachers were trained by researchers over six months, according to the following topics: nutrition, healthy eating, and strategies to increase physical activity. After each session, teachers were encouraged to develop activities in the classroom on the topics learned. Children's sociodemographic, anthropometric, dietary, and physical activity data were assessed at baseline and at the end of the intervention. The effect sizes ranged between small (Cohen's d = 0.12 on "other vegetables") to medium (0.56 on "fruit and vegetable"), and intervened children reported a significantly higher consumption of vegetables and fruit. Interventions involving trained teachers offer promise to increase consumption of fruit and vegetable in children. PMID- 22523665 TI - Independent benefits of meeting the 2008 physical activity guidelines to insulin resistance in obese latino children. AB - We examined the independent association between moderate-to-vigorous physical activity (MVPA) and insulin resistance (IR) among obese Latino children (N = 113; 7-15 years) who were enrolled in a community-based obesity intervention. Baseline information on physical activity was gathered by self-report. Clinical assessments of body composition, resting energy expenditure (REE), as well as glucose and insulin responses to an oral glucose tolerance test (OGTT) were performed after an overnight fast. Insulin resistance was defined as a 2 h insulin concentration >57 MUU.mL(-1). We observed that those obese children who met the 2008 Guidelines for MVPA (>=60 min/day) experienced a significantly lower odds of IR compared with those not meeting the Guidelines (OR = 0.29; 95% CI: (0.10-0.92)) and these findings were independent of age, sex, pubertal stage, acculturation, fasting insulin, and 2 h glucose concentrations. Efforts to promote 60 min or more of daily MVPA among children from ethnic minority and high risk communities should assume primary public health importance. PMID- 22523666 TI - Recent advances in potential clinical application of ghrelin in obesity. AB - Ghrelin is the natural ligand of the growth hormone secretagogue receptor (GHS R1a). Ghrelin is a 28 amino acid peptide possessing a unique acylation on the serine in position 3 catalyzed by ghrelin O-acyltransferase (GOAT). Ghrelin stimulates growth hormone secretion, but also appetite, food intake, weight gain, and gastric emptying. Ghrelin is involved in weight regulation, obesity, type 2 diabetes, and metabolic syndrome. Furthermore, a better understanding of ghrelin biology led to the identification of molecular targets modulating ghrelin levels and/or its biological effects: GOAT, ghrelin, and GHS-R1a. Furthermore, a recent discovery, showing the involvement of bitter taste receptor T2R in ghrelin secretion and/or synthesis and food intake, suggested that T2R could represent an additional interesting molecular target. Several classes of ghrelin-related pharmacological tools for the treatment of obesity have been or could be developed to modulate the identified molecular targets. PMID- 22523667 TI - The role of leptin in antipsychotic-induced weight gain: genetic and non-genetic factors. AB - Schizophrenia is a chronic and disabling mental illness affecting millions of people worldwide. A greater proportion of people with schizophrenia tends to be overweight. Antipsychotic medications have been considered the primary risk factor for obesity in schizophrenia, although the mechanisms by which they increase weight and produce metabolic disturbances are unclear. Several lines of research indicate that leptin could be a good candidate involved in pathways linking antipsychotic treatment and weight gain. Leptin is a circulating hormone released by adipocytes in response to increased fat deposition to regulate body weight, acting through receptors in the hypothalamus. In this work, we reviewed preclinical, clinical, and genetic data in order to infer the potential role played by leptin in antipsychotic-induced weight gain considering two main hypotheses: (1) leptin is an epiphenomenon of weight gain; (2) leptin is a consequence of antipsychotic-induced "leptin-resistance status," causing weight gain. PMID- 22523668 TI - The obesity paradox and cardiorespiratory fitness. AB - Cardiorespiratory fitness as an explanation for the obesity paradox warrants further examination. We evaluated independent and joint associations of cardiorespiratory fitness and adiposity with all-cause mortality in 811 middle aged (age, 53.3 +/- 7.2 years) male never smokers without documented cardiopulmonary disease or diabetes from the Veterans Exercise Testing Study (VETS). Cardiorespiratory fitness was quantified in metabolic equivalents (METs) using final treadmill speed and grade achieved on a maximal exercise test. Subjects were grouped for analysis by METs: unfit (lowest third) and fit (upper two-thirds); and by body mass index (kg/m(2)): nonobese (18.5-29.9) and obese (>=30.0). Associations of baseline fitness and adiposity measures with all-cause mortality were determined by Cox proportional hazards analysis adjusted for age, ethnicity, hypertension, hypercholesterolemia, family history of coronary artery disease, and cardiovascular medication use. In multivariate analysis, mortality risk for obese/fit men did not differ significantly from the nonobese/fit reference group. However, compared to the reference group, nonobese and obese unfit men were 2.2 (P = 0.01) and 1.9 (P = 0.03) times more likely to die, respectively. Cardiorespiratory fitness altered the obesity paradox such that mortality risk was lower for both obese and nonobese men who were fit. PMID- 22523669 TI - The impact of severe obesity on post-acute rehabilitation efficiency, length of stay, and hospital costs. AB - Background and Objective. The purpose of this retrospective observational study was to examine the influence of severe obesity on length of stay (LOS), rehabilitation efficiency, and hospital costs post-acute rehabilitation in a population-based, tertiary care, publicly-funded regional rehabilitation center. Participants. 42 severely obese subjects (mean age 53 y; mean BMI 50.9 kg/m(2)) and 42 nonobese controls (mean age 59 y; mean BMI 23.0 kg/m(2)) matched by sex and admitting diagnosis. Main Outcome Measures. Total LOS, rehab LOS, waiting for transfer LOS, Fuctional Independence Measure (FIM) efficiency, and hospital costs. Results. Compared to controls, severely obese subjects experienced longer total LOS (98.4 vs. 37.4 days; P = 0.03), rehabilitation LOS (55.8 vs. 37.4 days; P = 0.04), and waiting for transfer LOS (42.6 vs. 0 days; P = 0.006); increased hospital costs ($115,822 vs. $43,969; P = 0.03); and similar FIM efficiency (0.58 vs. 0.67; P = 0.27). Severe obesity was an independent predictor of total LOS (beta-coefficient 0.51; P = 0.03), rehab LOS (0.46; P = 0.02) but not FIM efficiency (-0.63; P = 0.06). Conclusion. Severe obesity adversely affects rehabilitation LOS and expenditures. Targeted interventions in severely obese individuals to optimize post-acute rehabilitation care delivery are needed. PMID- 22523670 TI - Combined effects of aerobic exercise and diet on lipids and lipoproteins in overweight and obese adults: a meta-analysis. AB - This study used the aggregate data meta-analytic approach to determine the combined effects of aerobic exercise and diet on lipids and lipoproteins in overweight and obese adults. Twelve studies representing 859 men and women (443 intervention, 416 control) were included. Using random-effects models, statistically significant, intervention minus control reductions were found for TC (-12.8 mg/dL, 95% CI, -19.9 to -5.7), TC : HDL-C (-0.5 mg/dL, 95% CI, -0.8 to 0.1), LDL-C (-6.8 mg/dL, 95% CI, -11.8 to -1.8), and TG (-13.1 mg/dL, 95% CI, 21.2 to -5.0) but not HDL-C (-0.4 mg/dL, 95% CI, -2.3 to 1.6). Results remained robust when adjusted for publication bias, deleting each study from the model once, and collapsing results for multiple groups from the same study into one effect size. These findings suggest that concurrent aerobic exercise and diet improve TC, LDL-C, TC : HDL-C, and TG, but not HDL-C, in overweight and obese adults. PMID- 22523671 TI - High physiological omega-3 Fatty Acid supplementation affects muscle Fatty Acid composition and glucose and insulin homeostasis in obese adolescents. AB - Obese adolescents have high concentrations of saturated fatty acids and low omega 3 long-chain polyunsaturated fatty acids (LCUFAs) in plasma phospholipids. We aimed to investigate effects of omega-3 LCPUFA supplementation to obese adolescents on skeletal muscle lipids and glucose and insulin homeostasis. Twenty five obese adolescents (14-17 years old, 14 females) completed a randomized double-blind crossover study supplying capsules containing either 1.2 g omega-3 LCPUFAs or placebo, for 3 months each with a six-week washout period. Fasting blood glucose, insulin, leptin, adiponectin, and lipids were measured. Intravenous glucose tolerance test (IVGTT) and euglycemic-hyperinsulinemic clamp were performed, and skeletal muscle biopsies were obtained at the end of each period. The concentrations of EPA, DHA, and total omega-3 PUFA in muscle phospholipids increased in both sexes. In the females, omega-3 LCPUFA supplementation improved glucose tolerance by 39% (P = 0.04) and restored insulin concentration by 34% (P = 0.02) during IVGTT. Insulin sensitivity improved 17% (P = 0.07). In males, none of these parameters was influenced by omega-3 supplementation. Thus, three months of supplementation of omega-3 LCPUFA improved glucose and insulin homeostasis in obese girls without influencing body weight. PMID- 22523672 TI - Inflammation as a Link between Obesity and Metabolic Syndrome. AB - The metabolic syndrome is a complex of clinical features leading to an increased risk for cardiovascular disease and type 2 diabetes mellitus in both sexes. Visceral obesity and insulin resistance are considered the main features determining the negative cardiovascular profile in metabolic syndrome. The aim of this paper is to highlight the central role of obesity in the development of a chronic low-grade inflammatory state that leads to insulin resistance, endothelial and microvascular dysfunctions. It is thought that the starting signal of this inflammation is overfeeding and the pathway origins in all the metabolic cells; the subsequent increase in cytokine production recruits immune cells in the extracellular environment inducing an overall systemic inflammation. This paper focuses on the molecular and cellular inflammatory mechanisms studied until now. PMID- 22523673 TI - Physical Activity and Health Beliefs among Saudi Women. AB - Background. Physical activity (PA) is associated with health benefits and disease prevention and is often prescribed in managing many health conditions. Understanding the cultural influences is relevant in order to effectively promote PA. The objective of this study was to assess the level of PA among Saudi women, measured by daily step count, and the association between PA and health beliefs. Methods. A total of 161 eligible participants were asked to complete two questionnaires to assess health beliefs: Health Locus of Control (HLC) and Self Efficacy Assessment Scale. Each participant was given a pedometer and a diary to record their daily PA for two weeks. Results. One hundred and five participants completed the two weeks pedometer data (mean age 26.3 +/- 7.1 years, BMI 25 +/- 4.2 kg/m(2)). The average pedometer score over two weeks was 5114 +/- 2213 steps. Step count had strong correlation with self-efficacy (r(s) = 0.75), mild correlation with internal HLC (r(s) = 0.42), and mild negative correlation with external HLC (r(s) = -0.35). Conclusion. The study demonstrates high level of inactivity among Saudi females in reference to the international recommendation for minimum activity. The data also reveal an association between PA and health beliefs. Ultimately, such information can be used to design gender- and culture sensitive interventions that could enhance adherence to PA. PMID- 22523674 TI - The metabolic syndrome and risk of chronic kidney disease: pathophysiology and intervention strategies. AB - Metabolic syndrome is characterized by a clustering of cardiovascular risk factors, including abdominal obesity, elevated blood pressure and glucose concentrations, and dyslipidemia. The presence of this clinical entity is becoming more pervasive throughout the globe as the prevalence of obesity increases worldwide. Moreover, there is increased recognition of the complications and mortality related to this syndrome. This paper looks to examine the link between metabolic syndrome and the development of chronic kidney disease. PMID- 22523675 TI - Changes in Body Mass Index across Age Groups in Iranian Women: Results from the National Health Survey. AB - Background. To investigate the associations between some factors with weight gain across age groups in Iranian women. Methods. Proportional odds model was used to estimate the probability of BMI categorized as a function of education, economic index, workforce, smoking, marital status, and place of residence adjusted for age, using data from the "National Health Survey in Iran" database. It included 14176 women aged 20-69 years. Results. For all covariates, age was directly associated with overweight and obesity before 60 years of age. Among women aged 20-40 years, the rates of change in probabilities of overweight and obesity were highest. Among women, being inactive, with high economic index, married, being nonsmoker, in an urban residence, with lower educational attainment, all increased the probabilities of overweight and obesity. Conclusions. Women aged 20 40 years gained weight faster than other groups. They may need additional information and more support on how to reduce their risk for weight gain through positive health behaviors. PMID- 22523676 TI - Pathobiochemical changes in diabetic skeletal muscle as revealed by mass spectrometry-based proteomics. AB - Insulin resistance in skeletal muscle tissues and diabetes-related muscle weakness are serious pathophysiological problems of increasing medical importance. In order to determine global changes in the protein complement of contractile tissues due to diabetes mellitus, mass-spectrometry-based proteomics has been applied to the investigation of diabetic muscle. This review summarizes the findings from recent proteomic surveys of muscle preparations from patients and established animal models of type 2 diabetes. The potential impact of novel biomarkers of diabetes, such as metabolic enzymes and molecular chaperones, is critically examined. Disease-specific signature molecules may be useful for increasing our understanding of the molecular and cellular mechanisms of insulin resistance and possibly identify new therapeutic options that counteract diabetic abnormalities in peripheral organ systems. Importantly, the biomedical establishment of biomarkers promises to accelerate the development of improved diagnostic procedures for characterizing individual stages of diabetic disease progression, including the early detection of prediabetic complications. PMID- 22523677 TI - Antenatal corticosteroids: a risk factor for the development of chronic disease. AB - Preterm birth remains a major health issue worldwide. Since the 1990s, women at risk for preterm birth received a single course of exogenous antenatal corticosteroids (ACSs) to facilitate fetal lung maturity. More recently, repeated or multiple courses of ACS have been supported to provide continued fetal maturity support for women with continued risk of preterm birth. However, exogenous ACS reduces birth weight which, in turn, is associated with adverse adult outcomes such as coronary heart disease, stroke, hypertension, and type 2 diabetes. The long-term effects of ACS exposure on HPA axis activity and neurological function are well documented in animal studies, and it appears that ACS, regardless of dose exposure, is capable of affecting fetal HPA axis development causing permanent changes in the HPA axis that persists through life and is manifested by chronic illness and behavioral changes. The challenge in human studies is to demonstrate whether an intervention such as ACS administration in pregnancy contributes to developmental programming and how this is manifested in later life. PMID- 22523678 TI - Increasing Age Is Associated with Worse Prognostic Factors and Increased Distant Recurrences despite Fewer Sentinel Lymph Node Positives in Melanoma. AB - Background. Advanced age is associated with a poorer prognosis in patients with melanoma. Despite this established finding, a decreased incidence of positive sentinel lymph nodes (SLNs) with advancing age has paradoxically been described. Methods. Using a single-institution database of melanoma patients between 1994 and 2009, the relationship between standard clinicopathologic variables and recurrence based on age was evaluated. Results. 1244 patients who underwent successful SLN biopsies were analyzed (mean followup 80.3 months). Increasing age was independently associated with worse survival on multivariable analysis (P = 0.02). SLN status was more likely to be negative if the patient was older (P = 0.01). Conclusions. Our data supports the paradox that increasing age is associated with a lower frequency of positive-SLN biopsies despite age itself being a poor prognostic factor. We propose that age-dependent variations in the primary tumor and the patient may predispose to a hematogenous route of spread for the older population, leading to worse survival. PMID- 22523679 TI - Prevalence and Characteristics of Incidentalomas Discovered by Whole Body FDG PETCT. AB - Objectives. To determine the prevalence of incidentalomas in a patient population with no known thyroid malignancy who underwent whole body FDG-PET/CT for staging or restaging of neoplasia. The additional aim of the study was to evaluate the feasibility of using PETCT as a screening tool for malignant thyroid incidentalomas. Methods. Retrospective review of medical records of all the thyroid exams done at our institution between January 1, 2000 and August 20, 2008. We made a criterion of PET/CT as the primary method of detection of incidentalomas. Results. From a total of 8464 thyroid exams, 156 incidentalomas were found and 40 incidentalomas underwent anatomopathology analysis, which was used as gold standard. Chi-square analysis was used to analyze the data. There is no significant association between SUV value and the prevalence of incidentalomas. Discussion. From January 1, 2000 to August 20, 2008, incidentalomas have a prevalence of 1.84% at our institution. 38% of the incidentalomas that were biopsied were characterized as representing malignant tumors. Conclusion. Focal, abnormal FDG uptake representing incidentalomas must be followed up with biopsies. It is impractical to use PET/CT as a screening tool to detect incidentalomas for the general population but it must be done in patients with history of any type of cancer. PMID- 22523680 TI - Dopamine D(2) Receptor-Mediated Heterologous Sensitization of AC5 Requires Signalosome Assembly. AB - Chronic dopamine receptor activation is implicated in several central nervous system disorders. Although acute activation of Galpha(i)-coupled D(2) dopamine receptors inhibits adenylyl cyclase, persistent activation enhances adenylyl cyclase activity, a phenomenon called heterologous sensitization. Previous work revealed a requirement for Galpha(s) in D(2)-induced heterologous sensitization of AC5. To elucidate the mechanism of Galpha(s) dependency, we expressed Galpha(s) mutants in Galpha(s)-deficient Gnas(E2-/E2-) cells. Neither Galpha(s) palmitoylation nor Galpha(s)-Gbetagamma interactions were required for sensitization of AC5. Moreover, we found that coexpressing betaARKct-CD8 or Sar1(H79G) blocked heterologous sensitization. These studies are consistent with a role for Galpha(s)-AC5 interactions in sensitization however, Gbetagamma appears to have an indirect role in heterologous sensitization of AC5, possibly by promoting proper signalosome assembly. PMID- 22523681 TI - The Concept of Divergent Targeting through the Activation and Inhibition of Receptors as a Novel Chemotherapeutic Strategy: Signaling Responses to Strong DNA Reactive Combinatorial Mimicries. AB - Recently, we reported the combination of multitargeted ErbB1 inhibitor-DNA damage combi-molecules with OCT in order to downregulate ErbB1 and activate SSTRs. Absence of translation to cell kill was believed to be partially due to insufficient ErbB1 blockage and DNA damage. In this study, we evaluated cell response to molecules that damage DNA more aggressively and induce stronger attenuation of ErbB1 phosphorylation. We used three cell lines expressing low levels (U87MG) or transfected to overexpress wildtype (U87/EGFR) or a variant (U87/EGFRvIII) of ErbB1. The results showed that Iressa +/- HN2 and the combi molecules, ZRBA4 and ZR2003, significantly blocked ErbB1 phosphorylation in U87MG cells. Addition of OCT significantly altered cell cycle distribution. Analysis of the DNA damage response pathway revealed strong upregulation of p53 by HN2 and the combi-molecules. Apoptosis was only induced by a 48 h exposure to HN2. All other treatments resulted in cell necrosis. This is in agreement with Akt-Bad pathway activation and survivin upregulation. Despite strong DNA damaging properties and downregulation of ErbB1 phosphorylation by these molecules, the strongest effect of SSTR activation was on cell cycle distribution. Therefore, any enhanced antiproliferative effects of combining ErbB1 inhibition with SSTR activation must be addressed in the context of cell cycle arrest. PMID- 22523683 TI - Reactive oxygen species: friends and foes of signal transduction. PMID- 22523682 TI - The role of MAPK in drug-induced kidney injury. AB - This paper focuses on the role that mitogen-activated protein kinases (MAPKs) play in drug-induced kidney injury. The MAPKs, of which there are four major classes (ERK, p38, JNK, and ERK5/BMK), are signalling cascades which have been found to be broadly conserved across a wide variety of organisms. MAPKs allow effective transmission of information from the cell surface to the cytosolic or nuclear compartments. Cross talk between the MAPKs themselves and with other signalling pathways allows the cell to modulate responses to a wide variety of external stimuli. The MAPKs have been shown to play key roles in both mediating and ameliorating cellular responses to stress including xenobiotic-induced toxicity. Therefore, this paper will discuss the specific role of the MAPKs in the kidney in response to injury by a variety of xenobiotics and the potential for therapeutic intervention at the level of MAPK signalling across different types of kidney disease. PMID- 22523684 TI - Cerebrovascular disorders: role of aging. PMID- 22523685 TI - New insights in the amyloid-Beta interaction with mitochondria. AB - Biochemical and morphological alterations of mitochondria may play an important role in the pathogenesis of Alzheimer's disease (AD). Particularly, mitochondrial dysfunction is a hallmark of amyloid-beta-induced neuronal toxicity in Alzheimer's disease. The recent emphasis on the intracellular biology of amyloid beta and its precursor protein (APP) has led researchers to consider the possibility that mitochondria-associated and mitochondrial amyloid-beta may directly cause neurotoxicity. Both proteins are known to localize to mitochondrial membranes, block the transport of nuclear-encoded mitochondrial proteins to mitochondria, interact with mitochondrial proteins, disrupt the electron transport chain, increase reactive oxygen species production, cause mitochondrial damage, and prevent neurons from functioning normally. In this paper, we will outline current knowledge of the intracellular localization of amyloid-beta. Moreover, we summarize evidence from AD postmortem brain as well as animal AD models showing that amyloid-beta triggers mitochondrial dysfunction through a number of pathways such as impairment of oxidative phosphorylation, elevation of reactive oxygen species production, alteration of mitochondrial dynamics, and interaction with mitochondrial proteins. Thus, this paper supports the Alzheimer cascade mitochondrial hypothesis such as the most important early events in this disease, and probably one of the future strategies on the therapy of this neurodegenerative disease. PMID- 22523686 TI - Could questions on activities of daily living estimate grip strength of older adults living independently in the community? AB - The aim of this study was to identify questions that could estimate grip strength. Twenty-six questions about the degree of perceived difficulty performing manual tasks as well as two questions concerning self-rated grip strength were developed and completed by 123 community-dwelling older adults, followed by grip strength measurements using a Martin vigorimeter. Multiple regression analyses with all of the participants revealed that the question about the difficulty of opening a jar (question 4) was most associated with grip strength. When analyses were done by gender, the same question showed the best correlation for women, whereas the one for men was self-rated grip strength compared with people the same age (question 28). For the women, age and question 4 together explained 54% of the variance in their grip strength and for the men, age and question 28 explained 46%. Further studies are needed to identify other information that could help to better estimate grip strength for use in epidemiological surveys. PMID- 22523687 TI - Transvaginal sonographic evaluation of the cervix in asymptomatic singleton pregnancy and management options in short cervix. AB - Preterm delivery (PTD), defined as birth before 37 completed weeks of gestation, is the leading cause of perinatal morbidity and mortality. Evaluation of the cervical morphology and biometry with transvaginal ultrasonography at 16-24 weeks of gestation is a useful tool to predict the risk of preterm birth in low- and high-risk singleton pregnancies. For instance, a sonographic cervical length (CL) > 30 mm and present cervical gland area have a 96-97% negative predictive value for preterm delivery at <37 weeks. Available evidence supports the use of progesterone to women with cervical length <=25 mm, irrespective of other risk factors. In women with prior spontaneous PTD with asymptomatic cervical shortening (CL <= 25 mm), prophylactic cerclage procedure must be performed and weekly to every two weeks follow-up is essential. This article reviews the evidence in support of the clinical introduction of transvaginal sonography for both the prediction and management of spontaneous preterm labour. PMID- 22523688 TI - Molecular mechanisms of preeclampsia. AB - Preeclampsia is one of the leading causes of maternal morbidity/mortality. The pathogenesis of preeclampsia is still under investigation. The aim of this paper is to present the molecular mechanisms implicating in the pathway leading to preeclampsia. PMID- 22523689 TI - Pattern and determinants of antiretroviral drug adherence among Nigerian pregnant women. AB - BACKGROUND: The need for a high level of adherence to antiretroviral drugs has remained a major hurdle to achieving maximal benefit from its use in pregnancy. This study was designed to determine the level of adherence and identify factors that influence adherence during pregnancy. METHOD: This is a cross-sectional study utilizing a semistructured questionnaire. Bivariate and multiple logistic regression models were used to determine factors independently associated with good drug adherence during pregnancy. RESULT: 137 (80.6%) of the interviewed 170 women achieved adherence level of >= 95% using 3 day recall. The desire to protect the unborn child was the greatest motivation (51.8%) for good adherence. Fear of being identified as HIV positive (63.6%) was the most common reason for nonadherence. Marital status, disclosure of HIV status, good knowledge of ART, and having a treatment supporter were found to be significantly associated with good adherence at bivariate analysis. However, after controlling for confounders, only HIV status disclosure and having a treatment partner retained their association with good adherence. CONCLUSION: Disclosure of HIV status and having treatment support are associated with good adherence. Maternal desire to protect the child was the greatest motivator for adherence. PMID- 22523690 TI - Lipids and lipoproteins in atherosclerosis. PMID- 22523691 TI - Nonsterol Triterpenoids as Major Constituents of Olea europaea. AB - Plant triterpenoids represent a large and structurally diverse class of natural products. A growing interest has been focused on triterpenoids over the past decade due to their beneficial effects on human health. We show here that these bioactive compounds are major constituents of several aerial parts (floral bud, leaf bud, stem, and leaf) of olive tree, a crop exploited so far almost exclusively for its fruit and oil. O. europaea callus cultures were analyzed as well. Twenty sterols and twenty-nine nonsteroidal tetra- and pentacyclic triterpenoids belonging to seven types of carbon skeletons (oleanane, ursane, lupane, taraxerane, taraxastane, euphane, and lanostane) were identified and quantified by GC and GC-MS as free and esterified compounds. The oleanane-type compounds, oleanolic acid and maslinic acid, were largely predominant in all the organs tested, whereas they are practically absent in olive oil. In floral buds, they represented as much as 2.7% of dry matter. In callus cultures, lanostane type compounds were the most abundant triterpenoids. In all the tissues analyzed, free and esterified triterpene alcohols exhibited different distribution patterns of their carbon skeletons. Taken together, these data provide new insights into largely unknown triterpene secondary metabolism of Olea europaea. PMID- 22523692 TI - Paraoxonase 1 in chronic kidney failure. AB - In this review we summarize the findings from the literature and our own laboratory on the decreased PON1 activity in renal failure, the mechanisms proposed and the effect of interventions. In addition to profound alterations in lipoproteins, reduced serum PON1 activity has been clearly established in the past decade and could contribute to accelerated development of atherosclerosis in ESRD and in HD. PON1 lactonase activity is lower in ESRD patients. Hemodialysis partially restores PON1 lactonase and the other activities. PON1 activity recovery after dialysis suggests that uremic toxins may play a mechanistic role in PON1 inactivation. Lower PON1 activity in CRF patients is associated with low thiol concentration, high CRP, and is beneficially enhanced with vitamin C and flavonoids. Changes in HDL subclasses, namely lower HDL(3) in these patients may also play a role in PON1 lower activity. Future research should focus on: (1) mechanistic studies on causes for low PON1 activity and mass; (2) prospective studies focusing on whether there is an added predictive value in measuring PON1 activity (and PON1 activity in HDL(3)) in this patient population; (3) intervention studies attempting to increase PON1 activity. PMID- 22523694 TI - Perinatal outcome in unbooked teenage pregnancies in the university of calabar teaching hospital, calabar, Nigeria. AB - Background. Teenage pregnancy being a high risk condition requires skilled attention for good outcome. Objectives. To determine the influence of antenatal care on perinatal outcome in teenage pregnancies in Calabar. Materials and Methods. A review of patient records in Calabar was conducted between 1st January, 2006 and 31st December, 2010, to determine perinatal outcome in teenage pregnancy. Results. Teenage pregnancy accounted for 644 (6.5%) of the total deliveries with 245 (38.0%) booked while 399 (62.0%) were unbooked. Teenage mothers contributed significantly to the proportion of women who were delivered without prior antenatal care (chi(2) = 6.360; P < 0.05). The mean duration of labour in booked teenagers was 10.85 +/- 4.2 hours, while unbooked teenagers was 23.31 +/- 3.6 hours (t-value = 77.1039; P < 0.05). There was statistically more caesarean sections among unbooked teenage pregnancies than booked (chi(2) = 36.75; P < 0.05). Stillbirth was statistically significant (chi(2) = 27.096; P < 0.05) among unbooked teenagers than booked. However, early neonatal death was not significantly different between booked and unbooked teenage pregnancies(chi(2) = 0.512; P < 0.05). Conclusion. Unbooked teenage pregnancies were significantly associated with increased operative intervention and poor perinatal outcome. PMID- 22523693 TI - Nuclear receptor variants in liver disease. AB - This review aims to provide a snapshot of the actual state of knowledge on genetic variants of nuclear receptors (NR) involved in regulating important aspects of liver metabolism. It recapitulates recent evidence for the application of NR in genetic diagnosis of monogenic ("Mendelian") liver disease and their use in clinical diagnosis. Genetic analysis of multifactorial liver diseases such as viral hepatitis or fatty liver disease identifies key players in disease predisposition and progression. Evidence from these analyses points towards a role of NR polymorphisms in common diseases, linking regulatory networks to complex and variable phenotypes. The new insights into NR variants also offer perspectives and cautionary advice for their use as handles towards diagnosis and treatment. PMID- 22523696 TI - The incidence of various antiphospholipid antibodies, measured by commercial based laboratory, with recurrent spontenous abortion and the impact of their profiles on reproductive outcome with active anticoagulant therapy. AB - Objective. To investigate the incidence of various antiphospholipid antibodies (aPLs), measured by commercial-based laboratory, with recurrent spontaneous abortion (RSA) patients and the impact of the species, isotype, titer, and number of positive aPLs on reproductive outcome in Japanese. Method. In this retrospective cohort study, 263 patients with RSA without possible causes were investigated. Of 131 patients with one or more positive aPL, 82 pregnant women under anticoagulant therapy were evaluated. Results. The incidence of various aPLs was almost consistent with previous report. Overall, successful pregnancy rate with anticoagulant therapy was 91.4% regardless of aPL profiles. There was no significant difference in the pregnancy maintenance rate between IgG and IgM groups or single positive and multiple positive groups, but there was a tendency for the rate with aspirin to be lower than with aspirin plus heparin in IgG group. Conclusion. aPL profile did not affect the pregnancy maintenance rate when anticoagulant therapy was actively introduced, however in IgG group, we recommend combination therapy with aspirin and heparin. PMID- 22523695 TI - Factors Associated with Vitamin D Deficiency and Inadequacy among Women of Childbearing Age in the United States. AB - Objective. To examine the prevalence and correlates of vitamin D deficiency and inadequacy among US women of childbearing age. Methods. Data from 1,814 female participants (20-44 y) in the 2003-2006 NHANES were analyzed to estimate the age adjusted prevalence and prevalence ratios with 95% confidence intervals (CIs) for vitamin D deficiency (defined as serum 25-hydroxyvitamin D [25(OH)D] <12.0 ng/mL) and inadequacy (defined as 25(OH)D: 12.0-<20.0 ng/mL). Results. The age-adjusted prevalence was 11.1% (95% CI: 8.8-14.0%) for vitamin D deficiency and 25.7% (95% CI: 22.3-29.5%) for vitamin D inadequacy. Race/ethnicity other than non-Hispanic white and obesity were associated with increased risks, whereas dietary supplement use, milk consumption of >=1 time/day, and potential sunlight exposure during May-October were associated with decreased risks for both vitamin D deficiency and inadequacy (P < 0.05). Current smoking and having histories of diabetes and cardiovascular disease were also associated with an increased risk for vitamin D deficiency (P < 0.05). Conclusions. Among women of childbearing age, periconceptional intervention programs may focus on multiple risk factors for vitamin D deficiency and inadequacy to ultimately improve their vitamin D nutrition. PMID- 22523697 TI - CD8 T-cell responses in incident and prevalent human papillomavirus types 16 and 18 infections. AB - CD8 T-cell responses were examined in subjects with incident (new following negative visits) or prevalent (lasting >= 4 months) human papillomavirus type 16 (HPV16) or human papillomavirus (HPV18) infection. The groups were chosen from a cohort of women being followed every 4 months with cervical cytology and HPV-DNA testing. Enzyme-linked immunospot (ELISPOT) assay was performed at enrollment (time zero) and one year later. At time zero, 1 (6%) of 17 subjects with incident HPV 16/18 infections had positive ELISPOT results which increased to 6 (35%) at one year. For the subjects with prevalent HPV 16/18 infections, the ELISPOT results were similar at time zero (2 (15%) of 15 subjects positive) and at one year (3 (20%)). While all of the 11 women with prevalent HPV16 infection showed clearance one year later, unexpectedly only 1 (25%) of 4 women with prevalent HPV18 infection demonstrated clearance one year later (P = .009). PMID- 22523698 TI - Reducing prescribing errors in paediatric patients by assessment and feedback targeted at prescribers. AB - Prescribing errors are the most common type of medical errors and can result in harm particularly in young children. Doctors were enrolled in a programme of written assessment in prescribing skills and individualized feedback. Pharmacists audited the impact. The setting was the paediatric wards and neonatal unit of a District General Hospital. 16 doctors were tested and received feedback. A total of 110 errors were identified in this test, out of a 51 were classified as major including wrong dose and frequency, and prescribing medication the patient had an allergy to. Audit of impact of this intervention revealed a reduction of errors from 47 to 21, and patients affected from 19 to 11 per 100 (P = 0.001) emergency admissions compared to an audit before the intervention. An intervention combining a comprehensive multifaceted assessment and detailed feedback can lead to reduction of prescribing errors in paediatric trainees. PMID- 22523699 TI - Pharmacodynamic modelling of biomarker data in oncology. AB - The development of pharmacodynamic (PD) biomarkers in oncology has implications for design of clinical protocols from preclinical data and for predicting clinical outcomes from early clinical data. Two classes of biomarkers have received particular attention. Phosphoproteins in biopsy samples are markers of inhibition of signalling pathways, target sites for many novel agents. Biomarkers of apoptosis in plasma can measure tumour cell killing by drugs in phase I clinical trials. The predictive power of PD biomarkers is enhanced by data modelling. With pharmacokinetic models, PD models form PK/PD models that predict the time course both of drug concentration and drug effects. If biomarkers of drug toxicity are also measured, the models can predict drug selectivity as well as efficacy. PK/PD models, in conjunction with disease models, make possible virtual clinical trials, in which multiple trial designs are assessed in silico, so the optimal trial design can be selected for experimental evaluation. PMID- 22523700 TI - How baccalaureate nursing students value an interprofessional patient safety course for professional development. AB - Nursing students need foundation knowledge and skills to keep patients safe in continuously changing health care environments. A gap exists in our knowledge of the value students place on interprofessional patient safety education. The purpose of this exploratory, mixed methods study was to understand nursing students' attitudes about the value of an interprofessional patient safety course to their professional development and its role in health professions curricula. Qualitative and quantitative data were collected from formative course performance measures, course evaluations, and interviews with six nursing students. The qualitative themes of awareness, ownership, and action emerged and triangulated with the descriptive quantitative results from student performance and course evaluations. Students placed high value on the course and essential nature of interprofessional patient safety content. These findings provide a first step toward integration of interprofessional patient safety education into nursing curricula and in meeting the Institute of Medicine's goals for the nursing profession. PMID- 22523701 TI - Ambient Sulphur Dioxide and Female ED Visits for Migraine. AB - Ambient sulphur dioxide (SO(2)) concentrations may affect the number of female emergency department (ED) visits for migraine. ED visits diagnosed as migraine among females in two cities in Canada, Toronto (N = 704) and Ottawa (N = 3, 358), were analyzed. In the study case-crossover design was used. Conditional logistic regression was realized to estimate odds ratios (ORs) and their 95% confidence intervals (CIs) relative to an increase in an interquartile range (IQR, in Toronto IQR = 2.9 ppb, in Ottawa IQR = 3.9 ppb) of sulphur dioxide. In the constructed conditional logistic regression models, temperature and relative humidity were adjusted in the form of natural splines. In Toronto positive and statistically significant associations of sulphur dioxide with migraine ED visits were obtained: all ages, OR = 1.04 (95% CI: 1.00, 1.08); age group [15, 50], OR = 1.05 (95% CI: 1.01, 1.09). In Ottawa positive correlations were observed: all ages, OR = 1.05 (95% CI: 0.97, 1.13); age group [15, 50], OR = 1.06 (95% CI: 0.97, 1.15). The results suggest that female migraine may be affected by ambient sulphur dioxide. PMID- 22523702 TI - Coloured filters enhance the visual perception of social cues in children with autism spectrum disorders. AB - Coloured filters have been found to reduce visual distortion of text in children with autism spectrum disorders (ASD). We investigated the effect of the overlays on the "mind in the eye" task in children with ASD and controls matched for age, gender, and nonverbal IQ. Children were shown photographs of the periocular region of various faces and were asked to judge which emotion was being expressed in the eyes. In children with ASD, the perception of the emotion was significantly improved when the photograph was covered by a coloured overlay. The improvement was significantly greater than in the controls, who showed no significant effect of the overlay. A perceptual impairment may contribute to the social difficulties shown in ASD. PMID- 22523704 TI - Resectable pediatric nonrhabdomyosarcoma soft tissue sarcoma: which patients benefit from adjuvant radiation therapy and how much? AB - It remains unclear which children and adolescents with resected nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) benefit from radiation therapy, as well as the optimal dose, volume, and timing of radiotherapy when used with primary surgical resection. This paper reviews the sparse literature from clinical trials and retrospective studies of resected pediatric NRSTS to discern local recurrence rates in relationship to the use of radiation therapy. PMID- 22523703 TI - Ewing's Sarcoma: Development of RNA Interference-Based Therapy for Advanced Disease. AB - Ewing's sarcoma tumors are associated with chromosomal translocation between the EWS gene and the ETS transcription factor gene. These unique target sequences provide opportunity for RNA interference(i)-based therapy. A summary of RNAi mechanism and therapeutically designed products including siRNA, shRNA and bi shRNA are described. Comparison is made between each of these approaches. Systemic RNAi-based therapy, however, requires protected delivery to the Ewing's sarcoma tumor site for activity. Delivery systems which have been most effective in preclinical and clinical testing are reviewed, followed by preclinical assessment of various silencing strategies with demonstration of effectiveness to EWS/FLI-1 target sequences. It is concluded that RNAi-based therapeutics may have testable and achievable activity in management of Ewing's sarcoma. PMID- 22523705 TI - Integrin signaling in mammary epithelial cells and breast cancer. AB - Cells sense and respond to the extracellular matrix (ECM) by way of integrin receptors, which facilitate cell adhesion and intracellular signaling. Advances in understanding the mammary epithelial cell hierarchy are converging with new developments that reveal how integrins regulate the normal mammary gland. But in breast cancer, integrin signaling contributes to the development and progression of tumors. This paper highlights recent studies which examine the role of integrin signaling in mammary epithelial cells and their malignant counterparts. PMID- 22523706 TI - Pathological fracture of the proximal femur in osteosarcoma: need for early radical surgery? AB - Seventeen patients underwent treatment for a pathological fracture of the proximal femur due to osteosarcoma. Their age range was from 9 to 84 (mean age 42) with nine patients under the age of 40 and eight above the age of 40. Twelve patients had a fracture at diagnosis and five developed a fracture after the diagnosis. Seven patients had metastatic disease at diagnosis. Five patients were referred after internal fixation of the fracture prior to diagnosis. Chemotherapy was used when appropriate and eight patients then underwent limb salvage surgery, six had an amputation, and three had palliative treatment. The estimated five year survival was 14%. These results are significantly worse than expected, and it proved impossible to identify any group who fared well. The high incidence of metastases both at diagnosis and subsequently suggests this group of patients are at very high risk. Review of multicentre data may suggest an optimum treatment for this patient group. PMID- 22523707 TI - Brain metastases from endometrial carcinoma. AB - This paper will focus on knowledge related to brain metastases from endometrial carcinoma. To date, 115 cases were documented in the literature with an incidence of 0.6% among endometrial carcinoma patients. The endometrial carcinoma was usually an advanced-stage and high-grade tumor. In most patients (~90%), brain metastasis was detected after diagnosis of endometrial carcinoma with a median interval from diagnosis of endometrial carcinoma to diagnosis of brain metastases of 17 months. Brain metastasis from endometrial carcinoma was either an isolated disease limited to the brain only (~50%) or part of a disseminated disease involving also other parts of the body (~50%). Most often, brain metastasis from endometrial carcinoma affected the cerebrum (~75%) and was solitary (~60%). The median survival after diagnosis of brain metastases from endometrial carcinoma was 5 months; however, a significantly better survival was achieved with multimodal therapy including surgical resection or stereotactic radiosurgery followed by whole brain radiotherapy (WBRT) and/or chemotherapy compared to WBRT alone. It is suggested that brain imaging studies should be considered in the routine follow up of patients with endometrial carcinoma and that the search for a primary source in females with brain metastases of unknown primary should include endometrial biopsy. PMID- 22523708 TI - High-grade prostate cancer: favorable results in the modern era regardless of initial treatment. AB - Purpose. We performed a retrospective study to determine the outcome of a modern cohort of patients with high-grade (Gleason score >= 8) prostate cancer treated with radical prostatectomy, radiation therapy, or hormone therapy. Methods. We identified 404 patients in the South Texas Veteran's Healthcare System Tumor Registry diagnosed with high grade prostate cancer between 1998 and 2008. Mean follow-up was 4.62 +/- 2.61 years. End points were biochemical failure-free survival, overall survival, metastasis-free survival, and cancer-specific survival. Results. 5-year overall survival for patients undergoing radical prostatectomy, radiation therapy, and hormone therapy was 88.9%, 76.3%, and 58.9%, respectively. 5-year metastasis-free survival for patients undergoing radical prostatectomy, radiation therapy, and hormone therapy was 96.8%, 96.6%, and 88.4%, respectively, and 5-year cancer-specific survival was 97.2%, 100%, and 89.9%, respectively. Patients with a Gleason score of 10 and pretreatment prostate-specific antigen > 20 ng/mL had decreased 5-year biochemical failure free and cancer-specific survival. Patients with a pretreatment prostate-specific antigen > 20 ng/mL had decreased 5-year overall survival. Discussion. Even for patients with high-grade disease, the outcome is not as dire in the modern era regardless of primary treatment modality chosen. While there is room for improvement, we should not have a nihilistic impression of how these patients will respond to treatment. PMID- 22523709 TI - In silico experimental modeling of cancer treatment. AB - In silico experimental modeling of cancer involves combining findings from biological literature with computer-based models of biological systems in order to conduct investigations of hypotheses entirely in the computer laboratory. In this paper, we discuss the use of in silico modeling as a precursor to traditional clinical and laboratory research, allowing researchers to refine their experimental programs with an aim to reducing costs and increasing research efficiency. We explain the methodology of in silico experimental trials before providing an example of in silico modeling from the biomathematical literature with a view to promoting more widespread use and understanding of this research strategy. PMID- 22523711 TI - Does number of ports affect outcomes in patients undergoing laparoscopic pyloromyotomy? Retrospective chart-review study. AB - Background. Although open Ramstedt's pyloromyotomy is the gold standard for the surgical management of infantile hypertrophic pyloric stenosis, laparoscopic pyloromyotomy has been found highly successful. Various factors, however, can affect the outcomes of surgical interventions in these patients. We observed a relationship between the number of ports used and outcome in patients undergoing laparoscopic pyloromyotomies. Methods. We retrospectively assessed the medical records of selected group of patients who underwent laparoscopic pyloromyotomy in our institution. Factors analyzed included operation time, length of hospital stay, postoperative complications, and time to postoperative full feeding. Results. We observed failure of myotomy in both two patients who underwent laparoscopic pyloromyotomy using only two working ports compared to successful myotomies in the remaining patients. Conclusion. Laparoscopy provides good results in terms of intraoperative exposure and cosmesis. However, standardized surgical technique with two working ports is advisable, and this can trigger further research to be ascertained. PMID- 22523710 TI - Recent advances in biomarkers and potential targeted therapies in head and neck squamous cell carcinoma. AB - Head and neck squamous cell carcinoma (HNSCC) is a devastating tumor of the upper aerodigestive tract with no significant change in treatment modality or improvement in survival over the last several decades. Biomarkers are important biological molecules that can be utilized in tumor detection, prognosis, and as targeted therapies. There are several important biomarkers and potential targets in the forefront, including biomarkers of tumorigenesis, signal transduction molecules, proteins involved in angiogenesis, and oncogenic viruses. The clinical applications of these biomarkers are in various states from in vitro and in vivo models, phase II and III clinical trials, to accepted modes of treatment in patients with HNSCC. Given the potential improvement in prognosis that biomarkers and their targeted therapies may have on the treatment of HNSCC, their investigation is both important and essential. PMID- 22523712 TI - Outcome Assessment of the Marshall Coughing Test during Cervix Reposition Maneuver in Women with Urinary Stress Incontinence with/without Genital Prolapse. AB - Objectives. Outcome assessment of the Marshall coughing test (MT) during cervix reposition maneuver (CRM) in women with urinary stress incontinence (USI) with/without genital prolapse (GP). Study Design. 268 patients, divided into USIg (n = 132) with isolated USI and USIGPg (n = 136) with USI and GP stage I/II, additionally divided into USIGP(A) (n = 78) with USI and GP stage I and USIGP(B) (n = 58) with USI and GP stage II, were evaluated with pelvic organ prolapse quantification (POPQ), MT, and CRM. Results. (a) 7.58% had (+) MT with CRM in USIg; (b) in up to 96.15% MT became negative during CRM in USIGP(A); (c) in 51.72% MT became positive only during CRM, as a sign for occult USI in USIGP(B); (d) point Aa (POPQ), which is bladder neck(BN) projection on the anterior vaginal wall, was situated higher in rest position (RP), but moved lower during the Valsalva maneuver (VM) in USIg versus USIGPg (P < 0.05). Conclusion. CRM could be useful arm in selection of (1) patients with isolated USI and great chance for postoperative failure; (2) patients with USI+GP stage I, who need GP repair during antistress surgery; (3) patients with USI + GP stage II, who need antistress procedure during vaginal hysterectomy. PMID- 22523713 TI - Morbidity and Quality of Life in Bladder Cancer Patients following Cystectomy and Urinary Diversion: A Single-Institution Comparison of Ileal Conduit versus Orthotopic Neobladder. AB - Objective. To evaluate and compare noncontinent and continent urinary diversion after radical cystectomy in patients with bladder cancer. Methods. A total of 301 patients submitted to radical cystectomy at the Charite-University Hospital Berlin from 1993 to 2007 including 146 with an ileal conduit and 115 with an ileal neobladder. Clinical and pathological data as well as oncological outcome were retrospectively analyzed and compared. Quality of life was analyzed using the EORTC QLQ-C30 and BLM30 questionnaires. Results. 69.1% and 69.6% of all patients who received an ileal conduit and ileal neobladder, respectively, developed early complications. The two groups differed significantly concerning the occurrence of postoperative ileus (P = 0.02) favoring patients who received an ileal conduit but not with regard to any other early-onset complication evaluated. Patients with ileal neobladder had a significantly better global health status and quality of life (P = 0.02), better physical functioning (P = 0.02), but also a higher rate of diarrhoea (P = 0.004). Conclusion. Cystectomy with any type of diversion remains a complication-prone surgery. Even if the patient groups are not homogeneous in all respects, there are many arguments in favor of the ileal neobladder as the urinary diversion of choice. PMID- 22523715 TI - Decreased vitamin b(12) levels in children with nocturnal enuresis. AB - Objectives. Nocturnal enuresis is a common pediatric problem, the etiology of which is unclear. In the present study, vitamin B(12) and folate levels were measured in children with nocturnal enuresis and compared with those in healthy control group children to investigate whether there was any relation with enuresis and neurogenic maturation as a first time in the literature. Methods. In this cross-sectional study, we included thirty children (16 girls, 14 boys) who had presented with primary nocturnal enuresis (PNE) complaints in the study group and 31 children (13 girls, 18 boys) in the control group. Body weight and height measurements were obtained and complete blood counts and vitamin B(12) and folate levels were measured in all children. Results. No difference was found in age, height, and weight between study and control groups. Also the mean levels of the hemoglobin, hematocrit, and mean corpuscular volume (MCV) were not different between the two groups. Significantly lower mean vitamin B(12) and folate levels were found in the enuresis group compared with the control group. Conclusions. Further studies are needed to clarify B(12) and folate deficiency in larger series so that these tests can be included in routine investigations of enuretic children. PMID- 22523714 TI - Antioncogenic effects of transient receptor potential vanilloid 1 in the progression of transitional urothelial cancer of human bladder. AB - The progression of normal cells to a tumorigenic and metastatic state involves the accumulation of mutations in multiple key signaling proteins, encoded by oncogenes and tumor suppressor genes. Recently, members of the TRP channel family have been included in the oncogenic and tumor suppressor protein family. TRPM1, TRPM8, and TRPV6 are considered to be tumor suppressors and oncogenes in localized melanoma and prostate cancer, respectively. Herein, we focus our attention on the antioncogenic properties of TRPV1. Changes in TRPV1 expression occur during the development of transitional cell carcinoma (TCC) of human bladder. A progressive decrease in TRPV1 expression as the TCC stage increases triggers the development of a more aggressive gene phenotype and invasiveness. Finally, downregulation of TRPV1 represents a negative prognostic factor in TCC patients. The knowledge of the mechanism controlling TRPV1 expression might improve the diagnosis and new therapeutic strategies in bladder cancer. PMID- 22523716 TI - Active Referral Intervention following Fragility Fractures Leads to Enhanced Osteoporosis Follow-Up Care. AB - At one major urban academic medical center, patients aged 50 years and older with fragility fractures were identified and scheduled or assisted in referral into osteoporosis medical management appointments. We evaluated the efficacy of an active intervention program at overcoming the logistical barriers and improving proper osteoporosis follow-up for persons who have sustained a fragility fracture. Of 681 patients treated for defined fractures, 168 were eligible and consented for the study of fragility fractures. Of those enrolled, 91 (54.2%) had appropriate osteoporosis follow-up on initial interview, and overall 120 (71.4%) had successful osteoporosis follow-up following our active intervention. Seventy patients (41.7%) were deemed to have no osteoporosis follow-up, and, of these, 48 were successfully referred to a scheduling coordinator. The scheduling coordinator was able to contact 37 (77%) patients to schedule proper follow-up, and, of these, 29 (78.4%) confirmed receiving an appropriate follow-up appointment. Active intervention and assisted scheduling for patients with recent fragility fractures improved the self-reported rate of osteoporosis follow-up from 54.2% to 71.4%. PMID- 22523717 TI - Secondary osteoporosis: endocrine and metabolic causes of bone mass deterioration. PMID- 22523718 TI - A 10-year experience in intraoperative parathyroid hormone measurements for primary hyperparathyroidism: a prospective study of 91 previous unexplored patients. AB - Introduction. Primary hyperparathyroidism (PHP) is characteristically determined by high levels of calcium and high or inappropriate levels of parathyroid hormone (PTH). Technological advances have dramatically changed the surgical technique over the years once intraoperative parathyroid hormone (IOPTH) assay had allowed for focused approaches. Objective. To evaluate our 10-year experience in employing a rapid intraoperative PTH assay for PHP. Methods. A prospective cohort of 91 PHP-operated patients in a tertiary institution in Sao Paulo, Brazil, from June 2000 to April 2011. Results. We had 85 (93.4%) successful parathyroidectomies, 6 (6.6%) failed parathyroidectomies in 91 previous unexplored patients, and 5 (100%) successful remedial surgeries. The IOPTH was true-positive in 88.5%, true-negative in 7.3%, false-positive in 2.1%, and false negative in 2.1% of the procedures. IOPTH was able to obviate additional exploration or to ask for additional exploration in 92 (95.8%) procedures. Conclusion. The IOPTH revealed to be an important technological adjunct in the current parathyroid surgery for PHP. PMID- 22523719 TI - Is Wireless Capsule pH Monitoring Better Than Catheter Systems? PMID- 22523720 TI - Can a mathematical model be used to estimate the contribution of acute gastroenteritis to the overall prevalence of irritable bowel syndrome? PMID- 22523721 TI - Hiccup: mystery, nature and treatment. AB - Hiccup is the sudden onset of erratic diaphragmatic and intercostal muscle contraction and immediately followed by laryngeal closure. The abrupt air rush into lungs elicits a "hic" sound. Hiccup is usually a self-limited disorder; however, when it is prolonged beyond 48 hours, it is considered persistent whereas episodes longer than 2 months are called intractable. A reflex arc involving peripheral phrenic, vagal and sympathetic pathways and central midbrain modulation is likely responsible for hiccup. Accordingly, any irritant in terms of physical/chemical factors, inflammation, neoplasia invading the arc leads to hiccups. The central causes of hiccup include stroke, space occupying lesions and injury etc, whereas peripheral causes include lesions along the arc such as tumors, myocardial ischemia, herpes infection, gastroesophageal reflux disease and applied instrumentations on human body etc. Besides, various drugs (eg, anti parkinsonism drugs, anesthetic agents, steroids and chemotherapies etc) are the possible etiology. An effective treatment of persistent hiccup may be established upon the correct diagnosis of lesion responsible for the serious event. The pharmacotherapy of hiccup includes chlorpromazine, gabapentin, baclofen, serotonergic agonists, prokinetics and lidocaine. Non-pharmacological approaches such as nerve blockade, pacing, acupuncture and measures to hold breathing are also successful. Finally, alternative medicines and remedies are convenient to treat hiccups with uncertain effect. In conclusions, hiccup is likely to result from lesions involving the hiccup reflex arc. The lesion may need to be localized correctly for ablative treatment in patients with intractable hiccup. Apart from lesion ablation, drugs acting on reflex arc may be effective, while some other conventional measures may also be tried. PMID- 22523722 TI - Gastric electrical stimulation for gastroparesis. AB - Gastric electrical stimulation (GES) for gastroparesis has been in use for more than a decade. Multiple publications, consisting almost entirely of open label single center studies, reported a beneficial effect on symptoms, quality of life and nutritional status. Some predictors of better response to GES have been lately identified, primarily diabetic etiology and nausea and vomiting as the predominant symptoms. However, individual response to GES remains difficult to predict. The mechanism of action of GES remains poorly understood. Stimulation parameters approved in clinical practice do not regulate gastric slow wave activity and have inconsistent effect on gastric emptying. Despite such limitations, gastric electrical stimulation remains a helpful intervention in some patients with severe gastroparesis who fail to respond to medical therapy. PMID- 22523725 TI - Bravo 48-hour Wireless pH Monitoring in Patients With Non-cardiac Chest Pain. Objective Gastroesophageal Reflux Disease Parameters Predict the Responses to Proton Pump Inhibitors. AB - BACKGROUND/AIMS: In patients with non-cardiac chest pain (NCCP), gastroesophageal reflux disease (GERD) is the commonest cause and ambulatory pH is of great value in identifying these patients. However, parameters in the context of predicting therapeutic response are still unknown. By extending the monitoring period, we could better evaluate the best evidence for GERD association. Our aims were (1) to compare the outcomes of 48-hour pH monitoring to 24-hour and (2) to determine whether objective parameters could predict the treatment success in patients with NCCP using Bravo pH system. METHODS: Pathological esophageal acid reflux (PEAR) and positive symptom index (SI) were calculated after 24-hour and compared to the 48-hour study. Evidence suggestive of GERD diagnosis was considered if PEAR and/or SI (+) were present on each different day. After pH study, all patients received proton pump inhibitor twice a day for 4 weeks. Treatment success was determined at the end of therapy. RESULTS: Thirty-two patients with NCCP participated. GERD was identified in 20 (62.5%) patients; 17 (53.1%) had PEAR, 3 (9.4%) SI (+) and 7 (22%) both. Twelve (41%) patients exhibited PEAR values on day 1, while 17 after 2 days; a 12.1% gain. SI (+) was found in 6 patients (18.8%) on day 1 and in 4 more on day 2, a gain of 12.5%. Significantly higher proportion of patients with GERD indicators showed improvement compared to those without (90% vs 16.7%, P < 0.005). CONCLUSIONS: In patients with NCCP, 48-hour pH measurement identified GERD as the cause of NCCP with an increased yield by almost 12% compared to 12 hours. Objective GERD parameters could predict response to antireflux therapy. PMID- 22523726 TI - The Therapeutic and Diagnostic Value of 2-week High Dose Proton Pump Inhibitor Treatment in Overlapping Non-erosive Gastroesophageal Reflux Disease and Functional Dyspepsia Patients. AB - BACKGROUND/AIMS: To evaluate the value of a 2-week high dose proton pump inhibitor (PPI) treatment on patients with overlapping non-erosive gastroesophageal reflux disease (NERD) and functional dyspepsia (FD). METHODS: Sixty overlapping NERD and FD patients with symptom onset > 3 months prior underwent 24-hour esophageal pH monitoring studies. All patients received rabeprazole 20 mg b.i.d. for 2 weeks. The reflux and dyspeptic symptoms were evaluated using a symptom questionnaire with 4-point Likert scales before and at the end of treatment. A positive PPI test was defined as score improvement in >= 50% from the baseline in the typical reflux symptoms. RESULTS: The prevalence of each reflux and dyspeptic symptom did not differ significantly between patients with positive and negative pH tests. After the PPI treatment, epigastric burning, acid regurgitation, heartburn, nausea, vomiting and chest discomfort scores were significantly improved compared to pretreatment values (P < 0.05), whereas postprandial abdominal fullness, early satiation, belching and food regurgitation were not. The proportion of patients who responded to the PPI treatment did not differ significantly between patients with positive and negative pH tests. The sensitivity, specificity, PPV, NPV and accuracy of 2-week high dose rabeprazole treatment for diagnosing gastroesophageal reflux disease were 47%, 38%, 50%, 35% and 43%, respectively. CONCLUSIONS: The two-week high dose PPI treatment was not effective for early satiation, postprandial abdominal fullness, regurgitation or belching symptoms in patients with overlapping NERD and FD. Acid exposure in the distal esophagus could not predict the response of symptoms to PPI. In addition, the 2-week PPI test provided limited value for gastroesophageal reflux disease diagnosis in patients with overlapping NERD and FD. PMID- 22523723 TI - Yin and Yang - the Gastric X/A-like Cell as Possible Dual Regulator of Food Intake. AB - Ingestion of food affects secretion of hormones from enteroendocrine cells located in the gastrointestinal mucosa. These hormones are involved in the regulation of various gastrointestinal functions including the control of food intake. One cell in the stomach, the X/A-like has received much attention over the past years due to the production of ghrelin. Until now, ghrelin is the only known orexigenic hormone that is peripherally produced and centrally acting to stimulate food intake. Subsequently, additional peptide products of this cell have been described including desacyl ghrelin, obestatin and nesfatin-1. Desacyl ghrelin seems to be involved in the regulation of food intake as well and could play a counter-balancing role of ghrelin's orexigenic effect. In contrast, the initially proposed anorexigenic action of obestatin did not hold true and therefore the involvement of this peptide in the regulation of feeding is questionable. Lastly, the identification of nesfatin-1 in the same cell in different vesicles than ghrelin extended the function of this cell type to the inhibition of feeding. Therefore, this X/A-like cell could play a unique role by encompassing yin and yang properties to mediate not only hunger but also satiety. PMID- 22523727 TI - Effects of Rikkunshito (TJ-43) on Esophageal Motor Function and Gastroesophageal Reflux. AB - BACKGROUND/AIMS: Rikkunshito (TJ-43), an herbal medicine, has been demonstrated to relieve gastroesophageal reflux symptoms. However, the effects of TJ-43 on esophageal motor functions have not been fully determined. This double-blind crossover study was performed to investigate the effects of TJ-43 on esophageal motor functions and gastroesophageal reflux. METHODS: The subjects were 10 normal male volunteers. Lower esophageal sphincter pressure and esophageal body peristaltic contractions with and without 1-week administration of TJ-43 were examined in a crossover fashion. Post-prandial gastroesophageal reflux was also determined using a multi-channel impedance pH dual monitor. RESULTS: TJ-43 at a standard dose of 7.5 g/day did not significantly augment esophageal peristaltic contraction pressure measured in the proximal, middle and distal segments of the esophagus, whereas increment of resting lower esophageal sphincter pressure was observed in a supine position. In addition, TJ-43 administration did not decrease post-prandial gastroesophageal acid, non-acid reflux events or accelerate esophageal clearance time. CONCLUSIONS: TJ-43 at a standard dose did not have a significant effect on esophageal motor activity or gastroesophageal reflux in healthy adults. PMID- 22523728 TI - Does Cholecystectomy Increase the Esophageal Alkaline Reflux? Evaluation by Impedance-pH Technique. AB - BACKGROUND/AIMS: The aim of this study is to investigate the reflux patterns in patients with galbladder stone and the change of reflux patterns after cholecystectomy in such patients. METHODS: Fourteen patients with cholecystolithiasis and a control group including 10 healthy control subjects were enrolled in this prospective study. Demographical findings, reflux symptom score scale and 24-hour impedance pH values of the 14 cholecystolithiasis cases and the control group were evaluated. The impedance pH study was repeated 3 months after cholecystectomy. RESULTS: Age, gender, and BMI were not different between the two groups. Total and supine weakly alkaline reflux time (%) (1.0 vs 22.5, P = 0.028; 201.85 vs 9.65, P = 0.012), the longest episodes of total, upright and supine weakly alkaline reflux mediums (11 vs 2, P = 0.025; 8.5 vs 1.0, P = 0.035; 3 vs 0, P = 0.027), total and supine weakly alkaline reflux time in minutes (287.35 vs 75.10, P = 0.022; 62.5 vs 1.4, P = 0.017), the number of alkaline reflux episodes (162.5 vs 72.5, P = 0.022) were decreased with statistical significance. No statistically significant difference was found in the comparison of symptoms between the subjects in the control group and the patients with cholecystolithiasis, in preoperative, postoperative and postcholecystectomy status. CONCLUSIONS: Significant reflux symptoms did not occur after cholecystectomy. Post cholecystectomy weakly alkaline reflux was decreased, but it was determined that acid reflux increased after cholecystectomy by impedance pH-metry in the study group. PMID- 22523729 TI - Influence of Full-body Water Immersion on Esophageal Motor Function and Intragastric Pressure. AB - BACKGROUND/AIMS: In Japan, it is customary to take a daily bath during which the body is immersed in water to the neck. During full-body immersion, hydrostatic pressure is thought to compress the chest and abdomen, which might influence esophageal motor function and intra-gastric pressure. However, whether water immersion has a significant influence on esophageal motor function or intragastric pressure has not been shown. The aim of this study was to clarify the influence of full-body water immersion on esophageal motor function and intragastric pressure. METHODS: Nine healthy male volunteers (mean age 40.1 +/- 2.8 years) were enrolled in this study. Esophageal motor function and intragastric pressure were investigated using a high-resolution 36-channel manometry device. RESULTS: All subjects completed the study protocol. Intragastric pressure increased significantly from 4.2 +/- 1.1 to 20.6 +/- 1.4 mmHg with full-body water immersion, while the lower esophageal high pressure zone (LEHPZ) value also increased from 20.5 +/- 2.2 to 40.4 +/- 3.6 mmHg, with the latter being observed regardless of dietary condition. In addition, peak esophageal peristaltic pressure was higher when immersed as compared to standing out of water. CONCLUSIONS: Esophageal motor function and intragastric pressure were altered by full-body water immersion. Furthermore, the pressure gradient between LEHPZ and intragastric pressures was maintained at a high level, and esophageal peristaltic pressure was elevated with immersion. PMID- 22523724 TI - Asian consensus report on functional dyspepsia. AB - BACKGROUND/AIMS: Environmental factors such as food, lifestyle and prevalence of Helicobacter pylori infection are widely different in Asian countries compared to the West, and physiological functions and genetic factors of Asians may also be different from those of Westerners. Establishing an Asian consensus for functional dyspepsia is crucial in order to attract attention to such data from Asian countries, to articulate the experience and views of Asian experts, and to provide a relevant guide on management of functional dyspepsia for primary care physicians working in Asia. METHODS: Consensus team members were selected from Asian experts and consensus development was carried out using a modified Delphi method. Consensus teams collected published papers on functional dyspepsia especially from Asia and developed candidate consensus statements based on the generated clinical questions. At the first face-to-face meeting, each statement was reviewed and e-mail voting was done twice. At the second face-to-face meeting, final voting on each statement was done using keypad voting system. A grade of evidence and a strength of recommendation were applied to each statement according to the method of the GRADE Working Group. RESULTS: Twenty-nine consensus statements were finalized, including 7 for definition and diagnosis, 5 for epidemiology, 9 for pathophysiology and 8 for management. Algorithms for diagnosis and management of functional dyspepsia were added. CONCLUSIONS: This consensus developed by Asian experts shows distinctive features of functional dyspepsia in Asia and will provide a guide to the diagnosis and management of functional dyspepsia for Asian primary care physicians. PMID- 22523730 TI - Estimating the contribution of acute gastroenteritis to the overall prevalence of irritable bowel syndrome. AB - BACKGROUND/AIMS: Recent studies reveal that acute gastroenteritis can precipitate irritable bowel syndrome (IBS) symptoms leading to the concept of post-infectious IBS. However, the overall contribution of gastroenteritis to the total IBS prevalence is unknown. In this exercise we try to estimate the contribution of gastroenteritis in IBS using the published literature and a longitudinal approach. METHODS: Existing literature was reviewed to determine the incidence of IBS after gastroenteritis, the rate of remission over time, data on rates of gastroenteritis in a given population and any patterns of resistance to these effects in human populations. This produced 3 models. The first assumed all humans were susceptible to gastroenteritis and its ability to produce IBS. The second assumed (using meta-analysis data) that 90% of humans in a given outbreak would be resistant to this effect. The third model used a high gastroenteritis exposure rate as might be seen in military deployment. RESULTS: In model 1, the prevalence was unrealistically high with an eventual steady state of 43.6% of the population affected by IBS. In a very conservative approach (model 2), steady state was achieved after 10 years to an overall prevalence of 8.9%. Interestingly, based on a high 1 year exposure rate such as military deployment, the maximum prevalence (steady state) was reached before 1 year suggesting high risk. CONCLUSIONS: Although hypothetical in approach, based on conservative estimates in existing literature the contribution of gastroenteritis to the overall prevalence of IBS is substantial. PMID- 22523731 TI - G-Protein Beta3 Subunit C825T Polymorphism in Patients With Overlap Syndrome of Functional Dyspepsia and Irritable Bowel Syndrome. AB - BACKGROUND/AIMS: Guanine nucleotide binding protein (G-protein) beta polypeptide 3 (GNB3) C825T polymorphism alters intracellular signal transduction, which may lead to motor or sensory abnormalities of the gastrointestinal tract. The aim of the present study was to evaluate the association of the GNB3 C825T polymorphism with susceptibility to overlap syndrome of functional dyspepsia (FD) and irritable bowel syndrome (IBS) in a Korean population. METHODS: One hundred sixty seven patients with FD alone, 60 patients with IBS alone, 85 patients with the overlap of FD and IBS, and 434 asymptomatic healthy subjects participated in the study. Genotyping for GNB3 C825T polymorphism was performed using their blood samples. RESULTS: No association of GNB3 genotypes in patients with FD alone, IBS alone or overlap phenotype, when compared to genotypes in controls, was detected. The frequency of CT and TT genotypes relative to the CC genotype for the phenotypes of FD alone, IBS alone and the coexistence of FD and IBS did not significantly differ. Comparison of the TT genotype with the CC/CT genotype showed no significant association for each phenotype group. CONCLUSIONS: There is no apparent association of the GNB3 C825T polymorphism with the susceptibility to FD, IBS or the overlap of FD and IBS. Larger-scale studies and further investigation on other candidate genes are required. PMID- 22523732 TI - How to interpret a functional or motility test - sphincter of oddi manometry. AB - To date, endoscopic manometry is the best method for evaluating the function of the sphincter. Sphincter of Oddi manometry (SOM) remains the gold standard to correctly diagnose the sphincter of Oddi dysfunction (SOD) and stratify therapy. Several dynamic abnormalities relating to the intensity, frequency, and propagation of sphincter contractions have been described. However, their clinical use generally has been abandoned in favor of basal sphincter pressure alone, because this measurement is stable over time, and has stronger interobserver reliablility, reproducibility on repeating testing, and is associated with the responsiveness to therapy. A significant elevated risk of pancreatitis was attributed to the technique. The risk of pancreatitits associated with manometric evaluation of the pancreatic sphincter is markedly reduced when manometry is performed with continous aspiration from the pancreatic duct via one of the 3 catheter lumens. This section reviews indications, conscious sedative drugs, techniques, and the appropriate interpretations of SOM. PMID- 22523733 TI - High-resolution Anorectal Manometry for Acquired Megarectum in a Patient With Parkinson's Disease. PMID- 22523734 TI - A patient with Dysphagia associated with opioid medication. PMID- 22523735 TI - Could carbon breath test measurement accurately reflect gastric emptying of liquid nutrient meal in the critically ill patients? (Gut 2011;60:1336-1343). PMID- 22523736 TI - Efficacy of ramosetron in male patients with irritable bowel syndrome with diarrhea (neurogastroenterol motil 2011;23:1098-1104). PMID- 22523737 TI - Colonic Transit Study Technique and Interpretation: Can These Be Uniform Globally in Different Populations With Non-uniform Colon Transit Time? PMID- 22523738 TI - Burden of dyspepsia in rural and urban Asia. PMID- 22523739 TI - Burden of Dyspepsia in Rural and Urban Asia: Author's Reply. PMID- 22523740 TI - Anti-enteric Neuronal Antibodies and the Irritable Bowel Syndrome: Are They Really the Accused? PMID- 22523742 TI - The roles of the DAZ family in spermatogenesis: More than just translation? AB - The DAZ family of genes are important fertility factors in animals, including humans. The family consists of Y-linked DAZ, and autosomal homologs Boule and Dazl. All three genes encode RNA-binding proteins that are nearly exclusively expressed in germ cells. The DAZ family is highly conserved, with ancestral Boule present in sea anemones through humans, Dazl conserved among vertebrates, and DAZ present only in higher primates. Here we review studies on DAZ family genes from multiple organisms, and summarize the common features of each DAZ gene and their roles during spermatogenesis in animals. DAZ family proteins are thought to activate the translation of RNA targets, but recent work has uncovered additional functions. Boule, Dazl, and DAZ likely function through similar mechanisms, and we present known functions of the DAZ family in spermatogenesis, and discuss possible mechanisms in addition to translation activation. PMID- 22523744 TI - SAXS anti-peaks reveal the length-scales of dual positive-negative and polar apolar ordering in room-temperature ionic liquids. AB - Structural patterns that have the same spatial periodicity but a phase offset give rise to peaks and anti-peaks (negative-going peaks) at the same q value in the SAXS structure function S(q). As an example, in ionic liquids we often find charge alternation, and at the distance where one finds a density enhancement of charges of the same type one also finds a depletion of charges of opposite sign. Another such situation arises with polar-apolar densities. At distances where there is enhancement of same-type (polar-polar or apolar-apolar) densities there is also a depletion of opposite-type (polar-apolar) density. This gives rise to prepeaks and what we call same spatial periodicity anti-prepeaks. PMID- 22523745 TI - Dinuclear single-molecule magnets with porphyrin-phthalocyanine mixed triple decker ligand systems giving SAP and SP coordination polyhedra. AB - Two terbium ions in a triple-decker complex (Pc)Tb(Pc)Tb(T(p-OMe)PP) (Pc = phthalocyaninato, T(p-OMe)PP = tetra-p-methoxyphenylporphyrinato) have shown sharply different magnetic behaviours depending on symmetry of the coordination polyhedron. The fast quantum tunnelling relaxation process in a square-prismatic site has been revealed to be hindered by magnetic-dipolar coupling between the f electronic systems. PMID- 22523743 TI - Developmental regulation of chromatin conformation by Hox proteins in Drosophila. AB - We present a strategy to examine the chromatin conformation of individual loci in specific cell types during Drosophila embryogenesis. Regulatory DNA is tagged with binding sites (lacO) for LacI, which is used to immunoprecipitate the tagged chromatin from specific cell types. We applied this approach to Distalless (Dll), a gene required for limb development in Drosophila. We show that the local chromatin conformation at Dll depends on the cell type: in cells that express Dll, the 5' regulatory region is in close proximity to the Dll promoter. In Dll nonexpressing cells this DNA is in a more extended configuration. In addition, transcriptional activators and repressors are bound to Dll regulatory DNA in a cell type-specific manner. The pattern of binding by GAGA factor and the variant histone H2Av suggest that they play a role in the regulation of Dll chromatin conformation in expressing and nonexpressing cell types, respectively. PMID- 22523746 TI - Hydrogenolysis of lignosulfonate into phenols over heterogeneous nickel catalysts. AB - We report a strategy for the catalytic conversion of lignosulfonate into phenols over heterogeneous nickel catalysts. Aryl-alkyl bonds (C-O-C) and hydroxyl groups (-OH) are hydrogenated to phenols and alkanes, respectively, without disturbing the arenes. The catalyst is based on a naturally abundant element, and is recyclable and reusable. PMID- 22523747 TI - Innovative ligand-assisted synthesis of NIR-activated iron oxide for cancer theranostics. AB - This work presents the development of a facile ligand-assisted hydrothermal reaction for the preparation of NIR-activated Fe(3)O(4) nanostructures that can directly upgrade the iron oxide with MR contrast ability to be a MRI/photothermal theranostic agent. PMID- 22523748 TI - Efficient luminescence from a copper(I) complex doped in organic light-emitting diodes by suppressing C-H vibrational quenching. AB - Efficient luminescence was realized by suppressing not only excited-state distortion but also C-H vibrational quenching in a Cu complex. Organic light emitting diodes containing the Cu complex as an emitting dopant exhibited a maximum external quantum efficiency of 7.4%. PMID- 22523749 TI - A remarkably simple alpha-oximation of aldehydes via organo-SOMO catalysis. AB - A novel alpha-oximation reaction of unactivated aldehydes has been achieved in excellent yields by reaction with NaNO(2)-FeCl(3) couple and in the presence of pyrrolidine as organocatalyst. PMID- 22523750 TI - Synthesis and application of poly(fluorene-alt-naphthalene diimide) as an n-type polymer for all-polymer solar cells. AB - A new alternating copolymer of fluorene and naphthalene diimide, PF-NDI, was synthesized and characterized. The highest power conversion efficiency of all polymer solar cells based on P3HT:PF-NDI reached 1.63% with a relatively high fill factor of 0.66 by using 1,8-diiodooctane as a solvent additive to optimize the mixing morphology. PMID- 22523751 TI - A + B -> C reaction fronts in Hele-Shaw cells under modulated gravitational acceleration. AB - The dynamics of A + B -> C reaction fronts is studied under modulated gravitational acceleration by means of a combination of parabolic flight experiments and numerical simulations. During modulated gravity the front position undergoes periodic modulation with an accelerated front propagation under hyper-gravity together with a slowing down under low gravity. The underlying reason for this is an amplification and a decay, respectively, of the buoyancy-driven double vortex associated with the front propagation under standard gravitational acceleration, as explained by reaction-diffusion convection simulations of convection around an A + B -> C front. Deeper insights into the correlation between grey-value changes in the experimental shadowgraph images and characteristic changes in the concentration profiles are obtained by a numerical simulation of the imaging process. PMID- 22523752 TI - Band-edge ultrafast pump-probe spectroscopy of core/shell CdSe/CdS rods: assessing electron delocalization by effective mass calculations. AB - CdSe/CdS dot/rods nanocrystals show interesting physical properties related to the band-alignment at the hetero-interface, which controls the band-edge electron delocalization over the rods. Here the differential transmission spectra of CdSe/CdS nanorod samples with different core sizes have been measured using excitation resonant to the core transition. The photo bleaching ratio between dot and rod transitions increases with the dot size, indicating a trend towards electron localization. This trend has been further quantified by performing effective mass calculations in which the conduction band misalignment was varied in order to reproduce the observed bleaching feature ratio. The best agreement was found for negligible conduction band misalignment for small dots of around 2.3 nm in diameter, and about -0.1 eV misalignment was estimated for the larger dots, above 3.5 nm in diameter. This shows that the band misalignment might be dependent on the geometry of the system, and we argue that this might be related to different strain developed at the hetero-interface. PMID- 22523753 TI - Synthesis of gold@carbon dots composite nanoparticles for surface enhanced Raman scattering. AB - Gold@carbon dots composite nanoparticles (Au@CDs) with ultrathin carbon dot (CD) shells of ca. 2 nm were prepared by reducing HAuCl(4) with CDs at 100 degrees C. By adjusting the feeding mass ratio of HAuCl(4) to CDs, the average diameters of Au@CDs can be modulated from 8 to 44 nm. The suspension of Au@CDs with an average diameter of ca. 24 nm was applied as a substrate for surface enhanced Raman scattering (SERS) and it exhibited a higher SERS effect for rhodamine 6G (Rh6G) than the suspension of pure Au nanoparticles with nearly the same size. The excellent SERS effect of Au@CDs is mainly attributed to their improved capability of adsorbing the aromatic probe molecules. PMID- 22523754 TI - Structural properties and energetics of Li2FeSiO4 polymorphs and their delithiated products from first-principles. AB - Structural properties, thermodynamic stability and delithiation process for Li(2)FeSiO(4) polymorphs are investigated by using density functional theory (DFT) within the DFT + U framework. Three Li(2)FeSiO(4) polymorphs crystallizing in space group Pmn2(1), P2(1)/n, and Pmnb have been considered. The investigations demonstrate that the strong Si-O bonds remain almost unchanged during the lithiation-delithiation process for all the polymorphs, which contribute significantly to the structural stability. On the other hand, the differences in local environment around FeO(4) tetrahedra will be translated into varying degrees of distortion, which shows a significant influence on the structural stability and average voltages. The average voltages obtained here are in good agreement with the experimental values. Furthermore, the possibility of extracting more than one lithium ions per formula unit from Li(2)FeSiO(4) of P2(1)/n is also discussed. PMID- 22523755 TI - A series of 1D Dy(III) compound showing slow magnetic relaxation: synthesis, structure, and magnetic studies. AB - In this work, we present the synthesis, structure, and magnetic studies of three 1D homo-spin Dy(III) compounds in detail. For 1, one crystallography-independent Dy(III) site is contained and the coordination surrounding is a distorted square antiprism geometry. Within 2, four crystallography-independent Dy(III) sites with largely distorted square-antiprism geometry are observed. As for 3, two crystallography-independent Dy(III) sites showing bicapped triangular-prism geometry are involved. The magnetic studies suggest weak ferromagnetic interactions for 1 and weak antiferromagnetic interactions for 2 and 3. Their dynamic magnetic properties are investigated by means of alternating current (ac) susceptibility measurement, revealing their slow magnetic relaxation. Moreover, a field-dependent ac signal is observed in 1, when by applying a static dc = 1000 Oe field, strong frequency-dependent ac signals and the peak of out-of-phase (chi'') can be clearly found. Ultimately, by fitting the Arrhenius law the energy barrier and relaxation time are estimated. PMID- 22523756 TI - Tripodal europium complex with triangulenium dye: a model bifunctional metallo organic system. AB - A new tripodal ligand has been designed by coupling pyridyldicarbonyl binding strands with a triazatriangulenium platform (TATA). The complexation reaction with europium provides a C(3)-symmetrical mononuclear compound that is characterized with NMR, ESMS and qualitatively with single-crystal X-ray crystallography. In addition, photophysical studies of this dual emissive system have been performed, since the combination of the TATA fluorophore with trivalent lanthanides is of potential interest for the further development of imaging applications. PMID- 22523758 TI - Epigenetics: the next big thing. PMID- 22523757 TI - Gene expression profile reveals that STAT2 is involved in the immunosuppressive function of human bone marrow-derived mesenchymal stem cells. AB - Emerging evidence of the potent immunosuppressive activity of mesenchymal stem cells (MSCs) by modulation of both innate and adaptive immune responses enables MSCs to be developed as a promising therapeutic modality for immune-related or inflammatory diseases. However, it is not clearly understood how MSCs exert their immunosuppressive effects on immune cells under inflammatory conditions. Using human bone marrow (BM)-derived clonal MSCs (hcMSCs), we obtained and analyzed a differentially expressed gene profile when stimulated with the inflammatory cytokines interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF alpha) to find novel candidate factors responsible for MSC immunomodulation. Microarray analysis showed that 5650 genes were upregulated and 5862 genes were downregulated with the cutoff of 2-fold expression change. Among these, the ICOSLG and STAT2 genes were drastically upregulated 173-fold and 154-fold, respectively. Reverse transcription-polymerase chain reaction analysis confirmed the microarray data. To evaluate whether their increased expression is related to MSC-mediated immunosuppression,siRNA-induced ICOSLG- or STAT2-knockdown hcMSCs were assessed for their T cell suppressive activity. We demonstrated that STAT2 but not ICOSLG is functionally involved in the immunosuppressive activity of hcMSCs as a novel regulator under inflammatory conditions. Gene ontology and pathway analyses further support the immunomodulatory function of hcMSCs when inflammatory stimulation was provided.Taken together, this study provides an informative genome-wide gene expression profile and molecular evidence for understanding the mechanisms underlying the modulation of immune cells by human BM-derived MSCs under inflammatory conditions. PMID- 22523761 TI - The Canadian Journal of Cardiology. PMID- 22523759 TI - Alien encounters. PMID- 22523762 TI - People's corner award: Heinrich R. Schelbert MD, PhD, receives Distinguished ACC Lifetime Achievement Award. PMID- 22523763 TI - The call of the mountains. PMID- 22523764 TI - Establishment and progress of the chest pain unit certification process in Germany and the local experiences of Mainz. AB - The establishment of chest pain units (CPUs) in the USA and UK has led to improvements in the prognosis of patients with chest pain and myocardial infarction, optimizing access to specialized diagnostic and therapeutic facilities and reducing costs. To establish a uniform implementation of this type of service in Germany, the German Cardiac Society (DGK) founded a 'CPU task force' in 2007, which developed a set of standard requirements and a nationwide certification programme. The recommendations for minimum standard requirements were published in 2008. As of November 2011, 132 CPUs were certified and 36 units were in the certification process. The aim of the DGK is to certify as many as 250 centres (units) throughout Germany within the next 2 years, to provide nationwide coverage. Applications from Switzerland are also being filed. Public awareness campaigns in cooperation with national league soccer teams were organized to raise awareness of the importance for early diagnosis and treatment of cardiac diseases and to publicize the existence of these new facilities. The German model of CPU certification allows nationwide and prospectively European wide standardization of patient care and to improve adherence to international guidelines. Coupled with awareness campaigns and with the launch of a German CPU Registry, this process is aimed at improving the education and treatment of patients with chest pain and to provide scientific information about the quality of patient care. PMID- 22523765 TI - Fluoroquinolones in the treatment of severe community-acquired. PMID- 22523767 TI - [Colonization, miscegenation, and the race issue: notes about mistakes and taboos of Brazilian historiography]. PMID- 22523768 TI - [Development, work, and agrarian reform in Brazil, 1950-64]. PMID- 22523771 TI - [Workers driven by cattle]. PMID- 22523769 TI - [Family and daily urban life in colonial Spanish America: Cartagena de Indias in the 18th century]. PMID- 22523772 TI - [Reflection on the Carnival in the historiography: some approaches]. PMID- 22523773 TI - [Salt, social justice, and royal authority: Sao Paulo in the early 18th century]. PMID- 22523774 TI - "Fashioning" the clothing product: technology and design at Marks & Spencer. PMID- 22523775 TI - Hand knitting, frame knitting and rotary frame knitting in the 17th, 18th and 19th centuries. a question of identification. PMID- 22523776 TI - Indigo in South and South-East Asia. PMID- 22523778 TI - The British hosiery and knitwear machine building industry since 1850. PMID- 22523780 TI - Hildesheim in an age of pestilence: on the political anthropology of birth, death, and resurrection of normalcy. PMID- 22523781 TI - [National solidarity associations? Jewish aid organizations, 1860-1914]. PMID- 22523783 TI - El Nino, El Viejo and the global reshaping of Latin America: surviving the UNCED coups. PMID- 22523784 TI - The Chittagong Hill Tracts: a case study in the political economy of "creeping" genocide. PMID- 22523785 TI - ["Cucina casareccia": culinary and social frontiers of the Atinesi immigrants in Tubize since 1947]. PMID- 22523786 TI - [Housing rents in Belgium, 1800-1920: construction and analysis of a national rent index]. PMID- 22523787 TI - [The medical market in the Netherlands, 1850-1950]. PMID- 22523790 TI - [Large or small: the development of hospital care in the Netherlands, 1890 1950]. PMID- 22523791 TI - [Illegal healers and fake patients: on the attraction of unorthodox forms of medicine, ca. 1900]. PMID- 22523792 TI - Neuroanalysis of therapeutic alliance in the symptomatically anxious: the physiological connection revealed between therapist and client. AB - This study was an attempt to establish neurophysiological correlates, particularly brain activity, during high therapeutic alliance (TA) between client and therapist. The aim was to assess electroencephalography (EEG) activity in clients with symptomatic anxiety during high TA using skin conductance resonance measurements from both client and therapist. Thirty clients, aged 43.8 +/- 11.5 years (males: n=15 females: n=15), underwent six, weekly, 1-hour sessions (180 hours of repeated measures). The EEG activity was measured from the prefrontal, temporal, parietal and occipital sites during the sessions. State and trait anxiety, Working Alliance Inventory (WAI) and heart rate measures were obtained before and after each session. Prefrontal, parietal and occipital sites were associated with TA. Anxiety and heart rate were found to decrease after therapy, and for both the client and the therapist, the WAI score increased significantly in later sessions. The results are discussed from the perspective of further understanding the neurophysiological associations to TA. PMID- 22523793 TI - Barely here to begin with and not-so-goodbyes: keeping the faith when working with turbulent patients. AB - Some patients are unable or unwilling to step into the difficult and uncharted explorations that psychoanalytic work entails; in this paper the author shows how the effort to establish analytic contact with each individual can provide a level of valuable support, containment, and growth for many patients. Such patients may display great resistance to the challenge of psychoanalytic treatment, subtly inviting the analyst, through projective identification processes, to succumb to countertransference acting out. These turbulent patients often leave treatment in very abrupt and unprocessed manners. It is suddenly all over and that is that. This abrupt dismissal is usually a continued expression of the remaining pathology and conflictual phantasies that had been played out in the transference throughout the span of the analytic process. We cannot always prevent this. Rather than seeing this as a complete failure, we can try to maintain ourselves within the depressive position by realizing we are being used by turbulent patients as provisional placeholders and temporary containers. This is a model of grieving in which we acknowledge and accept what we cannot have, what we are not, and what should be but is not. Struggling with these issues in the countertransference is critical to our ability to help such patients because these are the exact issues the patients cannot bear in their lives. And, if we cannot bear them, then the patient has no hope of ever surviving them. PMID- 22523794 TI - Development of the psychotherapy supervisor: review of and reflections on 30 years of theory and research. AB - The psychotherapy supervisor's development (i.e., the unfolding process of growth in being and becoming a supervisor) has long been considered a substantive issue in clinical supervision. Theory and clinical wisdom suggest that supervisors' level of development can have a significant and far-reaching impact on the supervision experience, potentially affecting supervisory alliance formation, in session conceptualization and strategy utilization, and even the outcomes experienced by both supervisees and patients. Consensus seems to be that there is a critical need for empirical study of psychotherapy supervisor development. But with a generation of theory and research on psychotherapy supervisor development behind us, what do we know (or not know); where does this area of inquiry stand today, and what do we need to know about supervisor development going forward? In this paper, I attempt to address those questions. I examine the last 30-year period (approximately) of supervisor development theory, measurement, and quantitative and qualitative study; provide a contemporary status report of sorts on this subject; and identify some important matters for research and practical consideration. Despite a generation of inquiry, the psychotherapy supervisor still remains the largely unknown party in the supervision experience. But that long-standing reality can be changed, some possibilities for doing so are presented, and the promise of supervisor development study is seen to be an ever inviting hope that awaits realization. PMID- 22523796 TI - [Chronic heart failure: progress in diagnosis and treatment. Advancement in medical practice for chronic heart failure]. PMID- 22523795 TI - Out of illness experience: metacognition-oriented therapy for promoting self awareness in individuals with psychosis. AB - Deficits in metacognitive abilities, which enable persons to make sense of their own mental states and those of others, often are observed among persons with schizophrenia. To address these deficits we have sought to develop a metacognition-oriented form of psychotherapy that may foster self-reflectivity leading to the ability to think critically about delusional beliefs and to engage in and sustain healthy social exchanges. To illustrate Metacognition Oriented Therapy, we analyzed its application in an early psychotherapy session with a young woman who had disorganized schizophrenia. In this paper we specifically explore how the therapist followed a sequence of steps aimed at: 1) reconstructing episodes in life-narratives, 2) helping the patient name distressing emotions that appear in the narrative episode, 3) validating and normalizing the patient's experiences, 4) promoting awareness of emotional triggers and the links between affects and social behavior, and 5) validating emerging subjective experiences. We stress how these procedures helped the patient eventually become more able to start questioning her own delusional beliefs. The generalization of these procedures to the psychotherapy of schizophrenia is discussed. PMID- 22523797 TI - [Chronic heart failure: progress in diagnosis and treatment. Topics: I. Progress in epidemiology and fundamental research; 1. Epidemiology of chronic heart failure]. PMID- 22523798 TI - [Chronic heart failure: progress in diagnosis and treatment. Topics: I. Progress in epidemiology and fundamental research; 2. Molecular mechanisms of chronic heart failure]. PMID- 22523799 TI - [Chronic heart failure: progress in diagnosis and treatment. Topics: I. Progress in epidemiology and fundamental research; 3. Pathophysiology of chronic heart failure]. PMID- 22523800 TI - [Chronic heart failure: progress in diagnosis and treatment. Topics: I. Progress in epidemiology and fundamental research; 4. Circulatory regulator]. PMID- 22523801 TI - [Chronic heart failure: progress in diagnosis and treatment. Topics: II. Progress in diagnosis; 1. Approach to the diagnosis for heart failure]. PMID- 22523802 TI - [Chronic heart failure: progress in diagnosis and treatment. Topics: II. Progress in diagnosis: 2. Biomarker]. PMID- 22523803 TI - [Chronic heart failure: progress in diagnosis and treatment. Topics: II. Progress in diagnosis: 3. Echocardiography]. PMID- 22523804 TI - [Chronic heart failure: progress in diagnosis and treatment. Topics: II. Progress in diagnosis 4. Myocardial imaging]. PMID- 22523805 TI - [Chronic heart failure: progress in diagnosis and treatment. Topics: III. Progress in prevention, control and treatment; 1. Prevention for chronic heart failure]. PMID- 22523806 TI - [Chronic heart failure: progress in diagnosis and treatment. Topics: III. Progress in prevention, control and treatment: 2. General measures in heart failure management]. PMID- 22523807 TI - [Chronic heart failure: progress in diagnosis and treatment. Topics: III. Progress in prevention, control and treatment: 3. Evidence-based pharmacologic therapy for chronic heart failure]. PMID- 22523808 TI - [Chronic heart failure: progress in diagnosis and treatment. Topics: III. Progress in prevention, control and treatment: 4. Pharmacologic therapy: antiarrhythmic drug therapy]. PMID- 22523809 TI - [Chronic heart failure: progress in diagnosis and treatment. Topics: III. Progress in prevention, control and treatment: 5. Non-pharmacological therapy (CRT, ICD, VAS)]. PMID- 22523810 TI - [Chronic heart failure: progress in diagnosis and treatment. Topics: III. Progress in prevention, control and treatment 6. Non-pharmacological treatment of chronic heart failure (positive pressure ventilation)]. PMID- 22523811 TI - [Chronic heart failure: progress in diagnosis and treatment. Topics: III. Progress in prevention, control and treatment: 7. Surgical treatment, heart transplantation]. PMID- 22523812 TI - [Chronic heart failure: progress in diagnosis and treatment. Topics: III. Progress in prevention, control and treatment: 8. Establishment of novel therapy for congestive heart failure using human iPS cell-derived regenerated cardiomyocytes]. PMID- 22523813 TI - [Discussion meeting on how to diagnose and treat the patients with heart failure- its past, present and future]. PMID- 22523814 TI - [Case report: a case of single dose azithromycin treatment being effective for fluoroquinolone-resistant shigellosis]. PMID- 22523815 TI - [Case report: a case of Behcet's disease difficult to differentiate from infectious meningitis]. PMID- 22523816 TI - [Case report: cardiac conduction defects coexisting with the VACTERL association: a case report]. PMID- 22523817 TI - [Case report: two cases of proteinase-3-antineutrophil cytoplasmic antibody (PR3 ANCA) positive infection related glomerulonephritis]. PMID- 22523818 TI - [Case report; A case of caesarean section after the Fontan repair]. PMID- 22523819 TI - [Case report: a case of IgG4-associated autoimmune pancreatitis accompanying liver inflammatory pseudotumor]. PMID- 22523820 TI - [The cutting-edge of medicine: the patho-physiology and development of therapy in immune thrombocytopenia]. PMID- 22523821 TI - [The Cutting-edge of Medicine: front line of the treatment of reflux esophagitis]. PMID- 22523822 TI - [The cutting-edge of medicine: progress of autoantibodies in polymyositis and dermatomyositis-biomarker for myositis-associated interstitial lung disease]. PMID- 22523823 TI - [Series: knowledge of emergency required for internist; acute abdomen]. PMID- 22523825 TI - [Series: for attending physicians: professionalism; informed consent forms as a dimension of medical communication]. PMID- 22523824 TI - [Series: clinical study from Japan and its reflections; impact of glycemic control on the clinical outcome in diabetic patients with percutaneous coronary intervention:--from the FU-registry--(UMIN registration no. 000005679)]. PMID- 22523826 TI - [Series: diagnosis at a glance]. PMID- 22523827 TI - Simultaneous liver metastasectomy at operation for primary colorectal or gynecologic malignancy. AB - BACKGROUND: Treatment of synchronous resectable colorectal liver metastases has traditionally involved a staged surgical approach. Specialized centers have demonstrated good results with simultaneous resection. We aim to report our outcomes at the University of Mississippi Medical Center (UMMC) with simultaneous liver metastasectomy at the time of operation for primary colorectal or gynecologic malignancy STUDY DESIGN: From January 2010- September 2011, 6 patients underwent simultaneous resection of liver metastases and primary colorectal or gynecologic malignancy. Operative, postoperative, and pathologic data were retrospectively reviewed. RESULTS: Four patients with colorectal primaries underwent simultaneous resection. One received abdominoperineal resection with resection of lesions in hepatic segments II and VII. A second received right hemicolectomy with en bloc resection of gallbladder and segments IV and V. The third and fourth patients both underwent left colectomy with resection of segments IV and V, respectively. All resections were non-anatomic, and frozen-sections were confirmed to be negative at the resection base. No patients suffered additional postoperative morbidity or mortality related to liver resection. Two patients had ovarian cancer with metastatic disease to the liver. The first underwent en bloc resection ofgallbladder and segments IV and V along with extensive debulking. The second had recurrent ovarian cancer with metastases with liver segments VI and VII. Both patients underwent simultaneous resection with no added postoperative morbidity or mortality attributed to hepatic resection. For gynecologic malignancy, the objective is to remove bulky disease, and although microscopic margins were positive, the goal of tumor load reduction was achieved. CONCLUSIONS: Liver resection at the time of operation for primary colorectal or gynecologic malignancy can safely be performed with the benefit of avoiding morbidity of a second laparotomy without compromising safety. PMID- 22523828 TI - About kidney transplantation. PMID- 22523829 TI - Focusing on professionalism. PMID- 22523830 TI - Paediatric endocrine aspects of ghrelin. AB - Ghrelin is a 28 amino-acid brain-gut peptide that is well-known for its orexigenic and metabolic effects leading to an overall positive energy balance. It stimulates appetite and growth hormone release via the GHS-R1a receptors. GOAT has been identified as the enzyme that acylates ghrelin, which is important for its endocrine function. The ghrelin/GHS-R/GOAT system has been studied extensively in view of its association with several endocrine diseases and the potential of developing an effective treatment. These include obesity, Prader Willi syndrome, anorexia nervosa and diabetes mellitus. Ghrelin system has also been associated with growth and stature. All these conditions can affect children and have a significant impact on the quality of health and life prognosis. In this review, we look into the association of ghrelin with appetite, growth and metabolic disorders in children. PMID- 22523831 TI - Umbilical cord blood-derived very small embryonic like stem cells (VSELs) as a source of pluripotent stem cells for regenerative medicine. AB - Umbilical cord blood-derived very small embryonic-like stem cells (UCB-VSELs) are the most primitive stem cells circulating in fetal peripheral blood. These very rare cells slightly smaller than red blood cells i) become mobilized during delivery, ii) are enriched in fraction of CD133+ Lin-CD45- cells iii) express markers of pluripotent stem cells (e.g., Oct4, Nanog, and SSEA-4) and iv) display a distinct morphology characterized by a high nuclear/ cytoplasmic ratio and undifferentiated chromatin. We envision that VSELs are released into neonatal peripheral blood as a migrating population of stem cells involved in regeneration of tissues that become damaged in the process of delivery. They may also be responsible for the occurrence of fetal-maternal chimerism. Our most recent data suggest that UCB-VSELs exhibit some characteristics of long-term repopulating hematopoietic stem cells (LT-HSCs). We propose that UCB-VSELs may eventually be employed as a source of pluripotent stem cells in regenerative medicine. PMID- 22523832 TI - Clinical implications of thyroid hormones effects on nervous system development. AB - Thyroid hormones have an important role throughout prenatal and postnatal nervous system development. They are involved in several processes such as neurogenesis, gliogenesis, myelination, synaptogenesis, etc., as shown in many cases of deficiency like congenital hypothyroidism or hypothyroxinemia. Those pathologies if untreated could lead to severe damages in cognitive, motor, neudoendocrine functions among other effects. Some could be reversed after adequate supplementation of thyroid hormones at birth, however there are other cellular processes highly sensitive to low levels of thyroid hormones and lasting a limited period of time during which if thyroid hormone action is lacking or deficient, the functional and structural damages would produce permanent defects. PMID- 22523833 TI - Dilemmas in choosing and using growth charts. AB - Human growth is both a target seeking process regulated by genes and environment, and a highly dynamic process that even under similar social and economic circumstances varies considerably both in amplitude (being short or tall) and tempo (maturing fast or slow). This has led to vivid discussions about which growth chart is the right chart to use. In contrast to wide-spread opinions emphasizing the similarity in early childhood growth among diverse ethnic groups, it has become apparent that a single "global" reference fails to adequately mirror the diversity in human growth. In view of the raising evidence that growth is also influenced by the peer group, we refer to novel, cost-effective procedures that facilitate producing growth references "on demand", for limited regional purposes, for ethnically, socio-economically or politically defined minorities, but also for matching geographically different groups of children and adolescents for international growth and registry studies. PMID- 22523834 TI - D-dimer levels in type 1 and type 2 diabetic children and adolescents; Relation to microvascular complications and dyslipidemia "own data and review". AB - BACKGROUND: Changes in the coagulation cascade have been implicated in the pathogenesis of the vascular diabetic complications. OBJECTIVE: to assess D-dimer level (as a marker of coagulation cascade/fibrinolysis activation) in type 1 and type 2 diabetics and its correlation with microvascular complications and serum total cholesterol (TC) level. METHODS: Ninety patients were included divided into two groups. Group 1; comprised 50 type 1 diabetics with a mean age of 13.56 years. Their disease duration ranged between 0.4-16 years. Group 2; comprised 40 type 2 diabetics with a mean age of 13.5 years. Their disease duration ranged between 0.4-8 years. Patients were compared to 60 healthy age and sex matched subjects served as controls. Laboratory investigations included; fasting blood glucose, glycosylated hemoglobin, quantitative urinary albumin creatinine ratio (ACR), serum TC and measurement of plasma D-dimer levels. RESULTS: Type 2 diabetics had significantly higher weight and body mass index (BMI) Standard deviation score (SDS) (p<0.0001) compared to type 1 diabetics. Type 2 diabetics had higher TC (p<0.04) and D-dimer levels (p<0.05) compared to type 1 diabetics. D-dimer level was highly significantly elevated among type 1 diabetics with retinopathy, neuropathy and nephropathy compared to non-complicated patients (p<0.01). D-dimer was significantly correlated with ACR (p<0.001) in both studied groups. In type 2 diabetics, TC level was positively correlated with BMI SDS (p<0.05), D-dimer level was significantly correlated with disease duration (p<0.05), blood pressure (p<0.01), and TC (p<0.05). In type 1 diabetics, D-dimer levels were positively correlated with blood pressure (p<0.01). In both types, D dimer is positively correlated with ACR (p<0.001). CONCLUSION: There was a tendency to hypercoagulability in both types of diabetes. This phenomenon may play a role in the development of diabetic microvascular complications. PMID- 22523835 TI - Ketoacidosis at onset of type 1 diabetes mellitus in pediatric age in Spain and review of the literature. AB - DKA at diagnosis of T1DM is a life-threatening situation that represents the main cause of morbidity and mortality in pediatric patients with T1DM. OBJECTIVE: To determine whether the occurrence and severity of DKA at diagnosis of T1DM has suffered any changes in recent years in the Spanish paediatric population. PATIENTS AND METHODS: Data from 1169 patients with T1DM under 15 years of age was retrospectively studied (2004 -2008) for the presence and severity of DKA at the onset of T1DM, and compared to previous available studies in Spain. This study is multicentric, nationwide with eleven major Paediatric Diabetes Units involved. RESULTS: Complete data were available from 1151 patients (98%). Frequency of DKA was 39.5%, which is not significantly different from previous Spanish studies. 33.8%, children of 0-4.9 years of age, 40.8% aged 5-10.9 and 25.2% aged 11-14.9 years. Mean age of patients with DKA was significantly lower than the one of patients without DKA (7.44 +/- 4.10 versus 8.47 +/- 3.63 years). Mild DKA was occurring more frequently than moderate and severe forms (47.8%, versus 34.4% versus 17.8%, p<0.0001). Incidence of severe DKA was significantly higher in children under 4.9 years of age, especially in those younger than 2 years (p<0.001). Severe DKA led to complications in three children (cerebral oedema [n=1]), cerebral infarction (n=1) and femoral vein thrombosis (n=1). CONCLUSION: Frequency of DKA at diagnosis of T1DM in Spain is still high although most cases were mild. Children under 2 years of age seem to be at increased risk for severe DKA. PMID- 22523836 TI - Highlights from the First Thalassaemia Forum on Growth and Endocrine Complications in Thalassemia Doha, (October 2-3, 2011). PMID- 22523837 TI - Israel Society for Metabolic Diseases, winter meeting Hadassah Medical Centre, Ein Kerem, Jerusalem, Israel (December 7, 2011). PMID- 22523838 TI - The 9th Annual World Congress on the Insulin Resistance Syndrome Pediatric Insulin Resistance. Los Angeles, CA. (November 3-5, 2011). PMID- 22523839 TI - [Microscopic diagnosis of amebiasis: an obsolete method but necessary in the developing world]. AB - Molecular biology-based diagnosis offers the best approach to detect amebiasis, but remains impractical in the clinical laboratories from the developing world. In these areas, the microscopic diagnosis remains the routine method. It is imperative that a series of fresh stool specimens be examined. The use of a concentration method should become a routine procedure. Permanent stained smears is the most critical and reliable diagnostic method for the microscopic detection of intestinal protozoa. If the direct or concentrate wet mounts were considered as a preliminary examination; and the use of iron-hematoxylin stained smears become a routine procedure, many of the misdiagnosis that frequently occur could be avoided. The iron-hematoxylin stained preparation is the method of choice for the microscopic detection of E. histolytica/E. dispar and other intestinal protozoa. PMID- 22523840 TI - [Pesticide residues in drinking water of an agricultural community in the state of Merida, Venezuela]. AB - The aim of this study was to determine the presence of pesticides in drinking water from six aqueducts in a region of intense agricultural activity in the state of Merida, Venezuela. The study was conducted for four continuous weeks, between May and June 2008. Pesticide residues were analyzed by solid phase extraction (SPE) and liquid chromatography (HPLC) with diode array detector (DAD). The method SPE-HPLC-DAD met the criteria of analytical validation, with good linearity (R2: 0.9840 to 0.9999), precision (coefficient of inter-day variability from 1.47 to 6.25%), accuracy (relative standard deviation 0.9 to 9.20%) and sensitivity (LOD < or = 0.012 microg/L; LOQ < or = 0.030 microg/L, except mancozeb with 0.400 microg/L). Seven of the thirteen selected pesticides have a recovery rate between 100% and 70%, the rest between 61% and 37%. Ten pesticides of the following chemical groups, were detected in 72 samples analyzed: organophosphates, carbamates, triazines and urea derivatives. The pesticides with the highest frequency of detection were: carbofuran and atrazine (39%), malathion (25%), dimethoate and metribuzin (19%). The pesticides found at high levels were diazinon (26.31 microg/L), methamidophos (10.99 microg/L), malathion (2.03 microg/L) and mancozeb (1.27 microg/L). Pesticide levels did not exceed the maximum allowed by Venezuelan law, however, according to international standards (EU and EPA-USA) values were above the maximum permissible levels. This study demonstrates the urgent need for systematic monitoring of the quality of water for human consumption in regions of high agricultural productivity. PMID- 22523841 TI - [In vitro synergisms among hydrazones, ajoeno and posaconazole against Cryptococcus spp]. AB - The aim of this study was to assess the in vitro susceptibility to novel antifungal compounds, the steroidal hydrazones, and to compare their antifungal activity and synergistic effects with other compounds, such as ajoeno and posaconazole on Cryptocococus spp isolates. Three Cryptococcus strains were used for this study (42794, 4050 and 44192) and their antifungal sensitivity and synergistic effects with ajoeno and posaconazole were evaluated according to the CLSI protocol number M27-A2. Candida albicans (ATCC 90028) and Candida parapsilosis (ATCC 22019) were used as controls. A plateau effect with hydrazones (H1, H2, H3, H4) was observed after 10 microM (CMI). However, with H4 only a mild inhibition on the growth was obtained. Combining hydrazone and ajoeno, CMI values between 25 and 50 microM were obtained. The highest inhibitions values were obtained with posaconazole and a CMI value of 6 microM for the strains 42794 and 44192, and a CMI value of 20 microM for the strain 4050. Synergy was observed combining posaconazole with ajoeno, ajoeno with hydrazone 3 and posaconazole with hydrazone 3. Fractional inhibitory concentrations were 0.24, 0.16 and 0.09 respectively, which might indicate a synergistic effect. Important synergistic effects were obtained with posaconazole and ajoeno, ajoeno and hydrazone 3 and posaconazole with hydrazone 3, which would be very useful for clinical trials in the future. PMID- 22523842 TI - [Cardiovascular risk: initial estimation in the study cohort "CDC of the Canary Islands in Venezuela"]. AB - In Venezuela as in the Canary Islands (Spain), cardiovascular disease is a major cause of morbidity and mortality. The purpose of this research is to estimate the cardiovascular risk in the Canary Islands migrants living in Venezuela and participating in the study cohort "CDC of the Canary Islands in Venezuela". 452 individuals, aged 18 to 93 years (54.9% women), were enrolled between June 2008 and August 2009. A data survey was performed and their weight, height, abdomen and hip circumferences, and blood pressure were measured. After a 12-hour fasting period, a blood sample was obtained for glucose and lipid profile determinations. 40.5% of the subjects were over 65 years of age and 8% corresponded to the younger group (18-30 years). In men, the average age was 57.69 +/- 18.17 years and the body mass index 29.39 +/- 5.71 kg/m2, whereas women were 56.50 +/- 16.91 years and 28.20 +/- 5.57 kg/m2, respectively. The prevalence of metabolic syndrome was 49.1%, overweight and obesity together 75,2%, abdominal obesity 85.4%, diabetes 17.4%, impaired fasting glucose (IFG) 12.2%, elevated blood pressure 52.9%, low HDL-cholesterol 53,8% and elevated serum triglycerides 31%. Among subjects without diabetes or IFG, a third showed a high triglycerides/HDL cholesterol ratio, indicating insulin resistance. We conclude that the Canarian Venezuelan community suffers high prevalence of cardiovascular risk factors (obesity, abdominal obesity, dyslipidemia, diabetes). In relation to the current population of the Canary Islands, they show a lower frequency of IFG and a higher frequency of low HDL-cholesterol. In comparison to the Venezuelan population (Zulia), they showed to have lower prevalence of IFG, low HDL cholesterol and elevated triglycerides. PMID- 22523843 TI - [Analysis of microdeletions in 22q11 in Colombian patients with congenital heart disease]. AB - Cardiac defects are the most frequent congenital malformations, with an incidence estimated between 4 and 12 per 1000 newborns. Their etiology is multifactorial and might be attributed to genetic predispositions and environmental factors. Since 1990 these types of pathologies have been associated with 22q11 microdeletion. In this study, the frequency of microdeletion 22q11 was determined in 61 patients with non-syndromic congenital heart disease. DNA was extracted from peripheral blood and TUPLE1 and STR D10S2198 genes were amplified by multiplex PCR and visualized in agarose gels. Gene content was quantified by densitometry. Three patients were found with microdeletion 22q11, representing a 4.9% frequency. This microdeletion was associated with two cases of Tetralogy of Fallot and a third case with atrial septal defect (ASD). In conclusion, the frequency for microdeletion 22q11 in the population analyzed was 4.9%. The cases that presented Teratology of Fallot had a frequency for this microdeletion of 7.4% and for ASD of 11.1%. PMID- 22523844 TI - Comparative analysis of three methods for HPV DNA detection in cervical samples. AB - High risk HPV infection is considered to play a central role in cervical carcinogenesis. HPV DNA testing has shown to be a very useful tool for screening and following cervical infections. The aim of this study was to compare three methods for HPV DNA detection, along with cytology and colposcopy analysis. Cervical samples were collected from 100 sexually active women in Merida, western Venezuela. HPV infection was screened using Hybrid-Capture 2 (HC2), L1-Nested-PCR and E6/E7-PCR assays. 40% of the samples (40/100) were HPV positive by at least one of the DNA detection methods. HC2 detected HPV in 12% specimens. L1- and E6/E7-PCRs showed 50% sensitivity and 77% specificity.The agreement rate between HC2 and both PCR assays was 65%. Kappa value showed moderate concordance between HC2 and both PCR methods (kappa=0.55; CI 95%). Also moderate concordance was seen when L1- and E6/E7-PCRs were compared (kappa=0.48; CI 95%). There was a significant association between the Schiller test and E6/E7-PCR (p=0.006) for HPV infection. An acceptable agreement between all three assays for HPV detection was observed. Nevertheless, different PCR formats need to be further analyzed in order to make the right choice of method for HPV testing. PMID- 22523845 TI - [Pulmonary actinomycosis. Fine needle aspiration diagnostic]. AB - We present four cases of pulmonary actinomycosis in patients over 40 years of age, two of them with chronic obstructive pulmonary disease (COPD), showing an increase in productive cough, episodes of dyspnea, hemoptysis and long-term fever. Routine chest radiographs revealed segmental air-space consolidation, suggestive of unresolved pneumonia or neoplasm. Computed tomography (CT) scan showed similar findings to the ones previously described. Sputum cultures for mycobacteriae and Mantoux tests were constantly negative. Due to the poor clinical and radiodological outcome of the patients, a fine needle aspiration (FNA) was made to rule out a neoplasm. Tridimensional filamentous colonies of Actinomyces were observed in cytology. Antibiotic treatment resulted in an improvement of symptoms. The follow-up showed a decrease of the consolidation areas. Pulmonary actinomycosis is rare nowadays and clinical symptoms are unspecific and can be confused with a neoplasm process. Therefore, in patients with risk factors, symptoms of subacute pneumonia and radiologic findings of consolidation, it is advisable to consider pulmonary actinomycosis as a diagnostic possibility. It is a treatable disease and its correct diagnosis by FNA, avoids performing invasive diagnostic tests, delays in the diagnosis and allows for a complete cure by antibiotic therapy. PMID- 22523846 TI - Immunological correlates of cure in the first American cutaneous leishmaniasis patient treated by immunotherapy in Argentina. A case report. AB - A patient with localized cutaneous leishmaniasis due to Leishmania (Leishmania) amazonensis infection was treated with an antigen containing heat-killed L. (L.) amazonensis promastigotes plus BCG. Expression of T-cell differentiation, memory and senescence receptors markers were analyzed on T cell subpopulations, in order to establish the correlation between the percentages of expression of these receptors and his clinical status, at different stages of his follow up. The following case reports on the achievement of a successful clinical outcome with complete resolution after receiving immunotherapy. A thorough clinical and immunological follow up supporting the healing process of this patient's lesion is presented in detail. PMID- 22523847 TI - [Prostate cancer and apoptosis]. AB - Prostate cancer presents an androgen-dependent growth mediated by the androgen receptor (AR). Androgen pathway blockage is the standard therapy for the treatment of prostate cancer at an advanced stage. In spite of an initial sensitivity, prostate cancer usually becomes refractory to hormone treatment. This resistance can be due to the amplification of the AR gene, AR mutations and the increase in co-activator protein expression. Likewise, growth factors and cytokines can induce AR phosphorylation, independently of ligand fixation. Moreover, there are other AR-independent pathways, such as the acquisition of the neuroendocrine phenotype. In this review, we examine the molecular mechanisms that are involved in the progression of prostate cancer, as well as the ways its cells evade apoptosis. PMID- 22523849 TI - Drug use trends for arthritis and other rheumatic conditions and effect of patient's age on treatment choice. AB - BACKGROUND: Little is known about the influence of the patient's age on selection of treatment for arthritis and other rheumatic conditions (AORCs). The aim of the present study was to examine drug use trends in patients with AORCs in ambulatory care and to study age-specific drug use. METHODS: Data from the National Ambulatory Medical Care Survey and the outpatient department component of the National Hospital Ambulatory Medical Care Survey were used to examine ambulatory visits for AORCs during 2001-2005. Use of nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics (narcotics and nonnarcotics), steroids, and disease modifying antirheumatoid drugs (DMARDs) was measured as the proportion of visits that resulted in a prescription. Age-specific drug use trends were determined separately for adult (19-64 years) and for elderly (> or = 65 years) patients. RESULTS: According to the national surveys, there were 208 million ambulatory visits for AORCs during the study period. Use of NSAIDs, analgesics, steroids, and DMARDs was found to be 33.3%, 23.5%, 15.7%, and 4.3%, respectively. Analgesic use increased from 18.3% in 2001 to 26.7% in 2005. DMARDs and NSAIDs were prescribed 1.2 times more to adult patients than to elderly patients. Steroids and analgesics were prescribed 1.3 and 1.2 times more, respectively, to elderly patients than to adult patients. LIMITATION: The findings do not translate to population-based prevalence measures, as the unit of analysis was the patient visit. CONCLUSIONS: NSAIDs remain the most frequently prescribed drug class for AORCs; however, there has been increased use of analgesics in recent years. The study findings suggest that the patient's age plays a role in the choice of drugs prescribed for AORCs. PMID- 22523850 TI - The increasing impact of human immunodeficiency virus infections, sexually transmitted diseases, and viral hepatitis in Durham County, North Carolina: a call for coordinated and integrated services. AB - BACKGROUND: Durham County, North Carolina, faces high rates of human immunodeficiency virus (HIV) infection (with or without progression to AIDS) and sexually transmitted diseases (STDs). We explored the use of health care services and the prevalence of coinfections, among HIV-infected residents, and we recorded community perspectives on HIV-related issues. METHODS: We evaluated data on diagnostic codes, outpatient visits, and hospitalizations for individuals with HIV infection, STDs, and/or hepatitis B or C who visited Duke University Hospital System (DUHS). Viral loads for HIV-infected patients receiving care were estimated for 2009. We conducted geospatial mapping to determine disease trends and used focus groups and key informant interviews to identify barriers and solutions to improving testing and care. RESULTS: We identified substantial increases in HIV/STDs in the southern regions of the county. During the 5-year period, 1,291 adults with HIV infection, 4,245 with STDs, and 2,182 with hepatitis B or C were evaluated at DUHS. Among HIV-infected persons, 13.9% and 21.8% were coinfected with an STD or hepatitis B or C, respectively. In 2009, 65.7% of HIV-infected persons receiving care had undetectable viral loads. Barriers to testing included stigma, fear, and denial of risk, while treatment barriers included costs, transportation, and low medical literacy. LIMITATIONS: Data for health care utilization and HIV load were available from different periods. Focus groups were conducted among a convenience sample, but they represented a diverse population. CONCLUSIONS: Durham County has experienced an increase in the number of HIV-infected persons in the county, and coinfections with STDs and hepatitis B or C are common. Multiple barriers to testing/treatment exist in the community. Coordinated care models are needed to improve access to HIV care and to reduce testing and treatment barriers. PMID- 22523851 TI - Seasonality of poor pregnancy outcomes in North Carolina. AB - BACKGROUND: Seasonal variation in poor pregnancy outcomes has not received the same level of research attention and rigor as has the well-established seasonal variation in births. METHODS: In this analysis of data from the 2001-2005 North Carolina Detailed Birth Record, we use season of conception as a proxy for environmental or other risk factors. We model the continuous pregnancy outcome of birth weight percentile for gestational age by use of linear regression. We use logistic regression to model the binary pregnancy outcomes of low birth weight (< 2500 g), preterm birth (< 37 weeks), and small for gestational age (< 10th percentile of birth weight for gestational age). RESULTS: We found significant seasonal patterns in poor pregnancy outcomes. Our results suggest that, in North Carolina, seasonal patterns are most pronounced among non-Hispanic white women living in urban areas. LIMITATIONS: The present study is limited by the restricted set of maternal and pregnancy variables available in this data set. Richer data, potentially including psychosocial and activity measures of the women, would allow us to more ably discern what is driving the seasonal patterns we observed. The pronounced increased risk associated with a spring season of conception provides an important clue for determining the true causative factors. CONCLUSIONS: Poor pregnancy outcomes in North Carolina follow a clear seasonal pattern based on timing of conception, with patterns most pronounced among non Hispanic white women living in urban areas. These seasonal patterns are suggestive of causative environmental factors and certainly warrant additional research. PMID- 22523852 TI - Agricultural health. Introduction. PMID- 22523853 TI - Harvest of need: addressing health and safety challenges on North Carolina's farms. AB - Agriculture is North Carolina's leading source of revenue and its most dangerous industry. This issue brief, along with the commentaries and sidebars in the associated policy forum, addresses the complexity of agricultural health and safety in North Carolina and concludes that the following activities are crucial to reducing the incidence of agricultural illness, injury, and death in the state: (1) positive promotion of safe and healthy farms, (2) increased funding for existing programs, (3) creation of a task force to develop a dedicated, comprehensive surveillance system for agricultural illness, injury, and fatality, (4) increased emphasis on and funding for training of health care professionals and emergency response personnel in agricultural health and safety, (5) funding to expand farm health and safety programs to all 100 counties, and (6) strong collaborations to further develop and strengthen a seamless, holistic system for addressing the state's agricultural health and safety needs. PMID- 22523854 TI - Injury and death on the farm: improving prevention through improved surveillance. AB - Work-related injury data suggest that agricultural workers in North Carolina are experiencing high rates of injury and death compared with workers in other occupations. However, current occupational injury data sources are insufficient to calculate accurate injury and mortality rates. We propose recommendations to improve existing farm injury surveillance, to guide prevention. PMID- 22523855 TI - Be seen and be safe highway safety with farm equipment program. PMID- 22523856 TI - Living and working safely: challenges for migrant and seasonal farmworkers. AB - Migrant and seasonal farmworkers are essential to North Carolina agriculture, yet they experience major health risks. This commentary describes the characteristics of North Carolina farmworkers, important hazards they face, and the status of regulatory protections. Finally, it presents a summary of policy needed to protect the health of farmworkers. PMID- 22523857 TI - The North Carolina Gold Star Grower program. PMID- 22523858 TI - Mountain Pesticide Education and Safety Outreach program: a model for community collaboration to enhance on-farm safety and health. AB - This article showcases the outcomes of the Mountain Pesticide Education and Safety Outreach program, a collaborative effort between Christmas tree growers, cooperative extension, farmworkers, farmworker health outreach staff, and others to reduce pesticide exposure and on-farm injuries. Lessons learned during the project that can be adopted by other communities will also be shared. PMID- 22523859 TI - North Carolina's preparedness to respond to on-farm emergencies. AB - North Carolina farm families, emergency services, and fire departments do not always have sufficient training to respond to on-farm emergencies. The main barrier to preparedness is lack of awareness of these needs. We recommend improved emergency response through collaborative education using AgriSafe of North Carolina and Certified Safe Farm North Carolina, two programs geared toward safety training. PMID- 22523860 TI - Consequences of respiratory exposures in the farm environment. AB - Depending on the type of farming practice, respiratory symptoms are common among agricultural workers. Farmers are at risk for pulmonary illnesses, including chronic bronchitis, organic dust toxic syndrome, farmer's lung diseases, allergic and nonallergic asthma, nasal irritation and polyps, and chemical pneumonitis. PMID- 22523861 TI - Aging farmers are at high risk for injuries and fatalities: how human-factors research and application can help. AB - Agriculture is a dangerous profession with an aging population, combining age related changes in physical and cognitive abilities with complex tasks performed under hazardous conditions. There are three general approaches to reducing injuries: designing for safety, providing positive reinforcement in prevention programs, and making safety a family affair. PMID- 22523862 TI - Health and safety on North Carolina farms. AB - Many rural areas in North Carolina do not receive the professional health care they deserve. North Carolina Farm Bureau recognized this unfilled need and implemented its Healthy Living for a Lifetime program in 2010. This initiative is one way to help improve the health of the state's 52,000 family farmers. PMID- 22523863 TI - Inpatient hospitalizations related to agricultural machine injuries in North Carolina, 2006-2010. PMID- 22523864 TI - North Carolina Farmworker Health program. PMID- 22523865 TI - North Carolina's nursing workforce: economic and sociological concerns. PMID- 22523866 TI - Creation of an advisory group for physician workforce studies in obstetrics and gynecology. AB - OBJECTIVE: A projected shortage of obstetrician-gynecologists prompted us to query other major national medical and surgical organizations about internal efforts to examine their specialty's physician workforce needs. STUDY DESIGN: We sought the experience of the top 20 academies, societies or colleges of those medical or surgical specialties. Each organization had approximately 10,000 or more physician members. Those identified as being the most knowledgeable about physician workforce efforts in their specialty were asked to electronically complete a 14-question survey about the existence, structure and function of any workforce office or advisory group in their specialty. RESULTS: Each organization responded to the survey. A task force, permanent committee or office (in large organizations) was formed to ascertain their specialty's workforce needs and projections. The results prompted the Executive Board of the American Congress of Obstetricians-Gynecologists to approve in July of 2010 the creation of an advisory group to conduct research and inform members about trends that affect the obstetrician-gynecologist workforce nationally and in individual districts. CONCLUSION: In response to the potential shortage of obstetrician-gynecologists, an advisory group was approved by the American Congress of Obstetricians and Gynecologists to undertake workforce studies. PMID- 22523867 TI - Emergency contraception after sexual assault: changes in provision from 2004 to 2009. AB - OBJECTIVE: A random sample (20%) of U.S. and territorial emergency departments were surveyed in 2004 and again in 2009 to obtain information about provision and counseling of emergency contraception (EC) to sexual assault victims. STUDY DESIGN: A representative sample of 20% of hospitals, stratified by state/ territory was prepared from the American Hospital Association list in order to conduct a 13-question telephone survey. Questions included (1) "Is there a written protocol for counseling about EC for sexual assault victims?" (2) "Are sexual assault victims at risk of pregnancy counseled about EC?" and (3) "Are sexual assault victims at risk of pregnancy provided EC?" A cross-sectional prevalence survey was administered in 2004 and 2009. RESULTS: Provision of EC has changed very little from 2004 to 2009 (63% vs. 64%, respectively). Provision varies by number of victims treated, region of country and status of state legislation. CONCLUSION: Prophylaxis against possible pregnancy is an important part of sexual assault treatment and should be maximized. EC provision for sexual assault victims in emergency departments has not greatly increased over time and does not reflect regulatory changes in accessibility. Prophylaxes against sexually transmitted infections and pregnancy are handled differently for sexual assault victims, reflecting distinct separation of sexual and reproductive health in clinical practice. PMID- 22523868 TI - Hemoglobin levels in normal-weight and obese patients during pregnancy. AB - OBJECTIVE: To determine if there is a difference in hemoglobin levels in normal weight patients compared with obese women during the second trimester of pregnancy. STUDY DESIGN: This was a retrospective cohort study of hemoglobin levels in the second trimester of pregnancy from 2009 to 2010 in 46 primarily indigent patients (23 normal weight and 23 obese) using the current body mass index classification. RESULTS: There were no differences in demographic and baseline characteristics between the two study groups except for body mass index as expected (p < 0.001). Mean second trimester hemoglobin levels in the obese group (10.8 g/dL) were 6.1% (0.7 g/dL) lower compared with normal-weight patients (mean 11.5 g/dL, p = 0.018). CONCLUSION: Second trimester hemoglobin levels are lower in obese patients when compared to their normal weight counterparts. These lower levels in obese patients may be clinically significant. PMID- 22523869 TI - Comfort in discussing vulvar pain in social relationships among women with vulvodynia. AB - OBJECTIVE: To assess women's likelihood of feeling comfortable in discussing vulvar pain. STUDY DESIGN: Using a survey of women with self-reported clinician diagnosed vulvodynia, we assessed the likelihood of comfort in discussing vulvar pain within four types of relationships: husband/partner, mother/sister, best friend, and other women friends. Separate multivariable models were fit for relationship type to determine whether vulvar pain characteristics (length, severity,family history) were associated with likelihood of feeling comfortable in discussing. RESULTS: A total of 67% of women with a partner were comfortable discussing their vulvar pain with that person, whereas 39% were comfortable with family and 26% were comfortable with women friends. Independent of age, the more years women had vulvodynia the less likely they would be comfortable discussing it. Compared to lower levels of vulvar pain, increasing levels (mild, moderate and severe) were associated with greater comfort in discussing their pain with friends; women were 10% more likely to be comfortable with each increase in pain level, and 12% more likely to be comfortable with other women friends. CONCLUSION: Our data suggest that vulvar pain characteristics may determine how comfortable a woman is to discuss her vulvar pain, but it varies by relationship type. PMID- 22523870 TI - Posttraumatic stress disorder, anxiety and depression following pregnancies conceived through fertility treatments: the effects of medically assisted conception on postpartum well-being. AB - OBJECTIVE: To compare the postpartum prevalence of Posttraumatic Stress Disorder (PTSD), anxiety and depression in women who conceived via medically assisted conception (MAC) and women who conceived naturally. STUDY DESIGN: All women (n = 907) who delivered under supervision of four independent midwifery practices and three hospitals in the Netherlands during a 3-month period were asked to complete questionnaires on demographic, logistic, psychosocial and obstetric characteristics two to six months postpartum. In this cross-sectional study PTSD was measured with the Traumatic Event Scale-B; anxiety and depression were measured with the Hospital Anxiety and Depression Scale. RESULTS: The response rate was 47% (428 participants). No significant differences were found in the prevalence of PTSD (0.0% vs. 1.3%; odds ratio [OR] = 0.0, confidence interval [CI]: 0-infinity), anxiety (28.1% vs. 22.2%; OR = 1.4, CI: 0.6-3.1) and depression (9.4% vs. 14.6%; OR = 0.6, CI: 0.8-2.0) between the 32 women who conceived via MAC and the 396 women who conceived naturally. CONCLUSION: We did not find significant differences in the prevalence of PTSD, anxiety and depression between women who conceived via MAC and women who conceived naturally. PMID- 22523871 TI - Results with GnRH antagonist protocols are equivalent to GnRH agonist protocols in comparable patient populations. AB - OBJECTIVE: To determine whether ovarian stimulation outcome and success rates are equivalent between GnRH agonist and GnRH antagonist regimens when all other variables are held constant. STUDY DESIGN: Retrospective analysis. Infertile patients (n = 1,277) < 35 years of age, with normal ovarian reserve, undergoing their first in vitro fertilization cycle with a GnRH antagonist or agonist were included. Outcome variables were analyzed and compared between both groups. RESULTS: Of the total number of patients included, 21% (n = 268) underwent stimulation with a GnRH antagonist protocol and 79% (n = 1,009) with an agonist protocol. While the mean number of embryos transferred was similar between both groups, as well as the implantation rate for blastocyst embryo transfers, the implantation rate was noted to be slightly higher for the down-regulation group who underwent a Day 3 embryo transfer (p = 0.01). However, the overall clinical pregnancy, loss and high-order multiple pregnancy rates were constant in both groups. CONCLUSION: Although numerous variables were analyzed in our study, the differences noted did not have an impact on our final results as the clinical pregnancy rates were maintained in the antagonist group. PMID- 22523872 TI - Does assisted reproductive technology itself or polycystic ovary syndrome as a cause of infertility have any effect on first trimester serum screening results? AB - OBJECTIVE: To determine whether assisted reproductive technology (ART) itself or polycystic ovary syndrome (PCOS) as a cause of infertility has any effect on first trimester serum screening results. STUDY DESIGN: First trimester serum screening results of ART pregnancies of women with PCOS (IVF-P group) were compared with those of women who underwent ART due to malefactor infertility (IVF H group) and women who conceived spontaneously. RESULTS: Comparison of the groups for crown-rump length (CRL) and nuchal translucency revealed no significance. There was significant difference between the IVF-H and IVF-P groups in terms of free beta-human chorionic gonadotropin (beta-hCG) levels. Although comparison of groups revealed no significance, pregnancy-associated plasma protein A (PAPP-A) values were higher in the IVF-P group than in the IVF-H group. CONCLUSION: CRL and nuchal translucency measurements were not affected by in vitro fertilization procedures or the presence of maternal PCOS. Use of ART decreased PAPP-A and increased free beta-hCG levels. Although not significant, PAPP-A was higher in PCOS patients who conceived with ART, which may in turn increase false negative rates in these cases. PMID- 22523873 TI - Amniotic fluid arborization in the diagnosis of previable preterm premature rupture of membranes. AB - OBJECTIVE: To determine the accuracy of using amniotic fluid arborization to diagnose preterm premature rupture of membranes (PPROM) in the second trimester using specimens collected from the vaginal pool. STUDY DESIGN: Women presenting for pregnancy termination between 14 and 22 weeks' gestation were enrolled. At the time of termination, amniotic fluid samples were collected directly from the amniotic sac and from the vaginal pool, air dried and examined for arborization. RESULTS: Arborization was detected in 51/59 (86.4%) samples collected from the amniotic sac and 41/59 (69.5%) samples collected from the vaginal pool. The sensitivity and specificity in detecting arborization in fluid collected by swabbing the vagina was 0.69 and 0.98, respectively (positive predictive value 0.98%, negative predictive value 0.76). CONCLUSION: While the presence of arborization in samples collected from the vaginal pool is predictive of PPROM in the second trimester, the absence of arborization should not rule out the diagnosis if there is strong clinical suspicion. PMID- 22523874 TI - Electromyography and vaginal pressure of the pelvic floor muscles in women with recurrent vulvovaginal candidiasis and vulvodynia. AB - OBJECTIVE: To evaluate the electrical potentials and pressure exerted by the pelvic floor muscles in women with recurrent vulvovaginal candidiasis (RVVC) or vulvodynia as compared to control women. STUDY DESIGN: A cross-sectional study performed in the Female Outpatient Clinic of Genital Infections in the Department of Obstetrics and Gynecology of the Universidade Estadual de Campinas analyzed and compared electromyography (EMG) and vaginal pressure of the pelvic floor muscles in 61 women. Of these 61 women, 19 had vulvodynia, 12 had RVVC and 30 women had no disorder (control group). For data collection, the instrument used was the Miotool Uro device and its software Biotrainer (Miotec Ltd., Porto Alegre, Rio Grande do Sul, Brazil). RESULTS: The EMG evaluation of the pelvic floor muscles showed significantly lower values in the vulvodynia group (tonic contractions) and RVVC group (phasic and tonic contractions) when compared to the control group. No significant differences in basal tone EMG and vaginal pressure values at rest or during pelvic floor muscle contractions were found among groups. The maximum time of sustained contraction in patients with RVVC or vulvodynia was significantly lower (p < 0.0001) than in controls. CONCLUSION: Women with vulvodynia and RVVC have more frequent pelvic floor muscle dysfunction than controls when observed by EMG evaluation. PMID- 22523875 TI - Intercellular adhesion molecule-1 K469E polymorphism: Is it associated with preeclampsia in the Korean population? AB - OBJECTIVE: To examine whether the distribution of genotypic and allelic frequencies of ICAM-1 K469 of Korean women with preeclampsia are different from that of a control group. STUDY DESIGN: In this case-control study the ICAM-1 K469E polymorphism was genotyped in 42 women with preeclampsia and 138 normotensive controls who had delivered at least two normal, term infants. A direct sequencing reaction method was used to detect a single nucleotide polymorphism. RESULTS: The distribution of genotype frequencies and the frequency of the K469 allele of the preeclampsia group were not significantly different from those of the controls. A similar trend was observed between the severe preeclampsia patients and the controls. CONCLUSION: The frequencies of the KK genotype and the K allele were higher in the preeclampsia group than those in the control group. However, there was no statistically significant difference. PMID- 22523876 TI - Personality and emotional adjustment in infertility. AB - OBJECTIVE: To examine the relationship between adjustment to diagnosed infertility and personality, anxiety, depression and stress (in general and inherent to infertility) in couples. STUDY DESIGN: A cross-sectional study, with a convenience sample of 35 couples attending infertility consultations, in a public health service in the Lisbon district. Data was collected using the following main outcome measures: NEO Personality Inventory--Short Form; Depression, Anxiety and Stress Scale; Fertility Problem Inventory; and Fertility Adjustment Scale. RESULTS: In women, neuroticism was associated with greater stress in situations of infertility, and depression was related with social, sexual and relational aspects of stress in infertility. Social aspects and need to be a parent expressed maladjustment to fertility. In men, personality was not related to stress in infertility; this was explained by the sexual and relational aspects. The maladjustment to fertility was explained by the need to be a parent. CONCLUSIONS: Infertile men and women are emotionally adjusted, determined to fulfill their goals while exhibiting low levels of anxiety, depression and stress. Thus, although it is relevant to identify the effects of infertility which may make one susceptible to maladjustment, psychological intervention is not always necessary in these couples. Although the results are very relevant, the sample's reduced dimension is a limitation. PMID- 22523877 TI - Full-term vaginal live birth after laparoscopic radiofrequency ablation of a large, symptomatic intramural fibroid: a case report. AB - BACKGROUND: This case study describes the first reported vaginal delivery following radiofrequency ablation (RFA) of fibroids. The subject was among a cohort of women seeking treatment for symptomatic fibroids. She was enrolled in a clinical trial studying outcomes of laparoscopic, ultrasound-guided RFA of symptomatic fibroids. CASE: A 38-year-old, G4P3, female was diagnosed with uterine fibroids following a spontaneous abortion and preterm delivery at 21 weeks of a nonviable infant. RFA was performed on 7 fibroids, the largest of which was measured by magnetic resonance imaging (MRI) to be a 6.1-cm, submucosal intramural, right posterior leiomyoma. The patient conceived approximately 3.5 months after RFA. She had a spontaneous labor at term with an uncomplicated vaginal delivery of a 3,487-g female infant (Apgars: 9, 9). Post-RFA and post delivery MRI images indicated a myometrial thickness of 9.6 mm throughout, including beneath the ablation site. CONCLUSION: The lack of a uterine defect following RFA in this case may have allowed this patient to progress to term without uterine rupture as has been reported with conventional myomectomy. The use of RFA in infertile women needs further study, and the decision to perform a cesarean section in women who have had RFA needs to be evaluated. The potential to treat many fibroid patients without requirement for subsequent cesarean section also needs further study. PMID- 22523878 TI - Utilization of instruments in the chairman's curio cabinet: a case report. AB - BACKGROUND: The use of fetal destructive instruments found in curio cabinets may be unfathomable; however, these instruments continue to have a role in select cases. CASE: A 30-year-old multigravida at 40 weeks' gestation had 3 prior normal vaginal deliveries in Africa followed by a cesarean delivery with a complicated postoperative course in the United States. She was intent on having a vaginal delivery, despite repeated recommendations for surgery due to nonreassuring fetal status. After fetal demise and subsequent arrest of labor, vaginal cephalocentesis and fetal extraction were used to achieve delivery. CONCLUSION Fetal destructive procedures, such as the one described here, have a role in modern obstetrics in select cases. In addition, despite an unfortunate fetal outcome, respect for patient autonomy is paramount and is consistent with the recommendations of the American Congress of Obstetricians and Gynecologists. (J Reprod PMID- 22523879 TI - Management options and prognosis of pancreatic adenocarcinoma at 16 weeks' gestation: a case report. AB - BACKGROUND: Antepartum diagnosis of pancreatic adenocarcinoma is extremely rare, with only 9 cases previously reported in the literature. We report on such a case and review the literature for management options and prognosis of this unfortunate condition. CASE: A 33-year-old woman, gravida 1, para 0, was referred at 16 weeks' gestation due to weakness, weight loss and anemia. Comprehensive investigation followed and a final diagnosis of pancreatic adenocarcinoma was made after pancreatic fine needle aspiration biopsy during endoscopic ultrasound of the upper abdomen. At 19 weeks' gestation fetal demise occurred. CONCLUSION: While early diagnosis may not alter long-term outcome, it may provide the patient with an earlier opportunity to evaluate decisions related to pregnancy. The two most important factors determining management options for pancreatic cancer during pregnancy are disease stage and gestational age. Prognosis is extremely poor, with 5-year survival after surgery being 20% versus 3-5% in unresectable disease. Prognosis depends on disease stage and on the interval between diagnosis and surgery. Delay for even one month may render the disease metastatic. Participation of a multidisciplinary team is critical in the management of such cases since, due to the rarity of the disease during pregnancy, there are no evidence-based data to guide decisionmaking. PMID- 22523880 TI - Spontaneous pregnancy reaches viability after low first trimester serum progesterone: a case report. AB - BACKGROUND: Progesterone is produced by the corpus luteum until completion of the luteal-placental shift at approximately 6-10 weeks following last menstruation. Studies have shown that first trimester progesterone levels are predictive of pregnancy viability, and some authors support a level of 5 ng/mL as an absolute threshold to indicate viability. CASE: A 47-year-old woman with recurrent pregnancy loss was noted to have a very low first trimester progesterone level (1.2 ng/mL), but the pregnancy progressed to viability. She unfortunately delivered an intrauterine fetal demise at 27 weeks and 3 days' gestation. CONCLUSION: A single serum progesterone level of < 5 ng/mL is suggestive, but not diagnostic, of a nonviable pregnancy. Routine uterine curettage during the evaluation of a pregnancy of unknown location using this level as an absolute cutoff may result in the interruption of a desired, viable pregnancy. PMID- 22523881 TI - Vulvar endometriosis presenting with dyspareunia: a case report. AB - BACKGROUND: Superficial dyspareunia can be caused by a multitude of medical and psychological conditions, including pathologic conditions of the vulva. Although infectious and inflammatory causes are more common, vulvar endometriosis is a rare and often overlooked etiology of dyspareunia. CASE: A 33-year-old woman, gravida 1, para 1, presented for a gynecologic consultation with a 2-year history of increasing dyspareunia and cyclical vulvar pain associated with a vulvar mass. Previous treatment with analgesics and sitz baths did not alleviate the symptoms. Pelvic examination revealed a right Bartholin's gland mass that was tender to palpation. The working diagnosis was a Bartholin's cyst as the cause of the dyspareunia, and the patient was scheduled for marsupialization and/or resection. Examination under anesthesia revealed an irregular, 5 cm, solid mass that extended into the labia majora, which was excised. Pathologic examination of the mass revealed endometriosis. The postoperative course was unremarkable and the patient reported complete resolution of symptoms. CONCLUSION: This case illustrates that superficial dyspareunia associated with cyclical vulvar pain can be caused by endometriosis involving the labia majora. PMID- 22523882 TI - Thoracic endometriosis: a case report. AB - BACKGROUND: Endometriosis is a benign gynecologic disorder that affects women of reproductive age. It can be asymptomatic or can cause pelvic pain or subfertility. On rare occasions it may manifest outside of the pelvis, leading to a multitude of symptoms that can be life-threatening if proper diagnosis is delayed. CASE: A 35-year-old, nulliparous female presented with dyspnea and pleuritic chest pain. She was diagnosed with a rare case of thoracic endometriosis. Her symptoms improved with combined surgical and medical management. CONCLUSION: The diagnosis of this rare entity often goes unrecognized unless physicians have a high clinical suspicion and make a temporal association between patients' pulmonary symptoms and menstruation. Diagnosis can be confirmed only by pathological examination and immunohistochemical staining. Management should be guided by symptom severity and the patient's desire to conserve future fertility. PMID- 22523883 TI - Uterine fibroid managed by uterine artery embolization and delivered vaginally by obstetric outlet forceps: a case report. AB - BACKGROUND: Fibroid embolization is a nonsurgical treatment of symptomatic fibroids and is particularly useful in patients with multiple comorbidities. CASE: A 44-year-old woman with multiple comorbidities underwent uterine artery embolization for uterine fibroids. The postprocedure symptoms were controlled with conservative management along with vaginal myomectomy using outlet forceps. CONCLUSION: Postprocedure symptom control is important, and some patients may need emergency medical management of pain and infection and surgical management of partially expelled fibroids. PMID- 22523884 TI - Cyndi Pittman: finance and quality work hand in hand. PMID- 22523885 TI - Consensus on Medicare savings is closer than it seems. PMID- 22523886 TI - 5 ways to create a culture of first-class service. PMID- 22523887 TI - Strategies for responding to RAC requests electronically. AB - Providers that would like to respond to complex RAC reviews electronically should consider three strategies: Invest in an EHR software package or a high-powered scanner that can quickly scan large amounts of paper. Implement an audit software platform that will allow providers to manage the entire audit process in one place. Use a CONNECT-compatible gateway capable of accessing the Nationwide Health Information Network (the network on which the electronic submission of medical documentation program runs). PMID- 22523888 TI - Preparing for Medicaid managed care. AB - As Medicaid enrollment continues to rise, hospitals and health systems could benefit from contracting with Medicaid managed care plans. Providers need to establish a Medicaid managed care strategy before beginning the contracting process. Revenue cycle leaders need to ensure that their front-end processes related to patient access, billing, and denials management are compatible with Medicaid managed care. PMID- 22523889 TI - The new wave of hospital consolidation. AB - Reimbursement challenges, spiraling healthcare costs, and a slow economic recovery are driving the latest wave of hospital consolidation. Health insurance companies and provider systems are forming partnerships in the consolidation field with the goal of reducing healthcare costs and improving quality. The "cost" of the acquisition may include debt and other obligations of the acquired hospital, such as pension liabilities, along with a multiyear capital commitment. PMID- 22523890 TI - Evolve and integrate: a new imperative for ambulatory care. AB - A highly evolved ambulatory care delivery system possesses four key attributes: high-quality care, exceptional levels of access, outstanding patient and staff satisfaction, and cost-effective delivery of care. Such a system seeks to ease management of the patient care continuum by delivering as many services as possible under one umbrella. High-quality, cost-effective care is achieved through improved care coordination and cost management, resulting from a tight connection between physicians and hospitals and between inpatient and outpatient settings. Improved access is an important means to improving patient satisfaction. PMID- 22523891 TI - Automation is key to managing a population's health. AB - Online tools for automating population health management can help healthcare organizations meet their patients' needs both during and between encounters with the healthcare system. These tools can facilitate: The use of registries to track patients' health status and care gaps. Outbound messaging to notify patients when they need care. Care team management of more patients at different levels of risk. Automation of workflows related to case management and transitions of care. Online educational and mobile health interventions to engage patients in their care. Analytics programs to identify opportunities for improvement. PMID- 22523892 TI - Right care, right time, right place, every time. AB - By improving its patient flow, Intermountain Healthcare was able to increase capacity and improve resource utilization. The project's guiding principle was to remove variation from patient flow processes, increase collaboration, and enhance the quality of care. A pilot project to redesign patient flow at Intermountain Medical Center focused on patient placement and care coordination. The pilot resulted in the creation of 21 virtual beds, reduced severity-adjusted average length of stay, enhanced patient satisfaction, and improved bed turn-around time. PMID- 22523893 TI - Physician acquisition: what to avoid after the deal is complete. AB - After a hospital acquires a physician practice, relations can become strained between the parties in any of four areas: Governance and decision making. Technology. Payment structures. Emotional factors related to the acquisition. PMID- 22523894 TI - Jon Kingsdale: benefits and challenges of health insurance exchanges. PMID- 22523895 TI - Predictive analytics can support the ACO model. AB - Predictive analytics can be used to rapidly spot hard-to-identify opportunities to better manage care--a key tool in accountable care. When considering analytics models, healthcare providers should: Make value-based care a priority and act on information from analytics models. Create a road map that includes achievable steps, rather than major endeavors. Set long-term expectations and recognize that the effectiveness of an analytics program takes time, unlike revenue cycle initiatives that may show a quick return. PMID- 22523896 TI - Gauging the financial impact of physicians on hospitals. AB - A study evaluated the impact of physicians on hospital finances in four basic areas of physician care: primary care, medical specialties, surgical specialties, and other specialties. The study highlighted inherent differences in the activity and revenue-generating patterns of physicians to provide insight into the financial implications of the clinical enterprise. The findings offer a useful perspective on hospitalist programs, particularly regarding the point at which a hospitalist program is likely to be financially self-sustaining. Such data could be used to determine the number of physicians needed to support a new or expanded clinical service. PMID- 22523897 TI - Achieving benchmark financial performance in CAHs: lessons from high performers. AB - CEOs and CFOs of 19 critical access hospitals (CAHs) that achieved benchmark financial performance over three years were interviewed regarding the strategies they use. The interviews identified nine success factors for exemplary financial performance that were common to all or most of the 19 hospitals. All of the participating executives agreed that other CAHs would likely benefit from applying these nine success factors. PMID- 22523898 TI - Making care coordination and clinical integration pay off. PMID- 22523899 TI - 7 tactics to reduce variation in clinical practice. PMID- 22523900 TI - Revenues and expenses declined in 2011, but show increases when patient severity is considered. PMID- 22523901 TI - Economic burden of asthma in Thailand. PMID- 22523902 TI - Shellfish allergy--an Asia-Pacific perspective. AB - BACKGROUND AND OBJECTIVE: Shellfish forms a common food source in the Asia Pacific and is also growing in the West. This review aims to summarize the current literature on the epidemiology and research on shellfish allergy with particular focus on studies emerging from the Asia-Pacific region. DATA SOURCES: A PubMed search using search strategies "Shellfish AND Allergy", "Shellfish Allergy Asia", and "Shellfish AND anaphylaxis" was made. In all, 244 articles written in English were reviewed. RESULTS: Shellfish allergy in the Asia-Pacific ranks among the highest in the world and is the most common cause of food-induced anaphylaxis. Shellfish are classified into molluscs and arthropods. Of the arthropods, the crustaceans in particular Penaeid prawns are the most common cause of allergy and are therefore most extensively studied. Several classes of allergens have been identified. The tropomyosins (class 1 allergens) are the best defined. Despite the establishment of molecular homology and allergenic cross reactivity between allergens of the same class, clinical cross-reactivity is more variable between patients and less clearly defined. There are two relatively unique clinical manifestations of IgE-mediated prawn allergy: (1) isolated oral allergy symptoms; and (2) wide spectrum of severity and sometimes even within the same individual. CONCLUSION: Shellfish allergy is common in the Asia Pacific. More research including food challenge-proven subjects are required to establish the true prevalence, as well as to understand clinical cross reactivity and variations in clinical features. PMID- 22523903 TI - Immune status monitoring of HIV/AIDS patients in resource-limited settings: a review with an emphasis on CD4+ T-lymphocyte determination. AB - CD4 T-lymphocytes play a vital role in maintaining the integrity of the human immune system. They are also the primary target cells for human immunodeficiency virus (HIV). The progressive depletion of these cells eventually results in weakening of the host's immune ability to fight against any pathogen, thus rendering the host susceptible to infections and leading ultimately to death of patients in the terminal stage of acquired immune deficiency syndrome (AIDS). Although several clinical and laboratory parameters have been used for monitoring disease progression and the effectiveness of HIV antiretroviral therapy (ART), it is the simple measurement of CD4+ T-lymphocytes that remains the single and most important parameter for management of HIV-infected patients in resource-limited settings. To date, flow cytometer is considered to be the most accepted technology for both percentage and absolute CD4+ T-lymphocyte determination because of its accuracy, precision and reproducibility. However, flow cytometer based CD4 testing is relatively expensive, complex and thus technically demanding. Simple innovative approaches applicable to the conventional flow cytometric system and new technologies have been successfully developed to increase cost saving especially for use in resource-challenged settings. Principles of the existing dual- and single-platform approaches as well as several affordable CD4 measurement technologies are discussed along with both internal and external quality control systems in the management of laboratories performing CD4 testing. PMID- 22523904 TI - Sleep quality in infants with atopic dermatitis: a community-based, birth cohort study. AB - BACKGROUND: Sleep disturbance has been reported in both pre-school and older children with atopic dermatitis (AD). There have been no studies examining whether sleep disturbance occurs at the onset of the AD, or develops later. OBJECTIVE: To evaluate sleep characteristics in infants with AD. METHODS: A cross sectional survey based on interviews with parents of infants aged 1 year. AD was diagnosed by showing the parents 3 pictures of typical AD. AD was considered as mild if the rash was a single occurrence or there was only 1 lesion and severe if there were 2 or 3 recurrent or persistent lesions. The infant's sleep behavior was evaluated through information on sleep onset, sleep duration, number of night wakings and the caregivers' perception of problematic sleep behaviors. RESULTS: Of the total sample, 96.2% (4085 of 4245) provided complete AD information and 148 infants (3.6%) had at least one AD skin lesion. Sleep duration was significantly reduced in infants with severe AD when compared to no-AD infants (542+67 vs 569+62 minutes, p 0.02). The percentage of infants who had night waking with parent intervention required to calm them down "often or always" was significantly higher in mild AD infants than in normal infants (61.7 vs 49.8%, p 0.02). No significant differences were noted between infants with or without AD for other infant sleep behavior. CONCLUSION: In AD patients, sleep disturbances can occur early following the onset of the disease. We suggest that clinical assessment of AD infants should take these aspects into consideration. PMID- 22523905 TI - Comparison of sensitization between beta-lactoglobulin and its hydrolysates. AB - BACKGROUND: Bovine beta-lactoglobulin is one of the first foreign antigens encountered by some newborn children, and it has been described as the main allergenic protein in cow's milk even when present at low concentration. OBJECTIVE: Enzymatic hydrolysis has been identified to be a very effective way to reduce the sensitization of beta-lg compared to other treatments. The aim of this study was to explore whether enzymatic hydrolysis could reduce the allergenicity of native bovine beta-lg. METHODS: beta-lg was hydrolyzed by trypsin. Twenty four BALB/c mice were divided into three groups and orally sensitized by native bovine beta-lg and its hydrolysates five times at weekly intervals. RESULTS: During the sensitization period, many serious systemic anaphylactic symptoms were observed in mice sensitized by native beta-lg compared to hydrolysates of beta-lg. Mice sensitized by hydrolysates of beta-lg showed a significantly lower spleen lymphocyte proliferation level than intact beta-lg. The beta-lg-specific IgE antibody levels in serum and intestinal fluid samples induced by native beta-lg were significantly elevated. Plasma histamine levels were also evaluated and showed the same trend as IgE. Moreover, the hydrolysates of beta-lg significantly up-regulated IFN-gamma and IL-10 production and down-regulated IL-4 and IL-5 secretions by murine splenocytes. CONCLUSION: These results suggested that enzymatic hydrolysis could partly reduce the allergenicity of beta-lg. PMID- 22523906 TI - Immediate hypersensitivity and serum IgE antibody responses in patients with dermatophytosis. AB - BACKGROUND: The association of dermatophytes with atopic patients and improvement in allergic signs with antifungal treatment suggest a possible link between chronic infection and atopy. OBJECTIVE: The purpose of this study was to determine skin reactivity and serum IgE antibody responses in patients with chronic and acute dermatophytosis. METHODS: One hundred and sixty-three patients with chronic dermatophytosis, 35 patients with acute dermatophytosis, 41 atopic patients and 49 healthy subjects were enrolled in this study. Sensitization to Trichophyton mentagrophytes (T. mentagrophytes), Candida albicans and Aspergillus fumigatus antigens has been evaluated in patients by skin prick test (SPT) and by the presence of specific IgE antibody in enzyme-linked immuno-sorbent assay (ELISA). RESULTS: Positive immediate hypersensitivity (IH) reactions were obtained in 95.1% of the atopic patients with chronic infection for T. mentagrophytes, representing a significant difference from other patient groups (P < 0.05). Specificanti-T. mentagrophytes IgE antibodies were detected in atopic patients with chronic (65.9%) and acute (50%) dermatophytosis, while none of the atopic subjects had positive IgE reactions to T. mentagrophytes. CONCLUSION: The results showed significant higher positive IH and specific anti-T. mentagrophytes IgE responses in atopic patients with chronic dermatophytosis than the other groups. PMID- 22523907 TI - Pre-transplant donor specific antibody and its clinical significance in kidney transplantation. AB - BACKGROUND: The traditional method for assessing HLA antibodies in recipient serum samples is the complement-dependent cytotoxicity testing (CDC). Recently, the highly sensitive microbead-based Luminex assay was introduced and can detect low levels of anti-HLA Abs. OBJECTIVE: To determine the impact of pretransplant donor-specific HLA antibodies (DSA) detectable by Luminex, despite a negative CDC crossmatch, on the outcomes of kidney transplantation. The correlation and cut off value of panel reactive antibody (PRA) and DSA was also evaluated. METHODS: Pre-transplant sera from 116 kidney transplant recipients with a negative CDC crossmatch were assessed for donor-specific HLA antibodies by using Luminex single antigen beads. The patients received kidney transplants at Ramathibodi Hospital between January 2003 and December 2007. The results were correlated with kidney graft outcomes. RESULTS: DSA were found in 24.1% (28/116) of all recipients. Of the twenty-eight DSA positive patients, four developed antibody mediated rejection (AMR) (4/28 = 14.3%). All these 4 patients had positive C4d staining in their biopsies. Of the eighty-eight DSA negative patients, two developed AMR (2/88 = 2.3%). The AMR occurred more frequently in the DSA positive group than in the DSA negative group (14.3% versus 2.3%. The patient and graft survival were similar in both groups. The strength of pre-transplant DSA was not associated with the incidence of rejection episodes. CONCLUSION: There was a higher incidence of AMR in patients with pre-transplant DSA despite a negative CDC crossmatch. However, pre-transplant DSA detected by Luminex had no statistically significant impact on delayed graft function, patient survival and graft survival. PMID- 22523908 TI - Clinical features and predictive factors in neuropsychiatric lupus. AB - BACKGROUND: Neuropsychiatric lupus (NPL) can present with a wide variety of clinical manifestations secondary to major organ involvement. These are often difficult to diagnose and treat with a high mortality. OBJECTIVE: This study aims to describe the prevalence, clinical features and predictive factors for NPL patients. METHODS: Patients with SLE were retrospectively reviewed for 10 years, between January 1996 [corrected] and August 2005. The prevalence, clinical features and predictive factors for NPL patients were studied. Neuropsychiatric (NP) syndromes were defined using the American College of Rheumatology (ACR) nomenclature and case definitions. RESULTS: 750 patients with SLE were studied; 13 patients were excluded due to incomplete data. The mean age was 35 +/- 11.7 years and 95.2% were female. The mean SLE disease duration was 6.9 +/ 5.6 years. Eleven of the 19 ACR NP syndromes were identified and NP manifestations occurred in 97 patients (13%) with a total of 103 NP events. Central nervous system (CNS) manifestations accounted for 87% (84 patients), while involvement of the peripheral nervous system (PNS) 13% (13 patients). The three most frequent manifestation were seizures (31.1%), followed by psychoses (223%), and cerebrovascular disease (22.3%). CNS involvement was strongly associated with hematologic and gastrointestinal involvements. The mortality rate in patients with NPSLE was 18.8%. CONCLUSION: Seizures, psychoses and cerebrovascular disease were the three most common NP features in SLE patients. CNS involvement was strongly associated with hematologic and gastrointestinal involvement. PMID- 22523909 TI - Clinical and pathological features of Churg Strauss syndrome among a Japanese population: a case series of 18 patients. AB - BACKGROUND: Many autoimmune diseases differ in individual of different races, but there has been very scarce information on the clinicopathological features of Churg Strauss syndrome (CSS) among Asians patients. OBJECTIVE: To clarify the clinicopathological details of Japanese CSS patients. METHODS: The medical records of CSS patients hospitalized in 1980-2007 were carefully reviewed. RESULTS: Seventeen patients fulfilled the Japanese Ministry of Health, Labour and Welfare (MHLW) criteria and all 18 fulfilled the American College of Rheumatology criteria. Sixteen patients (89%) had the history of asthma. Frequently involved organs were peripheral nerves (PNS) (94%), skin (50%), gastrointestinal tract (33%), kidney (22%), and heart (17%). The mean (range) eosinophil count, C reactive protein, and number of damaged organs was 18,108 (3,820-36,760)/microL, 51 (0-126) mg/L, and 2.7 (1-6), respectively. Four patients died, of whom three had heart involvement while only one without it died (100 versus 9%, respectively, p = 0.0088). Regarding the pathology, vasculitis was observed in six of seven skin but in only 2 of 10 PNS biopsies. Eosinophilia was found in all of the tissues except for PNS and muscle (40%). Granuloma was observed in only three of the total of 29 biopsies. CONCLUSION: The usefulness of MHLW criteria was verified. The clinical features of Japanese CSS patients were mostly similar to those previously reported, except for lower asthma- and ANCA-positivity rates. Regarding the pathology, vasculitis and eosinophilia were much more frequently observed in skin. PMID- 22523911 TI - Cryptococcal osteomyelitis in a child with a novel compound mutation of the IL12RB1 gene. AB - The IL-12p40/IL-12Rbeta1 and IFN-gammaR1/IFN-gammaR2/STAT1 signaling pathways are important for clearing intracellular bacteria. Genetic defects within these pathways are associated with increased susceptibility to intracellular pathogens. Among these, IL-12Rbeta1 deficiency is the most common defect and leads to infections with Salmonella and Mycobacterium spp. We report a child who presented with Cryptococcal osteomyelitis and history of disseminated Mycobacterial infection and recurrent Salmonella septicemia. Flow cytometry showed defective expression of IL-12Rbeta1. Mutation analysis revealed a novel compound heterozygous mutation of IL12RB1, c.625C>T, p.Q209X was found in exon 7 on the paternal allele and c.710delC, p.P237HfsX5 was found in exon 8 on the maternal allele. As these mutations each result in a stop codon before the last spliceable exon, the transcripts likely underwent nonsense mediated decay, leading to a lack of IL12Rbeta1 expression on the cell surface and eradicating signaling via the IL12 signaling pathway. PMID- 22523910 TI - Clinical profile and genetic basis of Wiskott-Aldrich syndrome at Chandigarh, North India. AB - BACKGROUND: The Wiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency disorder characterized by thrombocytopenia with small sized platelets, eczema, and recurrent infections. There is paucity of information on WAS from the Indian subcontinent. We describe the clinical and molecular profile of 8 patients with WAS as seen in the Pediatric Immunodeficiency Clinic at the Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India. METHODS: A detailed analysis of the clinical profiles, investigations and outcome of the 8 children diagnosed with WAS during the period 2006- 2010 was performed. Confirmation of the genetic diagnosis was done at the Service d'Hematologie, d'Immunologie et de Cytogenetique, Hopital de Bicetre, Le Kremlin-Bicetre, France and the National Defense Medical College, Saitama, Japan. RESULTS: 8 patients were diagnosed as WAS in 5 years. The ages at diagnosis ranged from 13 weeks to 9 years while the mean age of onset of the symptoms was 117 days +/- 136 days. The diagnosis was established within a mean period of 31 months (ranging 1-108 months) from the onset of symptoms. Recurrent infections and diarrhea were seen in 6 and 7 out of the 8 patients, respectively, while eczema was variable. Autoimmunity manifestations were observed in 2 children. Thrombocytopenia and small platelet size was the hallmark of the disease and the main clinical clue to diagnosis in our patients. Mutations in the WASP gene were seen in 8 children, out of which 2 were novel mutations. While one child successfully underwent bone marrow transplantation, two children are doing well on immunoglobulin replacement and cotrimoxazole prophylaxis. Out of 8 children 4 children in our cohort died--all had high WAS scores and could not be offered hematopoietic stem cell transplantation. CONCLUSION: WAS should be suspected clinically in any male infant with persistent unexplained thrombocytopenia and especially if the platelet size is small. Clinical presentation can be very variable and it is therefore important to recognize the entire spectrum of the disease. Understanding the molecular basis has important implications for the diagnosis, treatment, and genetic counseling of patients with WAS. PMID- 22523912 TI - Toxic epidermal necrolysis-like acute cutaneous lupus erythematosus (TEN-like ACLE) in SLE patients: a report of two cases. AB - BACKGROUND: Acute cutaneous lupus erythematosus (ACLE) is a specific lesion in systemic lupus erythematosus (SLE) patients. ACLE can be categorized into localized ACLE, generalized ACLE and toxic epidermal necrolysis-like ACLE. Toxic epidermal necrolysis (TEN) that occurs in SLE patients has been infrequently reviewed. This condition is complicated to diagnose because medication can produce a blistering eruption that resembles vesiculobullous disease in SLE. OBJECTIVE: To describe two cases of newly diagnosed SLE that had a cutaneous presentation compatible with TEN-like ACLE. CASE REPORTS: Characteristics of two patients presenting with TEN-like ACLE and SLE are presented. CONCLUSION: The authors have described two cases of TEN-like ACLE which occurred in the context of systemic involvement of SLE. The cutaneous lesion was gradually progressed, with less mucosal involvement and mainly photodistributed. The authors suggest that the complexity and rarity of this condition could be related to systemic severity of SLE. PMID- 22523913 TI - And the beat goes ON. PMID- 22523914 TI - Largest study ever published on end-of-life care. PMID- 22523915 TI - Nurses eating their young: are we teaching students more than nursing skills? PMID- 22523916 TI - Dialogue: a potential strategy for building healthy physician relationships. PMID- 22523918 TI - Health care providers should prepare now for the Version 5010/ICD-00 transition will you be ready? PMID- 22523917 TI - Think different: nursing innovation and Steve Jobs. PMID- 22523919 TI - Mercy tops nation's integrated health care networks. PMID- 22523920 TI - The International Society of Aesthetic Plastic Surgery (ISAPS). PMID- 22523921 TI - A basic introduction to statistics for the orthopaedic surgeon. AB - Orthopaedic surgeons should review the orthopaedic literature in order to keep pace with the latest insights and practices. A good understanding of basic statistical principles is of crucial importance to the ability to read articles critically, to interpret results and to arrive at correct conclusions. This paper explains some of the key concepts in statistics, including hypothesis testing, Type I and Type II errors, testing of normality, sample size and p values. PMID- 22523922 TI - Pelvic compartment syndrome: a systematic review. AB - Bilateral ureteral obstruction due to traumatic pelvic haematoma and increased pressure in the retroperitoneal space constitute an acute pelvic compartment syndrome. We systematically reviewed the available evidence concerning pelvic compartment syndrome using an online search of the MEDLINE databases OVID and PubMed. There were nine cases of pelvic compartment syndrome. A motor vehicle accident was the most frequent cause of pelvic compartment syndrome. Diagnosis was made using clinical and radiological methods in all cases. Treatment was by surgical decompression in 88% of cases. Observed complications were neurological deficits (44%), muscle atrophy (33%), and renal failure (33%). Pelvic compartment syndrome is as serious as the more common compartment syndromes, requiring high vigilance for diagnosis and surgical decompression for treatment. PMID- 22523923 TI - Basic kinematics and biomechanics of the patellofemoral joint part 2: the patella in total knee arthroplasty. AB - Patellar and femoral component in total knee arthroplasty are inextricably linked as a functional unit. The configuration of this unit has been a matter of ongoing debate, and the myriad of different patellar and femoral components currently available reflect the lack of consensus with respect to the ideal design. One of the major challenges is to overcome the biomechanical disadvantages of a small contact area through which high contact pressures are transferred, making this mechanical construct the weakest part of the prosthetic knee. Contact areas are highly dependent on the congruency of the patellofemoral joint articulation, and are significantly smaller for dome shaped patellar components compared to those of more anatomic designs. However, when exposed to 3-dimensional movements, the contact areas of the dome shaped patella are significantly greater, indicating enhanced forgiveness regarding patellar malpositioning. Although contact stresses, a function of implant design and surface conformity, can reach levels far beyond the yield strength of UHMWPE, catastrophic failure of resurfaced patellar components, commonly seen in metal backed patellae, fashionable in the 1980s, has rarely been observed since. Although plastic deformation and wear of UHMWPE continue to represent a problem, in the absence of suitable alternatives polyethylene remains the bearing surface of choice. The appreciation of the consequences of the mechanical environment on the behaviour of the patellofemoral joint is of particular importance in the endeavour to develop knee replacement systems which provide satisfactory function together with clinical long-term success. PMID- 22523924 TI - Percutaneous needle fasciotomy in Dupuytren's contracture: is it a viable technique? AB - The aim of this retrospective study was to evaluate the results of 44 percutaneous needle fasciotomies for Dupuytren's contracture, performed from March 2005 to June 2010. The mean age of the 36 patients was 58 years and the mean follow-up period was 28 months. The assessment was based on the clinical records and clinical evaluation. Pre-operative and postoperative total passive extension deficit and complications were registered. Recurrence and patient satisfaction were also noted. The results in stage I and II of Tubiana were interesting, with an average improvement of more than 70%. For more severe deformities, the correction obtained was not so satisfactory and decreased significantly over time. The cumulative rate of minor complications was significant (11/44) but there were no major complications or permanent sequelae. Most of the patients were satisfied with the result and would recommend the procedure or would be willing to repeat it if necessary. The recurrence rate was 9%. Percutaneous needle fasciotomy appeared in this study as a minimally invasive, simple and fast technique with low morbidity. These features make this technique a valid alternative in mild stages of Dupuytren's disease. PMID- 22523925 TI - Results of surgical treatment of athletes with sportsman's hernia. AB - Chronic groin pain in athletes is a difficult diagnostic and therapeutic condition. Between March 2004 and December 2009, 241 male athletes (mean age: 25.8 years, range: 16-41) in whom chronic sportsman's hernia was diagnosed, were surgically treated using a standardised technique. In this retrospective study, charts were analyzed for preoperative duration of symptoms and prior treatment. Perioperative complications were noted. Patients were contacted and were asked to answer a telephone questionnaire: 162 patients agreed to be questioned as part of the current study. A surgical intervention with reinforcement of the posterior inguinal wall and tenotomy of the adductors has lead to satisfactory results in over 90% of athletes with chronic groin pain who failed to improve with conservative treatment. PMID- 22523926 TI - The management of intracapsular hip fractures in the 'young elderly' internal fixation or total hip replacement? AB - There is a lack of consensus about how to treat intracapsular hip fractures in the 'young elderly' (50-75 years). Evidence for older more mobile patients seems to point towards Internal Fixation (IF) for undisplaced fractures and Total Hip Replacement (THR) for displaced fractures. Radiographs of 263 patients from the Norfolk and Norwich University Hospital, who have suffered an intracapsular hip fracture between 2000-2009 were reviewed. The complication and mortality rates were noted. A Hip function questionnaire (Oxford hip score (OHS)) and Numeric pain score (NPS) were sent out to patients, then methods of treatment (IF and THR) were compared. In displaced fractures THR compared favourably to IF, OHS (16.0 vs. 20.0 p 0.029), NPS (2.0 vs. 4.0 p 0.007), complications (Odds Ratio (OR) 2.90; p 0.006) and death rate (OR 3.61; p 0.007). Although not statistically significant when stratified for age, the youngest age group (50-60) still achieved better function with a THR (13.0 vs. 18.0 ; p 0.129). There was little difference in the results for undisplaced fractures. This retrospective cross sectional study showed IF is associated with a much higher complication rate than THR for patients who sustained a displaced hip fracture. THR also showed a better functional outcome and reduced pain. IF should be used in undisplaced fractures as there was no difference in functional outcome or complication rate. A large randomised controlled trial is needed to confirm these results. PMID- 22523927 TI - Revision of the well fixed Birmingham Hip Resurfacing acetabular component- results using a novel device. AB - Revision of well fixed uncemented Birmingham Hip Resurfacing (BHR) acetabular components is challenging due to their dual radius design and their stabilising fins. These features preclude use of the standard Explant device. We investigated a novel device designed to simplify revision of this socket. This prospective study included 6 male and 14 female patients. The reasons for revision, technique of revision and the scientific basis for use of this device are discussed. The sizes of revised and implanted components were measured and the amount of bone loss was calculated. Patient satisfaction was assessed as well as pre and post operative hip scores. Six men and fourteen women were included. Average ages were 58 and 623 years respectively. The average diameters of the explanted and re implanted sockets were 50.7 and 54.6 mm respectively. Average time for revision of the cup was less than 5 minutes. The average duration of follow-up was 13.2 months. All patients were satisfied with their outcomes. This device simplifies the use of the Explant in removing well fixed BHR sockets with predictably minimal loss of host bone. PMID- 22523928 TI - A systematic literature review of the Profix in primary total knee arthroplasty. AB - Despite more than a decade of use, there are currently no comprehensive reviews summarising clinical results with the Profix Total Knee System in primary total knee arthroplasty. Searching the PubMed and Google Scholar databases revealed 17 potentially relevant Profix manuscripts. After author review and exclusion of studies not meeting predetermined variables, 8 manuscripts were selected. Knee Society data were provided in all 8 and implant survival data in 4. Data for 987 patients (1152 knees) were available. The overall estimated implant survival was 98.6% at 5 years and 94.2% at 10 years with revision for any reason as an endpoint, and 100% at both time points with radiographic loosening as an endpoint. Mean/median preoperative Knee Society knee scores improved from 39.2/24.7 at baseline, to 91.4/92.1 at the last postoperative follow-up visit. Good medium-to long-term clinical results can be expected with the Profix in primary total knee arthroplasty. PMID- 22523929 TI - Mid-term results of rotating hinge knee prostheses. AB - Between December 2002 and December 2007, we retrospectively assessed the mid term results of the Nexgen rotating hinge prosthesis in the hands of a single surgeon in difficult primary and complex revision situations. Forty four patients (46 knees) were included in the study: they were followed for an average of 62 months. Knee Society knee score improved from a preoperative mean value of 47 to a mean value of 81 at follow-up (p < 0.05) whereas the mean function score improved from 17 (0-40) to 67.5 (0-90) at follow-up (p < 001). Mean flexion range improved from 65 degrees to 96 degrees at follow-up (p < 0.05). In conclusion, rotating hinge knees gave satisfactory results in difficult revision situations associated with major bone loss, instability or periprosthetic fracture. They also provided satisfactory results in selected cases of advanced primary osteoarthritis. PMID- 22523930 TI - Effectiveness of tranexamic acid in revision total knee arthroplasty. AB - The effectiveness of Tranexamic Acid (TXA, antifibrinolytic drug) in reducing allogeneic blood transfusion requirements has not been tested in revision total knee arthroplasty. The aim of this study was to assess the effectiveness of TXA after two intravenous doses of 1 g each. Between April 2006 and February 2010, 68 consecutive patients (19 male, 49 female) of 74 +/- 6 [m +/- SD] years of age were included and divided into three groups: control (28 patients), in which TXA was not administered but was not contraindicated; TXA (19 patients) who received TXA, and NO-TXA (21 patients), who were not administered TXA because of a contraindication. The proportions of patients transfused were 54%, 32% and 62% respectively in the control, TXA and NO-TXA group; the median numbers of RBC units transfused were respectively 2 [range: 1-4], 2 [range: 2-2] and 2.5 [range: 1-5], (p = 0.057). Mean total estimated blood loss was 1693 mL (SD: 689) in the control group, 1196 mL (SD: 665) in the TXA group and 2454 mL (SD: 2166) in the NO-TXA group, (p = 0.015). No adverse events were reported. TXA administration appeared as an effective and safe means of reducing blood transfusion requirements and blood loss in revision total knee arthroplasty. PMID- 22523931 TI - Blood loss following total knee replacement is reduced when using computer assisted versus standard methods. AB - Perioperative blood loss was compared in 136 patients (2 groups of 68 patients) who underwent total knee arthroplasty (TKA). Blood loss was significantly lower when using a computer-navigated technique in comparison to a method employing intramedullary femoral rods. Total blood loss was calculated from body weight, height and haematocrit change, using a model that has been shown to reliably estimate true blood loss. Average total blood loss was 1362 ml in the standard TKA group, and 1137 ml in the computer navigated TKA group. This difference was statistically significant (p = 0.016). This study, as compared to previous papers assessing the effects of navigation, used a larger sample size and a more reliable method of assessing blood loss, which takes account of "hidden" losses, and confirms their findings. PMID- 22523932 TI - Heterotopic ossification after cervical disc replacement: clinical significance and radiographic analysis. A prospective study. AB - Limited data is available regarding heterotopic ossification (HO) after cervical disc replacement (CDR). The goal of this study was to determine the incidence of HO after CDR with the Mobi-C artificial disc to identify the risk factors for HO, and to investigate whether HO affects clinical outcome and range of motion (ROM). Seventy one patients were included in this study. The mean follow-up was 21 months. Radiological evaluation included grading of HO and assessment of ROM for each level treated. HO was detectable in 23 treated segments (27.7%). The mean ROM was 8.1 degrees preoperatively and increased to 10.2 degrees at the last follow-up visit. Nevertheless, HO did not appear to affect clinical outcomes. HO appears to be a common complication after CDR. No specific risk factors have been clearly identified in our study. Long-term follow-up will be needed to assess the clinical significance of HO. PMID- 22523933 TI - Is it possible to save one lumbar segment in the treatment of thoracolumbar fractures? AB - Surgical treatment of unstable thoracolumbar fractures is controversial. Most authors reported that short segment fixation led to a high incidence of implant failure and correction loss. On the other hand, long segment fixation has the disadvantage of fusing more segments. We aimed to compare the outcomes of long segment fixation versus two or three levels above and one level below fixation for acute thoracolumbar fractures. Twenty six consecutive patients were assigned to two groups. Group 1 included 14 patients treated with long fixation, whereas group 2 included 12 patients treated with two or three levels above and one level below fixation. Fractures were classified according to the Mc Cormack, Magerl and Denis classifications. Clinical (Oswestry questionnaire, Visual analog score) and radiological (Sagittal index, percentage of anterior body height compression, local kyphosis and Cobb angle) outcomes were analysed. The average follow-up for the long and hybrid fixation groups were 28 and 20 months respectively. Clinical scores of both groups at the last follow-up were not significantly different. The preoperative, postoperative and follow-up sagittal index, anterior body height compression, local kyphosis angle and Cobb angle were not significantly different. Correction loss of 3.36 degrees was seen in the long segment fixation group, versus 2.75 degrees in the other group at the last follow-up. There was no significant difference between the results achieved in the patients who had transpedicular fixation two or three levels above and one level below the fractured vertebra and those who had long segment fixation for thoracolumbar burst fractures. PMID- 22523934 TI - Hybrid instrumentation for correction of adolescent idiopathic scoliosis. AB - New technology and instrumentation techniques are continually entering the spine field, leaving the scoliosis surgeon with a wide variety of options for the treatment of adolescent idiopathic scoliosis. All-screw constructs are currently the most popular. However, they remain controversial because of possible complications, and also because they have been associated with a decrease in thoracic kyphosis, not observed with hybrid instrumentation. The aim of the present study was to evaluate a hybrid construct: hooks and wires proximally, but pedicle screws distally. Forty-three patients with a minimum 2-year follow-up were included. The mean preoperative Cobb angle of the major curve was 60.85 degrees +/- 21 degrees. At the final evaluation it was reduced to 28.44 degrees +/- 11.9 degrees (mean correction 53.3%, p < 0.0001). The mean translation of the apical vertebra was corrected from -19.13 +/- 49 mm to -9.42 +/- 28.9 mm. The average thoracic kyphosis improved from 24 degrees +/- 14.3 degrees preoperatively to 30.7 degrees +/- 7.1 degrees, representing a mean correction of 28%. Kyphosis at the T10-L2 level was within normal values in all patients at the final evaluation. Complications included one superficial infection, one implant removal due to late onset wound infection, and 2 revisions to extend the fusion more distally. In other words, operative treatment with hybrid instrumentation yielded satisfactory results, with less risk of neurological damage. An excellent outcome in all planes could be safely achieved and maintained for a minimum of 2 years. CONCLUSION: why use an expensive all-screw construct, knowing that a hybrid construct is kyphosis sparing, cheaper, safer and more resistant to pull out? PMID- 22523935 TI - Complications related to cement leakage in sacroplasty. AB - Data concerning the safety of sacroplasty in terms of cement leakage is scarce. Frequency, distribution patterns and clinical consequences of cement leakage were assessed in 33 patients (28 female, mean age: 74 +/- 10 yrs; bilateral SIF: n = 30, 63 sacroplasties) treated with sacroplasty between 06/2003 and 11/2010 in a retrospective study using patients' records, operative notes and postoperative radiographs. Cement leakage was noted within the fracture gap (27%), into veins (6%), neuroforamina (3%) or in the intervertebral disc space L5/S1 (2%). In one patient, cement leakage into the fracture gap led to unilateral radiculopathy of the 5th lumbar nerve root. Leakage into the fracture gap is at high risk of affecting the 5th lumbar nerve root due to the special course of its ventral branch over the sacral promontory. The risks of cement leakage with neurological impairment should be explained to patients. PMID- 22523936 TI - Risk of ionising radiation to trainee orthopaedic surgeons. AB - We undertook this study to determine the amount of scattered radiation received by the primary surgeon, assistant and patient during dynamic hip screw fixation for proximal femoral fractures. Data was collected from fifty patients. Five registrars were included as operating surgeon and four senior house officers as assistant surgeon. Radiation was monitored by thermo luminescent dosimeters placed on the surgeon and assistant. The approximate distance of surgeon and assistant from the operative site was measured. A dosimeter on the unaffected hip of patients measured the radiation to the patient. The results show that the surgeon's dominant hand receives the highest dose of radiation and radiation exposure is dependent on the experience of the operator. Our study concludes that exposure to radiation during this procedure is well below the toxic levels; however greater awareness is needed for harmful effects of exposure to long term low dose radiation. PMID- 22523937 TI - The key-muscle concept: a long-term low-dose injection strategy for botulinum toxin A treatment in cerebral palsy. AB - Botulinum toxin (BoNT) is a well established treatment in cerebral palsy. A uniform dose strategy is, however, missing. We reviewed 35 children with spastic cerebral palsy treated with BoNT according to a newly-developed Key-Muscle concept. All patients received at least 4 BoNT treatments. Systemic side effects or secondary non-response were not observed. After a mean follow-up of 303 months, none of these patients needed bone surgery whereas 6 underwent soft tissue procedures. The Key-Muscle concept is a safe and effective treatment in spastic cerebral palsy. It respects the need for long-term therapy during motor development. Contractures and lever arm disease can be avoided. PMID- 22523938 TI - Hill-Sachs reconstruction and repair using a synthetic scaffold. AB - Dislocation of the shoulder joint is an unfortunate consequence of trauma to the shoulder girdle. It can occur in varying age groups with a complication of an impaction injury to the posterior aspect of the humeral head, termed a Hill-Sachs lesion. This can pose further problems leading to instability of the glenohumeral joint and recurrent dislocations. Varying surgical techniques have been developed to address this issue especially in young, active individuals. We describe another technique that can be used to treat Hill-Sachs lesions in patients with recurrent dislocations of the shoulder. PMID- 22523939 TI - Volar percutaneous transtrapezial fixation of scaphoid waist fractures: surgical technique. AB - Percutaneous screw fixation of scaphoid fractures has gained popularity over the years. The disadvantages of a long period of cast immobilisation are avoided and this technique allows a more rapid return to work and sports activities than conservative treatment. Consequently, percutaneous screw fixation is appealing for the young and active population. Biomechanical studies showed that greater fixation strength is obtained when the screw is placed centrally than eccentrically. Central screw placement can however be technically demanding. In the use of a volar percutaneous approach, the trapezium and the shape of the scaphoid impede central screw placement. Different approaches are available to overcome this difficulty. The volar percutaneous transtrapezial approach facilitates and allows more accurate central screw placement compared to approaches that try to avoid the trapezium. The surgical technique of this approach is described. PMID- 22523940 TI - Successful closed reduction of refractured wrist with a bent volar distal radius plate. AB - A case is presented of a 78-year-old woman who sustained a re-fracture of the distal radius after initial fixation with a volar locking plate. The fracture was located in the mid-portion of the volar plate with palmar apex bending of the plate and signs of median nerve compression. A successful closed reduction was performed without hardware failure. The fracture united uneventfully. PMID- 22523941 TI - Failure mechanism of a constrained liner: a case report. AB - Instability after primary and revision total hip arthroplasty continues to be a problem. The use of a constrained system helps manage this problem. A new constrained total hip arthroplasty, Trilogy constrained liner (Zimmer, Warsaw, IN), is currently in use. We report a case showing dislocation following a Trilogy constrained total hip arthroplasty. In this case, when an impingement between the femoral neck and the anterior part of the polyethylene liner occurred, the hip dislocated easily although both polyethylene and reinforcing ring were properly positioned. The lever-out test showed that the Trilogy constrained liner is safe and compares favourably with other implants. Surgeons should be aware that constrained acetabular systems are not infallible and they should pay attention to place implants in good position even when constrained THA is performed. PMID- 22523942 TI - Unilateral congenital dislocation of the knee and hip: a case report. AB - We report our experience with a unilateral congenital dislocation of the knee associated with a developmental dysplasia of the hip on the same side. Our case is a good example of congenital dislocation of the knee caused by abnormal intrauterine pressure leading to this type of congenital postural deformity. To our knowledge this is the first case of congenital dislocation of the knee reported after cervical cerclage of an incompetent cervix to prevent a pre-term delivery. The Pavlik Harness was used to treat the knee and the hip at the same time with a satisfactory result after 20 months of follow-up. PMID- 22523943 TI - Sacral insufficiency fracture diagnosed after vertebroplasty for L2 and L3 compression fractures: a case report. AB - Vertebroplasty for osteoporotic thoracolumbar vertebral compression fractures usually results in complete and immediate cessation of pain symptoms. Occasionally the procedure does not relieve pain and further intervention is required. We herein report the case of a 62-year-old female with L2 and L3 vertebral compression fractures treated with vertebroplasty. Her symptoms did not improve and subsequent magnetic resonance imaging showed focal changes in the S1 and S2 vertebral bodies; bone scintigraphy showed the characteristic Honda sign of a sacral insufficiency fracture. Sacroplasty at S1 and S2 completely relieved the patient's back pain. If a vertebroplasty fails to relieve back pain immediately after the procedure as expected, surgeons should be aware of the possibility of a concomitant sacral insufficiency fracture. PMID- 22523944 TI - Nanofibers: effective generation by electrospinning and their applications. AB - Electrospinning is the most versatile technology in use today, for the generation of polymer nanoscale fibers. The nano materials generated using this technology have a large surface area and are highly porous making it very useful in many applications in diverse fields such as energy storage, healthcare, biotechnology, environmental engineering, defense and security. The production of the fibers and the morphology can be easily controlled by modifications to the processing parameters. The relatively high production rate and simplicity of the setup makes electrospinning highly attractive. This review summarizes the effect of various processing parameters on the effective generation of nanofibers. By simple modifications to the electric field inside the electrospinning chamber the fiber collection can be easily controlled. In addition, the various applications of electrospun fibers in electronic devices, environmental sensors and filters, energy storage, and in biomedicine such as in tissue engineering, drug delivery and enzyme encapsulation are examined and the current research in each field is also explored in this review. PMID- 22523946 TI - Comparative sessile drop and dip pen nanolithography investigation for various hydrophilic ink/surface systems. AB - We present a dip pen nanolithography study of various hydrophilic ink/surface systems with application in the field of biosensors and novel nano-materials. The inking process was investigated by studying a number of inks, such as Deoxyribonucleic acid (DNA), Bovine serum albumin (BSA), Streptavidin, 16 mercaptohexadecanoic acid (MHA) and a 20 nm nanosphere (NS) polystyrene solution onto a range of substrates, namely glass, silicon, gold and tetrahedral amorphous carbon (taC). In the majority of cases, this resulted in patterns with sub-100 nm line widths and dot diameters. Importantly, contact angle measurements in the microl range showed a decrease of contact angle with drop volume, interpreted as a line tension effect. The significance of this to the nanoscale wetting behaviour is discussed. The effect of dwell time and writing speed indicates that the inking process is not solely defined by surface diffusion but also influenced by the ink dissolution rate from the tip. PMID- 22523945 TI - Preparation methodologies and nano/microstructural evaluation of metal/semiconductor thin films. AB - Metal/semiconductor thin films are a class of unique materials that are widespread technological applications, particularly in the field of microelectronic devices. Assessment strategies of fractal and tures are of fundamental importance in the development of nano/microdevices. This review presents the preparation methodologies and nano/microstructural evaluation of metal/semiconductor thin films including Au/Ge bilayer films and Pd-Ge alloy thin films, which show in the form of fractals and nanocrystals. Firstly, the extended version of Au/Ge thin films for the fractal crystallization of amorphous Ge and the formation of nanocrystals developed with improved micro- and nanostructured features are described in Section 2. Secondly, the nano/microstructural characteristics of Pd/Ge alloy thin films during annealing have been investigated in detail and described in Section 3. Finally, we will draw the conclusions from the present work as shown in Section 4. It is expected that the preparation methodologies developed and the knowledge of nano/microstructural evolution gained in metal/semiconductor thin films, including Au/Ge bilayer films and Pd-Ge alloy thin films, will provide an important fundamental basis underpinning further interdisciplinary research in these fields such as physics, chemistry, materials science, and nanoscience and nanotechnology, leading to promising exciting opportunities for future technological applications involving these thin films. PMID- 22523947 TI - Temperature dependant structural and electrical properties of ZnO nanowire networks. AB - In this paper, we report a successful growth of zinc oxide nanowire networks by simple thermal evaporation process using metallic zinc powder in the presence of oxygen. The morphological investigations of the synthesized nanowire networks are conducted by using field emission scanning electron microscopy (FESEM) which reveals that the grown products are in high-density over the whole substrate surface and possessing nanowire networks like structures. The structural and compositional properties of the grown nanowire networks are analyzed by X-ray diffraction (XRD), transmission electron microscopy (TEM) and energy dispersive spectroscopy (EDS), respectively which confirm that the synthesized products are well-crystalline, with wurtzite hexagonal phase ZnO. The as-grown ZnO nanowire networks grown on silicon substrate are utilized to fabricate n-ZnO/p-Si heterojunction diode and presented in this paper. The I-V characteristics of the fabricated heterojunction diode at different temperatures (77 K-477 K) are also investigated. High values of quality factor, which are obtained from this study, indicate a non-ideal behavior of the fabricated device. The mean barrier height of -0.84 eV is also estimated and presented in this paper. PMID- 22523948 TI - Dopant induced bandgap narrowing in Y-doped zinc oxide nanostructures. AB - In this report, hydrothermal synthesis and the absorption properties of the cubic shaped zinc oxide nanostructures doped with different amount of yttrium (Y) metal cation (0 to 15 at.%) are demonstrated. The structural and optical properties of chemically synthesized pure and Y doped ZnO powders are investigated by using powder X-ray diffraction (XRD), field emission scanning electron spectroscopy (FESEM) and transmission electron microscopy (TEM), ultraviolet-visible (UV-vis) absorbance, photoluminescence (PL), and Fourier transform infra-red spectroscopy (FT-IR). It is found that the dopant ions stabilize in wurtzite hexagonal phase of ZnO upto the concentration of less than 6 at.%, which is mainly due to the fact that the ZnO lattice expands and the optical bandgap energy decreases at this level. Increasing the dopant concentration to greater than 6 at.% leads to a contraction of the lattice, which in turn produces a significant structural disorder evidenced by shift in the XRD peaks due to additional interstitial incorporation of Y. The vibrational modes of the metal oxide groups have been identified from the IR transmission spectra. The optical absorption results show that the optical bandgap energy of Y:ZnO nanocrystals is much less as compared to that of the pure bulk ZnO particles. Doping ZnO with trivalent Y produces excess number of electrons in the conduction band and thus, shifts the absorption edge and narrows down to 80 meV approximately. PL spectra are used to study the dependence of doping on the deep-level emission, which show an enhanced blue emission after Y doping. The existence of near band edge (NBE) emission and blue emission, related to zinc interstitials are observed in the luminescence spectra of Zn(1-x)Y(x)O nanostructures. PMID- 22523949 TI - The effect of pH on the functionalization of nylon fabric with carbon nanotubes. AB - Single walled carbon nanotubes (SWCNTs) were dispersed in water and attached to nylon fabrics by a dip-drying procedure; scanning electron microscopy and Raman spectroscopy suggest the attachment of the SWCNTs. The electrical resistance of the functionalized fabrics is found to be pH-dependent, which is correlated with the quantity of SWCNTs dispersed in water at different values of pH. This can be further ascribed to the influence of the pK(a) of the acid (e.g., acetic acid in this study) used to tune pH. The acid may affect the dispersion of SWCNTs through two different mechanisms: (1) the free protons may protonate the amine and/or sulfonate group in the dye molecules, resulting in a variety of interactions among the dye molecules, SWCNTs and water molecules and (2) the resulting ions may increase the ionic strength of the solution, compressing the electric double layers of SWCNT colloids and thus impairing their stability. The former possibility is ruled out by data obtained using X-ray photoelectron spectroscopy, Raman spectroscopy, and ultraviolet-visible-near infrared spectroscopy; thus the latter is proposed to account for the experimental results. The colour strength of the functionalized fabrics increases with increasing pH, which is in agreement with their measured electrical properties. PMID- 22523950 TI - Morphology evolution of polyaniline microstructures via reverse micelles and their hydrophobicity. AB - Polyaniline morphology evolution in toluene has been observed for the first time. Various structures, including one-dimensional open-ended microtubes, three dimensional solid microspheres and two-dimensional novel solid microplates were controllably synthesized in the same reaction system. The structures obtained were sensitive to oxidant concentration and molar ratio of monomer to oxidant. Solid microplates were mainly formed on the glass beaker wall and bottom, while tubes and spheres were produced in solution by employing reverse micelles as soft templates. Studies on the effect of reaction temperature, mechanical stirring and the addition of more acid were also carried out. FTIR and UV-Vis results showed that the PANI products were in the emeraldine form. The PANI film prepared from spheres exhibited hydrophobic property due to its rough surface covered with nanoscale dots and the large distribution of sphere diameters. PMID- 22523951 TI - The preparation and characterization of non-covalently functionalized graphene. AB - Recently, much work has focused on the exfoliation of graphene through a combination of oxidation and sonication procedures, followed by reduction through chemical methods. We demonstrated that the individual graphene oxide sheets can be readily reduced by using phenolphthalin as both reducing agent and stabilizer. The obtained non-covalently functionalized chemically reduced graphene oxide (CRG) can be dispersed in organic solvents very well, such as alcohol, N,N dimethylformamide, N,N-Dimethylacetamide, N-methyl-2-pyrrolidone, etc., which can give practical applications in large scale production of oil dispersible graphene and have a potential in polymer nanocomposites fabrication. PMID- 22523952 TI - Effective chemical oxidation on the structure of multiwalled carbon nanotubes. AB - A two-step chemical oxidation of multiwalled carbon nanotubes (MWCNTs) with different oxidation reagents was particularly studied. The reagents used in first step were the acidic mixture of sulfuric acid and nitric acid, and the reagents used in the second step were a mixture of sulfuric acid and hydrogen peroxide for different time. After each treatment, the functionalization yield of the oxygen containing groups such as carboxylic group, hydroxyl functional groups and other functional groups on the surface of the carbon nanotubes (CNTs), was quantified by the analysis of XPS measurements. Two-step for a short period of time treated MWCNTs exhibited a larger fraction of carboxyl (COOH) groups compared to one step and two step for longer-time oxidative treatments, and the defect formation on the CNTs was verified mild by X-ray photoelectron spectroscopy (XPS) and Raman spectroscopy and transmission electron microscopy (TEM) graphs, which is necessary for derived reaction and better manipulation of the material and use in the application of the carbon nanotubes. PMID- 22523953 TI - Screening and determinations of tissue polypeptide antigen by label-free optical immunosensing method. AB - Based on the specificity of the immunoreaction of anti-body and antigen, and the resulting localized surface plasmon resonance extinction response of functionalized nano-Au monolayer on glass chip, a novel label-free optical immunosensor with amplified sensitivity has been developed for the detection of tissue polypeptide antigen (TPA). The nano-Au monolayer on glass chip was controllably prepared using 3-mercaptopropyltrimethoxysilane (MPTMOS) as linker by a solution self-assembly method. To analyze its quality, the nano-Au monolayer was characterized by UV-visible spectrum and atomic force microscopy (AFM). The resulting chip was modified by tissue polypeptide antigen antibody (anti-TPA), and then bovine serum albumin (BSA) was employed to block the possible remaining active sites of the nano-Au monolayer. An immunosensor was constructed with biocompatible monolayer nano-Au membrane and the desirable TPA antibody/BSA composite membrane, and it showed good selectivity, high sensitivity and a wide linear response to TPA in the range of 1-1000 ng L(-1) with a detection limit of 1.2 x 10(-3) ng L(-1), as well as good stability and long-term life. Owing to its ease of operation, low detection limit and low cost, it is expected that the proposed procedure may hold great promise in both research-based and clinical assays. PMID- 22523954 TI - Fullerene C60 prevents neurotoxicity induced by intrahippocampal microinjection of amyloid-beta peptide. AB - The dynamics of the state of hippocampal pyramidal neurons after intrahippocampal microinjections of (1) amyloid-beta25-35 (1.6 nmol/1 microl), (2) an aqueous molecule-colloidal solution of C60 (0.46 nmol/1 microl) and (3) an aqueous molecule-colloidal solution of C60 before amyloid-beta25-35 administration were analysed in rats. This model allowed us to study the role of amyloid-beta25-35 in the pathogenesis of Alzheimer's disease and to test anti-amyloid substances. Methods of fluorescent (acridine orange) and brightfield (cresyl violet and immunohistochemistry) microscopy were used. Acridine orange staining indicated changes in protein synthesis intensity due to alterations in the rRNA state of neuron ribosomes. One day after administration of amyloid-beta25-35, the intensity of protein synthesis in the population of morphologically intact cells decreased by 45%. By day 14, degeneration occurred in the majority of pyramidal cells, and amyloid-beta25-35 deposits were observed in the neuronal cytoplasm. In necrotic cells, acridine orange staining of the cytoplasm was drastically increased as a result of RNA degradation rather than due to an increase in protein synthesis. Because amyloid-beta25-35 administration provoked oxidative stress, we assumed that an aqueous molecule-colloidal solution of C60 administered before amyloid-beta25-35 prevented protein synthesis changes on day 1, while acting as an antioxidant, and by day 14 it inhibited neurodegeneration and amyloid-beta25-35 accumulation. Based on the data that an aqueous molecule colloidal solution of C60 prevented amyloid-beta25-35 aggregation in in vitro experiments and based on our present evidence on the antitoxicity of an aqueous molecule-colloidal solution of C60, we suggest that functionalised C60 prevents/diminishes amyloid-beta25-35 aggregation in vivo as well. Thus, an aqueous molecule-colloidal solution of C60 administered at a low concentration before amyloid-beta2-35, prevented disturbances in protein synthesis, neurodegeneration and formation amyloid-beta25-35 deposits in hippocampal pyramidal neurons in vivo. This evidence gives promise that functionalised C60 can be used to develop anti-amyloid drugs combining antioxidant and anti aggregative properties. PMID- 22523956 TI - Structural evolution and electronic properties of medium-sized gallium clusters from ab initio genetic algorithm search. AB - Using genetic algorithm incorporated with density functional theory, we have explored the size evolution of structural and electronic properties of neutral gallium clusters of 20-40 atoms in terms of their ground state structures, binding energies, second differences of energy, HOMO-LUMO gaps, distributions of bond length and bond angle, and electron density of states. In the size range studied, the Ga(n) clusters exhibit several growth patterns, and the core-shell structures become dominant from Ga31. With high point group symmetries, Ga23 and Ga36 show particularly high stability and Ga36 owns a large HOMO-LUMO gap. The atomic structures and electronic states of Ga(n) clusters significantly differ from the a solid but resemble beta solid and liquid to certain extent. PMID- 22523955 TI - A novel magnetic nanoparticle hyperthermia combined with ACMF-dependant drug release by DAMMs injection in VX-2 liver tumors. AB - In this paper, we investigated the feasibility and effect of a novel combination therapy of magnetic nanoparticles (MNPs) hyperthermia with anticancer drugs for solid malignancies using doxorubicin-loaded alginate-templated magnetic microcapsules (DAMMs) in an animal liver cancer model. Firstly, DAMMs containing 18 nm gamma-Fe2O3 with doxorubicin (Dox) were synthesized and characterized. Then, the particular behavior of Dox release under external alternating current magnetic filed (ACMF) was tested in vitro. Moreover, to obtain accurate thermotherapy, the dose of DAMMs and temperature rise were computed by Hyperthermia treatment plan (HTP) and a fiber optic temperature sensor (FOTS) was used to monitor the temperature rise during treatments on VX-2 liver tumor bearing rabbits. Furthermore, the therapeutic effect was studied by histopathological examinations and animal survival. The results showed that ACMF can induce Dox fast release during the treatment and the high MNPs content of DMMAs guaranteed the temperature rise for hyperthermia in tumors. The rabbits bearing VX-2 tumors in the magnetic hyperthermia using DMMAs group gained the most tumor necrosis and survival time. It was indicated that DAMMs-based magnetic hyperthermia could be a feasible and effective remedy which could be targeted at liver tumors by dual effects of hyperthermia and chemotherapy. PMID- 22523957 TI - The stability and optical gap of zinc oxide clusters (ZnO)n (n = 2-18). AB - The stability and the optical band gap of the Zinc Oxide clusters (ZnO)n (n = 2 18) are investigated by using density functional theory (DFT) and the time dependent density functional theory (TD-DFT), respectively. The differences between the HOMO-LUMO gap (delta(h-l)) and the optical gap (delta(opt)) are dramatic for small clusters (2 < or = n < or = 5). As the increasing of the cluster size, the differences become small. The results indicate that the stability and the optical gap are related to the sizes and symmetries of the clusters. Further, it is shown that the structures have much greater impact on the optical gap, there is the dipole-forbidden transition in the optical gap for high symmetric structures. PMID- 22523958 TI - Analysis of tomato microRNAs expression profile induced by Cucumovirus and Tobamovirus infections. AB - MicroRNAs (miRNAs) are a class of small RNAs that affect the morphological and physiological development of plants. In recent years, there is accumulating evidence that miRNAs are involved in defense mechanism of host plants. Therefore, investigating the alteration of miRNAs expression profiles after virus infection will provide new insights for understanding the sophisticated virus-host plant interaction. The current miRNA sequence database (miRBase) contains more than 1669 mature plant miRNAs across 25 species, but few tomato miRNAs are reported. Here we created a microarray suitable for detection of plant miRNAs based on the conservative character of miRNAs, and a total of 105 conserved plant miRNAs were detected from tomato leaf tissues. Among them, 85% of the detected miRNAs showed significant expression alterations when infected by different strains of cucumber mosaic virus (CMV) and N5 strain of tomato mosaic virus (ToMV). Combination with their symptoms development, interferences of CMV 2b protein and alleviated/aggravated satellite RNA on host miRNA pathway were discussed, and the differences in interference mechanisms between CMV and ToMV on host miRNA pathway were compared. Our results represent the comprehensive investigation of tomato miRNAs on a genome scale thus far and provide information to study the interaction between plant viruses and host plants. PMID- 22523960 TI - Monolayer assemblies of a sandwich-type double-decker porphyrin complex of cerium with an additional pendant porphyrin unit. AB - We have prepared a novel sandwich-type double-decker porphyrin complex with cerium, in which one of the porphyrins has long alkyl chains and the other has a pendant free-base porphyrin unit. The preparation of the complex was achieved with a Sonogashira coupling reaction between a preformed double-decker complex bearing an ethynyl moiety and an iodophenyl porphyrin. This complex forms moderately ordered self-assembled monolayers at the interface of 1-phenyloctane and highly oriented pyrolytic graphite. STM images with submolecular resolution revealed that the double-decker complexes form monolayers through adsorption of the alkyl-substituted porphyrin unit, presenting the other porphyrin having the additional porphyrin unit to the solution. All molecules are oriented in the same direction within single ordered domains. The double-decker complex and the corresponding free-base porphyrin form mixed monolayers due to their common adsorbing group and the matching unit cell parameters. The high spots for the double-decker cores are accompanied by lower spots, which can be assigned as the pendant free-base porphyrin units, revealing that the double-decker complexes predominantly take perpendicular orientation, in which the additional porphyrin unit orients perpendicular to the molecular row. Both the double-decker complex and the free-base porphyrin adsorb on the surface initially after the mixture was deposited, but the double-decker complex is gradually replaced by free-base porphyrin toward the thermodynamically stable assembly, in which the free-base porphyrin predominates. This behavior is unique to this particular complex among some analogous complexes with the same adsorbing group, which implies that groups not directly involved in adsorption may have profound effects on the adsorption and assembling properties of the molecule. PMID- 22523959 TI - Molten salt synthesis and luminescent properties of YVO4:Ln (Ln = Eu3+, Dy3+) nanophosphors. AB - Eu3+ and Dy(3+)-doped YVO4 nanocrystallites were successfully prepared at 400 degrees C in equal moles of NaNO3 and KNO3 molten salts. X-ray diffraction (XRD), Fourier transform infrared (FT-IR) spectroscopy, transmission electronic microscopy (TEM), photoluminescence (PL) spectrum and lifetime were used to characterize the nanocrystallites. XRD results demonstrate that NaOH concentration and annealing temperature play important roles in phase purity and crystallinity of the nanocrystallites, the optimum NaOH concentration and annealing temperature being 6:40 and 400 degrees C respectively. TEM micrographs show the nanocrystallites are well crystallized with a cubic morphology in an average grain size of about 18 nm. Upon excitation of the vanadate group at 314 nm, YVO4:Eu3+ and YVO4:Dy3+ nanocrystallites exhibit the characteristic emission of Eu3+ and Dy3+, which indicates that there is an energy transfer from the vanadate group to the rare earth ions. Moreover, the structure and luminescent properties of the nanocrystallites were compared with their bulk counterparts with same composition in detail. PMID- 22523961 TI - Synthesis, characterization, and antimicrobial activity of nano-hydroxyapatite zinc for bone tissue engineering applications. AB - The bone implants used in tissue repair are susceptible to infections caused by staphylococci, specifically Staphylococcus aureus. Hence, the development of better biological materials that provide antimicrobial activity in bone tissue engineering is required. The nanoparticles of hydroxyapatite (nHAp) and nHAp dopped with Zn (nHAp-Zn) were prepared by the wet chemical method and the ion exchange method, respectively. They were characterized using SEM, AFM, FTIR and XRD. The antibacterial activity of nHAp and nHAp-Zn was determined with Gram negative and Gram-positive bacterial strains. The results indicated that nHAp alone was acting as an inert matrix and when substituted with Zn, it showed better antibacterial activity. The nHAp-Zn was found to be non-toxic to osteoprogenitor cells. Thus, due to the antimicrobial property of nHAp-Zn nanoparticles, we suggest that they would have potential applications towards bone tissue engineering. PMID- 22523962 TI - Graphene oxide reinforced polyimide nanocomposites via in situ polymerization. AB - Graphene oxide (GO) reinforced polyimide nanocomposites were synthesized by in situ polymerization of monomers in the presence of GO sheets dispersed in N,N Dimethylacetamide (DMAc). The functional groups (e.g., hydroxyl, epoxide, and carboxyl groups) associated with the GO make GO excellent dispersion in the organic solvent, which benefits the subsequent in situ polymerization. This process enabled uniform dispersion of GO sheets in the polymer matrix. The resultant GO-polyimide nanocomposite films were studied by tensile test, TGA and SEM. The results showed that the GO sheets incorporated in the polymer matrix exhibited a layer-aligned structure without destruction of the thermal stability of the polymer matrix, and a loading of GO (10 wt%) resulted in a significant enhancement in elastic modulus (86.4%). PMID- 22523963 TI - Effect of bromine and substituted alkyl chain on the interfacial self-assembly of bromobenzene derivatives by scanning tunneling microscopy. AB - The self-assemblies of four compounds, 1-bromo-4-(hexadecyloxy)benzene (BHB-16), 1-bromo-4-(octadecyloxy)benzene (BOB-18), 1-bromo-4-(pentadecyloxy)benzene (BPB 15) and 1,4-dibromo-2,5-(dioctadecyloxy)benzene (DDB-18), have been studied on highly oriented pyrolytic graphite (HOPG) under ambient conditions by scanning tunneling microscopy (STM), with the aim of understanding the influence of the molecular structure and functional groups on the arrangements. It is found that the bromine atoms of the four molecules are in bright contrast and can be identified in STM images. The neighbouring phenyl head groups of the BHB-16, BOB 18 and BPB-15 molecules in one lamella, with an anti-parallel orientation, are interdigitated with different offset distance, while the aromatic cores of DDB-18 molecules in the same row are in a parallel orientation. Moreover, an odd-even effect is observed in the self-assemblies of the former three molecules as expected. The STM images of the four molecules resemble the calculated HOMO electron density contours somewhat with positive surface bias voltage. On the basis of comparative analysis between the STM images, it is suggested that the electrostatic attractions between the neighbouring molecules play an important role in the self-assemblies of BHB-16, BOB-18 and BPB-15, while it is the van der Waals force and the non-covalent halogen-halogen interaction that dominate the structure of DDB-18 adlayer. PMID- 22523964 TI - The rates of charge separation and energy destructive charge recombination processes within an organic dyad in presence of metal-semiconductor core shell nanocomposites. AB - Steady state and time resolved spectroscopic measurements were made at the ambient temperature on an organic dyad, 1-(4-Chloro-phenyl)-3-(4-methoxy naphthalen-1-yl)-propenone (MNCA), where the donor 1-methoxynaphthalene (1 MNT) is connected with the acceptor p-chloroacetophenone (PCA) by an unsaturated olefinic bond, in presence of Ag@TiO2 nanoparticles. Time resolved fluorescence and absorption measurements reveal that the rate parameters associated with charge separation, k(CS), within the dyad increases whereas charge recombination rate k(CR) reduces significantly when the surrounding medium is changed from only chloroform to mixture of chloroform and Ag@TiO2 (noble metal-semiconductor) nanocomposites. The observed results indicate that the dyad being combined with core-shell nanocomposites may form organic-inorganic nanocomposite system useful for developing light energy conversion devices. Use of metal-semiconductor nanoparticles may provide thus new ways to modulate charge recombination processes in light energy conversion devices. From comparison with the results obtained in our earlier investigations with only TiO2 nanoparticles, it is inferred that much improved version of light energy conversion device, where charge-separated species could be protected for longer period of time of the order of millisecond, could be designed by using metal-semiconductor core-shell nanocomposites rather than semiconductor nanoparticles only. PMID- 22523966 TI - High-yield chemical synthesis of hexagonal ZnO nanoparticles and nanorods with excellent optical properties. AB - Large yield and low temperature growth of nanostructures are key requirements for fulfilling the demand of large scale applications of nanomaterials. Here, we report a highly efficient chemical method to synthesize high quality hexagonal ZnO nanoparticle and nanorods utilizing the low temperature oxidation of metallic zinc powder in the presence of an appropriate catalyst. This one-step method has advantages such as low temperature (90 degrees C) and atmospheric pressure synthesis and a high yield (> 90%). Microstructure and optical properties of the as-synthesized ZnO nanoparticles are found to be identical or better than those of the commercial ZnO nanopower (Sigma-Aldrich). In particular, in comparison to the commercial nanopowder the as-grown ZnO nanorods and nanoparticles exhibit stronger UV absorption at 376 nm and intense UV photoluminescence emission at 382 nm, with negligible defect emission band. This method is suitable for large scale production of nanosized ZnO and could be extended for the synthesis of other metal oxides. PMID- 22523965 TI - Template-directed preparation of bovine serum albumin microporous multilayer films. AB - The fabrication of polymeric materials with ordered submicron-size void structures is potentially valuable for many applications such as catalysts, separation and adsorbent media. This paper reports the preparation of macroporous protein multilayer films with regular voids using silica nanospheres as templates. Both monodisperse silica colloids and highly ordered assembly silica multilayer films are used as templates to prepare microporous bovine serum albumin multilayer films with ruleless and ordered submicron-sized voids. Glutaraldehyde is used as a crosslinking agent to form a firm net-like protein film on the surface of silica templates. The microporous protein film is obtained after removing of silica templates. Compare with polymer film, protein film has good biocompatibility and biodegradability which will be beneficial to its biological applications. PMID- 22523967 TI - Evaluation of osteoinduction and proliferation on nano-Sr-HAP: a novel orthopedic biomaterial for bone tissue regeneration. AB - Hydroxyapatite (HAP), a CaP compound similar to the mineral phase present in bone, has excellent biocompatibility but little osseous inductivity. In this study, we evaluated the novel nano-Sr-HAP, in which the calcium of hydroxyapatite was substituted with strontium, which acts as a bone-forming agent. Its biocompatibility and osteoinduction were assayed using marrow mesenchymal stem cells (MSCs) and osteoblasts (OBs) in vitro. We were able to demonstrate that nano-Sr-HAP supported increased OB cell adhesion, proliferation and viability up to 4 days in culture when compared with nano-HAP. MSCs cultured with nano-Sr-HAP showed higher alkaline phosphatase (ALP) activity. More extracellular mineralized nodules were found with nano-Sr-HAP compared to nano-HAP, especially in images of ALP staining. We suggest that nano-Sr-HAP powders possess osteoconductive and osteoinductive properties and have the potential to be used in the repair of bone defects caused by osteoporotic fractures. PMID- 22523968 TI - A novel type of Ge nanotube arrays for lithium storage material. AB - Amorphous Ge nanotubes, featured of a top-closed tubular structure, were synthesized directly on metallic current collector substrates via a template technique. Measurement of electrochemical cycling reveals that these nanotubes can deliver reversible capacities of -1300 mAh/g (81% of the theoretical capacity) at the current density of C/20 (1C = 1600 mAh/g) and retain -700 mAh/g at 2C with columbic efficiencies over 99%. Such performance is comparable to that of the recently reported Ge nanowire anodes grown directly on the metallic substrates by the chemical vapor deposition, indicating that the present Ge nanotubes are a type of anode materials with high capacity and good rate performance for lithium storage. PMID- 22523969 TI - Biopolymer nanocomposite films reinforced with nanocellulose whiskers. AB - A xylan nanocomposite film with improved strength and barrier properties was prepared by a solution casting using nanocellulose whiskers as a reinforcing agent. The 13C cross-polarization magic angle spinning (CP/MAS) nuclear magnetic resonance (NMR) analysis of the spectral data obtained for the NCW/xylan nanocomposite films indicated the signal intensity originating from xylan cellulose interactions. Qualitatively, the spectral data obtained for the NCW/xylan nanocomposite films indicated that the amount of xylan adsorbed to cellulose increases with the addition of NCW. In an attempt to quantify this effect, non-linear least-squared spectral line fitting was used to deconvolute the adsorbed xylan peak at -82 ppm. The peak intensity ratio of adsorbed xylan peak and xylan C1 peak, which represents the total amount of xylan increases suggesting that upon the addition of NCW, the amount of adsorbed xylan increases. In an effort to further infer the structure-property relationships associated with the observed strength and barrier properties, 1H NMR T2 relaxation experiments were also conducted to investigate the change in the nature of carbohydrate-water interactions as a result of NCW incorporation. Water adsorbed into the 50% nanocomposite film had significantly shorter relaxation times with respect to the control xylan/sorbitol and all other NCW/xylan nanocomposite films. Additionally, X-ray diffraction of the nanocomposite films showed increased levels of crystalline material in the nanocomposites due to NCW addition. PMID- 22523970 TI - Biotemplated silica and titania nanowires: synthesis, characterization and potential applications. AB - A simple biotemplating method for the synthesis of silica (SiO2) and titania (TiO2) nanowires was designed on a fibrillar protein (alpha-synuclein) template. The diameter of SiO2 and TiO2 nanowires could be varied, between 20-100 nm, by varying the processing conditions. The nanowires were characterized by energy dispersive spectroscopy (EDS) and electron energy loss spectroscopy (EELS). Due to their high surface area and porosity, the nanowires were tested for potential applications in enzymatic biosensor design. PMID- 22523971 TI - Targeted biodegradable nanoparticles for drug delivery to smooth muscle cells. AB - Targeted delivery of therapeutic agents to prevent smooth muscle cell (SMC) proliferation is important in averting restenosis (a narrowing of blood vessels). Since platelet derived growth factor (PDGF) receptors are over-expressed in proliferating SMCs after injury from cardiovascular interventions, such as angioplasty and stent implantation, our hypothesis is that conjugation of PDGF-BB (platelet-derived growth factor BB (homodimer)) peptides to biodegradable poly (D,L-lactic-co-glycolide) (PLGA) nanoparticles (NPs) would exhibit an increased uptake of these NPs by proliferating SMCs. In this study, poly (D,L-lactide-co glycolide) (PLGA) nanoparticles containing dexamethasone were formulated and conjugated with PDGF-BB peptides. These NPs were stable, biocompatible, and exhibited a sustained drug release over 14 days. Various particle uptake studies using HASMCs (human aortic smooth muscle cells) demonstrated that PDGF-BB peptide conjugated nanoparticles significantly increased cellular uptake and decreased proliferation of HASMCs compared to control nanoparticles (without conjugation of PDGF-BB peptides). These NPs were internalized primarily by clathrin-mediated endocytosis and macropinocytosis. Our in vitro results suggest that PDGF-BB peptide-conjugated NPs could represent as an effective targeted, sustained therapeutic delivery system to reduce restenosis and neointimal hyperplasia. PMID- 22523972 TI - In vitro evaluation and finite element simulation of drug release from polydiacetylene-polyethylene glycol stearate nanovesicles. AB - Vesicles comprised of 10,12-pentacosadiynoic acid (PCDA) were modified, using polyethylene glycol 40 stearate (PEG40S), and crosslinked by ultraviolet (UV) irradiation to create polymerized nanovesicles for sustained drug release. Paclitaxel, a water-insoluble compound widely used in cancer chemotherapy, was used as a model drug to examine the physicochemical stability and release profiles of PCDA/PEG40S nanovesicles. TEM analysis revealed the formation of paclitaxel-encapsulated PCDA/PEG40S nanovesicles of 40 to 200 nm in size. Upon the addition of ethanol, instantaneous releases of paclitaxel in the amount of 28 microg/mL from polymerized PCDA/PEG40S nanovesicles and 108 microg/ml from unpolymerized ones were observed. This suggested the non-complete drug release from polymerized PCDA/PEG40S nanovesicles due to their enhanced physicochemical stability by ultraviolet irradiation-induced polymerization, if compared to unpolymerized ones. An in vitro study demonstrated that an accumulative release of 24.1 +/- 3.1% and 8.1 +/- 1.7% of paclitaxel was obtained within 24 hrs from nanovesicles comprised of PCDA/PEG40S at a 9:1 and 7:3 molar ratio, respectively. A finite element model that considered the diffusion-driven releases and the reversible drug-vesicle interaction captured the sustained release of paclitaxel from polymerized PCDA/PEG40S nanovesicles. PCDA/PEG40S nanovesicles capable of sustained release and with enhanced physicochemical stability thus possess great potential for applications in drug release. PMID- 22523973 TI - Fabrication of silica/PDMS hybrid nanoparticles by a novel solvent adjustment route. AB - The silica/polydimethylsilane (PDMS) hybrid nanoparticles were successfully synthesized by a novel solvent adjustment route. The as-prepared hybrid nanoparticles were characterized by transmission electron microscopy, UV-vis spectra, and IR spectra. The possible mechanism for the formation of silica/PDMS nanoparticles was discussed. The adjustment of solvents is a very important factor since it could tune the surface ligands and improve the coordination ability. On the other hand, it could also tune the interaction between precursors, intermediate or the target hybrid materials and guarantee the monodispersion of prepared nanoparticles. With the merits of PDMS and silica, the as-prepared SiO2-PDMS hybrid nanoparticles have a good application in hard coating material. PMID- 22523974 TI - Re-grown aligned carbon nanotubes with improved field emission. AB - In this work, a simple technique to improve the field emission property of multi walled carbon nanotubes is presented. Re-grown multi-walled carbon nanotubes are grown on the same substrates after the as-grown multi-walled carbon nanotubes are transferred to other substrates using polydimethylsiloxane as intermediation. For the duration of the synthesis of the re-grown multi-walled carbon nanotubes, similar synthesis parameters used in growing the as-grown multi-walled carbon nanotubes are utilized. As a form of possible application, field emission studies show -2.6 times improvement in field enhancement factor and more uniform emission for the re-grown multi-walled carbon nanotubes. In addition, the turn-on field is reduced from 2.85 V/microm to 1.40 V/microm. Such significant improvements are attributed to new emission sites comprising of sharp carbonaceous impurities encompassing both tip and upper portion of the multi-walled carbon nanotubes. As such, this technique presents a viable route for the production of multi-walled carbon nanotubes with better field emission quality. PMID- 22523975 TI - Synthesis of size-controlled Fe3O4@SiO2 magnetic nanoparticles for nucleic acid analysis. AB - We present a systematic study on the preparation, characteration and potential application of Fe3O4 and Fe3O4@SiO2 nanoparticles. Fe3O4 nanoparticles of controllable diameters were successfully synthesized by solvothermal system with tuning pH. The magnetic properties of nanoparticles were measured by vibration sample magnetometer. Fe3O4@ SiO2 nanoparticles were obtained via classic Stober process. Streptavidin coated Fe3O4@SiO2 nanoparticles were prepared by covalent interaction. The quantity of streptavidin bound to nanoparticles was determined by UV-Vis spectrometer. To evaluate the binding efficiency and capacity of nucleic acid on nanoparticles, the capture of biotinylated oligonucleotide on streptavidin coated Fe3O4@SiO2 nanoparticles at different concentration was estimated by fluorescence detection. Both Fe3O4 and Fe3O4@SiO2 nanoparticles exhibited well crystallization and magnetic properties. The maximal amount of streptavidin immobilized onto the Fe3O4@SiO2 nanoparticles was 29.3 microg/mg. The saturation ratio of biotinylated oligonucleotides captured on streptavidin coated Fe3O4@SiO2 nanoparticles was 5 microM/mg within 20 minutes, indicating that FeO4@SiO2 nanoparticles immobilized by streptavidin were excellent carriers in nucleic acid analysis due to their convenient magnetic-separation property. Therefore, the synthesized Fe3O4 and Fe3O4@SiO2 nanoparticles with controllable size and high magnetic saturation have shown great application potentials in nucleic acid research. PMID- 22523976 TI - Comparison of cytotoxicity of pristine and covalently functionalized multi-walled carbon nanotubes in RAW 264.7 macrophages. AB - Carbon nanotubes may be applied in different fields including biomedicine and mechanical engineering. It is important to understand the potential hazards of carbon nanotubes. In the present study, the toxicological effects of the pristine multi-walled carbon nanotubes (p-MWCNTs) and taurine functionalized multi-walled carbon nanotubes (tau-MWCNTs) were assessed on RAW 264.7 macrophages. We tested cell viability, GSH/GSSG ratio, apoptosis, intracellular calcium concentration, ultrastructural changes of cell morphology, and the release of IL-8. We observed the loss of cell viability, decline in the cellular GSH/GSSG ratio, increase of IL-8, and the increase of intracellular calcium concentration in RAW 264.7 macrophages when exposed to p-MWCNTs at high dosage. Additionally, exposure to p MWCNTs resulted in ultrastructural and morphological changes in RAW 264.7 macrophages. In contrast, the RAW 264.7 macrophages exposed to the tau-MWCNTs did not exhibit altered morphology. Our results conclude that the tau-MWCNTs show lower toxicity than that of p-MWCNTs. PMID- 22523977 TI - The Fermi energy of ellipsoidal nanoparticles. AB - We introduce a simple analytical model in order to find the energy spectrum of ellipsoidal samples. For this purpose, the perturbation theory is applied. The eigenvalues of the energy are of the size and shape dependent form, which leads to the dependence of the samples properties. In particular, the Fermi energy is discussed in the context of the deformation of single nanoparticle from spherical shape and their ensemble. PMID- 22523978 TI - Silica nanoparticles suppress fibronectin-mediated adhesion and migration in normal human keratinocytes. AB - Nanotechnology has been increasingly applied to various fields, such as biology, chemistry, physics, medicine and engineering. However, a major concern that has been the topic in nanoscience is whether exposure of humans to engineered nanoparticles might cause toxic effects. In the present in vitro study, the influence of silica nanoparticles on fibronectin-mediated cellular response was assessed in normal human keratinocytes. Our results demonstrated that silica nanoparticles but not silica microparticles significantly suppressed cell adhesion and migration to fibronectin. This phenomenon was not observed in cell response to Poly-L-Lysine, which mediates cell adhesion and migration in a way different from that of fibronectin. Moreover, it seemed that this suppression was not due to cytotoxic effects induced by silica nanoparticles. Subsequently, we also showed that silica nanoparticles impaired the fibronectin-induced activation of FAK and its downstream PI3K, AKT and Src. Taken together, our data suggests that silica nanoparticles may negatively modulate cell response to fibronectin. PMID- 22523979 TI - Fabrication of nano-porous hydroxyapatite modified electrode and its application for determination of p-chlorophenol. AB - Nano-porous hydroxyapatite (HAp) modified electrode was fabricated by simply electrodepositing HAp onto the glassy carbon electrode (GCE) from the electrolytes solution containing Ca(NO3)2 4H2O and NH4H2PO4, the resulting electrode (nano-HAp/GCE) was characterized with scanning electron microscopy (SEM). The electrochemical behavior of p-chlorophenol (p-CP) at nano-HAp/GCE was studied by cyclic voltammetry. The electrode displayed selective and enhanced electroanalytical response towards p-CP, obviously because p-CP is accumulated at the electrode. For the greater sensitivity, a semi-derivative technique was adopted to obtain the current signal. The results indicated that the nano-HAp/GCE exhibits substantial enhancement in electrochemical sensitivity for p-CP due to its large surface area and particular adsorbability. After accumulation of 4 min for p-CP on nano-HAp/GCE, the peak height was linearly related to the concentration of p-CP in the range of 1.0 x 10(-8) to 1.0 x 10(-7) mol L(-1). The detection limit was 4.0 x 10(-9) mol L-(1) at 3sigma level. Based on this, the modified electrode was successfully applied in water samples with low cost and high sensitivity. PMID- 22523980 TI - Optical and bio-sensing characteristics of ZnO nanotubes grown by hydrothermal method. AB - ZnO nanostructures were fabricated on copper substrates by hydrothermal method at an optimized growth temperature of -95 degrees C. Structural properties were investigated by field emission scanning electron and transmission electron microscopy. Distinct morphologies were found to be formed at different growth times. The formation of nanotubes mainly involved the initial nucleation followed by the growth of nanorods at 95 degrees C, and then with the increase of dissolution time at room temperature, the preferential chemical dissolution of the metastable Zn-rich [0001] polar surfaces resulted in removing the atoms from the surfaces, thus leading to the thinning of the wall of the nanostructures. Completely hollow ZnO nanotubes could be obtained at a high dissolution time. The room temperature photoluminescence and optical absorption properties of ZnO nanotubes have been studied as a function of dissolution time. The efficacy of ZnO nanotubes for glucose sensing applications has been studied. PMID- 22523981 TI - A gas-solid reaction growth of dense TiO2 nanowire arrays on Ti foils at ambient atmosphere. AB - In this paper, a facile method is demonstrated to directly fabricate dense titania nanowire arrays on titanium foils under the atmosphere without extra moist conditions. The influences of temperature, time, different catalysts, and concentrations of the respective catalysts on the growth of titania nanowires are discussed in detail. The morphology, composition and crystal structure of the titania nanostructures are revealed by scanning electron microscopy (SEM), powder X-ray diffraction (XRD) and transmission electron microscopy (TEM) techniques, by which a gas-solid reaction mechanism is suggested to explain the growth process of TiO2 nanowires on Ti substrate. PMID- 22523982 TI - Electrocatalytic activity of PtAu/C catalysts for glycerol oxidation. AB - The electrocatalytic oxidation of glycerol on PtAu/C catalysts has been investigated by cyclic voltammetry. PtAu bimetallic nanoparticles are prepared by chemical reduction. Carbon-supported PtAu catalysts are found to exhibit high electrocatalytic activity for the oxidation of glycerol in alkaline solution in terms of oxidation potential and current density as well as stability, and PtAu/C catalysts with different Pt:Au composition ratios show no much difference in catalytic activity. In acidic solution, PtAu/C catalysts exhibit similar to Pt/C catalysts in activity, but the advantage of the PtAu/C catalysts in terms of per unit mass of platinum is still obvious. The PtAu/C catalysts, in a wide Pt:Au ratio range, show a remarkable enhancement in the mass specific activity of platinum with decreasing platinum content in both alkaline and acidic solutions. This is of significance for reducing the usage of platinum and indicates that though platinum acts as main active sites, gold also plays an important role in the function of PtAu/C catalysts. PMID- 22523983 TI - In vitro evaluation on a model of blood brain barrier of idebenone-loaded solid lipid nanoparticles. AB - The aim of this study was to evaluate in vitro the permeation of the antioxidant agent Idebenone (IDE) loaded into solid lipid nanoparticles (SLN) across MDCKII MDR1 cell monolayer, selected as an in vitro model of the Blood Brain Barrier (BBB). SLN were prepared using cetyl palmitate as solid lipid and different non ionic surfactants, oleth-20, ceteth-20 and isoceth-20, by the phase inversion temperature (PIT) technique. The resulting SLN showed physiological pH and osmolarity values, a mean particle diameter in the range of 33-63 nm, a single peak in size distribution, and a zeta potential ranging from +3.14 to -2.89 mV. When incubating these SLN in Simulated Body Fluid (SBF), the particle size was maintained for all samples throughout the study. IDE permeability across MDCKII MDR1 cell monolayers from the SLN under investigation was 0.40-0.53 fold lower than free IDE and no significant difference was observed comparing IDE permeation from all the SLN tested. It is noteworthy that IDE loading into SLN avoided the use of an organic solvent to solubilize IDE, a poor water soluble compound, allowing the parenteral administration of this drug in aqueous vehicles. Furthermore, the results of in vitro transport studies, performed using fluorescein-dextran 4000 (FD4) and diazepam (DZ) as markers of the paracellular pathway and the transcellular pathway, respectively, pointed out that IDE could permeate via a transcellular pathway. Therefore, these novel nanocarriers could be regarded as a promising strategy to design delivery systems for IDE administration to the brain, deserving further investigations under in vivo conditions. PMID- 22523984 TI - Electrodeposition of zinc hydroxysulfate nanosheets and reduction to zinc metal microdendrites on polypyrrole films. AB - Nanothin sheets made of zinc sulfate hydroxide hydrate, ZnSO4[Zn(OH)2]3 x 5H2O, are easily and quickly prepared using an innovative electrochemical route onto polypyrrole-polystyrene sulfonate (PPy-PSS) films. The sheets are characterized using a range of experimental techniques. The deposits are formed on the film surface with instantaneous nucleation to grow into a network of entangled nanosheets. The effect of the experimental conditions on the deposition is reported. Interestingly, the formation of the nanosheets is observed on PPy-PSS films only, and not on films doped with other sulfate/sulfonate dopants. The zinc nanosheets can be easily electrochemically reduced to metallic zinc microdentrites. PMID- 22523985 TI - Studies of self-reciprocating characteristic of carbon nanotube film-based cantilevers under light and thermal radiation. AB - Self-reciprocating characteristic of carbon nanotube film (CNF)-Cu cantilevers upon exposure to light and thermal radiation was observed. This unique characteristic offers an attractive technical platform for harvesting solar and thermal energies on a single chip, which has been demonstrated recently. This paper reports the detailed experimental studies of this phenomenon. It reveals that the low-frequency self-reciprocation, sensitive to the thicknesses of CNF and Cu and the intensity of the light and thermal radiation, is mainly attributed to the electrostatic interaction among randomly connected carbon nanotubes (CNTs) in CNF. This is due to the fact that electrical currents in CNF induced by light and thermal radiation also exhibit an oscillating characteristic, similar to the self-reciprocating characteristic of the CNF-Cu cantilevers. The mechanism for this observed phenomenon is also discussed by relating the optical, thermal, electrical, elastic and mechanical properties of the CNF. PMID- 22523986 TI - Flexible carbon cloth electrode modified by hollow core-mesoporous shell carbon as a novel efficient bio-anode for biofuel cell. AB - A new approach is described to produce an efficient electrode material for biofuel cells using flexible carbon cloth (FCC) and hollow core-mesoporous shell carbon (HCMSC) nanospheres as bio-anode materials. The bio-electrochemical activity of glucose oxidase (GOx) enzyme adsorbed on this bio-anode was evaluated, with the maximum anodic current density varying from 80 microA cm(-2) to 180 microA cm-2 for glucose concentrations up to 5.0 mmol L(-1) for the FCC modified electrode with HCMSCs. The open circuit cell voltage was E(0) = 380 mV, and the catalytic electro-oxidation current of glucose reached 0.1 mA cm(-2) at 0.0 V versus Ag/AgCl. This new system employing HCMSC-based FCC is promising toward novel bio-anodes for biofuel cells using glucose as a fuel. PMID- 22523987 TI - Monolayer detection on flat metal surface via surface enhanced Raman spectroscopy and sum frequency generation spectroscopy. AB - Monolayer detection on metal surface requires ultra high sensitivity. Sum Frequency Generation Spectroscopy (SFG) and Surface Enhanced Raman Spectroscopy (SERS) are regarded as two powerful techniques with submolecular sensitivity to detect adsorbents on metal surface. However, in some cases it's still challenge to characterize molecules or groups with relatively high intramolecular symmetry, such as 4-Nitrothiophenol (4NTP), on flat metal surface even combining these two techniques. Basically, this is due to that 4NTP with para-substituted phenol groups is SFG insensitive while flat metal surface is unfavorable to yield strong SERS enhancement. In this concern, a simple and efficient method, silver mirror method, was employed to facilitate the detection of 4NTP SAM on flat gold surface. Silver nanopheres with diameters around 300 nm was fabricated through silver mirror reaction and in situ formed milky overlayer on top of 4NTP SAM adsorbed on gold surface. Significant enhancement on SERS signal can be achieved with such special assembly structure of the "metal-molecule-metal" system. Generally, the silver mirror method provided a complementary approach to facilitate the spectroscopic applications of molecule level detection on various metal surfaces in situ. PMID- 22523988 TI - Subcellular distribution of CdSe quantum dots (QDs) in breast cancer cells. AB - In spite of great advances in conventional cancer diagnosis and treatment, the early recognition and characterization for various cancers remain a technological bottleneck. The combined characteristics of board absorption and narrow emission make quantum dots (QDs) desirable fluorescent labels for cancer imaging and other applications in the biomedical field. In the current study, to the best of our knowledge, we first evidenced the preferential accumulation of QDs in cytoplasm of breast cancer cells. QDs therefore reveal considerable potentials in both tumor imaging and therapeutic application. PMID- 22523989 TI - Diameter controlled chemical vapor deposition synthesis of single-walled carbon nanotubes. AB - In this study, we systematically investigated the influence of catalyst preparation procedures on the mean diameter of single-walled carbon nanotubes (SWNTs) synthesized by the alcohol catalytic chemical vapor deposition (ACCVD) process. It was found that the SWNT diameter is dependent upon both reduction temperature and time, with lower reduction temperature and/or shorter reduction time resulting in smaller diameter SWNTs. The morphology of the SWNTs also changed from vertically aligned to randomly oriented when the reduction temperature was below 500 degrees C. We also found that introducing a small amount of water during the catalyst reduction stage significantly decreased the mean diameter of the SWNTs. Lastly, we report on the use of a new binary catalyst system in which rhodium was combined with cobalt. This new Co/Rh combination produced SWNTs of smaller diameter than the conventional Co/Mo catalyst. PMID- 22523990 TI - Polydiacetylene single-walled carbon nanotubes nano-hybrid for cellular imaging applications. AB - The functionalization of single-walled carbon nanotubes (SWCNTs) by forming self assembled supramolecular structure of 10,12-pentacosadiynoic acid (PCDA) on the carbon nanotube wall is reported. PCDA assemblies on SWCNTs (PCDA/SWCNTs) were polymerized by UV irradiation to extensively conjugated polydiacetylene (PDA). PDA/SWCNT was identified by absorption and emission spectroscopy, scanning and transmission electron microscopies (SEM and TEM) and atomic force microscopy (AFM). PDA/SCWNTs showed strong near-infrared (NIR) fluorescence caused by fluorescence resonance energy transfer (FRET) between PDA network and semiconducting SWCNT core. The micro-patterning of biotinylated PDA/SWCNT with FITC-avidin on biotinylated glass surface demonstrated the potential application for a bio-sensing device. Furthermore, the biocompatibility for mammalian cancer cells was tested by viability experiments, which revealed that the PDA/SWCNTs had very low toxicity below 31.3 mg/L in terms of pristine SWCNTs concentration. Also, PDA/SWCNTs inside the cells can be observed by NIR microscopy. This unique modular method of preparation can contribute to diverse functionalities for practical applications in various non-invasive cellular imaging. PMID- 22523991 TI - Complex structure of triangular graphene: electronic, magnetic and electromechanical properties. AB - We have investigated electronic and magnetic properties of graphene nanodisks (nanosize triangular graphene) as well as electromechanical properties of graphene nanojunctions. Nanodisks are nanomagnets made of graphene, which are robust against perturbation such as impurities and lattice defects, where the ferromagnetic order is assured by Lieb's theorem. We can generate a spin current by spin filter, and manipulate it by a spin valve, a spin switch and other spintronic devices made of graphene nanodisks. We have analyzed nanodisk arrays, which have multi-degenerate perfect flat bands and are ferromagnet. By connecting two triangular graphene corners, we propose a nanomechanical switch and rotator, which can detect a tiny angle rotation by measuring currents between the two corners. By making use of the strain induced Peierls transition of zigzag nanoribbons, we also propose a nanomechanical stretch sensor, in which the conductance can be switched off by a nanometer scale stretching. PMID- 22523992 TI - Construction and electro-optic properties of liquid-crystal display doped by rhodium nanoparticles. AB - We prepared 4'-pentylbiphenyl-4-carbonitrile (5CB)-stabilized rhodium (5CB-Rh) nanoparticles and poly(cyclodextrin) (PCyD)-stabilized rhodium (PCyD-Rh) nanoparticles. The average diameter of Rh nanoparticles stabilized by 5CB, PalphaCyD, PbetaCyD, and PgammaCyD are 1.2, 5.4, 6.8, and 5.2 nm, respectively. The nanoparticles were dispersed in liquid crystal 5CB to construct novel twisted nematic liquid crystal device (TN-LCD). Voltage holding ratio was measured for TN LCD fabricated by doping PbetaCyD-Rh nanoparticles. The decrement of the voltage was very much reduced for that doped with PbetaCyD-Rh. The response time of this TN-LCD in the presence of PbetaCyD-Rh nanoparticles was faster than that in the absence. PMID- 22523993 TI - Spectroelectrochemical reflection studies of gold nano-rod array membrane. AB - Gold nano-rod array membranes (Au-NRM) were prepared by modification of the template method. A simple two-electrode device was assembled by holding an electrolyte solution between the Au-NRM and a transparent electrode. Small reflectance changes (less than 2%) in the visible band were induced on the Au-NRM surface by applying a DC voltage to the device. These changes could be visually observed. It was found based on a further evaluation that the reflectance changes responded very fast (less than 100 ms) to the DC voltage application, and were stable during the switching repetition (over 5000 times). When the cyclic scanning of the applied voltage to the device was carried out between -1.5 V and +1.5 V, the reflectance changes were increased over +1.0 V (-1.0 V). It was suggested from these experimental results that the reflectance changes were attributed to the surface oxidation and the deformation or mechanical motion of the Au nano-rod. PMID- 22523994 TI - The influence of interlayer molecules in luminescence of self-assembled bilayer PbS quantum dot films. AB - We synthesized organic solvent-soluble and water-soluble PbS quantum dots (QDs) with different sizes. The organic solvent-soluble PbS QDs dispersed in tetrachloroethylene were used to prepare bilayers structures of QDs bound by dithiol linkers on GaAs. The water-soluble PbS QDs were used to prepare bilayer structures of QDs on quartz based on alternating adsorption of polyelectrolyte. For bilayer films on GaAs, it was found that the stacking sequence of QDs affects the quantum yield and emission wavelength of the larger QDs. However, for bilayer films with different stacking sequences on quartz, the larger QDs show similar PL intensities and emission wavelength independent of the sequence. The probable mechanism for this difference observed is discussed in terms of charge transfer between QDs. PMID- 22523995 TI - Effect of surface plasmon resonance on the photocatalytic activity of Au/TiO2 under UV/visible illumination. AB - In this study, gold-loaded titanium dioxide was prepared by an impregnation method to investigate the effect of surface plasmon resonance (SPR) on photoactivity. The deposited gold nanoparticles (NPs) absorb visible light because of SPR. The effects of both the gold content and the TiO2 size of Au/TiO2 on SPR and the photocatalytic efficiency were investigated. The morphology, crystal structure, light absorption, emission from the recombination of a photoexcited electron and hole, and the degree of aggregation were investigated using transmission electron microscopy (TEM), X-ray diffraction (XRD), UV-visible diffuse reflectance spectra (UV-VIS-DRS), photoluminescence (PL) spectroscopy, and turbidimetry, respectively. Photocatalytic activity was evaluated by the decolorization of methyl orange solution over modified titania under UV and UV/GLED (green light emitting diode) illumination. Au/TiO2 NPs exhibited an absorption peak (530-570 nm) because of SPR. The results of our photocatalytic experiments indicated that the UV-inducedly photocatalytic reaction rate was improved by simultaneously using UV and green light illumination; this corresponds to the adsorption region of SPR. Au/TiO2 could use the enhanced electric field amplitude on the surface of the Au particle in the spectral vicinity of its plasmon resonance and thus improve the photoactivity. Experimental results show that the synergistic effect between UV and green light for the improvement of photoactivity increases with increasing the SPR absorption, which in turn is affected by the Au content and TiO2 size. PMID- 22523996 TI - Charge trapping devices using a bilayer oxide structure. AB - This experiment is the first exploration of use of charge traps in the bulk of deposited top oxide and at the interface between thermal oxide and deposited top oxide. We report the operational characteristics of SiO2/SiO2 device structures with 0.5 microm gate width and length. Low power operations are achieved through very thin gate stacks of 3 nm of thermally grown oxide and 7 nm of deposited oxide. However, narrow memory windows have been acquired comparing with conventional silicon-oxide-nitride-oxide-silicon (SONOS) memory cells due to a low trap density at the interface between a grown oxide and a deposited oxide. Additionally, the electric field between the channel and the charge is determined by solving 1D Poisson equation at a given write voltage, then total tunneling current density is calculated to make a program modeling for charge trapping devices. Tunneling/trapping simulation based on Fowler-Nordheim (F-N) tunneling performed and it fits the programming curves well. The memory window is almost constant after 100,000 cycles, and the retention characteristics are deteriorated rapidly. PMID- 22523997 TI - Control of magnetic domains in Co/Pd multilayered nanowires with perpendicular magnetic anisotropy. AB - Magnetic domain wall (DW) motion induced by spin transfer torque in magnetic nanowires is of emerging technological interest for its possible applications in spintronic memory or logic devices. Co/Pd multilayered magnetic nanowires with perpendicular magnetic anisotropy were fabricated on the surfaces of Si wafers by ion-beam sputtering. The nanowires had different sized widths and pinning sites formed by an anodic oxidation method via scanning probe microscopy (SPM) with an MFM tip. The magnetic domain structure was changed by an anodic oxidation method. To discover the current-induced DW motion in the Co/Pd nanowires, we employed micromagnetic modeling based on the Landau-Lifschitz-Gilbert (LLG) equation. The split DW motions and configurations due to the edge effects of pinning site and nanowire appeared. PMID- 22523998 TI - Improvement in performances of dye-sensitized solar cell with SiO2-coated TiO2 photoelectrode. AB - The pure TiO2 and the nano-porous SiO2-coated TiO2 (STO) films were deposited on the FTO substrates by spray technique for the application of dye-sensitized solar cells (DSSCs). XRD pattern shows the pure TiO2 and STO films exhibits the same structure. We found that there is no much difference in dye absorption between the STO and the pure TiO2 films. The electrochemical impedance spectra reveal that insulating nature of the porous SiO2 increases surface resistance of the TiO2 film and supresses back transfer of the photogenerated electrons to the electrolyte. The field-emission scanning electron microscopy (FE-SEM) and energy dispersion X-ray spectroscopy (EDS) reveal that the surface morphology and the existence of SiO2 layer on the surface of the TiO2 films, respectively. The photoelectrochemical results show that the short-circuit photocurrent (J(SC)) increased from 16.73 mA cm(-2) to 18.31 mA cm(-2) and the open-circuit voltage (V(OC)) value changed from 0.71 V to 0.74 V for the STO films. The efficiency of cell has been greatly improved from 8.25 to 9.3%. PMID- 22523999 TI - Photochemical hydrogen production from water using three-dimensional Zn-Pd metal organic frameworks. AB - A Zn-Pd heterometallic metal-organic framework (MOF) based on 3,5-pyridine dicarboxylic acid (H2-pydc), namely [Zn2(H2O)3{PdCl2(pydc)2}]n (Zn-Pd-2) was successfully synthesized by a slow diffusion method and characterized by single crystal X-ray diffraction, CHN elemental analysis, FT-IR spectroscopy, thermogravimetric (TG) analysis and N2 gas adsorption measurement. The single crystal X-ray analysis revealed that the framework morphology of Zn-Pd-2 is as same as that of [Zn2(DMF)3{PtCl2(pydc)2}]n. The Zn-Pd-2 was found to be an effective catalytic performance for the photochemical reduction of water in a well-known photo-system made up of [Ru(bpy)3Cl2] (bpy = 2,2'-bipyridine), MV(2+) (methyl-viologen) and Na2 EDTA (Disodium ethylenediaminetetraacetate); 20.2 turnover based on Zn-Pd-2 was achieved at 4 h irradiation. PMID- 22524000 TI - Drop-on-demand printing of carbon black ink by electrohydrodynamic jet printing. AB - Electrohydrodynamic (EHD) jet printing is a technique using electric fields to eject inks through nozzle apertures. EHD jet printing is very attractive due to its non-contacting nature and compatibility with diverse materials and substrates. In this research, we have fabricated micron-sized dot arrays and line patterns with carbon black ink on Si wafer substrates using EHD jet printing. The effect of operating conditions such as applied voltage, working distance and stage speed on the size and shape of the jetted patterns and jetting cycles is investigated by using optical microscope, high speed camera and atomic force microscopy (AFM). We have also demonstrated the drop-on-demand feature of the EHD jet printing system by patterning carbon black ink lines with various widths and dot arrays with desired diameters and spacing by controlling the operating conditions. PMID- 22524001 TI - Fabrication of metal half-shells using colloidal particle monolayer and their application in surface-enhanced Raman scattering. AB - Three types of Au shells, an isolated half-shell, one-dimensional strings of shells, and two-dimensional films, were fabricated by using a monolayer of polystyrene (PS) particles with diameters of 213, 560, and 1360 nm. The three types of Au shells that were removed from the PS particle monolayer and the as deposited Au shells that adhered to PS particles were modified with 4 mercaptopyridine for use as platforms for surface-enhanced Raman scattering (SERS). We examined the effects of the shapes and sizes of Au shells on their SERS efficiency and found that the Au shells exhibited strong SERS signals and that Au shells prepared by using 560-nm PS particles were the most suitable platform for SERS at both 632.8- and 785-nm excitations. Further, we found that SERS enhancements depended on the shape of Au shells and on whether Au shells adhered to PS particles or not. PMID- 22524003 TI - Effect of surface modifications on ZnO nanorod arrays electrode for dye sensitized solar cells. AB - High quality, large area and well-oriented ZnO nanorod arrays electrodes were successfully synthesized on conductive transparent oxide substrates by low temperature hydrothermal methods for dye-sensitized solar cells. Aiming at getting further enhancement and study the effect of the surface modification on cell performance, ZnO thin film and ZnO nanoparticles are carried out to modify the as-grown ZnO nanorod arrays. The morphology, structure and photoluminescence property of the modified ZnO electrodes are characterized in detail. Furthermore, the I-V characterization result shows that these modification methods have distinct influences on the performance of the cell based on ZnO nanorod arrays electrode. The overall conversion efficiency can be optimized by choosing the suitable modification route. PMID- 22524002 TI - Effective supercontinuum generation by using highly nonlinear dispersion-shifted fiber incorporated with Si nanocrystals. AB - The dispersion-shifted fiber (DSF) incorporated with Si nanocrystals (Si-NCs) having highly nonlinear optical property was fabricated to investigate the effective supercontinuum generation characteristics by using the MCVD process and the drawing process. Optical nonlinearity was enhanced by incorporating Si nanocrystals in the core of the fiber and the refractive index profile of a dispersion-shifted fiber was employed to match its zero-dispersion wavelength to that of the commercially available pumping source for generating effective supercontinuum. The non-resonant nonlinear refractive index, n2, of the Si-NCs doped DSF measured by the cw-SPM method was measured to be 7.03 x 10(-20) [m2/W] and the coefficient of non-resonant nonlinearity, gamma, was 7.14 [W(-1) km(-1)]. To examine supercontinuum generation of the Si-NCs doped DSF, the femtosecond fiber laser with the pulse width of 150 fs (at 1560 nm) was launched into the fiber core. The output spectrum of the Si-NCs doped DSF was found to broaden from 1300 nm to wavelength well beyond 1700 nm, which can be attributed to the enhanced optical nonlinearity by Si-NCs embedded in the fiber core. The short wavelength of the supercontinuum spectrum in the Si-NCs doped DSF showed shift from 1352 nm to 1220 nm for the fiber length of 2.5 m and 200 m, respectively. PMID- 22524004 TI - Effect of glycerol on retention time and electrical properties of polymer bistable memory devices based on glycerol-modified PEDOT:PSS. AB - The addition of glycerol to Poly(3,4-ethylenedioxythiophene):Poly(styrene sulfonate) (PEDOT:PSS) films affected the bipolar switching characteristics of nonvolatile polymer memory devices (PMDs). Increasing the glycerol/PEDOT:PSS ratio caused increase in the OFF-current of the PMDs, but did not affect the ON current levels. This result demonstrates that highly-conductive current paths occur in the ON-state. The write-read-erase-read cycle test was operated > 10(5) times. And, the ON-retention time is largely dependent on the glycerol to PEDOT:PSS ratio and annealing temperature. In addition, AFM analysis on the G PEDOT:PSS films to see how the surface morphology of G-PEDOT:PSS layer influences the retention time properties was carried out. PMID- 22524005 TI - Direct-patterning of porphyrin dot arrays and lines using electrohydrodynamic jet printing. AB - In this research, we have fabricated micron-sized patterns of porphyrins on silicon substrates using an electrohydrodynamic (EHD) jet printing technique. Optical and fluorescence microscopies have been used to examine the shape and fluorescence property of porphyrin patterns. The morphology of the porphyrin patterns printed with variously formulated porphyrin inks and the effects of applied voltage, working distance, and substrate properties on the morphology of patterns were investigated using scanning electron microscopy (SEM) and atomic force microscopy (AFM). We have also demonstrated the acid-vapor sensing capability of the porphyrins by exposing the porphyrin patterns on Si substrates to nitric acid vapor. PMID- 22524006 TI - Plasma nano-modification of poly(ethylene terephthalate) fabric for pigment adhesion enhancement. AB - Poly(ethylene terephthalate) (PET) fabrics were modified by treating with radio frequency (RF) plasma of different gases, including argon (Ar), nitrogen (N2), oxygen (O2) and sulfur hexafluoride (SF6), under varied power (50-150 watt) and time period (0.5-20 min). Observations indicated that plasma has affected the morphology and roughness of PET fiber surface in the nano-scale level. After plasma treatment, test patterns were printed by inkjet printer directly onto the sample surface. The enhancement of color printing performance on PET fabric by plasma treatment was evaluated by color spectroscopy. The surface nano-modified PET fabrics by Ar, N2, O2, and SF6 plasmas all exhibited enhanced color yield. AFM, SEM, FTIR-ATR and XPS results suggested that the improved pigment color yield was neither clearly contributed by the wettability of the fabrics nor the polar group induced onto the fiber surfaces but rather mainly by the alteration of surface roughness. PMID- 22524007 TI - Synthesis of polyacrylamide-montmorillonite clay nanocomposite using non conventional electrochemical technique. AB - Synthesis of polymer-clay nanocomposite by in-situ incorporation of polyacrylamide in organically modified montmorillonite (MMT) clay layers is being reported using non-conventional electrochemical technique "plasma electrolysis." A luminous sheath of plasma is sustained between an electrode (anode) and the surface of surrounding liquid electrolyte at sufficiently high voltage, for synthesis of polymer or nanocomposite. Using this technique, radical generation capability is explored as a new tool for radical polymerization and in-situ composite formation of polyacrylamide. Polyacrylamide-MMT clay nanocomposite is synthesized by taking acrylamide and MMT clay in K2SO4 electrolyte solution at the anodic potential of 660 V. Polyacrylamide and polyacrylamide-MMT clay nanocomposites are characterized for their structural and thermal properties. Intercalation in MMT clay layers of homogeneous nanocomposite is supported by X ray diffraction, FTIR, DSC, TGA and SEM/TEM techniques. This novel method produces homogeneous interactive composite with high yield, and shows potential to replace chemical initiators based harsh synthetic processes used for conventional polymer-nanocomposites formation. PMID- 22524008 TI - Electronic structure of the buried interface between an organic semiconductor, N,N'-bis(3-methylphenyl)-N,N'-diphenylbenzidine (TPD), and metal surfaces. AB - The electronic structures of buried interfaces between an organic semiconductor, N,N'-bis(3-methylphenyl)-N,N'-diphenylbenzidine (TPD) and metal surfaces of Au, Ag, Al and Ca were examined by the new experimental method that we have developed recently. In this method the energy levels at the organic/metal interface can be examined without changing the film thickness and related physical parameters e.g., the vacuum levels of the sample in contrast to the widely-used thickness dependent photoemission experiments. The results were discussed in view of large interfacial dipole moment of the TPD and metal (Au and Ag) contacts. PMID- 22524009 TI - Surface-potential undulation of Alq3 thin films prepared on ITO, Au, and n-Si. AB - The surface potential (SP) morphology on thin films of tris(8-hydroxyquinolinato) aluminum (Alq3) was investigated with Kelvin probe force microscopy. Thin Alq3 films of 100 nm were prepared on ITO/glass substrates, Au/mica substrates, and n Si substrates. Cloud-like morphologies of the SP undulation with 200-400 nm in lateral size were observed for all three types of the substrates. New larger peaks were observed in the cloud-like morphologies when the surfaces were exposed shortly to a light, while the SP average was reduced monotonically. The nonuniform distribution of charged traps and mobility was deduced from the SP undulation morphology and its photoexposure dependences. PMID- 22524010 TI - Carbazole functionalized isocyanide brushes in heterojunction photovoltaic devices. AB - In this work, carbazole-containing polyisocyanide (PIACz) brushes were used for photovoltaic devices. A photovoltaic device was fabricated on top of the brushes by spin-coating a suitable acceptor and evaporating an Al cathode. Devices with a poly(N-vinylcarbazole) (PVK) bulk polymer were also prepared for comparison. Interestingly, the brushes showed better photovoltaic characteristics as compared to the blended PVK system. This is attributed to the specific morphologies of the polyisocyanide brushes, which provide a large interfacial area between the donor and acceptor for efficient photogeneration. It was found that the device performance varied according to the molecular size of the incorporated acceptors. PMID- 22524011 TI - Monitoring the layer-by-layer self-assembly of graphene and graphene oxide by spectroscopic ellipsometry. AB - Thin films of graphene oxide, graphene and copper (II) phthalocyanine dye have been successfully fabricated by electrostatic layer-by-layer (LbL) assembly approach. We present the first variable angle spectroscopic ellipsometry (VASE) investigation on these graphene-dye hybrid thin films. The thickness evaluation suggested that our LbL assembly process produces highly uniform and reproducible thin films. We demonstrate that the refractive indices of the graphene-dye thin films undergo dramatic variation in the range close to the absorption of the dyes. This investigation provides new insight to the optical properties of graphene containing thin films and shall help to establish an appropriate optical model for graphene-based hybrid materials. PMID- 22524012 TI - Multicenter uric acid biosensor based on tetrapod-shaped ZnO nanostructures. AB - In this work, we developed a tetrapod-shaped ZnO nanostructure (T-ZnO) biosensor to determine uric acid (UA), which is the primary end product of purine metabolism. The as-fabricated UA sensor presents a higher performance than that of the reported biosensors based on ZnO nanorods and ZnS quantum dots, etc. High quality ZnO nanotetrapods were characterized by field emission scanning electron microscopy (FESEM), energy dispersive X-ray spectra (EDX), X-ray diffraction (XRD) and Raman spectroscopy, respectively. A high affinity of uricase/ZnO to UA was revealed by cyclic voltammograms. The biosensor performance has been systematically investigated by amperometric response measurements. A fast current response time is within 9 s. It was also found that the uricase/T-ZnO biosensor presented a high and reproducible sensitivity of 80.0 microA cm(-2) mM(-1) and an experiment limit of detection of 0.8 microM. This study provides an insight utilizing the unique ZnO nanostructure to develop the highly sensitive and rapidly responsive nano-bio devices. PMID- 22524013 TI - Preparation and electrochemical characterization of polyaniline/activated carbon composites as an electrode material for supercapacitors. AB - Polyaniline (PANI)/activated carbon (AC) composites were prepared by a chemical oxidation polymerization. To find an optimum ratio between PANI and AC which shows superior electrochemical properties, the preparation was carried out in changing the amount of added aniline monomers. The morphology of prepared composites was investigated by scanning electron microscopy (SEM) and transmission electron microscope (TEM). The structural and thermal properties were investigated by Fourier transform infrared spectra (FT-IR) and thermal gravimetric analysis (TGA), respectively. The electrochemical properties were characterized by cyclic voltammetry (CV). Composites showed a summation of capacitances that consisted of two origins. One is double-layer capacitance by ACs and the other is faradic capacitance by redox reaction of PANI. Fiber-like PANIs are coated on the surface of ACs and they contribute to the large surface for redox reaction. The vacancy among fibers provided the better diffusion and accessibility of ion. High capacitances of composites were originated from the network structure having vacancy made by PANI fibers. It was found that the composite prepared with 5 ml of aniline monomer and 0.25 g of AC showed the highest capacitance. Capacitance of 771 F/g was obtained at a scan rate of 5 mV/s. PMID- 22524014 TI - Effect of various shapes of ZnO nanoparticles on cotton fabric via electrospinning for UV-blocking. AB - Various shapes of ZnO; multi-petals, rod and spherical were prepared and then applied on cotton fabric for UV-blocking. The ZnO particles were investigated by XRD and SEM. The mixture solution of ZnO with polyvinyl alcohol was applied onto cotton fabrics via electrospinning. The characteristics of the fabric coating were investigated by SEM, XRD, Tensile testing and Atomic absorption spectroscopy (AAS). UV-blocking property was determined by UV-vis spectrophotometer. The results of XRD and SEM on the ZnO powders show that we can produce various shape of ZnO. The investigation by SEM and AAS clearly revealed that ZnO in polyvinyl alcohol nanofibers was effectively deposited on the cotton surface. The sphericals-shaped ZnO coated fabrics show excellent UV-blocking properties. The shape of ZnO shows no considerable effect on the tensile strength of the samples. PMID- 22524015 TI - Effect of precursor supply on structural and morphological characteristics of fe nanomaterials synthesized via chemical vapor condensation method. AB - Various physical, chemical and mechanical methods, such as inert gas condensation, chemical vapor condensation, sol-gel, pulsed wire evaporation, evaporation technique, and mechanical alloying, have been used to synthesize nanoparticles. Among them, chemical vapor condensation (CVC) has the benefit of its applicability to almost all materials because a wide range of precursors are available for large-scale production with a non-agglomerated state. In this work, Fe nanoparticles and nanowires were synthesized by chemical vapor condensation method using iron pentacarbonyl (Fe(CO)5) as the precursor. The effect of processing parameters on the microstructure, size and morphology of Fe nanoparticles and nanowires were studied. In particular, we investigated close correlation of size and morphology of Fe nanoparticles and nanowires with atomic quantity of inflow precursor into the electric furnace as the quantitative analysis. The atomic quantity was calculated by Boyle's ideal gas law. The Fe nanoparticles and nanowires with various diameter and morphology have successfully been synthesized by the chemical vapor condensation method. PMID- 22524016 TI - Aqueous phase synthesized CdSe magic-sized clusters: solution composition dependence of adsorption layer structure. AB - We report dispersion solution composition dependence of the adsorption layer structure and the physical and optical properties of aqueous phase-synthesized semiconductor nanoparticles (NPs). We synthesized cysteine (Cys)-capped CdSe NPs with well-defined core structures, dispersed them in a series of aqueous solutions with different compositions, and then investigated their adsorption layer structure and physical and optical properties. Each CdSe NP consisted of a (CdSe)33 or (CdSe)34 magic-sized cluster (d - 1.45 nm) core, a ligand-Cys shell, and an adsorption layer. The dispersion solution composition strongly affected the adsorption layer structure of the CdSe NPs. The solution with a composition close to that of the as-prepared solution stabilized the physical and optical properties of the NPs. The solution with a composition different from that of the as-prepared solution, however, resulted in large changes in their adsorption layer structure and thus their physical and optical properties. The solution composed of neutral or weakly charged Cys and Cd-Cys complexes led to the adsorption layer with low charge density and that destabilized the NPs. The solution containing only neutral or weakly charged forms of Cys, without Cd-Cys complexes, was favorable to the formation of a thick adsorption layer with low charge density and that destabilized the NPs. The amount of adsorbed Cys in the adsorption layer depended on the dispersion solution composition. However, the amount of adsorbed Cd-Cys complexes in the adsorption layer was almost constant regardless of the dispersion solution composition. PMID- 22524017 TI - Laser detection of electrical service safety in a single ZnO nanowire. AB - The electrically induced quenching of the photoluminescence (PL) intensity and fracture in a single ZnO nanowire were investigated. As the applied voltage increases, the quenching of PL intensity and the red-shift of ultraviolet (UV) emission peak were clearly observed, which are explained by the current-induced Joule heating in the ZnO nanowire. By using this mechanism, the UV laser was successfully used to monitor the safe current density and identify the current induced fracture in a single ZnO nanowire. PMID- 22524018 TI - Control of swelling height of Si crystal by irradiating Ar beam. AB - It has been found that ion implantation can induce a swelling (step-height) phenomenon on crystal surface. In this paper, we studied about the control of swelling height of Si crystal by irradiating Ar beam under various parameters (fluence, charge and energy). These irradiation parameters were regulated by an irradiation facility that enables to achieve the multiple ionization. For both charges, the swelling height was studied with the various fluencies of two different charges Ar(1+) and Ar(4+). The swelling height increased with increasing the fluence. The swelling height was also studied by changing energy of Ar(4+) beam. The swelling height increased by increasing the energy. The obtained swelling heights are understood base on the contribution of ion-beam induced defect, which is evaluated by SRIM. By comparing with the previous results, it was found that the expansion phenomena also depend on irradiated ion. The swelling structures were found to be stable more than two months. The present results have shown that this method of producing swelling structure indicates the potential application to fabricate 3-D nanostructure. PMID- 22524019 TI - Unique ordered domains of biphenylthiol self-assembled monolayers on Au(111). AB - The surface structure and adsorption conditions of biphenylthiol (BPT) self assembled monolayers (SAMs) on Au(111) were examined using scanning tunneling microscopy (STM) and X-ray photoelectron microscopy (XPS). STM imaging revealed that the structural order of BPT SAMs formed in a 0.01 mM ethanol solution at 60 degrees C decreases with increasing immersion time. Interestingly, BPT SAMs formed after 30 min have unique ordered domains containing well-ordered (square root of 3 x square root of 3)R30 degrees structures and bright rows that are connected by small aggregated domains with a periodicity of approximately 10 angstroms, results that have never been observed for other thiol SAM systems. Distances between the bright rows were 20-35 angstroms. The bright small domains contained five or six BPT molecules each, which may have originated from differences in the adsorption orientations of biphenyl groups that were induced by localized interactions between them. XPS measurements for BPT SAMs on Au(111) showed the two sulfur peaks at 161.2 and 162.2 eV, implying the formation of chemisorbed monolayers. Our results are anticipated to be useful for understanding the formation and structure of BPT SAMs on gold surfaces. PMID- 22524020 TI - Quartz crystal microbalance sensor using ionophore for ammonium ion detection. AB - Ionophore-based quartz crystal microbalance (QCM) ammonium ion sensors with a detection limit for ammonium ion concentrations as low as 2.2 microM were fabricated. Ionophores are molecules, which selectively bind a particular ion. In this study, one of the known ionophores for ammonium, nonactin, was used to detect ammonium ions for environmental in-situ monitoring of aquarium water for the first time. To fabricate the sensing films, poly(vinyl chloride) was used as the matrix for the immobilization of nonactin. Furthermore, the anionic additive, tetrakis (4-chlorophenyl) borate potassium salt and the plasticizer dioctyl sebacate were used to enhance the sensor properties. The sensor allowed detecting ammonium ions not only in static solution, but also in flowing water. The sensor showed a nearly linear response with the increase of the ammonium ion concentration. The QCM resonance frequency increased with the increase of ammonium ion concentration, suggesting a decreasing weight of the sensing film. The detailed response mechanism could not be verified yet. However, from the results obtained when using a different plasticizer, nitrophenyl octyl ether, it is considered that this effect is caused by the release of water molecules. Consequently, the newly fabricated sensor detects ammonium ions by discharge of water. It shows high selectivity over potassium and sodium ions. We conclude that the newly fabricated sensor can be applied for detecting ammonium ions in aquarium water, since it allows measuring low ammonium ion concentrations. This sensor will be usable for water quality monitoring and controlling. PMID- 22524021 TI - Fabrication of Langmuir-Blodgett films using amphiphilic peptides. AB - To introduce self-organization ability of transmembrane proteins into Langmuir (L) and Langmuir-Blodgett (LB) techniques, we focused on "amphiphilic peptide" (AP) which is composed of two distinct hydrophilic and hydrophobic domains. Three types of APs of different average hydropathies were used to prepare the AP/lipid mixed L and LB films. According to the circular dichroism spectra, the secondary structures of APs were not uniform but were a mixture of alpha-helix, beta-strand and random coil. The fraction of alpha-helix was higher for lower hydropathy AP. The interaction between AP and lipid in the L film and the structure of the LB film were also depended on the APs used. PMID- 22524023 TI - Fabrication of arrayed Si nanowire-based nano-floating gate memory devices on flexible plastics. AB - Arrayed Si nanowire (NW)-based nano-floating gate memory (NFGM) devices with Pt nanoparticles (NPs) embedded in Al2O3 gate layers are successfully constructed on flexible plastics by top-down approaches. Ten arrayed Si NW-based NFGM devices are positioned on the first level. Cross-linked poly-4-vinylphenol (PVP) layers are spin-coated on them as isolation layers between the first and second level, and another ten devices are stacked on the cross-linked PVP isolation layers. The electrical characteristics of the representative Si NW-based NFGM devices on the first and second levels exhibit threshold voltage shifts, indicating the trapping and detrapping of electrons in their NPs nodes. They have an average threshold voltage shift of 2.5 V with good retention times of more than 5 x 10(4) s. Moreover, most of the devices successfully retain their electrical characteristics after about one thousand bending cycles. These well-arrayed and stacked Si NW-based NFGM devices demonstrate the potential of nanowire-based devices for large-scale integration. PMID- 22524022 TI - Composition dependence of magnetocaloric effect in Pr0.6Ca0.4Mn(1-x)Cr(x)O3 (x = 0.02-0.08). AB - We report the effect of varying Cr content on magnetic and magnetocaloric properties of Pr0.6Ca0.4Mn(1-x)Cr(x)O3 samples (x = 0, 0.02, 0.04, 0.06 and 0.08). While the parent compound (x = 0) is a charge ordered and antiferromagnetic insulator, Cr doped compounds are ferromagnetic metals with nearly same Curie temperature (T(c) approximately 140 K). We find unusual field induced meta-magnetic transition above T(c) in x = 0.02 and 0.04 which is absent in x = 0.06 and 0.08. It is suggested that the paramagnetic phase in these compounds is inhomogeneous with coexistence of nano-size ferromagnetic clusters and short range charge ordered clusters. Field induced growth of ferromagnetic nano-clusters and destruction of short-range charge ordering leads to the observed metamagnetic transition, which results in large magnetic entropy change of -deltaS(M) = 5.043, 6, 5.509 and 4.375 J/kg K under deltaH = 5 T, for x = 0.02, 0.04, 0.06 and 0.08, respectively. In addition, large relative cooling power (RCP) found in these materials (327.384, 286.36, 272.22 and 279.936 J/kg) makes it interesting for practical applications. Our study suggests that creation of ferromagnetic nano-clusters in the paramagnetic phase by Mn-site doping in charge ordered compounds provides an alternative approach to achieve high AS(M) and RCP values. PMID- 22524024 TI - Photochemical production of hydrogen from water using microporous porphyrin coordination lattices. AB - In this study, we investigated the photochemical production of hydrogen from water using bio-inspired heterogeneous microporous porphyrin coordination lattices (PCLs), [Ru2(MTCPP)BF4] (M = H2 (PCL-1), Zn (PCL-2); TCPP = Tetrakis(4 carboxyphenyl)porphyrin), under visible (380 nm <) and UV (320 nm <) light irradiations. In the presence of Na2EDTA (as a sacrificial donor) and MV2+ (methyl-vilologen; as a electron relay), PCLs exhibits photocatalytic activity for hydrogen evolution; the maximum amounts of turnover numbers (TONs) of PCL-1 and PCL-2 at 24 h irradiation were 20.8 and 29.9, respectively. In the catalytic reactions, the relation between PCLs and MV2+ was similar to the relation between a [cytochrome c3 hydrogenase] pair and lysine residues in enzymatic reactions. By using the hydrogen production rate and the MV+ (methyl-vilologen radical-cation) concentration, kinetic parameters such as affinities between MV+ and PCLs, maximum reaction rate, and total efficiency of the reaction are introduced using the Michaelis-Menten equation. These parameters indicated that PCLs are good artificial enzyme model catalysts. The stability of the PCLs after the catalytic reactions was confirmed by X-ray photoelectron spectroscopy and Fourier transform infrared spectra. These results indicated that the frameworks of PCLs are stable for this catalytic reaction. PMID- 22524025 TI - Polycrystalline silicon films with nanometer-sized dense fine grains formed by flash-lamp-induced crystallization. AB - Flash lamp annealing (FLA) with millisecond-order pulse duration can crystallize microm-order-thick a-Si films on glass substrates through explosive crystallization (EC), and flash-lamp-crystallized (FLC) poly-Si films consist of densely-packed nanometer-sized fine grains. We investigate the impact of the hydrogen concentration and the defect density of precursor a-Si films on crystallization mechanism and the microstructures of FLC poly-Si films, by comparing chemical-vapor-deposited (CVD) and sputtered precursor a-Si films. Transmission electron microscopy (TEM) observation reveals that FLC poly-Si films with similar periodic microstructures are formed by the FLA of the two kinds of precursor films, meaning no significant influence of hydrogen atoms and defect density on crystallization mechanism. This high flexibility of the properties of precursor a-Si films would contribute to a wide process window to reproducibly form FLC poly-Si films with the particular periodic microstructures. PMID- 22524026 TI - Non-catalytic facile synthesis of superhard phase of boron carbide (B13C2) nanoflakes and nanoparticles. AB - Boron Carbide is one the hardest and lightest material that is also relatively easier to synthesis as compared to other superhard ceramics like cubic boron nitride and diamond. However, the brittle nature of monolithic advanced ceramics material hinders its use in various engineering applications. Thus, strategies that can toughen the material are of fundamental and technological importance. One approach is to use nanostructure materials as building blocks, and organize them into a complex hierarchical structure, which could potentially enhance its mechanical properties to exceed that of the monolithic form. In this paper, we demonstrated a simple approach to synthesize one- and two-dimension nanostructure boron carbide by simply changing the mixing ratio of the initial compound to influence the saturation condition of the process at a relatively low temperature of 1500 degrees C with no catalyst involved in the growing process. Characterization of the resulting nano-structures shows B13C2, which is a superhard phase of boron carbide as its hardness is almost twice as hard as the commonly known B4C. Using ab-initio density functional theory study on the elastic properties of both B12C3 and B13C2, the high hardness of B13C2 is consistent to our calculation results, where bulk modulus of B13C2 is higher than that of B4C. High resolution transmission electron microscopy of the nanoflakes also reveals high density of twinning defects which could potentially inhibit the crack propagation, leading to toughening of the materials. PMID- 22524027 TI - Sub-micrometer particles produced by a low-powered AC electric arc in liquids. AB - The article presents the report of the production of composites of sub-micrometer metal particles in matrix consisted of the metal compounds by means of an AC electric arc in water and paraffin solutions using electrodes carbon-metal and metal-metal (metal: Ni, Fe, Co, Cu). The advantage of this method is the low electric power (from 5 to 10 W) needed in comparison to standard DC arc-discharge methods (0.8 to 3 kW). This method enables the production of particles from conductive material also in wide range of temperature and in solvent which could be either transparent to light or opaque. Moreover the solvent can be electrolyte or insulating liquid. The microstructure of the composite layer was investigated by scanning electron microscopy (SEM), Electron Probe Microanalysis (EPMA) and X ray. During particles production in water metal oxides were created. Additionally using cobalt-copper, nickel-copper as couple electrodes, insoluble in water copper (II) hydroxide crystal grains were created additionally which crystals shape was depended on transition metal. For iron-copper couple electrodes system the copper (II) hydroxide was not formed. Experiments with sequence production of Ni and Fe particles with C electrode assisting in molten paraffin let to obtain both Ni and Fe particles surrounded by paraffin. After solidification the material was insulator but if locally magnetic field influenced on the liquid solution in that place after solidification a new composite was created which was electric current conductor with resistivity around 0.1 omega x m, was attracted by magnetic field and presented magneto resistance around 0.4% in changing magnetic field in a range 150 mT. After mixing the concentrated paraffin with normal paraffin resistivity of the mixture increased and it became photosensitive and created small voltage under light influence. PMID- 22524028 TI - Synthesis and size characterization of silica nanospheres using sedimentation field-flow fractionation (SdFFF). AB - Silica nanoparticles were synthesized by a conventional emulsion polymerization by mixing ethanol, ammonium hydroxide, water and tetra ethyl orthosilicate (TEOS). A new reaction apparatus was assembled for a large scale synthesis of silica nanospheres in the laboratory, which was designed for uniform mixing of the reactants. The apparatus was equipped with a disc type agitator with six rectangular propellers. The new apparatus allowed high reproducibility in terms of the mean size and the size distribution of the silica nanoparticles with the relative standard deviation of less than about 6%. Sedimentation field-flow fractionation (SdFFF) was employed for determination of the size distribution of the silica nanoparticles. SdFFF provided size-based separation of the silica nanoparticles, with the retention time increasing with the size. When SdFFF analysis was repeated three times for the same sample, the standard deviation was less than 4%, showing reliability of SdFFF in size measurement. SdFFF seems to provide more accurate size distribution than DLS, particularly for those having broad and multimodal size distributions. Change in the agitation speed resulted in significant change in the mean diameter of the silica nanoparticles. Agitation speed of 400 rpm in 3 L reaction vessel yielded silica particles of about 100 nm in diameter, while at 200 rpm in 1 L vessel yielded those of about 500 nm. PMID- 22524029 TI - Simple and efficient biomimetic synthesis of Mn3O4 hierarchical structures and their application in water treatment. AB - Biotemplate synthesis of functional materials is interesting owing to low cost, high yield and easy way of preparation. Recently, we have developed a simple and cost effective biomimetic synthesis of hierarchical network like nanostructures of manganese oxide (Mn3O4). Readily available eggshell membrane with nucleating and capping sites were used as a template in our synthesis. The prepared material was characterized using scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy dispersive X-ray (EDX) analysis and X-ray Diffraction (XRD). The surface area was calculated using the Brunauer-Emmett-Teller (BET) theory, and pore size distribution was obtained by Barrett-Joyner-Helenda (BJH) method. The prepared Mn3O4 showed good ability to remove organic pollutants from water and expected to be useful in effluent treatment in textile industry. PMID- 22524030 TI - Efficiency improvement of organic solar cells by tuning hole transport layer with germanium oxide. AB - Improving optical property is critical for optimizing the power conversion efficiency of organic solar cells. In the present research, we show that modification of poly(3,4-ethylenedioxythiophene): poly(styrenesulfonate) (PEDOT:PSS) layer with GeO2 leads to 15% improvement of power conversion efficiency in a polymer solar cells through enhancement of short circuit currents. Modified PEDOT:PSS layer with optimized concentration of GeO2 assists active layer absorbing much light by playing a role of optical spacer. Using AFM and grazing incidence X-ray diffraction (GIXD) data, we also present the evidence that an addition of GeO2 does not affect crystallinity of active layer. PMID- 22524031 TI - Effect of Zn addition on non-resonant third-order optical nonlinearity of the Cu doped germano-silicate optical glass fiber. AB - Cu/Zn-codoped germano-silicate optical glass fiber was manufactured by using the modified chemical vapor deposition (MCVD) process and solution doping process. To investigate the reduction effect of Zn addition on Cu metal formation in the core of the Cu/Zn-codoped germano-silicate optical glass fiber, the optical absorption property and the non-resonant third-order optical nonlinearity were measured. Absorption peaks at 435 nm and 469 nm in the Cu/Zn-codoped germano-silicate optical glass fiber were contributed to Cu metal particles and ZnO semiconductor particles, respectively. The effective non-resonant optical nonlinearity, gamma, of the Cu/Zn-codoped germano-silicate optical glass fiber was measured to be 1.5097 W(-1) x km(-1) by using the continuous-wave self-phase modulation method. The gamma of the Cu/Zn-codoped germano-silicate optical glass fiber was about four times larger than that of the reference germano-silicate optical glass fiber without any dopants. The increase of the effective non-resonant optical nonlinearity, gamma, of the Cu/Zn-codoped germano-silicate optical glass fiber, can be attributed to the enhanced nonlinear polarization due to incorporated ZnO semiconductor particles and Cu metal ions in the glass network. The Cu/Zn-codoped germano-silicate optical glass fiber showed high nonlinearity and low transmission loss at the optical communication wavelength, which makes it suitable for high-speed-high-capacity optical communication systems. PMID- 22524032 TI - Facile control of DNA-templated inorganic nanoshell size. AB - We elaborated a facile method to control the size of CdS nanoshells obtained by DNA assisted "double templating" approach. By changing the concentration of NaCl in solution to vary the extent of DNA electrostatic deposition on cationic silica beads, we succeeded to control the density of DNA adsorbed on the beads, and further the density of CdS material grown on DNA. Further dissolution of the silica core triggers shrinking of CdS shell to a different extent depending on the CdS shell density and results in formation of CdS nanoshells of different sizes from ca. 100 nm to ca. 400 nm. Therefore, the main advantage of the proposed method is that it can be used to synthesize hollow nanoshells of various sizes, from ca. 25% to ca. 75% size of the primary template (silica bead), by using only one single primary template. PMID- 22524033 TI - Coating of diamond-like carbon nanofilm on alumina by microwave plasma enhanced chemical vapor deposition process. AB - Diamond-like carbon (DLC) nanofilms with thickness varied from under one hundred to a few hundred nanometers have been successfully deposited on alumina substrates by microwave plasma enhanced chemical vapor deposition (MW-PECVD) process. To obtain dense continuous DLC nanofilm coating over the entire sample surface, alumina substrates were pre-treated to enhance the nucleation density. Raman spectra of DLC films on samples showed distinct diamond peak at around 1332 cm(-1), and the broad band of amorphous carbon phase at around 1550 cm(-1). Full width at half maximum height (FWHM) values indicated good formation of diamond phase in all films. The result of nano-indentation test show that the hardness of alumina samples increase from 7.3 +/- 2.0 GPa in uncoated samples to 15.8 +/- 4.5 52.2 +/- 2.1 GPa in samples coated with DLC depending on the process conditions. It is observed that the hardness values are still in good range although the thickness of the films is less than a hundred nanometer. PMID- 22524034 TI - Reversible dispersion and aggregation of Ag2S nanoparticles capped with azobenzene-derivatized alkanethiols. AB - Ag2S nanoparticles (NPs) of 3.1 +/- 0.6, 8.1 +/- 1.0, and 10.2 +/- 1.6 nm in diameter capped with a long-chain amidoamine derivative (C18AA) were synthesized by a modified Brust method. Ag2S NPs capped with two types of azobenzene derivatized alkanethiol differing in chain length (2AM10SH and 8AM5SH) were obtained by the ligand exchange method. The trans to cis photoisomerization conversion of 2AM10SH and 8AM5SH on Ag2S NPs dispersed in toluene was above 95%. 2AM10SH-capped Ag2S NPs of 8.1 nm or more in toluene were found to show reversible dispersion-aggregation behavior under alternating irradiation with UV and visible lights, i.e., Ag2S NPs capped with trans- and cis-2AM10SH were in dispersed and aggregated states, respectively. However, Ag2S NPs of 3.1 nm capped with 2AM10SH and Ag2S NPs of 8.1 nm capped with 8AM5SH were always in a dispersed state regardless of whether 2AM10SH and 8AM5SH were in the trans or cis conformation. PMID- 22524035 TI - Preparation of Mo/Cu(In, Ga)Se2 thin films by one-step sputtering. AB - An attempt was made for preparing CIGS absorber layers by one-step sputtering of a quaternary target for eventual use such as large area CIGS solar cells. For fabricating the layers, a single quaternary target with pre-determined compositions of the constituents, Cu, In, Ga and Se was employed and the in-situ and post-annealing by RTP were performed. Then the layers were characterized by SEM, AFM, XPS, XRD and EDX. Indeed, the CIGS absorber layers with chalcopyrite structure could be successfully obtained. In addition, it was found that the very smooth surfaces could be obtained since the deposition was conducted by single step sputtering. The present work shows that the one-step sputtering method can be a potential route for the economic preparation of CIGS absorber layers. PMID- 22524036 TI - Properties of dye-sensitized solar cells with TiO2 passivating layers prepared by electron-beam evaporation. AB - The aim of this work is to prevent back transfer of electrons due to direct contact between the electrolyte and the FTO glass substrate using a TiO2 passivating layer. The TiO2 passivating layer was deposited on FTO glass by e beam evaporation. The TiO2 film was prepared with different deposition rates. The specific surface area was reduced with increasing deposition rate. The nanoporous TiO2 upper layer was coated by screen-printing on the TiO2 passivating layer prepared by e-beam evaporation. The optical transmittance and absorbance of the TiO2 films depend on the morphology of the TiO2 passivating layer. The dye sensitized solar cells influenced the surface morphology of the TiO2 passivating layer. The dye-sensitized solar cell using the TiO2 passivating layer recorded a maximum conversion efficiency of 4.93% due to effective prevention of the electron recombination to the electrolyte. PMID- 22524037 TI - The new iridium complexes involving pyridylpyridine derivatives for the saturated blue emission. AB - To obtain a saturated blue phosphorescent material with a good color purity, we have synthesized the new blue emitting iridium complexes with 2, 6-difluoro-3-(4 methylpyridin-2-yl)pyridine (4-Me-dfpypy) as a main ligand. We expected that the LUMO energy levels of the complex might increase upon introduction of an electron donating group such as a methyl group to the pyridyl moieties of the ligand, leading to a wide energy gap of the complex to give the saturated blue emission. We have also introduced a variety of the ancillary ligands to the iridium center to compare the effect of the ancillary ligards on the emission of their complexes. The resulting iridium complexes, Ir(4-Me-dfpypy)3, Ir(4-Me dfpypy)2(acac), Ir(4-Me-dfpypy)2(pic) and Ir(4-Me-dfpypy)2(trzl-CH3) where acac, pic, and trzl-CH3 represent acetylacetonate, picolinate, and 2-(5-methyl-2H-1,2,4 triazol-3-yl) pyridinate, respectively exhibited the blue emission at 451, 447, 440 and 425 nm in CH2Cl2 solution. The organic light emitting device (OLED) employing homoleptic Ir(4-Me-dfpypy), as the blue dopant was prepared and their electroluminescence was investigated. Ir(4-Me-dfpypy)3 exhibited the blue emission of CIE coordinates (0.22, 0.32). PMID- 22524038 TI - Deformation of carbon nanotubes colliding with a silicon surface and its dependence on temperature. AB - Using molecular dynamics simulation, we investigated the carbon nanotubes (CNTs) colliding with a silicon surface at a speed of 600 m/s, mimicking cold spray experiments of CNTs. Depending on temperature (300-900 K), the CNT is deposited on or bounces off the surface after impact on the surface. The CNT was more deformed as its temperature rose. The deformation of CNT was maximal for the collision geometry where the long axis of CNT lies parallel to the surface plane. However, its vibrational energy was maximal when the CNT collided with its long axis perpendicular to the surface. PMID- 22524039 TI - Thickness dependence of ferroelectricity in Langmuir-Blodgett multilayer films of hemicyanine dyes. AB - The thickness dependence of ferroelectricity in hemicyanine Langmuir-Boldgett multilayer films was reported in this paper. By the observed ferroelectric hysteresis loop, it was found that the coercive field decreased with increasing of film thickness monotonously and may be approximated by a power law Ec infinity N(-4/3) in the range from 30 to 200 nm, which is consistent with other conventional ferroelectric materials. The measurement of dielectric properties give the optimum thickness about 60 nm of hemicyanine LB films and their optimum value as ferroelectric storage-devices has the same order of magnitude as copolymer's P(VDF-TrFE) (70:30 mol%). PMID- 22524040 TI - Electrochemical properties of composite electrolytes based on poly(ethylene oxide)/poly(ethylene imine) containing the inorganic silica fillers. AB - In this study, poly(ethylene oxide) (PEO) and poly(ethylene imine) (PEI) polymer blends containing inorganic silica fillers were studied in order to enhance the ion conductivity and interfacial properties. Lithium perchlorate (LiCIO4) as a salt, and silica (SiO2) as the inorganic filler were introduced in the polymer electrolyte composites and were examined to evaluate their use to improve the ionic conductivity. The addition of inorganic fillers in polymer electrolytes has resulted in high ionic conductivity at a room temperature. The structure and morphology of the solid polymer electrolytes were evaluated using X-ray diffraction (XRD) and scanning electron microscope (SEM). The ionic conductivity was measured by an AC impedance method. The enhanced conductivity was dependent on the decreased crystallinity and more heterogeneous morphologies. PMID- 22524041 TI - Dynamin II involves in cell migration and actin formation of NIH3T3 cells. AB - It was previously reported that in Ras transformed NIH3T3 cells, dynamin II acts as an intermediate messenger in the Ras signal transduction pathway leading to membrane ruffling and cell migration. However, these results do not provide sufficient evidence of a relationship between dynamin II and the Ras signal transduction pathway leading to membrane ruffling and cell migration. The results showed that a dynamin II association with myosin II as a signaling molecule is involved in NIH3T3 cell migration through the Ras/PI3K signaling pathway, and is associated with the p85 subunit of PI3K. Confocal microscopy also revealed co localization between dynamin II and paxillin after PDGF stimulation. In addition, immunofluorescence results showed that dynamin II was colocalized with the actin filament. After stimulating the NIH3T3 cells with PDGF and treating them with an actin inhibitor, such as Cytochalasin D, it was observed that dynamin II with the myosin II complex inhibited binding to the actin. Therefore, dynamin II is localized in focal adhesion when cell migration is triggered and binds to the actin filament component, suggesting that it is a good candidate nanomolecule to regulate the cell attachment and migration to the materials such as implants etc. PMID- 22524042 TI - Fabrication of metallic nanostructures of sub-20 nm with an optimized process of E-beam lithography and lift-off. AB - A process consisting of e-beam lithography and lift-off was optimized to fabricate metallic nanostructures. This optimized process successfully produced gold and aluminum nanostructures with features size less than 20 nm. These structures range from simple parallel lines to complex photonic structures. Optical properties of gold split ring resonators (SRRs) were characterized with Raman spectroscopy. Surface-Enhanced Raman Scattering (SERS) on SRRs was observed with 4-mercaptopyridine (4-MPy) as molecular probe and greatly enhanced Raman scattering was observed. PMID- 22524043 TI - Biodistribution of aqueous suspensions of carbon nanotubes in mice and their biocompatibility. AB - In this study, we prepared two-types of water-dispersible carbon nanotubes (CNTs) and investigated their biodistribution in mice as well as bio-/cyto compatibility. After administration, their organs were excised at various post injection times, then observed using both optical and transmission electron microscopy (TEM). The color of the liver and lung markedly darkened, suggesting that administered CNTs reached these organs. By TEM observation, the CNTs were found in the liver and lung. They were observed even in the kidney and spleen, though their distributions in those organs were very low compared with that in liver and lung. Therefore, most of the administered CNTs would be accumulated in the liver or lung. However, the time profile of the body weight of CNT administered mice was close to that of control mice. In addition, we estimated the cytocompatibility of the water-dispersible CNTs for hepatocytes. According to a TNF-alpha assay of the cells cultured with CNTs, the expression level was almost the same as that of the control. These results suggested that the water dispersible CNTs have good bio-/cyto-compatibility under this condition. PMID- 22524044 TI - Carbon nanowires fabrications via top down approach. AB - Carbon nanowires are fabricated by the Langmuir Blodgett (LB) method via the top down approach on amorphous carbon. Thick a-C films (500 nm to 1 microm) have been successfully deposited after the treatment on silicon. The anisotropic etching of carbon using reactive ion etching (RIE) has been verified giving near vertical sidewalls. The LB method for depositing monolayer requires a hydrophilic surface. Plasma treatment is being performed on the silicon oxide hard mask to reduce the surface energy thereby making the surface from hydrophobic to hydrophilic. PS balls which are being deposited by LB method have one disadvantage which is the low adhesion of the PS ball to the silicon oxide surface. This adhesion is being improved by subjecting the PS ball to annealing which changes the shape and increase the contact area between the PS balls and the silicon oxide surface. As carbon and PS ball is vulnerable to oxygen plasma, a modified recipe of CF4:Ar was being used to etch the silicon oxide hard mask. There is almost little chemical reaction of the CF4 on carbon and PS ball. Carbon nanowires were successfully fabricated using polystyrene (PS) balls of diameter 450 nm. Through a series of steps, carbon nanowire of 500 nm in length and diameter approximately 250 nm can be produced. PMID- 22524045 TI - Gelation effect on the synthesis of high-aspect-ratio gold nanorods. AB - The growth process of high-aspect-ratio gold nanorods in gelled surfactant solution was studied. As for the application of gold nanorods, the surface plasmon is quite useful, whose absorption depends on their aspect ratio. Hence it is important to synthesize gold nanorods with favorable aspect ratio in high yield. For shorter nanorods (aspect ratio < -10), the synthesis and the growth mechanism have been studied well. For the longer nanorods (aspect ratio > -30), however, the growth mechanism has not yet been understood well, although it has been known that the high-aspect-ratio gold nanorods could be synthesized in high yield in gelled surfactant solution. In this paper, we studied the relationship between the growth process of high-aspect-ratio gold nanorods and the gelation of surfactant growth-solution. Small angle X-ray scattering (SAXS) revealed the microscopic feature of gelation as the structural transition of self-assembly of surfactant molecules from micellar to lamellar. These results will be helpful for better understanding on the growth mechanism of high-aspect-ratio gold nanorods. PMID- 22524046 TI - Preparation of poly(3-hexylthiophene)/[6,6]-phenyl-C61-butyric acid methyl ester Langmuir-Blodgett bulk hetero junctions on indium tin oxide. AB - Mono-layers of aggregated Poly(3-hexylthiophene) (P3HT) and [6,6]-phenyl-C61 butyric acid methyl ester (PCBM) molecules were obtained by using solutions of P3HT, PCBM and P3HT-PCBM mixture without stabilizers such as stearates in chloroform at an air-water interface. 1 to 10 cycle-lifted LB films of P3HT and PCBM were successfully transferred to cleaned bare indium-tin-oxide coated glass substrate by vertical lifting method excluding the first 1 to 2 cycle layer. The dependence of P3HT and PCBM film thickness on the transfer cycles has been explained by the molecular sizes, where four edge-on P3HT molecular and six PCBM molecular stacking which result in thickness was taken into account. Work functions of deposited LB-layers were consistent with those of the ordinary casted films. P3HT and PCBM LB-layers showed optical activity in both infra-red (IR) and visible absorption regions of the spectrum. P-polarized IR absorption owing to C=C and C=O stretching vibrations observed in LB-layered films clearly indicate the enhancement of the orientation of these bonds perpendicular to the substrate surface in contrast to the spin-coated one. Visible optical absorption intensity was increased well in proportion with the lift cycle-numbers of both P3HT and PCBM LB films. The photovoltaic characteristics have been observed in the devices fabricated with P3HT (5 cycles-layer)/PCBM (5 cycles-layer) LB hetero structure as an active layer of the solar cells. The surface pressure of LB compression for the mixture of P3HT and PCBM, that is, bulk hetero mixtures, has also been well built up to 30 mN/m. PMID- 22524047 TI - Synthesis of novel photoacid generator containing resist polymer for electron beam lithography. AB - Photoacid generators (PAGs) have been widely used as a key material in the development of novel photoresist materials. One of the important uses of PAGs is found in chemically amplified photoresists (CARs) because of their high photosensitivity and high resolution capability. Triphenylsulfonium salt methacrylate (TPSMA) as the PAG has been bounded in the main polymer backbone. TPSMA was employed for synthesis of terpolymers, poly(MMA-co-tBVPC-co-TPSMA) and poly(tBVPC-co-tBOCPOMI-co-TPSMA) as a positive tone photoresists by free radical polymerization using AIBN. Terpolymers with various ratio of TPSMA, MMA, tBVPC and tBOCOPMI were synthesized and well characterized by FTIR, NMR. Molecular weight distribution was analyzed by GPC. Thermal properties were studied using TGA, DSC which showed thermal stability of terpolymer up to 150 degrees C. We have applied E-beam lithography and KrF lithography in order to demonstrate the effect of the polymer bounded PAG resists. These positive tone resists were successfully applied for fabrication of nano-scale patterns. PMID- 22524048 TI - Crosslinkable nonlinear optical dendrimers synthesized by Diels-Alder reaction. AB - Crosslinkable NLO dendrimers based on azobenzene-type chromophores were synthesized by a Diels-Alder reaction. Their thermal and optical properties were investigated before and after poling at a high temperature. We found that the dendrimers retained good thermal stability up to 260 degrees C after curing at 130 degrees C for 10 min based on thermal analysis. Through in-situ poling and curing processes, the highest NLO activity of the dendrimers was d33 = 1.7 x 10( 6) esu at 1064 nm, which was determined by a Maker fringe experiment. PMID- 22524049 TI - Synthesis of Li(1+x)V3O8 by chemical route and its characterization. AB - Lithium trivanadate (Li(1+x)V3O8) nanorods have been synthesized by the simple polymer precursor route using the polymer, polyvinyl pyrrolidone (PVP) as the complexing agent. Thermal behavior of the precursor has been studied by the differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and differential thermal analysis (DTA) techniques. X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR) studies confirm the formation of the compound. High resolution scanning electron microscopy (HRSEM) analysis reveals the synthesized Li1.2V3O8 particles to be nanorods with an average diameter of 50 nm. PMID- 22524050 TI - Characterization of silver nanoparticle in the carboxymethyl cellulose hydrogel prepared by a gamma ray irradiation. AB - In this study, carboxymethyl cellulose (CMC) hydrogels were traditionally prepared by gamma-ray with an absorbed dose of 50 kGy from a 60Co source. The CMC hydrogels were absorbed and swelled in silver nitrate aqueous solution (0.01 M) by dipping for 1 hour, and then irradiated by gamma-ray at various doses to form silver nanoparticles (Ag NPs). The UV-Vis analysis indicated that the concentration of Ag NPs was enhanced by increasing of absorbed dose from 1 to 5 kGy in this situ reducing system. The FE-SEM and XPS measurements provided further evidence for the successful formation of Ag NPs. These CMC hydrogels stabilized Ag NPs also have been investigated for inhibiting the growth of Staphylococcus aureus and Escherichia coli strains in liquid as well as on solid growth media. The antibacterial tests indicated that the hydrogels containing Ag NPs have antibacterial activity. PMID- 22524051 TI - Surface nanomodification of cotton fiber for flame retardant application. AB - This paper presents efficient surface modification methodology to increase fire resistance properties of cotton by radio frequency (RF) plasma-induced graft copolymerization of vinyl phosphate ester as nanometer residue structure onto cotton surface. Methacryloyloxyethyl diphenyl phosphate (MEDP) monomer was synthesized and grafted onto the surface of cotton fabric by argon RF plasma at ambient temperature. Under optimum RF power (30 W), amounts of MEDP and N,N methylenebisacrylamide cross linking agent were varied to obtain optimum graft copolymerization conditions. Untreated and treated cotton were characterized by attenuated total reflectance infrared (ATR-IR) spectroscopy to investigate their functional group characteristics. This showed a strong covalent attachment between the surface of cotton and flame retardant material as the carbonyl functionality of the MEDP was clearly observed in the spectra. Scanning electron microscopic (SEM) analysis also showed grafted material as nanometer residue on cotton surface. Thermogravimetric analysis (TGA) revealed that the decomposition of phosphorus compound which occurs at lower temperature than the cotton itself resulted in the formation of char which covers cotton surface. This protects the fabric surface from further burning, therefore, higher amounts of remaining materials were observed as char in all cases. Furthermore, limiting oxygen index (LOI) had increased from 19 in untreated to 28 in grafted cotton. Detailed analysis on structural and thermal properties as well as surface grafting efficiency are presented. PMID- 22524052 TI - Fabrication of conducting poly(3-thiophene boronic acid)-grafted multi-walled carbon nanotubes by oxidative polymerization. AB - Composite materials of multi-walled carbon nanotubes (MWNTs) and a conducting polymer, poly(3-thiophene boronic acid) (PTBA) were prepared by in-situ oxidative polymerization of TBA in the presence of MWNTs and potassium dichromate. The MWNTs which were previously surface functionalized with acid chloride groups were reacted with TBA using a simple "chemical grafting" technique. It was observed that the nanotubes were dispersed uniformly in the pi-conjugated polymer matrix and entrapped by the polymer. The conductivity of the composites was higher than that of the pure polymer from a conventional four-probe technique, which indicates that the fabrication of MWNTs into the polymer matrix significantly improves the conductivity of the polymer due to the intrinsic properties of MWNTs. PMID- 22524053 TI - All solution processable organic photovoltaic cells using DMDCNQI as an organic N type buffer layer. AB - Organic photovoltaic cells consisting of ITO/PEDOT PSS/P3HT:PCBM/TiO(x)/DMDCNQI/Al have been fabricated by using dip-coated DMDCNQI layer as a cathode buffer material. We have investigated the physical effects of charge transfer complex and wettability of DMDCNQI between TiO(x)/P3HT:PCBM layer and Al cathode electrode on the performance of organic photovoltaic cell. The photovoltaic cell fabricated with a dip-coated DMDCNQI layer exhibited almost similar performance compared to the device using conventional evaporated DMDCNQI layer. Especially, the power conversion efficiency of the prepared organic photovoltaic cell using TiO(x)/DMDCNQI layer was improved to 3.1%, which is mainly due to the decrease in the low contact resistance of organic-metal interface. PMID- 22524054 TI - Detection of dopamine in dopaminergic cell using nanoparticles-based barcode DNA analysis. AB - Nanotechnology-based bio-barcode-amplification analysis may be an innovative approach to dopamine detection. In this study, we evaluated the efficacy of this bio-barcode DNA method in detecting dopamine from dopaminergic cells. Herein, a combination DNA barcode and bead-based immunoassay for neurotransmitter detection with PCR-like sensitivity is described. This method relies on magnetic nanoparticles with antibodies and nanoparticles that are encoded with DNA, and antibodies that can sandwich the target protein captured by the nanoparticle bound antibodies. The aggregate sandwich structures are magnetically separated from solution, and treated in order to remove the conjugated barcode DNA. The DNA barcodes were then identified via PCR analysis. The dopamine concentration in dopaminergic cells can be readily and rapidly detected via the bio-barcode assay method. The bio-barcode assay method is, therefore, a rapid and high-throughput screening tool for the detection of neurotransmitters such as dopamine. PMID- 22524055 TI - Coprecipitation synthesis and characterization of La0.8Sr0.2Ga(0.8 x)Mg0.2Co(x)O2.8 for intermediate temperature solid oxide fuel cell electrolytes. AB - La0.8Sr0.2Ga(0.8-x)Mg0.2CO(x)O2.8 (LSGMC) electrolyte powders containing different amount of Co (0 < or = x < or = 0.15) were prepared by ammonium carbonate coprecipitation method. The precursors, the calcined powders, and the sintered pellets were characterized by thermogravimetry/differential thermal analysis, X-ray diffractometry, scanning electron microscopy, and an impedance analyzer. The thermal decomposition of the LSGMC precursors was completed at around 900 degrees C with the total weight loss of approximately 35%. The LSGMC samples sintered at 1350 degrees C consisted of the pure perovskite structure. The ionic conductivity was significantly improved by Co doping for the Ga-site of the La0.8Sr0.2Ga0.8Mg0.2O2.8 (LSGM) electrolytes. The ionic conductivity of LSGMC (x = 0.1) exhibited the highest values of 1.6 x 10(-1) S cm(-1) at 700 degrees C with an activation energy for the oxide-ion conduction of 0.29 eV. The results of this study indicated that the Co-doped LSGM electrolytes had excellent properties for use as an electrolyte in an IT-SOFC and the ammonium carbonate coprecipitation process could be employed as the efficient method for the preparation of the Co-doped LSGM electrolytes. PMID- 22524056 TI - Study on the electron emission properties of ZnO nanorod arrays on different substrates. AB - Large area well-aligned ZnO nanorod arrays on different substrates were synthesized by hydrothermal methods. The electron emission properties of the ZnO nanorod arrays on different substrates were investigated under both direct current (DC) and pulse electric fields. Owing to the excellent conductivity of substrates, the array on stainless steel substrate had better electron emission properties than that on silicon substrate. Under the DC and pulse electric fields, the electron emission of arrays had different production mechanisms which were pure field emission and plasma-induced emission respectively. During the plasma-induced emission, the plasma formed on the array surface, and the maximum emission current density of arrays on stainless steel was 118.87 A/cm2. The plasma-induced emission of ZnO nanorod arrays were always distributed uniformly. In this work, the results show that the ZnO nanorod arrays are expected to be applied to different electronic devices as electron beam sources under different electric fields. PMID- 22524057 TI - Synthesis and characterization of poly(lactic acid)/ montmorillonite nanocomposites by in situ polycondensation catalyzed by non-metal-based compound. AB - Poly(lactic acid)/montmorillonite nanocomposites were prepared by using non-toxic catalysts, i.e., phthalic acid and succinimide, via in situ polycondensation in presence of silicate. Concentrations of catalysts and clay were varied in a range of 0-3% wt and 0-0.5% wt, respectively. The reaction condition was controlled at 180 degrees C for 24 hr under a reduced pressure. Viscosity average molecular weight of the synthesized polymers and nanocomposites were characterized and compared using an Ubbelohde viscometer. Pattern of silicate distribution in the composites was investigated by X-ray diffraction to correlate with thermal properties evaluated by differential scanning calorimetry and thermogravimetric analysis. The results showed that the addition of catalysts at 2% wt gave the highest product yield (55-60%). The presence of silicate affected on molecular weight reduction, and the diffracted patterns suggested an intercalated structure. With a small amount of added filler, a significant improvement in thermal property and crystallinity of the resultant composites was obtained compared to those of the catalyzed polymers, in which the composites with succinimide exhibited overall better thermal stability and higher crystallinity than the ones prepared with phthalic acid. PMID- 22524058 TI - Cross-linking carbon nanotubes by glycidyl azide polymer via click chemistry. AB - Functionalization and cross linking of carbon nanotubes was necessary to fabricate nanotube composites with good interfacial properties and mechanical performance. Glycidyl azide polymer was used as cross-linker of carbon nanotubes via a simple clickable one step reaction initiated by decomposition of azide groups. Both heating and UV irradiation were used to carry out the reaction. FTIR and Raman spectra confirmed the decomposition of azide groups and the anchoring of glycidyl azide polymer onto the surface of carbon nanotubes. Thermal gravity analysis showed that the polymer anchored onto carbon nanotubes was about 10% of the total mass in the solid product, but the efficiency of the reaction was low. The result of tensile test using bulky paper infiltrated with 10% GAP showed that cross linking could bring forth a higher strength, about 4 times higher than the not cross linked. The success of cross linking carbon nanotubes by glycidyl azide polymer paves a new way to fabrication of ultra strong carbon nanotube composites. PMID- 22524059 TI - Cellulose acetate electrospun fiber mats for controlled release of silymarin. AB - In this research, the silymarin-loaded electrospun cellulose acetate (CA) fibers were prepared which containing silymarin in various amounts (i.e., 2.5-20 wt.% based on the weight of CA powder). Incorporation of silymarin in the neat CA solution did not affect the morphology of the resulting fibers, as both the neat and the silymarin-loaded CA fibers were smooth. The average diameters of silymarin-loaded CA fiber ranged between 550-900 nm. No presence of the silymarin aggregates of any kind was observed on the surfaces of these fibers, suggesting that the silymarin was encapsulated well within the fibers. These results were confirmed by lowering the glass transition temperature and the melting temperature of the silymarin-loaded electrospun CA fibers which is determined by DSC technique. The release characteristic of silymarin from the silymarin-loaded CA fiber mats was investigated by the total immersion in the solution of 1/1 phosphate buffer/methanol medium pH 7.4 at 37 degrees C. The silymarin release from the silymarin-loaded electrospun CA fiber mat is monotonously increased to reach the maximum value at 480 min. The maximum amount of silymarin released from these materials increases with the increasing of initial silymarin loading in the spinning CA solutions. Since no aggregation of silymarin was found on the surface of the silymarin-loaded fibers, the release of the silymarin from fiber mats was mainly by the diffusion. PMID- 22524060 TI - Characteristics of nano-sized yttria powder synthesized by a polyvinyl alcohol solution route at low temperature. AB - Nano-sized yttria (Y2O3) powders were successfully synthesized at a low temperature of 400 degrees C by a simple polymer solution route. PVA polymer, as an organic carrier, contributed to an atom-scale homogeneous precursor gel and it resulted in fully crystallized, nano-sized yttria powder with high specific surface area through the low temperature calcination. In this process, the content of PVA, calcination temperature and heating time affected the microstructure and crystallization behavior of the powders. The development of crystalline phase and the final particle size were strongly dependant on the oxidation reaction from the polymer burn-out step and the PVA content. In this paper, the PVA solution technique for the fabrication of nano-sized yttria powders is introduced. The effects of PVA content and holding time on the powder morphology and powder specific surface area are also studied. The characterization of the synthesized powders is examined by using XRD, DTA/TG, SEM, TEM and nitrogen gas adsorption. The yttria powder synthesized from the PVA content of 3:1 ratio and calcined at 400 degrees C had a crystallite size of about 20 nm or less with a high surface areas of 93.95-120.76 m2 g(-1). PMID- 22524061 TI - Controlling microstructure of three-dimensional scaffolds from regenerated silk fibroin by adjusting pH. AB - For tissue engineering, it is very important to design and control the pore architecture of three-dimensional (3D) polymeric scaffolds, which plays an important role in directing tissue formation and function. In this study, 3D porous silk fibroin scaffolds produced using a freeze drying technique were prepared at pHs ranging from 5 to 9. The effects of pH on the pore microstructure of the silk fibroin scaffold were examined by rheometry, FESEM and FTIR. Different pore structures were formed according to the pH of silk fibroin because silk fibroin exhibits water-like behavior under basic conditions and gel-like behavior under acidic conditions. PMID- 22524062 TI - Flexible bio-composites based on silks and celluloses. AB - Biomaterials have attracted worldwide attention due to the concerns regarding health and the environment. Silk, a natural protein produced by several species of insects, has been examined as a potential material for applications in many biotechnological and biomedical fields. However, regenerated silk fibroin has poor ductility and mechanical properties. Therefore, in this study, silk fibroin cellulose composite films were prepared in an aqueous system to increase the ductility of regenerated silk fibroin. The morphology of the silk fibroin cellulose composite film was observed by field emission scanning electron microscopy. The structure of the silk fibroin-cellulose composite films was examined by Fourier transform-infrared spectroscopy. The flexibility was analyzed using a bending test. PMID- 22524063 TI - Mesoporous inverse opal TiO2 film as light scattering layer for dye-sensitized solar cell. AB - The light harvesting efficiency of dye-sensitized solar cells was enhanced by using a scattering layer. Such as sphere type TiO2, inverse photonic crystal TiO2, hollow spherical TiO2. Among these materials, the TiO2 with inverse photonic crystal (IPC) structure, synthesized by self-assembly using spherical templates, has attracted much attention due to their photonic crystal characteristics and light scattering effects. However, when applied in the DSSCs, the surface area of IPC is very low that caused insufficient adsorption amount of dye molecules. In the present work, a scattering layer with mesoporous inverse photonic crystal (MIPC) TiO2 film was fabricated by the sol-gel reactions with surfactant-assisted sol-gel method using poly(methyl methacrylate) as the template and titanium (IV) isopropoxide as the TiO2 precursor. After removing the PMMA and surfactant, a highly ordered macroporous structure with mesopores were successfully obtained. The surface area and total pore volume of the MIPC were 82 m2/g and 0.31 cm3/g, respectively, which is much larger than those of the IPC. The DSSCs with the scattering layer of MIPC film exhibited 18 and 10% higher photo-conversion efficiency than those of cells only with a nano-crystalline TiO2 film and with scattering layer of IPC film. From UV-visible spectra of dye solutions, the MIPC film showed a higher amount of absorbed dye molecules than those of the reference and IPC films. Accordingly, an increase in the photo current density through abundant adsorption of the dye, coupled with inherent light scattering ability can improve overall photo-conversion efficiency. PMID- 22524064 TI - Formation of nano-phase hydroxyapatite film on TiO2 nano-network. AB - Nano- and micro-phase HA film formed on TiO2 nano-network surface by simple electrochemical treatment. The range of lateral pore size of the network specimen was about 10-120 nm on Ti surface by anodized in 5 M NaOH solution at 0.3 A for 10 min. Nano-network TiO2 surface were formed by this anodization step which acted as templates and anchorage for growth of the HA during subsequent pulsed electrochemical deposition process at 85 degrees C. The phase and morphologies of deposits HA were influenced by the electrolyte concentration. The nano needle like precipitates formed under low SBF concentration were identified to be HA crystals orientated parallel to the c-axis direction. Increasing electrolyte concentration, needle-like deposits transferred to the plate-like and micro plate like precipitates in the case of high SBF concentration. PMID- 22524065 TI - TiO2-V2O5 nanocomposites as alternative energy storage substances for photocatalysts. AB - TiO2-V2O5 was prepared and evaluated as an energy storage material for photocatalysts with high capacity and initial charging rate. The compound was successfully obtained by sol-gel technique and effects of compound composition and calcination temperature on the energy storage ability were investigated. The synthesized compounds were characterized by means of X-ray powder diffraction (XRD), scanning electron microscopy equipped with energy-dispersive X-ray analysis (SEM-EDX) and transmission electron microscopy (TEM). The results reveals that the compound of Ti:V molar ratio equal to 1:0.11 calcined at 550 degrees C exhibited superior energy storage ability than parent substances and 1.7-times higher capacity and 2.3-times higher initial charging rate compared to WO3, indicating that the compound is a remarkable alternative to conventional energy storage substances. PMID- 22524066 TI - Fabrication of stem cell chip with peptide nanopatterned layer to detect cytotoxicity of environmental toxicants. AB - A stem cell chip with peptide nanopatterned layer was fabricated to detect the effects of environmental toxins on human neural stem cells (HB1 x F3) electrochemically. The cell chip was recently developed as in vitro monitoring tool for determining the cell viability simply and rapidly compared to the conventional methods. However, cell chip composed of neural stem cells have not been reported due to the difficulties for maintaining its stemness and cell attachment on the artificial electrode surface, which is critical for sensitive detection of cell viability electrochemically. In this study, we fabricated peptide nanopatterned layer on gold electrode for increasing the affinity between the stem cell and an artificial electrode surface by self-assembly technique. After the confirmation of fabricated nanopatterned surface, neural stem cells were immobilized on chip surface and the viability was measured by electrochemical method. Thereafter, neural stem cells were treated with two kinds of common environmental toxins, and the intensities of reduction peak obtained by cyclic voltammetry (CV) were decreased with the increase of concentrations of environmental toxins. These electrochemical results were validated by 3-(4,5 Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Our newly developed stem cell chip can be used as useful label-free analysis tool for detecting drug effects or for assessing the toxicity electrochemically. PMID- 22524067 TI - Polymer brushes on carbon nanotubes by thiol-lactam initiated radical polymerization of 2-hydroxyethyl methacrylate. AB - Water-soluble polymer brushes with multi-walled carbon nanotubes (MWNTs) as backbones were synthesized by grafting 2-hydroxyethyl methacrylate (HEMA) from surface functionalized MWNTs via in situ surface thiol-lactam initiated radical polymerization. MWNTs were functionalized with 2-mercaptoethanol and used as initiators in the polymerization of HEMA in the presence of butyrolactam. FT-IR, XPS, 1H NMR, GPC and TGA were used to determine chemical structure and the grafted polymer quantities of the resulting product. The covalent bonding of PHEMA to the MWNTs dramatically improved the water dispersibility of MWNTs. The average thicknesses of the polymer brushes in the functionalized MWNTs were detected with electron microscopy (SEM and TEM) and images indicated that the nanotubes were coated with polymer layer. PMID- 22524068 TI - Collapse in binary phospholipid monolayers at the air/water interface. AB - The behavior in the stochastic collapse of lipid monolayers of a 7:3 mixture of DPPC (dipalmitoylphosphatidylcholine) and POPG (palmitoyloleoylphosphatidylglycerol), a model system of pulmonary surfactant assembly, was studied using Langmuir isotherms, fluorescence microscopy, and atomic force microscopy. The monolayers at the air-water interface appeared to be phase separated under compression and retained the continuous liquid-expanded phase network surrounding islands of condensed phase even at a surface pressure approaching 70 mN/m. When the two-dimensional monolayers were compressed beyond the equilibrium surface pressure, they collapsed and assumed a three-dimensional formation. Collapse events involved folding of the monolayer on a micron scale, and each event produced a macroscopic jerk of the layer. The distribution of waiting times between events was estimated to be an exponential function, indicating that the events were independent. Folded regions coexisted with the flat monolayer, remained attached to the interface, and reversibly reincorporated into the monolayer upon expansion. PMID- 22524069 TI - Liquid crystal sol containing oleophilic Pd nanoparticles for liquid crystal device. AB - We have succeeded in preparation of liquid crystal sol containing oleophilic Pd nanoparticles (NPs) stabilized by multidentate copolymer and fabrication of the twisted nematic liquid crystal devices (TN-LCDs) by using Pd NP-containing liquid crystal sol. Oleophilic Pd NPs were prepared by refluxing Pd acetate solution in toluene/ethanol containing poly(N-vinyl-2-pyroridone-co-styrene). Oleophilic Pd NPs showed better solubility in liquid crystal medium than poly(N-vinyl-2 pyrrolidone)-stabilized NPs. The TN-LCDs were fabricated by using two kinds of practical liquid crystal materials doped with oleophilic Pd NPs. The NP-doped LCD showed 22% faster response than non-doped one at -20 degrees C without a chiral dopant. However, LCDs fabricated by liquid crystal materials with a chiral dopant were not affected by NPs. These results suggest that the effect of NPs on the electro-optic performance of LCD is incompatible with that of a chiral dopant. PMID- 22524070 TI - Ingestion of fluoride from dentifrices by young children and fluorosis of the teeth--a literature review. AB - The ADA recommends the use of fluoridated dentifrices as soon as the primary teeth erupt, so as to reduce the incidence of dental caries. However young children can ingest a significant amount of dentifrice during normal toothbrushing; this is a potential problem because the permanent teeth are at risk from fluorosis for the first seven years of life. AIMS: the objective of this paper was to review the literature on the role of fluoride dentifrices in causing dental fluorosis. METHODS: SEARCH STRATEGY: a search for literature was performed using MEDLINE, OVID with the key words fluorosis, dentifrice, ingestion, and children. The search was limited to English language publications. Subsequently, 31 articles were retrieved, additional relevant articles were collected from the references cited in the initially identified papers. Ultimately, 96 articles were retrieved for review. CONCLUSIONS: Fluoride, should be used with caution so that the benefits out-way the adverse affects. Oral health care providers need to systematically assess individual tooth brushing habits and emphasize the advantages of early use of a fluoridated dentifrice whilst still meeting the need for the prudent use of small quantities of dentifrice. Dentifrices with a low concentration of fluoride may be appropriate for young children who are considered to be at low caries risk and the risk of fluorosis is minimal for children who ingest this dentifrice; nevertheless, it appears that more research is still required on the therapeutic effects of fluoride dentifrices which contain fluoride at a low concentration. PMID- 22524071 TI - Esthetic restorative options for pulpotomized primary molars: a review of literature. AB - OBJECTIVE: The goal of this manuscript was to review the existing literature in regards to esthetic options to restore pulpotomized primary molars. STUDY DESIGN: A pubmed literature search has been performed and all relevant studies were assessed. RESULTS: Two laboratory, 3 restrospective and 4 prospective clinical studies were found, reviewed and analyzed. CONCLUSIONS: Based on the limited information available, we concluded that tooth colored and bonded restorations showed promising results as alternative materials to replace stainless steel crowns after pulpotomies in primary molars. Hybrid composites tend to perform better than compomers. Resin modified glass ionomer cements demonstrated excellent marginal seal and retention. More long-term follow up studies are necessary until more definitive recommendations can be made. PMID- 22524072 TI - Impact of pictorial story on pain perception, situational anxiety and behavior in children: a cognitive-behavioral schema. AB - AIM: The present study evaluated the effect of listening to a pictorial story about going to the dentist on pain perception, situational anxiety and behavioral feedback during dental treatment in pediatric dental patients. STUDY DESIGN: Eighty, 6-7-year-old children were included The childhood anxiety-related disorders using Screen for Child Anxiety Related Disorders (SCARED) Parent Version scale and intelligence quotient using Raven's Progressive Matrices were evaluated The subjects were randomly assigned to two groups, listening to a pictorial story about going to a dentist (test), or listening to a pictorial story about going to a barbershop (control). A dental treatment was performed on each subject, during which, behavior was assessed using Sound, Eye, and Motor Scale. Pain perception and situational anxiety were then assessed using Wong Baker Fasces Pain Rating Scale and Faces version of the Modified Child Dental Anxiety Scale, respectively. RESULTS: There was a significant decrease in pain perception (P=0.02) and situational anxiety (P<0.001) in the test group. In addition, the test intervention significantly improved children behavioral feedback during dental treatment (P<0.001). CONCLUSION: Preparation of children with pictorial story can be effective in decreasing pain perception and situational anxiety as well as improving behavior during dental treatment. PMID- 22524073 TI - Comparison of electrosurgical pulpotomy with zinc oxide eugenol or zinc polycarboxylate cements sub-base. AB - PURPOSE: The aim of this study was to compare the clinical and radiographic success rates of electrosurgical pulpotomy of human primary molars with zinc oxide eugenol (ZOE) and zinc polycarboxylate (ZPC) cements. METHODS: In this randomized clinical trial study, 120 primary second molar teeth were treated by electrosurgical pulpotomy. Teeth were randomly assigned to two groups according to whether ZOE or ZPC cement was used as a sub-base. Teeth were restored with stainless steel crowns and were evaluated clinically and radiographically after 3, 6, and 12 months by two independent examiners. Clinical treatment outcomes and radiographic findings were statistically analyzed using Fishers' exact test with statistically significant differences defined for P < 0.05. RESULTS: At 12 months, the clinical and radiographic success rates in the ZOE group were 98.2% and 84.2% and in the ZPC group were 96.2% and 75%, respectively (P > 0.05 for all). CONCLUSIONS: The outcomes of this study suggested that either ZPC or ZOE sub-base have similar clinical and radiographic success in electrosurgical pulpotomy. PMID- 22524074 TI - Evaluation of pulpal blood flow changes in primary molars with physiological root resorption by laser Doppler flowmetry and pulse oximetry. AB - AIM: The aim of this study was to undertake a comprehensive quantitative investigation ofpulpal bloodflow (PBF) changes in human non-carious primary molar teeth with variable degrees of root resorption by Laser Doppler Flowmetry (LDF) and Pulse Oximetry (PO) methods. MATERIALS AND METHODS: Data was collected from clinically and radiographically healthy 86 mandibular primary molars which have different physiological root resorption levels (PRRLs). PRRLs for each of the teeth were assessed using periapical radiographs and teeth were subdivided into three groups. RESULTS: The LDF values demonstrated a significant diference (p = 0.0001) between all groups although PO did not demonstrate any difference (p = 0.109). Statistical analysis of LDF values demonstrated significant differences between Groups A and C (p = 0.0001) and Groups B and C (p = 0.008). Furthermore, positive correlations were determined between LDF values and PRRL groups (p = 0.0001) and patients' ages (p = 0.0001). CONCLUSIONS: In our study, it was observed that the PBF values of human primary molars measured by LDF tended to increase with the progress of physiological root resorption and age. LDF was found to be a more effective method than PO to assess the pulpal vascularity changes of human primary molars. PMID- 22524075 TI - Effect of polyol gums on salivary S mutans levels. AB - The predominant sugar substitutes used in chewing gum are polyols which are low caloric substances. The polyols most frequently used in chewing gums are sorbitol and xylitol. AIM: The present study assessed the effectiveness of xylitol and sorbitol chewing-gums on levels of S mutans in saliva. METHOD: The study group consisted of 30 normal and healthy males aged between 13-17 years. A pellet of gum (sorbitol or xylitol) was given to each participant after breakfast (8am), lunch (2pm) and dinner (8pm) for the study period of 3 months. On the first day of the study, baseline salivary samples were collected after breakfast from all participants and assessed for S mutans levels. At the end of 3 months, salivary samples were collected and processed in a similar manner CONCLUSION: Salivary S mutans levels showed a significant reduction after the use of xylitol based chewing gum than with sorbitol based chewing gum. PMID- 22524076 TI - Palatal training appliances in children with mild to moderate oral dysfunctions. AB - OBJECTIVE: The objective of the study was to evaluate the efficacy of palatal training appliances on speech articulation and orofacial functions in children undergoing speech therapy. STUDY DESIGN: The material consisted of 134 boys and 34 girls who were referred by speech and language therapists to the Public Dental Health Service in Vantaa due to mild to moderate problems with speech articulation or in oral motor skills. The mean age of the children at the start of the palatal plate therapy was 6.4 years (SD 1.9). The articulation assessment was performed by five speech and language therapist while the palatal plate therapy was carried out by an experienced dentist. The mean treatment time with the oral plates was 4.4 months (SD 2.3). RESULTS: An improvement in speech articulation was observed by the speech and language therapists in 51% of the children. Tongue movements improved in 47%, and lip closure in 38% of the participants. Drooling decreased in 54% of the cases. A multiple logistic regression model revealed that with respect to speech articulation the best improvement was found in children with /r/-disorder and in those with a crossbite. CONCLUSIONS: Palatal training appliances during speech therapy seemed to be an efficient way to improve speech articulation and tongue movements in children with mild to moderate problems in orofacial functions. PMID- 22524077 TI - Eating disorders and their implications on oral health--role of dentists. AB - Eating disorders (EDs) are primary psychological conditions, often associated with severing medical complications. EDs are characterized by perturbed eating behavior patterns. Their increasing incidence and prevalence is causing concerns to healthcare professionals. Because eating disorders are a complex issue, a multidisciplinary approach to treatment is required and this team includes Psychiatrists, Psychologists and Nutritionists. The purpose of this paper is to review the role of the dentists especially the pediatric dentist and orthodontist in identifying oral manifestations of EDs, which may be utilized for oral diagnosis, referral and management of underlying psychiatric condition and also secondary oral conditions. PMID- 22524078 TI - Prevalence of five biofilm-related oral streptococci species from plaque. AB - OBJECTIVE: To examine the prevalence of five oral streptococci species of severe early childhood caries (S-ECC) and caries-free (CF) groups. STUDY DESIGN: Supra gingival plaque samples were obtainedfrom 198 Thai children with ages ranging from one to six years old Eighty-seven subjects had no caries (dmft=0), and 111 had S-ECC. After DNA extraction, S. mutans, S. sobrinus, S. sanguinis, S. oralis, and S. gordonii were identified by standard PCR using species-specific primers. Statistical analysis determined the differences among prevalence rates of each species using Pearson chi-square test. The relationship among dmft score, age, sex and caries status within each group was analyzed by logistical regression (p < or = 0.05). RESULTS: Sex was not correlated with any of the species detected in both groups (mean age =3.09, mean +/- SD of dmft = 11.04 +/- 7.89). S. mutans was found at greatest prevalence in both groups followed by S. oralis. S. gordonii was detected at a high prevalence, but S. sobrinus and S. sanguinis were lower in S-ECC when compared with those from the CF group. CONCLUSION: S. mutans was associated significantly with S-ECC (p < or = 0.05). Caries prevalence was highest (56.5%) in subjects infected by S. mutans alone. S. sanguinis prevalence was higher in the CF group, but not statiscally different. Infection with MS did not show higher caries prevalence. PMID- 22524079 TI - Dental pulp stem cells from primary teeth quality analysis: laboratory procedures. AB - OBJECTIVES: To present details of isolation, processing and differentiation of stem cells from inflamed dental pulp of primary teeth. MATERIALS AND METHODS: Tissue sample was collected from teeth indicated for a single visit pulp therapy. Samples were transported and processed in the laboratory which included culturing of cells, isolation and in vitro differentiation into multiple lineages. The results for the analysis of various cell surface markers used for dental pulp were compared with bone marrow. RESULTS: There was no statistically significant difference found in the expression of various surface markers between dental pulp and bone marrow. The stem cells from dental pulp were differentiated into multiple lineages. CONCLUSION: Isolation of cells from oral tissues is technique sensitive. PMID- 22524080 TI - Association of age specific body mass index, dental caries and socioeconomic status of children and adolescents. AB - AIMS AND OBJECTIVES: The purpose of this study was to determine the association of BMI-for-age with dental caries and socioeconomic status. METHOD: A random sample of 2033 school going children aged 6-15 years were selected from ten different schools located in the south of Bangalore city. Height and weight of each child was recorded to obtain BMI-for-age. The socioeconomic status (SES) was assessed based on educational status, profession and annual income of parents. Dental caries was recorded according to WHO criteria. A diet recording sheet was given to each child to record his/her dietary intake of the four basic food groups and snacks for 5 consecutive days including one weekend day. The data obtained was subjected to statistical analysis. RESULTS: The results showed that a higher number of children who were overweight and at a risk of overweight were seen in the upper SES and both showed a higher mean dietary intake of all the four food groups and snacks. The mean deft score was significantly higher in underweight children. A significantly higher mean DMFT score was observed in children at risk of overweight and overweight children. CONCLUSIONS: Children from the upper classes consumed more food, including snacks and were either at a risk of overweight or overweight. They had more caries in their permanent dentition. Underweight children were seen in the lower class. Although their intake of snacks was less, they had higher caries in their primary dentition. PMID- 22524081 TI - Dental caries and salivary alterations in Type I Diabetes. AB - Insulin dependent diabetes mellitus is a severe disease that raises blood glucose levels because of hyperglycemia and insulinopenia. Fluctuations in water and electrolyte levels may result in xerostomia and other changes in the salivary composition. Since diabetes has an influence on oral health, it is important for the dentist to be aware of newer advances in the field of diabetes and to recognize specific oral problems related to diabetes. Thus, the dentist becomes an important part of the health care team for the patients with diabetes. AIM: The present study correlated salivary flow rate, salivary pH and total salivary antioxidant levels and dental caries in type I diabetic patients. METHOD: A total of 200 children that included 100 known diabetic children (study group) and 100 healthy children (controls) of both the sexes and from similar socioeconomic backgrounds formed the part of this study. Dental caries was assessed using DMFT index. The salivary total anti-oxidant level was estimated using phospho molybdic acid using spectrophotometric method. The salivary flow rate was recorded using the Zunt method and the salivary pH using the pH indicating paper. The results were statistically analyzed using t-test. CONCLUSIONS: The analyzed parameters showed increase in salivary anti-oxidant levels, reduced salivary flow rate, increase incidence of dental caries, salivary pH was decreased when compared to the control group. PMID- 22524082 TI - Candida, mutans streptococci, oral hygiene and caries in children. AB - OBJECTIVE: to test the association between Candida and mutans streptococci (ms), oral hygiene and caries levels and in children. METHODS: 22 boys and 12 girls (age 6 to 14.5 years) participated in the study. Each participant received a toothbrush, and was asked to brush his/her teeth after proper instructions. Dental caries and oral hygiene were recorded. Candida and ms levels were determined in saliva samples. RESULTS: Candida colonies were observed in 70.5% of the children. No association was found between Candida and caries or plaque and gingival indices. C. albicans-positive children demonstrated significantly higher brushing scores. CONCLUSIONS: Our findings may suggest that there is no clear association between Candida in saliva, and levels of cariogenic bacteria and caries risk in children. PMID- 22524083 TI - Comparison of oral midazolam and triclofos in conscious sedation of uncooperative children. AB - OBJECTIVE: To compare the safety and efficacy of two orally administered conscious sedation agents, Triclofos 70mg/kg and Midazolam 0.5mg/kg in pediatric dental patients. STUDY DESIGN: In this cross over study twenty four sedation sessions were carried out with twelve children between the age group of 3 to 9 years. Children exhibiting negative behavior according to Frankl behavior rating scale (Rating No.2) were selected. Patients were randomly assigned to receive oral midazolam 0.5mg/kg or triclofos 70mg/kg. The alternate drug was administered at the next appointment. Patients' behavioral responses were recorded using a scoring system established by Houpt et al and modified by Badalaty et al considering the degree of sleep, body movement, crying and overall behavior Scoring was done for both midazolam and triclofos session as well as for the session which was tried without medication. Ratings were made during all the procedures like injection of LA, extraction, cavity preparation, restoration and pulp therapy. Statistical analysis was done using Friedman test and Wilcoxon sign rank test. RESULTS: Both the drugs showed significantly higher scores when compared to the session which was tried without medication although the scores for midazolam were significantly higher than triclofos. CONCLUSION: Oral midazolam in a dose of 0.5mg/kg is more effective in regulating patient behavior when compared to triclofos. PMID- 22524084 TI - Atypical orofacial conditions in Noonan syndrome: a case report. AB - Noonan syndrome (NS) is a relatively common condition characterized by chest deformation, congenital heart disease, short stature and distinctive facial features. Due to its genetic heterogeneity NS patients exhibit a range of clinical signs. Severe gingivitis and supernumerary teeth are rarely seen in connection with NS. In addition, there has not been a report on NS patients with atypical bilateral enlargement of the mental foramens and inferior-alveolar canals. This case report describes a NS patient who has undergone growth hormone (GH) therapy and is presenting with classical and rare NS phenotypes. PMID- 22524085 TI - Metastatic mandibular neuroblastoma: a rare cause of tooth mobility. AB - Neuroblastoma (NBL), a malignant embryonic tumor derived from neural crest cells, is the most common tumor worldwide among children less than 1 year of age. Metastasis to the mandible is uncommon. This article reports the case of a 15 month-old male diagnosed with NBL with bone metastasis including the mandible which resulted in severe tooth mobility. Dentists or pediatricians should consider the primary or metastatic tumors of the maxillofacial region in the differential diagnosis in children presenting with premature loss of teeth related to tooth mobility. PMID- 22524086 TI - Multiple supernumerary teeth associated with bony malformations. AB - Full blown cases of cleidocranial dysplasia (CCD) have been reported earlier but a case with a rarity of 60 teeth associated with bony malformations, is seldom observed Because of the oral findings this condition has been diagnosed at an early age, thus helping to achieve a better oral harmony. This article reports an atypical case with 16 supernumerary teeth associated with bony malformations. PMID- 22524087 TI - Preliminary study evaluating the accuracy of MRI images on CBCT images in the field of orthodontics. AB - OBJECTIVE: The purpose of this study was to explore the 3-dimensional (3D) accuracy of magnetic resonance imaging (MRI) on cone-beam computed tomography (CBCT) images after the registration of MRI images on CBCT images. MATERIALS AND METHODS: Three Japanese adult females volunteered for this study. To transform digital imaging and communication in medicine (DICOM) data derived from MRI and CBCT images into polygon data, five software programs were used. CBCT and MRI images were obtained within one week, and both were registered by the iterative closest point (ICP) method. To assess the accuracy of the composite MRI-CBCT, the measurement errors of the MRI-CBCT were verified Measurement values were compared using frontal and cephalometric soft-tissue landmarks. Differences were analyzed using the non-parametric Mann-Whitney U test. RESULTS: There were no significant linear measurement errors (P > 0.05) when the images were measured from the superimposed MRI-CBCT images. CONCLUSION: The MRI images attained from MRI - CBCT registration showed accurate 3D linear measurements. PMID- 22524088 TI - Oral and general health of Hispanic children with disabilities in the United States. AB - Hispanic residents are the fastest growing population of the U.S. Only recently have government agencies begun to identify the associated demographic facts and inequities which are specific to this population. In particular limited attention has been directed to Hispanic children with disabilities. Available government reports are used to provide a basic awareness of the oral and general health needs of this population of youngsters. PMID- 22524089 TI - The demise of the caboose... and the need for word consciousness. PMID- 22524090 TI - Deaf and hard of hearing students' problem-solving strategies with signed arithmetic story problems. AB - The use of problem-solving strategies by 59 deaf and hard of hearing children, grades K-3, was investigated. The children were asked to solve 9 arithmetic story problems presented to them in American Sign Language. The researchers found that while the children used the same general types of strategies that are used by hearing children (i.e., modeling, counting, and fact-based strategies), they showed an overwhelming use of counting strategies for all types of problems and at all ages. This difference may have its roots in language or instruction (or in both), and calls attention to the need for conceptual rather than procedural mathematics instruction for deaf and hard of hearing students. PMID- 22524091 TI - Family counseling in the Netherlands for Turkish-origin parents of deaf children with a cochlear implant. AB - Cultural elements such as language, beliefs about health, and family context play important roles in the uptake of rehabilitation and treatment of deafness. Because of cultural issues, minority groups often do not receive optimal care. Focusing on the Netherlands, the researchers explored how the rehabilitation and counseling of deaf children of Turkish-origin parents can be improved. The most important findings were that (a) most parents initially did not believe their child was deaf and regretted later that they did not start hearing rehabilitation earlier; (b) parents had little confidence in the Dutch health care system and sought a second opinion from a medical doctor of their own national origin; (c) parents did not know how to be actively involved in the care of their deaf child. Implications for practice aimed at improving rehabilitation and counseling for these children are described. PMID- 22524092 TI - Reread-adapt and answer-comprehend intervention with Deaf and hard of hearing readers: effect on fluency and reading achievement. AB - The researchers investigated the effect of the Reread-Adapt and Answer-Comprehend intervention (Therrien, Gormley, & Kubina, 2006) on the reading fluency and achievement of d/Deaf and hard of hearing elementary-level students. Children in the third, fifth, and sixth grades at a state school for d/Deaf and hard of hearing students received a fluency intervention that was supplemental to their regular reading instruction. Significant improvement was found on a generalized measure of reading fluency after intervention. Though the researchers found no significant improvement in performance on a generalized measure of comprehension after intervention, the students demonstrated consistently good comprehension on both literal and inferential questions during the intervention sessions. The findings support the importance of incorporating a comprehension monitoring strategy in fluency instruction. PMID- 22524093 TI - Chinese deaf and hard of hearing adolescents' awareness of thematic and taxonomic relations among ordinary concepts represented by pictures and written words. AB - Inspired by a previous study of Korean deaf and hard of hearing adolescents, the researchers conducted a priming task of living-nonliving categorization with a sample of Chinese deaf and hard of hearing adolescents. The sample in this study had significantly lower accuracy levels for the thematically related items than for the taxonomically related items and significantly larger differences in reaction times than a group of hearing adolescents when stimuli were changed from pictures to written words. However, they were not significantly different from the hearing adolescents in their performance with the taxonomically related written words. Furthermore, unlike the hearing adolescents, they did not have significantly different reaction times as the result of changes in positions of stimulus presentations. PMID- 22524094 TI - Addressing intersections in HIV/AIDS and mental health: the role of organizations for d/Deaf and hard of hearing individuals in South Africa. AB - Like south africans generally, d/Deaf and hard of hearing South Africans are at risk of HIV/AIDS and mental disorders resulting from barriers to communication and care. In interviews and a focus group, members of South African organizations for d/Deaf and hard of hearing individuals all gave priority to HIV/AIDS education and prevention, citing risks resulting from language and communication barriers, inadequate schooling, and insufficient information in South African Sign Language. Participants gave varied descriptions of HIV/AIDS programs in schools for d/Deaf and hard of hearing students and described school initiatives they had directed. Some participants gave mental health problems lesser priority; others said susceptibility to mental disorders may result from communication difficulties and therefore warrants specialized services. Others, seeing a need to address mental health in HIV/AIDS prevention, had designed programs accordingly. Such prevention efforts merit support, as do activities to reduce communication barriers. PMID- 22524095 TI - Promoting vocabulary learning in young children who are d/Deaf and hard of hearing: translating research into practice. AB - Vocabulary knowledge is strongly associated with reading achievement and becomes increasingly predictive of overall reading proficiency as children progress through the elementary grades. Children who are d/Deaf and hard of hearing often begin schooling with small meaning vocabularies, a disadvantage that puts them at risk of struggling to learn to read. Recent research on vocabulary intervention with young children who have typical hearing demonstrates the effectiveness of targeted, contextualized instruction on children's word learning and provides insights for early childhood educators of young d/Deaf and hard of hearing children. In the present essay, which is grounded in the qualitative similarity hypothesis (Paul, 2010, in press; Paul & Lee, 2010) and sociocultural theories of learning, the author argues for evidence-based vocabulary interventions for young d/Deaf and hard of hearing children that are rooted in the contemporary research literature. PMID- 22524096 TI - Healthcare board governance. AB - PURPOSE: In the light of failings of the board highlighted by the mid Staffordshire NHS Foundation Trust public inquiry, this paper seeks to offer insights about how boards in general might develop in order to discharge their responsibilities for quality and safety in health care more consistently in the future. The paper also proposes to examine wider questions about the role, purpose, and impact of boards on organisations. DESIGN/METHODOLOGY/APPROACH: The paper draws on literature from across the social sciences to assess the evidence for effective board working using a contingency and realist approach. FINDINGS: The examination leads to the identification of three key issues surrounding the construction and the development of boards. First, there is no evidence or consensus about an "ideal" board form. The rationale and evidence-base, for example for the 1991 model for NHS boards in the English NHS, has never been set out in an adequate manner. Second, the evidence about effective board working suggests that there are some key principles but also that local circumstances are really important in steering the focus and behaviours of effective boards. Third, there is an emerging proposition that boards, including in healthcare, need to embody a culture of high trust across the executive and non executive divide, together with robust challenge, and a tight grip on the business of delivering high quality patient care in a financially sustainable way (high trust - high challenge - high engagement). ORIGINALITY/VALUE: The paper argues that it is advisable to move away from a tendency to faith-based and exhortative approaches to guidance, training and development of boards and that it is time for a root and-branch inquiry into the composition, structure, processes and dynamics of healthcare boards in the interests of assuring patient safety. PMID- 22524097 TI - Reforms and clinical managers' responses: a study in Norwegian hospitals. AB - PURPOSE: This paper seeks to explore the legitimacy of budgets as management control processes in hospitals after comprehensive reforms were implemented in the Norwegian hospital sector in 2002. DESIGN/METHODOLOGY/APPROACH: The paper employs qualitative interviews with top level clinical managers in three large hospitals. FINDINGS: The study shows a variety of practices among the clinical managers as to management control adjustments. The managers use different strategies in order to cope with the budget frames. RESEARCH LIMITATIONS/IMPLICATIONS: This paper contributes to the current debate and research relating to the budgeting and performance management practices in hospital settings. PRACTICAL IMPLICATIONS: These findings contribute to contextual knowledge that is relevant in understanding the diverse practices of clinical managers in hospitals as complex service producing organizations. SOCIAL IMPLICATIONS: The findings give information to decision makers as to the diversity in management practices within knowledge intensive organizations. ORIGINALITY/VALUE: The paper challenges the idea that the strategies used by managers can be understood by the concepts of the means-end rationality prescribed in most of the reforms introduced into the hospital sector. PMID- 22524098 TI - Organizational culture, intersectoral collaboration and mental health care. AB - PURPOSE: This study aims to investigate whether and how organizational culture moderates the influence of other organizational capacities on the uptake of new mental health care roles by non-medical primary health and social care services. DESIGN/METHODOLOGY/APPROACH: Using a cross-sectional survey design, data were collected in 2004 from providers in 41 services in Victoria, Australia, recruited using purposeful sampling. Respondents within each service worked as a group to complete a structured interview that collected quantitative and qualitative data simultaneously. Five domains of organizational capacity were analyzed: leadership, moral support and participation; organizational culture; shared concepts, policies, processes and structures; access to resource support; and social model of health. A principal components analysis explored the structure of data about roles and capacities, and multiple regression analysis examined relationships between them. The unit of analysis was the service (n = 41). FINDINGS: Organizational culture was directly associated with involvement in two types of mental health care roles and moderated the influence of factors in the inter-organizational environment on role involvement. RESEARCH LIMITATIONS/IMPLICATIONS: Congruence between the values embodied in organizational culture, communicated in messages from the environment, and underlying particular mental health care activities may play a critical role in shaping the emergence of intersectoral working and the uptake of new roles. ORIGINALITY/VALUE: This study is the first to demonstrate the importance of organizational culture to intersectoral collaboration in health care, and one of very few to examine organizational culture as a predictor of performance, compared with other organizational-level factors, in a multivariate analysis. Theory is developed to explain the findings. PMID- 22524099 TI - Health tourism: definition focused on the Swiss market and conceptualisation of health(i)ness. AB - PURPOSE: This paper's purpose is to give an overview of current research regarding the concept of "health tourism" with a focus on Switzerland, and to determine whether a consensus on this concept and its embedding in existing/future markets can be found. DESIGN/METHODOLOGY/APPROACH: The paper is an explorative study combining literature review, questionnaires and qualitative interviews. Grounded theory was employed. FINDINGS: A service from the field of health care must have been provided prior to health tourism, allowing it to be classified under the health care system. Thus, health tourism is classified under the market for the sick and not under tourism which targets the healthy. Furthermore a new market for the healthy is emerging, which needs to be defined. As an example health(i)ness could help to clarify the terminology, to be seen as a gatekeeper of health and as a cultural paradigm change from cure to prevention. RESEARCH LIMITATIONS/IMPLICATIONS: Further research is needed, regarding the positioning and development of health tourism and its synergies, as the cost pressures in health care increase and will continue to have a sustainable impact on health tourism. PRACTICAL IMPLICATIONS: The paper provides better knowledge of the term health tourism, its general classification, and particular reference to Switzerland, and information about upcoming changes in health care. ORIGINALITY/VALUE: The findings add to the knowledge of how health tourism is embedded into health care and tourism, and show potential within the market for the healthy. It provides information to members of the tourism and health care market. PMID- 22524100 TI - Primary care in the United States: practice-based innovations and factors that influence adoption. AB - PURPOSE: This study aims to explore the use of specific innovations in primary care practices. The research seeks to examine whether a relationship exists between environmental factors and organizational characteristics and the level of innovation in primary care practices in Virginia. DESIGN/METHODOLOGY/APPROACH: The study utilized multiple secondary data sets and an organizational survey of primary care practices to define the external environment and the level of innovation. Institutional theory was used to explain the connection between innovations in primary care practices and institutional forces within the environment. Resource dependency theory was used to explain motivators for change based on a dependence on scarce financial, human, and information resources. FINDINGS: Results show a positive association between organizational size, organizational relationships, and stakeholder expectations on the level of innovation. A negative association was found between competition and the level of innovation. No relationship was found between degree of Medicare and managed care penetration and innovation, nor between knowledge of, and difficulty complying with, payer organization requirements and innovation. ORIGINALITY/VALUE: Primary care physician practices exist in a market-driven environment characterized by high pressure from regulatory sources, decreasing reimbursement levels, increasing rate of change in technologies, and increasing patient and community expectations. This study contributes new information on the relationship between organizational characteristics, the external environment and specific innovations in primary care practices. Information on the contributing factors to innovation in primary care is important for improving delivery of health care services and the ability of these practices to survive. PMID- 22524101 TI - Age-related attitudes: the influence on relationships and performance at work. AB - PURPOSE: This paper aims to examine the influence of age and age-related attitudes on relationship factors. In addition, it seeks to assess how both factors affect care service work performance. DESIGN/METHODOLOGY/APPROACH: The paper explores the influence of age and age-related attitudes on the relationship quality among employees, affecting performance in mentally and physically demanding work settings. The authors conducted the research in six residential homes for the elderly in Germany (152 respondents) and collected the data with questionnaires. Data are analyzed by multi-hierarchical regression analyses. FINDINGS: Results show that age-related attitudes (intergenerational cooperation and the perception of older employees' capabilities) are important factors influencing the perceived quality level of in-group cooperation. Both age-related attitudes and relationship factors influence perceived employee performance, and job satisfaction. RESEARCH LIMITATIONS/IMPLICATIONS: The findings contribute to understanding how age-related attitudes influence relationships among employees, the relationship between employees and supervisor, and the effect on service performance. The mono-cultural sample might be a limitation, as well as the composition of the sample: The majority of respondents were female. PRACTICAL IMPLICATIONS: For leaders, supervisors and managers the results contribute to understanding how employees' age-related attitudes, in mentally and physically demanding work settings, influence the quality level of relationships and outcomes. This is relevant in the context of leaders/supervisors promoting followers' individual development and group/team development. ORIGINALITY/VALUE: The paper shows that in care service work with an increasing number of older employees, the positive perception of age-related attitudes influences relationship quality and performance positively. PMID- 22524103 TI - [We are in the web]. AB - Dissemination of scientific knowledge is one of the most important aspects to be covered by a scientific publication, and the importance of computer networks in this respect, is well known. Towards this end, the journal Investigacion Clinica has established for more than a year its own website, with free access to all the numbers published by the journal in over a little more than 50 years. Our web site has been visited a total of 2,759 times, with an average of 3.04 published articles reviewed per visit and 61.92 % of new visits. As it is obviously expected, Venezuela was the most frequent country of origin of the visits, mainly from the cities of Maracaibo (700), Caracas (352), Merida (150), Maracay (47) and Valencia (32). Visits from other countries included Mexico (462), Spain (141), Argentina (122), United States (105), Brazil (81), Colombia (74), Peru (32), Chile (25) and Italy (13). The rest of the countries had a frequency close to ten visits. The aim of the editors of "Investigaci6n Clinica" is to achieve an even better scientific quality and scope of the journal and we consider that having it included in the web, will successfully assist in this purpose. PMID- 22524102 TI - Discursive construction of polyphony in healthcare management. AB - PURPOSE: The aim of the paper is to understand and define how the polyphony of management is constructed in interaction and to describe this through concrete management meeting cases. Polyphony refers to the diverse voices of various organization members, and how these voices are present, disclosed and utilized in management. DESIGN/METHODOLOGY/APPROACH: The study is based on the social constructionist and discursive perspectives of management, which question the traditional, individualistic approaches of management. The issue was examined through a qualitative case study by analysing the micro-level management discourse in three healthcare organizations. FINDINGS: Discursive practices that enhance or inhibit polyphony are often unnoticed and unconscious. Key moments of management discourse are an example of unconscious mundane practices through which members of organizations construct the reality of management. RESEARCH LIMITATIONS/IMPLICATIONS: The empirical results are locally contextual. In the future, research will be able to apply the approach to diverse contexts as well as link micro-level discourses to the construction of broader health and social management discourses. PRACTICAL IMPLICATIONS: The paper increases the understanding of how to enhance participation and staff contribution, and how to utilize the knowledge of all members of the organization. SOCIAL IMPLICATIONS: Both managers and other staff members are fully involved in the social construction of management. Micro-level discourse should be paid attention to in management work as well as in the education of managers and staff. ORIGINALITY/VALUE: The study increases the understanding of micro-level issues of management and challenges the conventional, taken-for-granted assumptions behind organization and management theories. PMID- 22524104 TI - [Comparative study of the urinary excretion of boron, calcium, magnesium and phosphorus in postmenopausal women with and without osteoporosis]. AB - In order to compare the possible relationship between urinary concentrations of boron, calcium, magnesium and phosphorus in serum and urine of postmenopausal women with and without osteoporosis, we selected 45 postmenopausal women over 47 years of age, divided into two groups: group I clinically healthy postmenopausal women and group II postmenopausal women with osteoporosis, without chronic kidney and hepatic diseases or diabetes mellitus. We determined the boron (B), phosphorus (P), total calcium (Ca) and total magnesium (Mg) in the urine of two hours, by atomic emission spectroscopy with induction-coupled plasma (ICPA-ES). Total calcium and total magnesium in serum were determined by atomic flame absorption spectroscopy (FAAS) and inorganic phosphorus in serum, and creatinine in serum and urine, by molecular absorption spectrometry. The preliminary results suggest the existence of a significant difference (p < 0.05) in boron and phosphorus concentrations in the urine of two hours between the groups. The model of linear regression analysis used showed a relationship between urinary concentrations of boron/creatinine index and calcium/ creatinine, magnesium/creatinine and phosphorus/creatinine indexes in the urine of postmenopausal women with osteoporosis. PMID- 22524105 TI - [The number needed to treat as a measure of effect in the treatment of primary immune thrombocytopenia]. AB - In randomized or comparative studies, when the outcomes are binary or dichotomous, the effect of a specific treatment can be reported using the absolute risk reduction (ARR) and the number needed to treat (NNT), which is the reciprocal of the ARR (1/ARR = NNT). The objective of the present study was to realize a review of the different modalities of treatment of primary immune thrombocytopenia (ITP), using as effect measurement the calculation of the ARR and NNT and their confidence intervals (CI 95%). The number needed to harm (NNH) can be calculated with the same formula of NNT, taking in account only the adverse events (CTCAE scale) of the treatment in relation with those in the control group. The results showed the effect of different types of treatment of ITP. The NNT was better in randomized studies than those of inferior design. The NNH calculation showed the safe level of the intervention. It can be observed that age (youth) and no splenectomy condition exhibited some influence in the favorable NNT report. In conclusion, given the advantages of the ARR and the NNT for clinical decision making, it can be suggested that these measurements of effect should also be reported, in addition to other statistical measurements for ITP treatment or any observational study with dichotomous or binary outcomes. PMID- 22524106 TI - [Possible role of enterotoxigenic Bacteroides fragilis in the etiology of infectious vaginitis]. AB - Vaginitis is a common gynecologic disorder. It is due to several causes, some even unknown. Bacteroides fragilis is the most important anaerobe in clinical bacteriology, some strains of this group are notable for being enterotoxigenic and they have been associated with intestinal and extraintestinal syndromes. They have recently been isolated from patients with vaginitis. The purpose of this study was to investigate a possible association of enterotoxigenic B. fragilis with infectious vaginitis. 265 samples of vaginal exudate were processed, 202 from symptomatic patients and 63 healthy women. The identification of the microorganisms was carried out by conventional methods. In 31.2% of symptomatic patients were identified: Gardnerella vaginalis, Mobiluncus, Candida albicans, Mycoplasma hominis, Ureaplasma urealyticum and Streptococcus agalactiae. B. fragilis was identified in 27 symptomatic patients and 5 healthy women. These strains were cultivated in liquid medium and incubated during 48 h at 36 degrees C in anaerobe chambers. Supernatant activity was assayed in HT-29 cells. Eighteen B. fragilis strains isolated from symptomatic patients were enterotoxigenic, because induced alterations in target cell morphology. It was not identified in healthy women (P < 0.05). 77.7% of enterotoxigenic B. fragilis strains were not associated with other specific pathogens. This fact suggests that enterotoxigenic B. fragilis could be a cause for vaginitis. The effect of enterotoxin on E cadherin of vaginal epithelium could facilitate invasion and its possible pathogenic role in the vagina. This is the first report that associates enterotoxigenic Bacteroides fragilis as a possible cause of infectious vaginitis. PMID- 22524107 TI - Migraine life-time prevalence in mental disorders: concurrent comparisons with first-degree relatives and the general population. AB - The authors quantified the prevalence of migraine in subjects with mental disorders, first-degree relatives and the adult general population (GP) in Merida, Venezuela. After validation, a modified, short version of the Lipton's diagnostic scale was administered to consecutively admitted in- and out-patients (n = 1059), their first-degree relatives (n = 445) and a probabilistic sample of the GP (n = 516). In the GP, the frequency of migraine (percentage and 95% confidence interval) was 14.9 (11.8-17.9). The migraine frequencies were (percentage and odd ratio probability against the GP: bipolar disorder (15.7%, p = 0.5), schizophrenia (8.3%, p = 0.08), depression and dysthimia (24.4%, p = 0.2), anxiety disorders (10.0%, p = 0.02), personality disorders (11.4%, p = 0.15), all other disorders (15.5%, p = 0.4), relatives of bipolar patients (4.4%, p < 0.001), relatives of schizophrenia patients (3.5%, p = 0.003), and relatives of patients with all other mental disorders (12.8%, p = 0.4). Migraine was more common in women (p < 0.001), and the bipolar patients presented the highest female to male ratio (8:1). A high variability was observed in migraine prevalence among the diagnostic categories, but it was particularly high in subjects with affective disorders, mainly in women, who thus deserve special attention from clinicians. PMID- 22524108 TI - [Uric acid, atherosclerosis and vascular calcifications in chronic kidney disease]. AB - Abstract. Epidemiological and clinical studies have shown that cardiovascular disease is associated with an increase in mortality in patients with chronic kidney disease (CKD). Vascular complications are mainly secondary to calcification and atherosclerosis. Interest in the association between uric acid levels and cardiovascular risk has been renewed in recent years. The objective of this research was to determine the relation between vascular calcification (VC) and atherosclerosis, through carotid ultrasound, with uric acid levels in patients with CKD in dialysis. VCs were observed in 56% of patients, 46% had ultrasound criteria for atherosclerosis with an overall average of 0.89 mm (SD +/ 0.28), being higher in patients with hypertension and diabetes; this group also showed increased susceptibility to VC (p = 0.01). The levels of urea (141.3 mg/dL) (p = 0.01) and uric acid (6.9 mg/dL) (p = 0.04) showed significant association with the presence of VC. Adverse cardiovascular events were observed mainly in patients with atherosclerosis and VC (p = 0.01). This investigation showed that an increase in uric acid levels above 6 mg/dL is associated with an increased risk of calcification and cardiovascular adverse events in CKD patients in dialysis. PMID- 22524109 TI - Design and in vitro evaluation of effervescent gastric floating drug delivery systems of propanolol HCl. AB - Abstract. The purpose of this research was to develop and evaluate effervescent gastric floating tablets of propranolol HCl. The oral delivery of antihypertensive propranolol HCl was facilitated by preparing an effervescent floating dosage form which could increase its absorption in the stomach by increasing the drug's gastric residence time. In the present work, effervescent floating tablets were prepared with a hydrophilic carrier such as polyethylene oxide (PEO WSR N 60K and PEO WSR 303) as a release retarding agent and sodium bicarbonate as a gas generating agent. The prepared tablets were evaluated for all their physicochemical properties, in vitro buoyancy, drug release and rate order kinetics. From the results, P9 was selected as an optimized formulation based on their 12 h drug release, minimal floating lag time and maximum total floating time. The optimized formulation followed first order rate kinetics with erosion mechanism. The optimized formulation was characterized with FTIR studies and no interaction between the drug and the polymers were observed. PMID- 22524110 TI - [Antimicrobial peptides: a potential arsenal against HIV infection]. AB - HIV (human immunodeficiency virus) infection is today a very important health issue worldwide, which demands new ways and strategies for its prevention and treatment. Several studies on the innate immunity against HIV infection have shown that antimicrobial peptides are associated with increased resistance to infection. In the present review, we briefly summarize the major characteristics of antimicrobial peptides from human and several species of plants, amphibians, insects and other animal species that have significant potential to be used as therapeutic or prophylactic agents. The mechanisms of infection inhibition and viral replication blockade are also described in the context of the biology of infection. PMID- 22524111 TI - [Ca2+ and sphingolipids as modulators for apoptosis and cancer]. AB - Ca2+ is a second messenger which regulates many functions directly related with cancer such as proliferation, differentiation and apoptosis. The intracellular Ca2+ concentration ([Ca2+],) is finely regulated by several mechanisms, among them ionic channels, the endoplasmic reticulum Ca2+-ATPase (SERCA), the plasma membrane calcium pump (PMCA) and the mitochondrial Ca2+ transport. In cancer, the tumour cell proliferates without control since the capacity to recognize apoptotic signals has been lost. The apoptosis is regulated by changes in several proteins, as caspases and the Bcl-2 family members, among others. Additionally, the "reticulum stress", promoted by the accumulation and aggregation of unfolded proteins in the interior of the endoplasmic reticulum (ER), ussually leads to apoptosis. The "reticulum stress" can be induced by several agents, remarkably with thapsigargin, a selective inhibitor of the SERCA, which in turn induces a large increment in [Ca2+],, leading to apoptosis. As a consequence, currently, derivatives of thapsigargin are successfully been assayed as anti-neoplastic agents. Ca2+ is then transferred to the mitochondria, where it is known to constitute a main apoptotic signal. On the other hand, several sphingolipids, such as ceramide and sphingosine, and their phosphorylated derivatives ceramide-1 phosphate and sphingosine-1-phosphate, directly involved in the [Ca2+]1 regulation, are also recognized as signal messengers related with cancer processes. In this review we discuss new evidences on the effect of several sphingolipids in the intracellular Ca2+ homeostasis and its relationship with apoptosis and cancer. PMID- 22524112 TI - [Writing a scientific paper]. PMID- 22524113 TI - Nutrition of children and women in Bangladesh: trends and directions for the future. AB - Although child and maternal malnutrition has been reduced in Bangladesh, the prevalence of underweight (weight-for-age z-score <-2) among children aged less than five years is still high (41%). Nearly one-third of women are undernourished with body mass index of <18.5 kg/m2. The prevalence of anaemia among young infants, adolescent girls, and pregnant women is still at unacceptable levels. Despite the successes in specific programmes, such as the Expanded Programme on Immunization and vitamin A supplementation, programmes for nutrition interventions are yet to be implemented at scale for reaching the entire population. Given the low annual rate of reduction in child undernutrition of 1.27 percentage points per year, it is unlikely that Bangladesh would be able to achieve the United Nations' Millennium Development Goal to address undernutrition. This warrants that the policy-makers and programme managers think urgently about the ways to accelerate the progress. The Government, development partners, non-government organizations, and the academia have to work in concert to improve the coverage of basic and effective nutrition interventions, including exclusive breastfeeding, appropriate complementary feeding, supplementation of micronutrients to children, adolescent girls, pregnant and lactating women, management of severe acute malnutrition and deworming, and hygiene interventions, coupled with those that address more structural causes and indirectly improve nutrition. The entire health system needs to be revitalized to overcome the constraints that exist at the levels of policy, governance, and service-delivery, and also for the creation of demand for the services at the household level. In addition, management of nutrition in the aftermath of natural disasters and stabilization of prices of foods should also be prioritized. PMID- 22524114 TI - Increasing antimicrobial resistance of Vibrio cholerae OI biotype E1 tor strains isolated in a tertiary-care centre in India. AB - The antimicrobial susceptibility patterns are on constant change with the recent emergence of multidrug-resistant strains of most bacteria. Results of recent studies in India showed that most isolates of Vibrio cholerae O1 were resistant to the commonly-used antibiotics. The study was conducted to determine the antibiotic susceptibility patterns of V. cholerae O1 isolated during 2008-2010 at the hospital of the Jawaharlal Nehru Institute of Post Graduate Medical Education and Research, Puducherry, India. In total, 154 strains of V. cholerae O1 from 2,658 stool specimens were reported during January 2008-December 2010--34 in 2008, 2 in 2009, and 118 in 2010. The isolates of V. cholerae O1 were subjected to antimicrobial susceptibility testing using the Kirby-Bauer method. The antibiotic disks tested were tetracycline (30 microg), furazolidone (100 microg), ampicillin (10 microg), ceftriaxone (30 microg), and ciprofloxacin (5 microg). Escherichia coli ATCC 25922 was used as the control organism. The minimum inhibitory concentrations (MICs) of ceftriaxone, ciprofloxacin, and tetracycline were determined using the agar dilution method for all the strains. The E-test method was used for the strains which had either intermediate resistance or were resistant to the antibiotics by the agar dilution method. The results of the agar dilution corroborated the results of the E-test. The MIC of ceftriaxone in 151 strains was <2 microg/mL while it was 16 microg/mL in three strains; the latter three strains were resistant to ceftriaxone by the disc-diffusion test. The MIC of ciprofloxacin in 150 strains was <0.5 microg/mL while the MIC of tetracycline was <1 microg/mL. In the remaining four strains, the MIC of tetracycline was >32 microg/mL, and the MIC of ciprofloxacin was >8 microg/mL. These four strains were resistant to both tetracycline and ciprofloxacin by the disc-diffusion test and were exclusive of the three ceftriaxone-resistant strains. The majority of the isolates were obtained from children aged 0-5 year(s)-70.3% (83 of 118) and 41.2% (14 of 34) were reported in 2010 and 2008 respectively. Since treating severe cases of cholera with antibiotics is important, the continuing spread of resistance in V. cholerae to the most important agents of therapy is a matter of concern. Also, chemoprophylaxis with antimicrobial agents is likely to become even more difficult. PMID- 22524115 TI - Storing drinking-water in copper pots kills contaminating diarrhoeagenic bacteria. AB - Microbially-unsafe water is still a major concern in most developing countries. Although many water-purification methods exist, these are expensive and beyond the reach of many people, especially in rural areas. Ayurveda recommends the use of copper for storing drinking-water. Therefore, the objective of this study was to evaluate the effect of copper pot on microbially-contaminated drinking-water. The antibacterial effect of copper pot against important diarrhoeagenic bacteria, including Vibrio cholerae O1, Shigella flexneri 2a, enterotoxigenic Escherichia coli, enteropathogenic E. coli, Salmonella enterica Typhi, and Salmonella Paratyphi is reported. When drinking-water (pH 7.83 +/- 0.4; source: ground) was contaminated with 500 CFU/mL of the above bacteria and stored in copper pots for 16 hours at room temperature, no bacteria could be recovered on the culture medium. Recovery failed even after resuscitation in enrichment broth, followed by plating on selective media, indicating loss of culturability. This is the first report on the effect of copper on S. flexneri 2a, enteropathogenic E. coli, and Salmonella Paratyphi. After 16 hours, there was a slight increase in the pH of water from 7.83 to 7.93 in the copper pots while the other physicochemical parameters remained unchanged. Copper content (177 +/- 16 ppb) in water stored in copper pots was well within the permissible limits of the World Health Organization. Copper holds promise as a point-of-use solution for microbial purification of drinking-water, especially in developing countries. PMID- 22524116 TI - Internalized HIV/AIDS-related stigma in a sample of HIV-positive people in Bangladesh. AB - Internalized stigma among people living with HIV/AIDS (PLHA) is prevalent in Bangladesh. A better understanding of the effects of stigma on PLHA is required to reduce this and to minimize its harmful effects. This study employed a quantitative approach by conducting a survey with an aim to know the prevalence of internalized stigma and to identify the factors associated with internalized stigma among a sample of 238 PLHA (male=152 and female=86) in Bangladesh. The findings suggest that there is a significant difference between groups with the low- and the high-internalized HIV/AIDS stigma in terms of both age and gender. The prevalence of internalized stigma varied according to the poverty status of PLHA. An exploratory factor analysis (EFA) found 10 of 15 items loaded highly on the three factors labelled self-acceptance, self-exclusion, and social withdrawal. About 68% of the PLHA felt ashamed, and 54% felt guilty because of their HIV status. More than half (87.5% male and 19.8% female) of the PLHA blamed themselves for their HIV status while many of them (38.2% male and 8.1% female) felt that they should be punished. The male PLHA more frequently chose to withdraw themselves from family and social gatherings compared to the female PLHA. They also experienced a higher level of internalized stigma compared to the female PLHA. The results suggest that the prevalence of internalized stigma is high in Bangladesh, and much needs to be done by different organizations working for and with the PLHA to reduce internalized stigma among this vulnerable group. PMID- 22524117 TI - Perceptions about probiotic yogurt for health and nutrition in the context of HIV/AIDS in Mwanza, Tanzania. AB - Recently, the food and malnutrition issues have taken centre stage within the arena of HIV/AIDS epidemic, with several calls being made for context-specific health and nutrition interventions to deal with the emerging food insecurity and malnutrition issues in settings with high burdens of HIV/AIDS. The use of probiotics as nutritional supplements in HIV/AIDS-affected and resource-poor settings has also been advocated. This paper presents the results of a qualitative study on community knowledge and perceptions about probiotics and their potential impact on people's everyday life in the context of the HIV/AIDS epidemic. In-depth interviews (n=26) were conducted with residents in Mwanza, Tanzania. The results showed that people living with HIV/AIDS, who were using probiotic yogurt produced through a joint partnership of Western Heads East, Tanzania Medical Research Institute and the Tukwamune Women's Group, reported perceived beneficial effects, such as gain in weight and improved health and well being. Yet, these beneficial effects might be resulting in growing misconceptions about probiotic yogurt being 'medicine' for the treatment of HIV/AIDS; this is leading some people living with HIV/AIDS to abandon taking their antiretroviral medications based on the view that the probiotic yogurt is making them feel much better. The findings illustrate the potential challenges with regard to the introduction of nutritional food supplements into new contexts plagued by malnutrition and infectious diseases. Public-health education and awareness programmes are needed when introducing novel foods into such contexts. PMID- 22524118 TI - Profile of neonatal septicaemia at a district-level sick newborn care unit. AB - Although sepsis is a major cause of morbidity and mortality among newborns in resource-poor countries, little data are available from rural areas on culture proven sepsis. The aim of the present study was to provide information in this regard. The study reports results on the incidence and aetiology of neonatal sepsis cases admitted to a facility in a rural area in eastern India. Blood culture was done for all babies, with suspected clinical sepsis, who were admitted to the sick newborn care unit at Suri where the study was conducted during March 2009-August 2010. A standard form was used for collecting clinical and demographic data. In total, 216 neonatal blood culture samples were processed, of which 100 (46.3%) grew potential pathogens. Gram-negative infection was predominant (58/100 cases) mainly caused by enteric Gram-negative bacteria. Klebsiella pneumoniae was the most common Gram-negative isolate. The emergence of fungal infection was observed, with 40% of the infection caused by yeast. Gram negative organisms exhibited 100% resistance to ampicillin, cefotaxime, and gentamicin. Amikacin and co-trimoxazole showed 95% (n=57) resistance, and ciprofloxacin showed 83.3% (n=50) resistance among the Gram-negative bacteria. Carbapenem showed emerging resistance (n=4; 6.6%). Results of analysis of risk factors showed an extremely significant association between gestation and sepsis and gender and sepsis. Gastrointestinal symptoms were highly specific for fungal infections. One-third of babies (n=29), who developed culture-positive sepsis, died. Blood culture is an investigation which is frequently unavailable in rural India. As a result, empirical antibiotic therapy is commonly used. The present study attempted to provide data for evidence-based antibiotic therapy given to sick newborns in such rural units. The results suggest that there is a high rate of antibiotic resistance in rural India. Urgent steps need to be taken to combat this resistance. PMID- 22524119 TI - Prevalence of food insecurity among women in northern Jordan. AB - Food insecurity--not having sufficient quantities of good-quality foods--is inversely related to physical and mental health and directly related to poor dietary intake. The objectives of this research were to (a) measure the prevalence of food insecurity among women in northern Jordan, (b) study the socioeconomic factors associated with an increased risk of food insecurity, and (c) investigate the relationship between household food insecurity and women's reported body-weight. This cross-sectional study was conducted using an interview based questionnaire. In total, 500 women were interviewed in the waiting rooms of the outpatient clinics of two major public hospitals in northern Jordan. Food insecurity was assessed using the short form of the U.S. food security survey module. The prevalence of food insecurity was 32.4%. Income below the poverty line, illiteracy, unemployment, rented housing, and woman heading the household were among the socioeconomic factors that increased the probability of food insecurity. No evidence was found to support the relationship between obesity and food insecurity. Except grains, food-insecure women with hunger had lower intake of all food-groups. This study demonstrated that the problem of food insecurity is present in Jordan. Food-insecure women with hunger are at a risk of malnutrition. Interventions that target reduction of the factors associated with food insecurity are necessary. PMID- 22524120 TI - Sex differences independent of other psycho-sociodemographic factors as a predictor of body mass index in black South African adults. AB - To better understand the sex differences in body mass index (BMI) observed in black South African adults in the Transition and Health during Urbanization of South Africans Study, the present study investigated whether these differences can be explained by the psycho-sociodemographic factors and/or health-related behaviours. A cross-sectional survey was undertaken among 1,842 black South African individuals from 37 study sites that represented five levels of urbanization. The behavioural factors that possibly could have an influence on the outcome of body-weight and that were explored included: diet, smoking, level of education, HIV infection, employment status, level of urbanization, intake of alcohol, physical activity, and neuroticism. The biological factors explored were age and sex. The prevalence of underweight, normal weight, and overweight among men and women was separately determined. The means of the variables were compared by performing Student's t-test for normally-distributed variables and Mann Whitney U-test for non-normally-distributed variables. The means for the underweight and overweight groups were tested for significant differences upon comparison with normal-weight individuals stratified separately for sex. The differences in prevalence were tested using chi-square tests (p<0.05). All the variables with a large number of missing values were tested for potential bias. The association between sex and underweight or overweight was tested using the Mantel-Haenszel method of odds ratio (OR) and calculation of 95% confidence interval (CI), with statistical significance set at p<0.05 level. Logistic regression was used for controlling for confounders and for testing for effect modification. Females were more likely to be overweight/obese (crude OR=5.1; CI 3.8-6.8). The association was attenuated but remained strong and significant even after controlling for the psycho-sociodemographic confounders. In this survey, the risk for overweight/obesity was strongly related to sex and not to the psycho sociodemographic external factors investigated. It is, thus, important to understand the molecular roots of sex- and gender-specific variability in distribution of BMI as this is central to the future development of treatment and prevention programmes against overweight/obesity. PMID- 22524121 TI - Physical inactivity is correlated with levels of quantitative C-reactive protein in serum, independent of obesity: results of the national surveillance of risk factors of non-communicable diseases in Iran. AB - Increased C-reactive protein (CRP) levels are associated with coronary heart disease, stroke, and mortality. Physical activity prevents cardiovascular disorders, which can be partly mediated through reducing inflammation, including serum CRP levels. The association of different intensities of physical activity, sedentary behaviours, and C-reactive protein (CRP) levels in serum was examined after adjustment for markers of adiposity, including waist-circumference and body mass index (BMI), in a large population-based study. Using data of the SuRFNCD 2007 study, a large national representative population-based study in Iran, the relationship between quantitative CRP concentrations in serum and physical activity was examined in a sample of 3,001 Iranian adults. The global physical activity questionnaire (GPAQ) was used for evaluating the duration and intensity of physical activity. Total physical activity (TPA) was calculated using metabolic equivalents for the intensity of physical activity. Quantitative CRP concentrations in serum were measured with high-sensitivity enzyme immunoassay. The CRP levels in serum significantly correlated with TPA (r=-0.103, p=0.021 in men and r=-0.114, p=0.017 in women), duration of vigorous-intensity activity (r= 0.122, p=0.019 in men and r=-0.109, p=0.026 in women), duration of moderate intensity activity (r=-0.107, p=0.031 in men and r=-0.118, p=0.020 in women), and duration of sedentary behaviours (r=0.092, p=0.029 in men and r=0.101, p=0.022 in women) after multiple adjustments for age, area of residence, BMI, waist circumference, smoking, and diabetes mellitus. Physical activity (of both moderate and vigorous intensity) is inversely associated with the quantitative CRP levels in serum, independent of diabetes and body adiposity. PMID- 22524122 TI - Patterns of alcohol consumption among male adults at a slum in Kolkata, India. AB - Globally, alcohol-abuse is a major cause of mortality and morbidity. Consumption of alcohol has increased in India in the recent decades. It is imperative to know the patterns of alcohol consumption among different types of consumers to launch a well-planned nationwide programme for the prevention and control of this devastating social pathology. This community-based, cross-sectional study was undertaken to identify the patterns of alcohol intake among different types of alcohol consumers and to assess the clinical signs of chronic harmful alcohol use. A predesigned, pretested, semi-structured alcohol-use disorders identification test (AUDIT) questionnaire was used for interviewing males, aged >18 years, selected by random sampling from an updated household list of a randomly-selected sector of the service area of the Urban Health Centre in Chetla, Kolkata, West Bengal, India. Written informed consents were obtained from all the respondents. Relevant clinical examination for chronic harmful alcohol use was done according to the AUDIT clinical screening procedures. The results revealed that 65.8% (150/228) were current consumers of alcohol; 14% were alcohol dependents; 8% were hazardous or harmful consumers, and 78% were non-hazardous non-harmful consumers. The mean age of the respondents at the initiation of drinking alcohol was 20.8+5.9 years. Eighty-six percent of dependents (n=21) took both Indian-made foreign liquor and locally-made alcoholic beverages. The proportions of alcohol consumers who drank alone among alcohol-dependents, hazardous or harmful consumers, and non-hazardous non-harmful consumers were 71.4%, 50%, and 7.7% respectively, and the difference was significant (p<0.01). Forty-one percent of the consumers drank at public places and workplaces, which may be socially harmful. About 38% of the dependents purchased alcohol from unlicensed liquor shops. Only 16% expressed concerns for their drinking habit mainly to the past illness. The proportion of the concerned respondents was higher in the hazardous and harmful drinking patterns than in the non-hazardous non-harmful drinking pattern, and the difference was significant (p<0.05). About 62% of the dependents had clinical signs of chronic alcohol consumption. The presence of a considerable proportion of alcohol-dependents, the low mean age at initiation of drinking alcohol, and the habit of drinking in public places and workplaces are the main areas that need special emphasis by intervention programmes. PMID- 22524123 TI - Income is a stronger predictor of mortality than education in a national sample of US adults. AB - Low socioeconomic status (SES) is associated with mortality in several populations. SES measures, such as education and income, may operate through different pathways. However, the independent effect of each measure mutually adjusting for the effect of other SES measures is not clear. The association between poverty-income ratio (PIR) and education and all-cause mortality among 15,646 adults, aged >20 years, who participated in the Third National Health and Nutrition Examination Survey in the USA, was examined. The lower PIR quartiles and less than high school education were positively associated with all-cause mortality in initial models adjusting for the demographic, lifestyle and clinical risk factors. After additional adjustment for education, the lower PIR quartiles were still significantly associated with all-cause mortality. The multivariable odds ratio (OR) [95% confidence interval (CI)] of all-cause mortality comparing the lowest to the highest quartile of PIR was 2.11 (1.52-2.95, p trend < or = 0.0001). In contrast, after additional adjustment for income, education was no longer associated with all-cause mortality [multivariable OR (95% CI) of all cause mortality comparing less than high school to more than high school education was 1.05 (0.85-1.31, p trend=0.57)]. The results suggest that income may be a stronger predictor of mortality than education, and narrowing the income differentials may reduce the health disparities. PMID- 22524124 TI - Seropositivity of toxoplasmosis in antenatal women with bad obstetric history in a tertiary-care hospital of Andhra Pradesh, India. AB - Toxoplasmosis is a well-documented cause of bad obstetric history (BOH) and a major reason of congenitally-acquired infection. The study was conducted to determine the seropositivity of toxoplasmosis in women with BOH, attending the antenatal clinic of the Mamata General Hospital, Khammam, Andhra Pradesh, India. The study subjects included 105 antenatal women with BOH and 105 antenatal women who had previous normal deliveries. A serological evaluation was carried out to determine the presence of Toxoplasma gondii-specific IgG and IgM antibodies, using commercial diagnostic kits, by the enzyme-linked immunosorbent assay method. The seropositivity for Toxoplasma was 49.52% in the study group compared to 12.38% in the control group. The difference in seropositivity was significant (p=0.00). The seroprevalence gradually increased with advancing age. Abortion (51.92%) was the commonest form of pregnancy wastage, followed by stillbirths (36.53%) and premature deliveries (7.69%). The seropositivity of toxoplasmosis was significantly higher in the study group than that in the control group, and the seropositivity played an important role in determining the foetal outcome. Considering the subclinical pattern of infection, routine serological test is recommended for all pregnant women for both IgG and IgM antibodies. PMID- 22524125 TI - Postpartum amenorrhoea among Manipuri women: a survival analysis. AB - Among the three major components of a closed birth interval, waiting time to conception can somehow be managed with effective contraceptives while gestation is universally constant in its duration; the duration of postpartum amenorrhoea (PPA) varies in complex nature. The present study aimed to investigate the proximate factors influencing the duration of PPA. A community-based, cross sectional study was conducted in four valley districts of Manipur, India, during 1 August-31 December 2009, to analyze the differentials and determinants of duration of PPA, applying the survival analysis technique. In total, 1,225 ever married women were selected through two-stage cluster sampling. The median duration of PPA was 5.7 months. Among the 11 explanatory variables of interest, only three variables--place of residence (p<0.05), infant mortality from preceding pregnancy (p<0.01), and duration of breastfeeding (p<0.01)--had a significant effect on the duration of PPA. The findings may be used as baseline information for future researchers and maternal health policy-makers. PMID- 22524126 TI - Availability and rational use of drugs in primary healthcare facilities following the national drug policy of 1982: is Bangladesh on right track? AB - In Bangladesh, the National Drug Policy (NDP) 1982 was instrumental in improving the supply of essential drugs of quality at an affordable price, especially in the early years. However, over time, evidence showed that the situation deteriorated in terms of both availability of essential drugs and their rational use. The study examined the current status of the outcome of the NDP objectives in terms of the availability and rational use of drugs in the primary healthcare (PHC) facilities in Bangladesh, including affordability by consumers. The study covered a random sample (n=30) of rural Upazila Health Complexes (UHCs) and a convenient sample (n=20) of urban clinics (UCs) in the Dhaka metropolitan area. Observations on prescribing and dispensing practices were made, and exit interviews with patients and their attendants, and a mini-market survey were conducted to collect data on the core drug-use indicators of the World Health Organization from the health facilities. The findings revealed that the availability of essential drugs for common illnesses was poor, varying from 6% in the UHCs to 15% in the UCs. The number of drugs dispensed out of the total number of drugs prescribed was higher in the UHCs (76%) than in the UCs (44%). The dispensed drugs were not labelled properly, although >70% of patients/care-givers (n=1,496) reported to have understood the dosage schedule. The copy of the list of essential drugs was available in 55% and 47% of the UCs and UHCs respectively, with around two-thirds of the drugs being prescribed from the list. Polypharmacy was higher in the UCs (46%) than in the UHCs (33%). An antibiotic was prescribed in 44% of encounters (n=1,496), more frequently for fever (36-40%) and common cold (26-34%) than for lower respiratory tract infection, including pneumonia (10 20%). The prices of key essential drugs differed widely by brands (500% or more), seriously compromising the affordability of the poor people. Thus, the availability and rational use of drugs and the affordability of the poor people have remained to be achieved in Bangladesh even 27 years after approving the much acclaimed NDP 1982. PMID- 22524127 TI - A rapidly-progressing outbreak of cholera in a shelter-home for mentally-retarded females, amta-II block, Howrah, West Bengal, India. AB - On 13 May 2010, a cluster of diarrhoeal disease cases was reported among the inmates of a shelter-home for mentally-retarded females in Parbaksi village of Howrah district in West Bengal, India. The outbreak was investigated to identify the aetiological agent and source of infection and to propose recommendations. A suspected case of cholera was defined as an acute onset of >3 loose watery stools in a female resident of the shelter-home since 1 May 2010. The demographic and clinical details were collected from the suspected case-patients, and the outbreak was described by time, place, and person. A retrospective cohort study was conducted to identify the risk factors associated with the illness. Of the 101 inmates, 91 (90%) developed diarrhoea, and three patients died (case fatality 3%). Four of the five stool specimens were positive for Vibrio cholerae O1 Ogawa. Drinking of water from the pond-connected tubewell (adjusted odds ratio=25.7, 95% confidence interval 2.7-236.4) was associated with the illness. Relocation of the pond-connected tubewell away from the groundwater tubewell, colour-coding of the tubewells meant for drinking purposes, and regular disinfection of the tubewells were recommended. PMID- 22524128 TI - Clinical and epidemiological profiles of severe malaria in children from Delhi, India. AB - Plasmodium vivax is traditionally known to cause benign tertian malaria, although recent reports suggest that P. vivax can also cause severe life-threatening disease analogous to severe infection due to P. falciparum. There are limited published data on the clinical and epidemiological profiles of children suffering from 'severe malaria' in an urban setting of India. To assess the clinical and epidemiological profiles of children with severe malaria, a prospective study was carried out during June 2008-December 2008 in the Department of Pediatrics, Guru Teg Bahadur Hospital, a tertiary hospital located in East Delhi, India. Data on children aged < or = 12 years, diagnosed with severe malaria, were analyzed for their demographic, clinical and laboratory parameters. All patients were categorized and treated as per the guidelines of the World Health Organization. In total, 1,680 children were screened for malaria at the paediatric outpatient and casualty facilities of the hospital. Thirty-eight children tested positive for malaria on peripheral smear examination (2.26% slide positivity rate). Of these, 27 (71%) were admitted and categorized as severe malaria as per the definition of the WHO while another 11 (29%) received treatment on outpatient basis. Most (24/27; 88.8%) cases of severe malaria (n=27) were infected with P. vivax. Among the cases of severe malaria caused by Plasmodium vivax (n=24), 12 (50%) presented with altered sensorium (cerebral malaria), seven (29.1%) had severe anaemia (haemoglobin <5 g/dL), and 17 (70.8%) had thrombocytopaenia, of which two had spontaneous bleeding (epistaxis). Cases of severe vivax malaria are clinically indistinguishable from severe falciparum malaria. Our study demonstrated that majority (88.8%) of severe malaria cases in children from Delhi and adjoining districts of Uttar Pradesh were due to P. vivax-associated infection. P. vivax should, thus, be regarded as an important causative agent for severe malaria in children. PMID- 22524129 TI - Eosinophilic fasciitis: what matters in management in a developing country--a case report with two and a half-year follow-up. AB - Eosinophilic fasciitis is an uncommon disorder of unknown aetiology and poorly understood pathogenesis. Since 1974, over 250 cases of eosinophilic fasciitis have been reported worldwide. The first case of eosinophilic fasciitis from Bangladesh is reported here. The challenges of diagnosis, treatment, and follow up, including family and social support, are discussed. PMID- 22524130 TI - [Current methods for optimization of the cervical cancer diagnosis]. PMID- 22524131 TI - [Feminorm good night to treat the menopause]. AB - Hot flashes are a common and distressing symptom of menopause, affecting approximately 62-83% of women undergoing the menopausal transition. Several pharmacologic treatments for hot flashes, including hormone replacement therapy (HRT) have been shown to reduce the frequency and intensity of hot flashes. However, some women prefer not to use HRT and seek alternative treatments, such as phytoestrogens. Feminorm, Feminorm Duo and Feminorm good night have a beneficial effect on vasomotor symptoms, depression, osteoporosis and cardio vascular diseases. PMID- 22524132 TI - [HE4--a new tumor marker for ovarian cancer]. AB - AIM: Ovarian cancer is the fourth most common cause of cancer-related death in women worldwide. In Europe, the mortality rate range is from 3.6 to 9.3 per 100 000 women; the symptoms are mostly unspecific. Compared to often used CA 125 HE4 is a tumor marker that provides more specific and earlier diagnostic of ovarian cancer. MATERIAL AND METHODS: The HE4 is a solid-phase, non-competitive immunoassay. After the required incubation an enzyme-linked monoclonal antibody are added; followed by substrate solution, which develops color reaction in proportion to the amount of HE4 in serum. RESULTS: For a period of seven months we investigate 55 patients for ovarian cancer. The age was between 25 and 60. In 17 cases the levels of HE4 and CA125 were both elevated. In 8 cases we found no deviation from the normal ranges. In the rest 30 cases the levels of He4 were high, in spite of low CA125 levels. The followed biopsies confirmed the diagnosis ovarian cancer. CONCLUSION: HE4 is vastly more specific and early-phase diagnosed tumor marker in cases with ovarian cancer. Its common usual would reduce the mortality from this social disease. PMID- 22524133 TI - [Hormone replacement therapy at women with fertility problems and proofs of hypergonadotropic hypoovarism]. AB - The premature ovarian failure (POF), is the main precondition for the origin and the progress of the hypergonadotropic hypoovarism in part of the women with infertility. The significant decrease of the ovarian reserve, makes the treatment of these patients very difficult and problematic, still pregnancy is observed at 5-10% of them. Objective of the research: To study the effect of the Hormone Replacement Therapy (HRT) on the values of FSH before and after the treatment of women with POF, as well as its effect on the percentage of effective pregnancy. 47 infertile women with high values of FSH were included in the study and they followed a 2-4 month treatment with Trisequens tabl. The results of the ART were reported after the reduction of the FSH levels to the normal values. At the end of the treatment followed, the values of the FSH of 41 from 47 patients (87,23%), were reduced to normal range and necessary reproductive procedures were performed. Dividing the patients in 5 groups by age, it was found that the results depend to the greatest extend on this factor. In the group of women up to 30, pregnancy occurred in 25%, between 30 and 35 years this percentage decreased to 22,2%; in the group 35-40 years it sharply decreased to 10% and over 40 years the percentage was 0%. The total percentage of conceived patients for the whole last contingent is 13,4%. The patients with POF and high levels of FSH are worth to follow a Hormone Replacement Therapy before undertaking the oocyte donation. PMID- 22524134 TI - [Current trends in the treatment of vaginitis]. PMID- 22524135 TI - [Content of the dietary iron supplement for oral administration for the treatment of iron-deficiency anemia in the obstetrics and gynecology practice]. AB - Iron deficiency is the most prevalent nutritional deficiency and the most common cause of amemia. Tot'hema ampoules contain an iron supplement in liquid form. The formulation includes Copper and Manganese which enhance its action. Tot'hema is indicated in iron deficiency anaemias, iron deficiency prophylaxis in pregnancy, newborns with an iron-deficient mother, and when adequate mounts of iron cannot be supplied by food intake. Tot'hema improves hematologic and biochemical index, completely supplies iron and copper deficiency, prevents of iron resistant form of IDA. Tot'hema has no side effects. PMID- 22524136 TI - [Our experience with management of inherited thrombophilia during pregnancy: preliminary report]. AB - It has become clear in the recent years that inherited thrombophilias (IT) are associated with serious abnormalities during pregnancy. This includes miscarriage, still birth, placental abruption, praeclamcspia and intrauterine fetal growth restriction. The aim of this study is to share our experience in the field. MATERIALS AND METHODS: 38 patients with medical history of abnormal pregnancies (miscarriage, still birth, placental abruption, praeclamcspia and intrauterine fetal growth reastriction). They were all tested for the following gene alterations: V Laidon- R506Q/phiVL-R506Q/, protrombin G/A 20210/pG/A20210/, Plasminogen activator inhibitor- PAI- 4G/4G /PAI 4G/5G/). IT were diagnosed in 24 patients. They were all treated by: Aspirin 75mg form prior to conception and low molecular Heparin after detection of fetal heart movement. Due to the observed NRDS in some of the newborns, the low molecular heparin intake was discontinued 30 days prior to expected delivery. RESULTS: keeping up to the therapeutic scheme, 70% (17) of women with IT gave birth to a term baby, and 30% (7)- to a preterm one, all pregnancies were successful. Amongst the patients with medical history of miscarriage, 72% were diagnosed with IT and 87.5% of them gave birth to a term newborn as a result of the anticoagulant treatment. CONCLUSIONS: Undiagnosed IT is a common cause of adverse pregnancy outcome. Uninterrupted anticoagulant treatment of these patients is very successful. The whole pregnancy should be followed up closely. Due to the higher risk of respiratory complications in the infants, delivery should be performed in a specialized hospital with neonatology department, capable of newborn resuscitation. PMID- 22524137 TI - [Treatment of preterm delivery--therapeutic algorithm]. AB - In the recent years the rate of preterm deliveries has not been brought down despite of the new therapeutic management and medications. The aim of this scientific report is to share our algorithm of preterm delivery prevention. MATERIALS AND METHODS: Our trial consisted of 23 patients between 26 and 36 weeks of gestation diagnosed with preterm delivery, for a one year period - May 2010 to May 2011. The following therapeutic algorithm was applied: magnesium preparations, B2-mymetics, if no improvement was seen in 24 hour period we continued with Utrogestan, Calcium channel blockers, Indomethacin. Progesterone, who hasn't so far been administered in this gestational age, followed this algorithm: loading dose of three tablets, followed by therapeutic dose of 1 to 2 tablets 3 times a day, and a maintenance dose of 1 tablet 3 times a day. Pregnant wemen under 35 completed gestational weeks were also administered steroid i.m. for prevention of neonatal RDS, followed by Ambroxol per orally. RESULTS: Our new algorithm prolonged pregnancy for more than 14 days in 82.6% of the cases. Delivery. was postponed with 7 days in 17.4% of the cases, with up to 14 days in 30.4%, with up to 21 days in 26.1% and with more than 21 days in 26.1% of the cases. CONCLUSIONS: Including progesterone in our common therapeutic scheme we were able to prolong pregnancy significantly. PMID- 22524138 TI - [Some aspects of prostaglandin administration in obstetrics: preliminary report]. AB - Prostaglandin preparations are widely used in the OB-GYN practice today. This is due to their high efficiency and their potency to prevent a surgical intervention and serious complications. The aim of this study is to share our experience in the prevention of hypo- and atonic, itra- and postoperative hemorrhage after Caesarian Section on multiple pregnancy. MATERIALS AND METHODS: 31 patients with multiple pregnancy for the period of Jan 2010 to June 2011, delivered by Cesarean Section due to unfavorable fetus presentation. Time of delivery- 34 to 38 weeks of gestation. 13 of them represented our work group, amongst them 11 with twin pregnancy and 2 with triplets. They were administered, in theatre, prostaglandin F2alpha as 1 ampule of Prostin 15M (Carboprost tromethamole 0.25 mg) in the uterus wall, as a prophylaxis. The control group consisted of 18 multiple pregnancy patients, chosen randomly and delivered again by C.S., 14 of them with twin pregnancy and 4 with triplets. RESULTS: In our work group the average maternal blood loss was 520 ml +/- 104 ml, compared to 760 +/- 80 ml in the control group. There were patients in the control group with average blood loss of 1500 ml leading to the need of urgent and lifesaving measures. CONCLUSIONS: Nevertheless the small number of cases we had, we dare to say the administration of Carboprost tromethamole - Prostin 15M, intramurally in the uterus during Cesarean section on multiple pregnancy, diminishes the risk of severe hypo- and atonic hemorrhage in theatre and postpartum. PMID- 22524139 TI - [Our treatment approach for preterm birth]. PMID- 22524140 TI - [Balloon-uterine tamponade in acute postpartum haemorrhage]. AB - Each year about 500,000 mothers die worldwide as 24 to 60% of deaths due to postpartum haemorrhage. The author presents a balloon-tamponade of the uterus as an effective weapon in the fight against postnatal bleeding. Requests are publications on the subject in different journals cited in Medline, Cochrane library, Nature, Science, Lancet, GyneWeb and others. PMID- 22524141 TI - [Researching the effectiveness and the relevancy of combined therapy with Polygynax and Pharmatex in the cases with proved HPV infection or suspicion of such infection]. AB - The HPV infection is the most frequent sexually transmitted disease. It can be estimated that approximately 80% of young women would be infected with it till their fiftieth anniversary. When there is a HPV infection in the zone of the external sexual organs and the introitus, in 90% of the cases, the cervix is also engaged. In the majority of the cases, there is a parallel fungal infection with often presence of bacterial component which sets the low local immunity and creates ideal environment for HPV infection. This fact serves as basis for the application of the therapeutic combination of Polygynax+Pharmatex at this first stage. Relying on the virucide action of the local non-hormonal contraception - Pharmatex and the wide action range of Polygynax, the present clinical research confirmed the rightfulness of our thesis and the efficiency of the suggested therapeutic model. PMID- 22524142 TI - [Diagnostic and clinical behaviour with Tarlov cyst in gynaecology practice]. AB - The following presents cases from the gynaecological practice which resulted in a surgical intervention due to the detection of cystic formations of origin out of the reproductive system. Although rare, Tarlov cyst has its place in the differential diagnostic plan of ovarian formations. MRI scan remains an alternative to the ultrasound imagery and is the main diagnostic method for obtaining the right diagnosis. This further aids the set of actions appropriate with patients suffering from Tarlov cyst. Thus, unnecessary abdominal surgical interventions are not to be undertaken. PMID- 22524143 TI - [The infants with very low birth weight and extremely low birth weight-obstetrics and medico-social problems]. PMID- 22524144 TI - [The age as risk factor for pre-eclampsia]. AB - Pre-eclampsia is a serious complication during pregnancy. It occurs after 20 weeks of pregnancy. The condition is defined by the following symptoms: hypertension, excess protein in the urine, oedema. The aim of this research is to determine the influence of age as risk factor for pre-eclampsia. The study was made at University Hospital-Pleven. Documentary method is used to collect information - medical history of patients. For the period of 2005/2010 the share of the hospitalized patients is relatively low, between 1,9-4,9% of the whole pathology The share of patients with pre-eclampsia after 30 years age is increasing. PMID- 22524146 TI - Deliquescence and efflorescence behavior of ternary inorganic/organic/water aerosol particles. AB - The deliquescence behavior of ternary inorganic (ammonium sulfate and ammonium nitrate)/organic (glutaric acid and malonic acid)/water aerosol particles has been investigated at 293 K using a novel surface aerosol microscopy (SAM) technique. The results obtained for the deliquescence relative humidities (DRH) for particles of variable inorganic/organic contents show a eutectic behavior with the mixed particles showing deliquescence at lower DRH compared to the pure inorganic and organic components, respectively. This behavior has been quantitatively modeled using the extended aerosol inorganics (E-AIM) thermodynamic model of Clegg et al. in combination with the UNIFAC group activity approach to account for organic molecular solutes. In addition, we have investigated the crystallization behavior of supersatured and formerly deliquesced ternary solution droplets using space resolved Raman spectroscopy. It is found that such droplets produce solid particles in which the inorganic and organic phases show some spatial separation with the organic component being predominantly found at the outer part of the particle. Independent measurements of the contact angles of such ternary droplets reveal that their angles are within experimental error identical to those of the purely organic/water solutions. PMID- 22524145 TI - Mercury/homocysteine ligation-induced ON/OFF-switching of a T-T mismatch-based oligonucleotide molecular beacon. AB - A molecular beacon (MB) with stem-loop (hairpin) DNA structure and with attached fluorophore-quencher pair at the ends of the strand has been applied to study the interactions of Hg(2+) ions with a thymine-thymine (T-T) mismatch in Watson-Crick base-pairs and the ligative disassembly of MB.Hg(2+) complex by Hg(2+) sequestration with small biomolecule ligands. In this work, a five base-pair stem with configuration 5'-GGTGG...CCTCC-3' for self-hybridization of MB has been utilized. In this configuration, the four GC base-pair binding energy is not sufficient to hybridize fully at intermediate temperatures and to form a hairpin MB conformation. The T-T mismatch built-in into the stem area can effectively bind Hg(2+) ions creating a bridge, T-Hg-T. We have found that the T-Hg-T bridge strongly enhances the ability of MB to hybridize, as evidenced by an unusually large MB melting temperature shift observed on bridge formation, DeltaT(m) = +15.1 +/- 0.5 degrees C, for 100 nM MB in MOPS buffer. The observed DeltaT(m) is the largest of the DeltaT(m) found for other MBs and dsDNA structures. By fitting the parameters of the proposed model of reversible MB interactions to the experimental data, we have determined the T-Hg-T bridge formation constant at 25 degrees C, K(1) = 8.92 +/- 0.42 * 10(17) M(-1) from mercury(II) titration data and K(1) = 1.04 +/- 0.51 * 10(18) M(-1) from the bridge disassembly data; DeltaG degrees = -24.53 +/- 0.13 kcal/mol. We have found that the biomarker of oxidative stress and cardiovascular disease, homocysteine (Hcys), can sequester Hg(2+) ions from the T-Hg-T complex and withdraw Hg(2+) ions from MB in the form of stable Hg(Hcys)(2)H(2) complexes. Both the model fitting and independent (1)H NMR results on the thymidine-Hg-Hcys system indicate also the high importance of 1:1 complexes. The high value of K(1) for T-Hg-T bridge formation enables analytical determinations of low concentrations of Hg(2+) (limit of detection LOD = 19 nM or 3.8 ppb, based on 3sigma method) and Hcys (LOD = 23 nM, 3sigma method). The conditional stability constants for Hg(Hcys)H(2)(2+) and Hg(Hcys)(2)H(2) at 52 degrees C have been determined, beta(112) = 5.37 +/- 0.3 * 10(46) M(-3), beta(122) = 3.80 +/- 0.6 * 10(68) M(-4), respectively. PMID- 22524148 TI - A co-actor's focus of attention affects stimulus processing and task performance: an ERP study. AB - When acting and attending together, we take each other's perceptual and intentional relations to the environment into account. The present study investigated whether people are also sensitive to a co-actor's attentional relation to jointly attended events. Two participants sat next to each other and performed a two-choice Navon task, responding to the identity of letters formed by identical (congruent) or different (incongruent) smaller letters while EEG was recorded. Crucially, participants either held the same focus of attention (e.g., both attending to local stimulus features) or different foci of attention (e.g., one attending to local and the other to global features). Results revealed a significant slow-down of responses when participants focused on different features. Amplitudes of the occipital P1 and parietal occipital P3 decreased when attentional foci differed. The amplitude of the fronto-central N2 increased when the other attended to local as compared to global features. These results suggest that representations of a co-actor's task can include a specification of his or her focus of attention. Taking into account the other's different attentional relation to stimuli likely induces a conflict at the level of task selection, impairing early allocation of attention (P1) and enhancing the need to monitor response initiation (P3). PMID- 22524147 TI - Differences in self-reported discrimination by primary type of drug used among New York City drug users. AB - BACKGROUND: Illicit drug users experience various forms of discrimination which may vary by type of drug used, as there are different levels of stigma associated with different types of drugs. OBJECTIVES: This study investigated self-report of perceived discrimination by primary type of drug used. METHODS: This analysis used data from "Social Ties Associated with Risk of Transition into Injection Drug Use" (START), a cross-sectional study of recently initiated injection drug users (IDUs) and prospective study of heroin/crack/cocaine-using non-IDUs (n = 652). Using log binomial regression, the relationship between primary drug used (i.e., single drug used most often) with discrimination due to drug use was examined. RESULTS: Heroin users were significantly more likely (Prevalence ratio (PR): 1.52 (95% Confidence interval (CI): 1.15-2.07)) to report discrimination due to drug use compared to cocaine users. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: More research is needed to understand the mechanism through which discrimination affects heroin users, and its potential relation with other discrimination-related outcomes, namely depression and drug treatment. PMID- 22524149 TI - Leaching of biocides from facades under natural weather conditions. AB - Biocides are included in organic building facade coatings as protection against biological attack by algae and fungi but have the potential to enter the environment via leaching into runoff from wind driven rain. The following field study correlates wind driven rain to runoff and measured the release of several commonly used organic biocides (terbutryn, Irgarol 1051, diuron, isoproturon, OIT, DCOIT) in organic facade coatings from four coating systems. During one year of exposure of a west oriented model house facade in the Zurich, Switzerland area, an average of 62.7 L/m(2), or 6.3% of annual precipitation came off the four facade panels installed as runoff. The ISO method for calculating wind driven rain loads is adapted to predict runoff and can be used in the calculation of emissions in the field. Biocide concentrations tend to be higher in the early lifetime of the coatings and then reach fairly consistent levels later, generally ranging on the order of mg/L or hundreds of MUg/L. On the basis of the amount remaining in the film after exposure, the occurrence of transformation products, and the calculated amounts in the leachate, degradation plays a significant role in the overall mass balance. PMID- 22524150 TI - Synthesis of enantioenriched tertiary boronic esters from secondary allylic carbamates. Application to the synthesis of C30 botryococcene. AB - Enantioenriched secondary allylic carbamates have been deprotonated with sBuLi and reacted with boronic esters. In contrast to other electrophiles, high alpha selectivity was observed and the boronate complexes were formed with almost complete retention of stereochemistry. The boronate complexes underwent a stereospecific 1,2-migration leading to tertiary allylic boronic esters with high er (>98:2). The scope of the reaction has been explored and found to embrace a broad range of both allylic carbamates and boronic esters. The methodology has been applied to an eight-step, stereoselective synthesis of each of the diastereoisomers of C30 botryococcene. PMID- 22524151 TI - Chromophobe renal cell carcinoma with prolonged response to targeted therapy: a case report. AB - INTRODUCTION: Chromophobe renal cell carcinoma is universally accepted as a distinct subtype of renal cell carcinoma. There are conflicting reports on prognosis, and few data on response to treatment exist. Currently, we do not have any effective treatment for the metastatic disease apart from surgical procedures. Current strategies are based on results obtained in the context of clear cell-type renal cell carcinoma. Separate trials for rare histologies seem unfeasible and are unlikely to be performed. For these cases, clinical observations are an important part for advancing therapeutic insight. In recent years, novel tyrosine kinase inhibitors have been shown to have significant clinical benefit in advanced renal cell carcinoma. CASE PRESENTATION: We present the case of a 43-year-old Caucasian man with advanced chromophobe renal cell carcinoma treated with the tyrosine kinase inhibitor sunitinib and subsequently with sorafenib and the mammalian target of the rapamycin inhibitor everolimus, achieving a prolonged response and significant clinical benefit. We report an unexpectedly high efficacy of everolimus as a third-line treatment in a patient with metastatic chromophobe renal cell carcinoma. CONCLUSIONS: Up to now, no published data from randomized clinical studies have addressed the question of efficacy of everolimus as a third-line treatment after failure of tyrosine kinase inhibitors. To the best of our knowledge, this case is the first report of chromophobe renal cell carcinoma treated successfully with sequential tyrosine kinase and mammalian target of rapamycin inhibitor therapy. Notably, the time on treatment with sunitinib exceeded four years. The case presented here implies that everolimus could be a viable option for patients with metastatic chromophobe renal cell carcinoma. PMID- 22524152 TI - RS-Predictor models augmented with SMARTCyp reactivities: robust metabolic regioselectivity predictions for nine CYP isozymes. AB - RS-Predictor is a tool for creating pathway-independent, isozyme-specific, site of metabolism (SOM) prediction models using any set of known cytochrome P450 (CYP) substrates and metabolites. Until now, the RS-Predictor method was only trained and validated on CYP 3A4 data, but in the present study, we report on the versatility the RS-Predictor modeling paradigm by creating and testing regioselectivity models for substrates of the nine most important CYP isozymes. Through curation of source literature, we have assembled 680 substrates distributed among CYPs 1A2, 2A6, 2B6, 2C19, 2C8, 2C9, 2D6, 2E1, and 3A4, the largest publicly accessible collection of P450 ligands and metabolites released to date. A comprehensive investigation into the importance of different descriptor classes for identifying the regioselectivity mediated by each isozyme is made through the generation of multiple independent RS-Predictor models for each set of isozyme substrates. Two of these models include a density functional theory (DFT) reactivity descriptor derived from SMARTCyp. Optimal combinations of RS-Predictor and SMARTCyp are shown to have stronger performance than either method alone, while also exceeding the accuracy of the commercial regioselectivity prediction methods distributed by Optibrium and Schrodinger, correctly identifying a large proportion of the metabolites in each substrate set within the top two rank-positions: 1A2 (83.0%), 2A6 (85.7%), 2B6 (82.1%), 2C19 (86.2%), 2C8 (83.8%), 2C9 (84.5%), 2D6 (85.9%), 2E1 (82.8%), 3A4 (82.3%), and merged (86.0%). Comprehensive datamining of each substrate set and careful statistical analyses of the predictions made by the different models revealed new insights into molecular features that control metabolic regioselectivity and enable accurate prospective prediction of likely SOMs. PMID- 22524153 TI - No correlation between the expression of FXR and genes involved in multidrug resistance phenotype of primary liver tumors. AB - Farnesoid X receptor (FXR) has been recently reported to enhance chemoresistance through bile acid-independent mechanisms. Thus, FXR transfection plus activation with GW4064 resulted in reduced sensitivity to cisplatin-induced toxicity. This is interesting because primary tumors of the liver, an organ where FXR is expressed, exhibit marked refractoriness to pharmacological treatment. Here we have determined whether FXR is upregulated in hepatocellular carcinoma (HCC), cholangiocarcinoma (CGC) and hepatoblastoma (HPB) and whether this is related with the expression of genes involved in mechanisms of chemoresistance. Using RT QPCR and Taqman low density arrays we have analyzed biopsies from healthy livers or surgically removed tumors from naive patients and cell lines derived from HCC (SK-HEP-1, Alexander and Huh7), CGC (TFK1) and HPB (HepG2), before and after exposure to cisplatin at IC50 for 72 h. In liver tumors FXR expression was not enhanced but significantly decreased (healthy liver > HCC > HPB ~ CGC). Except for CGC, this was not accompanied by changes in the proportions of FXR isoforms. Changes in 36 genes involved in drug uptake/efflux and metabolism, expression/function of molecular targets, and survival/apoptosis balance were found. Changes affecting SLC22A1, CYP2A1 and BIRC5 were shared by HCC, CGC and HPB. Similarity in gene expression profiles between cell lines and parent tumors was found. Pharmacological challenge with cisplatin induced changes that increased this resemblance. This was not dependent upon FXR expression. Thus, although FXR may play a role in inducing chemoresistance under certain circumstances, its upregulation does not seem to be involved in the multidrug resistance phenotype characteristic of HCC, CGC and HPB. PMID- 22524155 TI - A comparison of screening methods in two early phase oral leukoplakia clinical trials. AB - OBJECTIVES/INTRODUCTION: Clinical trial accrual for oral dysplasia is difficult in the United States and elsewhere. Patients with dysplastic oral leukoplakia progress to frank invasive carcinoma at a rate of 5-37% over 5 years. We compared two clinical trial screening efforts to hopefully devise better accrual strategies to these types of clinical trials. METHODS: For the first trial, we identified 244 patients with dysplastic oral leukoplakia in our university database and a media campaign. Patients were notified and screened by examination and biopsy. For the second clinical trial, we established a preneoplastic lesions clinic and teaching and communications network with regional oral healthcare professionals. RESULTS: Only one of 244 patients accrued to the first clinical trial through an organized screening effort based on database/medical records review. The second clinical trial accrued 16/30 screened patients through redirected efforts in teaching, communications, and a preneoplastic lesions clinic. CONCLUSION: We conclude that significant difficulties resulted from medical record/database review of leukoplakia patients as a screening method for leukoplakia clinical trial entry. We feel that persistent direct contact and education of healthcare professionals who are likely to examine leukoplakia patients improved accrual to the second clinical trial. PMID- 22524154 TI - Ethanol drinking microstructure of a high drinking in the dark selected mouse line. AB - BACKGROUND: The High Drinking in the Dark (HDID) selected mouse line was bred for high blood ethanol (EtOH) concentration (BEC) following the limited access drinking in the dark (DID) test and is a genetic animal model of binge-like drinking. This study examines the microstructure of EtOH drinking in these mice and their control line during 3 versions of the DID test to determine how drinking structure differences might relate to overall intake and BEC. METHODS: Male mice from the HDID-1 replicate line and HS/Npt progenitor stock were tested in separate experiments on 2- and 4-day versions of the DID test, and on a 2-day 2-bottle choice DID test with 20% EtOH and water. Testing took place in home cages connected to a continuous fluid intake monitoring system, and drinking during the DID test was analyzed for drinking microstructure. RESULTS: HDID-1 mice had more drinking bouts, shorter interbout interval, larger bout size, greater total EtOH intake, and higher BECs than HS/Npt mice on the second day of the 2-day DID test. The 4-day DID test showed greater bout size, total EtOH intake, and BEC in the HDID-1 mice than the HS/Npt mice. Total EtOH intake and BECs for the HDID-1 mice in the DID tests averaged 2.6 to 3.0 g/kg and 0.4 to 0.5 mg/ml, respectively. The 2-bottle choice test showed no genotype differences in drinking microstructure or total consumption but did show greater preference for the EtOH solution in HDID-1 mice than HS/Npt. CONCLUSIONS: These results suggest that inherent differences in EtOH drinking structure between the HDID-1 and HS/Npt mice, especially the larger bout size in the HDID-1 mice, contribute to the difference in intake during the standard DID test. PMID- 22524156 TI - A three-compartment chemically-driven molecular information ratchet. AB - We describe a three-compartment rotaxane information ratchet in which the macrocycle can be directionally transported in either direction along an achiral (disregarding isotopic labeling) track. Chiral DMAP-based catalysts promote a benzoylation reaction that ratchets the displacement of the macrocycle, transporting it predominantly to a particular end compartment determined by the handedness of the catalyst. PMID- 22524158 TI - SNP marker detection and genotyping in tilapia. AB - We have generated a unique resource consisting of nearly 175 000 short contig sequences and 3569 SNP markers from the widely cultured GIFT (Genetically Improved Farmed Tilapia) strain of Nile tilapia (Oreochromis niloticus). In total, 384 SNPs were selected to monitor the wider applicability of the SNPs by genotyping tilapia individuals from different strains and different geographical locations. In all strains and species tested (O. niloticus, O. aureus and O. mossambicus), the genotyping assay was working for a similar number of SNPs (288 305 SNPs). The actual number of polymorphic SNPs was, as expected, highest for individuals from the GIFT population (255 SNPs). In the individuals from an Egyptian strain and in individuals caught in the wild in the basin of the river Volta, 197 and 163 SNPs were polymorphic, respectively. A pairwise calculation of Nei's genetic distance allowed the discrimination of the individual strains and species based on the genotypes determined with the SNP set. We expect that this set will be widely applicable for use in tilapia aquaculture, e.g. for pedigree reconstruction. In addition, this set is currently used for assaying the genetic diversity of native Nile tilapia in areas where tilapia is, or will be, introduced in aquaculture projects. This allows the tracing of escapees from aquaculture and the monitoring of effects of introgression and hybridization. PMID- 22524159 TI - Simulation: a panacea for interprofessional learning? PMID- 22524161 TI - Pre-pubertal isolated plexiform neurofibroma of labium majus without clitoral involvement. PMID- 22524162 TI - A misprint in a description of microbeam irradiations of rats' heads. PMID- 22524163 TI - Safety assessment in the urban park environment in Alborz Province, Iran. AB - Urban parks, as one of the recreational and sports sectors, could cause serious injuries among different ages if the safety issues in their design are not considered. These injuries can result from the equipment in the park, including play and sports equipment, or even from environmental factors, too. Lack of safety benchmark in parks will impact on the development of future proposals. In this article, attempts are made to survey the important safety factors in the urban parks including playgrounds, fitness equipment, pedestrian surface and environmental factors into a risk assessment. Hence, a checklist of safety factors was used. A Yes or No descriptor was allocated to any factor for determining safety level. The study also suggests recommendations for future planning concerning existing failures for designers. It was found that the safety level of the regional and local parks differ from each other. PMID- 22524164 TI - Molecular diagnostic testing for Klinefelter syndrome and other male sex chromosome aneuploidies. AB - BACKGROUND: Male sex chromosome aneuploidies are underdiagnosed despite concomitant physical and behavioral manifestations. OBJECTIVE: To develop a non invasive, rapid and high-throughput molecular diagnostic assay for detection of male sex chromosome aneuploidies, including 47,XXY (Klinefelter), 47,XYY, 48,XXYY and 48,XXXY syndromes. METHODS: The assay utilizes three XYM and four XA markers to interrogate Y:X and X:autosome ratios, respectively. The seven markers were PCR amplified using genomic DNA isolated from a cohort of 323 males with aneuploid (n = 117) and 46,XY (n = 206) karyotypes. The resulting PCR products were subjected to Pyrosequencing, a quantitative DNA sequencing method. RESULTS: Receiver operator characteristic (ROC) curves were used to establish thresholds for the discrimination of aneuploid from normal samples. The XYM markers permitted the identification of 47,XXY, 48,XXXY and 47,XYY syndromes with 100% sensitivity and specificity in both purified DNA and buccal swab samples. The 48,XXYY karyotype was delineated by XA marker data from 46,XY; an X allele threshold of 43% also permitted detection of 48,XXYY with 100% sensitivity and specificity. Analysis of X chromosome-specific biallelic SNPs demonstrated that 43 of 45 individuals (96%) with 48,XXYY karyotype had two distinct X chromosomes, while 2 (4%) had a duplicate X, providing evidence that 48,XXYY may result from nondisjunction during early mitotic divisions of a 46,XY embryo. CONCLUSIONS: Quantitative Pyrosequencing, with high-throughput potential, can detect male sex chromosome aneuploidies with 100% sensitivity. PMID- 22524157 TI - Viral invasion of the amniotic cavity (VIAC) in the midtrimester of pregnancy. AB - INTRODUCTION: The prevalence of viral infections in the amniotic fluid (AF) has not yet been ascertained. The aim of this study was to determine the prevalence of specific viral nucleic acids in the AF and its relationship to pregnancy outcome. STUDY DESIGN: From a cohort of 847 consecutive women undergoing midtrimester amniocentesis, 729 cases were included in this study after exclusion of documented fetal anomalies, chromosomal abnormalities, unavailability of AF specimens and clinical outcomes. AF specimens were tested by quantitative real time PCR for the presence of genome sequences of the following viruses: adenoviruses, herpes simplex virus (HSV), varicella zoster virus (VZV), human herpesvirus 6 (HHV6), human cytomegalovirus (HCMV), Epstein-Barr virus (EBV), parvovirus B19 and enteroviruses. Viral nucleic acid testing was also performed in maternal blood and cord blood in the population of women in whom AF was positive for viruses and in a control group of 29 women with AF negative for viral nucleic acids. The relationship between the presence of viruses and pregnancy and neonatal outcome was examined. The correlation between the presence of nucleic acids of viruses in the AF and the concentration of the cytokine interleukin-6 (IL-6) and the T cell chemokine CXCL-10 (or IP-10) in AF and maternal blood were analyzed. RESULTS: Viral genome sequences were found in 16 of 729 (2.2%) AF samples. HHV6 was the most commonly detected virus (7 cases, 1.0%), followed by HCMV (6 cases, 0.8%), parvovirus B19 (2 cases, 0.3%) and EBV (1 case, 0.1%), while HSV, VZV, enteroviruses and adenoviruses were not found in this cohort. Corresponding viral DNA was also detected in maternal blood of six out of seven women with HHV6-positive AF and in the umbilical cord plasma, which was available in one case. In contrast, viral DNA was not detected in maternal blood of women with AF positive for parvovirus B19, HCMV, EBV or of women with AF negative for viruses. HHV6 genome copy number in AF and maternal blood was consistent with genomic integration of viral DNA and genetic infection in all women. There was no significant difference in the AF concentration of IL-6 and IP 10 between patients with and without VIAC. However, for HCMV, there was a significant relationship between viral copy number and IP-10 concentration in maternal blood and AF. The group of women with AF positive for viral DNA delivered at term healthy neonates without complications in 14 out of 16 cases. In one case of HHV6 infection in the AF, the patient developed gestational hypertension at term, and in another case of HHV6 infection in the AF, the patient delivered at 33 weeks after preterm premature rupture of membranes (PPROM). CONCLUSION: Viral nucleic acids are detectable in 2.2% of AF samples obtained from asymptomatic women in the midtrimester. HHV6 was the most frequently detected virus in AF. Adenoviruses were not detected. Vertical transmission of HHV6 was demonstrated in one case. PMID- 22524165 TI - Choosing models for health care cost analyses: issues of nonlinearity and endogeneity. AB - OBJECTIVE: To compare methods of analyzing endogenous treatment effect models for nonlinear outcomes and illustrate the impact of model specification on estimates of treatment effects such as health care costs. DATA SOURCES: Secondary data on cost and utilization for inpatients hospitalized in five Veterans Affairs acute care facilities in 2005-2006. STUDY DESIGN: We compare results from analyses with full information maximum simulated likelihood (FIMSL); control function (CF) approaches employing different types and functional forms for the residuals, including the special case of two-stage residual inclusion; and two-stage least squares (2SLS). As an example, we examine the effect of an inpatient palliative care (PC) consultation on direct costs of care per day. DATA COLLECTION/EXTRACTION METHODS: We analyzed data for 3,389 inpatients with one or more life-limiting diseases. PRINCIPAL FINDINGS: The distribution of average treatment effects on the treated and local average treatment effects of a PC consultation depended on model specification. CF and FIMSL estimates were more similar to each other than to 2SLS estimates. CF estimates were sensitive to choice and functional form of residual. CONCLUSIONS: When modeling cost or other nonlinear data with endogeneity, one should be aware of the impact of model specification and treatment effect choice on results. PMID- 22524166 TI - A delta-sarcoglycan gene polymorphism as a risk factor for hypertrophic cardiomyopathy. AB - BACKGROUND: The C allele of c.-94C>G polymorphism of the delta-sarcoglycan gene was associated as a risk factor for coronary spasm in Japanese patients with hypertrophic cardiomyopathy (HCM). AIM: We evaluated whether the c.-94C>G polymorphism can be a risk factor for HCM in Mexican patients. METHODS: The polymorphism was genotyped and the risk was estimated in 35 HCM patients and 145 healthy unrelated individuals. Data of this polymorphism reported in Mexican Amerindian populations were included. RESULTS: The C allele frequency in HCM patients was higher with an odds ratio (OR) of 2.37, and the risk for the CC genotype increased to 5.0. The analysis with Mexican Amerindian populations showed that the C allele frequency was significantly higher in HCM patients with an OR of 2.96 and for CC genotype the risk increased to 7.60. CONCLUSIONS: The C allele of the c.-94C>G polymorphism is a risk factor for HCM, which is increased by the Amerindian component and can play an important role in the etiology and progression of disease in Mexican patients. PMID- 22524167 TI - Facing the challenge of adapting to a life 'alone' in old age: the influence of losses. AB - AIM: The aim of this study is to explore older people's approaches to living a life characterized by losses and 'aloneness' and how this relates to loneliness. BACKGROUND: Loneliness is closely related to social status and health condition. Older people are vulnerable to experiences of loneliness due to losses, which follow the ageing process. METHOD: A qualitative interpretative design was used. Older people, aged 65 and above, living at home, in retirement villages, or in long-term care settings in Australia, Norway, and UK participated. Seventy-eight persons were included. Data were collected through open-ended interviews during autumn of 2006 and spring of 2007. The interviews were audio taped, transcribed, and analysed applying a hermeneutic, interpretative process. FINDINGS: Analyses revealed great differences in the way participants handled their life situation. Interviewees describing themselves as 'not lonely' viewed losses as normal, and they participated in meaningful activities, connected to other people and thrived in their own company. Those describing themselves as 'lonely' on the other hand, strove to create meaning in their lives, were overwhelmed by losses, had problems finding meaningful activities and difficulty keeping up social relations. CONCLUSION: Loneliness was associated with overwhelming losses, inactivity, meaninglessness, and social isolation. The contrasting findings between 'not lonely' and 'lonely' older people have implications for nursing in that nurses must seek to identify those who need help in managing their loneliness and give guidance and support. More research is needed to develop interventions that are effective in reducing loneliness. PMID- 22524168 TI - Event-related EEG time-frequency analysis and the Orienting Reflex to auditory stimuli. AB - Sokolov's classic works discussed electroencephalogram (EEG) alpha desynchronization as a measure of the Orienting Reflex (OR). Early studies confirmed that this reduced with repeated auditory stimulation, but without reliable stimulus-significance effects. We presented an auditory habituation series with counterbalanced indifferent and significant (counting) instructions. Time-frequency analysis of electrooculogram (EOG)-corrected EEG was used to explore prestimulus levels and the timing and amplitude of event-related increases and decreases in 4 classic EEG bands. Decrement over trials and response recovery were substantial for the transient increase (in delta, theta, and alpha) and subsequent desynchronization (in theta, alpha, and beta). There was little evidence of dishabituation and few effects of counting. Expected effects in stimulus-induced alpha desynchronization were confirmed. Two EEG response patterns over trials and conditions, distinct from the full OR pattern, warrant further research. PMID- 22524169 TI - Mapping the surface-exposed regions of papaya mosaic virus nanoparticles. AB - In general, the structure of the papaya mosaic virus (PapMV) and other members of the potexviruses is poorly understood. Production of PapMV coat proteins in a bacterial expression system and their self-assembly in vitro into nanoparticles is a very useful tool to study the structure of this virus. Using recombinant PapMV nanoparticles that are similar in shape and appearance to the plant virus, we evaluated surface-exposed regions by two different methods, immunoblot assay and chemical modification with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or diethyl-pyrocarbonate followed by mass spectrometry. Three regions were targeted by the two techniques. The N- and C-termini were shown to be surfaced exposed as expected. However, the region 125-136 was revealed for the first time as the major surface-exposed region of the nanoparticles. The presence of linear peptides at the surface was finally confirmed using antibodies directed to those peptides. It is likely that region 125-136 plays a key role in the lifecycle of PapMV and other members of the potexvirus group. PMID- 22524170 TI - Importance of assessing the effect of statins on the function of high- density lipoproteins on coronary plaque. AB - High-density lipoproteins (HDL) are small particles comprised of phospholipids and stabilizing proteins, which carry cholesterol and triglycerides in the blood stream. The incidence of cardiovascular events is high in patients with low level of HDL-cholesterol (HDL-C). In the present study, we defined The PH index [Deltacoronary plaque volume/DeltaHDL-C] index as a putative clinical index of cholesterol efflux capacity of HDL from atheromatous plaque. The present study investigated the PH index in response to treatment with different types of HMG CoA reductase inhibitors (statins), in contrast to similar changes in the PL index [Deltacoronary plaque volume/Deltalow-density lipoprotein-cholesterol (LDL C)] by the same statins. Using the 2000-2011 PubMed database, the search keywords were "statins" and "intravascular ultrasound (IVUS)" and "plaque volume". Cross references were checked. PubMed search identified 29 references, and finally 4 published studies were selected for data analysis. The PL index, representing the change in plaque volume induced by 1% reduction in LDL-C, showed no difference among the different statins. On the other hand, the PH index, representing the change in plaque volume induced by 1% increase in HDL-C, showed wide variability among the different statins; 1.4 by atorvastatin, 1.0 by pravastatin, -0.1 by simvastatin, -0.2 or -0.5 by rosuvastatin, and -1.8 by pitavastatin. In conclusion, the best coronary plaque regression index attributed to HDL cholesterol elevation (PH index) was found in pitavastatin treatment, in comparison with the other 4 statins (atorvastatin, pravastatin, simvastatin, rosuvastatin) investigated in the articles scanned by their search. PMID- 22524171 TI - Serum collagen markers and heart failure. AB - Increased myocardial collagen accumulation is present in almost every cardiac disease and plays an important role in the reduced heart function. N-terminal and C-terminal propeptides of collagen type I and III, the two major collagen types in the heart, can be assayed in serum.These propeptides (PINP, PIIINP, PICP, ICTP) reflect collagen synthesis and degradation. The use of these serum collagen biomarkers as prognostic or diagnostic tools is an area of active investigation. In this review article these studies will be discussed as well as the limitations of these serum biomarkers as indicators of cardiac fibrosis. PMID- 22524172 TI - Antithrombotic options for atrial fibrillation in 2012. AB - Atrial fibrillation (AF) is a common arrhythmia in clinical practice. An important component of the management of patients with AF involves prevention of thromboembolism and stroke. Coumarins, such as warfarin had been the only available oral antithrombotic agent for prevention of thromboembolism for many decades. Following intestinal absorption, coumarins inhibit multiple steps of the clotting cascade that leads to inhibition of coagulation factors II, VII, IX and X. In addition to delayed and variable inhibition of coagulation, coumarin therapy has a narrow therapeutic window for optimal balance of risk and benefit, which requires regular assessment of the international normalized ratio (INR) to monitor coagulation. A quest for safer, more effective therapies that do not need monitoring has led to the development of dabigatran, rivaroxaban, and apixaban. In this article, we review these newer antithrombotic agents and discuss role of these drugs in clinical practice. PMID- 22524173 TI - Role of genetic factors in statins side-effects. AB - Statins are relevant drugs involved in the reduction of cardiovascular events both in primary and secondary prevention. Related muscular side-effects are the most common cause of withdrawal and statins discontinuation could induce a negative rebound effect in terms of vascular events. Among factors in association with statins side-effects the combination with other drugs and the female sex are established conditions. However recent data suggest a specific genetic influence in intolerance development, at least for some statins. Indeed a genome-wide study in patients treated with simvastatin found an impressive association between single-nucleotide polymorphisms (SNPs) located within SLCO1B1 gene on chromosome 12 and established myopathy. Furthermore, the association between the SLCO1B1*5 variant and side-effects was found also in patients treated with atorvastatin but not, apparently, with pravastatin and categorized as carriers of mild-myopathy. Recently a similar evidence has been suggested in type 2 diabetic patients treated mainly with simvastatin. However another relevant issue is that, apart from genetic influence in liver transporters influencing drug levels, the complexity of mechanisms involved in the muscular side effects of statins has been addressed by the evidence of other influencing pathways such as the variant within the COQ2 gene involved in Coenzyme Q(10) mild-asymptomatic deficiency and skeletal muscle drug transporters expression. In conclusion, the picture of putative pharmacogenetic modulation of statins safety is reaching a growing body of evidence for translation into clinical practice but more specific studies for each single statin, in different clinical settings, both from genome-wide or competitive candidate genes evaluation, are needed before describing a definitive class-risk profile. PMID- 22524174 TI - Ambulatory blood pressure monitoring in prehypertensive subjects. AB - BACKGROUND: Although treatment of prehypertensives is feasible and effective, it is unclear how to define those who may benefit. We hypothesized that ambulatory blood pressure monitoring (ABPM) might be a tool for selecting prehypertensive subjects, classified according to the JNC 7, who later develop drug-treated hypertension. METHODS: Prehypertensives (n=107; 62 M, 45 F; age 50 +/- 14 years) with or without cardiovascular risk factors were assessed for drug-treated hypertension development. They underwent ABPM at entry examination and were clinically followed-up for an average of 99 +/- 42 months. Thereafter, subjects were divided into 2 groups according to the development of drug-treated hypertension. Stepwise logistic regression (LR) analysis was performed to assess the role of factors contributing independent prediction of outcome (i.e. drug treated hypertension onset). RESULTS: In LR analysis body mass index [odds ratio (OR)=1.29, confidence intervals (CI)95% 1.03-1.62], female gender (OR=11.10, CI95% 2.66-46.30), total cholesterol (OR=1.03, CI95% 1.01-1.05), smoking (OR=3.90, CI95% 0.94-16.20), daytime SBP (OR=1.10, CI95% 1.01-1.19) and 24h DBP (OR=1.23, CI95% 1.08-1.41) predicted the development of hypertension. The criteria combining BP and clinical variables were superior to BP or clinical criteria alone in the correct classification of true positives and true negatives. Altogether there was an improvement of 14.02% (p < 0.01) in comparison to only clinical criteria. CONCLUSIONS: In the setting of global cardiovascular risk assessment, ABPM, in the early diagnosis of hypertension in prehypertensive individuals, appears as a useful tool, both diagnostically and prognostically, to index subjects who are suspected to be masked hypertensives. PMID- 22524175 TI - Adaptation of human and simian immunodeficiency viruses for resistance to tetherin/BST-2. AB - Tetherin (BST-2 or CD317) is an interferon-inducible cellular factor that prevents the detachment of enveloped viruses from infected cells. The primate lentiviruses have evolved different countermeasures to tetherin. The majority of SIVs use Nef to antagonize the tetherin proteins of their nonhuman primate hosts. However, due to the absence of sequences in human tetherin required for antagonism by Nef, HIV-1 Vpu and HIV-2 Env evolved to serve this function in humans. We recently identified compensatory changes in the Env cytoplasmic domain of a pathogenic nef-deleted SIV that confers resistance to rhesus macaque tetherin. These observations highlight the extraordinary plasticity of the primate lentiviruses in adapting to the tetherin proteins of their respective hosts, and reveal a prominent role for tetherin in shaping the evolution of the primate lentiviruses. PMID- 22524177 TI - Transmembrane interactions of HIV-1 Vpu and tetherin. AB - Tetherin is a type II membrane protein that bears a N-terminal transmembrane domain, an extracellular coiled-coil structure and a C-terminal GPI anchor. This unique topology allows tetherin to block the release of a wide range of enveloped viruses from the cell surface. In order to overcome this host restriction, viruses have evolved various counter measures. In the case of human immunodeficiency virus type 1 (HIV-1), the viral protein U (Vpu) is able to down modulate cell surface tetherin, thus removing tetherin molecules from the site of virus budding. This activity of Vpu depends on its direct interaction with tetherin. In this review, we summarize the known molecular details of the interaction between Vpu and tetherin, and also discuss how tetherin is targeted by other viral antagonists. Following our summary, it is evident that each of the intracellular, transmembrane and extracellular domains of tetherin can become the target of viral antagonists for counteraction. PMID- 22524176 TI - Sites of action of HIV-1 Vpu in BST-2/tetherin downregulation. AB - The interferon-inducible host restriction factor bone marrow stromal antigen 2 (BST-2/tetherin) blocks the release of human immunodeficiency virus type 1 (HIV 1) by directly cross-linking virions to the membrane of infected cells. This antiviral effect is counteracted by the HIV-1 accessory protein viral protein U (Vpu) through mechanisms that remain unclear. Accumulating evidence suggests that Vpu antagonizes BST-2 by removing it from the plasma membrane; however, neither the cellular sites of interaction nor the effector mechanisms that result in the downregulation of BST-2 cell-surface expression have been fully determined. Based on current evidence regarding the subcellular localization of Vpu and BST-2 and the latter's trafficking defects induced by their interaction, three models have been proposed. In the first, Vpu is hypothesized to block the traffic of newly synthesized BST-2 towards the cell surface by retaining it in the biosynthetic/secretory compartment. The second model suggests that Vpu sequesters BST-2 within intracellular compartments corresponding to recycling endosomes and the trans-Golgi network by blocking its recycling after endocytosis. In the third model, we and others have proposed that Vpu directly internalizes BST-2 from the plasma membrane and induces its enhanced endolysosomal trafficking and degradation. As for its intracellular fate, the viral antagonism of BST-2 is likely dependent on the intracellular sequestration, or the proteasomal/lysosomal degradation of the restriction factor. This review summarizes the current advances in our understanding of the cellular pathways and sites of action of Vpu in the downregulation of cell-surface BST-2. PMID- 22524178 TI - Structural basis of tetherin function. AB - HIV-1 employs its structural proteins to orchestrate assembly and budding at the plasma membrane of host cells, which depends on numerous cellular factors. Although cells evolved interferon inducible restriction factors such as tetherin that act as a first line of defense, enveloped viruses, including HIV-1, developed countermeasures in the form of tetherin antagonists such as Vpu that decrease the effect of tetherin and permits normal viral replication in vivo. Here we review recent advances in the understanding of the dynamic structural properties of tetherin that provide the basis to physically retain HIV-1 by bridging plasma and virion membranes after completion of budding. PMID- 22524179 TI - beta-TrCP dependency of HIV-1 Vpu-induced downregulation of CD4 and BST 2/tetherin. AB - During evolution, pathogens have evolved strategies to counteract key cellular restriction mechanisms in order to efficiently invade target cells and fulfill essential steps of their replication cycle. Human Immunodeficiency Virus-1 and some Simian counterparts express a small multifunctional protein, Vpu, which influences viral replication. By acting as a multifunctional adapter, Vpu enhances viral particle release and infectivity. Therefore Vpu, an accessory protein, contributes to pathogenesis while avoiding superinfection. These effects rely mainly on the ability of Vpu to target the host proteins CD4 and BST 2/tetherin. Indeed, Vpu downregulates the cell surface expression of these receptors and subsequently induces their proteolysis via a mechanism involving a beta -TrCP-containing E3 ubiquitin ligase complex. In this review, we will detail recent research aimed at elucidating the mechanism of Vpu-mediated CD4 and BST 2/tetherin downregulation and degradation as well as their subsequent consequences on viral pathogenesis. PMID- 22524180 TI - Role of the endosomal ESCRT machinery in HIV-1 Vpu-induced down-regulation of BST2/tetherin. AB - The cellular protein "Bone marrow stromal antigen 2" (BST2 also called Tetherin, CD317, HM1.24) was identified as a major mediator of the innate immune defense against the dissemination of enveloped viruses. BST2 was shown to physically trap the de novo formed viral particles at the surface of infected cells, thereby reducing viral release. Lentiviruses have evolved specific strategies to down regulate the expression level of BST2 from the surface of the cells and as such promote viral egress. In Human Immunodeficiency Virus-1 (HIV-1), the accessory protein Vpu counters BST2 antiviral activity. However, the cellular and molecular mechanisms involved are not fully understood. Vpu-mediated antagonism of BST2 antiviral activity seems to involve complex interplay between the viral protein and host components regulating protein turnover and vesicular trafficking. This review focuses on the interplay between Vpu and the ubiquitin/endosomal pathway in countermeasures of HIV-1 to BST2 restriction, with a particular emphasis on the "Endosomal Sorting Complexes Required for Transport" (ESCRT) machinery. PMID- 22524183 TI - Interaction between amyloid fibril formation and extracellular matrix in the proceedings of VIIIth International Symposium on Familial Amyloidotic Polyneuropathy. AB - Pathological studies of FAP showed that TTR amyloid demonstrates organ and tissue tropism, and therefore, the mechanism of TTR fibril formation is thought to be closely related to the microenvironment in which amyloid fibrils form. However, many key issues, including the precise site of amyloid fibril formation and the effect of amyloid deposition on cells and tissues, remain largely unknown. In this study, we analyzed the relationship between amyloid fibril formation and extracellular matrix. Histopathological analyses showed an increase in the amount of the major components of the extracellular matrix with TTR amyloid deposition. In vitro studies also showed that TTR aggregates had a bioactivity to induce up regulation of these extracellular matrix components. To know the precise mechanism of this up-regulation may lead to deeper understanding of FAP pathogenesis. PMID- 22524182 TI - A feasibility study to investigate the clinical application of functional electrical stimulation (FES), for dropped foot, during the sub-acute phase of stroke - A randomized controlled trial. AB - PURPOSE: Functional electrical stimulation (FES), for dropped foot, has been shown to have positive benefits in chronic stroke. It has been suggested that similar benefits may be seen earlier after stroke. The aim of this feasibility study was to evaluate the trial methodology of undertaking a randomized controlled trial (RCT) of FES in sub-acute stroke. METHOD: This was a randomized feasibility study with non-blinded outcomes at 6 and 12 weeks. Sixteen sub-acute stroke in-patients with dropped foot were randomized into two groups (control, n = 7; intervention, n = 9). Both groups received routine gait re-education and an orthotic device, the control group used an ankle foot orthosis and the intervention group used FES. Outcome measures included gait velocity and cadence, Functional Ambulation Classification, Visual Analogue Scale of perception of walking, and the Stroke Impact Scale. RESULTS: Eligibility criteria developed for inclusion of participants in the trial were appropriate. Set-up of FES during sub acute stroke was feasible but more challenging than with chronic patients. Outcome measures were suitable and have informed the choice of measures for future work. CONCLUSIONS: It is feasible to undertake a trial evaluating FES during the sub-acute phase of recovery after stroke. A larger RCT is required. PMID- 22524181 TI - HIV-1 Vpu interference with innate cell-mediated immune mechanisms. AB - The HIV-1 accessory protein Vpu is emerging as a viral factor with a range of activities devoted to counteracting host innate immunity. Here, we review recent findings concerning the role of Vpu in hampering activation of cellular immune responses mediated by CD1d-restricted invariant natural killer T (iNKT) cells and natural killer (NK) cells. The two key findings are that Vpu interferes with CD1d expression and antigen presentation, and also with expression of the NK cell activation ligand NK-T and B cell antigen (NTB-A). Both these activities are mechanistically distinct from CD4 and Tetherin (BST-2) down-modulation. We summarize the mechanistic insights gained into Vpu interference with CD1d and NTB A, as well as important challenges going forward, and discuss these mechanisms in the context of the role that iNKT and NK cells play in HIV-1 immunity and immunopathogenesis. PMID- 22524185 TI - Type 2 diabetes in Asians: prevalence, risk factors, and effectiveness of behavioral intervention at individual and population levels. AB - This review summarizes the current data on diabetes risk factors, prevalence, and prevention efforts in Asia and Asian migrant populations. Studies indicate that type 2 diabetes mellitus is a large and growing threat to public health in Asian populations. Furthermore, Asian subgroups (e.g., South Asians/Asian Indians, Chinese) have unique risk factor profiles for developing diabetes, which differ from other populations and between Asian ethnic groups. Lifestyle intervention programs are effective in preventing diabetes in Asians, as with other ethnicities. The strength of these findings is lessened by the lack of systematically collected data using objective measurements. Large epidemiologic studies of diabetes prevalence and risk factor profiles and translational trials identifying sustainable and culturally acceptable lifestyle programs for Asian subgroups are needed. PMID- 22524186 TI - Lessons learned from randomized clinical trials of micronutrient supplementation for cancer prevention. AB - This review discusses the results of randomized clinical trials of supplemental micronutrients for cancer prevention completed over the past 20 years, including trials of beta-carotene and retinol, vitamins C and E, selenium, folic acid, and vitamin D. Some trials observed significant reductions in risk, whereas others observed significant increases in risk of the primary cancer endpoint. In considering these trials, it appears that supplementation targeted to populations with low status of the nutrient of interest may prevent cancer, whereas supplementation in populations with higher status or to achieve pharmacological exposures may promote cancer. Observational epidemiologic evidence coupled with these trial results supports the concept of a U-shaped curve for micronutrients in relation to cancer prevention. Based on these data, nutrient supplements are not currently recommended for cancer prevention in the general population. The hypothesis that groups with low nutrient status may benefit from supplementation has yet to be formally tested. PMID- 22524188 TI - The neurocognitive outcome of IUGR children born to mothers with and without preeclampsia. AB - OBJECTIVE: To examine long-term behavioral and neurodevelopmental outcome of children born growth restricted and exposed to hypertension in utero at 9 years of age. METHODS: Somatic growth and neurocognitive outcomes were evaluated at age 9-10 years of age in 42 children born with intra uterine growth restriction (IUGR) after pregnancies complicated by hypertensive disorder (17 with maternal preeclampsia and 25 after gestational hypertension). This study group was compared to a control group of 78 IUGR children born after normotensive pregnancy. RESULTS: Only weight was found to be significantly lower in the hypertensive-IUGR group, versus the normotensive IUGR children. No significant differences were found in any of the neurocognitive parameters including IQ, school achievements, and neurodevelopmental score at age 9-10 years. CONCLUSION: IUGR is a well known risk factor for later cognitive difficulties but maternal hypertensive disorder does not seem to add significantly to this risk. PMID- 22524189 TI - Infrared microspectroscopy of live cells in microfluidic devices (MD-IRMS): toward a powerful label-free cell-based assay. AB - Until nowadays most infrared microspectroscopy (IRMS) experiments on biological specimens (i.e., tissues or cells) have been routinely carried out on fixed or dried samples in order to circumvent water absorption problems. In this paper, we demonstrate the possibility to widen the range of in-vitro IRMS experiments to vibrational analysis of live cellular samples, thanks to the development of novel biocompatible IR-visible transparent microfluidic devices (MD). In order to highlight the biological relevance of IRMS in MD (MD-IRMS), we performed a systematic exploration of the biochemical alterations induced by different fixation protocols, ethanol 70% and formaldehyde solution 4%, as well as air drying on U937 leukemic monocytes by comparing their IR vibrational features with the live U937 counterpart. Both fixation and air-drying procedures affected lipid composition and order as well as protein structure at a different extent while they both induced structural alterations in nucleic acids. Therefore, only IRMS of live cells can provide reliable information on both DNA and RNA structure and on their cellular dynamic. In summary, we show that MD-IRMS of live cells is feasible, reliable, and biologically relevant to be recognized as a label-free cell-based assay. PMID- 22524187 TI - Inflammation in alcoholic liver disease. AB - Frank Burr Mallory's landmark observation in 1911 on the histopathology of alcoholic liver disease (ALD) was the first identification of a link between inflammation and ALD. In this review, we summarize recent advances regarding the origins and roles of various inflammatory components in ALD. Metabolism of ethanol generates a number of metabolites, including acetate, reactive oxygen species, acetaldehyde, and epigenetic changes, that can induce inflammatory responses. Alcohol and its metabolites can also initiate and aggravate inflammatory conditions by promoting gut leakiness of microbial products, by sensitizing immune cells to stimulation, and by activating innate immune pathways, such as complement. Chronic alcohol consumption also sensitizes nonimmune cells, e.g., hepatocytes, to inflammatory signals and impairs their ability to respond to protective signals. Based on these advances, a number of inflammatory targets have been identified with potential for therapeutic intervention in ALD, presenting new opportunities and challenges for translational research. PMID- 22524191 TI - Why the mechanisms of digermyne and distannyne reactions with H2 differ so greatly. AB - Despite their formal relationship to alkynes, Ar'GeGeAr', Ar'SnSnAr', and Ar*SnSnAr* [Ar' = 2,6-(2,6-iPr(2)C(6)H(3))(2)C(6)H(3); Ar* = 2,6-(2,4,6 iPr(3)C(6)H(2))(2)-3,5-iPr(2)C(6)H] exhibit high reactivity toward H(2), quite unlike acetylenes. Remarkably, the products are totally different. Ar'GeGeAr' can react with 1-3 equiv of H(2) to give mixtures of Ar'HGeGeHAr', Ar'H(2)GeGeH(2)Ar', and Ar'GeH(3). In contrast, Ar'SnSnAr' and Ar*SnSnAr* react with only 1 equiv of H(2) but give different types of products, Ar'Sn(MU H)(2)SnAr' and Ar*SnSnH(2)Ar*, respectively. In this work, this disparate behavior toward H(2) has been elucidated by TPSSTPSS DFT computations of the detailed reaction mechanisms, which provide insight into the different pathways involved. Ar'GeGeAr' reacts with H(2) via three sequential steps: H(2) addition to Ar'GeGeAr' to give singly H-bridged Ar'Ge(MU-H)GeHAr'; isomerization of the latter to the more reactive Ge(II) hydride Ar'GeGeH(2)Ar'; and finally, addition of another H(2) to the hydride, either at a single Ge site, giving Ar'H(2)GeGeH(2)Ar', or at a Ge-Ge joint site, affording Ar'GeH(3) + Ar'HGe:. Alternatively, Ar'Ge(MU-H)GeHAr' also can isomerize into the kinetically stable Ar'HGeGeHAr', which cannot react with H(2) directly but can be transformed to the reactive Ar'GeGeH(2)Ar'. The activation of H(2) by Ar'SnSnAr' is similar to that by Ar'GeGeAr'. The resulting singly H-bridged Ar'Sn(MU-H)SnHAr' then isomerizes into Ar'HSnSnHAr'. The subsequent facile dissociation of the latter gives two Ar'HSn: species, which then reassemble into the experimental product Ar'Sn(MU H)(2)SnAr'. The reaction of Ar*SnSnAr* with H(2) forms in the kinetically and thermodynamically more stable Ar*SnSnH(2)Ar* product rather than Ar*Sn(MU H)(2)SnAr*. The computed mechanisms successfully rationalize all of the known experimental differences among these reactions and yield the following insights into the behavior of the Ge and Sn species: (I) The active sites of Ar'EEAr' (E = Ge, Sn) involve both E atoms, and the products with H(2) are the singly H-bridged Ar'E(MU-H)EHAr' species rather than Ar'HEEHAr' or Ar'EEH(2)Ar'. (II) The heavier alkene congeners Ar'HEEHAr' (E = Ge, Sn) cannot activate H(2) directly. Instead, Ar'HGeGeHAr' must first isomerize into the more reactive Ar'GeGeH(2)Ar'. Interestingly, the subsequent H(2) activation by Ar'GeGeH(2)Ar' can take place on either a single Ge site or a joint Ge-Ge site, but Ar'SnSnH(2)Ar' is not reactive toward H(2). The higher reactivity of Ar'GeGeH(2)Ar' in comparison with Ar'SnSnH(2)Ar' is due to the tendency of group 14 elements lower in the periodic table to have more stable lone pairs (i.e., the inert pair effect) and is responsible for the differences between the reactions of Ar'EEAr' (E = Ge, Sn) with H(2). Similarly, the carbene-like Ar'HGe: is more reactive toward H(2) than is Ar'HSn:. (III) The doubly H-bridged Ar'E(MU-H)(2)EAr' (E = Ge, Sn) species are not reactive toward H(2). PMID- 22524190 TI - Nitrosation of aryl and heteroaryltrifluoroborates with nitrosonium tetrafluoroborate. AB - Organotrifluoroborates have emerged as an alternative to toxic and air- and moisture-sensitive organometallic species for the synthesis of functionalized aryl and heteroaryl compounds. It has been shown that the trifluoroborate moiety can be easily converted into a variety of different substituents in a late synthetic stage. In this paper, we disclose a mild, selective, and convenient method for the ipso-nitrosation of organotrifluoroborates using nitrosonium tetrafluoroborate (NOBF(4)). Aryl- and heteroaryltrifluoroborates were converted into the corresponding nitroso products in good to excellent yields. This method proved to be tolerant of a broad range of functional groups. PMID- 22524192 TI - Atmospheric chemistry of ethyl propionate. AB - Ethyl propionate is a model for fatty acid ethyl esters used as first-generation biodiesel. The atmospheric chemistry of ethyl propionate was investigated at 980 mbar total pressure. Relative rate measurements in 980 mbar N(2) at 293 +/- 0.5 K were used to determine rate constants of k(C(2)H(5)C(O)OC(2)H(5) + Cl) = (3.11 +/ 0.35) * 10(-11), k(CH(3)CHClC(O)OC(2)H(5) + Cl) = (7.43 +/- 0.83) * 10(-12), and k(C(2)H(5)C(O)OC(2)H(5) + OH) = (2.14 +/- 0.21) * 10(-12) cm(3) molecule(-1) s( 1). At 273-313 K, a negative Arrhenius activation energy of -3 kJ mol(-1) is observed.. The chlorine atom-initiated oxidation of ethyl propionate in 980 mbar N(2) gave the following products (stoichiometric yields): ClCH(2)CH(2)C(O)OC(2)H(5) (0.204 +/- 0.031), CH(3)CHClC(O)OC(2)H(5) (0.251 +/- 0.040), and C(2)H(5)C(O)OCHClCH(3) (0.481 +/- 0.088). The chlorine atom-initiated oxidation of ethyl propionate in 980 mbar of N(2)/O(2) (with and without NO(x)) gave the following products: ethyl pyruvate (CH(3)C(O)C(O)OC(2)H(5)), propionic acid (C(2)H(5)C(O)OH), formaldehyde (HCHO), and, in the presence of NO(x), PAN (CH(3)C(O)OONO(2)). The lack of acetaldehyde as a product suggests that the CH(3)CH(O)C(O)OC(2)H(5) radical favors isomerization over decomposition. From the observed product yields, we conclude that H-abstraction by chlorine atoms from ethyl propionate occurs 20.4 +/- 3.1%, 25.1 +/- 4.0%, and 48.1 +/- 8.8% from the CH(3)-, -CH(2)-, and -OCH(2)- groups, respectively. The rate constant and branching ratios for the reaction between ethyl propionate and the OH radical were investigated theoretically using quantum mechanical calculations and transition state theory. The stationary points along the reaction path were optimized using the CCSD(T)-F12/VDZ-F12//BH&HLYP/aug-cc-pVTZ level of theory; this model showed that OH radicals abstract hydrogen atoms primarily from the OCH(2)- group (80%). PMID- 22524193 TI - Variations of DOM quality in inflows of a drinking water reservoir: linking of van Krevelen diagrams with EEMF spectra by rank correlation. AB - Elevated concentrations of dissolved organic matter (DOM) such as humic substances in raw water pose significant challenges during the processing of the commercial drinking water supplies. This is a relevant issue in Saxony, Central East Germany, and many other regions worldwide, where drinking water is produced from raw waters with noticeable presence of chromophoric DOM (CDOM), which is assumed to originate from forested watersheds in spring regions of the catchment area. For improved comprehension of DOM molecular composition, the seasonal and spatial variations of humic-like fluorescence and elemental formulas in the catchment area of the Muldenberg reservoir were recorded by excitation emission matrix fluorescence (EEMF) and ultrahigh-resolution mass spectrometry (FT-ICR MS). The Spearman rank correlation was applied to link the EEMF intensities with exact molecular formulas and their corresponding relative mass peak abundances. Thereby, humic-like fluorescence could be allocated to the pool of oxygen-rich and relatively unsaturated components with stoichiometries similar to those of tannic acids, which are suspected to have a comparatively high disinfection byproduct formation potential associated with the chlorination of raw water. Analogous relationships were established for UV absorption at 254 nm (UV(254)) and dissolved organic carbon (DOC) and compared to the EEMF correlation. PMID- 22524194 TI - Proactive and reactive control in S-R compatibility: a brain potential analysis. AB - We investigated how proactive and reactive control facilitates performance in mixed stimulus-response compatibility (SRC) tasks. SRC effects were eliminated in mixed tasks and reversed following incompatible trials. In mixed tasks, early preferential response activation was present in stimulus-locked lateralized readiness potentials (LRPs) but reduced following incompatible trials. In event related potentials (ERPs), stimulus-locked N2 was enhanced in all mixed trials but was not significantly influenced by the preceding trial. A response-locked fronto-central negative component (N-120), peaking just before the response, was largest for mixed compatible trials preceded by incompatible trials. This N-120 was paired with an enhancement to the peak of the response-locked LRP. Proactive control is involved in selection of an S-R mapping via the indirect route of a dual-route model. Reactive control corrects the S-R mapping, particularly when alternating between S-R mappings. PMID- 22524195 TI - A nonparametric statistical method that improves physician cost of care analysis. AB - OBJECTIVE: To develop a compositing method that demonstrates improved performance compared with commonly used tests for statistical analysis of physician cost of care data. DATA SOURCE: Commercial preferred provider organization (PPO) claims data for internists from a large metropolitan area. STUDY DESIGN: We created a nonparametric composite performance metric that maintains risk adjustment using the Wilcoxon rank-sum (WRS) test. We compared the resulting algorithm to the parametric observed-to-expected ratio, with and without a statistical test, for stability of physician cost ratings among different outlier trimming methods and across two partially overlapping time periods. PRINCIPAL FINDINGS: The WRS algorithm showed significantly greater within-physician stability among several typical outlier trimming and capping methods. The algorithm also showed significantly greater within-physician stability when the same physicians were analyzed across time periods. CONCLUSIONS: The nonparametric algorithm described is a more robust and more stable methodology for evaluating physician cost of care than commonly used observed-to-expected ratio techniques. Use of such an algorithm can improve physician cost assessment for important current applications such as public reporting, pay for performance, and tiered benefit design. PMID- 22524196 TI - Retinal ganglion cell (RGC) death in glaucomatous beagles is not associated with mutations in p53 and NTF4 genes. AB - BACKGROUND: Glaucoma in humans is a second leading cause of irreversible vision loss in the world and can affect all age groups as well as all populations. The precise mechanism of retinal ganglion cell (RGC) death and progressive degeneration of optic nerve in glaucoma is not understood. It has been suggested that apoptosis is the common pathway that leads to the death of RGCs in glaucoma and that neurotrophin 4 (NTF4) protein plays a role in the protection of RGCs by activating tyrosine kinase receptors. Additionally, one previous study suggested that p53 codon 72 polymorphism (R72P) might have a greater susceptibility to apoptosis in some ethnic population. Glaucoma also occurs in dogs, and the primary glaucoma in beagles is inherited as an autosomal recessive trait. Although recently a candidate gene has been isolated, the mechanism underlying RGC death is not understood. METHOD: To understand whether the same p53 and NTF4 pathway mechanism is involved in a beagle model of glaucoma, we have isolated NTF4 gene from dog and analyzed both p53 and NTF4 genes for mutations in glaucomatous animals. RESULTS: Our analyses failed to identify any disease causing mutations in both genes with the exception of two polymorphisms in NTF4 gene. However, these are not pathogenic changes because they are also present in normal animals and are not segregated with the disease. CONCLUSION: These results suggest that impaired neurotrophin signaling or compromised trophic support to the retina and p53-mediated apoptosis may not be the underlying mechanism of RGCs death in a beagle model of glaucoma. PMID- 22524198 TI - A BAC library of the SP80-3280 sugarcane variety (saccharum sp.) and its inferred microsynteny with the sorghum genome. AB - BACKGROUND: Sugarcane breeding has significantly progressed in the last 30 years, but achieving additional yield gains has been difficult because of the constraints imposed by the complex ploidy of this crop. Sugarcane cultivars are interspecific hybrids between Saccharum officinarum and Saccharum spontaneum. S. officinarum is an octoploid with 2n = 80 chromosomes while S. spontaneum has 2n = 40 to 128 chromosomes and ploidy varying from 5 to 16. The hybrid genome is composed of 70-80% S. officinaram and 5-20% S. spontaneum chromosomes and a small proportion of recombinants. Sequencing the genome of this complex crop may help identify useful genes, either per se or through comparative genomics using closely related grasses. The construction and sequencing of a bacterial artificial chromosome (BAC) library of an elite commercial variety of sugarcane could help assembly the sugarcane genome. RESULTS: A BAC library designated SS_SBa was constructed with DNA isolated from the commercial sugarcane variety SP80-3280. The library contains 36,864 clones with an average insert size of 125 Kb, 88% of which has inserts larger than 90 Kb. Based on the estimated genome size of 760-930 Mb, the library exhibits 5-6 times coverage the monoploid sugarcane genome. Bidirectional BAC end sequencing (BESs) from a random sample of 192 BAC clones sampled genes and repetitive elements of the sugarcane genome. Forty-five per cent of the total BES nucleotides represents repetitive elements, 83% of which belonging to LTR retrotransposons. Alignment of BESs corresponding to 42 BACs to the genome sequence of the 10 sorghum chromosomes revealed regions of microsynteny, with expansions and contractions of sorghum genome regions relative to the sugarcane BAC clones. In general, the sampled sorghum genome regions presented an average 29% expansion in relation to the sugarcane syntenic BACs. CONCLUSION: The SS_SBa BAC library represents a new resource for sugarcane genome sequencing. An analysis of insert size, genome coverage and orthologous alignment with the sorghum genome revealed that the library presents whole genome coverage. The comparison of syntenic regions of the sorghum genome to 42 SS_SBa BES pairs revealed that the sorghum genome is expanded in relation to the sugarcane genome. PMID- 22524197 TI - Mitochondrial aldehyde dehydrogenase (ALDH2) protects against streptozotocin induced diabetic cardiomyopathy: role of GSK3beta and mitochondrial function. AB - BACKGROUND: Mitochondrial aldehyde dehydrogenase (ALDH2) displays some promise in the protection against cardiovascular diseases although its role in diabetes has not been elucidated. METHODS: This study was designed to evaluate the impact of ALDH2 on streptozotocin-induced diabetic cardiomyopathy. Friendly virus B(FVB) and ALDH2 transgenic mice were treated with streptozotocin (intraperitoneal injection of 200 mg/kg) to induce diabetes. RESULTS: Echocardiographic evaluation revealed reduced fractional shortening, increased end-systolic and -diastolic diameter, and decreased wall thickness in streptozotocin-treated FVB mice. Streptozotocin led to a reduced respiratory exchange ratio; myocardial apoptosis and mitochondrial damage; cardiomyocyte contractile and intracellular Ca2+ defects, including depressed peak shortening and maximal velocity of shortening and relengthening; prolonged duration of shortening and relengthening; and dampened intracellular Ca2+ rise and clearance. Western blot analysis revealed disrupted phosphorylation of Akt, glycogen synthase kinase-3beta and Foxo3a (but not mammalian target of rapamycin), elevated PTEN phosphorylation and downregulated expression of mitochondrial proteins, peroxisome proliferator activated receptor gamma coactivator 1alpha and UCP-2. Intriguingly, ALDH2 attenuated or ablated streptozotocin-induced echocardiographic, mitochondrial, apoptotic and myocardial contractile and intracellular Ca2+ anomalies as well as changes in the phosphorylation of Akt, glycogen synthase kinase-3beta, Foxo3a and phosphatase and tensin homologue on chromosome ten, despite persistent hyperglycemia and a low respiratory exchange ratio. In vitro data revealed that the ALDH2 activator Alda-1 and glycogen synthase kinase-3beta inhibition protected against high glucose-induced mitochondrial and mechanical anomalies, the effect of which was cancelled by mitochondrial uncoupling. CONCLUSIONS: In summary, our data revealed that ALDH2 acted against diabetes-induced cardiac contractile and intracellular Ca2+ dysregulation, possibly through regulation of apoptosis, glycogen synthase kinase-3beta activation and mitochondrial function independent of the global metabolic profile. PMID- 22524199 TI - Inflammasome polymorphisms confer susceptibility to sporadic malignant melanoma. AB - Genetic variants of NLRP3 and NLRP1 are known to modulate levels of pro inflammatory cytokine interleukin (IL)-1beta. The purpose of this study was to investigate the association of NLRP3/NLRP1 polymorphisms with susceptibility and clinical features of malignant melanoma in a Swedish case-control study. Common variants in NLRP3/NLRP1 were investigated in sporadic malignant melanoma patients and healthy controls followed by analysis using logistic regression. NLRP3 variant (rs35829419) was significantly more common in male patients than in controls (OR, 2.22; CI, 1.27-3.86). Upon stratification, significant association with nodular melanoma was observed (OR, 2.89; CI, 1.33-6.30), which intensified in male patients (OR 4.03, CI 1.40-11.59). The NLRP1 variant (rs12150220) was significantly more common in fair-skinned female patients (OR, 1.85; CI, 1.04 3.33) and showed strong associations with nodular melanoma (OR, 6.03; CI, 1.33 25). Our data suggest that NLRP3/NLRP1 polymorphisms are associated with melanoma susceptibility; these findings warrant validation in other independent populations. PMID- 22524200 TI - Utility of toluidine blue as a diagnostic adjunct in the detection of potentially malignant disorders of the oral cavity--a clinical and histological assessment. AB - BACKGROUND: The value of chairside adjunctive tests in the detection of oral potentially malignant disorders (OPMDs) remains uncertain. OBJECTIVES: To determine the effectiveness of toluidine blue in detecting leukoplakia and erythroplakia and its accuracy in identifying cases with oral epithelial dysplasia. MATERIALS AND METHODS: Ninety-two patients attending two oral medicine clinics in London, presenting with white and red patches of the oral mucosa, were investigated by the application of toluidine blue. Eighty-two patients were clinically diagnosed as OPMDs and 10 were frictional keratoses. A surgical biopsy was performed to assess epithelial dysplasia. RESULTS: Of 64 oral leukoplakias, 34 (53.1%) were positive for toluidine blue and among nine erythroplakias seven stained positive. Of 41 oral dysplasia cases, a little more than half of the lesions (n = 23) were stain positive, an estimated sensitivity of 56.1%. TBlue test had a higher sensitivity for detecting higher-grade dysplastic lesions (5/8 moderate dysplasia, sensitivity 62.5%; 5/7 severe dysplasia; sensitivity 71.4%) compared with lower grades of dysplasia, but the differences were not significant (P = 0.60). CONCLUSIONS: We report here the utility of TBlue for the detection of oral leukoplakia and erythroplakia. The test has the potential to detect OPMDs and yielded a sensitivity of 56.1% and specificity of 56.9% to detect oral epithelial dysplasia. PMID- 22524201 TI - Preimplantation genetic diagnosis with HLA matching - a way to save a child. AB - Preimplantation genetic diagnosis can be used to establish a pregnancy with an embryo that is human leukocyte antigen (HLA)-matched to a sibling having a hematological or immunological disease and needing a life-saving bone marrow transplantation. The ethical aspects of this procedure have been discussed intensively. The procedure applies where no unrelated HLA-matching donor is available or when transplantation from an HLA-matching sibling is considered a better solution. It is only offered in a limited number of centers in Europe as this is a challenging procedure. Where both HLA matching and diagnosis of a dominant disease are necessary, only a small proportion of the embryos can be used, and the procedure is not always technically feasible. The clinical pregnancy rate per cycle started is much lower than following normal in vitro fertilization (IVF) due to a high cycle cancellation rate, but the success rate is only somewhat lower when measured per transfer. PMID- 22524203 TI - Determination of structural building blocks in heavy petroleum systems by collision-induced dissociation Fourier transform ion cyclotron resonance mass spectrometry. AB - Collision-induced dissociation Fourier Transform ion cyclotron resonance mass spectrometry (CID-FTICR MS) was developed to determine structural building blocks in heavy petroleum systems. Model compounds with both single core and multicore configurations were synthesized to study the fragmentation pattern and response factors in the CID reactions. Dealkylation is found to be the most prevalent reaction pathway in the CID. Single core molecules exhibit primarily molecular weight reduction with no change in the total unsaturation of the molecule (or Z number as in chemical formula C(c)H(2c+Z)N(n)S(s)O(o)VNi). On the other hand, molecules containing more than one aromatic core will decompose into the constituting single cores and consequently exhibit both molecular weight reduction and change in Z-numbers. Biaryl linkage, C(1) linkage, and aromatic sulfide linkage cannot be broken down by CID with lab collision energy up to 50 eV while C(2)+ alkyl linkages can be easily broken. Naphthenic ring-openings were observed in CID, leading to formation of olefinic structures. Heavy petroleum systems, such as vacuum resid (VR) fractions, were characterized by the CID technology. Both single-core and multicore structures were found in VR. The latter is more prevalent in higher aromatic ring classes. PMID- 22524204 TI - Added-metal-free catalytic nucleophilic addition of Grignard reagents to ketones. AB - On the basis of the investigation of the combinational effect of quaternary ammonium salts and organic bases, an added-metal-free catalytic system for nucleophilic addition reactions of a variety of Grignard reagents to diverse ketones in THF solvent has been developed to produce tertiary alcohols in good to excellent yields. By using tetrabutylammonium chloride (NBu(4)Cl) as a catalyst and diglyme (DGDE) as an additive, this system strongly enhances the efficiency of addition at the expense of enolization and reduction. NBu(4)Cl should help to shift the Schlenk equilibrium of Grignard reagents to the side of dimeric Grignard reagents to favor the additions of Grignard reagents to ketones via a favored six-membered transition state to form the desired tertiary alcohols, and DGDE should increase the nucleophilic reactivities of Grignard reagents by coordination. This catalytic system has been applied in the efficient synthesis of Citalopram, an effective U.S. FDA-approved antidepressant, and a recyclable version of this catalytic synthesis has also been devised. PMID- 22524202 TI - The evolution of new lipoprotein subunits of the bacterial outer membrane BAM complex. AB - The beta-barrel assembly machine (BAM) complex is an essential feature of all bacteria with an outer membrane. The core subunit of the BAM complex is BamA and, in Escherichia coli, four lipoprotein subunits: BamB, BamC, BamD and BamE, also function in the BAM complex. Hidden Markov model analysis was used to comprehensively assess the distribution of subunits of the BAM lipoproteins across all subclasses of proteobacteria. A patchwork distribution was detected which is readily reconciled with the evolution of the alpha-, beta-, gamma-, delta- and epsilon-proteobacteria. Our findings lead to a proposal that the ancestral BAM complex was composed of two subunits: BamA and BamD, and that BamB, BamC and BamE evolved later in a distinct sequence of events. Furthermore, in some lineages novel lipoproteins have evolved instead of the lipoproteins found in E. coli. As an example of this concept, we show that no known species of alpha proteobacteria has a homologue of BamC. However, purification of the BAM complex from the model alpha-proteobacterium Caulobacter crescentus identified a novel subunit we refer to as BamF, which has a conserved sequence motif related to sequences found in BamC. BamF and BamD can be eluted from the BAM complex under similar conditions, mirroring the BamC:D module seen in the BAM complex of gamma proteobacteria such as E. coli. PMID- 22524205 TI - Serum dehydroepiandrosterone sulfate and adverse health outcomes in older men and women. AB - Low serum dehydroepiandrosterone sulfate (DHEAS) is common in older persons with poor health. The geriatric syndrome of physical frailty is associated with a higher risk of developing fatal and nonfatal health outcomes. However, the association of DHEAS with frailty is uncertain. This study investigated the association of serum DHEAS with frailty and its related adverse outcomes in 416 men and 504 women aged >=65 years from an Italian prospective population-based cohort study. At baseline, frailty status was defined according to the physical phenotype, and serum DHEAS was measured in a fasting venous blood sample. After 4 years, subjects were reassessed for incident frailty and occurrence of nonfatal frailty-related outcomes (hospital admission, nursing home placement, disability, falls, and fractures). All-cause mortality after 8 years was also recorded. Incident frailty was inversely associated with baseline log-transformed DHEAS in men (odds ratio [OR]=0.35, 95% confidence interval [CI] 0.14-0.88, p=0.026) but not in women. Independent of baseline frailty status, women in the lowest DHEAS quartile compared to the upper three quartiles had a higher risk of hospital admission (OR=0.44, 95% CI 0.21-0.91, p=0.027) and nursing home placement (OR=0.27, 95% CI 0.08-0.95, p=0.041). Baseline log-transformed serum DHEAS was also inversely associated with mortality risk, but limited to women with concurrent frailty (hazard ratio [HR]=0.27, 95% CI 0.11-0.68, p=0.005) or preexisting major diseases (HR=0.57, 95% CI 0.33-0.98, p=0.041). These findings suggest that DHEAS is associated with incident frailty in older men and with fatal and nonfatal frailty-related adverse outcomes in older women. PMID- 22524207 TI - Tubular conjugated polymer for chemosensory applications. AB - In this paper, we present the concept of a soluble tubular conjugated polymer (TCP). We report on a fluorescent 5,5'-Bicalixarene-based polymer where the calixarene units are seamlessly incorporated in the conjugated polymeric chain that can respond to a small molecule complexation inside the hydrophobic cavity. In particular, our system demonstrated a reversible rapid fluorescence quenching upon interaction of gaseous nitric oxide with the calixarene moiety. PMID- 22524206 TI - Quercetin and sesamin protect neuronal PC12 cells from high-glucose-induced oxidation, nitrosative stress, and apoptosis. AB - Complications of diabetes are now well-known to affect sensory, motor, and autonomic nerves. Diabetes is also thought to be involved in neurodegenerative processes characteristic of several neurodegenerative diseases. Indeed, it has been acknowledged recently that hyperglycemia-induced oxidative stress contributes to numerous cellular reactions typical of central nervous system deterioration. The goal of the present study was to evaluate the effects of the polyphenol quercetin and the lignan sesamin on high-glucose (HG)-induced oxidative damage in an in vitro model of dopaminergic neurons, neuronal PC12 cells. When incubated with HG (13.5 mg/mL), neuronal PC12 cells showed a significant increase of cellular death. Our results revealed that quercetin and sesamin defend neuronal PC12 cells from HG-induced cellular demise. An elevated level of reactive oxygen and nitrogen species is a consequence of improved oxidative stress after HG administration, and we demonstrated that this production diminishes with quercetin and sesamin treatment. We also found that quercetin and sesamin elicited an increment of superoxide dismutase activity. DNA fragmentation, Bax/Bcl-2 ratio, nuclear translocation of apoptosis-inducing factor, as well as poly(adenosine diphosphate [ADP]-ribose) polymerase cleavage were significantly reduced by quercetin and sesamin administration, affirming their antiapoptotic features. Also, HG treatment impacted caspase-3 cleavage, supporting caspase-3-dependent pathways as mechanisms of apoptotic death. Our results indicate a powerful role for these natural dietary compounds and emphasize preventive or complementary nutritional strategies for diabetes control. PMID- 22524208 TI - Transcription factor 7-like 2 gene polymorphisms and gestational diabetes mellitus. AB - OBJECTIVE: Transcription factor 7-like 2 (TCF7L2) gene polymorphisms were shown to be associated with insulin resistance. We examined two single nucleotide exchanges in this gene in women with gestational diabetes mellitus (GDM) and in women with normal glucose tolerance. METHODS: A total of 1800 unselected women were prospectively screened for GDM by oral glucose tolerance test (OGTT) between 24 and 28 weeks of gestation. Two hundred and fifty Caucasian women of this collective, 125 patients with pathological OGTT and 125 patients with normal glucose tolerance were randomly selected. DNA samples were isolated and TCF7L2 gene polymorphisms (TCF7L2rs12255372 and TCF7L2rs7903146) were analyzed. RESULTS: Women with GDM were significantly older (30.1 +/- 3.4 years vs. 28.2 +/- 4.8 years, p = 0.01), had a significantly higher body mass index (26.4 kg/m(2); interquartile range: 23.33-31.19 vs. 24.6 kg/m(2); interquartile range: 21.05 27.28, p = 0.02) and were significantly more often homozygous for the T allele of TCF7L2rs12255372 (17.2% vs. 2.6%, p = 0.002) than patients with normal glucose tolerance. Binary logistic regression analysis showed that the homozygous variant of TCF7L2rs12255372 (T/T) is an independent risk factor for GDM (OR 7.7, 95% CI: 1.71-34.60), but not the homozygous variant of TCF7L2rs7903146 (T/T). CONCLUSIONS: TCF7L2rs12255372 variant (T/T) is associated with increased risk of GDM in Caucasian women. PMID- 22524209 TI - Role of fetal echocardiography in stepwise sequential screening for chromosomal disorders (combined test associated with modified genetic sonography). AB - OBJECTIVES: To evaluate the contribution made by fetal echocardiography in identifying Down's syndrome (DS) and other chromosomal disorders in a stepwise sequential screening method (first step: combined test (CT), second step: modified genetic sonography (MGS) (major malformation and nuchal fold)), for DS in the general population of pregnant women. METHODS: Prospective study. During a 5-year study period (July 2005-June 2010) 17,911 pregnant women underwent CTs with MGS (with fetal cardiac morphological evaluation performed by obstetricians in a tertiary hospital) as a screening method for DS. We evaluated the sensitivity and false positive rate (FPR) (95% confidence interval (CI)) of three screening methods for DS and all chromosomal disorders: CT, CT + MGS, and CT + fetal echocardiography. RESULTS: A total of 17,911 cases were analyzed with 67 chromosome disorders and 45 DS cases being found. For DS, the CT sensitivity was 80% (95% CI; 68.3-91.7) (36/45) and 79.1% (95% CI; 69.4-88.8) (53/67) for all chromosome disorders, with a FPR of 4.2% (95% CI; 3.9-4.5) (752/17,866) and 4.1% (95% CI; 3.8-4.4) (735/17,844), respectively. For CT + MSG and CT + fetal echocardiography, the sensitivity for DS was 93.3% (95% CI; 85.9-0.99) (42/45) and 95.5% (95% CI; 90.5-0.99) (64/67) for all chromosome disorders. The FPR for CT + MSG was 4.8% (95% CI; 4.5-5.1) (860/17,866) and 4.6% (95% CI; 4.3-4.9) (836/17,844), respectively. The FPR of CT + fetal echocardiography was 4.4% (95% CI; 4.1-4.7) (792/17,866) for DS screening and 4.3% (95% CI; 4-4.6) (770/17,844) for chromosome abnormality screening. CONCLUSIONS: Fetal echocardiography is highly capable of identifying DS and other chromosomal disorders as a part of genetic sonography in stepwise sequential screening. PMID- 22524211 TI - Quantifying surface roughness effects on phonon transport in silicon nanowires. AB - Although it has been qualitatively demonstrated that surface roughness can reduce the thermal conductivity of crystalline Si nanowires (SiNWs), the underlying reasons remain unknown and warrant quantitative studies and analysis. In this work, vapor-liquid-solid (VLS) grown SiNWs were controllably roughened and then thoroughly characterized with transmission electron microscopy to obtain detailed surface profiles. Once the roughness information (root-mean-square, sigma, correlation length, L, and power spectra) was extracted from the surface profile of a specific SiNW, the thermal conductivity of the same SiNW was measured. The thermal conductivity correlated well with the power spectra of surface roughness, which varies as a power law in the 1-100 nm length scale range. These results suggest a new realm of phonon scattering from rough interfaces, which restricts phonon transport below the Casimir limit. Insights gained from this study can help develop a more concrete theoretical understanding of phonon-surface roughness interactions as well as aid the design of next generation thermoelectric devices. PMID- 22524210 TI - Molecular and cellular characterization of a new alpha-thalassemia mutation (HBA2:c.94A>C) generating an alternative splice site and a premature stop codon. AB - The identification of alpha-thalassemia (alpha-thal) due to point mutations has been increasing significantly with the advancement of molecular diagnostic tools. We describe here the molecular and cellular characteristics of the thalassemia mutation HBA2:c.94A>C, a novel point mutation affecting the alpha2-globin gene, causing a mild alpha-thal phenotype in a male patient of undisclosed ethnicity, investigated for unexplained microcytosis. The detected mutation is located at the penultimate nucleotide (nt) of the first exon which we postulated might affect pre mRNA splicing. While an in silico analysis did not predict any aberrant splice variants, experimental analysis using our in vitro model for gene expression studies showed utilization of a cryptic splice site at codon 15 that resulted in an aberrant splice variant. As a result, a frameshift in the reading frame of the mature mRNA was produced, leading to the formation of a premature termination codon (PTC) between codons 48 and 49 in exon 2. This in turn leads to nonsense mediated mRNA decay (NMD) and the phenotype of alpha-thal. PMID- 22524212 TI - Survival of stomach and esophagus cancer patients in Germany in the early 21st century. AB - BACKGROUND: Esophagus and stomach cancers are associated with poor prognosis. But most published population-based cancer survival estimates for stomach and esophagus cancer refer to survival experience of patients diagnosed in the 1990s or earlier years. The aim of this study was to provide up-to-date survival estimates and trends for patients with stomach and esophagus cancer in Germany. MATERIAL AND METHODS: Our analysis is based on data from 11 population-based cancer registries, covering 33 million inhabitants. Patients diagnosed with stomach and esophagus cancer in 1997-2006 were included. Period analysis was used to derive five-year relative survival estimates and trends by age, sex, cancer subsite, and stage for the time period of 2002-2006. German and US survival estimates were compared utilizing the SEER 13 database. RESULTS: Overall age standardized five-year relative survival was 31.8% and 18.3% for stomach and esophagus cancer, respectively, compared to 27.2% and 17.4% in the US. Survival was somewhat higher among female than among male patients for both cancer sites (33.6% vs. 30.6% and 21.5% vs. 17.5%, respectively) and much higher for non cardia stomach cancer (40.4%) than for cardia cancer (23.4%). From 2002 to 2006, a moderate increase in five-year relative survival by 2.7 percent units was observed for non-cardia stomach cancer patients in Germany (p < 0.001). CONCLUSION: Five-year relative cancer survival has reached levels around 40% for patients with non-cardia stomach cancer in Germany in the early 21st century, whereas it remained at lower levels around 20% for patients with esophagus and cardia cancer. PMID- 22524213 TI - Recurrence in region of spared parotid gland in patient receiving definitive intensity-modulated radiotherapy for nasopharyngeal cancer: a case report. PMID- 22524214 TI - Intrathecal trastuzumab: dose matters. PMID- 22524215 TI - Experimental investigation of the cytotoxicity of medium-borne signals in human prostate cancer cell line. AB - INTRODUCTION: Evidence exists that exposure of non-irradiated cells to Irradiated Cell Conditioned Medium (ICCM) can cause effects similar to those resulting from direct radiation damage. This study attempts to validate the stochastic model, relating absorbed dose to the emission and processing of cell death signals by non-irradiated cells, in vitro in PC3 human prostate cancer cell line. METHODS: The recipient cell survival was measured after exposure of cells to ICMM derived from donor cells: a) exposed to radiation doses from 2 Gy to 8 Gy and b) of concentrations varying from 2 * 10(2) to 6 * 10(6) irradiated with 2 Gy. RESULTS: Exposure to ICCM, irradiated with doses between 2-8 Gy, resulted in a significant (p < 0.001) decrease in clonogenic survival of non-irradiated recipient cells compared to the control group. However, dose dependency above 2 Gy was not observed, indicating that any dose threshold was below 2 Gy. A significant (p < 0.001) decrease in survival was found in recipient cells exposed to the ICCM, derived from different concentrations of donor cells exposed to 2 Gy, compared to the control group. The recipient cell survival following exposure to ICCM derived from 2 * 10(2) cells was significantly higher (p < 0.5) compared to the rest of donor cell concentrations, indicating that the toxicity of ICCM depends on the cellular concentration of donor cells. Non-linear regression data fitting provided reasonable agreement with the microdosimetric model for the induction of cell killing through medium-borne signals. CONCLUSION: For the given cell line and given experimental conditions, significant decreases in cell survival were observed in non-irradiated cells exposed to ICCM derived from donor cells of various concentrations and irradiated with different doses. PMID- 22524216 TI - Optical tomography. AB - The number of applications using optical tomography has significantly increased over the past decade. A literature research providing this term as keyword gives 26 hits for 1990, 719 for 2000, and 9,202 for 2010. With an increasing number of applications, the number of different imaging modalities is also increasing. This review summarizes recent developments in tomographic methods for scattering and nonscattering samples. These two different cases of optical tomography are typically represented by biomedical imaging and atmospheric tomography, representing high- and low-scattering samples, respectively. An essential prerequisite for tomographic analyses is an understanding of light propagation in different media, which allows for the development of specific reconstruction algorithms for the different tomographic tasks. PMID- 22524218 TI - Raman imaging. AB - The past decade has seen an enormous increase in the number and breadth of imaging techniques developed for analysis in many industries, including pharmaceuticals, food, and especially biomedicine. Rather than accept single dimensional forms of information, users now demand multidimensional assessment of samples. High specificity and the need for little or no sample preparation make Raman imaging a highly attractive analytical technique and provide motivation for continuing advances in its supporting technology and utilization. This review discusses the current tools employed in Raman imaging, the recent advances, and the major applications in this ever-growing analytical field. PMID- 22524217 TI - Probing embryonic stem cell autocrine and paracrine signaling using microfluidics. AB - Although stem cell fate is traditionally manipulated by exogenously altering the cells' extracellular signaling environment, the endogenous autocrine and paracrine signals produced by the cells also contribute to their two essential processes: self-renewal and differentiation. Autocrine and/or paracrine signals are fundamental to both embryonic stem cell self-renewal and early embryonic development, but the nature and contributions of these signals are often difficult to fully define using conventional methods. Microfluidic techniques have been used to explore the effects of cell-secreted signals by controlling cell organization or by providing precise control over the spatial and temporal cellular microenvironment. Here we review how such techniques have begun to be adapted for use with embryonic stem cells, and we illustrate how many remaining questions in embryonic stem cell biology could be addressed using microfluidic technologies. PMID- 22524219 TI - Scanning ion conductance microscopy. AB - Scanning ion conductance microscopy (SICM) is a versatile type of scanning probe microscopy for studies in molecular biology and materials science. Recent advances in feedback and probe fabrication have greatly increased the resolution, stability, and speed of imaging. Noncontact imaging and the ability to deliver materials to localized areas have made SICM especially fruitful for studies of molecular biology, and many examples of such use have been reported. In this review, we highlight new developments in the operation of SICM and describe some of the most exciting recent studies from this growing field. PMID- 22524220 TI - Surface plasmon-coupled emission: what can directional fluorescence bring to the analytical sciences? AB - Surface plasmon-coupled emission (SPCE) arose from the integration of fluorescence and plasmonics, two rapidly expanding research fields. SPCE is revealing novel phenomena and has potential applications in bioanalysis, medical diagnostics, drug discovery, and genomics. In SPCE, excited fluorophores couple with surface plasmons on a continuous thin metal film; plasmophores radiate into a higher-refractive index medium with a narrow angular distribution. Because of the directional emission, the sensitivity of this technique can be greatly improved with high collection efficiency. This review describes the unique features of SPCE. In particular, we focus on recent advances in SPCE-based analytical platforms and their applications in DNA sensing and the detection of other biomolecules and chemicals. PMID- 22524221 TI - Assessing nanoparticle toxicity. AB - Nanoparticle toxicology, an emergent field, works toward establishing the hazard of nanoparticles, and therefore their potential risk, in light of the increased use and likelihood of exposure. Analytical chemists can provide an essential tool kit for the advancement of this field by exploiting expertise in sample complexity and preparation as well as method and technology development. Herein, we discuss experimental considerations for performing in vitro nanoparticle toxicity studies, with a focus on nanoparticle characterization, relevant model cell systems, and toxicity assay choices. Additionally, we present three case studies (of silver, titanium dioxide, and carbon nanotube toxicity) to highlight the important toxicological considerations of these commonly used nanoparticles. PMID- 22524222 TI - Biofuel cells: enhanced enzymatic bioelectrocatalysis. AB - Enzymatic biofuel cells represent an emerging technology that can create electrical energy from biologically renewable catalysts and fuels. A wide variety of redox enzymes have been employed to create unique biofuel cells that can be used in applications such as implantable power sources, energy sources for small electronic devices, self-powered sensors, and bioelectrocatalytic logic gates. This review addresses the fundamental concepts necessary to understand the operating principles of biofuel cells, as well as recent advances in mediated electron transfer- and direct electron transfer-based biofuel cells, which have been developed to create bioelectrical devices that can produce significant power and remain stable for long periods. PMID- 22524223 TI - Chemical mapping of paleontological and archeological artifacts with synchrotron X-rays. AB - The application of the recently developed synchrotron rapid scanning X-ray fluorescence (SRS-XRF) technique to the mapping of large objects is the focus of this review. We discuss the advantages of SRS-XRF over traditional systems and the use of other synchrotron radiation (SR) techniques to provide corroborating spectroscopic and diffraction analyses during the same analytical session. After reviewing routine techniques used to analyze precious specimens, we present several case studies that show how SR-based methods have been successfully applied in archeology and paleontology. For example, SRS-XRF imaging of a seventh century Qur'an palimpsest and an overpainted original opera score from Luigi Cherubini is described. We also review the recent discovery of soft-tissue residue in fossils of Archaeopteryx and an ancient reptile, as well as work that has successfully resolved the remnants of pigment in Confuciusornis sanctus, a 120-million-year-old fossil of the oldest documented bird with a fully derived avian beak. PMID- 22524224 TI - Chemical sensing with nanowires. AB - Transformational advances in the performance of nanowire-based chemical sensors and biosensors have been achieved over the past two to three years. These advances have arisen from a better understanding of the mechanisms of transduction operating in these devices, innovations in nanowire fabrication, and improved methods for incorporating receptors into or onto nanowires. Nanowire based biosensors have detected DNA in undiluted physiological saline. For silicon nanowire nucleic acid sensors, higher sensitivities have been obtained by eliminating the passivating oxide layer on the nanowire surface and by substituting uncharged protein nucleic acids for DNA as the capture strands. Biosensors for peptide and protein cancer markers, based on both semiconductor nanowires and nanowires of conductive polymers, have detected these targets at physiologically relevant concentrations in both blood plasma and whole blood. Nanowire chemical sensors have also detected several gases at the parts-per million level. This review discusses these and other recent advances, concentrating on work published in the past three years. PMID- 22524226 TI - Digital microfluidics. AB - Digital microfluidics (DMF) is an emerging liquid-handling technology that enables individual control over droplets on an open array of electrodes. These picoliter- to microliter-sized droplets, each serving as an isolated vessel for chemical processes, can be made to move, merge, split, and dispense from reservoirs. Because of its unique advantages, including simple instrumentation, flexible device geometry, and easy coupling with other technologies, DMF is being applied to a wide range of fields. In this review, we summarize the state of the art of DMF technology from the perspective of analytical chemistry in sections describing the theory of droplet actuation, device fabrication and integration, and applications. PMID- 22524225 TI - Computational models of protein kinematics and dynamics: beyond simulation. AB - Physics-based simulation represents a powerful method for investigating the time varying behavior of dynamic protein systems at high spatial and temporal resolution. Such simulations, however, can be prohibitively difficult or lengthy for large proteins or when probing the lower-resolution, long-timescale behaviors of proteins generally. Importantly, not all questions about a protein system require full space and time resolution to produce an informative answer. For instance, by avoiding the simulation of uncorrelated, high-frequency atomic movements, a larger, domain-level picture of protein dynamics can be revealed. The purpose of this review is to highlight the growing body of complementary work that goes beyond simulation. In particular, this review focuses on methods that address kinematics and dynamics, as well as those that address larger organizational questions and can quickly yield useful information about the long timescale behavior of a protein. PMID- 22524227 TI - Distance-of-flight mass spectrometry: a new paradigm for mass separation and detection. AB - Distance-of-flight mass spectrometry (DOFMS) offers the advantages of physical separation of ions, array detection of ions, focusing of initial ion energy, great simplicity, and a truly unlimited mass range. DOFMS instrumentation is similar to that of time-of-flight mass spectrometry (TOFMS) and shares its ion source versatility, batch analysis, and rapid spectral-generation rate. With constant-momentum ion acceleration and an ion mirror, there is a time at which ions of all mass-to-charge values are energy focused at their particular distances along the flight path. A pulsed field orthogonal to the flight path drives the ions to reach the detector array at this specific time. Results from a 0.29-m proof-of-principle instrument verify the theoretically predicted energy focus and demonstrate how the range of mass-to-charge values that impinge on the detector array can be readily changed. DOFMS could be combined sequentially with TOFMS to enable simultaneous scanless tandem mass spectrometry. PMID- 22524228 TI - Nanoelectrodes: recent advances and new directions. AB - This article reviews recent work involving the development and application of nanoelectrodes in electrochemistry and related areas. We first discuss common analytical methods for characterizing the size, shape, and quality of nanoelectrodes, including electron microscopy, steady-state cyclic voltammetry, scanning electrochemical microscopy, and surface modification. We then emphasize recent developments in fabrication techniques that have led to structurally well defined nanoelectrodes. We highlight recent advances in the application of nanoelectrodes in important analytical chemistry areas, such as single-molecule studies, single-nanoparticle electrochemistry, and measurements of neurotransmitters from single neuronal cells. PMID- 22524229 TI - Optical spectroscopy of marine bioadhesive interfaces. AB - Marine organisms have evolved extraordinarily effective adhesives that cure underwater and resist degradation. These underwater adhesives differ dramatically in structure and function and are composed of multiple proteins assembled into functional composites. The processes by which these bioadhesives cure- conformational changes, dehydration, polymerization, and cross-linking--are challenging to quantify because they occur not only underwater but also in a buried interface between the substrate and the organism. In this review, we highlight interfacial optical spectroscopy approaches that can reveal the biochemical processes and structure of marine bioadhesives, with particular emphasis on macrofoulers such as barnacles and mussels. PMID- 22524230 TI - Influence of surface oxidation of multiwalled carbon nanotubes on the adsorption affinity and capacity of polar and nonpolar organic compounds in aqueous phase. AB - Adsorption of organic contaminants on carbon nanotubes (CNTs) is a critical behavior in the environmental application of CNTs as sorbents and in the environmental risk assessment of both organic contaminants and CNTs. Oxidation of CNTs may introduce oxygen-containing groups on CNTs' surface and then alter the adsorption of organic contaminants. In this study, adsorption of polar and nonpolar organic compounds on four multiwalled carbon nanotubes (MWCNTs) containing varied amounts of surface oxygen-containing groups were investigated to examine the influence of CNTs' surface oxidation on adsorption. We observed that surface oxidation of MWCNTs reduced the surface area-normalized adsorption capacity of organic compounds significantly because of the competition of water molecules but did not alter the adsorption affinity. The interactions (i.e., hydrophobic effect, pi-pi bonds, and hydrogen bonds) and the interaction strength for adsorption of organic molecules on MWCNTs could not be altered by the surface oxidation of MWCNTs and thus were responsible for the unaltered adsorption affinity. In addition, the decrease of surface area-normalized adsorption capacity of the organic compound with more polarity and higher adsorption affinity by surface oxidation was less because of the heterogeneous nature of hydrophilic sites of MWCNTs' surface. PMID- 22524231 TI - Supposed primary conjunctival lymphoma in a dog. AB - A 7-year-old, male mixed-breed dog was presented for evaluation of a well delineated, pink, oval and slightly firm mass with a smooth regular surface that was expanding approximately 60% of the lower eyelid conjunctiva and the lateral canthus. The dog had a supposed primary B-cell lymphoma at the temporal canthus of the upper eyelid conjunctiva of the same eye that had been removed approximately 3 years earlier. No metastases were detected at either presentation. Histologically, the conjunctival lamina propria was effaced by a well-delineated, unencapsulated and expansile highly cellular neoplasm composed of sheets of round cells that were immunohistochemically positive for CD20 and CD79a negative for CD3. Based on the microscopic and immunohistochemical findings, a diagnosis of supposed primary B cell conjunctival lymphoma was made. Primary ocular and adnexal ocular lymphomas in dogs are rarely reported and their behavior is poorly characterized. Further tumor recurrence was not observed one year post operatively. This case was considered unusual because of its conjunctival involvement and the clinical course with recurrence after three years of a surgical therapeutic procedure. PMID- 22524233 TI - Selective detection of iodide and cyanide anions using gold-nanoparticle-based fluorescent probes. AB - We developed two simple, rapid, and cost-effective fluorescent nanosensors, both featuring bovine serum albumin labeled with fluorescein isothiocyanate (FITC)) capped gold nanoparticles (FITC-BSA-Au NPs), for the selective sensing of cyanide (CN(-)) and iodine (I(-)) ions in high-salinity solutions and edible salt samples. During the preparation of FITC-BSA-Au NP probes, when AuNPs were introduced to the mixture containing FITC and BSA, the unconjugated FITC and FITC labeled BSA (FITC-BSA) adsorbed to the particles' surfaces. These probes operated on a basic principle that I(-) and CN(-) deposited on the surfaces of the Au NPs or the etching of Au NPs induced the release of FITC molecules or FITC-BSA into the solution, and thus restored the florescence of FITC. We employed FITC-BSA to protect the Au NPs from significant aggregation in high-salinity solutions. In the presence of masking agents such as S(2)O(8)(2-)/Pb(2+), FITC-BSA-Au NPs facilitated the selective detection of CN(-) (by at least 150-fold in comparison with other anions). We also demonstrated that the FITC-BSA-Au NPs in the presence of H(2)O(2) could selectively detect I(-) down to 50 nM. Taking advantages of their high stability and selectivity, we employed our FITC-BSA-Au NP-based probes for the detection of CN(-) and I(-) in water samples (pond water, tap water, and seawater) and detection of I(-) in edible salt samples, respectively. This simple, rapid, and cost-effective sensing system appears to demonstrate immense practical potential for the detection of anions in real samples. PMID- 22524232 TI - A possible role for inflammation in mediating apoptosis of oligodendrocytes as induced by the Lyme disease spirochete Borrelia burgdorferi. AB - BACKGROUND: Inflammation caused by the Lyme disease spirochete B. burgdorferi is an important factor in the pathogenesis of Lyme neuroborreliosis. Our central hypothesis is that B. burgdorferi can cause disease via the induction of inflammatory mediators such as cytokines and chemokines in glial and neuronal cells. Earlier we demonstrated that interaction of B. burgdorferi with brain parenchyma induces inflammatory mediators in glial cells as well as glial (oligodendrocyte) and neuronal apoptosis using ex vivo and in vivo models of experimentation. METHODS: In this study we evaluated the ability of live B. burgdorferi to elicit inflammation in vitro in differentiated human MO3.13 oligodendrocytes and in differentiated primary human oligodendrocytes, by measuring the concentration of immune mediators in culture supernatants using Multiplex ELISA assays. Concomitant apoptosis was quantified in these cultures by the in situ terminal deoxynucleotidyl transferase mediated UTP nick end labeling (TUNEL) assay and by quantifying active caspase-3 by flow cytometry. The above phenomena were also evaluated after 48 h of stimulation with B. burgdorferi in the presence and absence of various concentrations of the anti-inflammatory drug dexamethasone. RESULTS: B. burgdorferi induced enhanced levels of the cytokine IL 6 and the chemokines IL-8 and CCL2 in MO3.13 cells as compared to basal levels, and IL-8 and CCL2 in primary human oligodendrocytes, in a dose-dependent manner. These cultures also showed significantly elevated levels of apoptosis when compared with medium controls. Dexamethasone reduced both the levels of immune mediators and apoptosis, also in a manner that was dose dependent. CONCLUSIONS: This finding supports our hypothesis that the inflammatory response elicited by the Lyme disease spirochete in glial cells contributes to neural cell damage. As oligodendrocytes are vital for the functioning and survival of neurons, the inflammation and subsequent apoptosis of oligodendrocytes induced by B. burgdorferi could contribute to the pathogenesis of Lyme neuroborreliosis. PMID- 22524234 TI - Patterns of endogenous steroids in apathetic refugee children are compatible with long-term stress. AB - BACKGROUND: During the last few years, a number of children of asylum applicants in Sweden developed an apathetic or unconscious state. The syndrome was perceived as new, and various explanations were advanced such as factitious disorder, intoxication, or stress. Considering a potential association between traumatic stress and regulation of steroids biosynthesis, this study explored whether changes in concentrations of endogenous steroids were associated with the above syndrome. METHODS: Eleven children were recruited in the study. Concentrations of steroids in blood samples were determined using high sensitivity liquid chromatography tandem mass spectrometry methods. Symptoms were assessed with a clinical rating scale developed for the study. Steroid concentrations were measured at the entry into study and after recovery; and concentrations were evaluated for the association with the symptoms in apathetic children. RESULTS: Cortisol and cortisone concentrations at baseline were negatively associated with duration of the symptoms from entry into the study to clinical recovery. Higher concentrations of pregnanes (pregnenolone, 17-OH-pregnenolone, and dehydroepiandrosterone) were observed in the symptomatic state and the concentrations decreased after the recovery. CONCLUSIONS: Pattern of low cortisol concentrations found in apathetic children is consistent with long-term stress. An increase of upstream steroid metabolites (pregnanes) was found to be associated with the symptomatic state. PMID- 22524235 TI - Demonstrating emotional processing differences in psychopathy using affective ERP modulation. AB - Psychopaths exhibit abnormalities processing emotional information, but there is less certainty regarding the role attention plays in these processes. We present data from two affective picture-viewing tasks comparing event-related potential (ERP) modulation effects when emotional information is present but not task relevant (Task 1) followed by a condition directing attention to the categorization of emotional content (Task 2). Controls show a robust, persistent ERP positivity (200-900 ms) associated with emotional target photos compared to neutral targets in both tasks. Individuals with psychopathy only showed this differentiation when explicitly attending to the emotional content of the photos (Task 2), and these effects remained smaller than the amplitude differences demonstrated by controls. Although abnormal allocation of attention may play a critical role, this cannot completely account for emotional processing deficits associated with psychopathy. PMID- 22524236 TI - Conversion and origin of normal and abnormal temperature dependences of kinetic isotope effect in hydride transfer reactions. AB - The effects of substituents on the temperature dependences of kinetic isotope effect (KIE) for the reactions of the hydride transfer from the substituted 5 methyl-6-phenyl-5,6-dihydrophenanthridine (G-PDH) to thioxanthylium (TX(+)) in acetonitrile were examined, and the results show that the temperature dependences of KIE for the hydride transfer reactions can be converted by adjusting the nature of the substituents in the molecule of the hydride donor. In general, electron-withdrawing groups can make the KIE to have normal temperature dependence, but electron-donating groups can make the KIE to have abnormal temperature dependence. Thermodynamic analysis on the possible pathways of the hydride transfer from G-PDH to TX(+) in acetonitrile suggests that the transfers of the hydride anion in the reactions are all carried out by the concerted one step mechanism whether the substituent is an electron-withdrawing group or an electron-donating group. But the examination of Hammett-type free energy analysis on the hydride transfer reactions supports that the concerted one-step hydride transfer is not due to an elementary chemical reaction. The experimental values of KIE at different temperatures for the hydride transfer reactions were modeled by using a kinetic equation formed according to a multistage mechanism of the hydride transfer including a returnable charge-transfer complex as the reaction intermediate; the real mechanism of the hydride transfer and the root that why the temperature dependences of KIE can be converted as the nature of the substituents are changed were discovered. PMID- 22524237 TI - Molecular phylogeography and genetic diversity of East Asian goats. AB - The domestic goat is one of the most important livestock species, but its origins and genetic diversity still remain uncertain. Multiple highly divergent maternal lineages of goat have been reported in previous studies. Although one of the mitochondrial DNA lineages, lineage B, was detected only in eastern and southern Asia, the geographic distribution of these lineages was previously unclear. Here, we examine the genetic diversity and phylogeographic structure of Asian goats by mitochondrial DNA sequences and morphological characteristics. The analyses of a total of 1661 Asian goats from 12 countries revealed a high frequency of lineage B in Southeast Asia. The frequency of this lineage tended to be higher in mountain areas than in plain areas in Southeast Asian countries, and there was a significant correlation between its frequency and morphological traits. The results suggest an original predominance of lineage B in Southeast Asia and the recent infiltration of lineage A into Southeast Asian goats. PMID- 22524238 TI - Photocatalytic water splitting using modified GaN:ZnO solid solution under visible light: long-time operation and regeneration of activity. AB - Overall water splitting using GaN:ZnO solid solution photocatalyst modified with Rh(2-y)Cr(y)O(3) nanoparticles as H(2) evolution cocatalysts under visible light (400 < lambda < 500 nm) was examined with respect to long-term durability and regeneration of photocatalytic activity. The rate of visible light water splitting remained unchanged for 3 months (2160 h), producing H(2) and O(2) continuously at a stoichiometric amount. After 6 months of operation, a 50% loss of the initial activity occurred. Regeneration treatment of deactivated catalysts was attempted by reloading the Rh(2-y)Cr(y)O(3) cocatalyst. The degree of activity regeneration depended on the reloading amount. Up to 80% of the initial activity for H(2) evolution could be recovered under optimal treatment conditions. It was also found that deactivation of GaN:ZnO was suppressed to some extent by prior coloading of an O(2) evolution cocatalyst, which helped to suppress oxidative decomposition of GaN:ZnO by valence band holes, thereby improving the durability. PMID- 22524239 TI - Characterization of an endolysin, LysBPS13, from a Bacillus cereus bacteriophage. AB - Use of bacteriophages as biocontrol agents is a promising tool for controlling pathogenic bacteria including antibiotic-resistant bacteria. Not only bacteriophages but also endolysins, the peptidoglycan hydrolyzing enzymes encoded by bacteriophages, have high potential for applications as biocontrol agents against food-borne pathogens. In this study, a putative endolysin gene was identified in the genome of the bacteriophage BPS13, which infects Bacillus cereus. In silico analysis of this endolysin, designated LysBPS13, showed that it consists of an N-terminal catalytic domain (PGRP domain) and a C-terminal cell wall binding domain (SH3_5 domain). Further characterization of the purified LysBPS13 revealed that this endolysin is an N-acetylmuramyl-l-alanine amidase, the activity of which was not influenced by addition of EDTA. In addition, LysBPS13 demonstrated remarkable thermostability in the presence of glycerol, and it retained its lytic activity even after incubation at 100 degrees C for 30 min. Taken together, these results indicate that LysBPS13 can be considered a favorable candidate for a new antimicrobial agent to control B. cereus. PMID- 22524240 TI - Health systems and health equity: the challenge of the decade. AB - For decades, concerns regarding health systems have been prominent in the global health discourse, leading to numerous publications and laudable declarations, as well as compacts and consensus statements intended to guide policy and practice. This discussion paper is intended to neither summarise nor systematically review this vast field of interest. Instead, the paper reflects on some challenges for attaining health systems equity and raises questions related to the contributions of both national and the global health systems to this mission. PMID- 22524241 TI - Intra-amniotic inflammation predicts microbial invasion of the amniotic cavity but not spontaneous preterm delivery in preterm prelabor membrane rupture. AB - OBJECTIVE: To predict microbial invasion of the amniotic cavity (MIAC) and spontaneous preterm delivery within seven days using a panel of selected proteins from amniotic fluid in a Swedish population of preterm prelabor membrane rupture (PPROM). DESIGN: Prospective cohort study. SETTING: Evaluation of intra-amniotic inflammation in preterm premature rupture of membranes. POPULATION: Sixty-six pregnant women with preterm prelabor membrane rupture at 22(+0) -33(+6) weeks' gestational age. Methods. Twenty-seven amniotic fluid proteins were assayed by a multiple immunoassay. MAIN OUTCOME MEASURES: The intra-amniotic inflammatory response was evaluated according to the presence of MIAC and the risk of spontaneous preterm delivery within seven days. A prediction model was constructed using logistic regression. RESULTS: The overall rates of MIAC and spontaneous preterm delivery within seven days were 20 and 50%, respectively. There was a higher inflammatory response in women with MIAC than in those without. Earlier gestational age at delivery and lower birthweight were observed in the presence of microbial invasion of the amniotic cavity. Amniotic fluid interleukin (IL)-6 and IL-10 were the best predictors of MIAC in terms of sensitivity (69%), specificity (81%), positive predictive value (47%), negative predictive value (91%) and a positive likelihood ratio of 3.6. There were no differences in intra-amniotic inflammatory response according to the risk of spontaneous preterm delivery within seven days. CONCLUSION: Amniotic fluid IL-6 and IL-10 are the best inflammatory biomarkers to predict MIAC in women with PPROM. Intra-amniotic inflammation does not predict the occurrence of spontaneous preterm delivery within seven days of PPROM. PMID- 22524243 TI - Paper-based ion-selective potentiometric sensors. AB - A new approach to develop ultra low-cost, robust, rugged, and disposable potentiometric sensors is presented. A suspension of carbon nanotubes in a water surfactant mixture (carbon nanotubes ink) is applied on conventional filter papers to turn them into conductive papers, which are then used as a substrate to build ion-selective electrodes. The electrodes are made by drop casting a membrane on a small circular area of the conductive paper. In this way, the carbon nanotubes act as both electric conductors and ion-to-electron transducers of the potentiometric signal. Electrodes for sensing K(+), NH(4)(+), and pH were built and tested using this approach, and the results were compared with classical solid-state ion selective electrodes using carbon nanotubes as transducers and glassy carbon as a substrate. In all cases, the analytical performance (sensitivity, linear ranges, limits of detection, selectivity, etc.) of these disposable paper electrodes was similar to that obtained for the more conventional type of ion-selective-electrodes. This opens new avenues for very low-cost platforms for generation of chemical information. PMID- 22524242 TI - Rehospitalization in a national population of home health care patients with heart failure. AB - OBJECTIVE: Patients with heart failure (HF) have high rates of rehospitalization. Home health care (HHC) patients with HF are not well studied in this regard. The objectives of this study were to determine patient, HHC agency, and geographic (i.e., area variation) factors related to 30-day rehospitalization in a national population of HHC patients with HF, and to describe the extent to which rehospitalizations were potentially avoidable. DATA SOURCES: Chronic Condition Warehouse data from the Centers for Medicare & Medicaid Services. STUDY DESIGN: Retrospective cohort design. DATA EXTRACTION: The 2005 national population of HHC patients was matched with hospital and HHC claims, the Provider of Service file, and the Area Resource File. PRINCIPAL FINDINGS: The 30-day rehospitalization rate was 26 percent with 42 percent of patients having cardiac-related diagnoses for the rehospitalization. Factors with the strongest association with rehospitalization were consistent between the multilevel model and Cox proportional hazard models: number of prior hospital stays, higher HHC visit intensity category, and dyspnea severity at HHC admission. Substantial numbers of rehospitalizations were judged to be potentially avoidable. CONCLUSIONS: The persistently high rates of rehospitalization have been difficult to address. There are health care-specific actions and policy implications that are worth examining to improve rehospitalization rates. PMID- 22524244 TI - Analysis of giardin expression during encystation of Giardia lamblia. AB - The present study analyzed giardin transcription in trophozoites and cysts during encystation of Giardia lamblia . Encystment was induced using standard methods, and the numbers of trophozoites and cysts were counted at various time points during the process. At all time points, RNA from both stages were assayed for levels of alpha2-, beta-, and delta-giardin mRNA as well as for cyst wall protein 3 (CWP3) mRNA using quantitative RT-PCR. In encystation medium, the number of G. lamblia trophozoites decreased, while the number of cysts increased between 0 and 72 hr. In trophozoites, alpha2- and beta-giardin transcription decreased over time, while delta-giardin transcription remained unchanged during the same time period. CWP3 transcription exhibited a slight increase in trophozoites at 8 hr, followed by a decrease at subsequent time points. Expression of alpha2-giardin increased at 48 hr in cysts followed by decreased expression at 72 hr, while beta and delta-giardin expression was unchanged during encystation. CWP3 transcription gradually decreased from 24-72 hr in cysts. Consistent with previous studies, giardin proteins appeared to be disassembled into amorphous structures inside cysts during encystation. These findings represent the first analysis of giardin transcription in separate populations of trophozoites and cysts during encystation and indicate differential regulation of giardin mRNA expression by these developmental stages. PMID- 22524245 TI - F2C2: a fast tool for the computation of flux coupling in genome-scale metabolic networks. AB - BACKGROUND: Flux coupling analysis (FCA) has become a useful tool in the constraint-based analysis of genome-scale metabolic networks. FCA allows detecting dependencies between reaction fluxes of metabolic networks at steady state. On the one hand, this can help in the curation of reconstructed metabolic networks by verifying whether the coupling between reactions is in agreement with the experimental findings. On the other hand, FCA can aid in defining intervention strategies to knock out target reactions. RESULTS: We present a new method F2C2 for FCA, which is orders of magnitude faster than previous approaches. As a consequence, FCA of genome-scale metabolic networks can now be performed in a routine manner. CONCLUSIONS: We propose F2C2 as a fast tool for the computation of flux coupling in genome-scale metabolic networks. F2C2 is freely available for non-commercial use at https://sourceforge.net/projects/f2c2/files/. PMID- 22524246 TI - Strategies for reducing the incidence of skin complications in newborns treated with whole-body hypothermia. AB - OBJECTIVE: To present the results of a strategy designed to reduce the incidence of skin complications in newborns with hypoxic-ischemic encephalopathy treated with moderate whole-body hypothermia. DESIGN: Retrospective study. SETTING: Neonatal Intensive Care Unit (NICU). PATIENTS: Thirty-nine neonates cooled in the considered period. INTERVENTION: Starting from January 2008, for neonates treated with moderate whole-body hypothermia (33.5 degrees C), the cooling system was set in "automatic servo-controlled mode (ACM)", where the temperature of the circulating water could vary between 4 degrees C and 42 degrees C. Starting from January 2009, cooling blankets were used in another type of automatic mode, the "gradient variable mode (GVM)", where the circulating water was maintained at a specific pre-set gradient towards the patient's body temperature, and a specific nursing protocol (NP) was adopted. MEASUREMENTS AND MAIN RESULTS: Two of the eleven newborns treated with the "ACM" exhibited skin complications compatible with subcutaneous fat necrosis (SFN). None of the twenty-eight newborns treated with the "GVM" exhibited skin complications. A comparison of the biochemical and hematological data between these two groups revealed that newborns treated after the adopting of a NP and the "GVM" showed lower serum protein C and calcium levels, and higher platelet levels. CONCLUSIONS: Our data suggest that newborns undergoing therapeutic cooling may benefit from a specific NP and correct cooling unit setting. Should further studies confirm our data, this nursing approach could be easily adopted. PMID- 22524247 TI - Perceptions of fatigue - and perceived consequences - among Flemish obstetricians gynaecologists: a survey. AB - OBJECTIVES: The effects of fatigue on the performance of medical trainees have been extensively studied. Much less is known about the effects of fatigue among doctors who have completed their training. The aim of this study was to inquire about the perception of fatigue and its consequences among certified obstetricians-gynaecologists (OGs). METHODS: A questionnaire was mailed to all certified OGs working in Flanders (Northern Belgium). Descriptive statistics as well as uni- and multivariate analyses for potential determinants of fatigue are presented. RESULTS: Of the 450 questionnaires mailed, 260 (58%) were returned. Half (52%) of the doctors worked more than 60 h/week. During an average working day, four out of ten respondents indicated they experienced a certain degree of fatigue, and one in ten felt really tired. Fatigue was associated with long working hours and led in a sizeable proportion of respondents to dissatisfaction (29%) and to medical/surgical errors (19%). None of the perceived errors resulted in loss of life. Academic OGs worked more hours/week but fewer during the night than their colleagues in private practice. The former reported having made significantly more medical errors (26%) than the latter (11%). CONCLUSIONS: Tired OGs have less job satisfaction, and perceive they make more errors. None of the perceived errors resulted in loss of life. Certified OGs working more than 60 h/week are more frequently tired. PMID- 22524248 TI - Cluster-based networks: 1D and 2D coordination polymers based on {MnFe2(MU3-O)} type clusters. AB - A straightforward approach to heterometallic Mn-Fe cluster-based coordination polymers is presented. By employing a mixed-valent MU(3)-oxo trinuclear manganese(II/III) pivalate cluster, isolated as [Mn(II)Mn(III)(2)O(O(2)CCMe(3))(6)(hmta)(3)].(solvent) (hmta = hexamethylenetetramine; solvent = n-propanol (1), toluene (2)) in the reaction with a MU(3)-oxo trinuclear iron(III) pivalate cluster compound, [Fe(3)O(O(2)CCMe(3))(6)(H(2)O)(3)]O(2)CCMe(3).2Me(3)CCO(2)H, three new heterometallic {Mn(II)Fe(III)(2)} cluster-based coordination polymers were obtained: the one-dimensional polymer chain compounds {[MnFe(2)O(O(2)CCMe(3))(6)(hmta)(2)].0.5MeCN}(n) (3) and {[MnFe(2)O(O(2)CCMe(3))(6)(hmta)(2)].Me(3)CCO(2)H.(n-hexane)}(n) (4) and the two dimensional layer compound {[MnFe(2)O(O(2)CCMe(3))(6)(hmta)(1.5)].(toluene)}(n) (5). Single-crystal X-ray diffraction analysis reveals a MU(3)-oxo trinuclear pivalate cluster building block as the main constituent in all polymer compounds. Different M:hmta ratios in 1-5 are related to the different structural functions of the N-containing ligand. In clusters 1 and 2, three hmta ligands are monodentate, whereas in chains 3 and 4 two hmta ligands act as bridging ligands and one is a monodentate ligand; in 5, all hmta molecules act as bidentate bridges. Magnetic studies indicate dominant antiferromagnetic interactions between the metal centers in both homometallic {Mn(3)}-type clusters 1 and 2 and heterometallic {MnFe(2)}-type coordination polymers 3-5. Modeling of the magnetic susceptibility data to a isotropic model Hamiltonian yields least-squares fits for the following parameters: J(1)(Mn(II)-Mn(III)) = -6.6 cm(-1) and J(2)(Mn(III) Mn(III)) = -5.4 cm(-1) for 1; J(1) = -5.5 cm(-1) and J(2)(Mn(III)-Mn(III)) = -3.9 cm(-1) for 2; J(1)(Mn(II)-Fe(III)) = -17.1 cm(-1) and J(2)(Fe(III)-Fe(III)) = 43.7 cm(-1) for 3; J(1) = -23.8 cm(-1) and J(2) = -53.4 cm(-1) for 4; J(1) = 13.3 cm(-1) and J(2) = -35.4 cm(-1) for 5. Intercluster coupling plays a significant role in all compounds 1-5. PMID- 22524249 TI - Stable multi-infection of splenocytes during SIV infection--the basis for continuous recombination. AB - BACKGROUND: Recombination is an important mechanism in the generation of genetic diversity of the human (HIV) and simian (SIV) immunodeficiency viruses. It requires the co-packaging of divergent RNA genomes into the same retroviral capsid and subsequent template switching during the reverse transcription reaction. By HIV-specific fluorescence in situ hybridization (FISH), we have previously shown that the splenocytes from 2 chronically infected patients with Castelman's disease were multi-infected and thus fulfill the in vivo requirements to generate genetic diversity by recombination. In order to analyze when multi infection first occurs during a lentivirus infection and how the distribution of multi-infection evolves during the disease course, we now determined the SIV copy numbers from splenocytes of 11 SIVmac251-infected rhesus macaques cross sectionally covering the time span of primary infection throughout to end-stage immunodeficiency. RESULTS: SIV multi-infection of single splenocytes was readily detected in all monkeys and all stages of the infection. Single-infected cells were more frequent than double- or triple- infected cells. There was no strong trend linking the copy number distribution to plasma viral load, disease stage, or CD4 cell counts. CONCLUSIONS: SIV multi-infection of single cells is already established during the primary infection phase thus enabling recombination to affect viral evolution in vivo throughout the disease course. PMID- 22524250 TI - Imidazolopiperazines: lead optimization of the second-generation antimalarial agents. AB - On the basis of the initial success of optimization of a novel series of imidazolopiperazines, a second generation of compounds involving changes in the core piperazine ring was synthesized to improve antimalarial properties. These changes were carried out to further improve the potency and metabolic stability of the compounds by leveraging the outcome of a set of in vitro metabolic identification studies. The optimized 8,8-dimethyl imidazolopiperazine analogues exhibited improved potency, in vitro metabolic stability profile and, as a result, enhanced oral exposure in vivo in mice. The optimized compounds were found to be more efficacious than the current antimalarials in a malaria mouse model. They exhibit moderate oral exposure in rat pharmacokinetic studies to achieve sufficient multiples of the oral exposure at the efficacious dose in toxicology studies. PMID- 22524251 TI - Complementary prediction of cardiovascular events by estimated apo- and lipoprotein concentrations in the working age population. The Health 2000 Study. AB - BACKGROUND: Apolipoprotein A-I (apoA-I) and B (apoB) and multiple lipoprotein cardiovascular risk factors can be computationally estimated with our extended Friedewald approach (EFW) from classical inputs. Their impact on cardiovascular events and mortality in the working age population is not known. METHODS: The working age (<= 65 years, n = 5956) prospective population-based cohort (follow up of 7.8 +/- 0.9 years; 46,572 patient years, 409 non-fatal incident cardiovascular events, and 55 cardiovascular and 266 all-cause deaths) had their total serum cholesterol (TC), triglycerides (TG), and HDL-C measured. Continuous net reclassification improvement (NRI) was calculated. RESULTS: In Cox models adjusted with cardiovascular risk factors, EFW-HDL(2)-C (HR 0.78, 95% CI 0.67 0.91; NRI 16.5%), apoA-I (HR 0.78, 95% CI 0.69-0.89; NRI 15.2%), apoB/apoA-I (HR 1.23, 95% CI 1.08-1.40; NRI 20.6%), and VLDL-TG (HR 1.15, 95% CI 1.05-1.25; NRI 20.1%) were associated with incident non-fatal cardiovascular events and improved risk prediction compared with TC, LDL-C, or non-HDL-C. Cardiovascular deaths could be best predicted with EFW apoB (HR 1.81, 95% CI 1.18-2.77; NRI 77.3%). CONCLUSIONS: EFW approach-derived HDL(2)-C, apoA-I, apoB/apoA-I, and VLDL-TG improve prediction of non-fatal cardiovascular events, and apoB of cardiovascular mortality, and can be utilized for risk estimation in a working age population without extra cost. PMID- 22524252 TI - Interactive effect of hysteresis and surface chemistry on gated silicon nanowire gas sensors. AB - Gated silicon nanowire gas sensors have emerged as promising devices for chemical and biological sensing applications. Nevertheless, the performance of these devices is usually accompanied by a "hysteresis" phenomenon that limits their performance under real-world conditions. In this paper, we use a series of systematically changed trichlorosilane-based organic monolayers to study the interactive effect of hysteresis and surface chemistry on gated silicon nanowire gas sensors. The results show that the density of the exposed or unpassivated Si OH groups (trap states) on the silicon nanowire surface play by far a crucial effect on the hysteresis characteristics of the gated silicon nanowire sensors, relative to the effect of hydrophobicity or molecular density of the organic monolayer. Based on these findings, we provide a tentative model-based understanding of (i) the relation between the adsorbed organic molecules, the hysteresis, and the related fundamental parameters of gated silicon nanowire characteristics and of (ii) the relation between the hysteresis drift and possible screening effect on gated silicon nanowire gas sensors upon exposure to different analytes at real-world conditions. The findings reported in this paper could be considered as a launching pad for extending the use of the gated silicon nanowire gas sensors for discriminations between polar and nonpolar analytes in complex, real-world gas mixtures. PMID- 22524253 TI - Visual categorisation of the arch index: a simplified measure of foot posture in older people. AB - BACKGROUND: Foot posture is considered to be an important component of musculoskeletal assessment in clinical practice and research. However, many measurement approaches are not suitable for routine use as they are time consuming or require specialised equipment and/or clinical expertise. The objective of this study was therefore to develop and evaluate a simple visual tool for foot posture assessment based on the Arch Index (AI) that could be used in clinical and research settings. METHODS: Fully weightbearing footprints from 602 people aged 62 to 96 years were obtained using a carbon paper imprint material, and cut-off AI scores dividing participants into three categories (high, normal and low) were determined using the central limit theorem (i.e. normal = +/- 1 standard deviation from the mean). A visual tool was then created using representative examples for the boundaries of each category. Two examiners were then asked to use the tool to independently grade the footprints of 60 participants (20 for each of the three categories, randomly presented), and then repeat the process two weeks later. Inter- and intra-tester reliability was determined using Spearman's rho, percentage agreement and weighted kappa statistics. The validity of the examiner's assessments was evaluated by comparing their categorisations to the actual AI score using Spearman's rho and analysis of variance (ANOVA), and to the actual AI category using percentage agreement, Spearman's rho and weighted kappa. RESULTS: Inter- and intra-tester reliability of the examiners was almost perfect (percentage agreement = 93 to 97%; Spearman's rho = 0.91 to 0.95, and weighted kappas = 0.85 to 0.93). Examiner's scores were strongly correlated with actual AI values (Spearman's rho = 0.91 to 0.94 and significant differences between all categories with ANOVA; p < 0.001) and AI categories (percentage agreement = 95 to 98%; Spearman's rho = 0.89 to 0.94, and weighted kappas = 0.87 to 0.94). There was a slight tendency for examiners to categorise participants as having higher arches than their AI scores indicated. CONCLUSIONS: Foot posture can be quickly and reliably categorised as high, normal or low in older people using a simplified visual categorisation tool based on the AI. PMID- 22524254 TI - Redox-sensitive GFP2: use of the genetically encoded biosensor of the redox status in the filamentous fungus Botrytis cinerea. AB - The production of reactive oxygen species (ROS) is part of the defence reaction of plants against invading pathogens. The effect of ROS on filamentous fungi is still unclear. In this study, ratiometric redox-sensitive green fluorescent protein (roGFP) was introduced as a tool for in vivo measurement of the cellular redox status in filamentous fungi. A fungal expression system for roGFP2 was constructed. Expressed in Botrytis cinerea, roGFP2 reversibly responded to redox changes induced by incubation with H(2)O(2) or dithiothreitol, which was determined by confocal laser scanning microscopy imaging and fluorometry. As the sensor detects the redox potential of the cellular glutathione pool, it was used to analyse the kinetics of GSH (glutathione, reduced form) recovery after H(2)O(2) treatment. The transcription factor Bap1 is the main transcriptional regulator of H(2)O(2) -scavenging proteins in B. cinerea. When compared with the wild-type, GSH recovery in the Deltabap1 deletion mutant was affected after repeated H(2)O(2) treatment. ROS and intracellular redox changes can be used by fungi for signalling purposes. In planta experiments, performed in this study, indicated that redox processes seem to be important for the differentiation of penetration structures. During the penetration of onion epidermal cells, the status of the cellular glutathione pool differed between appressoria-like structures and infecting hyphae, being reduced in the presence of infecting hyphae and more oxidized around appressoria-like structures. PMID- 22524255 TI - Genotyping of beta-globin gene mutations in single lymphocytes: a preliminary study for preimplantation genetic diagnosis of monogenic disorders. AB - Hemoglobinopathies, especially beta-thalassemia (beta-thal), represent an important health burden in Mediterranean countries like Turkey. Some couples prefer the option of preimplantation genetic diagnosis (PGD). However, clinical application of PGD, especially for the monogenic disorders is technically demanding. To ensure reliable results, protocols need to be robust and well standardized. Ideally PGD-PCR (polymerase chain reaction) protocols should be based on multiplex and fluorescent PCR for analysis of the disease-causing mutation(s) along with linked markers across the disease-associated locus. In this study, we aimed to constitute a protocol in single cells involving first round multiplex PCR with primers to amplify the region of the beta-globin gene containing the most common mutations. Two microsatellites linked to the beta globin gene cluster (D11S4891, D11S2362) and two unlinked (D13S314, GABRB3) microsatellite markers, were used to rule out allele dropout (ADO) and contamination; followed by nested real-time PCR for genotyping the beta-globin mutations. We also investigated the allele frequencies and heterozygote rates of these microsatellites in the Turkish population that have not been reported to date. This protocol was tested in 100 single lymphocytes from heterozygotes with known beta-globin mutations. Amplification failure was detected in one lymphocyte (1%) and ADO was observed in two lymphocytes (2%). No contamination was detected. All results were concordant with the genotypes of the patients. Overall, this protocol was demonstrated to be sensitive, accurate, reliable and rapid for the detection of beta-globin mutations in single cells and shows potential for the clinical application of PGD for hemoglobinopathies in the Turkish population. PMID- 22524256 TI - Charge transfer and tunable ambipolar effect induced by assembly of Cu(II) binuclear complexes on carbon nanotube field effect transistor devices. AB - Assembly of paramagnetic Cu(2) complexes with a Schiff base scaffold possessing extended electron delocalization together with a quasi-planar structure onto carbon nanotubes induces a diameter-selective charge transfer from the complex to the nanotubes leading to an interestingly large and tunable ambipolar effect. We used complementary techniques such as electron paramagnetic resonance, absorption spectroscopy, and photoluminescence to ensure the success of the assembly process and the integrity of the complex in the nanohybrid. We carried out density functional theory type calculations to rationalize the experimental results, evidencing the selective enhanced interaction of the metal complexes with one type of nanotube. PMID- 22524257 TI - Interaction of MC1R and PMEL alleles on solid coat colors in Highland cattle. AB - Six solid colors occur in Highland cattle: black, dun, silver dun and red, yellow, and white. These six coat colors are explained by a non-epistatic interaction of the genotypes at the MC1R and PMEL genes. A three base pair deletion in the PMEL gene leading to the deletion of a leucine from the signal peptide is observed in dilute-colored Highland cattle (c.50_52delTTC, p.Leu18del). The mutant PMEL allele acts in a semi-dominant manner. Dun Galloway cattle also have one copy of the deletion allele, and silver dun Galloway cattle have two copies. The presence of two adjacent leucine residues at the site of this deletion is highly conserved in human, horse, mouse and chicken as well as in cattle with undiluted coat colors. Highland and Galloway cattle thus exhibit a similar dose-dependent dilution effect based on the number of PMEL :c.50_51delTTC alleles, as Charolais cattle with PMEL :c.64G>A alleles. The PMEL :c.64G>A allele was not found in Highland or Galloway cattle. PMID- 22524258 TI - Fatigue of survivors following cardiac surgery: positive influences of preoperative prayer coping. AB - OBJECTIVES: Fatigue symptoms are common among individuals suffering from cardiac diseases, but few studies have explored longitudinally protective factors in this population. This study examined the effect of preoperative factors, especially the use of prayer for coping, on long-term postoperative fatigue symptoms as one aspect of lack of vitality in middle-aged and older patients who survived cardiac surgery. METHOD: The analyses capitalized on demographics, faith factors, mental health, and on medical comorbidities previously collected via two-wave preoperative interviews and standardized information from the Society of Thoracic Surgeons' national database. The current participants completed a mailed survey 30 months after surgery. Two hierarchical regressions were performed to evaluate the extent to which religious factors predicted mental and physical fatigue, respectively, after controlling for key demographics, medical indices, and mental health. RESULTS: Preoperative prayer coping, but not other religious factors, predicted less mental fatigue at the 30-month follow-up, after controlling for key demographics, medical comorbidities, cardiac function (previous cardiovascular intervention, congestive heart failure, left ventricular ejection fraction, New York Heart Association Classification), mental health (depression, anxiety), and protectors (optimism, hope, social support). Male gender, preoperative anxiety, and reverence in secular context predicted more mental fatigue. Physical fatigue increased with age, medical comorbidities, and preoperative anxiety. Including health control beliefs in the model did not eliminate this effect. CONCLUSIONS: Prayer coping may have independent and positive influences on less fatigue in individuals who survived cardiac surgery. However, future research should investigate mechanisms of this association. PMID- 22524259 TI - Synthesis, characterization, and optical properties of 4H-pyran-4-ylidene donor based chromophores: the relevance of the location of a thiophene ring in the spacer. AB - A series of new 4H-pyran-4-ylidene donor-based chromophores with a thiophene ring in the spacer has been synthesized. The linear and nonlinear optical (NLO) properties of these compounds have been determined and compared with the results of computational calculations. The position of the thiophene ring proved essential to optimize the figure of merit MUbeta, with the best results obtained when the heterocyclic system was closer to the donor moiety. PMID- 22524260 TI - Diagnostic frequency, response to therapy, and long-term prognosis among horses and ponies with pituitary par intermedia dysfunction, 1993-2004. AB - BACKGROUND: Pituitary pars intermedia dysfunction (PPID) is common in older horses. OBJECTIVES: To determine diagnosis frequency, prognostic factors, long term survival, and owner satisfaction with treatment. ANIMALS: Medical records from horses diagnosed with PPID, 1993-2004. METHODS: A retrospective cohort design with data collected from the Veterinary Medical Data Base (VMDB) and a cohort of 3 VTHs. Proportional accessions, annual incidence, and demographics were compared for all accessions. During the same period, a subset of medical records (n = 44) was extracted and owners (n = 34) contacted to obtain long-term follow-up information. RESULTS: Diagnoses of PPID were reported for 217 horses that presented to VTHs and were reported to the VMDB. Proportional diagnosis increased from 0.25/1,000 in 1993 to 3.72/1,000 in 2002. For 44 horses included in the follow-up study, the most commons signs were hirsutism (84%) and laminitis (50%). Of 34 horse owners contacted, the average time from onset of signs to diagnosis was 180 days. Improvement in >= 1 signs, 2 months after diagnosis, was reported by 9/22 (41%) of horse owners. Clinical signs and clinicopathologic data were not associated with survival, and 50% of horses were alive 4.6 years after diagnosis. Cause of death among horses (15/20; 85%) was euthanasia, and 11/15 (73%) were euthanized because of conditions associated with PPID. Most horse owners (28/29; 97%) said they would treat a second horse for PPID. CONCLUSION AND CLINICAL IMPORTANCE: PPID was diagnosed with increasing frequency, and 50% of horses survived 4.5 years after diagnosis. Owners were satisfied with their horses' quality of life and would treat a second horse if diagnosed. PMID- 22524261 TI - Gene expression patterns of the Bcl-2 and Bax genes in preterm birth. AB - OBJECTIVE: The apoptotic genes Bax and Bcl-2 are both involved in the pathogenesis of preterm delivery in conjunction with additional factors. We characterized gene expression patterns of these apoptotic regulatory genes as well as relevant environmental factors. DESIGN: A gene expression study with evaluation of clinical data. SETTING: Semmelweis University, Budapest, Hungary. SAMPLE: Human placental samples from 104 preterm and 140 full-term pregnancies. METHODS: Gene tests were performed using real-time PCR to assess gene expression patterns of Bax and Bcl-2 in human placental samples. Clinical data were collected from our computerized database. MAIN OUTCOME MEASURES: Apoptotic gene expression pattern and clinical information against the background of preterm delivery. RESULTS: In placental samples from preterm delivery pregnancies, expression of the Bcl-2 gene was unchanged, whereas the Bax gene was overexpressed. Placental gene expression of Bax in preterm delivery was dependent on gestational age with gestational weeks 28-32 and 32-36 associated with overexpression, and no overexpression in gestational weeks 24-28. Preterm delivery began with premature rupture of membranes in 70.2% and spontaneous uterine activity in 29.8%. CONCLUSIONS: The Bax gene was overexpressed in preterm delivery, whereas expression of the Bcl-2 gene remained unchanged. After the 28(th) gestational week, apoptosis appears to be a key factor in the pathogenesis of preterm delivery. PMID- 22524262 TI - Evaluation of a smoke-free forensic hospital: patients' perspectives on issues and benefits. AB - INTRODUCTION AND AIMS: In 2008, a new high secure forensic mental health inpatient hospital was opened in New South Wales as a smoke-free facility. This study describes the experience of patients and the impact of the smoke-free policy on smoking intentions and practice. DESIGN AND METHODS: The study methods included: (1) four semi-structured focus groups with 21 current patients; (2) patient surveys collected from 45 current patients; and (3) follow-up survey from 15 discharged patients. All methods included questions related to smoking history, experience of moving to and living in the smoke-free environment and smoking intentions or status post discharge. RESULTS: Many focus group participants indicated that they were now off cigarettes for life while some were angry about the policy. Nearly all (80%) patients surveyed smoked prior to admission. Over one-third (39%) of patients were angry at being forced to stop smoking, while 42% wanted to give up when they were admitted. Most (62%) felt they had gained weight since they stopped smoking; however, 75% indicated that living in a smoke-free environment had a positive effect on their health. Over a third (36%) of patients indicated that they intended to smoke when discharged. Post discharge, of the 12 who smoked prior to admission, seven (58%) remained non smokers at follow up. DISCUSSION AND CONCLUSIONS: This study describes promising findings about the experience of patients moving to a smoke-free mental health inpatient facility, including improved health and potential for sustained smoking cessation post discharge. PMID- 22524263 TI - New rather than old? For working memory tasks with abstract patterns the P3 and the single-trial delta response are larger for modified than identical probe stimuli. AB - Memory-guided decision making is dynamic and context-dependent, even though many studies describe an enhancement of the P3 for recognized items in memory tasks ("old-new effect"). This study utilized a delay-dependent working memory task during which decision making could be optimized by focusing attention on detected changes instead of recognized similarities. Mean P3 amplitude and delta activity were analyzed from participants who classified probe stimuli as identical or modified. The P3 amplitudes were larger for modified than for identical probes, even when the probe occurred 4,000 ms after the primary stimulus. Enhanced single trial amplitude, trial-by-trial consistency, and frontoparietal phase coherence of delta activity contributed to the larger P3 for the modified probe. Thus, context-dependent attentional resource allocation supporting memory-guided decisions might explain the enhancement of the P3 for specific probe types. PMID- 22524264 TI - Residential segregation and the availability of primary care physicians. AB - OBJECTIVE: To examine the association between residential segregation and geographic access to primary care physicians (PCPs) in metropolitan statistical areas (MSAs). DATA SOURCES: We combined zip code level data on primary care physicians from the 2006 American Medical Association master file with demographic, socioeconomic, and segregation measures from the 2000 U.S. Census. Our sample consisted of 15,465 zip codes located completely or partially in an MSA. METHODS: We defined PCP shortage areas as those zip codes with no PCP or a population to PCP ratio of >3,500. Using logistic regressions, we estimated the association between a zip code's odds of being a PCP shortage area and its minority composition and degree of segregation in its MSA. PRINCIPAL FINDINGS: We found that odds of being a PCP shortage area were 67 percent higher for majority African American zip codes but 27 percent lower for majority Hispanic zip codes. The association varied with the degree of segregation. As the degree of segregation increased, the odds of being a PCP shortage area increased for majority African American zip codes; however, the converse was true for majority Hispanic and Asian zip codes. CONCLUSIONS: Efforts to address PCP shortages should target African American communities especially in segregated MSAs. PMID- 22524265 TI - Susceptibility of wild populations of Biomphalaria spp. from neotropical South America to Schistosoma mansoni and interference of Zygocotyle lunata. AB - Populations of Biomphalaria straminea, Biomphalaria peregrina , Biomphalaria tenagophila, Biomphalaria orbignyi, and Biomphalaria oligoza from different Argentine localities were exposed to miracidia of Schistosoma mansoni EC strain, and Biomphalaria tenagophila, in addition to the SJ2 strain. Biomphalaria straminea and B. tenagophila displayed different susceptibility and compatibility (Frandsen's total cercariae production index class 0-II), whereas B. orbigny and B. oligoza were incompatible. Although B. peregrina and B. tenagophila were found naturally infected with the amphistome Zygocotyle lunata, all 5 species could be experimentally infected with Z. lunata. Exposure to Z. lunata infections with S. mansoni were obtained in natural populations of B. straminea and B. tenagophila with the EC strain (13.5-17.1% and 1.2%), respectively, and in B. tenagophila with the SJ2 strain (2.6%), 60 days postexposure [PE]), and in B. orbignyi and B. oligoza (31.1% and 26.7% 60 days PE, respectively, including single infections with S. mansoni and double infections with Z. lunata). The high susceptibility of B. orbignyi and B. oligoza is noteworthy, as these 2 species are considered resistant to S. mansoni . PMID- 22524266 TI - Functional MRI evaluation of supplementary motor area language dominance in right and left-handed subjects. AB - Functional magnetic resonance imaging (fMRI) is a non-invasive brain imaging technique widely used in the evaluation of the brain function that provides images with high temporal and spatial resolution. Investigation of the supplementary motor area (SMA) function is critical in the pre-surgical evaluation of neurological patients, since marked individual differences and complex overlapping with adjacent cortical areas exist, and it is important to spare the SMA from lesions when adjacent cortical tissue is surgically removed. We used fMRI to assess the activity of SMA in six right-handed and six left handed healthy volunteers when a task requiring silent repetition of a series of words was given. Brain activation areas in each of the subjects were localized according to the standard Talairach coordinate space, and the individual voxels for each map were compared after 3D sagittal images were created and SMA was delimited. Quantitative analysis of hemispheric and bilateral SMA activation was described as mean +/- standard deviation of hot points/total points. The results show that the language task induced bilateral SMA activation. Left SMA activation was significantly higher than right SMA activation in both right-handed and left handed subjects. PMID- 22524267 TI - Stereoselectivity in metallocene-catalyzed coordination polymerization of renewable methylene butyrolactones: from stereo-random to stereo-perfect polymers. AB - Coordination polymerization of renewable alpha-methylene-gamma (methyl)butyrolactones by chiral C(2)-symmetric zirconocene catalysts produces stereo-random, highly stereo-regular, or perfectly stereo-regular polymers, depending on the monomer and catalyst structures. Computational studies yield a fundamental understanding of the stereocontrol mechanism governing these new polymerization reactions mediated by chiral metallocenium catalysts. PMID- 22524269 TI - Solvothermal synthesis of platinum alloy nanoparticles for oxygen reduction electrocatalysis. AB - Platinum alloy nanoparticles show great promise as electrocatalysts for the oxygen reduction reaction (ORR) in fuel cell cathodes. We report here on the use of N,N-dimethylformamide (DMF) as both solvent and reductant in the solvothermal synthesis of Pt alloy nanoparticles (NPs), with a particular focus on Pt-Ni alloys. Well-faceted alloy nanocrystals were generated with this method, including predominantly cubic and cuboctahedral nanocrystals of Pt(3)Ni, and octahedral and truncated octahedral nanocrystals of PtNi. X-ray diffraction (XRD) and high angle annular dark field scanning transmission electron microscopy (HAADF-STEM), coupled with energy dispersive spectroscopy (EDS), were used to characterize crystallite morphology and composition. ORR activities of the alloy nanoparticles were measured with a rotating disk electrode (RDE) technique. While some Pt(3)Ni alloy nanoparticle catalysts showed specific activities greater than 1000 MUA/cm(2)(Pt), alloy catalysts prepared with a nominal composition of PtNi displayed activities close to 3000 MUA/cm(2)(Pt), or almost 15 times that of a state-of-the-art Pt/carbon catalyst. XRD and EDS confirmed the presence of two NP compositions in this catalyst. HAADF-STEM examination of the PtNi nanoparticle catalyst after RDE testing revealed the development of hollows in a number of the nanoparticles due to nickel dissolution. Continued voltage cycling caused further nickel dissolution and void formation, but significant activity remained even after 20,000 cycles. PMID- 22524268 TI - Is S-nitrosylation of cochlear proteins a critical factor in cisplatin-induced ototoxicity? AB - S-nitrosylation is a redox-sensitive protein modification, which is a highly specific, but reversible mechanism that regulates several signal transduction cascades. Oxidative stress plays a causal role in the ototoxic effects of an anti neoplastic drug, cisplatin. Despite emerging evidence implicating nitroxidative stress as a critical factor in cisplatin toxicity, the significance of the cochlear protein S-nitrosylation in cisplatin ototoxicity is yet to be understood. In the present study, a 16-mg/kg dose of cisplatin, induced a significant shift in the amplitudes of distortion product otoacoustic emissions, a measure of outer hair cell activity, in Wistar rats, 3 days post-treatment. These ototoxic effects were accompanied by significant increases in the S nitrosylation of at least three cochlear proteins. Biological significance of these S-nitrosylated proteins was indicated by their immunolocalization in organ of Corti, stria vascularis, and spiral ganglions, which are known cochlear targets of cisplatin toxicity. In addition, co-treatment with Trolox, an inhibitor of peroxynitrite, attenuated cisplatin-induced S-nitrosylation of cochlear proteins and prevented the associated hearing loss. The cisplatin induced S-nitrosylation of inner ear proteins, their sensitive cochlear localization, and their potential association with cisplatin-induced hearing loss suggests that S-nitrosylation of cochlear proteins might play a crucial role in mediating cisplatin ototoxicity. PMID- 22524270 TI - The perceived sensitivity to medicines (PSM) scale: an evaluation of validity and reliability. AB - OBJECTIVES: We report on the development and psychometric properties of a scale to measure perceived sensitivity to medicines (PSM). Design. The internal consistency, test-retest reliability, criterion-related, and predictive validity of the PSM Scale were evaluated using data collected as part of four previously published studies and one unpublished data set. METHODS: Participants (n= 1,166) included patients receiving treatment for HIV infection and hypertension, individuals receiving a travel vaccination, and undergraduate students. Criterion related validity was assessed by examining associations between the PSM and beliefs about medicines (Beliefs about Medicines Questionnaire), anxiety and depression (Hospital Anxiety and Depression Scale). Predictive validity was assessed by examining associations between the PSM and medication adherence and with symptom reports following vaccination. Test-retest reliability was assessed in an undergraduate sample who completed the PSM on two occasions, 2 weeks apart. RESULTS: Test-retest reliability was high (r= .89, p < .001). Cronbach's alpha ranged from 0.79-0.94. Consistent with expectations, high PSM scores were associated with negative beliefs about medicines in general, strong concerns about potential adverse effects of prescribed medicines, and doubts about the necessity for treatment. High PSM scores predicted non-adherence to anti retroviral therapy and a higher incidence of symptoms following vaccination. CONCLUSION: The findings present preliminary evidence that the PSM is a valid and reliable measure of perceived sensitivity to medication. While further work is needed to develop and evaluate the scale, the findings support its use as a research tool in studies of the use and effects of medicines. STATEMENT OF CONTRIBUTION: What is already known on this subject? It is now well understood that beliefs about medicines have an important influence on whether patients start and continue with treatment. Research spanning a range of long-term conditions and across different countries has shown that treatment uptake and adherence are consistently related to specific beliefs about prescribed medicines, such as how patients judge their personal need relative to concerns about potential adverse effects as well as more general beliefs about medicines as a class of treatment. What does this study add? The paper reports on the development and psychometric properties of a new scale to measure patients' perceptions of their sensitivity to medicines. In five studies involving different groups of individuals we found the Perceived Sensitivity to Medicines (PSM) Scale to be a reliable and valid measure. The PSM may be useful for researchers and clinicians in explaining treatment decisions, adherence and reported side-effects. PMID- 22524271 TI - Centenarians and diet: what they eat in the Western part of Sicily. AB - This paper pays attention to the modifiable lifestyle factors such as diet and nutrition that might influence life extension and successful ageing. Previous data reported that in Sicily, the biggest Mediterranean island, there are some places where there is a high frequency of male centenarians with respect to the Italian average. The present data show that in Sicani Mountain zone there are more centenarians with respect to the Italian average. In fact, in five villages of Sicani Mountains, there were 19 people with an age range of 100-107 years old from a total population of 18,328 inhabitants. So, the centenarian number was 4.32-fold higher than the national average (10.37 vs. 2.4/10,000); the female/male ratio was 1.1:1 in the study area, while the national ratio is 4.54:1. Unequivocally, their nutritional assessment showed a high adherence to the Mediterranean nutritional profile with low glycemic index food consumed. To reach successful ageing it is advisable to follow a diet with low quantity of saturated fat and high amount of fruits and vegetables rich in phytochemicals. PMID- 22524272 TI - Kinetic analysis and test-retest variability of the radioligand [11C](R)-PK11195 binding to TSPO in the human brain - a PET study in control subjects. AB - BACKGROUND: Positron-emission tomography and the radioligand [11C](R)-PK11195 have been used for the imaging of the translocator protein (TSPO) and applied to map microglia cells in the brain in neuropsychiatric disorders. [11C](R)-PK11195 binding has been quantified using reference region approaches, with the reference defined anatomically or using unsupervised or supervised clustering algorithms. Kinetic compartment modelling so far has not been presented. In the present test retest study, we examine the characteristics of [11C](R)-PK11195 binding in detail, using the classical compartment analysis with a metabolite-corrected arterial input function. METHODS: [11C](R)-PK11195 binding was examined in six control subjects at two separate occasions, 6 weeks apart. Results of one-tissue and two-tissue compartment models (1TCM, 2TCM) were compared using the Akaike criteria and F-statistics. The reproducibility of binding potential (BPND) estimates was evaluated by difference in measurements (error in percent) and intraclass correlation coefficients (ICCs). RESULTS: [11C](R)-PK11195 binding could be described by 2TCM which was the preferred model. Measurement error (in percent) indicated good reproducibility in large brain regions (mean error: whole brain 4%, grey matter 5%), but not in smaller subcortical regions (putamen 25%, caudate 55%). The ICC values were moderate to low, highest for the white matter (0.73), whole brain and thalamus (0.57), and cortical grey matter (0.47). Sizeable [11C](R)-PK11195 BPND could be identified throughout the human brain (range 1.11 to 2.21). CONCLUSIONS: High intra-subject variability of [11C](R) PK11195 binding limits longitudinal monitoring of TSPO changes. The interpretation of [11C](R)-PK11195 binding by 2TCM suggests that the presence of specific binding to TSPO cannot be excluded at physiological conditions. PMID- 22524273 TI - Editorial. PMID- 22524275 TI - Correction to Synthesis, Structure-Affinity Relationships, and Radiolabeling of Selective High-Affinity 5-HT(4) Receptor Ligands as Prospective Imaging Probes for Positron Emission Tomography. PMID- 22524274 TI - Basic sleep mechanisms: an integrative review. AB - Regulation of the sleep-waking cycle is complex and involves diverse brain circuits and molecules. On one hand, an interplay among many neuroanatomical and neurochemical systems including acetylcholine, dopamine, noradrenaline, serotonin, histamine, and hypocretin has been shown to control the waking state. On the other hand the sleep-onset is governed by the activity of sleep-promoting neurons placed in the anterior hypothalamus that utilize GABA to inhibit wake promoting regions. Moreover, brainstem regions inhibited during wakefulness (W) and slow wave sleeps (SWS) become active during rapid eye movement (REM) sleep. Further complexity has been introduced by the recognition of sleep-promoting molecules that accumulate in the brain in prolonged W as well as the physiological role of gene expression during sleep. The sleep-wake cycle is currently undergoing intense research with many new findings leading to new paradigms concerning sleep regulation, brain organization and sleep function. This review provides a broader understanding of our present knowledge in the field of sleep research. PMID- 22524276 TI - Hippocampal involvement in processing of indistinct visual motion stimuli. AB - Perception of known patterns results from the interaction of current sensory input with existing internal representations. It is unclear how perceptual and mnemonic processes interact when visual input is dynamic and structured such that it does not allow immediate recognition of obvious objects and forms. In an fMRI experiment, meaningful visual motion stimuli depicting movement through a virtual tunnel and indistinct, meaningless visual motion stimuli, achieved through phase scrambling of the same stimuli, were presented while participants performed an optic flow task. We found that our indistinct visual motion stimuli evoked hippocampal activation, whereas the corresponding meaningful stimuli did not. Using independent component analysis, we were able to demonstrate a functional connectivity between the hippocampus and early visual areas, with increased activity for indistinct stimuli. In a second experiment, we used the same stimuli to test whether our results depended on the participants' task. We found task independent bilateral hippocampal activation in response to indistinct motion stimuli. For both experiments, psychophysiological interaction analysis revealed a coupling from posterior hippocampus to dorsal visuospatial and ventral visual object processing areas when viewing indistinct stimuli. These results indicate a close functional link between stimulus-dependent perceptual and mnemonic processes. The observed pattern of hippocampal functional connectivity, in the absence of an explicit memory task, suggests that cortical-hippocampal networks are recruited when visual stimuli are temporally uncertain and do not immediately reveal a clear meaning. PMID- 22524277 TI - Diminished whole-brain but enhanced peri-sylvian connectivity in absolute pitch musicians. AB - Several anatomical studies have identified specific anatomical features within the peri-sylvian brain system of absolute pitch (AP) musicians. In this study we used graph theoretical analysis of cortical thickness covariations (as indirect indicator of connectivity) to examine whether AP musicians differ from relative pitch musicians and nonmusicians in small-world network characteristics. We measured "local connectedness" (local clustering = gamma), "global efficiency of information transfer" (path length = lambda), "small-worldness" (sigma = gamma/lambda), and "degree" centrality as measures of connectivity. Although all groups demonstrated typical small-world features, AP musicians showed significant small-world alterations. "Degree" as a measure of interconnectedness was globally significantly decreased in AP musicians. These differences let us suggest that AP musicians demonstrate diminished neural integration (less connections) among distant brain regions. In addition, AP musicians demonstrated significantly increased local connectivity in peri-sylvian language areas of which the planum temporale, planum polare, Heschl's gyrus, lateral aspect of the superior temporal gyrus, STS, pars triangularis, and pars opercularis were hub regions. All of these brain areas are known to be involved in higher-order auditory processing, working or semantic memory processes. Taken together, whereas AP musicians demonstrate decreased global interconnectedness, the local connectedness in peri sylvian brain areas is significantly higher than for relative pitch musicians and nonmusicians. PMID- 22524278 TI - Occlusion of the inner limb of a coaxial Bain breathing system by a foreign object. PMID- 22524280 TI - Evaluation of the usefulness of the 'hormones with optional pelvic exam' programme offered at a family planning clinic. AB - OBJECTIVES: In the United States, access to hormonal contraception commonly requires medical procedures, including Pap smears, breast and pelvic examinations. Over the past 15 years, these procedures, which may constitute barriers to effective contraception, have been declared unnecessary by several organisations. This study aims to evaluate the usefulness of the hormonal contraception with optional pelvic exam (HOPE) programme offered in Southeastern Virginia. METHODS: A cross-sectional survey was conducted among women participating in the HOPE programme over a four-month period. Questionnaire items included demographics, reproductive history and perceptions concerning physical examinations and access to contraception. RESULTS: The HOPE programme was perceived as enhancing unintended pregnancy prevention by 73% of respondents. Most of them valued the opportunity to obtain contraception without Pap smears, breast or pelvic examinations. CONCLUSIONS: The HOPE programme, which provides access to contraception without the requirement for invasive examinations, increases and maintains effective levels of pregnancy prevention. HOPE patients were mostly satisfied with the programme. Lower expense and prompt appointment appear to weigh more than the optional pelvic examination programme in the choice of the modality of contraceptive guidance. PMID- 22524279 TI - Methods for visual mining of genomic and proteomic data atlases. AB - BACKGROUND: As the volume, complexity and diversity of the information that scientists work with on a daily basis continues to rise, so too does the requirement for new analytic software. The analytic software must solve the dichotomy that exists between the need to allow for a high level of scientific reasoning, and the requirement to have an intuitive and easy to use tool which does not require specialist, and often arduous, training to use. Information visualization provides a solution to this problem, as it allows for direct manipulation and interaction with diverse and complex data. The challenge addressing bioinformatics researches is how to apply this knowledge to data sets that are continually growing in a field that is rapidly changing. RESULTS: This paper discusses an approach to the development of visual mining tools capable of supporting the mining of massive data collections used in systems biology research, and also discusses lessons that have been learned providing tools for both local researchers and the wider community. Example tools were developed which are designed to enable the exploration and analyses of both proteomics and genomics based atlases. These atlases represent large repositories of raw and processed experiment data generated to support the identification of biomarkers through mass spectrometry (the PeptideAtlas) and the genomic characterization of cancer (The Cancer Genome Atlas). Specifically the tools are designed to allow for: the visual mining of thousands of mass spectrometry experiments, to assist in designing informed targeted protein assays; and the interactive analysis of hundreds of genomes, to explore the variations across different cancer genomes and cancer types. CONCLUSIONS: The mining of massive repositories of biological data requires the development of new tools and techniques. Visual exploration of the large-scale atlas data sets allows researchers to mine data to find new meaning and make sense at scales from single samples to entire populations. Providing linked task specific views that allow a user to start from points of interest (from diseases to single genes) enables targeted exploration of thousands of spectra and genomes. As the composition of the atlases changes, and our understanding of the biology increase, new tasks will continually arise. It is therefore important to provide the means to make the data available in a suitable manner in as short a time as possible. We have done this through the use of common visualization workflows, into which we rapidly deploy visual tools. These visualizations follow common metaphors where possible to assist users in understanding the displayed data. Rapid development of tools and task specific views allows researchers to mine large-scale data almost as quickly as it is produced. Ultimately these visual tools enable new inferences, new analyses and further refinement of the large scale data being provided in atlases such as PeptideAtlas and The Cancer Genome Atlas. PMID- 22524281 TI - Enhanced error-related negativity on flanker errors: error expectancy or error significance? AB - The present study investigated whether the error-related negativity, an electrophysiological marker for performance monitoring, reflects (1) the expectancy of errors, or (2) the significance of errors for the current task goal. In the first case, a larger error-related negativity is predicted for less expected errors, whereas in the second case, a larger error-related negativity is predicted for errors with greater significance. To test these predictions, we varied flanker size in a flanker task. With large flankers, more errors occurred by executing the response associated with the flankers (flanker errors) leading to a greater expectancy of flanker errors. As revealed by a multinomial model, these additional flanker errors represented highly significant attention errors, leading to an increased error significance. The error-related negativity was larger for flanker errors with large flankers, which supports the error significance account. PMID- 22524282 TI - Strained and unstrained macrocycles composed of carbazole and butadiyne units: electronic state and optical properties. AB - Cu(OAc)(2) catalyzes dehydrogenative condensation of 3,6-bis(2 ethynylphenyl)carbazole in the presence of O(2) to afford the cyclization product 1 and cyclodimer 2. Compound 1 contains bent carbazole and butadiyne groups, while 2 has a less strained structure with Z shape around the two parallel butadiyne groups. Optical properties of the compounds are discussed based on the electronic states estimated from electrochemical measurement and density functional theory calculation. PMID- 22524283 TI - Structure and magnetism of the topotactically reduced oxychloride Sr4Mn3O(6.5)Cl2. AB - Reaction of the n = 3 Ruddlesden-Popper oxychloride Sr(4)Mn(3)O(7.5)Cl(2) with calcium hydride yields the topotactically reduced phase Sr(4)Mn(3)O(6.5)Cl(2). The deintercalation of oxide ions from the central MnO(1.5) layer of the starting phase is accompanied by a rearrangement of the anion lattice, resulting in a layer of composition MnO(0.5) in the reduced material, consisting of chains of MnO(4) tetrahedra connected by edge and corner sharing. Magnetization and low temperature neutron diffraction data are consistent with antiferromagnetic coupling of manganese spins, but no long-range magnetic order is observed down to 5 K, presumably due to the large interlayer separation in the reduced phase. The influence of anion substitution on the structural selectivity of low-temperature reduction reactions is discussed. PMID- 22524284 TI - Two-phase microfluidic droplet flows of ionic liquids for the synthesis of gold and silver nanoparticles. AB - Droplet-based microfluidic platforms have the potential to provide superior control over mixing as compared to traditional batch reactions. Ionic liquids have advantageous properties for metal nanoparticle synthesis as a result of their low interfacial tension and complexing ability; however, droplet formation of ionic liquids within microfluidic channels in a two-phase system has not yet been attained because of their complex interfacial properties and high viscosities. Here, breakup of an imidazolium-based ionic liquid into droplets in a simple two-phase system has for the first time been achieved and characterized by using a microchannel modified with a thin film fluoropolymer. This microfluidic/ionic liquid droplet system was used to produce small, spherical gold (4.28 +/- 0.84 nm) and silver (3.73 +/- 0.77 nm) nanoparticles. PMID- 22524285 TI - Effects of interview mode on assessments of erectile and ejaculatory dysfunction among men with benign prostatic hyperplasia (BPH). AB - In a randomized experiment (N = 249; age 50 + years), this study examined if self reports of erectile dysfunction (ED) and ejaculatory dysfunction (EjD) symptomatology were influenced by the mode of interview administration (computer assisted self-interview [CASI], audio computer-assisted self-interview [ACASI], or computer-assisted personal interview [CAPI; involving an interviewer]). This study also examined if mode moderated person variables hypothesized to impact self-reports (social desirability, age, or depressive mood). No main or moderating effects of mode were found for self-reports of EjD symptoms. However, mode effects on reports of ED symptoms were observed, and these moderated age and social desirability effects on self-reports. Significantly more older (relative to younger) men reported high levels of ED symptoms when interview administration was by a live interviewer (CAPI) than with self-administration. Alternatively, significantly more younger men reported high levels of ED symptoms when administration was by an interviewer (CAPI) or by ACASI (vs. CASI). The Mode * Social Desirability effects were complex (see the Discussion section), showing hypothesized effects under ACASI and CAPI conditions, but an opposite effect under the CASI condition. The stability of self-reported ED symptoms did not vary by mode (based on test-retest comparisons); test-retest was significantly higher for EjD symptoms within the ACASI condition. The impact of mode of administration on self-reports of ED/EjD symptoms is less predictable and dramatic than one might conclude from prior research with other types of self-report outcomes. The findings are consistent with a small, but growing, body of studies that illustrate highly situational effects of interviewing, which may depend on a complex interplay between modes, person variables, and the interview topic/target items. Self-administered methods, in particular, may not be a universal solution to response bias. PMID- 22524286 TI - Knotting the NETs: analyzing histone modifications in neutrophil extracellular traps. PMID- 22524287 TI - Increased chemerin concentrations in fetuses of obese mothers and correlation with maternal insulin sensitivity. AB - OBJECTIVE: The aim of this study was to determine the effect of maternal obesity and gestational diabetes mellitus (GDM) on (i) the circulating concentrations of chemerin in cord and maternal plasma, and (ii) gene expression and release of chemerin from human placenta and adipose tissue. DESIGN: Chemerin concentrations were measured in maternal and cord plasma from 62 normal glucose tolerant women (NGT) and 69 women with GDM at the time of term elective Caesarean section. Placenta and adipose tissue expression and release of chemerin was measured from 22 NGT and 22 GDM women. RESULTS: There was no effect of maternal obesity or GDM on maternal chemerin concentrations. Chemerin concentrations were significantly higher in cord plasma from women with maternal obesity. Cord chemerin concentrations in NGT women negatively correlated with the concentrations of maternal insulin sensitivity. There was no effect of GDM on maternal and cord chemerin concentrations, and on the release of chemerin from placenta and adipose tissue. CONCLUSIONS: At the time of term Caesarean section, preexisting maternal obesity, and its associated insulin resistance, is associated with higher cord plasma chemerin concentrations. PMID- 22524288 TI - Qualitative bone CT as a tool to assess vascularization in irradiated bone: an animal study. AB - OBJECTIVE: The purpose of this paper was to find a correlation between laser doppler flowmetry (LDF) and the bone mineral density quotient (BMDQ) to evaluate irradiated bone quality preoperatively. MATERIALS AND METHODS: Premolars and molars were extracted from six minipigs. After a three-month healing period, three animals received irradiation at a total dose of 24 Gy. Three months after irradiation, quantitative computed tomography was performed using a calibration bone phantom to determine the 120-position BMDQ in the alveolar bone. A drill template was created to define the exact location for measurement. LDF was then recorded after osteotomy of the residual alveolar ridge. The correlation between the BMDQ and LDF was investigated. RESULTS: There was a linear negative correlation between LDF and BMDQ in non-irradiated bone (r = -0.435, P = 0.001) and less pronounced also in irradiated bone (r = -0.309, P = 0.017). In both non irradiated and irradiated bone, we found distinct differences between the maxilla and mandible with respect to BMDQ. However, a clear difference in mandibular and maxillary vascularity was only seen in non-irradiated bone. CONCLUSION: In non irradiated bone, LDF and BMDQ were inversely correlated. In irradiated bone, the BMDQ alone is not an adequate preoperative tool for evaluating bone quality because it was not correlated with bone perfusion. PMID- 22524289 TI - Longitudinal changes in phonological whole-word measures in 2-year-olds. AB - The purpose of this investigation was to describe changes in whole-word productions in the speech of children as they aged from 24 to 36 months. Spontaneous language samples were obtained from 12 participants during parent child interactions every 3 months, beginning with each participant's second birthday. Fifty different words from each sample were analysed to determine changes in a variety of whole-word measures including phonological mean length of utterance (PMLU) for target words and words produced, proportion of whole-word proximity (PWP), and proportion of words produced correctly (PWC). Significant changes in whole-word measures were evidenced by the participants over the course of the investigation, and those scores did not show stabilization by the age of 36 months. PMID- 22524290 TI - The primacy of positivity: practical applications for speech-language pathologists. AB - Healthcare professionals, including speech-language pathologists, generally assume that their clients will be happy after they have "gotten better" or somehow achieved their goals; which is not an unreasonable assumption, and which is a belief shared by the majority of clients. It may not, however, be entirely helpful. Such an approach may well contribute to a range of problems including negative, self-defeating emotions such as frustration which could impede treatment progress. Rather than waiting until success is achieved, happiness and positivity should come first and foremost. By promoting the "primacy of positivity" speech-language pathologists can help their clients better achieve their goals, leveraging off the energy and motivation created. PMID- 22524291 TI - Chemical synthesis and biological activity of analogues of the lantibiotic epilancin 15X. AB - Lantibiotics are a large family of antibacterial peptide natural products containing multiple post-translational modifications, including the thioether structures lanthionine and methyllanthionine. Efforts to probe structure-activity relationships and engineer improved pharmacological properties have driven the development of new methods to produce non-natural analogues of these compounds. In this study, solid-supported chemical synthesis was used to produce analogues of the potent lantibiotic epilancin 15X, in order to assess the importance of several N-terminal post-translational modifications for biological activity. Surprisingly, substitution of these moieties, including the unusual N-terminal D lactyl moiety, resulted in relatively small changes in the antimicrobial activity and pore-forming ability of the peptides. PMID- 22524292 TI - Resistance of Rhipicephalus microplus to amitraz and cypermethrin in tropical cattle farms in Veracruz, Mexico. AB - The objectives of this study were: (1) to determine the prevalence and factors associated with Rhipicephalus microplus , resistant to cypermethrin and amitraz, from cattle farms in Veracruz, Mexico, and (2) to determine in vitro mortality percentages of field populations of R. microplus exposed to discriminating doses (DD) of cypermethrin and amitraz. Fifty-three populations of R. microplus were tested by bioassays using DD of cypermethrin (0.05%) and amitraz (0.0002%). The prevalence of cattle farms with R. microplus ticks that were resistant to cypermethrin and amitraz, and co-resistant to both acaricides, was 90.6, 54.7, and 47.2%, respectively. The level of cypermethrin resistance, measured as a survival percentage, was higher as compared to amitraz. Cattle farms with <=50 animals (odds ratio [OR] = 3.84, 95% confidence interval [CI] = 1.07-13.70, P = 0.038) and a stocking density of >1 animal unit per ha (AU/ha) (OR = 4.21, 95% CI = 1.0-17.71, P = 0.050) had a higher probability to develop R. microplus tick populations co-resistant to both acaricides. In conclusion, there is a high prevalence of R. microplus populations on cattle farms in Veracruz, Mexico that are both resistant to cypermethrin and amitraz and co-resistant to both acaricides. The level of cypermethrin resistance is critical, and the exposition variables of <=50 cattle and a stocking density of >1 AU/ha were factors associated with R. microplus co-resistant to both acaricides. PMID- 22524293 TI - The role of psychological symptoms and social group memberships in the development of post-traumatic stress after traumatic injury. AB - OBJECTIVES: The costs associated with traumatic injury are often exacerbated by the development of post-traumatic stress symptoms. However, it is unclear what decreases the development of post-traumatic symptoms over time. The aim of the present research was to examine the role of psychological symptoms and social group memberships in reducing the development of post-traumatic stress symptoms after orthopaedic injuries (OIs) and acquired brain injuries (ABIs). DESIGN AND METHODS: A longitudinal prospective study assessed self-reported general health symptoms, social group memberships, and post-traumatic stress symptoms among participants with mild or moderate ABI (n= 62) or upper limb OI (n= 31) at 2 weeks (T1) and 3 months (T2) after injury. RESULTS: Hierarchical regressions revealed that having fewer T1 general health symptoms predicted lower levels of T2 post-traumatic stress symptoms after OI but forming more new group memberships at T1 predicted lower levels of T2 post-traumatic stress symptoms after ABI. CONCLUSION: A focus on acquiring group memberships may be particularly important in reducing the development of post-traumatic stress symptoms after injuries, such as ABI, which result in long-term life changes. PMID- 22524294 TI - The effect of stimulus number on the stability of responses for an extensive heat pain test. AB - BACKGROUND: The use of relatively lower stimulus presentation numbers in quantitative sensory testing may influence the computation accuracy of participants' discriminability. The minimum trial number for obtaining a stabilized participant discrimination ability was determined. MATERIALS AND METHODS: Twelve participants' ability to discriminate between noxious heat stimuli pairs (45 degrees C/46 degrees C, 46 degrees C/47 degrees C, and 47 degrees C/48 degrees C) was assessed using a six-category confidence rating scale. Heat stimuli were administered to the forearm. Two conditions with presentation numbers of 17 trials per stimulus (representing the median number of trials in previous studies) and 40 trials per stimulus (used in a previous study with a similar protocol) were used. RESULTS AND DISCUSSION: Participants' discriminability stabilized at approximately the 20th trial based on the lowest frequency of indeterminate and non-model conforming results under both conditions. A simple linear regression model showed a statistically significant positive relationship between discriminability for the two conditions (slope = 0.65, p < 0.001; constant = 0.33, p = 0.02; r(2 )= 0.51). As a rule of thumb, approximately 20 trials per stimulus intensity could be used to obtain a stabilized discriminability outcome. PMID- 22524295 TI - Inducing negative affect increases the reward value of appetizing foods in dieters. AB - Experiencing negative affect frequently precedes lapses in self-control for dieters, smokers, and drug addicts. Laboratory research has similarly shown that inducing negative emotional distress increases the consumption of food or drugs. One hypothesis for this finding is that emotional distress sensitizes the brain's reward system to appetitive stimuli. Using functional neuroimaging, we demonstrate that inducing negative affect in chronic dieters increases activity in brain regions representing the reward value of appetitive stimuli when viewing appetizing food cues. Thirty female chronic dieters were randomly assigned to receive either a negative (n = 15) or neutral mood induction (n = 15) immediately followed by exposure to images of appetizing foods and natural scenes during fMRI. Compared with chronic dieters in a neutral mood, those receiving a negative mood induction showed increased activity in the OFC to appetizing food images. In addition, activity to food images in the OFC and ventral striatum was correlated with individual differences in the degree to which the negative mood induction decreased participants' self-esteem. These findings suggest that distress sensitizes the brain's reward system to appetitive cues, thereby offering a mechanism for the oft-observed relationship between negative affect and disinhibited eating. PMID- 22524297 TI - "Positive biology": the centenarian lesson. AB - The extraordinary increase of the elderly in developed countries underscore the importance of studies on ageing and longevity and the need for the prompt spread of knowledge about ageing in order to satisfactorily decrease the medical, economic and social problems associated to advancing years, because of the increased number of individuals not autonomous and affected by invalidating pathologies.Centenarians are equipped to reach the extreme limits of human life span and, most importantly, to show relatively good health, being able to perform their routine daily life and to escape fatal age-related diseases. Thus, they are the best example of extreme longevity, representing selected people in which the appearance of major age-related diseases, such as cancer, and cardiovascular diseases among others, has been consistently delayed or escaped. To discuss the relevance of genetics and life style in the attainment of longevity, five papers mostly focused on Italian centenarians have been assembled in this series. The aim is to realize, through a" positive biology" approach (rather than making diseases the central focus of research, "positive biology" seeks to understand the causes of positive phenotypes, trying to explain the biological mechanisms of health and well-being) how to prevent and/or reduce elderly frailty and disability. PMID- 22524296 TI - Reward modulation of hippocampal subfield activation during successful associative encoding and retrieval. AB - Emerging evidence suggests that motivation enhances episodic memory formation through interactions between medial-temporal lobe (MTL) structures and dopaminergic midbrain. In addition, recent theories propose that motivation specifically facilitates hippocampal associative binding processes, resulting in more detailed memories that are readily reinstated from partial input. Here, we used high-resolution fMRI to determine how motivation influences associative encoding and retrieval processes within human MTL subregions and dopaminergic midbrain. Participants intentionally encoded object associations under varying conditions of reward and performed a retrieval task during which studied associations were cued from partial input. Behaviorally, cued recall performance was superior for high-value relative to low-value associations; however, participants differed in the degree to which rewards influenced memory. The magnitude of behavioral reward modulation was associated with reward-related activation changes in dentate gyrus/CA(2,3) during encoding and enhanced functional connectivity between dentate gyrus/CA(2,3) and dopaminergic midbrain during both the encoding and retrieval phases of the task. These findings suggests that, within the hippocampus, reward-based motivation specifically enhances dentate gyrus/CA(2,3) associative encoding mechanisms through interactions with dopaminergic midbrain. Furthermore, within parahippocampal cortex and dopaminergic midbrain regions, activation associated with successful memory formation was modulated by reward across the group. During the retrieval phase, we also observed enhanced activation in hippocampus and dopaminergic midbrain for high-value associations that occurred in the absence of any explicit cues to reward. Collectively, these findings shed light on fundamental mechanisms through which reward impacts associative memory formation and retrieval through facilitation of MTL and ventral tegmental area/substantia nigra processing. PMID- 22524298 TI - Determinants of emergency contraceptive use after unprotected intercourse: who seeks emergency contraception and who seeks abortion? AB - OBJECTIVE: To compare differences in contraceptive characteristics and the knowledge of emergency contraception (EC) between women who used EC after unprotected intercourse and those who sought abortion. DESIGN: A questionnaire survey. SETTING: A Hungarian university hospital. SAMPLE: Two large clinical groups were enrolled: women who were prescribed EC after unprotected intercourse (n= 952) (EC group) and women who presented for termination of pregnancy who had not taken EC after a contraceptive failure despite being suitable candidates to take EC (n= 577) (control group). METHODS: Questionnaire evaluation. MAIN OUTCOME MEASURES: Knowledge concerning, previous use of, and other factors related to EC use. RESULTS: The EC group experienced a condom failure significantly more often (odds ratio (OR) = 3.07), while the control group reported more failures with the contraceptive pill (OR = 0.69) and with periodic abstinence (OR = 0.09). Use of EC depended on age, education level, place of residence, accurate knowledge of EC (OR = 3.87) and previous EC use (OR = 1.16). Awareness of EC was influenced by information obtained from healthcare providers (OR = 3.63) or by school education (OR = 1.28). CONCLUSIONS: Women who use less reliable contraceptive methods should be targeted for health education that stresses the importance of reliable contraception and provides more detailed knowledge on EC and when it should be used. PMID- 22524299 TI - Ultrathin graphite foam: a three-dimensional conductive network for battery electrodes. AB - We report the use of free-standing, lightweight, and highly conductive ultrathin graphite foam (UGF), loaded with lithium iron phosphate (LFP), as a cathode in a lithium ion battery. At a high charge/discharge current density of 1280 mA g(-1), the specific capacity of the LFP loaded on UGF was 70 mAh g(-1), while LFP loaded on Al foil failed. Accounting for the total mass of the electrode, the maximum specific capacity of the UGF/LFP cathode was 23% higher than that of the Al/LFP cathode and 170% higher than that of the Ni-foam/LFP cathode. Using UGF, both a higher rate capability and specific capacity can be achieved simultaneously, owing to its conductive (~1.3 * 10(5) S m(-1) at room temperature) and three dimensional lightweight (~9.5 mg cm(-3)) graphitic structure. Meanwhile, UGF presents excellent electrochemical stability comparing to that of Al and Ni foils, which are generally used as conductive substrates in lithium ion batteries. Moreover, preparation of the UGF electrode was facile, cost-effective, and compatible with various electrochemically active materials. PMID- 22524300 TI - Evaluating a novel analgesic strategy for ring castration of ram lambs. AB - OBJECTIVE: To evaluate the analgesic efficacy of the NSAIDs flunixin and meloxicam administered locally to the scrotum before ring castration. STUDY DESIGN: Randomised, controlled, prospective study. ANIMALS: Forty eight single born male Merino lambs. METHODS: Lambs, aged approximately 4 weeks, were allocated to four groups for castration. Groups were: sham control; castration + saline; castration + flunixin; castration + meloxicam. Drugs (5 mL) were administered subcutaneously around the circumference of the scrotum immediately before castration. Cortisol, rectal temperature, haematology and plasma haptoglobin were measured before and up to 48 hours after treatment. Behaviour recorded by video for 12 hours after treatment was classified as pain avoidance behaviours in the first hour and postural behaviours in three 4 hour intervals. RESULTS: Ring castration (saline group) induced a bi-phasic increase in cortisol with peaks at 90 minutes and 24 hours but no significant changes in haematology, haptoglobin or rectal temperature. Pain avoidance behaviours were increased and teat seeking decreased. Normal lying and normal standing postures were decreased and abnormal ventral lying, statue standing, abnormal standing and total abnormal postures increased. Flunixin decreased cortisol at 90 minutes (60.3 versus 117.3 nmol L(-1) ) and cortisol AUC (0-6 hours), decreased elevated leg movement (2.5 versus 5.4 events) and sum of pain avoidance behaviours (8.5 versus 16.7 events), improved time spent in normal ventral lying and decreased abnormal ventral lying and total abnormal postures compared to saline treated lambs. In a similar contrast, meloxicam caused non-significant decreases in cortisol at 90 minutes, cortisol AUC (0-6 hours) and pain avoidance behaviours, and significantly improved the postural behaviours normal ventral lying (26.7 versus 15.4%) and normal standing (13.9 versus 7.5%), and reduced abnormal standing and total abnormal postures. Physiological and behavioural responses associated with ring castration for both NSAID treatment groups were generally greater than sham controls. CONCLUSIONS AND CLINICAL RELEVANCE: Locally administered NSAIDs provided partial analgesia for ring castration. PMID- 22524301 TI - Base-induced chemiluminescent decomposition of bicyclic dioxetanes bearing a (benzothiazol-2-yl)-3-hydroxyphenyl group: a radiationless pathway leading to marked decline of chemiluminescence efficiency. AB - Charge-transfer-induced decomposition (CTID) of bicyclic dioxetanes 1b-d bearing a 3-hydroxylphenyl moiety substituted with a benzothiazol-2-yl group at the 2-, 6 , or 5-position was investigated, and their chemiluminescence properties were compared to each other, based on those for a 4-benzothiazolyl analogue 1a. Dioxetanes 1c and 1d underwent CTID to give the corresponding oxido anions of keto esters 8c or 8d in the singlet excited state with high efficiencies similarly to the case of 1a. On the other hand, 1b showed chemiluminescence with quite low efficiency, though it gave exclusively keto ester 2b. The marked decline of chemiluminescence efficiency for 1b was attributed to 1b mainly being decomposed to 8b through a radiationless pathway, in which intramolecular nucleophilic attack of nitrogen in the benzothiazolyl group to dioxetane O-O took place to give cyclic intermediate cis-11. PMID- 22524303 TI - Characterization of different 5'-untranslated exons of the ASIP gene in black-and tan Doberman Pinscher and brindle Boxer dogs. AB - Differential expression of the ASIP gene and its interaction with MC1R have provided basic insight into pigment-type switching in mammals. Here, we report the characterization of a specific red-haired skin transcript and a specific black-haired skin transcript in the ASIP gene in the black-and-tan Doberman Pinscher. It is also shown that the brindle-haired skin of the Boxer exhibits a deregulated expression resulting in various 5'-untranslated exons. Comparative sequence analysis revealed a short interspersed element and a poly(A) stretch inserted within the promoter region of the ASIP in the Boxer. Genotyping studies have shown that both insertions are also present in brindle and fawn animals of the Boxer and Great Dane breeds. Furthermore, we genotyped MC1R and K loci for their known variants that affect coat color in dogs. As expected, all animals were homozygotes (E(M) /E(M) ) for the mask mutation, and fawn animals were k(y) /k(y) . Unexpectedly, we found that all brindle animals were heterozygotes k(B) /k(y) . Our results suggest that differential expression of ASIP determine pigment-type switching in a MC1R and K allele-dependent manner in dogs. PMID- 22524304 TI - Photoinduced electron transfer in Os(terpyridine)-biphenylene-(bi)pyridinium assemblies. AB - A series of linearly arranged donor-spacer-acceptor (D-S-A) systems 1-3, has been prepared and characterized. These dyads combine an Os(II)bis(terpyridine) unit as the photoactivable electron donor (D), a biphenylene (2) or phenylene-xylylene (3) fragment as the spacer (S), and a N-aryl-2,6-diphenylpyridinium electrophore (with aryl = 4-pyridyl or 4-pyridylium in 1 or 2/3, respectively) as the acceptor (A). Their absorption spectra, redox behavior, and luminescence properties (both at 77 K in rigid matrix and at 298 K in fluid solution) have been studied. The electronic structure and spectroscopic properties of a representative compound of the series (i.e., 2) have also been investigated at the theoretical level, performing Density Functional Theory (DFT)-based calculations. Time-dependent transient absorption spectra of 1-3 have also been recorded at room temperature. The results indicate that efficient photoinduced oxidative electron transfer takes place in the D-S-A systems at room temperature in fluid solution, for which rate constants (in the range 4 * 10(8)-2 * 10(10) s(-1)) depend on the driving force of the process and the spacer nature. In all the D-S-A systems, charge recombination is faster than photoinduced charge separation, in spite of the relatively large energy of the D(+)-S-A(-) charge-separated states (between 1.47 and 1.78 eV for the various species), which would suggest that the charge recombination occurs in the Marcus inverted region. Considerations based on superexchange mechanism suggest that the reason for the fast charge recombination is the presence of a virtual D-S(+)-A(-) state at low energy--because of the involvement of the easily oxidizable biphenylene spacer--which is beneficial for charge recombination via superexchange but unsuitable for photoinduced charge separation. To further support the above statement, we prepared a fourth D-S-A species, 4, analogous to 2 but with a (hardly oxidizable) single phenylene fragment serving as the spacer. For such a species, charge recombination (about 3 * 10(10) s(-1)) is slower than photoinduced charge separation (about 1 * 10(11) s(-1)), thereby confirming our suggestions. PMID- 22524302 TI - A comparison of feature selection and classification methods in DNA methylation studies using the Illumina Infinium platform. AB - BACKGROUND: The 27k Illumina Infinium Methylation Beadchip is a popular high throughput technology that allows the methylation state of over 27,000 CpGs to be assayed. While feature selection and classification methods have been comprehensively explored in the context of gene expression data, relatively little is known as to how best to perform feature selection or classification in the context of Illumina Infinium methylation data. Given the rising importance of epigenomics in cancer and other complex genetic diseases, and in view of the upcoming epigenome wide association studies, it is critical to identify the statistical methods that offer improved inference in this novel context. RESULTS: Using a total of 7 large Illumina Infinium 27k Methylation data sets, encompassing over 1,000 samples from a wide range of tissues, we here provide an evaluation of popular feature selection, dimensional reduction and classification methods on DNA methylation data. Specifically, we evaluate the effects of variance filtering, supervised principal components (SPCA) and the choice of DNA methylation quantification measure on downstream statistical inference. We show that for relatively large sample sizes feature selection using test statistics is similar for M and beta-values, but that in the limit of small sample sizes, M values allow more reliable identification of true positives. We also show that the effect of variance filtering on feature selection is study-specific and dependent on the phenotype of interest and tissue type profiled. Specifically, we find that variance filtering improves the detection of true positives in studies with large effect sizes, but that it may lead to worse performance in studies with smaller yet significant effect sizes. In contrast, supervised principal components improves the statistical power, especially in studies with small effect sizes. We also demonstrate that classification using the Elastic Net and Support Vector Machine (SVM) clearly outperforms competing methods like LASSO and SPCA. Finally, in unsupervised modelling of cancer diagnosis, we find that non negative matrix factorisation (NMF) clearly outperforms principal components analysis. CONCLUSIONS: Our results highlight the importance of tailoring the feature selection and classification methodology to the sample size and biological context of the DNA methylation study. The Elastic Net emerges as a powerful classification algorithm for large-scale DNA methylation studies, while NMF does well in the unsupervised context. The insights presented here will be useful to any study embarking on large-scale DNA methylation profiling using Illumina Infinium beadarrays. PMID- 22524305 TI - MRI and X-ray in axial spondyloarthritis: the relationship between inflammatory and structural changes. AB - Demonstration of an association between inflammation and spinal ankylosis has been challenging. Until the advent of MRI, prospective study was not possible due to inaccessibility of tissue. Recent studies using MRI have described an association between the presence of bone edema at vertebral corners on MRI and the subsequent development of syndesmophytes at the corresponding vertebral corners on radiography. Although reports have also highlighted the development of new syndesmophytes where the baseline MRI shows no inflammation, MRI has limited sensitivity for detection of spinal inflammation that is clearly evident on histopathology. There are also crucial methodological challenges because radiographic assessment is limited to the anterior corners of the cervical and lumbar spine while MRI lesions in the cervical spine are often small while spurious inflammatory signal is common in the lumbar spine. Follow-up MRI evaluation in two independent studies has also shown that inflammatory lesions that resolve after anti-TNF therapy are more prone to develop into syndesmophytes. It may be possible that very early inflammatory lesions resolve completely without sequelae if anti-TNF therapy is introduced before new bone formation becomes largely autonomous. For an individual patient the overall development of new bone during anti-TNF therapy may therefore depend on the balance between the number of early and more mature inflammatory lesions. Clinical trials of anti-TNF agents in early spondyloarthritis together with prospective MRI studies will allow more detailed testing of this hypothesis as a major priority for the research agenda in spondyloarthritis. PMID- 22524306 TI - An event-related potentials study of face naming: evidence of phonological retrieval deficit in the tip-of-the-tongue state. AB - A famous-face naming task was used to establish the electrophysiological characterization of the tip-of-the-tongue (TOT) state, successful naming (K), and nonrecognition (DK). The differences in the direct event-related potentials (ERPs) and in the lateralized readiness potential between those categories were studied. The ERP correlates of recognition and access to semantic and lexical information were similar between K and TOT, but showed amplitude differences with respect to DK. A delayed onset of the response selection was obtained in TOT in comparison with K, suggesting an insufficient activation of phonological information from 360 ms onwards. The continuous search for the name and the conflict monitoring in TOT led to differences in ERP amplitudes between TOT and the other categories from 750 ms onwards as well as to a delayed onset of response preparation, indicating a continuous engagement of processing resources. PMID- 22524307 TI - Low-potential synthesis of "clean" Au nanodendrites and their high performance toward ethanol oxidation. AB - The shape control of Au nanocrystals is crucial to their catalytic applications and optical properties. Well-defined Au nanodendrites (NDs) have been prepared on a glassy carbon electrode using low-potential synthesis, assisted by ethylenediamine (EDA). The effects of applied potential, deposition time, and HAuCl(4) (or EDA) concentrations on the morphology of the Au deposits are discussed in our work. The growth mechanism can be explained by a two-staged growth of dendrites: initial branching and subsequent dendritic growth. The Au NDs exhibits superior catalytic performance toward ethanol oxidation, in comparison with the polycrystalline Au nanoparticles. The simple and facile synthetic technique can be applied to the construction of other metals with complex hierarchical structures on a large-scale. PMID- 22524308 TI - Hepatitis B virus directly promotes collagen I expression of LX-2 cells without infection in vitro. AB - AIM: To investigate direct effects of hepatitis B virus (HBV) on collagen type I in vitro. METHODS: Collagen type I were measured after LX-2 cell cultured with purified or serum HBV for 12, 24 and 48 h. Furthermore, evidence of HBV infection to LX-2 were detected, and different inhibitors were used to identify pathways regulating collagen I expression. RESULTS: The 3 * 10(5) IU/mL purified/serum HBV increased collagen type I mRNA expression by 2.2-/3.2- and 1.3 /1.5-fold at 24 and 48 h, respectively. Collagen type I protein in the supernatant of purified/serum HBV group also increased compared to the control group (408.0 +/- 8.0/384.4 +/- 6.8 vs 262.7 +/- 15.7 ng/mL, P < 0.05). However, the 3 * 10(7) IU/mL purified/serum HBV increased collagen type I expression similar to that of 3 * 10(5) IU/mL, while 3 * 10(3) IU/mL group showed no effect. Human HBV immunoglobulin alleviated HBV-induced collagen I expression, but no evidence of HBV infection was found. Neutralization of transforming growth factor beta, tumor necrosis factor alpha, platelet-derived growth factor, extracellular signal-regulated kinase and TGF-beta receptor had no obvious inhibitory effects; only inhibition of p38 mitogen-activated protein kinase decreased collagen type I mRNA expression by 0.5-/0.4- and 0.4-/0.3-fold at 24 and 48 h, respectively. It reduced collagen type I protein in the purified/serum HBV group for 48 h (252.1 +/- 14.1/251.7 +/- 18.8 vs 403.9 +/- 4.9/385.0 +/- 4.2 ng/mL, P < 0.05). CONCLUSION: HBV directly promotes collagen type I expression of LX-2 cells without infection in vitro. PMID- 22524309 TI - What has fairness got to do with it? Tackling tobacco among Australia's disadvantaged. AB - ISSUE: While population wide smoking rates are falling steadily the rates remain high among the disadvantaged. The future we face is one where the differentials in smoking rates will continue to widen and will flow through to increased health inequalities. APPROACH: How best to reduce smoking rates among the disadvantaged? Alongside existing population level initiatives and social policy initiatives is an urgent need for a targeted, comprehensive approach that acknowledges the serious impact of smoking on the disadvantaged. In 2006 Cancer Council NSW embarked on a statewide, multi-component Tackling Tobacco Program to encourage and support non-government social and community services to address smoking among their clients. KEY FINDINGS: Tackling Tobacco Program results have shown that the 1600 staff from 400 organisations trained to provide smoking care can attain the knowledge and confidence to address tobacco and that clients are very receptive to receiving quit support from them. Improvements in quality of life for clients who do quit have been encouraging and the Tackling Tobacco Program has challenged assumptions and attitudes that disadvantaged people are uninterested and unable to quit. IMPLICATIONS: Alongside population and social policy approaches must be a serious investment in tackling smoking among the disadvantaged. CONCLUSIONS: Tackling Tobacco Program is an innovative example of how to engage disadvantaged smokers, de-normalise smoking and encourage and support quitting using familiar settings. Engaging Australia's large network of social and community services as allies in this work should be vigorously pursued. PMID- 22524310 TI - Extraperitoneal laparoscopic retroperitoneal lymph node dissection for early stage testicular nonseminomatous germ cell tumors: initial experience. AB - PURPOSE: To investigate a modified laparoscopic retroperitoneal lymph node dissection technique using an extraperitoneal approach and to evaluate its feasibility. PATIENTS AND METHODS: A group of consecutive patients from a single institution underwent extraperitoneal laparoscopic retroperitoneal lymph node dissection (EL-RLND) at weeks after orchiectomy for primary testicular nonseminomatous germ cell tumors (NSGCT). All patients were placed in the supine position and tilted up 15 degrees on the affected side. Four trocars were introduced. The templates of lymph node dissection conformed to those of Weissbach and Boedefeld. RESULTS: EL-RLND was successfully performed in 15 patients (left, 6 patients; right, 9 patients). The mean total operative time for the entire series was 164 +/- 49 minutes. The mean blood loss was 118 +/- 74 mL. One intraoperative complication was injury of the vena cava, which occurred in one patient. Ureteral obstruction occurred in another patient. The mean postoperative intestinal function recovery time was 2 days. The mean postoperative hospitalization was 5.5 +/- 1.1 days. Normal antegrade ejaculation was preserved in all patients. Pathologic studies revealed positive lymph nodes in three (20%) patients. No recurrence or distant metastasis occurred during 2 to 32 months of follow-up. CONCLUSIONS: EL-RLND is a safe and feasible procedure using an improved extraperitoneal approach that provides minimal invasion and rapid recovery of patients. PMID- 22524311 TI - Understanding the origin of seasonal epidemics of mycoplasmal conjunctivitis. AB - 1. Many host-pathogen systems show regular seasonal oscillations. 2. Seasonal variation in mycoplasmal conjunctivitis prevalence in house finches is an example of such oscillations. 3. An annual pulse of Mycoplasma gallisepticum-naive juveniles increasing the number of susceptibles, seasonal changes in flocking behaviour increasing transmission rate and a gradual loss of resistance to reinfection with time are sufficient to model the observed seasonal variation in disease prevalence. Nevertheless, experiments are needed to test the underlying mechanisms. 4. We carried out an 18-month experiment with small groups of birds in large aviaries to test two hypotheses. 5. To test the first hypothesis that an influx of naive juveniles in a group of recovered adults is sufficient to cause an outbreak, we added eight juveniles to a group of 11 adults that had recovered from an earlier infection. In all, three replicates juveniles became infected, but only after some of the adults relapsed. 6. To test the second hypothesis that reintroduction of M. gallisepticum into a multiage group of previously exposed but fully recovered house finches causes a new outbreak, we inoculated two birds in each group in March of the 2nd year. Contrary to what happens in the wild at that time disease prevalence increased rapidly after reintroduction of M. gallisepticum. 7. We conclude that asymptomatic, recovered adults can initiate an epidemic and transmit M. gallisepticum to naive house finches and that the reintroduction of M. gallisepticum is sufficient to cause a new outbreak, even at a time of the year when mycoplasmal conjunctivitis is low in free-living birds. Date, as such, seems to be less important to explain seasonal variation in conjunctivitis than the presence of naive juveniles or the introduction on M. gallisepticum. 8. Seasonality in outbreaks is most likely tightly linked to seasonal variation in bird movements and behaviour. PMID- 22524312 TI - Predisposing factors and effects of fetal bradycardia following cordocentesis at mid-pregnancy. AB - OBJECTIVES: To identify predisposing factors of fetal bradycardia following cordocentesis at mid-pregnancy and to compare the pregnancy outcomes to those without bradycardia. METHODS: All cordocenteses performed at 18-22 weeks of gestation were prospectively enrolled. The inclusion criteria consisted of: (i) singleton pregnancies; (ii) no fetal structural or chromosomal abnormalities; (iii) the procedures done by experienced operators. They were divided into two groups; procedures with fetal bradycardia (Group 1) and those without bradycardia (Group 2). Factors related to bradycardia were identified and pregnancy outcomes between the two groups were also compared. RESULTS: Of 6147 cordocenteses recruited, 2829 met the inclusion criteria. Of these,152 had fetal bradycardia whereas the remaining 2677 did not. The procedures involving placenta penetration, and umbilical cord bleeding were significantly related to a higher rate of fetal bradycardia. On the other hand, cordocenteses with fetal bradycardia had a significantly higher rate of fetal loss (11.8 vs. 1.9%, respectively, p = 0.001) as well as a higher rate of low birth weight and preterm birth. CONCLUSIONS: Cordocentesis with placenta penetration and umbilical cord bleeding carries a higher risk for fetal bradycardia and fetal bradycardia was an independent factor for a higher rate of fetal loss, preterm birth and low birth weight. PMID- 22524313 TI - Patch testing is an effective method for the diagnosis of carbamazepine-induced drug reaction, eosinophilia and systemic symptoms (DRESS) syndrome in an 8-year old girl. AB - Drug reaction, eosinophilia and systemic symptoms (DRESS) is an acute and life threatening disease, characterised by fever, rash and systemic symptoms, including lymphadenopathy, abnormal liver function, interstitial nephritis, pulmonary and cardiac infiltrates and haematological abnormalities with eosinophilia and atypical lymphocytes. The drugs mostly associated with DRESS are anticonvulsants, allopurinol, minocycline and sulfonamides. This syndrome is rarely seen in childhood even though a large number of children have anticonvulsant treatment. An 8-year-old girl was admitted with fever, lymphadenopathy and skin eruptions on her trunk. Her medical history was notable for epilepsy and carbamazepine treatment had been started 5 weeks previously. Laboratory studies showed a white cell count of 6200/uL (normal, 4100-11 200/uL) with 22% eosinophils and a gamma-glutamyl transpeptidase level of 296 U/L (normal, 0-23 U/L). Laboratory tests for infections and collagen diseases were in the normal range. Persistence of fever and maculopapular eruption with generalised desquamation and the appearance of cheilitis and facial angioedema suggested a hypersensitivity reaction to carbamazepine. The carbamazepine was replaced with levetiracetam. All clinical symptoms improved within a week with corticosteroids and antihistamine treatment. Six weeks after complete recovery an epicutaneous patch test with carbamazepine was performed and a carbamazepine induced positive skin reaction was observed at 48-h. Carbamazepine-induced DRESS syndrome is a rare entity in children. An epicutaneous patch test is a useful tool for identifying the inducing agent for the DRESS syndrome and for identifying a safe anticonvulsant drug. PMID- 22524314 TI - The N-end rule pathway. AB - The N-end rule pathway is a proteolytic system in which N-terminal residues of short-lived proteins are recognized by recognition components (N-recognins) as essential components of degrons, called N-degrons. Known N-recognins in eukaryotes mediate protein ubiquitylation and selective proteolysis by the 26S proteasome. Substrates of N-recognins can be generated when normally embedded destabilizing residues are exposed at the N terminus by proteolytic cleavage. N degrons can also be generated through modifications of posttranslationally exposed pro-N-degrons of otherwise stable proteins; such modifications include oxidation, arginylation, leucylation, phenylalanylation, and acetylation. Although there are variations in components, degrons, and hierarchical structures, the proteolytic systems based on generation and recognition of N degrons have been observed in all eukaryotes and prokaryotes examined thus far. The N-end rule pathway regulates homeostasis of various physiological processes, in part, through interaction with small molecules. Here, we review the biochemical mechanisms, structures, physiological functions, and small-molecule mediated regulation of the N-end rule pathway. PMID- 22524316 TI - The ubiquitin code. AB - The posttranslational modification with ubiquitin, a process referred to as ubiquitylation, controls almost every process in cells. Ubiquitin can be attached to substrate proteins as a single moiety or in the form of polymeric chains in which successive ubiquitin molecules are connected through specific isopeptide bonds. Reminiscent of a code, the various ubiquitin modifications adopt distinct conformations and lead to different outcomes in cells. Here, we discuss the structure, assembly, and function of this ubiquitin code. PMID- 22524315 TI - Lipid droplets and cellular lipid metabolism. AB - Among organelles, lipid droplets (LDs) uniquely constitute a hydrophobic phase in the aqueous environment of the cytosol. Their hydrophobic core of neutral lipids stores metabolic energy and membrane components, making LDs hubs for lipid metabolism. In addition, LDs are implicated in a number of other cellular functions, ranging from protein storage and degradation to viral replication. These processes are functionally linked to many physiological and pathological conditions, including obesity and related metabolic diseases. Despite their important functions and nearly ubiquitous presence in cells, many aspects of LD biology are unknown. In the past few years, the pace of LD investigation has increased, providing new insights. Here, we review the current knowledge of LD cell biology and its translation to physiology. PMID- 22524317 TI - Epidemiological, genetic and epigenetic aspects of the research on healthy ageing and longevity. AB - Healthy ageing and longevity in humans result from a number of factors, including genetic background, favorable environmental and social factors and chance.In this article we aimed to overview the research on the biological basis of human healthy ageing and longevity, discussing the role of epidemiological, genetic and epigenetic factors in the variation of quality of ageing and lifespan, including the most promising candidate genes investigated so far. Moreover, we reported the methodologies applied for their identification, discussing advantages and disadvantages of the different approaches and possible solutions that can be taken to overcome them. Finally, we illustrated the recent approaches to define healthy ageing and underlined the role that the emerging field of epigenetics is gaining in the search for the determinants of healthy ageing and longevity. PMID- 22524318 TI - Predictors of extradyadic sexual involvement in unmarried opposite-sex relationships. AB - Using a sample of unmarried individuals in opposite-sex romantic relationships that was representative of the United States (N = 933), the current study prospectively evaluated predictors of extradyadic sexual involvement (ESI) over 20 months (from 2007-2010). Data were collected with self-report questionnaires via U.S. mail. Participants were 18 to 35 years old, and 34.9% were male. Variables tested as predictors included involved-partner factors such as demographic characteristics, sexual history, and mental health, as well as relationship-related factors including communication, sexual dynamics, and aspects of commitment. Future ESI was significantly predicted by lower baseline relationship satisfaction, negative communication, aggression, lower dedication, absence of plans to marry, suspicion of partners' ESI, and partners' ESI. It was not predicted by sexual frequency, sexual dissatisfaction, or cohabitation status. Although more problems with alcohol use, more previous sex partners, and having parents who never married one another predicted future ESI, there were many involved-partner demographic factors that did not predict later ESI (e.g., gender, age, education, religiosity, having divorced parents, and having children). None of the results were moderated by gender. These results suggest that compared to demographic characteristics, relationship dynamics and negative interactions are more strongly predictive of future ESI. Implications for future research are discussed. PMID- 22524319 TI - Sixteenth century Gymnophalloides seoi infection on the coast of the Korean Peninsula. AB - Gymnophalloides seoi is a trematode species discovered as recently as 1993. Interestingly, ancient G. seoi eggs were identified in our earlier study on a 17th Century female mummy unearthed in a Korean county (HD-1) where G. seoi infection, according to a nationwide survey of 2001, was considered not to have been endemic. Although we suspected that the geographical distribution of G. seoi might have contracted over the past several hundred years from wider coastal areas on the Korean peninsula to the much more restricted region delineated by the survey, there has been only the single, above-noted report of an ancient G. seoi infection in a currently non-endemic area. As such, more evidence is needed before our contraction theory of G. seoi infection prevalence can be confirmed as fact. Our current report in this regard will perhaps help to end the controversy. In a newly discovered 17th Century male mummy found in another Korean county considered non-endemic by the 2001 survey, we identified a large number of ancient G. seoi eggs. We believe that this additional evidence for a wider distribution of G. seoi infection prior to the 20th Century is invaluable support for our earlier hypothesis. PMID- 22524320 TI - The sequential organ failure assessment (SOFA) score is an effective triage marker following staggered paracetamol (acetaminophen) overdose. AB - BACKGROUND: The sequential organ failure assessment (SOFA) score is an effective triage marker following single time point paracetamol (acetaminophen) overdose, but has not been evaluated following staggered (multiple supratherapeutic doses over >8 h, resulting in cumulative dose of >4 g/day) overdoses. AIM: To evaluate the prognostic accuracy of the SOFA score following staggered paracetamol overdose. METHODS: Time-course analysis of 50 staggered paracetamol overdoses admitted to a tertiary liver centre. Individual timed laboratory samples were correlated with corresponding clinical parameters and the daily SOFA scores were calculated. RESULTS: A total of 39/50 (78%) patients developed hepatic encephalopathy. The area under the SOFA receiver operator characteristic for death/liver transplantation was 87.4 (95% CI 73.2-95.7), 94.3 (95% CI 82.5-99.1), and 98.4 (95% CI 84.3-100.0) at 0, 24 and 48 h, respectively, postadmission. A SOFA score of <6 at tertiary care admission predicted survival with a sensitivity of 100.0% (95% CI 76.8-100.0) and specificity of 58.3% (95% CI 40.8-74.5), compared with 85.7% (95% CI 60.6-97.4) and 75.0% (95% CI 65.2-79.5) , respectively, for the modified Kings College criteria. Only 2/21 patients with an admission SOFA score <6 required renal replacement therapy or intracerebral pressure monitoring. SOFA significantly outperformed the Model for End-stage Liver Disease, but not APACHE II, at 0, 24-and 48-h following admission. CONCLUSIONS: A SOFA score <6 at tertiary care admission following a staggered paracetamol overdose, is associated with a good prognosis. Both the SOFA and APACHE II scores could improve triage of high-risk staggered paracetamol overdose patients. PMID- 22524321 TI - Controlled synthesis of heterogeneous metal-titania nanostructures and their applications. AB - We describe a new synthetic approach to heterogeneous metal-TiO(2) nanomaterials based on conversion of Ti(3+) to hydrous TiO(2) occurring uniquely on the nanostructured metallic surfaces such as Pt, Au, and Ni nanowires and nanoparticles. The TiO(2) growth mechanism was studied by designing an electrochemical cell. A variety of heterogeneous metal-TiO(2) nanostructures, such as segmented metal-TiO(2) nanowires, core-shell metal-TiO(2) nano/microparticles, and composite metal-TiO(2) nanotubes, can be fabricated by varying the morphology of the seeding metal nanostructure or controlling selective TiO(2) growth on different surfaces of the metallic nanomaterial. Altering the reaction time and Ti(3+) concentration allows the TiO(2) segment lengths or TiO(2) shell thicknesses to be finely tuned. Coaxial Au-TiO(2) nanorod arrays were demonstrated to be fast lithium-ion storage materials, while the core shell Ni-TiO(2) nanoparticles exhibited excellent photodegradation properties as magnetic recyclable photocatalysts. PMID- 22524322 TI - Near-normal incidence dark-field microscopy: applications to nanoplasmonic spectroscopy. AB - The spectroscopic characterization of individual nanostructures is of fundamental importance to understanding a broad range of physical and chemical processes. One general and powerful technique that addresses this aim is dark-field microscopy, with which the scattered light from an individual structure can be analyzed with minimal background noise. We present the spectroscopic analysis of individual plasmonic nanostructures using dark-field illumination with incidence nearly normal to the substrate. We show that, compared to large incidence angle approaches, the near-normal incidence approach provides significantly higher signal-to-background ratios and reduced retardation field effects. To demonstrate the utility of this technique, we characterize an individual chemically synthesized gold nanoshell and a lithographically defined heptamer exhibiting a pronounced Fano-like resonance. We show that the line shape of the latter strongly depends on the incidence angle. Near-normal incidence dark-field microscopy can be used to characterize a broad range of molecules and nanostructures and can be adapted to most microscopy setups. PMID- 22524323 TI - [V16O38(CN)]9-: a soluble mixed-valence redox-active building block with strong antiferromagnetic coupling. AB - A new discrete [V(16)O(38)(CN)](9-) cluster, which displays the hitherto unknown 8- charge on the cluster shell and is the first to encapsulate the cyanide anion, has been synthesized and characterized by IR and UV/vis/near-IR spectroscopy, electrochemistry, and magnetic susceptibility measurements. Bond valence sum calculations conducted on the basis of the crystal structure analysis of K(9)[V(16)O(38)(CN)].13H(2)O confirm that this new member of the polyoxovanadate series is a mixed-valence complex. The intervalence charge transfer bands arising from intrametal interactions reveal that a localized (class II) assignment is appropriate for the cluster; however, a small degree of electronic delocalization is present. Interesting possibilities exist for the incorporation of this unit into higher dimensionality framework structures, where the redox, optical, and magnetic properties can be exploited and tuned. PMID- 22524324 TI - Ancient DNA reveals kinship burial patterns of a pre-Columbian Andean community. AB - BACKGROUND: A detailed genetic study of the pre-Columbian population inhabiting the Tompullo 2 archaeological site (department Arequipa, Peru) was undertaken to resolve the kin relationships between individuals buried in six different chullpas. Kin relationships were an important factor shaping the social organization in the pre-Columbian Andean communities, centering on the ayllu, a group of relatives that shared a common land and responsibilities. The aim of this study was to evaluate whether this Andean model of a social organization had an influence on mortuary practices, in particular to determine whether chullpas served as family graves. RESULTS: The remains of forty-one individuals were analyzed with both uniparental (mtDNA, Y-chromosome) and biparental (autosomal microsatellites) markers. Reproducible HVRI sequences, autosomal and Y chromosomal STR profiles were obtained for 24, 16 and 11 individuals, respectively. Mitochondrial DNA diversity was comparable to that of ancient and contemporary Andean populations. The Tompullo 2 population exhibited the closest relationship with the modern population from the same region. A kinship analysis revealed complex pattern of relations within and between the graves. However mean relatedness coefficients regarding the pairs of individuals buried in the same grave were significantly higher than those regarding pairs buried in different graves. The Y chromosome profiles of 11 males suggest that only members of one male line were buried in the same grave. CONCLUSIONS: Genetic investigation of the population that inhabited Tompullo 2 site shows continuity between pre Columbian and modern Native Amerindian populations inhabiting the Arequipa region. This suggests that no major demographic processes have influenced the mitochondrial DNA diversity of these populations during the past five hundred years. The kinship analysis involving uni- and biparental markers suggests that the community that inhabited the Tompullo 2 site was organized into extended family groups that were buried in different graves. This finding is in congruence with known models of social organization of Andean communities. PMID- 22524326 TI - Alkoxyamine re-formation reaction. Effects of the nitroxide fragment: a multiparameter analysis. AB - A few years ago, Studer and co-workers (Macromolecules 2006, 39, 1347-1352) reported the dramatic effect of the reaction of re-formation of alkoxyamines on the fate of the nitroxide-mediated polymerization (NMP) of styrene. This prompted us to investigate more carefully the effects of the nitroxide structure on the re formation rate constant k(c). Ten new values of k(c) were obtained for the reaction of imidozalidine nitroxide and the phenethyl radical. These values were combined with the 21 values of k(c) reported in the literature for a multiparameter analysis (log(k(c)/M(-1) s(-1)) = (10.22 +/- 0.10) + (0.46 +/- 0.02)E(s) + (0.41 +/- 0.17)sigma(I)) using the electrical Hammett constant sigma(I) to describe both the stabilization and polar effects as well as the modified Taft steric constant E(s) of the nitroxide. The same analysis was performed for the k(c) values of the cross-coupling reaction of nitroxides with tert-butoxylcarbonyl-2-prop-2-yl radical (log(k(c)/M(-1) s(-1)) = (11.10 +/- 0.25) + (0.57 +/- 0.05)E(s) + (1.42 +/- 0.18)sigma(I)) and tert butoxycarbonylethyl radical (log(k(c)/M(-1) s(-1)) = (10.23 +/- 0.16) + (0.35 +/- 0.03)E(s) + (0.93 +/- 0.25)sigma(I)). These correlations were applied for the analysis of the NMP of styrene controlled by 6pi(*), 6theta(*), and 6rho(*) using a Fischer phase diagram. PMID- 22524327 TI - The effect of an 810-nm diode laser on postoperative pain and tissue response after modified Widman flap surgery: a pilot study in humans. AB - BACKGROUND: The purpose of this single-masked pilot clinical study is to compare the tissue response and postoperative pain after the use of a diode laser (810 nm) (DL) as an adjunct to modified Widman flap (MWF) surgery to that of MWF alone. METHODS: Thirteen patients with generalized severe chronic periodontitis completed the study. Control sites were randomly selected to receive an MWF and the contralateral test sites an MWF in conjunction with a DL. The study tooth/site was treated plus any additional teeth in the quadrant in which the site was located, if needed. Randomization was done using a coin flip. The DL was used to de-epithelialize the inner part of the periodontal flap and photo biostimulate the surgical area. Pain scale assessment (PS), pain medication consumption (PM), tissue edema (TE), and tissue color (TC) were evaluated 1 week after surgery. RESULTS: Statistically significant differences were seen for TE (P = 0.041), PM (P <0.001), and PS (P <0.001) favoring test sites. TC did not show a statistically significant difference (P = 0.9766). Patients rated the first surgical treatment (test or control; random assignment to first treatment) performed as more painful than the second (P <0.002). CONCLUSION: The use of an 810-nm diode laser provided additional benefits to MWF surgery in terms of less edema and postoperative pain. PMID- 22524328 TI - Mast cells act as phagocytes against the periodontopathogen Aggregatibacter actinomycetemcomitans. AB - BACKGROUND: Evidence to date shows that mast cells play a critical role in immune defenses against infectious agents, but there have been no reports about involvement of these cells in eliminating periodontopathogens. In this study, the phagocytic ability of mast cells against Aggregatibacter actinomycetemcomitans compared with macrophages is evaluated. METHODS: In vitro phagocytic assays were conducted using murine mast cells and macrophages, incubated with A. actinomycetemcomitans, either opsonized or not, with different bacterial load ratios. After 1 hour, cells were stained with acridine orange and assessed by confocal laser-scanning electron microscopy. RESULTS: Phagocytic ability of murine mast cells against A. actinomycetemcomitans was confirmed. In addition, the percentage of mast cells with internalized bacteria was higher in the absence of opsonization than in the presence of opsonization. Both cell types showed significant phagocytic activity against A. actinomycetemcomitans. However, the percentage of mast cells with non-opsonized bacteria was higher than that of macrophages with opsonized bacteria in one of the ratios (1:10). CONCLUSIONS: This is the first report about the participation of murine mast cells as phagocytes against A. actinomycetemcomitans, mainly in the absence of opsonization with human serum. Our results may indicate that mast cells act as professional phagocytes in the pathogenesis of biofilm-associated periodontal disease. PMID- 22524329 TI - Cyanoacrylate versus laser in the treatment of dentin hypersensitivity: a controlled, randomized, double-masked and non-inferiority clinical trial. AB - BACKGROUND: Dentin hypersensitivity (DH) is a painful, exaggerated response to normal stimuli, such as cold, sweetness, and brushing. The aim of the present controlled, randomized, double-masked, non-inferiority clinical trial is to evaluate the effectiveness of cyanoacrylate in the treatment of DH when compared to the application of low-intensity laser. METHODS: The study includes 434 sensitive teeth from 62 patients. A total of 216 teeth were treated with laser and 218 with cyanoacrylate. A numeric rating scale was used to record the parameters of pain related to the stimuli at baseline and after the treatment at intervals of 24 hours and 30, 90, and 180 days. RESULTS: Both groups had significant reductions in DH. However, there was no significant difference between the two groups <=6 months. Intragroup analysis showed that the effect of cyanoacrylate obtained at 24 hours remained for 90 days in response to air-jet test and 30 days for cold-spray test. There was a statistically significant difference between all other intragroup comparisons at the time intervals (P <0.001). CONCLUSIONS: It was concluded that cyanoacrylate is as effective as low intensity laser in reducing DH. In addition, it is a more accessible and low-cost procedure and can be safely used in the treatment of DH. PMID- 22524330 TI - Effect of recombinant human bone morphogenetic protein 2 associated with a variety of bone substitutes on vertical guided bone regeneration in rabbit calvarium. AB - BACKGROUND: A major challenge for dental implantology is to consistently obtain appropriate bone augmentation before implant placement. The aim of this study is to evaluate the effect of recombinant human bone morphogenetic protein 2 (rhBMP 2) associated with bone substitute materials beta-tricalcium phosphate (beta TCP), biphasic calcium phosphate (BCP), and bovine bone mineral on vertical guided bone regeneration (GBR) in rabbit calvarium. METHODS: Four titanium cylinders were fixed to the calvarium of 22 rabbits. In group 1 (n = 10), three cylinders were randomly filled with one of the test materials, and one cylinder was filled with a blood clot (CL). In group 2 (n = 12), the cylinders were randomly assigned to the same materials and CL but with the addition of rhBMP-2. Bone labels were injected over the course of 13 weeks, and euthanasia was performed 14 weeks after surgery in both groups. RESULTS: The mean volume and area of tissue growth was greater in group 2 (with rhBMP-2) than in group 1 (without rhBMP-2), irrespective of the material used (P <0.001). The mean volume of tissue growth in the CL cylinder was smaller than that observed with all other materials (P <0.001) in both groups. The mean area of regenerated bone in the CL cylinder was smaller than that observed in the beta-TCP cylinder (P = 0.028). The histologic study revealed more lamellar bone in the rhBMP-2 group, with a greater level of biodegradation of all the bone substitute materials tested. CONCLUSION: The use of rhBMP-2/absorbable collagen sponge (ACS) combined with all of the bone substitute materials tested resulted in a greater amount of bone formation than that produced with the bone substitute materials alone or rhBMP-2/(ACS) and CL using the rabbit calvarium GBR model. PMID- 22524331 TI - Efficacy of using PDGF and xenograft with or without collagen membrane for bone regeneration around immediate implants with induced dehiscence-type defects: a microcomputed tomographic study in dogs. AB - BACKGROUND: Use of collagen membrane (CM) with xenograft and recombinant human platelet-derived growth factor (rhPDGF) in guided bone regeneration (GBR) is debatable. The aim of this microcomputed tomographic experiment was to assess the efficacy of using PDGF and xenograft (with or without CM) for GBR around immediate implants with dehiscence defects. METHODS: Ten beagle dogs underwent atraumatic bilateral second and fourth premolar extractions from both arches. A standardized dehiscence defect (6 * 3 mm) was created on the buccal bone and immediate implants were placed in distal sockets in each site. Animals were randomly divided into three groups: 1) group 1, xenograft with rhPDGF was placed and covered with CM; 2) group 2, xenograft with rhPDGF was placed over the defects; and 3) group 3, four immediate implants were associated with dehiscence (controls). After 16 weeks, animals were sacrificed and jaw segments were assessed for buccal bone thickness (BBT), buccal bone volume (BBV), vertical bone height (VBH), and bone-to-implant contact (BIC) using microcomputed tomography. RESULTS: BBT was higher in group 2 (1.533 +/- 0.89 mm) than group 1 (0.745 +/- 0.322 mm) (P <0.001) and group 3 (0.257 +/- 0.232 mm) (P <0.05). BBV was higher in group 2 (67.87 +/- 19.83 mm(3)) than group 1 (42.47 +/- 6.78 mm(3)) (P <0.05) and group 3 (19.12 +/- 4.06 mm(3)) (P <0.001). VBH was higher in group 2 (6.36 +/ 1.37 mm) than group 3 (0.00 +/- 0.00 mm) (P <0.001). VBH was higher in group 1 (3.91 +/- 2.68 mm) than group 3 (0.00 +/- 0.00 mm) (P <0.05). BIC was higher in group 2 (67.25% +/- 13.42%) than group 1 (36.25% +/- 12.78%) (P <0.05) and group 3 (30.25% +/- 7.27%) (P <0.01). CONCLUSION: GBR around immediate implants with dehiscence defects using PDGF and xenograft alone resulted in higher BBT, BBV, VBH, and BIC than when performed in combination with CM. PMID- 22524332 TI - Periodontal condition of patients with autoimmune diseases and the effect of anti tumor necrosis factor-alpha therapy. AB - BACKGROUND: The aim of this study is to evaluate the effect of autoimmune diseases (AIs), as well as anti-tumor necrosis factor-alpha (TNF-alpha) therapy on the clinical and immunologic parameters of the periodontium. METHODS: Thirty six AI patients (12 rheumatoid arthritis [RA], 12 psoriatic arthritis, and 12 systemic sclerosis) were recruited together with 12 healthy (H) and 10 RA patients receiving anti-TNF-alpha therapy (RA+). Periodontal indices including plaque index, gingival index (GI), probing depth (PD), and bleeding on probing (BOP) were measured, and gingival crevicular fluid (GCF) was collected from five deepest pockets using papers strips. The TNF-alpha level was analyzed using enzyme-linked immunosorbent assay. Analysis of variance test was used for statistical comparison between groups, whereas Pearson linear correlation coefficient test was used to examine the association between TNF-alpha and periodontal status indices. RESULTS: The three AI subgroups were very similar in clinical and immunologic parameters. GI was greater in the AI patients compared to the H and RA+ groups (1.91 +/- 0.54, 1.21 +/- 0.67, and 1.45 +/- 0.30, respectively, P = 0.0005). AI patients exhibited significantly more BOP than H and RA+ (46.45% +/- 17.08%, 30.08% +/- 16.86%, and 21.13% +/- 9.51%, respectively, P = 0.0002). PD in H and RA+ groups were lower than in the AI (3.47 +/- 0.33, 3.22 +/- 0.41, and 3.91 +/- 0.49 mm, P = 0.0001). Number of sites with PD >4 mm was higher in AI patients compared to H and RA+ (42.44 +/- 17.5 versus 24.33 +/- 15.62 versus 33.3 +/- 6.6, P = 0.0002). GCF TNF-alpha was higher among the AI patients (1.67 +/- 0.58 ng/site) compared to 1.07 +/- 0.33 ng/site for the H group and 0.97 +/- 0.52 ng/site for the RA+ group (P = 0.0002). A significant positive correlation was found between PD and TNF-alpha levels in the GCF (r = 0.4672, P = 0.0002), BOP (r = 0.7491, P = 0.0001), and GI (r = 0.5420, P = 0.0001). CONCLUSIONS: Patients with AI diseases have higher periodontal indices and higher TNF-alpha levels in GCF than H controls. Anti-TNF-alpha treatment appears to reverse this phenomenon. PMID- 22524333 TI - High doses of oseltamivir phosphate induce acute respiratory arrest in anaesthetized rats. AB - It has been reported that one of the serious adverse events after the treatment of oseltamivir phosphate (OP) for influenza patients is sudden death resulting from cardiorespiratory arrest. To investigate the aetiology of such an adverse consequence, we examined effects of OP (expressed as free base) on blood pressure and ventilation in anaesthetized rats with vagotomy. Intravenous OP (30-200 mg/kg) caused dose-dependent hypotension and bradycardia in spontaneously breathing animals. Concomitantly with changes in blood pressure, the tracheal airflow increased. The ventilatory rate hastened during the injection and then transiently slowed around 1 min. after the administration (transient hypopnea). Thereafter, it gradually returned to control. The hypopnea increased with increasing dose and ventilatory arrest occurred at 200 mg/kg. Intraduodenal OP (500-1000 mg/kg) provoked cardioventilatory arrest 72-218 min. after the injection. Oseltamivir carboxylate (100-200 mg/kg, i.v.), an active metabolite of OP, had no significant effect on ventilation and blood pressure. In artificially ventilated animals, intravenous OP caused slowing of the respiratory rate around 1 min. after the injection in a dose-dependent manner. This effect of OP waned in 5 min. after the administration. The amplitude of phrenic nerve discharge was not changed at lower doses (30-100 mg/kg). The phrenic nerve stopped to discharge immediately after higher doses (150-200 mg/kg). We demonstrated that OP causes central suppression of the respiratory function in rats and suggest a relationship between the OP-induced cardiorespiratory arrest and sudden death observed in influenza patients after taking OP. PMID- 22524334 TI - Introduction to The neurosciences and music IV: learning and memory. AB - The conference entitled "The Neurosciences and Music-IV: Learning and Memory'' was held at the University of Edinburgh from June 9-12, 2011, jointly hosted by the Mariani Foundation and the Institute for Music in Human and Social Development, and involving nearly 500 international delegates. Two opening workshops, three large and vibrant poster sessions, and nine invited symposia introduced a diverse range of recent research findings and discussed current research directions. Here, the proceedings are introduced by the workshop and symposia leaders on topics including working with children, rhythm perception, language processing, cultural learning, memory, musical imagery, neural plasticity, stroke rehabilitation, autism, and amusia. The rich diversity of the interdisciplinary research presented suggests that the future of music neuroscience looks both exciting and promising, and that important implications for music rehabilitation and therapy are being discovered. PMID- 22524335 TI - Auditory brain development in premature infants: the importance of early experience. AB - Preterm infants in the neonatal intensive care unit (NICU) often close their eyes in response to bright lights, but they cannot close their ears in response to loud sounds. The sudden transition from the womb to the overly noisy world of the NICU increases the vulnerability of these high-risk newborns. There is a growing concern that the excess noise typically experienced by NICU infants disrupts their growth and development, putting them at risk for hearing, language, and cognitive disabilities. Preterm neonates are especially sensitive to noise because their auditory system is at a critical period of neurodevelopment, and they are no longer shielded by maternal tissue. This paper discusses the developmental milestones of the auditory system and suggests ways to enhance the quality control and type of sounds delivered to NICU infants. We argue that positive auditory experience is essential for early brain maturation and may be a contributing factor for healthy neurodevelopment. Further research is needed to optimize the hospital environment for preterm newborns and to increase their potential to develop into healthy children. PMID- 22524336 TI - Musical experience, plasticity, and maturation: issues in measuring developmental change using EEG and MEG. AB - The neuroscientific study of musical behavior has become a significant field of research during the last decade, and reports of this research in the popular press have caught the imagination of the public. This enterprise has also made it evident that studying the development of musical behavior can make a significant contribution to important questions in the field, such as the evolutionary origins of music, cross-cultural similarity and diversity, the effects of experience on musical processing, and relations between music and other domains. Studying musical development brings a unique set of methodological issues. We discuss a select set of these related to measurement of the electroencephalogram (EEG) and magnetoencephalogram (MEG). We use specific examples from our laboratory to illustrate the types of questions that can be answered with different data analysis techniques. PMID- 22524337 TI - Behavioral methods in infancy: pitfalls of single measures. AB - This paper outlines the principal behavioral methods used to study music processing in infancy. The advantages of conditioning procedures are offset by high attrition rates and restrictions on the stimuli that can be used. The head turn preference procedure is more user-friendly but poses greater interpretive challenges. In view of the multidimensional nature of infant attention, no single response measure, whether behavioral, physiological, or neural, can provide unambiguous information about music processing in infancy. Greater use of ecologically valid stimuli is likely to generate increased cooperation from infants and greater generality of the findings. PMID- 22524338 TI - Pediatric neuroimaging in early childhood and infancy: challenges and practical guidelines. AB - Structural and functional magnetic resonance imaging (fMRI) has been used increasingly to investigate typical and atypical brain development. However, in contrast to studies in school-aged children and adults, MRI research in young pediatric age groups is less common. Practical and technical challenges occur when imaging infants and children, which presents clinicians and research teams with a unique set of problems. These include procedural difficulties (e.g., participant anxiety or movement restrictions), technical obstacles (e.g., availability of child-appropriate equipment or pediatric MR head coils), and the challenge of choosing the most appropriate analysis methods for pediatric imaging data. Here, we summarize and review pediatric imaging and analysis tools and present neuroimaging protocols for young nonsedated children and infants, including guidelines and procedures that have been successfully implemented in research protocols across several research sites. PMID- 22524339 TI - Education through music--the model of the Musikkindergarten Berlin. AB - In 2005, the pianist and conductor Daniel Barenboim initiated the Musikkindergarten Berlin as the first kindergarten in which music is not only used as an occasional add-on but as the central education medium for the child every day. The skills of specially trained kindergarten teachers combined with regular visits by professional musicians of the Staatskapelle Berlin (the Berlin State Opera orchestra) form the basis of a new educational concept, in which children experience music in all its different aspects and in its unique capability as a transfer medium into all the other educational areas. In this context, the method, the aim, and the experimental ground is not only education in or with music, but through music. This paper provides information and examples about first-hand experiences over the last six years. PMID- 22524340 TI - From the model of El Sistema in Venezuela to current applications: learning and integration through collective music education. AB - Over the last years, El Sistema--the Venezuelan project started in 1975 and now acknowledged worldwide as the most significant example of collective music education--has inspired a profusion of remarkable initiatives on all continents. From the original impulse by founder Jose Antonio Abreu, strong social principles of integration are combined with specific musical approaches to achieve individual empowerment as a large-scale alternative to endemic juvenile crime, counteracting the risk factors of social unease, serving as a stimulating example toward emancipation, and providing professional opportunities to the talented. Such a network, in turn, proves to be a powerful instrument of cultural progress: the tenets of "Sistema" become shared values able to foster development, reaching into issues of disability and rehabilitation. This paper presents continuities and contrasts in various ramifications of such a successful trend and outlines perspectives for further impact of this powerful transformational agent. PMID- 22524341 TI - Making music in a group: synchronization and shared experience. AB - To consider the full impact of musical learning on the brain, it is important to study the nature of everyday, non-expert forms of musical behavior alongside expert instrumental training. Such informal forms of music making tend to include social interaction, synchronization, body movements, and positive shared experiences. Here, I propose that when designing music intervention programs for scientific purposes, such features may have advantages over instrumental training, depending on the specific research aims, contexts, and measures. With reference to a selection of classroom approaches to music education and to the shared affective motion experience (SAME) model of emotional responses to music, I conclude that group learning may be particularly valuable in music pedagogy. PMID- 22524342 TI - Neuroscience and "real world" practice: music as a therapeutic resource for children in zones of conflict. AB - Recent developments in music neuroscience are considered a source for reflection on, and evaluation and development of, musical therapeutic practice in the field, in particular, in relation to traumatized children and postconflict societies. Music neuroscience research is related to practice within a broad biopsychosocial framework. Here, examples are detailed of work from North Uganda, Palestine, and South Thailand. PMID- 22524343 TI - Tempo mediates the involvement of motor areas in beat perception. AB - Increasing evidence shows that the neural circuits involved in beat perception overlap with motor circuitry even in the absence of overt movement. This study investigated effects of tempo on beat-based processing by combining functional magnetic resonance imaging with a perceptual timing paradigm where participants made simple temporal judgments about short rhythmic sequences. Of central interest were judgments about ambiguous test rhythms where the perceived direction of a timing deviation ("speeding up" vs. "slowing down") depended on the induction of an implied beat. Successful beat induction was reduced when the implied beat was at a slower tempo (1,500 ms) than when it was at a faster tempo (600 ms). Decreased beat induction was accompanied by decreased functional activity in the basal ganglia, premotor and supplementary motor regions, and thalamus. Findings support the conclusion that rhythms presented at a slow tempo reduce involvement of a striato-thalamo-cortico network in beat-based processing. PMID- 22524344 TI - Without it no music: beat induction as a fundamental musical trait. AB - Beat induction (BI) is the cognitive skill that allows us to hear a regular pulse in music to which we can then synchronize. Perceiving this regularity in music allows us to dance and make music together. As such, it can be considered a fundamental musical trait that, arguably, played a decisive role in the origins of music. Furthermore, BI might be considered a spontaneously developing, domain specific, and species-specific skill. Although both learning and perception/action coupling were shown to be relevant in its development, at least one study showed that the auditory system of a newborn is able to detect the periodicities induced by a varying rhythm. A related study with adults suggested that hierarchical representations for rhythms (meter induction) are formed automatically in the human auditory system. We will reconsider these empirical findings in the light of the question whether beat and meter induction are fundamental cognitive mechanisms. PMID- 22524345 TI - Effects of perceptual experience on children's and adults' perception of unfamiliar rhythms. AB - Rhythm and meter are fundamental components of music that are universal yet also culture specific. Although simple, isochronous meters are preferred and more readily discriminated than highly complex, nonisochronous meters, moderately complex nonisochronous meters do not pose a problem for listeners who are exposed to them from a young age. The present work uses a behavioral task to examine the ease with which listeners of various ages acquire knowledge of unfamiliar metrical structures from passive exposure. We examined perception of familiar (Western) rhythms with an isochronous meter and unfamiliar (Balkan) rhythms with a nonisochronous meter. We compared discrimination by American children (5 to 11 years) and adults before and after a 2-week period of at-home listening to nonisochronous meter music from Bulgaria. During the first session, listeners of all ages exhibited superior discrimination of isochronous than in nonisochronous melodies. Across sessions, this asymmetry declined for young children but not for older children and adults. PMID- 22524347 TI - Cognitive and methodological considerations on the effects of musical expertise on speech segmentation. AB - Both speech and music are constituted by sequences of sound elements that unfold in time and require listeners to engage cognitive functions such as sequencing, attention, and memory. We recently ran a set of experiments with the aim of testing the effect of musical expertise on a rather high cognitive function: speech segmentation. Here, we will present the main concepts underlying the investigation of speech segmentation as well as its link to music and musical expertise. Interestingly, our results seem to show that musical training and expertise have effects on brain plasticity that may go beyond primary regions. Moreover, to facilitate and improve future research in this domain, we will here describe several delicate methodological precautions that need to be taken into account (e.g., the choice of stimuli, participants, data analyses). Finally, we will give some possible future directions to better understand the impact that music may have on speech processing. PMID- 22524346 TI - Cognitive factors shape brain networks for auditory skills: spotlight on auditory working memory. AB - Musicians benefit from real-life advantages, such as a greater ability to hear speech in noise and to remember sounds, although the biological mechanisms driving such advantages remain undetermined. Furthermore, the extent to which these advantages are a consequence of musical training or innate characteristics that predispose a given individual to pursue music training is often debated. Here, we examine biological underpinnings of musicians' auditory advantages and the mediating role of auditory working memory. Results from our laboratory are presented within a framework that emphasizes auditory working memory as a major factor in the neural processing of sound. Within this framework, we provide evidence for music training as a contributing source of these abilities. PMID- 22524348 TI - Musical expertise induces neuroplasticity of the planum temporale. AB - The present manuscript summarizes and discusses the implications of recent neuroimaging studies, which have investigated the relationship between musical expertise and structural, as well as functional, changes in an auditory-related association cortex, namely, the planum temporale (PT). Since the bilateral PT is known to serve as a spectrotemporal processor that supports perception of acoustic modulations in both speech and music, it comes as no surprise that musical expertise corresponds to functional sensitivity and neuroanatomical changes in cortical architecture. In this context, we focus on the following question: To what extent does musical expertise affect the functioning of the left and right plana temporalia? We discuss the relationship between behavioral, hemodynamic, and neuroanatomical data obtained from musicians in light of maturational and developmental issues. In particular, we introduce two studies of our group that show to what extent brains of musicians are more proficient in phonetic task performance. PMID- 22524349 TI - The OPERA hypothesis: assumptions and clarifications. AB - Recent research suggests that musical training enhances the neural encoding of speech. Why would musical training have this effect? The OPERA hypothesis proposes an answer on the basis of the idea that musical training demands greater precision in certain aspects of auditory processing than does ordinary speech perception. This paper presents two assumptions underlying this idea, as well as two clarifications, and suggests directions for future research. PMID- 22524350 TI - Becoming musically enculturated: effects of music classes for infants on brain and behavior. AB - Musical enculturation is a complex, multifaceted process that includes the development of perceptual processing specialized for the pitch and rhythmic structures of the musical system in the culture, understanding of esthetic and expressive norms, and learning the pragmatic uses of music in different social situations. Here, we summarize the results of a study in which 6-month-old Western infants were randomly assigned to 6 months of either an active participatory music class or a class in which they experienced music passively while playing. Active music participation resulted in earlier enculturation to Western tonal pitch structure, larger and/or earlier brain responses to musical tones, and a more positive social trajectory. Furthermore, the data suggest that early exposure to cultural norms of musical expression leads to early preferences for those norms. We conclude that musical enculturation begins in infancy and that active participatory music making in a positive social setting accelerates enculturation. PMID- 22524351 TI - Practiced musical style shapes auditory skills. AB - Musicians' processing of sounds depends highly on instrument, performance practice, and level of expertise. Here, we measured the mismatch negativity (MMN), a preattentive brain response, to six types of musical feature change in musicians playing three distinct styles of music (classical, jazz, and rock/pop) and in nonmusicians using a novel, fast, and musical sounding multifeature MMN paradigm. We found MMN to all six deviants, showing that MMN paradigms can be adapted to resemble a musical context. Furthermore, we found that jazz musicians had larger MMN amplitude than all other experimental groups across all sound features, indicating greater overall sensitivity to auditory outliers. Furthermore, we observed a tendency toward shorter latency of the MMN to all feature changes in jazz musicians compared to band musicians. These findings indicate that the characteristics of the style of music played by musicians influence their perceptual skills and the brain processing of sound features embedded in music. PMID- 22524352 TI - Expertise in folk music alters the brain processing of Western harmony. AB - In various paradigms of modern neurosciences of music, experts of Western classical music have displayed superior brain architecture when compared with individuals without explicit training in music. In this paper, we show that chord violations embedded in musical cadences were neurally processed in a facilitated manner also by musicians trained in Finnish folk music. This result, obtained by using early right anterior negativity (ERAN) as an index of harmony processing, suggests that tonal processing is advanced in folk musicians by their long-term exposure to both Western and non-Western music. PMID- 22524353 TI - ERP responses to cross-cultural melodic expectancy violations. AB - In this preliminary study, we measured event-related potentials (ERPs) to melodic expectancy violations in a cross-cultural context. Subjects (n= 10) were college age students born and raised in the United States. Subjects heard 30 short melodies based in the Western folk tradition and 30 from North Indian classical music. Each melody was presented in its original and deviation form, and subjects were asked to judge the congruence of the melody. Results indicated that subjects found the Indian melodies less congruous overall and were less sensitive to deviations in the Indian melody condition. ERP data were partly consistent with the behavioral data with significant P600 responses to deviations in both cultural conditions, but less robust in the Indian context. Results are interpreted in light of previous research on listeners' abilities to generate expectancies in unfamiliar cultures and the possibility of overlap in the scale systems influencing the findings. PMID- 22524354 TI - Effects of mono- and bicultural experiences on auditory perception. AB - The auditory system functions in the context of everyday life and the cultural environment in which we live. Although cultural-invariant, universal principles certainly contribute to sound processing, cultural factors play a role as well. In this review paper, we discuss two potential sources of cultural influence on auditory perception. We term the first type bottom-up, and use it to refer to the way that increased exposure to particular kinds of sound could shape our auditory and auditory-neural responses. The second type we term top-down, and use it to refer to the way our cultural upbringing broadly shapes how we think, which may in turn have an impact on how we perceive the world. An important consideration regarding cultural influences is that many individuals grow up with exposure to environmental stimulations of more than one culture. In our discussion, we will consider both mono- and bicultural experiences. PMID- 22524355 TI - A sensitive period for musical training: contributions of age of onset and cognitive abilities. AB - The experiences we engage in during childhood can stay with us well into our adult years. The idea of a sensitive period--a window during maturation when our brains are most influenced by behavior--has been proposed. Work from our laboratory has shown that early-trained musicians (ET) performed better on visual motor and auditory-motor synchronization tasks than late-trained musicians (LT), even when matched for total musical experience. Although the groups of musicians showed no cognitive differences, working memory scores correlated with task performance. In this study, we have replicated these findings in a larger sample of musicians and included a group of highly educated nonmusicians (NM). Participants performed six woodblock rhythms of varying levels of metrical complexity and completed cognitive subtests measuring verbal abilities, working memory, and pattern recognition. Working memory scores correlated with task performance across all three groups. Interestingly, verbal abilities were stronger among the NM, while nonverbal abilities were stronger among musicians. These findings are discussed in context of the sensitive period hypothesis as well as the debate surrounding cognitive differences between musicians and NM. PMID- 22524356 TI - Musical training and the role of auditory feedback during performance. AB - Recent research has shown that music training enhances music-related sensorimotor associations, such as the relationship between a key press on the keyboard and its associated musical pitch (auditory feedback). Such results suggest that the role of auditory feedback in performance may be based on learned associations that are task specific. Here, results from various studies will be presented that suggest that the real state of affairs is more complex. Several recent studies have shown similar effects of altered auditory feedback during piano performance for pianists and individuals with no piano training. Other recent research suggests dramatic differences between pianists and nonmusicians concerning the influence of auditory feedback on melody switching that suggest greater influence of auditory feedback among nonmusicians than pianists. Taken together, results suggest that musical training refines preexisting sensorimotor associations. PMID- 22524357 TI - The multisensory brain and its ability to learn music. AB - Playing a musical instrument requires a complex skill set that depends on the brain's ability to quickly integrate information from multiple senses. It has been well documented that intensive musical training alters brain structure and function within and across multisensory brain regions, supporting the experience dependent plasticity model. Here, we argue that this experience-dependent plasticity occurs because of the multisensory nature of the brain and may be an important contributing factor to musical learning. This review highlights key multisensory regions within the brain and discusses their role in the context of music learning and rehabilitation. PMID- 22524358 TI - Sensorimotor mechanisms in music performance: actions that go partially wrong. AB - Even expert musicians make errors occasionally, and overt responses that are correct may be accompanied by partial-error behavior that can be indicative of online error detection processes. We compare pianists' production of correct pitches, pitch errors, and partial errors (correct pitches with incorrect force or duration) by examining events prior to errors. Errors tended to be produced with slower durations and softer intensities (associated with force reduction) than correct events. In addition, pre-error events tended to have durations and intensities that fell between those of errors and correct responses, presumably due to response competition with upcoming errors that resulted in partial-error outcomes. These findings support the inference that partial information about upcoming (planned) sequence events is used to guide current responses, consistent with cascade models of activation during sequence production. PMID- 22524359 TI - Error monitoring is altered in musician's dystonia: evidence from ERP-based studies. AB - Musician's dystonia (MD) is a task-specific movement disorder characterized by a loss of voluntary motor control in highly trained movements like piano playing. Its underlying pathophysiology is defined by deficient functioning of neural pathways at different levels of the central nervous system. However, a few studies have examined the brain responses associated with executive functions such as error monitoring in MD. We recorded the electroencephalogram (EEG) in professional pianists during the performance of memorized music sequences at fast tempi. Event-related potentials (ERPs) locked to pitch errors were investigated in MD and a control group. In MD patients, significantly larger error-related brain responses before and following errors were observed as compared with healthy pianists. Our results suggest that in MD, the generalized degraded neural activity at all levels of the central nervous system is manifested in specific neural correlates of the executive functions that monitor an overlearned sensorimotor performance. PMID- 22524360 TI - Dynamic aspects of musical imagery. AB - Auditory imagery can represent many aspects of music, such as the starting pitches of a tune or the instrument that typically plays it. In this paper, I concentrate on more dynamic, or time-sensitive aspects of musical imagery, as demonstrated in two recently published studies. The first was a behavioral study that examined the ability to make emotional judgments about both heard and imagined music in real time. The second was a neuroimaging study on the neural correlates of anticipating an upcoming tune, after hearing a cue tune. That study found activation of several sequence-learning brain areas, some of which varied with the vividness of the anticipated musical memory. Both studies speak to the ways in which musical imagery allows us to judge temporally changing aspects of the represented musical experience. These judgments can be quite precise, despite the complexity of generating the rich internal representations of imagery. PMID- 22524361 TI - Mental imagery in music performance: underlying mechanisms and potential benefits. AB - This paper examines the role of mental imagery in music performance. Self-reports by musicians, and various other sources of anecdotal evidence, suggest that covert auditory, motor, and/or visual imagery facilitate multiple aspects of music performance. The cognitive and motor mechanisms that underlie such imagery include working memory, action simulation, and internal models. Together these mechanisms support the generation of anticipatory images that enable thorough action planning and movement execution that is characterized by efficiency, temporal precision, and biomechanical economy. In ensemble performance, anticipatory imagery may facilitate interpersonal coordination by enhancing online predictions about others' action timing. Overlap in brain regions subserving auditory imagery and temporal prediction is consistent with this view. It is concluded that individual differences in anticipatory imagery may be a source of variation in expressive performance excellence and the quality of ensemble cohesion. Engaging in effortful musical imagery is therefore justified when artistic perfection is the goal. PMID- 22524362 TI - Acuity of mental representations of pitch. AB - Singing in one's mind or forming expectations about upcoming notes both require that mental images of one or more pitches will be generated. As with other musical abilities, the acuity with which such images are formed might be expected to vary across individuals and may depend on musical training. Results from several behavioral tasks involving intonation judgments indicate that multiple memory systems contribute to the formation of accurate mental images for pitch, and that the functionality of each is affected by musical training. Electrophysiological measures indicate that the ability to form accurate mental images is associated with greater engagement of auditory areas and associated error-detection circuitry when listeners imagine ascending scales and make intonation judgments about target notes. A view of auditory mental images is espoused in which unified mental image representations are distributed across multiple brain areas. Each brain area helps shape the acuity of the unified representation based on current behavioral demands and past experience. PMID- 22524363 TI - Beyond auditory cortex: working with musical thoughts. AB - Musical imagery is associated with neural activity in auditory cortex, but prior studies have not examined musical imagery tasks requiring mental transformations. This paper describes functional magnetic resonance imaging (fMRI) studies requiring manipulation of musical information. In one set of experiments, listeners were asked to mentally reverse a familiar tune when presented backwards. This manipulation consistently elicits neural activity in the intraparietal sulcus (IPS). Separate experiments requiring judgments about melodies that have been transposed from one musical key to another also elicit IPS activation. Conjunction analyses indicate that the same portions of the IPS are recruited in both tasks. The findings suggest that the dorsal pathway of auditory processing is involved in the manipulation and transformation of auditory information, as has also been shown for visuomotor and visuospatial tasks. As such, it provides a substrate for the creation of new mental representations that are based on manipulation of previously experienced sensory events. PMID- 22524364 TI - Working memory for speech and music. AB - The present paper reviews behavioral and neuroimaging findings on similarities and differences between verbal and tonal working memory (WM), the influence of musical training, and the effect of strategy use on WM for tones. Whereas several studies demonstrate an overlap of core structures (Broca's area, premotor cortex, inferior parietal lobule), preliminary findings are discussed that imply, if confirmed, the existence of a tonal and a phonological loop in musicians. This conclusion is based on the findings of partly differing neural networks underlying verbal and tonal WM in musicians, suggesting that functional plasticity has been induced by musical training. We further propose a strong link between production and auditory WM: data indicate that both verbal and tonal auditory WM are based on the knowledge of how to produce the to-be-remembered sounds and, therefore, that sensorimotor representations are involved in the temporary maintenance of auditory information in WM. PMID- 22524366 TI - The dynamic audio-motor system in pianists. AB - This paper reports a preliminary study based on the theoretical assumption that continuous closed-loop audio-motor control could be disadvantageous for pianists. It is argued that the functional relationship between the intracerebral electrical activations in the auditory and premotor cortex should be rhythmically decreased and increased. To test this hypothesis, intracerebral electrical activations for the auditory and premotor cortex were estimated using scalp EEG and standardized low-resolution electrical tomography (sLORETA). The extracted times series were subjected to a Granger causality analysis, revealing a causal relationship from the auditory cortex to the premotor cortex that was considerably stronger during piano playing and weaker during rest. Importantly, this relationship varied rhythmically during the course of piano playing, with lags (obtained with cross-correlations) between 666 ms and 820 milliseconds. This study thus delivers evidence that the functional coupling between the auditory and premotor cortex varies during piano playing. PMID- 22524365 TI - When right is all that is left: plasticity of right-hemisphere tracts in a young aphasic patient. AB - Using an adapted version of Melodic Intonation Therapy (MIT), we treated an adolescent girl with a very large left-hemisphere lesion and severe nonfluent aphasia secondary to an ischemic stroke. At the time of her initial assessment 15 months after her stroke, she had reached a plateau in her recovery despite intense and long-term traditional speech-language therapy (approximately five times per week for more than one year). Following an intensive course of treatment with our adapted form of MIT, her performance improved on both trained and untrained phrases, as well as on speech and language tasks. These behavioral improvements were accompanied by functional MRI changes in the right frontal lobe as well as by an increased volume of white matter pathways in the right hemisphere. No increase in white matter volume was seen in her healthy twin sister, who was scanned twice over the same time period. This case study not only provides further evidence for MIT's effectiveness, but also indicates that intensive treatment can induce functional and structural changes in a right hemisphere fronto-temporal network. PMID- 22524367 TI - Tinnitus: the dark side of the auditory cortex plasticity. AB - Music has increasingly been used as a tool for investigation of human cognition and its underlying brain mechanisms. However, music can be used also for neurorehabilitation. Chronic tinnitus is a symptom with high prevalence, especially in industrialized countries. There is evidence that the tinnitus perception is related to unfavorable cortical plastic changes. Maladaptive auditory cortex reorganization may contribute to the generation and maintenance of tinnitus. Because cortical organization can be modified by behavioral training, potentially via reversing maladaptive auditory cortex reorganization, we attempted to reduce tinnitus loudness by exposing chronic tinnitus patients to self-chosen, enjoyable music that was modified ("notched") to contain no energy in the frequency range surrounding the individual tinnitus frequency and thus attracting lateral inhibition to the brain area generating tinnitus. On this basis, we have developed and evaluated a customized music training strategy that appears capable of both reducing cortical tinnitus-related neuronal activity and alleviating subjective tinnitus perception. PMID- 22524368 TI - Musician's cramp as manifestation of maladaptive brain plasticity: arguments from instrumental differences. AB - Musician's cramp is a task-specific movement disorder that presents itself as muscular incoordination or loss of voluntary motor control of extensively trained movements while a musician is playing the instrument. It is characterized by task specificity and gender bias, affecting significantly more males than females. The etiology is multifaceted: a combination of a genetic predisposition, termed endophenotype, and behavioral triggering factors being the leading features for the manifestation of the disorder. We present epidemiological data from 591 musician patients from our outpatient clinic demonstrating an influence of fine motor requirements on the manifestation of dystonia. Brass, guitar, and woodwind players were at greater risk than other instrumentalists. High temporospatial precision of movement patterns, synchronous demands on tonic and phasic muscular activation, in combination with fine-motor burdens of using the dominant hand in daily life activities, constitute as triggering factors for the disorder and may explain why different body parts are affected. PMID- 22524369 TI - Music listening after stroke: beneficial effects and potential neural mechanisms. AB - Music is an enjoyable leisure activity that also engages many emotional, cognitive, and motor processes in the brain. Here, we will first review previous literature on the emotional and cognitive effects of music listening in healthy persons and various clinical groups. Then we will present findings about the short- and long-term effects of music listening on the recovery of cognitive function in stroke patients and the underlying neural mechanisms of these music effects. First, our results indicate that listening to pleasant music can have a short-term facilitating effect on visual awareness in patients with visual neglect, which is associated with functional coupling between emotional and attentional brain regions. Second, daily music listening can improve auditory and verbal memory, focused attention, and mood as well as induce structural gray matter changes in the early poststroke stage. The psychological and neural mechanisms potentially underlying the rehabilitating effect of music after stroke are discussed. PMID- 22524370 TI - The involvement of audio-motor coupling in the music-supported therapy applied to stroke patients. AB - Music-supported therapy (MST) has been developed recently to improve the use of the affected upper extremity after stroke. MST uses musical instruments, an electronic piano and an electronic drum set emitting piano sounds, to retrain fine and gross movements of the paretic upper extremity. In this paper, we first describe the rationale underlying MST, and we review the previous studies conducted on acute and chronic stroke patients using this new neurorehabilitation approach. Second, we address the neural mechanisms involved in the motor movement improvements observed in acute and chronic stroke patients. Third, we provide some recent studies on the involvement of auditory-motor coupling in the MST in chronic stroke patients using functional neuroimaging. Finally, these ideas are discussed and focused on understanding the dynamics involved in the neural circuit underlying audio-motor coupling and how functional connectivity could help to explain the neuroplastic changes observed after therapy in stroke patients. PMID- 22524371 TI - Changes in neuromagnetic beta-band oscillation after music-supported stroke rehabilitation. AB - Precise timing of sound is crucial in music for both performing and listening. Indeed, listening to rhythmic sound sequences activates not only the auditory system but also the sensorimotor system. Previously, we showed the significance of neural beta-band oscillations (15-30 Hz) for the timing processing that involves such auditory-motor coordination. Thus, we hypothesized that motor rehabilitation training incorporating music playing will stimulate and enhance auditory-motor interaction in stroke patients. We examined three chronic patients who received Music-Supported Therapy following the protocols practiced by Schneider. Neuromagnetic beta-band activity was remarkably alike during passive listening to a metronome and during finger tapping, with or without the metronome, for either the paretic or nonparetic hand, suggesting a shared mechanism of the beta modulation. In the listening task, the magnitude of the beta decrease after the tone onset was more pronounced at the posttraining time point and was accompanied by improved arm and hand skills. The present case data give insight into the neural underpinnings of rehabilitation with music making and rhythmic auditory stimulation. PMID- 22524372 TI - Making music after stroke: using musical activities to enhance arm function. AB - A common long-term consequence of stroke is impaired arm function, which affects independence and quality of life in a considerable proportion of stroke survivors. There is a growing need for self-management strategies that enable stroke survivors to continue their recovery after rehabilitation has ceased. Interventions with high-intensity, repetitive task training and feedback are most likely to improve function. Achieving the required amount of self-practice is challenging, however. Innovative approaches are required to translate therapies into rewarding activities that can be undertaken independently. This paper describes the key principles and development of a novel intervention that integrates individuals' preferred music with game technology in upper limb rehabilitation. The "tap tempo" paradigm, which uses rhythmic auditory cueing, provides repetitive upper limb task training, which can be tailored to individual goals and progress (e.g., in terms of movement range and complexity), while providing sensitive quantitative feedback to promote skill acquisition and enhance self-management. PMID- 22524373 TI - Effective music therapy techniques in the treatment of nonfluent aphasia. AB - In music therapy for nonfluent aphasia patients who have difficulty producing meaningful words, phrases, and sentences, various benefits of singing have been identified: strengthened breathing and vocal ability, improved articulation and prosody of speech, and increased verbal and nonverbal communicative behaviors. This paper will introduce these various techniques used in clinical music therapy, and summarize findings based on our recent study to illustrate the strength of different techniques emphasizing rhythm, pitch, memory, and vocal/oral motor components dealing with different symptoms. The efficacy of each component is enhanced or diminished by the choice of music and the way it is interactively delivered. This indicates that neural mechanisms underlying speech improvement vary greatly with available acoustic and social cues in aphasic brain. PMID- 22524374 TI - Music: a unique window into the world of autism. AB - Understanding emotions is fundamental to our ability to navigate the complex world of human social interaction. Individuals with autism spectrum disorders (ASD) experience difficulties with the communication and understanding of emotions within the social domain. Their ability to interpret other people's nonverbal, facial, and bodily expressions of emotion is strongly curtailed. However, there is evidence to suggest that many individuals with ASD show a strong and early preference for music and are able to understand simple and complex musical emotions in childhood and adulthood. The dissociation between emotion recognition abilities in musical and social domains in individuals with ASD provides us with the opportunity to consider the nature of emotion processing difficulties characterizing this disorder. There has recently been a surge of interest in musical abilities in individuals with ASD, and this has motivated new behavioral and neuroimaging studies. Here, we review this new work. We conclude by providing some questions for future directions. PMID- 22524375 TI - Auditory-musical processing in autism spectrum disorders: a review of behavioral and brain imaging studies. AB - Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by atypical social and communication skills, repetitive behaviors, and atypical visual and auditory perception. Studies in vision have reported enhanced detailed ("local") processing but diminished holistic ("global") processing of visual features in ASD. Individuals with ASD also show enhanced processing of simple visual stimuli but diminished processing of complex visual stimuli. Relative to the visual domain, auditory global-local distinctions, and the effects of stimulus complexity on auditory processing in ASD, are less clear. However, one remarkable finding is that many individuals with ASD have enhanced musical abilities, such as superior pitch processing. This review provides a critical evaluation of behavioral and brain imaging studies of auditory processing with respect to current theories in ASD. We have focused on auditory musical processing in terms of global versus local processing and simple versus complex sound processing. This review contributes to a better understanding of auditory processing differences in ASD. A deeper comprehension of sensory perception in ASD is key to better defining ASD phenotypes and, in turn, may lead to better interventions. PMID- 22524377 TI - Memory disorders and vocal performance. AB - The ability to carry a tune, natural for the majority, is underpinned by a complex functional system (i.e., the vocal sensorimotor loop, VSL). The VSL involves various components, including perceptual mechanisms, auditory-motor mapping, motor control, and memory. The malfunction of one of these components can bring about poor-pitch singing. So far, disturbed perception and deficient sensorimotor mapping have been treated as important causes of poor singing. Yet, memory has been paid relatively little attention. Here, we review results obtained from both occasional singers and individuals suffering from congenital amusia, who were asked to produce from memory or imitate a well-known melody under conditions with different memory loads. The findings point to memory as a relevant source of impairment in poor-pitch singing and to imitation as a useful aid for poor singers. PMID- 22524376 TI - Atypical hemispheric asymmetry in the arcuate fasciculus of completely nonverbal children with autism. AB - Despite the fact that as many as 25% of the children diagnosed with autism spectrum disorders are nonverbal, surprisingly little research has been conducted on this population. In particular, the mechanisms that underlie their absence of speech remain unknown. Using diffusion tensor imaging, we compared the structure of a language-related white matter tract (the arcuate fasciculus, AF) in five completely nonverbal children with autism to that of typically developing children. We found that, as a group, the nonverbal children did not show the expected left-right AF asymmetry--rather, four of the five nonverbal children actually showed the reversed pattern. It is possible that this unusual pattern of asymmetry may underlie some of the severe language deficits commonly found in autism, particularly in children whose speech fails to develop. Furthermore, novel interventions (such as auditory-motor mapping training) designed to engage brain regions that are connected via the AF may have important clinical potential for facilitating expressive language in nonverbal children with autism. PMID- 22524378 TI - Is there potential for learning in amusia? A study of the effect of singing intervention in congenital amusia. AB - Congenital amusia is a neurodevelopmental disorder of musical perception and production. Much research has focused on characterizing the deficits within this special population; however, it is also important from both a psychological and educational perspective to determine which aspects of the disorder may be subject to change because this will also constrain theorizing about the nature of the disorder, as well as facilitating possible future remediation programs. In this small-scale study, a professional singing teacher used a broad-brush intervention approach with five individuals diagnosed with congenital amusia. The compensatory elements were designed to enhance vocal efficiency and health, singing technique, musical understanding, pitch perception, and production. Improvements were observed in most individuals in perception, indexed via the Montreal Battery for the Evaluation of Amusia scale subtest and in the vocal performance of familiar songs. The workshop setting gave a unique opportunity for observation and discussion to inform further investigations of this disorder. PMID- 22524379 TI - Impaired learning of event frequencies in tone deafness. AB - Musical knowledge is ubiquitous, effortless, and implicitly acquired all over the world via exposure to musical materials in one's culture. In contrast, one group of individuals who show insensitivity to music, specifically the inability to discriminate pitches and melodies, is the tone-deaf. In this study, we asked whether difficulties in pitch and melody discrimination among the tone-deaf could be related to learning difficulties, and, if so, what processes of learning might be affected in the tone-deaf. We investigated the learning of frequency information in a new musical system in tone-deaf individuals and matched controls. Results showed significantly impaired learning abilities in frequency matching in the tone-deaf. This impairment was positively correlated with the severity of tone deafness as assessed by the Montreal Battery for Evaluation of Amusia. Taken together, the results suggest that tone deafness is characterized by an impaired ability to acquire frequency information from pitched materials in the sound environment. PMID- 22524380 TI - Statistical learning of speech, not music, in congenital amusia. AB - The acquisition of both speech and music uses general principles: learners extract statistical regularities present in the environment. Yet, individuals who suffer from congenital amusia (commonly called tone-deafness) have experienced lifelong difficulties in acquiring basic musical skills, while their language abilities appear essentially intact. One possible account for this dissociation between music and speech is that amusics lack normal experience with music. If given appropriate exposure, amusics might be able to acquire basic musical abilities. To test this possibility, a group of 11 adults with congenital amusia, and their matched controls, were exposed to a continuous stream of syllables or tones for 21-minute. Their task was to try to identify three-syllable nonsense words or three-tone motifs having an identical statistical structure. The results of five experiments show that amusics can learn novel words as easily as controls, whereas they systematically fail on musical materials. Thus, inappropriate musical exposure cannot fully account for the musical disorder. Implications of the results for the domain specificity of statistical learning are discussed. PMID- 22524382 TI - Impact of interleukin-28B genotype on in vitro and in vivo systems of hepatitis C virus replication. AB - Identification of the relationship between the interleukin (IL)-28B genotype and the effect of peginterferon plus ribavirin treatment has had a great impact on the study of antiviral therapy for patients with chronic hepatitis C virus (HCV) infection. Differential expression levels of interferon-stimulated genes (ISG) in the liver and white blood cells based on the IL-28B genotype, which may in turn lead to differences in outcome of therapy, indicate that previous studies should be re-evaluated taking the effect of the IL-28B single nucleotide polymorphism (SNP) into consideration, although the exact mechanism of how variation in IL-28B SNPs affect HCV eradication remains unknown. These results suggest that the genotypes of multiple cell types, including liver and immune cells, contribute to the efficacy of therapy. Studies using human hepatocyte chimeric mice, in which effector cells of the human adaptive immune response are absent, showed that viral load, ISG expression levels and reduction of HCV RNA by interferon are affected by the IL-28B genotype. Genetic differences among hepatocytes may, therefore, contribute to differences in baseline viral loads and response to interferon therapy. Further studies should be done to clarify the mechanism of action of IL-28B SNP on viral load and effect of interferon treatment. Advances in cell culture systems and human hepatocyte chimeric mice, as well as upcoming in vitro and in vivo experimental systems, provide an effective platform to examine the effects of host and viral genetic variation on infection and response to interferon. PMID- 22524385 TI - Comparison of the photovoltaic response of oleylamine and inorganic ligand-capped CuInSe2 nanocrystals. AB - Thin film photovoltaic devices (PVs) were fabricated with CuInSe(2) (CIS) nanocrystals capped with either oleylamine, inorganic metal chalcogenide hydrazinium complexes (MCC), or S(2-), HS(-), and OH(-). A CIS nanocrystal layer deposited from solvent-based inks without high temperature processing served as the active light-absorbing material in the devices. The MCC ligand-capped CIS nanocrystal PVs exhibited power conversion efficiency under AM1.5 illumination (1.7%) comparable to the oleylamine-capped CIS nanocrystals (1.6%), but with significantly thinner absorber layers. S(2-)-capped CIS nanocrystals could be deposited from aqueous dispersions, but exhibited lower photovoltaic performance. PMID- 22524386 TI - Sculpting organs: mechanical regulation of tissue development. AB - The ramified architectures of organs such as the mammary gland and lung are generated via branching morphogenesis, a developmental process through which individual cells bud and pinch off of pre-existing epithelial sheets. Although specified by signaling programs, organ development requires integration of all aspects of the microenvironment. We describe the essential role of endogenous cellular contractility in the formation of branching tubes. We also highlight the role of exogenous forces in normal and aberrant branching. PMID- 22524387 TI - Mucosal vaccine design and delivery. AB - Mucosal surfaces are a major portal of entry for many human pathogens that are the cause of infectious diseases worldwide. Vaccines capable of eliciting mucosal immune responses can fortify defenses at mucosal front lines and protect against infection. However, most licensed vaccines are administered parenterally and fail to elicit protective mucosal immunity. Immunization by mucosal routes may be more effective at inducing protective immunity against mucosal pathogens at their sites of entry. Recent advances in our understanding of mucosal immunity and identification of correlates of protective immunity against specific mucosal pathogens have renewed interest in the development of mucosal vaccines. Efforts have focused on efficient delivery of vaccine antigens to mucosal sites that facilitate uptake by local antigen-presenting cells to generate protective mucosal immune responses. Discovery of safe and effective mucosal adjuvants are also being sought to enhance the magnitude and quality of the protective immune response. PMID- 22524388 TI - The effect of nanoparticle size, shape, and surface chemistry on biological systems. AB - An understanding of the interactions between nanoparticles and biological systems is of significant interest. Studies aimed at correlating the properties of nanomaterials such as size, shape, chemical functionality, surface charge, and composition with biomolecular signaling, biological kinetics, transportation, and toxicity in both cell culture and animal experiments are under way. These fundamental studies will provide a foundation for engineering the next generation of nanoscale devices. Here, we provide rationales for these studies, review the current progress in studies of the interactions of nanomaterials with biological systems, and provide a perspective on the long-term implications of these findings. PMID- 22524389 TI - Rapid prototyping for biomedical engineering: current capabilities and challenges. AB - A new set of manufacturing technologies has emerged in the past decades to address market requirements in a customized way and to provide support for research tasks that require prototypes. These new techniques and technologies are usually referred to as rapid prototyping and manufacturing technologies, and they allow prototypes to be produced in a wide range of materials with remarkable precision in a couple of hours. Although they have been rapidly incorporated into product development methodologies, they are still under development, and their applications in bioengineering are continuously evolving. Rapid prototyping and manufacturing technologies can be of assistance in every stage of the development process of novel biodevices, to address various problems that can arise in the devices' interactions with biological systems and the fact that the design decisions must be tested carefully. This review focuses on the main fields of application for rapid prototyping in biomedical engineering and health sciences, as well as on the most remarkable challenges and research trends. PMID- 22524391 TI - Flexible and stretchable electronics for biointegrated devices. AB - Advances in materials, mechanics, and manufacturing now allow construction of high-quality electronics and optoelectronics in forms that can readily integrate with the soft, curvilinear, and time-dynamic surfaces of the human body. The resulting capabilities create new opportunities for studying disease states, improving surgical procedures, monitoring health/wellness, establishing human machine interfaces, and performing other functions. This review summarizes these technologies and illustrates their use in forms integrated with the brain, the heart, and the skin. PMID- 22524392 TI - Behaviour and physiology shape the growth accelerations associated with predation risk, high temperatures and southern latitudes in Ischnura damselfly larvae. AB - 1. To better predict effects of climate change and predation risk on prey animals and ecosystems, we need studies documenting not only latitudinal patterns in growth rate but also growth plasticity to temperature and predation risk and the underlying proximate mechanisms: behaviour (food intake) and digestive physiology (growth efficiency). The mechanistic underpinnings of predator-induced growth increases remain especially poorly understood. 2. We reared larvae from replicated northern and southern populations of the damselfly Ischnura elegans in a common garden experiment manipulating temperature and predation risk and quantified growth rate, food intake and growth efficiency. 3. The predator induced and temperature-induced growth accelerations were the same at both latitudes, despite considerably faster growth rates in the southern populations. While the higher growth rates in the southern populations and the high rearing temperature were driven by both an increased food intake and a higher growth efficiency, the higher growth rates under predation risk were completely driven by a higher growth efficiency, despite a lowered food intake. 4. The emerging pattern that higher growth rates associated with latitude, temperature and predation risk were all (partly or completely) mediated by a higher growth efficiency has two major implications. First, it indicates that energy allocation trade-offs and the associated physiological costs play a major role both in shaping large-scale geographic variation in growth rates and in shaping the extent and direction of growth rate plasticity. Secondly, it suggests that the efficiency of energy transfer in aquatic food chains, where damselfly larvae are important intermediate predators, will be higher in southern populations, at higher temperatures and under predation risk. This may eventually contribute to the lengthening of food chains under these conditions and highlights that the prey identity may determine the influence of predation risk on food chain length. PMID- 22524390 TI - Nonlinear dynamics in cardiology. AB - The dynamics of many cardiac arrhythmias, as well as the nature of transitions between different heart rhythms, have long been considered evidence of nonlinear phenomena playing a direct role in cardiac arrhythmogenesis. In most types of cardiac disease, the pathology develops slowly and gradually, often over many years. In contrast, arrhythmias often occur suddenly. In nonlinear systems, sudden changes in qualitative dynamics can, counterintuitively, result from a gradual change in a system parameter-this is known as a bifurcation. Here, we review how nonlinearities in cardiac electrophysiology influence normal and abnormal rhythms and how bifurcations change the dynamics. In particular, we focus on the many recent developments in computational modeling at the cellular level that are focused on intracellular calcium dynamics. We discuss two areas where recent experimental and modeling work has suggested the importance of nonlinearities in calcium dynamics: repolarization alternans and pacemaker cell automaticity. PMID- 22524393 TI - The psych and inflammatory skin disease. PMID- 22524394 TI - Photopatch testing comes of age. PMID- 22524396 TI - Reporting and registering nonmelanoma skin cancers: a compelling public health need. PMID- 22524395 TI - Cutaneous lupus erythematosus and cancer risk. PMID- 22524397 TI - British Association of Dermatologists' guidelines for the management of alopecia areata 2012. PMID- 22524398 TI - Possible usefulness of growth hormone/insulin-like growth factor-I axis in Alzheimer's disease treatment. AB - Alzheimer's disease (AD) has been traditionally conceptualized as a clinicopathological entity, its definite diagnosis requiring the presence of characteristic pathology together with a dementia clinical picture. The fact that certain AD biomarkers show an acceptable sensitivity and specificity to detect AD pathology has shifted the diagnostic paradigm towards a clinicobiological approach. Neuropathological analysis of AD-affected brains reveals extensive atrophy due to neuronal loss, and accumulation of neurofibrillary tangles and neuritic plaques, surrounded by a tract of neuroinflammation and loss of neurons. Recently, emerging evidence supports the concept that AD is also a disorder of metabolic degeneration. Taken together, the neurochemical changes in the brain from patients with AD indicate multiple disturbances and it seems likely that the changes are secondary to more fundamental changes into the brain. There is a physiological decline of the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis with ageing and the possibility that the GH/ IGF-I axis is involved in cognitive deficits has been recognized for several years. The IGF-I is a potent neurotrophic as well neuroprotective factor found in the brain with a wide range of actions in both central and peripheral nervous system. IGF-I is a critical promoter of brain development and neuronal survival and plays a role in neuronal rescue during degenerative diseases. The investigations of GH releasing stimulation tests especially to GHRH in AD are equivocal and in some cases contradictory. When a cholinesterase inhibitor as rivastigmine, a drug for AD, is acutely administered the area under the curve of the GH response to GHRH doubled, showing that rivastigmine is a powerful drug to enhance GH release. Starting with a more accurate diagnosis not of the clinical syndrome, but of underlying molecular defects, that may eventually lead to a personalized, more effective treatment. Hence, the development of novel therapeutic approaches is urgently needed. PMID- 22524399 TI - BMP-2 and bFGF release and in vitro effect on human osteoblasts after adsorption to bone grafts and biomaterials. AB - OBJECTIVES: Combination of scaffolds and growth factors is a promising option for several clinical problems in bone biomaterials. Simplified growth factor loading by adsorption from aqueous solution is one important option for this technology. We evaluated the adsorption followed by PBS rinsing, release and biological effect of transient loading with basic fibroblast growth factor (bFGF) and bone morphogenic protein 2 (BMP-2) on fresh frozen bone, processed bone matrix, collagen, and a ceramic material with immunofluorescence, enzyme-linked immunosorbent assay (ELISA), and qRT-PCR. MATERIALS AND METHODS: The study consisted of three in vitro experiments (immunofluorescence, ELISA, and qRT-PCR) in human osteoblasts (HOB). The first evaluated the adsorption of the growth factors bFGF and BMP-2 to the biomaterials, analyzed by immunofluorescence assays. The second experiment used ELISA to analyze the release of the growth factors from the matrix. The biological effect of the growth factors on HOB was then studied with qRT-PCR experiments as the third step. RESULTS: Strongest sustained release peaks in ELISA were observed in bFGF loading on processed bone matrix (steam-resistant mineralized bone matrix, SMBM) with up to 553 pg/ml medium. BMP-2 loading was less effective in ELISA peak release experiments with up to 257 pg/ml medium in processed bone matrix (SMBM). bFGF showed also higher release peaks in collagen material (192 pg/ml) compared with BMP-2 (101 pg/ml). Cumulative release values 0-72 h were estimated. The expression of runX2, osteocalcin, and alkaline phosphatase as markers for osteoblast activity was correlating. CONCLUSION: The results showed sustained release of BMP-2 and bFGF after transient loading on bone biomaterials with a stronger effect in biological scaffolds. This is interesting for therapeutic growth factor loading as well as insights in natural growth factor matrix deposition during bone healing. PMID- 22524400 TI - Nonadherence to COPD treatment: what have we learned and what do we do next? PMID- 22524401 TI - Transport properties of graphene nanoroads in boron nitride sheets. AB - We demonstrate that the one-dimensional (1D) transport channels that appear in the gap when graphene nanoroads are embedded in boron nitride (BN) sheets are more robust when they are inserted at AB/BA grain boundaries. Our conclusions are based on ab initio electronic structure calculations for a variety of different crystal orientations and bonding arrangements at the BN/C interfaces. This property is related to the valley Hall conductivity present in the BN band structure and to the topologically protected kink states that appear in continuum Dirac models with position-dependent masses. PMID- 22524402 TI - Does pelvic lymph node dissection improve the biochemical relapse-free survival in low-risk prostate cancer patients treated by laparoscopic radical prostatectomy? AB - BACKGROUND AND PURPOSE: The roles and criteria for pelvic lymph node dissection (PLND) are not fully evaluated in patients with low-risk prostate cancer who are treated by laparoscopic radical prostatectomy (LRP). In this study, the outcome of PLND was assessed in terms of the biochemical relapse-free survival rates of low-risk prostate cancer patients who had undergone LRP. PATIENTS AND METHODS: Included were 286 consecutive patients who were treated with LRP without previous endocrine therapy between 2002 and 2006 at our institution. Failure rates for LRP were compared in 139 patients with low-risk prostate cancer between those who underwent PLND (n=85) and those who did not (n=54). Biochemical relapse-free survival for each group was estimated by Kaplan-Meier analysis. RESULTS: The mean number of retrieved lymph nodes was 5.4 +/- 0.4 (range 2-22). The 5- and 7-year biochemical relapse-free survival rates were 90.1% and 88.3% in patients with PLND, and 82.4% and 82.4% in those without PLND (P=0.278), respectively (median follow-up 69.4 mos). None of the 85 patients undergoing PLND had positive lymph nodes. Only one patient had symptomatic lymphocele, and he was treated as an inpatient. The average time needed for PLND was 16 minutes, which corresponded to 7% of the entire operative time. CONCLUSION: These results indicate that the dissection of pelvic lymph nodes is not related to biochemical relapse-free survival. The omission of PLND in patients with low-risk prostate cancer not only does not adversely affect biochemical relapse-free survival, but might decrease the incidence of complication and operative time of LRP. PMID- 22524404 TI - Trapping of bulky guests inside dimeric molecular capsules formed by a deep cavity cavitand. AB - The inclusion of three bulky guests, adamantyl(ferrocenylmethyl)amine (2), adamantylferrocenecarboxylamide (3), and 1,1'-bis(adamantylaminomethyl)ferrocene (4), inside dimeric molecular capsules formed by an octaacid deep-cavity cavitand (1) was investigated using (1)H NMR spectroscopy and voltammetric techniques. Guests 2 and 3 were encapsulated inside 1(2) assemblies, as evidenced by (1)H NMR spectroscopic data. Although both guests are electroactive, the supramolecular complexes 2@1(2) and 3@1(2) showed no voltammetric current responses in the potential window corresponding to the electrochemical oxidation of their ferrocenyl groups. In contrast, each of the adamantyl ends of compound 4 is bound by the cavitand 1, but the central ferrocene residue was not fully encapsulated in this supramolecular assembly and the voltammetric behavior of 4.1(2) was clearly detected. In marked contrast with the experimental results obtained with guests 2 and 3, we could not obtain any evidence for the simultaneous encapsulation of free ferrocene and adamantane inside the 1(2) capsular assembly. PMID- 22524403 TI - CHRNB3 is more strongly associated with Fagerstrom test for cigarette dependence based nicotine dependence than cigarettes per day: phenotype definition changes genome-wide association studies results. AB - AIMS: Nicotine dependence is a highly heritable disorder associated with severe medical morbidity and mortality. Recent meta-analyses have found novel genetic loci associated with cigarettes per day (CPD), a proxy for nicotine dependence. The aim of this paper is to evaluate the importance of phenotype definition (i.e., CPD versus Fagerstrom test for cigarette dependence (FTCD) score as a measure of nicotine dependence) on genome-wide association studies of nicotine dependence. DESIGN: Genome-wide association study. SETTING: Community sample. PARTICIPANTS: A total of 3365 subjects who had smoked at least one cigarette were selected from the Study of Addiction: Genetics and Environment (SAGE). Of the participants, 2267 were European Americans, 999 were African Americans. MEASUREMENTS: Nicotine dependence defined by FTCD score >=4, CPD. FINDINGS: The genetic locus most strongly associated with nicotine dependence was rs1451240 on chromosome 8 in the region of CHRNB3 [odds ratio (OR) = 0.65, P = 2.4 * 10(-8) ]. This association was further strengthened in a meta-analysis with a previously published data set (combined P = 6.7 * 10(-16) , total n = 4200). When CPD was used as an alternate phenotype, the association no longer reached genome-wide significance (beta = -0.08, P = 0.0004). CONCLUSIONS: Daily cigarette consumption and the Fagerstrom Test for Cigarette Dependence show different associations with polymorphisms in genetic loci. PMID- 22524405 TI - The application of genetics approaches to the study of exceptional longevity in humans: potential and limitations. AB - The average life-span of the population of industrialized countries has improved enormously over the last decades. Despite evidence pointing to the role of food intake in modulating life-span, exceptional longevity is still considered primarily an inheritable trait, as pointed out by the description of families with centenarian clusters and by the elevated relative probability of siblings of centenarians to become centenarians themselves. However, rather than being two separate concepts, the genetic origin of exceptional longevity and the more recently observed environment-driven increase in the average age of the population could possibly be explained by the same genetic variants and environmentally modulated mechanisms (caloric restriction, specific nutrients). In support of this hypothesis, polymorphisms selected for in the centenarian population as a consequence of demographic pressure have been found to modulate cellular signals controlled also by caloric restriction. Here, we give an overview of the recent findings in the field of the genetics of human exceptional longevity, of how some of the identified polymorphisms modulate signals also influenced by food intake and caloric restriction, of what in our view have been the limitations of the approaches used over the past years to study genetics (sib pair-, candidate gene association-, and genome-wide association-studies), and briefly of the limitations and the potential of the new, high-throughput, next generation sequencing techniques applied to exceptional longevity. PMID- 22524406 TI - Prevalence of Eimeria infection in yaks on the Qinghai-Tibet Plateau of China. AB - Few data are available on the prevalence of Eimeria spp. in yaks. An observational study was conducted to determine the prevalence of coccidial infection in yaks on the Qinghai-Tibet Plateau of China. A total of 324 fecal samples from 4 counties was examined, and oocysts were identified to the species level on the basis of morphological features. Eimeria oocysts were found in 113 (34.9%) samples. The species detected and their prevalence values included the following: Eimeria zuernii (54.9%), E. pellita (35.4%), E. canadensis (33.6%), E. bovis (23.0%), E. cylindrica (16.8%), E. subspherica (16.8%), E. ellipsoidalis (14.1%), E. brasiliensis (13.3%), E. wyomingensis (8.0%), E. alabamensis (7.1%), E. illinoisensis (5.3%), E. auburnensis (4.4%), E. bombayansis (3.5%), and E. bukidnonensis (2.7%). Mixed infections of 2 to 7 species were found in 66.4% of the animals. There was an age-related difference in the prevalence of infection. The highest prevalence (53.3%) was observed in calves, an intermediate prevalence in yearlings (36.1%), and the lowest was in adults (15.6%). The number of oocysts per g of feces was significantly higher in calves than in adults. More Eimeria species were indentified in calves. Eimeria zuernii was the most prevalent species in calves and adults, whereas in yearling yaks E. pellita was most common. The majority of calves and yearlings showed mixed infection, but adults tended to be infected with 1 species. The prevalence and intensity of Eimeria species were found to show statistically significant differences among different regions in Qinghai Province. PMID- 22524408 TI - pi-Face donation from the aromatic N-substituent of N-heterocyclic carbene ligands to metal and its role in catalysis. AB - In this work, we calculate the redox potential in a series of Ir and Ru complexes bearing a N-heterocyclic carbene (NHC) ligand presenting different Y groups in the para position of the aromatic N-substituent. The calculated redox potentials excellently correlate with the experimental DeltaE(1/2) potentials, offering a handle to rationalize the experimental findings. Analysis of the HOMO of the complexes before oxidation suggests that electron-donating Y groups destabilize the metal centered HOMO. Energy decomposition of the metal-NHC interaction indicates that electron-donating Y groups reinforce this interaction in the oxidized complexes. Analysis of the electron density in the reduced and oxidized states of representative complexes indicates a clear donation from the C(ipso) of the N-substituents to an empty d orbital on the metal. In case of the Ru complexes, this mechanism involves the Ru-alkylidene moiety. All of these results suggest that electron-donating Y groups render the aromatic N-substituent able to donate more density to electron-deficient metals through the C(ipso) atom. This conclusion suggests that electron-donating Y groups could stabilize higher oxidation states during catalysis. To test this hypothesis, we investigated the effect of differently donating Y groups in model reactions of Ru-catalyzed olefin metathesis and Pd-catalyzed C-C cross-coupling. Consistent with the experimental results, calculations indicate an easier reaction pathway if the N-substituent of the NHC ligand presents an electron-donating Y group. PMID- 22524409 TI - Non-inflammatory centrilobular sinusoidal fibrosis in pediatric liver transplant recipients under tacrolimus withdrawal. AB - AIM: We hypothesized that non-inflammatory central sinusoidal fibrosis (NICSF) is a sign of inadequate immunosuppression in children after living-donor liver transplantation. METHODS: In study 1, liver biopsy specimens of 158 patients who had undergone liver transplantation 10 years before or earlier were examined to study the relationship between NICSF and tacrolimus withdrawal. In study 2, tacrolimus was resumed in 18 patients with NICSF in follow-up biopsies after tacrolimus withdrawal and the subsequent histological changes were analyzed. RESULTS: In study 1, after excluding 95 patients with ongoing vascular, biliary and immunological complications, 47 of 63 patients (75%) had NICSF and significant (P = 0.0285) contributing factors were found to be episodes of tacrolimus withdrawal. In study 2, during withdrawal, tacrolimus administration had been discontinued in nine, reduced to once per month in three, twice per month in two, once a week in two and twice a week in two patients, and then finally resumed to daily administration in all. NICSF was scored as 4 in one, 3 in seven, 2 in four and 1 in six patients using modified Dixon's criteria (score, 0-4). After resumption, NICSF was improved in six, unchanged in 11 and aggravated in one patient. C4d deposition was improved in all NICSF-improved patients. Incidence of positive C4d prior to resumption was significantly greater in improved patients than non-improved patients (P = 0.0245). CONCLUSION: NICSF might be an indicator of inadequate immunosuppression in long-term followed recipients and its mechanism may be due to immune reactions including humoral immunity. PMID- 22524410 TI - Triple framework interpenetration and immobilization of open metal sites within a microporous mixed metal-organic framework for highly selective gas adsorption. AB - A three-dimensional triply interpenetrated mixed metal-organic framework, Zn(2)(BBA)(2)(CuPyen).G(x) (M'MOF-20; BBA = biphenyl-4,4'-dicarboxylate; G = guest solvent molecules), of primitive cubic net was obtained through the solvothermal reaction of Zn(NO(3))(2), biphenyl-4,4'-dicarboxylic acid, and the salen precursor Cu(PyenH(2))(NO(3))(2) by a metallo-ligand approach. The triple framework interpenetration has stabilized the framework in which the activated M'MOF-20a displays type-I N(2) gas sorption behavior with a Langmuir surface area of 62 m(2) g(-1). The narrow pores of about 3.9 A and the open metal sites on the pore surfaces within M'MOF-20a collaboratively induce its highly selective C(2)H(2)/CH(4) and CO(2)/CH(4) gas separation at ambient temperature. PMID- 22524407 TI - Complete genome sequence, lifestyle, and multi-drug resistance of the human pathogen Corynebacterium resistens DSM 45100 isolated from blood samples of a leukemia patient. AB - BACKGROUND: Corynebacterium resistens was initially recovered from human infections and recognized as a new coryneform species that is highly resistant to antimicrobial agents. Bacteremia associated with this organism in immunocompromised patients was rapidly fatal as standard minocycline therapies failed. C. resistens DSM 45100 was isolated from a blood culture of samples taken from a patient with acute myelocytic leukemia. The complete genome sequence of C. resistens DSM 45100 was determined by pyrosequencing to identify genes contributing to multi-drug resistance, virulence, and the lipophilic lifestyle of this newly described human pathogen. RESULTS: The genome of C. resistens DSM 45100 consists of a circular chromosome of 2,601,311 bp in size and the 28,312-bp plasmid pJA144188. Metabolic analysis showed that the genome of C. resistens DSM 45100 lacks genes for typical sugar uptake systems, anaplerotic functions, and a fatty acid synthase, explaining the strict lipophilic lifestyle of this species. The genome encodes a broad spectrum of enzymes ensuring the availability of exogenous fatty acids for growth, including predicted virulence factors that probably contribute to fatty acid metabolism by damaging host tissue. C. resistens DSM 45100 is able to use external L-histidine as a combined carbon and nitrogen source, presumably as a result of adaptation to the hitherto unknown habitat on the human skin. Plasmid pJA144188 harbors several genes contributing to antibiotic resistance of C. resistens DSM 45100, including a tetracycline resistance region of the Tet W type known from Lactobacillus reuteri and Streptococcus suis. The tet(W) gene of pJA144188 was cloned in Corynebacterium glutamicum and was shown to confer high levels of resistance to tetracycline, doxycycline, and minocycline in vitro. CONCLUSIONS: The detected gene repertoire of C. resistens DSM 45100 provides insights into the lipophilic lifestyle and virulence functions of this newly recognized pathogen. Plasmid pJA144188 revealed a modular architecture of gene regions that contribute to the multi-drug resistance of C. resistens DSM 45100. The tet(W) gene encoding a ribosomal protection protein is reported here for the first time in corynebacteria. Cloning of the tet(W) gene mediated resistance to second generation tetracyclines in C. glutamicum, indicating that it might be responsible for the failure of minocycline therapies in patients with C. resistens bacteremia. PMID- 22524411 TI - Traumatic chiasmal syndrome. AB - A case of closed head trauma, harbouring bitemporal hemianopsia is presented. The MRI evaluation describes chiasmal contusion as the cause behind visual deficits. Chiasmal injury may occur even in the absence bony chip impingement and features of hypo-pituitarism. Such a situation warrants MRI evaluation of optic pathways. PMID- 22524412 TI - "I am tired but if I don't try to have sex, my wife will think I've been fooling around in the city": work, migration, and sex among Vietnamese migrant laborers. AB - Mostly operating from a risk and risk-reduction paradigm, existing research on migrants in Vietnam tends to conceptualize sex and risky sexual behaviors as isolated life domains. This study begins to develop a contextually rich understanding of migrants' sex lives by examining the relationships among sex, work, and the constant pendulum-like migrating movements of 23 Vietnamese married migrants in Hanoi and Ho Chi Minh City. Using data from in-depth interviews, it was found that most participants had no sex in the city; this was followed by visits to the home village, where they had sex with their spouses as often as possible to make up for the "long drought" in the city. Within this sexual schema, sex came secondary, and even peripherally, to migrants' working lives; thus, exhaustion from work was cited by migrants as the overwhelming factor leading to their sexual problems. This study suggests that migrants' intimate lives are more strongly linked to their working lives than has previously been recognized, and that their sexual behaviors should be viewed in tandem with the hardships of their working lives. PMID- 22524413 TI - Multicolored pH-tunable and activatable fluorescence nanoplatform responsive to physiologic pH stimuli. AB - Tunable, ultra-pH responsive fluorescent nanoparticles with multichromatic emissions are highly valuable in a variety of biological studies, such as endocytic trafficking, endosome/lysosome maturation, and pH regulation in subcellular organelles. Small differences (e.g., <1 pH unit) and yet finely regulated physiological pH inside different endocytic compartments present a huge challenge to the design of such a system. Herein, we report a general strategy to produce pH-tunable, highly activatable multicolored fluorescent nanoparticles using commonly available pH-insensitive dyes with emission wavelengths from green to near IR range. The primary driving force of fluorescence activation between the ON (unimer) and OFF (micelle) states is the pH-induced micellization. Among three possible photochemical mechanisms, homo Forster resonance energy transfer (homoFRET)-enhanced decay was found to be the most facile strategy to render ultra-pH response over the H-dimer and photoinduced electron transfer (PeT) mechanisms. Based on this insight, we selected several fluorophores with small Stoke shifts (<40 nm) and established a panel of multicolored nanoparticles with wide emission range (500-820 nm) and different pH transitions. Each nanoparticle maintained the sharp pH response (ON/OFF < 0.25 pH unit) with corresponding pH transition point at pH 5.2, 6.4, 6.9, and 7.2. Incubation of a mixture of multicolored nanoparticles with human H2009 lung cancer cells demonstrated sequential activation of the nanoparticles inside endocytic compartments directly correlating with their pH transitions. This multicolored, pH-tunable nanoplatform offers exciting opportunities for the study of many important cell physiological processes, such as pH regulation and endocytic trafficking of subcellular organelles. PMID- 22524414 TI - Molecular thin films on solid surfaces: mechanisms of melting. AB - We use molecular dynamics simulations to study the melting of pentane and hexane monolayers adsorbed on the basal plane of graphite. For both of these systems, the temperature-dependent structures and the melting temperatures agree well with experiment. A detailed analysis reveals that a mechanism involving the promotion of molecules to the second layer underlies melting in these systems. In the second-layer promotion mechanism, a small fraction of molecules transition into the second layer around the melting temperature, leaving vacant space in the first layer to facilitate disordering. The second-layer promotion mechanism arises because of the weaker molecule-surface interaction in our study than that in previous studies. The weaker molecule-surface interaction is consistent with experimental temperature-programmed desorption studies. PMID- 22524416 TI - SOP: physical examination and laboratory testing for men with erectile dysfunction. AB - INTRODUCTION: Physical examination and laboratory evaluation of men with erectile dysfunction (ED) are opportunities to identify potentially life-threatening etiologies and comorbid conditions. AIM: To review genital anatomy, identify any physical abnormalities, assess for comorbid conditions, and reveal significant risk factors for ED. METHODS: Expert opinion was based on evidence-based medical literature and consensus discussions between members of this International Society for Sexual Medicine (ISSM) standards committee. RESULTS: For men with ED, a general examination including blood pressure and pulse measurements and a focused genital exam are advised. Fasting blood sugar, serum total testosterone, prolactin levels, and a lipid profile may reveal significant comorbid conditions. CONCLUSIONS: Though physical examination and laboratory evaluation of most men with ED may not reveal the exact diagnosis, these opportunities to identify critical comorbid conditions should not be missed. PMID- 22524415 TI - Diagnostic utility of the oesophageal balloon distension test in the evaluation of oesophageal chest pain. AB - BACKGROUND: Oesophageal balloon distension test (EBDT) has been advocated for the evaluation of functional oesophageal noncardiac chest pain (NCCP), but its diagnostic utility remains unclear. AIM: To prospectively assess the diagnostic yield of EBDT in clinical practice and compare its yield with standard oesophageal tests. METHODS: Over a period of 6 years, patients with chest pain and negative cardiac work-up underwent sequential testing with endoscopy/biopsy, oesophageal manometry, 24 h pH study and EBDT to elucidate an oesophageal source for their symptoms. Patients with a definite abnormality, for example, erosive oesophagitis on oesophagogastroduodenoscopy (EGD) were designated as having positive test and excluded from further work up. RESULTS: Of 348 (m/f = 105/243) suspected NCCP patients, 16 (5%) were excluded; 332 (95%) underwent oesophageal testing. Among these, 48 (14%) had macro/microscopic oesophagitis on endoscopy, 7 (2%) had achalasia and 96 (28%) had excessive acid reflux (pH study). The remaining 181 (52%) patients underwent EBDT; 128 (37%) had oesophageal hypersensitivity. Chest pain was reproduced in 97/128 (75%) subjects. There were no adverse effects. CONCLUSIONS: Oesophageal testing can reveal an oesophageal source for chest pain in 86% of NCCP subjects. The majority (42%) of patients had gastro-oesophageal reflux disease (GERD). Oesophageal balloon distension test identified hypersensitivity in over one-third of subjects. The oesophageal balloon distension test provides useful diagnostic information and should be performed routinely in patients with NCCP after excluding GERD. PMID- 22524417 TI - alpha-Fe2O3 nanoparticle-loaded carbon nanofibers as stable and high-capacity anodes for rechargeable lithium-ion batteries. AB - alpha-Fe(2)O(3) nanoparticle-loaded carbon nanofiber composites were fabricated via electrospinning FeCl(3).6H(2)O salt-polyacrylonitrile precursors in N,N dimethylformamide solvent and the subsequent carbonization in inert gas. Scanning electron microscopy, transmission electron microscopy, energy dispersive X-ray spectroscopy, X-ray photoelectron spectroscopy, X-ray diffraction, and elemental analysis were used to study the morphology and composition of alpha-Fe(2)O(3) carbon nanofiber composites. It was indicated that alpha-Fe(2)O(3) nanoparticles with an average size of about 20 nm have a homogeneous dispersion along the carbon nanofiber surface. The resultant alpha-Fe(2)O(3)-carbon nanofiber composites were used directly as the anode material in rechargeable lithium half cells, and their electrochemical performance was evaluated. The results indicated that these alpha-Fe(2)O(3)-carbon nanofiber composites have high reversible capacity, good capacity retention, and acceptable rate capability when used as anode materials for rechargeable lithium-ion batteries. PMID- 22524418 TI - Onset, duration and efficacy of four methods of local anesthesia of the horn bud in calves. AB - OBJECTIVE: To determine the onset, duration and efficacy of four local anesthetic methods for the horn bud in calves. STUDY DESIGN: Crossover study. ANIMALS: Eight, 2 month-old Holstein Friesian bull calves. METHODS: Calves were subjected to one of the four following treatments: 1) cornual nerve block (C), 2) ring block (R), 3) cornual nerve block using a percutaneous jet delivery technique (JET) all using 2% lidocaine with epinephrine (0.01 mg mL(-1)), and 4) topical eutectic mixture of local anesthetics (EMLA) cream. A peripheral nerve stimulator was used to assess cutaneous sensation over the horn bud using a graded response. Onset, duration and efficacy of anesthesia were determined. RESULTS: The efficacy of the blocks was as follows: C 87.5%, R 100%, JET 37.5%, EMLA 0%. The median onset time and duration of anesthesia for C and R were: 2 (range 0.5-5) and 304 (range 107-512), and 3.25 (range 1-9) and 147 (range 62-299) minutes, respectively. Three of eight JET injections had a median onset and duration of 8 (range 0.5-9) and 132 (range 101-155) minutes, respectively. The duration of the C block was significantly longer than the R block (p = 0.047). CONCLUSIONS AND CLINICAL RELEVANCE: The relatively rapid onset and long duration of anesthesia with C or R blocks using 2% lidocaine with epinephrine validates their practical use in dehorning calves while jet injection and EMLA cream provided insufficient analgesia to be clinically useful. The efficacy of the C block requires further study. PMID- 22524419 TI - Prediction of recurrence of hepatocellular carcinoma after curative hepatectomy using preoperative Lens culinaris agglutinin-reactive fraction of alpha fetoprotein. AB - AIM: Lens culinaris agglutinin A-reactive fraction of alpha-fetoprotein (AFP L3) status has been reported to be an independent prognostic factor in patients with hepatocellular carcinoma (HCC). In this study, we evaluated the clinical usefulness of measuring preoperative AFP-L3 to predict the recurrence and prognosis of HCC after curative hepatectomy. METHODS: One hundred and forty-two HCC patients who underwent curative hepatectomy were examined for the correlation between preoperative tumor marker, including AFP, des-gamma-carboxy prothrombin (DCP) and AFP-L3, and clinicopathological variables. The prognostic factors of disease-free survival rates and overall survival rates were also determined using clinicopathological variables including these three tumor markers. RESULTS: There were similar tendencies in the relationship between these three markers and malignant behaviors including lower grade tumor differentiation or vascular invasion. In multivariate analysis, increased AFP-L3 value (P = 0.019) was found to be an independent prognostic factor of disease-free survival after curative hepatectomy. In addition, elevated DCP (P = 0.013) and AFP-L3 values (P = 0.012) were found to be independent prognostic factors. Furthermore, the preoperative AFP-L3 value in the patients with early recurrence (within 1 year after hepatectomy) was significantly higher than that in those without early recurrence (26.9 +/- 19.5 % vs 14.2 +/- 19.8 %, P = 0.047). CONCLUSION: Preoperative AFP L3 value was strongly correlated to disease-free and overall survival rate and the timing of recurrence, so it appears that it would be useful to predict the recurrence and prognosis of HCC after curative hepatectomy. PMID- 22524421 TI - Inflammatory bowel disease: risk factors for adverse pregnancy outcome and the impact of maternal weight gain. AB - OBJECTIVE: To identify risk factors for adverse pregnancy outcome in women with inflammatory bowel disease (IBD) and to assess the effect of maternal pre pregnancy weight and weight gain during pregnancy on pregnancy outcome. METHODS: A retrospective, matched control study of all gravid women with IBD treated in a single tertiary center. Data were compared with healthy controls matched to by age, parity and pre-pregnancy BMI in a 3:1 ratio. RESULTS: Overall, 300 women were enrolled, 75 women in the study group (28 with ulcerative colitis and 47 with Crohn's disease) and 225 in the control group. The rates of preterm delivery and small for gestational age were higher in the study group (13.3 vs. 5.3% p = 0.02 and 6.7 vs. 0.9%, p = 0.004). The rate of cesarean section (36 vs. 19.1%; p = 0.002), NICU admission (10.7 vs. 4.0%, p = 0.03) and low 5-Min Apgar (4.0 vs. 0.4%, p = 0.02) were increased in the study group. Disease activity within 3 months of conception [OR 8.4 (1.3-16.3)] and maternal weight gain of less than 12 kg. [OR 3.6 (1.1-12.2)] were associated with adverse pregnancy outcome. CONCLUSION: Active disease at conception and inappropriate weight gain during pregnancy are associated with increased adverse pregnancy outcome in patients with IBD. PMID- 22524422 TI - Glycobiology of immune responses. AB - Unlike their protein "roommates" and their nucleic acid "cousins," carbohydrates remain an enigmatic arm of biology. The central reason for the difficulty in fully understanding how carbohydrate structure and biological function are tied is the nontemplate nature of their synthesis and the resulting heterogeneity. The goal of this collection of expert reviews is to highlight what is known about how carbohydrates and their binding partners-the microbial (non-self), tumor (altered self), and host (self)-cooperate within the immune system, while also identifying areas of opportunity to those willing to take up the challenge of understanding more about how carbohydrates influence immune responses. In the end, these reviews will serve as specific examples of how carbohydrates are as integral to biology as are proteins, nucleic acids, and lipids. Here, we attempt to summarize general concepts on glycans and glycan-binding proteins (mainly C-type lectins, siglecs, and galectins) and their contributions to the biology of immune responses in physiologic and pathologic settings. PMID- 22524424 TI - Glycans, galectins, and HIV-1 infection. AB - During sexual transmission, HIV-1 must overcome physiological barriers to establish a founder cell population. Viral adhesion represents a bottleneck for HIV-1 propagation that the virus widens by exploiting some specific host factors. Recognition of oligomannosyl glycans of gp120 by C-type lectins is one such example. Recent works suggest that complex glycans of gp120 are recognized by another host lectin, galectin-1. This interaction results in rapid association of HIV-1 to susceptible cells and facilitates infection. The peculiar presentation of complex glycans on gp120 seems to impart specificity for galectin-1, as another member of the same family, galectin-3, is unable to bind gp120 or enhance HIV-1 infection. Other studies have shown that galectin-9 could also increase HIV 1 infectivity but via an indirect mechanism. Thus, current research suggests that galectins play various roles in HIV-1 pathogenesis. Drug discovery approaches targeting host lectins at early steps could benefit the current arsenal of antiretrovirals. PMID- 22524425 TI - Beyond glycoproteins as galectin counterreceptors: tumor-effector T cell growth control via ganglioside GM1 [corrected]. AB - Glycoprotein glycan chains, by virtue of structure, topology of presentation and connection to signal-inducing units, are functional galectin counterreceptors. As example, cross-linking of the alpha(5)beta(1) integrin by galectin-1 on carcinoma cells leads to G(1) arrest or anoikis. Contact-dependent switching from proliferation to differentiation in cultured neuroblastoma cells (SK-N-MC) also utilizes galectin-1. Activity enhancement of a cell surface sialidase underlies the shift in glycan display to ganglioside GM1. Its pentasaccharide within microdomains becomes the target. Similarly, this recognition pair is upregulated upon T cell activation. Cross-linking of GM1 along with associated alpha(4)/alpha(5)beta(1) integrins elicits Ca(2+)-influx via TRPC5 channels as the relevant response for T effector cell (T(eff)) suppression. Unlike T(eff) cells from wild-type mice, those from genetically altered mice lacking GM1 are not suppressed by galectin-1 or regulatory T cells. Similarly, in the context of GM1 deficiency in NOD mice, T(eff) cells are associated with resistance to regulatory T cell suppression, which is reversed by applied GM1. The broad array of glycosphingolipid structures suggests the possible existence of several novel counterreceptors targeted to endogenous lectins, with sulfatide-galectin-4 interplay within apical delivery serving as recent example. PMID- 22524426 TI - Discovery and optimization of new benzimidazole- and benzoxazole-pyrimidone selective PI3Kbeta inhibitors for the treatment of phosphatase and TENsin homologue (PTEN)-deficient cancers. AB - Most of the phosphoinositide-3 kinase (PI3K) kinase inhibitors currently in clinical trials for cancer treatment exhibit pan PI3K isoform profiles. Single PI3K isoforms differentially control tumorigenesis, and PI3Kbeta has emerged as the isoform involved in the tumorigenicity of PTEN-deficient tumors. Herein we describe the discovery and optimization of a new series of benzimidazole- and benzoxazole-pyrimidones as small molecular mass PI3Kbeta-selective inhibitors. Starting with compound 5 obtained from a one-pot reaction via a novel intermediate 1, medicinal chemistry optimization led to the discovery of compound 8, which showed a significant activity and selectivity for PI3Kbeta and adequate in vitro pharmacokinetic properties. The X-ray costructure of compound 8 in PI3Kdelta showed key interactions and structural features supporting the observed PI3Kbeta isoform selectivity. Compound 8 achieved sustained target modulation and tumor growth delay at well tolerated doses when administered orally to SCID mice implanted with PTEN-deficient human tumor xenografts. PMID- 22524423 TI - Multifarious roles of sialic acids in immunity. AB - Sialic acids are a diverse family of monosaccharides widely expressed on all cell surfaces of vertebrates and so-called "higher" invertebrates, and on certain bacteria that interact with vertebrates. This overview surveys examples of biological roles of sialic acids in immunity, with emphasis on an evolutionary perspective. Given the breadth of the subject, the treatment of individual topics is brief. Subjects discussed include biophysical effects regulation of factor H; modulation of leukocyte trafficking via selectins; Siglecs in immune cell activation; sialic acids as ligands for microbes; impact of microbial and endogenous sialidases on immune cell responses; pathogen molecular mimicry of host sialic acids; Siglec recognition of sialylated pathogens; bacteriophage recognition of microbial sialic acids; polysialic acid modulation of immune cells; sialic acids as pathogen decoys or biological masks; modulation of immunity by sialic acid O-acetylation; sialic acids as antigens and xeno autoantigens; antisialoglycan antibodies in reproductive incompatibility; and sialic-acid-based blood groups. PMID- 22524427 TI - Carboxyhemoglobin levels during human inflammation. PMID- 22524428 TI - A review of monochromatic excimer light in vitiligo. AB - Phototherapy is a mainstay of vitiligo treatment and has varying rates of efficacy. Narrowband ultraviolet (UV) B (NB-UVB) and UVA have been used for decades, but it is only recently that monochromatic excimer light (MEL) was developed for use in dermatology and adapted for the treatment of vitiligo. The specific 308-nm radiation wavelength is delivered in a targeted form by the xenon chloride excimer laser and is also available in an incoherent form that is commonly referred to as the excimer lamp. MEL administered by both laser and lamp has shown efficacy superior to NB-UVB for the treatment of vitiligo and induces more changes at the cellular level than conventional UVB modalities. The excimer laser is effective in adults and children with vitiligo in all skin types as monotherapy or in combination with other established vitiligo therapeutics. Treatment regimens studied included excimer laser two to three times weekly for up to 36 weeks. Patients commonly achieved > 75% repigmentation. The laser has also been used in combination with topical corticosteroids, calcineurin inhibitors and vitamin D analogues, as well as surgery, thus further expanding treatment options for patients with vitiligo. The excimer lamp has been used for treatments one to three times a week for up to 24 weeks and was found to be equal to excimer laser in a head-to-head comparison. It has also been used in combination with topical corticosteroids and oral vitamin E. Both MEL modalities have a limited adverse side-effect profile. Long-term effects are yet to be determined; however, based on available data on UVB phototherapy as well as the properties of MEL devices, there is probably only a minimal increased malignancy risk. PMID- 22524429 TI - Impact of vertical loading on the implant-bone interface. AB - OBJECTIVES: The main aim of this study was to evaluate the impact of vertical loading occurring during removal of cemented restorations on the implant-bone interface. METHODS: Thirty-six titanium implants (Camlog 4.3 * 9 mm) were placed 1 mm supraosseous in the frontal skull of four minipigs. After a 13 week healing period the implants were exposed and the implant stability was measured. Three implants per minipig were vertically loaded using 20 or 100 impulses, respectively with an 18 Ns impulse imitating a crown removal. Three implants were left unloaded as control. The animals were sacrificed after 13 or 18 weeks. The harvested specimens were analyzed using scanning electron microscopy (SEM), light and fluorescence microscopy. RESULTS: No post operative complications or deaths of the minipigs occurred. All implants osseointegrated. The average bone-implant contact area (BIC) was 78 +/- 5.1%. No statistically significant difference could be found when comparing the BIC areas of the control and the experimental groups between the sacrificed animals at 13 weeks and 18 weeks (P > 0.05). Therefore, the results of each subgroup were pooled. No significant differences regarding the BIC area could be detected between the control and the experimental groups (P > 0.05). Except one failing implant no cracks due to vertical loading could be evaluated in the SEM. Fluorescence microscopy revealed a significantly higher bone remodeling activity in the vertically loaded groups. CONCLUSIONS: Removal of cemented implant restorations seems not to have an impact on the mechanical implant stability, but seems to increase bone remodeling activity. PMID- 22524431 TI - Determining a performance envelope for capture of kidney stones functionalized with superparamagnetic microparticles. AB - BACKGROUND AND PURPOSE: Complete stone removal is important in upper tract stone surgery. Unfortunately, even with the latest technologic advances, current methods only achieve 50% to 80% complete clearance of upper tract stones at the time of primary treatment. Our group has explored the novel use of peptide-coated iron oxide superparamagnetic microparticles that bind to calcium stones, allowing for extraction of these stones with magnetic tools. We present analytic and numeric models that characterize stone attraction performance for feasible magnetic tool sizes and stone magnetization levels. MATERIALS AND METHODS: Magnetostatics equations are applied to a simplified, one-dimensional scenario of a spherical target coated with a variable amount of superparamagnetic particles, placed under the influence of a magnetic field aimed at vertical attraction (capture) of the target. Equations are parameterized in terms of (a) target size, ranging from 0.5 mm to 3 mm to represent stone sizes of interest, (b) effective magnetization per surface area delivered by the particle binding chemistry, and (c) distance to the field source. RESULTS: Target capture is predicted to be effective in the low, single-digit millimeter distance range, favoring smaller stones and then up to a practical upper limit of 3 mm diameter. Higher iron loading chemistries have a direct improvement in magnetic force and therefore increase the viability of the technique, albeit along an asymptotic trendline. CONCLUSIONS: We are able to characterize the potential for kidney stone capture via magnetic attraction. Computer-developed models show good correlation with experimental results using actual magnetized stone samples. Future research efforts can use the proposed techniques to estimate the performance impact of advanced magnetic tools and surface chemistries. PMID- 22524430 TI - Genetics of longevity. data from the studies on Sicilian centenarians. AB - The demographic and social changes of the past decades have determined improvements in public health and longevity. So, the number of centenarians is increasing as a worldwide phenomenon. Scientists have focused their attention on centenarians as optimal model to address the biological mechanisms of "successful and unsuccessful ageing". They are equipped to reach the extreme limits of human life span and, most importantly, to show relatively good health, being able to perform their routine daily life and to escape fatal age-related diseases, such as cardiovascular diseases and cancer. Thus, particular attention has been centered on their genetic background and immune system. In this review, we report our data gathered for over 10 years in Sicilian centenarians. Based on results obtained, we suggest longevity as the result of an optimal performance of immune system and an over-expression of anti-inflammatory sequence variants of immune/inflammatory genes. However, as well known, genetic, epigenetic, stochastic and environmental factors seem to have a crucial role in ageing and longevity. Epigenetics is associated with ageing, as demonstrated in many studies. In particular, ageing is associated with a global loss of methylation state. Thus, the aim of future studies will be to analyze the weight of epigenetic changes in ageing and longevity. PMID- 22524432 TI - An evolutionary algorithm for de novo optimization of functional transition metal compounds. AB - Development of functional inorganic and transition metal compounds is usually based on ad hoc qualified guesses, with computational methods playing a lesser role than in drug discovery. A de novo evolutionary algorithm (EA) is presented that automatically generates transition metal complexes using a search space constrained around chemically meaningful structures assembled from three kinds of fragments: a part shared by all structures and typically containing the metal center itself, one or several parts consisting of ligand skeletons, and unconstrained parts that may grow and vary freely. In EA optimizations, using a cost-efficient fitness function based on a linear quantitative structure-activity relationship model for catalytic activity, we demonstrate the capabilities of the method by retracing the transition from the first-generation, phosphine-based Grubbs olefin metathesis catalysts to second-generation catalysts containing N heterocyclic carbene ligands instead of phosphines. Moreover, DFT calculations on selected high-fitness, last-generation structures from these evolutionary experiments suggest that, in terms of catalytic activity, the structures arrived at by virtual evolution alone compare favorably with existing, highly active catalysts. The structures from the evolution experiments are, however, complex and probably difficult to synthesize, but a set of manually simplified variations thereof might form the leads for a new generation of Grubbs catalysts. PMID- 22524433 TI - Clinical effects of isoflurane and sevoflurane in lambs. AB - OBJECTIVE: To compare isoflurane and sevoflurane in lambs undergoing prolonged anaesthesia for spinal surgery. STUDY DESIGN: Prospective randomised clinical study. ANIMALS: Eighteen Scottish blackface lambs 3-6 weeks of age and weighing 10-17 kg. METHODS: After intramuscular medetomidine, anaesthesia was induced and maintained with either isoflurane (group I) or sevoflurane (group S) delivered in oxygen. Meloxicam, morphine, a constant rate infusion of ketamine and atracurium were given intravenously (IV) during surgery. Lungs were ventilated to maintain normocapnia. with peak inspiratory pressures of 20-25 cmH(2) O. Ephedrine or dextran 40% was administered when mean arterial pressure (MAP) was <55 mmHg. Intrathecal morphine, and IV meloxicam and edrophonium were injected before recovery. Time to loss of palpebral reflex (TLPR) upon induction, cardiorespiratory variables, time at first swallowing and other movement, tracheal extubation, vocalisation, spontaneous head lifting (>1 minute), reunion with the ewe, and the number of MAP treatments were recorded. Statistical analysis utilised anova, Mann-Whitney, t-test or Pearson's correlation test as relevant. p < 0.05 was considered significant. RESULTS: End-tidal carbon dioxide (mean +/- SD) was significantly lower in group S (5.5 +/- 0.6 kPa) than in group I (5.8 +/- 0.5 kPa) while MAP (70 +/- 11 mmHg) and diastolic arterial blood pressure (60 +/- 11 mmHg) were higher in group S than in group I (65 +/- 12 and 54 +/- 11 mmHg, respectively). No differences were found with TLPR and MAP treatments. Time (median, range) from end of anaesthesia to ewe-lamb reunion was briefer (p = 0.018) in group S (48, 20-63 minutes). CONCLUSION: Isoflurane and sevoflurane are both suitable for maintaining general anaesthesia in lambs although sevoflurane, as used in this study, allows a more rapid reunion with the ewe. CLINICAL RELEVANCE: The principal advantage of sevoflurane over isoflurane during prolonged anaesthesia in lambs is a more rapid recovery. PMID- 22524434 TI - England's legislation on smoking in indoor public places and work-places: impact on the most exposed children. AB - AIMS: To examine whether English legislation to make virtually all indoor public places and work-places smoke-free on 1 July 2007 displaced smoking into the home and hence increased the proportion of children exposed to levels of second-hand smoke known to be detrimental to health. DESIGN: Repeated cross-sectional study with data from 10 annual surveys undertaken from 1996 to 2008. SETTING: England. PARTICIPANTS: Nationally representative samples of non-smoking children aged 4-15 years old living in private households. MEASUREMENTS: Salivary cotinine, parental smoking status, whether smoking is allowed within the house, socio-demographic variables. FINDINGS: The proportion of children exposed to damaging levels of second-hand smoke (defined as those with cotinine levels >1.7 ng/ml) has fallen over time, from 23.5% in 1996 to 12.6% in 2008. The legislation was not associated with further changes in the proportion of children above this threshold-the odds of having cotinine >1.7 ng/ml did not change after adjustment for the pre-legislative trend and confounders (odds ratio: 1.0, 95% confidence interval: 0.78, 1.4). Non-significant associations were also found when examining children by parental or household smoking status. CONCLUSIONS: Legislation to prohibit smoking in indoor public places and work-places does not increase the proportion of children exposed to damaging levels of second-hand smoke. Even in a country with a strong tobacco control climate, a significant proportion of children remain highly exposed to second-hand smoke and future policies need to include interventions to reduce exposure among these children. PMID- 22524435 TI - Speciation of copper(II) complexes in an ionic liquid based on choline chloride and in choline chloride/water mixtures. AB - A deep-eutectic solvent with the properties of an ionic liquid is formed when choline chloride is mixed with copper(II) chloride dihydrate in a 1:2 molar ratio. EXAFS and UV-vis-near-IR optical absorption spectroscopy have been used to compare the coordination sphere of the cupric ion in this ionic liquid with that of the cupric ion in solutions of 0.1 M of CuCl(2).2H(2)O in solvents with varying molar ratios of choline chloride and water. The EXAFS data show that species with three chloride ions and one water molecule coordinated to the cupric ion as well as species with two chloride molecules and two water molecules coordinated to the cupric ion are present in the ionic liquid. On the other hand, a fully hydrated copper(II) ion is formed in an aqueous solution free of choline chloride, and the tetrachlorocuprate(II) complex forms in aqueous choline chloride solutions with more than 50 wt % of choline chloride. In solutions with between 0 and 50 wt % of choline chloride, mixed chloro-aquo complexes occur. Upon standing at room temperature, crystals of CuCl(2).2H(2)O and of Cu(choline)Cl(3) formed in the ionic liquid. Cu(choline)Cl(3) is the first example of a choline cation coordinating to a transition-metal ion. Crystals of [choline](3)[CuCl(4)][Cl] and of [choline](4)[Cu(4)Cl(10)O] were also synthesized from molecular or ionic liquid solvents, and their crystal structures were determined. PMID- 22524436 TI - Development of an immunoassay for the derived-peptide of chromogranin A, vasostatin-I (1-76): assessment of severity in patients with sepsis. AB - CONTEXT: Proteolytic fragments of chromogranin A (CgA) including the CgA 1-76 fragment (called vasostatin-I [VS-I]) could be a useful biomarker of sepsis, but there is no available immunoassay. METHODS: A sandwich ELISA for VS-I was developed, and plasma VS-I was measured in 30 healthy controls and 60 critically ill patients with sepsis. RESULTS: The ELISA showed intra- and inter-assay coefficients of variations (CVs) below 4 and 9%. Plasma VS-I was significantly increased compared with controls in patients with sepsis, severe sepsis, and sepsis shock (p < 0.0001). Receiver operating curve (ROC) analyses indicated that plasma VS-I was more sensitive and specific than plasma CgA to diagnose sepsis and to assess its severity. CONCLUSIONS: The measurements of plasma VS-I with this new ELISA may be useful for the clinical investigation of patients with sepsis. PMID- 22524437 TI - Mitochondrial stress causes increased succination of proteins in adipocytes in response to glucotoxicity. AB - 2SC [S-(2-succino)-cysteine] is a chemical modification formed by a Michael addition reaction of fumarate with cysteine residues in proteins. Formation of 2SC, termed 'succination' of proteins, increases in adipocytes grown in high glucose medium and in adipose tissues of Type 2 diabetic mice. However, the metabolic mechanisms leading to increased fumarate and succination of protein in the adipocyte are unknown. Treatment of 3T3 cells with high glucose (30 mM compared with 5 mM) caused a significant increase in cellular ATP/ADP, NADH/NAD+ and Deltapsim (mitochondrial membrane potential). There was also a significant increase in the cellular fumarate concentration and succination of proteins, which may be attributed to the increase in NADH/NAD+ and subsequent inhibition of tricarboxylic acid cycle NAD+-dependent dehydrogenases. Chemical uncouplers, which dissipated Deltapsim and reduced the NADH/NAD+ ratio, also decreased the fumarate concentration and protein succination. High glucose plus metformin, an inhibitor of complex I in the electron transport chain, caused an increase in fumarate and succination of protein. Thus excess fuel supply (glucotoxicity) appears to create a pseudohypoxic environment (high NADH/NAD+ without hypoxia), which drives the increase in succination of protein. We propose that increased succination of proteins is an early marker of glucotoxicity and mitochondrial stress in adipose tissue in diabetes. PMID- 22524438 TI - Dicarboxylate recognition by two macrobicyclic receptors: selectivity for fumarate over maleate. AB - Two ditopic polyamine macrobicyclic compounds have been studied as receptors for the recognition of dicarboxylate anions of varying chain length in aqueous solution. One of the receptors consists of two tris(2-aminoethyl)amine-derived binding subunits separated by p-xylyl spacers, while the other is a heteroditopic compound, combining two different head units, a tren-derived and a 2,4,6 triethylbenzene-derived one, also separated by p-xylyl spacers. The acid-base behavior of the compounds as well as their binding ability with oxalate (oxa(2 )), malonate (mal(2-)), succinate (suc(2-)), glutarate (glu(2-)), maleate (male(2 )) and fumarate (fum(2-)) anions were studied by potentiometry at 298.2 K in aqueous solution and at ionic strength 0.10 M in KTsO. NMR studies were also performed to obtain structural information in solution on the supermolecules formed by association of the protonated macrobicycles with the dicarboxylate substrates. The results revealed that both compounds are able to form stable associations with the dianionic substrates in competitive aqueous solution, with unprecedented selectivity for fum(2-) over other dicarboxylate competitors, including its cis isomer male(2-). In addition it was found that although the selectivity pattern is unaffected by the introduction of the 2,4,6 triethylbenzene head unit, the affinity toward dicarboxylates is significantly reduced. Therefore, the comparison between the binding behavior of these two receptors showed the effect of the increased rigidity and lipophilicity of the receptor with the 2,4,6-triethylbenzene head unit in the binding properties and the selectivity pattern. PMID- 22524439 TI - A framework genetic map for Miscanthus sinensis from RNAseq-based markers shows recent tetraploidy. AB - BACKGROUND: Miscanthus (subtribe Saccharinae, tribe Andropogoneae, family Poaceae) is a genus of temperate perennial C4 grasses whose high biomass production makes it, along with its close relatives sugarcane and sorghum, attractive as a biofuel feedstock. The base chromosome number of Miscanthus (x = 19) is different from that of other Saccharinae and approximately twice that of the related Sorghum bicolor (x = 10), suggesting large-scale duplications may have occurred in recent ancestors of Miscanthus. Owing to the complexity of the Miscanthus genome and the complications of self-incompatibility, a complete genetic map with a high density of markers has not yet been developed. RESULTS: We used deep transcriptome sequencing (RNAseq) from two M. sinensis accessions to define 1536 single nucleotide variants (SNVs) for a GoldenGateTM genotyping array, and found that simple sequence repeat (SSR) markers defined in sugarcane are often informative in M. sinensis. A total of 658 SNP and 210 SSR markers were validated via segregation in a full sibling F1 mapping population. Using 221 progeny from this mapping population, we constructed a genetic map for M. sinensis that resolves into 19 linkage groups, the haploid chromosome number expected from cytological evidence. Comparative genomic analysis documents a genome-wide duplication in Miscanthus relative to Sorghum bicolor, with subsequent insertional fusion of a pair of chromosomes. The utility of the map is confirmed by the identification of two paralogous C4-pyruvate, phosphate dikinase (C4-PPDK) loci in Miscanthus, at positions syntenic to the single orthologous gene in Sorghum. CONCLUSIONS: The genus Miscanthus experienced an ancestral tetraploidy and chromosome fusion prior to its diversification, but after its divergence from the closely related sugarcane clade. The recent timing of this tetraploidy complicates discovery and mapping of genetic markers for Miscanthus species, since alleles and fixed differences between paralogs are comparable. These difficulties can be overcome by careful analysis of segregation patterns in a mapping population and genotyping of doubled haploids. The genetic map for Miscanthus will be useful in biological discovery and breeding efforts to improve this emerging biofuel crop, and also provide a valuable resource for understanding genomic responses to tetraploidy and chromosome fusion. PMID- 22524440 TI - Surface functionalization of silica nanoparticles supports colloidal stability in physiological media and facilitates internalization in cells. AB - The influence of the surface functionalization of silica particles on their colloidal stability in physiological media is studied and correlated with their uptake in cells. The surface of 55 +/- 2 nm diameter silica particles is functionalized by amino acids or amino- or poly(ethylene glycol) (PEG)-terminated alkoxysilanes to adjust the zeta potential from highly negative to positive values in ethanol. A transfer of the particles into water, physiological buffers, and cell culture media reduces the absolute value of the zeta potential and changes the colloidal stability. Particles stabilized by L-arginine, L-lysine, and amino silanes with short alkyl chains are only moderately stable in water and partially in PBS or TRIS buffer, but aggregate in cell culture media. Nonfunctionalized, N-(6-aminohexyl)-3-aminopropyltrimethoxy silane (AHAPS), and PEG-functionalized particles are stable in all media under study. The high colloidal stability of positively charged AHAPS-functionalized particles scales with the ionic strength of the media, indicating a mainly electrostatical stabilization. PEG-functionalized particles show, independently from the ionic strength, no or only minor aggregation due to additional steric stabilization. AHAPS stabilized particles are readily taken up by HeLa cells, likely as the positive zeta potential enhances the association with the negatively charged cell membrane. Positively charged particles stabilized by short alkyl chain aminosilanes adsorb on the cell membrane, but are weakly taken up, since aggregation inhibits their transport. Nonfunctionalized particles are barely taken up and PEG-stabilized particles are not taken up at all into HeLa cells, despite their high colloidal stability. The results indicate that a high colloidal stability of nanoparticles combined with an initial charge-driven adsorption on the cell membrane is essential for efficient cellular uptake. PMID- 22524441 TI - Direct nanoscale imaging of ballistic and diffusive thermal transport in graphene nanostructures. AB - We report direct imaging of nanoscale thermal transport in single and few-layer graphene with approximately 50 nm lateral resolution using high vacuum scanning thermal microscopy. We observed increased heat transport in suspended graphene where heat is conducted by ballistic phonons, compared to adjacent areas of supported graphene, and observed decreasing thermal conductance of supported graphene with increased layer number. Our nanothermal images suggest a mean-free path of thermal phonons in supported graphene below 100 nm. PMID- 22524442 TI - Manufacture of void-free electrospun polymer nanofiber composites with optimized mechanical properties. AB - Engineered fiber reinforced polymer composites require effective impregnation of polymer matrix within the fibers to form coherent interfaces. In this work, we investigated solution interactions with electrospun fiber mats for the manufacture of nanocomposites with optimized mechanical properties. Void free composites of electrospun nonwoven PA6 nanofibers were manufactured using a PVA matrix that is introduced into the nonwoven mat using a solution-based processing method. The highest failure stress of the composites was reported for an optimum 16 wt % of PVA in solution, indicating the removal of voids in the composite as the PVA solution both impregnates the nanofiber network and fills all the pores of the network with PVA matrix upon evaporation of the solvent. These processing methods are effective for achieving coherent nanofiber-matrix interfaces, with further functionality demonstrated for optically transparent electrospun nanofiber composites. PMID- 22524443 TI - Medical professionals' attitudes toward tube feeding for themselves or their families: a multicenter survey in Japan. AB - BACKGROUND: Many studies have shown a lack of advantages to tube feeding for elderly with advanced dementia, but tube feeding is still considered standard care in Japan. The aim of this study is to investigate what nutrition method health care professionals want for themselves or their families, if they fall into a bedridden state due to irreversible impaired cognition in old age. METHODS: In 2010 we surveyed 1321 Japanese health care professionals including 251 medical doctors and 1070 nurses. Their attitudes toward tube feeding were assessed by using an anonymous questionnaire, which included desired feeding methods for themselves or their families and propriety of card-based declaration of intent for end-of-life care. RESULTS: Rates of accepting tube feeding for themselves and their families were 14.4% and 43.4%, respectively. In multivariate analyses, working at a municipal hospital and high frequency of taking care of tube-fed elderly patients were predictors of refusing tube feeding for themselves. Working at a municipal hospital and being a medical doctor were predictors of refusing tube feeding for their families. The rate of welcoming card-based declaration of intent for end-of-life care including feeding methods was 65.2%. CONCLUSIONS: Many doctors and nurses, especially with more frequent contact with tubefed patients, rejected tube feeding for themselves on their own deathbed, but did not always refuse this option for their families. PMID- 22524444 TI - Hormonal causes of male sexual dysfunctions and their management (hyperprolactinemia, thyroid disorders, GH disorders, and DHEA). AB - INTRODUCTION: Besides hypogonadism, other endocrine disorders have been associated with male sexual dysfunction (MSD). AIM: To review the role of the pituitary hormone prolactin (PRL), growth hormone (GH), thyroid hormones, and adrenal androgens in MSD. METHODS: A systematic search of published evidence was performed using Medline (1969 to September 2011). Oxford Centre for Evidence Based Medicine-Levels of Evidence (March 2009) was applied when possible. MAIN OUTCOME MEASURES: The most important evidence regarding the role played by PRL, GH, thyroid, and adrenal hormone was reviewed and discussed. RESULTS: Only severe hyperprolactinemia (>35 ng/mL or 735 mU/L), often related to a pituitary tumor, has a negative impact on sexual function, impairing sexual desire, testosterone production, and, through the latter, erectile function due to a dual effect: mass effect and PRL-induced suppression on gonadotropin secretion. The latter is PRL level dependent. Emerging evidence indicates that hyperthyroidism is associated with an increased risk of premature ejaculation and might also be associated with erectile dysfunction (ED), whereas hypothyroidism mainly affects sexual desire and impairs the ejaculatory reflex. However, the real incidence of thyroid dysfunction in subjects with sexual problems needs to be evaluated. Prevalence of ED and decreased libido increase in acromegalic patients; however, it is still a matter of debate whether GH excess (acromegaly) may create effects due to a direct overproduction of GH/insulin-like growth factor 1 or because of the pituitary mass effects on gonadotropic cells, resulting in hypogonadism. Finally, although dehydroepiandrosterone (DHEA) and its sulfate have been implicated in a broad range of biological derangements, controlled trials have shown that DHEA administration is not useful for improving male sexual function. CONCLUSIONS: While the association between hyperprolactinemia and hypoactive sexual desire is well defined, more studies are needed to completely understand the role of other hormones in regulating male sexual functioning. PMID- 22524445 TI - Genetic evaluation of severe male factor infertility in Turkey: a cross-sectional study. AB - OBJECTIVE: To determine the frequency, types of chromosomal abnormalities and Y chromosome microdeletions in patients with severe male factor infertility, and the association between clinical background and genetic abnormality. STUDY DESIGN: A total of 322 infertile men; 136 men with severe oligozoospermia (sperm count <5 million/ml) and 196 with nonobstructive azoospermia were studied between April 2004 and November 2006 at the Dr. Zekai Tahir Burak Women's Health Education and Research Hospital, Ankara, Turkey. Blood, semen samples, and testicular biopsies of patients were obtained. Hormonal analysis (follicle stimulating hormone (FSH), luteinizing hormone (LH), and testosterone levels), semen analysis, karyotype analysis, and PCR screening for Y chromosome microdeletions were performed. RESULT(S): Forty-eight out of 332 (14%) infertile men had a genetic abnormality. Twenty-four (7.2%) cases with karyotype abnormality were detected. The frequencies of karyotype abnormalities were Klinefelter's syndrome 17/24 (71%), translocation 3/24 (12%), mix gonadal dysgenesis 2/24 (8%), XX male 1/24 (4%), and 46XYY 1/24 (4%). Twenty cases (6%) infertile men had only Y chromosome microdeletions. The frequencies of the deleted areas were azoospermia factor (AZF)c 42%, AZFb 25%, AZFa 21%, AZFb, c 8%, and AZFa, c 4%. Four of the cases with Y chromosome microdeletions also had a concurrent karyotype abnormality. CONCLUSION(S): All patients with nonobstructive azoospermia and severe oligozoospermia (sperm count <5 million/ml) should undergo genetic screening. PMID- 22524446 TI - Comprehensive guide to acetyl-carboxylases in algae. AB - Lipids from microalgae have become an important commodity in the last 20 years, biodiesel and supplementing human diets with omega-3 fatty acids are just two of the many applications. Acetyl-CoA carboxylase (ACCase) is a key enzyme in the lipid synthesis pathway. In general, ACCases consist of four functional domains: the biotin carboxylase (BC), the biotin carboxyl binding protein (BCCP), and alpha-and beta-carboxyltransferases (alpha-and beta-CT). In algae, like in plants, lipid synthesis is another function of the chloroplast. Despite being well researched in plants and animals, there is a distinct lack of information about this enzyme in the taxonomically diverse algae. In plastid-containing organisms, ACCases are present in the cytosol and the plastid (chloroplasts) and two different forms exist, the heteromeric (prokaryotic) and homomeric (eukaryotic) form. Despite recognition of the existence of the two ACCase forms, generalized published statements still list the heteromeric form as the one present in algal plastids. In this study, the authors show this is not the case for all algae. The presence of heteromeric or homomeric ACCase is dependent on the origin of plastid. The authors used ACCase amino acid sequence comparisons to show that green (Chlorophyta) and red (Rhodophyta) algae, with the exception of the green algal class Prasinophyceae, contain heteromeric ACCase in their plastids, which are of primary symbiotic origin and surrounded by two envelope membranes. In contrast, algal plastids surrounded by three to four membranes were derived through secondary endosymbiosis (Heterokontophyta and Haptophyta), as well as apicoplast containing Apicomplexa, contain homomeric ACCase in their plastids. Distinctive differences in the substrate binding regions of heteromeric and homomeric alpha-CT and beta-CT were discovered, which can be used to distinguish between the two ACCase types. Furthermore, the acetyl-CoA binding region of homomeric alpha-CT can be used to distinguish between cytosolic and plastidial ACCase. The information provided here will be of fundamental importance in ACCase expression and activity research to unravel impacts of environmental and physicochemical parameters on lipid content and productivity. PMID- 22524447 TI - Ventilator-associated pneumonia and ICU mortality in severe ARDS patients ventilated according to a lung-protective strategy. AB - INTRODUCTION: Ventilator-associated pneumonia (VAP) may contribute to the mortality associated with acute respiratory distress syndrome (ARDS). We aimed to determine the incidence, outcome, and risk factors of bacterial VAP complicating severe ARDS in patients ventilated by using a strictly standardized lung protective strategy. METHODS: This prospective epidemiologic study was done in all the 339 patients with severe ARDS included in a multicenter randomized, placebo-controlled double-blind trial of cisatracurium besylate in severe ARDS patients. Patients with suspected VAP underwent bronchoalveolar lavage to confirm the diagnosis. RESULTS: Ninety-eight (28.9%) patients had at least one episode of microbiologically documented bacterial VAP, including 41 (41.8%) who died in the ICU, compared with 74 (30.7%) of the 241 patients without VAP (P = 0.05). After adjustment, age and severity at baseline, but not VAP, were associated with ICU death. Cisatracurium besylate therapy within 2 days of ARDS onset decreased the risk of ICU death. Factors independently associated with an increased risk to develop a VAP were male sex and worse admission Glasgow Coma Scale score. Tracheostomy, enteral nutrition, and the use of a subglottic secretion-drainage device were protective. CONCLUSIONS: In patients with severe ARDS receiving lung protective ventilation, VAP was associated with an increased crude ICU mortality which did not remain significant after adjustment. PMID- 22524448 TI - Synergistic phage-antibiotic combinations for the control of Escherichia coli biofilms in vitro. AB - The potential application of phage therapy for the control of bacterial biofilms has received increasing attention as resistance to conventional antibiotic agents continues to increase. The present study identifies antimicrobial synergy between bacteriophage T4 and a conventional antibiotic, cefotaxime, via standard plaque assay and, importantly, in the in vitro eradication of biofilms of the T4 host strain Escherichia coli 11303. Phage-antibiotic synergy (PAS) is defined as the phenomenon whereby sub-lethal concentrations of certain antibiotics can substantially stimulate the host bacteria's production of virulent phage. Increasing sub-lethal concentrations of cefotaxime resulted in an observed increase in T4 plaque size and T4 concentration. The application of PAS to the T4 one-step growth curve also resulted in an increased burst size and reduced latent period. Combinations of T4 bacteriophage and cefotaxime significantly enhanced the eradication of bacterial biofilms when compared to treatment with cefotaxime alone. The addition of medium (10(4) PFU mL(-1)) and high (10(7) PFU mL(-1)) phage titres reduced the minimum biofilm eradication concentration value of cefotaxime against E. coli ATCC 11303 biofilms from 256 to 128 and 32 MUg mL(-1), respectively. Although further investigation is needed to confirm PAS, this study demonstrates, for the first time, that synergy between bacteriophage and conventional antibiotics can significantly improve biofilm control in vitro. PMID- 22524449 TI - Mo-substituted Keggin tungstosilicate microtubes: preparation and characterization. AB - The synthesis and characterization of microtubes of SiMoW(11) Keggin polyoxometalates containing either an Mo(V) or Mo(VI) atom is reported. The introduction of a Mo atom into the Keggin-type tungstosilicate microtubes endows them with new properties. The Mo-substituted microtubes may exert both W and Mo functionalities in electrocatalytic reactions and in the immobilization of noble metal nanoparticles. The degree of reduction of the Mo component in the SiMoW(11) microtubes is controllable simply by tuning the amount of reductant present in the mother liquor. Mo-substituted Keggin tungstosilicate microtubes in their reduced state are more stable than the all-tungsten Keggin tungstosilicate heteropoly blue microtubes. PMID- 22524450 TI - Discovery of new inhibitors of Cdc25B dual specificity phosphatases by structure based virtual screening. AB - Cell division cycle 25 (Cdc25) proteins are highly conserved dual specificity phosphatases that regulate cyclin-dependent kinases and represent attractive drug targets for anticancer therapies. To discover more potent and diverse inhibitors of Cdc25 biological activity, virtual screening was performed by docking 2.1 million compounds into the Cdc25B active site. An initial subset of top-ranked compounds was selected and assayed, and 15 were found to have enzyme inhibition activity at micromolar concentration. Among these, four structurally diverse inhibitors with a different inhibition profile were found to inhibit human MCF-7, PC-3, and K562 cancer cell proliferation and significantly affect the cell cycle progression. A subsequent hierarchical similarity search with the most active reversible Cdc25B inhibitor found led to the identification of an additional set of 19 ligands, three of which were confirmed as Cdc25B inhibitors with IC(50) values of 7.9, 4.2, and 9.9 MUM, respectively. PMID- 22524451 TI - Mechanotransduction and focal adhesions. AB - Cellular FAs (focal adhesions) respond to internal and external mechanical stresses which make them prime candidates for mechanotransduction. Recent observations showed that the FA proteins including vinculin, FAK (FA kinase) and p130Cas are crucial for the ability of cells to transmit forces and to generate cytoskeletal tension. When mechanically stimulated, cells respond by modulating the spreading area, remodel the actin cytoskeleton, activate actomyosin interactions, recruit integrins and reinforce FAs and cytoskeletal structures. These complex cellular responses are orchestrated such that mechanical stresses within the FA complex remained within a narrow range. PMID- 22524452 TI - Extending healthy ageing: nutrient sensitive pathway and centenarian population. AB - Ageing is a challenge for any living organism and human longevity is a complex phenotype. With increasing life expectancy, maintaining long-term health, functionality and well-being during ageing has become an essential goal. To increase our understanding of how ageing works, it may be advantageous to analyze the phenotype of centenarians, perhaps one of the best examples of successful ageing. Healthy ageing involves the interaction between genes, the environment, and lifestyle factors, particularly diet. Besides evaluating specific gene environment interactions in relation to exceptional longevity, it is important to focus attention on modifiable lifestyle factors such as diet and nutrition to achieve extension of health span. Furthermore, a better understanding of human longevity may assist in the design of strategies to extend the duration of optimal human health. In this article we briefly discuss relevant topics on ageing and longevity with particular focus on dietary patterns of centenarians and nutrient-sensing pathways that have a pivotal role in the regulation of life span. Finally, we also discuss the potential role of Nrf2 system in the pro ageing signaling emphasizing its phytohormetic activation. PMID- 22524453 TI - Off-clamp robot-assisted partial nephrectomy: initial Washington University experience. AB - BACKGROUND AND PURPOSE: Because of the impact warm ischemia time may have on renal function, various surgical techniques have been proposed to minimize or eliminate warm ischemia. The purpose of this study is to evaluate our initial renal functional outcomes of off-clamp robot-assisted partial nephrectomy (RAPN), while assessing the safety profile of this unconventional surgical approach. PATIENTS AND METHODS: We performed a retrospective review of our off-clamp RAPN experience between August 2007 and January 2012. All patients with baseline and postoperative serum creatinine determinations were included. Patient demographics, operative information, perioperative outcomes, and renal functional outcomes were evaluated for this cohort. RESULTS: Forty-two patients with a mean age of 59.9 years (standard deviation [SD]=12) had a median follow-up of 100 days (range 1-1007 days). In all cases, warm ischemia time was 0 minutes. Mean operative time was 143 minutes (SD=59), and median estimated blood loss was 138 mL (range 50-1500 mL). No intraoperative complications were encountered, and all surgical margins were negative. Our postoperative complication rate was 14.3%. At the most recent follow-up, the mean estimated glomerular filtration rate (eGFR) was 76.2 mL/min/1.73 m(2) (SD=27.6), compared with 78.5 mL/min/1.73 m(2) (SD=28.9) preoperatively (P=0.11). Therefore, the mean eGFR decline of 2.3 mL/min/1.73 m(2) (SD=9.1) was not significant. CONCLUSIONS: Off-clamp RAPN is associated with minimal morbidity and minimal decline in renal function on short term follow-up. Further studies and continued monitoring of renal function are needed to determine if off-clamp RAPN provides any advantage in renal function preservation relative to the traditional RAPN with vascular clamping. PMID- 22524454 TI - Lichen planus is not associated with human herpesvirus type 7. PMID- 22524455 TI - Construction of Bordetella pertussis strains with enhanced production of genetically-inactivated Pertussis Toxin and Pertactin by unmarked allelic exchange. AB - BACKGROUND: Acellular Pertussis vaccines against whooping cough caused by Bordetella pertussis present a much-improved safety profile compared to the original vaccine of killed whole cells. The principal antigen of acellular Pertussis vaccine, Pertussis Toxin (PT), must be chemically inactivated to obtain the corresponding toxoid (PTd). This process, however, results in extensive denaturation of the antigen. The development of acellular Pertussis vaccines containing PTd or recombinant PT (rPT) with inactivated S1, Filamentous Hemagglutinin (FHA), and Pertactin (PRN) has shown that the yield of PRN was limiting, whereas FHA was overproduced. To improve antigen yields and process economics, we have constructed strains of Bordetella pertussis that produce enhanced levels of both rPT and PRN. RESULTS: Three recombinant strains of Bordetella pertussis were obtained by homologous recombination using an allelic exchange vector, pSS4245. In the first construct, the segment encoding PT subunit S1 was replaced by two mutations (R9K and E129G) that removed PT toxicity and Bp WWC strain was obtained. In the second construct, a second copy of the whole cluster of PT structural genes containing the above mutations was inserted elsewhere into the chromosome of Bp-WWC and the Bp-WWD strain was obtained. This strain generated increased amounts of rPT (3.77 +/- 0.53 MUg/mL) compared to Bp WWC (2.61 +/- 0.16 MUg/mL) and wild type strain (2.2 MUg/mL). In the third construct, a second copy of the prn gene was inserted into the chromosome of Bp WWD to obtain Bp-WWE. Strain Bp-WWE produced PRN at 4.18 +/- 1.02 MUg/mL in the cell extract which was about two-fold higher than Bp-WWC (2.48 +/- 0.10 MUg/mL) and Bp-WWD (2.31 +/- 0.17 MUg/mL). Purified PTd from Bp-WWD at 0.8-1.6 MUg/well did not show any toxicity against Chinese hamster ovary (CHO) cell whereas purified PT from WT demonstrated a cell clustering endpoint at 2.6 pg/well. CONCLUSIONS: We have constructed Bordetella pertussis strains expressing increased amounts of the antigens, rPT or rPT and PRN. Expression of the third antigen, FHA was unchanged (always in excess). These strains will be useful for the manufacture of affordable acellular Pertussis vaccines. PMID- 22524456 TI - Risk for recurrence of preeclampsia and outcome of subsequent pregnancy in women with preeclampsia in their first pregnancy. AB - OBJECTIVE: To assess subsequent pregnancy outcome and to identify risk factors for recurrence of preeclampsia (PET) in women with PET in their first pregnancy. METHODS: A retrospective cohort study of all nulliparous women diagnosed with PET during the years 1996-2008 (PET group, N = 600). Outcome of subsequent pregnancy was compared with a control group of nulliparous women without PET matched by maternal age in a 3:1 ratio (N = 1800). RESULTS: Subsequent pregnancies in the PET group were characterized by a higher rate of preterm delivery at less than 37 and 34 weeks (15.2% vs. 5.7%, p < 0.001 and 3.8% vs. 0.8%, p < 0.001, respectively), placental abruption (1.7% vs. 0.2%, p = 0.004), IUGR (2.8% vs. 0.9%, p = 0.016), and PET (5.9% vs. 0.8%, p < 0.001). Risk factors for PET and adverse outcome in the subsequent pregnancy included: PET complicated by placental abruption in the index pregnancy (OR = 10.8, 95%-CI = 1.8-34.6), PET requiring delivery prior to 34 weeks in the index pregnancy (OR = 6.5, 95%-CI = 1.6-22.5), chronic hypertension (OR = 5.3, 95%-CI = 1.9-12.7), and maternal age > 35 (OR = 4.3, 95%-CI = 1.2-20.5). CONCLUSION: PET in the first pregnancy is independently associated with an increased risk for adverse pregnancy outcome and recurrence of PET in the subsequent pregnancy in a manner that is related to the severity of PET in the first pregnancy. PMID- 22524457 TI - Oral transmission as a route of infection for viral haemorrhagic septicaemia virus in rainbow trout, Oncorhynchus mykiss (Walbaum). AB - Surveys among wild marine fish have revealed occurrence of viral haemorrhagic septicaemia virus (VHSV) infections in a high number of diverse fish species. In marine aquaculture of rainbow trout, preying on invading wild fish might thus be a risk factor for introduction and adaptation of VHSV and subsequent disease outbreaks. Our objective was to determine whether an oral transmission route for VHSV in rainbow trout exists. Juvenile trout were infected through oral, waterborne and cohabitation transmission routes, using a recombinant virus strain harbouring Renilla luciferase as reporter gene. Viral replication in stomach and kidney tissue was detected through bioluminescence activity of luciferase and qRT PCR. Replication was detected in both tissues, irrespective of transmission route. Replication patterns, however, differed among transmission routes. In trout infected through oral transmission, replication was detected in the stomach prior to kidney tissue. In trout infected through waterborne or cohabitation transmission, replication was detected in kidney prior to stomach or in both tissues simultaneously. We demonstrate the existence of an oral transmission route for VHSV in rainbow trout. This implies that preying on invading infected wild fish is a risk factor for introduction of VHSV into marine cultures of rainbow trout. PMID- 22524458 TI - In vitro and in vivo antitumoral action of metformin on hepatocellular carcinoma. AB - AIMS: Metformin is a biguanide that has been widely used to treat type 2 diabetes. Several studies have shown that metformin is also effective in treating cancer, including hepatocellular carcinoma (HCC). The objective of this study was to evaluate the antitumor effects of metformin in HCC, and to investigate the potential molecular target(s) of metformin-mediated antitumor activity. METHODS: The antiproliferative effects of metformin were assessed in human HCC cell lines and normal human liver cells at various concentrations. Orthotopic xenograft tumors were established in athymic nude mice, and tumor growth was monitored after metformin treatment. Western blot analysis and cell cycle regulation were performed to determine the involvement of various mediators of apoptosis. RESULTS: Metformin specifically inhibited the growth of HCC cells without affecting the growth of normal liver cells both in vitro and in vivo. Metformin caused cell cycle arrest in HCC cells, which resulted in caspase-3 activation. Livin levels decreased in a dose-dependent manner upon metformin treatment. Metformin activated 5'-adenosine monophosphate-activated protein kinase, inhibited the mammalian target of rapamycin pathway and downregulated Livin protein expression. CONCLUSION: Our findings indicate that metformin is effective at initiating apoptosis and inhibiting key survival signaling pathways in HCC cells. These data provide a foundation for further studies to evaluate metformin in the clinic either as a single agent or in combination with other first-line agents as a treatment option for HCC. PMID- 22524459 TI - Aromatically functionalized cyclic tricholate macrocycles: aggregation, transmembrane pore formation, flexibility, and cooperativity. AB - The aggregation of macrocyclic oligocholates with introverted hydrophilic groups and aromatic side chains was studied by fluorescence spectroscopy and liposome leakage assays. Comparison between the solution and the membrane phase afforded insight into the solvophobically driven aggregation. The macrocycles stacked over one another in lipid membranes to form transmembrane nanopores, driven by a strong tendency of the water molecules in the interior of the amphiphilic macrocycles to aggregate in a nonpolar environment. The aromatic side chains provided spectroscopic signatures for stacking, as well as additional driving force for the aggregation. Smaller, more rigid macrocycles stacked better than larger, more flexible ones because the cholate building blocks in the latter could rotate outward and diminish the conformation needed for the water-templated hydrophobic stacking. The acceptor-acceptor interactions among naphthalenediimide (NDI) groups were more effective than the pyrene-NDI donor-acceptor interactions in promoting the transmembrane pore formation of the oligocholate macrocycles. PMID- 22524460 TI - Darwinian transformation of a 'scarcely nutritious fluid' into milk. AB - In an early challenge to an aspect of Darwin's theory of natural selection, Jackson Mivart contended that milk could not have evolved 'from a scarcely nutritious fluid from an accidentally hypertrophied cutaneous gland'. The evolutionary change from a gland secretion to milk involves an increase in calcium and protein concentrations by up to 100- and 1000-fold, respectively. Even so, the challenge, we suggest, is not just a problem of scale. An increase in the concentrations of calcium and phosphate brings an increased risk of calcification of the secretory gland because calcium phosphate is highly insoluble. In addition, two of the four constituent milk casein proteins (kappa and alpha(S2)) aggregate to produce toxic amyloid fibrils. It is proposed that both problems were solved through the cosecretion of ancestral beta- and kappa caseins to form a stable amorphous aggregate of both proteins with sequestered amorphous calcium phosphate, that is, a primordial casein micelle. Evolutionarily, a gradual increase in the concentration of casein micelles could therefore produce progressively more nutritious fluids for the neonate without endangering the reproductive potential of the mother. PMID- 22524461 TI - The joint meeting of the 44th annual meeting of Japanese Society for Connective Tissue Research and the 59th annual meeting of the Japan Matrix Club June 7-8, 2012, Tokyo, Japan. PMID- 22524462 TI - Late-onset familial neurohypophyseal diabetes insipidus due to a novel mutation in the AVP gene. AB - OBJECTIVE: Familial neurohypophyseal diabetes insipidus (FNDI) is mainly an autosomal dominant inherited disorder presenting with severe polydipsia and polyuria in early childhood. In this study, we aimed to determine the molecular genetics and clinical characteristics of a large Swedish-Norwegian family presenting with very late-onset autosomal dominant FNDI. PATIENTS: Six probands with a history of developing polyuria and polydipsia during adolescence were studied. MEASUREMENTS: Information on family demography was collected by personal interview with family members. The genetic cause of FNDI was identified by DNA sequencing analysis of the coding regions of the AVP gene. The clinical characteristics were determined by the measurement of basal urine production and osmolality as well as by measurements of concurrent levels of plasma AVP, plasma osmolality, and urine osmolality during fluid deprivation and bolus injection of DDAVP. The integrity of the neurohypophysis was evaluated by magnetic resonance imaging. RESULTS: The mean age of encountering the first clinical symptoms in the family was 14.8 years (range 3-30 years) (n = 17). All six affected subjects investigated were heterozygous for a novel mutation in the AVP gene (g.1848C>T) predicting a p.Pro84Leu substitution in the AVP precursor protein. We found partial deficiency in evoked AVP secretion during fluid deprivation in one subject and complete deficiency in another. The pituitary bright spot was absent in all six affected subjects studied. CONCLUSION: A novel mutation in the AVP gene predicted to cause a neurophysin II dimerization defect is causing surprisingly late onset of FNDI in a large, six generation, Swedish-Norwegian family. The mutation is associated with both complete and partial deficiency in evoked AVP secretion during fluid deprivation in patients who have suffered from FNDI for decades. PMID- 22524463 TI - Identification of protein domains on major pilin MrkA that affects the mechanical properties of Klebsiella pneumoniae type 3 fimbriae. AB - The Klebsiella pneumoniae type 3 fimbriae are mainly composed of MrkA pilins that assemble into a helixlike filament. This study determined the biomechanical properties of the fimbriae and analyzed 11 site-directed MrkA mutants to identify domains that are critical for the properties. Escherichia coli strains expressing type 3 fimbriae with an Ala substitution at either F34, V45, C87, G189, T196, or Y197 resulted in a significant reduction in biofilm formation. The E. coli strain expressing MrkAG189A remained capable of producing a normal number of fimbriae. Although F34A, V45A, T196A, and Y197A substitutions expressed on E. coli strains produced sparse quantities of fimbriae, no fimbriae were observed on the cells expressing MrkAC87A. Further investigations of the mechanical properties of the MrkAG189A fimbriae with optical tweezers revealed that, unlike the wild-type fimbriae, the uncoiling force for MrkAG189A fimbriae was not constant. The MrkAG189A fimbriae also exhibited a lower enthalpy in the differential scanning calorimetry analysis. Together, these findings indicate that the mutant fimbriae are less stable than the wild-type. This study has demonstrated that the C terminal beta strands of MrkA are required for the assembly and structural stability of fimbriae. PMID- 22524464 TI - The surface scattering-based detection of hydrogen in air using a platinum nanowire. AB - The performance of a single platinum (Pt) nanowire for detecting H(2) in air is reported. A Pt nanowire shows no resistance change upon exposure to H(2) in N(2), but H(2) exposure in air causes a reversible resistance decrease for H(2) concentrations above 10 ppm. The amplitude of the resistance change induced by H(2) exposure and the time rate of change of the nanowire resistance both increased with increasing temperature from 298 to 550 K. This resistance decrease of the Pt nanowire in the presence of H(2) results from reduced electron diffuse scattering at hydrogen-covered Pt surfaces as compared with oxygen-covered platinum surfaces, we hypothesize. The properties for the detection of H(2) in air of single Pt and Pd nanowires of similar size are compared in this study. Pt nanowires have a limit-of-detection for H(2) (LOD(H(2))) of 10 ppm; 3 orders of magnitude lower than for Pd nanowires of the same size, as well as a response time that is 1/100th of Pd for [H(2)] ~ 1%. PMID- 22524465 TI - ACE consensus meeting report: oocyte and embryo cryopreservation Sheffield 17.05.11. AB - The UK Association of Clinical Embryologists (ACE) held a consensus workshop on Oocyte and Embryo Cryopreservation in Sheffield, UK, on May 17th, 2011. This was organized in response to a number of considerations including the increasing prevalence of vitrification for oocyte and embryo cryopreservation in the UK and worldwide, coupled with an apparent lack of consensus over which methods of cryopreservation are optimal. The workshop included expert opinion and survey data on current practice provided by participating clinics. The workshop highlighted that an increasing number of clinics in the UK are choosing vitrification rather than controlled rate freezing, particularly for the storage of oocytes and blastocysts. It was evident that a variety of solutions are used in conjunction with open and closed containers. Data supplied by the participating clinics suggest that both freezing and vitrification can lead to similar outcomes in early embryos and blastocysts and at the moment there is no evidence base to recommend either method over the other. The delegates arrived at a number of consensus points which reflected current practice in the UK, but recognized the need for well-designed trials with careful follow up of the children born before optimal methods can be agreed. PMID- 22524466 TI - Flavonoids preservation and release by methacrylic acid-grafted (N-vinyl pyrrolidone). AB - CONTEXT: Flavonoids preservation and release. OBJECTIVE: Synthesis of a polymeric material able to prevent thermal and photo degradation of a flavonoid model compound, such as (+)-catechin, and suitable for a controlled/sustained delivery of this molecule in gastro-intestinal simulating fluids. MATERIALS AND METHODS: Methacrylic acid (MAA) was grafted onto poly(N-vinyl-pyrrolidone) (PVP) by a free radical grafting procedure involving a single-step reaction at room temperature. For this purpose, hydrogen peroxide/ascorbic acid redox pair was employed as water-soluble and biocompatible initiator system. RESULTS AND DISCUSSION: FT-IR spectra confirmed the insertion of MAA onto the polymeric chain. Stability studies, performed under various conditions, such as freeze-thaw cycles, exposure to strong light, thermal stability studies under constant humidity and with light protection at different temperatures, showed the preservative properties of the polymeric material towards flavonoids. Furthermore, the biocompatibility was highlighted by Hen's Egg Test-Chorioallantoic Membrane assay and in vitro release studies demonstrated the possibility to employ PVP-MAA copolymer as a device for gastro-intestinal release of flavonoids. CONCLUSION: The coupling of good preservative properties together with biocompatibility and the usefulness as carrier in controlled release make this kind of material very interesting from an industrial point of view for different applications in food, pharmaceutical, and cosmetic fields. PMID- 22524467 TI - AIDSImpact--more than a virus. PMID- 22524468 TI - Suspicious ultrasound characteristics predict BRAF V600E-positive papillary thyroid carcinoma. AB - BACKGROUND: Current American Thyroid Association (ATA) guidelines recommend routine cervical ultrasound (US) in thyroid nodule evaluation. Specific US characteristics can help diagnose papillary thyroid carcinoma (PTC). The aim of this blinded cohort study was to determine whether these specific US characteristics can also reliably detect the more aggressive variants of PTC that are often associated with the BRAF(V600E) mutation. METHODS: After Institutional Review Board approval, we identified a cohort of patients from January 2007 to December 2009 with histologic PTC>=1 cm who had cervical US, initial thyroid surgery, and molecular testing for BRAF(V600E) on fine-needle aspiration biopsy or histology. Preoperative US images were evaluated by a single radiologist, who was blinded to BRAF status, for nodule size and the presence or absence of the following suspicious US features: taller-than-wide shape, ill-defined margins, hypoechogenicity, calcifications, noncystic composition, and absent halo. RESULTS: BRAF-positivity was associated with most known suspicious US findings, including taller-than-wide shape (47% vs. 7%, p<0.001), ill-defined margins (42% vs. 9%, p<0.001), hypoechogenicity (83% vs. 36%, p<0.001), micro/macrocalcifications (87% vs. 24%, p<0.001), and absent halo (85% vs. 27%, p<0.001) but was not associated with noncystic composition. When >=3 suspicious US features were present, BRAF-positivity was predicted with a positive predictive value of 82%. The absence of suspicious US features together with negative BRAF testing predicted PTC without extrathyroidal extension or lymph node metastasis (negative predictive value 88%). CONCLUSIONS: With routine preoperative cervical US and molecular testing, a trained radiologist or surgeon can improve the preoperative characterization of PTC, potentially impacting risk stratification and initial surgical management. PMID- 22524469 TI - Ultrasound-guided fine-needle aspiration biopsy of clinically suspicious thyroid nodules with an automatic aspirator: a novel technique. AB - BACKGROUND: Fine-needle aspiration biopsy (FNAB) is a simple technique for the investigation of suspicious thyroid nodules. However, low success rates are reported in the literature. The aim of this prospective study was to compare the clinical performance and impact of an automatic aspirator, referred to here as Aspirator 3, to those of the manual technique for the FNAB of clinically suspicious thyroid nodules. METHODS: One hundred nine consecutive patients with 121 clinically suspicious thyroid nodules underwent a biopsy twice of the same site with the clinically approved Aspirator 3 and with the manual technique. The number of follicular cell formations and the total number of follicular cells in the aspirate were counted using the ThinPrep(r) method. RESULTS: With the Aspirator 3, the total number and the mean number of extracted cell formations were significantly higher than the values achieved with the manual technique (total: 3222 vs. 1951, p=0.02; mean: 27 vs. 16). The total number of cells that were biopsied was also higher when the Aspirator 3 was utilized (47,480 vs. 23,080, p=0.005). Overall, the Aspirator 3 was superior in 65 biopsies, and the manual technique was superior in 39 biopsies. CONCLUSIONS: In terms of cell formations and the total number of cells aspirated, the Aspirator 3 was superior to the manual technique. Further, the Aspirator 3 was more convenient to use and had a greater precision in needle guidance. PMID- 22524470 TI - Factors associated with positive F-18 flurodeoxyglucose positron emission tomography before thyroidectomy in patients with papillary thyroid carcinoma. AB - BACKGROUND: The role for pre-thyroidectomy (pre-Tx) imaging with F-18 flurodeoxyglucose (FDG) positron emission tomography (PET), FDG PET-computed tomography (CT), in differentiated thyroid cancer is controversial as is the significance of positive and negative FDG uptake in this setting. We reviewed the records of patients with papillary thyroid carcinoma (PTC) who had pre-Tx FDG PET CT to determine whether FDG uptake was associated with features noted on pre-Tx ultrasonography (US) and parameters determined after post-Tx. METHODS: Patients were selected for a retrospective review of their records if they had a total Tx with central lymph node dissection for PTC and pre-Tx FDG PET-CT and US between 2006 and 2009. Sixty patients who met these criteria were studied. Patients who had a history of head and neck irradiation, surgery, or sclerotherapy with ethanol in the last 3 months were excluded. The clinicopathologic factors-age, sex, size, tumor-node-metastasis (TNM) staging, the presence of extrathyroidal extention, multifocality, cervical lymph node metastases (CLNM), Hashimoto thyroiditis, and US characteristics-were evaluated to determine whether they were associated with positive pre-Tx FDG uptake. RESULTS: Forty-three (71.6%) of patients in the study had positive FDG uptake. Larger tumors and the presence of CLNM were associated with a greater likelihood of positive FDG uptake. The sensitivity, specificity, positive predictive value, and negative predictive value for CLNM detection by FDG PET-CT showed low statistical values. When considering the excellence of US for evaluating a thyroid nodule size and the presence of CLNM, the clinical value of pre-Tx FDG PET-CT is comparatively limited. CONCLUSION: Pre-Tx FDG PET is not recommended for routine use in patients with PTC. PMID- 22524472 TI - Varicocele is associated with erectile dysfunction: a population-based case control study. AB - INTRODUCTION: While many studies have been conducted investigating the efficacy of varicocele treatment on fertility, the literature is comparatively sparse concerning the association between varicocele, varicocelectomy, and erectile dysfunction (ED). AIM: This study aimed to estimate the associations between varicocele, varicocelectomy, and ED using a population-based dataset. METHODS: This study used data from the Longitudinal Health Insurance Database 2000 in Taiwan. A total of 32,856 cases and 98,568 randomly selected controls were included in this study. Conditional logistic regression analyses were used to examine associations between ED and having been previously diagnosed with varicocele or having underwent a varicocelectomy. MAIN OUTCOME MEASURE: The odds of prior varicocele or having underwent a varicocelectomy between cases and controls. RESULTS: Of the sampled patients, the prevalence of prior varicocele was 3.3% and 1.2% for cases and controls, respectively (P < 0.001). Conditional logistic regression analysis suggested that the odds ratio (OR) of being previously diagnosed with varicocele for cases was 3.09 (95% confidence interval [CI] = 2.67-3.49) when compared with controls after adjusting for monthly income, geographic location, hypertension, diabetes, coronary heart disease, hyperlipidemia, hypogonadism, obesity, and alcohol abuse/alcohol dependence syndrome. Furthermore, cases were 1.92 (95% CI = 1.52-2.43) times more likely to have undergone a varicocelectomy than controls. Furthermore, subjects aged between 18 and 29 had the highest ORs for prior varicocele among cases when compared with controls (OR = 5.20; 95% CI = 3.27-8.28). CONCLUSION: This investigation succeeded in identifying an association between both varicocele and ED. We also realized that varicocele patients who underwent a varicocelectomy had lower magnitudes of association with ED than those who did not. PMID- 22524471 TI - Effect of parotid gland massage on parotid gland Tc-99m pertechnetate uptake. AB - BACKGROUND: Salivary dysfunction is the most common side effect associated with (131)I therapy in patients with differentiated thyroid cancer. The purpose of this study was to evaluate the effect of parotid gland (PG) massage on radioisotope accumulation in the salivary gland. METHODS: Sixty patients were included in this study. Using Tc-99m pertechnetate, two salivary scans were performed in all patients. In 30 patients, PG massage was performed between the two salivary gland scans, whereas in the other 30 patients no massage was performed between the two scans. Total counts of both PGs and accumulation ratios were calculated. RESULTS: In the patients who received massage, no difference was observed between the mean PG counts of first and second images (8556.9+/-3333.4 count vs. 8598.3+/-3341.3 count, p=0.39). In the patients who did not receive massage, the mean PG count on second images was significantly higher than that on first images (8581.2+/-3618.0 count vs. 9096.4+/-3654.0 count, p<0.01). Mean accumulation ratio in the patients who received massage was significantly lower than in the patients who did not receive massage (0.5%+/-3.3% vs. 6.8%+/-3.8%, p<0.01). Further, among the patients who received massage there was a higher percentage of patients with a negative accumulation ratio than among the patients who did not receive massage (43.3% vs. 0%, p<0.01). CONCLUSIONS: PG massage can reduce Tc-99m pertechnetate accumulation in the PG, and thus, should be helpful to prevent salivary damage associated with (131)I therapy. PMID- 22524473 TI - Carbonylation of 1-lithiobutadiene with carbon monoxide followed by intramolecular acyllithiation of C?C double bond and intermolecular acylation with acid chloride: scope, applications, and mechanistic aspects. AB - The carbonylation of a 1-lithio-1,3-butadiene derivative with CO gave rise to a butadienyl acyllithio intermediate, which underwent an immediate intramolecular acyllithiation of the C?C double bond, affording a lithio cyclopentadienyl enolate. The X-ray structural analysis of the enolate revealed a dimer connected with a "Li(2)O(2)" four-membered ring. Subsequent intermolecular acylation of this enolate with acid chlorides afforded beta-keto-3-cyclopentenones, gamma-keto 2-cyclopentenones, or cyclopentadienyl ester derivatives. The stereo- and regioselectivity of the in situ generated lithio cyclopentadienyl enolate with various acid chlorides was investigated and analyzed, showing that the formation of the above products was significantly dependent on both the substituents on the butadienyl skeleton and the bulkiness of acid chlorides. PMID- 22524474 TI - High levels of RNA-editing site conservation amongst 15 laboratory mouse strains. AB - BACKGROUND: Adenosine-to-inosine (A-to-I) editing is a site-selective post transcriptional alteration of double-stranded RNA by ADAR deaminases that is crucial for homeostasis and development. Recently the Mouse Genomes Project generated genome sequences for 17 laboratory mouse strains and rich catalogues of variants. We also generated RNA-seq data from whole brain RNA from 15 of the sequenced strains. RESULTS: Here we present a computational approach that takes an initial set of transcriptome/genome mismatch sites and filters these calls taking into account systematic biases in alignment, single nucleotide variant calling, and sequencing depth to identify RNA editing sites with high accuracy. We applied this approach to our panel of mouse strain transcriptomes identifying 7,389 editing sites with an estimated false-discovery rate of between 2.9 and 10.5%. The overwhelming majority of these edits were of the A-to-I type, with less than 2.4% not of this class, and only three of these edits could not be explained as alignment artifacts. We validated 24 novel RNA editing sites in coding sequence, including two non-synonymous edits in the Cacna1d gene that fell into the IQ domain portion of the Cav1.2 voltage-gated calcium channel, indicating a potential role for editing in the generation of transcript diversity. CONCLUSIONS: We show that despite over two million years of evolutionary divergence, the sites edited and the level of editing at each site is remarkably consistent across the 15 strains. In the Cds2 gene we find evidence for RNA editing acting to preserve the ancestral transcript sequence despite genomic sequence divergence. PMID- 22524475 TI - Hepatitis A, B, C and E virus markers in Chinese residing in Tokyo, Japan. AB - AIM: Recently, the number of foreigners living in Japan has been increasing, with the majority originating from China. It is important for us to know the prevalence of hepatitis virus markers among them, as proper medical practices and vaccinations should be prepared when seeing them and their offspring. METHODS: We examined the relationship between the prevalence of hepatitis virus markers: hepatitis B surface antigen (HBsAg), anti-HBs, anti-hepatitis C virus (HCV), anti hepatitis A virus (HAV) and anti-hepatitis E virus immunoglobulin (Ig)G, and background such as age, birthplace and length of stay in Japan, of 568 Chinese residing in Tokyo, and also of 55 indigenous Japanese. RESULTS: The prevalence of HBV and HAV markers in Chinese staying in Tokyo is higher than in indigenous Japanese (HBsAg, 10% vs 1.8%; anti-HBs, 45% vs 9.0%; anti-HAV, 90% vs 14%). There were no differences in anti-HCV and anti-HEV IgG between the two groups. CONCLUSION: Indigenous Japanese subjects have less immunity against HAV and HBV. The HBV carrier rate is higher in Chinese subjects, and attention should be paid to this issue in clinical practice. It might be important to control hepatitis viruses in Chinese subjects when doctors see them in Japan. PMID- 22524477 TI - Impact of water fluoride concentration on the fluoride content of infant foods and drinks requiring preparation with liquids before feeding. AB - OBJECTIVES: To measure the fluoride (F) content of infant foods and drinks requiring reconstitution with liquids prior to consumption and to determine the impact of water F concentration on their F content, as consumed, by measuring F content before and after preparation. METHODS: In total, 58 infant powdered formula milks, dry foods and concentrated drinks were prepared with deionized water (<0.02 ppm F) nonfluoridated (0.13 ppm F) and fluoridated (0.90 ppmF) water. The F concentrations of drink samples were measured directly using a fluoride-ion-selective electrode after addition of TISAB III, and food samples and formula milks measured indirectly by an acid diffusion method. RESULTS: The overall range of F concentrations of all the nonreconstituted samples, in their prepreparation dry or concentrated forms, was from 0.06 to 2.99 MUg/g with the highest F concentration for foods found in the dry 'savoury meals' (a combination of vegetables and chicken or cheese or rice) group. However, when the samples were reconstituted with nonfluoridated water, the mean F concentrations of prepared 'concentrated juices', 'pasta and rice', 'breakfast cereals', 'savoury meals' and 'powdered infant formula milks' were 0.38, 0.26, 0.18, 0.16 and 0.15 MUg/g, respectively. The corresponding mean F concentrations were 0.97, 1.21, 0.86, 0.74 and 0.91 MUg/g, respectively, when the same samples were prepared with fluoridated water. CONCLUSION: Although some nonreconstituted infant foods/drinks showed a high F concentration in their dry or concentrated forms, the concentration of F in prepared foods/drinks primarily reflected the F concentration of liquid used for their preparation. Some infant foods/drinks, when reconstituted with fluoridated water, may result in a F intake in infants above the suggested optimum range (0.05-0.07 mg F/kg body weight) and therefore may put infants at risk of developing dental fluorosis. Further research is necessary to determine the actual F intake of infants living in fluoridated and nonfluoridated communities using reconstituted infant foods and drinks. PMID- 22524478 TI - The spectrum of monoclonal gammopathies affecting the kidney. PMID- 22524476 TI - Early administration of probiotic Lactobacillus acidophilus and/or prebiotic inulin attenuates pathogen-mediated intestinal inflammation and Smad 7 cell signaling. AB - Immaturity of gut-associated immunity may contribute to pediatric mortality associated with enteric infections. A murine model to parallel infantile enteric disease was used to determine the effects of probiotic, Lactobacillus acidophilus (La), prebiotic, inulin, or both (synbiotic, syn) on pathogen-induced inflammatory responses, NF-kappaB, and Smad 7 signaling. Newborn mice were inoculated bi-weekly for 4 weeks with La, inulin, or syn and challenged with Citrobacter rodentium (Cr) at 5 weeks. Mouse intestinal epithelial cells (CMT93) were exposed to Cr to determine temporal alterations in NF-Kappa B and Smad 7 levels. Mice with pretreatment of La, inulin, and syn show reduced intestinal inflammation following Cr infection compared with controls, which is associated with significantly reduced bacterial colonization in La, inulin, and syn animals. Our results further show that host defense against Cr infection correlated with enhanced colonic IL-10 and transforming growth factor-beta expression and inhibition of NF-kappaB in syn-treated mice, whereas mice pretreated with syn, La, or inulin had attenuation of Cr-induced Smad 7 expression. There was a temporal Smad 7 and NF-kappaB intracellular accumulation post-Cr infection and post-tumor necrosis factor stimulation in CMT93 cells. These results, therefore, suggest that probiotic, La, prebiotic inulin, or synbiotic may promote host protective immunity and attenuate Cr-induced intestinal inflammation through mechanisms affecting NF-kappaB and Smad 7 signaling. PMID- 22524479 TI - The contribution of Facebook to the 2011 Tunisian revolution: a cyberpsychological insight. AB - The influence of Facebook in social life keeps constantly growing. Recently, the communication of information has been vital to the success of the Tunisian revolution, and Facebook was its main "catalyst." This study examines the key reasons that explain Facebook's contribution to this historical event, as perceived by Tunisian Internet users. To do so, we launched this study 5 days after the fall of the regime using an online questionnaire in which participants (N=333) first rated the importance of Facebook in the Tunisian revolution and then explained the reasons for their ratings. A cluster analysis based on the Euclidean distance between the most frequent words in the participants' text corpus (6,640 words), revealed three main clusters that we interpret as follows: 1: Facebook political function, 2: Facebook informational function, and 3: Facebook media platform function. It is likely that these factors reflect the dynamic of Tunisian cyberspace and the Tunisian Internet users' collective consciousness during the revolution. PMID- 22524480 TI - Interrelations between virtual-world and real-world activities: comparison of genders, age groups, and pathological and nonpathological Internet users. AB - After the Internet Revolution, people have started to spend most of their everyday time online carrying out virtual activities. A limited number of studies tried to answer whether virtual activities match our real-world (RW) activities. Moreover, to our knowledge, there was no study that dealt with these interrelations between virtual and RW activities among the pathological and nonpathological users of the Internet (i.e. PIUs and NPIUs). The primary aim of this study was to fill this gap and to investigate the correlations between virtual-world (VW) and RW activities among PIUs and NPIUs. The secondary aim was to examine the perceptions of the Internet and motivations to go online for PIUs and NPIUs. The third aim was to compare virtual and RW activities across gender and age groups. The results indicated that correlations between most of the activities in RW and VW were high among men and women, among age groups, and also among PIUs and NPUs. However, beyond these similarities, perceptions of the Internet and motivations to browse into VW were differed among PIUs and NPIUs. In other words, PIUs, but not NPIUs, perceived VW activities more gratified and had motivations to go online for gratified functions. PMID- 22524481 TI - Using an eye-tracker to assess the effectiveness of a three-dimensional riding simulator in increasing hazard perception. AB - A crucial factor contributing to the high rate of road accidents involving young people is inexperience, in particular the inability to promptly identify risky situations. The aim of this study is to test the effectiveness of a riding simulator in improving this skill in young inexperienced riders. We use the first fixation latency to measure the improvement in detecting the hazardous object. Results show that four training sessions can significantly affect promptness in detecting new hazardous objects as they appear, decreasing the time needed to orient the eyes to the hazard. PMID- 22524482 TI - What women want - quantifying the perception of hair amount: an analysis of hair diameter and density changes with age in caucasian women. AB - BACKGROUND: It has long been known that women lose satisfaction with their hair with ageing. Our data show that caucasian women perceive a decrease in hair amount in their mid 40s with a further decrease in the mid to late 50s, which leads to this dissatisfaction. Neither loss of density (hairs per cm(2) ) nor shaft diameter alone can fully account for this perception. A new metric, 'hair amount', is proposed as a quantitative metric combining the impact of both density and diameter on the perception of hair loss. OBJECTIVES: Creation of a single parameter combining the contribution of diameter and density to perception of female age-related hair loss. METHODS: In total, 1099 caucasian women (ages 18 66 years) with self-perceived hair loss and 315 caucasian women (ages 17-86 years) with no complaint of hair loss were evaluated. Scalp hair diameter was measured using optical fibre diameter and image analysis. Scalp hair density was measured by phototrichogram with manual or automated counting. RESULTS: Parietal scalp hair diameter increased from ages 20 to 40-45 years, then decreased. Hair density was highest in the youngest group, age 20-30 years, and decreased thereafter with increasing rate. In women self-perceiving hair loss, the rate of decrease in density was significantly faster than for women with no self perception of hair loss. The combined metric 'hair amount' was relatively constant at younger ages, increasing very slightly to age 35 years, then decreasing significantly. CONCLUSIONS: Increasing hair shaft diameter offsets decreasing hair density through the mid 30s. After that, a lower rate of diameter increase combined with the decrease in density begins to significantly impact the perception of hair amount so that thinning becomes increasingly more noticeable in the mid 40s to the mid to late 50s. Quantitative determination of hair amount is a useful tool to combine the contributions of hair density and diameter to women's perception of age-related hair loss. PMID- 22524483 TI - Design, synthesis, and antiviral activity of entry inhibitors that target the CD4 binding site of HIV-1. AB - The CD4 binding site on HIV-1 gp120 has been validated as a drug target to prevent HIV-1 entry to cells. Previously, we identified two small molecule inhibitors consisting of a 2,2,6,6-tetramethylpiperidine ring linked by an oxalamide to a p-halide-substituted phenyl group, which target this site, specifically, a cavity termed "Phe43 cavity". Here we use synthetic chemistry, functional assessment, and structure-based analysis to explore variants of each region of these inhibitors for improved antiviral properties. Alterations of the phenyl group and of the oxalamide linker indicated that these regions were close to optimal in the original lead compounds. Design of a series of compounds, where the tetramethylpiperidine ring was replaced with new scaffolds, led to improved antiviral activity. These new scaffolds provide insight into the surface chemistry at the entrance of the cavity and offer additional opportunities by which to optimize further these potential-next-generation therapeutics and microbicides against HIV-1. PMID- 22524485 TI - A new route to fabricate large-area, compact Ag metal mesh films with ordered pores. AB - Ordered Si nanowire (SiNW) arrays can be fabricated by metal-assisted chemical etching. The metal mesh films (MMFs) are extremely important for achieving a high quality of the SiNWs. We have developed a two-step chemical deposition method to obtain compact porous Ag MMFs. By the separation of the nucleation and growth stages of the metal in the two-step deposition processes, the overgrowth of the metals to form randomly aggregated irregular metal particles can be overcome. Hexagonally arranged polystyrene (PS) latex microspheres have been employed as a template for the deposition of porous Ag MMFs. The spacing of the pores in the Ag MMFs is determined by the diameter of PS microspheres, and the pore size can also be tuned by changing Ar plasma etching time. One of the main advantages of the two-step deposition method lies in that Ag MMFs can be produced with PS microspheres that are not limited to a single layer, which dramatically simplifies the tedious processes of producing a monolayered PS template. The two step chemical deposition method shows great potential in metal-assisted chemical etching. PMID- 22524484 TI - An evolving perspective on physical activity counselling by medical professionals. AB - BACKGROUND: Physical inactivity is a modifiable risk factor for many chronic conditions and a leading cause of premature mortality. An increasing proportion of adults worldwide are not engaging in a level of physical activity sufficient to prevent or alleviate these adverse effects. Medical professionals have been identified as potentially powerful sources of influence for those who do not meet minimum physical activity guidelines. Health professionals are respected and expected sources of advice and they reach a large and relevant proportion of the population. Despite this potential, health professionals are not routinely practicing physical activity promotion. DISCUSSION: Medical professionals experience several known barriers to physical activity promotion including lack of time and lack of perceived efficacy in changing physical activity behaviour in patients. Furthermore, evidence for effective physical activity promotion by medical professionals is inconclusive. To address these problems, new approaches to physical activity promotion are being proposed. These include collaborating with community based physical activity behaviour change interventions, preparing patients for effective brief counselling during a consultation with the medical professional, and use of interactive behaviour change technology. SUMMARY: It is important that we recognise the latent risk of physical inactivity among patients presenting in clinical settings. Preparation for improving patient physical activity behaviours should commence before the consultation and may include physical activity screening. Medical professionals should also identify suitable community interventions to which they can refer physically inactive patients. Outsourcing the majority of a comprehensive physical activity intervention to community based interventions will reduce the required clinical consultation time for addressing the issue with each patient. Priorities for future research include investigating ways to promote successful referrals and subsequent engagement in comprehensive community support programs to increase physical activity levels of inactive patients. Additionally, future clinical trials of physical activity interventions should be evaluated in the context of a broader framework of outcomes to inform a systematic consideration of broad strengths and weaknesses regarding not only efficacy but cost-effectiveness and likelihood of successful translation of interventions to clinical contexts. PMID- 22524486 TI - A home-based approach to managing multi-drug resistant tuberculosis in Uganda: a case report. AB - This case report describes an HIV-positive patient with recurrent tuberculosis in Uganda. After several failed courses of treatment, the patient was diagnosed with multi-drug resistant tuberculosis (MDR-TB). As adequate in-patient facilities were unavailable, we advised the patient to remain at home, and he received treatment at home via his family and a community nurse. The patient had a successful clearance of tuberculosis. This strategy of home-based care represents an important opportunity for treatment of patients in East Africa, where human resource constraints and inadequate hospital facilities exist for complex patients at high risk of infection to others. PMID- 22524487 TI - Intubation of the morbidly obese patient: GlideScope((r)) vs. FastrachTM. AB - BACKGROUND: Several potential problems can arise from airway management in morbidly obese patients, including difficult mask ventilation and difficult intubation. We hypothesised that endotracheal intubation of morbidly obese patients would be more rapid using the GlideScope((r)) (GS) (Verathon Inc Corporate Headquarters, Bothell, WA, USA) than with the FastrachTM (FT) (The Laryngeal Mask Company Ltd, Le Rocher, Victoria, Mahe, Seychelles). METHODS: One hundred patients who were scheduled for bariatric surgery were randomised to tracheal intubation using either a GS or an FT. The inclusion criteria were age 18-60 years and a body mass index of >= 35 kg/m(2) . The primary end point was intubation time, and if intubation was not achieved after two attempts, the other method was used for the third attempt. RESULTS: The mean intubation time was 49 s using the GS and 61 s using the FT (P = 0.86). A total of 92% and 84% of the patients were intubated on the first attempt using the GS and the FT, respectively. One tracheal intubation failed on the second attempt when the GS was used, and five failed on the second attempt when the FT was used. There were no incidents of desaturation and no differences between the groups in terms of mucosal damage or intubation difficulty. We experienced one oesophageal intubation using GS and six oesophageal intubations in five patients using FT. There was no difference between the pain scores or incidence of post-operative hoarseness associated with the two intubation techniques. CONCLUSION: No significant difference between the two methods was found. The GS and the FT may therefore be considered to be equally good when intubating morbidly obese patients. PMID- 22524488 TI - Fecal calprotectin levels are increased in infants with necrotizing enterocolitis. AB - OBJECTIVE: To investigate the value of fecal calprotectin in diagnosis and predicting severity of necrotizing enterocolitis (NEC) in preterm infants. METHODS: A prospective controlled study was conducted including preterm infants with stage 2 to 3 NEC, and birth weight and gestational age-matched controls. Fecal samples were obtained both at the time of NEC diagnosis and 3-5 days later from the patients, and at similar postnatal age from controls. RESULTS: Twenty five infants with stage 2 to 3 NEC and 25 controls were enrolled. Median fecal calprotectin concentrations were 1,282 and 365 ug/g at diagnosis in infants with NEC and controls, respectively. Fecal calprotectin levels of infants with NEC were significantly higher than those of the control group both in the first and second samples. Although the fecal calprotectin levels gradually decreased from the time of diagnosis to the second sampling time in stage 2 NEC, in stage 3 NEC fecal calprotectin concentrations increased to a higher level. A fecal calprotectin value of 792 ug/g was found to be 76% sensitive and 92% specific for the diagnosis of definite NEC. CONCLUSION: Fecal calprotectin increases in infants with NEC and serial measurements may be useful as a noninvasive prognostic marker for progression of disease. PMID- 22524489 TI - Preparation, stability, and structural characterization of plutonium(VII) in alkaline aqueous solution. AB - A freshly prepared solution of Pu(VI) in 2 M NaOH was oxidized to Pu(VII), via ozonolysis, while simultaneously collecting X-ray absorption spectra. Analyses of the XANES (X-ray absorption near edge structure) and EXAFS (extended X-ray absorption fine structure) data, acquired throughout the in situ experiments, show a dioxo coordination environment for Pu(VI), PuO(2)(2+), typical for it and the hexavalent actinyl species of U and Np, and its evolution into a tetraoxo coordination environment for Pu(VII), PuO(4)(-), like that known for Np(VII). The EXAFS data provide average Pu-O distances of 1.79(1) and 1.88(1) A, respectively. The second coordination shells, also fit as O atoms, provide Pu-O distances of 2.29-2.32 A that are independent of the Pu oxidation state. The coordination numbers for the distant O atoms in sums with those for the nearest O atoms are consistent with 6-O environments for both Pu(VI) and Pu(VII) ions in accordance with their previously proposed speciation as [Pu(VI)O(2)(OH)(4)](2-) and [Pu(VII)O(4)(OH)(2)](3-), respectively. This solution speciation accounts precisely for the Pu(VI) and Pu(VII) coordination environments reported in various solid state structures. The Pu(VII) tetraoxo-dihydroxo anion was found to have a half-life of 3.7 h. Its instability is attributed to spontaneous reduction to Pu(VI) and not to a measurable extent of disproportionation. We found no direct evidence for Pu(VIII) in the X-ray data and, furthermore, the stoichiometry of the oxidation of Cr(III) by Pu is consistent with that expected for a valence-pure Pu(VII) preparation by ozonation and, in turn, stoichiometrically equivalent to the established Np(VII)/Cr(III) redox reaction. PMID- 22524490 TI - One-step synthesis of highly functionalized monofluorinated cyclopropanes from electron-deficient alkenes. AB - The unique combination of Zn/LiCl allowed generation of reactive zinc enolate from ethyl dibromofluoroacetate. This fluorinated enolate reacts efficiently with a wide range of functionalized electron-deficient alkenes to afford the corresponding monofluorinated cyclopropylcarboxylates in good yields. PMID- 22524491 TI - The steric hypothesis for DNA replication and fluorine hydrogen bonding revisited in light of structural data. AB - In DNA, bases pair in a molecular interaction that is both highly predictable and exquisitely specific. Therefore researchers have generally believed that the insertion of the matching nucleotide opposite a template base by DNA polymerases (pols) required Watson-Crick (W-C) hydrogen bond formation. However pioneering work by Kool and co-workers using hydrophobic base analogs such as the thymine (T) isostere 2,4-difluorotoluene (F) showed that shape rather than H-bonding served as the primary source of specificity in DNA replication by certain pols. This steric hypothesis for DNA replication has gained popularity, perhaps discouraging further experimental studies to address potential limitations of this new idea. The idea that shape trumps H-bonding in terms of pol selectivity largely hinges on the belief that fluorine is a poor H-bond acceptor. However, the shape complementarity model was embraced in the absence of any detailed structural data for match (F:A) and mismatch pairs (F:G, F:C, F:T) in DNA duplexes or at active sites of pols. Although the F and T nucleosides are roughly isosteric, it is unclear whether F:A and T:A pairs exhibit similar geometries. If the F:A pair is devoid of H-bonding, it will be notably wider than a T:A pair. Because shape and size and H-bonding are intimately related, it may not be possible to separate these two properties. Thus the geometries of an isolated F:A pair in water may differ considerably from an F:A pair embedded in a stretch of duplex DNA, at the tight active site of an A-family replicative pol, or within the spacious active site of a Y-family translesion pol. The shape complementarity model may have more significance for pol accuracy than efficiency: this model appears to be most relevant for replicative pols that use specific residues to probe the identity of the nascent base pair from the minor groove side. However, researchers have not fully considered the importance of such interactions that include H-bonds compared with W-C H-bonds in terms of pol fidelity and the shape complementarity model. This Account revisits the steric hypothesis for DNA replication in light of recent structural data and discusses the role of fluorine as an H-bond acceptor. Over the last 5 years, crystal structures have emerged for nucleic acid duplexes with F paired opposite to natural bases or located at the active sites of DNA pols. These data permit a more nuanced understanding of the role of shape in DNA replication and the capacity of fluorine to form H-bonds. These studies and additional research involving RNA or other fluorine-containing nucleoside analogs within duplexes indicate that fluorine engages in H-bonding in many cases. Although T and F are isosteric at the nucleoside level, replacement of a natural base by F in pairs often changes their shapes and sizes, and dF in DNA behaves differently from rF in RNA. Similarly, the pairing geometries observed for F and T opposite dATP, dGTP, dTTP, or dCTP and their H-bonding patterns at the active site of a replicative pol differ considerably. PMID- 22524492 TI - Producing sperm, egg and embryo donors' pen portraits and other personal information for later use by donor offspring: an exploratory study of professional practices. AB - This study considered professional input into collecting personalized donor information for later release to donor offspring. Existing studies report the importance of such information for identity completion, to satisfy curiosity, and to allay anxiety about genetic inheritance. The study used a three-pronged approach: a literature search of professional practices in this and related fields; key informant telephone interviews with donor-conceived adults, sperm and egg donors, and professionals and a postal survey of UK clinics' practices and views. The literature revealed only one previous study, which suggested gendered approaches to pen portraits were used in commercial donor banks. Key informants agreed on the importance of information for offspring well-being and the need for support services in its compilation and on release. Donors reported inadequate professional assistance to date. The postal survey of clinics revealed variable practices in the process of acquiring and storing later life information and variable success in achieving its completion. Respondents identified factors that hinder completion (donor anxiety, lack of guidance, shortage of staff time) and factors that help (donor belief in the importance of later life information, staff belief, dedicated staff time). Further research, including intervention studies, is needed into the processes and skills involved in collecting later life information. PMID- 22524494 TI - Simultaneous detection of the IPN and ISA viruses in outbreaks of clinical disease and mortality in farmed Atlantic salmon, Salmo salar L., in Chile. PMID- 22524493 TI - Trait and state corticostriatal dysfunction in bipolar disorder during emotional face processing. AB - OBJECTIVES: Convergent evidence supports limbic, anterior paralimbic, and prefrontal cortex (PFC) abnormalities in emotional processing in bipolar disorder (BD) and suggests that some abnormalities are mood-state dependent and others persist into euthymia. However, few studies have assessed elevated, depressed, and euthymic mood states while individuals processed emotional stimuli of varying valence to investigate trait- and state-related neural system responses. Here, regional brain responses to positive, negative, and neutral emotional stimuli were assessed in individuals with BD during elevated, depressed, and euthymic mood states. METHODS: One hundred and thirty-four subjects participated in functional magnetic resonance imaging scanning while processing faces depicting happy, fearful, and neutral expressions: 76 with BD (18 in elevated mood states, 19 depressed, 39 euthymic) and 58 healthy comparison (HC) individuals. Analyses were performed for BD trait- and mood state-related features. RESULTS: Ventral anterior cingulate cortex (VACC), orbitofrontal cortex (OFC), and ventral striatum responses to happy and neutral faces were decreased in the BD group, compared to the HC group, and were not influenced by mood state. Elevated mood states were associated with decreased right rostral PFC activation to fearful and neutral faces, and depression was associated with increased left OFC activation to fearful faces. CONCLUSIONS: The findings suggest that abnormal VACC, OFC, and ventral striatum responses to happy and neutral stimuli are trait features of BD. Acute mood states may be associated with additional lateralized abnormalities of diminished right rostral PFC responses to fearful and neutral stimuli in elevated states and increased left OFC responses to fearful stimuli in depressed states. PMID- 22524495 TI - Measuring memory monitoring with judgements of retention (JORs). AB - Most prior research has examined predictions of future memory performance by eliciting judgements of learning (JOLs). In six experiments, we explored monitoring with an alternative prospective measure. Specifically, participants made judgements of retention (JORs) predicting how long (in min) they would be able to remember information. Results revealed that participants provided relatively short predictions of how long they would remember information. Further, participants' JORs were sensitive to recall performance as well as manipulations that influenced memory performance indicating that they were able to effectively monitor learning using JORs. JORs influenced study decisions as well, with participants selecting more items for restudy following JORs than following JOLs or no monitoring judgement. However, restudy selection did not vary between a JOR and a JOL condition framed in terms of forgetting. Thus, we suggest that, much like forget-framed JOLs, JORs may bring different information such as memory failure-to mind. In all, the inferential mechanisms underlying metacognitive monitoring with JOLs extends to monitoring when measured with JORs. Assessing monitoring with JORs provides information not available with JOLs (i.e., memory duration estimates) and a different basis for study decisions from remember-framed JOLs. PMID- 22524496 TI - Erect posture of humans leads to male infertility, BPH and prostate cancer. PMID- 22524497 TI - Postsurgical pathology reporting of thyroid cancer in New South Wales, Australia. AB - BACKGROUND: Clear, accurate, and complete reporting of postsurgical pathology is crucial for the correct evaluation and management of thyroid cancer patients. This study aimed to describe the completeness, as defined by international guidelines, of pathology reporting in a cohort of newly diagnosed thyroid cancer patients in New South Wales (NSW) and to identify factors associated with the completeness of reports. METHODS: Postsurgical pathology reports, held by the NSW Central Cancer Registry, for 448 thyroid cancer patients were reviewed. Presence or absence of recommended key features (tumor histology type, maximum dimension, focality, completeness of excision, extrathyroidal extension, lymphovascular invasion, and lymph node involvement) was recorded. Associations between the number of key items reported and several patient characteristics were investigated. RESULTS: For 285 (63.6%) patients one or more key pathological features were missing, with 177 (39.5%) missing one only, 88 (19.6%) missing two, and 20 (4.5%) missing three or more. Extrathyroidal extension was the most poorly reported key feature, being present in only 228 (50.9%) reports [95% confidence interval 46.2, 55.6]. Pathology reports were less complete for patients with small tumor size (p<0.001) or localized spread (p<0.001). Synoptic reports were significantly more complete than narrative-style reports (98.3% vs. 27.1%, p<0.001). CONCLUSIONS: Postsurgical pathology reporting of differentiated thyroid cancer in NSW was found to be far from complete, with 64% of reports missing information on at least one feature that is considered internationally to be a critical factor in the prognosis and treatment of thyroid cancer patients. Synoptic reporting reduces the number of key features missing from pathology reports. PMID- 22524498 TI - Histological patterns of locoregional recurrence in Hurthle cell carcinoma of the thyroid gland. AB - BACKGROUND: Hurthle cell carcinoma (HCC) is regarded as an aggressive variant of follicular thyroid carcinoma based in part on its propensity to metastasize regionally and recur locally. The current treatment recommendation of formal regional lymph node dissection is largely based on the presumption of lymphatic dissemination to cervical lymph nodes as the main mechanism of regional spread. The purpose of this study was to better define the distribution of locoregional recurrence in HCC, and specifically to differentiate soft-tissue implants from true nodal metastases. METHODS: The surgical pathology files of The Johns Hopkins Hospital were searched for cases of HCC with locoregional recurrences. The slides were reviewed to assess the histologic patterns of tumor spread, including the presence or absence of lymph node metastasis. Elastic staining was used to confirm vessel invasion. RESULTS: Twenty-four cases from 19 patients were identified. Thirteen were men, and the patients ranged in age from 35 to 83 years (mean 66). All had total or near-total thyroidectomies, and 16 received postoperative radioactive iodine. The time from primary diagnosis to first recurrence ranged from 0 to 12 years (mean 5 years). The locoregional disease involved the lateral neck (n=16), central neck (n=18), and larynx/trachea (n=4). In all 24 cases, the dominant tumor nodule was present as a rounded nodule of carcinoma within the soft tissues and unassociated with lymphoid tissue. Of 22 cases evaluated by elastic staining, 13 had tumor nodules within veins. True lymph node metastases were present in only six (25%) cases, and in all but one case, the lymph node metastases were <0.5 cm. CONCLUSIONS: When HCC spreads in the neck, it usually does so as soft-tissue implants likely resulting from spread within venous channels. True lymph node metastases are not a major source of nodular recurrences in the neck. Resolving the pattern of tumor spread could help guide and refine the management of locoregional recurrence for patients with HCC. PMID- 22524499 TI - Differentiated thyroid carcinoma after 131I-MIBG treatment for neuroblastoma during childhood: description of the first two cases. AB - BACKGROUND: It is well known that the thyroid gland is sensitive to the damaging effects of irradiation (X-radiation or (131)I-). For this reason, during exposure to (131)I- metaiodobenzylguanidine (MIBG) in children with neuroblastoma (NBL), the thyroid gland is protected against radiation damage by the administration of either potassium iodide (KI) or a combination of KI, thyroxine, and methimazole. Although hypothyroidism and benign thyroid nodules are frequently encountered during follow-up of these children, differentiated thyroid carcinoma (DTC) has never been reported after treatment with (131)I-MIBG in children who have not been given external beam irradiation. Here, we describe the first two cases of DTC after (131)I-MIBG-therapy. PATIENT FINDINGS: A 6-year-old boy, treated with (131)I-MIBG for NBL at the age of 4 months, and a 13-year-old girl, treated at the age of 9 months, were both diagnosed with DTC at 5 and 12 years after (131)I MIBG treatment, respectively. Both children received thyroid protection during exposure to (131)I-MIBG. In each child DTC was discovered in nonpalpable nodules by thyroid ultrasound. SUMMARY: The first two pediatric patients with DTC after treatment with (131)I-MIBG are reported. CONCLUSIONS: Both these cases of DTC after (131)I-MIBG for childhood NBL underline the importance of adequate thyroid protection against radiation exposure during treatment for NBL. Children who have been treated with (131)I-MIBG should be given life-long follow-up, not only with regard to thyroid function, but also with surveillance for the development of thyroid nodules and thyroid cancer. PMID- 22524500 TI - Dietary shifts affect the gastrointestinal microflora of the giant panda (Ailuropoda melanoleuca). AB - Giant pandas exhibit seasonal changes in bamboo plant part preference. The influences on the gastrointestinal tracts (GIT) microbial populations were evaluated during a 14-month period for a pair of adult male and female giant pandas housed at the Memphis Zoo using traditional culturing methods to enumerate eight bacterial groups (total anaerobes, total aerobes (TAR), streptococci (STR), total enterics, Escherichia coli, Bacteroides spp., lactobacilli and Clostridium spp.). Both the male and female pandas altered bamboo consumption behaviours, with a sharp decrease in leaf preference in April 2010 and returning to high levels of leaf preference from June to October, corresponding to significant shifts in the densities of TAR, STR, and lactobacilli and Bacteroides spp. These findings indicate seasonal changes in food preference affect the assemblages of microbial populations within the GIT of the giant panda and contribute to a better understanding of the importance of bamboo in this species' foraging strategy. PMID- 22524501 TI - Cognitive structures in women with sexual dysfunction: the role of early maladaptive schemas. AB - INTRODUCTION: Cognitive schemas are often related to psychological problems. However, the role of these structures within sexual problems is not yet well established. AIM: The aim of this study was to evaluate the presence and importance of early maladaptive schemas on women's sexual functioning and cognitive schemas activated in response to negative sexual events. METHODS: A total of 228 women participated in the study: a control sample of 167 women without sexual problems, a subclinical sample of 37 women with low sexual functioning, and a clinical sample of 24 women with sexual dysfunction. MAIN OUTCOME MEASURES: Participants completed several self-reported measures: the Schema Questionnaire, the Questionnaire of Cognitive Schema Activation in Sexual Context, the Brief Symptom Inventory, the Beck Depression Inventory, and the Female Sexual Function Index. RESULTS: Findings indicated that women with sexual dysfunction presented significantly more early maladaptive schemas from the Impaired Autonomy and Performance domain, particularly failure (P < 0.001, eta(2) = 0.08), dependence/incompetence (P < 0.05, eta(2) = 0.03), and vulnerability to danger (P < 0.05, eta(2) = 0.04). Additionally, in response to negative sexual events, women with sexual dysfunction presented significantly higher scores on incompetence (P < 0.001, eta(2) = 0.16), self-depreciation (P < 0.01, eta(2) = 0.05), and difference/loneliness (P < 0.01, eta(2) = 0.05) schemas. CONCLUSIONS: Results supported differences between women with and without sexual problems regarding cognitive factors. This may have implications for the knowledge, assessment, and treatment of sexual dysfunction in women. PMID- 22524502 TI - Regio- and stereoselectivity in the reactions of organometallic reagents with an electron-deficient and an electron-rich vinyloxirane: applications for sequential bis-allylic substitution reactions in the generation of vicinal stereogenic centers. AB - Vinyloxiranes provide opportunities for bis-allylic substitution reactions and the generation of new vicinal stereogenic centers if regio- and stereocontrol can be achieved. Ethyl (E)-4,5-epoxy-2-hexenoate affords excellent S(N)2':S(N)2 regioselectivity and anti:syn product diastereoselectivity with dialkyzinc reagents in the presence of CuCN, and conversion of the resultant allylic alcohol to the acetate affords good syn:anti product diastereoselectivity in S(N)2' selective allylic substitutions with alkylcyanocuprates in THF. (E)-1-(tert Butyldimethylsilyloxy)-2,3-epoxy-4-hexenonate gives excellent S(N)2':S(N)2 regioselectivity and anti:syn product diastereoselectivity with dialkyzinc reagents in THF or DMF or Grignard reagents in Et(2)O/THF (10/1) in the presence of CuCN. Conversion of the product allylic alcohol into the allylic phosphate affords excellent S(N)2' regioselectivity and syn:anti product diastereoselectivity with lithium alkylcyanocuprates for primary and secondary alkyl transferable ligands, while S(N)2 regioselectivity is observed for the tert butyl ligand. Reaction conditions have been developed for regio- and stereocontrolled bis-allylic substitution reactions on both electron-rich and electron-deficient alkenyloxiranes, providing a methodology for the generation of vicinal alkane stereogenic centers. PMID- 22524503 TI - Scope and limitations of surface functional group quantification methods: exploratory study with poly(acrylic acid)-grafted micro- and nanoparticles. AB - The amount of grafted poly(acrylic acid) on poly(methyl methacrylate) micro- and nanoparticles was quantified by conductometry, (13)C solid-state NMR, fluorophore labeling, a supramolecular assay based on high-affinity binding of cucurbit[7]uril, and two colorimetric assays based on toluidine blue and nickel complexation by pyrocatechol violet. The methods were thoroughly validated and compared with respect to reproducibility, sensitivity, and ease of use. The results demonstrate that only a small but constant fraction of the surface functional groups is accessible to covalent surface derivatization independently of the total number of surface functional groups, and different contributing factors are discussed that determine the number of probe molecules which can be bound to the polymer surface. The fluorophore labeling approach was modified to exclude artifacts due to fluorescence quenching, but absolute quantum yield measurements still indicate a major uncertainty in routine fluorescence-based surface group quantifications, which is directly relevant for biochemical assays and medical diagnostics. Comparison with results from protein labeling with streptavidin suggests a porous network of poly(acrylic acid) chains on the particle surface, which allows diffusion of small molecules (cutoff between 1.6 and 6.5 nm) into the network. PMID- 22524505 TI - Categorized or continuous? Strength of an association - and linear regression. PMID- 22524504 TI - Stabilization of fenofibrate in low molecular weight hydroxypropylcellulose matrices produced by hot-melt extrusion. AB - The objective of this study was to improve the dissolution rate and to enhance the stability of a poorly water-soluble and low glass-trasition temperature (T(g)) model drug, fenofibrate, in low molecular weight grades of hydroxypropylcellulose matrices produced by hot-melt extrusion (HME). Percent drug loading had a significant effect on the extrudability of the formulations. Dissolution rate of fenofibrate from melt extruded pellets was faster than that of the pure drug (p < 0.05). Incorporation of sugars within the formulation further increased the fenofibrate release rates. Differential scanning calorimetry results revealed that the crystalline drug was converted into an amorphous form during the HME process. Fenofibrate is prone to recrystallization due to its low T(g). Various polymers were evaluated as stabilizing agents among which polyvinylpyrrolidone 17PF and amino methacrylate copolymer exhibited a significant inhibitory effect on fenofibrate recrystallization in the hot-melt extrudates. Subsequently immediate-release fenofibrate tablets were successfully developed and complete drug release was achieved within 5 min. The dissolution profile was comparable to that of a currently marketed formulation. The hot-melt extruded fenofibrate tablets were stable, and exhibited an unchanged drug release profile after 3-month storage at 40 degrees C/75% RH. PMID- 22524506 TI - Materials for rechargeable lithium-ion batteries. AB - The lithium-ion battery is the most promising battery candidate to power battery electric vehicles. For these vehicles to be competitive with those powered by conventional internal combustion engines, significant improvements in battery performance are needed, especially in the energy density and power delivery capabilities. Recent discoveries and advances in the development of electrode materials to improve battery performance are summarized. Promising substitutes for graphite as the anode material include silicon, tin, germanium, their alloys, and various metal oxides that have much higher theoretical storage capacities and operate at slightly higher and safer potentials. Designs that attempt to accommodate strain owing to volumetric changes upon lithiation and delithiation are presented. All known cathode materials have storage capacities inferior to those of anode materials. In addition to variations on known transition metal oxides and phosphates, other potential materials, such as metal fluorides, are discussed as well as the effects of particle size and electrode architecture. New electrolyte systems and additives as well as their effects on battery performance, especially with regard to safety, are described. PMID- 22524507 TI - Advances in bioactive hydrogels to probe and direct cell fate. AB - Advanced cell culture techniques are increasingly needed to better understand basic cell physiology, predict in vivo response, and engineer de novo functional tissue substitutes. Toward this concept, hydrogels have emerged as biomimetic in vitro culture systems that allow cells to be grown in or on user-defined microenvironments that recapitulate many critical aspects of native tissue. Hydrogel biofunctionality can be engineered predictably and precisely via the tailorability of the hydrogel's chemical and mechanical properties, each of which directly influences cell fate. In this review, we highlight state-of-the-art hydrogel platforms that have been used to assay and define cell behavior, placing an emphasis on recent directions in systems that offer dynamic control of material properties in time and space. We review current understanding of cell material interactions in 2D and discuss recent and future efforts, as well as challenges, in extending this work to 3D. Ultimately, advances in hydrogel culture systems, synthetic approaches, and biological assays that can be performed in 3D are providing new opportunities to recapitulate fully the native cell niche. PMID- 22524508 TI - Flavone-based novel antidiabetic and antidyslipidemic agents. AB - The hybrid congeners 62-90 of 6- and 7-hydroxyflavones with aminopropanol have been synthesized and evaluated for their antidiabetic activity in sucrose challenged low-dosed streptozotocin (STZ)-induced diabetic rats and db/db mice. The optical enantiomers 70a, 70b, 90a, and 90b of two congeners 70 and 90 exhibiting consistent antidiabetic and antidyslipidemic activities were also prepared, and their antidiabetic activity results indicate its association mainly with S isomers. These compounds also lower cholesterol and TG profiles while improving high-density lipoprotein cholesterol to CHOL ratio in db/db mice. The bioavailability of compound 70 and its isomer varies between 27 and 29% whereas that of the more polar compound 90a is poor as determined in rat by oral and intraperitoneal administrations. PMID- 22524509 TI - Patient satisfaction with post-operative telephone calls after Mohs micrographic surgery: a New Zealand and U.K. experience. AB - BACKGROUND: Mohs micrographic surgery (MMS) is regarded as the gold standard for treating nonmelanoma skin cancers of the head and neck. Surgical interventions can generate anxiety for patients and efforts to minimize this may enhance their experience. OBJECTIVES: To assess the perceived patient benefits of post-operative telephone follow-up (TFU) calls after MMS. METHODS: A prospective, controlled, questionnaire-based assessment of patient satisfaction with TFU calls in patients undergoing MMS was conducted in two centres (New Zealand and U.K.) over a 4-month period from June to September 2011. All individuals in the study group were telephoned on the evening of their surgery by the operating surgeon. Questionnaires were completed by all patients at the time of suture removal. RESULTS: The median Likert score on a 10-point scale relating to patients' perception of the TFU service was higher in the study group compared with the control group (10 vs. 9), with no correlation to closure type of the surgical defect. Overall patient satisfaction with the TFU service was high (94% New Zealand; 96% U.K.), and this was independent of the patient's place of residence. There was no age or sex difference in the minority who did not find the TFU call helpful. The majority of patients felt the best time to call was the night of the surgery (89% New Zealand; 94% U.K.). All patients who had undergone MMS previously found the TFU call just as useful as the first time. The majority of patients (94% New Zealand; 96% U.K.) did not need to call the doctor post surgery, although 7% of patients in the control group rang the surgeon with issues that could have been readily dealt with by the TFU service. Comparatively, more patients from the U.K. felt their satisfaction would have been the same with a nurse-led TFU call service compared with New Zealand (94% vs. 66%). A significant proportion of those who preferred to be called by the doctor underwent cutaneous flap closures. Patients felt that other specialities that perform surgical procedures under local anaesthetic should adopt a TFU service post-surgery. CONCLUSIONS: TFU calls post-MMS are a cost-effective, time efficient way of achieving high levels of patient satisfaction. PMID- 22524511 TI - 1,2,3-triazole: unique ligand in promoting iron-catalyzed propargyl alcohol dehydration. AB - A 1,2,3-traizole-promoted iron(III)-catalyzed propargyl alcohol dehydration was developed for the synthesis of conjugated enynes. The desired conjugated enynes were prepared in good to excellent yields (up to 95%) with a large substrate scope and excellent stereoselectivity (only Z-isomers). PMID- 22524510 TI - The potential role of the antioxidant and detoxification properties of glutathione in autism spectrum disorders: a systematic review and meta-analysis. AB - BACKGROUND: Glutathione has a wide range of functions; it is an endogenous anti oxidant and plays a key role in the maintenance of intracellular redox balance and detoxification of xenobiotics. Several studies have indicated that children with autism spectrum disorders may have altered glutathione metabolism which could play a key role in the condition. METHODS: A systematic literature review and meta-analysis was conducted of studies examining metabolites, interventions and/or genes of the glutathione metabolism pathways i.e. the gamma-glutamyl cycle and trans-sulphuration pathway in autism spectrum disorders. RESULTS: Thirty nine studies were included in the review comprising an in vitro study, thirty two metabolite and/or co-factor studies, six intervention studies and six studies with genetic data as well as eight studies examining enzyme activity. CONCLUSIONS: The review found evidence for the involvement of the gamma-glutamyl cycle and trans-sulphuration pathway in autistic disorder is sufficiently consistent, particularly with respect to the glutathione redox ratio, to warrant further investigation to determine the significance in relation to clinical outcomes. Large, well designed intervention studies that link metabolites, cofactors and genes of the gamma-glutamyl cycle and trans-sulphuration pathway with objective behavioural outcomes in children with autism spectrum disorders are required. Future risk factor analysis should include consideration of multiple nutritional status and metabolite biomarkers of pathways linked with the gamma-glutamyl cycle and the interaction of genotype in relation to these factors. PMID- 22524512 TI - Tongue numbness following laryngeal mask airway SupremeTM and i-gelTM insertion: two case reports. AB - We present two cases of transient lingual nerve injury that were associated with the use of a laryngeal mask airway SupremeTM (The Laryngeal Mask Company, Singapore) during lumbar discectomy in a 43-year-old female and i-gelTM (Intersurgical, Berkshire, UK) during ovum pick up in a 33-year-old female. They presented with numbness at the tip of their tongues and spontaneously and fully recovered 2 weeks after their operations. PMID- 22524513 TI - JAK2V617F allele burden is associated with transformation to myelofibrosis. AB - The JAK2V617F mutation has emerged in recent years as a diagnostic as well as treatment target in patients with polycythemia vera (PV). We analyzed JAK2V617F allele burden (JAK2(V617F)) in a Jewish population with PV. Results were correlated with disease symptoms and complications. Median JAK2(V617F) was 48% and 54% in patients of Ashkenazi and non-Ashkenazi origin, respectively (p =0.75). Higher JAK2(V617F) was seen in patients with imaging-proven splenomegaly (p =0.01). A correlation between JAK2(V617F) and the weekly hydoxyurea dose needed for disease control was found (p =0.043). In addition, a trend for higher allele burden in patients with longer disease duration (p =0.064) and those treated with cytoreductive drugs other than hydroxyurea (p =0.056) was noted. Higher JAK2(V617F) was seen in patients with transformation to myelofibosis (p =0.0001), but not in patients with vascular complications. JAK2(V617F) may assist in prognostic stratification of patients with PV. PMID- 22524514 TI - Cross-talk between the general stress response and sporulation initiation in Bacillus subtilis - the sigma(B) promoter of spo0E represents an AND-gate. AB - The general stress response and the decision-making processes of sporulation initiation are interconnected pathways in the regulatory network of Bacillus subtilis. In a previous study we provided evidence for a mechanism capable of impairing sporulation by sigma(B) -dependent induction of spo0E, encoding a phosphatase specifically inactivating the sporulation master regulator Spo0A~P. Here we show that the sigma(B) promoter (Psigma(B)) of spo0E is responsive to sub inhibitory levels of ethanol stress, producing a sigma(B) -dependent sporulation deficient phenotype. In addition to positive regulation by sigma(B) , we identified Rok, the repressor of comK, to be a direct repressor of spo0E expression from Psigma(B) . This constellation provides the possibility to integrate signals negatively acting on sporulation initiation through the sigma(B) branch as well as a positive feedback loop acting on Psigma(B) by Rok that is most likely a direct consequence of Spo0A~P activity. Thus, the molecular mechanism described here offers the opportunity for cross-talk between the general stress response and sporulation initiation in the adaptational gene expression network of B. subtilis. PMID- 22524515 TI - Photoisomerization and proton-coupled electron transfer (PCET) promoted water oxidation by mononuclear cyclometalated ruthenium catalysts. AB - Photoisomeric transformations in ruthenium polypyridyl complexes have been rarely reported. Herein we report the geometrical transformation of cyclometalated trans [Ru(tpy)(PAD)(OH(2))](+) ([1](+)) to the cis-[Ru(tpy)(PAD)(OH(2))](+) ([1a](+)) (tpy = 2,2';6',2"-terpyridine, PAD = 2-(pyrid-2'-yl)acridine) isomer upon irradiation of visible light (lambda >=420 nm). Due to a proton-induced tautomeric equilibrium between the Ru-C bond and Ru?C coordination, the pi* energy levels of PADH are lower than those of tpy by 12.61 and 12.24 kcal mol( 1), respectively, in [1](+) and [1a](+). Isomers [1](+) and [1a](+) both act as catalytic oxygen-evolving complexes (OECs) chemically as well as electrochemically. PMID- 22524516 TI - 3D macroporous graphene frameworks for supercapacitors with high energy and power densities. AB - In order to develop energy storage devices with high power and energy densities, electrodes should hold well-defined pathways for efficient ionic and electronic transport. Herein, we demonstrate high-performance supercapacitors by building a three-dimensional (3D) macroporous structure that consists of chemically modified graphene (CMG). These 3D macroporous electrodes, namely, embossed-CMG (e-CMG) films, were fabricated by using polystyrene colloidal particles as a sacrificial template. Furthermore, for further capacitance boost, a thin layer of MnO(2) was additionally deposited onto e-CMG. The porous graphene structure with a large surface area facilitates fast ionic transport within the electrode while preserving decent electronic conductivity and thus endows MnO(2)/e-CMG composite electrodes with excellent electrochemical properties such as a specific capacitance of 389 F/g at 1 A/g and 97.7% capacitance retention upon a current increase to 35 A/g. Moreover, when the MnO(2)/e-CMG composite electrode was asymmetrically assembled with an e-CMG electrode, the assembled full cell shows remarkable cell performance: energy density of 44 Wh/kg, power density of 25 kW/kg, and excellent cycle life. PMID- 22524517 TI - Association between pregnancy-associated plasma protein-A and gestational diabetes requiring insulin treatment at 11-14 weeks of gestation. AB - OBJECTIVE: To evaluate whether gestational diabetes mellitus (GDM) requiring insulin treatment (White's classification A2) is associated with an alteration of pregnancy-associated plasma protein-A (PAPP-A) serum levels at first-trimester screening between 11 and 14 weeks of gestation. METHODS: We collected data (2007 2010) of all women who developed GDM requiring insulin treatment and completed first-trimester combined screening program including the determination of serum PAPP-A and free beta-human chorionic gonadotropin (beta-hCG). A total of 288 women were included in this study. Each of the 72 women who developed GDM was matched with three unaffected controls. RESULTS: Women with GDM were significantly older (34.2 +/- 5.9 vs. 32.3 +/- 5.5 years, P = 0.007) and delivered significantly earlier (38.40 +/- 2.25 vs. 39.1 +/- 2.2 gestational weeks, P = 0.01). Multiple regression analysis revealed, that PAPP-A and beta-hCG were independently associated with each other (P = 0.04) but there was no association between GDM/no GDM and the first-trimester serum markers (P = 0.77). CONCLUSION: Our data suggest that women who are developing GDM needing insulin treatment do not have altered PAPP-A levels at 11-14 weeks. PMID- 22524519 TI - Impact of the nanoparticle-protein corona on colloidal stability and protein structure. AB - In biological fluids, proteins may associate with nanoparticles (NPs), leading to the formation of a so-called "protein corona" largely defining the biological identity of the particle. Here, we present a novel approach to assess apparent binding affinities for the adsorption/desorption of proteins to silver NPs based on the impact of the corona formation on the agglomeration kinetics of the colloid. Affinities derived from circular dichroism measurements complement these results, simultaneously elucidating structural changes in the adsorbed protein. Employing human serum albumin as a model, apparent affinities in the nanomolar regime resulted from both approaches. Collectively, our findings now allow discrimination between the formation of protein mono- and multilayers on NP surfaces. PMID- 22524518 TI - Apolipoprotein E COG 133 mimetic peptide improves 5-fluorouracil-induced intestinal mucositis. AB - BACKGROUND: Intestinal mucositis is one of the major troublesome side effects of anticancer chemotherapy leading to poor patient compliance. In this study we addressed the role of the novel apolipoprotein E (ApoE) COG 133 mimetic peptide in 5-fluorouracil (5-FU)-challenged Swiss mice and IEC-6 cell monolayers. Experiments were also conducted in C57BL6J ApoE knock-out mice to assess the effects of apoE peptide treatment. METHODS: Experimental groups were as follows: unchallenged controls, 5-FU-challenged mice (450 mg/kg, i.p) with or without the ApoE peptide (0.3, 1, and 3 MUM, given twice daily i.p. for 4 days). Mice were sacrificed 3 days after 5-FU challenge. Proximal small intestinal samples were harvested for molecular biology and histological processing. We conducted ELISA assays and RT-PCR to target IL-1beta, TNF-alpha, IL-10, iNOS, and myeloperoxidase (MPO) to assess intestinal inflammation. Cell death and NF-kappaB assays were also conducted in apoE knock-out mice. In our in vitro models, IEC-6 cells were exposed to 1 mM of 5-FU in glutamine free media with or without the ApoE peptide (0.02, 0.2, 2, 5, 10, and 20 MUM). We investigated IEC-6 cell proliferation and migration, 24 h after the 5-FU challenge. Additionally, apoptotic IEC-6 cells were measured by Tunel and flow cytometry. Equimolar doses of the ApoA-I (D4-F) peptide were also used in some experiments for comparative studies. RESULTS: Villus blunting and heavy inflammatory infiltrates were seen in the 5-FU challenged group, findings that were partially ameliorated by the ApoE peptide. We found increased intestinal MPO and pro-inflammatory IL-1beta and TNF-alpha levels, and TNF-alpha and iNOS transcripts, and reduction of IL-10 following 5-FU treatment, each of which were partially abrogated by the peptide. Improvements were also found in IEC-6 cell apoptosis and migration following ApoE and D-4F treatment. CONCLUSION: Altogether, these findings suggest that the novel ApoE COG 133 mimetic peptide can reduce 5-FU-induced intestinal changes and potentially benefit mucositis. PMID- 22524520 TI - Out of your hand's reach, out of my eyes' reach. AB - When witnessing another's action, people recruit the same motor resources that enable them to efficiently perform that action, thus gazing at its target well before the agent's hand. But just to what extent does this recruitment help people in grabbing another's action target? If the latter seems to be out of the agent's reach, will this impact on people's gaze behaviour? We recorded proactive eye movements while participants witnessed someone else trying to reach for and grasp objects located either within or outside his reach. Proactivity of gaze was impaired when the targets were just out of the agent's reach. This effect is likely to be due to an interpersonal bodily space representation that allows one to map another's reaching space, thus prompting proactive eye movements towards the target just in case the agent is in the position to act upon it. PMID- 22524521 TI - Infectivity study of Streptococcus phocae to seven fish and mammalian cell lines by confocal microscopy. AB - Streptococcus phocae is a beta-haemolytic bacterium that causes systemic infections in Atlantic salmon, Salmo salar L., cultured in southern Chile and also in seals. In this study, the host-pathogen interaction between S. phocae and seven types of cell lines (fish and mammalian) was examined using an indirect fluorescent antibody and confocal microscopy (CM). Chinook salmon embryo (CHSE 214), epithelioma papulosum cyprini (EPC), salmon head kidney (SHK-1) and Atlantic salmon kidney were used as the fish cell lines, while human cervix epithelial adenocarcinoma (HeLa), African green monkey kidney fibroblast (Cos-7) and mouse leukaemic monocyte macrophage (Raw 264.7) were included as mammalian cell lines. Streptococcus phocae type strain ATCC 51973(T) and isolates LM-08-Sp and P23 were selected as representatives from the salmon and seal host, respectively. For the CM examination, monolayers seeded on round coverslips were studied at 2- and 20-h post-inoculation (pi). The results showed that there is no common infectivity pattern between the three S. phocae strains at 2-h pi and the cell lines tested, regardless of the source of isolation (seal or salmon). All S. phocae strains could internalize and were found inside the fish and mammalian cell cytoplasm after 20-h pi. Regardless of the cells studied (fish or mammal) and incubation (2 and 20 h), S. phocae was never observed inside the nuclei. Seal and salmon isolates showed the highest number of bacteria entering into the primate cell lines (HeLa and Cos-7) from 2-h pi, while ATCC 51973(T) was not found outside or inside the HeLa and Cos-7 cells. PMID- 22524522 TI - S-testosterone decrease after a mixed meal in healthy men independent of SHBG and gonadotrophin levels. AB - Reproducible and accurate assessment of serum testosterone (S-T), S-LH and S-SHBG is of crucial importance for assessment of testicular endocrine function and diagnosis of hypogonadism and investigating male health in a broader sense. Testosterone secretion has a circadian rhythm with the highest component in the morning and is influenced by a series of factors including physical activity, mental stress and nutrition. For diagnostic purposes, analysis of morning samples is recommended and reference values are generally based on samples drawn between 7 and 10 am. In the literature, there are also indications that food intake can influence serum levels but fasting has not been a standard procedure. To carefully address the influence of food intake, we analysed S-testosterone, S-LH and S-SHBG after an overnight fasting compared to samples taken after a standard meal of 550 kcal. We found no change in S-LH or S-SHBG but a decline of S-T of 30% from 60 to 120 min after food intake compared to samples taken in the fasting state. This decline may give false low S-T values and overestimate the number of men with suspected hypogonadism. Until the mechanism behind this effect has been explored, we suggest that assessment of S-T for diagnostic purposes should be collected in the morning after an overnight fasting. PMID- 22524524 TI - Dosing of insulin glargine to achieve the treatment target in Japanese type 2 diabetes on a basal supported oral therapy regimen in real life: ALOHA study subanalysis. AB - AIM/INTRODUCTION: Subsample analysis was performed to examine whether dose optimization of insulin glargine (Lantus((r)); Sanofi-Aventis K.K., Tokyo, Japan) contributed to achieving a target glycosylated hemoglobin (HbA1c) (<7.0%) by using the data from the Add-on Lantus to Oral Hypoglycemic Agents (ALOHA) study, a 24-week observational study of Japanese type 2 diabetes patients. We investigated the conditions of optimal dose titration by identifying patient background of dose-achiever and non-achiever subgroups. SUBJECTS AND METHODS: The insulin-naive patients (n=3,180) were categorized into four groups depending on their HbA1c and insulin glargine dose at 24 weeks: patients with HbA1c <7.0% and dose <8.5 U/day (Group 1), HbA1c <7.0% and dose >=8.5 U/day (Group 2), HbA1c >=7.0% and dose <8.5 U/day (Group 3), and HbA1c >=7.0% and dose >=8.5 U/day (Group 4). RESULTS: The greatest reduction in HbA1c was observed in Group 2 ( 2.7%, P<0.001 vs. Group 3 or 4). Fasting plasma glucose (FPG) in Group 2 at 24 weeks (113.3 mg/dL) was significantly lower than in either Group 3 or 4 (135.4 mg/dL and 150.0 mg/dL, respectively; P<0.001 for both). The starting dose and the change of insulin glargine dose were significantly greater in Group 2 than in Group 3 (0.142 vs. 0.086 U/kg/day [P<0.001] and +5.0 vs. +1.1 U/day [P<0.001], respectively), whereas the baseline HbA1c levels and body mass index were comparable (9.3% vs. 9.4% and 23.5 kg/m(2) vs. 23.3 kg/m(2), respectively). CONCLUSIONS: Our results suggest that appropriate starting dosage and subsequent dose adjustment are essential to achieve target HbA1c (<7%) and that the FPG level should be decreased to be 110 mg/dL or below for this achievement. PMID- 22524523 TI - Synthesis of phidianidines A and B. AB - Reaction of a substituted indole-3-acetyl chloride with N-5-azidopentyl-N' hydroxyguanidine generated a substituted 3-(5-azidopentylamino)-5-((indol-3 yl)methyl)-1,2,4-oxadiazole. Reduction of the azide with zinc and ammonium formate afforded the amine, which was elaborated to the guanidine, completing short and efficient syntheses of the cytotoxic natural products phidianidines A and B in 19% overall yield by a convergent route that will make analogues readily available for biological evaluation. Initial screening in the NCI 60 cell line at 10(-5) M indicated that the bromine on the indole is necessary for activity and that the amine precursor to phidianidine A is more potent than phidianidine A. PMID- 22524525 TI - Beyond "Initiate-Build-Operate-Transfer" strategy for creating sustainable telemedicine programs: lesson from the first decade. AB - BACKGROUND: December 10, 2012 will mark the 10th anniversary of the implementation of telemedicine in the Balkans. This first decade of development and function is due to the passion, creativity, experience, and implementation know-how of the award-winning concept of the International Virtual e-Hospital (IVeH) Foundation. The objective of this article is to analyze the results of the IVeH's core strategy, "Initiate-Build-Operate-Transfer" (IBOT), which has been instrumental in establishing telemedicine in the Balkans and has been adopted by many other countries worldwide, and to describe the lessons learned that go beyond IBOT. MATERIALS AND METHODS: A retrospective review of the results of IVeH engagement in establishing telemedicine in developing countries was conducted. RESULTS: Using IBOT, the IVeH has successfully established two national programs: one in Kosova and one in Albania. Together, they have connected 16 hospitals. Currently IVeH is in the process of creating such programs in many countries around the world. During the analysis of the first decade, we have identified eight factors that should be considered when establishing telemedicine programs. CONCLUSION: IBOT has been successful, but further studies are needed to demonstrate its effectiveness in countries beyond the Balkans. PMID- 22524526 TI - Specific and nonspecific effects of glycosylation. AB - Glycosylation regulates vital cellular processes and dramatically influences protein folding and stability. In particular, experiments have demonstrated that asparagine (N)-linked disaccharides drive a "conformational switch" in a model peptide. The present work investigates this conformational switch via extensive atomically detailed replica exchange molecular dynamics simulations in explicit solvent. To distinguish the effects of specific and nonspecific interactions upon the peptide conformational ensemble, these simulations considered model peptides that were N-linked to a disaccharide and to a steric crowder of the same shape. The simulations are remarkably consistent with experiment and provide detailed insight into the peptide structure ensemble. They suggest that steric crowding by N-linked disaccharides excludes extended conformations, but does not significantly impact the tetrahedral structure of the surrounding solvent or otherwise alter the peptide free energy surface. However, the combination of steric crowding with specific hydrogen bonds and hydrophobic stacking interactions more dramatically impacts the peptide ensemble and stabilizes new structures. PMID- 22524528 TI - Characterization of an endophytic whorl-forming Streptomyces from Catharanthus roseus stems producing polyene macrolide antibiotic. AB - An endophytic whorl-forming Streptomyces sp. designated as TS3RO having antifungal activity against a large number of fungal pathogens, including Sclerotinia sclerotiorum, Rhizoctonia solani, Colletotrichum gloeosporioides, Cryphonectria parasitica, Fusarium oxysporum, Pyrenophora tritici-repentis, Epidermophyton floccosum, and Trichophyton rubrum, was isolated from surface sterilized Catharanthus roseus stems. Preliminary identification showed that Streptomyces cinnamoneus subsp. sparsus was its closest related species. However, strain TS3RO could readily be distinguished from this species using a combination of phenotypic properties, 16S rDNA sequence similarity, and phylogenetic analyses. Thus, the whorl-forming Streptomyces sp. strain TS3RO is likely a new subspecies within the Streptomyces cinnamoneus group. Direct bioautography on a thin-layer chromatography plate with Cladosporium cucumerinum was conducted throughout the purification steps for bioassay-guided isolation of the active antifungal compounds from the crude extract. Structural elucidation of the isolated bioactive compound was obtained via LC-MS spectrometry, UV-visible spectra, and nuclear magnetic resonance data. It revealed that fungichromin, a known methylpentaene macrolide antibiotic, was the main antifungal component of TS3RO strain, as shown by thin-layer chromatography bioautography. This is the first report of an endophytic whorl-forming Streptomyces isolated from the medically important plant Catharanthus roseus. PMID- 22524527 TI - Structure-based design of novel inhibitors of the MDM2-p53 interaction. AB - Structure-based rational design led to the discovery of novel inhibitors of the MDM2-p53 protein-protein interaction. The affinity of these compounds for MDM2 was improved through conformational control of both the piperidinone ring and the appended N-alkyl substituent. Optimization afforded 29 (AM-8553), a potent and selective MDM2 inhibitor with excellent pharmacokinetic properties and in vivo efficacy. PMID- 22524529 TI - Schizophyllum commune as an emerging fungal pathogen: a review and report of two cases. AB - We report Schizophyllum commune as the aetiological agent of one case each of allergic broncho-pulmonary mycosis (ABPM) and pulmonary fungal ball, and present a literature review. The fungus was characterised by clamp connections, hyphal spicules, and formation of basidiocarps with basidiospores. The phenotypic identification was confirmed by sequencing of the ITS region. To-date, ABPM and pulmonary fungal ball to S. commune have been reported exclusively from Japan and North America respectively. Of the 71 globally reported cases due to S. commune, 45 (63%) were bronchopulmonary, 22 (31%) sinusitis and 4 extrapulmonary. Taken together, cases of bronchopulmonary disease and sinusitis numbered 67 (94%), indicating the respiratory tract as the primary target of disease. Concerning the country-wise distribution, Japan topped the list with 33 cases (46%), followed by Iran - 7 cases (10%), U.S.A. - 6 cases (9%), and a lower prevalence of 1.4-6% for the remaining 12 countries. The preponderance of the disease in Japan may be attributed to its greater awareness vis-a-vis that in other countries rather than to any geographical/climatic factors. We believe that the burden of S. commune incited disease is currently underestimated, warranting comprehensive prospective studies to determine its prevalence. PMID- 22524530 TI - TNF-alpha, erectile dysfunction, and NADPH oxidase-mediated ROS generation in corpus cavernosum in high-fat diet/streptozotocin-induced diabetic rats. AB - INTRODUCTION: Patients with diabetes-associated erectile dysfunction (ED) are characterized by an increase in circulating tumor necrosis factor-alpha (TNF alpha). However, no study has indicated whether and how TNF-alpha plays a role in the pathogenesis of ED associated with diabetes. AIM: We examined the effects and potential mechanism of infliximab (INF), a chimeric monoclonal antibody to TNF alpha, on reactive oxygen species (ROS) generation in corpus cavernosum and ED in diabetic rats. METHODS: Four groups of male rats were used: age-matched normal controls; diabetic rats induced by a high-fat diet (HFD) combined with a single streptozotocin (STZ) injection (35 mg/kg body weight, intraperitoneal [i.p.]); nondiabetic rats receiving INF (5 mg/kg body weight/week, i.p.), and diabetic rats receiving INF. Erectile function was assessed with electrical stimulation of the cavernous nerve after 8 weeks. The blood and penile tissues were harvested for plasma biochemical determinations, serum TNF-alpha measurement, penile ROS detection, and molecular assays of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, endothelial nitric oxide synthase (eNOS), phospho-eNOS, and neural nitric oxide synthase (nNOS) in the penis. MAIN OUTCOME MEASURES: The effect of INF on HFD/STZ-induced diabetic ED and NADPH oxidase-mediated ROS generation was studied in diabetic corpus cavernosum. RESULTS: Untreated diabetic rats displayed significantly decreased erectile parameters, and increased plasma TNF-alpha levels, penile ROS production, p47(phox) and gp91(phox) expression compared with nondiabetic controls. INF neutralized TNF-alpha and significantly reduced ED in diabetic rats, in which marked decreases in p47(phox) and gp91(phox) expression and ROS generation in corpus cavernosum were noted. The ratio of phospho-eNOS to eNOS and expression of nNOS in the penis were significantly increased in INF-treated vs. untreated diabetic rats. CONCLUSIONS: Increased TNF-alpha expression associated with diabetes contributes to ED by promoting NAPDH oxidase-mediated ROS generation in corpus cavernosum. INF protects against diabetic ED by neutralizing TNF-alpha. PMID- 22524531 TI - Lung elastance and transpulmonary pressure can be determined without using oesophageal pressure measurements. AB - INTRODUCTION: The aim of the present study was to demonstrate that lung elastance and transpulmonary pressure can be determined without using oesophageal pressure measurements. METHODS: Studies were performed on 13 anesthetized and sacrificed ex vivo pigs. Tracheal and oesophageal pressures were measured and changes in end expiratory lung volume (DeltaEELV) determined by spirometry as the cumulative inspiratory-expiratory tidal volume difference. Studies were performed with different end-expiratory pressure steps [change in end-expiratory airway pressure (DeltaPEEP)], body positions and with abdominal load. RESULTS: A PEEP increase results in a multi-breath build-up of end-expiratory lung volume. End-expiratory oesophageal pressure did not increase further after the first expiration, constituting half of the change in DeltaEELV following a PEEP increase, even though end-expiratory volume continued to increase. This resulted in a successive left shift of the chest wall pressure-volume curve. Even at a PEEP of 12 cmH(2) O did the end-expiratory oesophageal (pleural) pressure remain negative. CONCLUSIONS: A PEEP increase resulted in a less than expected increase in end expiratory oesophageal pressure, indicating that the chest wall and abdomen gradually can accommodate changes in lung volume. The rib cage end-expiratory spring-out force stretches the diaphragm and prevents the lung from being compressed by abdominal pressure. The increase in transpulmonary pressure following a PEEP increase was closely related to the increase in PEEP, indicating that lung compliance can be calculated from the ratio of the change in end expiratory lung volume and the change in PEEP, DeltaEELV/DeltaPEEP. PMID- 22524532 TI - A Monte Carlo study comparing PIV, ULS and DWLS in the estimation of dichotomous confirmatory factor analysis. AB - We conducted a Monte Carlo study to investigate the performance of the polychoric instrumental variable estimator (PIV) in comparison to unweighted least squares (ULS) and diagonally weighted least squares (DWLS) in the estimation of a confirmatory factor analysis model with dichotomous indicators. The simulation involved 144 conditions (1,000 replications per condition) that were defined by a combination of (a) two types of latent factor models, (b) four sample sizes (100, 250, 500, 1,000), (c) three factor loadings (low, moderate, strong), (d) three levels of non-normality (normal, moderately, and extremely non-normal), and (e) whether the factor model was correctly specified or misspecified. The results showed that when the model was correctly specified, PIV produced estimates that were as accurate as ULS and DWLS. Furthermore, the simulation showed that PIV was more robust to structural misspecifications than ULS and DWLS. PMID- 22524533 TI - microRNA profiling in duodenal ulcer disease caused by Helicobacter pylori infection in a Western population. AB - Although the connection of microRNAs (miRNAs) to some diseases is well established, their involvement in chronic infections such as Helicobacter pylori has received less attention. The aim was to compare miRNA expression profiling in patients with duodenal ulcer (DU) due to H. pylori infection with that in infected patients without DU and in uninfected patients. The miRNA expression profile was determined by microarrays in antral mucosal samples from well characterized dyspeptic patients (n = 46). The most significant set of miRNAs was subsequently analysed in an independent validation group of patients (n = 42). Transcripts for IL8, IL12p40, IL12p35 and IL23p19, the signalling molecules MYD88, GATA6, SOCS2 and STAT6 and H. pylori virulence factors cagA and VacA were analysed. Microarray experiments showed that 17 miRNAs were deregulated in the mucosa of H. pylori-infected patients. No significant differences were observed between normal and DU patients. PCR confirmed the up-regulation of miR-9, miR 146a, miR-155 and miR-650 and the down-regulation of miR-96 and miR-204 in the independent validation set of patients. Importantly, miR-9, miR-96, miR-146a and miR-650 expression was specific to chronic-active gastritis. H. pylori-infected patients showed higher levels of IL8 and IL12p40 mRNAs and lower levels of GATA6 and SOCS2 mRNAs. The antral mucosa of patients with non-active or chronic-active gastritis showed significantly lower levels of GATA6, MYD88, SOCS2 and STAT6 mRNAs compared with patients without gastritis. The down-regulation of these factors was not correlated with the expression of any of the validated miRNAs. The exact role of the miRNA changes observed will require further study. PMID- 22524535 TI - Laser-induced periodic surface structures nanofabricated on poly(trimethylene terephthalate) spin-coated films. AB - Here we present a precise morphological description of laser-induced periodic surface structures (LIPSS) nanofabricated on spin-coated poly(trimethylene terephthalate) (PTT) films by irradiation with 266 nm, 6 ns laser pulses and by using a broad range of fluences and number of pulses. By accomplishing real and reciprocal space measurements by means of atomic force microscopy and grazing incidence wide- and small-angle X-ray scattering respectively on LIPSS samples, the range of optimum structural order has been established. For a given fluence, an increase in the number of pulses tends to improve LIPSS in PTT. However, as the pulse doses increase above a certain limit, a distortion of the structures is observed and a droplet-like morphology appears. It is proposed that this effect could be related to a plausible decrease of the molecular weight of PTT due to laser-induced chain photo-oxidation by irradiation with a high number of pulses. A concurrent decrease in viscosity enables destabilization of LIPSS by the formation of droplets in a process similar to surface-limited dewetting. PMID- 22524534 TI - Access to spirocyclic oxindoles via N-heterocyclic carbene-catalyzed reactions of enals and oxindole-derived alpha,beta-unsaturated imines. AB - A diastereoselective access to beta-lactam fused spirocyclic oxindoles and related compounds bearing all carbon spiro centers is described. This N heterocyclic carbene-catalyzed process employed challenging beta,beta disubstituted alpha,beta-unsaturated imines to react with enals. PMID- 22524536 TI - Neonatal outcome of the pregnancies associated with placental villous thrombosis thrombophilic status of the mothers and the infants. AB - OBJECTIVE: To analyze the relationship of obstetric complications and neonatal outcomes with the thrombophilic status of the mother-infant couples in case of demonstrated placental villous thrombosis in histopathological evaluation after delivery. METHODS: Placentas of high-risk pregnancies, unexplained fetal loss or infants who needed neonatal intensive care unit (NICU) admission were collected at the time of delivery. RESULTS: In a 6 months period, placental villous thrombosis was detected in 30 among 800 placentas. Half of the mothers had a bad obstetric outcome previously, such as at least one abortus or stillbirth. Eighteen neonates (60%) were premature. Seventy-five percent of the neonates (n = 24) needed NICU admission and the mortality rate was 9.3 %. Five of the patients had congenital anomalies. Thrombophilic mutations could be evaluated in seven mothers-infant couples, all of whom had at least one positive mutation for thrombosis. CONCLUSIONS: Severe fetal vasculopathy appears to be a predisposing factor for adverse neonatal outcomes. Analyzing placentas will yield advantages as the same pathological process may repeat in subsequent pregnancies. Thrombophilic mutations should be evaluated to provide the etiology of the adverse outcome and to give prophylaxis for the future pregnancies. PMID- 22524537 TI - Stereoselective synthesis of (S)-3-(methylamino)-3-((R)-pyrrolidin-3 yl)propanenitrile. AB - (S)-3-(methylamino)-3-((R)-pyrrolidin-3-yl)propanenitrile (1) is a key intermediate in the preparation of PF-00951966, (1) a fluoroquinolone antibiotic for use against key pathogens causing community-acquired respiratory tract infections including multidrug resistant (MDR) organisms. The current work describes the development of a highly efficient and stereoselective synthesis of 1 in 10 steps with an overall yield of 24% from readily available benzyloxyacetyl chloride. Two key transformations in the synthetic sequence involve (a) catalytic asymmetric hydrogenation with chiral DM-SEGPHOS-Ru(II) complex to afford beta hydroxy amide 11b in good yield (73%) and high stereoselectivity (de 98%, ee >99%) after recrystallization and (b) S(N)2 substitution reaction with methylamine to provide diamine 14 with inversion of configuration at the 1' position in high yield (80%), after efficient purification using a simple acid/base extraction protocol. PMID- 22524538 TI - Ageing and secondary-distinctiveness-based effects: the orthographic distinctiveness effect is more robust than the bizarreness effect. AB - Differences related to ageing were investigated in two cases of secondary distinctiveness-based effects: the bizarreness effect and the orthographic distinctiveness effect. A secondary distinctiveness effect means that items that are unusual compared to one's general knowledge stored in permanent memory are better remembered than common items. Experiment 1 confirmed that ageing diminishes the facilitative effects of bizarreness in a mixed list design with equal numbers of bizarre and common images. We suggest that the impaired bizarreness effect in older adults (above age 70) may be due to reduced attentional resources, since no bizarreness effect was observed for younger adults in the divided attention condition. Experiment 2 studied the orthographic distinctiveness effect in ageing for the first time. Contrary to our expectations, an orthographic distinctiveness effect was observed for all participants including older adults and younger adults in a divided attention condition. Because reduced attentional resources due to normal ageing or to experimental manipulation did not impact the facilitative effects of orthographic distinctiveness, our findings suggest that the orthographic distinctiveness effect may be mediated by more automatic processing. PMID- 22524539 TI - Isolation and characterization of Aeromonas schubertii from diseased snakehead, Channa maculata (Lacepede). AB - Pure bacterial cultures were isolated from diseased snakeheads, Channa maculata (Lacepede), suffering high mortality in a farm in Zhongshan, southern China. Three isolates, namely ZS20100725, ZS20100725-1 and ZS20100725-2, were identified as Aeromonas schubertii. All the isolates showed high 16S rRNA sequence similarities with A. schubertii. The isolates exhibited strong virulence to snakeheads in experimental challenges with LD(50) ranging between 1.4 * 10(4) and 6.4 * 10(6) CFU g(-1). Two of the isolates were positive for haemolysin, elastase, lipase and lecithinase by phenotypic determination, which was further confirmed by PCR amplification of the haemolysin and elastase genes. In sterile liquid medium, the best growth conditions of strain ZS20100725 were 30 degrees C, pH 7 and 0.5% salinity (w/v). Antibiotic susceptibility tests showed that strain ZS20100725 was susceptible to cefoxitin, cefoperazone and chloramphenicol. Furthermore, histopathology of diseased snakeheads infected with A. schubertii showed necrosis and congestion in liver, kidney and spleen and also damage to the cardiac muscle, intestine and gills. PMID- 22524541 TI - Does arsenic trioxide impact fertility? PMID- 22524540 TI - Conservation of promoter melting mechanisms in divergent regions of the single subunit RNA polymerases. AB - The single-subunit RNA polymerases make up a widespread family of proteins found in phage, mitochondria, and chloroplasts. Unlike the phage RNAPs, the eukaryotic RNAPs require accessory factors to melt their promoters and diverge from the phage RNAPs in the regions where functions associated with promoter melting in the latter have been mapped, suggesting that promoter melting mechanisms in the eukaryotic RNAPs diverge from those in the phage enzymes. However, here we show that an element in the yeast mitochondrial RNAP, identified by sequence alignment with the T7 phage RNAP, fulfills a role in promoter melting similar to that filled by the T7RNAP "intercalating hairpin". The yeast mitochondrial RNAP intercalating hairpin appears to be as important in promoter melting as the mitochondrial transcription factor, MTF1, and both a structurally integral hairpin and MTF1 are required to achieve high levels of transcription on a duplex promoter. Deletions from the hairpin also relieve MTF1 inhibition of promoter escape on premelted promoters, likely because such deletions disrupt interactions with the upstream edge of the transcription bubble. These results are consistent with recent structural and functional studies of human mitochondrial RNAP and further reveal the surprising extent of mechanistic conservation between the eukaryotic and phage-encoded members of the single-subunit RNAP family. PMID- 22524542 TI - Insulin-like growth factor-1 lowers spreading depression susceptibility and reduces oxidative stress. AB - Spreading depression (SD), the likely cause of migraine aura and perhaps migraine, is triggered by widespread and unfettered neuronal hyperexcitability. Migraine and the initiating hyperexcitability of seizure, which involve oxidative stress (OS), are likely interrelated. Environmental enrichment (EE) decreases seizure and can reduce migraine. EE's well-characterized neuroprotective effect involves insulin-like growth factor-1 (IGF-1). Accordingly, we asked if IGF-1 could mitigate the hyperexcitability that initiates SD using rat hippocampal slice cultures. We demonstrate that IGF-1 significantly decreased SD susceptibility and related OS. We mimicked OS of SD and observed that IGF-1 abolished hyperexcitability from OS. Application of an antioxidant significantly decreased SD susceptibility and co-administration of an antioxidant with IGF-1 produced no additive effect, whereas an oxidizer significantly increased SD, and this effect was abrogated by IGF-1. Moreover, IGF-1 significantly decreased baseline OS, despite seemingly paradoxically increasing CA3 bursting. These results suggest that IGF-1 increased endogenous antioxidants to levels sufficient to buffer against the OS of SD. Insulin similarly mitigated SD susceptibility, but required a far greater dose. Since brain IGF-1 increases with EE, and, like insulin, independently functions as an EE mimetic, we suggest that EE mimetics are a novel source of therapeutics for SD, and by extension, migraine. PMID- 22524543 TI - PAPupuncture has localized and long-lasting antinociceptive effects in mouse models of acute and chronic pain. AB - Acupuncture has been used for millennia to treat pain, although its efficacy and duration of action is limited. Acupuncture also has brief (1-2 h) antinociceptive effects in mice and these effects are dependent on localized adenosine A1 receptor (A1R) activation. Intriguingly, adenosine 5'-monophosphate (AMP) is basally elevated near acupuncture points. This finding suggested that it might be possible to inhibit nociception for a longer period of time by injecting prostatic acid phosphatase (PAP, ACPP) into acupuncture points. PAP is an ectonucleotidase that dephosphorylates extracellular AMP to adenosine, has a long half-life in vivo and is endogenously found in muscle tissue surrounding acupuncture points. Here, we found that injection of PAP into the popliteal fossa -a space behind the knee that encompasses the Weizhong acupuncture point--had dose- and A1R-dependent antinociceptive effects in mouse models of acute and chronic pain. These inhibitory effects lasted up to six days following a single injection, much longer than the hour-long inhibition provided by acupuncture. Antinociception could be transiently boosted with additional substrate (AMP) or transiently blocked with an A1R antagonist or an inhibitor of phospholipase C. This novel therapeutic approach--which we term "PAPupuncture"--locally inhibits pain for an extended period of time (100x acupuncture), exploits a molecular mechanism that is common to acupuncture, yet does not require acupuncture needle stimulation. PMID- 22524544 TI - Efficient synthesis of single gold nanoparticle hybrid amphiphilic triblock copolymers and their controlled self-assembly. AB - We report on a robust approach to the size-selective and template-free synthesis of asymmetrically functionalized ultrasmall (<4 nm) gold nanoparticles (AuNPs) stably anchored with a single amphiphilic triblock copolymer chain per NP. Directed NP self-assembly in aqueous solution can be facilely accomplished to afford organic/inorganic hybrid micelles, vesicles, rods, and large compound micelles by taking advantage of the rich microphase separation behavior of the as synthesized AuNP hybrid amphiphilic triblock copolymers, PEO-AuNP-PS, which act as the polymer-metal-polymer analogue of conventional amphiphilic triblock copolymers. Factors affecting the size-selective fabrication and self-assembly characteristics and the time-dependent morphological evolution of NP assemblies were thoroughly explored. PMID- 22524546 TI - Incidentally discovered distant cutaneous metastasis of sacral chordoma: a case with variation in S100 protein expression (compared to the primary tumor) and review of the literature. AB - Chordomas represent rare malignant primary bone tumors most often occurring in the sacral area. These tumors uncommonly involve the skin and often follow a progressive course with multiple recurrences, metastases and eventual death. Reports of cutaneous metastases from chordoma are very rare. The immunohistochemical staining characteristics of these cutaneous metastases with comparison to the primary tumors are similarly rarely addressed in the literature. We report a rare case of incidentally discovered, small, solitary distant cutaneous metastasis of sacral chordoma that developed on the right upper back of a 44-year-old man with a history of multiple completely excised melanomas who had also been previously diagnosed with chordoma involving the sacrum 12 years earlier. We describe its pathologic features with comparison to the primary tumor and briefly review the literature. Immunohistochemically, the cutaneous metastasis and primary tumor both stained positively for pancytokeratin and vimentin, as expected. However, the cutaneous metastasis unexpectedly lacked S100 protein expression, whereas the primary tumor was S100 positive. This phenomenon has only been documented in one other case report. We demonstrate that late, incidentally discovered cutaneous metastasis with unexpected immunohistochemical staining features rarely occur and can present a diagnostic challenge. PMID- 22524545 TI - Volumetric BOLD fMRI simulation: from neurovascular coupling to multivoxel imaging. AB - BACKGROUND: The blood oxygenation-level dependent (BOLD) functional magnetic resonance imaging (fMRI) modality has been numerically simulated by calculating single voxel signals. However, the observation on single voxel signals cannot provide information regarding the spatial distribution of the signals. Specifically, a single BOLD voxel signal simulation cannot answer the fundamental question: is the magnetic resonance (MR) image a replica of its underling magnetic susceptibility source? In this paper, we address this problem by proposing a multivoxel volumetric BOLD fMRI simulation model and a susceptibility expression formula for linear neurovascular coupling process, that allow us to examine the BOLD fMRI procedure from neurovascular coupling to MR image formation. METHODS: Since MRI technology only senses the magnetism property, we represent a linear neurovascular-coupled BOLD state by a magnetic susceptibility expression formula, which accounts for the parameters of cortical vasculature, intravascular blood oxygenation level, and local neuroactivity. Upon the susceptibility expression of a BOLD state, we carry out volumetric BOLD fMRI simulation by calculating the fieldmap (established by susceptibility magnetization) and the complex multivoxel MR image (by intravoxel dephasing). Given the predefined susceptibility source and the calculated complex MR image, we compare the MR magnitude (phase, respectively) image with the predefined susceptibility source (the calculated fieldmap) by spatial correlation. RESULTS: The spatial correlation between the MR magnitude image and the magnetic susceptibility source is about 0.90 for the settings of TE = 30 ms, B0 = 3 T, voxel size = 100 micron, vessel radius = 3 micron, and blood volume fraction = 2%. Using these parameters value, the spatial correlation between the MR phase image and the susceptibility-induced fieldmap is close to 1.00. CONCLUSION: Our simulation results show that the MR magnitude image is not an exact replica of the magnetic susceptibility source (spatial correlation ~ 0.90), and that the MR phase image conforms closely with the susceptibility-induced fieldmap (spatial correlation ~ 1.00). PMID- 22524547 TI - Production of porcine hemoglobin peptides at moderate temperature and medium pressure under a nitrogen stream. Functional and antioxidant properties. AB - A new hydrolysis method for producing peptides from porcine hemoglobin has been developed. Current processes are based on the use of expensive enzymes or high hydrostatic pressures. In the present study, a cheap and effective process has been assayed to produce peptides from purified porcine hemoglobin. A solution of purified hemoglobin is heated at different temperatures and pressurized at 4 MPa while a stream of nitrogen is injected into the reactor. A total of 82% of initial hemoglobin was transformed into peptides presenting an average size of 3.2 kDa. Some preferential hydrolyzed bonds have been detected. The peptide size distribution was evaluated at different times and temperatures. It has been demonstrated that this technique produces large amounts of peptides possessing good antioxidant properties. Furthermore, functional properties are conserved, and a desirable decrease in color (80%) is achieved. PMID- 22524548 TI - Diabetes empowerment, medication adherence and self-care behaviors in adults with type 2 diabetes. AB - BACKGROUND: Evidence suggests that empowerment is an important factor to address everyday aspects of dealing with a chronic disease. This study evaluated the effect of diabetes empowerment on medication adherence and self-care behaviors in adults with type 2 diabetes. SUBJECTS AND METHODS: Data on 378 subjects with type 2 diabetes recruited from two primary care clinics in the southeastern United States were examined. Previously validated scales were used to measure diabetes empowerment, medication adherence, diabetes knowledge, and diabetes self-care behaviors (including diet, physical activity, blood sugar testing, and foot care). Multiple linear regression was used to assess the independent effect of diabetes empowerment on medication adherence and self-care behaviors controlling for relevant covariates. RESULTS: Eighty-three percent were non-Hispanic blacks, 69% were women, 22% were 65 years or older, 68% were not married, 26% had less than high school education, 60% were unemployed, 39% were uninsured, and 47% had a yearly income <$10,000. Empowerment had significant correlations with medication adherence (r=0.17, P<0.003), diabetes knowledge (r=0.16, P=0.007), diet (r=0.24, P<0.001), exercise (r=0.25, P<0.001), blood sugar testing (r=0.12, P=0.043), and foot care (r=0.18, P=0.002). In the regression model, diabetes empowerment was significantly associated with medication adherence (beta=-0.04, P=0.001), diabetes knowledge (beta=0.09, P=0.012), diet (beta=0.09, P<0.001), exercise (beta=0.10, P<0.001), blood sugar testing (beta=0.07, P=0.016), and foot care (beta=0.08, P=0.001). CONCLUSIONS: In this sample, diabetes empowerment was related to better diabetes knowledge, medication adherence and improved self-care behaviors. Emphasis on empowerment and self-efficacy is relevant to improve outcomes in the management of diabetes. PMID- 22524549 TI - Effects of sensor-augmented pump therapy on glycemic variability in well controlled type 1 diabetes in the STAR 3 study. AB - BACKGROUND: Compared with multiple daily injections (MDI), sensor-augmented pump (SAP) insulin therapy may reduce glycemic variability and oxidative stress in type 1 diabetes in a glycosylated hemoglobin (A1C)-independent manner. SUBJECTS AND METHODS: The STAR 3 study compared SAP with MDI therapy for 1 year. Week-long continuous glucose monitoring studies were conducted at baseline and 1 year for assessment of glycemic variability in both groups. Soluble CD40 ligand (CD40L), a biomarker of inflammation and thrombocyte function, was measured at baseline and 1 year. Subjects were classified according to treatment group and 1-year A1C levels (<6.5%, 6.5-6.9%, 7-7.9%, >=8%). Glycemic parameters were compared between SAP and MDI subjects in each A1C cohort. RESULTS: At 1 year, sensor glucose values at A1C levels >=6.5% were similar in the SAP and MDI groups. However, sensor glucose SD and coefficient of variation (CV) values were lower at A1C levels <8% among SAP than among MDI subjects; the overall between-group difference was significant for both SD (P<0.01) and CV (P=0.01). The overall mean amplitude of glycemic excursion was similar in MDI and SAP groups (P=0.23). CD40L levels fell over the course of the study in both groups, but the between-group difference was not significant (P=0.18). CD40L concentrations were unrelated to A1C, change in A1C from baseline, or glycemic variability. CONCLUSIONS: At comparable A1C levels of <8%, SAP reduced glycemic variability as measured by SD and CV compared with MDI. SAP may provide beneficial reductions in the number and severity of glycemic excursions. PMID- 22524550 TI - Confocal laser scanning microscopy as a new valuable tool in the diagnosis of onychomycosis - comparison of six diagnostic methods. AB - Onychomycosis is common and can mimic several different nail disorders. Accurate diagnosis is essential to choose the optimum antifungal therapy. The aim of this study was to evaluate the use of confocal laser scanning microscopy (CLSM) and optical coherence tomography (OCT) as new non-invasive diagnostic tools in onychomycosis and to compare them with the established techniques. In a prospective trial, 50 patients with suspected onychomycosis and 10 controls were examined by CLSM and OCT. Parallel KOH preparation, culture, PAS-staining and PCR were performed. PCR showed the highest sensitivity, followed by CLSM, PAS and KOH preparation. OCT offered the second best sensitivity but displayed the lowest specificity. CLSM and KOH preparation showed a high specificity and CLSM offered the best positive predictive value, similar to KOH preparation and OCT. Fungal culture showed the lowest sensitivity and the worst negative predictive value, yet culture and PCR are the only techniques able to identify genus and species. In summary, CLSM was comparable to PAS staining and superior to KOH preparation. Due to the low specificity we assess OCT not as appropriate. In the differentiation of species PCR outplays the fungal culture in terms of time and sensitivity. PMID- 22524551 TI - Regarding: "access to mobile communication technology and willingness to participate in automated telemedicine calls among chronically ill patients in Honduras". PMID- 22524552 TI - Regarding: "home management of oral anticoagulation via telemedicine versus conventional hospital-based treatment". PMID- 22524553 TI - Regarding: "management of electronic patient record systems in primary healthcare in a Finnish county". PMID- 22524554 TI - The role of pregnancy awareness on female sexual function in early gestation. AB - INTRODUCTION: Female sexual function is negatively influenced by pregnancy due to the physical and emotional changes. Although the most significant effect is seen in the third trimester of pregnancy, a considerable decrease in the frequency of intercourse and sexual desire in the first trimester has also been shown. AIM: To investigate the factors that affect sexuality in early pregnancy and the impact of awareness of pregnancy on female sexual function in the first trimester of pregnancy using two self-reported questionnaires. METHODS: In this cross sectional study, 130 healthy, married pregnant women who were admitted to the gynecology clinic between the 4th and 10th week of gestation were asked to complete a self-administered questionnaire and the female sexual function index (FSFI). MAIN OUTCOME MEASURES: The factors associated with FSFI score and monthly sexual activity frequency in the first trimester, as well as the differences in sexual activity frequency and FSFI scores between the women who were previously aware of their pregnancy and those who were yet unaware of their pregnancy. RESULTS: Women who were unaware of their pregnancy had significantly higher coitus frequency in comparison with the aware group (P = 0.002). Total FSFI score was 21.99 +/- 8.13 in the aware group and 24.66 +/- 3.76 in the unaware group (P = 0.02). None of the obstetric and sociodemographic variables had an influence on desire and pain scores. Arousal, lubrication, and satisfaction scores were adversely affected by awareness of pregnancy. Orgasm scores were influenced negatively by awareness and positively by love marriage; however, in multivariate linear regression analysis none of these were defined as independent factor for orgasm scores. Overall FSFI scores and monthly frequency of sexual activity were only affected by awareness. CONCLUSION: The results of this study suggest that in early gestation, awareness of pregnancy is associated with lower female sexual function. Furthermore, obstetric and sociodemographic factors seem to be ineffective on sexual function in early pregnancy. PMID- 22524555 TI - Ferrocenylselenoamides: synthesis, characterization and cytotoxic properties. AB - A new series of ferrocenyl selenoamides 7-11 (FcSeNH(CH(2))(n)CH(2)(R)OH, n = 1, 2, 3, R = H, Me, Ph) were prepared in good yields by selenative demetalation of Fischer aminocarbene complexes. The crystal structures of 7 [FcSeNH(CH(2))(2)OH] and 19 [PhSeNH(CH(2))(2)OH] reveal their capability to form intermolecular hydrogen bonding in solid state. Results of SRB assays show that these new selenium compounds have a good anticancer potency superior to tamoxifen and cisplatin, with IC(50) values ranging from 4.5 to 13.32 MUM against human breast cancer cell lines. A preliminary model to explain the structure-cytotoxic activity relation is proposed where different structural parameters such as the alkyl chain length, the presence of bulky groups in the same chain, the effect of hydroxyl group, and also the role of ferrocene moiety are included as being responsible for the cytotoxic response. PMID- 22524556 TI - The role of dexamethasone in the treatment of bacterial meningitis - a systematic review. AB - Corticosteroids are used as an adjunct to antibiotics in the treatment of bacterial meningitis in an attempt to attenuate the intrathecal inflammatory response and thereby reduce mortality and morbidity. The purpose of the present paper is to provide a review of clinical studies of corticosteroids in the treatment of bacterial meningitis. Relevant literature was found in PubMed, the Cochrane databases, and references in studies. Forty-four publications of relevance were identified, comprising 29 publications of randomised studies, 10 publications reporting either non- or quasi-randomised studies, and five reporting retrospective studies, and nine meta-analyses. Taken together, dexamethasone treatment may be associated with a lower mortality in adults and fewer neurological and auditory sequelae in adults and children from high-income countries, in particular in adults suffering from pneumococcal meningitis. In contrast, studies conducted in developing countries have yielded less favourable results. PMID- 22524558 TI - UV-induced amino -> imino hydrogen-atom transfer in 1-methylcytosine. AB - Monomers of 1-methylcytosine, isolated in low-temperature argon matrixes, were excited with narrowband tunable UV light. Irradiation at lambda = 314 nm resulted in syn-anti photoisomerizations between the two minor imino-oxo forms of the compound, while the dominating amino-oxo form stayed intact. Subsequent irradiations at 308 nm (as well as at shorter wavelengths) led to the amino -> imino hydrogen-atom transfer converting the biologically relevant amino-oxo tautomer into the imino-oxo forms. This is the first report on the amino -> imino phototautomerism in 1-methylcytosine. The observed UV-induced syn-anti photoisomerizations within the imino-oxo forms of 1-methylcytosine were found to lead to photostationary states. The photostationary [syn]/[anti] population ratio depended on the wavelength of the exciting UV light. This dependence was not monotonous. Spectral indications of the open-ring isocyanate product, generated from the amino-oxo tautomer upon UV (lambda <= 308 nm) irradiation, were also observed. PMID- 22524557 TI - Factors governing the regulation of Sclerotinia sclerotiorum cutinase A and polygalacturonase 1 during different stages of infection. AB - Sclerotinia sclerotiorum releases hydrolytic enzymes that sequentially degrade the plant cuticle, middle lamellae, and primary and secondary cell walls. The cuticle was found to be a barrier to S. sclerotiorum infection, as leaves stripped of epicuticular wax were more rapidly colonized. Consequently, the factors affecting the regulation of genes encoding polygalacturonase 1 (SsPG1) and a newly identified cutinase (SsCUTA) were examined. In vitro, SsCutA transcripts were detected within 1 h postinoculation of leaves, and expression was primarily governed by contact of mycelia with solid surfaces. Expression of SsPg1 was moderately induced by contact with solid surfaces including the leaf, and expression was restricted to the expanding margin of the lesion as the infection progressed. SsPg1 expression was induced by carbohydrate starvation but repressed by galacturonic acid. Glucose supported a basal level of SsPg1 expression but accentuated expression when provided to mycelia used to inoculate leaves. These observations were contrary to earlier reports indicating that glucose repressed SsPg1 expression while galacturonic acid induced expression. Pharmacological studies showed that disruption of calcium signalling affected SsCutA and SsPg1 expression and decreased S. sclerotiorum virulence, whereas elevated cAMP levels reduced virulence without affecting gene expression. The mechanisms involved in coordinating the expression of S. sclerotiorum hydrolytic enzymes throughout the various stages of the infection are discussed. PMID- 22524559 TI - In vitro validation of a new respiratory ultrasonic plethysmograph. AB - OBJECTIVE: The in-vitro validation of a novel Respiratory Ultrasonic Plethysmography (RUP) system designed to detect circumference changes of rib cage and abdominal compartments in large and small animals. STUDY DESIGN: Experimental in vitro study. METHODS: The experimental system includes two compliant fluid filled rubber tubes functioning as ultrasonic waveguides. Each has an ultrasonic transmitter and a detector at the opposing ends. Sensor length can be individually adapted in the range of 0.15-2 m. Data are downloaded to a computer at a sampling rate of 10 or 100 Hz. Measurements have a resolution of 0.3 mm. Baseline stability, linearity and repeatability were investigated with dedicated experiments. The base line drift was tested measuring a fixed distance for 2 hours continuously and then 18 hours later. A hand-operated horse thorax dummy (elliptically shaped, circumference 1.73 m) was used to compare waveforms of RUP with a respiratory inductive plethysmograph (RIP). The electromagnetic interference was tested by approaching metallic objects. RESULTS: Baseline drift and repeatability (10 repeated steps of 1.6% and 6.6% elongations and contractions) were within +/- 0.3 mm. The response of the system for tube stretching up to 11% of total length was linear with a coefficient of determination for linearity of 0.998. In contrast to RIP, electromagnetic interference could not be observed with RUP. CONCLUSIONS AND CLINICAL RELEVANCE: The low baseline drift and the lack of electromagnetic interference favours the use of RUP compared to an RIP device when studying the breathing pattern and end expiratory lung volume changes in conscious and anaesthetized animals. PMID- 22524560 TI - Charge transport through Geobacter sulfurreducens biofilms grown on graphite rods. AB - Biofilms of the electroactive bacterium Geobacter sulfurreducens were induced to grow on graphite-rod electrodes under a potential of 0 V (vs Ag/AgCl) in the presence of acetate as an electron donor. Increased anodic currents for bioelectrocatalytic oxidation of acetate were obtained when the electrodes were incubated for longer periods with periodic electron-donor feeding. The maximum current density for acetate oxidation increased 2.8-fold, and the biofilm thickness increased by 4.25-fold, over a time period of 83-147 h. Cyclic voltammetry in the presence of acetate supports a model of heterogeneous electron transfer, one electron at time, from biofilm to electrode through a dominant redox species centered at -0.41 V vs Ag/AgCl. Voltammetry performed under nonturnover conditions provided an estimate of the surface coverage of the redox species of 25 nmol/cm(2). This value was used to estimate a redox species concentration of 7.3 mM within the 34-MUm-thick biofilm and a charge-transport diffusion coefficient of 3.6 * 10(-7) cm(2)/s. This value of diffusion coefficient is greater than that observed in traditional thin-film voltammetric studies with redox polymer films containing much higher surface concentrations of redox species and might be associated with proton transport to ensure electroneutrality within the biofilm upon electrolysis. PMID- 22524561 TI - Improved procedure to determine non-extractable polymeric proanthocyanidins in plant foods. AB - Proanthocyanidins (PA) or condensed tannins, a major group of oligomeric and polymeric dietary polyphenols, have an essential role on the organoleptic and health-related properties of plant foods. Their content is usually determined by HPLC analysis of aqueous-organic extracts. However, appreciable amounts of polymeric PA that remain in the residues of extraction usually are not considered for the analysis. A complete quantification of PA requires an additional determination of these non-extractable PA (NEPA). The objective of this work was to develop a new procedure to determine the content of NEPA, based in depolymerization by butanolysis, which yields anthocyanidin monomers and xanthylium compounds. Samples and standard are treated with butanol/HCl with FeCl3 (100 degrees C, 60 min), and absorbances at 555 nm (anthocyanidins) and 450 nm (xanthylium compounds) are measured in the hydrolysates. NEPA content determined in some plant foods suggests that procedures based just on anthocyanidin concentration overestimate the actual content. PMID- 22524562 TI - Solid-solutioned homojunction nanoplates with disordered lattice: a promising approach toward "phonon glass electron crystal" thermoelectric materials. AB - The concept of "phonon glass electron crystal" (PGEC) was proposed in the mid 1990s to maximize the ZT value for thermoelectric materials, based on its combined advantages of low thermal conductivity as in a glass but high electricity as in a well-ordered crystal. Although a great amount of research in complex materials systems for achieving this concept has been done, a perfect "PGEC" material has not been acquired yet. Herein, we first put forward a solid solutioned homojunction in high temperature phase with disordered lattice, which possesses both high electrical conductivity and low thermal conductivity, as an effective way to optimize the low/mid-temperature thermoelectric property. As an example, nonambient cubic phase AgBiSe(2) was successfully stabilized to room temperature through the formation of a solid solution by Sb incorporation for the first time, and furthermore, in situ formed homojunctions on the surface of solid solutioned nanoplates were also first achieved through a simple colloidal method. A significant enhancement of thermoelectric performance at low/mid-temperature was realized through synergistical regulation on electronic and thermal transport. As a result, compared to that of original AgBiSe(2) (ZT = 0.03 at 550 K), the ZT value of AgBi(0.5)Sb(0.5)Se(2) was increased to 0.51 at 550 K by the formation of a solid solution, and then further increased to 1.07 at 550 K by the formation of solid-solutioned homojunction. PMID- 22524564 TI - "Object categorization: reversals and explanations of the basic-level advantage" (Rogers & Patterson, 2007): a simplicity account. AB - T. T. Rogers and K. Patterson (2007), in their article "Object Categorization: Reversals and Explanations of the Basic-Level Advantage" (Journal of Experimental Psychology: General, 136, 451-469), reported an impressive set of results demonstrating a reversal of the highly robust basic-level advantage both in patients with semantic dementia and in healthy individuals engaged in a speeded categorization task. To explain their results, as well as the usual basic-level advantage seen in healthy individuals, the authors employed a parallel distributed processing theory of conceptual knowledge. In this paper, we introduce an alternative way of explaining the results of Rogers and Patterson, which is premised on a more restricted set of assumptions born from standard categorization theory. Specifically, we provide evidence that their results can be accounted for based on the predictions of the simplicity model of unsupervised categorization. PMID- 22524565 TI - Development and validation of a range of endogenous controls to support the implementation of practical Taqman real-time PCR-based surveillance for fish diseases within aquaculture. AB - The use of Taqman real-time PCR-based technology has recently become more frequent in the detection of pathogens in the aquaculture industry. This interest has necessitated the development of robust and reliable pathogen-detection assays. The development of a range of endogenous control assays to be run alongside these diagnostic assays works to further increase confidence in the latter. This study describes the design of a range of endogenous control assays based on the elongation factor 1-alpha (EF1-alpha) gene specific to a range of fish species including Atlantic salmon, Salmo salar; rainbow trout, Oncorhynchus mykiss; brown trout, Salmo trutta; cod, Gadus morhua; haddock, Melanogrammus aeglefinus; saithe, Pollachius virens; whiting, Merlangius merlangus; Norway pout, Trisopterus esmarkii; carp (family Cyprinidae), roach, Rutilus rutilus; European eel, Anguilla anguilla; and herring, Clupea harengus, as well as a number of fish cell lines. Evidence is provided of the validation of these assays for specific species, a range of tissue types and cell lines as well as an example of the potential uses of these assays. PMID- 22524563 TI - Ketone bodies protection against HIV-1 Tat-induced neurotoxicity. AB - HIV-1-associated neurocognitive disorder (HAND) is a syndrome that ranges clinically from subtle neuropsychological impairments to profoundly disabling HIV associated dementia. Not only is the pathogenesis of HAND unclear, but also effective treatments are unavailable. The HIV-1 transactivator of transcription protein (HIV-1 Tat) is strongly implicated in the pathogenesis of HAND, in part, because of its well-characterized ability to directly excite neurons and cause neurotoxicity. Consistent with previous findings from others, we demonstrate here that HIV-1 Tat induced neurotoxicity, increased intracellular calcium, and disrupted a variety of mitochondria functions, such as reducing mitochondrial membrane potential, increasing levels of reactive oxygen species, and decreasing bioenergetic efficiency. Of therapeutic importance, we show that treatment of cultured neurons with ketone bodies normalized HIV-1 Tat induced changes in levels of intracellular calcium, mitochondrial function, and neuronal cell death. Ketone bodies are normally produced in the body and serve as alternative energy substrates in tissues including brain and can cross the blood-brain barrier. Ketogenic strategies have been used clinically for treatment of neurological disorders and our current results suggest that similar strategies may also provide clinical benefits in the treatment of HAND. PMID- 22524566 TI - Constraints to exclusive breastfeeding practice among breastfeeding mothers in Southwest Nigeria: implications for scaling up. AB - BACKGROUND: The practice of exclusive breastfeeding is still low despite the associated benefits. Improving the uptake and appropriating the benefits will require an understanding of breastfeeding as an embodied experience within a social context. This study investigates breastfeeding practices and experiences of nursing mothers and the roles of grandmothers, as well as the work-related constraints affecting nurses in providing quality support for breastfeeding mothers in Southwest Nigeria. METHODS: Using a concurrent mixed method approach, a structured questionnaire was administered to 200 breastfeeding mothers. In depth interviews were also held with breastfeeding mothers (11), nurses (10) and a focus group discussion session with grandmothers. RESULTS: Breastfeeding was perceived as essential to baby's health. It strengthens the physical and spiritual bond between mothers and their children. Exclusive breastfeeding was considered essential but demanding. Only a small proportion (19%) of the nursing mothers practiced exclusive breastfeeding. The survey showed the major constraints to exclusive breastfeeding to be: the perception that babies continued to be hungry after breastfeeding (29%); maternal health problems (26%); fear of babies becoming addicted to breast milk (26%); pressure from mother-in law (25%); pains in the breast (25%); and the need to return to work (24%). In addition, the qualitative findings showed that significant others played dual roles with consequences on breastfeeding practices. The desire to practice exclusive breastfeeding was often compromised shortly after child delivery. Poor feeding, inadequate support from husband and conflicting positions from the significant others were dominant constraints. The nurses decried the effects of their workload on providing quality supports for nursing mothers. CONCLUSION: Breastfeeding mothers are faced with multiple challenges as they strive to practice exclusive breastfeeding. Thus, scaling up of exclusive breastfeeding among mothers requires concerted efforts at the macro, meso and micro levels of the Nigerian society. PMID- 22524567 TI - Toward understanding the mechanism of ion transport activity of neuronal uncoupling proteins UCP2, UCP4, and UCP5. AB - Neuronal uncoupling proteins (UCP2, UCP4, and UCP5) have crucial roles in the function and protection of the central nervous system (CNS). Extensive biochemical studies of UCP2 have provided ample evidence of its participation in proton and anion transport. To date, functional studies of UCP4 and UCP5 are scarce. In this study, we show for the first time that, despite a low level of amino acid sequence identity with the previously characterized UCPs (UCP1-UCP3), UCP4 and UCP5 share their functional properties. Recombinantly expressed in Escherichia coli, UCP2, UCP4, and UCP5 were isolated and reconstituted into liposome systems, where their conformations and ion (proton and chloride) transport properties were examined. All three neuronal UCPs are able to transport protons across lipid membranes with characteristics similar to those of the archetypal protein UCP1, which is activated by fatty acids and inhibited by purine nucleotides. Neuronal UCPs also exhibit transmembrane chloride transport activity. Circular dichroism spectroscopy shows that these three transporters exist in different conformations. In addition, their structures and functions are differentially modulated by the mitochondrial lipid cardiolipin. In total, this study supports the existence of general conformational and ion transport features in neuronal UCPs. On the other hand, it also emphasizes the subtle structural and functional differences between UCPs that could distinguish their physiological roles. Differentiation between structure-function relationships of neuronal UCPs is essential for understanding their physiological functions in the CNS. PMID- 22524568 TI - Neuropathies associated with oxaliplatin therapy. PMID- 22524569 TI - Intra-arterial infusion of chemotherapy for advanced hepatocellular carcinoma: an Asian perspective. PMID- 22524570 TI - Posterior reversible encephalopathy syndrome following chemotherapy with oxaliplatin and a fluoropyrimidine: a case report and literature review. AB - Posterior reversible encephalopathy syndrome (PRES) is a neuro-radiological syndrome characterized by seizures, altered level of consciousness and visual disturbance. PRES is associated with hyperintense lesions on magnetic resonance imaging (MRI) most commonly seen in the posterior regions. In most cases symptoms and radiological lesions are reversible. The aims of this article are: (i) to review the literature for all cases involving oxaliplatin, fluoropyrimidine and bevacizumab and (ii) highlight the increasing number of cases attributed to anti neoplastic agents. An in-depth literature review was conducted by utilizing Pubmed's MEDLINE and Google Scholar databases. We found that there have been nine cases of PRES associated with oxaliplatin or fluoropyrimidine therapy; five cases also involved therapy with bevacizumab. Eight of the nine patients made a full recovery with a complete resolution of MRI changes. This is the first Australian case of PRES following treatment with oxaliplatin and a fluoropyrimidine and only the second case reported in which the patient did not recover despite appropriate medical management. It appears that PRES maybe more commonly associated with multi-agent therapies and although reversible in most cases, PRES may result in adverse outcomes despite rapid intervention. PMID- 22524571 TI - Primary nasopharyngeal adenocarcinoma: a review. AB - Primary nasopharyngeal adenocarcinoma (NAC) accounts for approximately 0.5% of all nasopharyngeal cancer. The diagnosis, staging and treatment of NAC has not been well described. This article presents a literature review on NAC and identifies its characteristics and management. The NAC group of diseases contains various pathological types and has a series of specific clinical characteristics, including slow progression, a low incidence of neck masses and frequent cranial neuropathy. The Epstein-Barr virus may not play an important role in NAC carcinogenesis. The rarity of the disease makes the staging classification and treatment strategies of NAC parallel to those recommended for nasopharyngeal squamous carcinoma. Some patients might benefit from surgery, and radiotherapy using precise techniques might achieve good control for treating NAC, but the roles of chemotherapy and target therapy are not clear. The proper staging system and optimal treatment strategies need to be established in NAC. PMID- 22524572 TI - Management of sunitinib adverse events in renal cell carcinoma patients: the Asian experience. AB - Sunitinib is the gold standard of care for patients with metastatic renal cell carcinoma, demonstrating an overall survival benefit of over 2 years in a pivotal phase 3 trial of 750 patients. While sunitinib is generally well tolerated with most adverse events, manifesting as mild to moderate in severity and manageability, it has a distinctive adverse event profile that benefits from careful monitoring during treatment. As sunitinib gains widespread use across the globe, best practices are being developed for specific patient groups. This review will focus on the current clinical trial data in Asian populations and on the mechanism, incidence and management of selected sunitinib-related adverse events, including hand-foot syndrome, hypertension, proteinuria, cardiac toxicities, myelosupression, fatigue/asthenia, hypothyroidism, diarrhea and hepatotoxicity. Taken together, the developing body of literature reviewed here demonstrates that sunitinib is well tolerated in Asian patients and provides efficacy that is similar, if not superior, to other patient groups. Asian patients, like all patients, should begin treatment of sunitinib at 50 mg on Schedule 4/2 (4 weeks on treatment/2 weeks off). Prophylactic measures, good communication between patient and health-care providers, and early, aggressive intervention at the development of adverse events can limit the dose reductions required and maximize both patients' response to treatment and their quality of life. PMID- 22524573 TI - Triple-negative breast cancer: making the most of a misnomer. AB - Triple-negative breast cancer (TNBC) is defined by its lack of (or minimal) estrogen receptor and progesterone receptor expression, together with the absence of human epidermal growth factor receptor 2 overexpression or gene amplification. It can be a particularly aggressive form of breast cancer, often characterized by early systemic relapse. This subtype, absent from traditional pathology classifications, has quietly crept into the oncologist's lexicon over the last decade and aroused considerable research interest. Based on tumor pathology, immunohistochemistry and gene profiling studies, TNBC is likely to represent a heterogeneous mix of breast cancer subtypes. This observation will have important implications for the selection of optimal therapies, which are yet to be defined. This article reviews recent insights in the classification and ontogeny of TNBC, current approaches to its management and promising therapeutic targets that are forming the basis for innovative early and late phase clinical trials. PMID- 22524574 TI - Sorafenib in combination with transarterial chemoembolization and bronchial arterial chemoinfusion in the treatment of hepatocellular carcinoma with pulmonary metastasis. AB - AIM: Hepatocelluar carcinoma (HCC) with pulmonary metastasis is considered incurable. This study addresses the efficacy of the combination of systemic therapy using sorafenib and local treatment using transarterial chemoembolization (TACE) for intrahepatic and bronchial transarterial chemoinfusion (TAI) for pulmonary lesions for this condition. METHODS: In all, 52 HCC patients with pulmonary metastasis were treated with sorafenib and TACE/TAI for intrahepatic and intrapulmonary lesions. Response to treatment, progression-free survival (PFS), overall survival (OS) and treatment-induced adverse effects were analyzed. RESULTS: With a median follow-up time of 11.4 months, radiologically confirmed complete response (CR), partial response (PR), stable disease and disease progression for intrahepatic disease were observed in 0, 22, 23 and seven patients, respectively; radiologically confirmed CR, PR, stable disease and disease progression observed for intrapulmonary lesions were in 1, 8, 25 and 18 patients, respectively. Median OS and PFS was 12.0 and 10.0 months, respectively. Median OS of patients who achieved response (i.e., CR + PR + stable disease) in their gross lesion(s) was 14.0 and 13.0 months, respectively, as compared to 4.0 and 3.0 months for patients who progressed (P < 0.003). Significant prognosticators for OS and PFS included performance status, Barcelona Clinic Liver Cancer stage and response to treatment. The combined treatment strategy was well tolerated. CONCLUSION: The combination of sorafenib, TACE and TAI produced median OS and PFS of 12 and 10 months, respectively, in HCC patients with lung metastasis. The outcomes of patients who achieved a response to their gross lesions were significantly better than those who had disease progression. Further investigation is warranted to test the efficacy of this treatment combination. PMID- 22524575 TI - The efficacy of hepatic arterial infusion chemotherapy as an alternative to sorafenib in advanced hepatocellular carcinoma. AB - AIMS: Sorafenib is the only systemic treatment shown to be effective against advanced hepatocellular carcinoma (HCC). Hepatic arterial infusion chemotherapy (HAIC) has been selected as an alternative therapeutic option for advanced HCC. We investigated the efficacy and safety of HAIC as an alternative treatment for sorafenib in advanced HCC. METHODS: Between May 2008 and March 2011, 20 consecutive patients were treated with sorafenib monotherapy as a first-line treatment and 21 consecutive patients who could not take sorafenib because of cost were treated with HAIC monotherapy as an alternative. Sorafenib was administered in 400 mg b.i.d. doses. For HAIC, daily cisplatin (7 mg/m(2) on days 1-5) and 5-FU (170 mg/m(2) on days 1-5) were infused every 4 weeks. We assessed overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and toxicity. RESULTS: Median OS was 4.9 months (95% CI, 3.4-6.4) for sorafenib and 7.3 months (95% CI, 4.5-10.2) for HAIC (P = 0.599). Median PFS was 2.0 months (95% CI, 1.96-2.05) versus 3.0 months (95% CI, 1.98-4.02) for sorafenib and HAIC, respectively (P = 0.303). ORR and disease control rate (DCR) for sorafenib were 10.0 and 35.0% versus 19.0 and 38.1% for HAIC (ORR, P = 0.413; DCR, P = 0.837). Patients treated with HAIC more frequently exhibited grade 3/4 neutropenia (23.8 vs 0% for sorafenib), whereas sorafenib therapy showed grade 3/4 hand-foot skin reaction in 10% of patients. CONCLUSION: HAIC is a useful alternative treatment for advanced HCC and further prospective investigations are required. PMID- 22524576 TI - A retrospective cohort study of metastatic colorectal cancer patients treated with oxaliplatin-based chemotherapy, with an exploratory analysis of changing serum carcinoembryonic antigen levels. AB - AIM: To examine the relationship between changes in serum carcinoembryonic antigen (CEA) levels and survival during oxaliplatin-based chemotherapy for metastatic colorectal cancer (mCRC). METHODS: A retrospective review of 142 patients with mCRC who were treated with oxaliplatin-based chemotherapies (mostly FOLFOX 6 or XELOX) by St Vincent's Hospital, from October 1999 until 30 November 2007. Survival analysis was used to determine median overall survival (OS) from commencement of chemotherapy. A CEA response was defined by >=50% decline compared with baseline, maintained on two consecutive occasions at least 4 weeks apart. The Cox proportional hazard model and a landmark analysis at 3 months were used to evaluate survival differences between CEA responders (rCEA) and non responders (non-rCEA). RESULTS: The median OS was 14.7 months. Using an intention to-treat analysis, 76 (53.5%) patients achieved a CEA response, while 66 (46.5%) did not. Using the landmark analysis at 3 months, rCEA had a longer survival than non-rCEA (median 16.0 vs 7.8 months, P < 0.0001). The hazard ratio for patients dying of mCRC in non-rCEA was 2.2 (P < 0.0001). In multivariate analysis, CEA response and better baseline Eastern Cooperative Oncology Group (ECOG) predicted for survival (P < 0.0001 for both), while age, gender and histology grade did not. CONCLUSION: The median OS of our patients is similar to published randomized trials. A CEA response of >=50% at 3 months and good ECOG were independent predictors of OS of patients with mCRC treated with oxaliplatin-based chemotherapies. PMID- 22524577 TI - Serum vascular endothelial growth factor-C combined with multi-detector CT in the preoperative diagnosis of lymph node metastasis of gastric cancer. AB - AIM: To investigate whether serum vascular endothelial growth factor-C (SVEGF-C) and multi-detector computed tomography (MDCT) can predict lymph node metastasis (LNM) in gastric cancer (GC). METHODS: The SVEGF-C level of 80 patients with GC was examined by enzyme linked immunosorbent assay. An MDCT scan of the abdomen was performed. Kaplan - Meier survival analysis was used to analyse survival. RESULTS: In patients with GC, a higher level of SVEGF-C was found in the LNM group (650.9 +/- 198.6 vs 451.0 +/- 115.5 pg/mL, P = 0.000) and in patients with distant metastases (834.3 +/- 80.0 pg/mL vs 557.9 +/- 187.0 pg/mL, P = 0.000). With a cut-off value of 542.5 pg/mL, the sensitivity, specificity, accuracy, positive predictive value and negative predictive value of SVEGF-C for predicating LNM were 82.8, 81.8, 82.5, 92.3 and 64.3%, respectively. MDCT could not be employed to detect the LNM. When SVEGF-C associated with MDCT was employed to determine LNM in GC, the sensitivity, specificity, accuracy, positive predictive value and negative predictive value were 91.4, 86.4, 90.0, 94.6 and 79.2%, respectively. No difference of SVEGF-C level was found among N1, N2 and N3 groups (P > 0.05). The 5-year overall survival was 47.5%. A shorter mean survival time were found in patients with SVEGF-C >834.3 pg/ml (43.3 +/- 2.8 months vs 67.4 +/- 2.5 months, P = 0.000) and in patients who were MDCT-positive (42.7 +/- 3.8 months vs 60.8 +/- 2.2 months, P = 0.0034). CONCLUSION: SVEGF-C may be a biomarker for a preoperative diagnosis of LNM. In conjunction with MDCT, SVEGF-C can improve the accuracy of a diagnosis of LNM in GC. A higher SVEGF-C level and an MDCT-positive finding could predict the poorer prognosis of GC. PMID- 22524578 TI - Male breast cancer: a 30-year experience in South Australia. AB - AIMS: Male breast cancer (MBC) is an uncommon disease with a paucity of information in the literature. The treatment of MBC has traditionally been extrapolated from experience with female breast cancer. This study reports on the treatment and outcomes of this disease in South Australia over a 30-year period. METHODS: From 1977 to 2007 63 patients with a median age of 62 years (range 33-85 years) were identified and treated for MBC. Data obtained, included initial stage, pathological features, treatment and outcomes. RESULTS: With a median follow up of 4.9 years (range 2 months to 19 years) the 5-year overall survival (OS) rate was 85% with median survival of 5.5 years. In all, 18 (29%) were diagnosed with recurrent disease, while 45 (72%) remained disease free. The median time to recurrence was 2.5 years. One patient failed locally, three (4%) had locoregional recurrence and distant recurrence was noted in 14 patients (22%). Disease stage at presentation was a significant predictor of 5-year OS and recurrence (P = 0.012 and P = 0.0001). Tumor diameter was also a significant predictor of 5-year OS and recurrence (P = 0.006 and P = 0.021). CONCLUSION: This retrospective series has a 5-year OS that compares favorably with other published series of MBC. The positive findings may help change the misperception that MBC is an inherently aggressive disease process with a poor clinical outcome. Further studies are needed to carefully and thoroughly investigate this rare but treatable disease. PMID- 22524579 TI - Is chemotherapy in elderly patients with metastatic or recurrent gastric cancer as tolerable and effective as in younger patients? AB - AIM: To analyze the chemotherapy regimens and outcomes of advanced gastric cancer (AGC) patients older than 70 years of age. METHODS: Between May 2001 and October 2009, 1135 patients with metastatic or recurrent gastric cancer received palliative chemotherapy. Of these patients 56 (4.9%) were >=70 years old and were analyzed retrospectively. RESULTS: The median age at the time of first-line chemotherapy was 73 years (range, 70-85) and the median Charlson comorbidity index was 0 (0-5). In all 17 patients (30%) received surgery with curative or palliative intent; 43 (77%) were treated by doublet or triplet first-line chemotherapy regimens and 13 patients (23%) received single agent chemotherapy. Median progression-free survival for first-line chemotherapy was 3.97 months (95% CI 2.05-5.89) with an overall response rate of 26%. After the first-line chemotherapy, only 18 of 56 (32%) patients received second-line chemotherapy. The median overall survival (OS) was 12.4 months (95% CI 2.81-21.99). In multivariate analysis, receiving surgery and disease control for first-line chemotherapy were independent prognostic factors for increased OS for all 56 patients. CONCLUSION: Patients older >=70 years with metastatic or recurrent gastric cancer might achieve clinical benefit from chemotherapy. Receiving surgery and response of over more stable disease for first-line chemotherapy were independent prognostic factors for increased OS. PMID- 22524580 TI - Acute inflammatory demyelinating polyradiculoneuropathy in a patient receiving oxaliplatin-based chemotherapy. AB - We report a case of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) that developed in a patient with cholangiocarcinoma after receiving oxaliplatin-based chemotherapy. A 62-year-old man had multiple hypodense lesions with delayed enhancement in the both lobes of the liver on abdominal computed tomography. He was treated with 5-fluorouracil, leucovorin and oxaliplatin (100 mg/m(2)). After eight cycles of treatment and a cumulative oxaliplatin dose of 780 mg/m(2), he developed an unsteady gait, dysphagia, weakness of both the upper and lower limbs and impairment of all sensory modalities. Nerve conduction studies confirmed the diagnosis of AIDP. Immunoglobulin G i.v. was administered for 5 days but the neurological deficits of both his upper and lower limbs did not improve. This case highlights unusual peripheral nervous system manifestations in a patient who received chemotherapy with oxaliplatin. PMID- 22524581 TI - Guillain-Barre syndrome in colorectal cancer. AB - Guillain-Barre syndrome has been reported in the setting of different malignancies. To the best of our knowledge, the association of Guillain-Barre syndrome and colorectal cancer has been reported in only two cases. As Guillain Barre syndrome is potentially life threatening, it should be considered in the differential diagnosis of patients with colorectal cancer with neurological findings. Here we report two cases of Guillain-Barre syndrome in the setting of metastatic colorectal cancer. PMID- 22524584 TI - Effects of beta-amylolysis on the resistant starch formation of debranched corn starches. AB - Retrograded amylose is resistant to digestion by amylolytic enzymes, which is known as resistant starch type III (RS3). In this study we investigated the effect of beta-amylase hydrolysis on the formation and physicochemical properties of RS3 from debranched corn starches. Three types of corn starch (Hylon VII, Hylon V, and common corn) were first gelatinized and then hydrolyzed using beta amylase to varying degrees. The resultant hydrolyzed starch was debranched with isoamylase and then exposed to temperature cycling to promote RS formation. A broad endotherm from approximately 45 to 120 degrees C and a small endotherm above 150 degrees C were noted for all retrograded starches. All three corn starches had increased RS contents after moderate beta-amylolysis, with Hylon V having the highest RS content at 70.7% after 4 h of beta-amylolysis. The results suggest that RS3 formation is affected by the starch composition as well as the starch structure and can be increased by moderate beta-amylolysis. PMID- 22524586 TI - An investigation of multidisciplinary complex health care interventions--steps towards an integrative treatment model in the rehabilitation of people with multiple sclerosis. AB - BACKGROUND: The Danish Multiple Sclerosis Society initiated a large-scale bridge building and integrative treatment project to take place from 2004-2010 at a specialized Multiple Sclerosis (MS) hospital. In this project, a team of five conventional health care practitioners and five alternative practitioners was set up to work together in developing and offering individualized treatments to 200 people with MS. The purpose of this paper is to present results from the six year treatment collaboration process regarding the development of an integrative treatment model. DISCUSSION: The collaborative work towards an integrative treatment model for people with MS, involved six steps: 1) Working with an initial model 2) Unfolding the different treatment philosophies 3) Discussing the elements of the Intervention-Mechanism-Context-Outcome-scheme (the IMCO-scheme) 4) Phrasing the common assumptions for an integrative MS program theory 5) Developing the integrative MS program theory 6) Building the integrative MS treatment model. The model includes important elements of the different treatment philosophies represented in the team and thereby describes a common understanding of the complexity of the courses of treatment. SUMMARY: An integrative team of practitioners has developed an integrative model for combined treatments of People with Multiple Sclerosis. The model unites different treatment philosophies and focuses on process-oriented factors and the strengthening of the patients' resources and competences on a physical, an emotional and a cognitive level. PMID- 22524585 TI - Effect of feeding fescue seed containing ergot alkaloid toxins on stallion spermatogenesis and sperm cells. AB - The cellular effects of tall fescue grass-associated toxic ergot alkaloids on stallion sperm and colt testicular tissue were evaluated. This was a continuation of an initial experiment where the effects of toxic ergot alkaloids on the stallion spermiogram were investigated. The only spermiogram parameter in exposed stallions that was affected by the toxic ergot alkaloids was a decreased gel-free volume of the ejaculate. This study examined the effect of toxic ergot alkaloids on chilling and freezing of the stallion sperm cells. The effect of toxic ergot alkaloids on chilled extended sperm cells for 48 h at 5 degrees C was to make the sperm cells less likely to undergo a calcium ionophore-induced acrosome reaction. The toxic ergot alkaloids had no effect on the freezability of sperm cells. However, if yearling colts were fed toxic ergot alkaloids, then the cytological analysis of meiotic chromosome synapsis revealed a significant increase in the proportion of pachytene spermatocytes showing unpaired sex chromosomes compared to control spermatocytes. There was little effect of ergot alkaloids on adult stallions, but there might be a significant effect on yearling colts. PMID- 22524587 TI - First trimester contingent test as a screening method for Down's syndrome. A prospective study in the general population. AB - OBJECTIVES: To evaluate the possibility of implementing a contingent test as a screening method for Down's syndrome (DS) in the first trimester of pregnancy, and assess its sensitivity (Sen) and false positive rate (FPR). METHODS: Prospective study covering a 4-year study period (July 2006-June 2010). Pregnant women were offered a combined test (CT) as the first step of a contingent test. An intermediate risk group is identified in the CT (1/101 and 1/1000) and offered an ultrasound assessment of secondary s (nasal bone, ductus venosus, tricuspid regurgitation). RESULTS: CTs were performed on 10,452 pregnant women (24 cases of DS). In the intermediate risk group, which had 7 cases of DS, we performed secondary ultrasound marker assessment on 98.1% (1,017/1,036). The CT and the contingent test had a Sen of 83% (95% CI; 67.9-98) (20/24) and 70.8% (95% CI; 52.6-88.9) (17/24) with an FPR of 3% (95% CI; 2.7-3.3) (316/10,430) and 2% (95% CI; 1.7-2.3) (220/10,408), respectively. CONCLUSIONS: With the contingent test, we managed to reduce the FPR, but the Sen was too low for use as a screening method for DS. PMID- 22524588 TI - Combined intraepidermal neuroendocrine (Merkel cell) and squamous cell carcinoma in situ with CM2B4 negativity and p53 overexpression(*). AB - Primary cutaneous neuroendocrine carcinoma, also known as Merkel cell carcinoma (MCC), usually presents as a dermal and/or subcutaneous tumor. Rarely, it is confined to the epidermis or adnexal epithelium [MCC in situ (MCCIS)]. Little is known about the spectrum of features and biology of MCCIS. Herein, we report a case of MCCIS arising on the cheek of a 77-year-old Caucasian male, which was associated with squamous cell carcinoma in situ. The tumor cells of both the neuroendocrine and squamous components prominently involved adnexal structures but did not invade the dermis. The tumor cells with neuroendocrine features were immunoreactive for cytokeratin-20, chromogranin and synaptophysin. They also expressed p53 but were non-reactive with the monoclonal antibody CM2B4. Lack of labeling for CM2B4 is in keeping with prior observations of combined squamous and MCC. Our findings support the concept of a distinct subtype of virus-independent cutaneous neuroendocrine carcinoma that differs from conventional MCC. The observed overexpression of p53 suggests that the development of this tumor type may be related to chronic ultraviolet damage. PMID- 22524589 TI - Haemodynamic stability and pulmonary shunt during spontaneous breathing and mechanical ventilation in porcine lung collapse. AB - BACKGROUND: We investigated the haemodynamic stability of a novel porcine model of lung collapse induced by negative pressure application (NPA). A secondary aim was to study whether pulmonary shunt correlates with cardiac output (CO). METHODS: In 12 anaesthetized and relaxed supine piglets, lung collapse was induced by NPA (-50 kPa). Six animals resumed spontaneous breathing (SB) after 15 min; the other six animals were kept on mechanical ventilation (MV) at respiratory rate and tidal volume (V(T) ) that corresponded to SB. All animals were followed for 135 min with blood gas analysis and detailed haemodynamic monitoring. RESULTS: Haemodynamics and gas exchange were stable in both groups during the experiment with arterial oxygen tension (PaO(2) )/inspired fraction of oxygen (FiO(2) ) and pulmonary artery occlusion pressure being higher, venous admixture (Q(va) /Q(t) ) and pulmonary perfusion pressure being lower in the SB group. CO was similar in both groups, showing slight decrease over time in the SB group. During MV, Q(va) /Q(t) increased with CO (slope: 4.3 %min/l; P < 0.001), but not so during SB (slope: 0.55 %min/l; P = 0.16). CONCLUSIONS: This porcine lung collapse model is reasonably stable in terms of haemodynamics for at least 2 h irrespective of the mode of ventilation. SB achieves higher PaO(2) /FiO(2) and lower Q(va) /Q(t) compared with MV. During SB, Q(va) /Q(t) seems to be less, if at all, affected by CO compared with MV. PMID- 22524590 TI - Psychosocial correlates of continuous glucose monitoring use in youth and adults with type 1 diabetes and parents of youth. AB - BACKGROUND: Continuous glucose monitoring (CGM) has been shown to improve glycemic control and reduce hypoglycemia with consistent use. Youth, however, are unlikely to use CGM consistently. We compared psychological characteristics of youth with type 1 diabetes, their parents, and adults with type 1 diabetes randomized to CGM or standard blood glucose monitoring (BGM). This study was an ancillary study, and participants completed the questionnaires at the 6-month visit of the main study. SUBJECTS AND METHODS: Participants enrolled at a single site of the Juvenile Diabetes Research Foundation CGM trial completed questionnaires and provided diabetes management data. Participants were randomized to the CGM or BGM group for 6 months. RESULTS: Parents in both groups reported more fear of hypoglycemia than youth in the corresponding groups. CGM youth and parents reported more negative affect around BGM than those in the BGM group. CGM youth reported more trait anxiety than BGM youth, whereas CGM adults reported less state and trait anxiety than BGM adults. CGM parent-proxy report of depression was significantly higher than that reported by BGM parents. CONCLUSIONS: Youth, their parents, and adults report different psychological impacts of CGM use. In some groups and with some variables, CGM use was associated with a positive psychosocial impact, whereas in others CGM use was associated with a negative psychosocial impact. Future research should explore the psychological consequences of CGM use. PMID- 22524591 TI - A mobile health intervention for inner city patients with poorly controlled diabetes: proof-of-concept of the TExT-MED program. AB - OBJECTIVE: Numerous mobile health (mHealth) interventions are being developed to aid in management of complex chronic medical conditions. However, the acceptance of mHealth programs by low-income, bilingual populations has not yet been evaluated. The Trial to Examine Text-based mHealth for Emergency department patients with Diabetes (TExT-MED) program is a text message-based mHealth program designed specifically for resource-poor patients with diabetes. We conducted a prospective proof-of-concept trial to assess satisfaction and preliminary effectiveness of the TExT-MED program. RESEARCH DESIGN AND METHODS: A consecutive sample of adult patients in the emergency department with diabetes and a text message-capable mobile phone was enrolled in the TExT-MED program. Participants received three text messages daily for 3 weeks in English or Spanish in the following domains: educational/motivational, medication reminders, healthy living challenges, diabetes trivia, and links to free diabetes management tools. RESULTS: Twenty-three patients with diabetes (median hemoglobin A1c, 8.9%) were enrolled in TExT-MED. In the week before TExT-MED, 56.5% of subjects reported eating fruits/vegetables daily versus 83% after, 43.5% reported exercising before versus 74% after, and 74% reported performing foot checks before versus 85% after. Self-efficacy, measured by the Diabetes Empowerment Scale-Short Form, improved from 3.9 to 4.2. Scores on the Morisky Medication Adherence Scale improved more dramatically from 3.5 to 4.75. Ninety percent of participants indicated they would like to continue the program, and 100% would recommend the program to family or friends. CONCLUSIONS: This pilot trial of the TExT-MED program demonstrated increased healthy behaviors, improved diabetes self-efficacy and medication adherence, and received excellent satisfaction scores in resource poor, inner city patients with diabetes. PMID- 22524592 TI - Lack of hydroxylated fullerene toxicity after intravenous administration to female Sprague-Dawley rats. AB - Hydroxylated fullerenes (C60OH(x)) or fullerols are water-soluble carbon nanoparticles that have been explored for potential therapeutic applications. This study assesses acute in vivo tolerance in 8-wk-old female Sprague-Dawley rats to intravenous (iv) administration of 10 mg/kg of well-characterized C60(OH)30. Complete histopathology and clinical chemistries are assessed at 8, 24, and 48 h after dosing. Minor histopathology changes are seen, primarily in one animal. No clinically significant chemistry changes were observed after treatment. These experiments suggest that this fullerol was well tolerated after iv administration to rats. PMID- 22524593 TI - Cadmium risk assessment in relation to background risk of chronic kidney disease. AB - Cadmium's noncancer effects on the kidney represent a useful case study of the unified approach to toxicity assessment described in a recent National Academy of Science report. Cadmium (Cd) is recognized to exert toxic effects on the kidney at low dose without a demonstrable threshold. The implications of current dietary exposure and regulatory limits can be understood in terms of risk for chronic kidney disease (CKD) since both Cd adverse effects and CKD are defined by the same continous parameter (loss in glomerular filtration rate [GFR]). The Cd dose response on GFR derived from a study of Swedish women was applied to the baseline population distribution of GFR to determine the effect of Cd on CKD risk. The baseline population of 47.8-yr-old women was estimated to carry a 10% rate of Stage 3 CKD, similar to national statistics in the United States. A chronic daily dose of Cd at 1 MUg/kg/d produced a left shift in this distribution and increased the population risk of CKD by an estimated 25%. A 10-fold lower Cd dose was associated with an increase in population risk of 2.7%, and this rose to 3.4% in 75-yr-olds. These estimates (1) provide additional perspective to the traditional risk/no risk approaches used in setting U.S. Environmental Protection Agency (EPA) reference doses (RfD) and Agency for Toxic Substances and Disease Registry (ATSDR) minimum risk levels (MRL) and (2) demonstrate the utility of considering chemical additivity to background disease in assessing human risk. PMID- 22524594 TI - A comparative analysis to study editing of small noncoding BC200- and Alu transcripts in brain of prion-inoculated rhesus monkeys (M. Mulatta). AB - Small retroelements (short interspersed elements, abbreviated SINEs) are abundant in vertebrate genomes. Using RNA isolated from rhesus monkey cerebellum and buffy coat, reverse-transcription polymerase chain reaction (RT PCR) was applied to clone cDNA of BC200 and Alu RNAs. Transcripts containing Alu-SINE sequences may be subjected to extensive RNA editing by ADAR (adenosine deaminases that act on RNA) deamination. Abundance of Alu transcripts was determined with real-time RT PCR and was significantly higher than BC200 (brain cytoplasmic) in cerebellum. BC200 transcripts were absent from buffy coat cells. Availability of the rhesus genome sequence allowed the BC200 transcripts to be mapped to the specific locus on chromosome 13. Both the qualitative and quantitative characteristics of BC 200 expression argue for the BC 200 transcripts being generated by RNA polymerase III. In cerebellum, Alu transcripts often possessed base exchanges (A to G) consistent with ADAR editing and, somewhat unexpectedly, C to T exchanges consistent with APOBEC (apolipoprotein B editing complex) editing. In contrast, the BC200 transcripts, which as RNA POLIII transcripts play a role in dendritic RNA translation, appeared not to be deaminated, despite the presence of editing of Alu in the same tissue. To assess whether neuronal disease might influence editing of BC200 and Alu-SINE transcripts in cerebellum, RNA was isolated from two rhesus monkeys that were inoculated with prions from human variant Creutzfeldt-Jakob disease (vCJD). Regardless of prion-induced neurodegeneration, no BC200 RNA editing was observed, while Alu RNA continued to show both ADAR and APOBEC editing. Thus, BC200 RNAs do not appear to become accessible to editing enzymes despite infected neurons being subjected to severe stress, damage, and eventually cell death. PMID- 22524595 TI - The association between chronic exposure to traffic-related air pollution and ischemic heart disease. AB - Increasing evidence links air pollution to the risk of cardiovascular disease. This study investigated the association between ischemic heart disease (IHD) prevalence and exposure to traffic-related air pollution (nitrogen dioxide [NO2], fine particulate matter [PM2.5], and ozone [O3]) in a population of susceptible subjects in Toronto. Local (NO2) exposures were modeled using land use regression based on extensive field monitoring. Regional exposures (PM2.5, O3) were modeled as confounders using inverse distance weighted interpolation based on government monitoring data. The study sample consisted of 2360 patients referred during 1992 to 1999 to a pulmonary clinic at the Toronto Western Hospital in Toronto, Ontario, Canada, to diagnose or manage a respiratory complaint. IHD status was determined by clinical database linkages (ICD-9-CM 412-414). The association between IHD and air pollutants was assessed with a modified Poisson regression resulting in relative risk estimates. Confounding was controlled with individual and neighborhood-level covariates. After adjusting for multiple covariates, NO2 was significantly associated with increased IHD risk, relative risk (RR) = 1.33 (95% confidence interval [CI]: 1.2, 1.47). Subjects living near major roads and highways had a trend toward an elevated risk of IHD, RR = 1.08 (95% CI: 0.99, 1.18). Regional PM2.5 and O3 were not associated with risk of IHD. PMID- 22524596 TI - Modeling of the role of conformational dynamics in kinetics of the antigen antibody interaction in heterogeneous phase. AB - A novel approach that may potentially be used to study biomolecular interactions including the simultaneous determination of structural and kinetic binding parameters is described in this Article for the first time. It allows a rigid distinction between the possible reaction mechanisms of biomolecular recognition, induced fit and conformational selection. The relative importance of the two pathways is determined not by comparing rate constants but the structural aspects of the interaction instead. So the exact location of antigen molecules with respect to the capture antibody is depicted experimentally, avoiding the use of X ray crystallography. The proposed pattern is applied to study the anti-BSA Immunoglobulin G (IgG)-free Bovine Serum Albumin (BSA) interaction, in which IgG is anchored on a silicon chip sensing surface in an oriented manner. The exact location of the receptor with respect to the ligand was monitored during the binding process, thus drawing the full reaction scheme. IgG forms an asymmetric (FabBSA)2 complex with BSA molecules, even though it has two identical fragment antigen binding arms. This is thought to be due to steric hindrance caused by the binding of the first BSA molecule. Furthermore, the proposed model allows one to characterize reaction intermediates without the need of isolating them. These intermediates not characterized in situ so far are the keystone to understand how antibodies are able to identify antigens. PMID- 22524597 TI - Changing aetiology, clinical features, antimicrobial resistance, and outcomes of bloodstream infection in neutropenic cancer patients. AB - Recent changes in the management of patients with haematological malignancies might have influenced the aetiology, characteristics, antimicrobial resistance and outcomes of bloodstream infection (BSI) during neutropenia. We compared 272 episodes of BSI in adult neutropenic patients with cancer prospectively collected from January 1991 to December 1996 (first period), when quinolone prophylaxis was used, with 283 episodes recorded from January 2006 to March 2010 (second period), when antibacterial prophylaxis was stopped. Patients in the second period were significantly older and were more likely to have graft-versus-host disease and a urinary catheter in place, whereas the presence of a central venous catheter, parenteral nutrition, corticosteroids and antifungal and quinolone prophylaxis, were more frequent in the first period. More patients in the first period had mucositis and soft-tissue infection as the origin of BSI, but an endogenous source was more common during the second. Gram-positive BSI was more frequent in the first period (64% versus 41%; p <0.001), mainly due to coagulase-negative staphylococci and viridans group streptococci. In the second period gram-negative BSI increased (28% versus 49%; p <0.001), quinolone susceptibilities were recovered, but multidrug-resistant gram-negative BSI also increased (1% versus 6%; p <0.001). Although patients in the second period were more likely to need admission to the intensive-care unit, overall case-fatality rate was similar in the two periods (19% versus 15%). The aetiology of BSI in neutropenic patients with cancer has shifted from gram-positive to gram-negative organisms. Multidrug resistance among gram-negative bacilli is emerging as a therapeutic challenge. Overall case-fatality rate remains high. PMID- 22524598 TI - High-density chemical intercalation of zero-valent copper into Bi2Se3 nanoribbons. AB - A major goal of intercalation chemistry is to intercalate high densities of guest species without disrupting the host lattice. Many intercalant concentrations, however, are limited by the charge of the guest species. Here we have developed a general solution-based chemical method for intercalating extraordinarily high densities of zero-valent copper metal into layered Bi(2)Se(3) nanoribbons. Up to 60 atom % copper (Cu(7.5)Bi(2)Se(3)) can be intercalated with no disruption to the host lattice using a solution disproportionation redox reaction. PMID- 22524599 TI - A "multicellular" step to understand the development of the nervous system. PMID- 22524600 TI - Molecular mechanisms of cell shape changes that contribute to vertebrate neural tube closure. AB - During early development of the central nervous system, the neuroepithelial cells undergo dynamic changes in shape, cumulative action of which cause the neural plate to bend mediolaterally to form the neural tube. The apicobasal elongation changes the cuboidal cells into columnar ones, whereas apical constriction minimizes the cell apices, causing them to adopt wedge-like shapes. To achieve the morphological changes required for the formation of a hollow structure, these cellular changes must be controlled in time and space. To date, it is widely accepted that spatial and temporal changes of the cytoskeletal organization are fundamental to epithelial cell shape changes, and that noncetrosomal microtubules assembled along apicobasal axis and actin filaments and non-muscle myosin II at the apical side are central machineries of cell elongation and apical constriction, respectively. Hence, especially in the last decade, intracellular mechanisms regulating these cytoskeletons have been extensively investigated at the molecular level. As a result, several actin-binding proteins, Rho/ROCK pathway, and cell-cell adhesion molecules have been proven to be the central regulators of apical constriction, while the regulatory mechanisms of cell elongation remain obscure. In this review, we first describe the distribution and role of cytoskeleton in cell shape changes during neural tube closure, and then summarize the current knowledge about the intracellular proteins that directly modulate the cytoskeletal organization and thus the neural tube closure. PMID- 22524601 TI - Control of asymmetric cell division of mammalian neural progenitors. AB - Although the vertebrate brain commonly stems from the neuroepithelial tube, the size and complexity of the pseudostratified organization of the brain have drastically expanded during mammalian evolution, resulting in the formation of a highly folded cortex. Developmental controls of neural progenitor divisions underlie these events. In this review, we introduce recent progress in understanding the control of proliferation and differentiation of neural progenitors from a structural point of view. We particularly shed light on the roles of epithelial structure and mitotic spindle orientation in the generation of various types of neural progenitors. PMID- 22524602 TI - An oblique view on the role of spindle orientation in vertebrate neurogenesis. AB - Neurogenesis is a dynamic process that produces a diverse number of glial and neural cell types from a limited number of neural stem cells throughout development and into adulthood. After an initial period of amplification through symmetric division, neural stem cells rely on asymmetric modes of division to self-renew while producing more committed progeny. Understanding the molecular mechanisms regulating the choice between symmetric and asymmetric modes of division is essential to understand human brain development and pathologies, and to explain the increasing cortical complexity observed in evolution. A popular model states the existence of a causal relationship between the orientation of the axis of division of stem cells and the fate of their progeny in many different tissues, but the validity of the model in neural stem cells is not clear. In this review, we briefly present the diversity of neural stem cells and intermediate progenitors in the developing central nervous system. We then draw a historic overview of the assumed causal relationship between spindle orientation and fate determination. We show how this prompted a search for regulators of spindle orientation, and present the current state of knowledge on the mechanism. Finally, we review data on the effect of defective spindle orientation and try to integrate conflicting observations by presenting alternative mechanisms that may regulate the choice between symmetric and asymmetric outcomes. PMID- 22524604 TI - Small leucine rich proteoglycan family regulates multiple signalling pathways in neural development and maintenance. AB - The small leucine-rich repeat proteoglycan (SLRPs) family of proteins currently consists of five classes, based on their structural composition and chromosomal location. As biologically active components of the extracellular matrix (ECM), SLRPs were known to bind to various collagens, having a role in regulating fibril assembly, organization and degradation. More recently, as a function of their diverse proteins cores and glycosaminoglycan side chains, SLRPs have been shown to be able to bind various cell surface receptors, growth factors, cytokines and other ECM components resulting in the ability to influence various cellular functions. Their involvement in several signaling pathways such as Wnt, transforming growth factor-beta and epidermal growth factor receptor also highlights their role as matricellular proteins. SLRP family members are expressed during neural development and in adult neural tissues, including ocular tissues. This review focuses on describing SLRP family members involvement in neural development with a brief summary of their role in non-neural ocular tissues and in response to neural injury. PMID- 22524603 TI - Interkinetic nuclear migration: a mysterious process in search of a function. AB - During interkinetic nuclear migration (INM), the nuclei in many epithelial cells migrate between the apical and basal surfaces, coordinating with the cell cycle, and undergoing cytokinesis at the apical surface. INM is observed in a wide variety of tissues and species. Recent advances in time-lapse microscopy have provided clues about the mechanisms and functions of INM. Whether actin or microtubules are responsible for nuclear migration is controversial. How mitosis is initiated during INM is poorly understood, as is the relationship between the cell cycle and nuclear movement. It is possible that the disagreements stem from differences in the tissues being studied, since epithelia undergoing INM vary greatly in terms of cell height and cell fates. In this review we examine the reports addressing the mode and mechanisms that regulate INM and suggest possible functions for this dramatic event. PMID- 22524605 TI - An essential role for Rax in retina and neuroendocrine system development. AB - In vertebrates, the central nervous system (CNS) develops as a highly hierarchical, patterned organ with a vast diversity of neuronal and glial cell types. The vertebrate retina is developmentally a part of the CNS. Establishment of the vertebrate retina requires a series of developmental steps including specification of the anterior neural plate, evagination of the optic vesicles from the ventral forebrain, and differentiation of cells. The transcription factor RAX is a paired-type homeoprotein that plays a critical role in the eye and forebrain development of vertebrate species. Rax is initially expressed in the anterior neural region of developing mouse embryos, and later in the retina, pituitary gland, hypothalamus, and pineal gland. The targeted deletion of Rax in the mouse results in no eye formation and abnormal forebrain formation. In humans, mutations in the RAX gene lead to anophthalmia and microphthalmia. These observations indicate that RAX plays a pivotal role in the establishment of the retina. In addition, recent studies have reported that retina and pituitary gland tissues can be induced in a culture system from embryonic stem cells, using RAX expression as an indicator of neuronal progenitor cells in the induced tissue, and suggesting that the Rax gene is a key factor in neuronal regeneration. This review highlights the biological functions and molecular mechanisms of RAX in retina, pituitary, hypothalamus, and pineal gland development. PMID- 22524606 TI - GABAergic interneuron migration and the evolution of the neocortex. AB - A neocortex is present in all mammals but is not present in other classes of vertebrates, and the neocortex is extremely elaborate in humans. Changes in excitatory projection neurons and their progenitors within the developing dorsal pallium in the most recent common ancestor of mammals are thought to have been involved in the evolution of the neocortex. Our recent findings suggest that changes in the migratory ability of inhibitory interneurons derived from outside the neocortex may also have been involved in the evolution of the neocortex. In this article we review the literature on the migratory profile of inhibitory interneurons in several different species and the literature on comparisons between the intrinsic migratory ability of interneurons derived from different species. Finally, we propose a hypothesis about the mammalian-specific evolution of the migratory ability of interneurons and its potential contribution to the establishment of a functional neocortex. PMID- 22524607 TI - Development and evolution of cerebellar neural circuits. AB - The cerebellum controls smooth and skillful movements and it is also involved in higher cognitive and emotional functions. The cerebellum is derived from the dorsal part of the anterior hindbrain and contains two groups of cerebellar neurons: glutamatergic and gamma-aminobutyric acid (GABA)ergic neurons. Purkinje cells are GABAergic and granule cells are glutamatergic. Granule and Purkinje cells receive input from outside of the cerebellum from mossy and climbing fibers. Genetic analysis of mice and zebrafish has revealed genetic cascades that control the development of the cerebellum and cerebellar neural circuits. During early neurogenesis, rostrocaudal patterning by intrinsic and extrinsic factors, such as Otx2, Gbx2 and Fgf8, plays an important role in the positioning and formation of the cerebellar primordium. The cerebellar glutamatergic neurons are derived from progenitors in the cerebellar rhombic lip, which express the proneural gene Atoh1. The GABAergic neurons are derived from progenitors in the ventricular zone, which express the proneural gene Ptf1a. The mossy and climbing fiber neurons originate from progenitors in the hindbrain rhombic lip that express Atoh1 or Ptf1a. Purkinje cells exhibit mediolateral compartmentalization determined on the birthdate of Purkinje cells, and linked to the precise neural circuitry formation. Recent studies have shown that anatomy and development of the cerebellum is conserved between mammals and bony fish (teleost species). In this review, we describe the development of cerebellar neurons and neural circuitry, and discuss their evolution by comparing developmental processes of mammalian and teleost cerebellum. PMID- 22524608 TI - Localization mechanisms of the axon guidance molecule UNC-6/Netrin and its receptors, UNC-5 and UNC-40, in Caenorhabditis elegans. AB - Netrin is an evolutionarily conserved, secretory axon guidance molecule. Netrin's receptors, UNC-5 and UNC-40/DCC, are single trans-membrane proteins with immunoglobulin domains at their extra-cellular regions. Netrin is thought to provide its positional information by establishing a concentration gradient. UNC 5 and UNC-40 act at growth cones, which are specialized axonal tip structures that are generally located at a long distance from the neural cell body. Thus, the proper localization of both Netrin and its receptors is critical for their function. This review addresses the localization mechanisms of UNC-6/Netrin and its receptors in Caenorhabditis elegans, focusing on our recent reports. These findings include novel insights on cytoplasmic proteins that function upstream of the receptors. PMID- 22524609 TI - Formation of axon-dendrite polarity in situ: initiation of axons from polarized and non-polarized cells. AB - Neurons are polarized cells that extend a single axon and several dendrites. Historically, how neurons establish their axon-dendrite polarity has been extensively studied using dissociated hippocampal cells in culture. Although such studies have identified the cellular and molecular mechanisms underlying axon dendrite polarization, the conclusions have been limited to in vitro conditions. Recent progress using live imaging has enabled us to directly observe axon formation in situ, revealing distinct cellular mechanisms that regulate axon dendrite polarization in vivo. In this review, we compare the cellular events during axon formation studied in various systems both in vivo and in vitro and discuss possible common mechanisms underlying the axon-dendrite polarization. PMID- 22524610 TI - Development of larval motor circuits in Drosophila. AB - How are functional neural circuits formed during development? Despite recent advances in our understanding of the development of individual neurons, little is known about how complex circuits are assembled to generate specific behaviors. Here, we describe the ways in which Drosophila motor circuits serve as an excellent model system to tackle this problem. We first summarize what has been learned during the past decades on the connectivity and development of component neurons, in particular motor neurons and sensory feedback neurons. We then review recent progress in our understanding of the development of the circuits as well as studies that apply optogenetics and other innovative techniques to dissect the circuit diagram. New approaches using Drosophila as a model system are now making it possible to search for developmental rules that regulate the construction of neural circuits. PMID- 22524611 TI - Ascidians as excellent chordate models for studying the development of the nervous system during embryogenesis and metamorphosis. AB - The swimming larvae of the chordate ascidians possess a dorsal hollowed central nervous system (CNS), which is homologous to that of vertebrates. Despite the homology, the ascidian CNS consists of a countable number of cells. The simple nervous system of ascidians provides an excellent experimental system to study the developmental mechanisms of the chordate nervous system. The neural fate of the cells consisting of the ascidian CNS is determined in both autonomous and non autonomous fashion during the cleavage stage. The ascidian neural plate performs the morphogenetic movement of neural tube closure that resembles that in vertebrate neural tube formation. Following neurulation, the CNS is separated into five distinct regions, whose homology with the regions of vertebrate CNS has been discussed. Following their larval stage, ascidians undergo a metamorphosis and become sessile adults. The metamorphosis is completed quickly, and therefore the metamorphosis of ascidians is a good experimental system to observe the reorganization of the CNS during metamorphosis. A recent study has shown that the major parts of the larval CNS remain after the metamorphosis to form the adult CNS. In contrast to such a conserved manner of CNS reorganization, most larval neurons disappear during metamorphosis. The larval glial cells in the CNS are the major source for the formation of the adult CNS, and some of the glial cells produce adult neurons. PMID- 22524612 TI - Lipopolysaccharide induces rapid loss of follicular dendritic cell-secreted protein in the junctional epithelium. AB - Oshiro A, Iseki S, Miyauchi M, Terashima T, Kawaguchi Y, Ikeda Y, Shinomura T. Lipopolysaccharide induces rapid loss of follicular dendritic cell-secreted protein in the junctional epithelium. J Periodont Res 2012; 47: 689-694. (c) 2012 John Wiley & Sons A/S Background and Objective: We have previously reported that mRNA encoding follicular dendritic cell-secreted protein (FDC-SP) is expressed specifically in the junctional epithelium at the gingival crevice. Other tissues, such as tonsil, prostate gland and trachea, also express high levels of FDC-SP. These tissues participate in a range of functions closely related to innate immunity. Therefore, it is hypothesized that FDC-SP plays a crucial role in close association with the host defense system within the gingival crevice. Accordingly, the main aim of this study was to investigate the expression and localization of FDC-SP in and around the junctional epithelium and to observe the dynamic changes of FDC-SP in experimental inflammation. MATERIAL AND METHODS: We examined, immunohistochemically, the expression of FDC-SP in the junctional epithelium using a specific antibody raised in rabbit after immunization with a synthetic peptide derived from the hydrophilic region of FDC-SP. Experimental inflammation was induced in the upper molars of Wistar rats by applying bacterial lipopolysaccharide (LPS; 5 mg/mL in sterile saline) for 1 h. RESULTS: We confirmed that FDC-SP is present in the junctional epithelium in a pattern that is consistent with the expression of FDC-SP mRNA. Of special interest is that no FDC-SP was detectable in the junctional epithelium 3 h after transient topical treatment with LPS. CONCLUSION: The presence of FDC-SP in the junctional epithelium and its loss after LPS treatment strongly support our hypothesis of FDC-SP playing a crucial role in close association with the host defense system within the gingival crevice. PMID- 22524613 TI - Presence of the resistance genes vanC1 and pbp5 in phenotypically vancomycin and ampicillin susceptible Enterococcus faecalis. AB - Ampicillin and vancomycin are important antibiotics for the therapy of Enterococcus faecalis infections. The ampicillin resistance gene pbp5 is intrinsic in Enterococcus faecium. The vanC1 gene confers resistance to vancomycin and serves as a species marker for Enterococcus gallinarum. Both genes are chromosomally located. Resistance to ampicillin and vancomycin was determined in 484 E. faecalis of human and porcine origin by microdilution. Since E. faecalis are highly skilled to acquire resistance genes, all strains were investigated for the presence of pbp5 (and, in positive strains, for the penicillin-binding protein synthesis repressor gene psr) and vanC1 (and, in positive strains, for vanXYc and vanT) by using polymerase chain reaction (PCR). One porcine and one human isolate were phenotypically resistant to ampicillin; no strain was vancomycin resistant. Four E. faecalis (3/1 of porcine/human origin) carried pbp5 (MIC=1 mg/L), and four porcine strains were vanC1 positive (minimum inhibitory concentration [MIC]=1 mg/L). Real-time reverse transcriptase (RT)-PCR revealed that the genes were not expressed. The psr gene was absent in the four pbp5-positive strains; the vanXYc gene was absent in the four vanC1-positive strains. However, vanT of the vanC gene cluster was detected in two vanC1 positive strains. To our knowledge, this is the first report on the presence of pbp5, identical with the "E. faecium pbp5 gene," and of vanC1/vanT in E. faecalis. Even if resistance is not expressed in these strains, this study shows that E. faecalis have a strong ability to acquire resistance genes-and potentially to spread them to other bacteria. Therefore, close monitoring of this species should be continued. PMID- 22524615 TI - Staphylococcus prevails in the skin microbiota of long-term immunodeficient mice. AB - Host-commensal relationships in the skin are a complex system governed by variables related to the host, the bacteria and the environment. A disruption of this system may lead to new steady states, which, in turn, may lead to disease. We have studied one such disruption by characterizing the skin microbiota in healthy and immunodepressed (ID) mice. A detailed anatomopathological study failed to reveal any difference between the skin of healthy and ID mice. We sequenced the 16S rDNA V1-V2 gene region to saturation in 10 healthy and 10 ID 8 week-old mice, and found than all of the healthy and two of the ID mice had bacterial communities that were similar in composition to that of human skin, although, presumably because of the uniform raising conditions, less interindividual variation was found in mice. However, eight ID mice showed microbiota dominated by Staphylococcus epidermidis. Quantitative PCR amplification of 16S rDNA gene and of the Staphylococcus-specific TstaG region confirmed the previous results and indicated that the quantitative levels of Staphylococcus were similar in both groups while the total number of 16S copies was greater in the healthy mice. Thus, it is possible that, under long-term immunodeficiency, which removes the acquired but not the native immune system, S.epidermidis may inhibit the growth of other bacteria but does not cause a pathogenic state. PMID- 22524616 TI - Fluorocyclopentenyl-cytosine with broad spectrum and potent antitumor activity. AB - On the basis of the potent biological activity of cyclopentenyl-pyrimidines, fluorocyclopentenyl-pyrimidines were designed and synthesized from D-ribose. Among these, the cytosine derivative 5a showed highly potent antigrowth effects in a broad range of tumor cell lines and very potent antitumor activity in a nude mouse tumor xenograft model implanted with A549 human lung cancer cells. However, its 2'-deoxycytidine derivative 5b did not show any antigrowth effects, indicating that 2'-hydroxyl group is essential for the biological activity. PMID- 22524614 TI - Enhancement of alpha-helix mimicry by an alpha/beta-peptide foldamer via incorporation of a dense ionic side-chain array. AB - We report a new method for preorganization of alpha/beta-peptide helices, based on the use of a dense array of acidic and basic side chains. Previously we have used cyclically constrained beta residues to promote alpha/beta-peptide helicity; here we show that an engineered ion pair array can be comparably effective, as indicated by mimicry of the CHR domain of HIV protein gp41. The new design is effective in biochemical and cell-based infectivity assays; however, the resulting alpha/beta-peptide is susceptible to proteolysis. This susceptibility was addressed via introduction of a few cyclic beta residues near the cleavage site, to produce the most stable, effective alpha/beta-peptide gp41 CHR analogue identified. Crystal structures of an alpha- and alpha/beta-peptide (each involved in a gp41-mimetic helix bundle) that contain the dense acid/base residue array manifest disorder in the ionic side chains, but there is little side-chain disorder in analogous alpha- and alpha/beta-peptide structures with a sparser ionic side-chain array. These observations suggest that dense arrays of complementary acidic and basic residues can provide conformational stabilization via Coulombic attractions that do not require entropically costly ordering of side chains. PMID- 22524617 TI - Chemical and sensory quality of lamb meat burgers from Manchego Spanish breed. AB - This study examines the nutritional composition, fatty acid profile and sensory properties of two types of lamb burgers from the Spanish Manchego breed (formula 1 = L: completely from leg lamb meat; formula 2 = LNB with 2/3 leg and 1/3 neck and breast meat). A significant effect of the formulation type was found since Formula 1 had a lower fat percentage (p < 0.001) and higher protein content (p < 0.05). The percentage of total fatty acids and the profile varied for both formulas and consequently their indexes. In addition, the levels of saturated and polyunsaturated fatty acids were slightly lower (p < 0.001) and higher (p < 0.001), respectively, in burgers L than in LNB although both types of burgers raised fatty acid indexes in a healthy threshold. As regarding the sensorial analysis, non-significant differences were described among both formulas. In conclusion, meat quality characteristics were similar for both formulation types being the storage time, the only factor affecting lamb burger stability. PMID- 22524618 TI - The combination of olaparib and camptothecin for effective radiosensitization. AB - BACKGROUND: Poly (ADP-ribose) polymerase-1 (PARP-1) is a key enzyme involved in the repair of radiation-induced single-strand DNA breaks. PARP inhibitors such as olaparib (KU-0059436, AZD-2281) enhance tumor sensitivity to radiation and to topoisomerase I inhibitors like camptothecin (CPT). Olaparib is an orally bioavailable inhibitor of PARP-1 and PARP-2 that has been tested in multiple clinical trials. The purpose of this study was to investigate the characteristics of the sensitizing effect of olaparib for radiation and CPT in order to support clinical application of this agent. METHODS: DLD-1 cells (a human colorectal cancer cell line) and H1299 cells (a non-small cell lung cancer cell line) with differences of p53 gene status were used. The survival of these cells was determined by clonogenic assay after treatment with drugs and X-ray irradiation. The gammaH2AX focus formation assay was performed to examine the influence of olaparib on induction and repair of double-stranded DNA breaks after exposure to radiation or CPT. RESULTS: A radiosensitizing effect of olaparib was seen even at 0.01 MUM. Its radiosensitizing effect after exposure for 2 h was similar to that after 24 h. H1299 cells with depletion or mutation of p53 were more radioresistant than H1299 cells with wild-type p53. However, similar enhancement of radiosensitization by olaparib was observed with all of the tested cell lines regardless of the p53 status. Olaparib also sensitized cells to CPT. This sensitizing effect was seen at low concentrations of olaparib such as 0.01 MUM, and its sensitizing effect was the same at both 0.01 MUM and 1 MUM. The combination of olaparib and CPT had a stronger radiosensitizing effect. The results of the gammaH2AX focus assay corresponded with the clonogenic assay findings. CONCLUSION: Olaparib enhanced sensitivity to radiation and CPT at low concentrations and after relatively short exposure times such as 2 h. The radiosensitizing effect of olaprib was not dependent on the p53 status of tumor cells. These characteristics could be advantageous for clinical radiotherapy since tumor cells may be exposed to low concentrations of olaparib and/or may have different levels of p53 mutation. The combination of olaparib and CPT had a stronger radiosensitizing effect, indicating that combining a PARP inihibitor with a topoiomerase I inhibitor could be promising for clinical radiosensitization. PMID- 22524619 TI - Branchiomycosis in tambaqui, Colossoma macropomum (Cuvier), from the eastern Brazilian Amazon. PMID- 22524620 TI - IFN-gamma induction on carbohydrate binding module of fungal immunomodulatory protein in human peripheral mononuclear cells. AB - FIP-fve is a protein that is isolated from Flammulina velutipes . Its known immunomodulatory activities are elicitation of the production of type II interferon from human peripheral mononuclear cells (hPBMCs) and hemagglutination. How the target receptors mediate activation of FIP-fve-induced immunomodulatory effects remains to be elucidated. This study postulates the three-dimensional structures to determine whether the carbohydrate binding module family 34 (CBM 34) on FIP-fve is conserved to site N of Thermoactinomyces vulgaris R-47 alpha amylase I. Experimental site-directed mutagenesis data as well as ligand-specific binding competition assay are adopted to identify the key residues W24, T28, D34, T90, I91, and W111 of FIP-fve that participate in binding to polysaccharides that are linked to the membrane of immune cells. Treatments of hPBMCs with tunicamycin and deglycosylation enzymes that removed the carbohydrate moieties reduced the secretion of IFN-gamma induction from hPBMCs. In conclusion, the experiments herein demonstrated the ligand-binding CBM-34 on FIP-fve and ligand-like glycoproteins on the surface of hPBMCs must be required to induce physiological immunomodulatory effects. PMID- 22524622 TI - Measurement of alkaline phosphatase in canine seminal plasma--an update. AB - In dogs, diagnosis of incomplete ejaculation and azoospermia can be made by measuring the activity of the enzyme alkaline phosphatase (AP) in seminal plasma. However, even though upper cut-off value of 5000 IU/l is given in the literature, results by different assays may vary considerably. Furthermore, no data exist concerning the stability of the enzyme during storage of frozen seminal plasma, and no recommendations for pre-analytic dilutions can be found. During the present study, we compared results from a conventional large scale wet chemistry analyzer to a widely used dry chemistry point of care system (POC) and established a best practice for pre-analytical dilutions. Furthermore, stability of enzyme activities in seminal plasma during storage at -18 degrees C for 24 h was evaluated. The average activity of AP in the 2nd fraction of normal ejaculates measured by Reflotron(r) was 107,328 IU/l. After 24 h of frozen storage, activities did not differ significantly (96,844 IU / l, p > 0.05). Fresh and frozen samples were analysed in parallel by the POC and conventional chemistry analyser, and the results compared that did not reveal a significant difference (p > 0.05). A dilution of seminal plasma with physiologic saline 1:100 prior to analysis was sufficient for the qualitative information whether AP activity is below or above 5000 IU/l. Present data show that AP measurement by a POC dry chemistry system is sufficiently accurate in diluted seminal plasma for the diagnosis of azoospermia and that seminal plasma can be stored frozen for 24h before analysis. PMID- 22524623 TI - Left-right holistic integration of human bodies. AB - Holistic integration of faces has been widely studied. More recently, investigations have explored whether similar processing is used for human bodies. Here we show that holistic processing, as measured by the composite task, does occur for bodies but is stronger for left and right halves than for top and bottom halves. We also found composite effects for left-right halves of inverted bodies. Standard composite effects were found for top halves of faces, tested as a control. We argue that our results suggest that holistic processing of faces and bodies might not exclusively occur for identification, but instead may also have evolved to aid communication and/or decisions about mate choice (through judging symmetry). PMID- 22524621 TI - Lack of association between GTF2H4 genetic variants and AERD development and FEV1 decline by aspirin provocation. AB - Aspirin-exacerbated respiratory disease (AERD) is prevalent in about 10% of asthma patients and is characterized by a severe decline in forced expiratory volume in 1-s (FEV(1) ), an important phenotype for total lung capacity, upon ingestion of aspirin. The general transcription factor IIH subunit 4 (GTF2H4) is positioned at 6p21.33, a part of the major histocompatibility complex (MHC) class II region that contains a number of genes that play an important role in the immune system. In addition, genetic variants in another general transcription factor IIH gene have revealed significant association with lung disease. To investigate whether GTF2H4 genetic variants could be a causative factor for AERD development and FEV(1) decline by aspirin provocation, five common single nucleotide polymorphisms (SNPs) were genotyped in 93 patients with AERD and 96 aspirin-tolerant asthma (ATA) controls. As a result, when adjusted for age, gender, smoking status and atopy as covariates, the rs1264307 variant and two haplotypes showed nominal signals in the association with AERD (P = 0.02-0.04), but the significances disappeared after corrections for multiple testing (corrected P > 0.05). In further multiple regression analysis, no genetic variants of GTF2H4 showed significant associations with FEV(1) decline by aspirin provocation in asthmatics (P > 0.05). Despite the need for replications in larger cohorts, our preliminary findings suggest that GTF2H4 variants may not be associated with susceptibility to AERD and obstructive symptoms in asthmatics. PMID- 22524625 TI - Geometry optimizations of open-shell systems with the fragment molecular orbital method. AB - The ability to perform geometry optimizations on large molecular systems is desirable for both closed- and open-shell species. In this work, the restricted open-shell Hartree-Fock (ROHF) gradients for the fragment molecular orbital (FMO) method are presented. The accuracy of the gradients is tested, and the ability of the method to reproduce adiabatic excitation energies is also investigated. Timing comparisons between the FMO method and full ab initio calculations are also performed, demonstrating the efficiency of the FMO method in modeling large open-shell systems. PMID- 22524624 TI - Crystal structures of Xanthomonas campestris OleA reveal features that promote head-to-head condensation of two long-chain fatty acids. AB - OleA is a thiolase superfamily enzyme that has been shown to catalyze the condensation of two long-chain fatty acyl-coenzyme A (CoA) substrates. The enzyme is part of a larger gene cluster responsible for generating long-chain olefin products, a potential biofuel precursor. In thiolase superfamily enzymes, catalysis is achieved via a ping-pong mechanism. The first substrate forms a covalent intermediate with an active site cysteine that is followed by reaction with the second substrate. For OleA, this conjugation proceeds by a nondecarboxylative Claisen condensation. The OleA from Xanthomonas campestris has been crystallized and its structure determined, along with inhibitor-bound and xenon-derivatized structures, to improve our understanding of substrate positioning in the context of enzyme turnover. OleA is the first characterized thiolase superfamily member that has two long-chain alkyl substrates that need to be bound simultaneously and therefore uniquely requires an additional alkyl binding channel. The location of the fatty acid biosynthesis inhibitor, cerulenin, that possesses an alkyl chain length in the range of known OleA substrates, in conjunction with a single xenon binding site, leads to the putative assignment of this novel alkyl binding channel. Structural overlays between the OleA homologues, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase and the fatty acid biosynthesis enzyme FabH, allow assignment of the two remaining channels: one for the thioester-containing pantetheinate arm and the second for the alkyl group of one substrate. A short beta-hairpin region is ordered in only one of the crystal forms, and that may suggest open and closed states relevant for substrate binding. Cys143 is the conserved catalytic cysteine within the superfamily, and the site of alkylation by cerulenin. The alkylated structure suggests that a glutamic acid residue (Glu117beta) likely promotes Claisen condensation by acting as the catalytic base. Unexpectedly, Glu117beta comes from the other monomer of the physiological dimer. PMID- 22524626 TI - Vascular stem cells in diabetic complications: evidence for a role in the pathogenesis and the therapeutic promise. AB - Long standing diabetes leads to structural and functional alterations in both the micro- and the macro-vasculature. Vascular endothelial cells (ECs) are the primary target of the hyperglycemia-induced adverse effects. Vascular stem cells that give rise to endothelial progenitor cells (EPCs) and mesenchymal progenitor cells (MPCs) represent an attractive target for cell therapy for diabetic patients. A number of studies have reported EPC dysfunction as a novel participant in the culmination of the diabetic complications. The controversy behind the identity of EPCs and the similarity between these progenitor cells to hematopoietic cells has led to conflicting results. MPCs, on the other hand, have not been examined for a potential role in the pathogenesis of the complications. These multipotent cells, however, do show a therapeutic role. In this article, we summarize the vascular changes that occur in diabetic complications highlighting some of the common features, the key findings that illustrate an important role of vascular stem cells (VSCs) in the pathogenesis of chronic diabetic complications, and provide mechanisms by which these cells can be used for therapy. PMID- 22524627 TI - Distinctive heat-shock response of bioleaching microorganism Acidithiobacillus ferrooxidans observed using genome-wide microarray. AB - Temperature plays an important role in the heap bioleaching. The maldistribution of ventilation in the heap leads to local hyperthermia, which does exert a tremendous stress on bioleaching microbes. In this study, the genome-wide expression profiles of Acidithiobacillus ferrooxidans at 40 degrees C were detected using the microarray. The results showed that some classic proteases like Lon and small heat-shock proteins were not induced, and heat-inducible membrane proteins were suggested to be under the control of sigma(E). Moreover, expression changes of energy metabolism are noteworthy, which is different from that in heterotrophic bacteria upon heat stress. The induced enzymes catalyzed the central carbon metabolism pathway that might mainly provide precursors of amino acids for protein synthesis. These results will deepen the understanding of the mechanisms of heat-shock response on autotrophic bacteria. PMID- 22524628 TI - Extended nodal dissection reduces sexual function recovery after robot-assisted laparoscopic prostatectomy. AB - BACKGROUND AND PURPOSE: Considering the anatomic proximity of the internal iliac lymph nodes and the pelvic plexus, it may be expected that more extensive pelvic nodal dissection is associated with an increased risk of damage to the small pelvis neural and vascular structures. We evaluate whether nodal dissection is associated with functional outcome after robot-assisted radical prostatectomy (RARP). PATIENTS AND METHODS: In a series of 798 RARP procedures, 325 (40.7%) patients underwent a lymph node dissection. Continence, sexual function, and lower urinary tract symptoms (LUTS) were assessed using the International Consultation of Incontinence Questionnaire short form (ICIQ)-SF), International Index of Erectile Function-15, and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ)-PR25 questionnaires before and at 6 months intervals after RARP. RESULTS: Preoperative ICIQ-SF, IIEF 15, and PR25-LUTS scores were similar for men with and without nodal dissection. Normal postoperative erectile function (IIEF-EF >24) at 6 months was reported by 1.7%, 9.1%, and 50.4% of men with no, unilateral, and bilateral nerve preservation and normal preoperative erectile function. All domains of the IIEF 15 score showed a negative correlation with the number of removed lymph nodes. In 70 of 325 (21%) cases with nodal dissection, more than 10 nodes were removed. Men with more than 10 nodes removed had lower IIEF-15 domain scores compared with men with 1 to 10 removed lymph nodes. The postoperative ICIQ-SF and PR25-LUTS scores were not associated with extent of nodal dissection. Nodal metastases were found in 5.9% and 15.7% of men with <= 10 nodes and >10 nodes removed (P=0.005). In a multivariate analysis, extent of fascia preservation (FP-score), preoperative IIEF-EF, and number of removed nodes were the strongest independent predictors of postoperative erectile function recovery. CONCLUSION: More extensive nodal dissection was associated with impaired postoperative sexual function recovery but not continence and voiding function after RARP, independent of preoperative function and nerve preservation. PMID- 22524629 TI - Is more expensive medical technology better? The use of analytics in the evaluation of clinical outcomes for different material compositions of total knee implants. PMID- 22524630 TI - Seasonal variation in placental abruption. AB - OBJECTIVE: To characterize seasonal patterns of placental abruption among Jewish and Bedouin parturients in the Southern part of Israel. METHODS: A retrospective population-based study comparing all singleton pregnancies of patients with and without placental abruption was conducted. Deliveries occurred between the years 1988 and 2010. A 'classical' model of time series was used, allowing to assess trend and periodic patterns of placental abruption. RESULTS: During the study period, 241,408 deliveries took place, of which 1685 (0.7%) were complicated with placental abruption. Placental abruption was significantly more common among Bedouin parturients: 0.77% (n = 948) vs. 0.623% (n = 737), p < 0.001. A non linear negative correlation was noted in the incidence of placental abruption (coefficient = -0.002) during the entire study period. Time series analysis demonstrated annual cycle frequency, seasonal cycle and weekly cycle of placental abruption. The seasonal incidence of placental abruption was higher during spring (B = 7.15) and lower during summer (reference) for both populations (Jewish and Bedouins). Weekly cycle showed significantly higher incidence on Saturday (B = 3.4) and lowest on Tuesday (B = -4.66) for both groups. The daily differences were accentuated in the Bedouin population (B = 3.7 vs. B = 2.93 in the Jewish population). CONCLUSION: Placental abruption was significantly more common in the Bedouin population. Both populations demonstrated the same annual and seasonal patterns, with higher incidence in spring and autumn. PMID- 22524631 TI - Ambulatory tonometric blood pressure measurements in patients with diabetes. AB - BACKGROUND: Arterial tonometry is a novel technique for measuring ambulatory blood pressure (AMBP). The watch-like device BPro((r)) (HealthSTATS International, Singapore) captures radial pulsewave reflection and calculates brachial blood pressure (BP). In this study we investigate if arterial tonometry is applicable and reliable in patients with diabetes. SUBJECTS AND METHODS: We compared tonometric (BPro) to cuff-based oscillometric and auscultatoric BPs (Takeda model TM2421, A&D Medical, Tokyo, Japan) in 25 Caucasian patients with type 1 or type 2 diabetes. Patients were seen twice within 2 weeks. At visit 1, a 15-min rest was followed by the recording of three cuff-based BPs and 2-min continuous tonometric BPs. At both visits 24-h AMBP measurements were recorded with the BPro device. RESULTS: At Visit 1, auscultatoric BP (mean+/-SD) was 136+/ 19/72+/-8 mm Hg versus 138+/-19/78+/-8 mm Hg with the tonometric device. Visit 1 AMBP was 131+/-20/76+/-9 mm Hg versus 131+/-12/75+/-9 mm Hg at Visit 2. Mean 24-h AMBP, daytime BP, nighttime BP, and dipping at the two visits were similar (P>0.40). Linear and intraclass correlations coefficients between auscultatoric and tonometric systolic and diastolic BP were r=0.86 and 0.65, respectively (P<0.001 for both), and r=0.83 and 0.77, respectively (P<0.001 for both). The mean differences between devices were 1.9+/-10 and 5.5+/-6.6 mm Hg for systolic and diastolic BP, respectively. CONCLUSIONS: In patients with diabetes tonometric and cuff-based BPs are comparable, and tonometric AMBPs are reproducible and feasible. PMID- 22524632 TI - The gonadal hormone regulates the plasma lactate levels in type 2 diabetes treated with and without metformin. AB - OBJECTIVE: Our previous study showed there was a gender difference in plasma lactate concentrations in subjects with type 2 diabetes. This study investigated the effect of sex hormone levels on plasma lactic acid (LA) levels in type 2 diabetes with and without metformin therapy. SUBJECTS AND METHODS: Fasting whole blood specimens of 392 type 2 diabetes patients treated with metformin (n=199) or not (n=193) were collected. LA was measured with an enzyme-electrode assay. Levels of sex hormones, including testosterone (T) and estradiol (E(2)), were measured with a chemiluminescence microparticle immunoassay. Spearman's or Pearson's correlation and logistic regression analysis were performed for the factors associated with LA. RESULTS: The LA level in the metformin group was significantly higher than that in the non-metformin group (1.26+/-0.43 vs. 1.14+/ 0.49 mmol/L, P<0.001), and LA levels of females were significantly higher than those of males (P<0.001). LA concentrations were positively correlated with E(2) level but negatively correlated with metformin and T levels (P<0.01). The logistic regression analysis showed that gender, creatinine, E(2), metformin, and T were independent factors influencing lactate levels. Analysis of subgroups demonstrated that the LA concentrations increased with the elevation of E(2) level (P<0.05) but decreased with the rising of T level (P<0.05). CONCLUSIONS: Sex hormones play an important role on regulating plasma lactate levels in diabetes patients treated with metformin. E(2) up-regulates but T tend to down regulate lactate levels. PMID- 22524634 TI - Effect of hydrophilicity or hydrophobicity of polyelectrolyte on the interaction between polyelectrolyte and surfactants: molecular dynamics simulations. AB - The effect of hydrophilicity or hydrophobicity of polyelectrolyte on the interaction between polyelectrolyte and oppositely charged surfactants was investigated by using coarse-grained molecular dynamics simulations. The aggregation of surfactants on the hydrophilic polyelectrolyte is significantly different from that on the hydrophobic polyelectrolyte. The complexes evolve from the "bottle brush", through the "necklace", then to the micelle. However, the rod like micelle, in which polyelectrolyte wraps around the micelle surface, only appears in the hydrophilic polyelectrolyte system. For the hydrophobic polyelectrolyte system, the spherical micelle is formed, and the polyelectrolyte penetrates into the hydrophobic core of complexes. The hydrophobic nature of the surfactant tails induces the surfactant's tendency to depart from the hydrophilic polyelectrolyte and point toward the bulk phase, but it is apt to combine with the hydrophobic polyelectrolyte, leading to a parallel configuration between the surfactants and the polyelectrolyte. When the charge ratio (Z) of surfactant to polylelectrolyte is lower, the polyelectrolyte shows extended structure, and with the increase of Z, the polyelectrolyte collapse undergoes either a continuous or an abrupt change depending on if it is a hydrophobic or hydrophilic polyelectrolyte. At higher charge density of the hydrophilic polyelectrolyte, there is a synergistic effect of the electrostatic interaction between surfactant and polyelectrolyte, with the hydrophobic interaction among the adsorbed surfactants. For the hydrophobic polyelectrolyte system, no synergistic effect is observed. PMID- 22524633 TI - Early removal of urinary catheter leads to greater post-void residuals in patients with thoracic epidural. AB - BACKGROUND: A recent study showed that the removal of a bladder catheter is safe in presence of thoracic epidural analgesia (TEA). However, the ability to void satisfactorily can be affected. The aim of this investigation is to determine whether patients with TEA are able to recover the micturition process. METHODS: On the morning after the surgery patients were randomised into two groups: the early removal group (ERG) (n = 101), with the bladder catheter removed at the same time, and the standard group (SG) (n = 104), where the bladder catheter was kept as long as TEA was functioning (on average 3-5 days after surgery). Following the first micturition, patients underwent regular ultrasound scanning of the bladder until a post-void residual (PVR) less than 200 ml was reached. RESULTS: All of the patients in the ERG and in the SG started to void and recovered satisfactorily their ability to void, reaching a PVR < 200 ml without requiring a transurethral catheterisation. However, the length of time to reach a PVR < 200 ml in the ERG was significantly longer compared with the SG (345 min +/ 169 vs. 207 min +/- 122, P < 0.0001). CONCLUSION: In the presence of TEA, the removal of the bladder catheter on the morning after surgery leads to a transient impairment of the lower urinary tract function with no need for re catheterisation. PMID- 22524635 TI - Selective cleavage of periodic mesoscale structures: two-dimensional replication of binary colloidal crystals into dimpled gold nanoplates. AB - Specific crystallographic planes of binary colloidal crystals consisting of silica nanoparticles are two-dimensionally replicated on the surface of gold nanoplates. The selectivity of the surface patterns is explained by the geometrical characteristics of the binary colloidal crystals as templates. The binary colloidal crystals with the AlB(2)- and NaZn(13)-type structures are fabricated from aqueous dispersions of stoichiometrically mixed silica nanoparticles with different sizes. The stoichiometry is precisely controlled on the basis of a seed growth of silica nanoparticles. Dimpled gold nanoplates are formed by the two-dimensional growth of gold between partially cleaved surfaces of templates. The selectivity of the surface patterns is explained using the AlB(2)-type binary colloidal crystal as a template. The surface pattern is determined by the preferential cleavage of the plane with the lowest density of particle-particle connections. The tendency to form well-defined cleavage in binary colloidal crystals is crucial to formation of dimpled gold nanoplates, which is explained using the NaZn(13)-type binary colloidal crystal as a template. Its complex structure does not show well-defined cleavage, and only distorted nanoplates are obtained. Therefore, the mechanism of the two dimensional replication of binary colloidal crystals is reasonably explained on the basis of their periodic mesoscale structures and crystal-like properties. PMID- 22524636 TI - Phthalide and isocoumarin derivatives produced by an Acremonium sp. isolated from a mangrove Rhizophora apiculata. AB - Nine new fungal metabolites, one phthalide derivative, acremonide (1), and eight isocoumarin derivatives, acremonones A-H (2-9), were isolated from the mangrove derived fungus Acremonium sp. PSU-MA70 together with 10 known compounds. Their structures were determined by NMR analysis. The known 8-deoxytrichothecin and trichodermol exhibited moderate antifungal activity against Candida albicans and Cryptococcus neoformanns, respectively. PMID- 22524637 TI - Multilocus sequence typing of serial Candida albicans isolates from children with cancer, children with cystic fibrosis and healthy controls. AB - Candida albicans is a fungal pathogen, but also a commensal in many individuals. Since detailed molecular studies of children carrying C. albicans are lacking, we longitudinally investigated fecal and tonsillopharyngeal samples from 10 children undergoing treatment for cancer, six children treated for cystic fibrosis (CF), and seven healthy children during the time period of 1999-2008. Multilocus sequence typing (MLST) was performed on 62 C. albicans isolates. Only three of the 23 children (13%) were colonized with genetically unrelated strains in the longitudinal follow-up. We identified 32 different diploid sequence types (DSTs), but only one (409) was shared by two siblings. Most often, the fecal strain types were identical or closely related to the tonsillopharyngeal reservoirs. We found no closely related strain types in children who were hospitalized in the same ward or in children attending the same day care center. There was no sign of resistance to fluconazole, caspofungin, amphotericin B or flucytosine over time. This study shows that both children with cancer or CF, and healthy children usually harbor the same C. albicans strain over time. We did not find indications of clonal spread between children in the same environments, except in a pair of siblings. PMID- 22524638 TI - Invasive Scopulariopsis brevicaulis infection in an immunocompromised patient and review of prior cases caused by Scopulariopsis and Microascus species. AB - Scopulariopsis species and their Microascus teleomorphs are cosmopolitan fungi that are uncommonly associated with invasive disease. This report describes a case of fatal disseminated Scopulariopsis brevicaulis disease in a patient with diffuse large B cell lymphoma who underwent high-dose chemotherapy followed by a matched unrelated donor stem cell transplant. This case is compared with 32 prior cases of proven invasive Scopulariopsis (Microascus) infections reported in the literature. A focus of this report is the diagnostic methods utilized which included histopathology and culture with both micromorphologic and genotypic procedures employed to confirm the species identification. PMID- 22524640 TI - Psychometric properties of functional mobility tools in hereditary spastic paraplegia and other childhood neurological conditions. AB - AIM: To evaluate studies on the psychometric properties of measurement tools used to quantify functional mobility in children with hereditary spastic paraplegia (HSP) and other childhood neurological conditions. METHOD: Two independent reviewers identified measures previously used by clinicians to quantify functional mobility. Because our primary interest was HSP, the first search identified measurement tools in studies that included those with HSP. To enhance the generalizability, the second search examined the reliability, validity, and responsiveness of tools in children with a range of neurological conditions such as cerebral palsy, spinal muscular atrophy, Down syndrome, and traumatic brain injury. The Consensus-based Standards for the Selection of Health Measurement Instruments was used to rate the methodological quality of identified articles. RESULTS: The Gillette Functional Assessment Questionnaire (FAQ), the Functional Mobility Scale (FMS), the Gross Motor Function Measure (GMFM), the Rivermead Motor Assessment, and the Walking Index for Spinal Cord Injury II were identified for quantifying functional mobility. The FMS and GMFM were reliable, valid, and responsive to changes across a range of childhood neurological conditions. The FAQ was reliable and valid for measuring functional mobility in similar populations. INTERPRETATION: The FAQ, FMS, and GMFM are valid, reliable, and responsive measures in children with a range of neurological conditions. PMID- 22524639 TI - Serum galactomannan in cystic fibrosis patients colonized with Aspergillus species. AB - Cystic fibrosis patients are often colonized by Aspergillus species. Sera from 138 pediatric and adult cystic fibrosis patients were tested for the presence of galactomannan. All serum samples were negative for galactomannan and there was no difference among patients who were chronically, intermittently, and never colonized with Aspergillus. PMID- 22524641 TI - Graphene-ferroelectric hybrid structure for flexible transparent electrodes. AB - Graphene has exceptional optical, mechanical, and electrical properties, making it an emerging material for novel optoelectronics, photonics, and flexible transparent electrode applications. However, the relatively high sheet resistance of graphene is a major constraint for many of these applications. Here we propose a new approach to achieve low sheet resistance in large-scale CVD monolayer graphene using nonvolatile ferroelectric polymer gating. In this hybrid structure, large-scale graphene is heavily doped up to 3 * 10(13) cm(-2) by nonvolatile ferroelectric dipoles, yielding a low sheet resistance of 120 Omega/? at ambient conditions. The graphene-ferroelectric transparent conductors (GFeTCs) exhibit more than 95% transmittance from the visible to the near-infrared range owing to the highly transparent nature of the ferroelectric polymer. Together with its excellent mechanical flexibility, chemical inertness, and the simple fabrication process of ferroelectric polymers, the proposed GFeTCs represent a new route toward large-scale graphene-based transparent electrodes and optoelectronics. PMID- 22524642 TI - Mucoepidermoid carcinoma of the parotid presenting as periauricular cystic nodules: a series of four cases. AB - Mucoepidermoid carcinoma is a relatively common neoplasm of the major and minor salivary glands that can secondarily involve skin. In the vicinity of the ear lobe, mimicry of a benign cyst, both clinically and histopathologically is a diagnostic pitfall to avoid. The clinical manifestations, diagnostic histopathology, and clinical course of mucoepidermoid carcinoma of the parotid gland presenting as a clinically benign periauricular cystic nodule in four patients ranging in age from 11 to 63 years, are analyzed in the present report. Illustrating the challenge of accurate diagnosis, three of the four cases were initially misinterpreted on biopsy as benign cystic lesions. Multiple biopsies displayed foamy histiocytes around mucinous extravasations into dermis that mimicked ruptured epithelial cysts in two cases before malignancy was ascertained. This series demonstrates the need to include parotid tumor in the differential diagnosis of odd periauricular cyst-like expansions and adenosquamous proliferations. Mucoepidermoid carcinoma in particular can explain indolent, infra-auricular 'mucinous cysts'. Familiarity with this syndrome should arouse suspicion of parotid carcinoma when a 'cyst' or nodule is located near the earlobe. Delay in diagnosis results in larger surgical procedures than are otherwise necessary. PMID- 22524644 TI - Applying the precautionary principle. PMID- 22524643 TI - Characterization of the high affinity Zn transporter from Noccaea caerulescens, NcZNT1, and dissection of its promoter for its role in Zn uptake and hyperaccumulation. AB - * In this paper, we conducted a detailed analysis of the ZIP family transporter, NcZNT1, in the zinc (Zn)/cadmium (Cd) hyperaccumulating plant species, Noccaea caerulescens, formerly known as Thlaspi caerulescens. NcZNT1 was previously suggested to be the primary root Zn/Cd uptake transporter. Both a characterization of NcZNT1 transport function in planta and in heterologous systems, and an analysis of NcZNT1 gene expression and NcZNT1 protein localization were carried out. * We show that NcZNT1 is not only expressed in the root epidermis, but also is highly expressed in the root and shoot vasculature, suggesting a role in long-distance metal transport. Also, NcZNT1 was found to be a plasma membrane transporter that mediates Zn but not Cd, iron (Fe), manganese (Mn) or copper (Cu) uptake into plant cells. * Two novel regions of the NcZNT1 promoter were identified which may be involved in both the hyperexpression of NcZNT1 and its ability to be regulated by plant Zn status. * In conclusion, we demonstrate here that NcZNT1 plays a role in Zn and not Cd uptake from the soil, and based on its strong expression in the root and shoot vasculature, could be involved in long-distance transport of Zn from the root to the shoot via the xylem. PMID- 22524645 TI - Effects of short-term exposure to powerline-frequency electromagnetic field on the electrical activity of the heart. AB - ABSTRACT The heart is a contractile organ that can generate its own rhythm. The contraction, or the rhythm, of the heart may be influenced by electromagnetic field (EMF) exposure, because of the heart's excitability characteristic. In previous studies, different methods have been used to study the possible effects of an extremely low frequency electromagnetic field (ELF-EMF) on the heart. But the studies' designs were not similar, and the results were also different. Recent studies have shown some evidence that short-term EMF exposure can influence the heart more than long-term exposure. This study investigated how the heart is affected in the first EMF exposure. In a simulation of the daily exposure of humans to a power frequency, Wistar albino rats were used. By utilizing the Helmholtz-coil set, we obtained a 50-Hz, 1-MUT EMF and examined rat heart activity during short-term EMF exposure. No effect was observed under this exposure condition. The results obtained do not confirm a possible mechanism in the electrical activity of the rat heart model. PMID- 22524646 TI - The frequency and causes of occupational injuries among nursing students in Turkey. AB - The aim of this study is to determine the number and causes of occupational incidents that occurred in nursing students. This study was a descriptive, cross sectional study performed at a military nursing school in Turkey in June 2009 with 218 nursing students as subjects. A data collection form for identifying the characteristics of the students and their exposure to incidents was used. The frequency of incidents increased with the increase in the number of years enrolled in the nursing program. It was determined that needlesticks (47.3%) and broken ampules during medication preparation (37.8%) were the 2 most common reasons for injuries. This study showed that although nursing students had high percentage of penetrating injuries, the overall incidence of injury was low. For prevention of occupational incidents, information about occupational incidents, risks, and prevention methods must be included in the nursing curriculum. PMID- 22524647 TI - Occupational exposure to pesticides and nerve conduction studies among Korean farmers. AB - This study aimed to determine whether occupational exposure to pesticides was associated with decreased nerve conduction studies among farmers. On 2 separate occasions, the authors performed a cross-sectional study of a group of 31 male farmers who periodically applied pesticides. The study included questionnaire interviews and nerve conduction studies on the median, ulnar, posterior tibial, peroneal, and sural nerves. Although all mean values remained within laboratory normal limits, significant differences between the first and second tests were found in sensory conduction velocities on the median and sural nerves, and motor conduction velocities on the posterior tibial nerve. Lifetime days of pesticide application was negatively associated with nerve conduction velocities at most nerves after adjusting for potential confounders. These findings may reflect a link between occupational pesticide exposure and peripheral neurophysiologic abnormality that deserves further evaluation. PMID- 22524648 TI - Chest imaging and lung function impairment after long-term occupational exposure to low concentrations of chrysotile. AB - The aim of the present study was the investigation of radiographic findings in relation to lung function after occupational exposure to permissible levels of relatively pure chrysotile (0.5-3% amphiboles). We studied 266 out of the total 317 employees who have worked in an asbestos cement factory during the period 1968-2004 with chest x-ray, high-resolution computed tomography (HRCT) and lung function tests. Sensitivity of chest x-ray was 43% compared to HRCT. Abnormal HRCT findings were found in 75 subjects (67%) and were related to age, occupational exposure duration, and spirometric data. The presence of parenchymal or visceral pleural lesions (exclusively or as the predominant abnormality) was being accompanied by lower total lung capacity and diffusion capacity. HRCT was much more sensitive than chest x-ray for occupational chrysotile exposure. Lung function impairment was related with parenchymal but not with pleural HRCT abnormalities. PMID- 22524649 TI - Prevalence of sensitization to Anisakis simplex among professionally exposed populations in Sicily. AB - Anisakis simplex (AS) is a cause of allergic sensitization and potential occupational risk is suggested in fishermen and workers assigned to fish processing and sale. A cross-sectional study was conducted in order to assess possible health effects of occupational exposure to AS in workers recruited from western Sicily fisheries sector. Social, demographic, and occupation-related data were collected. Serum total immunoglobulin E (IgE) and specific IgE levels to AS (threshold >0.35 kU/L) were determined by an fluoroimmunoassay technique. Ninety four subjects with potential occupational exposure (fishmongers, fishermen, fish industry employees) were recruited. Specific AS IgEs were detected in 20.2% of the study population. AS IgE seroprevalence was elevated 6.7-fold (p = .03) among fishermen/sailors compared with fish industry workers. The study suggested the importance to adopt specific prevention strategies against exposure to AS in the occupational setting. PMID- 22524650 TI - Work-related musculoskeletal complaints among workers of Iranian aluminum industries. AB - In developing countries, musculoskeletal complaints are considered as main cause of occupational complications and disability. Economic burden of these complications more than workers has impact on organization and society in general. In Iranian aluminum industries, workers are directly involved in production process and physical activities such as manual material handling and awkward postures are very common. The present study was performed for assessment of musculoskeletal complaints prevalence among workers of Iranian aluminum industries. Participants in this cross-sectional study were 493 workers of 3 Iranian aluminum industries with random selection. Data of musculoskeletal complaints were gathered by means of the standardized Nordic self-reporting questionnaire. Demographic and work-related data were collected into the checklist. Findings of this study showed that 65.5% of workers in past week and 77.5% of workers in past year had claimed one of the musculoskeletal complaints in their work places. Lumbar, knee(s), and upper back had the most musculoskeletal complaints prevalence in participants. Musculoskeletal complaints in past week and year had significant association with job duration and age in these workers. Musculoskeletal complaints in Iranian aluminum industries happened in high rate. Ergonomic intervention strategies in the workplaces must be the focus for elimination of environmental hazards such as apposition on the time of work and manual handling of heavy loads. PMID- 22524651 TI - The relationship of ambient ozone and PM(2.5) levels and asthma emergency department visits: possible influence of gender and ethnicity. AB - ABSTRACT An investigation of the relationship of air pollution and emergency department (ED) visits for asthma was an opportunity to assess environmental risks for asthma exacerbations in an urban population. A total of 6,979 individuals with a primary discharge diagnosis of asthma presented to 1 of 6 EDs in the Pittsburgh, Pennsylvania, area between 2002 and 2005. Using a case crossover methodology, which controls for the effects of subject-specific covariates such as gender and race, a 2.5% increase was observed in asthma ED visits for each 10 ppb increase in the 1-hour maximum ozone level on day 2 (odds ratio [OR] = 1.025, p < .05). Particulate matter with an aerodynamic diameter <=2.5 MUm (PM(2.5)) had an effect both on the total population on day 1 after exposure (1.036, p < .05), and on African Americans on days 1, 2, and 3. PM(2.5) had no significant effect on Caucasian Americans alone. The disparity in risk estimates by race may reflect differences in residential characteristics, exposure to ambient air pollution, or a differential effect of pollution by race. PMID- 22524652 TI - Knowledge and practices of farmers with reference to pesticide management: implications on human health. AB - A study was conducted to assess the knowledge and practices of Ethiopian farmers about pesticide management: implications for human health. A pretested standardized questionnaire was administered. The results revealed that the great majority 174 (99.4%) farmers had ample awareness about pesticide impact on human health. However, various hazardous practices have also been documented. One hundred thirty-five (77.2%) farmers make use of the empty pesticide containers for various household purposes. The most frequent self-reported toxicity symptoms associated with pesticide use were headache (58.8%), salivation and vomiting (38.2%), nausea (36.5%), and sneezing (12.5%). Chi-square analysis revealed a strong association between the farmer's educational status and reported toxicity symptoms (p = .0001; chi(2) = 498.2; df = 30). Creating awareness about safe usage of pesticide is extremely vital by special orientation programs. Besides, promoting alternative pest control strategies such as use of biopesticides and integrated pest management (IPM) could be productive. PMID- 22524654 TI - Benefiting from boring. PMID- 22524653 TI - Psychiatric morbidity and emotional exhaustion among hospital physicians and nurses: association with perceived job-related factors. AB - The objective of this study was to evaluate psychiatric morbidity and emotional exhaustion among physicians and nurses of a general hospital in central Italy, examining the association with perceived job-related factors. Anonymous questionnaires were distributed to all 323 hospital physicians and 609 nurses of a nonprofit health organization in Rome, Italy. Standardized instruments were used to evaluate psychiatric morbidity (General Health Questionnaire), burnout (Maslach Burnout Inventory), and perceived job-related factors. Logistic regression was used to examine the association between job-related factors, psychiatric morbidity, and burnout, controlling for demographic factors. Questionnaires were returned by 155 physicians and 216 nurses (overall response rate 40%). Estimated prevalence of psychiatric morbidity was 25% among physicians and 36.9% among nurses. Burnout on the emotional exhaustion scale affected 38.7% of physicians and 46.4% of nurses. Personnel with emotional exhaustion was at higher risk of psychiatric morbidity (p < .001). The likelihood of psychiatric morbidity among physicians was increased by perceived insufficient recognition of personal commitments by the unit's head (odds ratio [OR] = 4.21; 95% confidence interval [CI] 1.2-15.1; p = .027), insufficient managerial ability of the unit's head (OR = 3.45; 95% CI 1.2-10.1; p = .023), and unsatisfactory communication (OR = 5.30; 95% CI 1.6-17.6; p = .006). Among nurses, psychiatric morbidity was associated with insufficient ability of the unit's head to solve conflicts, insufficient decisional power in relation to responsibilities, insufficient economic rewards and career possibilities, and working in surgery. Similar job related factors were associated also with emotional exhaustion. Psychiatric morbidity and emotional exhaustion were relatively high, particularly among nurses. Specific job-related factors were associated with psychiatric morbidity and burnout. Improving these aspects is important for the well-being of hospital staff and the quality of patient care. PMID- 22524656 TI - Breast cancer pathology: the impact of molecular taxonomy on morphological taxonomy. AB - The concept of having an 'intrinsic subtype,' or a molecular taxonomy, lets us clearly recognize that breast cancers have characteristically different patterns of gene expression, thus giving newfound significance to morphological taxonomy. In this review, the concept of the 'intrinsic subtype' is discussed, research questions are introduced to refine the significance of morphological taxonomy, and a corresponding example is presented between microarray analysis and 'immunohistochemical subtype,' or histological taxonomy. PMID- 22524657 TI - Establishment of a monoclonal anti-pan HLA class I antibody suitable for immunostaining of formalin-fixed tissue: unusually high frequency of down regulation in breast cancer tissues. AB - A novel monoclonal anti-pan human leukocyte antigen (HLA) class I heavy chain antibody, EMR8-5, was established. It could detect HLA-A, -B, and -C antigens in formalin-fixed paraffin embedded tissues. By immunohistochemical staining using the EMR8-5 antibody, various cancer tissues from 246 cases were examined for HLA class I expression. It was found that HLA class I expression was decreased in 20% to 42% of the cases of lung cancer, hepatocellular carcinoma, colon cancer, renal cell carcinoma, and urothelial carcinoma. In contrast, 85% of breast cancer cases had loss of or decreased HLA class I expression. Of the 35 breast cancer cases that had decreased HLA class I heavy chain expression, 33 (94%) also had decreased beta2-microglobulin expression detected by immunohistochemical staining. It was suggested that HLA class I down-regulation might be a common characteristic of breast cancer mostly caused by the down-regulation of beta2 microglobulin expression. PMID- 22524658 TI - CXCR7: a novel tumor endothelial marker in renal cell carcinoma. AB - Tumor angiogenesis is necessary for progression and metastasis of solid tumor. Tumor blood vessels are morphologically different from their normal counterparts. In this study, we isolated tumor endothelial cells (TECs) and revealed their abnormalities. We have compared the gene expression profiles of TECs and normal endothelial cells (NECs) by microarray analysis and found that several genes were upregulated in TECs. Expression of the chemokine receptor CXCR7 mRNA was higher in TECs than in NECs. However, information regarding the expression of CXCR7 in the tumor vessels of renal cell carcinoma is limited. CXCR7 and its ligand CXCL12 have been implicated in tumor cell survival. In this study, the expression of CXCR7 in the tumor vessels of renal cell carcinoma (RCC) was investigated. Real time PCR revealed higher expression level of CXCR7 in cultured TECs than in cultured NECs. Furthermore, similar to mouse TECs, immunostaining revealed strong expression of CXCR7 in vivo in human tumor vessels. These findings suggest that CXCR7 is a novel TEC marker and a target for antiangiogenic therapy for RCC. PMID- 22524659 TI - Analysis of VH gene rearrangement and somatic hypermutation in type 1 autoimmune pancreatitis. AB - Type 1 autoimmune pancreatitis (AIP) is the pancreatic manifestation of systemic fibroinflammatory disease called immunoglobulin G4-associated systemic disease. Although this inflammatory process is considered to be a disease with an autoimmune mechanism, its pathogenesis still remains unclear. To clarify the characteristics of B cells infiltrating the lesion, we analyzed the immunoglobulin heavy chain variable region (VH) gene rearrangement and somatic hypermutation of invasive lymphoid cells in type 1 AIP (n= 3), in comparison with obstructive pancreatitis (n= 3) as a control. DNA was extracted from the affected inflammatory lesions. After PCR amplification of the rearranged VH gene, the clones were subcloned, and recombinant clones were randomly selected and sequenced. More than 60 clones per case were analyzed. Monoclonal VH rearrangement was not detected in any of the cases examined. There was no VH family or VH fragment specific to type 1 AIP and obstructive pancreatitis. However, the rate of unmutated VH fragments in type 1 AIP (17%) was higher than that in obstructive pancreatitis (5.1%) (P= 0.010). Our study suggests that an increased rate of unmutated or less mutated VH genes may be characteristic of type 1 AIP and might play a role in the development of this disease. PMID- 22524660 TI - RET finger protein expression is associated with prognosis in lung cancer with epidermal growth factor receptor mutations. AB - The RET finger protein (RFP) is a transcription factor belonging to the TRIM (tripartite motif) superfamily of proteins. RFP is expressed in a variety of human and rodent tumor cell lines and in several kinds of human cancer. Expression of RFP is associated with prognosis of colon and endometrial cancers. In the present study, we evaluated the expression of RFP in lung cancer and assessed its clinical significance. Tissue microarrays were constructed from 108 cases of lung cancer, and the sections were analyzed for RFP expression by immunohistochemistry. RFP expression was detected in the nucleus in 66.7% of lung cancer tissues examined. RFP expression was statistically significantly associated with thyroid transcription factor 1 (TTF-1) expression (P= 0.028). However, no significant association was observed between RFP expression and other clinicopathological or genetic factors, including epidermal growth factor receptor (EGFR) mutations. Interestingly, we found that RFP expression correlated with poor prognosis in patients with EGFR mutations (P= 0.032). Our results suggest that RFP has a role in mutated EGFR signaling and that RFP status may be a prognostic factor for lung cancer with EGFR mutations. PMID- 22524661 TI - Double neuroendocrine ductal carcinomas in situ coexisting with a background of diffuse idiopathic neuroendocrine cell hyperplasia of breast: a case report and hypothesis of neuroendocrine tumor development. AB - This article reports the case of a 72-year-old woman with two nodules of neuroendocrine (NE) ductal carcinoma in situ coexistent with a background of NE cell hyperplasia. Both tumors, 15 and 3 mm in size, were incidentally revealed on computed tomography without any apparent clinical symptoms. The tumors showed similar histological features, and more than 50% of the tumor cells patchily expressed NE markers, such as chromogranin A, synaptophysin, CD56, and somatostatin receptor type 2. The surrounding nontumor ductal cells also showed spotty or linear positivity for NE markers in contrast to the cells of normal atrophic breasts, which rarely present with NE cells. Moreover, focal mucin production was also observed in the peripheral ducts. It is hypothesized that idiopathic breast NE cell hyperplasia with multiple small nests of NE cells may extend to form a true mass of NE neoplasms. PMID- 22524662 TI - Metachronous aortic aneurysms due to sarcoidosis. AB - A 62-year-old male developed metachronous aortic aneurysms at different locations over an interval of one year and three months. He was diagnosed to have sarcoid aneurysms due to the presence of noncaseating epithelioid granulomas in the aortic wall and lymph nodes. The patient was treated with steroids, but his sarcoidosis progressed gradually and extended into other major organs, and the lungs and heart were clinically determined to have been involved by sarcoidosis. He died of cardiac tamponade four years after the first operation for an aortic aneurysm. PMID- 22524663 TI - Intraductal tubulopapillary neoplasm of pancreas with stromal osseous and cartilaginous metaplasia; a case report. AB - Recently, a surgically resected case of intraductal tubulopapillary neoplasm (ITPN) with stromal osseous and cartilaginous metaplasia was encountered. A CT scan showed calcification at the tail of the pancreas two years before the operation. In the resected specimen, macroscopically, the main pancreatic duct was dilated and filled with a whitish solid mass without mucinous material. The tumor showed mainly a solid and papillary growth pattern. The tumor cells had no evidence of acinar differentiation. The tumor cells, at the tail of the pancreas, invaded focally to surrounding pancreatic parenchyma with stromal desmoplastic and fibrosclerotic reaction and also formed nodular stromal osseous and cartilaginous metaplasia. The tumor did not invade extrapancreatic tissue and showed no lymph node metastasis. As there were no signs of chronic calcifying pancreatitis, it is hypothesized that the metaplastic stroma was formed by a stromal reaction due to the tumor growth. It is thought, therefore, that the intraducal component of the tumor had existed at least for two years. This case suggests that ITPN is a relatively indolent tumor with a better prognosis than that of other types of invasive ductal adenocarcinoma of the pancreas. PMID- 22524664 TI - A case of endocrine mucin-producing sweat gland carcinoma. AB - Endocrine mucin-producing sweat gland carcinoma (EMPSGC), which is an uncommon sweat gland tumor with a predilection for the eyelids, is morphologically analogous to solid papillary carcinoma of the breast. We report the case of a 55 year-old man with a subcutaneous tumor of the upper cheek. The pathological findings for this patient were compatible with those of reported cases of EMPSGC, and p63 staining revealed partial microinvasion into the dermis. On the basis of these findings, the patient was diagnosed with EMPSGC. It is reported that EMPSGC is a precursor of invasive mucinous carcinoma of the skin. Therefore, this patient was treated and followed up as if he had mucinous carcinoma of the skin. To the best of our knowledge, this is the first report of such a case from Japan. PMID- 22524665 TI - Plasmablastic lymphoma in an elderly immunocompetent patient. AB - Plasmablastic lymphoma (PBL) is a distinct type of diffuse B cell lymphoma that typically occurs in the oral cavity of patients with HIV infection or immunodeficiency status. PBL is characterized by its plasmablastic morphology and an immunophenotype indicative of a plasma cell differentiation. We present a case of a 75-year-old HIV-negative and Epstein-Barr virus (EBV)-negative patient presenting with an isolated oral cavity mass. The tumor consisted of a monotonous proliferation of undifferentiated large cells with relatively abundant cytoplasm, eccentrically located round nuclei with prominent nucleoli and numerous mitoses. Immunohistochemically, these cells were negative for CD45 and B cell antigens, while they showed diffuse positivity of CD138 and focal staining for epithelial membrane antigen (EMA), indicating plasma cell differentiation. Based on these histopathological and immunohistochemical characteristics, we diagnosed it as PBL. The patient received chemotherapy and is alive with locally persistent disease 3 years after diagnosis. To date, only several cases of oral PBL have been reported in HIV-negative, EBV-negative and immunocompetent patients. PBL should be included in the differential diagnosis of oral mass lesions and careful evaluation of the morphology and awareness of the existence of this uncommon type of lymphoma can lead to a correct diagnosis. PMID- 22524666 TI - Extended gastritis cystica profunda associated with Epstein-Barr virus-positive dysplasia and carcinoma with lymphoid stroma. AB - We report a case of gastritis cystica porfunda (GCP) associated with gastric carcinoma with lymphoid stroma (CLS). There was dysplastic change in the transitional area between GCP and CLS. Epstein-Barr virus (EBV) in situ hybridization (ISH) revealed positive reaction at the dysplastic area as well as at the CLS area. Immunohistochemical staining disclosed that dysplastic epithelium was similar to GCP in CK 20, MUC5AC, and E-cadherin expression, but similar to CLS in MUC6, CEA, p53, c-erb-B2, and EBV-ISH expression. Results of the EBV-ISH suggested that EBV infection may play a role in dysplastic change. PMID- 22524667 TI - Anal canal neuroendocrine carcinoma associated with squamous intraepithelial neoplasia: a human papillomavirus 18-related lesion. AB - Neuroendocrine carcinoma (NEC) of the anal canal is exceedingly rare and its histogenesis is poorly understood. We present a case of small-cell NEC of the anal canal in a 70-year-old woman. The NEC appeared as a submucosal tumor at the dentate line and was associated with squamous intraepithelial neoplasia (SIN). The NEC was positive for neuroendocrine markers including synaptophysin, chromogranin A and CD56, whereas the SIN component did not express any of these markers. Both components exhibited p16 overexpression. A PCR analysis revealed that both the SIN and NEC components were positive for human papillomavirus (HPV) 18 DNA. Our observations imply that SIN may be a precursor of anal canal NEC and that HPV18 may play an important role in the histogenesis of anal canal NEC, similar to its role in cervical NEC. PMID- 22524668 TI - Pathological profile of lymphomas in a tertiary care centre in Kerala. PMID- 22524669 TI - A well circumscribed uterine endometrial stromal tumor with smooth muscle differentiation recurred as a low grade endometrial stromal sarcoma: is tumor margin enough for the diagnosis? PMID- 22524670 TI - Rapid and direct low micromolar NMR method for the simultaneous detection of hydrogen peroxide and phenolics in plant extracts. AB - A rapid and direct low micromolar 1H NMR method for the simultaneous identification and quantification of hydrogen peroxide and phenolic compounds in plant extracts was developed. The method is based on the highly deshielded 1H NMR signal of H2O2 at ~10.30 ppm in DMSO-d6 and the combined use of picric acid and low temperature, near the freezing point of the solution, in order to achieve the minimum proton exchange rate. Line widths of H2O2 below 3.8 Hz were obtained for several Greek oregano extracts which resulted in a detection limit of 0.7 MUmol L 1. Application of an array of NMR experiments, including 2D 1H-13C HMBC, spiking of the samples with H2O2, and variable temperature experiments, resulted in the unequivocal assignment of H2O2 precluding any confusion with interferences from intrinsic phenolics in the extract. PMID- 22524671 TI - Removal of seminal plasma enhances membrane stability on fresh and cooled stallion spermatozoa. AB - Fertility is reduced after semen cooling for a considerable number of stallions. The main hypotheses include alterations in plasma membrane following cooling and deleterious influence of seminal plasma. However, interindividual variability is controversial. We hypothesized that the removal of seminal plasma could enhance motility in some 'poor cooler' stallions, but could also affect, negatively or positively, membrane quality in some stallions. This study examined the effect of centrifugation, followed or not by removal of seminal plasma, on parameters indicating semen quality after 48 h at 4 degrees C: motility, plasma membrane integrity as evaluated by hypo-osmotic swelling test, acrosome integrity and response to a pharmacological induction of acrosome reaction using ionophore A23187. Sixty-six ejaculates from 14 stallions were used, including stallions showing high or low sperm motility after cooled storage. Centrifugation without removal of seminal plasma did not affect sperm parameters. Removal of seminal plasma did not affect motility, but significantly stabilized sperm membranes, as demonstrated by a higher response to the osmotic challenge, and a reduced reactivity of the acrosome. Moreover, for the same semen sample, the response to an induction of acrosome reaction was significantly higher when the induction was performed in the presence of seminal plasma, compared with the induction in the absence of seminal plasma. This was observed both for fresh and cooled semen. When the induction of acrosome reaction with ionophore A23187 is used to evaluate sperm quality, care must therefore be taken to standardize the proportion of seminal plasma between samples. For the 10 stallions serving at least 25 mares, the only variable significantly correlated with fertility was motility. The influence of membrane stabilization regarding fertility requires further investigations. PMID- 22524672 TI - Canonical word order and interference-based integration costs during sentence comprehension: the case of Spanish subject- and object-relative clauses. AB - Object-relative clauses are generally harder to process than subject-relative clauses. Increased processing costs for object-relatives have been attributed either to working memory demands for the establishment of long-distance dependencies or to difficulties processing unexpected, noncanonical structures. The current study uses self-paced reading to contrast the impact of both kinds of factors in Spanish object-relative clauses, manipulating the interposition of the subject of the relative clause between object and verb. In addition, object relatives were unambiguously marked at their onset with the Spanish preposition "a". Reading times increased at the onset and final regions of object-relative clauses, regardless of interference-based working memory costs, although interference costs may affect the processing of post-relative-clause regions. These results suggest that, beyond interference-related working memory costs, end of-clause integration processes may be affected by a preference for canonical structures, thus increasing processing difficulties when confronted with a noncanonical form. PMID- 22524673 TI - Immunomodulating antibodies in the treatment of metastatic melanoma: the experience with anti-CTLA-4, anti-CD137, and anti-PD1. AB - Clinical activity of anti-CTLA-4 (cytotoxic T-lymphocyte antigen-4) monoclonal antibodies (mAb) has changed the approaches for the treatment of cancer in terms of patterns of response, duration of response, and adverse event profiles. In fact, antibodies that block the interaction of CTLA-4 with its ligands B7.1 and B7.2 can enhance immune responses, including anti-tumor immunity. Two recent studies using ipilimumab (an anti-CTLA-4 mAb) demonstrated improvements in overall survival in the treatment of advanced melanoma. These studies utilized two different schedules of treatment in different patient categories (first and second line of treatment). However, the results were quite similar despite the different dosage used and the combination with dacarbazine in the first line treatment. Ongoing clinical studies will establish the efficacy of ipilimumab as monotherapy or in combination with other drugs for the treatment of metastatic melanoma and a variety of other cancers. Other antibodies, such as CD137 agonists and PD-1 antagonists, are currently in various stages of pre-clinical and clinical development. Agonist antibodies directed against CD137 (4-1BB) on the surface of antigen-primed T-lymphocytes increase tumor immunity that is curative against some transplantable murine tumors. Programmed death-1 (PD1) is a surface molecule delivering inhibitory signals important to maintain T-cell functional silence against their cognate antigens. Interference with PD1 or its ligand PD-L1 (B7-H1) increases anti-tumor immunity. As a result, human mAbs anti-PD1 and anti PD-L1 are under clinical development. This paper reviews recent studies in the treatment of advanced melanoma with these types of monoclonal antibodies. Ipilimumab can be considered a cornerstone of a new era in melanoma treatment. However, the aim is to optimize the therapy with anti-CTLA-4 antibodies to define the best schedule for next combination regimens (other immunomodulatory antibodies, BRAF/MEK inhibitors, vaccines, etc.) that represent the natural evolution of future melanoma therapy. PMID- 22524674 TI - Methane activation by MH+ (M = Os, Ir, and Pt) and comparisons to the congeners of MH+ (M = Fe, Co, Ni and Ru, Rh, Pd). AB - The mechanism of ligated-transition-metal- [MH(+) (M = Os, Ir, and Pt)] catalyzed methane activation has been computed at the B3LYP level of density functional theory. The B3LYP energies of important species on the potential energy surfaces were compared to CCSD(T) single-point energy calculations. Newer kinetic and dispersion-corrected methods such as M05-2X provide significantly better descriptions of the bonding interactions. The reactions take place more easily along the low-spin potential energy surface. The minimum-energy pathway proceeds as MH(+) + CH(4) -> M(H)(2)(CH(3))(+) -> TS -> MH(CH(2))(H(2))(+) -> MH(CH(2))(+) + H(2). The ground states are (5)Pi, (4)Sigma(-), and (1)Sigma(+) for OsH(+), IrH(+), and PtH(+), respectively. The energy level differences of the reactants between the high- and low-spin states gradually become smaller from OsH(+) to PtH(+), being 30.66, 9.17, and 0.09 kcal/mol, respectively. The C-H bond can be readily activated by MH(+) (M = Os, Ir, and Pt) with a negligible barrier in the low-spin state; thus, OsH(+), IrH(+), and PtH(+) are likely to be excellent mediators for the activition of the C-H bond of methane. H(2) elimination is quite facile without barriers in the presence of excess reactants. The products of the reactions of MH(+) (M = Os, Ir, and Pt) + methane are all carbene complexes MH(CH(2))(+). The exothermicities of the reactions are 3.99, 15.66, and 12.14 kcal/mol, respectively. The results for MH(+) (M = Os, Ir, and Pt) are compared with those for the first- and second-row congeners, and the differences in behavior and mechanism are discussed. PMID- 22524676 TI - The efficient expression of human fibroblast collagenase in Escherichia coli and the discovery of flavonoid inhibitors. AB - Human skin fibroblast collagenase also known as Matrix Metalloproteinase-1 (MMP 1) is a key enzyme in remodeling and degradation of extracellular matrix, and the inhibitors of human MMP-1 are effective drug candidates for the treatment of cancer. In this study, we report an improved method for high-level expression of soluble human MMP-1 catalytic domain (cd-MMP-1) in E.coli. The enzymatic activity is found maximum at pH 7.5 and temperature 40 degrees C with a Km value of 13.02 uM. Effects of 17 structure-related flavonoids on MMP-1 activity are evaluated using a fluorescent assay, 6 inhibitors are identified with IC50 < 10 uM. Fisetin is the most active agent with an IC50 value of 1.35 uM and is identified as a mixed type inhibitor. Our improved soluble cd-MMP-1 expression method provides a basis for inhibitors identification and may be beneficial to discover novel anti cancer agent targeting human MMP-1. PMID- 22524675 TI - Acinetobacter, Aeromonas and Trichococcus populations dominate the microbial community within urban sewer infrastructure. AB - We evaluated the population structure and temporal dynamics of the dominant community members within sewage influent from two wastewater treatment plants (WWTPs) in Milwaukee, WI. We generated > 1.1 M bacterial pyrotag sequences from the V6 hypervariable region of 16S rRNA genes from 38 influent samples and two samples taken upstream in the sanitary sewer system. Only a small fraction of pyrotags from influent samples (~ 15%) matched sequences from human faecal samples. The faecal components of the sewage samples included enriched pyrotag populations from Lactococcus and Enterobacteriaceae relative to their fractional representation in human faecal samples. In contrast to the large number of distinct pyrotags that represent faecal bacteria such as Lachnospiraceae and Bacteroides, only one or two unique V6 sequences represented Acinetobacter, Aeromonas and Trichococcus, which collectively account for nearly 35% of the total sewage community. Two dominant Acinetobacter V6 pyrotags (designated Acineto tag 1 and Acineto tag 2) fluctuated inversely with a seasonal pattern over a 3-year period, suggesting two distinct Acinetobacter populations respond differently to ecological forcings in the system. A single nucleotide change in the V6 pyrotags accounted for the difference in these populations and corresponded to two phylogenetically distinct clades based on full-length sequences. Analysis of wavelet functions, derived from a mathematical model of temporal fluctuations, demonstrated that other abundant sewer associated populations including Trichococcus and Aeromonas had temporal patterns similar to either Acineto tag 1 or Acineto tag 2. Populations with related temporal fluctuations were found to significantly correlate with the same WWTP variables (5-day BOD, flow, ammonia, total phosphorous and suspended solids). These findings illustrate that small differences in V6 sequences can represent phylogenetically and ecologically distinct taxa. This work provides insight into microbial community composition and dynamics within the defined environment of urban sewer infrastructure. PMID- 22524677 TI - Interaction of superoxide dismutase with the glycine zipper regions of beta amyloid peptides: is there an implication towards Alzheimer's disease and oxidative stress? AB - Not only are beta-amyloid peptides and senile plaque deposits characteristics in Alzheimer's disease but there is growing evidence to suggest that oxidative stress also plays a role with a decrease in levels of brain superoxide dismutase (SOD), an enzyme that catalyses the dismutation of superoxide radicals into molecular oxygen and hydrogen peroxide. We show through kinetic and fluorescence analysis that beta-amyloid peptides, in the glycine zipper region [Abeta29-33 and Abeta25-37] of Abeta1-40 interact with, and inhibit, SOD directly. The enzyme was purified 15.7-fold from bovine brain by DEAE-Sepharose ion exchange chromatography in a yield of 68.8% and specific activity of 3.66 U.mg(-1). The subunit structure of the enzyme was monomeric with a molecular mass of 13 kDa, as estimated by SDS-PAGE. Inhibitor constants (Ki) and dissociation constants (Kd) were calculated as 14.44, 13.16 and 11.72 uM and 9.38, 15.7 and 12.13 for Abeta25 37, Abeta29-33 and Abeta1-40, respectively; the number of binding sites on the enzyme for the peptides was 1. PMID- 22524678 TI - Effect of the o-methyl catechols apocynin, curcumin and vanillin on the cytotoxicity activity of tamoxifen. AB - Apocynin (APO), curcumin (CUR) and vanillin (VAN) are o-methyl catechols widely studied due their antioxidant and antitumour properties. The effect of treatment with these o-methyl catechols on tamoxifen (TAM)-induced cytotoxicity in normal and tumour cells was studied. The cytotoxicity of TAM on red blood cells (RBC) was performed by haemoglobin or K(+)release and on polymorphonuclear leukocytes (PMNs) by trypan blue dye exclusion method. Cytotoxic activity was assessed in human chronic myeloid leukemia (K562) cell line by (3-[4,5-dimethylthiazol-2-yl] 2,5-diphenyltetrazolium bromide). According the release of haemoglobin and K(+), the CUR showed a decrease in TAM cytotoxicity on RBC; however, in PMN, APO, CUR and VAN showed increased of these cells viability. VAN presented the highest cytotoxicity on K562 cells, followed by APO and CUR. These results point the potential therapeutic value of these o-methyl catechols with TAM, particularly of CUR, which potentiates the cytotoxic effects of TAM on K562 cells and also decreases TAM-associated cytotoxicity on RBC and PMN. PMID- 22524679 TI - Carvedilol suppresses fatty acid oxidation and stimulates glycolysis in C2C12 cells. AB - Beta adrenergic receptor blocking drugs (beta-blockers) are used chronically in many cardiovascular diseases such as hypertension, ischemic heart disease, arrhythmia, and heart failure. Beneficial effects are associated with the inhibition of symphathetic nervous system hyperactivity, reduction of heart rate, and remodeling by blocking the mitogenic activity of catecholamines. A possible effect of beta-blockers on substrate metabolism has also been suggested. The direct effects of beta-blockers on mouse C2C12 cells were investigated in this study. C2C12 cells were grown in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and differentiated into myotubes in the same medium that contained 1% FBS. Palmitic acid oxidation and glycolysis were measured by using [9,10-(3)H]palmitate and [5-(3)H]glucose, respectively. The amount of (3)H(2)O was measured as an indicator of substrate usage. Carvedilol (100 umol/L) inhibited palmitate oxidation and increased glycolysis by nearly 50%. Prazosin altered substrate metabolism in a similar fashion as carvedilol, whereas propranolol or bisoprolol were devoid of metabolic effects. When added to mimic sympathetic activation, epinephrine stimulated glycolysis but did not alter fatty acid oxidation. Based on these results, carvedilol appears to have direct effects on substrate metabolism that are related to the blockade of alpha1 adrenergic receptors. PMID- 22524680 TI - Pregnant woman with fatal complication after laparoscopic Roux-en-Y gastric bypass. AB - In Europe, an increasing number of women have bariatric surgery; therefore, obstetricians are likely to encounter these patients. We report a 22-year-old woman, who had previously undergone uncomplicated laparoscopic Roux-en-Y gastric bypass. She was admitted with severe abdominal pain at 35 weeks of gestation. A cesarean section with delivery of a healthy baby in combination with an exploratory laparotomy was performed. Internal herniation was suspected, but not identified during surgery. Three days later she died of a severely gangrenous small bowel secondary to internal herniation. This fatal case illustrates a potential complication and difficulties in the management of pregnant women who have undergone Roux-en-Y gastric bypass. In these women, observation and investigations based on a multidisciplinary approach are vital if abdominal pain develops, with involvement of intestinal surgeons experienced in bariatric surgery, as well as radiologists with specific knowledge of relevant imaging procedures. PMID- 22524681 TI - Modeling of mixing acetone and water: how can their full miscibility be reproduced in computer simulations? AB - The free energy of mixing of acetone and water is calculated at 298 K by means of thermodynamic integration considering combinations of three acetone and six water potentials. The Anisotropic United Atom 4 (AUA4) and Transferable Potential for phase Equilibria (TraPPE) models of acetone are found not to be miscible with any of the six water models considered, although the free energy cost of the mixing of any of these model pairs is very small, being below the mean kinetic energy of the molecules along one degree of freedom of 0.5RT. On the other hand, the combination of the Pereyra, Asar, and Carignano (PAC) acetone and TIP5P-E water models turns out to be indeed fully miscible, and it is able to reproduce the change of the energy, entropy, and Helmholtz free energy of mixing of the two neat components very accurately (i.e., within 0.8 kJ/mol, 2.5 J/(mol K), and 0.3 kJ/mol, respectively) in the entire composition range. The obtained results also suggest that the PAC model of acetone is likely to be fully miscible with other water models, at least with SPC and TIP4P, as well. PMID- 22524682 TI - Improving the management of diabetes in hospitalized patients: the results of a computer-based house staff training program. AB - BACKGROUND: Poorly controlled diabetes in hospitalized patients is associated with poor clinical outcomes. We hypothesized that computer-based diabetes training could improve house staff knowledge and comfort for the management of diabetes in a large tertiary-care hospital. METHODS: We implemented a computer based training program on inpatient diabetes for internal medicine house staff at the Brigham and Women's Hospital (Boston, MA) in September 2009. House staff were required to complete the program and answer a set of questions, before and after the program, to evaluate their level of comfort and knowledge of inpatient diabetes. Chart reviews of all non-critically ill patients with diabetes managed by house staff in August 2009 (before the program) and December 2009 (after the program) were performed. Chart reviews were also performed for August 2008 and December 2008 to compare house staff management practices when the computer-based educational program was not available. RESULTS: A significant increase in comfort levels and knowledge in the management of inpatient diabetes was seen among house staff at all levels of training (P<0.02), but the increase was smaller for senior house staff compared with junior house staff. Nonsignificant trends suggesting increased use of basal-bolus insulin (P=0.06) and decreased use of sliding-scale insulin (P=0.10) were seen following the educational intervention in 2009, whereas no such change was seen in 2008 (P>0.90). Overall, house staff evaluated the training program as "very relevant" and the technology interface as "good." CONCLUSIONS: A computer-based diabetes training program can improve the comfort and knowledge of house staff and potentially improve their insulin administration practices at large academic centers. PMID- 22524683 TI - Cullin 7 and Fbxw 8 expression in trophoblastic cells is regulated via oxygen tension: implications for intrauterine growth restriction? AB - OBJECTIVE: The F-box protein Fbxw8 is a cofactor of Cullin 7 (Cul7), which regulates protein transfer to the proteasome and cell growth. Cul7 or Fbxw8 deficiency is associated with intrauterine growth restriction (IUGR) due to abnormal placental development leading to poor oxygen supply to the fetus. We studied the role of hypoxia for Fbxw8 and Cul7 expression in trophoblastic cells. METHODS: Immunomagnetic bead-separated extravillous trophoblast (EVT) and villous trophoblast (VT) and trophoblast cell lines were incubated with 1 or 8% O(2). Fbxw8 and Cul7 expression was determined in IUGR versus matched control placentas. RESULTS: Fbxw8 was expressed uniformly in trophoblasts, whereas Cul7 expression was most prominent in trophoblast cell lines. Hypoxia reduced expression of Cul7 and Fbxw8 in all trophoblastic cells, except for villous trophoblasts. In vivo, Cul7 and Fbxw8 were detected in syncytiotrophoblast cells, VT, and EVT cells. Although no significant changes in expression levels of Fbxw8 or Cul7 were noted in IUGR compared with control placentas, Fbxw8 expression correlated negatively with gestational age in the control, but not in the IUGR group. CONCLUSION: Fbxw8 and Cul7 expression reveals a complex regulation in trophoblastic cells. Our findings suggest that dysregulation of Cul7 and Fbxw8 expression might affect trophoblast turnover in IUGR. PMID- 22524684 TI - Characterization of MENX-associated pituitary tumours. AB - AIMS: The aim of this study is to evaluate the pathological features, serum hormone levels and ex vivo cultures of pituitary adenomas that occur in rats affected by MENX syndrome. MENX is multiple endocrine neoplasia syndrome caused by a germline mutation in the cell cycle inhibitor p27. Characterization of MENX adenomas is a prerequisite to exploit this animal model for molecular and translational studies of pituitary adenomas. METHODS: We investigated MENX pituitary adenomas with immunohistochemistry, double immunofluorescence, electron microscopy, reverse transcription polymerase chain reaction (RT-PCR), measurement of serum hormone levels and ex vivo cultures. RESULTS: Adenomas in MENX rats belong to the gonadotroph lineage. They start from 4 months of age as multiple neoplastic nodules and progress to become large lesions that efface the gland. Adenomas are composed of chromophobic cells predominantly expressing the glycoprotein alpha-subunit (alphaGSU). They show mitotic activity and high Ki67 labelling. A few neoplastic cells co-express gonadotropins and the transcription factor steroidogenic factor 1, together with growth hormone or prolactin and Pit 1, suggesting that they are not fully committed to one cell lineage. Ex vivo cultures show features similar to the primary tumour. CONCLUSIONS: Our results suggest that p27 function is critical to regulate gonadotroph cells growth. The MENX syndrome represents a unique model to elucidate the physiological and molecular mechanisms mediating the pathogenesis of gonadotroph adenomas. PMID- 22524685 TI - Reduced lung function is independently associated with increased risk of type 2 diabetes in Korean men. AB - BACKGROUND: Reduced lung function is associated with incident insulin resistance and diabetes. The aim of this study was to assess the relationship between lung function and incident type 2 diabetes in Korean men. METHODS: This study included 9,220 men (mean age: 41.4 years) without type 2 diabetes at baseline who were followed for five years. Subjects were divided into four groups according to baseline forced vital capacity (FVC) (% predicted) and forced expiratory volume in one second (FEV1) (% predicted) quartiles. The incidence of type 2 diabetes at follow-up was compared according to FVC and FEV1 quartiles. RESULTS: The overall incidence of type 2 diabetes was 2.2%. Reduced lung function was significantly associated with the incidence of type 2 diabetes after adjusting for age, BMI, education, smoking, exercise, alcohol, and HOMA-IR. Both FVC and FEV1 were negatively associated with type 2 diabetes (P < 0.05). In non-obese subjects with BMI < 25, the lowest quartile of FVC and FEV1 had a significantly higher odds ratio for type 2 diabetes compared with the highest quartile after adjusting for age and BMI (2.15 [95% CI 1.02-4.57] and 2.19 [95% CI 1.09-4.42]). CONCLUSIONS: Reduced lung function is independently associated with the incidence of type 2 diabetes in Korean men. PMID- 22524686 TI - Human NK cell recognition of target cells in the prism of natural cytotoxicity receptors and their ligands. AB - The matter of the pathogen- and cancer-associated ligands recognized by the Natural Cytotoxicity Receptors (NCRs) has been a subject of intense research ever since the identification of the NCRs more than 12 years ago by Alessandro and Lorenzo Moretta: NKp46 in 1997, NKp44 in 1998, and finally NKp30 in 1999. Expression patterns recognized by NCRs include pathogen-derived, pathogen induced, and cancer-associated cellular 'self' ligands. Pathogen-exposed cells may exhibit both types of pathogen-associated ligands. Transformed cells, in contrast, exhibit only 'self' ligands which are derived from both the intracellular- and membrane-associated milieu of self molecules. These expression patterns allow for NCR-based NK cell discrimination between healthy and affected cells, in the realms of both pathogenic infection and potential tumorigenesis. The focus of this review is on the current knowledge regarding the identities of NCR ligands and the type of target cells expressing these ligands. PMID- 22524687 TI - Simultaneous analysis of free phytosterols/phytostanols and intact phytosteryl/phytostanyl fatty acid and phenolic acid esters in cereals. AB - An approach based on solid-phase extraction for the effective separation of free phytosterols/phytostanols and phytosteryl/phytostanyl fatty acid and phenolic acid esters from cereal lipids was developed. The ester conjugates were analyzed in their intact form by means of capillary gas chromatography. Besides free sterols and stanols, up to 33 different fatty acid and phenolic acid esters were identified in four different cereal grains via gas chromatography-mass spectrometry. The majority (52-57%) of the sterols and stanols were present as fatty acid esters. The highest levels of all three sterol and stanol classes based on dry matter of ground kernels were determined in corn, whereas the oil extract of rye was 1.7 and 1.6 times richer in fatty acid esters and free sterols/stanols than the corn oil. The results showed that there are considerable differences in the sterols/stanols and their ester profiles and contents obtained from corn compared to rye, wheat, and spelt. The proposed method is useful for the quantification of a wide range of free phytosterols/phytostanols and intact phytosteryl/phytostanyl esters to characterize different types of grain. PMID- 22524689 TI - Weight gain after childhood traumatic brain injury: a matter of concern. AB - AIM: The aim of the study was to assess weight changes after traumatic brain injury (TBI) in children and the factors influencing them. METHOD: We conducted a longitudinal observational study of children with TBI of mixed severity who were consecutively admitted to one rehabilitation department (39 children; 23 males, 16 females; median age 8y 7mo; 25th to 75th centiles 3y 7mo-11y 6mo). Weight and height before TBI were obtained from the children's records and were measured monthly for 1 year after TBI. Body mass index (BMI) and BMI z-scores were calculated, and pre-TBI values were compared with the final values using paired tests. Linear mixed-effect interaction models were used to assess the effect of various factors on z-score evolution. RESULTS: Z-score curves revealed early weight loss followed by a rapid increase in weight. The mean BMI gain over the period under study was 0.9 kg/m2 (p < 0.001) and the mean z-score gain was 0.4 (p = 0.006). Six children had become overweight by the time of final assessment. Factors associated with a greater rate of increase in the post-TBI z-score were mobility restriction, male sex, and older age. Global pre- to post-TBI weight gain was significantly higher in males (z-score 0.7). Pituitary hormonal testing was available for 17 children at 3 months and for 27 at 1 year. Growth hormone deficiency was detected in one child. INTERPRETATION: Weight gain of children during the first year after TBI was rapid and excessive. Male sex was a risk factor for excessive weight gain. PMID- 22524688 TI - Applicability of BCLC stage for prognostic stratification in comparison with other staging systems: single centre experience from long-term clinical outcomes of 1717 treatment-naive patients with hepatocellular carcinoma. AB - BACKGROUND: The most informative staging system regarding survival outcomes for treatment-naive hepatocellular carcinoma (HCC) remains debated. We evaluated prognostic values of Barcelona Clinic Liver Cancer (BCLC) stage compared with other staging systems, and identified discrepancies between treatment options chosen in Korean clinical practice and BCLC guidelines. METHODS: Between 2003 and 2008, 1717 prospectively enrolled patients with treatment-naive HCC were analysed. Prognostic ability of each staging system was assessed using time dependent receiver-operating characteristic (ROC) curves. RESULTS: The most common aetiology was hepatitis B virus (1238, 72.1%); 167 (9.8%) patients were classified as BCLC stage 0, 526 (30.6%) as A, 333 (19.4%) as B, 608 (35.4%) as C and 83 (4.8%) as D. Median overall survival was 22.5 months, and 1-, 2-, 3-, 4-, and 5-year survival rates were 62.6, 48.3, 39.9, 34.7, and 29.3% respectively. Of six staging systems, BCLC had the highest area under ROC (AUROC; 0.821) for overall survival, followed by JIS (0.809), Tokyo score (0.771), CLIP (0.746), CUPI (0.701) and GRETCH (0.685) system. In both subgroups stratified according to treatment strategy (curative vs. palliative), BCLC also showed the best AUROCs (curative, 0.708/palliative, 0.807) for overall survival. Regarding discrepancies between treatment options chosen in our cohort and BCLC guidelines, more than half with very early/early-stage HCC underwent transarterial chemoembolization, rather than resection or local ablative therapy; most of those with advanced stage HCC received intra-arterial chemotherapy-based treatments rather than sorafenib. CONCLUSION: BCLC was the best long-term prognostic model for treatment naive HCC in a large-scale Korean cohort. However, treatment modalities did not exactly match BCLC paradigm. PMID- 22524691 TI - Isomer-selected photoelectron spectroscopy of isolated DNA oligonucleotides: phosphate and nucleobase deprotonation at high negative charge states. AB - Fractionation according to ion mobility and mass-to-charge ratio has been used to select individual isomers of deprotonated DNA oligonucleotide multianions for subsequent isomer-resolved photoelectron spectroscopy (PES) in the gas phase. Isomer-resolved PE spectra have been recorded for tetranucleotides, pentanucleotides, and hexanucleotides. These were studied primarily in their highest accessible negative charge states (3-, 4-, and 5-, respectively), as provided by electrospraying from room temperature solutions. In particular, the PE spectra obtained for pentanucleotide tetraanions show evidence for two coexisting classes of gas-phase isomeric structures. We suggest that these two classes comprise: (i) species with excess electrons localized exclusively at deprotonated phosphate backbone sites and (ii) species with at least one deprotonated base (in addition to several deprotonated phosphates). By permuting the sequence of bases in various [A(5-x)T(x)](4-) and [GT(4)](4-) pentanucleotides, we have established that the second type of isomer is most likely to occur if the deprotonated base is located at the first or last position in the sequence. We have used a combination of molecular mechanics and semiempirical calculations together with a simple electrostatic model to explore the photodetachment mechanism underlying our photoelectron spectra. Comparison of predicted to measured photoelectron spectra suggests that a significant fraction of the detected electrons originates from the DNA bases (both deprotonated and neutral). PMID- 22524690 TI - Rosiglitazone protects dopaminergic neurons against lipopolysaccharide-induced neurotoxicity through inhibition of microglia activation. AB - Recent evidence has suggested that microglia activation plays an important role in the pathogenesis of Parkinson's disease (PD). Activated microglia secrete various proinflammatory cytokines and neurotoxic mediators, which may contribute to the development of PD. Thus, the inhibition of microglia activation may have a therapeutic benefit in the treatment of PD. In the present study, using mesencephalic neuron-microglia mixed culture and microglia-enriched culture, we investigated whether rosiglitazone (RGZ), a member of peroxisome proliferator activated receptor gamma (PPARgamma) agonists, could inhibit microglia activation. Our results showed that RGZ significantly inhibited lipopolysaccharide (LPS)-induced microglia activation and the production of tumor necrosis factor-alpha (TNF-alpha), nitric oxide (NO), and superoxide. We further investigated the intracellular signaling pathways regulating the production of TNF-alpha and NO in LPS-activated microglia. The results showed that RGZ inhibited the phosphorylation and nuclear translocation of the p65 subunit of NF kappaB, and the phosphorylation of p38 mitogen-activated protein kinase (p38MAPK). Taken together, our results suggested that the therapeutic effects of RGZ were partially mediated by modulating microglia activation. PMID- 22524692 TI - Cerium oxide nanoparticles protect cardiac progenitor cells from oxidative stress. AB - Cardiac progenitor cells (CPCs) are a promising autologous source of cells for cardiac regenerative medicine. However, CPC culture in vitro requires the presence of microenvironmental conditions (a complex array of bioactive substance concentration, mechanostructural factors, and physicochemical factors) closely mimicking the natural cell surrounding in vivo, including the capability to uphold reactive oxygen species (ROS) within physiological levels in vitro. Cerium oxide nanoparticles (nanoceria) are redox-active and could represent a potent tool to control the oxidative stress in isolated CPCs. Here, we report that 24 h exposure to 5, 10, and 50 MUg/mL of nanoceria did not affect cell growth and function in cardiac progenitor cells, while being able to protect CPCs from H(2)O(2)-induced cytotoxicity for at least 7 days, indicating that nanoceria in an effective antioxidant. Therefore, these findings confirm the great potential of nanoceria for controlling ROS-induced cell damage. PMID- 22524693 TI - No association between transmembrane protein-tyrosine phosphatase receptor type C (PTPRC) exon A 77C>G transversion and liver transplant rejection. AB - This study was carried out to evaluate the association between 77C>G transversion (rs17612648) in exon A of the PTPRC gene and liver transplant rejection. No significant differences in genotype and allele frequencies of the 77C>G transversion were detected between recipients without rejection (n = 106) and recipients with rejection (n = 104). In conclusion, there was no evidence for the contribution of the 77C>G transversion in susceptibility to liver transplant rejection in a Caucasian population. PMID- 22524697 TI - Rising ozone concentrations decrease soybean evapotranspiration and water use efficiency whilst increasing canopy temperature. AB - * Here, we investigated the effects of increasing concentrations of ozone ([O(3)]) on soybean canopy-scale fluxes of heat and water vapor, as well as water use efficiency (WUE), at the Soybean Free Air Concentration Enrichment (SoyFACE) facility. * Micrometeorological measurements were made to determine the net radiation (R(n)), sensible heat flux (H), soil heat flux (G(0)) and latent heat flux (lambdaET) of a commercial soybean (Glycine max) cultivar (Pioneer 93B15), exposed to a gradient of eight daytime average ozone concentrations ranging from approximately current (c. 40 ppb) to three times current (c. 120 ppb) levels. * As [O(3)] increased, soybean canopy fluxes of lambdaET decreased and H increased, whereas R(n) and G(0) were not altered significantly. Exposure to increased [O(3)] also resulted in warmer canopies, especially during the day. The lower lambdaET decreased season total evapotranspiration (ET) by c. 26%. The [O(3)] induced relative decline in ET was half that of the relative decline in seed yield, driving a 50% reduction in seasonal WUE. * These results suggest that rising [O(3)] will alter the canopy energy fluxes that drive regional climate and hydrology, and have a negative impact on productivity and WUE, key ecosystem services. PMID- 22524698 TI - A nine-dimensional calculation of the vibrational OH stretching and HOH bending spectrum of the water trimer. AB - We have studied the vibrational high-frequency spectrum of the water trimer computationally. We expand an earlier study [J. Chem. Phys. A 2009, 113, 9124 9132] where we approximated the water trimer as three individually vibrating water monomer units. Some intramolecular potential energy coupling terms are now included in the previous model. The six OH bond lengths and the three HOH bending angles are used as the internal coordinates. The kinetic energy operator is a sum of the kinetic energy operators of the monomer units. We use the coupled cluster method with single, double, and perturbative triple excitations method [CCSD(T)] with augmented correlation consistent polarized valence triple-zeta (aug-cc-pVTZ) basis set to calculate the potential energy surface (PES). The counterpoise correction is included in the one-dimensional part of the PES. We calculate the vibrational energy eigenvalues using the variational method. The corresponding eigenfunctions are used to obtain the absorption intensities. PMID- 22524699 TI - Implicit response-irrelevant number information triggers the SNARC effect: evidence using a neural overlap paradigm. AB - There is evidence from the SNARC (spatial-numerical association of response codes) effect and NDE (numerical distance effect) that number activates spatial representations. Most of this evidence comes from tasks with explicit reference to number, whether through presentation of Arabic digits (SNARC) or through magnitude decisions to nonsymbolic representations (NDE). Here, we report four studies that use the neural overlap paradigm developed by Fias, Lauwereyns, and Lammertyn (2001) to examine whether the presentation of implicit and task irrelevant numerosity information (nonsymbolic arrays and auditory numbers) is enough to activate a spatial representation of number. Participants were presented with either numerosity arrays (1-9 circles or triangles) to which they made colour (experiment 1) or orientation (experiment 2) judgements, or auditory numbers coupled with an on-screen stimulus to which they made a colour (experiment 3) or orientation (experiment 4) judgement. SNARC effects were observed only for the orientation tasks. Following the logic of Fias et al., we argue that this SNARC effect occurs as a result of overlap in parietal processing for number and orientation judgements irrespective of modality. Furthermore, we found stronger SNARC effects in the small number range (1-4) than in the larger number range (6-9) for both nonsymbolic displays and auditory numbers. These results suggest that quantity is extracted (and interferes with responses in the orientation task) but this is not exact for the entire number range. We discuss a number of alternative models and mechanisms of numerical processing that may account for such effects. PMID- 22524700 TI - Early and late preterm delivery rates - a comparison of differing tocolytic policies in a single urban population. AB - OBJECTIVE: Preterm delivery results in neonatal morbidity and mortality. We set out to estimate the difference in rates of preterm delivery in two institutions, serving a single population, with differing policies regarding use of tocolytic drugs for the prevention of preterm delivery. STUDY DESIGN: A retrospective study comparing preterm delivery rates between 2002 and 2007 in two large tertiary hospitals serving a single urban population with similar risk factor profile located less than 2 miles from each other. During the study period Hospital A routinely used tocolytic therapy, Hospital B operates a policy of never using any tocolytic drugs. Rates of delivery prior to 26, 30, 34 and 37 weeks were compared for each hospital. RESULTS: During the study period there were 90,843 deliveries between the two hospitals. The overall rates of preterm delivery at less than 37 weeks gestation were comparable with 6.62% (2794/42,232) in Hospital A and 6.15% (2989/48,611) in Hospital B (p = 0.99). There was no significant difference in the numbers delivering at less than 34 weeks, 995/42,232 (2.36%) versus 1134/48,611 (2.33%), p = 0.59, less than 30 weeks, 403/42,232 (0.95%) versus 429/48,611 (0.88%), p = 0.87 or prior to 26 weeks, 126/42,232 (0.29%) versus 121/48,611 (0.25%), p= 0.08. CONCLUSION: In this large population routine use of tocolytic drugs in the treatment of threatened preterm labor does not alter rates of early or late preterm delivery. While this study is limited by its retrospective nature, it calls into question the practice of tocolysis. PMID- 22524701 TI - Capturing phenotypic heterogeneity in MPS I: results of an international consensus procedure. AB - BACKGROUND: Mucopolysaccharidosis type I (MPS I) is traditionally divided into three phenotypes: the severe Hurler (MPS I-H) phenotype, the intermediate Hurler Scheie (MPS I-H/S) phenotype and the attenuated Scheie (MPS I-S) phenotype. However, there are no clear criteria for delineating the different phenotypes. Because decisions about optimal treatment (enzyme replacement therapy or hematopoietic stem cell transplantation) need to be made quickly and depend on the presumed phenotype, an assessment of phenotypic severity should be performed soon after diagnosis. Therefore, a numerical severity scale for classifying different MPS I phenotypes at diagnosis based on clinical signs and symptoms was developed. METHODS: A consensus procedure based on a combined modified Delphi method and a nominal group technique was undertaken. It consisted of two written rounds and a face-to-face meeting. Sixteen MPS I experts participated in the process. The main goal was to identify the most important indicators of phenotypic severity and include these in a numerical severity scale. The correlation between the median subjective expert MPS I rating and the scores derived from this severity scale was used as an indicator of validity. RESULTS: Full consensus was reached on six key clinical items for assessing severity: age of onset of signs and symptoms, developmental delay, joint stiffness/arthropathy/contractures, kyphosis, cardiomyopathy and large head/frontal bossing. Due to the remarkably large variability in the expert MPS I assessments, however, a reliable numerical scale could not be constructed. Because of this variability, such a scale would always result in patients whose calculated severity score differed unacceptably from the median expert severity score, which was considered to be the 'gold standard'. CONCLUSIONS: Although consensus was reached on the six key items for assessing phenotypic severity in MPS I, expert opinion on phenotypic severity at diagnosis proved to be highly variable. This subjectivity emphasizes the need for validated biomarkers and improved genotype-phenotype correlations that can be incorporated into phenotypic severity assessments at diagnosis. PMID- 22524703 TI - The true incidence of placental mesenchymal dysplasia. PMID- 22524702 TI - Significance of the frequency of CD4+CD25+CD127- T-cells in patients with pulmonary tuberculosis and diabetes mellitus. AB - BACKGROUND AND OBJECTIVE: Pulmonary tuberculosis and diabetes mellitus (DM) are closely associated. The objective of this study was to determine whether the expression of CD4+CD25+CD127- T-cells (regulatory T-cells (Treg)) is associated with diabetic pulmonary tuberculosis. METHODS: Flow cytometry was used to determine the frequencies of CD4+CD25+ and CD4+CD25+CD127- T-cells in peripheral blood, bronchoalveolar lavage fluid (BALF) and pleural effusions from 120 patients (30 with pulmonary tuberculosis and DM (TBDM), 30 with pulmonary tuberculosis without DM (TB), 30 with tuberculous pleurisy without DM (TBP) and 30 healthy volunteers). The concentrations of interferon (IFN)-gamma and interleukin (IL)-10 in BALF and pleural effusions were determined by enzyme linked immunosorbent assay. RESULTS: Treg frequencies in peripheral blood were significantly higher in patients with TBDM, TB and TBP than in the control group, with the frequency in TBDM being the highest (P < 0.01 for all). In TBP patients, Treg frequencies were significantly lower in pleural effusions than in peripheral blood. In TB patients, Treg frequencies in BALF and peripheral blood were not significantly different. However, in TBDM patients, Treg frequencies were significantly higher in BALF than in peripheral blood. IL-10 expression was significantly higher, and IFN-gamma expression was significantly lower in BALF of TBDM patients compared with BALF and pleural effusions of TB patients. CONCLUSIONS: In patients with pulmonary tuberculosis and DM, the imbalance between Treg and effector T-cells at pathological sites may be associated with weakened immunity and clinical manifestations of TB. PMID- 22524704 TI - Generation of proliferating human hepatocytes using Upcyte(r) technology: characterisation and applications in induction and cytotoxicity assays. AB - 1. We have developed a novel technique which causes primary human hepatocytes to proliferate by transducing them with genes that upregulate their proliferation. 2. Upcyte((r)) hepatocytes did not form colonies in soft agar and are not immortalised anchorage-independent cells. Confluent cultures expressed liver specific proteins, produced urea and stored glycogen. 3. CYP activities were low but similar to that in 5-day cultures of primary human hepatocytes. CYP1A2 and CYP3A4 were inducible; moreover, upcyte((r)) hepatocytes predicted the in vivo induction potencies of known CYP3A4 inducers using the "relative induction score" prediction model. Placing cells into 3D culture increased their basal CYP2B6 and CYP3A4 basal activities and induction responses. 4. Phase 2 activities (UGTs, SULTs and GSTs) were comparable to activities in freshly isolated hepatocytes. 5. Upcyte((r)) hepatocytes were markedly more sensitive to the hepatotoxin, alpha amanitin, than HepG2 cells, indicating functional OATP1B3 uptake. The cytotoxicity of aflatoxin B(1), was decreased in upcyte((r)) hepatocytes by co incubation with the CYP3A4 inhibitor, ketoconazole. Upcyte((r)) hepatocytes also differentiated between ten hepatotoxic and eight non-hepatotoxic compounds. 6. In conclusion, upcyte((r)) hepatocyte cultures have a differentiated phenotype and exhibit functional phase 1 and 2 activities. These data support the use of upcyte((r)) hepatocytes for CYP induction and cytotoxicity screening. PMID- 22524705 TI - Stimulant abuse and dependence: are novel treatment approaches on the horizon? PMID- 22524706 TI - Discovery of environmental rhodamine B contamination in paprika during the vegetation process. AB - Recently, rhodamine B (RhB) in paprika and chilli has attracted much attention. Almost all the literature has deemed that the detectable RhB was attributed to malicious intents in the fabrication process. However, the occurrence of increasing cases with ultratrace levels of RhB was difficult to understand on the basis of that statement. Here, we report on the discovery of environmental RhB contamination in paprika during its vegetation process. Samples including paprika, soils, and stems collected from seven fields in the Xinjiang Region, China, were detected by ultraperformance liquid chromatography-tandem mass spectrometry. Far from any anthropogenic addition, the ultratrace RhB concentrations in all the paprika samples provided unambiguous evidence that environmental RhB contamination in paprika had really occurred over its growth period. Further illation suggests that the soil contaminated by RhB is one of the major contamination sources and that there may be a degradation of RhB in paprika during the late maturation stage. The discovery has significant implications for re-evaluating the origin of the RhB in paprika- and chilli-containing products. PMID- 22524707 TI - The fraction dose absorbed, in humans, and high jejunal human permeability relationship. AB - The drug intestinal permeability (P(eff)) measure has been widely used as one of the main factors governing both the rate and/or extent of drug absorption (F(abs)) in humans following oral administration. In this communication we emphasize the complexity behind and the care that must be taken with this in vivo P(eff) measurement. Intestinal permeability, considering the whole of the human intestine, is more complex than generally recognized, and this can lead to misjudgment regarding F(abs) and P(eff) in various settings, e.g. drug discovery, formulation design, drug development and regulation. Setting the adequate standard for the low/high permeability class boundary, the different experimental methods for the permeability measurement, and segmental-dependent permeability throughout the human intestine due to different mechanisms are some of the main points that are discussed. Overall, the use of jejunal P(eff) as a surrogate for extent of absorption is sound and scientifically justified; a compound with high jejunal P(eff) will have high F(abs), eliminating the risk for misclassification as a BCS class I drug. Much more care should be taken, however, when jejunal P(eff) does not support a high-permeability classification; a thorough examination may reveal high-permeability after all, attributable to e.g. segmental-dependent permeability due to degree of ionization or transporter expression. In this situation, the use of multiple permeability experimental methods, including the use of metabolism, which except for luminal degradation requires absorption, is prudent and encouraged. PMID- 22524709 TI - Inactivation of PbTopo IIIbeta causes hyper-excision of the Pathogenicity Island HAI2 resulting in reduced virulence of Pectobacterium atrosepticum. AB - Topoisomerase III enzymes are present only in a limited set of bacteria and their physiological role remains unclear. Here, we show that PbTopo IIIbeta, a homologue of topoisomerase III encoded on the chromosome of Pectobacterium atrosepticum strain SCRI1043 (Pba SCRI1043), is involved in excision of HAI2, a discrete ~100 kb region, from the Pba SCRI1043 chromosome. HAI2 is a Pathogenicity Island (PAI) that encodes coronafacic acid (Cfa), a major virulence determinant required for infection of potato. PAIs are horizontally acquired genetic elements that in some instances are able to excise from the chromosome of their host cell to form a circular episome prior to transfer to a recipient bacterium. We demonstrate excision of HAI2 from the chromosome, a process that is independent of growth phase and that results in the production of a circular intermediate. Inactivation of PbTopo IIIbeta causes a 10(3) - to 10(4) -fold increase in excision, leading to reduced fitness in vitro and a decrease in the virulence of Pba SCRI1043 on potato. These results suggest that PbTopo IIIbeta is required for stable maintenance of HAI2 in the chromosome of Pba SCRI1043 and may control as yet unidentified genes involved in viability and virulence of Pba SCRI1043 on potato. PMID- 22524710 TI - Weight gain after childhood traumatic brain injury. PMID- 22524708 TI - Myelin basic protein induces inflammatory mediators from primary human endothelial cells and blood-brain barrier disruption: implications for the pathogenesis of multiple sclerosis. AB - AIM: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, characterized by demyelination of white matter, loss of myelin forming oligodendrocytes, changes in the blood-brain barrier (BBB) and leucocyte infiltration. Myelin basic protein (MBP) is a component of the myelin sheath. Degradation of myelin is believed to be an important step that leads to MS pathology. Transmigration of leucocytes across the vasculature, and a compromised BBB participate in the neuroinflammation of MS. We examined the expression and regulation of the chemokine (C-C motif) ligand 2 (CCL2) and the cytokine interleukin-6 (IL-6) in human endothelial cells (EC), a component of the BBB, after treatment with MBP. METHODS: EC were treated with full-length MBP. CCL2 and IL-6 protein were determined by ELISA. Western blot analysis was used to determine signalling pathways. A BBB model was treated with MBP and permeability was assayed using albumin conjugated to Evan's blue dye. The levels of the tight junction proteins occludin and claudin-1, and matrix metalloprotease (MMP)-2 were assayed by Western blot. RESULTS: MBP significantly induced CCL2 and IL-6 protein from EC. This induction was partially mediated by the p38 MAPK pathway as there was phosphorylation after MBP treatment. MBP treatment of a BBB model caused an increase in permeability that correlated with a decrease in occludin and claudin 1, and an induction of MMP2. CONCLUSION: These data demonstrate that MBP induces chemotactic and inflammatory mediators. MBP also alters BBB permeability and tight junction expression, indicating additional factors that may contribute to the BBB breakdown characteristic of MS. PMID- 22524711 TI - The effect of mold sensitization and humidity upon allergic asthma. AB - INTRODUCTION: Humidity is commonly associated with increased airway hyperresponsiveness in asthma. OBJECTIVE: To examine mold sensitization in patients with allergic asthma or allergic rhinitis and self-reports of humidity as exacerbating factors of clinical symptoms. METHODS: A retrospective, cross sectional study at a University hospital outpatient allergy and asthma clinic was performed. A total of 106 patients with either allergic asthma or allergic rhinitis completed standard prick-puncture skin testing with 17 allergens and controls and completed standardized forms addressing trigger factors for clinical symptoms. RESULTS: Allergic asthmatics sensitized to Cladosporium were more likely to have a more severe asthma severity class (odds ratio = 4.26, confidence interval = 1.30-16.93). Sensitization to Alternaria, Cladosporium, Helminthosporium, Aspergillus and Dermatophagoides pteronyssinus in asthma was associated with higher likelihood for previous hospitalization, while sensitization to Cladosporium, Helminthosporium, Aspergillus, Dermatophagoides pteronyssinus and cockroach in asthma was associated with higher likelihood of having reduced pulmonary function based on forced expiratory volume in 1s. Furthermore, allergic asthmatics more commonly reported humidity as an exacerbating factor of symptoms than did patients only with allergic rhinitis (68.42% vs 42.86%, respectively; P < 0.05). CONCLUSION: Mold sensitization is highly associated with more severe asthma, while humidity is more of an exacerbating factor in patients with allergic asthma as compared with allergic rhinitis alone. Further delineation between mold sensitization and humidity is needed to determine whether these are independent factors in asthma. PMID- 22524712 TI - The globalization of the dental laboratory industry. PMID- 22524713 TI - Contemporary approaches to orthodontic retention. PMID- 22524714 TI - Preprosthetic orthodontic intervention for management of a partially edentulous patient with generalized wear and malocclusion. AB - Prosthodontic management of patients with generalized wear of dentition has been well documented in the literature. Although prosthodontic treatment is designed to correct minor malocclusion and interdental spacing, patients with severe malocclusion accompanied by generalized wear may require preprosthetic orthodontic intervention. Few articles have described the comprehensive treatment of adult orthodontic patients with severe wear of teeth. This article describes the multidisciplinary management of an adult patient with multiple missing posterior teeth, malocclusion, and severe wear of anterior teeth. Preprosthetic orthodontic treatment was planned using occlusograms, visualized treatment objective, and sectioned diagnostic waxing for movement of teeth, according to the prosthodontic treatment plan. Temporary anchorage devices were used to accomplish complex orthodontic tooth movements. The definitive treatment included reestablishing appropriate esthetics, and occlusion and restoration of the entire maxillary arch and posterior mandibular dentition with metal ceramic and full gold restorations. At a 2.5-year follow-up, positions of teeth and integrity of the restorations remained stable. Importance of preprosthetic orthodontic treatment and challenges in management of complex esthetic and functional rehabilitations are discussed in this article. PMID- 22524715 TI - Commentary. Preprosthetic orthodontic intervention for management of a partially edentulous patient with generalized wear and malocclusion. PMID- 22524717 TI - Commentary. Treatment of herpes labialis: comparison of two OTC drugs and untreated controls. PMID- 22524716 TI - Treatment of herpes labialis: comparison of two OTC drugs and untreated controls. AB - STATEMENT OF THE PROBLEM: Rapid resolution of active herpes labialis lesions is of great benefit to the patient not only in terms of controlling pain and disfigurement, but in disruption of needed dental treatment. PURPOSE OF THE STUDY: Using three groups, this retrospective study investigated the time required to complete healing and the loss of discomfort. METHODS AND MATERIALS: Based on 180 completed surveys, responses were divided into three groups: One group used Abreva (GlaxoSmithKline, Parsippany, NJ, USA). The second used Viroxyn (Quadex Pharmaceuticals, West Jordan, UT, USA). The third group, the Control group, consisted of untreated lesions. All three groups were asked about past experiences with lesions treated using Abreva and/or Viroxyn, and lesions which were left untreated. In addition, 58 participants who had used Viroxyn only responded. Participants were provided standardized responses from which to choose. RESULTS: For both the time to healing and time to loss of discomfort, participants in both the Abreva and Viroxyn groups experienced significant improvements. Relative to the Abreva, Viroxyn provided significant improvement in both outcomes (all t-tests; all p < 0.001). Relative to the Control group, Viroxyn and Abreva offered an 8.0 and 4.0 day reduction in time to healing, respectively. Loss of discomfort occurred within 3.0 days and 1 hour for Abreva and Viroxyn, respectively. CONCLUSION: Relative to the untreated controls, both Abreva and Viroxyn offered a significant reduction in both the time to healing and time to loss of discomfort. Furthermore, Viroxyn offered a significant reduction relative to Abreva. . PMID- 22524718 TI - A survey of dentulous and edentulous patient preference among different denture esthetic concepts. AB - STATEMENT OF PROBLEM: Most esthetic preference research and anatomical average analysis come from dentulous populations. If edentulous patients have a different preference, application of this data during denture construction is problematic. PURPOSE: The aim of this survey was to compare dentulous and edentulous respondent preference among three different denture esthetic concepts. MATERIAL AND METHODS: A questionnaire and test booklet of standardized full-face digital photographs were used. It included three arrangements during maximum smile for six subjects. Dentulous and edentulous respondents were asked questions about their preference among the three randomly ordered concept photographs for each of the six subjects. A total of 167 dentulous and 269 edentulous questionnaires were analyzed descriptively and with Chi-squared tests to compare the esthetic preference of the respondents. RESULTS: There was no statistically significant difference overall between dentulous and edentulous preference. Respondent preference varied significantly depending upon subject set and gender. Preference data compared closely to previous research. CONCLUSION: Within the limitations of this survey, dentulous and edentulous respondent preference among the three esthetic concepts was not significantly different. Questionnaire respondents continued to frequently prefer appearances that are far from the anatomical average. PMID- 22524719 TI - Commentary. A survey of dentulous and edentulous patient preference among different denture esthetic concepts. PMID- 22524721 TI - Commentary. The effectiveness of low-intensity red laser for activating a bleaching gel and its effect in temperature of the bleaching gel and the dental pulp. PMID- 22524720 TI - The effectiveness of low-intensity red laser for activating a bleaching gel and its effect in temperature of the bleaching gel and the dental pulp. AB - STATEMENT OF THE PROBLEM: The effectiveness of low-intensity red laser for activating a bleaching gel and its effect in pulp temperature was not investigated in dental literature. PURPOSE: The objective of this study was to assess the effectiveness of low-intensity red laser for activating a bleaching gel, as well as its effect in temperature of the bleaching gel and the dental pulp. MATERIALS AND METHODS: Forty extracted bovine teeth were immersed in a solution of coffee 14 days for darkening. The initial colors were recorded by spectrophotometric analysis. The specimens were randomly distributed into two groups (N = 20): the control, which did not receive light and the experimental group that received light from an appliance fitted with three red light-emitting laser diodes (lambda = 660 nm). A green-colored, 35% H(2) O(2) -based bleaching gel was applied for 30 minutes, and changed three times. After bleaching, the colors were again measured to obtain the L*a*b* values. Color variation was calculated (DeltaE) and the data submitted to the non-paired t-test (5%). To assess temperature, 10 human incisors were prepared, in which one thermocouple was placed on the bleaching gel applied on the surface of the teeth and another inside the pulp chamber. RESULTS: There was a significant difference between the groups (p = 0.016), and the experimental group presented a significantly higher mean variation (7.21 +/- 2.76) in comparison with the control group (5.37 +/- 1.76). There was an increase in pulp temperature, but it was not sufficient to cause damage to the pulp. CONCLUSION: Bleaching gel activation with low-intensity red laser was capable of increasing the effectiveness of bleaching treatment and did not increase pulp temperature to levels deleterious to the pulp. PMID- 22524722 TI - Computer-aided-design/computer-assisted-manufactured adhesive restoration of molars with a compromised cusp: effect of fiber-reinforced immediate dentin sealing and cusp overlap on fatigue strength. AB - STATEMENT OF PROBLEM: Cracked teeth may traditionally require the use of complete coverage crowns. Alternative conservative treatments involve the use of adhesive inlays/onlays with the possibility of including a fiber patch to reinforce the cracked cusp. PURPOSE: The purpose of this study was to evaluate the fatigue strength of compromised molars restored with computer-aided-design/computer assisted-manufactured (CAD/CAM) composite resin inlays/onlays with and without fiber-reinforced immediate dentin sealing (IDS). METHODS AND MATERIALS: Large mesio-occluso-distal preparations with cracked/undermined palatal cusps were simulated on 40 extracted maxillary molars. All teeth received IDS (Optibond FL, Kerr, Orange, CA, USA), and composite resin (Paradigm MZ100, 3M-ESPE, St. Paul, MN, USA) inlays (N = 20) and onlays (N = 20). A fiber patch (Ribbond, Ribbond Inc., Seattle, WA, USA) was applied in half of the preparations. Restorations were adhesively luted with pre-heated composite resin (Z100, 3-M ESPE) and submitted to cyclic isometric loading at 5 Hz, starting with a load of 50 N (5,000 cycles), followed by stages of 150, 300, 450, 600, 750, 900, and 1,050 N at a maximum of 25,000 cycles each. Specimens were loaded until fracture or to a maximum of 180,000 cycles. Groups were compared using the life table survival analysis. RESULTS: Differences in survival probability were found (p = 0.04). The inlay group with fiber patch failed at an average load of 870 N, and none of the specimens withstood all 180,000 load cycles; survival rates of inlays and onlays without fibers, and onlays with fibers were 10, 30, and 50%, respectively. CONCLUSIONS: Onlays (with or without fibers) increased the fatigue resistance of compromised molars in this in vitro study. PMID- 22524723 TI - Commentary. Computer-aided-design/computer-assisted-manufactured adhesive restoration of molars with a compromised cusp: effect of fiber-reinforced immediate dentin sealing and cusp overlap on fatigue strength. PMID- 22524724 TI - Critical appraisal. Partial caries excavation. AB - Regular readers will note that we depart from our normal Critical Appraisal format in this issue of the Journal. This particular Critical Appraisal resembles an expanded Contemporary Issues feature and describes a protocol for partial caries excavation that was recently implemented in the student clinics of the University of North Carolina (UNC) School of Dentistry. PMID- 22524729 TI - An adiabatic capture theory and quasiclassical trajectory study of C + NO and O + CN on the 2A', 2A", and 4A" potential energy surfaces. AB - The adiabatic capture centrifugal sudden approximation (ACCSA) has been applied to the C + NO and O + CN reactions, along with quasiclassical trajectory simulations. Existing global analytic fits to the potential energy surfaces of the CNO system in the (2)A', (2)A", and (4)A" electronic states have been used. Thermal rate constants for reaction in each of the electronic states have been calculated. In all cases a strong temperature dependence is evident in the calculated rate constants. The agreement between the calculated adiabatic capture and quasiclassical trajectory rate constants is excellent in some cases, but these rate constants differ considerably in other cases. This behavior is analyzed in terms of the anisotropy of the potential energy surfaces. On the basis of this analysis, we propose a new diagnostic for the reliability of ACCSA capture calculations. PMID- 22524731 TI - Giant subcapsular hematoma of the spleen complicating recurrent pancreatitis. PMID- 22524730 TI - Severe diabetes and leptin resistance cause differential hepatic and renal transporter expression in mice. AB - BACKGROUND: Type-2 Diabetes is a major health concern in the United States and other Westernized countries, with prevalence increasing yearly. There is a need to better model and predict adverse drug reactions, drug-induced liver injury, and drug efficacy in this population. Because transporters significantly contribute to drug clearance and disposition, it is highly significant to determine whether a severe diabetes phenotype alters drug transporter expression, and whether diabetic mouse models have altered disposition of acetaminophen (APAP) metabolites. RESULTS: Transporter mRNA and protein expression were quantified in livers and kidneys of adult C57BKS and db/db mice, which have a severe diabetes phenotype due to a lack of a functional leptin receptor. The urinary excretion of acetaminophen-glucuronide, a substrate for multidrug resistance-associated proteins transporters was also determined. The mRNA expression of major uptake transporters, such as organic anion transporting polypeptide Slco1a1 in liver and kidney, 1a4 in liver, and Slc22a7 in kidney was decreased in db/db mice. In contrast, Abcc3 and 4 mRNA and protein expression was more than 2 fold higher in db/db male mouse livers as compared to C57BKS controls. Urine levels of APAP-glucuronide, -sulfate, and N-acetyl cysteine metabolites were higher in db/db mice. CONCLUSION: A severe diabetes phenotype/presentation significantly altered drug transporter expression in liver and kidney, which corresponded with urinary APAP metabolite levels. PMID- 22524732 TI - Single incision laparoscopic surgery for the treatment of ruptured ectopic pregnancy. PMID- 22524733 TI - Gossypiboma of the breast. PMID- 22524735 TI - Characteristics of extrahepatic second primary malignancies after hepatectomy for hepatocellular carcinoma in Japan. PMID- 22524734 TI - Is dexmedetomidine the agent of choice in the resection of pheochromocytoma? PMID- 22524736 TI - Isolated situs inversus of the thoracic duct, injury after esophagectomy. PMID- 22524737 TI - Intramuscular myxoma of trapezius in an adult woman. PMID- 22524738 TI - Duodenitis associated with non-steroidal anti-inflammatory drug use causing mesenteric panniculitis. PMID- 22524739 TI - Pseudoaneurysm of the proximal innominate artery after blunt trauma. PMID- 22524740 TI - Heterotopic pancreas: a clinical analysis of nine patients and review of literature. PMID- 22524741 TI - Invasive papillary carcinoma of the breast: an overview of twenty-four cases. PMID- 22524742 TI - Delayed esophago-pericardial fistula after ablation for atrial fibrillation. PMID- 22524743 TI - Hemobilia secondary to acute gangrenous cholecystitis. PMID- 22524744 TI - Post-ejaculatory pain as a harbinger of extraperitoneal pelvic metastasis occurring seven years after curative surgery for gastric cancer. PMID- 22524745 TI - Duodenoportal fistula resulting from peptic ulcer after extended right hepatectomy for cholangiocarcinoma. PMID- 22524746 TI - Management of pheochromocytoma during pregnancy: laparoscopic adrenalectomy. PMID- 22524747 TI - Small bowel perforation after capsule endoscopy in a patient with occult gastrointestinal bleeding and undiagnosed Crohn's disease. PMID- 22524748 TI - A purely laparoscopic approach to intra-abdominal abscess drainage and retrieval of retained penile prosthesis reservoir. PMID- 22524749 TI - Pancreatoduodenectomy in patients with periampullary cancer after radical subtotal gastrectomy for gastric cancer. PMID- 22524750 TI - Esophageal achalasia with recurrent aspiration pneumoniae treated by laparoscopic Heller myotomy. PMID- 22524751 TI - A rare finding of an ectopic parathyroid gland within a cervical thymic cyst presenting as a lateral neck mass. PMID- 22524752 TI - Esophageal reconstruction with remnant stomach after distal gastrectomy. PMID- 22524753 TI - Do basic laboratory tests add value in predicting the severity of appendicitis in an adult patient population and does it make a difference in how severity is defined? PMID- 22524754 TI - Unicentric Castleman disease mimicking a pancreatic neoplasm. PMID- 22524755 TI - Gastrocutaneous fistula after laparoscopic sleeve gastrectomy and stent placement: postoperative endoleak? PMID- 22524756 TI - Diagnosis of a metastatic neuroendocrine tumor of the pancreas by transaortic endoscopic ultrasound-guided fine-needle aspiration. PMID- 22524757 TI - A giant breast lipoma. PMID- 22524758 TI - Heterotopic pancreas as a lead point for ileoileal intussusception. PMID- 22524759 TI - Retroperitoneal inflammatory myofibroblastic tumor. PMID- 22524760 TI - An inverted hyperplastic polyp mimicking nonpolypoid colon cancer. PMID- 22524761 TI - The twisted colon: a review of sigmoid volvulus. AB - Sigmoid volvulus (SV) is the third leading cause of colon obstruction in adults. In infants and children, it is exceedingly rare with only sporadic cases reported so far. SVs from secondary causes, with congenital megacolon being the most important, are nevertheless more common in young people. The etiology of this disorder is not completely understood. It is known to occur in the setting of redundant sigmoid loop, which rotates around its narrow and elongated mesentery. Although the latter occurs in the setting of constipation, a congenitally elongated colon, and other predisposing factors, there is no consensus on the precipitating factor leading to SV formation. The symptoms are suggestive of small bowel obstruction, but the presentations can be acute or indolent. Plain abdominal radiography is used to diagnose SV in most cases with computed tomography scan or magnetic resonance imaging as the confirmatory tests when necessary. After it has been untwisted, the definitive and standard therapy for SV is sigmoid resection and primary anastomosis. The nonresective alternatives have also been widely used with mixed success, but a large, randomized controlled trial is needed to compare their efficacy with resection and primary anastomosis. Laparoscopic surgery in SV management is unwarranted and costly. Complications of SV include hemorrhagic infarction, perforation, septic shock, and death. The mortality data from SV vary, but the latest literature cites an overall range of 14 to 45 per cent. PMID- 22524762 TI - Christian Albert Theodor Billroth, M.D., founding father of abdominal surgery (1829-1894). PMID- 22524763 TI - Theodor Billroth and his musical life. PMID- 22524764 TI - Management of choledochal cysts and their complications. AB - Choledochal cysts are increasingly reported in adults. The presence of cyst related complications alters its presentation and complicates the management. We reviewed our experience to find the clinical presentation, complications, and the management of choledochal cysts. The records of 132 patients with choledochal cysts presented to us between 2003 and 2010 maintained as a prospective database were analyzed for demography, clinical presentation, radiological investigation, management, and outcome. There were 12 children and 120 adults. Based on preoperative cholangiogram, 93 (71%) patients had Type I and 39 (29%) Type IVA cysts. The overall incidence of complicated choledochal cyst was 4 of 12 (33%) in children and 85 of 120 (71%) in adults. The most common complication was cystolithiasis (49%) followed by cholangitis (32%), acute pancreatitis (10%), hepatolithiasis (7%), malignancy (3%), portal hypertension (2%), and chronic pancreatitis (2%). Acute pancreatitis and cholangitis were managed conservatively. Endoscopic stenting was performed in patients with cholangitis and those requiring staged treatment as a result of portal hypertension. Overall 114 patients underwent cyst excision with Roux-en-y hepaticojejunostomy. The overall morbidity was 17.5 per cent (wound infection 13% and bilioenteric anastomotic leak 7%). There was one postoperative death resulting from cardiac failure. Three patients developed anastomotic stricture and underwent redo hepaticojejunostomy. Choledochal cysts in adults are often associated with complications. Complications are more common in adults compared with children. Acute pancreatitis, cholangitis and portal hypertension are managed conservatively and then followed up by definitive surgery. Cyst excision with Roux-en-Y hepaticojejunostomy is necessary to prevent the recurrence of complications. PMID- 22524765 TI - Esophagectomy in the state of Florida: is regionalization of care warranted? AB - Centralization of cancer care needs to be based on evidence that regionalization will improve outcomes in a given region. We analyzed outcomes for esophagectomy performed in Florida using the Agency for Health Care Administration database. We determined the risk-adjusted mortality rate for the procedure in low-volume and high-volume centers. From 1997 to 2006, 991 esophagectomies were performed in Florida. The incidence of esophagectomy significantly increased from 1997 to 2001 compared with 2002 to 2006, and the postoperative mortality decreased in the latter time period (odds ratio [OR], 1.87; confidence interval [CI], 1.16-3.03). The risk-adjusted postoperative mortality was significantly lower (OR, 0.54; CI, 0.32-0.92) in high-volume centers (5.1 vs 10.4%). The anastomotic leak rates were 8.2 per cent in both high- and low-volume centers. In the largest population based study for esophagectomy in Florida, outcomes are better in high-volume centers. These data support the regionalization of esophagectomy to high-volume locations in Florida to reduce procedure-related mortality. PMID- 22524766 TI - The reward is worth the wait: a prospective analysis of 100 consecutive organ donors. AB - Aggressive donor management protocols have evolved to maximize the number of procured organs. Our study assessed donor management time and the number and types of organs procured with the hypothesis that shorter management time yields increased organ procurement and transplant rates. We prospectively analyzed 100 donors managed by a regional organ procurement organization (OPO) during 2007 to 2008. Data included patient demographics, number and types of organs procured and transplanted, patient management time by the OPO, and achievement of donor preprocurement goals. One hundred consecutive organ donors were managed with a mean age 41 +/- 18 years and mean management time 23 +/- 9 hours; 376 organs were procured and 327 successfully transplanted. Donors managed greater than 20 hours yielded significantly more heart (5 vs 26, P < 0.01) and lung (6 vs 40, P < 0.01) procurements, more organs procured per donor (3.2 +/- 1.4 vs 4.2 +/- 1.6, P < 0.01), and more organs transplanted per donor (2.6 +/- 1.5 vs 3.7 +/- 1.8, P < 0.01) than those managed 20 hours or less. No difference in the attainment of donor management goals was observed between these populations. Contrary to our initial hypothesis, donor management times greater than 20 hours yielded increased organ procurement and transplant rates, particularly for hearts and lungs, despite no differences in the achievement of donor preprocurement management goals. PMID- 22524767 TI - Extrahepatic portal vein ligation in major hepatectomies performed under selective vascular exclusion: a case-control study. AB - The aim of our study is to assess the effect of extrahepatic ipsilateral portal vein branch ligation in hepatectomies conducted under selective hepatic vascular exclusion with sharp transection of the liver parenchyma. Twenty-six patients (Group A) underwent major hepatectomy from January 2007 to December 2009, and hemostasis was achieved by ligation of the ipsilateral portal vein branch in addition to suture ligation of the cut surface vessels. A control group (Group B) was composed of 26 matched patients picked from our hospital's database, in which hemostasis was achieved by suture ligation of the cut surface vessels only. Warm ischemia time, intraoperative blood loss, blood transfusions, and liver function were compared. Reduced blood loss (450 vs 680 mL, P = 0.03), less transfusions (8 vs 20% of the patients, P = 0.04), and decreased warm ischemia time (34 vs 42 minutes, P = 0.04) were observed in Group A. Extrahepatic ligation of the ipsilateral portal vein branch is simple, safe, and effective in reducing blood loss and warm ischemia time in major hepatectomies performed under selective vascular exclusion. PMID- 22524768 TI - Use of positron emission tomography in initial staging of nonsmall cell lung carcinoma: a regional teaching hospital experience. AB - The ability to accurately diagnose mediastinal lymph node involvement is significantly important in patients with nonsmall cell lung cancer (NSCLC). Positron emission tomography (PET) imaging has become a standard technique to assess lymph node involvement in patients with NSCLC. The purpose of this study is to evaluate the accuracy of PET scan imaging as a mediastinal staging tool in patients with NSCLC at our regional teaching institution. We performed a single institution, retrospective review of patients diagnosed with NSCLC from January 1, 2006, through December 31, 2007. We included only those patients who underwent computed tomography (CT), PET, and pathologic assessment of mediastinal lymph nodes. Using pathologic assessment as the criterion standard, the overall accuracy, sensitivity, specificity, and positive and negative predictive values of CT and PET were calculated. One hundred seventeen patients were identified for inclusion in the study. The overall accuracy was 81.2 per cent for CT and 91.5 per cent for PET. Sensitivity was 42.1 per cent for CT and 52.6 per cent for PET. Specificity was 88.8 per cent for CT and 99.0 per cent for PET. Positive predictive values were 42.1 per cent for CT and 90.9 per cent for PET; negative predictive values were 88.8 per cent for CT and 91.5 per cent for PET. False negative result rates were 9.4 per cent for CT and 7.7 per cent for PET; false positive result rates were 9.4 per cent for CT and 0.9 per cent for PET. Our analysis confirms the use of PET scan imaging in the staging of patients with NSCLC at a regional teaching institution. PMID- 22524770 TI - The impact of early hormonal therapy in catastrophic brain-injured patients and its effect on organ procurement. AB - The purpose of this study was to evaluate the impact of early hormonal therapy on organ procurement from catastrophic brain-injured patients. All catastrophic brain-injured patients admitted to a high-volume academic Level I trauma center who underwent successful organ procurement over a 3-year period (2006 to 2008) were reviewed. Patients were divided into two groups, those who received hormone therapy (HT) before brain death (BD) declaration and those who received HT after BD declaration. Thirty-two (60.4%) received HT before BD and 21 (39.6%) HT after BD. Trauma was the most common cause of brain injury in both groups (before BD 96.9 vs after BD 90.5%, P = 0.324). There were no significant differences in demographics and clinical data. Patients receiving HT before BD were more hypotensive on admission (28.2 vs 9.5%, P = 0.048); however, they required vasopressors less frequently (62.5 vs 100.0%, P = 0.001), for a shorter duration (17.2 +/- 16.3 hours vs 33.1 +/- 34.9 hours, P = 0.043), and at a lower dosage. Time from admission to procurement did not differ between the two groups (109.8 +/- 83.1 hours vs 125.0 +/- 79.9 hours, P = 0.505). Patients receiving HT before BD had significantly more organs procured (4.5 +/- 1.5 vs 3.5 +/- 1.3, P = 0.023). Although catastrophic brain-injured patients receiving early hormonal therapy were more hypotensive, they required less vasopressors and had higher procurement rates. The early use of hormonal therapy may decrease the need for vasopressors and increase the salvage of potentially transplantable organs. PMID- 22524769 TI - Clinical features and management of pseudoaneurysmal bleeding after pancreatoduodenectomy. AB - A ruptured pseudoaneurysm is the most serious and life-threatening cause of postpancreatoduodenectomy (PD) hemorrhages. We have evaluated the clinical course and management of pseudoaneurysms after PD. Of 586 patients who underwent PD for periampullary tumors in Asan Medical Center between March 2003 and March 2011, 27 experienced pseudoaneurysmal bleeding. Bleeding developed at a median of 21 days (range, 8 to 45 days) after surgery, including 9 patients who developed bleeding more than 4 weeks after surgery. Before development of bleeding, 26 patients showed pancreatic fistula. Bleeding was developed from the gastroduodenal artery stump in 12 patients, the common hepatic artery in eight, the proper hepatic artery in five, and the left hepatic artery in two. Of the angiographic group, 21 patients underwent with microcoil embolization, four underwent stent insertion, and one experienced technical failure. Only one patient required emergent laparotomy without angiography. Of 25 patients with angiographic procedures, all patients achieved hemostasis. The mortality rate was 22.2 per cent (6 patients). Delayed hemorrhage after PD is closely associated with pancreatic fistula and carried a significantly higher mortality rate. The patients with pancreatic fistula should be carefully monitored, even more than 4 weeks after surgery. Selective microcoil embolization or stent graft is effective for pseudoaneurysmal bleeding. PMID- 22524771 TI - Surgeon's requirement for obesity reduction: its influence on weight loss. AB - The objective of this study was to examine whether preoperative recommendation for specific reductions in body mass index (BMI) influenced weight loss in obese surgical patients. We retrospectively reviewed the electronic medical records of 48 patients who enrolled between January 2007 to June 2010 in an 800-calorie per day liquid meal replacement (LMR) weight loss program. Of these, 9 patients (surgical group) enrolled as a result of general surgeon-directed weight loss to enable nonbariatric surgery and 39 enrolled seeking weight loss (medical group). Patients enrolled in the LMR program before bariatric surgery were excluded from analysis. All patients were seen in the setting of a comprehensive weight loss program supervised by a medical bariatrician and followed for a period of 4 months. There were no significant differences in mean initial BMI between surgical and medical patients (41.7 +/- 4.55 and 41.6 +/- 8.54 kg/m(2), respectively) or participation time in the weight loss program (120 days vs 133 days). Of the nine surgical patients, only five (56%) reached their weight goal and underwent the planned surgical procedure. Weight loss was significantly less in the surgical compared with medical patients (BMI reduction 4.03 +/- 3.99 vs 7.75 +/- 4.90 kg/m(2), respectively; P < 0.05). Weight loss was significantly lower in patients directed to undergo BMI reduction to enable a general surgical procedure. Future studies are needed to assess factors influencing weight loss (metabolism, exercise capacity, motivation) in patients requiring weight loss to enable a surgical procedure. PMID- 22524772 TI - Diabetes mellitus and cerebrovascular disease as independent determinants for increased hospital costs and length of stay in open appendectomy in comparison with laparoscopic appendectomy: a nationwide cohort study. AB - Comorbidity has been proven to increase hospital costs and length of hospital stays in patients receiving appendectomy for the treatment of acute appendicitis. However, the specific comorbidities that independently influence discrepancy of hospital costs and length of stay between open appendectomy and laparoscopic appendectomy still need to be elucidated. Using multivariate linear analysis, administrative claims data were obtained from Taiwan's National Health Institute Research Database to compare differences of hospitalization costs and length of stay between open appendectomy and laparoscopic appendectomy categorized by various comorbidities defined in Charlson comorbidity score. Of 103,653 patients, 81,479 open appendectomies and 22,174 laparoscopic appendectomies were performed for the treatment of acute appendicitis in Taiwan between 2004 and 2008. In multilinear regression models, the adjusted costs and length of stay for open appendectomy in patients with cerebrovascular diseases or diabetes mellitus were significantly higher than that for laparoscopic appendectomy. To reduce costs and length of stay, patients with cerebrovascular diseases or diabetes mellitus should be particularly recommended to receive laparoscopic approach rather than an open approach for the treatment of acute appendicitis. PMID- 22524773 TI - Management of traumatic vascular injuries to the neck: a 7-year experience at a Level I trauma center. AB - Injury to the carotid artery results in significant mortality and morbidity. The general consensus is to repair all injuries to the common and internal carotid arteries. Ligation is usually reserved for neurologic or hemodynamic instability. We report our experience at a Level I trauma center with vascular injuries to the neck. Retrospective chart review of all patients with vascular injuries in the neck resulting from either blunt or penetrating trauma treated at a Level I trauma center between January 2000 and February 2007. Demographics and outcomes were collected from a chart review. Twenty-five patients with vascular injuries to the neck were identified. There were 13 carotid artery injuries (CAI), five internal jugular vein (IJV) injuries, and 13 external jugular vein (EJV) injuries. Of the carotid artery injuries, six (50%) underwent operative repair (4 primary repairs and 2 bypasses), five (38%) were managed nonoperatively, and one was treated using endovascular techniques. No patient had a postoperative decrease in Glasgow Coma Scale score. There were five isolated IJV injuries (3 primary repair and 2 ligations). Four of the venous injuries (all internal jugular veins) were repaired and the remaining 13 were ligated. Vascular injuries to the neck have significant mortality and morbidity. Treatment of these injuries must be individualized. All CAI in noncomatose patients should be repaired if hemodynamically stable. All IJV injuries should be repaired but may be ligated if hemodynamically unstable. All EJV injuries can be ligated without reservation regardless of neurological status. PMID- 22524774 TI - Increased risk of neoplasm in appendicitis treated with interval appendectomy: single-institution experience and literature review. AB - Appendicitis is a common diagnosis encountered by the acute care surgeon. Management of complicated appendicitis is controversial and often involves initial nonoperative therapy with interval appendectomy. This study reviews single-institutional experience with management of complicated appendicitis with interval appendectomy and addresses an unusually high occurrence of incidental appendiceal malignancies observed with a review of relevant literature. A retrospective review of all diagnoses of appendicitis was performed over 5 years at a tertiary care center. Patient demographics, time to surgery, operative technique, pathologic diagnosis, and clinical outcomes were examined. Three hundred fifteen patients were diagnosed with acute appendicitis. Of these, 24 (7.6%) were deemed complicated and did not undergo immediate appendectomy, and 18 ultimately underwent appendectomy at our institution and were included in analysis. There were no statistical demographic or symptomatic differences between the immediate and interval appendectomy patients. Ninety-nine per cent of the immediate appendectomy patients were treated laparoscopically; 78 per cent of the interval group underwent attempted laparoscopic treatment with 56 per cent completed without conversion to open (P < 0.01). Neoplasms were discovered in 1 per cent of the acute appendectomy group and 28 per cent of the interval appendectomy group (P < 0.0001). Two of the three neoplasms in the acute group were carcinoid, whereas three of the five neoplasms in the interval group were adenocarcinoma. Surgeons should consider appendiceal or colonic neoplasms in cases of complicated appendicitis when nonoperative management is considered. This is most important in patients older than 40 years, in those who forego interval appendectomy, or in those who could be lost to follow-up. PMID- 22524775 TI - Doppler-guided hemorrhoidal artery ligation: experience with 2 years follow-up. AB - Doppler-guided hemorrhoidal artery ligation (DGHAL) is a nonexcisional surgical technique for the treatment of hemorrhoidal disease, consisting of the ligation of the distal branches of the superior rectal artery, resulting in a reduction of blood flow and decongestion of hemorrhoidal plexus resulting in fibrosis. The aim of the study was to assess the efficacy and safety of DGHAL, define its indications, and identify its possible advantages and limitations for the treatment of second- and third-degree hemorrhoids. The procedure was performed using a specially designed proctoscope. The Doppler probe was used to locate all the terminal branches of hemorrhoidal arteries, which were then sutured. Patients were followed up for 2 years. From November 2006 to May 2009, 50 patients (29 female, mean age 38.2 years) underwent this procedure. The procedure was performed under local anesthesia. An average of five ligatures was placed. Average length of hospital stay was 2 hours and return to work was 2.5 days. The mean postoperative pain score was 1.72. There were no intra- or immediate postoperative major complications. In 44 patients (88%), surgery resolved the symptoms completely in a 2-year follow-up period. DGHAL is a safe and effective procedure. DGHAL can be the choice for second- and third-degree hemorrhoids with minimal postoperative pain and quick recovery. PMID- 22524776 TI - Antegrade versus retrograde cerebral protection in repair of acute ascending aortic dissection. AB - The objective of this study was to compare retrograde with antegrade cerebral protection during acute aortic dissection repair using cerebral oximetry measurements. Fifty consecutive acute ascending aortic dissection repairs were analyzed. Cerebral oximetry data were collected for 41 of 50. Eight patients who had antegrade cerebral protection alone and 29 of 41 had retrograde cerebral protection alone. The per cent change in cerebral oximetry values during deep hypothermic circulatory arrest from baseline and from prearrest values was compared for the two groups using Student t test. The per cent change from baseline for the antegrade patients was: right 13.8 per cent and left -2.5 per cent; the per cent change from baseline for retrograde patients was: right 0.8 per cent and left 0.2 per cent (P values 0.216 and 0.725, respectively). The per cent change from the prearrest value for the antegrade patients was: right -12 per cent and left -15 per cent; the per cent change from prearrest for retrograde patients was: right -15 per cent and left -16 per cent (P values 0.514 and 0.956, respectively). No compelling evidence for an advantage to either antegrade or retrograde cerebral perfusion was detected. Further study with a focus on neurologic outcomes is warranted. PMID- 22524777 TI - Predictive factors for postoperative severe hypocalcaemia after parathyroidectomy for primary hyperparathyroidism. AB - Hypocalcaemia is a complication of parathyroidectomy. We retrospectively analyzed data on patients who underwent parathyroidectomy for primary hyperparathyroidism (pHPT) to identify predictive factors for severe postoperative hypocalcaemia. Since 2004 we performed 87 parathyroidectomies for pHPT. We divided the patients into two groups: subjects who presented with postoperative hypocalcaemia (group B) or otherwise (group A). We looked for a correlation between several variables and the incidence of postoperative hypocalcaemia. The median calcemia in group B (19 patients) was 6.9 mg/dL on the first postoperative day and 7.6 mg/dL on the third day. We observed hypocalcemia related clinical symptoms in every patient. In all 19 cases the reduction of intraoperative parathyroid hormone above 85 per cent after parathyroidectomy was related to the development of severe postoperative hypocalcaemia (P = 0.042). We found that the reduction of intraoperative parathyroid hormone over 85 per cent after parathyroidectomy can be considered a reliable predictive factor of postoperative hypocalcaemia after parathyroidectomy for primary hyperparathyroidism. PMID- 22524778 TI - Antibiotic prophylaxis in patients undergoing open mesh repair of inguinal hernia: a meta-analysis. AB - The use of antibiotic prophylaxis in hernia repair is still under debate. The aim of this meta-analysis was to assess the effect of antibiotic prophylaxis in patients undergoing open mesh repair of inguinal hernia with respect to incidence of postoperative surgical site infection (SSI). A literature search was conducted in databases of MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials. Study selection, data extraction, quality assessment, and meta analysis were conducted according to the recommendations by Cochrane collaboration. Nine randomized controlled trials were included. Incidence of surgical site infection was 39/1642 (2.38%) in the antibiotic group and 70/1676 (4.18%) in the control group. Antibiotics showed a protective effect in preventing SSI after mesh inguinal hernia repair (odds ratio: 0.61, 95% confidence interval: 0.40-0.92, I(2): 0%). Antibiotic prophylaxis did reduce the incidence of SSI in hernia patients undergoing mesh hernioplasty. The cost effectiveness of antibiotic prophylaxis needs further evaluation. PMID- 22524779 TI - Incidental findings in trauma patients during focused assessment with sonography for trauma. AB - During the initial assessment of trauma patients they usually undergo a Focused Assessment with Sonography for Trauma (FAST) in which there are occasionally incidental findings of other surgical conditions. In this audit we discuss the incidence, demographics, and implications of these findings and we propose a management algorithm. Within 2 years we managed 6041 trauma patients in the emergency department based on the Advanced Trauma Life Support protocols, 95 per cent of which underwent a FAST ultrasound. Incidental findings were reported in 468 patients (7.8%), whereas in a further 11.2 per cent of these patients there was a second finding. The mean age of these patients was 57.55 years (15-105), and most of them were men (51.1%). The vast majority of the findings were related to the liver and biliary tree (52.1%) followed by the urinary track (27.1% + 8%). In multivariate analysis only the age was a significant factor associated with incidental findings (P < 0.001) whereas in univariate analysis both the gender [men (54.1%) vs women (45.9), P = 0.013] and the mechanism of trauma (P < 0.001) were as important as the age (P < 0.001). The patients who had incidental findings were 15 years older than the rest. The detection of unknown surgical conditions in FAST may lead to managerial and possible medico-legal issues rendering the development of a proper algorithm mandatory. PMID- 22524780 TI - The true Ramirez components separation. PMID- 22524781 TI - Appendicitis, is it an emergency? PMID- 22524783 TI - Granulocyte colony-stimulating factor expressing retroperitoneal dedifferentiated liposarcoma. PMID- 22524784 TI - Wortmannin treatment induces changes in Arabidopsis root proteome and post-Golgi compartments. AB - Wortmannin is a widely used pharmaceutical compound which is employed to define vesicular trafficking routes of particular proteins or cellular compounds. It targets phosphatidylinositol 3-kinase and phosphatidylinositol 4-kinases in a dose-dependent manner leading to the inhibition of protein vacuolar sorting and endocytosis. Combined proteomics and cell biological approaches have been used in this study to explore the effects of wortmannin on Arabidopsis root cells, especially on proteome and endomembrane trafficking. On the subcellular level, wortmannin caused clustering, fusion, and swelling of trans-Golgi network (TGN) vesicles and multivesicular bodies (MVBs) leading to the formation of wortmannin induced multivesicular compartments. Appearance of wortmannin-induced compartments was associated with depletion of TGN as revealed by electron microscopy. On the proteome level, wortmannin induced massive changes in protein abundance profiles. Wortmannin-sensitive proteins belonged to various functional classes. An inhibition of vacuolar trafficking by wortmannin was related to the downregulation of proteins targeted to the vacuole, as showed for vacuolar proteases. A small GTPase, RabA1d, which regulates vesicular trafficking at TGN, was identified as a new protein negatively affected by wortmannin. In addition, Sec14 was upregulated and PLD1 alpha was downregulated by wortmannin. PMID- 22524786 TI - Social control of the brain. AB - In the course of evolution, social behavior has been a strikingly potent selective force in shaping brains to control action. Physiological, cellular, and molecular processes reflect this evolutionary force, particularly in the regulation of reproductive behavior and its neural circuitry. Typically, experimental analysis is directed at how the brain controls behavior, but the brain is also changed by behavior over evolution, during development, and through its ongoing function. Understanding how the brain is influenced by behavior offers unusual experimental challenges. General principles governing the social regulation of the brain are most evident in the control of reproductive behavior. This is most likely because reproduction is arguably the most important event in an animal's life and has been a powerful and essential selective force over evolution. Here I describe the mechanisms through which behavior changes the brain in the service of reproduction using a teleost fish model system. PMID- 22524785 TI - Multiple functions of endocannabinoid signaling in the brain. AB - Despite being regarded as a hippie science for decades, cannabinoid research has finally found its well-deserved position in mainstream neuroscience. A series of groundbreaking discoveries revealed that endocannabinoid molecules are as widespread and important as conventional neurotransmitters such as glutamate or GABA, yet they act in profoundly unconventional ways. We aim to illustrate how uncovering the molecular, anatomical, and physiological characteristics of endocannabinoid signaling has revealed new mechanistic insights into several fundamental phenomena in synaptic physiology. First, we summarize unexpected advances in the molecular complexity of biogenesis and inactivation of the two endocannabinoids, anandamide and 2-arachidonoylglycerol. Then, we show how these new metabolic routes are integrated into well-known intracellular signaling pathways. These endocannabinoid-producing signalosomes operate in phasic and tonic modes, thereby differentially governing homeostatic, short-term, and long term synaptic plasticity throughout the brain. Finally, we discuss how cell type- and synapse-specific refinement of endocannabinoid signaling may explain the characteristic behavioral effects of cannabinoids. PMID- 22524787 TI - The attention system of the human brain: 20 years after. AB - Here, we update our 1990 Annual Review of Neuroscience article, "The Attention System of the Human Brain." The framework presented in the original article has helped to integrate behavioral, systems, cellular, and molecular approaches to common problems in attention research. Our framework has been both elaborated and expanded in subsequent years. Research on orienting and executive functions has supported the addition of new networks of brain regions. Developmental studies have shown important changes in control systems between infancy and childhood. In some cases, evidence has supported the role of specific genetic variations, often in conjunction with experience, that account for some of the individual differences in the efficiency of attentional networks. The findings have led to increased understanding of aspects of pathology and to some new interventions. PMID- 22524788 TI - Under pressure: cellular and molecular responses during glaucoma, a common neurodegeneration with axonopathy. AB - Glaucoma is a complex neurodegenerative disorder that is expected to affect 80 million people by the end of this decade. Retinal ganglion cells (RGCs) are the most affected cell type and progressively degenerate over the course of the disease. RGC axons exit the eye and enter the optic nerve by passing through the optic nerve head (ONH). The ONH is an important site of initial damage in glaucoma. Higher intraocular pressure (IOP) is an important risk factor for glaucoma, but the molecular links between elevated IOP and axon damage in the ONH are poorly defined. In this review and focusing primarily on the ONH, we discuss recent studies that have contributed to understanding the etiology and pathogenesis of glaucoma. We also identify areas that require further investigation and focus on mechanisms identified in other neurodegenerations that may contribute to RGC dysfunction and demise in glaucoma. PMID- 22524789 TI - Circuits for skilled reaching and grasping. AB - From an evolutionary perspective, it is clear that basic motor functions such as locomotion and posture are largely controlled by neural circuitries residing in the spinal cord and brain-stem. The control of voluntary movements such as skillful reaching and grasping is generally considered to be governed by neural circuitries in the motor cortex that connect directly to motoneurons via the corticomotoneuronal (CM) pathway. The CM pathway may act together with several brain-stem systems that also act directly with motoneurons. This simple view was challenged by work in the cat, which lacks the direct CM system, showing that the motor commands for reaching and grasping could be mediated via spinal interneurons with input from the motor-cortex and brain-stem systems. It was further demonstrated that the spinal interneurons mediating the descending commands for reaching and grasping constitute separate and distinct populations from those involved in locomotion and posture. The aim of this review is to describe populations of spinal interneurons that are involved in the control of skilled reaching and grasping in the cat, monkey, and human. PMID- 22524790 TI - Theoretical insights into pyridinium-based photoelectrocatalytic reduction of CO2. AB - The role of pyridinium cations in electrochemistry has been believed known for decades, and their radical forms have been proposed as key intermediates in modern photoelectrocatalytic CO(2) reduction processes. Using first-principles density functional theory and continuum solvation models, we have calculated acidity constants for pyridinium cations and their corresponding pyridinyl radicals, as well as their electrochemical redox potentials. Contrary to previous assumptions, our results show that these species can be ruled out as active participants in homogeneous electrochemistry. A comparison of calculated acidities and redox potentials indicates that pyridinium cations behave differently than previously thought, and that the electrode surface plays a critical (but still unknown) role in pyridinium reduction. This work substantially alters the mechanistic view of pyridinium-catalyzed photoelectrochemical CO(2) reduction. PMID- 22524791 TI - Gender differences on the semantic flanker task using transposed-letter target words. AB - Previous research has demonstrated that men and women are differentially influenced by irrelevant distractors. Other lines of evidence have suggested that increasing the perceptual load of a task reduces distractor interference for participants generally. The present study examined these effects using a semantic version of the flanker task; participants made speeded responses to category target words that were flanked by irrelevant distractors. The response mapping between the target and flanker words was either congruent (mapped to the same motor response) or incongruent (target word mapped to a different motor response to that of the flankers). Target words were presented either normally (e.g., table: low perceptual load) or with the beginning letters transposed (e.g., atble: high perceptual load). The results revealed that women showed a larger congruency effect than men but this was not due to greater interference on incongruent trials. While men and women made faster responses to normal than to transposed target words, this was similar in magnitude. The magnitude of the flanker effect for normal and transposed target words was significantly correlated in men but not in women. These findings are consistent with the view that women may process target words to a deeper level than men and therefore may engage in more conflict monitoring then men. PMID- 22524792 TI - Oxygen radical-mediated oxidation reactions of an alanine peptide motif - density functional theory and transition state theory study. AB - BACKGROUND: Oxygen-base (O-base) oxidation in protein backbone is important in the protein backbone fragmentation due to the attack from reactive oxygen species (ROS). In this study, an alanine peptide was used model system to investigate this O-base oxidation by employing density functional theory (DFT) calculations combining with continuum solvent model. Detailed reaction steps were analyzed along with their reaction rate constants. RESULTS: Most of the O-base oxidation reactions for this alanine peptide are exothermic except for the bond-breakage of the Calpha-N bond to form hydroperoxy alanine radical. Among the reactions investigated in this study, the activated energy of OH alpha-H abstraction is the lowest one, while the generation of alkylperoxy peptide radical must overcome the highest energy barrier. The aqueous situation facilitates the oxidation reactions to generate hydroxyl alanine peptide derivatives except for the fragmentations of alkoxyl alanine peptide radical. The Calpha-Cbeta bond of the alkoxyl alanine peptide radical is more labile than the peptide bond. CONCLUSION: the rate determining step of oxidation in protein backbone is the generation of hydroperoxy peptide radical via the reaction of alkylperoxy peptide radical with HO2. The stabilities of alkylperoxy peptide radical and complex of alkylperoxy peptide radical with HO2 are crucial in this O-base oxidation reaction. PMID- 22524793 TI - A peptidomimetic tight junction modulator to improve regional analgesia. AB - The paracellular flux of solutes through tissue barriers is limited by transmembrane tight junction proteins. Within the family of tight junction proteins, claudin-1 seems to be a key protein for tightness formation and integrity. In the peripheral nervous system, the nerve fibers are surrounded with a barrier formed by the perineurium which expresses claudin-1. To enhance the access of hydrophilic pharmaceutical agents via the paracellular route, a claudin 1 specific modulator was developed. For this purpose, we designed and investigated the claudin-1 derived peptide C1C2. It transiently increased the paracellular permeability for ions and high and low molecular weight compounds through a cellular barrier model. Structural studies revealed a beta-sheet potential for the functionality of the peptide. Perineurial injection of C1C2 in rats facilitated the effect of hydrophilic antinociceptive agents and raised mechanical nociceptive thresholds. The mechanism is related to the internalization of C1C2 and to a vesicle-like distribution within the cells. The peptide mainly colocalized with intracellular claudin-1. C1C2 decreased membrane localized claudin-1 of cells in culture and in vivo in the perineurium of rats after perineurial injection. In conclusion, a novel tool was developed to improve the delivery of pharmaceutical agents through the perineurial barrier by transient modulation of claudin-1. PMID- 22524794 TI - Inpatient rehabilitation following stroke: amount of therapy received and associations with functional recovery. AB - PURPOSE: Canada's Best Practice Recommendations for Stroke Care state that a minimum of one hour per day of each of the relevant core therapies be provided to patients admitted for inpatient rehabilitation. We examined whether this standard was met on a single, specialized stroke rehabilitation unit and if amount of therapy was an independent contributor to functional improvement. METHODS: One hundred and twenty-three, consecutive patients admitted to a 30-bed stroke rehabilitation program over a 6-month period with the confirmed diagnosis of stroke, were included. Workload measurement data were used to estimate the amount of therapy that patients received from core therapists during their inpatient stay. A multivariable model to predict Functional Independence Measure (FIM) gains achieved was also developed using variables that were significantly correlated with functional gain on univariate analysis. RESULTS: On average, patients received 37 min of active therapy from both physiotherapists (PT) and occupational therapists (OT) and 13 min from speech-language pathologists per day. Admission FIM, length of stay, total OT and PT therapy time (hrs) were significantly correlated with FIM gain. In the final model, which explained 35% of the variance, admission FIM score and total amount of occupational therapy (OT) emerged as significant predictors of FIM gain. CONCLUSIONS: Patients admitted to a specialized rehabilitation unit received an average of 37 min a day engaged in therapeutic activities with both occupational and physical therapists. Although this value did not reach the standard of one hour, total amount of OT time contributed significantly to gains in FIM points during hospital stay. PMID- 22524795 TI - Six-minute walk distance and work relationship with incremental treadmill cardiopulmonary exercise test in COPD. AB - INTRODUCTION: Cardiopulmonary exercise testing (CPET) is increasingly used to evaluate the overall impact of the illness on patients with chronic obstructive pulmonary disease (COPD). While laboratory tests of exercise performance are costly, the 6-min walk test (6-MWT) can be more easily performed. Although the main outcome commonly used in this field test is the distance walked in 6 min (6 MWD), this measure does not account for differences in body weight. Previous studies showed a good correlation between the work performed during the 6-MWT with incremental cycling CPET, an exercise modality more associated with quadriceps fatigability and with lower peak oxygen consumption than incremental walking tests. OBJECTIVE: Evaluate the correlation between the 6-MWD and its derivative body weight-walking distance product, an estimation of the work performed during the 6-MWT, with peak from a treadmill CPET. METHODS: Thirty COPD patients [forced expiratory volume in 1 s (FEV1) = 39 +/- 13%; peak predicted] performed CPET to the limit of tolerance on a treadmill and 6-MWT, 48 h apart.6 MWD and work were correlated to resting and exercise functional variables. RESULTS: The work of walking during the 6-MWT provided greater associations with peak than observed with 6-MWD. This was the case for FEV1, forced vital capacity, inspiratory capacity, lung diffusion capacity for carbon monoxide, peak , carbon dioxide output, minute ventilation and double product (r = 0.57, r = 0.57, r = 0.73, r = 0.7, r = 0.75, r = 0.65, r = 0.51 and r = 0.4, respectively; all P < 0.05). CONCLUSION: A better association was found between the work estimated from the 6-MWT and peak achieved during CPET, in this case with a treadmill, than the 6-MWD alone. PMID- 22524796 TI - Outcome of singleton pregnancy in women >= 45 years old: a retrospective cohort study. AB - OBJECTIVE: To investigate prematurity rate in women aged >= 45 carrying a singleton pregnancy. Other maternal and neonatal outcomes are also described. DESIGN: Retrospective cohort study. SETTING: Women delivering a singleton pregnancy at a single tertiary medical center. POPULATION: The study included all women aged 45 years and over who delivered at 20 weeks gestation or beyond over a 9-year period from May 2000 to May 2009. METHODS: Women aged 45 years and over were identified. The study group was compared to a control group of women <40 years with singleton pregnancies conceived by in vitro fertilization (IVF) who delivered during the same time period. MAIN OUTCOME MEASURE(S): Maternal complications during pregnancy and neonatal outcome. RESULTS: During the study period 278 women >= 45 years delivered a singleton pregnancy. The control group included 304 women. The rate of delivery before 37 weeks as well as before 32 weeks were very high in our study group (18.7 vs. 10.9%, p = 0.009 and 5.4 vs. 2.0%, p = 0.04, respectively). In multivariate analysis, older maternal age was not independently related to prematurity. Chronic hypertension (HTN) was found to be a major risk factor associated with prematurity in advanced maternal age. CONCLUSIONS: Women >= 45-years-old with a singleton pregnancy carry a higher risk of maternal and perinatal complications. Preterm birth is a significant complication in this age group and is associated with preexisting chronic HTN. PMID- 22524797 TI - Clinical application of the adenosine triphosphate-based response assay in intravesical chemotherapy for superficial bladder cancer. AB - OBJECTIVE: To investigate correlations between adenosine triphosphate chemotherapy response assay (ATP-CRA) and clinical outcomes after ATP-CRA-based chemotherapy for drug selection in patients receiving intravesical chemotherapy to prevent recurrence of superficial bladder cancer after surgery. METHODS: The chemosensitivities of 12 anticancer drugs were evaluated, including 5-Fu ADM, and EPI, using ATP-CRA and primary tumor cell culture in 54 patients. In addition, a further 58 patients were treated according to clinical experience. Differences in post-chemotherapeutical effects between drug sensitivity assay and experience groups were compared. RESULTS: The evaluable rate of the test was 96.3%, the clinical effective rate was 80.8%, the sensitivity rate was 97.6% (41/42), the specificity was 20%, the total predicting accuracy was 74.3%, the positive predictive value was 83.7% (41/49), the negative predictive value was 66.7% (2/3); in the drug sensitivity test group, the clinical effective rate was 80.8%, the experience group response rate was 63.8%, with a significant difference in clinical effects between the ATP-based sensitivity and experience groups (chi2 =7.0153, P<0.01). CONCLUSION: ATP-CRA is a stable, accurate and potentially practical chemosensitivity test providing a predictor of chemotherapeutic response in patients with superficial bladder cancer. PMID- 22524798 TI - The socioeconomic burden of cancer in member countries of the Association of Southeast Asian Nations (ASEAN)--stakeholder meeting report. AB - The ACTION (Asean CosTs In ONcology) Study will be one of the largest observational studies of the burden of cancer ever conducted in Asia. The study will involve 10,000 newly diagnosed patients with cancer and will be carried out across eight low- and middle income countries within the ASEAN region (Indonesia, Thailand, Malaysia, Cambodia, Myanmar, Viet Nam, Laos and the Philippines). Patients will be interviewed three times over 12 months to assess their health, use of health care services, out of pocket costs related to their illness, social and quality of life issues. The project is a collaboration between the George Institute for Global Health, the ASEAN Foundation and Roche. The aim of the study is to assess the health and socioeconomic impact of cancer on patients in ASEAN communities, and the factors that may impact on these outcomes. PMID- 22524799 TI - The burden of cancer in member countries of the Association of Southeast Asian Nations (ASEAN). AB - This paper presents the most recent data on cancer rates and the burden of cancer in the ASEAN region. Epidemiological data were sourced from GLOBOCAN 2008 and disability adjusted life years (DALYs) lost were estimated using the standard methodology developed within the World Health Organization's Global Burden of Disease study. Overall, it was estimated there were over 700,000 new cases of cancer and 500,000 cancer deaths in ASEAN in the year 2008, leading to approximately 7.5 million DALYs lost in one year. The most commonly diagnosed cancers were lung (98,143), breast (86,842) and liver cancers (74,777). The most common causes of cancer death were lung cancer (85,772), liver cancer (69,115) and colorectal cancer (44,280). The burden of cancer in terms of DALYs lost was highest in Laos, Viet Nam and Myanmar and lowest in Brunei, Singapore and the Philippines. Significant differences in the patterns of cancer from country to country were observed. Another key finding was the major impact played by population age distribution on cancer incidence and mortality. Cancer rates in ASEAN are expected to increase with ageing of populations and changes in lifestyles associated with economic development. Therefore, ASEAN member countries are strongly encouraged to put in place cancer-control health care policies, focussed on strengthening the health systems to cope with projected increases in cancer prevention, treatment and management needs. PMID- 22524800 TI - Socioeconomic impact of cancer in member countries of the Association of Southeast Asian Nations (ASEAN): the ACTION study protocol. AB - Cancer can be a major cause of poverty. This may be due either to the costs of treating and managing the illness as well as its impact upon people's ability to work. This is a concern that particularly affects countries that lack comprehensive social health insurance systems and other types of social safety nets. The ACTION study is a longitudinal cohort study of 10,000 hospital patients with a first time diagnosis of cancer. It aims to assess the impact of cancer on the economic circumstances of patients and their households, patients' quality of life, costs of treatment and survival. Patients will be followed throughout the first year after their cancer diagnosis, with interviews conducted at baseline (after diagnosis), three and 12 months. A cross-section of public and private hospitals as well as cancer centers across eight member countries of the Association of Southeast Asian Nations (ASEAN) will invite patients to participate. The primary outcome is incidence of financial catastrophe following treatment for cancer, defined as out-of-pocket health care expenditure at 12 months exceeding 30% of household income. Secondary outcomes include illness induced poverty, quality of life, psychological distress, economic hardship, survival and disease status. The findings can raise awareness of the extent of the cancer problem in South East Asia and its breadth in terms of its implications for households and the communities in which cancer patients live, identify priorities for further research and catalyze political action to put in place effective cancer control policies. PMID- 22524802 TI - Psychological impact of health risk appraisal of Korean women at different levels of breast cancer risk: neglected aspect of the web-based cancer risk assessment tool. AB - OBJECTIVE: Health risk appraisal is often utilized to modify individual's health behavior, especially concerning disease prevention, and web-based health risk appraisal services are being provided to the general public in Korea. However, little is known about the psychological effect of the health risk appraisal even though poorly communicated information by the web-based service may result in unintended adverse health outcomes. This study was conducted to explore the psychological effect of health risk appraisal using epidemiological risk factor profile. METHODS: We conducted a randomized trial comparing risk factor list type health risk appraisal and risk score type health risk appraisal. We studied 60 women aged 30 years and older who had no cancer. Anxiety level was assessed using the Spielberger State-Trait Anxiety Inventory YZ. RESULTS: The results of multivariate analysis showed that risk status was the independent predictors of increase of state anxiety after health risk appraisal intervention when age, education, health risk appraisal type, numeracy, state anxiety, trait anxiety, and health risk appraisal type by risk status interaction was adjusted. Women who had higher risk status had an odd of having increased anxiety that was about 5 times greater than women who had lower risk status. CONCLUSIONS: Our findings indicate that communicating the risk status by individual health risk appraisal service can induce psychological sequelae, especially in women having higher risk status. Hospitals, institutes, or medical schools that are operating or planning to operate the online health risk appraisal service should take side effects such as psychological sequelae into consideration. PMID- 22524801 TI - Natural products for cancer-targeted therapy: citrus flavonoids as potent chemopreventive agents. AB - Targeted therapy has been a very promising strategy of drug development research. Many molecular mechanims of diseases have been known to be regulated by abundance of proteins, such as receptors and hormones. Chemoprevention for treatment and prevention of diseases are continuously developed. Pre-clinical and clinical studies in chemoprevention field yielded many valuable data in preventing the onset of disease and suppressing the progress of their growth, making chemoprevention a challenging and a very rational strategy in future researches. Natural products being rich of flavonoids are those fruits belong to the genus citrus. Ethanolic extract of Citrus reticulata and Citrus aurantiifolia peels showed anticarcinogenic, antiproliferative, co-chemotherapeutic and estrogenic effects. Several examples of citrus flavonoids that are potential as chemotherapeutic agents are tangeretin, nobiletin, hesperetin, hesperidin, naringenin, and naringin. Those flavonoids have been shown to possess inhibition activity on certain cancer cells' growth through various mechanisms. Moreover, citrus flavonoids also perform promising effect in combination with several chemotherapeutic agents against the growth of cancer cells. Some mechanisms involved in those activities are through cell cycle modulation, antiangiogenic effect, and apoptosis induction. Previous studies showed that tangeretin suppressed the growth of T47D breast cancer cells by inhibiting ERK phosphorylation. While in combination with tamoxifen, doxorubicin, and 5-FU, respectively, it was proven to be synergist on several cancer cells. Hesperidin and naringenin increased cytotoxicitity of doxorubicin on MCF-7 cells and HeLa cells. Besides, citrus flavonoids also performed estrogenic effect in vivo. One example is hesperidin having the ability to decrease the concentration of serum and hepatic lipid and reduce osteoporosis of ovariectomized rats. Those studies showed the great potential of citrus fruits as natural product to be developed as not only the source of co-chemotherapeutic agents, but also phyto-estrogens. Therefore, further study needs to be conducted to explore the potential of citrus fruits in overcoming cancer. PMID- 22524803 TI - Reduced telomere length in colorectal carcinomas. AB - PURPOSE: Telomeres play a key role in the maintenance of chromosome integrity and stability, and telomere shortening is involved in initiation and progression of malignancies. The aim of this study was to determine whether telomere length is associated with the colorectal carcinoma. PATIENTS AND METHODS: A total of 148 colorectal cancer (CRC) samples and corresponding adjacent non-cancerous tissues were evaluated for telomere length, P53 mutation, and cyclooxygenase-2 (COX-2) mutation detected by fluorescent immunohistochemistry. Telomere length was estimated by real-time PCR. Samples with a T/S>1.0 have an average telomere length greater than that of the standard DNA; samples with a T/S<1.0 have an average telomere length shorter than that of the standard DNA. RESULTS: Telomeres were shorter in CRCs than in adjacent tissues, regardless of tumor stage and grade, site, or genetic alterations (P=0.004). Telomere length in CRCs also had differences with COX-2 status (P=0.004), but did not differ with P53 status (P=0.101), tumor progression (P=0.244), gender (P=0.542), and metastasis (0.488). There was no clear trend between T/S optimal cut-off values (<1 or > 1) and colorectal tumor progression, metastasis, gender, P53 and COX-2 status. CONCLUSION: These findings suggesting that telomere shortening is associated with colorectal carcinogenesis but does not differ with tumor progression, gender, and metastasis. PMID- 22524804 TI - Video-assisted thoracic surgery versus thoracotomy for non-small-cell lung cancer. AB - Video-assisted thoracic surgery (VATS) has been recommended as more optimal surgical technique than traditional thoracotomy for lobectomy in lung cancer, but it is not well defined. Here, we compared VATS and traditional thoracotomy based on clinical data. From November 2008 to November 2010, 180 patients underwent lobectomy for non-small-cell lung cancer (NSCL) identified by computerized tomography. Of them, 83 cases were performed with VATS and 97 by thoracotomy. Clinical parameters, consisting of blood loss, operating time, number of lymph node dissection, days of pleural cavity drainage, and length of stay were recorded and evaluated with t test. No significant difference was observed between the VATS and thoracotomy groups in the average intraoperative blood loss, number of lymph node dissections, and days of pleural cavity drainage. While the average operating time in the VATS group was significantly longer than that in thoracotomy group, recurrence was only present in one case, as opposed to 7 cases in the thoracotomy group In conclusion, similar therapeutic effects were demonstrated in VATS and thoracotomy for NSCL. However, VATS lobectomy was associated with fewer complications, recurrence and shorter length of stay. PMID- 22524805 TI - CpG island methylation profile of estrogen receptor alpha in Iranian females with triple negative or non-triple negative breast cancer: new marker of poor prognosis. AB - One decade early onset of the breast cancer in Iranian females was reported but the basis of the observed difference has remained unclear and difference in gene silencing by epigenetic processes is suggested. Hence, this study was sought to map the methylation status of ER gene CpG islands and its impact on clinicopathological factors of triple negative and non-triple negative ductal cell carcinoma of the breast in Iranian females. Surgically resected formalin fixed paraffin-embedded breast tissues from sixty Iranian women with confirmed invasive ductal carcinoma were assessed by methylation-specific PCR using primer sets encompassing some of the 29 CpGs across the ER gene CpG island. The estrogen and progesterone receptors, Her-2 overexpression, and nuclear accumulation of P53 were examined using immunohistochemistry (IHC). Methylated ER3, ER4, and ER5 were found in 41.7, 11.3, and 43.3% of the samples, respectively. Significantly higher methylation of ER4 was found in the tumors with nuclear accumulation of P53, and significantly higher methylation of ER5 was found in patients with lymph node involvement and tumor with bigger size or higher grades. Furthermore, significantly higher rate of ER5 methylation was found in patients with Her-2+ tumors and in postmenopausal patients with ER-, PgR-, or ER-/PgR- tumors. However, no significant difference in ERs methylation status was found between triple negative and non-triple negative tumors in pre- and postmenopausal patients. Findings revealed that aberrant hypermethylation of ER-a gene frequently occur in Iranian women with invasive ductal cell carcinoma of the breast. However, methylation of different CpG islands produced a diverse impact on the prognosis of breast cancer, and ER5 was found to be the most frequently methylated region in the Iranian women, and could serve as a marker of poor prognosis. PMID- 22524806 TI - Breast cancer subtypes identified by the ER, PR and HER-2 status in Thai women. AB - Expression of estrogen-receptor (ER), progesterone-receptor (PR) and HER-2 has recently been linked with various breast cancer subtypes identified by gene microarray. This study aimed to document breast cancer subtypes based on ER, PR and HER-2 status in Thai women, where expression of these subtypes may not be similar to those evident in Western women. During 2009 to 2010, histological findings from 324 invasive ductal carcinomas (IDC) at Siriraj Hospital were studied. Various subtypes of IDC were identified according to expression of ER, PR and HER-2: luminal-A (ER+;PR+/-;HER-2-), luminal-B (ER+;PR+/-;HER-2+), HER-2 (ER-;PR- ;HER-2+) and basal-like (ER-;PR-;HER-2-). As well, associations of tumor size, tumor grade, nodal status, angiolymphatic invasion (ALI), multicentricity and multifocality with different breast cancer subtypes were studied. Of 324 IDCs, 143 (44.1%), 147 (45.4%), 15 (4.6%) and 12 (3.7%) were T1, T2, T3 and T4, respectively. Most tumors were grade 2 (54.9%) and had no nodal involvement (53.4%). According to ER, PR and HER-2 status, 192 (59.3%), 40 (12.3%), 43 (13.3%) and 49 (15.1%) tumors were luminal-A, luminal-B, HER-2 and basal-like subtypes. HER-2 subtype presented with large tumor (p=0.04, ANOVA). Luminal-A IDC was associated with single foci (p<0.01, chi2). HER-2 and basal-like subtypes were likely to have high tumor grade (p<0.01, chi2). In addition, HER-2 subtype had higher number of nodal involvement (p=0.048, chi2). In conclusion, the luminal-A subtype accounted for the majority of IDCs in Thai women. Percentages of HER-2 and basal-like IDCs were high, compared with a recent study from the USA. The HER-2 subtype was related with high nodal invasion. The findings may highlight biological differences between IDCs occurring in Asian and Western women. PMID- 22524807 TI - Efficacy and toxicity of gemcitabine plus docetaxel combination as a second line therapy for patients with advanced stage soft tissue sarcoma. AB - PURPOSE: To assess the safety and efficacy of a gemcitabine plus docetaxel regimen as a second line therapy for patients with advanced soft tissue sarcoma (STS) resistant to doxorubicin and ifosfamide-based therapy. PATIENTS AND METHODS: Medical records of 64 patients with advanced STS who received gemcitabine plus docetaxel regimen as a second line treatment between May 2006 and June 2011 were examined. All patients had been previously treated with doxorubicin plus ifosfamide-based regimen at first line setting. Patients received gemcitabine 900 mg/m2 on days one and eight intravenously over 90 minutes, followed by docetaxel 75 mg/m2 on day eight intravenously over one hour. Cycles were repeated every 3 weeks. RESULTS: The male-to-female ratio was 37/27 and the median age was 44 years (range; 19-67 years). Objective responses were observed in 13 (20.3%) patients (2 CR, 11 PR) and stable disease in 21 (32.8%). Total clinical benefit (CR+PR+SD) was observed in 34 (53.1%). Median overall survival (OS) was 18 months (95% confidence interval (CI):12.1-23.9) and Median time to progression (TTP) was 4.8 months (95% CI: 3.6-6). A total of 243 cycles of chemotherapy were administered. The median number of cycle was 3 (range; 1 11). The most common grade 3-4 hematologic toxicity was neutropenia (35.9%). The most common nonhematologic toxicities consisted of nausea/vomiting (37.5%), mucositis (32.8%), peripheral neuropathy (29.7%), and fatigue (26%). There was no toxicity-related death. CONCLUSION: The combination of gemcitabine plus docetaxel is an active and tolerable regimen as a second line therapy for patients with advanced soft tissue sarcoma who have failed doxorubicin and ifosfamide-based therapy. PMID- 22524808 TI - p16(INK4a) is a useful marker of human papillomavirus integration allowing risk stratification for cervical malignancies. AB - The present study was conducted to assess utility of p16(INK4a) immunopositivity as a surrogate marker for genomic integration of high-risk human papillomavirus infection (hrHPV). A total of 29 formalin-fixed, paraffin-embedded cervical low grade squamous intraepithelial lesions (LSILs), 27 high-grade squamous intraepithelial lesions (HSILs) and 53 invasive squamous cell carcinomas (SCCs), histologically-diagnosed between 1st January 2006 to 31st December 2008 at the University of Malaya Medical Centre were stained for p16(INK4a) (CINtec Histology Kit (REF 9511, mtm laboratories AG, Heidelberg, Germany). Immunopositvity was defined as diffuse staining of the squamous cell cytoplasm and or nucleus (involving > 75% of the intraepithelial lesions or SCCs). Staining of basal and parabasal layers of intraepithelial lesions was pre-requisite. One (3.4%) LSIL, 24 (88.9%) HSIL and 46 (86.8%) SCC were p16(INK4a) immunopositive. All normal squamous epithelium did not express p16(INK4). p16(INK4a) expression was significantly lower (p<0.05) in LSIL compared with HSIL and SCC with no difference in expression between HSIL and SCC.The increased p16(INK4a) immunopositivity in HSIL and SCC appears in line with the integrated existence of the hrHPV and may provide more insightful information on risk of malignant transformation of cervical squamous intraepithelial lesions than mere hrHPV detection. PMID- 22524809 TI - HIF-1alpha siRNA and cisplatin in combination suppress tumor growth in a nude mice model of esophageal squamous cell carcinoma. AB - INTRODUCTION: The esophagus squamous cell carcinoma (ESCC) is one of the most deadly malignances, and a current challenge is the development of effective therapeutic agents. Our present work addressed the effect of HIF-1alpha siRNA alone or in combination with cisplatin on the growth of ESCC in nude mice. MATERIALS AND METHODS: Xenografts were established by inoculating ESCC TE-1 cells in nude mice, and transplanted tumors were treated with HIF-1alpha siRNA, cisplatin alone or together. Growth was assessed by measuring tumor volume. HIF 1alpha mRNA and protein expression were detected using RT-PCR and immunohistochemistry, respectively. Apoptosis of ESCC TE-1 cells was analyzed by flow cytometry. RESULTS: In our nude mice model, HIF-1alpha siRNA effectively inhibited the growth of transplanted ESCC, downregulating HIF-1alpha mRNA and protein expression, and inducing ESCC TE-1 cell apoptosis. Notably when combinated with cisplatin, HIF-1alpha siRNA showed synergistic interaction in suppressing tumor growth. Furthermore, the proportion of apoptotic cells in HIF- 1alpha siRNA plus cisplatin group was significantly higher than that in cisplatin or HIF-1alpha siRNA-treated groups (P<0.05). CONCLUSIONS: Down-regulated HIF 1alpha expression induced by siRNA could effectively suppress the growth of transplanted ESCC in vivo. HIF-1alpha siRNA could enhance the cytotoxicity of cisplatin, which suggests that a combination of these two agents may have potential for therapy of advanced ESCC. PMID- 22524810 TI - Positive effects of soy isoflavone food on survival of breast cancer patients in China. AB - AIM: Soy foods are the major source of isoflavones, which are believed to play important roles in genesis of breast cancer and its progression. We here conducted a prospective study to evaluate the association of soy isoflavone food consumption with breast cancer prognosis. METHODS: A prospective study was performed from January 2004 and January 2006 in China. Trained interviewers conducted face-to-face interviews using a structured questionnaire to collect information on dietary habits and potential confounding factors. The relative risk [hazard ratio (HR)] and 95% CI were calculated from the Cox regression model for all significant predictors from cancer diagnosis to the endpoint of the study (event). RESULTS: After a median follow up of 52.1 months (range, 9-60 months), a total of 79 breast cancer related deaths were recorded in our study, risk being inversely associated with a high intake of soy isoflavone. With an average intake of soy isoflavone above 17.3 mg/day, the mortality of breast cancer can be reduced by about 38-36%. We also found the decreased breast cancer death with high soy protein intake, with a HR (95% CI) of 0.71 (0.52-0.98). Stratified analysis with reference to the ER status, further demonstrated a better prognosis of ER positive breast cancer with a high intake of soy isoflavone (HR 0.59, 0.40 0.93). CONCLUSION: Our study shows the soy food intake is associated with longer survival and low recurrence among breast cancer patients. A cohort study with a larger sample size and long term follow-up is now needed. PMID- 22524811 TI - Long-term prognosis in hepatocellular carcinoma patients after hepatectomy. AB - BACKGROUND: The hepatocellular carcinoma is very common in China. Our aim in this report was to investigate clinical and pathological factors based on the current decade data that could influence prognosis of HCC patients after hepatectomy. METHODS: Between 2002 and 2009, all patients undergoing hepatectomy for HCC were followed up and reviewed retrospectively. Prognostic factors were studied by univariate and multivariate analysis, with Kaplan-Meier and Cox multivariate survival analyses. RESULTS: Complete clinicopathologic and follow-up data were available for 114 patients. The estimated cumulative survival rates at 1, 3, and 5 yr were 84.6%, 60.2% and 51.8%, respectively. On univariate analysis, key prognostic factors were AFP level, GGT level, tumor size, number of tumors, portal vein invasion, liver cirrhosis status and TNM stage. In the multivariate analysis, tumor size, GGT level, liver cirrhosis status and portal vein invasion were significantly associated with patients' prognosis. CONCLUSION: Through follow-up of a relatively large cohort of Chinese patients, tumor size, GGT level, liver cirrhosis status, portal vein invasion were revealed as important factors for long-term survival after hepatectomy. Early diagnosis for tumor and the improvement of liver function before surgery are important ways to improve the prognosis. PMID- 22524812 TI - Zinc and zinc related enzymes in precancerous and cancerous tissue in the colon of dimethyl hydrazine treated rats. AB - Trace element zinc deficiency or excess is implicated in the development or progression of some cancers. The exact role of zinc in the etiology of colon cancer is unclear. To cast light on this question, an experimental model of colon carcinogenesis was applied here. Six week old rats were given sub cutaneous injections of DMH (30 mg/kg body weight) twice a week for three months and sacrificed after 4 months (precancer model) and 6 months (cancer model). Plasma zinc levels showed a significant decrease (p<0.05) at 4 months and a greater significant decrease at 6 months (p<0.01) as compared with controls. In the large intestine there was a significant decrease in tissue zinc levels (p<0.005) and in CuZnSOD, and alkaline phosphatase activity (p<0.05) in the pre-cancerous model and a greater significant decrease in tissue zinc (p<0.0001), and in CuZnSOD and alkaline phosphatase activity (p<0.001), in the carcinoma model. The tissue zinc levels showed a significant decrease in the small intestine and stomach (p<0.005) and in liver (p<0.05) in the cancer model. 87% of the rats in the precancer group and 92% rats in the cancer group showed histological evidence of precancerous lesions and carcinomas respectively in the colon mucosa. This study suggests that the decrease in plasma zinc, tissue zinc and activity of zinc related enzymes are associated with the development of preneoplastic lesions and these biochemical parameters further decrease with progression to carcinoma in the colon. PMID- 22524813 TI - Hepatic angiomyolipoma: contrast patterns with SonoVue-enhanced real-time gray scale ultrasonography. AB - This study was conducted to retrospectively evaluate the pattern of contrast enhancement with SonoVue on gray-scale ultrasonography of hepatic angiomyolipoma (HAML). Imaging features of 33 pathologically proven HAML lesions in 33 patients who underwent baseline ultrasound and contrast-enhanced ultrasonography (CEUS) were assessed retrospectively. All lesions were enhanced in the arterial phase and showed whole-tumor filling in. Thirty-two of 33 (97%) lesions showed early positive enhancement in the arterial phase. Twenty-three of these exhibited isoechoic or hyperechoic features in the portal phase. HAML demonstrate characteristic manifestations with SonoVue-enhanced real-time gray-scale ultrasonography. PMID- 22524814 TI - Norcantharidin anti-angiogenesis activity possibly through an endothelial cell pathway in human colorectal cancer. AB - The present study was based on the unexpected discovery that norcantharidin exerted anti-angiogenesis activity when effects on growth of human colon cancer were studied. The aim was to further verify this finding and explore possible mechanisms using a tumor xenograft model in nude mice. We confirmed that norcantharidin (5 or 15 mg/kg) could inhibit angiogenesis of human colon cancer in vivo. In vitro, crossing river assay, cell adhesion assay and tube formation assay indicated that NCTD could reduce the migration, adhesion and vascular network tube formation ability of HUVECs. At the same time, the expression levels of VEGF and VEGFR-2 proteins which play important roles in angiogenesis were reduced as examined by western blotting analysis. Taken together, the results firstly showed NCTD could inhibit angiogenesis of human colon cancer in vivo, probably associated with effects on migration, adhesion and vascular network tube formation of HUVECs and expression levels of VEGF and VEGFR-2 proteins. PMID- 22524815 TI - Application of MMP-7 and MMP-10 in assisting the diagnosis of malignant pleural effusion. AB - BACKGROUND: Matrix metalloproteinases (MMP) are proteolytic enzymes that are essentially involved in turnover of the extracellular matrix (ECM). The aim was to investigate the diagnostic value of MMP-7 and MMP-10 as tumor markers in pleural effusion (PE) and evaluate the value of combining MMP-7, MMP-10 and carcinoembryonic antigen (CEA) assays as diagnostic aids for malignant cells. MATERIALS AND METHODS: A total of 179 patients with PE (87 malignant and 92 benign) were included in this study. The levels of MMP-7 and MMP-10 were measured using ELISA. RESULTS: Values for MMP-7 and MMP-10 were significantly higher in malignant PE than those in benign PE (P<0.01). Among all variables evaluated, logistic regression found that MMP-7 and MMP-10 were significantly correlated with the presence of malignant disease (P<0.01). Analysis of receiver operating characteristics (ROC) curves showed that the area under the curve of MMP-10 (0.806) was significantly larger than that of MMP-7 (0.771) and CEA (0.789) (P<0.01). With parallel interpretation, the combination of MMP-10 and CEA achieved the higher sensitivity of 94.6%. The combination of MMP-7 and CEA in serial interpretation was able to boost the specificity to 95.7%. The combination of MMP-7, MMP-10 and CEA produced better sensitivity, specificity, PPV and NPV than MMP-7 and MMP-10 alone. CONCLUSION: MMP-7 and MMP-10 in PE may represent helpful adjuncts to conventional diagnostic tools in ruling out malignancy as a probable diagnosis, thus guiding the selection of patients who might benefit from further invasive procedures. PMID- 22524816 TI - p53 exon 4 (codon 72) polymorphism and exon 7 (codon 249) mutation in breast cancer patients in southern region (Madurai) of Tamil Nadu. AB - BACKGROUND: We investigated the association between polymorphisms in the p53 tumor suppressor gene and breast cancer risk in women especially in the Southern part of India. METHODS: Genotyping was performed for 50 breast cancer women and 50 controls to determine the status of p53 exon 4 codon 72 polymorphism and exon 7 codon 249 mutation and their possible role in breast cancer risk. RESULTS: Frequency of Arg/Arg at codon 72 was 18% in controls and 28% in patients, Arg/Pro frequency was 56% and 66%, Pro/Pro genotype was 8% in controls and 8% in patients. No significance was observed for breast cancer risk with either Arg/Arg or Pro/Pro genotype in codon 72 polymorphism. Similarly, mutation analysis of exon 7 codon 249 revealed that 72% of breast cancer patients have mutation, which is not statistically significant. However, there is a strong association between increase in exon 7 codon 249 mutation and exposure to pollution. CONCLUSION: The results suggested that there is no risk for exon 4 with Arg/Arg or Pro/Pro polymorphisms in the p53 gene and there is no strong correlation between breast cancer patients and mutation in exon 7 codon 249 in South Indian women. PMID- 22524817 TI - Outcome of single agent generic gemcitabine in platinum-resistant ovarian cancer, fallopian tube cancer and primary peritoneal adenocarcinoma. AB - Single original gemcitabine is commonly used as salvage treatment in platinum resistant ovarian cancer, fallopian tube cancer and primary peritoneal adenocarcinoma (PPA) with a satisfactory outcome. However, efficacy data fro this regimen are limited. We therefore conducted a retrospective study to evaluate the outcome of patients who received single-agent generic gemcitabine (GEMITA) after development of clinical platinum resistance. The study period was between May 2008 and December 2010. Gemcitabine was administered intravenously in two different schedules: 1,000 mg/m2 on day 1,8, and 15 every 28 days; and on days 1 and 8 every 21 days with the same dosage. Administration was until disease progression was noted. The response rate was evaluated using the Gynecologic Cancer Intergroup (GCIG ) criteria while toxicity was evaluated according to WHO criteria. Sixty-six patients met the inclusion criteria in the study period. Two thirds of them received gemcitabine as the second and third line regimen. The overall response rate was 12.1%. The median progression free survival and overall survival was 2 and 10 months, respectively. With the total 550 courses of chemotherapy, the patients developed grades 3 and 4 hematologic toxicity as follows: anemia, 1.5%; leukopenia, 13.7%; neutropenia, 27.3%; and thrombocytopenia, 3.0%. In conclusion, single agent generic gemcitabine revealed a modest efficacy in patients with platinum-resistant ovarian cancer, fallopian tube cancer and PPA without serious toxicity. PMID- 22524818 TI - Low microsomal epoxide hydrolase expression is associated with bladder carcinogenesis and recurrence. AB - Microsomal epoxide hydrolase (mEH) plays a significant role in the metabolism of numerous xenobiotics and is associated with several forms of cancer. Here, we investigated the role of mEH expression in bladder carcinogenesis, subsequent progression and recurrence. The expression of mEH was analyzed by Western blot in 50 bladder urothelial carcinoma and 20 normal epithelial tissues. There was a significantly higher mEH expression in the normal epithelium (P<0.05) and mEH expression was lower in high stage than in low stage tumors (P<0.05). Further, immunohistochmistry in 106 bladder urothelial carcinoma demonstrated mEH expression to be negatively correlated with histological grade, pT stage and recurrence (P<0.05). These findings suggest the important role of mEH in bladder carcinogenesis, cancer development and recurrence, providing support for efforts to develop mEH-based gene therapy. PMID- 22524819 TI - An integrated approach to worksite tobacco use prevention and oral cancer screening among factory workers in Mumbai, India. AB - BACKGROUND: Tobacco control and cessation interventions are among the most cost effective medical interventions but health systems in low resource countries lack the infrastructure to promote prevention and cessation among tobacco users. Workplace settings have the potential to provide opportunities and access for tobacco prevention interventions. METHODS: This is a single group study evaluating tobacco use prevention and cessation through a structured three stage intervention program for tobacco users comprising education on harmful effects of tobacco, oral cancer screening and behavior therapy for tobacco cessation at the worksite. RESULTS: All the 739 workers who were invited participated in tobacco awareness program and were screened for oral pre cancer lesions. 291 (39.4%) workers were found to be users of tobacco in some form. Education, gender and alcohol use (p<0.0001) were some of the factors associated with tobacco user status. The prevalence of clinical oral precancer lesions among tobacco users was 21.6%. Alcohol consumption (p<0.001), the type of tobacco consumed (p<0.018), personal medical history of chronic diseases (p<0.007) and combined use of alcohol and tobacco (p<0.001) were some factors found to be associated with presence of oral pre cancer lesions. CONCLUSION: An integrated approach for worksite based tobacco use prevention with oral cancer screening program showed good acceptance and participation and was effective in addressing the problem of tobacco consumption among the factory workers. PMID- 22524820 TI - Predictors of quitting tobacco--results of a worksite tobacco cessation service program among factory workers in Mumbai, India. AB - BACKGROUND: Tobacco cessation would provide the most immediate benefits of tobacco control to prevent tobacco related disease morbidity and mortality. METHODS: A tobacco cessation program involving individual and group behavior therapy was implemented in three stages at a worksite. Tobacco quit rates were assessed at the end of each contact session. RESULTS: Out of the 291 tobacco users identified, 224 participated in the tobacco cessation interventions. At the end of three interventions, 38 (17%) users had successfully quit tobacco use. Presence of clinical oral pre-cancer lesion was found to be associated with quitting (p =0.02 ). Also tobacco users with oral pre-cancer lesions were around three times more likely to quit than those with no lesions (OR= 2.70 95% C.I= 1.20 - 6.05). CONCLUSION: Cost effective multi-pronged tobacco cessation approaches, inbuilt into other occupational health and welfare activities, are acceptable and feasible to achieve long term sustainable tobacco cessation programs at worksites. PMID- 22524821 TI - Global school personnel survey among 5200 school personnel in India: comparison of the results for the years 2009 and 2006. AB - BACKGROUND: The results of the Global School Personnel Survey (GSPS) conducted in India in 2009 are compared with 2006 GSPS to assess any change in 2009 on tobacco use and knowledge and attitudes to tobacco use, training and availability of tobacco control teaching material in schools and the existence of school tobacco control policies. METHODS: GSPS is a cross sectional survey conducted twice (2006 and 2009) in entire India. A total of 180 schools were surveyed each time. RESULTS: Of the participating school personnel, 2660 in 2006 and 2575 in 2009, about 95% were teachers and the balance administrators. In 2009, compared to 2006 the prevalence of current smoking of cigarettes (19.6% in 2006 and 10.3% in 2009) and bidis (21.5% in 2006 and 13.9% in 2009) was found to be significantly lower; the percentage of teachers receiving training on preventing youth tobacco use has significantly reduced (16.7% in 2006 and 10.1% in 2009); access of teachers to educational materials on tobacco use and how to prevent its use among youth had not increased (34.6% in 2006 and 37.8% in 2009); there was no change in policy prohibiting tobacco use among students and school personnel; however, ever use of any tobacco on school premises was significantly lower (15.6% in 2006 and 9.6% in 2009). CONCLUSIONS: The prevalence of current smoking (cigarettes/bidis) among school personnel and use of any tobacco on school premises were significantly decreased in 2009 as compared to 2006. Necessary action should be planned to increase the number of teachers trained and the availability of teaching materials on preventing youth tobacco use in order to have effective prevention of tobacco use among students. PMID- 22524822 TI - Validity and reliability of a dish-based, semi-quantitative food frequency questionnaire for Korean diet and cancer research. AB - This study evaluated the validity and reliability of applying a newly developed dish-based, semi-quantitative food frequency questionnaire (FFQ) for Korean diet and cancer research. The subjects in the present study were 288 Korean adults over 30 years of age who had completed two FFQs and four 3-day diet records (DRs) from May 2008 to February 2009. Student's t-tests, Chi-square tests, and Spearman's rank correlation coefficients were used to estimate and compare intakes from different dietary assessment tools. Agreement in quintiles was calculated to validate agreement between the results of the second FFQ (FFQ-2) conducted in February 2009 and the DRs. Median Spearman's correlation coefficients between the intake of nutrients and foods assessed by the FFQ-1 and FFQ-2 were 0.59 and 0.57, respectively, and the coefficients between the intake of nutrients and foods assessed by the FFQ-2 and the DRs were 0.31 and 0.29, respectively. The quintile classifications of same or adjacent quintile for intake of nutrients and foods were 64% and 65%, respectively. Misclassification into opposite quintiles occurred in less than 5% for all dietary factors. Thus this newly-developed, Korean dish-based FFQ demonstrated moderate correspondence with the four 3-day DRs. Its reliability and validity are comparable to those reported in other studies. PMID- 22524823 TI - Mandibular reconstruction with vascularized osseous free flaps: a review of the literature. AB - PURPOSE: This article reviews a few of the commonly used types of vascularized osseous free flaps in maxillofacial reconstruction, which still represents the gold standard of restoration. We also discuss the developing concepts in maxillofacial reconstruction. RECENT FINDINGS: Most of the literature reconfirms the established patterns of reconstruction with the aid of vascularized osseous free flaps. This method of free-tissue transfer is also feasible in cases of osteoradionecrosis or bisphosphonate-related osteonecrosis of the jaw. These flaps are also suitable for prosthetic restoration using osseointegrated dental implants. SUMMARY: Vascularized osseous free flaps still remain the standard of care. Improvements upon the free-tissue transfer method employing vascularized osseous free flaps, such as distraction osteogenesis, tissue engineering, and imaging techniques, currently require further development, but these technologies could lead to improved outcomes of maxillofacial reconstruction in the near future. PMID- 22524824 TI - Distinctions between clinicopathological factors and prognosis of alpha fetoprotein negative and positive hepatocelluar carcinoma patients. AB - Serum alpha-fetoprotein (AFP) is a significant marker for clinical diagnosis and prognosis evaluation in hepatocellular carcinoma (HCC) patients. However, some proportion of liver cancer patients are AFP-negative (AFP <=20 ng/ml). In order to study the differences between clinicopathological factors and prognosis of alpha-fetoprotein negative and positive patients, a total of 114 cases (41 AFP negative and 73 AFP-positive) were selected for our research. By systematically statistical analysis, the results demonstrated that compared with AFP-negative patients, AFP-positive examples were more likely to feature cirrhosis nodules, non-complete neoplasm capsules, and a poor Edmondson-steiner grade. Furthermore, AFP-negative patients demonstrated a favorable long-term prognosis. By univariate analysis and multivariate analysis with Cox's proportional hazards model, multiple tumors were found to be independent risk factors for worse survival of AFP negative patients; however, less tumor-free margins, multiple tumors and Edmondson-steiner grades III/IV, proved to be independent risk factors leading to a poor prognosis of AFP positive cases. Finally, we can infer that high levels of AFP signify a highly malignant tumor and unfavorable prognosis. PMID- 22524825 TI - Novel hydrophilic taxane analogues inhibit growth of cancer cells. AB - In our era there has been several anti-cancer drugs which have undergone both experimental and clinical trials; however, due to their poor solubilities, numerous side effects, insufficient bioavailability and poor compliance, many have resulted into poor outcomes. Therefore, our aim was to investigate the effects of novel hydrophilic taxanes analogues CQMU-0517 and CQMU-0519 on growth of A549 lung, SKVO3 ovary and MCF7 breast carcinoma cell lines. Different concentrations of original paclitaxel, CQMU-0517, original docetaxel and CQMU 0519 were utilized on three cell lines, where cell growth was assessed using cell culture kit-8 and flow cytometry analysis. The results unveiled that CQMU-0517 and CQMU-0519 suppressed cell growth in the three particular cell lines, cell cycle arrest being evident in the G2/M phase. Hence, the results showed that these new taxane analogues have potential and warrant future clinical trials. PMID- 22524826 TI - Methylenetetrahydrofolate reductase gene polymorphisms as predictive and prognostic biomarkers in ovarian cancer risk. AB - Early diagnosis and better prognosis of ovarian cancer is still a challenge. Besides environmental risk factors, genetic factors have established a role in pathogenesis of ovarian cancer. METHODS: A case-control and a prospective study design conducted in 224 ovarian cancer patients and 432 controls in Chinese population. MTHFR C677T genotyping was done by PCR-RFLP. RESULTS: Patients with ovarian cancer is associated with a higher less number of delivery and less frequent oral contraceptive use. When potential confounding factors adjusted logistic regression analysis between cases and controls were performed, significant association was obtained for 677T/T genotype and ovarian cancer (OR=3.13, 95% CI=1.59-5.72). Cox regression survival analysis showed individuals carrying T/T genotype had significantly increased HR for death in ovarian cancer patients (HR=2.86, 95% CI=1.27-7.93). In conclusion, we observed that the MTHFR C677T polymorphism is associated with the susceptibility and survival of ovarian cancer in Chinese population. PMID- 22524828 TI - SULT1A1 Arg213His polymorphism and lung cancer risk: a meta-analysis. AB - BACKGROUND: The SULT1A1 Arg213His polymorphism is reported to be associated with lung cancer risk. However, this relationship remains controversial. For better understanding a meta-analysis was therefore performed. METHODS: An extensive search was performed to identify all case-control studies investigating association between SULT1A1 Arg213His polymorphism and lung cancer risk. The strength was assessed by odds ratio (OR) with the corresponding 95% confidence interval (95%CI). RESULTS: A total of five publications covering 1,669 cases and 1,890 controls were included in this meta-analysis. No significant association between SULT1A1 Arg213His polymorphism and lung cancer risk was observed in overall comparisons in all genetic models (dominant model: OR=1.33, 95%CI=1.00 1.76, P=0.05; additive model: OR=1.30, 95%CI=0.93-1.81, P=0.12; recessive model: OR=1.21, 95%CI=0.89-1.66, P=0.23). However, on subgroup analysis, an elevated risk in mixed populations with variant His allele was revealed in the dominant model (OR=1.66, 95% CI=1.06-2.62, P=0.03). Furthermore, the SULT1A1 Arg213His polymorphism was associated with an increased risk of lung cancer in both females and males in the dominant model (females: OR=1.72, 95%CI=1.29-2.27, P=0.00; males: OR=1.46, 95%CI=1.19-1.78, P=0.00). No significant association between this polymorphism and different smoking status (smokers and non-smokers) and the other ethnicities (Asians and Caucasians) was shown. CONCLUSIONS: The results of this meta-analysis indicate that the SULT1A1 Arg213His polymorphism is not associated with lung cancer risk in Asians and Caucasians, but possible elevation for genotype (GA/AA) in mixed populations and males and females needs further investigation. PMID- 22524827 TI - Posttransplant malignancies in renal transplant recipients: 22-years experience from a single center in Pakistan. AB - OBJECTIVE: To study the incidence, types and distribution pattern of malignant tumors in renal transplant recipients at a single center in Pakistan. MATERIALS AND METHODS: This retrospective study was conducted at Sindh Institute of Urology and Transplantation (SIUT) and included all transplant patients on regular follow up from November 1986 to December 2008. The original biopsy reports and case files of all patients who developed posttransplant malignancies were reviewed and relevant demographic, clinical, radiological, and histopathological data were retrieved and analyzed. SPSS version 10.0 was used for statistical analysis. RESULTS: Over 22 years of study period, 1816 renal transplants were carried out at our center. Among these, 44 patients developed malignancies constituting an overall incidence rate of 2.4%. All patients in this study were males with a mean age of 34.9+/-9.5 years (range: 9 to 60 years). The most common type of malignancy was lymphoma (27 patients, 61.4%), followed by Kaposi's sarcoma (11 patients, 25%) and skin malignancies (3 patients, 6.8%). One case each of adenocarcinoma of the gallbladder, acute myeloid leukemia (AML), conjunctival carcinoma-in-situ and seminoma were also diagnosed. CONCLUSION: Posttransplant malignancies occurring in our renal transplant recipients show different incidence rates and patterns as compared with western studies. PMID- 22524829 TI - Oral and pharyngeal cancer among the Arab population in Israel from 1970 to 2006. AB - BACKGROUND: Israeli Arabs are considered as a developing society characterized by poverty and high levels of smoking among men. The purpose of this study was to describe their incidence, mortality and survival rates for oral and pharyngeal cancer between the years 1970-2006. Studies such as this in the Arab world, where the population is almost the same as the Arab population in Israel, are rare. METHODS: The incidence and survival data were derived from all relevant registered data at the National Cancer Registry. The group of lesions included cancer of the lips, tongue, buccal mucosa, floor of the mouth, salivary glands, gums, palate and pharynx. Morphological description was according to WHO classification. RESULTS: Most diagnosed patients were male. The mean age was 54.4 years, and mean years of survival were 3.83. The oropharynx was the most common site (28.3%) while the palate was the least frequent (3.12%). Squamous cell carcinoma (SCC) was the most common histological feature (66.3%), while basal cell carcinoma (BCC) was the least (3.9%). The overall 5 years survival rate was 59.4%, this being highest for BCC (82.1%), while SCC was significantly lower (56.2%) (p<0.001). Lip cancers survived better than other sites. CONCLUSIONS: Data from this society are similar to other developing societies in the majority of the results. The incidence of oral and pharyngeal cancer is lower among the Arab population, in comparison to the Jewish population in Israel. PMID- 22524830 TI - MicroRNAs and metastasis-related gene expression in Egyptian breast cancer patients. AB - AIM AND BACKGROUND: MicroRNAs (miRNAs) are a class of naturally occurring small noncoding RNAs that regulate gene expression, cell growth, differentiation and apoptosis by targeting mRNAs for translational repression or cleavage. The present study was conducted to study miRNAs in Egyptian breast cancer (BC) and their relation to metastasis, tumor invasion and apoptosis in addition to their association with the ER and PR statuses. METHODS: Real Time RT-PCR was performed to identify the miRNA expression level of eight miRNAs and eight metastatic related genes in 40 breast cancer samples and their adjacent non-neoplastic tissues. The expression levels of each miRNA relative to U6 RNA were determined. Also, miRNA expression profiles of the BC and their corresponding ANT were evaluated. RESULTS: The BC patients showed an up-regulation in miRNAs (mir-155, mir-10, mir-21 and mir-373) with an upregulation in MMP2, MMp9 and VEGF genes. We found down regulation in mir-17p, mir-126, mir-335, mir-30b and also TIMP3, TMP1 and PDCD4 genes in the cancer tissue compared to the adjacent non-neoplastic tissues. Mir -10b, mir -21, mir-155 and mir373 and the metastatic genes MMP2, MMP9 and VEGF were significantly associated with an increase in tumor size (P<0.05). No significant difference was observed between any of the studied miRNAs regarding lymph node metastasis. Mir-21 was significantly over-expressed in ER-/PR- cases. CONCLUSION: Specific miRNAs (mir-10, mir-21, mir-155, mir-373, mir-30b, mir-126, mir-17p, mir-335) are associated with tumor metastasis and other clinical characteristics for BC, facilitating identification of individuals who are at risk. PMID- 22524831 TI - Whole genome analysis of human papillomavirus type 16 multiple infection in cervical cancer patients. AB - The characterization of the whole genome of human papillomavirus type 16 (HPV16) from cervical cancer specimens with multiple infections in comparison with single infection samples as the oncogenic potential of the virus may differ. Cervical carcinoma specimens positive for HPV16 by PCR and INNO-LiPA were randomly selected for whole genome characterization. Two HPV16 single infection and six HPV16 multiple infection specimens were subjected to whole genome analysis by using conserved primers and subsequent sequencing. All HPV16 whole genomes from single infection samples clustered in the European (E) lineage while all multiple infection specimens belonged to the non-European lineage. The variations in nucleotide sequences in E6, E7, E2, L1 and Long control region (LCR) were evaluated. In the E6 region, amino acid changes at L83V were related to increased cancer progression. An amino acid variation N29S within the E7 oncoprotein significantly associated with severity of lesion was also discovered. In all three domains of the E2 gene non synonymous mutations were found. The L1 region showed various mutations which may be related to conformation changes of viral epitopes. Some transcription factor binding sites in the LCR region correlated to virulence were shown on GRE/1, TEF- 1, YY14 and Oct-1. HPV16 European variant prone to single infection may harbor a major variation at L83V which significantly increases the risk for developing cervical carcinoma. HPV16 non European variants prone to multiple infections may require many polymorphisms to enhance the risk of cervical cancer development. PMID- 22524832 TI - Stimulation of dendritic cell maturation and induction of apoptosis in leukemia cells by a heat-stable extract from azuki bean (Vigna angularis), a promising immunopotentiating food and dietary supplement for cancer prevention. AB - Non-toxic stimulation of dendritic cells (DCs), which are central immunomodulators, may aid the prevention of cancer. Furthermore, induction of apoptosis in cancer cells by anticancer agents contributes to the induction of DC maturation. We previously reported that extracts from Pinus parviflora Sieb. et Zucc pine cone and Mucuna seed induce differentiation of mouse bone marrow cells into mature dendritic cells and also induce apoptosis in various human cancer cell lines. In the present study, we screened 31 kinds of edible beans with biological activity similar to that of extracts from pine cone and Mucuna and found that the heat-stable extract from azuki bean (Vigna angula) stimulated differentiation of bone marrow cells into immature DCs with the greatest efficacy. The level of IL-6 produced by sequential treatment of DCs with azuki extract and lipopolysaccharide was the highest among the examined beans. Azuki extract also inhibited the growth of human leukemia U937 cells, leading to induction of apoptosis. These results suggest that azuki bean and its extract are immunopotentiating foods that can be used as a dietary supplement for cancer prevention and immunotherapy. PMID- 22524833 TI - Expression of Tiam1 in lung cancer and its clinical significance. AB - The aim of this study was to analyze T-cell lymphoma invasion and metastasis inducing factor 1 (Tiam1) expression in lung cancer patients. A total of 204 patients with lung cancer tissue lesions were enrolled in the present study, along with 40 cases of normal lung tissue and 40 of normal fetal lung tissue. Tiam1 protein expression level was determined using intensity quantitative analysis, for comparison in lung cancer, metastatic, normal lung, and fetal lung tissue. The positive unit (PU) of Tiam1 was 13.5 +/- 5.42 in lung cancer, 5.67 +/ 1.56 in normal epithelial cells, and 5.89 +/- 1.45 in fetal lung epithelial cells. The value in the lung cancer tissue was significantly higher than that in the normal lung tissue and the fetal lung tissue (P<0.01). The Tiam1 PU values with lymph node metastasis and without lymph node metastasis were 15.2 +/- 4.34 and 12.5 +/- 4.23, respectively, and the difference was statistically significant (P<0.05). The Tiam1 PU values in different tumor, nodes, metastasis (TNM) stages, III-IV period, and I-II phase were 14.7 +/- 4.14 and 11.0 +/- 5.34 (P <0.05). A correlation was found between Tiam1 expression and the age of patient, tumor size, tumor type, and tumor differentiation. Tiam1 protein expression in the lung tumor tissue is significantly higher than that in the normal lung tissue and fetal lung tissue. Tiam1 expression may be closely related to lung cancer development and metastasis. PMID- 22524834 TI - Early efficacy of taxotere and cisplatin chemo-radiotherapy for advanced cervical cancer. AB - The aim of this study was to investigate the early outcome of the taxotere and cisplatin chemoradiotherapy to the advanced cervical cancer. Fifty-six cases with cervical cancer (FIGO II b to IVa) were divided randomly into two groups: radiotherapy alone (28 cases) and radiation plus chemotherapy (TP) group. There was no difference of radiotherapy between the two groups. The RT+C cases who received TP regimen during the radiation, and DDP once weekly injection of vain, according to 20 mg/m2 and taxotere once weekly i.v. according to 35 mg/m2.These regimen were given for 4~5 weeks, and some medicine for vomiting was given to the RT+C cases. Two groups were received an oral medicine MA 160 mg every day during the treatment. The early outcome: the complete remission rate was 64.3% and partial remission rate was 35.7% in RT+C. the complete remission rate was 32.1% and partial remission rate was 39.3% in RT. The total response rate and complete remission of RT+C group was higher than that of the RT group. There was significant difference between the two groups. The taxotere and cisplatin chemoradiotherapy can improve the early outcome of the advanced cervical cancer, the adverse effects being endurable. PMID- 22524835 TI - Genetic variants in interleukin-2 and risk of lymphoma among children in Korea. AB - To estimate the genetic susceptibility for childhood lymphoma, we conducted an association study for 23 cases and 148 controls. Total 1536 tag single nucleotide polymorphisms (SNPs) were selected in 138 candidate gene regions related to immune responses, apoptosis, the cell cycle, and DNA repair. Twelve SNPs were significantly associated with the risk of lymphoma (P(trend)<0.05) in six genes (IL1RN, IL2, IL12RB1, JAK3, TNFRSF13B, and XRCC3). The most significant association was seen for IL2 variant rs2069762 (OR(TG+GG) vs. TT=3.43 (1.29 9.11), P(trend)=0.002, minP=0.005). These findings suggest that common genetic variants in IL2 might play a role in the pathogenesis of childhood lymphoma. PMID- 22524836 TI - Reversion of multidrug resistance by SKI-II in SGC7901/DDP cells and exploration of underlying mechanisms. AB - In order to investigate whether SKI-II could reverse drug resistance and its possible mechanisms, we treated SGC7901/DDP cells with SKI-II or SKI-II in combination with DDP. Then cell growth, apoptosis, micro- morphological changes, and expression of SphK1, P-gp, NF-kB, Bcl-2 and Bax were assessed by MTT assay, flow cytometry, electron microscopy, immunocytochemistry and Western blot assay respectively. SGC7901/DDP cells were insensitive to cisplatin 2.5 mg/L, but when pretreated with SKI-II, their proliferation was inhibited by cisplatin 2.5mg/L significantly, the inhibition rate increasing with time and dose. The apoptosis rate was also significantly elevated. Expression of SphK1 and P-gp was decreased significantly, Pearson correlation analysis showing significant correlation between the two (r=0.595, P<0.01). Expression of NF-kB and Bcl-2 was decreased significantly, while that of Bax was increased, compared to the control group. There were significant correlations between SphK1 and NF-kB(r=0.723, P<0.01), and NF-kB and Bcl-2(r=0.768, P<0.01). All these data indicated that SKI-II could reverse drug resistance of SGC7901/DDP to cisplatin by down-regulating expression of P-gp and up-regulating apoptosis through down-regulation of SphK1. The increased apoptotic sensitivity of SGC7901/ DDP to cisplatin was due to the decreasing proportion of Bcl-2/Bax via down-regulating NF-kB. PMID- 22524837 TI - Knockdown of a proliferation-inducing ligand (PRIL) suppresses the proliferation of gastric cancer cells. AB - PURPOSE: PRIL (proliferation-inducing ligand) is a newly identified member of the tumor necrosis factor (TNF) family and modulates death ligand-induced apoptosis. Here, we investigated the effect of PRIL on cellular characteristics relating to tumor progression in human gastric cancer. METHOD: Recombinant lentivirus containing APRIL siRNA was constructed and then infected MGC803 and SGC7901 gastric cancer cells. MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] colony formation and cell cycle analysis were used to study the effect of APRIL knockdown on gastric cancer cell proliferation. RESULTS: PRIL expression in lentivirus infected cells was significantly reduced as evidenced by quantitative real-time PCR. Cell viability and colony formation of MGC803 and SGC7901 cells were significantly hampered in PRIL knock-down cells. Moreover, the cell cycle was arrested at G2/M phase, elucidating the mechanism underlying the inhibitory effect of siRNA on cell proliferation. CONCLUSIONS: Our study indicated that PRIL functions in promoting cell growth, and lentivirus-mediated PRIL gene knockdown might be a promising strategy in the treatment of gastric cancer. PMID- 22524838 TI - Descriptive epidemiology of primary brain and CNS tumors in Delhi, 2003-2007. AB - The Delhi Population Based Cancer Registry data during the period 2003-2007 were used to describe the epidemiology of primary malignant brain and central nervous system tumors in Delhi. A total of 1989 brain and CNS tumors cases in 1291 males and 698 females were registered during the period 1st January 2003 to 31st December 2007. The age adjusted (world population) incidence rates were 3.9 per 100,000 for males and 2.4 per 100,000 for females. Gliomas were the most frequently reported histology both in males (26.6%) and females (23.2%). A male predominance in incidence was observed for all histological classifications. The rates in Delhi are low compared to the incidences reported from developed countries. PMID- 22524839 TI - Endo-sulfatase Sulf-1 protein expression is down-regulated in gastric cancer. AB - In our recent report on gene expression in gastric cancer we identified the endo sulfatase Sulf-1 gene to be up-regulated in gastric tumors relative to apparently normal (AN), and paired normal (PN) gastric tissue samples. In the present report we investigate the protein expression levels of Sulf-1 gene in gastric tumors, AN and PN samples using tissue microarray (TMA) and immunohistochemistry. Expression data was collected from two sets of TMA's containing replicate sections of tissue samples. Scoring data from TMA set-1 revealed a significant difference in Sulf-1 immunoreactivity between tumors and "normals" (PN and AN) (p-value = 0.001928). Also, Sulf-1 expression in tumors was also significantly different from either PN (p-value = 0.019) or AN (p-value = 0.006) samples. Similar results were obtained from analysis of scoring data from the second set of arrays. Comparison of mRNA expression and protein expression in gastric tumor tissues revealed that in 6/20 (30%) tumor samples showed up-regulated protein expression concordant with over expression of mRNA. However, a discord with mRNA being over-expressed relative to down regulated protein expression was observed in majority 14/20 (70%) of tumor samples. Our study indicates down regulation of Sulf-1 protein expression in gastric tumors relative to PN and AN samples which is discordant with mRNA over expression seen in tumors. PMID- 22524840 TI - Folate intake, methylenetetrahydrofolate reductase polymorphisms in association with the prognosis of esophageal squamous cell carcinoma. AB - AIM: An epidemiological study was conducted based on an esophageal cancer patient's cohort to investigate the association of folate intake and MTHFR C677T polymorphism with the prognosis of esophageal cancer in a Chinese population. METHODS: 167 patients aged 37-75 years who had histological confirmed diagnosis of esophageal squamous cell cancer were collected from Jan. 2006 to Jan. 2008. MTHFR genotypes at the C677T site were analyzed by PCR-based RFLP methods, and the folate intake was computed by multiplying the food intake (in grams) and the folate content (per gram) of food in our questionnaire. RESULTS: We found associations between the prognosis of esophageal cancer and smoking status, T and N stages. Individuals carrying the MTHFR 677CT and TT genotypes showed a shorter survival time than with the CC genotype, with adjusted HRs (95% CI) of 1.20 (0.56 2.15) and 2.29 (1.30-4.28), respectively. Similarly, those carrying MTHFR 677T allele had a 1.86-fold risk of death. A higher folate concentration showed a significant decreased risk of death, with an HR (95% CI) of 0.45 (0.18-0.87). Individuals with high folate intake and the MTHFR 677CC genotype showed a significant decreased risk of esophageal cancer (0.43, 0.25-0.89). CONCLUSION: Our findings supports the hypothesis that high folate intake and active MTHFR C677T polymorphism may exert protective roles in the prognosis of esophageal cancer in the Chinese population. PMID- 22524841 TI - Eryngium foetidum suppresses inflammatory mediators produced by macrophages. AB - OBJECTIVE: This study assessed anti-inflammatory and antioxidant activities of E. foetidum leaf extract on LPS-activated murine macrophages. METHODS: RAW264.7 cells were pretreated with or without E. foetidum extract for 1 h prior to incubation with LPS for 24 h. Anti-inflammatory activity was evaluated with reference to iNOS, COX-2, TNF-alpha and IL-6 gene expression. In addition, NO and intracellular ROS generation were determined by Griess method and fluorescence intensity and activation of MAPKs and IkappaB by Western blotting. RESULTS: Prior treatment with E. foetidum leaf extract inhibited elevation of IL-6, TNF-alpha, iNOS and COX-2, together with their cognate mRNAs in a dose-dependent manner. NO and intracellular ROS contents were similarly reduced. These effects were due to inhibition of LPS-induced phosphorylation of JNK and p38 as well as IkappaB. E. foetidum ethanol extract was shown to contain lutein, beta-carotenes, chlorogenic acid, kaempferol and caffeic acid, compounds known to exert these bioactive properties. CONCLUSIONS: E. foetidum leaf extract possesses suppressive effects against pro-inflammatory mediators. Thus, E. foetidum has a high potential to be used as a food supplement to reduce risk of cancer associated with inflammation. PMID- 22524842 TI - Genetic polymorphisms of DNA repair genes XRCC1 and XRCC3 and risk of colorectal cancer in Chinese population. AB - AIM: The distribution of DNA repair gene XRCC1 and XRCC3 genotypes was used to assess the potential influence of genetic polymorphisms on risk of colorectal cancer, and interactions with other factors. METHODS: A 1:2 matched case-control study was conducted with 485 cases and 970 controls. XRCC1 and XRCC2 genotype polymorphisms were based upon duplex polymerase-chain-reaction with the confronting-two-pairprimer (PCR-CTPP) method. RESULTS: The XRCC1 399Cln allele polymorphism was found to be associated with an increased colorectal cancer risk, while an non-significant inversely association was noted for XRCC3 241Thr/Thr genotype. We also found that individuals with the XRCC1 399 Gln and XRCC3 241Met alleles had an elevated risk, while XRCC3241Thr/Thr was proctective. CONCLUSION: This study is the first to provide evidence of importance of XRCC1 and XRCC3 gene polymorphisms for risk of colorectal cancer in the Chinese population. PMID- 22524843 TI - Oncologists experience with second primary cancer screening: current practices and barriers and potential solutions. AB - OBJECTIVES: Screening for second primary cancer (SPC) is one of the key components of cancer survivorship care. The aim of the present study was to explore oncologists' experience with promoting second primary cancer screening. METHODS: Two focus group interviews were conducted with 12 oncologists of diverse backgrounds. Recurrent issues were identified and placed into thematic categories. RESULTS: Most of the oncologists did not consider SPC screening promotion as their responsibility and did not cover it in routine care. All of the study participants had experience with unexpected SPC cases, and they were under emotional tress. There was no systematic manner of providing SPC screening. Oncologists usually prescribe SPC screening in response to patients' requests, and there was no active promotion of SPC screening. Short consultation time, limited knowledge about cancer screening, no established guideline for SPC screening, and disagreement with patients about oncologists' roles were major barriers to its promotion. An institution-based shared care model was suggested as a potential solution for promoting SPC screening given current oncology practices in Korea. CONCLUSION: Oncologists could not effectively deal with the occurrence of SPC, and they were not actively promoting SPC screening. Lack of knowledge, limited health care resources, and no established guidelines were major barriers for promoting SPC screening to cancer survivors. More active involvement of oncologists and a systematic approach such as shared-care models would be necessary for promoting SPC screening considering increasing number of cancer survivors who are vulnerable. PMID- 22524844 TI - Clinical significance of axin and beta-catenin protein expression in primary hepatocellular carcinomas. AB - The aim of the present research was to investigate clinicopathologic correlations of immunohistochemically- demonstrated axin (axis inhibition) and beta-catenin expression in primary hepatocellular carcinomas (HCCs), in comparison with paraneoplastic, cirrhotic and normal liver tissues. Variation in Axin expression across groups were significant (P < 0.01), correlating with alpha fetoprotein (AFP), HBsAg, cancer plugs in the portal vein, and clinical stage of HCCs(P < 0.05); however, there were no links with sex, age, and tumour size (P > 0.05). Differences in cell membrane beta-catenin expression were also statistically significant (P < 0.01), again correlated with AFP, HBsAg, cancer plugs in the portal vein, and clinical stage in HCCs (P < 0.05) but not with sex, age, and tumour size (P > 0.05). Axin expression levels in tissues with reduced membrane beta-catenin were low (P < 0.05), also being low with nuclear beta-catenin expression (P < 0.05). Axin and beta-catenin may play an important role in the genesis and progression of HCC via the Wnt signal transmission pathway. Simultaneous determination of axin, beta-catenin, AFP, and HBsAg may be useful for early diagnosis, and metastatic and clinical staging of HCCs. PMID- 22524845 TI - Association between the Ku70-1310C/G promoter polymorphism and cancer risk: a meta-analysis. AB - Ku70 plays an important role in DNA double-strand break repair. Studies revealing conflicting results on the role of the Ku70-1310C/G promoter polymorphism on cancer risk led us to perform a meta-analysis to investigate this relationship. Ten case-control studies with 2566 cases and 3058 controls were identified. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of associations. The overall results suggested no association between the Ku70 1310C/G promoter polymorphism and total cancer risk. However, on stratified analysis, significantly increased risks were observed among the Asian population (GG vs. CC: OR=1.50, 95%CI=1.10-2.06; GG vs. CC/CG: OR=1.47, 95%CI=1.07-2.01) and population-based case- control studies (GG vs. CC: OR=1.57, 95%CI=1.12-2.22; CG vs. CC: OR=1.35, 95%CI=1.11-1.64; CG/GG vs. CC: OR=1.37, 95%CI=1.14-1.65). Additionally, variant genotypes were associated with a significantly increased breast cancer risk (GG vs. CC: OR=1.80, 95%CI=1.26-2.56; GG vs. CC/CG: OR=1.40, 95%CI=1.01-1.95). PMID- 22524846 TI - Clinicopathologic profile of breast cancer patients in Pakistan: ten years data of a local cancer hospital. AB - Breast cancer is the most frequent cancer of women worldwide, with considerable geographic and racial/ethnic variation. Data are generally derived from population based cancer registries in the developed countries but hospital data are the most reliable source in the developing countries. Ten years data from 1st Jan 2000 to 31st Dec 2009 of a cancer hospital in Pakistan were here analyzed by descriptive statistics to evaluate the clinicopathologic profile of local breast cancer patients. Among 28,740 cancer patients, 6,718 were registered as breast cancer. The female to male ratio was 100:2. Breast cancer accounted for 23% of all and 41% of female cancers. Some 46% were residents of Lahore, with a mean age of 47+/-12 years. Less than 1% were at Stage 0 and 10%, 32%, 35% and 23% were at Stage I, II, III and IV respectively. Histopathology was unknown in 4% while 91%, 2% and 1% had invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC) and mucinous carcinoma respectively. Rare carcinomas accounted for the rest. Tumor grade 1, 2 and 3 was 11%, 55% and 34% among the known. Profile of breast cancer patients in Pakistan follows a pattern similar to that of other developing countries with earlier peak age and advanced disease stage at presentation. The male breast cancer accounts for higher proportion in the local population. Local women have higher frequency of IDC and lower frequency of ILC and DCIS, owing probably to a different risk profile. Use of hospital information systems and establishment of population based cancer registry is required to have accurate and detailed local data. Promotion of breast health awareness and better health care system is required to decrease the burden of advanced disease. PMID- 22524847 TI - Quantitative assessment of the relative antineoplastic potential of the n butanolic leaf extract of Annona muricata Linn. in normal and immortalized human cell lines. AB - Natural products have been the target for cancer therapy for several years but there is still a dearth of information on potent compounds that may protect normal cells and selectively destroy cancerous cells. The present study was aimed to evaluate the cytotoxic potential of n-butanolic leaf extract of Annona muricata L. on WRL-68 (normal human hepatic cells), MDA-MB-435S (human breast carcinoma cells) and HaCaT (human immortalized keratinocyte cells) lines by XTT assay. Prior to cytotoxicity testing, the extract was subjected to phytochemical screening for detecting the presence of compounds with therapeutic potential. Their relative antioxidant properties were evaluated using the reducing power and DPPH* radical scavenging assay. Since most of the observed chemo-preventive potential invariably correlated with the amount of total phenolics present in the extract, their levels were quantified and identified by HPLC analysis. Correlation studies indicated a strong and significant (P<0.05) positive correlation of phenolic compounds with free radical scavenging potential. The results revealed that the extract was moderately cytotoxic to normal cells with a mean IC50 value of 52.4 MUg when compared with those obtained for cancerous cells (IC50 values of 29.2 MUg for MDA-MB-435S and 30.1 MUg for HaCaT respectively). The study confirms the presence of therapeutically active antineoplastic compounds in the n-butanolic leaf extract of Annona muricata. Isolation of the active metabolites from the extract is in prospect. PMID- 22524848 TI - Factors associated with smoking, quit attempts and attitudes towards total smoking bans at university: a survey of seven universities in England, Wales and Northern Ireland. AB - OBJECTIVES: This study assessed the associations between socio-demographic, health and wellbeing variables (independent variables) and daily smoking, attempts to quit smoking, and agreement with smoking ban (dependent variables). METHODS: Data from 3,706 undergraduate students were collected from seven universities in England, Wales, and Northern Ireland using a standardised questionnaire. RESULTS: About 15.8% of the whole sample reported daily smoking, while 12% were occasional smokers. Smoking was significantly more prevalent among males, but the difference was due to a higher rate of occasional smokers. About every second smoker (55%) had attempted to quit smoking. Almost 45% of the whole sample agreed or strongly agreed with implementing a total smoking ban on campus. Daily smoking was more likely among students with not sufficient income, students whose fathers had at least a bachelor degree; and, students who reported binge drinking. Conversely, daily smoking was less likely among students who rated their health as very good/excellent, those who ate >=5 portions of fruit or vegetables, and those who had never taken illicit drugs. Previous attempt/s to quit smoking were more likely among students who have never taken illicit drugs and those who agreed with a total smoking ban; and less likely among those with not sufficient income. Daily smokers were less likely to report quit attempts as compared to occasional smokers. An agreement with smoking ban was more likely among students who rated their health as very good/excellent, those who ate >=5 portions of fruit or vegetables daily, and those who had never taken illicit drugs, but less likely among daily smokers. CONCLUSION: Favourable health practices and positive attitudes towards smoking ban were associated with each other. Interventions would need to comprise multi-component programmes that do not solely focus on smoking prevention/cessation, but also on other health promoting practices as well. PMID- 22524849 TI - Clinico-pathological significance of MHC-I type chain-associated protein A expression in oral squamous cell carcinoma. AB - The current research concerns the clinicopathological significance of MHC class I chain-related protein A (MICA) expression in oral squamous cell carcinomas (OSCCs). The expression and location of MICA protein in 14 normal oral mucous and 45 cancerous and para-cancerous tissues were assessed by immunohistochemistry and levels of MICA mRNA expression in 29 cancerous and para-cancerous tissues were determined by the real-time polymerase chain reaction. Data were analyzed with the SPSS16.0 software package. MICA was found to be located in the cytoplasm and plasma membrane. Expression was higher in para-cancerous than in cancerous tissues (P<0.05). However, no statistical difference was found between the following: 1) para-cancerous tissue with normal mucosa; 2) normal mucosa with cancerous tissue;and 3) among different clinicopathological parameters in OSCC (P>0.05). The level of MICA mRNA was higher in OSCCs than in para-cancerous tissues, and was correlated with the regional lymph node status and disease stage (P<0.05). The levels of MICA protein and mRNA expression differ among normal oral mucosa, para-cancerous tissue, and cancerous tissue. MICA may contribute to the tumorigenesis and progression of OSCC. PMID- 22524850 TI - Clinical significance of expression and amplification of the DcR3 gene in pancreatic carcinomas. AB - This study aimed to investigate the clinical significance of expression and amplification of decoy receptor 3 (DcR3) in pancreatic carcinomas (PC). mRNA expression was detected by PQ-PCR, and amplification was determined. DcR3 protein expression was detected by immunohistochemistry and ELISA. Correlations between DcR3 expression and clinical pathological factors were analyzed. The relative amount of DcR3 in PC tissues and non-cancerous tissues showed a statistically significant difference, 21 cases displaying more than two fold DcR3 amplification, while no such amplification was found in normal pancreatic tissues. DcR3 positive cell staining was located in the cytoplasm. The positive rate of DcR3 in PC and non-cancerous tissues showed a significant difference. DcR3 mRNA expression was correlated with clinical staging, size of the tumor, lymph node metastasis and histological staging, while protein expression was correlated with clinical data like tumor size. DcR3 gene amplification only correlated with tumor size. The level of DcR3 in serum of the PC resectable group before operation was 72.2+/-10.2 pg/ml, showing a significant difference compared to gallbladder carcinoma group (GC) or pancreatic benign tumor (PBT) group (P <0.01). In conclusion, DcR3 amplification is correlated with DcR3 expression in PC tissues, especially those clinical pathological factors which reflect tumor progression. Assessment of DcR3 level in sera of PC patients may be helpful for the early diagnosis and prognostic judgement. PMID- 22524851 TI - Diagnosis and cure experience of hepatolithiasis-associated intrahepatic cholangiocarcinoma in 66 patients. AB - BACKGROUND: The management of hepatolithiasis combined with intrahepatic cholangicarcinoma (IHHCC) remains a challenge due to poor prognosis. The aim of this study was to summarize our diagnosis and cure experience of IHHCC over the recent 10 years. METHODS: From January 1996 to January 2006, 66 patients with IHHCC were reviewed retrospectively. RESULTS: Of the 66 patients, 52 underwent surgical resection (radical resection in 38 and palliative in 14) and 8 patients abdominal exploration, while the other 6 cases received endoscopic retrograde biliary internal drainage and stent implantation. In this series, correct diagnosis of advanced stage was made during operation in 8 cases (8/60, 13.3%) and all of them (underwent unnecessary abdominal exploration, among them the positive rate of CA19-9 was 100%, and the positive rate of CEA was 87.6% (7/8), incidence rate of ascites was 100% and short-term significant weight loss was 100%, with median overall survival of only 4 months. CONCLUSION: Radical resection is mandatory for IHHCC patient to achieve long-term survival, the CT and MR imaging features of IHHCC being concentric enhancement. Patients with IHHCC have significant higher CA199 and significant higher CEA and short-term significant weight loss and ascites should be considered with advanced stage of IHHCC and unnecessary non-therapeutic laparotomies should be avoided. PMID- 22524852 TI - Factors associated with attending the National Cancer Screening Program for liver cancer in Korea. AB - BACKGROUND AND AIMS: The National Cancer Screening Program (NCSP) for liver cancer was initiated in 2003 in Korea. The objective of this study was to evaluate the participation rate of the program and to provide preliminary information on its results based on data collected by the NCSP in 2009. METHODS: The target population of the NCSP for liver cancer in 2009 was comprised of 373,590 adults aged >=40 years at high risk for liver cancer. Participation rates and positivity rates were assessed in this population. Multivariate logistic regression analysis was performed to determine the factors associated with participation in the NCSP for liver cancer. RESULTS: The overall participation rate was 37.9% and 1,126 participants were positive at screening. The highest participation rates were observed in women, those in their 60s, National Health Insurance beneficiaries, and individuals positive for hepatitis B surface antigen. Positivity rates for men, those in their 70s, Medical Aid Program recipients and individuals with liver cirrhosis were the highest in the respective categories of gender, age, health insurance type, and risk factor for liver cancer. CONCLUSIONS: The participation rates of the NCSP for liver cancer are still low, despite the fact that the program targets a high-risk group much smaller than the general population. Efforts to facilitate participation and to reduce disparities in liver cancer screening among Korean men and women are needed. These results provide essential data for evidence-based strategies for liver cancer control in Korea. PMID- 22524853 TI - Microwave ablation treatment of liver cancer with a 2,450-MHz cooled-shaft antenna: pilot study on safety and efficacy. AB - To evaluate efficacy of microwave ablation in a primary clinical study, sixty patients (44 men, 16 women; mean age 53 years) with 96, 1-8 cm (mean 3.20 +/- 0.17 cm) liver cancers were treated with 2,450-MHz internally cooled-shaft antenna. Complete ablation (CA) and local tumor progression (LTP) rates as well as complications were determined. CA rates in small (<3.0 cm), intermediate (3.1 5.0 cm) and large (5.1-8.0 cm) liver cancers were 96.4% (54/56), 92.3% (24/26) and 78.6% (11/14), respectively. During a mean follow-up period of 17.17 ? 6.52 months, LTP occurred in five (5.21%) treated cases. There was no significant difference in the CA and LTP rates between the HCC and liver metastasis patient subgroups (P<0.05). Microwave ablation provides a reliable, efficient, and safe technique to perform hepatic tumor ablation. PMID- 22524854 TI - The physiological implications of primary xylem organization in two ferns. AB - Xylem structure and function are well described in woody plants, but the implications of xylem organization in less-derived plants such as ferns are poorly understood. Here, two ferns with contrasting phenology and xylem organization were selected to investigate how xylem dysfunction affects hydraulic conductivity and stomatal conductance (g(s)). The drought-deciduous pioneer species, Pteridium aquilinum, exhibits fronds composed of 25 to 37 highly integrated vascular bundles with many connections, high g(s) and moderate cavitation resistance (P50 = -2.23 MPa). By contrast, the evergreen Woodwardia fimbriata exhibits sectored fronds with 3 to 5 vascular bundles and infrequent connections, low g(s) and high resistance to cavitation (P50 = -5.21 MPa). Xylem specific conductivity was significantly higher in P. aqulinium in part due to its wide, efficient conduits that supply its rapidly transpiring pinnae. These trade offs imply that the contrasting xylem organization of these ferns mirrors their divergent life history strategies. Greater hydraulic connectivity and g(s) promote rapid seasonal growth, but come with the risk of increased vulnerability to cavitation in P. aquilinum, while the conservative xylem organization of W. fimbriata leads to slower growth but greater drought tolerance and frond longevity. PMID- 22524855 TI - Treatment of multiple scrotal cysts with a 910-nm short-pulsed diode laser. AB - Scrotal cysts are rare cutaneous findings seen in youngsters and young adults. These lesions may eventually lead to scrotal calcification. Standard treatment is surgical removal. A young patient presented with multiple cysts was treated by short-pulsed 910-nm diode laser with rapid and aesthetically excellent improvement. PMID- 22524856 TI - Long-term outcome after cognitive and behavioral regression in nonlesional epilepsy with continuous spike-waves during slow-wave sleep. AB - PURPOSE: To present the long-term follow-up of 10 adolescents and young adults with documented cognitive and behavioral regression as children due to nonlesional focal, mainly frontal, epilepsy with continuous spike-waves during slow wave sleep (CSWS). METHODS: Past medical and electroencephalography (EEG) data were reviewed and neuropsychological tests exploring main cognitive functions were administered. KEY FINDINGS: After a mean duration of follow-up of 15.6 years (range, 8-23 years), none of the 10 patients had recovered fully, but four regained borderline to normal intelligence and were almost independent. Patients with prolonged global intellectual regression had the worst outcome, whereas those with more specific and short-lived deficits recovered best. The marked behavioral disorders resolved in all but one patient. Executive functions were neither severely nor homogenously affected. Three patients with a frontal syndrome during the active phase (AP) disclosed only mild residual executive and social cognition deficits. The main cognitive gains occurred shortly after the AP, but qualitative improvements continued to occur. Long-term outcome correlated best with duration of CSWS. SIGNIFICANCE: Our findings emphasize that cognitive recovery after cessation of CSWS depends on the severity and duration of the initial regression. None of our patients had major executive and social cognition deficits with preserved intelligence, as reported in adults with early destructive lesions of the frontal lobes. Early recognition of epilepsy with CSWS and rapid introduction of effective therapy are crucial for a best possible outcome. PMID- 22524857 TI - On the reversal of liver cirrhosis: mystery or reality? PMID- 22524858 TI - Anti-inflammatory treatment in patients after percutaneous coronary intervention: another potential use for berberine? PMID- 22524859 TI - Proteins within the intracellular calcium store determine cardiac RyR channel activity and cardiac output. AB - SUMMARY: The contractile function of the heart requires the release of Ca(2+) from intracellular Ca(2+) stores in the sarcoplasmic reticulum (SR) of cardiac muscle cells. The efficacy of Ca(2+) release depends on the amount of Ca(2+) loaded into the Ca(2+) store and the way in which this 'Ca(2+) load' influences the activity of the cardiac ryanodine receptor Ca(2+) release channel (RyR2). The effects of the Ca(2+) load on Ca(2+) release through RyR2 are facilitated by: (i) the sensitivity of RyR2 itself to luminal Ca(2+) concentrations; and (ii) interactions between the cardiac Ca(2+) -binding protein calsequestrin (CSQ) 2 and RyR2, transmitted through the 'anchoring' proteins junctin and/or triadin. Mutations in RyR2 are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT) and sudden cardiac death. The tachycardia is associated with changes in the sensitivity of RyR2 to luminal Ca(2+) . Triadin-, junctin- or CSQ null animals survive, but their longevity and ability to tolerate stress is compromised. These studies reveal the importance of the proteins in normal muscle function, but do not reveal the molecular nature of their functional interactions, which must be defined before changes in the proteins leading to CPVT and heart disease can be understood. Herein, we discuss known interactions between the RyR, triadin, junctin and CSQ with emphasis on the cardiac isoforms of the proteins. Where there is little known about the cardiac isoforms, we discuss evidence from skeletal isoforms. PMID- 22524860 TI - Mesh-related complications in urogynecology - a multidisciplinary challenge. AB - Diagnoses of complications in women who underwent pelvic floor surgery using meshes and the multidisciplinary management of these cases at two national referral urogynecological centers between January and June 2011 are presented in a series of cases of mesh complications, which provide an indication of the wide range of symptoms and, at times, the long time span over which they may be encountered. Complications included infection, erosion (extrusion/exposure), fistulas, perforation into the surrounding organs (such as urethra, bladder and/or bowel), chronic pelvic pain (often radiating into buttocks, groins and/or thighs), dysuria, dyschezia, voiding difficulties, constipation, stool evacuation difficulties, de novo overactive bladder, urinary and fecal incontinence and prolapse recurrences. Although meshes have the ability to provide adequate anatomical support, the emergence of such a multitude of complications has resulted in restrictions for their use, as well as being a multidisciplinary challenge. PMID- 22524868 TI - How strongly do word reading times and lexical decision times correlate? Combining data from eye movement corpora and megastudies. AB - We assess the amount of shared variance between three measures of visual word recognition latencies: eye movement latencies, lexical decision times, and naming times. After partialling out the effects of word frequency and word length, two well-documented predictors of word recognition latencies, we see that 7-44% of the variance is uniquely shared between lexical decision times and naming times, depending on the frequency range of the words used. A similar analysis of eye movement latencies shows that the percentage of variance they uniquely share either with lexical decision times or with naming times is much lower. It is 5 17% for gaze durations and lexical decision times in studies with target words presented in neutral sentences, but drops to 0.2% for corpus studies in which eye movements to all words are analysed. Correlations between gaze durations and naming latencies are lower still. These findings suggest that processing times in isolated word processing and continuous text reading are affected by specific task demands and presentation format, and that lexical decision times and naming times are not very informative in predicting eye movement latencies in text reading once the effect of word frequency and word length are taken into account. The difference between controlled experiments and natural reading suggests that reading strategies and stimulus materials may determine the degree to which the immediacy-of-processing assumption and the eye-mind assumption apply. Fixation times are more likely to exclusively reflect the lexical processing of the currently fixated word in controlled studies with unpredictable target words rather than in natural reading of sentences or texts. PMID- 22524869 TI - Comprehensive quantification of monolignol-pathway enzymes in Populus trichocarpa by protein cleavage isotope dilution mass spectrometry. AB - The economic value of wood/pulp from many tree species is largely dictated by the quantity and chemical properties of lignin, which is directly related to the composition and linkages of monolignols comprising the polymer. Although much is known regarding the monolignol biosynthetic pathway, our understanding is still deficient due to the lack of quantitative information at the proteomic level. We developed an assay based on protein cleavage isotope dilution mass spectrometry (PC-IDMS) for the determination of all potential, primary enzymes involved in the biosynthesis of monolignols and the peroxidases responsible for their polymerization to form lignin in the model tree species, Populus trichocarpa. Described is the identification of quantitative surrogate peptides through shotgun analysis of native and recombinant proteins, optimization of trypsin proteolysis using fractional factorial design of experiments, and development of a liquid chromatography-selected reaction monitoring method for specific detection of all targeted peptides. Of the 25 targeted enzymes, three were undetected in the normal xylem tissues, and all but two of the detectable species showed good day-to-day precision (CV < 10%). This represents the most comprehensive assay for quantification of proteins regulating monolignol biosynthesis and will lead to a better understanding of lignin formation at a systems level. PMID- 22524894 TI - Oral HPV infection and MHC class II deficiency (A study of two cases with atypical outcome). AB - BACKGROUND: Major histocompatibility complex class II deficiency, also referred to as bare lymphocyte syndrome is a rare primary Immunodeficiency disorder characterized by a profondly deficient human leukocyte antigen class II expression and a lack of cellular and humoral immune responses to foreign antigens. Clinical manifestations include extreme susceptibility to viral, bacterial, and fungal infections. The infections begin in the first year of life and involve usually the respiratory system and the gastrointestinal tract. Severe malabsorption with failure to thrive ensues, often leading to death in early childhood. Bone marrow transplantation is the curative treatment. CASE REPORTS: Here we report two cases with a late outcome MHC class II deficiency. They had a long term history of recurrent bronchopulmonary and gastrointestinal infections. Bone marrow transplantation could not be performed because no compatible donor had been identified. At the age of 12 years, they developed oral papillomatous lesions related to HPV (human papillomavirus). The diagnosis of HPV infection was done by histological examination. HPV typing performed on the tissue obtained at biopsy showed HPV type 6. The lesions were partially removed after two months of laser treatment. CONCLUSIONS: Viral infections are common in patients with MHC class II and remain the main cause of death. Besides warts caused by HPV infection do not exhibit a propensity for malignant transformation; they can cause great psychosocial morbidity. PMID- 22524895 TI - Use of endovascular embolization to treat a ruptured arteriovenous malformation in a pregnant woman: a case report. AB - INTRODUCTION: Pregnancy has been linked to increased rates of arteriovenous malformation rupture. This link remains a matter of debate and very few studies have addressed the management of arteriovenous malformation in pregnancy. Unruptured arteriovenous malformations in pregnant woman generally warrant conservative management due to the low rupture risk. When pregnant women present with ruptured arteriovenous malformation, however, surgery is often indicated due to the increased risk of re-rupture and associated mortality. Endovascular embolization is widely accepted as an important component of contemporary, multimodal therapy for arteriovenous malformations. Although rarely curative, embolization can facilitate subsequent surgical resection or radiosurgery. No previous reports have been devoted to the endovascular management of an arteriovenous malformation in a pregnant woman. CASE PRESENTATION: A 23-year-old Caucasian woman presented with headache and visual disturbance after the rupture of a left parieto-occipital arteriovenous malformation in the 22nd week of her pregnancy. After involving high-risk obstetric consultants and taking precautions to shield the fetus from ionizing radiation, we proceeded with a single stage of endovascular embolization followed soon after by open surgical resection of the arteriovenous malformation. There were several goals for the angiography in this patient: to better understand the anatomy of the arteriovenous malformation, including the number and orientation of feeding arteries and draining veins; to look for associated pre-nidal or intra-nidal aneurysms; and to partially embolize the arteriovenous malformation via safely-accessible feeders to facilitate surgical resection and minimize blood loss and operative morbidity. CONCLUSION: From our experience and review of the literature, we maintain that ruptured arteriovenous malformations in pregnancy may be managed in a similar manner to those in non-gravid women. Precautions should be taken to reduce the operative time and exposure of the fetus to ionizing radiation and contrast agents. PMID- 22524896 TI - Foetal and neonatal outcomes in women reporting ingestion of low or very low alcohol intake during pregnancy. AB - OBJECTIVE: This study aimed to assess the pregnancy outcomes of women who reported social intake of low or very low alcohol levels during pregnancy. METHODS: Obstetric and foetal outcomes were assessed in a prospective cohort of 1667 pregnant women who reported low or very low alcohol consumption during pregnancy (cases) and 1840 alcohol-abstainer women (controls). RESULTS: Among cases, alcohol consumption occurred during the first 4.4 (median) weeks of pregnancy, with a median ingestion of 1.0 (0.01-6.0) drinks/week, equivalent to 7.6 (0.09-47.5) g/week. Cigarette smoking was reported approximately four times more often in the exposed group than in the controls (p < 0.001). Pregnancy outcomes were similar between groups. There were 37 (2.4%) babies born with malformations in the exposed group and 41 (2.4%) in the control group (p = 0.9). CONCLUSIONS: Low-to-very low levels of alcohol ingestion during pregnancy do not appear to be associated with adverse maternal or foetal outcomes. PMID- 22524897 TI - Long-lasting paracrine effects of human cord blood cells on damaged neocortex in an animal model of cerebral palsy. AB - Neonatal asphyxia is an important contributor to cerebral palsy (CP), for which there is no effective treatment to date. The administration of human cord blood cells (hUCBCs) is emerging as a therapeutic strategy for the treatment of neurological disorders. However, there are few studies on the application of hUCBCs to the treatment of neonatal ischemia as a model of CP. Experiments and behavioral tests (mainly motor tests) performed on neonatal hypoxia/ischemia have been limited to short-term effects of hUCBCs, but mechanisms of action have not been investigated. We performed a study on the use of hUCBCs in a rat model of neonatal hypoxia/ischemia and investigated the underlying mechanism for therapeutic benefits of hUCBC treatment. hUCBCs were intravenously transplanted into a rat model of neonatal hypoxia ischemia. hUCBCs increased microglia temporarily in the periventricular striatum in the early phase of disease, protected mature neurons in the neocortex from injury, paved the way for the near normalization of brain damage in the subventricular zone (SVZ), and, in consequence, significantly improved performance in a battery of behavioral tests compared to the vehicle-treated group. Although the transplanted cells were rarely observed in the brain 3 weeks after transplantation, the effects of the improved behavioral functions persisted. Our preclinical findings suggest that the long-lasting positive influence of hUCBCs is derived from paracrine effects of hUCBCs that stimulate recovery in the injured brain and protect against further brain damage. PMID- 22524898 TI - ESX-1-mediated translocation to the cytosol controls virulence of mycobacteria. AB - Mycobacterium species, including Mycobacterium tuberculosis and Mycobacterium leprae, are among the most potent human bacterial pathogens. The discovery of cytosolic mycobacteria challenged the paradigm that these pathogens exclusively localize within the phagosome of host cells. As yet the biological relevance of mycobacterial translocation to the cytosol remained unclear. In this current study we used electron microscopy techniques to establish a clear link between translocation and mycobacterial virulence. Pathogenic, patient-derived mycobacteria species were found to translocate to the cytosol, while non pathogenic species did not. We were further able to link cytosolic translocation with pathogenicity by introducing the ESX-1 (type VII) secretion system into the non-virulent, exclusively phagolysosomal Mycobacterium bovis BCG. Furthermore, we show that translocation is dependent on the C-terminus of the early-secreted antigen ESAT-6. The C-terminal truncation of ESAT-6 was shown to result in attenuation in mice, again linking translocation to virulence. Together, these data demonstrate the molecular mechanism facilitating translocation of mycobacteria. The ability to translocate from the phagolysosome to the cytosol is with this study proven to be biologically significant as it determines mycobacterial virulence. PMID- 22524899 TI - The evaluation of atherosclerosis in migraine patients. AB - A potential association might exist between atherosclerosis and migraine. Carotid intima-media thickness (CIMT) is a marker of generalized atherosclerosis; hence, we aimed to assess CIMT in migraine patients. This study included 30 patients and 60 healthy controls aged between 20 and 40 years. Episodic migraine diagnosis was made according to the criteria of International Headache Society (IHS). Healthy controls who do not suffer any headache problems were selected from among hospital and laboratory staffs. All subjects were evaluated regarding some parameters and features known to be associated with migraine and vascular changes, that is, gender, age, body mass index, blood pressure, cholesterol, smoking habits, used hormonal contraceptives, and history of disease. The left common carotid arteries of the subjects were examined, and CIMT was measured with real-time gray-scale sonography. Mean values and standard deviations were calculated. All measurements were made in migraine-free periods. Migraine patients and control subjects were well matched for those parameters known to be associated with vascular changes, that is, gender, age, BMI, blood pressure, and cholesterol. CIMT values were higher in patients. The results showed that the mean CCA IMT values were 0.493 +/- 0.074 mm and 0.409 +/- 0.053 mm in migraine patients and controls, respectively (P < 0.001). There is a relationship between atherosclerosis and inflammation in migraine patients. The risk of cranial inflammatory arteriopathy increases in repeated attacks of migraine. Our study also supports that high number of attacks and attack duration are important in the development of atherosclerosis. PMID- 22524901 TI - Acute spontaneous scrotal haematoma presenting with haemorrhagic shock: a case report. AB - We report an unusual case of acute spontaneous scrotal haematoma presenting with haemorrhagic shock requiring resuscitation. PMID- 22524902 TI - Infection of laparoscopically inserted inguinal hernia repair mesh following subsequent emergency open surgery: a report of two cases. AB - We present two cases of laparoscopically inserted mesh for inguinal hernia repair that became infected following emergency open bowel surgery. We believe that there is an increased risk of infection due to the larger size of mesh used in the laparoscopic repair but also due to the patient not volunteering the information because of the minimally invasive nature of the procedure. PMID- 22524903 TI - Catheterisation. PMID- 22524904 TI - Massive spontaneous diaphragmatic rupture in Ehlers-Danlos syndrome. AB - Ehlers-Danlos syndrome (EDS) is a rare disorder caused by abnormalities in the synthesis and structure of collagen. The resultant tissue fragility and weakness can lead to multiple surgical conditions. In this report we present the very rare and life threatening case of a massive spontaneous diaphragmatic rupture in a 35 year-old man with EDS and reflect on the literature, highlighting points to consider when managing such complex patients. PMID- 22524905 TI - Entonox(r) inhalation to reduce pain in common diagnostic and therapeutic outpatient urological procedures: a review of the evidence. AB - INTRODUCTION: Entonox((r)) (50% nitrous oxide and 50% oxygen; BOC Healthcare, Manchester, UK) is an analgesic and anxiolytic agent that is used to successfully reduce pain and anxiety during dental, paediatric and emergency department procedures. In this article we review the application and efficacy of Entonox((r)) in painful local anaesthesia urological procedures by performing a systematic review of the literature. METHODS: A MEDLINE((r)) search was performed using the terms 'nitrous oxide', 'Entonox', 'prostate biopsy', 'flexible cystoscopy' and 'extracorporeal shock wave lithotripsy'. English language publications of randomised studies were identified and reviewed. RESULTS: The search yielded five randomised studies that investigated the clinical efficacy of Entonox((r)) as an analgesic for day case urological procedures. Three randomised controlled trials (RCTs) investigated Entonox((r)) in transrectal ultrasonography guided prostate biopsy. All three reported significant reductions in pain score in the Entonox((r)) versus control groups. One RCT reported significant reduction in pain during male flexible cystoscopy in the Entonox((r)) group compared with the control group. One RCT, which examined the use of Entonox((r)) during extracorporeal shock wave lithotripsy, found its use significantly decreased the pain score compared with the control group and this was comparable to intravenous pethidine. CONCLUSIONS: Evidence from varied adult and paediatric procedures has shown Entonox((r)) to be an effective, safe and patient acceptable form of analgesia. All published studies of its use in urological day case procedures have found it to significantly reduce procedural pain. There is huge potential to use this cheap, safe, effective analgesic in our current practice. PMID- 22524906 TI - Congenital diaphragmatic hernia: an unusual cause of obstructive jaundice. AB - Congenital diaphragmatic hernias in adults are exceedingly rare. They have been reported to cause dyspnoea, gastric reflux and intestinal obstruction. We present the case of a young woman with obstructive jaundice secondary to a Bochdalek hernia of the right hemidiaphragm. We discuss the aetiologies, presentation, investigation and treatment of the disorder, and make recommendations on the management. PMID- 22524907 TI - Liposarcoma of the spermatic cord: a report of two cases. AB - Liposarcomas of the spermatic cord are unusual and rarely reported in the literature. These tumours can sometimes be mistaken for the common scrotal swellings such as hydrocoeles and hernias. Careful clinical and radiological examination will help in appropriate preoperative planning and surgery by an experienced surgical team. We report our experience of two cases of such scrotal swellings. PMID- 22524909 TI - Outcomes in the repair of pilonidal sinus disease excision wounds using a parasacral perforator flap. AB - INTRODUCTION: The ideal treatment for pilonidal sinus disease has yet to be defined. There are many approaches described in the literature. METHODS: Thirty five consecutive patients who underwent wide excision of pilonidal sinus disease had the wound repaired using a parasacral perforator flap. Outcomes were assessed by case notes analysis and follow-up telephone and postal questionnaires. RESULTS: There were ten minor complications including six minor wound edge dehiscences. There were two ischaemic complications, with one flap loss. There were 3 recurrences of pilonidal disease at a mean follow-up of 33 months, giving a 5-year recurrence free rate of 86%. Of the patients questioned, all would recommend the procedure to someone else despite 69% being dissatisfied with the cosmetic outcome. CONCLUSIONS: This series indicates that the parasacral perforator flap technique is able to repair pilonidal sinus excision wounds successfully with minimal morbidity and a low recurrence rate at a mean of follow up of 33 months. The study suggests that it may be a technique best reserved for recurrent cases of pilonidal sinus disease. Patients feel the procedure is successful despite reservations regarding the cosmetic outcome. PMID- 22524910 TI - An acute groin lump: surgical exploration is not always the best option. AB - This is a case of a very unusual cause of an acute groin lump in a 71-year-old woman that was presumed initially to either be an incisional or inguinal hernia. However, with subsequent computed tomography it was shown to be thrombophlebitis of collateral vessels secondary to a previous deep vein thrombosis. This case demonstrates how surgical exploration of acute groin lumps is not without its dangers. PMID- 22524911 TI - Novel surgical reconstruction of a mycotic abdominal aortic aneurysm using cryopreserved femoral arterial allograft from the NHS tissue bank: a new resource for UK vascular surgeons. AB - The treatment of mycotic abdominal aortic aneurysms remains a significant surgical challenge associated with significant morbidity and mortality. In the following case report, we describe our successful management of a patient with a mycotic abdominal aortic aneurysm using two cryopreserved superficial femoral artery allografts (available from the UK NHS tissue bank) to create a Y-shaped allograft to permit immediate aortic reconstruction after surgical debridement. To our knowledge, this is the first time such a reconstruction has been reported in the literature. PMID- 22524912 TI - The impact of surgeon-based ultrasonography for parathyroid disease on a British endocrine surgical practice. AB - INTRODUCTION: Surgeon-based ultrasonography (SUS) for parathyroid disease has not been widely adopted by British endocrine surgeons despite reports worldwide of accuracy in parathyroid localisation equivalent or superior to radiology-based ultrasonography (RUS). The aim of this study was to determine whether SUS might benefit parathyroid surgical practice in a British endocrine unit. METHODS: Following an audit to establish the accuracy of RUS and technetium sestamibi (MIBI) in 54 patients, the accuracy of parathyroid localisation by SUS and RUS was compared prospectively with operative findings in 65 patients undergoing surgery for primary hyperparathyroidism (pHPT). RESULTS: The sensitivity of RUS (40%) was below and MIBI (57%) was within the range of published results in the audit phase. The sensitivity (64%), negative predictive value (86%) and accuracy (86%) of SUS were significantly greater than RUS (37%, 77% and 78% respectively). SUS significantly increased the concordance of parathyroid localisation with MIBI (58% versus 32% with RUS). CONCLUSIONS: SUS improves parathyroid localisation in a British endocrine surgical practice. It is a useful adjunct to parathyroid practice, particularly in centres without a dedicated parathyroid radiologist, and enables more patients with pHPT to benefit from minimally invasive surgery. PMID- 22524913 TI - Spontaneous diaphragmatic rupture related to local invasion by retroperitoneal liposarcoma. AB - We report a case of the female patient who was admitted to the hospital because of syncope experienced while climbing stairs. Diagnostic workup raised the suspicion of a right diaphragmatic rupture that was eventually confirmed by surgery (right-sided thoracotomy). Surgery also revealed tissue protruding through the rupture site from within the retroperitoneum that was proven subsequently to be a dedifferentiated liposarcoma. Second surgery was performed to completely remove the liposarcoma tissue and repair a coincident old right lumbar region hernia. The patient recovered fully. Spontaneous rupture of the diaphragm is rare and this is especially true for the right hemidiaphragm. We report the first case of diaphragmatic rupture caused by local infiltration by a retroperitoneal liposarcoma. This and similar reports emphasise that in cases with high clinical suspicion of diaphragmatic rupture, diagnosis should be pursued even in the absence of a preceding traumatic event. PMID- 22524914 TI - Benign biliary papillomatosis in a patient with a choledochal cyst presenting as haemobilia: a case report. AB - Biliary papillomatosis is a rare condition usually detected on imaging or postoperative histopathology. It may be asymptomatic or present with features of cholangitis. We report the management of a patient presenting with haemobilia. PMID- 22524915 TI - Penile actinomycosis clinically diagnosed as an epidermal cyst: a case report. AB - A 27-year-old man presented at our hospital with a 1.5 cm, spherical, soft and movable subcutaneous mass at the mid portion of the ventral aspect of the penile shaft. The possibility of an epidermal cyst was considered and a simple resection was performed. Histologically, the lesion was a unilocular cyst without an epithelial lining, containing eosinophilic necrotic material and a few dispersed scalloped sheets of actinomycotic granules. The centre of the largest granular body demonstrated many fragments of foreign substance. The patient was treated successfully with combined antibiotic therapy. PMID- 22524916 TI - Computed tomography findings of bowel wall thickening: its significance and relationship to endoscopic abnormalities. AB - INTRODUCTION: The aim of this study was to conduct retrospective analysis of abdominopelvic computed tomography (CT) reports, identifying those patients in whom bowel wall thickening (BWT) was observed, and to correlate these reports with subsequent endoscopic evaluation. METHODS: Formal reports for all patients undergoing abdominopelvic CT between February 2007 and September 2009 were reviewed. Where patients were identified as having colorectal 'wall thickening', results of subsequent endoscopic evaluations were documented. Only those patients with a report of BWT who had follow-up endoscopy (colonoscopy, sigmoidoscopy) were included in the analysis. RESULTS: A total of 165 patients were included. Abnormalities on endoscopy at the exact site of the BWT on CT were found in 95 patients (57.58%); in 36 cases (21.82%) this was a malignant lesion. BWT of the transverse colon was significantly more likely to correspond to an endoscopic finding of cancer than other sites (p=0.034). Rectal bleeding was reported significantly more often in patients with BWT and neoplastic disease on endoscopy compared with those with normal endoscopy (p=0.04). Excluding patients with inflammatory/diverticular lesions, 59.02% of Caucasians had a neoplastic lesion at the site of reported BWT, significantly higher than the other ethnic groups (p=0.008). There were 38 patients (23.03%) who did not present with bowel symptoms and, of these, 6 were diagnosed subsequently with colorectal cancer. CONCLUSIONS: This study supports endoscopic evaluation to investigate patients with CT evidence of BWT, especially in cases involving the transverse colon, in Caucasian patients or in association with symptoms of rectal bleeding. PMID- 22524917 TI - A case of a giant cystic lymphangioma mimicking acute appendicitis. AB - Cystic lymphangiomas are rare tumours that can mimic various causes of acute abdomen including appendicitis. They exhibit variations in two characteristics on presentation: they can arise from a wide range of organs including various intra abdominal structures and they can have a wide variation in size on presentation. We report a case of a gigantic cystic lymphangioma presenting as an acute abdomen closely mimicking acute appendicitis and we conduct a review of the relevant literature. PMID- 22524918 TI - Post-coital haemoperitoneum: a downside to intercourse. AB - We present the case of a 43-year-old multiparous female patient presenting with post-coital haemoperitoneum secondary to a ruptured uterine fibroid. This is a rare case demonstrating the need to elicit full gynaecological history in patients presenting with an acute abdomen. PMID- 22524919 TI - Accuracy of prognostic scores in decision making and predicting outcomes in metastatic spine disease. AB - INTRODUCTION: Management of metastatic spinal disease has changed significantly over the last few years. Different prognostic scores are used in clinical practice for predicting survival. The aim of this study was to assess the accuracy of prognostic scores and the role of delayed presentation in predicting the outcome in patients with metastatic spine disease. METHODS: Retrospectively, four years of data were collected (2007-2010). Medical records review included type of tumour, duration of symptoms, expected survival and functional status. The Karnofsky performance score was used for functional assessment. Modified Tokuhashi and Tomita scores were used for survival prediction. RESULTS: A total of 55 patients who underwent surgical stabilisation were reviewed. The mean age was 63 years (range: 32-87 years). The main primary sources of tumours included myeloma, breast cancer, lymphoma, lung cancer, renal cell cancer and prostate cancer. Of the cases studied, 29 patients had posterior instrumented stabilisation alone, 10 patients had an anterior procedure alone and 16 patients (with an expected survival of more than one year) had both anterior and posterior procedures performed. Twenty-three patients presented with spinal cord compression. The mean follow-up duration was 9 months (range: 1-39 months). Patients who were treated within one week of referral survived longer than anticipated. Patients were divided into three groups based on their expected survival. Actual survival was better in all three groups after surgery. Discrepancies in scores were prominent in patients with myeloma, breast and prostate cancers. Functional outcome was better in patients under 65 years of age. CONCLUSIONS: The prognostic scoring systems are not uniformly effective in all types of primary tumours. However, they are useful in decision making for surgical intervention, taking other factors into account, in particular the age of the patient, the type and stage of the primary tumour and general health. PMID- 22524920 TI - A tricky tracheotomy: airway management dilemma following unusual stab injury to the mouth. AB - Traumatic wounding to the upper aerodigestive tract can cause acute airway compromise. In these circumstances establishment of a safe airway is vital. We present a case report illustrating the decision making pathway in such a difficult case. PMID- 22524921 TI - Traumatic plastic deformation of the tibia: case report and literature review. AB - Plastic deformation refers to the deformation of a bone, without fracture of its cortices, that persists once the deforming force has been removed. It is not a common condition but is seen more frequently in children than in adults. Of the cases published, there have been only three previous reports of tibial involvement, with the forearm being the most commonly affected site. We describe the case of a 10-year-old girl who, after falling down a slope, came to a sudden stop when her right foot hit a rock. This resulted in a fracture of the fibula and bowing of the tibia. We discuss the dilemmas faced in treatment and recommend regular follow up until the patient reaches skeletal maturity. PMID- 22524922 TI - Topical negative pressure for the treatment of neonatal post-sternotomy wound dehiscence. AB - The use of topical negative pressure (TNP) dressings for sternal wound dehiscence or mediastinitis in the neonatal population is rare. The majority of case reports have focused on wound healing as an endpoint and have not discussed the physiological advantage that TNP dressings may impart with regard to sternal stabilisation, improved respiratory function and early weaning from mechanical ventilation. We present a case of the use of TNP in neonatal post-sternotomy wound dehiscence and mediastinitis, from a UK perspective, with an emphasis on wound healing and physiological optimisation. As well as an improvement in sternal wound healing due to the local effects of the TNP system, serial arterial blood gas analysis revealed a significant improvement in systemic physiological parameters, including a reduction in pCO(2) in the period (days 20-31) after application of TNP (p<0.0001) compared to the period before where simple occlusive dressings were applied. Hydrogen ion concentration also significantly reduced in this period (p=0.0058). The use of the TNP system in association with systemic antibiotics successfully treated the mediastinitis. A sealed, controlled wound environment also allowed ease of nursing and an expedited return to care by the parents. We would recommend the consideration of TNP dressings in similar cases of neonatal and paediatric sternal wound dehiscence. Not only do we observe the local effects of improved wound healing, the systemic effects of improved lung function are also valuable in the early management of such complex cases. PMID- 22524923 TI - Operative fixation for complex tibial fractures. AB - INTRODUCTION: The management of open tibial shaft fractures remains challenging. Intramedullary nailing and external fixation are the most commonly used fixation techniques although the optimal fixation technique remains unresolved. In this article the outcomes of these two surgical techniques are compared. METHODS: A comprehensive literature search was conducted through MEDLINE((r)) using Ovid((r)) and MeSH (Medical Subject Heading) terms for articles published in the English literature between 1999 and 2009. The outcome measures compared were time to fracture union, infection rates and complications. RESULTS: Forty-one studies were identified, of which only three met the inclusion criteria. The average time to union was variable. Delayed union and non-union appeared to be more prevalent in the external fixator group although this was not statistically significant. Both techniques were associated with secondary procedures as well as infection. CONCLUSIONS: The current literature indicates little evidence to suggest the superiority of one fixation technique over another for open tibial fractures. PMID- 22524924 TI - Use of internal iliac artery as a side-to-end anastomosis in renal transplantation. AB - The internal iliac artery is less commonly used in renal transplantation in comparison to the external iliac artery due to its size and the risk of compromising distal vascular supply to the pelvis. We report a cadaveric renal transplant in which we performed a side-to-end anastomosis using the internal iliac artery. This technique can provide adequate perfusion to the transplant kidney without the associated risks and complications in the patient whose internal iliac artery is of a good diameter and quality. PMID- 22524925 TI - Spontaneous subcutaneous emphysema associated with mephedrone usage. AB - Subcutaneous emphysema in the head and neck is a rare condition, normally caused by major underlying injury to the airway or gastrointestinal tract. We report a non-traumatic occurrence of spontaneous cervical subcutaneous emphysema in a 30 year-old man who had been snorting mephedrone. The patient made an uneventful recovery, being managed conservatively, and did not require airway support. The occurrence of spontaneous cervical emphysema associated with snorting mephedrone has not been previously described in the literature. PMID- 22524926 TI - Pacemaker placement and shoulder surgery: is there a risk? AB - INTRODUCTION: Surgery to the anterior aspect of the shoulder is performed by many surgical specialties but the techniques used by our cardiology colleagues for insertion of cardiac pacemaker wires are often not appreciated by the surgical community. The deltopectoral approach has been used for open pacemaker wire insertion for many years by cardiologists. METHODS: We surveyed a group of subspecialty shoulder surgeons as well as orthopaedic trainees to see if this approach for pacemakers is well recognised. We tried to assess what level of knowledge exists regarding pacemaker placement in general as well as specific risks. RESULTS: There appears to be a paucity of knowledge regarding pacemaker placement and related patient safety issues in both surveyed groups. There was no difference between the two groups, suggesting that the level of knowledge does not increase with experience and specialisation. CONCLUSIONS: There is the potential to cause harm to patients if the insertion site and type of device is not identified before commencing surgery in this region and steps must be taken to minimise any intra-operative risk. There is a risk from direct injury to the pacemaker and/or leads as well as the hazards of using diathermy in close proximity to a pacemaker. There must be more widespread dissemination of this information in order to minimise risks to patients with pacemakers in situ. PMID- 22524927 TI - A case of odontogenic brain abscess arising from covert dental sepsis. AB - Odontogenic infections can spread to any organ of the body and in some cases cause life threatening infections. We report a case of multiple odontogenic brain abscesses resulting from undetected tooth decay. Whereas most odontogenic brain abscesses occur following dental treatment, this report documents brain abscesses prior to dental treatment, signifying the dangers of covert dental infections. This case report updates the literature on the topic of odontogenic brain abscesses. PMID- 22524929 TI - Leiomyosarcoma of the rectum following pelvic irradiation: a difficult histological diagnosis. AB - Rectal leiomyosarcomas are very rare mesenchymal tumours. This is a case report of a rectal leiomyosarcoma diagnosed initially as a leiomyoma in a patient who had undergone pelvic radiotherapy several years previously. In addition to its pathological rarity, this case is of particular interest because it reinforces the association between pelvic irradiation and rectal leiomyosarcomas and it highlights the importance of treating suspicious cases aggressively in spite of favourable preoperative radiological and histological assessment. PMID- 22524928 TI - Health-related quality of life, surgical and aesthetic outcomes following microvascular free flap reconstructions: an 8-year institutional review. AB - INTRODUCTION: Microvascular free flap reconstruction has revolutionised the reconstruction of complex defects of traumatic, oncological, congenital and infectious aetiologies. Complications of microvascular free flap procedures impact negatively on patient post-operative course and outcome. METHODS: We performed a retrospective analysis of 102 consecutive patients undergoing 108 free flap procedures at a tertiary referral centre over an 8-year period. Logistic regression analysis was used to identify factors predictive of free flap complications. Health-related quality of life (HRQoL) and aesthetic outcomes were assessed using the Short Form 36 questionnaire and a satisfaction visual analogue scale respectively. RESULTS: In total, 108 free tissue transfers were performed; 23% were fasciocutaneous free flaps, 69% musculocutaneous and 8% osteoseptocutaneous. The overall flap success rate was 92.6%. Over a third of patients (34.3%) had flap-related complications ranging from minor wound dehiscence to total flap loss. ASA (American Society of Anesthesiologists) grade >=2 (OR: 16.9, 95% CI: 15.3-18.1, p<0.009), history of smoking (OR: 6.1, 95% CI: 5.5-7.2, p<0.049), body mass index >=25 kg/m(2) (OR: 21.3, 95% CI: 20.8-22.1, p<0.003), low albumin (odds ratio [OR]: 2.2, 95% confidence interval [CI]: 1.2 3.9, p<0.003) and peripheral vascular disease (OR: 6.9, 95% CI: 5.9-7.5, p<0.036) were identified as factors independently predictive of free flap complications. CONCLUSIONS: Patients undergoing uncomplicated free flap surgery and those reporting superior post-operative flap aesthesis have higher HRQoL scores. Microvascular free tissue transfer has revolutionised our approach to the reconstruction of complex defects, providing a safe, reliable procedure to restore functionality and quality of life for patients. PMID- 22524930 TI - Paediatric admissions to the British military hospital at Camp Bastion, Afghanistan. AB - INTRODUCTION: International humanitarian law requires emergency medical support for both military personnel and civilians, including children. Here we present a detailed review of paediatric admissions with the pattern of injury and the resources they consume. METHODS: All paediatric admissions to the hospital at Camp Bastion between 1 January and 29 April 2011 were analysed prospectively. Data collected included time and date of admission, patient age and weight, mechanism of injury, extent of wounding, treatment, length of hospital stay and discharge destination. RESULTS: Eighty-five children (65 boys and 17 girls, median age: 8 years, median weight: 20 kg) were admitted. In 63% of cases the indication for admission was battle related trauma and in 31% non-battle trauma. Of the blast injuries, 51% were due to improvised explosive devices. Non-battle emergencies were mainly due to domestic burns (46%) and road traffic accidents (29%). The most affected anatomical area was the extremities (44% of injuries). Over 30% of patients had critical injuries. Operative intervention was required in 74% of cases. The median time to theatre for all patients was 52 minutes; 3 patients with critical injuries went straight to theatre in a median of 7 minutes. A blood transfusion was required in 27 patients; 6 patients needed a massive transfusion. Computed tomography was performed on 62% of all trauma admissions and 40% of patients went to the intensive care unit. The mean length of stay was 2 days (range: 1-26 days) and there were 7 deaths. CONCLUSIONS: Paediatric admissions make up a small but significant part of admissions to the hospital at Camp Bastion. The proportion of serious injuries is very high in comparison with admissions to a UK paediatric emergency department. The concentration of major injuries means that lessons learnt in terms of teamwork, the speed of transfer to theatre and massive transfusion protocols could be applied to UK paediatric practice. PMID- 22524932 TI - A novel laparoscopic approach for the surgical management of buried bumper syndrome. PMID- 22524933 TI - Originality in the technical section. PMID- 22524934 TI - A useful technique for retrieving the distal segment of a fractured femoral nail. PMID- 22524935 TI - Figure-of-eight 'iceberg stitch' facilitates easy removal of supraclavicular lymph nodes. PMID- 22524936 TI - Use of Roeder knot with vicryl-reel ligature for laparoscopic appendicectomy: have we forgotten how to tie knots? PMID- 22524937 TI - A simple set up for wrist arthroscopy in the district general hospital. PMID- 22524938 TI - Feeding a urethral catheter over a guidewire using an intravenous cannula. PMID- 22524939 TI - A technique for soft tissue handling during knee surgery. PMID- 22524940 TI - Maintaining an adequate surgical field during laparoscopic surgery. PMID- 22524941 TI - Hospital mortality under surgical care. PMID- 22524942 TI - Staged bilateral knee replacements. PMID- 22524943 TI - Suspected testicular torsion. PMID- 22524944 TI - Muscular and mental fatigue in surgeons. PMID- 22524945 TI - Closure of skin lacerations under tension: comment 1. PMID- 22524946 TI - Fingerless gloves for hand trauma cases. PMID- 22524947 TI - Closure of skin lacerations under tension: comment 2. PMID- 22524948 TI - Closure of skin lacerations under tension: comment 3. PMID- 22524950 TI - RDF/SRF: which perspective for its future in the EU. PMID- 22524953 TI - Fourier transform infrared spectrochemical imaging: review of design and applications with a focal plane array and multiple beam synchrotron radiation source. AB - The beamline design, microscope specifications, and initial results from the new mid-infrared beamline (IRENI) are reviewed. Synchrotron-based spectrochemical imaging, as recently implemented at the Synchrotron Radiation Center in Stoughton, Wisconsin, demonstrates the new capability to achieve diffraction limited chemical imaging across the entire mid-infrared region, simultaneously, with high signal-to-noise ratio. IRENI extracts a large swath of radiation (320 hor. * 25 vert. mrads(2)) to homogeneously illuminate a commercial infrared (IR) microscope equipped with an IR focal plane array (FPA) detector. Wide-field images are collected, in contrast to single-pixel imaging from the confocal geometry with raster scanning, commonly used at most synchrotron beamlines. IRENI rapidly generates high quality, high spatial resolution data. The relevant advantages (spatial oversampling, speed, sensitivity, and signal-to-noise ratio) are discussed in detail and demonstrated with examples from a variety of disciplines, including formalin-fixed and flash-frozen tissue samples, live cells, fixed cells, paint cross-sections, polymer fibers, and novel nanomaterials. The impact of Mie scattering corrections on this high quality data is shown, and first results with a grazing angle objective are presented, along with future enhancements and plans for implementation of similar, small-scale instruments. PMID- 22524954 TI - A developed optical-feedback cavity ring-down spectrometer and its application. AB - A developed spectrometer based on optical-feedback cavity ring-down spectroscopy (OF-CRDS) has been demonstrated with a distributed feedback laser diode and a V shaped glass ceramic cavity. The laser is coupled to the V-shaped cavity, which creates an absorption path length greater than 2.8 km, and resonance between the laser frequency and the cavity modes is realized by modulating the cavity length instead of tuning the laser wavelength to obtain a higher resolution. A noise equivalent absorption coefficient of ~2.6 * 10(-8) cm(-1)Hz(-1/2) (1sigma) is determined with spectral resolution of ~0.003 cm(-1) and spectral range of 1.2 cm(-1). As an application example, the absorption spectrum measurement of water vapor in the spectral range of 6590.3~6591.5 cm(-1) is demonstrated with this spectrometer. PMID- 22524955 TI - A compact wide-range spectrometer with image intensifier: unexpected advantages, new functions, and a variety of applications. AB - Gated intensified spectrometers are very efficient instruments not only in time resolved applications but also in all other fields were traditional non-gated and non-intensified devices are so popular today. This paper describes the design and performance of a simple, reliable, and relatively inexpensive wide-range gated intensified spectrometer that was conceived as a prototype for volume production. With 200-900 nm spectral range, 3 ns temporal resolution, variable optical gain up to 4000, repetition rate up to 200 kHz, spectral resolution 2 nm (0.9 nm with deconvolution), and affordable price, such a device may be useful for budget research laboratories working in the fields of cell biology, laser-induced breakdown spectroscopy, molecular kinetics, plasma diagnostics, materials characterization, combustion analysis, and forensic analysis. PMID- 22524956 TI - X-ray photoelectron spectroscopy (XPS) investigation of the surface film on magnesium powders. AB - Magnesium (Mg) and its alloys are attractive for use in automotive and aerospace applications because of their low density and good mechanical properties. However, difficulty in forming magnesium and the limited number of available commercial alloys limit their use. Powder metallurgy may be a suitable solution for forming near-net-shape parts. However, sintering pure magnesium presents difficulties due to surface film that forms on the magnesium powder particles. The present work investigates the composition of the surface film that forms on the surface of pure magnesium powders exposed to atmospheric conditions and on pure magnesium powders after compaction under uniaxial pressing at a pressure of 500 MPa and sintering under argon at 600 degrees C for 40 minutes. Initially, focused ion beam microscopy was utilized to determine the thickness of the surface layer of the magnesium powder and found it to be ~10 nm. The X-ray photoelectron analysis of the green magnesium sample prior to sintering confirmed the presence of MgO, MgCO(3).3H(2)O, and Mg(OH)(2) in the surface layer of the powder with a core of pure magnesium. The outer portion of the surface layer was found to contain MgCO(3).3H(2)O and Mg(OH)(2), while the inner portion of the layer is primarily MgO. After sintering, the MgCO(3).3H(2)O was found to be almost completely absent, and the amount of Mg(OH)(2) was also decreased significantly. This is postulated to occur by decomposition of the compounds to MgO and gases during the high temperature of sintering. An increase in the MgO content after sintering supports this theory. PMID- 22524957 TI - Automatic baseline subtraction of vibrational spectra using minima identification and discrimination via adaptive, least-squares thresholding. AB - A method of automated baseline correction has been developed and applied to Raman spectra with a low signal-to-noise ratio and surface-enhanced infrared absorption (SEIRA) spectra with bipolar bands. Baseline correction is initiated by dividing the raw spectrum into equally spaced segments in which regional minima are located. Following identification, the minima are used to generate an intermediate second-derivative spectrum where points are assigned as baseline if they reside within a locally defined threshold region. The threshold region is similar to a confidence interval encountered in statistics. To restrain baseline and band point discrimination to the local level, the calculation of the confidence region employs only a predefined number of already-accepted baseline minima as part of the sample set. Statistically based threshold criteria allow the procedure to make an unbiased assessment of baseline points regardless of the behavior of vibrational bands. Furthermore, the threshold region is adaptive in that it is further modified to consider abrupt changes in baseline. The present procedure is model-free insofar as it makes no assumption about the precise nature of the perturbing baseline nor requires treatment of spectra prior to execution. PMID- 22524958 TI - Noninvasive, quantitative analysis of drug mixtures in containers using spatially offset Raman spectroscopy (SORS) and multivariate statistical analysis. AB - In this paper, spatially offset Raman spectroscopy (SORS) is demonstrated for noninvasively investigating the composition of drug mixtures inside an opaque plastic container. The mixtures consisted of three components including a target drug (acetaminophen or phenylephrine hydrochloride) and two diluents (glucose and caffeine). The target drug concentrations ranged from 5% to 100%. After conducting SORS analysis to ascertain the Raman spectra of the concealed mixtures, principal component analysis (PCA) was performed on the SORS spectra to reveal trends within the data. Partial least squares (PLS) regression was used to construct models that predicted the concentration of each target drug, in the presence of the other two diluents. The PLS models were able to predict the concentration of acetaminophen in the validation samples with a root-mean-square error of prediction (RMSEP) of 3.8% and the concentration of phenylephrine hydrochloride with an RMSEP of 4.6%. This work demonstrates the potential of SORS, used in conjunction with multivariate statistical techniques, to perform noninvasive, quantitative analysis on mixtures inside opaque containers. This has applications for pharmaceutical analysis, such as monitoring the degradation of pharmaceutical products on the shelf, in forensic investigations of counterfeit drugs, and for the analysis of illicit drug mixtures which may contain multiple components. PMID- 22524959 TI - Direct determination of unsaturation level of milk fat using Raman spectroscopy. AB - We have demonstrated the potential of visible Raman spectroscopy in combination with chemometric analysis as a fast and simple tool for the determination of the unsaturation level of milk fat. The Raman measurements have been performed directly on liquid milk and on fat extracted from liquid milk. The Raman spectra taken from the extracted fat showed a higher resolution. The spectra directly obtained from the milk samples had some fluorescence background but nevertheless yielded the desired information. For calibration purposes, the iodine value (IV) was determined in all cases in order to evaluate the unsaturation level of the investigated samples. Two separate calibration models have been constructed; one for the milk samples and the second one for the extracted fat. The accuracy of these calibration models was estimated using the root mean square error of calibration and validation (RMSE) and the coefficient of determination (R(2)) between actual and predicted values. PMID- 22524960 TI - Effects of etching on zircon grains and its implications for the fission track method. AB - Studies of zircon grains using optical microscopy, micro-Raman spectroscopy, and scanning electron microscopy (SEM) have been carried out to characterize the surface of natural zircon as a function of etching time. According to the surface characteristics observed using an optical microscope after etching, the zircon grains were classified as: (i) homogeneous; (ii) anomalous, and (iii) hybrid. Micro-Raman results showed that, as etching time increases, the crystal lattice is slightly altered for homogeneous grains, it is completely damaged for anomalous grains, and it is altered in some areas for hybrid grains. The SEM (energy dispersive X-ray spectroscopy, EDS) results indicated that, independent of the grain types, where the crystallinity remains after etching, the chemical composition of zircon is approximately 33% SiO(2):65% ZrO(2) (standard natural zircon), and for areas where the grain does not have a crystalline structure, there are variations of ZrO(2) and, mainly, SiO(2). In addition, it is possible to observe a uniform surface density of fission tracks in grain areas where the determined crystal lattice and chemical composition are those of zircon. Regarding hybrid grains, we discuss whether the areas slightly altered by the chemical etching can be analyzed by the fission track method (FTM) or not. Results of zircon fission track and U-Pb dating show that hybrid and homogeneous grains can be used for dating, and not only homogeneous grains. More than 50 sedimentary samples from the Bauru Basin (southeast Brazil) were analyzed and show that only a small amount of grains are homogeneous (10%), questioning the validity of the rest of the grains for thermo-chronological evolution studies using zircon FTM dating. PMID- 22524961 TI - Quality and statistical classification of Brazilian vegetable oils using mid infrared and Raman spectroscopy. AB - Palm oil, soy oil, sunflower oil, corn oil, castor oil, and rapeseed oil were analyzed with Fourier transform infrared (FT-IR) and FT-Raman spectroscopy. The quality of different oils was evaluated and statistically classified by principal component analysis (PCA) and a partial least squares (PLS) regression model. First, a calibration set of spectra was selected from one sampling batch. The qualitative variations in spectra are discussed with a prediction of oil composition (saturated, mono- and polyunsaturated fatty acids) from mid-infrared analysis and iodine value from FT-Raman analysis, based on ratioing the intensity of bands at given wavenumbers. A more robust and convincing oil classification is obtained from two-parameter statistical models. The statistical analysis of FT-Raman spectra favorably distinguishes according to the iodine value, while the mid-infrared spectra are most sensitive to hydroxyl moieties. Second, the models are validated with a set of spectra from another sampling batch, including the same oil types as-received and after different aging times together with a hydrogenated castor oil and high-oleic sunflower oil. There is very good agreement between the model predictions and the Raman measurements, but the statistical significance is lower for mid-infrared spectra. In the future, this calibration model will be used to check vegetable oil qualities before using them in polymerization processes. PMID- 22524962 TI - Fourier transform infrared (FT-IR) imaging coupled with principal component analysis (PCA) for the study of photooxidation of polypropylene. AB - Fourier transform infrared (FT-IR) imaging coupled with principal component analysis (PCA) is used to characterize the photooxidation of polypropylene (PP) and identify the photooxidative products at different oxidation times. PP slices were exposed to ultraviolet (UV) irradiation for times up to 60 hours and spatially resolved spectra were acquired with a transmission FT-IR imaging system in order to view the steric inhomogeneity of the photooxidation process of PP. The evolution of the oxidized products with irradiation time is shown through the application of PCA. Carboxylic acid is the major oxidized product in the initial period from 0 h to 8 h while ketone becomes the major product with the increase of irradiation time. Carboxylic anhydride is identified for the first time to our knowledge in oxidized PP after 16 h irradiation. Carboxylate ester is also observed in the oxidized PP after 32 h irradiation. Possible mechanisms forming these products have been discussed. PMID- 22524963 TI - Application of mid-infrared spectroscopy to the development and transfer of a manufacturing process for an active pharmaceutical ingredient. AB - The use of in situ mid-infrared spectroscopy to support the development of a pharmaceutical manufacturing process is disclosed. Data on this two-stage telescoped reaction from several reaction scales (<50 mL to 1600 liters) and at multiple manufacturing locations is shown. In addition to providing data on both reactions in the telescope, the mid-IR data has been used to monitor an intermediate distillation operation and therefore it has been possible to profile the whole process. Data is also shown on aliquot addition during the first chemical transformation, which is used to check the instrumentation. PMID- 22524964 TI - Characterization of a water-dispersible metal protective coating with Fourier transform infrared spectroscopy, modulated differential scanning calorimetry, and ellipsometry. AB - An ethylene-methacrylic acid copolymer, formulated by BASF as a waterborne suspension of its alkylammonium salt and used, among other applications, in art conservation as a temporary protective coating was characterized using Fourier transform infrared (FT-IR) spectroscopy aided by modulated differential scanning calorimetry (MDSC) and ellipsometry. The thermal conversion of thin copolymer films from the freshly applied state, where carboxylic acid and carboxylate ion functional groups co-exist, to a purely acidic working state was spectroscopically followed. Transmission mid-infrared data of the working state showed a 1 : 12 ratio of methacrylic acid towards ethylene units. The glass transition temperature (T(g)) in the same state was found at 45 degrees C. Copolymer films spin-coated on mechanically polished bronze and iron coupons were characterized with transflection infrared spectroscopy and compared to corresponding transmission mid-infrared spectra of copolymer films spin-coated on silicon wafers. In the case of bronze coupons, evidence for interaction of the carboxylate ion with the copper substrate was obtained. The chemical structure and the thermal behavior of the coating, as well as some implications on its protective capability towards iron and copper alloys, is discussed as this material has received considerable attention in the field of metal conservation and coatings. PMID- 22524965 TI - Spectroscopic evidence for atmospheric stabilization of aluminum borohydride in polydimethylsiloxane grease. AB - Raman and infrared vibrational spectroscopy were used to confirm the presence of aluminum borohydride dissolved in a commercial polydimethylsiloxane vacuum grease at room temperature. Spectroscopic evidence for an adduct between the aluminum borohydride and polydimethylsiloxane is also presented. Once dissolved in the polydimethylsiloxane grease, the aluminum borohydride was stabilized with respect to its usual pyrophoric reactivity in wet or dry air. PMID- 22524966 TI - Evaluation of apparent viscosity of Para rubber latex by diffuse reflection near infrared spectroscopy. AB - Near-infrared spectroscopy in diffuse reflection mode was used to evaluate the apparent viscosity of Para rubber field latex and concentrated latex over the wavelength range of 1100 to 2500 nm, using partial least square regression (PLSR). The model with ten principal components (PCs) developed using the raw spectra accurately predicted the apparent viscosity with correlation coefficient (r), standard error of prediction (SEP), and bias of 0.974, 8.6 cP, and -0.4 cP, respectively. The ratio of the SEP to the standard deviation (RPD) and the ratio of the SEP to the range (RER) for the prediction were 4.4 and 16.7, respectively. Therefore, the model can be used for measurement of the apparent viscosity of field latex and concentrated latex in quality assurance and process control in the factory. PMID- 22524967 TI - In situ real-time diffuse reflection infrared Fourier transform spectroscopy (DRIFTS) study of hydrogen adsorption and desorption on Ir/SiO2 catalyst. AB - The adsorption and desorption of hydrogen on Ir/SiO(2) catalyst were studied by using in situ diffuse reflection infrared Fourier transform spectroscopy (DRIFTS) combined with curve-fitting analysis. The results indicate that there are three different surface species formed on the catalyst that correspond to the peaks at 1950, 2010, and 2035 cm(-1), respectively, when exposed in H(2) flow at 130 degrees C. These surface species display different adsorption and desorption trends. Surface hydride forms after the catalyst is cooled to 80 degrees C and it disappears after the catalyst is heated to 130 degrees C again. This study may help us understand the interaction between hydrogen and noble metals and thus give more insights to heterogeneous catalytic mechanism involving hydrogen and hydrogen storage using metal materials. PMID- 22524968 TI - Discrimination of the hard keratins animal horn and chelonian shell using attenuated total reflection-infrared spectroscopy. AB - The ability to discriminate between objects manufactured from animal horn and chelonian (turtle, tortoise, or terrapin) shell is important from a cultural and archeological perspective such that it may allow conservators to determine the appropriate treatment and long-term care solution. It would also aid curators in identifying and cataloging items manufactured from these materials. Discrimination and classification is also a valuable tool for those involved in tracking the illegal trade in restricted materials of this nature. Attenuated total reflection infrared (ATR-IR) spectroscopy, using a single reflection diamond internal reflection element (IRE), coupled with discrimination analysis was used to analyze a total of thirty-nine samples (29 calibration samples, 10 validation samples). A discrimination analysis model was constructed using Mahalanobis distances to classify spectra into one of two classes. The model was then subsequently used to successfully classify all validation samples and correctly identify them as animal horn or chelonian shell based on second derivative spectra of the amide I and II regions. This technique requires minimal to no sample preparation and may be used to nondestructively identify very small samples successfully without performing detailed secondary structural curve fitting routines. This model should be a valuable resource to museums, conservators, and wildlife management programs for rapidly and reliably discriminating between animal horn and chelonian shell. PMID- 22524969 TI - Addition of a low dose of rimonabant to orlistat therapy decreases weight gain and reduces adiposity in dietary obese rats. AB - 1. The aim of the present study was to determine whether the addition of a subeffective dose of rimonabant (1 mg/kg) to orlistat would be beneficial in the treatment of diet-induced obesity in rats compared with orlistat monotherapy. 2. Male rats were divided into five groups: (i) rats fed a low-fat diet for 4 months; (ii) rats fed a high-fat diet (HFD) for 4 months and treated daily with vehicle (0.2% Tween-80 solution); (iii) orlistat (10 mg/kg per day)-treated HFD fed rats; (iv) rimonabant (1 mg/kg per day)-treated HFD-fed rats; and (v) HFD-fed rats treated with a combination of orlistat plus rimonabant. Fasting blood glucose, serum insulin, leptin and adiponectin levels were measured. Liver and adiposity indices were calculated and liver and adipose tissues were processed for histological examination. 3. Over the 4 months of the study, vehicle-treated HFD-fed rats exhibited increased cumulative food intake, bodyweight and liver and adiposity indices. Moreover, vehicle-treated HFD-fed rats exhibited a deterioration in liver function and an abnormal lipid profile. Insulin resistance and serum leptin were increased in this group, whereas serum adiponectin levels were decreased. Orlistat monotherapy or combination therapy with orlistat plus rimonabant improved all these parameters. 4. The addition of the low subeffective dose of rimonabant to orlistat therapy ameliorated HFD-induced obesity to a much greater extent than orlistat monotherapy. This combination showed better weight control and metabolic profile compared with orlistat alone. Therefore, the results of the present study encourage reassessment of the use of a low dose of rimonabant to potentiate the effect of orlistat in the clinical management of obesity if proper clinical safety data are available. PMID- 22524970 TI - Polycyclic aromatic hydrocarbons (PAHs) in Mississippi seafood from areas affected by the Deepwater Horizon Oil Spill. AB - Seafood samples from the fishing ground closure areas of Mississippi Gulf Coast that were affected by the Deepwater Horizon Oil Spill Disaster were collected and analyzed for twenty-five 2- to 6-ring PAHs, about one month after the first day of incident. A total of 278 seafood samples consisting of 86 fishes, 65 shrimps, 59 crabs, and 68 oysters were collected and analyzed weekly from May 27, 2010 until October 2010 and monthly thereafter until August 2011. Statistically higher levels of total PAHs were detected in all four types of seafood samples during early part of the sampling period compared to the later months. There was no significant concentration difference between PAHs detected in the oyster samples for the current study and the 10-year historical data from the NOAA Mussel Watch program. The PAH levels in the tested seafood samples were similar to those detected in commonly consumed processed foods purchased from local grocery stores and restaurants. Overall, the levels of PAHs in all the tested seafood samples collected within one-year period after the Oil Spill incident were far below the public health Levels of Concern (LOC) established jointly by the NOAA/FDA/Gulf Coast states under the protocol to reopen state and federal waters. PMID- 22524971 TI - Spontaneous splenic rupture and Anisakis appendicitis presenting as abdominal pain: a case report. AB - INTRODUCTION: Anisakidosis, human infection with nematodes of the family Anisakidae, is caused most commonly by Anisakis simplex. Acquired by the consumption of raw or undercooked marine fish or squid, anisakidosis occurs where such dietary customs are practiced, including Japan, the coastal regions of Europe and the United States. Rupture of the spleen is a relatively common complication of trauma and many systemic disorders affecting the reticuloendothelial system, including infections and neoplasias. A rare subtype of rupture occurring spontaneously and arising from a normal spleen has been recognized as a distinct clinicopathologic entity. Herein we discuss the case of a woman who presented to our institution with appendicitis secondary to Anisakis and spontaneous spleen rupture. CASE PRESENTATION: We report the case of a 53 year-old Caucasian woman who presented with hemorrhagic shock and abdominal pain and was subsequently found to have spontaneous spleen rupture and appendicitis secondary to Anisakis simplex. She underwent open surgical resection of the splenic rupture and the appendicitis without any significant postoperative complications. Histopathologic examination revealed appendicitis secondary to Anisakis simplex and splenic rupture of undetermined etiology. CONCLUSIONS: To the best of our knowledge, this report is the first of a woman with the diagnosis of spontaneous spleen rupture and appendicitis secondary to Anisakis simplex. Digestive anisakiasis may present as an acute abdomen. Emergency physicians should know and consider this diagnosis in patients with ileitis or colitis, especially if an antecedent of raw or undercooked fish ingestion is present. Spontaneous rupture of the spleen is an extremely rare event. Increased awareness of this condition will enhance early diagnosis and effective treatment. Further research is required to identify the possible risk factors associated with spontaneous rupture of the spleen. PMID- 22524972 TI - Abnormal structural and functional brain connectivity in gray matter heterotopia. AB - PURPOSE: Periventricular nodular heterotopia (PNH) is a malformation of cortical development associated with epilepsy and dyslexia. Evidence suggests that heterotopic gray matter can be functional in brain malformations and that connectivity abnormalities may be important in these disorders. We hypothesized that nodular heterotopia develop abnormal connections and systematically investigated the structural and functional connectivity of heterotopia in patients with PNH. METHODS: Eleven patients were studied using diffusion tensor tractography and resting-state functional connectivity MRI with bold oxygenation level-dependent (BOLD) imaging. Fiber tracks with a terminus within heterotopic nodules were visualized to determine structural connectivity, and brain regions demonstrating resting-state functional correlations to heterotopic nodules were analyzed. Relationships between these connectivity results and measures of clinical epilepsy and cognitive disability were examined. KEY FINDINGS: A majority of heterotopia (69%) showed structural connectivity to discrete regions of overlying cortex, and almost all (96%) showed functional connectivity to these regions (mean peak correlation coefficient 0.61). Heterotopia also demonstrated connectivity to regions of contralateral cortex, other heterotopic nodules, ipsilateral but nonoverlying cortex, and deep gray matter structures or the cerebellum. Patients with the longest durations of epilepsy had a higher degree of abnormal functional connectivity (p = 0.036). SIGNIFICANCE: Most heterotopic nodules in PNH are structurally and functionally connected to overlying cortex, and the strength of abnormal connectivity is higher among patients with the longest duration of epilepsy. Along with prior evidence that cortico-cortical tract defects underlie dyslexia in this disorder, the current findings suggest that altered connectivity is likely a critical substrate for neurologic dysfunction in brain malformations. PMID- 22524973 TI - Characteristics of stroke mechanisms in patients with medullary infarction. AB - BACKGROUND: Few studies have focused on the mechanisms underlying medullary infarctions. Our aim in this study was to investigate stroke mechanisms in patients with medullary infarctions and to determine the clinical, radiological and laboratory characteristics of these patients with different underlying stroke etiologies. METHODS: Consecutive patients with medullary infarction were analysed. Stroke mechanisms were classified as large artery disease (LAD), cardiogenic embolism (CE), small vessel disease (SVD), arterial dissection or undetermined etiology. Clinical, radiological and laboratory factors were analysed according to the location of the lesion and stroke mechanisms. RESULTS: A total of 77 patients were enrolled in this study. Amongst them, 53 (68.8%) patients had lateral medullary infarction (LMI), 22 (28.6%) had medial medullary infarction (MMI), and the remaining 2 (2.6%) had hemimedullary infarction. In both LMI and MMI patients, LAD was the most frequently encountered stroke mechanism. Arterial dissection was the second most common cause followed by SVD and CE in patients with LMI, whereas SVD was more frequently observed (P < 0.001) and dissection and CE were less prevalent (P < 0.001 and P = 0.024, respectively) in MMI than in LMI. Regarding differences amongst stroke etiologies, patients with dissection were younger and had a significantly lower incidence of metabolic syndrome (P = 0.002 and P = 0.009, respectively) than patients with LAD and SVD. Patients in the LAD (19/34, 60%) and dissection groups (12/14, 75%) had abnormal perfusion-weighted MRI (PWI) findings, whereas all patients with SVD (9/9) had normal PWI findings (P < 0.001). CONCLUSIONS: Stroke mechanisms in medullary infarction differ between LMI and MMI. Clinical and radiological characteristics, especially PWI features, are helpful in discriminating the etiologies of stroke in these patients. PMID- 22524975 TI - The effect of a controlled 8-week metabolic ward based lysine supplementation on muscle function, insulin sensitivity and leucine kinetics in young men. AB - BACKGROUND & AIMS: The 2007 FAO/WHO/UNU lysine requirement is 30 mgkg(-1)d(-1). Developing country populations may be at risk of lysine deficiency, with effects on muscle and its function. The effect of an 8 wk lysine supplementation diet on muscle mass and function was assessed. METHODS: Healthy, under and well-nourished men were studied before and after 8 wk, during which low (n=20) and high (n=20) lysine diets were consumed. The low lysine diets (~25 and ~40 mgkg(-1)d(-1) for under and well-nourished respectively) were based on the subjects' habitual lysine intake, while the high lysine diet supplied 80 mgkg(-1)d(-1). Anthropometry, muscle function, insulin sensitivity (IS) and leucine kinetics were measured before and after the experimental period. RESULTS: The high lysine diet had a small positive effect (about +7.5%) on muscle strength, but no effect on other parameters. Over the 8 wk period in the whole group, the change in muscle strength correlated with the change in muscle mass (r=0.5, P=0.001), while the change in muscle mass correlated with the change in IS (r=0.3, P=0.04), but there were no intake specific differences. CONCLUSION: Over an 8 wk controlled feeding period, an intake of 80 mg lysine kg(-1)d(-1) had a small positive effect on muscle strength, but no other effects. PMID- 22524974 TI - Directed therapy for patients with myelodysplastic syndromes (MDS) by suppression of cyclin D1 with ON 01910.Na. AB - BACKGROUND: We previously demonstrated upregulation of c-myc, survivin, and cyclin D1 in CD34+ bone marrow mononuclear cells (BMMNCs) of patients with trisomy 8 and monosomy 7 myelodysplastic syndromes (MDS). "Knockdown" of cyclin D1 by RNA interference decreased trisomy 8 cell growth, suggesting that this might be a therapeutic target in MDS. EXPERIMENTAL DESIGN: We performed preclinical studies using BMMNCs from patients with MDS and AML to examine the effects of the styryl sulfone ON 01910.Na on cyclin D1 accumulation, aneuploidy, and CD34+ blast percentage. We next treated twelve patients with higher risk MDS and two trisomy 8 AML patients with ON 01910.Na on a phase I clinical protocol (NCT00533416). RESULTS: ON 01910.Na inhibited cyclin D1 expression, and was selectively toxic to trisomy 8 cells in vitro. Flow cytometry studies demonstrated increased mature CD15+ myeloid cells and decreased CD34+ blasts. Three patients treated with ON 01910.Na on a clinical had decreased bone marrow blasts by >= 50%, and three patients had hematologic improvements, one of which was sustained for 33 months. Patients with hematologic responses to ON 01910.Na had decreased cyclin D1 expression in their CD34+ cells. CONCLUSIONS: The preclinical results and responses of patients on a clinical trial warrant further investigation of ON 01910.Na as a potential novel targeted therapy for higher risk MDS patients. PMID- 22524976 TI - Three-dimensional determination of variability in colon anatomy: applications for numerical modeling of the intestine. AB - BACKGROUND: Precise knowledge of variability in colonic anatomy is of great importance for numerical modeling studies of the abdomen. This knowledge would allow the creation of personalized models for the gastrointestinal tract used for surgical simulations or in studies of virtual trauma. MATERIALS AND METHODS: To determine the colonic configuration in the general population and define its variability by gender, age, and corpulence, the layout of the colon was determined via the following reference points: ileocecal junction, left and right colonic flexures, and colosigmoid junction (CSJ). Three-dimensional coordinates for each point were recorded on scanned sections of 100 healthy adults to examine the colonic layout under physiological conditions. Coordinates were repositioned in a new anatomical reference for comparison. The average points' coordinates, standard deviations, and distances between them were compared for each group. RESULTS: The right colonic flexure was the most variable point. The CSJ was the least variable. Gender affected mainly the height of the colonic flexures and the length of its segments. Age affected the length of the transverse mesocolon root. Corpulence affected both the position of the ileocecal and CSJs and the length of the right colon. Differences in size and perivisceral fat distribution between groups explained these differences. Three-dimensional anatomical models of the colon were defined for each group by statistical equations. CONCLUSION: These equations, combined with data concerning the actual lengths of the colonic segments, enable reconstruction of different anatomical models of the colon that are representative according to gender, age, and corpulence. PMID- 22524977 TI - Factors associated with phyllodes tumor of the breast after core needle biopsy identifies fibroepithelial neoplasm. AB - BACKGROUND: Phyllodes tumors represent less than 1% of all breast neoplasms and can mimic fibroadenoma on core needle biopsy (CNB). The treatment of fibroepithelial (FE) neoplasms identified on CNB is controversial. We sought to identify factors that were associated with phyllodes tumors after CNB suggested FE neoplasm. MATERIALS AND METHODS: A retrospective database was queried for all patients diagnosed with FE neoplasm on CNB at Ben Taub General Hospital over a 10 y period. One hundred twenty-three patients were identified and demographic, clinical, and outcome data were analyzed. RESULTS: Of the 123 patients, 46 (37%) were found to have fibroadenomatous features and 59 (48%) were found to have FE features. All went on to have surgical excision. Forty (38%) contained phyllodes tumors, and 65 (62%) found no phyllodes tumor on final pathology. There were significant differences in the median size of the masses (4 cm versus 2.4 cm P < 0.002) and density of the masses (P < 0.001) between the group that contained phyllodes tumors and the group that did not on preoperative imaging. Further evaluation did not show any significant differences on preoperative imaging between benign and borderline/malignant phyllodes tumors. Hispanic ethnicity correlated with a higher chance of phyllodes tumor after CNB (P < 0.001). CONCLUSIONS: Women commonly present to clinics for evaluation of palpable breast masses. Based on the results of CNB, clinical decisions can be made to help direct treatment. If CNB identifies phyllodes tumor, surgical excision remains the standard of care; however, patients with suspicious FE neoplasms represent a treatment dilemma as many will prove to be benign. Preoperative size and the density of the mass on imaging and ethnicity were associated with phyllodes tumors on final pathology. PMID- 22524978 TI - The simulated ward: ideal for training clinical clerks in an era of patient safety. AB - INTRODUCTION: Work rules have changed medical education. Knowledge previously acquired by experience must now be actively taught to avoid prolonging the training period. We report the feasibility of and clinical clerk opinions regarding a novel simulated floor management course to teach patient care concepts required on the surgical wards. METHODS: We created a hospital ward with simulators exhibiting physical exam findings and active vital signs. Surgical clerks gathered data during "morning rounds," wrote notes, and provided care. An acute event allowed students to participate in active evaluation and treatment. Findings and plans were communicated to their "chief resident," a surgical attending. We distributed a survey to participants to determine attitudes and opinions about the course. RESULTS: The course required five faculty, two medical educators, four surgical house staff, and 2.5 h to accommodate 40-50 students. Faculty and surgical house staff provided guidance and feedback on clinical skills. Fifty students completed the survey (56% response rate). Most clinical clerks thought that the simulated floor management course improved their understanding of medical management of surgical issues (66%) and their documentation skills (78%). Clinical clerks reported that attending involvement made the experience more valuable (89%) and was not intimidating (66%). Most expressed an interest in participating in more clinical scenarios (72%). CONCLUSIONS: A simulation course for teaching patient care concepts is feasible and regarded positively by clinical clerk participants. Further development and use of such simulated patient care exercises may be an effective adjunct for training future house staff and hospital staff in patient care in a time of shifting work hour paradigms. PMID- 22524979 TI - Plasma and cerebrospinal fluid pharmacokinetic parameters after single-dose administration of intravenous, oral, or rectal acetaminophen. AB - BACKGROUND: This is the first study to compare plasma and cerebrospinal fluid (CSF) pharmacokinetics of intravenous (IV), oral (PO), or rectal (PR) formulations of acetaminophen. METHODS: Healthy male subjects (N = 6) were randomized to receive a single dose of IV (OFIRMEV((r)) ; Cadence) 1,000 mg (15 minute infusion), PO (2 Tylenol((r)) 500 mg caplets; McNeil Consumer Healthcare), or PR acetaminophen (2 Feverall((r)) 650 mg suppositories; Actavis) with a 1-day washout period between doses. The 1,300 mg PR concentrations were standardized to 1,000 mg. Acetaminophen plasma and CSF levels were obtained at T0, 0.25, 0.5, 0.75, 1, 2, 3, 4, and 6 hours. RESULTS: IV acetaminophen showed earlier and higher plasma and CSF levels compared with PO or PR administration. CSF bioavailability over 6 hours (AUC(0-6)) for IV, PO, and PR 1 g was 24.9, 14.2, and 10.3 MUg.h/mL, respectively. No treatment-related adverse events were reported. One subject was replaced because of premature failure of his lumbar spinal catheter. The mean CSF level in the IV group was similar to plasma from 3 to 4 hours and higher from 4 hours on. Absorption phase, variability in plasma, and CSF were greater in PO and PR groups than variability with IV administration. CONCLUSIONS: These results demonstrate that earlier and greater CSF penetration occurs as a result of the earlier and higher plasma peak with IV administration compared with PO or PR. PMID- 22524980 TI - The Dalhousie Health Mentors Program: introducing students to collaborative patient/client-centered practice. AB - The Dalhousie Health Mentors Program builds on a long history of interprofessional health education initiatives by introducing students in health and social care professions to chronic conditions and disabilities, patient/client-centredness, interprofessional learning, and team functioning. This large interprofessional education program (16 participating programs, 650 students) connects interprofessional student teams with Health Mentors, who are adult volunteers with chronic conditions, for a learning experience that extends over one academic year. Students explore their mentor's life story and chronic condition journey, the impact the condition has had on her/his life, and her/his experience with health care in general and interprofessional collaboration in particular. All aspects of the program planning, management, implementation, and evaluation have been interprofessional in nature. Lessons have been learned regarding. PMID- 22524981 TI - Challenges to elderly safety in Safe Community movements in Japan. AB - In Japan, with the longest life expectancy in the world over the last two decades, a great emphasis has been placed on the safety of the elderly, which has in turn influenced their well-being. Meantime, the concept of Safe Community (SC) has drawn more attention as one of the potential measures to sustain and improve the health conditions of the elderly. In hope of improving the effectiveness and efficiency of current efforts for elderly safety, the SC model is expected to provide features with which communities can make the better use of current limited resources. This article examines how the SC model makes a difference in these efforts by utilising existing programmes and how elderly safety can be promoted at the community level. Six communities working safety promotion based on the SC model were selected for the study. Although there are limitations to the information due to the insufficient experience in SC in Japan, it was found that two features make SC significant in promoting safety: (1) systematic evidence-based plan-do-check-action processes and (2) a framework of cross sectoral collaboration. However, to examine and identify the effectiveness of SC on elderly health, further observation is required to develop strategies while accumulating longitudinal data. PMID- 22524982 TI - A knowledge-based clinical toxicology consultant for diagnosing single exposures. AB - OBJECTIVE: Every year, toxic exposures kill 1200 Americans. To aid in the timely diagnosis and treatment of such exposures, this research investigates the feasibility of a knowledge-based system capable of generating differential diagnoses for human exposures involving unknown toxins. METHODS: Data mining techniques automatically extract prior probabilities and likelihood ratios from a database managed by the Florida Poison Information Center. Using observed clinical effects, the trained system produces a ranked list of plausible toxic exposures. The resulting system was evaluated using 30,152 single exposure cases. In addition, the effects of two filters for refining diagnosis based on a minimum number of exposure cases and a minimum number of clinical effects were also explored. RESULTS: The system achieved accuracies (calculated as the percentage of exposures correctly identified in top 10% of trained diagnoses) as high as 79.8% when diagnosing by substance and 78.9% when diagnosing by the major and minor categories of toxins. CONCLUSIONS: The results of this research are modest, yet promising. At this time, no similar systems are currently in use in the United States and it is hoped that these studies will yield an effective medical decision support system for clinical toxicology. PMID- 22524983 TI - Comprehensive identification of substrates for F-box proteins by differential proteomics analysis. AB - Although elucidation of enzyme-substrate relations is fundamental to the advancement of biology, universal approaches to the identification of substrates for a given enzyme have not been established. It is especially difficult to identify substrates for ubiquitin ligases, given that most such substrates are immediately ubiquitylated and degraded as a result of their association with the enzyme. We here describe the development of a new approach, DiPIUS (differential proteomics-based identification of ubiquitylation substrates), to the discovery of substrates for ubiquitin ligases. We applied DiPIUS to Fbxw7alpha, Skp2, and Fbxl5, three of the most well-characterized F-box proteins, and identified candidate substrates including previously known targets. DiPIUS is thus a powerful tool for unbiased and comprehensive screening for substrates of ubiquitin ligases. PMID- 22524984 TI - Isolation, cultivation and identification of nanobacteria from placental calcification. AB - OBJECTIVE: The etiology of placental calcification (PC) is lack of research. To detect the bacterial infection mechanisms for PC, the experiment of isolating, culturing and identifying the nanobacteria in PC was done. METHOD: The calcified placental tissues from 18 confirmed PC cases with normal placental tissue samples from 18 cases were studied by transmission electron microscopy (TEM), special nanobacterial culture methods, and identification of 16S rRNA sequence. RESULT: Under transmission electron microscope (TEM), Nanobacteria-like particles (NLP) in extra-cellular matrix (ECM) of calcified placental tissues were found, they were 50-500 nm in diameter, existed aggregation, among hydroxyapatite (HAP) crystals. Isolation and culture of NLP from the calcified tissues with methods described for nanobacteria were successful. All calcified placental tissue samples showed white granular deposition, which were firmly attached to the bottom of the culture tubes visible to the naked eyes. In the control group they could not be seen. According to 16S rRNA gene sequences analysis and was amplified adopting PCR and obtained 1407 bp fragment. Submit to GenBank after sequencing with accession number JN029830. CONCLUSION: Indicating that nanobacteria infection is related with placental calcification. PMID- 22524985 TI - Levetiracetam induced angioedema in a patient with previous anticonvulsant hypersensitivity reaction to phenytoin and lamotrigine. AB - Allergic reactions to antiepileptic drugs in the form of skin rash are not uncommon but angioedema, an acute life threatening reaction is rare. Angioedema has been reported with the use of oxcarbazepine and carbamazepine. We report a case of a 33-year-old woman with focal epilepsy who developed angioedema following levetiracetam monotherapy. The patient had previous skin rashes with both phenytoin and lamotrigine. Levetiracetam was stopped and she improved after treatment with norepinephrine, antihistamines and corticosteroids. PMID- 22524986 TI - Treatment of reperfused ischemia with adipose-derived stem cells in a preclinical Swine model of myocardial infarction. AB - The aim of the study was to determine the long-term effect of transplantation of adipose-derived stromal cells (ADSCs) in a preclinical model of ischemia/reperfusion (I/R). I/R was induced in 28 Goettingen minipigs by 120 min of coronary artery occlusion followed by reperfusion. Nine days later, surviving animals were allocated to receive transendocardial injection of a mean of 213.6 +/- 41.78 million green fluorescent protein (GFP)-expressing ADSCs (n = 7) or culture medium as control (n = 9). Heart function, cell engraftment, and histological analysis were performed 3 months after transplantation. Transplantation of ADSCs induced a statistically significant long-lasting (3 months) improvement in cardiac function and geometry in comparison with control animals. Functional improvement was associated with an increase in angiogenesis and vasculogenesis and a positive effect on heart remodeling with a decrease in fibrosis and cardiac hypertrophy in animals treated with ADSCs. Despite the lack of cell engraftment after 3 months, ADSC transplantation induced changes in the ratio between MMP/TIMP. Our results indicate that transplantation of ADSCs, despite the lack of long-term significant cell engraftment, increases vessel density and prevents adverse remodeling in a clinically relevant model of myocardial infarction, strongly suggesting a paracrine-mediated effect. ADSCs thus constitute an attractive candidate for the treatment of myocardial infarction. PMID- 22524988 TI - Birth dating of midbrain dopamine neurons identifies A9 enriched tissue for transplantation into parkinsonian mice. AB - Clinical trials have provided proof of principle that new dopamine neurons isolated from the developing ventral midbrain and transplanted into the denervated striatum can functionally integrate and alleviate symptoms in Parkinson's disease patients. However, extensive variability across patients has been observed, ranging from long-term motor improvement to the absence of symptomatic relief and development of dyskinesias. Heterogeneity of the donor tissue is likely to be a contributing factor in the variable outcomes. Dissections of ventral midbrain used for transplantation will variously contain progenitors for different dopamine neuron subtypes as well as different neurotransmitter phenotypes. The overall impact of the resulting graft will be determined by the functional contribution from these different cell types. The A9 substantia nigra pars compacta dopamine neurons, for example, are known to be particularly important for motor recovery in animal models. Serotonergic neurons, on the other hand, have been implicated in unwanted dyskinesias. Currently little knowledge exists on how variables such as donor age, which have not been controlled for in clinical trials, will impact on the final neuronal composition of fetal grafts. Here we performed a birth dating study to identify the time course of neurogenesis within the various ventral midbrain dopamine subpopulations in an effort to identify A9-enriched donor tissue for transplantation. The results show that A9 neurons precede the birth of A10 ventral tegmental area dopamine neurons. Subsequent grafting of younger ventral midbrain donor tissue revealed significantly larger grafts containing more mitotic dopamine neuroblasts compared to older donor grafts. These grafts were enriched with A9 neurons and showed significantly greater innervation of the target dorso-lateral striatum and DA release. Younger donor grafts also contained significantly less serotonergic neurons. These findings demonstrate the importance of standardized methods to improve cell therapy for Parkinson's disease and have significant implications for the generation and selectivity of dopamine neurons from stem cell based sources. PMID- 22524987 TI - Enforced Pax6 expression rescues alcohol-induced defects of neuronal differentiation in cultures of human cortical progenitor cells. AB - BACKGROUND: Alcohol is the most widely consumed substance of abuse, and its use during pregnancy can lead to serious disorders of brain development. The precise molecular action of alcohol on human brain development, however, is still unknown. We previously enriched multipotent progenitor cells, radial glia (RG) cells, from human fetal forebrain and demonstrated that they express transcription factor Pax6 that is necessary for their neurogenic fate. METHODS: Enriched human fetal RG cells were maintained in vitro as either control or Pax6 expressing retrovirus infected cells. Cultures were treated with increasing doses of alcohol to evaluate Pax6 expression, proliferation, and differentiation of RG cells by immunocytochemistry, Western blot, and RT-PCR methods. RESULTS: In vitro treatment with alcohol reduced the expression of transcription factor Pax6 and proliferation of RG cells, which decreased neurogenesis. Consistent with this finding, the overexpression of Pax6 in RG cells under alcohol treatment rescued cell proliferation and restored the generation of neurons. In contrast to this effect on neurogenesis, the overexpression of Pax6 inhibits the generation of astroglia regardless of alcohol treatment, implying lineage-specific effects. CONCLUSIONS: These findings suggest that the effect of alcohol on human neurogenesis is partially due to the reduced expression of transcription factor Pax6 in RG cells. PMID- 22524989 TI - Huperzine A ameliorates experimental autoimmune encephalomyelitis via the suppression of T cell-mediated neuronal inflammation in mice. AB - Huperzine A (HupA), a sesquiterpene alkaloid and a potent and reversible inhibitor of acetylcholinesterase, possesses potential anti-inflammatory properties and is used for the treatment of certain neurodegenerative diseases such as Alzheimer's disease. However, it is still unknown whether this chemical is beneficial in the treatment of multiple sclerosis, a progressive inflammatory disease of the central nervous system. In this study, we examined the immunomodulatory properties of HupA in experimental autoimmune encephalomyelitis (EAE), a T-cell mediated murine model of multiple sclerosis. The following results were obtained: (1) intraperitoneal injections of HupA significantly attenuate the neurological severity of EAE in mice. (2) HupA decreases the accumulation of inflammatory cells, autoimmune-related demyelination and axonal injury in the spinal cords of EAE mice. (3) HupA down-regulates mRNA levels of the pro-inflammatory cytokines (IFN-gamma and IL-17) and chemokines (MCP-1, RANTES, and TWEAK) while enhancing levels of anti-inflammatory cytokines (IL-4 and IL-10) in the spinal cords of EAE mice. (4) HupA inhibits MOG(35-55) stimulation-induced T-cell proliferation and IFN-gamma and IL-17 secretion in cultured splenocytes. (5) HupA inhibition of T-cell proliferation is reversed by the nicotinic acetylcholinergic receptor antagonist mecamylamine. We conclude that HupA can ameliorate EAE by suppressing autoimmune responses, inflammatory reactions, subsequent demyelination and axonal injury in the spinal cord. Therefore, HupA may have a potential therapeutic value for the treatment of multiple sclerosis and as a neuroimmunomodulatory drug to control human CNS pathology. PMID- 22524991 TI - Implementation and acceptability of Mindful Awareness in Body-oriented Therapy in women's substance use disorder treatment. AB - OBJECTIVES: The purpose of this study was to examine the implementation and acceptability of Mindful Awareness in Body-oriented Therapy (MABT), a novel adjunctive approach to substance use disorder (SUD) treatment. The primary aims of the study were to examine implementation of MABT as an adjunct to addiction treatment, and MABT acceptability to study participants and treatment staff. METHODS: MABT was delivered to participants randomly assigned to the intervention in a larger ongoing trial. This study focuses only on the implementation and acceptability of the intervention, as outcomes are not yet available. MABT was delivered once weekly for 8 weeks (1.5-hour sessions) and spanned inpatient and outpatient programs at a women-only treatment facility. Descriptive statistics were used to examine participant recruitment and retention to the intervention. To measure MABT acceptability, survey and written questionnaires were administered; analysis involved descriptive statistics and content analysis using Atlas.ti software. RESULTS: Thirty-one (31) of the women enrolled in the study were randomized to MABT. Eighteen (18) participants completed 75%-100% of the MABT sessions. Intervention implementation required flexibility on the part of both the researchers and the clinic staff, and minor changes were made to successfully implement MABT as an adjunct to usual care. MABT was perceived to increase emotional awareness and provide new tools to cope with stress, and to positively influence SUD treatment by facilitating emotion regulation. CONCLUSIONS: It was feasible to implement MABT and to recruit and retain women to MABT in women's chemical-dependency treatment. MABT acceptability and perceived benefit was high. PMID- 22524992 TI - beta-adrenoceptor pathway enhances mitochondrial function in human neural stem cells via rotary cell culture system. AB - The structure and function of the human nervous system are altered in space when compared with their state on earth. To investigate directly the influence of simulated microgravity conditions which may be beneficial for cultivation and proliferation of human neural stem cells (hNSCs), the rotary cell culture system (RCCS) developed at the National Aeronautics and Space Administration (NASA) was used. RCCS allows the creation of a unique microgravity environment of low shear force, high-mass transfer and enables three-dimensional (3D) cell culture of dissimilar cell types. The results show that simulated microgravity using an RCCS would induce beta-adrenoceptor, upregulate cAMP formation and activate both PKA and CREB (cAMP response element binding protein) pathways. The expression of intracellular mitochondrial genes, including PGC1alpha (PPAR coactivator 1alpha), nuclear respiratory factors 1 and 2 (NRF1 and NRF2) and mitochondrial transcription factor A (Tfam), regulated by CREB, were all significantly increased at 72 h after the onset of microgravity. Accordingly and importantly, the ATP level and amount of mitochondrial mass were also increased. These results suggest that exposure to simulated microgravity using an RCCS would induce cellular proliferation in hNSCs via an increased mitochondrial function. In addition, the RCCS bioreactor would support hNSCs growth, which may have the potential for cell replacement therapy in neurological disorders. PMID- 22524993 TI - Automated optimization of a reduced layer 5 pyramidal cell model based on experimental data. AB - The construction of compartmental models of neurons involves tuning a set of parameters to make the model neuron behave as realistically as possible. While the parameter space of single-compartment models or other simple models can be exhaustively searched, the introduction of dendritic geometry causes the number of parameters to balloon. As parameter tuning is a daunting and time-consuming task when performed manually, reliable methods for automatically optimizing compartmental models are desperately needed, as only optimized models can capture the behavior of real neurons. Here we present a three-step strategy to automatically build reduced models of layer 5 pyramidal neurons that closely reproduce experimental data. First, we reduce the pattern of dendritic branches of a detailed model to a set of equivalent primary dendrites. Second, the ion channel densities are estimated using a multi-objective optimization strategy to fit the voltage trace recorded under two conditions - with and without the apical dendrite occluded by pinching. Finally, we tune dendritic calcium channel parameters to model the initiation of dendritic calcium spikes and the coupling between soma and dendrite. More generally, this new method can be applied to construct families of models of different neuron types, with applications ranging from the study of information processing in single neurons to realistic simulations of large-scale network dynamics. PMID- 22524990 TI - Rodent neonatal germinal matrix hemorrhage mimics the human brain injury, neurological consequences, and post-hemorrhagic hydrocephalus. AB - Germinal matrix hemorrhage (GMH) is the most common neurological disease of premature newborns. GMH causes neurological sequelae such as cerebral palsy, post hemorrhagic hydrocephalus, and mental retardation. Despite this, there is no standardized animal model of spontaneous GMH using newborn rats to depict the condition. We asked whether stereotactic injection of collagenase type VII (0.3 U) into the ganglionic eminence of neonatal rats would reproduce the acute brain injury, gliosis, hydrocephalus, periventricular leukomalacia, and attendant neurological consequences found in humans. To test this hypothesis, we used our neonatal rat model of collagenase-induced GMH in P7 pups, and found that the levels of free-radical adducts (nitrotyrosine and 4-hyroxynonenal), proliferation (mammalian target of rapamycin), inflammation (COX-2), blood components (hemoglobin and thrombin), and gliosis (vitronectin and GFAP) were higher in the forebrain of GMH pups, than in controls. Neurobehavioral testing showed that pups with GMH had developmental delay, and the juvenile animals had significant cognitive and motor disability, suggesting clinical relevance of the model. There was also evidence of white-matter reduction, ventricular dilation, and brain atrophy in the GMH animals. This study highlights an instructive animal model of the neurological consequences after germinal matrix hemorrhage, with evidence of brain injuries that can be used to evaluate strategies in the prevention and treatment of post-hemorrhagic complications. PMID- 22524994 TI - Automated multi-slice extracellular and patch-clamp experiments using the WinLTP data acquisition system with automated perfusion control. AB - WinLTP is a data acquisition program for studying long-term potentiation (LTP) and other aspects of synaptic function. Earlier versions of WinLTP (J. Neurosci. Methods, 162:346-356, 2007) provided automated electrical stimulation and data acquisition capable of running nearly an entire synaptic plasticity experiment, with the primary exception that perfusion solutions had to be changed manually. This automated stimulation and acquisition was done by using 'Sweep', 'Loop' and 'Delay' events to build scripts using the 'Protocol Builder'. However, this did not allow automatic changing of many solutions while running multiple slice experiments, or solution changing when this had to be performed rapidly and with accurate timing during patch-clamp experiments. We report here the addition of automated perfusion control to WinLTP. First, perfusion change between sweeps is enabled by adding the 'Perfuse' event to Protocol Builder scripting and is used in slice experiments. Second, fast perfusion changes during as well as between sweeps is enabled by using the Perfuse event in the protocol scripts to control changes between sweeps, and also by changing digital or analog output during a sweep and is used for single cell single-line perfusion patch-clamp experiments. The addition of stepper control of tube placement allows dual- or triple-line perfusion patch-clamp experiments for up to 48 solutions. The ability to automate perfusion changes and fully integrate them with the already automated stimulation and data acquisition goes a long way toward complete automation of multi-slice extracellularly recorded and single cell patch-clamp experiments. PMID- 22524995 TI - The prediction of 30-day mortality in patients with primary pontine hemorrhage: a scoring system comparison. AB - BACKGROUND AND PURPOSE: Owing to its low morbidity but high mortality, no accurate scoring system focuses on primary pontine hemorrhage (PPH) has been established. We aim to compare the performances of the Acute Physiology and Chronic Health Evaluation (APACHE) II and the Simplified Acute Physiology Score (SAPS) II with the ICH score in predicting the 30-day mortality in patients with PPH. METHODS: We conducted a retrospective analysis of patients admitted with a diagnosis of PPH to a university-affiliated hospital in southern China from May 2000 to June 2011. Data related to patient demographics and that necessary to calculate APACHE II, SAPS II, and ICH score were recorded. Performances of these scoring systems were presented as calibration and discrimination, which were measured by the Hosmer-Lemeshow goodness-of-fit test and the area under the receiver operating characteristic (ROC) curve, respectively. RESULTS: Among 75 patients with PPH finally included, 31 (41.3%) died within 30 days. SAPS II (chi(2) = 6.57, P = 0.682) had the best calibration, followed by APACHE II (chi(2) = 8.06, P = 0.428) and ICH score (chi(2) = 4.94, P = 0.176). Furthermore, in terms of area under the ROC curve, APACHE II (0.919) was more discriminative than SAPS II (0.890) and ICH score (0.844). CONCLUSIONS: In predicting 30-day mortality in patients with PPH, SAPS II has the best calibration, while APACHE II has the highest discrimination. The ICH score, which is easier and simpler to calculate, should be modified for PPH. PMID- 22524996 TI - The role of the premotor cortex and the primary motor cortex in action verb comprehension: evidence from Granger causality analysis. AB - Although numerous studies find the premotor cortex and the primary motor cortex are involved in action language comprehension, so far the nature of these motor effects is still in controversy. Some researchers suggest that the motor effects reflect that the premotor cortex and the primary motor cortex make functional contributions to the semantic access of action verbs, while other authors argue that the motor effects are caused by comprehension. In the current study, we used Granger causality analysis to investigate the roles of the premotor cortex and the primary motor cortex in processing of manual-action verbs. Regions of interest were selected in the primary motor cortex (M1) and the premotor cortex based on a hand motion task, and in the left posterior middle temporal gyrus (lexical semantic area) based on the reading task effect. We found that (1) the left posterior middle temporal gyrus had a causal influence on the left M1; and (2) the left posterior middle temporal gyrus and the left premotor cortex had bidirectional causal relations. These results suggest that the premotor cortex and the primary motor cortex play different roles in manual verb comprehension. The premotor cortex may be involved in motor simulation that contributes to action language processing, while the primary motor cortex may be engaged in a processing stage influenced by the meaning access of manual-action verbs. Further investigation combining effective connectivity analysis and technique with high temporal resolution is necessary for better clarification of the roles of the premotor cortex and the primary motor cortex in action language comprehension. PMID- 22524998 TI - Awareness of the Fruits and Veggies-More Matters campaign, knowledge of the fruit and vegetable recommendation, and fruit and vegetable intake of adults in the 2007 Food Attitudes and Behaviors (FAB) Survey. AB - Increased consumption of fruits and vegetables is recommended to reduce chronic disease risk. Few studies have examined awareness of the current fruit and vegetable campaign in the United States, Fruits and Veggies-More Matters. This study assessed awareness of the Fruits and Veggies-More Matters campaign and knowledge of the 7-13 serving recommendation for fruit and vegetable consumption among adults, and determined whether these were associated with fruit and vegetable intake. Cross-sectional data from 3021 adults in the United States' National Cancer Institute's 2007 Food Attitudes and Behaviors Survey were analyzed. Few participants were aware of the Fruits and Veggies-More Matters campaign (2%) and the 7-13 recommendation (6%) for adults. More participants were aware of the former 5 A Day campaign (29%) and recommendation (30%). Thirty-nine percent reported consuming >=5 servings of fruits and vegetables daily. Participants were more likely to consume >=5 servings of fruits and vegetables/day if they were aware of the 5 A Day/Fruits and Veggies-More Matters campaign, and reported that the recommendation for adults was >=5 servings/day. Findings suggest the need to increase awareness of the Fruits and Veggies-More Matters campaign, and the 7-13 recommendation among adults to support high fruit and vegetable intake. PMID- 22524999 TI - Making healthy food choices using nutrition facts panels. The roles of knowledge, motivation, dietary modifications goals, and age. AB - Nutrition facts panels (NFPs) contain a rich assortment of nutrition information and are available on most food packages. The importance of this information is potentially even greater among older adults due to their increased risk for diet related diseases, as well as those with goals for dietary modifications that may impact food choice. Despite past work suggesting that knowledge and motivation impact attitudes surrounding and self-reported use of NFPs, we know little about how (i.e., strategies used) and how well (i.e., level of accuracy) younger and older individuals process NFP information when evaluating healthful qualities of foods. We manipulated the content of NFPs and, using eye tracking methodology, examined strategies associated with deciding which of two NFPs, presented side-by side, was healthier. We examined associations among strategy use and accuracy as well as age, dietary modification status, knowledge, and motivation. Results showed that, across age groups, those with dietary modification goals made relatively more comparisons between NFPs with increasing knowledge and motivation; but that strategy effectiveness (relationship to accuracy) depended on age and motivation. Results also showed that knowledge and motivation may protect against declines in accuracy in later life and that, across age and dietary modification status, knowledge mediates the relationship between motivation and decision accuracy. PMID- 22525001 TI - Reflections and unprompted observations by healthcare students of an interprofessional shadowing visit. AB - This paper reports work from a Centre for Interprofessional Practice in a higher education institution in the UK that offers four levels of interprofessional learning (IPL) to all healthcare students. The second level (IPL2) integrates professional practice into the learning process, requiring students to shadow a qualified healthcare professional (from a different profession) for half a day. Students complete a reflective statement upon their learning experience on their return. A study was undertaken to analyse students' reflective statements in depth to see their observations and reflections on the shadowing visit. Using frame analysis, 160 reflective statements were analyzed, identifying common words and phrases used by students, which were then grouped together under six themes. Three of these related directly to the assignment: communication styles and techniques; communication between healthcare professionals and comparison of students' own and other healthcare professionals' roles. Three themes emerged from student's own interpretation of observations and reflections made during the shadowing of a different professional: attitudes toward other professions; power structures between professionals and patients and between professionals and impact of communication on patient care. Interprofessional shadowing gives students an opportunity to observe communication between healthcare professionals and patients and to reflect on broader issues surrounding collaborative working. PMID- 22525000 TI - Trajectory analyses in alcohol treatment research. AB - BACKGROUND: Various statistical methods have been used for data analysis in alcohol treatment studies. Trajectory analyses can better capture differences in treatment effects and may provide insight on the optimal duration of future clinical trials and grace periods. This improves on the limitation of commonly used parametric (e.g., linear) methods that cannot capture nonlinear temporal trends in the data. METHODS: We propose an exploratory approach, using more flexible smoothing mixed effects models, more accurately to characterize the temporal patterns of the drinking data. We estimated the trajectories of the treatment arms for data sets from 2 sources: a multisite topiramate study, and the Combined Pharmacotherapies (acamprosate and naltrexone) and Behavioral Interventions study. RESULTS: Our methods illustrate that drinking outcomes of both the topiramate and placebo arms declined over the entire course of the trial but with a greater rate of decline for the topiramate arm. By the point-wise confidence intervals, the heavy drinking probabilities for the topiramate arm might differ from those of the placebo arm as early as week 2. Furthermore, the heavy drinking probabilities of both arms seemed to stabilize at the end of the study. Overall, naltrexone was better than placebo in reducing drinking over time yet was not different from placebo for subjects receiving the combination of a brief medical management and an intensive combined behavioral intervention. CONCLUSIONS: The estimated trajectory plots clearly showed nonlinear temporal trends of the treatment with different medications on drinking outcomes and offered more detailed interpretation of the results. This trajectory analysis approach is proposed as a valid exploratory method for evaluating efficacy in pharmacotherapy trials in alcoholism. PMID- 22525002 TI - Gestational diabetes: women's concerns, mood state, quality of life and treatment satisfaction. AB - OBJECTIVE: The aim of this observational cohort study was to explore concerns, mood state, quality of life (QoL) and treatment satisfaction of women treated for gestational diabetes (GDM). METHODS: Twenty-seven diet-treated and 18 insulin treated women participated in a semi-structured interview and completed a series of three different questionnaires. RESULTS: Qualitative analysis identified "the baby's health" as dominant concern, but also as main motivational treatment factor. Treatment satisfaction was generally high and further increased, whereas QoL and mood state significantly dropped over time. CONCLUSIONS: Acknowledgment of women's concerns and precise information may improve treatment compliance and outcome. PMID- 22524997 TI - Eating behaviour, insulin resistance and cluster of metabolic risk factors in European adolescents. The HELENA study. AB - The present study examined the associations of food behaviours and preferences with markers of insulin resistance and clustered metabolic risk factors score after controlling for potential confounders, including body fat in European adolescents. A cross-sectional study "Healthy Lifestyle in Europe by Nutrition in Adolescence Cross-Sectional Study" of 3546 European adolescents aged 12.5-17.5 years was conducted, using a complete dataset on at least glucose, insulin and "Food Choice Questionnaire". Results indicated skipping breakfast, as well as the preference of some foods such as nuts, chocolate, burgers and pizzas, soft drinks or juices, explain part of homeostasis model assessment index variance. In addition, snacking regularly during school day is associated with higher metabolic risk score in females. In conclusion, the present findings suggest that intervention studies aimed to prevent insulin resistance and metabolic risk factors in youth should focus not only in influencing food and drink preferences, but also to ensure healthy food behaviour in adolescents. The harmful consequences in the choice of certain foods or drinks and food habits can be countered with proper planning and intervention programs to prevent insulin resistance and metabolic risk factors. PMID- 22525003 TI - Comparison of non-invasive and implanted telemetric measurement of blood pressure and electrocardiogram in conscious beagle dogs. AB - INTRODUCTION: The objective of this study was to evaluate the ability of a non invasive telemetry monitoring system to detect and quantify changes in blood pressure and electrocardiogram (ECG) parameters in response to vehicle, L-NAME or minoxidil administration to freely moving beagle dogs. Data from a non-invasive telemetry monitoring system were compared to data captured from an invasive telemetry implant in the same animals. METHODS: Blood pressure and ECG data were simultaneously acquired from male dogs using a non-invasive and an invasive implanted telemetry system for 2 hours predose and 24 hours post dosing with vehicle (n=5), minoxidil at 1 mg/kg (n=4) and L-NAME at 10 mg/kg (n=5) on separate test days. Values for mean blood pressure, systolic blood pressure, diastolic blood pressure, pulse pressure, heart rate, RR, PR, QRS, QT and QTcL (heart rate corrected QT interval) interval were reported for both methods. RESULTS: Statistically significant reductions in blood pressure and pulse pressure and increases in heart rate, with associated ECG interval changes were apparent following dosing with minoxidil using both methods. Statistically significant increases in blood pressure and pulse pressure were apparent following dosing with L-NAME when using the invasive telemetry system, changes were apparent when using the non-invasive telemetry system, however, no change was apparent for pulse pressure, they were of shorter duration and not statistically significant. Statistically significant decreases in heart rate, with associated changes in ECG intervals, were apparent following treatment with L-NAME for both invasive and non-invasive methods. DISCUSSION: This study shows that the non-invasive system can be successfully used to acquire both ECG and blood pressure data in freely moving jacketed dogs for at least 26 hours, yet requires further technique refinement to improve system sensitivity to detect smaller changes in blood pressure. PMID- 22525004 TI - Adipose-derived stem cells improve renal function in a mouse model of IgA nephropathy. AB - T-cell dysregulation plays an important role in the pathogenesis of immunoglobulin A nephropathy (IgAN). Adipose-derived stem cells (ASCs) have been reported to be able to prevent tissue damage through immune-modulating effects. To evaluate the effects of ASCs in high IgA ddY (HIGA) mice, ASCs were isolated from HIGA mice with different stages of IgAN before and after disease onset. ASCs were injected at a dose of 5*10(6) cells/kg body weight through the tail vein every 2 weeks for 3 months. Although the administered ASCs were rarely detected in the glomeruli, 24-h proteinuria was markedly decreased in all ASC-treated groups. Although glomerular deposition of IgA was not significantly different among groups, mesangial proliferation and glomerulosclerosis were dramatically decreased in most ASC treatment groups. In addition, levels of fibrotic and inflammatory molecules were markedly decreased by ASC treatment. Interestingly, ASC therapy significantly decreased Th1 cytokine activity in the kidney and caused a shift to Th2 responses in spleen T-cells as determined by FACS analysis. Furthermore, conditioned media from ASCs abrogated aggregated IgA-induced Th1 cytokine production in cultured HIGA mesangial cells. These results suggest that the beneficial effects of ASC treatment in IgAN occur via paracrine mechanisms that modulate the Th1/Th2 cytokine balance. ASCs are therefore a promising new therapeutic agent for the treatment of IgAN. PMID- 22525005 TI - Assessing patient outcomes after palliative radiotherapy using image-guided intensity-modulated radiotherapy. PMID- 22525006 TI - Simultaneous immunisation with a Wilms' tumour 1 epitope and its ubiquitin fusions results in enhanced cell mediated immunity and tumour rejection in C57BL/6 mice. AB - Protein fusion to ubiquitin results in its targeting to proteasome and processing through MHC class I pathway. We used this approach to induce cytotoxic T lymphocyte (CTL) response against a MHC class I epitope. Therefore, two known proteasome targeting systems, "ubiquitin fusion degradation" (UFD) and "N-end rule", were used to immunise C57BL/6 mice. Two plasmids encoding an epitope from Wilms' Tumour 1 (WT1-126), fused N-terminally to ubiquitin, were constructed. They were designated as "pUbVVPT" and "pUbGRPT", targeting the fused epitope to UFD and N-end pathways, respectively. A plasmid encoding WT1-126 without ubiquitin fusion (pPT) was also constructed as control. Three mice groups were immunised using these constructs (UGR, UVV and PT groups). Two other groups received mixed immunisations of pUbVVPT or pUbGRPT plus pPT plasmids (UVV+PT and UGR+PT). All mice received a WT1-126 peptide booster. Lymphoproliferative responses following stimulation with WT1-126 were observed in all immunisation groups, with mice receiving the mixture of plasmids eliciting the highest proliferation (UVV+PT>UGR+PT>PT). Moreover, In vivo cytotoxicity assay results revealed highest specific lysis of target cells in UVV+PT group. Tumour growth was decreased in all immunised groups, and was completely abrogated in UGR+PT group. In addition, T(H)1 type cytokines patterns were detected from all immunised groups and WT1-126-specific IFNgamma producing lymphocytes were developed in them. These results suggest that the delivery of ubiquitin-fused epitopes along with epitopes alone can be used to optimise the effect of DNA vaccines on the induction of anti-tumour immunity. PMID- 22525007 TI - Evidence for a novel biological role for the multifunctional beta-1,3-glucan binding protein in shrimp. AB - beta-1,3-Glucan binding proteins (betaGBPs) are soluble pattern recognition proteins/receptors that bind to beta-1,3-glucans from fungi cell walls. In crustaceans, betaGBPs are abundant plasmatic proteins produced by the hepatopancreas, and have been proved to play multiple biological functions. Here, we purified and characterized novel members of the betaGBP family from the hemolymph of two Brazilian shrimps, Farfantepenaeus paulensis (FpbetaGBP) and Litopenaeus schmitti (LsbetaGBP). As observed for other crustacean species, FpbetaGBP and LsbetaGBP are monomeric proteins (~100kDa) able to enhance the activation of the prophenoloxidase system, a potent antimicrobial defense conserved in arthropods. More interestingly, we provided here evidence for a novel biological activity for shrimp betaGBPs: the agglutination of fungal cells. Finally, we investigated the modulation of the betaGBP gene in F. paulensis shrimps experimentally infected with a cognate fungal pathogen, Fusarium solani. From our expression data, betaGBP gene is constitutively expressed in hepatopancreas and not modulated upon a non-lethal fungal infection. Herein, we have improved our knowledge about the betaGBP family by the characterization of a novel biological role for this multifunctional protein in shrimp. PMID- 22525008 TI - Different degrees of loss of function between GEFS+ and SMEI Nav 1.1 missense mutants at the same residue induced by rescuable folding defects. AB - Generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI) differ in their clinical severity and prognosis even though mutations of the Na(v) 1.1 sodium channel are responsible for both disorders. We compared the electrophysiologic properties of two mutant Na(v) 1.1 channels characterized by distinct amino acid substitutions at the same residue position: GEFS+ (A1685V) and SMEI (A1685D). Both the mutants showed complete loss of function when expressed alone. However, the function of A1685V can be partly rescued by the beta(1) subunit, consistently with a folding defect, whereas that of A1685D was not rescued. These electrophysiologic differences are consistent with the divergence in clinical severity between GEFS+ and SMEI. PMID- 22525009 TI - Yoga breathing for cancer chemotherapy-associated symptoms and quality of life: results of a pilot randomized controlled trial. AB - BACKGROUND: Many debilitating symptoms arise from cancer and its treatment that are often unrelieved by established methods. Pranayama, a series of yogic breathing techniques, may improve cancer-related symptoms and quality of life, but it has not been studied for this purpose. OBJECTIVES: A pilot study was performed to evaluate feasibility and to test the effects of pranayama on cancer associated symptoms and quality of life. DESIGN: This was a randomized controlled clinical trial comparing pranayama to usual care. SETTING: The study was conducted at a university medical center. SUBJECTS: Patients receiving cancer chemotherapy were randomized to receive pranayama immediately or after a waiting period (control group). INTERVENTIONS: The pranayama intervention consisted of four breathing techniques taught in weekly classes and practiced at home. The treatment group received pranayama during two consecutive cycles of chemotherapy. The control group received usual care during their first cycle, and received pranayama during their second cycle of chemotherapy. OUTCOME MEASURES: Feasibility, cancer-associated symptoms (fatigue, sleep disturbance, anxiety, depression, stress), and quality of life were the outcomes. RESULTS: Class attendance was nearly 100% in both groups. Sixteen (16) participants were included in the final intent-to-treat analyses. The repeated-measures analyses demonstrated that any increase in pranayama dose, with dose measured in the number of hours practiced in class or at home, resulted in improved symptom and quality-of-life scores. Several of these associations--sleep disturbance (p=0.04), anxiety (p=0.04), and mental quality of life (p=0.05)--reached or approached statistical significance. CONCLUSIONS: Yoga breathing was a feasible intervention among patients with cancer receiving chemotherapy. Pranayama may improve sleep disturbance, anxiety, and mental quality of life. A dose-response relationship was found between pranayama use and improvements in chemotherapy associated symptoms and quality of life. These findings need to be confirmed in a larger study. PMID- 22525010 TI - New genomic characteristics of highly pathogenic porcine reproductive and respiratory syndrome viruses do not lead to significant changes in pathogenicity. AB - Highly pathogenic porcine reproductive and respiratory syndrome (HP-PRRS) initially emerged in China and currently prevails in other Asian countries as well, resulting in immense economic losses. HP-PRRS virus (HP-PRRSV) has undergone rapid evolution since its first recognition in 2006. To analyze the genomic and pathogenic characteristics of 2010 HP-PRRSV, we tested 919 clinical samples collected from China, Laos and Vietnam, sequenced 29 complete genomes of HP-PRRSV isolates, and determined the pathogenicity of seven HP-PRRS viruses isolated from 2006 to 2010. HP-PRRSV was detected from 45.2% (415/919) samples, while only 0.1% (1/919) was classical PRRSV, indicating that HP-PRRSV isolates with a unique discontinuous deletion of 30 amino acids (aa) in non-structural protein 2 (Nsp2) are still the predominant viruses. 2010 HP-PRRSV together with 2009 HP-PRRSV isolates form a new evolutionary branch based on phylogenetic analyses. The numbers of potential N-glycosylation sites are variable in major glycoprotein GP5 but are conserved in minor glycoproteins GP2, GP3 and GP4. Pathogenicity studies showed that HP-PRRS viruses isolated from 2006 to 2010 maintain similar level of high pathogenicity, which caused high fever (>41 degrees C for at least four days), 100% morbidity, and 40-100% mortality in 4-10 weeks old pigs. Real time monitoring information from this study could help to understand the genetic and pathogenic evolution of HP-PRRSV and assist in the control of HP-PRRS in Asia. PMID- 22525011 TI - Evidence for BTV-4 circulation in free-ranging red deer (Cervus elaphus) in Cabaneros National Park, Spain. AB - Bluetongue (BT) is an infectious disease of wild and domestic ruminants caused by bluetongue virus (BTV). BTV-4 spread through southern Spain from 2004 to 2006, whereas a BTV-1 outbreak that started in southern Spain in 2007 is still ongoing. Vaccination and movement restriction regulations are applied to domestic ruminants to control BT, but the potential reservoir role of wild European ungulates has not been clarified so far. The aim of this study was to describe the epidemiology of BTV in the wild free-ranging red deer (Cervus elaphus) population of Cabaneros National Park (CNP) in central Spain during the BTV-4 and BTV-1 epizootics, assessing the potential role of this deer population as a BTV reservoir. Blood samples from 2885 (2542 adults, 208 calves and 135 undetermined) wild red deer were collected from 2005 to 2010 in CNP and surrounding hunting estates. All sera were tested for antibodies against the BTV VP7 protein by ELISA. Ninety-four of the ELISA-positive samples were analysed by serum neutralization to detect BTV-4 and BTV-1 specific antibodies, and 142 blood samples were analysed by RT-PCR for BTV RNA. A total of 371 (12.9%) out of the 2,885 deer (35/208 calves, 307/2,542 adults, and 29/135 undetermined) were positive for antibodies against BTV. Prevalence increased in adult deer from 2005 2006 to 2008-2009, declining thereafter. No positive samples for BTV-1 were found by serum neutralization, whereas 43 deer (38 adults, four calves and one undetermined) were positive for BTV-4 specific antibodies. No BTV RNA positive deer were found by RT-PCR. Antibody detection throughout the study period suggests a maintained circulation of BTV in red deer. However, the lack of BTV RNA detection suggests a minor transmission risk to livestock. PMID- 22525012 TI - Low altitude remote-sensing method to monitor marine and beach litter of various colors using a balloon equipped with a digital camera. AB - This study aims to establish a low-altitude remote sensing system for surveying litter on a beach or the ocean using a remote-controlled digital camera suspended from a balloon filled with helium gas. The resultant images are processed to identify the litter using projective transformation method and color difference in the CIELUV color space. Low-altitude remote sensing experimental observations were conducted on two locations in Japan. Although the sizes of the litter and the areas covered are distorted in the original photographs taken at various angles and heights, the proposed image process system is capable of identifying object positions with a high degree of accuracy (1-3 m). Furthermore, the color difference approach in the CIELUV color space used in this study is well capable of extracting pixels of litter objects of various colors allowing us to estimate the number of objects from the photographs. PMID- 22525014 TI - Phenotypic 'variant' forms of Trichomonas vaginalis trophozoites from cervical neoplasia patients. AB - The protozoan Trichomonas vaginalis a sexually transmitted protozoan parasite causes vaginitis, urethritis and cervicitis in humans. The present study highlights phenotypic 'variant' forms of trophozoites isolated from patients suffering from cervical neoplasia condition. The growth curve of 10 isolates i.e., four non-cervical neoplasia (NCN) isolates (NCN1-NCN4) and six cervical neoplasia (CN) isolates (CN1-CN6) showed two distinct and different in vitro growth profiles. The parasite count and growth rates were significantly higher in trophozoites from CN isolates in cultures of day 2 up to day 8 (p<0.05, Mann Whitney test). The average generation time was 1.84+/-0.40 and 3.38+/-0.55h for NCN and CN isolates respectively. The nucleus of trophozoites in CN isolates using acridine orange and DAPI showed more intense staining revealing higher nuclear content. The FITC-labeled Concanavalin A stained stronger green fluorescence with surface of trophozoites in CN isolates showing more rough and creased surface with numerous deep micropores. Transmission electron microscopy studies revealed that there was higher numbers of vacuoles and hydrogenosomes in these forms. The study mounted staining techniques, growth profiles, morphology, morphometry studies using scanning and transmission electron microscopy and confirms that the trophozoites from cervical neoplasia proliferates at a higher rate, shows higher FITC-labeled Concanavalin A binding with rough and creased surface implying that these are virulent forms which can aggravate or exacerbate cervical neoplasia conditions. The large numbers of hyrogenosomes and vacuoles implies that these forms are active and implicates a possible role in such conditions. PMID- 22525013 TI - The translational repressor T-cell intracellular antigen-1 (TIA-1) is a key modulator of Th2 and Th17 responses driving pulmonary inflammation induced by exposure to house dust mite. AB - T-cell intracellular antigen-1 (TIA-1) is a translational repressor that dampens the production of proinflammatory cytokines and enzymes. In this study we investigated the role of TIA-1 in a mouse model of pulmonary inflammation induced by exposure to the allergenic extract (Df) of the house dust mite Dermatophagoides farinae. When intranasally challenged with a low dose of Df, mice lacking TIA-1 protein (Tia-1(-/-)) showed more severe airway and tissue eosinophilia, infiltration of lung bronchovascular bundles, and goblet cell metaplasia than wild-type littermates. Tia-1(-/-) mice also had higher levels of Df-specific IgE and IgG(1) in serum and ex vivo restimulated Tia-1(-/-) lymph node cells and splenocytes transcribed and released more Th2/Th17 cytokines. To evaluate the site of action of TIA-1, we studied the response to Df in bone marrow chimeras. These experiments revealed that TIA-1 acts on both hematopoietic and non-hematopoietic cells to dampen pulmonary inflammation. Our results identify TIA-1 as a negative regulator of allergen-mediated pulmonary inflammation in vivo. Thus, TIA-1 might be an important player in the pathogenesis of bronchial asthma. PMID- 22525015 TI - Modulation of the extinction of two different fear-motivated tasks in three distinct brain areas. AB - The hippocampus, basolateral amygdala and ventromedial prefrontal cortex participate in the extinction of inhibitory avoidance and contextual fear conditioning. We studied the effect of drugs acting on receptors involved in synaptic modulation on extinction of both tasks. The drugs were given bilaterally right after the first of two sessions of extinction in each task through cannulae implanted into the mentioned areas. The doses used are known to influence memory consolidation of the original tasks. Their effects were evaluated on a second extinction session 24h later, and assumed to result from influences on the consolidation of extinction. The glutamate NMDA receptor stimulant d-serine (50 MUg/side) and the histamine methyl-transferase inhibitor SKF9188 (12.5 MUg/side) enhanced, and the NMDA antagonist amino-phosphonopentanoate (5 MUg/side) and the H2 histamine receptor antagonist ranitidine (17.5 MUg/side) inhibited, extinction of both tasks regardless of the region into which they were administered. Thus, glutamate NMDA receptors are involved in the consolidation of extinction of both tasks, and histamine H2 receptors modulate that process in all areas studied. Norepinephrine (1 MUg/side), the beta-adrenoceptor antagonist timolol (1 MUg/side), the D1 dopamine receptor agonist SKF38393 (12.5 MUg/side) and the D1 antagonist SCH23390 (1.5 MUg/side) also affected extinction of both tasks, but their effects varied with the task and with the site of infusion, suggesting that extinction modulation by beta- and D1 receptors is more complex. In conclusion, extinction of two different aversive tasks is modulatable by various systems, which bears upon the behavioral and pharmacological treatment of fear-motivated brain disorders. PMID- 22525016 TI - The effects of light on bleaching and tooth sensitivity during in-office vital bleaching: a systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the influence of light on bleaching efficacy and tooth sensitivity during in-office vital bleaching. DATA SOURCES: We performed a literature search using Medline, EMBASE and Cochrane Central up to September 2011. STUDY SELECTION: All randomised controlled trials (RCTs) or quasi-RCTs comparing the light-activated bleaching system with non-activation bleaching system were included. Reports without clinical data concerning bleaching efficacy or tooth sensitivity were excluded. RESULTS: Eleven studies were included in the meta-analysis. A light-activated system produced better immediate bleaching effects than a non-light system when lower concentrations of hydrogen peroxide (15-20% HP) were used (mean difference [MD], -1.78; 95% confidence interval [CI]: [-2.30, -1.26]; P<0.00001). When high concentrations of HP (25-35%) were employed, there was no difference in the immediate bleaching effect (MD, -0.39; 95% CI: [-1.15, 0.37]; P=0.32) or short-term bleaching effect (MD, 0.25; 95% CI: [-0.47, 0.96]; P=0.50) between the light-activated system and the non-light system. However, the light-activated system produced a higher percentage of tooth sensitivity (odds ratio [OR], 3.53; 95% CI: [1.37, 9.10]; P=0.009) than the non light system during in-office bleaching. CONCLUSIONS: Light increases the risk of tooth sensitivity during in-office bleaching, and light may not improve the bleaching effect when high concentrations of HP (25-35%) are employed. Therefore, dentists should use the light-activated system with great caution or avoid its use altogether. Further rigorous studies are, however, needed to explore the advantages of this light-activated system when lower concentrations of HP (15 20%) are used. PMID- 22525017 TI - Applicability of CIELAB/CIEDE2000 formula in visual color assessments of metal ceramic restorations. AB - OBJECTIVES: To investigate the applicability of color-difference formula (CIELAB or CIEDE2000) in visual color assessments of metal-ceramic specimens in small color-difference ranges. METHODS: Metal-ceramic specimens using mixture of gradient ratio porcelain powders were fabricated to create a color pool. Color differences of specimen pairs were calculated using the CIELAB (DeltaE(ab)(*)) and CIEDE2000 (DeltaE(00)). A questionnaire, composed of 1 target and 3 enactment specimens, was designed. For formula-determination, the enactment specimen with the minimum DeltaE to the target specimen was registered as FS. For visual assessment, twenty participants were asked to finish the questionnaire by choosing the most color-matched enactment specimen to the target. The percentage of the FS been selected (P(FS)) was calculated, which was used to represent the consistence of formula-determination and visual-assessment. Binomial Tests were used to compare the differences between P(FS) values and 33% (the randomized probability of the FS been selected was one out of three, approximate 33%). Regression analysis was used to determine the correlation between DeltaE(ab)(*) and DeltaE(00) values. RESULTS: A linear regression equation was drawn as DeltaE(00)=-0.049+0.619*DeltaE(ab)(*). There were no significant differences between P(FS) values and 33% within the range of DeltaE(ab)(*)<2.0, whereas P(FS) values were significantly higher than 33% when DeltaE(ab)(*)>2.0 (P<0.001). There was a tendency of selecting the enactment specimens with lower L* values and higher b* or C' values, within the range of 1.0 1 y old). Additionally, an acute murine hindlimb ischemia model was created to evaluate thrombus samples in mice. Human sections were immunostained for the H2A/H2B/DNA complex, myeloperoxidase, fibrinogen, and von Willebrand factor. Mouse sections were immunostained with the H2A antibody. All samples were further evaluated after hematoxylin and eosin and Masson trichrome staining. RESULTS: An extensive network of extracellular histone/DNA complex was demonstrated in the matrix of human ex vivo thrombus. This network is present throughout the highly cellular acute thrombus. However, in chronic thrombi, detection of the histone/DNA network was predominantly in regions of low collagen content and high cell density, which were mostly near the lumen. These regions of high cell density contained neutrophils and monocytes. Similarly, sections from the acute murine hindlimb ischemia model also exhibited extensive immunoreactivity to the histone antibody in the extracellular space within murine thrombi. CONCLUSIONS: Extensive detection of genomic DNA associated with histones in the extracellular matrix of human and mouse thrombi suggest the presence of a new thrombus-associated scaffold. PMID- 22525029 TI - Nasogastric tube found in the right atrium. PMID- 22525030 TI - Symptomatic ascites caused by a longstanding posttraumatic mesenteric arteriovenous fistula. PMID- 22525031 TI - Intraoperative portal vein stent placement in pediatric living donor liver transplantation. PMID- 22525032 TI - Synthesis, DNA-binding, DNA-photonuclease profiling and antimicrobial activity of novel tetra-aza macrocyclic Ni(II), Co(II) and Cu(II) complexes constrained by thiadiazole. AB - A new tetra-aza macrocyclic ligand, L (C(24)H(16)N(12)O(2)S(4)) and its complexes of type, [MLCl(2)] and [CuL]Cl(2) (where M=Ni(II), Co(II); L=N,N'-(benzene-1,3 diyldi-1,3,4-thiadiazole-5,2-diyl)bis{2-[(5-benzene-1,3-diyl-1,3,4-thiadiazol-2 yl)amino]acetamide}) were synthesized and characterized by the spectral and analytical techniques. An octahedral geometry has been proposed for Ni(II) and Co(II) complexes while Cu(II) complex exhibit a square planar geometry. All the synthesized metal complexes were screened for their in vitro antimicrobial activity against selected species of pathogenic bacteria and fungi. The binding property of the complexes with CT-DNA was studied by absorption spectral analysis, followed by viscosity measurement and thermal denaturation studies. The photo induced cleavage studies revealed that the complexes possess photonuclease property against pUC19 DNA under UV-visible irradiation. PMID- 22525033 TI - Analytical detection and method development of anticancer drug Gemcitabine HCl using gold nanoparticles. AB - A simple, rapid, cost effective and extractive UV spectrophotometric method was developed for the determination of Gemcitabine HCl (GMCT) in bulk drug and pharmaceutical formulation. It was based on UV spectrophotometric measurements in which the drug reacts with gold nanoparticles (AuNP) and changes the original colour of AuNP and forms a dark blue coloured solution which exhibits absorption maximum at 688nm. The apparent molar absorptivity and Sandell's sensitivity coefficient were found to be 3.95*10(-5)lmol(-1)cm(-1) and 0.060MUgcm(-2) respectively. Beer's law was obeyed in the concentration range of 2.0-40MUgml( 1). This method was tested and validated for various parameters according to ICH guidelines. The proposed method was successfully applied for the determination of GMCT in pharmaceutical formulation (parental formulation). The results demonstrated that the procedure is accurate, precise and reproducible (relative standard deviation <2%). As it is simple, cheap and less time consuming, it can be suitably applied for the estimation of GMCT in dosage forms. PMID- 22525034 TI - Synthesis of trimethoprim metal complexes: Spectral, electrochemical, thermal, DNA-binding and surface morphology studies. AB - Complexes of trimethoprim (TMP), with Cu(II), Zn(II), Pt(II), Ru(III) and Fe(III) have been synthesized. Then, these complexes have been characterized by spectroscopic techniques involving UV-vis, IR, mass and (1)H NMR. CHN elemental analysis, electrochemical and thermal behavior of complexes have also been investigated. The electrochemical properties of all complexes have been investigated by cyclic voltammetry (CV) using glassy carbon electrode. The biological activity of the complexes has been evaluated by examining their ability to bind to calf-thymus DNA (CT DNA) with UV spectroscopy and cyclic voltammetry. UV studies of the interaction of the complexes with DNA have shown that these compounds can bind to CT DNA. The binding constants of the complexes with CT DNA have also been calculated. The cyclic voltammograms of the complexes in the presence of CT DNA have shown that the complexes can bind to CT DNA by both the intercalative and the electrostatic binding mode. The antimicrobial activity of these complexes has been evaluated against three Gram-positive and four Gram-negative bacteria. Antifungal activity against two different fungi has been evaluated and compared with the reference drug TMP. Almost all types of complexes show excellent activity against all type of bacteria and fungi. The morphology of the CT DNA, TMP, metal ions and metal complexes has been investigated by scanning electron microscopy (SEM). To get the SEM images, the interaction of compounds with CT DNA has been studied by means of differential pulse voltammetry (DPV) at CT DNA modified pencil graphite electrode (PGE). The decrease in intensity of the guanine oxidation signals has been used as an indicator for the interaction mechanism. PMID- 22525035 TI - Synthesis, spectroscopy and thermal study of some nickel(II) complexes containing tridentate Schiff bases and substituted amine ligands, X-ray crystal structure of nickel(II) complex. AB - Some new tridentate ONO and ONS Schiff base complexes of [NiL(amine)] (L=Salicylidene2-aminophenol and Salicylidene2-aminothiophenol, amine=benzylamine, morpholine, pyrrolidine and piperidine) were synthesized and characterized by IR, UV-vis, (1)H NMR spectroscopy and elemental analysis. The geometry of [NiL(2)(bzlan)] determined by X-ray crystallography indicates that the complex has planar structure and has four coordinate in the solid state. The thermogravimmetry (TG) and differential thermoanalysis (DTA) of the synthesized complexes were carried out in the range of 20-700 degrees C, leading to decomposition of ONO type in two stages and of ONS type in three stages. The ONO and ONS complexes were decomposed to NiO and NiS respectively. Thermal decomposition of the complexes is closely the depends upon nature of the Schiff base ligands and proceeds via first order kinetics. PMID- 22525037 TI - A novel histidine kinase gene, ZmHK9, mediate drought tolerance through the regulation of stomatal development in Arabidopsis. AB - Plants have developed complex signaling networks to regulate biochemical and physiological acclimation, environmental signals were perceived and transmitted to cellular machinery to activate adaptive responses. Here, a novel drought responsive histidine kinase gene was identified and designated as ZmHK9. Under normal conditions, ZmHK9 was predominantly expressed in roots, and the roots of ZmHK9-OX transgenic lines are markedly hypersensitive to ABA and ethylene, as compare to wild type. Consistent with its expression induced by PEG and exogenous ABA treatment, promoter sequence of this gene possessed drought and ABA responsive element. Moreover, the transgenic plants were much less affected by drought stress and recovered quickly after rewatering, stomatal complex size and stomatal density in the transgenic plants are significantly smaller and lower than those of the wild-type plants. In addition, ABA induced stomatal closure and the stomatal aperture of ZmHK9-OX lines was smaller than that of wild type. Collectively, it can be concluded that ZmHK9 regulates root elongation, stomatal development and drought tolerance through ABA dependent signaling pathway in Arabidopsis. PMID- 22525036 TI - Neonatal side effects of maternal labetalol treatment in severe preeclampsia. AB - OBJECTIVE: Labetalol is often used in severe preeclampsia (PE). Hypotension, bradycardia and hypoglycemia are feared neonatal side effects, but may also occur in (preterm) infants regardless of labetalol exposure. We analyzed the possible association between intrauterine labetalol exposure and such side effects. STUDY DESIGN: From 1 January 2003 through 31 March 2008, all infants from mothers suffering severe PE admitted to one tertiary care center were included. Severe PE was defined according to the International Society for the Study of Hypertension in Pregnancy (ISSHP) criteria. Infants exposed to labetalol in utero (labetalol infants) were compared with infants, who were not exposed to labetalol (controls). Neonatal records were reviewed for hypotension (RRT in GPR30 and 4 known SNPs. The experimental conditions determined in this study for HRM analysis are useful for high throughput assays to detect unknown mutations within the GPR30 ORF. PMID- 22525041 TI - Relationships between single nucleotide polymorphisms of antioxidant enzymes and disease. AB - The presence and progression of numerous diseases have been linked to deficiencies in antioxidant systems. The relationships between single nucleotide polymorphisms (SNPs) arising from specific antioxidant enzymes and diseases associated with elevated oxidative stress have been studied with the rationale that they may be useful in screening for diseases. The purpose of this narrative review is to analyse evidence from these studies. The antioxidant enzyme SNPs selected for analysis are based on those most frequently investigated in relation to diseases in humans: superoxide dismutase (SOD2) Ala16Val (80 studies), glutathione peroxidise (GPx1) Pro197Leu (24 studies) and catalase C-262T (22 studies). Although the majority of evidence supports associations between the SOD2 Ala16Val SNP and diseases such as breast, prostate and lung cancers, diabetes and cardiovascular disease, the presence of the SOD2 Ala16Val SNP confers only a small, clinically insignificant reduction (if any) in the risk of these diseases. Other diseases such as bladder cancer, liver disease, nervous system pathologies and asthma have not been consistently related to this SOD SNP genotype. The GPx1 Pro197Leu and catalase C-262T SNP genotypes have been associated with breast cancer, but only in a small number of studies. Thus, currently available evidence suggests antioxidant enzyme SNP genotypes are not useful for screening for diseases in humans. PMID- 22525042 TI - Specific binding of HLA-B44 to human macrophage MHC receptor 1 on monocytes. AB - Allograft (H-2D(d)K(d))-induced macrophages (AIM) in C57BL/6 (H-2D(b)K(b)) mice exhibit major histocompatibility complex (MHC) haplotype-specific killing of allografts in a macrophage MHC receptor 1 (MMR1; for H-2D(d))- and MMR2 (for H 2K(d))-dependent manner. Recently, we showed HLA-B62 to be a ligand for the human homologue of mouse MMR2. In the present study, we isolated a cDNA encoding the human homologue of mouse MMR1 and found HLA-B44 to be the sole ligand specific for the human MMR1 by using beads that had been conjugated with 80 kinds of HLA proteins. Flow cytometric analyses revealed that HLA-B44-conjugated beads are specifically bound to HEK293T cells expressing human MMR1, that HLA-B44 tetramers are bound to the human MMR1-transfected HEK293T cells with a dissociation constant of 3.0*10(-9) M, and that the interaction was completely inhibited by the addition of R15 monoclonal antibody specific for mouse MMR1. The MMR1 cDNA (1537-bp) encoded a 473-amino acid polypeptide and was expressed at least in part in the brain and peripheral blood mononuclear cells (PBMCs) or monocytes, but not in granulocytes or lymphocytes. PBMCs from 7 non-H-2D(d) (non-self), but none from 5 H-2D(d) (self), in-bred mice expressed mouse MMR1 specific for H-2D(d). In contrast, PBMCs from none of the 16 human volunteers expressed HLA-B44; whereas those from only 3 of these 16 volunteers expressed human MMR1. These results reveal that human MMR1 on monocytes is a novel receptor specific for HLA-B44. PMID- 22525043 TI - E-cadherin and beta-catenin expression in well-differentiated and moderately differentiated oral squamous cell carcinoma: relations with clinical variables. AB - The aim of this study was to establish the expression and localisation of E cadherin and beta-catenin in oral squamous cell carcinomas (SCC) so that we could correlate the findings with prognostically-relevant clinicopathological variables. E-cadherin and beta-catenin expression in normal oral mucosa and in oral squamous cell carcinomas were examined immunohistochemically, and their association with clinicopathological factors and prognosis were then analysed in 69 patients who had been operated on for oral SCC. E-cadherin expression was found in all 69 cases: in 11 cases (16%) it was weak; in 21 (30%) moderate, and in 37 (54%) high. beta-Catenin expression was found in 64 cases (93%): in 18 cases (26%) cell-membrane expression was weak; in 26 (38%) it was moderate; in 19 (28%) it was high, and in one case (1%) there was cytoplasmic staining. No nuclear staining was detected. E-cadherin was significantly associated with histological grade (p=0.002) and alcohol consumption (p=0.05), and beta-catenin was significantly associated with nodal stage (p=0.02), TNM stage (p=0.009), and E-cadherin expression (p=0.01). However, none of them were independent prognostic factors in the disease-specific survival analysis. E-cadherin is closely linked to beta-catenin expression in oral SCC and to tumour differentiation. Alcohol consumption could increase the aggressiveness of SCC, leading to reduced expression of E-cadherin. beta-catenin could be an early marker for the identification of occult metastases in patients with oral SCC. PMID- 22525044 TI - University students' online habits and their use of the Internet for health information. AB - Studies have explored the use of the Internet for health information, but few have focused on the young adult population, a population that is known to have difficulties in accessing mainstream health services. It has been acknowledged that young people are active users of the Internet, and this mode of health service delivery warrants further exploration. This study aimed to determine university students' online habits and their use of the Internet for health information using a quantitative descriptive design. Data were collected from 922 university students in Ireland, aged between 18 and 24 years. The findings indicated that university students are active users of the Internet and of social networking sites, particularly for communication purposes. It was also found that 66.1% of participants had used the Internet to search for health information, for a variety of reasons, including information on specific illnesses, sexual health, and fitness and nutrition. It is concluded that the use of the Internet to communicate with young people in relation to their health needs to be explored. PMID- 22525045 TI - Adoption of an electronic observation chart with an integrated early warning scoring system on pilot wards: a descriptive report. AB - The charting of physiological variables in hospital inpatients allows for recognition and treatment of deteriorating patients. The use of electronic records to capture patients' vital signs is still in its infancy in the United Kingdom. The main objective of this article was to describe the adoption of an electronic observation charting function integrated into an established bedside e prescribing record system on acute wards in a large English university hospital. This new function also has the capability of contacting Critical Care Outreach and clinical staff when patients deteriorate. Data captured over a 4-month period from the pilot wards showed that 80% of observation sets were completed sufficiently to produce early warning scores over the time period. A daily average of 419 Standardized Early Warning Score produced 74 alerts to clinical staff, and two critical alarms per day were e-mailed to the Outreach team. The wards showed different levels of completeness of observations (from 69% to 92%). Although a good overall rate of completeness of physiological data was found, traditional gaps in observation recording documented in the literature (eg, recording of respiratory rate) were still apparent. This system can be used for audit for targeted staff education and to evaluate the Critical Care Outreach service. PMID- 22525046 TI - Modeling factors that influence personal health records adoption. AB - The purpose of this article was to describe the Personal Health Records Adoption Model and how it was developed. Older adults who often find themselves managing their own care or the care of their families have expressed interest in using electronic personal health records as a management tool, but few are using them. The literature does not provide a comprehensive model of personal health record adoption among older adults with chronic illness; therefore, essential barriers and facilitators were synthesized from existing literature to create the model. The model derivation and synthesis process drew upon candidate theoretical frameworks, including two behavioral theories, an informatics theory, and a self management theory, while using the Informatics Research Organizing Model as an organizing framework. The Personal Health Records Adoption Model captures important barriers and facilitators that could predict adoption of personal health records among older adults with chronic illness. The long-term goal is to use this explanatory model to develop interventions that will maximize the facilitators and minimize the barriers to personal health record adoption. PMID- 22525047 TI - Treatment of refractory uveitis with adalimumab: a prospective multicenter study of 131 patients. AB - OBJECTIVE: To evaluate adalimumab therapy in refractory uveitis. DESIGN: Prospective case series. PARTICIPANTS: A total of 131 patients with refractory uveitis and intolerance or failure to respond to prednisone and at least 1 other systemic immunosuppressive drug participated. INTERVENTION: Patients received a 40 mg adalimumab subcutaneous injection every other week for 6 months. The associated immunosuppressants were tapered after administering 3 adalimumab injections (week 6). MAIN OUTCOME MEASURES: Degree of anterior and posterior chamber inflammation (Standardization of Uveitis Nomenclature Working Group criteria), immunosuppression load (as defined by Nussenblatt et al), visual acuity (logarithm of the minimal angle of resolution [logMAR]), and macular thickness (optical coherence tomography). RESULTS: There were 61 men and 70 women (mean age, 27.3 years). The most common causes were juvenile idiopathic arthritis in 39 patients, pars planitis in 16 patients, and Behcet's disease in 13 patients. Twenty-seven patients had uveitis of idiopathic origin. Inflammation in the anterior chamber was present in 82% of patients and in the vitreous cavity in 59% of patients. Anterior chamber inflammation and vitreous inflammation decreased significantly (P < 0.001) from a mean of 1.51 and 1.03 at baseline to 0.25 and 0.14, respectively, at 6 months. Macular thickness was 296 (102) MU at baseline versus 240 (36) MU at the 6-month visit (P < 0.001). Visual acuity improved by -0.3 logMAR in 32 of 150 eyes (21.3%) and worsened by +0.3 logMAR ( 15 letters) in 5 eyes (3.3%). The dose of corticosteroids also decreased from 0.74 (3.50) to 0.20 (0.57) mg/kg/day (P < 0.001). Cystoid macular edema, which was present in 40 eyes at baseline, showed complete resolution in 28 eyes at 6 months. The mean suppression load decreased significantly (8.81 [5.05] vs 5.40 [4.43]; P < 0.001). Six months after the initiation of the study, 111 patients (85%) were able to reduce at least 50% of their baseline immunosuppression load. Only 9 patients (6.9%) had severe relapses during the 6 months of follow-up. CONCLUSIONS: Adalimumab seems to be well tolerated and helpful in decreasing inflammatory activity in refractory uveitis and may reduce steroid requirement. Further controlled studies of adalimumab for uveitis are warranted. PMID- 22525049 TI - Recurrence of Paget's disease: total vaginal occlusion and partial occlusion of urethra. PMID- 22525048 TI - Tofacitinib (CP-690,550), a Janus kinase inhibitor for dry eye disease: results from a phase 1/2 trial. AB - OBJECTIVE: To evaluate safety and efficacy of topical ophthalmic tofacitinib (CP 690,550), a novel Janus kinase inhibitor, in treating dry eye disease (DED). DESIGN: A phase 1/2 prospective, randomized, double-masked, multicenter, vehicle- and comparator-controlled trial (NCT00784719). PARTICIPANTS: Patients (n = 327) 18 years of age and older with a DED diagnosis for 6 months or more. METHODS: Tofacitinib (0.0003% twice daily, n = 46; 0.001% in both eyes twice daily, n = 47; 0.003% twice daily, n = 48; 0.005% twice daily, n = 48; 0.005% once daily, n = 44) results were compared with those of groups receiving active treatment cyclosporine ophthalmic emulsion 0.05% twice daily (n = 47) and vehicle twice daily (n = 47). Safety and efficacy evaluations were performed at baseline and throughout the 8-week study. MAIN OUTCOME MEASURES: Schirmer wetting, corneal staining, tear film break-up time, conjunctival staining, Ocular Comfort Index (OCI), and Ocular Surface Disease Index (OSDI). RESULTS: All tofacitinib doses were well tolerated, exhibiting better patient-reported ocular tolerability than cyclosporine. For the proportion of patients achieving 10 mm or more Schirmer wetting (without anesthesia) at week 8 (primary end point), greater response rates were observed in the tofacitinib 0.001% twice daily (27.3%), 0.005% twice daily (25.5%), and 0.005% once daily (26.1%) groups versus vehicle (20.0%); however, the differences were not statistically significant. Mean increase in Schirmer wetting (without anesthesia) from baseline was statistically significant (P<0.2, 2-sided) for all tofacitinib doses (1.7-3.1 mm), cyclosporine (3.9 mm), and vehicle (1.4 mm). For corneal staining (total score), significant improvement (reduction) from baseline was observed for all tofacitinib doses (-0.9 to -1.9) and vehicle (-2.0), but not for cyclosporine. The proportion of patients with complete corneal clearing (CCC; 100%) at week 8 was greatest with tofacitinib 0.005% once daily (15.9%) versus vehicle (6.7%). Symptom scores (OCI, OSDI) at week 8 showed significant improvements from baseline for all tofacitinib groups, and tofacitinib demonstrated greater improvements than cyclosporine. The tofacitinib 0.005% once daily group showed significant improvements in both a sign (Schirmer wetting without anesthesia) and symptom (OSDI environmental triggers subscale) versus vehicle and also demonstrated the highest response rate for CCC (16.7%) at week 8. CONCLUSIONS: This phase 1/2 study of tofacitinib demonstrated a trend for improving both signs and symptoms of dry eye. All doses of tofacitinib exhibited a reasonable safety profile and were well tolerated by patients with DED. PMID- 22525051 TI - Stress and strain localization in stretched collagenous tissues via a multiscale modelling approach. AB - Mechanobiology of cells in soft collagenous tissues is highly affected by both tissue response at the macroscale and stress/strain localization mechanisms due to features at lower scales. In this paper, the macroscale mechanical behaviour of soft collagenous tissues is modelled by a three-level multiscale approach, based on a multi-step homogenisation technique from nanoscale up to the macroscale. Nanoscale effects, related to both intermolecular cross-links and collagen mechanics, are accounted for, together with geometric nonlinearities at the microscale. Moreover, an effective submodelling procedure is conceived in order to evaluate the local stress and strain fields at the microscale, which is around and within cells. Numerical results, obtained by using an incremental finite element formulation and addressing stretched tendinous tissues, prove consistency and accuracy of the model at both macroscale and microscale, confirming also the effectiveness of the multiscale modelling concept for successfully analysing physiopathological processes in biological tissues. PMID- 22525050 TI - Linguistic validation of translation of the Self-Assessment Goal Achievement (SAGA) questionnaire from English. AB - BACKGROUND: A linguistic validation of the Self-Assessment Goal Achievement (SAGA) questionnaire was conducted for 12 European languages, documenting that each translation adequately captures the concepts of the original English language version of the questionnaire and is readily understood by subjects in the target population. METHODS: Native-speaking residents of the target countries who reported urinary problems/lower urinary tract problems were asked to review a translation of the SAGA questionnaire, which was harmonized among 12 languages: Danish, Dutch, English (UK), Finnish, French, German, Greek, Icelandic, Italian, Norwegian, Spanish, and Swedish. During a cognitive debriefing interview, participants were asked to identify any words that were difficult to understand and explain in their own words the meaning of each sentence in the questionnaire. The qualitative analysis was conducted by local linguistic validation teams (original translators, back translator, project manager, interviewer, and survey research expert). RESULTS: Translations of the SAGA questionnaire from English to 12 European languages were well understood by the participants with an overall comprehension rate across language of 98.9%. In addition, the translations retained the original meaning of the SAGA items and instructions. Comprehension difficulties were identified, and after review by the translation team, minor changes were made to 7 of the 12 translations to improve clarity and comprehension. CONCLUSIONS: Conceptual, semantic, and cultural equivalence of each translation of the SAGA questionnaire was achieved thus confirming linguistic validation. PMID- 22525052 TI - PI3K signaling in the regulation of branching morphogenesis. AB - Branching morphogenesis drives the formation of epithelial organs including the mammary gland, lung, kidney, salivary gland and prostate. Branching at the cellular level also drives development of the nervous and vascular systems. A variety of signaling pathways are orchestrated together to establish the pattern of these branched organs. The phosphoinositide 3-kinase (PI3K) signaling network is of particular interest because of the diverse outcomes it generates, including proliferation, motility, growth, survival and cell death. Here, we focus on the role of the PI3K pathway in the development of branched tissues. Cultured cells, explants and transgenic mice have revealed that the PI3K pathway is critical for the regulation of cell proliferation, apoptosis and motility during branching of tissues. PMID- 22525054 TI - Developmental times and age-specific life tables for Lygus lineolaris (Heteroptera: Miridae), reared at multiple constant temperatures. AB - Developmental times and survivorship of tarnished plant bug nymphs, Lygus lineolaris (Palisot de Beauvois), and longevity and reproduction of adult tarnished plant bug adults reared on green beans were studied at multiple constant temperatures. The developmental time for each life stage and the total time from egg to adult decreased with increasing temperature. Eggs required the longest time to develop followed by fifth instars and then first-instars. Total developmental time from egg to adult was shortest at 32 degrees C, requiring 18.0 +/- 0.3 d and 416.7 +/- 31.3 DD above 7.9 degrees C, the estimated minimum temperature for development from egg to adult. Sex did not affect total developmental times and did not affect median survival time. Adults lived significantly fewer days at high temperatures (30-32 degrees C: 17-19 d) compared with temperatures below 30 degrees C (range: 24.5-39.4 d) and the number of eggs laid per day increased from ~ 4 at 18 degrees C to a maximum of 9.5 eggs per day at 30 degrees C. Total egg production over the lifetime of female tarnished plant bugs increased with temperature reaching a maximum of 175 eggs on average at 27 degrees C, total egg production declined at temperatures above 27 degrees C (30 degrees C: 110.8, 32 degrees C: 77.3 eggs per female). The highest net reproductive rate 74.5 (R(0)) was obtained from insects maintained at 27 degrees C. The intrinsic rate of natural increase (r(m)) increased linearly with temperature to a maximum value of 0.1852 at 30 degrees C, and then decreased at 32 degrees C. Generation and doubling times of the population were shortest at 30 degrees C, 21.0 and 3.7 d, respectively. PMID- 22525053 TI - Functional characterizations of malonyl-CoA:acyl carrier protein transacylase (MCAT) in Eimeria tenella. AB - Eimeria tenella, an apicomplexan parasite in chickens, possesses an apicoplast and its associated metabolic pathways including the Type II fatty acid synthesis (FAS II). Malonyl-CoA:acyl-carry protein transacylase (MCAT) encoded by the fabD gene is one of the essential enzymes in the FAS II system. In the present study, the entire E. tenella MCAT gene (EtfabD) was cloned and sequenced. Immunolabeling located this protein in the apicoplast organelle in coccidial sporozoites. Functional replacement of the fabD gene with amber mutation of E. coli temperature-sensitive LA2-89 strain by E. tenella EtMCAT demonstrated that EcFabD and EtMCAT perform the same biochemical function. The recombinant EtMCAT protein was expressed and its general biochemical features were also determined. An alkaloid natural product corytuberine (CAS: 517-56-6) could specifically inhibit the EtMCAT activity (IC(50)=16.47MUM), but the inhibition of parasite growth in vitro by corytuberine was very weak (the predicted MIC(50)=0.65mM). PMID- 22525055 TI - Seasonal abundance, number of annual generations, and effect of an entomopathogenic fungus on Phlebotomus papatasi (Diptera: Psychodidae). AB - The monthly density of the sand fly, Phlebotomus Papatasi Scopoli (Diptera: Psychodidae), was monitored during 2009 at Burg El-Arab, a rural district located close to the Mediterranean coast of Egypt. The number of annual generations and the efficacy of microbial control by the entomopathogenic fungus, Metrahizium anisopliae (Metsch.) Sorok (Ma79), were determined in the laboratory under atmospheric conditions, simulating those of the animal shelters in the study area. We used two collecting techniques; CDC light traps and oiled paper traps, to quantify sand fly density inside houses and in the open field. Adult flies exhibited a seasonal range from April to December. The seasonal pattern was bimodal, with one peak in July and the second one in October. Calculations of the correlation coefficient (r) revealed a significant role of temperature and relative humidity in the monthly abundance of the sand flies in the study area. P. papatasi colony completed seven annual generations under semifield conditions, but the mean developmental time of each immature stage and the mean total duration of development from egg to adult for each generation varied according to the prevailing temperature. The longest generation time was observed in winter (the mean +/- SD was 118 +/- 11.70 d), and the shortest one occurred at the highest temperatures in summer (the mean +/- SD was 25.21 +/- 2.04 d). In microbial control studies, the entomopathogenic fungus, M. anisopliae, was used at 15 * 10(8) spores/g food as a standard dose against the second-instar larvae of P. papatasi at the different seasons during 2009. Mortality reached 100% in winter and decreased to 56.0% as the prevailing temperature increased during the summer season. PMID- 22525056 TI - Population dynamics of stable flies Stomoxys calcitrans (Diptera: Muscidae) at an organic dairy farm in Denmark based on mark-recapture with destructive sub sampling. AB - A population of stable flies, Stomoxys calcitrans (L.), was studied on a Danish cattle farm in two successive years. Flies were captured monthly by sweep nettings and marked with fluorescent dust. Absolute population size, dilution rate, loss rate, and adult longevity were estimated by means of a modified version of Bailey's triple catch method. In both years, the abundance of flies peaked in July. Using a statistical model, we were able to explain 86.6% of the variation in the per capita growth rate r as a function of current temperature, precipitation, and population size. Omitting precipitation from the model, it still explained 69.3%. The model predicts that stable flies have a temperature optimum at 21.8 degrees C, and that no development will take place when temperatures inside the stable are below 10.2 degrees C or above 33.5 degrees C. At the optimal temperature the intrinsic rate of natural increase is 0.070 d(-1). The per capita dilution rate increased with temperature and decreased with population size, whereas no effect of these factors on the per capita loss rate could be shown. Mean adult survival time was estimated to 6.3 d with 95% CL ranging from 4.3 to 11.1 d. The study points at the possibility of developing predictive models as tools for achieving better, and more environmentally sound, control of stable flies. PMID- 22525057 TI - A comparison of artificial diet and hybrid sweet corn for the rearing of Helicoverpa armigera (Hubner) (Lepidoptera: Noctuidae) based on life table characteristics. AB - The demographic characteristics of Helicoverpa armigera (Hubner) reared on hybrid sweet corn (Zea mays L. variety saccharata) (hybrid super sweet corn KY bright jean) and on an artificial diet were compared by using the age-stage, two-sex life table. Because the hatch rate of eggs varies with maternal age, age-specific fecundity was calculated based on the numbers of hatched eggs to reveal the biological characteristics of H. armigera accurately. The intrinsic rate of increase (r), finite rate (lambda) and mean generation time (T) of H. armigera were 0.0853 d(-1), 1.0890 d(-1), and 46.6 d, respectively, on Z. mays and 0.1015 d(-1), 1.1068 d(-1), and 46.3 d, respectively, on the artificial diet. There were significant differences in the intrinsic rate of increase and finite rate between two treatments. The age-stage life expectancy and reproductive value also were calculated. The relationships among the net reproductive rate, the mean female fecundity, the number of emerged females, and the total number of individuals used in the life table study are consistent with theoretical expectations. We recommend the age-stage, two-sex life table for use in insect demographic studies to incorporate both sexes and the variation in developmental rate among individuals and to obtain accurate population parameters. The artificial diet is more suitable for the mass rearing of H. armigera. PMID- 22525058 TI - The biology and preliminary host range of Megacopta cribraria (Heteroptera: Plataspidae) and its impact on kudzu growth. AB - The bean plataspid, Megacopta cribraria (F.), recently was discovered in the United States feeding on kudzu, Pueraria montana Lour. (Merr.) variety lobata (Willd.), an economically important invasive vine. We studied its biology on kudzu and its impact on kudzu growth. We also tested its ability to use other common forest legumes for oviposition and development. Flight intercept traps operated from 17 May 2010 to 31 May 2011 in a kudzu field near Athens, GA showed three peaks of adult flight activity suggesting there are two generations per year on kudzu. Vine samples examined for eggs from April 2010 to April 2011 and June to October 2011 showed two periods of oviposition activity in 2010, which coincided with the peaks in adult activity. In 2011, the second period of oviposition began on or before 24 June and then egg abundance declined gradually thereafter until late August when we recovered <2 eggs/0.5 m of vine. Samples of the five nymphal instars and adults on vines did not show similar trends in abundance. Adults did not lay eggs on the various legume species tested in 2010 in a no-choice test possibly because the cages were too small. In the 2011 field host range experiments conducted in a kudzu field by using 12 legume species, M. cribraria preferentially oviposited on kudzu over soybean, Glycine max Merrill., but they still laid 320 eggs per plant on soybean. Lespedeza hirta (L.) Hornem. and Lespedeza cuneata (Dum. Cours.) G. Don had 122.2 and 108.4 eggs per plant, respectively. Kudzu and soybean were the only species M. cribraria completed development on. Plots protected from M. cribraria feeding by biweekly insecticide applications had 32.8% more kudzu biomass than unprotected plots. Our results show that M. cribraria has a significant impact on kudzu growth and could help suppress this pest weed. PMID- 22525059 TI - Fitness components of Aphytis melinus (Hymenoptera: Aphelinidae) reared in five California insectaries. AB - Shipments of 50,000 commercially reared Aphytis melinus DeBach were obtained from each of the five insectaries that produce and sell this parasitoid to citrus growers in California for control of California red scale, Aonidiella aurantii (Maskell). Shipments were received from each insectary every 2 mo over a period of a year to assess variability in quality through time and between insectaries. As indices of quality, we assessed the percentage of live parasitoids (both sexes) 1, 3, 7, 14, and 28 d after receipt of the shipment, shipment sex ratio, and the size of female wasps. We found a fair amount of variation in the percentage of A. melinus that were alive on different sampling days. Despite the fact that all insectaries rear A. melinus in temperature controlled rooms and all of our studies were done at 22 degrees C, wasp mortality occurred more quickly in the colder months of November, January through February, and March. Similar trends were observed with sex ratios; many of the insectaries had male-biased sex ratios in the colder months, especially January through February. Wasp size varied significantly for each of the insectaries throughout the year, with the summer months of July through August yielding significantly smaller females than other months. Collectively our results have important implications for biological control on citrus in California. PMID- 22525060 TI - Homopterans and an invasive red ant, Myrmica rubra (L.), in Maine. AB - Myrmica rubra (L.), is an invasive ant that is spreading across eastern North America. It is presently found in over 40 communities in Maine and areas in Vermont, New Hampshire, Massachusetts, New York, and several provinces in the Canadian Maritimes and Ontario. In addition to disrupting native ant faunas, invasive ants also have been shown to influence homopteran abundance and species composition. We conducted surveys of Homoptera in infested and noninfested sites and conducted manipulative experiments to quantify the effects of M. rubra on homopteran abundance and composition in the summers of 2003, 2006, and 2007 on Mount Desert Island, ME. In 2003, Homoptera family-level richness was higher in infested sites compared with noninfested sites with two out of three sampling methods. Homopteran abundance in infested compared with noninfested sites depended upon the site. The sites with the highest population of M. rubra were associated with significant differences in Homoptera population abundance. In 2006 and 2007, two out of three host plants sampled had significantly higher abundances of the aphids, Aphis spiraephila Patch and Prociphilus tessellatus Fitch. An ant exclusion field experiment on the native plant, meadowsweet (Spiraea alba Du Roi), resulted in higher abundances of A. spiraephila with M. rubra tending compared with native ant tending. A predator exclusion field experiment was conducted on meadowsweet using adult ladybeetles, Hippodamia convergens Guerin-Meneville, larval green lacewings, Chyrsoperla carnea Stephens, and no predators. Predator impacts on aphid populations were reduced in the presence of M. rubra with C. carnea and moderately reduced with H. convergens. PMID- 22525061 TI - Ground beetle (Coleoptera: Carabidae) diversity, activity density, and community structure in a diversified agroecosystem. AB - Diversity and abundance of ground beetles (Coleoptera: Carabidae) can be enhanced in vegetable and field intercropping systems, but the complexity of polycultures precludes the application of generalized assumptions of effects for novel intercropping combinations. In a field experiment conducted at Lacombe and Ellerslie, Alberta, Canada, in 2005 and 2006, we investigated the effects of intercropping canola (Brassica napus L.) with wheat (Triticum aestivum L.) on the diversity and community structure of carabid beetles, and on the activity density responses of individual carabid species. Shannon-Wiener diversity index scores and species evenness increased significantly as the proportion of wheat comprising total crop plant populations increased in one site-year of the study, indicating a positive response to enhanced crop plant species evenness in the intercrops, and in that same site-year, ground beetle communities in intercrops shifted to more closely approximate those in wheat monocultures as the percentage of wheat in the intercrops increased. Individual carabid species activity densities showed differing responses to intercropping, although activity densities of some potential root maggot (Delia spp.) (Diptera: Anthomyiidae) predators were greater in intercrops with high proportions of wheat than in canola monocultures. The activity density of Pterostichus melanarius (Illiger), the most abundant species collected, tended to be greater in canola monocultures than high-wheat intercrops or wheat monocultures. We conclude that intercrops of canola and wheat have the potential to enhance populations of some carabid species, therefore possibly exerting increased pressure on some canola insect pests. PMID- 22525062 TI - Light brown apple moth in California: a diversity of host plants and indigenous parasitoids. AB - The light brown apple moth, Epiphyas postvittana (Walker), an Australia native tortricid, was found in California in 2006. A field survey of host plants used by E. postvittana was conducted in an urban region of the San Francisco Bay Area. An inspection of 152 plant species (66 families), within a 23-ha residential community, found E. postvittana on 75 species (36 families). Most (69 species) host plants were not Australian natives, but had a wide geographic origin; 34 species were new host records for E. postvittana. Heavily infested species were the ornamental shrubs Myrtus communis L., Pittosporum tobira (Thunb.) W.T. Aiton, Euonymus japonicus Thunb., and Sollya heterophylla Lindl. To survey for parasitoids, four urban locations were sampled, with E. postvittana collected from five commonly infested plants [M. communis, P. tobira, E. japonicus, Rosmarinus officinalis L., and Genista monspessulana (L.) L.A.S. Johnson]. Twelve primary parasitoid species and two hyperparasitoids were reared; the most common were the egg parasitoid Trichogramma fasciatum (Perkins), the larval parasitoids Meteorus ictericus Nees, and Enytus eureka (Ashmead), and the pupal parasitoid Pediobius ni Peck. Meteorus ictericus accounted for >80% of the larval parasitoids, and was recovered from larvae collected on 39 plant species. Across all samples, mean parasitism was 84.4% for eggs, 43.6% for larvae, and 57.5% for pupae. The results are discussed with respect to the potential for resident parasitoid species to suppress E. postvittana populations. PMID- 22525063 TI - Community composition and phenology of native Siricidae (Hymenoptera) attracted to semiochemicals in Minnesota. AB - As a result of the introduction of Sirex noctilio F. into North America, there has been increased interest in the poorly-described native Siricidae communities. To date, few studies have surveyed specifically for Siricidae, and many reports of native siricid populations are byproducts of sampling efforts targeting Coleoptera. We report results from a survey targeted specifically at native and exotic Siricidae in Minnesota. We used Lindgren funnel traps from 2006 to 2008 baited with alpha/beta-pinene (Sirex lure), ethanol (EtOH), EtOH + alpha-pinene, or Ips 3-part lures. We captured 704 native Siricidae comprising seven species, of which none were exotic. To our knowledge, this is one of the largest field collections of Siricidae from a single discrete set of localities in existence. Adult Siricidae began flying in June and continued into October each year. The alpha/beta-pinene lure was most effective, but the EtOH + alpha-pinene lure was also moderately effective. We compare our data with those from several states and provinces in the Great Lakes Region of North America. Our data provide insight into the community composition of native Siricidae in Minnesota, while concurrently providing evidence that S. noctilio populations have not yet reached this far into the continental United States. PMID- 22525064 TI - Identification and location of symbionts associated with potato psyllid (Bactericera cockerelli) lifestages. AB - The potato psyllid (Bactericera cockerelli, Sulc) is an invasive pest of solenaceous plants including potatoes (Solanum tuberosum L.)and tomatoes (Solanum lycopersicum L.). The insect transmits the phytopathogen Candidatus Liberibacter solanacearum, which has been identified as the causal agent of Zebra Chip in potatoes. The microbiome of the potato psyllid provides knowledge of the insect's bacterial makeup which enables researchers to develop targeted biological control strategies. In this study, the microbes associated with four B. cockerelli life stages were evaluated by 16S bTEFAP pyrosequencing. The sequences were compared with a 16S-rDNA database derived from NCBI's GenBank. Some bacteria identified are initial discoveries. Species of Wolbachia, Rhizobium, Gordonia, Mycobacterium, Xanthomonas and others were also detected and an assessment of the microbiome associated with B. cockerelli was established. PMID- 22525065 TI - Midgut and fat body bacteriocytes in neotropical cerambycid beetles (Coleoptera: Cerambycidae). AB - Xylophagous insects derive nutrients from intractable substrates by producing or ingesting cellulolytic enzymes, or by maintaining associations with symbiotic microbes. Wood-boring cerambycid beetle larvae sometimes house maternally transmitted endosymbiotic yeasts that are presumed to provide their hosts with nutritional benefits. These are thought to be absent from species in the large subfamily Lamiinae; nevertheless yeasts have been repeatedly isolated from the guts of neotropical lamiines. The objective of this study was to conduct transmission electron microscopy (TEM) studies of cerambycid larval midgut tissues to determine if gut yeasts were intracellular, or simply present in the gut lumen. Nine cerambycid larvae were harvested from two trees in the Brazil nut family (Lecythidaceae) in the rain forest of SE Peru; seven were identified using mtDNA sequence data and processed for TEM. Yeasts cultured from larval frass or exuvia, and identified with rDNA sequence data, were identical or similar to yeasts previously isolated from beetles. In TEM analyses yeast cells were found only in the gut lumens, sometimes associated with fragments of thick-walled xylem cells. Apparent bacteriocytes were found in either midgut or fat body tissue of three larval specimens, including two lamiines. This is the first report of a potential fat body symbiosis in a cerambycid beetle. Future studies of cerambycid symbiosis should distinguish the identities and potential roles of free-living organisms in the gut lumen from those of organisms harbored within gut epithelial or fat body tissue. PMID- 22525066 TI - Host-range testing of Eucryptorrhynchus brandti (Coleoptera: Curculionidae), a candidate for biological control of tree-of-heaven, Ailanthus altissima. AB - Ailanthus altissima (Mill.) Swingle, tree-of-heaven, is an invasive species native to Asia. It first was introduced into the United States in the 1700 s and now is distributed throughout much of North America. Mechanical and chemical controls are current suppression tactics, however, implementation is costly. A weevil, Eucryptorrhynchus brandti (Harold), was identified in China and imported for quarantine testing in 2004 as a potential biological control agent. Host specificity tests on adult feeding, larval development, and oviposition of this weevil were conducted from 2007 to 2011 on A. altissima and 29 nontarget species. Eucryptorrhynchus brandti adults fed significantly more on A. altissima foliage when compared with all test species. Range of means for feeding on A. altissima was 32.5-106.5 mm(2)/adult/d. In no-choice tests, Simarouba glauca DC, Leitneria floridana Chapm., and Citrus limon (L.) Burm. F., had feeding rates of only 10, 49, and 10%, respectively, compared with the level of feeding on A. altissima. The mean range of adult feeding by E. brandti on all other test species was <7% of feeding on A. altissima (0.0-3.3 +/- 5.0 mm(2)/adult/d). In the no-choice larval inoculation tests, larval development only occurred in two of 10 L. floridana seedlings compared with seven of 10 A. altissima seedlings. In the no choice oviposition tests, oviposition and subsequent larval development did not occur in L. floridiana, whereas all seven A. altissima seedlings supported oviposition and subsequent larval development. The weevil did not appear to be a threat to L. floridana or any other nontarget species tested. Therefore, we conclude that Eucryptorrhynchus brandti is highly host specific to A. altissima. PMID- 22525067 TI - Host preference of cotton fleahopper, Pseudatomoscelis seriatus (Reuter) is not labile to geographic origin and prior experience. AB - Several phytophagous insects exhibit distinct preference for their host plants. In widely distributed generalist insects, host preference can be influenced by geographic variation in host plant distribution and abundance as well as by prior experience. We have studied host preference of the cotton fleahopper, Pseudatomoscelis seriatus (Reuter), a pest of cotton in Texas and other neighboring states, by measuring olfactory orientation to horsemint (Monarda punctata L.) and cotton (Gossypium hirsutum L.). Horsemint is one of the primary, native, wild hosts of cotton fleahopper during late-spring and early summer in Texas, and it is commonly believed to be the main source of this pest in cotton. Although the abundance of horsemint, and therefore the fleahopper exposure to it, varies geographically, cotton fleahopper's preference for this native host-plant is maintained across two ecoregions in Texas, TX High Plains (Lubbock area) and Brazos Valley (College Station area). Similarly, preference for horsemint was retained regardless of prior experience with cotton throughout all the life stages of the insect. This fixed preference of cotton fleahopper to horsemint could be because of their ancestral insect-plant interaction, better fitness of cotton fleahopper on horsemint, and relatively low abundance of horsemint compared with cotton. Information gained from this study could be used to implement cultural control practices such as trap cropping, to develop attractants to monitor this pest, or both. PMID- 22525068 TI - Efficacy of traps, lures, and repellents for Xylosandrus compactus (Coleoptera: Curculionidae) and other ambrosia beetles on Coffea arabica plantations and Acacia koa nurseries in Hawaii. AB - The black twig borer, Xylosandrus compactus (Eichhoff) (Coleoptera: Curculionidae: Scolytinae), is a pest of coffee and many endemic Hawaiian plants. Traps baited with chemical attractants commonly are used to capture ambrosia beetles for purposes of monitoring, studying population dynamics, predicting outbreaks, and mass trapping to reduce damage. The objectives of this research were to optimize trapping systems for X. compactus and other ambrosia beetles such as Xylosandrus crassiusculus (Motschulsky) and Xyleborinus saxesenii (Ratzeburg) by comparing efficacy of several attractants, repellents, and trap types. The ability of certain chemicals to act as beetle repellents and thus interfere with trap catch was tested for purposes of protecting host plants from attack. Potential attractants and application methods tested were as follows: ethyl alcohol pouch delivery system, ethyl alcohol vial delivery system, alpha pinene in Eppendorf tubes, eugenol bubblecaps, ginger oil bubblecaps, manuka oil bubblecaps, phoebe oil bubblecaps, and an unbaited control. Potential repellents tested were limonene and verbenone. Ethyl alcohol vials were as attractive as ethyl alcohol sleeves, and were more effective than traps baited with eugenol and alpha-pinene. Japanese beetle traps were more effective for black twig borer trapping than Lindgren funnel traps, and were easier to deploy. Verbenone and limonene significantly reduced trap catch of Xylosandrus compactus and X. crassiusculus, suggesting that they may be effective for reducing attraction to host plants. These results show the importance of developing a combination of several monitoring techniques to enhance management procedures for the black twig borer. PMID- 22525069 TI - A simulation study of how simple mark-recapture methods can be combined with destructive subsampling to facilitate surveys of flying insects. AB - Mark-recapture techniques are used for studies of animal populations. With only three sampling occasions, both Bailey's triple-catch (BTC) and Jolly-Seber's (J S) stochastic method can be applied. As marking and handling of fragile organisms may harm them, and thereby affect their chances of being recaptured, handling should be minimized. This can be achieved by taking a subsample before the main sample at the second sampling occasion. Individuals in the main sample are marked and released, whereas those in the subsample are only used for identifying recaptures. Monte-Carlo simulation was used to compare the subsampling method with the ordinary mark-recapture methods. Model-generated populations were sampled with and without subsampling to provide estimates of population size, loss, and dilution rates. The estimated parameters were compared with their true values to identify biases associated with the sampling methods, using 81 different combinations of population size, dilution rate, loss rate, and sampling effort. Each combination was replicated 1,000 times. In no cases did subsampling perform more poorly than the ordinary methods. J-S was slightly more accurate than BTC to estimate the population size, but only when sampling effort was high. The relative biases associated with estimates of dilution and loss rates were substantial, but declined with increasing population size and sampling effort. Confidence limits for the population parameters generally were reliable and tended to be conservative. We therefore conclude that ordinary mark-recapture methods can be supplemented with subsampling without sacrificing accuracy. Subsampling is especially advantageous in cases where marks are difficult to observe under field conditions. PMID- 22525070 TI - Estimating reproductive success of Aethina tumida (Coleoptera: Nitidulidae) in honey bee colonies by trapping emigrating larvae. AB - The small hive beetle (Aethina tumida Murray) is a scavenger and facultative predator in honey bee colonies, where it feeds on pollen, honey, and bee brood. Although a minor problem in its native Africa, it is an invasive pest of honey bees in the United States and Australia. Adult beetles enter bee hives to oviposit and feed. Larval development occurs within the hive, but mature larvae leave the hive to pupate in soil. The numbers leaving, which can be estimated by trapping, measure the reproductive success of adult beetles in the hive over any given period of time. We describe a trap designed to intercept mature larvae as they reach the end of the bottom board on their way to the ground. Trap efficiency was estimated by releasing groups of 100 larvae into empty brood boxes and counting the numbers trapped. Some larvae escaped, but mean efficiency ranged from 87.2 to 94.2%. We envision the trap as a research tool for study of beetle population dynamics, and we used it to track numbers of larvae leaving active hives for pupation in the soil. The traps detected large increases and then decreases in numbers of larvae leaving colonies that weakened and died. They also detected small numbers of larvae leaving strong European and African colonies, even when no larvae were observed in the hives. PMID- 22525071 TI - Effect of soil temperature and moisture on survival of eggs and first-instar larvae of Delia radicum. AB - Edaphic factors such as soil temperature and moisture influence soil-dwelling insects, whose most vulnerable stages typically are eggs and young larvae. In this study, the survival of eggs and first-instar larvae of the cabbage maggot, Delia radicum L., was measured under laboratory conditions after exposure to a range of soil temperatures and moistures. When eggs were exposed to constant temperature (20-29 degrees C) and humidity (5-200% [wt:wt]), temperature had no significant effect on survival, whereas humidity <25% [wt:wt] caused egg mortality. The gradual exposure of eggs to high temperatures resulted in low mortality below 33 degrees C, but <5% of eggs survived at 40 degrees C. When first-instar larvae were exposed to constant temperature (17-29 degrees C) and humidity (5-100% [wt:wt]), both factors as well as their interaction had a significant effect on larval survival, which was nil at 5% (wt:wt) for all temperatures but increased from 21.9 to 42.8% at 17 degrees C and from 34.1 to 55.0% at 29 degrees C, for soil moisture contents of 15% and 100% (wt:wt), respectively. Eggs of D. radicum are resistant to low soil moisture and high temperature conditions. Larval survival tends to increase with an increase in soil temperature and moisture. It is suggested that soil temperature be integrated into insect development simulation models instead of air temperature, to build more effective models for cabbage maggot management. PMID- 22525072 TI - Age- and density-dependent prophylaxis in the migratory, cannibalistic Mormon cricket Anabrus simplex (Orthoptera: Tettigoniidae). AB - As a result of the increased potential for disease transmission, insects are predicted to show an increased constitutive immunity when crowded. Cannibalistic aggressive interactions further increase the risk of wounding and pathogen transmission in crowds. Nymphal Mormon crickets Anabrus simplex Haldeman were collected in Montana and reared in the laboratory either solitarily or at densities similar to that experienced by Mormon crickets in migratory bands. As teneral adults, solitarily-reared Mormon crickets tended to have greater phenoloxidase activity than those reared in groups. Sampling enzyme activity a second time when the adults were nearing reproductive maturity, group-reared Mormon crickets had elevated levels of prophenoloxidase and encapsulated foreign objects faster than solitarily-reared insects. Rearing density did not have a significant effect on either the darkness of the cuticle or antibacterial activity. This is the first report of age-related responses of adult insect immunity to crowding. PMID- 22525073 TI - Cold hardiness of Helicoverpa zea (Lepidoptera: Noctuidae) pupae. AB - An insect's cold hardiness affects its potential to overwinter and outbreak in different geographic regions. In this study, we characterized the response of Helicoverpa zea (Boddie) pupae to low temperatures by using controlled laboratory measurements of supercooling point (SCP), lower lethal temperature (LT(50)), and lower lethal time (LLTime). The impact of diapause, acclimation, and sex on the cold hardiness of the pupae also were evaluated. Sex did not significantly affect the SCP, LT(50), or LLTime. However, the mean SCP of diapausing pupae (-19.3 degrees C) was significantly lower than nondiapausing pupae (-16.4 degrees C). Acclimation of nondiapausing pupae to constant temperatures from 10 to 20 degrees C before supercooling also produced a significantly lower SCP than nondiapausing pupae held at 25 degrees C. The LT(50)s of nondiapausing and diapausing were not significantly different, but confirmed that H. zea pupae are chill-intolerant because these lethal temperatures are warmer than the corresponding mean SCPs. Diapausing pupae survived longer than nondiapausing pupae at the same, constant, cold temperatures, a finding consistent with the SCP results. Both of these results suggest enhanced cold hardiness in diapausing pupae. When laboratory results were compared with field temperatures and observed distributions of H. zea in the contiguous United States, the laboratory results corroborated what is currently perceived to be the northern overwintering limit of H. zea; approximately the 40(th) parallel. Moreover, our research showed that areas north of this limit are lethal to overwintering pupae not because of low temperature extremes, but rather the length of time spent at near-zero temperatures. PMID- 22525074 TI - Overwintering physiology and microhabitat use of Phyllocnistis populiella (Lepidoptera: Gracilliariidae) in interior Alaska. AB - We investigated the overwintering physiology and behavior of Phyllocnistis populiella Chambers, the aspen leaf miner, which has caused severe and widespread damage to aspen in Alaska over the past 10 yr. Active P. populiella moths caught in spring and summer supercooled to an average temperature of -16 degrees C, whereas dormant moths excavated from hibernacula in the leaf litter during fall and winter supercooled to an average of -32 degrees C. None of the moths survived freezing in the laboratory. Counts of overwintering moths in leaf litter across microhabitats in interior Alaska demonstrated that moths occurred at significantly higher density beneath white spruce trees than beneath the aspen host, several other hardwood species, or in open areas among trees. During winter, the temperature 1-2 cm below the surface of the leaf litter beneath white spruce trees was on average 7-9 degrees C colder than beneath aspen trees, and we estimate that during at least one period of the winter the temperature under some white spruce trees may have been cold enough to cause mortality. However, the leaf litter under white spruce trees was significantly drier than the litter from other microhabitats, which may assist P. populiella moths to avoid inoculative freezing because of physical contact with ice. We conclude that in interior Alaska, P. populiella overwinter in a supercooled state within leaf litter mainly under nonhost trees, and may prefer relatively dry microhabitats over moister ones at the expense of lower environmental temperature. PMID- 22525075 TI - Genetic structure of Tribolium castaneum (Coleoptera: Tenebrionidae) populations in mills. AB - The red flour beetle, Tribolium castaneum (Herbst), is primarily found associated with human structures such as wheat and rice mills. Such structures are predicted to be spatially isolated resource patches with frequent population bottlenecks that should influence their genetic structure. Genetic diversity and differentiation among nine populations of T. castaneum collected from wheat and rice mills (ranging from <1-5,700 km apart) were investigated using eight polymorphic loci (microsatellites and other insertion-deletion polymorphisms, each with 3-14 alleles). Seventy-two locus-by-population combinations were evaluated, of which 31 deviated significantly from Hardy-Weinberg equilibrium, all because of a deficiency of heterozygotes. AMOVA analysis indicated significant differences among populations, with 8.3% of the variation in allele frequency resulting from comparisons among populations, and commodity type and geographic region not significant factors. Although there were significant differences in genetic differentiation among populations (F(ST) values = 0.018 0.149), genetic distance was not significantly correlated with geographic distance. Correct assignment to the source population was successful for only 56% of individuals collected. Further analyses confirmed the occurrence of recent genetic bottlenecks in five out of nine populations. These results provide evidence that populations of T. castaneum collected from mills show spatial genetic structure, but the poor ability to assign individuals to source populations and lack of isolation by distance suggest greater levels of gene flow than predicted originally. PMID- 22525076 TI - Enhanced antitumor efficacy, biodistribution and penetration of docetaxel-loaded biodegradable nanoparticles. AB - To investigate the antitumor effect, biodistribution and penetration in tumors of docetaxel (DOC)-loaded polyethylene glycol-poly(caprolactone) (mPEG-PCL) nanoparticles on hepatic cancer model, DOC-loaded nanoparticles (DOC-NPs) were prepared with synthesized mPEG-PCL by nano-precipitated method with satisfactory encapsulation efficiency, loading capacity and size distribution. The fabricated nano-drugs were effectively transported into tumoral cells through endocytosis and localized around the nuclei in the cytoplasm. In vitro cytotoxicity test showed that DOC-NPs inhibited the murine hepatic carcinoma cell line H22 in a dose-dependent manner, which was similar to Taxotere, the commercialized formulation of docetaxel. The in vivo biodistribution performed on tumor-bearing mice by NIRF real-time imaging demonstrated that the nanoparticles achieved higher concentration and longer retention in tumors than in non-targeted organs after intravenous injection. The immunohistochemical analysis demonstrated that the nanoparticles located not only near the tumoral vasculatures, but also inside the tumoral interior. Therefore, DOC-NPs could penetrate into tumor parenchyma, leading to high intratumoral concentration of DOC. More importantly, the in vivo anti-tumor evaluation showed that DOC-NPs significantly inhibited tumor growth by tumor volume measurement and positron emission tomography and computed tomography (PET/CT) imaging observation. Taken together, the reported drug delivery system here could shed light on the future targeted therapy against hepatic carcinoma. PMID- 22525077 TI - Novel nanostructural photosensitizers for photodynamic therapy: in vitro studies. AB - Photosensitizing properties of 5,10,15,20-tetrakis(4-hydroxyphenyl)porphyrin (p THPP) functionalized by covalent attachment of one chain of poly(ethylene glycol) (PEG) with a molecular weight of 350, 2000, or 5000 Da (p-THPP-PEG(350), p-THPP PEG(2000), p-THPP-PEG(5000)) were studied in vitro. Dark and photo cytotoxicity of these photosensitizers delivered in solution or embedded in liposomes were evaluated on two cell lines: a human colorectal carcinoma cell line (HCT 116) and a prostate cancer cell line (DU 145), and compared with these treated with free p THPP. The attachment of PEG chains results in the pronounced reduction of the dark cytotoxicity of the parent porphyrin. Cell viability tests have demonstrated that the phototoxicity of pegylated porphyrins is dependent on the length of PEG chain and p-THPP-PEG(2000) exhibited the highest photodynamic efficacy for both cell lines. The encapsulation into liposomes did not improve the PDT effect. However, the liposomal formulation of p-THPP-PEG(2000) showed a greater tendency to induce apoptosis in both cell lines than the parent or pegylated porphyrin delivered in solution. The colocalization of p-THPP, p-THPP-PEG(2000) and p-THPP PEG(2000) enclosed in liposomes with fluorescent markers for lysosomes, mitochondria, endoplasmatic reticulum (ER) and Golgi apparatus (GA) was determined in the HCT 116 line. The p-THPP exhibited ubiquitous intracellular distribution with a preference for membranes: mitochondria, ER, GA, lysosomes and plasma membrane. Fluorescence of p-THPP-PEG(2000) was observed within the cytoplasm, with a stronger signal detected in membranous organelle: mitochondria, ER, GA and lysosomes. In contrast, p-THPP-PEG(2000) delivered in liposomes gave a distinct lysosomal pattern of localization. PMID- 22525078 TI - Agitation during lipoplex formation harmonizes the interaction of siRNA to cationic liposomes. AB - We recently demonstrated that agitation during lipoplex formation (vorLTsiR) improves the gene knockdown effect of siRNA because the resultant decrease in lipoplex size leads to an enhanced uptake by cells. In furthering this line of research, the present study was focused on the interaction of siRNA to cationic liposomes during lipoplex preparation. A fluorescence resonance energy transfer (FRET) study indicated that the application of agitation in the presence of siRNA effectively reorganized positively charged lipids (DC-6-14 and DOPE) in an order that effectively promoted further electrostatic interaction between the negatively charged phosphate backbone of siRNA and the positively charged lipids in the cationic liposome membrane. A circular dichroism (CD) study indicated that the agitation did not bring about a change in the A-form helix of siRNA, therefore the interactions between the lateral anionic groups of siRNA - responsible for the characteristic bands of the A-form helix - and cationic liposomes were effectively promoted. Factorial design coupled with response surface methodology was used to statistically analyze the influence of vortex speed and time and siRNA dose on the in vitro gene knockdown effects of siRNA lipoplex that were spontaneously formulated (spoLTsiR) along with that formulated under agitation (vorLTsiR). The analysis indicated that vortex speed plays the most important role in enhancing the gene knockdown effect of siRNA among the three variables, although all three are important. It was concluded that the high energy transmitted by applying agitation during lipoplex formation harmonized the interaction of siRNA to positively charged lipids (DC-6-14 and DOPE) in cationic liposomes, resulting in a superior gene knockdown efficacy of vorLTsiR compared to spoLTsiR. Our study suggests that the preparation procedure is one of the critical factors in producing the enhanced gene knockdown effect of siRNA. PMID- 22525079 TI - Development and characterization of anionic liposaccharides for enhanced oral drug delivery. AB - The aim of this study was to synthesize charged amphoteric molecules, which after complexation with poorly bioavailable drugs would have the potential to improve their oral uptake. Novel anionic liposaccharide derivatives containing d-glucose and lipoamino acids were synthesized by solution phase peptide synthesis. High sensitivity isothermal titration microcalorimetry was used to determine the critical aggregation concentration and the thermodynamic profiles. Hemolytic and cytotoxic activities of the liposaccharides were studied and they revealed that the liposaccharides were non-toxic at the concentration used for oral administration. Mixing a model drug, tobramycin, with the liposaccharide containing two lipids formed aggregates around 200 nm, which increased tobramycin partitioning between n-octanol/water. The results suggested that the studied liposaccharide with two lipids was safe to apply biologically and may have an absorption enhancing activity on hydrophilic, orally poorly available drugs. PMID- 22525080 TI - Swallowing dysfunction and dysphagia is an unrecognized challenge for oral drug therapy. AB - There is evidence that swallowing issues and dysphagia are an increasing problem of the aging population in the coming decades that is affecting oral medication administration. There is a variety of clinical expressions of swallowing dysfunction caused by aging, acute or chronic disease conditions, decline in physiological functions and adverse drug reactions. About one third of patients in long term care facilities experience serious difficulties with swallowing solid oral dosage forms (SODF). Manipulations of the solid oral drug products occur frequently in nursery homes leading to medication errors and potential changes in drug product performance. The alteration of the drug products is performed with the best intention of the care giver to help the patients but bears concerns about safety and lawfulness. Alternative SODF and drug delivery technologies should be considered in the development of new and generic products and their prescription to overcome medication administration problems in patients with swallowing difficulties of SODF. PMID- 22525081 TI - Pulmonary and nasal deposition of ketorolac tromethamine solution (SPRIX) following intranasal administration. AB - Ketorolac tromethamine is a racemic, non-steroidal, anti-inflammatory drug (NSAID). An intra-nasal (IN) formulation, SPRIX((r)), is approved for the treatment of short term (up to 5 days) acute moderate to moderately severe pain. The primary objective of this study was to determine whether (99m)Tc diethylenetriaminepenta acetic acid (DTPA) radiolabelled ketorolac tromethamine formulation (31.5 mg) was deposited in the lungs of healthy subjects (4 men and 9 women) following nasal inhalation of different intensities (gentle or vigorous sniff) and under different postural conditions (upright or semi-supine). The secondary objectives were to determine the deposition pattern of radiolabelled ketorolac solution in the nasal cavity and the clearance of the radiolabel over a 6h period post-administration. The nasal spray pump delivery device used showed a droplet size distribution with a volume mean diameter (VMD) of 50 MUm and approximately 85% of the aerosol mass contained in droplets >10 MUm diameter. The fraction of the dose recorded from the lung regions averaged <0.5%, and was considered to represent scattered radiation rather than true pulmonary deposition. This fraction was not affected by posture or by inhalation manoeuvre. The majority of the radiolabelled intranasal dose was deposited in the nasal cavity. The visual spread patterns within the nasal cavity were most uniform following administration in the upright position regardless of inhalation manoeuvre. Clearance from the nasal cavity was initially very rapid, with only 16 30% of the dose remaining after 10 min and 6-14% after 6 h. Retention was greatest following gentle inhalation. PMID- 22525082 TI - Enhanced systemic exposure of fexofenadine via the intranasal administration of chitosan-coated liposome. AB - The present study aimed to develop the intranasal delivery system of fexofenadine for the prolonged drug release via the preparation of mucoadhesive liposome. By using thin layer film hydration method, liposome of fexofenadine was prepared with DPPC/DPPG, resulting in the small lipid vesicles (359 +/- 5.5 nm) with narrow size distribution (PI<0.1). Subsequently, the surface of anionic liposome was coated by chitosan and in vitro characteristics of liposomes were evaluated along with the pharmacokinetic studies in rats. Chitosan coated liposomes were stable for 6-month storage at 4 degrees C without any significant size change and drug leakage. Furthermore, it exhibited strong mucoadhesive properties in mucin adsorption test, which was 3-fold higher than uncoated liposomes. Compared to the oral delivery of powder formulation, the intranasal delivery of fexofenadine significantly (p<0.05) increased systemic exposure of fexofenadine in rats. Particularly, the intranasal administration of chitosan coated liposome exhibited approximately 5 fold enhancement of AUC with more sustained drug release in rats compared to the oral delivery. In conclusion, intranasal administration of chitosan coated liposome appeared to be effective to enhance the bioavailability as well as prolonged exposure of fexofenadine in rats. PMID- 22525083 TI - Designing a novel in vitro drug-release-testing method for liposomes prepared by pH-gradient method. AB - In order to evaluate the drug-release behavior from pH-gradient liposomal formulation, a simple release-testing method without using biological components was newly designed on the basis of inversed ammonia gradient principle. Various factors influencing drug-release (releasing factor) were examined. As a result, releasing factor's concentration, pH, osmolarity in test fluid, and releasing factor's structure were found to be the critical factors to be optimized. Various vincristine-loaded liposomes with different lipid compositions or with different lipid/cholesterol ratio were tested for drug-release behavior and successfully obtained drug-release profiles reflecting differences in the physicochemical properties of individual liposomes. Furthermore, since the comparative release study of vincristine-loaded liposomes and doxorubicin-loaded liposomes could reproduce the phenomena as other researchers recently reported, a possibility was suggested for the proposed method to estimate the physicochemical status of drug inside of liposomes. Proof of concept study concluded, as a whole, that the novel release-testing method would be useful for a formulation study and also useful as a tool for the quality assurance or quality control in the manufacturing of pH gradient liposomal products. PMID- 22525084 TI - Absorption-promoting effects of chitosan in airway and intestinal cell lines: a comparative study. AB - This work explored the interaction of chitosan with Calu-3 and Caco-2 cell lines, as models of the airway and intestinal epithelium, respectively. The toxicity, tight junction opening and mucoadhesive effects of chitosan were compared in the two cell lines. Additionally, the role of mucus in the absorption-promoting activity of chitosan was studied systematically. Notably, chitosan exhibited a different degree of toxicity on the Calu-3 and Caco-2 cells. Chitosan's tight junction-opening effect, observed in terms of reduction of transepithelial electrical resistance and permeability enhancement, was apparent in both cell lines, though somewhat lower in Caco-2 compared to Calu-3 cell layers (though overall permeability was higher in the former). Tight junction opening and association of chitosan with the epithelial cell layers were more prominent in mucus-containing than in mucus-depleted Calu-3 cells and non mucus-excreting Caco 2 monolayers. Overall, the work suggests that chitosan exhibits a different level of toxicity in airway, as compared to intestinal cells and although absorption enhancement is apparent in both cell lines, enabling its potential use as an absorption-promoting excipient in both pulmonary and oral macromolecular delivery, the magnitude and the duration of the effect are dependent on the level of mucus present on the epithelial surfaces. PMID- 22525085 TI - A floating multiparticulate system for ofloxacin based on a multilayer structure: In vitro and in vivo evaluation. AB - The purpose of this research was to develop a novel gastroretentive multiparticulate system with floating ability. This system was designed to provide drug-loaded pellets coated with three successive coatings-the retarding film (ethyl cellulose), the effervescent layer (sodium bicarbonate) and the gas entrapped polymeric membrane (Eudragit RL 30D). The floating pellets were evaluated for SEM, floating characteristic parameters, in vitro release and bioavailability in New Zealand rabbits. The zero-order release theory model is designed to interpret the release processes. Due to the swelling property, high flexibility and high water permeability, Eudragit RL 30D was used as a gas entrapped polymeric membrane. The obtained pellets exhibit excellent floating ability and release characteristics. Analysis of the release mechanism showed a zero-order release for the first 8h because of the osmotic pressure of the saturated solution inside of the membrane, which was in accordance with that predicted. Abdominal X-ray images showed that the gastroretention period of the floating barium sulfate-labeled pellets was no less than 6h. The relative bioavailability of the floating pellets compared with reference tablets was 113.06 +/- 23.83%. All these results showed that the floating pellets are a feasible approach for the gastroretentive drug delivery system. PMID- 22525086 TI - Differential efficacy of DOTAP enantiomers for siRNA delivery in vitro. AB - DOTAP, as a racemic mixture, is a cationic lipid and a widely used transfection reagent. In this study, the effect of DOTAP's stereochemical structure on transfection efficiency was evaluated in vitro. Racemic and enantiomerically pure DOTAP were used in lipoplex formulations to deliver siRNA to MCF-7 cells, targeting the aromatase enzyme. At the 50 nM siRNA concentration and lipid-to-RNA charge ratios of 4 and 5, the R enantiomer of DOTAP was found to perform better than either the S- or the racemic agent. In addition, at 10 nM siRNA concentration and a charge ratio of 3, the R- lipoplex formulation silenced aromatase by ~50% whereas the S and racemic formulations caused no significant target downregulation. Differences in lipid packing were modeled using membrane simulations. The results showed that, when combined with cholesterol, pure R DOTAP and S-DOTAP enantiomers had 105% and 115% of lipid density relative to racemic DOTAP, respectively. These findings suggest an important role of lipid chirality in future development of lipid based siRNA delivery systems. PMID- 22525087 TI - Folate-targeting magnetic core-shell nanocarriers for selective drug release and imaging. AB - One of the most urgent medical requirements for cancer diagnosis and treatment is how to construct a multifunctional vesicle for simultaneous diagnostic imaging and therapeutic applications. In our study, superparamagnetic iron oxide nanocrystals (SPIONs) and doxorubicin hydrochloride (DOX) are co-encapsulated into PLGA/polymeric liposome core-shell nanocarriers for achieving simultaneous magnetic resonance imaging and targeting drug delivery. The core-shell nanocarrier was self-assembled from a hydrophobic PLGA core and a hydrophilic folate coated PEGlated lipid shell. The experiment showed that folate-targeting magnetic core-shell nanocarriers show clear core-shell structure, excellent magnetism and controlled drug release behavior. Importantly, the core-shell nanoparticles achieve the possibility of co-delivering drugs and SPIONs to the same cells for enhancing magnetic resonance imaging (MRI) effect and improving drug delivery efficiency simultaneously. Our data suggests that the folate targeting magnetic core-shell nanocarriers (FMNs) could provide effective cancer targeting and MRI as well as drug delivery. The FMNs may become a useful nanomedical carrier system for cancer diagnosis and treatment. PMID- 22525088 TI - Jozef Stefan and the dissolution-diffusion phenomena--not only a historical note. AB - In a series of papers published from 1871 to 1889, Jozef (Josef) Stefan dealt with several diffusion processes, including also multicomponent systems. In his last paper on diffusion, which appeared in 1889, he studied the dissolution diffusion process with a moving interface, and gave an analytical solution to this problem. However, Stefan's dissolution-diffusion analysis is not mentioned in literature, and its existence seems to be unknown in scientific community. The present paper summarizes the main Stefan ideas on dissolution of solids governed by diffusion of solute in the adjacent solvent phase thus making his results accessible to wider scientific circles. PMID- 22525089 TI - GUSB and ATP2B4 are suitable reference genes for CFTR gene expression data normalization in nasal epithelium cells. AB - BACKGROUND: CFTR expression studies contribute in understanding the relationship between CFTR transcripts and clinical outcomes. Normalization of qPCR data is an essential step to determine target gene expression. Consequently, appropriate reference genes must be selected for each gene/tissue. In this work, we have assessed the suitability of four potential reference genes for CFTR expression analysis in nasal epithelium. METHODS: B2M, GUSB, HPRT1 and ATP2B4 expression was evaluated in nasal epithelium samples (CFTR-wt controls, n=21; CFTR-splicing group, n=18) by RT-qPCR. Calibration curves were built and different analyses (geNorm, NormFinder, Mann-Whitney) were performed to evaluate gene expression stability between samples as well as between groups. RESULTS AND CONCLUSIONS: We have applied an accurate approach to select reference genes for CFTR expression analysis in nasal epithelium. From the four genes assessed, GUSB and ATP2B4 have been validated as a reliable gene combination for CFTR gene qPCR data normalization. PMID- 22525090 TI - The effect of bone marrow transplantation on oxidative stress in X-linked adrenoleukodystrophy. AB - Oxidative stress plays an important role in the pathophysiology of neurodegenerative diseases, including X-linked adrenoleukodystrophy (X-ALD). In the present work, we evaluated lipid (malondialdehyde [MDA] content) and protein (sulfhydryl and carbonyl contents) oxidative damage parameters in plasma from X ALD patients before and after bone marrow transplant (BMT), in order to verify if this treatment is capable to alter the oxidative parameters studied. We also evaluated the plasma concentration of hexacosanoic acid (C26:0) from X-ALD patients and correlated it with the oxidative damage parameters investigated. We observed that MDA content was significantly increased in plasma of X-ALD patients before BMT and after BMT when compared to controls, and that it was significantly reduced in plasma of X-ALD after BMT when compared to the before BMT group. These results indicate that lipid peroxidation is stimulated in X-ALD patients but there is a significant reduction of lipid peroxidation after BMT. Next, we observed a significant reduction of sulfhydryl content in plasma of X-ALD patients before BMT compared to controls indicating protein oxidative damage and that this measurement was increased in these patients after BMT as compared to before BMT. We found no significant differences in plasma carbonyl content in X ALD patients before and after BMT as compared to controls. However, we observed a significant reduction in this parameter in X-ALD patients after BMT compared to before BMT. Finally, C26:0 plasma concentration was significantly reduced in X ALD patients after BMT when compared to before BMT. We found no significant correlations between MDA and carbonyl values with C26:0 levels of the patients before BMT and after BMT, but a significant inverse correlation between sulfhydryl content and C26:0 levels was detected. In conclusion, the present study reinforces the hypothesis that lipid peroxidation and protein damage are induced in plasma of X-ALD patients and, in addition, demonstrates that BMT treatment is capable to reduce this pathogenic process. Taken together, the data obtained from plasma of X-ALD patients before and after BMT showing induction and protection, respectively, of oxidative stress, allowed to suggest that BMT, when well succeeded and under the recommendations, is effective to reduce C26:0 plasma levels and the increased lipid and protein oxidative damage in X-ALD. PMID- 22525091 TI - Skeletal response to lentiviral mediated gene therapy in a mouse model of MPS VII. AB - Mucopolysaccharidosis VII (MPS VII) is an autosomal recessive, lysosomal storage disorder caused by beta-glucuronidase (GUSB) deficiency, resulting in the accumulation of glycosaminoglycans (GAGs), in a variety of cell types. Severe, progressive skeletal pathology, termed dysostosis multiplex, is a prominent clinical feature of MPS VII. We have evaluated a gene therapy protocol for its efficacy in preventing the development and progression of bone pathology in MPS VII mice treated with a lentiviral vector at birth or at 7 weeks. Two weeks after injections, high levels of vector expression were observed in liver, spleen and bone marrow and to a lesser extent in kidney, lung and heart. Widespread clearance of GAG storage was observed in somatic tissues of both groups and some clearance of neuronal storage was observed in mice treated from birth. Micro-CT analysis demonstrated a significant decrease in vertebral and femoral bone mineral volume, trabecular number, bone surface density and cortical bone thickness in both treatment groups. Lumbar and femoral bone lengths were significantly decreased in untreated MPS VII mice, while growth plate heights were increased and these parameters did not change upon treatment. Small improvements in performance in the open field and rotarod behaviour tests were noted. Overall, systemic lentiviral-mediated gene therapy results in a measurable improvement in parameters of bone mass and architecture as well as biochemical and enzymatic correction. Conversely, growth plate chondrocytes were not responsive to treatment, as evidenced by the lack of improvement in vertebral and femoral bone length and growth plate height. PMID- 22525092 TI - Automobile Shredder Residues in Italy: characterization and valorization opportunities. AB - At the moment Automobile Shredder Residue (ASR) is usually landfilled worldwide, but European draft Directive 2000/53/CE forces the development of alternative solutions, stating the 95%-wt recovery of an End of Life Vehicle (ELV) weight to be fulfilled by 2015. This work describes two industrial tests, each involving 250-300 t of ELVs, in which different pre-shredding operations were performed. The produced ASR materials underwent an extended characterization and some post shredding processes, consisting of dimensional, magnetic, electrostatic and densimetric separation phases, were tested on laboratory scale, having as main purpose the enhancement of ASR recovery/recycling and the minimization of the landfilled fraction. The gathered results show that accurate depollution and dismantling operations are mandatory to obtain a high quality ASR material which may be recycled/recovered and partially landfilled according to the actual European Union regulations, with particular concern for Lower Heating Value (LHV), heavy metals content and Dissolved Organic Carbon (DOC) as critical parameters. Moreover post-shredding technical solutions foreseeing minimum economic and engineering efforts, therefore realizable in common European ELVs shredding plants, may lead to multi-purposed (material recovery and thermal valorization) opportunities for ASR reuse/recovery. PMID- 22525093 TI - Ovulatory activity and plasma prolactin concentrations in wild and domestic ewes exposed to artificial photoperiods between the winter and summer solstices. AB - Mouflon and domestic Manchega sheep differ in the timing of their reproductive season under natural photoperiod (NP) conditions. This study examines whether they also differ in their reproductive responses to artificial photoperiod cues. For this, mouflons (n=24) and ewes (n=24) were exposed between the winter and summer solstices to artificial long days (LD: 16 h light/day), to short days (SD) simulated via the use of melatonin implants, or to NP conditions (controls), and their ovulatory activity monitored. The effects of these treatments on annual changes in prolactin concentration were also recorded. In the LD mouflon ewes, the offset and onset (7 March +/- 5 and 2 October +/- 4, respectively) of cyclic ovulatory activity occurred earlier (P<0.001) than in the NP animals (26 April +/ 6 and 20 October +/- 2, respectively), but no differences were seen (P>0.05) between the SD and NP mouflon ewes in either the onset of anoestrus (12 May +/- 6 and 26 April +/- 6, respectively) or the onset of subsequent ovulatory activity (13 October +/- 8 and 20 October +/- 2, respectively); however the duration of the anoestrus period was significantly reduced in the SD. In LD Manchega ewes, the onset of anoestrus was advanced (2 February +/- 5 vs 15 March +/- 11), but ovulatory activity started at the same time as in NP Manchega ewes (16 July +/- 4 vs 5 July +/- 8). In the SD Manchega ewes, two animals showed continuous cyclic ovulatory activity over the course of the experiment while the remainder entered anoestrus two months later (16 May +/- 6, P<0.001) than their NP counterparts. In these SD ewes, the onset of cyclic ovarian activity was very variable. An annual rhythm of plasma prolactin concentration was seen in both the mouflon and Manchega ewes under all three photoperiod conditions. However, the amplitudes of the changes seen in prolactin concentration were smaller in both the LD and SD animals than in the corresponding NP animals (P<0.001). In conclusion, the results show that these two types of Mediterranean sheep differ in their ovulatory response when subjected to artificial photoperiods. The results also suggest that refractoriness to SDs may be the most important physiological mechanism regulating the onset of anoestrus in highly seasonal breeds, but not in less seasonal breeds. PMID- 22525094 TI - Prenatal and neonatal flutamide administration increases proliferation and reduces apoptosis in large antral follicles of adult pigs. AB - Ovarian follicular atresia is regulated by androgens directly via androgen receptors and indirectly after conversion to estrogens. The balance between proliferation and cell apoptosis is crucial for the physiological functioning of the follicles. The disorder between these processes leads to reproductive failure, such as cyst formation. Recent research suggests maternally or neonatally mediated effects of antiandrogen flutamide on reproductive functions during adulthood. Therefore, the current study was performed to determine whether late gestational or neonatal exposure to flutamide influences proliferation and apoptosis rates in large antral follicles of adult porcine ovary. These periods are critical in ovarian biology and may determine female fertility in adulthood. Flutamide was injected into pregnant gilts between days 80 and 88 of gestation, and into female piglets between days 2 and 10 postnatally. The ovaries were collected from treated and control adult pigs, and healthy large antral follicles were excised. In large antral follicles, granulosa and theca cells revealed elevated (p<0.001) proliferation index measured by immunolocalization of Ki-67 following maternal and neonatal flutamide exposure. The percentage of apoptotic granulosa cells detected using TUNEL assay significantly decreased (p<0.01) after flutamide administration, that paralleled with down-regulation (p<0.01) of caspase-3 protein expression. Moreover, plasma testosterone decreased (p<0.001) in flutamide-treated animals, whereas 17beta-estradiol was elevated following flutamide exposure. The present research indicates increased proliferation and diminished apoptosis rates within large antral follicles of adult pigs following prenatal and neonatal flutamide administration, which might influence the normal development of the follicles and pigs fertility as a consequence. PMID- 22525095 TI - Array-based characterization of an interstitial de-novo deletion of chromosome 4q in a patient with a neuronal migration defect and hypocalcemia plus a literature review. PMID- 22525096 TI - Nanostructured giant magneto-impedance multilayers deposited onto flexible substrates for low pressure sensing. AB - Nanostructured FeNi-based multilayers are very suitable for use as magnetic sensors using the giant magneto-impedance effect. New fields of application can be opened with these materials deposited onto flexible substrates. In this work, we compare the performance of samples prepared onto a rigid glass substrate and onto a cyclo olefin copolymer flexible one. Although a significant reduction of the field sensitivity is found due to the increased effect of the stresses generated during preparation, the results are still satisfactory for use as magnetic field sensors in special applications. Moreover, we take advantage of the flexible nature of the substrate to evaluate the pressure dependence of the giant magneto-impedance effect. Sensitivities up to 1 Omega/Pa are found for pressures in the range of 0 to 1 Pa, demostrating the suitability of these nanostructured materials deposited onto flexible substrates to build sensitive pressure sensors. PMID- 22525097 TI - Plausible Transition States for glycosylation reactions. AB - The Transition State (TS) for any chemical glycosylation reaction is not known with certainty. Both experimental and computational approaches have been limited due to the complexity of the problem. This work describes a preliminary computational ionization approach using density functional theory calculations to arrive at hypothetical TSs. The new TSs contain the glycosyl donor as anomeric triflates, the acceptor as methanol, some CH(2)Cl(2) molecules, and a Li(+) ion promoter. In this computational approach all glycosylations are disassociative in that the C-1-O(Tf) bond length is greater then 2 A before any nucleophilic attack. All nucleophilic attack requires some preassociation of the nucleophile with examples of the pre-attack complexation to donor oxygens. These hypothetical models are intended to guide both experimental and computational approaches to finding TSs for glycosylation reactions that can be used to optimize stereoselectivity of glycosylation. PMID- 22525098 TI - Catalytic mechanism of human UDP-glucose 6-dehydrogenase: in situ proton NMR studies reveal that the C-5 hydrogen of UDP-glucose is not exchanged with bulk water during the enzymatic reaction. AB - Human UDP-glucose 6-dehydrogenase (hUGDH) catalyzes the biosynthetic oxidation of UDP-glucose into UDP-glucuronic acid. The catalytic reaction proceeds in two NAD(+)-dependent steps via covalent thiohemiacetal and thioester enzyme intermediates. Formation of the thiohemiacetal adduct occurs through attack of Cys(276) on C-6 of the UDP-gluco-hexodialdose produced in the first oxidation step. Because previous studies of the related enzyme from bovine liver had suggested loss of the C-5 hydrogen from UDP-gluco-hexodialdose due to keto-enol tautomerism, we examined incorporation of solvent deuterium into product(s) of UDP-glucose oxidation by hUGDH. We used wild-type enzyme and a slow-reacting Glu(161)->Gln mutant that accumulates the thioester adduct at steady state. In situ proton NMR measurements showed that UDP-glucuronic acid was the sole detectable product of both enzymatic transformations. The product contained no deuterium at C-5 within the detection limit (<=2%). The results are consistent with the proposed mechanistic idea for hUGDH that incipient UDP-gluco hexodialdose is immediately trapped by thiohemiacetal adduct formation. PMID- 22525099 TI - Synthesis of beta-D-fructofuranosyl-(2->1)-2-acetamido-2-deoxy-alpha-D glucopyranoside (N-acetylsucrosamine) using beta-fructofuranosidase-containing Aspergillus oryzae mycelia as a whole-cell catalyst. AB - Using soft granules consisting of Celite 535 and dried Aspergillus oryzae NBRC100959 mycelia containing beta-fructofuranosidase as a whole-cell catalyst, N acetylsucrosamine [beta-D-fructofuranosyl-(2->1)-2-acetamido-2-deoxy-alpha-D glucopyranoside] was produced from sucrose and 2-acetamido-2-deoxy-D-glucose by enzymatic transfructosylation. The isolated yield of N-acetylsucrosamine from the reaction mixture was 22.1% (from sucrose). The result of N-terminal amino acid sequence analysis indicated that the enzyme involved in the synthesis of N acetylsucrosamine is a product from gene (NCBI accession number; NW_001884675, locus tag; AOR_1_1114084) encoding putative beta-fructofuranosidase on chromosome 6 of strain NBRC100959. The N-acetylsucrosamine we produced is highly soluble in water and is more stable in acidic solution than sucrose. The disaccharide was also produced using dried mycelia prepared from another A. oryzae strains. PMID- 22525100 TI - Chondroitin-4-O-sulfatase from Bacteroides thetaiotaomicron: exploration of the substrate specificity. AB - Bacterial sulfatases can be good tools to increase the molecular diversity of glycosaminoglycan synthetic fragments. A chondroitin 4-O-sulfatase from the human commensal bacterium Bacteroides thetaiotaomicron has recently been identified and expressed. In order to use this enzyme for synthetic purposes, the minimal structure required for its activity has been determined. For that, four 4-O sulfated monosaccharides and one 4-O-sulfated disaccharide have been synthesized and used as substrates with the sulfatase. The minimum structure was shown to be a disaccharide but in contrast to the natural substrate, which must have a 4,5 insaturation, the enzyme accepts as substrate, a disaccharide with a saturated glucuronic acid at the non-reducing end and even a glucopyranosyl moiety without the carboxylic acid functionality. PMID- 22525101 TI - Synthesis of variously sulfated biotinylated oligosaccharides from the linkage region of proteoglycans. AB - The synthesis of a collection, as biotinylated conjugates, of various sulfoforms of the trisaccharide beta-D-GlcpA-(1->3)-beta-D-Galp-(1->3)-beta-D-Galp, structures encountered in the linkage region of proteoglycans, is reported herein for the first time. An efficient and stereocontrolled preparation was achieved using common key intermediates in a divergent manner. These molecules should be useful probes to study the substrate specificity of the glycosyltransferases involved at the bifurcation point in the biosynthesis of proteoglycans. PMID- 22525102 TI - Interrupting intimate partner violence in developing countries. PMID- 22525103 TI - Open to the public: how adolescents blur the boundaries online between the private and public spheres of their lives. PMID- 22525104 TI - Addressing the critical health problem of adolescent substance use through health care, research, and public policy. AB - The use of addictive substances-tobacco, alcohol, and other drugs-during adolescence interferes with brain development and increases the risk of serious health and mental health conditions, including addiction. Yet, adolescents live in a culture in which family, social, community, and media influences regularly bombard them with pro-substance use messages, creating an environment in which substance use is considered an expected behavior, rather than a considerable health risk. To prevent the significant harm that falls to teens and young adults because of substance use, The National Center on Addiction and Substance Abuse at Columbia University (CASA Columbia) undertook a study to explore how adolescent brain development relates to the risk of substance use and addiction; the cultural influences that create an environment in which substance use is considered normative behavior; individual factors that make some teens more disposed to substance use and addiction; and evidence-based prevention and treatment strategies for addressing this problem. The recently published report Adolescent Substance Use: America's #1 Public Health Problem concludes that risky substance use is a major public health problem that can be ameliorated through evidence-based public health measures, including education about the disease and its risk factors, screenings, and clinical interventions, and that addiction can be treated and managed effectively within routine health care practice and specialty care. PMID- 22525105 TI - Male adolescents' attitudes toward wife beating: a multi-country study in South Asia. AB - PURPOSE: This study has aimed to address the gaps in knowledge about male adolescents and their attitudes toward wife beating in multi-country study in Bangladesh, India, and Nepal. METHODS: The study used secondary data generated from nationally representative samples of male adolescents (aged 15-19 years) in the demographic and health surveys data in Bangladesh, India, and Nepal. These were household surveys using structured questionnaires, with 275 boys in Bangladesh, 13,078 boys in India, and 939 boys in Nepal. Chi-square tests and logistic regressions were used to assess the associations. RESULTS: In Bangladesh, 42% of 275 respondents had justified wife beating; in India, 51% of 13,078 male adolescents had supported wife beating; and in Nepal, 28% of 939 respondents had supported wife abuse. Individual-level factors, such as rural residency, low educational attainment, low economic status, being unemployed, and having a history of family violence, were positively associated with the justification of wife abuse. CONCLUSIONS: This multi-country study indicates a general trend of male adolescents' strong supportive attitude toward wife beating, and hence may suggest that policy makers can specifically target young groups of the population for various interventions for reducing violence against women. PMID- 22525106 TI - Racial differences in the consequences of childhood maltreatment for adolescent and young adult depression, heavy drinking, and violence. AB - PURPOSE: This study examined racial differences in the consequences of childhood maltreatment for depression, heavy drinking, and violence during adolescence and young adulthood among black and white young men. METHODS: Data were obtained from the Pittsburgh Youth Study, a prospective longitudinal study of urban males (N = 971, 56% black). Childhood maltreatment was defined as substantiated physical or sexual abuse, physical neglect, emotional maltreatment, or moral/legal/educational maltreatment, with the first referral before 12 years of age. Self-reports of depressive symptoms and heavy drinking (consuming more than six drinks on a single occasion) and official, parent, and self-reports of violent offending were assessed between 12 and 17 years of age (adolescence) and at 24/25 years of age (young adulthood). Regression analyses were conducted to examine childhood maltreatment and race, as well as maltreatment-by-race interactions, as predictors of the three outcomes. RESULTS: Prevalence of childhood maltreatment was higher for black than for white boys; however, there were no racial differences in timing, type, severity, and chronicity of maltreatment. When socioeconomic status and cohort were controlled, childhood maltreatment significantly predicted depressive symptoms and violence in adolescence but none of the outcomes in young adulthood. Race was a significant predictor of heavy drinking and violence during adolescence, and of all three outcomes in young adulthood. No significant race-by-maltreatment interaction effects were found. CONCLUSIONS: Childhood maltreatment has similar negative consequences for black and white male youth during adolescence. Extending intervention efforts through adolescence is important to alleviate these problems among victims. PMID- 22525107 TI - Romantic relationship characteristics and alcohol use: longitudinal associations with dual method contraception use. AB - PURPOSE: Dual method contraception use, or the use of one type of contraceptive intended to prevent pregnancy combined with another type intended to reduce the risk of sexually transmitted infection, may be the most effective method to prevent both unintended pregnancy and sexually transmitted infection. This study tested the association between relationship length, relationship type (married, cohabiting, dating but not cohabiting), global alcohol use, and situational alcohol use and the probability of dual method contraception use from 20 to 23 years of age. METHODS: Hierarchical linear modeling analyses were conducted using longitudinal data from 754 sexually active male and female young adults aged 20 23 years. Dependent variables included both any dual method contraception use and consistent dual method contraception use. RESULTS: Between 15% and 20% of respondents reported consistent dual method contraception use at each time point. Longer relationship length and more committed relationship type were associated with a lower probability of both any and consistent dual method contraception use. Situational alcohol use (drinking before sex), but not global alcohol use, also was related to a lower probability of both any and consistent dual method contraception use. Increasing age was associated with a lower probability of any dual method contraception use, but was not related to consistent dual method use. CONCLUSIONS: Efforts to promote dual method contraception among young adults should include messages discouraging drinking before sex and supporting dual method use even in the context of committed relationships. PMID- 22525108 TI - Beyond age at first sex: patterns of emerging sexual behavior in adolescence and young adulthood. AB - PURPOSE: Although the emergence of sexual expression during adolescence and early adulthood is nearly universal, little is known about patterns of initiation. METHODS: We used latent class analysis to group 12,194 respondents from waves I and IV of the National Longitudinal Study of Adolescent Health (Add Health) into one of five classes based on variety, timing, spacing, and sequencing of oral genital, anal, and vaginal sex. Multinomial logistic regression models, stratified by biological sex, examined associations between sociodemographic characteristics and class membership. RESULTS: Approximately half of respondents followed a pattern characterized predominately by initiation of vaginal sex first, average age of initiation of approximately 16 years, and spacing of >1 year between initiation of the first and second behaviors; almost one-third initiated sexual activity slightly later but reported first experiences of oral genital and vaginal sex within the same year. Classes characterized by postponement of sexual activity, initiation of only one type of behavior, or adolescent initiation of anal sex were substantially less common. Compared with white respondents, black respondents were more likely to appear in classes characterized by initiation of vaginal sex first. Respondents from lower socioeconomic backgrounds were more likely to be in classes distinguished by early/atypical patterns of initiation. CONCLUSIONS: A small number of typical and atypical patterns capture the emergence of sexual behavior during adolescence, but these patterns reveal complex associations among different elements of emerging sexuality that should be considered in future research. PMID- 22525109 TI - Risk perceptions after human papillomavirus vaccination in HIV-infected adolescents and young adult women. AB - PURPOSE: To examine risk perceptions (perceived risk of human papillomavirus [HPV], perceived risk of other sexually transmitted infections [STIs], and need for safer sexual behaviors) and to determine factors associated with these risk perceptions after HPV vaccination. METHODS: Data were collected at the baseline visit of an HPV-6, -11, -16, -18 vaccine clinical trial in 16-23-year-old HIV infected young women (N = 99). Immediately after receiving the first vaccine dose, participants completed a confidential questionnaire that included three 5 item scales measuring perceived risk of HPV, perceived risk of other STIs, and need for safer sexual behaviors. Linear and logistic regression models were used to examine associations between baseline characteristics (demographic characteristics; cluster of differentiation antigen 4 (CD4(+)) count; HIV viral load; knowledge about HPV and HPV vaccines; sexual behaviors; and STI diagnosis) and each measure of risk perceptions. RESULTS: Most participants perceived themselves to be at lower risk for HPV (mean scale score = 19.5/50), most perceived that they were not at lower risk for other STIs (mean = 31.2/50), and the vast majority reported that there was still a need for safer sexual behaviors after vaccination (mean = 43.1/50). Multivariate analyses indicated that knowledge about HPV and HPV vaccines was associated with perceived need for safer sexual behaviors (OR = 1.05, 95% CI = 1.0-1.1). CONCLUSIONS: Although almost all young women in this study believed that safer sexual behaviors were still important after HPV vaccination, a subset believed they were at less risk for STIs other than HPV. Educational interventions are needed to prevent misperceptions and promote healthy behaviors after vaccination. PMID- 22525110 TI - Predictors of highly active antiretroviral therapy utilization for behaviorally HIV-1-infected youth: impact of adult versus pediatric clinical care site. AB - OBJECTIVES: We evaluated highly active antiretroviral therapy (HAART) utilization in youth infected with HIV through risk behaviors who met treatment criteria for HAART. We assessed the impact of receiving care at an adult or pediatric HIV clinical site on initiation and discontinuation of the first HAART regimen in behaviorally infected youth (BIY). METHODS: This was a retrospective analysis of treatment-naive BIY, aged 12-24 years, who enrolled in the HIV Research Network between 2002 and 2008 and who met criteria for HAART. The outcomes were time from meeting criteria to initiation of HAART and time to discontinuation of the first HAART regimen. Analyses were conducted using Cox proportional hazards regression. RESULTS: Of 287 treatment-eligible youth, 198 (69%) received HAART; of these 198 youth, 58 (29.3%) subsequently discontinued HAART. In multivariable analyses, there was no significant difference in the time between meeting treatment criteria and initiating HAART for BIY followed at adult or pediatric HIV clinical sites. However, BIY followed at adult sites discontinued HAART sooner than BIY followed at pediatric HIV clinical sites (adjusted hazard ratio [AHR]: 3.19 [1.26 8.06]). CONCLUSIONS: Two-thirds of treatment-eligible BIY in the HIV Research Network cohort initiated HAART; however, one-third who initiated HAART discontinued it during the study period. Identifying factors associated with earlier HAART initiation and sustainability can inform interventions to enhance HAART utilization among treatment-eligible youth. The finding of earlier HAART discontinuation for youth at adult care sites deserves further study. PMID- 22525112 TI - Socioeconomic status and bone mass in Spanish adolescents. The HELENA Study. AB - PURPOSE: Socioeconomic status (SES) has been frequently associated with body composition, particularly fat mass and obesity. However, the SES-bone mass association is not clear. We aimed to evaluate the associations between different SES indicators (Family Affluence Scale, parental education, and occupation) and bone mineral content in Spanish adolescents. METHODS: Participants were 322 adolescents (164 boys and 158 girls, 12.5-17.5 years) from the Healthy Lifestyle in Europe by Nutrition in Adolescence study. The social background of the adolescents was self-reported using an SES questionnaire, and the bone variables were measured using dual-energy x-ray absorptiometry. Physical activity was measured using accelerometers. Calcium intake was estimated from two nonconsecutive 24 hours recalls. One-way analysis of covariance was performed to examine the relationships between SES indicators and bone mass using different sets of confounders: basic model (sex + sexual maturation), model 1 (basic model + height), model 2 (basic model + lean mass), and model 3 (basic model + calcium intake + average physical activity). RESULTS: Adjusted results showed no association between SES indicators and whole-body or total hip bone mineral content. Additional analyses were performed in lumbar spine, pelvis, and hip subregions (femoral neck, trochanter, and intertrochanter), and no significant associations were observed at these sites either. CONCLUSIONS: Our data do not support a link between different SES indicators (Family Affluence Scale, parental education, and occupation) and bone mass in adolescents. PMID- 22525111 TI - A prospective study of overeating, binge eating, and depressive symptoms among adolescent and young adult women. AB - PURPOSE: To investigate the temporal relationship between depressive symptoms and overeating and binge eating among adolescent and young adult females in the United States. METHODS: We investigated incident overeating, binge eating, and depressive symptoms among 4,798 females in the Growing Up Today Study, a prospective cohort study of adolescents and young adults throughout the United States. Participants who reported at least monthly episodes of eating a very large amount of food in a short amount of time in the past year, but not experiencing a loss of control, were classified as overeaters. Those who reported a loss of control while overeating were classified as binge eaters. Depressive symptoms were assessed with the McKnight Risk Factor Survey. Participants were followed between 1999 and 2003. Generalized estimating equations were used for lagged analysis with time-varying covariates. Analyses were adjusted for age, age at menarche, body mass index, and follow-up time. RESULTS: Females reporting depressive symptoms at baseline were two times more likely than their peers to start overeating (odds ratio [OR] = 1.9; 95% confidence interval [CI] = 1.4, 2.5) and binge eating (OR = 2.3; 95% CI = 1.7, 3.0) during the follow-up. Similarly, females engaging in overeating (OR = 1.9; 95% CI = 1.1, 3.4) or binge eating (OR = 1.9; 95% CI = 1.2, 2.9) at baseline were two times more likely than their peers to develop depressive symptoms during the follow-up. CONCLUSIONS: These results indicate that it is important to consider depressive symptoms in overeating and binge eating prevention and treatment initiatives targeting adolescent and young adult females. PMID- 22525113 TI - Longitudinal trajectories of metabolic control across adolescence: associations with parental involvement, adolescents' psychosocial maturity, and health care utilization. AB - PURPOSE: To predict trajectories of metabolic control across adolescence from parental involvement and adolescent psychosocial maturity, and to link metabolic control trajectories to health care utilization. METHODS: Two hundred fifty-two adolescents (M age at study initiation = 12.5 years, SD = 1.5, range = 10-14 years) with type 1 diabetes (54.4% female, 92.8% Caucasian, length of diagnosis M = 4.7 years, SD = 3.0, range = 1-12 years) participated in a 2-year longitudinal study. Metabolic control was gathered from medical records every 3 months. Adolescents completed measures of self-reliance (functional autonomy and extreme peer orientation), self-control (self-control and externalizing behavior), and parental involvement in diabetes care (acceptance, monitoring, and frequency of help). At the end of the study, mothers reported health care utilization (diabetes-related emergency room visits and hospitalizations) over the past 6 months. RESULTS: Latent class growth analyses indicated two distinct trajectories of metabolic control across adolescence: moderate control with slight deterioration (92% of the sample; average HbA1c = 8.18%) and poor control with rapid deterioration (8% of the sample; average HbA1c of 12.09%). Adolescents with poor and rapidly deteriorating metabolic control reported lower paternal monitoring and frequency of help with diabetes management, lower functional autonomy, and lower self-control than others. Those with poor and rapidly deteriorating metabolic control were 6.4 times more likely to report diabetes related emergency room visits, and 9.3 times more likely to report diabetes related hospitalizations near the end of the study. CONCLUSIONS: Parental involvement and adolescents' psychosocial maturity predict patterns of deteriorating metabolic control across adolescence and could be targeted for intervention. PMID- 22525114 TI - Cardiorespiratory fitness and proximity to commercial physical activity facilities among 12th grade girls. AB - PURPOSE: To investigate the relationship between proximity to commercial physical activity (PA) facilities and cardiorespiratory fitness of 12th grade girls. METHODS: Adolescent girls (n = 786, 60% African American, mean age = 17.6 +/- .6 years) performed a submaximal fitness test (Physical Work Capacity 170 test). Commercial PA facilities were mapped and counted within a .75-mile street-network buffer around girls' homes using Geographic Information Systems. Sedentary activities and vigorous physical activity (>=6 metabolic equivalents) were determined by the average number of 30-minute blocks reported per day on the 3 Day Physical Activity Recall. Mixed model regressions were calculated using school as a random variable. RESULTS: Girls had higher weight-relative Physical Work Capacity 170 test scores if there was a commercial PA facility (n = 186, 12.4 +/- 4.2 kg m/min/kg) within a .75-mile street-network buffer of home as compared with girls without a nearby facility (n = 600, 11.2 +/- 3.6 kg m/min/kg). After adjusting for demographic variables, sports participation, sedentary behaviors, and vigorous physical activity, having one or more commercial PA facilities within a .75-mile street-network buffer of homes was significantly related to cardiorespiratory fitness. CONCLUSIONS: Both with and without adjustment for covariates, the presence of a commercial PA facility within a .75-mile street-network buffer of a girl's home was associated with higher cardiorespiratory fitness. PMID- 22525115 TI - Bidirectional prospective associations between physical activity and depressive symptoms. The TRAILS Study. AB - PURPOSE: Low levels of physical activity (PA) have been shown to be associated with depression in adults. The few studies that focused on adolescents yielded mixed and inconsistent results. Efforts to examine the direction of this relationship have been inconclusive up to now. The aims of this study were therefore to investigate (1) the direction of the inverse association between PA and depressive symptoms over time, and (2) whether these associations are specific to particular clusters of depressive symptoms in adolescents. METHODS: Depressive symptoms and PA were assessed in a population sample of adolescents (N = 2,230) who were measured at three waves between age 10 and age 17. Depressive symptoms were measured by the Affective Problems scale of the Youth Self-Report and Child Behavior Checklist, whereas PA was operationalized as the amount of time spent on physical exercise. Structural equation modeling was used to examine bidirectional effects of PA and depressive symptoms over time. RESULTS: We found significant cross-lagged paths from prior PA to later depression as well as from prior depression to later PA (beta values = -.039 to -.047). After subdividing depression into affective and somatic symptoms, the affective symptoms were reciprocally related to PA, whereas the paths between somatic symptoms and PA did not reach statistical significance. CONCLUSIONS: An inverse bidirectional association between PA and general depressive symptoms was observed. This association was restricted to affective symptoms. PMID- 22525116 TI - Low back pain and comorbidity clusters at 17 years of age: a cross-sectional examination of health-related quality of life and specific low back pain impacts. AB - PURPOSE: Comorbidities in adults negatively affect the course of low back pain (LBP). Little is known of the presence and/or impact of LBP comorbidities in adolescents. METHODS: Subjects from the Raine Study cohort at age 17 years (n = 1,391) provided self-report of diagnosed medical conditions/health complaints, health-related quality of life (36-Item Short Form Health Survey [SF-36]), lifetime experience of LBP, and specific LBP impacts (taking medication, missing school/work, interference with normal/physical activities). Latent class analysis was used to estimate clusters of comorbidities based on diagnosed disorders. Profiles of SF-36 and impact were examined between clusters. RESULTS: Four distinct comorbidity clusters were identified: cluster 1: Low probability of diagnosed LBP or any other medical condition (79.7%); cluster 2: High probability of diagnosed LBP and neck/shoulder pain, but a low probability of other diagnosed health conditions (9.6%); cluster 3: Moderate probability of diagnosed LBP and high probability of diagnosed anxiety and depression (6.9%); cluster 4: Moderate probability of diagnosed LBP and high probability of diagnosed behavioral and attention disorders (3.8%). The clusters had different SF-36 and LBP impact profiles, with clusters 3 and 4 having poorer SF-36 scores, and clusters 2 to 4 having greater risk for specific LBP impacts, than cluster 1. CONCLUSIONS: Identified comorbidity clusters support adolescent and adult studies reporting associations between LBP, other pain areas, psychological disorders, and disability. Tracking these clusters into adulthood may provide insight into health care utilization in later life, whereas identification of these individuals early in the life span may help optimize intervention opportunities. PMID- 22525117 TI - Adolescents' self-presentation on a teen dating web site: a risk-content analysis. AB - PURPOSE: To analzye adolescents' profiles on MyLol.net, a teen dating Web site, for risk content. We hypothesized that risk content would vary by age and gender. METHODS: We selected and coded 752 publicly viewable profiles of adolescents aged 14-18 years for the following five risks: sex, alcohol, drugs, cigarettes, and violence. RESULTS: Of the total profiles, 27.7% contained risk-related content: 15.8% sexual behavior, 13.8% alcohol use, 1.6% drug use, 6.8% cigarette smoking, and .9% violence activity. Being female, "single" relationship status, and use of profanity (p < .05) were associated with risk content. CONCLUSIONS: Females' profiles were most likely to include risky content, especially sexual content. Adolescent females who have internalized social norms that place a high value on female sexuality may reflect this in their online profiles. Online mention of interest/involvement in risky behavior may have negative consequences (e.g., cyberbullies and sexual predators). Stronger universal Internet policies and education are needed to help protect adolescents. PMID- 22525118 TI - Cyber and bias-based harassment: associations with academic, substance use, and mental health problems. AB - PURPOSE: To examine how two forms of interstudent harassment, cyber and bias based harassment, are associated with academic, substance use, and mental health problems. METHODS: We used a population-based survey of 17,366 middle and high school students that assessed harassment due to race/ethnicity or sexual orientation, and harassment through the Internet or text messaging along with other forms of interstudent harassment. RESULTS: Odds ratios indicated that students experiencing both cyber and bias-based harassment were at the greatest risk for adjustment problems across all indicators, with suicidal ideation and attempts having the largest risk differences. CONCLUSIONS: Assessments of adolescent health and adjustment should include questions regarding both cyber and bias-based harassment. PMID- 22525119 TI - Suicidal ideation and self-harm behavior in a community sample of preadolescent youth: a case-control study. AB - OBJECTIVE: Research has focused on understanding risk factors associated with suicidal ideation and self-harm behaviors in older youth, but less is known regarding these behaviors in preadolescents. We examined characteristics associated with suicidal ideation and self-harm behavior in youth aged 10-13 years. DESIGN/METHODS: A community sample of 387 youth was enrolled in a prospective study assessing precursors of risk behaviors. Twenty-three subjects endorsing items regarding suicidal ideation or self-harm behaviors (Achenbach's Youth Self-Report) (endorsers) were matched with 23 non-endorsers. Groups were compared on problem behaviors, impulsivity, neurocognitive function, risk behaviors, and other variables. RESULTS: Endorsers had higher levels of impulsivity, were more likely in borderline/clinical range on 5 of 8 Youth Self Report Syndrome scales, and reported more risk taking. Endorsers and non endorsers were similar in neurocognitive function. More non-endorsers were on stimulants, but groups were similar in parental monitoring and parental report of behavioral/emotional issues, socioeconomic status, and marital status. CONCLUSION: In this study, preadolescent endorsers report significantly more problem behaviors than non-endorsers. However, parental monitoring and parent report of problems were similar between groups. Given these findings, we suggest that at-risk youth may be underrecognized at young ages. PMID- 22525120 TI - "What if you already know everything about sex?" Content analysis of questions from early adolescents in a middle school sex education program. AB - PURPOSE: To assess sixth graders' knowledge and curiosity about sex-related topics that can guide the development of sexual health education and healthcare delivery. METHODS: Sixth graders (n = 795) in eight ethnically diverse schools participating in an evaluation of a sex education curriculum submitted 859 anonymous questions that were content analyzed. The chi(2) analysis examined whether the themes varied by coed/single-sex environments or by school-level sexual risk. RESULTS: Sexual activity, female anatomy, reproduction, and puberty were the most frequently mentioned topics, whereas, questions on STIs, sexual violence, and drug/alcohol use were fewer. Questions that avoided sexual topics came from lower sexual-risk schools; students at higher-risk schools asked about sexual initiation, contraception, vaginal and anal sex, general health, and pain during sex. Single-sex classrooms elicited more direct and explicit questions about sex. CONCLUSIONS: The results are relevant to educators and healthcare providers who ask and answer questions from early adolescents regarding sexual health. PMID- 22525121 TI - Diffuse peritoneal chlamydial infection presenting as possible ovarian peritoneal carcinomatosis in an adolescent female. AB - A 17-year-old girl presented with significant abdominal ascites associated with periumbilical pain. On examination, her abdomen was found to be soft and moderately distended with left lower quadrant tenderness. Abdominal computed tomographic scan demonstrated not only ascites but also diffuse peritoneal enhancement, a left-sided enhancing adnexal mass displacing the uterus to the right, as well as omental caking. Alpha fetoprotein level was normal, whereas carcinoembryonic antigen (3.4 ng/mL) and cancer antigen 125 (315 U/mL) were mildly elevated. Based on these findings, a presumptive diagnosis of peritoneal carcinomatosis of ovarian origin was made. However, intraoperative biopsy of the left adnexal mass showed only a lymphoplasmacytic infiltrate. Chlamydial polymerase chain reaction of an intraoperative cervical sample was positive, and the final diagnosis was complicated pelvic inflammatory disease. The patient responded well to a prolonged course of antibiotics. PMID- 22525122 TI - Rationale for reducing the spread of human papillomavirus in adolescents: strategies to improve outcomes (CME multimedia activity). AB - As detailed in this online CME activity (http://cmeaccess.com/cme/JAH_HPV_program/index.asp?link_id=2), human papillomavirus (HPV) infection is the cause of cervical cancer and neoplasias in women, and genital warts in men and women. In addition, 35%-85% of vaginal, vulvar, anal, penile, and oropharyngeal cancers are attributable to HPV. An estimated 80% of females and 50% of males in the United States will become infected at some point in their lives; however, the incidence of this highly prevalent infection peaks in adolescents and young adults. Owing to the importance of vaccination before this elevated risk of exposure, the Centers for Disease Control and Prevention recommends HPV vaccination for girls aged 11-12 years with either the bivalent or quadrivalent vaccine. Recently, the quadrivalent vaccine, which also protects against genital warts and anal neoplasias and cancer, was approved for use in boys as well. Although the coverage rate has increased steadily in the 5 years since the vaccine's introduction, it remains below 50%. To overcome barriers to vaccination, including lack of awareness about adolescents' HPV risk and challenges associated with preventive care in this age group in general, healthcare providers must be able to educate parents/patients about HPV and the vaccine, as well as maximize opportunities to vaccinate adolescents at every office visit. PMID- 22525123 TI - Circumferential iris transillumination defects in exfoliation syndrome. AB - PURPOSE: We identified a pattern of concentric circular transillumination defects (TIDs) in a few patients with exfoliation syndrome (XFS) using an infrared detection system. This pattern of iris abnormality has also been observed in a mouse model of XFS. The objective of the current study is to determine whether concentric iris TIDs are specific to XFS and may have some diagnostic utility for identifying early cases of disease. MATERIALS AND METHODS: A total of 68 volunteers from the University of Iowa Glaucoma Clinic with normal eyes (n=21) or diagnoses of either XFS (n=12), pigment dispersion syndrome (PDS) (n=8), or primary open-angle glaucoma (POAG) (n=27) were enrolled in the study. The irides of these subjects were each examined by 4 ophthalmologists masked to their diagnosis, using infrared videography. The presence of concentric, circular TIDs on the videos was graded as none (grade 0), possible (grade 1), definite (grade 2), or prominent (grade 3) by 4 examiners. We searched for an association between the presence of concentric bands of transillumination and the diagnosis of XFS after removing the effect of different raters was evaluated using the Cochran Mentel-Haenszel test. We performed the same analysis for PDS and for POAG. RESULTS: The presence of any concentric, circular iris TIDs (grades 1 to 3) was detected in a mean of 38% normal subjects, 35% POAG patients, 53% PDS patients, and 77% of XFS patients. When the frequency of concentric, circular iris transillumination (grades 1 to 3 pooled) was compared between each of the patient groups and normal controls, a significant difference was detected between XFS patients and controls (P=0.000019). No significant difference was detected between POAG and controls (P=0.64) or between PDS and controls (P=0.20). Furthermore, prominent concentric, circular iris transillumination (grade 3) was only observed in XFS. CONCLUSIONS: Detection of concentric, circular iris TIDs with an infrared system is easy, inexpensive, rapid, and relatively specific in XFS. Future larger studies will be needed to confirm the findings of this small pilot study. Furthermore, this examination technique has the potential to help physicians to make earlier diagnoses of XFS and to better plan for future surgeries to minimize risk of complication. PMID- 22525125 TI - Familial juvenile normal-tension glaucoma with anterior segment dysgenesis: a clinical report of a new phenotype. AB - PURPOSE: To describe a new familial syndrome consisting of anterior segment dysgenesis, glaucomatous optic neuropathy, and intraocular pressure (IOP) in the normal range. DESIGN: Observational case series. METHODS: Subjects were available for examination from a 2-generation pedigree. Ophthalmic examination and photography, visual field examination, and optical coherence tomography of the peripapillary retinal nerve fiber layer were performed. In some subjects, medical work-up was performed. RESULTS: Eight affected subjects were identified. All had signs of Axenfeld-like anterior segment dysgenesis, ranging from a single fine iris process to diffuse broad iris synechiae extending to a prominent posterior embryotoxon. Four of the 8 subjects had glaucoma-appearing optic nerve heads with corresponding visual field defects; in a fifth subject, glaucoma was suspected on the basis of optic nerve appearance, but the visual field was full. IOP was consistently in the low-teens to mid-teens except in 1 eye in which it was 22 mm Hg, the highest recorded pressure in all examined subjects. CONCLUSIONS: A new phenotype is presented, characterized by IOP in the normal range, glaucomatous appearing optic nerve cupping, and anterior segment dysgenesis. The suggested mode of inheritance is autosomal dominant with marked intrafamilial variability. PMID- 22525124 TI - The impact of surgical intraocular pressure reduction on visual function using various criteria to define visual field progression. AB - PURPOSE: To examine the impact of surgical intraocular pressure (IOP) reduction on visual function using various methods to define visual field (VF) progression. METHODS: A retrospective chart review was conducted on consecutive glaucoma patients who underwent surgical IOP reduction between January 1, 2002 and December 31, 2007. All subjects had glaucomatous optic neuropathy, a minimum of 5 preoperative and 5 postoperative VFs, and were followed for a minimum of 2 years both before and after surgery. VF progression was determined using guided progression analysis, linear regression analysis of the visual field index, and individual sensitivity values using Progressor software. RESULTS: Seventeen eyes of 17 patients (mean age 77.9+/-9.9 y) were enrolled. Subjects were followed for a mean 5.8+/-2.4 years before surgery and 4.5+/-1.5 years after surgery. The mean postoperative IOP (11.3+/-4.2 mm Hg) and medications (1.3+/-1.3) were significantly (P<0.001 and P=0.01) reduced compared with before surgery (18.0+/ 3.9 mm Hg, 2.4+/-0.9, respectively). The number of eyes judged to have VF progression using any method during the postoperative period (3 of 17, 17.6%) was significantly (P=0.03) reduced compared with the preoperative period (9 of 17 eyes, 52.9%). Using visual field index criteria, 8 eyes were judged to have preoperative VF progression and 1 eye had persistent VF progression during the postoperative period. None of the eyes judged to have preoperative VF progression using Early Manifest Glaucoma Trial (n=4) and Progressor criteria (n=1) demonstrated persistent VF progression during the postoperative period. Among eyes with preoperative VF progression, the postoperative slope of mean deviation (-0.21+/-0.23 dB/y) was significantly (P=0.03) reduced compared with before surgery (-1.01+/-0.23 dB/y). CONCLUSIONS: Despite differences in the criteria used to define VF progression, glaucoma surgical IOP reduction significantly reduces the incidence and rate of VF progression. PMID- 22525126 TI - High-resolution live imaging of cell behavior in the developing neuroepithelium. AB - The embryonic spinal cord consists of cycling neural progenitor cells that give rise to a large percentage of the neuronal and glial cells of the central nervous system (CNS). Although much is known about the molecular mechanisms that pattern the spinal cord and elicit neuronal differentiation, we lack a deep understanding of these early events at the level of cell behavior. It is thus critical to study the behavior of neural progenitors in real time as they undergo neurogenesis. In the past, real-time imaging of early embryonic tissue has been limited by cell/tissue viability in culture as well as the phototoxic effects of fluorescent imaging. Here we present a novel assay for imaging such tissue for long periods of time, utilizing a novel ex vivo slice culture protocol and wide-field fluorescence microscopy (Fig. 1). This approach achieves long-term time-lapse monitoring of chick embryonic spinal cord progenitor cells with high spatial and temporal resolution. This assay may be modified to image a range of embryonic tissues. In addition to the observation of cellular and sub-cellular behaviors, the development of novel and highly sensitive reporters for gene activity (for example, Notch signaling) makes this assay a powerful tool with which to understand how signaling regulates cell behavior during embryonic development. PMID- 22525128 TI - High-speed retinal imaging with polarization-sensitive OCT at 1040 nm. AB - PURPOSE: To demonstrate the ability of a new high-speed polarization-sensitive optical coherence tomography (PS-OCT) system for retinal imaging at 1040 nm. METHODS: A new polarization-sensitive swept source OCT system in the 1 MUm wavelength range is used to image the retina of healthy volunteers. The instrument is operated at an A-scan rate of 100 kHz which is about three times faster than previously reported PS-OCT instruments in this wavelength region. The increased imaging speed can be used to record densely sampled volumes of the retina. Moreover, it enables averaging of several B-scans recorded at the same location to obtain high-definition B-scans without the use of an eye tracker. RESULTS: Polarization-sensitive images of healthy volunteers clearly show the retinal pigment epithelium as a depolarizing layer. In addition, the good tissue penetration of the system allows the visualization of the sclera, which is highly birefringent and therefore shows increased image contrast with PS-OCT. CONCLUSIONS: PS-OCT in the 1 MUm wavelength region shows similar polarization effects as in the 840 nm wavelength range. The high speed enables averaging of several B-scans to obtain high-definition polarization-sensitive images. The new system provides excellent penetration depth into the choroid and sclera. PMID- 22525129 TI - Infrared imaging of meibomian gland structure using a novel keratograph. AB - PURPOSE: To examine the ability of a novel non-contact device (Keratograph 4) to image the meibomian gland (MG) structures and their morphological changes in the upper and lower eyelids. METHODS: Thirty-seven participants (mean age 57.8 +/- 8.5 years; 3 males and 34 females) completed the Ocular Surface Disease Index questionnaire to assess dryness symptoms. Meibum secretion quality score, number of blocked gland orifices, and meibum expressibility scores were assessed. The lower lid (LL) and upper lid (UL) of all subjects were everted and images of the MGs were taken using the Keratograph 4 (OCULUS). A MG dropout score (MGDS) due to complete or partial gland loss of both lids was obtained using a subjective 4 grade scoring system, and digital analysis of the images using ImageJ was performed. Presence of tortuosity and visible acinar changes of the MGs were also noted. RESULTS: MGDS for both lids was significantly positively correlated with the Ocular Surface Disease Index score (r = 0.51; p < 0.05). The MGDS determined using the digital grading was also significantly positively correlated (UL: r = 0.68, p < 0.05; LL: r = 0.42, p < 0.05). The sum of the MGDS for both lids using the subjective grading scale was significantly different between the non-MGD and MGD group (1.3 +/- 1.0 vs. 3.1 +/- 1.1; p = 0.0004). MGDS assessment using the digital grading was significantly different between non-MGD (UL = 6%, LL = 8%) and MGD group (UL = 32%, LL = 42%; p = 0.001). Tortuous MG was observed only on the UL in 6% of the participants. Visible acinar changes were noted in 40% of the study participants. CONCLUSIONS: Infrared meibography is now possible in a clinical setting using commercially available devices, and meibography can help determine differences in MG structure in subjects symptomatic of dry eye. PMID- 22525127 TI - Factors associated with macular thickness in the COMET myopic cohort. AB - PURPOSE: To determine whether macular thickness is associated with ethnicity, gender, axial length (AL), and severity of myopia in a cohort of young adults from the Correction of Myopia Evaluation Trial (COMET). METHODS: Eleven years after their baseline visit, 387/469 (83%) subjects returned for their annual visit. In addition to the protocol-specific measures of spherical equivalent refractive error (SER) and AL, high-resolution macular imaging also was performed with optical coherence tomography (RTVue). From these scans, full-thickness values for the central (1 mm), parafoveal (1 to 3 mm), and perifoveal (3 to 5 mm) annular regions were calculated. Gender, ethnicity, AL, and SER were examined for associations with macular thickness using univariate and multivariable linear regression analyses. RESULTS: In the 377 subjects with usable data (mean age = 21.0 +/- 1.3 years), the mean SER +/- SD was -5.0 +/- 1.9 D and mean AL was 25.4 +/- 0.9 mm. Mean foveal thickness was 252.0 +/- 20.1 MUm in the center, 315.6 +/- 14.0 MUm in the parafovea, and 284.4 +/- 12.9 MUm in the perifovea. In the best fit multivariable model that adjusted for gender, ethnicity, and AL, females had significantly thinner maculas than males for all three regions (p < 0.0001), with the largest difference in the center (12.8 MUm, 95% confidence interval: 9.2 to 16.4). The effect of ethnicity was strongest in the central fovea, with African Americans, Asians, Hispanics, and mixed ethnic groups having thinner maculas than whites (all p values < 0.005). Increased AL was significantly associated with slightly thicker central foveas (p = 0.001) and thinner parafoveal (p = 0.02) and perifoveal (p < 0.0001) regions. CONCLUSIONS: In this ethnically diverse cohort of moderate and high myopes, females and African-Americans were found to have the thinnest central foveas. Whether such thinning in the macula as a young adult is a risk factor for future disease remains to be determined. PMID- 22525130 TI - A method of imaging lipids on silicone hydrogel contact lenses. AB - PURPOSE: To determine whether Nile Red and Oil Red O stains are able to detect tear film lipids deposited on silicone hydrogel contact lenses. METHODS: Eight unworn lotrafilcon A lenses were individually soaked in successively decreasing amounts of cholesterol oleate solution (5.6 to 0.00 mg/ml) for 1 day in triplicate for each staining procedure (etafilcon A lenses were also soaked as a control). The sets of lenses were then stained with Nile Red or Oil Red O. The lenses were then individually visualized with a Nikon Eclipse 80i florescent microscope at 100* magnification, and two representative photos were taken of each lens. Both staining procedures were repeated with human worn lotrafilcon A lenses. RESULTS: The Nile Red stain detected variable yet decreasing amounts of lipids when lenses were incubated in lipid concentrations >=0.09 mg/ml. Oil Red O detected decreasing amounts of lipids when lenses were soaked in lipid concentrations >=0.35 mg/ml. The Nile Red stain produced considerably more background staining than Oil Red O, and approximately half of the negative control lenses stained with Nile Red while there was minimal staining of lenses stained with Oil Red O. Etafilcon A lenses yielded decreasing amounts of lipid when soaked in successively lower concentrations of lipid when stained with Nile Red. Human-worn lotrafilcon A lenses yielded similar lipid characteristics when compared with in vitro lenses, with variable amounts of lipid detection when comparing individual subjects. CONCLUSIONS: Nile Red and Oil Red O are both able to detect lipids on soft lenses in both in vitro and ex vivo conditions. Oil Red O appears to be a better stain for silicone hydrogel lenses as it offers a higher signal to noise ratio. PMID- 22525131 TI - Subclinical capillary changes in non-proliferative diabetic retinopathy. AB - PURPOSE: To establish adaptive optics scanning laser ophthalmoscopy as a method to detect and characterize microscopic signs of diabetic retinopathy in capillaries and cone photoreceptors in the parafovea. METHODS: Recently, adaptive optics scanning laser ophthalmoscope (AOSLO) has enabled noninvasive assessment of photoreceptors, capillaries, and leukocytes in the retinas of live human subjects. Repeated application of AOSLO imaging along with comparison to fluorescein angiography was used to track individual capillaries near the foveal avascular zone (FAZ) from one eye affected with severe non-proliferative diabetic retinopathy. Fluorescein angiography was used to identify clinical signs of diabetic retinopathy, such as microaneurysms and intraretinal microvascular abnormalities, and corresponding regions were imaged and assessed using the AOSLO. In addition, the structural integrity of photoreceptors and the spatial distribution of leukocytes around the parafoveal capillary network were quantitatively assessed. RESULTS: Capillaries and cone photoreceptors were visualized using the AOSLO without the use of injected contrast agents. Although the majority of capillaries were stable over a period of 16 months, one capillary at the edge of the FAZ dropped out, leading to a small but significant increase in FAZ size. Longitudinal assessment of the capillaries also showed microaneurysm formation and disappearance as well as the formation of tiny capillary bends similar in appearance to intraretinal microvascular abnormalities. The leukocytes in the capillary network were found to preferentially travel through the same routes in all four visits, suggesting that these channels are robust against small changes to the surrounding capillaries. In this eye, cone photoreceptor spacing was increased in the fovea when compared with normal data but stable across all visits. CONCLUSIONS: AOSLO imaging can be used to longitudinally track capillaries, leukocytes, and photoreceptors in diabetic retinopathy. Capillary changes that can be detected include dropout of individual capillaries as well as formation and disappearance of microaneurysms. PMID- 22525132 TI - Substance P release in response to cardiac ischemia from rat thoracic spinal dorsal horn is mediated by TRPV1. AB - Spinal cord stimulation (SCS) inhibits substance P (SP) release and decreases the expression of the transient receptor potential vanilloid 1 (TRPV1) in the spinal cord at thoracic 4 (T4) during cardiac ischemia in rat models (Ding et al., 2007). We hypothesized that activation of TRPV1 in the T4 spinal cord segment by intermittent occlusion of the left anterior descending coronary artery (CoAO) mediates spinal cord SP release. Experiments were conducted in urethane anesthetized Sprague-Dawley male rats using SP antibody-coated microprobes to measure SP release at the central terminal endings of cardiac ischemic-sensitive afferent neurons (CISAN) in the spinal T4 dorsal horns. Vehicle, capsaicin (CAP; TRPV1 agonist) and capsazepine (CZP; TRPV1 antagonist) were injected into the left T4 prior to stimulation of CISAN by intermittent CoAO (with or without upper cervical SCS). CAP induced endogenous SP release from laminae I and II in the T4 spinal cord above baseline. Conversely, CZP injections significantly inhibited SP release from laminae I-VII in the T4 spinal cord segment below baseline. CZP also attenuated CoAO-induced SP release, while T4 injections of CZP with SCS completely restored SP release to basal levels during CoAO activation. CAP increased the number of c-Fos (a marker for CISAN activation) positive T4 dorsal horn neurons compared to sham-operated animals, while CZP (alone or during CoAO and SCS+CoAO) significantly reduced the number of c-Fos positive neurons. These results suggest that spinal release of the putative nociceptive transmitter SP occurs, at least in part, via a TRPV1 mechanism. PMID- 22525134 TI - Notch signaling pathway regulates proliferation and differentiation of immortalized Muller cells under hypoxic conditions in vitro. AB - Previous studies have indicated that Muller glia in chick and fish retinas can re enter the cell cycle, express progenitor genes, and regenerate neurons via the Notch signaling pathway in response to retinal damage or growth factors. Here, we investigated the role of Notch signaling and the effect of hypoxia, as a means to induce retinal damage, on the proliferation of an immortalized Muller cell line (rMC-1 cells). Our data showed that rMC-1 cells expressed Muller glia and neural and retinal progenitor markers but did not express neuronal or retinal markers. Hypoxia increased rMC-1 cell proliferation by activating the positive cell-cycle regulators, cyclins A and D1, as well as the neural and retinal progenitor markers, Notch1, Hes1, nestin, Sox2, Msi1, Pax6, and NeuroD1. However, hypoxia did not significantly influence the expression of Muller glial markers GS, CRALBP, and cyclin D3 or the death of the rMC-1 cells. The increase in cell proliferation induced by hypoxia was greatly attenuated by blocking Notch signaling with the inhibitor DAPT, resulting in the reduced expression of positive cell-cycle regulators (cyclins A and D1) and neural and retinal progenitor markers (Notch1, Hes1, Sox2, Pax6, and NeuroD1). Blockade of the Notch signaling pathway by DAPT after hypoxia promoted the differentiation of rMC-1 cells to neurons, as demonstrated by the induction of neural marker (Tuj1), retinal amacrine (Syntaxin1), and retinal ganglion cell (Brn3b) markers, although the expression of the latter marker was low. Taken together, our data indicate that Notch signaling is required for proliferation under hypoxic conditions either by activating the positive cell-cycle regulators or by skewing their de differentiation towards a neural progenitor lineage. These findings indicate that the Notch signaling pathway regulates hypoxia-induced proliferation and differentiation of Muller glia. PMID- 22525133 TI - Diverse populations of intrinsic cholinergic interneurons in the mouse olfactory bulb. AB - Cholinergic activities affect olfactory bulb (OB) information processing and associated learning and memory. However, the presence of intrinsic cholinergic interneurons in the OB remains controversial. As a result, morphological and functional properties of these cells are largely undetermined. We characterized cholinergic interneurons using transgenic mice that selectively mark choline acetyltransferase (ChAT)-expressing cells and immunolabeling. We found a significant number of intrinsic cholinergic interneurons in the OB. These interneurons reside primarily in the glomerular layer (GL) and external plexiform layer (EPL) and exhibit diverse distribution patterns of nerve processes, indicating functional heterogeneity. Further, we found these neurons express ChAT and vesicular acetylcholine transporter (VAChT), but do not immunoreact to glutamatergic, GABAergic or dopaminergic markers and are distinct from calretinin expressing interneurons. Interestingly, the cholinergic population partially overlaps with the calbindin D28K-expressing interneuron population, revealing the neurotransmitter identity of this sub-population. Additionally, we quantitatively determined the density of VAChT labeled cholinergic nerve fibers in various layers of the OB, as well as the intensity of VAChT immunoreactivity within the GL, suggesting primary sites of cholinergic actions. Taken together, our results provide clear evidence showing the presence of a significant number of cholinergic interneurons and that these morphologically and distributionally diverse interneurons make up complex local cholinergic networks in the OB. Thus, our results suggest that olfactory information processing is modulated by dual cholinergic systems of local interneuron networks and centrifugal projections. PMID- 22525135 TI - GABA(B) receptor-mediated selective peripheral analgesia by the non-proteinogenic amino acid, isovaline. AB - Peripherally restricted analgesics are desirable to avoid central nervous system (CNS) side effects of opioids. Nonsteroidal anti-inflammatory drugs produce peripheral analgesia but have significant toxicity. GABA(B) receptors represent peripheral targets for analgesia but selective GABA(B) agonists like baclofen cross the blood-brain barrier. Recently, we found that the CNS-impermeant amino acid, isovaline, produces analgesia without apparent CNS effects. On observing that isovaline has GABA(B) activity in brain slices, we examined the hypothesis that isovaline produces peripheral analgesia mediated by GABA(B) receptors. We compared the peripheral analgesic and CNS effect profiles of isovaline, baclofen, and GABA (a CNS-impermeant, unselective GABA(B) agonist). All three amino acids attenuated allodynia induced by prostaglandin E2 injection into the mouse hindpaw and tested with von Frey filaments. The antiallodynic actions of isovaline, baclofen, and GABA were blocked by the GABA(B) antagonist, CGP52432, and potentiated by the GABA(B) modulator, CGP7930. We measured Behavioural Hyperactivity Scores and temperature change as indicators of GABAergic action in the CNS. ED(95) doses of isovaline and GABA produced no CNS effects while baclofen produced substantial sedation and hypothermia. In a mouse model of osteoarthritis, isovaline restored performance during forced exercise to baseline values. Immunohistochemical staining of cutaneous layers of the analgesic test site demonstrated co-localization of GABA(B1) and GABA(B2) receptor subunits on fine nerve endings and keratinocytes. Isovaline represents a new class of peripherally restricted analgesics without CNS effects, mediated by cutaneous GABA(B) receptors. PMID- 22525136 TI - Lateral asymmetry of early seizure manifestations in experimental generalized epilepsy. AB - Reorganization of seizure networks during epileptogenesis involves cortico subcortical and interhemispheric interactions. In the audiogenic kindling (AK) model of generalized tonic-clonic seizures, upstream seizure propagation along ascending brainstem-to-forebrain pathways determines progressive intensification of repeated sound-induced convulsions. Full-blown audiogenic seizures are bilaterally symmetric and their repetition results in bisynchronous recruiting the cortex in secondary epileptogenesis. The present study describes lateral asymmetry of initial behavioral and EEG manifestations of audiogenic seizures and AK in Wistar and WAG/Rij rats with acoustic hypersensitivity. These rats exhibit consistent individual lateralization of running seizures (run directionality) induced by repeated binaural stimulation. Since this initial preconvulsive running reflects seizure onset in the auditory brainstem, the running asymmetry suggests non-symmetric early epileptic activation of brainstem substrates by sound in these rats. Repetition of the asymmetric brainstem seizures led to asynchronous recruiting the cortex into seizure network and lateralization of running seizures was predictive for asymmetry of early cortical seizure manifestations in Wistar and WAG/Rij rats. Both electrographic markers of AK, spreading depression (SD) and post-running afterdischarge, first appeared in the cortex ipsilateral to run direction, suggesting lateralized brainstem-to forebrain seizure generalization during AK. At the population level, no bias in lateralization of running and SD was found in Wistar and WAG/Rij rats but incidence of secondary cortical seizures varied, depending on strain and run laterality. Among Wistar rats, cortical seizures developed more rarely in right runners than in left-runners, suggesting enhanced resistance of the right hemisphere to epileptogenesis in rats of this strain. WAG/Rij rats with mixed (absence and audiogenic) epilepsy showed weak lateralization of early cortical seizures and no left-right difference in their incidence during AK. Present findings suggest (1) lateralized brainstem-to-forebrain seizure propagation and hemispheric difference in its facility in Wistar rats, (2) alterations of intra- and interhemispheric seizure propagation in WAG/Rij rats with genetic absence epilepsy. PMID- 22525137 TI - Prostate cancer: One step closer to personalized therapy with cell capturing. PMID- 22525139 TI - Prostate cancer: Does the distribution of proerectile nerves support the use of a high anterior incision? PMID- 22525138 TI - Bladder cancer: LASP-1-a promising urine marker for detection of bladder cancer. PMID- 22525140 TI - Sexual dysfunction: Psychological inputs to sexual dysfunction. PMID- 22525141 TI - Prostate cancer: Hypoxia predicts relapse and recurrence after radiotherapy. PMID- 22525142 TI - Prostate cancer: Bone Scan Index made easy, at last. PMID- 22525143 TI - Prostate cancer: New light shed on the anticancer effects of zoledronic acid. PMID- 22525144 TI - Prostatitis: Insights into chronic pelvic pain. PMID- 22525145 TI - Kidney cancer: radiofrequency ablation of small renal masses--more work required. PMID- 22525146 TI - Haemoglobin predicts length of hospital stay after hip fracture surgery in older patients. AB - OBJECTIVES: Treating anaemia in older patients who have undergone hip fracture surgery is to enhance functional recovery. The relationship between peri operative haemoglobin levels and outcome after hip fracture surgery are controversial. We assessed whether higher haemoglobin levels predict length of hospital stay after hip fracture surgery in elderly subjects. STUDY DESIGN: A follow-up study in a historical cohort was performed in 317 patients aged 65 years old undergoing hip fracture surgery over the period 2004-2006 at the Leiden University Medical Centre. MEAN OUTCOME MEASURES: Linear regression analysis was used to assess the association between pre- and post-operative haemoglobin level and length of hospital stay after controlling for age and sex. RESULTS: Anaemia after hip fracture surgery was present among 86% of the patients. Length of hospital stay after hip fracture surgery in elderly subjects with post-operative anaemia (10.7 days) was significantly longer than in elderly subjects without post-operative anaemia (7.5 days, p=0.007). Post-operative haemoglobin levels and length of hospital stay were inversely related (p=0.013). The length of hospital stay was not related with pre-operative haemoglobin level. CONCLUSION: Higher postoperative haemoglobin levels predict shorter length of hospital stay after hip fracture surgery in the elderly. A definitive randomized clinical trial has to demonstrate whether this association is causal. PMID- 22525148 TI - Clinical spectrum of primary cutaneous CD30-positive anaplastic large cell lymphoma: an analysis of the Mannheim Cutaneous Lymphoma Registry. AB - BACKGROUND: Primary cutaneous CD30(+) anaplastic large cell lymphomas (C-ALCL) have indolent clinical behavior with an estimated 5-year survival rate of 95%. The clinical features and disease courses of C-ALCL identified in the lymphoma registry of Mannheim University hospital are described in the following. PATIENTS AND METHODS: All C-ALCL patients identified in the database were analyzed in regard to clinical picture, histology, immunohistochemistry, molecular biology, staging, therapy, follow-up, and outcome. RESULTS: 14 C-ALCL patients were identified. The mean age was 69 years and 57% were men. Solitary skin lesions in one anatomical region were seen in 12 patients upon initial diagnosis. Two patients presented with multiple lesions at different anatomical sites. In 2 patients there was specific lymph node involvement. In one C-ALCL patient, follow up over 17 months revealed extracutaneous infiltration. Half of the patients relapsed and 36% had multiple episodes. The majority of our patients were treated with surgical excision followed by electron beam radiotherapy. The 5-year survival rate was 93% in C-ALCL. CONCLUSIONS: The clinical presentation of C-ALCL varies. Staging procedures and a close clinical pathological correlation at initial diagnosis are essential. Due to a high rate of relapses and the possibility of developing extranodal manifestations over the course of the disease, close follow-up is recommended. PMID- 22525151 TI - Multiple eruptive keratoacanthomas associated with myelodysplastic syndrome. PMID- 22525153 TI - Methotrexate therapy in dermatology. PMID- 22525155 TI - Competency assessment: it's time to expect more from our simulator. PMID- 22525156 TI - Colorectal cancer screening: why immunochemical faecal occult blood test performs as well with either one or two samples. AB - BACKGROUND: Immunochemical faecal occult blood tests perform as well with either one or two samples, and better than guaiac tests with 6 samples. AIMS: Clarifying relationship between tests' performance, bleeding pattern and observation level. METHODS: The data of 32,225 average-risk subjects who performed both Hemoccult II (guaiac) and Magstream (immunochemical) tests were re-analysed by varying the cutoff and number of samples of Magstream. RESULTS: The identical performances obtained using one or two samples of Magstream (lower cutoff for one sample) at the population level were explained by opposite patterns of bleeding according to the presence of advanced neoplasias. They translated into discrepancy at the individual level: for example a 60% increase in sensitivity and 20% in specificity observed with one (39ng Hb/ml cutoff) or two samples (63ng Hb/ml cutoff) Magstream compared with Hemoccult II meant that 28.5% of the subjects testing positive with one sample (18.0% in subjects with advanced neoplasias) would have been considered negative by using two samples of Magstream at a higher cutoff (and reciprocal). CONCLUSION: The identical performance of immunochemical tests using one or two samples (different cutoff), explained by opposite pattern of bleeding according to advanced neoplasias is true only at the population level, the appropriate level for mass screening. PMID- 22525157 TI - Morphological and functional reversal of phenotypes in a mouse model of Rett syndrome. AB - Rett syndrome is a neurological disorder caused by mutation of the X-linked MECP2 gene. Mice lacking functional Mecp2 display a spectrum of Rett syndrome-like signs, including disturbances in motor function and abnormal patterns of breathing, accompanied by structural defects in central motor areas and the brainstem. Although routinely classified as a neurodevelopmental disorder, many aspects of the mouse phenotype can be effectively reversed by activation of a quiescent Mecp2 gene in adults. This suggests that absence of Mecp2 during brain development does not irreversibly compromise brain function. It is conceivable, however, that deep-seated neurological defects persist in mice rescued by late activation of Mecp2. To test this possibility, we have quantitatively analysed structural and functional plasticity of the rescued adult male mouse brain. Activation of Mecp2 in ~70% of neurons reversed many morphological defects in the motor cortex, including neuronal size and dendritic complexity. Restoration of Mecp2 expression was also accompanied by a significant improvement in respiratory and sensory-motor functions, including breathing pattern, grip strength, balance beam and rotarod performance. Our findings sustain the view that MeCP2 does not play a pivotal role in brain development, but may instead be required to maintain full neurological function once development is complete. PMID- 22525158 TI - Quantitative classification of primary progressive aphasia at early and mild impairment stages. AB - The characteristics of early and mild disease in primary progressive aphasia are poorly understood. This report is based on 25 patients with aphasia quotients >85%, 13 of whom were within 2 years of symptom onset. Word-finding and spelling deficits were the most frequent initial signs. Diagnostic imaging was frequently negative and initial consultations seldom reached a correct diagnosis. Functionality was preserved, so that the patients fit current criteria for single domain mild cognitive impairment. One goal was to determine whether recently published classification guidelines could be implemented at these early and mild disease stages. The quantitative testing of the recommended core and ancillary criteria led to the classification of ~80% of the sample into agrammatic, logopenic and semantic variants. Biological validity of the resultant classification at these mild impairment stages was demonstrated by clinically concordant cortical atrophy patterns. A two-dimensional template based on orthogonal mapping of word comprehension and grammaticality provided comparable accuracy and led to a flexible road map that can guide the classification process quantitatively or qualitatively. Longitudinal evaluations of initially unclassifiable patients showed that the semantic variant can be preceded by a prodromal stage of focal left anterior temporal atrophy during which prominent anomia exists without word comprehension or object recognition impairments. Patterns of quantitative tests justified the distinction of grammar from speech abnormalities and the desirability of using the 'agrammatic' designation exclusively for loss of grammaticality, regardless of fluency or speech status. Two patients with simultaneous impairments of grammatical sentence production and word comprehension displayed focal atrophy of the inferior frontal gyrus and the anterior temporal lobe. These patients represent a fourth variant of 'mixed' primary progressive aphasia. Quantitative criteria were least effective in the distinction of the agrammatic from the logopenic variant and left considerable latitude to clinical judgement. The widely followed recommendation to wait for 2 years of relatively isolated and progressive language impairment before making a definitive diagnosis of primary progressive aphasia has promoted diagnostic specificity, but has also diverted attention away from early and mild disease. This study shows that this recommendation is unnecessarily restrictive and that quantitative guidelines can be implemented for the valid root diagnosis and subtyping of mildly impaired patients within 2 years of symptom onset. An emphasis on early diagnosis will promote a better characterization of the disease stages where therapeutic interventions are the most likely to succeed. PMID- 22525160 TI - Electron crystallography--the waking beauty of structural biology. AB - Since its debut in the mid 1970s, electron crystallography has been a valuable alternative in the structure determination of biological macromolecules. Its reliance on single-layered or double-layered two-dimensionally ordered arrays and the ability to obtain structural information from small and disordered crystals make this approach particularly useful for the study of membrane proteins in a lipid bilayer environment. Despite its unique advantages, technological hurdles have kept electron crystallography from reaching its full potential. Addressing the issues, recent initiatives developed high-throughput pipelines for crystallization and screening. Adding progress in automating data collection, image analysis and phase extension methods, electron crystallography is poised to raise its profile and may lead the way in exploring the structural biology of macromolecular complexes. PMID- 22525159 TI - Effective connectivity of AKT1-mediated dopaminergic working memory networks and pharmacogenetics of anti-dopaminergic treatment. AB - Working memory is a limited capacity system that integrates and manipulates information across brief periods of time, engaging a network of prefrontal, parietal and subcortical brain regions. Genetic control of these heritable brain processes have been suggested by functional genetic variations influencing dopamine signalling, which affect prefrontal activity during complex working memory tasks. However, less is known about genetic control over component working memory cortical-subcortical networks in humans, and the pharmacogenetic implications of dopamine-related genes on cognition in patients receiving anti dopaminergic drugs. Here, we examined predictions from basic models of dopaminergic signalling in cortical and cortical-subcortical circuitries implicated in dissociable working memory maintenance and manipulation processes. We also examined pharmacogenetic effects on cognition in the context of anti dopaminergic drug therapy. Using dynamic causal models of functional magnetic resonance imaging in normal subjects (n = 46), we identified differentiated effects of functional polymorphisms in COMT, DRD2 and AKT1 genes on prefrontal parietal and prefrontal-striatal circuits engaged during maintenance and manipulation, respectively. Cortical synaptic dopamine monitored by the COMT Val158Met polymorphism influenced prefrontal control of both parietal processing in working memory maintenance and striatal processing in working memory manipulation. DRD2 and AKT1 polymorphisms implicated in DRD2 signalling influenced only the prefrontal-striatal network associated with manipulation. In the context of anti-psychotic drugs, the DRD2 and AKT1 polymorphisms altered dose response effects of anti-psychotic drugs on cognition in schizophrenia (n = 111). Thus, we suggest that genetic modulation of DRD2-AKT1-related prefrontal subcortical circuits could at least in part influence cognitive dysfunction in psychosis and its treatment. PMID- 22525161 TI - Sensorimotor incongruence exacerbates symptoms in patients with chronic whiplash associated disorders: an experimental study. AB - OBJECTIVES: Incongruence between sensory feedback and motor output may serve as an ongoing source of nociception inside the CNS, and hence may contribute to the development of chronic whiplash associated disorder (WAD). It has been demonstrated that sensorimotor incongruence exacerbates symptoms and provokes additional sensations in patients with chronic pain. This study aimed to evaluate whether a visually mediated incongruence between motor output and sensory input aggravates symptoms and triggers additional sensations in patients with chronic WAD. METHODS: Thirty-five patients with chronic WAD and 31 healthy controls were subjected to a coordination test. They performed congruent and incongruent arm movements while viewing a whiteboard or mirror. RESULTS: All patients with chronic WAD (n = 35) reported sensory changes such as increased pain, tightness, loss of control, dizziness or feelings of peculiarity at some stage of the test protocol. No significant differences in frequency and intensity of sensory changes were found between the various test stages (P > 0.05). In the healthy control group, 18 (58%) subjects reported sensory changes at some stage of the test protocol, with the highest number during the incongruent mirror stage (n = 17), corresponding to the highest level of sensorimotor incongruence. The pattern of reported sensory changes during the congruent and incongruent stages was significantly different between both groups (P < 0.05). CONCLUSION: This study demonstrates an exacerbation of symptoms and/or additional sensory changes due to reducing or disturbing the visual input during action, indicating altered sensorimotor central nervous processing and altered perception of distorted visual feedback in chronic WAD. PMID- 22525162 TI - Which hyperopic patients are destined for trouble? PMID- 22525163 TI - Arguing with success: pulley surgery versus conventional surgery for convergence excess esotropia. PMID- 22525164 TI - Incidence of strabismus and amblyopia in preverbal children previously diagnosed with pseudoesotropia. AB - PURPOSE: To determine how frequently children diagnosed with pseudoesotropia before 3 years of age are later found to have true strabismus or amblyopia. METHODS: Records of all patients presenting to one pediatric ophthalmologist between January 1, 2001, and February 26, 2010, were reviewed retrospectively. Patients diagnosed with pseudoesotropia who had an otherwise normal examination were included. RESULTS: A total of 306 patients were diagnosed with pseudoesotropia with no significant refractive error on initial examination. Of these, 201 had the follow-up examination recommended for all 306 patients. The average age at the time of the initial examination was 13 months (range, 2-33). The average age at follow-up was 33 months (range, 4-120). Of the 201 patients, 20 were later found to have strabismus (10%) and 5 were later found to have significant refractive error and mild refractive amblyopia (2%). Of the 20 children found to have strabismus, 15 had esodeviation, 3 had exodeviation, 1 had Duane syndrome, and 1 had Prader-Willi syndrome with esotropia. CONCLUSIONS: Of children initially diagnosed with pseudoesotropia under age 3 who returned for follow-up, 12% were later found to have strabismus or mild refractive amblyopia. The ultimate prevalence of strabismus or amblyopia was higher in children diagnosed with pseudoesotropia than would be expected in the general population. PMID- 22525165 TI - Variability of angle of deviation measurements in children with intermittent exotropia. AB - BACKGROUND: A change in the angle of deviation is often used to monitor the change in severity of intermittent exotropia over time; nevertheless, thresholds for a clinically significant change in angle have not been determined. We analyzed variability associated with test-retest differences and short-term variability in the condition, to provide thresholds for assessing clinically significant, long-term change in angle of intermittent exotropia. METHODS: Twenty six children with intermittent exotropia (median age, 7; range, 1-13 years) underwent repeat prism and alternate cover test measures during 3 or 4 examinations (2 hours apart) over the course of a day; 95% repeatability coefficients were derived to determine test-retest differences at distance and near fixation. RESULTS: Derived 95% repeatability coefficients at distance were 3.4(Delta) (95% CI, 0.7(Delta)-6.2(Delta)) for angles <=20(Delta) and 7.2(Delta) (95% CI, 4.4(Delta)-9.9(Delta)) for angles >20(Delta); at near, 6.6(Delta) (95% CI, 3.7(Delta)-9.6(Delta)) for angles <=20(Delta) and 12.8(Delta) (95% CI, 5.3(Delta)-20.3(Delta)) for angles >20(Delta). CONCLUSIONS: Test-retest reliability data in this study provide thresholds to help determine clinically significant change in angle of strabismus in children with intermittent exotropia. These data should facilitate evidence-based assessment of long-term change in intermittent exotropia over time. PMID- 22525166 TI - Medial rectus muscle pulley posterior fixation sutures in accommodative and partially accommodative esotropia with convergence excess. AB - BACKGROUND: The use of medial rectus pulley posterior fixation sutures to treat esotropia with convergence excess has limited support in the literature. We describe our results using this technique to treat patients with large near distance disparities. METHODS: We retrospectively analyzed records of patients with accommodative or partially accommodative esotropia and convergence excess 13(Delta) or greater treated with bilateral medial rectus muscle recessions augmented by pulley posterior fixation. Surgical doses of recessions were calculated for the mean of distance and near deviations. Primary outcome measures were ocular alignment at distance and near and near-distance disparity. RESULTS: A total of 26 patients were identified by the record review. Mean age at surgery was 5.4 years (range, 1.8-11.0 years) and mean follow-up time 12.7 months (range, 1.0-37.6 months). Mean preoperative distance esotropia was 22.9(Delta) (range, 0(Delta)-53(Delta)), with a mean near-distance disparity of 26.4(Delta) (range, 13(Delta)-53(Delta)). At 1 to 3 months postoperatively, mean distance deviation was 0.5(Delta) exotropia (range, 18(Delta) exotropia to 12(Delta) esotropia), with a statistically significant decrease in mean near-distance disparity to 4.5(Delta) (range, 0(Delta)-26(Delta); P < 0.001). Three-quarters of patients (77%) achieved 0(Delta) to 9(Delta) esotropia at 1 to 3 months, with 4 overcorrections for distance and 2 undercorrections for distance and near. At final follow-up 2 patients had persistent exotropia less than 10(Delta). CONCLUSIONS: Augmentation of bilateral medial rectus recessions with pulley posterior fixation resulted in a significant decrease in near-distance disparity in this group of patients with accommodative and partially accommodative esotropia and convergence excess, with a low rate of persistent overcorrection for distance. PMID- 22525167 TI - Comparison of superior oblique suture spacers and superior oblique silicone band expanders. AB - PURPOSE: To compare suture spacers with silicone band expanders in superior oblique-weakening surgery. METHODS: We retrospectively reviewed the charts of consecutive patients who had superior oblique weakening with either suture spacers or silicone expanders and had been followed for a minimum follow-up of 6 months. The ductions, versions, and the degree of fundus torsion were analyzed in all patients before and after surgery. In addition, surgery time and postoperative complications were analyzed. RESULTS: The record review identified 25 patients, of whom 13 had been treated with superior oblique muscle suture spacers and 12 with superior oblique muscle silicone expanders. Both groups showed improved ductions and versions. In patients with Brown syndrome, complete normalization of superior oblique muscle overaction occurred in 67% of patients who had suture spacers and 67% of patients who had silicone expanders. In patients with A-pattern strabismus, normal function of the superior oblique muscle occurred in 75% of patients with suture spacers and 67% of patients with silicone expanders. Surgery time was significantly less in patients who had suture spacers. Severe orbital inflammation occurred in 1 patient around the silicone band and was managed by removal of the implant. CONCLUSIONS: Both suture spacers and silicone expanders improved the comitance of versions and normalized superior oblique muscle function. Longer surgery time and more severe inflammatory reaction are possible drawbacks of silicone expanders. PMID- 22525168 TI - Intraoperative monitoring of torsion to prevent vertical deviations during augmented vertical rectus transposition surgery. AB - BACKGROUND: Total transposition of the superior and inferior rectus muscle laterally, with augmentation sutures, may be complicated by induction of an undesirable vertical deviation. Induced vertical misalignment may be associated with changes in torsion. We have developed a simple method to monitor intraoperative torsion that may reduce the incidence of vertical deviations. METHODS: We reviewed consecutive cases of total abducens palsy or esotropic Duane syndrome treated with augmented lateral transposition of the superior and inferior rectus muscles, where the 12 o'clock and 6 o'clock intraoperative positions were initially marked with a dot at the limbus using a surgical pen. The location of the marks was monitored during tying of the augmentation sutures; changes in torsion were monitored intraoperatively. RESULTS: Records of 9 cases of augmented vertical rectus transposition were reviewed. On the basis of intraoperative assessment of torsion, by observing the position of preplaced limbal dots, the inferior rectus augmentation suture was tied less tightly than the superior rectus suture, leaving a gap of 1 to 3 mm between the inferior and lateral rectus muscles in 8 of 9 cases. The augmentation suture was totally removed in 1 case. After these intraoperative adjustments, there was no induced intraoperative torsion, whereas further tightening of the inferior suture induced extorsion. Six weeks postoperatively, 8 of 9 patients did not experience a symptomatic vertical deviation. CONCLUSIONS: When performing augmented transposition procedures, intraoperative monitoring of torsion may reduce the incidence of inadvertent vertical deviations and torsion. This technique may also be useful in other cases where correction or avoidance of torsion is needed. PMID- 22525170 TI - Unilateral rectus muscle recession in the treatment of Duane syndrome. AB - PURPOSE: To determine the outcome of unilateral single horizontal rectus recession surgery in patients with Duane retraction syndrome. METHODS: A retrospective review was conducted of 27 medical records of patients with Duane syndrome who underwent unilateral medial rectus recession for esodeviations and lateral rectus recession for exodeviations. The criteria for evaluating surgical success included improvement of abnormal head position, reduction of strabismus deviation, and preservation or improvement of stereoacuity. RESULTS: Patients had an average recession of 6.3 mm and were followed for an average of 4 years. Of the 27 patients treated with unilateral horizontal rectus muscle recession, 93% had a postoperative head turn of <10 degrees in primary position and 85% an ocular deviation of <10(Delta). An excellent outcome, defined as a combination of stereoacuity of <100 arcsec, head turn <10 degrees , and strabismus of <10(Delta), was achieved by 63% of patients. CONCLUSIONS: Unilateral single horizontal rectus muscle recession improves or eliminates head turn, corrects strabismus in primary position of gaze, and maintains good stereoacuity in a majority of patients with Duane syndrome. PMID- 22525169 TI - Torsional augmentation for the treatment of lateropulsion and torticollis in partial ocular tilt reaction. AB - PURPOSE: We describe a new surgical treatment for lateropulsion and torticollis arising from an ocular tilt reaction. METHODS: Visual sensory parameters and postural abnormalities were retrospectively reviewed in a patient with a partial ocular tilt reaction who was treated with horizontal transposition of the vertical rectus muscles to surgically augment preexisting binocular torsion. RESULTS: Torsional augmentation eliminated the sensation of lateropulsion and produced almost complete resolution of her torticollis and associated body tilt. CONCLUSIONS: Binocular torsional augmentation can be used to reduce both lateropulsion and torticollis in the setting of an ocular tilt reaction. PMID- 22525172 TI - Fixation control and eye alignment in children treated for dense congenital or developmental cataracts. AB - BACKGROUND: Many children treated for cataracts develop strabismus and nystagmus; however, little is known about the critical period for adverse ocular motor outcomes with respect to age of onset and duration. METHODS: Children who had undergone extraction of dense cataracts by the age of 5 years were enrolled postoperatively. Ocular alignment was assessed regularly throughout follow-up. Fixation stability and associated ocular oscillations were determined from eye movement recordings at >=5 years old. Multivariate logistic regression was used to evaluate whether laterality (unilateral vs bilateral), age at onset, and/or duration of visual deprivation were associated with adverse ocular motor outcomes and to determine multivariate odds ratios (ORs). RESULTS: A total of 41 children were included. Of these, 27 (66%) developed strabismus; 29 (71%) developed nystagmus. Congenital onset was associated with significant risk for strabismus (OR, 5.3; 95% CI, 1.1-34.1); infantile onset was associated with significant risk for nystagmus (OR, 13.6; 95% CI, 1.6-302). Duration >6 weeks was associated with significant risk for both strabismus (OR, 9.1; 95% CI, 1.9-54.2) and nystagmus (OR, 46.2; 95% CI, 6.0-1005). Congenital onset was associated with significant risk for interocular asymmetry in severity of nystagmus (OR, 25.0; 95% CI, 2.6 649), as was unilateral cataract (OR, 58.9; 95% CI, 5.1-2318). CONCLUSIONS: Laterality (unilateral vs bilateral) and age at onset were significant nonmodifiable risk factors for adverse ocular motor outcomes. Duration of deprivation was a significant modifiable risk factor for adverse ocular motor outcomes. The current study demonstrated that reduced risk for nystagmus and strabismus was associated with deprivation <=6 weeks. PMID- 22525171 TI - Predictors of adherence to occlusion therapy 3 months after cataract extraction in the Infant Aphakia Treatment Study. AB - BACKGROUND: Little information is available on factors that predict adherence to patching in infants. We evaluated data from the Infant Aphakia Treatment Study, a randomized clinical trial of treatment for infants with unilateral congenital cataracts, to investigate factors associated with successful adherence to patching protocols. METHODS: In the Infant Aphakia Treatment Study, patching was prescribed 1 hour daily per month of age until 8 months of age and 50% of waking hours thereafter. A centrally located staff member inquired about the patient's adherence to patching in a phone interview with the primary caregiver. Analyses used chi(2) tests of independence and logistic regression to identify predictors of reported adherence and of achieving adherence rates of at least 75% ("good") and 90% ("excellent"). RESULTS: A total of 104 caregivers provided data on patching 3 months after surgery, at which time 60% reported patching at least 75% of the prescribed time. Reported adherence was not associated with the type of treatment (P = 0.73) but was better in children with private insurance (P = 0.01) and for children with mothers reporting lower levels of parenting stress (P = 0.03). CONCLUSIONS: Most caregivers reported being able to adhere to prescribed patching shortly after extraction of a unilateral congenital cataract. The type of correction (intraocular lens vs contact lens) was not associated with the amount of patching achieved, whereas family socioeconomic status and maternal stress appeared to play a role. PMID- 22525173 TI - Clinical characteristics, course, and visual prognosis of partial cataracts that seem to be visually insignificant in children. AB - PURPOSE: To report the clinical characteristics and visual prognosis of pediatric partial cataracts that seem to be visually insignificant. METHODS: In this retrospective case series, the morphologic type and etiology, laterality, best corrected visual acuity (BCVA), progression, and visual prognosis of partial cataracts in children with more than 1 year of follow-up were evaluated. RESULTS: Of 110 children (184 eyes), 74 (67%) had bilateral and 36 (33%) had unilateral cataracts. The most common type of cataract was posterior subcapsular (36%), followed by nuclear (18%) cataracts. The most common etiology was idiopathic (51%), followed by steroid-induced (28%). Cataracts progressed to surgery in 21 eyes (11%). Among these patients, BCVA was 20/38 at final examination (average follow-up 5.1 years). Among those in whom cataracts did not progress, BCVA was 20/28 at final examination (average follow-up 6.1 years). Initial BCVA was better in the nonprogression group than in the progression group (P = 0.04), but final BCVA did not differ between the groups (P = 0.96). CONCLUSIONS: Most patients with partial cataracts that seemed to be visually insignificant and were treated without surgery did not progress and showed favorable visual outcomes. In children who had progressive vision loss, surgery was necessary: these patients also had favorable visual outcomes. PMID- 22525174 TI - Periorbital infections after Dermabond closure of traumatic lacerations in three children. AB - PURPOSE: To report the occurrence of periorbital infections in 3 children treated with the tissue adhesive 2-octyl cyanoacrylate (Dermabond) after traumatic periorbital laceration. METHODS: We retrospectively reviewed the records of consecutive patients referred to Vanderbilt Children's Hospital for the treatment of periorbital infections to identify cases associated with the use of Dermabond. The clinical features and outcomes of each case were reviewed. We performed a meta-analysis of published cases to identify any association of tissue adhesive with wound infection rate. RESULTS: The review identified 3 patients, all of whom were younger than 3 years of age and developed cellulitis within 24 hours of wound closure. Broad-spectrum intravenous antibiotic therapy was started in less than 3 hours in all cases. Cultures were obtained in 2 of the 3 cases; both grew Streptococcus pyogenes. Two cases required surgical intervention, including one with necrotizing fasciitis. In the meta-analysis, the wound infection rate was 1.8% in tissue adhesive closure and 0.3% in standard wound closure (odds ratio 6.0; 95% confidence interval 0.7-50.3, P = 0.06). CONCLUSIONS: The development of periorbital cellulitis after the closure of periorbital lacerations with Dermabond should alert the physician to the possibility of periorbital infection, including necrotizing fasciitis. The literature review suggests a trend toward an increased infection rate with tissue adhesive closure. We propose that ineffective wound sterilization before tissue adhesive wound closure may be a contributing factor. PMID- 22525175 TI - Success rates of primary probing for congenital nasolacrimal obstruction in children. AB - PURPOSE: To determine the success rate of nasolacrimal duct probing for the treatment of congenital nasolacrimal duct obstruction and to identify the age at which the success rate decreases. METHODS: Records for probing procedures from 2005 to 2010, over a 56-month period, were reviewed. Successful probing was defined as complete resolution of epiphora 3 months after treatment. Success rates were compared between children <3 years of age and children >=3 years of age at the time of the procedure. RESULTS: A total of 168 eyes (128 children, mean age 32.2 +/- 23.8 months) had undergone a probing procedure, and the overall success rate was 72%. Children aged <36 months had a success rate of 78%; children aged >=36 months had a success rate of 50%. Multivariate analysis demonstrated that age at the time of procedure was a significant risk factor for failed probing (P = 0.035; OR, 1.67; 95% CI, 1.04-2.69), whereas sex and bilateral surgery were not. CONCLUSIONS: The success rate of primary probing for congenital nasolacrimal duct obstruction was significantly reduced when performed on children >=3 years of age. PMID- 22525176 TI - Training fellows for retinopathy of prematurity care: a Web-based survey. AB - PURPOSE: To characterize the training received by pediatric ophthalmology and retina fellows in retinopathy of prematurity (ROP) management. METHODS: Pediatric ophthalmology and retina fellowship programs were emailed a Web-based survey to assess fellowship training in ROP management. RESULTS: Of 140 programs contacted, 42 (30%) participated, resulting in 87 surveys for analysis. Of the 87 respondents, 25 (29%) reported that two-thirds or less of ROP examinations performed by fellows were also seen by an attending. When stratified by specialty, this trend was statistically different between pediatric ophthalmology and retina fellows (P = 0.03). Additionally, pediatric ophthalmology fellows performed fewer laser photocoagulation procedures than retina fellows (P < 0.001). Regarding fellows' perceived competency in ROP management, 3 of 51 (6%) felt competent at the start of their fellowship and 43 of 51 (84%) felt competent at the time of the survey. Only 7% of respondents reported the use of formal evaluations at their programs to assess fellow competence in ROP examination. CONCLUSIONS: Training programs for fellows in pediatric ophthalmology and retina vary greatly with respect to ROP training and the quality of clinical care. Many clinical ROP examinations are being performed by pediatric ophthalmology and retina fellows without involvement and/or direct supervision by attending ophthalmologists. Our findings have important implications for the development of a future workforce for ROP management. PMID- 22525177 TI - The prevalence of ocular structural disorders and nystagmus among preschool-aged children. AB - PURPOSE: To describe the prevalence of structural disorders of the eye and nystagmus in preschool-aged children. METHODS: Population-based evaluation of children 6 months through 71 months of age in Baltimore, Maryland, United States. RESULTS: Among 4,132 children identified from 54 census tracts, 3,990 eligible children (97%) were enrolled and 2,546 children (62%) were examined. Structural disorders were found in 41 children and nystagmus in 9 children for an overall prevalence of 1.96% (95% CI, 1.46%-2.59%). Only 11 (0.43%; 95% CI, 0.22%-0.77%) had vision loss in at least one eye, most often due to posterior segment disease. CONCLUSIONS: Structural ocular abnormalities and nystagmus combined are present in nearly 2% of preschool-aged children in this population-based study. Vision loss due to these abnormalities is uncommon. PMID- 22525178 TI - Testability of refraction, stereopsis, and other ocular measures in preschool children: the Sydney Paediatric Eye Disease Study. AB - PURPOSE: To determine the testability and lower age limits for applying common eye tests to preschool children. METHODS: Investigators from the Sydney Paediatric Eye Disease Study examined 2,461 children aged 6 to 72 months between 2007 and 2009. Cycloplegic autorefraction was measured with Retinomax and Canon autorefractors. Ocular biometry was measured by the use of IOLMaster in children aged >30 months. The Randot Preschool Stereoacuity test, Lang-Stereotest II, and the Stereo Smile II test were administered to assess stereoacuity. Fundus photography was performed with the subjects' pupils dilated. Testability was defined as the ability to successfully complete tests in both eyes. RESULTS: There were 2,189 children with complete data. Most were testable with the Retinomax (71.8%) and Canon (66.0%) autorefractors. Testability improved with age (P for trend <0.0001) for both, and Retinomax achieved >70% testability when a subject was 24 months of age, half the age limit (48 months) found for Canon. IOLMaster was mostly testable in children aged 48+ months. Lang-Stereotest II could be used in children aged 6 months and achieved the greatest testability (94.4%) of all stereotests. White children performed better than children of some other ethnicities on Randot (P = 0.007), with girls performing better than boys (P = 0.01). Bilateral photography was achieved in >70% of preschool children 48 months of age. CONCLUSIONS: The testability of all measures was strongly age related, with mostly no sex or ethnicity effects found. The handheld Retinomax could be tested in >70% of children aged 24 months, younger than that found for the stationary Canon autorefractor (48 months). Testability measures for most eye tests in this preschool sample are comparable to other preschool studies. PMID- 22525180 TI - Developmental conjunctival cyst of the eyelid in a child. AB - Conjunctival cysts unrelated to surgery or trauma are uncommon adnexal lesions in children and may be difficult to recognize. We report the clinical and pathological findings of an apparently spontaneous conjunctival cyst in the upper eyelid of a child whose first ophthalmological examination was at 7 months of age. The cyst was surgically excised at 5 years of age. PMID- 22525181 TI - Iris cyst after iris-sutured intraocular lens implantation in a child. AB - Iris cysts are uncommon in childhood and can present diagnostic and therapeutic challenges. We present the case of a 5-year-old boy with Marfan syndrome who, 9 months after an uncomplicated lensectomy with iris-sutured intraocular lens (IOL), developed a translucent epithelial inclusion cyst. The cyst was observed without treatment and no complications developed. To our knowledge, this is the first case of an iris cyst in a child after implantation of an iris-sutured IOL. This potential complication should be considered when implanting IOLs in children. PMID- 22525179 TI - Chronic keratoconjunctivitis with dermatitis as a presenting sign of child abuse. AB - A 13-month-old girl presented with chronic keratoconjunctivitis with dermatitis. She was initially diagnosed with corneal abrasion and mild preseptal cellulitis and was treated with topical and oral antibiotics. After failing to respond to standard therapy, she was eventually identified as a victim of abuse. We discuss key findings that could have provoked earlier recognition. PMID- 22525182 TI - Lens-preserving excision of congenital hyperplastic pupillary membranes with clinicopathological correlation. AB - Persistent pupillary membrane is a congenital, incomplete involution of the tunica vasculosa lentis. These membranes are usually tenacious, with fine fibrils attached to the iris collarette on one side, with the other end either free floating or attached to the lens or iris focally on the opposite side. This condition is thought to represent ectopic iris tissue on the lens with abnormal iris stroma caused by aberrant involutional changes in the primitive embryological vascular system of anterior segment. Dense and thick membranes, particularly within the pupil, may result in deprivation amblyopia. We report clinical and histopathological findings in a case of a 12-year-old boy with bilateral extensive hyperplastic persistent pupillary membrane that was surgically removed without injury to the crystalline lens. PMID- 22525183 TI - Coats-like retinopathy in an infant with preclinical facioscapulohumeral dystrophy. AB - Facioscapulohumeral dystrophy (FSHD) is an autosomal-dominant disorder characterized by weakness of the face, upper arm, shoulder, and lower limb musculature, with an onset between the first and third decades. Coats disease is a congenital disorder of retinal vascular development characterized by unilateral peripheral retinal telangiectasia and progressive subretinal and intraretinal exudation. This condition has a predilection for children and is usually isolated. Retinal vascular changes similar to those seen in Coats disease have been demonstrated by fluorescein angiography in 40% to 75% of patients with FSHD. Most patients have asymptomatic retinal telangiectasia found at ocular screening in adulthood after diagnosis of FSHD. We report a 7-month-old infant with bilateral Coats-like retinopathy in which the eye disease was discovered before findings of FSHD were clinically evident. To our knowledge, this patient represents the youngest reported case of preclinical FSHD with ocular disease. PMID- 22525184 TI - Nonarteritic anterior ischemic optic neuropathy in a child with optic disk drusen. AB - Optic disk drusen are calcific deposits that form in the optic nerve head secondary to abnormalities in axonal metabolism and degeneration. The clinical course is variable, ranging from stable vision to acute or progressive visual loss. We evaluated a healthy 12-year-old boy with a history of asymptomatic bilateral disk drusen who presented with acute painless unilateral visual loss after hiking to an altitude of 11,000 feet. Findings were consistent with nonarteritic anterior ischemic optic neuropathy. PMID- 22525185 TI - Sequential presentation of bilateral Brown syndrome. AB - Brown syndrome, characterized by a limitation of elevation in adduction and positive forced duction testing, is usually unilateral but occurs bilaterally in 10% of all cases. It may present as a congenital condition in one eye and develop in the other eye with no apparent cause. We present a case of bilateral Brown syndrome in which the right eye became involved within 1 year of surgery on the left eye for congenital Brown syndrome. PMID- 22525188 TI - Primary superior oblique muscle-levator muscle synkinesis. PMID- 22525190 TI - Globe perforation during strabismus surgery in an animal model. PMID- 22525194 TI - An in silico chimeric multi subunit vaccine targeting virulence factors of enterotoxigenic Escherichia coli (ETEC) with its bacterial inbuilt adjuvant. AB - Enteric infections resulting in diarrheal diseases remain as major global health problems. Among bacteria, enterotoxigenic Escherichia coli (ETEC) causes the largest number of diarrheal cases. There is a great interest in developing an effective ETEC vaccine. An ETEC vaccine could focus on virulence factors present in ETEC pathogens and nontoxic Heat-labile B subunit (LTB). Chimeric proteins carrying epitopes, or adjuvant sequences increase the possibility of eliciting a broad cellular or humoral immune response. In-silico tools are highly suited to study, design and evaluate vaccine strategies. Colonization factors are among the virulence factor studied in the present work employing bioinformatic tools. A synthetic chimeric gene, encoding CfaB, CstH, CotA, and LTB was designed. Modeling was done to predict the 3D structure of protein. This model was validated using Ramachandran plot statistics. The predicted B-cell epitopes were mapped on the surface of the model. Validation result showed that 97.2% residues lie in favored or additional allowed region of Ramachandran plot. VaxiJen analysis of the protein showed high antigenicity. Linear and conformational B cell epitopes were identified. The identified T-cell epitopes are apt to bind MHC molecules. The epitopes in the chimeric protein are likely to induce both the B cell and T-cell mediated immune responses. PMID- 22525195 TI - Ciclosporin modulates the responses of canine progenitor epidermal keratinocytes (CPEK) to toll-like receptor agonists. AB - Toll-like receptor (TLR) 2 dependent pathways have an important role in the antimicrobial defense of human keratinocytes, and various factors and compounds have been shown to affect those pathways. Investigating Toll-like receptor function in canine keratinocytes and the potential for their modulation is of similar relevance in dogs due to the frequency of staphylococcal skin infections in this species, particularly in the context of canine atopic dermatitis. This pilot study hypothesized that ciclosporin would have a modulatory effect on the cytokine and TLR mRNA expression of canine progenitor epidermal keratinocytes in response to TLR2 agonists. No detectable up-regulation of TLR2, TLR4, IL-8 and TNF-alpha mRNA was detected following exposure to FSL-1, Pam3CSK4 and staphylococcal peptidoglycan (PGN). Ciclosporin alone did not alter the expression levels of these transcripts but in the presence of ciclosporin, TNF alpha mRNA expression was upregulated in response to all three agonists and both TNF-alpha and IL-8 transcript abundance was increased in response to Pam3CSK4. The enhanced responsiveness of canine keratinocytes to TLR2 agonists in response to ciclosporin may imply that administration of this drug might enhance the innate immune barrier of skin. PMID- 22525196 TI - Echo intensity is associated with skeletal muscle power and cardiovascular performance in elderly men. AB - The purpose of the present study was to investigate the relationship between echo intensity, neuromuscular and cardiorespiratory performances in the elderly. Thirty-one healthy elderly men (65.5+/-5.0) participated in this study. Echo intensity of rectus femoris and quadriceps femoris muscle thicknesses was determined by ultrasound images. Lower-body isometric and isokinetic peak torques (60, 180 and 360 degrees (.s-1)), as well as rate of force development were evaluated as strength parameters. In addition, torque per unit of muscle mass was evaluated by the quotient between isometric peak torque of the knee extensors and the quadriceps femoris muscle thickness. The peak oxygen uptake (VO(2peak)), maximum aerobic workload (W(max)), absolute (VT(1) and VT(2)) ventilatory thresholds, as well as workloads at VT(1) and VT(2) (W(VT1) and W(VT2)) were evaluated during a maximal incremental test on a cycle ergometer. There were significant negative correlations between the individual values of echo intensity with the corresponding individual values of isometric and isokinetic peak torques (60, 180 and 360 degrees (.s-1)) (r=-0.48 to r=-0.64; P<0.05), as well as with W(VT1) (r=-0.46) and W(VT2) (r=-0.50) (P<0.05). In addition, significant positive correlations were observed between torque per unit of muscle mass and cardiovascular parameters (r=0.52 to r=0.60; P<0.001). The present results suggest that the echo intensity analysis using computer-aided gray-scale analysis is a low cost, easily accessible, and a safe method to evaluate the muscle quality, and may contribute to the research of neuromuscular and cardiovascular performances in the elderly. PMID- 22525197 TI - The heterojunction effects of TiO2 nanotubes fabricated by atomic layer deposition on photocarrier transportation direction. AB - The heterojunction effects of TiO2 nanotubes on photoconductive characteristics were investigated. For ITO/TiO2/Si diodes, the photocurrent is controlled either by the TiO2/Si heterojunction (p-n junction) or the ITO-TiO2 heterojunction (Schottky contact). In the short circuit (approximately 0 V) condition, the TiO2 Si heterojunction dominates the photocarrier transportation direction due to its larger space-charge region and potential gradient. The detailed transition process of the photocarrier direction was investigated with a time-dependent photoresponse study. The results showed that the diode transitioned from TiO2-Si heterojunction-controlled to ITO-TiO2 heterojunction-controlled as we applied biases from approximately 0 to -1 V on the ITO electrode. PMID- 22525198 TI - EURACT: European Academy of Teachers in General Practice and Family Medicine. PMID- 22525199 TI - Hypertension and aortorenal disease in Alagille syndrome. AB - Alagille syndrome is a rare congenital multisystem disorder that may involve heart disease and pulmonary or peripheral artery stenosis. We report the clinical and radiological presentation of five adult patients with Alagille syndrome, hypertension and renal artery stenosis. All had systolic hypertension and a narrowing of the abdominal aorta, corresponding to a secondary midaortic syndrome. Renovascular disease progressed during follow-up, with increases in blood pressure, decreases in glomerular filtration rate and/or kidney atrophy. A literature review identified several anecdotal reports of Alagille syndrome associated with hypertension, renal artery stenosis and/or midaortic syndrome. We discuss this condition, focusing on diagnosis, differential diagnosis, associated conditions and management. Cardiologists, nephrologists and radiologists should be aware of this rare cause of renovascular hypertension and of the need for clinical, biological and echographic follow-up. PMID- 22525200 TI - Pharmacogenetic implications for eight common blood pressure-associated single nucleotide polymorphisms. AB - OBJECTIVE: We aimed to test whether eight common recently identified single nucleotide polymorphisms (SNPs), strongly associated with blood pressure (BP) in the population, also have impact on the degree of BP reduction by antihypertensive agents with different mechanisms. METHODS: In 3863 Swedish hypertensive patients, we related number of unfavorable alleles of each SNP (i.e. alleles associated with higher baseline BP) to the magnitude of BP reduction during 6 months of monotherapy with either a beta-blocker, a thiazide diuretic or diltiazem. RESULTS: For six SNPs (rs16998073, rs1378942, rs3184504, rs1530440, rs16948048, rs17367504) no pharmacogenetic interactions were suggested, whereas two SNPs showed nominal evidence of association with treatment response: PLCD3 rs12946454 associated with more SBP (beta = 1.53 mmHg per unfavorable allele; P = 0.010) and DBP (beta = 0.73 mmHg per unfavorable allele; P = 0.014) reduction in patients treated with diltiazem, in contrast to those treated with beta-blockers or diuretics wherein no treatment response association was found. CYP17A1 rs11191548 associated with less DBP reduction (beta = -1.26 mmHg per unfavorable allele; P = 0.018) in patients treated with beta-blockers or diuretics, whereas there was no treatment response association in diltiazem-treated patients. However, if accounting for multiple testing, the significant associations for rs12946454 and rs11191548 were attenuated. CONCLUSION: For a majority of these, eight recently identified BP-associated SNPs, there are probably no important pharmacogenetic interactions for BP reduction with use of beta-blockers, diuretics or diltiazem. Whether the nominally significant associations for rs12946454 and rs11191548 are true signals and could be of possible clinical relevance for deciding treatment of polygenic essential hypertension should be further tested. PMID- 22525201 TI - Clinical differences between resistant hypertensives and patients treated and controlled with three or less drugs. AB - BACKGROUND AND AIM: Clinical characteristics of resistant hypertensive patients in comparison to controlled patients have not been fully investigated in large cohorts. The aim of the study was to evaluate clinical differences, target organ damage and ambulatory blood pressure monitoring in resistant hypertensive patients and patients controlled on three or less drugs. METHODS: In December 2010, from the Spanish Ambulatory Blood Pressure Monitoring Registry, we identified 14 461 patients fulfilling criteria of resistant hypertension and 13 436 hypertensive patients controlled on three or less drugs. Clinical characteristics were compared between these two groups. RESULTS: Compared to controlled patients, those having resistant hypertension were older, more obese and had longer hypertension duration. They also had more frequently diabetes, dyslipidemia, reduced renal function, microalbuminuria, left-ventricular hypertrophy and previous history of cardiovascular events. In multivariate analyses, hypertension duration, obesity, abdominal obesity, left-ventricular hypertrophy, reduced estimated glomerular filtration rate, and microalbuminuria were independently associated with resistant hypertension. Resistant hypertensive patients had higher ambulatory blood pressures, but differences between office and ambulatory blood pressure (white-coat effect) were also more pronounced in this group, revealing a proportion of 40% of patients with normal 24-h blood pressure. On the contrary, values of 24-h blood pressure above 130 and/or 80 mmHg (masked hypertension) were present in 31% of apparently controlled patients. CONCLUSION: Resistant hypertension is associated with obesity, longer hypertension duration and kidney and cardiac damage. Ambulatory blood pressure monitoring reveals that white-coat hypertension is common among resistant hypertensive patients, as well as is masked hypertension among apparently controlled patients. PMID- 22525202 TI - Workplace social capital and risk of chronic and severe hypertension: a cohort study. AB - OBJECTIVE: The association between workplace factors and the development of hypertension remains uncertain. We examined the risk of hypertension as a function of workplace social capital, that is, social cohesion, trust and reciprocity in the workplace. METHODS: A total of 11 777 male and 49 145 female employees free of chronic hypertension at baseline in 2000-2004 were followed up for incident hypertension until the end of 2005 (the Finnish Public Sector Study). We used survey responses from the participants and their coworkers in the same work unit to assess workplace social capital at baseline. Follow-up for incident hypertension was based on record linkage to national health registers (mean follow-up 3.5 years, 1424 incident hypertension cases). RESULTS: Male employees in work units characterized by low workplace social capital were 40-60% more likely to develop chronic hypertension compared to men in work units with high social capital [age-adjusted hazard ratio 1.57, 95% confidence interval (CI) 1.15-2.14 for self-assessed social capital and 1.41, 95% CI 1.01-1.97 for coworkers' assessment]. According to path analysis adjusted for covariates, the association between low self-reported social capital and hypertension was partially mediated by obesity (P for pathway = 0.02) and alcohol consumption (P = 0.03). For coworker-assessed social capital, the corresponding mediation pathways did not reach statistical significance (P = 0.055 and 0.22, respectively). No association between workplace social capital and hypertension was found for women. CONCLUSION: These data suggest that low self-reported workplace social capital is associated with increased near-term risk of hypertension in men in part due to unhealthy lifestyle. PMID- 22525203 TI - Liver growth factor treatment reverses vascular and plasmatic oxidative stress in spontaneously hypertensive rats. AB - BACKGROUND: Liver growth factor (LGF) is an albumin-bilirubin complex with antioxidant actions in vitro. In spontaneously hypertensive rats (SHRs), short LGF treatment exerts antihypertensive and antifibrotic effects. METHOD: We aimed to determine if LGF treatment (4 i.p. injections, 4.5 MUg/rat over 12 days) reduces oxidative stress in SHRs using Wistar-Kyoto (WKY) as control strain. We assessed the following: plasma oxidative stress biomarkers [protein-bound malondialdehyde (MDA); protein carbonyls and advanced glycation end products (AGEs)]; superoxide anion basal production in carotid artery-derived vascular smooth muscle cells (VSMCs) detected by dihydroethidium and confocal microscopy; and expression (western blot) and activities (spectroscopic methods) of NADPH and xanthine oxidases, CuZn, Mn and extracellular superoxide dismutases (SODs) and catalase in carotid arteries. RESULTS: LGF treatment had the following effects: reversed the increase in plasma MDA and protein carbonyls and VSMC superoxide anion levels observed in SHRs, without any effect on WKY strain; reversed the alterations in SHR vascular p22phox expression as well as NADPH oxidase, xanthine oxidase and catalase activities; had no effect on vascular CuZn-SOD and Mn-SOD expression or total SOD activity; and reversed the elevation in SHR vascular glycated/free extracellular-SOD expression ratio and plasma glucose without changes in plasma AGEs. CONCLUSION: LGF treatment of SHRs normalizes the level of plasma oxidative stress biomarkers through a reduction of vascular superoxide anion produced by NADPH and xanthine oxidases. These effects might be linked to the cardiovascular regenerative actions of LGF. PMID- 22525204 TI - Involvement of membrane tubulin in erythrocyte deformability and blood pressure. AB - OBJECTIVE: To test the hypothesis that erythrocyte deformability is influenced by changes in the content of membrane tubulin (Mem-tub). METHODS AND RESULTS: Human erythrocytes contain tubulin distributed in three pools (membrane, sedimentable, soluble). Erythrocytes from hypertensive humans have a higher proportion of Mem tub. Increased Mem-tub content in hypertensive patients was correlated with decreased erythrocyte deformability. Treatment of erythrocytes from normotensive individuals with taxol increased Mem-tub content and reduced deformability, whereas treatment of hypertensive patients erythrocytes with nocodazole had the opposite effect. In-vivo experiments with rats were performed to examine the possible relationship between Mem-tub content, erythrocyte deformability, and blood pressure. Spontaneously hypertensive rats (SHRs) showed lower erythrocyte deformability than normotensive Wistar rats. During the development of hypertension in SHR, tubulin in erythrocytes is translocated to the membrane, and this process is correlated with decreased deformability. In-vivo treatment (intraperitoneal injection) of SHR with nocodazole decreased Mem-tub content, increased erythrocyte deformability, and decreased blood pressure, whereas treatment of Wistar rats with taxol had the opposite effects. CONCLUSION: These findings indicate that increased Mem-tub content contributes to reduced erythrocyte deformability in hypertensive animals. PMID- 22525205 TI - Dietary habits of the hypertensive population of Spain: accordance with the DASH diet and the Mediterranean diet. AB - OBJECTIVES: Dietary treatment is appropriate for all patients with hypertension. However, only a few population-based studies have evaluated the diet of hypertensive individuals, and none of them has been conducted in Europe. This study examined accordance with the Dietary Approaches to Stop Hypertension (DASH) diet and the Mediterranean diet in the hypertensive population of Spain. METHODS: A cross-sectional study conducted in 2008-2010 among 12 948 individuals representative of the Spanish population aged at least 18 years. Blood pressure was measured with validated devices under standardized conditions. Habitual food consumption was assessed with a computerized diet history. DASH accordance was defined as at least 4.5 points on a score using nine nutrient targets, and Mediterranean diet accordance as at least 9 points on the Mediterranean Diet Adherence Screener score. RESULTS: Among the diagnosed hypertensive individuals, 17.3% [95% confidence interval (CI) 15.4-19.2%] had a DASH-accordant diet, and 17.2% (95% CI 15.4-19.1%) had a Mediterranean-accordant diet. The frequency of DASH accordance increased with age, was higher among women and hypercholesterolaemic individuals, and lower in current smokers. Similar results were found for Mediterranean diet accordance. Only 60% of the diagnosed hypertensive individuals reported receiving and following a diet prescribed to control hypertension; this group showed a better accordance with the DASH diet [age and sex-adjusted odds ratio (aOR) 1.43; 95% CI 1.08-1.88]. As compared with the 1518 hypertensive individuals unaware of their condition, those who were diagnosed showed a similar frequency of accordance with the DASH diet (aOR 1.08; 95% CI 0.87-1.34) and the Mediterranean diet (aOR 0.98; 95% CI 0.79-1.20). CONCLUSION: The diet of hypertensive individuals in Spain has a low accordance with the DASH and Mediterranean dietary patterns. The similarity in healthy-diets accordance between the diagnosed and undiagnosed hypertensive individuals suggests that nutritional interventions in hypertensive patients are poor, a problem that should be compellingly addressed. PMID- 22525206 TI - Metformin-based treatment for obesity-related hypertension: a randomized, double blind, placebo-controlled trial. AB - OBJECTIVES: Obesity and hypertension are associated with an adverse metabolic profile and systemic low-grade inflammation. Metformin reduces weight and inflammation in patients with diabetes, but it is unclear whether it has beneficial effects in patients without diabetes. The objective was to explore whether metformin-based treatment could benefit obesity-related hypertension without diabetes. METHODS: A randomized, double-blind, placebo-controlled factorial trial was conducted in 360 obese hypertensive patients without diabetes in Chongqing, China. After a 1-2-week run-in period, patients were randomly assigned to metformin (500 mg once per day) or placebo, as well as to an antihypertensive medication. Change in blood pressure, obesity measurements and metabolic profile were assessed at 24 weeks. RESULTS: The 180 participants randomized to metformin and 180 randomized to placebo were similar at baseline. At 24 weeks, metformin compared with placebo did not have significant effects on blood pressure, blood glucose, high-density or low-density lipoprotein cholesterol, but it did reduce total serum cholesterol (0.2 mmol/l, P = 0.038). Metformin also significantly reduced weight (-0.7 kg, P = 0.006), BMI (-0.2 kg/m, P = 0.024), waist circumference (-0.9 cm, P = 0.008), and both subcutaneous (-6.1 cm, P = 0.043) and visceral adiposity (-5.4 cm, P = 0.028) as measured by computed tomography, and lowered serum high-sensitivity C-reactive protein levels (-0.6 mg/dl, P < 0.001). There was no significant difference in adverse events (P = 0.785). CONCLUSIONS: Metformin has no effect on blood pressure and blood glucose levels, but it does reduce total cholesterol, abdominal obesity and C reactive protein levels in obese hypertensive patients without diabetes. PMID- 22525207 TI - Assessment of flow-mediated dilation reproducibility: a nationwide multicenter study. AB - OBJECTIVE: Impaired flow-mediated dilation (FMD) is associated with cardiovascular risk factors and provides prognostic information. Despite the noninvasive nature of this technique, a major limitation to its widespread use is low reproducibility. The aim of this study was to evaluate impact of methodological standardization among different investigation sites on brachial artery FMD reproducibility. METHODS: Seven Italian centers recruited 135 healthy volunteers, aged 20-60 years. FMD was assessed by high-resolution ultrasound equipped with a stereotactic probe-holding device. Certified sonographers recorded brachial artery scans at baseline (day 1a), 1 h after (day 1b), and 1 month later (day 30). Endothelium-independent vasodilation (EIVD) to sublingual glyceril-trinitrate was recorded at day 1 and day 30. FMD and EIVD were blindly evaluated at the coordinating center by an automated edge detection system. The intra-session (day 1a versus 1b) and inter-session (day 1a versus 30) coefficients of variation were calculated. RESULTS: FMD was not significantly (P = 0.91) different at day 1a, day 1b and day 30 (6.52 +/- 2.9, 6.42 +/- 3.1, 6.57 +/- 2.8%, respectively). The FMD intra-session coefficient of variation was 9.9 +/- 8.4% (from 7.6 to 11.9% across centers). The FMD inter-session coefficient of variation was 12.9 +/- 11.6% (from 11.6 to 16.1% across centers). Inter-session coefficient of variation for EIDV was 19.7 +/- 16.8%. CONCLUSIONS: This study shows a homogeneous coefficient of variation for FMD among different centers. The inter-session coefficient of variation was similar to the intra-session coefficient of variation, representing the intrinsic FMD variability. We demonstrate for the first time that rigorous and standardized procedure may provide reproducible FMD assessment to study endothelial function in multicenter clinical trials. PMID- 22525208 TI - Use of animal model of sepsis to evaluate novel herbal therapies. AB - Sepsis refers to a systemic inflammatory response syndrome resulting from a microbial infection. It has been routinely simulated in animals by several techniques, including infusion of exogenous bacterial toxin (endotoxemia) or bacteria (bacteremia), as well as surgical perforation of the cecum by cecal ligation and puncture (CLP). CLP allows bacteria spillage and fecal contamination of the peritoneal cavity, mimicking the human clinical disease of perforated appendicitis or diverticulitis. The severity of sepsis, as reflected by the eventual mortality rates, can be controlled surgically by varying the size of the needle used for cecal puncture. In animals, CLP induces similar, biphasic hemodynamic cardiovascular, metabolic, and immunological responses as observed during the clinical course of human sepsis. Thus, the CLP model is considered as one of the most clinically relevant models for experimental sepsis. Various animal models have been used to elucidate the intricate mechanisms underlying the pathogenesis of experimental sepsis. The lethal consequence of sepsis is attributable partly to an excessive accumulation of early cytokines (such as TNF, IL-1 and IFN-gamma) and late proinflammatory mediators (e.g., HMGB1). Compared with early proinflammatory cytokines, late-acting mediators have a wider therapeutic window for clinical applications. For instance, delayed administration of HMGB1-neutralizing antibodies beginning 24 hours after CLP, still rescued mice from lethality, establishing HMGB1 as a late mediator of lethal sepsis. The discovery of HMGB1 as a late-acting mediator has initiated a new field of investigation for the development of sepsis therapies using Traditional Chinese Herbal Medicine. In this paper, we describe a procedure of CLP-induced sepsis, and its usage in screening herbal medicine for HMGB1 targeting therapies. PMID- 22525209 TI - Common polymorphisms in TLR4 gene associated with susceptibility to pulmonary tuberculosis in the Sudanese. AB - SETTING: Host genetic risk factors influence susceptibility to tuberculosis (TB). There is ample evidence supporting the involvement of toll-like receptor 4 (TLR4) in mycobacterial infection. OBJECTIVE: To study the relationship between the TLR4 gene and TB susceptibility in the Sudanese population. DESIGN: A case-control study was conducted among 207 patients with pulmonary TB and 395 healthy controls. Ten tag single nucleotide polymorphisms (SNPs) of the TLR4 gene were genotyped using restriction digestion or hybridisation assays, and analysed. RESULTS: The genotypes were in Hardy-Weinberg equilibrium. After controlling for sex using the Mantel-Haenszel test, four SNPs showed significant differences between cases and controls, even after correction of multiple comparisons by Bonferroni procedure. The Mantel-Haenszel estimates of allelic odds ratios for the high-risk alleles were 1.67 for rs1927911 (P = 0.0001), 1.85 for rs5030725 (P = 0.0008), 2.14 for rs7869402 (P = 1.87e-07) and 2.31 for rs1927906 (P = 1.23e 10). Haplotype analysis showed that rs1927911 and rs5030725 were in one haplotype block, and rs7869402 and rs1927906 were in another haplotype block. Conditional haplotype analysis suggested the presence of one causal variant downstream of a recombination hot spot at the 3' region of the TLR4 gene. CONCLUSION: This is the first study to show that common TLR4 polymorphisms are associated with TB susceptibility in the Sudanese population. PMID- 22525210 TI - A Phase II study of systemic chemotherapy with docetaxel, cisplatin, and S-1 (DCS) followed by surgery in gastric cancer patients with extensive lymph node metastasis: Japan Clinical Oncology Group study JCOG1002. AB - A Phase II trial was initiated in Japan to evaluate the efficacy and safety of preoperative chemotherapy with docetaxel, cisplatin and S-1 for gastric cancer with extensive lymph node metastasis. Patients are eligible to participate in the study if they have para-aortic lymph node metastases (stations no. 16a2/16b1) and/or a bulky lymph node (>=3 cm * 1 or >=1.5 cm * 2) along the celiac, splenic, common or proper hepatic arteries or the superior mesenteric vein, while patients with other distant metastases are ineligible. A total of 50 patients will be enrolled over 2.5 years. The primary endpoint is the response rate of the preoperative chemotherapy, which will be assessed based on the Response Evaluation Criteria in Solid Tumors ver. 1.0. The secondary endpoints are %3-year survival, %5-year survival, proportion of patients with R0 resection, proportion of patients who complete the preoperative chemotherapy and surgery, proportion of patients who complete the protocol treatment, pathological response rate and adverse events. This trial was registered at the UMIN Clinical Trials Registry (www.umin.ac.jp/ctr/) as UMIN000006069. PMID- 22525211 TI - Fatal pneumonia associated with temozolomide therapy in patients with malignant glioma. AB - This report presents the cases of three patients with fatal pneumonia that was highly suspected to be Pneumocystis pneumonia (PCP) based on serological diagnosis. Their chest radiographs showed bilateral pneumonia and each had presented with severe respiratory failure requiring mechanical ventilation when they arrived at the hospital. Although bronchoscopical sampling could not be performed, their chest computed tomography imaging and a marked elevation of serum KL-6 and beta-D-glucan levels were characteristic of Pneumocystis pneumonia. All three were found to have been treated with temozolomide after surgery for malignant glioma. Temozolomide can cause Pneumocystis pneumonia. The three patients did not receive prophylactic medication against Pneumocystis pneumonia during treatment with temozolomide, and their histories suggested that all had delayed seeking treatment. It may be difficult to diagnose Pneumocystis pneumonia because the symptoms are not specific for Pneumocystis pneumonia and they tend to be similar to those of common respiratory infectious diseases. Therefore, patients who receive temozolomide therapy have the potential to develop fatal pneumonia and should be carefully observed. The patients should also be adequately informed about Pneumocystis pneumonia, and prophylaxis against Pneumocystis pneumonia should be considered proactively before treatment with temozolomide is initiated. PMID- 22525212 TI - Successful control of intractable hypoglycemia using radiopharmaceutical therapy with strontium-89 in a case with malignant insulinoma and bone metastases. AB - This report describes the case of a 57-year-old woman with liver and bone metastases from malignant insulinoma, who was afflicted with severe hypoglycemia. Treatment of the liver metastases using octreotide, diazoxide and transarterial embolization failed to raise her blood glucose level and she required constant glucose infusion (about 1000 kcal/day) and oral feeding (about 2200 kcal/day) to avoid a hypoglycemic attack. Subsequently, 110 MBq (2.0 MBq/kg) of strontium-89 were administered by intravenous injection. Three weeks after the strontium-89 injection, we could reduce the dose of constant glucose infusion while maintaining a euglycemic status. Six weeks after the injection, the constant glucose infusion was discontinued. Although strontium-89 therapy is indicated for patients with multiple painful bone metastases, it was also useful as a means of inhibiting tumor activity and controlling hypoglycemia in this case. To our knowledge, this is the first report to provide evidence that strontium-89 can be useful in controlling intractable hypoglycemia in patients with malignant insulinoma with bone metastases. PMID- 22525213 TI - Diversity of head shaking nystagmus in peripheral vestibular disease. AB - OBJECTIVES: To evaluate the characteristics of head shaking nystagmus in various peripheral vestibular diseases. STUDY DESIGN: Retrospective case series. SETTING: Tertiary referral center. MATERIALS AND METHODS: Data of 235 patients with peripheral vestibular diseases including vestibular neuritis, Meniere's disease, and benign paroxysmal positional vertigo, were retrospectively analyzed. All subjects presented between August 2009 and July 2010. Patients were tested for vestibular function including head shaking nystagmus and caloric information. Regarding vestibular neuritis, all tests were again performed during the 1-month follow-up. Head shaking nystagmus was classified as monophasic or biphasic and, according to the affected ear, was divided as ipsilesional or contralesional. RESULTS: Of the 235 patients, 87 patients revealed positive head shaking nystagmus. According to each disease, positive rates of head shaking nystagmus were as follows: 35 (100%) of 35 cases of vestibular neuritis, 11 (68.8%) of 16 cases of Meniere's disease, and 41 (22.2%) of 184 cases of benign paroxysmal positional vertigo. All cases of vestibular neuritis initially presented as a monophasic, contralesional beating, head shaking nystagmus. However, 1 month after first visit, the direction of nystagmus was changed to biphasic (contralesional first then ipsilesional beating) in 25 cases (72.5%) but not in 10 cases (27.5%). There was a significant correlation between the degree of initial caloric weakness and the biphasic conversion of head shaking nystagmus (p = 0.02). CONCLUSION: In 72.5% of vestibular neuritis cases, head shaking nystagmus was converted to biphasic during the subacute period. The larger the initial canal paresis was present, the more frequent the biphasic conversion of head shaking nystagmus occurred. However, Meniere's disease and benign paroxysmal positional vertigo did not have specific patterns of head shaking nystagmus. PMID- 22525214 TI - Reporting standard compliance in publications of vestibular schwannoma patients treated with microsurgery. AB - BACKGROUND: In 2003, Kanzaki and colleagues published a set of reporting standards for vestibular schwannoma (VS) to serve as a guide for future publication, with the specific purpose of promoting standardization of reporting results in VS. OBJECTIVE: Here, the current published body of literature on VS cases treated with microsurgery was reviewed to determine its degree of adherence to consensus guidelines. METHODS: A comprehensive search of the English language literature was performed to identify studies reporting outcome data in patients treated with microsurgery for VSs. Each publication was reviewed to determine whether it had properly reported each of the 7 items relevant to surgical management described in the Consensus Meeting reporting guidelines. The number of studies that had included each of the key items before and after the publication of the reporting guidelines was compared. RESULTS: After the publication of the standards, there were a significantly greater proportion of studies that properly reported the nature of the tumor and facial nerve function. Since the publication of the Consensus Meeting Guidelines, there also were trends toward greater proportions of articles that properly reported the size, hearing function, preoperative symptoms, and postoperative complications of the patients treated. CONCLUSION: Since the release of the reporting system guidelines for VS, the focus of the publications seems to have shifted away from basic clinical characteristics and toward posttreatment neurologic function. Future studies reporting the clinical characteristics and surgical outcomes for patients with VS cases should strive to include all the elements described in the Consensus Meeting guidelines. PMID- 22525215 TI - Gene transfer targeting mouse vestibule using adenovirus and adeno-associated virus vectors. AB - HYPOTHESIS: The present study assessed how to inject a gene into the mouse vestibule and which is the optimum gene to the mouse vestibule adenovirus (AdV) vector or adeno-associated virus (AAV) vector. BACKGROUND: Loss of vestibular hair cell is seen in various balance disorder diseases. There have been some reports concerning gene delivery to the mouse vestibule in recent years. To effectively induce transgene expression at the vestibule, we assessed the efficiency of inoculating the mouse inner ear using various methods. METHODS: We employed an AdV- and AAV-carrying green fluorescent protein using a semicircular canal approach (via a canalostomy) and round window approach. RESULTS: AAV injection via canalostomy induced gene expression at the hair cells, supporting cells, and fibrocytes at the vestibular organs without auditory or balance dysfunction, suggesting it was the most suitable transfection method. This method is thus considered to be a promising strategy to prevent balance dysfunction. CONCLUSION: AAV injection via canalostomy to the vestibule is the noninvasive and highly efficient transfection method, and this study may have the potential to repair balance disorders in human in the future. PMID- 22525216 TI - Otitic meningitis, superior semicircular canal dehiscence, and encephalocele: a case series. AB - BACKGROUND: Otitic meningitis in the postantibiotic era is still a serious condition, requiring intensive treatment and prolonged rehabilitation. In view of the significant morbidity and mortality rate, conditions that may increase the likelihood of otitic meningitis developing should be treated promptly. The incidence of meningitis after asymptomatic encephaloceles of the middle cranial fossa varies greatly, and the management differs between elective surgical repair and expectant careful observation. Superior semicircular canal dehiscences (SSCDs) are postulated to have a congenital origin and are associated with a thin or dehiscent tegmen. Several cases of simultaneous SCCD and tegmen defects have been reported, but the findings of otitic meningitis, SCCD, and encephaloceles has, to the best of our knowledge, not been previously explored in the literature. METHODS: We reviewed a series of 4 patients who all presented with a combination of otitic meningitis, encephaloceles, and SSCD. RESULTS: All the 4 patients we reviewed had meningitis secondary to otitis media with computed tomographic scans confirming the presence of SCCD with ipsilateral tegmen tympani defects and associated cephaloceles. All patients were treated with intravenous antibiotics and underwent surgery that ranged from myringotomy and ventilation tube insertions, mastoidectomy, and burr hole drainage for temporal lobe abscess. They were all associated with intensive care unit admission, significant morbidity, and prolonged hospital stays. There were no mortalities. CONCLUSION: We propose that in all SSCD patients, a careful computed tomographic examination of the cranial base should be undertaken to exclude other associated tegmen tympani defects. In cases of SSCD requiring surgery, we support the view that elective surgical repair be recommended where asymptomatic ipsilateral encephaloceles are found, to reduce the risk of otitic meningitis. PMID- 22525217 TI - Air-bone gap component of inner-ear origin in audiograms of cochlear implant candidates. AB - BACKGROUND: Experimental studies have shown that creating a window in the bony cover of the cochlea and vestibular parts of the inner ear, with preservation of membranous and middle-ear functions, induces an air-bone gap (ABG). This study sought to determine if a similar mechanism explains the ABG frequently observed in audiograms of cochlear implant candidates. METHOD: The study group included 47 candidates for a cochlear implant (94 ears) attending a university-affiliated tertiary medical center who had an ABG component in the audiogram in the absence of external or middle-ear abnormalities. Air- and bone-conduction thresholds on pure-tone audiometry were analyzed for 250 to 8,000 Hz and 250 to 4,000 Hz, respectively. In the 25 patients operated on during the study period, differences in the ABG and in cerebrospinal fluid (CSF) leak were compared between those with and without anomalies on computed tomography. RESULTS: Imaging revealed an abnormal inner-ear structure in 46% of cases, mostly a large vestibular aqueduct, alone or combined with other cochlear or vestibular malformations. ABG was evident over high and low frequencies and was significantly larger at low frequencies and in ears with structural anomalies. A high rate of CSF leak was observed in patients with an ABG and structural anomalies imaging as well as in those with an ABG and normal imaging findings. CONCLUSION: In cochlear implant candidates, the presence of a third window could cause an ABG because of stapes motion-induced shunting of acoustic energy outside the cochlear duct in response to air-conducted stimuli while bone conduction is preserved. PMID- 22525218 TI - Idiopathic sudden sensorineural hearing loss and comorbid benign paroxysmal positional vertigo: some pathogenic additional considerations. PMID- 22525219 TI - Regarding: "Do high-speed drills generate high-frequency noise in mastoid surgery?". PMID- 22525220 TI - Founders' lecture: John D. Briggs - the spirit of SIP. PMID- 22525221 TI - Processes of psoriasis health care in Germany--long-term analysis of data from the statutory health insurances. AB - BACKGROUND: To evaluate health care provision for psoriasis patients, and to better allocate resources, precise knowledge of the health care situation is essential. The goal of this study is to analyze prescription behavior and resource utilization for psoriasis patients in Germany. METHODS: We performed a secondary analysis of routinely collected psoriasis data from 2004-2007 from members of a nationwide statutory health insurance company (Gmunder Ersatzkasse). A descriptive analysis was done on physician care, hospitalizations, and medications and related costs. RESULTS: 34,728 of the 913,145 continuously insured patients were diagnosed with psoriasis (one-year prevalence: 2.3-2.5%). At the time of the initial diagnosis, 68% of patients were treated by a dermatologist and 28% by a general practitioner (GP). Over the next 21 months, the proportion of patients seen by a dermatologist decreased to 22% and the proportion seen by a GP increased to around 70%. 15.2% of patients were absent at least once from work. 79.5% received prescriptions with an average cost of ? 135 per patient per year. 97.5% of patients received topical therapy; 11% got systemic therapies. Biologics were given to about 0.1% of patients. Significant differences in prescription behavior were seen between regions and physician groups. CONCLUSION: Psoriasis is an important economic and medical issue. The majority of insured patients take prescription therapies. Dermatologists are most often the first health care provider. PMID- 22525223 TI - Quadriceps volumes are reduced in people with patellofemoral joint osteoarthritis. AB - OBJECTIVES: This study aimed to (1) compare the volumes of vastus medialis (VM), vastus lateralis (VL), vastus intermedius and rectus femoris and the ratio of VM/VL volumes between asymptomatic controls and patellofemoral joint osteoarthritis (PFJ OA) participants; and (2) assess the relationships between cross-sectional area (CSA) and volumes of the VM and VL in individuals with and without PFJ OA. METHODS: Twenty-two participants with PFJ OA and 11 controls aged >= 40 years were recruited from the community and practitioner referrals. Muscle volumes of individual quadriceps components were measured from thigh magnetic resonance (MR) images. The CSA of the VM and lateralis were measured at 10 equally distributed levels (femoral condyles to lesser femoral trochanter). RESULTS: PFJ OA individuals had smaller normalized VM (mean difference 0.90 cm(3) . kg(-1), alpha = 0.011), VL (1.50 cm(3) . kg(-1), alpha = 0.012) and rectus femoris (0.71 cm(3) . kg(-1), alpha = 0.009) volumes than controls. No differences in the VM/VL ratio were observed. The CSA at the third level (controls) and fourth level (PFJ OA) above the femoral condyles best predicted VM volume, whereas the VL volume was best predicted by the CSA at the seventh level (controls) and sixth level (PFJ OA) above the femoral condyles. CONCLUSION: Reduced quadriceps muscle volume was a feature of PFJ OA. Muscle volume could be predicted from CSA measurements at specific levels in PFJ OA patients and controls. PMID- 22525222 TI - Agropyrenol and agropyrenal, phytotoxins from Ascochyta agropyrina var. nana, a fungal pathogen of Elitrigia repens. AB - A strain of Ascochyta agropyrina var. nana, a fungal pathogen of the perennial weed Elytrigia repens, produced several toxins in a liquid medium, and its primary toxin, named agropyrenol, was characterized as a substituted salicylaldehyde on the basis of its chemical and spectroscopic properties. Its absolute stereochemistry was determined by Mosher's method. Two other minor metabolites were isolated from the same culture and named agropyrenal and agropyrenone, respectively. They were characterized as a trisubstituted naphthalene carbaldehyde and a pentasubstituted 3H-benzofuranone, respectively, using the same techniques. When assayed on leaves of several weed plants, i.e., Mercurialis annua, Chenopodium album and Setaria viridis, agropyrenol proved to be phytotoxic, causing the appearance of necrotic lesions, agropyrenal was less active, while agropyrenone was inactive. None of the compounds showed antibiotic, fungicidal or zootoxic activity. PMID- 22525224 TI - Results of a phase II study of sirolimus and cyclophosphamide in patients with advanced sarcoma. AB - BACKGROUND: Activation of the mammalian target of rapamycin (mTOR) pathway has been demonstrated in sarcoma. Trials using mTOR inhibitor in sarcoma have shown low objective response rates but progression-free survival (PFS) rates suggest cytostatic effects. The combination of sirolimus and cyclophosphamide demonstrated synergistic anti-sarcoma activity in preclinical models; therefore, we conducted a phase II trial of sirolimus and cyclophosphamide in patients with advanced sarcoma. METHODS: Patients received 4 mg sirolimus daily and 200mg cyclophosphamide d1-7 and 15-21 every 28 days. The primary objective was to estimate the 24-week PFS rate with a target of >= 25%. Patients were followed for World Health Organisation (WHO) criteria tumour response by imaging every 8 weeks. Serum levels of sirolimus, lipids and vascular endothelial growth factor were measured. Tumour tissue was analysed for mTOR, S6 ribosomal protein and cytochrome P450 3A4/5 by quantitative immunofluorescence. RESULTS: Forty-nine eligible patients were enrolled from September 2008 to December 2009. Patients received a median of four cycles of therapy. Starting doses of drugs were tolerated in 79%. One patient achieved partial tumour response, 10 were progression-free for >= 24 weeks and two completed 12 cycles of treatment. Median PFS and overall survival (OS) were 3.4 and 9.9 months, respectively. Serious adverse events attributed to therapy occurred in 11% and included infection, pneumonitis and thrombosis. Hypertriglyceridaemia from treatment and lower tumour phosphorylated-mTOR are associated with longer survival. CONCLUSIONS: Sirolimus and cyclophosphamide were tolerated by the majority of patients. About 20% of patients had stable sarcoma for at least 6 months but objective tumour response was infrequent. PMID- 22525227 TI - The epidemiology and clinical characteristics of respiratory syncytial virus infection in children at a public pediatric referral hospital in Mexico. AB - OBJECTIVES: The aim of this study was to determine the epidemiological and clinical characteristics of children with respiratory syncytial virus (RSV) treated at a public referral children's hospital in Mexico. METHODS: We reviewed RSV infection in patients aged 0-18 years who were treated at Hospital Infantil from January 2004 to December 2008. RESULTS: During the 5 years, 2797 samples were tested for respiratory viruses; 356 samples were positive for any virus, including 266 (74.7%) positive for RSV. Complete clinical information was available for 205 RSV patients. The mean age was 22 months, and 33.7% of the infections were nosocomially acquired. Hospitalization occurred in 187 children. Of 14 deaths, nine were directly attributed to RSV infection. During the study, RSV infections were seen throughout the year, predominating in the colder months. Of the 205 patients, 79.0% (162/205) had an underlying disease. Congenital heart disease was found in 30.2% (49/162), including three children (33.3%) who died of RSV. Thirty-three patients (16.1%) with RSV required mechanical ventilation. None of the children with RSV received palivizumab or ribavirin. CONCLUSIONS: RSV caused high hospitalization rates and admission to intensive care units, especially among those with underlying illnesses and young infants. The data presented here will be useful for strategies to improve outcomes in children at risk of complications. PMID- 22525225 TI - Hippo signalling in the G2/M cell cycle phase: lessons learned from the yeast MEN and SIN pathways. AB - Over the past decade Hippo kinase signalling has been established as an essential tumour suppressor pathway controlling tissue growth in flies and mammals. All members of the Hippo core signalling cassette are conserved from yeast to humans, whereby the yeast analogues of Hippo, Mats and Lats are central components of the mitotic exit network and septation initiation network in budding and fission yeast, respectively. Here, we discuss how far core Hippo signalling components in Drosophila melanogaster and mammals have reported similar mitotic functions as already established for their highly conserved yeast counterparts. PMID- 22525228 TI - [One year follow-up after doppler-guided haemorrhoidal artery ligation]. AB - INTRODUCTION: The Doppler-guided haemorrhoidal artery ligation (DG-HAL) is a non exeresis technique for the treatment of haemorrhoids, consisting in the ligature of the distal branches of the upper rectal artery. The aim of this work is to evaluate the safety and efficacy of this technique after one year of follow-up. MATERIAL AND METHOD: A total of 30 patients were operated on using DG-HAL for grade II or III haemorrhoids. The mean age was 49.9 years (30-70 years). The THD(r) (Transanal Haemorrhoidal Dearterialisation) device was employed in all cases. The procedures were performed under intradural anaesthesia in a short-stay surgery unit. The operating time, pain, bleeding, postoperative stay, and complications and symptoms after 3-6 months and 12 months were recorded. RESULTS: The mean operating time was 23minutes (15-50). The pain according to a visual analogue scale (VAS) was 5.5 during the first day (90% required analgesia). Only 2 patients required analgesia after the second day. One patient described persistent pain up to 3 months, and 2 slight bleeding. A further operation was performed due to a haemorrhoidal thrombosis on the 10(th) day. There were no other complications and no re-admissions. The mean hospital stay was 1.4 days (0 2), and normal daily activity re-established at 7-8 days. A large majority (87%) of patients described having tenesmus, which disappeared in 3 months. After one year, two patients had had further operations, 3 had recurrences (2 slight prolapses and 1 occasional bleeding). The success rate was 80%. CONCLUSIONS: Haemorrhoidal dearterialisation using Doppler-guided arterial ligation seems to be effective after one year, with a low percentage of complications. PMID- 22525232 TI - EB symposium introduction: productive translational research: tools for connecting research cultures and managing conflict. PMID- 22525229 TI - Evidence that AKT and GSK-3beta pathway are involved in acute hyperhomocysteinemia. AB - Homocysteine is a neurotoxic amino acid that accumulates in several disorders including homocystinuria, neurodegenerative and neuroinflammatory diseases. In the present study we evaluated the effect of acute and chronic hyperhomocysteinemia on Akt, NF-kappaB/p65, GSK-3beta, as well as Tau protein in hippocampus of rats. For acute treatment, rats received a single injection of homocysteine (0.6 MUmol/g body weight) or saline (control). For chronic treatment, rats received daily subcutaneous injections of homocysteine (0.3-0.6 MUmol/g body weight) or saline (control) from the 6th to the 28th days-of-age. One or 12h after the last injection, rats were euthanized, the hippocampus was removed and samples were submitted to electrophoresis followed by Western blotting. Results showed that acute hyperhomocysteinemia increases Akt phosphorylation, cytosolic and nuclear immunocontent of NF-kappaB/p65 subunit and Tau protein phosphorylation, but reduces GSK-3beta phosphorylation at 1h after homocysteine injection. However, 12h after acute hyperhomocysteinemia there is no effect on Akt and GSK-3beta phosphorylation. Furthermore, chronic hyperhomocysteinemia did not alter Akt and GSK-3beta phosphorylation at 1h and 12h after the last administration of this amino acid. Our data showed that Akt, NF-kappaB/p65, GSK-3beta and Tau protein are activated in hippocampus of rats subjected to acute hyperhomocysteinemia, suggesting that these signaling pathways may be, at least in part, important contributors to the neuroinflammation and/or brain dysfunction observed in some hyperhomocystinuric patients. PMID- 22525233 TI - Collaboration and team science: from theory to practice. AB - Interdisciplinary efforts are becoming more critical for scientific discovery and translational research efforts. Highly integrated and interactive research teams share a number of features that contribute to their success in developing and sustaining their efforts over time. Through analysis of in-depth interviews with members of highly successful research teams and others who did not meet their goals or ended because of conflicts, we identified key elements that are critical for team success and effectiveness. There is no debate that the scientific goal sits at the center of the collaborative effort. However, supporting features need to be in place to avoid the derailment of the team. Among the most important of these is trust: without trust, the team dynamic runs the risk of deteriorating over time. Other critical factors of which both leaders and participants need to be aware include developing a shared vision, strategically identifying team members and purposefully building the team, promoting disagreement while containing conflict, and setting clear expectations for sharing credit and authorship. Self-awareness and strong communication skills contribute greatly to effective leadership and management strategies of scientific teams. While all successful teams share the characteristic of effectively carrying out these activities, there is no single formula for execution with every leader exemplifying different strengths and weaknesses. Successful scientific collaborations have strong leaders who are self-aware and are mindful of the many elements critical for supporting the science at the center of the effort. PMID- 22525234 TI - Tools for productively managing conflict. AB - In scientific teams as in life, conflicts arise. This paper aims to provide an introduction to tools and skills to help in managing conflicts in practice. Using a structured approach enables the concerns and interests of all involved to be identified and clarified. It also permits a better understanding of yourself and others and will help empower those in conflict to find acceptable and workable resolutions. PMID- 22525235 TI - Developing your career in an age of team science. AB - Academic institutions and researchers are becoming increasingly involved in translational research to spur innovation in addressing many complex biomedical and societal problems and in response to the focus of the National Institutes of Health and other funders. One approach to translational research is to develop interdisciplinary research teams. By bringing together collaborators with diverse research backgrounds and perspectives, these teams seek to blend their science and the workings of the scientists to push beyond the limits of current research.While team science promises individual and team benefits in creating and implementing innovations, its increased complexity poses challenges. In particular, because academic career advancement commonly focuses on individual achievement, team science might differentially impact early stage researchers. The need to be recognized for individual accomplishments to move forward in an academic career may give rise to research team conflicts. Raising awareness to career-related aspects of team science will help individuals (particularly trainees and junior faculty) take steps to align their excitement and participation with the success of both the team and their personal career advancement. PMID- 22525237 TI - Linkage analysis of alternative anxiety phenotypes in multiply affected panic disorder families. AB - BACKGROUND: The choice of phenotype definitions for genetic studies of panic and phobic disorders is complicated by family, twin, and neurobiological data indicating both distinct and shared risk factors as well as heterogeneity within categories. We have previously reported a genome scan in 120 multiplex panic disorder (PD) families using a phenotype that closely adhered to the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., PD definition. Here, we extend this work by carrying out exploratory linkage analyses in this same pedigree set using ten additional literature-based panic and phobia-related phenotypes that take into account aspects of these hypothesized complexities. METHODS: Multiply affected families (>2 individuals with PD) were recruited from clinical and nonclinical sources, evaluated by a clinician-administered semistructured interview and a subsequent blind consensus best estimate procedure. Each phenotype was analyzed under dominant and recessive models using parametric two-point (homogeneity and heterogeneity), multipoint, and nonparametric methods. Empirically based permutations were used to estimate model specific and global (across all phenotypes) P-values. RESULTS: The highest score was a two-point lod (4.27, global P<0.08) on chromosome 13 (D13S793, 76 cM) for the phenotype 'specific or social phobia' under a recessive model and conditions of homogeneity. There was minimal support for linkage to any of the remaining nine phenotypes. CONCLUSION: Although the interpretation of findings is limited by the sample size and the large number of phenotypes and models analyzed, these data suggest a region on chromosome 13 as a potential site for further exploration in relation to the risk for specific and social phobias. PMID- 22525238 TI - T3SS-dependent differential modulations of the jasmonic acid pathway in susceptible and resistant genotypes of Malus spp. challenged with Erwinia amylovora. AB - Fire blight is a bacterial disease of Maloideae caused by Erwinia amylovora (Ea). This necrogenic enterobacterium uses a type III secretion system (T3SS) to inject type III effectors into the plant cells to cause disease on its susceptible hosts, including economically important crops like apple and pear. The expressions of marker genes of the salicylic acid (SA) and jasmonic acid (JA) defense regulation pathways were monitored by RT-qPCR in leaves of two apple genotypes, one susceptible and one resistant, challenged with a wild type strain, a T3SS-deficient strain or water. The transcriptional data taken together with hormone level measurements indicated that the SA pathway was similarly induced in both apple genotypes during infection by Ea. On the contrary, the data clearly showed a strong T3SS-dependent down-regulation of the JA pathway in leaves of the susceptible genotype but not in those of the resistant one. Accordingly, methyl jasmonate treated susceptible plants displayed an increased resistance to Ea. Bacterial mutant analysis indicated that JA manipulation by Ea mainly relies on the type III effector DspA/E. Taken together, our data suggest that the T3SS dependent down-regulation of the JA pathway is a critical step in the infection process of Malus spp. by Ea. PMID- 22525239 TI - Rice MAPK phosphatase IBR5 negatively regulates drought stress tolerance in transgenic Nicotiana tabacum. AB - The mitogen-activated protein kinase (MAPK) phosphatases (MKPs) are important negative regulators in the MAPK signaling pathways, which play crucial roles in plant growth, regulation of development and response to environment stresses. Several MAPKs have been reported to be involved in the drought stress response, however, there is no evidence for the specific function of MKPs in drought stress. Here, a putative MKP in rice (Oryza sativa), OsIBR5, was characterized. Expression of OsIBR5 was induced by PEG6000, abscisic acid (ABA) and hydrogen peroxide (H(2)O(2)). Overexpression of OsIBR5 in tobacco plants resulted in hypersensitivity to drought and H(2)O(2) treatments. Drought and ABA-induced stomatal closure was significantly reduced in OsIBR5-overexpressing tobacco plants compared with controls. Moreover, OsIBR5 was found to interact with tobacco MAPKs SIPK and WIPK, and drought-induced WIPK activity was impaired in OsIBR5-overexpressing tobacco plants. These results indicated that OsIBR5 is a MKP which was induced by abiotic stresses and decreased tolerance to drought stress in transgenic tobacco plants. PMID- 22525240 TI - A set of GFP organelle marker lines for intracellular localization studies in Medicago truncatula. AB - Genomics advances in the model legume, Medicago truncatula, have led to an increase in the number of identified genes encoding proteins with unknown biological function. Determining the intracellular location of uncharacterized proteins often aids in the elucidation of biological function. To expedite such localization studies, we have generated a set of intracellular organelle green fluorescence protein (GFP) marker lines in M. truncatula. In addition to fluorescent detection, this set of organelle marker lines can also be used in immunohistochemical and cellular fractionation detection assays. Moreover, this set of marker lines is compatible with both transient and stable expression systems. Thus, this marker set should prove to be a useful resource for the M. truncatula research community. PMID- 22525241 TI - Protein turnover and plant RNA and phosphorus requirements in relation to nitrogen fixation. AB - Phosphorus (P) is the proximate (immediate) limiting element for primary productivity in some habitats, and is generally the ultimate limiting element for primary productivity. Although RNA can account for over half of the non-storage P in photosynthetic organisms, some primary producers have more ribosomes than the minimum needed for the observed rate of net protein synthesis; some of this RNA may be needed for protein turnover. Two cases of protein turnover which can occur at a much faster rate than the bulk protein turnover are those of photodamaged photosystem II and O(2)-damaged nitrogenase. While RNA involved in photosystem II repair accounts for less than 1% of the non-storage P in photosynthetic organisms, a maximum, of 12% of non-storage P could occur in RNA associated with replacement of damaged nitrogenase and/or O(2) damage avoidance mechanism in diazotrophic (N(2) fixing) organisms. There is a general trend in published data towards lower P use efficiency (g dry matter gain per day per mol P in the organism) for photosynthetic diazotrophic organisms growing under P limitation with N(2) as their nitrogen source, rather than with NH(4)(+), urea or NO(3)(-). Additional work is needed to examine the generality of a statistically verified decrease in P use efficiency for diazotrophic growth relative to growth on other nitrogen sources and, if this is confirmed, further investigation of the mechanism is needed. The outcome of such work would be important for relating the global distribution of diazotrophy to P availability. There are no known P acquisition mechanisms specific to diazotrophs. Phosphorus (P) is the proximate (immediate) limiting element for primary productivity in some habitats, and is generally the ultimate limiting element for primary productivity. Although RNA can account for over half of the non-storage P in photosynthetic organisms, some primary producers have more ribosomes than the minimum needed for the observed rate of net protein synthesis; some of this RNA may be needed for protein turnover. Two cases of protein turnover which can occur at a much faster rate than the bulk protein turnover are those of photodamaged photosystem II and O(2) damaged nitrogenase. While RNA involved in photosystem II repair accounts for less than 1% of the non-storage P in photosynthetic organisms, a maximum, of 12% of non-storage P could occur in RNA associated with replacement of damaged nitrogenase and/or O(2) damage avoidance mechanism in diazotrophic (N(2) fixing) organisms. There is a general trend in published data towards lower P use efficiency (g dry matter gain per day per mol P in the organism) for photosynthetic diazotrophic organisms growing under P limitation with N(2) as their nitrogen source, rather than with NH(4)(+), urea or NO(3)(-). Additional work is needed to examine the generality of a statistically verified decrease in P use efficiency for diazotrophic growth relative to growth on other nitrogen sources and, if this is confirmed, further investigation of the mechanism is needed. The outcome of such work would be important for relating the global distribution of diazotrophy to P availability. There are no known P acquisition mechanisms specific to diazotrophs. PMID- 22525242 TI - Inheritance and fine mapping of a restorer-of-fertility (Rf) gene for the cytoplasmic male sterility in soybean. AB - The cytoplasmic male sterility (CMS) line FuCMS5A and its restorer line FuHui9 were crossed to produce a segregating F(2) population for pollen fertility assay and the genetic mapping of restorer-of-fertility (Rf) gene. Results showed that the individual F(2) plants were fertile or semi-fertile based on their pollen fertility characteristics. The average ratios of viable pollen were 96.90% and 50.00% for each class of individuals. The segregation of F(2) plants showed a good fit to a 1:1 ratio, which reflects a typical heredity pattern of gametophytic CMS with fertility restorer being controlled by a single dominant gene. Using bulk segregation analysis (BSA) and genetic mapping, the Rf gene was mapped on molecular linkage group J (chromosome 16), between the simple sequence repeat (SSR) makers BARCSOYSSR-16-1064 and BARCSOYSSR-16-1082 with the distances of 0.59 and 0.83 cM, respectively. Four SSR markers (BARCSOYSSR-16-1070, Sctt011, BARCSOYSSR-16-1076 and BARCSOYSSR-16-1077) were cosegregating with this Rf gene in the mapping population. These makers will greatly facilitate the maker assisted selection procedures in CMS breeding programs and it lays a foundation for further map-base cloning of the Rf gene. PMID- 22525243 TI - Sucrose accelerates flower opening and delays senescence through a hormonal effect in cut lily flowers. AB - Sugars are generally used to extend the vase life of cut flowers. Such beneficial effects have been associated with an improvement of water relations and an increase in available energy for respiration by floral tissues. In this study we aimed at evaluating to what extent (i) endogenous levels of sugars in outer and inner tepals, androecium and gynoecium are altered during opening and senescence of lily flowers; (ii) sugar levels increase in various floral tissues after sucrose addition to the vase solution; and (iii) sucrose addition alters the hormonal balance of floral tissues. Results showed that endogenous glucose levels increased during flower opening and decreased during senescence in all floral organs, while sucrose levels increased in outer and inner tepals and the androecium during senescence. Sucrose treatment accelerated flower opening, and delayed senescence, but did not affect tepal abscission. Such effects appeared to be exerted through a specific increase in the endogenous levels of sucrose in the gynoecium and of glucose in all floral tissues. The hormonal balance was altered in the gynoecium as well as in other floral tissues. Aside from cytokinin and auxin increases in the gynoecium; cytokinins, gibberellins, abscisic acid and salicylic acid levels increased in the androecium, while abscisic acid decreased in outer tepals. It is concluded that sucrose addition to the vase solution exerts an effect on flower opening and senescence by, among other factors, altering the hormonal balance of several floral tissues. PMID- 22525244 TI - Transcriptional response of abscisic acid (ABA) metabolism and transport to cold and heat stress applied at the reproductive stage of development in Arabidopsis thaliana. AB - The phytohormone abscisic acid (ABA) plays an important role in developmental processes in addition to mediating plant adaptation to stress. In the current study, transcriptional response of 17 genes involved in ABA metabolism and transport has been examined in vegetative and reproductive organs exposed to cold and heat stress. Temperature stress activated numerous genes involved in ABA biosynthesis, catabolism and transport; however, several ABA biosynthesis genes (ABA1, ABA2, ABA4, AAO3, NCED3) were differentially expressed (up- or down regulated) in an organ-specific manner. Key genes (CYP707As) involved in ABA catabolism responded differentially to temperature stress. Cold stress strongly activated ABA catabolism in all organs examined, whereas heat stress triggered more subtle activation and repression of select CYP707A genes. Genes involved in conjugation (UGT71B6), hydrolysis (AtBG1), and transport (ABCG25, ABCG40) of ABA or ABA glucose ester responded to temperature stress and displayed unique organ specific expression patterns. Comparing the transcriptional response of vegetative and reproductive organs revealed ABA homeostasis is differentially regulated at the whole plant level. Taken together our findings indicate organs in close physical proximity undergo vastly different transcriptional programs in response to abiotic stress and developmental cues. PMID- 22525245 TI - The impact of long-term CO2 enrichment on sun and shade needles of Norway spruce (Picea abies): photosynthetic performance, needle anatomy and phenolics accumulation. AB - Norway spruce (Picea abies L. Karst) grown under ambient (365-377 MUmol(CO(2)) mol(-1); AC) and elevated (700 MUmol(CO(2)) mol(-1); EC) CO(2) concentrations within glass domes with automatically adjustable windows and on an open-air control site were studied after 8 years of treatment. The effect of EC on photosynthesis, mesophyll structure and phenolics accumulation in sun and shade needles was examined. Photosynthetic assimilation and dark respiration rates were measured gasometrically; the structural parameters of mesophyll were determined using confocal microscopy and stereological methods. The contents of total soluble phenolics and lignin were assessed spectrophotometrically, and localizations of different phenolic groups were detected histochemically on needle cross-sections. EC enhanced the light-saturated CO(2) assimilation rate and reduced dark respiration in the current-year needles. No effects of CO(2) enrichment on mesophyll structural parameters were observed. Similarly, the accumulation and localization of phenolics and lignin remained unaffected by EC treatment. Needles differentiated into sun and shade ecotypes in the same manner and to the same extent irrespective of CO(2) treatment. Based on these results, it is apparent that the EC-induced enhancement of photosynthesis is not related to changes in the examined structural parameters of mesophyll and accumulation of phenolic compounds. PMID- 22525246 TI - Manipulating plant architecture with members of the CETS gene family. AB - The shape or architecture of a plant is specified through the activities of indeterminate and determinate meristems, and the sum of these events sharply impacts plant growth habit, productivity, and crop management. The CENTRORADIALIS/TERMINAL FLOWER 1/SELF-PRUNING (CETS) gene family shares homology to phosphatidylethanolamine binding protein (PEBP) genes and is prominent in controlling the timing and location of the developmental transition from indeterminate to determinate growth, with different family members balancing the activities of others through antagonistic functions. The CETS members FLOWERING LOCUS T (FT) of Arabidopsis and related genes (e.g. SINGLE FLOWER TRUSS, SFT, in tomato) are important in promoting the transition to determinate growth while TERMINAL FLOWER 1 (TFL1) and its homologs (e.g. tomato SELF PRUNING, SP) oppose this activity by maintaining meristems in an indeterminate state. FT orthologs, and perhaps other CETS family members, act as mobile proteinaceous hormones, and can amplify their impact by accumulating in recipient organs. A universal model is emerging for the timing and placement of determinate and indeterminate growth through a balance of FT-like and TFL1-like gene activities, and it is now clear that the domestication of many wild exotics into crops with desired growth habits resulted from selection of altered FT/TFL1 balances. Manipulating this ratio further, through transgenic or viral-based technologies, holds promise for improved agricultural sustainability. PMID- 22525247 TI - Plastid thioredoxins f and m are related to the developing and salinity response of post-germinating seeds of Pisum sativum. AB - Plastid thioredoxins (TRXs) f and m have long been considered to regulate almost exclusively photosynthesis-related processes. Nonetheless, some years ago, we found that type-f and m TRXs were also present in non-photosynthetic organs such as roots and flowers of adult pea plants. In the present work, using pea seedlings 2-5 days old, we have determined the mRNA expression profile of the plastid PsTRX f, m1, and m2, together with the ferredoxin NADP reductase (FNR). Our results show that these TRX isoforms are expressed in cotyledons, underlying similar expression levels in roots for PsTRX m2. We have also noted plastid TRX expression in cotyledons of etiolated seedlings of Arabidopsis thaliana lines carrying constructs corresponding to PsTRX f and m1 promoters fused to the reporter gene GUS, pointing to a role in reserve mobilization. Furthermore, the response of plastid TRXs to NaCl and their capacity in restoring the growth of a TRX-deficient yeast under saline conditions suggest a role in the tolerance to salinity. We propose that these redox enzymes take part of the reserve mobilization in seedling cotyledons and we suggest additional physiological functions of PsTRX m2 in roots and PsTRX m1 in the salinity-stress response during germination. PMID- 22525248 TI - Antioxidant response resides in the shoot in reciprocal grafts of drought tolerant and drought-sensitive cultivars in tomato under water stress. AB - Recently grafted plants have been used to induce resistance to different abiotic stresses. In our work, grafted plants of tomato cultivars differing in water stress tolerance (Zarina and Josefina) were grown under moderate stress, to test the roles of roots and shoots in production of foliar biomass and antioxidant response. Stress indicators and activities of selected enzymes related to antioxidant response were determined. Our results showed that when shoots are of the drought tolerant genotype Zarina, the changes in antioxidant enzyme activities were large and consistent. However, when shoots are of the drought sensitive genotype Josefina, the antioxidant enzyme activities were more limited and the oxidative stress was evident. These results reflect that the technique of grafting using Zarina as scion can be useful and effective for improving the antioxidant response in tomato under water stress. PMID- 22525249 TI - AtSUC2 has a role for sucrose retrieval along the phloem pathway: evidence from carbon-11 tracer studies. AB - The location of the phloem within a plant, and its vulnerability to disruption, make it a difficult tissue to study and therefore non-invasive studies of phloem functionality are important. Here we compare, phloem transport, measured non invasively, in wild type Arabidopsis thaliana, and transposon-insertion mutants for AtSUC1 or AtSUC2, giving in vivo information on the importance of these sucrose transporters for phloem transport. The suc2 mutant showed an increase in both phloem leakage and transport time, consistent with reduced sucrose uptake into both transport and collection phloem. The results are consistent with the AtSUC2 transporter being important for retrieval of leaked sucrose in the transport phloem of Arabidopsis. There was no difference in phloem transport properties between the wild type and the suc1 mutants, implying that the AtSUC1 transporter does not play a significant role within the transport phloem of Arabidopsis under the conditions of our study. PMID- 22525251 TI - Retraction notice to "Redox regulation of the glutathione reductase/iso glutaredoxin system in germinating pea seed exposed to cadmium" [Plant Sci. 179 (5) (2010) 423-436]. PMID- 22525250 TI - Structure and expression of the quinolinate phosphoribosyltransferase (QPT) gene family in Nicotiana. AB - Synthesis of wound-inducible pyridine alkaloids is characteristic of species in the genus Nicotiana. The enzyme quinolinate phosphoribosyltransferase (QPT) plays a key role in facilitating the availability of precursors for alkaloid synthesis, in addition to its ubiquitous role in enabling NAD(P)(H) synthesis. In a previous study, we reported that Nicotiana tabacum L. var. NC 95 possesses a QPT RFLP pattern similar to its model paternal progenitor species, Nicotiana tomentosiformis Goodsp. Here we show that although some varieties of N. tabacum (e.g. NC 95 and LAFC 53) possess QPT genomic contributions from only its paternal progenitor species, this is not the case for many other N. tabacum varieties (e.g. Xanthi, Samsun, Petite Havana SR1 and SC 58) where genomic QPT sequences from both diploid progenitor species have been retained. We also report that QPT is encoded by duplicate genes (designated QPT1 and QPT2) not only in N. tabacum, but also its model progenitor species Nicotiana sylvestris Speg. and Comes and N. tomentosiformis as well as in the diploid species Nicotiana glauca Graham. Previous studies have demonstrated that the N. tabacum QPT2 gene encodes a functional enzyme via complementation of a nadC(-)Escherichia coli mutant. Using a similar experimental approach here, we demonstrate that the N. tabacum QPT1 gene also encodes a functional QPT protein. We observe too that QPT2 is the predominate transcript present in both alkaloid and non-alkaloid synthesising tissues in N. tabacum and that promoter regions of both QPT1 and QPT2 are able to produce GUS activity in reproductive tissues. In N. tabacum and in several other Nicotiana species tested, QPT2 transcript levels increase following wounding or methyl jasmonate treatment whilst QPT1 transcript levels remain largely unaltered by these treatments. Together with conclusions from recently published studies involving functional interaction of MYC2-bHLH and specific ERF-type and transcription factors with QPT2-promoter sequences from N. tabacum, our results suggest that whilst both members of the QPT gene family can contribute to the transcript pool in both alkaloid producing and non-producing tissues, it is QPT2 that is regulated in association with inducible defensive pyridine alkaloid synthesis in species across the genus Nicotiana. PMID- 22525252 TI - [Prostate-specific antigen use among men without prostate cancer in France (2008 2010)]. AB - This study evaluated the rate of prostate-specific antigen (PSA) dosage in men age 40 or older, affiliated to the general social security system in France between 2008 and 2010: 10.9 million men, excluding those with known prostate cancer. In 2010, 30.7% of this male population had at least one dosage of PSA, i.e. 12.3% of those between 40 and 54, 47.7% of those between 55 and 74, and 47.6% of those 75 years old or older. Percentages of men who had at least one dosage in the three-year period were 26.2%, 77.3% and 75.6% for the same age brackets, respectively. Overall, 13% of men age 40 or older, and in particular 21% of men 75 years old or older had more than three PSA dosages during the three year time period. Eighty-eight percent of PSA dosages performed in 2010 were prescribed by a general practitioner and 3.2% by an urologist. Conflicting with French and internationally published recommendations regarding PSA dosage, the present results demonstrate a shift toward chaotic mass screening of prostate cancer particularly in men aged 75 or older. PMID- 22525253 TI - Objective evaluation of the latissimus dorsi flap for breast reconstruction using three-dimensional imaging. AB - BACKGROUND: The latissimus dorsi muscle flap is a common method for the reconstruction of the breast following mastectomy. The study aimed to assess the quality of this reconstruction using a three-dimensional (3D) imaging method. The null hypothesis was that there was no difference in volume between the reconstructed breast and the opposite side. METHODS: This study was conducted in forty-four patients who had had immediate unilateral breast reconstruction by latissimus dorsi muscle flap. The breast was captured using the 3D imaging system. Ten landmarks were digitised on the 3D images. The volume of each breast was measured by the application of Breast Analysis Tool software. The symmetry of the breast was measured using Procrustes analysis. The impact of breast position, orientation, size and intrinsic shape on the overall breast asymmetry was investigated. RESULTS: The null hypothesis was rejected. The reconstructed breast showed a significantly smaller volume when compared to the opposite side, p < 0.0001, a mean difference of 176.8 cc and 95% CI (103.5, 250.0). The shape and the position of the reconstructed breast were the main contributing factors to the measured asymmetry score. CONCLUSIONS: 3D imaging was efficient in evaluating the outcome of breast surgery. The latissimus dorsi muscle flap on its own for breast reconstruction did not restore the volume and shape of the breast fully lost due to complete mastectomy. The modification of this method and the selection of other or additional surgical techniques for breast reconstruction should be considered. The asymmetry analysis through reflection and Procrustes matching was a useful method for the objective shape analysis of the female breast and presented a new approach for breast shape assessment. The intrinsic breast shape and the positioning of the breast were major components of postoperative breast asymmetry. The reconstructed breast was smaller overall than the un-operated breast at a significant level when assessing the breast volume using the surface area. 3D imaging by multiple stereophotogrammetry was a useful tool for volume measurements, shape analysis and the evaluation of symmetry. PMID- 22525254 TI - Outcomes of 52 patients with congenital melanocytic naevi treated with UltraPulse Carbon Dioxide and Frequency Doubled Q-Switched Nd-Yag laser. AB - BACKGROUND: A variety of treatment options exist for the management of congenital melanocytic naevi (CMN). Surgical treatment has been the traditional approach. Recently, lasers have been introduced to treat CMN. This study assesses the effectiveness of UltraPulse Carbon Dioxide (UCO2) and Frequency Doubled Q Switched (FDQS) Nd-Yag laser up to a 15 year period which is the longest follow up period of any study, as far as we are aware. MATERIALS & METHODS: We performed a retrospective review of 52 patients with 314 CMN, treated with UCO2 laser and FDQS Nd-Yag laser. The reduction in visible pigmentation, signs of recurrence and any adverse skin changes were evaluated clinically by two clinicians independent to the laser operator. RESULTS: There was minimal visible pigmentation after completion of treatment in 40 patients. Treatment failure occurred in 5 patients, recurrence in 5 and partial success in 2. 5 patients developed hypertrophic scarring, 1 developed hyperpigmentation and 1 patient developed an intracranial melanoma. 87% of patients were satisfied with their treatment and in hindsight would not have chosen surgery. Mean follow-up period was 8 years (interquartile range 3-11 years). CONCLUSION: UCO2 and FDQS Nd-Yag lasers are clinically useful treatment options for patients with CMN and have minimal complications. This combined laser regime is particularly effective for the treatment of CMN in cosmetically sensitive and anatomically critical areas, especially when surgical excision may not be straight forward and/or leave unacceptable scars. PMID- 22525255 TI - Findings of computed tomography in stage IIB and IIC melanoma: a six-year retrospective study in the South-East of Scotland. AB - INTRODUCTION: Patient prognosis in malignant melanoma is directly related to clinical stage, and accurate staging is key to appropriate management. Revised BAD/BAPS (British Association of Dermatologists/British association of Plastic Surgeons) 2010 guidelines for the management of cutaneous melanoma recommend that Computed Tomography (CT) is no longer indicated for AJCC (American Joint Cancer Committee) IIB and IIC disease (Breslow thickness 2.01 - 4 mm with ulceration or >4 mm), unless the patient is symptomatic. Previous UK guidelines had recommended that all patients with AJCC IIB or worse disease should have chest, abdomen and pelvic CT as staging investigations. New guidelines also now include head CT in their recommendations. Our aim was to investigate regional CT findings in those patients diagnosed with AJCC IIB and IIC disease, and establish whether our findings affirmed new UK guidelines. METHODS AND PATIENT GROUP: A retrospective review of case notes was performed on 172 cases of AJCC IIB and IIC disease referred across Lothian, Borders and Fife to melanoma services during the period of January 2004 to January 2010. Clinical findings, results of initial and follow up CT scans along with changes in patient management were noted. Chest, abdomen and pelvic CT scan were defined as one scan as they were always performed together. CT head and CT neck were defined as separate scans. A positive CT result was defined as those reported with metastasis or an indeterminate result leading to further investigations. Change in management was defined as specific active treatment started or stopped eg surgery or chemo/radiotherapy. RESULTS: A total of 269 scans were performed on 130/172 patients. One hundred and four initial staging CT scans were performed on 75 patients, and detected one (1.3%) occult melanoma metastasis. At follow-up, 165 scans were performed in 82 patients and detected 56 metastasis in 32(39%) patients leading to a change in management in 29(35%). Two of these 32 patients had occult melanoma metastasis. Symptomatic patients had statistically significant more metastatic disease diagnosed at follow-up CT scanning than asymptomatic patients p < 0.0001. Head CT detected 15/56 (27%) of all metastasis. CONCLUSION: CT scanning should only be performed in AJCC IIB and IIC melanoma patients if symptoms of clinical metastatic disease are present. Head CT should be included in the staging process. Our regional results concur with new BAD/BAPS 2010 guidelines. PMID- 22525256 TI - Downregulation of microRNA-126 in endothelial progenitor cells from diabetes patients, impairs their functional properties, via target gene Spred-1. AB - Diabetes mellitus (DM) adversely affects the number and function of circulating endothelial progenitor cells (EPCs). Consequently, there is also a reduction in the repair mechanism of these cells, which is a critical and initiating factor in the development of diabetic vascular disease. The aim of the present study was to analyze miR expression profiles in EPCs from patients with DM and choose the most significantly regulated miR to study its possible role on EPC dysfunction and elucidate its mechanism of action. EPCs were collected from subjects with Type II DM and non-diabetic control subjects. Total RNA was harvested from EPCs, and a total of 5 candidate miRNAs were identified by microarray screening and were quantified by TaqMan real-time PCR. Lentiviral vectors expressing miR-126 and miR 126 inhibitor (anti-miR-126) were transfected into EPCs, and the EPC colony forming capacity, proliferation activity, migratory activity, differentiation capacity, and apoptotic susceptibility were determined and Western Blotting and mRNA real-time PCR analyses were performed. To study the mechanisms, lentiviral vectors expressing Spred-1 and a short interfering RNA (siRNA) targeting Spred-1 were prepared. Five miRs were aberrantly downregulated in EPCs from DM patients. These miRs included miR-126, miR-21, miR-27a, miR-27b and miR-130a. Anti-miR-126 inhibited EPC proliferation, migration, and enhanced apoptosis. Restored miR-126 expression in EPCs from DM promoted EPC proliferation, migration, and inhibited EPC apoptosis ability. Despite this, miR-126 had no effect on EPC differentiation. miR-126 overexpression significantly downregulated Spred-1 in EPCs. The knockdown of Spred-1 expression in EPCs from DM promoted proliferation, migration, and inhibited apoptosis of the cells. The signal pathway of miR-126 effecting on EPCs is partially mediated through Ras/ERK/VEGF and PI3K/Akt/eNOS regulation. This study provides the first evidence that miR-126 is downregulated in EPCs from diabetic patients, and impairs EPCs-mediated function via its target, Spred-1, and through Ras/ERK/VEGF and PI3K/Akt/eNOS signal pathway. PMID- 22525257 TI - Microfluidic mixers for studying protein folding. AB - The process by which a protein folds into its native conformation is highly relevant to biology and human health yet still poorly understood. One reason for this is that folding takes place over a wide range of timescales, from nanoseconds to seconds or longer, depending on the protein. Conventional stopped flow mixers have allowed measurement of folding kinetics starting at about 1 ms. We have recently developed a microfluidic mixer that dilutes denaturant ~100-fold in ~8 MUs. Unlike a stopped-flow mixer, this mixer operates in the laminar flow regime in which turbulence does not occur. The absence of turbulence allows precise numeric simulation of all flows within the mixer with excellent agreement to experiment. Laminar flow is achieved for Reynolds numbers Re <=100. For aqueous solutions, this requires micron scale geometries. We use a hard substrate, such as silicon or fused silica, to make channels 5-10 MUm wide and 10 MUm deep (See Figure 1). The smallest dimensions, at the entrance to the mixing region, are on the order of 1 MUm in size. The chip is sealed with a thin glass or fused silica coverslip for optical access. Typical total linear flow rates are ~1 m/s, yielding Re~10, but the protein consumption is only ~0.5 nL/s or 1.8 MUL/hr. Protein concentration depends on the detection method: For tryptophan fluorescence the typical concentration is 100 MUM (for 1 Trp/protein) and for FRET the typical concentration is ~100 nM. The folding process is initiated by rapid dilution of denaturant from 6 M to 0.06 M guanidine hydrochloride. The protein in high denaturant flows down a central channel and is met on either side at the mixing region by buffer without denaturant moving ~100 times faster (see Figure 2). This geometry causes rapid constriction of the protein flow into a narrow jet ~100 nm wide. Diffusion of the light denaturant molecules is very rapid, while diffusion of the heavy protein molecules is much slower, diffusing less than 1 MUm in 1 ms. The difference in diffusion constant of the denaturant and the protein results in rapid dilution of the denaturant from the protein stream, reducing the effective concentration of the denaturant around the protein. The protein jet flows at a constant rate down the observation channel and fluorescence of the protein during folding can be observed using a scanning confocal microscope. PMID- 22525258 TI - Experimental study for growth potential of unicellular alga Chlorella pyrenoidosa on dairy waste water: an integrated approach for treatment and biofuel production. AB - This communication presents an integrated approach to study the potential of Chlorella pyrenoidosa for treatment of dairy wastewater (DWW) and biofuel extraction. The experiment was set up in two steps. The step-1 of the experiment was designed for treatment of dairy wastewater. The physical and chemical parameters of wastewater quality such as nitrate, phosphate, chloride, fluoride, hardness, etc., were studied. The level of nitrate and phosphate known, agents of eutrophication in water bodies was reduced by 60% and 87% in influent, 49% and 83% in the effluent, respectively. The step-2 of the experiment was designed for biofuel extraction by harvesting the biomass (algal strain) grown in dairy waste water. The result of this study shows that algal strain C. pyrenoidosa is not only an agent for mitigation of pollutant load, but it can also be used as potential agent for biofuel production. PMID- 22525259 TI - Growth characteristics of Chlorella sorokiniana in airlift and bubble column photobioreactors. AB - The present study investigated the feasibility of bioCO(2) sequestration using Chlorella sorokiniana. It was found that 5% CO(2) (v/v) in air was the most suitable concentration for the growth of this organism. At this concentration, the maximum rate of CO(2) sequestered and the biomass obtained were found to be 1.21 g L(-1)d(-1) and 4.4 g L(-1) respectively. Modeling and simulation of the growth profile was obtained using the logistic equation. Further, at higher CO(2) concentrations, pH drop in the growth media, TAP [-acetate], was prevented by replacing NH(4)Cl by NaNO(3.) Additionally, the study evaluated the performance of two reactors namely: bubble column and airlift reactor based on their growth profile and transport properties like K(L)a and mixing time. The growth profile was better in airlift reactor and it provides cyclic axial mixing of media. K(L)a of downcomer was significantly lower than the riser in airlift reactor. PMID- 22525260 TI - Release characteristics of alkali and alkaline earth metallic species during biomass pyrolysis and steam gasification process. AB - Investigating the release characteristics of alkali and alkaline earth metallic species (AAEMs) is of potential interest because of AAEM's possible useful service as catalysts in biomass thermal conversion. In this study, three kinds of typical Chinese biomass were selected to pyrolyse and their chars were subsequently steam gasified in a designed quartz fixed-bed reactor to investigate the release characteristics of alkali and alkaline earth metallic species (AAEMs). The results indicate that 53-76% of alkali metal and 27-40% of alkaline earth metal release in pyrolysis process, as well as 12-34% of alkali metal and 12-16% of alkaline earth metal evaporate in char gasification process, and temperature is not the only factor to impact AAEMs emission. The releasing characteristics of AAEMs during pyrolysis and char gasification process of three kinds of biomass were discussed in this paper. PMID- 22525261 TI - Utilization of wasted sardine oil as co-substrate with pig slurry for biogas production--a pilot experience of decentralized industrial organic waste management in a Portuguese pig farm. AB - This work aimed to demonstrate in a pig farm and in real conditions, the possibilities to co-digest wasted sardine oil (WSO) and pig slurry (PS) at farm scale. A biogas mobile pilot plant, was set up in the farm and operated in real conditions during 4 months. Dynamic mesophilic (35-37 degrees C) continuous pilot trials were performed during four different periods of time. In each period a different organic loading rate (OLR) based on the chemical oxygen demand (COD) was operated sequentially, with pig slurry (PS) (OLR = 1.6 kg COD/m(3) d(-1)) and with mixtures of WSO:PS with a volumetric composition (% v/v) of 2:98 (OLR = 3.0 kg COD/m(3) d(-1)), 3:97 (OLR = 3.7 kg COD/m(3) d(-1)) and 5:95 (OLR = 5.2 kg COD/m(3) d(-1)). Biomass adapted very fast in metabolise the WSO and biogas productivity was raised substantially for different compositions of WSO:PS. Process stability indicators pH and Total volatile fatty acids/bicarbonate alkalinity (T-VFA/BA) ratio, suggests that the co-digestion process was robust. It was concluded that WSO could be easily co-digested in farm scale biogas plants. PMID- 22525262 TI - Optimizing the torrefaction of mixed softwood by response surface methodology for biomass upgrading to high energy density. AB - The optimal conditions for the torrefaction of mixed softwood were investigated by response surface methodology. This showed that the chemical composition of torrefied biomass was influenced by the severity factor of torrefaction. The lignin content in the torrefied biomass increased with the SF, while holocellulose content decreased. Similarly, the carbon content energy value of torrefied biomass ranged from 19.31 to 22.12 MJ/kg increased from 50.79 to 57.36%, while the hydrogen and oxygen contents decreased. The energy value of torrefied biomass ranged from 19.31 to 22.12 MJ/kg. This implied that the energy contained in the torrefied biomass increased by 4-19%, when compared with the untreated biomass. The energy value and weight loss in biomass slowly increased as the SF increased up until 6.12; and then dramatically increased as the SF increased further from 6.12 to 7.0. However, the energy yield started decreasing at SF value higher than 6.12; and the highest energy yield was obtained at low SF. PMID- 22525264 TI - Electron transfer capacity as a rapid and simple maturity index for compost. AB - Electron transfer capacity (ETC) of dissolved organic matter (DOM) is proposed as the maturity index to predict the composting status, based on the fact that the compositions of DOM strongly associate with the degree of decomposition. ETC, including electron accept capacity (EAC) and electron recycle rate (ERR), increases as the composting goes on, showing a close correlationship with the germination index (GI). The correlation coefficient between EAC and GI is 0.9273, and that between ERR and GI is 0.9501. The measurements of these ETC parameters require no chemical reagent preparations before analyses and can be obtained very rapidly. The results of this study indicate that these simply and rapidly obtainable ETC parameters can be potential alternatives to evaluate the composting process. PMID- 22525263 TI - Synthesis of galactooligosaccharides by CBD fusion beta-galactosidase immobilized on cellulose. AB - The beta-galactosidase gene (bgaL3) was cloned from Lactobacillus bulgaricus L3 and fused with cellulose binding domain (CBD) using pET-35b (+) vector in Escherichia coli. The resulting fusion protein (CBD-BgaL3) was directly adsorbed onto microcrystalline cellulose with a high immobilization efficiency of 61%. A gram of cellulose was found to absorb 97.6 U of enzyme in the solution containing 100mM NaCl (pH 5.8) at room temperature for 20 min. The enzymatic and transglycosylation characteristics of the immobilized CBD-BgaL3 were similar to the free form. Using the immobilized enzyme as the catalyst, the yield of galactooligosaccharides (GOS) reached a maximum of 49% (w/w) from 400 g/L lactose (pH 7.6) at 45 degrees C for 75 min, with a high productivity of 156.8 g/L/h. Reusability assay was subsequently performed under the same reaction conditions. The immobilized enzyme could retain over 85% activity after twenty batches with the GOS yields all above 40%. PMID- 22525265 TI - Hydrothermal conversion of big bluestem for bio-oil production: the effect of ecotype and planting location. AB - Three ecotypes (CKS, EKS, IL) and one cultivar (KAW) of big bluestem (Andropogon gerardii) that were planted in three locations (Hays, KS; Manhattan, KS; and Carbondale, IL) were converted to bio-oil via hydrothermal conversion. Significant differences were found in the yield and elemental composition of bio oils produced from big bluestem of different ecotypes and/or planting locations. Generally, the IL ecotype and the Carbondale, IL and Manhattan, KS planting locations gave higher bio-oil yield, which can be attributed to the higher total cellulose and hemicellulose content and/or the higher carbon but lower oxygen contents in these feedstocks. Bio-oil from the IL ecotype also had the highest carbon and lowest oxygen contents, which were not affected by the planting location. Bio-oils from big bluestem had yield, elemental composition, and chemical compounds similar to bio-oils from switchgrass and corncobs, although mass percentages of some of the compounds were slightly different. PMID- 22525266 TI - Effects of turning on the microbial consortia and the in situ temperature preferences of microorganisms in a laboratory-scale swine manure composting. AB - The effects of turning on the microbial consortia during swine manure composting were investigated. To focus on microbial migration, two types of composting runs, with and without turning, were conducted. In both cases, the material was composted in three separate reactors set at 30, 50, and 70 degrees C. For the runs with turning, the material was removed from the reactors, pooled, mixed, and redistributed daily, whereas for those without turning, the compost was agitated inside the reactors. The microbial consortia were compared by PCR-DGGE for composting without turning at different temperatures; this revealed the temperature preferences of the microorganisms, in situ--i.e., whether they were mesophilic, thermotolerant, thermophilic, or microorganisms that could adapt to a wide range of temperatures. Moreover, most of these microorganisms, except for the enteric bacteria, survived stably during composting with turning, irrespective of the temperature, and the microbial consortia became similar across the three reactors. PMID- 22525267 TI - Somatic embryogenesis receptor kinases control root development mainly via brassinosteroid-independent actions in Arabidopsis thaliana. AB - Brassinosteroids (BRs), a group of plant steroidal hormones, play critical roles in many aspects of plant growth and development. Previous studies showed that BRI1-mediated BR signaling regulates cell division and differentiation during Arabidopsis root development via interplaying with auxin and other phytohormones. Arabidopsis somatic embryogenesis receptor-like kinases (SERKs), as co-receptors of BRI1, were found to play a fundamental role in an early activation step of BR signaling pathway. Here we report a novel function of SERKs in regulating Arabidopsis root development. Genetic analyses indicated that SERKs control root growth mainly via a BR-independent pathway. Although BR signaling pathway is completely disrupted in the serk1 bak1 bkk1 triple mutant, the root growth of the triple mutant is much severely damaged than the BR deficiency or signaling null mutants. More detailed analyses indicated that the triple mutant exhibited drastically reduced expression of a number of genes critical to polar auxin transport, cell cycle, endodermis development and root meristem differentiation, which were not observed in null BR biosynthesis mutant cpd and null BR signaling mutant bri1-701. PMID- 22525268 TI - The NF2 tumor suppressor regulates microtubule-based vesicle trafficking via a novel Rac, MLK and p38(SAPK) pathway. AB - Neurofibromatosis type 2 patients develop schwannomas, meningiomas and ependymomas resulting from mutations in the tumor suppressor gene, NF2, encoding a membrane-cytoskeleton adapter protein called merlin. Merlin regulates contact inhibition of growth and controls the availability of growth factor receptors at the cell surface. We tested if microtubule-based vesicular trafficking might be a mechanism by which merlin acts. We found that schwannoma cells, containing merlin mutations and constitutive activation of the Rho/Rac family of GTPases, had decreased intracellular vesicular trafficking relative to normal human Schwann cells. In Nf2-/- mouse Schwann (SC4) cells, re-expression of merlin as well as inhibition of Rac or its effector kinases, MLK and p38(SAPK), each increased the velocity of Rab6 positive exocytic vesicles. Conversely, an activated Rac mutant decreased Rab6 vesicle velocity. Vesicle motility assays in isolated squid axoplasm further demonstrated that both mutant merlin and active Rac specifically reduce anterograde microtubule-based transport of vesicles dependent upon the activity of p38(SAPK) kinase. Taken together, our data suggest loss of merlin results in the Rac-dependent decrease of anterograde trafficking of exocytic vesicles, representing a possible mechanism controlling the concentration of growth factor receptors at the cell surface. PMID- 22525269 TI - A mouse model with T58A mutations in Myc reduces the dependence on KRas mutations and has similarities to claudin-low human breast cancer. AB - Expression of c-Myc is highly prevalent in human breast cancer and stability of the oncoprotein is regulated through Ras-regulated phosphorylation at serine 62 and threonine 58. Previous studies have illustrated the importance of accumulation of KRas mutations in Myc-mediated tumor formation. To examine Myc dependence upon Ras mutations we have generated MMTV regulated Myc and Myc T58A transgenic mice. Expression of the more stable T58A Myc allele resulted in a reduction in KRas-activating mutations. However, in a low-level expression T58A Myc transgenic, the majority of the tumors were squamous or epithelial-to mesenchymal in nature and accumulated KRas mutations at a higher frequency. Interestingly, we show that these mice develop similar gene expression patterns and signaling pathway utilization as a subtype of human claudin-low breast cancer. Indeed, our results demonstrate a clear division in human claudin-low tumors based on Myc pathway activation and target genes. Together, our results demonstrate that Myc expression and stability has critical effects on molecular heterogeneity in mouse mammary tumors that parallel subtypes of human breast cancer. PMID- 22525270 TI - A20/TNFAIP3 inhibits NF-kappaB activation induced by the Kaposi's sarcoma associated herpesvirus vFLIP oncoprotein. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) K13/vFLIP (viral Flice-inhibitory protein) induces transcription of numerous genes through NF-kappaB activation, including pro-inflammatory cytokines, which contribute to the pathogenesis of Kaposi's sarcoma (KS). In this study, we report that KSHV vFLIP induces the expression of the NF-kappaB regulatory proteins A20, ABIN-1 and ABIN-3 (A20 binding NF-kappaB inhibitors) in primary human endothelial cells, and that KS spindle cells express A20 in KS tissue. In reporter assays, A20 strongly impaired vFLIP-induced NF-kappaB activation in 293T cells, but ABIN-1 and ABIN-3 did not. Mutational analysis established that the C-terminal domain (residues 427-790) is critical for A20 modulation of NF-kappaB, but the ubiquitin-editing OTU (ovarian tumor) domain is not. In functional assays, A20 inhibited vFLIP-induced expression of the chemokine IP-10, reduced vFLIP-induced cell proliferation and increased IKK1 protein levels. Thus, we demonstrate that A20 negatively regulates NF-kappaB activation directly induced by KSHV vFLIP. By attenuating excessive and prolonged vFLIP-induced NF-kappaB activation that could be harmful to KSHV infected cells, A20 likely has an important role in the pathogenesis of KSHV associated diseases, in which vFLIP is expressed. PMID- 22525272 TI - The autophagy-associated factors DRAM1 and p62 regulate cell migration and invasion in glioblastoma stem cells. AB - The aggressiveness of glioblastoma multiforme (GBM) is defined by local invasion and resistance to therapy. Within established GBM, a subpopulation of tumor initiating cells with stem-like properties (GBM stem cells, GSCs) is believed to underlie resistance to therapy. The metabolic pathway autophagy has been implicated in the regulation of survival in GBM. However, the status of autophagy in GBM and its role in the cancer stem cell fraction is currently unclear. We found that a number of autophagy regulators are highly expressed in GBM tumors carrying a mesenchymal signature, which defines aggressiveness and invasion, and are associated with components of the MAPK pathway. This autophagy signature included the autophagy-associated genes DRAM1 and SQSTM1, which encode a key regulator of selective autophagy, p62. High levels of DRAM1 were associated with shorter overall survival in GBM patients. In GSCs, DRAM1 and SQSTM1 expression correlated with activation of MAPK and expression of the mesenchymal marker c MET. DRAM1 knockdown decreased p62 localization to autophagosomes and its autophagy-mediated degradation, thus suggesting a role for DRAM1 in p62-mediated autophagy. In contrast, autophagy induced by starvation or inhibition of mTOR/PI 3K was not affected by either DRAM1 or p62 downregulation. Functionally, DRAM1 and p62 regulate cell motility and invasion in GSCs. This was associated with alterations of energy metabolism, in particular reduced ATP and lactate levels. Taken together, these findings shed new light on the role of autophagy in GBM and reveal a novel function of the autophagy regulators DRAM1 and p62 in control of migration/invasion in cancer stem cells. PMID- 22525271 TI - PTPN14 interacts with and negatively regulates the oncogenic function of YAP. AB - The Hippo signaling pathway regulates cellular proliferation and survival, thus exerting profound effects on normal cell fate and tumorigenesis. The pivotal effector of this pathway is YAP, a transcriptional co-activator amplified in mouse and human cancers where it promotes epithelial-to-mesenchymal transition and malignant transformation. Here, we report a novel regulatory mechanism for the YAP oncogenic function via direct interaction with non-receptor tyrosine phosphatase 14 (PTPN14) through the WW domain of YAP and the PPxY domain of PTPN14. We also found that YAP is a direct substrate of PTPN14. In addition, luciferase reporter assay showed that the inhibition of the YAP transcriptional co-activator function by PTPN14 is mediated through their protein interactions and may result from an increase in the inactive cytoplasmic form of YAP. Last, knockdown of PTPN14 induces the nuclear retention of YAP and increases the YAP dependent cell migration. In summary, our results indicate a potential regulatory role of PTPN14 on YAP and demonstrate a novel mechanism in YAP regulation. PMID- 22525273 TI - Identification of a pivotal endocytosis motif in c-Met and selective modulation of HGF-dependent aggressiveness of cancer using the 16-mer endocytic peptide. AB - Since c-Met has an important role in the development of cancer, it is considered as an attractive target for cancer therapy. Although molecular mechanisms for oncogenic property of c-Met have been actively investigated, regulatory elements for c-Met endocytosis and its effect on c-Met signaling remain unclear. In this study, we identified a pivotal endocytic motif in c-Met and tested it for selective modulation of HGF-induced c-Met response. Using various chimeric constructs with the cytoplasmic tail of c-Met, we were able to demonstrate that a dileucine motif located in the C-terminus of c-Met acts to regulate its endocytosis. Synthetic peptide Ant-3S, consisting of antennapedia-derived protein transduction domain (designated as Ant) and c-Met-derived 16 amino-acids (designated as 3S, spanning amino-acids 1378 to 1393), rapidly moved into cancer cells and disrupted c-Met trafficking. Importantly, an extension of c-Met retention time on the membrane by Ant-3S peptide significantly decreased phosphorylation-dependent c-Met signal transduction. Additionally, the peptide effectively inhibited HGF-induced cell growth, scattering and migration. The underlying molecular mechanism for these observations has been investigated and revealed that the dileucine motif interacts with endocytic machinery, including adaptin beta and caveolin-1, for sustained and enhanced signal transduction. Finally, Ant-3S peptide specifically blocked internalization of interleukin-2 receptor alpha-subunit/3S chimeric protein, but not the other receptors, including Glut4, Glut8 and transferrin receptor. Such results indicate the presence of a selective endocytic assembly for c-Met. It also suggests a potential for c-Met-specific anti-cancer therapy using the identified endocytic motif in this study. PMID- 22525274 TI - ADAR2-editing activity inhibits glioblastoma growth through the modulation of the CDC14B/Skp2/p21/p27 axis. AB - Grade IV astrocytoma or glioblastoma multiforme (GBM) is one of the most aggressive and lethal tumors affecting humans. ADAR2-mediated A-to-I RNA editing, an essential post-transcriptional modification event in brain, is impaired in GBMs and astrocytoma cell lines. However, the role of ADAR2 editing in astrocytomas remains to be defined. Here, we show that ADAR2 editing rescue in astrocytomas prevents tumor growth in vivo and modulates an important cell cycle pathway involving the Skp2/p21/p27 proteins, often altered in glioblastoma. We demonstrate that ADAR2 deaminase activity is essential to inhibit tumor growth. Indeed, we identify the phosphatase CDC14B, which acts upstream of the Skp2/p21/p27 pathway, as a novel and critical ADAR2 target gene involved in glioblastoma growth. Specifically, ADAR2-mediated editing on CDC14B pre-mRNA increases its expression with a consequent reduction of the Skp2 target protein, as shown both in vitro and in vivo. We found that, compared to normal brain, both CDC14B editing and expression are progressively impaired in astrocytomas from grade I to IV, being very low in GBMs. These findings (1) demonstrate that post transcriptional A-to-I RNA editing might be crucial for glioblastoma pathogenesis, (2) identify ADAR2-editing enzyme as a novel candidate tumor suppressor gene and (3) provide proof of principle that ADAR2 or its substrates may represent a suitable target(s) for possible novel, more effective and less toxic approaches to the treatment of GBMs. PMID- 22525275 TI - Lenalidomide promotes p53 degradation by inhibiting MDM2 auto-ubiquitination in myelodysplastic syndrome with chromosome 5q deletion. AB - Allelic deletion of the RPS14 gene is a key effector of the hypoplastic anemia in patients with myelodysplastic syndrome (MDS) and chromosome 5q deletion (del(5q)). Disruption of ribosome integrity liberates free ribosomal proteins to bind to and trigger degradation of mouse double minute 2 protein (MDM2), with consequent p53 transactivation. Herein we show that p53 is overexpressed in erythroid precursors of primary bone marrow del(5q) MDS specimens accompanied by reduced cellular MDM2. More importantly, we show that lenalidomide (Len) acts to stabilize MDM2, thereby accelerating p53 degradation. Biochemical and molecular analyses showed that Len inhibits the haplodeficient protein phosphatase 2A catalytic domain alpha (PP2Acalpha) phosphatase resulting in hyperphosphorylation of inhibitory serine-166 and serine-186 residues on MDM2, and displaces binding of RPS14 to suppress MDM2 autoubiquitination whereas PP2Acalpha overexpression promotes drug resistance. Bone marrow specimens from del(5q) MDS patients resistant to Len overexpressed PP2Acalpha accompanied by restored accumulation of p53 in erythroid precursors. Our findings indicate that Len restores MDM2 functionality in the 5q- syndrome to overcome p53 activation in response to nucleolar stress, and therefore may warrant investigation in other disorders of ribosomal biogenesis. PMID- 22525276 TI - The miR-99 family regulates the DNA damage response through its target SNF2H. AB - Chromatin remodeling factors are becoming known as crucial facilitators of recruitment of repair proteins to sites of DNA damage. Multiple chromatin remodeling protein complexes are now known to be required for efficient double strand break repair. In a screen for microRNAs (miRNAs) that modulate the DNA damage response, we discovered that expression of the miR-99 family of miRNAs correlates with radiation sensitivity. These miRNAs were also transiently induced following radiation. The miRNAs target the SWI/SNF chromatin remodeling factor SNF2H/SMARCA5, a component of the ACF1 complex. We found that by reducing levels of SNF2H, miR-99a and miR-100 reduced BRCA1 localization to sites of DNA damage. Introduction of the miR-99 family of miRNAs into cells reduced the rate and overall efficiency of repair by both homologous recombination and non-homologous end joining. Finally, induction of the miR-99 family following radiation prevents an increase in SNF2H expression and reduces the recruitment of BRCA1 to the sites of DNA damage following a second dose of radiation, reducing the efficiency of repair after multiple rounds of radiation, as used in fractionated radiotherapy. PMID- 22525277 TI - Phosphodiesterase-4 promotes proliferation and angiogenesis of lung cancer by crosstalk with HIF. AB - Lung cancer is the leading cause of cancer death worldwide. Recent data suggest that cyclic nucleotide phosphodiesterases (PDEs) are relevant in various cancer pathologies. Pathophysiological role of phosphodiesterase 4 (PDE4) with possible therapeutic prospects in lung cancer was investigated. We exposed 10 different lung cancer cell lines (adenocarcinoma, squamous and large cell carcinoma) to hypoxia and assessed expression and activity of PDE4 by real-time PCR, immunocytochemistry, western blotting and PDE activity assays. Expression and activity of distinct PDE4 isoforms (PDE4A and PDE4D) increased in response to hypoxia in eight of the studied cell lines. Furthermore, we analyzed various in silico predicted hypoxia-responsive elements (p-HREs) found in in PDE4A and PDE4D genes. Performing mutation analysis of the p-HRE in luciferase reporter constructs, we identified four functional HRE sites in the PDE4A gene and two functional HRE sites in the PDE4D gene that mediated hypoxic induction of the reporter. Silencing of hypoxia-inducible factor subunits (HIF1alpha and HIF2alpha) by small interfering RNA reduced hypoxic induction of PDE4A and PDE4D. Vice versa, using a PDE4 inhibitor (PDE4i) as a cyclic adenosine monophosphate (cAMP) -elevating agent, cAMP analogs or protein kinase A (PKA)-modulating drugs and an exchange protein directly activated by cAMP (EPAC) activator, we demonstrated that PDE4-cAMP-PKA/EPAC axis enhanced HIF signaling as measured by HRE reporter gene assay, HIF and HIF target genes expression ((lactate dehydrogenase A), LDHA, (pyruvate dehydrogenase kinase 1) PDK1 and (vascular endothelial growth factor A) VEGFA). Notably, inhibition of PDE4 by PDE4i or silencing of PDE4A and PDE4D reduced human lung tumor cell proliferation and colony formation. On the other hand, overexpression of PDE4A or PDE4D increased human lung cancer proliferation. Moreover, PDE4i treatment reduced hypoxia induced VEGF secretion in human cells. In vivo, PDE4i inhibited tumor xenograft growth in nude mice by attenuating proliferation and angiogenesis. Our findings suggest that PDE4 is expressed in lung cancer, crosstalks with HIF signaling and promotes lung cancer progression. Thus, PDE4 may represent a therapeutic target for lung cancer therapy. PMID- 22525278 TI - Multidrug-resistant cells overexpressing P-glycoprotein are susceptible to DNA crosslinking agents due to attenuated Src/nuclear EGFR cascade-activated DNA repair activity. AB - We synthesized several novel bifunctional alkylating derivatives of 3a-aza cyclopenta[a]indene (BO-1012, BO-1005, BO-1099 and BO-1101) that are potent DNA interstrand crosslinking agents. In in vitro cytotoxicity assay, these compounds were more cytotoxic to multidrug-resistant (MDR) cells, such as KBvin10, KBtax50 and CEM/VBL, than their parental cells. Using a xenograft model, BO-1012, at a dose of 5 mg/kg, partially suppressed the growth of parental KB cells but completely suppressed the growth of KBvin10 cells in nude mice. In exploring the possible mechanism, we found that DNA double-strand break (DSB) repair activity in MDR cells, KBvin10 and CEM/VBL, was significantly reduced compared with their parental cells, KB and CEM. Reduced DSB repair activity in KBvin10 cells was likely due to a defect in nuclear translocation of DNA-dependent protein kinase (DNA-PK), a component of the non-homologous end-joining repair machinery. Furthermore, BO-1012-induced DNA-PK translocation from the cytosol into the nucleus in KB cells is associated with the activation of the Src/nuclear epidermal growth factor receptor (EGFR) cascade, which is defective in MDR cells. As knockdown of P-glycoprotein (P-gp) by siRNA reactivated the Src/nuclear EGFR cascade, DNA-PK translocation and DNA repair activity in MDR cells, overexpression of P-gp attenuates the activity of DNA DSB repair through suppression of Src/nuclear EGFR cascade. Therefore, DNA interstrand crosslinking agents may have potential therapeutic use against P-gp-overexpressing MDR cells. PMID- 22525279 TI - Waterpipe tobacco and cigarette smoking among university students in Jordan. AB - SETTING: While waterpipe and cigarette smoking have been well studied in Syria and Lebanon, data from Jordan are limited. OBJECTIVES: To characterize the relative prevalence of waterpipe tobacco and cigarette smoking among university students in Jordan, and to compare the demographic and environmental factors associated with each form of tobacco use. DESIGN: We surveyed 1845 students randomly recruited from four universities in Jordan. We used multivariable logistic regression controlling for clustering of individuals within universities to determine associations between demographic and environmental covariates and waterpipe tobacco and cigarette use. RESULTS: Waterpipe tobacco smoking rates were 30% in the past 30 days and 56% ever, while cigarette smoking rates were 29% in the past 30 days and 57% ever. Past 30-day waterpipe tobacco smoking rates were 59% for males and 13% for females. Females had substantially lower odds than males of being current waterpipe (OR 0.12, 95%CI 0.10-0.15) or cigarette (OR 0.08, 95%CI 0.05-0.14) smokers. Current cigarette smoking was more significantly associated with markers of high socio-economic status (SES) than waterpipe tobacco smoking. CONCLUSION: Waterpipe tobacco smoking is as common as cigarette smoking among Jordanian university students. While cigarette smoking is consistently associated with high SES, waterpipe tobacco smoking is more evenly distributed across various populations. PMID- 22525280 TI - Evidence that the serotonin transporter does not shift into the cytosol of remaining neurons after neonatal brain injury. AB - Following neonatal hypoxia-ischemia (HI) serotonin (5-hydroxytryptamine, 5-HT) levels are decreased in the brain. The regulation of brain 5-HT is dependent on the serotonin transporter (SERT) localised at the neuronal pre-synaptic cell membrane. However SERT can also traffic away from the cell membrane into the cytosol and, after injury, may contribute to the cell's inability to maintain 5 HT levels. Whether this occurs after neonatal HI brain injury is not known. In addition, there is contradictory evidence that glial cells may also contribute to the clearance of 5-HT in the brain. Using a postnatal day 3 (P3) HI rat pup model (right carotid ligation+30 min 6% O(2)), we found, in both control and P3 HI animals, that SERT is retained on the cell membrane and is not internalised in the cytosol. In addition, SERT was only detected on neurons. We found no evidence of SERT co-localisation on microglia or astrocytes. We conclude that neuronal SERT is the primary regulator of synaptic 5-HT availability in the intact and P3 HI-injured neonatal brain. Furthermore, since concomitant reductions in 5-HT, SERT and serotonergic neurons occur after neonatal HI, it is plausible that the decrease in brain 5-HT is a consequence of SERT being lost as neurons degenerate as opposed to remaining neurons internalising SERT or clearance by glial cells. PMID- 22525281 TI - Memory-based pre-attentive auditory N1 elicited by sound movement. AB - Quickly detecting changes in the surrounding environment is one of the most important functions of sensory processing. Comparison of a new event with preceding sensory conditions is necessary for the change-detection process. A sudden change in a continuous sound elicits auditory evoked potentials that peak approximately 100 ms after the onset of the change (Change-N1). In the present study, we recorded Change-N1 under an oddball paradigm in 19 healthy subjects using an abruptly moving sound (SM-stimulus) as a deviant stimulus and investigated effects of the probability of the SM-stimulus to reveal whether Change-N1 is a memory-based response. We compared the amplitude and latency of Change-N1 elicited by the SM-stimulus among three probability conditions (33, 50 and 100%). As the probability of the SM-stimulus decreased, the amplitude of Change-N1 increased and its latency decreased. The present results indicate that the preceding sensory history affects Change-N1 elicited by the SM-stimulus. PMID- 22525282 TI - A forever legacy from the legendary Jeanne Quint Benoliel, PhD, RN, FAAN. PMID- 22525283 TI - Cancer nurse as cancer survivor. PMID- 22525284 TI - Retrospective analysis of the effect of postoperative analgesia on survival in patients after laparoscopic resection of colorectal cancer. AB - BACKGROUND: Surgical excision of colorectal cancer can reduce immune function during the postoperative period, which may affect long-term survival. There is evidence that regional analgesia may attenuate the immunosuppressive effect of surgery. Opioid analgesia also suppresses cell-mediated immunity, notably natural killer cell activity. Therefore, using either epidural or spinal analgesia rather than systemic opioids during the postoperative period could affect long-term survival and disease recurrence. METHODS: A retrospective analysis of a prospective database of all patients undergoing laparoscopic colorectal resection for adenocarcinoma between October 2003 and December 2010 was performed. Patients received either an epidural, spinal block, or a morphine patient-controlled analgesia (PCA) for their primary postoperative analgesia. Overall survival and disease-free survival were analysed. RESULTS: A total of 457 laparoscopic colorectal resections were performed during the period analysed; 424 cases were suitable for analysis (epidural=107, spinal=144, and PCA=173). There was no significant difference between the groups for age, gender, conversion rate, operation performed, TNM stage, tumour differentiation, extramural venous, or lymphovascular invasion. The epidural group had significantly more ASA category III patients (P=0.006). The median length of stay was significantly longer in the epidural group at 5 days compared with 3 days for spinal and PCA (P<0.0005). There was no significant difference in overall survival (P=0.622) or disease-free survival (P=0.490) at 5 yr between the groups. CONCLUSIONS: In this study, there appears to be no significant advantage to be gained in overall or disease-free survival with the use of regional analgesia compared with opioid analgesia after laparoscopic colorectal resection. PMID- 22525285 TI - The complex challenges of administrative research for the future. PMID- 22525286 TI - Strategy as solution: developing a nursing strategic plan. AB - This month, the Executive Director of the American Nurses Credentialing Center provides a look at the importance of having a nursing strategic plan especially when working to create a research agenda. PMID- 22525287 TI - CGEAN position statement on the educational preparation of nurse executives and nurse managers. PMID- 22525288 TI - Measuring actual scope of nursing practice: a new tool for nurse leaders. AB - OBJECTIVE: : This project describes the development and testing of the actual scope of nursing practice questionnaire. BACKGROUND: : Underutilization of the skill sets of registered nurses (RNs) is a widespread concern. Cost-effective, safe, and efficient care requires support by management to facilitate the implementation of nursing practice at the full scope. METHODS: : Literature review, expert consultation, and face validity testing were used in item development. The instrument was tested with 285 nurses in 22 medical units in 11 hospitals in Canada. RESULTS: : The 26-item, 6-dimension questionnaire demonstrated validity and reliability. The responses suggest that nurses practice at less than their optimal scope, with key dimensions of professional practice being implemented infrequently. CONCLUSIONS: : This instrument can help nurse leaders increase the effective use of RN time in carrying out the full scope of their professional practice. PMID- 22525289 TI - Destination bedside: using research findings to visualize optimal unit layouts and health information technology in support of bedside care. AB - This study explored the impact of unit design and healthcare information technology (HIT) on nursing workflow and patient-centered care (PCC). Healthcare information technology and unit layout-related predictors of nursing workflow and PCC were measured during a 3-phase study involving questionnaires and work sampling methods. Stepwise multiple linear regressions demonstrated several HIT and unit layout-related factors that impact nursing workflow and PCC. PMID- 22525290 TI - A multi-instrument evaluation of the professional practice environment. AB - This study identified organizational characteristics that are highly correlated with the work satisfaction of RNs using 2 practice environment measurement tools. In the sample, the organizational characteristics of autonomy, control over practice, and internal work motivation are critical to RNs' sense of work satisfaction. As care redesign efforts ensue, the need to preserve and strengthen the professional practice environment remains a priority for nurse executives. PMID- 22525291 TI - Factors affecting nurse retention at an academic Magnet(r) hospital. AB - OBJECTIVE: : The aim of this study was to examine the factors affecting the retention of registered nurses (RNs) and validate the revised Casey-Fink Nurse Retention Survey (2009). BACKGROUND: : Creating an organizational culture of retention may reduce nurse turnover. Focusing on why nurses leave and identifying factors why nurses stay are essential. METHODS: : A descriptive survey design gathered data from RNs with 1 or more years of experience providing direct patient care and employed in inpatient/ambulatory settings in an acute care, academic, Magnet hospital. CONCLUSIONS: : There were no statistically significant relationships between nurse respondents' perceptions of work environment/support/encouragement and age or years of experience. However, there were significant differences between inpatient and ambulatory nurse responses in several key areas including job satisfaction, mentorship, and educational support. Overall, nurses reported feeling a lack of support and recognition from managers. Results provide evidence to support improved strategies to foster nurse retention. PMID- 22525292 TI - Stress ratings and health promotion practices among RNs: a case for action. AB - OBJECTIVE: : The objective of this study was to investigate associations between RN perceptions of their stress levels, health-promoting behaviors, and associated demographic variables. BACKGROUND: : Stress and burnout are occupational hazards resulting in absenteeism, illness, and staff turnover, factors important to nurse administrators. Personal health behaviors among nurses have been linked to less stress and the delivery of health-promotion teaching. METHOD: : An electronic survey with 2 standardized measures and demographic questions was completed by 2,247 staff nurses from a large Midwestern academic medical center. FINDINGS: : Stress levels were inversely correlated with overall health-promoting behavior scores. Outside caregiver responsibilities were associated with higher stress and lower health-promoting behaviors scores. CONCLUSIONS: : Findings support work site interventions that promote nurses' health and wellness, reduce work and home stress, and influence positive patient care and outcomes. PMID- 22525293 TI - Designing strategies to implement research-based policies and procedures: a set of recommendations for nurse leaders based on the PARiHS framework. AB - Organizational policies and procedures are one vehicle for translating research into nursing practice and improving quality and patient and organizational outcomes. However, their existence alone is not sufficient to ensure use. In this article, we describe the Promoting Action on Research Implementation in Health Services framework and how nurse leaders can use the framework to support the implementation of research-based policies and procedures. PMID- 22525294 TI - Mono-(2-ethylhexyl) phthalate affects the steroidogenesis in rat Leydig cells through provoking ROS perturbation. AB - Di-2-ethylhexyl phthalate (DEHP), one of the most widely used plasticizers in a number of day-life products, exerts both short-term and long-lasting effects on testicular steroidogenesis during in utero exposure. These actions might be caused by its primary metabolite, mono-(2-ethylhexyl) phthalate (MEHP). In the present study, we investigated the effects of MEHP on steroidogenesis of different stages of rat Leydig cells, progenitor (PLCs), immature (ILCs) and adult (ALCs). Results showed that MEHP affected reactive oxygen species (ROS) generation as well as androgen production in ALCs, but not in PLCs and ILCs, which coincided with hydrogen peroxide (H(2)O(2)). Low concentrations of MEHP (20 200MUM) provoked ROS perturbation and caused the stimulation of steroidogenic acute regulatory (StAR), cytochrome P450 side-chain cleavage (P450scc), 3beta hydroxysteroid dehydrogenases (3beta-HSD) and 17beta-hydroxysteroid dehydrogenases (17beta-HSD) activities which elevated T production of ALCs. Contrast to the effect in low doses, high levels of MEHP (2000MUM and over) induced overloaded oxidative stress and inhibited steroidogenesis by reducing the activities of these enzymes in ALCs. These results indicated that oxidative stress and subsequent steroidogenic enzymes changes in ALCs were the potential underlying mechanism of the biphasic effects of DEHP on androgen production. PMID- 22525295 TI - Evaluating biotoxicity with fibroblasts derived from human embryonic stem cells. AB - To investigate the use of differentiated fibroblasts from human embryonic stem cells as a cellular model for cytotoxicity and genotoxicity screening. The EBf-H9 cells were derived from human embryonic stem cells (H9) via embryonic body (EB) and treated with Sodium fluoride (NaF) and Formaldehyde (FA). Proliferation, specific gene and protein expression and karyotype of cells were analyzed by MTT assay, RT-PCR, immunocytochemistry and karyotype analysis, respectively. Cytotoxicity was detected by MTT assay and flow cytometry, and genotoxicity was studied by micronucleus test (MNT), sister chromatid exchange (SCE) and comet assay. EBf-H9s were spindle-shaped with a diploid karyotype. They expressed the fibroblast markers prolyl 4-hydroxylase beta and vimentin but did not express Oct 4 and Sox-2, and decreased expression of Nanog. The proliferation of EBf-H9 and murine L929 cells was inhibited by sodium fluoride (NaF) and formaldehyde (FA), and the cell cycle was arrested in different phases with the treatments. In genotoxicity assays with NaF and FA, positive responses were detected in human EBf-H9s comparable to those in the murine L929 cell line. EBf-H9 may be a suitable new cell source for toxicity research on biomaterials and other agents. PMID- 22525296 TI - A rare confounder in a case of ovarian torsion. PMID- 22525297 TI - A potency of plasminogen activation system in long-term prognosis of endometrial cancer: a pilot study. AB - OBJECTIVE: Plasminogen activators released from cancer cells lead to degradation of basement membrane proteins and extracellular matrix, and facilitate cancer cell invasion into surrounding tissues and the blood stream. The aim of this study was to evaluate a complex tissue immunohistochemical expression of the plasminogen activation system--urokinase-type plasminogen activator (uPA) and its receptor (uPAR), tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor (PAI)-1--in endometrial cancer, and to correlate obtained results with disease progression and course. STUDY DESIGN: The study group was composed of 100 patients classified in three sub-groups according to the FIGO 2010 tumour stratification (G1=70, G2=19, G3=11). Expression of uPA, tPA, uPAR and PAI-1 was examined by means of immunohistochemical staining. RESULTS: Immunohistochemical expressions of all the studied markers did not differ between G1 and G2 patients. However, G3 subjects were found to have a significantly lower expression of uPA, PAI-1 and tPA. In addition, the patients who survived were found to be PAI-1 negative, while study participants with an unfavourable disease course were PAI-1 positive. CONCLUSIONS: A significantly higher immunohistochemical expression of PAI-1 was found to correlate with shorter relapse-free and overall survival in patients classified as stages IB and II of endometrial cancer. PMID- 22525298 TI - Two type I crustacean hyperglycemic hormone (CHH) genes in Morotoge shrimp (Pandalopsis japonica): cloning and expression of eyestalk and pericardial organ isoforms produced by alternative splicing and a novel type I CHH with predicted structure shared with type II CHH peptides. AB - Crustacean hyperglycemic hormone (CHH) peptide family members play critical roles in growth and reproduction in decapods. Three cDNAs encoding CHH family members (Pj-CHH1ES, Pj-CHH1PO, and Pj-CHH2) were isolated by a combination of bioinformatic analysis and conventional cloning strategies. Pj-CHH1ES and Pj CHH1PO were products of the same gene that were generated by alternative mRNA splicing, whereas Pj-CHH2 was the product of a second gene. The Pj-CHH1 and Pj CHH2 genes had four exons and three introns, suggesting the two genes arose from gene duplication. The three cDNAs were classified in the type I CHH subfamily, as the deduced amino acid sequences had a CHH precursor-related peptide sequence positioned between the N-terminal signal sequence and C-terminal mature peptide sequence. The Pj-CHH1ES isoform was expressed at a higher level in the eyestalk X organ/sinus gland (XO/SG) complex and at a lower level in the gill. The Pj-CHH1PO isoform was expressed at higher levels in the XO/SG complex, brain, abdominal ganglion, and thoracic ganglion and at a lower level in the epidermis. Pj-CHH2 was expressed at a higher level in the thoracic ganglion and at a lower level in the gill. Real-time polymerase chain reaction was used to quantify the effects of eyestalk ablation on the mRNA levels of the three Pj-CHHs in the brain, thoracic ganglion, and gill. Eyestalk ablation reduced expression of Pj-CHH1ES in the brain and Pj-CHH1PO and Pj-CHH2 in the thoracic ganglion. Sequence alignment of the Pj-CHHs with CHHs from other species indicated that Pj-CHH2 had an additional alanine at position #9 of the mature peptide. Molecular modeling showed that the Pj-CHH2 mature peptide had a short alpha helix (alpha1) in the N-terminal region, which is characteristic of type II CHHs. This suggests that Pj-CHH2 differs in function from other type I CHHs. PMID- 22525299 TI - Characterization and expression analysis of phospholipid hydroperoxide glutathione peroxidase cDNA from Chironomus riparius on exposure to cadmium. AB - Phospholipid-hydroperoxide glutathione peroxidase (PHGPx) is an antioxidant enzyme in the glutathione peroxidases (GPx) family that reduces hydroperoxides of phospholipids and maintains the integrity of biomembranes. Here, we report the identification and characterization of a full length cDNA of PHGPx from the ecotoxicologically important aquatic midge Chironomus riparius (CrPHGPx1) from the Expressed Sequence Tags (ESTs) database generated through pyrosequencing. The 837 base pair (bp) cDNA contained an open reading frame of 597 bp, and a 75 bp 5' and a 159 bp 3'untranslated region. The theoretical molecular mass of the deduced amino acid (aa) sequence (197 aa) was 22.40 kDa with an estimated pI of 8.77. The Cys-codon was present at residue 74 and also the active site residues Gln(91) and Trp(164). The active-site motifs and GPx family signature motifs LAFPCNQF(101 108) and WNFTK(163-168) were also found. Phylogenetic analysis showed that CrPHGPx1 is grouped with PHGPx1 from other species and is more closely related to insects belonging to the dipteran order. The mRNA of CrPHGPx1 was detected in larvae, pupae and adults. The expression of CrPHGPx1 is induced by cadmium exposure indicating that the mRNA expression of CrPHGPx1 is differently regulated in response to oxidative stress caused by environmental stressors. PMID- 22525300 TI - Hypoxia-inducible factors: crosstalk between inflammation and metabolism. AB - Hypoxia-inducible factors (HIFs) are oxygen-sensitive transcription factors that allow adaptation to hypoxic environments. HIFs function in the cellular response to stress: metabolic, hypoxic, or inflammatory. Metabolic changes occur during tumorigenesis that are, in part, under hypoxia and HIF regulation. Additionally, inflammatory signaling and infiltration secondary to hypoxia are clear drivers of tumor progression. HIF-1alpha and HIF-2alpha have opposing and occasionally overlapping roles in both tumor cells and inflammatory cells within the tumor microenvironment and crosstalk between these populations has clear effects on tumor metabolism, inflammation, and progression. It is becoming increasingly apparent that HIFs are one common link between hypoxia, chronic inflammation, metabolic adaptation, and tumor progression through its function in macrophages during cancer development. PMID- 22525302 TI - [Which platform to support a personalized lung cancer treatment?]. AB - Considerable progress has been achieved in the understanding of lung cancer biology. Molecular driver mutations have been identified and different targeted therapies have been developed. Thus, the management of small size biopsies is essential and needs a strong collaboration between the different medical partners, particularly pulmonologist, pathologist, molecular biologist and oncologist. The aim is to optimise histological and molecular analyses allowing patients access to novel biotherapies. The French National Cancer Institute set up platforms for molecular genetics at university hospitals with expertise in molecular and pathological analysis. Mutational status of EGFR is analyzed routinely in non-small lung cancer. Treatment with EGFR inhibitors as first line therapy is limited to lung cancer patients harboring an EGFR mutation. More recently, ALK rearrangements have been identified as a rare driver mutation in lung cancer. Crizotinib, an ALK inhibitor is a new therapeutic standard in ALK rearranged tumors. Other biomarkers as RAS, BRAF, HER2 or PIK3CA have potential clinical relevance with possible approval of novel tailored treatment and will be discussed in this report. The project "BIOMARQUEURS France" will underscore the results of the French platform of more than 15 000 French patients. PMID- 22525303 TI - Update on the management and treatment of hepatitis C virus infection: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program Office. AB - Chronic hepatitis C virus (HCV) infection affects approximately 1.3 % of the United States population and 4 % of veterans who use Department of Veterans Affairs medical services. Chronic HCV is the primary cause of cirrhosis, hepatocellular carcinoma (HCC), and end-stage liver disease requiring liver transplantation in the United States. Management of chronic HCV is aimed at halting disease progression, preventing cirrhosis decompensation, reducing the risk of HCC, and treating extrahepatic complications of the infection. As part of a comprehensive HCV management strategy, peginterferon alfa and ribavirin, along with the addition of a hepatitis C protease inhibitor therapy for many genotype 1 infected patients, are the current standard of care. Antiviral therapy should be provided to those individuals who are clinically stable, have moderate liver disease or compensated cirrhosis, and are motivated to pursue therapy. Many patients have comorbid medical and psychiatric conditions, which may affect their adherence to antiviral therapy or worsen while on antiviral therapy. To optimally manage hepatitis C and associated comorbidities, patients benefit from multidisciplinary teams that can provide HCV-specific care and treatment. Sustained virologic response is associated with "cure" of chronic HCV, and results in improved liver disease outcomes and prolonged survival. PMID- 22525304 TI - Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis. AB - OBJECTIVES: Several studies have raised concern regarding the possible association between proton-pump inhibitors (PPIs) and Clostridium difficile infection (CDI). We aimed to perform a systematic review of incident and recurrent CDI in PPI users, and to evaluate the relative impact of concurrent antibiotic use, or switching acid suppression to histamine-2-receptor antagonists (H2RAs). METHODS: We searched MEDLINE and EMBASE from inception to December 2011 for controlled observational studies that reported on the risk of CDI with and without PPI use. We performed random effects meta-analysis and assessed statistical heterogeneity using the I(2) statistic. RESULTS: We included 42 observational studies (30 case-control, 12 cohort) totalling 313,000 participants overall. Pooled analysis of 39 studies showed a statistically significant association between PPI use and risk of developing CDI, odds ratio (OR) 1.74 (95% confidence interval (CI) 1.47-2.85, P<0.001, I(2)=85%) compared with non-users. A pooled analysis of three studies showed a significant associated risk of recurrent CDI associated with PPIs, OR 2.51 (95% CI 1.16-5.44, P=0.005, I(2)=78%). Subgroup analysis failed to fully clarify the source of the substantial statistical heterogeneity. Adjusted indirect comparison demonstrated that use of H2RAs as an alternative carried a lower-risk OR 0.71 (95% CI 0.53 0.97) compared with PPIs. Conversely, concomitant use of PPI and antibiotics conferred a greater-risk OR 1.96 (95% CI 1.03-3.70) above that of PPIs alone. For PPI and antibiotics, the Rothman's synergy index was 1.36 and attributable proportion of risk from interaction 0.19, indicating an increased risk from interaction beyond the effects of each drug alone. CONCLUSIONS: Despite the substantial statistical and clinical heterogeneity, our findings indicate a probable association between PPI use and incident and recurrent CDI. This risk is further increased by concomitant use of antibiotics and PPI, whereas H2RAs may be less harmful. PMID- 22525305 TI - Cancer risks for relatives of patients with serrated polyposis. AB - OBJECTIVES: Serrated polyposis (hyperplastic polyposis) is characterized by multiple polyps with serrated architecture in the colorectum. Although patients with serrated polyposis are known to be at increased risk of colorectal cancer (CRC) and possibly extracolonic cancers, cancer risk for their relatives has not been widely explored. The aim of this study was to estimate the risks of CRC and extracolonic cancers for relatives of patients with serrated polyposis. METHODS: A cohort of the 1,639 first- and second-degree relatives of 100 index patients with serrated polyposis recruited regardless of a family history of polyps or cancer from genetic clinics in Australia, New Zealand, Canada, and the USA, were retrospectively analyzed to estimate the country-, age-, and sex-specific standardized incidence ratios (SIRs) for relatives compared with the general population. RESULTS: A total of 102 CRCs were observed in first- and second relatives (SIR 2.25, 95% confidence interval (CI) 1.75-2.93; P<0.001), with 54 in first-degree relatives (SIR 5.16, 95% CI 3.70-7.30; P<0.001) and 48 in second degree relatives (SIR 1.38, 95% CI 1.01-1.91; P=0.04). Six pancreatic cancers were observed in first-degree relatives (SIR 3.64, 95% CI 1.70-9.21; P=0.003). There was no statistical evidence of increased risk for cancer of the stomach, brain, breast, or prostate. CONCLUSIONS: Our finding that relatives of serrated polyposis patients are at significantly increased risk of colorectal and pancreatic cancer adds to the accumulating evidence that serrated polyposis has an inherited component. PMID- 22525307 TI - Exposure to lead in water and cysteine non-oxidative metabolism in Pelophylax ridibundus tissues. AB - Chronic, low-level exposure to metals is an increasing global problem. Lead is an environmentally persistent toxin that causes many lead-related pathologies, directly affects tissues and cellular components or exerts an effect of the generation of reactive oxygen species causing a diminished level of available sulfhydryl antioxidant reserves. Cysteine is one of substrates in the synthesis of glutathione - the most important cellular antioxidant, and it may also undergo non-oxidative desulfuration that produces compounds containing sulfane sulfur atoms. The aim of the experiment was to examine changes of the non-oxidative metabolism of cysteine and the levels of cysteine and glutathione in the kidneys, heart, brain, liver and muscle of Marsh frogs (Pelophylax ridibundus) exposed to 28mg/L Pb(NO(3))(2) for 10 days. The activities of sulfurtransferases, enzymes related to the sulfane sulfur metabolism - 3-mercaptopyruvate sulfurtransfearse, gamma-cystathionase and rhodanese - were detected in tissue homogenates. The activity of sulfurtransferases was much higher in the kidneys of frogs exposed to lead in comparison to control frogs, not exposed to lead. The level of sulfane sulfur remained unchanged. Similarly, the total level of cysteine did not change significantly. The total levels of glutathione and the cysteine/cystine and GSH/GSSG ratios were elevated. Thus, it seems that the exposure to lead intensified the metabolism of sulfane sulfur and glutathione synthesis in the kidneys. The results presented in this work not only confirm the participation of GSH in the detoxification of lead ions and/or products appearing in response to their presence, such as reactive oxygen species, but also indicate the involvement of sulfane sulfur and rhodanese in this process (e.g. brain). As long as the expression of enzymatic proteins (rhodanese, MPST and CST) is not examined, no answer will be provided to the question whether changes in their activity are due to differences in the concentrations of substrates and/or compounds affecting their activity or to changes in their level in response to some parameters, e.g. associated with oxidative stress. PMID- 22525306 TI - Incidence of post-infectious irritable bowel syndrome and functional intestinal disorders following a water-borne viral gastroenteritis outbreak. AB - OBJECTIVES: Post-infectious irritable bowel syndrome (PI-IBS) may develop in 4 31% of affected patients following bacterial gastroenteritis (GE), but limited information is available on long-term outcome of viral GE. During summer 2009, a massive outbreak of viral GE associated with contamination of municipal drinking water (Norovirus) occurred in San Felice del Benaco (Lake Garda, Italy). To investigate the natural history of a community outbreak of viral GE, and to assess the incidence of PI-IBS and functional gastrointestinal disorders, we carried out a prospective population-based cohort study with a control group. METHODS: Baseline questionnaires were administered to the resident community within 1 month of the outbreak. Follow-up questionnaires of the Italian version of Gastrointestinal Symptom Rating Scale (GSRS, a 15-item survey scored according to a 7-point Likert scale) were mailed to all patients responding to baseline questionnaire at 3 and 6 months, and to a cohort of unaffected controls, living in the same geographical area, at 6 months after the outbreak. The GSRS item were grouped in five dimensions: abdominal pain, reflux, indigestion, diarrhea, and constipation. At month 12, all patients and controls were interviewed by a health assistant to verify Rome III criteria of IBS. Student's t-test and chi(2)- or Fisher's exact test were used as appropriate. RESULTS: Baseline questionnaires were returned by 348 patients: mean age +/- s.d. 45 +/- 22 years, 53% female. At outbreak, nausea (scored >=4), vomiting, and diarrhea lasting 2-3 days or more were reported by 66, 60, and 77% of patients, respectively. A total of 50% reported fever and 19% reported weight loss (mean 3 kg). Follow-up surveys were returned at month 6 by 186 patients and 198 controls: mean GSRS score was significantly higher in patients than in controls for abdominal pain, diarrhea, and constipation. At month 12, we identified 40 patients with a new diagnosis of IBS (Rome III criteria), in comparison with 3 subjects in the control cohort (P<0.0001; odds ratio 11.40; 95% confidence intervals 3.44-37.82). The 40 cases of PI-IBS were subtyped according to the predominant stool pattern as follows: 4 IBS with constipation, 7 IBS with diarrhea, 16 with mixed IBS, and 13 with unsubtyped IBS. CONCLUSIONS: Our study provides evidence that Norovirus GE leads to the development of PI-IBS in a substantial proportion of patients (13%), similar to that reported after bacterial GE. PMID- 22525308 TI - Explanatory power does not equal clinical importance: study of the use of the Brief ICF Core Sets for Spinal Cord Injury with a purely statistical approach. AB - STUDY DESIGN: Psychometric study analyzing the data of a cross-sectional, multicentric study with 1048 persons with spinal cord injury (SCI). OBJECTIVE: To shed light on how to apply the Brief Core Sets for SCI of the International Classification of Functioning, Disability and Health (ICF) by determining whether the ICF categories contained in the Core Sets capture differences in overall health. METHODS: Lasso regression was applied using overall health, rated by the patients and health professionals, as dependent variables and the ICF categories of the Comprehensive ICF Core Sets for SCI as independent variables. RESULTS: The ICF categories that best capture differences in overall health refer to areas of life such as self-care, relationships, economic self-sufficiency and community life. Only about 25% of the ICF categories of the Brief ICF Core Sets for the early post-acute and for long-term contexts were selected in the Lasso regression and differentiate, therefore, among levels of overall health. CONCLUSION: ICF categories such as d570 Looking after one's health, d870 Economic self sufficiency, d620 Acquisition of goods and services and d910 Community life, which capture changes in overall health in patients with SCI, should be considered in addition to those of the Brief ICF Core Sets in clinical and epidemiological studies in persons with SCI. PMID- 22525311 TI - Epidemiology of traumatic cervical spinal cord injury in Tianjin, China. AB - STUDY DESIGN: A retrospective epidemiological study. OBJECTIVE: To describe the recent epidemiological characteristics of traumatic cervical spinal cord injury (TCSCI) in adults in Tianjin. SETTING: Tianjin Medical University General Hospital. METHODS: This study included all TCSCI patients aged >= 15 years who were admitted to a general hospital from December 2008 to November 2011. Epidemiological characteristics including gender, age, marital status, occupation, etiology, level of injury, severity and America Spinal Injury Association (ASIA) impairment scale were recorded. RESULTS: A total of 143 patients with TCSCI were included in the study. Mean age was 54.6 +/- 14.6 years (men 53.5 +/- 14.9 years, women 54.2 +/- 12.1 years), with a range of 18-87 years, and the male/female ratio was 5:1. The leading cause was falls (49.7%), followed by motor vehicle accidents (36.4%). The most common injury site was C5, accounting for 42%. In all, 74 (51.7%) patients had complications; the most common complication was hyponatremia (30.1%), followed by urinary infection (23.1%), respiratory infection (18.2%), bedsore (9.8%) and deep venous thrombosis (4.9%). As for the severity, ASIA grade D was encountered most frequently. Six patients died, five of whom died from respiratory failure. CONCLUSION: The epidemiology of TCSCI has its own characteristics. Falls were the leading causes, and TCSCI occurred most frequently in the middle-aged and elders. Therefore, establishing public policies aimed at preventing injuries should focus on falls and more attention should be paid to the aged regarding their vulnerability to low fall. Additionally, complications should be prevented in TCSCI patients. PMID- 22525310 TI - Autologous incubated macrophage therapy in acute, complete spinal cord injury: results of the phase 2 randomized controlled multicenter trial. AB - STUDY DESIGN: Randomized controlled trial with single-blinded primary outcome assessment. OBJECTIVES: To determine the efficacy and safety of autologous incubated macrophage treatment for improving neurological outcome in patients with acute, complete spinal cord injury (SCI). SETTING: Six SCI treatment centers in the United States and Israel. METHODS: Participants with traumatic complete SCI between C5 motor and T11 neurological levels who could receive macrophage therapy within 14 days of injury were randomly assigned in a 2:1 ratio to the treatment (autologous incubated macrophages) or control (standard of care) groups. Treatment group participants underwent macrophage injection into the caudal boundary of the SCI. The primary outcome measure was American Spinal Injury Association (ASIA) Impairment Scale (AIS) A-B or better at >=6 months. Safety was assessed by analysis of adverse events (AEs). RESULTS: Of 43 participants (26 treatment, 17 control) having sufficient data for efficacy analysis, AIS A to B or better conversion was experienced by 7 treatment and 10 control participants; AIS A to C conversion was experienced by 2 treatment and 2 control participants. The primary outcome analysis for subjects with at least 6 months follow-up showed a trend favoring the control group that did not achieve statistical significance (P=0.053). The mean number of AEs reported per participant was not significantly different between the groups (P=0.942). CONCLUSION: The analysis failed to show a significant difference in primary outcome between the two groups. The study results do not support treatment of acute complete SCI with autologous incubated macrophage therapy as specified in this protocol. PMID- 22525312 TI - Predicted errors in children's early sentence comprehension. AB - Children use syntax to interpret sentences and learn verbs; this is syntactic bootstrapping. The structure-mapping account of early syntactic bootstrapping proposes that a partial representation of sentence structure, the set of nouns occurring with the verb, guides initial interpretation and provides an abstract format for new learning. This account predicts early successes, but also telltale errors: Toddlers should be unable to tell transitive sentences from other sentences containing two nouns. In testing this prediction, we capitalized on evidence that 21-month-olds use what they have learned about noun order in English sentences to understand new transitive verbs. In two experiments, 21 month-olds applied this noun-order knowledge to two-noun intransitive sentences, mistakenly assigning different interpretations to "The boy and the girl are gorping!" and "The girl and the boy are gorping!". This suggests that toddlers exploit partial representations of sentence structure to guide sentence interpretation; these sparse representations are useful, but error-prone. PMID- 22525313 TI - Tetrahydro-naphthols as orally available TRPV1 inhibitors. AB - Starting from a naphthol-based lead series with low oral bioavailability, we have identified potent TRPV1 antagonists with oral bioavailability in rats. These compounds emerged from SAR studies aimed at replacing the lead's phenol structure whilst maintaining potency. Compound rac-6a is an orally available TRPV1 antagonist with single-digit nanomolar activity. The enantiomers show a low eudismic ratio at the receptor level. PMID- 22525314 TI - Acylated Gly-(2-cyano)pyrrolidines as inhibitors of fibroblast activation protein (FAP) and the issue of FAP/prolyl oligopeptidase (PREP)-selectivity. AB - A series of N-acylated glycyl-(2-cyano)pyrrolidines were synthesized with the aim of generating structure-activity relationship (SAR) data for this class of compounds as inhibitors of fibroblast activation protein (FAP). Specifically, the influence of (1) the choice of the N-acyl group and (2) structural modification of the 2-cyanopyrrolidine residue were investigated. The inhibitors displayed inhibitory potency in the micromolar to nanomolar range and showed good to excellent selectivity with respect to the proline selective dipeptidyl peptidases (DPPs) DPP IV, DPP9 and DPP II. Additionally, selectivity for FAP with respect to prolyl oligopeptidase (PREP) is reported. Not unexpectedly, the latter data suggest significant overlap in the pharmacophoric features that define FAP or PREP-inhibitory activity and underscore the importance of systematically evaluating the FAP/PREP-selectivity index for inhibitors of either of these two enzymes. Finally, this study forwards several compounds that can serve as leads or prototypic structures for future FAP-selective-inhibitor discovery. PMID- 22525315 TI - Ianthellamide A, a selective kynurenine-3-hydroxylase inhibitor from the Australian marine sponge Ianthella quadrangulata. AB - Ianthellamide A (1), a novel octopamine derivative, was isolated from the Australian marine sponge Ianthella quadrangulata. Compound 1 selectively inhibited the activity of kynurenine 3-hydroxylase with an IC(50) value of 1.5 MUM. It also significantly increased the level of endogenous kynurenic acid in rat brain and hence has the potential as a neuroprotective agent in the treatment of neurodegenerative disorders. PMID- 22525316 TI - The effect of vindoline C-16 substituents on the biomimetic coupling reaction: synthesis and cytotoxicity evaluation of the corresponding vinorelbine analogues. AB - A new series of vinorelbine analogues are designed and synthesized to explore the vindoline C-16 substituent effects on the biomimetic coupling with catharanthine, and the structure-activity relationships of these vinorelbine analogues as cytotoxic agents are also studied. The results show that introduction of severe steric hindrance and/or electron-withdrawing group at C-16 site are not propitious to improving the yields of the coupling reaction, and the SAR information collected so far suggests that small alkyl groups substituted at C-16 of vindoline are conductive to maintaining the cytotoxicity. PMID- 22525317 TI - Derivatives of 8-hydroxyquinoline--antibacterial agents that target intra- and extracellular Gram-negative pathogens. AB - Small molecule screening identified 5-nitro-7-((4-phenylpiperazine-1-yl )methyl)quinolin-8-ol INP1750 as a putative inhibitor of type III secretion (T3S) in the Gram-negative pathogen Yersinia pseudotuberculosis. In this study we report structure-activity relationships for inhibition of T3S and show that the most potent compounds target both the extracellular bacterium Y. pseudotuberculosis and the intracellular pathogen Chlamydia trachomatis in cell based infection models. PMID- 22525318 TI - Feto-placental morphological effects of prenatal exposure to drugs of abuse. AB - The aim of the study was to find morphological changes in the feto-placental unit due to prenatal exposure to drugs of abuse. A blind histomorphometric study was performed using 225 placentas. Based on meconium testing, the fetuses were classified as exposed or unexposed to opiates, cocaine, cannabis or alcohol. To establish prenatal tobacco exposure, cotinine in cord blood was analyzed. At the microscopic level a non statistically significant reduction of placental vascularization was observed in cocaine, opiates and alcohol using mothers. In addition, alcohol-consuming mothers did not present with larger placental vessel diameter than controls. Prenatal use of cocaine and tobacco was associated with a decrease in newborn weight and length. Furthermore, tobacco use was associated with a higher rate of previous abortions. In conclusion, placentas from mothers using tobacco, cocaine, opiates or alcohol during pregnancy present vasculature changes that may explain the adverse perinatal outcomes in their newborns. PMID- 22525319 TI - Optimization of ultrasonic extraction process of polysaccharides from Ornithogalum Caudatum Ait and evaluation of its biological activities. AB - Ultrasonic extraction technique (UET) was used to extract crude polysaccharides (OCAP) from Ornithogalum Caudatum Ait (OCA), an orthogonal experiment (L(9) (3)(4)) was applied to optimize extraction conditions. Membrane separation technology and gel filtration chromatography were used to fractionate OCAP, the antioxidant and immunomodulatory activities were evaluated by radical scavenging and spleen lymphocyte proliferation assay. The optimal conditions were determined: extraction time 60min, ultrasound power 500W, ratio of water to raw material 30ml/g and extraction number 3. Under these conditions, the yield of OCAP was 36.77+/-1.76%. OCAP was fractionated into three major fractions (OCAP-I, OCAP-II and OCAP-II), that all fractions possessed considerable antioxidant activity. OCAP-II and OCAP-III exhibited good immunomodulatory activities. The results indicated that UET is a very useful method for extraction bioactive polysaccharides from plant materials. OCAP could be explored as a potential antioxidant and immunostimulating agent for use in medicine or functional foods. PMID- 22525320 TI - Optimising the self-assembly of siRNA loaded PEG-PCL-lPEI nano-carriers employing different preparation techniques. AB - Amphiphilic cationic block copolymers consisting of poly(ethylene glycol), poly(epsilon-caprolactone) and poly(ethylene imine) spontaneously assemble to nano-sized particulate carriers, which can be utilised for complexation of nucleic acids (small-interfering RNA), representing a multifunctional vector system, designed for drug and gene delivery. Apart from polymer design and charge ratio, a more homogeneous complexation could lead to a more uniform charge distribution, subsequently increasing colloidal stability, RNA protection and consequently transfection efficiency. Microfluidic mixing techniques, bringing cationic polymer and nucleic acid together at a constant ratio during the entire mixing process, have the potential for a gentler complexation. In the present study carriers were prepared by a solvent displacement technique. In a first step complex size for addition of RNA during (addition to the aqueous or the organic phase) or after (classical pipetting or microfluidic mixing) carrier assembly was determined by dynamic light scattering. Suitable N/P ratios have previously been selected by measuring size and zeta-potential as a function of N/P. Subsequently, for the most promising techniques (loading after assembly), colloidal stability, the ability to protect RNA as well as transfection efficiency in vitro were compared. Finally, parameters for the superior microfluidic mixing process were optimised with the help of a central composite design. Generally, gentler loading leads to more homogeneous complexes. Hence, possibly due to a more consistent surface coating, loading after carrier assembly resulted in less aggregation. In comparison to bulk mixing, microfluidic assembly exhibited smaller diameters (179+/-11 vs. 230+/-97nm), less heterogeneity (PDI=0.205+/-0.028 vs. 0.353+/ 0.161), enhanced RNA protection (RNA recovery=30.6+/-1.0 vs. 15.4+/-1.4%) as well as increased transfection performance (34.8+/-1.5 vs. 24.5+/-2.2% knockdown). Therefore, microfluidic complexation represents a reproducible alternative for formulating gene delivery carriers with superior colloidal stability, RNA protection and transfection efficiency. PMID- 22525321 TI - Academy expands research initiatives. PMID- 22525322 TI - Noninvasive respiratory management of high level spinal cord injury. AB - This article describes noninvasive acute and long-term management of the respiratory muscle paralysis of high spinal cord injury (SCI). This includes full setting, continuous ventilatory support by noninvasive intermittent positive pressure ventilation (NIV) to support inspiratory muscles and mechanically assisted coughing (MAC) to support inspiratory and expiratory muscles. The NIV and MAC can also be used to extubate or decannulate 'unweanable' patients with SCI, to prevent intercurrent respiratory tract infections from developing into pneumonia and acute respiratory failure (ARF), and to eliminate tracheostomy and resort to costly electrophrenic/diaphragm pacing (EPP/DP) for most ventilator users, while permitting glossopharyngeal breathing (GPB) for security in the event of ventilator failure. PMID- 22525323 TI - Clinical usefulness of the transobturator sub-urethral tape in the treatment of stress urinary incontinence in female patients with spinal cord lesion. AB - OBJECTIVES: To evaluate the clinical usefulness of transobturator sub-urethral tapes for the treatment of stress urinary incontinence in women with spinal cord injury. METHOD AND SUBJECTS: Chart review for all female patients with spinal cord injury who underwent implantation of a transobturator sub-urethral tape for treatment of stress urinary incontinence at our institution. RESULTS: Nine women, median age 45.1 years, received a sub-urethral transobturator tape in the period November 2007 to September 2010. Four patients had paraplegia and five had tetraplegia. Seven women performed intermittent catheterization. At follow up, three of the nine patients were either cured or vastly improved. One major late complication (urethral erosion) occurred. Five of the six patients without treatment success underwent second-line treatment (artificial sphincter or urinary diversion). CONCLUSION: In our case series, implantation of transobturator sub-urethral tapes in women with stress urinary continence due to intrinsic sphincter deficiency and a low leak point pressure led to unfavorable results. PMID- 22525324 TI - A report of anticipated benefits of functional electrical stimulation after spinal cord injury. AB - BACKGROUND: Functional electrical stimulation (FES) has been regularly used to offset several negative body composition and metabolic adaptations following spinal cord injury (SCI). However, the outcomes of many FES trials appear to be controversial and incoherent. OBJECTIVE: To document the potential consequences of several factors (e.g. pain, spasms, stress and lack of dietary control) that may have attenuated the effects on body composition and metabolic profile despite participation in 21 weeks of FES training. PARTICIPANT: A 29-year-old man with T6 complete SCI participated in 21 weeks of FES, 4 days per week. METHODS: Prior to and following training, the participant performed arm-crank-graded exercise testing to measure peak VO(2). Tests conducted included anthropometrics and dual energy X-ray absorptiometry body composition assessments, resting energy expenditure, plasma lipid profiles and intravenous glucose tolerance tests. RESULTS: The participant frequently reported increasing pain, stress and poor eating habits. VO(2) peak decreased by 2.4 ml/kg/minute, body mass increased by 8.5 kg, and body mass index increased from 25 to 28 kg/m(2). Waist and abdominal circumferences increased by 2-4 cm, while %fat mass increased by 5.5%. Absolute increases in fat mass and fat-free mass of 8.4 and 1 kg, respectively, were reported. Fasting and peak plasma glucose increased by 12 and 14.5%, while lipid panel profiles were negatively impacted. CONCLUSION: Failure to control for the listed negative emerging factors may obscure the expected body composition and metabolic profile adaptations anticipated from FES training. PMID- 22525325 TI - Cervical instability presenting as thoracic pain: case report and literature review. AB - STUDY DESIGN: Case report. OBJECTIVE: To report a case of cervical instability from an os odontoideum that presented as posterior thoracic pain and to present a review of the literature. BACKGROUND: Thoracic posterior paraspinal spasms and pain are common chief complaints in individuals with spinal abnormalities. METHODS: A 19-year-old man presented with posterior thoracic pain for nearly 1 year following a college sports-related injury (lacrosse). Computed tomography and magnetic resonance imaging did not reveal any significant thoracic or lumbar spinal cord or nerve root pathology, but did reveal an incidental finding of an os odontoideum. RESULTS: Surgical stabilization of the atlantoaxial instability resulting from the os odontoideum resulted in complete resolution of the patient's thoracic pain. CONCLUSIONS: Thoracic back pain without a clear thoracic spine etiology warrants further workup to rule out the possibility of spinal instability. PMID- 22525327 TI - Statins and noncardiac vascular disease. AB - PURPOSE OF REVIEW: To discuss the beneficial effects of statin treatment in patients with peripheral arterial disease (PAD), abdominal aortic aneurysms (AAAs), atherosclerotic renal artery stenosis (ARAS) and carotid artery disease. RECENT FINDINGS: Evidence suggests that statins may reduce the progression (or even reverse the development) of carotid artery stenosis and AAAs. Statins also improve several indices (e.g. serum creatinine) and preserve renal function in ARAS. In patients with PAD, statins are associated with improved claudication distance and time, reduced cardiovascular events, and improved graft patency rates should these patients undergo surgery. Finally, statins are associated with improved perioperative and long-term morbidity and mortality rates in all vascular patients whether they undergo surgery or endovascular procedures. SUMMARY: Routine statin treatment should be implemented for all vascular patients to ensure a reduced progression of their disease, as well as a reduction in cardiovascular events. PMID- 22525328 TI - Is the lower blood pressure target for patients with chronic kidney disease supported by evidence? AB - PURPOSE OF REVIEW: Major guidelines recommend a blood pressure (BP) target of less than 130/80 mmHg for patients with chronic kidney disease (CKD) even though the optimal BP target in this population is unclear. This review summarizes the evidence on BP target in CKD and highlights recent pertinent publications. RECENT FINDINGS: Clinical trials in CKD have not definitively shown that setting a BP target that is lower than the standard target of less than 140/90 mmHg provides additional benefit for important clinical outcomes. However, subgroup analyses from the recently published posttrial cohort of the African-American Study of kidney disease and a systematic review of BP target trials in CKD suggest that lower than the standard BP target may be beneficial in patients with proteinuria level of more than 300 or 1000 mg/day. SUMMARY: Evidence supports a BP target of less than 140/90 mmHg in most patients with CKD. A lower target may be chosen in CKD patients with proteinuria after individualized risk-benefit assessment. Treatment to a lower target may require greater vigilance to monitor for and avoid possible symptoms and adverse events from hypotension. PMID- 22525329 TI - Do angiotensin receptor blockers prevent myocardial infarctions as well as other initial therapies? AB - PURPOSE OF REVIEW: As their introduction, angiotensin receptor blockers (ARBs) have been widely promulgated as an acceptable alternative to angiotensin converting enzyme inhibitors (ACEIs). Beyond a simple antihypertensive effect, ACEIs have been shown to reduce the rates of myocardial infarction (MI), stroke, and new-onset heart failure, and appear to have a 'blood pressure independent' effect. Given the shared mechanism of preventing action of angiotensin II, the effects of ARB therapy on reduction in cardiovascular and renal outcomes were anticipated to be equal to that of ACEI. RECENT FINDINGS: The role of ARBs in the prevention of MI has not only been disputed, but also has at times cast the class as a causative agent in increasing the risk of MI. This potentially deleterious effect was proposed after results from the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial, in which the use of valsartan (ARB) was compared with amlodipine in patients at high cardiovascular disease risk, found an excess of MIs among patients in the valsartan arm. Subsequent clinical trials and meta analyses have largely laid to rest the question of whether ARBs contribute to cardiovascular risk. SUMMARY: The definitive answer of whether ARBs are effective, if at all, in preventing MI remains difficult to parse out. Current evidence from newer clinical trials and comprehensive meta-analyses suggests that ARBs, while effective antihypertensive agents that protect against risk of stroke, renal disease, diabetes, and heart failure, are likely to have a neutral effect upon reduction of MI when compared with other antihypertensive agents. PMID- 22525331 TI - The usefulness of intraoperative neurophysiological monitoring in cervical spine surgery: a retrospective analysis of 200 consecutive patients. AB - The usefulness of intraoperative neurophysiological monitoring (IONM), including somatosensory-evoked potential (SSEP) and transcranial electrical motor-evoked potentials (TcMEPs) in cervical spine surgery still needs to be evaluated. We retrospectively reviewed 200 cervical spine surgery patients from 2008 to 2009 to determine the role of IONM in cervical spine surgery. Total intravenous anesthesia was used for all patients. IONM alerts were defined as a 50% decrease in amplitude, a 10% increase in latency, or a unilateral change for SSEP and an increase in stimulation threshold of more than 100 V for TcMEP. Three patients had SSEP alerts that were related to arm malposition (2 patients) and hypotension (1 patient). Five patients had TcMEP alerts: 4 alerts were caused by hypotension and 1 by bone graft compression of the spinal cord. All alerts were resolved when causative reasons were corrected. There was no postoperative iatrogenic neurological injury. The sensitivities of SSEP and TcMEP alerts for detecting impending neurological injury were 37.5% and 62.5%, respectively. The sensitivity of both SSEP and TcMEP used in combination was 100%. No false-positive and false negative alerts were identified in either SSEP or TcMEP (100% specificity). The total intravenous anesthesia technique optimizes the detection of SSEP and TcMEP and therefore improves the sensitivity and specificity of IONM. SSEP is sensitive in detecting alerts in possible malposition-induced ischemia or brachial plexus nerve injury. TcMEP specifically detects hypotension-induced spinal functional compromises. Combination use of TcMEP and SSEP enhances the early detection of impeding neurological damage during cervical spine surgery. PMID- 22525330 TI - Non-muscle myosin IIA transports a Golgi glycosyltransferase to the endoplasmic reticulum by binding to its cytoplasmic tail. AB - The mechanism of the Golgi-to-ER transport of Golgi glycosyltransferases is not clear. We utilize a cell line expressing the core 2 N acetylglucosaminyltransferase-M (C2GnT-M) tagged with c-Myc to explore this mechanism. By immunoprecipitation using anti-c-Myc antibodies coupled with proteomics analysis, we have identified several proteins including non-muscle myosin IIA (NMIIA), heat shock protein (HSP)-70 and ubiquitin activating enzyme E1 in the immunoprecipitate. Employing yeast-two-hybrid analysis and pulldown experiments, we show that the C-terminal region of the NMIIA heavy chain binds to the 1-6 amino acids in the cytoplasmic tail of C2GnT-M. We have found that NMIIA co-localizes with C2GnT-M at the periphery of the Golgi. In addition, inhibition or knockdown of NMIIA prevents the brefeldin A-induced collapse of the Golgi as shown by the inhibition of the migration of both Giantin, a Golgi matrix protein, and C2GnT-M, a Golgi non-matrix protein, to the ER. In contrast, knockdown of HSP70 retains Giantin in the Golgi but moves C2GnT-M to the ER, a process also blocked by inhibition or knockdown of NMIIA. Also, the intracellular distribution of C2GnT-M is not affected by knockdown of beta-coatomer protein with or without inhibition of HSPs, suggesting that the Golgi-to-ER trafficking of C2GnT-M does not depend on coat protein complex-I. Further, inhibition of proteasome results in accumulation of ubiquitinated C2GnT-M, suggesting its degradation by proteasome. Therefore, NMIIA and not coat protein complex-I is responsible for transporting the Golgi glycosyltransferase to the ER for proteasomal degradation. The data suggest that NMIIA is involved in the Golgi remodeling. PMID- 22525332 TI - Structural insights into DndE from Escherichia coli B7A involved in DNA phosphorothioation modification. PMID- 22525334 TI - Leucyl-tRNA synthetase: double duty in amino acid sensing. AB - The cellular response to amino acids is controlled at the molecular level by TORC1. While many of the elements that participate in TORC1 signaling are known, we still have no clear idea how cells sense amino acids. Two recent studies found that leucyl-tRNA synthetase (LRS) is a leucine sensor for TORC1, in both yeast and mammalian cells. PMID- 22525335 TI - Early exposure to germs and the Hygiene Hypothesis. AB - A recent paper suggests that reduced exposure to germs results in the expansion of a cell type called natural killer T cells, which predisposes to colitis and asthma. Such a scenario could explain the Hygiene Hypothesis, which has been a puzzle for decades. PMID- 22525336 TI - Onconase downregulates microRNA expression through targeting microRNA precursors. PMID- 22525333 TI - Polarized sorting and trafficking in epithelial cells. AB - The polarized distribution of proteins and lipids at the surface membrane of epithelial cells results in the formation of an apical and a basolateral domain, which are separated by tight junctions. The generation and maintenance of epithelial polarity require elaborate mechanisms that guarantee correct sorting and vectorial delivery of cargo molecules. This dynamic process involves the interaction of sorting signals with sorting machineries and the formation of transport carriers. Here we review the recent advances in the field of polarized sorting in epithelial cells. We especially highlight the role of lipid rafts in apical sorting. PMID- 22525337 TI - Epithelial self-defense against cancer. AB - It is not clearly understood what happens at the interface between normal and transformed epithelial cells at the first step of carcinogenesis. A recent study reveals that the organized epithelial structure suppresses clonal expansion of transformed cells. Translocation from the epithelium or perturbation of intercellular adhesions may be required for transformed cells to evade the suppressive environments. PMID- 22525338 TI - ROS-induced DNA damage and PARP-1 are required for optimal induction of starvation-induced autophagy. AB - In response to nutrient stress, cells start an autophagy program that can lead to adaptation or death. The mechanisms underlying the signaling from starvation to the initiation of autophagy are not fully understood. In the current study we show that the absence or inactivation of PARP-1 strongly delays starvation induced autophagy. We have found that DNA damage is an early event of starvation induced autophagy as measured by gamma-H2AX accumulation and comet assay, with PARP-1 knockout cells displaying a reduction in both parameters. During starvation, ROS-induced DNA damage activates PARP-1, leading to ATP depletion (an early event after nutrient deprivation). The absence of PARP-1 blunted AMPK activation and prevented the complete loss of mTOR activity, leading to a delay in autophagy. PARP-1 depletion favors apoptosis in starved cells, suggesting a pro-survival role of autophagy and PARP-1 activation after nutrient deprivation. In vivo results show that neonates of PARP-1 mutant mice subjected to acute starvation, also display deficient liver autophagy, implying a physiological role for PARP-1 in starvation-induced autophagy. Thus, the PARP signaling pathway is a key regulator of the initial steps of autophagy commitment following starvation. PMID- 22525339 TI - Smoking and alcohol consumption in relation to risk of thyroid cancer in postmenopausal women. AB - BACKGROUND: Few cohort studies have examined smoking and alcohol consumption in relation to risk of thyroid cancer, and their findings are conflicting. METHODS: We therefore assessed the association of smoking and alcohol intake with risk of thyroid cancer in a cohort of 159,340 women enrolled in the Women's Health Initiative. Over 12.7 years of follow-up 331 cases of thyroid cancer, of which 276 were papillary thyroid cancer, were identified. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Compared to never smokers, ever smokers did not have altered risk. Current smokers had reduced risk for all thyroid cancer (HR 0.54, 95% CI 0.29 1.00) and for papillary thyroid cancer (HR 0.34, 95% CI 0.15-0.78); however, the number of current smokers among cases was small. No associations or trends were seen for amount smoked, age of starting smoking, or age at quitting. Smokers of >=40 pack-years had a significantly reduced risk of papillary thyroid cancer (HR 0.44, 95% CI 0.21-0.89). In contrast, women who had smoked for < 20 years had increased risk of thyroid cancer (HR 1.35, 95% CI 1.05-1.74) and papillary cancer (HR 1.43, 95% CI 1.09-1.89). Alcohol intake was not associated with risk. CONCLUSION: Our findings suggest that current smoking and having higher pack years of exposure are associated with a modestly reduced risk of thyroid cancer, whereas alcohol consumption does not appear to affect risk. PMID- 22525340 TI - How is an electronic screening and brief intervention tool on alcohol use received in a student population? A qualitative and quantitative evaluation. AB - BACKGROUND: A previous study among Antwerp college and university students showed that more male (10.2%-11.1%) than female (1.8%-6.2%) students are at risk for problematic alcohol use. The current literature shows promising results in terms of feasibility and effectiveness for the use of brief electronic interventions to address this health problem in college and university students. We evaluated this type of intervention and cite existing literature on the topic. OBJECTIVE: To develop a website, www.eentjeteveel.be, to motivate college and university students with problematic alcohol use to reduce alcohol consumption and increase their willingness to seek help. METHOD: The website contained a questionnaire (Alcohol Use Disorders Identification Test [AUDIT]) for students to test their alcohol use. According to their answers, the students immediately received personalized feedback (personal AUDIT score and additional information on risks associated with alcohol use) and a suggestion for further action. Afterward, students could send an email to a student counselor for questions, guidance, or advice. To obtain in-depth qualitative information on the opinions and experiences of students, we held 5 focus group discussions. The topics were publicity, experiences, impressions, and effects of the website. We analyzed the quantitative results of the online test in SPSS 15.0. RESULTS: More than 3500 students visited www.eentjeteveel.be; over half were men (55.0%). A total of 34 students participated in the focus group discussions. The mixture of quantitative and qualitative methods to evaluate the intervention allowed a thorough analysis and provided complementary results. The intervention was well received by the student population. However, some minor aspects should be reconsidered, such as website publicity and providing students with options that were added after intermediate evaluation. The intervention increased the motivation of students to think about their alcohol use but could not stimulate them to change their behavior. The website attracted relatively more male than female students and more students in the high-risk group than in the low-risk group. The high-risk group was more inclined to seek advice or guidance (23/400, 6%; chi(2) (2 = 32.4), P < .001) than the low-risk group (34/1714, 2%; chi(2) (2 = 32.4), P < .001). CONCLUSIONS: We gained unique insight into students' experiences, opinions, and perceptions with regard to the intervention. The results show that the intervention was positively received in the population, and the willingness to seek help was increased. However, real behavior change needs further research. The results of this study can assist health providers and researchers in better understanding college and university students' perceptions of eHealth initiatives. PMID- 22525342 TI - Sympathetic and vascular dysfunction in adult patients with Fontan circulation. AB - BACKGROUND: Patients with Fontan circulation are known to have increased systemic vascular resistance (SVR) however the underlying mechanisms are uncertain. We therefore further investigated the haemodynamic and vascular profile of Fontan patients. METHODS: Eighteen adult subjects aged 25 +/- 1 years who had undergone the Fontan procedure in their childhood (at age 6 +/- 1 years) and not in clinical failure at the time of study were assessed for: 1) autonomic function, including direct muscle sympathetic nerve activity (MSNA) recording and sympathetic and cardiac baroreflex function, 2) endothelial function by means of reactive hyperaemia using the Endopat peripheral arterial tonometry (PAT) technique and plasma endothelin concentration and gene expression, 3) pulse wave reflections (digital and central augmentation index (AI)) and 4) haemodynamic changes to head-up tilt. Data were compared to that obtained in a group of 23 age and weight-matched healthy subjects. RESULTS: Fontan participants presented with elevated MSNA compared with controls (40 +/- 5 vs 27 +/- 3 bursts per 100 heartbeats), decreased cardiac baroreflex function (16.0 +/- 3.3 versus 30.9 +/- 3.7 ms . mm Hg(-1)), normal sympathetic baroreflex function, decreased endothelial function (PAT ratio=0.35 +/- 0.09 vs 0.77 +/- 0.11), and increased digital (5.9 +/- 3.0% vs -9.7 +/- 2.3%) and central (1.4 +/- 2.7% vs -10.2 +/- 3.9%) AI. Ten minute head-up tilt (60 degrees ) induced greater reductions in cardiac output (CO) and stroke volume (SV) in Fontan patients (CO: -28% vs -11%, SV: -40% vs -25%). CONCLUSION: Adult Fontan patients have increased MSNA and altered endothelial function that are likely to contribute to their known increased SVR. Therapies aiming at reducing the peripheral resistances should target endothelial function and sympathetic activity. PMID- 22525341 TI - A potent soluble epoxide hydrolase inhibitor, t-AUCB, acts through PPARgamma to modulate the function of endothelial progenitor cells from patients with acute myocardial infarction. AB - BACKGROUND: Epoxyeicosatrienoic acids (EETs) are natural angiogenic mediators regulated by soluble epoxide hydrolase (sEH). Inhibitors of sEH can stabilize EETs levels and were reported to reduce atherosclerosis and inhibit myocardial infarction in animal models. In this work, we investigated whether increasing EETs with the sEH inhibitor t-AUCB would increase angiogenesis related function in endothelial progenitor cells (EPCs) from patients with acute myocardial infarction (AMI). METHODS AND RESULTS: EPCs were isolated from 50 AMI patients and 50 healthy subjects (control). EPCs were treated with different concentrations of t-AUCB for 24h with or without peroxisome proliferator activated receptor gamma (PPARgamma) inhibitor GW9662. Migration of EPCs was assayed in trans-well chambers. Angiogenesis assays were performed using a Matrigel-Matrix in vitro model. The expression of vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1alpha (HIF-1alpha) mRNA and protein in EPCs was measured by real-time PCR or Western blot, respectively. Also, the concentration of EETs in the culture supernatant was detected by ELISA. The activity of EPCs in the AMI patient group was reduced compared to healthy controls. Whereas increasing EET levels with t-AUCB promoted a dose dependent angiogenesis and migration in EPCs from AMI patients. Additionally, the t-AUCB dose dependently increased the expression of the angiogenic factors VEGF and HIF alpha. Lastly, we provide evidence that these effects were PPARgamma dependent. CONCLUSION: The results demonstrate that the sEH inhibitor positively modulated the functions of EPCs in patients with AMI through the EETs-PPARgamma pathway. The present study suggests the potential utility of sEHi in the therapy of ischemic heart disease. PMID- 22525344 TI - Advanced glycation end products: a mysterious shadow beyond the relationship between HbA1c and atrial fibrillation. PMID- 22525343 TI - A randomized placebo controlled double blind crossover study of pioglitazone on left ventricular diastolic function in type 2 diabetes. AB - BACKGROUND/OBJECTIVES: Thiazolidinediones (TZDs), such as pioglitazone, are widely used to treat type 2 diabetes but there is evidence that their use is associated with an increased risk of heart failure. We compared the effect of pioglitazone vs. placebo on left ventricular (LV) diastolic and systolic function in people with type 2 diabetes. METHODS AND RESULTS: 24 male or female patients with type 2 diabetes were randomized to pioglitazone (45 mg/day) or placebo in addition to current therapy for 12 weeks using a prospective double blind crossover protocol following a run-in period >1 week and a 2 week washout period at crossover. Tissue Doppler early peak velocity (e'), a measure of LV diastolic function, was the primary outcome. Pioglitazone significantly increased e' by 0.7(0.1, 1.3) cm/s (mean (95% confidence interval); p=0.02) compared with placebo. Pioglitazone also increased E/A and mitral deceleration index, ejection fraction, stroke volume and weight, whereas fasting glucose, HbA1c, total peripheral resistance and LV meridional end systolic stress were decreased. CONCLUSIONS: Treatment with pioglitazone for 12 weeks improves left ventricular diastolic and systolic function in people with type 2 diabetes. PMID- 22525345 TI - Complexity and rationality of Avicenna's pulsology: a step towards understanding the past for today's applications. PMID- 22525346 TI - Takotsubo-syndrome presenting with supraventricular tachycardia, stroke, and thrombocytopenia. PMID- 22525347 TI - Left ventricular assist device in Duchenne cardiomyopathy: can we change the natural history of cardiac disease? PMID- 22525348 TI - YKL-40 levels and atrial fibrillation in the general population. AB - BACKGROUND: Atrial fibrillation is associated with inflammation. In contrast to inflammatory markers like C-reactive protein (CRP) and fibrinogen produced in the liver, YKL-40 is produced at the site of inflammation including in the myocardium. We hypothesized that elevated plasma YKL-40 levels associate with increased risk of atrial fibrillation. METHOD AND RESULTS: We measured plasma YKL 40 in 8731 participants from the prospective Copenhagen City Heart Study including 896 individuals who developed atrial fibrillation during up to 18 years of follow-up. Additionally, we measured YKL-40 in 6621 individuals from the cross sectional Copenhagen General Population Study including 337 cases with atrial fibrillation. A YKL-40 level >95% percentile (>204 MUg/L) versus <25% percentile (<36 MUg/L) associated prospectively with a 2.10-fold (95%CI:1.43-3.09) increased risk of atrial fibrillation. Hazard ratios attenuated slightly after multifactorial adjustment to 2.01 (1.35-2.98), and further after additional adjustment for heart failure to 1.89 (1.27-2.80), for plasma CRP to 1.79 (1.20 2.67), and for fibrinogen levels to 1.89 (1.27-2.81). Adjusting multifactorially including both heart failure, CRP, and fibrinogen attenuated the risk of atrial fibrillation to 1.79 (1.20-2.67). These findings were supported in the cross sectional study with an odds ratio of 2.73 (1.46-5.11) for a YKL-40 level >95% percentile versus <25% percentile, attenuating to an odds ratio of 2.13 (1.09 4.18) when adjusting multifactorially including heart failure, CRP, and fibrinogen. CONCLUSIONS: Elevated plasma YKL-40 levels robustly associated with increased risk of atrial fibrillation originating from hospital admissions or visits to the emergency department, independent of heart failure, and CRP and fibrinogen levels. These findings need to be confirmed in other independent studies. PMID- 22525349 TI - Effects of exercise training and RhoA/ROCK inhibition on plaque in ApoE-/- mice. AB - BACKGROUND: The molecular mechanisms of exercise-induced cardioprotection are poorly understood. We recently reported that exercise training down-regulated gene expression of the Ras homolog gene family member A (RhoA). RhoA and its first effectors, the Rho-kinases (ROCK), have already been implicated in the pathogenesis of cardiovascular disease. The aim of this study was to compare the effects of a RhoA/ROCK inhibitor (fasudil) and exercise in the Apolipoprotein E knockout (ApoE(-/-)) mouse model of atherosclerosis. METHODS: Four groups of 14 week old ApoE(-/-) mice were randomised as follows (n=12/group): i) sedentary controls (Cont); ii) fasudil (Fas) treatment (100mg/kg bodyweight/day) for 8 weeks; iii) exercise intervention (Ex:free access to running wheel for 8 weeks) and iv) exercise intervention and fasudil treatment (ExFas) for 8 weeks. RESULTS: Phosphorylation of myosin light chain was significantly reduced in the brachiocephalic artery of all treatment groups compared with sedentary controls, implying an inhibitory effect of exercise and fasudil on the RhoA/ROCK pathway. Furthermore, atherosclerotic lesions were significantly smaller in all treatment and intervention groups compared with the control group (Fas: 34.7%, Ex: 48.3%, ExFas: 40.9% less than Control). The intima:media ratio was reduced by both exercise intervention and fasudil treatment alone or in combination (Fas: 23.6%, Ex: 35.5%, ExFas: 43.9% less than Control). Exercise alone and fasudil treatment alone also showed similar effects on plaque composition, increasing both smooth muscle cell and macrophage density. CONCLUSION: These results suggest that the protective effects of exercise on atherogenesis are similar to the inhibitory effects on the RhoA/ROCK signalling pathway. PMID- 22525350 TI - Therapeutic efficacy of an antibiotic-loaded nanosheet in a murine burn-wound infection model. AB - Polymeric ultra-thin films (nanosheets) possess unique properties that make them suitable materials for various biomedical applications. In our previous study, we assessed the use of an antibiotic (tetracycline, TC)-loaded nanosheet (or "TC nanosheet") for the treatment of gastrointestinal tissue defects. The nanosheet consisted of three functional layers: layer-by-layer nanosheet as a stable platform, TC as an antimicrobial agent with autofluorescence for tracing, and a poly(vinyl acetate) nanosheet to act as a protecting layer. The TC-nanosheet has high flexibility, adhesive strength and transparency. Here, we evaluated the effectiveness of the TC-nanosheet in preventing full thickness burn-wound infections. In an in vivo study, murine dorsal skin was injured by full-thickness burns and then infected with Pseudomonas aeruginosa (P. aeruginosa), a common bacterium causing burn-associated infections. The wound site was treated either with a TC-nanosheet, TC-unloaded nanosheet or left untreated. Wound management was facilitated by the high transparency of the TC-nanosheet. The TC-nanosheet significantly improved burn-wound infection by P. aeruginosa in mice. Indeed, all mice treated with the TC-nanosheet survived, whereas the other treatment groups displayed increased rates of mortality due to bacterial infection. According to histological analyses and viable bacterial counting in the liver (bacterial translocation), the TC-nanosheets were able to prevent not only the local inflammation but also systemic inflammation. We conclude that the TC-nanosheet can act as an effective treatment for full-thickness burn-wound infection. Hence, the TC-nanosheet is a promising therapeutic tool for burn-wound management in severely burn-injured patients. PMID- 22525351 TI - Platelet-mediated mesenchymal stem cells homing to the lung reduces monocrotaline induced rat pulmonary hypertension. AB - Bone marrow mesenchymal stem cell (BM-MSC) transplantation has been suggested to be a promising method for the treatment of pulmonary arterial hypertension (PAH), a fatal disease currently without effective preventive/therapeutic strategies. However, the detailed mechanisms underlying BM-MSC therapy are largely unknown. We designed the present study to test the hypothesis that circulating platelets facilitate BM-MSC homing to the lung vasculature in a rat model of PAH induced by monocrotalin (MCT). A single subcutaneous administration of MCT induced a marked rise in right ventricular systolic pressure (RVSP) and the weight ratio of right to left ventricle plus septum (RV/LV+S) 3 weeks after injection. The injection of MSCs via tail vein 3 days after MCT significantly reduced the increase of RVSP and RV/LV+S. The fluorescence-labeled MSCs injected into the PAH rat circulation were found mostly distributed in the lungs, particularly on the pulmonary vascular wall, whereas cell homing was abolished by an anti-P-selectin antibody and the GPIIb/IIIa inhibitor tirofiban. Furthermore, using an in vitro flow chamber, we demonstrated that MSC adhesion to the major extracellular matrix collagen was facilitated by platelets and their P-selectin and GPIIb/IIIa. Therefore, the current study suggested that platelet-mediated MSC homing prevented the aggravation of MCT-induced rat PAH, via P-selectin and GPIIb/IIIa mediated mechanisms. PMID- 22525352 TI - Make way for the 'next generation': application and prospects for genome-wide, epigenome-specific technologies in endocrine research. AB - Epigenetic changes, which target DNA and associated histones, can be described as a pivotal mechanism of interaction between genes and the environment. The field of epigenomics aims to detect and interpret epigenetic modifications at the whole genome level. These approaches have the potential to increase resolution of epigenetic changes to the single base level in multiple disease states or across a population of individuals. Identification and comparison of the epigenomic landscape has challenged our understanding of the regulation of phenotype. Additionally, inclusion of these marks as biomarkers in the early detection or progression monitoring of disease is providing novel avenues for future biomedical research. Cells of the endocrine organs, which include pituitary, thyroid, thymus, pancreas ovary and testes, have been shown to be susceptible to epigenetic alteration, leading to both local and systemic changes often resulting in life-threatening metabolic disease. As with other cell types and populations, endocrine cells are susceptible to tumour development, which in turn may have resulted from aberration of epigenetic control. Techniques including high throughput sequencing and array-based analysis to investigate these changes have rapidly emerged and are continually evolving. Here, we present a review of these methods and their promise to influence our studies on the epigenome for endocrine research and perhaps to uncover novel therapeutic options in disease states. PMID- 22525353 TI - New insight into the mechanisms associated with the rapid effect of T3 on AT1R expression. AB - The angiotensin II type 1 receptor (AT1R) is involved in the development of cardiac hypertrophy promoted by thyroid hormone. Recently, we demonstrated that triiodothyronine (T3) rapidly increases AT1R mRNA and protein levels in cardiomyocyte cultures. However, the molecular mechanisms responsible for these rapid events are not yet known. In this study, we investigated the T3 effect on AT1R mRNA polyadenylation in cultured cardiomyocytes as well as on the expression of microRNA-350 (miR-350), which targets AT1R mRNA. The transcriptional and translational actions mediated by T3 on AT1R levels were also assessed. The total content of ubiquitinated proteins in cardiomyocytes treated with T3 was investigated. Our data confirmed that T3 rapidly raised AT1R mRNA and protein levels, as assessed by real-time PCR and western blotting respectively. The use of inhibitors of mRNA and protein synthesis prevented the rapid increase in AT1R protein levels mediated by T3. In addition, T3 rapidly increased the poly-A tail length of the AT1R mRNA, as determined by rapid amplification of cDNA ends poly-A test, and decreased the content of ubiquitinated proteins in cardiomyocytes. On the other hand, T3 treatment increased miR-350 expression. In parallel with its transcriptional and translational effects on the AT1R, T3 exerted a rapid posttranscriptional action on AT1R mRNA polyadenylation, which might be contributing to increase transcript stability, as well as on translational efficiency, resulting to the rapid increase in AT1R mRNA expression and protein levels. Finally, these results show, for the first time, that T3 rapidly triggers distinct mechanisms, which might contribute to the regulation of AT1R levels in cardiomyocytes. PMID- 22525354 TI - Identification of gene pathways altered by deletion of the androgen receptor specifically in mineralizing osteoblasts and osteocytes in mice. AB - Androgens play a key role in skeletal growth and maintenance in males and can mediate their actions, at least in part, via the androgen receptor (AR) in osteoblasts. To investigate the mechanisms by which androgens exert their effects via the AR in mineralizing osteoblasts and osteocytes, we identified gene targets/pathways regulated by the AR using targeted gene expression and microarray approaches on bone isolated from mice in which the AR is specifically deleted in mineralizing osteoblasts and osteocytes (mOBL-ARKOs). Gene ontology mining indicated a number of biological processes to be affected in the bones of mOBL-ARKOs including skeletal and muscular system development and carbohydrate metabolism. All genes identified to have altered expression in the bones of mOBL ARKOs were confirmed by Q-PCR for their androgen responsiveness in an androgen deprivation and replacement mouse model. The osteoblast genes Col1a1 and Bglap and the osteoclast genes Ctsk and RANKL (Tnfs11) were upregulated in the bones of mOBL-ARKOs, consistent with the increased matrix synthesis, mineralization, and bone resorption observed previously in these mice. Of significant interest, we identified genes involved in carbohydrate metabolism (adiponectin and Dpp4) and in growth and development (GH, Tgfb (Tgfb2), Wnt4) as potential targets of androgen action via the AR in mineralizing osteoblasts. PMID- 22525356 TI - Neuronal morphology in subdivisions of the inferior colliculus of chicken (Gallus gallus). AB - The avian inferior colliculus (IC), also referred to as the nucleus mesencephalicus lateralis pars dorsalis (MLd), is an auditory midbrain nucleus that converges auditory cues from tonotopically organized brainstem nuclei. This information is relayed onto the optic tectum on the one hand and to nucleus ovoidalis on the other hand. Morphologically, there has been considerable debate about the number and nomenclature of the subnuclei within the IC. Here, we provide morphological characteristics of single cells in five IC subnuclei in chicken. The cellular structure within the IC was studied by whole-cell patch technique and biocytin iontophoresis. In addition, histological staining was performed, to delineate the borders between subnuclei of the IC. We were able to discriminate between 5 subnuclei: the core of the central nucleus (ICCc), the medial and lateral shell of the central nucleus (ICCms and ICCls), the external nucleus (ICX) and the superficial nucleus (ICS) of the IC. Our findings suggest the existence of at least two different morphologies of neurons with two subtypes each. The IC in chicken is a largely homogenous nucleus in terms of neuronal anatomy on a cellular level. However, its compartmentation into diversified subnuclei with different neurophysiological characteristics suggests a complex system to process auditory information. The auditory system in chicken is not as hypertrophied as in specialists such as the barn owl, but appears to have comparable connectivity and cellular morphology. PMID- 22525357 TI - Imagining the present: amnesia may impair descriptions of the present as well as of the future and the past. AB - Recent evidence suggests that in some patients with amnesia the capacity to imagine the future is impaired in parallel with the capacity to remember the past. This paper asks whether descriptions of the present may be similarly affected. We recruited 7 patients with amnesic syndromes of varying aetiologies who were matched for age, sex and education with 7 control participants. Patients showed no deficits on subjective measures of visual imagery. They were impaired by comparison with controls on measures of imagination and future thinking. However there was an even more marked impairment on tasks requiring them to give descriptions of their current experience. Potential explanations include effects of amnesia on narrative construction or on the texture of experience itself, and the confounding influence of cognitive impairments outside the memory domain. We conclude that tasks requiring descriptions of current experience provide a valuable control condition in studies examining the relationship between memory and imagination. PMID- 22525358 TI - In situ evaluation of the genotoxic potential of the river Nile: II. Detection of DNA strand-breakage and apoptosis in Oreochromis niloticus niloticus (Linnaeus, 1758) and Clarias gariepinus (Burchell, 1822). AB - This work is part of a wider eco-toxicological study proposed to evaluate the biological impact of contaminants along the whole course of the river Nile, Egypt. Here we present data on the presence of DNA strand-breaks and apoptotic cells assessed by use of comet and diffusion assays in erythrocytes of Nile tilapia (Oreochromis niloticus niloticus) and African catfish (Clarias gariepinus). The results showed high degrees of DNA damage and increased frequencies of apoptotic nuclei in blood of fish collected from downstream compared with those sampled from upstream river Nile. Qualitative analysis revealed a shift in the frequency of DNA-damage classes towards higher damage levels correlating with the increasing pollution gradient. The degree of DNA damage measured by use of comet assay and diffusion assay exhibited seasonal variations. Both fish species showed significant increases in DNA damage during the summer. The results of our study indicated that the alkaline comet assay seems to be a useful technique for in situ genotoxic monitoring. At the same time the diffusion assay is sensitive enough to detect low frequencies of apoptotic nuclei. The results reveal species-specific differences in sensitivities, suggesting that Nile tilapia may serve as a more sensitive test species compared with the African catfish. Based on the outcome of the comet and diffusion assays, it can be concluded that the water quality of the river Nile with respect to the presence of genotoxic compounds needs to be improved, especially in its estuaries. As far as we know this is the first time that the comet and diffusion assays are used for genotoxic monitoring of the river Nile. PMID- 22525359 TI - DNA damage in peripheral blood mononuclear cells of patients undergoing anti tuberculosis treatment. AB - Tuberculosis (TB), a chronic infectious disease, is a major cause of morbidity and mortality worldwide. Expression of iNOS and consequent production of NO during the inflammatory process is an important defense mechanism against TB bacteria. We have tested whether pulmonary TB patients undergoing anti tuberculosis treatment present DNA damage, and whether this damage is related to oxidative stress, by evaluating total hydrophilic antioxidant capacity and iNOS expression. DNA damage in peripheral blood mononuclear cells from patients and healthy tuberculin test (PPD) positive controls was evaluated by single-cell gel electrophoresis (comet assay), and iNOS expression was measured by qPCR. We also evaluated total hydrophilic antioxidant capacity in plasma from patients and controls. Compared to controls, pulmonary TB patients under treatment presented increased DNA damage, which diminished during treatment. Also, the antioxidant capacity of these individuals was increased at the start of treatment, and reduced during treatment. TB patients showed lower iNOS expression, but expression tended to increase during treatment. Our results indicate that pulmonary TB patients under anti-TB treatment exhibit elevated DNA damage in peripheral blood mononuclear cells. This damage was not related to nitric oxide but may be due to other free radicals. PMID- 22525360 TI - The micronucleus assay as a biological dosimeter in hospital workers exposed to low doses of ionizing radiation. AB - The health risk associated with low levels of ionizing radiation is still a matter of debate. A number of factors, such as non-target effects, adaptive responses and low-dose hypersensitivity, affect the long-term outcome of low-dose exposures. Cytogenetic bio-dosimetry provides a measure of the absorbed dose, taking into account the individual radiation sensitivity. The aim of the present study is to evaluate the value of the micronucleus (MN) test as a bio-dosimeter in hospital workers exposed to low doses of ionizing radiation. Blood samples were obtained from 30 subjects selected among workers exposed to X- and gamma radiation, and 30 controls matched for sex, age and smoking from the same hospital. Micronucleus frequencies were analyzed by use of the cytokinesis-block method. The MN frequency was compared among the groups considering the confounding factors and the length of employment. No increase in the number of bi nucleated cells with MN (BNMN), but a significant increase in the number of mono nucleated cells with micronuclei (MOMN) was observed in exposed subjects compared with the controls. The relationship between MN frequency and accumulated dose (mSv) was evaluated. The length of employment did not affect the extent of MN frequency, but an increase of BNMN and MOMN cells was observed based on the accumulated radiation dose. Our study shows the sensitivity of the MN test in the detection of cytogenetic effects of cumulative exposure levels, suggesting the potential usefulness of this assay in providing a biological index in medical surveillance programs. PMID- 22525361 TI - Induction of an adaptive response in human blood lymphocytes exposed to radiofrequency fields: influence of the universal mobile telecommunication system (UMTS) signal and the specific absorption rate. AB - The induction of an adaptive response (AR) was examined in human peripheral blood lymphocytes exposed to non-ionizing radiofrequency fields (RF). Cells from nine healthy human volunteers were stimulated for 24h with phytohaemagglutinin and then exposed for 20h to an adaptive dose (AD) of a 1950MHz RF UMTS (universal mobile telecommunication system) signal used for mobile communications, at different specific absorption rates (SAR) of 1.25, 0.6, 0.3, and 0.15W/kg. This was followed by treatment of the cells at 48h with a challenge dose (CD) of 100ng/ml mitomycin C (MMC). Lymphocytes were collected at the end of the 72h total culture period. The cytokinesis-block method was used to record the frequency of micronuclei (MN) as genotoxicity end-point. When lymphocytes from six donors were pre-exposed to RF at 0.3W/kg SAR and then treated with MMC, these cells showed a significant reduction in the frequency of MN, compared with the cells treated with MMC alone; this result is indicative of induction of AR. The results from our earlier study indicated that lymphocytes that were stimulated for 24h, exposed for 20h to a 900MHz RF GSM (global system for mobile communication) signal at 1.25W/kg SAR and then treated with 100ng/ml MMC, also exhibited AR. These overall data suggest that the induction of AR depends on RF frequency, type of the signal and SAR. Further characterization of RF-induced AR is in progress. PMID- 22525362 TI - Use of 'omics to elucidate mechanism of action and integration of 'omics in a systems biology concept. PMID- 22525363 TI - Use of hepatotoxic drugs in chronic liver disease. AB - Cirrhosis and chronic liver disease are common illnesses that cause high mortality and require treatment. Medication use in these patients may be challenging because of idiosyncratic or dose-dependent drug toxicity. Therefore, drug choice and drug dose adaptations play an important role. The objective of this clinical review is to discuss the literature about and challenges in drug use in patients with chronic liver disease. To make good decisions regarding drug choice and dose adjustments in these patients, well-defined clinical information about diagnoses and laboratory results (creatinine, international normalized ratio, bilirubin, and serologies) as well as in some instances, pathological findings like liver biopsies are needed. In a second step, these data should be organized in electronically supported clinical decision systems, which can then assist providers in making choices about medication selection and dosage. In summary, although substantial research has been done in the field of drug use in patients with liver dysfunction, a great deal also remains to be learned. Although many of these patients can now be identified, it is still very difficult to assess their individual level of hepatic function. The degree of risk associated with drug use and how best to use medications in these patients represents an important area for further study. In the future, pharmacogenomics and electronic linking of clinical data may well prove helpful for making decisions about optimal drug choices in this complex group of patients. PMID- 22525364 TI - Incident reporting at a tertiary care hospital in Saudi Arabia. AB - OBJECTIVE: This study aimed to examine the rates and categories of incident reports in an academic tertiary care center in Saudi Arabia both hospital-wide and in the intensive care unit (ICU). Such information would help in redesigning systems and in planning and developing strategies with the goal of improving patient safety and quality of care. METHODS: In this descriptive study, we evaluated all incident reports submitted through the paper-based reporting system in the hospital and the ICU for the year 2008. Incident report rates were calculated as the number of incident reports per 1000 patient days. We also reviewed the major and minor categories of the generated reports. RESULTS: A total of 3041 incident reports were submitted from all hospital areas; yielding a rate of 5.8 per 1000 patient days. Sixty-two incident reports were reported from the ICU, yielding a rate of 5.8 per 1000 patient days. The most frequent type of incident reports was procedural variances (37%), followed by behavior and communication incidents (34%), hazardous and safety incidents (9.5%), and medication errors (7.4%). In the ICU, the most frequently reported type of incidents was behavior and communication incidents (30.6%), followed by procedural variances (21%) and medication errors (13%). CONCLUSIONS: Rates of incident reports at a tertiary care center in Saudi Arabia were low compared with reported international rates. The main categories of incident reports were related to procedural variances and behavior and communication incidents. These findings suggest that patient safety initiatives should focus primarily on these 2 domains. Additional prospective research is needed in this important area to further understand patient safety challenges and reporting practice and culture in the country. PMID- 22525365 TI - GPi and STN deep brain stimulation can suppress dyskinesia in Parkinson's disease. AB - OBJECTIVES: To compare subthalamic nucleus (STN) to globus pallidus internus (GPi) deep brain stimulation (DBS) for control of motor fluctuations and for potential dyskinesia-suppressing qualities. METHODS: We conducted a retrospective database review of all patients who underwent GPi or STN DBS for idiopathic Parkinson's disease. Direct dyskinesia suppression (dDS) was defined as improvement in dyskinesia subscore of the unified Parkinson's disease rating scale (UPDRS) part IV (items 32-34), despite lack of reduction in dopaminergic medication dosage. We analyzed the data using methods appropriate for a case control study. RESULTS: A total of 133 patients were evaluated. At the last evaluation Dyskinesia scores and motor fluctuations significantly improved in both the GPi (p < 0.0001) and STN groups (p < 0.0001). The GPi group was more likely than the STN group to experience dDS (odds ratio = 1.95, 95% CI = 0.556, 3.21). However, the association between DBS target and dDS was not statistically significant (Pearson chi-square = 2.286, p = 0.131). CONCLUSIONS: The overall clinical outcome of STN and GPi DBS for control of dyskinesia and motor fluctuations was similar. STN and GPi DBS both had some direct dyskinesia suppression effects. PMID- 22525366 TI - LRRK2 I2020T mutation is associated with tau pathology. AB - Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of autosomal-dominant familial Parkinson's disease (FPD). The variable pathological features of LRRK2-linked FPD include Lewy bodies, degeneration of anterior horn cells associated with axonal spheroids, neurofibrillary tangles (NFTs) and TAR DNA-binding protein of 43 kDa (TDP-43) positive inclusion bodies. Furthermore, abnormal hyperphosphorylation of microtubule associated protein tau, in part generated by catalysis of protein kinases, has been reported to be involved in progressive neurodegeneration in a number of diseases, including FPD. Thus, we examined six patients carrying the LRRK2 I2020T mutation, a pathogenic mutation associated with PARK8, and found abnormal tau phosphorylation depositions in the brainstem. Additionally, we found LRRK2 I2020T enhanced tau phosphorylation in cultured cells co-expressing LRRK2-I2020T and 3 or 4-repeated tau. This is the first report describing the relationship between hyperphosphorylation of tau and LRRK2 I2020T. PMID- 22525367 TI - Imaging in young adults with intracerebral hemorrhage. AB - OBJECTIVE: Vascular malformations are a common yet treatable cause of intracerebral hemorrhage (ICH) in the young. The goal of this study was to review the implementation of appropriate secondary angiographic/venographic imaging to identify vascular malformations in young adults with ICH at our specialist neuroscience center. METHODS: A retrospective analysis was undertaken of five years of prospectively recorded referral data to the on-call neurosurgery service at the Greater Manchester Neuroscience Centre. RESULTS: The authors identified 111 ICH patients aged 18-40 over the five-year period, with a wide etiologic spectrum. When assessing the implementation of secondary imaging, they focused on 90 individuals, incorporating those without an identifiable precipitant for their ICH and those with recent recreational drug use and hypertension. Of these 90, 52 (58%) were admitted to the neuroscience center for further management; when excluding three with bilateral fixed and dilated pupils, the remaining 49 all underwent appropriate secondary imaging. Of the 38 subjects not accepted to the neuroscience center, 13 (34%) had bilateral fixed and dilated pupils, 10 (26%) underwent appropriate secondary imaging, and 15 did not - all but two of these 15 were referred outside of normal working hours. The positive yield from secondary imaging was 63%. CONCLUSION: Young adults with ICH are more likely to get appropriate imaging to identify vascular malformations in a specialist neuroscience center compared to a non-specialist center. Out of hours care appears to be a significant contributor to this shortfall. This study suggests a need for service redevelopment and specialist neuroscience center input for all cases of young ICH. PMID- 22525368 TI - Toxoplasma gondii tachyzoites cross retinal endothelium assisted by intercellular adhesion molecule-1 in vitro. AB - Retinal infection is the most common clinical manifestation of toxoplasmosis. The route by which circulating Toxoplasma gondii tachyzoites cross the vascular endothelium to enter the human retina is unknown. Convincing studies using murine encephalitis models have strongly implicated leukocyte taxis as one pathway used by the parasite to access target organs. To establish whether tachyzoites might also interact directly with vascular endothelium, we populated a transwell system with human ocular endothelial cells. Human retinal endothelial monolayers permitted transmigration of tachyzoites of RH and three natural isolate strains. Antibody blockade of intercellular adhesion molecule-1 significantly reduced this migration, but did not impact tachyzoite movement across an endothelial monolayer derived from the choroid, which lies adjacent to the retina within the eye. In demonstrating that tachyzoites are capable of independent migration across human vascular endothelium in vitro, this study carries implications for the development of therapeutics aimed at preventing access of T. gondii to the retina. PMID- 22525369 TI - Introduction: Brain Stimulation in cognitive neuroscience. PMID- 22525370 TI - Endothelin-1 stimulates oral fibroblasts to promote oral cancer invasion. AB - AIMS: The aims of this study were to examine the role of endothelin-1 (ET-1), a pleiotropic peptide found at elevated levels in a number of malignancies and which has been shown to influence oral cancer cell behaviour via paracrine signalling pathways, on the phenotype of oral fibroblasts. MAIN METHODS: The effect of ET-1 on proliferation and migration of human primary oral fibroblasts was assessed using MTS and scratch assays, respectively. The ability of ET-1 to affect fibroblast contractility was analysed using type-I collagen gels. Changes in gene expression in oral fibroblasts exposed to ET-1 were examined using quantitative PCR. The invasiveness of oral cancer cells in the presence of conditioned media collected from ET-1 treated fibroblasts was determined using 2D Matrigel assays. KEY FINDINGS: Here we provide evidence that ET-1 increases the migration of oral fibroblasts and induces a more contractile phenotype which is not associated with changes in gene expression indicative of myofibroblast transdifferentiation. In addition we provide evidence that conditioned medium of ET-1-stimulated oral fibroblasts promotes invasion of OSCC cells in vitro. SIGNIFICANCE: In oral squamous cell carcinoma, a frequently fatal and increasingly common epithelial malignancy of the oral cavity, ET-1 is known to contribute to pro-migratory paracrine signalling between stromal fibroblasts and cancer cells. The ability of ET-1 to modulate the phenotype of human oral stromal fibroblasts, however, has not previously been reported. The findings presented here suggest that targeting the stromal endothelin system may be a viable and novel therapeutic strategy for invasive oral cancer. PMID- 22525371 TI - Is preconditioning by oxytocin administration mediated by iNOS and/or mitochondrial K(ATP) channel activation in the in vivo anesthetized rabbit heart? AB - AIMS: Oxytocin (OXT) pretreatment protects the heart during ischemia-reperfusion injury by activating ATP-dependent potassium (K(ATP)) channels. The aim of the current study was to elucidate the roles of nitric oxide synthaseNOS and myocardial biochemistry in the cardioprotective effects of OXT and ischemic preconditioning (IPC). MAIN METHODS: Male New Zealand White anesthetized rabbits (13 groups) were subjected to 30 min of occlusion of the left coronary artery and 120 min of reperfusion with or without IPC. KEY FINDINGS: IPC (1 cycle), OXT (0.03 MUg/kg, i.p.) or IPC + OXT yield significant infarct size reductions (21.8+/-1.5%, 20.5+/-1.2% and 19.4+/-1.4%, respectively, versus 38.9+/-3.5% in the S-CONT group; P<0.01) and antiarrhythmic effects, including VF (0%, 0% and 0%, versus 50% in S-CONT group; P<0.05) sustained VT (13%, 13% and 13%, versus 100% in S-CONT group; P<0.005) and other arrhythmias (25%, 13% and 25%, versus 100% in S-CONT group; P<0.005, P<0.01 and P<0.005, respectively). Atosiban (ATO, a selective OXT receptor antagonist), 5-HD and L-NAME (a nonspecific NOS inhibitor) abolished the beneficial effects of IPC and OXT, suggesting that the benefits are achieved via selective activation of OXT receptors, mitochondrial K(ATP) channels and NO. An iNOS inhibitor (1400 W) blocked the beneficial effects of IPC but not OXT. The IPC, OXT, IPC + OXT and 1400 W + OXT interventions significantly preserved ATP levels in the heart. SIGNIFICANCE: This study demonstrates similarities between acute OXT pretreatment and IPC in terms of infarct size reduction, antiarrhythmic activity, and metabolic status. PMID- 22525372 TI - Houttuyninum, an active constituent of Chinese herbal medicine, inhibits phosphorylation of HER2/neu receptor tyrosine kinase and the tumor growth of HER2/neu-overexpressing cancer cells. AB - AIMS: The overexpression of HER2/neu receptor plays a key role in tumorigenesis and tumor progression. Small molecules targeting HER2/neu have therapeutic value in cancers that overexpress HER2. In this present study, the effect of houttuyninum, a component in the Chinese herbal medicine Houttuynia cordata Thunb, on HER2/neu tyrosine phosphorylation and its in vivo antitumour activity was investigated. MAIN METHODS: The phosphorylation and expression of proteins were determined by Western blot analysis. The MTT assay was employed to examine the inhibition of cell proliferation in vitro. Xenografts were established in nude mice for evaluating the antitumour activity of houttuyninum in vivo. KEY FINDINGS: Houttuyninum inhibited phosphorylation of HER2 in a dose-dependent manner with an IC50 of 5.52 MUg/ml without reducing HER2/neu protein expression in MDA-MB-453 cells. Houttuyninum also inhibited the activation of ERK1/2 and AKT, downstream molecules in the HER2/neu-mediated signal transduction pathway. In contrast, tyrosine phosphorylation of EGFR was unaffected when the concentration of houttuyninum was increased to 40 MUg/ml in both A431 cells and MDA-MB-468 cells. Additionally, houttuyninum preferentially inhibited the growth of MDA-MB-453 cells that overexpressed HER2/neu; the MDA-MB-468 cells that overexpress EGFR remained unaffected. Administration of houttuyninum in vivo resulted in a significant reduction of phosphorylated HER2 levels and in tumor volumes of the BT474 and N87 xenografts, which both overexpress HER2/neu. SIGNIFICANCE: Our findings showed that houttuyninum can inhibit the HER2/neu signalling pathway and the tumor growth of cancer cells that overexpress HER2/neu. This drug may provide therapeutic value in the treatment of cancers that involve overexpression of HER2/neu. PMID- 22525373 TI - Synaptic and nonsynaptic mitochondria demonstrate a different degree of calcium induced mitochondrial dysfunction. AB - AIMS: Since variety in response to Ca(2+)-induced mitochondrial dysfunction in different neuronal mitochondrial populations is associated with the pathogenesis of several neurological diseases, we investigated the effects of Ca(2+) overload on synaptic (SM) and nonsynaptic mitochondrial (NM) dysfunction and probed the effects of cyclosporin A (CsA), 4'-chlorodiazepam (CDP) and Ru360 on relieving mitochondrial damage. MAIN METHODS: SM and NM mitochondria were isolated from rats' brains (n=5/group) and treated with various concentrations (5, 10, 100, and 200 MUM) of Ca(2+), with and without CsA (mPTP blocker), CDP (PBR/TSPO blocker) and Ru360 (MCU blocker) pretreatments. Mitochondrial function was determined by mitochondrial swelling, ROS production and mitochondrial membrane potential changes (DeltaPsim). KEY FINDINGS: At 200-MUM Ca(2+), SM presented mitochondrial swelling to a greater extent than NM. At 100 and 200-MUM Ca(2+), the ROS production of SM was higher than that of NM and DeltaPsim dissipation of SM was also larger. CsA, CDP and Ru360 could reduce ROS production of SM and NM with exposure to 200-MUM Ca(2+). However, only Ru360 could completely inhibit ROS generation in both SM and NM, whereas CsA and CDP could only partially reduce the ROS level in SM. Moreover, CsA and CDP pretreatments were not able to restore DeltaPsim. However, Ru360 pretreatment could protect DeltaPsim dissipation in both SM and NM, with complete protection observed only in NM. SIGNIFICANCE: Our findings suggested that mitochondrial calcium uniporter is a possible major pathway for calcium uptake in both mitochondrial populations. However, SM might have additional pathways involved in the calcium uptake. PMID- 22525374 TI - DNase activation by hypoxia-acidosis parallels but is independent of programmed cell death. AB - AIMS: Hypoxia, acidosis and programmed cell death are each hallmarks of acute myocardial infarction (AMI). We previously described a death pathway of cardiac myocytes mediated by hypoxia-acidosis that was characterized by activation of the Bcl2-family protein Bnip3 and programmed necrosis. The pathway included extensive DNA fragmentation that was sensitive to inhibition of the mitochondrial permeability transition pore (mPTP) and calpain inhibitors, but not caspase inhibitors. We did not identify the DNases responsible for DNA cleavage. MAIN METHODS: Neonatal rat cardiomyocytes were subjected to hypoxia with and without concurrent acidosis, and the cellular localization of apoptosis-inducing factor (AIF), DNase II and caspase-dependent DNase (CAD) were determined. KEY FINDINGS: Here we report the occurrence of biphasic pH-dependent translocations of AIF and DNase II but no change in CAD or its inhibitor ICAD. AIF co-localized with the mitochondria under aerobic and hypoxia-neutral conditions but translocated to the nucleus at pH ~6.7 coincident with a decrease of the mitochondrial membrane potential. DNase II co-localized with lysosomes under normoxia and hypoxia neutral conditions, and translocated to the nucleus at pH ~6.1 coincident with the appearance of single strand DNA cuts. Inhibition of the mPTP pore with BH4 TAT peptide, calpain inhibition with PD150606, or knockdown (KD) of Bnip3 failed to prevent nuclear translocation of these DNase although Bnip3 KD blocked mitochondrial fission. SIGNIFICANCE: These results suggest that caspase independent DNA fragmentation is precisely regulated and occurs in parallel but independently from programmed necrosis mediated by hypoxia-acidosis. PMID- 22525376 TI - Autophagic predisposition in the insulin resistant diabetic heart. AB - Existence of a diabetic cardiopathology, independent of vascular abnormalities, has been well reported. Diffuse interstitial fibrosis throughout the diabetic myocardium (even in the absence of an acute coronary event) suggests widespread cardiomyocyte attrition and cytokine activity. In addition to apoptotic and necrotic events, there is now good evidence that significant cardiomyocyte loss in the diabetic heart is driven by a different, non-apoptotic type of programmed cell death: autophagy. Although considered to be beneficial and pro-survival as a short term strategy to deal with acute stress, when chronically elevated or constitutive, excess autophagic activity has potential to be lethal. The insulin resistant myocardium exhibits various pro-autophagic characteristics: suppression of the PI3K(I)-Akt signaling pathway, oxidative stress and metabolic dysregulation, rendering the diabetic heart vulnerable to autophagic demise. There is compelling new evidence that in the diabetic myocardium cardiomyocyte attrition can be linked to autophagic upregulation. PMID- 22525375 TI - Critical metabolic roles of beta-cell M3 muscarinic acetylcholine receptors. AB - Muscarinic acetylcholine (ACh) receptors (mAChRs; M(1)-M(5)) regulate the activity of an extraordinarily large number of important physiological processes. We and others previously demonstrated that pancreatic beta-cells are endowed with M(3) mAChRs which are linked to G proteins of the G(q) family. The activation of these receptors by ACh or other muscarinic agonists leads to the augmentation of glucose-induced insulin release via multiple mechanisms. Interestingly, in humans, ACh acting on human beta-cell mAChRs is released from adjacent alpha cells which express both choline acetyltransferase (ChAT) and the vesicular acetylcholine transporter (vAChT), indicative of the presence of a non-neuronal cholinergic system in human pancreatic islets. In order to shed light on the physiological roles of beta-cell M(3) receptors, we recently generated and analyzed various mutant mouse models. Specifically, we carried out studies with mice which overexpressed M(3) receptors or mutant M(3) receptors in pancreatic beta-cells or which selectively lacked M(3) receptors or M(3)-receptor-associated proteins in pancreatic beta-cells. Our findings indicate that beta-cell M(3) receptors play a key role in maintaining proper insulin release and whole body glucose homeostasis and that strategies aimed at enhancing signaling through beta cell M(3) receptors may prove useful to improve beta-cell function for the treatment of type 2 diabetes (T2D). PMID- 22525377 TI - Renal, retinal and cardiac changes in type 2 diabetes are attenuated by macitentan, a dual endothelin receptor antagonist. AB - AIMS: Diabetes is known to cause alteration of the endothelin (ET) system. We have previously demonstrated that ETs regulate augmented production of extracellular matrix proteins causing structural alterations in type 1 diabetes. Here we investigated the effects of macitentan, an orally-active, tissue targeting dual ET receptor antagonist on chronic complications in type 2 diabetes. MAIN METHODS: db/db mice and their age- and sex-matched controls were examined after 2 and 4 months of diabetes. Groups of diabetic animals were treated with oral macitentan (25mg/kg/day). The animals were monitored with respect to body weight and blood glucose. Urine analyses were performed for albumin. Cardiac hemodynamic studies were carried out. Renal, cardiac and retinal tissues were analyzed for ET-1, transforming growth factor-beta1 (TGF-beta1), vascular endothelial growth factor (VEGF), fibronectin (FN), extradomain B containing FN (EDB(+)FN) and collagen alpha-I (IV) mRNA. Cardiac atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were measured. Protein expressions were measured by ELISA and Western blot. Microscopic analyses were performed in the kidneys. KEY FINDINGS: Diabetic animals showed hyperglycemia, increased urinary albumin and augmented serum creatinine levels. Diabetes caused increased renal, cardiac and retinal ET-1, TGF-beta1, VEGF, FN, EDB(+)FN, collagen alpha-I(IV) mRNA expression along with increased FN and collagen protein and NF-kappaB activation. Diabetic mice also demonstrated mesangial expansion, cardiac dysfunction and increased expression of ANP and BNP. Treatment with macitentan attenuated such abnormalities. SIGNIFICANCE: These experiments confirmed that ET system plays a significant role in the pathogenesis of chronic complications in type 2 diabetes. Such diabetes induced changes can be reduced macitentan therapy. PMID- 22525378 TI - Blockade of nicotinic and muscarinic receptors facilitates spontaneous migration of human peripheral granulocytes: failure in cystic fibrosis. AB - AIMS: Circulating leucocytes express muscarinic (m) and nicotinic (n) receptors and synthesize acetylcholine (ACh) regulating various cell functions. Leucocytes from patients with cystic fibrosis contain less ACh; therefore it was tested whether the regulation of cellular functions like migration differed from healthy volunteers. MAIN METHODS: Peripheral blood (10-20 ml) was used, leucocytes were isolated by Ficoll(r) gradient and the commercial MIGRATEST(r) combined with flow cytometric analysis was applied (pore size 3 MUm). KEY FINDINGS: In the absence of test substances 4900+/-1800 (n=10) leucocytes migrated within a time period of 2 h. In the presence of tubocurarine (TC, 30 MUM) the cell number increased to 7500+/-2700 [n=10] corresponding to an increase of 162+/-20% (mean of individual experiments; p<0.02). Atropine (1 MUM) was not effective (120+/-17%, n=7). Simultaneous application of atropine and TC produced a slightly higher effect than TC alone (185+/-23%; n=8); a 10-fold increase of TC and atropine resulted to a somewhat stronger effect (248+/-39%; n=8). When migration time was reduced to 30 min or the chemoattractant fMLP (0.05 MUM) present neither atropine nor TC affected migration. Granulocytes isolated from patients with cystic fibrosis did not respond (2h migration) to 30 MUM TC (control: 5180+/-1400 cells [n=10]; TC: 5800+/-1400 [n=10]). Also in the presence of atropine (1 MUM) and TC (30 MUM) a significant effect was not detected (5800+/-1300 [n=10]). SIGNIFICANCE: Auto paracrine acetylcholine limits the migration of unstimulated peripheral granulocytes. This effect is impaired in cystic fibrosis most likely because of a reduced endogenous cholinergic tone. PMID- 22525379 TI - The cannabinoid receptor-2 is involved in allergic inflammation. AB - AIM: To investigate the role of cannabinoid receptor-2 (CB2) in allergic inflammation in CB2 knockout (CB2-KO) mice. MAIN METHODS: The swelling reaction of the pinna to various stimuli was compared between CB2-KO and wild-type (WT) mice in terms of edema and acanthosis. KEY FINDINGS: Ear swelling induced by repeated application of 2,4-dinitrofluorobenzene in CB2-KO mice was significantly decreased compared with that in WT mice. In an ovalbumin model, pinna edema was significantly suppressed in CB2-KO mice in comparison with that in WT mice. The contribution of CB2 to edema was investigated in a more extreme dermatitis model using oxazolone. Delayed-type hypersensitivity reactions in this model were also suppressed in CB2-KO mice. In each of these three different allergic dermatitis models, there was a significant decrease in edema and acanthosis in CB2-KO mice compared with WT mice. SIGNIFICANCE: These results clearly demonstrate that CB2 and its endogenous ligands participate not only in the acute, edematous phase of allergic dermatitis, but also in the chronic irreversible acanthosis reaction. PMID- 22525380 TI - The effect of tumor necrosis factor-alpha inhibitor soon after hypoxia-ischemia on heart in neonatal rats. AB - AIMS: Perinatal hypoxic-ischemic insult has acute and long term deleterious effects on many organs including heart. Although tumor necrosis factor alpha (TNF alpha) has been reported to increase soon after hypoxia, the inhibition of this mediator has not been documented. The aim of this study was to investigate the effects of a TNF-alpha inhibitor (etanercept) on contractility and ultrastructure of rat heart muscles exposed to hypoxia-ischemia during neonatal period. MAIN METHODS: Forty-five seven-day old rats divided into three groups were included in this study. The right carotid arteries of Saline and Etanercept groups of rats were ligated and kept in a hypoxia chamber containing 8% oxygen for 2h. Immediately after hypoxia, while Etanercept group was administered 10mg/kg etanercept, Saline group had only saline intraperitoneally. The carotid arteries of rats in Sham group were located without ligation and hypoxia. Mechanical activity of heart was recorded and tissue samples were examined by electron microscopy in the sixteenth week following the hypoxia-ischemia. KEY FINDINGS: While atrial contractile force in Etanercept group was similar to Sham group, there was significant decrease in Saline group (p<0.001). However, there was only non-significant decrease in ventricular contractility of Saline group comparing to Sham group (p>0.05). After hypoxia-ischemia, ultrastructural degenerative changes and mitochondrial damage in atriums of Etanercept group were significantly less severe than Saline group. SIGNIFICANCE: This study demonstrated that neonatal hypoxia-ischemia caused long term cardiac dysfunction and ultrastructural degenerative changes in the heart of rats. TNF-alpha inhibitor administration soon after hypoxia-ischemia may have heart protective effect. PMID- 22525382 TI - Is early laparoscopic cholecystectomy for acute cholecystitis preferable to delayed surgery?: Best evidence topic (BET). AB - A best evidence topic was written according to a structured protocol. The question addressed was whether early laparoscopic cholecystectomy (ELC) in patients presenting with a short history of acute cholecystitis provides better post-operative outcomes than a delayed laparoscopic cholecystectomy (DLC). A total of 92 papers were found using the reported searches of which 10 represented the best evidence; 3 meta-analyses, 4 randomized control trials, 1 prospective controlled study and 2 retrospective cohort studies were included. The authors, date, journal, study type, population, main outcome measures and results were tabulated. No significant difference in complication or conversion rates were shown between the ELC and the DLC group, in the meta-analyses of Gurusamy et al, Lau et al and Siddiqui et al. The ELC group had a decreased hospital stay whereas the DLC group presented a considerable risk for subsequent emergency surgery during the interval period, with a high rate of conversion to open cholecystectomy. All three meta-analyses were based on the randomized control trials of Lo et al, Lai et al, Kolla et al and Johansson et al; the results of each study are summarized. We conclude that there is strong evidence that early laparoscopic cholecystectomy for acute cholecystitis offers an advantage in the length of hospital stay without increasing the morbidity or mortality. The operating time in ELC can be longer, however the incidence of serious complications (i.e. common bile duct injury), is comparable to the DLC group. Larger randomized studies are required before solid conclusions are reached. PMID- 22525383 TI - Sentinel lymph node biopsy before mastectomy and immediate breast reconstruction may predict post-mastectomy radiotherapy, reduce delayed complications and improve the choice of reconstruction. AB - BACKGROUND: Adjuvant post-mastectomy radiotherapy (RT), which is often unpredicted, is known to increase complications following immediate breast reconstruction (IBR). AIM: To investigate the role of sentinel lymph node biopsy (SLN) in predicting RT and improving the choice of IBR. PATIENTS AND METHODS: All patients who had mastectomy and IBR between January 2004 and January 2007 were reviewed retrospectively. Axillary staging (clearance or SLN) was performed at the same time until October 2005 (Group 1), when the Unit's protocol was updated to perform SLN initially prior to mastectomy and IBR (Group 2). Patients in Group 2 with positive SLN were offered either a delayed reconstruction or a temporary subpectoral immediate tissue expander, while all options were offered if SLN was negative and in Group 1 patients. RESULTS: One hundred and thirty-nine patients were reviewed. 20 patients received unexpected RT in Group 1 (14 tissue expander, 4 Latissimus Dorsi flap with an implant and 2 DIEP flaps) compared to 11 patients in Group 2 who had a temporary tissue expander due to expected RT (P=0.03). Unexpected RT caused delayed complications in 14 patients (70%) compared to no delayed complications in patients who received expected RT in Group 2. CONCLUSION: SLN biopsy before IBR helps to predict RT and avoids its complications on breast reconstruction. Patients with positive SLN biopsy are best offered a temporary subpectoral tissue expander for IBR. PMID- 22525384 TI - Efficacy of mometasone furoate nasal spray for nasal symptoms, quality of life, rhinitis-disturbed sleep, and nasal nitric oxide in patients with perennial allergic rhinitis. AB - Intranasal corticosteroid therapy has exhibited effectiveness for improving nasal symptoms and quality of life (QOL) scores associated with seasonal allergic rhinitis. We prospectively investigated the efficacy of mometasone furoate nasal spray (MFNS) for improving the total nasal symptom score, QOL score, and sleep quality in subjects with perennial allergic rhinitis (PAR). Nasal airway conditions were also objectively assessed by measuring nasal nitric oxide (NO). Fifty-seven patients with PAR were randomized to MFNS or placebo for a 14-day, double-blind, crossover study. The subjects recorded their symptoms on nasal symptom forms and a visual analog scale. QOL and sleep quality were surveyed in accordance with the Japanese version of the Rhinoconjunctivitis Quality of Life Questionnaire (JRQLQ) and the Japanese version of the Epworth Sleepiness Scale. Nasal NO was measured during a single exhalation using a chemiluminescence analyzer. MFNS treatment achieved significant reductions versus placebo for total nasal symptoms (p < 0.001). There were significant decreases of the usual daily activity domain (p < 0.005), outdoor activities (p < 0.01), social function (p < 0.05), and the overall QOL score (p < 0.05) of JRQLQ with MFNS therapy versus placebo. A significant reduction of the sleepiness scale was also observed in the MFNS group with high sleep disturbance (p < 0.01). A significant decrease of nasal NO was found in the MFNS group (p < 0.01), especially among patients with severe nasal symptoms (p < 0.005). This prospective study indicated that MFNS therapy significantly improves nasal symptoms, QOL, sleep quality, and upper airway condition in Japanese subjects with PAR. PMID- 22525386 TI - Effectiveness of trivalent inactivated influenza vaccine in influenza-related hospitalization in children: a case-control study. AB - Influenza is known to be associated with asthma exacerbation but the effectiveness of the trivalent inactivated flu vaccine (TIV) in children, especially children with asthma, in preventing hospitalization is unknown. We assessed the effectiveness of the TIV in all children and especially children with asthma to prevent hospitalization with influenza. We conducted a nested case control study of all pediatric subjects (6 months to 18 years old) who were evaluated at the Mayo Clinic, Rochester, MN, who had laboratory-confirmed influenza during each flu season from 1999 to 2006 to evaluate the efficacy of TIV in preventing hospitalization. A case-control analysis was performed with the cases and the controls being the subjects who did and did not required hospitalization with the influenza illness, respectively. There were 261 subjects with laboratory-confirmed influenza from 1996 to 2006. There was an overall trend toward higher rates of hospitalization in subjects who got the TIV when compared with the ones who did not get the TIV (odds ratio [OR], 3.67; CI, 1.6, 8.4). Using the Cochran-Mantel-Haenszel test for asthma status stratification, there was a significant association between hospitalization in asthmatic subjects and TIV (p = 0.001). TIV did not provide any protection against hospitalization in pediatric subjects, especially children with asthma. On the contrary, we found a threefold increased risk of hospitalization in subjects who did get the TIV vaccine. This may be a reflection not only of vaccine effectiveness but also the population of children who are more likely to get the vaccine. PMID- 22525385 TI - Efficacy of prophylactic treatment with montelukast and montelukast plus add-on loratadine for seasonal allergic rhinitis. AB - Cysteinyl leukotriene and leukotriene receptor occupancy have been linked to several processes in seasonal allergic rhinitis (SAR), including nasal congestion, rhinorrhea, and recruitment of inflammatory cells. We investigated whether add-on loratadine, an antihistamine, might be effective for SAR patients showing unsatisfactory control of symptoms with the leukotriene receptor antagonist (LTRA) montelukast alone. Patients with SAR caused by Japanese cedar pollen (SAR-JCP; mean age, 29.4 years) were given prophylactic montelukast for 1 month before peak JCP dispersal. Patients recorded the severity of the symptoms (sneezing, rhinorrhea, nasal congestion, and ocular symptoms) daily on visual analog scale (VAS). We selected patients with VAS scores of >50 for any of the symptoms just before the peak pollen season (March 2 to March 8) and designated them as "poorly controlled" patients. Then, in the peak JCP season (from March 9), we conducted a randomized, double-blind, placebo-controlled study to determine whether add-on loratadine might be effective for these "poorly controlled" patients. Montelukast alone was effective, as evaluated by improvement of the VAS scores, in 95 of the 137 patients (69.3%). Add-on loratadine significantly decreased the total scores for nasal symptoms (p < 0.05), sneezing (p < 0.05), and rhinorrhea (p < 0.05) when compared with placebo. The symptoms of SAR in two of three SAR-JP patients could be controlled (VAS score[s] under 50) by prophylactic treatment with montelukast alone under the condition of mild JCP dispersal. Furthermore, the effect of add-on antihistamine on sneezing and rhinorrhea was found in selected SAR-JCP patients. PMID- 22525387 TI - Aspirin-exacerbated respiratory disease: burden of disease. AB - Aspirin-exacerbated respiratory disease (AERD) is characterized by adult onset of asthma, chronic rhinosinusitis (CRS), nasal polyposis, and aspirin sensitivity. In this syndrome, each disease component has deleterious effects on the patient's health and quality of life. Latest figures from the Centers for Disease Control indicate 8.2% of the U.S. population has asthma and among adult asthmatic patients, up to 9% have AERD. Approximately 13% of the population suffers from CRS and 15% of patients with CRS with nasal polyposis have AERD. A review of the impact that each component of AERD has on patients will delineate the considerable burden of AERD, especially when considering the cumulative effects of the tetrad. PMID- 22525388 TI - One hundred years of immunotherapy: review of the first landmark studies. AB - In 2011, one hundred years of allergen immunotherapy was celebrated. Several landmark studies date from the first decades of experience with this treatment and are still cited today, often without analysis of the original articles. Original articles of the oldest landmark studies on subcutaneous immunotherapy (SCIT) and sublingual immunotherapy were sought and reviewed in detail, together with some publications on their authors' historical background. Details that might be of importance to the present allergists are highlighted in this article. Study design, preparation of allergen extracts used for immunotherapy and clinical findings of the following studies are discussed. For the European school, Noon 1911 was the first report of successful application of grass pollen extract; Frankland 1954 was the first double-blind placebo-controlled randomized trial (DBPC-RCT) in SCIT. For the European school: Noon published the first report of successful application of grass pollen extract (1911); Frankland was the first double-blind placebo-controlled randomized trial (DBPC-RCT) in SCIT (1954). For the American line: Clowes published the first successful trial of ragweed SCIT (1913); Cooke used skin prick testing as diagnostic method (1915); Loveless used venom immunotherapy with purified venom (not whole body extract) (1956); in 1961/1968 Johnstone showed in a DBPC-RCT dose-effect of an allergen mix and highly significant asthma reduction after up to 14 yrs of treatment of asthmatic children; Lowell and Franklin did the first DB-RCT demonstrating ragweed pollen efficacy as part of a multi-allergen mix and 1967 ragweed pollen extract dose response. We discuss the first studies for SLIT in 1927 from Black (oral-IT versus SCIT) and 1986 from Scadding, DBPC-RCT with house dust mite extract. We conclude that an in-depth review of investigators' observations, methods, and thoughts, however, can also be enriching for investigators in the field today. PMID- 22525389 TI - Allergic conjunctivitis: the evolution of therapeutic options. AB - The eye has become the target of intense pharmacologic development because it represents one of the most active sites of allergic inflammation, due to it having no mechanical barrier to prevent the impact of allergens such as pollen on its surface. Over the past 20 years, we have witnessed an astonishing growth in therapeutic advances, ranging essentially from derivatives of simple aspirin to various newly developed biological immunomodulatory agents, using implantable drug delivery devices that exceed the safety and efficacy of those available for other organ systems and resorting to advanced surgical techniques for the correction of sight-threatening, disease-related complications. Overall, with the expanding knowledge base, the intricacy of ocular inflammation appears to be becoming ever more manageable and the clinical allergist/immunologist has an increasing role in the treatment outcomes of patients with anterior inflammatory disorders of the ocular surface primarily allergic conjunctivitis but also including dry eye syndromes. PMID- 22525390 TI - Do inhaled corticosteroid/long-acting beta2-agonist fixed combinations provide superior clinical benefits compared with separate inhalers? A literature reappraisal. AB - Current asthma management guidelines emphasize the importance of disease control. Although effective drug therapies are available, real-life data indicate that the general level of asthma control is still low. Fixed-dose combinations of inhaled corticosteroids/long-acting beta(2)-agonists (ICS/LABAs) are now increasingly used in the management of asthma. A number of studies have compared the clinical benefits of ICS/LABA fixed combinations with the monocomponents administered using two separate inhalers. We conducted a database search to identify all published studies that have assessed whether fixed-dose combinations achieve greater asthma control compared with administration by separate inhalers. Among fixed combinations, only extrafine beclomethasone/formoterol provided significantly greater asthma control compared with separate inhalers administered as larger aerosol particles. This greater effect may be explained by increased delivery to the small airways by the extrafine formulation. PMID- 22525391 TI - Physician approaches to beta-lactam use in patients with penicillin hypersensitivity. AB - Beta-lactam antibiotics are widely used, but hypersensitivity reactions are common and difficult to manage. This study was designed to identify lack of knowledge regarding the safe use of alternative beta-lactams in penicillin allergic patients and assess management differences between allergists and nonallergists. An electronic physician survey was sent to 623 providers in allergy, internal medicine, pediatrics, and family medicine, querying beta-lactam use in patients with a history of penicillin allergy. A total of 110 (17.7%) surveys were completed. For patients with a prior maculopapular rash to penicillin, most providers were uncomfortable prescribing penicillins again, although they would use other beta-lactams. In patients with an exfoliative dermatitis to penicillin, 46% of responders would not prescribe any beta-lactam again. For patients with a positive skin test to penicillin, only 45.1% of nonallergists were comfortable prescribing monobactams versus 62.5% of allergists; 30.3% of all responders would give a carbapenem. In patients with urticaria to penicillin, pediatricians were the most comfortable prescribing third- or fourth-generation cephalosporins. Providers (both allergists and nonallergists) were unfamiliar with the safety of prescribing penicillin in patients with history of maculopapular rash, the safety of monobactams, and low cross-reactivity with carbapenems in penicillin-allergic individuals. Nonallergists were also unfamiliar with the usefulness of penicillin skin testing. Improved education is needed to address these areas. Additionally, we found variability in responses regarding exfoliative dermatitis and comfort prescribing cephalosporins in patients with suspected IgE-mediated drug allergy to penicillin, highlighting the need for additional research in these areas. PMID- 22525392 TI - Alkali-treated penicillin G solution is a better option than penicillin G as an alternative source of minor determinants for penicillin skin test. AB - Both benzylpenicilloyl-polylysine (PPL) and minor determinant mixture (MDM) are the recommended standard reagents for penicillin skin testing. However, penicillin G is commonly suggested as an alternative source of minor determinants. This study evaluated the accuracy of penicillin G and alkali treated penicillin G compared with the standardized MDM for skin testing. Sixty eight patients with histories of allergies to penicillin or semisynthetic penicillins were skin tested with commercial Kit penicillin allergenic determinants (DAP) (PPL and DAP-MDM; Diater Laboratorios, Madrid, Spain). The in house MDM (IH-MDM), prepared by alkali-treated aged penicillin, and fresh penicillin G sodium (PGs) were tested alongside DAP-MDM. Positive penicillin skin test results were identified in 22 patients (32.4%) using commercial reagents (PPL+ DAP-MDM) and 19 of them reacted to DAP-MDM alone or together with PPL. The accuracy of IH-MDM and PGs compared with DAP-MDM was 89.7 and 76.5%, respectively. Our study shows that alkali-treated penicillin G is a better option than penicillin G as an alternative source of MDM for skin testing in case the commercialized MDM is not available. Minor determinants play a significant role for penicillin allergy in Thailand and should be included in the penicillin skin test panel to verify suspected cases of penicillin allergy. (ClinicalTrials.gov number: NCT00789217). PMID- 22525393 TI - The importance of vancomycin in drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. AB - Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome characterized by fever, rash, eosinophilia, atypical lymphocytes, and multiorgan involvement has a significant mortality. Inpatient vancomycin use is increasing and appears to be emerging as an important etiology of DRESS syndrome. This study highlights the importance of vancomycin as a cause of DRESS syndrome. We reviewed all cases of DRESS syndrome among inpatients consulted by the Allergy & Immunology service at Massachusetts General Hospital (MGH) from July 2009 through December 2010. We also reviewed the use of inpatient parenteral vancomycin over the past 4 years at MGH. Six patients fulfilled clinical criteria for DRESS syndrome, including rash, fever, eosinophilia, and hepatitis, with five (83%) having vancomycin as the attributable cause. Onset of symptoms varied from 12 days to 4 weeks after start of vancomycin treatment. Systemic findings included atypical lymphocytes, lymphadenopathy, nephritis, hypotension, tachycardia, and pharyngitis. Treatment with corticosteroids was required in three cases. Recurrence of peripheral eosinophilia was a marker of disease relapse. In three of the five patients (60%), elevated human herpesvirus 6 (HHV6) IgG titers correlated with greater systemic involvement and prolonged time to resolution. MGH pharmacy records indicate a progressive increase in the number of patients treated with parenteral vancomycin over the last 4 years. Causative agents for DRESS syndrome in an inpatient setting is likely different from that seen in the general population. With increasing use of vancomycin, we are likely to see more cases of DRESS syndrome caused by vancomycin. Recognition of vancomycin as a common cause of inpatient DRESS syndrome is important. PMID- 22525394 TI - Omalizumab and asthma control in patients with moderate-to-severe allergic asthma: a 6-year pragmatic data review. AB - Controlled clinical trials have shown the recombinant humanized monoclonal anti IgE antibody omalizumab to improve asthma control and reduce symptom exacerbations in patients with moderate-to-severe allergic asthma who remain clinically unstable despite optimal medical therapy. An objective retrospective review compared clinical experience with the data reported in the controlled studies. Data tracking for 167 patients progressively enrolled between 2003 and 2010 treated with omalizumab included symptoms, forced expiratory volume at 1 second (FEV(1)), systemic steroid bursts, and need for short-acting bronchodilator rescue measured at the start of therapy; 3, 6, and 12 months after starting treatment, and yearly thereafter. Exacerbations were compared for the 12 months before and the 12 months after starting treatment in a subgroup of patients. Asthma control improved with omalizumab over time (up to 6 years) as indicated by fewer symptoms and less need for rescue medication (p < 0.001 for both). FEV(1) remained stable. The number of patients reporting asthma exacerbations requiring urgent care decreased by 49% during the first 12 months of treatment (p <= 0.01), and significant reductions in exacerbations were also evident when measured by hospitalizations or systemic corticosteroid bursts (p < 0.001 for both). This is the first long-term pragmatic review of omalizumab. Our clinical experience (up to 6 years in some patients) supports the results of earlier controlled studies, confirming the usefulness of adding omalizumab to the long-term management of patients with difficult-to-treat disease who suffer from persistent symptoms despite optimal therapy with medications. PMID- 22525395 TI - Ecallantide for treatment of acute hereditary angioedema attacks: analysis of efficacy by patient characteristics. AB - Hereditary angioedema (HAE) is characterized by episodic attacks of edema. HAE is caused by low levels of the protein C1 esterase inhibitor, which inhibits plasma kallikrein, the enzyme responsible for converting high-molecular-weight kininogen to bradykinin. Unregulated production of bradykinin leads to the characteristic clinical symptoms of swelling and pain. Ecallantide is a novel plasma kallikrein inhibitor effective for treatment of acute HAE attacks. This study was designed to analyze the efficacy of ecallantide for treating HAE attacks by attack location, attack severity, patient gender, and body mass index (BMI). An analysis of integrated data from two double-blind, placebo-controlled trials of ecallantide for treatment of acute HAE attacks was undertaken. For the purpose of analysis, symptoms were classified by anatomic location and, for each location, by the patient-assessed severity of the attack. Efficacy versus placebo was examined using two validated patient-reported outcomes: treatment outcome score and mean symptom complex severity score. One hundred forty-three attacks were analyzed (73 ecallantide and 70 placebo). Ecallantide was equally effective in both male and female subjects. Ecallantide had decreased efficacy for patients with BMI > 30 kg/m(2). Ecallantide showed efficacy for treatment of severe and moderate attacks, and was effective for abdominal, internal head and neck, external head and neck, and cutaneous locations. In summary, ecallantide is effective for treatment of acute HAE attacks of different symptom locations and severity; outcomes were similar for men and women. However, the standard dose was less effective for obese patients. PMID- 22525396 TI - Adaptation and validation of the Urticaria Patient Daily Diary for adolescents. AB - The Urticaria Patient Daily Diary, including the Urticaria Activity Score, has recently been validated in adults with chronic idiopathic urticaria (CIU), but its validity in adolescents is unknown. This study was designed to (1) assess the content validity of the Adolescent Urticaria Patient Daily Diary and, (2) collect exploratory data on symptom experiences, sleep interference, and health-related quality of life (HRQOL) of adolescents with CIU. The Urticaria Patient Daily Diary was modified to increase its relevance with an adolescent population. A qualitative, cross-sectional, multicenter study was then conducted in the United States so that adolescent subjects could provide information on the impact of urticaria on their lives and comment on the diary. Data were collected via in person semistructured interviews with subjects 12-17 years of age with moderate to-severe CIU. The most bothersome symptom was itching (44%). The impact of CIU on HRQOL varied. The majority of subjects (78%) reported waking up at least once a night. Overall, subjects found the diary to be clear, easy to comprehend, and easy to complete. Revisions were made to the diary based on feedback from subjects. After nine interviews, no new information was received. The symptoms of CIU are bothersome to adolescents, particularly itch, and urticaria has a negative impact on the sleep of adolescent patients. The final Adolescent Urticaria Patient Daily Diary has evidence of content validity in patients with CIU ranging from 12 to 17 years of age. PMID- 22525397 TI - Pretests or advance organizers for Web-based allergy-immunology medical education? A randomized controlled trial. AB - Web-based modules may facilitate instruction on core topics in allergy and immunology (AI). Pretests (PTs) have been shown to improve learning in Web-based courses, but their effectiveness in comparison with advance organizers (AOs) is unknown. We performed a randomized controlled trial of a Web-based educational intervention for teaching the practical aspects of allergen immunotherapy (AIT). AI Fellows-in-Training were randomly assigned to receive the introduction to the modules in an AO outline (AO group) or as PT questions (PT group). The primary outcome was the difference in posttest scores between groups. The secondary outcome was the difference in PT and posttest scores in the PT group. Thirty participants in the AO group and 35 in the PT group completed the modules and the posttest. The mean (SD) posttest score for the AO group was 74% (14%) compared with 73% (9%) for the PT group, a mean difference of -1% (95% CI, -7%, 5%; p = 0.67). A multivariate analysis controlling for year-in-training and total time spent on the modules revealed virtually identical results. The mean (SD) PT score for the PT group increased from 49 (10%) to 73% (9%), a mean difference of 24% (95% CI, 19%, 28%; p < 0.0001). Introducing Web-based allergy education with PT questions or an AO resulted in similar posttest scores. Posttest scores in the PT group improved significantly compared with PT scores. PMID- 22525398 TI - Efficacy and safety of ribosome-component immune modulator for preventing recurrent respiratory infections in socialized children. AB - Attending day care is associated with recurrent respiratory infections (RRIs) and asthma. Ribosomal immunotherapy may confer protection against RRIs in children. This study was designed to assess the efficacy of a ribosome-component immune modulator (RCIM) as preventive treatment of respiratory infections in socialized children aged <=5 years, with or without a history of frequent RRI. In a multicenter, Italian, randomized, double-blind, placebo-controlled, parallel group study, 164 socialized day care center children (mean age, 3.8 +/- 1.1 years) were treated with RCIM or placebo for 6 months and followed-up for additional 6 months. Outcomes are presented for the intent-to-treat population. In socialized children with five or less RRIs (n = 95; 49 RCIM and 46 placebo, group A) the duration of the infectious episodes was significantly shorter with RCIM than with placebo (6 months, 3.7 +/- 2.1 versus 4.5 +/- 1.9 days, p = 0.040; 12 months, 3.6 +/- 2.0 versus 4.7 +/- 2.5 days, p = 0.015). The proportion of patients reporting no respiratory infectious episodes with RCIM at 6 and 12 months was also significantly larger in group A (20.4% versus 4.4% placebo; p = 0.028). No such differences were found in children with more than five RRIs in the preceding year (n = 63; 32 RCIM and 31 placebo, group B). In all children, general well-being improved significantly more under RCIM than under placebo (11.6 +/- 1.8% versus 10.2 +/- 1.8%; p = 0.002). No statistically significant between-treatment differences were observed for other end points. Both treatments were similarly well tolerated. Six-month treatment with RCIM effectively prevented the 12-month risk of RRIs in children <5 years old and with five or less RRIs in the preceding year. PMID- 22525399 TI - A 44-year-old man with bilateral eyelid swelling. AB - Swollen eyelids are commonly ascribed to allergic conjunctivitis, contact dermatitis, eczema, angioedema, or acute sinusitis. The differential diagnosis extends to thyroid eye disease; blepharitis; Sjogren's syndrome; Churg-Strauss vasculitis; Wegener's granulomatosis; Gleich syndrome; orbital and ocular lymphoid hyperplasia or adnexal lymphoma; idiopathic orbital inflammatory disease/idiopathic sclerosing orbital inflammation; rarely, orbital parasitosis; and IgG4-related diseases. The likely diagnosis proceeds from the more to the less common in patients without a history of allergy or infection. Both ocular lymphoid hyperplasia and ocular adnexal lymphoma must be considered in the differential diagnosis of persistent disease, and neither of these entities can be recognized or differentiated from one another clinically or radiologically. Early diagnosis is essential because therapy may consist of frequent follow-up and/or active intervention. Outcomes in patients treated early and appropriately are often favorable. PMID- 22525400 TI - Cavity-enhanced absorption using an atomic line source: application to deep-UV measurements. AB - Optical cavities are commonly used to increase the sensitivity of absorption measurements, but have not been extensively used below 300 nm, mainly owing to the limited light sources at these wavelengths. While some progress has been made using cavity ring-down spectroscopy, these systems rely on complex and expensive lasers. Here we investigate an approach combining Cavity-Enhanced Absorption Spectroscopy (CEAS) with an inexpensive low vapour pressure mercury lamp for sensitive absorption measurements at 253.7 nm. We demonstrate that the CEAS absorption in our system is 50 times greater than the absorption found in a single-pass configuration; using this approach, we obtained limits of detection of 8.1 pptv (66 ng m(-3)) for gaseous elemental mercury and 8.4 ppbv for ozone. We evaluate the performance of the system and discuss potential improvements and applications of this approach. PMID- 22525401 TI - Never say never: a descriptive study of hospital-acquired pressure ulcers in a hospital setting. AB - PURPOSE: The purposes of this study were to describe the characteristics of patients who experienced hospital-acquired pressure ulcers (HAPUs); explore risk factors with these patients, including comorbid conditions; and describe risk reduction measures in patients who developed HAPUs. SUBJECTS AND SETTING: Eighty two patients with at least 1 HAPU were identified at an urban Midwestern trauma center over 1 year. DESIGN: A prospective study was conducted that included chart review and patient assessment. METHODS: Assessment criteria for the data collection form were obtained from the literature. The novel instrument was designed to capture intrinsic conditions, for example, medical diagnoses; extrinsic conditions, such as microclimate factors; and organ failure. Characteristics of all patients with at least 1 HAPU were collected by a certified wound care nurse. Data were analyzed using descriptive statistics. RESULTS: Most patients who developed HAPUs were ill enough to require extended hospital stays and discharged to extended care facilities. All patients with HAPUs had multiple risk factors, categorized as intrinsic, extrinsic, or organ failures, yet nearly one-quarter were identified by current standards as "low risk." Many of the measured variables are well-established risk factors, but several were comorbid diagnoses that are not assessed on the Braden Scale for Pressure Sore Risk. Eighty percent of subjects had 6 or more risk factors associated with an increased risk for PU development (mean = 9.2). Two-thirds of the sample group experienced failure of at least 1 organ system. Data on the use of 5 preventive interventions was tallied. A vast majority of patients (84.1%) were using 4 or 5 (mean = 4.3, SD = 1.0) of the interventions prior to the occurrence of the HAPU. CONCLUSION: Current risk assessment methods do not assess organ failures and the effect of multiple comorbid associated with HAPU occurrence. Current risk prevention methods may not be sufficient to prevent HAPUs in all patients. PMID- 22525404 TI - development of a therapeutic approach to rare cancers in children: the Children's Oncology Group experience. AB - Rare tumors are a heterogenous group of infrequent tumors with varied biology and clinical presentation. Although individually rare, in aggregate they account for 15% of all cancers in children younger than 20 years of age. The management of these tumors can be challenging, as there are no pediatric protocols or treatment guidelines. In an effort to improve the management of these rare tumors, the Children's Oncology Group rare tumor committee, brought together a panel of experts to develop therapeutic recommendations for these rare tumors. These recommendations are being presented in this journal issue. PMID- 22525402 TI - beta-ureidopropionase deficiency: phenotype, genotype and protein structural consequences in 16 patients. AB - beta-ureidopropionase is the third enzyme of the pyrimidine degradation pathway and catalyzes the conversion of N-carbamyl-beta-alanine and N-carbamyl-beta aminoisobutyric acid to beta-alanine and beta-aminoisobutyric acid, ammonia and CO(2). To date, only five genetically confirmed patients with a complete beta ureidopropionase deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 11 newly identified beta-ureidopropionase deficient patients as well as the analysis of the mutations in a three dimensional framework. Patients presented mainly with neurological abnormalities (intellectual disabilities, seizures, abnormal tonus regulation, microcephaly, and malformations on neuro-imaging) and markedly elevated levels of N-carbamyl beta-alanine and N-carbamyl-beta-aminoisobutyric acid in urine and plasma. Analysis of UPB1, encoding beta-ureidopropionase, showed 6 novel missense mutations and one novel splice-site mutation. Heterologous expression of the 6 mutant enzymes in Escherichia coli showed that all mutations yielded mutant beta ureidopropionase proteins with significantly decreased activity. Analysis of a homology model of human beta-ureidopropionase generated using the crystal structure of the enzyme from Drosophila melanogaster indicated that the point mutations p.G235R, p.R236W and p.S264R lead to amino acid exchanges in the active site and therefore affect substrate binding and catalysis. The mutations L13S, R326Q and T359M resulted most likely in folding defects and oligomer assembly impairment. Two mutations were identified in several unrelated beta ureidopropionase patients, indicating that beta-ureidopropionase deficiency may be more common than anticipated. PMID- 22525405 TI - Management of thyroid carcinoma in children and young adults. AB - Thyroid cancers represent the largest group of pediatric carcinomas. Unlike other cancers of childhood, they have not been prospectively studied; instead adult data has been extrapolated to childhood and adolescent treatment. In this article we review the treatment of both well differentiated thyroid cancer (WDTC), as well as medullary thyroid cancer (MTC). The approach to both cancers relies on a low threshold of suspicion, and a willingness to biopsy suspicious lesions. Surgery remains the primary method of curing these patients, although radioactive iodine (RAI) may offer some benefit in WDTC for selected patients. For patients with MTC new medications, such as Vandetanib, may offer some adjuvant benefit following surgery. Lastly, suppression of thyroid stimulating hormone (TSH) may be one of the most beneficial treatments for WDTC. PMID- 22525406 TI - Management of pancreatoblastoma in children and young adults. AB - Pancreatoblastoma is a very rare childhood tumor originating from the epithelial exocrine cells of the pancreas. It is the most common malignant pancreatic tumor in young children and has a mean age of diagnosis of 5 years. It is slow growing and its presentation is varied and often non-specific. Tumors tend to be quite large and appropriate cross sectional imaging is very important to assess for extent, metastatic disease, and resectability. Biopsy for tissue diagnosis is essential. Complete surgical resection is the goal of therapy although many patients are unresectable at initial diagnosis and require neoadjuvant chemotherapy. Adjuvant chemotherapy is also recommended and chemotherapeutic regimens involve cisplatin and doxorubicin. Even with curative resections, these lesions have a high recurrence rate and patients must be followed closely. Knowledge of this rare tumor is important for the clinician confronted with a large retroperitoneal mass in a young child. PMID- 22525407 TI - Management of melanomas in children and young adults. AB - Melanoma is rare in children and young adults. The incidence is rising yearly in this population. The clinical features of the disease in the pediatric population have been well documented through single-institution experiences and population based analyses. Still, our understanding of the etiologic factors in the majority of children remains unclear, and diagnosis of melanoma remains challenging in certain cases. Because of its rarity, the staging, management and treatment of melanoma in this population is adopted from adult guidelines. In this review, we provide information on the epidemiology, clinical presentation, staging, prognosis and management of melanoma in children and young adults. PMID- 22525408 TI - Management of ovarian and testicular sex cord-stromal tumors in children and adolescents. AB - Pediatric ovarian and testicular sex cord-stromal tumors are distinct from germ cell neoplasms and may present with palpable mass or signs of hormone production. Both may be associated with specific genetic syndromes. Staging for ovarian sex cord-stromal tumors is based on the International Federation of Gynecology and Obstetrics classification for ovarian carcinoma. Treatment for those with high risk disease includes multiagent chemotherapy. Testicular stromal tumors often, though not always, follow a benign course. Additional research will help to define optimal treatment strategies for children with these rare tumors. PMID- 22525409 TI - Management of neuroendocrine tumors in children, adolescents, and young adults. AB - Neuroendocrine tumors, often referred to as carcinoid tumors, are relatively rare within the pediatric and young adult populations. However, when they do occur, the more aggressive tumors can be associated with significant morbidity and even mortality in this younger age group. This article reviews the history of pediatric neuroendocrine tumors, typical clinical presentation, appropriate diagnostic studies, staging, and treatment of this unusual cancer. PMID- 22525410 TI - Treatment guidelines for gastrointestinal stromal tumors in children and young adults. AB - Gastrointestinal stromal tumor (GIST) occurring in the pediatric population has a unique biology and natural history when compared to GIST occurring in adults. As a result of these unique features, management of GIST in children may need to differ from management of GIST in adults. GIST is a very rare disease in children. Consequently prospective clinical trials have not been performed. A review of the biology, clinical presentation and natural history of GIST in children is presented. Guidelines for diagnostic evaluation and management of GIST in children are presented. The presented guidelines are based on clinical experience and data from case reports and case series. PMID- 22525411 TI - Management of desmoplastic small round-cell tumors in children and young adults. AB - Desmoplastic small round cell tumor (DSRCT) is a rare type of sarcoma which is primarily abdominal in origin. Less than 200 cases have been reported. DSRCT presents with multifocal tumors believed to begin in the peritoneal surfaces of the abdominal cavity. Up to hundreds of tumors can be found in the abdominal cavity. Adolescent males are primarily affected. Because of the rarity of the tumor and the unusually aggressive presentation, treatment is challenging and has not been standardized. Here we summarize the clinical presentation, diagnosis and management options of this rare tumor. PMID- 22525412 TI - Management of colorectal carcinoma in children and young adults. AB - Colorectal Carcinoma (CRC) is rare in patients less than 20 years of age. Although presenting symptoms are similar to adults, this diagnosis is rarely considered in the initial differential diagnosis of young patients. We will review what is published about the incidence, epidemiology, and clinical presentation of CRC in children, adolescents and young adults. Because of its rarity in this age group, few pediatric oncologists will have experience with CRC, and clinical trials will rarely be available. The treatment of CRC in adults is evolving rapidly and consultation with medical oncologists experience in treating adults with CRC is essential to develop the best treatment plan for a young patient diagnosed with CRC. PMID- 22525413 TI - Raman spectroscopy--a potential new method for the intra-operative assessment of axillary lymph nodes. AB - Sentinel Lymph Node Biopsy has become the standard surgical procedure for the sampling of axillary lymph nodes in breast cancer. Intra-operative node assessment of these nodes would allow definitive axillary surgery to take place immediately with associated benefits for patient management. Our experimental study aims to demonstrate that a Raman spectroscopy probe system could overcome many of the disadvantages of current intra-operative methods. 59 axillary lymph nodes, 43 negative and 16 positive from 58 patients undergoing breast surgery at our district general hospital were mapped using Raman micro-spectroscopy. These maps were then used to model the effect of using a Raman spectroscopic probe by selecting 5 and 10 probe points across the mapped images and evaluating the impact on disease detection. Results demonstrated sensitivities of up to 81% and specificities of up to 97% when differentiating between positive and negative lymph nodes, dependent on the number of probe points included. The results would have concurred with histopathology assessment in 89% and 91% of cases in the 5 and 10 point models respectively. Using Raman spectroscopy in this way could allow lymph node assessment within a time-frame suitable for intra-operative use. PMID- 22525414 TI - Is pancreaticoduodenectomy justified in elderly patients? AB - BACKGROUND: Although mortality & morbidity for pancreaticoduodenectomy (PD) have improved significantly over the last two decades, the concern for elderly undergoing PD remains. This study examines the outcome of the elderly patients who had pancreaticoduodenectomy in our institution. METHODS: A prospective database comprising 69 patients who underwent pancreaticoduodenectomy between 2001 and May 2008 was analyzed. Using WHO definition, elderly patient is defined as age 65 and above in this study. Two groups of patients were compared [Group 1: Age <=65 & Group 2: Age >65]. RESULTS: The mean age of our patients was 62 +/- 11 years. There were 37 (54%) patients in Group 1 and 32 (46%) patients in Group 2. There was no statistical difference between the two groups in terms of gender and race. However, there were more patients in the Group 2 with >2 comorbidities (p = 0.03). The median duration of operation was significantly longer in Group 2 (550 min vs 471 min, p = 0.04). Morbidity rate in Group 2 was higher (56% vs. 44%, p = 0.04). There was higher proportion of post-operative pancreatic fistula (POPF) in the elderly group (37.5% vs. 16.7%, p = 0.05). Majority of them are Grade A POPF according to the ISG definition. The median post-operative length-of-stay (LOS) in hospital was 9 days longer in Group 2 (p = 0.01). Mortality rate between the 2 groups of patients was comparable (0% vs. 3%, p = 0.28). CONCLUSION: Elderly patients are at increased risk of morbidity in pancreatocoduodenectomy, in particular POPF. However, morbidity and mortality rates are acceptable. It is therefore justified to offer PD to elderly patients who do not have significant cardiopulmonary comorbidities. PMID- 22525415 TI - An inconvenient truth: treatment of displaced paediatric supracondylar humeral fractures. AB - The need for emergent management of displaced paediatric supracondylar humeral fractures is being questioned in the literature. Open reduction rates of up to 46% have been reported in the non-emergent management of these injuries. At our institution these fractures are managed as operative emergencies by senior personnel. To examine the ongoing need for this policy we reviewed our results. All patients managed over a five year period with Gartland type IIB or III paeditric supracondylar humeral fractures were identified and a comprehensive chart and radiographic review undertaken. The mean time from injury to fracture reduction and stabilization was 6.6 h. Consultants performed or supervised 90% of cases. Open reduction was necessary in 5% of cases. Complications included a perioperative nerve injury rate of 6% and a superficial pin site infection rate of 3%. This study suggests that, despite the challenge to trauma on-call rostering, the emergency management of these injuries is advantageous to patients in units of our size. Based on the data presented here we continue our practice of emergent management. We suggest that units of a similar size to our own would show a benefit from an analogous policy albeit an inconvenient truth. PMID- 22525416 TI - Platelet plasma rich products in musculoskeletal medicine: any evidence? AB - Platelet reach plasma (PRP) is considered to accelerate muscle and tendon healing and allow early return to elite competition, and it is often recommend as best practice for management of musculoskeletal injuries. Even though several growth factors abundant in PRPs have been extensively studied in tissue regeneration, the key factors are yet unknown. Given our rudimentary knowledge of the mechanism of action of the PRPs, it is challenging to use this technology to promote early healing, and produce improved and accelerated functional recovery. We prompt researchers to undertake appropriately powered level I studies with adequate and relevant outcome measures and clinically appropriate follow up. PMID- 22525417 TI - Liver resection as part of multi-modality treatment of late relapse of germ cell cancer following high dose chemotherapy. PMID- 22525418 TI - TNM staging of neoplasms of the endocrine pancreas: results from a large international cohort study. AB - BACKGROUND: Both the European Neuroendocrine Tumor Society (ENETS) and the International Union for Cancer Control/American Joint Cancer Committee/World Health Organization (UICC/AJCC/WHO) have proposed TNM staging systems for pancreatic neuroendocrine neoplasms. This study aims to identify the most accurate and useful TNM system for pancreatic neuroendocrine neoplasms. METHODS: The study included 1072 patients who had undergone previous surgery for their cancer and for which at least 2 years of follow-up from 1990 to 2007 was available. Data on 28 variables were collected, and the performance of the two TNM staging systems was compared by Cox regression analysis and multivariable analyses. All statistical tests were two-sided. RESULTS: Differences in distribution of sex and age were observed for the ENETS TNM staging system. At Cox regression analysis, only the ENETS TNM staging system perfectly allocated patients into four statistically significantly different and equally populated risk groups (with stage I as the reference; stage II hazard ratio [HR] of death = 16.23, 95% confidence interval [CI] = 2.14 to 123, P = .007; stage III HR of death = 51.81, 95% CI = 7.11 to 377, P < .001; and stage IV HR of death = 160, 95% CI = 22.30 to 1143, P < .001). However, the UICC/AJCC/WHO 2010 TNM staging system compressed the disease into three differently populated classes, with most patients in stage I, and with the patients being equally distributed into stages II-III (statistically similar) and IV (with stage I as the reference; stage II HR of death = 9.57, 95% CI = 4.62 to 19.88, P < .001; stage III HR of death = 9.32, 95% CI = 3.69 to 23.53, P = .94; and stage IV HR of death = 30.84, 95% CI = 15.62 to 60.87, P < .001). Multivariable modeling indicated curative surgery, TNM staging, and grading were effective predictors of death, and grading was the second most effective independent predictor of survival in the absence of staging information. Though both TNM staging systems were independent predictors of survival, the UICC/AJCC/WHO 2010 TNM stages showed very large 95% confidence intervals for each stage, indicating an inaccurate predictive ability. CONCLUSION: Our data suggest the ENETS TNM staging system is superior to the UICC/AJCC/WHO 2010 TNM staging system and supports its use in clinical practice. PMID- 22525419 TI - Heart ablation using a planar rectangular high intensity ultrasound transducer and MRI guidance. AB - The aim of this study was to evaluate a flat rectangular (3*10mm(2)) MRI compatible transducer operating at 5MHz. The main task was to explore the feasibility of creating deep lesions in heart at a depth of at least 15mm. The size of thermal necrosis in heart tissue was estimated as a function of power and time using a simulation model. The system was then tested in an excised lamb heart. In this study, we were able to create lesions of 15mm deep with acoustic power of 6W for an exposure of approximately 1min. The contrast to noise ratio (CNR) between lesion and heart tissue was evaluated using fast spin echo (FSE). The CNR value was approximately 22 using T1W FSE. Maximum CNR was achieved with repetition time (TR) between 300 and 800ms. Using T2W FSE, the corresponding CNR was approximately 13 for the 14 in vivo experiments. The average lesion depth was 11.93mm with a standard deviation of 0.62mm. In vivo irradiation conditions were 6W for 60s. The size of the lesion in the other two dimensions was close to 3*10mm(2) (size of the transducer element). PMID- 22525420 TI - The relative contributions of the prosthetic and sound limb to balance control in unilateral transtibial amputees. AB - In unilateral transtibial amputees maintenance of standing balance is compromised due to the lack of active ankle control in the prosthetic limb. The purpose of this study is to disentangle the contribution of the prosthetic and sound limb to balance control following waist-pull perturbations. We compared the contribution of the hip and ankle joints to balance control of 15 unilateral transtibial amputees and 13 able-bodied controls after been externally perturbed through release of a pulling force. Perturbations were applied in four different directions. Outcome measure was the proportion of joint moment integrated over time generated by the hip and ankle joints in order to restore static stability after perturbation. Analyses revealed that perturbations in backward/forward direction were recovered mainly by the ankle strategy. The amputees compensated for the absence of active ankle control in the prosthetic limb by increasing the ankle moment in the sound limb. Interestingly, the passive properties of the prosthetic foot contributed to balance control, which has important implications for prosthetic fitting and standing stability in lower limb amputees. Amputees and controls resisted perturbations in medio-lateral direction by generating the necessary hip moments. Finally, these findings are discussed with respect to prosthetic design and rehabilitation processes. PMID- 22525421 TI - Correlation of radiographic and pedobarograph measurements in planovalgus foot deformity. AB - Planovalgus foot deformity is common in children with cerebral palsy. Several pathologies contribute to the deformity. It begins with the lateral displacement of the navicular and the talar head becomes uncovered and prominent in the medial side of the midfoot. The purpose of this study was to assess the correlation between the radiographic and the pedobarographic measurements and the ability to predict foot pressure components using radiographic measurement. The patient sample included 43 patients with cerebral palsy who were ambulatory and had planovalgus foot deformity (76 feet). Medial midfoot pressure showed correlation with talonavicular uncoverage index, talonavicular angle, medial arch angle, Meary angle, and lateral talocalcaneal angle. Heel impulse showed negative correlation with talonavicular uncoverage index and talonavicular angle. Simple linear regression was used to assess the relationship between radiographic and foot pressure component measurements. For every unit change in talonavicular uncoverage index, the predicted value of medial midfoot pressure was [9.9+27 (talonavicular uncoverage index)]. This equation accounted for 17.9% of the changes in the medial midfoot pressure. Tibial foot angle and maximum knee extension also contributed to the heel impulse. The radiographic indices of the planovalgus foot can explain the changes in some foot pressure components. PMID- 22525422 TI - Balance impairment in people with multiple sclerosis: preliminary evidence for the Balance Evaluation Systems Test. AB - This study examined the validity of the Balance Evaluation Systems Test (BESTest) to identify balance impairments in people with multiple sclerosis (MS) by evaluating differences in BESTest performance between people with and without MS. We also assessed the BESTest's validity by correlation with objective measures of postural performance as well as with disease severity and fall status. Thirteen subjects with MS (Expanded Disability Status Scale; EDSS: 0-4.5) and 13 matched subjects without MS were evaluated on the BESTest, asked about fall history, and assessed by force plates and motion capture as they performed laboratory tasks of step initiation, forward leaning to the limits of stability, and postural responses to rotations of the support surface. Compared to subjects without MS, subjects with MS exhibited lower total BESTest scores (mean (95%) score for subjects with MS=91 (83-99); subjects without MS=105 (104-107)) as well as section scores pertaining to mechanical constraints, limits of stability, anticipatory postural adjustments, and gait. BESTest scores significantly correlated with objective laboratory measures of step velocity during step initiation (Pearson r(2)=0.48, P<0.01) as well as center-of-pressure displacements during both the leaning (Pearson r(2)=0.55, P<0.005) and postural response tasks (Pearson r(2)=0.76, P<0.0001). BESTest total scores were 92% accurate to identify fallers and non-fallers, and BESTest scores significantly correlated with EDSS scores (Spearman's rho=0.85, P<0.0005). Thus, the BESTest provides a valid clinical assessment of balance impairments in people with MS. PMID- 22525423 TI - Restricted myogenic potential of mesenchymal stromal cells isolated from umbilical cord. AB - Nonhematopoietic cord blood cells and mesenchymal cells of umbilical cord Wharton's jelly have been shown to be able to differentiate into various cell types. Thus, as they are readily available and do not raise any ethical issues, these cells are considered to be a potential source of material that can be used in regenerative medicine. In our previous study, we tested the potential of whole mononucleated fraction of human umbilical cord blood cells and showed that they are able to participate in the regeneration of injured mouse skeletal muscle. In the current study, we focused at the umbilical cord mesenchymal stromal cells isolated from Wharton's jelly. We documented that limited fraction of these cells express markers of pluripotent and myogenic cells. Moreover, they are able to undergo myogenic differentiation in vitro, as proved by coculture with C2C12 myoblasts. They also colonize injured skeletal muscle and, with low frequency, participate in the formation of new muscle fibers. Pretreatment of Wharton's jelly mesenchymal stromal cells with SDF-1 has no impact on their incorporation into regenerating muscle fibers but significantly increased muscle mass. As a result, transplantation of mesenchymal stromal cells enhances the skeletal muscle regeneration. PMID- 22525424 TI - Poly(3-hydroxyalkanoate)-derived amphiphilic graft copolymers for the design of polymersomes. AB - Amphiphilic graft copolymers composed of biocompatible bacterial poly(3 hydroxyalkanoate) and poly(ethylene glycol) have been synthesized by thiol-ene addition. They were demonstrated to form well-defined nanoscale vesicles in water by cryo-transmission electron microscopy. PMID- 22525425 TI - IFNgamma contributes to the development of gastric epithelial cell metaplasia in Huntingtin interacting protein 1 related (Hip1r)-deficient mice. AB - Huntingtin interacting protein 1 related (Hip1r) is an F-actin- and clathrin binding protein involved in vesicular trafficking that is crucial for parietal cell function and epithelial cell homeostasis in the stomach. Gastric parietal cells in Hip1r-deficient mice are lost by apoptotic cell death, which leads to a progressive epithelial cell derangement, including glandular hypertrophy, zymogenic cell loss and expansion of a metaplastic mucous cell lineage known as spasmolytic polypeptide-expressing metaplasia (SPEM). The epithelial cell changes are associated with infiltration of inflammatory cells. As inflammatory mediators, such as IFNgamma, have been shown to contribute to the development of the gastric epithelial cell metaplasia after Helicobacter infection, we tested whether IFNgamma played a role in the spontaneous progressive epithelial metaplasia observed in Hip1r-deficient mice. Hip1r-deficient mice were crossed with IFNgamma-deficient mice and single- and double-mutant mice were analyzed at 3 and 12 months of age. Histopathology scoring showed that loss of IFNgamma tempered the spontaneous development of metaplastic lesions in Hip1r-deficient mice. Loss of IFNgamma was observed to abrogate the glandular hypertrophy evident in Hip1r mutant stomach, although increased epithelial cell proliferation and elevated gastrin levels were not affected by the presence or absence of this pro inflammatory cytokine. An analysis of cell lineage markers in the double-mutant mice demonstrated that IFNgamma specifically affected the development of metaplastic mucous cells in the neck region, whereas the parietal cell, surface mucous cell and zymogenic cell alterations remained similar to the histopathology in the Hip1r mutant. Morphometric analysis showed that IFNgamma was required for the mucous cell hypertrophy and hyperplasia observed in Hip1r-deficient mice. Together, these findings demonstrate that IFNgamma is critical for the development of the gastric epithelial cell metaplasia that results from parietal cell atrophy in the Hip1r-deficient mice. PMID- 22525426 TI - Insulin promotes macrophage foam cell formation: potential implications in diabetes-related atherosclerosis. AB - The prevalence of atherosclerotic cardiovascular disease is higher in patients with type 2 diabetes, a disorder characterized by hyperinsulinemia and insulin resistance. The role of hyperinsulinemia as an independent participant in the atherogenic process has been controversial. In the current study, we tested the effect of insulin and the insulin sensitizer, adiponectin, on human macrophage foam cell formation. We found that both insulin and adiponectin increased the expression of the type 2 scavenger receptor CD36 by approximately twofold and decreased the expression of the ATP-binding cassette transporter ABCA1 by >80%. In both cases regulation was post-transcriptional. As a consequence of these changes, we found that oxidized LDL (oxLDL) uptake was increased by 80% and cholesterol efflux to apolipoprotein A1 (apoA1) was decreased by ~25%. This led to two- to threefold more cholesterol accumulation over a 16-h period. As reported previously in studies of murine systems, scavenger receptor-A (SR-A) expression on human macrophages was downregulated by insulin and adiponectin. Insulin and adiponectin did not affect oxLDL-induced secretion of monocyte attractant protein-1 (MCP-1) and interleukin-6 (IL-6). These studies suggest that hyperinsulinemia could promote macrophage foam cell formation and thus may contribute to atherosclerosis in patients with type 2 diabetes. PMID- 22525428 TI - Loss of microRNA-205 expression is associated with melanoma progression. AB - In this study, we used formalin-fixed paraffin-embedded melanocytic tumors to demonstrate reproducible alterations in microRNA expression in nevi compared with melanomas using a microarray platform. We validated those results in an independent set of nevi and melanomas by quantitative RT-PCR. miR-205 demonstrated a statistically significant, progressive diminution in expression from nevi to primary melanomas to metastatic melanomas. Enforced miR-205 expression in melanoma cells profoundly impairs cell motility and migration along with significantly decreased F-actin polymerization with only a modest reduction in cell proliferation. Using a xenograft model, melanoma cells overexpressing miR 205 exhibit a reduced migratory capacity compared with control tumor cells. Mechanistically, miR-205 overexpression results in decreased expression of the zinc-finger E-box binding homeobox 2 (ZEB2) mRNA and protein. This coincides with increased expression of E-cadherin mRNA and protein. Furthermore, re-introduction of ZEB2 into melanoma cells overexpressing miR-205 rescues these phenotypic effects and results in a restoration of cell migration and F-actin polymerization with a concomitant reduction in E-cadherin expression. Together, these results provide in vitro and in vivo evidence for miR-205 as a critical suppressor of melanoma cell migration. PMID- 22525429 TI - 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor simvastatin ameliorates renal fibrosis through HOXA13-USAG-1 pathway. AB - Epidemiological data have suggested that 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) prevent the progression of chronic kidney diseases (CKDs), whereas the precise mechanism explaining in vitro to in vivo is missing. This study is aimed at exploring a new mechanism of action by statins on renal fibrosis, a hallmark of CKD, using mouse renal fibrosis model in vivo and Madin Darby canine kidney (MDCK) cells expressing USAG-1 in vitro. C57/BL6 mice fed a 0.2% adenine-containing diet for 4 weeks developed renal dysfunction accompanied with severe tubulointerstitial fibrosis. Subsequent simvastatin (SIM) treatment (50 mg/kg per day) for 2 weeks significantly suppressed fibrosis progression. We found that SIM enhanced bone morphogenetic protein-7 (BMP-7)-mediated anti fibrotic signaling with the reduced expression of uterine sensitization associated gene-1 (USAG-1), a BMP-7 antagonist produced by renal distal tubular epithelial cells. Therefore, MDCK cells were incubated with transforming growth factor-beta1 and showed increased expression of USAG-1 and alpha-smooth muscle actin; SIM significantly reduced them. SIM significantly increased E-cadherin expression. Gene knockdown experiments using MDCK suggested that homeobox protein Hox-A13 (HOXA13) played a suppressive role in the USAG-1 gene and thus SIM reduced USAG-1 by increasing HOXA13 expression. The data from our study demonstrate that SIM, one of statins, contributes to prevent the progression of renal fibrosis by upregulating BMP-7-mediated anti-fibrotic signaling and that one aspect of crucial efficacies is achieved by regulating HOXA13 and USAG-1. HOXA13-USAG-1 pathway is a newly identified mechanism in renal fibrosis and will be a new therapeutic target for preventing renal fibrosis progression in CKDs. PMID- 22525427 TI - Estriol preserves synaptic transmission in the hippocampus during autoimmune demyelinating disease. AB - Cognitive deficits occur in over half of multiple sclerosis patients, with hippocampal-dependent learning and memory commonly impaired. Data from in vivo MRI and post-mortem studies in MS indicate that the hippocampus is targeted. However, the relationship between structural pathology and dysfunction of the hippocampus in MS remains unclear. Hippocampal neuropathology also occurs in experimental autoimmune encephalomyelitis (EAE), the most commonly used animal model of MS. Although estrogen treatment of EAE has been shown to be anti inflammatory and neuroprotective in the spinal cord, it is unknown if estrogen treatment may prevent hippocampal pathology and dysfunction. In the current study we examined excitatory synaptic transmission during EAE and focused on pathological changes in synaptic protein complexes known to orchestrate functional synaptic transmission in the hippocampus. We then determined if estriol, a candidate hormone treatment, was capable of preventing functional changes in synaptic transmission and corresponding hippocampal synaptic pathology. Electrophysiological studies revealed altered excitatory synaptic transmission and paired-pulse facilitation (PPF) during EAE. Neuropathological experiments demonstrated that there were decreased levels of pre- and post synaptic proteins in the hippocampus, diffuse loss of myelin staining and atrophy of the pyramidal layers of hippocampal cornu ammonis 1 (CA1). Estriol treatment prevented decreases in excitatory synaptic transmission and lessened the effect of EAE on PPF. In addition, estriol treatment prevented several neuropathological alterations that occurred in the hippocampus during EAE. Cross-modality correlations revealed that deficits in excitatory synaptic transmission were significantly correlated with reductions in trans-synaptic protein binding partners known to modulate excitatory synaptic transmission. To our knowledge, this is the first report describing a functional correlate to hippocampal neuropathology in any MS model. Furthermore, a treatment was identified that prevented both deficits in synaptic function and hippocampal neuropathology. PMID- 22525430 TI - Pathological crosstalk in vitro between T lymphocytes and lesional keratinocytes in psoriasis: necessity of direct cell-to-cell contact. AB - Psoriasis, a chronic autoimmune-related skin disease, involves both immune and non-immune cells like T cells and keratinocytes. This study investigates the regulatory role of T cells-keratinocyte interactions during psoriasis on immune factors production. Cytokines and chemokines were evaluated by multiplex and ELISA assays in an in vitro model of co-culture of keratinocytes with T lymphocytes. Keratinocytes were from psoriatic skin lesions or healthy skin. T lymphocytes were from healthy volunteers. Psoriatic keratinocytes (PKs) alone generated concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL) 6, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-1beta, IL-8, monocyte chemotactic protein (MCP)-1, interferon-gamma-induced protein 10 kDa (IP 10) and vascular endothelial growth factor (VEGF) higher than those produced by healthy keratinocytes (HKs). In contrast, IL-1alpha and IL-Ra production was reduced in PKs. Normal T cells, which had no effect on HKs, increased the production of TNF-alpha, IL-6, GM-CSF, IL-8, MCP-1 and IP-10 by PKs, but did not influence PK production of IL-1beta, IL-1alpha, IL-Ra and VEGF. The most striking effects were obtained with PK- and IL-2-stimulated T lymphocytes: most of the above cytokines and chemokines were greatly upregulated, except IL-1beta and VEGF that were decreased or unchanged, respectively. In addition, fractalkine was overproduced in this latter condition only. Our results indicate (1) a functional interaction between keratinocytes and T lymphocytes that requires a direct cellular contact, and (2) a reciprocal influence that depends on cytokine and chemokine types. In conclusion, lesional keratinocytes from psoriasis vulgaris alter functions of normal T lymphocytes that conversely modulate these keratinocytes. PMID- 22525431 TI - Metformin protects against the development of fructose-induced steatosis in mice: role of the intestinal barrier function. AB - To test the hypothesis that metformin protects against fructose-induced steatosis, and if so, to elucidate underlying mechanisms, C57BL/6J mice were either fed 30% fructose solution or plain water for 8 weeks. Some of the animals were concomitantly treated with metformin (300 mg/kg body weight/day) in the drinking solution. While chronic consumption of 30% fructose solution caused a significant increase in hepatic triglyceride accumulation and plasma alanine aminotransferase levels, this effect of fructose was markedly attenuated in fructose-fed mice concomitantly treatment with metformin. The protective effects of the metformin treatment on the onset of fructose-induced non-alcoholic fatty liver disease (NAFLD) were associated with a protection against the loss of the tight junction proteins occludin and zonula occludens 1 in the duodenum of fructose-fed mice and the increased translocation of bacterial endotoxin found in mice only fed with fructose. In line with these findings, in metformin-treated fructose-fed animals, hepatic expression of genes of the toll-like receptor-4 dependent signalling cascade as well as the plasminogen-activator inhibitor/cMet regulated lipid export were almost at the level of controls. Taken together, these data suggest that metformin not only protects the liver from the onset of fructose-induced NAFLD through mechanisms involving its direct effects on hepatic insulin signalling but rather through altering intestinal permeability and subsequently the endotoxin-dependent activation of hepatic Kupffer cells. PMID- 22525433 TI - How to explain the re-emergence of chikungunya infection in Reunion Island in 2010? AB - In March 2010, a new outbreak of chikungunya infection was detected in the west of Reunion Island. An investigation was launched to describe the incident cases occurrence and to raise hypotheses on factors that could explain the occurrence of this outbreak. All probable or confirmed cases detected by the surveillance system in the western area between March 1st and July 2nd, 2010 were included in the investigation. A standardized questionnaire was performed by phone, including sociodemographic, environmental and behaviour data. A total of 74 cases were described (i.e. response rate of 72%). They were mainly women (sex ratio M/F=0.7), all ages were represented. Most of them (76%) resided in a house; 31% had recently moved, including 22% from metropolitan France. They reported to have been more exposed to mosquitoes and to infected patients than during the major epidemic of 2005-2006. In addition, 41% reported to have reduced their protection against mosquitoes. The results suggest that several concomitant factors contributed to this outbreak: the reintroduction of the chikungunya virus in the island, the population characteristics and environmental factors. PMID- 22525432 TI - Spontaneous recurrent mutations and a complex rearrangement in the MECP2 gene in the light of current models of mutagenesis. AB - Mutations in the methyl-CpG-binding protein 2 (MECP2) gene are associated with Rett syndrome (RTT). The MECP2 gene has some unique characteristics: (1) it is mainly affected by de novo mutations, due to recurrent independent mutational events in a defined "hot spot" regions or positions; (2) complex mutational events along a single allele are frequently found in this gene; (3) most mutations arise on paternal X chromosome. The recurrent point mutations involve mainly CpG dinucleotides, where C>T transitions are explained by methylation mediated deamination. The complex mutational events might be explained by the genomic architecture of the region involving the MECP2 gene. The finding that most spontaneous mutations arise on paternal X-chromosome supports the higher contribution of replication-mediated mechanism of mutagenesis. We present 9 types of mutations in the MECP2 gene, detected in a group of 22 Bulgarian and 6 Romanian classical RTT patients. Thirteen patients were clarified on molecular level (46.4%). The point mutations in our sample account for 61.5%. One intraexonic deletion was detected in the present study (7.7%). One novel insertion c.321_322insGAAG, p.(Lys107_Leu108insGluAlafs2*) was found (7.7%). Large deletions and complex mutations account for 23%. A novel complex mutational event c.[584_624del41insTT; 638delTinsCA] was detected in a Romanian patient. We discuss different types of the MECP2 mutations detected in our sample in the light of the possible mechanisms of mutagenesis. Complex gene rearrangements involving a combination of deletions and insertions have always been most difficult to detect, to specify precisely and hence to explain in terms of their underlying mutational mechanisms. PMID- 22525434 TI - Assessing the role of spatial heterogeneity and human movement in malaria dynamics and control. AB - Mathematical models developed for studying malaria dynamics often focus on a single, homogeneous population. However, human movement connects environments with potentially different malaria transmission characteristics. To address the role of human movement and spatial heterogeneity in malaria transmission and malaria control, we consider a simple malaria metapopulation model incorporating two regions, or patches, connected by human movement, with different degrees of malaria transmission in each patch. Using our two-patch model, we calculate and analyze the basic reproduction number, R(0), an epidemiologically important threshold quantity that indicates whether malaria will persist or go extinct in a population. Although R(0) depends on the rates of human movement, we show that R(0) is always bounded between the two quantities R(01) and R(02)-the reproduction numbers for the two patches if isolated. If without migration, the disease is endemic in one patch but not in the other, then the addition of human migration can cause the disease to persist in both patches. This result indicates that regions with low malaria transmission should have an interest in helping to control or eliminate malaria in regions with higher malaria endemicity if human movement connects them. Performing a sensitivity analysis of R(0) and the endemic equilibrium to various parameters in the two-patch model allowed us to determine, under different parameterizations of the model, which patch will be the better target for control measures, and within that patch, what type of control measure should be implemented. In the analysis of R(0), we found that if the extrinsic incubation period is shorter than the average mosquito lifespan, the control measures should be targeted towards reducing the mosquito biting rate. On the other hand, if the extrinsic incubation period is longer than the average mosquito lifespan, control measures targeting the mosquito death rate will be more effective. Intuitively, one might think that resources for malaria control should be allocated to the region with higher malaria transmission. However, our sensitivity analyses indicated that this is not always the case. In fact, if migration into the lower transmission patch is much faster than migration into the higher transmission patch, the lower transmission patch is potentially the better target for malaria control efforts. While human movement between regions poses challenges to malaria control and elimination, if estimates of relevant parameters in the model are known, including migration rates, our results can help inform which region to target and what type of control measure to implement for the greatest success. PMID- 22525435 TI - Montmorillonite/poly-(epsilon-caprolactone) composites as versatile layered material: reservoirs for anticancer drug and controlled release property. AB - This work evaluates intercalation of tamoxifen (Tmx) in interlayer gallery of Na(+)-MMT (Montmorillonite, MMT) (Tmx-MMT), which is further compounded with poly (epsilon-caprolactone) (PCL) (Tmx-MMT/PCL, MPs), for oral chemotherapy of breast cancer. The X-ray diffraction patterns, thermal and spectroscopic analyses indicated the intercalation of Tmx into the MMT interlayer that stabilized in the longitudinal monolayer mode by electrostatic interaction. No significant change in structural and functional properties of Tmx was found in the MMT layers. In vitro study of drug release profiles showed controlled release pattern. The genotoxic effect of drug was in vitro evaluated in human lymphocyte cell culture by comet assay, and results indicated moderate reduction in DNA damage when pristine Tmx was intercalated with MMT and formulated in composites. The Tmx-MMT hybrid efficacy was also confirmed on HeLa and A549 cancer cells by in vitro cell viability assay. In vivo pharmacokinetics (PK) of formulated Tmx in rats was examined and the results showed that plasma Tmx levels were within therapeutic window as compared to pristine Tmx. Therefore, Tmx-MMT hybrid and microcomposite particles (MPs) can be of considerable value in chemotherapy of malignant neoplastic disease with reduced side effects. This study clearly indicated that MMT not only plays a role as a delivery matrix for drug, but also facilitates significant increase in the delivery proficiency. PMID- 22525437 TI - Synthesis and cytotoxic activity of some novel N-pyridinyl-2-(6-phenylimidazo[2,1 b]thiazol-3-yl)acetamide derivatives. AB - A series of novel compounds bearing imidazo[2,1-b]thiazole scaffolds were designed and synthesized based on the optimization of the virtual screening hit compound N-(6-morpholinopyridin-3-yl)-2-(6-phenylimidazo[2,1-b]thiazol-3 yl)acetamide (5a), and tested for their cytotoxicity against human cancer cell lines, including HepG2 and MDA-MB-231. The results indicated that the compound 2 (6-(4-chlorophenyl)imidazo[2,1-b]thiazol-3-yl)-N-(6-(4-(4-methoxybenzyl)piperazin 1-yl)pyridin-3-yl)acetamide (5l), with slightly higher inhibition on VEGFR2 than 5a (5.72% and 3.76% inhibitory rate at 20 MUM, respectively), was a potential inhibitor against MDA-MB-231 (IC(50) = 1.4 MUM) compared with sorafenib (IC(50) = 5.2 MUM), and showed more selectivity against MDA-MB-231 than HepG2 cell line (IC(50) = 22.6 MUM). PMID- 22525436 TI - PEGylation for drug delivery to ischemic myocardium: pharmacokinetics and cardiac distribution of poly(ethylene glycol)s in mice with normal and ischemic myocardium. AB - PEGylation now plays an important role in drug delivery and is considered as the method of choice for improving the pharmacokinetics and stability of parenteral agents. However, its application in treating cardiac diseases is still limited. To guide the design of PEGylation for drug delivery to ischemic myocardium, the effects of the molecular weight of PEG and the myocardial ischemic conditions on PEG levels in plasma and myocardium were studied in this work following intravenous administration of fluorescein isothiocyanate-labeled 20- and 40-kDa mPEGs to mice with normal and ischemic myocardium. The results show that myocardial ischemia caused some consistent changes in pharmacokinetic parameters of mPEGs. Due to the enhanced permeability and retention (EPR) effect caused by ischemia, the distribution of 20- and 40-kDa mPEGs in ischemic hearts was approximately 1.47- and 1.92-fold higher than that in normal hearts, respectively. Under the same heart condition (either normal or ischemic), the cardiac AUC(0.5-24h)s of the two mPEGs were comparable, although their plasma AUCs differed by nearly 4-fold; however, a smoother cardiac level-time profile was achieved by 40-kDa mPEG. This study addressed the relative importance of the EPR effect of ischemic zones and the molecular size of PEG in cardiac drug delivery, which is believed to be helpful for macromolecular drug design. PMID- 22525438 TI - Synthesis, molecular docking and preliminary in-vitro cytotoxic evaluation of some substituted tetrahydro-naphthalene (2',3',4',6'-tetra-O-acetyl-beta-D-gluco/ galactopyranosyl) derivatives. AB - A facile, convenient and high yielding synthesis of novel S-glycosides and N glycosides incorporating 1,2,3,4-tetrahydronaphthalene and or 1,2 dihydropyridines moieties has been described. The aglycons 2, 4, and 7 were coupled with different activated halosugars in the presence of basic and acidic medium. The preliminary in-vitro cytotoxic evaluation revealed that compounds 3c, 3f, 5c and 7b show promising activity. A molecular docking study was performed against tyrosine kinase (TK) (PDB code: 1t46) by Autodock Vina. The docking output was analyzed and some compounds have shown hydrogen bond (H-B) formation with reasonable distances ranged from 2.06 A degrees to 3.06 A degrees with Thr 670 and Cys 673 residues found in the specified pocket. No hydrogen bond was observed with either Glu 640 nor Asp 810 residues, as was expected from pdbsum. PMID- 22525439 TI - Simultaneous determination of salidroside and its aglycone metabolite p-tyrosol in rat plasma by liquid chromatography-tandem mass spectrometry. AB - Salidroside and its aglycone p-tyrosol are two major phenols in the genus Rhodiola and have been confirmed to possess various pharmacological properties. In our present study, p-tyrosol was identified as the deglycosylation metabolite of salidroside after intravenous (i.v.) administration to rats at a dose of 50 mg/kg, but was not detectable after intragastric gavage (i.g.) administration through HPLC-photodiode array detection (PDA) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Next, an accurate and precise LC-MS/MS method was developed to quantitatively determine salidroside and p-tyrosol in rat plasma samples. Samples were analyzed by LC-MS/MS on a reverse-phase xTerra MS C18 column which was equilibrated and eluted with an isocratic mixture of acetonitrile-water (1:9, v/v) at a flow rate of 0.3 mL/min. The analytes were monitored by multiple reaction monitoring (MRM) under the negative electrospray ionization mode. The precursor/product transitions (m/z) were 299.0 -> 118.8 for salidroside, 137.0 -> 118.9 for p-tyrosol and 150.1 -> 106.9 for the internal standard (IS), paracetamol, respectively. The calibration curve was linear over the concentration ranges of 50-2,000 ng/mL for salidroside and 20-200 ng/mL for p tyrosol. The inter- and intra-day accuracy and precision were within +/- 15%. The method has been successfully applied to the pharmacokinetic study and the oral bioavailability was calculated. PMID- 22525440 TI - Dynamic action of carotenoids in cardioprotection and maintenance of cardiac health. AB - Oxidative stress has been considered universally and undeniably implicated in the pathogenesis of all major diseases, including those of the cardiovascular system. Oxidative stress activate transcriptional messengers, such as nuclear factor kappaB, tangibly contributing to endothelial dysfunction, the initiation and progression of atherosclerosis, irreversible damage after ischemic reperfusion, and even arrhythmia, such as atrial fibrillation. Evidence is rapidly accumulating to support the role of reactive oxygen species (ROS) and reactive nitrogen species (RNS) as intracellular signaling molecules. Despite this connection between oxidative stress and cardiovascular disease (CVD), there are currently no recognized therapeutic interventions to address this important unmet need. Antioxidants that provide a broad, "upstream" approach via ROS/RNS quenching or free radical chain breaking seem an appropriate therapeutic option based on epidemiologic, dietary, and in vivo animal model data. Short-term dietary intervention trials suggest that diets rich in fruit and vegetable intake lead to improvements in coronary risk factors and reduce cardiovascular mortality. Carotenoids are such abundant, plant-derived, fat-soluble pigments that functions as antioxidants. They are stored in the liver or adipose tissue, and are lipid soluble by becoming incorporated into plasma lipoprotein particles during transport. For these reasons, carotenoids may represent one plausible mechanism by which fruits and vegetables reduce the risk of chronic diseases as cardiovascular disease (CVD). This review paper outlines the role of carotenoids in maintaining cardiac health and cardioprotection mediated by several mechanisms including redox signaling. PMID- 22525441 TI - Umbilical myiasis. PMID- 22525443 TI - Multiple micronutrient supplementation does not reduce diarrhoea morbidity in Ugandan HIV-infected children: a randomised controlled trial. AB - OBJECTIVES: To determine the effect of multiple micronutrient supplementation on the incidence and prevalence of diarrhoea in Ugandan HIV-infected children aged 1 5 years. METHODS: We enrolled 847 HIV-infected Ugandan children in a randomised trial of a supplement containing 14 micronutrients (MMS) given at twice the recommended dietary allowance (RDA) versus a six-multivitamin (MV) supplement given in one RDA as the 'standard of care'. The participants were stratified into a highly active antiretroviral therapy (HAART) group of 85/847 (10%) and a non HAART group of 762/847 (90%) participants. The supplements were given daily for 6 months. Episodes of diarrhoea assessed at routine visits, sick visits and those reported within 2 weeks before the routine visit were counted against weeks of observation for each participant. Diarrhoea incidence per child was calculated as the number of episodes per child year. Rate ratios were used to compare person time rates in the two groups. RESULTS: The incidence of diarrhoea was 3.8 (95% CI 3.4-4.3) in the MMS and 3.5 (95% CI 3.1-4.0) in the MV group per child year. The rate ratio was 1.1 (0.9-1.3), similar in both strata, except that HAART-treated children had a lower incidence rate of diarrhoea. The prevalence of diarrhoea at 6 months was also similar in the two groups. CONCLUSION: The 14-multiple micronutrient supplement given in two RDA doses compared with a six-multivitamin 'standard of care' supplement given in one RDA dose did not reduce the incidence or prevalence of diarrhoea in HIV-infected children aged 1-5 years. PMID- 22525442 TI - Prevention of vitamin D deficiency in mothers and infants worldwide - a paradigm shift. AB - Vitamin D deficiency in mothers and infants is a global health disorder despite recognition that it is preventable. Recent data support the theory that vitamin D deficiency in adults and children may increase the risk of infections and auto immune diseases. In most cases, vitamin D deficiency is caused by sunlight deprivation and inadequate corrective vitamin D intake. There is a strong mother/infant vitamin D relationship that affects vitamin D status both in utero and in infancy. Recognition that vitamin D deficiency is a worldwide mother/infant health problem is a basis on which to modify public health strategies to reduce the burden of disease and improve maternal and child vitamin D nutrition. This review provides an update on vitamin D function and the global scope and implications of vitamin D deficiency as it relates to pregnancy and infancy. It also addresses a combined strategy to prevent vitamin D deficiency during pregnancy, lactation and infancy. PMID- 22525444 TI - Potential risk of hypoxaemia in patients with severe pneumonia but no hypoxaemia on initial assessment: a prospective pilot trial. AB - BACKGROUND: The World Health Organization recommends oxygen therapy for children under 5 years of age with pneumonia and lower chest indrawing. In patients with severe pneumonia who are initially normoxaemic, there is little information on the risk of subsequently developing hypoxaemia and the benefit of routine oxygen therapy. OBJECTIVES: To study the incidence of subsequent hypoxaemia in initially normoxaemic children with pneumonia and lower chest indrawing. METHODS: Children (n = 58, 3-59 mths) with pneumonia, lower chest indrawing and normoxaemia (SpO(2) >90%) were randomly assigned to receive supplemental oxygen (nasal prongs, 1-2 L/min flow) (n = 29) or room air (n = 29). Vital signs and SpO(2) were monitored continuously and recorded every 6 hours. Outcome variables were incidence of hypoxaemia, length of tachypnoea and lower chest indrawing. RESULTS: The two groups had similar demographic and clinical profiles. Thirty-one patients (53%) developed hypoxaemia later, without significant differences between the two arms (RR 0.61, 95% CI 0.36-1.04). Patients who developed hypoxaemia later were similar to those who did not, except for a lower SpO(2) on enrolment. However, they took more time to recover from tachypnoea (P<0.05), chest indrawing (P<0.05) and fever, indicating that they had more severe disease. Early oxygen therapy did not alter the course of disease. CONCLUSIONS: About half of the normoxaemic patients with severe pneumonia developed hypoxaemia after enrolment, indicating a significant potential risk. Children hospitaled with severe pneumonia might benefit from routine oxygen therapy. Alternatively, oxygen might be provided to those who develop hypoxaemia identified by a pulse oximeter. PMID- 22525445 TI - Utility of plasma transferrin receptor, ferritin and inflammatory markers in children with sickle cell disease. AB - BACKGROUND: Soluble transferrin receptor (sTfR) is generally unaffected by inflammatory status, whereas ferritin increases along with acute-phase proteins. The utility of these iron biomarkers in relation to inflammatory markers in children with sickle cell disease (SCD) with differing grades of severity is unclear. OBJECTIVES: To describe iron biomarker profiles and inflammatory responses in relation to disease severity in children with SCD. METHODS: This cross-sectional study describes plasma levels of sTfR, ferritin, C-reactive protein (CRP) and serum amyloid A (SAA) among 102 Yemeni children with SCD in relation to clinical profiles and disease severity. RESULTS: Median (IQR) sTfR was 58.5 mg/L (38-81), and concentration was positively correlated with reticulocyte count (r = +0.31, P = 0.002) and splenic enlargement (r = +0.20, P = 0.04), and was negatively correlated with Hb (r = -0.28, P = 0.004). Subcategories of children in a steady state were identified using ferritin and CRP cut-off values to discriminate iron status. In children in a steady state, the prevalence of iron deficiency was 25%, iron repletion 48% and marginal or normal status 27%. Ferritin concentration correlated positively with Hb and 23% of iron-deficient children had severe anaemia. CRP and SAA were increased in the steady state and were higher with acute disease complications (P<0.05 and <0.001, respectively). There was no association between sTfR or sTfR-ferritin index and inflammatory markers or disease severity score. CONCLUSION: In SCD, elevated sTfR is related to hypererythropoietic activity and does not correlate with inflammatory status or disease severity. Iron deficiency prevalence was estimated to be 25%. A classification of iron status is proposed. PMID- 22525446 TI - Evaluating the QuikRead(r) C-reactive protein test as a point-of-care test. AB - BACKGROUND: Available tests to diagnose infection in neonates often provide results after 12-24 hours. A bedside test that is reliable will facilitate earlier exclusion or diagnosis of infection. OBJECTIVE: To validate a bedside C reactive protein (CRP) test against the currently available laboratory CRP test in neonates with suspected sepsis. METHODS: This was a prospective observational study where a bedside CRP was done concurrently with and validated against a laboratory CRP in neonates with suspected sepsis. The sensitivities, specificities and predictive values for the bedside CRP tests were calculated using the laboratory CRPs as the reference test. RESULTS: There were 209 measured CRP-sample pairs. Seventy per cent of these had suspected early-onset neonatal sepsis and 30% had suspected late-onset neonatal sepsis. Twelve per cent had culture-proven sepsis. At the recommended cut-off of 8.0 mg/L for the bedside CRP test, the sensitivity, specificity, positive and negative predictive values were 84%, 80%, 30% and 97%, respectively. Adjusting the cut-off value from 8.0 to 15.0 mg/L improved the specificity to 88%. The sensitivity, specificity and positive and negative predictive values were not different between early-onset and late onset sepsis. The receiver operating characteristic curve had an area below the curve of 0.84 for the cut-off at 16.2 mg/L on the beside CRP test. CONCLUSIONS: The bedside CRP test may be used as a screening test to aid decisions to either commence or discontinue antibiotics in circumstances where the clinical diagnosis of sepsis is in doubt. By using a cut-off of 16.0 mg/L for the bedside CRP test, the possibility of a false negative result is minimised. PMID- 22525447 TI - Cardiac troponin T as a marker of myocardial injury in a group of asphyxiated African neonates. AB - BACKGROUND: In caucasian newborns, troponin T (cTnT) is a specific marker for myocardial injury in perinatal asphyxia. This is the first such study in negroid neonates. AIMS: To evaluate myocardial injury in a group of asphyxiated African newborns and determine the influence of mode of delivery on cTnT levels. METHODS: Serum cTnT and clinical parameters in 40 asphyxiated and 40 healthy negroid neonatal controls were measured within the first 72 hours of life by chemiluminescence immune-assay. Perinatal asphyxia was assessed by APGAR score. The infants were followed up until discharge or death. RESULTS: Mean (SD) cTnT values were significantly higher in asphyxiated infants [0.03 (0.04) ng/ml] than in healthy controls [0.01 (0.006) ng/ml, P = 0.002]. Asphyxiated infants delivered by forceps and vacuum extraction had significantly higher levels of cTnT [0.04 (0.018) ng/ml] than those born by caesarian section [0.02 (0.008) ng/ml] and by normal delivery [0.03 (0.01) ng/ml, P = 0.003]. cTnT levels were higher in infants who died (P = 0.037). CONCLUSION: In the asphyxiated infants, mean cTnT levels were significantly higher than in controls. They were also significantly higher in those born by vacuum and forceps delivery and asphyxiated infants who died. PMID- 22525448 TI - Myasthenia gravis in Jamaican children: a 12-year institutional review. AB - BACKGROUND: Myasthenia gravis is uncommon in children. The clinical characteristics in children of the English-speaking Caribbean have not been documented previously. OBJECTIVE: To describe the clinical characteristics and outcome of children with myasthenia gravis at two tertiary hospitals in Jamaica. METHODS: The case-notes of all children with a diagnosis of myasthenia gravis managed at the University Hospital of the West Indies and Bustamante Hospital for Children between January 1994 and December 2005 were reviewed. RESULTS: There were 34 children; mean age of onset of illness was 7.5 years and mean period of follow-up was 38.5 months. The male-to-female ratio was 1:1.3. Nineteen (59%) presented with ocular manifestations; 47% of these developed signs of generalised involvement. Most were treated with pyridostigmine and prednisone. Eight patients had thymectomy. Four patients (12%) entered remission. There were two deaths. CONCLUSIONS: Myasthenia gravis in Jamaican children is similar to that in other populations. It is more common in female children. Most children present with ocular manifestations and remission occurs infrequently. PMID- 22525449 TI - Unusual norovirus and rotavirus genotypes in Ethiopia. AB - BACKGROUND: Gastro-enteritis is associated with significant mortality in low- and middle-income countries, and rotavirus and norovirus are the principal viral agents implicated. AIMS: To investigate the molecular epidemiology and burden of disease associated with rotavirus and norovirus in children attending a health centre in Ethiopia. METHODS: A cross-sectional study was conducted in children attending a health centre in Awassa, southern Ethiopia. Children with diarrhoea (cases) and without diarrhoea (controls) were recruited over a 6-month period from December 2008 to May 2009. Rotavirus was detected by ELISA and genotyped by RT-PCR, and norovirus was amplified by RT-PCR with genotyping by sequence analysis of RT-PCR products. RESULTS: Rotavirus was detected in 44/200 (22%) cases and in none of the controls, with genotypes G3P[6] (48%), G1P[8] (27%) and G2P[4] (7%) being the strains most commonly identified. Norovirus was detected in 16 (8%) of 200 cases and in 4 (7%) of 57 controls. Norovirus GII.3 was the strain most commonly detected (40%: 8/20) and ten other genotypes were also detected. CONCLUSION: Rotavirus is a common cause of severe gastro-enteritis in children in Ethiopia; however, norovirus occurred with a similar frequency in cases and controls. A globally uncommon strain type, G3P[6], predominated within the rotavirus strains detected. PMID- 22525450 TI - Umbilical myiasis in a healthy newborn. AB - A rare case of umbilical myiasis in a healthy newborn caused by Musca domestica is presented. Poor umbilical hygiene provides an ideal site for egg-laying by the common housefly. PMID- 22525451 TI - Umbilical myiasis in a neonate. AB - There are very few reports of myiasis in neonates and umbilical myiasis is the rarest form. The umbilical stump of a 7-day-old neonate in the postnatal ward was found to be infested with maggots secondary to hatching of housefly eggs. PMID- 22525452 TI - Ulnar mononeuropathy associated with eosinophilia. AB - A boy aged 4.5 years presented with isolated left ulnar nerve motor neuropathy and moderate eosinophilia. There was no evidence of parasitic infection. He was commenced on empirical diethylcarbamazine citrate and albendazole. Improvement occurred 6 days later with complete recovery by 2 weeks. It is presumed that he had a parasitic infection. PMID- 22525453 TI - Arthroscopic release for shoulder internal rotation contracture secondary to brachial plexus birth palsy: clinical and magnetic resonance imaging results on glenohumeral dysplasia. AB - Internal rotation contracture of the shoulder in brachial plexus birth palsy frequently leads to shoulder dysplasia. Six children underwent anterior arthroscopic release sparing the subscapularis. Clinical examination and MRI were performed preoperatively and repeated at the 5-year follow-up. MRI was carried out for assessment of glenohumeral dysplasia. Passive external rotation was improved by 63.3 degrees without any limitation of active internal rotation. Active antepulsion/abduction was improved by 90 degrees . Remodeling of the glenoid and improved coverage of the humeral head were observed in all cases. Shoulder arthroscopic release sparing the subscapularis seems to be an efficient procedure to restore external rotation without affecting active internal rotation. PMID- 22525454 TI - Resection interposition arthroplasty of calcaneonavicular coalition using a lateral supramalleolar adipofascial flap: case report. AB - Space after the resection of calcaneonavicular coalition has been interposed by fat graft or the extensor digitorum brevis muscle. Nonvascularity of fat graft and insufficient volume of the extensor digitorum brevis muscle cause regrowth of the coalition. A pedicled lateral supramalleolar adipofascial flap was interposed into the space created by resection of the calcaneonavicular bar in the case of a 10-year-old boy. Regrowth of the coalition was successfully prevented by sufficient volume of the vascularized fatty tissue. The range of motion of the affected right ankle joint was similar to that of the unaffected side at 32 months postoperatively. PMID- 22525455 TI - [Treatment of Wernicke encephalopathy]. PMID- 22525456 TI - Electrocoagulation versus chemical coagulation: coagulation/flocculation mechanisms and resulting floc characteristics. AB - Electrocoagulation (EC) and chemical coagulation (CC) are employed in water treatment for particle removal. Although both are used for similar purposes, they differ in their dosing method - in EC the coagulant is added by electrolytic oxidation of an appropriate anode material, while in CC dissolution of a chemical coagulant is used. These different methods in fact induce different chemical environments, which should impact coagulation/flocculation mechanisms and subsequent floc formation. Hence, the process implications when choosing which to apply should be significant. This study elucidates differences in coagulation/flocculation mechanisms in EC versus CC and their subsequent effect on floc growth kinetics and structural evolution. A buffered kaolin suspension served as a representative solution that underwent EC and CC by applying aluminum via additive dosing regime in batch mode. In EC an aluminum anode generated the active species while in CC, commercial alum was used. Aluminum equivalent doses were applied, at initial pH values of 5, 6.5 and 8, while samples were taken over pre-determined time intervals, and analyzed for pH, particle size distribution, zeta potential, and structural properties. EC generated fragile flocs, compared to CC, over a wider pH range, at a substantially higher growth rate, that were prone to restructuring and compaction. The results suggest that the flocculation mechanism governing EC in sweep floc conditions is of Diffusion Limited Cluster Aggregation (DCLA) nature, versus a Reaction Limited Cluster Aggregation (RLCA) type in CC. The implications of these differences are discussed. PMID- 22525457 TI - Baseline isotope data for Spirodela sp.: nutrient differentiation in aquatic systems. AB - The excessive addition of nitrogen to watersheds is recognized as one of the main causes of the global deterioration of aquatic ecosystems and an increasing number of studies have shown that delta15N signatures of macrophytes may reflect the N loading of the system under investigation. This study investigated isotopic equilibration rates and concentration level effects of KNO3 and cow manure nutrient solutions on the delta15N and delta13C signatures, C/N ratios, % N and % C of Spirodela sp. over time, to determine the feasibility of their use in monitoring anthropogenic N-loading in freshwater systems. Spirodela delta15N signatures clearly distinguished between nutrient types within 2 days of introduction, with plants grown in KNO3 showing extremely depleted delta15N values (-15.00 to -12.000/00) compared to those growing in cow manure (14.00 18.000/00). Isotopic equilibration rates could not be determined with certainty, but plant isotopic differentiation between nutrient regimes became apparent after 2 days and started to equilibrate by day 4. Concentration level effects were also apparent, with Spirodela tissue displaying more depleted and enriched delta15N values in higher concentrations of KNO3 and cow manure respectively. delta13C signatures of some plants grown in manure were more enriched than plants grown in KNO3 and reverse osmosis (RO) water. However, nutrient induced differences in delta13C were small and are likely to be obscured in the natural environment. Decreased C/N ratios and increases in plant % N in zero N concentration treatments confirmed the presence of a commensal cyanobacterial-duckweed association within Spirodela sp., reducing its effectiveness as an in-situ incubator in low nutrient environments. However, indications are that Spirodela may make a useful isotope monitoring tool under conditions of long-term, continuous nutrient inputs such as systems impacted by sewage outfalls and/or wastewater inputs. PMID- 22525458 TI - Aqueous chlorination of diclofenac: kinetic study and transformation products identification. AB - Diclofenac reactivity and fate during water chlorination was investigated in this work. In the first step, chlorination kinetic of diclofenac (DCF) was studied in the pH range of 4-10 at 20 +/- 2 degrees C and in the presence of an excess of total chlorine. A second-order reaction (first-order relative to DCF concentration and first-order relative to free chlorine concentration) was shown with rate constant about 3.89 +/- 1.17 M(-1) s(-1) at pH 7. The elementary reactions (i.e. reactions of hypochlorous acid (HOCl) with neutral and ionized forms of DCF, and acid-catalysed reaction of HOCl with neutral and ionized forms of DCF) were proposed to explain the pH-dependence of the rate constants and intrinsic constant of each of them were calculated. In the second step, several degradation products formed during chlorination of DCF were identified. These compounds could come from an initial chlorine electrophilic attack on aromatic ring or amine function of DCF. Some of these chlorinated derivatives seem to accumulate in solution in the presence of an excess of chlorine. PMID- 22525459 TI - Bacteriophage performance against Staphylococcus aureus in milk is improved by high hydrostatic pressure treatments. AB - The combined effect of bacteriophages, vB_SauS-phi-IPLA35 (phiIPLA35) and vB_SauS phi-IPLA88 (phiIPLA88), and high hydrostatic pressure (HHP) on Staphylococcus aureus Sa9 was evaluated in pasteurized whole milk under a simulated cold chain break, which was simulated by incubation of milk at 25 degrees C for 48 h. Four hundred MPa was found to be the most suitable pressure to be used in combination with these phages. Two different levels of staphylococcal initial contamination (1*10(4) and 1*10(6) CFU/mL) were tested. A synergistic effect between HHP and phages was observed in both cases. Compared to each single treatment, the combined treatment was able to reduce the initial S. aureus contamination below the detection limit (<10 CFU/mL). Bacteriophage performance in pressurize milk against S. aureus enabled milder hydrostatic pressure treatments, therefore phages can be regarded as a valuable hurdle on minimally processed food. PMID- 22525460 TI - Dry Beriberi and Wernicke's encephalopathy following gastric lap band surgery. AB - The incidence of neurologic complications from bariatric surgery is rising with the prevalence of obesity and the increasing number of bariatric surgeries. We report a 25-year-old woman who developed subacute progressive weakness and areflexia followed by confusion, ophthalmoplegia, and nystagmus following bariatric surgery. While the differential of generalized weakness with altered mental status is broad, vitamin deficiency should be routinely suspected after bariatric surgery to prevent permanent neurological injury. Multifocal neurological dysfunction in our patient represented beriberi and Wernicke's encephalopathy related to vitamin B1 deficiency. PMID- 22525461 TI - Down-regulation of miR-183 promotes migration and invasion of osteosarcoma by targeting Ezrin. AB - Recent studies have emphasized causative links between aberrant microRNA expression patterns and cancer progression. miR-183 is dysregulated in certain types of human cancers. The expression pattern, clinical significance, and biological role of miR-183 in osteosarcoma, however, remain largely undefined. In this paired analysis, we found that miR-183 was markedly down-regulated in osteosarcoma cells and tissues compared with matching normal bone tissues using RT-qPCR. Statistical analyses revealed that the expression levels of miR-183 significantly correlated with lung metastasis as well as with local recurrence of osteosarcoma. miR-183 expression was inversely correlated with Ezrin mRNA and protein expression levels in osteosarcoma cells as well as in a subset of primary osteosarcoma. Ectopically expressed miR-183 inhibited migratory and invasive abilities of osteosarcoma cells, whereas knockdown of endogenous miR-183 significantly enhanced these abilities. Using a luciferase reporter carrying the 3'-untranslated region (3'-UTR) of Ezrin, we identified Ezrin as a direct target of miR-183. Moreover, ectopic expression of Ezrin could significantly rescue miR 183-suppressed migration and invasion. Of interest, suppression of Ezrin by miR 183 caused a reduction of phosphorylated p44/42 (p-p44/42). Finally, suppression of Ezrin by RNAi mimicked miR-183 action in the suppression of migration and invasion, which was associated with down-regulation of p-p44/42. Taken together, these results suggest that as a tumor suppressor miRNA, miR-183 plays an important role in the aggressiveness of osteosarcoma. PMID- 22525462 TI - The critical role of TAK1 in accentuated epithelial to mesenchymal transition in obliterative bronchiolitis after lung transplantation. AB - Therapies to limit or reverse fibrosis have proven unsuccessful, highlighting the need for a greater understanding of basic mechanisms that drive fibrosis and, in particular, the link between fibrosis and inflammation. It has been shown that pro-fibrotic transforming growth factor beta1 (TGF-beta1)-driven epithelial-to mesenchymal transition (EMT) can be accentuated by tumor necrosis factor alpha (TNF-alpha). TGF-beta-activated kinase 1 (TAK1) is activated by both TGF-beta1 and TNF-alpha, activating both nuclear factor kappa-light-chain-enhancer of activated B cells and mitogen-activated protein kinase signaling pathways. In this study, we evaluated the potential for TAK1 to modulate the synergistic effect between TGF-beta1 and TNF-alpha in driving EMT. Co-stimulation with TGF beta1 and TNF-alpha induced an accentuated and extended phosphorylation of TAK1 compared to either alone. TAK1 signaled downstream via nuclear factor kappa-light chain-enhancer of activated B cells, and Jun N-terminal kinase-2, but independent of Jun N-terminal kinase-1, extracellular signal-regulated kinase-1/2, or p38 mitogen-activated protein kinase signaling to drive EMT in bronchial epithelial cells. Blocking either TAK1 or Jun N-terminal kinase-2 inhibited EMT. TAK1 phosphorylation was increased in the airway epithelium of patients with fibrotic airway disease. These data identify factors leading to and affected by accentuated and extended TAK1 phosphorylations potential novel therapeutic targets in inflammation-driven fibrotic diseases. PMID- 22525463 TI - Primary Open-Angle Glaucoma: A Transforming Growth Factor-beta Pathway-Mediated Disease. PMID- 22525464 TI - A single point mutation (Y89F) within the non-structural protein 1 of influenza A viruses limits epithelial cell tropism and virulence in mice. AB - The nonstructural protein 1 (A/NS1) of influenza A viruses (IAV) harbors several src homology (SH)-binding motifs (bm) that mediate interactions with cellular proteins. In contrast to the sequence variability of the second SH3bm, tyrosine 89, within the SH2bm is a highly conserved residue among IAV strains. This prompted us to evaluate the necessity of this SH2bm for IAV virulence. In an in vivo mouse model, we observed drastic reductions in weight loss, mortality, and virus titers in lung and bronchoalveolar lavage fluid after infection with the mutant virus PR8 A/NS1-Y89F (PR8 Y89F) when compared with wild-type virus (PR8 wt). Concomitantly, we observed decreased inflammation and less severe pathologic changes, reflecting reduced levels of virus titers. At histologic analysis, lungs infected with PR8 wt virus showed widespread destruction of the bronchiolar epithelium, with extensive distribution of virus antigen within tracheal, bronchial, bronchiolar, and alveolar epithelium. In marked contrast, the bronchiolar epithelium after infection with the mutant PR8 Y89F virus was entirely intact, and the severity and extent of viral infection was reduced and strongly restricted to alveoli. These findings demonstrate that change of a single residue of the highly conserved SH2bm within the A/NS1 results in restricted virus spread in mouse lung and strongly reduced virulence, which illustrates the necessity of the SH2bm for IAV-induced pathogenicity. PMID- 22525465 TI - Warm and awake with histamine. PMID- 22525466 TI - Ataxia-telangiectasia mutated and the Mre11-Rad50-NBS1 complex: promising targets for radiosensitization. AB - Radiotherapy plays a central part in cancer treatment, and use of radiosensitizing agents can greatly enhance this modality. Although studies have shown that several chemotherapeutic agents have the potential to increase the radiosensitivity of tumor cells, investigators have also studied a number of molecularly targeted agents as radiosensitizers in clinical trials based on reasonably promising preclinical data. Recent intense research into the DNA damage-signaling pathway revealed that ataxia-telangiectasia mutated (ATM) and the Mre11-Rad50-NBS1 (MRN) complex play central roles in DNA repair and cell cycle checkpoints and that these molecules are promising targets for radiosensitization. Researchers recently developed three ATM inhibitors (KU 55933, CGK733, and CP466722) and an MRN complex inhibitor (mirin) and showed that they have great potential as radiosensitizers of tumors in preclinical studies. Additionally, we showed that a telomerase-dependent oncolytic adenovirus that we developed (OBP-301 [telomelysin]) produces profound radiosensitizing effects by inhibiting the MRN complex via the adenoviral E1B55kDa protein. A recent Phase I trial in the United States determined that telomelysin was safe and well tolerated in humans, and this agent is about to be tested in combination with radiotherapy in a clinical trial based on intriguing preclinical data demonstrating that telomelysin and ionizing radiation can potentiate each other. In this review, we highlight the great potential of ATM and MRN complex inhibitors, including telomelysin, as radiosensitizing agents. PMID- 22525467 TI - Sleep duration and overweight among elementary schoolchildren: a population-based study in Japan. AB - Although a number of studies have investigated the relationship of sleep duration to overweight and obesity, studies conducted among population-based elementary schoolchildren have been limited in Japan. The aim of the present study was to investigate the relationship between sleep duration and overweight among elementary schoolchildren in Japan. The study subjects were all fourth-grade schoolchildren (9 or 10 years of age) in Ina-town, Saitama Prefecture, Japan from 1999 to 2008. Information concerning each subject's sex, age, and lifestyle was obtained using a self-administered questionnaire, while measurements of his or her height and weight were carried out. Childhood overweight was determined according to the definition established by the International Obesity Task Force. Data from 3,433 children were analyzed. In logistic regression analysis, a statistically significant dose-response relationship was observed between sleep duration and overweight among boys (p for trend = 0.014) but not among girls (p for trend = 0.149). Short sleep duration was associated with childhood overweight, and the sex difference in the association was observed. These findings suggested that it is important to consider sleep duration as part of any program to prevent overweight among elementary schoolchildren, especially among boys. PMID- 22525468 TI - Comparison of VF-14 scores among different ophthalmic surgical interventions. AB - To clarify surgical outcomes for 5 ophthalmic diseases in terms of vision-related quality of life (QOL), we sent a self-administered Visual Function Questionnaire 14 (VF-14) to patients 3 months postoperatively, and the VF-14 scores for the surgical outcome of strabismus were compared with those of patients with diabetic macular edema (DME), cataract, glaucoma, and epiretinal membrane (ERM). Test retest repeatability of VF-14 was evaluated with Bland-Altman analysis. Of the 625 eligible patients who were referred for enrollment, 48 with comitant strabismus, 50 with incomitant strabismus, 45 with DME, 38 with cataract, 129 with glaucoma, and 73 with ERM agreed to answer. Eighty percent of subjects showed 95% limits of agreement with the VF-14 evaluated by repeated measurements. The gain by surgery for incomitant strabismus was not different from that of cataract (p = 0.5551), but it was significantly better than those of DME (p = 0.0266), comitant strabismus (p = 0.0128), ERM (p = 0.0021), glaucoma with cataract (p < 0.0001), and glaucoma alone (p < 0.0001). The surgical outcome in terms of QOL for patients with incomitant strabismus was good and comparable to that of patients with cataract surgery. PMID- 22525469 TI - Neurite outgrowth of PC12 mutant cells induced by orange oil and d-limonene via the p38 MAPK pathway. AB - We studied the effects of natural essential oil on neurite outgrowth in PC12m3 neuronal cells to elucidate the mechanism underlying the action of the oils used in aromatherapy. Neurite outgrowth can be induced by nerve growth factor (NGF), where ERK and p38 MAPK among MAPK pathways play important roles in activating intracellular signal transduction. In this study, we investigated whether d limonene, the major component of essential oils from oranges, can promote neurite outgrowth in PC12m3 cells, in which neurite outgrowth can be induced by various physical stimulations. We also examined by which pathways, the ERK, p38 MAPK or JNK pathway, d-limonene acts on PC12m3 cells. Our results showed that neurite outgrowth can be induced when the cells are treated with d-limonene. After treatment with d-limonene, we observed that p38 MAPK is strongly activated in PC12m3 cells, while ERK is weakly activated. In contrast, JNK shows little activity. A study using an inhibitor of p38 MAPK revealed that neurite outgrowth in PC12m3 cells is induced via the activation of p38 MAPK by d-limonene. The results thus indicate that d-limonene may promote neural cell differentiation mainly via activation of the p38 MAPK pathway. PMID- 22525470 TI - Different responses to 5-fluoraouracil in mutagenicity and gene expression between two human lymphoblastoid cell lines with or without TP53 mutation. AB - Human lymphoblastoid TK6 and WTK-1 cells are widely used to detect mutagens in vitro. TK6 cells have wild-type TP53 alleles, while WTK-1 cells have one allele of mutated TP53. Both cells were treated with 5-fluorouracil (5-FU), and gene mutation assay and micronucleus assay were performed to clarify the differential response related to the TP53 gene status. The effects of 5-FU on gene expression were assessed by microarray and quantitative RT-PCR analyses. In WTK-1 cells, 5 FU increased the frequency of cells with micronucleus and mutation. In TK6 cells, frequency of cells with micronucleus was increased but the mutation frequency was not. The cytotoxicity induced by 5-FU was more prominent in TK6 cells than in WTK 1 cells. Analysis of gene expression showed that the genes involved in the TP53 pathway were up-regulated in TK6 cells but not in WTK-1 cells. The differential responses to 5-FU between these cell lines appeared to be due to the difference in the TP53 gene status, thus providing a molecular basis for the bioassays using these cell lines in the toxicology field. Our results indicate that the clinical efficacy of 5-FU chemotherapy may depend on the TP53 genotype. PMID- 22525471 TI - Prognosis of hepatocellular carcinoma with portal vein tumor thrombus:assessment based on clinical and computer tomography characteristics. AB - Patients with hepatocellular carcinoma (HCC) complicated by portal vein tumor thrombus (PVTT) have an extremely poor prognosis. It is important to select adequate therapeutic options based on reliable prognostic factors using imaging studies and clinical data. Prognostic factors were analyzed in patients with HCC with PVTT in the first branch or main trunk of the portal vein. From 2000 to 2007, 107 consecutive patients with HCC with PVTT in the major portal vein were reviewed, and diagnostic images and clinical characteristics were retrospectively observed. Thirty-eight possible prognostic factors for survival were analyzed by the log-rank test and multivariate analysis using Cox's proportional hazards model. Median overall survival was 14 months following PVTT diagnosis. Survival rates at 6 months, 1, 2, and 3 years were 72.1%, 52.6%, 32.6%, and 29.6%, respectively. Independent prognostic factors for longer survival included:patient age < 65 years, Child-Pugh classification A/B, PVTT treatment, accumulation of Lipiodol in the PVTT after TACE, initial radical treatment for HCC, HCC located in a single lobe of the liver, and no invasion of HCC to the hepatic vein or bile duct. Survival was associated with liver function, tumor extension, and treatment for HCC and PVTT. PMID- 22525472 TI - Attenuated sensory deprivation-induced changes of parvalbumin neuron density in the barrel cortex of FcgammaRllB-deficient mice. AB - Recent studies have demonstrated the important role of immune molecules in the development of neuronal circuitry and synaptic plasticity. We have detected the presence of FcgammaRllB protein in parvalbumin-containing inhibitory interneurons (PV neurons). In the present study, we examined the appearance of PV neurons in the barrel cortex and the effect of sensory deprivation in FcgammaRllB-deficient mice (FcgammaRllB-/-) and wild-type mice. There was no substantial difference in the appearance of PV neurons in the developing barrel cortex between FcgammaRllB /- and wild-type mice. Sensory deprivation from immediately after birth (P0) or P7 to P12-P14 induced an increase in PV neurons. In contrast, sensory deprivation from P7 or P14 to P28, but not from P21 to P28, decreased PV neurons in wild-type mice. However, sensory deprivation from P0 or P7 to P12-P14 did not increase PV neurons and sensory deprivation from P7 or P14 to P28 did not decrease or only modestly decreased PV neurons in FcgammaRllB-/- mice. The results indicate that expression of PV is regulated by sensory experience and the second and third postnatal weeks are a sensitive period for sensory deprivation, and suggest that FcgammaRllB contributes to sensory experience-regulated expression of PV. PMID- 22525473 TI - Design of hemispherical radio frequency (RF) capacitive-type electrode free of edge effects for treatment of intracavitary tumors. AB - A new hemispherical electrode to heat oral cavity cancer is proposed. The electrode does not produce a hot spot around its edge, a feature that usually arises when using radio frequency (RF) capacitive-type heating. The hemispherical electrode was designed by computer simulation using a 3-D finite element method. To assess its practicality and effectiveness, we built a prototype hemispherical electrode and evaluated its heating characteristics by phantom experiments. The heating effects on the phantom were measured by thermography. The concave phantom surface in contact with the hemispherical electrode showed a uniform increase in temperature, with no obvious edge effect. The proposed electrode allows non invasive RF capacitive-type heating for intracavity tumors that was not previously considered possible, and should contribute to the multidisciplinary treatment of intracavity tumors. PMID- 22525474 TI - Long-term effects of cabergoline and levodopa in Japanese patients with early Parkinson's disease: a 5-year prospective study. AB - Several international studies have suggested that treatment of early Parkinson's disease (PD) with a dopamine agonist instead of levodopa delays the occurrence of motor complications. This 5-year prospective, open, multicenter randomized study aimed to compare the effects of cabergoline on the onset of motor complications with those of levodopa in Japanese patients with early PD. Patients who had never been treated with dopamine agonists or levodopa were enrolled in this study. Four of 45 patients in the cabergoline group and 11 of 46 patients in the levodopa group developed motor complications. The estimated cumulative incidence of motor complications in the cabergoline and levodopa groups was 17% and 34% (hazard ratio, 0.57;95% confidence interval, 0.18-1.81; p = 0.347). Thirty-five adverse events (AEs) were reported in 24 patients in the cabergoline group, while 16 AEs were reported in 13 patients in the levodopa group. Patients in the cabergoline group showed fewer motor complications than did those in the levodopa group, although the difference was not statistically significant. However, the hazard ratio found in this study was similar to those in previous reports. PMID- 22525475 TI - Severe superimposed preeclampsia with obesity, diabetes and a mild imbalance of angiogenic factors. AB - Preeclampsia may be due to an excess of circulating anti-angiogenic growth factors derived from the placenta, but metabolic syndrome-like disorders may also set off a cascade of placental and systemic inflammation and oxidative stress. We present a case of severe superimposed preeclampsia with obesity, diabetes and a mild imbalance of angiogenic factors, in which diet therapy ameliorated the preeclamptic signs while improving the adiponectin level. A 41-year-old pregnant woman with obesity and diabetes was referred to our hospital because of severe proteinuria and hypertension at 22 weeks of gestation. After administration of insulin and hydralazine with diet therapy, her hypertension and proteinuria were ameliorated with a 15-kg weight loss. Her adiponectin level was low and her leptin level was high, but her angiogenic factor levels were within the normal ranges for pregnant women at admission. The diet therapy ameliorated her hypertension and proteinuria while improving her adiponectin level as she achieved weight loss. This case suggests that diet therapy for obese preeclampsia patients with a mild imbalance of anti-and pro-angiogenic factors may play an important role in managing preeclampsia. Measurements of maternal adipocytokines and angiogenic factors may be important to distinguish the main cause of preeclampsia, i.e., poor placentation or maternal constitutional factors, for managing preeclampsia in patients with obesity. PMID- 22525476 TI - Resection of metachronous lymph node metastases from hepatocellular carcinoma after hepatectomy: report of four cases. AB - We report 4 cases of surgical resection of metachronous lymph node (LN) metastases from hepatocellular carcinoma (HCC) following hepatectomy. Clinicopathological features and results of LN dissection were investigated in the 4 patients. One patient was found to have a single metastasis in the mediastinal LNs, another had multiple metastases in the mediastinal and abdominal LNs, and the other 2 had single metastases in the abdominal LN. The locations of the abdominal LN metastases were behind the pancreas head in 2 patients and around the abdominal aorta in 1 patient. They all underwent surgical resection of metastatic LNs and had no postoperative complications. The 3 patients whose LN metastases were solitary have been alive for more than 2 years after LN resection, and one of them is free from recurrence. The patient with multiple LN metastases died 13 months after LN resection due to carcinomatosis. With the expectation of long-term survival, a single metachronous LN metastasis from HCC after hepatectomy should be resected in patients without uncontrollable intrahepatic or extrahepatic tumors. PMID- 22525477 TI - Calmodulin antagonizes amyloid-beta peptides-mediated inhibition of brain plasma membrane Ca(2+)-ATPase. AB - The synaptosomal plasma membrane Ca(2+)-ATPase (PMCA) plays an essential role in regulating intracellular Ca(2+) concentration in brain. We have recently found that PMCA is the only Ca(2+) pump in brain which is inhibited by amyloid-beta peptide (Abeta), a neurotoxic peptide implicated in the pathology of Alzheimer's disease (AD) [1], but the mechanism of inhibition is lacking. In the present study we have characterized the inhibition of PMCA by Abeta. Results from kinetic assays indicate that Abeta aggregates are more potent inhibitors of PMCA activity than monomers. The inhibitory effect of Abeta could be blocked by pretreating the purified protein with Ca(2+)-calmodulin, the main endogenous activator of PMCA, and the activity of truncated PMCA lacking the calmodulin binding domain was not affected by Abeta. Dot-overlay experiments indicated a physical association of Abeta with PMCA and also with calmodulin. Thus, calmodulin could protect PMCA from inhibition by Abeta by burying exposed sites on PMCA, making them inaccessible to Abeta, and also by direct binding to the peptide. These results suggest a protective role of calmodulin against neuronal Ca(2+) dysregulation by PMCA inhibition induced by Abeta. PMID- 22525478 TI - Age-related differences in peak handgrip strength between wrestlers and nonathletes during the developmental years. AB - This study examined the development of peak handgrip strength from childhood to adulthood in wrestlers (n = 122) and nonathlete controls (n = 122). The effect of hand preference on handgrip strength and the relationship of anthropometrical characteristics with handgrip strength in wrestlers and controls were also evaluated. Participants were assigned into age groups: children, young adolescents, late adolescents, and adults. Body height and mass, hand dimensions (length, span, and width), and absolute handgrip (in kilograms) were measured. Handgrip strength was similar in wrestlers and controls in the younger age groups (i.e., in children and young adolescents), whereas late adolescent and adult wrestlers exhibited significantly greater peak handgrip strength (p < 0.05) than their control peers. Nonathletes older than 15 years demonstrated an approximately 10% greater peak handgrip strength (p < 0.05) with their preferred hand compared with the nonpreferred hand. In contrast, late adolescent and adult wrestlers exhibited similar handgrip strength with both hands. Peak handgrip strength exhibited a significant linear correlation with all the anthropometric measures examined; however, a higher percentage in the variation in peak handgrip strength was explained by body height and hand length than the other anthropometric variables in both groups. In conclusion, wrestlers exhibit a sport specific pattern of handgrip strength changes during the developmental years. Body height and hand length exhibited the strongest correlations with handgrip strength during the developmental years in wrestlers and in controls. The training adaptations of wrestling resulted in symmetrical handgrip strength development in both hands at late adolescence and adulthood. These data serve to provide a descriptive profile of handgrip strength in wrestlers, to assist both coaches and health professionals for talent selection and/or development of training programs for performance enhancement and rehabilitation. PMID- 22525479 TI - Evaluation of an aerobic composting process for the management of Specified Risk Materials (SRM). AB - In Nova Scotia (NS), approximately 2700 tonnes of Specified Risk Materials (SRM) are produced annually. SRM disposal is a serious concern for abattoirs and the beef industry. Composting offers a low risk and simple means to transform raw SRM into a more stable and easily managed material. In this project, wheat straw and sawdust were used to compost with SRM on a pilot scale. The study evaluated changes over time in total carbon, total nitrogen, pH, temperature, moisture content and electrical conductivity. Compost temperatures in all treatments met the Canadian Council of Ministers of the Environment (CCME) guidelines for pathogen kill. The compost maturity tests showed that the evolution of CO(2)-C in all the final compost products was less than 1 mg g(-1) organic matter day(-1). Wheat straw performed well as a composting feedstock for raw SRM as sawdust. While the wheat straw has advantages including greater availability, lower cost and easily decomposable carbon compounds more management is required to maintain adequate compost temperatures. The influences of seasonal variations due to temperate climatic conditions on SRM composting were also studied with wheat straw. The results suggest no significant differences in composting effectiveness between the two seasons. PMID- 22525480 TI - Effects of four CeO2 nanocrystalline catalysts on early-life stages of zebrafish Danio rerio and crustacean Daphnia magna. AB - Effects of four different nanocrystalline CeO(2)-based catalysts on crustaceans Daphnia magna and early-life stages of zebrafish Danio rerio were studied. Pure CeO(2) and CuO-CeO(2) mixed oxides with a nominal 10, 15 and 20 mol.% CuO content were tested. Pure CeO(2) provoked no effects, but CuO-CeO(2) mixed oxides induced some sublethal effects on fish and affected daphnids' survival. The most pronounced effects were found on fish body growth, which was reduced at 10 mg/L in case of CuCe20 and 50 mg/L in cases of CuCe10 and CuCe15. Daphnids' survival was affected above 80 mg/L of CuCe20, while CuCe10 and CuCe15 did not affect daphnids. None of the materials was highly toxic to daphnids and fish in comparison to some other environmental pollutants. Differences in effects between the materials could not be explained by their specific physicochemical properties. This work indicates that more attention should be placed at potential toxicity of nanostructured materials, such as nanocrystalline mixed-oxides. PMID- 22525481 TI - Volatility and leachability of heavy metals and radionuclides in thermally treated HEPA filter media generated from nuclear facilities. AB - The purpose of the present study was to apply thermal treatments to reduce the volume of HEPA filter media and to investigate the volatility and leachability of heavy metals and radionuclides during thermal treatment. HEPA filter media were transformed to glassy bulk material by thermal treatment at 900 degrees C for 2h. The most abundant heavy metal in the HEPA filter media was Zn, followed by Sr, Pb and Cr, and the main radionuclide was Cs-137. The volatility tests showed that the heavy metals and radionuclides in radioactive HEPA filter media were not volatilized during the thermal treatment. PCT tests indicated that the leachability of heavy metals and radionuclides was relatively low compared to those of other glasses. XRD results showed that Zn and Cs reacted with HEPA filter media and were transformed into crystalline willemite (ZnO.SiO(2)) and pollucite (Cs(2)OAl(2)O(3)4SiO(2)), which are not volatile or leachable. The proposed technique for the volume reduction and transformation of radioactive HEPA filter media into glassy bulk material is a simple and energy efficient procedure without additives that can be performed at relatively low temperature compared with conventional vitrification process. PMID- 22525482 TI - Determination of nanomolar chromate in drinking water with solid phase extraction and a portable spectrophotometer. AB - Determination of chromate at low concentration levels in drinking water is an important analytical objective for both human health and environmental science. Here we report the use of solid phase extraction (SPE) in combination with a custom-made portable light-emitting diode (LED) spectrophotometer to achieve detection of chromate in the field at nanomolar levels. The measurement chemistry is based on a highly selective reaction between 1,5-diphenylcarbazide (DPC) and chromate under acidic conditions. The Cr-DPC complex formed in the reaction can be extracted on a commercial C18 SPE cartridge. Concentrated Cr-DPC is subsequently eluted with methanol and detected by spectrophotometry. Optimization of analytical conditions involved investigation of reagent compositions and concentrations, eluent type, flow rate (sample loading), sample volume, and stability of the SPE cartridge. Under optimized conditions, detection limits are on the order of 3 nM. Only 50 mL of sample is required for an analysis, and total analysis time is around 10 min. The targeted analytical range of 0-500 nM can be easily extended by changing the sample volume. Compared to previous SPE-based spectrophotometric methods, this analytical procedure offers the benefits of improved sensitivity, reduced sample consumption, shorter analysis time, greater operational convenience, and lower cost. PMID- 22525483 TI - Removal efficiency of vapour/particulate phase PAHs by using alternative protective respirators in PAHs exposure workers. AB - Due to the high heat environment in foundry industries, it is difficult for foundry workers to wear masks during their workday. Thus, how to prevent inhaling vapour or the particulate phase of polycyclic aromatic hydrocarbons (PAHs) is important for occupational hazard management. The present study assesses the characteristics of PAHs emission in foundry and plastic industries to evaluate the removal efficiencies of PAHs while workers use alternative personal protective equipment. The highest 1-hydroxypyrene (1-OHP) level was found for workers who used a cotton-fabric face mask (1.19 MUg/g creatinine) and activated carbon face mask (1.16 MUg/g creatinine), compared to a lower level in workers who wore a surgical face mask (0.27 MUg/g creatinine) and a N95 respirator (0.51 MUg/g creatinine). The urinary 1-OHP in end-of-shift samples correlated to the airborne vapour phase Bapeq, but not for the particulate phase Bapeq in the foundry industry. This is probably because workers wore personal protective equipment that only removed the particulate phase PAH. The current study suggests that future work focus on developing an appropriate and comfortable respirator with high removal efficiency for ultrafine particulates and vapour phase PAHs simultaneously in PAH work environments. PMID- 22525484 TI - Vagal afferents contribute to exacerbated airway responses following ozone and allergen challenge. AB - Brown-Norway rats (n=113) sensitized and challenged with nDer f 1 allergen were used to examine the contribution of lung sensory nerves to ozone (O(3)) exacerbation of asthma. Prior to their third challenge rats inhaled 1.0ppm O(3) for 8h. There were three groups: (1) control; (2) vagus perineural capsaicin treatment (PCT) with or without hexamethonium; and (3) vagotomy. O(3) inhalation resulted in a significant increase in lung resistance (R(L)) and an exaggerated response to subsequent allergen challenge. PCT abolished the O(3)-induced increase in R(L) and significantly reduced the increase in R(L) induced by a subsequent allergen challenge, while hexamethonium treatment reestablished bronchoconstriction induced by allergen challenge. Vagotomy resulted in a significant increase in the bronchoconstriction induced by O(3) inhalation and subsequent challenge with allergen. In this model of O(3) exacerbation of asthma, vagal C-fibers initiate reflex bronchoconstriction, vagal myelinated fibers initiate reflex bronchodilation, and mediators released within the airway initiate bronchoconstriction. PMID- 22525485 TI - Effect of sublingual nitrate on respiratory reflexes arising from stimulation of juxta-pulmonary capillary (J) receptors by i.v. lobeline and short duration exercise. AB - Juxta-pulmonary capillary (J or pulmonary C fiber) receptors are stimulated by an increase in pulmonary blood flow and give rise to respiratory acceleration and related sensations and inhibit exercise. However, the reverse, i.e., the effect of reducing pulmonary blood flow on their reflexes, is as yet not known. This was investigated by carrying out a placebo-controlled study on the acute effects of a single dose (0.4 mg) of sublingual glyceryl nitrate (GTN), known to shift blood from the central to the peripheral circulation, on the respiratory parameters of exercising healthy subjects and on their responses to i.v. lobeline. In 10 subjects, GTN use delayed the first appearance of respiratory sensations from 9.08 +/- 0.9 min to 11 min (P=0.002), reduced the increase in minute ventilation by the end of 10 min of exercise (P=0.003) and increased its duration by 1-4s and doubled it in the remaining one subject. In a majority of 8 of them, the effect of GTN on i.v. lobeline-induced respiratory reflexes and sensations was a significant increase in the dose required (P=0.006) for producing threshold effects and in the latency of their appearance (P=0.003). The latter feature points to a reduction in blood flow in the lung parenchyma where these receptors are located and to which they are sensitive. As this would have led to a reduced stimulation of these receptors, it would account for the delayed appearance of respiratory symptoms, a reduction in ventilatory increase and prolongation of exercise duration. We demonstrated a mechanism of reducing the stimulus level of J receptors by reducing pulmonary blood flow by means of pharmacological sequestration with GTN use, which then led to a reduction in the magnitude of respiratory and viscerosomatic reflexes, while noting at the same time that changes in blood flow in the pulmonary bed do not directly influence limb muscles, tendons and joints which also determine exercise output. PMID- 22525486 TI - The neuroprogressive nature of major depressive disorder: pathways to disease evolution and resistance, and therapeutic implications. AB - In some patients with major depressive disorder (MDD), individual illness characteristics appear consistent with those of a neuroprogressive illness. Features of neuroprogression include poorer symptomatic, treatment and functional outcomes in patients with earlier disease onset and increased number and length of depressive episodes. In such patients, longer and more frequent depressive episodes appear to increase vulnerability for further episodes, precipitating an accelerating and progressive illness course leading to functional decline. Evidence from clinical, biochemical and neuroimaging studies appear to support this model and are informing novel therapeutic approaches. This paper reviews current knowledge of the neuroprogressive processes that may occur in MDD, including structural brain consequences and potential molecular mechanisms including the role of neurotransmitter systems, inflammatory, oxidative and nitrosative stress pathways, neurotrophins and regulation of neurogenesis, cortisol and the hypothalamic-pituitary-adrenal axis modulation, mitochondrial dysfunction and epigenetic and dietary influences. Evidence-based novel treatments informed by this knowledge are discussed. PMID- 22525487 TI - Risk of future depression in people who are obese but metabolically healthy: the English longitudinal study of ageing. AB - There is some evidence to suggest that obesity is a risk factor for the development of depression, although this is not a universal finding. This discordance might be ascribed to the existence of a 'healthy obese phenotype'- that is, obesity in the absence of the associated burden of cardiometabolic risk factors. We examined whether the association of obesity with depressive symptoms is dependent on the individual's metabolic health. Participants were 3851 men and women (aged 63.0+/-8.9 years, 45.1% men) from the English Longitudinal Study of Ageing, a prospective study of community dwelling older adults. Obesity was defined as body mass index >=30 kg m(-2). Based on blood pressure, high-density lipoprotein cholesterol, triglycerides, glycated haemoglobin and C-reactive protein, participants were classified as 'metabolically healthy' (0 or 1 metabolic abnormality) or 'unhealthy' (>=2 metabolic abnormalities). Depressive symptoms were assessed at baseline and at 2 years follow-up using the 8-item Centre of Epidemiological Studies Depression (CES-D) scale. Obesity prevalence was 27.5%, but 34.3% of this group was categorized as metabolically healthy at baseline. Relative to non-obese healthy participants, after adjustment for baseline CES-D score and other covariates, the metabolically unhealthy obese participants had elevated risk of depressive symptoms at follow-up (odds ratio (OR)=1.50; 95% confidence interval (CI), 1.05-2.15), although the metabolically healthy obese did not (OR=1.38; 95% CI, 0.88-2.17). The association between obesity and risk of depressive symptoms appears to be partly dependent on metabolic health, although further work is required to confirm these findings. PMID- 22525488 TI - Cocaine dependence: a fast-track for brain ageing? PMID- 22525489 TI - Exposure to violence during childhood is associated with telomere erosion from 5 to 10 years of age: a longitudinal study. AB - There is increasing interest in discovering mechanisms that mediate the effects of childhood stress on late-life disease morbidity and mortality. Previous studies have suggested one potential mechanism linking stress to cellular aging, disease and mortality in humans: telomere erosion. We examined telomere erosion in relation to children's exposure to violence, a salient early-life stressor, which has known long-term consequences for well-being and is a major public health and social-welfare problem. In the first prospective-longitudinal study with repeated telomere measurements in children while they experienced stress, we tested the hypothesis that childhood violence exposure would accelerate telomere erosion from age 5 to age 10 years. Violence was assessed as exposure to maternal domestic violence, frequent bullying victimization and physical maltreatment by an adult. Participants were 236 children (49% females; 42% with one or more violence exposures) recruited from the Environmental-Risk Longitudinal Twin Study, a nationally representative 1994-1995 birth cohort. Each child's mean relative telomere length was measured simultaneously in baseline and follow-up DNA samples, using the quantitative PCR method for T/S ratio (the ratio of telomere repeat copy numbers to single-copy gene numbers). Compared with their counterparts, the children who experienced two or more kinds of violence exposure showed significantly more telomere erosion between age-5 baseline and age-10 follow-up measurements, even after adjusting for sex, socioeconomic status and body mass index (B=-0.052, s.e.=0.021, P=0.015). This finding provides support for a mechanism linking cumulative childhood stress to telomere maintenance, observed already at a young age, with potential impact for life-long health. PMID- 22525490 TI - Metabolic engineering of beta-oxidation in Penicillium chrysogenum for improved semi-synthetic cephalosporin biosynthesis. AB - Industrial production of semi-synthetic cephalosporins by Penicillium chrysogenum requires supplementation of the growth media with the side-chain precursor adipic acid. In glucose-limited chemostat cultures of P. chrysogenum, up to 88% of the consumed adipic acid was not recovered in cephalosporin-related products, but used as an additional carbon and energy source for growth. This low efficiency of side-chain precursor incorporation provides an economic incentive for studying and engineering the metabolism of adipic acid in P. chrysogenum. Chemostat-based transcriptome analysis in the presence and absence of adipic acid confirmed that adipic acid metabolism in this fungus occurs via beta-oxidation. A set of 52 adipate-responsive genes included six putative genes for acyl-CoA oxidases and dehydrogenases, enzymes responsible for the first step of beta-oxidation. Subcellular localization of the differentially expressed acyl-CoA oxidases and dehydrogenases revealed that the oxidases were exclusively targeted to peroxisomes, while the dehydrogenases were found either in peroxisomes or in mitochondria. Deletion of the genes encoding the peroxisomal acyl-CoA oxidase Pc20g01800 and the mitochondrial acyl-CoA dehydrogenase Pc20g07920 resulted in a 1.6- and 3.7-fold increase in the production of the semi-synthetic cephalosporin intermediate adipoyl-6-APA, respectively. The deletion strains also showed reduced adipate consumption compared to the reference strain, indicating that engineering of the first step of beta-oxidation successfully redirected a larger fraction of adipic acid towards cephalosporin biosynthesis. PMID- 22525491 TI - Chemosensory learning and flavour: perception, preference and intake. AB - Recent approaches to perception that have emphasised multi-sensory interactions have been crucial in developing a view of flavour as a cognitive construct derived from a synthesis of gustatory, olfactory and oral somatosensory inputs. The perceptual interactions between these distinct sensory channels provide evidence for the existence of a functional flavour system. This system is characterised by a dependence on associative learning in which odours and tastes come to share common features. In addition, studies in which attention is directed to the flavour or its elements during learning provide evidence for a view that flavour is encoded as a configural stimulus following spatial and temporal pairing of the different sensory inputs. Such encoding produces changes in the perceptual properties of odours/flavours - as illustrated by sweet smelling odours - but is also responsible for changes in hedonic valence through flavour-flavour and flavour-consequence learning. In turn, flavour and odours can act as conditioned cues that have appetitive effects. PMID- 22525492 TI - The role of a generalized ultraviolet cue for blackbird food selection. AB - Birds utilize ultraviolet (UV) wavelengths for plumage signaling and sexual selection. Ultraviolet cues may also be used for the process of avian food selection. The aim of our study was to investigate whether a UV cue and a postingestive repellent can be used to condition food avoidance in red-winged blackbirds (Agelaius phoeniceus). We found that birds conditioned with an UV absorbent, postingestive repellent subsequently avoided UV-absorbent food. Thus, the UV-absorbent cue (coupled with 0-20% of the conditioned repellent concentration) was used to maintain avoidance for up to 18 days post conditioning. Similarly, birds conditioned with the UV-absorbent, postingestive repellent subsequently avoided UV-reflective food. Thus, conditioned avoidance of an UV-absorbent cue can be generalized to an unconditioned, UV-reflective cue for nutrient selection and toxin avoidance. These findings support the hypothesized function of UV vision for avian food selection, the implications of which remain to be explored for the sensory and behavioral ecology within agronomic and natural environments. PMID- 22525493 TI - Microfluidic single cell analysis: from promise to practice. AB - Methods for single-cell analysis are critical to revealing cell-to-cell variability in biological systems, especially in cases where relevant minority cell populations can be obscured by population-averaged measurements. However, to date single cell studies have been limited by the cost and throughput required to examine large numbers of cells and the difficulties associated with analyzing small amounts of starting material. Microfluidic approaches are well suited to resolving these issues by providing increased senstitivity, economy of scale, and automation. After many years of development microfluidic systems are now finding traction in a variety of single-cell analytics including gene expression measurements, protein analysis, signaling response, and growth dynamics. With newly developed tools now being applied in fields ranging from human haplotyping and drug discovery to stem cell and cancer research, the long-heralded promise of microfluidic single cell analysis is now finally being realized. PMID- 22525494 TI - A new mechanobiological era: microfluidic pathways to apply and sense forces at the cellular level. AB - Fueled by technological advances in micromanipulation methodologies, the field of mechanobiology has boomed in the last decade. Increasing needs for clinical solutions to better maintain our major mechanosensitive tissues (muscle, bone, and cartilage) with increasing age and new insights into cellular adaptations to mechanical stresses beckon for novel approaches to meet the needs of the future. In particular, the emergence of microfluidics has inspired new interdisciplinary strategies to decipher cellular mechanotransduction on the biochemical as well as macromolecular level. Cellular actuation by locally varying fluid shear can serve to accurately alter membrane surface tension as well as produce direct compressive and strain forces onto cells. Moreover, incorporating microelectronic technologies into microfluidic platforms has led to further advances in actuation and readout possibilities. In this review, we discuss the application of microfluidics to mechanobiological research with particular focus on microfluidic platforms that are able to simultaneously monitor cellular adaptation to mechanical forces and interpret biochemical mechanotransduction. PMID- 22525495 TI - Cellular uptake of covalent conjugates of oligonucleotide with membrane-modifying peptide, peptaibol. AB - Using the membrane-modifying peptide, trichorovin-XIIa (TV-XIIa), which is an 11 residual peptaibol isolated from the fungus Trichoderma viride, we synthesized covalent conjugates of 20-mer oligonucleotide with TV-XIIa to examine the potential use of TV-XIIa in cellular delivery. The results indicated that the conjugates were progressively taken up by human lung carcinoma A549 cells. Next, the antisense effects of the conjugates on p53 protein expression were examined. The p53 expression was significantly decreased by ca. 20-50% in the presence of the conjugates upon treatment with the transfection solution at the concentration of 5 MUM. PMID- 22525496 TI - Abscinazole-E2B, a practical and selective inhibitor of ABA 8'-hydroxylase CYP707A. AB - We developed abscinazole-E2B (Abz-E2B), a practical and specific inhibitor of abscisic acid (ABA) 8'-hydroxylase (CYP707A), by structural modification of abscinazole-E1 (Abz-E1), another compound we developed. A butoxy group was introduced to Abz-E2B instead of the tosylate group of Abz-E1, in expectation of better water solubility, because the calculated logP value of Abz-E2B is 3.47, which is smaller than that of Abz-E1 (4.02). The water solubility of Abz-E2B was greater than 90% at a concentration of 100 MUM, at which the solubility of Abz-E1 was 20%. The enzyme specificity was improved significantly. In in vitro assays constructed using recombinant enzymes, (+/-)-Abz-E2B was a considerably weaker inhibitor than (+/-)-Abz-E1 for CYP701A, a GA biosynthetic enzyme, which is a target of S-uniconazole (S-UNI), a lead compound of Abz-E1. (+/-)-Abz-E2B application to plants resulted in improved desiccation tolerance and an increase in endogenous ABA, with little retardation of growth. We also prepared optically pure Abz-E2B and determined its absolute configuration. The R-enantiomer of Abz E2B was the more potent inhibitor of CYP707A, unlike UNI, whereas both enantiomers were markedly less effective than S-UNI in inhibiting CYP701A. Because S-Abz-E2B arrested the growth of rice seedlings at 100 MUM, probably because of off-target effects, R-Abz-E2B should be used as a chemical tool for research focusing on CYP707A when 100 MUM or higher concentration is required, although (+/-)-Abz-E2B may be useful as an alternative option at a lower concentration. PMID- 22525497 TI - [Pathological grading analysis of liver biopsies in chronic hepatitis B virus carriers of different age ranges]. AB - OBJECTIVE: To study the best time of taking liver biopsy for chronic HBV carriers of age ranges and then guiding antiretroviral treatment. METHOD: The liver biopsy pathologic results of 292 cases of chronic HBV carriers were collected from the First Affiliated Hospital of Kunming Medical College. The patients were divided into three groups according to ages. The differences between groups were compared by calculating the ratio of inflammation above G2 or fibrosis staging above S2. RESULT: The percentages of the chronic HBV carriers with liver histopathology inflammation graded above G2 or fibrosis staging above S2 were 26.5% (36/136) in 11 to 29 year-old group, 39.4% (37/94) in 30-39 year-old group and 58.1% (36/62) in 40-60 year-old group. Significant difference existed among groups in general (P less than 0.01). 39.4% (37/94) of chronic HBV carriers were found with inflammation graded above G2 or fibrosis staging above S2 in 30-39 year-old group, no statistically significant difference found between group 30-39 years old and group and 40-60 years old 58.1% (36/62) (P less than 0.01). 26.5% (36/136) of chronic HBV carriers under 30 years old were with inflammation graded above G2 or fibrosis staging above S2 as compared with the percentage of 46.8% (73/156) in the chronic HBV carriers over 30 years old group, and significant difference existed between the two groups (P less than 0.01). CONCLUSION: The best time choice of taking liver biopsy should be at the ages elder than or equal to 30. PMID- 22525498 TI - [Optimization and assessment of a reverse hybridization system for the detection of HBV drug-resistant mutations]. AB - OBJECTIVE: To establish a detection method for HBV drug-resistant mutations related to lamivudine, adefovir and entecavir by optimization and assessment of reverse hybridization system. METHOD: 26 degenerated probes covering 10 drug resistant hotspots of 3 drugs were synthesized and immobilized on the same positively charged nylon membrane. PCR products labeled with digoxigenin were hybridized with corresponding probes. To improve the sensitivity and specificity, 4 reaction steps of reverse hybridization were optimized including the number of labeled digoxigenin, the energy intensity of UV cross-linking, hybridization and stringency wash conditions. To prove the feasibility, the specificity, sensitivity and accuracy of this system were assessed respectively. RESULT: Sensitive and specific results are obtained by the optimization of the following 4 reaction steps: the primers labeled with 3 digoxigenin, energy intensity of UV cross-linking for 1500 x 0.1 mJ/cm2, hybridization at 42 degrees C and stringency wash with 0.5 x SSC and 0.1% SDS solution at 44 degrees C for 30 min. In the assessment of system, the majority of probes have high specificity. The quantity of PCR product with a concentration of 10 ng/MUl or above can be detected by this method. The concordant rate between reverse hybridization and direct sequencing is 93.9% in the clinical sample test. CONCLUSION: Though the specificity of several probes needs to be improved further, it is a simple, rapid and sensitive method which can detect HBV resistant mutations related to lamivudine, adefovir and entecavir simultaneously. Due to the short distance between 180 and 181, likewise 202 and 204, the sequence of the same probe covers two codon positions, and hybridization will be interfered by each other. To avoid such interference, the possible solution is that probes are designed by arranging and combining various forms of two near codons. PMID- 22525499 TI - [Quality of life in patients with chronic hepatitis C after PEG-Interferon a-2a therapy]. AB - OBJECTIVE: To evaluate the quality of life (QOL) in the patients with chronic hepatitis C (CHC) after PEG-Interferon a-2a therapy. METHODS: A study based on 102 CHC patients (group A, before PEG- Interferon a-2a therapy, T0) and 44 healthy persons (group B) was carried out using the general quality of life inventory (GQOLI-74) questionnaire, and QOL were compared between the two groups. Patients in group A were divided into subgroup A1 (72 patients ) which was given PEG-Interferon a-2a plus Ribavirin for one year and subgroup A2 (30 patients) without any antivirus therapy. QOL of patients in these two subgroups was investigated using GQOLI-74 questionnaire on the end of PEG-Interferon a-2a plus Ribavirin therapy (T1) and half one year after the end of PEG-Interferon a-2a plus Ribavirin therapy (T2). QOL of CHC patients (group A1 and A2) were compared at T0, T1 and T2, respectively. RESULTS: Compared with group B, patients in group A had lower QOL (P < 0.05) on other scales and total scores of the GQOLI-74 questionnaire except psychological function(P > 0.05). Both on T1 and T2, patients in subgroup A1 had higher QOL on physical function, psychological function, social function and total scores than patients in subgroup A2 at the same time (P < 0.05). Patients in subgroup A1 at T1 had higher QOL on physical function, psychological function, social function and total scores than at T0 (P < 0.05). Patients in subgroup A1 at T2 had higher QOL on social function than that at T1 (P < 0.05). CONCLUSIONS: QOL of CHC patients is more impaired than healthy persons. PEG-Interferon a-2a therapy will improve the QOL. PMID- 22525500 TI - [HCV NS5A protein down-regulates hepcidin gene expression and increases hepatic intracellular iron storage]. AB - OBJECTIVE: To investigate whether the nonstructural protein 5A (NS5A) encoded by the hepatitis C virus RNA genome affects the expression of hepcidin gene. METHODS: HCV NS5A expression plasmid (pCN5A) and pRc/CMV were transfected into QSG7701 cells individually, RT-PCR was employed to detect the HCV NS5A and hepcidin mRNA transcription. Western blot was used for detection of HCV NS5A and hepcidin proteins. Iron was stained to evaluate the intracellular iron level. RESULTS: HCV NS5A plasmid was successfully transfected into QSG7701 cells, which was evidenced by HCV NS5A mRNA and protein from the transfected cells. The hepcidin mRNA relative quantification in untransfected cells, pRc/CMV transfected cells and pCNS5A transfected cells were 0.711+/-0.049, 0.718+/-0.052 and 0.264+/ 0.030 respectively. The transcription of hepcidin mRNA decreased remarkably in the cells transfected with pCNS5A plasmid as compared to the untransfected cells and pRc/CMV transfected cells (P less than 0.01). The level of hepcidin protein expression was found also significantly lower in the pCN5A plasmid transfected cells as compared to the untransfected cells and pRc/CMV transfected cells. The intracellular iron staining was remarkably higher in the pcNS5A transfected cells than untransfected or pRc/CMV transfected cells. CONCLUSIONS: HCV NS5A inhibits the transcription of hepcidin mRNA and expression of hepcidin protein, inducing hepatic intracellular iron storage. PMID- 22525501 TI - [Relationship between CD44 expression or glycosylation and hepatocellular carcinoma metastasis]. AB - OBJECTIVE: To explore the relationship of CD44 expression or glycosylation and hepatocellular carcinoma (HCC) metastasis. METHODS: IHC, Quantum dots detection, RT-PCR, Western blot, Cellular immune fluorescence and MS-PCR were used to identify CD44 expression in HCC samples and a series of human HCC cell lines with different metastatic potentials. Lectin array was used to reveal the relationship of CD44v6 glycosylation and human HCC metastasis. RESULTS: Immunohistochemistry analysis showed that CD44v6 was mainly distributed on the cell membrane, while CD44S immunoreactivity was prominently in the cytoplasm, CD44v3 and CD44v4/5 were in cytoplasm on membrane. Among CD44S and those CD44 variants, only the expression of CD44v6 was higher in metastasis HCC samples as compared to that in non-metastasis group (x2=8.828, P less than 0.05). This result was also re confirmed by the result of Quantum dots (t = 2.392, P < 0.05) and serum detection (t = 2.56, P < 0.05). We found completely methylation of CD44v6 gene in Hep3B and incomplete methylation in MHCC97H and MHCC97L cell lines with metastatic potentials. The lectin affinity assay indicated that lectin MAL, SNA and WGA showed more affinity to MHCC97H and MHCC97Lcell lines than that of the non metastatic Hep3B cell lines. CONCLUSIONS: CD44v6 over-expression presents a positive correlation with HCC metastatic potential, which may be associated with DNA methylation level in promoter sequence. The increasing sialic acid modified glycan of CD44v6 might be related to HCC metastatic ability. PMID- 22525502 TI - [Identification of metastasis-related osteopontin expression and glycosylation in hepatocellular carcinoma]. AB - OBJECTIVE: To test expression level and glycosylation level of OPN in HCC cell lines with different metastatic potential and HCC tissues, and investigate the correlation between the glycosylation change and the liver cancer transporting as well as its significance. METHODS: The level of OPN expression in liver cancer tissue(6 cases of non-metastasis and 7 cases of metastasis)as well as HCC cell lines with different metastatic potential (L02, Hep3B, MHCC97L, MHCC97H, HCCLM3, HCCLM6)was identified by immunohistochemistry and Western Blot, and then OPN was purified from HCC tissues by immunoprecipitation, followed by glycosylation detection of OPN from non-metastatic and metastatic HCC tissues by multiple lectin blot. Data were analyzed by t-test and variance analysis. RESULTS: Different levels of OPN expression were observed in HCC cell lines with different metastatic potential (F = 5.04, P = 0.008). Additionally, OPN expression level in HCC tissues with metastasis was higher than that in non-metastasis group (t = 2.447, P < 0.05). Relative optical density value was 0.69 +/- 0.21 and 0.45 +/- 0.14 respectively. OPN in liver cancer tissue was successfully purified using immunoprecipitation. Followed lectin blotting result showed that OPN protein in metastasis group showed lower affinity to MAL, PHAE, DSA, ConA as compared with that in non-metastasis group (P < 0.05). CONCLUSIONS: The expression of OPN was positively correlated with the enhanced metastasis potential of HCC. OPN from metastasis HCC tissues presented lower level of some specific glycan structures such as a2, 3- sialic acid, bisecting GlcNAc, biantennary, muti-antennary and high mannose type N-glycan structure. This study not only indicates the role of OPN in HCC metastasis for the first time, but also provide experimental support for the mechanism of the function of OPN in the transportation of liver cancer cells as well as offer potential target for clinical treatment. PMID- 22525503 TI - [Subcellular proteomic analysis of Tetrazanbigen on human hepatocellular carcinoma cell line QGY-7701]. AB - OBJECTIVE: To investigate the clinical efficacy of cryotherapy ablation treatment for advanced hepatocellular carcinoma, and to analyse the predictive factors of cryotherapy ablation treatment. METHODS: 190 patients of hepatitis B-related advanced HCC from 2005 to 2008 in our hospital underwent curative cryoablation. We used clinical cohort method to analyze cryoablation group (147 cases) and control group (43 cases). The median OS (over survival time) and TTP (time to disease progression) were compared. We also evaluated the clinical significance of age, gender, location of portal vein tumor thrombus, HBeAg, tumor histological grade, Child-Pugh classification, end-stage liver disease (MELD) score, advanced liver cancer prediction system (ALCPS) score and the Eastern Cooperative Oncology Group performance status (ECOG PS) score for predicting the efficacy of cryoablation. Two Groups were compared with the x2 test. Survival rates were estimated by the Kaplan-Meier method and compared by the log rank test. The Cox proportional hazards model was used to determine the independent factors on survival based on the variables selected in univariate analysis. RESULTS: Median survival time of cryoablation group and Control group were 7.5 (4.2 to 14.6) months and 3.2 (1.2 to 8.6) months, median TTP were 3.5 (2.5 to 4.5) months and 1.5 (1.0 to 3.5 months), the differences between were statistically significant (P < 0.05). Median OS and TTP of advanced HCC patients who had Well differentiated tumor, Child-pugh A-class and low score of MELD score, ALCPS score; ECOG PS score were significantly longer than that of the poorly differentiated tumor, Child-pugh B-class and the high those scores (P < 0.05). ECOG PS (P less than 0.05, 95% CI 1.074 - 2.143) and ALCPS (P < 0.05, 95% CI 1.005-2.121) were independent predictors for OS of advanced HCC. CONCLUSIONS: Cryoablation treatment can prolong median OS and TTP of advanced HCC. ECOG PS and ALCPS are important predictors for survival time of advanced HCC. PMID- 22525504 TI - [TNFalpha induced IL-8 production through p38 MAPK- NF-kB pathway in human hepatocellular carcinoma cells]. AB - OBJECTIVE: To identify the role of p38 MAPK- NF-kB signaling pathway in TNF-alpha induced IL-8 production in human hepatocellular carcinoma cells. METHODS: The concentrations of IL-8 from MHCC-97H cells were measured by an enzyme-linked immunosorbent assay (ELISA). The phosphorylation of p38 MAPK was analyzed by Western blot and immunofluorescence. NF-kB p65 protein nuclear translocation was determined by non-radioactive NF-kB p50 / p65 transcription factor activity kit and immunofluorescence. RESULTS: The IL-8 production from MHCC-97H cells challenged with TNFa significantly increased in a time-dependent (F = 144.04, P < 0.01) and dose-dependent (F = 364.14, P < 0.01) manners, as compared with those without TNFa challenge. TNFa up-regulated the phosphorylation levels of p38 MAPK and increased the translocation of NF-kB p65 protein into the nucleus, also proved by immunofluorescence staining. p38 MAPK inhibitor (SB203580) could significantly inhibit IL-8 production in a dose-dependent manners (F = 65.47, P < 0.01), and partially inhibited NF-kB p65 nuclear translocation in a dose dependent manner (F=141.20, P < 0.05). CONCLUSION: TNF-alpha could increase the production of IL-8 in MHCC-97H cells and p38 MAPK- NF-kB pathways seem to play a central role in the regulation of IL-8 production. PMID- 22525505 TI - [Adiponectin inhibits the activation of hepatic stellate cells induced by TGFb1 via up-regulating the expression of eNOS]. AB - OBJECTIVE: To investigate the molecular mechanism of adiponectin inhibiting activation of hepatic stellate cells in non-alcoholic fatty liver fibrosis. METHODS: The rat models of non-alcoholic fatty liver fibrosis were successfully established by fat-rich diet administration. The expression of adiponectin mRNA and protein were respectively detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. LX-2 cells were cultured in an adipogenic differentiation mixture to induce quiescent adipocytic phenotypes, and then they were treated with TGFbeta1, adiponectin and TGFbeta1 + adiponectin, respectively. RT-PCR and Western blot were used to determine the expressions of mRNAs and proteins of a-smooth muscle actin (a-SMA), Collagen, adenosine monophosphate activated protein kinase (AMPK), inducible nitric oxide synthase (iNOS), and endothelial NOS (eNOS). The results were analyzed using one-way ANOVA, Student Newman-Keuls test, and linear correlation analysis. A P value of less than 0.05 was considered as statistically significant. RESULTS: In vivo, with the progress of non-alcoholic fatty liver fibrosis, the model rats gradually showed hepatic steatosis, inflammation, necrosis and fibrosis. Compared with the control group, the level of serum adiponectin (2.49 +/- 0.86 vs 5.81 +/- 0.87, P < 0.05) and hepatic expressions of adiponectin mRNA and protein (0.26 +/- 0.04 vs 0.72 +/- 0.08; 0.64 +/- 0.07 vs 0.21 +/- 0.07, all P < 0.05) were all decreased in the 24th week group, and were negatively correlated with the level of Collagen which increased gradually. In vitro, TGFbeta1 could activate quiescent LX-2 cells by decreasing mRNA and protein expression of eNOS (0.30 +/- 0.10 vs 0.44 +/- 0.08; 0.30 +/- 0.09 vs 0.46 +/- 0.07, all P < 0.05) and increasing the expression of iNOS (0.53 +/- 0.07 vs 0.37 +/- 0.04; 0.55 +/- 0.07 vs 0.39 +/- 0.05, all P < 0.05). Recombinant adiponectin not only maintained the quiescent phenotype of LX 2 cells but also inhibited LX-2 cells activation due to TGFbeta1 by increasing the expression of eNOS (0.43 +/- 0.08 vs 0.30 +/- 0.10; 0.42 +/- 0.07 vs 0.30 +/- 0.09, all P < 0.05) and phosphorylation of AMPK (0.43 +/- 0.07 vs 0.24 +/- 0.04, P < 0.05) and decreasing the expression of iNOS (0.44 +/- 0.05 vs 0.53 +/- 0.07; 0.46 +/- 0.07 vs 0.55 +/- 0.07, all P < 0.05). CONCLUSIONS: Data suggested that adiponectin could play a protective role on the pathogenesis of non-alcoholic fatty liver fibrosis by inhibiting the activation of hepatic stellate cells via up-regulating the expression of eNOS, which might associate with increased phosphorylation of AMPK. PMID- 22525506 TI - [Study on between magnetic resonance venography and digital subtraction angiography on the inferior vena cava obstructive interface morphology of Budd Chiari syndrome]. AB - OBJECTIVE: To evaluate magnetic resonance venography (MRV) in diagnosing obstructive interface morphology of Budd-Chiari syndrome(BCS). METHODS: MRV examination was performed on 44 cases of BCS, and the images of obstructive interface morphology of the inferior vena cava were reviewed by two radiologists. RESULTS: In all 44 cases, there were 37 cases with complete obstruction and 7 with incomplete obstruction. MRV showed 4 cases with membrane with hole of incomplete obstruction. The morphologies MRV demonstrated that the proximal part of the 37 cases with complete obstruction were mainly divided into the cone type (36 cases) and the planum type (1 case). Besides, the type of distal end of obstruction were the cone type (30 cases), the planum type (4 cases) and the irregular type (3 cases). The overall sensitivity, specificity, positive and negative predictive values for the diagnosis of MRV were respectively 100%%, 57.1%, 92.5% and 100% as compared to the DSA. CONCLUSION: The examination of MRV is capable of revealing the obstructive interface morphology of the inferior vena cava, especially for the distal end of obstruction. MRV can provide guidelines in interventional treatment of Budd-Chiari syndrome. PMID- 22525507 TI - [Effect of baicalin on liver fatty acid binding protein in oxidative stress model in vitro]. AB - OBJECTIVE: To investigate the effect of baicalin on liver fatty acid binding protein in oxidative stress model in vitro. METHODS: (1) Cellular oxidative stress in vitro was induced by incubating cells with 400MUmol/L hydrogen peroxide (H2O2) for 20 minutes at 37 degrees C in the dark. After Chang liver cell line was treated with different dose of baicalin for 24, 48 and 72 hours. MTT assay was employed to detect cell viability, and then the hydrogen peroxide (TC50) of the different dose of baicalin was calculated. (2) Based on MTT assay, cells were treated with three different doses of baicalin (25, 50, 100 MUmol/L) for 24 and 48 hours before being exposed to 400 MUmol/L H2O2 for 20 minutes at 37 degrees C. Then, reactive oxygen species (ROS) assay and activity assays of superoxide dismutase (SOD) and reduced glutathione hormone (GSH) were evaluated. (3) Realtime PCR and Western blotting were applied to explore the influence of baicalin on the expression level of L-FABP. (4) One-way ANOVA was used for results statistical analysis. RESULT: (1) MTT assay showed baicalin treatment at 25, 50, 100 MUmol/L for 24 and 48 hours was feasible (83.60% +/- 3.47%, 72.36% +/ 2.18%, 70.16% +/- 2.04% for 24 hours; 84.93% +/- 3.11%, 76.16% +/- 2.45%, 72.72% +/- 2.31% for 48 hours, P > 0.05, F = 386.24, 475.92 respectively). Meanwhile, we found by the linear regression model that the median toxic concentration of baicalin for 48 hours was 170.6 MUmol/L, and the median toxic concentration of baicalin for 24 hours was 153.2 MUmol/L. (2) ROS assay showed dichlorofluorescin in all baicalin-treated cells after stress was significantly reduced (37.0 +/- 3.30, 22.90 +/- 3.84, 29.60 +/- 2.52 for 24 hours respectively, P < 0.05, F = 70.06; 35.77 +/- 2.35, 21.80 +/- 3.10, 23.87 +/- 1.98 for 48 hours respectively, P < 0.05, F = 110.92) as compared with the H2O2-treated cells. Moreover, 50 MUmol/L baicalin treatment for 48 hours was the optimal condition against ROS generation (21.80 +/- 3.10, P < 0.01, F = 110.92). Furthermore, the activities of intracellular SOD and GSH was increased significantly (51.53 +/- 1.91 MUg/mg for SOD, P < 0.05, F = 93.81; 49.85 +/- 1.45 U/mg for GSH, P < 0.05, F = 92.51). (3) Although realtime PCR analysis indicated 50 MUmol/L baicalin treatment for 48 hours could have no changes of the level of L-FABP expression under the oxidative stress condition, western blotting analysis indicated 50 MUmol/L baicalin treatment for 48 hours could increase up to about 80% for the level of L-FABP expression. CONCLUSION: Baicalin was suggested to be able to enhance both L-FABP expression and activity of intracellular SOD and GSH, and therefore protected hepatocytes from oxidative stress. PMID- 22525508 TI - The effect of a mismatched center of rotation on the clinical outcomes and flexion-extension range of motion: lumbar total disk replacement using mobidisc at a 5.5-year follow-up. AB - STUDY DESIGN: Retrospective clinical and radiographic assessment of 21 levels of 18 consecutive patients treated using total lumbar disk replacement (TDR) for degenerative disk disease. OBJECTIVES: To report clinical and radiographic outcomes after TDR using the Mobidisc prosthesis. In addition, to determine whether there is a correlation between clinical and radiologic outcomes and prosthesis positioning. SUMMARY OF BACKGROUND DATA: TDR for lumbar degenerative disk disease is reported to provide good clinical and radiographic outcomes. However, TDR can alter the kinematics of the facet joint during flexion and extension. If prosthesis positioning is poor, the facet joint loading is increased upto 2.5-fold. No study has examined whether differences between the prosthesis center of rotation (COR) and the individual's COR have an effect on the clinical or radiographic outcomes after TDR. METHODS: A retrospective study of 21 levels from 18 consecutive degenerative disk disease patients who underwent lumbar TDR. The Mobidisc prosthesis was used in all cases. Clinical parameters measured were lower back and leg pain [both assessed using the Oswestry Disability Index (ODI)]. These parameters were measured preoperatively and at the last follow-up. Radiographic assessment involved examining standard lateral flexion/extension views taken at the preoperative, postoperative 6-month, and the last follow-up assessments to determine disk space height (DSH) and range of motion (ROM). Patient satisfaction (subjective outcome) was determined by telephone questioning. For analysis, TDR cases were categorized into 3 groups on the basis of the size of the "COR index," which represented the difference between an individual's inherent COR and the inherent prosthesis COR. Group 1, COR index <5 mm, consisted of 13 levels; group 2, COR index >5 mm, and <10 mm, consisted of 5 levels; and group 3, COR index >10 mm, consisted of 3 levels. RESULTS: Overall, 77.8% of patients stated that they were highly satisfied with their surgical outcome. Low back pain visual analogue scale scores decreased from 7.61+/-2.17 (mean+/-SD) preoperatively to 2.33+/-2.679 at the last follow-up (P<0.001). The function increased postoperatively (ODI: 25.89+/-7.77 preoperative vs. 5.89+/-7.21 at last follow-up; P<0.001). The difference between preoperative and the last follow-up ODI was greater in group 1 than in groups 2 and 3 (P=0.034). Radiographic findings showed that TDR resulted in improved disk space height and segmental ROM (P<0.05). Analysis of the 3 groups showed that ROM preservation decreased as the COR index increased. CONCLUSIONS: The present study found that lumbar TDR using the Mobidisc prosthesis resulted in good clinical and radiologic outcomes and good patient satisfaction. Furthermore, we found that patient satisfaction, function, and ROM preservation correlated with correct COR positioning of the prosthesis. PMID- 22525509 TI - Sorption of ionic liquids onto soils: experimental and chemometric studies. AB - Chemometric analyses are a great tool to support typical experimental studies of the interactions of xenobiotics with natural environment. Such interpretations are able to determine statistically significant correlations and finally lead to identification of the major sorption factors. However, to effectively use chemometrics a bigger data set is required. Even though the ionic liquids are intensively studied, their complete fate or prediction of their behavior in the natural environment is still unclear. Therefore, to evaluate and distinguish the patterns of interactions of ILs in soil environment by chemometrics, sorption of nine ionic liquids (imidazolium and pyridinium chlorides) on 11 types of various soils was tested. Experimental studies indicated that compounds with longer alkyl side chains were sorbed far more strongly than weakly lipophilic ones. Moreover, salts with short and/or hydroxylated derivatives were more mobile in soils/sediments and thus, might cause a danger of contamination of surface or ground waters. Cluster analysis revealed that ionic liquids form two major clusters according to interaction with soil surface - one grouping compounds with short and hydroxylated alkyl side chains and the second with the rest of compounds. Pairwise scatterplots for correlations between soil variables and sorption coefficients indicated that the main soil parameter responsible for the sorption was cation exchange capacity. Correlation of sorption coefficients, K(d), with pH indicated the existence of lower sorption potency in lower pH values. PMID- 22525511 TI - Ultrasound-guided aspiration and corticosteroid injection compared to horizontal therapy for treatment of knee osteoarthritis complicated with Baker's cyst: a randomized, controlled trial. AB - BACKGROUND: Combining different therapies, physical therapy agents, pharmacological and physical therapies, generally produces better outcomes for symptoms of knee osteoarthritis (OA) than do isolated therapies. AIM: To demonstrate if horizontal therapy (HT) and aspiration alone and corticosteroid injection alone or in combination determine pain relief and functional improvement in a group of patients with knee OA complicated with Baker's cyst (BC). DESIGN: We designed a randomized controlled trial (RCT). SETTING: Outpatients. POPULATION: Sixty patients with a knee OA and diagnosis of BC confirmed by means of standard ultrasound (US) evaluation. METHODS: The trial was conducted as a randomized, controlled trial. Patients who satisfied the inclusion criteria were randomized to either the US-guided (Ultrasound Guided BC aspiration and corticosteroid injection group (Group A), the Horizontal Therapy group (Group B) or the US-guided BC aspiration and corticosteroid injection plus Horizontal therapy group (Group C). Outcome measures included: 1) pain reduction as measured by visual analogue scale (VAS); 2) functional improvement, as measured by WOMAC; and 3) US evaluation at baseline (T0), at one (T1) and four (T2) weeks follow-up. RESULTS: A total of 60 patients were randomized into group A (N.=20), group B (N.=20) or Group C (N.=20). Patients in group A and in group C, but not those in group B maintained lower pain level at T2 than at baseline, with significant lower VAS values in Group C. As regards US measurements, the maximum axial area did not change as a consequence of the treatment in any of the three groups (P=0.259). Contrarily, sagittal area measurements were influenced by time (P<0.01). CONCLUSION: Our results show that the group with the best performance for pain, functionality and dimension of BC was that in which combined use was made of horizontal and corticosteroid injection therapies. CLINICAL REHABILITATION IMPACT: In this study we want to demonstrate the effectiveness of Horizontal Therapy in the treatment of knee OA complicated by BC. PMID- 22525510 TI - Formation of PCDD/Fs from oxidation of 2-monochlorophenol over an Fe2O3/silica surface. AB - The role of iron in surface-mediated formation of polychlorinated dibenzo-p dioxins and dibenzofurans (PCDD/Fs) from 2-chlorophenol (2-MCP) was investigated over the temperature range of 200-550 degrees C under oxidative conditions. In order to compare and contrast with previous work on copper and ferric oxide mediated pyrolysis of 2-MCP, identical reaction conditions were maintained (50 ppm 2-MCP, model fly-ash particles containing 5% Fe(2)O(3) on silica). Observed products included dibenzo-p-dioxin (DD), 1-monochlorodibenzo-p-dioxin (1-MCDD), dibenzofuran (DF), 4,6-dichlorodibenzofuran (4,6-DCDF), 2,4- and 2,6 dichlorophenol, 2,4,6-trichlorophenol, quinone, catechol, chloro-o-quinone, chlorocatechol and polychlorinated benzenes. Yields of DD and 1-MCDD were 2 and 5 times higher than under pyolysis conditions, respectively. Although 4,6-DCDF was the major PCDD/F product formed with a yield that was 2.5* greater than under pyrolysis, the yield of non-chlorinated DF, which was the dominant PCDD/F product under pyrolysis, decreased by a factor of 3. Furthermore, the ~2* higher yield of PCDDs under oxidative conditions resulted in a PCDD to PCDF ratio of 0.75 compared to a relatively low ratio of 0.39 previously observed under pyrolytic conditions. PMID- 22525512 TI - Bone matrix osteonectin limits prostate cancer cell growth and survival. AB - There is considerable interest in understanding prostate cancer metastasis to bone and the interaction of these cells with the bone microenvironment. Osteonectin/SPARC/BM-40 is a collagen binding matricellular protein that is enriched in bone. Its expression is increased in prostate cancer metastases, and it stimulates the migration of prostate carcinoma cells. However, the presence of osteonectin in cancer cells and the stroma may limit prostate tumor development and progression. To determine how bone matrix osteonectin affects the behavior of prostate cancer cells, we modeled prostate cancer cell-bone interactions using the human prostate cancer cell line PC-3, and mineralized matrices synthesized by wild type and osteonectin-null osteoblasts in vitro. We developed this in vitro system because the structural complexity of collagen matrices in vivo is not mimicked by reconstituted collagen scaffolds or by more complex substrates, like basement membrane extracts. Second harmonic generation imaging demonstrated that the wild type matrices had thick collagen fibers organized into longitudinal bundles, whereas osteonectin-null matrices had thinner fibers in random networks. Importantly, a mouse model of prostate cancer metastases to bone showed a collagen fiber phenotype similar to the wild type matrix synthesized in vitro. When PC-3 cells were grown on the wild type matrices, they displayed decreased cell proliferation, increased cell spreading, and decreased resistance to radiation-induced cell death, compared to cells grown on osteonectin-null matrix. Our data support the idea that osteonectin can suppress prostate cancer pathogenesis, expanding this concept to the microenvironment of skeletal metastases. PMID- 22525513 TI - Gene therapy by targeted adenovirus-mediated knockdown of pulmonary endothelial Tph1 attenuates hypoxia-induced pulmonary hypertension. AB - Serotonin is produced by pulmonary arterial endothelial cells (PAEC) via tryptophan hydroxylase-1 (Tph1). Pathologically, serotonin acts on underlying pulmonary arterial cells, contributing to vascular remodeling associated with pulmonary arterial hypertension (PAH). The effects of hypoxia on PAEC-Tph1 activity are unknown. We investigated the potential of a gene therapy approach to PAH using selective inhibition of PAEC-Tph1 in vivo in a hypoxic model of PAH. We exposed cultured bovine pulmonary arterial smooth muscle cells (bPASMCs) to conditioned media from human PAECs (hPAECs) before and after hypoxic exposure. Serotonin levels were increased in hypoxic PAEC media. Conditioned media evoked bPASMC proliferation, which was greater with hypoxic PAEC media, via a serotonin dependent mechanism. In vivo, adenoviral vectors targeted to PAECs (utilizing bispecific antibody to angiotensin-converting enzyme (ACE) as the selective targeting system) were used to deliver small hairpin Tph1 RNA sequences in rats. Hypoxic rats developed PAH and increased lung Tph1. PAEC-Tph1 expression and development of PAH were attenuated by our PAEC-Tph1 gene knockdown strategy. These results demonstrate that hypoxia induces Tph1 activity and selective knockdown of PAEC-Tph1 attenuates hypoxia-induced PAH in rats. Further investigation of pulmonary endothelial-specific Tph1 inhibition via gene interventions is warranted. PMID- 22525515 TI - Purification and identification of two carnosine-cleaving enzymes, carnosine dipeptidase I and Xaa-methyl-His dipeptidase, from Japanese eel (Anguilla japonica). AB - Three enzymes, carnosine dipeptidase I (EC 3.4.13.20, CNDP1), carnosine dipeptidase II (EC 3.4.13.18, CNDP2), and Xaa-methyl-His dipeptidase (or anserinase: EC 3.4.13.5, ANSN), are known to be capable of catalyzing the hydrolysis of carnosine (beta-alanyl-l-histidine), in vertebrates. Here we report the purification and identification of two unidentified carnosine-cleaving enzymes from Japanese eel (Anguilla japonica). Two different dipeptidases were successfully purified to homogeneity from the skeletal muscle; one exhibited a broad substrate specificity, while the other a narrow specificity. N-terminal amino-acid sequencing, deglycosylation analysis, and genetic analysis clearly revealed that the former is a homodimer of glycosylated subunits, encoded by ANSN, and the latter is another homodimer of glycosylated subunits, encoded by CNDP1; that is, Xaa-methyl-His dipeptidase, and carnosine dipeptidase I respectively. This is the first report on the identification of carnosine dipeptidase I from a non-mammal. Database search revealed presence of a CNDP1 ortholog only from salmonid fishes, including Atlantic salmon and rainbow trout, but not from other ray-finned fish species, such as zebrafish, fugu, and medaka whose genomes have been completely sequenced. The mRNAs of CNDP1 and ANSN are strongly expressed in the liver of Japanese eel, compared with other tissues, while that of CNDP2 is widely distributed in all tissues tested. PMID- 22525514 TI - In vivo gene delivery by nonviral vectors: overcoming hurdles? AB - The promise of cancer gene therapeutics is hampered by difficulties in the in vivo delivery to the targeted tumor cells, and systemic delivery remains to be the biggest challenge to be overcome. Here, we concentrate on systemic in vivo gene delivery for cancer therapy using nonviral vectors. In this review, we summarize the existing delivery barriers together with the requirements and strategies to overcome these problems. We will also introduce the current progress in the design of nonviral vectors, and briefly discuss their safety issues. PMID- 22525517 TI - Current world literature. PMID- 22525516 TI - Modeling the human skin barrier--towards a better understanding of dermal absorption. AB - Many drugs are presently delivered through the skin from products developed for topical and transdermal applications. Underpinning these technologies are the interactions between the drug, product and skin that define drug penetration, distribution, and elimination in and through the skin. Most work has been focused on modeling transport of drugs through the stratum corneum, the outermost skin layer widely recognized as presenting the rate-determining step for the penetration of most compounds. However, a growing body of literature is dedicated to considering the influence of the rest of the skin on drug penetration and distribution. In this article we review how our understanding of skin physiology and the experimentally observed mechanisms of transdermal drug transport inform the current models of drug penetration and distribution in the skin. Our focus is on models that have been developed to describe particular phenomena observed at particular sites of the skin, reflecting the most recent directions of investigation. PMID- 22525519 TI - Blockade of endothelial G(i) protein enhances early engraftment in intraportal cell transplant to mouse liver. AB - The limited availability of liver donors and recent progress in cell therapy technologies has centered interest on cell transplantation as a therapeutic alternative to orthotopic liver transplant for restoring liver function. Following transplant by intraportal perfusion, the main obstacle to cell integration in the parenchyma is the endothelial barrier. Transplanted cells form emboli in the portal branches, inducing ischemia and reperfusion injury, which cause disruption of endothelial impermeability and activate the immune system. Approximately 95% of transplanted cells fail to implant and die within hours by anoikis or are destroyed by the host immune system. Intravascular perfusion of Bordetella pertussis toxin (PTx) blocks endothelial G(i) proteins and acts as a reversible inducer of actin cytoskeleton reorganization, leading to interruption of cell confluence in vitro and increased vascular permeability in vivo. PTx treatment of the murine portal vascular tree 2 h before intraportal perfusion of embryonic stem cells facilitated rapid cell engraftment. By 2 h postperfusion, the number of implanted cells in treated mice was more than fivefold greater than in untreated controls, a difference that was maintained to at least 30 days posttransplant. We conclude that prior to cell transplant, PTx blockade of the G(i) protein pathway in liver endothelium promotes rapid, efficient cell implantation in liver parenchyma, and blocks chemokine receptor signaling, an essential step in early activation of the immune system. PMID- 22525520 TI - Antinociceptive effect of peripheral serotonin 5-HT2B receptor activation on neuropathic pain. AB - Serotonin is critically involved in neuropathic pain. However, its role is far from being understood owing to the number of cellular targets and receptor subtypes involved. In a rat model of neuropathic pain evoked by chronic constriction injury (CCI) of the sciatic nerve, we studied the role of 5-HT(2B) receptor in dorsal root ganglia (DRG) and the sciatic nerve. We showed that 5 HT(2B) receptor activation both prevents and reduces CCI-induced allodynia. Intrathecal administration of 5-HT(2B) receptor agonist BW723C86 significantly attenuated established mechanical and cold allodynia; this effect was prevented by co-injection of RS127445, a selective 5-HT(2B) receptor antagonist. A single application of BW723C86 on the sciatic nerve concomitantly to CCI dose dependently prevented mechanical allodynia and significantly reduced cold allodynia 17 days after CCI. This behavioral effect was accompanied with a marked decrease in macrophage infiltration into the sciatic nerve and, in the DRG, with an attenuated abnormal expression of several markers associated with local neuroinflammation and neuropathic pain. CCI resulted in a marked upregulation of 5-HT(2B) receptor expression in sciatic nerve and DRG. In the latter structure, it was biphasic, consisting of a transient early increase (23-fold), 2 days after the surgery and before the neuropathic pain emergence, followed by a steady (5 fold) increase, that remained constant until pain disappeared. In DRG and sciatic nerve, 5-HT(2B) receptors were immunolocalized on sensory neurons and infiltrating macrophages. Our data reveal a relationship between serotonin, immunocytes, and neuropathic pain development, and demonstrate a critical role of 5-HT(2B) receptors in blood-derived macrophages. PMID- 22525522 TI - The Huxley-Simmons manoeuvre: is still lacking the experimental evidence that the quick release is a pure elastic phenomenon. AB - The analysis of the quick release is usually made by fitting a straight line to the first few experimental points of the tension-length curve. The line is then extrapolated to zero force. The fact that the tension-length curve can be represented by a straight line does not grant, however, that the quick release is a pure elastic process. As a matter of fact the experimental precision is not such to exclude a small nonlinearity from the curve and thus to mistake a visco elastic process for an elastic one. At least two are the consequences of such a mistake: (1) stiffness is overestimated; (2) energy balance is incorrect. PMID- 22525521 TI - Examination of the carboxylesterase phenotype in human liver. AB - Carboxylesterases (CES) metabolize esters. Two CES isoforms are expressed in human liver (CES1 and CES2) and liver extracts are used in reaction phenotyping studies to discern interindividual metabolic variation. We tested the hypothesis that an individual's CES phenotype can be characterized by reporter substrates/probes that interrogate native CES1 and CES2 activities in liver and immunoblotting methods. We obtained 25 livers and found that CES1 is the main hydrolytic enzyme. Moreover, although CES1 protein levels were similar, we observed large interindividual variation in bioresmethrin hydrolysis rates (17 fold), a pyrethroid metabolized by CES1 but not CES2. Bioresmethrin hydrolysis rates did not correlate with CES1 protein levels. In contrast, procaine hydrolysis rates, a drug metabolized by CES2 but not CES1, were much less variant (3-fold). Using activity-based fluorophosphonate probes (FP-biotin), which covalently reacts with active serine hydrolases, CES1 protein was the most active enzyme in the livers. Finally, using bioorthogonal probes and click chemistry methodology, the half-life of CES 1 and 2 in cultured HepG2 cells was estimated at 96 h. The cause of the differential CES1 activities is unknown, but the underlying factors will be important to understand because several carboxylic acid ester drugs and environmental toxicants are metabolized by this enzyme. PMID- 22525523 TI - Quantitative measurement of optical parameters of cell lines 5-8F and 6-10B using polarization sensitive optical coherence tomography. AB - The aim was to test whether the typical NPC cell lines of 5-8F (high tumorigenesis and metastasis) and 6-10B (low tumorigenesis and metastasis) could be differentiated by polarization sensitive optical coherence tomography (PS OCT). We imaged the two types of low cellular differentiated NPC cell lines 5-8F and 6-10B pellets using PS-OCT; then extracted the optical parameters of attenuate coefficient and anisotropy from the A-scan lines based on the multiple scattering model; and compared their phase retardation. The fitting scattering coefficients were MUs=10.91+/-0.45 and MUs=11.33+/-0.27 cm(-1) for 5-8F and 6-10B pellets (p<0.05), respectively; and the anisotropy factors were g=0.900+/-0.013 and g=0.885+/-0.008 for 5-8F and 6-10B pellets (p<0.01), respectively. While the phase retardation of 6-10B was a little faster than 5-8F. These results indicated that PS-OCT could differentiate the two cell lines, and had the potential ability for typing the tissue of NPC. PMID- 22525524 TI - Resistance mechanisms and drug susceptibility testing of nontuberculous mycobacteria. AB - Nontuberculous mycobacteria (NTM) are increasingly recognized as causative agents of opportunistic infections in humans. For most NTM infections the therapy of choice is drug treatment, but treatment regimens differ by species, in particular between slow (e.g. Mycobacterium avium complex, Mycobacterium kansasii) and rapid growers (e.g. Mycobacterium abscessus, Mycobacterium fortuitum). In general, drug treatment is long, costly, and often associated with drug-related toxicities; outcome of drug treatment is poor and is likely related to the high levels of natural antibiotic resistance in NTM. The role of drug susceptibility testing (DST) in the choice of agents for antimicrobial treatment of NTM disease, mainly that by slow growers, remains subject of debate. There are important discrepancies between drug susceptibility measured in vitro and the activity of the drug observed in vivo. In part, these discrepancies derive from laboratory technical issues. There is still no consensus on a standardized method. With the increasing clinical importance of NTM disease, DST of NTM is again in the spotlight. This review provides a comprehensive overview of the mechanisms of drug resistance in NTM, phenotypic methods for testing susceptibility in past and current use for DST of NTM, as well as molecular approaches to assess drug resistance. PMID- 22525525 TI - Identification of membrane progestin receptors (mPR) in goldfish oocytes as a key mediator of steroid non-genomic action. AB - One of the most extensively investigated and well characterized models of non genomic steroid actions initiated at the cell surface is the induction of oocyte maturation (OM) in fish and amphibians by progestin. Gonadotropin induces the final phase of oocyte maturation indirectly by inducing the synthesis of maturation inducing steroids (MIS) by the ovarian follicles via its membrane receptor, membrane progestin receptor (mPR). Three mPR subtypes (alpha, beta and gamma) have been identified by cDNA cloning or by in silico analysis of genome sequence databases. Previously, we described the cloning of the mPRalpha cDNA from a goldfish ovarian cDNA library and obtained experimental evidence that the mPRalpha protein is an intermediary in MIS induction of OM in goldfish. Then we cloned one beta and two gamma subtypes (hereafter referred to as gamma-1 and gamma-2) from a goldfish ovarian cDNA library. RT-PCR showed different tissue expression patterns of the mRNAs for these mPR subtypes. However, in addition to mPRalpha, the beta, gamma-1 and gamma-2 subtypes were also expressed in follicle enclosed oocytes. Microinjection of goldfish oocytes with a morpholino antisense oligonucleotide to mPRbeta blocked the induction of oocyte maturational competence, whereas injection of antisense oligonucleotides to mPRgamma-1 and gamma-2 were ineffective. These results suggest that goldfish mPRbeta protein acts as an intermediary during MIS induction of OM in goldfish, in a manner similar to mPRalpha. We are establishing mutant strains of Medaka fish to investigate the roles of mPR proteins in vivo produced by Targeting Induced Local Lesions in Genomes (Tilling) strategy. By the screening, we have selected three strains in which a point mutation was induced in each strain at the coding sequence of mPRalpha. In near future results of phenotypic analysis of mPRalpha defective fish will be introduced. PMID- 22525526 TI - A post-processing technique for cranial CT image identification. AB - OBJECTIVE: A major challenge in radiographic identification is the inconsistent orientation between clinical (ante-mortem, AM) and post-mortem (PM) radiographs. The objectivity and accuracy of radiological identification would be greatly enhanced by post-processing techniques that allow quantitative comparison of PM CT data in the same orientation as the AM CT data. METHODS: We applied a post processing technique to reposition a multislice computed tomography (MSCT) scan for spatial registration with a CT radiograph from the same patient. A second set of MSCT images from different individuals served as the non-matched control group. The consistency in radiographic positioning eliminated subjectivity in the comparison and identification process because the radiograph superposition provided objective evidence that confirmed the identification with fine detail. RESULTS: A quantitative comparison with statistical validation was achieved by measuring a set of 14 landmarks from the images. Discrimination of identity based on logistic regression analysis of the earlier CT patient scans (the AM group) versus subsequent MSCT scans (the PM group) was objective and reliable. CONCLUSION: This quantitative comparison depends less on subjective judgment and the experience of the examiner, and so may meet legal standards. PMID- 22525527 TI - Voltammetric determination of Delta9-THC in glassy carbon electrode: An important contribution to forensic electroanalysis. AB - A new voltammetric method for the determination of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) is described. The voltammetric experiments were accomplished in N N dimethylformamide/water (9:1, v/v), using tetrabutylammonium tetrafluoroborate (TBATFB) 0.1mol/L as supporting electrolyte and a glassy carbon disk electrode as the working electrode. The anodic peak current was observed at 0.0V (vs. Ag/AgCl) after a 30s pre-concentration step under an applied potential of -1.2V (vs. Ag/AgCl). A linear dependence of Delta(9)-THC detection was obtained in the concentration range 2.4-11.3ng/mL, with a linear correlation coefficient of 0.999 and a detection limit of 0.34ng/mL. The voltammetric method was used to measure the content of Delta(9)-THC in samples (hemp and hashish) confiscated by the police. The elimination of chemical interferences from the samples was promptly achieved through prior purification using the TLC technique, by employing methanol/water (4:1, v/v) as the mobile phase. The results showed excellent correlation with results attained by HPLC. PMID- 22525528 TI - Man with oropharyngeal trauma. Oropharyngeal high-pressure injection injury. PMID- 22525529 TI - Boarding of pediatric patients in the emergency department. Policy statement. PMID- 22525530 TI - Intravenous multivitamins ("banana bags") for emergency patients who may have nutritional deficits. PMID- 22525531 TI - Multivitamin "banana bags" provide little value in emergency department patients. PMID- 22525532 TI - Report on residency training information (2011-2012), American Board of Emergency Medicine. AB - The American Board of Emergency Medicine (ABEM) gathers extensive background information on emergency medicine residency training programs and the residents in those programs. We present the 2012 annual report on the status of US emergency medicine training programs. PMID- 22525534 TI - Change of shift. It's this texting thing. PMID- 22525535 TI - Some think antibiotics are candy, but we know they're not. PMID- 22525536 TI - Infant with head injury. Ping-pong fracture. PMID- 22525537 TI - Crisis standard of care is altered care, not an altered standard. PMID- 22525539 TI - The truth about the increase in computed tomography utilization. PMID- 22525542 TI - Medical relief after earthquakes: don't forget the local response! PMID- 22525543 TI - A woman with painless swelling in the right lower abdominal quadrant. Pott's abscess. PMID- 22525544 TI - Imaging mass spectrometry of thin tissue sections: a decade of collective efforts. AB - Imaging mass spectrometry (MS) allows to monitor the spatial distribution and abundance of endogenous and administered compounds present within tissue specimens. Several different but complementary imaging MS technologies have been developed allowing the analysis of a wide variety of compounds including inorganic elementals, metabolites, lipids, peptides, proteins and xenobiotics with spatial resolutions from micrometer to nanometer scales. In the past decade, an enormous collective body of work has been done to develop and improve the imaging MS technology. This article gives a historical perspective, an overview of the principle and status of the technology and lists the main fields of applications. It also enumerates some of the critical challenges we need to collectively address for imaging MS to be considered a mainstream analytical method. PMID- 22525545 TI - A brief history of laparoscopy. PMID- 22525546 TI - Does the nasogastric tube has a role in elective colo-rectal surgery? AB - INTRODUCTION: Routine use of nasogastric tubes (NGT) after abdominal operations is intended to hasten the return of bowel function, diminish the risk of anastomotic leakage and prevent pulmonary complications. The aim of our study was to prospectively assess the tolerability and the safety of the non use of NGT after elective colorectal open operations. PATIENTS AND METHODS: Between March 2009 and December 2010, 110 consecutive patients underwent colo-rectal elective open surgery for neoplasm without nasogastric decompression. We analyzed the incidence of nausea and vomiting, the pulmonary complications, the return of bowel function the deep wound breakdown (fascial dehiscence) and the anastomotic leakage. RESULTS: Only 15 patients (13,6%) reported nausea without vomiting immediately after surgery and 9 cases of vomiting were observed (8%), requiring the insertion of the NGT (nasogastric tube) in 5 (4,5%). A total of 105 patients (96,3%) were NGT free. No deep wound dehiscence was observed and only one real pneumonia occurred. Anastomotic dehiscence occurred in 4 patients (3,6%) and a second surgical procedure was needed in three cases. The return of bowel function, except in the last four patients, occurred in 3,8 days average (range 2 7 days). CONCLUSION: We confirm the uselessness of the NGT in the framework of fast track program adopted in elective open colo-rectal surgery. PMID- 22525547 TI - Extra-adrenal perirenal myelolipoma. A case report and review of literature. AB - Myelolipomas are rare tumours which are most commonly found in association with the adrenal glands. However, extra-adrenal sites have been described, but limited to case reports. They are characterized by a normal adrenal gland function and absence of haematopoesis which differentiates them from extramedullary haematopoetic tumours. We present a rare case of perirenal extra-adrenal myelolipoma and we review the imaging characteristics and management options for this condition. PMID- 22525548 TI - Liver trauma. Diagnosis and treatment. AB - The authors summarize the essential steps in liver surgery. Modern imaging techniques are of great help in establishing a circumstantiated diagnosis of post traumatic lesions of the intra-abdominal parenchymatous organs, and especially the liver. Such diagnosis must always be based on the AAST (American Association for the Surgery of Trauma) classification, essential for a correct approach. Each therapeutic choice must be based on a careful clinical evaluation to establish whether emergency exploration of the abdomen or simple patient monitoring is indicated. Organ injuries and consequent hemoperitoneum must be found and quantified. In any case, diagnosis and treatment must only begin once all measures have been taken to ensure the maintenance of vital functions and the normalization of the main blood chemistry parameters. PMID- 22525549 TI - The role of laparoscopy and intraoperative ultrasound in the diagnosis and staging of lymphomas. AB - Laparoscopic surgery plays today an important role in the diagnosis and staging of abdominal lymphomas; in fact it provides adequate lymph node sampling for histological typing and immunophenotyping. The mini-invasive procedure is safe and effective. Intra-operative ultrasound permits to study the parenchimal organs in addition to intra-abdominal lymph node and/or masses. PMID- 22525551 TI - Ischemic necrosis with sigmoid perforation in a patient with Systemic Lupus Erythematosus (SLE): case report. AB - Systemic Lupus Erythematosus (SLE) is a chronic inflammatory rheumatic disease which affects the connective tissue. Its etiology is as yet unknown, while its pathogenesis involves the immune system. Both genetic and environmental and hormonal factors play a key role in the impaired immune regulation. A correlation with estrogens is demonstrated by the fact that the greatest incidence is found in young women, when estrogen secretion is at its highest. The disease is also reported to worsen in women taking oral contraceptives. It is therefore believed that the components of oral contraceptives, estrogens (ethinyl estradiol) and progestins, can affect the immune profile. Of the various complications attributed to systemic lupus erythematosus, gastrointestinal disorders are less common but potentially by far the most serious. We report a case of ischemic necrosis with sigma perforation in a patient with SLE. Signs and symptoms of acute abdomen in patients with SLE are rare (0.2%), but serious. Most patients require an exploratory laparotomy, as the causes are often linked with vasculitis. PMID- 22525550 TI - Emergency hemicolectomy for intestinal primary aspergillosis in acute myeloid leukemia. AB - Intestinal aspergillosis is an infection with a very high death rate especially in leukemic patients. Here we describe a case of a 46 years old woman with acute myeloid leukemia (LAM M5) who developed intestinal primary aspergillosis. This patient was diagnosed with LAM M5 through bone marrow aspiration and bone biopsy in March 2004. Symptoms of the disease were slight persistent fever, weight loss, asthenia, anemia, thrombocytopenia,and leukocytosis with high number of blasts in peripheral blood. After induction chemotherapy with ICE (Ifosfamide, Carboplatin, Etoposide), she developed neutropenia and high fever without apparent infective foci. She was treated with empiric antibiotic therapy, nevertheless she developed an intense diarrhea and ileo-cecal distention. Diagnostic exams didn't show signs of a focal lesion. Despite the change in antibiotic treatment and the transfusions of granulocytes and blood cells, the patient developed extremely critical conditions with persistence of neutropenia and abdominal distention. A surgical treatment was decided at the time. We treated the patient with a two steps surgical procedure. The first step was a right abdominal ileostomy followed by improvement of general conditions and then the second step a right colectomy. The histological morphology confirmed necrotizing colitis with Aspergillus ife. At that time , treatment with voriconazole was started. The general conditions of the patient improved rapidly and we were able to treat the patient with other medical anti-leukemic therapies. The patient is now cured and in healthy state. We obtained a good clinical result as only in other few cases described in literature. PMID- 22525552 TI - Usefulness of ultrasounds in the management of breast phyllodes tumors. AB - INTRODUCTION: Breast phyllodes tumors (PT) are uncommon fibroepithelial lesions having potential malignant features. These tumors have characteristic features, like pleomorphism, mitoses and overgrowth of the stroma with possible infiltrative margins. The clinical behaviour could be unpredictable, since the relatively high recurrence rate despite correct surgical strategy. Conventional diagnostic examinations show high sensitivity and specificity, but cannot demonstrate the differences between benign and malignant PT. MRI is not more effective. PATIENTS AND METHODS: Sixteen patients affected by PT have been surgically treated at our Institution. All patients received mammography and ultrasonography (US) as preoperative diagnostic work-up. RESULTS: in 13 patients, US was effective in preoperative diagnosis of PT. Mammography was uneffective in detecting breast lesions in 5 cases, while in 11 cases mammographic findings presented benign features, with a round opacity with moderate tissue density and well-defined wall. CONCLUSION: US remains the most useful diagnostic test in detecting PT. However, there is no test effective in identifying malignat PT. In case of suspicion, fine needle biopsy should be performed. PMID- 22525553 TI - A rare case of giant papillary adenoma of the breast. AB - The authors present a case of giant papillary adenoma of the breast and discuss their therapeutic strategy. The patient subsequently returned due to a local recurrence, which was treated with oncoplastic surgery, with satisfactory aesthetic results. The authors conclude by stressing the considerable rarity of this disease and the need for effective cooperation between surgeons and pathologists. PMID- 22525554 TI - Subfascial endoscopic perforator surgery (SEPS) in chronic venous insufficiency. A 14 years experience. AB - INTRODUCTION: Subfascial Endoscopic Perforator Surgery (SEPS) enables the direct visualization and section of perforating veins. Morbidity and duration of hospitalization are both less than with conventional open surgery (Linton's or Felder's techniques). PATIENTS AND METHODS: A total of 322 legs from 285 patients with a mean age of 56 years (range 23-90) were treated at our Department from May 1996 to January 2010. In 309 cases, an endoscope (ETM Endoskopische Technik GmbH, Berlin, Germany) was introduced through a transverse incision approximately 1.5 cm in length and 10 cm from the tibial tuberosity, as with Linton's technique. A spacemaker balloon dissector for SEPS, involving a second incision 6 cm from the first, was used in only 13 cases. RESULTS: The procedure used in each case was decided on the basis of preoperative evaluation. SEPS and stripping were performed in 238 limbs (73.91%), SEPS and short stripping in 7 limbs (2.17%), SEPS and crossectomy in 51 limbs (15.84%), and SEPS alone in 26 limbs (8.07%). 103 patients presented a total of 158 trophic ulcers; the healing time was between 1 and 3 months, with a healing rate of 82.91% after 1 month and 98.73% after 3 months. CONCLUSION: Subfascial ligature of perforating veins is superior to sclerotherapy and minimally invasive suprafascial treatment for the treatment of CVI. It is easy to execute, minimally invasive and has few complications. PMID- 22525555 TI - Prosthetic carotid bypass graft for in-stent restenosis performed for post endarterectomy recurrent stenosis: technical details. AB - AIM: Carotid artery stenting (CAS) is the treatment of choice for recurrent stenosis after carotid endarterectomy (CEA). However a significative incidence of in-stent restenosis could be occurred. Despite classical CEA leads to good results, in selective cases bypass graft may be the best treatment of in-stent restenosis. CASE REPORTS: We describe two cases of carotid bypass graft performed to treat a recurrent in-stent stenosis after CAS for post-CEA restenosis. No death and cardiac complication occurred and no cranial nerves impairment was detected. CONCLUSION: Prosthetic bypass graft is safe and effective in treatment of in-stent recurrent restenosis after CEA restenosis. PMID- 22525556 TI - Vascular image patterns of lymph nodes for the prediction of metastatic disease during EBUS-TBNA for mediastinal staging of lung cancer. AB - INTRODUCTION: The aims of this study were to establish and assess the utility of Power/Color Doppler-mode vascular image pattern classification of lymph nodes (LN) during mediastinal staging by endobronchial ultrasound (EBUS) for the prediction of metastasis in patients with lung cancer. METHODS: One hundred and seventy-three LNs were retrospectively evaluated. The convex probe EBUS was used with the endoscopic ultrasound scanner. The vascular image patterns were graded as follows: Grade 0, no blood flow or small amounts of flow; Grade I, a few main vessels running toward the center of the LN from the hilum; Grade II, a few punctiforms or rod-shaped flow signals or a few small vessels found as a long strip of a curve; and Grade III, rich flow, more than four vessels found with different diameters or twist- or helical -low signal. The blood flow from the bronchial artery (BA) toward the LN was also recorded using Color Doppler imaging as a sign for BA inflow. RESULTS: When we defined Grade 0 and I as "benign" and Grade II and III as "malignant," the sensitivity, specificity, and diagnostic accuracy rate were 87.7%, 69.6%, and 78.0%, respectively. The accuracy of predicting metastasis solely from a positive BA inflow sign was 80.3%. Of the LNs, 84.5% were shown to be metastatic when they were determined as malignant, and 84.7% were proven nonmetastatic when it was determined as benign. CONCLUSIONS: Vascular image patterns of LN using Power/Color Doppler mode is helpful in the prediction of metastatic LN during EBUS-TBNA. PMID- 22525557 TI - Effusion immunocytochemistry as an alternative approach for the selection of first-line targeted therapy in advanced lung adenocarcinoma. AB - INTRODUCTION: Tumor tissue is often not obtainable or suitable for molecular based epidermal growth factor receptor (EGFR) mutational analysis in advanced non small-cell lung cancer (NSCLC). This retrospective and single-institution study was conducted to evaluate the role of effusion immunocytochemistry using two EGFR mutant-specific antibodies for the detection of relevant EGFR mutations in NSCLC, along with the selection of candidates for first-line therapy with EGFR tyrosine kinase inhibitors (TKIs). METHODS: Immunocytochemistry using two antibodies binding specifically to the major forms of mutant EGFR, L858R, and E746-A750 deletion (delE746-A750), was performed on cell blocks of malignant pleural effusion (MPE) from 78 patients with lung adenocarcinoma, who received first-line EGFR TKIs. The yield of EGFR-mutation detection and prediction of response rate and progression-free survival to TKI treatment by immunocytochemistry were compared with those by clinical characteristics and EGFR sequencing using cell derived RNA from MPEs. RESULTS: Of the 78 MPE samples, direct sequencing using cell-derived RNA identified L858R mutation in 42 cases, deletions in exon 19 in 12 cases (delE746-A750 in eight cases), other types of mutations in three cases, and wild-type EGFR in 21 cases. Effusion immunocytochemistry with these two mutant-specific antibodies exhibited a sensitivity of 71% and 88% and a specificity of 86% and 96% for identifying predefined L858R and delE746-A750 mutations, respectively. Effusion immunocytochemistry provided a superior prediction of tumor response and progression-free survival to first-line EGFR TKIs than did clinical characteristics like sex and smoking status. Patients whose effusion immunocytochemistry showed a reaction to either of the two antibodies had a comparable TKI response rate (67% versus 72%) to those with EGFR mutations assessed by direct sequencing from cell-derived RNA. CONCLUSIONS: Effusion immunocytochemistry could be introduced into clinical practice to identify more NSCLC patients likely to have benefit from first-line TKI treatment, especially for those without adequate tissue for molecular-based EGFR analysis. PMID- 22525559 TI - Elevated corrosion rates and hydrogen sulfide in homes with 'Chinese Drywall'. AB - In December 2008, the U.S. Consumer Product Safety Commission (CPSC) began receiving reports about odors, corrosion, and health concerns related to drywall originating from China. In response, a detailed environmental health and engineering evaluation was conducted of 41 complaint and 10 non-complaint homes in the Southeast U.S. Each home investigation included characterization of: 1) drywall composition; 2) indoor and outdoor air quality; 3) temperature, moisture, and building ventilation; and 4) copper and silver corrosion rates. Complaint homes had significantly higher hydrogen sulfide concentrations (mean 0.82 vs. 0.1), time of serum amylase recovery (3.98+/-2.02 d vs. 5.11+/-2.22 d, P>0.1), and hospital costs (P>0.1) did not show significant difference. Early endoscopic treatment can reduce the complication of ABP and shorten the hospital stay. It could be adopted as the preferred treatment for ABP in hospitals. PMID- 22525562 TI - Plaque regression and improved clinical outcomes following statin treatment in atherosclerosis. AB - 3-hydroxy-3-methylglutaryl-coenzymeA reductase inhibitors, or statins, represent an important class of agents that improve clinical outcomes in atherosclerotic cardiovascular disease. Aside from lowering total and low density lipoprotein cholesterol, statins have important pleiotropic effects that include anti inflammatory, antioxidant, antithrombotic actions as well as mobilization of endothelial progenitor cells and modification of plaque cholesterol crystallization. These combined effects lead to atherosclerotic plaque stabilization that is both quantitative (slowing of plaque progression or plaque volume regression) as well as qualitative (reduced inflammation and amount of lipid rich necrotic plaque) in nature. Statins have been shown to reduce overall mortality when used for either primary or secondary prevention of cardiovascular disease in multiple randomized clinical trials, but such trials involve a large sample size, long treatment duration and enormous financial cost. Imaging of change in plaque burden by various means such as coronary angiography, intravascular and B mode ultrasound and magnetic resonance imaging represents a means of measuring surrogate endpoints by directly assessing statin effects on plaque regression. Multiple imaging studies have demonstrated plaque stabilization or regression with statin treatment that paralleled improvement in lipid profile and clinical outcomes, although it is unlikely that imaging modalities can replace hard clinical outcomes in assessing treatment efficacy. PMID- 22525563 TI - The antioxidant properties of high-density lipoproteins in atherosclerosis. AB - High-density lipoprotein (HDL) is protective against atherosclerosis development. Other than its central role in reverse cholesterol transport, HDL exhibits several other mechanisms by which it is protective. These include antioxidative, anti-inflammatory and antiapoptopic activities and the normalisation of vascular function. In light of the current view that oxidative modification of low-density lipoprotein (LDL) is essential for the initiation and progression of atherosclerosis, the antioxidative properties of HDL may be an important protective mechanism. HDL can retard the oxidation of LDL and limit its atherogenicity. Several proteins are present on HDL and the evidence that some of them metabolise lipid peroxidation products of phospholipids, cholesteryl esters and triglycerides associated with LDL and vascular cell membranes are discussed in this review. PMID- 22525564 TI - A physician's guide for the management of hypertriglyceridemia: the etiology of hypertriglyceridemia determines treatment strategy. AB - Hypertriglyceridemia is a common lipid disorder associated to different, highly prevalent metabolic derangements like diabetes mellitus, the metabolic syndrome and obesity. The choice of treatment depends on the underlying pathogenesis and the consequences for atherosclerosis or pancreatitis. A family history, physical examination and analysis of the lipid profile including measurement of apolipoprotein B or non-HDL-C are necessary to establish the underlying primary or secondary cause. Due to physiological diurnal variations of triglycerides (TG), the time of measurement (fasting or postprandial) should be taken into account when evaluating TG values. Increased awareness arises concerning the impact of postprandial hypertriglyceridemia on the development of atherosclerosis. Hypertriglyceridemia is strongly associated to postprandial hyperlipidemia, remnant accumulation, increased small dense LDL concentrations, low HDL-C, increased oxidative stress, endothelial dysfunction, leukocyte activation and insulin resistance. All these factors are strongly linked to the development of atherosclerosis. Treatment should be aimed at reducing the secretion of triglyceride-rich lipoproteins, increasing intravascular lipolysis and reducing the number of circulating remnants. The main intervention is a change of lifestyle with decreased alcohol consumption, increased physical activity, dietary changes and, if applicable, adaptation of used medication. Fibrates, fish oil and nicotinic acid are the first choice of treatment in sporadic and familial hypertriglyceridemia to reduce the risk of pancreatitis, whereas high dose statins, sometimes in combination with fibrates, nicotinic acid, or fish oil capsules, are indicated for familial combined hyperlipidemia. Statins are necessary to reach low LDL-C concentrations in patients with type 2 diabetes mellitus and statin dosage should be increased when hypertriglyceridemia is present to reach secondary treatment targets for apolipoprotein B or non-HDL C. Finally, family screening is mandatory to detect familial lipid disorders for early intervention in other family members. PMID- 22525565 TI - Management of statin-intolerant patient. AB - Large scale clinical trials have undoubtedly demonstrated that statins are effective in reducing cardiovascular events and all-cause mortality in almost all patient populations. Also the short and long-term safety of statin therapy has been well established in the majority of treated patients. Nevertheless, intolerance to statins must be frequently faced in the clinical practice. The most commonly observed adverse effects of statins are muscle symptoms and elevation of hepatic aminotransferase and creatinine kinase (CK) levels. Overall, myalgia (muscle pain with or without plasma CK elevations) and a single abnormally elevated liver function test constitute approximately two-thirds of reported adverse events during statin therapy. These side effects raise concerns in the patients and are likely to reduce patient's adherence and, consequently, the cardiovascular benefit. Therefore, it is mandatory that clinicians improve knowledge on the clinical aspects of side effects of statins and the ability to manage patients with intolerance to statins. Numerous different approaches to statin-intolerant patients have been suggested, but an evidence-based consensus is difficult to be reached due to the lack of controlled trials. Therefore, it might be useful to review protocols and procedures to control statin intolerance. The first step in managing intolerant patients is to determine whether the adverse events are indeed related to statin therapy. Then, the switching to another statin or lower dosage, the alternate dosing options and the use of non statin compounds may be practical strategies. However, the cardiovascular benefit of these approaches has not been established, so that their use has to be employed after a careful clinical assessment of each patient. PMID- 22525566 TI - Biomarkers in obstructive respiratory diseases: an update. AB - Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation of the airways, with the involvement of many inflammatory cells and mediators. Traditionally, this inflammation is thought to spread to a systemic level, thus inducing damage of different organs. However, other pathogenetic mechanisms could take part to the above-described process, and some open questions need to be solved. Due to the burden and increasing prevalence of COPD, the opportunity to find biomarkers that can potentially be useful in identifying individuals with the disease, or better, prior to symptoms onset, to diagnose and properly manage the respiratory symptoms, as well as to evaluate the response to treatment and to select specific subtypes of patients for tailored treatments is strongly advocated. Several mediators, enzymes, hormones and cells have been claimed to adhere to this objective. Moreover, the presence of comorbid or concomitant diseases can variably influence the concentration of specific biomarkers in samples of individuals with COPD, and age-related functional and structural changes (inflammaging) can further confuse the biological pattern. Several observations have been performed in the last decades; nevertheless, no biomarker is currently considered as satisfying all the above-mentioned issues. The "Evaluation of COPD longitudinally to identify predictive surrogates and points (ECLIPSE)" study has specifically explored the possibility to identify novel biomarkers that correlate with clinically relevant COPD subtypes and with markers of disease progression. Among the thirty-four biomarkers considered, 15 resulted to be increased in COPD patients rather than in smoker and non-smoker controls. Specific lung proteins such as CC-16 and SPD are promising in detecting lung damage, exacerbation susceptibility or responsiveness to treatment. The ECLIPSE findings confirm that, to date, the use of a single biomarker is not sufficient, but the combination of novel biomarkers with the already existing tools could improve our skills in optimizing treatment of COPD patients. PMID- 22525567 TI - Exogenous hyaluronic acid and wound healing: an updated vision. AB - Hyaluronic acid (HA), an endogenous substance whose concentration increases during the process of wound repair, can be manufactured in order to use it as an exogenous intervention able to reduce the time to wound repair and improve the quality of the scar. The role of HA as a key component of the extracellular matrix structure has been recognized for many decades, while its actions on cells involved in the process of tissue repair has been partly clarified only in the last few years. Fibroblasts, endothelial cells and macrophages are key players in the tissue repair process and a concerted activation of specific functions of these cells may substantially improve the process of wound closure. Hyaluronan, as well as its degradation products that are generated in the wounds, are capable to activate specific responses in all the cells involved in the process; in particular, fibroblast proliferation and new vessel formation have been extensively studied. The molecular patterns leading to cell activation have been substantially clarified and it is now widely accepted that cellular actions of hyaluronic acid are mediated by specific surface receptors, including CD44, RHAMM and toll like receptors. Elucidation of the mechanisms of cellular activation will allow an optimal use of exogenous hyaluronan and its derivatives in the wound care setting. PMID- 22525568 TI - Prevention points for plate exposure in the mandibular reconstruction. AB - INTRODUCTION: The rate of complications for mandibular reconstruction after segmental mandibulectomy is higher with reconstruction plates than with vascularised bone grafts. We have experience of over 100 patients using reconstructive plates for reconstruction immediately after segmental mandibulectomy and have considered factors contributing to plate exposure. PATIENTS AND METHODS: Seventeen cases utilised our prevention methods in which reconstructive plates were used for mandibular reconstruction were reviewed. The flaps used with reconstruction plates were rectus abdominis myocutanenous flaps in 10 cases, anterolateral thigh flaps combined vastus lateralis muscle in four cases, and the omentum in one case; no flap was transferred in two cases. RESULTS: In only one of 17 cases was a plate exposed at 3 months postoperatively. No plate exposure occurred during the follow-up period in the other 16 cases. Because no flap had been transferred in the patient with plate exposure, a possible contributing factor was the persistence of dead space beneath the plate. CONCLUSION: This series suggests that factors other than flap selection contribute to the exposure of reconstructive plates. Use of a reconstruction plate is a useful reconstructive method, especially for patients who cannot tolerate transfer of a vascularised bone graft. PMID- 22525569 TI - Translating the therapeutic potential of neurotrophic factors to clinical 'proof of concept': a personal saga achieving a career-long quest. AB - While the therapeutic potential of neurotrophic factors has been well-recognized for over two decades, attempts to translate that potential to the clinic have been disappointing, largely due to significant delivery obstacles. Similarly, gene therapy (or gene transfer) emerged as a potentially powerful, new therapeutic approach nearly two decades ago and despite its promise, also suffered serious setbacks when applied to the human clinic. As advances continue to be made in both fields, ironically, they may now be poised to complement each other to produce a translational breakthrough. The accumulated data argue that gene transfer provides the 'enabling technology' that can solve the age-old delivery problems that have plagued the translation of neurotrophic factors as treatments for chronic central nervous system diseases. A leading translational program applying gene transfer to deliver a neurotrophic factor to rejuvenate and protect degenerating human neurons is CERE-120 (AAV2-NRTN). To date, over two dozen nonclinical studies and three clinical trials have been completed. A fourth (pivotal) clinical trial has completed all dosing and is currently evaluating safety and efficacy. In total, eighty Parkinson's disease (PD) subjects have thus far been dosed with CERE-120 (some 7 years ago), representing over 250 cumulative patient-years of exposure, with no serious safety issues identified. In a completed sham-surgery, double-blinded controlled trial, though the primary endpoint (the Unified Parkinson's Disease Rating Scale (UDPRS) motor off score measured at 12 months) did not show benefit from CERE-120, several important motor and quality of life measurements did, including the same UPDRS-motor-off score, pre-specified to also be measured at a longer, 18-month post-dosing time point. Importantly, not a single measurement favored the sham control group. This study therefore, provided important, well-controlled evidence establishing 'clinical proof of concept' for gene transfer to the CNS and the first controlled evidence for clinical benefit of a neurotrophic factor in a human neurodegenerative disease. This paper reviews the development of CERE-120, starting historically with the long-standing interest in the therapeutic potential of neurotrophic factors and continuing with selective accounts of past efforts to translate their potential to the clinic, eventually leading to the application of gene transfer and its role as the 'enabling technology'. Because of growing interest in translational R&D, including its practice in industry, the paper is uniquely oriented from the author's personal, quasi-autobiographic perspective and career-long experiences conducting translational research and development, with a focus on various translational neurotrophic factor programs spanning 30+ years in Big Pharma and development-stage biotech companies. It is hoped that by sharing these perspectives, practical insight and information might be provided to others also interested in translational R&D as well as neurotrophic factors and gene therapy, offering readers the opportunity to benefit from some of our successes, while possibly avoiding some of our missteps. PMID- 22525570 TI - Effects of environmental manipulations in genetically targeted animal models of affective disorders. AB - Mental illness is the leading cause of disability worldwide. We are only just beginning to reveal and comprehend the complex interaction that exists between the genetic makeup of an organism and the potential modifying effect of the environment in which it lives, and how this translates into mediating susceptibility to neurological and psychiatric conditions. The capacity to address this issue experimentally has been facilitated by the availability of rodent models which allow the precise manipulation of genetic and environmental factors. In this review, we discuss the valuable nature of animal models in furthering our understanding of the relationship between genetic and environmental factors in affective illnesses, such as anxiety and depressive disorders. We first highlight the behavioral impairments exhibited by genetically targeted animal models of affective disorders, and then provide a discussion of the underlying neurobiology, focusing on animal models that involve exposure to stress. This is followed by a review of recent studies that report of beneficial effects of environmental manipulations such as environmental enrichment and enhanced physical activity and discuss the likely mechanisms that mediate those benefits. PMID- 22525572 TI - Metastasis: SIX1 of the best. PMID- 22525571 TI - Ampakines promote spine actin polymerization, long-term potentiation, and learning in a mouse model of Angelman syndrome. AB - Angelman syndrome (AS) is a neurodevelopmental disorder largely due to abnormal maternal expression of the UBE3A gene leading to the deletion of E6-associated protein. AS subjects have severe cognitive impairments for which there are no therapeutic interventions. Mouse models (knockouts of the maternal Ube3a gene: 'AS mice') of the disorder have substantial deficits in long-term potentiation (LTP) and learning. Here we report a clinically plausible pharmacological treatment that ameliorates both deficits. AS mice were injected ip twice daily for 5 days with vehicle or the ampakine CX929; drugs of this type enhance fast EPSCs by positively modulating AMPA receptors. Theta burst stimulation (TBS) produced a normal enhancement of field EPSPs in hippocampal slices prepared from vehicle-treated AS mice but LTP decreased steadily to baseline; however, LTP in slices from ampakine-treated AS mice stabilized at levels found in wild-type controls. TBS-induced actin polymerization within dendritic spines, an essential event for stabilizing LTP, was severely impaired in slices from vehicle-treated AS mice but not in those from ampakine-treated AS mice. Long-term memory scores in a fear conditioning paradigm were reduced by 50% in vehicle-treated AS mice but were comparable to values for littermate controls in the ampakine-treated AS mice. We propose that AS is associated with a profound defect in activity-driven spine cytoskeletal reorganization, resulting in a loss of the synaptic plasticity required for the encoding of long-term memory. Notably, the spine abnormality along with the LTP and learning impairments can be reduced by a minimally invasive drug treatment. PMID- 22525573 TI - Stem cells: Marking stem cells. PMID- 22525575 TI - Metabolism: Unravelling metabolic dependencies. PMID- 22525576 TI - Initiation, evolution, phenotype and outcome of BRCA1 and BRCA2 mutation associated breast cancer. PMID- 22525577 TI - BRCA1 and BRCA2: a common pathway of genome protection but different breast cancer subtypes. PMID- 22525579 TI - Lymphoma complicating primary immunodeficiency syndromes. AB - PURPOSE OF REVIEW: One of the strongest arguments for the immune surveillance network of antibodies and sensitized cytotoxic T cells is the extraordinary incidence of lymphoid malignancy in the many types of primary immunodeficiency. RECENT FINDINGS: This review updates the literature that seems to wax and wane on the importance of specific immunity to malignant cell antigens by previous authors. This new survey strongly supports the tenet that immune responses protect from malignant cell growth and development, much like it protects against a hostile microbial world. As more genetic lesions are discovered that cause various forms of immune deficiency, each with their consequent type of infection or malignancy, the notion that certain devastating infections or malignancies develop by chance is becoming less likely. The predominance of B-cell lymphoma in immune-deficient patients is both interesting and vexing. One might reasonably ask why the entire spectrum of malignancies is not seen in primary immunodeficiency. SUMMARY: Regardless of continuing debate on immune surveillance of malignancy, the evidence presented in this review strongly supports that it has a key role in preventing lymphoid malignancy. PMID- 22525580 TI - Minimal residual disease monitoring in childhood acute lymphoblastic leukemia. AB - PURPOSE OF REVIEW: This review summarizes recent advances in the application of minimal residual disease (MRD) testing in childhood acute lymphoblastic leukemia (ALL). RECENT FINDINGS: Polymerase chain reaction amplification of antigen receptor genes, one of the two main methods to study MRD in ALL, could be made more rapid, sensitive and informative by the application of next-generation sequencing technologies. Advances in flow cytometric detection of MRD, the other main method, include the identification of new immunophenotypic markers to recognize ALL cells, the development of computerized approaches to automate data analysis, and the generation of instruments that can rapidly screen large number of cells for immunophenotypic abnormalities while visualizing their morphology. Recent data further corroborate the prognostic value of MRD at early time points during therapy, demonstrate the prognostic significance of MRD among ALL subtypes, and indicate that presenting features can complement the prognostic utility of MRD. SUMMARY: MRD is replacing morphology to measure treatment response in ALL and is being used, with promising results, for risk stratification in clinical protocols. Recent studies provide further evidence of its prognostic significance and point to possible strategies to increase the reliability, applicability and sensitivity of MRD testing. PMID- 22525581 TI - Selective treatment of mixed-lineage leukemia leukemic stem cells through targeting glycogen synthase kinase 3 and the canonical Wnt/beta-catenin pathway. AB - PURPOSE OF REVIEW: Leukemia carrying mutation of the mixed-lineage leukemia (MLL) gene is particularly refractory to current treatment, and is associated with frequent relapse. We will review the biology of MLL leukemia, and explore the potential of targeting multiple signaling pathways deregulated in MLL leukemic stem cells (LSCs). RECENT FINDINGS: Glycogen synthase kinase 3 (GSK3) plays a critical role in mediating Hox/MEIS1 transcriptional program and its inhibition shows promise in suppressing leukemia carrying MLL fusions or aberrant Hox expression. However, recent evidence indicates that GSK3 inhibition can be overcome by hyperactivation of the canonical Wnt signaling pathway in MLL LSCs, whereas suppression of beta-catenin resensitizes MLL LSCs to the GSK3 inhibitor treatment. These results suggest a differential GSK3 dependence in different subsets of leukemic populations during disease development. SUMMARY: On the basis of the results from preclinical model studies, a combination treatment targeting both GSK3 and the canonical Wnt signaling pathway emerges as a promising avenue to eradicate MLL LSCs. Future effort in identifying the key tractable components along these signaling pathways will be critical for the development of effective inhibitors to target this aggressive disease. PMID- 22525582 TI - Effect of long-term propranolol treatment on hepatocellular carcinoma incidence in patients with HCV-associated cirrhosis. AB - Propranolol bears antioxidant, anti-inflammatory, and antiangiogenic properties and antitumoral effects and therefore is potentially active in the prevention of hepatocellular carcinoma (HCC). We retrospectively assessed the impact of propranolol treatment on HCC occurrence in a cohort of 291 patients with compensated viral C (HCV) cirrhosis, prospectively followed and screened for HCC detection. Of the 291 patients included in the cohort, 93 patients [50 males: mean age, 59.5 +/- 12 years; body mass index (BMI), 25.7 +/- 4.4 kg/m(2); and platelet count, 111 +/- 53 Giga/L] developed esophageal varices (OV) or had OV at inclusion and 198 patients (111 males: mean age, 55.8 +/- 13 years; BMI, 25.7 +/- 5 kg/m(2); platelet count, 137 +/- 59 Giga/L) did not. Among patients with OV, 50 received treatment by propranolol. During a median follow-up of 54 months interquartile range (32-82), 61 patients developed an HCC. The 3- and 5-year HCC incidence was 4% and 4%, and 10% and 20% for patients treated and not treated by propranolol, respectively (Gray test, P = 0.03). In multivariate analysis, propranolol treatment was associated with a decrease risk of HCC occurrence [HR, 0.25; 95% confidence interval (CI), 0.09-0.65; P = 0.004], and was the only independent predictive factor of HCC occurrence in patients with OV (HR, 0.16; CI, 0.06-0.45; P = 0.0005). The benefit of propranolol was further supported by propensity scores analyses. CONCLUSION: This retrospective long-term observational study suggests that propranolol treatment may decrease HCC occurrence in patients with HCV cirrhosis. These findings need to be verified by prospective clinical trial. PMID- 22525583 TI - Can a national lung cancer screening program in combination with smoking cessation policies cause an early decrease in tobacco deaths in Italy? AB - Objective is to predict smoking attributable deaths (SAD) for lung cancer and all causes in Italy, 2015 to 2040, assuming a yet unimplemented tobacco control policies (TCP) and a national, low-dose, lung cancer, computed tomography (CT) annual screening program (CT screen). A dynamic model describing the evolution of smoking habits was developed to estimate quit rates, 1986 to 2009, and to predict SAD under different scenarios: keeping the status quo; raising cigarette taxes by 20%; implementing cessation treatment policies (funding treatment, setting up an active quitline, promoting counseling among health professionals); introducing a three-round annual CT screen for current and former heavy smokers aged 55 to 74, 70% compliance, 20% lung cancer mortality reduction; combining all the above mentioned measures. The CT screen brought a 3.0% constant annual reduction in lung cancer SAD and decreased or postponed all-cause SAD by 1.7% annually (a half due to respiratory diseases), relative to the status quo scenario. The effect was noticeable after few years from its introduction. TCP showed a steadily strengthening effect starting from 5 to 10 years after implementation. The lung cancer and all-cause SAD under cessation treatment policies, for instance, were reduced by 8.4% and 12.0% in 2030, respectively, and by 16.1% and 20.0% in 2040. TCP gave a greater effect than CT screen in reducing all-cause SAD because cessation brought about a reduction in smoking-related SAD other than lung cancer and respiratory diseases. Combining TCP and CT screen could bring about an early decrease in lung cancer and respiratory disease SAD due to CT screen, followed by a more substantial drop in all-cause SAD in subsequent decades due to TCP. PMID- 22525584 TI - Sheep psoroptic mange: an update. AB - Psoroptic mange is one of the most severe skin conditions of sheep. This highly contagious disease is responsible for huge economical losses in many sheep raising countries. It is also a significant welfare concern. Our understanding of the biology of Psoroptes ovis and of the host-parasite relationship during psoroptic mange made remarkable progress during the last decade. These data combined with the availability of powerful molecular tools have opened new avenues of research. Clearly, there is still a long way to go before a vaccine becomes a reality. Additionally, other diagnostic tools and control methods should be further investigated such as breeding for genetic resistance and the use of biocontrol agents. PMID- 22525585 TI - A new host record of Sphaerospora epinepheli (Myxosporea: Bivalvulida) occurring on orange-spotted grouper Epinephelus coioides from Thailand: epidemiology, histopathology and phylogenetic position. AB - In 1991, the first record of Sphaerospora epinepheli was described as a kidney parasite of wild and cultured malabar grouper, Epinephelus malabaricus, along coastlines of Thailand, the Gulf of Thailand and the Andaman Sea. However, the present study detected high infection of this parasite in kidney renal tubes of orange spotted grouper, Epinephelus coioides, collected from Andaman Sea. The highest infection rate of 36.82% was observed during the rainy season in 2009 in Phang-Nga Bay, in the north of Andaman Sea, which is an important grouper production site in Thailand. The biological and histopathological data of the parasite in this new host record are presented. Species classification is described based on morphological data of mature spore and molecular analysis of myxosporean 18S rDNA phylogeny including that of S. epinepheli which infected E. malabaricus. The genetic position of this parasite found in two host species was also studied. The phylogenetic tree analysis of small-subunit rDNA sequences of S. epinepheli from both infected hosts was constructed using two algorithms, maximum likelihood (ML) and Bayesian inference (BI). They were placed in the clustered basal sphaerosporid clade that contain four long SSU rDNA sphaerosporid species including Sphaerospora truttae, Sphaerospora elegans, Sphaerospora ranae, Sphaerospora fugu and Bipteria formosa with strong bootstrap supports. Histopathologically, renal intratubular myxosporean spores were associated with tubulonephosis, tubular necrosis, chronic interstitial nephritis and mimic membranoproliferative glomerulonephritis. This myxosporean parasite appears to be a significant pathogen on the basis of pathological changes in the renal tubules and is highly distributed in orange-spotted grouper. PMID- 22525586 TI - Emerging parasitic diseases of sheep. AB - There have been changes in the emergence and inability to control of a number of sheep parasitic infections over the last decade. This review focuses on the more globally important sheep parasites, whose reported changes in epidemiology, occurrence or failure to control are becoming increasingly evident. One of the main perceived driving forces is climate change, which can have profound effects on parasite epidemiology, especially for those parasitic diseases where weather has a direct effect on the development of free-living stages. The emergence of anthelmintic-resistant strains of parasitic nematodes and the increasing reliance placed on anthelmintics for their control, can exert profound changes on the epidemiology of those nematodes causing parasitic gastroenteritis. As a consequence, the effectiveness of existing control strategies presents a major threat to sheep production in many areas around the world. The incidence of the liver fluke, Fasciola hepatica, is inextricably linked to high rainfall and is particularly prevalent in high rainfall years. Over the last few decades, there have also been increasing reports of other fluke associated diseases, such as dicroceliosis and paramphistomosis, in a number of western European countries, possibly introduced through animal movements, and able to establish with changing climates. External parasite infections, such as myiasis, can cause significant economic loss and presents as a major welfare problem. The range of elevated temperatures predicted by current climate change scenarios, result in an elongated blowfly season with earlier spring emergence and a higher cumulative incidence of fly strike. Additionally, legislative decisions leading to enforced changes in pesticide usage and choices have resulted in increased reports and spread of ectoparasitic infections, particularly mite, lice and tick infestations in sheep. Factors, such as dip disposal and associated environmental concerns, and, perhaps more importantly, product availability have led to a move away from more traditional methods of pesticide application, particularly dipping, to the use of injectable endectocides. This has coincided with increased reports of sheep scab and lice infestations in some countries. Reduction in the use of organophosphate dips appears to have to some extent contributed to reported increased populations of ticks and tick activity, a consequence of which is not only of significance to sheep, but also many other hosts, including increased human zoonotic risks. PMID- 22525587 TI - Genetic aspects of sheep parasitic diseases. AB - There is evidence of genetically determined host resistance mechanisms for most of the sheep parasites evaluated. The mechanisms vary; from no or reduced establishment, early expulsion, to suppression of parasites resulting in reduced size and fecundity. There is a need to integrate breeding for parasite resistance with the genetic improvement of production traits in farm animals, aiming for optimum solutions for potentially conflicting responses. Sustainable parasite control must be based on Integrated Parasite Management utilising an interdisciplinary approach. PMID- 22525588 TI - A platform for the development of patient applications in the domain of personalized health. AB - Personalized health (p-health) systems can contribute significantly to the sustainability of healthcare systems, though their feasibility is yet to be proven. One of the problems related to their development is the lack of well established development tools for this domain. As the p-health paradigm is focused on patient self-management, big challenges arise around the design and implementation of patient systems. This paper presents a reference platform created for the development of these applications, and shows the advantages of its adoption in a complex project dealing with cardio-vascular diseases. PMID- 22525589 TI - Blood vessel segmentation methodologies in retinal images--a survey. AB - Retinal vessel segmentation algorithms are a fundamental component of automatic retinal disease screening systems. This work examines the blood vessel segmentation methodologies in two dimensional retinal images acquired from a fundus camera and a survey of techniques is presented. The aim of this paper is to review, analyze and categorize the retinal vessel extraction algorithms, techniques and methodologies, giving a brief description, highlighting the key points and the performance measures. We intend to give the reader a framework for the existing research; to introduce the range of retinal vessel segmentation algorithms; to discuss the current trends and future directions and summarize the open problems. The performance of algorithms is compared and analyzed on two publicly available databases (DRIVE and STARE) of retinal images using a number of measures which include accuracy, true positive rate, false positive rate, sensitivity, specificity and area under receiver operating characteristic (ROC) curve. PMID- 22525590 TI - Hormesis: Toxicological foundations and role in aging research. AB - The field of toxicology adopted the threshold dose response in the early decades of the 20th century. The model was rapidly incorporated into governmental regulatory assessment procedures and became a central feature of chemical evaluation and assessment. The toxicological community never validated the capacity of this model to make accurate predictions throughout the remainder of the 20th century. A series of recent investigations have demonstrated that the threshold and linear dose response model failed to make accurate predictions in the low dose zone. Such findings demonstrate a profound failure by the toxicology community on the central pillar of its discipline and one with profound public health, medical and economic implications. Ironically, the hormetic dose response, which was rejected by the toxicology community during the early decades of the 20th century, accurately predicted responses in the low dose zone in the same three large-scale validation assessments. Within the past two decades hormetic dose responses have been frequently reported in the experimental biogerontology literature, associated with endpoints associated enhancing healthy aging and longevity. The low dose stimulatory response of the hormetic dose response model represents the quantification of enhanced biological performance in the experimental facilitation of aging quality via multiple endpoints and mechanisms and in the extension of lifespan in such animal models research. PMID- 22525591 TI - Establishing cellular stress response profiles as biomarkers of homeodynamics, health and hormesis. AB - Aging is the progressive shrinkage of the homeodynamic space. A crucial component of the homeodynamic space is the stress response (SR), by virtue of which a living system senses disturbance and initiates a series of events for maintenance, repair, adaptation, remodeling and survival. Here we discuss the main intracellular SR pathways in human cells, and argue for the need to define and establish the immediate and delayed stress response profiles (SRP) during aging. Such SRP are required to be established at several age-points, which can be the molecular biomarkers of homeodynamic space and the health status of cells and organisms. SRP can also be useful for testing potential protectors and stimulators of homeodynamics, and can be a standard for monitoring the efficacy of potential pro-survival, health-promoting and aging-modulating conditions, food components and other compounds. An effective strategy, which makes use of SRP for achieving healthy aging and extending the healthspan, is that of strengthening the homeodynamics through repeated mild stress-induced hormesis by physical, biological and nutritional hormetins. Furthermore, SRP can also be the basis for defining health as a state of having adequate physical and mental independence of activities of daily living, by identifying a set of measurable parameters at the most fundamental level of biological organization. PMID- 22525592 TI - Of MEWS and men. PMID- 22525593 TI - Neonatal resuscitation: science of reflective learning. PMID- 22525594 TI - Cardiac arrest in infancy; is it always depressing? PMID- 22525595 TI - Low dose dual-source CT angiography in infants with complex congenital heart disease: a randomized study. AB - OBJECTIVES: To investigate the radiation dose and image quality of prospective ECG-triggering dual-source CT angiography in infants with complex congenital heart disease (CHD) in comparison with retrospective ECG-gated scanning. METHODS: Ninety-six infants less than 1 year old (60/36 male/female, age: 4.8 +/- 2.7 months, weight: 5.8 +/- 1.8 kg) with complex CHD were enrolled. Three image acquisition protocols were set: group 1: 80 kV, 100 mA, retrospective ECG-gated protocol; group 2: 80 kV, 100 mA, prospective ECG-triggering protocol with acquisition window of 380 ms; group 3: 80 kV, 100 mA, prospective ECG-triggering protocol with acquisition window of 200 ms. Patients were selected to any one of the protocols randomly. The signal-to-noise ratios (SNR) were calculated in the ascending aorta and the pulmonary artery trunk. Image quality was assessed by a five-point score. A score of <3 represents non-diagnostic. Effective radiation dose (ED) was calculated. RESULTS: Image quality score of groups 1, 2 and 3 were 4.1 +/- 0.4, 4.0 +/- 0.6 and 4.2 +/- 0.6 (p = 0.224). SNR of ascending aorta and pulmonary artery trunk among them had no statistical difference (all p>0.05). The average ED (median) of groups 1, 2 and 3 were 1.17 +/- 0.07 mSv (1.25 mSv), 0.72 +/- 0.24 mSv (0.78 mSv) and 0.48 +/- 0.41 mSv (0.39 mSv). Any two of the three groups had significant differences (all p<0.001). CONCLUSION: Prospective ECG triggering DSCT angiography associated with a significantly lower ED than retrospective protocol, while maintaining image quality for diagnosis. Prospective ECG-triggering DSCT angiography could be used as a very important second-line diagnostic tool in infants with complex CHD. PMID- 22525596 TI - A new, preoperative, MRI-based scoring system for diagnosing malignant axillary lymph nodes in women evaluated for breast cancer. AB - OBJECTIVE: Malignant axillary lymph nodes are an important predictor for breast cancer recurrence, but invasive dissection or biopsy is required for the diagnosis. We determined whether and how malignant nodes could be diagnosed preoperatively with magnetic resonance (MR) imaging. MATERIALS AND METHODS: We obtained MR images of all women evaluated for breast cancer at the Sun Yat-Sen University Cancer Center in 2010 and correlated the image characteristics of each axillary node with the pathologic diagnosis of the same node. RESULTS: We analyzed 251 nodes (117 benign; 134 malignant) from 136 women (mean age, 44 years; range, 20-67). Mean diameter of the nodes was 18 mm (range, 5-58 mm). With pathologic diagnosis as the reference standard, MRI-based interpretations were 66.4% sensitive, 94% specific, and 79% accurate. Diameter, pathologic type, apparent diffusion coefficient value (ADC, b=500 and 800), time-intensity curve (TIC) type of breast tumors correlated with node metastasis; ADC value (b=500 and 800), TIC type, early enhancement rate, long-axis, short-axis, shape, margin and the location of nodes correlated with node metastasis (P<0.001 for all). Tumor immunohistochemistry results for estrogen receptors, progesterone receptors, c erbB-2, vascular endothelial growth factor, and Ki67 were not. An MRI-based lymph node scoring system based on these correlations had a specificity of 91%, a sensitivity of 93%, and an area under the ROC curve of 0.95 (P<0.001). CONCLUSION: Metastatic axillary lymph nodes can be accurately diagnosed by MR in women with early breast cancer preoperatively and non-invasively. The scoring system appears to be superior to current methods. PMID- 22525597 TI - A preliminary study of the T1rho values of normal knee cartilage using 3T-MRI. AB - INTRODUCTION: To investigate the degree of the effect of aging and weight-bearing on T1rho values in normal cartilage. MATERIALS AND METHODS: Thirty-two asymptomatic patients were examined using 3.0-T magnetic resonance imaging (MRI) to determine knee cartilage T1rho values and T2 values. The femoral and tibial cartilage was divided into weight-bearing (WB-Rs) and less-weight-bearing (LWB Rs) regions. Single regression analysis was used to assess the relationship between cartilage T1rho values and age and between T2 values and age. Analysis of variance and post hoc-testing were used to evaluate differences in WB-Rs and LWB Rs cartilage T1rho values and T2 values. Multiple linear regression modeling was performed to predict cartilage T1rho values. RESULTS: Cartilage T1rho values correlated positively with age for all cartilage regions tested (p<0.001). There were no significant correlations between cartilage T2 values and age. In both the medial femoral and tibial cartilage, T1rho values were significantly higher in WB Rs than in LWB-Rs (p<0.05). There were no significant differences in T2 values between WB-Rs and LWB-Rs. Multiple linear regression analysis showed that both age and weight-bearing were significant predictors of increased medial knee cartilage T1rho values (p<0.001). CONCLUSIONS: Aging and the degree of weight bearing correlate with the change in cartilage T1rho values. Based on multiple regression modeling, aging may be a more important factor than weight-bearing for cartilage T1rho values. PMID- 22525598 TI - Surface modified liposomes by mannosylated conjugates anchored via the adamantyl moiety in the lipid bilayer. AB - The aim of the present study was to encapsulate mannosylated 1-aminoadamantane and mannosylated adamantyltripeptides, namely [(2R)-N-(adamant-1-yl)-3 (alpha,beta-d-mannopyranosyloxy)-2-methylpropanamide and (2R)-N-[3-(alpha-d mannopyranosyloxy)-2-methylpropanoyl]-d,l-(adamant-2-yl)glycyl-l-alanyl-d isoglutamine] in liposomes. The characterization of liposomes, size and surface morphology was performed using dynamic light scattering (DLS) and atomic force microscopy (AFM). The results have revealed that the encapsulation of examined compounds changes the size and surface of liposomes. After the concanavalin A (ConA) was added to the liposome preparation, increase in liposome size and their aggregation has been observed. The enlargement of liposomes was ascribed to the specific binding of the ConA to the mannose present on the surface of the prepared liposomes. Thus, it has been shown that the adamantyl moiety from mannosylated 1-aminoadamantane and mannosylated adamantyltripeptides can be used as an anchor in the lipid bilayer for carbohydrate moiety exposed on the liposome surface. PMID- 22525599 TI - Enhancing membrane disruption by targeting and multivalent presentation of antimicrobial peptides. AB - In order to enhance the membrane disruption of antimicrobial peptides both targeting and multivalent presentation approaches were explored. The antimicrobial peptides anoplin and temporin L were conjugated via click chemistry to vancomycin and to di- and tetravalent dendrimers. The vancomycin unit led to enhanced membrane disruption of large unilamellar vesicles (LUVs) displaying the vancomycin target lipid II, but only for temporin L and not for anoplin. The multivalent presentation led to enhanced LUV membrane disruption in the case of anoplin but not for temporin L. PMID- 22525600 TI - A Ser residue influences the structure and stability of a Pro-kinked transmembrane helix dimer. AB - When localized adjacent to a Pro-kink, Thr and Ser residues can form hydrogen bonds between their polar hydroxyl group and a backbone carbonyl oxygen and thereby modulate the actual bending angle of a distorted transmembrane alpha helix. We have used the homo-dimeric transmembrane cytochrome b(559)' to analyze the potential role of a highly conserved Ser residue for assembly and stabilization of transmembrane proteins. Mutation of the conserved Ser residue to Ala resulted in altered heme binding properties and in increased stability of the holo-protein, most likely by tolerating subtle structural rearrangements upon heme binding. The results suggest a crucial impact of an intrahelical Ser hydrogen bond in defining the structure of a Pro-kinked transmembrane helix dimer. PMID- 22525601 TI - Mapping of unfolding states of integral helical membrane proteins by GPS-NMR and scattering techniques: TFE-induced unfolding of KcsA in DDM surfactant. AB - Membrane proteins are vital for biological function, and their action is governed by structural properties critically depending on their interactions with the membranes. This has motivated considerable interest in studies of membrane protein folding and unfolding. Here the structural changes induced by unfolding of an integral membrane protein, namely TFE-induced unfolding of KcsA solubilized by the n-dodecyl beta-d-maltoside (DDM) surfactant is investigated by the recently introduced GPS-NMR (Global Protein folding State mapping by multivariate NMR) (Malmendal et al., PlosONE 5, e10262 (2010)) along with dynamic light scattering (DLS) and small-angle X-ray scattering (SAXS). GPS-NMR is used as a tool for fast analysis of the protein unfolding processes upon external perturbation, and DLS and SAXS are used for further structural characterization of the unfolding states. The combination allows addressing detergent properties and protein conformations at the same time. The mapping of the states reveals that KcsA undergoes a series of rearrangements which include expansion of the tetramer in several steps followed by dissociation into monomers at 29% TFE. Supplementary studies of DDM and TFE in the absence of KcsA suggest that the disintegration of the tetramer at 29% TFE is caused by TFE dissolving the surrounding DDM rim. Above 34% TFE, KcsA collapses to a new structure that is fully formed at 44% TFE. PMID- 22525602 TI - Adult-derived human liver progenitor cells in long-term culture maintain appropriate gatekeeper mechanisms against transformation. AB - The use of human liver progenitor cells in the development of clinical cell therapy depends on their constant availability and unaltered properties during culture. The present study investigates the effects of long-term in vitro culture on the specific characteristics of these cells and on their genetic stability. Adult-derived human liver progenitor cells (ADHLPCs) were isolated from 12 donors and cultured until senescence and cell death. Cells were analyzed at different time points for their phenotype stability and differentiation potential. In addition, growth characteristics, chromosomal karyotype, telomere maintenance mechanisms, and activity of cell cycle-related genes were studied. Finally, their in vivo tumorigenicity was investigated in a xenograft assay. The long-term culture of ADHLPCs revealed a variable proliferation capacity. Cells maintained their original phenotype and acquired hepatocyte-like metabolic functions after differentiation. Eight of the 12 cell populations grew fast (doubling time of 6.3 days) during a limited time period (mean, 116.2 days), and mainly presented normal cytogenetic features. The four other cell cultures presented an early decline in growth potential (doubling time of 28.6 days) and premature senescence. Chromosomal alterations were detected in three of four cultures at passage 6. Cytogenetic anomalies were not correlated with tumorigenic potential in vitro or in vivo, and expression of cell cycle-related genes was appropriately upregulated, inducing senescence. Although chromosomal anomalies may occur in long-term cell cultures, neither transformation nor alteration of their characteristics was noted during in vitro expansion. All ADHLPCs reached senescence and growth arrest. Presenescent ADHLPCs might therefore be considered as a suitable source for liver-based cell therapy. PMID- 22525603 TI - Expression of podoplanin and ABCG2 in oral erythroplakia correlate with oral cancer development. AB - Oral erythroplakia (OE) is a notoriously aggressive oral premalignant lesion with a high tendency to oral cancer development, but it's biological behavior is largely unknown. The objective of the current study was to determine podoplanin and ABCG2 immunoexpression in OE and both correlation to malignant transformation of OE. In a retrospective follow-up study, the expression patterns of podoplanin and ABCG2 were determined using immunohistochemistry in samples from 34 patients with OE, including patients with untransformed lesions (n=17) and patients with malignant transformed lesions (n=17). Podoplanin and ABCG2 expression was observed in 15 (44.1%) and 21 (61.8%) of 34 patients, respectively. Multivariate analysis revealed that podoplanin and ABCG2 expression was associated with 6.31 fold (95% confidence interval [CI], 1.02-38.92; P=0.047) and 14.39-fold (95% CI, 2.02-102.29; P=0.008) increased the risk of transformation, respectively. Point prevalence analysis revealed that 90.9% (95% CI, 70.7-100) of the patient with both podoplanin and ABCG2 positivity developed oral cancer. Collectively, our data indicated that the expression patterns of podoplanin and ABCG2 in OE were associated with oral cancer development, suggesting that podoplanin and ABCG2 may be valuable predictors for evaluating oral cancer risk. PMID- 22525605 TI - Development of oral cancer screening test by detection of squamous cell carcinoma among exfoliated oral mucosal cells. AB - OBJECTIVES: The early detection of oral cancer improves patient outcomes. However, despite our growing knowledge of oral cancers, patients often present with advanced disease. The development of simple screening methods is desirable to provide an alternative to screening examinations by specialists. Thus, we developed a method of oral cancer detection among exfoliated oral mucosal cells, and we evaluated the feasibility of implementing an oral cancer screening test that is examiner independent. MATERIAL AND METHODS: The study population consisted of 185 subjects: 89 with oral cancer, 18 with oral leukoplakia, and 78 controls. We used real-time polymerase chain reaction (PCR) to detect the biomarkers serpin peptidase inhibitor B3 (SCCA1), interleukin 15 (IL-15), and thrombomodulin (THBD). RESULTS: The sensitivities for the detection of oral cancer and oral leukoplakia were 72.0% (77/107) with SCCA1, 75.7% (81/107) with IL-15, and 56.1% (60/107) with THBD, and the specificities were 73.1% (57/78) with SCCA1, 64.1% (50/78) with IL-15, and 78.2% (61/78) with THBD. Analysis of the sensitivity according to tumor size revealed that sensitivity was lower for large tumors. When analyzing the sensitivity according to the clinical growth pattern, the sensitivity was observed to be low for endophytic tumors. CONCLUSION: We developed an oral cancer screening test based on real-time PCR analysis of SCCA1 that is examiner independent, and the sensitivity and specificity were approximately 70%; therefore, we concluded that the performance of this method using a single biomarker was suboptimal. PMID- 22525606 TI - Bisphosphonate-related osteonecrosis of the jaws--a review. AB - The aim was to evaluate the knowledge about bisphosphonate-related osteonecrosis of the jaws (BRONJ). A bibliographic search in Medline, PubMed and the Cochrane Register of controlled clinical trials was performed between 2003 and 2010 by using the terms bisphosphonate and osteonecrosis of the jaw. The amount of publications per year, the type of journal for publication, and the evidence level of the trial were evaluated. Next to this the incidences and the success of treatment strategies for BRONJ were identified. A total of 671 publications were reviewed. Since 2006 more than 100 publications on BRONJ per year (with an upward trend) have been published, mostly in dental journals. The evidence level could be determined for 176 publications and only one grade Ia study was found. The studies showed a wide variety in design, most of them being retrospective. The incidence of BRONJ is strongly dependent on oral or intravenous application and varies between 0.0% and 27.5%. There is no scientific data to sufficiently support any specific treatment protocol for the management of BRONJ. Further clinical studies are needed to evaluate the incidence and treatment strategies at a higher level of evidence. Therefore uniform study protocols would be favourable. PMID- 22525604 TI - A systematic review of head and neck cancer quality of life assessment instruments. AB - Although quality of life (QOL) is an important treatment outcome in head and neck cancer (HNC), cross-study comparisons have been hampered by the heterogeneity of measures used and the fact that reviews of HNC QOL instruments have not been comprehensive to date. We performed a systematic review of the published literature on HNC QOL instruments from 1990 to 2010, categorized, and reviewed the properties of the instruments using international guidelines as reference. Of the 2766 articles retrieved, 710 met the inclusion criteria and used 57 different head and neck-specific instruments to assess QOL. A review of the properties of these utilized measures and identification of areas in need of further research is presented. Given the volume and heterogeneity of QOL measures, there is no gold standard questionnaire. Therefore, when selecting instruments, researchers should consider not only psychometric properties but also research objectives, study design, and the pitfalls and benefits of combining different measures. Although great strides have been made in the assessment of QOL in HNC and researchers now have a plethora of quality instruments to choose from, more work is needed to improve the clinical utility of these measures in order to link QOL research to clinical practice. This review provides a platform for head and neck specific instrument comparisons, with suggestions of important factors to consider in the systematic selection of QOL instruments, and is a first step towards translation of QOL assessment into the clinical scene. PMID- 22525607 TI - The strength/weakness of the AJCC/UICC staging system (7th edition) for nasopharyngeal cancer and suggestions for future improvement. AB - BACKGROUND AND PURPOSE: To evaluate the current AJCC/UICC staging system (7th edition) for nasopharyngeal carcinoma and to explore for future improvement. MATERIALS AND METHODS: A total of 985 patients, initially staged with preceding 5 6th edition, were retrospectively re-staged with the 7th edition. All were assessed by magnetic resonance imaging, and all 945 non-disseminated patients were irradiated with conformal/intensity-modulated technique. RESULTS: Staging factors by both the 5-6th edition and the 7th edition were strongly significance for important endpoints (p<0.001). Down-staging of the previous T2a to T1 and, stages IIA to I in the 7th edition was appropriate. However, the impacts on overall stage distribution and prognostication were minimal. Further down-staging of the current T2 to T1, N2 to N1, stages II to I, and merging of N3a and N3b, stages IVA and IVB were suggested. With the 7th edition, the 5-year disease specific survival (DSS) was 100% for stage I, 95% for II, 90% for III, 67% for IVA, 68% for IVB and 18% for IVC. The corresponding DSS for the proposed stages I, II, III and IV were 95%, 86%, 67% and 18%, respectively. CONCLUSIONS: The changes introduced in the 7th edition were appropriate, but the magnitude of improvement was minimal. With improving results by modern management, further simplification of the staging system is suggested. The proposed system could lead to more accurate prognostication, further validation is warranted. PMID- 22525608 TI - Do diabetic patients living in racially segregated neighborhoods experience different access and quality of care? AB - BACKGROUND: Place of residence, particularly residential segregation, has been implicated in health and health care disparities. However, prior studies have not focused on care for diabetes, a prevalent condition for minority populations. OBJECTIVE: To examine the association of residential segregation with a range of access and quality of care outcomes among black and Hispanics with diabetes using a nationally representative US sample. RESEARCH DESIGN: Cross-sectional study using data for 1598 adult patients with diabetes from the 2006 Medical Expenditure Panel Survey linked to residential segregation information for blacks and Hispanics on the basis of the 2000 census. Relationships of 5 dimensions of residential segregation (dissimilarity, isolation, clustering, concentration, and centralization) with access and quality of care outcomes were examined using linear, logistic, and multinomial logistic regression models, controlling for respondent characteristics and community utilization and hospital capacity. RESULTS: Black and Hispanics with diabetes had comparable or better access to providers, but received fewer recommended services. Living in a segregated community was associated with more recommended services received, but also problems with seeing a specialist. The relationship of residential segregation to diabetes care varied depending on type of segregation and race/ethnic group assessed. CONCLUSIONS: Residential segregation influences the care experience of patients with diabetes in the United States. Our study highlights the importance of investigating how different types of segregation may affect diabetes care received by patients from different race and ethnic groups. PMID- 22525610 TI - Reallocation of operating room capacity using the due-time model. AB - BACKGROUND: Demand for surgical treatment is rising while operating room (OR) resources are limited. Requests for more resources therefore can only be partly met by repartitioning the existing sparse resources. OBJECTIVE: Our goal is to define a method to allocate OR block times among surgical disciplines in such a way that patients can be treated within an acceptable time after the need for surgery is established. In this paper, we introduce and explore the potential of the concept of the individual patient deviation from the optimal due time (DT) as a potential driver for OR (re-) allocation. STUDY DESIGN AND SETTING: Using retrospective data for abdominal and gynecologic surgery, we analyzed DT deviation and 3 additional modifiers. From this analysis, a reallocation of OR time to the different (sub-) specialties was calculated using a simple model. RESULTS: The results show the capability of measuring and visualizing relative overcapacity versus undercapacity of OR resources with respect to this patient centered metric of DT. The reallocation results from the model show a potentially significant shift between programs. CONCLUSIONS: We propose the "due-time" concept as a valid measure to quantify OR resource use. The use of a DT-based model provides a transparent, acceptable system for regular reallocation of OR times between and within specialties. PMID- 22525609 TI - Risk-adjusted payment and performance assessment for primary care. AB - BACKGROUND: Many wish to change incentives for primary care practices through bundled population-based payments and substantial performance feedback and bonus payments. Recognizing patient differences in costs and outcomes is crucial, but customized risk adjustment for such purposes is underdeveloped. RESEARCH DESIGN: Using MarketScan's claims-based data on 17.4 million commercially insured lives, we modeled bundled payment to support expected primary care activity levels (PCAL) and 9 patient outcomes for performance assessment. We evaluated models using 457,000 people assigned to 436 primary care physician panels, and among 13,000 people in a distinct multipayer medical home implementation with commercially insured, Medicare, and Medicaid patients. METHODS: Each outcome is separately predicted from age, sex, and diagnoses. We define the PCAL outcome as a subset of all costs that proxies the bundled payment needed for comprehensive primary care. Other expected outcomes are used to establish targets against which actual performance can be fairly judged. We evaluate model performance using R(2)'s at patient and practice levels, and within policy-relevant subgroups. RESULTS: The PCAL model explains 67% of variation in its outcome, performing well across diverse patient ages, payers, plan types, and provider specialties; it explains 72% of practice-level variation. In 9 performance measures, the outcome specific models explain 17%-86% of variation at the practice level, often substantially outperforming a generic score like the one used for full capitation payments in Medicare: for example, with grouped R(2)'s of 47% versus 5% for predicting "prescriptions for antibiotics of concern." CONCLUSIONS: Existing data can support the risk-adjusted bundled payment calculations and performance assessments needed to encourage desired transformations in primary care. PMID- 22525611 TI - Effect of early preventive dental visits on subsequent dental treatment and expenditures. AB - OBJECTIVE: Professional organizations recommend a preventive dental visit by 1 year of age. This study compared dental treatment and expenditures for Medicaid children who have a preventive visit before the age of 18 months with those who have a visit at age 18-42 months. METHODS: This retrospective cohort study used reimbursement claims for 19,888 children enrolled in North Carolina Medicaid (1999-2006). We compared the number of dental treatment procedures at age 43-72 months for children who had a visit by age 18 months with children who had a visit at ages 18-24, 25-30, 31-36, and 37-42 months using a zero-inflated negative binomial model. The likelihood and amount of expenditures at age 43-72 months were compared by group using a logit and ordinary least squares regression. RESULTS: Children who had a primary or secondary preventive visit by age 18 months had no difference in subsequent dental outcomes compared with children in older age categories. Among children with existing disease, those who had a tertiary preventive visit by age 18 months had lower rates of subsequent treatment [18-24 mo incidence density ratio (IDR): 1.19, 95% confidence interval (CI), 1.03-1.38; 25-30 mo IDR: 1.21, 95% CI, 1.06-1.39; 37-42 mo IDR: 1.39, 95% CI, 1.22-1.59] and lower treatment expenditures compared with children in older age categories. CONCLUSIONS: In this sample of preventive dental users in Medicaid, we found that children at highest risk of dental disease benefited from a visit before the age of 18 months, but most children could delay their first visit until the age of 3 years without an effect on subsequent dental outcomes. PMID- 22525612 TI - Patient notification for bloodborne pathogen testing due to unsafe injection practices in the US health care settings, 2001-2011. AB - BACKGROUND: Syringe reuse and other unsafe injection practices can expose patients to bloodborne pathogens (eg, hepatitis B and C viruses and human immunodeficiency virus). Evidence of such infection control lapses has resulted in patient notifications, but the scope and magnitude of these events have not been well characterized. OBJECTIVES: To summarize patient notification events resulting from unsafe injection practices in the US health care settings. METHODS: We examined records of events that involved communications to groups of patients, conducted during 2001-2011, advising bloodborne pathogen testing stemming from potential exposures to unsafe injection practices. RESULTS: We identified 35 patient notification events related to unsafe injection practices in at least 17 states, resulting in an estimated total of 130,198 patients notified. Among the identified notification events, 83% involved outpatient settings and 74% occurred since 2007, including the 4 largest events (>5000 patients per event). The primary breach identified (>=16 events; 44%) was syringe reuse to access shared medications (eg, single-dose or multidose vials). Twenty two (63%) notifications stemmed from the identification of viral hepatitis transmission, whereas 13 (37%) were prompted by the discovery of unsafe injection practices, absent evidence of bloodborne pathogen transmission. CONCLUSIONS: Unsafe injection practices represent a form of medical error that have manifested as large-scale adverse events, affecting thousands of patients in a wide variety of health care settings. Our findings suggest that increased oversight and attention to basic infection control are needed to maintain patient safety, along with research to identify best practices for triggering and managing patient notifications. PMID- 22525613 TI - An observational study to evaluate 2 target times for elective coronary bypass surgery. AB - BACKGROUND: Guidelines for timing of elective bypass surgery were established by expert opinion; yet, there is little evidence to support the recommended target times. OBJECTIVES: To estimate the effect of timing of the procedure on in hospital mortality by comparing groups of patients that differ in the duration of time between decision to operate and performed procedure. RESEARCH DESIGN: We used a population-based registry to identify patients who underwent surgical coronary revascularization and their hospital discharge summaries to identify in hospital death. SUBJECTS: We studied 9593 patients who underwent surgical revascularization between 1992 and 2006 after registration on a wait list for first-time isolated coronary artery bypass grafting on an elective basis. MEASURES: The outcome was postoperative in-hospital death. The study variable was the timing of surgery, categorized as short, prolonged, and excessive delays according to the guidelines. METHODS: The probability of in-hospital death in relation to timing of surgery was modeled by logistic regression that included a precalculated risk score for in-hospital death, with weighting observations by inverse propensity scores for the 3 surgery timing groups. RESULTS: In-hospital death among patients with short delays was one third as likely as among those with excessive delays: adjusted odds ratio=0.32 (95% confidence interval 0.20 0.51). The protective effect was smaller and not significant for patients with prolonged delays; odds ratio=0.78 (95% confidence interval, 0.38-1.63). CONCLUSIONS: Our findings suggest a survival benefit from performing elective surgical revascularization within the time frame recommended by the stricter of the 2 guidelines. Our results have implications for health systems that provide universal coverage and that budget the annual number of procedures. PMID- 22525614 TI - A conceptual model of physician work intensity: guidance for evaluating policies and practices to improve health care delivery. AB - BACKGROUND: Physician work intensity, although a major factor in determining the payment for medical services, may potentially affect patient health outcomes including quality of care and patient safety, and has implications for the redesign of medical practice to improve health care delivery. However, to date, there has been minimal research regarding the relationship between physician work intensity and either patient outcomes or the organization and management of medical practices. A theoretical model on physician work intensity will provide useful guidance to such inquiries. OBJECTIVE: To describe an initial conceptual model to facilitate further investigations of physician work intensity. RESEARCH DESIGN: A conceptual model of physician work intensity is described using as its theoretical base human performance science relating to work intensity. For each of the theoretical components, we present relevant empirical evidence derived from a review of the current literature. RESULTS: The proposed model specifies that the level of work intensity experienced by a physician is a consequence of the physician performing the set of tasks (ie, demands) relating to a medical service. It is conceptualized that each medical service has an inherent level of intensity that is experienced by a physician as a function of factors relating to the physician, patient, and medical practice environment. CONCLUSIONS: The proposed conceptual model provides guidance to researchers as to the factors to consider in studies of how physician work intensity impacts patient health outcomes and how work intensity may be affected by proposed policies and approaches to health care delivery. PMID- 22525615 TI - The effect of dental insurance on dental care use and selection bias. AB - OBJECTIVES: We examine the effect of dental insurance coverage on the probability of having a dental care visit in light of selection bias. METHODS: We use data from the 2003 Medical Expenditure Panel Survey and use 3 different approaches to control for selection bias. First, we use a probit specification and include a rich set of independent variables that we posit control for unobserved attitudes toward risk and health care. Second, we use an instrumental variable model with family employment status as our instrument. Finally, we use a nonparametric approach to identify the upper and lower bounds of a dental insurance effect. We also ran a base probit model that did not include controls for attitudes toward risk and health care. RESULTS: The base probit, the probit including measure of attitudes, and the instrumental variable models provided similar estimates of the effect of dental insurance on the probability to seek dental care. This may indicate that selection bias may not be a concern. All estimates were within the bounds obtained through the nonparametric approach. CONCLUSIONS: Despite concerns of the potential endogeneity of dental insurance in models that estimate dental care use, we find evidence that these concerns may be unfounded. PMID- 22525616 TI - Sex-based differences in end-of-life decision making in Flanders, Belgium. AB - BACKGROUND: Sex-related differences in end-of-life decisions (EOLD) are underresearched and unexplored. OBJECTIVES: To investigate whether there are (1) differences in demographic and/or clinical characteristics between male and female decedents; (2) differences between men and women in the prevalence of EOLD with a possible or certain life-shortening effect; (3) differences in EOL decision making between men and women. METHODS: In 2007, we performed a postmortem survey in Flanders, Belgium among physicians certifying a large representative sample (n=6927) of death certificates. Response rate was 58.4%. RESULTS: Of patients with nonsudden death, women more often die in a care home than men (31.4% vs. 18.2%) who more often die at home (24.1% vs. 17.9%). Men tend to die more often from cancer than women (45.4% vs. 32.1%). Decisions to withhold or withdraw potentially life-prolonging treatment are more often made in women (28.0% vs. 22.8%, P=0.003); euthanasia and pain and symptoms treatment [alleviation of pain and symptoms (APS)] occur more often in men (3.6% vs. 2.1% euthanasia, P=0.023; 41.8% vs. 36.9% APS, P=0.012). These differences disappear after controlling for confounders. Bivariate associations were found between sex and EOL decision making. Some of them remained after controlling for confounders. CONCLUSIONS: It is not the patient's sex in itself that determines the likelihood of an EOLD, but the different clinical profiles of men and women at the end of life. Although sex is not a determining factor in the prevalence of EOLD, it influences the decision-making process, indicating that there may be a difference in the way that male and female patients participate in EOL decision making. PMID- 22525617 TI - [Cost study of transient ischemic attack patients in a transient ischemic attack clinic]. AB - BACKGROUND: Patients with transient ischemic attacks (TIA) may be studied on a hospital admission or an outpatient clinic basis. There are few studies evaluating the costs of TIA treating on outpatient basis. Our aims were to determine the total cost per patient with TIA evaluated in a weekly TIA Clinic and to compare the costs of treating as ambulatory with the ones of inpatient treatment. METHODS: Direct costs to the health care services (primary and secondary care), direct costs outside the health care services and indirect costs were assessed in consecutive patients with TIA evaluated in the TIA Clinic of Hospital de Santa Maria, between October 2006 and May 2007. The time horizon was one month, estimated from the date of TIA. The study perspective was the society. The main instrument for data collection was a questionnaire applied in an interview immediately after the first TIA Clinic visit. The TIA clinic database was consulted to extract information subsequent to the first visit. The monetary valuation of the different items was done in accordance with the officially fixed values. RESULTS: Thirty-two patients were evaluated, with a mean of 65 years (41 85), 23 (71.9%) males. Mean total costs (direct and indirect) was 802.71 ?/patient. Mean total direct costs for the health care services was 691.16 ?/patient, corresponding to 89.7% of the total direct costs. Primary care costs represented 1.7% and secondary care 98.3%. Mean total direct costs outside the health care services was 79.49 ?/patient. Mean total direct costs (of the health care services and outside the health care services) was 770.65 ?/patient. Mean total indirect costs was 32.06 ?/patient. Diagnostic tests and exams represented 45.2% of the direct costs per category, hospital emergency 19.8%, TIA clinic 8.4% and drugs 4.0%. The estimated cost for inpatient treatment was 1.214.29 ?/patient (DRG 832). CONCLUSION: Most of the direct costs were supported by the health care services. Cost of treatment in ambulatory basis was lower than that estimated in inpatient basis. This study suggests that immediate evaluation of TIA patients is possible in a outpatient TIA Clinic and may reduce hospital admission and costs in low risk patients. PMID- 22525618 TI - [Breast cancer at Pico Island (1998-2008): an epidemiological perspective]. AB - INTRODUCTION: Neoplasic disease has been assuming an increasingly relevant role in the world's public health. Breast cancer is the most common cancer and the second cause of death by neoplasia in women. In the Portuguese population, breast cancer is the main cause of death by neoplasia in females. Among the Azorean women, the most frequently diagnosed malignant tumor is breast cancer, Pico Island being the third in terms of cancer incidence in the region. The risk factors are well known, well established and some of them can be prevented. Despite the great incidence of breast cancer, in the general population, particularly among the youngest, the knowledge about the disease is quite limited. The aims of this study are to characterize and identify the risk factors of women with breast cancer diagnose between 1998 and 2008 residing in Pico's island and, simultaneously to evaluate the knowledge of the students in Pico island about this disease. METHODS AND POPULATION: The method used for the gathering of the data in both cases was an anonymous and confidential questionnaire. In study 1 the questionnaire was conducted by an interviewer after the women's consent. Study 2 was performed in the three secondary schools of Pico island. RESULTS: The incidence rate of breast cancer in Pico island women is higher than the national incidence rate. There was an enormous variability in the incidence rates calculated for each year, with no clear tendency. The main responsible for the appearance of breast cancer in this population could be a conjugation of factors and not only a single isolated factor. The risk factors that stand out are: sedentariness (71.4%), family history (47.6%) and obesity (44.4%). The 295 students interviewed aged between 15 and 21 years. Of the total, 43 had relatives with breast cancer, however the majority (56.3%) assumes to be little informed about this disease. CONCLUSIONS: Through study 1 we conclude that there is a combination of hereditary and environmental risk factors, modifiable and non modifiable risk factors that may contribute to the onset of breast cancer. It is important to encourage changes in the life style of the women and rising of awareness towards risk factors. For the study of the student population, we conclude that the students have a very limited degree of knowledge of the disease; however, they assumed the will to more information, which leaves an open door for future formation and awareness actions. PMID- 22525619 TI - [Chorionicity and perinatal complications in twin pregnancy: a 10 years case series]. AB - OVERVIEW AND AIMS: Multiple pregnancy accounts for about 3% of all pregnancies. The monochorionic pregnancy presents a relatively constant incidence (1:250 pregnancies) unlike the dichorionic, which is influenced by race, heredity, maternal age, parity and medically assisted procreation. The purpose of this work was to evaluate the impact of chorionicity on perinatal morbidity of twin pregnancy. POPULATION AND METHODS: Retrospective, longitudinal, descriptive and analytical study of women with twin pregnancy whose birth occurred in our maternity hospital since January/1999 until December/2008. INCLUSION CRITERIA: monochorionic and dichorionic twin pregnancies confirmed by ultrasound. EXCLUSION CRITERIA: monochorionic monoamniotic gestation. Demographic data, delivery variables and perinatal morbidity and mortality were studied. Data were evaluated using the chi2 test (qualitative variables), t-Student (continuous quantitative variables) and Mann-Whitney test (quantitative discrete variables). RESULTS: We studied 504 pregnancies (356 dichorionic diamniotic and 148 monochorionic diamniotic). The monochorionic pregnancy had a higher incidence of threatened preterm labor (43,9% vs 31,5%, p<0,05), of oligohydramnios/hydramnios (9,8% vs 3,3%, p<0,001), discordant fetal growth (26,8% vs 14,8%, p<0,001) and intrauterine growth restriction (7,4% vs 3,7%, p<0,05). Prematurity was more common in the monochorionic group (p<0,001). The cesarean delivery rate was higher in monochorionic pregnancy (58,8% vs 50,3%, p<0,05) and the average weight of newborns was lower in monochorionic pregnancies (1983g vs 2233g, p<0,001). Newborns in the monochorionic group had higher incidence of hyaline membrane disease (5,8% vs 2,8%, p<0,05) and intraventricular haemorrhage (2,1% vs 0,4%, p<0,05). The perinatal mortality was higher in the monochorionic group (7,8% vs 1,8%, p<0,001). CONCLUSIONS: As the morbidity and mortality associated with monochorionic pregnancies are higher, it is essential to perform an early detection of chorionicity by ultrasound (11-13 weeks) in order to place differentiated prenatal and appropriate peripartum surveillance. PMID- 22525620 TI - [Infertility prevalence in the city of Porto]. AB - OBJECTIVES: To determine the prevalence of infertility in Porto and to assess the association between infertility and women's year of birth and socioeconomic status. MATERIAL AND METHODS: In a cross-sectional study were evaluated in Porto, in 1999-2003, 1540 women aged 18-90 years. Structured face-to-face interviews comprising information on social, demographic, personal and family history, gynaecological and obstetric history, cognitive capacity and behavioural characteristics were performed. Gynaecological history included lifetime infertility. Primary infertility was defined as never being able to achieve a pregnancy after more than one year trying to conceive. Secondary infertility means that the woman has already conceived, but subsequently was unable, for at least a period of one year. Socioeconomic status was evaluated by education and job. RESULTS: The prevalence of lifetime infertility was 12.0% (95% confidence interval: 10.4%-13.7%). The prevalence of primary infertility was 7.7% and secondary infertility was 3.8%. The prevalence of infertility was not significantly different according to women's year of birth, education or job. Infertility was significantly more frequent among married/cohabiting/widow/divorced women (13.9%) compared to single women (1.7%). CONCLUSION: These findings do not confirm the increase of infertility with more recent birth cohorts. There appeared no association between infertility and socioeconomic status. It was found higher prevalence on married/cohabiting/widow/divorced women comparative to single group women, and these differences were statistically significant. PMID- 22525621 TI - Epstein-Barr virus in healthy individuals from Portugal. AB - INTRODUCTION: The Epstein-Barr virus (EBV) persists for long periods in latent state inside B-lymphocytes after primary infections, and reactivation usually occurs associated to immunosuppression conditions of the host. Recently, the detection of EBV DNA in circulation has been suggested as a predictor marker for the development of EBV related malignancies. AIM OF THE STUDY: The aim of our study was to characterize the frequency of circulating EBV in healthy individuals (n=508) from the North region of Portugal, using peripheral blood samples. Detection was performed by Nested-PCR which amplifies a fragment from the BamHIW region of the EBV genome. RESULTS: Our results revealed an overall frequency of 37.2% positive cases for EBV in circulation, with distinct distribution according to genre (39.7% in male individuals and 33.2% in females). We also found that EBV is more frequent in individuals with more than 56 years old compared to individuals with less than 56 years old (p=0.032; RR=1.41), mainly in the male group (p=0.024; OR=1.51). CONCLUSION: This is the first study which characterizes the frequency of EBV in circulation in healthy donors from the Northern Region of Portugal, revealing increased frequency of EBV in circulation in healthy individuals with differences depending on gender or age. Further studies are required to analyze the role of circulating EBV in the definition of susceptibilities to EBV associated diseases. PMID- 22525622 TI - [Validation of the Ottawa rules for the Portuguese population: a prospective study]. AB - Acute ankle injury is one of the main reasons for observation of patients in the emergency department. Only 15% present with clinically significant fractures, but they are almost always referred for radiography. The Ottawa ankle rules have provided specific directions for carrying out radiography in these situations, allowing a reduction in hospital costs and reducing exposure to ionizing radiation. The aim of the study is to verify that the protocol of the Ottawa rules for evaluating ankle trauma can adapt to a sample of the Portuguese population. MATERIAL AND METHODS: This prospective study was done in the Emergency Department of Orthopedics, for a period of 9 months, integrating all patients who presented with complaints in the ankle with less than 48 hours development. All patients underwent radiography of the injured area. Radiographic images were evaluated by the orthopaedic doctor in the emergency department. Patients were reassessed in about 10-15 days after injury by the same observer. RESULTS: We evaluated 123 patients. The average age was 35.2 (range, 7 to 88) years. Sixty had positive criteria for radiological assessment, of which 43 had fracture; none of the patients with negative criteria had fratures. Sensitivity of Ottawa ankle rules for detecting fractures was 100%. CONCLUSION: The implementation of the Ottawa ankle rules appears to have potential to reduce the number of radiographs for the assessment of these patients by about 51%. The results of this study demonstrate no false negatives and are consistent with the results of other similar studies which sensitizes us to implement these criteria in our emergency services. PMID- 22525624 TI - [Carbon monoxide intoxications in Portugal]. AB - The prevalence of carbon monoxide intoxication in the World shows that this is a common situation. In Portugal, there are no concrete data available in literature and its incidence remains unknown. Currently, the use of hyperbaric oxygen is a valid therapeutic for carbon monoxide poisoning management. However, its effectiveness and its proper handling are still controversial. The first aim of this study was to estimate the incidence of carbon monoxide intoxication in Portugal and to analyze its demographic characteristics. The second objective of this work was to evaluate the possible change in the type of treatment applied in areas near de hyperbaric chamber of Unidade Local de Saude de Matosinhos, since its opening in June 2006. To achieve these objectives, we conducted a survey on admissions data for carbon monoxide intoxication occured between January first, 2000 and December 31, 2007. These data was collected in seven hospitals and in the Administracao Central do Sistema de Saude, I.P. Nationally, 621 hospitalizations were recorded, which represents an incidence of 5,86/100000 in 8 years. In the seven hospitals, there were 93 hospitalizations due to carbon monoxide intoxication during the same period of time. There was a peak of incidence during winter, between November and March and there was a similar distribution in men (47,3%) and women (52,7%). Since June 2006, date of opening of the hyperbaric chamber, the Unidade Local de Saude de Matosinhos, E.P.E. recorded a sharp increase in the number of hospitalization for carbon monoxide intoxication. The number of admissions in the 19 months after the chamber opening was double the number of all cases occurred in that institution in the 65 months prior. We concluded that, in Portugal, carbon monoxide intoxication is an uncommon situation but it's still an important cause of hospitalization. The referral of cases to the Unidade Local de Saude de Matosinhos, E.P.E. since the opening of hyperbaric chamber objectively increased. Thus, we can assume that peripheral hospitals are aware of the existence of hyperbaric chamber and its potential in treatment of carbon monoxide poisoning. PMID- 22525623 TI - [Relationship of pattern hyperlipidic intake with quality of diet, insulin resistance and homocysteinemia in adults]. AB - OBJECTIVES: To evaluate the association between the consumption of different dietary fats with the quality of the diet, insulin resistance, and hyperhomocysteinemia in adults. METHODS: Cross-sectional study conducted with 624 overweight subjects (73.7% females). Assessments of food intake (24h food recall and health eating index-HEI), anthropometry, and biochemical assays of fasting glucose, insulin (HOMA-IR and beta calculus) and homocysteinemia were performed. RESULTS: The low quality of diet was associated with the vegetable oil at 3rd quintile (>=1.5-2.0 servings) showed risk 2.9 times and cholesterol at quintiles 2nd, 3rd, and 4th was 2.0 times. HOMA-IR was higher at 5th quintile of saturated fat (>=10,7% - total caloric value) with risk of 60% and hyperhomocysteinemia the vegetable oil at 3rd quintile (>1.5-2.0 servings) with risk of 12.0 times and 5th (>=3.5 servings) 7.1 times. However, significance disappeared when adjusted for anthropometric variables. CONCLUSION: Dietary fats were associated with the harm diet quality, insulin resistance, andhyperhomocysteinemia. However, associations are dependant of demographic variables, dietetic, and nutritional state. PMID- 22525625 TI - [Burkitt's lymphoma]. AB - BACKGROUND: Burkitt's lymphoma (BL) is a highly aggressive B-cell neoplasm characterized by the translocation and deregulation of the c-myc gene on chromosome 8. Three distinct clinical forms of BL are recognized: endemic, sporadic, and human immunodeficiency-associated. BL is a rapidly growing neoplasm requiring immediate diagnosis and treatment. AIM: We described and analyzed our experience with Burkitt's lymphoma (BL) diagnosis, treatment and outcome, during ten years. MATERIALS AND METHODS: Retrospective study; clinical records of all children admitted with BL between 1st January 1998 and 31st December 2008 were analyzed. The following data were collected: age at admission, gender, clinical presentation, and time elapsed from initial complaints until diagnosis, disease localization, treatment and evolution. RESULTS: During the time period 21 children were admitted (19 boys), seven (33.3%) of which were diagnosed in 2008. The median age at diagnosis was seven years with a mean delay to diagnosis of 20,8 days (range 2-125 days). The most frequent site of primitive tumour was the abdomen (13), followed by tonsils (three), orbit (one), central nervous system CNS (two), tongue (one) and nasopharynx (one). The majority of patients in our study were presenting with a painfull abdominal mass. Diagnosis was established through tumour biopsy in 17 children, three by paracentesis or toracocentesis and one case was diagnosed only by genetic tests to the bone marrow. Genetic tests were positive in 11 patients. According to the Murphy classification, there were three stage II, 12 stage III and six stage IV tumours; 29% and 19% had bone marrow and central nervous system involvement, respectively. One child relapsed and was successfully treated with Rituximab(r) and autologous stem cell transplantation. The overall survival rate was 100%. PMID- 22525626 TI - [Club drugs]. AB - Club drugs are the following substances: Methylenedioxymethamphetamine (MDMA); Methamphetamine; Lysergic Acid Diethylamide (LSD); Ketamine; Gamma hydroxybutyrate (GHB) and Flunitrazepam. These substances are mainly used by adolescents and young adults, mostly in recreational settings like dance clubs and rave parties. These drugs have diverse psychotropic effects, are associated with several degrees of toxicity, dependence and long term adverse effects. Some have been used for several decades, while others are relatively recent substances of abuse. They have distinct pharmacodynamic and pharmacokinetic properties, are not easy to detect and, many times, the use of club drugs is under diagnosed. Although the use of these drugs is increasingly common, few health professionals feel comfortable with the diagnosis and treatment. The authors performed a systematic literature review, with the goal of synthesising the existing knowledge about club drugs, namely epidemiology, mechanism of action, detection, adverse reactions and treatment. The purpose of this article is creating in Portuguese language a knowledge data base on club drugs, that health professionals of various specialties can use as a reference when dealing with individual with this kind of drug abuse. PMID- 22525627 TI - [Functional somatization: a conceptual review]. AB - The authors have brought together and analised texts about the history of the concept of hysteria. In these texts hysteria is fundamentally considered a disease of organic origin (of the womb), and, in the Middle Age, evidence of demonic possession. From the XVII century onwards, apart from the etiopathogenic concepts, also taken into consideration are aspects connected to the differential diagnosis with other similar entities and the therapy used each period. Even, in subsequent centuries, authors such as Syndenham, who consider hysteria to be a multidimensional entity, are rare. Empiricism has contributed to discoveries in biology and physiology, both general and of the nervous system itself, and given birth to the formulation of the Spinal Irritation Theory and Reflex Theory. These theories have led to strictly organic treatment of hysteria, in the same way that hysterectomies were performed to alleviate somatic symptoms connected to this disease. The introduction of hypnosis in medical practice, with Charcot in X1X century, allowed for the element of suggestion to be observed ( a non organic element) which accompanies the symptoms of hysteria. Two of his disciples, Janet and Freud, would define and isolate psychic mechanisms in the symptoms of hysteria: Dissociation of the consciousness (Janet) and Conversion (Freud). The last one developed a therapeutic method of a psychological nature for hysteria. The therapeutic implications and the pertinence of the distinction between unspecific somatization or functional (of somatic origin) somatization and somatization linked to disassociation mechanisms and conversion (psychic origin) are discussed as well as the evolution of international classification systems of somatization and the questions posed by the algorithms chosen for the cataloguing of symptoms. A revision of the relevant empirical studies about the association of somatization with depressive and anxiety disorders, within the general population, is made. The characteristics that permeate the clinical descriptions of somatoform disorders (whose validity criteria remain weak) and are not integrated within the diagnostic criteria for somatoform disorders are considered. We draw conclusions about the difficulties and consequences of the changes that some authors advocate in relation to the new classification system for somatoform syndromes. PMID- 22525628 TI - [Association amongst physical activity, aging and dementia]. AB - The human possibility of becoming old - the so called Nestor Effect -, as an evolutionary adaptation, is beneficial only if there is some preservation of a certain cognitive character. Differing neuropathological conditions, such as neurodegenerative diseases, due to an abnormal aggregation of certain proteins, may induce chronic inflammatory processes. As so, physical activity increases aerobic fitness and the brain's blood flow capacity, contributing to the decrease of the central nervous system's chronic inflammation, promoting neuroplasticity, and neural circuitry's reorganisation. PMID- 22525629 TI - [Tools to evaluate potentially inappropriate prescription in the elderly: a systematic review]. AB - INTRODUCTION: Prescription of potentially inappropriate medication (PIM) in the elderly has gained growing attention from healthcare professionals, researchers, healthcare providers and politicians worldwide for safety issues. Taking into consideration the increased susceptibility of elderly patients to certain medicines, criteria to identify PIM and to alert professionals to prevent their prescription have been created. OBJECTIVES: To gather published evidence regarding the characteristics and use of criteria to identify PIM. METHODS: systematic review of studies published between 1990 and 2007. A literature retrieval using Pubmed and The Cochrane Database of Systematic Reviews was performed followed by a manual search of cited references. Cross-sectional studies using the most recent version of PIM criteria in patients aged 65 years or more were included. Studies which analyzed PIM in a single clinical condition of therapeutic class exclusively or those not attaining 75% of the quality score were excluded. RESULTS: the search retrieved 124 studies, being 10 of them selected for inclusion in the systematic review. The studies selected were conducted in Europe and the United States and the Beers criteria updated in 2003 were the most frequently used. Some authors, adapted PIM criteria according to differences in authorized medicines in their respective countries. Studies revealed a high prevalence of PIM, especially those using the 2003 Beers criteria. Most articles suggested strategies to reduce the PIM prevalence in the elderly such as: pre- and post-graduate education, the use of computerized systems to alert healthcare professionals, and creating restrictive policies by means of formularies. CONCLUSIONS: The Beers criteria were the most commonly used criteria to identify PIM in the elderly, revealing a high prevalence of inappropriate prescription in this population. Criteria were adapted to country specific needs when used outside the United States. Different strategies to reduce PIM prevalence in the elderly have been suggested. PMID- 22525630 TI - [Metabolic syndrome and physical activity]. AB - Because the metabolic syndrome (MS) poses a growing public health problem, it is crucial to identify related modifiable risk factors. The MS is a multifaceted syndrome, however, physical activity (PA) is thought to be one of the protective factors in MS occurrence. The purpose of this study is to analyse recent literature on the association between PA and MS. Studies seem to agree in the protective effect of PA in MS occurrence, but associations are only seen in moderate or high PA levels. Differences observed in studies are probably related to different study methods. According to recent literature adequate PA levels can help to lower the risk of developing MS; PA can decrease body weight, visceral fat accumulation, improve insulin sensitivity, decrease plasma level of triglycerides, increase plasma levels of HDL cholesterol and decrease blood pressure. PMID- 22525631 TI - [Current management of gout]. AB - Gout, one of the most prevalent rheumatic diseases in the world, results from deposition of uric acid crystals in several locations, particularly in joints, subcutaneous tissues and kidney. The classical treatments, although effective, are often poorly tolerated or contraindicated. Recently, new drugs have emerged for the treatment of hyperuricemia and gout, including febuxostat and uricase, which proved to be quite promising. Some drugs already used in other diseases, such as losartan, atorvastatin, fenofibrate and amlodipine also seem to have a role in monitoring the serum uric acid. This article reviews the pathophysiology, clinical management and current therapeutic options for Hyperuricemia and Gout. PMID- 22525632 TI - [Renal morphophysiological changes in Wistar rats with malnutrition intra uterine]. AB - BACKGROUND: Many epidemiological studies suggest that the intra uterine environment is extremely important in determining the future of individual health. Changes in maternal nutritional status, reflected in birth weight may program the offspring to the development of diseases in adulthood. Studies with animals exposed to intrauterine malnutrition have suggested a reduction in the number of clusters in addition to increased blood pressure. OBJECTIVE: To review the literature morphophysiology changes in the kidney of adult Wistar rats exposed to malnutrition during intrauterine life. METHODS: We performed a search in the following databases: PubMed, MEDLINE, SCIENCE DIRECT, LILACS. The main search terms were malnutrition and renal function in Portuguese and English. We included original articles involving albino rats. We excluded review articles as well as those involving humans. RESULTS: According to Franco et al (2009) renal function and the number of glomeruli reduced by poor on intrauterine development, predisposing offspring to kidney disease in adulthood. According to Chen (2009) ultra-glomerular structure is not affected by maternal malnutrition suggesting that this factor does not contribute to the pathogenesis of hypertension after maternal malnutrition. Viana-son et al (2009) believes that stress on placents, causes disruption on sodium pumps in the proximal tubules of the kidney, resulting hypertension. CONCLUSION: The intrauterine malnutrition appears to interfere with the programming of kidney function with changes in glomerular morphophysiology, however, its mechanisms remain uncertain. We suggest further studies of the type and randomized clinical trials aimed at understanding the factors that trigger this process. PMID- 22525633 TI - Traumatic brain injury and shaken baby syndrome. AB - Shaken baby syndrome is a serious form of physical child abuse, which is frequently overlooked. It is defined as vigorous manual shaking of an infant who is being held by the extremities or shoulders, leading to whiplash-induced intracranial and intraocular bleeding and no external signs of head trauma. This syndrome is seen most commonly in children under 2 years, mainly in children under 6 months. This article summarizes issues related to clinical presentation, diagnosis, risk factors, and interventions for healthcare professionals. PMID- 22525634 TI - [Contrast-induced nephropathy]. AB - Contrast-induced nephropathy (CIN) is an iatrogenic disorder, resulting from procedures requiring the intravascular administration of iodinated contrast media. It has an association with increased morbidity and mortality, increased costs and it remains the third most common cause of hospital-acquired kidney failure. CIN is usually defined as an increase in serum creatinine by either at least 0.5 mg/dl or by 25% from baseline within the first 48 hours after contrast administration, in the absence of other causes of renal function impairment. In its pathogenesis have been implicated 2 main mechanisms: renal vasoconstriction resulting in medullary hypoxia and direct cytotoxic effects of the contrast agents. There are several risk factors for radiocontrast nephrotoxicity but patients with underlying renal insufficiency or diabetic nephropathy with renal insufficiency have the greatest risk. Other classic risk factors include: advanced age, peri-procedural intravascular depletion, congestive heart failure. Finally, toxicity also depends on the volume, type of contrast administered and concomitant use of other nephrotoxic drugs. Since there is no specific treatment for CIN and it is limited to supportive measures, prevention is the best way to deal with this condition. In this setting it is important to use lower doses of a low or iso-osmolal agent and avoid volume depletion. Nowadays it is recommended to do volume expansion prior to and continued for several hours after the procedure. Randomized controlled trials suggest that isotonic intravenous fluids, particularly isotonic bicarbonate, confer better protection. Several pharmacologic approaches have been tested to decrease the risk of CIN in patients with preexisting renal disease, based in the mechanisms by which contrast medium is believed to cause nephrotoxicity. However, with the exception of some antioxidant agents, few of those adjunctive therapies have shown any consistent benefit. N-Acetylcysteine is the most widely studied of all prophylactic strategies and despite conflicting data it is advised to do an elevated dosage orally twice daily, the day before and the day of the procedure, based upon its potential for benefit, low toxicity and cost. This article pretends to review CIN pathogenesis, risk factors, clinical course, treatment and prevention. The authors propose themselves a prevention protocol for risk patients based on the latest clinical evidence. PMID- 22525635 TI - [Painful thyroid palpation]. AB - A 37-years-old woman, complaining of fever, malaise, myalgia, sore throat and dysphagia lasting for 15 days, had been taking antibiotics and paracetamol for 7 days, without symptoms' improvement. The clinical examination revealed hyperaemic oropharynx and enlarged, painful thyroid. Further exams showed increased analytic inflammatory serum parameters as well as thyrotoxicosis. The thyroid gland had heterogeneous echostructure, with markedly hypoechoic areas and significant capsular oedema as well as decreased radionuclide uptake in the scintigraphy. Both symptoms and imaging improved with paracetamol and ibuprofen. Thyroid gland function normalized in two months. The patient remains in follow-up. This case reports the clinical features of subacute or De Quervain's thyroiditis. The differential medical approach to the patient with painful thyroid palpation is discussed. The diagnosis is essentially clinic, highlighting the importance of a rigorous physical exam. These patients' follow-up is required, considering the clinical and analytic progression. PMID- 22525636 TI - [Antibiomania: a case of a manic episode induced by clarithromycin]. AB - Antibiomania, or mania induced by antibiotics, is a rare, but important side effect of clarithromycin and others antibiotics. Although underestimated due to low clinical incidence, this phenomenon is being reported in a growing number of cases of mania associated with administration of antibiotics, in patients without a previous diagnosis of Bipolar Affective Disorder. The importance of Antibiomania in current clinical practice is associated with the increasing introduction and prescription of new antibiotics, and to the need for awareness of the phenomenon as a possible differential diagnosis of secondary mania. There are several theories that may explain Antibiomania, one of the most studied is related to the interaction of antibiotics with neurotransmitters, including the gamma butyric acid (GABA). However, the mechanism is still unknown. The authors present a case of a manic episode triggered by clarithromycin in a patient with no clinical history of disturbance of mood, followed by a brief literature review of the subject, including treatment strategies. PMID- 22525637 TI - [Autoimmune lymphoproliferative syndrome]. AB - The Autoimmune Lymphoproliferative Syndrome (ALPS) is an impairment of lymphocyte apoptosis expressed by generalized non-malignant lymphoproliferation, lymphadenopathy and/or splenomegaly. This article describes a seven and 14 year old males. The first one was admitted at 3 years of age with fever, bicytopenia and generalized lymphadenopathy. Hystopathological analysis of lymph nodes showed reactive follicular hyperplasia and marked paracortical expansion. He was readmitted three years later presenting herpes zoster and similar clinical features. High levels of IL-10 and increasing tendency of Fas-L in plasma and serum. The second child was admitted at 13 years of age presenting thigh and gluteus cellulitis, anemia and neutropenia. T lymphocytes abeta+CD4-CD8- 3,1%. Hystopathological analysis of lymph nodes showed marked paracortical hyperplasia. Both children are treated with mycophenolate mofetil with good response. ALPS is an underestimated entity that must be considered in non malign lymphoproliferation, autoimmunity and expansion of an unusual population of a/betaCD3+CD4-CD8-(double-negative T cells>1%). PMID- 22525638 TI - [Digital ulcers in systemic sclerosis: use of endotheline antagonists]. AB - INTRODUCTION: Systemic sclerosis (SSc) is a systemic disease, characterized by fibrosis and vasculopathy, with variable internal organ involvement. Skin is very often involved, namely digital ulcers (DU), seldom treatment resistant, responsible for important functional limitation. The DU can evolve from sclerodactily with superficial ulcers, isquemic lesions, deep necrosis, gangrene, loss of tissue, and consequently, to finger amputation. METHODS: The authors describe the case of a 36 year old female patient, with SSc diagnosed 6 years previously, with skin, lung and gut manifestations. The patient showed uncontrolled Raynaud's phenomenon (RF), despite the adequate treatment using nifedidpine and general local warming measures, with progressively worsening DU and isquemia, especially in cold seasons. Bosentan, 62.5 mg twice daily was started, and a significant improvement in the peripheral isquemic lesions was achieved. The ulcers' healing was fast, the patient totally recovered function and regained quality of life, and no further lesions developed. CONCLUSION: The authors review the RF and DU in SSc, as well as the use of bosentan, an endotheline receptor antagonist, and its indications. Although it is not formally approved, the use of bosentan in SS has shown benefits in reducing the incidence of DU, and despite no influence in the healing process, this drug prevents the development of new lesions. PMID- 22525639 TI - [Carcinoid tumors: echocardiographic contribution to the diagnosis]. AB - INTRODUCTION: Carcinoid tumors are rare, most commonly originating from the neuroendocrine cells in the gastrointestinal tract. Carcinoid syndrome is characterized by flushing, diarrhea, and bronchospasm. Half of these patients have carcinoid heart disease, affecting the right side of the heart, causing tricuspid and pulmonary regurgitation and stenosis and subsequently right heart failure. CASE REPORT: 73-year-old female was admitted with heart failure associated with episodes of diarrhea and flushing. The echocardiogram showed typical characteristics of carcinoid heart diasease. The CT scan of abdomen showed a small bowel mass. The 24-hour urine 5-hydroxyindoleacetic acid (5HIAA) and indium-111-pentetreotide scintigraphy confirmed the diagnosis. The patient was treated with furosemide, warfarine, digoxin and octreotide and there was clinical improvement. CONCLUSION: The echocardiogram was very useful, establishing the provisory diagnosis of a rare disease based on pathognomonic echocardiographic features. PMID- 22525640 TI - [Duodenocaval fistula]. AB - Duodenocaval fistula is a type of digestive fistula rarely described in the literature. It usually manifests by sepsis associated with gastrointestinal bleeding. The treatment is surgical and the prognosis usually not favorable. We describe the case of a woman admitted to our hospital with sepsis, having been diagnosed with a duodenocaval fistula secondary to perforation of the digestive tract by a foreign body. Surprisingly, the fistula sealed by itself, without the need of surgery, and with a favorable evolution. PMID- 22525641 TI - [Churg-Strauss syndrome: a disabling disease]. AB - Churg-Strauss syndrome (CSS) is an infrequent vasculitis that affects small to medium-sized vessels. We describe a 51 year-old-female admitted to our inpatient unit with bullae on her right foot and forearm with pain, paresthesias and impotence of the foot. There was rapid clinical deterioration with lost of gait and peripheral eosinophilia. Histopathology showed many extravascular eosinophils. Bone marrow had an increased number of eosinophils and their precursors with no neoplastic cells infiltration. Electromyogram revealed mononeuritis multiplex with bilateral sciatic and right femoral nerve involvement. She fulfilled the eligibility criteria of American College of Rheumatology (ACR) and Chapell Hill Conference Consensus (CHCC) of CSS so corticosteroids and cyclophosphamide and rehabilitation program were begun with good clinical and laboratorial response. This report illustrates the importance of identifying atypical cutaneous features of CSS for the early diagnosis of this rare condition and the role of a multidisciplinary team in this multissystemic disease. PMID- 22525642 TI - [Abdominal aortic aneurysm: an uncommon presentation]. AB - Most abdominal aortic aneurysms are asymptomatic, being accidentally found on physical examination or in routinely performed imaging studies. They only require surveillance (which is variable according to the aneurism size) and medical therapy in order to achieve risk factor reduction. However, in certain situations, according to the risk of aneurism rupture, elective surgery or endovascular procedure may be necessary. About 80% of the cases of aneurism rupture occur into the retroperitoneal space, with a high mortality rate. There are uncommon presentations of aneurism rupture as the aorto-caval fistula, which also require fast diagnosis and intervention. The authors present the case of a 71-year-old man, with the previous diagnosis of hypertension, acute myocardial infarction 2 months earlier (undergone primary Percutaneous Coronary Intervention) and tabagism, who was admitted at the emergency department with intense 24-hour-evolution epigastric pain. On physical examination, the Blood Pressure values measured at the lower limbs were about half the ones measured at the upper limbs and there was an abdominal pulsatile mass, with a high-intensity murmur. As the authors suspected aortic dissection, aneurysm, coarctation or thrombosis, it was done a Computed Tomography scanning with intravenous contrast, which revealed a ruptured abdominal aorta aneurysm with a mural thrombus. The doppler ultrasound confirmed the presence of a high debit aorto-caval fistula. The patient was immediately transferred to the Vascular Surgery. However he died 2 hours later, during surgery. PMID- 22525644 TI - Anticoagulation in children. AB - Neonates and children are receiving anticoagulation therapy much more frequently now than at any time in the past. There are a multitude of factors which contribute to this trend and they are well described elsewhere. The majority of recent reviews of anticoagulation therapy in children have focussed, not inappropriately, on the specific anticoagulant agents used, and our lack of knowledge about their basic pharmacokinetics, pharmacodynamics, and impact on commonly used monitoring tests. This review will address some of the difficulties of anticoagulation in children from the other perspective, considering specific patient populations such as neonates and adolescents, and also specific clinical situations which increase the complexity of anticoagulation such as in children with cancer, or children who need invasive procedures. There remains just as much research required into how best to manage these populations and circumstances as is required to understand the basic mechanisms of anticoagulant interactions with paediatric plasma. PMID- 22525643 TI - Turning promise into progress for antiangiogenic agents in epithelial ovarian cancer. AB - Despite efforts to improve chemotherapeutic efficacy in epithelial ovarian cancer, outcome for patients with advanced disease has remained unchanged since the introduction of standard carboplatin and paclitaxel. Interest has therefore shifted toward molecularly targeted therapies that interfere with important features of ovarian carcinogenesis, such as angiogenesis. Several angiogenesis inhibitors, targeting vascular endothelial growth factor (VEGF) ligands (bevacizumab, VEGF-Trap) or their receptors (VEGFR-targeted tyrosine kinase inhibitors) have been clinically evaluated. These agents demonstrated efficacy in phase II clinical trials. Results from phase III trials, in which bevacizumab was added to standard frontline chemotherapy, show a modest effect. Although the initial expectations for angiogenesis inhibitors have been tempered, further research is warranted to define their precise place in the treatment of ovarian cancer. This review summarizes the performed and ongoing studies with regard to angiogenesis inhibitors in ovarian cancer, and the available data on biomarkers for response prediction. Preclinical studies evaluating alternative angiogenesis inhibitors will also be discussed. PMID- 22525645 TI - Importance of epoch length and registration time on accelerometer measurements in younger children. AB - AIM: The aim of this study was to investigate the effect of epoch length on accumulation of minutes of physical activity per day over a spectrum of intensities, and the effect that selection of number of hours of acceptable registration required per day had on number of days that were considered acceptable. METHODS: Participants were 696 children (369 boys and 327 girls) aged 6.7+/-0.4 yrs, from a population-based cohort. Physical activity was assessed by the Actigraph accelerometer for four days. RESULTS: Main findings were that epoch length had a profound impact on accumulation of minutes of physical activity per day for higher intensities, whereas it had no effect on mean counts per minute. The chosen number of hours for an acceptable registration per day heavily influenced the number of days that were considered acceptable. CONCLUSION: The findings in the present investigation should be taken into consideration when planning objective measurements of daily physical activity in younger children, and highlight the need for setting international recommendations for physical activity measurements with accelerometers, if different studies are to be comparable. PMID- 22525646 TI - Influence of massage, active and passive recovery on swimming performance and blood lactate. AB - AIM: Recovery is an important part of athletic training. The aim of this study was to evaluate influences of three methods of recovery including massage, active and passive recovery on blood lactate concentration and subsequent swimming performance of elite swimmers. METHODS: Seventeen professional male swimmers (age:21+/- 2.4 years, height: 175.35+/-9.1 cm, weight: 67.66+/- 11.88 kg) voluntarily participated in this study. Two Swimming trials performed in every session which involved 200 m of front crawl swimming with maximal effort separated by ten minutes interval (recovery) period. Statistical method of repeated measures was used for analysis of data. RESULTS: There was significant difference in blood lactate after three types of recovery (P<0.05). Significant difference was observed between passive and active (P=0.001), passive and massage (P=0.031) and active and massage (P=0.001). Blood lactate decreased after active, massage and passive recovery (blood lactate mean +/- SD: 5.72+/-1.44, 7.10+/ 1.27, 10.94+/-2.05 mmol/L, respectively). A significant difference was observed between performance time after three type of delivery (P=0.001, F=2.238). Significant differences was observed between passive and active recovery (P=0.003), passive and massage (P=0.001), but no significant difference was observed between performance time after active and massage recovery (P=1.00). CONCLUSION: the results indicated that active recovery was more effective than massage and massage was more effective compared to passive recovery in removing blood lactate. Active and massage recovery were more effective in improving swimming performance than passive recovery. PMID- 22525647 TI - Effect of a typical in-season week on strength jump and sprint performances in national-level female basketball players. AB - AIM: The aim of this study was to investigate the effect of a typical in-season week including four practice sessions and one competitive game on strength, jump and sprint performances in national-level female basketball players. METHODS: Nine female basketball players (24.3+/-4.1 years old, 173.0+/-7.9 cm, 65.1+/-10.9 kg, 21.1+/-3.8% body fat) participated in ten testing sessions, before and immediately after practices and game (five pre- and five post-tests). Each session involved isokinetic peak torque measurements of the quadriceps and hamstrings of the dominant leg at 60o.s-1, countermovement jump (CMJ) and 20-m sprint. Fluid loss and subjective training load were measured during each practice session, while the frequencies of the main movements performed during the game were recorded. A two-way ANOVA was used to asses the effect of each practice/game and the effect of the day of the week on performances, and the relationship between performance variations and variables recorded during practices/game were analyzed by a Pearson correlation coefficient. RESULTS: Individual sessions induced significant decreases in lower limb strength (from 4.6 to 10.9%, P<0.05), CMJ (12.6% to 19.6%, P<0.05) and 20-m sprint (1.3% to 7.3%, P<0.05). Performances returned to baseline before the subsequent pre-test session, except on day 3. CONCLUSION: These impairments in performance highlight that coaches should plan conditioning programmes based on repeated sprint and repeated jump ability, and monitor the recovery of their players' strength, sprint and jump capacities following specific sessions. PMID- 22525648 TI - Hyperoxia does not accelerate quadriceps muscle deoxygenation kinetics at the onset of heavy exercise cycle. AB - AIM: The aim of this study was to determine whether an increase in O2 availability induces an alteration of the balance between O2 consumption ((V)O2) and O2 delivery ((Q)O2) at the muscle level. For that, we examined the effect of moderate hyperoxia on muscle deoxygenation kinetics at the onset of heavy intensity cycling exercise. METHODS: Eight young male adults performed step transitions from 35 W to heavy-intensity exercise corresponding to a power output half-way between the first ventilatory threshold and (V)O2max in normoxia and in hyperoxia (FIO2=0.30). Muscle deoxygenation (HHb) and total hemoglobin (Hbtot) were monitored continuously by near-infrared spectroscopy. HHb data were fit with a mono-exponential model from the onset of exercise up to 90 seconds. RESULTS: Hyperoxia neither altered the delay before the increase in HHb (normoxia: 10.7+/ 1.8 s vs. hyperoxia: 9.5+/-1.9 s; NS) nor the HHb mean response time (normoxia: 20.6+/-2.8 s vs. hyperoxia: 19.6+/-2.3 s; NS). Likewise, Hbtot was not different between normoxia and hyperoxia. CONCLUSION: These results indicate that moderate hyperoxia has no effect on muscle deoxygenation kinetics at the onset of heavy exercise. It suggests that muscle (V)O2 increases at the same rate than O2 delivery when O2 availability is enhanced. PMID- 22525649 TI - Preliminary baropodometric analysis of young soccer players while walking: geometric morphometrics and comparative evaluation. AB - AIM: The plantar support and its modifications are widely studied because of their bearing on posture. In particular, past studies have focused on the support modification during specific athletic tasks to highlight the eventual correlations between foot type and the most frequent sport injuries, due to intrinsic and extrinsic components that involve the structural and functional dynamics that act on the plantar vault during static and dynamic condition. These studies have been conducted by analyzing the morphological variation of the footprint during the performance. METHODS: In the present study the variation in shape of the baropodometrical footprint of young soccer players, has been analyzed using geometric morphometrics. This approach permits a quantification of the morphological variation of the subjects using Cartesian coordinates placed at specific points on the footprint outline, and to correlate them with physical variables. RESULTS: In the present study the young soccer players displayed a narrowing of the footprint due to a transversal variation on the isthmus, when compared to children of the same age who did not play soccer. These results suggest a physiological and biomechanical organization of the foot type in soccer due to the specific athletic tasks involved. CONCLUSION: As the foot type, in sport, is strictly associated to recurrent injuries, the result obtained in this study should be considered as indicative for future analysis. In fact, a clear and univocal knowledge of this phenomenon would be useful in the planning of a training protocol to reduce the incidence of sport related injuries. PMID- 22525650 TI - Effect of various ratios of carbohydrate-protein supplementation on resistance exercise-induced muscle damage. AB - AIM: Previous studies have indicated that exercise-induced muscle damage might be attenuated by coingestion of protein and carbohydrate supplement. The purpose of this study was to compare the effect of three various ratios of carbohydrate protein (CHO+PRO) supplements on resistance exercise-induced muscle damage indices. METHODS: Twenty-eight untrained male students voluntarily participated in this study and were randomly assigned to one of the four groups: 1) CHO+PRO 2:1 ratio, N.=7; 2) CHO+PRO 3:1 ratio, N.=8; 3) CHO+PRO 4:1 ratio, N.=7; 4) placebo group, N.=6. They performed a single bout of resistance exercise (whole body: 3 set*8-10 reps with 70-75% 1RM), with eccentric concentration. Every group consumed prepared CHO/PRO beverages (9% concentration, 10 mL/kg/bw-1 at different ratios) or the same amount of placebo beverage before and in 15 min intervals during exercise. Blood samples were taken before the exercise bout and also at 1 and 24 h post-exercise. In addition, muscle soreness scores were recorded before and 1, 24, and 48 h postexercise. Repeated measures ANOVA (between-within design) and Bonferroni post hoc test were used to analyze dependent measures (alpha=0.05). RESULTS: Serum creatine kinase (CK) and myoglobin (Mb) increased in all groups compared with pre-exercise but the significant difference among groups was observed in 24 h postexercise, in a way that both CK and Mb levels were higher in placebo group. Muscle soreness increased for all groups from pre to postexercise, but there was not any significant difference among groups at any time point. CONCLUSION: Findings of this study showed that CHO+PRO decreased serum CK and Mb at 24 h post exercise, but did not affect muscle soreness at any time points after exercise. Moreover, there were no significant differences between various ratios of CHO-PRO supplementation. PMID- 22525651 TI - Effect of local cold application on glycogen recovery. AB - The purpose of this study was to investigate the effect of local cold application on muscle glycogen re-synthesis after exercise. Recreationally active male subjects (n=11) completed a 90-minute glycogen depleting ride, followed by 4 h of recovery. During recovery, ice was applied intermittently to one leg (IL) while the subjects other leg (CL) acted as a control. Intramuscular and rectal temperature was recorded continuously. A carbohydrate (1.8 g?kg-1 bodyweight) beverage was supplied at 0 and 2 h post exercise. Muscle biopsies were taken immediately after exercise from the vastus lateralis and at 4 h post exercise for the analysis of muscle glycogen and muscle lactate. Leg circumference was measured 30, 60, 120, 180, and 240 minutes into recovery. The IL was colder than the CL from 15 minutes after initial ice application until the end recovery (P<0.05). Immediate post-exercise glycogen was similar between legs (55.3+/-7.4 vs. 56.1+/-7 mmol?kg-1 wet weight for the iced vs. control, respectively). However, muscle glycogen was lower in the IL compared to the CL at 4 h post exercise (72+/-8.4 vs. 95+/-8.4 mmol?kg-1 wet weight, respectively; P<0.05). Muscle lactate was lower in the IL after 4 h of recovery compared to the CL (1.6+/-.2 vs. 2.6+/-.2 mmol?L-1, respectively; P<0.05). There was no difference in circumference between IL and CL. These data demonstrate a reduction in muscle glycogen re-synthesis with local cold application. PMID- 22525652 TI - Creatine ingestion effects on oxidative stress in a steady-state test at 75% VO(2max). AB - AIM: The present study was carried out with the aim to analyze the role of creatine on oxidative stress during exercise, i.e. whether creatine is a pro oxidative or an antioxidant substance. METHODS: In a randomized double-blind study involving 30 adult males, we examined plasma lactate, oxidative stress markers (malondialdehyde, MDA) and glutathione redox ratio (GSSG.GSH-1), antioxidative systems (vitamins A, E, C), and ergospirometric responses (respiratory quotient and relative oxygen uptake) before and after 30 min steady state tests 75% VO2max (placebo and creatine). RESULTS: Ergospirometric tests, hematocrit values, blood lactate as well as vitamins A, E and C concentrations did not show significant differences between creatine and placebo testing. Conversely, oxidative stress markers MDA and GSSG.GSH-1 increased during placebo trials much more than in creatine trials. CONCLUSION: This is the first report documenting that a creatine loading, i.e., a 0.3 g/kg/die of creatine ingestion for 5 consecutive days, could reduce the oxidative stress, whereas its consumption may not have a clear metabolic advantage in certain aerobic activities. PMID- 22525653 TI - Effect of methylsulfonylmethane supplementation on exercise - Induced muscle damage and total antioxidant capacity. AB - AIM: The aim of this study was to evaluate effect of 10-day methylsulfonylmethane (MSM) supplementation on exercise-induced muscle damage. METHODS: Eighteen healthy, non-smoking, active young men were recruited to participate in this study. Participants were randomized in a double-blind placebo-controlled fashion into two groups: MSM (M) (N.=9) and placebo (P) (N.=9). Subjects consumed daily either placebo (200 mL water) or MSM supplement (50 mg/kg MSM in 200 mL water) for 10 days. Afterward, participants ran 14 km. Blood samples were taken before supplementation, before exercise, immediately, 30 min, 2, 24 and 48 h after exercise. RESULTS: CK and bilirubin significantly increased in P group 24 h after exercise compared to M group (P=0.041 and P=0.002, respectively). TAC increased immediately post, 30 min, 2 and 24 h after exercise just in M group (P<0.05). TAC showed significant increase in M group 2 and 24 h after exercise compared to P group (P=0.014 and P=0.033, respectively). CONCLUSION: It seems that 10-day supplementation with MSM has allowed to decrease muscle damage via effect on antioxidant capacity. PMID- 22525654 TI - Subacute blood pressure behavior in elderly hypertensive women after resistance exercise session. AB - AIM: The objective of this study was to determine the subacute blood pressure behavior of pharmacologically-treated elderly hypertensive patients after a session of resistance exercise. This was a controlled clinical trial carried out on 30 elderly hypertensive women. The study procedures took place over three days with an interval of 48 hours, and included a test session, an experimental protocol (EP) and a control protocol (CP). METHODS: A 10RM test was carried out to define the EP load for the following exercises: leg press, knee extension, pull-up, biceps curl and machine bench press. In the EP, three sets of exercises with 8 to 10 repetitions were carried out at 2-minute intervals. In the CP all procedures were the same as in the EP, but without the exercises. BP was measured before, immediately after and every ten minutes up to 60 minutes after the EP and CP. RESULTS: There was no significant variation in systolic blood pressure (SBP) or diastolic blood pressure (DBP) in either the EP or the CP immediately after the exercises. In the period up to sixty minutes after the exercises, there was a significant difference in BP, with a decrease in SBP and DBP for both EP and CP. CONCLUSION: The data from the present study offer a good indication that resistance exercises may be prescribed safely to this group of patients. The pressure reduction appears to be influenced by the rest that occurred after the protocols and not by exercise. PMID- 22525655 TI - Physical fitness measures among children and adolescents: are they all necessary? AB - AIM: The aim of this paper was to investigate the relationship among health and skill-related physical fitness variables, and with anthropometric measures in a sample of children and adolescents. METHODS: A cross-sectional study was conducted with 526 Brazilian students aged 7-15 years. Physical fitness abilities/skills were assessed through a battery of eight tests: sit-and-reach, standing long jump, 1-minute curl-up, modified pull-up, medicine-ball throw, 9 minute run, 20-meter run and 4 meter shuttle-run. Anthropometric measures considered were weight, height, body mass index (BMI) and wingspan. Analyses included descriptive statistics, Pearson correlations, multiple linear regression and principal component analysis. RESULTS: Anthropometric measures were directly associated between each other. Weight and BMI were negatively associated with the performance in all physical tests requiring propulsion or lifting of the body mass. Direct associations between tests persisted after adjustments for sex, age, type of school and geographic region of school. CONCLUSION: Results from the principal component analysis evidenced that all physical abilities/motor skills, except flexibility, are strongly associated with each other, suggesting that one test can reflect the overall fitness among youth. Although it is unclear from these analyses which test would be the single choice indicator, previous work on the health impact of cardiorespiratory fitness would suggest that. PMID- 22525656 TI - Variation of the different attributes that support the physical function in community-dwelling older adults. AB - AIM: This study investigated the variation with age of different attributes that support the physical functioning in community-dwelling older adults having as reference scores from young adults. METHODS: The study was a cross-sectional study. Participants were 559 older adults and 79 young adults grouped according to gender and age (Y:20-29, A:60-64, B:65-69, C:70-74, D:75-79 and E:>= 80 years). Strength, flexibility, agility, aerobic endurance, and balance were evaluated by Fullerton tests. RESULTS: ANOVA and Bonferroni post-hoc tests showed that compared to young, the 60-64 years group showed decreased values in almost all attributes of physical function. In older adults, additional differences were observed in females mainly between the 60-64 years group and the 70-74 years, 75 79 years, and:>= 80 years groups, and in males between the 60-64 years group and the >= 80 years group (P<0.05). Comparisons between standardized physical function attributes (T-scores) done by repeated measures and contrasts demonstrated that, across age groups, agility and dynamic balance showed the highest rate loss in both genders, and lower body flexibility showed the lowest (P<0.01). CONCLUSION: Physical function reduction seems to occur earlier in women than in men and abilities involving multiple structures such as balance, agility, and aerobic endurance showed the most loss. PMID- 22525657 TI - Osteoprotegerin, RANK and RANKL are not modified by acute exercise in elite rugby players. AB - AIM: The OPG-RANK-RANKL system is a new family of bone metabolism biomarkers belonging to the immune system. In this study, were evaluated these biomarkers in professional rugby players after a single-bout of training session. METHODS: The study has been performed on 30 professional male rugby players during a training camp of the Italian National Team, in July, before the start of the competitive season. Blood drawings were performed before and after training in the same day. Levels of soluble OPG, RANKL RANK in serum specimens were measured by commercially available according to the manufacturers' protocols. RESULTS: All the bone markers examined displayed no significative changes after training session. CONCLUSION: Short exercise is insufficient for modifying serum concentrations of these osteoimmunologic markers, as previously indicated for commonly used bone metabolism markers. Future studies will be conducted over an entire competition season in order to define a common profile of bone markers in rugby players. PMID- 22525658 TI - Apoptotic and inflammatory cytokine protein expression in intestinal lymphocytes after acute treadmill exercise in young and old mice. AB - AIM: Gastrointestinal disturbances are common in athletes following intense exercise. Variations in apoptotic protein expression and cell death may contribute to acute exercise-induced intestinal inflammation. The effect of age on apoptotic protein response in the intestinal compartment in response to exercise is not known. Using a mouse model, we examined the effects of a single bout of treadmill running in young and old mice on intestinal lymphocyte (IL) expression of the apoptosis-inducing cytokine TNF-alpha, the pro-apoptotic proteins caspase-3 and 7, the anti-apoptotic protein Bcl-2, and IL apoptotic status (% AnnexinV+). METHODS: Young (3-4 months, N.=44) and old (13-14 months, N.=45) female C57Bl/6 mice were randomized to treadmill exercise (10 min warm-up, 20 min at 22 m min-1, 30 min at 25 m min-1, 30 min at 28 m min-1, 2o slope) with sacrifice immediately (IMM) or 2hr after (2Hr), or to a non-exercised control (SED). IL were removed and prepared for analysis of % apoptosis (flow cytometry) and determination of apoptotic protein and cytokine expression (Western blotting). Plasma corticosterone and 8-iso-PGF2alpha were measured by EIA. RESULTS: Exercise was associated with a higher IL expression of caspase-3 in IMM and 2Hr groups vs. SED (P<0.001), a higher expression of TNF-alpha in the IMM group vs. SED (P<0.001), and a lower Bcl-2 expression in the IMM and 2Hr groups vs. SED (P<0.01). There was a trend (P=0.07) for increased caspase-7 expression after exercise. IL caspase-3 and 7 and TNF-alpha expression did not differ by age whereas Bcl-2 expression was lower (P<0.001) and % Annexin V+ IL was higher (P<0.05) in old vs. young mice. Plasma corticosterone and 8-iso-PGF2alpha were higher (P<0.001 and P<0.05) in IMM vs. SED mice but did not differ by age. CONCLUSION: The expression of the pro-apoptotic proteins, caspase-3 and caspase 7, and the apoptosis-inducing cytokine, TNF-alpha, in IL did not differ by age in this animal model in response to a single intense exercise challenge. However, Old mice had lower expression of the 'protective' anti-apoptotic protein Bcl-2 and a higher percentage of early apoptotic IL. Whether repeated exercise results in less IL resiliency in elderly individuals remains to be determined. PMID- 22525659 TI - Effect of long-term physical exercise of peripheral nerve: comparison of nerve conduction study and ultrasonography. AB - AIM: The aim of this study was to assess the effects of long-term physical exercise on peripheral nerve using both nerve conduction study (NCS) and ultrasonography (US). METHODS: The authors measured nerve conduction study and ultrasonography in 15 male (mean, 20+/-1.5 years) handball players and 13 male (mean, 21.3+/-1.9 years) control subjects. Cross-sectional area of the median nerve was evaluated using ultrasonography at the carpal tunnel and 6 cm proximal to the wrist, and the ulnar nerve at 6 cm proximal to the wrist crease, 2 cm proximal to the medial epicondyle, the epicondyle, and 2 cm distal to epicondyle. RESULTS: US shows significantly increased cross-sectional area of both median and ulnar nerve in the players compared with that in the controls, and the latency times in both nerves were significantly delayed in the players compared with that in the controls. Cross-sectional area of the median nerve showed a significant correlation with latency (r=0.330, P<0.01). CONCLUSION: This study suggests that the players have a tendency toward having both median and ulnar motor nerve damage in the wrist or elbow region although they are asymptomatic. PMID- 22525660 TI - Acute ghrelin administration reverses depressive-like behavior induced by bilateral olfactory bulbectomy in mice. AB - This study aims to examine the antidepressant-like action of Ghrelin (Ghr), a hormone synthesized predominantly by gastrointestinal endocrine cells and released during periods of negative energy balance, in two behavioral models: tail suspension test (TST), a predictive model of antidepressant activity, and the olfactory bulbectomy (OB), an established animal model of depression. The reduction in the immobility time in the TST was the parameter used to assess antidepressant-like effect of Ghr. The depressive-like behavior in olfactory bulbectomized mice was inferred through the increase in the immobility time in the TST and the hyperlocomotor activity in the open-field test. Ghr produced antidepressant-like effect in TST (0.3 nmol/MUl, i.c.v.), and reversed OB-induced depressive-like behavior. In conclusion, these results provide clear evidence that an acute administration of ghrelin produce antidepressant-like effect in the TST and OB. PMID- 22525661 TI - Analysis of variance: variably complex. PMID- 22525662 TI - The neuroscience-systems biology disconnect: towards the NeuroPhysiome. PMID- 22525663 TI - The knack of resisting increases in intravascular pressure: the potential role for epithelial Na(+) channel protein subunits in arterial myogenic reactivity. PMID- 22525664 TI - Ataxia telangiectasia mutated kinase in the heart: currency for myocyte apoptosis. PMID- 22525665 TI - Sympathovagal balance from heart rate variability: an obituary. PMID- 22525666 TI - Humic substance-mediated Fe(III) reduction by a fermenting Bacillus strain from the alkaline gut of a humus-feeding scarab beetle larva. AB - Humus-feeding macroinvertebrates play an important role in the transformation of soil organic matter. Their diet contains significant amounts of redox-active components such as iron minerals and humic substances. In soil-feeding termites, acid-soluble Fe(III) and humic acids are almost completely reduced during gut passage. Here, we show that the reduction of Fe(III) and humic acids takes place also in the alkaline guts of scarab beetle larvae. Sterilized gut homogenates of Pachnoda ephippiata no longer converted Fe(III) to Fe(II), indicating an essential role of the gut microbiota in the process. From Fe(III)-reducing enrichment cultures inoculated with highly diluted gut homogenates, we isolated several facultatively anaerobic, alkali-tolerant bacteria that were closely related to metal-reducing isolates in the Bacillus thioparans group. Strain PeC11 showed a remarkable capacity for dissimilatory Fe(III) reduction, both at pH 7 and 10. Rates were strongly stimulated by the addition of the redox mediator 2,6 antraquinone disulfonate and by redox-active components in the fulvic-acid fraction of humus. Although the contribution of strain PeC11 to intestinal Fe(III) reduction in P. ephippiata remains to be further elucidated, our results corroborate the hypothesis that the lack of oxygen and the solubilization of humic substances in the extremely alkaline guts of humivorous soil fauna provide favorable conditions for the efficient reduction of Fe(III) and humic substances by a primarily fermentative microbiota. PMID- 22525667 TI - A comparative assessment of survival between propensity score-matched patients with peritoneal dialysis and hemodialysis in Taiwan. AB - Studies comparing mortality for Asian populations with end-stage renal disease (ESRD) on hemodialysis (HD) and peritoneal dialysis (PD) are limited. We compared mortality between patients treated with PD and HD in Taiwan, the population with the highest incidence of ESRD worldwide. Using the population-based insurance claims data of Taiwan from 1997 to 2006, we identified 4721 patients treated with PD and randomly selected 4721 patients treated with HD who were frequency-matched to the PD patients based on their propensity scores. In follow-up analyses we measured mortalities and hazard ratios associated with comorbidities in 2 different 5-year cohorts (1997-2001 and 2002-2006).In the 10-year period from 1997 to 2006, the overall mortality rates were similar in patients treated with PD and in patients treated with HD (12.0 vs. 11.7 per 100 person-years, respectively), with a PD-to-HD hazard ratio of 1.02 (95% confidence interval [CI], 0.96-1.08). In the first 5-year period (1997-2001), the hazard ratio for mortality was higher for PD (1.33; 95% CI, 1.21-1.46), but there was no difference between PD and HD in the 2002-2006 cohort. Of note, younger patients who received PD had better survival than younger patients who received HD; this was especially true for patients aged younger than 40 years.In summary, in this Asian population, no significant survival differences were noted between propensity score-matched PD and HD patients. The selection of a dialysis modality must be tailored to the individual patient. Studies in which patients who are appropriate for either modality are randomly assigned to HD or PD may provide helpful information to clinicians and patients. PMID- 22525669 TI - Accuracy of self-reported physical activity as an indicator of cardiovascular fitness depends on education level. AB - OBJECTIVE: To determine whether there is a relationship between the level of education and the accuracy of self-reported physical activity as a proxy measure of aerobic fitness. DESIGN: Data from the National Health and Nutrition Examination from the years 1999 to 2004 were used. Linear regression was performed for measured maximum oxygen consumption (Vo(2)max) versus self-reported physical activity for 5 different levels of education. SETTING: This was a national survey in the United States. PARTICIPANTS: Participants included adults from the general U.S. population (N=3290). INTERVENTIONS: None. MAIN OUTCOME MEASURE: Coefficients of determination obtained from models for each education level were used to compare how well self-reported physical activity represents cardiovascular fitness. These coefficients were the main outcome measure. RESULTS: Coefficients of determination for Vo(2)max versus reported physical activity increased as the level of education increased. CONCLUSIONS: In this preliminary study, self-reported physical activity is a better proxy measure for aerobic fitness in highly educated individuals than in poorly educated individuals. PMID- 22525670 TI - Long-term outcomes in fibromyalgia patients treated with noninvasive cortical electrostimulation. AB - OBJECTIVE: To evaluate long-term outcomes of a noninvasive cortical stimulation technology in the treatment of fibromyalgia (FM). DESIGN: After trial follow-up survey of subjects who had completed a randomized, controlled, double-blind study of noninvasive cortical stimulation therapy some 45 months previously. SETTING: General community. PARTICIPANTS: Patients with FM (N=69) who participated in the previous study, 39 of whom were mailed surveys. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Changes in the Fibromyalgia Impact Questionnaire. RESULTS: There was a 64% survey return rate. The total Fibromyalgia Impact Questionnaire score was 52.6 at baseline, 35.7 at end of study, and 31.8 at follow-up (P<.001). Subjects reported symptom improvements lasting at least 2 years, with a reduction or elimination of medicine use and need to see physicians for FM. CONCLUSIONS: A high percentage of patients with FM treated with noninvasive cortical stimulation continued to experience worthwhile improvement at follow-up. PMID- 22525668 TI - Women's cardiovascular health: perspectives from South-East Asia. AB - Cardiovascular disease (CVD) is an under-recognized major health problem among women in South-East Asia. The prevalence of cardiovascular risk factors such as hypertension, diabetes mellitus, dyslipidemia, physical inactivity, and being overweight or obese has shown a significantly increasing trend among women in the region, with the exception of Singapore. The problem is compounded by low awareness that CVD is a health problem for women as well as for men, by misconceptions about the disease, and by the lack of suitable, locally available health literature. Efforts have been made by the national heart associations and other organizations to increase heart health awareness and promote healthy lifestyles. Singapore initiated these prevention programs in the early 1990s and has been successful in reducing the prevalence of cardiovascular risk factors. The governments of the region, in accordance with the Noncommunicable Disease Alliance, have begun implementing appropriate preventive strategies and improving health-delivery systems. However, psychological, social, and cultural barriers to cardiovascular health awareness in women need to be addressed before these programs can be fully and successfully implemented. PMID- 22525671 TI - Valproic acid enhances anti-tumor effect of mesenchymal stem cell mediated HSV-TK gene therapy in intracranial glioma. AB - Suicide gene therapy of glioma based on herpes simplex virus type I thymidine kinase (HSV-TK) and prodrug ganciclovir (GCV) suffers from the lack of efficacy in clinical trials, which is mostly due to low transduction efficacy and absence of bystander effect in tumor cells. Recently, stem cells as cellular delivery vehicles of prodrug converting gene has emerged as a new treatment strategy for malignant glioma. In this study, we evaluated the anti-glioma effect of suicide gene therapy using human bone marrow mesenchymal stem cells expressing HSV-TK (MSCs-TK) combined with valproic acid (VPA), which can upregulate the gap junction proteins and may enhance the bystander effect of suicide gene therapy. Expression of HSV-TK in MSCs was confirmed by RT-PCR analysis and the sensitivity of MSCs-TK to GCV was assessed. A bystander effect was observed in co-cultures of MSCs-TK and U87 glioma cells by GCV in a dose-dependent manner. VPA induced the expression of the gap junction proteins connexin (Cx) 43 and 26 in glioma cell and thereby enhanced the bystander effect in co-culture experiment. The enhanced bystander effect was inhibited by the gap junction inhibitor 18-beta glycyrrhetinic acid (18-GA). Moreover, the combined treatment with VPA and MSCs TK synergistically enhanced apoptosis in glioma cells by caspase activation. In vivo efficacy experiments showed that combination treatment of MSCs-TK and VPA significantly inhibited tumor growth and prolonged the survival of glioma-bearing mice compared with single-treatment groups. In addition, TUNEL staining also demonstrated a significant increase in the number of apoptotic cells in the combination treated group compared with single-treatment groups. Taken together, these results provide the rational for designing novel experimental protocols to increase bystander killing effect against intracranial gliomas using MSCs-TK and VPA. PMID- 22525672 TI - Feed-back regulation of disabled-2 (Dab2) p96 isoform for GATA-4 during differentiation of F9 cells. AB - F9 embryonic carcinoma (EC) cells undergo extra-embryonic endodermal (ExE) differentiation in response to retinoic acid (RA) treatment, which induces the expression of two isoforms (p96 and p67) of the adaptor protein, Disabled-2 (Dab2). In the current study, constitutive and ectopic expression of the p96 isoform induced ExE differentiation in F9 EC cells in the absence of RA treatment via the activation of GATA-4 by p96. During the RA-induced differentiation process, Dab2 expression is induced by the GATA factors in a coherent feed forward loop; on the other hand, we showed that p96 regulates GATA-4 in a positive feed-back manner in this study. Our results indicate that p96 Dab2 plays a key role in the ExE differentiation process. PMID- 22525674 TI - pH-dependence of the specific binding of Cu(II) and Zn(II) ions to the amyloid beta peptide. AB - Metal ions like Cu(II) and Zn(II) are accumulated in Alzheimer's disease amyloid plaques. The amyloid-beta (Abeta) peptide involved in the disease interacts with these metal ions at neutral pH via ligands provided by the N-terminal histidines and the N-terminus. The present study uses high-resolution NMR spectroscopy to monitor the residue-specific interactions of Cu(II) and Zn(II) with (15)N- and (13)C,(15)N-labeled Abeta(1-40) peptides at varying pH levels. At pH 7.4 both ions bind to the specific ligands, competing with one another. At pH 5.5 Cu(II) retains its specific histidine ligands, while Zn(II) seems to lack residue specific interactions. The low pH mimics acidosis which is linked to inflammatory processes in vivo. The results suggest that the cell toxic effects of redox active Cu(II) binding to Abeta may be reversed by the protective activity of non redox active Zn(II) binding to the same major binding site under non-acidic conditions. Under acidic conditions, the protective effect of Zn(II) may be decreased or changed, since Zn(II) is less able to compete with Cu(II) for the specific binding site on the Abeta peptide under these conditions. PMID- 22525673 TI - Antiangiogenic properties of cafestol, a coffee diterpene, in human umbilical vein endothelial cells. AB - As angiogenesis plays important roles in tumor growth and metastasis, searching for antiangiogenic compounds is a promising tactic for treating cancers. Cafestol, a diterpene found mainly in unfiltered coffee, provides benefit through varied biological activity, including antitumorigenic, antioxidative, and anti inflammatory effects. This study aimed to investigate the effects of cafestol on angiogenesis and to uncover the associated mechanism. We show that cafestol inhibits angiogenesis of human umbilical vascular endothelial cells. This inhibition affects the following specific steps of the angiogenic process: proliferation, migration, and tube formation. The inhibitory effects of cafestol are accompanied by decreasing phosphorylation of FAK and Akt and by a decrease in nitric oxide production. Overall, cafestol inhibits angiogenesis by affecting the angiogenic signaling pathway. PMID- 22525675 TI - Rab21 attenuates EGF-mediated MAPK signaling through enhancing EGFR internalization and degradation. AB - Epidermal growth factor (EGF) receptor (EGFR) signal transduction is regulated by endocytosis where many Rab proteins play an important role in the determination of the receptor recycle or degradation. In an effort to better understand how EGF signaling is regulated, we examined the role of Rab21 in regulation of the degradation and signal transduction of the EGFR. Using a transient expression protocol in HEK293T and HeLa cells, we found that Rab21 enhanced the degradation of EGFR through accelerating its internalization in both EGF-independent and EGF dependent manners. We further demonstrated that Rab21 interacted with EGFR by immunoprecipitation experiments. Interestingly, we observed that overexpression of Rab21 attenuated EGF-mediated mitogen-activated protein kinase (MAPK) signaling by inducing EGFR degradation. Taken together, these data suggest that Rab21 plays a negative role in the EGF-mediated MAPK signaling pathway. PMID- 22525676 TI - Conversion of 3-oxo steroids into ecdysteroids triggers molting and expression of 20E-inducible genes in Drosophila melanogaster. AB - Ecdysteroids, steroid hormones in insects, coordinate major developmental transitions. During postembryonic development, ecdysone is biosynthesized from dietary cholesterol in the prothoracic gland (PG). Despite extensive studies, the initial conversion process, the so-called "Black Box", has not been characterized. A cytochrome P450 enzyme, Spookier (Spok), is speculated as a rate limiting enzyme in the Black Box during larval-pupal transitions in Drosophila melanogaster. RNAi mediated knockdown of spok expression in the PG results in arrest of molting. Because the developmental arrest can be rescued by application of an appropriate intermediate, we examined potential activities of candidate intermediates in the RNAi-treated larvae. We found that two 3-oxo steroids, cholesta-4,7-diene-3,6-dione-14alpha-ol (Delta(4)-diketol) and 5beta [H]cholesta 7-ene-3,6-dione-14alpha-ol (diketol), triggered molting of the RNAi-treated larvae. We also detected an enhancement of the amounts of ecdysteroids in the RNAi-treated larvae by feeding the Delta(4)-diketol or diketol, indicating that the dietary 3-oxo steroids were incorporated and converted into ecdysteroids in vivo. Furthermore, 20-hydroxyecdysone inducible genes were induced in the RNAi treated larvae by feeding the Delta(4)-diketol or diketol. These results indicate that Delta(4)-diketol and diketol are components of the ecdysteroid biosynthetic pathway and lie downstream of a step catalyzed by Spok. PMID- 22525677 TI - The chemical chaperone 4-phenylbutyric acid attenuates pressure-overload cardiac hypertrophy by alleviating endoplasmic reticulum stress. AB - Evidence has shown that endoplasmic reticulum stress (ERS) is associated with the pathogenesis of cardiac hypertrophy. The aim of this study was to investigate whether direct alleviation of ER stress by 4-phenylbutyric acid (PBA), a known chemical chaperone drug, could attenuate pressure-overload cardiac hypertrophy in mice. The effects of orally administered PBA (100mg/kg body weight daily for a week) were examined using mice undergoing transverse aortic constriction (TAC mice), an animal model to produce pressure overload. TAC application for 1 week led to a 1.8-fold increase in the ratio of the heart weight over body weight (HW/BW) and up-regulation of the hypertrophy markers ANF and BNF accompanied by up-regulation of ERS markers (GRP78, p-PERK, and p-elF2alpha). The oral administration of PBA to the TAC-mice reduced hypertrophy (19%) and severely downregulated the fibrosis-related genes (transforming growth factor-beta1, phospho-smad2, and pro-collagen isoforms). We conclude that ERS is induced as a consequence of remodeling during pathological hypertrophy and that PBA may help to relieve ERS and play a protective role against cardiac hypertrophy and possibly heart failure. We suggest PBA as a novel therapeutic agent for cardiac hypertrophy and fibrosis. PMID- 22525678 TI - Metformin-induced AMP-activated protein kinase activation regulates phenylephrine mediated contraction of rat aorta. AB - The aim of the present study is to determine the effects and molecular mechanisms by which activation of LKB1-AMP-activated protein kinase (AMPK) by metformin regulates vascular smooth muscle contraction. The essential ability of vascular smooth muscle cells (VSMCs) to contract and relax in response to an elevation and reduction in intravascular pressure is necessary for appropriate blood flow regulation. Thus, vessel contraction is a critical mechanism for systemic blood flow regulation. In cultured rat VSMCs, AMPK activation through LKB1 by metformin inhibited phenylephrine-mediated myosin light chain kinase (MLCK) and myosin light chain phosphorylation (p-MLC). Conversely, inhibition of AMPK and LKB1 reversed phenylephrine-induced MLCK and p-MLC phosphorylation. Measurement of the tension trace in rat aortic rings also showed that the effect of AMPK activation by metformin decreased phenylephrine-induced contraction. Metformin inhibited PE induced p-MLC and alpha-smooth muscle actin co-localization. Our results suggest that activation of AMPK by LKB1 decreases VSMC contraction by inhibiting MLCK and p-MLC, indicating that induction by the AMPK-LKB1 pathway may be a new therapeutic target to lower high blood pressure. PMID- 22525679 TI - GABA induction of the Saccharomyces cerevisiae UGA4 gene depends on the quality of the carbon source: role of the key transcription factors acting in this process. AB - Yeast cells are able to adapt their metabolism according to the quality of both carbon and nitrogen sources available in the environment. Saccharomyces cerevisiae UGA4 gene encodes a permease capable of transporting gamma aminobutyric acid (GABA) into the cells. Yeast uses this amino acid as a nitrogen source or as a carbon skeleton that enters the tricarboxylic acid cycle. The quality of the carbon source modulates UGA4 expression through two parallel pathways, each one acting on different regulatory elements, the UAS(GATA) and the UAS(GABA). In the presence of a fermentable carbon source, UGA4 expression is induced by GABA while in the presence of a non-fermentable carbon source this expression is GABA-independent. The aim of this work was to study the mechanisms responsible for the differences in the profiles of UGA4 expression in both growth conditions. We found that although the subcellular localization of Gln3 depends on the carbon source and UGA4 expression depends on Tor1 and Snf1, Gln3 localization does not depend on these kinases. We also found that the phosphorylation of Gln3 is mediated by two systems activated by a non-fermentable carbon source, involving the Snf1 kinase and an unidentified TORC1-regulated kinase. We also found that the activity of the main transcription factors responsible for UGA4 induction by GABA varies depending on the quality of the carbon source. In a fermentable carbon source such as glucose, the negative GATA factor Dal80 binds to UGA4 promoter; only after the addition of the inducer, the positive factors Uga3, Dal81 and Gln3 interact with the promoter removing Dal80 and leading to gene induction. In contrast, in the non-fermentable carbon source acetate the negative GATA factor remains bound to UGA4 promoter in the presence or absence of GABA, the positive factors are not detected bound in any of these conditions and in consequence, UGA4 is not induced. PMID- 22525680 TI - The syntheses of amphiphilic antimony(V)-phthalocyanines and spectral investigation on their aggregation behaviors in aqueous and non-aqueous solutions. AB - Three amphiphilic antimony(V)-phthalocyanines have been synthesized by treating [Sb(R(4)Pc)(OH)(2)](+) salts in concentrated H(2)SO(4) and isolated as zwitter ions, [Sb(R(4)Pc)(SO(4)H)(SO(4))], where R(4)Pc denotes tetra-substituted phthalocyaninate; R(4)Pc=pc (R=H), tbpc (R=(t)Bu), and tObpc (R=O(n)Bu). Their solubility (R=tbpc>pc >>tObpc in H(2)O (much improved by the presence of surfactant or alcohol) while tbpc>tObpc >>pc in CH(2)Cl(2)) and aggregation behaviors are highly sensitive to the nature of the peripheral substituents. The pc and tbpc derivatives form well-behaved J-aggregates in aqueous media in the presence of surfactant or alcohol. PMID- 22525681 TI - Catalases negatively regulate methyl jasmonate signaling in guard cells. AB - Methyl jasmonate (MeJA)-induced stomatal closure is accompanied by the accumulation of hydrogen peroxide (H2O2) in guard cells. In this study, we investigated the roles of catalases (CATs) in MeJA-induced stomatal closure using cat mutants cat2, cat3-1 and cat1 cat3, and the CAT inhibitor, 3-aminotriazole (AT). When assessed with 2',7'-dichlorodihydrofluorescein, the reduction of catalase activity by means of mutations and the inhibitor accumulated higher basal levels of H2O2 in guard cells whereas they did not affect stomatal aperture in the absence of MeJA. In contrast, the cat mutations and the treatment with AT potentiated MeJA-induced stomatal closure and MeJA-induced H2O2 production. These results indicate that CATs negatively regulate H2O2 accumulation in guard cells and suggest that inducible H2O2 production rather than constitutive elevation modulates stomatal apertures in Arabidopsis. PMID- 22525682 TI - Kavalactones and the endocannabinoid system: the plant-derived yangonin is a novel CB1 receptor ligand. AB - To investigate the possible interactions between kavalactone-based molecules and proteins of the endocannabinoid system and provide novel and synthetically accessible structural scaffolds for the design of cannabinoid receptor ligands sharing pharmacological properties with kavapyrones, a preliminary SAR analysis was performed on five commercially available natural kavalactones and nine kavalactone-analogues properly synthesized. These compounds were investigated for assessing their cannabinoid receptor binding affinity and capability of inhibiting the activity of the two major metabolic enzymes of the endocannabinoid system, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). Among the molecules tested, only yangonin exhibited affinity for the human recombinant CB1 receptor with a K(i)=0.72 MUM and selectivity vs. the CB2 receptor (K(i)>10 MUM). None of the compounds exhibited strong inhibitory effects on the two enzymes analyzed. The CB1 receptor affinity of yangonin suggests that the endocannabinoid system might contribute to the complex human psychopharmacology of the traditional kava drink and the anxiolytic preparations obtained from the kava plant. PMID- 22525683 TI - Creating rigidly stabilized fractures for assessing intramembranous ossification, distraction osteogenesis, or healing of critical sized defects. AB - Assessing modes of skeletal repair is essential for developing therapies to be used clinically to treat fractures. Mechanical stability plays a large role in healing of bone injuries. In the worst-case scenario mechanical instability can lead to delayed or non-union in humans. However, motion can also stimulate the healing process. In fractures that have motion cartilage forms to stabilize the fracture bone ends, and this cartilage is gradually replaced by bone through recapitulation of the developmental process of endochondral ossification. In contrast, if a bone fracture is rigidly stabilized bone forms directly via intramembranous ossification. Clinically, both endochondral and intramembranous ossification occur simultaneously. To effectively replicate this process investigators insert a pin into the medullary canal of the fractured bone as described by Bonnarens. This experimental method provides excellent lateral stability while allowing rotational instability to persist. However, our understanding of the mechanisms that regulate these two distinct processes can also be enhanced by experimentally isolating each of these processes. We have developed a stabilization protocol that provides rotational and lateral stabilization. In this model, intramembranous ossification is the only mode of healing that is observed, and healing parameters can be compared among different strains of genetically modified mice, after application of bioactive molecules, after altering physiological parameters of healing, after modifying the amount or time of stabilization, after distraction osteogenesis, after creation of a non union, or after creation of a critical sized defect. Here, we illustrate how to apply the modified Ilizarov fixators for studying tibial fracture healing and distraction osteogenesis in mice. PMID- 22525684 TI - Plasma xenin concentrations in children. AB - INTRODUCTION: Xenin is a newly discovered peptide in humans. The concentration of xenin in human plasma increases after meals and therefore this peptide is considered as a marker of satiety. The mechanism of xenin action in humans has not been thoroughly examined. MEDLINE database contains only few reports about the role of xenin in adults and none of them were performed in children. AIM OF THE STUDY: The aim of the study was to evaluate the concentration of xenin in children with energy balance disorders. MATERIAL AND METHODS: Plasma xenin concentration was measured in children with inflammatory bowel syndrome (IBD) (n=53; age 14+/-3 years) before, during and after treatment, obese children (n=26; age 14+/-2.8 years) during the OGGT test and in healthy children (n=10; age 15.7+/-2.2 years). Xenin was determined in the plasma using the radioimmunological method. RESULTS: The mean plasma xenin concentration in the healthy children was 371+/-36 pg/ml. In the children with an acute phase of IBD the mean concentration of xenin was 367+/-96 pg/ml and an increase during the treatment to the mean value 399+/-55 pg/ml was noted. The highest mean value of xenin concentration (412+/-55 pg/ml) was found during early remission. In obese children, the mean concentration of xenin (198+/-69 pg/ml) was significantly lower as compared to children with IBD and to control (p<0.001 in both cases). The glucose load did not have any effect on xenin concentration in obese children. CONCLUSIONS: Xenin takes part in the regulation of energy balance in children. PMID- 22525685 TI - [TNF-alpha and soluble receptor TNF-alpha type 1 in children with diabetes mellitus type 1]. AB - INTRODUCTION: TNF-alpha, and its soluble form sTNFR1, as proinflammatory hormone plays a great role in pathogenesis of auto immunological diseases, insulin resistance, both carbohydrates and fat metabolism and development of late complications in type 1 diabetes mellitus (DMT1) patients. AIM OF THE STUDY: To asses TNF-alpha and sTNFR1 levels in children with DMT1 and to analyze the correlation with anthropometric parameters, metabolic control and the influence of the kind of insulin therapy. MATERIAL AND METHODS: 67 patients, aged from 3.71 to 14.81 years (mean+/-SD: 10.33+/-2.21). All the children were prepubertal (T ?2), suffering for DMT1, without any coexisting diseases. The duration of the disease varied from 1.83 to 9 years (mean+/-SD: 4,0+/-1,6), and the age at diagnosis oscillated between 1.84 to 10.81 years. All the patients were divided into subgroups according to the kind of therapy which was not changed in the last 6 months. 15 agematched healthy children were included into the study. There were no statistically significant differences between the groups as to the metabolic control, age, weight, height and BMI. RESULTS: TNF-alpha levels in the study group ranged from 0.30 to 14.20 ng/ml (mean+/-1.62 +/- 0.41 pg/ml) and were lower than in the control group: from 0.20 to 19.00 pg/ml (mean+/-SD: 1.67+/-1.41 pg/ml) (p >0.05). The highest TNF-alpha levels were observed in the insulin pump group, lower in the multiple insulin injection group and in the conventional insulin therapy group. The sTNFR1 in the study group ranged from 707.00 to 1646.00 pg/ml (mean+/-SD: 1028.18+/-181.24 pg/ml) and was higher than in the control group: 613.0 to 1310.00 pg/ml (mean+/-SD: 978.00+/-203.03 pg/ml) (p >0.05). The highest sTNFR1 levels were observed in the insulin pump group, lower in the multiple insulin injection group and the lowest in the conventional insulin therapy group. CONCLUSIONS: TNF-alpha levels are lower in DMT1 children, correlate only with height and do not depend on the kind of insulin therapy. sTNFR1 levels are higher in children with DMT1, correlate with anthropometric parameters and do not depend on the kind of insulin therapy. PMID- 22525686 TI - [Evaluation of respiratory function tests in children and adolescents with type 1 diabetes]. AB - INTRODUCTION: Changes in the respiratory system are little known, tardive complications of diabetes. The mechanisms which lead to dysfunctions of the respiratory system in patients with diabetes might be: microangiopathy of pulmonary vessels, changes of alveoli's structure, vegetative neuropathy of the respiratory system, changes of bronchi's reactivity and dysfunctions of the mobility of the thorax. AIM OF THE STUDY: Evaluation of spirometry parameters in children and adolescents with type 1 diabetes mellitus and in the control group. Assessment of influence of metabolic control and duration of type 1 diabetes on chosen spirometric parameters among the patients from the study group. MATERIAL AND METHODS: Thirty five patients with type 1 diabetes mellitus and thirty eight healthy subjects underwent spirometry. Forced expiratory volume in the 1st second (FEV1), forced expiratory vital capacity (FVC EX), vital capacity (VC), peak expiratory flow (PEF), FEV1 to FVC EX ratio were compared with normal values and expressed as a percentage of normal in both groups. Kruskal-Wallis test and variant analysis were used to study differences in a few groups, while Mann Whitney test or t-Student's test were used to study differences in two groups. RESULTS: No statistical difference between vital capacity VC [%] in the study compared to the control group was found. In the study group, the FEV1 to FVC EX ratio was significantly higher than in the control group (p=0.00094). In the study group, peak expiratory flow PEF [%] was significantly lower than in the control group (p=0.01091). No statistical difference between FEV1 [%], FVC EX [%] in the study and control group was found. In the group of patients with HbA1c >7% vital capacity VC [%] was statistically lower (p=0.03729) compared to the control group. The FEV1 [%] values were in the normal range (>80% predicted values) for 34 patients. In one child from the study group the FEV1 [%] was under normal range. Values of FVC EX [%] were in the normal range (>80% predicted values) in 34 patients. Only in one child from the study group FVC EX [%] was under normal range. The FEV1 to FVC EX ratio was in the normal range (>70% predicted values) in 35 patients. The vital capacity value VC [%] was in the normal range (>80% predicted values) in 33 patients and in two of them VC [%] was under normal range. CONCLUSIONS: No relation was found between the duration of type 1 diabetes, HbA1c percentage and chosen spirometric parameters among the patients from the study group. Poor metabolic control accounts for reduction of vital capacity among the diabetic patients. PMID- 22525687 TI - [Estimation of influence of congenital-adrenal hyperplasia treatment on bone mineralisation evaluated with densitometry]. AB - INTRODUCTION: Doses of glucocorticoids used when treating congenital adrenal hyperplasia (CAH) are larger than physiological secretion of hydrocortisone in healthy people. Optimal dosage should provide metabolic control and should not cause complications of steroid therapy. AIM OF THE STUDY: 1. Evaluation of the influence of CAH treatment on bone mineralisation established with densitometry. 2. Evaluation of steroid profiles usage, in estimation of bone mineralisation disorders risk in patients with CAH. MATERIAL AND METHODS: A total number of 28 patients with CAH, aged 2.7-27 years and receiving treatment with glucocorticoids was examined. Therapeutic coefficient and steroidal coefficient which relate to doses of hydrocortisone used were established using urine steroid profiling, which was effectuated by gas chromatography/mass spectrometry (GC/MS). Additionally dual energy x-ray absorptiometry (DXA) of the lumbar spine (L1-L4) was conducted, where bone mineral density (BMD) was established in g/cm(2), and interpreted as Z-score. RESULTS: BMD presented in Z-score, evaluated in correlation to bone age was significantly lower (p <0.01) than BMD presented in Z score in correlation to chronological age. It was proved that greater hormonal treatment efficacy (lower steroidal coefficient or greater therapeutic coefficient) correlates with greater bone mineralisation deficits in relation to chronological age. CONCLUSIONS: 1. Greater efficiency of hormonal treatment links with larger bone mineralisation deficits in relation to CAH patients' chronological age. 2. Evaluation of steroid profiles, as one of the estimation methods for metabolic control of the disease, described by steroidal coefficient and therapeutic coefficient, allows for practical application of the above mentioned in prediction of bone mineralisation risk in patients with CAH. PMID- 22525688 TI - The physique and body composition of students studying physical education: a preliminary report. AB - INTRODUCTION: Young people who study physical education are a priori regarded as having proper body structure and body composition. This assumption cannot be confirmed in the subject literature. AIM OF THE STUDY: To determine the basic auxological parameters in youth who study physical education. MATERIAL AND METHODS: 235 first-year students studying physical education were examined: 32% women (n=74) and 68% men (n=161). The students' body height, weight, waist, and hip circumference were measured. Body composition (bioimpedance method), specifying the body fat percentage (FM%) and fat free mass (FFM%) was also assessed. RESULTS: The mean normalized height of the female body was 0.48+/-1.07 SDS, and for the male body 0.51+/-1.04 SDS. The mean normalized weight for women was 0.4+/-0.94 SDS, and for men it was 0.83+/-0.9 SDS. The mean fat percentage in the body composition of women and men was, respectively, 21.5+/-5.06, ranging from 10.16% to 35.06%, and 12.5+/-3.97, ranging from 4.36% to 22.28%. In one third of the women, the percentage of fat in the body composition was higher than 25%. CONCLUSIONS: 1. Young people who choose to study physical education and physical culture are characterized by greater height and greater body weight than the general population, regardless of gender. 2. Short persons study physical education less often than tall individuals. 3. The greater body weight observed in the majority of students studying physical education, in comparison to that of the general population, was caused by a dominant percentage of lean body mass in body composition; unexpectedly, however, some women were observed to have relatively high fat content. 4. Use of the body mass index and waist-hip ratio was not a sufficiently sensitive screening examination to detect fatness in physically active young adults; therefore, it should not substitute for the determination of fat content in body composition. PMID- 22525689 TI - [Fat content in young adults determined by skinfolds and body composition analyzator]. AB - INTRODUCTION: Body composition analysis is essential in assessing the nutritional status, as well as the risk of developing diseases associated with abnormal body fat content. At present, many methods are available to measure the amount and distribution of body fat. Among them, of particular importance are those methods that are simple, do not require expensive equipment and allow the assessment of the body composition of a large number of people (population study). However, previous observations show that they provide different results, and, therefore, further analysis and comparisons should be conducted in different age, sex and body composition groups. AIM OF THE STUDY: The goal was to compare the anthropometric and bioelectrical impedance analysis (BIA) methods used to assess body composition in young women and men. MATERIAL AND METHODS: 65 women and 109 men, physical education students, took part in the study. Average chronological age of the women was 20.5+/-3.1 years and men 19.9+/-1.4 years. Body weight, height and thickness of 4 skinfolds (SF; over the biceps, triceps, subscapular, suprailiac) were measured. The percentage of body fat in the anthropometric method was calculated using the Durnin and Womersley's equation. Assessment of body composition was also made by the BIA method. All the measurements in every person were made on the same day. RESULTS: The mean BMI was 21.4+/-1.9 in women and 23.9+/-2.4 in men. The mean percentage of body fat obtained by anthropometric method was 16.7+/-7.1% in women and 10.2+/-6.6% in men. The amount of body fat estimated by the BIA method was higher than that calculated by skinfold thickness among female students by about 5% (p <0.001), while for male students by 3% (p <0.001). The correlation coefficients between the anthropometric method and BIA method for women and men were 0.448 (p <0.05) and 0.380 (p <0.05), respectively. CONCLUSIONS: The anthropometric and BIA methods provide different results of body fat content, especially in women, so they should not be used interchangeably. PMID- 22525690 TI - Megaloblastic anaemia in infancy or early childhood and diabetes as leading symptoms of the TRMA syndrome. AB - Diabetes mellitus may occur in children and adolescents as an independent disease, most frequently as autoimmune type 1 diabetes, or can coexist with other abnormalities. If diabetes coincides with other disorders occurring sequentially, a syndromic form of monogenic diabetes should be suspected. Thiamine-responsive megaloblastic anaemia (TRMA) syndrome is an example of a rare form of monogenic diabetes coexisting with anaemia and deafness. In the paper, we discuss clinical features and treatment of TRMA syndrome - a unique syndromic form of vitamin dependent monogenic diabetes. The review might be useful in establishing a prompt diagnosis and initiating optimal management in children and adolescents with the disease. PMID- 22525691 TI - Nonketotic hyperosmolar syndrome as an acute complication of type 1 diabetes onset in a 20-month-old boy with congenital central nervous system defect. AB - Hyperglycemic hyperosmolar syndrome (HHS) is one of the most severe acute complications of type 2 diabetes, but may also be developed in type 1 diabetes. Similar to ketoacidosis,HHS still remains one of the major causes of morbidity and mortality in patients with diabetes,despite a significant progress in understanding its pathogenesis and greater consensus on HHS diagnosis and treatment. It is mainly observed in elderly patients with type 2 diabetes. However,it may also occur in children,especially in infants and those with concomitant central nervous system (CNS) defects or suffering from severe infections associated with dehydration. The authors report a case of HHS in a 20 month-old child with central nervous system abnormality. Symptoms observed in our patient are characteristic for HHS. It must be emphasized that HHS may accompany diabetes onset also in children. PMID- 22525692 TI - [Glucokinase gene mutation as a causative factor of permanent neonatal diabetes mellitus]. AB - INTRODUCTION: The most frequent type of diabetes in childhood is type 1 diabetes. Thanks to the development of genetic testing, the rare monogenic forms of that disease have been defined. One of them is neonatal diabetes identified within the first 6 months of life and often associated with the mutation in KCNJ11, ABCC8 or insulin gene. A less frequent mutation in the glucokinase gene can cause both permanent neonatal diabetes as well as mild diabetes MODY 2. CASE REPORT: A 33 day-old boy admitted to hospital because of hyperglycemia from the first day of life. Treatment with intravenous infusion of insulin since 5 days of life. A child born out of the first pregnancy in the 37th week of gestation, with hypotrophy symptoms. The pregnancy had been complicated by gestational diabetes. Birth weight 2030 g. Insulin and c-peptide level significantly below normal. Immunologic markers of type 1 diabetes were negative. A continuous subcutaneous insulin infusion using a personal insulin pump was begun in the 60th day of life. Irregularities in the economy of carbohydrates were found in the parents. A double mutation in the glucokinase gene in genetic testing explained the cause of neonatal diabetes. The boy had inherited from his parents two different mutations in glucokinase gene: from the mother S384L and from the father T207M. He is a complex heterozygote. CONCLUSIONS: Genetic diagnosis helped determine the cause of neonatal diabetes in the child and MODY 2 diabetes in the parents. Personal insulin pump therapy is the most effective treatment in children during infancy. PMID- 22525693 TI - Severe Pasteurella multocida infection after a dog bite. PMID- 22525694 TI - Prostatitis or prostatic abscess. PMID- 22525695 TI - Bedside ultrasound for hip dislocations. AB - BACKGROUND: Bedside ultrasound in the emergency department is being used with increasing frequency and for an increasing scope of conditions. OBJECTIVES: Demonstrate the use of bedside ultrasound as an adjunct for diagnosis of hip dislocation. CASE REPORT: A traumatic anterior hip dislocation was diagnosed with bedside ultrasound after an initial normal plain radiograph. CONCLUSION: Although the current standard of care for diagnosis of hip dislocation is plain radiographs, this case demonstrates that bedside ultrasound may be used as a diagnostic adjunct in this time-sensitive and potentially catastrophic diagnosis. PMID- 22525696 TI - Uncommon clavicle fracture that could be easily overlooked. PMID- 22525697 TI - Pseudocholinesterase levels are not decreased in grayanotoxin (mad honey) poisoning in most patients. AB - BACKGROUND: The symptoms of mad honey poisoning resemble those of cholinergic toxidromes; however, it is not clear whether they share a common biochemical basis. OBJECTIVES: The aim of this study was to investigate a possible resemblance between mad honey poisoning and cholinergic toxidromes. METHODS: This is a descriptive study performed prospectively in patients presenting to a University Medical Faculty Emergency Medicine Department emergency service with mad honey poisoning over 1 year, from September 2008 to September 2009. Adult patients with clinical findings suggesting mad honey poisoning (i.e., bradycardia, hypotension, syncope, and vertigo) and with a history of honey consumption were enrolled. Pseudocholinesterase levels in blood samples taken from the mad honey-poisoned patients were analyzed to determine whether these were lower than normal pseudocholinesterase levels for adults (5400-13,200 U/L). RESULTS: The most common symptoms of the 30 patients enrolled in the study were vertigo and nausea. Low blood pressure and bradycardia were the most frequently observed physical examination findings. None of the patients enrolled had a history of disease that might cause low pseudocholinesterase. Mean pseudocholinesterase levels in our patients with mad honey poisoning were 7139.30 +/- 2316.41 U/L (min-max: 1785-12,835). Blood pseudocholinesterase levels were within normal limits in 90% of patients and below normal in 10%. CONCLUSION: A low pseudocholinesterase level was found in 3 (10%) of our 30 patients. These biochemical data do not support the hypothesis that mad honey poisoning should be regarded as cholinergic poisoning. PMID- 22525698 TI - Emergency physicians' and nurses' attitudes towards alcohol-intoxicated patients. AB - BACKGROUND: Emergency physicians and nurses are frequently dissatisfied professionally when treating alcohol-intoxicated patients, and have negative attitudes towards this patient population and alcohol rehabilitation. STUDY OBJECTIVES: The goal of this study is to examine differences in attitudes between emergency physicians and nurses towards alcohol-intoxicated patients. METHODS: This single-site survey study evaluated emergency physicians' and nurses': 1) attitudes of personal professional satisfaction and dissatisfaction when caring for intoxicated patients; 2) attitudes towards the difficulty in caring for alcohol-intoxicated patients; 3) attitudes towards respect of the alcohol intoxicated patient; 4) attitudes towards the adequacy of training in caring for intoxicated patients; 5) attitudes towards rehabilitation and counseling of alcohol-intoxicated patients. RESULTS: Physicians were less satisfied and more dissatisfied than nurses when caring for alcohol-intoxicated patients. Physicians found treating alcohol-intoxicated patients more difficult than nurses did. Physicians were more likely to agree that alcohol-intoxicated patients should be treated with respect. Physicians felt more adequately trained than nurses in caring for alcohol-intoxicated patients. Nurses were more likely to believe that alcohol-related rehabilitation is ineffective compared with physicians. Both nurses and physicians refer alcohol-intoxicated patients to rehabilitation to a similar extent. CONCLUSIONS: Emergency physicians and nurses have similar attitudes but significant differences in the extent of these attitudes towards the care of the alcohol-intoxicated patient. PMID- 22525699 TI - Emergency ultrasound diagnosis of ovarian hyperstimulation syndrome: case report. AB - BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) is an exaggerated response to ovulation induction therapy. It is a known complication of ovarian stimulation in patients undergoing treatment for infertility. As assisted reproductive technology and the use of ovulation induction agents expands, it is likely that there will be more cases of OHSS presenting to the Emergency Department (ED). OBJECTIVES: OHSS has a broad spectrum of clinical manifestations, from mild abdominal pain to severe cases where there is increased vascular permeability leading to significant fluid accumulation in body cavities and interstitial space. Severe cases may present to the ED with ascites, pericardial effusions, pleural effusions, and lower extremity edema. Through a case report, we review OHSS with an emphasis on early diagnosis by Emergency Physician (EP)-performed bedside ultrasonography. CASE REPORT: We present a case of a patient undergoing treatment for infertility who presented to the ED with shortness of breath and abdominal pain. The diagnosis of severe OHSS was made, largely based on EP performed bedside ultrasonography showing peritoneal free fluid and bilateral pleural effusions, as well as multiple ovarian follicles. CONCLUSIONS: This report reviews the pathophysiology of OHSS, its clinical features, and pertinent diagnostic and management issues. This report emphasizes the importance of early EP-performed bedside ultrasonography. PMID- 22525700 TI - Neuroplastic changes in depression: a role for the immune system. AB - Accumulating evidence suggests that there is a rich cross-talk between the neuroimmune system and neuroplasticity mechanisms under both physiological conditions and pathophysiological conditions in depression. Anti-neuroplastic changes which occur in depression include a decrease in proliferation of neural stem cells (NSCs), decreased survival of neuroblasts and immature neurons, impaired neurocircuitry (cortical-striatal-limbic circuits), reduced levels of neurotrophins, reduced spine density and dendritic retraction. Since both humoral and cellular immune factors have been implicated in neuroplastic processes, in this review we present a model suggesting that neuroplastic processes in depression are mediated through various neuroimmune mechanisms. The review puts forward a model in that both humoral and cellular neuroimmune factors are involved with impairing neuroplasticity under pathophysiological conditions such as depression. Specifically, neuroimmune factors including interleukin (IL)-1, IL 6, tumour necrosis factor (TNF)-alpha, CD4+CD25+T regulatory cells (T reg), self specific CD4+T cells, monocyte-derived macrophages, microglia and astrocytes are shown to be vital to processes of neuroplasticity such as long-term potentiation (LTP), NSC survival, synaptic branching, neurotrophin regulation and neurogenesis. In rodent models of depression, IL-1, IL-6 and TNF are associated with reduced hippocampal neurogenesis; mechanisms which are associated with this include the stress-activated protein kinase (SAPK)/Janus Kinase (JNK) pathway, hypoxia-inducible factors (HIF)-1alpha, JAK-Signal Transducer and Activator of Transcription (STAT) pathway, mitogen-activated protein kinase (MAPK)/cAMP responsive element binding protein (CREB) pathway, Ras-MAPK, PI-3 kinase, IKK/nuclear factor (NF)-kappaB and TGFbeta activated kinase-1 (TAK-1). Neuroimmunological mechanisms have an active role in the neuroplastic changes associated with depression. Since therapies in depression, including antidepressants (AD), omega-3 polyunsaturated fatty acids (PUFAs) and physical activity exert neuroplasticity-enhancing effects potentially mediated by neuroimmune mechanisms, the immune system might serve as a promising target for interventions in depression. PMID- 22525701 TI - Mice expressing activated PI3K rapidly develop advanced colon cancer. AB - Aberrations in the phosphoinositide 3-kinase (PI3K) signaling pathway play a key role in the pathogenesis of numerous cancers by altering cellular growth, metabolism, proliferation, and apoptosis. Mutations in the catalytic domain of PI3K that generate a dominantly active kinase are commonly found in human colorectal cancers and have been thought to drive tumor progression but not initiation. However, the effects of constitutively activated PI3K upon the intestinal mucosa have not been previously studied in animal models. Here, we show that the expression of a dominantly active form of the PI3K protein in the mouse intestine results in hyperplasia and advanced neoplasia. Mice expressing constitutively active PI3K in the epithelial cells of the distal small bowel and colon rapidly developed invasive adenocarcinomas in the colon that spread into the mesentery and adjacent organs. The histologic characteristics of these tumors were strikingly similar to invasive mucinous colon cancers in humans. Interestingly, these tumors formed without a benign polypoid intermediary, consistent with the lack of aberrant WNT signaling observed. Together, our findings indicate a noncanonical mechanism of colon tumor initiation that is mediated through activation of PI3K. This unique model has the potential to further our understanding of human disease and facilitate the development of therapeutics through pharmacologic screening and biomarker identification. PMID- 22525703 TI - Long-lived genotypes for studies of life extension in Drosophila melanogaster. AB - Numerous single-gene mutations obtained by insertion of P elements in white (w) genetic backgrounds have been reported to extend the life span of Drosophila melanogaster, but life extension is sometimes observed only in relatively short lived backgrounds. The objective of this study was to develop long- and short lived, high and low fertility backgrounds in which to test the reproducibility and possible additivity of effects of prospective life-extending treatments. Flies previously reported to be long- or short-lived, following artificial selection for early or delayed reproduction and inbreeding, were rendered essentially isogenic, and a w visible marker was introduced. Isogeny adversely affected both life span and fertility, but w had little or no effect on either trait. Unexpectedly, none of these lines or a stock under uninterrupted selection for delayed reproduction lived any longer than an unselected, highly fertile y w strain used in earlier studies of longevity. Strains derived from one artificial selection experiment were found to contain functional P elements, as did the two longest-lived genotypes in this study, which were inbred without artificial selection. The y w background appears to be at least equally as long-lived as any other currently available for tests of life extension by P{w(+)} mutations. PMID- 22525702 TI - Mcl-1 Phosphorylation defines ABT-737 resistance that can be overcome by increased NOXA expression in leukemic B cells. AB - ABT-737 is a small molecule Bcl-2 homology (BH)-3 domain mimetic that binds to the Bcl-2 family proteins Bcl-2 and Bcl-xL and is currently under investigation in the clinic. In this study, we investigated potential mechanisms of resistance to ABT-737 in leukemia cell lines. Compared with parental cells, cells that have developed acquired resistance to ABT-737 showed increased expression of Mcl-1 in addition to posttranslational modifications that facilitated both Mcl-1 stabilization and its interaction with the BH3-only protein Bim. To sensitize resistant cells, Mcl-1 was targeted by two pan-Bcl-2 family inhibitors, obatoclax and gossypol. Although gossypol was effective only in resistant cells, obatoclax induced cell death in both parental and ABT-737-resistant cells. NOXA levels were increased substantially by treatment with gossypol and its expression was critical for the gossypol response. Mechanistically, the newly generated NOXA interacted with Mcl-1 and displaced Bim from the Mcl-1/Bim complex, freeing Bim to trigger the mitochondrial apoptotic pathway. Together, our findings indicate that NOXA and Mcl-1 are critical determinants for gossypol-mediated cell death in ABT-737-resistant cells. These data therefore reveal novel insight into mechanisms of acquired resistance to ABT-737. PMID- 22525704 TI - A complex dietary supplement modulates nitrative stress in normal mice and in a new mouse model of nitrative stress and cognitive aging. AB - We examined whether transgenic growth hormone mice (Tg) that exhibit accelerated cognitive aging and exceptional free radical damage also express elevated nitrative stress. We characterized age-related patterns of 3-nitrotyrosine (3-NT) in brain homogenate and mitochondria of Tg and normal (Nr) mice as modulated by a complex anti-aging dietary supplement. Levels of 3-NT rose rapidly with age in Tg brain homogenate whereas normal controls maintained constant lower levels. The age-related slope for 3-NT was 3.6-fold steeper in untreated Tg compared to treated Tg (p<0.009), although treated Tg showed elevation in youth. Opposite to Tg, treated Nr mice had reduced 3-NT in youth (p<0.02). The age-related pattern of mitochondrial 3-NT in Nr mice was parabolic (p<0.005). Remarkably, levels in treated Nr were reduced by ~50% (p<0.0007). Untreated Tg showed strongly increasing mitochondrial 3-NT with higher mitochondrial activity (p<0.01) whereas treated Tg showed lower nitrosylation at higher levels of mitochondrial activity. Tg mice also expressed a postural abnormality that is a biomarker of neurodegeneration and/or nitrative stress. Tg represent a promising new model of nitrative stress associated with brain deterioration and results provide proof of principle that complex dietary supplements may be ameliorating. PMID- 22525705 TI - Positive effects of computer-based cognitive training in adults with mild cognitive impairment. AB - Considering the high risk for individuals with amnestic Mild Cognitive Impairment (A-MCI) to progress towards Alzheimer's disease (AD), we investigated the efficacy of a non-pharmacological intervention, that is, cognitive training that could reduce cognitive difficulties and delay the cognitive decline. For this, we evaluated the efficacy of a 12-week computer-based memory-attention training program based on recognition in subjects with A-MCI and compared their performances with those of A-MCI controls trained in cognitively stimulating activities. The effect of training was assessed by comparing outcome measures in pre- and post-tests 15 days before and after training. To evaluate the duration of training benefits, a follow-up test session was performed 6 months after memory and attention training or cognitively stimulating activities. Outcome measures showed that the trained group, compared to control group, improved episodic recall and recognition. Six months after training, scores remained at the level of the post-test. Since the training program was exclusively based on recognition, our results showed a generalization from recognition to recall processes, which are memory components that represent part of the core cognitive impairments in individuals at risk of converting to AD. Thus, cognitive training based on recognition holds promise as a preventive therapeutic method and could be proposed as a non-pharmacological early-intervention strategy. Future investigations need to focus on methodological constraints and delineating possible neuroplastic mechanisms of action. PMID- 22525706 TI - The burden of pain with menopause. PMID- 22525707 TI - The combined effects of menopause and dietary glucosamine on the development of insulin resistance. PMID- 22525708 TI - Exercise as much as you can: solid advice for postmenopausal women. PMID- 22525709 TI - Adjuvant treatment of GIST: patient selection and treatment strategies. AB - Tyrosine kinase inhibitors that target the key molecular drivers of gastrointestinal stromal tumour (GIST) are effective treatments of advanced-stage GIST. Yet, most of these patients succumb to the disease. Approximately 60% of patients with GIST are cured by surgery, and these individuals can be identified by risk stratification schemes based on tumour size, mitosis count and site, and assessment of rupture. Two large randomized trials have evaluated imatinib as adjuvant treatment for operable, KIT-positive GIST; adjuvant imatinib substantially improved time to recurrence. One of these trials reported that 3 years of adjuvant imatinib improves overall survival of patients who have a high estimated risk for recurrence of GIST compared with 1 year of imatinib. The optimal adjuvant strategy remains unknown and some patients might benefit from longer than 3 years of imatinib treatment. However, a strategy that involves GIST risk assessment following surgery using a validated scheme, administration of adjuvant imatinib for 3 years, patient monitoring during and after completion of imatinib to detect recurrence early, and reinstitution of imatinib if GIST recurs is a reasonable choice for care of patients with high-risk GIST. PMID- 22525713 TI - Genetics: Polyglutamine repeats or cancer? PMID- 22525715 TI - Incentive and selection effects of Medigap insurance on inpatient care. AB - The Medicare program, which provides insurance coverage to the elderly in the United States, does not protect them fully against high out-of-pocket costs. For this reason private supplementary insurance, named Medigap, has been available to cover Medicare gaps. This paper studies how Medigap affects the utilization of inpatient care, separating the incentive and selection effects of supplementary insurance. For this purpose, we use two alternative estimation methods: a standard recursive bivariate probit and a discrete multivariate finite mixture model. We find that estimated incentive effects are modest and quite similar across models. There seems to be very significant selection, with the presence of both adversely and advantageously selected individuals, stemming from the multidimensional nature of residual heterogeneity. PMID- 22525716 TI - Regulation and competition in the Taiwanese pharmaceutical market under national health insurance. AB - This article investigates the determinants of the prices of pharmaceuticals and their impact on the demand for prescription drugs in the context of Taiwan's pharmaceutical market where medical providers earn profit directly from prescribing and dispensing drugs. Based on product-level data, we find evidence that the profit-seeking behavior of the medical providers in the prescription drug market transfers the force of competition from the unregulated wholesale market to the regulated retail market and hence market competition still plays an important role in the determination of the regulated price. We also find that the profit-seeking behavior plays a similar role to advertising in that it increases the brand loyalty and hence lowers price elasticity. An important implication of our study is that the institutional features in the pharmaceutical market matter in shaping the nature of pharmaceutical competition and the responsiveness of pharmaceutical consumption with respect to changes in price. PMID- 22525710 TI - Overcoming disappointing results with antiangiogenic therapy by targeting hypoxia. AB - Cancer cells rely on angiogenesis to fulfil their need for oxygen and nutrients; hence, agents targeting angiogenic pathways and mediators have been investigated as potential cancer drugs. Although this strategy has demonstrated delayed tumour progression--leading to progression-free survival and overall survival benefits compared with standard therapy--in some patients, the results are more modest than predicted. A significant number of patients either do not respond to antiangiogenic agents or fairly rapidly develop resistance to them, which raises questions about how resistance develops and how it can be overcome. Furthermore, whether cancers, once they develop resistance, become more invasive or lead to metastatic disease remains unclear. Several mechanisms of resistance have been recently proposed and emerging evidence indicates that, under certain experimental conditions, antiangiogenic agents increase intratumour hypoxia by promoting vessel pruning and inhibiting neoangiogenesis. Indeed, several studies have highlighted the possibility that inhibitors of VEGF (and its receptors) can promote an invasive metastatic switch, in part by creating an increasingly hypoxic tumour microenvironment. As a potential remedy, a number of therapeutic approaches have been investigated that target the hypoxic tumour compartment to improve the clinical outcome of antiangiogenic therapy. PMID- 22525717 TI - Differences in NGFI-B, Nurr1, and NOR-1 expression and nucleocytoplasmic translocation in glutamate-treated neurons. AB - NGFI-B (NR4A1, Nur77 or TR3) together with Nurr1 (NR4A2) and NOR-1 (NR4A3) constitute the NR4A subgroup of orphan nuclear receptors. They play critical roles in proliferation, differentiation, survival and apoptosis in different cell types, including neurons, immature T-cells, and different cancer cells. As ligand independent and constitutively active receptors, the diverse biological activities of NGFI-B, Nurr1 and NOR-1 depend on their levels of expression, post translational modifications and subcellular localization. Nuclear localization of the NR4A proteins leads to transcriptional activity, whereas NGFI-B and recently also NOR-1 have been shown to induce apoptosis by a more direct mechanism when localized at mitochondria. In the present study we investigated mRNA expression and subcellular translocation of the NR4A proteins during glutamate excitotoxicity in rat cerebellar granule neurons. NGFI-B and Nurr1 mRNA, but not NOR-1 mRNA, were induced by treatments associated with calcium influx, although their regulation seemed to be different. NR4A(gfp) fusion proteins showed a predominant nuclear localization in untreated cells. After glutamate treatment NGFI-B(gfp) translocated to cytosol and mitochondria within a few hours, whereas Nurr1(gfp) translocation was delayed, and NOR-1(gfp) mainly stayed in the nucleus. Subcellular targeting of NGFI-B seems to be tightly regulated, as a single mutation of threonine 142 altered NGFI-B(gfp) localization. Differences in expression and subcellular translocation of NGFI-B, Nurr1, and NOR-1 may reflect different functions in neurons in glutamate excitotoxicity. PMID- 22525719 TI - Acute evaluation of pediatric patients with minor traumatic brain injury. AB - PURPOSE OF REVIEW: This review focuses on minor traumatic brain injury (TBI), evaluates the most recent literature regarding clinical prediction rules for the use of cranial computed tomography (CT) in children presenting with minor TBI, reviews the evidence on the need for hospitalization in children with minor TBI, and evaluates the role of S100B testing. RECENT FINDINGS: The majority of children presenting to an emergency department (ED) after TBI have a Glasgow Coma Scale (GCS) of 14-15, and the rate of clinically significant intracranial injury is exceedingly rare. Nevertheless, the number of cranial CTs performed in the US has increased dramatically over the past two decades. Several clinical prediction rules have been developed to aid the clinician in identifying children with low risk TBI, but only the Pediatric Emergency Care Applied Research Network (PECARN) rules have been sufficiently validated to warrant clinical application. Two recent studies provide evidence that children with low-risk TBI can be safely discharged from the ED and do not require prolonged hospitalization for neurologic observation. Lastly, studies evaluating the diagnostic utility of S100B in patients with TBI have shown that it may be a useful adjunct to the clinical evaluation and aid in minimizing neuroimaging. SUMMARY: Clinical prediction rules, most notably the PECARN rules, can be applied to determine children with low-risk TBI and help decrease unnecessary CT use and hospitalizations. S100B testing requires further investigation, but may serve as an adjunct in determining children with low-risk TBI. PMID- 22525720 TI - Current challenges in the diagnosis and management of fever. AB - PURPOSE OF REVIEW: We review recommendations from recent publications on the management of fever with antipyretics, the classification and diagnosis of fevers of unknown origin (FUO), and the evaluation of fever in infants under 90 days of age. RECENT FINDINGS: Anxiety about fever persists in the population, while the toxicity of antipyretics is an increasing concern. The numerous opportunities for overdosing with antipyretics have been emphasized by the American Academy of Pediatrics (AAP). The practice of alternating acetaminophen and ibuprofen has limited value. Nonclassic FUO and pseudo-FUO are as important to consider as true FUO, and clinicians should become familiar with the variety of periodic fever syndromes. The clinical utility of low-risk criteria to identify febrile infants at low risk for serious bacterial infection (SBI) was demonstrated in a systematic review of studies. SUMMARY: Pediatricians should spend more time educating parents about fever and antipyretic use. Not all persistent fever is FUO, and testing should be targeted to the child's clinical condition. Existing low-risk criteria should be used to identify febrile infants who can be managed without extensive work-up and antibiotics. Adherence to evidence-based recommendations will lessen the morbidity and mortality associated with febrile illnesses in children. PMID- 22525721 TI - Effects of passive ankle dorsiflexion stiffness on ankle mechanics during drop landings. AB - OBJECTIVES: Vertical landing tasks strain the Achilles tendon and plantar flexors, increasing acute and overuse strain injury risk. This study aimed to determine how passive ankle dorsiflexion stiffness affected ankle mechanics during single limb drop landings at different vertical descent velocities. DESIGN: Cross-sectional study. METHODS: Passive ankle dorsiflexion stiffness and passive weight-bearing dorsiflexion range of motion (DROM) were quantified for 42 men. Participants were then grouped as having low (LPS: 0.94+/-0.15 Nm degrees 1; n=16) or high (HPS: 2.05+/-0.36 Nm degrees -1; n=16; p<0.001) passive ankle dorsiflexion stiffness. Three-dimensional ankle joint kinematics was quantified while participants performed drop landings onto a force platform at two vertical descent velocities (slow: 2.25+/-0.16 ms-1; fast: 3.21+/-0.17 ms-1). RESULTS: Although affected by landing velocity, there were no significant effects of passive ankle dorsiflexion stiffness, nor any significant ankle dorsiflexion stiffness*vertical descent velocity interactions on any outcome variables characterising ankle mechanics during drop landings. Furthermore, there was no significant difference between the groups for passive weight-bearing DROM (LPS: 43.9+/-4.1 degrees ; HPS: 42.5+/-5.7 degrees ), indicating that the results were not confounded by between-group differences in ankle range of motion. CONCLUSIONS: Neither high nor low passive ankle dorsiflexion stiffness was found to influence ankle biomechanics during drop landings at different descent velocities. Landing strategies were moderated more by the demands of the task than by passive ankle dorsiflexion stiffness, indicating that passive ankle dorsiflexion stiffness may not affect plantar-flexor strain during a drop landing. PMID- 22525722 TI - The curative efficacy of namitecan (ST1968) in preclinical models of pediatric sarcoma is associated with antiangiogenic effects. AB - Namitecan (ST1968), a novel hydrophilic camptothecin analog of the 7 oxyiminomethyl series, was selected for clinical development on the basis of its promising preclinical efficacy. Since there is clinical evidence of efficacy of camptothecins against pediatric tumors, this study was performed to explore the antitumor and antiangiogenic activity of the camptothecin derivative in pediatric sarcoma models. With the exception of an undifferentiated rhabdomyosarcoma (A204), namitecan exhibited curative efficacy even at well-tolerated suboptimal doses in a panel of five models. The good therapeutic index of namitecan likely reflected a high and persistent drug accumulation at tumor site. The four responsive tumors were characterized by high topoisomerase I expression. In the RD/TE-671 rhabdomyosarcoma model the drug activity was associated with a marked antiangiogenic effect, which was consistent with the downregulation of proangiogenic factors, including VEGF, bFGF and the multifunctional chemokines CCL-2 and CXCL16. In agreement with this modulation, the combination of low doses of namitecan with other antiangiogenic agents, such as bevacizumab (a humanized anti-VEGF antibody) and sunitinib (a multitarget tyrosine kinase inhibitor effective against receptors implicated in the angiogenesis process), enhanced the antitumor effects. In conclusion, this preclinical study provides evidence of curative efficacy of namitecan at well-tolerated doses against pediatric sarcoma models, likely reflecting a contribution of antiangiogenic effects. Based on the promising therapeutic profile, namitecan is a good candidate for clinical evaluation in pediatric sarcomas. PMID- 22525723 TI - Role of chemokine receptor CXCR7 in bladder cancer progression. AB - Bladder cancer is one of the most common tumors of the genitourinary tract; however, the molecular events underlying growth and invasion of the tumor remain unclear. Here, role of the CXCR7 receptor in bladder cancer was further explored. CXCR7 protein expression was examined using high-density tissue microarrays. Expression of CXCR7 showed strong epithelial staining that correlated with bladder cancer progression. In vitro and in vivo studies in bladder cancer cell lines suggested that alterations in CXCR7 expression were associated with the activities of proliferation, apoptosis, migration, invasion, angiogenesis and tumor growth. Moreover, CXCR7 expression was able to regulate expression of the proangiogenic factors IL-8 or VEGF, which may involve in the regulation of tumor angiogenesis. Finally, we found that signaling by the CXCR7 in bladder cancer cells activates AKT, ERK and STAT3 pathways. The AKT and ERK pathways may reciprocally regulate, which are responsible for in vitro and in vivo epithelial to mesenchymal transition (EMT) process of bladder cancer. Simultaneously targeting the two pathways by using U0126 and LY294002 inhibitors or using CCX733, a selective CXCR7 antagonist drastically reduced CXCR7-induced EMT process. Taken together, our data show for the first time that CXCR7 plays a role in the development of bladder cancer. Targeting CXCR7 or its downstream-activated AKT and ERK pathways may prove beneficial to prevent metastasis and provide a more effective therapeutic strategy for bladder cancer. PMID- 22525724 TI - SBF-1, a synthetic steroidal glycoside, inhibits melanoma growth and metastasis through blocking interaction between PDK1 and AKT3. AB - In the present study, we demonstrate that SBF-1, a synthetic steroidal glycoside, has a strong antitumor activity against melanoma cells in vitro and in vivo. SBF 1 induced cell cycle arrest with a reduced expression of various cell cycle related proteins in B16BL6 melanoma cells without causing apoptosis. SBF-1 dramatically inhibited kinase activity of 3-phosphoinositide dependent protein kinase 1 (PDK1) and thus down-regulated phosphorylation of protein kinase B (AKT). Among three known isoforms of AKT, PDK1 only interacted with AKT3 in B16BL6 melanoma cells, and SBF-1 almost completely blocked this interaction. In addition, adhesion to fibronectin and expression of integrin alpha4 were significantly reduced in a concentration-dependent manner. Knockdown of AKT3 resulted in the decrease in integrin alpha4 expression and cell adhesion. Moreover, SBF-1 inhibited the growth of melanoma xenografts and down-regulated the phosphorylation of AKT in vivo. In a mouse model of spontaneous metastasis, SBF-1 at very low doses of 1 and 3 MUg/kg enormously inhibited melanoma metastasis into draining popliteal lymph nodes. Taken together, this study shows a small molecular compound SBF-1 with a very strong anti-melanoma activity both in vitro and in vivo. Its mechanism underlying such antitumor effect is related to the blockage of the interaction between PDK1 and AKT3. PMID- 22525725 TI - A simple method to protect the great saphenous vein and saphenous nerve in percutaneous plate fixation of distal tibial fractures. PMID- 22525726 TI - [Ocular ischemic syndrome with rubeosis iridis]. PMID- 22525728 TI - Adrenal gland: DNA methylation profiling--a new tool for adrenal tumour diagnosis? PMID- 22525729 TI - Diabetes: hyperfiltration-a risk factor for nephropathy in T1DM? PMID- 22525730 TI - The pituitary tumour epigenome: aberrations and prospects for targeted therapy. AB - Global and gene-specific changes in the epigenome are hallmarks of most tumour types, including those of pituitary origin. In contrast to genetic mutations, epigenetic changes (aberrant DNA methylation and histone modifications) are potentially reversible. Drugs that specifically target or inhibit DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) can be used to restore the expression of epigenetically silenced genes. These drugs can potentially increase the sensitivity of tumour cells to conventional treatment modalities, such as chemotherapy and radiotherapy. Drug-induced reversal of transcriptional silencing can also be used to restore dopamine-D(2)-receptor negative, hormone-refractory tumours to their previous receptor-positive, hormone responsive status. Synergy between HDAC and DNMT inhibitors makes these pharmacological agents more therapeutically effective when administered in combination than when used alone. Studies in pituitary tumour cell lines show that drug-induced re-expression of the epigenetically silenced dopamine D(2) receptor leads to an increase in apoptosis mediated by a receptor agonist. Collectively, the use of drugs to directly or indirectly reverse gene-specific epigenetic changes, in combination with conventional therapeutic interventions, has potential for the clinical management of multiple tumour types-including those of pituitary origin. Furthermore, these drugs can be used to identify epigenetically regulated genes that could be novel, tumour-specific therapeutic targets. PMID- 22525734 TI - Growth and development: Growth hormone replacement therapy and mortality. PMID- 22525735 TI - Reproductive endocrinology: less estrogen, more neuroinflammation? PMID- 22525731 TI - Nutritional deficiencies after bariatric surgery. AB - Lifestyle intervention programmes often produce insufficient weight loss and poor weight loss maintenance. As a result, an increasing number of patients with obesity and related comorbidities undergo bariatric surgery, which includes approaches such as the adjustable gastric band or the 'divided' Roux-en-Y gastric bypass (RYGB). This Review summarizes the current knowledge on nutrient deficiencies that can develop after bariatric surgery and highlights follow-up and treatment options for bariatric surgery patients who develop a micronutrient deficiency. The major macronutrient deficiency after bariatric surgery is protein malnutrition. Deficiencies in micronutrients, which include trace elements, essential minerals, and water-soluble and fat-soluble vitamins, are common before bariatric surgery and often persist postoperatively, despite universal recommendations on multivitamin and mineral supplements. Other disorders, including small intestinal bacterial overgrowth, can promote micronutrient deficiencies, especially in patients with diabetes mellitus. Recognition of the clinical presentations of micronutrient deficiencies is important, both to enable early intervention and to minimize long-term adverse effects. A major clinical concern is the relationship between vitamin D deficiency and the development of metabolic bone diseases, such as osteoporosis or osteomalacia; metabolic bone diseases may explain the increased risk of hip fracture in patients after RYGB. Further studies are required to determine the optimal levels of nutrient supplementation and whether postoperative laboratory monitoring effectively detects nutrient deficiencies. In the absence of such data, clinicians should inquire about and treat symptoms that suggest nutrient deficiencies. PMID- 22525736 TI - Parathyroid gland: Which surgery for MEN1 patients? PMID- 22525737 TI - Paired nanoinjection and electrophysiology assay to screen for bioactivity of compounds using the Drosophila melanogaster giant fiber system. AB - Screening compounds for in vivo activity can be used as a first step to identify candidates that may be developed into pharmacological agents. We developed a novel nanoinjection/electrophysiology assay that allows the detection of bioactive modulatory effects of compounds on the function of a neuronal circuit that mediates the escape response in Drosophila melanogaster. Our in vivo assay, which uses the Drosophila Giant Fiber System (GFS, Figure 1) allows screening of different types of compounds, such as small molecules or peptides, and requires only minimal quantities to elicit an effect. In addition, the Drosophila GFS offers a large variety of potential molecular targets on neurons or muscles. The Giant Fibers (GFs) synapse electrically (Gap Junctions) as well as chemically (cholinergic) onto a Peripheral Synapsing Interneuron (PSI) and the Tergo Trochanteral Muscle neuron (TTMn. The PSI to DLMn (Dorsal Longitudinal Muscle neuron) connection is dependent on Dalpha7 nicotinic acetylcholine receptors (nAChRs). Finally, the neuromuscular junctions (NMJ) of the TTMn and the DLMn with the jump (TTM) and flight muscles (DLM) are glutamatergic. Here, we demonstrate how to inject nanoliter quantities of a compound, while obtaining electrophysiological intracellular recordings from the Giant Fiber System and how to monitor the effects of the compound on the function of this circuit. We show specificity of the assay with methyllycaconitine citrate (MLA), a nAChR antagonist, which disrupts the PSI to DLMn connection but not the GF to TTMn connection or the function of the NMJ at the jump or flight muscles. Before beginning this video it is critical that you carefully watch and become familiar with the JoVE video titled "Electrophysiological Recordings from the Giant Fiber Pathway of D. melanogaster" from Augustin et al, as the video presented here is intended as an expansion to this existing technique. Here we use the electrophysiological recordings method and focus in detail only on the addition of the paired nanoinjections and monitoring technique. PMID- 22525738 TI - Simulations of induced visual scene fading with boundary offset and filling-in. AB - Blurred images can appear to fade to uniform brightness and color when viewed with some types of visual transient stimuli. Simons et al. (2006) identified the conditions where such scene fading occurs and noted that their findings were inconsistent with mechanisms that have been used to explain other fading effects. We show that their empirical findings are consistent with a neural model of visual perception that hypothesizes filling-in of brightness and color that is constrained by signals from a boundary contour system. Certain types of transients can weaken the boundary responses and thereby induce scene fading. The simulations explain how even small transient changes can produce scene fading effects across large parts of an image. PMID- 22525739 TI - Distribution of carbonaceous matter in lithofacies: impacts on HOC sorption nonlinearity. AB - Both the composition and distribution of the lithocomponents within an aquifer impact hydrophobic organic compound (HOC) transport. Using samples from the sandy, low fraction organic carbon content (f(oc)~0.02%) Borden aquifer, we demonstrate how HOC sorption is controlled by the carbonaceous matter (CM) associated with calcareous sedimentary lithocomponents. Two-point isotherms using perchloroethene (PCE) as a sorbate showed that medium-grained lithofacies have a broader range of K(f) (Freundlich coefficient), 1/n (Freundlich parameter) and f(oc) than fine-grained facies. Dual-mode (linear+Freundlich) sorption modeling, fraction inorganic carbon (f(ic)) and laboratory analyses confirm that both the magnitude and variability of PCE K(d) (sorption distribution coefficient) in the Borden aquifer are controlled by the presence of heterogeneous CM in dark and very dark carbonate lithocomponents. Laboratory analyses and model results confirmed that the CM type controlling PCE sorption behavior in the Borden aquifer is in a condensed form, likely kerogen, contained within the carbonate matrix of the grains. The dark carbonate grains comprise a small proportion of the aquifer sediment (?1%) and are found predominantly in medium-grained lithofacies in the Borden aquifer. These results show that increased heterogeneity, HOC mass storage and sorption nonlinearity associated with medium grained lithofacies impact HOC transport in historically contaminated sedimentary aquifers. PMID- 22525740 TI - Plasma poltergeists: a negative cortisol interference leading to a false diagnosis of adrenal insufficiency. AB - INTRODUCTION: Adrenal insufficiency is a rare life threatening condition with non specific clinical signs and symptoms. This necessitates a high level of reliance on laboratory results for making the diagnosis. METHODS: We report a case involving an interference in cortisol measurement leading to spuriously low cortisol measurements and the incorrect diagnosis and treatment of adrenal insufficiency. We also discuss the testing used to confirm the presence and nature of the interferent. RESULTS: Interference with an IgG antibody was demonstrated, and the patient was found to have a normally functioning adrenal axis. CONCLUSION: Interference in immunoassay is well described but often difficult to detect in clinical practice. Negative interference in cortisol measurement can occur and may lead to inappropriate diagnosis and treatment. PMID- 22525741 TI - Characterization of urinary bile acids in a pediatric BRIC-1 patient: effect of rifampicin treatment. AB - BACKGROUND: Benign recurrent intrahepatic cholestasis type 1 (BRIC-1), a rare autosomal recessive disorder characterized by recurrent episodes of jaundice and pruritus, is caused by mutations in the ATP8B1 gene. Rifampicin has been reported to be an effective treatment of jaundice and pruritus in patients with BRIC. Proposed mechanisms of effect for rifampicin include enhancement of multidrug resistance protein 2 expression, activation of the enzymes of uridine diphosphate glucuronosyltransferase 1A1 and cytochrome P450 3A4, and stimulation of 6alpha hydroxylation of bile acids. METHODS: To confirm the diagnosis of BRIC-1 and demonstrate the effect of rifampicin treatment on bile acid metabolism, we analyzed the patient's ATP8B1 gene and bile acids in urine. RESULTS: We detected 2 heterozygous mutations in the ATP8B1 gene, and increasing amounts of unusual bile acids such as 1beta-hydroxylated cholic acid, 2beta-hydroxylated cholic acid, 4beta-hydroxylated cholic acid, 6alpha-hydroxylated cholic acid, and hyocholic acid in urine during rifampicin treatment. CONCLUSIONS: We diagnosed a jaundiced pediatric patient with BRIC-1 caused by 2 novel mutations (1226delA/2210delA) in the ATP8B1 gene. Rifampicin was effective in treating cholestasis. Results of urinary bile acid analyses during rifampicin treatment in this patient, suggested that rifampicin might stimulate 1beta-, 2beta-, and 4beta hydroxylation of bile acids in addition to 6alpha-hydroxylation. PMID- 22525742 TI - Biologic variability of C-reactive protein: is the available information reliable? AB - BACKGROUND: C-reactive protein (CRP) is recognized as a marker of cardiovascular risk. The biologic variability of CRP is crucial to understanding its significance in estimation of individual risk and subsequent changes in serial analyses. METHODS: We systematically reviewed publications on biologic variation of CRP to evaluate the consistency of available data. Data was evaluated with attention to number and type of enrolled subjects, duration of study, frequency of sample collection, sample type, sample storage, analytical methodology, assay sensitivity and statistical analysis. RESULTS: A total of eleven studies on CRP biologic variability were recruited from literature. The majority of studies were limited by choice of analytic methodology, population selection, protocol application, and statistical analysis. Unfortunately, the only study that fulfilled all major pre-analytical, analytical and post-analytical requirements derived biologic variability from logarithmically transformed data, thus making application to clinical practice difficult. CONCLUSIONS: There is a paucity of robust data on biologic CRP variability in serum. It is obvious that additional well defined studies are needed to define reliable values of reference change values and of number of samples required to estimate the individual's cardiovascular risk by CRP. PMID- 22525745 TI - AMPA/kainate receptors in the ventromedial hypothalamus mediate the effects of glutamate on estrus termination in the rat. AB - Infusions of glutamate or its selective receptor agonists to the VMH of ovariectomized (OVX) female rats primed with estradiol benzoate (EB) and progesterone (P) inhibit both appetitive and consummatory aspects of sexual behavior whereas selective glutamate receptor antagonists facilitate these measures in females primed with EB alone. Because vaginocervical stimulation (VCS) activates glutamate neurons in the VMH, and induces a faster termination of estros behavior, the present study examined the effects of the AMPA/kainate receptor antagonist DNQX on the induction of estrus termination by manual VCS. Ovx, sexually-experienced rats were primed with EB and P and subsequently received either 1 or 50 distributed VCSs, over the course of an hour, 12 h before a test with sexually vigorous males. Half of the females in each stimulus group received bilateral infusions of 1 MUl/side of either DNQX (19.8 mmol/MUl) or saline aimed at the VMH immediately prior to VCS or sham stimulation. Saline infused females given VCS had lower lordosis quotients compared to females given sham stimulation. In contrast, females infused with DNQX prior to VCS displayed more appetitive behaviors and higher lordosis quotients and magnitudes compared to females infused with saline. These data indicate that activation of AMPA/kainate receptors in the VMH by increased glutamate transmission induced by VCS mediates estrus termination. PMID- 22525744 TI - Synergistic effects of dopamine D2-like receptor antagonist sulpiride and beta blocker propranolol on learning in the carousel maze, a dry-land spatial navigation task. AB - Spatial navigation attracts the attention of neuroscientists as an animal analogue of human declarative memory. The Carousel maze is a dry-land navigational paradigm, which proved to be useful in studying neurobiological substrates of learning. The task involves avoidance of a stable sector on a rotating arena and is highly dependent upon the hippocampus. The present study aims at testing hypothesis that sulpiride (a centrally-active dopamine D2-like receptor antagonist) and propranolol (a beta-blocker) impair spatial learning in the Carousel maze after combined systemic administration. These doses were previously shown to be subthreshold in this task. Results showed that both substances affected behavior and significantly potentiated their negative effects on spatial learning. This suggests central interaction of both types of receptors in influencing acquisition of this dynamic-environment task. PMID- 22525746 TI - In vitro P-glycoprotein efflux inhibition by atypical antipsychotics is in vivo nicely reflected by pharmacodynamic but less by pharmacokinetic changes. AB - BACKGROUND: P-glycoprotein (P-gp), an efflux transporter of the blood-brain barrier, limits the access of multiple xenobiotics to the central nervous system (CNS). Thus drug-dependent inhibition, induction or genetic variation of P-gp impacts drug therapy. METHODS: We investigated atypical antipsychotics and their interaction with P-gp. Amisulpride, clozapine, N-desmethylclozapine, olanzapine, and quetiapine were assessed in vitro on their inhibitory potential and in vivo on their disposition in mouse serum and brain, and behaviourally on the RotaRod test. In vivo wildtype (WT) and mdr1a/1b double knockout mice (mdr1a/1b (-/-, -/ ); KO) were investigated. RESULTS: In rhodamine 123 efflux assay drugs inhibitory potency to P-gp could be ranked quetiapine>N desmethylclozapine>clozapine>olanzapine. When treating WT and KO mice i.p. and assessing brain and serum levels by HPLC analysis, P-gp expression has the highest but a rather short effect on the distribution of amisulpride, whereas the others ranked N-desmethylclozapine>olanzapine>quetiapine>clozapine; contrasted by in vivo behavioral changes at various time points. Here quetiapine>clozapine>olanzapine impacts behavior most when P-gp is lacking. Present results indicate the relevance of P-gp expression for CNS-drug therapy. CONCLUSIONS: Combination of in vitro, and in vivo methods highlights that inhibitory potency did not reflect P-gp related drug disposition. But, when drugs were ranked for inhibitory potency, this order is reflected in pharmacodynamic changes or vice versa. Pharmacodynamic effects otherwise were at most correlated to drug brain levels, which however, were present only to a limited extent (by positron emission tomography) accessible in humans. PMID- 22525747 TI - Beyond the detergent effect: a binding site for sodium dodecyl sulfate (SDS) in mammalian apoferritin. AB - Although sodium dodecyl sulfate (SDS) is widely used as an anionic detergent, it can also exert specific pharmacological effects that are independent of the surfactant properties of the molecule. However, structural details of how proteins recognize SDS are scarce. Here, it is demonstrated that SDS binds specifically to a naturally occurring four-helix bundle protein: horse apoferritin. The X-ray crystal structure of the apoferritin-SDS complex was determined at a resolution of 1.9 A and revealed that the SDS binds in an internal cavity that has previously been shown to recognize various general anesthetics. A dissociation constant of 24 +/- 9 uM at 293 K was determined by isothermal titration calorimetry. SDS binds in this cavity by bending its alkyl tail into a horseshoe shape; the charged SDS head group lies in the opening of the cavity at the protein surface. This crystal structure provides insights into the protein-SDS interactions that give rise to binding and may prove useful in the design of novel SDS-like ligands for some proteins. PMID- 22525748 TI - X-ray-excited optical luminescence of protein crystals: a new tool for studying radiation damage during diffraction data collection. AB - During X-ray irradiation protein crystals radiate energy in the form of small amounts of visible light. This is known as X-ray-excited optical luminescence (XEOL). The XEOL of several proteins and their constituent amino acids has been characterized using the microspectrophotometers at the Swiss Light Source and Diamond Light Source. XEOL arises primarily from aromatic amino acids, but the effects of local environment and quenching within a crystal mean that the XEOL spectrum of a crystal is not the simple sum of the spectra of its constituent parts. Upon repeated exposure to X-rays XEOL spectra decay non-uniformly, suggesting that XEOL is sensitive to site-specific radiation damage. However, rates of XEOL decay were found not to correlate to decays in diffracting power, making XEOL of limited use as a metric for radiation damage to protein crystals. PMID- 22525749 TI - Peptide inhibitors of botulinum neurotoxin serotype A: design, inhibition, cocrystal structures, structure-activity relationship and pharmacophore modeling. AB - Clostridium botulinum neurotoxins are classified as Category A bioterrorism agents by the Centers for Disease Control and Prevention (CDC). The seven serotypes (A-G) of the botulinum neurotoxin, the causative agent of the disease botulism, block neurotransmitter release by specifically cleaving one of the three SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins and induce flaccid paralysis. Using a structure-based drug design approach, a number of peptide inhibitors were designed and their inhibitory activity against botulinum serotype A (BoNT/A) protease was determined. The most potent peptide, RRGF, inhibited BoNT/A protease with an IC(50) of 0.9 uM and a K(i) of 358 nM. High-resolution crystal structures of various peptide inhibitors in complex with the BoNT/A protease domain were also determined. Based on the inhibitory activities and the atomic interactions deduced from the cocrystal structures, the structure-activity relationship was analyzed and a pharmacophore model was developed. Unlike the currently available models, this pharmacophore model is based on a number of enzyme-inhibitor peptide cocrystal structures and improved the existing models significantly, incorporating new features. PMID- 22525750 TI - S-SAD phasing study of death receptor 6 and its solution conformation revealed by SAXS. AB - A subset of tumour necrosis factor receptor (TNFR) superfamily members contain death domains in their cytoplasmic tails. Death receptor 6 (DR6) is one such member and can trigger apoptosis upon the binding of a ligand by its cysteine rich domains (CRDs). The crystal structure of the ectodomain (amino acids 1-348) of human death receptor 6 (DR6) encompassing the CRD region was phased using the anomalous signal from S atoms. In order to explore the feasibility of S-SAD phasing at longer wavelengths (beyond 2.5 A), a comparative study was performed on data collected at wavelengths of 2.0 and 2.7 A. In spite of sub-optimal experimental conditions, the 2.7 A wavelength used for data collection showed potential for S-SAD phasing. The results showed that the R(ano)/R(p.i.m.) ratio is a good indicator for monitoring the anomalous data quality when the anomalous signal is relatively strong, while d''/sig(d'') calculated by SHELXC is a more sensitive and stable indicator applicable for grading a wider range of anomalous data qualities. The use of the 'parameter-space screening method' for S-SAD phasing resulted in solutions for data sets that failed during manual attempts. SAXS measurements on the ectodomain suggested that a dimer defines the minimal physical unit of an unliganded DR6 molecule in solution. PMID- 22525751 TI - Novel beta-structure of YLR301w from Saccharomyces cerevisiae. AB - When the Z-type variant of human alpha(1)-antitrypsin was overexpressed in Saccharomyces cerevisiae, proteomics analysis identified YLR301w as one of the up regulated proteins. YLR301w is a 27.5 kDa protein with no sequence homology to any known protein and has been reported to interact with Sec72 and Hrr25. The crystal structure of S. cerevisiae YLR301w has been determined at 2.3 A resolution, revealing a novel beta-structure. It consists of an N-terminal ten stranded beta-barrel with two short alpha-helices connected by a 23-residue linker to a seven-stranded half-barrel with two short helices at the C-terminus. The N-terminal barrel has a highly conserved hydrophobic channel that can bind hydrophobic molecules such as PEG. It forms a homodimer both in the crystal and in solution. YLR301w binds Sec72 with a K(d) of 6.2 uM, but the biological significance of this binding requires further investigation. PMID- 22525752 TI - An analysis of subdomain orientation, conformational change and disorder in relation to crystal packing of aspartic proteinases. AB - The analysis reported here describes detailed structural studies of endothiapepsin (the aspartic proteinase from Endothia parasitica), with and without bound inhibitors, and human pepsin 3b. Comparison of multiple crystal structures of members of the aspartic proteinase family has revealed small but significant differences in domain orientation in different crystal forms. In this paper, it is shown that these differences in domain orientation do not necessarily correlate with the presence or absence of bound inhibitors, but appear to stem at least partly from crystal contacts mediated by sulfate ions. However, since the same inherent flexibility of the structure is observed for other enzymes in this family such as human pepsin, the native structure of which is also reported here, the observed domain movements may well have implications for the mechanism of catalysis. PMID- 22525753 TI - Structure of phosphoserine aminotransferase from Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis (Mtb), the causative agent of TB, remains a serious world health problem owing to limitations of the available drugs and the emergence of resistant strains. In this context, key biosynthetic enzymes from Mtb are attractive targets for the development of new therapeutic drugs. Here, the 1.5 A resolution crystal structure of Mtb phosphoserine aminotransferase (MtbPSAT) in complex with its cofactor, pyridoxal 5'-phosphate (PLP), is reported. MtbPSAT is an essential enzyme in the biosynthesis of serine and in pathways of one-carbon metabolism. The structure shows that although the Mtb enzyme differs substantially in sequence from other PSAT enzymes, its fold is conserved and its PLP-binding site is virtually identical. Structural comparisons suggest that this site remains unchanged throughout the catalytic cycle. On the other hand, PSAT enzymes are obligate dimers in which the two active sites are located in the dimer interface and distinct differences in the MtbPSAT dimer are noted. These impact on the substrate-binding region and access channel and suggest options for the development of selective inhibitors. PMID- 22525754 TI - Structural changes caused by radiation-induced reduction and radiolysis: the effect of X-ray absorbed dose in a fungal multicopper oxidase. AB - X-ray radiation induces two main effects at metal centres contained in protein crystals: radiation-induced reduction and radiolysis and a resulting decrease in metal occupancy. In blue multicopper oxidases (BMCOs), the geometry of the active centres and the metal-to-ligand distances change depending on the oxidation states of the Cu atoms, suggesting that these alterations are catalytically relevant to the binding, activation and reduction of O(2). In this work, the X ray-determined three-dimensional structure of laccase from the basidiomycete Coriolopsis gallica (Cg L), a high catalytic potential BMCO, is described. By combining spectroscopic techniques (UV-Vis, EPR and XAS) and X-ray crystallography, structural changes at and around the active copper centres were related to pH and absorbed X-ray dose (energy deposited per unit mass). Depletion of two of the four active Cu atoms as well as low occupancies of the remaining Cu atoms, together with different conformations of the metal centres, were observed at both acidic pH and high absorbed dose, correlating with more reduced states of the active coppers. These observations provide additional evidence to support the role of flexibility of copper sites during O(2) reduction. This study supports previous observations indicating that interpretations regarding redox state and metal coordination need to take radiation effects explicitly into account. PMID- 22525755 TI - Ribosome engineering to promote new crystal forms. AB - Crystallographic studies of the ribosome have provided molecular details of protein synthesis. However, the crystallization of functional complexes of ribosomes with GTPase translation factors proved to be elusive for a decade after the first ribosome structures were determined. Analysis of the packing in different 70S ribosome crystal forms revealed that regardless of the species or space group, a contact between ribosomal protein L9 from the large subunit and 16S rRNA in the shoulder of a neighbouring small subunit in the crystal lattice competes with the binding of GTPase elongation factors to this region of 16S rRNA. To prevent the formation of this preferred crystal contact, a mutant strain of Thermus thermophilus, HB8-MRCMSAW1, in which the ribosomal protein L9 gene has been truncated was constructed by homologous recombination. Mutant 70S ribosomes were used to crystallize and solve the structure of the ribosome with EF-G, GDP and fusidic acid in a previously unobserved crystal form. Subsequent work has shown the usefulness of this strain for crystallization of the ribosome with other GTPase factors. PMID- 22525756 TI - Sensitivity of lysozyme crystallization to minute variations in concentration. AB - It is well known that the crystallization of proteins is strongly dependent on the crystallization conditions, which are sometimes very sensitive to environmental disturbances. Parameters such as the concentration of precipitants or protein, pH, temperature and many others are known to affect the probability of crystallization, and the task of crystallizing a new protein often involves a trial-and-error test using numerous combinations of crystallization conditions. These crystallization parameters, such as the concentration of either the protein or the precipitant, are important because they directly affect the driving force of crystallization: the supersaturation of the solution. Although it is common sense that the concentration can affect the crystallization process, the sensitivity of the crystallization process to variations in the concentration has seldom been addressed. Owing to the difficulty of directly preparing solutions with very small concentration variations, it is hard to carry out an investigation of their effect on the crystallization process. In this paper, a simple but novel method for studying the effect of minute concentration variations on the success rate of protein crystallization is presented. By evaporating the crystallization droplet, a fine concentration gradient could be created. With this fine-tuned concentration gradient, it was possible to observe the effects of minute variations in the concentration or supersaturation on the crystallization. A very minor change in concentration (as low as 0.13% of the initial concentration, i.e. 0.026 mg ml(-1) for lysozyme and 0.052 mg ml(-1) for NaCl in the current study) or a very minor change in supersaturation (as small as 0.018) could cause a clear difference in the crystallization success rate, indicating that the crystallization of proteins is very sensitive to the concentration level. Such sensitive behaviour may be one reason for the poor reproducibility of protein crystallization. PMID- 22525757 TI - In situ macromolecular crystallography using microbeams. AB - Despite significant progress in high-throughput methods in macromolecular crystallography, the production of diffraction-quality crystals remains a major bottleneck. By recording diffraction in situ from crystals in their crystallization plates at room temperature, a number of problems associated with crystal handling and cryoprotection can be side-stepped. Using a dedicated goniometer installed on the microfocus macromolecular crystallography beamline I24 at Diamond Light Source, crystals have been studied in situ with an intense and flexible microfocus beam, allowing weakly diffracting samples to be assessed without a manual crystal-handling step but with good signal to noise, despite the background scatter from the plate. A number of case studies are reported: the structure solution of bovine enterovirus 2, crystallization screening of membrane proteins and complexes, and structure solution from crystallization hits produced via a high-throughput pipeline. These demonstrate the potential for in situ data collection and structure solution with microbeams. PMID- 22525758 TI - Structural studies of the effect that dimethyl sulfoxide (DMSO) has on cisplatin and carboplatin binding to histidine in a protein. AB - The anticancer complexes cisplatin and carboplatin target the DNA major groove, forming intrastrand and interstrand cross-links between guanine bases through their N7 atoms, causing distortion of the DNA helix and apoptotic cell death. A major side effect of these drugs is toxicity, which is caused via binding to many proteins in the body. A range of crystallographic studies have been carried out involving the cocrystallization of hen egg-white lysozyme (HEWL) as a test protein with cisplatin and carboplatin in aqueous and dimethyl sulfoxide (DMSO) conditions. Different cryoprotectants, glycerol and Paratone, were used for each of the cisplatin and carboplatin cocrystallization cases, while silicone oil was used for studies involving N-acetylglucosamine (NAG). Both cisplatin and carboplatin do not bind to HEWL in aqueous media on the timescales of the conditions used here, but upon addition of DMSO two molecules of cisplatin or carboplatin bind either side of His15, which is the only His residue in lysozyme and is assumed to be an imidazolyl anion or a chemical resonance moiety, i.e. both imidazole N atoms are chemically reactive. To identify the platinum-peak positions in the 'with DMSO conditions', anomalous scattering maps were calculated as a cross-check with the F(o) - F(c) OMIT maps. Platinum-occupancy sigma values were established using three different software programs in each case. The use of EVAL15 to process all of the diffraction data sets provided a consistent platform for a large ensemble of data sets for the various protein and platinum-compound model refinements with REFMAC5 and then SHELXTL. Overall, this extensive set of crystallization and cryoprotectant conditions allowed a systematic evaluation of cisplatin and carboplatin binding to lysozyme as a test protein via detailed X-ray crystal structure characterizations. DMSO is used as a super-solvent for drug delivery as it is deemed to cause no effect upon drug binding. However, these results show that addition of DMSO causes the platinum anticancer drugs to bind to HEWL. This effect should be considered in toxicity assessments of these drugs and perhaps more widely. PMID- 22525759 TI - Notes of a protein crystallographer: on the high-resolution structure of the PDB growth rate. PMID- 22525760 TI - Mechanisms for improved running economy in beginner runners. AB - Controversy surrounds whether running mechanics make good predictors of running economy (RE) with little known about the development of an economical running gait. PURPOSE: The aim of this study was to identify if mechanical or physiological variables changed during 10 wk of running in beginners and whether these changes could account for any change in RE. METHODS: A 10-wk running program (10 wkRP) was completed by 10 female beginner runners. A bilateral three dimensional kinematic and kinetic analysis, in addition to RE and lower body flexibility measurements, was performed before and after the 10 wkRP. The Balke Ware graded walking exercise test was performed before and after the 10 wkRP to determine VO2max. RESULTS: Seven kinematic and kinetic variables significantly changed from before to after training, in addition to a significant decrease in calf flexibility (27.3 degrees +/- 6.3 degrees vs 23.9 degrees +/- 5.6 degrees , P < 0.05). A significant improvement was seen in RE (224 +/- 24 vs 205 +/- 27 mL . kg(-1) . km(-1), P < 0.05) and treadmill time to exhaustion (16.4 +/- 3.2 vs 17.3 +/- 2.8 min, P < 0.05); however, VO2max remained unchanged from before to after training (34.7 +/- 5.1 vs 34.3 +/- 5.6 mL . kg(-1) . min(-1)). Stepwise regression analysis showed three kinematic variables to explain 94.3% of the variance in change in RE. They were a less extended knee at toe off (P = 0.004), peak dorsiflexion occurring later in stance (P = 0.001), and a slower eversion velocity at touchdown (P = 0.042). The magnitude of change for each variable was 1.5%, 4.7%, and 34.1%, respectively. CONCLUSIONS: These results show that beginner runners naturally developed their running gait as they became more economical runners. PMID- 22525761 TI - High-intensity training reduces CD8+ T-cell redistribution in response to exercise. AB - PURPOSE: We examined whether exercise-induced lymphocytosis and lymphocytopenia are impaired with high-intensity training. METHODS: Eight trained cyclists (VO(2max) = 64.2 +/- 6.5 mL . kg(-1) . min(-1)) undertook 1 wk of normal intensity training and a second week of high-intensity training. On day 7 of each week, participants performed a cycling task, consisting of 120 min of submaximal exercise followed by a 45-min time trial. Blood was collected before, during, and after exercise. CD8(+) T lymphocytes (CD8(+)TLs) were identified, as well as CD8(+)TL subpopulations on the basis of CD45RA and CD27 expression. RESULTS: High intensity training (18,577 +/- 10,984 cells per microliter * ~165 min) was associated with a smaller exercise-induced mobilization of CD8(+)TLs compared with normal-intensity training (28,473 +/- 16,163 cells per microliter * ~165 min, P = 0.09). The response of highly cytotoxic CD8(+)TLs (CD45RA(+)CD27(-)) to exercise was smaller after 1 wk of high-intensity training (3144 +/- 924 cells per microliter * ~165 min) compared with normal-intensity training (6417 +/- 2143 cells per microliter * ~165 min, P < 0.05). High-intensity training reduced postexercise CD8(+)TL lymphocytopenia (-436 +/- 234 cells per microliter) compared with normal-intensity training (-630 +/- 320 cells per microliter, P < 0.05). This was driven by a reduced egress of naive CD8(+)TLs (CD27(+)CD45RA(+)). High-intensity training was associated with reduced plasma epinephrine (-37%) and cortisol (-15%) responses (P < 0.05). CONCLUSIONS: High-intensity training impaired CD8(+)TL mobilization and egress in response to exercise. Highly cytotoxic CD8(+)TLs were primarily responsible for the reduced mobilization of CD8(+)TLs, which occurred in parallel with smaller neuroendocrine responses. The reduced capacity for CD8(+)TLs to leave blood after exercise with high-intensity training was accounted for primarily by naive, and also, highly cytotoxic CD8(+)TLs. This impaired CD8(+)TL redistribution in athletes undertaking intensified training may imply reduced immune surveillance. PMID- 22525762 TI - Efficacy and safety of diclofenac diethylamine 2.32% gel in acute ankle sprain. AB - BACKGROUND: Topical diclofenac diethylamine (DDEA) 2.32% gel achieves lasting efficacy in localized pain with two applications per day, while maintaining the favorable safety profile of topical diclofenac and potentially improving convenience and patient compliance. METHODS: This randomized double-blind controlled study enrolled patients with acute ankle sprain treated with DDEA 2.32% gel two times per day (bid) (n = 80) or three times per day (tid) (n = 80) or placebo (n = 82). Efficacy (including pain and swelling) and local tolerability were evaluated during 8 +/- 1 d. RESULTS: By day 5, the reduction in pain on movement (POM) (primary efficacy variable) with DDEA bid and tid (49.1 and 49.7 mm, respectively; 100-mm visual analog scale) was almost double that with placebo (25.4 mm) (P < 0.0001). In patients with severe baseline POM (>= 80 mm), mean change in POM from baseline to day 5 with DDEA bid or tid was 30-40 mm greater than that with placebo, which was double the difference (15-20 mm) in patients with mild-moderate baseline POM (<80 mm). More than 70% of all DDEA patients experienced >= 50% reduction in POM between days 1 and 5 versus 21% of placebo patients (P < 0.0001). By study end (day 8), ankle swelling in patients treated with DDEA (0.3 cm) was one-third that in those treated with placebo (0.9 cm) (P < 0.0001), which had still not achieved the level of ankle joint function seen with DDEA on day 5 (P < 0.0001). At day 5, treatment satisfaction was "good" to "excellent" in almost 90% of DDEA patients but only "good" or "very good" in 23% of placebo patients (P < 0.0001). DDEA 2.32% gel was well tolerated. CONCLUSIONS: DDEA 2.32% gel twice daily (applied in the morning and evening) was well tolerated and provided lasting relief from pain, improved function, and reduced symptomatic healing time in uncomplicated ankle sprain. PMID- 22525763 TI - Acute effect of Fatmax exercise on the metabolism in overweight and nonoverweight girls. AB - INTRODUCTION: Acute exercise can reduce postprandial insulin concentrations and increase fat oxidation in adults, which may have important implications for insulin resistance and weight control. However, similar studies with young people or comparing overweight (OW) and nonoverweight (NO) individuals are sparse. Therefore, the acute effect of Fatmax exercise on glucose, insulin, and fat oxidation was examined in 12 OW and 15 NO girls. METHODS: Participants completed two 2-d conditions in a counterbalanced order. On day 1, participants either expended 2.09 MJ (500 kcal) during treadmill exercise at individual Fatmax (EX) or 0.47 MJ (112 kcal) during rest (CON). On day 2, capillary blood and expired air samples were taken in the fasting state and at regular intervals for 2 h after high-glycemic-index breakfast consumption. Subsequently, blood glucose and plasma insulin concentrations were determined, and fat oxidation was estimated. RESULTS: Blood glucose was similar between conditions in both groups (P > 0.05). Fasting plasma insulin (P = 0.047) and total area under the 2-h curve (P = 0.049) were reduced for EX compared with CON in the NO, but not OW girls (P > 0.05). Fasting fat oxidation was higher for EX than for CON in the NO girls (P = 0.036) and fat oxidation total area under the 2-h curve was higher for EX in both groups of girls (P <= 0.05). CONCLUSIONS: A bout of Fatmax exercise performed ~16 h before high-glycemic-index breakfast consumption reduced fasting and postprandial insulin concentrations in NO girls and increased fat oxidation in both OW and NO girls. The higher postintervention energy and CHO intake in the OW compared with the NO girls or differences in metabolism between the two groups may have compromised potential exercise-induced reductions in insulin the OW girls. PMID- 22525765 TI - Identifying Impairments after concussion: normative data versus individualized baselines. AB - PURPOSE: This study aimed to determine whether agreement exists between baseline comparison (comparison of postconcussion scores to individualized baseline scores) and normative comparison (comparison of postconcussion scores to a normative mean) in identifying impairments after concussion. METHODS: A total of 1060 collegiate student-athletes completed baseline testing as part of an ongoing clinical program. Gender-specific normative means were obtained from a subset of 673 athletes with no history of self-reported concussion, learning disabilities, or attention-deficit disorders. Concussions were later diagnosed in 258 athletes who had completed baseline testing. The athletes completed their first assessment within 10 d after injury. Athletes completed a computerized neurocognitive test (Automated Neuropsychological Assessment Metrics), postural control assessment (Sensory Organization Test), and a 15-item graded symptom checklist at baseline and again after injury. We computed two postconcussion difference scores for each outcome measure: 1) baseline difference = postconcussion score--individualized baseline score and 2) normative difference = postconcussion score--normative mean. Athletes were considered impaired if postconcussion difference exceeded the reliable change parameters. McNemar tests were used to assess agreement on impairment status (impaired and unimpaired) between comparison methods for each outcome measure. RESULTS: The baseline comparison method identified 2.6 times more impairments than the normative comparison method for the Simple Reaction Time Test 1 (P = 0.043). The normative comparison method identified 7.6 times more impairments than the baseline comparison method for Mathematical Processing (P < 0.001). No other disagreements were observed for postural control or symptom severity. CONCLUSIONS: Our findings suggest that, when using these concussion assessment tools, clinicians may consider using normative data in lieu of individualized baseline measures. This may be especially useful to clinicians with limited resources and an inability to capture valid baselines on all athletes. PMID- 22525766 TI - Artificial neural networks to predict activity type and energy expenditure in youth. AB - Previous studies have demonstrated that pattern recognition approaches to accelerometer data reduction are feasible and moderately accurate in classifying activity type in children. Whether pattern recognition techniques can be used to provide valid estimates of physical activity (PA) energy expenditure in youth remains unexplored in the research literature. PURPOSE: The objective of this study is to develop and test artificial neural networks (ANNs) to predict PA type and energy expenditure (PAEE) from processed accelerometer data collected in children and adolescents. METHODS: One hundred participants between the ages of 5 and 15 yr completed 12 activity trials that were categorized into five PA types: sedentary, walking, running, light-intensity household activities or games, and moderate-to-vigorous-intensity games or sports. During each trial, participants wore an ActiGraph GT1M on the right hip, and VO2 was measured using the Oxycon Mobile (Viasys Healthcare, Yorba Linda, CA) portable metabolic system. ANNs to predict PA type and PAEE (METs) were developed using the following features: 10th, 25th, 50th, 75th, and 90th percentiles and the lag one autocorrelation. To determine the highest time resolution achievable, we extracted features from 10-, 15-, 20-, 30-, and 60-s windows. Accuracy was assessed by calculating the percentage of windows correctly classified and root mean square error (RMSE). RESULTS: As window size increased from 10 to 60 s, accuracy for the PA-type ANN increased from 81.3% to 88.4%. RMSE for the MET prediction ANN decreased from 1.1 METs to 0.9 METs. At any given window size, RMSE values for the MET prediction ANN were 30-40% lower than the conventional regression-based approaches. CONCLUSIONS: ANNs can be used to predict both PA type and PAEE in children and adolescents using count data from a single waist mounted accelerometer. PMID- 22525764 TI - Regulation of physiological and metabolic function of muscle by female sex steroids. AB - The ability of female sex steroids to regulate tissue function has long been appreciated; however, their role in the regulation of striated muscle function has received considerably less attention. The purpose of this symposium review was to document recent evidence indicating the role female sex steroids have in defining the functional characteristics of striated muscle. The presentations provide substantial evidence indicating that estrogens are critical to the physiological and metabolic regulations of striated muscle; thus, when considering women's health issues, striated muscle must included as an important target tissue along with other classically thought of estrogen-sensitive tissues. PMID- 22525767 TI - Advantage of distance- versus time-based estimates of walking in predicting adiposity. AB - PURPOSE: Physical activity recommendations are defined in terms of time spent being physically active (e.g., 30 min of brisk walking, 5 d . wk(-1)). However, walking volume may be more naturally assessed by distance than by time. Analyses were therefore performed to test whether time or distance provides the best metric for relating walking volume to estimated total and regional adiposity. METHODS: Linear and logistic regression analyses were used to relate exercise dose to body mass index (BMI), body circumferences, and obesity in a cross sectional sample of 12,384 female and 3434 male walkers who reported both usual distance walked and time spent walking per week on survey questionnaires. Metabolic equivalent hours per day (MET . h . d(-1), 1 MET = 3.5 mL O2 . kg(-1) . min(-1)) were calculated from the time and pace, or distance and pace, using published compendium values. RESULTS: Average MET-hours per day walked was 37% greater when calculated from time spent walking versus usual distance in women and was 32% greater in men. Per MET-hours per day, declines in BMI and circumferences (slope +/- SE) were nearly twice as great, or greater, for distance- versus time-derived estimates for kilograms per squared meter of BMI (females = -0.58 +/- 0.03 vs -0.31 +/- 0.02, males = -0.35 +/- 0.04 vs -0.15 +/- 0.02), centimeter of waist circumference (females = -1.42 +/- 0.07 vs -0.72 +/- 0.04, males = -0.96 +/- 0.10 vs -0.45 +/- 0.07), and reductions in the odds for total obesity (odds ratio: females = 0.72 vs 0.84, males = 0.84 vs 0.92) and abdominal obesity (females = 0.74 vs 0.85, males = 0.79 vs 0.91, all comparisons significant). CONCLUSIONS: Distance walked may provide a better metric of walking volume for epidemiologic obesity research, and better public health targets for weight control, than walking duration. Additional research is required to determine whether these results, derived in a sample that regularly walks for exercise, apply more generally. PMID- 22525768 TI - Exercise patterns and peak oxygen uptake in a healthy population: the HUNT study. AB - PURPOSE: The objective of this study is to examine how different approaches of the current exercise recommendations for adults associate with VO(2peak) in a large healthy population. We further examined how a lower duration than recommended, if performed at very vigorous intensity, was related to VO(2peak). METHODS: A total of 4631 healthy adults age 19-89 yr (2263 men and 2368 women) were tested for VO(2peak) (mean = 44.3 and 35.9 mL.kg(-1).min(-1) for men and women, respectively). Information on exercise habits was collected through a questionnaire, including questions on frequency, duration, and relative intensity (Borg scale 6-20). A general linear model was applied to assess the associations between physical activity and VO(2peak). RESULTS: VO(2peak) did not differ considerably between people who reported to exercise >= 150 min.wk(-1) (average = 216 min.wk(-1) , VO(2peak) = 45.2 and 36.5 mL.kg(-1).min(-1)for men and women, respectively) with moderate intensity and people who reported 75-149 min.wk(-1) (average = 112.5 min.wk(-1) , VO(2peak) = 47.5 and 37.3 mL.kg(-1).min(-1) for men and women) with vigorous intensity, but it was higher than that in people who reported inactivity (VO(2peak) = 40.1 and 32.3 mL.kg(-1).min(-1)for men and women) or low-intensity exercise (VO(2peak) = 41.2 and 40.1 mL.kg(-1).min(-1)for men and women). Reporting exercise at very vigorous intensity but with a duration of less than 75 min.wk(-1) (average = 49 min.wk(-1) ) was associated with a VO(2peak) that was similarly high (47.6 and 36.7 mL.kg(-1).min(-1) for men and women). CONCLUSION: Our findings support current recommendations by showing that exercise of both "moderate intensity-long duration" and "vigorous intensity-short duration" was associated with similarly high VO(2peak). Our results also suggest that exercising at very vigorous intensity may be beneficial for VO(2peak) even with considerably lower total exercise time than expressed in today's recommendations. PMID- 22525769 TI - Sudden cardiac arrest and death in United States marathons. AB - PURPOSE: There is no reporting system for marathon-associated sudden cardiac arrest (SCA) or sudden cardiac death in the United States. The purpose of this study was to estimate and characterize the risk of marathon-related SCA to assist with emergency planning. METHODS: A retrospective Web-based survey was sent out to all US marathon medical directors (n = 400) to gather details of SCA including demographics, resuscitation efforts, mortality, and autopsy results, if available. RESULTS: A total of 88 surveys (22%) were returned from marathons run from 1976 to 2009 for a total of 1,710,052 participants. Risks of SCA and sudden cardiac death were 1 in 57,002 and 1 in 171,005, respectively. Men made up the vast majority of SCA victims (93%, mean age = 49.7 yr, range = 19-82 yr). Arrest site distributions were 0-5, 6-14, 15-22, and 23-26.2 miles. CAD was reported as the cause of death at autopsy in 7 of the 10 fatalities. An automated external defibrillator (AED) was used in 20/30 cases and associated with a higher survival (17/20 survivors vs 3/10 deaths, P = 0.0026). CONCLUSIONS: SCA occurs in approximately 1 in 57,000 marathon runners, is more common in older males, and usually occurs in the last 4 miles of the racecourse. Prompt resuscitation including early use of an AED improves survival. Emergency planning to include trained medical staff and sufficient AEDs throughout the racecourse is recommended. PMID- 22525770 TI - Maintenance of cognitive control during and after walking in preadolescent children. AB - OBJECTIVE: The present study evaluated the effects of an acute bout of moderate intensity treadmill walking on aspects of cognitive control underlying successful academic achievement. METHODS: The study used a within-subjects counterbalanced design with a sample of 36 preadolescent children. Cognitive performance was assessed using a modified flanker task and a modified spatial n-back task to assess inhibition and working memory, respectively. RESULTS: No changes in task performance were observed while individuals were actively walking or at seated rest across both tasks. However, during the flanker task, increased response accuracy was observed after exercise relative to post-seated rest. Further observation revealed decrements to response accuracy after seated rest relative to baseline. No such effect was observed for the n-back task. CONCLUSIONS: These findings suggest selective exercise-induced changes to cognitive control for aspects of inhibitory control and attention but not for working memory. Furthermore, the findings suggest that short bouts of exercise may be efficacious for maintaining cognitive performance, which may have implications for scholastic achievement. PMID- 22525771 TI - Preexercise galactose and glucose ingestion on fuel use during exercise. AB - PURPOSE: This study determined the effect of ingesting galactose and glucose 30 min before exercise on exogenous and endogenous fuel use during exercise. METHODS: Nine trained male cyclists completed three bouts of cycling at 60% W(max) for 120 min after an overnight fast. Thirty minutes before exercise, the cyclists ingested a fluid formulation containing placebo, 75 g of galactose (Gal), or 75 g of glucose (Glu) to which (13)C tracers had been added, in a double-blind randomized manner. Indirect calorimetry and isotope ratio mass spectrometry were used to calculate fat oxidation, total carbohydrate (CHO) oxidation, exogenous CHO oxidation, plasma glucose oxidation, and endogenous liver and muscle CHO oxidation rates. RESULTS: Peak exogenous CHO oxidation was significantly higher after Glu (0.68 +/- 0.08 g.min(-1), P < 0.05) compared with Gal (0.44 +/- 0.02 g.min(-1)); however, mean rates were not significantly different (0.40 +/- 0.03 vs. 0.36 +/- 0.02 g.min(-1), respectively). Glu produced significantly higher exogenous CHO oxidation rates during the initial hour of exercise (P < 0.01), whereas glucose rates derived from Gal were significantly higher during the last hour (P < 0.01). Plasma glucose and liver glucose oxidation at 60 min of exercise were significantly higher for Glu (1.07 +/- 0.1 g.min(-1), P < 0.05, and 0.57 +/- 0.08 g.min(-1), P < 0.01) compared with Gal (0.64 +/- 0.05 and 0.29 +/- 0.03 g.min(-1), respectively). There were no significant differences in total CHO, whole body endogenous CHO, muscle glycogen, or fat oxidation between conditions. CONCLUSION: The preexercise consumption of Glu provides a higher exogenous source of CHO during the initial stages of exercise, but Gal provides the predominant exogenous source of fuel during the latter stages of exercise and reduces the reliance on liver glucose. PMID- 22525772 TI - Assessment of wear/nonwear time classification algorithms for triaxial accelerometer. AB - PURPOSE: The objective of this study is to assess the performance of existing wear/nonwear time classification algorithms for accelerometry data collected in the free-living environment using a wrist-worn triaxial accelerometer and a waist worn uniaxial accelerometer in older adults. METHODS: Twenty-nine adults age 76 to 96 yr wore wrist accelerometers for approximately 24 h per day and waist accelerometers during waking for approximately 7 d of free living. Wear and nonwear times were classified by existing algorithms (Alg([ActiLife]), Alg([Troiano]), and Alg([Choi])) and compared with wear and nonwear times identified by data plots and diary records. With the use of bias and probability of correct classification, the performance of the algorithms, two time windows (60 and 90 min), and vector magnitude (VM) versus vertical axis (V) counts from a triaxial accelerometer were compared. RESULTS: Automated algorithms (Alg([Choi]) and Alg([Troiano])) classified wear/nonwear time intervals more accurately from VM than V counts. The use of the 90-min time window improved wear/nonwear classification accuracy when compared with the 60-min window. The Alg([Choi]) and Alg([Troiano]) performed better than the manufacturer-provided algorithm (Alg([ActiLife])), and the Alg([Choi]) performed better than the Alg([Troiano]) for wear/nonwear time classification using the data collected by both accelerometers. CONCLUSIONS: Triaxial wrist-worn accelerometer can be used for an accurate wear/nonwear time classification in free-living older adults. The use of the 90-min window and the VM counts improves the performance of commonly used algorithms for wear/nonwear classification for both uniaxial and triaxial accelerometers. PMID- 22525773 TI - Effects of exercise therapy on cardiorespiratory fitness in patients with schizophrenia. AB - BACKGROUND: Increased mortality in schizophrenia is caused largely by coronary heart disease (CHD). Low cardiorespiratory fitness (CRF) is a key factor for CHD mortality. We compared CRF in patients with schizophrenia to CRF of matched healthy controls and reference values. Also, we examined the effects of exercise therapy on CRF in patients with schizophrenia and in controls. METHODS: Sixty three patients with schizophrenia and 55 controls, matched for gender, age, and socioeconomic status, were randomized to exercise (n = 31) or occupational therapy (n = 32) and controls to exercise (n = 27) or life as usual (n = 28). CRF was assessed with an incremental cardiopulmonary exercise test and defined as the highest relative oxygen uptake (VO(2peak)) and peak work rate (W(peak)). Minimal compliance was 50% of sessions (n = 52). RESULTS: Male and female patients with schizophrenia had a relative VO(2peak) of 34.3 +/- 9.9 and 24.0 +/- 4.5 mL.kg( 1).min(-1), respectively. Patients had higher resting HR (P < 0.01) and lower peak HR (P < 0.001), peak systolic blood pressure (P = 0.02), relative VO(2peak) (P < 0.01), W(peak) (P < 0.001), RER (P < 0.001), minute ventilation (P = 0.02), and HR recovery (P < 0.001) than controls. Relative VO(2peak) was 90.5% +/- 19.7% (P < 0.01) of predicted relative VO(2peak) in male and 95.9% +/- 14.9% (P = 0.18) in female patients. In patients, exercise therapy increased relative VO(2peak) compared with decreased relative VO(2peak) after occupational therapy. In controls, relative VO(2peak) increased after exercise therapy and to a lesser extent after life as usual (group, P < 0.01; randomization, P = 0.03). Exercise therapy increased W(peak) in patients and controls compared with decreased W(peak) in nonexercising patients and controls (P < 0.001). CONCLUSION: Patients had lower CRF levels compared with controls and reference values. Exercise therapy increased VO(2peak) and W(peak) in patients and controls. VO(2peak) and W(peak) decreased in nonexercising patients. PMID- 22525774 TI - Absence of blood oxidative stress in trained men after strenuous exercise. AB - Exercise has been noted in some, but not all, studies to elicit an oxidative stress. The discrepancy in findings may be related to differences in exercise intensity across protocols, as well as to differences in training status of participants. PURPOSE: We compared blood oxidative stress biomarkers in exercise trained men after three different bouts of exercise of varying intensity and duration, as well as a nonexercise condition. METHODS: On different days, men (n = 12, 21-35 yr) performed aerobic cycle exercise (60 min at 70% HR reserve) and cycle sprints (five 60-s sprints at 100% maximum wattage obtained during graded exercise testing and ten 15-s sprints at 200% maximum wattage obtained during graded exercise testing). Blood was collected before and 0, 30, and 60 min after exercise and analyzed for malondialdehyde, hydrogen peroxide (H(2)O(2)), advanced oxidation protein products, and nitrate/nitrite (NO(x)). As indicators of antioxidant status, Trolox equivalent antioxidant capacity, superoxide dismutase, catalase, and glutathione peroxidase were measured. RESULTS: No differences were noted in malondialdehyde, H(2)O(2), advanced oxidation protein product, or NO(x) between conditions or across time (P > 0.05). Antioxidant capacity was generally highest at 30 and 60 min after exercise and lowest at 0 min after exercise. CONCLUSIONS: In trained men, and considering the limitations of the current design (e.g., inclusion of selected oxidative stress and antioxidant biomarkers measured in blood only), strenuous bouts of exercise do not result in a significant increase in blood oxidative stress during the 1-h postexercise period. These findings may be related to attenuation in reactive oxygen species production as an adaptation to chronic exercise training and/or a protective effect of the antioxidant system in response to acute strenuous exercise. PMID- 22525775 TI - Aerobic and resistance training effects on energy intake: the STRRIDE-AT/RT study. AB - PURPOSE: Our study characterizes food and energy intake responses to long-term aerobic training (AT) and resistance training (RT) during a controlled 8-month trial. METHODS: In the STRRIDE-AT/RT trial, overweight/obese sedentary dyslipidemic men and women were randomized to AT (n = 39), RT (n = 38), or a combined treatment (AT/RT, n = 40) without any advice to change their food intakes. Quantitative food intake assessments and food frequency questionnaires were collected at baseline (before training) and after 8 months of training (end of training); body mass (BM) and fat-free mass (FFM) were also assessed. RESULTS: In AT and AT/RT, respectively, meaningful decreases in reported energy intake (REI) (-217 and -202 kcal, P < 0.001) and in intakes of fat (-14.9 and -14.9 g, P < 0.001, P = 0.004), protein (-8.3 and -10.7 g, P = 0.002, P < 0.001), and carbohydrate (-28.1 and -14.7 g, P = 0.001, P = 0.030) were found by food frequency questionnaires. REI relative to FFM decreased (P < 0.001 and P = 0.002), as did intakes of fat (-0.2 and -0.3 g, P = 0.003 and P = 0.014) and protein (-0.1 and -0.2 g, P = 0.005 and P < 0.001) in AT and AT/RT and carbohydrate (-0.5 g, P < 0.003) in AT only. For RT, REI by quantitative daily dietary intake decreased (-3.0 kcal.kg(-1) FFM, P = 0.046), as did fat intake ( 0.2 g, P = 0.033). BM decreased in AT (-1.3 kg, P = 0.006) and AT/RT (-1.5 kg, P = 0.001) but was unchanged (0.6 kg, P = 0.176) in RT. CONCLUSIONS: Previously sedentary subjects completing 8 months of AT or AT/RT reduced their intakes of calories and macronutrients and BM. In RT, fat intakes and REI (when expressed per FFM) decreased, BM was unchanged, and FFM increased. PMID- 22525776 TI - Effects of fatigue on running mechanics associated with tibial stress fracture risk. AB - PURPOSE: The purpose of this study was to investigate the acute effects of progressive fatigue on the parameters of running mechanics previously associated with tibial stress fracture risk. METHODS: Twenty-one trained male distance runners performed three sets (Pre, Mid, and Post) of six overground running trials at 4.5 m.s(-1) (+/- 5%). Kinematic and kinetic data were collected during each trial using a 12-camera motion capture system, force platform, and head and leg accelerometers. Between tests, each runner ran on a treadmill for 20 min at their corresponding lactate threshold (LT) speed. Perceived exertion levels (RPE) were recorded at the third and last minute of each treadmill run. RESULTS: RPE scores increased from 11.8 +/- 1.3 to 14.4 +/- 1.5 at the end of the first LT run and then further to 17.4 +/- 1.6 by the end of the second LT run. Peak rearfoot eversion, peak axial head acceleration, peak free moment and vertical force loading rates were shown to increase (P < 0.05) with moderate-large effect sizes during the progression from Pre to Post tests, although vertical impact peak and peak axial tibial acceleration were not significantly affected by the high intensity running bouts. CONCLUSION: Previously identified risk factors for impact-related injuries (such as tibial stress fracture) are modified with fatigue. Because fatigue is associated with a reduced tolerance for impact, these findings lend support to the importance of those measures to identify individuals at risk of injury from lower limb impact loading during running. PMID- 22525777 TI - Randomized controlled trial of the effects of a trunk stabilization program on trunk control and knee loading. AB - BACKGROUND: Many athletic maneuvers involve coordination of movement between the lower and upper extremities, suggesting that better core muscle use may lead to improved athletic performance and reduced injury risk. PURPOSE: To determine to what extent a training program with quasistatic trunk stabilization (TS) exercises would improve measures of core performance, leg strength, agility, and dynamic knee loading compared with a program incorporating only resistance training (RT). METHODS: Thirty-seven male subjects were randomly assigned to either an RT-only or a resistance and TS training program, each lasting 6 wk. Core strength and endurance, trunk control, knee loading during unanticipated cutting, leg strength, and agility were collected pre- and posttraining. RESULTS: Between-group analyses showed that the TS group significantly improved only core endurance when compared with the RT group (side bridge, P = 0.050). Within-group analyses showed that the TS group improved lateral core strength (maximum pull, cable on nondominant side; 44.5 +/- 61.3 N, P = 0.037). Both groups increased leg strength (deadlift 1 repetition maximum; TS: 55.1 +/- 46.5 lb, P = 0.003; RT: 33.4 +/- 17.5 lb, P < 0.001) and decreased sagittal plane trunk control (sudden force release test; cable in front; TS: 2.54 degrees +/- 3.68 degrees , P = 0.045; RT: 3.47 degrees +/- 2.83 degrees , P = 0.004), but only the RT group decreased lateral trunk control (sudden force release; cable on dominant side; 1.36 degrees +/- 1.65 degrees , P = 0.029). The RT group improved standing broad jump (73.2 +/- 108.4 mm, P = 0.049) but also showed increased knee abduction moment during unanticipated cutting (1.503-fold increase (percentage body weight * height), P = 0.012). CONCLUSIONS: Quasistatic TS exercises did not improve core strength, trunk control, or knee loading relative to RT potentially because of a lack of exercises, including unexpected perturbations and dynamic movement. Together, these results suggest the potential importance of targeted trunk control training to address these known anterior cruciate ligament injury risk factors. PMID- 22525778 TI - Meeting physical activity guidelines and musculoskeletal injury: the WIN study. AB - INTRODUCTION: The United States Department of Health and Human Services disseminated physical activity (PA) guidelines (PAGs) for Americans in 2008. The guidelines are based on appropriate quantities of moderate-to-vigorous aerobic PA and resistance exercise (RE) associated with decreased morbidity and mortality risk and increased health benefits. However, increases in PA levels are associated with increased risk of musculoskeletal injuries (MSIs). We related the amount and type of PA conducted on a weekly basis with the risk of MSI. METHODS: A prospective, observational study using weekly Internet tracking of moderate-to vigorous PA and RE behaviors and MSIs in 909 community-dwelling women for up to 3 yr was conducted. The primary outcome was self-reported MSIs (total, PA related, and non-PA related) interrupting typical daily work and/or exercise behaviors for >= 2 d or necessitating health care provider visit. RESULTS: Meeting versus not meeting PAGs was associated with more MSIs during PA (HR = 1.39, 95% confidence interval [CI] = 1.05-1.85, P = 0.02) but was not associated with MSIs unrelated to PA (HR = 0.99, 95% CI = 0.75-1.29, P = 0.92) or with MSIs overall (HR = 1.15, 95% CI = 0.95-1.39, P = 0.14). CONCLUSIONS: The results illustrate the risk of MSI with PA. MSI risk rises with increasing PA. Despite this modest increase in MSIs, the known benefits of aerobic and resistance PAs should not hinder physicians from encouraging patients to meet current PAGs for both moderate-to vigorous exercise and RE behaviors with the intent of achieving health benefits. PMID- 22525779 TI - Active travel and physical activity across the school transition: the PEACH project. AB - PURPOSE: Physical activity in youth decreases with age, with the transition from primary to secondary school being a key period for change. Active travel to school has been associated with higher physical activity in youth compared with those who travel by car. This study investigated whether change in travel mode to/from school was associated with change in physical activity among young people transitioning from primary to secondary school. METHODS: One thousand three hundred and seven final year UK primary school children (11.0 +/- 0.4 yr) were recruited, of whom 953 (72.9%) were followed-up 1 yr later in their first year of secondary school. Physical activity was measured by accelerometer, and travel mode to/from school was self-reported. Change in moderate-to-vigorous physical activity (MVPA) associated with change in travel mode between primary and secondary school was measured in 500 children who provided valid accelerometer data and used a consistent travel mode to/from school at each time point. RESULTS: Total MVPA was slightly higher in secondary school than primary school (60.6 +/- 21.6 vs. 63.1 +/- 23.6 min, respectively, P = 0.017). Daily MVPA increased by 11.4% in children who walked both to primary and secondary school (63.4 +/- 22.0 vs. 70.6 +/- 23.0 min, P < 0.001). In those who changed from walking to car travel, MVPA decreased by 15.5% (62.5 +/- 22.0 vs. 52.8 +/- 21.5 min, P = 0.003), whereas adoption of bus travel was associated with smaller reductions. A change from car travel to walking was associated with 16.1% more daily MVPA (50.1 +/- 14.3 vs. 58.2 +/- 20.6 min, P = 0.038). CONCLUSION: Change from active to passive transportation to school may contribute to the decline in physical activity seen between primary and secondary school. PMID- 22525780 TI - Cardiac implantable electronic device therapy for bradyarrhythmias and tachyarrhythmias. AB - Pacemakers originally were developed for patients with profound bradycardia and complete heart block who, without them, usually suffered from syncope, heart failure and an early demise. Since that time, devices have evolved to include pacing and shock therapies for the management of tachyarrhythmias and heart failure with the aim of improving quality, and if possible, length of life. Whether to insert a device depends on a balance between the potential benefits of device therapy and its risks, which are not inconsiderable. We discuss current agreed indications for pacemakers and implantable defibrillators and some current controversies surrounding their use. PMID- 22525781 TI - Corneal ulceration in a LASIK patient due to vitamin a deficiency after bariatric surgery. AB - PURPOSE: To review the case of a 41-year-old woman who underwent bariatric surgery in 2000. She subsequently underwent laser in situ keratomileusis (LASIK) surgery in 2008 and complained of dry eye since the LASIK surgery. In November 2010, she was diagnosed with a corneal melt and was treated with aggressive lubrication, followed by eventual amniotic membrane placement and a tarsorrhaphy. She then presented for consultation at the Bascom Palmer Eye Institute when she developed a corneal infiltrate. She was diagnosed with fungal keratitis with corneal xerosis. At that time, vitamin A levels were measured and were less than 2 MU/dL. The patient admitted noncompliance with nutritional supplements. METHODS: Case report. RESULTS: The patient was treated with aggressive lubrication and natamycin. Vitamin supplements were restarted, and the patient experienced dramatic improvement in symptoms with resolution of the infection. A central corneal scar with corneal thinning remains. The patient underwent a penetrating keratoplasty for visual rehabilitation. CONCLUSIONS: Patient education with emphasis on compliance with nutritional supplements is essential after bariatric surgery. Consider vitamin A deficiency in the differential diagnosis of dry eye after LASIK surgery. PMID- 22525782 TI - The use of 1% toluidine blue eye drops in the diagnosis of ocular surface squamous neoplasia. AB - PURPOSE: To evaluate the use of in vivo toluidine blue (TB) dye in the diagnosis of ocular surface squamous neoplasia and to correlate staining intensity with the histopathological diagnosis. METHODS: A prospective study was performed at the Federal University of Sao Paulo, Brazil. Patients with conjunctival epithelial lesions were examined by slit-lamp biomicroscopy, with and without 1% TB eye drops, and the results were photo documented. Before the instillation of the dye, 1% proxymetacaine HCl eye drops were used. All patients were submitted to surgery and histopathological analysis to confirm the diagnosis. The patients were grouped according to the histopathological aspects of the lesions into 3 groups: group 1-patients with ocular surface squamous neoplasia; group 2-patients with premalignant lesions; and group 3-patients with pterygium. The digital images were analyzed by 2 masked examiners who had no previous access to the histopathological results. The photographs were classified according to the positivity and intensity of the staining. The statistical analysis method chosen depended on the type of data, with the level of significance set as P < 0.05. RESULTS: Forty-seven patients were included in the study: 10 had benign lesions (pterygium), 10 had premalignant lesions (actinic keratosis), and 27 had malignant lesions (conjunctival intraepithelial neoplasia and conjunctival squamous cell carcinoma). Agreement between observers regarding the analysis of the digital photographs was 100% for positivity and 82.9% for intensity of staining (kappa = 0.938). Ninety percent of patients with premalignant lesions and all patients with malignant lesions showed positive staining with 1% TB. One patient had positive staining, but histopathological examination revealed a benign lesion (false positive). CONCLUSIONS: The use of 1% TB eye drops is an efficient method for the clinical diagnosis of ocular surface squamous neoplasia and premalignant lesions. Nevertheless, the intensity of the staining does not correlate with the degree of malignancy of these tumors. PMID- 22525783 TI - Effect of central corneal thickness on the long-term outcome of selective laser trabeculoplasty as primary treatment for ocular hypertension and primary open angle glaucoma. AB - PURPOSE: To determine if central corneal thickness (CCT) impacts the intraocular pressure (IOP)-lowering effect of selective laser trabeculoplasty (SLT) in patients with ocular hypertension (OHT) and primary open-angle glaucoma (POAG). METHODS: A retrospective chart review of consecutive patients, who underwent SLT as primary treatment for OHT and POAG, between 2002 and 2005, was performed. Partial correlation analysis was performed to correlate the CCT to the percentage of IOP reduction at 3 to 30 months after SLT. Independent samples t test was performed to compare mean percentage of IOP reduction in eyes with CCT less than 555 MUm versus CCT 555 MUm or greater. RESULTS: Eighty eyes of 47 patients were identified. The partial correlation coefficient value between the CCT and percentage of IOP reduction after SLT at 3 months was -0.253 (P = 0.025), at 12 months it was -0.22 (P = 0.049), and at 30 months it was 0.301 (P = 0.007). Independent samples t test showed that the mean percentage of IOP reduction in eyes with thinner corneas (CCT < 555 MUm) was greater than that in thicker corneas (CCT >= 555 MUm) at 3-, 6-, 9-, 12-, and 30-month post-SLT (P < 0.05). CONCLUSIONS: In patients with POAG and OHT, percentage of IOP reduction after SLT was significantly greater in eyes with thinner corneas (CCT < 555 MUm). These findings indicate that patients treated with SLT as primary therapy who had thinner corneas demonstrated better IOP control for at least 30 months after SLT. PMID- 22525784 TI - Tacrolimus ointment 0.03% for treatment of refractory childhood phlyctenular keratoconjunctivitis. AB - PURPOSE: To report 2 cases of refractory phlyctenular keratoconjunctivitis treated with topical tacrolimus 0.03% ointment (Protopic). METHODS: Two white children, aged 5 years and 6 years, respectively, presented with refractory phlyctenular keratoconjunctivitis in 1 eye (left). Both were using corticosteroids and oral erythromycin at presentation with no relief. Examination revealed the presence of catarrhal corneal infiltrates and neovascularization associated with corneal thinning. Topical tacrolimus was added to topical steroids and oral erythromycin twice daily. RESULTS: Topical tacrolimus 0.03% ointment was applied into the lower fornix twice a day. In both the patients, improvement in symptoms and signs started within a week of therapy. After 3 weeks of treatment, both patients showed complete resolution of corneal infiltrates and neovascularization. Tacrolimus was successfully tapered in both the patients. There were no side effects. CONCLUSIONS: Topical tacrolimus 0.03% ointment may be considered in treating severe refractory phlyctenular conjunctivitis. PMID- 22525785 TI - A case of recipient bed melt and wound dehiscence after penetrating keratoplasty and subconjunctival injection of bevacizumab. AB - We describe a case of recipient bed melt and wound dehiscence after uneventful penetrating keratoplasty and subconjunctival injection of bevacizumab. Three weeks postoperatively, the patient presented with limbal ischemia, recipient bed melt, and wound dehiscence corresponding to the area of bevacizumab injection. The melt was managed by application of cyanoacrylate glue along with bandage contact lens. Although the graft survived, there was a problem in re epithelization. This case highlights the need for further studies to elucidate the therapeutic dose, side effects, and correct timing of using bevacizumab with respect to corneal transplant surgery. PMID- 22525786 TI - Risk profiles among adolescent nonmedical opioid users in the United States. AB - Although prior research has provided data on nonmedical use of opioids in adolescents, studies examining the heterogeneity of risk are limited. The present study extends prior research by deepening the understanding of adolescent nonmedical opioid use by specifying empirically meaningful profiles of risk. Using data on adolescent non-medical opioid users (N=1783) from the 2008 US National Survey on Drug Use and Health (NSDUH), latent class analysis and multinomial logistic regression were employed to identify latent classes and determine the effects of covariates on class membership. Four latent classes provided the best fit to the data. Classes consisted of a low risk class (33.7%), a high delinquency/low substance use class (17.8%), a high substance use/low delinquency class (34.2%), and finally a high risk class (14.3%) characterized by high levels of both substance use and delinquent behavior. Study findings advance the understanding of adolescent nonmedical opioid use by specifying distinct latent classes. Results suggest that intervention efforts can fruitfully target a number of risk domains especially programs that enhance effective parenting and supervision. PMID- 22525787 TI - Isothermal folding of G-quadruplexes. AB - Thermodynamic studies of G-quadruplex stability are an essential complement to structures obtained by NMR or X-ray crystallography. An understanding of the energetics of quadruplex folding provides a necessary foundation for the physical interpretation of quadruplex formation and reactivity. While thermal denaturation methods are most commonly used to evaluate quadruplex stability, it is also possible to study folding using isothermal titration methods. G-quadruplex folding is tightly coupled to specific cation binding. We describe here protocols for monitoring the cation-driven quadruplex folding transition using circular dichroism or absorbance, and for determination of the distribution of free and bound cation using a fluorescence indicator. Together these approaches provide insight into quadruplex folding at constant temperature, and characterize the linkage between cation binding and folding. PMID- 22525789 TI - Chromosome conformation capture on chip in single Drosophila melanogaster tissues. AB - Chromosomes are protein-DNA complexes that encode life. In a cell nucleus, chromosomes are folded in a highly specific manner, which connects strongly to some of their paramount functions, such as DNA replication and gene transcription. Chromosome conformation capture methodologies allow researchers to detect chromosome folding, by quantitatively measuring which genomic sequences are in close proximity in nuclear space. Here, we describe a modified chromosome conformation capture on chip (4C) protocol, which is specifically designed for detection of chromosome folding in a single Drosophila melanogaster tissue. Our protocol enables 4C analyses on a limited number of cells, which is crucial for fly tissues, because these contain relatively low numbers of cells. We used this protocol to demonstrate that target genes of Polycomb group proteins interact with each other in nuclear space of third instar larval brain cells. Major benefits of using D. melanogaster in 4C studies are: (1) powerful and tractable genetic approaches can be incorporated; (2) short generation time allows use of complex genotypes; and (3) compact and well annotated genome. We anticipate that our sensitized 4C method will be generally applicable to detect chromosome folding in other fly tissues. PMID- 22525790 TI - Selection within organisms in the nineteenth century: Wilhelm Roux's complex legacy. AB - Selectionism, or the extension of darwinian chance/selection dynamics beyond the individual level, has a long history in biological thought. It has generated important theories in immunology or neurology, and turns out to be a convincing framework to account for the intrinsic stochastic nature of core events in cellular biology. When looking back at the intellectual origins of selectionism, the essay by the German embryologist Wilhelm Roux, Der Kampf der Theile im Organismus (The Struggle of the Parts in the Organism - 1881) might be one, if not the earliest reference after the darwinian revolution. It describes the individual as a multilevel structure, where each level results from a 'darwinian' struggle of its parts (molecules, cells, tissues, organs). But Roux's theory, far from being a simple extension of natural selection, has complex and even conflictual relationships with darwinism. This essay is worth rediscovering as a subtle historical testimony of the evolutionary and developmental life sciences debates of its time. Moreover, some of its theses may also enrich some current debates among evolutionary biologists over levels of selection, and among cellular and molecular biologists over the status of determinism in biology today. PMID- 22525788 TI - Molecular dynamics simulations of G-DNA and perspectives on the simulation of nucleic acid structures. AB - The article reviews the application of biomolecular simulation methods to understand the structure, dynamics and interactions of nucleic acids with a focus on explicit solvent molecular dynamics simulations of guanine quadruplex (G-DNA and G-RNA) molecules. While primarily dealing with these exciting and highly relevant four-stranded systems, where recent and past simulations have provided several interesting results and novel insight into G-DNA structure, the review provides some general perspectives on the applicability of the simulation techniques to nucleic acids. PMID- 22525791 TI - Ordered mesoporous phenolic resins: highly versatile and ultra stable support materials. AB - Ordered mesoporous phenolic resins and carbons - an advanced class of ultra stable mesoporous materials - offer potential applications in the field of catalysis, electrodes and adsorbents. This review gives an extensive overview of the main principles and the recent progress made in the synthesis of these innovative materials using the soft-template method. Furthermore, the versatility towards functionalization and the incorporation of hetero-atoms in the organic framework of the mesoporous resins and carbons are considered. Finally, the broad range of potential applications is discussed and future perspectives in the field of mesoporous polymers and carbons are given. PMID- 22525793 TI - Synthesis of phenothiazines via ligand-free CuI-catalyzed cascade C-S and C-N coupling of aryl ortho-dihalides and ortho-aminobenzenethiols. AB - A ligand-free CuI-catalyzed cascade C-S and C-N cross coupling of (hetero)aryl ortho-dihalides and ortho-aminobenzenethiols has been developed, and various phenothiazines were synthesized with excellent regioselectivity. A possible mechanism is proposed for the cascade coupling. PMID- 22525794 TI - Critical episodes in the understanding and control of epidemic meningococcal meningitis. AB - Epidemic meningococcal meningitis continues to be an important worldwide cause of morbidity and mortality, especially in developing countries. Throughout its relatively brief history, especially over the past century, a number of 'critical episodes' have occurred that have enhanced our understanding of the disease and allowed for its potential control. This article reviews three such 'episodes': the first effective treatment for the disease; the development of the first effective meningococcal vaccine; and the description of its epidemiology in sub Saharan Africa, where the majority of epidemic meningococcal disease continues to occur. These historical 'episodes' have informed current strategies that may lead to eventual control of epidemic meningococcal meningitis. PMID- 22525796 TI - Cost-effectiveness of routine vaccination of adolescent females against cytomegalovirus. AB - BACKGROUND: Congenital cytomegalovirus (CMV) infection is associated with significant infant morbidity and mortality. A prophylactic vaccine to prevent congenital CMV infection is expected to be available in the near future, and will likely be targeted to adolescent females. METHODS: Using a decision tree, we compared the costs, potential clinical impacts, and cost-effectiveness of the current strategy of no CMV vaccination versus a strategy where all adolescent females are vaccinated against CMV prior to their first pregnancy. Both maternal outcomes related to vaccination, and infant outcomes related to congenital CMV infection, were considered in the model. RESULTS: Under base-case conditions, our analysis suggested that vaccinating all adolescent females against cytomegalovirus would be both less costly and with greater clinical benefits than not vaccinating. Among a population of 100,000 adolescent females, the vaccination strategy cost $32.3 million dollars less than not vaccinating, and avoided substantial numbers of infants affected with hearing loss, vision loss, and mental retardation, and 8 infant deaths. Our model was most sensitive to variations in vaccine efficacy. When vaccine efficacy against disease was less than 61%, not vaccinating became the preferred strategy because it was less expensive than vaccinating, without substantial changes in clinical benefits to the population. CONCLUSIONS: Under a wide variety of conditions, universal vaccination of adolescent females to protect their future children against congenital CMV infection was cost effective. However, for this to be preferred over not vaccinating, our results suggest that vaccine efficacy against disease would need to be at least 61%. PMID- 22525795 TI - Natural killer cell mediated pathogenesis determines outcome of central nervous system infection with Venezuelan equine encephalitis virus in C3H/HeN mice. AB - TC83 is a human vaccine with investigational new drug status and is used as a prototype Venezuelan equine encephalitis virus for pathogenesis and antiviral research. Differing from other experimental models, the virus causes high titer infection in the brain and 90-100% mortality in the C3H/HeN murine model. To better characterize the susceptibility to disease development in C3H/HeN mice, we have analyzed the gene transcriptomes and cytokine production in the brains of infected mice. Our analysis indicated the potential importance of natural killer cells in the encephalitic disease development. This paper describes for the first time a pathogenic role for natural killer cells in VEEV encephalitis. PMID- 22525798 TI - Status of medical parasitology in South Africa: new challenges and missed opportunities. AB - In South Africa medical parasitology is neglected due to a shift in funding priorities to focus on HIV, tuberculosis and malaria. Evidence suggests that helminth infections have deleterious effects on HIV and tuberculosis. A multisectoral approach involving key government and research institutions is required to rekindle interest in medical parasitology. PMID- 22525797 TI - Use of surveillance data to estimate the effectiveness of the 7-valent conjugate pneumococcal vaccine in children less than 5 years of age over a 9 year period. AB - BACKGROUND: Case-control studies evaluating post-licensure effectiveness of conjugate vaccines can be laborious and costly. We applied an indirect cohort method to evaluate the effectiveness of seven-valent pneumococcal conjugate vaccine (PCV7) against invasive pneumococcal disease (IPD) and compared the results to the effectiveness measured using a standard case-control study conducted during the same time period. METHODS: IPD cases among children 2-59 months old were identified through the Active Bacterial Core surveillance system during 2001-2009. We used logistic regression to calculate the odds ratio of vaccination (versus no vaccination) among cases (PCV7-type IPD cases) and non cases (non-PCV7-type IPD cases), controlling for the presence of underlying conditions. Vaccine effectiveness (VE) was calculated as one minus the adjusted odds ratio. RESULTS: Among 4225 IPD cases reported during 2001-2009, 2680 (63%) had serotype information and vaccine history. Effectiveness of >= 1 dose of PCV7 against PCV7-types was 88% (95% confidence interval (CI) 78-94%) among children with comorbid conditions and 97% (95% CI 92-98%) among healthy children. Among healthy children, VE was higher in 2001-2003 (97%, 95% CI 95-98%) compared to 2004-2009 (81%, 95% CI 64-90%). The annual estimates of VE in 2004-2009 showed great variability and wide confidence intervals due to the small number of PCV7 type cases. CONCLUSIONS: An indirect cohort design using IPD surveillance data confirms the findings of the case-control study and, therefore, appears suitable for estimating PCV7 effectiveness. This method would be most useful shortly after vaccine introduction, and less useful in a setting of very high vaccine coverage and fewer vaccine-type cases. PMID- 22525799 TI - A functional motor unit in the culture dish: co-culture of spinal cord explants and muscle cells. AB - Human primary muscle cells cultured aneurally in monolayer rarely contract spontaneously because, in the absence of a nerve component, cell differentiation is limited and motor neuron stimulation is missing. These limitations hamper the in vitro study of many neuromuscular diseases in cultured muscle cells. Importantly, the experimental constraints of monolayered, cultured muscle cells can be overcome by functional innervation of myofibers with spinal cord explants in co-cultures. Here, we show the different steps required to achieve an efficient, proper innervation of human primary muscle cells, leading to complete differentiation and fiber contraction according to the method developed by Askanas. To do so, muscle cells are co-cultured with spinal cord explants of rat embryos at ED 13.5, with the dorsal root ganglia still attached to the spinal cord slices. After a few days, the muscle fibers start to contract and eventually become cross-striated through innervation by functional neurites projecting from the spinal cord explants that connecting to the muscle cells. This structure can be maintained for many months, simply by regular exchange of the culture medium. The applications of this invaluable tool are numerous, as it represents a functional model for multidisciplinary analyses of human muscle development and innervation. In fact, a complete de novo neuromuscular junction installation occurs in a culture dish, allowing an easy measurement of many parameters at each step, in a fundamental and physiological context. Just to cite a few examples, genomic and/or proteomic studies can be performed directly on the co-cultures. Furthermore, pre- and post-synaptic effects can be specifically and separately assessed at the neuromuscular junction, because both components come from different species, rat and human, respectively. The nerve-muscle co-culture can also be performed with human muscle cells isolated from patients suffering from muscle or neuromuscular diseases, and thus can be used as a screening tool for candidate drugs. Finally, no special equipment but a regular BSL2 facility is needed to reproduce a functional motor unit in a culture dish. This method thus is valuable for both the muscle as well as the neuromuscular research communities for physiological and mechanistic studies of neuromuscular function, in a normal and disease context. PMID- 22525800 TI - Intraparenchymal injection of bone marrow mesenchymal stem cells reduces kidney fibrosis after ischemia-reperfusion in cyclosporine-immunosuppressed rats. AB - Ischemia-reperfusion and immunosuppressive therapy are a major cause of progressive renal failure after kidney transplantation. Recent studies have shown that administration of bone marrow mesenchymal stem cells (MSCs) improves kidney functional recovery in the acute phase of post ischemia-reperfusion injury. In the present study, we used an original model of renal ischemia-reperfusion in immunosuppressed rats (NIRC) to investigate the effects of bone marrow MSCs on progression of chronic renal failure and the mechanisms potentially involved. Left renal ischemia-reperfusion (IR) was induced in unilateral nephrectomized Lewis rats. After IR, rats were treated daily with cyclosporine (10 mg/kg SC) for 28 days. MSCs were injected into the kidney at day 7 after IR. At day 28 after IR, kidneys were removed for histomorphological, biochemical, and gene expression analysis. The effect of conditioned media from MSCs on epithelial-mesenchymal transition was studied in vitro on HK2 cells. Our results show that, as compared to untreated NIRC rats, rats treated by intrarenal injection of MSCs 7 days after IR displayed improvement in renal function, reduction of interstitial fibrosis, and decrease in chronic tubule injury. These effects were associated with a decrease in interstitial alpha-SMA accumulation and MMP2 activity, markers of fibroblast/fibroblast-like cell activation, and renal remodeling, respectively. Finally, experiments in vitro showed that MSC-conditioned medium prevented epithelial-mesenchymal transition induced by TGF-beta in HK2 cells. In conclusion, our results show that, in immunosuppressed animals, a single intrarenal administration of MSCs reduced renal fibrosis and promoted the recovery of renal function. PMID- 22525801 TI - Implementation and practical application of the nutrition care process in the dialysis unit. AB - The Nutrition Care Process (NCP) was introduced in 2003 (Lacey and Pritchett, J Am Diet Assoc. 2003;103:1061-1071). Since then, dietitians have been encouraged to incorporate the NCP into their daily practice, yet it has not been totally adopted in all dialysis units (Dent and McDuffie, J Ren Nutr. 2011;1:205-207). The renal dietitian has the benefit of being able to follow-up with the dialysis patient on a monthly basis. During these monthly visits, as information unfolds, a unique relationship culminates with the dialysis patient. The NCP allows the dietitian to make precise nutrition diagnoses, which reflect the complexity of the renal dietitian's involvement with the dialysis patient. The purpose of this article is to provide a brief description of the NCP as it relates to dialysis, offer a framework on how to begin using the NCP in the dialysis unit, and provide an example of a monthly nutrition note. PMID- 22525803 TI - Development of a cancer clinical trials multi-media intervention: clinical trials: are they right for you? AB - OBJECTIVE: To describe processes used to develop a multi-media psycho-educational intervention to prepare patients for a discussion about cancer clinical trials (CTs). METHODS: Guided by a Steering Committee, formative research was conducted to develop an informative and engaging tool about cancer CTs. Twenty-three patients and caregivers participated in formative in-depth interviews to elicit information about perceptions of cancer CTs to inform production of a new media product. RESULTS: Formative research revealed participants had concerns about experimentation, held beliefs that cancer CTs were for patients who had no other treatment options, and wanted a balance of information about pros and cons of CT participation. The value of physicians as credible spokespersons and the use of patients as role-models were supported. Using iterative processes, the production team infused the results into creation of a multimedia psycho-educational intervention titled Clinical Trials: Are they Right for You? CONCLUSION: An intervention, developed through an iterative consumer-focused process involving multiple stakeholders and formative research, may result in an engaging informative product. PRACTICE IMPLICATIONS: If found to be efficacious, Clinical Trials: Are they Right for You? is a low-cost and easily disseminated multimedia psycho-educational intervention to assist cancer patients with making an informed decision about cancer CTs. PMID- 22525804 TI - Clients as conversational agents. AB - OBJECTIVE: Conversational agency is our invented term that orients us to ways in which clients participate in therapeutic dialogues. In this study we examined how clients' conversational correctives and initiatives influenced collaborative therapeutic consultations. METHODS: Thirty-five single-session lifestyle consultations were videotaped in which adult clients volunteered to discuss concerns of non-clinical severity with a counselor. We discursively microanalyzed excerpts where clients initiated topic shifts or corrected counselor misunderstandings and how counselors responded to them. RESULTS: Clients were actively involved in co-managing conversational developments during the consultations. They influenced the content and course of the conversations with the counselors by correcting, interrupting, or speaking from positions contrary or unrelated to those of the counselors. CONCLUSION: Clients observably influenced the conversational agenda through their correctives and initiatives if counselors were responsive during face-to-face consultations. PRACTICE IMPLICATIONS: Clinicians should demonstrate increased sensitivity and relational responsivity by intentionally engaging with clients' agentive contributions to consultative dialogues. PMID- 22525802 TI - The use of financial incentives in promoting smoking cessation. AB - OBJECTIVE: Cigarette smoking is the leading cause of preventable death in the United States and world. Despite the availability of numerous therapies for smoking cessation, additional efficacious interventions are greatly needed. We provide a narrative review of published studies evaluating financial incentives for smoking cessation and discuss the parameters important for ensuring the efficacy of incentive interventions for smoking cessation. METHODS: Published studies that evaluated the impact of incentives to promote smoking cessation and included an appropriate control or comparison condition were identified and reviewed. RESULTS: Incentives are efficacious for promoting smoking abstinence across the general population of smokers as well as substance abusers, adolescents, patients with pulmonary disease, patients with serious mental illness and other challenging subgroups. To develop and implement an effective incentive treatment for smoking, special attention should be paid to biochemical verification of smoking status, incentive magnitude and the schedule of incentive delivery. CONCLUSION: Consistent with the extensive literature showing that incentives are effective in reducing illicit drug use, a large body of evidence supports their effectiveness in reducing smoking. Continued efforts are warranted to further develop and disseminate incentive-based treatments for smoking cessation across clinical settings and populations. PMID- 22525805 TI - Platinum nanoparticles reduce ovariectomy-induced bone loss by decreasing osteoclastogenesis. AB - Platinum nanoparticles (PtNP) exhibit remarkable antioxidant activity. There is growing evidence concerning a positive relationship between oxidative stress and bone loss, suggesting that PtNP could protect against bone loss by modulating oxidative stress. Intragastric administration of PtNP reduced ovariectomy (OVX)- induced bone loss with a decreased level of activity and number of osteoclast (OC) in vivo. PtNP inhibited OC formation by impairing the receptor activator of nuclear factor-kappaB ligand (RANKL) signaling. This impairment was due to a decreased activation of nuclear factor-kappaB and a reduced level of nuclear factor in activated T-cells, cytoplasmic 1 (NFAT2). PtNP lowered RANKL-induced long lasting reactive oxygen species as well as intracellular concentrations of Ca(2+) oscillation. Our data clearly highlight the potential of PtNP for the amelioration of bone loss after estrogen deficiency by attenuated OC formation. PMID- 22525807 TI - Parenting behaviors of African American and Caucasian families: parent and child perceptions, associations with child weight, and ability to identify abnormal weight status. AB - This study examined the agreement between parent and child perceptions of parenting behaviors, the relationship of the behaviors with the child's weight status, and the ability of the parent to correctly identify weight status in 176 parent-child dyads (89 Caucasian and 87 African American). Correlational and regression analyses were used. Findings included moderate to weak correlations in child and parent assessments of parenting behaviors. Caucasian dyads had higher correlations than African American dyads. Most parents correctly identified their own and their child's weight status. Parents of overweight children used increased controlling behaviors, but the number of controlling behaviors decreased when the parent expressed concern with their child's weight. PMID- 22525806 TI - The inhibitory effect of rapamycin on the oval cell response and development of preneoplastic foci in the rat. AB - Oval cell activation occurs under conditions of severe liver injury when normal hepatocyte proliferation is blocked. Recent studies have shown that a subset of hepatocellular carcinomas expresses oval cell markers, suggesting that these cells are targets of hepatocarcinogens. However, the signaling pathways that control oval cell activation and proliferation are not well characterized. Based on the role of the nutrient signaling kinase complex, mTORC1, in liver development, we investigated the role of this pathway in oval cell activation. Oval cell proliferation was induced in male Fisher rats by a modification of the traditional choline deficient plus ethionine model (CDE) or by 2 acetylaminoflourene treatment followed by 2/3 partial hepatectomy with or without initiation by diethylnitrosamine. To assess the role of mTOR in the oval cell response and development of preneoplastic foci, the effect of the mTORC1 inhibitor, rapamycin, was studied in all models. Rapamycin induced a significant suppression of the oval cell response in both models, an effect that coincided with a decrease in oval cell proliferation. Rapamycin administration did not affect the abundance of neutrophils or natural killer cells in CDE-treated liver or the expression of key cytokines. Gene expression studies revealed the fetal hepatocyte marker MKP-4 to be expressed in oval cells. In an experimental model of hepatic carcinogenesis, rapamycin decreased the size of preneoplastic foci and the rate of cell proliferation within the foci. mTORC1 signaling plays a key role in the oval cell response and in the development of preneoplastic foci. This pathway may be a target for the chemoprevention of hepatocellular carcinoma. PMID- 22525808 TI - Coping with autism: a journey toward adaptation. AB - As the number of individuals with autism grows, it is critical for nurses in all settings to understand how autism influences the family unit, as they will likely interact with these children, the adults, and their families. The intent of this descriptive narrative study was to explore the experiences of families of individuals with autism as perceived by the mother. Through personal interviews, 16 mothers' perceptions of the impact of autism on the family unit during different stages of the life cycle were revealed through a constructivist lens. Pediatric nurses employed in acute care settings, community, and schools are poised to assess and support these families following diagnosis and throughout the child's life. PMID- 22525809 TI - Social regulation of the stress response in the transitional newborn: a pilot study. AB - The purpose of the study was to explore relationships between caregiver holding and feeding behaviors and the transitional newborn infant's cortisol response. Behaviors of 46 mothers, fathers, and their term transitional newborn infants were measured with the Index of Mother-Infant Separation (IMIS). Repeated measures of infant salivary cortisol were used to calculate area under the curve. A higher percentage of observations in which mother was holding infant was related to lower infant total cortisol during the first 6 hours after birth (r = .24, p = .05, one-tailed). PMID- 22525810 TI - Pediatric trichotillomania: clinical presentation, treatment, and implications for nursing professionals. AB - Trichotillomania (TTM), or compulsive hair pulling, is a disorder that typically onsets in childhood. It is mistaken to believe that children will "age out" of this behavior, as pediatric TTM often has a chronic, debilitating course that does not remit without treatment, resulting in considerable psychological and physical impairment. Because most children with TTM will be seen initially by nursing professionals in the practices of dermatologists, pediatricians, gastroenterologists, and other disciplines, raising nurses' awareness of this disorder is of the utmost importance for accurate nursing diagnosis and assessment. As the health care providers who spend the greatest amount of time with patients, nurses' detection and diagnosis of TTM can make a critical difference in the initiation of early intervention. Therefore, the purpose of this article is to provide an overview of pediatric TTM, including its epidemiology, clinical presentation, and treatment options, from the perspective of nurses who may interact with such patients in their workplace. PMID- 22525811 TI - Skin Protection for (SPF) Kids Program. AB - Skin cancer is increasing faster than any other cancer in the United States. Individuals who have had excessive sun exposure during childhood and adolescence set the stage for the development of skin cancers later in life. In 2009, there were more than 1 million newly diagnosed cases of skin cancer in the United States. This primary prevention program combined the guidelines in the literature resulting in a unique evidence-based program for teachers and informational guidelines for parents. These guidelines were used in classrooms and at home, supporting intervention among school-age children, specifically those in kindergarten through fifth grade. PMID- 22525812 TI - Temperature measurement in pediatrics: a comparison of the rectal method versus the temporal artery method. AB - The purpose of this study was to determine if there is a difference between temperature readings obtained using two different electronic temperature devices: one measuring temporal artery temperature (TAT) and one measuring rectal temperature (RT). A comparative single-group design was used with each participant acting as his or her control. The sample consisted of 47 pediatric patients between 3 and 36 months of age. Data analysis revealed no statistically significant differences between TAT and RT; however, concerns related to statistical significance versus clinical significance are discussed. PMID- 22525813 TI - The impact of child tube feeding on maternal emotional state and identity: a qualitative meta-analysis. AB - Literature on mothers' acceptance of their children's tube feeding is heterogeneous. When a child is fed via gastrostomy, parents may report higher quality of life and higher stress levels. Qualitative research suggests that tube feeding can conflict with fundamental expectations about the mothering role. In this qualitative meta-analysis, parental statements from various studies have been excerpted and theory-based analyzed. Data suggest that feeding a child orally is not only an important aspect of mothering but also a key element for the development of a motherhood identity. Nonoral feeding often results in psychological stress and a struggle to negotiate the motherhood identity successfully and may result in traumatization of the mother. Preventive psychological guidance is recommended to decrease the risk of posttraumatic stress disorder in mothers and disturbances in the mother-child relationship and to assist in maternal coping with a child's feeding disorder. PMID- 22525814 TI - Self-reported health, self-management, and the impact of living with inflammatory bowel disease during adolescence. AB - Perceptions of living with inflammatory bowel disease (IBD) during adolescence were explored in a cross-sectional study with a multimethod design. The adolescents as a group described general well-being and ability to handle the disease, which was related to their self-reported self-esteem. However, a subgroup of adolescents with a severe disease course reported a more negative view of the impact of IBD in their daily lives. Encouraging adolescents to communicate in different ways may help professionals to identify vulnerable subgroups with impaired health and to provide more appropriate support and treatment for those most in need. PMID- 22525815 TI - Rectal versus axillary temperatures: is there a significant difference in infants less than 1 year of age? AB - There are identified gaps regarding the accuracy of axillary temperatures as a means of predicting core temperatures in infants and children. This article discusses the relationship between rectal and axillary temperatures in infants less than 1 year of age. This quality improvement project evaluated 425 paired temperature measurements in 86 infants admitted to an inpatient pediatric unit over a 2-month period. A correlation analysis showed statistically significant differences between the two measurements. The results of this project promoted the development of a standard of care for temperature measurement at the project facility. PMID- 22525816 TI - New knowledge, innovations, and improvement in a Magnet(r) Children's Hospital Cardiac Center. AB - Bedside nurses involved in research and evidence-based practice (EBP) have the ability to change policies, patient care, and outcomes. This article describes the journey of a research committee using the Magnet(r) component of new knowledge, innovation, and improvements. Using several tools, the unit-based committee developed skills in meeting management, nursing research methods, and EBP. Focusing to improve family and nurse communication about the plan of care, the committee recommended changes in the existing Plan of Care tool, including family input and recommendations for families to view and add to the sheet and participate in daily rounds, which was not the standard practice. Since this intervention was implemented, patient satisfaction has increased, as well as nurse engagement and intent to stay. This project exemplifies how nurse-driven innovations and family partnership led to new knowledge, innovations in learning about research, applying it to practice, and improving practice. PMID- 22525817 TI - Asymmetric pore occupancy in crystal structure of OmpF porin from Salmonella typhi. AB - OmpF is a major general diffusion porin of Salmonella typhi, a Gram-negative bacterium, which is an obligatory human pathogen causing typhoid. The structure of S. typhi Ty21a OmpF (PDB Id: 3NSG) determined at 2.8 A resolution by X-ray crystallography shows a 16-stranded beta-barrel with three beta-barrel monomers associated to form a trimer. The packing observed in S. typhi Ty21a rfOmpF crystals has not been observed earlier in other porin structures. The variations seen in the loop regions provide a starting point for using the S. typhi OmpF for structure-based multi-valent vaccine design. Along one side of the S. typhi Ty21a OmpF pore there exists a staircase arrangement of basic residues (20R, 60R, 62K, 65R, 77R, 130R and 16K), which also contribute, to the electrostatic potential in the pore. This structure suggests the presence of asymmetric electrostatics in the porin oligomer. Moreover, antibiotic translocation, permeability and reduced uptake in the case of mutants can be understood based on the structure paving the way for designing new antibiotics. PMID- 22525818 TI - Angiotensin II type I receptor and miR-155 in endometrial cancers: synergistic antiproliferative effects of anti-miR-155 and losartan on endometrial cancer cells. AB - OBJECTIVE: MicroRNA-155 (miR-155) is one of the micro RNAs (miRNA) most consistently involved in neoplastic diseases, and it is known to repress the angiotensin II type 1 receptor (AGTR1). The aim of the present study was to evaluate the expressions of miR-155 and AGTR1, and to clarify the potential efficacy of anti-miR-155, alone and in combination with AGTR1 blocker losartan in endometrial cancers. METHODS: Expressions of miR-155 and AGTR1 were evaluated using real-time PCR and immunohistochemistry. And the MTT assay was performed in endometrial cancer cells following anti-miR-155 and AGTR1 blocker (losartan) treatment, alone and in combination. RESULTS: miR-155 was over-expressed and AGTR1 was underexpressed in endometrial carcinoma tissues. AGTR1 immunoreactivity was found in six of ten (60.0%) normal endometrium, 11 of 14 (78.6%) endometrial hyperplasia, and 27 of 62 (43.5%) endometrial carcinoma tissues (P=0.051), and patients with AGTR1 expression showed trend towards improved survival after multivariate analysis (P=0.08). We checked that abolishing the function of miR 155 and AGTR1 by anti-miR-155 or losartan inhibited cell survival of endometrial carcinoma cells, respectively, and furthermore, combined treatment showed synergistic effects. CONCLUSIONS: In this study, we characterized the expressions of miR-155 and AGTR1 in endometrial tissues. The combined treatment with anti-miR 155 and losartan has a synergistic antiproliferative effect and an improved understanding is required to clarify whether miR-155 and AGTR1 can be used as a novel therapeutic target in endometrial cancer. PMID- 22525819 TI - HE4 is an independent prognostic marker in endometrial cancer patients. AB - OBJECTIVE: To evaluate the prognostic value of pretherapeutic serum HE4 in endometrial cancer in comparison to CA125. METHODS: HE4 and CA125 serum levels were analyzed by means of chemiluminescent microparticle immunoassays in 183 patients with endometrial cancer treated at the Department of Obstetrics and Gynecology, Innsbruck Medical University, between 1999 and 2009. The Kaplan-Meier method and Cox's proportional hazards analysis were performed to determine the prognostic significance of HE4, CA125 and the combination of both markers. RESULTS: In univariate analysis both markers, HE4 and CA125, were of prognostic value for overall survival (p<0.001 and p=0.028) and disease-free survival (p=0.015 and p=0.045). In multivariate analysis HE4 was seen to have independent prognostic value in overall survival (HR 2.407, p=0.017) in contrast to CA125. The combination of both markers showed a higher hazard ratio (HR 4.04, p=0.023) for overall survival in comparison to HE4 alone. In the subgroup endometrioid histological type (n=132) only HE4 was of prognostic value for overall survival in univariate (p=0.001) and multivariate analysis (p=0.023). CONCLUSIONS: Pretherapeutic serum HE4 levels alone and in combination with CA125 are an independent prognostic marker in endometrial cancer patients. PMID- 22525820 TI - Clear cell carcinoma of the ovary: a review of the literature. AB - OBJECTIVE: Different histologic types of epithelial ovarian cancer may represent different diseases with unique clinical and molecular characteristics. Clear cell carcinoma (CCC) of the ovary has been reported as having a worse prognosis than high grade serous epithelial ovarian cancer (EOC). This article critically reviews the literature pertinent to the pathology, pathogenesis, diagnosis, management, and outcome of patients with ovarian CCC. METHODS: MEDLINE was searched for all research articles published in English between January 01, 1977 and January 30, 2012 which reported on patients diagnosed with ovarian CCC. Given the rarity of this tumor, studies were not limited by design or number of reported patients. RESULTS: Ovarian CCC tumors represent 5-25% of ovarian cancers. Its histologic diagnosis can be challenging, resulting often times in misclassification of these tumors. Ovarian CCC tends to present at earlier stages and has been associated with endometriosis, ARID1A and PIK3CA mutations. When compared to stage-matched controls, patients with early-stage ovarian CCCs may have a better prognosis than patients with high-grade serous tumors. For those with advanced stage disease, high-grade serous histology confers a better prognosis than ovarian CCC. Patients with Stage IC-IV have a relatively poor prognosis and efforts should center in discovery of more effective treatment strategies. CONCLUSIONS: Ovarian CCC is a biologically distinct entity, different from high-grade serous EOC. Future studies should explore the role of targeted therapies in the management of ovarian CCC. PMID- 22525821 TI - Inter-hemispheric competition relieved in both: hypotheses for autism and schizophrenia from problem theory. AB - A logical relationship exists among six general problems that people face in life. Using hope about something for its subjective probability, its expected likelihood, the problems form a series where the method of assessing hope changes in a simple manner from one problem to the next. The central hypothesis is that human beings exploit this. Brain structures and predispositions have evolved accordingly, leading to the hemispheres having different predispositions. The hemispheres are effectively joined at 5 months. Infants will then find that they engage in two unrelated activities. Typical infants label the activities in detail, using visual images, as part of gaining control over them. Hypotheses are: (a) autistic children fail labelling at the start, and hence they encounter uncontrolled competition between the hemispheres; (b) with some, serotonin abnormality impairs sensory information processing and hence the labelling; (c) with some, a delay in myelination from autoimmune effects disrupts labelling; (d) the likelihood of this 'delay autism' is reduced by long chain omega oils; (e) self-pressuring, which underlies taking on challenges and play like Hide and Seek, brings relief from the competition by raising the influence of one side; (f) the same left-right competition occurs in confused episodes and schizophrenia in vulnerable people who encounter pressures to use both hemispheres at the same time; (g) some symptoms raise the influence on one side ideationally. This leads to coherent theories of autism and schizophrenia. In both competition between the hemispheres is relieved primarily by self-pressuring, which raises influence on one side. PMID- 22525822 TI - Association between traditional cholesterol parameters, lipoprotein particle concentration, novel biomarkers and carotid plaques in retired National Football League players. AB - OBJECTIVES: We assessed whether low-density lipoprotein particle concentration (LDL-P) and high-sensitivity C-reactive protein [hs-CRP] can identify subclinical atherosclerosis better than traditional cholesterol parameters in retired National Football League (NFL) players. BACKGROUND: It is not known whether LDL-P and the biomarker hs-CRP can identify subclinical atherosclerosis better than low density lipoprotein cholesterol (LDL-C) or non-high-density-lipoprotein cholesterol (non-HDL-C) in retired NFL players, given high prevalence of metabolic syndrome in these players. METHODS: Carotid artery plaque screening was performed with traditional lipids, LDL-P, and hs-CRP in 996 retired players. Logistic regression analyses comparing highest with the lowest quartile were performed. RESULTS: Carotid artery plaques were seen in 41%. LDL-C (odds ratio [OR] 1.66, 95% confidence interval [CI] 1.06-2.59), non-HDL-C (OR 1.67, 95% CI 1.04-2.67), and LDL-P (OR 2.21, 95% CI 1.35-3.62) were associated with plaques in adjusted models. Among 187 retired players with metabolic syndrome, LDL-C (OR 1.40, 95% CI 0.53-3.72) was not associated with carotid plaques, whereas LDL-P (OR 3.71, 95% CI 1.16-11.84) and non-HDL-C (OR 2.63, 95% CI 0.91-7.63, p=0.07; borderline significant) were associated with carotid plaques. hs-CRP (OR 1.13, 95% CI 0.71-1.79) was not associated with carotid plaques. CONCLUSION: Carotid artery plaques were common in retired NFL players and were strongly associated with LDL-P, especially among those with metabolic syndrome. hs-CRP was not associated with carotid plaques in this cohort. PMID- 22525823 TI - Antidepressant-like effect of the novel MAO inhibitor 2-(3,4-dimethoxy-phenyl) 4,5-dihydro-1H-imidazole (2-DMPI) in mice. AB - Monoamine oxidase (MAO) inhibitors were the first antidepressant drugs to be prescribed and are still used today with great success, especially in patients resistant to other antidepressants. In this study, we evaluated the MAO inhibitory properties and the potential antidepressant action of 2-(3,4-dimethoxy phenyl)-4,5-dihydro-1H-imidazole (2-DMPI) in mice. We found that 2-DMPI inhibited both MAO isoforms (K(i) values were 1.53 (1.3-1.8) MUM and 46.67 (31.8-68.4) MUM for MAO-A and MAO-B, respectively) with 30-fold higher selectivity toward MAO-A. In relation to the nature of MAO-A inhibition, 2-DMPI showed to be a mixed and reversible inhibitor. The treatment with 2-DMPI (100-1000 MUmol/kg, s.c.) caused a significant decrease in immobility time in the tail suspension test (TST) without affecting locomotor activity, motor coordination or anxiety-related activities. Conversely, moclobemide (1000 MUmol/kg, s.c.) caused a significant increase in immobility time in the TST, which appeared to be mediated by a nonspecific effect on motor coordination function. 2-DMPI (300 MUmol/kg, s.c.) decreased serotonin turnover in the cerebral cortex, hippocampus and striatum, whereas dopamine turnover was diminished only in the striatum, and norepinephrine turnover was not changed. The antidepressant-like effect of 2-DMPI was inhibited by the pretreatment of mice with methysergide (2 mg/kg, s.c., a non-selective serotonin receptor antagonist), WAY100635 (0.1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist) or haloperidol (0.05 mg/kg, i.p., a non-selective dopamine receptor antagonist). These results suggest that 2-DMPI is a prototype reversible and preferential MAO-A inhibitor with potential antidepressant activity, due to its modulatory effect on serotonergic and dopaminergic systems. PMID- 22525824 TI - cAMP pathway and pituitary tumorigenesis. AB - The pituitary is the target of different neurohormones that have a crucial role in the control of cell differentiation, cell proliferation and hormone secretion by recognizing specific receptors belonging to the G Protein-Coupled Receptor super-family (GPCR). Evidence from in vitro studies and naturally occurring human diseases indicate that several endocrine cells, and particularly somatotrophs, recognize cAMP as a growth factor. Accordingly, mutations of the alpha subunit of the stimulatory G protein gene (GNAS) leading to the constitutive activation of adenylyl cyclase (i.e. gsp oncogene) have been recognized in a significant proportion of GH-secreting pituitary adenomas. The role of cAMP in the control of cell proliferation in selected cell types and in particular in somatotroph cells has been further confirmed by identification of genetics defect affecting the regulatory subunit IA of PKA. The role of cAMP in the control of cell proliferation as well as the crosstalk with different intracellular signalling pathways will be discussed. PMID- 22525825 TI - Occurrence and distribution of antibiotics in the Beibu Gulf, China: impacts of river discharge and aquaculture activities. AB - The occurrence and distribution of eleven selected antibiotics belonging to three groups were investigated in the Beibu Gulf. In addition, the potential effects of water discharged from four rivers and aquaculture activities were analyzed. Erythromycin-H2O, sulfamethoxazole and trimethoprim were the most frequently detected compounds, with mean concentrations ranging from 0.51 to 6.30 ng L-1. The concentrations of the rivers were generally higher than those of the gulf, implying that river discharge has an important effect on the Beibu Gulf. The concentrations of erythromycin-H2O, sulfamethoxazole and sulfadimidine in the vicinity of aquaculture activities were higher, suggesting that a higher intensity of aquaculture activities could contribute to increasing levels of antibiotics in the environment. According to MEC (measured environmental concentration)/PNEC (predicted no-effect concentration), erythromycin, sulfamethoxazole and clarithromycin may present possible environmental risk to Pseudokirchneriella subcapitata, Synechococcus leopoliensis and P. subcapitata, respectively; therefore, attention should be given to the long-term ecological effects caused by the continuous discharge of antibiotics in the Beibu Gulf. PMID- 22525827 TI - Liver transplantation: Left lobe living donor liver transplantation could improve donor outcomes. PMID- 22525828 TI - IBD: Mucosal healing--EXTENDing our knowledge in Crohn's disease. PMID- 22525830 TI - Particle counting and microbiological air sampling: results of the simultaneous use of both procedures in different types of hospital rooms. AB - INTRODUCTION: In order to assess the relationship between the concentrations of airborne fungi and particles, particle counting was combined with fungal air sampling in several rooms of a hospital. METHODS: Concentrations of >=0.5MUm particles (P05) and >=1MUm particles (P1) were measured using a particle counter; fungal air sampling was performed with volumetric air samplers, which impacted air on Rodac plates with Sabouraud chloramphenicol agar. Particle counts were categorised according to ISO 14644-1 standard cut-off points; their association with fungal detection was assessed with Fisher's exact test. RESULTS: Forty-two simultaneous samplings were carried out: 24 in operating rooms, 13 in rooms for burns or haematology patients, 3 in pharmacy clean rooms, and two in other procedure rooms. Filamentous fungi were recovered in 5 samples, which also had higher particle counts. No fungi were detected in 12 samplings with both P05 and P1 concentrations below the maximum for class 6 clean rooms; 4 of 7 samplings with both concentrations within the range for class 8 clean rooms were positive for fungi. The association between fungal detection and higher particle counts was statistically significant, both for P05 (p=.004) and P1 (p=.003). There was a partial overlap between the concentrations of particles of samplings which were positive or negative for fungi. CONCLUSIONS: There is a relationship between the concentrations of P05 and P1 and airborne fungi in hospital rooms. When both P05 and P1 concentrations are below the maximum for class 6 clean rooms, a negative fungal detection can be predicted. PMID- 22525831 TI - Critical thinking in clinical nurse education: application of Paul's model of critical thinking. AB - Nurse educators recognize that many nursing students have difficulty in making decisions in clinical practice. The ability to make effective, informed decisions in clinical practice requires that nursing students know and apply the processes of critical thinking. Critical thinking is a skill that develops over time and requires the conscious application of this process. There are a number of models in the nursing literature to assist students in the critical thinking process; however, these models tend to focus solely on decision making in hospital settings and are often complex to actualize. In this paper, Paul's Model of Critical Thinking is examined for its application to nursing education. I will demonstrate how the model can be used by clinical nurse educators to assist students to develop critical thinking skills in all health care settings in a way that makes critical thinking skills accessible to students. PMID- 22525829 TI - [Costs and cost-efficacy analysis of the preferred treatments by GESIDA/National Plan for AIDS for the initial antiretroviral therapy in adult human immunodeficiency virus (HIV) infected patients in 2012]. AB - INTRODUCTION: The GESIDA and National AIDS Plan panel of experts propose "preferred regimens" of antiretroviral treatment (ART) as initial therapy in HIV infected patients for 2012. The objective of this study is to evaluate the costs and the efficiency of initiating treatment with these "preferred regimens". METHODS: Economic assessment of costs and efficiency (cost/efficacy) using decision tree analysis model. Efficacy was defined as the probability of having a viral load <50 copies/ml at week 48, in an intention-to-treat analysis. Cost of initiating treatment with an ART regime was defined as the costs of ART and all its consequences (adverse effects, changes of ART regime, and drug resistance analyses) during the first 48 weeks. The perspective of the analysis is that of the National Health System, considering only differential direct costs: ART (official prices), management of adverse effects, studies of resistance and determination of HLA B 5701. The setting is Spain and the costs are those of 2012. A sensitivity deterministic analysis was conducted, building three scenarios for each regime: baseline, most favourable, and most unfavourable cases. RESULTS: In the baseline case scenario, the cost of initiating treatment ranges from 6,895 euros for TDF/FTC+NVP to 12,067 euros for TDF/FTC+RAL. The efficacy ranges between 0.66 for ABC/3TC+LPV/r and 0.87 for TDF/FTC+RAL. Efficiency, in terms of cost/efficacy, varies between 9,387 and 13,823 euros per responder at 48 weeks, for TDF/FTC/EFV and TDF/FTC+RAL, respectively. In the most unfavourable scenario, the most efficient regime is TDF/FTC+NVP (9,742 per responder). CONCLUSION: Considering the official prices of ART, the most efficient regimens are TDF/FTC/EFV (baseline case and most favourable scenarios), and TDF/FTC+NVP (most unfavourable scenario). PMID- 22525832 TI - Ex vivo mimicry of normal and abnormal human hematopoiesis. AB - Hematopoietic stem cells require a unique microenvironment in order to sustain blood cell formation; the bone marrow (BM) is a complex three-dimensional (3D) tissue wherein hematopoiesis is regulated by spatially organized cellular microenvironments termed niches. The organization of the BM niches is critical for the function or dysfunction of normal or malignant BM(5). Therefore a better understanding of the in vivo microenvironment using an ex vivo mimicry would help us elucidate the molecular, cellular and microenvironmental determinants of leukemogenesis. Currently, hematopoietic cells are cultured in vitro in two dimensional (2D) tissue culture flasks/well-plates requiring either co-culture with allogenic or xenogenic stromal cells or addition of exogenous cytokines. These conditions are artificial and differ from the in vivo microenvironment in that they lack the 3D cellular niches and expose the cells to abnormally high cytokine concentrations which can result in differentiation and loss of pluripotency. Herein, we present a novel 3D bone marrow culture system that simulates the in vivo 3D growth environment and supports multilineage hematopoiesis in the absence of exogenous growth factors. The highly porous scaffold used in this system made of polyurethane (PU), facilitates high-density cell growth across a higher specific surface area than the conventional monolayer culture in 2D. Our work has indicated that this model supported the growth of human cord blood (CB) mononuclear cells (MNC) and primary leukemic cells in the absence of exogenous cytokines. This novel 3D mimicry provides a viable platform for the development of a human experimental model to study hematopoiesis and to explore novel treatments for leukemia. PMID- 22525833 TI - Degradation and detoxification of 4-nitrophenol by advanced oxidation technologies and bench-scale constructed wetlands. AB - The degradation and detoxification towards the duckweed Lemna minor of 4 nitrophenol (4NP) was studied by means of bench-scale constructed wetlands (CWs), TiO(2)-photocatalysis and Fenton + photoFenton reactions. The main goal of this work was to compare the three treatment techniques to evaluate their possible combination for the efficient, low cost treatment of 4NP effluents. In CWs, adsorption on the substrate of 4NP was found to achieve 34-45%. Low concentrations (up to 100 ppm) of 4NP were successfully treated by CWs in 8-12 h. The microbial degradation of 4NP started after a lag phase which was longer with higher initial concentrations of the pollutant. The greatest degradation rate was found to occur at initial concentrations of 4NP between 60 and 90 ppm. Solar TiO(2)-photocatalysis was faster than the CWs. The greatest removals in terms of mass of 4NP removed after 6 h of irradiation were found to occur at 4NP concentrations of about 200 ppm. Fenton reaction provided complete 4NP degradation up to 500 ppm in only 30 min but TOC was removed by only about 40%. The resulting toxicities were below 20% for initial 4NP concentrations below 300 ppm. It was the Fenton + photoFenton combination (180 min in total) that provided TOC reductions up to 80% and negative L. minor growth inhibition for almost all the 4NP concentrations tested. The combination of solar TiO(2)-photocatalysis (6 h) with CWs (16 h) was able to completely treat and detoxify 4NP effluents with concentrations as high as 200 ppm of the organic. PMID- 22525834 TI - Atomized sludges via spray-drying at low temperatures: an alternative to conventional wastewater treatment plants. AB - Removal of sludges from Wastewater Treatment Plants (WWTP) represents a serious worldwide environmental problem for which alternatives other than their simple incineration are investigated. In this work the treatment of raw sludge from urban WWTP by means of a minimization process through spray-drying is analyzed as well as some proposals for revaluating the resulting dry product. Analysis is supported by some experimental results obtained with a laboratory spray dryer. The experimental procedure at laboratory scale is extrapolated to an industrial plant scale. An economic analysis of the proposal in relation to other possible sludge treatments is presented, taking into account in this case the comparison between the costs of the processes of sludge thickening, stabilization and dehydratation and the costs of spray-drying (especially power consumption), minimization of the final waste and reuse options. Finally, an environmental balance of the process is presented. In contrast with the classical treatment line, this alternative allows transforming sludges, i.e., a waste, into a valuable product with several applications. PMID- 22525835 TI - Retinal capillary morphology in the Abyssinian cat with hereditary retinal degeneration. PMID- 22525836 TI - p38 mitogen-activated protein kinase inhibitor reduces neurocan production in cultured spinal cord astrocytes. AB - Chondroitin sulfate proteoglycans are formed in scar tissue after a spinal cord injury and inhibit axon regrowth. The production of neurocan, one of these chondroitin sulfate proteoglycans, in cultured spinal cord astrocytes increased after the addition of epidermal growth factor (EGF) in a dose-dependent manner (2 200 ng/ml). In astrocytes stimulated by 20 ng/ml of EGF, neurocan production was inhibited after the addition of the p38 mitogen-activated protein kinase (MAPK) inhibitor (SB203580: 3-10 MUM) in a dose-dependent manner. These results suggest that the activation of p38 MAPK is one of the mechanisms of neurocan production in EGF-stimulated astrocytes. The p38 MAPK inhibitor may reduce neurocan production and accelerate axonal regrowth after a spinal cord injury. PMID- 22525837 TI - Human placental decidua basalis-derived mesenchymal stem cells differentiate into dopamine neuron-like cells with no response to long-term culture in vitro. AB - Human placental decidua basalis-derived mesenchymal stem cells (DBMSCs) have been identified as valuable sources for cell transplantation. In this study, we found that DBMSCs could be induced to form neural stem cells in the form of neurospheres. These neurospheres were further differentiated into dopamine neuron like cells with a cocktail of cytokines. The differentiated DBMSCs were verified through the presence of a neuron-like morphology, the expression of specific dopamine neuron makers, and the production of dopamine. In addition, this differentiation capacity of DBMSCs was not affected by long-term culture, and the cells maintained a normal karyotype in vitro. The dopamine neuronal differentiation and the relative safety transplantation potential of DBMSCs may facilitate stem cell therapeutic approaches to Parkinson's disease. PMID- 22525839 TI - Vitamin D: metabolism. AB - The biologically active metabolite of vitamin D, 1,25(OH)(2)D(3), affects mineral homeostasis and has numerous other diverse physiologic functions including effects on growth of cancer cells and protection against certain immune disorders. This article reviews the role of vitamin D hydroxylases in providing a tightly regulated supply of 1,25(OH)(2)D(3). The role of extrarenal 1alpha(OH)ase in placenta and macrophages is also discussed, as well as regulation of vitamin D hydroxylases in aging and chronic kidney disease. Understanding specific factors involved in regulating the hydroxylases may lead to the design of drugs that can selectively modulate the hydroxylases. The ability to alter levels of these enzymes would have therapeutic potential for the treatment of various diseases, including bone loss disorders and certain immune diseases. PMID- 22525838 TI - Tumor rejection effects of allorestricted tumor peptide-specific CD4(+) T cells on human cervical cancer cell xenograft in nude mice. AB - Generation of tumor specific alloreactive CD4(+) T cells is important to circumvent tumor tolerance. Here, we generate allorestricted peptide-specific CD4(+) T cells by coculture of lymphocytes and autologous monocytes bearing allogeneic HLA-DR15 molecule associated with its restricted peptide. Binding of a dimeric HLA-DR15/IgG1-Fc fusion protein (the dimer) to HLA-DR15 negative (HLA DR15-ve) monocytes made the monocytes coated with the allogeneic epitope. An increased proliferation of CD4(+) T cells and induction of Th1 cells appeared after coculturing of HLA-DR15-ve lymphocytes and the autologous monocytes loaded with the dimer. The cocultural bulks showed an increased frequency of the specific dimer-stained CD4(+) T cells and the expanded CD4(+) T cells exhibited an elevated IFN-gamma production in response to specific TCR ligand. Tumor rejection effects of the allorestricted E7-specific CD4(+) T cells raised by the coculture were observed in nude mice challenged with human cervical cancer cell SiHa expressing both HLA-DR15 and E7 antigens, as the tumor avoidance and life span of the mice were improved after adoptive transfer of the CD4(+) T cells. This study may help to develop strategies to separate graft-versus-leukemia or graft-versus-tumor reaction from graft-versus-host disease, and add to the pool of human high-avidity TCRs specific for tumor or virus antigens. PMID- 22525840 TI - The vitamin D receptor: new paradigms for the regulation of gene expression by 1,25-dihydroxyvitamin D3. AB - This article represents a summary of what is known of the VDR protein and its molecular mechanism of action at target genes. New methodologies now used, such as ChIP-chip and ChIP-seq, as well as novel reporter studies using large BAC clones stably transfected into culture cells or introduced as transgenes in mice, are providing new insights into how 1,25(OH)2D3-activated VDR modulates the expression of genes at single gene loci and at the level of gene networks. Many of these insights are unexpected and suggest that gene regulation is even more complex than previously appreciated. These studies also highlight new technologies and their central role in establishing fundamental biologic principles. PMID- 22525841 TI - Assessment and interpretation of circulating 25-hydroxyvitamin D and 1,25 dihydroxyvitamin D in the clinical environment. AB - The assessment of circulating 25(OH)D and, to a lesser degree, 1,25(OH)2D is rapidly becoming an important clinical tool in the diagnosis and management of many diverse pathologies. At present, the reference ranges for circulating 25(OH)D and 1,25(OH)2D are 32 to 100 ng/mL and 16 to 56 ng/mL, respectively, and are largely based on clinical data derived from the FDA-cleared DiaSorin assay procedures. PMID- 22525842 TI - Low vitamin D status: definition, prevalence, consequences, and correction. AB - Low vitamin D status is extremely common worldwide due to low dietary intake and low skin production. Suboptimal vitamin D status contributes to many conditions, including osteomalacia/rickets, osteoporosis, falls, and fractures. It is possible or even likely that low vitamin D status increases risk for a multitude of other conditions. Although consensus does not exist, it appears that circulating 25(OH)D concentrations greater than 30 to 32 ng/mL are needed for optimal health. To achieve this, daily intakes of at least 1000 IU of D3 daily are required, and it is probable that substantially higher amounts are required to achieve such values on a population basis. It seems premature to recommend widespread screening for 25(OH)D measurement. Targeted measurement in those at increased risk for vitamin D deficiency and those most likely to have a prompt positive response to supplementation is appropriate. Widespread optimization of vitamin D status likely will lead to prevention of many diseases with attendant reduction of morbidity, mortality, and expense. PMID- 22525843 TI - Maternal vitamin D status: implications for the development of infantile nutritional rickets. AB - The mother is the major source of circulating 25-OHD concentrations in the young infant. Thus maternal vitamin D status is an important factor in determining the vitamin D status of the infant and their risk of developing vitamin D deficiency and infantile nutritional rickets. As a result, breastfed infants of mothers with vitamin D deficiency who are unsupplemented and who receive little sunlight exposure are at high risk of developing vitamin D deficiency or rickets. Despite food fortification policies in many countries and recommendations for vitamin D supplementation of at-risk groups, vitamin D deficiency and infantile rickets remain major public health challenges in many developed and developing countries. There is evidence that the current supplementation recommendations, particularly for pregnant and lactating women, are inadequate to ensure vitamin D sufficiency in these groups. A widespread and concerted effort is needed to ensure daily supplementation of breastfed and other infants at high risk with vitamin D 400 IU from birth and pregnant women in high risk communities with at least 600 IU; awareness needs to be developed among the public and medical practitioners of the urgent need to improve the vitamin D status of pregnant and lactating mothers and their infants. Further studies are required to determine the optimal doses of vitamin D supplementation in pregnancy and during lactation, and for normalizing vitamin D stores in infancy to reduce the prevalence of infantile nutritional rickets. Operational research studies also need to be conducted to understand the best methods of implementing supplementation programs and the factors that are likely to impede their success. PMID- 22525844 TI - Osteomalacia as a result of vitamin D deficiency. AB - Osteomalacia is an end-stage bone disease of chronic and severe vitamin D or phosphate depletion of any cause. Its importance has increased because of the rising incidence of vitamin D deficiency. Yet, not all cases of osteomalacia are cured by vitamin D replacement, and furthermore, not all individuals with vitamin D deficiency develop osteomalacia. Although in the past osteomalacia was commonly caused by malabsorption, nutritional deficiency now is more common. In addition, recent literature suggests that nutritional vitamin D deficiency osteomalacia follows various bariatric surgeries for morbid obesity. Bone pain, tenderness, muscle weakness, and difficulty walking are all common clinical manifestations of osteomalacia. Diagnostic work-up involves biochemical assessment of vitamin D status and may also include a transiliac bone biopsy. Treatment is based on aggressive vitamin D repletion in most cases with follow-up biopsies if patients are started on antiresorptive or anabolic agents. PMID- 22525845 TI - Genetic disorders and defects in vitamin D action. AB - The biochemical and genetic analysis of the VDR in patients with HVDRR has yielded important insights into the structure and function of the receptor in mediating 1,25(OH)2D3 action. Similarly, study of children affected by HVDRR continues to provide a more complete understanding of the biologic role of 1,25(OH)2D3 in vivo. A concerted investigative approach to HVDRR at the clinical, cellular, and molecular levels has proved valuable in gaining knowledge of the functions of the domains of the VDR and elucidating the detailed mechanism of action of 1,25(OH)2D3. These studies have been essential to promote the well being of the families with HVDRR and in improving the diagnostic and clinical management of this rare genetic disease. PMID- 22525846 TI - Vitamin D and fracture prevention. AB - Based on evidence from double-blind RCTs, vitamin D supplementation reduces falls and nonvertebral fractures, including those at the hip. However, this benefit is dose-dependent. According to 2 meta-analysis in 2009 of double-blind RCTs, no fall reduction was observed for a dose of less than 700 IU per day. A higher dose of 700 to 1000 IU supplemental vitamin D per day reduced falls by 19%. Similarly, no fracture reduction was observed for a received dose of 400 IU or less per day. A higher received dose of 482 to 770 IU supplemental vitamin D per day reduced nonvertebral fractures by 20% and hip fractures by 18%. The antifracture effect was present in all subgroups of the older population and was most pronounced among community-dwellers (-29%) and those ages 65 to 74 years (-33%). Consistently, fall prevention and nonvertebral fracture prevention increased significantly with higher achieved 25-hydroxyvitamin D levels in the 2009 meta analyses. Fall prevention occurred with 25-hydroxyvitamin D levels of 60 to 95 nmol/L; levels of 75 to 112 nmol/L were required for nonvertebral fracture prevention. Given the absence of data beyond this beneficial range, these recent meta-analyses do not preclude the possibility that higher doses or higher achieved 25-hydroxyvitamin D concentrations would have been even more efficient in reducing falls and nonvertebral fractures. PMID- 22525847 TI - Vitamin D in kidney disease: pathophysiology and the utility of treatment. AB - CKD is associated with decreased vitamin D metabolites, both the storage form 25(OH)D and the active form 1,25-dihydroxyvitamin D. This contributes to hyperparathyroidism, and increased levels of PTH mobilize minerals from the skeleton and increase the risk for fractures. Treatment with vitamin D sterols efficiently reduces secondary hyperparathyroidism of CKD. Observational studies suggest survival and other potential benefits of vitamin D treatment in the CKD population. These observations need to be verified with controlled prospective trials. PMID- 22525848 TI - Vitamin D and the immune system: new perspectives on an old theme. AB - It is almost 30 years since an interaction between vitamin D and the immune system was first documented. Although this was initially proposed as a nonclassic effect of vitamin D associated with granulomatous diseases, our current view is now changed considerably. Recent studies have shown a potential physiologic role for vitamin D in regulating normal innate and adaptive immunity. Future studies now need to focus on the clinical implications of vitamin D-mediated immunity and, in particular, the possible beneficial effects of supplementary vitamin D with respect to infectious and autoimmune diseases. PMID- 22525849 TI - Vitamin D: extraskeletal health. AB - Vitamin D deficiency is the most common nutritional deficiency and likely the most common medical condition in the world. There is a multitude of causes of vitamin D deficiency, but the major cause has been the lack of appreciation that the body requires 5- to 10-fold higher intakes than is currently recommended by the Institute of Medicine and other health agencies. It is likely that our hunter gatherer fore-fathers being exposed to sunlight on a daily basis were making several thousand IU of vitamin D a day. The fact that 100 IU of vitamin D prevented overt signs of rickets led to the false security that ingesting twice this amount was more than adequate to satisfy the body's vitamin D requirement. Although this may be true for preventing overt skeletal deformities associated with rickets, there is now overwhelming and compelling scientific and epidemiologic data suggesting that the human body requires a blood level of 25(OH)D above 30 ng/mL for maximum health. The likely reason is that essentially every tissue and cell in the body has a VDR and thus, to have enough vitamin D to satisfy all of these cellular requirements, the blood level of 25(OH)D needs to be above 30 ng/mL. It has been estimated that for every 100 IU of vitamin D ingested that the blood level of 25(OH)D increases by 1 ng/mL. Thus to theoretically achieve a blood level above 30 ng/mL requires the ingestion of 3000 IU of vitamin D a day. There is evidence, however, that when the blood levels of 25(OH)D are less than 15 ng/mL, the body is able to more efficiently use vitamin D to raise the blood level to about 20 ng/mL. To raise the blood level of 25(OH)D above 20 ng/mL requires the ingestion of 100 IU of vitamin D for every 1-ng increase; therefore to increase the blood level to the minimum 30 ng/mL requires the ingestion of at least 1000 IU of vitamin D a day for adults. There is a great need to significantly increase the recommended adequate intakes of vitamin D. All neonates during the first year of life should take at least 400 IU/d of vitamin D, and increasing it to 1000 IU/d may provide additional health benefits. Children 1 year and older should take at least 400 IU/d of vitamin D as recently recommended by the American Academy of Pediatrics, but they should consider increasing intake up to 2000 IU/d derive maximum health benefits from vitamin D. Prepubertal and teenage girls who received 2000 IU of vitamin D per day for a year showed improvement in their musculoskeletal health with no untoward toxicity. All adults should be taking 2000 IU of vitamin D per day. A recent study reported that adults who took 50,000 IU of vitamin D once every 2 weeks, which is equivalent to taking 3000 IU of vitamin D a day, for up to 6 years was effective in maintaining blood levels of 25(OH)D of between 40 and 60 ng/mL without any toxicity. There is no downside to increasing either a child's or adult's vitamin D intake, with the exception of acquired disorders such as granulomatous diseases including sarcoidosis and tuberculosis, as well as some lymphomas with activated macrophages that produce 1,25(OH)2D3 in an unregulated fashion. PMID- 22525851 TI - Vitamin D and diabetes. AB - There is no doubt that vitamin D deficiency is the cause of several metabolic bone diseases, but vitamin D status is also linked to many major human diseases including immune disorders. Mounting data strengthen the link between vitamin D and diabetes, in particular T1D and T2D. Despite some inconsistencies between studies that associate serum 25(OH)D levels with the risk of developing T1D or T2D, there seems to be an overall trend for an inverse correlation between levels of 25(OH)D and both disorders. There is also compelling evidence that 1,25(OH)2D regulates b-cell function by different mechanisms, such as influencing insulin secretion by regulating intracellular levels of Ca2+, increasing beta-cell resistance to apoptosis, and perhaps also increasing beta-cell replication. The capacity of vitamin D, more specifically 1,25(OH)2D, to modulate immune responses is of particular interest for both the therapy and prevention of diabetes. In the case of T1D, vitamin D supplementation in prediabetic individuals could help prevent or reduce the initiation of autoimmune processes possibly by regulating thymic selection of the T-cell repertoire, decreasing the numbers of autoreactive T cells, and inducing Treg cells. Although immune modulation is generally discussed for the treatment of T1D, it is also relevant for T2D. Indeed, recent studies have shown that T2D patients have increased systemic inflammation and that this state can induce beta-cell dysfunction and death. Supplementation trials with regular vitamin D for the protection against the development of T1D and T2D have generated some contradictory data, but many weaknesses can be identified in these trials as most were underpowered or open-labeled. However, the overwhelming strength of preclinical data and of the observational studies make vitamin D or its analogues strong candidates for the prevention or treatment of diabetes or its complications. However, proof of causality needs well-designed clinical trials and if positive, adequate dosing, regimen, and compound studies are needed to define the contribution of vitamin D status and therapy in the global diabetes problem. There are many confounding factors that need to be taken into consideration when translating successful vitamin D therapies in animal models into humans, for example, gender, age, lifestyle, and genetic background. To come to solid conclusions on the potential of vitamin D or its analogues in the prevention of or therapy for all forms of diabetes, it is clear that large prospective trials with carefully selected populations and end points will be needed, but should also receive high priority. PMID- 22525850 TI - The role of vitamin D in cancer prevention and treatment. AB - Considerable data described in the first part of this review suggest that there is a role for vitamin D in cancer therapy and prevention. Although the preclinical data are persuasive and the epidemiologic data intriguing, no well designed clinical trial of optimal administration of vitamin D as a cancer therapy has ever been conducted. Had there been the opportunity and insight to develop calcitriol as any other cancer drug, the following studies would have been completed: 1. Definition of the MTD. 2. Definition of a phase II dose, as a single agent and in combination with cytotoxic agents. 3. Studies to define a biologically optimal dose. 4. Phase II (probably randomized phase II) studies of calcitriol alone and chemotherapy +/- calcitriol. 5. Then, randomized phase III trials would be conducted and designed such that the only variable was the administration of calcitriol. Prerequisites 1 to 5 have not been completed for calcitriol. Preclinical data provide considerable rationale for continued development of vitamin D analogue-based cancer therapies. However, design of future studies should be informed by good clinical trials design principles and the mistakes of the past not repeated. Such studies may finally provide compelling data to prove whether or not there is a role for vitamin D analogues in cancer therapy. PMID- 22525852 TI - Vitamin D analogs. AB - Vitamin D has gone through a renaissance with the association of vitamin D deficiency with a wide array of common diseases including breast, colorectal and prostate cancers, cardio-vascular disease, autoimmune conditions and infections. Vitamin D analogs constitute a valuable group of compounds which can be used to regulate gene expression in functions as varied as calcium and phosphate homeostasis, as well as cell growth regulation and cell differentiation of a wide spectrum of cell types. This review will discuss the full range of vitamin D compounds currently available, some of their possible uses, and potential mechanisms of action. PMID- 22525853 TI - Rheumatic Disease Clinics of North America. Vitamin D. Preface. PMID- 22525854 TI - Characterising switching behaviour in perceptual multi-stability. AB - When people experience an unchanging sensory input for a long period of time, their perception tends to switch stochastically and unavoidably between alternative interpretations of the sensation; a phenomenon known as perceptual bi stability or multi-stability. The huge variability in the experimental data obtained in such paradigms makes it difficult to distinguish typical patterns of behaviour, or to identify differences between switching patterns. Here we propose a new approach to characterising switching behaviour based upon the extraction of transition matrices from the data, which provide a compact representation that is well-understood mathematically. On the basis of this representation we can characterise patterns of perceptual switching, visualise and simulate typical switching patterns, and calculate the likelihood of observing a particular switching pattern. The proposed method can support comparisons between different observers, experimental conditions and even experiments. We demonstrate the insights offered by this approach using examples from our experiments investigating multi-stability in auditory streaming. However, the methodology is generic and thus widely applicable in studies of multi-stability in any domain. PMID- 22525856 TI - Central retroperitoneal recurrences from colorectal cancer: are lymph node and locoregional recurrences the same disease? AB - BACKGROUND: Central retroperitoneal recurrences (CRRs) from colorectal carcinoma carry a poor prognosis. A CRR is sometimes defined as a locoregional recurrence (LR) and sometimes as a lymph node recurrence (NR). This study was conducted to determine the nature of CRR and evaluate prognostic factors after complete CRR resection. METHODS: Between January 1988 and December 2008, 31 patients underwent a complete resection of CRR. CRRs were divided into NR (n = 23) and LR (n = 8), whether pathological examination disclosed lymph node involvement or not. RESULTS: No differences were found between LR and NR regarding TNM stage, primary tumour location, time interval from primary tumour resection to CRR, number of metastatic sites, number of metastatic lesions and therapeutic management. The median preoperative CEA level was higher in the NR group (p = 0.003). After a median follow-up of 47 months NRs were associated with better overall survival (OS) (p = 0.03). Three-year OS and disease-free survival (DFS) in the LR and NR groups were 27% and 0% versus 81% and 26%, respectively. Twenty-seven (87%) patients developed a re-recurrence within a median interval of 15 months. The number of metastatic sites or lesions, the size of the CRR, the type of chemotherapy, radiotherapy, the interval between the primary resection and CRR and the TNM stage had no impact on OS. CONCLUSION: LR in patients with CRR had a poorer prognosis than NR. A multimodality approach with complete resection may yield long-term survival for NR. PMID- 22525857 TI - Total mesopancreas excision in pancreatic head adenocarcinoma: The same impact as total mesorectal excision in rectal carcinoma? Comment on article "surgical technique and results of total mesopancreas excision in pancreatic tumours" by Adham M and Singhirunnusorn J, Eur J Surg Oncol, 2012. PMID- 22525858 TI - Cultural influences on antiretroviral therapy adherence among HIV-infected Puerto Ricans. AB - Adherence to antiretroviral therapy (ART) is integral to the successful treatment of HIV infection. Research has indicated that HIV-infected Latinos may have difficulty adhering to ART. While studies have demonstrated strong relationships between numerous psychosocial factors and ART adherence, no research has examined if cultural factors are also involved in ART adherence among Latinos. Our study examined the relationship between acculturation to mainstream U.S. culture, bicultural self-efficacy, and ART adherence among HIV-infected Puerto Rican adults living in the United States. Participants with >= 95% adherence scored higher on U.S.- and Latino-involvement acculturation scales and on a measure of bicultural self-efficacy compared to those with suboptimal adherence. Among bicultural HIV-infected Puerto Ricans, both acculturation and self-efficacy to navigate between cultures were positively related to adherence. Understanding the role of an individual's sociocultural experience may help elucidate why HIV infected Latinos have difficulties achieving optimal ART adherence and improve ART adherence interventions. PMID- 22525859 TI - Anti-inflammatory activity of Korean thistle Cirsium maackii and its major flavonoid, luteolin 5-O-glucoside. AB - The anti-inflammatory activity of whole Cirsium maackii (family Compositae) plants and of its major flavonoid, luteolin 5-O-glucoside, was evaluated for their ability to inhibit lipopolysaccharide (LPS)-induced nitric oxide (NO) production, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) protein expression, and tert-butylhydroperoxide (t-BHP)-induced reactive oxygen species (ROS) generation in RAW 264.7 murine macrophage cells. The methanolic extract of C. maackii showed strong anti-inflammatory activity, and was thus fractionated with several solvents. The ethyl acetate-soluble fraction, exhibiting the highest anti-inflammatory activity potential, was further to yield a major flavonoid, luteolin 5-O-glucoside. We found that luteolin 5-O-glucoside, at a non-toxic concentration, inhibited LPS-induced NO production and t-BHP induced ROS generation in a dose-dependent manner in RAW 264.7 cells. It also suppressed the expression of iNOS and COX-2 in LPS-stimulated macrophages. Furthermore, the efficacies of the methanolic extract of C. maackii in inhibiting both NO and ROS were attributed to its flavonoid content by HPLC analysis. These results indicated that C. maackii whole plants and its flavonoids inhibit the expression of iNOS and COX-2 in through the inhibition of ROS generation, and therefore can be considered as a useful therapeutic and preventive approach for the treatment of various inflammatory and oxidative stress-related diseases. PMID- 22525860 TI - Ameliorative effects of SLC22A2 gene polymorphism 808 G/T and cimetidine on cisplatin-induced nephrotoxicity in Chinese cancer patients. AB - To investigate the roles of SLC22A2 gene polymorphism 808 G/T and cimetidine on cisplatin-induced nephrotoxicity, a total of 123 Chinese cancer patients treated with cisplatin alone (n = 55) or in combination with cimetidine (n = 68) were genotyped. The changes of serum creatinine (SCr), blood urea nitrogen (BUN) and cystatin C levels were used as biomarkers for the evaluation of cisplatin-induced nephrotoxicity. The changes of BUN and SCr levels showed no significant difference between groups divided by genotypes and treatments (P > 0.05). However, patients with mutant genotype (GT/TT) or with cimetidine treatment had smaller increase of the cystatin C levels compared to those with wild genotype (GG) or without cimetidine treatment (P < 0.05). In the non-cimetidine-treated group, the changes of cystatin C level in patients with mutant genotype (GT/TT) was significantly smaller than those with wild genotype (GG) (P = 0.043). In the wild type group, the cystatin C level change of patients without cimetidine treatment was significantly larger than those with cimetidine treatment (P = 0.007). These results suggested that SLC22A2 gene polymorphism 808 G/T and cimetidine could attenuate cisplatin nephrotoxicity in Chinese cancer patients. But the renoprotection mechanism of cimetidine might be damaged by the mutation. PMID- 22525861 TI - Determination of myristicin in commonly spices applying SPE/GC. AB - The increasing use of myristicin (a component of nutmeg) as a cheap hallucinogenic intoxicant requires from the world of science the elaboration of new methods for determination of this compound in daily-use foodstuffs. The present study describes a fast, simple and sensitive method of myristicin analysis in nutmeg and spices containing it using gas chromatography combined with ultrasonic solvent extraction and solid phase extraction processes. The developed method is characterized by high recovery (almost 100%), a low detection limit 1.35 ng g(-1) and good repeatability (average RDS value equal 2.39%). The presented analytical approach constitutes a substantial improvement on previously reported methods for myristicin analysis and seems to be the method of choice for determining the amount of the compound in spices containing nutmeg. PMID- 22525862 TI - Acute and repeated-doses (28 days) toxicity study of Hypericum polyanthemum Klotzsch ex Reichardt (Guttiferare) in mice. AB - Hypericum polyanthemum, a South Brazilian species showed antidepressant-like and antinociceptive effects in rodents. Since limited information is available on the toxicity and safety profile of the Hypericum genus, we therefore investigated whether H. polyanthemum cyclo-hexane extract (POL) treatment could be associated with toxicity in preclinical setting using mice as an experimental model. These toxicity studies were based on the guidelines of the Organization for Economic Cooperation and Development (OECD-guidelines 423 and 407). Animals received POL single dose (2000 mg/kg, p.o.) or daily for 28-days (90, 450 and 900 mg/kg, p.o.). Acute toxicity study did not detect any clinical signs, changes in behavior or mortality. In repeated dose toxicity study, POL affected the body weight gain and induced biochemical, hematological and liver histological changes at 450 and 900 mg/kg. Mice treated with POL 90 mg/kg did not show any toxicity signs. In conclusion H. polyanthemum can be classified as safe (category 5) according to OECD acute toxicity parameters. However, the alterations observed after repeated treatment with high doses suggest that the liver could be the target organ on potential H. polyanthemum toxicity and point to the need of further toxicity studies. PMID- 22525863 TI - Cytotoxic effects of cadmium in mammary epithelial cells: protective role of the macrocycle [15]pyN5. AB - Human exposure to cadmium (Cd) occurs via different routes, including diet. The increasing amount of data linking Cd with different cellular effects in the mammary gland justifies additional toxicological assessments using human mammary epithelial cells. This work aimed therefore to assess the cytotoxic effects of Cd in MCF10A cells and to characterize the cytoprotective role of the macrocycle [15]pyN(5) in the form of calcium salt. Cadmium chloride revealed to be cytotoxic to MCF10A cells, decreasing cell viability and proliferation in a concentration dependent manner. Comparable dose-response curves and IC50 values (57-63 MUM, 24h treatment) were obtained using the MTT reduction, crystal violet and BrdU assays. In terms of reactive oxygen species formation, only a slight increase in superoxide radical anion was observed at very high Cd concentrations (>=100 MUM). Chelation should thus constitute the primary strategy to mitigate the cytotoxic effects induced by Cd in mammary cells. In this context, [15]pyN(5) which presents appropriate chemical and thermodynamic features was studied as a Cd chelator. This macrocycle (25 and 50 MUM) significantly reduced or even abolished Cd-induced cytotoxicity. Protective effects were observed in terms of cell viability, cell proliferation and morphological alterations, being the protection mostly attributed to a chelating-based mechanism. PMID- 22525864 TI - Agrimonia eupatoria protects against chronic ethanol-induced liver injury in rats. AB - This study examined the hepatoprotective effects of Agrimonia eupatoria water extract (AE) against chronic ethanol-induced liver injury. Rats were fed a Lieber DeCarli liquid diet for 8 weeks. Animals were treated orally with AE at 10, 30, 100, and 300 mg/kg/day. After chronic consumption of ethanol, serum aminotransferase activities and pro-inflammatory cytokines markedly increased, and those increases were attenuated by AE. The cytochrome P450 2E1 activity and lipid peroxidation increased after chronic ethanol consumption, while reduced glutathione concentration decreased. Those changes were attenuated by AE. Chronic ethanol consumption increased the levels of Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 protein expression, inducible nitric oxide synthase and cyclooxygenase-2 protein and mRNA expression, and nuclear translocation of nuclear factor-kappa B, which was attenuated by AE. Our results suggest that AE ameliorates chronic ethanol-induced liver injury, and that protection is likely due to the suppression of oxidative stress and TLR-mediated inflammatory signaling. PMID- 22525865 TI - Chemical characterization of chestnut cultivars from three consecutive years: chemometrics and contribution for authentication. AB - Four Castanea sativa Miller cultivars (Aveleira, Boaventura, Judia and Longal) belonging to the Protected Designation of Origin "Castanha da Terra Fria", from the Northeast of Portugal, were selected in 2006, 2007 and 2008. Their nutritional, fatty acids, triacylglycerols and tocopherols profiles were evaluated. Water was the major component, followed by carbohydrates, protein and fat, with energetic values lower than 190 kcal/100g of fresh fruit. Oleic, linoleic and palmitic were the major fatty acids, 1-oleoyl-2-linoleoyl-3 linoleoyl-sn-glycerol, 1-linoleoyl-2-linoleoyl-3-palmitoyl-sn-glycerol, 1-oleoyl 2-linoleoyl-3-oleoyl-sn-glycerol and 1-linoleoyl-2-oleoyl-3-palmitoyl-sn-glycerol were the prevalent triacylglycerols and gamma-tocopherol was the most abundant tocopherol. In each parameter, differences between cultivars, harvest year and the possible cultivar * year interaction were screened through a two-way analysis of variance. Differences among cultivars have been attenuated by the variability among years, leading, in general, to a significant interaction effect, which resulted in a relative homogeneity regarding chemical parameters, showing that nutritional and chemical composition was influenced by seasonal variability. A stepwise linear discriminant model, based on 10 (alpha-tocopherol, gamma tocotrienol, LLL, OLLn, delta-tocopherol, gamma-tocopherol, delta-tocotrienol, PLLn, protein and OOO) of the 38 initial evaluated variables was also established. The model allowed the complete discrimination of cultivars with overall sensibilities and specificities of 100%, for both original grouped data and leave-one-out cross-validation procedures. Furthermore, similar results were also obtained using only tocopherols data, showing their usefulness as a discriminant factor for chestnut cultivars. PMID- 22525866 TI - Multiple spectroscopic studies on the interaction between olaquindox, a feed additive, and bovine serum albumin. AB - The interaction between olaquindox (OLA) and bovine serum albumin (BSA) was investigated using fluorescence, UV-vis absorption and circular dichroism (CD) spectroscopy. The results showed that the fluorescence quenching of BSA by OLA was a static quenching process induced by the formation of OLA-BSA complex. The binding constant of OLA-BSA complex was calculated to be 1.299 * 10(4)L mol(-1) (293K). The negative values of DeltaH(0) and DeltaS(0) indicated that hydrogen bond and van der Waals interactions played major roles in stabilizing the complex. Site probe competition experiments and number of binding sites (n) revealed that OLA could bind to site I in subdomain IIA of BSA, and the binding distance (r) was evaluated to be 3.643 nm according to Forster's non-radiative energy transfer theory. The results of CD and three-dimensional fluorescence spectra suggested some conformational changes of BSA after OLA binding. PMID- 22525867 TI - Enhancement of cisplatin cytotoxicity by benzyl isothiocyanate in HL-60 cells. AB - Cis-diamminedichloroplatinum (II) (cisplatin) is one of the most widely used chemotherapeutic drugs, but its effectiveness is limited by tumor cell resistance and the severe side effects it causes. One strategy for overcoming this problem is the concomitant use of natural dietary compounds as therapeutic agents. Benzyl isothiocyanate (BITC) is a promising chemopreventive agent found in cruciferous vegetables and papaya fruits. The aim of this study was to investigate the effects of BITC on cisplatin-induced cytotoxicity in human promyelocytic leukemia cells and normal human lymphocytes. The combined treatment of HL-60 cells with BITC followed by cisplatin (BITC/cisplatin) caused a significant decrease in cell viability. BITC also increased apoptotic cell death compared to cisplatin treatment alone. In normal human lymphocytes, BITC did not enhance the cytotoxic effects of cisplatin. Cellular exposure to BITC/cisplatin increased reactive oxygen species (ROS) generation but decreased the total glutathione (GSH) level in HL-60 cells. Pretreatment of HL-60 cells with N-acetylcysteine or glutathione monoethyl ester effectively decreased BITC/cisplatin-induced cell death. The addition of the extracellular signal-regulated kinase (ERK) inhibitor PD98059 abolished BITC/cisplatin-induced apoptosis. Taken together, our results suggest that BITC enhances cisplatin-induced cytotoxicity through the generation of ROS, depletion of GSH, and ERK signaling in HL-60 cells. PMID- 22525868 TI - Diallyl trisulfide as an inhibitor of benzo(a)pyrene-induced precancerous carcinogenesis in MCF-10A cells. AB - Diallyl trisulfide (DATS) is a garlic organosulfide that is toxic to cancer cells, however, little is known about its effect in the initiation phase of carcinogenesis. We sought to determine whether DATS could inhibit the carcinogen, benzo(a)pyrene (BaP), from inducing precancerous activity, in vitro. MCF-10A cells were either pre-treated (PreTx) or concurrently treated (CoTx) with 1 MUM BaP, and 6 or 60 MUM DATS for up to 24h. The DATS 6 and 60 MUM CoTx inhibited BaP induced cell proliferation by an average of 71.1% and 120.8%, respectively, at 6h. The 60 MUM DATS pretreatment decreased BaP-induced G2/M cell cycle transition by 127%, and reduced the increase in cells in the S-phase by 42%; whereas 60 MUM DATS CoTx induced a 177% increase in cells in G1. DATS effectively inhibited (P<0.001) BaP-induced peroxide formation by at least 54%, which may have prevented the formation of BaP-induced DNA strand breaks. In this study, we reveal mechanisms involved in DATS inhibition of BaP-induced carcinogenesis, including inhibition of cell proliferation, regulation of cell cycle, attenuation of ROS formation, and inhibition of DNA damage. At the doses evaluated, DATS appears to be an effective attenuator of BaP-induced breast carcinogenesis, in vitro. PMID- 22525869 TI - Hemoglobin adducts as a measure of variations in exposure to acrylamide in food and comparison to questionnaire data. AB - Measurement of haemoglobin (Hb) adducts from acrylamide (AA) and its metabolite glycidamide (GA) is a possibility to improve the exposure assessment in epidemiological studies of AA intake from food. This study aims to clarify the reliability of Hb-adduct measurement from individual single samples for exposure assessment of dietary AA intake. The intra-individual variations of AA- and GA adduct levels measured in blood samples collected over 20 months from 13 non smokers were up to 2-fold and 4-fold, respectively. The corresponding interindividual variations observed between 68 non-smokers, with large differences in AA intake, were 6-fold and 8-fold, respectively. The intra individual variation of the GA-to-AA-adduct level ratio was up to 3-fold, compared to 11-fold between individuals (n = 68). From AA-adduct levels the average AA daily intake (n = 68) was calculated and compared to that estimated from dietary history methodology: 0.52 and 0.67 MUg/kg body weight and day, respectively. At an individual level the measures showed low association (Rs = 0.39). CONCLUSIONS: Dietary AA is the dominating source to measured AA-adduct levels and corresponding inter- and intra-individual variations in non-smokers. Measurements from single individual samples are useful for calculation of average AA intake and its variation in a cohort, and for identification of individuals only from extreme intake groups. PMID- 22525870 TI - Investigation of porous graphitic carbon for triterpenoids and natural resinous materials analysis by high performance liquid chromatography hyphenated to mass spectrometry. AB - Natural resinous materials are mainly composed of pentacyclic triterpenes which exhibit a large number of interesting medicinal activities. However, the presence of numerous isomers within the active substances makes their screening by HPLC very challenging. Porous graphitic carbon was investigated as stationary phase to achieve triterpenes isomers separation. The influence of various parameters (temperature, formic acid concentration and mobile phase composition) on the retention was considered. A usual decrease of the retention of triterpenes was observed with the increase of the temperature. Therefore, separation in resinous materials was performed at 25 degrees C. Acetonitrile-isopropanol mixture was chosen as mobile phase in gradient elution and leads to the best compromise between efficiency and high resolution. The lack of chromophore groups in the pentacyclic triterpenes structures required the use of mass spectrometry detection. Moreover, atmospheric pressure photo-ionisation mass spectrometry prevents compounds fragmentation which was helpful for spectra interpretation and compounds identification. PMID- 22525871 TI - On-line fractionated size exclusion chromatography-nuclear magnetic resonance of polymers with 1H and 2H nuclear magnetic resonance detection. AB - A new approach for on-line SEC-NMR is introduced. The method combines time slicing, fractionation with adjusted loop collection and automatic stop-flow NMR analysis. It will be called on-line fractionated SEC-NMR. This technique allows the precise determination of molar mass distributions for any polymer which can be detected by NMR. It is a significant improvement of sensitivity and accuracy compared to onflow SEC-NMR and exhibits a much easier experimental setup than off line SEC-NMR fractionation. The new method was applied to protonated and deuterated block copolymers by using 1H NMR and for the first time also 2H NMR detection. In this case block copolymers can be correctly characterized according to their block length distributions. As the consequence very precise molar mass parameters M(n) and M(w) can be determined. The results of the on-line fractionated SEC-NMR are in very good agreement with the multi detector analysis. The new technique also proposes a method for separating the true copolymer and low molar mass fractions in the mixture, whose structures are confirmed by HPLC FTIR and 2D chromatography. PMID- 22525872 TI - Excess adsorption of binary aqueous organic mixtures on various reversed-phase packing materials. AB - Excess adsorption isotherms of acetonitrile and methanol from water were measured on eight commercial columns. Columns used in this study represent latest examples in column development and include three different poroshell columns (Kinetex-C18, Acsentis-C18 and Halo-C18) as well as conventional columns with significantly different adsorbent geometry (Allure-C18, YMC-C18) and various hybrid-silica columns (Gemini-C18, Xterra-C18 and XBridge-C18). Comparison of the excess adsorption isotherms measured on all these columns and expressed in surface specific form demonstrated significant similarity of the adsorption properties of all columns, which allows us to introduce the "standard adsorption isotherm" for reversed-phase C18-type columns. The methodology of the evaluation of the total amount of adsorbent in the column and effective surface area of the C18 modified adsorbent is also discussed. These terms are critical for successful evaluation of surface specific parameters. PMID- 22525873 TI - Removal of potentially genotoxic acetamide and arylsulfonate impurities from crude drugs by molecular imprinting. AB - The present study describes the synthesis and preliminary testing of molecularly imprinted polymers (MIPs) as scavenger resins for removal of the genotoxic impurities (GTI) acetamide and arylsulfonates from active pharmaceutical ingredients (API). The MIPs were synthesized as monoliths using acetamide or methyl tosylate respectively as templates. The polymers were crushed and subsequently tested in the batch and chromatographic mode for template recognition and potential removal efficiency. Both the acetamide and the tosylate MIPs exhibited a strong memory effect for their templates and selectivity with respect to model APIs. For instance the MIP for acetamide preferentially retained acetamide over other amides, such as formamide, acrylamide, methacrylamide, benzamide and N-tert-butylacrylamide. Moreover, passing model API crude contaminated with the acetamide through the MIPs led to the quantitative removal of acetamide. PMID- 22525874 TI - Identification and quantification of potential metabolites of Gd-based contrast agents by electrochemistry/separations/mass spectrometry. AB - Oxidative and potentially metabolic pathways of the five most frequently used contrast agents for magnetic resonance imaging (MRI) based on gadolinium (Gd) are examined. The oxidation of gadopentetate (Gd-DTPA) was studied with a focus on electrochemical oxidation coupled to analytical separation methods and mass spectrometric detection. Mass voltammograms generated with online electrochemistry/electrospray ionization mass spectrometry (EC/ESI-MS) gave a first overview of oxidation products. Two potential metabolites could be detected, with the major metabolite originating from an N-dealkylation (M1). Four other Gd complexes used as MRI contrast agents showed similar reactions in the EC/ESI-MS set-up. To obtain more information about the properties and the quantity of the generated products, a wide range of separation and detection techniques was applied in further experiments. Gd-DTPA and its N-dealkylation product were successfully separated by capillary electrophoresis (CE) and detected by ESI-MS and inductively coupled plasma (ICP)-MS, respectively. CE experiments indicated that the second oxidation product (M2) detected in the mass voltammogram is unstable and decomposes to M1. Employing EC/CE/ICP-MS, the quantification of the metabolites could be achieved. Under the employed conditions, 8.8% of Gd-DTPA was oxidized. Online experiments with high performance liquid chromatography (HPLC) coupled to ESI-MS confirmed the decomposition of M2. Time-resolved measurements showed a decrease of M2 and a simultaneous increase in M1 within only a few minutes, confirming the conclusion that M2 degrades to M1, while EC/LC/ICP-MS measurements provided quantitative evidence as well. The EC/MS simulation shows that a metabolic transformation should not be disregarded in further research regarding the trigger of nephrogenic systemic fibrosis (NSF), a disease exclusively observed for several hundred dialysis patients after delivery of Gd-based MRI contrast agents with linear structure. Furthermore, the used methods may allow the prediction of options for the oxidative removal of these contrast agents from wastewaters. PMID- 22525875 TI - Very early modulation of brain responses to neutral faces by a single prior association with an emotional context: evidence from MEG. AB - Recent electrophysiological studies have demonstrated modulations of the very first stages of visual processing (<100 ms) due to prior experience. This indicates an influence of a memory trace on the earliest stages of stimulus processing. Here we investigated if emotional audio-verbal information associated with faces on first encounter can affect the very early responses to those faces on subsequent exposure. We recorded magneto-encephalographic (MEG) responses to neutral faces that had been previously associated with positive (happy), negative (angry) or neutral auditory verbal emotional contexts. Our results revealed a very early (30-60 ms) difference in the brain responses to the neutral faces according to the type of previously associated emotional context, with a clear dissociation between the faces previously associated to positive vs. negative or neutral contexts. Source localization showed that two main regions were involved in this very early association effect: the bilateral ventral occipito-temporal regions and the right anterior medial temporal region. These results provide evidence that the memory trace of a face integrates positive emotional cues present in the context of prior encounter and that this emotional memory can influence the very first stages of face processing. These experimental findings support the idea that face perception can be shaped by experience from its earliest stages and in particular through emotional association effects. PMID- 22525876 TI - Resting-state functional connectivity of the vermal and hemispheric subregions of the cerebellum with both the cerebral cortical networks and subcortical structures. AB - The human cerebellum is a heterogeneous structure, and the pattern of resting state functional connectivity (rsFC) of each subregion has not yet been fully characterized. We aimed to systematically investigate rsFC pattern of each cerebellar subregion in 228 healthy young adults. Voxel-based analysis revealed that several subregions showed similar rsFC patterns, reflecting functional integration; however, different subregions displayed distinct rsFC patterns, representing functional segregation. The same vermal and hemispheric subregions showed either different patterns or different strengths of rsFCs with the cerebrum, and different subregions of lobules VII and VIII displayed different rsFC patterns. Region of interest (ROI)-based analyses also confirmed these findings. Specifically, strong rsFCs were found: between lobules I-VI and vermal VIIb-IX and the visual network; between hemispheric VI, VIIb, VIIIa and the auditory network; between lobules I-VI, VIII and the sensorimotor network; between lobule IX, vermal VIIIb and the default-mode network; between lobule Crus I, hemispheric Crus II and the fronto-parietal network; between hemispheric VIIb, VIII and the task-positive network; between hemispheric VI, VIIb, VIII and the salience network; between most cerebellar subregions and the thalamus; between lobules V, VIIb and the midbrain red nucleus; between hemispheric Crus I, Crus II, vermal VIIIb, IX and the caudate nucleus; between lobules V, VI, VIIb, VIIIa and the pallidum and putamen; and between lobules I-V, hemispheric VIII, IX and the hippocampus and amygdala. These results confirm the existence of both functional integration and segregation among cerebellar subregions and largely improve our understanding of the functional organization of the human cerebellum. PMID- 22525877 TI - Determination of insulin in humans with insulin-dependent diabetes mellitus patients by HPLC with diode array detection. AB - A simple and reliable high-performance liquid chromatographic method with diode array detection has been developed and validated for the determination of insulin in human plasma. A good chromatographic separation was achieved on a C18 column with a mobile phase consisting of acetonitrile and 0.2M sodium sulfate (pH 2.4), 25:75 (v/v). Its flow rate was 1.2 mL/min. Calibration curve was linear within the concentration range of 0.15-25 ug/mL. Intra-day and inter-day relative standard deviations for insulin in human plasma were less than 6.3 and 8.5%, respectively. The limits of detection and quantification of insulin were 0.10 and 0.15 ug/mL, respectively. Also, this assay was applied to determine the pharmacokinetic parameters of insulin in eight insulin-dependent diabetes mellitus patients after subcutaneous injection of 25 IU of Actrapid HM. PMID- 22525878 TI - Relative determination of dehydroevodiamine in rat plasma by LC-MS and study on its pharmacokinetics. AB - The lack of purified standards is a bottleneck on assaying herbs in vitro and in vivo. This present work proposed a strategy of relative quantification that used a herb extract as a relative standard. A rapid and selective liquid chromatography tandem mass spectrometry method was similarly developed and validated for the relative determination of dehydroevodiamine in rat plasma according to the absolute quantification. Protein precipitation was used for the pretreatment of plasma samples. Chromatographic separation was achieved on a Diamonsil C18 column with an isocratic mobile phase of a 70:30 (v/v) acetonitrile 0.3% formic acid mixture at a flow rate of 0.45 mL/min. The assay was validated in the range 100.0 ~ 50,000.0 ngH/mL (r(2) = 0.9804), the lowest level of this range being the lower limit of quantification based on 50 uL of plasma. The precision and accuracy were within recommended limits of nominal values. The method was applied to evaluate the comparative pharmacokinetics of dehydroevodiamine in rats following oral administration of Evodia rutaecarpa and Rhizoma coptidis-Evodia rutaecarpa couple. This approach was found to be capable of providing complete pharmacokinetic parameters as well as the typical pharmacokinetic assay calibrated by authentic standards, except for the absolute plasma concentrations. PMID- 22525879 TI - Validated and optimized high-performance liquid chromatographic determination of tizoxanide, the main active metabolite of nitazoxanide in human urine, plasma and breast milk. AB - A high-performance liquid chromatographic method was optimized and validated for the determination of desacetyl nitazoxanide (tizoxanide), the main active metabolite of nitazoxanide in human plasma, urine and breast milk. The proposed method used a CN column with mobile phase consisting of acetonitrile-12mM ammonium acetate-diethylamine in the ratio of 30:70:0.1 (v/v/v) and buffered at pH 4.0 with acetic acid, with a flow rate of 1.5 mL/min. Quantitation was achieved with UV detection at 260 nm using nifuroxazide as internal standard. A simplified direct injection of urine samples without extraction in addition to the urinary excretion pattern were calculated using the proposed method. Also, the effectiveness of protein precipitation and a clean-up procedure were investigated for biological plasma and human breast milk samples. The validation study of the proposed method was successfully carried out in an assay range between 0.2 and 20 ug/mL. PMID- 22525880 TI - [Deep vein thrombosis (except lower limb and abdominal veins)]. PMID- 22525881 TI - Precision pork production: predicting the impact of nutritional strategies on carcass quality. AB - Variation is inherent to living systems. Because feeding strategies are applied to groups of pigs, it contributes to the inefficient use of natural resources and may even amplify the variation among pigs at slaughter. Precision pork production and precision feeding, through management of the variation among individuals, may contribute to improving the efficiency of animal production systems. This approach relies on the prediction of the response of the animal to the nutrient supply, the continuous monitoring of the response, and a system to control nutrient supply. Most nutritional models of pig growth are based on the partitioning of nutrients between energy expenditure, and protein and lipid deposition. However, the link between chemical body composition and tissue growth, tissue composition and thus carcass quality remains a challenge in modeling. The potential of precision pork production also depends on the (real time) information that can be obtained to control growth and carcass quality. PMID- 22525884 TI - Risk factors for advanced neoplasia within subcentimetric polyps: implications for diagnostic imaging. AB - OBJECTIVE: Diagnostic imaging by CT colonography and capsule endoscopy is used to detect colonic lesions. Controversy exists regarding the work-up of subcentimetric lesions. The aim of this study was to identify risk indicators for advanced neoplasia (AN) in subcentimetric polyps. DESIGN: Colonoscopies were classified on the basis of the largest lesion found. AN was defined as high-grade dysplasia, villous histology, or cancer. Logistic regression models were developed to identify risk factors for AN, and validated on separate datasets. A risk index based on the logistic regression was generated, and the number needed to screen (NNS) to detect AN was determined. RESULTS: 1,077,956 colonoscopies identified 106,270 intermediate (5-9 mm) and 198,954 diminutive (<= 4 mm) lesions; 13% of intermediate and 3.7% of diminutive lesions contained AN. The risk of AN was higher in intermediate than in diminutive lesions (OR 3.1; 95% CI 3.0 to 3.3). Age >= 85 versus <45 years was associated with ORs of 2.4 (95% CI 1.8 to 3.1) for intermediate polyps and 3.2 (95% CI 2.3 to 4.5) for diminutive polyps. Pedunculated versus sessile morphology was associated with a higher risk of AN in intermediate (OR 2.0; 95% CI 1.9 to 2.2) and diminutive (OR 3.5; 95% CI 2.9 to 4.1) lesions. In the combined analysis for subcentimetric lesions, ORs were 2.7 (95% CI 2.2 to 3.3) for age >= 85 versus <45 years, 1.1 (95% CI 1.1 to 1.2) for male sex, 1.6 (95% CI 1.4 to 1.7) for occult blood, 1.3 (95% CI 1.2 to 1.5) for overt blood in stool, 1.3 (95% CI 1.2 to 1.4) for more than four lesions, and 2.2 (95% CI 2.1 to 2.3) for pedunculated versus sessile lesions. At median risk index values, the NNS was 9.3 (95% CI 9.1 to 9.5) in individuals with intermediate lesions and 29.4 (95% CI 28.5 to 30.2) in those with diminutive lesions. Compared with the NNS of 15 of the whole cohort, the majority of intermediate, but a minority of diminutive, lesions were deemed at high risk of AN. CONCLUSION: This study successfully identified risk factors and established a risk index for subcentimetric lesions. This has implications for the work-up of patients with subcentimetric lesions identified on diagnostic imaging. PMID- 22525883 TI - Endoscopic improvement of mucosal lesions in patients with moderate to severe ileocolonic Crohn's disease following treatment with certolizumab pegol. AB - OBJECTIVE: To evaluate the efficacy of certolizumab pegol (CZP) in improving endoscopic lesions in patients with active ileocolonic Crohn's disease (CD). METHODS: This phase IIIB multicentre open-label clinical trial enrolled 89 adult patients with active endoscopic disease (ulceration in >=2 intestinal segments with a Crohn's Disease Endoscopic Index of Severity (CDEIS) score >=8 points). Patients received subcutaneous CZP 400 mg at weeks 0, 2 and 4 and every 4 weeks up to week 52. Endoscopic evaluations were performed at weeks 0, 10 and 54. The primary outcome was mean change in CDEIS score at week 10; secondary outcome measures included endoscopic response (decrease in CDEIS score >5 points), remission (CDEIS score <6), complete remission (CDEIS score <3) and mucosal healing (no ulcer) at weeks 10 and 54. RESULTS: In the intention-to-treat population (n=89) the mean+/-SD CDEIS score was 14.5+/-5.3 at baseline; the mean decrease in CDEIS score at week 10 was 5.7 (95% CI 4.6 to 6.8, p<0.0001). Rates of endoscopic response, endoscopic remission, complete endoscopic remission and mucosal healing at week 10 were 54%, 37%, 10% and 4%, respectively. At week 54 the corresponding rates were 49%, 27%, 14% and 8%, respectively. The safety profile was consistent with that of previous CZP trials. CONCLUSIONS: Following CZP treatment in patients with active CD, endoscopic lesions were improved as shown by the decrease in mean CDEIS score and by endoscopic response and remission rates. These benefits were achieved as early as week 10 and were generally maintained through week 54. CLINICAL TRIAL REGISTRATION NUMBER: NCT00297648. PMID- 22525886 TI - A metagenomic insight into our gut's microbiome. AB - Advances in sequencing technology and the development of metagenomic and bioinformatics methods have opened up new ways to investigate the 10(14) microorganisms inhabiting the human gut. The gene composition of human gut microbiome in a large and deeply sequenced cohort highlighted an overall non redundant genome size 150 times larger than the human genome. The in silico predictions based on metagenomic sequencing are now actively followed, compared and challenged using additional 'omics' technologies. Interactions between the microbiota and its host are of key interest in several pathologies and applying meta-omics to describe the human gut microbiome will give a better understanding of this crucial crosstalk at mucosal interfaces. Adding to the growing appreciation of the importance of the microbiome is the discovery that numerous phages, that is, viruses of prokaryotes infecting bacteria (bacteriophages) or archaea with a high host specificity, inhabit the human gut and impact microbial activity. In addition, gene exchanges within the gut microbiota have proved to be more frequent than anticipated. Taken together, these innovative exploratory technologies are expected to unravel new information networks critical for gut homeostasis and human health. Among the challenges faced, the in vivo validation of these networks, together with their integration into the prediction and prognosis of disease, may require further working hypothesis and collaborative efforts. PMID- 22525885 TI - Risk adjusted benchmarking of abdominoperineal excision for rectal adenocarcinoma in the context of the Belgian PROCARE improvement project. AB - OBJECTIVE: The abdominoperineal excision (APE) rate, a quality of care indicator in rectal cancer surgery, has been criticised if not adjusted for confounding factors. This study evaluates variability in APE rate between centres participating in PROCARE, a Belgian improvement initiative, before and after risk adjustment. It also explores the effect of merging the Hartmann resections (HR) rate with that of APE on benchmarking. DESIGN: Data of 3197 patients who underwent elective radical resection for invasive rectal adenocarcinoma up to 15 cm were registered between January 2006 and March 2011 by 59 centres, each with at least 10 patients in the registry. Variability of APE or merged APE/HR rates between centres was analysed before and after adjustment for gender, age, ASA score (3 or more), tumour level (rectal third), depth of tumour invasion (cT4) and preoperative incontinence. RESULTS: The overall APE rate was 21.1% (95% CI 19.7 to 22.5%). Significant variation of the APE rate was observed before and after risk adjustment (p<0.0001). For cancers in the lower rectal third, the overall APE rate increased to 45.8% (95% CI 43.1 to 48.5%). Also, variation between centres increased. Risk adjustment influenced the identification of outliers. HR was performed in only 2.6% of patients. However, merging of risk adjusted APE and HR rates identified other centres with outlying definitive colostomy rates than APE rate alone. CONCLUSION: Significant variation of the APE rate was observed. Adjustment for confounding factors as well as merging HR with APE rates were found to be important for the assessment of performances. PMID- 22525887 TI - A rhythmic placenta? Circadian variation, clock genes and placental function. AB - Physiological rhythms entrained by the circadian clock are present in virtually all organs including those of the reproductive system. In mammals, circadian timing is driven by a 'master clock' in the suprachiasmatic nucleus that influences peripheral tissue clocks via endocrine, autonomic and behavioral cues. The molecular clock machinery comprises a network of 'clock' genes, namely Clock, Bmal1, Per1, Per2, Per3, Cry1 and Cry2. These clock genes generate endogenous oscillations that drive rhythmic expression of downstream genes and thus physiological and behavioral processes. Importantly, disturbances in clock gene expression are implicated in a range of pathologies including cancer and obesity. The recent recognition that clock genes are expressed in the placenta, together with observations linking circadian disruption with compromised placental function, suggests that circadian variation may be an important component of the normal placental phenotype. In this review we consider this possibility in the context of maternal circadian physiology in pregnancy. While there is good evidence for rhythmic expression of several genes in the rodent placenta, the conventional transcriptional-translational feedback loops of the clock machinery appear less robust and coordinated. Further study is needed to elucidate the function of the placental clock genes across gestation and among different species, particularly those in which greater circadian development occurs in utero. Such studies will likely provide important insights into placental physiology and pathology. PMID- 22525888 TI - NK cells in human disease: an evolving story. PMID- 22525889 TI - Emerging therapies for systemic lupus erythematosus--focus on targeting interferon-alpha. AB - Current therapies for systemic lupus erythematosus (SLE), a debilitating, potentially lethal, multifactorial systemic autoimmune disease, are limited to suppressing disease activity and are associated with multiple adverse effects. Recent advances in basic and translational sciences have elucidated a crucial role for the interferon-alpha (IFNalpha) pathway in the pathogenesis of this enigmatic disease. The so-called "type I interferon signature" has emerged as a major risk factor for disease activity of SLE. Multiple genes encoding for molecules within the type I interferon pathway have been associated with SLE in genome wide association studies. In addition, innate immune receptors are thought to be triggered by either endogenous and/or exogenous stimuli that lead to hypersecretion of IFNalpha. We review the multiple emerging treatment strategies targeting IFNalpha-related pathways. These include monoclonal antibodies against IFNalpha, anti-IFNalpha antibody-inducing vaccines, and inhibitors of Toll-like receptors. We also summarize the current status of these pharmaceutical agents in early clinical trials. PMID- 22525890 TI - Generation of induced regulatory T cells from primary human naive and memory T cells. AB - The development and maintenance of immunosuppressive CD4+ regulatory T cells (Tregs) contribute to the peripheral tolerance needed to remain in immunologic homeostasis with the vast amount of self and commensal antigens in and on the human body. Perturbations in the balance between Tregs and inflammatory conventional T cells can result in immunopathology or cancer. Although therapeutic injection of Tregs has been shown to be efficacious in murine models of colitis, type I diabetes, rheumatoid arthritis and graft versus host disease, several fundamental differences in human versus mouse Treg biology has thus far precluded clinical use. The lack of sufficient number, purity, stability and homing specificity of therapeutic Tregs necessitated a dynamic platform of human Treg development on which to optimize conditions for their ex vivo expansion. Here we describe a method for the differentiation of induced Tregs (iTregs) from a single human peripheral blood donor which can be broken down into four stages: isolation of peripheral blood mononuclear cells, magnetic selection of CD4+ T cells, in vitro cell culture and fluorescence activated cell sorting (FACS) of T cell subsets. Since the Treg signature transcription factor forkhead box P3 (FoxP3) is an activation-induced transcription factor in humans and no other unique marker exists, a combinatorial panel of markers must be used to identify T cells with suppressor activity. After six days in culture, cells in our system can be demarcated into naive T cells, memory T cells or iTregs based on their relative expression of CD25 and CD45RA. As memory and naive T cells have different reported polarization requirements and plasticities, pre-sorting of the initial T cell population into CD45RA(+) and CD45RO(+) subsets can be used to examine these discrepancies. Consistent with others, our CD25(Hi)CD45RA(-) iTregs express high levels of FoxP3, GITR and CTLA-4 and low levels of CD127. Following FACS of each population, resultant cells can be used in a suppressor assay which evaluates the relative ability to retard the proliferation of carboxyfluorescein succinimidyl ester (CFSE)-labeled autologous T cells. PMID- 22525891 TI - Insights from honeybee (Apis mellifera) and fly (Drosophila melanogaster) nicotinic acetylcholine receptors: from genes to behavioral functions. AB - Nicotinic acetylcholine receptors (nAChRs) are widely expressed throughout the central nervous system of insects where they supply fast synaptic excitatory transmission and represent a major target for several insecticides. The unbalance is striking between the abundant literature on nAChR sensitivity to insecticides and the rarity of information regarding their molecular properties and cognitive functions. The recent advent of genome sequencing disclosed that nAChR gene families of insects are rather small-sized compared to vertebrates. Behavioral experiments performed in the honeybee demonstrated that a subpopulation of nAChRs sensitive to the venom alpha-bungarotoxin and permeant to calcium is necessary for the formation of long-term memory. Concomitant data in Drosophila reported that repetitive exposure to nicotine results in a calcium-dependent plasticity of the nAChR-mediated response involving cAMP signaling cascades and indicated that ACh-induced Ca++ currents are modulated by monoamines involved in aversive and appetitive learning. As in vertebrates, in which glutamate and NMDA-type glutamate receptors are involved in experience-associated synaptic plasticity and memory formation, insects could display a comparable system based on ACh and alpha-Bgt-sensitive nAChRs. PMID- 22525892 TI - Gremlin-mediated decrease in bone morphogenetic protein signaling promotes aristolochic acid-induced epithelial-to-mesenchymal transition (EMT) in HK-2 cells. AB - Ingestion of aristolochic acid (AA) is associated with the development of aristolochic acid nephropathy (AAN), which is characterized by progressive tubulointerstitial fibrosis, chronic renal failure and urothelial cancer. Our previous study showed that bone morphogenetic protein-7 (BMP-7) could attenuate AA-induced epithelial-to-mesenchymal transition (EMT) in human proximal tubule epithelial cells (PTEC). However, how gremlin (a BMP-7 antagonist) antagonizes the BMP-7 action in PTEC remained unsolved. The aim of the current study was to investigate the role of gremlin in AA-induced EMT in PTEC (HK-2 cells). HK-2 cells were treated with AA (10 MUmol/L) for periods up to 72 h. Cell viability was determined by tetrazolium dye (MTT) assay. Morphological changes were assessed by phase-contrast microscopy. Markers of EMT, including E-cadherin and alpha-smooth muscle actin (alpha-SMA) were detected by indirect immunofluorescence stains. The BMP-7 and gremlin mRNA and protein expression in HK-2 cells were analyzed by quantitative real-time PCR (real-time RT-PCR) and western blotting after exposure to AA. The level of phosphorylated Smad1/5/8, a marker of BMP-7 activity, was also determined by western blot analysis. Cells were transfected with gremlin siRNA to determine the effects of gremlin knockdown on markers of EMT following treatment with AA. Our results indicated that AA induced EMT was associated with acquisition of fibroblast-like cell shape, loss of E-cadherin, and increases of alpha-SMA and collagen type I. Interestingly, exposure of HK-2 cells to 10 MUmol/L AA increased the mRNA and protein expression of gremlin in HK-2 cells. This increase was in parallel with a decrease in BMP-7 expression and a down-regulation of phosphorylated Smad1/5/8 protein levels. Moreover, transfection with siRNA to gremlin was able to recover BMP-7 signaling activity, and attenuate EMT-associated phenotypic changes induced by AA. Together, these observations strongly suggest that gremlin plays a critical role in the modulation of reno-protective action of BMP, and that inhibition of gremlin will be a promising means of developmenting novel treatments for AAN. PMID- 22525893 TI - Understanding motivations for abstinence among adolescent young women: insights into effective sexual risk reduction strategies. AB - INTRODUCTION: Pregnancy and sexually transmitted infections pose a significant threat to the health and well-being of adolescent women. Abstinence, when practiced, provides the most effective means of preventing these problems, yet the perspective of abstinent young women is not well understood. The purpose of this investigation was to characterize female adolescents' motivations for abstinence. METHOD: As part of a larger, cross-sectional quantitative study investigating predictors of HIV risk reduction behaviors, qualitative responses from study participants who never had intercourse were analyzed in a consensus based process using content analysis and frequency counts. An urban primary care site in a tertiary care center served as the setting, with adolescent young women ages 15-19 years included in the sample. RESULTS: Five broad topic categories emerged from the data that characterized motivations for abstinence in this sample: personal readiness, fear, beliefs and values, partner worthiness, and lack of opportunity. DISCUSSION: A better understanding of the motivations for abstinence may serve to guide the development of interventions to delay intercourse. PMID- 22525894 TI - Static and dynamic loading of mandibular condyles and their positional changes after bilateral sagittal split advancement osteotomies. AB - This study analysed the effects of change of direction of masseter (MAS) and medial pterygoid muscles (MPM) and changes of moment arms of MAS, MPM and bite force on static and dynamic loading of the condyles after surgical mandibular advancement. Rotations of the condyles were assessed on axial MRIs. 16 adult patients with mandibular hypoplasia were studied. The mandibular plane angle (MPA) was <39 degrees in Group I (n=8) and >39 degrees in Group II (n=8). All mandibles were advanced with a bilateral sagittal split osteotomy (BSSO). In Group II, BSSO was combined with Le Fort I osteotomy. Pre and postoperative moment arms of MAS, MPM and bite force were used in a two-dimensional model to assess static loading of the condyles. Pre and postoperative data on muscle cross sectional area, volume and direction were introduced in three-dimensional dynamic models of the masticatory system to assess the loading of the condyles during opening and closing. Postsurgically, small increases of static condylar loading were calculated. Dynamic loading decreased slightly. Minor rotations of the condyles were observed. The results do not support the idea that increased postoperative condylar loading is a serious cause for condylar resorption or relapse. PMID- 22525896 TI - Effect of lateral heterogeneity in mixed surfactant-stabilized interfaces on the oxidation of unsaturated lipids in oil-in-water emulsions. AB - The development of lipid oxidation in oil-in-water (O/W) emulsions is widely influenced by the properties of the interfacial layer, which separates the oil and water phases. In this work, the effect of the structure of the interface on the oxidative stability of surfactant stabilized O/W emulsions was investigated. Emulsions were prepared with either single Tween 20 or Tween 20/co-surfactant mixtures in limiting amounts. The co-surfactants, Span 20 and monolauroyl glycerol have the same hydrophobic tail as Tween 20 but differ by the size and composition of their polar headgroup. Metal-initiated lipid oxidation, monitored through the measurement of oxygen uptake, formation of conjugated dienes and volatile compounds, developed more rapidly in the emulsions stabilized by the surfactant mixture than in the single Tween 20-stabilized emulsion. The reconstitution of Tween 20/co-surfactant films at the air-water interface and their surface-pressure isotherms highlighted that, contrary to single Tween 20 molecules, Tween 20/co-surfactant mixtures exhibited an heterogeneous distribution within the interfacial layer, offering probably easier access of water-soluble pro-oxidants to the oil phase. These observations provide direct information about the link between the homogeneity of the interface layer and the oxidative stability of emulsions. PMID- 22525898 TI - Detrimental effect of induced or spontaneous menses before ovulation induction on pregnancy outcome in patients with polycystic ovary syndrome. PMID- 22525899 TI - 2011 Pitkin Award and 2011 Kaminetzky Prize Paper. PMID- 22525901 TI - Antenatal steroids for treatment of fetal lung immaturity after 34 weeks of gestation: an evaluation of neonatal outcomes. AB - OBJECTIVE: To estimate whether antenatal corticosteroids given after fetal lung immaturity in pregnancies at 34 weeks of gestation or more would improve neonatal outcomes and, in particular, respiratory outcomes. METHODS: We compared outcomes of 362 neonates born at 34 weeks of gestation or more after fetal lung maturity testing: 102 with immature fetal lung indices were treated with antenatal corticosteroids followed by planned delivery within 1 week; 76 with immature fetal lung indices were managed expectantly; and 184 were delivered after mature amniocentesis. Primary outcomes were composites of neonatal and respiratory morbidity. RESULTS: Compared with corticosteroid-exposed neonates those born after mature amniocentesis had lower rates of adverse neonatal (26.5% compared with 14.1%, adjusted odds ratio [OR] 0.51, 95% confidence interval [CI] 0.27 0.96) and adverse respiratory outcomes (9.8% compared with 3.3%, adjusted OR 0.33, 95% CI 0.11-0.98); newborns born after expectant management had significantly less respiratory morbidity (1.3% compared with 9.8%, adjusted OR 0.11, 95% CI 0.01-0.92) compared with corticosteroid-exposed newborns. CONCLUSION: Administration of antenatal corticosteroids after immature fetal lung indices did not reduce respiratory morbidity in neonates born at 34 weeks of gestation or more. Our study supports prolonging gestation until delivery is otherwise indicated. LEVEL OF EVIDENCE: II. PMID- 22525900 TI - Endometrial shedding effect on conception and live birth in women with polycystic ovary syndrome. AB - OBJECTIVE: To estimate whether progestin-induced endometrial shedding, before ovulation induction with clomiphene citrate, metformin, or a combination of both, affects ovulation, conception, and live birth rates in women with polycystic ovary syndrome (PCOS). METHODS: A secondary analysis of the data from 626 women with PCOS from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Cooperative Reproductive Medicine Network trial was performed. Women had been randomized to up to six cycles of clomiphene citrate alone, metformin alone, or clomiphene citrate plus metformin. Women were assessed for occurrence of ovulation, conception, and live birth in relation to prior bleeding episodes (after either ovulation or exogenous progestin-induced withdrawal bleed). RESULTS: Although ovulation rates were higher in cycles preceded by spontaneous endometrial shedding than after anovulatory cycles (with or without prior progestin withdrawal), both conception and live birth rates were significantly higher after anovulatory cycles without progestin-induced withdrawal bleeding (live births per cycle: spontaneous menses 2.2%; anovulatory with progestin withdrawal 1.6%; anovulatory without progestin withdrawal 5.3%; P<.001). The difference was more marked when rate was calculated per ovulation (live births per ovulation: spontaneous menses 3.0%; anovulatory with progestin withdrawal 5.4%; anovulatory without progestin withdrawal 19.7%; P<.001). CONCLUSION: Conception and live birth rates are lower in women with PCOS after a spontaneous menses or progestin-induced withdrawal bleeding as compared with anovulatory cycles without progestin withdrawal. The common clinical practice of inducing endometrial shedding with progestin before ovarian stimulation may have an adverse effect on rates of conception and live birth in anovulatory women with PCOS. LEVEL OF EVIDENCE: II. PMID- 22525903 TI - Maternal drug use and its effect on neonates: a population-based study in Washington State. AB - OBJECTIVE: To estimate the effect of maternal illicit and prescription drug use on neonates in Washington State between 2000 and 2008. METHODS: We used state linked birth certificate and hospital discharge (mother and neonate) data to calculate prenatal drug exposure and neonatal abstinence syndrome rates, and compared state neonatal abstinence syndrome rates with national-level data from the Nationwide Inpatient Sample. We identified the drugs of exposure, examined predictors of drug exposure and neonatal abstinence syndrome, and assessed perinatal outcomes among drug-exposed and neonatal abstinence syndrome-diagnosed neonates compared with unexposed neonates. RESULTS: Drug exposure and neonatal abstinence syndrome rates increased significantly between 2000 and 2008, neonatal abstinence syndrome rates being consistently higher than national figures (3.3 compared with 2.8 per 1,000 births in 2008; P<.05). The proportion of neonatal abstinence syndrome-diagnosed neonates exposed prenatally to opioids increased from 26.4% in 2000 to 41.7% in 2008 (P<.05). Compared with unexposed neonates, drug-exposed and neonatal abstinence syndrome-diagnosed neonates had a lower mean birth weight, longer birth hospitalization, were more likely to be born preterm, experience feeding problems, and have respiratory conditions (all P<.001). CONCLUSION: Maternal use of illicit and prescription drugs was associated with considerable neonatal morbidity and significantly higher rates of drug exposure and neonatal abstinence syndrome in recent years. Data suggest that opioid analgesics contributed to the increase in prenatal drug exposure and neonatal abstinence syndrome in Washington State. In accordance with current guidelines, our findings emphasize the need for clinicians to screen pregnant women for illicit and prescription drug use and minimize use of opioid analgesics during pregnancy. LEVEL OF EVIDENCE: II. PMID- 22525904 TI - Mood symptoms after natural menopause and hysterectomy with and without bilateral oophorectomy among women in midlife. AB - OBJECTIVE: To examine whether mood symptoms increased more for women in the years after hysterectomy with or without bilateral oophorectomy relative to natural menopause. METHODS: Using data from the Study of Women's Health Across the Nation (n=1,970), depression and anxiety symptoms were assessed annually for up to 10 years with the Center for Epidemiological Studies Depression Index and four anxiety questions, respectively. Piece-wise hierarchical growth models were used to relate natural menopause, hysterectomy with ovarian conservation, and hysterectomy with bilateral oophorectomy to trajectories of mood symptoms before and after the final menstrual period or surgery. Covariates included educational attainment, race, menopausal status, age the year before final menstrual period or surgery, and time-varying body mass index, self-rated health, hormone therapy, and antidepressant use. RESULTS: By the tenth annual visit, 1,793 (90.9%) women reached natural menopause, 76 (3.9%) reported hysterectomy with ovarian conservation, and 101 (5.2%) reported hysterectomy with bilateral oophorectomy. For all women, depressive and anxiety symptoms decreased in the years after final menstrual period or surgery. These trajectories did not significantly differ by hysterectomy or oophorectomy status. The Center for Epidemiological Studies Depression Index means were 0.72 standard deviations lower and anxiety symptoms were 0.67 standard deviations lower 5 years after final menstrual period or surgery. CONCLUSION: In this study, mood symptoms continued to improve after the final menstrual period or hysterectomy for all women. Women who undergo a hysterectomy with or without bilateral oophorectomy in midlife do not experience more negative mood symptoms in the years after surgery. LEVEL OF EVIDENCE: II. PMID- 22525905 TI - Caffeine intake and risk of urinary incontinence progression among women. AB - OBJECTIVE: To estimate the association between long-term caffeine intake and risk of urinary incontinence (UI) progression over 2 years among women with moderate UI. METHODS: We conducted a prospective cohort study in 21,564 women with moderate UI enrolled in the Nurses' Health Study and Nurses' Health Study II. Incontinence progression was identified from questionnaires during 2 years of follow-up. Baseline caffeine intake (ie, average intake during the previous year) and change in caffeine intake during the 4 years before baseline were measured using food frequency questionnaires. Odds ratios (ORs) for incontinence progression according to caffeine intake were calculated for each cohort separately, and then for both cohorts combined. RESULTS: The percentage of women with UI progression was similar across categories of baseline level of caffeine intake and change in caffeine intake before baseline. For example, percentages were 21% compared with 22% comparing 450 mg or more to less than 150 mg of caffeine per day (adjusted OR 0.87, 95% confidence interval 0.70-1.08). Comparing women with increased caffeine intake to those with stable caffeine intake, percentages with progression were 22% compared with 20% (OR 1.08, 95% confidence interval 0.95-1.22). Results were similar in separate analyses of urge and stress UI. CONCLUSION: Long-term caffeine intake over 1 year was not associated with risk of UI progression over 2 years among women with moderate incontinence, although we could not examine acute effects of caffeine. Improved understanding of the effect of caffeine on the bladder is needed to better-advise women with incontinence about caffeine intake. LEVEL OF EVIDENCE: II. PMID- 22525906 TI - Long-term visual functioning after eclampsia. AB - OBJECTIVE: Complete neurocognitive recovery after eclampsia has been questioned with the expression of neurocognitive deficits by affected women and demonstration of cerebral white matter lesions on magnetic resonance imaging years after eclampsia. We hypothesized that formerly eclamptic women may experience impaired vision-related quality of life (QOL) and visual field loss as a result of the presence of such lesions in the cerebral visual areas. METHODS: Using the National Eye Institute Visual Function Questionnaire-39/Nederlands questionnaire, vision-related QOL was compared between formerly eclamptic women and control participants after normotensive pregnancies. Furthermore, in formerly eclamptic women, visual fields were assessed using automated perimetry, and presence of white matter lesions was evaluated using cerebral magnetic resonance imaging. Presence of a relationship between these lesions and National Eye Institute Visual Function Questionnaire-39/Nederlands scores was estimated. RESULTS: Forty-seven formerly eclamptic women and 47 control participants participated 10.1+/-5.2 and 11.5+/-7.8 years after their index pregnancy, respectively. Composite scores and 4 out of 12 National Eye Institute Visual Function Questionnaire-39/Nederlands subscale scores were significantly lower in formerly eclamptic women than in control participants (P<.01 for composite scores). This could not be explained by visual field loss, because all formerly eclamptic women who underwent perimetry (n=43) demonstrated intact visual fields. White matter lesions were present in 35.7% of formerly eclamptic women who underwent magnetic resonance imaging (n=42) and were associated with lower vision related QOL scores (P<.05 for composite scores). CONCLUSION: Formerly eclamptic women express lower vision-related QOL than control participants, which seemed at least partly related to the presence of white matter lesions. However, such women do not have unconscious visual field loss. Vision-related QOL impairment expressed by formerly eclamptic women may therefore be related to problems with higher-order visual functions. LEVEL OF EVIDENCE: II. PMID- 22525907 TI - Structural capillary rarefaction and the onset of preeclampsia. AB - OBJECTIVE: To estimate if reduced capillary density (ie, capillary rarefaction) precedes the onset of preeclampsia and if it could play a role in its pathogenesis. Capillary rarefaction is a consistent finding in essential hypertension. METHODS: In this longitudinal cohort study, we recruited 322 consecutive white women, of whom 305 women completed the study. We used intravital video microscopy to measure basal (ie, functional) and maximal (ie, structural) skin capillary densities according to a well-validated protocol and measured plasma angiogenic and antiangiogenic factors. Women were studied at five consecutive predetermined visits. RESULTS: Preeclampsia occurred in 16 women (mean onset at 35.6+/-4.8 weeks of gestation), 272 women had normal pregnancies, eight had hypertension, and nine pregnancies were complicated by intrauterine growth restriction. In women with a normal pregnancy, significant reduction in maximal capillary density occurred at 27-32 weeks but had resolved by the puerperium. In contrast, in women who later developed preeclampsia, structural rarefaction was greater and occurred earlier at 20-24 weeks of gestation and persisted into the puerperium. We also found that the change in soluble Endoglin from 11-16 weeks of gestation to 27-32 weeks of gestation was significantly correlated with the change in structural capillary density. CONCLUSION: Significant structural capillary rarefaction precedes the onset of preeclampsia and could play a role in its pathogenesis. LEVEL OF EVIDENCE: II. PMID- 22525908 TI - Community-level and individual-level influences of intimate partner violence on birth spacing in sub-Saharan Africa. AB - OBJECTIVE: To estimate the extent to which intimate partner violence (IPV), at the levels of the individual and the community, is associated with shortened interbirth intervals among women in sub-Saharan Africa. METHODS: We analyzed demographic and health survey data from 11 countries in sub-Saharan Africa. Only multiparous women were included in the analysis. Interbirth interval was the primary outcome. Personal history of IPV was measured using a modified Conflict Tactics Scale. Community prevalence of IPV was measured as the proportion of women in each village reporting a personal history of IPV. We used multilevel modeling to account for the hierarchical structure of the data, allowing us to partition the variation in birth intervals to the four different levels (births, individuals, villages, and countries). RESULTS: Among the 46,697 women in the sample, 11,730 (25.1%) reported a personal history of physical violence and 4,935 (10.6%) reported a personal history of sexual violence. In the multivariable regression model, interbirth intervals were inversely associated with personal history of physical violence (regression coefficient b=-0.60, 95% confidence interval -0.91 to -0.28) and the community prevalence of physical violence (b= 1.41, 95% confidence interval -2.41 to -0.40). Estimated associations with sexual violence were of similar statistical significance and magnitude. CONCLUSION: Both personal history of IPV and the community prevalence of IPV have independent and statistically significant associations with shorter interbirth intervals. LEVEL OF EVIDENCE: II. PMID- 22525909 TI - Relationship of subclinical thyroid disease to the incidence of gestational diabetes. AB - OBJECTIVE: To estimate if there is a relationship between subclinical thyroid disease and gestational diabetes. METHODS: Between November 2000 and April 2003, serum thyrotropin screening was performed on all women who presented for prenatal care. Women identified with abnormal thyrotropin had a serum free thyroxine reflexively determined. Those women with abnormal serum free thyroxine values were referred for further evaluation and excluded from further analysis. For this analysis, normal thyrotropin values were those between the 2.5th and 97.5th percentiles (0.03-4.13 milliunits/L) not corrected for gestational age and serum free thyroxine were considered normal if they ranged from 0.9 to 2.0 mg/dL. Women with an elevated serum thyrotropin but a normal serum free thyroxine were designated to have subclinical hypothyroidism and those with a low thyrotropin and a normal serum free thyroxine level were designated to have subclinical hyperthyroidism. Euthyroid women had both normal thyrotropin and normal serum free thyroxine values. The incidence of gestational diabetes was compared among these three groups. RESULTS: Of the 24,883 women included in the study, 23,771 (95.5%) were euthyroid, 584 (2.3%) had subclinical hyperthyroidism, and 528 (2%) had subclinical hypothyroidism. The likelihood of gestational diabetes increased with thyrotropin level (P=.002). For example, when a pregnant Hispanic woman of average age and weight was used, the predicted percent of gestational diabetes increased from 1.9% to 4.9% as thyrotropin increased from 0.001 to 10 milliunits/L (P=.001). CONCLUSION: The risk of developing gestational diabetes increases with thyrotropin level. This supports a relationship between subclinical hypothyroidism and diabetes diagnosed during pregnancy. LEVEL OF EVIDENCE: III. PMID- 22525902 TI - Effect of antenatal corticosteroids on fetal growth and gestational age at birth. AB - OBJECTIVE: To estimate the effect of multiple courses of antenatal corticosteroids on neonatal size, controlling for gestational age at birth and other confounders, and to determine whether there was a dose-response relationship between number of courses of antenatal corticosteroids and neonatal size. METHODS: This is a secondary analysis of the Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study, a double-blind randomized controlled trial of single compared with multiple courses of antenatal corticosteroids in women at risk for preterm birth and in which fetuses administered multiple courses of antenatal corticosteroids weighed less, were shorter, and had smaller head circumferences at birth. All women (n=1,858) and children (n=2,304) enrolled in the Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study were included in the current analysis. Multiple linear regression analyses were undertaken. RESULTS: Compared with placebo, neonates in the antenatal corticosteroids group were born earlier (estimated difference and confidence interval [CI]: -0.428 weeks, CI -0.10264 to -0.75336; P=.01). Controlling for gestational age at birth and confounding factors, multiple courses of antenatal corticosteroids were associated with a decrease in birth weight (-33.50 g, CI 66.27120 to -0.72880; P=.045), length (-0.339 cm, CI -0.6212 to -0.05676]; P=.019), and head circumference (-0.296 cm, -0.45672 to -0.13528; P<.001). For each additional course of antenatal corticosteroids, there was a trend toward an incremental decrease in birth weight, length, and head circumference. CONCLUSION: Fetuses exposed to multiple courses of antenatal corticosteroids were smaller at birth. The reduction in size was partially attributed to being born at an earlier gestational age but also was attributed to decreased fetal growth. Finally, a dose-response relationship exists between the number of corticosteroid courses and a decrease in fetal growth. The long-term effect of these findings is unknown. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00187382. LEVEL OF EVIDENCE: II. PMID- 22525910 TI - Efficacy, safety, and tolerability of a monophasic oral contraceptive containing nomegestrol acetate and 17beta-estradiol: a randomized controlled trial. AB - OBJECTIVE: To estimate the efficacy, cycle control, tolerability, and safety of a monophasic combined oral contraceptive containing nomegestrol acetate and 17beta estradiol (E2) in comparison with drospirenone and ethinyl E2. METHODS: In a randomized, open-label, comparative multicenter trial, healthy women (n=2,281; age 18-50 years) at risk for pregnancy and in need of contraception were allocated in a 3:1 ratio to receive nomegestrol acetate (2.5 mg) and 17beta-E2 (1.5 mg) in a 24-4-day regimen (investigational drug) or drospirenone (3.0 mg) and ethinyl E2 (30 micrograms) in a 21-7-day regimen (comparator) for 13 consecutive, 28-day cycles. The primary end point was the Pearl Index. RESULTS: The Pearl Indices for 18- to 35-year-old women in the investigational (n=1,375) and comparator (n=463) groups were 1.27 (95% confidence interval [CI] 0.66-2.22) and 1.89 (95% CI 0.69-4.11), respectively. Respective 1-year cumulative pregnancy rates were 1.22 (95% CI 0.69-2.16) and 1.82 (95% CI 0.81-4.05). By the end of the trial, shorter, lighter scheduled bleeding or an absence of scheduled bleeding occurred with greater frequency (32.9%) in the investigational group, whereas unscheduled bleeding or spotting episodes were low (16.2% and 15.0% in the investigational and comparator groups, respectively). Acne prevalence decreased from approximately 33% at baseline to 22% and 14% at cycle 13 in the respective groups. In the investigational group, the most frequently reported adverse events were acne (16.4%), weight gain (9.5%), and irregular withdrawal bleeding (9.1%). CONCLUSION: Nomegestrol acetate and 17beta-E2 were well tolerated and provided excellent contraceptive efficacy and acceptable cycle control. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, www.clinicaltrials.gov, NCT00413062. LEVEL OF EVIDENCE: I. PMID- 22525911 TI - Diagnostic accuracy of maternal serum macrophage inhibitory cytokine-1 and pregnancy-associated plasma protein-A at 6-10 weeks of gestation to predict miscarriage. AB - OBJECTIVE: To determine whether serum macrophage inhibitory cytokine-1, pregnancy associated plasma protein-A (PAPP-A), anandamide, or beta-human chorionic gonadotropin (hCG) measured in an asymptomatic population in the middle of the first trimester with a viable fetus predicts subsequent miscarriage. METHODS: We undertook a prospective cohort study at Mercy Hospital for Women between 2004 and 2008. Participants (N=782) were recruited from prenatal clinics, where samples were taken from asymptomatic women at 6 0/7 to 10 6/7 weeks of gestation. We collected samples from only those women for whom we were able to obtain ultrasound evidence of a singleton with fetal cardiac activity. Serum macrophage inhibitory cytokine-1, PAPP-A, anandamide, and beta-hCG concentrations were assayed. RESULTS: Twenty-one (2.7%) miscarried and 761 did not. Among those who miscarried, macrophage inhibitory cytokine-1 and PAPP-A were significantly decreased at 63% (multiples of the median (MOM) 0.63, 25th-75th percentiles 0.33 0.88) and 23% (MOM 0.23, 25th-75th percentiles 0.12-0.48) of levels seen among those with ongoing pregnancies (P<.001 for both comparisons). In contrast, neither serum beta-hCG (MOM 0.99, 25th-75th percentiles 0.46-1.86) nor anandamide (MOM 1.07, 25th-75th percentiles 0.87-1.19) was elevated or decreased among those who miscarried compared with those with ongoing pregnancies. At a fixed 10% false positive rate (90% specificity), a test combining macrophage inhibitory cytokine 1 and PAPP-A yielded 63% sensitivity and a 6.6 positive likelihood ratio in predicting miscarriage. CONCLUSION: Low serum levels of macrophage inhibitory cytokine-1 and PAPP-A measured from asymptomatic women at 6-10 weeks of gestation with viable pregnancies can predict subsequent miscarriage. These analytes are likely to have an important biological role in early pregnancy and are likely to be useful clinical biomarkers for miscarriage and other early pregnancy complications. LEVEL OF EVIDENCE: II. PMID- 22525912 TI - Chlamydia trachomatis antigens recognized in women with tubal factor infertility, normal fertility, and acute infection. AB - OBJECTIVE: To identify Chlamydia trachomatis antigens associated with tubal factor infertility and acute infection. METHODS: A C trachomatis proteome array was used to compare antibody profiles among women with tubal factor infertility, normal fertility, and acute C trachomatis infection. RESULTS: Thirteen immunodominant antigens reacted with 50% or more sera from all women (n=73). Six C trachomatis antigens were uniquely recognized in women with tubal factor infertility. Combining fragmentation of the six antigens with serum sample dilution, chlamydial antigens HSP60, CT376, CT557, and CT443 could discriminate between women with tubal factor infertility and women with normal fertility with a sensitivity of 63% (95% confidence interval [CI] 0.41-0.77) and specificity of 100% (95% CI 0.91-1), respectively. These antigens were designated as tubal factor infertility-associated antigens. However, these tubal factor antigens were unable to distinguish tubal factor infertility patients from those with acute infection. A combination of CT875 and CT147 distinguished women with acute infection from all other C trachomatis-exposed women with a detection sensitivity of 63% (95% CI 0.41-0.77) and specificity of 100% (95% CI 0.95-1), respectively. Thus, CT875 and CT147 were designated as acute infection-associated antigens. CONCLUSION: A sequential screening of antibodies against panels of C trachomatis antigens can be used to identify women with tubal factor infertility and acute C trachomatis infection. LEVEL OF EVIDENCE: II. PMID- 22525913 TI - Distribution of American Congress of Obstetricians and Gynecologists fellows and junior fellows in practice in the United States. AB - OBJECTIVE: To develop effective policies addressing access to health care for all women in the United States, we report the distribution of the American Congress of Obstetricians and Gynecologists (ACOG) Fellows and Junior Fellows in practice at county and state levels. METHODS: Data were gathered from the 2010 U.S. County Census File for adult women (aged 15 years or older) and reproductive-aged women (15-44 years old) and from the 2010 membership roster of ACOG. The number of postresidency, actively practicing physicians trained in general obstetrics and gynecology per targeted population were recorded at state and district levels and mapped at county levels using uDig GIS software and U.S. Census TIGER/Line Shapefiles. RESULTS: In 2010, the 33,624 general obstetrician-gynecologists (ob gyns) in the United States, comprised 5.0% of the total 661,400 physicians. There were 2.65 ob-gyns per 10,000 women and 5.39 ob-gyns per 10,000 reproductive-aged women. The density of ob-gyns declined from metropolitan to micropolitan and to rural counties. Approximately half (1,550, 49%) of the 3,143 U.S. counties lacked a single ob-gyn, and 10.1 million women (8.2% of all women) lived in those predominantly rural counties. Such counties, located especially in the central and mountain west regions, were commonly in designated Health Professional Shortage Areas. CONCLUSION: An uneven distribution of ACOG Fellows and Junior Fellows in practice exists throughout the United States and may worsen if resident graduates continue to cluster in metropolitan areas. Meeting the needs of women in underserved areas requires creative innovations in enhancing a more uniform geographic distribution of providers. LEVEL OF EVIDENCE: III. PMID- 22525914 TI - Promotion rates for assistant and associate professors in obstetrics and gynecology. AB - OBJECTIVE: To estimate promotion rates of physician faculty members in obstetrics and gynecology during the past 30 years METHODS: Data were collected annually by the Association of American Medical Colleges from every school between 1980 and 2009 for first-time assistant and associate professors to determine whether and when they were promoted. Data for full-time physician faculty were aggregated by decade (1980-1989, 1990-1999, 2000-2009). Faculty were included if they remained in academia for 10 years after beginning in rank. Data were analyzed by constructing estimated promotion curves and extracting 6-year and 10-year promotion rates. RESULTS: The 10-year promotion rates (adjusted for attrition) declined significantly for assistant professors from 35% in 1980-1989 to 32% in 1990-1999 to 26% in 2000-2009 (P<.001), and for associate professors from 37% to 32% to 26%, respectively (P<.005). These declines most likely resulted from changes in faculty composition. The most recent 15 years saw a steady increase in the proportion of entry-level faculty who were women (now 2:1) and primarily on the nontenure track. The increasing number of faculty in general obstetrics and gynecology had lower promotion probabilities than those in the subspecialties (odds ratio 0.16; P<.001). Female faculty on the nontenure track had lower promotion rates than males on the nontenure track, males on the tenure track, and females on the tenure track (odds ratio 0.8 or less; P<.01). CONCLUSION: A decline in promotion rates during the past 30 years may be attributable to changes in faculty composition. LEVEL OF EVIDENCE: II. PMID- 22525915 TI - Paracervical block for pain control in first-trimester surgical abortion: a randomized controlled trial. AB - OBJECTIVE: Despite lack of efficacy data, the majority of first-trimester surgical abortions are performed with a paracervical block. Women may be unnecessarily exposed to a painful injection and potentially noxious medication. Our objective was to estimate the effect of a paracervical block and the effect of gestational age on patient pain perception. METHODS: This was a randomized, single-blind trial of patients undergoing abortion receiving paracervical block or sham stratified by gestational age (early: less than 8 weeks of gestation, n=60; late: 8-10 6/7 weeks of gestation, n=60). Premedicated with ibuprofen and lorazepam, all participants received 2 mL 1% buffered lidocaine injected at the tenaculum site followed by a slow, deep injection of 18 mL at four sites (block) or no injection (sham) with a 3-minute wait. The primary outcome was dilation pain (100-mm visual analog scale). Secondary outcomes included pain at additional time points, satisfaction, need for more analgesics, and adverse events. RESULTS: Full enrollment occurred (n=120). We used intent-to-treat analysis. Demographics did not differ between groups. Paracervical block administration was painful (mean 55 mm compared with sham 30 mm, P<.001) but decreased dilation pain (42 mm compared with 79 mm, P<.001) and aspiration pain (63mm compared with 89 mm, P<.001). These results were consistent for both gestational age strata; however, paracervical block benefit was greater at an earlier gestation. Satisfaction scores with pain control and the procedure were significantly higher in the block group. CONCLUSION: Although paracervical block is painful, it reduces first trimester abortion pain regardless of gestational age, but the benefit on dilation pain was greater at earlier gestations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01094366. LEVEL OF EVIDENCE: I. PMID- 22525916 TI - Combined hormonal contraceptives and venous thromboembolism: putting the risks into perspective. AB - To date, 13 studies have provided data on the risk of venous thromboembolism associated with combined oral contraceptives containing drospirenone or the norelgestromin-containing contraceptive patch. The studies varied in their conclusions about whether these methods are associated with higher risks than combined oral contraceptives containing other progestins: the primary reported measures of association (adjusted odds ratios, incidence rate ratios, or hazard ratios) ranged from 0.9 to 3.3. All of the studies had weaknesses in population selection, data validity or completeness, or analysis that may have led to biased or spurious findings. Venous thromboembolism is rare; if the contraceptive methods of interest do confer a higher risk of thromboembolism, only an additional 5-10 per 10,000 users per year would be affected. The important message for patients, clinicians, and policy makers is that the benefits of all contraceptive methods markedly outweigh their risks, primarily because they prevent pregnancy, an inherently hazardous condition. Product labels for hormonal contraceptives should emphasize their substantial health benefits and established safety. PMID- 22525917 TI - Human trafficking: a call for heightened awareness and advocacy by obstetrician gynecologists. PMID- 22525918 TI - Retirement musings. PMID- 22525919 TI - She's just a little girl. PMID- 22525920 TI - What is new in reproductive endocrinology?: best articles from the past year. PMID- 22525921 TI - Promoting health after gestational diabetes: a National Diabetes Education Program call to action. PMID- 22525923 TI - Application of criteria developed by the Task Force on Neonatal Encephalopathy and Cerebral Palsy to acutely asphyxiated neonates. PMID- 22525930 TI - ACOG Committee Opinion No. 523: Re-entering the practice of obstetrics and gynecology. AB - Re-entering the practice of obstetrics and gynecology after a period of inactivity can pose a number of obstacles for a physician. Preparing for the leave of absence may help reduce the difficulties physicians may face upon re entering practice. PMID- 22525931 TI - ACOG Committee Opinion No. 524: Opioid abuse, dependence, and addiction in pregnancy. AB - Opioid use in pregnancy is not uncommon, and the use of illicit opioids during pregnancy is associated with an increased risk of adverse outcomes. The current standard of care for pregnant women with opioid dependence is referral for opioid assisted therapy with methadone, but emerging evidence suggests that buprenorphine also should be considered. Medically supervised tapered doses of opioids during pregnancy often result in relapse to former use. Abrupt discontinuation of opioids in an opioid-dependent pregnant woman can result in preterm labor, fetal distress, or fetal demise. During the intrapartum and postpartum period, special considerations are needed for women who are opioid dependent to ensure appropriate pain management, to prevent postpartum relapse and a risk of overdose, and to ensure adequate contraception to prevent unintended pregnancies. Patient stabilization with opioid-assisted therapy is compatible with breastfeeding. Neonatal abstinence syndrome is an expected and treatable condition that follows prenatal exposure to opioid agonists. PMID- 22525932 TI - ACOG Committee Opinion No. 525: Health care for lesbians and bisexual women. AB - Lesbians and bisexual women encounter barriers to health care that include concerns about confidentiality and disclosure, discriminatory attitudes and treatment, limited access to health care and health insurance, and often a limited understanding as to what their health risks may be. Health care providers should offer quality care to all women regardless of sexual orientation. The American College of Obstetricians and Gynecologists endorses equitable treatment for lesbians and bisexual women and their families, not only for direct health care needs, but also for indirect health care issues. PMID- 22525933 TI - ACOG Committee Opinion No. 526: Standardization of practice to improve outcomes. AB - Protocols and checklists have been shown to improve patient safety through standardization and communication. Standardization of practice to improve quality outcomes is an important tool in achieving the shared vision of patients and their health care providers. PMID- 22525934 TI - Comparing the population neurodevelopmental burdens associated with children's exposures to environmental chemicals and other risk factors. AB - To estimate the population burden of an exposure that is associated with neurodevelopmental impairment, it is necessary to consider both the effect size associated with the exposure (i.e., the decrease in function per unit increase in biomarker level) and the prevalence of the exposure. An exposure with a modest effect size might, nevertheless, be associated with a substantial population burden if many children are exposed at levels at which the exposure is known to have a detrimental impact. This illustrates the important distinction between individual risk and population risk. A method is described that can be used to compare different risk factors in terms of their contributions to the population burden of neurodevelopmental impairment. Combining estimates of the incidence/prevalence/distribution of different conditions or exposures with estimates, derived from meta-analyses, for the impact of different risk factors on children's Full-Scale IQ scores (FSIQ), the total FSIQ losses associated with each were calculated for the U.S. population of children less than 5 years of age. The losses associated with non-chemical risk factors ranged widely: 34,000,000 FSIQ points for preterm birth, 17,000,000 for Attention Deficit Hyperactivity Disorder, 9,000,000 for iron deficiency, 136,000 for acute lymphocytic leukemia, and 37,000 for brain tumors. The FSIQ losses could be estimated for three chemicals: lead, 23,000,000 points; methylmercury, 285,000 points; and organophosphate pesticides, 17,000,000 points. Many caveats attend these calculations, but the findings suggest that in continuing to apply standards appropriate to evaluating the impact of chemical exposures on an individual child rather than on the population as a whole, we risk underestimating the population burdens associated with them. PMID- 22525935 TI - Low level of glutathione can intensify the toxic effect of salsolinol in SH-SY5Y neuroblastoma cell line. AB - There is increasing evidence that endogenously produced toxins may be involved in the development of a number of neurodegenerative diseases such as Alzheimer's, Parkinson's or Huntington's disease and that the mechanisms leading to cell loss are a combination of oxidative stress, mitochondrial dysfunction and a decrease in antioxidant defenses. The purpose of this study was to investigate the effects of glutathione on 3-hydroxykynurenine, 6-hydroxydopamine and salsolinol mediated neurotoxicity in the human neuroblastoma SH-SY5Y cell line in order to find a possible therapeutic application of this compound to neurodegenerative disorders. In this study, we tested the protective effect of glutathione on SH-SY5Y cells against 3-hydroxykynurenine, 6-hydroxydopamine and salsolinol induced cytotoxicity and demonstrated that glutathione inhibits cell death and adenosine 5'triphosphate depletion caused by 3-hydroxykynurenine and 6-hydroxydopamine. However, unexpectedly salsolinol neurotoxicity toward SH-SY5Y cells was potentiated during treatment with concentrations of glutathione below 250 MUM, whereas glutathione concentrations above 250 MUM resulted in protection against salsolinol induced neuronal cell death. We also report that the incubation of salsolinol and low concentrations of glutathione led to increased apoptosis. Hence, salsolinol in the presence of low glutathione concentration may be involved in neurodegeneration. These data may provide new promising insights into the pathophysiology of neudegenerative disorders such as Parkinson's disease. PMID- 22525936 TI - In vivo administration of fluorescent dextrans for the specific and sensitive localization of brain vascular pericytes and their characterization in normal and neurotoxin exposed brains. AB - We have aimed to develop novel histochemical markers for the labeling of brain pericytes and characterize their morphology in the normal and the excitotoxin exposed brain, as this class of cells has received little attention until recently. Pericyte labeling was accomplished by the intracerebroventricular injection of certain fluorescent dextran conjugates, such as Fluoro-Gold-dextran, FR-dextran, FITC-dextran and Fluoro-Turquoise (FT)-dextran. 1-7 days after the tracer injection, extensive labeling of vascular pericytes was seen throughout the entire brain. These cells were found distal to the endothelial cells and exhibited large dye containing vacuoles. The morphology of the pericytes was somewhat variable, exhibiting round or amoeboid shapes within larger intracellular vesicles, while those wrapping around capillaries exhibited a more elongated appearance with finger-like projections. The use of FG-dextran resulted in bluish yellow fluorescently labeled pericytes, while FR-dextran resulted in red fluorescent labeled pericytes, FITC-dextran exhibited green fluorescent pericytes and FT-dextran showed fluorescent blue pericytes in the brain. We have used these tracers to study possible changes in morphology and pericyte number following kainic acid insult, observing that the number of pericytes in the injured or lesioned areas of the brain is dramatically reduced compared to the non-injured areas. These novel fluorochromes should be of use for studies involving the detection and localization of pericytes in both normal and pathological brain tissues. PMID- 22525937 TI - The relationship between the fish consumption and blood total/methyl-mercury concentration of costal area in Korea. AB - The purpose of this study was to evaluate the relationship between fish consumption and blood THg/MeHg concentration in Korean adults by measuring MeHg concentration in blood directly. The study subjects consisted of 400 adults aged 20 or older from 30 subareas in Busan, Ulsan and Gyeongsangnam-do province in Korea from August to October, 2010. We tried to recruit the same number of male and female participants in different age groups (20s, 30s, 40s, 50s and 60s) and allocated 13-16 subjects by district to represent Hg concentration in the research areas. The geometric means of THg and MeHg concentration in blood were 5.27 MUg/L (5.00-5.57) and 4.05 MUg/L (3.81-4.32), respectively. The proportion of MeHg/THg concentration was 78.53% (77.09-79.97). MeHg concentration was higher in coastal areas (4.26 MUg/L) than in inland areas (3.52 MUg/L) and was higher in men (4.68 MUg/L) than in women (3.52 MUg/L). In male participants, blood MeHg concentration increased with increasing annual fish consumption, and the proportion of MeHg/THg concentration showed an upward trend as THg concentration increased. However, none of the measures of the proportion of MeHg/THg showed significant differences. This is the first report in Korea about the relationship between blood MeHg concentration and related factors. Our findings suggest that MeHg concentration is affected by fish consumption as well as by gender difference and drinking status. Since the pathological mechanism has not been clarified, additional studies are needed for explaining the biological and lifestyle differences in the risk of adverse health effects by Hg exposure. PMID- 22525938 TI - Proximal humeral fracture fixation: a biomechanical comparison of two constructs. AB - BACKGROUND: Different options exist for stabilizing proximal humeral fractures. This study compared the mechanical stability of 2 common proximal humeral fixation plates in bending and torsion. METHODS: Tests were conducted on 40 synthetic and 10 matched pairs of cadaveric humeri (evenly fixed with DePuy S3 proximal humeral plating system [DePuy Orthopaedics, Warsaw, IN, USA] and Synthes proximal humerus locking compression plate [Synthes, Paoli, PA, USA]). Half of the humeri were tested by cantilevered bending in flexion, extension, varus, and valgus for 100 cycles of +/-5 mm of displacement at 1 mm/s before loading to failure in varus. The other half were tested in torsion for 100 cycles of +/-8 degrees of rotational displacement at 1 degrees /s before loading to failure in external rotation. RESULTS: Peak cyclic loads for synthetic constructs were higher for DePuy plates than Synthes plates in varus and valgus (P < .0001), but a difference was not detected in extension (P > .40) or flexion (P = .0675). Peak cyclic loads for cadaveric constructs showed a significant difference in extension and flexion (Synthes > DePuy, P < .0001) and in varus (DePuy > Synthes, P < .05) but not in valgus (P > .10). Bending stiffness during varus failure testing was higher for DePuy plates than Synthes plates (P < .0001) for synthetic constructs. Regarding torsion of synthetic and cadaveric constructs, DePuy plates experienced higher peak cyclic torques over all cycles in both directions (P < .0001). For synthetic constructs, DePuy plates showed higher torsional stiffness in external failure than Synthes plates (P < .0001). CONCLUSIONS: The DePuy plate was stiffer than the Synthes plate with varus and valgus bending, as well as in torsion. The Synthes plate tended to be stiffer in flexion and extension. PMID- 22525939 TI - Effect of different statistical methods on union or time to union in a published study about clavicular fractures. AB - BACKGROUND: Time to union is a suspect measure for comparing treatments given the absence of a consensus definition of union, the limited reliability of diagnostic tests, and inconsistency in evaluation times. The purpose of this study was to quantify the variations in union and time to union according to different statistical methods and different approaches to missing data. MATERIALS AND METHODS: Data from a published multicenter, randomized trial comparing operative and nonoperative treatment of clavicular fractures were reanalyzed. Two main types of missing data were encountered: (1) lost to follow-up or died before union and (2) missed appointment. We studied the effect of four statistical methods-comparison of means, comparison of medians, chi(2), and Kaplan-Meier curves-for comparing union or time to union between cohorts for the following scenarios: strict intention-to-treat, intention-to-treat with exclusion of patients with less than 12 months of follow-up, as-treated analysis, and four different imputation methods for missing data. RESULTS: Mean and median time to union varied up to 17%, but comparative statistics consistently demonstrated shorter time to union among operatively treated patients. There were significant differences in the odds ratio, chi(2) values, and the number needed to treat (8% 62%) of union vs nonunion for the three principal analyses. CONCLUSION: Different strategies for handling missed evaluations seem to influence categoric results (eg, union or nonunion) more than continuous measures such as time to union. PMID- 22525940 TI - Fast food for thought: how to survive and thrive in the corporate university. AB - Michael Oakeshott warned in 1950 that the very existence of the university as a place of learning and scholarship was under threat from corporate interests, and that the provision of education was being replaced by the sale of qualifications. By the end of the century, Bill Readings had pronounced that the university was in ruins, just as nurse education in the UK was making the move into higher education. It is against this backdrop of a corporate university sector that is increasingly coming to resemble a fast-food business that nurse academics are struggling to assert their values and make a difference to nursing practice through education, research and scholarship. As it becomes ever more difficult to make our way in the university with any degree of integrity, this paper offers some thoughts and suggests some strategies for not only surviving in the corporate university, but for thriving both personally and professionally in ways that do not compromise our commitments and values as healthcare professionals and human beings. It is offered as a personal reflection, based on nearly 40 years of experiences in UK universities, firstly as a student and latterly as a lecturer and a professor of nursing. As such, it is delivered from a particular geographical and disciplinary perspective, the only perspective I can talk from with any real authority and authenticity. However, I believe that these ideas, thoughts and suggestions can be applied with a degree of success to other healthcare disciplines in other parts of the world. PMID- 22525941 TI - Insights into the phylogenetic and taxonomy of philasterid ciliates (Protozoa, Ciliophora, Scuticociliatia) based on analyses of multiple molecular markers. AB - Scuticociliates are a rich assemblage of species with mostly unresolved phylogenetic relationships, especially in the order Philasterida. In the present work, 48 new sequences for three linked genes are characterized and phylogenetic trees are constructed to assess the inter- and intra-generic relationships of philasterids. Results reveal the following: (1) the combined three-gene tree provides more resolution in nodes than in the SSU-rDNA topologies; (2) the family Orchitophryidae is non-monophyletic as it is split into two parts and Paranophrys magna, Metanophrys sp. and Metanophrys sinensis are designated incertae sedis at the familial level; (3) Uronematidae is non-monophyletic and Homalogastra setosa is designated incertae sedis; (4) Parauronematidae becomes a junior synonym of Uronematidae and the clade containing A. haemophila, Miamiensis avidus, and Glauconema trihymene might stand for a new family; (5) Parauronema being a junior synonym of Uronema is supported and P. longum should be removed from the genus Parauronema; (6) Uronema is not monophyletic and molecular analyses reveal that Uronema sp. QD shares a more recent common ancestor with Uronemella species than with other Uronema species; (7) Metanophrys is polyphyletic; (8) multiple samples of two highly controversial species, viz., Mesanophrys pugettensis and M. chesapeakensis have identical ITS1-5.8S-ITS2 region sequence and we propose they should be synonymous with M. carcini, and (9) there may be cryptic species in M. carcini and M. avidus. PMID- 22525942 TI - An improved phylogeny of the Andean tit-tyrants (Aves, Tyrannidae): more characters trump sophisticated analyses. AB - The phylogeny of the flycatcher genus Anairetes was previously inferred using short fragments of mitochondrial DNA and parsimony and distance-based methods. The resulting topology spurred taxonomic revision and influenced understanding of Andean biogeography. More than a decade later, we revisit the phylogeny of Anairetes tit-tyrants using more mtDNA characters, seven unlinked loci (three mitochondrial genes, six nuclear loci), more closely related outgroup taxa, partitioned Bayesian analyses, and two coalescent species-tree approaches (Bayesian estimation of species trees, BEST; Bayesian evolutionary analysis by sampling trees, (*)BEAST). Of these improvements in data and analyses, the fourfold increase in mtDNA characters was both necessary and sufficient to incur a major shift in the topology and near-complete resolution. The species-tree analyses, while theoretically preferable to concatenation or single gene approaches, yielded topologies that were compatible with mtDNA but with weaker statistical resolution at nodes. The previous results that had led to taxonomic and biogeographic reappraisal were refuted, and the current results support the resurrection of the genus Uromyias as the sister clade to Anairetes. The sister relationship between these two genera corresponds to an ecological dichotomy between a depauperate humid cloud forest clade and a diverse dry-tolerant clade that has diversified along the latitudinal axis of the Andes. The species-tree results and the concatenation results each reaffirm the primacy of mtDNA to provide phylogenetic signal for avian phylogenies at the species and subspecies level. This is due in part to the abundance of informative characters in mtDNA, and in part to its lower effective population size that causes it to more faithfully track the species tree. PMID- 22525943 TI - Quantitative imaging of lineage-specific Toll-like receptor-mediated signaling in monocytes and dendritic cells from small samples of human blood. AB - Individual variations in immune status determine responses to infection and contribute to disease severity and outcome. Aging is associated with an increased susceptibility to viral and bacterial infections and decreased responsiveness to vaccines with a well-documented decline in humoral as well as cell-mediated immune responses. We have recently assessed the effects of aging on Toll-like receptors (TLRs), key components of the innate immune system that detect microbial infection and trigger antimicrobial host defense responses. In a large cohort of healthy human donors, we showed that peripheral blood monocytes from the elderly have decreased expression and function of certain TLRs and similar reduced TLR levels and signaling responses in dendritic cells (DCs), antigen presenting cells that are pivotal in the linkage between innate and adaptive immunity. We have shown dysregulation of TLR3 in macrophages and lower production of IFN by DCs from elderly donors in response to infection with West Nile virus. Paramount to our understanding of immunosenescence and to therapeutic intervention is a detailed understanding of specific cell types responding and the mechanism(s) of signal transduction. Traditional studies of immune responses through imaging of primary cells and surveying cell markers by FACS or immunoblot have advanced our understanding significantly, however, these studies are generally limited technically by the small sample volume available from patients and the inability to conduct complex laboratory techniques on multiple human samples. ImageStream combines quantitative flow cytometry with simultaneous high resolution digital imaging and thus facilitates investigation in multiple cell populations contemporaneously for an efficient capture of patient susceptibility. Here we demonstrate the use of ImageStream in DCs to assess TLR7/8 activation mediated increases in phosphorylation and nuclear translocation of a key transcription factor, NF-kappaB, which initiates transcription of numerous genes that are critical for immune responses. Using this technology, we have also recently demonstrated a previously unrecognized alteration of TLR5 signaling and the NF-kappaB pathway in monocytes from older donors that may contribute to altered immune responsiveness in aging. PMID- 22525944 TI - Short-term PTH administration increases dentine apposition and microhardness in mice. AB - OBJECTIVE: The purpose of this study is to investigate the effects of intermittent parathyroid hormone (PTH) administration on the apposition rate and structural features of dentine from mouse incisors. METHODS: Young male A/J Unib mice were treated daily for 6 and 10 days with 40 MUg/kg of hPTH 1-34 or a vehicle. Dentine apposition rates measured by fluorescent labels (tetracycline and calcein) and alkaline phosphatase (ALP) plasma levels were evaluated after 6 days of treatment. Knoop microhardness testing and element content measurements in at.% of calcium (Ca), phosphorus (P), oxygen (O), and magnesium (Mg) in the peritubular and intertubular dentine were performed by Energy Dispersive X-ray (EDX) microanalysis via Scanning Electron Microscopy (SEM) after 10 days of treatment. RESULTS: Histometric analysis revealed an increase of 5% in the apposition rate of dentine and 25% in the ALP plasma levels in the PTH treated group. In addition, knoop microhardness testing revealed that the animals treated with PTH had a greater microhardness (11%). EDX microanalysis showed that PTH treatment led to increases in P (23%) and Ca (53%) at.% content, as well as the Ca/P ratio (24%) in peritubular dentine. The chemical composition of intertubular dentine did not vary between the groups. CONCLUSIONS: These findings indicate that intermittent administration of hPTH (1-34) increases apposition and mineralization of the dentine during young mice incisor formation. PMID- 22525945 TI - Oxytocin promotes bone formation during the alveolar healing process in old acyclic female rats. AB - OBJECTIVE: OT was reported to be a direct regulator of bone mass in young rodents, and this anabolic effect on bone is a peripheral action of OT. The goal of this study was to investigate the peripheral action of oxytocin (OT) in the alveolar healing process in old female rats. MATERIALS AND METHODS: Females Wistar rats (24-month-old) in permanent diestrus phase, received two ip (12h apart) injections of saline (NaCl 0.15M - control group) or OT (45MUg/rat - treated group). Seven days later, the right maxillary incisor was extracted and analyses were performed up to 28 days of the alveolar healing process (35 days after saline or OT administration). RESULTS: Calcium and phosphorus plasma concentrations did not differ between the groups. The plasma biochemical bone formations markers, alkaline phosphatase (ALP) and osteocalcin were significantly higher in the treated group. Histomorphometric analyses confirmed bone formation as the treated group presented the highest mean value of post-extraction bone formation. Tartrate-resistant acid phosphatase (TRAP) was significantly reduced in the treated group indicating an anti-resorptive effect of OT. Immunohistochemistry reactions performed in order to identify the presence of osteocalcin and TRAP in the bone cells of the dental socket confirmed these outcomes. CONCLUSIONS: OT was found to promote bone formation and to inhibit bone resorption in old acyclic female rats during the alveolar healing process. PMID- 22525946 TI - Ternary SNARE complexes in parallel versus anti-parallel orientation: examination of their disassembly using single-molecule force spectroscopy. AB - Interactions between the proteins of the ternary soluble N-ethyl maleimide sensitive fusion protein attachment protein receptor (SNARE) complex, synaptobrevin 2 (Sb2), syntaxin 1A (Sx1A) and synaptosome-associated protein of 25 kDa (SNAP25) can be readily assessed using force spectroscopy single-molecule measurements. We studied interactions during the disassembly of the ternary SNARE complex pre-formed by binding Sb2 in parallel or anti-parallel orientations to the binary Sx1A-SNAP25B acceptor complex. We determined the spontaneous dissociation lifetimes and found that the stability of the anti-parallel ternary SNARE complex is ~1/3 less than that of the parallel complex. While the free energies were very similar, within 0.5 k(B)T, for both orientations, the enthalpy changes (42.1 k(B)T and 39.8 k(B)T, for parallel and anti-parallel orientations, respectively) indicate that the parallel ternary complex is energetically advantageous by 2.3 k(B)T. Indeed, both ternary SNARE complex orientations were much more stable (by ~4-13 times) and energetically favorable (by ~9-13 k(B)T) than selected binary complexes, constituents of the ternary complex, in both orientations. We propose a model which considers the geometry for the vesicle approach to the plasma membrane with favorable energies and stability as the basis for preferential usage of the parallel ternary SNARE complex in exocytosis. PMID- 22525947 TI - In this issue/abstract thinking: evolving picture of susceptibility factors in autism spectrum disorders. PMID- 22525948 TI - Our baby: commentary on foster care for young children: why it must be developmentally informed. PMID- 22525950 TI - The long road ahead to mental health parity. PMID- 22525951 TI - Autism risk factors: moving from epidemiology to translational epidemiology. PMID- 22525952 TI - The voices go, but the song remains the same: how can we rescue cognition in early-onset schizophrenia? PMID- 22525953 TI - Parental socioeconomic status and risk of offspring autism spectrum disorders in a Swedish population-based study. AB - OBJECTIVE: Epidemiological studies in the United States consistently find autism spectrum disorders (ASD) to be overrepresented in high socioeconomic status (SES) families. These findings starkly contrast with SES gradients of many health conditions, and may result from SES inequalities in access to services. We hypothesized that prenatal measures of low, not high, parental SES would be associated with an increased risk of offspring ASD, once biases in case ascertainment are minimized. METHOD: We tested this hypothesis in a population based study in Sweden, a country that has free universal healthcare, routine screening for developmental problems, and thorough protocols for diagnoses of ASD. In a case-control study nested in a total population cohort of children aged 0 to 17 years living in Stockholm County between 2001 and 2007 (N = 589,114), we matched ASD cases (n = 4,709) by age and sex to 10 randomly selected controls. We retrieved parental SES measures collected at time of birth by record linkage. RESULTS: Children of families with lower income, and of parents with manual occupations (OR = 1.4, 95% CI = 1.3-1.6) were at higher risk of ASD. No important relationships with parental education were observed. These associations were present after accounting for parental ages, migration status, parity, psychiatric service use, maternal smoking during pregnancy, and birth characteristics; and regardless of comorbid intellectual disability. CONCLUSIONS: Lower, not higher, socioeconomic status was associated with an increased risk of ASD. Studies finding the opposite may be underestimating the burden of ASD in lower SES groups. PMID- 22525954 TI - Advancing maternal age is associated with increasing risk for autism: a review and meta-analysis. AB - OBJECTIVE: We conducted a meta-analysis of epidemiological studies investigating the association between maternal age and autism. METHOD: Using recommended guidelines for performing meta-analyses, we systematically selected, and extracted results from, epidemiological scientific studies reported before January 2012. We calculated pooled risk estimates comparing categories of advancing maternal age with and without adjusting for possible confounding factors. We investigated the influence of gender ratio among cases, ratio of infantile autism to autism spectrum disorder (ASD), and median year of diagnosis as effect moderators in mixed-effect meta-regression. RESULTS: We found 16 epidemiological papers fulfilling the a priori search criteria. The meta-analysis included 25,687 ASD cases and 8,655,576 control subjects. Comparing mothers >= 35 years with mothers 25 to 29 years old, the crude relative risk (RR) for autism in the offspring was 1.52 (95% confidence interval [CI] = 1.12-1.92). Comparing mothers >= 35 with mothers 25-29, [corrected] the adjusted relative risk (RR) for autism in the offspring was 1.31 (95% CI = 1.19-1.45). [corrected] For mothers <20 compared with mothers 25 to 29 years old, there was a statistically significant decrease in risk (RR = 0.76; 95% confidence interval = 0.60-0.97). Almost all studies showed a dose-response effect of maternal age on risk of autism. The meta-regression suggested a stronger maternal age effect in the studies with more male offspring and for children diagnosed in later years. CONCLUSIONS: The results of this meta-analysis support an association between advancing maternal age and risk of autism. The RR increased monotonically with increasing maternal age. The association persisted after the effects of paternal age and other potential confounders had been considered, supporting an independent relation between higher maternal age and autism. PMID- 22525955 TI - Longitudinal follow-up of children with autism receiving targeted interventions on joint attention and play. AB - OBJECTIVE: This study examines the cognitive and language outcomes of children with an autism spectrum disorder (ASD) over a 5-year period after receiving targeted early interventions that focused on joint attention and play skills. METHOD: Forty children from the original study (n = 58) had complete data at the 5-year follow-up. RESULTS: In all, 80% of children had achieved functional use of spoken language with baseline play level predicting spoken language at the 5-year follow-up. Of children who were using spoken language at age 8 years, several baseline behaviors predicted their later ability, including earlier age of entry into the study, initiating joint attention skill, play level, and assignment to either the joint attention or symbolic play intervention group. Only baseline play diversity predicted cognitive scores at age 8 years. CONCLUSIONS: This study is one of the only long-term follow-up studies of children who participated in preschool early interventions aimed at targeting core developmental difficulties. The study findings suggest that focusing on joint attention and play skills in comprehensive treatment models is important for long-term spoken language outcomes. PMID- 22525956 TI - Neurocognitive outcomes in the Treatment of Early-Onset Schizophrenia Spectrum Disorders study. AB - OBJECTIVE: To assess neurocognitive outcomes following antipsychotic intervention in youth enrolled in the National Institute of Mental Health (NIMH)-funded Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS). METHOD: Neurocognitive functioning of youth (ages 8 to 19 years) with schizophrenia or schizoaffective disorder was evaluated in a four-site, randomized, double-blind clinical trial comparing molindone, olanzapine, and risperidone. The primary outcomes were overall group change from baseline in neurocognitive composite and six domain scores after 8 weeks and continued treatment up to 52 weeks. Age and sex were included as covariates in all analyses. RESULTS: Of 116 TEOSS participants, 77 (66%) had post-baseline neurocognitive data. No significant differences emerged in the neurocognitive outcomes of the three medication groups. Therefore, the three treatment groups were combined into one group to assess overall neurocognitive outcomes. Significant modest improvements were observed in the composite score and in three of six domain scores in the acute phase, and in four of six domain scores in the combined acute and maintenance phases. Partial correlation analyses revealed very few relationships among Positive and Negative Syndrome Scale (PANSS) baseline or change scores and neurocognition change scores. CONCLUSIONS: Antipsychotic intervention in youth with early-onset schizophrenia spectrum disorders (EOSS) led to modest improvement in measures of neurocognitive function. The changes in cognition were largely unrelated to baseline symptoms or symptom change. Small treatment effect sizes, easily accounted for by practice effects, highlight the critical need for the development of more efficacious interventions for the enduring neurocognitive deficits seen in EOSS. Clinical trial registry information-Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS); http://www.clinicaltrials.gov; NCT00053703. PMID- 22525957 TI - Psychiatric diagnostic interviews for children and adolescents: a comparative study. AB - OBJECTIVE: To compare examples of three styles of psychiatric interviews for youth: the Diagnostic Interview Schedule for Children (DISC) ("respondent based"), the Child and Adolescent Psychiatric Assessment (CAPA) ("interviewer based"), and the Development and Well-Being Assessment (DAWBA) ("expert judgment"). METHOD: Roughly equal numbers of males and females of white and African American ethnicity, aged 9 to 12 and 13 to 16 years, were recruited from primary care pediatric clinics. Participants (N = 646) were randomly assigned to receive two of the three interviews, in counterbalanced order. Five modules were used: any depressive disorder, anxiety disorders, oppositional defiant disorder, conduct disorder, and attention-deficit/hyperactivity disorder. At two sessions about 1 week apart, parent and child completed one of two interviews plus five screening questionnaires. RESULTS: When interviewed with the DAWBA, 17.7% of youth had one or more diagnoses, compared with 47.1% (DISC) and 32.4% (CAPA). The excess of DISC diagnoses was accounted for by specific phobias. Agreement between interview pairs was 0.13 to 0.48 for DAWBA-DISC comparisons, 0.21 to 0.61 for DISC-CAPA comparisons, and 0.23 to 0.48 for CAPA-DAWBA comparisons. DAWBA-only cases were associated with higher parent-report questionnaire scores than DISC/DAWBA cases, but equivalent child-report scores. CONCLUSIONS: The DAWBA is shorter and cases were probably more severe, making it a good choice for clinical trials, but the user cannot examine the data in detail. The DISC and CAPA are similar in length and training needs. Either would be a better choice where false negative results must be avoided, as in case-control genetic studies, or when researchers need to study individual symptoms in detail. PMID- 22525958 TI - Examining overgeneral autobiographical memory as a risk factor for adolescent depression. AB - OBJECTIVE: Identifying risk factors for adolescent depression is an important research aim. Overgeneral autobiographical memory (OGM) is a feature of adolescent depression and a candidate cognitive risk factor for future depression. However, no study has ascertained whether OGM predicts the onset of adolescent depressive disorder. OGM was investigated as a predictor of depressive disorder and symptoms in a longitudinal study of high-risk adolescents. In addition, cross-sectional associations between OGM and current depression and OGM differences between depressed adolescents with different clinical outcomes were examined over time. METHOD: A 1-year longitudinal study of adolescents at familial risk for depression (n = 277, 10-18 years old) was conducted. Autobiographical memory was assessed at baseline. Clinical interviews assessed diagnostic status at baseline and follow-up. RESULTS: Currently depressed adolescents showed an OGM bias compared with adolescents with no disorder and those with anxiety or externalizing disorders. OGM to negative cues predicted the onset of depressive disorder and depressive symptoms at follow-up in adolescents free from depressive disorder at baseline. This effect was independent of the contribution of age, IQ, and baseline depressive symptoms. OGM did not predict onset of anxiety or externalizing disorders. Adolescents with depressive disorder at both assessments were not more overgeneral than adolescents who recovered from depressive disorder over the follow-up period. CONCLUSIONS: OGM to negative cues predicted the onset of depressive disorder (but not other disorders) and depressive symptoms over time in adolescents at familial risk for depression. Results are consistent with OGM as a risk factor for depression. PMID- 22525959 TI - The phenomenology and course of depression in parentally bereaved and non bereaved youth. AB - OBJECTIVE: To compare the phenomenology and course of bereavement-related depression to depression that occurred later in the course of bereavement and to depression in non-bereaved youth. METHOD: This sample is drawn from a cohort of parentally bereaved youth and non-bereaved controls followed for approximately 5 years. Three groups of depressed youth were compared with respect to symptoms, severity, duration, risk for recurrence, and correlates and risk factors: (1) a group with bereavement-related depression (BRD, n = 42), with the onset of a depressive episode within the first 2 months after parental loss; a group with later bereavement depression (LBD, n = 30), with onset at least 12 months after parental loss; and a non-bereaved control group with depression (CD, n = 30). RESULTS: BRD episodes were similar to LBD and CD with respect to number of symptoms, severity, functional impairment, duration, risk for recurrence, and most risk factors and correlates. BRD, compared with both CD and LBD, were younger, exposed to fewer life events, and less likely to have experienced feelings of worthlessness. Also, caregivers of BRD showed higher rates of depression and post-traumatic stress disorder at the time of the depression compared with each of the other two groups. CONCLUSION: BRD is similar to both LBD and CD in phenomenology, course, and risk factors, supporting a diagnostic and therapeutic approach to BRD similar to that for non-bereavement-related depressions. In the bereaved child who presents with depression shortly after parental death, the clinician should also be alert to caregiver depression and post-traumatic stress disorder. PMID- 22525962 TI - Bystander effect on brain tissue of mesoangioblasts producing neurotrophins. AB - Neurotrophic factors (NTFs) are involved in the regulation of neuronal survival and function and, thus, may be used to treat neurological diseases associated with neuronal death. A major hurdle for their clinical application is the delivery mode. We describe here a new strategy based on the use of progenitor cells called mesoangioblasts (MABs). MABs can be isolated from postnatal mesoderm tissues and, because of a high adhesin-dependent migratory capacity, can reach perivascular targets especially in damaged areas. We generated genetically modified MABs producing nerve growth factor (MABs-NGF) or brain-derived neurotrophic factor (MABs-BDNF) and assessed their bystander effects in vitro using PC12 cells, primary cultures, and organotypic cultures of adult hippocampal slices. MABs-NGF-conditioned medium induced differentiation of PC12 cells, while MABs-BDNF-conditioned medium increased viability of cultured neurons and slices. Slices cultured with MABs-BDNF medium also better retained their morphology and functional connections, and all these effects were abolished by the TrkB kinase blocker K252a or the BDNF scavenger TrkB-IgG. Interestingly, the amount of BDNF released by MABs-BDNF produced greater effects than an identical amount of recombinant BDNF, suggesting that other NTFs produced by MABs synergize with BDNF. Thus, MABs can be an effective vehicle for NTF delivery, promoting differentiation, survival, and functionality of neurons. In summary, MABs hold distinct advantages over other currently evaluated approaches for NTF delivery in the CNS, including synergy of MAB-produced NTF with the neurotrophins. Since MABs may be capable of homing into damaged brain areas, they represent a conceptually novel, promising therapeutic approach to treat neurodegenerative diseases. PMID- 22525961 TI - Practice Parameter for psychodynamic psychotherapy with children. AB - This Practice Parameter describes the principles of psychodynamic psychotherapy with children and is based on clinical consensus and available research evidence. It presents guidelines for the practice of child psychodynamic psychotherapy, including indications and contraindications, the setting, verbal and interactive (play) techniques, work with the parents, and criteria for termination. PMID- 22525963 TI - Testosterone concentrations, using different assays, in different types of ovarian insufficiency: a systematic review and meta-analysis. AB - BACKGROUND: Increasing age and post-menopausal status are associated with decreasing androgen concentrations in females. Women with premature loss of ovarian function, such as primary ovarian insufficiency (POI) or iatrogenic menopause may be at increased risk for diminished testosterone levels at a relatively young age. Differentiation between a hypoandrogenic or normoandrogenic state in women with premature loss of ovarian function is problematic due to trueness and precision problems using various testosterone assays. The current meta-analysis was conducted to evaluate current literature reporting serum total testosterone concentrations under these conditions, including stratification for various testosterone assays. METHODS: A systematic review and meta-analysis of controlled observational studies were performed. The electronic databases of Pubmed, Embase and the Cochrane Library were systematically searched until October 2011 for comparative studies on total testosterone concentrations in women with spontaneous POI or iatrogenic menopause compared with controls. The literature search, data extraction and critical appraisal, using the Newcastle Ottawa Scale, were performed by two independent investigators. The effect measure was the weighted mean difference (WMD) with 95% confidence interval (95% CI) in a random effects model. RESULTS: A total of 206 articles for spontaneous POI and 1358 for iatrogenic menopause were reviewed, of which 9 and 17 papers, respectively, were selected for final analysis. Both groups demonstrated significantly lower total testosterone concentrations compared with controls [WMD (95% CI) -0.38 (-0.55 to -0.22) nmol/l, and -0.29 (-0.39 to -0.18) nmol/l, respectively], but with substantial between-study heterogeneity. Subgroup analysis for assay type was statistically significant for spontaneous POI only. Sensitivity analyses of high-quality studies did not change the results, and resulted in a substantial decrease in heterogeneity in spontaneous POI studies. CONCLUSIONS: The current meta-analysis demonstrates that total testosterone concentrations are decreased in women with spontaneous POI or iatrogenic menopause. The potential implications of hypoandrogenism in these women remain to be elucidated. PMID- 22525964 TI - Vasculitis: Will LAMP enlighten us about ANCA-associated vasculitis? PMID- 22525965 TI - Effectiveness of esophagus detection by three-dimensional electroanatomical mapping to avoid esophageal injury during ablation of atrial fibrillation. AB - AIMS: Esophageal-left atrial (LA) fistula during atrial fibrillation (AF) ablation is a fatal event. We explored the relation of the esophagus-to-ablated point distance and esophageal temperature rise. METHODS: Consecutive patients (n=106) underwent complex fractionated atrial electrogram-guided AF ablation using CartoMerge; the pulmonary veins were isolated in 23 patients. Maximum radiofrequency (RF) power near the esophagus was 15 W. Ablated points with esophageal temperature rise (monitored with a probe) to >=38.0 degrees C were tagged; if >=39.0 degrees C, RF was discontinued. RESULTS: Of 1647 ablated points near the esophagus, 274 were associated with a temperature rise to 38.0-38.9 degrees C and 241 points to >=39.0 degrees C. Distances (mm) from points to esophagus were 5.1 +/- 0.6 (no rise), 4.2+/-3.1 (38.0-38.9 degrees C), 2.9 +/- 2.5 (>=39.0 degrees C). Altogether, 15.5% of points in the upper LA posterior wall, 41.5% in the middle, and 30.2% in the lower caused rises to >=38.0 degrees C; 8.7%, 24.6%, and 11.0% caused rises to >=39.0 degrees C. The middle wall was most affected (p<0.01), as shown by multiple logistic regression analysis (both temperatures). Points causing a rise increased significantly as distance decreased (p<0.001). The odds ratio for rise to >=38.0 degrees C compared with <4.0 to >5.0 mm distance was 2.28 (p=0.004). The longest distance for >=38.0 degrees C rise was 18.5 mm. CONCLUSION: Distance is an important predictor of esophageal temperature rise. The middle LA posterior wall is most vulnerable. A dose of 15 W is too high for ablation, especially <4.0 mm from the esophagus. Points >20.0 mm away are relatively safe. PMID- 22525966 TI - Elevated plasma brain natriuretic peptide levels predict left atrial appendage dysfunction in patients with acute ischemic stroke. AB - BACKGROUND: It is well known that left atrial appendage (LAA) dysfunction plays an important role in the occurrence of cardioembolic stroke. The atrium is the main source of brain natriuretic peptide (BNP) in patients with atrial fibrillation (AF). We hypothesized that the plasma BNP level would be a sensitive predictor of LAA dysfunction in patients with acute ischemic stroke. METHODS AND RESULTS: Transesophageal echocardiography was performed and plasma BNP levels were measured in 223 patients (145 males, age 69 +/- 14 years), within 7 days after the onset of acute ischemic stroke. None of the patients had a history of congestive heart failure. LAA thrombus was detected in 23 of 77 (30%) patients with AF. Plasma BNP levels were markedly higher in patients with cardioembolic stroke compared to those without (144 pg/ml vs. 35 pg/ml, p<0.05). Plasma BNP levels were significantly correlated with LAA emptying flow velocity regardless of sinus rhythm (R=-0.352) or AF (R=-0.436). Furthermore, among patients with cardioembolic stroke, plasma BNP levels were markedly higher in patients with cardiogenic stroke, as diagnosed by transesophageal echocardiography, than in those with cryptogenic stroke (193 pg/ml vs. 14 pg/ml, p<0.05). Multivariate logistic regression analysis showed that a BNP concentration >90 pg/ml was an independent predictor of cardiogenic stroke (odds ratio 41.39, 95% confidence interval 1.28-138; p=0.0358). CONCLUSION: Elevated plasma BNP concentrations may be a reliable surrogate marker for the prediction of LAA dysfunction and cardiogenic stroke in patients with acute ischemic stroke. PMID- 22525967 TI - Links between sleep disordered breathing, coronary atherosclerotic burden, and cardiac biomarkers in patients with stable coronary artery disease. AB - BACKGROUND: Sleep disordered breathing (SDB) is highly prevalent in patients with cardiovascular disease, although it is not clear whether SDB has any link to coronary atherosclerotic burden in patients with stable coronary artery disease (CAD). This study sought to analyze the links between SDB, coronary atherosclerotic burden, and cardiac biomarkers in stable CAD patients. METHODS AND RESULTS: We studied 83 consecutive patients who underwent coronary angiography or scheduled percutaneous coronary intervention. SDB was evaluated by an ambulatory polysomnographic monitoring device. Coronary atherosclerotic burden was evaluated by the Gensini score, and myocardial stress/injury were assessed by measuring plasma levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high sensitivity troponin T (hs-TnT). Patients with an apnea hypopnea index (AHI)?15 events/h (n=32) showed significantly higher Gensini score (35.7+/-38.0 vs 20.1+/-19.7, p=0.033) than those with AHI<15. The higher AHI group showed significantly higher NT-proBNP (275.8+/-402.6 pg/ml vs 131.9+/-146.3 pg/ml, p=0.047) and hs-TnT levels (0.011+/-0.005 ng/ml vs 0.008+/-0.003 ng/ml, p=0.015). Furthermore it was revealed that AHI significantly correlated with the Gensini score (r=0.253, p=0.036), NT-proBNP (r=0.266, p=0.027), and hs-TnT (r=0.274, p=0.023), and multiple stepwise linear regression analysis revealed that AHI (beta=0.257, p=0.029) and history of smoking (beta=0.244, p=0.038) were independently correlated with Gensini score among clinical and SDB-related parameters. CONCLUSIONS: Severity of SDB has a significant link to the severity of coronary atherosclerotic burden, which also reflected elevated NT-proBNP and hs-TnT as silent myocardial ischemia and minute myocardial injury even in stable CAD patients. PMID- 22525969 TI - Multiplicity adjustment for composite binary endpoints. AB - BACKGROUND: Binary composite outcome measures are increasingly used as primary endpoints in clinical trials. Composite endpoints combine several events of interest within a single variable. However, as the effect observed for the composite does not necessarily reflect the effects for the individual components, it is recommended in the literature to additionally evaluate each component separately. OBJECTIVES: The task is to define an adequate multiple test procedure which focuses on the composite outcome measure but allows for a confirmatory interpretation of the components in case of large effects. METHODS: In this paper, we determine the correlation matrix for a multiple binary endpoint problem of a composite endpoint and its components based on the normal approximation test statistic for rates. Thereby, we assume multinomial distributed components. We use this correlation to calculate the adjusted local significance levels. We discuss how to use our approach for a more informative formulation of the test problem. Our work is illustrated by two clinical trial examples. RESULTS: By taking into account the special correlation structure between a binary composite outcome and its components, an adequate multiple test procedure to assess the composite and its components can be defined based on an approximate multivariate normal distribution without much loss in power compared to a test problem formulated exclusively for the composite. CONCLUSIONS: By incorporating the correlation under the null hypotheses, the global power for the multiple test problem assessing both the composite and its components can be increased as compared to simple Bonferroni-adjustment. Thus, a confirmatory analysis of the composite and its components might be possible without a large increase in sample size as compared to a single endpoint problem formulated exclusively for the composite. PMID- 22525970 TI - Retraction note to: Familial aplasia of the olfactory bulb: a report of two cases. PMID- 22525971 TI - Biomarkers of vulnerable plaque: can better ways to quantitate Pregnancy Associated Plasma Protein A (PAPP-A) help? PMID- 22525972 TI - [Remission of incomplete paraplegia after thoracic stent graft implantation. Case report and review of the literature]. PMID- 22525975 TI - Homoarginine deficiency is associated with increased bone turnover. PMID- 22525973 TI - [Pregnancy-linked endotheliopathy. A disease with multiple variants?]. PMID- 22525977 TI - Vitamin D deficiency in UK South Asian Women of childbearing age: a comparative longitudinal investigation with UK Caucasian women. AB - SUMMARY: This is the first 1-year longitudinal study which assesses vitamin D deficiency in young UK-dwelling South Asian women. The findings are that vitamin D deficiency is extremely common in this group of women and that it persists all year around, representing a significant public health concern. INTRODUCTION: There is a lack of longitudinal data assessing seasonal variation in vitamin D status in young South Asian women living in northern latitudes. Studies of postmenopausal South Asian women suggest a lack of seasonal change in 25-hydroxy vitamin D [25(OH)D], although it is unclear whether this is prevalent among premenopausal South Asians. We aimed to evaluate, longitudinally, seasonal changes in 25(OH)D and prevalence of vitamin D deficiency in young UK-dwelling South Asian women as compared with Caucasians. We also aimed to establish the relative contributions of dietary vitamin D and sun exposure in explaining serum 25(OH)D. METHODS: This is a 1-year prospective cohort study assessing South Asian (n = 35) and Caucasian (n = 105) premenopausal women living in Surrey, UK (51 degrees N), aged 20-55 years. The main outcome measured was serum 25(OH)D concentration. Secondary outcomes were serum parathyroid hormone, self-reported dietary vitamin D intake and UVB exposure by personal dosimetry. RESULTS: Serum 25(OH)D <25 nmol/L was highly prevalent in South Asians in the winter (81 %) and autumn (79.2 %). Deficient status (below 50 nmol/L) was common in Caucasian women. Multi-level modelling suggested that, in comparison to sun exposure (1.59, 95 %CI = 0.83-2.35), dietary intake of vitamin D had no impact on 25(OH)D levels (-0.08, 95 %CI = -1.39 to 1.23). CONCLUSIONS: Year-round vitamin D deficiency was extremely common in South Asian women. These findings pose great health threats regarding the adverse effects of vitamin D deficiency in pregnancy and warrant urgent vitamin D public health policy and action. PMID- 22525976 TI - Non-hip, non-spine fractures drive healthcare utilization following a fracture: the Global Longitudinal Study of Osteoporosis in Women (GLOW). AB - We evaluated healthcare utilization associated with treating fracture types in >51,000 women aged >=55 years. Over the course of 1 year, there were five times more non-hip, non-spine fractures than hip or spine fractures, resulting in twice as many days of hospitalization and rehabilitation/nursing home care for non-hip, non-spine fractures. INTRODUCTION: The purpose of this study is to evaluate medical healthcare utilization associated with treating several types of fractures in women >=55 years from various geographic regions. METHODS: Information from the Global Longitudinal Study of Osteoporosis in Women (GLOW) was collected via self-administered patient questionnaires at baseline and year 1 (n = 51,491). Self-reported clinically recognized low-trauma fractures at year 1 were classified as incident spine, hip, wrist/hand, arm/shoulder, pelvis, rib, leg, and other fractures. Healthcare utilization data were self-reported and included whether the fracture was treated at a doctor's office/clinic or at a hospital. Patients were asked if they had undergone surgery or been treated at a rehabilitation center or nursing home. RESULTS: During 1-year follow-up, there were 195 spine, 134 hip, and 1,654 non-hip, non-spine fractures. Clinical vertebral fractures resulted in 617 days of hospitalization and 512 days of rehabilitation/nursing home care; hip fractures accounted for 1,306 days of hospitalization and 1,650 days of rehabilitation/nursing home care. Non-hip, non spine fractures resulted in 3,805 days in hospital and 5,186 days of rehabilitation/nursing home care. CONCLUSIONS: While hip and vertebral fractures are well recognized for their associated increase in health resource utilization, non-hip, non-spine fractures, by virtue of their 5-fold greater number, require significantly more healthcare resources. PMID- 22525979 TI - Alopecia associated with strontium ranelate use in a 62-year-old woman. AB - Strontium ranelate is an effective drug that was developed for treating osteoporosis. Here, we report the case of a 62-year-old woman who developed headache and diffuse scalp hair loss 1 week after receiving strontium ranelate treatment for osteoporosis. The treatment was subsequently stopped because of the intractable headache. Nevertheless, the patient continued to lose hair for 6 weeks following treatment discontinuation. Histopathological analysis of scalp tissues revealed anagen effluvium. The patient's hair started regrowing slowly 2 months after treatment with strontium ranelate was discontinued. PMID- 22525978 TI - Association of serum sclerostin with bone mineral density, bone turnover, steroid and parathyroid hormones, and fracture risk in postmenopausal women: the OFELY study. AB - SUMMARY: Sclerostin is a key regulator of bone formation. In a population of 572 postmenopausal women (mean age, 67 years) followed prospectively for a median of 6 years, there was no significant association between baseline levels of serum sclerostin and incidence of all fractures which occurred in 64 subjects. INTRODUCTION: Sclerostin, an osteocyte soluble factor, is a major negative regulator of osteoblastic activity. Circulating sclerostin levels were reported to increase with age and to be modestly associated with bone mineral density (BMD) and bone turnover, but there are no data on the association with fracture risk. METHODS: We investigated 572 postmenopausal women (mean age, 67 +/- 8.5 years) from the OFELY population-based cohort. The associations of serum sclerostin measured with a new two-site ELISA and spine and hip BMD by DXA, serum beta-isomerized C-terminal crosslinking of type I collagen (CTX), intact N terminal propeptide of type I collagen (PINP), intact PTH, 25-hydroxyvitamin D [25(OH)D], estradiol, testosterone, and fracture risk were analyzed. At the time of sclerostin measurements, 98 postmenopausal women had prevalent fractures. After a median of 6 years (interquartile range, 5-7 years) follow-up, 64 postmenopausal sustained an incident fracture. RESULTS: Serum sclerostin correlated positively with spine (r = 0.35, p < 0.0001) and total hip (r = 0.25, <0.0001) BMD. Conversely, serum sclerostin was weakly negatively associated with the bone markers PINP (r = -0.10, p = 0.014) and CTX (r = -0.13, p = 0.0026) and with intact PTH (r = -0.13, p = 0.0064). There was no significant association of serum sclerostin with 25(OH)D, estradiol, free estradiol index, or testosterone. Serum sclerostin considered as a continuous variable or in quartiles was not significantly associated with the risk of prevalent or incident fracture. CONCLUSION: Serum sclerostin is weakly correlated with BMD, bone turnover, and PTH in postmenopausal women. It was not significantly associated with the risk of all fractures, although the number of incident fractures recorded may not allow detecting a modest association. PMID- 22525980 TI - In memoriam: Sergio Ragi-Eis, MD. PMID- 22525981 TI - Iron homeostasis in osteoporosis and its clinical implications. AB - Osteoporosis has until now been considered to be a disease associated with abnormal calcium metabolism. However, an increasing number of clinical observations strongly suggest the association of iron overload with bone diseases, particularly in osteoporosis in menopausal women. The recent identification of hepcidin sheds new light into the crucial role of iron homeostasis in bone metabolism. Decreasing iron overload in cell studies as well as in animal experiments has been shown to improve bone cell metabolism and growth in vitro and in vivo. In view of the significant iron overload found in the aging population, especially in females, the therapeutic potential of lowering iron overload for the treatment of osteoporosis is suggested. PMID- 22525982 TI - Skeletal health in adult patients with classic galactosemia. AB - SUMMARY: This study evaluated bone health in adults with galactosemia. Associations between bone mineral density (BMD) and nutritional and biochemical variables were explored. Calcium level predicted hip and spine BMD, and gonadotropin levels were inversely associated with spinal BMD in women. These results afford insights into management strategies for these patients. INTRODUCTION: Bone loss is a complication of galactosemia. Dietary restriction, primary ovarian insufficiency in women, and disease-related alterations of bone metabolism may contribute. This study examined relationships between clinical factors and BMD in patients with galactosemia. METHODS: This cross-sectional sample included 33 adults (16 women) with classic galactosemia, mean age 32.0 +/- 11.8 years. BMD was measured by dual-energy X-ray absorptiometry, and was correlated with age, height, weight, fractures, nutritional factors, hormonal status, and bone biomarkers. RESULTS: There was a significant difference in hip BMD between women and men (0.799 vs. 0.896 g/cm(2), p = 0.014). The percentage of subjects with BMD-Z <-2.0 was also greater for women than men [33 vs. 18 % (spine), 27 vs. 6 % (hip)], and more women reported sustaining fractures. Bivariate analyses yielded correlations between BMI and BMD-Z [at the hip in women (r = 0.58, p < 0.05) and spine in men (r = 0.53, p < 0.05)]. In women, weight was also correlated with BMD-Z (r = 0.57, p < 0.05 at hip), and C telopeptides (r = -0.59 at spine and -0.63 hip, p < 0.05) and osteocalcin (r = 0.71 at spine and -0.72 hip, p < 0.05) were inversely correlated with BMD-Z. In final regression models, higher gonadotropin levels were associated with lower spinal BMD in women (p = 0.017); serum calcium was a significant predictor of hip (p = 0.014) and spine (p = 0.013) BMD in both sexes. CONCLUSIONS: Bone density in adults with galactosemia is low, indicating the potential for increased fracture risk, the etiology of which appears to be multifactorial. PMID- 22525983 TI - Active commuting reduces the risk of wrist fractures in middle-aged women-the UFO study. AB - SUMMARY: Middle-aged women with active commuting had significantly lower risk for wrist fracture than women commuting by car/bus. INTRODUCTION: Our purpose was to investigate whether a physically active lifestyle in middle-aged women was associated with a reduced risk of later sustaining a low-trauma wrist fracture. METHODS: The Umea Fracture and Osteoporosis (UFO) study is a population-based nested case-control study investigating associations between lifestyle and fragility fractures. From a cohort of ~35,000 subjects, we identified 376 female wrist fracture cases who had reported data regarding their commuting habits, occupational, and leisure physical activity, before they sustained their fracture. Each fracture case was compared with at least one control drawn from the same cohort and matched for age and week of reporting data, yielding a total of 778 subjects. Mean age at baseline was 54.3 +/- 5.8 years, and mean age at fracture was 60.3 +/- 5.8 years. RESULTS: Conditional logistic regression analysis with adjustments for height, body mass index, smoking, and menopausal status showed that subjects with active commuting (especially walking) were at significantly lower risk of sustaining a wrist fracture (OR 0.48; 95 % CI 0.27 0.88) compared with those who commuted by car or bus. Leisure time activities such as dancing and snow shoveling were also associated with a lower fracture risk, whereas occupational activity, training, and leisure walking or cycling were unrelated to fracture risk. CONCLUSION: This study suggests that active commuting is associated with a lower wrist fracture risk, in middle-aged women. PMID- 22525984 TI - Long-term lethal toxicity test with the crustacean Artemia franciscana. AB - Our research activities target the use of biological methods for the evaluation of environmental quality, with particular reference to saltwater/brackish water and sediment. The choice of biological indicators must be based on reliable scientific knowledge and, possibly, on the availability of standardized procedures. In this article, we present a standardized protocol that used the marine crustacean Artemia to evaluate the toxicity of chemicals and/or of marine environmental matrices. Scientists propose that the brine shrimp (Artemia) is a suitable candidate for the development of a standard bioassay for worldwide utilization. A number of papers have been published on the toxic effects of various chemicals and toxicants on brine shrimp (Artemia). The major advantage of this crustacean for toxicity studies is the overall availability of the dry cysts; these can be immediately used in testing and difficult cultivation is not demanded. . Cyst-based toxicity assays are cheap, continuously available, simple and reliable and are thus an important answer to routine needs of toxicity screening, for industrial monitoring requirements or for regulatory purposes. The proposed method involves the mortality as an endpoint. The numbers of survivors were counted and percentage of deaths were calculated. Larvae were considered dead if they did not exhibit any internal or external movement during several seconds of observation. This procedure was standardized testing a reference substance (Sodium Dodecyl Sulfate); some results are reported in this work. This article accompanies a video that describes the performance of procedural toxicity testing, showing all the steps related to the protocol. PMID- 22525986 TI - Life cycle assessment and carbon footprint in the wine supply-chain. AB - Global warming represents one of the most critical internationally perceived environmental issues. The growing, and increasingly global, wine sector is one of the industries which is under increasing pressure to adopt approaches for environmental assessment and reporting of product-related greenhouse gas emissions. The International Organization for Vine and Wine has recently recognized the need to develop a standard and objective methodology and a related tool for calculating carbon footprint (CF). This study applied this tool to a wine previously analyzed using the life cycle assessment (LCA) methodology. The objective was to test the tool as regards both its potential and possible limitations, and thus to assess its suitability as a standard tool. Despite the tool's user-friendliness, a number of limitations were noted including the lack of accurate baseline data, a partial system boundary and the impossibility of dealing with the multi-functionality issue. When the CF and LCA results are compared in absolute terms, large discrepancies become obvious due to a number of different assumptions, as well as the modeling framework adopted. Nonetheless, in relative terms the results seem to be quite consistent. However, a critical limitation of the CF methodology was its focus on a single issue, which can lead to burden shifting. In conclusion, the study confirmed the need for both further improvement and adaptation to additional contexts and further studies to validate the use of this tool in different companies. PMID- 22525987 TI - Risk and cooperation: managing hazardous fuel in mixed ownership landscapes. AB - Managing natural processes at the landscape scale to promote forest health is important, especially in the case of wildfire, where the ability of a landowner to protect his or her individual parcel is constrained by conditions on neighboring ownerships. However, management at a landscape scale is also challenging because it requires cooperation on plans and actions that cross ownership boundaries. Cooperation depends on people's beliefs and norms about reciprocity and perceptions of the risks and benefits of interacting with others. Using logistic regression tests on mail survey data and qualitative analysis of interviews with landowners, we examined the relationship between perceived wildfire risk and cooperation in the management of hazardous fuel by nonindustrial private forest (NIPF) owners in fire-prone landscapes of eastern Oregon. We found that NIPF owners who perceived a risk of wildfire to their properties, and perceived that conditions on nearby public forestlands contributed to this risk, were more likely to have cooperated with public agencies in the past to reduce fire risk than owners who did not perceive a risk of wildfire to their properties. Wildfire risk perception was not associated with past cooperation among NIPF owners. The greater social barriers to private private cooperation than to private-public cooperation, and perceptions of more hazardous conditions on public compared with private forestlands may explain this difference. Owners expressed a strong willingness to cooperate with others in future cross-boundary efforts to reduce fire risk, however. We explore barriers to cooperative forest management across ownerships, and identify models of cooperation that hold potential for future collective action to reduce wildfire risk. PMID- 22525988 TI - The impact of map and data resolution on the determination of the agricultural utilisation of organic soils in Germany. AB - Due to its nature, agricultural land use depends on local site characteristics such as production potential, costs and external effects. To assess the relevance of the modifying areal unit problem (MAUP), we investigated as to how a change in the data resolution regarding both soil and land use data influences the results obtained for different land use indicators. For the assessment we use the example of the greenhouse gas (GHG) emissions from agriculturally used organic soils (mainly fens and bogs). Although less than 5 % of the German agricultural area in use is located on organic soils, the drainage of these areas to enable their agricultural utilization causes roughly 37 % of the GHG emissions of the German agricultural sector. The abandonment of the cultivation and rewetting of organic soils would be an effective policy to reduce national GHG emissions. To assess the abatement costs, it is essential to know which commodities, and at what quantities, are actually produced on this land. Furthermore, in order to limit windfall profits, information on the differences of the profitability among farms are needed. However, high-resolution data regarding land use and soil characteristics are often not available, and their generation is costly or the access is strictly limited because of legal constraints. Therefore, in this paper, we analyse how indicators for land use on organic soils respond to changes in the spatial aggregation of the data. In Germany, organic soils are predominantly used for forage cropping. Marked differences between the various regions of Germany are apparent with respect to the dynamics and the intensity of land use. Data resolution mainly impairs the derived extent of agriculturally used peatland and the observed intensity gradient, while its impact on the average value for the investigated set of land-use indicators is generally minor. PMID- 22525989 TI - Introduction of participatory conservation in Croatia, residents' perceptions: a case study from the Istrian peninsula. AB - Croatia, like many other transition countries has undergone radical changes in its nature protection models. This paper discusses a historical overview, present situation and future possibilities for nature conservation in Croatia. A conservative top-down approach to nature protection was applied in the past in Croatia and is now being replaced by a prevalent bottom-up approach. Social context is crucial to introducing participatory conservation, therefore special concern is given to the perception of the local population towards protected area management in Istria as a case study in Croatia. Survey data were used to assess the conservation knowledge of local populations and their perception towards Protected Areas (PAs), leadership activities and management authorities in Istria County. This paper examines the perceptions of 313 residents living in and around six natural PAs located in Istria. The results revealed a moderate general knowledge about PAs in Istria and environmental issues, and a low awareness of institutions managing PAs, eagerness to participate in the activities of PAs and general support for the conservation cause. Understanding the perception of local residents enables the creation of feasible, long-term strategies for the implementation of participatory conservation. The research identifies the need for greater human, technical and financial efforts to strengthen the management capabilities of local agencies responsible for PAs. The process of participatory conservation optimization in Croatia is underway and world experiences must be observed in order to create a congruent, site-specific model with the best possible results. PMID- 22525990 TI - Evaluation of deposited sediment and macroinvertebrate metrics used to quantify biological response to excessive sedimentation in agricultural streams. AB - The objective of this study was to evaluate which macroinvertebrate and deposited sediment metrics are best for determining effects of excessive sedimentation on stream integrity. Fifteen instream sediment metrics, with the strongest relationship to land cover, were compared to riffle macroinvertebrate metrics in streams ranging across a gradient of land disturbance. Six deposited sediment metrics were strongly related to the relative abundance of Ephemeroptera, Plecoptera and Trichoptera and six were strongly related to the modified family biotic index (MFBI). Few functional feeding groups and habit groups were significantly related to deposited sediment, and this may be related to the focus on riffle, rather than reach-wide macroinvertebrates, as reach-wide sediment metrics were more closely related to human land use. Our results suggest that the coarse-level deposited sediment metric, visual estimate of fines, and the coarse level biological index, MFBI, may be useful in biomonitoring efforts aimed at determining the impact of anthropogenic sedimentation on stream biotic integrity. PMID- 22525991 TI - Participation, process quality, and performance of marine protected areas in the wider Caribbean. AB - Throughout the wider Caribbean, marine protected areas (MPAs) are rapidly gaining momentum as a conservation tool, but management performance of existing MPAs is considered low. To enhance MPA management performance, stakeholders are increasingly being invited to discuss, debate, and develop rules about how people should interact with marine ecosystems. Using social and ecological data from a rapid assessment of 31 MPAs and their associated communities in the wider Caribbean, this study investigates stakeholder participation in MPA planning and management, and how participants' views of process quality relate to MPA performance. Findings indicate that (1) participants tended to be male, resource users, participate in community organizations, and have lived fewer years in the community associated with an MPA than non-participants; (2) simply participating was not associated with perceptions of the social and ecological performance of MPAs, however, perceptions of process quality were positively related to views of performance; and (3) resource users' perceptions of an MPA's ecological performance were likely shaped by a variety of factors. Conservation practitioners should be aware that participatory MPA processes are complex and require careful planning if they are to contribute positively to marine conservation efforts. PMID- 22525992 TI - Managing sustainable development conflicts: the impact of stakeholders in small scale hydropower schemes. AB - The growing importance of the environment and its management has simultaneously emphasized the benefits of hydroelectric power and its environmental costs. In a changing policy climate, giving importance to renewable energy development and environmental protection, conflict potential between stakeholders is considerable. Navigation of conflict determines the scheme constructed, making sustainable hydropower a function of human choice. To meet the needs of practitioners, greater understanding of stakeholder conflict is needed. This paper presents an approach to illustrate the challenges that face small-scale hydropower development as perceived by the stakeholders involved, and how they influence decision-making. Using Gordleton Mill, Hampshire (UK), as an illustrative case, soft systems methodology, a systems modeling approach, was adopted. Through individual interviews, a range of problems were identified and conceptually modeled. Stakeholder bias towards favoring economic appraisal over intangible social and environmental aspects was identified; costs appeared more influential than profit. Conceptual evaluation of the requirements to meet a stakeholder-approved solution suggested a complex linear systems approach, considerably different from the real-life situation. The stakeholders introduced bias to problem definition by transferring self-perceived issues onto the project owner. Application of soft systems methodology caused a shift in project goals away from further investigation towards consideration of project suitability. The challenge of sustainable hydropower is global, with a need to balance environmental, economic, and social concerns. It is clear that in this type of conflict, an individual can significantly influence outcomes; highlighting the need for more structured approaches to deal with stakeholder conflicts in sustainable hydropower development. PMID- 22525993 TI - The capacity to detect change stream fish communities characteristics at the site level in the Lake Ontario basin. AB - We investigate natural inter-annual variability of fish community measures within streams of the Lake Ontario basin. Given this variability, we examined coefficients of variation (CV) among the community measures and three scenarios pertaining to the capacity of biologists to detect changes in the fish community at the stream site level. Results indicate that Ontario's stream fish communities are highly variable in time. Young-of-the-year rainbow trout growth was the least variable whereas biomass density scored the highest CV of 0.50 among streams (range 0.22-0.99). Given the CVs and relatively equal sample sizes, our measures of the fish community can be ranked from least to most powerful: biomass, density, richness, diversity, and growth of young-of-the-year rainbow trout. Only large changes in measures can typically be detected. For instance, it would take 4-6 years of monitoring before and after a pulse perturbation to detect a 50 % change in species richness or diversity. We suggest that monitoring abundance is unlikely to result in the detection of small impacts within a short period of time and that large effects can be masked by low statistical power. This evidence voices the need for more research into better sampling methods, experimental designs, and choice of indicators to support monitoring programs for flowing waters. PMID- 22525994 TI - Effectiveness of the California state ban on the sale of Caulerpa species in aquarium retail stores in southern California. AB - The invasion of the aquarium strain of the green alga Caulerpa taxifolia and subsequent alteration of community structure in the Mediterranean Sea raised awareness of the potential for non-native seaweeds to impact coastal communities. An introduction of C. taxifolia in southern California in 2000, presumably from the release of aquarium specimens, cost ~$7 million for eradication efforts. Besides C. taxifolia, other Caulerpa species being sold for aquarium use also may have the potential to invade southern Californian and U.S. waters. Surveys of the availability of Caulerpa species in southern California aquarium retail stores in 2000-2001 revealed that 26 of 50 stores sold at least one Caulerpa species (52 %) with seven stores selling C. taxifolia. In late 2001, California imposed a ban on the importation, sale, or possession of nine Caulerpa species; the City of San Diego expanded these regulations to include the entire genus. To determine the effectiveness of the California ban, we resurveyed Caulerpa availability at 43 of the 50 previously sampled retail stores in southern California in ~2006, ~4 years following the ban. Of the 43 stores, 23 sold Caulerpa (53 %) with four stores selling C. taxifolia. A chi(2) test of frequency of availability before and after the California ban suggests that the ban has not been effective and that the aquarium trade continues to represent a potential vector for distributing Caulerpa specimens, including C. taxifolia. This study underscores the need for increased enforcement and outreach programs to increase awareness among the aquarium industry and aquarium hobbyists. PMID- 22525995 TI - Update on the future of nursing: campaign for action. PMID- 22525996 TI - Medical evaluation for child physical abuse: what the PNP needs to know. AB - Physical abuse is a problem of epidemic proportions. Pediatric nurse practitioners (PNPs) will most likely encounter physically abused children in their practice. This continuing education offering will help PNPs develop the skills necessary to recognize an injury that raises the concern for abuse based on characteristics of the injury such as appearance, location, or severity and characteristics of the history given for the injury. The link between corporal punishment and physical abuse will be discussed. Cutaneous findings of abuse, oral injuries, skeletal injuries, abdominal trauma, and abusive head trauma will also be discussed. PMID- 22525997 TI - Are urban low-income children from unplanned pregnancy exposed to higher levels of environmental tobacco smoke? AB - INTRODUCTION: The negative consequences of environmental tobacco smoke (ETS) in children have been well documented. Our objective is to assess whether children of unplanned pregnancies are at increased risk for ETS exposure. METHOD: Data were collected through interviews of mothers who accompanied their children to the Children's Hospital of Michigan, Detroit, Michigan. Associations of ETS exposure with unplanned pregnancy were analyzed using the chi2 test and stratified by maternal smoking status. Results from the bivariate analysis were further verified using a multiple logistic regression method to control for significant covariates. RESULTS: Among the sample of 399 children, 125 (31.3%) were born from unplanned pregnancies; 47.2% of the unplanned children and 25.6% of the planned children were exposed to ETS (chi2 = 18.4, p < .01). Unplanned children of non-smoking mothers also experienced higher levels of exposure to ETS compared with planned children (22.45% vs. 10.05%, chi(2) = 5.50, p < .05). The association remained significant after controlling for covariates (adjusted odds ratio = 2.45; 95% confidence interval = 1.03, 5.84; p < .05). DISCUSSION: Findings of this study suggest the importance of preventing ETS in urban children, particularly those from unplanned pregnancies. PMID- 22525998 TI - Perspectives of youths and adults improve the care of hospitalized adolescents in Spain. AB - PURPOSE: The purpose of this study was to determine and compare the preferences and priorities of youths and adults about the best ways to improve hospitals to have an impact on the quality of life of hospitalized adolescents. METHOD: Participants in this study were 364 adolescents between 14 and 17 years of age (96 hospitalized) and 148 adults (96 parents of patients and 52 health professionals). All the participants completed a questionnaire about their preferences and priorities with regard to hospitalization. RESULTS: A high degree of agreement among the youths and the adults was observed, especially regarding the importance assigned to agreeableness of clinical staff to improveadolescents' experience of hospitalization. Some discrepancies also were observed. The youths granted more importance to issues related to filling in time, specifically to the leisure technology available for patients. The adults assigned more importance to the organization of the hospital stay, in particular, for adolescents to be admitted with patients of the same age and for them to receive academic support in the hospital. CONCLUSIONS: Adolescents express a coherent perspective about the aspects that may help them feel better in the hospital that in some ways is different from the perspective of the adults who care for them. PMID- 22525999 TI - Bone health in children with cerebral palsy and epilepsy. AB - Children with disabilities that limit mobility are at increased risk for osteoporosis. In the United States, 10 million people have osteoporosis and 34 million people are estimated to be at risk of acquiring this condition. Typically, bone fragility and osteoporosis have been associated with older adults; however, these problems can also affect children. The childhood and adolescent years are critically important in producing healthy bone mass. Yet cerebral palsy and epilepsy, which are both chronic disorders that frequently coexist, are predictors of muscular and skeletal compromise. Nurse practitioners should be aware of recommendations for promoting and achieving optimal bone health in children with these disabilities and screening patients who are at risk of sustaining fractures. PMID- 22526000 TI - Prophylactic use of antipyretic agents with childhood immunizations and antibody response: reason for concern? AB - INTRODUCTION: In the pediatric primary care setting, well-child visits constitute over 50% of all encounters, treating over 24 million children annually. Anticipatory guidance topics vary based on different ages, but immunizations are a focal point of all well-child visits. This article addresses the prophylactic use of antipyretic agents with the administration of immunizations as a potential reason of concern. METHODS: A literature review of the use of antipyretic agents in conjunction with immunizations and the effectiveness of treatment was performed. RESULTS: Based on several studies, the standard recommendation of administering antipyretic agents with immunization administration was a routine. Twenty years later, the scientific evidence was questioned. A pivotal study questioned these standards, noting no benefit and potential decreased immune response. DISCUSSION: Although the prophylactic use of antipyretics has been a standard in pediatrics, the lack of scientific support in the reduction of adverse effects of the vaccinations and the possibility of decreased immune response warrants further research. PMID- 22526001 TI - Acute and non-acute lower extremity pain in the pediatric population: part II. PMID- 22526004 TI - [Cross-linking in an artificial human cornea via induction of tissue transglutaminases]. AB - PURPOSE: In recent years many three-dimensional cornea models have been developed. However, they show poor collagen stability in the stroma. Transglutaminases (Tgases) are calcium-dependent proteins which play an important role in cross-linking of the corneal stroma. The purpose of this study was to find out whether it is possible to induce in vitro cross-linking of the stroma in an artificial hemicornea model with the help of Tgases. MATERIALS AND METHODS: For the construction of the hemicornea, human SV40 adenovector corneal epithelial cells (HCE) and human SV40 adenovector corneal keratocytes (HCK) were cultivated. Confluent HCK cells were treated for 24 h with transforming growth factor beta (TGFb) 1, 2 and 3 at different concentrations as well as with other growth factors and the treated cells were compared to untreated cultivated cells. The quantification of the expression of the Tgases by HCKs was examined with the use of real time PCR, Western blot imaging and immunochemistry. RESULTS: All concentrations of TGFbs used resulted in a significant increase of Tgase-mRNA, Tgase protein level and Tgase activity. The Tgases remained unaffected after treatment with other growth factors in comparison to untreated control cells. Treatment of the hemicornea with TGFb2 showed a very strong contraction and haze in comparison to the untreated hemicornea. CONCLUSION: It has been shown for the first time that TGFb induces a strong expression of Tgases in HCK cells. This effect caused an undesired contraction and haze of the human hemicornea model. Further research is necessary in order to find out whether the induction of Tgases in the HCK cells can be regulated without losing stability of the constructed hemicornea. PMID- 22526003 TI - Nanotechnology-novel therapeutics for CNS disorders. AB - Research into treatments for diseases of the CNS has made impressive strides in the past few decades, but therapeutic options are limited for many patients with CNS disorders. Nanotechnology has emerged as an exciting and promising new means of treating neurological disease, with the potential to fundamentally change the way we approach CNS-targeted therapeutics. Molecules can be nanoengineered to cross the blood-brain barrier, target specific cell or signalling systems, respond to endogenous stimuli, or act as vehicles for gene delivery, or as a matrix to promote axon elongation and support cell survival. The wide variety of available nanotechnologies allows the selection of a nanoscale material with the characteristics best suited to the therapeutic challenges posed by an individual CNS disorder. In this Review, we describe recent advances in the development of nanotechnology for the treatment of neurological disorders-in particular, neurodegenerative disease and malignant brain tumours-and for the promotion of neuroregeneration. PMID- 22526005 TI - [Spontaneous macula hemorrhage. Subhyaloid/sub-inner limiting membrane (ILM)]. AB - This case study describes the clinical findings of two patients with spontaneous subhyaloid and sub-inner limiting membrane preretinal macular hemorrhage including ophthalmoscopy, optical coherence tomography (OCT) and fluorescein angiography (FAG), which are typical for a Valsalva retinopathy. The improvement of the decreased visual acuity was achieved in one case by spontaneous resorption and in the other case by pars plana vitrectomy. The etiology, diagnostic criteria and therapeutic options are discussed. PMID- 22526006 TI - [Bilateral visual loss in a young male patient]. AB - We present the case of a 36-year-old male patient who presented with an increasing bilateral loss of vision which had existed for several years. Slit lamp examination revealed a conical anterior protusion of the lens and funduscopy showed a discreet perimacular dot and fleck retinopathy. In consideration of all clinical findings the patient was diagnosed with anterior lenticonus as an ocular manifestation of an Alport's syndrome which is a rare X-linked disease. Besides renal failure and hearing loss which occur early, ocular changes usually manifest later on. Patients with a anterior lenticonus can be effectively treated with phacoemulsification and intraocular lens implantation. The visual outcome after surgery is excellent. PMID- 22526007 TI - [Dirofilariosis: subconjunctival infection with Dirofilaria repens]. AB - A 45-year-old female patient from Bosnia complained of recurrent swelling and redness of the upper eyelid and 24 h later the patient consulted the Salzburg eye hospital because of a subconjunctival swelling. The slit lamp investigation showed a living Dirofilaria repens which could be removed by forceps. On the basis of this case the infection pathway, possible increasing incidence and therapy are discussed. PMID- 22526008 TI - [Light adjustable lens. New options for customized correction of presbyopia]. AB - PURPOSE: The aim of this study was a prospective evaluation of new algorithms for the treatment of presbyopia using a light-adjustable intraocular lens (LAL). PATIENTS AND METHODS: A total of 15 patients scheduled for routine cataract surgery were included in the study. Following cataract removal a LAL (CalhounVision, Pasadena, CA) was implanted. At approximately 2 weeks after implantation the IOL was adjusted to correct any residual refractive error (sphere and cylinder) followed by the creation of a customized near add (CNA) that was based on the individual patient pupil size in one eye. The fellow eye was corrected for emmetropia. A final lock-in treatment was then performed. RESULTS: There were no complications observed during the surgery or power adjustments. All patients demonstrated an improvement in near vision (0.97 +/- 0.18) and distance vision (0.78 +/- 0.18) with good intermediate vision (0.92 +/- 0.12) months after the final lock-in. CONCLUSION: This preliminary study showed that the creation of a CNA based on the individual patient's pupil size, provided patients with a good range of near, intermediate and distance vision following implantation of the LAL. PMID- 22526009 TI - [Vascular anomaly of the iris]. AB - A 48-year-old man presented with a vascular anomaly of the iris in the left eye. Slit-lamp microscopy revealed dilated and tortuous vessels of the iris between 12 and 4 o'clock. Fluorescein angiography confirmed a diagnosis of arteriovenous (AV) malformation of the iris. The vessel originated at the iris base, passed to the pupillary margin and returned to the base. Such AV-malformations of the iris are very rare, benign vascular anomalies that have to be distinguished from other, potentially malignant pathologies of the iris (e. g. tortuous vessels in iris melanoma). PMID- 22526010 TI - [Old immune system- new information? Importance of mononuclear phagocytes in corneal allograft rejection]. AB - Mononuclear phagocytes are derived from bone marrow precursor cells and are part of the innate immune system. These cells circulate in the blood as monocytes but differentiate in the peripheral circulation into tissue macrophages and dendritic cells under the influence of various cytokines. In addition to antimicrobial properties, macrophages also participate in wound healing; however, they also support degenerative and inflammatory processes. In cases of acute corneal allograft rejection, mononuclear cells initially form the main component of the cellular anterior chamber infiltrate. How monocytes are recruited into the anterior chamber is currently uncertain. Furthermore, no information is available about the possible cytotoxic effects on corneal endothelial cells. Gaining insight into these mechanisms may lead to potential pharmacological interventions. PMID- 22526011 TI - The role of ghrelin-octanoyl-acyl-transferase in thermoregulation. AB - BACKGROUND: Ghrelin is a gastrointestinal peptide that promotes a positive energy balance. The enzyme ghrelin O-acyltransferase (GOAT) esterifies an n-octanoic acid to the peptide, thereby enabling ghrelin to bind and activate the ghrelin receptor. Although ghrelin has previously been implicated in the control and maintenance of body core temperature (BCT), the role that this acylation may play in thermoregulation has not been examined. AIM: We aimed to investigate the endogenous role of ghrelin acylation in thermoregulation. METHODS: In this study, we exposed mice lacking the enzyme GOAT as well as wild-type (WT) control mice to cold temperatures under ad libitum and fasting conditions. Additionally, we investigated the role of GOAT in metabolic adaptation to cold temperatures by analyzing BCT and energy metabolism in mice with and without GOAT that were progressively exposed to low ambient temperatures (31-7 C). RESULTS: We find that regardless of nutritional status, mice lacking GOAT maintain a similar BCT as their WT counterparts during an 8 h cold exposure. Furthermore, mice lacking GOAT maintain a similar BCT and metabolic adaptation asWT controls during acclimatization to low ambient temperatures. CONCLUSIONS: We conclude that the absence of the enzyme GOAT does not play a significant role in maintenance of BCT or metabolic adaptation during exposure to low external temperatures. PMID- 22526012 TI - gyrA/B fluoroquinolone resistance allele profiles amongst Mycobacterium tuberculosis isolates from mainland China. AB - Fluoroquinolones are important second-line drugs for the treatment of tuberculosis. A comprehensive profile of resistance mutation patterns of DNA gyrase, the major target of fluoroquinolones, is crucial for molecular diagnosis of drug resistance and improvement of treatment efficacy. To investigate the mutation types of the genes encoding the A and B subunits of DNA gyrase (gyrA and gyrB, respectively) in ofloxacin- and levofloxacin-resistant Mycobacterium tuberculosis strains prevalent in mainland China, 177 clinical drug-resistant isolates collected by the National Tuberculosis Reference Laboratory of China were analysed. The GyrB single mutations (Glu498 and Gly551) and double mutation (Thr539Asn-Gly551Arg) as well as a GyrA double mutation (Asp94Asn-Gly112His) were reported to be involved in fluoroquinolone resistance for the first time. To simplify quantification of the contribution of each mutation type and mutation site to overall fluoroquinolone resistance, a mathematical method was established by assigning each resistance allele a numerical score between 5 and 50 (the larger the number, the higher the resistance level). The score of double mutants is the sum of the scores for the two single alleles. The double mutation types, including Asn538Ile(GyrB)-Asp94Ala(GyrA), Ala543Val(GyrB)-Asp94Asn(GyrA) and Ala543Val(GyrB)-Asp94Gly(GyrA) scored relatively high by this methodology. PMID- 22526014 TI - Penetration of moxifloxacin into liver tissue. AB - Moxifloxacin is considered for treatment of pyogenic liver abscesses as well as antibiotic prophylaxis in the case of hepatobiliary interventions. The aim of this study was to provide data on the pharmacokinetic (PK) profile of moxifloxacin in serum and liver tissue of patients undergoing liver resection due to primary or secondary tumours of the liver. Patients scheduled for liver resection (n=34) received moxifloxacin 400 mg at randomised time intervals prior to surgery. Blood and healthy liver tissue were sampled 1.5-26 h after administration of moxifloxacin. Immediately after centrifugation, plasma was separated, frozen and stored until analysis. In a subgroup of 19 patients, additional plasma specimens were obtained after 2, 4, 8, 12, 24, 36 and 48 h to assess the PK profile. PK parameters of moxifloxacin were calculated applying a two-compartment model. Median (interquartile range) PK parameters were as follows: peak concentration at the end of moxifloxacin infusion (C(max)), 6.0 mg/L (4.8-7.1 mg/L); area under the concentration-time curve extrapolated to infinity (AUC(0-infinity)), 51.1 mgh/L (40.3-57.7 mgh/L); elimination half-life, 13.2h (11.0-14.1 h); volume of distribution at steady state (V(ss)), 138.7 L (102.7-168.5 L); and total body clearance (CL), 7.8 L/h (6.9-9.9L/h). Mean tissue concentrations were 9.13 mg/kg after 1.6-2.4 h, 7.62 mg/kg after 2.6-4.9h, 7.48 mg/kg after 5.6-10.0 h and 6.24 mg/kg after 22.9-26.5 h. Mean tissue:serum ratios were 2.9, 3.4, 5.0 and 12.3, respectively. The lowest tissue concentration found in the study at any time point was 2.8 mg/kg. In conclusion, moxifloxacin rapidly penetrates into the liver tissue where its concentration remains high following intravenous administration. Therefore, intravenously applied moxifloxacin might be used for the treatment of bacterial liver infections such as pyogenic liver abscess as well as in pre-operative prophylaxis. PMID- 22526013 TI - Identification and molecular characterisation of New Delhi metallo-beta-lactamase 1 (NDM-1)- and NDM-6-producing Enterobacteriaceae from New Zealand hospitals. AB - The global spread of New Delhi metallo-beta-lactamase (NDM) is of significant public health concern. This study sought to determine whether bla(NDM) was present in Enterobacteriaceae isolates displaying resistance to carbapenems that were submitted to the National Antibiotic Reference Laboratory, Institute of Environmental Science and Research (Porirua, New Zealand) during 2009 and 2010. Isolates were tested for the presence of beta-lactamase genes and 16S rRNA methylase genes by polymerase chain reaction (PCR) and sequencing. Plasmid transfer studies were undertaken on isolates found to be harbouring bla(NDM). Molecular typing was performed by multilocus sequence typing (MLST). The bla(NDM 1) gene was identified in four Enterobacteriaceae isolates (two Escherichia coli, one Klebsiella pneumoniae and one Proteus mirabilis) from four patients in New Zealand hospitals in 2009 and 2010. In addition, the bla(NDM-6) gene, which differed from bla(NDM-1) by a point mutation at position 698 (C->T), was also identified in an E. coli isolate from the same patient who harboured the bla(NDM 1)-positive P. mirabilis. All four patients had recently been hospitalised or received health care in India. Four of the isolates also produced a CTX-M-15 extended-spectrum beta-lactamase and/or plasmid-mediated AmpC beta-lactamase, and all five isolates harboured the plasmid-mediated 16S rRNA methylase rmtC gene. The E. coli types were diverse by MLST, and the K. pneumoniae isolate belonged to the internationally disseminated sequence type 11 (ST11) clone. These findings further illustrate the diversity of phenotypic and genotypic features found in association with bla(NDM), in addition to documenting the international spread of this resistance mechanism, notably into a country with historically low rates of antimicrobial resistance. PMID- 22526015 TI - Activity of ceftobiprole against Streptococcus pneumoniae isolates exhibiting high-level resistance to ceftriaxone. AB - Tracking Resistance in the US Today (TRUST) 2008 surveillance data showed that 6% of Streptococcus pneumoniae were non-susceptible to ceftriaxone [minimum inhibitory concentration (MIC) >= 2 MUg/mL] and that 8% of the ceftriaxone-non susceptible isolates exhibited high-level resistance (MIC >= 8 MUg/mL). Here we describe the activity of ceftobiprole against ceftriaxone-resistant isolates and characterise the genotypic traits associated with resistance. Thirty isolates with ceftriaxone MICs >= 8 MUg/mL were analysed by sequencing of penicillin binding protein (PBP) and murM genes. Sequencing of pbp1a, pbp2b and pbp2x showed nine PBP patterns, with the most common (n=17) being: PBP1a T371S (STMK motif), P432T (SRNVP motif); PBP2b T446A (SSNT motif), A619G (KTGTA motif); and PBP2x T338A and M339F (STMK motif), L364F, I371T, R384G, M400T, L546V (LKSGT motif); six isolates had the same pattern without the PBP2b A619G change. For these 23 isolates, MICs were 8 MUg/mL for ceftriaxone, 4-8 MUg/mL for penicillin and 0.5-2 MUg/mL for ceftobiprole. The remaining seven isolates with higher MICs (ceftriaxone 8-32 MUg/mL, penicillin 4-32 MUg/mL and ceftobiprole 2-4 MUg/mL) had fewer PBP active-site motif substitutions. The majority of isolates (17/30) had murM alleles similar to the wild-type, whilst the rest had alleles reflecting a mosaic structure. No murM alleles were associated with higher MICs. Against these 30 isolates, ceftobiprole was 4-16-fold more active than ceftriaxone. Widely described PBP and MurM substitutions probably account for the high ceftriaxone MICs (8 MUg/mL) in the majority of isolates. However, seven isolates with ceftriaxone MICs of 8-32 MUg/mL had fewer PBP substitutions in active-site motifs, suggesting either that there is another resistance mechanism or that unique PBP mutations may contribute to high-level beta-lactam resistance. PMID- 22526016 TI - Mitochondrial DNA polymorphisms specifically modify cerebral beta-amyloid proteostasis. AB - Several lines of evidence link mutations and deletions in mitochondrial DNA (mtDNA) and its maternal inheritance to neurodegenerative diseases in the elderly. Age-related mutations of mtDNA modulate the tricarboxylic cycle enzyme activity, mitochondrial oxidative phosphorylation capacity and oxidative stress response. To investigate the functional relevance of specific mtDNA polymorphisms of inbred mouse strains in the proteostasis regulation of the brain, we established novel mitochondrial congenic mouse lines of Alzheimer's disease (AD). We crossed females from inbred strains (FVB/N, AKR/J, NOD/LtJ) with C57BL/6 males for at least ten generations to gain specific mitochondrial conplastic strains with pure C57BL/6 nuclear backgrounds. We show that specific mtDNA polymorphisms originating from the inbred strains differentially influence mitochondrial energy metabolism, ATP production and ATP-driven microglial activity, resulting in alterations of cerebral beta-amyloid (Abeta) accumulation. Our findings demonstrate that mtDNA-related increases in ATP levels and subsequently in microglial activity are directly linked to decreased Abeta accumulation in vivo, implicating reduced mitochondrial function in microglia as a causative factor in the development of age-related cerebral proteopathies such as AD. PMID- 22526017 TI - Distinct disease-risk groups in pediatric supratentorial and posterior fossa ependymomas. AB - No reliable classification is in clinical use for the therapeutic stratification of children with ependymoma, such that disease risk might be identified and patients treated to ensure a combination of maximal cure rates and minimal adverse therapeutic effects. This study has examined associations between clinicopathologic and cytogenetic variables and outcome in a trial cohort of children with ependymoma, with the aim of defining a practical scheme for stratifying this heterogeneous tumor. Intracranial ependymomas (n = 146) from children treated on the RT1 trial at St. Jude Children's Research Hospital were evaluated for the status of multiple pathological features. Interphase FISH (iFISH) defined the status of loci on chromosomes 1q (EXO1), 6q (LATS1) and 9, including 9p21 (CDKN2A). Data relating to these clinicopathological and cytogenetic variables were compared with survival data in order to model disease risk groups. Extent of surgical resection was a significant determinant of outcome in both supratentorial and infratentorial compartments. Tumor cell density and mitotic count were associated with outcome among children with posterior fossa ependymomas (n = 119). Among pathologic features, only brain invasion was associated with outcome in children with supratentorial ependymomas (n = 27). For posterior fossa tumors, gain of 1q was independently associated with outcome and in combination with clinicopathological variables defined both a two-tier and three-tier system of disease risk. Among children developing posterior fossa ependymomas treated with maximal surgical resection and conformal radiotherapy, key clinicopathological variables and chromosome 1q status can be used to define tiers of disease risk. In contrast, risk factors for pediatric supratentorial tumors are limited to sub-total resection and brain invasion. PMID- 22526018 TI - Next generation sequencing for molecular diagnosis of neuromuscular diseases. AB - Inherited neuromuscular disorders (NMD) are chronic genetic diseases posing a significant burden on patients and the health care system. Despite tremendous research and clinical efforts, the molecular causes remain unknown for nearly half of the patients, due to genetic heterogeneity and conventional molecular diagnosis based on a gene-by-gene approach. We aimed to test next generation sequencing (NGS) as an efficient and cost-effective strategy to accelerate patient diagnosis. We designed a capture library to target the coding and splice site sequences of all known NMD genes and used NGS and DNA multiplexing to retrieve the pathogenic mutations in patients with heterogeneous NMD with or without known mutations. We retrieved all known mutations, including point mutations and small indels, intronic and exonic mutations, and a large deletion in a patient with Duchenne muscular dystrophy, validating the sensitivity and reproducibility of this strategy on a heterogeneous subset of NMD with different genetic inheritance. Most pathogenic mutations were ranked on top in our blind bioinformatic pipeline. Following the same strategy, we characterized probable TTN, RYR1 and COL6A3 mutations in several patients without previous molecular diagnosis. The cost was less than conventional testing for a single large gene. With appropriate adaptations, this strategy could be implemented into a routine genetic diagnosis set-up as a first screening approach to detect most kind of mutations, potentially before the need of more invasive and specific clinical investigations. An earlier genetic diagnosis should provide improved disease management and higher quality genetic counseling, and ease access to therapy or inclusion into therapeutic trials. PMID- 22526020 TI - Localization of fused in sarcoma (FUS) protein to the post-synaptic density in the brain. AB - Mutations in the fused in sarcoma (FUS) gene are linked to a form of familial amyotrophic lateral sclerosis (ALS), ALS6. The FUS protein is a major component of the ubiquitin-positive neuronal cytoplasmic inclusions in both ALS6 and some rare forms of frontotemporal lobar degeneration (FTLD). The latter are now collectively referred to as FTLD-FUS. In the present study, we investigated the localization of FUS in human and mouse brains. FUS was detected by western blot as an approximately 72 kDa protein in both human and mouse brains. Immunohistochemistry using lightly fixed tissue sections of human and mouse brains revealed FUS-positive granular staining in the neuropil, in addition to nuclear staining. Such granules are abundant in the gray matter of the brainstem and spinal cord. They are not frequent in the telencephalon. At the light microscopic level, FUS-positive granules are often co-localized with synaptophysin and present in association with microtubule-associated protein 2 positive dendrites. In the synaptosomal fraction of mouse brain, FUS is detected mainly in the post-synaptic density fraction. Thus, while FUS is primarily a nuclear protein, it may also play a role in dendrites. In the brains of patients with FTLD with TDP-43 deposition (FTLD-TDP), the number of FUS-positive granules in the cortex is increased compared with control cases. The increase in Alzheimer's disease (AD) is less remarkable but still significant. The dendritic localization of FUS and its increase in FTLD-TDP and AD may have some implication for the pathophysiology of neurodegenerative diseases. PMID- 22526019 TI - CSF biomarkers cutoffs: the importance of coincident neuropathological diseases. AB - The effects of applying clinical versus neuropathological diagnosis and the inclusion of cases with coincident neuropathological diagnoses have not been assessed specifically when studying cerebrospinal fluid (CSF) biomarker classification cutoffs for patients with neurodegenerative diseases that cause dementia. Thus, 142 neuropathologically diagnosed neurodegenerative dementia patients [71 Alzheimer's disease (AD), 29 frontotemporal lobar degeneration (FTLD), 3 amyotrophic lateral sclerosis, 7 dementia with Lewy bodies, 32 of which cases also had coincident diagnoses] were studied. 96 % had enzyme-linked immunosorbant assay (ELISA) CSF data and 77 % had Luminex CSF data, with 43 and 46 controls for comparison, respectively. Abeta(42), total, and phosphorylated tau(181) were measured. Clinical and neuropathological diagnoses showed an 81.4 % overall agreement. Both assays showed high sensitivity and specificity to classify AD subjects against FTLD subjects and controls, and moderate sensitivity and specificity for classifying FTLD subjects against controls. However, among the cases with neuropathological diagnoses of AD plus another pathology (26.8 % of the sample), 69.4 % (ELISA) and 96.4 % (Luminex) were classified as AD according to their biomarker profiles. Use of clinical diagnosis instead of neuropathological diagnosis led to a 14-17 % underestimation of the biomarker accuracy. These results show that while CSF Abeta and tau assays are useful for diagnosis of AD and neurodegenerative diseases even at MCI stages, CSF diagnostic analyte panels that establish a positive diagnosis of Lewy body disease and FTLD are also needed, and must be established based on neuropathological rather than clinical diagnoses. PMID- 22526021 TI - Distinct TDP-43 pathology in ALS patients with ataxin 2 intermediate-length polyQ expansions. AB - Amyotrophic lateral sclerosis (ALS) is a progressive, adult-onset neurodegenerative disease characterized by degeneration of motor neurons, resulting in paralysis and death. A pathological hallmark of the degenerating motor neurons in most ALS patients is the presence of cytoplasmic inclusions containing the protein TDP-43. The morphology and type of TDP-43 pathological inclusions is variable and can range from large round Lewy body-like inclusions to filamentous skein-like inclusions. The clinical significance of this variable pathology is unclear. Intermediate-length polyglutamine (polyQ) expansions in ataxin 2 were recently identified as a genetic risk factor for ALS. Here we have analyzed TDP-43 pathology in a series of ALS cases with or without ataxin 2 intermediate-length polyQ expansions. The motor neurons of ALS cases harboring ataxin 2 polyQ expansions (n = 6) contained primarily skein-like or filamentous TDP-43 pathology and only rarely, if ever, contained large round inclusions, whereas the ALS cases without ataxin 2 polyQ expansions (n = 13) contained abundant large round and skein-like TDP-43 pathology. The paucity of large round TDP-43 inclusions in ALS cases with ataxin 2 polyQ expansions suggests a distinct pathological subtype of ALS and highlights the possibility for distinct pathogenic mechanisms. PMID- 22526022 TI - Neuromyelitis optica IgG and natural killer cells produce NMO lesions in mice without myelin loss. AB - The pathogenesis of neuromyelitis optica (NMO) involves targeting of NMO immunoglobulin G (NMO-IgG) to aquaporin-4 (AQP4) on astrocytes in the central nervous system. Prior work provided evidence for complement-dependent cytotoxicity (CDC) in NMO lesion development. Here, we show that antibody dependent cellular cytotoxicity (ADCC), in the absence of complement, can also produce NMO-like lesions. Antibody-dependent cellular cytotoxicity was produced in vitro by incubation of mouse astrocyte cultures with human recombinant monoclonal NMO-IgG and human natural killer cells (NK-cells). Injection of NMO IgG and NK-cells in mouse brain caused loss of AQP4 and GFAP, two characteristic features of NMO lesions, but little myelin loss. Lesions were minimal or absent following injection of: (1) control (non-NMO) IgG with NK-cells; (2) NMO-IgG and NK-cells in AQP4-deficient mice; or (3) NMO-IgG and NK-cells in wild-type mice together with an excess of mutated NMO-IgG lacking ADCC effector function. NK cells greatly exacerbated NMO lesions produced by NMO-IgG and complement in an ex vivo spinal cord slice model of NMO, causing marked myelin loss. NMO-IgG can thus produce astrocyte injury by ADCC in a complement-independent and dependent manner, suggesting the potential involvement of ADCC in NMO pathogenesis. PMID- 22526024 TI - Accelerated and enhanced effect of CCR5-transduced bone marrow neural stem cells on autoimmune encephalomyelitis. AB - The suppressive effect of neural stem cells (NSCs) on experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), has been reported. However, the migration of NSCs to inflammatory sites was relatively slow as was the onset of rather limited clinical benefit. Lack of, or low expression of particular chemokine receptors on NSCs could be an important factor underlying the slow migration of NSCs. To enhance the therapeutic effect of NSCs, in the present study we transduced bone marrow (BM)-derived NSCs with CCR5, a receptor for CCL3, CCL4, and CCL5, chemokines that are abundantly produced in CNS inflamed foci of MS/EAE. After i.v. injection, CCR5-NSCs rapidly reached EAE foci in larger numbers, and more effectively suppressed CNS inflammatory infiltration, myelin damage, and clinical EAE than GFP-NSCs used as controls. CCR5-NSC-treated mice also exhibited augmented remyelination and neuron/oligodendrocyte repopulation compared to PBS- or GFP-NSC-treated mice. We inferred that the critical mechanism underlying enhanced effect of CCR5-transduced NSCs on EAE is the early migration of chemokine receptor-transduced NSCs into the inflamed foci. Such migration at an earlier stage of inflammation enables NSCs to exert more effective immunomodulation, to reduce the extent of early myelin/neuron damage by creating a less hostile environment for remyelinating cells, and possibly to participate in the remyelination/neural repopulation process. These features of BM-derived transduced NSCs, combined with their easy availability (the subject's own BM) and autologous properties, may lay the groundwork for an innovative approach to rapid and highly effective MS therapy. PMID- 22526026 TI - Differential effects of environmental chemicals and food contaminants on adipogenesis, biomarker release and PPARgamma activation. AB - Eleven environmental relevant chemicals were investigated for their ability to affect adipogenesis in vitro, biomarker release from adipocytes and PPARalpha and gamma activation. We found that butylparaben stimulated adipogenesis in 3T3-L1 adipocytes and increased release of leptin, adiponectin and resistin from the cells. Butylparaben activated PPARgamma as well, which may be a mediator of the adipogenic effect. Polychlorinated biphenyl (PCB)153 also stimulate adipogenesis and biomarker release, but did not affect PPARs. The data indicates that PPARgamma activating chemicals often stimulate adipocyte differentiation although PPARgamma activation is neither a requirement nor a guarantee for stimulation. Four out of the eleven chemicals (bisphenol A, mono-ethylhexyl phthalate, butylparaben, PCB 153) caused increased adipogenesis. The release of adipocyte secreted hormones was sometimes but not always correlated with the effect on adipocyte differentiation. Eight chemicals were able to cause increased leptin release. These findings strengthen the hypothesis that chemicals can interfere with pathways related to obesity development. PMID- 22526027 TI - Osteoarthritis: Probing knee OA as a system responding to a stimulus. PMID- 22526030 TI - Fluorescence-microscopy screening and next-generation sequencing: useful tools for the identification of genes involved in organelle integrity. AB - This protocol describes a fluorescence microscope-based screening of Arabidopsis seedlings and describes how to map recessive mutations that alter the subcellular distribution of a specific tagged fluorescent marker in the secretory pathway. Arabidopsis is a powerful biological model for genetic studies because of its genome size, generation time, and conservation of molecular mechanisms among kingdoms. The array genotyping as an approach to map the mutation in alternative to the traditional method based on molecular markers is advantageous because it is relatively faster and may allow the mapping of several mutants in a really short time frame. This method allows the identification of proteins that can influence the integrity of any organelle in plants. Here, as an example, we propose a screen to map genes important for the integrity of the endoplasmic reticulum (ER). Our approach, however, can be easily extended to other plant cell organelles (for example see(1,2)), and thus represents an important step toward understanding the molecular basis governing other subcellular structures. PMID- 22526031 TI - Phylogenetic classification of diverse LysR-type transcriptional regulators of a model prokaryote Geobacter sulfurreducens. AB - The protein family of LysR-type transcriptional regulators (LTTRs) is highly abundant among prokaryotes. We analyzed 10,145 non-redundant microbial sequences with homology to eight LysR family regulators of a model prokaryote, Geobacter sulfurreducens, and employed phylogenetic tree inference for LTTR classification. We also analyzed the arrangement of genome clusters containing G. sulfurreducens LTTR genes and searched for LTTR regulatory motifs, suggesting likely regulatory targets of G. sulfurreducens LTTRs. This is the first study to date providing a detailed classification of LTTRs in the deltaproteobacterial family Geobacteraceae. PMID- 22526032 TI - Diagnostic value of FDG-PET/CT for lymph node metastasis of colorectal cancer. AB - BACKGROUND: Lymph node metastasis is an important prognostic factor in patients with colorectal cancer. We assessed the ability of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) to diagnose lymph node metastases in colorectal cancer patients. METHODS: We retrospectively analyzed the records of 473 patients who underwent preoperative FDG-PET/CT, followed by curative surgery for colorectal cancer. Lymph node metastases were assessed as proximal or distal, depending on their anatomical location. We analyzed the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of FDG-PET/CT and CT for detecting lymph node metastases. RESULTS: In detecting proximal lymph nodes, FDG-PET/CT had a sensitivity of 66 %, a specificity of 60 %, a PPV of 63 %, an NPV of 62 %, and an accuracy of 63 %; whereas CT had a sensitivity of 87 %, a specificity of 29 %, a PPV of 57 %, an NPV of 68 %, and an accuracy of 59 % (P = 0.245). FDG-PET/CT and CT also showed similar accuracy in detecting distal lymph nodes (87 vs. 88 %, P = 0.620). CONCLUSION: Preoperative FDG-PET/CT and CT have comparable accuracy in detecting lymph node metastases of colorectal cancer. PMID- 22526033 TI - Incidence and risk factors of the intraoperative localization failure of nonpalpable breast lesions by radio-guided occult lesion localization: a retrospective analysis of 579 cases. AB - BACKGROUND: The radio-guided occult lesion localization (ROLL) technique allows the identification of nonpalpable breast lesions by means of the preoperative, intratumoral injection of a radiotracer. Our study aimed to determine the incidence and risk factors of ROLL failure. METHODS: We collected data about all women who underwent ROLL in our department from 2002 to 2009, focusing on patient characteristics such as breast size and density, lesion size, localization, histology, radiologist, and surgeon experience. Data were analyzed using R v2.10.1, considering p < 0.05 significant. RESULTS: A total of 579 ROLLs were performed on 555 women with a mean age of 58.7 (+/- 10.96) years. Incidence of ROLL failure at the first intervention was 4 % (23/579). Through monovariate analysis, ROLL failure was significantly influenced by stereotactic mammography guided procedure, invasive tumors, pathological and radiological lesion size <= 5 mm, and the lesion's location in the central or upper breast quadrants. Through multivariate analysis, the most predictive factors for ROLL failure were as follows: lesion localization in the central quadrant, lesion radiological size <= 5 mm, and radiologist inexperience. CONCLUSIONS: The main risk factors for ROLL failure were the radiologist's inexperience, lesion size <= 5 mm, and its localization in the central subareolar quadrant, probably due to an unfavorable radiological and surgical reaching of the breast area. PMID- 22526034 TI - Worsening central sarcopenia and increasing intra-abdominal fat correlate with decreased survival in patients with adrenocortical carcinoma. AB - BACKGROUND: Accurate prediction of survival from adrenocortical carcinoma (ACC) is difficult and current staging models are unreliable. Central sarcopenia as part of the cachexia syndrome is a marker of frailty and predicts mortality. This study seeks to confirm that psoas muscle density (PMD), lean psoas muscle area (LPMA), lumbar skeletal muscle index (LSMI), and intra-abdominal (IA) or subcutaneous fat (SC) can be used in combination to more accurately predict survival in ACC patients. METHODS: PMD, LPMA, IA, and SC fat were measured on serial CT scans of patients with ACC. Clinical outcome was correlated with quantitative data from patients with ACC and analyzed. A linear regression model was used to describe the relationship between PMD, LPMA, LSMI, IA, and SC fat, time to recurrence, and length of survival according to tumor stage. RESULTS: One hundred twenty-five ACC patients (94 females) were treated from 2005 to 2011. Significant morphometric predictors of survival include PMD, LPMA, and IA fat (p <= 0.0001, <= 0.0024, <0.0001, respectively) and improve prediction of survival compared to using stage alone. A 100-mm(2) increase in LPMA confers an 8 % lower hazard of death. LSMI does not change significantly between stages (p = 0.3196). CONCLUSION: Decreased PMD, LPMA, and increased IA fat suggest decreased survival in ACC patients and correlate with traditional staging systems. A more precise prediction of survival may be achieved when staging systems and morphometric measures are used in combination. Serial measurements of morphometric data are possible. The rate of change of these variables over time may be more important than the absolute value. PMID- 22526036 TI - Circular stapler size and risk of anastomotic complications in gastroduodenostomy for gastric cancer. AB - BACKGROUND: A Billroth I reconstruction with a mechanically sutured anastomosis is commonly performed in gastric cancer patients. Some surgeons prefer to use large circular staplers during suturing to minimize risks for anastomotic stricture and gastric stasis after surgery. The effect of stapler size on anastomotic complications has not been validated. METHODS: This study was conducted with 1,031 patients who underwent gastrectomy and Billroth I reconstruction at Samsung Medical Center in Seoul, Korea, between January 2007 and October 2008. Patients were assigned to group A (384 patients) or group B (647 patients) depending on the size of the circular stapler that the surgeon selected for mechanical anastomosis. A 25 mm circular stapler was used for patients in group A, and a 28 or 29 mm circular stapler was used for patients in group B. Postoperative complications were analyzed retrospectively. RESULTS: The incidence of complications (e.g., gastric stasis, anastomotic stricture, and bleeding) did not differ significantly between groups. Age greater than 60 years was the only significant risk factor for anastomotic complications identified in univariate and multivariate analyses. CONCLUSIONS: Stapler size was unrelated to complications, such as stricture and gastric stasis. Age was the only significant risk factor for anastomotic complications after gastroduodenostomy. PMID- 22526035 TI - Does obesity affect outcomes in patients undergoing esophagectomy for cancer? A meta-analysis. AB - BACKGROUND: The incidence of esophageal carcinoma and the global prevalence of obesity are both increasing. As a result, there is an increased number of esophagectomies being performed on obese patients. The identification of specific complications in obese patients undergoing esophagectomy may allow improved risk assessment and postoperative management to reduce morbidity and mortality. This meta-analysis aimed to determine whether obese patients are at increased risk of postoperative complications, mortality, and compromised survival compared to non obese patients following esophageal resection. METHODS: A Medline, Embase, Ovid, and Cochrane database search was performed on all articles between January 1980 and January 2012 comparing post-esophagectomy outcomes between obese and non obese patients. This study was conducted in accordance with the recommendations of the Cochrane Collaboration and the Quality of Reporting of Meta-Analyses guidelines. RESULTS: There was no significant difference between obese and non obese patients with respect to extent of tumor resection, cardiorespiratory complications, anastomotic leakage, reoperation rates, wound infection, or postoperative mortality. Meta-regression analysis showed that diabetes in obese patients was associated with a significant impact on the risk of anastomotic leakage (coefficient = -7.94 [-15.24-0.65, P = 0.03) and atrial fibrillation (coefficient = -6.94 [-12.79-1.10], P = 0.02). Overall, obese patients had significantly better long-term survival than non-obese patients (Hazard Ratio = 0.78 [0.64-0.96], P = 0.02). CONCLUSIONS: In patients who are eligible for surgery, obesity alone does not increase risk of postoperative complications or mortality and should not be an independent contraindication for esophagectomy. However, the presence of diabetes mellitus in conjunction with obesity may be associated with increased risk of anastomotic leakage and atrial fibrillation. Because of the adverse physiological remodeling in obesity, surgeons should maintain a low threshold for the investigation and management of complications and ensure meticulous management of co-morbidities. Obesity may also improve long term postoperative survival after esophageal surgery, although further studies with higher levels of evidence are necessary to fully determine any advantageous effects of obesity following oncological esophageal surgery. PMID- 22526038 TI - Trauma quality improvement in low and middle income countries of the Asia-Pacific region: a mixed methods study. AB - BACKGROUND: Quality Improvement (QI) programs have been shown to be a valuable tool to strengthen care of severely injured patients, but little is known about them in low and middle income countries (LMIC). We sought to explore opportunities to improve trauma QI activities in LMIC, focusing on the Asia Pacific region. METHODS: We performed a mixed methods research study using both inductive thematic analysis of a meeting convened at the Royal Australasian College of Surgeons, Melbourne, Australia, November 21-22, 2010 and a pre-meeting survey to explore experiences with trauma QI activities in LMIC. Purposive sampling was employed to invite participants with demonstrated leadership in trauma care to provide diverse representation of organizations and countries within Asia-Pacific. RESULTS: A total of 22 experts participated in the meeting and reported that trauma QI activities varied between countries and organizations: morbidity and mortality conferences (56 %), monitoring complications (31 %), preventable death studies (25 %), audit filters (19 %), and statistical methods for analyzing morbidity and mortality (6 %). Participants identified QI gaps to include paucity of reliable/valid injury data, lack of integrated trauma QI activities, absence of standards of care, lack of training in QI methods, and varying cultures of quality and safety. The group highlighted barriers to QI: limited engagement of leaders, organizational diversity, limited resources, heavy clinical workload, and medico-legal concerns. Participants proposed establishing the Asia-Pacific Trauma Quality Improvement Network (APTQIN) as a tool to facilitate training and dissemination of QI methods, injury data management, development of pilot QI projects, and advocacy for quality trauma care. CONCLUSIONS: Our study provides the first description of trauma QI practices, gaps in existing practices, and barriers to QI in LMIC of the Asia Pacific region. In this study we identified opportunities for addressing these challenges, and that work will be supported by APTQIN. PMID- 22526037 TI - Endocrine surgeon-performed US guided thyroid FNAC is accurate and efficient. AB - BACKGROUND: Ultrasound guided fine needle aspiration cytology (US-FNAC) is a key diagnostic technique used to assess thyroid nodules. This procedure has been the domain of radiologists, but it is increasingly performed by endocrine surgeons. In the present study we aimed to assess the accuracy and clinical efficiency of US-FNAC performed by endocrine surgeons. PATIENTS AND METHODS: This study was a retrospective review of consecutive patients in a 3-year period who underwent US FNAC performed by endocrine surgeons and radiologists. Medical records, cytology results, and surgical pathology results were collected and analyzed. RESULTS: A total of 576 US-FNAC were performed on 402 patients during the study period. The endocrine surgeons and radiologists performed 299 and 277 US-FNAC, respectively. The FNAC inadequacy rate was 5.3 % for the endocrine surgeons and 9.3 % for the radiologists (p = 0.05). For thyroid cancer, the sensitivity, specificity, and false negatives of the US-FNAC for the endocrine surgeons was 87 %, 98 %, and 3 %, respectively while that for the radiologists was 88 %, 95 %, and 3.5 %, respectively. Patients with thyroid cancer had a shorter time to surgery in the endocrine surgeons' group (mean 15.3 days) compared to the radiologists' group (mean: 53.3 days; p = 0.01). CONCLUSIONS: US-FNAC performed by an experienced endocrine surgeon is accurate and allows efficient surgical management for patients with thyroid cancer. PMID- 22526039 TI - Preoperative cholangitis and metastatic lymph node have a negative impact on survival after resection of extrahepatic bile duct cancer. AB - BACKGROUND: The significance of the presence of preoperative inflammation for the prognosis of patients with extrahepatic bile duct cancer (BDCA) was evaluated. METHODS: The clinical data of 84 patients who underwent surgery for BDCA from August 2003 to May 2009 were reviewed, and survival analysis was performed. The patients were classified into two groups according to the presence of preoperative cholangitis: Group A had no cholangitis (n = 59), and group B had cholangitis (n = 25). RESULTS: There were no differences in sex, mean age, TNM stage, biliary drainage, type of resection, or radicality between the two groups (p > 0.05). The 3-year disease-specific survival (DSS) and disease-free survival (DFS) rates for the group B patients (21.5 and 11.9 %, respectively) were significantly lower than those for the group A patients (66.1 and 57.3 %, respectively; p = 0.013 and 0.001, respectively). The multivariate analysis showed that preoperative inflammation and lymph node metastasis were the independent prognostic factors for both overall survival (OS) [p = 0.021, relative risk (RR) = 2.224 and p = 0.015, RR = 2.367, respectively] and DFS (p = 0.014; RR = 2.192 and p = 0.013; RR = 2.240, respectively). The rates of angiolymphatic and perineural invasion were higher for group B than those for group A (p = 0.016 and 0.030, respectively). CONCLUSIONS: The presence of preoperative inflammation is an independent poor prognostic factor for OS and DFS for patients with BDCA. PMID- 22526040 TI - Stapler and nonstapler closure of the pancreatic remnant after distal pancreatectomy: multicenter retrospective analysis of 388 patients. AB - BACKGROUND: The pancreatic fistula rate following distal pancreatectomy ranges widely, from 13.3 to 64.0 %. The optimal closure method of the pancreatic remnant remains controversial, especially regarding whether to use a stapler. METHODS: All patients who underwent distal pancreatectomy in five Japanese hospitals from January 2001 to June 2009 were included in this study. All relevant, anonymized medical records were entered into an electronic case report form. Complications and pancreatic fistulas were classified according to the Clavien-Dindo classification and the International Study Group of Pancreatic Surgery grading system, respectively. RESULTS: Of the 388 patients, stapler closure and nonstapler closure were used after distal pancreatectomy in 224 patients (57.7 %) and 164 patients (42.3 %), respectively. Clinically relevant pancreatic fistulas (grades B and C) occurred in 47 patients (21.0 %) treated by stapler closure, which was a significantly lower rate than that for the 83 patients (50.6 %) treated by nonstapler closure. There were no surgical mortalities or in-hospital deaths. The distribution of postoperative complications was grade 1, 30.7 % (n = 119); grade 2, 40.2 % (n = 156); grade 3a, 0.1 % (n = 5); grade 3b, 0.3 % (n = 1); grade 4a, 0.3 % (n = 1). In the multivariate analysis, diabetes mellitus, previous laparotomy, operating time, and method of stump closure were found to be independently associated with the development of a clinical pancreatic fistula. CONCLUSIONS: Stapler closure is a safe, efficient alternative to standard suture closure techniques because the clinical fistula rate is significantly lower. PMID- 22526041 TI - Endoscopic nasobiliary drainage should be initially selected for preoperative biliary drainage in patients with perihilar bile duct cancer. PMID- 22526042 TI - Rate of clinically significant postoperative pancreatic fistula in pancreatic neuroendocrine tumors. AB - BACKGROUND: In 2005, the International Study Group of Pancreatic Fistula (ISGPF) developed a definition and grading system for postoperative pancreatic fistula (POPF). The authors sought to determine the rate of POPF after enucleation and/or resection of pancreatic neuroendocrine tumors (PNET) and to identify clinical, surgical, or pathologic factors associated with POPF. METHODS: A retrospective analysis of pancreatic enucleations and resections performed from March 1998 to April 2010. We defined a clinically significant POPF as a grade B that required nonoperative intervention and grade C. RESULTS: One hundred twenty-two patients were identified; 62 patients had enucleations and 60 patients had resections of PNET. The rate of clinically significant POPF was 23.7 % (29/122). For pancreatic enucleation, the POPF rate was 27.4 % (17/62, 14 grade B, 3 grade C). The pancreatic resection group had a POPF rate of 20 % (12/60, 10 grade B, 2 grade C). This difference was not significant (p = 0.4). In univariate analyses, patients in the enucleation group with hereditary syndromes (p = 0.02) and non insulinoma tumors (p = 0.02) had a higher POPF rate. Patients in the resection group with body mass index (BMI) > 25 (p < 0.01), multiple endocrine neoplasia type 1 (MEN-1; p < 0.01) and those who underwent simultaneous multiple procedures (p = 0.02) had a higher POPF rate. Multivariate analyses revealed that hereditary syndromes were able to predict POPF in the enucleation group, while having BMI > 25 and increasing lesion size were also associated with POPF in the group undergoing resection. CONCLUSIONS: We found a clinically significant POPF rate after surgery in PNET to be 23.7 % with no difference by the type of operation. Our POPF rate is comparable to that reported in the literature for pancreatic resection for other types of tumors. Certain inherited genetic diseases-von Hippel-Lindau disease (VHL) and MEN-1-were associated with higher POPF rates. PMID- 22526043 TI - Does evidence permeate all surgical areas equally? Publication trends in wound care compared to breast cancer care: a longitudinal trend analysis. AB - BACKGROUND: Evidence-based decision making has permeated the daily practice of healthcare professionals. However, in wound care this seems more difficult than in other medical areas, such as breast cancer, which has a similar incidence, variety of etiologies, financial burden, and diversity of treatment options. This incongruence could be due to a lack in quantity and quality of available evidence. We therefore compared worldwide publication trends to answer whether research in wound care lags behind that in breast cancer. METHODS: In order to assess the trends in quantity and methodological quality of publications as to wound care and breast cancer treatments, we examined relevant publications over the last five decades. Publications in MEDLINE were classified into seven study design categories: (1) guidelines, (2) systematic reviews (SR), (3) randomized (RCT), and controlled clinical trials (CCT), (4) cohort studies, (5) case-control studies, (6) case series and case reports, and (7) other publications. RESULTS: We found a 30-fold rise in publications on wound care, versus a 70-fold increase in those on breast cancer. High-quality study designs like SR, RCT, or CCT were less frequent in wound care (difference 1.9, 95 % CI 1.8-2.0 %) as were guidelines; 76 on wound care versus 231 for breast cancer. CONCLUSIONS: Publications on wound care fall behind in quantity and quality as compared to breast cancer. Nevertheless, SR, RCT, and CCT in wound care are becoming more numerous. These high-quality study designs could motivate clinicians to make evidence-based decisions and researchers to perform proper research in wound care. PMID- 22526044 TI - Commentary: preoperative evaluation in cryptorchidism. PMID- 22526045 TI - Patients with multiple hepatocellular carcinomas within the UCSF criteria have outcomes after curative resection similar to patients within the BCLC early-stage criteria. AB - BACKGROUND: Surgical strategies for the treatment of multiple hepatocellular carcinomas (HCC) remain controversial. This study compared the prognostic power of the University of California, San Francisco (UCSF) criteria with the Barcelona Clinic Liver Cancer (BCLC) early-stage criteria. METHODS: Clinical and survival data of 162 multiple-HCC patients in Child-Pugh class A who underwent curative resection were retrospectively reviewed. Prognostic risk factors were analyzed using univariate and multivariate analyses. RESULTS: UCSF criteria were shown to independently predict overall and disease-free survival. In patients within the UCSF criteria, 3-year overall and disease-free survivals were significantly better than in those exceeding the UCSF criteria (68 vs. 34 % and 54 vs. 26 %, respectively; both p < 0.001). There were no significant differences in 3-year overall and disease-free survival between patients within the UCSF criteria but exceeding the BCLC early stage and patients with BCLC early-stage disease (71 vs. 66 %, p = 0.506 and 57 vs. 50 %, p = 0.666, respectively). Tumors within the UCSF criteria were associated with a lower incidence of high-grade tumor (p = 0.009), microvascular invasion (p = 0.005), 3-month death (p = 0.046), prolonged Pringle's maneuver (p = 0.005), and surgical margin <0.5 cm (p < 0.001) than those exceeding the UCSF criteria. Tumors within the UCSF criteria but exceeding the BCLC early stage had invasiveness and surgical difficulty similar to those within the BCLC early-stage criteria. CONCLUSIONS: Multiple HCC patients within the UCSF criteria benefit from curative resection. Expansion of curative treatment is justified. PMID- 22526046 TI - Esophagogastric trauma in Scotland. AB - BACKGROUND: This study was designed to investigate the incidence of esophageal (ET) and gastric trauma (GT) in Scotland and to identify factors associated with adverse outcome. METHODS: Population-based study of a prospective multicenter database of 52,887 trauma patients, admitted to 25 hospitals from 1992 to 2002. RESULTS: Thirty patients [0.06 %; median age, 32 year (range, 15-79); 86.7 % male] sustained ET [17 (56.7 %) blunt vs. 13 (43.3 %) penetrating]. The most common causes of injury were road traffic accidents (RTAs; n = 11; 36.7 %) and assaults (n = 10; 33.3 %). Most patients (n = 25; 83.3 %) had injury severity scores (ISS) >15, consistent with severe trauma. Fifteen patients (50 %) underwent surgery, of whom 8 (53.3 %) died. Another 13 patients died, yielding an overall mortality rate of 70 %. In contrast, 149 patients [0.29 %; median age, 28 year (range, 13-74); 90.6 % male] sustained GT [124 (83.2 %) penetrating vs. 25 (16.8 %) blunt]. The predominant cause was assault (n = 119; 79.9 %). Most patients (n = 134; 89.9 %) underwent surgery, of which 23 (17.2 %) died. Another 12 patients died, yielding an overall mortality rate of 23.5 %. Factors associated independently with GT mortality included higher ISS, lower Glasgow coma scale (GCS), and hemodynamic compromise. CONCLUSIONS: Esophagogastric trauma occurs predominantly in young males. The incidence of GT, although low, is five times that of ET. Predominant mechanisms of GT are penetrating compared with blunt for ET. Both ET and GT are commonly found in the presence of other multiple injuries, and are associated with high mortality. Operative management of GT is associated with reduced mortality, but outcome is worse for patients with hemodynamic compromise, low GCS, and high ISS. PMID- 22526049 TI - Clinical significance of gastric cancer surveillance in renal transplant recipients. AB - BACKGROUND: Posttransplant malignancy is one of the major causes inhibiting long term graft survival. Gastric adenocarcinoma is the most common malignancy in Korea and occurs more frequently in renal transplant recipients compared to that in Western countries. We aimed to analyze the clinical features of the post-renal transplant gastric cancer and assess factors that can affect the difference in survival. METHODS: Of the 2,157 recipients who underwent renal transplantation at Asan Medical Center between January 1992 and April 2008, the 13 patients diagnosed with gastric adenocarcinoma after transplantation were retrospectively reviewed. We analyzed the effects of primary disease causing end-stage renal disease, type of donor, type of immunosuppressant, induction therapy, and organ rejection on survival after cancer diagnosis. In addition, we evaluated the need for regular gastric cancer screening after transplantation by analyzing the difference in survival between the patients who were and were not screened on a regular basis. RESULTS: Gastric adenocarcinoma occurred 3.44 times more often in men and 8.33 times more often in women than in the same age group of the general population in Korea (176.4/100,000 in men and 67.6/100,000 in women). Except for endoscopic screening, survival had no relation to the primary disease, type of donor, type of immunosuppressive drug, induction therapy, or the presence of rejection. The 5-year survival rates of recipients who were and were not screened by regular gastroscopic surveillance were 100 and 53.6 %, respectively (p = 0.06). CONCLUSIONS: Regular gastric surveillance might be needed for renal transplant recipients with a high risk of gastric malignancy. PMID- 22526048 TI - Effect of chronic anal fissure components on isosorbide dinitrate treatment. AB - BACKGROUND: Chronic anal fissure is diagnosed in the presence of persistent symptoms: The classic triad includes a linear mucosal tear exposing the internal sphincter fibers, hypertrophied anal papilla, and a sentinel skin tag. Thus, chronic anal fissure can be divided into three components: the fissure itself; hypertrophied anal papilla; the sentinel skin tag. Not every chronic anal fissure has all three components; some have two components, and others present with only a persistent fissure. The success rate of medical treatment for chronic anal fissure is reported as 42-86 %. In this study, we intended to observe the effect of said components on healing with isosorbide dinitrate treatment. METHODS: A total of 105 patients with chronic anal fissures were admitted and were divided into three groups. Patients in group I had a single component (only the fissure with a linear mucosal tear exposing the internal sphincter fibers); group II had two components (skin tag or hypertrophied papilla in addition to the fissure); group III had all three components (fissure, skin tag, hypertrophied papilla). Isosorbide dinitrate 0.25 % was applied three times a day. RESULTS: The success rates in the study groups were 93, 74, and 64 %, respectively. The success rate was significantly higher for group I than for groups II and III. CONCLUSIONS: Chronic anal fissure components should be considered when evaluating the success rates of studies reporting the results of various medical treatments. The number of components seems to be an important factor that affects the results of isosorbide dinitrate treatment. PMID- 22526047 TI - MicroRNAs: relevant tools for a colorectal surgeon? AB - Colorectal cancer is the third most common malignancy and cause of cancer-related deaths worldwide. Approximately half of the patients diagnosed with colorectal cancer ultimately die of the condition. Death from colorectal cancer can be prevented by early detection, but unfortunately presentation is often late, with a worse prognosis. Screening by fecal occult blood testing reduces disease specific mortality, but there is a need for sensitive and specific noninvasive biomarkers to facilitate detecting the disease, staging it, and predicting the best therapeutic options. MicroRNAs (miRNAs) are short noncoding RNA sequences that have a crucial role in the regulation of gene expression. They have significant regulatory functions in basic cellular processes, such as cell differentiation, proliferation, and apoptosis. Evidence suggests that miRNAs may function as both tumor suppressors and oncogenes. The main mechanism for changes in the function of miRNAs in cancer cells is due to aberrant gene expression. Accurate discrimination of miRNA profiles between tumor and normal mucosa in colorectal cancer allows definition of specific expression patterns of miRNAs, giving good potential as diagnostic and therapeutic targets. MiRNAs expressed in colorectal cancers are also abundantly present and stable in stool and plasma samples. Their extraction from these three sources is feasible and reproducible. The ease and reliability of determining miRNA profiles in plasma or stool makes them potential molecular markers for colorectal cancer screening. This review summarizes the role miRNAs have in colorectal cancer, highlighting particularly the potential diagnostic, prognostic, and therapeutic implications in the future treatment of the disease. PMID- 22526050 TI - Fast-track surgery improves postoperative clinical recovery and immunity after elective surgery for colorectal carcinoma: randomized controlled clinical trial. AB - BACKGROUND: Few clinical studies or randomized clinical trial results have reported the impact of fast-track surgery on human immunity. This study aimed to investigate the clinical and immune impact of fast-track surgery in colorectal cancer patients undergoing elective open surgery. METHODS: A controlled randomized clinical trial was conducted from November 2008 to January 2009 with a 1-month postdischarge follow-up. A total of 70 patients with colorectal carcinoma requiring colorectal resection were randomized into two groups: a fast-track group (35 cases) and a conventional care group (35 cases). All included patients underwent elective open colorectal resection with combined tracheal intubation and general anesthesia. Clinical parameters and markers of immune function were evaluated in both groups postoperatively. RESULTS: In all, 62 patients completed the study: 32 in the fast-track group and 30 in the conventional care group. Our findings revealed a significantly shorter postoperative hospital stay and faster return of gastrointestinal function in patients undergoing fast-track rehabilitation. In addition, we found a quicker response of white blood cells in the fast-track group than in the conventional care group. We also found that blood levels of globulin, immunoglobulin G, and complement 4 on postoperative day 3 were higher in the fast-track group than in the conventional care group. CONCLUSIONS: Fast-track surgery accelerates clinical recovery and improves postoperative immunity after elective open surgery for colorectal carcinoma. PMID- 22526051 TI - Intraoperative blood transfusion contributes to decreased long-term survival of patients with esophageal cancer: comments on regression model estimation. PMID- 22526053 TI - Towards an integrated echocardiographic assessment of valvular mechanics by three dimensional volumetric imaging. PMID- 22526054 TI - Non-cardiac findings: now you see them... PMID- 22526055 TI - Our board: charting a path to the future. PMID- 22526056 TI - Observations of sonographer participants on the ASE Global: Focus on India Outreach Trip. PMID- 22526057 TI - Vascular medicine in Singapore: an infant that is growing. PMID- 22526059 TI - Re: bovine aortic arch: a novel association with thoracic aortic dilation. PMID- 22526060 TI - [Vascular diseases of the spinal cord]. PMID- 22526062 TI - [New treatment strategies for intraventricular hemorrhage]. AB - The presence of additional intraventricular hemorrhage (IVH) in patients with intracerebral hemorrhage (ICH) is associated with a much higher mortality and worse functional outcome. Although evidence-based specific treatment options for this entity are still lacking, knowledge about the pathophysiology of IVH has grown in recent decades, leading to the development of promising treatment strategies. Intraventricular fibrinolysis (IVF) accelerates IVH resolution and removal from the ventricular system. The additional usage of lumbar drains probably reduces the incidence of permanent posthemorrhagic hydrocephalus. The influence of these treatment modalities on functional outcome is currently being investigated in ongoing studies. The present article gives an overview of pathophysiological and clinical aspects of IVH, emphasizing novel treatment options. PMID- 22526063 TI - [Emergency trauma room management in severely and most severely injured patients. A multidisciplinary task]. AB - The treatment of most severely injured patients represents a great challenge for the trauma room team. Besides the time factor, which is a crucial cornerstone of the treatment in general and of the appropriate treatment of life-threatening injuries in particular, minor injuries and non-life-threatening injuries must also be taken into account. For this task, multidisciplinary processes play a paramount role. Advanced Trauma Life Support(r), Definitive Surgical Trauma Care and the European Trauma Course represent training concepts, which predefine structured diagnostic and treatment procedures. These concepts allocate the highest treatment priority to injuries that may be immediately fatal for the patient. Besides those life-threatening injuries that are commonly summarised under the term "deathly six", other minor traumas should also be assessed and treated in a structured manner as they may often considerably affect the quality of life after trauma. PMID- 22526065 TI - Present situation and prospect of medical knowledge based systems in German speaking countries: results of an online survey. AB - BACKGROUND: After a decrease of interest in classical medical expert systems, the publication activity concerning the medical application of Artificial Intelligence and the interest in medical decision support have markedly increased. Nonetheless, no systematic exploratory study has yet been carried out, which directly considers the actual fields of applications, exemplary approaches, obstacles, challenges, and future prospect as seen by pioneering users and developers in a given region. OBJECTIVES: This paper reports the results of an online survey designed to fill this gap with the "Knowledge Based Systems" working group of the German Society for Medical Informatics, Biometry and Epidemiology (GMDS) in 2010. METHODS: The survey was based on an online questionnaire (5 single and multiple choice questions, 8 Likert-scaled items, 7 free text questions) consented to by the working group. The answers were analyzed by descriptive statistics and a qualitative analysis (bottom-up coding). All academic institutions of Medical Informatics in the German-speaking countries and contributors reporting KBS-related projects at the relevant scientific conferences and in a journal specialized in the field were invited to participate. RESULTS: The survey reached a response rate of 33.4%. The results show a gap between the reported obstacles of medical KBS (mainly low acceptance and rare use in clinical practice) and their future prospect as stated by the participants. Problems previously discussed in the literature like low acceptance, integration, and sustainability of KBS projects were confirmed. The current situation was characterized by naming exemplary existing systems and specifying promising fields of application. CONCLUSIONS: The field of KBS in medicine is more diversified and has evolved beyond expectations in the German speaking countries. PMID- 22526066 TI - Hyperparathyroidism in the elderly: shifting the focus from bone to brain. PMID- 22526067 TI - Controlled-release oxycodone tablets after transdermal-based opioid therapy in patients with cancer and non-cancer pain. AB - BACKGROUND AND AIMS: Several publications and guidelines stress the efficacy and safety of opioid-based therapy for cancer and non-cancer pain management. The first point of the World Health Organization (WHO) guidelines recommends that, if possible, analgesics should be given by mouth. This advice fully matches the European Society for Medical Oncology (ESMO) guidelines, which advise that opioids should be titrated to take effect as rapidly as possible. The European Association for Palliative Care (EAPC) guidelines specify that transdermal fentanyl should be administered only in patients with stable analgesic requirements. The aim of this study was to assess the efficacy and influence on the quality of life of controlled- release (CR) oxycodone in patients who had obtained no or only partial pain relief after transdermal (TTD)-based opioid therapy. METHODS: Forty-one consecutive patients experiencing persistent cancer and non-cancer related pain and in treatment with transdermal- based opioid therapy for at least 5 days were enrolled in this open-label, multicenter observational study. All patients were switched from transdermal to oral opioid therapy with oxycodone CR for 21 days. Pain intensity was rated on a numeric rating scale (NRS) from 0 to 10 (0=no pain, 10=maximum severity). Patients were asked to rate their perceptions on efficacy and pain interference on the quality of life on an NRS from 0 to 10 (0=no interference, 10=maximum interference). RESULTS: After 3 days with oxycodone CR, pain intensity decreased by 38.83% (p<0.001) and maintained a significant decrease throughout the period (T0-T7: 59.71%, p<0.001; T0-T21: -65.75%, p<0.001). The average daily dose of oxycodone CR increased from 68.75 mg at baseline to 72.39 mg after 7 days and was maintained stable until the study ended. At T0, 56.10% of patients suffered from severe pain (NRS 7- 10); this percentage had decreased to 2.56% at the end of the study. About 7% of patients considered transdermal therapy effective at baseline; after 21 days, 72.22% and 19.44% of patients considered it effective and very effective, respectively. Quality of life improved significantly during the 21 days with the oral treatment (p<0.001). CONCLUSIONS: Switching from transdermal opioid to oxycodone CR treatment is effective and leads to patients' improved satisfaction and quality of life. PMID- 22526068 TI - Changes in skin mechanical properties after long-term application of cream containing green tea extract. AB - BACKGROUND AND AIMS: We studied longterm application of cream containing green tea extract, to obtain knowledge of its effects on epidermal mechanics by 2-mm diameter Cutometer probe. METHODS: Using this non-invasive device, we assessed the effects of green tea extract cream on skin mechanical properties. Healthy male volunteers (n=10) were included in this study, which lasted 60 days. The biomechanical properties of the skin were examined by a non-invasive suction device (Cutometer) and the cheeks were defined as the test area. RESULTS: Statistically significant (p<0.05) results were notable for the R6 (Uv/Ue) parameter with respect to time (ANOVA); R0, R2 (Ua/Uf) and R7 (Ur/Uf) parameters were found statistically not significant by ANOVA. This study demonstrates that green tea formulation has a certain effect on R6 (Uv/Ue) parameter when applied regularly for a certain period of time. CONCLUSIONS: These results indicate that the formulation has no pronounced overall effects on skin elastic or biological properties, but significant R6 (Uv/Ue) values indicate that it does have definite effects on the viscoelastic properties of the skin. PMID- 22526070 TI - Cardiovascular mortality and C-reactive protein in elderly patients beginning dialysis: reverse epidemiology? AB - BACKGROUND AND AIMS: Cardiovascular disease is a major cause of mortality in end stage renal disease patients (ESRD). The rate of elderly and polypathologic patients in ESRD is increasing. Elevated levels of C-reactive protein (CRP) have been shown to be associated with increased mortality in ESRD patients. The aim of this study was to examine whether, in elderly ESRD patients, the conventional relationship between elevated CRP and cardiovascular mortality is maintained. METHODS: This prospective European cohort study included 150 ESRD patients. Data obtained at baseline included demographics, comorbidity, late referral to a nephrologist, high-sensitivity CRP, and serum albumin and hemoglobin levels. Cardiovascular events were analysed as a combined end-point. RESULTS: The mean age of the cohort was 61 years (22-90), with 33.3% of patients over 70 years (75 yrs, 70-83 yrs). Forty-two patients (28.2%) experienced at least one cardiovascular event. Interaction between age over 70 years and CRP exceeding 3 mg/L was a protective factor. Patients over 70 years beginning dialysis with a CRP value <3 mg/L had a higher cardiovascular risk than those with a CRP value >3 mg/L. Multivariate analysis showed that the independent risk factors for cardiovascular events were, in the whole cohort, age over 70 years, previous cardiovascular comorbidity, and interaction between age and CRP. CONCLUSIONS: This trial shows a reverse relation between cardiovascular risk in dialysis patients over 70 and CRP level. This may be a useful element in evaluating older patients before long-term dialysis. PMID- 22526069 TI - Comorbid cognitive impairment and functional trajectories in low vision rehabilitation for macular disease. AB - BACKGROUND AND AIMS: Comorbid cognitive impairment is common among visually impaired older adults. This study investigated whether baseline cognitive status predicts functional trajectories among older adults in low vision rehabilitation (LVR) for macular disease. METHODS: The Telephone Interview for Cognitive Status modified (TICS-m) was administered to macular disease patients aged >= 65 years receiving outpatient LVR. Mixed models assessed the rate of change in instrumental activities of daily living and visual function measures over a mean follow-up of 115 days. RESULTS: Of 91 participants, 17 (18.7%) had cognitive impairment (TICS-m score <= 27) and 23 (25.3%) had marginal impairment (TICS-m scores 28 to 30). Controlling for age and gender, baseline cognitive status did not predict most functional outcomes. However, participants with marginal cognitive impairment experienced worse functional trajectories in ability to prepare meals (p=0.03) and activities that require distance vision (p=0.05). CONCLUSION: Patients with mild to moderate cognitive impairment should not be excluded from LVR, but programs should be prepared to detect and accommodate a range of cognitive ability. PMID- 22526071 TI - Association between disease-related factors and balance and falls among the elderly with COPD: a cross-sectional study. AB - BACKGROUND AND AIMS: To investigate the relationship between disease-related factors and balance, and a history of falls in chronic obstructive pulmonary disease (COPD). METHODS: Thirty-six patients with COPD and twenty healthy individuals were studied. Pulmonary function (pulmonary function test), hypoxemia (analysis of arterial blood gases), history of falls and tripping (number of falls and tripping in the past year), balance (Berg's Balance Scale-BBS), quadriceps femoris muscle strength (manual muscle test), and exercise capacity (6 minute walking test-6MWT) were assessed. RESULTS: BBS scores were significantly different between groups (p=0.001). BBS scores, frequency of falls and tripping were correlated in COPD patients (p <= 0.01). BBS score and frequency of falls were correlated with dyspnea and peripheral oxygen saturation measured after the 6MWT, partial arterial oxygen pressure, and arterial oxygen saturation values in COPD patients (p<0.05). CONCLUSIONS: According to our results, hypoxemia, dyspnea and fatigue are disease- related factors, which are related with balance impairment and falls in COPD patients. For this reason, we suggest that assessment of and training to improve balance impairment among the elderly with COPD should be a component of pulmonary rehabilitation programs in clinical practice. PMID- 22526072 TI - Measurement error and minimum detectable change in 4-meter gait speed in older adults. AB - BACKGROUND AND AIMS: Gait speed is a commonly-used assessment and outcomes measure in geriatric clinical and research settings. Although relative reliability of usual gait speed has been well studied in community- dwelling older adults, less emphasis has been placed on a measure of absolute reliability (the standard error of measurement [SEM]), and on an associated clinically relevant index of real change in gait speed, minimum detectable change (MDC). The purpose of this study was to quantify measurement error and MDC for usual gait speed over 4 meters in community-dwelling older adults ambulating at intermediate and fast speeds. METHODS: Community-dwelling older adults ambulating at intermediate gait speed (IGS), (n=15, mean age 74.2 yrs) and fast gait speed (FGS), (n=15, mean age 72.1) were included in this study. Participants performed two trials of gait speed over a distance of 4 meters. SEM and MDC at the 95% confidence level (MDC95) were computed for the IGS and FGS groups. RESULTS: Mean gait speed was 85.4 cm/s (IGS) and 129.9 cm/s (FGS). Measurement error (<5% of mean gait speed) and minimum detectable change (<13% of mean gait speed) were low in both groups. MDC95 was computed as 10.8 cm/s and 14.4 cm/s for the IGS and FGS groups, respectively. CONCLUSIONS: To be considered real change beyond the bounds of measurement error, change in 4-meter gait speed should exceed 10.8 cm/s (for intermediate speed ambulators) or 14.4 cm/s (for fast speed ambulators). Low measurement error in assessing 4-meter gait speed in community-dwelling older adults suggests that gait speed assessed over short distances has excellent reproducibility across trials. Low minimum change values suggest that 4-meter gait speed may be responsive and sensitive to change. PMID- 22526073 TI - Prediction of functional decline in older hospitalized patients: a comparative multicenter study of three screening tools. AB - BACKGROUND AND AIMS: Older hospitalized patients are at risk of functional decline, which is associated with several negative outcomes. The aim of this study was to compare the predictive accuracy of the Identification of Seniors At Risk (ISAR), Variable Indicative for Placement risk (VIP) and the Flemish version of the Triage Risk Screening Tool (TRST) in predicting functional decline. METHODS: A prospective cohort study with 30 days follow-up in geriatric, medical and surgical wards in 25 hospitals was conducted. 752 participants aged 75 years or older were eligible for inclusion. Baseline data were gathered within 72 hours of admission. Functional decline was defined as an increase of one point or more from the premorbid Katz score to the score 30 days post-discharge. Positive predictive value (PPV) and negative predictive value (NPV) were calculated on 2 x 2 tables as well as by Bayes' theorem. RESULTS: Functional decline at 30 days postdischarge was observed in 279 participants (39%). ISAR and Flemish TRST showed high sensitivity (88% - 78%) and fair NPV (62% - 67%), but low specificity (19% - 30%) and low PPV (47% - 48%) using the original cut-off of >= 2. The sensitivity of VIP with cut-off >= 2 was too low (62%), but could be optimized with cut-off >= 1, showing sensitivity, specificity, PPV and NPV of 88%, 21%, 48% and 68%, respectively. Accuracy varied between 40% and 61% for all instruments on all calculated cut-offs. CONCLUSIONS: All three instruments performed similarly well, showing good sensitivity and fair NPV, the two major characteristics for good screening tools. False positives could be filtered out according to the clinical expert opinion of a care team. PMID- 22526074 TI - Opportunities to improve healthcare outcomes for elderly people and reduce re hospitalization. PMID- 22526075 TI - Daily and hourly frequency of the sit to stand movement in older adults: a comparison of day hospital, rehabilitation ward and community living groups. AB - BACKGROUND AND AIMS: The sit to stand (STS) movement is commonly performed in daily life, and can be used as an indicator of activity. This study aimed to quantify the usual frequency and distribution of the STS movement performed by older adults in both home and rehabilitation settings. METHODS: Three groups of older adults were recruited; healthy older adults living in the community, older adults living in the community attending rehabilitation services at a day hospital, and frail older patients in a rehabilitation ward. Participants wore an activity monitor, which reported posture continuously for a week. The number of STS movements was the primary outcome measure, and mean values of daily STS frequency were reported. The pattern of activity was investigated using median values of STS hourly rate. RESULTS: Healthy older adults living in the community performed significantly more STS movements per day (n=20; 71+/-25) than either older adults attending a day hospital (n=20; 57+/-23) or frail older patients in a rehabilitation ward (n=30; 36+/-16). For all participants, the hourly rate of STS movements ranged from zero to 48, although the median hourly rate was two (healthy older adults) and one (both rehabilitation groups). CONCLUSION: Measurement of the number of STS movements performed over the course of a week in three groups of older adults, demonstrated significant differences in daily number of STS movements and in the hourly pattern between the groups. Activity patterns can provide additional information on clinically relevant aspects of physical activity and function to daily averages. PMID- 22526076 TI - Admission Norton scale scores correlate with rehabilitation outcome and length in elderly patients following cerebrovascular accident. AB - AIMS: To determine whether Norton scale scores used for evaluating pressure sore risk also correlate with rehabilitation outcome and length following cerebrovascular accident (CVA) in elderly patients. METHODS: A retrospective study was conducted at a geriatric rehabilitation department in a tertiary medical center during 2009. The medical charts of consecutive elderly (>=65 years) patients admitted for rehabilitation after CVA were studied for the following measurements: admission Norton scale scores, admission albumin serum levels, mini-mental status examination (MMSE) scores, discharge walking functional independence measure (FIM) scores, discharge transfer FIM scores, and rehabilitation length in days. RESULTS: The cohort included 110 patients, 64 (58.2%) women and 46 (41.8%) men. The mean age of the entire group was 80.5+/-7.4 years. Most patients had ischemic CVA (90.9%) and a first CVA (79.1%). The mean discharge walking FIM score was 4.7+/-1.4, the mean discharge transfer FIM score was 5.0+/-1.4, and the mean length of rehabilitation was 28.2+/-15.3 days. Admission Norton scale scores correlated with discharge walking FIM scores (r=0.51; p<0.0001), discharge transfer FIM scores (r=0.43; p<0.0001), and length of rehabilitation (r=-0.45; p<0.0001) after adjustment for age, albumin serum levels, and MMSE scores. Linear regression analysis showed that admission Norton scale scores were associated (p<0.0001) with the discharge walking FIM scores, the discharge transfer FIM scores and rehabilitation length, independent of age, gender, albumin serum levels, MMSE scores, type of CVA, and the appearance of pressure sores. CONCLUSIONS: The Norton scoring system may be used to predict the outcome and duration of rehabilitation in elderly patients after CVA. PMID- 22526077 TI - Depressive symptoms and fear of falling in previously community-dwelling older persons recovering from proximal femoral fracture. AB - BACKGROUND AND AIMS: Depression and fear of falling are common problems following proximal femoral fracture. The role of fear of falling in depressive symptoms after such a fracture has not yet been investigated. The aim of this study was to establish possible changes during recovery in fear of falling and depressive symptoms following rehabilitation in this population and to explore their association. METHODS: Observational study with pre-post design at a single geriatric rehabilitation hospital in Germany. Data were collected during in hospital rehabilitation and four months later at participants' home. The data of 51 participants living in the community at the time of fracture could be analysed. MAIN MEASURES: Fear of falling, depressive symptoms, cognition, pain, ADL functioning, and physical performance. RESULTS: Although physical and ADL performance improved between admission to rehabilitation and follow-up four months later, the prevalence of depressive symptoms increased, and levels of fear of falling remained at the same level. There was a significant correlation between fear of falling and depressive symptoms at follow-up, but the two were not significantly correlated at baseline. Fear of falling and depressive symptoms were not significantly associated in a path analysis model. CONCLUSIONS: Fear of falling and depressive symptoms are highly prevalent after proximal femoral fracture. Yet there seems to be no simple association between either psychological parameter in older persons recovering from fall-related fractures. Further research is warranted, in order to develop interventions targeting these psychological outcomes. PMID- 22526078 TI - Hand osteoarthritis in longevity populations. AB - BACKGROUND AND AIMS: Previous studies have reported that centenarians escape the major agerelated diseases. No studies on prevalence and severity of osteoarthritis (OA) in longevity population have previously been reported. Because OA is associated with morbidity and mortality, we hypothesized that radiographic hand OA would generally be less prevalent and would develop at a later age in longevity populations vs non-longevity populations. Aim was to evaluate the prevalence and mode of development of radiographic hand OA in three longevity populations (Abkhazians, Azerbaijanis and Georgians) and in one non longevity population (Russians). METHODS: Crosssectional observational study. Longevity index was calculated as a ratio of the number of individuals aged >90 years vs the number of people aged >60, expressed per mil (0/00). A population with longevity index >400/00was considered as a longevity population. Radiographic hand OA was evaluated using the left hand radiograms in 14 joints according to Kellgren and Lawrence's (K-L) grading system. Each individual was characterized by the total number of affected (K-L>=2) joints (NAJ). Prevalence of hand OA was defined as the presence of at least one affected joint. Statistical analyses included prevalence estimation, linear, logistic and polynomial regressions, and ANOVA. RESULTS: A significant difference (p<0.003) in age standardized prevalence of hand OA was found between each pair of studied samples, except between Russians and Georgians and between Azerbaijanis and Abkhazians (p>0.05). The lowest age-standardized prevalence was found in Abkhazians, followed by Azerbaijanis and Georgians. The highest prevalence was found in Russians. ANOVA showed significant differences (p<0.01) between the age adjusted means of NAJs. The lowest age-adjusted NAJ was found in the Abkhazian population, followed by Azerbaijanis and Georgians. The highest NAJ was found in Russians. CONCLUSIONS: We observed that the pattern of radiographic hand OA in longevity populations differs from the pattern in non-longevity populations. On average, first joints with OA appear at an older age, and progression of hand OA, measured by NAJ, is slower. PMID- 22526079 TI - An epidemiological study of Alzheimer's disease in elderly Mongolian and Han populations living in rural areas of Inner Mongolia. AB - BACKGROUND AND AIMS: This study investigated the current status and distribution of Alzheimer's disease (AD) among Mongolian and Han individuals who were at least 55 years old and living in rural areas of Inner Mongolia. This study sought to provide basic epidemiological data to better understand and treat Alzheimer's disease. METHODS: Individuals with AD who were at least 55 old and living in one of 27 communities and two settlements in Mongolia, took part in an AD epidemiological survey from June 2008 to June 2009. Stratified, multistage random cluster sampling was used to analyze data. The first level of random-cluster sampling consisted of data collected from questionnaires and home-visit interviews of individuals living in four Qi (a county level administration region in Mongolia) and in one city in the Xilin Guole League. Data from individuals in four district offices and ten towns from the first level random-cluster formed the second level of random-cluster sampling. RESULTS: The final sample for this epidemiological investigation consisted of 9266 individuals. Analyses revealed that the prevalence rate of AD was 4.79% (SD=4.71%) in the combined Mongolian and Han populations of individuals at least 55 years old and living in rural areas of Inner Mongolia. The individual AD prevalence rates in the Mongolian and Han populations were 4.63% (SD=4.84%) and 4.89% (SD=4.60%), respectively. The AD prevalence rate for women was higher than for men (p<0.05). The AD prevalence rate for individuals aged 65 and older in the two combined populations was 8.06% (SD=8.55%); the rate in the Mongolian population was 7.81% (SD=8.38%) and 8.18% (SD=8.57%) in the Han population. Gender and age were risk factors for the development of AD (p<0.05) in both populations. CONCLUSIONS: 1) There was no significant difference in the AD prevalence rate between the Mongolian and Han populations consisting of individuals aged 55 and older, living in rural areas of Inner Mongolia. However, the AD prevalence rates in these populations were higher than the national average. 2) Gender and age were risk factors for the development of AD in the Mongolian and Han populations. PMID- 22526080 TI - Validity of the interRAI Acute Care based on test content: a multi-center study. AB - BACKGROUND AND AIMS: The MDS inter- RAI Acute Care is a comprehensive geriatric assessment tool for hospitalized older persons. The aim was to examine its validity based on test content by use in daily clinical practice. METHODS: Clinical staff of multiple disciplines assessed 256 older persons (83.2+/-5.2 years; 60% female) in a cross-sectional multicenter study in nine acute hospitals. Test content was empirically tested by frequency distribution of clinical deficits, missing, and invalid data. Item relevance was quantified by the content validity index (CVI) and modified kappa statistics (kappa*) based on assessors' judgment. RESULTS: Clinical deficits exceeded 30% in the majority of items (67%) across all assessment periods. Mean missing data for premorbid, admission, day-14 and discharge assessments were 9.7%, 5.3%, 29.3% and 13.7%, respectively. Invalid scores ranged from 3.9% to 26.7%. Of the 98 items, 82 had excellent CVI (>=0.78). Item relevance was excellent for 82 (kappa*>=0.75), good for 9 (0.60<=kappa*<=0.74) and fair for 3 items (0.40<=kappa*<0.60). Item revision may optimize clinical relevance: removing 4 items with poor relevance would increase the overall CVI from 0.89 to 0.91, meeting the standard of excellent content validity (CVIaverage>=0.90). CONCLUSIONS: Although the frequency distribution provides evidence that item selection of the interRAI Acute Care is appropriate for the targeted population, its use in a clinical context reveals a substantial number of missing and invalid data. To improve validity, training should pay specific attention to items with low compliance and invalid records. Software applications should also be designed to improve data quality. PMID- 22526081 TI - Assessment of working-memory deficits in patients with mild cognitive impairment and Alzheimer's dementia using Wechsler's Working Memory Index. AB - BACKGROUND AND AIMS: Although episodic memory deficits are a hallmark in mild cognitive impairment (MCI) and Alzheimer's dementia (AD), little attention has been paid so far to the ability to maintain and manipulate information during a brief period of time, i.e. working memory. In this study, we examine verbal working memory in both cognitively unimpaired older people and MCI and AD patients. METHODS: Seventy- five participants were examined with either no cognitive impairment (n=25), MCI (n=25) or AD (n=25). Working memory was investigated with Wechsler's Working Memory Index tests (Digit Span, Letter Number Sequencing and Arithmetic). RESULTS: Both MCI and AD patients performed worse on all three working-memory tests compared with controls, the subtest Letter-Number Sequencing also revealing worse performance in AD compared with MCI patients. CONCLUSIONS: Workingmemory deficits are already present in MCI patients and worsen in AD patients, suggesting that working memory should be assessed as part of neuropsychological testing. PMID- 22526082 TI - Geriatric assessment of a giant splenic artery aneurysm accidentally diagnosed. AB - Giant splenic artery aneurysms (GSAAs) larger than 8 cm in diameter have rarely been reported, particularly in older people. They are clinically important lesions, often asymptomatic and related to an increased risk of complications such as abrupt rupture, requiring emergency surgical treatment. Comprehensive geriatric assessment (CGA), originally developed for multidimensional clinical evaluation in several geriatric settings, was recently proposed as a fundamental preoperative aid for treatment planning of older patients undergoing elective surgery and preventing adverse post-operative outcomes. We present the first case of an asymptomatic 9-cm partially thrombosed GSAA, accidentally diagnosed during abdominal ultrasound in a 63-year-old woman from the Apulia region in Southern Italy. She successfully underwent aneurysmectomy, highlighting the usefulness of CGA in elective surgical patients. PMID- 22526083 TI - A rare but significant cause of priapism in the elderly: multiple myeloma. AB - Priapism is a rare symptom with diverse etiological factors. Although most cases in adults are secondary to drug use and intracavernosal injections, blood dyscrasias and hypercoagulable states, vasculitis, penile metastases, neurological conditions, spider bites, carbon monoxide poisoning, and total parenteral nutrition may also result in priapism. We report a case of recurrent and refractory priapism in a 61-year-old man which was diagnosed as multiple myeloma after emergence of hypercalcemia and renal failure due to progression of the underlying pathology. The value of the initial diagnostic approach is emphasized. PMID- 22526084 TI - Spinal anterior epidural hematoma in an elderly man with unrecognized lupic anticoagulant taking warfarin. AB - Spinal epidural hematoma (SEH) is a rare acute condition defined as a hematoma occurring at spinal epidural level. It is defined as "spontaneous" (SSEH) when possible causes have been ruled out; in other cases, clotting disorders and systemic lupus erythematosus have been associated with SEH. If identified rapidly, SEH can be completely cured, with complete recovery in about 50% of cases. We describe the case of an 86-year-old man affected by SEH, with rare anterior location, presenting with painful paraparesis and bladder dysfunction. The patient was taking warfarin for chronic atrial fibrillation. A prolongation of partial thromboplastin time was observed, consistent with the presence, in plasma, of previously unrecognized lupus anticoagulant antibodies (LA). The diagnosis of SEH was confirmed by MRI, and the patient was not surgically treated. Following a rehabilitation program, the patient had complete neurological recovery. Although the epidural lesion might have been a true case of SSEH, anticoagulation therapy and AL may have played a role in the pathogenesis, spread and spontaneous resolution of SEH. In cases of acute thoracic pain, associated with signs and symptoms of spinal cord compression, the diagnosis of SEH, which is a potentially devastating condition, must be carefully investigated by clinicians. PMID- 22526085 TI - Association of past diseases with levels of cadmium and tubular dysfunction markers in urine of adult women in non-polluted areas in Japan. AB - BACKGROUND AND OBJECTIVES: Whereas information has been accumulating on the association of anemia and other diseases with cadmium (Cd) burden, histories of past diseases of the examinees are often not taken in account when the results of health examination are evaluated for cadmium exposure-related health effects on general populations. The present study was initiated to examine the possible association of previous diseases with Cd exposure parameters, taking advantage of compiled data on adult women. METHODS: Data were cited from previous publications of this research group on Cd, alpha1-microglobulin (alpha1-MG), beta2 microglobulin (beta2-MG), N-acetyl-beta-D-glucosaminidase (NAG) and urine density makers (i.e., creatinine and specific gravity) in the urine of more than 17,000 adult women in non-polluted areas in Japan. Information on previous disease history together with age and smoking habits was obtained by self-administered questionnaires, and 13,031 never-smoking women were selected for the present analyses. To compare the cases with disease history, control cases were randomly selected after stratification by 5 years of age at a ratio of one case to three controls from those with no disease history; summation for all age strata made up the control groups for the disease group in concern. The random sampling to set up control groups was repeated three times in total. The difference between the disease group and control groups was considered valid in cases the difference was statistically significant (p ? 0.05), in all three cases after correction (or non correction) for urine density, and the same results were obtained when compared with the three different control groups. RESULTS: In the anemia group, Cd-U was higher over corresponding three control groups, although none of alpha1-MG-U, beta2-MG-U or NAG-U showed significant changes. In the diabetes mellitus group, NAG-U was higher than in the controls, but such differences were not observed in Cd-U or beta2-MG-U. The elevation in alpha1-MG-U was not reproducible. In the case of the hypertension group, the elevations in Cd-U, alpha1-MG-U, and beta2-MG U were observed, but changes in NAG-U could not be confirmed. In the analysis of dose-response relationship, the diabetes mellitus group showed increases in the slope for beta2-MG-U and in the intercept for NAG-U. No changes in dose-response relationship were observed in other disease groups as compared with the corresponding control groups. CONCLUSIONS: Care should be taken in evaluating Cd related health examination results for those with history of diseases such as hypertension, anemia and diabetes mellitus in particular. PMID- 22526086 TI - Autonomic nerve system responses for normal and slow rewarmers after hand cold provocation: effects of long-term cold climate training. AB - PURPOSE: Differences among individuals concerning susceptibility to local cold injury following acute cold exposure may be related to function of the autonomic nervous system. We hypothesized that there are differences in heart rate variability (HRV) between individuals with normal or more pronounced vasoconstriction following cold exposure and that there is an adaptation related to prolonged cold exposure in autonomic nervous system response to cold stimuli. METHODS: Seventy-seven young men performed a cold provocation test, where HRV was recorded during cold hand immersion and recovery. Forty-three subjects were re examined 15 months later, with many months of cold weather training between the tests. Subjects were analyzed as 'slow' and 'normal' rewarmers according to their thermographic rewarming pattern. RESULTS: For the 'pre-training' test, before cold climate exposure, normal rewarmers had higher power for low-frequency (PLF) and high-frequency (PHF) HRV components during the cold provocation test (ANOVA for groups: p = 0.04 and p = 0.005, respectively). There was an approximately 25 % higher PHF at the start in normal rewarmers, in the logarithmic scale. Low frequency-to-high frequency ratio (PLF/PHF) showed lower levels for normal rewarmers (ANOVA for groups: p = 0.04). During the 'post-training' cold provocation test, both groups lacked the marked increase in heart rate that occurred during cold exposure at the 'pre-training' setting. After cold acclimatization (post-training), normal rewarmers showed lower resting power values for the low-frequency and high-frequency HRV components. After winter training, the slow rewarmers showed reduced low-frequency power for some of the cold provocation measurements but not all (average total PLF, ANOVA p = 0.05), which was not present before winter training. CONCLUSIONS: These HRV results support the conclusion that cold adaptation occurred in both groups. We conclude that further prospective study is needed to determine whether cold adaptation provides protection to subjects at higher risk for cold injury, that is, slow rewarmers. PMID- 22526087 TI - Effectiveness of cleaning of workplace cytotoxic surface. AB - PURPOSE: To minimize the risk of chronic occupational exposure of antineoplastic drugs, cleaning procedures must be evaluated. This study was conducted to compare the detergent efficiency of cleaning solutions (two hydro-alcoholic solutions, three disinfectants and two detergents) used in different cleaning protocols. METHODS: The central surface of a stainless steel plate (30 * 50 cm) was exposed to a carboplatin solution equivalent to 105,100 ng of platinum. After cleaning according to a standardized protocol, residual platinum contaminations were assayed on 10 * 10 cm sections. RESULTS: After standardized cleaning, the residual quantity of platinum on the surface of the deposit accounted for between 1.0 and >15 % of the initial deposit. Spread of contamination on the plate depended on the cleaning movement and was between 2.1 and 53.9 % of the total quantity on the plate. The two detergents were more efficient (2,793-4,780 ng/plate) than hydro-alcoholic solutions (>20,000 ng/plate). The efficacy of the disinfectant was intermediate (5,891-6,122 ng/plate for solutions and 15,360 ng/plate for pre-soaked gauze). The cleaning protocol was also important with better efficiency of 8 mL of cleaning solution for 1,500 cm(2) (versus 4 mL), sprayed directly on the plate (versus wiping) with no contact time (versus 5 min). CONCLUSION: The efficacy of chemical decontamination of cytotoxic work surfaces depends not only on the cleaning solution used, but also on the cleaning protocol. It is necessary to adapt the protocol to the surface to clean and it must be standardized and validated. This work is an example of an experimental procedure to evaluate the efficacy of cleaning solutions and protocols used at a workstation after exposure to antineoplastic drugs. PMID- 22526088 TI - The role of perceived pollution and health risk perception in annoyance and health symptoms: a population-based study of odorous air pollution. AB - OBJECTIVES: Health effects associated with air pollution at exposure levels below toxicity may not be directly related to level of exposure, but rather mediated by perception of the air pollution and by top-down processing (e.g., beliefs that the exposure is hazardous). The aim of the study was to test a model that describes interrelations between odorous air pollution at non-toxic exposure levels, perceived pollution, health risk perception, annoyance and health symptoms. METHODS: A population-based questionnaire study was conducted in a Swedish community of residents living near a biofuel facility that emitted odorous substances. Individuals aged 18-75 years were selected at random for participation (n = 1,118); 722 (65 %) agreed to participate. Path analyses were performed to test the validity of the model. RESULTS: The data support a model proposing that exposure level does not directly influence annoyance and symptoms, and that these relations instead are mediated by perceived pollution and health risk perception. CONCLUSIONS: Perceived pollution and health risk perception play important roles in understanding and predicting environmentally induced annoyance and health symptoms in odorous environments at non-toxic levels of exposure. PMID- 22526090 TI - The association between health and sickness absence among Danish and non-Western immigrant cleaners in Denmark. AB - PURPOSE: The aim of the study is to investigate the association between health and sickness absence among Danish and non-Western immigrant cleaners in Denmark. METHODS: This study is based on a cross-sectional analysis of baseline data from 2007 to 2008. The study population includes 276 cleaners, 144 Danish and 132 non Western immigrant cleaners. Cumulative sickness absences during a 6-month period from administrative records were subdivided into no sickness absence (0 days), low occurrence of sickness absence (1-10 days) and high occurrence of sickness absence (over 10 days). Measures of health consisted of self-report and objective assessments. The relationship between sickness absence and health was analyzed through multinomial logistic regression, stratified by immigrant status. RESULTS: For both Danish and non-Western immigrant cleaners, poor self-reported health was significantly related to high occurrence of sickness absence. Among Danish cleaners, high blood pressure was related to high occurrence of sickness absence. Among non-Western immigrant cleaners, total body pain and having one or more diagnosed chronic disease were related to high occurrence of sickness absence. No association between health and low occurrence of sickness absence was found. CONCLUSIONS: The findings confirm the importance of health for high occurrence of sickness absence, in both ethnic groups. Moreover, low occurrence of sickness absence was not related to the health conditions investigated. PMID- 22526089 TI - Burnout syndrome in seafarers in the merchant marine service. AB - PURPOSE: As seafarers face a wide range of psychosocial stressors on board, they may be endangered to develop burnout syndrome. This study aims to investigate respective indicators. METHODS: In a cross-sectional study, 251 seafarers were asked about demographic data and job-related stressors. Particularly, the subscale emotional exhaustion (EE) of the Maslach Burnout Inventory and the Epworth Sleepiness Scale were used to assess the respective risks of job-related burnout and daytime sleepiness among seafarers. The statistical analysis was carried out using multiple logistic regression. RESULTS: Within the whole study group, the EE score was elevated in 10.8 %. A higher EE score was found in 10.7 % of officers, in 4.5 % of lower crew ranks and in 25.0 % of the galley staff (p = 0.05). Furthermore, long working days were associated with an elevated EE score [OR 3.83 (CI 1.46-10.03)]. Emotional exhaustion was associated with a subjective perception of enough sleep on board [OR 3.33 (CI 1.17-9.46)], lack of care taken by the shipboard superiors and/or the shipping company [OR 1.19 (CI 1.04-1.36)], with high responsibility for work organisation of those involved in leadership [OR 1.46 (CI 1.20-1.78)] and with social problems due to the long periods of separation from their families [OR 1.19 (CI 1.02-1.39)], taking into account relevant demographic parameters. CONCLUSIONS: Compared with the majority of on shore occupations, the burnout risk in seafaring seems to be moderate. To reduce the EE among seafarers, it is recommended to extend the sleeping time, to avoid long working hours, to improve the superiors' communication and leadership skills, to diminish the superiors' stress load caused by organisational duties and to support low-price telecommunication possibilities at home. PMID- 22526091 TI - Positioning of the sensor cell on the sensing area using cell trapping pattern in incubation type planar patch clamp biosensor. AB - Positioning the sensor cell on the micropore of the sensor chip and keeping it there during incubation are problematic tasks for incubation type planar patch clamp biosensors. To solve these problems, we formed on the Si sensor chip's surface a cell trapping pattern consisting of a lattice pattern with a round area 5 MUm deep and with the micropore at the center of the round area. The surface of the sensor chip was coated with extra cellular matrix collagen IV, and HEK293 cells on which a chimera molecule of channel-rhodopsin-wide-receiver (ChR-WR) was expressed, were then seeded. We examined the effects of this cell trapping pattern on the biosensor's operation. In the case of a flat sensor chip without a cell trapping pattern, it took several days before the sensor cell covered the micropore and formed an almost confluent state. As a result, multi-cell layers easily formed and made channel current measurements impossible. On the other hand, the sensor chip with cell trapping pattern easily trapped cells in the round area, and formed the colony consisted of the cell monolayer covering the micropore. A laser (473 nm wavelength) induced channel current was observed from the whole cell arrangement formed using the nystatin perforation technique. The observed channel current characteristics matched measurements made by using a pipette patch clamp. PMID- 22526092 TI - Quantification of bias in direct effects estimates due to different types of measurement error in the mediator. AB - Assessing whether the effect of exposure on an outcome is completely mediated by a third variable is often done by conditioning on the intermediate variable. However, when an association remains, it is not always clear how this should be interpreted. It may be explained by a causal direct effect of the exposure on the disease, or the adjustment may have been distorted due to various reasons, such as error in the measured mediator or unknown confounding of association between the mediator and the outcome.In this paper, we study various situations where the conditional relationship between the exposure and the outcome is biased due to different types of measurement error in the mediator. For each of these situations, we quantify the effect on the association parameter. Such formulas can be used as tools for sensitivity analysis or to correct the association parameter for the bias due to measurement error. The performance of the bias formulas is studied by simulation and by applying them to data from a case control study (Leiden Thrombophilia Study) on risk factors for venous thrombosis. In this study, the question was the extent to which the relationship between blood group and venous thrombosis might be mediated through coagulation factor VIII. We found that measurement error could have strongly biased the estimated direct effect of blood group on thrombosis. The formulas we propose can be a guide for researchers who find a residual association after adjusting for an intermediate variable and who wish to explore other possible explanations before concluding that there is a direct causal effect. PMID- 22526095 TI - Phenotypic and functional characterization of endothelial colony forming cells derived from human umbilical cord blood. AB - Longstanding views of new blood vessel formation via angiogenesis, vasculogenesis, and arteriogenesis have been recently reviewed. The presence of circulating endothelial progenitor cells (EPCs) were first identified in adult human peripheral blood by Asahara et al. in 1997 bringing an infusion of new hypotheses and strategies for vascular regeneration and repair. EPCs are rare but normal components of circulating blood that home to sites of blood vessel formation or vascular remodeling, and facilitate either postnatal vasculogenesis, angiogenesis, or arteriogenesis largely via paracrine stimulation of existing vessel wall derived cells. No specific marker to identify an EPC has been identified, and at present the state of the field is to understand that numerous cell types including proangiogenic hematopoietic stem and progenitor cells, circulating angiogenic cells, Tie2+ monocytes, myeloid progenitor cells, tumor associated macrophages, and M2 activated macrophages participate in stimulating the angiogenic process in a variety of preclinical animal model systems and in human subjects in numerous disease states. Endothelial colony forming cells (ECFCs) are rare circulating viable endothelial cells characterized by robust clonal proliferative potential, secondary and tertiary colony forming ability upon replating, and ability to form intrinsic in vivo vessels upon transplantation into immunodeficient mice. While ECFCs have been successfully isolated from the peripheral blood of healthy adult subjects, umbilical cord blood (CB) of healthy newborn infants, and vessel wall of numerous human arterial and venous vessels. CB possesses the highest frequency of ECFCs that display the most robust clonal proliferative potential and form durable and functional blood vessels in vivo. While the derivation of ECFC from adult peripheral blood has been presented, here we describe the methodologies for the derivation, cloning, expansion, and in vitro as well as in vivo characterization of ECFCs from the human umbilical CB. PMID- 22526096 TI - Particle-size distribution of polycyclic aromatic hydrocarbons in urban road dust of Masan, Korea. AB - Concentrations and compositions of polycyclic aromatic hydrocarbons (PAHs) in particle size fractions of road dust sampled from contrasting areas of an industrialised city in Korea are reported. The largest amounts of road dust were present in industrial areas, followed by areas subject to heavy traffic, and the lowest amounts were associated with a residential area. The highest concentrations of PAHs were recorded in road dust sampled from the areas with the heaviest traffic (0.45-4.1 MUg/g), followed by industrial areas (0.1-3.56 MUg/g), with the lowest concentrations associated with a residential area (0.32-1.95 MUg/g). PAH concentrations in the fractionated dust from the industrialised areas exhibited an inverse correlation with particle size. Although a similar general pattern was observed in the areas of heavy traffic, some increased concentrations associated with larger particles possibly reflect petrogenic contributions. Particles in road dusts from the residential area were generally smaller than those from the other areas, with PAH composition dominated by pyrogenic sources. PAH compositional profiles, evaluated through diagnostic isomeric ratios, indicate that exhaust emissions, rather than crankcase oils or tire and asphalt abrasion, are the major polluting source. PMID- 22526098 TI - Chemoembolic hepatopulmonary shunt reduction to allow safe yttrium-90 radioembolization lobectomy of hepatocellular carcinoma. AB - Yttrium-90 ((90)Y) radioembolization represents an emerging transcatheter treatment option for the management of hepatocellular carcinoma (HCC). Elevation of the hepatopulmonary shunt fraction risks nontarget radiation to the lungs and may limit the use of (90)Y therapy in patients with locally advanced disease with vascular invasion, who often demonstrate increased shunting. We present two cases in which patients with HCC and portal vein invasion resulting in elevated hepatopulmonary shunt fractions underwent chemoembolic shunt closure to allow safe (90)Y radioembolization. Both patients demonstrated excellent tumor response and patient survival. On this basis, we propose a role for chemoembolic reduction of the lung shunt fraction before (90)Y radioembolization in patients with extensive tumor-related hepatopulmonary shunting. PMID- 22526099 TI - Radioembolization as locoregional therapy of hepatic metastases in uveal melanoma patients. AB - PURPOSE: To retrospectively evaluate the overall survival, safety, and efficacy of metastatic uveal melanoma patients after radioembolization as salvage therapy. MATERIALS AND METHODS: Thirteen patients were treated with radioembolization of branches of the hepatic artery with resin-based yttrium-90 ((90)Y)-labelled microspheres. Twelve patients underwent a single application, and 1 patient underwent 4 interventions. Dosages from 644 to 2,450 MBq (mean activity 1,780) were applied. Treatment response was evaluated by way of liver magnetic resonance imaging and computed tomography (CT) as well as whole-body fluorodeoxyglucose positron emission tomography (PET)/CT with evaluation of percentage changes in SUV(max) before and at 2-3 months after therapy. Kaplan-Meier analysis was calculated to determine overall survival. RESULTS: Partial remission (PR) was observed in 8 (62 %), stable disease (SD) in 2 (15 %), and progressive disease (PD) in 3 (23 %) patients under terms of standard criteria and PR in 3 (23 %), SD in 3 (23 %), and PD in 7 (54 %) patients according to PET criteria. Neither RECIST nor PET criteria showed a significant difference in predicting overall survival (P = 0.12 and 0.11, respectively). Median survival time after radioembolization was 7 months. No acute toxicity with in-hospital morbidity was observed. One patient developed hepatomegaly, and 1 patient developed gastric ulceration. Throughout follow-up, progression of extrahepatic metastases was observed. CONCLUSION: Radioembolization may be a promising therapy in uveal melanoma patients with predominant hepatic metastases. At first follow-up, we observed PR or SD in 77 % patients under terms of standard criteria with an acceptable toxicity profile. PMID- 22526100 TI - Entrapment of guide wire in an inferior vena cava filter: a technique for removal. AB - Entrapment of a central venous catheter (CVC) guide wire in an inferior vena cava (IVC) filter is a rare, but reported complication during CVC placement. With the increasing use of vena cava filters (VCFs), this number will most likely continue to grow. The consequences of this complication can be serious, as continued traction upon the guide wire may result in filter dislodgement and migration, filter fracture, or injury to the IVC. We describe a case in which a J-tipped guide wire introduced through a left subclavian access without fluoroscopic guidance during CVC placement was entrapped at the apex of an IVC filter. We describe a technique that we used successfully in removing the entrapped wire through the left subclavian access site. We also present simple useful recommendations to prevent this complication. PMID- 22526101 TI - Radioembolization after portal vein embolization in a patient with multifocal hepatocellular carcinoma. AB - Radioembolization is an effective locoregional therapy for patients with intermediate or advanced stage hepatocellular carcinoma (HCC). It has been shown that radioembolization is safe in patients with portal vein thrombosis. This case report describes safe radioembolization after portal vein embolization in a patient with multifocal HCC. PMID- 22526102 TI - Pancreaticoportal fistula and disseminated fat necrosis after revision of a transjugular intrahepatic portosystemic shunt. AB - A 59-year old man with alcohol related cirrhosis and portal hypertension was referred for transjugular intrahepatic portosystemic shunt (TIPS) to treat his refractory ascites. Ten years later, two sequential TIPS revisions were performed for shunt stenosis and recurrent ascites. After these revisions, he returned with increased serum pancreatic enzyme levels and disseminated superficial fat necrosis; an iatrogenic pancreaticoportal vein fistula caused by disruption of the pancreatic duct was suspected. The bare area of the TIPS was subsequently lined with a covered stent-graft, and serum enzyme levels returned to baseline. In the interval follow-up period, the patient has clinically improved. PMID- 22526103 TI - Percutaneous retrograde recanalization of the celiac artery by way of the superior mesenteric artery for chronic mesenteric ischemia. AB - A 52-year-old man presented with recurrent postprandial abdominal pain, sitophobia, and progressive weight loss. Chronic mesenteric ischemia (CMI) due to subtotal occlusion of the superior mesenteric artery (SMA) and flush occlusion of the celiac artery (CA) was diagnosed. Retrograde recanalization of the CA by way of a collateral channel from the SMA was performed using contemporary recanalization equipment. The CA and SMA were then stented, resulting in sustained resolution of CMI-related symptoms. PMID- 22526104 TI - Hybrid repair of complex thoracic aortic arch pathology: long-term outcomes of extra-anatomic bypass grafting of the supra-aortic trunk. AB - PURPOSE: Hybrid repair constitutes supra-aortic debranching before thoracic endovascular aortic repair (TEVAR). It offers improved short-term outcome compared with open surgery; however, longer-term studies are required to assess patient outcomes and patency of the extra-anatomic bypass grafts. METHODS: A prospectively maintained database of 380 elective and urgent patients who had undergone TEVAR (1997-2011) was analyzed retrospectively. Fifty-one patients (34 males; 17 females) underwent hybrid repair. Median age was 71 (range, 18-90) years with mean follow-up of 15 (range, 0-61) months. RESULTS: Perioperative complications included death: 10 % (5/51), stroke: 12 % (6/51), paraplegia: 6 % (3/51), endoleak: 16 % (8/51), rupture: 4 % (2/51), upper-limb ischemia: 2 % (1/51), bypass graft occlusion: 4 % (2/51), and cardiopulmonary complications in 14 % (7/51). Three patients (6 %) required emergency intervention for retrograde dissection: (2 aortic root repairs; 2 innominate stents). Early reintervention was performed for type 1 endoleak in two patients (2 proximal cuff extensions). One patient underwent innominate stenting and revision of their bypass for symptomatic restenosis. At 48 months, survival was 73 %. Endoleak was detected in three (6 %) patients (type 1 = 2; type 2 = 1) requiring debranching with proximal stent graft (n = 2) and proximal extension cuff (n = 1). One patient had a fatal rupture of a mycotic aneurysm and two arch aneurysms expanded. No bypass graft occluded after the perioperative period. CONCLUSIONS: Hybrid operations to treat aortic arch disease can be performed with results comparable to open surgery. The longer-term outcomes demonstrate low rates of reintervention and high rates of graft patency. PMID- 22526105 TI - Spontaneous rupture of superficial femoral artery repaired with endovascular stent-grafting with use of rendez-vous technique, followed by delayed infection. AB - This is the case of a 72-year-old man with lower limb ischemia due to spontaneous rupture of nonaneurysmal superficial femoral artery that developed into thigh hematoma. After failure of a Fogarty revascularization, an emergency endovascular procedure was performed to restore the arterial continuity. A rendezvous procedure was performed with a double femoral and popliteal approach and two covered stent-grafts were deployed. Patient's clinical conditions immediately improved, but 4 months later the stent-grafts were surgically removed for infection and exteriorization. A femoropopliteal bypass was performed. After 1 year follow-up, the patient is in good clinical condition. PMID- 22526106 TI - Secure transhepatic biliary access can be recovered by skewering a displaced looped biliary drainage catheter. PMID- 22526107 TI - Cisplatin pharmacokinetics in nontumoral pig liver treated with intravenous or transarterial hepatic chemoembolization. AB - PURPOSE: To evaluate cisplatin (CDDP) pharmacokinetics after its intravenous (IV) or intrahepatic arterial administration (IHA) in healthy pigs with or without embolization by absorbable gelatine. MATERIAL AND METHODS: We analysed plasmatic and hepatic drug concentration in four groups of six mini-pigs each according to the modality of administration of CDDP (1 mg/kg): IV, IHA, IHA with partial embolization using absorbable gelatine (IHA-Pe), and IHA with complete embolization (IHA-Te). Unbounded plasmatic and hepatic platinum concentrations were measured. Concentration and pharmacokinetics parameters were compared using analysis of variance. RESULTS: For all groups, there was a rapid and biexponential decrease in free platinum concentration. Plasmatic terminal half life (T(1/2)) was significantly decreased after embolization at 191, 178, 42, and 41 min after IV, IHA, IHA-Pe, and IHA-Te administration, respectively. Maximal plasmatic concentration and systemic exposure to CDDP (AUC(24)) values were significantly decreased after embolization (C(max) p = 0.0075; AUC(24) p = 0.0053). Hepatic CDDP concentration rapidly peaked and then decreased progressively. After 24 h, the residual concentration represented 45, 47, 60, and 63 % of C(max), respectively, after IV, IHA, IHA-Pe, and IHA-Te. Hepatic T(1/2) and AUC(infinity) values were increased after embolization, but the differences were not statistically significant. CONCLUSION: This preliminary study confirms the feasibility of a pig model to study systemic and hepatic CDDP pharmacokinetics. Systemic exposure is lower after embolization, which could minimize systemic toxicity. Hepatic T(1/2) elimination and hepatic exposition values are increased with IHA compared with IV administration. PMID- 22526108 TI - The amplatzer vascular plug: a review of the device and its clinical applications. AB - The Amplatzer Vascular Plug (AVP) is an established embolic device that can be an excellent alternative to coils or detachable balloons to embolize medium to large vessels with high flow. The device is easy to use and can be precisely deployed in the target vessel with high resistance to migration and a low recanalization rate. The technical success of this device is high, indications for use are expanding, and no absolute contraindications have been reported. Since its introduction, the AVP has grown from a single device to a group of 4 models (AVP, AVP II, AVP III, and AVP 4). Each model has a unique design and features that fit different vascular anatomies, hemodynamic situations, and clinical scenarios. Therefore, the new models cannot simply be treated as replacements for older ones. Unpredictable occlusion time remains a major shortcoming for the new models of the AVP. Large vessel size, high flow status, and coagulopathy can prolong the occlusion time, which can offset the cost benefit, reduced procedure time, and reduced radiation dose typically seen with use of the AVP alone. Coils or multiple AVPs can be used to expedite the occlusion process, and large Gelfoam particles also can be used as an adjunct to achieve rapid and reliable occlusion with minimal cost. PMID- 22526109 TI - Uterine artery embolization versus laparoscopic uterine artery occlusion: the outcomes of a prospective, nonrandomized clinical trial. AB - PURPOSE: To compare outcomes of two different types of occlusive therapy of uterine fibroids. METHODS: Women with fibroid(s) unsuitable for laparoscopic myomectomy (LM) were treated with uterine artery embolization (UAE) or laparoscopic uterine artery occlusion (LUAO). RESULTS: Before the procedure, patients treated with UAE (n = 100) had a dominant fibroid greater in size (68 vs. 48 mm) and a mean age lower (33.1 vs. 34.9 years) than surgically treated patients (n = 100). After 6 months, mean shrinkage of fibroid volume was 53 % after UAE and 39 % after LUAO (p = 0.063); 82 % of women after UAE, but only 23 % after LUAO, had complete myoma infarction (p = 0.001). Women treated with UAE had more complications (31 vs. 11 cases, p = 0.006) and greater incidence of hysteroscopically verified intrauterine necrosis (31 vs. 3 %, p = 0.001). Both groups were comparable in markers of ovarian functions and number of nonelective reinterventions. The groups did not differ in pregnancy (69 % after UAE vs. 67 % after LUAO), delivery (50 vs. 46 %), or abortion (34 vs. 33 %) rates. The mean birth weight of neonates was greater (3270 vs. 2768 g, p = 0.013) and the incidence of intrauterine growth restriction lower (13 vs. 38 %, p = 0.046) in post-UAE patients. CONCLUSION: Both methods are effective in the treatment of women with future reproductive plans and fibroids not suitable for LM. UAE is more effective in causing complete ischemia of fibroids, but it is associated with greater risk of intrauterine necrosis. Both methods have low rate of serious complications (except for a high abortion rate). PMID- 22526110 TI - Nematocytes' activation in Pelagia noctiluca (Cnidaria, Scyphozoa) oral arms. AB - Nematocytes' discharge is triggered to perform both defense and predation strategies in cnidarians and occurs under chemico-physical stimulation. In this study, different compounds such as amino acids and proteins (mucin, albumin, poly L: -lysine, trypsin), sugars and N-acetylate sugars (N-acetyl neuraminic acid, N acetyl galactosamine, sucrose, glucose, agarose and trehalose), nucleotides (ATP and cAMP), were tested as chemosensitizers of nematocyte discharge in the oral arms of the scyphozoan Pelagia noctiluca, particularly abundant in the Strait of Messina (Italy). Excised oral arms were submitted to a combined chemico-physical stimulation by treatment with different compounds followed by mechanical stimulation by a non-vibrating test probe. Discharge induced by a chemico physical stimulation was more significant than that obtained after mechanical stimulation alone. A chemosensitizing mechanism, with a dose-dependent effect, was observed after treatment with sugars, amino compounds such as glutathione, nucleotides and mucin, according to that already seen in sea anemones. Such findings suggest that, though Anthozoa and Scyphozoa exhibit different divergence times during the evolutionary process, the discharge activation exhibits common features, probably derived from their last common ancestor. PMID- 22526111 TI - Evidence of red sensitive photoreceptors in Pygopleurus israelitus (Glaphyridae: Coleoptera) and its implications for beetle pollination in the southeast Mediterranean. AB - A very well-documented case of flower-beetle interaction is the association in the Mediterranean region between red bowl-shaped flowers and beetles of the family Glaphyridae. The present study examines the visual mechanisms by which Pygopleurus israelitus (Glaphyridae: Scarabaeoidea: Coleoptera) would perceive the colors of flowers they visit by characterizing the spectral sensitivity of its photoreceptors. Our measurements revealed the presence of three types of photoreceptors, maximally sensitive in the UV, green and red areas of the spectrum. Using color vision space diagrams, we calculated the distribution of beetle-visited flower colors in the glaphyrid and honeybee color space and evaluated whether chromatic discrimination differs between the two types of pollinators. Respective color loci in the beetle color space are located on one side of the locus for green foliage background, whereas in the honeybee the flower color loci surround the locus occupied by green foliage. Our results represent the first evidence of a red sensitive photoreceptor in a flower visiting coleopteran species, highlighting Glaphyridae as an interesting model group to study the role of pollinators in flower color evolution. PMID- 22526112 TI - Ants swimming in pitcher plants: kinematics of aquatic and terrestrial locomotion in Camponotus schmitzi. AB - Camponotus schmitzi ants live in symbiosis with the Bornean pitcher plant Nepenthes bicalcarata. Unique among ants, the workers regularly dive and swim in the pitcher's digestive fluid to forage for food. High-speed motion analysis revealed that C. schmitzi ants swim at the surface with all legs submerged, with an alternating tripod pattern. Compared to running, swimming involves lower stepping frequencies and larger phase delays within the legs of each tripod. Swimming ants move front and middle legs faster and keep them more extended during the power stroke than during the return stroke. Thrust estimates calculated from three-dimensional leg kinematics using a blade-element approach confirmed that forward propulsion is mainly achieved by the front and middle legs. The hind legs move much less, suggesting that they mainly serve for steering. Experiments with tethered C. schmitzi ants showed that characteristic swimming movements can be triggered by submersion in water. This reaction was absent in another Camponotus species investigated. Our study demonstrates how insects can use the same locomotory system and similar gait patterns for moving on land and in water. We discuss insect adaptations for aquatic/amphibious lifestyles and the special adaptations of C. schmitzi to living on an insect trapping pitcher plant. PMID- 22526113 TI - Modulation of network pacemaker neurons by oxygen at the anaerobic threshold. AB - Previous in vitro and in vivo studies showed that the frequency of rhythmic pyloric network activity in the lobster is modulated directly by oxygen partial pressure (PO(2)). We have extended these results by (1) increasing the period of exposure to low PO(2) and by (2) testing the sensitivity of the pyloric network to changes in PO(2) that are within the narrow range normally experienced by the lobster (1 to 6 kPa). We found that the pyloric network rhythm was indeed altered by changes in PO(2) within the range typically observed in vivo. Furthermore, a previous study showed that the lateral pyloric constrictor motor neuron (LP) contributes to the O(2) sensitivity of the pyloric network. Here, we expanded on this idea by testing the hypothesis that pyloric pacemaker neurons also contribute to pyloric O(2) sensitivity. A 2-h exposure to 1 kPa PO(2), which was twice the period used previously, decreased the frequency of an isolated group of pacemaker neurons, suggesting that changes in the rhythmogenic properties of these cells contribute to pyloric O(2) sensitivity during long-term near anaerobic (anaerobic threshold, 0.7-1.2 kPa) conditions. PMID- 22526114 TI - Testosterone dynamics during encounter: role of emotional factors. AB - This study attempts to develop a new theory to explain the varying dynamics of testosterone levels in dominant (winners) and subordinate (losers) males, both pre- and post-encounter. The crux of our new theory consists of the following four theses: (1) the strengthening of testosterone synthesis is a result of not only the existence of challenges, but also of a positive mood before an encounter that is associated with the anticipation of a victory; (2) in situations where the anticipation of victory is present but the positive mood is absent, no rise in testosterone levels will occur; (3) testosterone acts as a "pleasure" hormone and usually releases in situations where the individual achieves or anticipates possible satisfaction; (4) an increased release of testosterone to the blood not only decreases anxiety but also elevates the mood, which increases animal's/human's assertiveness and consequently aggressiveness. PMID- 22526115 TI - [Importance of PET/CT in lymphoma diagnostics]. AB - CLINICAL/METHODICAL ISSUE: Staging or re-staging of lymphomas using conventional imaging modalities is based on morphological changes, usually on the diameter of lesions. However, vitality of tumors cannot be evaluated. STANDARD RADIOLOGICAL METHODS: In this context computed tomography (CT) has been used as a standard modality. METHODICAL INNOVATIONS: Since the introduction of positron emission tomography (PET), evaluation of tumor vitality has become possible. Moreover PET/CT hybrid scanners were brought onto the market one decade ago. PERFORMANCE: The fluorodeoxyglucose (FDG) PET/CT technique is now accepted as one of the most accurate modalities in the diagnosis of aggressive lymphomas due to a high FDG uptake (overall accuracy > 90%, sensitivity >90%). However, indolent lymphomas suffer from lower FDG uptake due to a moderate metabolic activity. After the introduction of PET/CT hybrid imaging the specificity of this diagnostic technique increased significantly compared to PET alone (from > 80% to > 90%). With the utilization of PET approximately 20% more lesions are detected when comparing to CT alone and in up to 15% of the patients this also results in a change of the therapeutic regime. As post-chemotherapy scar tissue usually persists for months, evaluation of vitality within residual bulks using FDG-PET can predict therapy response much earlier than CT, enabling therapy stratification. Other PET tracers apart from FDG have low impact in imaging of lymphomas and only the thymidine analogue fluorothymidine (FLT) is used in some cases for non-invasive measurement of proliferation. ACHIEVEMENTS: Despite the capability of FDG-PET/CT there is no evidence that the improvement in diagnostics is translated into a better patient outcome and therefore warrants the high costs. False positive findings in PET can result in unnecessary treatment escalation with subsequent higher therapy-associated toxicity and costs. PRACTICAL RECOMMENDATIONS: Some pitfalls can be avoided by scheduling PET scans carefully. As treatment-induced inflammation early after therapy can be misinterpreted as vital tumor tissue, it is recommended to wait at least 3 weeks between the last treatment cycle and the subsequent FDG-PET follow-up. Until the results of the prospective multicenter trials "PETAL" and "HD-18" become available, in Germany FDG-PET is only recommended generally for restaging Hodgkin's disease with a known rest bulk of > 2.5 cm in justifiable individual cases or in clinical trials. PMID- 22526116 TI - [Computer-assisted diagnostic procedure for multislice computed tomography for assessment of the pulmonary arterial circulation. Clinical relevance]. AB - BACKGROUND: A recently developed CAD software which highlights intravascular thrombotic structures from multislice computed tomography (MSCT) data was tested regarding feasibility, interobserver reliability and effect on radiology reports. MATERIAL AND METHODS: The CAD system ImageChecker(r) CT-Lung was tested in a randomized double-blinded study on 160 MSCT datasets (standardized technical conditions) performed for suspected pulmonary embolism (PE). The CAD data and images were analyzed by three radiologists in an independent and blinded fashion. RESULTS: The data from all 160 cases could be analyzed and 604 CAD prompts were set. Using the CAD analysis significantly more PEs were found in the peripheral pulmonary arterial circulation than described in the initial report. In 38 cases the 3 radiologists in consensus scored the images with the CAD adjunct as PE positive in peripheral vessels, which were initially reported as negative. Despite differences in the evaluation between two radiologists the amended assessment of the imaging data using the CAD softwear was reliable. There was a significant correlation between D-dimer values and the number of embolic structures detected by the CAD analysis. CONCLUSION: The recently developed CAD system is a useful adjunct as second reader to detect subtle emboli in peripheral vessels of MSCT datasets. PMID- 22526117 TI - [Treatment of acute ischemic stroke]. AB - Ischemic stroke is a medical emergency requiring fast and effective collaboration of neurologists and radiologists. Currently there are promising new developments in the treatment of acute ischemic stroke with efforts being made to reduce the door-to-needle time and to improve recanalization of occluded vessels by new endovascular techniques. Clinical trials have also demonstrated the efficacy of thrombolysis up to 4.5 h and confirmed the importance of the time to treatment for positive outcome. PMID- 22526119 TI - [Safety in intensive care medicine. Can we learn from aviation?]. AB - Safety is of extraordinary value in commercial aviation. Therefore, sophisticated and complex systems have been developed to ensure safe operation. Within this system, the pilots are of specific concern: they form the human-machine interface and have a special responsibility in controlling and monitoring all aircraft systems. In order to prepare pilots for their challenging task, specific selection of suitable candidates is crucial. In addition, for every commercial pilot regulatory requirements demand a certain number of simulator training sessions and check flights to be completed at prespecified intervals. In contrast, career choice for intensive care medicine most likely depends on personal reasons rather than eligibility or aptitude. In intensive care medicine, auditing, licensing, or mandatory training are largely nonexistent. Although knowledge of risk management and safety culture in aviation can be transferred to the intensive care unit, the diversity of corporate culture and tradition of leadership and training will represent a barrier for the direct transfer of standards or procedures. To accomplish this challenging task, the analysis of appropriate fields of action with regard to structural requirements and the process of change are essential. PMID- 22526120 TI - [Communication in intensive care medicine]. AB - Communication plays a crucial role in the intensive care unit. Posttraumatic stress syndromes develop in a significant number of patients and their relatives after being in an intensive care unit. The syndromes may persist for several years. Regular open and empathic communication with patients and family members reduces the frequency and severity of the disease. Among the physicians and nurses in the intensive care unit, there is a high prevalence of burnout syndrome. The precipitating factors are mostly conflicts within the working staff, work overload and end-of-life situations. Working team communication reduces the rate of exhaustion syndromes. Rounds of discussions among the work groups are the basis for a healthy team structure. Inadequate communication, e.g., during emergencies or shift change, endangers the safety of patients and in the worst case, results in treatment mistakes. Measures for improved communication in the intensive care unit should always be implemented. PMID- 22526121 TI - [Quality management in intensive care medicine. Indispensable for daily routine]. AB - In areas requiring maximum safety like intensive care units or operating room departments, modern quality management and risk management are essential. Treatment of critically ill patients is associated with high risk and, therefore, demands risk management and quality management. External quality assessment in intensive care medicine has been developed based on a core data set and quality indicators. A peer review procedure has been established. In addition, regional networks of intensive care physicians result in improved local networking. In intensive care medicine, this innovative modular system of quality management and risk management is pursued more consequently than in any other specialty. PMID- 22526122 TI - [Intensive care medicine--the center of attention is the human being]. PMID- 22526123 TI - [Delirium in the intensive care unit : Overview for nurses and physicians]. AB - Delirium is a severe but frequent organ dysfunction in intensive care units (ICU) affecting nearly 80% of mechanically ventilated patients and up to 50% of non ventilated patients. Although guidelines for diagnosis and treatment of delirium exist it often remains underdiagnosed due to the lack of implementation of these guidelines. Therefore, the chance of a positive outcome for patients can be significantly reduced. Delirium results in longer mechanical ventilation, extended hospital stay, more nosocomial infections and an increased mortality. Measures which improve the frequency of diagnosis and increase the quality of treatment will only be successful if physicians, nursing staff and other medical staff on ICUs realize strategies together and raise their awareness on delirium. PMID- 22526124 TI - [Tachycardias. What must the emergency physician know?]. AB - Clinical characteristics and the surface electrocardiogram (ECG) are important diagnostic tools for patients with tachycardias. Tachycardias are characterized by a ventricular heart rate > 100/min and have been divided into those with narrow (QRS width < 0.12 s) or wide QRS complex tachycardias (QRS width >= 0.12 s). In broad complex tachycardias, AV dissociation, negative or positive concordant pattern in V(1)-V(6), a notch in V(1) and qR complexes in V(6) in tachycardias with left bundle-branch block morphologies are findings indicating ventricular tachycardia (VT). In addition, an R/S relation <1 in V(6) favors VT when right bundle-branch block tachycardia morphologies are present. By analyzing the surface ECG in the right way with a systematic approach, the specificity and sensitivity of correctly identifying supraventricular tachycardia or VT can be > 95%. Therapeutic options in supraventricular or ventricular tachyarrhythmias are preferentially adenosine, ajmaline, amiodarone, and adrenaline. If antiarrhythmic drugs fail, electric cardioversion using short-acting anesthesia is recommended. PMID- 22526125 TI - [Incessant or recurrent ventricular tachycardia. Indications for emergency ablation]. AB - Incessant ventricular tachycardia and "electrical storms" are emergencies, requiring urgent action in a close cooperation between critical care physicians and cardiologists. The leading cause of such events is advanced cardiac disease. Besides the patient's history, an ECG and, if applicable, an implantable cardioverter-defibrillator (ICD) interrogation is required for a reliable diagnosis. Further diagnostics include laboratory parameters, an echocardiogram, and possibly a coronary angiography. The medical therapy, consisting of amiodarone and beta-blockers, should immediately be initiated after diagnosis. In the case of failed drug therapy, urgent catheter ablation is indicated. This is a complex procedure, in which the clinical tachycardia or the electrical substrate is modified by using an irrigated catheter. The acute success rate of this life saving procedure is high. However, there might also be complications due to the required extensive procedures. PMID- 22526127 TI - Abstracts of the International Symposium on Osteoporosis 2012. April 25-28, 2012. Orlando, Florida, USA. PMID- 22526126 TI - [Prehospital cardiac arrest. Therapeutic hypothermia in adults]. AB - Therapeutic hypothermia is one of the few advances in recent years that has improved survival and neurological outcome of survivors of cardiac arrest. Therapeutic hypothermia is part of current guidelines and, therefore, should be part of the routine procedure in postresuscitation care of patients still comatose after primarily successful resuscitation. Early induction of hypothermia may be achieved even in the prehospital setting with different cooling techniques which, however, are less suitable to maintain a constant temperature and additionally do not allow precisely controlled re-warming. To achieve the goal of a target temperature of 32-34 degrees C for 12-24 h, controlled feedback systems are more reliable and also can be used for patients during percutaneous coronary intervention. The optimal time point to start cooling is not well defined, even if theoretical considerations and animal experiments are in favor of beginning early. Another question is whether therapeutic hypothermia is of benefit for patients with cardiac arrest due to asystole and pulseless electrical activity in contrast to patients with ventricular fibrillation where it is of proven value. PMID- 22526128 TI - Dietary attitudes and diseases of comfort. AB - This article reviews Western dietary attitudes and lifestyle choices by identifying the environmental, social and personal factors that determine said attitudes and choices. Environmental factors exert a major influence on, and complicate, dietary behavior, primarily by facilitating the consumption of meals away from home and by minimizing time dedicated to meal preparation and consumption. Social factors, from mass media to advertising and cultural traditions, also influence food intake, to an extent that is still underestimated. Ignorance of the real influence of environment and society on food choices could well blind consumers to the real significance of such choices. Accordingly, this review discusses differing aspects of emerging dietary trends and/or philosophies, and underlines their potentially harmful influence on health. Western countries are increasingly witnessing a dichotomy between the findings of nutritional science and the choices that dietary trends propose and impose. Coinciding with the obesity epidemic and the spread of other food-related diseases, this dichotomy calls for the development of effective preventive strategies. PMID- 22526129 TI - Eating-related anxiety in individuals with eating disorders. AB - Although previous research has supported the importance of anxiety as an etiological and maintenance factor for eating disorders, the specific mechanisms are not well understood. The role of anxiety in the context of eating behavior is especially unclear. The purpose of this study was to identify anxiety-eliciting eating situations and anxiety management strategies patients use to mitigate anxiety experienced in the context of eating as determined by diagnostic groups and symptom patterns. Fifty-three eating disorder outpatients were administered the Eating and Anxiety Questionnaire (EAQ) and the Eating Disorder Diagnostic Scale. Ratings indicated significant anxiety in most eating situations, whereas management strategies were more limited yet regularly employed. Factor analysis of the EAQ revealed a 6-factor solution for anxiety management strategies and a 4 factor solution for anxiety-eliciting situations. These results indicate patients with eating disorders report high levels of anxiety associated with eating behaviors but utilize limited yet consistent anxiety management strategies. Effective intervention strategies for managing eating-related anxiety should be incorporated into treatment and may need to be specified for different diagnostic subgroups. PMID- 22526130 TI - Prevalence of overweight and obesity in Thai population: results of the National Thai Food Consumption Survey. AB - Overweight and obesity are considered a serious health problem in Thailand. This study examined the prevalence of overweight and obesity in a nationally representative sample of Thai children and adults based on international standards. A cross-sectional population survey of 16,596 Thais aged 3 years and over was conducted. Heights and weights were obtained using standardized methods. Estimates of the overweight and obesity prevalence in children, adolescents, and adults were computed. The prevalence of overweight and obesity among children and adolescents aged 3 to 18 years was 7.6% and 9.0%, respectively, and was higher among boys than girls. Among adults, using the the Regional Office for the Western Pacific (WPRO) standard, 17.1% of adults were classified as overweight [body mass index (BMI) 23.0-24.9 kg/m2], 19.0% as class I obesity (BMI 25.0-29.9 kg/m2), and 4.8% as class II obesity (BMI >= 30.0 kg/m2). Using the World Health Organization (WHO) definition, 19.0% were overweight (BMI 25-29.9 kg/m2), 4.0% class I obesity (BMI 30.0-34.9 kg/m2), 0.8% class II obesity (BMI 35.0-39.9 kg/m2), and 0.1% class III obesity (BMI >= 40.0 kg/m2). There was a vast difference in obesity prevalence between the WHO and the WPRO criteria. Obesity prevalence when using the WPRO definition (23.8%) was almost five times greater than when defined with the WHO standard (4.9%). The present study found a high prevalence of overweight and obesity in nationally representative sample of the Thai population. Higher rates of overweight and obesity prevalence were computed using the WPRO standard when compared to the WHO standard. PMID- 22526132 TI - Adaptation and evaluation of an Internet-based prevention program for eating disorders in a sample of women with subclinical eating disorder symptoms: a pilot study. AB - OBJECTIVE: Women reporting subclinical eating disorder (ED) symptoms are at higher risk for the development of an ED. Preventive interventions should therefore be specifically tailored for this subgroup. Accordingly, the aim of this pilot study was to test the feasibility of the adapted Internet-based prevention program "Student BodiesTM" for women with subclinical ED and to obtain effect size and sample size estimates for a subsequent randomized controlled trial. METHOD: Twenty-two women with subclinical ED participated in the 8-week intervention; pre-post data are available for 12 women. Measures of ED symptoms and established risk factors, such as weight and shape concerns, were assessed at preand post-intervention. RESULTS: Completers' adherence and appraisal of the program were good. At post-intervention, completers reported significantly fewer ED symptoms and reduced weight and shape concerns. Pre-post-effect sizes ranged from medium to large. CONCLUSION: The pilot study showed the feasibility of the adapted online intervention and gave indications for its effectiveness. PMID- 22526131 TI - Binge eating in surgical weight-loss treatments. Long-term associations with weight loss, health related quality of life (HRQL), and psychopathology. AB - BACKGROUND: Studies that have investigated the relationship between binge eating and the long-term outcome of bariatric surgery have shown mixed results. Does binge eating affect long-term BMI, health-related quality of life (HRQL), or psychopathology after surgery? METHODS: We assessed 173 bariatric patients before and three years after weight loss surgery with regard to weight, binge eating, HRQL, and psychopathology. RESULTS: Binge eating before and after weight loss surgery was unrelated to long-term BMI outcome. Binge eating after weight loss surgery was associated with more psychopathology and lower HRQL. CONCLUSIONS: Binge eating before or after weight loss surgery does not predict long-term BMI outcome. Therefore, exclusions from surgery for this reason alone are difficult to motivate. However, results show that binge eating after weight loss surgery is common and is associated with more psychopathology and lower HRQL, which might increase the vulnerability for future weight regain and complications beyond the follow-up period of the present study. The high rate of binge eating after surgery and its negative association with HRQL and psychopathology suggest that we need to be observant of the occurrence and potential effects of binge eating in the context of bariatric surgery. PMID- 22526133 TI - Socio-demographic and clinical characteristics of individuals with diagnoses of eating disorder in a university hospital in Istanbul. AB - OBJECTIVE: This paper reports the first-ever description of a clinical eating disorder population from Turkey. The aim of this study was to examine the socio demographic and clinical characteristics of individuals with diagnosis of eating disorders (IDED) referred to a university psychiatry clinic in Istanbul between 2003 and 2009. METHOD: The diagnoses and subtype of 111 IDEDs, the referral type to the hospital, setting of treatment, and state of involuntary hospitalization were evaluated by interview and semi-structured questionnaire. RESULTS: The clinical sample included 64 individuals with anorexia nervosa (AN), 38 with bulimia nervosa (BN), and 9 with eating disorder not otherwise specified (EDNOS), including only one male. Younger individuals and those with a lower BMI were significantly more likely to be family referred and hospitalized involuntarily. DISCUSSION: The overall socio-demographic features of the sample are generally consistent with data collected in other communities. However, aspects of the clinical features, referral types of eating disorders and subtypes exhibit some characteristics peculiar to our sample. PMID- 22526135 TI - What you use decides what you get: comparing classificatory procedures for the Adult Attachment Interview in eating disorder research. AB - Studies of attachment and eating disorders use different types of measures, including different coding procedures for the Adult Attachment Interview (AAI). Generalizability of findings across studies is therefore uncertain. We compare the Main & Goldwyn procedure with the Dynamic Maturational Method, the two most common procedures for classifying AAI in eating disorder research. The sample consists of 20 female patients with a diagnosis of anorexia nervosa (mean age 22.9 (3.5) years). Attachment insecurity is by far most common, regardless of procedure. Within the insecure categories, there is little overlap between procedures in comparable categories. Both procedures discriminate between Anorexia subgroups (restricting vs bingeing), but do so differently. Findings suggest that comparing findings across methods, beyond the secure/insecure dichotomy, should be avoided. PMID- 22526134 TI - The level of associated depression and anxiety traits improves during weight regain in eating disorder patients. AB - We assessed whether re-nutrition and weight gain have an influence on comorbid depression and anxiety in patients hospitalised for chronic eating disorders (ED). Seventy-five inpatients agreed to participate by completing the Eating Attitudes Test (EAT-40), the Beck Depression Inventory (BDI-13), and the State Trait Anxiety Inventory (STAI-Y) before, during and after three months of treatment. Patients suffering from either anorexia nervosa or bulimia nervosa successfully regained weight during treatment. This weight gain was accompanied by statistically significant reductions in ED symptoms. Anxiety and, to a lesser extent, depressive symptoms diminished, but remained at pathological levels, with between diagnostic subtype differences. Improvement of depressive (r=0.77) and anxiety (r=0.64) levels were significantly (p<0.001) and positively correlated with the reduction of eating attitudes (EAT). These results are discussed in the context of re-orienting the therapeutic strategies aimed at reducing emotional suffering in patients with ED. PMID- 22526136 TI - The risks of disordered eating in Hong Kong adolescents. AB - OBJECTIVE: This study examines the risks of disordered eating among Hong Kong adolescents. SUBJECTS: A total of 893 students (12-18 years old) participated in a cross-sectional study in 2007. METHODS: Students' height and weight were measured and the Eating Attitudes Test (EAT-26) was completed. The risks of disordered eating were assessed by EAT-26 results and weight status. Sex differences in the risks of disordered eating were examined by logistic regression models with adjustment for age. RESULTS: Based on the EAT-26 results, 18.5% of boys and 26.6% of girls were at risk of disordered eating with a significant adjusted odds ratio (OR) of 1.58 [95% confidence interval (CI) 1.15 2.18] for sex. A significant OR of 1.60 (95%CI 1.21-2.13) for sex was also obtained when both EAT-26 results and weight status were used for the screening. CONCLUSIONS: Hong Kong adolescent girls have a higher risk of disordered eating than boys. EAT-26 results together with measured weight status are useful criteria for screening disordered eating attitudes and behaviors in adolescents. PMID- 22526137 TI - Psychometric evaluation of the "Body Checking and Avoidance Questionnaire--BCAQ" adapted to Brazilian Portuguese. AB - OBJECTIVE: Adapt and validate the Brazilian Portuguese version of the Body Checking and Avoidance Questionnaire (BCAQ). METHODS: The study consisted of: translation and back translation; technical review and assessment of semantic equivalences, factor analysis and discriminant and concurrent validity in a sample of subjects with and without eating disorders. RESULTS: The instrument was adapted and was found to be easy to understand (mean scores higher than 3.4; maximum score: 5.0) and showed excellent concordance (Cronbach's alpha: 0.94). Factor analysis identified five components with eigenvalues greater than 1. It was able to discriminate the two groups (p<0.001) and correlated with the Eating Attitudes Test (EAT) (r=0.50), body shape questionnaire (BSQ) (r=0.68) and Beck Depression Inventory (BDI) scales (0.51). DISCUSSION: The Brazilian Language version showed suitable internal consistency and external validation, and was easy to understand. The results were similar to the original version and its use is recommended for evaluation of body checking in the Brazilian population in subjects with or without eating disorders. PMID- 22526138 TI - Treatment of anorexia nervosa with TNF-alpha down-regulating agents. PMID- 22526141 TI - Graft shrinkage and survival rate of implants after sinus floor elevation using a nanocrystalline hydroxyapatite embedded in silica gel matrix: a 1-year prospective study. AB - OBJECTIVES: The aims of this study were (1) to evaluate the vertical shrinkage percentage of nanocrystalline hydroxyapatite embedded in silica gel used for maxillary sinus floor elevation (SFE) and (2) to determine the survival rate of the implants 1 year after placement in the healed grafted sinuses. MATERIALS AND METHODS: Eleven maxillary sinuses were augmented in eight patients with NanoBone. After a healing period averaging 14.42 months, 19 implants were placed and followed up with clinical and radiographic evaluation. Panoramic radiographs were taken immediately after SFE and at 12 months after grafting. Measurements of changes in height were made by a computerized measuring technique using an image editing software. RESULTS: The mean graft height shrinkage percentage at 12 months after surgery was 8.84% (+/-5.32). One implant was lost before loading. All the 18 remaining osseointegrated implants received the prosthetic rehabilitation and were controlled after 3 months of functional loading. The implant survival rate at the 1-year interval was 94.74%. CONCLUSIONS: A 100% NanoBone alloplastic graft used in lateral SFE procedures presented limited height shrinkage. Implants placed in these grafted sinuses showed survival rates similar to those found in published data. These results should be interpreted cautiously considering the study's reduced sample size. PMID- 22526139 TI - A fast, automatic segmentation algorithm for locating and delineating touching cell boundaries in imaged histopathology. AB - BACKGROUND: Automated analysis of imaged histopathology specimens could potentially provide support for improved reliability in detection and classification in a range of investigative and clinical cancer applications. Automated segmentation of cells in the digitized tissue microarray (TMA) is often the prerequisite for quantitative analysis. However overlapping cells usually bring significant challenges for traditional segmentation algorithms. OBJECTIVES: In this paper, we propose a novel, automatic algorithm to separate overlapping cells in stained histology specimens acquired using bright-field RGB imaging. METHODS: It starts by systematically identifying salient regions of interest throughout the image based upon their underlying visual content. The segmentation algorithm subsequently performs a quick, voting based seed detection. Finally, the contour of each cell is obtained using a repulsive level set deformable model using the seeds generated in the previous step. We compared the experimental results with the most current literature, and the pixel wise accuracy between human experts' annotation and those generated using the automatic segmentation algorithm. RESULTS: The method is tested with 100 image patches which contain more than 1000 overlapping cells. The overall precision and recall of the developed algorithm is 90% and 78%, respectively. We also implement the algorithm on GPU. The parallel implementation is 22 times faster than its C/C++ sequential implementation. CONCLUSION: The proposed segmentation algorithm can accurately detect and effectively separate each of the overlapping cells. GPU is proven to be an efficient parallel platform for overlapping cell segmentation. PMID- 22526142 TI - Histological analysis of soft and hard tissues in a periimplantitis lesion: a human case report. AB - BACKGROUND: Little is known regarding the histologic hard and soft tissue changes that occur in chronic periimplantitis situations in humans. It is critical to gain an understanding of all aspects of periimplantitis to develop appropriate therapeutic approaches. METHODS: An 83-year-old African American man presented with a fractured implant affected by severe, chronic periimplantitis and surrounded by keratinized gingiva. A trephine biopsy of the implant and surrounding tissues was analyzed histologically. RESULTS: Histological analysis of the periimplantitis specimen revealed significant inflammatory infiltrate consisting predominantly of lymphocytes and plasma cells. In addition, epithelial migration and bone loss to the apical vent were noted. CONCLUSION: This case report documents a single case of periimplantitis that was left untreated for 7 years. The presence of significant keratinized tissue and a smooth surface implant failed to prevent fibrous encapsulation of the implant. PMID- 22526143 TI - Mechanism of YB-1-mediated translational induction of GluR2 mRNA in response to neural activity through nAChR. AB - BACKGROUND: We have reported previously that YB-1 induces translation of GluR2 mRNA in response to neural activity, and that HSP60 affects the association of YB 1 with polysomes. Here we examined the mechanism of YB-1-mediated translational activation of GluR2 mRNA through the nAChR. METHODS: Expression of nAChRs in NG108-15 cells was verified. Translation of GluR2 mRNA and YB-1/HSP60 interaction were examined in nicotine-treated NG108-15 cells. Effects of inhibition of alpha7 nAChR and the PI3K/Akt pathway were investigated. The ratios of YB-1 to GluR2 mRNA and to HSP60 were explored in polysomal and non-polysomal fractions, respectively, and the role of HSP60 in cytoplasmic retention of YB-1 was evaluated. RESULTS: Nicotine treatment transiently induced translation of GluR2 mRNA and Akt phosphorylation with a concomitant increase of YB-1/HSP60 interaction. Both alpha-bungarotoxin and LY294002 abolished the effects of nicotine. On a sucrose gradient, nicotine treatment shifted the distribution of YB-1 to much heavier-sedimenting polysome fractions. In these fractions, the ratio of YB-1 to its binding GluR2 mRNA was decreased, and ribosome association with the YB-1-bound GluR2 mRNA was increased. HSP60 was distributed only in the non-polysomal fractions as its binding to YB-1 increased. In HSP60-depleted cells, nicotine treatment induced nuclear localization of YB-1. CONCLUSION: YB-1 is released from GluR2 mRNA during alpha7-nAChR-mediated neurotransmission, causing the PI3K/Akt pathway to recruit ribosomes into the translational machinery, and HSP60 is involved in cytoplasmic retention of polysome-free YB-1. GENERAL SIGNIFICANCE: Activation of the PI3K/Akt pathway through the alpha7-nAChR and YB-1/HSP60 interaction are important for YB-1-mediated translational activation of GluR2 mRNA. PMID- 22526144 TI - Distribution and metabolism of selenite and selenomethionine in the Japanese quail. AB - Compared to the many studies on the physiological and toxicological effects of selenium (Se) in mammals, avian Se metabolism is still an unexplored topic. Some birds are useful as poultry for human nutrition. Moreover, birds belong to higher trophic levels in the biosphere and thus may play an important role in Se circulation in the ecosystem in the same way as mammals do. In this study, we analyzed the distribution and metabolism of Se in an experimental bird, the Japanese quail, which was fed drinking water containing sodium selenite or selenomethionine (SeMet). The highest concentration of Se was detected in the pancreas, followed by down feathers, liver, and kidneys. SeMet was more efficiently incorporated into the quail than selenite. The specific and preferable distribution of Se to the high molecular weight fraction in the serum of the quail was observed only in the SeMet-ingestion group. As in mammals, selenosugar and trimethylselenonium were the major metabolites in quail excreta. Three unknown Se metabolites were detected by HPLC-ICP-MS. Although part of the metabolic pathway of Se in the Japanese quail fed selenite and SeMet was the same as that observed in mammals, the bird also showed certain avian-specific metabolic process for Se. PMID- 22526145 TI - Probiotic factors partially prevent changes to caspases 3 and 7 activation and transepithelial electrical resistance in a model of 5-fluorouracil-induced epithelial cell damage. AB - The potential efficacy of a probiotic-based preventative strategy against intestinal mucositis has yet to be investigated in detail. We evaluated supernatants (SN) from Escherichia coli Nissle 1917 (EcN) and Lactobacillus rhamnosus GG (LGG) for their capacity to prevent 5-fluorouracil (5-FU)-induced damage to intestinal epithelial cells. A 5-day study was performed. IEC-6 cells were treated daily from days 0 to 3, with 1 mL of PBS (untreated control), de Man Rogosa Sharpe (MRS) broth, tryptone soy roth (TSB), LGG SN, or EcN SN. With the exception of the untreated control cells, all groups were treated with 5-FU (5 MUM) for 24 h at day 3. Transepithelial electrical resistance (TEER) was determined on days 3, 4, and 5, while activation of caspases 3 and 7 was determined on days 4 and 5 to assess apoptosis. Pretreatment with LGG SN increased TEER (p < 0.05) compared to controls at day 3. 5-FU administration reduced TEER compared to untreated cells on days 4 and 5. Pretreatment with MRS, LGG SN, TSB, and EcN SN partially prevented the decrease in TEER induced by 5-FU on day 4, while EcN SN also improved TEER compared to its TSB vehicle control. These differences were also observed at day 5, along with significant improvements in TEER in cells treated with LGG and EcN SN compared to healthy controls. 5-FU increased caspase activity on days 4 and 5 compared to controls. At day 4, cells pretreated with MRS, TSB, LGG SN, or EcN SN all displayed reduced caspase activity compared to 5-FU controls, while both SN groups had significantly lower caspase activity than their respective vehicle controls. Caspase activity in cells pretreated with MRS, LGG SN, and EcN SN was also reduced at day 5, compared to 5-FU controls. We conclude that pretreatment with selected probiotic SN could prevent or inhibit enterocyte apoptosis and loss of intestinal barrier function induced by 5-FU, potentially forming the basis of a preventative treatment modality for mucositis. PMID- 22526146 TI - Clarifications on oxycodone-naloxone combination in cancer pain management. PMID- 22526147 TI - Effects of exercise training on exercise capacity in patients with non-small cell lung cancer receiving targeted therapy. AB - PURPOSE: Peak oxygen consumption (VO(2peak)) is an important predictive factor for long-term prognosis in patients with non-small cell lung cancer (NSCLC). The purpose of this study was to investigate whether 8 weeks of exercise training improves exercise capacity, as assessed by VO(2peak), and other related factors in patients with NSCLC receiving targeted therapy. METHODS: A total of 24 participants with adenocarcinoma were randomly assigned to either the control group (n = 11) or the exercise group (n = 13). Subjects in the exercise group participated in individualized, high-intensity aerobic interval training of exercise. The outcome measures assessed at baseline and after 8 weeks were as follows: VO(2peak) and the percentage of predicted VO(2peak) (%predVO(2peak)), muscle strength and endurance of the right quadriceps, muscle oxygenation during exercise, insulin resistance as calculated by the homeostasis model, high sensitivity C-reactive protein, and quality of life (QoL) questionnaire inventory. RESULTS: No exercise-related adverse events were reported. After exercise training, VO(2peak) and %predVO(2peak) increased by 1.6 mL kg(-1) min( 1) and 5.3% (p < 0.005), respectively; these changes were associated with improvements in circulatory, respiratory, and muscular functions at peak exercise (all p = 0.001). The exercise group also had less dyspnea (p = 0.01) and favorably lower fatigue (p = 0.05) than baseline. CONCLUSIONS: Patients with NSCLC receiving targeted therapy have quite a low exercise capacity, even with a relatively high QoL. Exercise training appears to improve exercise capacity and alleviate some cancer-related symptoms. PMID- 22526148 TI - The relatives' perspective on advanced cancer care in Denmark. A cross-sectional survey. AB - PURPOSE: In order to improve advanced cancer care, evaluations are necessary. An important element of such evaluations is the perspective of the patient's relatives who have the role of being caregivers as well as co-users of the health care system. The aims were to investigate the scale structure of the FAMCARE scale, to investigate satisfaction with advanced cancer care from the perspective of the relatives of a representative sample of advanced cancer patients, and to investigate whether some sub-groups of relatives were more dissatisfied than others. METHOD: From 977 patients treated at 54 different Danish hospital departments, 569 patients provided us with the name and address of their relative. Of these, 544 received the FAMCARE scale that measures the families' satisfaction with advanced cancer care. For the four FAMCARE sub-scales, internal consistency was analyzed using Cronbach's alpha; convergent and discriminant validity was analyzed using multitrait-scaling analysis. Associations between the relatives' dissatisfaction and clinical and sociodemographic variables were investigated in explorative analyses using multiple logistic regressions. RESULTS: Of the relatives receiving the questionnaire, 467 (86%) responded. The original scale structure of FAMCARE could not be supported in the present sample, and therefore, results are reported at singe-item level. The proportion of dissatisfied relatives ranged from 5% to 28% (median 13%). Highest levels of dissatisfaction were found for time taken to make a diagnosis (28%) and the speed with which symptoms were treated (25%). Younger relatives were more dissatisfied than older relatives. Other sociodemographic and clinical variables had little impact on the relatives' levels of satisfaction. CONCLUSION: The relatives' level of dissatisfaction with some of the areas included in this survey needs to be taken seriously. Younger relatives were most dissatisfied. PMID- 22526149 TI - Psychological states and coping strategies after bereavement among spouses of cancer patients: a quantitative study in Japan. AB - PURPOSE: The purposes of this study were (1) to characterize psychological states and coping strategies after bereavement among spouses of cancer patients in Japan and (2) to explore the factors associated with psychological states in oncology settings. METHODS: In March 2009, questionnaires to assess spouses' psychological states, coping strategies, and mental health states (GHQ-28) were sent after patients died at the National Cancer Center of Japan. To address the first purpose, exploratory factor analysis, gender comparison, and calculation of correlation with age, time since bereavement, and mental health states were conducted. Hierarchical regression analysis was conducted to address the second purpose. RESULTS: A total of 821 spouses experiencing bereavement for 7 months to 7 years participated in the study. Psychological states revealed three factor structures: "Anxiety/Depression/Anger", "Yearning", and "Acceptance/Future Oriented Feelings". Coping strategies also revealed three factor structures: "Distraction", "Continuing Bonds", and "Social Sharing/Reconstruction". Coping strategies represented 18 % to 34 % of each factor associated with psychological states, whereas the characteristics of bereaved spouses and deceased patients represented 6 % and less than 6 %, respectively. More "Distraction and Social Sharing/Reconstruction" and less "Continuing Bonds" were significantly associated coping strategies for achieving "Acceptance/Future-Oriented Feelings" (p < 0.01). CONCLUSIONS: Both psychological states and coping strategies after bereavement revealed three factor structures. Coping strategies was the primary, bereaved spouses' characteristics was the secondary, and deceased patients' characteristics was the tertiary factor associated with psychological states. Enhancing "Distraction" and "Social Sharing/Reconstruction", and reducing "Continuing Bonds" might be promising strategies for achieving positive psychological states of the bereaved. PMID- 22526150 TI - The use of cancer treatment summaries and care plans among Massachusetts physicians. AB - PURPOSE: Cancer survivorship presents many challenges for affected individuals and their health care providers. Reports from The Institute of Medicine document these challenges and recommend the use of survivorship treatment summaries and care plans to improve communication and coordination of care for cancer survivors. The purpose of our study was to assess current use of treatment summaries and care plans in Massachusetts and identify obstacles to greater use. METHODS: A survey was mailed to cancer specialist physicians (CSPs) and primary care physicians (PCPs) in Massachusetts. The survey asked CSPs about their preparation of treatment summaries and care plans for their cancer survivor patients and perceived barriers to the provision of these documents. PCPs were asked about receipt and utility of treatment summaries and care plans and information they would like to see in these reports. RESULTS: One hundred eight CSPs and 400 PCPs answered the survey. Fifty-six percent of CSPs reported that they, or their staff, prepared treatment summaries for their cancer survivor patients; however, only 14% reported preparing care plans. Fifty-four percent of PCPs reported ever receiving a treatment summary, but only 16% ever received a care plan. CSPs cited lack of training, reimbursement, and templates as barriers to preparing care plans. CONCLUSIONS: Interventions are needed to make treatment summaries and care plans a part of standard care for all cancer survivors. Increasing the use of treatment summaries and care plans will require specific training and reimbursement and may be facilitated by templates that capture automated data. PMID- 22526151 TI - Emergency department visits for symptoms experienced by oncology patients: a systematic review. AB - PURPOSE: The aim of this review was to explore the range and prevalence of cancer treatment or disease-related symptoms in the emergency department and their associated outcomes. METHODS: A systematic review examined studies cited in Medline, Embase, PsycINFO, and CINAHL published from 1980 to July 2011. Eligible studies measured emergency department visits for symptom assessment in adult oncology patients. Two reviewers independently screened citations and double data extraction was used. Descriptive analysis was conducted. RESULTS: Of 1,298 citations, six prospective and 12 retrospective descriptive studies were included. Of these, eight focused on multiple symptoms and 10 targeted specific symptoms. The studies were published between 1995 and 2011, conducted in seven countries, and had a median sample size of 143 (range 9-27,644). Of the 28 symptoms reported, the most common were febrile neutropenia, infection, pain, fever, and dyspnea. Definitions provided for individual symptoms were inconsistent. Of 16 studies reporting admission rates, emergency visits resulted in hospital admissions 58 % (median) of the time in multi-symptom studies (range 31 % to 100 %) and 100 % (median) of the time in targeted symptoms studies (range 39 % to 100 %). Of 11 studies reporting mortality rates, 13 % (median) of emergency visits captured in multi-symptom studies (range 1 % to 56 %) and 20 % (median) of visits in targeted symptoms studies (range 4 % to 67 %) resulted in death. CONCLUSIONS: Individuals with cancer present to emergency departments with a myriad of symptoms. Over half of emergency department visits resulted in hospital admissions. Few symptoms were defined adequately to compare data across studies, thereby revealing an important gap in cancer symptom reporting. PMID- 22526152 TI - Prevalence of sarcopenia and relevance of body composition, physiological function, fatigue, and health-related quality of life in patients before allogeneic hematopoietic stem cell transplantation. AB - PURPOSE: Cachexia in patients with hematological malignancies is often related to sarcopenia. We believe that allogeneic hematopoietic stem cell transplant (allo HSCT) patients often exhibit sarcopenia prior to transplantation. Here, we aimed to investigate the prevalence of sarcopenia and its relationship with body composition, physiological function, nutrition, fatigue, and health-related quality of life (QOL) in patients before allo-HSCT. We further investigated the confounding factors associated with sarcopenia. METHODS: We included 164 patients with allo-HSCT in this study. Body composition, handgrip, knee extensor strength, and 6-min walk test were evaluated. Furthermore, fatigue, nutritional status, and health-related QOL were also evaluated. RESULTS: Eighty-three patients (50.6 %) enrolled in our study had sarcopenia prior to allo-HSCT. Patients with sarcopenia experienced decreased muscular strength and increased fatigue compared with patients without sarcopenia (p < 0.05). Patients with sarcopenia showed significantly lower scores in physical functioning, bodily pain, and vitality in health-related QOL than those without sarcopenia. Multivariate regression analysis revealed that only gender and body mass index were significantly related to sarcopenia (gender, odds ratio, 3.09; body mass index, odds ratio, 0.70; p < 0.01). CONCLUSIONS: Sarcopenia is common in patients before allo-HSCT and related to low muscle strength, fatigue, and health-related QOL. Male patients may be more susceptible to sarcopenia than female patients before allo-HSCT. Further study of rehabilitation with gender insight is warranted for patients receiving allo-HSCT. PMID- 22526153 TI - Meta-analysis of the association between hOGG1 Ser326Cys polymorphism and risk of colorectal cancer based on case--control studies. AB - PURPOSE: Oxidative DNA damage caused by reactive oxygen species plays an important role in cancer development. The association between colorectal cancer and hOGG1 Ser326Cys polymorphisms has been analyzed in several published studies, but mixed findings have been reported. The main purpose of this study was to integrate previous results and explore whether the polymorphism of hOGG1 is associated with susceptibility to colorectal cancer. METHODS: PubMed, Embase, Google Scholar, and Cbmdisc were searched for studies on the relationship of hOGG1 SNPs and the incidence of colorectal cancer (CRC). Eligible articles were included for data extraction. The main outcome was the frequency of hOGG1 Ser326Cys polymorphisms between cases and controls. Comparison of the distribution of SNP was mainly performed using Review Manager 5.0. RESULTS: A total of 4,174 cases and 6,196 controls from 12 studies were included for this meta-analysis. Overall, stratified by ethnicity or population source, no significant associations between the hOGG1 Ser326Cys polymorphism and colorectal cancer risk were found for Cys/Cys allele (OR = 1.146; 95 % CI: 0.978-1.342, P = 0.091), Cys/Cys + Cys/Ser versus Ser/Ser (OR = 1.045; 95 % CI: 0.975-1.121, P = 0.213) Cys/Cys Versus Ser/Ser (OR = 1.243; 95 % CI: 0.979-1.578, P = 0.074) and Cys/Cys versus Cys/Ser + Ser/Ser (OR = 1.198; 95 % CI: 0.959-1.496, P = 0.111) in a recessive model and (OR = 1.494; 95 % CI: 1.023-2.181, P = 0.038) in a homozygote contrast. However, if apart from sensitivity analysis, there was some evidence to indicate that significantly increased risks were found among European plus American subjects, who are mostly Caucasian (OR = 1.444; 95 % CI: 1.017-2.05 Cys/Cys vs. Ser/Cys + Ser/Ser; P = 0.04). In the subgroup analyses, we also did not found any association between hOGG1 Ser326Cys polymorphism and certain populations and smokers. CONCLUSIONS: This meta-analysis suggests that there is no robust association between hOGG1 Ser326Cys polymorphism and colorectal cancer. Because of the limitation of meta-analysis, this finding demands further investigation. PMID- 22526154 TI - DJ-1, a novel biomarker and a selected target gene for overcoming chemoresistance in pancreatic cancer. AB - PURPOSE: Aberrant expression of DJ-1 has been proven to be associated with tumorigenesis in many carcinomas. However, its role in pancreatic cancer is unknown. The aims of this study were to investigate whether the serum DJ-1 might be a potential biomarker for pancreatic cancer and to determine the biologic function of DJ-1 expression in gemcitabine-induced chemoresistance of pancreatic cancer. METHODS: The serum level of DJ-1 was higher in 128 pancreatic cancer patients compared with 62 healthy controls by ELISA. To determine the effect of DJ-1 on pancreatic tumor chemoresistance, a siRNA-targeting DJ-1 was synthesized and a stably transfected cell line with DJ-1 over-expression was constructed. The mechanism of tumor chemoresistance was assessed by multiple methods, such as MTT assay, real-time PCR, Western blot and flow cytometry. RESULTS: The serum level of DJ-1 was higher in pancreatic cancer patients than healthy controls, and it has the relationship with tumor differentiation in pancreatic cancer. Down regulation of DJ-1 enhanced gemcitabine-induced apoptosis in three pancreatic cancer cell lines. On the contrary, over-expression of DJ-1 desensitized the MIA PaCa-2 to the induction of apoptosis by gemcitabine. CONCLUSIONS: Our results suggest that the serum level of DJ-1 may be a potential biomarker for pancreatic cancer, and that DJ-1 plays critical roles in the pancreatic tumor chemoresistance, supporting the development of chemotherapeutic approaches targeting this oncogene. PMID- 22526155 TI - Roles of ABCB1 gene polymorphisms and haplotype in susceptibility to breast carcinoma risk and clinical outcomes. AB - PURPOSE: Genetic variants of ABCB1 gene contributed to cancer susceptibility and interindividual differences in chemotherapy response. Therefore, we investigated the relevance between genetic variations in ABCB1 gene and both risk and clinical outcomes of breast carcinoma. METHODS: A case-control study was performed on the SNPs C3435T, C1236T and G2677T/A in 1,173 Chinese breast carcinoma patients and 1,244 age- and sex-matched controls. These SNPs were typed by PCR-restriction fragment length polymorphism assays. RESULTS: We found the following: (1) ABCB1 C3435T, G2677T/A variants and haplotype 3435T-1236T-2677T significantly increased the risk of breast carcinoma [adjusted OR (95 % CI): 1.281 (1.021-1.285), 1.326 (1.182-1.487) and 1.707 (1.498-1.945), respectively]. (2) A significantly enhanced therapeutic response was observed in both C3435T variants and haplotype 3435T-1236T-2677T after neoadjuvant anthracycline-based chemotherapy (n = 148) [adjusted OR (95 % CI): 2.695 (1.172-6.211) and 8.064 (1.085-58.823), respectively]. (3) Cox proportional hazards regression models showed that the hazards ratio (HR) for progression-free survival (PFS) associated with C3435T CC genotype was 1.664 (95 % CI: 1.022-2.708, P = 0.041). Kaplan-Meier curve showed that C3435T CC carriers had a poor prognosis than those with CT/TT carriers after anthracycline-based chemotherapy (P = 0.043, n = 762). Furthermore, ABCB1 C3435T variants showed a significantly prolonged both PFS and overall survival (OS) in patients with triple-negative (ER-/PR-/HER2-) status (P = 0.001 and P = 0.016, respectively; n = 135). In addition, there was a significantly longer OS in patients with HER2-negative status who had G2677T/A variants (P = 0.036, n = 487). However, we did not find statistically significant association between C1236T genotypes and the risk or prognosis of breast carcinoma. CONCLUSIONS: These results suggest that ABCB1 gene C3435T, G2677T/A variations and haplotype 3435T-1236T-2677T relate to the risk and clinical outcomes of breast carcinoma and may function as candidate molecular markers of anthracycline chemosensitivity in breast carcinoma. PMID- 22526156 TI - EGFR L861Q mutation is a frequent feature of pulmonary mucoepidermoid carcinoma. AB - PURPOSE: The purpose of this study is to assess the feasibility of targeted treatment for pulmonary mucoepidermoid carcinoma (PMEC) by investigating track record of the epidermal growth factor receptor (EGFR) mutation status in PMEC. METHODS: From January 2001 to December 2009, 20 PMEC patients (11 males and 9 females) received treatment in our center. All the patients received surgery and were diagnosed by pathology. Sequencing analysis was used to monitor exons 18-21 of the EGFR gene mutation. RESULTS: The exon 21 L861Q heterozygous mutation was confirmed in five patients. There was no case with any deletion in exon 19 or exon 21 L858R mutation. One case was with a homonymy exon 18 mutation (I760I). Exon 20 G2607A (Q787Q) SNP was found in 12 of those 20 patients. CONCLUSION: L861Q mutation in exon 21 is the most frequent feature of heterozygous mutation in our study. Further investigations will be required to validate our findings. PMID- 22526158 TI - Chemotherapy as primary treatment for brain metastases from breast cancer: analysis of 115 one-year survivors. AB - PURPOSE: Given the potential toxicity of whole brain radiotherapy, we introduced systemic therapy as possible primary treatment for brain metastases (BM) from breast cancer. This study aims to evaluate the feasibility of this therapeutic approach. METHODS: Review of 115 breast cancer patients treated for BM with at least 1 year of follow-up. RESULTS: Patients with single BM without extracranial disease were usually treated with surgery, patients with multiple BM and controlled extracranial disease usually with RT, and those with progressive extracranial disease usually with systemic therapy as primary treatment for BM. Primary treatment for BM was surgery in 30 patients, RT in 26 patients, RT combined with systemic therapy in 33 patients, and systemic therapy as single treatment in 27 patients (chemotherapy n = 20; hormonal therapy n = 7). Response rate to surgery was 100 %, to RT 85 %, to RT+systemic therapy 87 %, to chemotherapy 70 %, and to hormonal therapy 14 %. Duration of neurological response and of extracranial response to chemotherapy as single treatment was similar (8 and 7 months, respectively). Patients with single BM and patients without extracranial disease had a better survival but the difference was not significant. CONCLUSION: Chemotherapy as single treatment for BM from breast cancer is feasible and should not be restricted to salvage treatment. PMID- 22526157 TI - Successful treatment of patients with newly diagnosed/untreated multiple myeloma and advanced renal failure using bortezomib in combination with bendamustine and prednisone. AB - PURPOSE: Renal failure is a frequent complication of multiple myeloma (MM) and, if present at diagnosis, a considerable risk factor for outcome. Treatment with chemotherapy and/or new agents may result in recovery of renal function in up to 50 % of patients. The window of opportunity to reverse renal impairment is, however, rather small, making an immediate and highly active treatment strategy mandatory. Bortezomib as well as bendamustine has been demonstrated to be potent drugs in the treatment of MM. METHODS: A total of 18 patients with newly diagnosed/untreated MM and renal insufficiency (GFR < 35 ml/min) were treated with bendamustine, prednisone, and bortezomib (BPV). RESULTS: The majority of them (n = 15; 83 %) responded after at least one cycle of chemotherapy with three sCR, five nCR, five VGPR, and two PR. With a median follow-up of 17 months, PFS at 18 months was 57 % and OS was 61 %. The myeloma protein decreased rapidly, reaching the best response after the first cycle in four and after the second cycle in additional seven patients. Thirteen patients (72 %) improved their renal function after treatment. CONCLUSION: We conclude that the combination of bortezomib, bendamustine, and prednisone is effective and well tolerated in patients with a newly diagnosed MM and renal failure. PMID- 22526159 TI - A prospective multicenter study of treosulfan in elderly patients with recurrent ovarian cancer: results of a planned safety analysis. AB - BACKGROUND: Treosulfan, an alkylating agent, has demonstrated activity in recurrent ovarian carcinoma. It is equieffective as oral (p.o.) and intravenous (i.v.) formulation. To explore the preference and compliance of elderly patients regarding p.o. or i.v. treosulfan for the treatment of relapsed ovarian carcinoma, women aged 65 years or older were included in this prospective multicenter study. Since elderly patients usually have several concomitant diseases and experience more treatment toxicity, an interim safety analysis was planned and performed after 25 patients finished therapy to assess the tolerability of the treatment regimens. METHODS: Patients had a free choice of treosulfan i.v. (7,000 mg/m(2) day 1 of a 28-day cycle) or p.o. (600 mg/m(2) day 1-28 of a 56-day cycle) for a maximum of 12 cycles (i.v.) or 12 months (p.o.). Indecisive patients were randomized. Toxicity was evaluated according to the NCI CTC version 2.0. RESULTS: Twenty-five of 51 recruited patients completed therapy at the time of the planned interim analysis (median age, 75 years; range, 70-82). Median ECOG was 1, and median number of prior chemotherapy regimens was 2. A median number of 4 cycles (range, 1-12) were administered per patient. Anemia was the most common hematological toxicity (88 % of patients). Most frequent non hematological toxicities were nausea (76 %), constipation (68 %), and fatigue (64 %). CONCLUSION: Treatment was generally well tolerated despite the fact that most patients suffered from multiple comorbidities and were heavily pretreated. There were no unexpected hematological or non-hematological toxicities. Based on this safety analysis, the next step of study recruitment was continued. PMID- 22526160 TI - External validity of the Tokuhashi score in patients with vertebral metastasis. AB - PURPOSE: To calculate the accuracy of the Tokuhashi score (TS) in recent patients with vertebral metastasis (VM), candidates or not to surgical treatment, and thus to assess the external validity of TS. METHODS: Retrospective analysis of prospectively collected data from 90 patients (55 men, 35 women) with VM between 2004 and 2006. For each patient, data on the primary tumor (PT), date of diagnosis, TS at the time of VM diagnosis and date of death were retrieved from the electronic medical records and civil registry. True survival time and TS survival time were estimated to calculate the accuracy rate of the TS. A Kaplan Meier analysis was used to study the survival function by prognostic groups. A correlation study between survival time and other variables was performed. RESULTS: PT distribution was as follows: breast (22.2 %), lung (20 %), prostate (17.8 %), rectum (10 %), unknown (11 %), and others (18 %). Average overall survival after the VM diagnosis was 11.8 months (SD, 11 m): breast, 20 months (SD, 20 m); lung, 5.8 months (SD, 5.9 m); prostate, 14.5 months (SD, 13.4 m); rectum, 9.4 months (SD, 9.3); and unknown tumors, 2.7 months (SD, 5 m). Survival time was accurately predicted with the TS in 63 % of patients with a short life expectancy (survival, <6 months; TS, 0-8), 16 % of patients in the intermediate group (survival, 6-12 months; TS, 9-11), and 77 % of patients with a good prognosis (survival >12 months; TS, 12-15). By specific PT, the accuracy rate of the TS was low for breast cancer metastasis (35 %). The Kaplan-Meier curves show a significant separation among the prognostic groups (p < 0.05), but the log-rank test showed a statistically significant difference in survival only between short expectancy group and good prognostic group. Age at PT diagnosis and at VM diagnosis negatively correlated with survival (r = 0.22; p = 0.032 and r = 0.3, p = 0.04). CONCLUSIONS: The TS was not highly accurate for predicting survival in patients with VM, treated or not surgically, and it was particularly imprecise in patients with an intermediate score (9-11 points) and those with breast cancer, so it is possible that the TS currently has a poor external validity. PMID- 22526161 TI - MicroRNA-21 correlates with tumorigenesis in malignant peripheral nerve sheath tumor (MPNST) via programmed cell death protein 4 (PDCD4). AB - PURPOSE: We investigated the miRNA profile in peripheral nerve tumors and clarified the involvement of miRNA in the development and progression of MPNST in comparison with neurofibroma (NF). In addition, we attempted to seek associations between the miRNA and their potential targets in MPNST. METHODS: Global miRNA expression profiling was investigated for clinical samples of 6 MPNSTs and 6 NFs. As detected by profiling analysis, the expressions of miR-21 in clinical samples of 12 MPNSTs, 11 NFs, and 5 normal nerves, and 3 MPNST cell lines were compared using quantitative real-time reverse transcription PCR. MPNST cell line (YST-1) was transfected with miR-21 inhibitor to study its effects on cell proliferation, caspase activity, and the expression of miR-21 targets. RESULTS: Analysis of miRNA expression profiles in MPNST and NF revealed significantly altered expression levels of nine miRNAs, one of those, miR-21, and its putative target, programmed cell death protein 4 (PDCD4), were selected for further studies. miR 21 expression level in MPNST was significantly higher than that in NF (P < 0.05). In MPNST cells, transfection of miR-21 inhibitor significantly increased caspase activity (P < 0.01), significantly suppressed cell growth (P < 0.05), and upregulated protein level of PDCD4, indicating that miR-21 inhibitor could induce cell apoptosis of MPNST cells. CONCLUSIONS: These results suggest that miR-21 plays an important role in MPNST tumorigenesis and progression through its target, PDCD4. MiR-21 and PDCD4 may be candidate novel therapeutic targets against the development or progression of MPNSTs. PMID- 22526162 TI - Clinical outcomes of single or oligo-fractionated stereotactic radiotherapy for head and neck tumors using micromultileaf collimator-based dynamic conformal arcs. AB - PURPOSE: To assess the clinical outcomes of single or oligo-fractionated stereotactic radiotherapy (SRT) using dynamic conformal arcs (DCA) for head and neck tumors (HNTs). METHODS: Thirty-four consecutive patients with 35 lesions treated between 2005 and 2009 were retrospectively evaluated, of whom 85.7 % had recurrent or metastatic disease, and 45.7 and 34.3 % had previous radiotherapy and surgery, respectively. The median SRT dose was 22.3 Gy (11.2-32.8) in 2-4 fractions with a median interval of 7 days and 10.4 Gy (9.2-12.4) in one fraction. SRT was combined with upfront conventionally fractionated RT in 48.6 % of patients. RESULTS: The median follow-up periods were 18.4 months (2-84.1) for the entire cohort and 49.6 months for the survivors. The 1- and 2-year local control (LC) rates were 84.3 and 70.5 %, with the 1- and 2-year overall survival (OS) rates of 78.6 and 51.6 %. LC was significantly better for tumor volumes <25.6 cm(3) (p = 0.001). OS was significantly longer in patients without any disease outside the SRT site (p < 0.001), whereas LC after the SRT did not affect the OS. Late adverse events occurred in 9 patients, including cranial nerve (CN) injury (grade 3/4) in 2, brain radionecrosis in 5 (grade 1), and fatal bleeding in 2 patients harboring uncontrolled lesions abutting the carotid artery. CONCLUSIONS: DCA-based SRT can confer relatively long-term LC with acceptable toxicity in selected patients with HNTs. The patients with CN involvement or tumor volume >=25.6 cm(3) were deemed unsuitable for this treatment regimen. PMID- 22526163 TI - Role of the functional MKK4 promoter variant (-1304T>G) in a decreased risk of prostate cancer: case-control study and meta-analysis. AB - PURPOSE: MKK4 has been suggested as a tumor suppressor. The functional variant ( 1304T>G) in the MKK4 promoter has been implicated as a risk factor for many types of cancer. However, its role in prostate cancer (PCa) is unclear. To determine whether this SNP constitutes a risk factor for PCa susceptibility and to derive a more precise estimation of the associations between this SNP and cancer risk, we performed a case-control study and then a meta-analysis covering previous case control studies. METHODS: In this study, 222 male patients with PCa and 244 cancer-free controls were evaluated MKK4-1304T>G genotype. The transcriptional activity of MKK4 gene was measured by luciferase assay, and MKK4 serum expression was measured by ELISA. RESULTS: As a whole, we found that compared to the most common -1304TT genotype, carriers of -1304G variant genotypes had a decreased risk of PCa (OR = 0.670; 95 % CI = 0.452-0.993, P = 0.046 for TG, and OR = 0.647; 95 % CI = 0.441-0.948, P = 0.025 for TG + GG). We found that carriers of the 1304G variant genotypes had greater transcriptional activity and serum expression of MKK4 than carriers of the -1304T allele. Our meta-analysis also suggested that the -1304G variant contributes to decreased risk of various cancers. CONCLUSION: Our results suggest that the functional -1304G variant in the MKK4 promoter decreases the risk of PCa by increasing the promoter activity. In the future, prospective researches on patients from many parts of the world may validate our findings. PMID- 22526164 TI - Hypofractionated stereotactic radiotherapy (hfSRT) after tumour resection of a single brain metastasis: report of a single-centre individualized treatment approach. AB - PURPOSE: Standard treatment of single brain metastases so far is tumour resection in combination with postoperative whole-brain radiotherapy or stereotactic radiosurgery. Here, we report retrospectively our first experience with postoperative hypofractionated stereotactic radiotherapy (hfSRT) to the resection cavity in order to replace upfront WBRT with respect to treatment efficacy and safety. METHODS: Between March 2006 and October 2011, 33 patients with a single newly diagnosed intracranial metastasis were treated with hfSRT following microsurgical resection. Fractionation concepts were 10 * 4 Gy (n = 22), 7 * 5 Gy (n = 7) and 5 * 6 Gy (n = 4). Planning target volume enclosed the tumour resection cavity with a safety margin of 4 mm. RESULTS: No patient demonstrated toxicity grade 2 or higher. Actuarial median overall survival summed up to 20.2 months, and 12-month survival was 64 %. Actuarial mean local brain control was 30.6 months, median distant brain control 12.4 months and intracranial control 8.8 months, respectively. Actuarial 1-year rates of local, distant brain and intracranial control were 71, 57 and 43 %. Salvage whole-brain radiotherapy due to recurrent brain metastases was performed in 13 patients (39 %). CONCLUSION: Postoperative hfSRT appears to be a feasible treatment option in patients with a single newly diagnosed brain metastasis. Replacing the standard postoperative whole-brain radiotherapy necessitates compliant patients and regular MRI follow up analysis. PMID- 22526165 TI - Randomized study on early detection of lung cancer with MSCT in Germany: study design and results of the first screening round. AB - PURPOSE: Low-dose multislice-CT (MSCT) detects many early-stage lung cancers with good prognosis, but whether it decreases lung cancer mortality and at which costs is yet insufficiently explored. Scope of the present study is to examine within a common European effort whether MSCT screening is capable to reduce the lung cancer mortality by at least 20 % and at which amount of undesired side effects this could be achieved. METHODS: Overall 4,052 heavy smoking men and women were recruited by a population-based approach and randomized into a screening arm with five annual MSCT screens and an initial quit-smoking counseling, and a control arm with initial quit-smoking counseling and five annual questionnaire inquiries. RESULTS: In the first screening round, 2,029 participants received a MSCT providing 1,488 negative and 540 suspicious screens with early recalls (early recall rate 26.6 %) leading to 31 biopsies (biopsy rate 1.5 %) and 22 confirmed lung cancers (detection rate 1.1 %). Among the lung cancers, 15 were adenocarcinomas, 3 squamous cell carcinomas, one small-cell lung cancer, and 3 others, whereby 18 were in clinical stage I, one in stage II, and 3 in stage III. One interval cancer occurred. CONCLUSIONS: The indicated performance indicators fit into the range observed in comparable trials. The study continues finalizing the second screening round and for the first participants even the last screening round. The unresolved issue of the precise amount of side effects and the high early recall rate precludes currently the recommendation of MSCT as screening tool for lung cancer. PMID- 22526166 TI - Anti-EGFR (cetuximab) combined with irinotecan for treatment of elderly patients with metastatic colorectal cancer (mCRC). AB - PURPOSE: This study was conducted to test the efficacy and toxicity of cetuximab and irinotecan as a biweekly regimen in treatment of elderly patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Forty-nine elderly patients (>=65 years) with mCRC who progressed after at least one previous line of treatment were enrolled into this study from May 2008 to January 2011. All recruited patients received cetuximab 500 mg/m(2) and irinotecan 180 mg/m(2) every 2 weeks. RESULTS: Thirty-seven patients (76 %) were men, and 76 % of patients had colonic cancer in origin. Median age was 69 years. Median overall survival time was 7 months, and median progression-free survival was 4 months. Grade 3-4 skin rash occurred in 20 % of patients, grade 3-4 diarrhea in 18 % of patients, and neutropenia in 28 % of patients. CONCLUSION: Cetuximab combined with irinotecan when administered biweekly is safe and effective for treatment of pretreated elderly patients with mCRC. PMID- 22526167 TI - Estimation of the brain stem volume by stereological method on magnetic resonance imaging. AB - Neuron loss that occurs in some neurodegenerative diseases can lead to volume alterations by causing atrophy in the brain stem. The aim of this study was to determine the brain stem volume and the volume ratio of the brain stem to total brain volume related to gender and age using new Stereo Investigator system in normal subjects. For this purpose, MR images of 72 individuals who have no pathologic condition were evaluated. The total brain volumes of female and male were calculated as 966.81 +/- 77.44 and 1,074.06 +/- 111.75 cm3, respectively. Brain stem volumes of female and male were determined as 18.99 +/- 2.36 and 22.05 +/- 4.01 cm3, respectively. The ratios of brain stem volume to total brain volume were 1.96 +/- 0.17 in female and 2.05 +/- 0.29 in male. The total brain and brain stem volumes were observed smaller in female and it is statistically significant. Among the individuals whose ages are between 20 and 40, total brain and brain stem volume measurements with aging were not statistically significant. As a result, we believe that the measurement of brain stem volume with an objective and efficient calculation method will contribute to the early diagnosis of neurodegenerative diseases, as well as to determine the rate of disease progression, and the outcomes of treatment. PMID- 22526168 TI - Hip abductor muscle volume in women with lateral hip pain: a case-controlled study. AB - Pathology of the hip abductor muscles and their associated tendons is implicated in the aetiology of lateral hip pain (LHP). Muscle atrophy is an important factor to consider in the diagnosis of this condition as it could result in reduced muscle volume and associated decreases in strength. PURPOSE: (1) To estimate the volumes of the gluteus medius (GMed), gluteus minimus (GMin) and tensor fascia lata (TFL) muscles, and (2) to examine pathological changes of the soft tissues in the vicinity of the hip joint, in women with and without LHP. METHODS: Twenty female participants (10 with LHP and 10 age-matched controls) underwent magnetic resonance imaging. Two radiologists reviewed the images for signs of pathological changes. Hip abductor muscle volumes were estimated using cross-sectional areas and Cavalieri's method. Differences in volume between sides, study groups and the three muscles were assessed. RESULTS: The volume of GMed was the largest (292.5 +/- 33.3 cm3), followed by GMin (82.1 +/- 12.1 cm3), then TFL (49.7 +/- 18.9 cm3). No differences were evident in the volumes of the hip abductor muscles in individuals with LHP when compared to age- and sex-matched controls (GMed, p = 0.30; GMin, p = 0.40; TFL, p = 0.90). Pathology of the soft tissues was not specific to the symptomatic hips. CONCLUSIONS: Novel muscle volume data are presented for GMed, GMin and TFL in the context of LHP. Further research is needed to determine if symptom severity and duration have an impact on the extent of muscle atrophy in this population. PMID- 22526169 TI - Stereological evaluation of the volume and volume fraction of newborns' brain compartment and brain in magnetic resonance images. AB - PURPOSE: Brain development in early life is thought to be critical period in neurodevelopmental disorder. Knowledge relating to this period is currently quite limited. This study aimed to evaluate the volume relation of total brain (TB), cerebrum, cerebellum and bulbus+pons by the use of Archimedes' principle and stereological (point-counting) method and after that to compare these approaches with each other in newborns. METHODS: This study was carried out on five newborn cadavers mean weighing 2.220 +/- 1.056 g with no signs of neuropathology. The mean (+/-SD) age of the subjects was 39.7 (+/-1.5) weeks. The volume and volume fraction of the total brain, cerebrum, cerebellum and bulbus+pons were determined on magnetic resonance (MR) images using the point-counting approach of stereological methods and by the use of fluid displacement technique. RESULTS: The mean (+/-SD) TB, cerebrum, cerebellum and bulbus+pons volumes by fluid displacement were 271.48 +/- 78.3, 256.6 +/- 71.8, 12.16 +/- 6.1 and 2.72 +/- 1.6 cm3, respectively. By the Cavalieri principle (point-counting) using sagittal MRIs, they were 262.01 +/- 74.9, 248.11 +/- 68.03, 11.68 +/- 6.1 and 2.21 +/- 1.13 cm3, respectively. The mean (+/- SD) volumes by point-counting technique using axial MR images were 288.06 +/- 88.5, 275.2 +/- 83.1, 19.75 +/- 5.3 and 2.11 +/- 0.7 cm3, respectively. There were no differences between the fluid displacement and point-counting (using axial and sagittal images) for all structures (p > 0.05). CONCLUSION: This study presents the basic data for studies relative to newborn's brain volume fractions according to two methods. Stereological (point-counting) estimation may be accepted a beneficial and new tool for neurological evaluation in vivo research of the brain. Based on these techniques we introduce here, the clinician may evaluate the growth of the brain in a more efficient and precise manner. PMID- 22526170 TI - Human adipose-derived stromal cells for cell-based therapies in the treatment of systemic sclerosis. AB - The present study was designed to evaluate the clinical outcome of cell-based therapy with cultured adipose derived stromal cells (ASCs) for the treatment of cutaneous manifestations in patients affected by systemic sclerosis (SSc). ASCs have an extraordinary developmental plasticity, including the ability to undergo multilineage differentiation and self-renewal. Moreover, ASCs can be easily harvested from small volumes of liposuction aspirate, showing great in vitro viability and proliferation rate. Here we isolated, characterized, and expanded ASCs, assessing both their mesenchymal origin and their capability to differentiate towards the adipogenic, osteogenic, and chondrogenic lineage. We developed an effective method for ASCs transplantation into sclerodermic patients by means of a hyaluronic acid (HA) solution, which allowed us to achieve precise structural modifications. ASCs were isolated from subcutaneous adipose tissue of six sclerodermic patients and cultured in a chemical-defined medium before autologous transplantation to restore skin sequelae. The results indicated that transplantation of a combination of ASCs in HA solution determined a significant improvement in tightening of the skin without complications such as anechoic areas, fat necrosis, or infections, thus suggesting that ASCs are a potentially valuable source of cells for skin therapy in rare diseases such as SSc and generally in skin disorders. PMID- 22526172 TI - [Chemotherapy for bladder cancer: 2012 Update. From AUO ("Arbeitsgemeinschaft Urologische Onkologie") and IABC ("Interdisziplinare Arbeitsgruppe BlasenCarcinom")]. AB - This article summarizes contemporary standards in systemic therapy for urothelial carcinoma as well as updated results of peer-reviewed publications and international bladder cancer meetings in 2011. Both neoadjuvant and adjuvant trials for locally advanced carcinoma and data on systemic chemotherapy for metastatic bladder cancer are discussed. PMID- 22526171 TI - [Briard's sagittal sliding osteotomy of the lateral condyle in total knee arthoplasty of the severe valgus knee]. AB - OBJECTIVE: Distalization of the insertion of the lateral collateral ligament and popliteus tendon by sliding osteotomy of the lateral femur condyle in order to correct a residual contracture in extension in total knee arthroplasty (TKA) of the severe valgus deformity. INDICATIONS: Genuine and other valgus deformity of the knee. CONTRAINDICATIONS: Severe laxity of the medial collateral ligament; common contraindications of joint replacement. SURGICAL TECHNIQUE: Lateral parapatellar approach and stepwise osteotomy of the tubercle of the tibia, subperiostal release of the lateral contracted structures such as iliotibial band (ITB) and lateral collateral ligament (LCL) in flexion. Tibia first technique, verification of a balanced and stable flexion gap parallel to the epicondylar line. Posterior cruciate ligament (PCL) is preserved. Referencing of the distal femoral cut by a spacer filled only in the medial extension gap. Finishing femoral chamfer cuts. If extension gap remains trapezoidal, further release of the residual lateral contracted structures in extension by means of sliding osteotomy of the lateral condyle and subperiostal release of the capsule and the lateral septum intermusculare is required. Termporary fixation of the lateral condyle by K-wires, resection of the bony excess, trial of test components, definite screw fixation. POSTOPERATIVE MANAGEMENT: Comparable to TKA in varus deformities by a medioparapatellar approach. RESULTS: A total of 79 patients (61 women, 18 men, average age 71 years at the time of surgery) with fixed valgus deformities were operated between June 2001 and December 2010 using TKA and sliding osteotomy of the lateral femoral condyle. The preoperative valgus angle under defined valgus and varus stress was 19.5 degrees (8-40), postoperative 4.7 degrees (2-11). Mean medial angle (valgus stress) of the follow-up was 2.1 degrees (0.5-5 degrees ), lateral angle (varus stress) 2.3 degrees (0.5-5 degrees ). A total of 35 patients were followed-up, at a mean of 73.3 month (24 109 months). The postoperative Knee Society Score was 95 points (56-100 points), while the postoperative Function Score was 90 points (55-100 points) postoperatively. The Oxford Score improved from 22 points (3-43 points) preoperatively to 45 points (21-48 points) postoperatively. One knee had to be revised due to infection, one knee due to non-union of the tibial tubercle. Finally, there were 3 cases with complications associated with the procedure due to the sliding osteotomy of the lateral femoral condyle; all were revised successfully. No conversion to a semi-constrained or constrained knee prosthesis was necessary. PMID- 22526173 TI - [The German Museum for the History of Medicine: a museum tour from the perspective of urology]. AB - In 1973, Germany's first museum of the history of medicine was founded in the former anatomical theatre of Ingolstadt University. Today, the baroque building with its beautiful medical garden is one of the attractions of the old city of Ingolstadt. The paper gives a round tour through the permanent exhibition, the medical technology wing and the herbal garden. The emphasis is put on those objects and plants which have a connection to the history of urology, from a "ladies urinal" to the world's first ESWL apparatus. PMID- 22526174 TI - [Radical prostatectomy - pro laparoscopic]. AB - Recent publications have failed to demonstrate significant differences in perioperative oncological and functional outcomes between laparoscopic radical prostatectomy (LRPE) and R-LRPE. Reports suggesting better functional results, in particular better potency rates for R-LRPE, are rare. However, to date no large prospective, randomized, multicenter studies have compared the two methods. With an experienced operator both methods produce comparably good results. The monopoly of the intuitive system with extremely high cost of purchase and maintenance are the major disadvantages of R-LRPE. PMID- 22526175 TI - [Pyeloplasty: pro laparoscopic]. AB - With increasing experience and availability of the da Vinci(r) robotic surgery system there has been an extension of the indications from initially exclusively ablative interventions, such as nephrectomy and radical prostatectomy to reconstructive interventions, such as pyeloplasty, bladder augmentation and urinary diversion. Laparocopic pyeloplasty has been established for both adults and children, with results comparable to the open procedure. In comparison the conventional laparoscopic procedure is little cost-intensive and therefore widely used. The available literature has to be analysed to find advantages for the cost intensive, robot-assisted laparoscopic pyeloplasty from which patients can profit. PMID- 22526176 TI - [Partial nephrectomy - pro laparoscopy]. AB - Partial nephrectomy has become the most frequently used surgical procedure in the treatment of renal cell cancer. The current role of laparoscopy for this indication has to be defined.The technique of laparoscopic partial nephrectomy has undergone a continuous development to become mature. Once the learning curve of the individual surgeon has been overcome the results are comparable to those of open surgery. This is true for ischemia time, complication rate and oncologic outcome. In addition there is the advantage of the minimally invasive approach in laparoscopy sparing a painful flank incision. Laparoscopic partial nephrectomy is not yet a standard of care but yields excellent results in the hands of experts. There are no conclusive studies comparing standard and da Vinci(r)-assisted laparoscopy. No clear advantages become obvious, but the costs of the robot are substantial. PMID- 22526177 TI - [Nephrectomy - pro laparoscopic]. AB - Laparoscopic radical nephrectomy (LRN) is considered as a standard of care for T2 renal masses and T1 tumors not treatable by nephron-sparing surgery. It can be performed transperitoneally, retroperitoneoscopic or hand-assisted. However, the morbidity after laparoscopic nephrectomy has been shown to be lower than the open procedure and patients seem to benefit from early mobilization, less pain medication, shorter hospital stays and an earlier return to normal daily activities. Furthermore, the extent of perioperative activation of the systemic stress response appears to be less during laparoscopic procedures. This has been shown to have evidently beneficial clinical impact on patient's recovery; however, its importance for the oncologic prognosis is somewhat unclear. In addition, the progression-free and overall tumor-specific survival rates for laparoscopic nephrectomy are equivalent to those for open surgery. The experiences with robot-assistance for laparoscopic nephrectomy reported so far show no significant advantages over traditional laparoscopic nephrectomy. However, the problem of high costs of acquisition and operation of robots still remains unsolved. For the future, prospective studies are needed in order to compare the functional and oncological outcomes and cost-effectiveness of different methods of radical nephrectomy. PMID- 22526178 TI - [Sacrocolpopexy - pro laparoscopic]. AB - Innovative techniques have a really magical attraction for physicians as well as for patients. The number of robotic-assisted procedures worldwide has almost tripled from 80,000 procedures in the year 2007 to 205,000 procedures in 2010. In the same time the total number of Da Vinci surgery systems sold climbed from 800 to 1,400. Advantages, such as three-dimensional visualization, a tremor-filter, an excellent instrument handling with 6 degrees of freedom and better ergonomics, together with aggressive marketing led to a veritable flood of new Da Vinci acquisitions in the whole world. Many just took the opportunity to introduce a new instrument to save a long learning curve and start immediately in the surgical master class.If Da Vinci sacrocolpopexy is compared with the conventional laparoscopic approach, robotic-assisted sacrocolpopexy shows a significantly longer duration of the procedure, a higher need for postoperative analgesics, much higher costs and an identical functional outcome without any advantage over the conventional laparoscopic approach. Although the use of robotic-assisted systems shows a significantly lower learning curve for laparoscopic beginners, it only shows minimal advantages for the experienced laparoscopic surgeon. Therefore it remains uncertain whether robotic-assisted surgery shows a significant advantage compared to the conventional laparoscopic surgery, especially with small reconstructive laparoscopic procedures such as sacrocolpopexy. PMID- 22526179 TI - [Retroperitoneal lymphadenectomy - pro laparoscopy]. AB - The functional and oncological results of laparoscopic retroperitoneal lymphadenectomy (L-RPLND) have proven to be as efficacious as open series (O RPLND) after 5 year follow-up. In the most recent publication series from high volume laparoscopy centres, there was a trend towards fewer complications in L RPLND compared to O-RPLND. Up to now only two case series of four treated patients have been reported adopting a robotic-assisted retroperitoneal lymphadenectomy for testicular cancer so that it is not yet possible to judge whether it is useful tool or not. PMID- 22526180 TI - [Prolapse surgery. With abdominal or vaginal meshes?]. AB - In prolapse surgery several surgical techniques are available. The different open, laparoscopic and vaginal approaches are distinguished by distinct success and relapse rates and operation-specific complications. A safe and optimal therapeutic pelvic floor surgery should be based on the three support levels according to DeLancy and be individually adjusted for every patient. The vaginal approach may be used for all kinds of female genital prolapse and is a comparatively less invasive technique with a short time of convalescence. Apart from stress incontinence there is no need for synthetic meshes in primary approaches and excellent results with low complication and relapse rates can be achieved. An uncritical application of synthetic material is to be avoided in vaginal repair at all times. Abdominal surgical techniques, both open and laparoscopic, present their strengths in the therapeutic approach to level 1 defects or stress incontinence. They provide excellent functional and anatomical corrections and low relapse rates. Abdominally inserted meshes have lower complication rates than vaginal ones. PMID- 22526181 TI - [Intermittent androgen deprivation as therapy for androgen-sensitive prostate cancer. Sense or nonsense?]. AB - Androgen deprivation is the predominant therapy for advanced prostate cancer. There is accumulating evidence that phases of intermission in androgen deprivation may have benefits regarding side effects, albeit there is as yet no general recommendation for intermittent androgen deprivation therapy. Recent systematic reviews at least substantiate a benefit from such regimens for general quality of life without therapy compromisation. In addition, preclinical data revealed further potential strategies for intermittent androgen deprivation therapy. Future studies must prove, however, that such approaches can be implemented in the clinical situation. PMID- 22526182 TI - [Organ-limited prostate cancer with positive resection margins. Importance of adjuvant radiation therapy]. AB - For pT3 prostate cancer with positive resection margins, the importance of postoperative radiation therapy is confirmed by a high level of evidence. However, for the pT2,R1 situation prospective, randomized studies concerning this question are lacking. Despite better local tumor control in the pT2 stage the PSA recurrence rate lies between 25% and 40% and positive margins are an independent factor for recurrence. Retrospective studies suggest a positive effect of adjuvant or salvage radiation for the oncological outcome in the pT2,R1 situation. On the other hand the side effects profile, with a potentially negative influence of postoperative continence and various delayed toxicities, is not insignificant despite modern radiation techniques and in the era of ultrasensitive PSA analysis should be considered in the risk-benefit assessment. As long as the optimal initiation of postoperative radiation therapy is unclear, the assessment of indications for adjuvant or salvage radiation for organ-limited prostate cancer with positive resection margins should be made after an individual patient consultation and under consideration of the recurrence risk factors, such as the Gleason grade and the localization and extent of the resection margins. PMID- 22526183 TI - [Radical prostatectomy - pro robotic]. AB - Anatomical radical prostatectomy was introduced in the early 1980s by Walsh and Donker. Elucidation of key anatomical structures led to a significant reduction in the morbidity of this procedure. The strive to achieve similar oncological and functional results to this gold standard open procedure but with further reduction of morbidity through a minimally invasive access led to the establishment of laparoscopic prostatectomy. However, this procedure is complex and difficult and is associated with a long learning curve. The technical advantages of robotically assisted surgery coupled with the intuitive handling of the device led to increased precision and shortening of the learning curve. These main advantages, together with a massive internet presence and aggressive marketing, have resulted in a rapid dissemination of robotic radical prostatectomy and an increasing patient demand. However, superiority of robotic radical prostatectomy in comparison to the other surgical therapeutic options has not yet been proven on a scientific basis. Currently robotic-assisted surgery is an established technique and future technical improvements will certainly further define its role in urological surgery. In the end this technical innovation will have to be balanced against the very high purchase and running costs, which remain the main limitation of this technology. PMID- 22526184 TI - [Pyeloplasty - pro robotic-assisted]. AB - Open pyeloplasty is still the gold standard in the treatment of ureteropelvic junction (UPJ) obstructions in many clinics. Similar functional results could be shown in diverse publications using conventional laparoscopic pyeloplasty (CLPP). The reconstruction of the UPJ is the main step during this type of surgery and constitutes a major challenge to surgeons working with minimally invasive techniques. The more complex the surgery the more obvious the benefits of robotic assistance (seven grades of freedom, 3D view etc.) in comparison to conventional laparoscopy. Thus robotic assistance is optimally suitable for pyeloplasty. The robotic-assisted laparoscopic pyeloplasty (RLPP) facilitates intracorporeal suturing and shortens the learning curve. Residents benefit from this shortened learning curve. Disorders caused by the non-physiological position during conventional laparoscopy are avoided during RLPP, which is an additionally benefit. Robotics also seem to be the optimum platform for the future of reconstructive LESS. The RLPP rather than the CLPP technique has therefore the potential to replace open pyeloplasty as the gold standard in treatment of UPJ. PMID- 22526185 TI - [Comments on pyeloplasty - laparoscopic versus robotic]. PMID- 22526186 TI - [Comments on partial nephrectomy - laparoscopic versus robotic]. PMID- 22526187 TI - [Radical cystectomy - pro robotic]. AB - The standard therapy for muscle invasive bladder cancer is radical cystectomy and urinary diversion. For open surgery this procedure has notable perioperative morbidity. Performing laparoscopic cystectomy can reduce this morbidity. So far it remains unclear, whether the oncologic outcome of the laparoscopic approach is comparable to open surgery or not due to a lack of long-term follow-up data. Important surgical steps, such as extended lymphadenectomy, sparing of the neurovascular bundle for preservation of potency, preparation of the urethra for orthotopic neobladder and intracorporeal construction of a urinary diversion can be achieved much more easily with a robot-assisted approach than with conventional laparoscopy. Furthermore, the learning curve for robot-assisted cystectomy is much steeper. Therefore, if a laparoscopic cystectomy is performed, it should be performed using a robot-assisted approach. PMID- 22526188 TI - [Comments on radical cystectomy - laparoscopic versus robotic]. PMID- 22526189 TI - [Nephrectomy - pro robotic]. AB - The last two decades have witnessed the rapid dissemination of robot-assisted laparoscopic urological surgery related to the technical advantages of this new laparoscopic tool. Master-slave systems ease intracorporeal anastomosis and the performance of technically highly demanding procedures, as reflected by a steep learning curve. Robot-assistance is particularly useful for partial nephrectomy, live-donor kidney transplantation, extended procedures, e.g. upper and lower urogenital tract resection and difficult anatomy as encountered in obese patients or patient with a history of multiple intraperitoneal procedures. PMID- 22526190 TI - [Comments on nephrectomy - laparoscopic versus robotic]. PMID- 22526191 TI - [Sacropolpopexy - pro robotic]. AB - Abdominal sacrocolpopexy is a standard procedure for the correction of pelvic organ prolapse of all three compartments and can also be performed minimally invasively without compromising efficacy as by open techniques. In comparison to conventional laparoscopy robotic-assisted laparoscopic sacrocolpopexy benefits from several technical stand-alone features, such as three-dimensional view, increased degrees of freedom through angulated instruments, tremor filter and up and down scaling of instrument movements. These advantages facilitate preparation of the vesicovaginal and rectovaginal spaces as well as suturing and reperitonealization, which should lead to decreased operation time and anesthesia time in extreme Trendelenburg position. Surgeon also benefit from the much more ergonomic working conditions of the da Vinci(r) system: however, comparative studies are rare and conclusions are preliminary. The German reimbursement system (DRG) does not adequately cover da Vinci expenses which, despite the obvious advantages represents the most significant obstacle in the propagation of this technique. PMID- 22526192 TI - [Comments on sacrocolpoplexy - laparoscopic versus robotic]. PMID- 22526193 TI - A comparative analysis between fixed bearing total knee arthroplasty (PFC Sigma) and rotating platform total knee arthroplasty (PFC-RP) with minimum 3-year follow up. AB - BACKGROUND: Since the introduction of mobile bearing total knee designs nearly 30 years back, many studies have been done to evaluate its long-term result. Comparison with fixed bearing designs has been done in the past, but the studies were confounded by variables such as disease, surgeon, bone quality, pain tolerance, etc. We attempt to eliminate these variables in this study. METHODS: A total of 50 patients who had bilateral arthritis of the knee with similar deformity and pre-operative range of motion on both sides agreed to have one knee replaced with mobile bearing total knee design (PFC-RP) and the other with a fixed bearing design (PFC Sigma) were prospectively evaluated. Comparative analysis of both the designs was done at a mean follow-up of 40 months, minimizing patient, surgeon and observer related bias. Clinical and radiographic outcome, survival and complication rates were compared. RESULTS: At a mean follow up of 40 months (range 36-47 months), no benefit of mobile bearing (PFC-RP) over fixed bearing design (PFC Sigma) could be demonstrated with respect to Knee Society scores, pain scores, range of flexion, subject preference or patello femoral complication rates. Radiographs showed no difference in prosthetic alignment. No patient required a revision surgery till last follow-up. CONCLUSIONS: Our study demonstrated no advantage of the mobile-bearing arthroplasty over fixed bearing arthroplasty with regard to clinical results at short-term follow-up. However, longer follow-up is necessary to confirm whether these results are sustained. PMID- 22526194 TI - Medial coracoclavicular ligament revisited: an anatomic study and review of the literature. AB - The medial coracoclavicular ligament (MCCL), up to now rarely reported in the literature, was studied in a formol-fixed cadaver by means of dissection, morphometry, and light microscopy. This entity represents a true ligament within the coracoclavicular fascia. Although longer and narrower than its lateral counterpart, the medial coracoclavicular ligament follows the same morphological pattern, including the cartilage at the level of the coracoidal attachment. Its clinical significance and implications together with a review of the literature is presented. PMID- 22526195 TI - Determination of cephazolin, ceftazidime, and ceftriaxone distribution in nucleus pulposus. AB - BACKGROUND: The intervertebral disc is the largest avascular structure in the adult body and minimal blood flow through capillary beds only supplying the outer regions of the disc, which relies on the passive diffusion as a major factor for nutrition and uptake of molecules, including antibiotics. This study is to detect the serum and nucleus pulposus (NP) levels of cephazolin, ceftazidime, and ceftriaxone and to assess this antibiotic permeability into the intervertebral disc. METHODS: Forty-five consecutive patients undergoing lumbar interbody fusion surgery were divided into three groups to participate in the study. Approximately 30 min before the procedures, a bolus dose 2 g antibiotic of cephazolin, ceftazidime, and ceftriaxone was administered intravenously. The NP tissue and serum sample levels of antibiotic were assayed by high performance liquid chromatography. RESULTS: Three cases failed in the ceftriaxone group because the NP tissue contaminates the blood. Average time between antibiotic injection and tissue/blood collection was 41 min (range 27-57 min). The antibiotic concentration level of cephazolin, ceftazidime, and ceftriaxone was 144.26 +/- 29.15, 127.19 +/- 30.22, and 227.81 +/- 51.48 MUg/ml in serum and 2.33 +/- 0.45, 3.74 +/- 1.91, and 2.23 +/- 1.86 MUg/g in NP, respectively. The antibiotic penetration in to NP of cephazolin was 1.67 +/- 0.44, 2.99 +/- 1.99 of ceftazidime, and 1.08 +/- 1.44 of ceftriaxone. CONCLUSIONS: The antibiotics of cephazolin, ceftazidime, and ceftriaxone had concentration in the NP tissue, which was higher than the stated MIC. Ceftazidime had highest penetration in to NP tissue, and ceftriaxone had the lowest penetration in to NP tissue. PMID- 22526196 TI - Fibrin sealants in orthopaedic surgery: practical experiences derived from use of QUIXIL(r) in total knee arthroplasty. AB - BACKGROUND: Total knee arthroplasty is associated with a significant postoperative blood loss even without any form of perioperative anticoagulation. METHODS: The potential role of QUIXIL((r)), a fibrin sealant used in orthopaedic surgery to control blood loss and avoid blood transfusions in patients undergoing total knee arthroplasty was evaluated in a prospective randomized trial with twenty-four patients diagnosed with primary osteoarthritis of the knee. RESULTS: Results showed that application of 2 ml QUIXIL((r)) adds costs to treatment without reducing the number of transfused red blood cell counts and postoperative haemoglobin loss. However, significant lower levels of postoperative fluid loss (P = 0.026) was detected in QUIXIL((r)) treated patients. CONCLUSION: Regarding cost effectiveness and benefit no indication for the use of 2 ml QUIXIL((r)) fibrin sealant in standard knee arthroplasty could be proofed statistically. PMID- 22526197 TI - Contralateral hip fractures and other osteoporosis-related fractures in hip fracture patients: incidence and risk factors. An observational cohort study of 1,229 patients. AB - PURPOSE: To report risk factors, 1-year and overall risk for a contralateral hip and other osteoporosis-related fractures in a hip fracture population. METHODS: An observational study on 1,229 consecutive patients of 50 years and older, who sustained a hip fracture between January 2005 and June 2009. Fractures were scored retrospectively for 2005-2008 and prospectively for 2008-2009. Rates of a contralateral hip and other osteoporosis-related fractures were compared between patients with and without a history of a fracture. Previous fractures, gender, age and ASA classification were analysed as possible risk factors. RESULTS: The absolute risk for a contralateral hip fracture was 13.8 %, for one or more osteoporosis-related fracture(s) 28.6 %. First-, second- and third-year risk for a second hip fracture was 2, 1 and 0 %. Median (IQR) interval between both hip fractures was 18.5 (26.6) months. One-year incidence of other fractures was 6 %. Only age was a risk factor for a contralateral hip fracture, hazard ratio (HR) 1.02 (1.006-1.042, p = 0.008). Patients with a history of a fracture (33.1 %) did not have a higher incidence of fractures during follow-up (16.7 %) than patients without fractures in their history (14 %). HR for a contralateral hip fracture for the fracture versus the non-fracture group was 1.29 (0.75-2.23, p = 0.360). CONCLUSION: The absolute risk of a contralateral hip fracture after a hip fracture is 13.8 %, the 1-year risk was 2 %, with a short interval between the 2 hip fractures. Age was a risk factor for sustaining a contralateral hip fracture; a fracture in history was not. PMID- 22526198 TI - Tape versus cast for non-operative treatment of primary patellar dislocation: a randomized controlled trial. AB - PURPOSE: We hypothesized that taping results in better short-term functional outcome and comparable redislocation rates. METHODS: In a prospective randomised clinical trial, 18 patients with a primary patellar dislocation >=18 years old without accompanying fractures or previous surgery to the knee were included. After 1 week of dorsal splinting, they were randomized into two groups: taping and cylinder cast immobilization. Physical examination and knee function according to the Lysholm Knee Scoring Scale were taken at 1-, 6- and 12-week and at 1- and 5-year follow-up. We also compared the redislocation rates. RESULTS: Taping resulted in a significantly better Lysholm score at 6 and 12 weeks post dislocation (P < 0.05), and also after 5-year follow-up (P < 0.01). Knee function was better at 1-year follow-up. There were no cases of recurrent dislocation. CONCLUSION: Tape bandage immobilization seems superior to a cylinder cast even after 5 years. PMID- 22526199 TI - Role of bone patellar tendon allograft in revision ACL reconstruction. PMID- 22526200 TI - Treatment of an open distal tibia fracture with segmental bone loss in combination with a closed proximal tibia fracture: a case report. AB - The treatment of open distal tibia fractures remains challenging, particularly when the fracture is infected and involves segmental bone loss. We report the case of a 38-year-old man who sustained an open distal tibiofibular fracture with segmental bone loss and a closed proximal tibial fracture. The fractures were initially fixed with a temporary external fixator. The open distal tibial fracture was infected, and the skin was covered after the wound became culture negative. The tibia was then internally transported with a ring external fixator; the closed fracture of the proximal tibia served as the corticotomy for internal transport without conventional corticotomy. After 5 cm internal transport, the docking site of the distal tibia was fixed with a locking plate and autogenous cancellous bone graft. Bone graft was also used to the distal tibiofibular space to achieve distal tibiofibular synostosis. We describe one treatment option for an infected open fracture of the distal tibia with segmental bone loss that is accompanied by a closed fracture of the proximal tibia. This method can treat two fractures simultaneously. PMID- 22526201 TI - Increased transcription in hydroxyurea-treated root meristem cells of Vicia faba. AB - Hydroxyurea (HU), an inhibitor of ribonucleotide reductase, prevents cells from progressing through S phase by depletion of deoxyribonucleoside triphosphates. Concurrently, disruption of DNA replication leads to double-strand DNA breaks. In root meristems of Vicia faba, HU triggers cell cycle arrest (preferentially in G1/S phase) and changes an overall metabolism by global activation of transcription both in the nucleoplasmic and nucleolar regions. High level of transcription is accompanied by an increase in the content of RNA polymerase II large subunit (POLR2A). Changes in transcription activation and POLR2A content correlate with posttranslational modifications of histones that play a role in opening up chromatin for transcription. Increase in the level of H4 Lys5 acetylation indicates that global activation of transcription following HU treatment depends on histone modifications. PMID- 22526204 TI - Cloning and characterization of 2-C-methyl-D-erythritol-4-phosphate pathway genes for isoprenoid biosynthesis from Indian ginseng, Withania somnifera. AB - Withania somnifera (L.) is one of the most valuable medicinal plants used in Ayurvedic and other indigenous medicines. Pharmaceutical activities of this herb are associated with presence of secondary metabolites known as withanolides, a class of phytosteroids synthesized via mevalonate (MVA) and 2-C-methyl-D erythritol-4-phosphate pathways. Though the plant has been well characterized in terms of phytochemical profiles as well as pharmaceutical activities, not much is known about the genes responsible for biosynthesis of these compounds. In this study, we have characterized two genes encoding 1-deoxy-D-xylulose-5-phosphate synthase (DXS; EC 2.2.1.7) and 1-deoxy-D-xylulose-5-phosphate reductase (DXR; EC 1.1.1.267) enzymes involved in the biosynthesis of isoprenoids. The full-length cDNAs of W. somnifera DXS (WsDXS) and DXR (WsDXR) of 2,154 and 1,428 bps encode polypeptides of 717 and 475 amino acids residues, respectively. The expression analysis suggests that WsDXS and WsDXR are differentially expressed in different tissues (with maximal expression in flower and young leaf), chemotypes of Withania, and in response to salicylic acid, methyl jasmonate, as well as in mechanical injury. Analysis of genomic organization of WsDXS shows close similarity with tomato DXS in terms of exon-intron arrangements. This is the first report on characterization of isoprenoid biosynthesis pathway genes from Withania. PMID- 22526203 TI - Strasburger's legacy to mitosis and cytokinesis and its relevance for the Cell Theory. AB - Eduard Strasburger was one of the most prominent biologists contributing to the development of the Cell Theory during the nineteenth century. His major contribution related to the characterization of mitosis and cytokinesis and especially to the discovery of the discrete stages of mitosis, which he termed prophase, metaphase and anaphase. Besides his observations on uninucleate plant and animal cells, he also investigated division processes in multinucleate cells. Here, he emphasised the independent nature of mitosis and cytokinesis. We discuss these issues from the perspective of new discoveries in the field of cell division and conclude that Strasburger's legacy will in the future lead to a reformulation of the Cell Theory and that this will accommodate the independent and primary nature of the nucleus, together with its complement of perinuclear microtubules, for the organisation of the eukaryotic cell. PMID- 22526202 TI - Controlling the cortical actin motor. AB - Actin is the essential force-generating component of the microfilament system, which powers numerous motile processes in eukaryotic cells and undergoes dynamic remodeling in response to different internal and external signaling. The ability of actin to polymerize into asymmetric filaments is the inherent property behind the site-directed force-generating capacity that operates during various intracellular movements and in surface protrusions. Not surprisingly, a broad variety of signaling pathways and components are involved in controlling and coordinating the activities of the actin microfilament system in a myriad of different interactions. The characterization of these processes has stimulated cell biologists for decades and has, as a consequence, resulted in a huge body of data. The purpose here is to present a cellular perspective on recent advances in our understanding of the microfilament system with respect to actin polymerization, filament structure and specific folding requirements. PMID- 22526206 TI - Rotavirus infection and the current status of rotavirus vaccines. AB - Among children, rotaviruses are the most common cause of severe gastroenteritis worldwide and of diarrheal deaths in developing countries. Current vaccines (e.g., Rotarix, GlaxoSmithKline Biologicals; RotaTeq, Merck and Company) effectively reduce rotaviral gastroenteritis, emergency department visits, and hospitalizations. The tremendous burden of rotavirus-related diarrhea in children across the world continues to drive the remarkable pace of vaccine development. This review assesses the global epidemiological and economic burden of rotavirus diseases, summarizes the relevant principles of the development of rotavirus vaccines, and presents data on the efficacy and effectiveness of currently licensed vaccines in both developed and developing countries. PMID- 22526205 TI - Detection of Phl p 1, Phl p 5, Phl p 7 and Phl p 12 specific IgE antibodies in the sera of children and adult patients allergic to Phleum pollen. AB - BACKGROUND: Grasses belong to major sources of inhaled allergens. The knowledge of particular molecules responsible for hypersensitivity is of crucial importance for better understanding of individual differences among single allergic subjects and allergic populations living in various world-areas. METHODS: Specific-IgE antibodies against Phl p 1, Phl p 5, Phl p 7, Phl p 12 were detected in a group of 130 Phleum-allergic-subjects (82 children, 48 adults). RESULTS: Phl p 1 antibodies were detected in most pediatric and adult patients, however, the children were associated with higher RAST classes more often. Anti-Phl p 5 antibodies were found more frequently in adults. An increase was observed in the number of pediatric patients reacting to Phl p 7 and Phl p 12. There were no differences in concentrations of specific-IgE against Phl p 5, Phl p 7 and Phl p 12 depending on age. Almost 10% of allergic children produced antibodies directed exclusively against minor allergens or did not produce specific-IgE-antibodies against tested molecules. Part of the patients reacted to profilin and calcium binding protein originating from only one source (Phl p 12/Bet v 2 and Phl p 7/Bet v 4). CONCLUSIONS: Antibodies against Phl p 1 and Phl p 5 can be used as a marker of allergy to grasses in adult patients. Children reacted exclusively to minor allergens more frequently than adults. Prolonged allergen exposure is evidently necessary to induce sensitization to Phl p 5. A high level of homology between profilins and calcium-binding proteins enables only one allergen to be used for diagnostic purposes but a possibility of a reaction to species-bound epitopes should be taken into account. PMID- 22526207 TI - beta-catenin expression in areca quid chewing-associated oral squamous cell carcinomas and upregulated by arecoline in human oral epithelial cells. AB - BACKGROUND/PURPOSE: Nuclear localization of beta-catenin is known to associate with malignant transformation of many squamous cell carcinomas. The aim of this study was to compare beta-catenin expression in normal human oral epithelium and areca quid chewing associated oral squamous cell carcinomas (OSCCs) and further to explore the potential mechanisms that may lead to induce beta-catenin expression. METHODS: A total of 40 areca quid chewing-associated OSCCs and 10 normal oral tissue biopsy samples without areca quid chewing were analyzed by immunohistochemistry. The oral epithelial cell line GNM cells were challenged with arecoline, a major areca nut alkaloid, by using Western blot analysis. Furthermore, extracellular signal-regulated protein kinase inhibitor PD98059, glutathione precursor N-acetyl-l-cysteine (NAC), tyrosine kinase inhibitor herbimycin-A, p38 inhibitor SB203580, and phosphatidylinositaol 3-kinase inhibitor LY294002 were added to find the possible regulatory mechanisms. RESULTS: beta-catenin expression was significantly higher in OSCC specimens than that in normal oral epithelial specimens (p < 0.05). It was demonstrated that normal oral epithelium showed only membranous staining for beta-catenin, and membranous staining was lost or reduced with an increase in cytoplasmic/nuclear staining in OSCCs. Arecoline was found to elevate beta-catenin expression in a dose-dependent manner (p < 0.05). The addition of PD98059, NAC, herbimycin-A, SB203580, and LY294002 markedly inhibited the arecoline-induced beta-catenin expression (p < 0.05). CONCLUSION: beta-catenin expression is significantly upregulated in areca quid chewing-associated OSCC. The localization of beta catenin expression is correlated with the tumor size and clinical stage. In addition, beta-catenin expression induced by arecoline is downregulated by PD98059, NAC, herbimycin-A, SB203580, and LY294002. PMID- 22526208 TI - Impact of increasing alanine aminotransferase levels within normal range on incident diabetes. AB - BACKGROUND/PURPOSE: Abnormal alanine aminotransferase level (ALT) levels might be associated with type 2 diabetes, but whether higher ALT levels within the normal range predict the risk is unknown. METHODS: We followed a community-based cohort of 3446 individuals who were >=35 years old without diabetes and hepatitis B or C in southern Taiwan for 8 years (1997-2004) to study the risk for type 2 diabetes with different normal ALT levels. RESULTS: Among the 337 incident diabetes cases, 16.0% were from those with ALT levels <10 IU/L, 44.5% with ALT levels 10-19 IU/L, 30.0% with ALT levels 20-39 IU/L, and only 9.5% with ALT levels >=40 IU/L. A cumulative hazard function test showed that the higher the ALT levels, the greater the cumulative incidence rate of diabetes (p < 0.001, log-rank test). A multiple Cox proportional hazards analysis showed that increasing age, lower educational levels, higher body mass index levels (>=25 vs. <25), and higher ALT levels (vs. the reference group, ALT <10 IU/L), from hazard ratio (HR) = 1.8, for ALT = 10-19, HR = 3.7 for ALT = 20-39, to HR = 4.5 for ALT >=40, were significant factors for developing diabetes (p < 0.001). The hazard ratios of higher ALT levels in the participants without alcohol consumption were similar to or higher than those in the total cohort. CONCLUSION: Higher ALT levels, even within the normal range, are strong predictors of type 2 diabetes independently of body mass index levels with a dose-response relationship. PMID- 22526209 TI - Reduction of cystometric bladder capacity and bladder compliance with time in patients with end-stage renal disease. AB - BACKGROUND/PURPOSE: Reduced bladder capacity and compliance in patients with end stage renal disease (ESRD) may affect storage and voiding function after kidney transplantation. This study evaluated the bladder capacity, compliance, and lower urinary tract dysfunction in ESRD patients with duration after dialysis and anuria. MATERIALS AND METHODS: Adults with ESRD on kidney transplantation waiting list were consecutively enrolled. The survey items included videourodynamic study (VUDS), renal ultrasound, and cystoscopy. The analytical variables assessed included the duration of dialysis, the duration of anuria, cystometric bladder capacity and bladder compliance, voiding phases in VUDS, and cystoscopic findings. RESULTS: A total of 62 patients with a mean dialysis duration of 58.9 +/- 6.3 months were enrolled. The mean cystometric bladder capacity was 178 +/- 14 mL and decreased significantly with duration of dialysis (p < 0.001). Anuria was diagnosed in 26 patients, and the mean cystometric bladder capacity decreased significantly with the duration of anuria (p = 0.002). Among the 26 patients with anuria, 16 had a poor bladder compliance. VUDS revealed abnormal storage function in 44 (71.0%) patients and bladder outlet obstruction due to bladder neck dysfunction or urethral narrowing in the voiding phase in 32 (51.6%). Abnormal cystoscopic findings were also noted in 30 (48.4%) patients. CONCLUSION: Cystometric bladder capacity and bladder compliance decreased with longer duration of dialysis, and the presence of anuria contributed to further decreases in cystometric bladder capacity and bladder compliance. More than two-thirds of patients with ESRD had abnormal findings on VUDS. PMID- 22526210 TI - Comparison of oral health between inpatients with schizophrenia and disabled people or the general population. AB - BACKGROUND/PURPOSE: There is little comparative research evidence to support the claim that there is disparity in dental care between inpatients with schizophrenia and the disabled people or the general population. This study aimed to investigate whether schizophrenia inpatients had poorer dental care and worse oral health than the disabled people and the general population, respectively. METHODS: An oral health survey was conducted in a specific-psychiatric long-term care institution in Taiwan in 2006. The results of this survey were compared with the findings of oral health investigations of the disabled people or the general population in Taiwan using proportion test and t-test. RESULTS: This study used decayed, missing, and filled teeth index (DMFT) to describe the condition of dental caries. Compared with the disabled people, schizophrenia inpatients aged 19 to 44 years had a lower subjects' filling rate of DMFT index (FI) and a higher caries experience, but schizophrenia inpatients aged 45 or more had a lower mean number of DMFT. Compared with the general population, schizophrenia inpatients had higher caries experience, mean number of DMFT, percentage edentulous, and community periodontal index and lower FI and number of remaining tooth among various gender or age groups. CONCLUSION: In Taiwan, inpatients with schizophrenia have a lower FI than the disabled people and a worse overall oral health status than the general population. PMID- 22526211 TI - Clinical manifestations and outcomes of pediatric chronic neutropenia. AB - BACKGROUND/PURPOSE: Neutropenia is a decrease in the number of circulating neutrophils. When neutropenia persists for more than 3 months, it becomes chronic. A heterogeneous group of diseases in children can cause chronic neutropenia. The aim of the present study was to categorize the diseases and present their clinical manifestations, treatment, and outcomes. METHODS: Medical charts of patients with pediatric chronic neutropenia from the last 21 years (1988-2008) were reviewed in a tertiary referral center. RESULTS: Twenty-nine patients were documented during the study period: seven with congenital neutropenia syndromes (CNSs), seven with autoimmune neutropenia (AIN), and 15 with chronic idiopathic neutropenia (CIN). Three CNS patients had severe chronic neutropenia, one had the Chediak-Higashi syndrome, one had the hyper-IgM syndrome, one had the glycogen storage disease type Ib, and one had the Barth syndrome. CNS patients had severe neutropenia early with frequent infections causing high morbidity and mortality. CNS patients usually required prophylactic antibiotics, granulocyte colony-stimulating factor therapies, or umbilical cord blood transplantations to improve or correct clinical conditions. However, most AIN and CIN patients later recovered spontaneously and did not require granulocyte colony-stimulating factor therapy. The mean absolute neutrophil count at onset, the mean onset age of neutropenia, and the mean duration of neutropenia of the two groups of patients did not significantly differ. Some AIN patients had anemia, and some CIN patients had anemia and/or thrombocytopenia. CONCLUSION: It is difficult and risky to draw any conclusion from such a small-scale study; however, we believe that promptly diagnosing underlying diseases and administering appropriate disease-oriented therapy would be crucial for the treatment of patients with chronic neutropenia, particularly with regard to CNSs. PMID- 22526212 TI - Hepatosplenic actinomycosis in an immunocompetent patient. AB - Hepatosplenic abscess caused by Actinomyces is rare and often misdiagnosed as malignancy. Herein, we report a case of hepatosplenic actinomycosis in a 37-year old immunocompetent man with a 2-month clinical history of intermittent fever and upper left abdominal pain. Physical examination revealed a mildly ill-appearing man with a low-grade fever (38 degrees C) and upper left quadrant abdominal tenderness. Abdominal sonographic examination showed the presence of a 6.3 cm * 6.5 cm heterogeneous abscess with a hypoechoic center and honeycomb appearance in an enlarged spleen (8 cm * 5 cm). Computerized tomography of the abdomen revealed a multiloculated splenic lesion, and laparotomy showed multiple hepatic nodules and a splenic abscess. Histopathological examination of the biopsy revealed filamentous branching bacilli and sulfur granules in the hepatosplenic abscess. The patient successfully underwent splenectomy accompanied by intravenous and oral penicillin treatment. Proper and prompt diagnosis of hepatosplenic actinomycosis is important because the therapeutic plan and prognosis of this pathogen are quite different from other microorganisms and malignancies. PMID- 22526213 TI - Congenital toxoplasmosis in a neonate with significant neurologic manifestations. PMID- 22526214 TI - Infections due to different genospecies of the Acinetobacter calcoaceticus-A baumannii complex. PMID- 22526215 TI - A novel method of fetal cardioversion. AB - The ideal treatment for fetal arrhythmias associated with hydrops is not known. This case report describes a novel approach to fetal cardioversion using oral maternal bolus dosing of flecainide. PMID- 22526216 TI - Stress transient hypertrophic cardiomyopathy and B-type natriuretic peptide role. AB - This report describes a transient hypertrophic cardiomyopathy with right ventricle outlet tract obstruction (RVOTO) induced by perinatal stress due to a major surgical procedure in a female newborn with congenital abnormalities. On day 10, she presented with heart failure, abnormal B-type natriuretic peptide (BNP), and an echocardiogram showing normal wall thickness. An in-hospital follow up echocardiogram showed biventricular hypertrophy and RVOTO. At discharge, the infant was asymptomatic, with a normal echocardiogram and BNP. Transient RVOTO triggered by surgical stress and abnormal BNP have not been reported previously. Pathophysiology, the role of BNP, and clinical characteristics are discussed. PMID- 22526217 TI - Azygos approach for pacemaker placement in an infant. AB - A pacemaker insertion through the azygos vein in a child is presented. When both the low weight of the child and mediastinitis precluded standard approaches, the azygos approach proved to be an alternative and a straightforward bailout solution. PMID- 22526218 TI - Visual diagnosis of severe hyperkalemia in a young infant. PMID- 22526219 TI - Normal interstage growth after the norwood operation associated with interstage home monitoring. AB - After stage 1 palliation (S1P) with a Norwood operation, infants commonly experience growth failure during the initial interstage period. Growth failure during this high-risk period is associated with worse outcomes. This study evaluated the growth patterns of patients enrolled in the authors' interstage home-monitoring program (HMP), which uses a multidisciplinary team approach to nutrition management. From 2000 to 2009, 148 infants were enrolled in the HMP after S1P. Families recorded daily weights during the interstage period and alerted the interstage monitoring team about protocol violations of nutritional goals. Interstage monitoring and inpatient data from the S1P hospitalization were reviewed to identify risk factors for poor growth. Growth outcomes were compared with published norms from the Centers for Disease Control. Interstage survival for patients in the HMP was 98 % (145/148). Growth velocity during the interstage period was 26 +/- 8 g/day. The weight-for-age z-scores decreased from birth to discharge after S1P (-0.4 +/- 0.9 to -1.3 +/- 0.9; p < 0.001) but then increased during the interstage period to the time of S2P (-0.9 +/- 1; p < 0.001). The factors associated with improved growth during the interstage period included male gender, greater birth weight, full oral feeding at S1P discharge, and a later birth era. After S1P, infants enrolled in an HMP experienced normal growth velocity during the interstage period. Daily observation of oxygen saturation, weight change, and enteral intake together with implementation of a multidisciplinary feeding protocol is associated with excellent interstage growth and survival. PMID- 22526221 TI - Assessment of aortic stenosis from the right parasternal view: when the answer is just on the opposite side. AB - We present the case of a man with severe aortic stenosis in whom diagnosis was established by evaluating the transvalvular gradient from the right parasternal view, since classical measurements from the apical five-chamber view were discordant with the indexed aortic valve area obtained in the short-axis view. PMID- 22526220 TI - Elevated homocysteine and asymmetric dimethyl arginine levels in pulmonary hypertension associated with congenital heart disease. AB - Pulmonary arterial hypertension (PAH) is a major cause of morbidity and mortality among patients with congenital heart disease (CHD). This study was designed to determine biomarker levels in patients with PAH associated with CHD (PAH-CHD) and CHD patients without PAH and to investigate the relationship of these potential biomarkers with hemodynamic findings. In this prospective single-center study, patients with CHD were analyzed according to the presence or absence of PAH and compared with healthy control subjects. Cardiac catheterization and echocardiographs were performed. Plasma homocysteine, asymmetric dimethyl arginine (ADMA), and nitric oxide (NO) levels were determined by enzyme-linked immunosorbent assay. Homocysteine and ADMA levels were higher in the PAH-CHD group (n = 30) than among CHD patients with left-to-right shunting but no PAH (n = 20; P < 0.001) and healthy control subjects (n = 20; P < 0.001). There was no difference in NO levels. Cyanotic PAH-CHD patients had significantly higher homocysteine than acyanotic patients in the same group. No correlation was shown between echocardiographic/hemodynamic parameters and homocysteine, ADMA, and NO levels. Homocysteine and ADMA levels are increased in patients with PAH-CHD. These parameters have the potential to be used as biomarkers in the diagnosis and follow-up evaluation of patients with PAH-CHD. However, large, multicentered prospective studies are required to facilitate routine use of these biologic markers in the clinical setting. PMID- 22526222 TI - A new electrophysiology era: zero fluoroscopy. AB - Catheter ablations are traditionally performed under fluoroscopic guidance. Besides other peri-interventional risks, radiation exposure should be considered for its stochastic and deterministic effects on health. These effects are cumulative and lifelong and raise great concerns especially in the younger population. A document of the American College of Cardiology recommends that all catheterization laboratories adopt the principles of 'ALARA' (radiation doses 'As Low As Reasonably Achievable'), making radiation reduction an ethical issue. In electrophysiology, thanks to the recent development of electroanatomic navigation systems, we are witnessing the birth of a new era in which almost all arrhythmias may be treated without the use of fluoroscopy. In the present review, we start by describing risks to health due to radiation exposure for conventional transcatheter ablations and we continue by reporting the current state of art of the zero fluoroscopy approach. PMID- 22526223 TI - Stentless pericardial valve for acute aortic valve endocarditis with annular destruction. AB - Surgery for aortic-valve endocarditis is still challenging, particularly in combination with destruction of the annulus. Freedom Solo (Solo) is a bovine stentless prosthesis for aortic valve replacement. It is implanted supra annularly into the aortic wall with a single suture line, without requiring an 'intact' annulus. Thirteen patients received a Solo for endocarditis with annular destruction. Our results showed a low reinfection rate and no patient-prosthesis mismatch. Our contribution intends to show the feasibility of implantation also in case of complicated anatomical conditions, such as destruction of the annulus. PMID- 22526224 TI - Early vessel healing of the Avantgarde cobalt-chromium coronary stent: the ON GARDE OCT study. AB - INTRODUCTION: Uncoverage and malapposition of stent struts at optical coherence tomography (OCT) have been associated with stent thrombosis. Stent uncoverage by OCT is being used as a surrogate to address the propensity of a stent to develop thrombosis. We aimed to appraise early vessel healing in patients with ST elevation myocardial infarction (STEMI) treated with the novel Avantgarde stent. METHODS: Patients with STEMI and multivessel disease were enrolled. The stent deployed on the infarct-related artery was imaged by frequency domain-OCT during deferred intervention (4-7 days apart). The primary end-point was the percentage of uncovered struts. Secondary end-points were the percentage of malapposed struts and struts covered with thrombus. RESULTS: Twenty patients (20 lesions) were enrolled, with 18 (18 stents) achieving a complete OCT pull-back and thus entering the final analysis (1497 cross-sections, 11 446 struts). Uncovered struts were 3.9%, whilst 8.0% of struts were malapposed and 2.6% were covered by thrombus. At per-stent analysis, all stents but two had a homogeneous distribution of strut coverage (i.e. % of uncovered struts >=10). CONCLUSIONS: This study, originally exploiting OCT data early after stenting in STEMI patients, shows that the Avantgarde stent is associated with favourable vessel healing features. PMID- 22526225 TI - Postpericardiotomy syndrome: a proposal for diagnostic criteria. AB - The post-pericardiotomy syndrome (PPS) affects 10-40% of patients after cardiac surgery, depending on the adopted diagnostic criteria, institution and type of surgery. On this basis, there is a need for standardized criteria for epidemiological and clinical purposes, which we propose on the basis of the largest published clinical trials on PPS prevention. Proposed diagnostic criteria for the PPS include: fever without alternative causes, pleuritic chest pain, friction rub, evidence of new or worsening pleural effusion, and evidence of new or worsening pericardial effusion. At least two of these criteria should be present for the diagnosis. These criteria may be adopted in future clinical trials and studies on the PPS. PMID- 22526226 TI - Activity of pegylated liposomal doxorubicin in combination with gemcitabine in triple negative breast cancer with skin involvement: two case reports. AB - Breast carcinoma (BC) is a heterogeneous disease in terms of histology, therapeutic response, dissemination patterns to distant sites and patient outcomes. Triple-negative breast cancer (TNBC), defined by the lack of protein expression of estrogen and progesterone receptors and the absence of HER2 protein overexpression (ER-/PR-/HER2-) has significant clinical implications due to their poor prognosis and the lack of targeted agents. Skin involvement is one of the most distressing presentations of locally recurrent breast cancer and few studies have identified effective agents in this setting. In fact, the increasing use of anthracycline/taxane-based chemotherapy in the neoadjuvant and/or adjuvant settings has led to investigate new cytotoxic therapies such as the combination of pegylated liposomal doxorubicin (PLD) with gemcitabine. Here, we report two cases of disseminated TNBC with extensive cutaneous metastases and a remarkable response to PLD in combination with gemcitabine. Further investigations are needed to confirm the efficacy of this regimen in skin involvement and TNBC. PMID- 22526227 TI - Comparison between Acuros XB and Brainlab Monte Carlo algorithms for photon dose calculation. AB - PURPOSE: The Acuros(r) XB dose calculation algorithm by Varian and the Monte Carlo algorithm XVMC by Brainlab were compared with each other and with the well established AAA algorithm, which is also from Varian. METHODS: First, square fields to two different artificial phantoms were applied: (1) a "slab phantom" with a 3 cm water layer, followed by a 2 cm bone layer, a 7 cm lung layer, and another 18 cm water layer and (2) a "lung phantom" with water surrounding an eccentric lung block. For the slab phantom, depth-dose curves along central beam axis were compared. The lung phantom was used to compare profiles at depths of 6 and 14 cm. As clinical cases, the CTs of three different patients were used. The original AAA plans with all three algorithms using open fields were recalculated. RESULTS: There were only minor differences between Acuros and XVMC in all artificial phantom depth doses and profiles; however, this was different for AAA, which had deviations of up to 13% in depth dose and a few percent for profiles in the lung phantom. These deviations did not translate into the clinical cases, where the dose-volume histograms of all algorithms were close to each other for open fields. CONCLUSION: Only within artificial phantoms with clearly separated layers of simulated tissue does AAA show differences at layer boundaries compared to XVMC or Acuros. In real patient CTs, these differences in the dose-volume histogram of the planning target volume were not observed. PMID- 22526228 TI - A survival score for patients with metastatic spinal cord compression from prostate cancer. AB - BACKGROUND: This study aimed to develop and validate a survival scoring system for patients with metastatic spinal cord compression (MSCC) from prostate cancer. PATIENTS AND METHODS: Of 436 patients, 218 patients were assigned to the test group and 218 patients to the validation group. Eight potential prognostic factors (age, performance status, number of involved vertebrae, ambulatory status, other bone metastases, visceral metastases, interval from cancer diagnosis to radiotherapy of MSCC, time developing motor deficits) plus the fractionation regimen were retrospectively investigated for associations with survival. Factors significant in the multivariate analysis were included in the survival score. The score for each significant prognostic factor was determined by dividing the 6-month survival rate (%) by 10. The total score represented the sum of the scores for each factor. The prognostic groups of the test group were compared to the validation group. RESULTS: In the multivariate analysis of the test group, performance status, ambulatory status, other bone metastases, visceral metastases, and interval from cancer diagnosis to radiotherapy were significantly associated with survival. Total scores including these factors were 20, 21, 22, 24, 26, 28, 29, 30, 31, 32, 33, 35, 37, or 39 points. In the test group, the 6-month survival rates were 6.5% for 20-24 points, 44.6% for 26-33 points, and 95.8% for 35-39 points (p < 0.0001). In the validation group, the 6 month survival rates were 7.4%, 45.4%, and 94.7%, respectively (p < 0.0001). CONCLUSIONS: Because the survival rates of the validation group were almost identical to the test group, this score can be considered valid and reproducible. PMID- 22526229 TI - Use of the Graded Prognostic Assessment (GPA) score in patients with brain metastases from primary tumours not represented in the diagnosis-specific GPA studies. AB - BACKGROUND AND PURPOSE: Assessment of prognostic factors might influence treatment decisions in patients with brain metastases. Based on large studies, the diagnosis-specific graded prognostic assessment (GPA) score is a useful tool. However, patients with unknown or rare primary tumours are not represented in this model. A pragmatic approach might be use of the first GPA version which is not limited to specific primary tumours. PATIENTS AND METHODS: This retrospective analysis examines for the first time whether the GPA is a valid score in patients not eligible for the diagnosis-specific GPA. It includes 71 patients with unknown primary tumour, bladder cancer, ovarian cancer, thyroid cancer or other uncommon primaries. Survival was evaluated in uni- and multivariate tests. RESULTS: The GPA significantly predicted survival. Moreover, improved survival was seen in patients treated with surgical resection or radiosurgery (SRS) for brain metastases. The older recursive partitioning analysis (RPA) score was significant in univariate analysis. However, the multivariate model with RPA, GPA and surgery or SRS versus none showed that only GPA and type of treatment were independent predictors of survival. CONCLUSION: Ideally, cooperative research efforts would lead to development of diagnosis-specific scores also for patients with rare or unknown primary tumours. In the meantime, a pragmatic approach of using the general GPA score appears reasonable. PMID- 22526230 TI - Relapsing high grade mucoepidermoid carcinoma. Long-lasting complete response following reirradiation and EGFR blockade. AB - BACKGROUND AND PURPOSE: The treatment strategy for inoperable recurrent mucoepidermoid carcinoma (MEC) is not well established. Here, we present a case of a relapsed high grade MEC of the salivary glands of the hard palate that was successfully treated with a reirradiation (re-RT) and cetuximab, an antibody against epidermal growth factor receptor (EGFR). CASE REPORT: Twelve years after resection and adjuvant radiotherapy for high grade MEC of the salivary glands, a patient presented with inoperable recurrent disease. She received another 59.4 Gy. In addition, 400 mg/m(2) cetuximab was administered in the first week, followed by six additional weekly courses at 250 mg/m(2). RESULTS: Treatment was well tolerated. The patient is doing well and continuous radiological complete response (CR) is documented for 25 months after completion of the combined treatment. CONCLUSION: Combined re-RT and targeted inhibition of EGFR with cetuximab may be a valuable therapeutic strategy in patients with recurrent localized high grade MEC who are not candidates for radical surgery. PMID- 22526231 TI - Intensity-modulated arc therapy with cisplatin as neo-adjuvant treatment for primary irresectable cervical cancer. Toxicity, tumour response and outcome. AB - PURPOSE: The goal of this work was to evaluate the feasibility and outcome of intensity-modulated arc therapy +/- cisplatin (IMAT +/- C) followed by hysterectomy for locally advanced cervical cancer. PATIENTS AND METHODS: A total of 30 patients were included in the study. The primary tumour and PET-positive lymph node(s) received a simultaneous integrated boost. Four weeks after IMAT +/- C treatment, response was evaluated. Resection consisted of hysterectomy with or without lymphadenectomy. Tumour response, acute and late radiation toxicity, postoperative morbidity and outcome were evaluated. RESULTS: All hysterectomy specimens were macroscopically tumour-free with negative resection margins; pathological complete response was 40%. In 2 patients, one resected lymph node was positive. There was no excess in postoperative morbidity. Apart from two grade 3 hematologic toxicities, no grade 3 or 4 acute radiation toxicity was observed. No grade 3, 1 grade 4 (4%) intestinal, and 4 grade 3 (14%) urinary late toxicities were observed. The 2-year local and regional control rates were 96% and 100%, respectively. The 2-year distant control rate was 92%. Actuarial 2-year progression free survival rate was 89%. Actuarial 1- and 2-year overall survival rates were 96% and 91%, while 3-year overall survival was 84%. CONCLUSION: Surgery after IMAT +/- C is feasible with low postoperative morbidity and radiation toxicity. Local, regional, distant control and survival rates are promising. PMID- 22526234 TI - The effect of point mutation on the equilibrium structural fluctuations of ferric Myoglobin. AB - The ultrafast equilibrium fluctuations of the Fe(III)-NO complex of a single point mutation of Myoglobin (H64Q) have been studied using Fourier Transform 2D IR spectroscopy. Comparison with data from wild type Myoglobin (wt-Mb) shows the presence of two conformational substates of the mutant haem pocket where only one exists in the wild type form. One of the substates of the mutant exhibits an almost identical NO stretching frequency and spectral diffusion dynamics to wt-Mb while the other is distinctly different in both respects. The remarkably contrasting dynamics are largely attributable to interactions between the NO ligand and a nearby distal side chain which provides a basis for understanding the roles of these side chains in other ferric haem proteins. PMID- 22526232 TI - Chemoradiation in patients with unresectable extrahepatic and hilar cholangiocarcinoma or at high risk for disease recurrence after resection : Analysis of treatment efficacy and failure in patients receiving postoperative or primary chemoradiation. AB - BACKGROUND: The purpose of this work was to determine efficacy, toxicity, and patterns of recurrence after concurrent chemoradiation (CRT) in patients with extrahepatic bile duct cancer (EHBDC) and hilar cholangiocarcinoma (Klatskin tumours) in case of incomplete resection or unresectable disease. PATIENTS AND METHODS: From 2003-2010, 25 patients with nonmetastasized EHBDC and hilar cholangiocarcinoma were treated with radiotherapy and CRT at our institution in an postoperative setting (10 patients, 9 patients with R1 resections) or in case of unresectable disease (15 patients). Median age was 63 years (range 38-80 years) and there were 20 men and 5 women. Median applied dose was 45 Gy in both patient groups. RESULTS: Patients at high risk (9 times R1 resection, 1 pathologically confirmed lymphangiosis) for tumour recurrence after curative surgery had a median time to disease progression of 8.7 months and an estimated mean overall survival of 23.2 months (6 of 10 patients are still under observation). Patients undergoing combined chemoradiation in case of unresectable primary tumours are still having a poor prognosis with a progression-free survival of 7.1 months and a median overall survival of 12.0 months. The main site of progression was systemic (liver, peritoneum) in both patient groups. CONCLUSION: Chemoradiation with gemcitabine is safe and can be applied safely in either patients with EHBDC or Klatskin tumours at high risk for tumour recurrence after resection and patients with unresectable tumours. Escalation of systemic and local treatment should be investigated in future clinical trials. PMID- 22526236 TI - Phosphine-mediated cascade reaction of azides with MBH-acetates of acetylenic aldehydes to substituted pyrroles: a facile access to N-fused pyrrolo heterocycles. AB - One-pot synthesis of substituted pyrroles by a cascade reaction of azides with Morita-Baylis-Hillman acetates of acetylenic aldehydes is described and the reaction is efficiently mediated by triphenyl phosphine at room temperature. Sodium azide is successfully used to provide N-unsubstituted pyrroles, while alkyl azides afforded the corresponding N-alkylated pyrroles through a sequence of allylic substitution/azide reduction/cycloisomerization reactions. The obtained products have provided a new entry to indolizino indoles, pyrrolo isoquinolines and 8-oxo-5,6,7,8-tetrahydroindolizine. PMID- 22526237 TI - 123I-FP-CIT SPECT imaging of the dopaminergic state. Visual assessment of dopaminergic degeneration patterns reflects quantitative 2D operator-dependent and 3D operator-independent techniques. AB - 123I-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl)nortropan (123I FP-CIT) single photon emission computed tomography (SPECT) can be evaluated by both visual assessment and quantitative analysis to assess the striatal dopamine state in vivo. The aim of our study was to investigate if visual assessment according to a predefined image grading scale reflects the results of quantitative assessment techniques. PATIENTS, METHODS: 195 patients with a clinical diagnosis of idiopathic Parkinson's disease (n = 134), atypical parkinsonian syndrome (n = 47) or essential tremor (n = 14) were examined with 123I-FP-CIT SPECT and included in this retrospective study. Results were analysed according to predefined visual patterns of dopaminergic degeneration and graded as normal (grade 5) or abnormal (grade 1-4) independently by three raters. Quantitative two-dimensional (2D) operator-dependent, manual and three dimensional (3D) operator-independent, automated approaches were used for quantitative analysis of the specific 123I-FP-CIT tracer binding ratio (SBR) for caudate and putamen. RESULTS: Sensitivity, specificity, PPV, NPV and diagnostic accuracy of visual assessment of 123I-FP-CIT SPECT for the diagnosis of a neurodegenerative Parkinson's syndrome were 99%, 86%, 99%, 86% and 98%, respectively. Visual assessment and quantitative analysis agreed well in evaluating the degree of dopaminergic degeneration. Significant differences (p<0.001) were found between degeneration patterns. Only between the so-called eagle wing degeneration and the normal pattern no significant differences in SBR caudate and putamen were found, neither by the quantitative manual (p = 1.00; p = 0.196) nor by the quantitative automated method (p=1.0; p = 0.785). Inter-rater agreement for visual assessment was substantial for all possible pairs of the three raters (kappa = 0.70 to 0.74). Strong correlations were observed between the quantitative manual and quantitative automated methods for quantification of SBR caudatum (r = 0.920, r2 = 0.846, p<0.001) and SBR putamen (r = 0.908, r2=0.824, p < 0.001). CONCLUSION: Visual assessment was highly consistent with the results obtained by quantitative analysis and showed a substantial inter rater agreement between experienced and inexperienced raters. Our findings indicate that visual assessment might be a reliable analysis approach for clinical routine. PMID- 22526238 TI - Glutamate: a truly functional amino acid. AB - Glutamate is one of the most abundant of the amino acids. In addition to its role in protein structure, it plays critical roles in nutrition, metabolism and signaling. Post-translational carboxylation of glutamyl residues increases their affinity for calcium and plays a major role in hemostasis. Glutamate is of fundamental importance to amino acid metabolism, yet the great bulk of dietary glutamate is catabolyzed within the intestine. It is necessary for the synthesis of key molecules, such as glutathione and the polyglutamated folate cofactors. It plays a major role in signaling. Within the central nervous system, glutamate is the major excitatory neurotransmitter and its product, GABA, the major inhibitory neurotransmitter. Glutamate interaction with specific taste cells in the tongue is a major component of umami taste. The finding of glutamate receptors throughout the gastrointestinal tract has opened up a new vista in glutamate function. Glutamate is truly a functional amino acid. PMID- 22526239 TI - Carnosine in exercise and disease: introduction to the International Congress held at Ghent University, Belgium, July 2011. PMID- 22526240 TI - The effects of oral taurine administration on behavior and hippocampal signal transduction in rats. AB - Taurine, 2-aminoethylsulfonic acid, is one of the most abundant amino acids in the brain. It has various important physiological functions as a neuromodulator and antioxidant. Taurine is expected to be involved in depression; however, knowledge regarding its function in relation to depression is limited. In this study, we attempted to elucidate the effects of oral taurine administration on antidepressant-like behaviors in rats and depression-related signal transduction in the hippocampus. In behavioral tests, rats fed a high taurine (HT: 45.0 mmol/kg taurine) diet for 4 weeks (HT4w) showed decreased immobility in the forced swim test (FS) compared to controls. However, rats fed a low taurine (LT: 22.5 mmol/kg taurine) diet for 4 weeks or an HT diet for 2 weeks (HT2w) did not show a significant difference in FS compared to controls. In biochemical analyses, the expression of glutamic acid decarboxylase (GAD) 65 and GAD67 in the hippocampus was not affected by taurine administration. However, the phosphorylation levels of extracellular signal-regulated kinase1/2 (ERK1/2), protein kinase B (Akt), glycogen synthase kinase3 beta (GSK3beta) and cAMP response element-binding protein (CREB) were increased in the hippocampus of HT4w and HT2w rats. Phospho-calcium/calmodulin-dependent protein kinase II (CaMKII) was increased in the hippocampus of HT4w rats only. Moreover, no significant changes in these molecules were observed in the hippocampus of rats fed an HT diet for 1 day. In conclusion, our findings suggest that taurine has an antidepressant-like effect and an ability to change depression-related signaling cascades in the hippocampus. PMID- 22526241 TI - Effect of hydrocarbon stapling on the properties of alpha-helical antimicrobial peptides isolated from the venom of hymenoptera. AB - The impact of inserting hydrocarbon staples into short alpha-helical antimicrobial peptides lasioglossin III and melectin (antimicrobial peptides of wild bee venom) on their biological and biophysical properties has been examined. The stapling was achieved by ring-closing olefin metathesis, either between two S 2-(4'-pentenyl) alanine residues (S (5)) incorporated at i and i + 4 positions or between R-2-(7'-octenyl) alanine (R (8)) and S (5) incorporated at the i and i + 7 positions, respectively. We prepared several lasioglossin III and melectin analogs with a single staple inserted into different positions within the peptide chains as well as analogs with double staples. The stapled peptides exhibited a remarkable increase in hemolytic activity, while their antimicrobial activities decreased. Some single stapled peptides showed a higher resistance against proteolytic degradation than native ones, while the double stapled analogs were substantially more resistant. The CD spectra of the singly stapled peptides measured in water showed only a slightly better propensity to form alpha-helical structure when compared to native peptides, whereas the doubly stapled analogs exhibited dramatically enhanced alpha-helicity. PMID- 22526242 TI - Effect of structural modification on the gastrointestinal stability and hepatic metabolism of alpha-aminoxy peptides. AB - alpha-Aminoxy peptide AxyP1 has been reported to form synthetic chloride channel in living cells, thus it may have therapeutic potential for the treatment of diseases associated with chloride channel dysfunction. However, this study revealed significant gastrointestinal (GI) instability and extensive hepatic metabolism of AxyP1. To improve its GI and metabolic stability, structural modifications were conducted by replacing the isobutyl side chains of AxyP1 with methyl group (AxyP2), hydroxymethyl group (AxyP3), 4-aminobutyl group (AxyP4) and 3-carboxyl propyl group (AxyP5). Compared with AxyP1 (41 and 47 % degradation), GI stability of the modified peptides was significantly improved by 8-fold (AxyP2), 9-fold (AxyP3) and 12-fold (AxyP5) with no degradation for AxyP4 in simulated gastric fluid within 1 h, and by 12-fold (AxyP2) and 9-fold (AxyP3) with no degradation for AxyP4 and AxyP5 in simulated intestinal fluid within 3 h, respectively. The hepatic metabolic stability of the four modified peptides within 30 min in rat liver S9 preparation was also improved significantly with no metabolism of AxyP5 and threefold (AxyP2 and AxyP4) and eightfold (AxyP3) less metabolism compared with AxyP1 (39 % metabolism). Unlike hydrolysis as the major metabolism of peptides of natural alpha-amino acids, oxidation mediated by the cytochrome P450 enzymes, especially CYP3A subfamily, to form the corresponding mono-hydroxyl metabolites was the predominant hepatic metabolism of the five alpha-aminoxy peptides tested. The present findings demonstrate that structural modification can significantly improve the GI and metabolic stability of alpha aminoxy peptides and thus increase their potential for therapeutic use in the treatment of chloride channel related diseases. PMID- 22526243 TI - Cyclic enediyne-amino acid chimeras as new aminopeptidase N inhibitors. AB - Enediyne-peptide conjugates were designed with the aim to inhibit aminopeptidase N, a widespread ectoenzyme with a variety of functions, like protein digestion, inactivation of cytokines in the immune system and endogenous opioid peptides in the central nervous system. Enediyne moiety was embedded within the 12-membered ring with hydrophobic amino acid alanine, valine, leucine or phenylalanine used as carriers. Aromatic part of the enediyne bridging unit and the amino acid side chains were considered as pharmacophores for the binding to the aminopeptidase N (APN) active site. Additionally, the fused enediyne-amino acid "heads" were bound through a flexible linker to the L-lysine, an amino group donor. The synthesis included building the aromatic enediyne core at the C-terminal of amino acids and subsequent intramolecular N-alkylation. APN inhibition test revealed that the alanine-based derivative 9a inhibits the APN with IC(50) of 34 +/- 11 MUM. Enediyne-alanine conjugate 12 missing the flexible linker was much less effective in the APN inhibition. These results show that enediyne-fused amino acids have potential as new pharmacophores in the design of APN inhibitors. PMID- 22526244 TI - Hypothesis with abnormal amino acid metabolism in depression and stress vulnerability in Wistar Kyoto rats. AB - While abnormalities in monoamine metabolism have been investigated heavily per potential roles in the mechanisms of depression, the contribution of amino acid metabolism in the brain remains not well understood. In additional, roles of the hypothalamus-pituitary-adrenal axis in stress-regulation mechanisms have been of much focus, while the contribution of central amino acid metabolism to these mechanisms has not been well appreciated. Therefore, whether depression-like states affect amino acid metabolism and their potential roles on stress regulatory mechanisms were investigated by comparing Wistar Kyoto rats, which display depression-like behaviors and stress vulnerability, to control Wistar rats. Brain amino acid metabolism in Wistar Kyoto rats was greatly different from normal Wistar rats, with special reference to lower cystathionine and serine levels. In addition, Wistar Kyoto rats demonstrated abnormality in dopamine metabolism compared with Wistar rats. In the case of stress response, amino acid levels having a sedative and/or hypnotic effect were constant in the brain of Wistar Kyoto rats, though these amino acid levels were reduced in Wistar rats under a stressful condition. These results suggest that the abnormal amino acid metabolism may induce depression-like behaviors and stress vulnerability in Wistar Kyoto rats. Therefore, we hypothesized that abnormalities in amino acid and monoamine metabolism may induce depression, and amino acid metabolism in the brain may be related to stress vulnerability. PMID- 22526245 TI - Molecularly imprinted polymers for histamine recognition in aqueous environment. AB - Molecularly imprinted polymers (MIP) for histamine using methacrylic acid were developed and recognition mechanisms were thoroughly characterized for the first time in this study. The binding affinity of imprinted polymer with structurally related compounds was studied in organic and aqueous media, at various conditions. In organic media, MIP was found to bind histamine two and six times more than ranitidine and fluoxetine, respectively, whereas higher selectivity was observed in the case of dimentidene or disodium cromoglycate. The specific binding sites of MIP recognized histamine over L-histidine in aqueous conditions, while higher affinity for histamine compared to ranitidine, disodium cromoglycate, putrescine and to a putrescine analogue was observed. A combination of NMR and UV spectroscopy analyses for investigation of imprinting and recognition properties revealed that strong specific interactions between the functional monomer and histamine in the prepolymerization and in the aqueous solutions were probably responsible for histamine recognition. The preparation of histamine MIPs and elucidation of imprinting and recognition mechanism may serve as useful insight for future application of MIPs. PMID- 22526246 TI - Large scale metal-free synthesis of graphene on sapphire and transfer-free device fabrication. AB - Metal catalyst-free growth of large scale single layer graphene film on a sapphire substrate by a chemical vapor deposition (CVD) process at 950 degrees C is demonstrated. A top-gated graphene field effect transistor (FET) device is successfully fabricated without any transfer process. The detailed growth process is investigated by the atomic force microscopy (AFM) studies. PMID- 22526247 TI - Influence of acute dietary nitrate supplementation on 50 mile time trial performance in well-trained cyclists. AB - Dietary nitrate supplementation has been reported to improve short distance time trial (TT) performance by 1-3 % in club-level cyclists. It is not known if these ergogenic effects persist in longer endurance events or if dietary nitrate supplementation can enhance performance to the same extent in better trained individuals. Eight well-trained male cyclists performed two laboratory-based 50 mile TTs: (1) 2.5 h after consuming 0.5 L of nitrate-rich beetroot juice (BR) and (2) 2.5 h after consuming 0.5 L of nitrate-depleted BR as a placebo (PL). BR significantly elevated plasma [NO(2) (-)] (BR: 472 +/- 96 vs. PL: 379 +/- 94 nM; P < 0.05) and reduced completion time for the 50 mile TT by 0.8 % (BR: 136.7 +/- 5.6 vs. PL: 137.9 +/- 6.4 min), which was not statistically significant (P > 0.05). There was a significant correlation between the increased post-beverage plasma [NO(2) (-)] with BR and the reduction in TT completion time (r = -0.83, P = 0.01). Power output (PO) was not different between the conditions at any point (P > 0.05) but oxygen uptake ([Formula: see text]O(2)) tended to be lower in BR (P = 0.06), resulting in a significantly greater PO/[Formula: see text]O(2) ratio (BR: 67.4 +/- 5.5 vs. PL: 65.3 +/- 4.8 W L min(-1); P < 0.05). In conclusion, acute dietary supplementation with beetroot juice did not significantly improve 50 mile TT performance in well-trained cyclists. It is possible that the better training status of the cyclists in this study might reduce the physiological and performance response to NO(3) (-) supplementation compared with the moderately trained cyclists tested in earlier studies. PMID- 22526248 TI - The magnitude and duration of post-exercise hypotension after land and water exercises. AB - The objective of the study was to determine and compare the magnitude and duration of post-exercise hypotension (PEH) during free-living conditions after an acute session of concurrent water and land exercise in individuals with prehypertension and hypertension. Twenty-one men and women (aged 52 +/- 10 years) volunteered for the study. Participants completed a no exercise control session, a water exercise session and a land exercise session in random order. After all three sessions, participants underwent 24-h monitoring using an Ergoscan ambulatory BP monitoring device. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were monitored to determine changes from resting values after each session and to compare the PEH responses between land and water exercises. During daytime, both land and water exercises resulted in significantly lower SBP (12.7 and 11.3 mmHg) compared to the control session (2.3 mmHg). The PEH response lasted for 24 h after land exercise and 9 h after water exercise. There was no difference in the daytime DBP for the three treatments (P > 0.05). Although all three groups showed significant reductions during nighttime, both exercise treatments showed greater nocturnal falls in BP than the control treatment. This is the first study to show that the magnitude of the PEH response is similar for land and water exercises, although the duration of PEH may be longer for land exercise. These results suggest that water exercise is a safe alternative exercise modality for individuals with suspected and known hypertension. PMID- 22526249 TI - The influence of rowing-related postures upon respiratory muscle pressure and flow generating capacity. AB - During the rowing stroke, the respiratory muscles are responsible for postural control, trunk stabilisation, generation/transmission of propulsive forces and ventilation (Bierstacker et al. in Int J Sports Med 7:73-79, 1986; Mahler et al. in Med Sci Sports Exerc 23:186-193, 1991). The challenge of these potentially competing requirements is exacerbated in certain parts of the rowing stroke due to flexed (stroke 'catch') and extended postures (stroke 'finish'). The purpose of this study was to assess the influence of the postural role of the trunk muscles upon pressure and flow generating capacity, by measuring maximal respiratory pressures, flows, and volumes in various seated postures relevant to rowing. Eleven male and five female participants took part in the study. Participants performed two separate testing sessions using two different testing protocols. Participants performed either maximal inspiratory or expiratory mouth pressure manoeuvres (Protocol 1), or maximal flow volume loops (MFVLs) (Protocol 2), whilst maintaining a variety of specified supported or unsupported static rowing-related postures. Starting lung volume was controlled by initiating the test breath in the upright position. Respiratory mouth pressures tended to be lower with recumbency, with a significant decrease in P (Emax) in unsupported recumbent postures (3-9 % compared to upright seated; P = 0.036). There was a significant decrease in function during dynamic manoeuvres, including PIF (5-9 %), FVC (4-7 %) and FEV(1) (4-6 %), in unsupported recumbent postures (p < 0.0125; Bonferroni corrected). Thus, respiratory pressure and flow generating capacity tended to decrease with recumbency; since lung volumes were standardised, this may have been, at least in part, influenced by the postural co contraction of the trunk muscles. PMID- 22526250 TI - Time course of arterial remodelling in diameter and wall thickness above and below the lesion after a spinal cord injury. AB - Physical inactivity in response to a spinal cord injury (SCI) represents a potent stimulus for conduit artery remodelling. Changes in conduit artery characteristics may be induced by the local effects of denervation (and consequent extreme inactivity below the level of the lesion), and also by systemic adaptations due to whole body inactivity. Therefore, we assessed the time course of carotid (i.e. above lesion) and common femoral artery (i.e. below lesion) lumen diameter and wall thickness across the first 24 weeks after an SCI. Eight male subjects (mean age 35 +/- 14 years) with a traumatic motor complete spinal cord lesion between T5 and L1 (i.e. paraplegia) were included. Four subjects were measured across the first 6 weeks after SCI, whilst another four subjects were measured from 8 until 24 weeks after SCI. Ultrasound was used to examine the diameter and wall thickness from the carotid and common femoral arteries. Carotid artery diameter did not change across 24 weeks, whilst femoral artery diameter stabilised after the rapid initial decrease during the first 3 weeks after the SCI. Carotid and femoral artery wall thickness showed no change during the first few weeks, but increased both between 6 and 24 weeks (P < 0.05). In conclusion, SCI leads to a rapid and localised decrease in conduit artery diameter which is isolated to the denervated and paralyzed region, whilst wall thickness gradually increases both above and below the lesion. This distinct time course of change in conduit arterial diameter and wall thickness suggests that distinct mechanisms may contribute to these adaptations. PMID- 22526251 TI - Heat acclimation decreased oxidative DNA damage resulting from exposure to high heat in an occupational setting. AB - Heat acclimation is a physiologically and biochemically adapted process when species transition from one environmental temperature to one of the increased temperature. There is very limited epidemiological evidence on the heat-related impacts during exposure to extremely high heat in an occupational environment. This study sought to identify a potential biomarker of heat acclimation and the burden of heat on the body. The aim of this study was to elucidate oxidative DNA damage and heat acclimation through a self-comparison study design in navy boiler tenders, subjects exposed to extremely high heat in an occupational setting. Fifty-eight male soldiers who work in a boiler room were recruited for this study. The subjects were initially assessed with a health examination and body composition assessment before sailing. In order to compare the within-subject differences before and after heat exposure, the index-related heat exposure was collected before and after a routine 5-h work shift and 7-day sailing. Urinary 8 hydroxy-2'-deoxyguanosine (8-OHdG), a useful marker of oxidative DNA damage was the measurement by liquid chromatography/tandem mass spectrometry. The median of the change in urinary 8-OHdG was 0.78 MUg/g creatinine, as the urinary 8-OHdG after sailing was significantly higher than before sailing (p < 0.01). The urinary 8-OHdG was significantly decreased in heat-acclimated boiler tenders. Oxidative DNA damage was significantly decreased in heat-acclimated subjects. Urinary 8-OHdG can be used as a biomarker to assess the effect of heat stress as a result of occupational exposure to extremely high heat conditions. PMID- 22526252 TI - Exercise-induced muscle damage from bench press exercise impairs arm cranking endurance performance. AB - The effects of exercise-induced muscle damage (EIMD) on the physiological, metabolic and perceptual responses during upper body arm cranking exercise are unknown. Nine physically active male participants performed 6 min of arm cranking exercise at ventilatory threshold (VT), followed by a time to exhaustion (TTE) trial at a workload corresponding to 80 % of the difference between VT and [Formula: see text] 48 h after bench pressing exercise (10 * 6 repetitions at 70 % one repetition maximum) or 20 min sitting (control). Reductions in isokinetic strength and increased muscle soreness of the elbow flexors and extensors were evident at 24 and 48 h after bench pressing exercise (P < 0.05). Despite no change in [Formula: see text], [Formula: see text], HR and blood lactate concentration ([Bla]) between conditions (P > 0.05), rating of perceived exertion (RPE) was higher during the 6 min arm cranking after bench pressing exercise compared to the control condition (P < 0.05). TTE was reduced in the treatment condition (207.2 +/- 91.9 cf. 293.4 +/- 75.6 s; P < 0.05), as were end [Formula: see text] (P < 0.05) and [Bla] at 0, 5 and 10 min after exercise (P < 0.05). RPE during the TTE trial was higher after bench pressing (P < 0.05), although end RPE was not different between conditions (P > 0.05). This study provides evidence that EIMD caused by bench pressing exercise increases the sense of effort during arm cranking exercise that leads to a reduced exercise tolerance. The findings have implications for individuals participating in concurrent endurance and resistance training of the upper body. PMID- 22526254 TI - Programmable self-assembly of homo- or hetero-metallomacrocycles using 4-(1H pyrazolyl-4-yl)pyridine. AB - The dimetallic [M(2)(bpy)(2)(NO(3))(2)](NO(3))(2) moieties (M = Pd(II) or Pt(II)) react preferentially at the pyrazolyl end of the pyridyl-pyrazole ligand, giving rise to dimetallic corners. Subsequently, the dimetallic corner building blocks featuring two pyridine donors are coordinated by monometallic [M(bpy)(NO(3))(2)] moieties (M = Pd(II) or Pt(II)) to form homo- or hetero-metallomacrocycles. PMID- 22526253 TI - Isometric strength training lowers the O2 cost of cycling during moderate intensity exercise. AB - The effect of maximal voluntary isometric strength training of knee extensor muscles on pulmonary V'O(2) on-kinetics, the O(2) cost of cycling and peak oxygen uptake (V'O(2peak)) in humans was studied. Seven healthy males (mean +/- SD, age 22.3 +/- 2.0 years, body weight 75.0 +/- 9.2 kg, V'O(2peak) 49.5 +/- 3.8 ml kg( 1) min(-1)) performed maximal isometric strength training lasting 7 weeks (4 sessions per week). Force during maximal voluntary contraction (MVC) increased by 15 % (P < 0.001) after 1 week of training, and by 19 % (P < 0.001) after 7 weeks of training. This increase in MVC was accompanied by no significant changes in the time constant of the V'O(2) on-kinetics during 6 min of moderate and heavy cycling intensities. Strength training resulted in a significant decrease (by ~7 %; P < 0.02) in the amplitude of the fundamental component of the V'O(2) on kinetics, and therefore in a lower O(2) cost of cycling during moderate cycling intensity. The amplitude of the slow component of V'O(2) on-kinetics during heavy cycling intensity did not change with training. Training had no effect on the V'O(2peak), whereas the maximal power output reached at V'O(2peak) was slightly but significantly increased (P < 0.05). Isometric strength training rapidly (i.e., after 1 week) decreases the O(2) cost of cycling during moderate-intensity exercise, whereas it does not affect the amplitude of the slow component of the V'O(2) on-kinetics during heavy-intensity exercise. Isometric strength training can have beneficial effects on performance during endurance events. PMID- 22526255 TI - Brain-targeted (pro)renin receptor knockdown attenuates angiotensin II-dependent hypertension. AB - The (pro)renin receptor is a newly discovered member of the brain renin angiotensin system. To investigate the role of brain (pro)renin receptor in hypertension, adeno-associated virus-mediated (pro)renin receptor short hairpin RNA was used to knockdown (pro)renin receptor expression in the brain of nontransgenic normotensive and human renin-angiotensinogen double-transgenic hypertensive mice. Blood pressure was monitored using implanted telemetric probes in conscious animals. Real-time PCR and immunostaining were performed to determine (pro)renin receptor, angiotensin II type 1 receptor, and vasopressin mRNA levels. Plasma vasopressin levels were determined by ELISA. Double transgenic mice exhibited higher blood pressure, elevated cardiac and vascular sympathetic tone, and impaired spontaneous baroreflex sensitivity. Intracerebroventricular delivery of (pro)renin receptor short-hairpin RNA significantly reduced blood pressure, cardiac and vasomotor sympathetic tone, and improved baroreflex sensitivity compared with the control virus treatment in double-transgenic mice. (Pro)renin receptor knockdown significantly reduced angiotensin II type 1 receptor and vasopressin levels in double-transgenic mice. These data indicate that (pro)renin receptor knockdown in the brain attenuates angiotensin II-dependent hypertension and is associated with a decrease in sympathetic tone and an improvement of the baroreflex sensitivity. In addition, brain-targeted (pro)renin receptor knockdown is associated with downregulation of angiotensin II type 1 receptor and vasopressin levels. We conclude that central (pro)renin receptor contributes to the pathogenesis of hypertension in human renin-angiotensinogen transgenic mice. PMID- 22526256 TI - Preeclampsia: the role of aldosterone in hypertension and inflammation. PMID- 22526257 TI - Blood pressure change in normotensive, gestational hypertensive, preeclamptic, and essential hypertensive pregnancies. AB - We compared patterns of blood pressure (BP) change among normotensive women, women who developed gestational hypertension or preeclampsia, and women who had essential hypertension to examine how distinct these conditions are and whether rates of BP change may help to identify women at risk for hypertensive disorders. We used antenatal clinic BP measurements (median, 14 per woman) of 13016 women from the Avon Longitudinal Study of Parents and Children who had a singleton or twin live birth surviving until >= 1 year. Linear spline models were used to describe changes in systolic and diastolic BPs in different periods of pregnancy (8-18, 18-30, 30-36, and >= 36 weeks' gestation). Women who had essential hypertension and those who developed gestational hypertension or preeclampsia had higher BP at 8 weeks' gestation (baseline) compared with normotensive women. The decrease in BP until 18 weeks was smaller in gestational hypertensive compared with normotensive pregnancies. BP rose more rapidly from 18 weeks onward in gestational hypertensive and preeclamptic pregnancies and from 30 weeks onward in essential hypertensive compared with normotensive pregnancies. Women who developed preeclampsia had a more rapid increase in BP from 30 weeks onward than those who developed gestational hypertension or had essential hypertension. Our findings indicate notable patterns of BP change that distinguish women with essential hypertension, gestational hypertension, and preeclampsia from each other and from normotensive women, even from early pregnancy. These distinct patterns may be useful for identifying women at risk of developing a hypertensive disorder later in pregnancy. PMID- 22526258 TI - The circadian protein period 1 contributes to blood pressure control and coordinately regulates renal sodium transport genes. AB - The circadian clock protein period 1 (Per1) contributes to the regulation of expression of the alpha subunit of the renal epithelial sodium channel at the basal level and in response to the mineralocorticoid hormone aldosterone. The goals of the present study were to define the role of Per1 in the regulation of additional renal sodium handling genes in cortical collecting duct cells and to evaluate blood pressure (BP) in mice lacking functional Per1. To determine whether Per1 regulates additional genes important in renal sodium handling, a candidate gene approach was used. Immortalized collecting duct cells were transfected with a nontarget small interfering RNA or a Per1-specific small interfering RNA. Expression of the genes for alpha-epithelial sodium channel and Fxyd5, a positive regulator of Na, K-ATPase activity, decreased in response to Per1 knockdown. Conversely, mRNA expression of caveolin 1, Ube2e3, and ET-1, all negative effectors of epithelial sodium channel, was induced after Per1 knockdown. These results led us to evaluate BP in Per1 KO mice. Mice lacking Per1 exhibit significantly reduced BP and elevated renal ET-1 levels compared with wild-type animals. Given the established role of renal ET-1 in epithelial sodium channel inhibition and BP control, elevated renal ET-1 is one possible explanation for the lower BP observed in Per1 KO mice. These data support a role for the circadian clock protein Per1 in the coordinate regulation of genes involved in renal sodium reabsorption. Importantly, the lower BP observed in Per1 KO mice compared with wild-type mice suggests a role for Per1 in BP control as well. PMID- 22526259 TI - Chlorthalidone compared with hydrochlorothiazide in reducing cardiovascular events: systematic review and network meta-analyses. AB - Hydrochlorothiazide (HCTZ) is widely used for hypertension, and prescriptions for HCTZ outnumber those for chlorthalidone (CTDN) by >20-fold in 2 recent surveys. Some have recently expressed a preference for CTDN. However, head-to-head trials testing the effect of the 2 drugs on cardiovascular events (CVEs) are lacking. We conducted a systematic review of randomized trials in which 1 arm was based on either HCTZ or CTDN followed by 2 types of network meta-analyses, a drug-adjusted analysis and an office systolic blood pressure-adjusted analysis. Nine trials were identified: 3 based on HCTZ and 6 based on CTDN. In the drug-adjusted analysis (n = 50946), the percentage of risk reduction in congestive heart failure for CTDN versus HCTZ was 23 (95% CI, 2-39; P = 0.032); and in all CVEs was 21 (95% CI, 12-28; P<0.0001). In the office systolic blood pressure-adjusted analysis (n = 78350), the percentage of risk reduction in CVEs for CTDN versus HCTZ was 18 (95% CI, 3-30; P = 0.024). When the reduction in office systolic blood pressure was identical in the 2 arms, the risk for CVEs in HCTZ arms was 19% higher than in its nondiuretic comparator arms (P = 0.021). Relative to HCTZ, the number needed to treat with CTDN to prevent 1 CVE over 5 years was 27. In conclusion, CTDN is superior to HCTZ in preventing cardiovascular events. This cannot be attributed entirely to the lesser effect of HCTZ on office systolic blood pressure but may be attributed to the pleomorphic effects of alternative medications or to the short duration of action of HCTZ. PMID- 22526260 TI - Thermoregulatory changes anticipate hibernation onset by 45 days: data from free living arctic ground squirrels. AB - Hibernation is a strategy of reducing energy expenditure, body temperature (T(b)) and activity used by endotherms to escape unpredictable or seasonally reduced food availability. Despite extensive research on thermoregulatory adjustments during hibernation, less is known about transitions in thermoregulatory state, particularly under natural conditions. Laboratory studies on hibernating ground squirrels have demonstrated that thermoregulatory adjustments may occur over short intervals when animals undergo several brief, preliminary torpor bouts prior to entering multiday torpor. These short torpor bouts have been suggested to reflect a resetting of hypothalamic regions that control T(b) or to precondition animals before they undergo deep, multiday torpor. Here, we examined continuous records of T(b) in 240 arctic ground squirrels (Urocitellus parryii) prior to hibernation in the wild and in captivity. In free-living squirrels, T(b) began to decline 45 days prior to hibernation, and average T(b) had decreased 4.28 degrees C at the onset of torpor. Further, we found that 75 % of free living squirrels and 35 % of captive squirrels entered bouts of multiday torpor with a single T(b) decline and without previously showing short preliminary bouts. This study provides evidence that adjustments in the thermoregulatory component of hibernation begin far earlier than previously demonstrated. The gradual reduction in T(b) is likely a component of the suite of metabolic and behavioral adjustments, controlled by an endogenous, circannual rhythm, that vary seasonally in hibernating ground squirrels. PMID- 22526261 TI - HIF-1alpha regulation in mammalian hibernators: role of non-coding RNA in HIF 1alpha control during torpor in ground squirrels and bats. AB - A potential role for non-coding RNAs, miR-106b and antisense hypoxia inducible transcription factor-1 (HIF-1alpha), in HIF-1alpha regulation during mammalian hibernation was investigated in two species, the thirteen-lined ground squirrel (Ictidomys tridecemlineatus) and the little brown bat (Myotis lucifugus). Both species showed differential regulation of HIF-1alpha during hibernation. HIF 1alpha protein levels increased significantly in skeletal muscle of both species when animals entered torpor, as well as in bat liver. HIF-1alpha mRNA levels correlated with the protein increase in bat skeletal muscle and liver but not in squirrel skeletal muscle. Antisense HIF-1alpha transcripts were identified in skeletal muscle of both hibernators. The expression of antisense HIF-1alpha was reduced in skeletal muscle of torpid bats compared with euthermic controls, suggesting that release of inhibition by the antisense RNA contributes to regulating HIF-1alpha translation in this tissue during torpor. The expression of miR-106b, a microRNA associated with HIF-1alpha regulation, also decreased during torpor in both skeletal muscle and liver of bats and in ground squirrel skeletal muscle. These data present the first evidence that non-coding RNA provides novel post-transcriptional mechanisms of HIF-1alpha regulation when hibernators descend into deep cold torpor, and also demonstrate that these mechanisms are conserved in two divergent mammalian orders (Rodentia and Chiroptera). PMID- 22526262 TI - 'No cost of echolocation for flying bats' revisited. AB - Echolocation is energetically costly for resting bats, but previous experiments suggested echolocation to come at no costs for flying bats. Yet, previous studies did not investigate the relationship between echolocation, flight speed, aerial manoeuvres and metabolism. We re-evaluated the 'no-cost' hypothesis, by quantifying the echolocation pulse rate, the number of aerial manoeuvres (landings and U-turns), and the costs of transport in the 5-g insectivorous bat Rhogeessa io (Vespertilionidae). On average, bats (n = 15) travelled at 1.76 +/- 0.36 m s-1 and performed 11.2 +/- 6.1 U-turns and 2.8 +/- 2.9 ground landings when flying in an octagonal flight cage. Bats made more U-turns with decreasing wing loading (body weight divided by wing area). At flight, bats emitted 19.7 +/- 2.7 echolocation pulses s-1 (range 15.3-25.8 pulses s-1), and metabolic rate averaged 2.84 +/- 0.95 ml CO2 min-1, which was more than 16 times higher than at rest. Bats did not echolocate while not engaged in flight. Costs of transport were not related to the rate of echolocation pulse emission or the number of U turns, but increased with increasing number of landings; probably as a consequence of slower travel speed when staying briefly on ground. Metabolic power of flight was lower than predicted for R. io under the assumption that energetic costs of echolocation call production is additive to the aerodynamic costs of flight. Results of our experiment are consistent with the notion that echolocation does not add large energetic costs to the aerodynamic power requirements of flight in bats. PMID- 22526264 TI - Activity and selectivity of histidine-containing lytic peptides to antibiotic resistant bacteria. AB - Lytic peptides are a group of membrane-acting peptides that are active to antibiotic-resistant bacteria but demonstrate high toxicity to tissue cells. Here, we reported the construction of new lytic peptide derivatives through the replacement of corresponding lysine/arginine residues in lytic peptide templates with histidines. Resulting lytic peptides had the same lethality to antibiotic resistant bacteria, including methicillin-resistant Staphylococcus aureus, but showed greatly improved selectivity to bacteria. When incubated with co-cultured bacteria and tissue cells, these histidine-containing lytic peptide derivatives killed bacteria selectively but spared co-cultured human cells. Membrane insertion and peptide-quenching studies revealed that histidine protonation controlled peptide interactions with cell membranes determined the bacterial selectivity of lytic peptide derivatives. Compared with parent peptides, lytic peptide derivatives bound to bacteria strongly and inserted deeply into the bacterial cell membrane. Therefore, histidine-containing lytic peptides represent a new group of antimicrobial peptides for bacterial infections in which the antibiotic resistance has developed. PMID- 22526265 TI - A TonB-dependent outer membrane receptor of Pseudomonas fluorescens: virulence and vaccine potential. AB - Pseudomonas fluorescens is a Gram-negative bacterium and a common aquaculture pathogen. In this study, we identified from a pathogenic P. fluorescens strain a TonB-dependent outer membrane receptor, TdrA, as a secreted protein and examined its function and vaccine potential. TdrA is composed of 746 residues and possesses conserved structural domains of TonB-dependent outer membrane receptors. Quantitative real-time reverse transcriptase-PCR analysis showed that expression of tdrA was upregulated under conditions of iron starvation and during infection of host cells. Consistently, iron depletion induced increased production of TdrA protein in the outer membrane. Compared to the wild type, a tdrA-knock out mutant (1) was unable to grow in the absence of iron, (2) exhibited drastically attenuated overall bacterial virulence, and (3) was impaired in the ability to establish lethal infection in host tissues. Purified recombinant TdrA (rTdrA), when used as a subunit vaccine to immunize flounder, was able to induce strong protective immunity, including production of serum specific antibodies that resulted in effective protection against lethal-dose P. fluorescens challenge. Together, these results indicate that TdrA is an outer membrane receptor and a protective immunogen that is likely to be involved in iron acquisition and, as a result, required for optimal bacterial virulence. PMID- 22526263 TI - Cystic fibrosis transmembrane conductance regulator in the gills of the climbing perch, Anabas testudineus, is involved in both hypoosmotic regulation during seawater acclimation and active ammonia excretion during ammonia exposure. AB - This study aimed to clone and sequence the cystic fibrosis transmembrane conductance regulator (cftr) from, and to determine the effects of seawater acclimation or exposure to 100 mmol l-1 NH4Cl in freshwater on its mRNA and protein expressions in, the gills of Anabas testudineus. There were 4,530 bp coding for 1,510 amino acids in the cftr cDNA sequence from A. testudineus. The branchial mRNA expression of cftr in fish kept in freshwater was low (<50 copies of transcript per ng cDNA), but significant increases were observed in fish acclimated to seawater for 1 day (92-fold) or 6 days (219-fold). Branchial Cftr expression was detected in fish acclimated to seawater but not in the freshwater control, indicating that Cl- excretion through the apical Cftr of the branchial epithelium was essential to seawater acclimation. More importantly, fish exposed to ammonia also exhibited a significant increase (12-fold) in branchial mRNA expression of cftr, with Cftr being expressed in a type of Na+/K+-ATPase immunoreactive cells that was apparently different from the type involved in seawater acclimation. It is probable that Cl- excretion through Cftr generated a favorable electrical potential across the apical membrane to drive the excretion of NH4+ against a concentration gradient through a yet to be determined transporter, but it led to a slight loss of endogenous Cl-. Since ammonia exposure also resulted in significant decreases in blood pH, [HCO3-] and [total CO2] in A. testudineus, it can be deduced that active NH4+ excretion could also be driven by the exit of HCO3- through the apical Cftr. Furthermore, A. testudineus uniquely responded to ammonia exposure by increasing the ambient pH and decreasing the branchial bafilomycin-sensitive V-type H+-ATPase activity, which suggests that its gills might have low NH3 permeability. PMID- 22526266 TI - The biosynthetic pathway to a novel derivative of 4,4'-diapolycopene-4,4'-oate in a red strain of Sporosarcina aquimarina. AB - In a red bacterial strain SF238 belonging to Sporosarcina aquimarina, a C(30) carotenoid biosynthetic pathway was identified. It has been reconstructed by analysis of intermediates that accumulate in two different pigment mutants. It starts with the synthesis of 4,4'-diapophytoene and proceeds with its desaturation to 4,4'-diapolycopene, which is then oxidized to 4,4'-diapolycopene 4,4'-dioate. Using a combination of HPLC-PDA and LC-MS/MS analyses, the final product of this pathway was identified as acetyl-4,4'-diapolycopene-4,4'-dioate. This is a novel carotenoid not reported in any organisms to date. It could be demonstrated that this carotenoid has excellent antioxidative properties to protect from photosensitized peroxidation reactions like other related 4,4' diapolycopene-4,4'-dioate derivatives. PMID- 22526267 TI - Thiofractor thiocaminus gen. nov., sp. nov., a novel hydrogen-oxidizing, sulfur reducing epsilonproteobacterium isolated from a deep-sea hydrothermal vent chimney in the Nikko Seamount field of the northern Mariana Arc. AB - A novel chemolithoautotrophic hydrogen-oxidizing and sulfur-reducing bacterium, strain 496Chim(T), was isolated from a deep-sea hydrothermal vent chimney collected from the hydrothermal field at the summit of Nikko Seamount field, in the Mariana Arc. Cells were rods or curved rods, motile by means of a single polar flagellum. Growth was observed between 15 and 45 degrees C (optimum 37 degrees C; doubling time, 2.1 h) and between pH 5.3 and 8.0 (optimum pH 6.0). The isolate was a strictly anaerobic, obligate chemolithoautotroph capable of growth using molecular hydrogen as the sole energy source, carbon dioxide as the sole carbon source, ammonium or nitrate as the sole nitrogen source, and elemental sulfur as the electron acceptor. The G+C content of genomic DNA was 35 mol%. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the new isolate belonged to the class Epsilonproteobacteria, but the isolate was distantly related to the previously described Epsilonproteobacteria species potentially at the genus level (<90 %). On the basis of its physiological and molecular characteristics, strain 496Chim(T) (=DSM 22050(Tau) = JCM 15747(Tau) = NBRC 105224(Tau)) represents the sole species of a new genus, Thiofractor, for which the name Thiofractor thiocaminus is proposed. PMID- 22526268 TI - Relations between phenotypic changes of spores and biofilm production by Bacillus atrophaeus ATCC 9372 growing in solid-state fermentation. AB - Bacillus spp. spores are usually obtained from strains cultivated in artificial media. However, in natural habitats, spores are predominantly formed from bacteria present in highly surface-associated communities of cells. Solid-state fermentation (SSF) is the culture method that best mimetizes the natural environment of many microorganisms that grow attached to the surface of solid particles. This study aims to confirm that sporulation through SSF of Bacillus atrophaeus occurs by biofilm formation and that this model of fermentation promotes important phenotypic changes in the spores. Sporulation on standard agar and by SSF with sand and sugarcane bagasse as support was followed by a comparative study of the formed spores. Growth characteristics, metabolic and enzymatic profiles confirmed that sporulation through SSF occurs by biofilm formation promoting important phenotypic changes. It was possible to demonstrate that spores coat had different structure and the presence of ridges only on SSF spores' surface. The sporulation conditions did not affect the dry-heat spore resistance. The type of support evaluated also influenced in the phenotypic alterations; however, the used substrates did not cause interference. This work provides novel information about B. atrophaeus response when submitted to different sporulation conditions and proposes a new concept about bacterial biofilm formation by SSF. PMID- 22526269 TI - Predicting survival after living and deceased donor liver transplantation in adult patients with acute liver failure. AB - BACKGROUND: Post-transplant outcomes for acute liver failure (ALF) are unsatisfactory, and there are debates about the most suitable type of graft. Given the critical shortage of donor organs, accurate assessment of post transplant outcome in ALF patients is crucial to avoid a futile liver transplantation (LT). METHODS: A database of 160 consecutive adult ALF patients who underwent primary LT between 2000 and 2009 in a tertiary LT center was analyzed. RESULTS: The most common causes of ALF were hepatitis B virus infection (30%) and herbal/folk medicine use (30%). Thirty-six (22.5%) and 124 (77.5%) patients underwent deceased-donor LT (DDLT) and adult-to-adult living-donor LT (LDLT), respectively. During a median follow-up period of 38 (range 1-132) months, the DDLT and LDLT groups showed similar patient (P = 0.99) and graft (P = 0.97) survival rates. The overall 1- and 3-year patient survival rates were 78.8 and 74.6%, respectively. Five predictors of patient survival were identified by bootstrapping and multivariate analysis: vasopressor requirement, estimated glomerular filtration rate, serum sodium concentration, recipient age, and donor age, at the time of transplant. By summing scores weighted in each of these predictor categories, we designed a prognostic scoring system (scores from -2 to 20) that estimated 1-year post-transplant mortality from 0 to 100% (c statistic 0.79). CONCLUSIONS: Long-term outcomes after LDLT and DDLT were comparable in adult patients with ALF. A simple prognostic scoring system that includes 5 predictive variables at the time of LT may help estimate post-transplant survival in ALF patients, regardless of the type of transplant. PMID- 22526270 TI - Assessment of Gd-EOB-DTPA-enhanced MRI for HCC and dysplastic nodules and comparison of detection sensitivity versus MDCT. AB - BACKGROUND: We aimed to evaluate gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) for the detection of hepatocellular carcinomas (HCCs) and dysplastic nodules (DNs) compared with dynamic multi-detector row computed tomography (MDCT), and to discriminate between HCCs and DNs. METHODS: Eighty-six nodules diagnosed as HCC or DNs were retrospectively investigated. Gd-EOB-DTPA-enhanced MRI and dynamic MDCT were compared with respect to their diagnostic ability for hypervascular HCCs and detection sensitivity for hypovascular tumors. The ability of hepatobiliary images of Gd-EOB-DTPA-enhanced MRI to discriminate between these nodules was assessed. We also calculated the EOB enhancement ratio of the tumors. RESULTS: For hypervascular HCCs, the diagnostic ability of Gd-EOB-DTPA-enhanced MRI was significantly higher than that of MDCT for tumors less than 2 cm (p = 0.048). There was no difference in the detection of hypervascular HCCs between hepatobiliary phase images of Gd-EOB-DTPA-enhanced MRI (43/45: 96%) and dynamic MDCT (40/45: 89%), whereas the detection sensitivity of hypovascular tumors by Gd EOB-DTPA-enhanced MRI was significantly higher than that by dynamic MDCT (39/41: 95% vs. 25/41: 61%, p = 0.001). EOB enhancement ratios were decreased in parallel with the degree of differentiation in DNs and HCCs, although there was no difference between DNs and hypovascular well-differentiated HCCs. CONCLUSION: The diagnostic ability of Gd-EOB-DTPA-enhanced MRI for hypervascular HCCs less than 2 cm was significantly higher than that of MDCT. For hypovascular tumors, the detection sensitivity of hepatobiliary phase images of Gd-EOB-DTPA-enhanced MRI was significantly higher than that of dynamic Gd-EOB-DTPA-enhanced MRI and dynamic MDCT. It was difficult to distinguish between DNs and hypovascular well differentiated HCCs based on the EOB enhancement ratio. PMID- 22526271 TI - One- and two-step self-expandable metal stent placement for distal malignant biliary obstruction: a propensity analysis. AB - BACKGROUND: Although self-expandable metal stents (SEMS) are widely used for distal malignant biliary obstruction, one-step SEMS (direct placement without a prior plastic stent) and two-step SEMS (placement at second endoscopic retrograde cholangiopancreatography [ERCP] following plastic stent placement) have not been fully compared. METHODS: In this multicenter retrospective study, patients were included who underwent first-time endoscopic SEMS placement between September 1994 and December 2010. We compared the one-step and two-step strategies using a propensity analysis. RESULTS: In total, 370 patients were identified and one-step SEMS was performed in 59 patients. After adjustment using propensity scores, the median times to dysfunction were 116 and 219 days, respectively, for one-step and two-step SEMS (P = 0.058). Stent migration was more frequently observed in one step SEMS as compared with two-step SEMS (25 vs. 11 %, P = 0.031). In one-step SEMS, the number of days of hospitalization associated with first-time SEMS placement was shorter compared with that in two-step SEMS (21 vs. 30 days, P = 0.001), and the total costs of SEMS-related interventions within 6 months were lower (6510 and 8100 USD, P = 0.004). The pathological diagnosis rates for pancreatic and biliary tract cancer at initial ERCP were 52 and 61 %. After failed diagnosis at initial ERCP, pathological diagnosis rates for pancreatic cancer were 32 versus 76 % (P = 0.005) by repeated ERCP versus endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA). CONCLUSIONS: One-step SEMS was associated with increased stent migration, despite having potential cost effectiveness. The additional yield of pathological diagnosis at repeated ERCP was low compared with that yielded by EUS-guided FNA. PMID- 22526272 TI - Autoimmune hepatitis: a review. AB - Autoimmune hepatitis (AIH) is an inflammatory liver disease that predominantly affects females. The disease is characterized histologically by interface hepatitis, biochemically by increased aspartate and alanine aminotransferase levels, and serologically by the presence of autoantibodies and elevated levels of immunoglobulin G. AIH affects both adults and children, and is particularly aggressive in the latter group. It is a relatively rare but devastating disease, which progresses rapidly unless immunosuppressive treatment is started promptly. Treatment is often successful at inducing remission of disease, and this can lead to a normal life expectancy. However, progression to cirrhosis can and does occur in some. For those with advanced-stage disease and complications, consideration of liver transplantation is appropriate. PMID- 22526273 TI - Rabeprazole reduces the recurrence risk of peptic ulcers associated with low-dose aspirin in patients with cardiovascular or cerebrovascular disease: a prospective randomized active-controlled trial. AB - BACKGROUND: Patients using low-dose aspirin (LDA) have an increased risk of gastroduodenal mucosal lesions and upper gastrointestinal symptoms. We aimed to clarify the efficacy of rabeprazole for preventing peptic ulcer, esophagitis, and gastrointestinal symptoms associated with LDA. METHODS: Patients with a history of peptic ulcers who were receiving LDA for cardiovascular or cerebrovascular disease were randomly assigned to receive rabeprazole at 10 mg daily, rabeprazole at 20 mg daily, or gefarnate (a cytoprotective anti-ulcer agent) at 50 mg twice daily. The primary endpoint was the development of gastric and/or duodenal ulcer at 12 weeks. The modified Lanza score (MLS) and gastrointestinal symptoms were evaluated at baseline and at 12 weeks. RESULTS: The full analysis set comprised 261 patients (rabeprazole 10 mg: n = 87, rabeprazole 20 mg: n = 89, gefarnate 100 mg: n = 85). The cumulative incidences of gastroduodenal ulcers at 12 weeks in the 10 mg rabeprazole group, 20 mg rabeprazole group, and gefarnate group were 7.4, 3.7, and 26.7 %, respectively (rabeprazole group 5.5 % vs. gefarnate group 26.7 %, hazard ratio [HR] 0.179; 95 % confidence interval [CI] 0.082-0.394; p < 0.0001). The proportions of patients with an MLS of >=1 and erosive esophagitis were significantly lower in the rabeprazole group than in the gefarnate group at 12 weeks (gastric lesions 33.5 vs. 62.4 %, p < 0.0001; duodenal lesions 5.7 vs. 24.7 %, p < 0.0001; erosive esophagitis 5.8 vs. 19.4 %, p < 0.0001). Rabeprazole was significantly more effective than gefarnate for the resolution and prevention of gastrointestinal symptoms (resolution 53.6 vs. 25.0 %, p = 0.017; occurrence 9.2 vs. 28.3 %, p = 0.0026). CONCLUSIONS: Rabeprazole is more effective than gefarnate for reducing the risk of recurrence of peptic ulcer, esophagitis, and gastrointestinal symptoms in LDA users. PMID- 22526274 TI - Do genetic variants in the SPINK1 gene affect the level of serum PSTI? AB - BACKGROUND: The serine protease inhibitor Kazal type 1 (SPINK1), also known as pancreatic secretory trypsin inhibitor (PSTI), is a peptide secreted by pancreatic acinar cells. Genetic studies have shown an association between SPINK1 gene variants and chronic pancreatitis or recurrent acute pancreatitis. The aim of this study was to clarify whether the SPINK1 variants affect the level of serum PSTI. METHODS: One hundred sixty-three patients with chronic pancreatitis or recurrent acute pancreatitis and 73 healthy controls were recruited. Serum PSTI concentrations were determined with a commercial radioimmunoassay kit. RESULTS: Ten patients with the p.N34S variant, 7 with the IVS3+2T>C variant, two with both the p.N34S and the IVS3+2T>C variants, and one with the novel missense p.P45S variant in the SPINK1 gene were identified. The serum PSTI level in patients with no SPINK1 variants was 14.3 +/- 9.6 ng/ml (mean +/- SD), and that in healthy controls was 10.7 +/- 2.2 ng/ml. The PSTI level in patients carrying the IVS3+2T>C variant (5.1 +/- 3.4 ng/ml), but not in those with the p.N34S variant (8.9 +/- 3.5 ng/ml), was significantly lower than that in the patients without the SPINK1 variants and the healthy controls. The serum PSTI level in the patient with the p.P45S variant was 4.9 ng/ml. Low levels of serum PSTI (<6.0 ng/ml) showed sensitivity of 80 %, specificity of 97 %, and accuracy of 96 % in the differentiation of IVS3+2T>C and p.P45S carriers from non-carriers. CONCLUSION: Serum PSTI levels were decreased in patients with the IVS3+2T>C and p.P45S variants of the SPINK1 gene. PMID- 22526275 TI - FDG-avid lesions on PET scans without corresponding pathological findings. PMID- 22526276 TI - Reply to the letter by A. S. Ravi Kumar et al. regarding "Detectability of colorectal neoplasia with FDG-PET/CT". PMID- 22526277 TI - Radially asymmetric gastroesophageal acid reflux in the distal esophagus: examinations with novel pH sensor catheter equipped with 8 pH sensors. AB - BACKGROUND: Esophageal mucosal breaks in patients with Los Angeles (LA) grade A or B esophagitis are mainly found in the right anterior wall of the distal esophagus. The aim of this study was to reveal radial acid exposure in the distal esophagus and determine whether radial asymmetry of acid exposure is a possible cause of radially asymmetric distribution of the lesions. METHODS: We developed a novel pH sensor catheter using a polyvinyl chloride catheter equipped with 8 antimony pH sensors radially arrayed at the same level. Four healthy volunteers, 5 patients with non-erosive reflux disease (NERD), and 10 with LA grade A or B esophagitis were enrolled. The sensors were set 2 cm above the upper limit of the lower esophageal sphincter, and post-prandial gastroesophageal acid reflux was monitored for 3 h with the subjects in a sitting position. RESULTS: We successfully examined radial acid exposure in the distal esophagus in all subjects using our novel pH sensor catheter. Radial variations of acid exposure in the distal esophagus were not observed in the healthy subjects. In contrast, the patients with NERD and those with reflux esophagitis had radial asymmetric acid exposure that was predominant on the right wall of the distal esophagus. In the majority of patients with reflux esophagitis, the directions of longer acid exposure coincided with the locations of mucosal breaks. CONCLUSIONS: Radial acid exposure could be examined using our novel 8-channel pH sensor catheter. We found that the directions of longer acid exposure were associated with the locations of mucosal breaks. PMID- 22526278 TI - Colloid cyst of the third ventricle associated with anterior cerebral artery trifurcation and agenesis of the corpus callosum: findings on MRI and CT angiography. AB - We report MRI with diffusion-weighted imaging, and multidetector CT angiography findings in a child with complete agenesis of the corpus callosum associated with a colloid cyst and trifurcation of the anterior cerebral artery. Although rare, a colloid cyst should be considered in the differential diagnosis of midline lesions in children with agenesis of the corpus callosum since it may require surgical intervention. PMID- 22526279 TI - Diagnosis and subsequent US-guided percutaneous drainage of an adrenal abscess in a 5-week-old infant. AB - Adrenal abscess is an uncommon finding in neonates and young infants. It may have a fatal outcome if inadequately treated. This case report describes the successful diagnosis and treatment of a left-sided adrenal abscess in a 5-week old girl. Abdominal US and antigranulocyte antibody-scintigraphy showed an encapsulated suprarenal mass with debris suspicious for an adrenal abscess. Treatment is generally surgical. In this case, however, we performed US-guided percutaneous drainage combined with intravenous antibiotic treatment. The child recovered fully. PMID- 22526280 TI - Digital radiography: optimization of image quality and dose using multi-frequency software. AB - BACKGROUND: New developments in processing of digital radiographs (DR), including multi-frequency processing (MFP), allow optimization of image quality and radiation dose. This is particularly promising in children as they are believed to be more sensitive to ionizing radiation than adults. OBJECTIVE: To examine whether the use of MFP software reduces the radiation dose without compromising quality at DR of the femur in 5-year-old-equivalent anthropomorphic and technical phantoms. MATERIALS AND METHODS: A total of 110 images of an anthropomorphic phantom were imaged on a DR system (Canon DR with CXDI-50 C detector and MLT[S] software) and analyzed by three pediatric radiologists using Visual Grading Analysis. In addition, 3,500 images taken of a technical contrast-detail phantom (CDRAD 2.0) provide an objective image-quality assessment. RESULTS: Optimal image quality was maintained at a dose reduction of 61% with MLT(S) optimized images. Even for images of diagnostic quality, MLT(S) provided a dose reduction of 88% as compared to the reference image. Software impact on image quality was found significant for dose (mAs), dynamic range dark region and frequency band. CONCLUSION: By optimizing image processing parameters, a significant dose reduction is possible without significant loss of image quality. PMID- 22526281 TI - Contrast enema findings in patients presenting with poor functional outcome after primary repair for Hirschsprung disease. AB - BACKGROUND: The radiologic evaluation of Hirschsprung disease is well described in the literature. However, there is a paucity of literature describing the appearance of the neo-rectum and colon after repair, specifically describing findings in patients with poor functional outcome, which would suggest the need for reoperation. OBJECTIVE: We describe findings on contrast enema and correlate them with surgical findings at reoperation in children with poor functional outcome after primary repair for Hirschsprung disease who suffer from bowel dysfunction that can manifest with either soiling or obstructive symptoms such as enterocolitis. MATERIALS AND METHODS: Children were identified from our colorectal surgery database. At the time of abstract submission, 35 children had contrast enemas prior to reoperation. Additional children continue to present for evaluation. The majority of children included in the study had their primary repair performed elsewhere. The initial procedures included: Duhamel (n = 11), Soave (n = 20) or Swenson (n = 3). One child had undergone a primary Soave repair and subsequently had a Swenson-type reoperation but continued to have a poor outcome. One child's initial surgical repair could not be determined. Images were reviewed by a staff pediatric radiologist and a pediatric radiology fellow. RESULTS: Findings encountered on contrast enema in these children include a distal narrowed segment due to stricture or aganglionic/transitional zone segment (8), dilated/hypomotile distal segment (7), thickened presacral space due to compressing Soave cuff (11), dilated Duhamel pouch (8), active enterocolitis (3) and partially obstructing twist of the pull-through segment (1). CONCLUSION: Multiple anatomical and pathological complications exist that can lead to bowel dysfunction in children after repair of Hirschsprung disease. Little recent literature exists regarding the radiographic findings in children. We had the opportunity to review a substantial series of these children, describe the contrast enema findings in these difficult cases and correlate them with operative findings. Radiologic evaluation is key to assessing such patients; it defines the potential anatomical problem with the pull-through and facilitates surgical planning. PMID- 22526282 TI - Injection of gadolinium contrast through pediatric central venous catheters: a safety study. AB - BACKGROUND: Catheter rupture during CT angiography has prompted policies prohibiting the use of electronic injectors with peripherally inserted central venous catheters (PICCs) not only for CT but also for MRI. Consequently, many institutions mandate hand injection for MR angiography, limiting precision of infusion rates and durations of delivery. OBJECTIVE: To determine whether electronic injection of gadolinium-based contrast media through a range of small caliber, single-lumen PICCs would be safe without risk of catheter rupture over the range of clinical protocols and determine whether programmed flow rates and volumes were realized when using PICCs for contrast delivery. MATERIALS AND METHODS: Experiments were performed and recorded using the Medrad Spectris Solaris EP MR Injection System. PICC sizes, contrast media and flow rates were based on common institutional protocols. RESULTS: No catheters were damaged during any experiments. Mean difference between programmed and delivered volume was 0.07 +/- 0.10 mL for all experiments. Reduced flow rates and prolonged injection durations were observed when the injector's pressure-limiting algorithm was triggered, only in protocols outside the clinical range. CONCLUSION: PICCs commonly used in children can withstand in vitro power injection of gadolinium based contrast media at protocols significantly above clinical levels. PMID- 22526283 TI - Deep sedation during pneumatic reduction of intussusception. AB - BACKGROUND: Pneumatic reduction of intussusception under fluoroscopic guidance is a routine procedure. The unsedated child may resist the procedure, which may lengthen its duration and increase the radiation dose. We use deep sedation during the procedure to overcome these difficulties. OBJECTIVE: The purpose of this study was to summarize our experience with deep sedation during fluoroscopic reduction of intussusception and assess the added value and complication rate of deep sedation. MATERIALS AND METHODS: All children with intussusception who underwent pneumatic reduction in our hospital between January 2004 and June 2011 were included in this retrospective study. Anesthetists sedated the children using propofol. The fluoroscopic studies, ultrasound (US) studies and the childrens' charts were reviewed. RESULTS: One hundred thirty-one attempted reductions were performed in 119 children, of which 121 (92%) were successful and 10 (8%) failed. Two perforations (1.5%) occurred during attempted reduction. Average fluoroscopic time was 1.5 minutes. No complication to sedation was recorded. CONCLUSIONS: Deep sedation with propofol did not add any complication to the pneumatic reduction. The fluoroscopic time was short. The success rate of reduction was high,raising the possibility that sedation is beneficial, possibly by smooth muscle relaxation. PMID- 22526284 TI - Ultrasound of the pediatric chest. AB - Historically, the evaluation of the pediatric chest has been accomplished via CT and conventional radiography. Our objective is to discuss and illustrate the role of US as a non-ionizing radiation alternative in the evaluation of the pediatric chest. US is a valuable tool in the evaluation of the pediatric chest. It can be used as a first-line modality in the evaluation of superficial lumps and bumps of the chest wall, diaphragmatic motion, the thymus and pleural effusions, and it can play a valuable secondary role in evaluation of mediastinal masses and pulmonary parenchymal disease. PMID- 22526285 TI - Synergistic insecticidal and repellent effects of combined pyrethroid and repellent-impregnated bed nets using a novel long-lasting polymer-coating multi layer technique. AB - New and improved strategies for malaria control and prevention are urgently needed. As a contribution to an optimized personal protection strategy, a novel long-lasting insecticide and repellent-treated net (LLIRN) has been designed by binding combinations of permethrin plus N,N-diethyl-m-toluamide (DEET), or insect repellent 3535 (IR3535), and etofenprox plus DEET, onto fibres of bed net fabric employing a new multi-layer polymer-coating technique. Protective repellent efficacy, toxicological effectiveness and residual activity of 12 LLIRN types have been evaluated by laboratory testing against adult Aedes aegypti. The novel multi-layer LLIRN design allowed simultaneous embedding at concentrations up to 5,930 mg/m(2) for DEET, 3,408 mg/m(2) for IR3535, 2,296 mg/m(2) for permethrin and 2,349 mg/m(2) for etofenprox, respectively. IR3535 layers prevented co binding of additional pyrethroid-containing polymer layers, thus making pyrethroids plus DEET LLIRNs an ideal combination. All LLIRNs revealed synergistic insecticidal effects which, when measured against concentration controls of the isolated compounds, were significant in all LLIRN types designed. DEET in DEET plus permethrin LLIRNs significantly (p < 0.0001) reduced the concentration-dependent permethrin 100 % knockdown (KD) time from 55 to 75 %, the corresponding 100 % kill time (p < 0.0001) from 55 to 64 %. DEET in DEET plus etofenprox LLIRNs reduced the dose-specific 100 % knockdown (KD) time of etofenprox from 42 to 50 % (p = 0.004), the 100 % kill time from 25 to 38 % (p < 0.0001). Permethrin or etofenprox did not influence spatial repellency of DEET or IR3535 on LLIRNs. Vice versa, DEET and IR3535 increased spatial and excitatory repellency and reduced landing and probing frequency on LLIRNs resulting in strongly enhanced biting protection, even at low concentrations. One hundred percent biting and probing protection of stored LLIRNs was preserved for 83 weeks with the 5,930 mg/m(2) DEET and 2,139 mg/m(2) etofenprox LLIRN, for 72 weeks with the 5,002 mg/m(2) DEET and 2,349 mg/m(2) etofenprox LLIRN, for 63 weeks with the 3,590 mg/m(2) DEET and 1,208 mg/m(2) permethrin LLRN, and for 61 weeks with the 4,711 mg/m(2) DEET and 702 mg/m(2) etofenprox LLIRN. Because 100 % bite protection with up to 75 % quicker contact toxicity of pyrethroids were documented, synergistic toxicological and repellent effects of multi-layer polymer-coating LLIRNs may overcome LLIN-triggered selection pressure for development of new kdr- and metabolic pyrethroid resistances while simultaneously increasing protective efficacy also against kdr- and metabolic pyrethroid resistant mosquitoes substantially due to the repellent-induced effects of LLIRNs thus indicating that this approach is a promising new candidate for future bed net, curtain, and window screen impregnation aiming at optimized prevention from mosquito-borne diseases. PMID- 22526286 TI - Bioaccumulation of six PCB indicator congeners in a heavily polluted water reservoir in Eastern Slovakia: tissue-specific distribution in fish and their parasites. AB - Concentrations of six indicator PCB congeners (IUPAC nos. 28, 52, 101, 138, 153, and 180) were measured in several organs and adipose tissue of a freshwater predatory fishes (European perch, northern pike, pike perch, wels catfish) as well as in nonpredators (common carp, freshwater bream, goldfish, white bream) and in acanthocephalan Acanthocephalus lucii from the water reservoir Zemplinska sirava (Eastern Slovakia), which is considered to be one of the most PCB contaminated places in Europe. Concentration of PCBs was determined by capillary gas chromatography in samples from May to September 2009. The two-way main-effect ANOVA confirmed that feeding habits of fish (P < 0.00001) and peculiarity of individual fish organs (P < 0.01) affect PCB bioaccumulation. The total amount of PCBs was significantly higher (P < 0.05) in predators compared to nonpredators. Tissue-specific differences were found in PCB accumulation in both fish groups. PCBs were predominantly accumulated in the liver and hard roe. Individual congeners were not distributed homogeneously within the investigated organs and adipose tissue. PCB 153 was present in higher concentrations than the other congeners in all fish organs as well as in adipose tissue comprising an average 31 and 34 % of SigmaPCB in predators and nonpredators, respectively. Acanthocephalans, attached to the intestine of perch, absorbed significantly higher concentrations of PCBs (P < 0.001) than the muscles, liver, kidney, brain, and adipose tissue of their host. About 20 times lower amount of PCBs was detected in the liver and almost 3 times in muscles of infected perch. Data on PCB accumulation in perch infected with acanthocephalans demonstrated a decline of PCB values in all organs as well as in adipose tissue compared to noninfected fish. About 20 times lower amount of PCBs was detected in the liver and almost 3 times in muscles of infected perch. Present results could indicate that some parasitic organisms may influence positively their hosts in PCB-contaminated environment. PMID- 22526287 TI - Molecular cloning and characterization of a cyclophilin A homologue from Schistosoma japonicum. AB - Cyclophilins belong to a group of proteins that have peptidyl-prolyl cis-trans isomerase activity and have been identified in all cell types and all organisms studied. In both prokaryotes and eukaryotes, they have been characterized as functional chaperones and involved in cell signaling. In the present study, Sj cyclophilin A (CyPA) was cloned, characterized, and subcloned into a prokaryotic expression vector to produce soluble recombinant rSjCyPA protein. qPCR analysis revealed that SjCyPA was expressed at each schistosome developmental stage tested, but reached its highest levels at days 7 and 13. In addition, the gene was also found to be significantly downregulated in adult worms from Microtus fortis. The SjCyPA protein was located on the subtegumental musculature of Schistosoma japonicum as determined by immunohistochemical staining analysis. Direct administration of recombinant SjCyPA to mice induced partial protective efficacy against subsequent schistosome infection. Length and width of adult worms and expression of SjCyPA were significantly decreased in the immunized groups, at 42 days post-infection, indicating that immunization with recombinant SjCyPA may suppress the schistosomes development. rSjCyPA can also react with sera from S. japonicum-infected rabbits at different time points. The data presented here suggest that SjCyPA may be an important molecule in the schistosome life-cycle and may be useful as a therapeutic target to treat schistosomiasis infection or as a potential diagnostic antigen. PMID- 22526288 TI - Effects of aqueous extract of Capsicum frutescens (Solanaceae) against the fish ectoparasite Ichthyophthirius multifiliis. AB - Ichthyophthirius multifiliis is an important fish ectoparasite that often results in significant economic losses to freshwater aquaculture. The search of alternative substances to control infections of I. multifiliis became stringent after malachite green, an effective and widely used chemotherapeutant, is banned on fish farms because of its carcinogenicity and teratogenicity. In this study, the effects of the aqueous extract of Capsicum frutescens, which is readily available and affordable, were evaluated under in vitro and in vivo conditions. The results in the in vitro conditions showed that the aqueous extracts of C. frutescens with the ratios (V (SS)/V (T)-V (SS), the volume of stock solution; V (T), the volume of total solution) of 1:32 and 1:64 led to more than 70 % mortality of I. multifiliis theronts during 4 h of exposure and significantly reduced the survival of the tomonts and the total number of theronts released by the tomonts within 22 h (P < 0.05). A 96-h bioassay was carried out to determine the acute toxicity of the aqueous extract of C. frutescens to goldfish. No visible effect was observed in the treatments with the aqueous extracts of C. frutescens with the ratios (V (SS)/V (T)) of 1:32, 1:64 and 1:128, while in the other treatments, the erratic behaviour of fish was noted. In addition, in vitro tests demonstrated that the aqueous extract of C. frutescens had an adverse effect on I. multifiliis trophonts in situ. Fish treated with the aqueous extracts of C. frutescens in ratios V (SS)/V (T) of 1:32 and 1:64 carried significantly fewer parasites than the control and the other treatments (P < 0.05). These results suggest, therefore, that aqueous extracts of C. frutescens have potential for the control of ichthyophthiriasis in the aquaculture industry, though further phytochemical studies will need to be performed for isolation and identification of the active compounds. PMID- 22526289 TI - Prevalence of endoparasites in stray and fostered dogs and cats in Northern Germany. AB - To get an overview of the current state of endoparasite prevalences in stray and not well-cared dogs and cats, faecal samples of 445 stray and foster dogs and 837 stray and foster cats were collected at their arrival at animal shelters in Lower Saxony (Germany). They were investigated for infections with endoparasites by the use of sedimentation-flotation method. Additionally, 341 canine and 584 feline samples were investigated by IDEXX SNAP(r) Giardia test. Stages of endoparasites were found coproscopically in 9.4 % (n = 42) of the canine samples, 4.0 % were positive for Toxocara canis, 0.9 % for hookworms, 0.4 % for Toxascaris leonina and 0.2 % for Hammondia-like oocysts. Giardia-coproantigen was detected in 11.4 % of the canine samples. In cats, 33.6 % (n = 281) were coproscopically positive for helminths and/or protozoa. Toxocara cati was found in 27.1 %, Isospora spp. in 7.5 %, Capillaria spp. 5.0 %, Taeniidae in 2.0 %, hookworms in 1.1 %, Giardia sp. in 0.7 %, Aelurostrongylus abstrusus in 1.0 % and Toxoplasma-like oocysts in 0.1 %. Coproantigen specific for Giardia sp. was detected in 6.8 % of the feline samples. Dogs and cats up to 1 year of age were more frequently infected with endoparasites than animals over 1 year of age (p < 0.001). Toxocara spp. and Isospora spp. were detected significantly more often in younger dogs and cats, respectively (p < 0.05 and p < 0.001). Stray dogs or cats older than 1 year were significantly more frequently infected with endoparasites than dropped off animals of the same age group (p < 0.05). Using the faecal egg count reduction test, the therapeutic efficacy of some anthelmintics was tested. All tested anthelmintics showed high efficacy and no suspected anthelmintic resistance was found. However, endoparasite-infected stray and free-roaming cats and dogs may contribute considerably to the contamination of public parks, playgrounds and sandpits with zoonotic parasites and therefore have to be considered a public health problem. PMID- 22526291 TI - The potential of Elephantorrhiza elephantina as an anthelminthic in goats. AB - Elephantorrhiza elephantina Bruch. Skeels. is used by farmers in the Eastern Cape Province to control helminths in goats. An in vitro study revealed efficacy of its fractions against adult Haemonchus contortus. This study was conducted to validate efficacy of fractions in vivo, on gastrointestinal nematodes in naturally infected goats. A total of 36 goats (18 males and 18 females) between ages of 8 and 12 months were used; these were randomly assigned to six treatments (A-F). For treatments A and B, goats received Prodose orange(r) (Albendazole 1.92 % m/v, closantel 3.94 % mv) at 2 ml/10 kg and distilled water at 0.5 ml/kg per os, respectively, whereas those under treatments C to E received aqueous fractions of E. elephantina at concentrations of 12. 5, 25, 50 and 75 mg/ml, dosed at 2 ml/10 kg. On days 1, 28 and 56, faecal samples were collected for faecal egg counts (FEC) and larval count, blood samples taken for packed cell volume (PCV) and body weights recorded to assess weight changes. The aqueous fraction caused highest the total faecal egg count reductions (TFECR) % of 81.7 %, 96.8 % and 98.6 % at doses of 25, 50 and 75 mg/kg, respectively, on day 56. This was comparable to the commercial drug Prodose orange(r), which caused TFECR% of 94.9 % at the same time. The fraction also caused reduction of Haemonchus contortus and strongyloides larvae at all dose levels, but these were not significantly different (P > 0.05) to the negative control. There was an increase in body weights of animals at dose concentrations of 25, 50 and 75 mg/kg. Animals receiving the fraction had weight increases of between 3 and 4 kg by end of experiment (over 56 days), but those drenched with Prodose orange (r) gained by less than 2 kg. The fraction also increased PCV levels at all doses on days 28 and 56 and this was comparable to the group on commercial drug. The reductions of FEC and worm larvae, as well as increase in PCVs are indicative that E. elephantina posses some antihelmintic properties against gastrointestinal parasites in goats. With a minimum dose concentration of 25 mg/ml being effective, this means that farmers can use little material. Increase in weight gain revealed in this study may indicate that the plant may have some nutritional value; further study is therefore called for to validate the plant for its nutritive value. PMID- 22526292 TI - How do host sex and reproductive state affect host preference and feeding duration of ticks? AB - Parasitism is one of the most notable forms of symbiosis in the biological world, with nearly all organisms hosting parasites. In many vertebrates, males have higher ectoparasite burdens than females, especially when testosterone concentrations are elevated. Furthermore, reproductive females may have higher ectoparasite burdens than non-reproductive females. It is possible that testosterone-stimulated behaviors in males and offspring investment by females incur energetic costs that inhibit immune function. If questing ticks can sense host sex or reproductive condition prior to attachment, they could potentially choose hosts with the poorest immune function, thereby leading to improved feeding success and decreased feeding duration. In this study, we examined the host-parasite relationship between western fence lizards (Sceloporus occidentalis) and the western black-legged tick (Ixodes pacificus) to test the following hypotheses: (1) ticks prefer male lizards to female lizards. (2) Ticks prefer male lizards with higher testosterone. (3) Ticks prefer reproductive female lizards to non-reproductive female lizards. (4) Ticks feed to repletion more rapidly (decreased feeding duration) on reproductive females and males with higher testosterone. In all three experiments, ticks failed to show a preference for one group over another as demonstrated by similar attachment rates between groups. This suggests that observed differences in ectoparasite loads in free ranging lizards is due to some other factor than host choice. However, tick feeding duration on female lizards was shorter when hosts were reproductive, suggesting that host reproductive condition alters tick feeding, possibly due to a decreased immune response. Interestingly, ticks fed more slowly on male lizards with elevated testosterone, suggesting that testosterone may actually improve immune function against ectoparasites. PMID- 22526294 TI - Chemical composition and amoebicidal activity of Croton pallidulus, Croton ericoides, and Croton isabelli (Euphorbiaceae) essential oils. AB - Acanthamoeba is a free-living amoebae genus that causes amoebic keratitis which is a painful sight-threatening disease of the eyes. Its treatment is difficult, and the search for new drugs is very important. Here, essential oils obtained from the aerial parts of Croton pallidulus, Croton isabelli, and Croton ericoides (Euphorbiaceae), native plants of Southern Brazil, were tested against Acanthamoeba polyphaga and analyzed by gas chromatography and gas chromatography mass spectrometry. The essential oils of C. pallidulus and C. isabelli were characterized by the presence of sesquiterpenes: germacrene D (15.5 %), terpinen 4-ol (13.2 %), and beta-caryophyllene (13.1 %) in C. pallidulus and bicyclogermacrene (48.9 %) in C. isabelli. The essential oil of C. ericoides presented mainly monoterpenes, beta-pinene (39.0 %) being the main component. Laboratory tests were carried out to determine the effect of the essential oils against A. polyphaga trophozoites. The essential oil of C. ericoides was the most active, killing 87 % of trophozoites at the concentration of 0.5 mg/mL. The essential oil of C. pallidulus killed only 29 % of the trophozoites at the same concentration. The essential oil of C. isabelli presented the lowest activity, killing only 4 % of the trophozoites at the concentration of 10 mg/mL. The essential oils of the three species showed cytotoxic effect by the methyl thiazolyl tetrazolium (MTT) method in Vero cells. The oil of C. ericoides, which showed the highest amoebicidal activity, was the most cytotoxic on these mammalian cells. PMID- 22526293 TI - Ectoparasite infestation patterns of domestic dogs in suburban and rural areas in Borneo. AB - Domestic dogs, Canis lupus, have been one of the longest companions of humans and have introduced their own menagerie of parasites and pathogens into this relationship. Here, we investigate the parasitic load of 212 domestic dogs with fleas (Siphonaptera) chewing lice (Phthiraptera), and ticks (Acarina) along a gradient from rural areas with near-natural forest cover to suburban areas in Northern Borneo (Sabah, Malaysia). We used a spatially-explicit hierarchical Bayesian model that allowed us to impute missing data and to consider spatial structure in modelling dog infestation probability and parasite density. We collected a total of 1,968 fleas of two species, Ctenocephalides orientis and Ctenocephalides felis felis, from 195 dogs (prevalence, 92 %). Flea density was higher on dogs residing in houses made of bamboo or corrugated metal (increase of 40 % from the average) compared to timber or stone/compound houses. Host dependent and landscape-level environmental variables and spatial structure only had a weak explanatory power. We found adults of the invasive chewing louse Heterodoxus spiniger on 42 dogs (20 %). The effect of housing conditions was opposite to those for fleas; lice were only found on dogs residing in stone or timber houses. We found ticks of the species Rhipicephalus sanguineus as well as Haemaphysalis bispinosa gp., Haemaphysalis cornigera, Haemaphysalis koenigsbergi, and Haemaphysalis semermis on 36 dogs (17 %). The most common tick species was R. sanguineus, recorded from 23 dogs. Tick infestations were highest on dogs using both plantation and forest areas (282 % increase in overall tick density of dogs using all habitat types). The infestation probability of dogs with lice and ticks decreased with elevation, most infestations occurred below 800 m above sea level. However, the density of lice and ticks revealed no spatial structure; infestation probability of dogs with these two groups revealed considerable autocorrelation. Our study shows that environmental conditions on the house level appeared to be more influential on flea and lice density whereas tick density was also influenced by habitat use. Infestation of dogs with Haemaphysalis ticks identified an important link between dogs and forest wildlife for potential pathogen transmission. PMID- 22526290 TI - Tick-borne viruses in Europe. AB - The aim of this review is to present briefly background information on 27 tick borne viruses ("tiboviruses") that have been detected in Europe, viz flaviviruses tick-borne encephalitis (TBEV), louping-ill (LIV), Tyuleniy (TYUV), and Meaban (MEAV); orthobunyaviruses Bahig (BAHV) and Matruh (MTRV); phleboviruses Grand Arbaud (GAV), Ponteves (PTVV), Uukuniemi (UUKV), Zaliv Terpeniya (ZTV), and St. Abb's Head (SAHV); nairoviruses Soldado (SOLV), Puffin Island (PIV), Avalon (AVAV), Clo Mor (CMV), Crimean-Congo hemorrhagic fever (CCHFV); bunyavirus Bhanja (BHAV); coltivirus Eyach (EYAV); orbiviruses Tribec (TRBV), Okhotskiy (OKHV), Cape Wrath (CWV), Mykines (MYKV), Tindholmur (TDMV), and Bauline (BAUV); two thogotoviruses (Thogoto THOV, Dhori DHOV); and one asfivirus (African swine fever virus ASFV). Emphasis is laid on the taxonomic status of these viruses, range of their ixodid or argasid vectors and vertebrate hosts, pathogenicity for vertebrates including humans, and relevance to public health. In general, three groups of tibovirus diseases can be recognized according to main clinical symptoms produced: (i) febrile illness-usually with a rapid onset, fever, sweating, headache, nausea, weakness, myalgia, arthralgia, sometimes polyarthritis and rash; (ii) the CNS affection-meningitis, meningoencephalitis or encephalomyelitis with pareses, paralysis and other sequelae; (iii) hemorrhagic disease. Several "European" tiboviruses cause very serious human (TBEV, CCHFV) or animal (LIV, ASFV) diseases. Other arboviruses play definite role in human or animal pathology though the disease is usually either less serious or infrequently reported (TYUV, BHAV, AVAV, EYAV, TRBV, DHOV, THOV). The other European arboviruses are "orphans" without a proven medical or veterinary significance (BAHV, MTRV, MEAV, GAV, PTVV, ZTV, SAHV, UUKV, SOLV, PIV, AVAV, CMV, OKHV, CWV, MYKV, TDMV, BAUV). However, certain arbovirus diseases of free-living vertebrates (but also those of domestic animals and even man) may often pass unnoticed or misdiagnosed and eventually, they might potentially appear as emerging diseases. Active search for new tiboviruses or for new, pathogenic variants of the known tiboviruses in Europe should therefore continue. PMID- 22526295 TI - Efficacy of alphacypermetrin pour-on against natural Werneckiella equi infestation on donkeys (Equus asinus). AB - The chewing louse Werneckiella equi is an ectoparasite of donkeys and other equids. Alphacypermethrin (ACYP) is a pyrethroid insecticide commonly used for the control of insects of veterinary and public health concerns. A trial was conducted to assess the efficacy of ACYP against W. equi on naturally infested donkeys. Parasitological investigations were performed on 13 animals. On day 0, the donkeys received ACYP pour-on at the manufacturer's recommended dose rate for cattle. Louse counts were performed on days -1, 7, 14, 21, 28, 35, 42, 49, and 56 at seven predilection sites on the skin of each donkey. ACYP was completely effective (100 %) from day 7, until the end of the study. ACYP was well tolerated by all animals as there were no observed clinical adverse reactions. ACYP was highly effective, safe, user-friendly, and considered to be suitable for the treatment of donkeys for W. equi infestation. PMID- 22526296 TI - Mosquito larvicidal activity of alkaloids and limonoids derived from Evodia rutaecarpa unripe fruits against Aedes albopictus (Diptera: Culicidae). AB - In recent years, uses of environment friendly and biodegradable natural insecticides of plant origin have received renewed attention as agents for vector control. During a screening program for new agrochemicals from Chinese medicinal herbs and local wild plants, the ethanol extract of Evodia rutaecarpa Hook f. et Thomas (Rutaceae) unripe fruits was found to possess larvicidal activity against the mosquitoes. The aim of this research was to determine larvicidal activity of the ethanol extract of E. rutaecarpa unripe fruits and the isolated constituents against the larvae of the Culicidae mosquito Aedes albopictus. The powder, 5 kg of the fruit material, was extracted with 30 l of 95 % ethanol, filtered, and evaporated to dryness in a rotary vacuum evaporator. The crude extract was then partitioned between methanol-water and n-hexane. The n-hexane fraction was evaporated off to given n-hexane extract. The aqueous layer was repartitioned with chloroform to provide chloroform extract after evaporation of the solvent. Further partitioning with ethyl acetate gave a residue after evaporation of the solvent. Bioactivity-directed chromatographic separation of chloroform extract on repeated silica gel columns led to the isolation of three alkaloids (evodiamine, rutaecarpine, and wuchuyuamide I) and two limonoids (evodol and limonin). The structures of the constituent compounds were elucidated based on high-resolution electron impact mass spectrometry and nuclear magnetic resonance. Evodiamine, rutaecarpine, and wuchuyuamide I exhibited strong larvicidal activity against the early fourth instar larvae of A. albopictus with LC(50) values of 12.51, 17.02, and 26.16 MUg/ml, respectively. Limonin and evodol also possessed larvicidal activity against the Asian tiger mosquitoes with LC(50) values of 32.43 and 52.22 MUg/ml, respectively, while the ethanol extract had a LC(50) value of 43.21 MUg/ml. The results indicated that the ethanol extract of E. rutaecarpa and the five isolated constituents have a good potential as a source for natural larvicides. PMID- 22526297 TI - Inhibition of soluble epoxide hydrolase limits niacin-induced vasodilation in mice. AB - BACKGROUND: The use of niacin in the treatment of dyslipidemias is limited by the common side effect of cutaneous vasodilation, commonly termed flushing. Flushing is thought to be due to release of the vasodilatory prostanoids prostaglandin D2 (PGD2) and prostaglandin E2 from arachidonic acid metabolism through the cyclooxygenase pathway. Arachidonic acid is also metabolized by the cytochrome P450 system, which is regulated, in part, by the enzyme soluble epoxide hydrolase (sEH). METHODS: These experiments used an established murine model in which ear tissue perfusion was measured by laser Doppler to test the hypothesis that inhibition of sEH would limit niacin-induced flushing. RESULTS: Niacin-induced flushing was reduced from 506 +/- 126% to 213 +/- 39% in sEH knockout animals. Pharmacologic treatment with 3 structurally distinct sEH inhibitors similarly reduced flushing in a dose-dependent manner, with maximal reduction to 143% +/- 15% of baseline flow using a concentration of 1 mg/kg TPAU (1 trifluoromethoxyphenyl-3-(1-acetylpiperidin-4-yl) urea). Systemically administered PGD2 caused ear vasodilation, which was not changed by either pharmacologic sEH inhibition or sEH gene deletion. CONCLUSIONS: Inhibition of sEH markedly reduces niacin-induced flushing in this model without an apparent effect on the response to PGD2. sEH inhibition may be a new therapeutic approach to limit flushing in humans. PMID- 22526298 TI - Improving cardiac conduction with a skeletal muscle sodium channel by gene and cell therapy. AB - The voltage-gated Na+ channel is a critical determinant of the action potential (AP) upstroke. Increasing Na+ conductance may speed AP propagation. In this study, we propose use of the skeletal muscle Na+ channel SkM1 as a more favorable gene than the cardiac isoform SCN5A to enhance conduction velocity in depolarized cardiac tissue. We used cells that electrically coupled with cardiac myocytes as a delivery platform to introduce the Na+ channels. Human embryonic kidney 293 cells were stably transfected with SkM1 or SCN5A. SkM1 had a more depolarized (18 mV shift) inactivation curve than SCN5A. We also found that SkM1 recovered faster from inactivation than SCN5A. When coupled with SkM1 expressing cells, cultured myocytes showed an increase in the dV/dtmax of the AP. Expression of SCN5A had no such effect. In an in vitro cardiac syncytium, coculture of neonatal cardiac myocytes with SkM1 expressing but not SCN5A expressing cells significantly increased the conduction velocity under both normal and depolarized conditions. In an in vitro reentry model induced by high-frequency stimulation, expression of SkM1 also enhanced angular velocity of the induced reentry. These results suggest that cells carrying a Na+ channel with a more depolarized inactivation curve can improve cardiac excitability and conduction in depolarized tissues. PMID- 22526299 TI - In vivo expression of angiotensin-(1-7) lowers blood pressure and improves baroreflex function in transgenic (mRen2)27 rats. AB - Transgenic (mRen2)27 rats are hypertensive with impaired baroreflex sensitivity for control of heart rate compared with Hannover Sprague-Dawley rats. We assessed blood pressure and baroreflex function in male hemizygous (mRen2)27 rats (30-40 weeks of age) instrumented for arterial pressure recordings and receiving into the cisterna magna either an Ang-(1-7) fusion protein or a control fusion protein (CTL-FP). The maximum reduction in mean arterial pressure achieved was -38 +/- 7 mm Hg on day 3, accompanied by a 55% enhancement in baroreflex sensitivity in Ang (1-7) fusion protein-treated rats. Both the high-frequency alpha index (HF-alpha) and heart rate variability increased, suggesting increased parasympathetic tone for cardiac control. The mRNA levels of several components of the renin angiotensin system in the dorsal medulla were markedly reduced including renin ( 80%), neprilysin (-40%), and the AT1a receptor (-40%). However, there was a 2 fold to 3-fold increase in the mRNA levels of the phosphatases PTP-1b and dual specificity phosphatase 1 in the medulla of Ang-(1-7) fusion protein-treated rats. Our finding that replacement of Ang-(1-7) in the brain of (mRen2)27 rats reverses in part the hypertension and baroreflex impairment is consistent with a functional deficit of Ang-(1-7) in this hypertensive strain. We conclude that the increased mRNA expression of phosphatases known to counteract the phosphoinositol 3 kinase and mitogen-activated protein kinases, and the reduction of renin and AT1a receptor mRNA levels may contribute to the reduction in arterial pressure and improvement in baroreflex sensitivity in response to Ang-(1-7). PMID- 22526300 TI - A plasmid-encoded class 1 integron contains GES-type extended-spectrum beta lactamases in Enterobacteriaceae clinical isolates in Mexico. PMID- 22526302 TI - Susceptibility of herpes simplex virus isolated from genital herpes lesions to ASP2151, a novel helicase-primase inhibitor. AB - ASP2151 (amenamevir) is a helicase-primase inhibitor against herpes simplex virus type 1 (HSV-1), HSV-2, and varicella-zoster virus. To evaluate the anti-HSV activity of ASP2151, susceptibility testing was performed on viruses isolated from patients participating in a placebo- and valacyclovir-controlled proof-of concept phase II study for recurrent genital herpes. A total of 156 HSV strains were isolated prior to the dosing of patients, and no preexisting variants with less susceptibility to ASP2151 or acyclovir (ACV) were detected. ASP2151 inhibited HSV-1 and HSV-2 replication with mean 50% effective concentrations (EC(50)s) of 0.043 and 0.069 MUM, whereas ACV exhibited mean EC(50)s of 2.1 and 3.2 MUM, respectively. Notably, the susceptibilities of HSV isolates to ASP2151 and ACV were not altered after dosing with the antiviral agents. Taken together, these results demonstrate that ASP2151 inhibits the replication of HSV clinical isolates more potently than ACV, and HSV resistant to this novel helicase-primase inhibitor as well as ACV may not easily emerge in short-term treatment for recurrent genital herpes patients. PMID- 22526301 TI - The posttranslocational chaperone lipoprotein PrsA is involved in both glycopeptide and oxacillin resistance in Staphylococcus aureus. AB - Understanding in detail the factors which permit Staphylococcus aureus to counteract cell wall-active antibiotics is a prerequisite to elaborating effective strategies to prolong the usefulness of these drugs and define new targets for pharmacological intervention. Methicillin-resistant S. aureus (MRSA) strains are major pathogens of hospital-acquired and community-acquired infections and are most often treated with glycopeptides (vancomycin and teicoplanin) because of their resistance to most penicillins and a limited arsenal of clinically proven alternatives. In this study, we examined PrsA, a lipid-anchored protein of the parvulin PPIase family (peptidyl-prolyl cis/trans isomerase) found ubiquitously in all Gram-positive species, in which it assists posttranslocational folding at the outer surface of the cytoplasmic membrane. We show by both genetic and biochemical assays that prsA is directly regulated by the VraRS two-component sentinel system of cell wall stress. Disruption of prsA is tolerated by S. aureus, and its loss results in no detectable overt macroscopic changes in cell wall architecture or growth rate under nonstressed growth conditions. Disruption of prsA leads, however, to notable alterations in the sensitivity to glycopeptides and dramatically decreases the resistance of COL (MRSA) to oxacillin. Quantitative transcriptional analysis reveals that prsA and vraR are coordinately upregulated in a panel of stable laboratory and clinical glycopeptide-intermediate S. aureus (GISA) strains compared to their susceptible parents. Collectively, our results point to a role for prsA as a facultative facilitator of protein secretion or extracellular folding and provide a framework for understanding why prsA is a key element of the VraRS-mediated cell wall stress response. PMID- 22526303 TI - Contribution of Phe-7 to Tat-dependent export of beta-lactamase in Xanthomonas campestris. AB - Strains of Xanthomonas campestris pv. campestris isolated in Taiwan are commonly resistant to ampicillin owing to the constitutive expression of a chromosomally encoded beta-lactamase that is secreted into the periplasm. In this study, we found that levels of beta-lactamase vary among X. campestris pv. campestris strains, a difference that can be attributed to amino acid substitutions at least at positions 7 and 206, with the former having the major impact. Bioinformatic and PCR analyses indicated that X. campestris pv. campestris possesses tatABC genes and that the signal peptide of X. campestris pv. campestris pre-Bla contains the typical twin-arginine motif (N-R-R-Q-F-L at amino acid residues 3 to 8 in strain X. campestris pv. campestris strain 11), suggesting that Bla is secreted via the Tat pathway. To assess the importance of Phe(7) in the efficient export of X. campestris pv. campestris Bla, we prepared mutant constructs containing amino acid substitutions and monitored their expression by measuring enzyme activity and detecting Bla protein by Western blotting. The results indicate that replacement of Phe(7) with Leu severely inhibited Bla export whereas replacement with Pro almost abolished it. Although a change to Arg caused moderate inhibition of export, replacement with Tyr had no effect. These results suggest that for efficient export of Bla by X. campestris pv. campestris, the aromatic-aromatic interactions and stability of protein structure around the twin arginine motif are important, since only proteins that can attain a folded state in the cytoplasm are competent for export via the Tat pathway. PMID- 22526304 TI - Drug efflux by a small multidrug resistance protein is inhibited by a transmembrane peptide. AB - Drug-resistant bacteria use several families of membrane-embedded transporters to remove antibiotics from the cell. One such family is the small multidrug resistance proteins (SMRs) that, because of their relatively small size (ca. 110 residues with four transmembrane [TM] helices), must form (at least) dimers to efflux drugs. Here, we use a Lys-tagged synthetic peptide with exactly the same sequence as TM4 of the full-length SMR Hsmr from Halobacterium salinarum [TM4 sequence: AcA(Sar)(3)-VAGVVGLALIVAGVVVLNVAS-KKK (Sar = N-methylglycine)] to compete with and disrupt the native TM4-TM4 interactions believed to constitute the locus of Hsmr dimerization. Using a cellular efflux assay of the fluorescent SMR substrate ethidium bromide, we determined that bacterial cells containing Hsmr are able to remove cellular ethidium via first-order exponential decay with a rate constant (k) of 10.1 * 10(-3) +/- 0.7 * 10(-3) s(-1). Upon treatment of the cells with the TM4 peptide, we observed a saturable ~60% decrease in the efflux rate constant to 3.7 * 10(-3) +/- 0.2 * 10(-3) s(-1). In corresponding experiments with control peptides, including scrambled sequences and a sequence with d-chirality, a decrease in ethidium efflux either was not observed or was marginal, likely from nonspecific effects. The designed peptides did not evoke bacterial lysis, indicating that they act via the alpha-helicity and membrane insertion propensities of the native TM4 helix. Our overall results suggest that this approach could conceivably be used to design hydrophobic peptides for disruption of key TM-TM interactions of membrane proteins and represent a valuable route to the discovery of new therapeutics. PMID- 22526305 TI - A pharmacodynamic model of ganciclovir antiviral effect and toxicity for lymphoblastoid cells suggests a new dosing regimen to treat cytomegalovirus infection. AB - In bone marrow transplantation, the efficacy of ganciclovir in cytomegalovirus (CMV) disease treatment or prophylaxis remains partial. Because its hematological toxicity is dose limiting, optimization of the dosing schedule is required to increase its therapeutic index. The goal of our study was to describe the influence of the ganciclovir concentration and duration of exposure on cell survival and antiviral efficacy. The study was carried out in vitro on cultures of lymphoblastoid cells infected or not with the CMV AD169 reference strain and exposed to ganciclovir at different concentrations for 1, 2, 7, or 14 days. The data were analyzed by a mathematical model that allowed a quantitative characterization of ganciclovir pharmacodynamics and its variability. Simulations of the model were undertaken to determine the optimal concentration profile for maximizing the ganciclovir therapeutic index. Ganciclovir had very little toxic and antiviral effect, even at 20 mg liter(-1), when the duration of exposure was <= 7 days. A biologically significant effect was observed only with a 14-day exposure. Complete inhibition of viral replication was obtained at 20 mg liter( 1). The utility function, assuming equal weights for antiviral effect and toxicity, showed that maximal utility was reached around 10 mg liter(-1). The optimal ganciclovir concentration profile consisted of maintaining the concentration at 20 mg liter(-1) at the intervals 0 to 2 days and 7.58 to 9.58 days and a null concentration at other times. This optimal profile could be obtained by intravenous (i.v.) ganciclovir at 10 mg/kg of body weight twice daily (b.i.d.) at days 1, 2, 8.5, and 9.5 in stem cell transplant patients with normal renal function. PMID- 22526306 TI - Malachite green interferes with postantibiotic recovery of mycobacteria. AB - The genus Mycobacterium comprises slow-growing species with generation times ranging from hours to weeks. The protracted incubation time before colonies appear on solid culture medium can result in overgrowth by faster-growing microorganisms. To prevent contamination, the solid media used in laboratories and clinics for cultivation of mycobacteria contain the arylmethane compound malachite green, which has broad-spectrum antimicrobial activity. Malachite green has no impact on the plating efficiency of mycobacteria when cells are grown under normal conditions. However, we found that malachite green interfered with colony formation when bacteria were preexposed to antibiotics targeting cell wall biogenesis (isoniazid, ethionamide, ethambutol). This inhibitory effect of malachite green was not observed when bacteria were preexposed to antibiotics targeting cellular processes other than cell wall biogenesis (rifampin, moxifloxacin, streptomycin). Sputum specimens from tuberculosis patients are routinely evaluated on solid culture medium containing high concentrations of malachite green. This practice could lead to underestimation of bacterial loads and overestimation of chemotherapeutic efficacy. PMID- 22526307 TI - Intrapulmonary distribution and pharmacokinetics of laninamivir, a neuraminidase inhibitor, after a single inhaled administration of its prodrug, laninamivir octanoate, in healthy volunteers. AB - A single inhaled dose of laninamivir octanoate (LO), a long-acting neuraminidase inhibitor, exhibits efficacy in treating both adult and pediatric patients with influenza virus infection. The intrapulmonary pharmacokinetics (PK) of LO and laninamivir, a pharmacologically active metabolite, were investigated by a single center, open-label study of healthy adult volunteers. Subgroups of five subjects each underwent bronchoalveolar lavage (BAL) 4, 8, 24, 48, 72, 168, and 240 h following a single inhaled administration of LO (40 mg). Plasma, BAL fluid, and alveolar macrophages (AM) were analyzed to determine LO and laninamivir concentrations, using validated liquid chromatography-tandem mass spectrometry methods. The concentrations in epithelial lining fluid (ELF) and AM from the first and subsequent BAL fluid samples were determined separately to explore the drug distribution in airways. Mean laninamivir concentrations in ELF, calculated using the first BAL fluids and BAL fluids collected 4 h after inhaled administration, were 8.57 and 2.40 MUg/ml, respectively. The laninamivir concentration in ELF decreased with a longer half-life than that in plasma, and it exceeded the 50% inhibitory concentrations for viral neuraminidases at all time points examined for 240 h after the inhalation. Laninamivir exposure in ELF from the first BAL samples was 3.2 times higher than that in ELF from the subsequent BAL fluid samples. ELF concentration profiles of laninamivir support its long-lasting effect for treatment of patients with influenza virus infection by a single inhaled administration. PMID- 22526308 TI - Metabolic activation of the anti-hepatitis C virus nucleotide prodrug PSI-352938. AB - PSI-352938 is a novel cyclic phosphate prodrug of beta-D-2'-deoxy-2'-alpha-fluoro 2'-beta-C-methylguanosine-5'-monophosphate with potent anti-HCV activity. In order to inhibit the NS5B RNA-dependent RNA polymerase, PSI-352938 must be metabolized to the active triphosphate form, PSI-352666. During in vitro incubations with PSI-352938, significantly larger amounts of PSI-352666 were formed in primary hepatocytes than in clone A hepatitis C virus (HCV) replicon cells. Metabolism and biochemical assays were performed to define the molecular mechanism of PSI-352938 activation. The first step, removal of the isopropyl group on the 3',5'-cyclic phosphate moiety, was found to be cytochrome P450 (CYP) 3A4 dependent, with other CYP isoforms unable to catalyze the reaction. The second step, opening of the cyclic phosphate ring, was catalyzed by phosphodiesterases (PDEs) 2A1, 5A, 9A, and 11A4, all known to be expressed in the liver. The role of these enzymes in the activation of PSI-352938 was confirmed in primary human hepatocytes, where prodrug activation was reduced by inhibitors of CYP3A4 and PDEs. The third step, removal of the O(6)-ethyl group on the nucleobase, was shown to be catalyzed by adenosine deaminase-like protein 1. The resulting monophosphate was consecutively phosphorylated to the diphosphate and to the triphosphate PSI-352666 by guanylate kinase 1 and nucleoside diphosphate kinase, respectively. In addition, formation of nucleoside metabolites was observed in primary hepatocytes, and ecto-5'-nucleotidase was able to dephosphorylate the monophosphate metabolites. Since CYP3A4 is highly expressed in the liver, the CYP3A4-dependent metabolism of PSI-352938 makes it an effective liver-targeted prodrug, in part accounting for the potent antiviral activity observed clinically. PMID- 22526309 TI - Development of novel PCR assays to detect azole resistance-mediating mutations of the Aspergillus fumigatus cyp51A gene in primary clinical samples from neutropenic patients. AB - The increasing incidence of azole resistance in Aspergillus fumigatus causing invasive aspergillosis (IA) in immunocompromised/hematological patients emphasizes the need to improve the detection of resistance-mediating cyp51A gene mutations from primary clinical samples, particularly as the diagnosis of invasive aspergillosis is rarely based on a positive culture yield in this group of patients. We generated primers from the unique sequence of the Aspergillus fumigatus cyp51A gene to establish PCR assays with consecutive DNA sequence analysis to detect and identify the A. fumigatus cyp51A tandem repeat (TR) mutation in the promoter region and the L98H and M220 alterations directly in clinical samples. After testing of the sensitivity and specificity of the assays using serially diluted A. fumigatus and human DNA, A. fumigatus cyp51A gene fragments of about 150 bp potentially carrying the mutations were amplified directly from primary clinical samples and subsequently DNA sequenced. The determined sensitivities of the PCR assays were 600 fg, 6 pg, and 4 pg of A. fumigatus DNA for the TR, L98H, and M220 mutations, respectively. There was no cross-reactivity with human genomic DNA detectable. Sequencing of the PCR amplicons for A. fumigatus wild-type DNA confirmed the cyp51A wild-type sequence, and PCR products from one azole-resistant A. fumigatus isolate showed the L98H and TR mutations. The second azole-resistant isolate revealed an M220T alteration. We consider our assay to be of high epidemiological and clinical relevance to detect azole resistance and to optimize antifungal therapy in patients with IA. PMID- 22526310 TI - Modeling approach to characterize intraocular doripenem pharmacokinetics after intravenous administration to rabbits, with tentative extrapolation to humans. AB - The aim of this study was to determine the penetration of doripenem administered intravenously into the rabbit aqueous and vitreous humors. Nineteen New Zealand White rabbits received a 20-mg dose of doripenem intravenously over 60 min. Specimens of aqueous humor, vitreous humor, and blood were obtained 30 min (n = 5), 1 h (n = 5), 2 h (n = 5), and 3 h (n = 4) after the beginning of the infusion and analyzed by high-performance liquid chromatography (HPLC). A pharmacokinetic (PK) model was developed to fit the experimental data. Doripenem concentrations in aqueous humor were lower than those in plasma ultrafiltrates at all sampling times, with an average aqueous humor-to-plasma ultrafiltrate area under the concentration-time curve ratio estimated as 8.3%. A pharmacokinetic model with peripheral elimination described the data adequately and was tentatively used to predict concentration-versus-time profiles and pharmacokinetic-pharmacodynamic (PK-PD) target attainment in patients under various dosing regimens. In conclusion, systematically administered doripenem does not seem to be a promising approach for the treatment of intraocular infections, especially since it could not be detected in the vitreous humor. However, this study has provided an opportunity to develop a new PK modeling approach to characterize the intraocular distribution of doripenem administered intravenously to rabbits, with tentative extrapolation to humans. PMID- 22526311 TI - In vitro activity of MK-7655, a novel beta-lactamase inhibitor, in combination with imipenem against carbapenem-resistant Gram-negative bacteria. AB - Carbapenem-resistant bacteria represent a significant treatment challenge due to the lack of active antimicrobials available. MK-7655 is a novel beta-lactamase inhibitor under clinical development. We investigated the combined killing activity of imipenem and MK-7655 against four imipenem-resistant bacterial strains, using a mathematical model previously evaluated in our laboratory. Time kill studies (TKS) were conducted with imipenem and MK-7655 against a KPC-2 producing Klebsiella pneumoniae isolate (KP6339) as well as 3 Pseudomonas aeruginosa isolates (PA24226, PA24227, and PA24228) with OprD porin deletions and overexpression of AmpC. TKS were performed using 25 clinically achievable concentration combinations in a 5-by-5 array. Bacterial burden at 24 h was determined in triplicate by quantitative culture and mathematically modeled using a three-dimensional response surface. Mathematical model assessments were evaluated experimentally using clinically relevant dosing regimens of imipenem, with or without MK-7655, in a hollow-fiber infection model (HFIM). The combination of imipenem and MK-7655 was synergistic for all strains. Interaction indices were as follows: for KP6339, 0.50 (95% confidence interval [CI], 0.42 to 0.58); for PA24226, 0.60 (95% CI, 0.58 to 0.62); for PA24227, 0.70 (95% CI, 0.66 to 0.74); and for PA24228, 0.55 (95% CI, 0.49 to 0.61). In the HFIM, imipenem plus MK-7655 considerably reduced the bacterial burden at 24 h, while failure with imipenem alone was seen against all isolates. Sustained suppression of bacterial growth at 72 h was achieved with simulated doses of 500 mg imipenem plus 500 mg MK-7655 in 2 (KP6339 and PA24227) strains, and it was achieved in an additional strain (PA24228) when the imipenem dose was increased to 1,000 mg. Additional studies are being conducted to determine the optimal dose and combinations to be used in clinical investigations. PMID- 22526312 TI - In vitro activities of the new antitubercular agents PA-824 and BTZ043 against Nocardia brasiliensis. AB - The in vitro activity of PA-824 and BTZ043 against 30 Nocardia brasiliensis isolates was tested. The MIC(50) and MIC(90) values for PA-824 were both >64 MUg/ml. The same values for BTZ043 were 0.125 and 0.250 MUg/ml. Given the MIC values for benzothiazinone (BTZ) compounds, we consider them good candidates to be tested in vivo against N. brasiliensis. PMID- 22526313 TI - Front-loaded linezolid regimens result in increased killing and suppression of the accessory gene regulator system of Staphylococcus aureus. AB - Front loading is a strategy used to optimize the pharmacodynamic profile of an antibiotic through the administration of high doses early in therapy for a short duration. Our aims were to evaluate the impact of front loading of linezolid regimens on bacterial killing and suppression of resistance and on RNAIII, the effector molecule of the accessory gene regulator system (encoded by agr) in methicillin-resistant Staphylococcus aureus (MRSA). Time-killing experiments over 48 h were utilized for linezolid against four strains of MRSA: USA100, USA300, USA400, and ATCC 29213. A hollow-fiber infection model simulated traditional and front-loaded human therapeutic regimens of linezolid versus USA300 at 10(6) CFU/ml over 240 h. Over 48 h in time-kill experiments, linezolid displayed bacteriostatic activity, with reductions of >1 log(10) CFU/ml for all strains. Front-loaded regimens that were administered over 5 days, 1,200 mg every 12 h (q12h) (total, 10 doses) and 2,400 mg q12h (total, 10 doses) followed by 300 mg q12h thereafter, resulted in sustained bactericidal activity, with reductions of the area under the CFU curve of -6.15 and -6.03, respectively, reaching undetectable limits at the 10-day study endpoint. All regimens displayed a reduction in RNAIII relative expression at 24 h and 240 h compared with that of the growth control. Monte Carlo simulations predicted a <1.27* increase in the fractional decreases in platelets for all front-loaded regimens versus the 600 mg q12h regimen, except for the highest-dose front-loaded regimen. Front-loading strategies for linezolid are promising and may be of utility in severe MRSA infections, where early aggressive therapy is necessary. PMID- 22526314 TI - Pharmacokinetic comparison of a single oral dose of polymorph form i versus form V capsules of the antiorthopoxvirus compound ST-246 in human volunteers. AB - ST-246, a novel compound that inhibits egress of orthopoxvirus from mammalian cells, is being tested as a treatment for pathogenic orthopoxvirus infections in humans. This phase I, double-blind, randomized, crossover, exploratory study was conducted to compare the pharmacokinetics (PK) of a single daily 400-mg oral dose of ST-246 polymorph form I versus polymorph form V administered to fed, healthy human volunteers. Both forms appeared to be well tolerated, with no serious adverse events. The order of administration of the two forms had no effect on the results of the PK analyses. Form I and form V both exhibited comparable plasma concentration versus time profiles, but complete bioequivalence between the two forms was not found. Maximum drug concentration (C(max)) met the bioequivalence criteria, as the 90% confidence interval (CI) was 80.6 to 96.9%. However, the area under the concentration-time curve from time zero to time t (AUC(0-t)) and AUC(0-infinity) did not meet the bioequivalence criteria (CIs of 67.8 to 91.0% and 73.9 to 104.7%, respectively). The extent of absorption of form I, as defined by AUC(0-infinity), was 11.7% lower than that of form V. Since ST-246 form I is more thermostable than form V, form I was selected for further development and use in all future studies. PMID- 22526315 TI - Impact of first-line antifungal agents on the outcomes and costs of candidemia. AB - Candida species are the leading causes of invasive fungal infection among hospitalized patients and are responsible for major economic burdens. The goals of this study were to estimate the costs directly associated with the treatment of candidemia and factors associated with increased costs, as well as the impact of first-line antifungal agents on the outcomes and costs. A retrospective study was conducted in a sample of 199 patients from four university-affiliated tertiary care hospitals in Korea over 1 year. Only costs attributable to the treatment of candidemia were estimated by reviewing resource utilization during treatment. Risk factors for increased costs, treatment outcome, and hospital length of stay (LOS) were analyzed. Approximately 65% of the patients were treated with fluconazole, and 28% were treated with conventional amphotericin B. The overall treatment success rate was 52.8%, and the 30-day mortality rate was 47.9%. Hematologic malignancy, need for mechanical ventilation, and treatment failure of first-line antifungal agents were independent risk factors for mortality. The mean total cost for the treatment of candidemia was $4,743 per patient. Intensive care unit stay at candidemia onset and antifungal switch to second-line agents were independent risk factors for increased costs. The LOS was also significantly longer in patients who switched antifungal agents to second line drugs. Antifungal switch to second-line agents for any reasons was the only modifiable risk factor of increased costs and LOS. Choosing an appropriate first line antifungal agent is crucial for better outcomes and reduced hospital costs of candidemia. PMID- 22526316 TI - Role of common blaOXA-24/OXA-40-carrying platforms and plasmids in the spread of OXA-24/OXA-40 among Acinetobacter species clinical isolates. AB - The spread of OXA-24/OXA-40 (OXA-24/40)-producing Acinetobacter spp. in the Iberian Peninsula has been strongly influenced by clonal expansion, but the role of horizontal gene transfer has scarcely been explored. bla(OXA-24/40)-carrying plasmids and genetic environments were characterized in representative (n = 15) Acinetobacter species clinical isolates (obtained between 2001 and 2007) by Acinetobacter baumannii PCR-based replicon typing, sequencing, hybridization, and restriction fragment length polymorphism. Besides the identification of bla(OXA 24/40) within the chromosomes of some isolates, the circulation of common bla(OXA 24/40)-carrying plasmids (30-kb repA_AB; 10-kb aci2) and genetic backbones among Acinetobacter spp. was demonstrated. PMID- 22526317 TI - Prominence of an O75 clonal group (clonal complex 14) among non-ST131 fluoroquinolone-resistant Escherichia coli causing extraintestinal infections in humans and dogs in Australia. AB - Fluoroquinolone (FQ)-resistant extraintestinal pathogenic Escherichia coli (FQ(r) ExPEC) strains from phylogenetic group B2 are undergoing epidemic spread. Isolates belonging to phylogenetic group B2 are generally more virulent than other E. coli isolates; therefore, resistance to FQs among group B2 isolates is concerning. Although clonal expansion of sequence type 131 (ST131) is a major factor, the contribution of additional clonal groups has not been quantified. Group B2 FQ(r) ExPEC isolates from humans (n = 250) and dogs (n = 12) in Australia were screened for ST131, a recently recognized and rapidly emerging multidrug-resistant and virulent clonal group that is important in both human and companion animal medicine. Non-ST131 isolates underwent virulence genotyping, PCR based O typing, partial multilocus sequence typing (MLST), pulsed-field gel electrophoresis (PFGE), and FQ resistance mechanism analysis. Of 49 non-ST131 isolates (45 human, 4 canine), 49% (24 human, 2 canine) represented O-type O75 and exhibited conserved virulence genotypes (F10 papA allele, iha, fimH, sat, vat, fyuA, iutA, kpsMII, usp, ompT, malX, K1/K5 capsule) and MLST allele profiles corresponding with clonal complex CC14. Two clusters, each containing canine and human isolates, were identified by PFGE (differentiated by K1 and K5 capsules). Australian FQ(r) O75 isolates exhibited commonality with an historical FQ susceptible O75 urosepsis isolate (also CC14). The isolation from humans and dogs of highly similar FQ(r) derivatives of the classic O75:K1/K5 (CC14) ExPEC lineage suggests recent acquisition of FQ resistance and potential cross-host-species transfer. This lineage should be targeted with ST131 in future epidemiological investigations of FQ(r) ExPEC. PMID- 22526318 TI - Isolation and characterization of signermycin B, an antibiotic that targets the dimerization domain of histidine kinase WalK. AB - The WalK (histidine kinase)/WalR (response regulator) two-component signal transduction system is a master regulatory system for cell wall metabolism and growth. This system is conserved in low G+C Gram-positive bacteria, including Bacillus subtilis, Staphylococcus aureus, Enterococcus faecalis, and Streptococcus mutans. In this study, we found the first antibiotic that functions as a WalK inhibitor (signermycin B) by screening 10,000 Streptomyces extracts. The chemical structure (C(23)H(35)NO(4); molecular weight, 389.5) comprises a tetramic acid moiety and a decalin ring. Signermycin B exhibited antimicrobial activity, with MIC values ranging from 3.13 MUg/ml (8 MUM) to 6.25 MUg/ml (16 MUM) against Gram-positive bacteria that possess the WalK/WalR two-component signal transduction system, including the drug-resistant bacteria methicillin resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis. The half-maximal inhibitory concentrations of signermycin B against WalK in these organisms ranged from 37 to 61 MUM. To determine the mechanism of action of signermycin B, surface plasmon resonance response analysis with the two WalK domains of Bacillus subtilis and competition assay with ATP were performed. The results showed that signermycin B binds to the dimerization domain but not the ATP-binding domain of WalK. In the presence of the cross-linker glutaraldehyde, signermycin B did not cause protein aggregation but interfered with the cross linking of WalK dimers. These results suggest that signermycin B targets the conserved dimerization domain of WalK to inhibit autophosphorylation. In Bacillus subtilis and Staphylococcus aureus, signermycin B preferentially controlled the WalR regulon, thereby inhibiting cell division. These phenotypes are consistent with those of cells starved for the WalK/WalR system. PMID- 22526319 TI - Combined spatial limitation around residues 16 and 108 of Plasmodium falciparum dihydrofolate reductase explains resistance to cycloguanil. AB - Natural mutations of Plasmodium falciparum dihydrofolate reductase (PfDHFR) at A16V and S108T specifically confer resistance to cycloguanil (CYC) but not to pyrimethamine (PYR). In order to understand the nature of CYC resistance, the effects of various mutations at A16 on substrate and inhibitor binding were examined. Three series of mutations at A16 with or without the S108T/N mutation were generated. Only three mutants with small side chains at residue 16 (G, C, and S) were viable from bacterial complementation assay in the S108 series, whereas these three and an additional four mutants (T, V, M, and I) with slightly larger side chains were viable with simultaneous S108T mutation. Among these combinations, the A16V+S108T mutant was the most CYC resistant, and all of the S108T series ranged from being highly to moderately sensitive to PYR. In the S108N series, a strict requirement for alanine was observed at position 16. Crystal structure analyses reveal that in PfDHFR-TS variant T9/94 (A16V+S108T) complexed with CYC, the ligand has substantial steric conflicts with the side chains of both A16V and S108T, whereas in the complex with PYR, the ligand only showed mild conflict with S108T. CYC analogs designed to avoid such conflicts improved the binding affinity of the mutant enzymes. These results show that there is greater spatial limitation around the S108T/N residue when combined with the limitation imposed by A16V. The limitation of mutation of this series provides opportunities for drug design and development against antifolate resistant malaria. PMID- 22526320 TI - Chromosome-encoded extended-spectrum class A beta-lactamase MIN-1 from Minibacterium massiliensis. AB - Minibacterium massiliensis strain CIP107820 is a recently discovered waterborne Gram-negative rod isolated from hospital water samples. It harbors a chromosomally located gene encoding an Ambler class A extended-spectrum beta lactamase termed MIN-1, sharing 56%, 54%, and 51% amino acid identities with beta lactamases LUT-1, KPC-2, and CTX-M-2, respectively. beta-Lactamase MIN-1 hydrolyzes penicillins, narrow-spectrum cephalosporins, cefotaxime, and, less efficiently, cefepime, while ceftazidime and carbapenems are very poor substrates, and cephamycins and aztreonam are not hydrolyzed. PMID- 22526322 TI - Dissociative and non-dissociative adsorption dynamics of N2 on Fe(110). AB - We study the adsorption dynamics of N(2) on the Fe(110) surface. Classical molecular dynamics calculations are performed on top of a six-dimensional potential energy surface calculated within density functional theory. Our results show that N(2) dissociation on this surface is a highly activated process that takes place along a very narrow reaction path with an energy barrier of around 1.1 eV, which explains the measured low reactivity of this system. By incorporating energy exchange with the lattice in the dynamics, we also study the non-dissociative molecular adsorption process. From the analysis of the potential energy surface, we observe the presence of two distinct N(2) adsorption wells. Our dynamics calculations show that the relative population of these adsorption sites varies with the incident energy of the molecule and the surface temperature. We find an activation energy of around 150 meV that prevents molecular adsorption under thermal and hypothermal N(2) gas exposure of the surface. This finding is also consistent with the available experimental information. PMID- 22526321 TI - Etravirine concentrations in the cervicovaginal compartment in HIV-1-infected women receiving etravirine-containing antiretroviral therapy: DIVA 02 study. AB - We studied the penetration of etravirine and HIV shedding in the genital tract among 12 HIV-1-infected women receiving an etravirine-containing regimen who had <40 copies/ml blood plasma (BP) HIV RNA. None of the cervicovaginal fluid (CVF) samples showed detectable HIV RNA. Median etravirine concentrations were 663 ng/ml in BP and 857 ng/ml in CVF, with a CVF/BP etravirine ratio of approximately 1.2. This good penetration of etravirine may contribute to the control of viral replication in the female genital tract. PMID- 22526323 TI - Histamine release-neutralization assay for sera of patients with atopic dermatitis and/or cholinergic urticaria is useful to screen type I hypersensitivity against sweat antigens. AB - We previously reported that about 80 % of patients with atopic dermatitis and 60 % with cholinergic urticaria revealed type I allergy against sweat, by means of skin test against autologous sweat and/or histamine-release test for peripheral blood basophils with semi-purified sweat antigen. In this study, we developed an assay for sera to neutralize histamine-releasing activity of semi-purified sweat antigen. The semi-purified sweat antigen was pre-incubated with serially diluted sera for 30 min at 37 degrees C and was subjected to histamine-release activity. Histamine release-neutralization (HRN) activities were calculated by measuring the amount of histamine release from basophils in the presence or absence of semi purified sweat antigen. Of 62 subjects, 39 showed positive histamine release (>=5 %) from their basophils in response to semi-purified sweat antigen, and sera of 34 out of 39 subjects (87.2 %) were also positive in HRN activity (>=10 %). The specificity of the HRN assay was 0.522. Moreover, HRN activities in sera were largely correlated with degrees of histamine release from peripheral blood basophils of the same donors in response to sweat antigen. To identify the substance that neutralizes histamine-release activity, we removed IgE and IgG from the sera of HRN (+) subjects by column chromatography. The HRN activities in 30 out of 42 sera were largely reduced by the removal of IgG. On the other hand, sera of four subjects lost HRN activity by the removal of IgE, suggesting that the majority of HRN (+) subjects have serum IgG against the sweat antigen as well as IgE bound to peripheral basophils. Thus, the HRN assay maybe useful for the screening of type I allergy against sweat antigen. PMID- 22526324 TI - Patented natural avocado sugar modulates the HBD-2 and HBD-3 expression in human keratinocytes through toll-like receptor-2 and ERK/MAPK activation. AB - Keratinocytes stimulated by microbial organisms secrete not only a variety of cytokines, chemokines and growth factors, but also antimicrobial peptides such as beta-defensins (HBDs) such as HBD-2 and HBD-3. AV119, a patented blend of avocado sugar, triggers the up-regulation of HBD-2 in skin epithelia upon contact with AV119, but the signalling mechanisms involved are not completely understood. The purpose of this study was to determine if AV119 was able to induce also the expression of HBD-3 in human keratinocytes. In addition, the receptor and intracellular pathways involved in the AV119 up-regulation of HBD-2 and HBD-3 were investigated. Our results demonstrated that AV119 induces a significantly increase of the expression of HBD-3. In addition, the HBD-2 and HBD-3 AV119 induced gene expression and release are TLR-2 dependent. Finally, we demonstrated that AV119 induced ERK/MAPK phosphorylation in human keratinocytes, thus providing evidence that HBD-2 and HBD-3 secretion is through the same transductional pathway. The ability of AV119 to induce also HBD-3 may amplify its therapeutic potential against a broader spectrum of bacterial and yeast strains responsible for human skin disorders. PMID- 22526325 TI - Angiogenin levels are increased in lesional skin and sera in patients with erythrodermic cutaneous T cell lymphoma. AB - Angiogenin is a member of the ribonuclease superfamily that is associated with the angiogenic process. Angiogenesis is regarded as an important step to support primary and metastatic tumor growth. In cutaneous T cell lymphoma (CTCL), angiogenesis in lesional skin is increased, suggesting that interaction between tumor cells and their microvasculature are likely to occur during progression of CTCL. Patients with hematological malignancies show increased serum angiogenin levels, which are related with poor overall survival. To investigate possible roles of angiogenin in development of CTCL, we measured serum angiogenin levels in 36 patients with CTCL and 21 healthy controls by enzyme-linked immunosorbent assay. We also investigated angiogenin mRNA and protein expression in lesional skin of CTCL by quantitative RT-PCR and immunohistochemistry. Serum angiogenin levels in patients with CTCL were significantly higher than those in healthy controls. When classified with types of skin lesions, serum angiogenin levels were elevated only in erythrodermic CTCL patients. Angiogenin mRNA expression levels in lesional skin were significantly elevated in erythrodermic CTCL compared to normal skin. Immunohistochemical study revealed that angiogenin was expressed by keratinocytes, endothelial cells, and infiltrating lymphocytes in CTCL. Our results suggest that enhanced angiogenin expression may be related with a poor prognosis of erythrodermic CTCL. As angiogenin acts as an inhibitor of polymorphonuclear leukocyte degranulation, angiogenin may also be linked to impaired host defense in erythrodermic CTCL. PMID- 22526327 TI - Copper(II)-mediated oxidative cyclization of enamides to oxazoles. AB - The copper(II)-mediated oxidative cyclization of enamides to oxazoles is reported. A range of 2,5-disubstituted oxazoles were prepared in moderate to good yields in two steps from simple amide and alkyne precursors. PMID- 22526326 TI - Preincubation with Sn-complexes causes intensive intracellular retention of (99m)Tc in thyroid cells in vitro. AB - Technetium radiopharmaceuticals are well established in nuclear medicine. Besides its well-known gamma radiation, (99m)Tc emits an average of five Auger and internal conversion electrons per decay. The biological toxicity of these low energy, high-LET (linear energy transfer) emissions is a controversial subject. One aim of this study was to estimate in a cell model how much (99m)Tc can be present in exposed cells and which radiobiological effects could be estimated in (99m)Tc-overloaded cells. METHODS: Sodium iodine symporter (NIS)-positive thyroid cells were used. (99m)Tc-uptake studies were performed after preincubation with a non-radioactive (cold) stannous pyrophosphate kit solution or as a standard (99m)Tc pyrophosphate kit preparation or with pure pertechnetate solution. Survival curves were analyzed from colony-forming assays. RESULTS: Preincubation with stannous complexes causes irreversible intracellular radioactivity retention of (99m)Tc and is followed by further pertechnetate influx to an unexpectedly high (99m)Tc level. The uptake of (99m)Tc pertechnetate in NIS-positive cells can be modified using stannous pyrophosphate from 3-5% to >80%. The maximum possible cellular uptake of (99m)Tc was 90Bq/cell. Compared with nearly pure extracellular irradiation from routine (99m)Tc complexes, cell survival was reduced by 3-4 orders of magnitude after preincubation with stannous pyrophosphate. CONCLUSIONS: Intracellular (99m)Tc retention is related to reduced survival, which is most likely mediated by the emission of low-energy electrons. Our findings show that the described experiments constitute a simple and useful in vitro model for radiobiological investigations in a cell model. PMID- 22526328 TI - Improved trehalose production from biodiesel waste using parent and osmotically sensitive mutant of Propionibacterium freudenreichii subsp. shermanii under aerobic conditions. AB - Trehalose is an important nutraceutical of wide commercial interest in the food processing industry. Recently, crude glycerol was reported to be suitable for the production of trehalose using a food microbe, Propionibacterium freudenreichii subsp. shermanii, under static flask conditions. Similarly, enhanced trehalose yield was reported in an osmotically sensitive mutant of the same strain under anaerobic conditions. In the present study, an effort was made to achieve higher production of trehalose, propionic acid, and lactic acid using the parent and an osmotically sensitive mutant of P. freudenreichii subsp. shermanii under aeration conditions. Under aeration conditions (200 rpm in shake flasks and 30 % air saturation in a batch reactor), biomass was increased and approximately 98 % of crude glycerol was consumed. In the parent strain, a trehalose titre of 361 mg/l was achieved, whereas in the mutant strain a trehalose titre of 1.3 g/l was produced in shake flask conditions (200 rpm). In the mutant strain, propionic and lactic acid yields of 0.53 and 0.21 g/g of substrate were also achieved with crude glycerol. Similarly, in controlled batch reactor culturing conditions a final trehalose titre of approximately 1.56 g/l was achieved with the mutant strain using crude glycerol as the substrate. Enhanced production of trehalose using P. freudenreichii subsp. shermanii from waste under aeration conditions is reported here. Higher production of trehalose was not due to a higher yield of trehalose but to a higher final biomass concentration. PMID- 22526329 TI - Control of redox potential in hybridoma cultures: effects on MAb production, metabolism, and apoptosis. AB - Culture redox potential (CRP) has proven to be a valuable monitoring tool in several areas of biotechnology; however, it has been scarcely used in animal cell culture. In this work, a proportional feedback control was employed, for the first time, to maintain the CRP at different constant values in hybridoma batch cultures for production of a monoclonal antibody (MAb). Reducing and oxidant conditions, in the range of -130 and +70 mV, were maintained in 1-l bioreactors through automatic control of the inlet gas composition. Cultures at constant DOT, in the range of 3 and 300 %, were used for comparison. The effect of constant CRP on cell concentration, MAb production, metabolism of glucose, glutamine, thiols, oxygen consumption, and programmed cell death, was evaluated. Reducing conditions resulted in the highest viable cell and MAb concentrations and thiols production, whereas specific glucose and glutamine consumption rates remained at the lowest values. In such conditions, programmed cell death, particularly apoptosis, occurred only after nutrient exhaustion. The optimum specific MAb production rate occurred at intermediate CRP levels. Oxidant conditions resulted in a detrimental effect in all culture parameters, increasing the specific glucose, glutamine, and oxygen consumption rates and inducing the apoptotic process, which was detected as early as 24 h even when glutamine and glucose were present at non-limiting concentrations. In most cases, such results were similar to those obtained in control cultures at constant DOT. PMID- 22526330 TI - Production host selection for asymmetric styrene epoxidation: Escherichia coli vs. solvent-tolerant Pseudomonas. AB - Selection of the ideal microbe is crucial for whole-cell biotransformations, especially if the target reaction intensively interacts with host cell functions. Asymmetric styrene epoxidation is an example of a reaction which is strongly dependent on the host cell owing to its requirement for efficient cofactor regeneration and stable expression of the styrene monooxygenase genes styAB. On the other hand, styrene epoxidation affects the whole-cell biocatalyst, because it involves toxic substrate and products besides the burden of additional (recombinant) enzyme synthesis. With the aim to compare two fundamentally different strain engineering strategies, asymmetric styrene epoxidation by StyAB was investigated using the engineered wild-type strain Pseudomonas sp. strain VLB120DeltaC, a styrene oxide isomerase (StyC) knockout strain able to accumulate (S)-styrene oxide, and recombinant E. coli JM101 carrying styAB on the plasmid pSPZ10. Their performance was analyzed during fed-batch cultivation in two-liquid phase biotransformations with respect to specific activity, volumetric productivity, product titer, tolerance of toxic substrate and products, by product formation, and product yield on glucose. Thereby, Pseudomonas sp. strain VLB120DeltaC proved its great potential by tolerating high styrene oxide concentrations and by the absence of by-product formation. The E. coli-based catalyst, however, showed higher specific activities and better yields on glucose. The results not only show the importance but also the complexity of host cell selection and engineering. Finding the optimal strain engineering strategy requires profound understanding of bioprocess and biocatalyst operation. In this respect, a possible negative influence of solvent tolerance on yield and activity is discussed. PMID- 22526331 TI - Reduction of N-terminal methionylation while increasing titer by lowering metabolic and protein production rates in E. coli auto-induced fed-batch fermentation. AB - A standard fed-batch fermentation process using 1 mM isopropyl-beta-D: thiogalactopyranoside (IPTG) induction at 37 degrees C in complex batch and feed media had been developed for manufacturing of a therapeutic protein (TP) expressed in inclusion bodies (IBs) by E. coli BL21 (DE3) driven by T7 promoter. Six unauthentic TP N-terminal variants were identified, of which methionylated TP (Met-TP) ratio was predominant. We hypothesized that lowering metabolic and protein production rates would reduce the Met-TP ratio while improving TP titer. The standard process was surprisingly auto-induced without added IPTG due to galactose in the complex media. Without changing either the clone or the batch medium, a new process was developed using lower feed rates and auto-induction at 29 degrees C after glucose depletion while increasing induction duration. In comparison to the standard process, the new process reduced the unauthentic Met TP ratio from 23.6 to 9.6 %, increased the TP titer by 85 %, and the specific production yield from 210 to 330 mg TP per gram of dry cell weight. Furthermore, the TP recovery yield in the purified IBs was improved by ~20 %. Adding together, ~105 % more TP recovered in the purified IBs from per liter of fermentation broth for the new process than the standard process. The basic principles of lowering metabolic and production rates should be applicable to other recombinant protein production in IBs by fed-batch fermentations. PMID- 22526332 TI - Isolation and characterization of a novel GH67 alpha-glucuronidase from a mixed culture. AB - Hemicelluloses represent a large reservoir of carbohydrates that can be utilized for renewable products. Hydrolysis of hemicellulose into simple sugars is inhibited by its various chemical substituents. The glucuronic acid substituent is removed by the enzyme alpha-glucuronidase. A gene (deg75-AG) encoding a putative alpha-glucuronidase enzyme was isolated from a culture of mixed compost microorganisms. The gene was subcloned into a prokaryotic vector, and the enzyme was overexpressed and biochemically characterized. The DEG75-AG enzyme had optimum activity at 45 degrees C. Unlike other alpha-glucuronidases, the DEG75 AG had a more basic pH optimum of 7-8. When birchwood xylan was used as substrate, the addition of DEG75-AG increased hydrolysis twofold relative to xylanase alone. PMID- 22526334 TI - Of long nights, lactation, and love. PMID- 22526333 TI - Production of reactive oxygen species by multipotent stromal cells/mesenchymal stem cells upon exposure to fas ligand. AB - Multipotent stromal cells (MSCs) can be differentiated into osteoblasts and chondrocytes, making these cells candidates to regenerate cranio-facial injuries and lesions in long bones. A major problem with cell replacement therapy, however, is the loss of transplanted MSCs at the site of graft. Reactive oxygen species (ROS) and nonspecific inflammation generated at the ischemic site have been hypothesized to lead to MSCs loss; studies in vitro show MSCs dying both in the presence of ROS or cytokines like FasL. We questioned whether MSCs themselves may be the source of these death inducers, specifically whether MSCs produce ROS under cytokine challenge. On treating MSCs with FasL, we observed increased ROS production within 2 h, leading to apoptotic death after 6 h of exposure to the cytokine. N-acetyl cysteine, an antioxidant, is able to protect MSCs from FasL induced ROS production and subsequent ROS-dependent apoptosis, though the MSCs eventually succumb to ROS-independent death signaling. Epidermal growth factor (EGF), a cell survival factor, is able to protect cells from FasL-induced ROS production initially; however, the protective effect wanes with continued FasL exposure. In parallel, FasL induces upregulation of the uncoupling protein UCP2, the main uncoupling protein in MSCs, which is not abrogated by EGF; however, the production of ROS is followed by a delayed apoptotic cell death despite moderation by UCP2. FasL-induced ROS activates the stress-induced MAPK pathways JNK and p38MAPK as well as ERK, along with the activation of Bad, a proapoptotic protein, and suppression of survivin, an antiapoptotic protein; the latter two key modulators of the mitochondrial death pathway. FasL by itself also activates its canonical extrinsic death pathway noted by a time-dependent degradation of c FLIP and activation of caspase 8. These data suggest that MSCs participate in their own demise due to nonspecific inflammation, holding implications for replacement therapies. PMID- 22526335 TI - Warm breastshields and breast milk pumping. PMID- 22526337 TI - The AAP updates its policy on breastfeeding and reaches consensus on recommended duration of exclusive breastfeeding. PMID- 22526338 TI - Breastfeeding protection, promotion, and support in the United States: a time to nudge, a time to measure. AB - BACKGROUND: Strong evidence-based advocacy efforts have now translated into high level political support and concrete goals for improving breastfeeding outcomes among women in the United States. In spite of this, major challenge remain for promoting, supporting and especially for protecting breastfeeding in the country. OBJECTIVES: The goals of this commentary are to argue in favor of: A) Changes in the default social and environmental systems, that would allow women to implement their right to breastfeed their infants, B) A multi-level and comprehensive monitoring system to measure process and outcomes indicators in the country. METHODS: Evidence-based commentary. RESULTS: Breastfeeding rates in the United States can improve based on a well coordinated social marketing framework. This approach calls for innovative promotion through mass media, appropriate facility based and community based support (e.g., Baby Friendly Hospital Initiative, WIC coordinated community based peer counseling), and adequate protection for working women (e.g., longer paid maternity leave, breastfeeding or breast milk extraction breaks during the working day) and women at large by adhering and enforcing the WHO ethics Code for the Marketing of Breast Milk Substitutes. Sound infant feeding practices monitoring systems, which include WIC administrative food package data, are needed. CONCLUSIONS: Given the current high level of political support to improve breastfeeding in the United States, a window of opportunity has been opened. Establishing breastfeeding as the social norm in the USA will take time, but the global experience indicates that it can be done. PMID- 22526339 TI - RoundTable discussion: Use of alternative feeding methods in the hospital. PMID- 22526340 TI - Implementing change: steps to initiate a human donor milk program in a US Level III NICU. AB - Initiating a pasteurized human donor milk (PDM) program in a level III neonatal intensive care unit (NICU) can be a difficult process that requires commitment by a multidisciplinary team, education, sufficient funding, and "buy-in" from NICU staff, families, and hospital administration. We began planning for our program in February 2011 and started using PDM in June 2011. This paper describes the steps taken and the obstacles overcome to initiate a PDM program for our hospital's tiniest, sickest, and most vulnerable patients. PMID- 22526341 TI - Exclusive breastfeeding through 6 months: infant intake and growth patterns. PMID- 22526342 TI - Blood flow characteristics of the human lactating breast. AB - BACKGROUND: Despite the increased metabolic activity of the lactating breast, no studies have been carried out to determine mammary blood flow (MBF) parameters or the relationship between MBF and milk production in women. The aim of this study was to measure the MBF in the internal mammary artery (IMA) and lateral thoracic artery (LTA) of lactating women and determine if these were related to milk production. METHODS: Blood flow in the IMA and LTA was measured with color Doppler ultrasound in 55 lactating women. Twenty-four-hour milk production was determined with the test-weigh method. RESULTS: IMA contributed the greater proportion of blood flow to the lactating breast (70%). MBF was highly variable between women but consistent between the left (126 L/24 h; interquartile range, 76-169) and right (110 L/24 h) breasts. No relationship between MBF and milk production was demonstrated. For 3 women, MBF was markedly reduced in 1 breast that was synthesizing almost no milk compared to the other that was producing a normal volume of milk. DISCUSSION: Although no relationship between MBF and milk production was found, the substantial reduction in blood flow in the breasts of lactating women producing almost no milk suggests a threshold below which milk production is compromised. CONCLUSION: Doppler ultrasound did not demonstrate a relationship between MBF and milk production in lactating women. Further investigation is required to fully understand the role of blood flow in milk synthesis. PMID- 22526343 TI - Weight loss in exclusively breastfed infants delivered by cesarean birth. AB - BACKGROUND: Rates of exclusive breastfeeding during the postpartum hospital stay are a key measure of quality maternity care. Often, however, concern for excessive in-hospital weight loss leads to formula supplementation of breastfed infants. The American Academy of Pediatrics defines 7% weight loss as acceptable for breastfed newborns regardless of mode of delivery. Typical weight loss in exclusively breastfed infants delivered by cesarean birth has not been studied nor have possible correlates of greater weight loss in this population. OBJECTIVES: To determine average weight loss in a cohort of exclusively breastfed infants delivered by cesarean birth and to identify correlates of greater than expected weight loss. METHODS: We performed a retrospective chart review of exclusively breastfed infants delivered via cesarean birth at a Baby-Friendly hospital between 2005 and 2007. Average weight loss was calculated, and multivariate regression analysis was performed. RESULTS: Average weight loss during the hospital stay in our cohort of 200 infants was 7.2% +/- 2.1% of birth weight, slightly greater than the American Academy of Pediatrics guideline of 7%. Absence of labor prior to delivery was significantly associated with a greater percentage of weight loss (P = .0004), as were lower gestational age (P = .0004) and higher birth weight (P < .0001). Maternal age, gravity, parity, infant sex, Apgar scores, and prior cesarean birth were not significantly associated. CONCLUSIONS: We conclude that for exclusively breastfed infants delivered by cesarean birth in a Baby-Friendly hospital, absence of labor prior to cesarean birth may be a previously unreported risk factor for greater than expected weight loss. PMID- 22526344 TI - Vitamin D status among 4-month-old infants in New England: a prospective cohort study. AB - BACKGROUND: Concerns over vitamin D deficiency in infants and children recently prompted the American Academy of Pediatrics to recommend increased supplementation. Few studies have examined vitamin D status in the same infants over time. Also, while many researchers label "breastfeeding" as a risk factor for vitamin D deficiency, few differentiate between any breastfeeding, exclusive breastfeeding, and supplemented or unsupplemented breastfeeders. OBJECTIVE: To determine predictors of 25(OH)D deficiency at 4 months in a group of children previously tested at birth. METHODS: We enrolled newborns from 2005 to 2007 at an urban Boston hospital. Maternal and infant blood samples were collected within 72 hours of birth. At 4 months, we obtained a second infant blood sample. RESULTS: At 4 months, 11.9% of the 177 infants were vitamin D deficient compared to 37.5% at birth (25(OH)D <20 ng/mL). Median 25(OH)D was 35.2 ng/mL (range, 5-100.8; 95% confidence interval [CI], 32.8-37.6). At 4 months, 40% of unsupplemented infants were deficient. Lack of supplementation was significantly associated with increased risk of deficiency (adjusted odds ratio [AOR], 19.3; 95% CI, 4.80 77.2). Being outside at least 10 minutes a day, once per week, was protective (AOR, 0.12; 95% CI, 0.02-0.66), as was increasing gestational age (AOR, 0.36; 95% CI, 0.19-0.69). In 48.4% of patients, physicians failed to prescribe vitamin D at 2 months. CONCLUSIONS: Despite inconsistent supplementation, a smaller proportion of infants were vitamin D deficient at 4 months than at birth. While supplemented breastfed infants were not at risk of deficiency, unsupplemented exclusively breastfed infants were at high risk of severe deficiency. PMID- 22526345 TI - Association between acculturation and breastfeeding among Hispanic women: data from the Pregnancy Risk Assessment and Monitoring System. AB - BACKGROUND: Breastfeeding rates are typically higher among Hispanic women; however, they vary by acculturation status in that those more acculturated are less likely to breastfeed than those who are less acculturated. This study examined the association between acculturation and breastfeeding behaviors using population-based data. METHODS: Data (N = 8942) from the Pregnancy Risk Assessment Monitoring System (PRAMS) were used for analysis. Acculturation status was determined using self-reported Hispanic ethnicity and the language in which the women responded to the PRAMS survey, either English or Spanish. Hispanic women who responded to the survey in Spanish were categorized as less acculturated than those who responded in English. Breastfeeding indicators used were: initiation, duration to >= 10 weeks, and exclusive breastfeeding to >= 10 weeks. RESULTS: The prevalence rates of breastfeeding initiation, duration, and exclusive breastfeeding to >= 10 weeks were significantly higher among less acculturated than among highly acculturated. More acculturated were less likely to initiate breastfeeding (prevalence ratio [PR] = 0.88; 95% CI, 0.86-0.90), less likely to breastfeed >= 10 weeks (PR = 0.77; 95% CI, 0.72-0.82), and less likely to report exclusive breastfeeding to >= 10 weeks (PR =,0.70; 95% CI, 0.58-0.85). The relationship between breastfeeding continuation and acculturation persisted after adjusting for covariates in that more acculturated were less likely to breastfeed to >= 10 weeks (adjusted prevalence ratio [APR] = 0.81; 95% CI, 0.75 0.87), as did the relationship between exclusivity and acculturation; more acculturated were less likely to report exclusive breastfeeding (APR = 0.69; 95% CI, 0.55-0.87). CONCLUSIONS: Breastfeeding promotion efforts must include culturally/linguistically supportive services to assure that women are able to make optimal infant feeding decisions. PMID- 22526346 TI - The economic burden of infant formula on families with young children in the Philippines. AB - BACKGROUND: Infant formula usage places children at risk for illness and death. Studies in the United States demonstrated high economic burden, health care costs, and absenteeism of caregivers associated with formula usage. Despite high formula usage in developing countries, no economic studies were found. This study examines the financial burden of purchasing infant formula and increased health care expenditure in the Philippines, a developing country with a per capita income of $3930. The average exchange rate of the peso to the US dollar for 2003 was $1 to P52, according to Bangko Sentral ng Pilipinas (BSP). METHODS: This is a secondary analysis of the 2003 Family Income and Expenditure Survey, a national cross-sectional multistage cluster survey of 42 094 households. RESULTS: Almost half of Philippine families with a young child and one-third of families living on less than $2 per day purchase formula. Nationally, $260 million was spent on infant formula in 2003. Formula-buying families with young children had spent an aggregate of $143.9 million on medical care compared to $56.6 million by non formula-buying families. After adjusting for income and nonmilk family expenditures, the average formula-purchasing Philippine family spent an additional $0.30 (95% CI: 0.24 - 0.36; r(2) = 0.08) on medical expenditure for every $1 spent on formula. CONCLUSIONS: The economic burden from infant formula purchase and out-of-pocket medical expenditure exceeded $400 million in 2003. This cost was aside from other costs, such as absenteeism and the risk of childhood death and illness. These expenses caused an unnecessary burden on Filipino families and could instead have been invested in education and other social services. PMID- 22526347 TI - Breastfeeding patterns among Palestinian infants in the first 6 months in Nablus refugee camps: a cross-sectional study. AB - BACKGROUND: Several studies in Palestine, including some performed in refugee camps, showed that breastfeeding is a common practice, however, exclusive breastfeeding was practiced less frequently. The social and cultural patterns in relation to different types of infant feeding were not studied. OBJECTIVES: This study aimed to evaluate the association between mothers' and infants' sociodemographic factors and breastfeeding patterns during the first 6 months of infant life. METHODS: This cross-sectional study evaluated data of 690 clinic files from 3 refugee camps in Nablus, Palestine in 2007. Maternal age, age at marriage, parity, mother's and father's education, type of delivery and infant's gender were studied in relation to 3 types of breastfeeding: exclusive breastfeeding, partial breastfeeding, and exclusive formula feeding in the first 6 months of life. Bivariate analysis and logistic regression were applied for data analysis. RESULTS: A total of 69.7% of infants aged 0-6 months were exclusively breastfed and only 14.3% were exclusively formula fed. Older mothers at marriage (risk ratio [RR], 0.13; 95% confidence interval [CI], 0.06-0.28), and cesarean birth (RR, 0.59; 95% CI, 0.41-0.81) were negatively associated with EBF. CONCLUSION: Breastfeeding educational and health promotion program and policy for EBF implemented by UNRWA (United Nations Relief and Works Agency for Palestine Refugees in the Near East) should continue with special attention to older mothers at marriage, and to babies born by cesarean section. PMID- 22526350 TI - Novel NDE1 homozygous mutation resulting in microhydranencephaly and not microlyssencephaly. AB - Lissencephaly is characterized by deficient cortical lamination. Recently homozygous NDE1 mutations were reported in three kindred afflicted with extreme microcephaly with lissencephaly or microlissencephaly. Another severe developmental defect that involves the brain is microhydranencephaly which manifests with microcephaly, motor and mental retardation and brain malformations that include gross dilation of the ventricles with complete absence of the cerebral hemispheres or severe delay in their development. In the three related patients with microhydranencephaly that we had reported previously, we identified a homozygous deletion that encompasses NDE1 exon 2 containing the initiation codon. The mutation is predicted to result in a null allele. Herein we compare the clinical phenotypes of our research patients to those reported as microlissencephaly. The clinical findings in our patients having the fourth NDE1 mutation reported so far widen the spectrum of brain malformations resulting from mutations in NDE1. PMID- 22526351 TI - A novel double mutation in cis in MFN2 causes Charcot-Marie-Tooth neuropathy type 2A. AB - Mutations in mitofusin-2 (MFN2) are the most common cause of axonal Charcot-Marie Tooth (CMT) neuropathy. Herein, we report a novel double mutation in cis (c.[474+4A>G; 668T>A]) in a Korean family with late-onset autosomal dominant mild axonal CMT. Transcriptional analysis demonstrated aberrant splicing with exon 5 skipping and premature termination of translation before the missense mutation in exon 7. Interestingly, the aberrant splicing was incomplete, with some of the primary transcripts being spliced correctly and expressing the downstream missense mutation. The pathogenic relevance of the missense mutation would not be appreciated without the leaky aberrant splicing and the insensitivity of MFN2 to haploinsufficiency. PMID- 22526353 TI - A boron-containing carbazole dimer: synthesis, photophysical properties and sensing properties. AB - A novel boron-containing pi-conjugated compound has been synthesized by the introduction of electron-acceptors (dimesitylboron groups) at the 3,3'-positions of a carbazole dimer (electron-donor). The compound possesses excellent electrochemical properties and high fluorescence quantum yields. In addition, is a sensitive fluorescence sensor with remarkable colour changes and the results could be confirmed through theoretical calculations of the compounds and [(n)Bu(4)N](+)(2)[.(F)(2)](2-). Our studies indicate that could be used as an excellent optoelectronic material in OLED devices and a ratiometric fluorescent chemosensor. PMID- 22526352 TI - TRPV4 mutations in children with congenital distal spinal muscular atrophy. AB - Inherited disorders characterized by motor neuron loss and muscle weakness are genetically heterogeneous. The recent identification of mutations in the gene encoding transient receptor potential vanilloid 4 (TRPV4) in distal spinal muscular atrophy (dSMA) prompted us to screen for TRPV4 mutations in a small group of children with compatible phenotype. In a girl with dSMA and vocal cord paralysis, we detected a new variant (p.P97R) localized in the cytosolic N terminus of the TRPV4 protein, upstream of the ankyrin-repeat domain, where the great majority of disease-associated mutations reside. In another child with congenital dSMA, in this case associated with bone abnormalities, we detected a previously reported mutation (p.R232C). Functional analysis of the novel p.P97R mutation in a heterologous system demonstrated a loss-of-function mechanism. Protein localization studies in muscle, skin, and cultured skin fibroblasts from both patients showed normal protein expression. No TRPV4 mutations were detected in four children with dSMA without bone or vocal cord involvement. Adding to the clinical and molecular heterogeneity of TRPV4-associated diseases, our results suggest that molecular testing of the TRPV4 gene is warranted in cases of congenital dSMA with bone abnormalities and vocal cord paralysis. PMID- 22526354 TI - CuproCleav-1, a first generation photocage for Cu+. AB - By utilizing thioether ligands, CuproCleav-1 stabilizes Cu(+) complexes in aqueous solution and releases the guest metal ion upon photolysis of the nitrobenzyl group. The photocage has an apparent K(d) of 54 pM for Cu(+), and metal ion release has been demonstrated using the fluorescent sensor CS1. PMID- 22526355 TI - A general linear framework for the comparison and evaluation of models of sensorimotor synchronization. AB - Sensorimotor synchronization (SMS), the temporal coordination of a rhythmic movement with an external rhythm, has been studied most often in tasks that require tapping along with a metronome. Models of SMS use information about the timing of preceding stimuli and responses to predict when the next response will be made. This article compares the theoretical structure and empirical predictions of four two-parameter models proposed in the literature: Michon (Timing in temporal tracking, Van Gorcum, Assen, 1967), Hary and Moore (Br J Math Stat Psychol 40:109-124, 1987b), Mates (Biol Cybern 70:463-473, 1994a; Biol Cybern 70:475-484, 1994b), and Schulze et al. (Mus Percept 22:461-467, 2005). By embedding these models within a general linear framework, the mathematical equivalence of the Michon, Hary and Moore, and Schulze et al. models is demonstrated. The Mates model, which differs from the other three, is then tested empirically with new data from a tapping experiment in which the metronome alternated between two tempi. The Mates model predictions are found to be invalid for about one-third of the trials, suggesting that at least one of the model's underlying assumptions is incorrect. The other models cannot be refuted as easily, but they do not predict some features of the data very accurately. Comparison of the models' predictions in a training/test procedure did not yield any significant differences. The general linear framework introduced here may help in the formulation of new models that make better predictions. PMID- 22526356 TI - A computational model for the modulation of the prepulse inhibition of the acoustic startle reflex. AB - The acoustic startle reflex (ASR), a defensive response, is a contraction of the skeletal and facial muscles in response to an abrupt, intense (>80 db) auditory stimulus, which has been extensively studied in rats and humans. Prepulse inhibition (PPI) of ASR is the normal suppression of the startle reflex when an intense stimulus is preceded by a weak non-starting pre-stimulus. PPI, a measure of sensory motor gating, is impaired in various neuropsychiatric disorders, including schizophrenia, and is modulated by cognitive and emotional contexts such as fear and attention. We have modeled the fear modulation of PPI of ASR based on its anatomical substrates and taking into account data from behaving rats and humans. The model replicates the principal features of both phenomena and predicts underlying neural mechanisms. In addition, the model yields testable predictions. PMID- 22526357 TI - A CORF computational model of a simple cell that relies on LGN input outperforms the Gabor function model. AB - Simple cells in primary visual cortex are believed to extract local contour information from a visual scene. The 2D Gabor function (GF) model has gained particular popularity as a computational model of a simple cell. However, it short-cuts the LGN, it cannot reproduce a number of properties of real simple cells, and its effectiveness in contour detection tasks has never been compared with the effectiveness of alternative models. We propose a computational model that uses as afferent inputs the responses of model LGN cells with center surround receptive fields (RFs) and we refer to it as a Combination of Receptive Fields (CORF) model. We use shifted gratings as test stimuli and simulated reverse correlation to explore the nature of the proposed model. We study its behavior regarding the effect of contrast on its response and orientation bandwidth as well as the effect of an orthogonal mask on the response to an optimally oriented stimulus. We also evaluate and compare the performances of the CORF and GF models regarding contour detection, using two public data sets of images of natural scenes with associated contour ground truths. The RF map of the proposed CORF model, determined with simulated reverse correlation, can be divided in elongated excitatory and inhibitory regions typical of simple cells. The modulated response to shifted gratings that this model shows is also characteristic of a simple cell. Furthermore, the CORF model exhibits cross orientation suppression, contrast invariant orientation tuning and response saturation. These properties are observed in real simple cells, but are not possessed by the GF model. The proposed CORF model outperforms the GF model in contour detection with high statistical confidence (RuG data set: p<10(-4), and Berkeley data set: p<10(-4)). The proposed CORF model is more realistic than the GF model and is more effective in contour detection, which is assumed to be the primary biological role of simple cells. PMID- 22526358 TI - Dynamical estimation of neuron and network properties II: Path integral Monte Carlo methods. AB - Hodgkin-Huxley (HH) models of neuronal membrane dynamics consist of a set of nonlinear differential equations that describe the time-varying conductance of various ion channels. Using observations of voltage alone we show how to estimate the unknown parameters and unobserved state variables of an HH model in the expected circumstance that the measurements are noisy, the model has errors, and the state of the neuron is not known when observations commence. The joint probability distribution of the observed membrane voltage and the unobserved state variables and parameters of these models is a path integral through the model state space. The solution to this integral allows estimation of the parameters and thus a characterization of many biological properties of interest, including channel complement and density, that give rise to a neuron's electrophysiological behavior. This paper describes a method for directly evaluating the path integral using a Monte Carlo numerical approach. This provides estimates not only of the expected values of model parameters but also of their posterior uncertainty. Using test data simulated from neuronal models comprising several common channels, we show that short (<50 ms) intracellular recordings from neurons stimulated with a complex time-varying current yield accurate and precise estimates of the model parameters as well as accurate predictions of the future behavior of the neuron. We also show that this method is robust to errors in model specification, supporting model development for biological preparations in which the channel expression and other biophysical properties of the neurons are not fully known. PMID- 22526359 TI - Developing structural constraints on connectivity for biologically embedded neural networks. AB - In this article, we analyse under which conditions an abstract model of connectivity could actually be embedded geometrically in a mammalian brain. To this end, we adopt and extend a method from circuit design called Rent's Rule to the highly branching structure of cortical connections. Adding on recent approaches, we introduce the concept of a limiting Rent characteristic that captures the geometrical constraints of a cortical substrate on connectivity. We derive this limit for the mammalian neocortex, finding that it is independent of the species qualitatively as well as quantitatively. In consequence, this method can be used as a universal descriptor for the geometrical restrictions of cortical connectivity. We investigate two widely used generic network models: uniform random and localized connectivity, and show how they are constrained by the limiting Rent characteristic. Finally, we discuss consequences of these restrictions on the development of cortex-size models. PMID- 22526360 TI - Decreased indoleamine 2,3-dioxygenase expression in dendritic cells and role of indoleamine 2,3-dioxygenase-expressing dendritic cells in immune thrombocytopenia. AB - Indoleamine 2,3-dioxygenase (IDO) expression in dendritic cells (DCs) can induce or maintain peripheral immune tolerance. Impaired IDO-mediated tryptophan catabolism has been observed in autoimmune diseases. In order to investigate the effects of IDO-mediated tryptophan catabolism and IDO-expressing DCs in immune thrombocytopenia, the concentrations of kynurenine were detected by high-pressure liquid chromatography. The expressions of IDO were analyzed by flow cytometry and western blot analysis. The effects of IDO(+) DCs stimulated with CTLA-4-Ig on T cells proliferation and activation, lymphocyte apoptosis, and Tregs were measured by flow cytometry. We found that the expression of IDO in DCs of immune thrombocytopenia (ITP) patients was significantly decreased. CTLA-4-Ig significantly increased the expression of functional IDO in DCs of ITP patients. IDO(+) DCs stimulated with CTLA-4-Ig suppressed T cells proliferation and activation, promoted lymphocyte apoptosis, and increased the percentage of Tregs. These results suggest that decreased IDO expression in DCs may play a critical role in ITP. CTLA-4-Ig successfully corrected the disorder of IDO expression in ITP. IDO(+) DCs stimulated with CTLA-4-Ig inhibited immune responses by an IDO dependent mechanism. Increasing the expression and activity of IDO in DCs might be a promising therapeutic approach for ITP. PMID- 22526362 TI - Flow cytometry in myelodysplastic syndrome: analysis of diagnostic utility using maturation pattern-based and quantitative approaches. AB - Flow cytometry (FCM) is being increasingly evaluated for the diagnosis of myelodysplastic syndrome (MDS). We employed multiple FCM approaches to assess MDS. Five-color FCM, morphology blind, was done on bone marrow aspirates of 57 suspected MDS and 31 normal controls. Maturation pattern, quantitative FCM for low-grade MDS that awards FCM score, and expression of selected antigens on erythroid cells and CD34(+) blasts were evaluated. FCM results were correlated with clinical and laboratory workup. Patients (n = 57) included proven MDS (n = 14), suspected MDS (n = 13), and non-MDS (n = 30). By pattern-based approach, all proven cases were FCM positive. In suspected MDS, 11 (84.61 %) were positive including morphology-negative cases, and two (15.38 %) were intermediate. In non MDS cases, 27 of 30 (90 %) were FCM negative, 2 of 30 (6.67 %) intermediate, and 1 of 30 (3.33 %) a hematinic-responsive case, positive. Quantitative parameters that characterized MDS included FCM score of >3, percentage CD34(+) B cells, and expression of CD11b, CD15, and CD56 on myeloblasts. CD71 MFI on CD235a(+) erythroblasts and CD38 MFI on myeloblasts were significantly lower in MDS. The former was present in FCM-intermediate suspected MDS but not FCM-intermediate non MDS cases. Used in the overall clinical context, both maturation pattern recognition and quantitative approaches, the latter for low-grade MDS, are sensitive methods of diagnosing MDS, including cases negative by morphology and cytogenetics, especially if combined with evaluation of selected antigens, CD71 on CD235a(+) cells and CD38 on CD34(+) cells. The value of FCM in morphology negative cases needs better definition of specificity through more extensive evaluation of secondary dyspoiesis. PMID- 22526361 TI - Immunological aspects in chronic lymphocytic leukemia (CLL) development. AB - Chronic lymphocytic leukemia (CLL) is unique among B cell malignancies in that the malignant clones can be featured either somatically mutated or unmutated IGVH genes. CLL cells that express unmutated immunoglobulin variable domains likely underwent final development prior to their entry into the germinal center, whereas those that express mutated variable domains likely transited through the germinal center and then underwent final development. Regardless, the cellular origin of CLL remains unknown. The aim of this review is to summarize immunological aspects involved in this process and to provide insights about the complex biology and pathogenesis of this disease. We propose a mechanistic hypothesis to explain the origin of B-CLL clones into our current picture of normal B cell development. In particular, we suggest that unmutated CLL arises from normal B cells with self-reactivity for apoptotic bodies that have undergone receptor editing, CD5 expression, and anergic processes in the bone marrow. Similarly, mutated CLL would arise from cells that, while acquiring self reactivity for autoantigens-including apoptotic bodies-in germinal centers, are also still subject to tolerization mechanisms, including receptor editing and anergy. We believe that CLL is a proliferation of B lymphocytes selected during clonal expansion through multiple encounters with (auto)antigens, despite the fact that they differ in their state of activation and maturation. Autoantigens and microbial pathogens activate BCR signaling and promote tolerogenic mechanisms such as receptor editing/revision, anergy, CD5+ expression, and somatic hypermutation in CLL B cells. The result of these tolerogenic mechanisms is the survival of CLL B cell clones with similar surface markers and homogeneous gene expression signatures. We suggest that both immunophenotypic surface markers and homogenous gene expression might represent the evidence of several attempts to re educate self-reactive B cells. PMID- 22526364 TI - The impact of age, Charlson comorbidity index, and performance status on treatment of elderly patients with diffuse large B cell lymphoma. AB - Treatment intensity will affect outcome in elderly patients with diffuse large B cell lymphoma (DLBCL). We retrospectively reviewed 333 DLBCL patients aged over 60 years who were diagnosed between January 2003 and December 2010 to evaluate the difference between different treatment regimens. The median age was 73 years; 56.8 % of patients received treatment with rituximab-containing regimens. In univariate analysis, patients with younger age, better performance status, early Ann Arbor stage, lower International Prognostic Index (IPI), normal serum lactate dehydrogenase, normal serum albumin, or normal serum beta-2 microglobulin received more intensive treatment regimens. In multivariate analysis, patients with younger age (p < 0.001) or better performance status (p = 0.027) received treatment of more intensive regimens. The treatment regimens were not different between patients with lower and higher Charlson comorbidity index (CCI). Female gender, normal serum beta-2 microglobulin, lower CCI, lower IPI, and treatment with more intensive regimens predicted better progression-free survival and overall survival in multivariate analysis. Patients treated with rituximab containing regimens had better progression-free survival (median 22.2 vs. 9.9 months, p = 0.005) and better overall survival (median 34.9 vs. 21.8 months, p = 0.042) as compared to those treated without rituximab. In conclusion, our results showed that patients with younger age or better performance status received more intensive treatment. The treatment regimen was not different between patients with lower and higher CCI. Rituximab-containing regimens improved the outcome of elderly patients with DLBCL. PMID- 22526363 TI - A randomized comparison of cyclophosphamide vs. reduced dose cyclophosphamide plus fludarabine for allogeneic hematopoietic cell transplantation in patients with aplastic anemia and hypoplastic myelodysplastic syndrome. AB - Recently, a less toxic regimen comprising reduced cyclophosphamide (Cy), fludarabine, and anti-thymocyte globulin (ATG) (Cy-Flu-ATG) was used to condition high-risk patients scheduled for allogeneic hematopoietic cell transplantation (alloHSCT) instead of standard Cy-ATG in patients with severe aplastic anemia (AA). We performed a randomized phase III study to compare the regimen-related toxicities (RRTs) of two different conditioning regimens: Cy-ATG vs. Cy-Flu-ATG. Patients in the Cy-ATG arm received Cy at 200 mg/kg. Those in the Cy-Flu-ATG arm received fludarabine (Flu) at 150 mg/m(2) and Cy at 100 mg/kg. A total of 83 patients (40 in the Cy-ATG and 43 in the Cy-Flu-ATG) were enrolled. Seventy-nine patients had AA and four had MDS. All predefined RRTs were significantly lower in patients of the Cy-Flu-ATG arm (23.3 vs. 55.0 %; p = 0.003). Infection with identified causative organism and sinusoidal obstruction syndrome, hematuria, febrile episodes, and death from any cause tended to be more frequent in Cy-ATG arm but did not differ significantly between arms. There was no difference in neutrophil engraftment failure (2.5 vs. 2.33 %; p = 0.959), acute graft-versus host disease (GvHD) (15.0 vs. 23.3 %; p = 0.388), and chronic GvHD (16.7 vs. 16.2 %; p = 0.961) between Cy-ATG and Cy-Flu-ATG arms. The 4-year survival rate did not differ between the Cy-ATG and Cy-Flu-ATG arms. Preconditioning with Cy-Flu ATG was superior to that afforded by Cy-ATG in terms of reducing RRT levels without increasing engraftment failure. PMID- 22526365 TI - Impact of the Epstein-Barr virus positivity on Hodgkin's lymphoma in a large cohort from a single institute in Korea. AB - Epstein-Barr virus (EBV) is considered a prognostic marker in Hodgkin lymphoma (HL) patients, but previous studies have yielded mixed findings because of the confounding effects of factors including age. We examined the prognostic impact of EBV status on 159 patients with HL. The median age at diagnosis was 32 years (range, 4-77 years). The median follow-up time was 5.83 years (range, 0.33-19.69 years). Tumor cell EBV status was positive in 34.5 %. EBV-positive HL was associated with age of >= 25 years, male gender, B symptoms, advanced stage, high risk IPS, nonnodular sclerosis subtype, and treatment with chemotherapy only (P < 0.05). The 5-year disease-specific survival (DSS) rates were 94.1 and 76.4 % for the EBV-negative and EBV-positive HL, respectively, (P < 0.001). On univariate analysis, event-free survival, DSS, and overall survival (OS) were significantly associated with age 40 years or older, B symptoms, and high-risk international prognostic score (>= 4). On multivariate analysis, EBV positivity was found to be a significant prognostic factor for DSS, particularly in adults 25 years or older. Subgroup analysis showed significant association of EBV-positive HL with poorer DSS and OS in adults 25 years or older with advanced stage disease. In the present series of HL patients, the presence of EBV in tumor cells is associated with adverse prognostic factors. EBV-positive HL is significantly associated with poorer DSS in all age groups. PMID- 22526366 TI - A national registry of haemoglobinopathies in Greece: deducted demographics, trends in mortality and affected births. AB - Haemoglobinopathies are the most common hereditary disorders in Greece. Although there is a successful national prevention program, established 35 years ago, there is lack of an official registry and collection of epidemiological data for haemoglobinopathies. This paper reports the results of the first National Registry for Haemoglobinopathies in Greece (NRHG), recently organized by the Greek Society of Haematology. NRHG records all patients affected by thalassaemia major (TM), thalassaemia intermedia (TI), "H" Haemoglobinopathy (HH) and sickle cell disease (SCD). Moreover, data about the annual rate of new affected births along with deaths, between 2000 and 2010, are reported. A total of 4,506 patients are registered all over the country while the number of affected newborns was significantly decreased during the last 3 years. Main causes for still having affected births are: (1) lack of medical care due to financial reasons or low educational level; (2) unawareness of time limitations for prenatal diagnosis (PD); due either to obstetricians' malpractice or to delayed demand of medical care of couples at risk; and (3) religious, social or bioethical reasons. Cardiac and liver disorders consist main causes for deaths while life expectancy of patients lengthened after 2005 (p < 0.01). The NRHG of patients affected by haemoglobinopathies in Greece provides useful data about the haemoglobinopathies in the Greek population and confirms the efficacy of the National Thalassaemia Prevention Program on impressively decreasing the incidence of TM and sickle cell syndromes. PMID- 22526367 TI - Increased yet iron-restricted erythropoiesis in postpartum mothers. AB - Iron deficiency in the postpartum period is common and associated with impaired quality of life. Interpretation of ordinary laboratory parameters is considered to be simple in postpartum women, as normalization of pregnancy induced physiological changes is assumed to take place in the early postpartum period. We have studied changes in erythrocyte and iron parameters during the first 11 postpartum months. Erythrocyte parameters and iron markers, serum ferritin, and soluble transferrin receptor (sTfR), and an inflammation marker, neopterin, were investigated in healthy mothers 6 weeks (n = 104), 4 months (n = 100), and 11 months (n = 43) after giving birth to a term infant. Healthy nonpregnant and nonlactating women (n = 61) were included as controls. The hemoglobin level increased throughout the first 11 postpartum months and was significantly higher from 4 months on, compared to control women. At all time points, the mothers had significantly lower mean corpuscular volume (MCV) and higher erythrocyte count and percentage of hypochromic erythrocytes. sTfR levels were significantly higher over the whole serum ferritin distribution during the first 4 postpartum months compared to the controls, indicative of an increased cell production. At 6 weeks, postpartum mothers had higher neopterin levels and this was associated with markers of a low iron status, not including sTfR. Substantial changes in erythrocyte and iron parameters were observed in the postpartum period, consistent with an increased, but iron restricted erythropoiesis. The increased erythropoietic activity was reflected in higher sTfR concentrations. Given the vital role for iron in both mothers and infants, further studies are warranted for establishing proper cut off levels for sTfR as an iron marker in postpartum women. PMID- 22526368 TI - Asymptomatic elevation of the hyperchromic red blood cell subpopulation is associated with decreased red cell deformability. AB - Hyperchromasia of the red blood cells (RBC), defined as an elevation of the hyperchromic subpopulation, has been described for various medical conditions. However, neither the association of hyperchromasia with an altered RBC membrane nor with other medical conditions has been investigated in a systematic way so far. Since the percentage of hyperchromic RBC is measured on a routine basis by many hematologic laboratories, we evaluated the predictive value of this parameter for the detection of RBC disorders. An extensive workup of all patients undergoing standard hematogram during a period of 6 months at our institution with a fraction of hyperchromic RBC larger than 10 % was collected by reviewing the medical history and performing osmotic gradient ektacytometry on RBC from a part of these patients. Thirty-two thousand two hundred twenty-six individuals were screened; of which, 162 (0.5 %) showed more than 10 % hyperchromic RBC. All of the patients examined by ektacytometry featured abnormal membrane deformability. Hereditary spherocytosis was found in 19 out of these 32 patients, in most cases unknown to the patient and currently asymptomatic. Another 17.9 % of the patients with an elevated subpopulation of hyperchromic RBC suffered from viral infection (human immunodeficiency virus, hepatitis). Our study shows that an elevated proportion of hyperchromic erythrocytes larger than 10 % is associated with both hereditary and acquired RBC membrane disorders and further follow-up should be considered. PMID- 22526369 TI - Comparative study of BCR-ABL1 quantification: Xpert assay, a feasible solution to standardization concerns. AB - The level of BCR-ABL1 reached after treatment with tyrosine kinase inhibitors is an effective marker of the therapeutic response and a good survival predictor in chronic myeloid leukemia (CML) patients. However, no agreement has yet been achieved about either the standardization of the technique to determine BCR-ABL1 or the interpretation of the results. The aim of this study was to compare the method currently recommended by the European Leukemia Net, which includes the application of a conversion factor to express the results in international scale, with an automated method (Xpert BCR-ABLTM, Cepheid). BCR-ABL1 transcript quantification was performed in 117 samples from CML patients in two different laboratories by both methods, and the results were compared by statistical procedures. A high linear correlation was obtained in the results between the two methods. The concordance at logarithmic intervals reached 62 %. When the major molecular response (MMR) was analyzed, 85 % agreement was achieved. The automated method provides reproducible results and does not show significant differences compared with the traditional method. As a clinical tool, Xpert correctly classified the patients in MMR and can be considered a useful alternative for the molecular follow-up of CML patients. PMID- 22526370 TI - B cell-activating factor: its clinical significance in multiple myeloma patients. AB - B cell-activating factor (BAFF) is a cytokine that plays a major role in the maintenance of normal B-cell development and homeostasis. It has been suggested that in multiple myeloma (MM) it might have regulatory effects on the proliferation and viability of malignant plasma cells. The aim of this study was to evaluate serum levels of BAFF in 52 newly diagnosed MM patients, with varying disease severity, in order to see the correlations between BAFF and indices of MM activity, such as interleukin-6, C-reactive protein, lactate dehydrogenase, and beta-2 microglobulin, and to explore the clinical significance of BAFF in predicting the disease activity of MM. We found increased BAFF serum levels in MM patients, increased in advanced stages, and decreased in plateau phase. We also found significant correlations between BAFF serum levels with the above parameters of disease activity. We conclude that BAFF may play an important role in pathogenesis of MM, could be used as a marker of disease activity, and a possible therapeutic target. PMID- 22526371 TI - Effects of aging and exercise training on the histological and mechanical properties of articular structures in knee joints of male rat. AB - The impact of aging on joints can have a profound effect on an individual's functioning. Our objectives were to assess the histological and mechanical properties of the knee joint capsule and articular cartilage with aging, and to examine the effects of exercise on age-related changes in the knee joint. 2-year old Wistar rats were divided into a sedentary control group and an exercise trained group. 10-week-old animals were used to investigate the changes with aging. The joint capsule and cartilage were evaluated with histological, histomorphometric, immunohistochemical, and mechanical analyses. Severe degenerative changes in articular cartilage were observed with aging, whereas exercise apparently did not have a significant effect. The articular cartilage of aged rats was characterized by damage to the cartilage surface, cell clustering, and an abnormal cartilage matrix. Histomorphometric analysis further revealed changes in cartilage thickness as well as a decreased number of chondrocytes. Aging led to stiffness of the articular cartilage and reduced the ability to dissipate the load and distribute the strain generated within the joint. Joint stiffness with aging was independent of capsular stiffness and synovitis was not a characteristic feature of the aging joint. This study confirms that aging alone eventually leads to joint degeneration in a rat model. The lack of recovery in aging joint changes may be due to several factors, such as the duration of the intervention and the regeneration ability of the cartilage. PMID- 22526372 TI - Allele diversity for the apoplastic invertase inhibitor gene from potato. AB - In planta the enzymatic activity of apoplastic and vacuolar invertases is controlled by inhibitory proteins. Although these invertase inhibitors (apoplastic and vacuolar forms) have been implicated as contributing to resistance to cold-induced sweetening (CIS) in tubers of potato (Solanum tuberosum L.), there is a lack of information on the structure and allelic diversity of the apoplastic invertase inhibitor genes. We have PCR-isolated and sequenced the alleles of the apoplastic invertase inhibitor gene (Stinh1) from three tetraploid potato genotypes: 1021/1 (a genotype with very high tolerance to CIS), 'Karaka' and 'Summer Delight' (two cultivars that are highly susceptible to CIS). In total, five alleles were identified in these genotypes, of which four (Stinh1-c, Stinh1-d, Stinh1-e, Stinh1-f) were novel. An analysis of allele diversity was conducted by incorporating previously published sequences of apoplastic invertase inhibitors from potato. Eight alleles were assessed for sequence polymorphism in the two exons and the single hypervariable intron. Contrary to the hypervariable intron, only 65 single nucleotide polymorphisms were observed in the exons, of which 42 confer amino acid substitutions. Phylogenetic analysis of amino acid sequences indicates that the alleles of the invertase inhibitor are highly conserved amongst members of the Solanaceae family. PMID- 22526373 TI - Barium inhibits arsenic-mediated apoptotic cell death in human squamous cell carcinoma cells. AB - Our fieldwork showed more than 1 MUM (145.1 MUg/L) barium in about 3 MUM (210.7 MUg/L) arsenic-polluted drinking well water (n = 72) in cancer-prone areas in Bangladesh, while the mean concentrations of nine other elements in the water were less than 3 MUg/L. The types of cancer include squamous cell carcinomas (SCC). We hypothesized that barium modulates arsenic-mediated biological effects, and we examined the effect of barium (1 MUM) on arsenic (3 MUM)-mediated apoptotic cell death of human HSC-5 and A431 SCC cells in vitro. Arsenic promoted SCC apoptosis with increased reactive oxygen species (ROS) production and JNK1/2 and caspase-3 activation (apoptotic pathway). In contrast, arsenic also inhibited SCC apoptosis with increased NF-kappaB activity and X-linked inhibitor of apoptosis protein (XIAP) expression level and decreased JNK activity (antiapoptotic pathway). These results suggest that arsenic bidirectionally promotes apoptotic and antiapoptotic pathways in SCC cells. Interestingly, barium in the presence of arsenic increased NF-kappaB activity and XIAP expression and decreased JNK activity without affecting ROS production, resulting in the inhibition of the arsenic-mediated apoptotic pathway. Since the anticancer effect of arsenic is mainly dependent on cancer apoptosis, barium-mediated inhibition of arsenic-induced apoptosis may promote progression of SCC in patients in Bangladesh who keep drinking barium and arsenic-polluted water after the development of cancer. Thus, we newly showed that barium in the presence of arsenic might inhibit arsenic-mediated cancer apoptosis with the modulation of the balance between arsenic-mediated promotive and suppressive apoptotic pathways. PMID- 22526374 TI - Melatonin attenuates gentamicin-induced nephrotoxicity and oxidative stress in rats. AB - The present study investigated the protective effects of melatonin (MT) against gentamicin (GM)-induced nephrotoxicity and oxidative stress in rats. We also investigated the effects of MT on induction of apoptotic cell death and its potential mechanisms in renal tissues in response to GM treatment. The following four experimental groups were evaluated: (1) vehicle control, (2) MT (15 mg/kg/day), (3) GM (100 mg/kg/day), and (4) GM&MT. GM caused severe nephrotoxicity as evidenced by increased serum blood urea nitrogen and creatinine levels, increased renal tubular cell apoptosis, and increased Bcl2-associated X protein and cleaved caspase-3 protein expression. Additionally, GM treatment caused an increase in levels of inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-kappaB) protein expression in renal tissues. The significant decreases in glutathione content, catalase, superoxide dismutase, glutathione-S-transferase, glutathione peroxidase, and glutathione reductase activities and the increase in malondialdehyde content indicated that GM-induced tissue injury was mediated through oxidative reactions. In contrast, MT treatment protected kidney tissue against the oxidative damage and the nephrotoxic effect caused by the GM treatment. Histopathological studies confirmed the renoprotective effect of MT. These results indicate that MT prevents nephrotoxicity induced by GM in rats, presumably because it is a potent antioxidant, restores antioxidant enzyme activity, and blocks NF-kappaB and iNOS activation in rat kidney. PMID- 22526375 TI - Recent developments in nanotoxicology. PMID- 22526376 TI - Rotenone-induced apoptosis and role of calcium: a study on Neuro-2a cells. AB - Rotenone causes cytotoxicity in astrocytic cell culture by glial activation, which is linked to free radical generation. The present study is an investigation to explore whether rotenone could also cause cellular toxicity in mouse neuroblastoma cells (Neuro-2a) under treatment similar to astroglial cells. The effect of rotenone (0.1, 1, and 10 MUM) on mitochondrial dehydrogenase enzyme activity by MTT reduction assay, PI uptake, total reactive oxygen species (ROS)/superoxide levels, nitrite levels, extent of DNA damage (by comet assay), and nuclear morphological alteration by Hoechst staining was studied. Caspase-3 and Ca+2/calmodulin-dependent protein kinase II (CaMKIIalpha) gene expression was determined to evaluate the apoptotic cell death and calcium kinase, respectively. Calcium level was estimated fluorometrically using fura-2A stain. Rotenone decreased mitochondrial dehydrogenase enzyme activity and generated ROS, superoxide, and nitrite. Rotenone treatment impaired cell intactness and nuclear morphology as depicted by PI uptake and chromosomal condensation of Neuro-2a cells, respectively. In addition, rotenone resulted in increased intracellular Ca+2 level, caspase-3, and CaMKIIalpha expression. Furthermore, co-exposure of melatonin (300 MUM), an antioxidant to cell culture, significantly suppressed the rotenone-induced decreased mitochondrial dehydrogenase enzyme activity, elevated ROS and RNS. However, melatonin was found ineffective to counteract rotenone induced increased PI uptake, altered morphological changes, DNA damage, elevated Ca+2, and increased expression of caspase-3 and CaMKIIalpha. The study indicates that intracellular calcium rather than oxidative stress is a major factor for rotenone-induced apoptosis in neuronal cells. PMID- 22526377 TI - A novel approach to isoindolo[2,1-a]indol-6-ones. AB - A convenient route to isoindolo[2,1-a]indol-6-ones has been developed starting from the appropriate 2-(N-phthaloyl)benzoic acids. Formation of the acid chlorides with thionyl chloride followed by heating with triethyl phosphite in a suitable solvent resulted in a multistep reaction giving tetracyclic beta ketophosphonates that on reduction with sodium borohydride gave the required indolones in good overall yields. Analogous beta-ketophosphonates were also prepared starting with N,N-(1,8-naphthaloyl)-2-aminobenzoic acid and 2-(2,5-dioxo 2,5-dihydro-1H-pyrrol-1-yl)benzoic acids although of these only the naphthaloyl product could be reduced with sodium borohydride without cleaving the amide bond in the ring system. PMID- 22526378 TI - Persistent coronary artery spasm documented by follow-up coronary angiography in patients with symptomatic remission of variant angina. AB - For patients with variant angina it is very important to start medical therapy using calcium-channel blockers. However, the decision of physicians regarding whether to decrease the dose of the drug or discontinue it is controversial. We investigated whether the nature of spasm is remissive and whether the termination of medications is safe. The subjects studied were included in the Vasospastic Angina in Catholic Medical Center Registry from March 2001 to December 2009. We analyzed 37 patients (62 lesions) with variant angina, diagnosed using coronary angiography (CAG) and he acetylcholine provocation test, without any organic coronary stenosis, whose symptoms were well controlled after medication. The follow-up CAG with provocation test was performed at a median interval of 44 months. The characteristics of spasm were analyzed on each pair of CAGs. The study group consisted of 23 men (62.2 %) and 14 women (37.8 %) with a mean age of 59 +/- 11.1 years. The follow-up CAG with provocation test showed that the characteristics of the spasmodic nature were consistent with the first test in all patients. Although the patients with variant angina had no chest pain after medical treatment, the spasmodic nature of coronary arteries still remained. We may decrease the drug dosage after carefully checking the patient's symptoms but recommend not discontinuing therapy, even if the patient is asymptomatic. PMID- 22526379 TI - Comparison of inflammatory response after implantation of sirolimus- and paclitaxel-eluting stents in patients on hemodialysis. AB - Because systemic inflammation after coronary intervention places patients at increased risk of subsequent cardiac events, we aimed to compare clinical outcomes and chronic serum inflammation markers of paclitaxel-eluting stents (PES) and sirolimus-eluting stents (SES) in hemodialysis patients. Paclitaxel eluting stents and SES were implanted in 36 patients with 46 lesions, and 32 patients with 40 lesions, respectively. In addition to 1-year major adverse cardiac event (MACE) rates, high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), neopterin, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) were also compared before and 9 months after percutaneous coronary intervention (PCI). The incidence of MACE was significantly lower in the PES group than in the SES group (11.1 vs. 25.0 %, respectively, P = 0.042), mainly due to the reduction of target lesion revascularization in the PES group (6.5 vs. 17.5 %, P = 0.003). The logarithm of hs-CRP as well as IL-6 decreased significantly 9 months post-PCI compared with pre-PCI in the PES group (hs-CRP: 3.65 +/- 0.35 vs. 2.91 +/- 0.48, P = 0.007; IL 6: 6.73 +/- 3.66 vs. 2.61 +/- 2.29, P = 0.017) but not in the SES group (hs-CRP: 3.33 +/- 0.29 vs. 3.42 +/- 0.27, P not significant; IL-6: 6.08 +/- 4.97 vs. 5.66 +/- 4.29, P not significant). However, neopterin, ICAM-1, and VCAM-1 remained unchanged both pre-PCI and 9 months post-PCI in both groups. Moreover, MACE were less frequent in patients with decreased hs-CRP levels 9 months post-PCI compared with patients without decreased hs-CRP levels (P = 0.002) in all patients. Paclitaxel-eluting stents appear to be more effective than SES in reducing MACE rates, especially target lesion revascularization, and may be able to stabilize local inflammatory changes of target lesions specifically in patients on hemodialysis. Thus PES, which inhibit in-stent restenosis and cardiac events in hemodialysis patients, may play an important role in suppression of chronic inflammatory response in target lesions as compared with SES. Chronic continuous inflammation plays an important role after implantation of both types of stent with regard to in-stent restenosis in patients on hemodialysis. PMID- 22526380 TI - Differences in hemodynamic responses between intravenous carperitide and nicorandil in patients with acute heart failure syndromes. AB - While recent guidelines for the treatment of acute heart failure syndromes (AHFS) recommend pharmacotherapy with vasodilators in patients without excessively low blood pressure (BP), few reports have compared the relative efficiency of vasodilators on hemodynamics in AHFS patients. The present study aimed to assess the differences in hemodynamic responses between intravenous carperitide and nicorandil in patients with AHFS. Thirty-eight consecutive patients were assigned to receive 48-h continuous infusion of carperitide (n = 19; 0.0125-0.05 MUg/kg/min) or nicorandil (n = 19; 0.05-0.2 mg/kg/h). Hemodynamic parameters were estimated at baseline, and 2, 24, and 48 h after drug administration using echocardiography. After 48 h of infusion, systolic BP was significantly more decreased in the carperitide group compared with that in the nicorandil group (22.1 +/- 20.0 % vs 5.3 +/- 10.4 %, P = 0.003). While both carperitide and nicorandil significantly improved hemodynamic parameters, improvement of estimated pulmonary capillary wedge pressure was greater in the carperitide group (38.2 +/- 14.5 % vs 26.5 +/- 18.3 %, P = 0.036), and improvement of estimated cardiac output was superior in the nicorandil group (52.1 +/- 33.5 % vs 11.4 +/- 36.9 %, P = 0.001). Urine output for 48 h was greater in the carperitide group, but not to a statistically significant degree (4203 +/- 1542 vs 3627 +/- 1074 ml, P = 0.189). Carperitide and nicorandil were differentially effective in improving hemodynamics in AHFS patients. This knowledge may enable physicians in emergency wards to treat and manage patients with AHFS more effectively and safely. PMID- 22526381 TI - Left atrial thickness under the catheter ablation lines in patients with paroxysmal atrial fibrillation: insights from 64-slice multidetector computed tomography. AB - A detailed understanding of the left atrial (LA) anatomy in patients with atrial fibrillation (AF) would improve the safety and efficacy of the radiofrequency catheter ablation. The objective of this study was to examine the myocardial thickness under the lines of the circumferential pulmonary vein isolation (CPVI) using 64-slice multidetector computed tomography (MDCT). Fifty-four consecutive symptomatic drug-refractory paroxysmal AF patients (45 men, age 61 +/- 12 years) who underwent a primary CPVI guided by a three-dimensional electroanatomic mapping system (Carto XP; Biosense-Webster, Diamond Bar, CA, USA) with CT integration (Cartomerge; Biosense-Webster) were enrolled. Using MDCT, we examined the myocardial thickness of the LA and pulmonary vein (PV) regions in all patients. An analysis of the measurements by the MDCT revealed that the LA wall was thickest in the left lateral ridge (LLR; 4.42 +/- 1.28 mm) and thinnest in the left inferior pulmonary vein wall (1.68 +/- 0.27 mm). On the other hand, the thickness of the posterior wall in the cases with contact between the esophagus and left PV antrum was 1.79 +/- 0.22 mm (n = 30). After the primary CPVI, the freedom from AF without any drugs during a 1-year follow-up period was 78 % (n = 42). According to the multivariate analysis, the thickness of the LLR was an independent positive predictor of an AF recurrence (P = 0.041). The structure of the left atrium and PVs exhibited a variety of myocardial thicknesses in the different regions. Of those, only the measurement of the LLR thickness was associated with an AF recurrence. PMID- 22526382 TI - Metabolic syndrome and risk of progression of chronic kidney disease: a single center cohort study in Japan. AB - Metabolic syndrome (MetS) is a risk factor for the development of diabetes and cardiovascular disease, and recently was linked to incident chronic kidney disease (CKD). The purpose of this study is to examine whether MetS is associated with CKD progression in Japanese at a single center. Outcome variables were a decrease in estimated glomerular filtration rate (eGFR) of 50 % or 25 ml/min/1.73 m(2), end-stage renal disease (ESRD), death, or a composite outcome of all three. There were 213 subjects in the analysis, 40.4 % of whom met the criteria for MetS. The group of subjects with MetS had higher urinary albumin-to-creatinine (UACR) levels. Survival curves stratified by MetS status showed early separation of the curves and a significantly higher survival rate in the group without MetS (P = 0.0086). Comparisons with normoalbuminuria and microalbuminuria showed that macroalbuminuria was equally associated with predicted composite outcome (GFR, ESRD, or death) both in the presence and absence of MetS. Multivariate analyses for all covariates showed that eGFR (hazard ratio (HR) 8.286, 95 % confidence interval (CI) 2.360-28.044, P = 0.0012) and the UACR (HR 2.338, 95 % CI 1.442 3.861, P = 0.0005) at baseline were independently associated with the composite outcomes. The results show that MetS was associated with albuminuria in a cohort of Japanese CKD patients, and both MetS and albuminuria were independently associated with CKD progression. PMID- 22526383 TI - The first report of disseminated Nocardia concava infection, in an immunocompromised patient, in South Korea. AB - A new Nocardia species, N. concava, was first reported in Japan in 2005. To date, there have been only 3 case reports of N. concava infection worldwide (2 in Japan and 1 in China), and only 1 of these reports has detailed the clinical characteristics of N. concava, in China. Here we report the first case of disseminated infection caused by N. concava- in a patient with a history of glucocorticoid use-in South Korea. Species identification of N. concava was done with 16S rRNA sequencing and was confirmed by biochemical tests using urea, xanthine, tyrosine, and hypoxanthine decomposition. The patient was successfully treated with trimethoprim-sulfamethoxazole. PMID- 22526385 TI - Fatal candidemia caused by azole-resistant Candida tropicalis in patients with hematological malignancies. AB - Candida tropicalis is one of the most important Candida species causative of candidemia that is isolated from the blood of patients with hematological malignancies. Candidemia caused by C. tropicalis is known to be highly virulent in neutropenic patients. C. tropicalis has been shown to be favorably sensitive to azole agents in general. Here we discuss 5 cases of candidemia caused by C. tropicalis in patients with hematological malignancies in our unit, and we note that 4 isolates were resistant to azole agents, including fluconazole, itraconazole, and voriconazole. In addition, 2 patients developed breakthrough candidemia caused by C. tropicalis while receiving prophylaxis with azole agents. Interestingly, 2 of the 4 patients with azole-resistant C. tropicalis isolates had never received any antifungal drugs. We also examined the susceptibilities of C. tropicalis to antifungal agents, using 39 non-blood isolates detected from 2003 to 2009. Around 40 % of the isolates were resistant to azole agents, and all of them were highly sensitive to amphotericin B and micafungin. The resistance to azoles was not associated with previous exposure to those agents. In our unit, 2 of the 4 cases of candidemia caused by azole-resistant C. tropicalis resulted in a poor prognosis. These findings suggested that empirical therapeutic strategies for candidemia should be modified based on the local antifungal resistance pattern. PMID- 22526386 TI - Influenza B-associated encephalopathy in two adults. AB - Influenza virus is associated with a variety of neurological complications, of which the most commonly encountered are seizures and encephalopathy. Acute encephalitis and postinfectious encephalopathy have been reported infrequently in association with influenza A and B virus infections. We describe two previously healthy adults who presented with encephalopathy with a virologically documented influenza B infection. PMID- 22526387 TI - Efficacy and safety of short- and long-term treatment of itraconazole on chronic necrotizing pulmonary aspergillosis in multicenter study. AB - In the respiratory field, chronic pulmonary aspergillosis, such as chronic necrotizing pulmonary aspergillosis (CNPA) or aspergilloma, is important. We examined the efficacy and safety of short- and long-term itraconazole (ITCZ) administration, involving a switch from injection to an oral preparation, in patients with CNPA. In all hospitals participating in this study, the protocol was approved by the ethics review board. This study started after UMIN registration (UMIN000001727). Subjects enrolled in this study were patients who were clinically or definitively diagnosed with CNPA in the respiratory field, according to the diagnostic criteria of the Japanese "Guidelines for management of deep-seated mycosis 2007," in 16 hospitals that participated in this study between May 2008 and March 2011. Treatment was started with ITCZ injection. Subsequently, the agent was switched to an oral preparation. Efficacy was evaluated with major items (clinical symptoms, fever, imaging findings) and minor items (nutritional status, inflammatory markers). Twenty-nine patients were enrolled; safety was evaluated in 24 and efficacy in 23. Of the 23 patients, 10 (43.5 %) responded. With respect to the administration period, the response rates in 8 patients treated for a short period and 15 treated for a long period were 25.0 % and 53.3 %, respectively. Trough blood concentration of ITCZ reached a level at which ITCZ may be effective for aspergillosis at 3 days after the start of ITCZ injection therapy. After changing to high-dose capsules, its level was also maintained. Adverse events such as liver dysfunction and heart failure were observed in 9 of the 24 patients. Furthermore, 6 patients died. However, there was no relationship between these events and ITCZ. Step-down therapy from ITCZ injection to oral administration may be a useful treatment option in CNPA patients requiring long-term treatment. PMID- 22526388 TI - A successful diagnostic case of Pneumocystis pneumonia by the loop-mediated isothermal amplification method in a patient with dermatomyositis. AB - Pneumocystis pneumonia (PCP) can occur in patients with many causes of the immunocompromised state other than human immunodeficiency virus (HIV). It is quite difficult to diagnose PCP without HIV because there is no method for detecting Pneumocystis jirovecii. Thus, non-HIV PCP continues to have high mortality. Recently, loop-mediated isothermal amplification (LAMP) is becoming an established nucleic acid amplification method offering rapid, accurate, and cost effective diagnosis of infectious diseases. We report a non-HIV PCP case successfully diagnosed by the LAMP method. It was previously reported that PCR in BALF specimens had been the most sensitive method in the diagnosis of PCP without HIV. The LAMP method would be more sensitive than conventional PCR and an effective tool in the early diagnosis of PCP. PMID- 22526389 TI - A rapid PFGE protocol for typing Legionella isolates from fresh or frozen samples. AB - Within the realm of studies on nosocomial infections and epidemiology, pulsed field gel electrophoresis (PFGE) is often considered as the "gold standard" for typing of Legionella or other bacteria. Performing this protocol usually requires 2-5 days; this excessive time requirement, lack of a standardized procedure, and high cost have limited its use. However, recently the typing of Legionella with PFGE has been reduced to about 2 days, and we further shortened the procedure by reducing the time for the plug preparation and electrophoresis steps. To shorten plug preparation, we used a strong thermal shock and high-temperature washes to reduce cell lysis and DNA isolation time, and we stressed the electrophoresis to obtain comparable macrorestriction patterns among strains in 16 h. The DNA digestion phase was not altered. We also applied this protocol directly to frozen bacteria from strain collections with the aim of shortening the entire procedure. We developed a protocol that can be completed in 24 h, or less if necessary, while avoiding some typical artifacts of traditional procedures. This new protocol also provides good results when directly applied to frozen material from strain collections, thus saving bacteria growth time. Our observations indicate that PFGE tolerates a wide range of adjustments, allowing its application to fresh or frozen samples in a short amount of time. PMID- 22526390 TI - Efficient enhancement of lentiviral transduction efficiency in murine spermatogonial stem cells. AB - Spermatogonial stem cells (SSCs) are the foundation of spermatogenesis throughout postnatal life in male and have the ability to transmit genetic information to the subsequent generation. In this study, we have optimized the transduction efficiency of SSCs using a lentiviral vector by considering different multiplicity of infection (MOI), duration of infection, presence or absence of feeder layer and polycationic agents. We tested MOI of 5, 10 or 20 and infection duration of 6, 9 or 12 h respectively. After infection, cells were cultured for 1 week and as a result, the number of transduced SSCs increased significantly for MOI of 5 and 10 with 6 h of infection. When the same condition (MOI of 5 with 6 hours) was applied in presence or absence of STO feeder layer and infected SSCs were cultured for 3 weeks on the STO feeder layer, a significant increase in the number of transduced cells was observed for without the feeder layer during infection. We subsequently studied the effects of polycationic agents, polybrene and dioctadecylamidoglycyl spermine (DOGS), on the transduction efficiency. Compared with the polybrene treatment, the recovery rate of the transduced SSCs was significantly higher for the DOGS treatment. Therefore, our optimization study could contribute to the enhancement of germ-line modification of SSCs using lentiviral vectors and in generation of transgenic animals. PMID- 22526391 TI - Betulinic acid induces Bax/Bak-independent cytochrome c release in human nasopharyngeal carcinoma cells. AB - Betulinic acid (BetA) is an effective and potential anticancer chemical derived from plants. BetA can kill a broad range of tumor cell lines, but has no effect on untransformed cells. The chemical also kills melanoma, leukemia, lung, colon, breast, prostate and ovarian cancer cells via induction of apoptosis, which depends on caspase activation. However, no reports are yet available about the effects of BetA on nasopharyngeal carcinoma (NPC), a widely spread malignancy in the world, especially in East Asia. In this study, we first showed that BetA can effectively kill CNE2 cells, a cell line derived from NPC. BetA-induced CNE2 apoptosis was characterized by typical apoptosis hallmarks: caspase activation, DNA fragmentation, and cytochrome c release. Overexpression of Bcl-2 and Bcl-xL could partially prevent apoptosis caused by BetA. Moreover, Bax was not activated during the induction of apoptosis. Bax/Bak knockdown and wild-type CNE2 cells showed the same kinetics of cytochrome c release. We then showed that BetA may impair mitochondrial permeability transition pores (mPTPs), which may partially contribute to cytochrome c release. These observations suggest that BetA may serve as a potent and effective anticancer agent in NPC treatment. Further exploration of the mechanism of action of BetA could yield novel breakthroughs in anti-cancer drug discovery. PMID- 22526392 TI - Functional HSF1 requires aromatic-participant interactions in protecting mouse embryonic fibroblasts against apoptosis via G2 cell cycle arrest. AB - The present study highlighted the aromatic-participant interactions in in vivo trimerization of HSF1 and got an insight into the process of HSF1 protecting against apoptosis. In mouse embryonic fibroblasts (MEFs), mutations of mouse HSF1 (W37A, Y60A and F104A) resulted in a loss of trimerization activity, impaired binding of the heat shock element (HSE) and lack of heat shock protein 70 (HSP70) expression after a heat shock. Under UV irradiation, wild-type mouse HSF1 protected the MEFs from UV-induced apoptosis, but none of the mutants offered protection. We found that normal expression of HSF1 was essential to the cell arrest in G2 phase, assisting with the cell cycle checkpoint. The cells that lack normal HSF1 failed to arrest in the G2 phase, resulting in the process of cell apoptosis. We conclude that the treatment with UV or heat shock stresses appears to induce the approach of HSF1 monomers directly via aromatic-participant interactions, followed by the formation of a HSF1 trimer. HSF1 protects the MEFs from the stresses through the expression of HSPs and a G2 cell cycle arrest. PMID- 22526393 TI - Transduced Tat-DJ-1 protein protects against oxidative stress-induced SH-SY5Y cell death and Parkinson disease in a mouse model. AB - Parkinson's disease (PD) is a well known neurodegenerative disorder characterized by selective loss of dopaminergic neurons in the substantia nigra pars compact (SN). Although the exact mechanism remains unclear, oxidative stress plays a critical role in the pathogenesis of PD. DJ-1 is a multifunctional protein, a potent antioxidant and chaperone, the loss of function of which is linked to the autosomal recessive early onset of PD. Therefore, we investigated the protective effects of DJ-1 protein against SH-SY5Y cells and in a PD mouse model using a cell permeable Tat-DJ-1 protein. Tat-DJ-1 protein rapidly transduced into the cells and showed a protective effect on 6-hydroxydopamine (6-OHDA)-induced neuronal cell death by reducing the reactive oxygen species (ROS). In addition, we found that Tat-DJ-1 protein protects against dopaminergic neuronal cell death in 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP)-induced PD mouse models. These results suggest that Tat-DJ-1 protein provides a potential therapeutic strategy for against ROS related human diseases including PD. PMID- 22526394 TI - Lactobacillus plantarum lipoteichoic acid alleviates TNF-alpha-induced inflammation in the HT-29 intestinal epithelial cell line. AB - We recently observed that lipoteichoic acid (LTA) isolated from Lactobacillus plantarum inhibited endotoxin-mediated inflammation of the immune cells and septic shock in a mouse model. Here, we examined the inhibitory role of L. plantarum LTA (pLTA) on the inflammatory responses of intestinal epithelial cells (IEC). The human colon cell line, HT-29, increased interleukin (IL)-8 expression in response to recombinant human tumor necrosis factor (TNF)-alpha, but not in response to bacterial ligands and interferon (IFN)-gamma. TNF-alpha also increased the production of inducible nitric oxide synthase (iNOS), nitric oxide (NO), and intercellular adhesion molecule 1 (ICAM-1) through activation of p38 mitogen-activated protein kinase (MAPK) from HT-29 cells. However, the inflammatory response of HT-29 on TNF-alpha stimulation was significantly inhibited by pLTA treatment. This pLTA-mediated inhibition accompanied the inhibition of nuclear factor (NF)-kappa B and MAPKs. Our data suggest that pLTA regulates cytokine-mediated immune responses and may be a good candidate for maintaining intestinal homeostasis against excessive inflammation. PMID- 22526395 TI - Possible dual regulatory circuits involving AtS6K1 in the regulation of plant cell cycle and growth. AB - The role of Arabidopsis S6 Kinase 1 (AtS6K1), a downstream target of TOR kinase, in controlling plant growth and ribosome biogenesis was characterized after generating transgenic plants expressing AtS6K1 under auxin-inducible promoter. Down regulation of selected cell cycle regulatory genes upon auxin treatment was observed in the transgenic plants, confirming the negative regulatory role of AtS6K1 in the plant cell cycle progression reported earlier. Callus tissues established from these transgenic plants grew to larger cell masses with more number of enlarged cells than untransformed control, demonstrating functional implication of AtS6K1 in the control of plant cell size. The observed negative correlation between the expression of AtS6K1 and the cell cycle regulatory genes, however, was completely reversed in protoplasts generated from the transgenic plants expressing AtS6K1, suggesting a possible existence of dual regulatory mechanism of the plant cell cycle regulation mediated by AtS6K1. An alternative method of kinase assay, termed "substrate-mediated kinase pull down", was employed to examine the additional phosphorylation on other domains of AtS6K1 and verified the phosphorylation of both amino- and carboxy-terminal domains, which is a novel finding regarding the phosphorylation target sites on plant S6Ks by upstream regulatory kinases. In addition, this kinase assay under the stress conditions revealed the salt- and sugar-dependencies of AtS6K1 phosphorylations. PMID- 22526396 TI - Retroviral infection of hES cells produces random-like integration patterns. AB - Retroviral integration provides us with a powerful tool to realize prolonged gene expressions that are often critical to gene therapy. However, the perturbation of gene regulations in host cells by viral genome integration can lead to detrimental effects, yielding cancer. The oncogenic potential of retroviruses is linked to the preference of retroviruses to integrate into genomic regions that are enriched in gene regulatory elements. To better navigate the double-edged sword of retroviral integration we need to understand how retroviruses select their favored genomic loci during infections. In this study I showed that in addition to host proteins that tether retroviral pre-integration complexes to specific genomic regions, the epigenetic architecture of host genome might strongly affect retroviral integration patterns. Specifically, retroviruses showed their characteristic integration preference in differentiated somatic cells. In contrast, retroviral infections of hES cells, which are known to display decondensed chromatin, produced random-like integration patterns lacking of strong preference for regulatory-element-rich genomic regions. Better identification of the cellular and viral factors that determine retroviral integration patterns will facilitate the design of retroviral vectors for safer use in gene therapy. PMID- 22526398 TI - Time-energy mapping of photoelectron angular distribution: application to photoionization stereodynamics of nitric oxide. AB - The time-energy mapping of the photoionization integral cross section and laboratory-frame photoelectron angular distribution is used to study photoionization stereodynamics of a diatomic molecule. The general theoretical formalism [Y. Suzuki and T. Suzuki, Mol. Phys., 2007, 105, 1675] is simplified for application to a diatomic molecule, and a high-resolution photoelectron imaging apparatus is used to determine the transition dipole moments and phase shifts of photoelectron partial waves in near-threshold and non-dissociative photoionization of NO from the A(2)Sigma(+) state. The transition dipoles and phase shifts thus determined are in reasonable agreement with those by state-to state photoionization experiment and Schwinger variational calculations. The difference of the phase shifts from those expected from the quantum defects of Rydberg states suggests occurrence of weak hybridization of different l-waves, in addition to the well-known s-d super complex. The circular dichroism in photoelectron angular distribution is also simulated from our results. PMID- 22526397 TI - Reverse signaling through the co-stimulatory ligand, CD137L, as a critical mediator of sterile inflammation. AB - CD137 (also called 4-1BB and TNFRSF9) has recently received attention as a therapeutic target for cancer and a variety of autoimmune and inflammatory diseases. Stimulating CD137 in vivo enhances CD8(+) T cell-activity and results in strong immunosuppression in some contexts. This paradoxical phenomenon may be partially explained by the ability of CD137-stimulating reagents (usually agonistic monoclonal antibodies against CD137) to overactivate T cells and other CD137-expressing cells. This over-activity is associated with deleting pathogenic T cells and B cells or generating a tolerogenic microenvironment. Recent studies, however, suggest that the biology of CD137 and its ligand (CD137L) are more complex, mainly due to bidirectional signaling between CD137 and CD137L. For example, signaling through CD137L in non-hematopoietic cells such as epithelial cells and endothelial cells has been shown to play an essential role in sterile inflammation by regulating immune cell recruitment. One outstanding, and clinically important, issue is understanding how bidirectional signaling through CD137 and CD137L controls the vicious cycle of sterile inflammation (e.g., ischemia-reperfusion tissue injury and meta-inflammatory diseases). PMID- 22526399 TI - Voltage-independent inhibition of Ca(V)2.2 channels is delimited to a specific region of the membrane potential in rat SCG neurons. AB - Neurotransmitters and hormones regulate Ca(V)2.2 channels through a voltage independent pathway which is not well understood. It has been suggested that this voltage-independent inhibition is constant at all membrane voltages. However, changes in the percent of voltage-independent inhibition of Ca(V)2.2 have not been tested within a physiological voltage range. Here, we used a double-pulse protocol to isolate the voltage-independent inhibition of Ca(V)2.2 channels induced by noradrenaline in rat superior cervical ganglion neurons. To assess changes in the percent of the voltage-independent inhibition, the activation voltage of the channels was tested between -40 and +40 mV. We found that the percent of voltage-independent inhibition induced by noradrenaline changed with the activation voltage used. In addition, voltage-independent inhibition induced by oxo-M, a muscarinic agonist, exhibited the same dependence on activation voltage, which supports that this pattern is not exclusive for adrenergic activation. Our results suggested that voltage-independent inhibition of Ca(V)2.2 channels depends on the activation voltage of the channel in a physiological voltage range. This may have relevant implications in the understanding of the mechanism involved in voltage-independent inhibition. PMID- 22526400 TI - Ultrastructure, molecular phylogenetics, and chlorophyll a content of novel cyanobacterial symbionts in temperate sponges. AB - Marine sponges often harbor photosynthetic symbionts that may enhance host metabolism and ecological success, yet little is known about the factors that structure the diversity, specificity, and nature of these relationships. Here, we characterized the cyanobacterial symbionts in two congeneric and sympatric host sponges that exhibit distinct habitat preferences correlated with irradiance: Ircinia fasciculata (higher irradiance) and Ircinia variabilis (lower irradiance). Symbiont composition was similar among hosts and dominated by the sponge-specific cyanobacterium Synechococcus spongiarum. Phylogenetic analyses of 16S-23S rRNA internal transcribed spacer (ITS) gene sequences revealed that Mediterranean Ircinia spp. host a specific, novel symbiont clade ("M") within the S. spongiarum species complex. A second, rare cyanobacterium related to the ascidian symbiont Synechocystis trididemni was observed in low abundance in I. fasciculata and likewise corresponded to a new symbiont clade. Symbiont communities in I. fasciculata exhibited nearly twice the chlorophyll a concentrations of I. variabilis. Further, S. spongiarum clade M symbionts in I. fasciculata exhibited dense intracellular aggregations of glycogen granules, a storage product of photosynthetic carbon assimilation rarely observed in I. variabilis symbionts. In both host sponges, S. spongiarum cells were observed interacting with host archeocytes, although the lower photosynthetic activity of Cyanobacteria in I. variabilis suggests less symbiont-derived nutritional benefit. The observed differences in clade M symbionts among sponge hosts suggest that ambient irradiance conditions dictate symbiont photosynthetic activity and consequently may mediate the nature of host-symbiont relationships. In addition, the plasticity exhibited by clade M symbionts may be an adaptive attribute that allows for flexibility in host-symbiont interactions across the seasonal fluctuations in light and temperature characteristic of temperate environments. PMID- 22526402 TI - Diversity and antimicrobial activity of culturable fungi isolated from six species of the South China Sea gorgonians. AB - Fungi in gorgonians are now known to cause gorgonian diseases, but little attention has been paid to the nature of fungal communities associated with gorgonians. The diversity of culturable fungi associated with six species of healthy South China Sea gorgonians were investigated using a culture-dependent method followed by analysis of fungal internal transcribed spacer sequences. A total of 121 fungal isolates were recovered and identified using the Basic Local Alignment Search Tool search program. These belonged to 41 fungal species from 20 genera. Of these, 30 species and 12 genera are new reports for gorgonians, and the genera Aspergillus and Penicillium were the most diverse and common in the six gorgonian species. Comparison of the fungal communities in the six gorgonian species, together with results from previous relevant studies, indicated that different gorgonian species and the same gorgonian species living in different geographic locations had different fungal communities. The gorgonian Dichotella gemmacea harbored the most fungal species and isolates, while Echinogorgia aurantiaca had the least fungal diversity. Among the six media used for fungal isolation, potato glucose agar yielded the highest isolates (27 isolates), while glucose peptone starch agar had the best recoverability of fungal species (15 species). The antimicrobial activity of the 121 fungal isolates was tested against three marine bacteria and two marine gorgonian pathogenic fungi. A relatively high proportion (38 %) of fungal isolates displayed distinct antibacterial and antifungal activity, suggesting that the gorgonian-associated fungi may aid their hosts in protection against pathogens. This is the first report comparing the diversity of fungal communities among the South China Sea gorgonians. It contributes to our knowledge of gorgonian-associated fungi and further increases the pool of fungi available for natural bioactive product screening. PMID- 22526403 TI - Information and support needs during recovery from postpartum psychosis. AB - Postpartum Psychosis (PP) is a severe and debilitating psychiatric illness with acute onset in the days following childbirth. Recovering from an episode can be a long and difficult process. The aim of this study was to gain an understanding of the difficulties faced by recovering women and to inform the planning of post discharge information and support services. A study was designed collaboratively by service user and academic researchers. Women with experience of PP were trained in qualitative research methodology. Service user researchers (SURs) led in-depth interviews into women's experiences of recovery. PP is a life-changing experience that challenges women's sense of personal and social identity. Recovery themes are organised around ruminating and rationalising, rebuilding social confidence, gaining appropriate health service support, the facilitation of family functioning, obtaining appropriate information, and understanding that recovery will take time. Women suffering from PP must be adequately supported following discharge from psychiatric hospital if we are to address maternal suicide rates. We describe a successful collaboration between academics and service users exploring the needs of women and their families. PMID- 22526401 TI - Long-term characterization of free-living and particle-associated bacterial communities in Lake Tiefwaren reveals distinct seasonal patterns. AB - Seasonal changes in environmental conditions have a strong impact on microbial community structure and dynamics in aquatic habitats. To better elucidate the response of bacterial communities to environmental changes, we have measured a large variety of limnetic variables and investigated bacterial community composition (BCC) and dynamics over seven consecutive years between 2003 and 2009 in mesotrophic Lake Tiefwaren (NE Germany). We separated between free-living (FL, >0.2, <5.0 MUm) and particle-associated (PA, >5.0 MUm) bacteria to account for different bacterial lifestyles and to obtain a higher resolution of the microbial diversity. Changes in BCC were studied by DGGE based on PCR-amplified 16S rRNA gene fragments. Sequencing of DGGE bands revealed that ca. 70 % of all FL bacteria belonged to the Actinobacteria, whereas PA bacteria were dominated by Cyanobacteria (43 %). FL communities were generally less diverse and rather stable over time compared to their PA counterpart. Annual changes in reoccurring seasonal patterns of dominant freshwater bacteria were supported by statistical analyses, which revealed several significant correlations between DGGE profiles and various environmental variables, e.g. temperature and nutrients. Overall, FL bacteria were generally less affected by environmental changes than members of the PA fraction. Close association of PA bacteria with phytoplankton and zooplankton suggests a tight coupling of PA bacteria to organisms of higher trophic levels. Our results indicate substantial differences in bacterial lifestyle of pelagic freshwater bacteria, which are reflected by contrasting seasonal dynamics and relationships to a number of environmental variables. PMID- 22526405 TI - Interpersonal psychotherapy versus brief supportive therapy for depressed infertile women: first pilot randomized controlled trial. AB - Infertility is strongly associated with depression, yet treatment research for depressed infertile women is sparse. This study tested for the first time the feasibility and preliminary efficacy of interpersonal psychotherapy (IPT), the evidence-based antidepressant intervention with the greatest peripartum research support, as treatment for depressed women facing fertility problems. Patients who met DSM-IV criteria for major depressive disorder of at least moderate severity were randomized to either 12 sessions of IPT (n = 15) or brief supportive psychotherapy (BSP; n = 16), our control intervention. Eighty percent of IPT and 63 % of BSP patients completed the 12 sessions of therapy. Patients in both treatments improved. IPT produced a greater response rate than BSP, with more than two-thirds of women achieving a >50 % reduction in scores on the Montgomery Asberg Depression Rating Scale (MADRS). IPT also tended to have lower posttreatment scores on the Beck Depression Inventory, Clinical Global Impression Severity Scale, and anxiety subscale of the Hamilton Depression Rating Scale, with between-group effect sizes ranging from 0.61 to 0.76. Gains persisted at 6 month follow-up. This pilot trial suggests that IPT is a promising treatment for depression in the context of infertility and that it may fare better than a rigorous active control condition. Should subsequent randomized controlled trials support these findings, this will inform clinical practice and take an important step in assuring optimal care for depressed women struggling with infertility. PMID- 22526404 TI - Does activity matter: an exploratory study among mothers with preterm infants? AB - The purpose of this study was to describe the daytime activity levels and their association with sleep, fatigue, depressive symptoms, and quality of life. Wrist actigraphy and questionnaires were used to examine 51 mothers with a preterm infant during their second week postpartum. Circadian activity rhythms (CAR) were less synchronized in these mothers; they experienced sleep disturbances, fatigue, depressive symptoms, and poor health-related quality of life (H-QOL). Compared to high-activity mothers, mothers with low activity levels slept less during nighttime but napped more during daytime, and reported more postpartum depressive symptoms. Further research is needed to examine the effect of low activity level and sleep loss on postpartum depression, and to develop interventions for improving rest/activity patterns for new mothers. PMID- 22526406 TI - Fear of childbirth, mental health, and medication use during pregnancy. AB - The aim of this work was to study the associations between medication use, fear of childbirth, and maternal mental health. Pregnant women (n = 1,984) were recruited through routine antenatal care at a Norwegian hospital from November 2008 through April 2010. Data were collected by three self-completed questionnaires at pregnancy week 17 and 32 and at 8 weeks postpartum. Fear of childbirth was measured by the Wijma Delivery Expectancy Questionnaire (W-DEQ). Symptoms of anxiety were measured by the Hopkins Symptom Checklist (SCL-25) and symptoms of depression by the Edinburgh Postnatal Depression Scale (EPDS). In total, 57.7 % of the women used medications during pregnancy. Analgesics were used by 55.8 % of the women and psychotropic medications by 1.8 %. In all, 7.8 % of the women reported fear of childbirth (W-DEQ >85), the prevalence of anxiety (SCL >18) was 11.8 % and the prevalence of depression (EPDS >13) was 8.1 %. Fear of childbirth was significantly associated with use of psychotropic drugs (OR 3.63; 95 % CI 1.39-9.43) but not with the use of analgesics or medications in general. The presence of symptoms of anxiety or depression increased the magnitude of this association. Fear of childbirth is associated with an increased use of psychotropic medication. This finding could not only be explained by an overlap between fear of childbirth and impaired mental health. PMID- 22526407 TI - Postnatal depression, maternal bonding failure, and negative attitudes towards pregnancy: a longitudinal study of pregnant women in Japan. AB - Postnatal depression and bonding failure after childbirth are major mental health issues. We investigated 99 pregnant women on three occasions (late in pregnancy and 5 days and 1 month postnatally). Anxiety during pregnancy predicted postnatal depression and bonding failure, whereas negative attitudes towards pregnancy predicted bonding failure. The effect of negative attitudes towards pregnancy on postnatal depression was possibly mediated by bonding failure. Postnatal depression and bonding failure are correlated with different risk factors and run rather independently over the course of the puerperium. Postnatal depression may be predicted by bonding failure. PMID- 22526408 TI - Bone marrow stromal cell-mediated tissue sparing enhances functional repair after spinal cord contusion in adult rats. AB - Bone marrow stromal cell (BMSC) transplantation has shown promise for repair of the spinal cord. We showed earlier that a BMSC transplant limits the loss of spinal nervous tissue after a contusive injury. Here, we addressed the premise that BMSC-mediated tissue sparing underlies functional recovery in adult rats after a contusion of the thoracic spinal cord. Our results reveal that after 2 months BMSCs had elicited a significant increase in spared tissue volumes and in blood vessel density in the contusion epicenter. A strong functional relationship existed between spared tissue volumes and blood vessel density. BMSC-transplanted rats exhibited significant improvements in motor, sensorimotor, and sensory functions, which were strongly correlated with spared tissue volumes. Retrograde tracing revealed that rats with BMSCs had twice as many descending brainstem neurons with an axon projecting beyond the contused spinal cord segment and these correlated strongly with the improved motor/sensorimotor functions but not sensory functions. Together, our data indicate that tissue sparing greatly contributes to BMSC-mediated functional repair after spinal cord contusion. The preservation/formation of blood vessels and sparing/regeneration of descending brainstem axons may be important mediators of the BMSC-mediated anatomical and functional improvements. PMID- 22526409 TI - Metronomic oral combination chemotherapy with capecitabine and cyclophosphamide: a phase II study in patients with HER2-negative metastatic breast cancer. AB - PURPOSE: Metronomic combination chemotherapy with the oral fluoropyrimidine doxifluridine/5'-deoxy-5-fluorouridine (5 -DFUR) and oral cyclophosphamide (C) showed promising efficacy in a single-arm study. The oral fluoropyrimidine capecitabine was designed to deliver 5-fluorouracil preferentially to tumors, potentially improving efficacy over doxifluridine. We conducted a phase II multicenter study to evaluate an all-oral XC combination in patients with HER2 negative metastatic breast cancer (MBC). MATERIALS AND METHODS: Patients received capecitabine 828 mg/m(2) twice daily with cyclophosphamide 33 mg/m(2) twice daily, days 1-14 every 3 weeks. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Between May 2007 and April 2009, 51 patients were enrolled and 45 were included in the efficacy analysis. The median follow-up was 18.1 months. ORR was 44.4% and stable disease (>=24 weeks) was achieved in 13.4%, resulting in a 57.8% clinical benefit response rate. Median PFS was 12.3 months (95% confidence interval: 8.9-18.9 months). Median PFS was 10.7 months in triple-negative disease and 13.2 months in estrogen-receptor positive, HER2 negative disease. The 1- and 2-year OS rates were 86 and 71%, respectively. Median OS has not been reached. Grade 3 adverse events comprised leukopenia (26%), neutropenia (16%), and decreased hemoglobin (2%). There was no grade 3 hand-foot syndrome. CONCLUSIONS: Oral XC is an effective first- or second-line therapy for MBC, demonstrating high activity in both luminal A and triple negative disease with few severe side effects. This metronomic oral combination chemotherapy could be beneficial for the treatment of HER2-negative MBC. PMID- 22526410 TI - Novel physiologically based pharmacokinetic modeling of patupilone for human pharmacokinetic predictions. AB - PURPOSE: Patupilone (EPO906) is a novel potent microtubule stabilizer, which has been evaluated for cancer treatment. A novel physiologically based pharmacokinetics (PBPK) model was developed based on nonclinical data to predict the disposition of patupilone in cancer patients. METHODS: After a single intravenous dose (1.2 mg/kg) in male Han-Wistar rats, the tissue distribution of (14)C-patupilone was investigated by quantitative whole-body autoradiography (QWBA). The blood radioactivity and patupilone concentration were determined by LC-MS/MS and liquid scintillation counting. A novel PBPK model was developed based on rat tissue concentration data to predict blood concentration-time profiles of patupilone in cancer patients. PBPK parameters derived from the rat were applied to a human PBPK model. Phase I clinical pharmacokinetic data in Caucasian and Japanese cancer patients at various doses ranging from 0.75 to 10 mg/m(2) were successfully described using the PBPK approach. RESULTS: Patupilone dispositions in lung, heart, muscle, spleen, liver, brain, adipose, and testes of rats were well described using the PBPK model developed assuming a perfusion rate limited distribution between different compartments. For skin and bone marrow, concentration-time profiles were modeled assuming a permeability-limited distribution between different compartments. The simulated human pharmacokinetic profiles from the PBPK model showed good agreement with observed clinical pharmacokinetic data, where the model predicted AUC, t(1/2), V(ss), and CL values were within approximately twofold of the observed values for all dose groups. CONCLUSIONS: The distribution of patupilone in rats was well described by a PBPK model based on measured tissue distribution profiles generated by QWBA combined with metabolism data. The human PBPK model adequately predicted blood pharmacokinetics of patupilone in cancer patients. The PBPK model based upon preclinical tissue distribution data can aid in successful prediction of pharmacokinetics in humans. PMID- 22526411 TI - Open-label, phase I, pharmacokinetic studies of abiraterone acetate in healthy men. AB - PURPOSE: To evaluate pharmacokinetics, safety, and tolerability of abiraterone acetate (AA) in healthy men. METHODS: Two phase I studies (dose-escalation study and dose-proportionality study) were conducted in healthy men aged 18-55 years. All subjects received 4 consecutive single doses of AA (250, 500, 750 and 1,000 mg). The dose-escalation study subjects (N = 33) received AA doses in a sequential manner, starting with the lowest dose. The dose-proportionality study subjects (N = 32) were randomly allocated (1:1:1:1) to receive each of the 4 doses in a four-way crossover design. RESULTS: A dose-related increase in abiraterone exposure was observed in both studies. Over the evaluated dose range, the mean abiraterone maximum plasma concentrations increased from 26 to 112 ng/mL in dose-escalation study and from 40 to 125 ng/mL in dose-proportionality study; the mean area under the plasma concentration-time curve from 0 to the last measurable plasma concentration increased from 155 to 610 ng.h/mL in dose escalation study, and from 195 to 607 ng.h/mL in dose-proportionality study. In the dose-proportionality study, abiraterone exposure was dose proportional between 1,000 and 750 mg doses; however, the exposure was slightly greater than dose proportional when exposures at 500 and 250 mg doses were compared with the exposure at 1,000 mg. Single doses of AA were well tolerated in healthy men, and safety profile was consistent with its known toxicities in CRPC patients. CONCLUSION: Systemic exposure to abiraterone increased with increasing doses of AA (250-1,000 mg) in healthy men; AA was well tolerated in this population. PMID- 22526412 TI - The "survivin suppressants" NSC 80467 and YM155 induce a DNA damage response. AB - PURPOSE: To establish whether NSC80467, a novel fused naphthquinone imidazolium, has a similar spectrum of activity to the well-characterized "survivin suppressant" YM155 and to extend mechanistic studies for this structural class of agent. METHODS: NSC80467 and YM155 were analyzed in parallel using assays measuring viability, survivin suppression, inhibition of DNA/RNA/protein synthesis and the cellular response to DNA damage. RESULTS: GI(50) values generated for both compounds in the NCI-60 screen yielded a correlation coefficient of 0.748, suggesting significant concordance. Both agents were also shown to inhibit protein expression of survivin [BIRC5]. COMPARE analysis identified DNA damaging agents chromomycin A3 and bisantrene HCl and one DNA directed inhibitor of transcription, actinomycin D, as correlating with the activity of NSC80467 and YM155. Furthermore, both agents were shown to preferentially inhibit DNA, over RNA and protein synthesis. Thus, the ability of NSC80467 and YM155 to induce a DNA damage response was examined further. Treatment of PC3 cells with either agent resulted in dose-dependent induction of gammaH2AX and pKAP1, two markers of DNA damage. The concentrations of agent required to stimulate gammaH2AX were considerably lower than those required to inhibit survivin, implicating DNA damage as an initiating event. The DNA damage response was then confirmed in a panel of cell lines treated with NSC80467 or YM155, suggesting that gammaH2AX and pKAP1 have potential as response biomarkers. CONCLUSIONS: These data provide the first evidence that NSC80467 and YM155 are DNA damaging agents where suppression of survivin is a secondary event, likely a consequence of transcriptional repression. PMID- 22526413 TI - [Influence of the calcitonin assay on the definition of biochemical cure in patients with medullary thyroid carcinoma]. AB - AIM: Calcitonin (hCT) is an important diagnostic parameter in medullary thyroid carcinoma (MTC). We determined the variability of the reference ranges of several currently available immunometric assays for "biochemically cured" MTC patients. PATIENTS, METHODS: We compared six assays [Nichols ICMA, Biomerica IEMA, Immulite 2000 (Siemens), Calcitonin-IRMA magnum (Medipan), SELco-IRMA (Medipan) and Calcitonin IRMA (Medgenix)] in subgroups of 198 patients with differentiated thyroid cancer (DTC) after total thyroidectomy as a model for curatively treated MTC patients. In addition, hCT was measured after pentagastrin stimulation in 13 DTC patients and 13 patients with MTC. RESULTS: The basal hCT concentrations were below the detection limit of the respective assay in 100% of all thyroidectomized DTC patients for Nichols ICMA (n = 138) and Immulite 2000 (n = 60), in 97% for Biomerica IEMA (n = 57), and in 85% for IRMA magnum (n = 20). However, basal hCT was mostly within the reference range in Selco-IRMA (n = 20) and Medgenix IRMA (n = 76). In all DTC patients and 9/13 MTC patients the pentagastrin stimulated hCT was below the detection limit for the Nichols ICMA and Immulite 2000, all four MTC patients with elevated stimulated hCT developed a recurrence during follow up. CONCLUSIONS: For assays with high monomer specificity (Nichols ICMA, Biomerica IEMA, Immulite 2000, to a lesser degree IRMA magnum) biochemical cure is defined by basal and stimulated calcitonin levels below the detection limit. For assays with low monomer specificity (SELco-IRMA, IRMA Medgenix) calcitonin levels in the reference range of patients without thyroid diseases are consistent with "biochemical cure". PMID- 22526414 TI - Surgical treatment of gastroesophageal reflux disease. AB - BACKGROUND: Gastroesophageal reflux disease is by far the most prevalent disorder of the foregut. For a long time during the twentieth century, surgical therapy was the mainstay of treatment and the only chance for cure for patients with severe symptoms. Later, after introduction of proton pump inhibitor therapy in the early 1990 s, surgical therapy was considered widely a second choice option due to its potential morbidity and side effects. More recently, however, there is growing evidence that long-term antisecretory therapy might be associated to a number of adverse effects such as osteoporosis and increased risk of cardiovascular events. This is the rationale why interventional and surgical options are coming back into focus. PURPOSE: The purpose of this review is to analyze and to discuss the current spectrum of surgical therapy of gastroesophageal reflux disease. PMID- 22526415 TI - Reduction of wound infections in laparoscopic-assisted colorectal resections by plastic wound ring drapes (REDWIL)?--A randomized controlled trial. AB - INTRODUCTION: Surgical site infections (SSIs) are frequent complications in colorectal surgery and may lead to burst abdomen, incisional hernia, and increased perioperative costs. Plastic wound ring drapes (RD) were introduced some decades ago to protect the abdominal wound from bacteria and reduce SSIs. There have been no controlled trials examining the benefit of RD in laparoscopic colorectal surgery. The Reduction of wound infections in laparoscopic assisted colorectal resections by plastic wound ring drapes (REDWIL) trial was thus designed to assess their effectiveness in preventing SSIs after elective laparoscopic colorectal resections. MATERIALS/METHODS: REDWIL is a randomized controlled monocenter trial with two parallel groups (experimental group with RD and control group without RD). Patients undergoing elective laparoscopic colorectal resection were included. The primary endpoint was SSIs. Secondary outcomes were colonization of the abdominal wall with bacteria, reoperations/readmissions, early/late postoperative complications, and cost of hospital stay. The duration of follow-up was 6 months. RESULTS: Between January 2008 and October 2010, 109 patients were randomly assigned to the experimental or control group (with or without RD). Forty-six patients in the RD group and 47 patients in the control group completed follow-up. SSIs developed in ten patients with RD (21.7 %) and six patients without RD (12.8 %) (p = 0.28). An intraoperative swab taken from the abdominal wall was positive in 66.7 % of patients with RD and 57.5 % without RD (p = 0.46). The number of species cultured within one swab was significantly higher in those without RD (p = 0.03). The median total inpatient costs including emergency readmissions were 3,402 +/- 4,038 in the RD group and 3,563 +/- 1,735 in the control group (p = 0.869). CONCLUSIONS: RD do not reduce the rate of SSIs in laparoscopic colorectal surgery. The inpatient costs are similar with and without RD. PMID- 22526416 TI - Ca2+-activated Cl- channels at a glance. PMID- 22526418 TI - Meiotic actin rings are essential for proper sporulation in fission yeast. AB - Sporulation is a unique form of cytokinesis that occurs following meiosis II in many yeasts, during which four daughter cells (spores) are generated within a single mother cell. Here we characterize the role of F-actin in the process of sporulation in the fission yeast Schizosaccharomyces pombe. As shown previously, we find that F-actin assembles into four ring structures per ascus, referred to as the meiotic actin ring (MeiAR). The actin nucleators Arp2/3 and formin For3 assemble into ring structures that overlap with Meu14, a protein known to assemble into the so-called leading edge, a ring structure that is known to guide forespore membrane assembly. Interestingly, F-actin makes rings that occupy a larger region behind the leading edge ring. Time-lapse microscopy showed that the MeiAR assembles near the spindle pole bodies and undergoes an expansion in diameter during the early stages of meiosis II, followed by closure in later stages of meiosis II. MeiAR closure completes the process of forespore membrane assembly. Loss of the MeiAR leads to excessive assembly of forespore membranes with a deformed appearance. The rate of closure of the MeiAR is dictated by the function of the septation initiation network (SIN). We conclude that the MeiAR ensures proper targeting of the membrane biogenesis machinery to the leading edge, thereby ensuring the formation of spherical spores. PMID- 22526417 TI - The Capicua repressor--a general sensor of RTK signaling in development and disease. AB - Receptor tyrosine kinase (RTK) signaling pathways control multiple cellular decisions in metazoans, often by regulating the expression of downstream genes. In Drosophila melanogaster and other systems, E-twenty-six (ETS) transcription factors are considered to be the predominant nuclear effectors of RTK pathways. Here, we highlight recent progress in identifying the HMG-box protein Capicua (CIC) as a key sensor of RTK signaling in both Drosophila and mammals. Several studies have shown that CIC functions as a repressor of RTK-responsive genes, keeping them silent in the absence of signaling. Following the activation of RTK signaling, CIC repression is relieved, and this allows the expression of the targeted gene in response to local or ubiquitous activators. This regulatory switch is essential for several RTK responses in Drosophila, from the determination of cell fate to cell proliferation. Furthermore, increasing evidence supports the notion that this mechanism is conserved in mammals, where CIC has been implicated in cancer and neurodegeneration. In addition to summarizing our current knowledge on CIC, we also discuss the implications of these findings for our understanding of RTK signaling specificity in different biological processes. PMID- 22526420 TI - Butanol production from lignocellulosics. AB - Clostridium spp. produce n-butanol in the acetone/butanol/ethanol process. For sustainable industrial scale butanol production, a number of obstacles need to be addressed including choice of feedstock, the low product yield, toxicity to production strain, multiple-end products and downstream processing of alcohol mixtures. This review describes the use of lignocellulosic feedstocks, bioprocess and metabolic engineering, downstream processing and catalytic refining of n butanol. PMID- 22526419 TI - Regulation of nuclear TDP-43 by NR2A-containing NMDA receptors and PTEN. AB - The dysfunction of TAR DNA-binding protein-43 (TDP-43) is implicated in neurodegenerative diseases. However, the function of TDP-43 is not fully elucidated. Here we show that the protein level of endogenous TDP-43 in the nucleus is increased in mouse cortical neurons in the early stages, but return to basal level in the later stages after glutamate accumulation-induced injury. The elevation of TDP-43 results from a downregulation of phosphatase and tensin homolog (PTEN). We further demonstrate that activation of NR2A-containing NMDA receptors (NR2ARs) leads to PTEN downregulation and subsequent reduction of PTEN import from the cytoplasm to the nucleus after glutamate accumulation. The decrease of PTEN in the nucleus contributes to its reduced association with TDP 43, and thereby mediates the elevation of nuclear TDP-43. We provide evidence that the elevation of nuclear TDP-43, mediated by NR2AR activation and PTEN downregulation, confers protection against cortical neuronal death in the late stages after glutamate accumulation. Thus, this study reveals a NR2AR-PTEN-TDP-43 signaling pathway by which nuclear TDP-43 promotes neuronal survival. These results suggest that upregulation of nuclear TDP-43 represents a self-protection mechanism to delay neurodegeneration in the early stages after glutamate accumulation and that prolonging the upregulation process of nuclear TDP-43 might have therapeutic significance. PMID- 22526421 TI - Biocatalytic resolution of benzyl glycidyl ether and its derivates by Talaromyces flavus: effect of phenyl ring substituents on enantioselectivity. AB - Talaromyces flavus containing a constitutive epoxide hydrolase (EH) resolved racemic benzyl glycidyl ether and nine derivatives into their (R)-enantiomers. After optimization of the fermentation conditions, the specific EH activity and biomass concentration were improved from 13.5 U/g DCW and 14.8 g DCW/l to 26.2 U/g DCW and 31.3 g DCW/l, respectively, with final values for e.e. ( s ) of 96 % and E of 13 with (R)-benzyl glycidyl ether. Substituents on the phenyl ring, however, gave low enantioselectivities. PMID- 22526422 TI - Esterification of fatty acids using Candida antarctica lipase A in water-abundant systems. AB - The feasibility of using native lipase A from Candida antarctica (CAL-A) to esterify fatty acids with water-insoluble alcohols in the presence of excess water was investigated in stirred-tank reactors. For high reaction rates, a ratio of water:substrates of 0.6-1.4:1 (v/v) was required. CAL-A showed higher substrate selectivity for the esterification of saturated palmitic acid with branched-chain 2-ethyl-1-hexanol than for unsaturated oleic acid with linear alcohol (1-decanol). After 18 h at 70 degrees C in a 1.5 l bulk stirred-tank reactor, an 2-ethyl-1-hexyl palmitic acid ester was obtained near 100 % yield [molar ratio palmitic acid:2-ethyl-1-hexanol ~1:1.25, with 1.11 % (w/w) Novocor ADL (based on palmitic acid weight)]. PMID- 22526423 TI - In vitro evaluation of a mammary gland specific expression vector encoding recombinant human lysozyme for development of transgenic dairy goat embryos. AB - A vector expressing human lysozyme (pBC1-hLYZ-GFP-Neo) was evaluated for gene and protein expression following liposome-mediated transformation of C-127 mouse mammary cancer cells. Cultures of G418-resistant clones were harvested 24-72 h after induction with prolactin, insulin and hydrocortisone. Target gene expression was analyzed by RT-PCR and Western blot and recombinant human lysozyme (rhLYZ) bacteriostatic activity was also evaluated. The hLYZ gene was correctly transcribed and translated in C-127 cells and hLYZ inhibited gram-positive bacterial growth, indicating the potential of this expression vector for development of a mammary gland bioreactor in goats. Guanzhong dairy goat skin fibroblasts transfected with pBC1-hLYZ-GFP-Neo were used to construct a goat embryo transgenically expressing rhLYZ by somatic nuclear transplantation with a blastocyst rate of 9.0 +/- 2.8 %. These data establish the basis for cultivation of mastitis-resistant hLYZ transgenic goats. PMID- 22526424 TI - Key cytomembrane ABC transporters of Saccharomyces cerevisiae fail to improve the tolerance to D-limonene. AB - ATP-binding cassette transporters (ABC) are important detoxification proteins and were proposed to play important roles in monoterpene resistance in Saccharomyces cerevisiae. In this work, the transcriptional levels of typical ABC transporters of S. cerevisiae under 85 mg D-limonene/l were evaluated using real-time quantitative PCR. Only the transcriptional level of PDR5, YOR1 and PDR15 were upregulated but overexpression of these genes in S. cerevisiae failed to improve D-limonene tolerance suggesting that other mechanisms are involved in tolerance of yeast to monoterpenes. PMID- 22526425 TI - Relationship between bile salt hydrolase activity, changes in the internal pH and tolerance to bile acids in lactic acid bacteria. AB - The effect of the conjugated bile acid (BA) on the microbial internal pH (pHin) values in lactic acid bacteria with and without ability to hydrolyze bile salts (BSH[+] and BSH[-] strains, respectively) was evaluated. BSH(+) strains showed a gradual increase in the pHin following the addition of conjugated BA; this behavior was more pronounced with GDCA than with TDCA may be due to the higher affinity of BSH for the glyco-conjugates acids. Conversely, the BSH(-) strains showed a decrease in internal pH probably as a consequence of weak acid accumulation. As expected, a decrease in the cytoplasmatic pH affected the cell survival in this last group of strains, while the BSH(+) strains were more resistant to the toxic effect of BA. PURPOSE OF WORK: To evaluate bile salt hydrolase activities, changes in the internal pH and cell survival to bile acids in lactic acid bacteria to establish the relationship between these parameters. PMID- 22526427 TI - Comprehensive gene expression analysis of the NAC gene family under normal growth conditions, hormone treatment, and drought stress conditions in rice using near isogenic lines (NILs) generated from crossing Aday Selection (drought tolerant) and IR64. AB - The NAC (NAM, ATAF1/2 and CUC2) genes are plant-specific transcriptional factors known to play diverse roles in various plant developmental processes. We describe the rice (Oryza sativa) OsNAC genes expression profiles (GEPs) under normal and water-deficit treatments (WDTs). The GEPs of the OsNAC genes were analyzed in 25 tissues covering the entire life cycle of Minghui 63. High expression levels of 17 genes were demonstrated in certain tissues under normal conditions suggesting that these genes may play important roles in specific organs. We determined that 16 genes were differentially expressed under at least 1 phytohormone (NAA, GA3, KT, SA, ABA, and JA) treatment. To investigate the GEPs in the root, leaf, and panicle of three rice genotypes [e.g., 2 near-isogenic lines (NILs) and IR64], we used two NILs from a common genetic combination backcross developed by Aday Selection and IR64. WDTs were applied using the fraction of transpirable soil water at severe, mild, and control conditions. Transcriptomic analysis using a 44K oligoarray from Agilent was performed on all the tissue samples. We identified common and specific genes in all tissues from the two NILs under both WDTs, and the majority of the OsNAC genes that were activated were in the drought tolerant IR77298-14-1-2-B-10 line compared with the drought-susceptible IR77298 14-1-2-B-13 or IR64. In IR77298-14-1-2-B-10, seventeen genes were very specific in their expression levels. Approximately 70 % of the genes from subgroups SNAC and NAM/CUC3 were activated in the leaf, but 37 % genes from subgroup SND were inactivated in the root compared with the control under severe stress conditions. These results provide a useful reference for the cloning of candidate genes from the specific subgroup for further functional analysis. PMID- 22526428 TI - Modulation of gene expression in cold-induced sweetening resistant potato species Solanum berthaultii exposed to low temperature. AB - Cold-induced sweetening (CIS) is a crucial factor influencing the processing quality of potato tubers. To better understand the molecular events of potato CIS and different CIS-sensitivity among various potato species, a suppression subtractive hybridization library and cDNA microarray gene filters were developed. A total of 188 genes were found to be differentially expressed (DE) in Solanum berthaultii (ber) upon cold stimulation. These functional genes were mostly related to cell rescue, defense and virulence, metabolism, energy and protein fate, included in various processes of plant defense against abiotic stresses. Four expression patterns of these DE genes were profiled by qRT-PCR using the cold-stored tubers of both CIS-resistant (ber) and CIS-sensitive (E potato 3, a variety of S. tuberosum) potatoes. The expression pattern and abundance of many DE genes encoding proteins involved in metabolism were different in these two potato tubers, especially genes associated with amylolysis, sucrose decomposition and glycolysis pathways, indicating distinct regulatory mechanisms between ber and E3 in response to cold stress, which may be crucial for potato CIS. Further investigation of these cold-regulated genes will deepen our understanding of the regulatory mechanisms of potato CIS and direct approaches for the genetic improvement of potato processing quality. PMID- 22526429 TI - Genome-wide analysis and expression profiling of the DREB transcription factor gene family in Malus under abiotic stress. AB - The dehydration responsive element binding (DREB) transcription factor family is one of the most promising regulons for genetic engineering of plant responses to abiotic stresses. However, knowledge about apple DREB genes is limited. In the present study, we found, for the first time, 68 MdDREB genes that could be further classified into six subgroups against the entire genome of apple. All putative proteins from those genes contained a typical APETALA 2 domain and shared similar motifs. The predicted MdDREBs were distributed with different densities over 12 chromosomes, with five tandem duplication sites occurring simultaneously. Both Genevestigator and expressed sequence tags were used for preliminary investigations of expression patterns. Results from quantitative real time PCR showed that transcript levels of some putative MdDREB genes were up regulated significantly under various abiotic-stress treatments, which indicated their vital roles during stress adaptation. Identifying these genes and profiling their expression provides useful information and constitutes a foundation for their further, practical utilization in apple through gene-transfer techniques. PMID- 22526430 TI - Fine genetic mapping of the Co locus controlling columnar growth habit in apple. AB - Tree architecture is an important, complex and dynamic trait affected by diverse genetic, ontogenetic and environmental factors. 'Wijcik McIntosh', a columnar (reduced branching) sport of 'McIntosh' and a valuable genetic resource, has been used intensively in apple-breeding programs for genetic improvement of tree architecture. The columnar growth habit is primarily controlled by the dominant allele of gene Co (columnar) on linkage group-10. But the Co locus is not well mapped and the Co gene remains unknown. To precisely map the Co locus and to identify candidate genes of Co, a sequence-based approach using both peach and apple genomes was used to develop new markers linked more tightly to Co. Five new simple sequence repeats markers were developed (C1753-3520, C18470-25831, C6536 31519, C7223-38004 and C7629-22009). The first four markers were obtained from apple genomic sequences on chromosome-10, whereas the last (C7629-22009) was from an unanchored apple contig that contains an apple expressed sequence tag CV082943, which was identified through synteny analysis between the peach and apple genomes. Genetic mapping of these five markers in four F(1) populations of 528 genotypes and 290 diverse columnar selections/cultivars (818 genotypes in total) delimited the Co locus in a genetic interval with 0.37 % recombination between markers C1753-3520 and C7629-22009. Marker C18470-25831 co-segregates with Co in the 818 genotypes studied. The Co region is estimated to be 193 kb and contains 26 predicted gene in the 'Golden Delicious' genome. Among the 26 genes, three are putative LATERAL ORGAN BOUNDARIES (LOB) DOMAIN (LBD) containing transcription factor genes known of essential roles in plant lateral organ development, and are therefore considered as strong candidates of Co, designated MdLBD1, MdLBD2, and MdLBD3. Although more comprehensive studies are required to confirm the function of MdLBD1-3, the present work represents an important step forward to better understand the genetic and molecular control of tree architecture in apple. PMID- 22526431 TI - Is it fluid or air causing anesthesia mumps? PMID- 22526432 TI - Management of general anesthesia for a patient with Maroteaux type acromesomelic dysplasia complicated with obstructive sleep apnea syndrome and hereditary myopathy. PMID- 22526433 TI - A case of atrioventricular block (Wenckebach type) induced by sugammadex. PMID- 22526434 TI - Postoperative continuous intravenous infusion of fentanyl is associated with the development of orthostatic intolerance and delayed ambulation in patients after gynecologic laparoscopic surgery. AB - PURPOSE: Early ambulation is essential for rapid functional recovery after surgery; however, orthostatic intolerance may delay recovery and cause syncope, leading to potential serious complications such as falls. Opioids may contribute to orthostatic intolerance because of reduced arterial pressure and associated reduction in cerebral blood flow and oxygenation. This study aimed to examine the effect of postoperative continuous infusion of fentanyl on orthostatic intolerance and delayed ambulation in patients after gynecologic laparoscopic surgery. METHODS: In this retrospective cohort study, data from 195 consecutive patients who underwent gynecologic laparoscopic surgery were analyzed to evaluate the association between postoperative continuous infusion of fentanyl and the incidence of orthostatic intolerance or delayed ambulation. The primary outcome was defined as delayed ambulation, an inability to ambulate on postoperative day 1. The secondary outcome was defined as orthostatic intolerance and symptoms associated with ambulatory challenge, including dizziness, nausea and vomiting, feeling hot, blurred vision, and eventual syncope. Multivariate logistic regression was used to determine the independent predictors of delayed ambulation and orthostatic intolerance. RESULTS: There were 24 cases with documented orthostatic intolerance and 5 with delayed ambulation. After multivariate logistic regression modeling, postoperative continuous infusion of fentanyl was found to be significantly associated with both orthostatic intolerance [adjusted odds ratio (95% confidence interval), 34.78 (11.12-131.72)] and delayed ambulation [adjusted odds ratio (95% confidence interval), 8.37 (1.23-72.15)]. CONCLUSION: Postoperative continuous infusion of fentanyl is associated with increased orthostatic intolerance and delayed ambulation in patients after gynecologic laparoscopic surgery. PMID- 22526435 TI - Life-threatening hemorrhagic shock after laparoscopic surgery: a case of postoperative thrombotic thrombocytopenic purpura. AB - We report the successful management of a female patient who developed postoperative thrombotic thrombocytopenic purpura (TTP) after an uneventful laparoscopic oophorocystectomy. The patient underwent uneventful laparoscopic surgery for ovarian cystoma. One hour after completion of surgery, the patient suddenly went into shock, with her blood pressure dropping to 60/40 mmHg. Hemorrhage into the abdominal cavity with an estimated blood loss of 2,000 ml was confirmed by exploratory laparotomy. Initially, anemia and thrombocytopenia were attributed to blood consumption or disseminated intravascular coagulation (DIC). However, blood tests revealed evidence of hemolytic anemia, with fragmented erythrocytes observed on peripheral blood smear examination. Serum levels of lactate dehydrogenase, blood urea nitrogen, and creatinine were elevated. Based on the findings, postoperative TTP was suspected. High-dose steroids and plasma infusions were administered but proved ineffective. Plasma exchange was performed three times, resulting in resolution of postoperative TTP. TTP is an idiopathic disorder, known to be triggered by surgical trauma. Postoperative TTP is difficult to distinguish clinically from DIC because of its close similarity with the latter and subtle differences from other postoperative hematological complications. It is important to bear in mind the possibility of postoperative TTP in patients with unexplained hemorrhagic shock after uneventful surgery. PMID- 22526436 TI - Obesity and postoperative early complications in open heart surgery. AB - PURPOSE: We investigated the distribution of early clinical outcomes among normal, obese, and morbidly obese patients undergoing open heart surgery. METHODS: Medical records of 1,000 patients undergoing open heart surgery since February 2011 at our hospital were investigated retrospectively after permission was obtained from the Council of Education Planning of the hospital. The comorbidities and perioperative and discharge data were analyzed for 279 patients with a body mass index (BMI) score between 18 and <30 [non-obese reference group (NRG, n = 279)]; 166 patients with BMI between 30 and <35 [obese group (OG, n = 166); and 192 seriously obese patients with BMI >=35 [extreme obese group (EOG, n = 192)]. Distribution of the patients according to BMI scores was found to represent the BMI distribution of the Turkish population. RESULTS: Pulmonary and infective complications were significantly higher in EOG patients compared to NRG based on crude confidence interval. Based on adjusted multiple logistic regression analysis, by adjusting the effects of age, sex, comorbidities (diabetes mellitus, hypertension, hyperlipidemia, chronic obstructive pulmonary disease), and smoking, the incidence of pulmonary and gastrointestinal complications in EOG was higher compared to NRG. Discharge with morbidity was significantly higher in OG and EOG compared to NRG. CONCLUSIONS: We found that obesity does not increase short-term mortality for open heart surgery; however, it increases the risk of postoperative pulmonary and gastrointestinal complications and discharge with morbidity. PMID- 22526437 TI - Reduction of pain on injection of propofol: combination of nitroglycerin and lidocaine. AB - PURPOSE: Pain on propofol injection is a common adverse effect. This study examined the effect of a combination of nitroglycerin and lidocaine on pain during propofol injection compared to lidocaine alone. METHODS: In a double blind, prospective trial, 90 patients scheduled to undergo elective plastic surgery were allocated randomly to three groups, to receive lidocaine 20 mg (n = 30), a combination of lidocaine 20 mg and nitroglycerin 0.1 MUg/kg (n = 30), or normal saline as a placebo (n = 30), with venous occlusion for 1 min, followed by the administration of 25 % of the total calculated dose of propofol (2 mg/kg) into a dorsal hand vein. The pain intensity during the propofol injection was assessed using a four-point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe). Hemodynamic variables-mean arterial pressure and heart rate-were measured during the preoperative and intraoperative periods. RESULTS: A significantly higher proportion of patients in the placebo group (83 %) experienced pain compared to the lidocaine and combination groups (43 and 7 %, respectively; both, P < 0.01). The incidence of pain in the combination group was lower than that in the lidocaine group (P < 0.01). The pain score (median) was lower in the lidocaine (0) and combination (0) groups than in the placebo group (2); (P < 0.01). The hemodynamic variables were similar in the three groups. CONCLUSION: A combination of nitroglycerin 0.1 MUg/kg and lidocaine 20 mg with venous occlusion for 1 min was more effective than lidocaine 20 mg alone in decreasing pain during propofol injection. PMID- 22526438 TI - Outcomes of Chiari I-associated scoliosis after intervention: a meta-analysis of the pediatric literature. AB - PURPOSE: Various series have reported successful management of scoliosis after surgical treatment of the associated Chiari malformation, syrinx, or bracing. Multiple factors have been associated with curve progression, but interpretation of outcomes is confounded by the wide range of reported results and size of individual series. We attempted to evaluate the outcomes of Chiari I-associated scoliosis by performing a meta-analysis of currently published data. METHODS: We conducted a systematic review of published articles using Medline, PubMed (from 1950 to January 2010), and reference lists of identified articles for Chiari malformation and scoliosis. RESULTS: One hundred and twenty patients were identified in 12 studies, of them, 37 % were male. The mean age at the time of surgery was 9.7 +/- 4.1 years. The mean curve magnitude at presentation was 34.4 +/- 13.0 degrees and progressed to a mean value of 38.9 +/- 20.2 degrees , with an average follow-up of 48.3 +/- 48.2 months. After surgical intervention, curve magnitude improved in 37 % of patients (n = 42); there was no change in 18 % (n = 20), and curves progressed in 45 % (n = 51). Age (p = 0.0097) and presence of surgical intervention (foramen magnum decompression [p = 0.0099] and syrinx shunting/drainage [p = 0.0039]) were statistically associated with improvement of the scoliotic curve. Surgical decompression of the foramen magnum had the greatest impact on the scoliotic curves. CONCLUSIONS: Data accrued from our analysis suggest that curve magnitude will improve after surgical treatment of the Chiari malformation in one third of patients, and curve progression will stabilize or improve in one half. PMID- 22526439 TI - The cranial dura mater: a review of its history, embryology, and anatomy. AB - INTRODUCTION: The dura mater is important to the clinician as a barrier to the internal environment of the brain, and surgically, its anatomy should be well known to the neurosurgeon and clinician who interpret imaging. METHODS: The medical literature was reviewed in regard to the morphology and embryology of specifically, the intracranial dura mater. A historic review of this meningeal layer is also provided. CONCLUSIONS: Knowledge of the cranial dura mater has a rich history. The embryology is complex, and the surgical anatomy of this layer and its specializations are important to the neurosurgeon. PMID- 22526440 TI - Citrobacter brain abscesses in neonates: early surgical intervention and review of the literature. AB - PURPOSE: Citrobacter koseri, a facultatively anaerobic, lactose-fermenting, gram negative bacilli, has a strong propensity to form cerebral abscesses. C. koseri brain abscesses can be a devastating disease of infancy and childhood with more than 30% succumbing to the disease and more than 50% suffering severe neurological deficits. METHODS: This study represents a retrospective review of two cases of C. koseri brain abscesses along with a review of the literature regarding diagnosis and treatment. RESULTS: Early aggressive surgical and medical treatment resulted in favorable outcomes for two children with C. koseri brain abscesses, one diagnosed at 6 weeks of age and the other at 2 months of age. CONCLUSION: C. koseri brain abscesses can be devastating and have been associated historically with significant morbidity and mortality. However, favorable outcomes are possible, and aggressive surgical and medical management should be considered for patients with C. koseri abscesses. PMID- 22526441 TI - Expression of AMPA receptor subunits in hippocampus after status convulsion. AB - OBJECTIVE: The expression of 2-amino-3-(5-methyl-3-oxo-1, 2-oxazol-4-yl) propanoic acid receptor (AMPAR) subunits in the hippocampus of naive immature and adult rats (IRs, ARs) was investigated after status convulsion (SC). METHODS: Seizures were induced in IRs and ARs with intraperitoneal injections of lithium and pilocarpine. Rats were killed at four time points (3 h, 1 day, 3 days, and 7 days) after SC. The proportion of apoptotic cells was quantified by Annexin V FITC apoptosis detection. The location and type of apoptotic cells were assessed by using terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining. Immunoblotting techniques were used to demonstrate changes in AMPAR subunit expression. RESULTS: Severe seizures induced neuronal apoptosis in the hippocampus. The proportion of apoptotic cells in IRs was consistently lower than that in ARs after SC. The expressions of four AMPAR subunits in IRs were consistently lower than those in ARs before and after SC. SC for 1 h inhibited the expression of glutamate receptors (GluR1-4) in the hippocampus of IRs and ARs and altered the subunit composition of AMPARs. GluR2 was the predominant AMPAR subunit in the hippocampus of normal ARs, while the GluR2/3 subunits were predominantly expressed 7 days after SC. GluR3/4 subunits were mainly expressed in the hippocampus of normal IRs, which had the lowest levels of GluR2. CONCLUSIONS: Immature brain was more resistant to seizure-induced neural damage. The time course of reduction and recovery differed for each subunit and was dependent on developmental stage. The increased expression of GluR2 could confer early but transient protection in the immature brain after SC. PMID- 22526442 TI - Effects of the implantation of Ommaya reservoir in children with tuberculous meningitis hydrocephalus: a preliminary study. AB - OBJECTIVE: The role of Ommaya reservoir implantation in children with tuberculous meningitis hydrocephalus (TBMH) has been seldomly reported. Therefore, we performed this study to determine the role of the Ommaya reservoir in the treatment of children with TBMH. METHODS: We retrospectively analyzed the effects of Ommaya reservoir implantation in 12 children with TBMH. Intracapsular puncture of the reservoir was performed for draining the cerebrospinal fluid and the TBM was treated by intraventricular injection of isoniazid. RESULTS: The ideal treatment outcome was observed in nine (75 %) of the 12 children; two (16.7 %) children developed serious disabilities and one of them (8.3 %) eventually died. The treatment method was effective for all six (100 %) children with Palur grade II TBM but showed no effect in three (50 %) children with grade III and IV TBM. The number of leukocytes in the cerebrospinal fluid decreased to 20 * 10(6)/L (75 %) within 2 weeks after implantation of the reservoirs. Finally, the Ommaya reservoirs in eight children were removed but were retained in four children. Four children had to undergo ventriculoperitoneal shunt. CONCLUSION: Ommaya reservoir implantation has been shown to be effective in treating children with TBMH. This method may be largely suitable for children with early grade II TBM or partly in children with grade III TBM who have mild or moderate hydrocephalus that can alleviate after short-term treatment. Thus, a good proportion of children who undergo Ommaya reservoir implantation can avoid ventriculoperitoneal shunt surgery. PMID- 22526443 TI - Detection of hidden pseudotumour cerebri behind Chiari 1 malformation: value of telemetric ICP monitoring. PMID- 22526444 TI - Lateral compression of the foramen magnum with the Chiari I malformation: case illustrations. PMID- 22526445 TI - Caudal regression syndrome with bilateral popliteal webbing without maternal diabetes: a rare entity. PMID- 22526446 TI - Association of persistent hyperglycemia with outcome of severe traumatic brain injury in pediatric population. AB - PURPOSE: Hyperglycemia is a common secondary insult associated with an increased risk of mortality and poor outcome in traumatic brain injury (TBI), but the effect of hyperglycemia on outcomes of severe TBI in children and adolescents is less apparent. The aim of this study was to evaluate the association of hyperglycemia with mortality in pediatric patients with severe TBI. METHODS: In this cross-sectional study, data of all children and adolescents with severe TBI admitted to Poursina Hospital in Rasht, including age, gender, Glasgow Coma Scale (GCS) upon admission, mortality rate, hospital length of stay, and serial blood glucose during the first three consecutive ICU days following admission, were reviewed from April 2007 to May 2011. After univariate analysis and adjustment for related covariates, logistic regression model was established to determine the association between persistent hyperglycemia and outcome. RESULTS: One hundred and twenty-two children were included with a median admission GCS of 6 (interquartile range (IQR) 5-7) and a median age of 13 years (IQR 7.75-17). Among them, 91 were boys (74.6%) and 31 were girls (26.6%); the overall mortality was 40.2% (n=49). Patients who died had a significantly greater blood glucose levels than survivors for the first 3 days of admission (P=0.003, P<0.001, P=0.001, respectively). Moreover, persistent hyperglycemia during the first 3 days of admission had an adjusted odds ratio of 11.11 for mortality (P<0.001). CONCLUSION: Early hyperglycemia is associated with poor outcome, and persistent hyperglycemia is a powerful and independent predictor of mortality in children and adolescents with severe TBI. PMID- 22526447 TI - Clinical diagnosis and complications of paratubal cysts: review of the literature and report of uncommon presentations. AB - INTRODUCTION: Paraovarian or paratubal cysts (PTCs) constitute about 10 % of adnexial masses. Although they are not uncommon; they rarely cause symptoms and are usually incidentally found. Actual incidence is not known. The symptoms occur when they grow excessively, or in case of hemorrhage, rupture or torsion. METHODS: Here, literature review reporting the incidence, presentation and complications of PTCs is performed. Uncommon presentations of PTCs in three different cases, a giant PTC, torsion of PTC and borderline paratubal tumor, are also reported and discussed. RESULTS: Ultrasonography, CT or MRI may be performed in preoperative evaluation; but none of these imaging techniques have specific criteria for diagnosis. So, in most cases misdiagnosis as an ovarian mass remains to be a problem. CONCLUSION: Paratubal cysts can become extremely big before causing symptoms. Torsion is another urgent issue regarding PTCs, necessiating urgent surgery for preservation of the ovary and the tube. Although malignancy is rare, borderline paratubal tumors have been reported in the literature. PMID- 22526448 TI - Efficacy of cryoanalgesia in decreasing pain during second trimester genetic amniocentesis: a randomized trial. AB - OBJECTIVE: To evaluate the effectiveness of cryoanalgesia in decreasing the degree of pain sensation during second trimester genetic amniocentesis. MATERIALS AND METHODS: We performed a prospective randomized study comparing the anticipated and actual pain before and after second trimester genetic amniocentesis between pregnant women who received and did not receive cryoanalgesia. The pain was measured using the visual analog score (VAS), ranging from 0 to 10. RESULTS: Three hundred and seventy-two pregnant women participated in our study. One hundred and eighty-four and 188 pregnant women were randomized to cryoanalgesia received and non-cryoanalgesia received groups, respectively. The pre-procedure anxiety mean VAS scores and the anticipated pain mean VAS scores between the groups were not significantly different (P = 0.25 and 0.18, respectively). The pre-procedure anxiety and the anticipated pain mean +/- SD VAS scores in the cryoanalgesia and non-cryoanalgesia groups were 5.7 +/- 0.37 vs. 8.0 +/- 0.82 and 5.4 +/- 1.34 vs. 5.6 +/- 1.42, respectively. The post-procedure pain and anxiety mean VAS scores in the cryoanalgesia group were statistically less significant than those from the non-cryoanalgesia group (mean +/- SD = 3.2 +/- 1.60 and 3.8 +/- 1.58, respectively, P = 0.004). Most pregnant women claimed to have experienced moderate pain and accepted to undergo a second trimester genetic amniocentesis again if indicated. CONCLUSION: Cryoanalgesia is effective in decreasing the pain sensation and could be routinely applied to all pregnant women before the second trimester genetic amniocentesis. PMID- 22526449 TI - Kidney injury during pregnancy: associated comorbid conditions and outcomes. AB - PURPOSE: To investigate the characteristics of women who have kidney injury during pregnancy. METHODS: Medical records of all women who gave birth at our institution between January 1, 2005, and December 31, 2010, were retrospectively reviewed electronically. We identified those who incurred a kidney injury [defined by modified Acute Kidney Injury Network (AKIN) criteria: serum creatinine (sCr) increase >=0.3 mg/dL] during pregnancy or within 30 days postpartum. Identified case records were reviewed in detail. RESULTS: During the study period, 54 women had a kidney injury (0.4 % estimated incidence) with a mean (SD) increase in sCr of 0.46 (0.29) mg/dL; most injuries were AKIN stage 1 with transient increases in sCr. Most of the women (n = 48, 87.3 %) had substantial preexisting or pregnancy-associated comorbid conditions (e.g., kidney disease, hypertension, diabetes), complications (e.g., preeclampsia, HELLP syndrome), or a complicated obstetric course (hemorrhage, infections) that could have contributed to the development of a kidney injury. Two patients had AKIN stage 3 injuries: a previously healthy patient who had a massive hemorrhage during cesarean delivery, and a patient with a renal transplant who had deterioration and eventual postpartum failure of her transplanted kidney. CONCLUSIONS: The majority of pregnancy-associated kidney injuries were transient and occurred in women with substantial comorbid conditions or complicated pregnancies. PMID- 22526450 TI - Paraneoplastic vasculitis with digital necrosis: a rare presentation of advanced ovarian cancer. PMID- 22526451 TI - Comparison of uterine artery Doppler in pregnant women with thrombophilia treated by LMWHs and without thrombophilia. AB - OBJECTIVE: The aim of this study was to use uterine artery Doppler ultrasonography to investigate the cases of women with thrombophilia who used LMWH during the 18-22-week period of gestation. METHODS: This retrospective study was conducted at our university between January 2005 and July 2010. 64 patients were treated with low-dose LMWHs (enoxaparine 40 mg) from the beginning of pregnancy until 36 weeks of gestation. Fifty control subjects were also included in this study. Transabdominal ultrasound examination and bilateral uterine artery Doppler measurements pulsatility index (PI), resistive index (RI), and systole/diastole measurement (S/D) were performed during the 18-22-weeks period of gestation. RESULTS: No significant differences were found between the groups with respect to maternal age or gestational age at the time of uterine artery Doppler. However, the mean PI (1.07 +/- 0.46 for LMWH group and 0.91 +/- 0.31 for control, p = 0.036) and the mean RI (0.59 +/- 0.12 for LMWH group and 0.54 +/- 0.10 for control, p = 0.021) were significantly higher in the trombophilia group. CONCLUSION: Women with trombophilia still have an increased mean PI and RI, as determined by uterine artery Doppler ultrasonography during the 18-22-week period of gestation, even if they use LMWH. PMID- 22526452 TI - Fetal growth restriction: current knowledge to the general Obs/Gyn. AB - BACKGROUND: Fetal growth restriction (FGR) is a condition that affects 5-10 % of gestations, and it is the second primary cause of perinatal mortality. In this review the most recent knowledge about FGR is presented focusing on its concept, etiology, classification, diagnosis, management, and prognosis. METHODS: Searches were conducted in Pubmed, Embase and Lilacs database using the term fetal growth restriction. RESULTS: FGR is classified as type I (symmetric), manifested early, in which there is a proportional reduction of all fetal parts, generally associated with chromosome abnormalities; type II (asymmetric), with late onset, in which there is a more accentuated reduction of the abdomen, generally related to placental insufficiency; and type III (mixed), with early manifestation, resulting from infections or exposure to toxic agents. Diagnosis may be clinical, although ultrasound associated with arterial and venous Doppler is essential for diagnosis and follow-up. Currently there is no treatment capable of controlling FGR, and the moment of interruption of pregnancy is of vital importance in order to protect maternal and fetal interests. CONCLUSION: Early diagnosis of FGR is very important, because it permits the etiological identification and adequate monitoring of fetal vitality, minimizing the risks related to prematurity and intrauterine hypoxia. PMID- 22526453 TI - Surgical repair of traumatic cloaca. PMID- 22526454 TI - Non-mydriatic wide field fundus photography in bilateral serous retinal detachment due to HELLP syndrome. PMID- 22526455 TI - Initial solid electrolyte interphase formation process of graphite anode in LiPF6 electrolyte: an in situ ECSTM investigation. AB - Understanding the structure and formation dynamics of the solid electrolyte interphase (SEI) on the electrode/electrolyte interface is of great importance for lithium ion batteries, as the properties of the SEI remarkably affect the performances of lithium ion batteries such as power capabilities, cycling life, and safety issues. Herein, we report an in situ electrochemical scanning tunnelling microscopy (ECSTM) study of the surface morphology changes of a highly oriented pyrolytic graphite (HOPG) anode during initial lithium uptake in 1 M LiPF(6) dissolved in the solvents of ethylene carbonate plus dimethyl carbonate. The exfoliation of the graphite originating from the step edge occurs when the potential is more negative than 1.5 V vs. Li(+)/Li. Within the range from 0.8 to 0.7 V vs. Li(+)/Li, the growth of clusters on the step edge, the decoration of the terrace with small island-like clusters, and the exfoliation of graphite layers take place on the surface simultaneously. The surface morphology change in the initial lithium uptake process can be recovered when the potential is switched back to 2.0 V. Control experiments indicate that the surface morphology change can be attributed to the electrochemical reduction of solvent molecules. The findings may lead to a better understanding of SEI formation on graphite anodes, optimized electrolyte systems for it, as well as the use of in situ ECSTM for interface studies in lithium ion batteries. PMID- 22526456 TI - Profiling immunohistochemical expression of NOTCH1-3, JAGGED1, cMET, and phospho MAPK in 100 carcinomas of unknown primary. AB - Cancer of unknown primary (CUP) is a heterogeneous entity, managed on the basis of "one size fits all" therapeutic concepts; insights into the molecular biology of CUP are urgently needed. We retrospectively examined the immunohistochemical (IHC) expression of Notch1, 2, 3, Jagged1, cMET, and pMAPK biomolecules in 100 CUP tumors using tissue microarrays, aiming to study their correlation to clinicopathologic characteristics and prognostic utility for patient outcome. Notch3 and pMAPK were most frequently expressed (97 and 91 %, respectively). A linear correlation of Notch3 and cMET expression was found (p = 0.001), while pMAPK emerged as the major adverse prognostic factor (median overall survival OS 9 vs. 17 months, p = 0.016), carrying also a significantly positive predictive value (p = 0.02). Our study indicated a favorable prognostic impact of cMET expression in CUP, both in univariate (median OS 15 vs. 9 months, p = 0.05) and in multivariate analysis (Relative Risk RR for death 0.48, p = 0.025). cMET and Notch3 expression were found to be statistically more frequent in squamous carcinomas (positive in 90 % of cases), associated with a unique metastatic IHC pattern (cMET-high in soft tissue/lymph node metastases, p < 0.001, Notch3-high in visceral, peritoneal/pleural and soft tissue/lymph node metastases, p < 0.001). Our study points to the MAPK and cMET axes as crucial in defining cancer progression and outcome in CUP patients and, if validated, could justify attempts at their therapeutic modulation. PMID- 22526458 TI - Regulation of ENaC biogenesis by the stress response protein SERP1. AB - Cystic fibrosis lung disease is caused by reduced Cl(-) secretion along with enhanced Na(+) absorption, leading to reduced airway surface liquid and compromised mucociliary clearance. Therapeutic strategies have been developed to activate cystic fibrosis transmembrane conductance regulator (CFTR) or to overcome enhanced Na(+) absorption by the epithelial Na(+) channel (ENaC). In a split-ubiquitin-based two-hybrid screening, we identified stress-associated ER protein 1 (SERP1)/ribosome-associated membrane protein 4 as a novel interacting partner for the ENaC beta-subunit. SERP1 is induced during cell stress and interacts with the molecular chaperone calnexin, thus controlling early biogenesis of membrane proteins. ENaC activity was measured in the human airway epithelial cell lines H441 and A549 and in voltage clamp experiments with ENaC overexpressing Xenopus oocytes. We found that expression of SERP1 strongly inhibits amiloride-sensitive Na(+) transport. SERP1 coimmunoprecipitated and colocalized with betaENaC in the endoplasmic reticulum, together with the chaperone calnexin. In contrast to the inhibitory effects on ENaC, SERP1 appears to promote expression of CFTR. Taken together, SERP1 is a novel cochaperone and regulator of ENaC expression. PMID- 22526457 TI - CCL27-CCR10 and CXCL12-CXCR4 chemokine ligand-receptor mRNA expression ratio: new predictive factors of tumor progression in cutaneous malignant melanoma. AB - CXCR4, CCR7 and CCR10 chemokine receptors are known to be involved in melanoma metastasis. Our goal was to compare the relative intratumoral mRNA expression of these receptors with that of their corresponding chemokine ligands, CXCL12, CCL19, CCL21, and CCL27 across the full spectrum of human melanoma progression: thin and thick primary melanomas, as well as "in transit", lymph node, and distant metastases. Expression was quantified by real-time RT-PCR in 103 melanoma samples: 51 primary tumors and 52 metastases. Particular emphasis was focused on chemokine ligand-receptor expression ratios. Immunohistochemistry was performed to identify the cell types expressing these molecules. CXCL12-CXCR4 and CCL27 CCR10 ratios were higher in thin than in thick primary melanomas, and all four chemokine-receptor ratios were higher in primary tumors than in melanoma metastases. CCL27-CCR10 and CXCL12-CXCR4 expression ratios in primary tumors were inversely associated with the development of distant metastases, and improved the predictive value of tumor thickness for distant metastasis, which is important since chemokine ligand-receptor ratios are not affected by the endogenous gene employed for normalizing mRNA expression. Both receptor and ligand immunolabeling were detected in neoplastic cells suggesting autocrine mechanisms. Our results support the concept that low CCL27/CCR10 and CXCL12/CXCR4 intratumoral mRNA ratios are associated with melanoma progression, and in combination with Breslow thickness, are the best predictive factors for the development of distant metastases in primary cutaneous melanoma. PMID- 22526459 TI - Mitochondrial morphology and dynamics in hepatocytes from normal and ethanol-fed rats. AB - Mitochondrial structure and function are central to cell physiology and are mutually interdependent. Mitochondria represent a primary target of the alcohol induced tissue injury, particularly in the liver, where the metabolic effects of ethanol are predominant. However, the effect of ethanol on hepatic mitochondrial morphology and dynamics remain to be established. In the present work, we employed the organelle-targeted photoactivatable fluorescent protein technology and electron microscopy to study hepatic mitochondrial structure and dynamics. Hepatocytes in perfused liver as well as in primary cultures showed mostly discrete globular or short tubular mitochondria. The mitochondria showed few fusion events and little movement activity. By contrast, human hepatoma (HepG2) derived VL-17A cells, expressing the major hepatic ethanol metabolizing enzymes, alcohol dehydrogenase and cytochrome P450 2E1, have elongated and interconnected mitochondria showing matrix continuity and many fusion events. Hepatocytes isolated from chronically ethanol-fed rats showed some increase in mitochondrial volume and exhibited a substantial suppression of mitochondrial dynamics. In VL 17A cells, prolonged ethanol exposure also caused decreased mitochondrial continuity and dynamics. Collectively, these results indicate that mitochondria in normal hepatocytes show relatively slow dynamics, which is very sensitive to suppression by ethanol exposure. PMID- 22526460 TI - Regulation of the mitochondrial proton gradient by cytosolic Ca2+ signals. AB - Mitochondria convert the energy stored in carbohydrate and fat into ATP molecules that power enzymatic reactions within cells, and this process influences cellular calcium signals in several ways. By providing ATP to calcium pumps at the plasma and intracellular membranes, mitochondria power the calcium gradients that drive the release of Ca2+ from stores and the entry of Ca2+ across plasma membrane channels. By taking up and subsequently releasing calcium ions, mitochondria determine the spatiotemporal profile of cellular Ca2+ signals and the activity of Ca2+-regulated proteins, including Ca2+ entry channels that are themselves part of the Ca2+ circuitry. Ca2+ elevations in the mitochondrial matrix, in turn, activate Ca2+-dependent enzymes that boost the respiratory chain, increasing the ability of mitochondria to buffer calcium ions. Mitochondria are able to encode and decode Ca2+ signals because the respiratory chain generates an electrochemical gradient for protons across the inner mitochondrial membrane. This proton motive force (Deltap) drives the activity of the ATP synthase and has both an electrical component, the mitochondrial membrane potential (DeltaPsi(m)), and a chemical component, the mitochondrial proton gradient (DeltapH(m)). DeltaPsi(m) contributes about 190 mV to Deltap and drives the entry of Ca2+ across a recently identified Ca2+-selective channel known as the mitochondrial Ca2+ uniporter. DeltapH(m) contributes ~30 mV to Deltap and is usually ignored or considered a minor component of mitochondria respiratory state. However, the mitochondrial proton gradient is an essential component of the chemiosmotic theory formulated by Peter Mitchell in 1961 as DeltapH(m) sustains the entry of substrates and metabolites required for the activity of the respiratory chain and drives the activity of electroneutral ion exchangers that allow mitochondria to maintain their osmolarity and volume. In this review, we summarize the mechanisms that regulate the mitochondrial proton gradient and discuss how thermodynamic concepts derived from measurements in purified mitochondria can be reconciled with our recent findings that mitochondria have high proton permeability in situ and that DeltapH(m) decreases during mitochondrial Ca2+ elevations. PMID- 22526461 TI - Hepatic multiple myelolipoma with severe coelomic edema in a red-bellied tamarin (Saguinus labiatus). AB - This report describes hepatic multiple myelolipoma with severe coelomic edema in a 14-year-old, male red-bellied tamarin (Saguinus labiatus). Multiple small and large nodules were formed in all lobes of the liver. Histopathologically, the nodules comprised mature and normal adipocytes and hematopoietic elements at various ratios that were composed of granulocytic, erythrocytic, and megakaryocytic series in various phases of maturation. All nodules were encapsulated and demarcated hepatocytes around masses. Myelolipoma in the liver is rare, and there are no reports of any cases to date. To our knowledge, this is the first report of hepatic multiple myelolipoma in a red-bellied tamarin. PMID- 22526462 TI - Muscle dimensions in the Japanese macaque hand. AB - Macaques have been used as an important paradigm for understanding the neural control mechanisms of human precision grip capabilities. Therefore, we dissected the forearms and hands of two male Japanese macaques to systematically record the muscle mass, fascicle length and physiological cross-sectional area (PCSA). Comparisons of the mass fractions and PCSA fractions of the hand musculature among the Japanese macaque, chimpanzee, and human demonstrated that the sizes of the thenar and hypothenar eminence muscle groups are more balanced in the macaque and chimpanzee, but those of the thenar eminence group are much larger in the human, indicating that the capacity to generate force at the tip of the thumb is more restricted in macaques, despite their high manual dexterity. In the macaque, however, the extrinsic flexor muscles are much larger, possibly to facilitate weight bearing by the forelimbs in pronograde quadrupedal locomotion and forceful grasping of arboreal supports in gap-crossing movements such as leaping. Taking such anatomical differences imposed on the hand musculoskeletal system into consideration seems to be an important method of clarifying the mechanisms of precision grip in macaques. PMID- 22526463 TI - Phosphine-catalyzed intramolecular gamma-umpolung addition of alpha aminoalkylallenic esters: facile synthesis of 3-carbethoxy-2-alkyl-3-pyrrolines. AB - An array of N-tosylated alpha-aminoalkylallenic esters was prepared and their cyclization under the influence of nucleophilic phosphine catalysts was explored. The alpha-aminoalkylallenic esters were prepared through aza-Baylis-Hillman reactions or novel DABCO-mediated decarboxylative rearrangements of allenylic carbamates. Conversion of these substrates to 3-carbethoxy-2-alkyl-3-pyrrolines was facilitated through Ph(3)P-catalyzed intramolecular gamma-umpolung addition. PMID- 22526464 TI - Comparative study of the interaction of fullerenol nanoparticles with eukaryotic and bacterial model membranes using solid-state NMR and FTIR spectroscopy. AB - Native fullerene is notoriously insoluble in water and forms aggregates toxic to cell membranes, thus limiting its use in nanomedicine. In contrast, water-soluble fullerenol is compatible with biological systems and shows low in vivo toxicity on human cell lines. The interaction mechanism between these hydrophilic nanoparticles and biological membranes is however not well understood. Therefore, in this work, the effect of fullerenol on model eukaryotic and bacterial membranes was investigated using (31)P- and (2)H solid-state NMR as well as FTIR spectroscopy. DPPC/cholesterol and DPPC/DPPG bilayers were used to mimic eukaryotic and bacterial cell membranes, respectively. Our results show low affinity of fullerenol for DPPC/cholesterol bilayers but a clear interaction with model bacterial membranes. A preferential affinity of fullerenol for the anionic phospholipids DPPG in DPPC/DPPG membranes is also observed. Our data suggest that fullerenol remains at the water/bilayer interface of eukaryote-like membranes. They also indicate that the presence of a polar group such as DPPG's hydroxyl moiety at the bilayer surface plays a key role in the interaction of fullerenol with membranes. Hydrogen bonding of fullerenol nanoparticles with DPPGs' OH groups is most likely responsible for inducing lipid segregation in the lipid bilayer. Moreover, the location of the nanoparticles in the polar region of DPPG rich regions appears to disturb the acyl chain packing and increase the membrane fluidity. The preferential interaction of fullerenol with lipids mostly found in bacterial membranes is of great interest for the design of new antibiotics. PMID- 22526465 TI - Dihydrolipoic acid reduces cytochrome b561 proteins. AB - Cytochrome b561 (Cyt-b561) proteins constitute a family of trans-membrane proteins that are present in a wide variety of organisms. Two of their characteristic properties are the reducibility by ascorbate (ASC) and the presence of two distinct b-type hemes localized on two opposite sides of the membrane. Here we show that the tonoplast-localized and the putative tumor suppressor Cyt-b561 proteins can be reduced by other reductants than ASC and dithionite. A detailed spectral analysis of the ASC-dependent and dihydrolipoic acid (DHLA)-dependent reduction of these two Cyt-b561 proteins is also presented. Our results are discussed in relation to the known antioxidant capability of DHLA as well as its role in the regeneration of other antioxidant compounds of cells. These results allow us to speculate on new biological functions for the trans membrane Cyt-b561 proteins. PMID- 22526466 TI - Solid-phase synthesis of tetrasubstituted pyrrolo[2,3-d]pyrimidines. AB - A facile solid phase synthesis of 2,4,6,7-tetrasubstituted pyrrolo[2,3 d]pyrimidines is described. The synthesis involves a highly efficient five-step route starting from resin-bound dimeric peptoids. To demonstrate the versatility of our method, a representative library of 108 tetrasubstituted pyrrolo[2,3 d]pyrimidines of high quality was synthesized. PMID- 22526467 TI - Human neural stem cells genetically modified to express human nerve growth factor (NGF) gene restore cognition in the mouse with ibotenic acid-induced cognitive dysfunction. AB - Alzheimer's disease (AD) is characterized by degeneration and loss of neurons and synapses throughout the brain, causing the progressive decline in cognitive function leading to dementia. No effective treatment is currently available. Nerve growth factor (NGF) therapy has been proposed as a potential treatment of preventing degeneration of basal forebrain cholinergic neurons in AD. In a previous study, AD patient's own fibroblasts genetically modified to produce NGF were transplanted directly into the brain and protected cholinergic neurons from degeneration and improved cognitive function in AD patients. In the present study, human neural stem cells (NSCs) are used in place of fibroblasts to deliver NGF in ibotenic acid-induced learning-deficit rats. Intrahippocampal injection of ibotenic acid caused severe neuronal loss, resulting in learning and memory deficit. NGF protein released by F3.NGF human NSCs in culture medium is 10-fold over the control F3 naive NSCs at 1.2 ug/10(6) cells/day. Overexpression of NGF in F3.NGF cells induced improved survival of NSCs from cytotoxic agents H2O2, Abeta, or ibotenic acid in vitro. Intrahippocampal transplantation of F3.NGF cells was found to express NGF and fully improved the learning and memory function of ibotenic acid-challenged animals. Transplanted F3.NGF cells were found all over the brain and differentiated into neurons and astrocytes. The present study demonstrates that human NSCs overexpressing NGF improve cognitive function of learning-deficit model mice. PMID- 22526468 TI - Epidemiology and clinical presentations of celiac disease. AB - Evidence of the prevalence of celiac disease comes from serological screening studies. These have revealed that celiac disease is common, occurring in about 1 % of the population worldwide. There are some countries with higher prevalence rates such as Finland and others with lower rates, for example Germany. The disease is found in most continents and appears to be increasing. Most people with the disease are not currently diagnosed though women are diagnosed more frequently than men. The mode of presentation has changed both in children and adults with diarrhea and a malabsorption syndrome becoming less common. Abdominal pain and growth issues are major modes of presentation in children, while anemia, osteoporosis, and recognition at endoscopy performed for GERD are seen as modes of presentation in adults. Screening of at risk groups is a major mode of presentation for both adults and children. PMID- 22526469 TI - Thymoquinone improves aging-related endothelial dysfunction in the rat mesenteric artery. AB - Aging-related endothelial dysfunction is characterized by blunted nitric oxide (NO)- and endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxations in arteries, which may be due, at least in part, to increased oxidative stress. Endothelial dysfunction will promote the initiation and development of major cardiovascular diseases such as atherosclerosis and hypertension. Thymoquinone (TQ) is the most active constituent of the volatile oil of Nigella sativa seeds with well-documented antioxidative properties and vasodilator effects. This study determined whether TQ improves the endothelial function in middle-aged rats. Control young rats (16 weeks) received solvent (ethanol, 3% v/v), and middle-aged rats (46 weeks) either solvent or TQ (10 mg/kg/day) in the drinking water. Mesenteric artery reactivity was determined in organ chambers, vascular oxidative stress by dihydroethidine and MitoSOX staining, and expression of target proteins by immunohistochemical staining. Aging-related blunted NO- and EDHF-mediated responses were associated with downregulation of endothelial NO synthase (eNOS) and calcium-activated potassium channels (SK(Ca) and IK(Ca)) expression. Endothelial dysfunction was also associated with oxidative stress and an upregulation of angiotensin II and AT1 receptor expressions. Intake of TQ for 14 days restored NO- and EDHF-mediated relaxations, normalized oxidative stress, the expression level of eNOS, SK(Ca), IK(Ca), and the components of the angiotensin system in the mesenteric artery of middle-aged rats. Thus, TQ improves endothelial function in aging, at least in part, through inhibition of oxidative stress and normalization of the angiotensin system. TQ may represent a novel therapeutic approach for aging-associated vascular diseases. PMID- 22526470 TI - Selective inhibitors of cardiac ADPR cyclase as novel anti-arrhythmic compounds. AB - ADP-ribosyl cyclases (ADPRCs) catalyse the conversion of nicotinamide adenine dinucleotide to cyclic adenosine diphosphoribose (cADPR) which is a second messenger involved in Ca(2+) mobilisation from intracellular stores. Via its interaction with the ryanodine receptor Ca(2+) channel in the heart, cADPR may exert arrhythmogenic activity. To test this hypothesis, we have studied the effect of novel cardiac ADPRC inhibitors in vitro and in vivo in models of ventricular arrhythmias. Using a high-throughput screening approach on cardiac sarcoplasmic reticulum membranes isolated from pig and rat and nicotinamide hypoxanthine dinuleotide as a surrogate substrate, we have identified potent and selective inhibitors of an intracellular, membrane-bound cardiac ADPRC that are different from the two known mammalian ADPRCs, CD38 and CD157/Bst1. We show that two structurally distinct cardiac ADPRC inhibitors, SAN2589 and SAN4825, prevent the formation of spontaneous action potentials in guinea pig papillary muscle in vitro and that compound SAN4825 is active in vivo in delaying ventricular fibrillation and cardiac arrest in a guinea pig model of Ca(2+) overload-induced arrhythmia. Inhibition of cardiac ADPRC prevents Ca(2+) overload-induced spontaneous depolarizations and ventricular fibrillation and may thus provide a novel therapeutic principle for the treatment of cardiac arrhythmias. PMID- 22526471 TI - Therapeutic potential of 7,8-dimethoxycoumarin on cisplatin- and ischemia/reperfusion injury-induced acute renal failure in rats. AB - This study was designed to investigate the role of 7,8-dimethoxycoumarin on cisplatin- and ischemia/reperfusion (I/R)-induced acute renal failure in rats. Acute renal failure was induced in rats by administration of a single dose of cisplatin (CP) (6 mg/kg, intraperitoneally on day 6) and occlusion of the left renal artery for 45 min (I) and opened for the next 24 h (R). The drug samples of 7,8-dimethoxycoumarin (DMC, 50, 75, and 100 mg/kg) and cyclosporin A (50 MUM/kg) were administered orally for six consecutive days. Administration of a single dose of cisplatin and I/R event has significantly raised blood urea nitrogen and creatinine, N-acetyl beta-D: -glucosaminidase, and thiobarbituric acid reactive substances but decreased FrNa, creatinine clearance, reduced glutathione (GSH), mitochondrial cytochrome c oxidase, and adenosine triphosphate levels. Further, pretreatment of DMC (50, 75, and 100 mg/kg, p.o., for six consecutive days) has ameliorated the CP- and I/R-induced biochemical and histopathological changes in a dose-dependent manner. Furthermore, 75 and 100 mg/kg of 7,8-dimethoxycoumarin has shown to possess the significant renoprotective effect similar to that of the cyclosporin A-treated group which served as positive control. Based on the results of the present study, it has been concluded that 7,8-dimethoxycoumarin protects the kidney against the CP and I/R injury via antioxidant, anti inflammatory, and inactivation of mitochondrial permeability transition pore opening. PMID- 22526474 TI - Evaluation of 20 years experience of fibrodysplasia ossificans progressiva in Iran: lessons for early diagnosis and prevention. AB - Fibrodysplasia ossificans progressiva (FOP) is a rare genetic inflammatory disorder characterized by progressive heterotopic ossification presenting as recurrent soft tissue masses and swelling which may cause disabling, restricted joint mobility. Congenital malformations of the hallux are characteristic features of classic FOP, predating the appearance of disabling features. As no definite treatment is available, the early diagnosis and prevention of exacerbating factors may lead to significant benefits in terms of the life quality of patients. A retrospective study of 12 consecutive FOP patients referred to and admitted in the rheumatology unit at an urban tertiary care academic center between 1991 and 2011. Data, such as age, gender, and past medical history, were collected from the medical history, physical examination, and skeletal survey in order to characterize the clinical presentations. All 12 children (six boys and six girls; ages 2.0-13.5 years) had congenital malformations of the great toes (microdactyly and hallux valgus deformity), in addition to heterotopic ossification presenting as multiple soft tissue tumor like swellings. Spinal involvement, most notably in the cervical region, suggestive of an early FOP, was present in 83.3 %. Eleven patients (91.6 %) had a prior history of direct physical trauma, while 7 of 11 (63.6 %) had undergone invasive diagnostic procedures, both correlating with the exacerbations of their condition. Clinical awareness of fibrodysplasia ossificans progressiva and its early diagnostic features, particularly congenital malformations of the hallux, during a thorough neonatal examination may lead to an early diagnosis preventing the development of disabling, practically irreversible lesions of heterotopic ossification. Genetic and molecular studies can play a considerable role in the diagnosis of FOP in suspected cases. Early institution of prophylactic and precautionary measures, such as categorical avoidance of trauma and invasive procedures, can significantly reduce the debilitating acute exacerbations of the condition. PMID- 22526472 TI - Aspirin metabolites are GPR35 agonists. AB - Aspirin is widely used as an anti-inflammatory, anti-platelet, anti-pyretic, and cancer-preventive agent; however, the molecular mode of action is unlikely due entirely to the inhibition of cyclooxygenases. Here, we report the agonist activity of several aspirin metabolites at GPR35, a poorly characterized orphan G protein-coupled receptor. 2,3,5-Trihydroxybenzoic acid, an aspirin catabolite, was found to be the most potent GPR35 agonist among aspirin metabolites. Salicyluric acid, the main metabolite of aspirin, was also active. These results suggest that the GPR35 agonist activity of certain aspirin metabolites may contribute to the clinical features of aspirin. PMID- 22526475 TI - Normal QT dispersion in colchicine-resistant familial Mediterranean fever (FMF). AB - The association between familial Mediterranean fever (FMF) and subclinical cardiac disease remains controversial. The aim of the current study was to evaluate whether FMF patients, who do not respond to colchicine treatment, and thereby endure persistent inflammation, have increased QT dispersion (QTd) values. Twenty-two FMF patients and 22 age- and sex-matched control subjects were included in the study. Repolarization and QT dispersion parameters were computed from 12-lead ECG recording using designated computer software, and results of five beats were subsequently averaged. Both FMF patients and controls had similar comorbidities, similar values of average QT, average corrected QT interval length, average QTd interval, average QT corrected dispersion, QT dispersion ratio, JT dispersion (JTd), and JT corrected dispersion. In conclusion, FMF patients who were unresponsive to colchicine treatment and did not develop amyloidosis had normal QTd and JTd parameters, indicating a non-increased risk for repolarization-associated ventricular arrhythmias. PMID- 22526476 TI - Validity and reliability of the Persian versions of WOMAC Osteoarthritis Index and Lequesne Algofunctional Index. AB - The WOMAC Osteoarthritis Index and Lequesne Algofunctional Index have not been translated and validated for Iranian patients with osteoarthritis (OA) of the knee or hip. The aim of this study was to validate the Persian form of WOMAC OA Index and Lequesne Algofunctional Index and to assess their test-retest reliability and convergent validity. Forward/backward translations and consensus panels were conducted to obtain the Persian versions of WOMAC OA Index and Lequesne Algofunctional Index. A non-probability sample of 116 patients with knee/hip osteoarthritis was asked to complete the WOMAC OA Index and Lequesne Algofunctional Index as well as Medical Outcomes Study-20-Item Short Form (SF-20) questionnaires, a visual analogue scales (VAS) of pain and demographic information form. Internal consistency (using Cronbach's alpha) and convergent validity (by examining the Pearson's correlation coefficients) were evaluated to determine the psychometric properties of the questionnaires. In order to evaluate test-retest reliability, 20 randomly selected patients completed the questionnaires, on a second occasion, 7-10 days later. Cronbach's alpha coefficients and intraclass correlation coefficients for the WOMAC OA Index and Algofunctional Index subscales ranged from 0.63 to 0.94 and from 0.53 to 0.96, respectively. Statistically significant correlations were found between WOMAC OA Index, Algofunctional Index and SF-20 subscales and VAS for pain. The Persian version of WOMAC demonstrated a more acceptable validity, internal consistency and reliability compared with the Lequesne Algofunctional Index. However, both indices are valid and reliable instruments for evaluating the OA severity of knee/hip in Iran. PMID- 22526477 TI - Hearing and cochlear function of patients with ankylosing spondylitis. AB - Ankylosing spondylitis (AS) is a chronic systemic inflammatory disorder that primarily affects the spine and sacroiliac joints. Recent studies described audiovestibular impairment in AS patients. The aim of this study was to evaluate the hearing and function of the cochlear system in patients with AS. Thirty-seven AS patients and 20 healthy controls were evaluated prospectively. Otorhinolaryngologic examinations were performed in all patients together with pure tone audiometry, speech discrimination test, tympanometry, and distortion product otoacoustic emission (DPOE). Disease duration, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores, and hematologic findings (CRP and ESR) were also collected. Pure tone audiometry findings of the patients and controls were significantly different in all frequencies (p < 0.01). Speech discrimination scores were also significantly different (p < 0.01). No significant difference was found between DPOE responses of the patients and controls (p > 0.05). There was no correlation between disease duration, BASDAI scores, hematological findings, and audiometry findings (p > 0.05). This study demonstrated that there is an association between AS and hearing loss, but the cochlea is not the main source of hearing loss. PMID- 22526478 TI - Effect of exercise on cardiac autonomic function in females with rheumatoid arthritis. AB - The objective of this study is to evaluate the effect of exercise on cardiac autonomic function as measured by short-term heart rate variability (HRV) in females suffering from rheumatoid arthritis (RA). Females with confirmed RA were randomly assigned to an exercise group (RAE) and a sedentary group (RAC). RAE was required to train under supervision two to three times per week, for 3 months. Three techniques (time domain, frequency domain and Poincare plot analyses) were used to measure HRV at baseline and study completion. At baseline, RAC (n = 18) had a significantly higher variability compared to RAE (n = 19) for most HRV indicators. At study completion, the variables showing significant changes (p = 0.01 to 0.05) favoured RAE in all instances. Wilcoxon signed rank tests were performed to assess changes within groups from start to end. RAE showed significant improvement for most of the standing variables, including measurements of combined autonomic influence, e.g. SDRR (p = 0.002) and variables indicating only vagal influence, e.g. pNN50 (p = 0.014). RAC mostly deteriorated with emphasis on variables measuring vagal influence (RMSSD, pNN50, SD1 and HF (ms(2)). Study results indicated that 12 weeks of exercise intervention had a positive effect on cardiac autonomic function as measured by short-term HRV, in females with RA. Several of the standing variables indicated improved vagal influence on the heart rate. Exercise can thus potentially be used as an instrument to improve cardiac health in a patient group known for increased cardiac morbidity. PMID- 22526479 TI - Treatment of dyslipidemia in idiopathic inflammatory myositis: results of the International Myositis Assessment and Clinical Studies Group survey. AB - Recent data suggest that atherosclerotic disease is increased in patients with idiopathic inflammatory myositis (IIM) and that dyslipidemia is a significant risk factor for cardiovascular events. Lipid-lowering agents may be associated with myopathic side effects. The current work evaluates the use of lipid-lowering therapy in patients with IIM treated by IIM specialists belonging to the International Myositis Assessment and Clinical Studies (IMACS) Group. The IMACS Group is a multidisciplinary coalition of experts with significant interest and experience in IIM. IMACS members were asked to complete an 18-item online survey detailing their clinical practice on monitoring and treating hypercholesterolemia in IIM patients. Specific questions regarding the types of lipid-lowering therapies used in IIM patients and any side effects associated with treatment were asked. Sixty-three IMACS members representing 23 countries and a minimum of 1,641 IIM patients participated in the online survey. Seventy-six percent of these specialists treating adult IIM patients use lipid-lowering therapies in their patients. HMG co-enzymeA reductase inhibitors (statins) were the most commonly used agents (93 %). Thirty-six cases of worsening myositis associated with statin use were reported in over 300 patients using lipid-lowering therapies. Seven of eight responders who reported worsening in myositis with lipid-lowering therapies reported cases in which the myositis improved after holding therapy. This survey suggests that statins are commonly used by physicians specializing in the treatment of patients with IIM and that some myositis patients worsen with statin use and may improve on dechallenge. More research regarding the safety of lipid-lowering agents in patients with IIM is warranted. PMID- 22526480 TI - Distribution of effusion in knee arthritis as measured by high-resolution ultrasound. AB - Information about the distribution of effusion within the arthritic knee joint should be considered in selecting an anatomical approach for arthrocentesis. We recorded ultrasound measurements of fluid distribution in the knees of patients attending our clinic for knee injections under ultrasound guidance. In a cross sectional observational study, we used high-resolution ultrasound (US) to record measurements of maximum fluid depth in the medial, midline and lateral regions of the suprapatellar pouch (SPP) in 46 patients with arthritis attending for routine US-guided injection of the knee. Mean fluid depth [in millimetres, (SD)] was significantly greater in the lateral SPP [9.2 (5.1)] than in the medial [6.5 (4.6)] or the midline [5.9 (3.7)] regions with the knee in relaxed full extension (p < 0.001 for comparison of lateral SPP with both midline and medial SPP). Small effusions were more commonly detected in the lateral SPP than elsewhere. In patients with painful knee arthritis, fluid distributes maximally to the lateral SPP in the extended knee. This has implications regarding the anatomical approach to arthrocentesis that clinicians should choose to perform and teach. PMID- 22526481 TI - Risk of malignancy in follicular thyroid neoplasm: predictive value of thyrotropin. AB - The cytological diagnosis of follicular neoplasm is a common finding in fine needle aspiration cytology (FNAC) of thyroid nodules and includes benign disease as well as differentiated thyroid cancer. The aim of the study is to determine if thyrotropin is a predictive factor for a malignant nature of follicular neoplasm. PATIENTS, METHODS: The records of 119 patients with follicular neoplasm on FNAC, who underwent surgery for final diagnosis, were reviewed retrospectively. The predictive value of serum parameters including thyrotropin, thyroglobulin, and anti-thyroid antibodies, ultrasonographic criteria and clinical variables was evaluated by univariate analysis and logistic regression analysis. RESULTS, DISCUSSION: Patients with malignant nodules showed a higher thyrotropin concentration compared to patients with benign nodules (median 1.6 mU/l, interquartile range 1.4-3.0 mU/l vs. median 1.2 mU/l, interquartile range 0.8-1.6 mU/l, p < 0.01). ROC-analysis of thyrotropin revealed an optimal cut off value to differentiate benign and malignant nodules of 1.34 mU/l. The incidence of malignancy was 30.3% for a thyrotropin concentration higher than 1.34 mU/l compared to 6.4% for a thyrotropin concentration lower than or equal to 1.34 mU/l. On univariate analysis thyroglobulin higher than 300 ng/ml, positive anti thyroid antibodies, hypoechogenicity, and ill-defined margins, respectively, were also significantly associated with malignancy. On logistic regression analysis higher thyrotropin concentrations, ill-defined margins, and thyroglobulin higher than 300 ng/ml, respectively, were independent predictive factors for malignancy (OR 20.0, 10.7, and 22.7, respectively). CONCLUSION: Higher thyrotropin concentrations are predictive for a malignant nature of follicular neoplasm. PMID- 22526483 TI - Renal disease progression in autosomal dominant polycystic kidney disease. AB - BACKGROUND: Autosomal dominant polycystic kidney disease is a lifelong progressive disorder. However, how age, blood pressure, and stage of chronic kidney disease (CKD) affect the rate of kidney function deterioration is not clearly understood. METHODS: In this long-term observational case study up to 13.9 years (median observation period for slope was 3.3 years), serum creatinine was serially measured in 255 mostly adult patients. The glomerular filtration rate was estimated (eGFR) using a modified Modification of Diet in Renal Disease Study method. The total kidney volume (TKV) has been measured in 86 patients at one center since 2006. RESULTS: As age increased, eGFR declined significantly (P < 0.0001), but the annual rate of decline of eGFR did not correlate with age or initially measured eGFR. In patients with CKD stage 1, eGFR declined at a rate which was not significantly different from other advanced CKD stages. Hypertensive patients had lower eGFR and larger TKV than normotensive patients at a young adult age. The slopes of regression lines of eGFR and TKV in relation to age were not different between high and normal blood pressure groups. CONCLUSION: The declining rate of eGFR was relatively constant and did not correlate with age or eGFR after adolescence. eGFR was already low in young adult patients with hypertension. As age increased after adolescence, eGFR declined and TKV increased similarly between normal and high blood pressure groups. eGFR starts to decline in patients with normal eGFR, suggesting that the decline starts earlier than previously thought. PMID- 22526484 TI - Updated height- and creatinine-based equation and its validation for estimation of glomerular filtration rate in children from developing countries. AB - BACKGROUND: Since the original Schwartz formula overestimates glomerular filtration rate (GFR), it is proposed that the constant (k) that accounts for the method of creatinine estimation be derived locally. We derived a new k for height (cm)/serum creatinine (mg/dl) (ht/scr) equation by regression analysis. METHODS: In a cross-sectional observational study, 197 children (2-18 years) with chronic kidney disease (CKD), who underwent reference GFR measurement by plasma clearance of diethylenetriamine pentaacetic acid (dGFR) at a tertiary care hospital, formed the index dataset for deriving the prediction equations for estimating GFR. Serum creatinine was estimated by the kinetic Jaffe method. The prediction equations were validated on a separate cohort of 225 children with CKD. RESULTS: The median creatinine was 0.7 mg/dl and dGFR was 80.5 (interquartile range 18.1-137.5) ml/min/1.73 m(2). The new k (regression coefficient of height/creatinine) was 0.42 (R(2) = 0.61) and the updated equation was GFR = 0.42 * (ht/scr). Addition of age and mid-arm circumference (MAC) to this equation improved R (2) to 62.3%. Based on the above parameters, the new equation for estimating GFR was GFR (ml/min/1.73 m(2)) = 0.257 * [ht/scr](0.95) * [age (year)](-0.19) * [MAC (cm)](0.397). The two equations performed comparably, with a mean bias <2 ml/min/1.73 m(2). The updated ht/scr equation yielded 74% and 24% estimated GFR values that were within 30% and 10% of the measured dGFR, respectively. CONCLUSIONS: The updated equation, with a k value of 0.42, provides a reasonably accurate bedside estimate of GFR in children in countries where creatinine is estimated by the kinetic Jaffe method. PMID- 22526485 TI - Transcatheter renal artery embolization improves lung function in patients with autosomal dominant polycystic kidney disease on hemodialysis. AB - BACKGROUND: Since 1996, transcatheter renal artery embolization (renal TAE) has been performed to reduce the volume of the kidneys in patients with autosomal dominant polycystic kidney disease (ADPKD) and complications of nephromegaly at our hospital. Respiratory dysfunction is often a serious problem in these patients before TAE. PATIENTS AND METHODS: Between January 2006 and October 2008, renal TAE was performed and lung function testing [percent vital capacity (%VC) and percent forced expiratory volume in 1 s (%FEV(1.0))] was done by spirometry in 28 patients on maintenance hemodialysis who had respiratory symptoms. RESULTS: Renal volume was 6,330.5 +/- 3,126.5 cm(3) (range 1,771-12,761 cm(3)) before TAE, and decreased significantly to 2,892.2 +/- 1,841.7 cm(3) (range 622-6,961 cm(3)) by 12 months after TAE (p = 0.0001). The percent decrease of renal volume at 12 months after TAE versus baseline was 45.6 +/- 14.6% (range 6.6-67.3%). %VC showed a significant increase from 95.9 +/- 14.8% (range 63-127%) before renal TAE to 100.1 +/- 11.7% (range 78-120%) at 12 months after TAE (p < 0.01). %FEV(1.0) was also significantly increased from 87.9 +/- 15.0% (range 55-110%) before renal TAE to 92.5 +/- 14.4% (range 58.0-115.0%) at 12 months after TAE (p < 0.01). The changes of VC (DeltaVC%) and FEV(1.0) (DeltaFEV(1.0)%) both showed a significant positive correlation with the reduction of renal volume (Delta renal volume) (p = 0.001 and p = 0.004, respectively). CONCLUSION: Since TAE not only led to a significant decrease of renal volume in ADPKD patients with nephromegaly, but also improved lung function (both %VC and %FEV(1.0)), pulmonary dysfunction should be recognized as one of the extrarenal complications of ADPKD. PMID- 22526486 TI - Phenotypic change of macrophages in the progression of diabetic nephropathy; sialoadhesin-positive activated macrophages are increased in diabetic kidney. AB - BACKGROUND: Inflammatory process is involved in pathogenesis of diabetic nephropathy, although the activation and phenotypic change of macrophages in diabetic kidney has remained unclear. Sialoadhesin is a macrophage adhesion molecule containing 17 extracellular immunoglobulin-like domains, and is an I type lectin which binds to sialic acid ligands expressed on hematopoietic cells. The aim of this study is to clarify the activation and phenotypic change of macrophages in the progression of diabetic nephropathy. METHODS: We examined the expression of surface markers for pan-macrophages, resident macrophages, sialoadhesin, major histocompatibility complex class II and alpha-smooth muscle actin in the glomeruli of diabetic rats using immunohistochemistry at 0, 1, 4, 12, and 24 weeks after induction of diabetes by streptozotocin. Expression of type IV collagen and the change of mesangial matrix area were also measured. The mechanism for up-regulated expression of sialoadhesin on macrophages was evaluated in vitro. RESULTS: The number of macrophages was increased in diabetic glomeruli at 1 month after induction of diabetes and the increased number was maintained until 6 months. On the other hand, sialoadhesin-positive macrophages were increased during the late stage of diabetes concomitantly with the increase of alpha-smooth muscle actin-positive mesangial cells, mesangial matrix area and type IV collagen. Gene expression of sialoadhesin was induced by stimulation with interleukin (IL)-1beta and tumor necrosis factor-alpha but not with IL-4, transforming growth factor-beta and high glucose in cultured human macrophages. CONCLUSION: The present findings suggest that sialoadhesin-positive macrophages may contribute to the progression of diabetic nephropathy. PMID- 22526488 TI - Effects of veraguensin and galgravin on osteoclast differentiation and function. AB - The dried flower buds of Magnolia sp. are widely used as herbal medicines because of their anti-inflammatory, anti-malarial and anti-platelet activities. Here, we found that veraguensin and galgravin, lignan compounds derived from Magnolia sp., dose-dependently inhibited osteoclast formation in co-cultures of bone marrow cells and osteoblastic cells. These compounds also inhibited receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclast differentiation in RAW264.7 cells and bone marrow macrophages. In the RANKL-induced signaling pathway, veraguensin and galgravin reduced p38 phosphorylation and suppressed the expression of c-Fos, a key transcription factor for osteoclastogenesis. Veraguensin and galgravin also inhibited osteoclastic pit formation, which was accompanied by decreased mature osteoclast viability. In conclusion, these results indicate that veraguensin and galgravin can inhibit bone resorption and may offer novel compounds for the development of drugs to treat bone-destructive diseases such as osteoporosis. PMID- 22526487 TI - Protein-energy wasting and peritoneal function in elderly peritoneal dialysis patients. AB - BACKGROUND: Nutritional status is important in peritoneal dialysis (PD) patients. We aimed to compare the peritoneal transport (PT) characteristics and indicators of nutritional status in elderly and non-elderly PD patients. METHODS: One hundred and four consecutive patients were divided into either the elderly (>65 years old; n = 44) or the non-elderly (<=65 years old; n = 60) group. PT was assessed via the peritoneal equilibration test, Kt/V (K dialyzer clearance of urea, t dialysis time, V volume of distribution of urea), total creatinine clearance (CrCl), and glomerular filtration rate. Subjective global assessment (SGA), serum albumin (ALB), hemoglobin, prealbumin (PA), transferrin (TF), fat free edema-free body mass (fat-free edema-free BM), and normalized protein intake (nPNA) were determined, and were used to indicate nutritional status. RESULTS: Elderly PD patients had higher dialysate to plasma creatinine ratios (D/P Cr) and CrCl, but lower serum creatinine body weights, ALB, PA, TF, fat-free edema-free BM, SGA, and nPNA than the non-elderly group. Multivariate analysis indicated that, after adjusting for PD time, body weight, diabetes mellitus, age, and sex, SGA negatively correlated with D/P Cr, whereas after adjusting for PD time, diabetes mellitus, and sex, D/P Cr positively correlated with age in all patients. CONCLUSIONS: Protein-energy wasting and a high PT are more common in elderly than non-elderly PD patients. Nutritional status should be carefully considered when prescribing the PD dose and frequency, especially in elderly patients. PMID- 22526489 TI - A new flow co-culture system for studying mechanobiology effects of pulse flow waves. AB - Artery stiffening is known as an important pathological change that precedes small vessel dysfunction, but underlying cellular mechanisms are still elusive. This paper reports the development of a flow co-culture system that imposes a range of arterial-like pulse flow waves, with similar mean flow rate but varied pulsatility controlled by upstream stiffness, onto a 3-D endothelial-smooth muscle cell co-culture. Computational fluid dynamics results identified a uniform flow area critical for cell mechanobiology studies. For validation, experimentally measured flow profiles were compared to computationally simulated flow profiles, which revealed percentage difference in the maximum flow to be <10, <5, or <1% for a high, medium, or low pulse flow wave, respectively. This comparison indicated that the computational model accurately demonstrated experimental conditions. The results from endothelial expression of proinflammatory genes and from determination of proliferating smooth muscle cell percentage both showed that cell activities did not vary within the identified uniform flow region, but were upregulated by high pulse flow compared to steady flow. The flow system developed and characterized here provides an important tool to enhance the understanding of vascular cell remodeling under flow environments regulated by stiffening. PMID- 22526490 TI - Osteogenic differentiation of human placenta-derived mesenchymal stem cells (PMSCs) on electrospun nanofiber meshes. AB - Numerous challenges remain in the successful clinical translation of cell-based therapeutic studies for skeletal tissue repair, including appropriate cell sources and viable cell delivery systems. Poly(ethylene glycol)-poly(epsilon caprolactone) (PEG-PCL) amphiphilic block copolymers have been extensively explored in microspheres preparation. Due to the introduction of hydrophilic PEG segments into PCL backbones, these copolymers have shown much more potentials in carrying protein, lipophilic drugs or genes than commonly used poly (epsilon caprolactone) (PCL) and poly (lactic acid). The aim of this study is to investigate the attachment and osteogenic differentiation of human placenta derived mesenchymal stem cells (PMSCs) on PEG-PCL triblock copolymers nanofiber scaffolds. Here we demonstrated that PMSCs proliferate robustly and can be effectively differentiated into osteogenic-like cells on nanofiber scaffolds. This study provides evidence for the use of nanofiber scaffolds as an ideal supporting material for in vitro PMSCs culture and an in vivo cell delivery vehicle for bone repair. PMID- 22526491 TI - Inhibition of leptin gene expression and secretion by silibinin: possible role of estrogen receptors. AB - Leptin plays the role of mitogenic factor in the breast carcinogenesis. Therefore, it could be considered as a target for breast cancer therapy. Leptin gene expression could be modulated by activation of estrogen receptors. Silibinin is an herbal compound with anti-cancer activity on prostate and colorectal cancers. Based on the fact that targeting of leptin can be considered as a novel strategy for breast cancer therapy, the aim of this study was the investigation of potentiality of silibinin for inhibition of leptin gene expression and secretion, and its link with expression of estrogen receptors. Cytotoxic effect of silibinin on T47D breast cancer cells was investigated by MTT assay test after 24, 48 and 72 h treatments with different concentrations of silibinin. The levels of leptin, estrogen receptor alpha and estrogen receptor beta genes expression was measured by reverse-transcription real-time PCR. The amount of secreted leptin in the culture medium was determined by ELISA. Data were statistically analyzed by one-way ANOVA test. Silibinin inhibits growth of T47D cells in a time and dose dependent manner. There was significant difference between control and treated cells in the levels of leptin, estrogen receptor beta expression levels and the quantity of secreted leptin was decreased in the treated cells in comparison to control cells. In conclusion, silibinin inhibits the expression and the secretion of leptin and in the future it might probably be a drug candidate for breast cancer therapy through leptin targeting. PMID- 22526492 TI - In vitro studies on chemoprotective effect of borax against aflatoxin B1-induced genetic damage in human lymphocytes. AB - A common dietary contaminant, aflatoxin B1 (AFB1), has been shown to be a potent mutagen and carcinogen in humans and many animal species. Since the eradication of AFB1 contamination in agricultural products has been rare, the use of natural or synthetic free radical scavengers could be a potential chemopreventive strategy. Boron compounds like borax (BX) and boric acid are the major components of industry and their antioxidant role has recently been reported. In the present report, we evaluated the capability of BX to inhibit the rate of micronucleus (MN) and sister chromatid exchange (SCE) formations induced by AFB1. There were significant increases (P < 0.05) in both SCE and MN frequencies of cultures treated with AFB1 (3.12 ppm) as compared to controls. However, co-application of BX (1, 2 and 5 ppm) and AFB1 resulted in decreases of SCE and MN rates as compared to the group treated with AFB1 alone. Borax gave 30-50 % protection against AFB1 induced SCEs and MNs. In conclusion, the support of borax was especially useful in aflatoxin-toxicated blood tissue. Thus, the risk on target tissues of AFB1 could be reduced and ensured early recovery from its toxicity. PMID- 22526493 TI - Dedifferentiated fat cells differentiate into osteoblasts in titanium fiber mesh. AB - Mature adipocyte-derived dedifferentiated fat (DFAT) cells rapidly differentiate into osteoblasts under three-dimensional culture conditions. However, it has not been demonstrated that DFAT cells can differentiate into osteoblasts in a rigid scaffold consisting of titanium fiber mesh (TFM). We examined the proliferation and osteogenic differentiation ability of DFAT cells using TFM as a scaffold. DFAT cells derived from rabbit subcutaneous fat were seeded into TFM and cultured in osteogenic medium containing dexamethasone, L-ascorbic acid 2-phosphate and beta-glycerophosphate for 14 days. In scanning electron microscopy (SEM) analysis, well-spread cells covered the titanium fibers on day 3, and appeared to increase in number from day 3 to 7. Numerous globular accretions were found and almost completely covered the fibers on day 14. Cell proliferation, as measured by DNA content in the TFM, was significantly higher on day 7 compared with that of day 1. Osteocalcin and calcium content in the TFM were significantly higher on day 14 compared to those of days 1, 3, and 7, indicating DFAT cells differentiated into osteoblasts. We theorize that globular accretions observed in SEM analysis may be calcified matrix resulting from osteocalcin secreted by osteoblasts binding calcium contained in fetal bovine serum. In this study, we demonstrated that DFAT cells differentiate into osteoblasts and deposit mineralized matrices in TFM. Therefore, the combination of DFAT cells and TFM may be an attractive option for bone tissue engineering. PMID- 22526494 TI - Altered placental expression of kisspeptin and its receptor in pre-eclampsia. AB - Kisspeptin, originally identified as metastatin, important in preventing cancer metastasis, has more recently been shown to be important in pregnancy. Roles indicated for kisspeptin in pregnancy include regulating trophoblast invasion and migration during placentation. The pregnancy-specific disorder pre-eclampsia (PE) is now accepted to begin with inadequate trophoblast invasion and the current study therefore sets out to characterise placental expression of both kisspeptin (KISS1) and its receptor (KISS1R) throughout pregnancy and in PE. Placental tissue was obtained from women undergoing elective surgical termination of early pregnancy (n=10) and from women following Caesarean section at term in normal pregnancy (n=10) and with PE (n=10). Immunohistochemistry of paraffin embedded sections and western immunoblotting were performed to assess protein localisation and expression. Quantitative real-time PCR was carried out to evaluate mRNA expression of both KISS1 and KISS1R. Protein and mRNA expression was found to mirror each other with KISS1 expression found to be reduced in PE compared with that in normal term pregnancy. Interestingly, KISS1R expression at both the mRNA and protein levels was found to be increased in PE compared with that in normal term pregnancy. The current findings of increased KISS1R expression may represent a mechanism by which functional activity of KISS1 is higher in PE than in normal pregnancy. Higher levels of activity of KISS1R may be involved in inhibition of trophoblast invasion and angiogenesis, which are associated with PE. PMID- 22526495 TI - Nitrogen availability impacts oilseed rape (Brassica napus L.) plant water status and proline production efficiency under water-limited conditions. AB - Large amounts of nitrogen (N) fertilizers are used in the production of oilseed rape. However, as low-input methods of crop management are introduced crops will need to withstand temporary N deficiency. In temperate areas, oilseed rape will also be affected by frequent drought periods. Here we evaluated the physiological and metabolic impact of nitrate limitation on the oilseed rape response to water deprivation. Different amounts of N fertilizer were applied to plants at the vegetative stage, which were then deprived of water and rehydrated. Both water and N depletion accelerated leaf senescence and reduced leaf development. N deprived plants exhibited less pronounced symptoms of wilting during drought, probably because leaves were smaller and stomata were partially closed. Efficiency of proline production, a major stress-induced diversion of nitrogen metabolism, was assessed at different positions along the whole plant axis and related to leaf developmental stage and water status indices. Proline accumulation, preferentially in younger leaves, accounted for 25-85% of the free amino acid pool. This was mainly due to a better capacity for proline synthesis in fully N-supplied plants whether they were subjected to drought or not, as deduced from the expression patterns of the proline metabolism BnP5CS and BnPDH genes. Although less proline accumulated in the oldest leaves, a significant amount was transported from senescing to emerging leaves. Moreover, during rehydration proline was readily recycled. Our results therefore suggest that proline plays a significant role in leaf N remobilization and in N use efficiency in oilseed rape. PMID- 22526496 TI - Arabidopsis BPG2: a phytochrome-regulated gene whose protein product binds to plastid ribosomal RNAs. AB - BPG2 (Brz-insensitive pale green 2) is a dark-repressible and light-inducible gene that is required for the greening process in Arabidopsis. Light pulse experiments suggested that light-regulated gene expression of BPG2 is mediated by phytochrome. The T-DNA insertion mutant bpg2-2 exhibited a reduced level of chlorophyll and carotenoid pigmentation in the plastids. Measurements of time resolved chlorophyll fluorescence and of fluorescence emission at 77 K indicated defective photosystem II and altered photosystem I functions in bpg2 mutants. Kinetic analysis of chlorophyll fluorescence induction suggested that the reduction of the primary acceptor (QA) is impaired in bpg2. The observed alterations resulted in reduced photosynthetic efficiency as measured by the electron transfer rate. BPG2 protein is localized in the plastid stroma fraction. Co-immunoprecipitation of a formaldehyde cross-linked RNA-protein complex indicated that BPG2 protein binds with specificity to chloroplast 16S and 23S ribosomal RNAs. The direct physical interaction with the plastid rRNAs supports an emerging model whereby BPG2 provides light-regulated ribosomal RNA processing functions, which are rate limiting for development of the plastid and its photosynthetic apparatus. PMID- 22526497 TI - The perichromatin region of the plant cell nucleus is the area with the strongest co-localisation of snRNA and SR proteins. AB - The spatial organisation of the splicing system in plant cells containing either reticular (Allium cepa) or chromocentric (Lupinus luteus) nuclei was studied by immunolabelling of SR proteins, snRNA, and the PANA antigen, known markers for interchromatin granule clusters in mammalian cells. Electron microscope results allowed us to determine the distribution of these molecules within the structural domains of the nucleus. Similar to animal cells, in both plant species SR proteins were localised in interchromatin granules, but contrary to animal cells contained very small amounts of snRNA. The area with the strongest snRNA and SR protein co-localisation was the perichromatin region, which may be the location of pre-mRNA splicing in the plant cell nuclei. The only observable differences in the organisation of reticular and chromocentric nuclei were the size of the speckles and the number of snRNA pools in the condensed chromatin. We conclude that, despite remarkable changes in the nuclear architecture, the organisation of the splicing system is remarkably similar in both types of plant cell nuclei. PMID- 22526499 TI - Translational fusion and redirection to thylakoid lumen as strategies to improve the accumulation of a camelid antibody fragment in transplastomic tobacco. AB - Fragments from camelid single-chain antibodies known as VHHs or nanobodies represent a valuable tool in diagnostics, investigation and passive immunity therapy. Here, we explored different strategies to improve the accumulation of a neutralizing VHH antibody against rotavirus in tobacco transplastomic plants. First, we attempted to express the VHH in the chloroplast stroma and then two alternative strategies were carried out to improve the expression levels: expression as a translational fusion to the beta-glucuronidase enzyme (GUS-E VHH), and redirection of the VHH into the thylakoid lumen (pep-VHH). Every attempt to produce transplastomic plants expressing the VHH in the stroma was futile. The transgene turned out to be unstable and the presence of the VHH protein was almost undetectable. Although pep-VHH plants also presented some of the aforementioned problems, higher accumulation of the nanobody was observed (2 3% of the total soluble proteins). The use of beta-glucuronidase as a partner protein turned out to be a successful strategy and expression levels reached 3% of the total soluble proteins. The functionality of the VHHs produced by pep-VHH and GUS-E-VHH plants was studied and compared with that of the antibody produced in Escherichia coli. This work contributes to optimizing the expression of VHH in transplastomic plants. Recombinant proteins could be obtained either by accumulation in the thylakoid lumen or as a fusion protein with beta glucuronidase, and both strategies allow for further optimization. PMID- 22526498 TI - Physiological and molecular changes in plants grown at low temperatures. AB - Apart from water availability, low temperature is the most important environmental factor limiting the productivity and geographical distribution of plants across the world. To cope with cold stress, plant species have evolved several physiological and molecular adaptations to maximize cold tolerance by adjusting their metabolism. The regulation of some gene products represents an additional mechanism of cold tolerance. A consequence of these mechanisms is that plants are able to survive exposure to low temperature via a process known as cold acclimation. In this review, we briefly summarize recent progress in research and hypotheses on how sensitive plants perceive cold. We also explore how this perception is translated into changes within plants following exposure to low temperatures. Particular emphasis is placed on physiological parameters as well as transcriptional, post-transcriptional and post-translational regulation of cold-induced gene products that occur after exposure to low temperatures, leading to cold acclimation. PMID- 22526500 TI - Genome-wide identification of microRNAs in larch and stage-specific modulation of 11 conserved microRNAs and their targets during somatic embryogenesis. AB - MicroRNAs (miRNAs) are emerging as essential regulators of biological processes. Somatic embryogenesis is one of the most important techniques for gymnosperm breeding programs, but there is little understanding of its underlying mechanism. To investigate the roles of miRNAs during somatic embryogenesis in larch, we constructed a small RNA library from somatic embryos. High-throughput sequencing of the library identified 83 conserved miRNAs from 35 families, 16 novel miRNAs, and 14 plausible miRNA candidates, with a high proportion specific to larch or gymnosperms. qRT-PCR analysis demonstrated that both the conserved and novel or candidate miRNAs were expressed in larch. Several miRNA precursor sequences were obtained via RACE. We predicted 110 target genes using bioinformatics, and validated 9 of them by 5' RACE. 11 conserved miRNA families including 17 miRNAs with critical functions in plant development and six target mRNAs were detected by qRT-PCR in the larch SE. Stage-specific expression of miRNAs and their targets indicate their possible modulation on SE of larch: miR171a/b might exert function on PEMs, while miR171c acts in the induction process of larch SE; miR397 and miR398 mainly involved in modulation of PEM propagation and transition to single embryo; miR162 and miR168 exert their regulatory function during total SE process, especially during stages 5-8; miR156, miR159, miR160, miR166, miR167, and miR390 might play regulatory roles during cotyledonary embryo development. These findings indicate that larch and possibly other gymnosperms have complex mechanisms of gene regulation involving specific and common miRNAs operating post transcriptionally during embryogenesis. PMID- 22526501 TI - The response to daylight or continuous ozone of phenylpropanoid and lignin biosynthesis pathways in poplar differs between leaves and wood. AB - Ozone induces a stimulation of the phenylpropanoid and lignin biosynthesis pathways in leaves but the response of wood, the main lignin-producing tissue, is not well documented. The purpose of this study was to compare the responses of phenylpropanoid and lignin pathways in leaves and stem wood by a simultaneous analysis of both organs. Young poplars (Populus tremula*alba) were subjected either to daylight ozone (200 nL L(-1) during light period) or continuous ozone (200 nL L(-1) during light and dark periods) in controlled chambers. The trees were tilted so as to limit the formation of tension wood to the upper side of the stem and that of opposite wood to the lower side. Continuous ozone fumigation induced more pronounced effects in leaves than daylight ozone. Tension wood and opposite wood displayed similar responses to ozone. Enzyme activities involved in phenylpropanoid and lignin biosynthesis increased in the leaves of ozone-treated poplars and decreased in the wood. All steps involved in phenylpropanoid and monolignol synthesis in leaves and stem wood, were also altered at the transcript level (except coniferyl aldehyde 5-hydroxylase in leaves) suggesting that the responses were tightly coordinated. The response occurred rapidly in the leaves and much later in the wood. Phenylpropanoid and lignin biosynthesis is probably first involved in a defensive role against ozone in the leaves, which would lead to considerable rerouting of the carbon skeletons. The later response of phenylpropanoid and lignin metabolism in wood seemed to result from readjustment to the reduced carbon supply. PMID- 22526502 TI - Iron and reactive oxygen responses in Pinus sylvestris root cortical cells infected with different species of Heterobasidion annosum sensu lato. AB - Defence mechanisms in trees are not well understood. We assessed whether distribution of iron ions and their co-localisation with reactive oxygen species in Pinus sylvestris root cells reflect differential preferences of the pathogens Heterobasidion annosum sensu stricto, H. parviporum and H. abietinum to the host. Strains of H. annosum s.s. characterised by a greater preference for P. sylvestris induced accumulation of superoxide (O(2)(-)) in host cells 6 h after inoculation, whereas two peaks in accumulation of O(2)(-) (after 4 and 48 h) were observed after infection with strains of the pathogens H. parviporum and H. abietinum, which have a lower preference for P. sylvestris. Moreover, strains of H. annosum s.s. caused increased production of hydrogen peroxide (H(2)O(2)) in P. sylvestris cells, in contrast with strains of the other two species (H. parviporum and H. abietinum). Following inoculation with H. annosum s.s. strains, H(2)O(2) was correlated negatively with O(2)(-) and correlated positively with ferrous iron (Fe(2+)). Co-localisation of Fe(3+) with H(2)O(2) may suggest that they are involved in inducing hypersensitive responses and eventually cell death in roots inoculated with H. annosum s.s. strains, in contrast with H. parviporum, in which other mechanisms operate when the host is parasitised. PMID- 22526503 TI - Damage to photosystem II due to heat stress without light-driven electron flow: involvement of enhanced introduction of reducing power into thylakoid membranes. AB - Under a moderately heat-stressed condition, the photosystems of higher plants are damaged in the dark more easily than they are in the presence of light. To obtain a better understanding of this heat-derived damage mechanism that occurs in the dark, we focused on the involvement of the light-independent electron flow that occurs at 40 degrees C during the damage. In various plant species, the maximal photochemical quantum yield of photosystem (PS) II (Fv/Fm) decreased as a result of heat treatment in the dark. In the case of wheat, the most sensitive plant species tested, both Fv/Fm and oxygen evolution rapidly decreased by heat treatment at 40 degrees C for 30 min in the dark. In the damage, specific degradation of D1 protein was involved, as shown by immunochemical analysis of major proteins in the photosystem. Because light canceled the damage to PSII, the light-driven electron flow may play a protective role against PSII damage without light. Light-independent incorporation of reducing power from stroma was enhanced at 40 degrees C but not below 35 degrees C. Arabidopsis mutants that have a deficit of enzymes which mediate the incorporation of stromal reducing power into thylakoid membranes were tolerant against heat treatment at 40 degrees C in the dark, suggesting that the reduction of the plastoquinone pool may be involved in the damage. In conclusion, the enhanced introduction of reducing power from stroma into thylakoid membranes that occurs around 40 degrees C causes over reduction of plastoquinone, resulting in the damage to D1 protein under heat stress without linear electron flow. PMID- 22526504 TI - Root metabolic response of rice (Oryza sativa L.) genotypes with contrasting tolerance to zinc deficiency and bicarbonate excess. AB - Plants are routinely subjected to multiple environmental stresses that constrain growth. Zinc (Zn) deficiency and high bicarbonate are two examples that co-occur in many soils used for rice production. Here, the utility of metabolomics in diagnosing the effect of each stress alone and in combination on rice root function is demonstrated, with potential stress tolerance indicators identified through the use of contrasting genotypes. Responses to the dual stress of combined Zn deficiency and bicarbonate excess included greater root solute leakage, reduced dry matter production, lower monosaccharide accumulation and increased concentrations of hydrogen peroxide, phenolics, peroxidase and N-rich metabolites in roots. Both hydrogen peroxide concentration and root solute leakage were correlated with higher levels of citrate, allantoin and stigmasterol. Zn stress resulted in lower levels of the tricarboxylic acid (TCA) cycle intermediate succinate and the aromatic amino acid tyrosine. Bicarbonate stress reduced shoot iron (Fe) concentrations, which was reflected by lower Fe dependent ascorbate peroxidase activity. Bicarbonate stress also favoured the accumulation of the TCA cycle intermediates malate, fumarate and succinate, along with the non-polar amino acid tyrosine. Genotypic differentiation revealed constitutively higher levels of D-gluconate, 2-oxoglutarate and two unidentified compounds in the Zn-efficient line RIL46 than the Zn-inefficient cultivar IR74, suggesting a possible role for these metabolites in overcoming oxidative stress or improving metal re-distribution. PMID- 22526505 TI - Cell wall polysaccharides are involved in P-deficiency-induced Cd exclusion in Arabidopsis thaliana. AB - The physiological and molecular mechanisms leading to the competitive interactions between phosphorus (P) and metal elements are a matter of debate. In this study, we found that P deficiency can alleviate cadmium (Cd) toxicity in Arabidopsis thaliana (Col-0). Under P deficiency (-P), less Cd was accumulated in the plants and the root cell walls, indicating the operation of a P-deficiency induced Cd exclusion mechanism. However, organic acid efflux was similar under P+Cd and +Cd treatments, suggesting that organic acid efflux is not responsible for the Cd exclusion. Interestingly, P deficiency significantly decreased cell wall polysaccharides (pectin and hemicellulose) contents and pectin methylesterase activity, and decreased the Cd retained by the extracted root cell wall. Therefore, we conclude that the modification of cell wall composition is responsible for the Cd exclusion of the root under P deficiency. PMID- 22526506 TI - Substituent-specific antibody against glucuronoxylan reveals close association of glucuronic acid and acetyl substituents and distinct labeling patterns in tree species. AB - Immunolabeling can be used to locate plant cell wall carbohydrates or other components to specific cell types or to specific regions of the wall. Some antibodies against xylans exist; however, many partly react with the xylan backbone and thus provide limited information on the type of substituents present in various xylans. We have produced a monoclonal antibody which specifically recognizes glucopyranosyl uronic acid (GlcA), or its 4-O-methyl ether (meGlcA), substituents in xylan and has no cross-reactivity with linear or arabinofuranosyl substituted xylans. The UX1 antibody binds most strongly to (me)GlcA substitutions at the non-reducing ends of xylan chains, but has a low cross reactivity with internal substitutions as well, at least on oligosaccharides. The antibody labeled plant cell walls from both mono- and dicotyledons, but in most tissues an alkaline pretreatment was needed for antibody binding. The treatment removed acetyl groups from xylan, indicating that the vicinity of glucuronic acid substituents is also acetylated. The novel labeling patterns observed in the xylem of tree species suggested that differences within the cell wall exist both in acetylation degree and in glucuronic acid content. PMID- 22526507 TI - Cloning and selection of carotenoid ketolase genes for the engineering of high yield astaxanthin in plants. AB - beta-Carotene ketolase (BKT) catalyzes the rate-limiting steps for the biosynthesis of astaxanthin. Several bkt genes have been isolated and explored to modify plant carotenoids to astaxanthin with limited success. In this study, five algal BKT cDNAs were isolated and characterized for the engineering of high-yield astaxanthin in plants. The products of the cDNAs showed high similarity in sequence and enzymatic activity of converting beta-carotene into canthaxanthin. However, the enzymes exhibited extremely different activities in converting zeaxanthin into astaxanthin. Chlamydomonas reinhardtii BKT showed the highest conversion rate (ca 85%), whereas, Neochloris wimmeri BKT exhibited very poor activity of ketolating zeaxanthin. Expression of C. reinhardtii BKT in tobacco led to a twofold increase of total carotenoids in the leaves with astaxanthin being the predominant. The bkt genes described here provide a valuable resource for metabolic engineering of plants as cell factories for astaxanthin production. PMID- 22526508 TI - Increased expression of BAG-1 in rat brain cortex after traumatic brain injury. AB - BAG-1 protein was initially identified as a Bcl-2-binding protein. It was reported to enhance Bcl-2 protection from cell death, suggesting that BAG-1 represents a new type of anti-cell death gene. Moreover, recent study has shown that BAG-1 can enhance the proliferation of neuronal precursor cells, attenuate the growth inhibition induced by siah1. However, its function and expression in the central nervous system lesion are not been understood very well. In this study, we performed a traumatic brain injury (TBI) model in adult rats and investigated the dynamic changes of BAG-1 expression in the brain cortex. Double immunofluorescence staining revealed that BAG-1 was co-expressed with NEURON and glial fibrillary acidic protein (GFAP). In addition, we detected that proliferating cell nuclear antigen had the co-localization with GFAP, and BAG-1. All our findings suggested that BAG-1 might involve in the pathophysiology of brain after TBI. PMID- 22526510 TI - Microvesicles released from hormone-refractory prostate cancer cells facilitate mouse pre-osteoblast differentiation. AB - Bone metastasis is often occurs in patients with prostate cancer. There is a vicious cycle for bone metastases involving prostate cancer cells, osteoblasts, and osteoclasts. Acting among those cells during the process of metastasis are several molecules such as bone morphogenetic proteins, platelet-derived growth factor, endothelin-1, matrix metalloproteases, vascular endothelial growth factor, transforming growth factor-beta, and insulin-like growth factors. Cell derived microvesicles are endogenous carriers transporting proteins, mRNAs and miRNAs between cells, which is a candidate for participation in the bone metastasis of these cells. Here, we demonstrated that prostate cancer cells in vitro released microvesicles into the culture medium (PCa-MVs), which was shown by electron microscopic study and nanoparticle tracking analysis. In this study, we found for the first time that these PCa-MVs enhanced osteoblast differentiation mainly through the delivery of PCa cell-derived v-ets erythroblastosis virus E26 oncogene homolog 1, which is an osteoblast differentiation related-transcriptional factor. PMID- 22526509 TI - Lead neurotoxicity: effects on brain nitric oxide synthase. AB - Lead (Pb), a ubiquitous and potent neurotoxicant, induces several neurophysiological and behavioural changes, while Pb alters the function of multiple organs and systems, it primarily affects the central nervous system. In human adults, encephalopathy resulting from Pb intoxication is often characterized by sleeplessness, poor attention span, vomiting, convulsions and coma; in children, Pb-induced encephalopathy is associated with mental dullness, vomiting, irritability and anorexia; diminished cognitive function resulting in a mental deficit has been also observed during Prolonged exposure to Pb. Pb can produce oxidative stress, disrupt the blood-brain barrier and alter several Ca(2+)-dependent processes, including physiological processes that involve nitric oxide synthesis on central nervous system in development and adult animals. This review summarizes recent evidence showing that Pb can interfere with the production of nitric oxide and can disrupt the function of nitric oxide synthase. Lead interferes with nitric oxide-related physiological mechanisms, and Pb neurotoxicity may affect processes involved in learning and memory. PMID- 22526511 TI - Editorial: models of invertebrate neurons in culture. PMID- 22526512 TI - Dynamic aspects during the cylinder grip--flexion sequence of the finger joints analyzed using a sensor glove. AB - The purpose of this study was to assess whether there is a universal pattern of movement of the finger joints while performing a cylinder grip. A sensor glove was used to record the finger joint motion of 48 participants. Our observations showed that when examining the fingers, flexion motion began either at the metacarpophalangeal (MP) or proximal interphalangeal (PIP) joints, with the distal interphalangeal (DIP) joints always last to move (p = 0.0052). The sequence of the joints at the end of the gripping motion was different than at the beginning. Here, the only statistically significant observation was that the DIP joints fully flexed only once the MP joints had flexed fully. Apart from that, it was completely variable which joint reached its final position first or last. The analysis also revealed that synchronization of four identical joints (i.e. the four PIP joints) was significantly higher than synchronization of the 12 finger joints. Although synchronization was already high at the beginning of the flexion motion, it increased significantly by the time the joints completed their movement. PMID- 22526513 TI - Brachialis muscle transfer to the forearm for the treatment of deformities in spastic cerebral palsy. AB - The use of the brachialis muscle for tendon transfers in cerebral palsy has not been described previously. In this study, the brachialis muscle was used for transfer in 11 patients with spastic cerebral palsy for the restoration of forearm supination, wrist extension, or finger extension. Four patients underwent brachialis rerouting supinatorplasty. Active supination increased in two (60 degrees and 50 degrees ), minimally increased in one (5 degrees ), and did not change in one patient. Five patients had a brachialis to extensor carpi radialis brevis transfer. The mean gain in postoperative active wrist extension was 65 degrees . Two patients with finger flexion deformity and no active metacarpophalangeal joint movement underwent a brachialis to extensor digitorum communis transfer, and they attained an improved posture of finger extension although their postoperative metacarpophalangeal flexion-extension movement arc was 5 degrees and 25 degrees . None of the patients developed any loss of active flexion at the elbow. Our preliminary experience suggests that the brachialis muscle may serve as an alternative tendon transfer in cerebral palsy. PMID- 22526514 TI - Bony avulsion injury of flexor digitorum profundus -- description of a new subtype. PMID- 22526515 TI - Why is joint range of motion limited in patients with cerebral palsy? AB - Patients with spastic cerebral palsy of the upper limb typically present with various problems including an impaired range of motion that affects the positioning of the upper extremity. This impaired range of motion often develops into contractures that further limit functioning of the spastic hand and arm. Understanding why these contractures develop in cerebral palsy will affect the selection of patients suitable for surgical treatment as well as the choice for specific surgical procedures. The generally accepted hypothesis in patients with spastic cerebral palsy is that the hyper-excitability of the stretch reflex combined with increased muscle tone result in extreme angles of the involved joints at rest. Ultimately, these extreme joint angles are thought to result in fixed joint postures. There is no consensus in the literature concerning the pathophysiology of this process. Several hypotheses associated with inactivity and overactivity have been tested by examining the secondary changes in spastic muscle and its surrounding tissue. All hypotheses implicate different secondary changes that consequently require different clinical approaches. In this review, the different hypotheses concerning the development of limited joint range of motion in cerebral palsy are discussed in relation to their secondary changes on the musculoskeletal system. PMID- 22526516 TI - Genetic variability at the TREX1 locus is not associated with natural resistance to HIV-1 infection. AB - Three prime repair exonuclease 1 (TREX1) degrades excess HIV-1 DNA, thereby preventing recognition by innate immunity receptors and type I interferon responses. Analyses performed in two HIV-exposed seronegative (HESN) cohorts did not show any differences in TREX1 sequence, single nucleotide polymorphisms frequency, or expression in HESN compared to controls, suggesting that, despite its central role in the HIV-1 infection process, genetic diversity at TREX1 is not a major determinant of susceptibility to infection in humans. PMID- 22526517 TI - A phase II randomized controlled trial adding oral flucytosine to high-dose fluconazole, with short-course amphotericin B, for cryptococcal meningitis. AB - BACKGROUND: Cryptococcal meningitis in Africa is associated with up to 70% mortality at 3 months and 500 000 deaths annually. We examined strategies to improve on fluconazole (FLU) monotherapy: addition of flucytosine (5-FC) and/or addition of short-course amphotericin B (AmB). METHODS: In step 1, previously reported, patients were randomized to receive FLU 1200 mg per day with or without 5-FC 100 mg/kg per day for 14 days. In step 2, 43 patients were similarly randomized, with addition of AmB 1 mg/kg per day for 7 days to both arms. After 2 weeks, patients received FLU monotherapy and were followed to 10 weeks. The primary endpoint was rate of clearance of infection (early fungicidal activity, EFA). Secondary endpoints related to safety and mortality. RESULTS: Forty patients (25% with Glasgow Coma Scale <15) were analyzed. EFA for the triple combination arm was greater than that for AmB-FLU: -0.50 +/- 0.15 log CFU/day vs. -0.38 +/- 0.19 log colony forming units per day (P=0.03); and greater than that for step 1 with FLU-5-FC (-0.28 +/- 0.17) or FLU alone (-0.11 +/- 0.09). Combined analysis across steps revealed that addition of 5-FC and AmB had significant, independent additive effects on EFA, with trends toward fewer early deaths with addition of 5-FC (4/41 vs. 11/39, P = 0.05) and fewer deaths overall with addition of AmB (13/39 vs. 20/40, P = 0.1). CONCLUSION: Addition of 5-FC and short-course AmB to high-dose FLU significantly enhanced EFA and may be associated with favorable trends in survival. Both these strategies should be tested in a larger phase III study. PMID- 22526518 TI - Chronic progressive HIV-1 infection is associated with elevated levels of myeloid derived suppressor cells. AB - OBJECTIVES: Myeloid-derived suppressor cells (MDSCs) have been described as suppressors of T-cell functions in many tumor models. However, MDSC in HIV-1 infection have not been studied to date. As impaired T-cell function is a hallmark of chronic progressive HIV-1 infection, we hypothesized that MDSC also play a role here. METHODS: Surface staining and flow cytometry analysis were performed on freshly isolated peripheral blood mononuclear cells (PBMC) of HIV infected individuals and compared to healthy controls and individuals with lung carcinoma. MDSC of late-stage HIV-infected individuals were isolated using magnetic beads and cocultured with the respective CD8 T cells for evaluation of proliferative capacity. RESULTS: We found that chronically HIV-infected HAART naive individuals had significantly higher CD11bCD14CD33CD15 MDSC levels than healthy controls (P = 0.01). MDSC frequencies showed a positive correlation with viral load (r = 0.24, P = 0.0002) and a negative correlation with CD4 cell count (r = 0.29, P < 0.0001). Initiation of HAART led to a rapid drop in MDSC levels. MDSC from HIV-infected progressors restricted the proliferative capacity of CD8 T cells from healthy donors and of Gag/Nef-specific CD8 T cells from HIV controllers in vitro. Furthermore, CD11bCD14CD33CD15 MDSC induced the expansion of CD4CD25FoxP3 regulatory T cells when coincubated with PBMC from controllers in vitro. CONCLUSION: We conclude that chronic uncontrolled HIV-infection is associated with elevated levels of MDSC, which potentially contribute to the impaired T-cell responses characteristic for the progressive disease stage. PMID- 22526520 TI - The prognostic value of baseline CD4(+) cell count beyond 6 months of antiretroviral therapy in HIV-positive patients in a resource-limited setting. AB - OBJECTIVE: The risk of death is highest in the first few months after initiation of antiretroviral therapy (ART). We examined whether initial CD4 cell count maintains a strong prognostic value among patients with at least 6 months follow up after the initiation of ART. DESIGN: Observational study of HIV patients in Uganda aged 14 years or older enrolled in 10 clinics across Uganda. METHODS: Baseline CD4 cell count of patients with more than 6 months of follow-up were stratified into categories (<50, 50-99, 100-149, 150-249, >250 cells/MUl). A Kaplan-Meier survival analysis and Cox proportional hazards regression was used to model the associations between baseline CD4 cell count and mortality. RESULTS: Of 22 315 patients, 20 730 (92.8%) had more than 6 months of follow-up. Six hundred and eleven (2.9%) patients died during follow-up and 737 (3.6%) were lost to follow-up. Relative to a baseline CD4 cell counts of less than 50 cells/MUl, the adjusted hazard ratios for death were 0.83 [95% confidence interval (CI) 0.67 1.02], 0.71 (95% CI 0.57-0.88), 0.52 (95% CI 0.42-0.64), and 0.55 (95% CI 0.42 0.70) favouring those with baseline CD4 cell counts of 50-99, 100-149, 150-249, and at least 250 cells/MUl, respectively. Differing ages and male sex increased the likelihood of mortality. CONCLUSION: Among patients with more than 6 months of follow-up after initiation of ART, baseline CD4 cell count at initiation still has important prognostic value. This suggests that active engagement and earlier treatment initiation is important for long-term survival. PMID- 22526521 TI - Prevalence and risk factors associated with pulmonary hypertension in HIV infected patients on regular follow-up. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is uncommon among HIV-positive patients. However, it is a potentially life-threatening condition. Transthoracic echocardiography (TTE) is a noninvasive tool validated for PAH screening. The aim of our study was to establish the prevalence and factors associated with PAH in HIV-infected patients. METHODS: Consecutive HIV-infected individuals attended at one HIV reference clinic in Madrid, Spain, during year 2011 were examined. Demographics and clinical data were recorded and a Doppler echocardiography was performed in all individuals. PAH was considered when right ventricular pressure was more than 35 mmHg (mild if <40 mmHg, moderate if 40-65 mmHg, and severe if >65 mmHg). RESULTS: Three hundred and ninety-two individuals were examined (83.4% men, median age 47 years, 53% were men who have sex with men and 53% former intravenous drug addicts). Overall, 84% were on HAART, 76% had undetectable HIV viral load and median CD4 cell counts were 577 cells/MUl. Cardiovascular risk factors were smoking 50%, arterial hypertension 16% and diabetes mellitus 9%. A total of 28.5 and 4.8% had chronic hepatitis C (CHC) and 4.8% chronic hepatitis B, respectively. PAH was diagnosed in 9.9% of patients (6.4% mild, 2.8% moderate and 0.8% severe). Multivariate logistic regression analysis [odds ratio (OR), 95% confidence interval (CI)] showed that detectable plasma HIV-RNA [OR, 3.3; 95% CI, 1.04-10], CHC [OR, 3.1; 95% CI 1.2-8.2] and female sex [OR, 2.9; 95% CI, 1.04 8.3] were independently associated with PAH. CONCLUSION: The prevalence of PAH HIV-infected patients on regular follow-up approaches 10%, being moderate-severe in nearly 4% of cases. Patients with CHC and/or uncontrolled HIV replication exhibit a higher risk of PAH. PMID- 22526522 TI - The mode of inheritance in tetraploid cut roses. AB - Tetraploid hybrid tea roses (Rosa hybrida) represent most of the commercial cultivars of cut roses and form the basis for breeding programmes. Due to intensive interspecific hybridizations, modern cut roses are complex tetraploids for which the mode of inheritance is not exactly known. The segregation patterns of molecular markers in a tetraploid mapping population of 184 genotypes, an F(1) progeny from a cross of two heterozygous parents, were investigated for disomic and tetrasomic inheritance. The possible occurrence of double reduction was studied as well. We can exclude disomic inheritance, but while our observations are more in line with a tetrasomic inheritance, we cannot exclude that there is a mixture of both inheritance modes. Two novel parental tetraploid linkage maps were constructed using markers known from literature, combined with newly generated markers. Comparison with the integrated consensus diploid map (ICM) of Spiller et al. (Theor Appl Genet 122:489-500, 2010) allowed assigning numbers to each of the linkage groups of both maps and including small linkage groups. So far, the possibility of using marker-assisted selection in breeding of tetraploid cut roses and of other species with a tetrasomic or partly tetrasomic inheritance, is still limited due to the difficulties in establishing marker trait associations. We used these tetraploid linkage maps to determine associations between markers, two morphological traits and powdery mildew resistance. The knowledge on inheritance and marker-trait associations in tetraploid cut roses will be of direct use to cut rose breeding. PMID- 22526525 TI - Development and psychometric evaluation of the Chronic Illness Anticipated Stigma Scale. AB - The Chronic Illness Anticipated Stigma Scale (CIASS) was developed to measure anticipated stigma (i.e., expectations of prejudice, stereotyping, and discrimination) among people living with chronic illnesses. The CIASS is a 12 item scale with three subscales differentiating among sources of anticipated stigma, including friends and family members, work colleagues, and healthcare workers. Results support the reliability, validity, and generalizability of the CIASS in two samples of people living with chronic illnesses. The CIASS was correlated with other stigma-related constructs as well as indicators of mental health, physical health, and health behaviors. The CIASS can help researchers gauge the degree to which people living with chronic illnesses anticipate stigma, better understand the processes by which anticipated stigma contributes to the health and behavior of people living with chronic illnesses, and compare the extent to which people living with different types of chronic illnesses anticipate stigma. PMID- 22526527 TI - Premature to conclude no genetic basis to the association between smoking and major depressive disorder. PMID- 22526526 TI - Gender-based violence, alcohol use, and sexual risk among female patrons of drinking venues in Cape Town, South Africa. AB - Gender-based violence is a well-recognized risk factor for HIV infection among women. Alcohol use is associated with both gender-based violence and sexual risk behavior, but has not been examined as a correlate of both in a context of both high HIV risk and hazardous drinking. The purpose of this paper is to examine the association between recent abuse by a sex partner with alcohol and sexual risk behavior among female patrons of alcohol serving venues in South Africa. Specifically, the aim of this study is to determine whether sexual risk behaviors are associated with gender-based violence after controlling for levels of alcohol use. We surveyed 1,388 women attending informal drinking establishments in Cape Town, South Africa to assess recent history of gender-based violence, drinking, and sexual risk behaviors. Gender-based violence was associated with both drinking and sexual risk behaviors after controlling for demographics among the women. A hierarchical logistic regression analysis showed that after controlling for alcohol use sexual risk behavior remained significantly associated with gender-based violence, particularly with meeting a new sex partner at the bar, recent STI diagnosis, and engaging in transactional sex, but not protected intercourse or number of partners. In South Africa where heavy drinking is prevalent women may be at particular risk of physical abuse from intimate partners as well as higher sexual risk. Interventions that aim to reduce gender based violence and sexual risk behaviors must directly work to reduce drinking behavior. PMID- 22526528 TI - Genetics of smoking and depression. AB - Smoking and depression are significant public health problems with multiple etiological dimensions and outcomes. Although each condition is important by itself, they are important because they often potentiate each other. Consequently, it is also essential to understand the nature their relationship. This representative review focuses on the genetic etiology of the relationship in the context of reviewing first the epidemiology of depression and smoking, and then by exploring behavioral and molecular genetic studies, and other psychiatric and medical comorbidities. At this point, epidemiological evidence for a relationship between depression and smoking/nicotine dependence is compelling. Although behavioral genetic results differ somewhat by gender and in accordance with specific definitions of depression and smoking variables, recent studies show converging evidence for common genetic factors underlying the relationship, often in addition to non-shared environmental factors. The search for underlying genes and genetic mechanisms is at an early stage, but shows promising candidate genes and genetic approaches for future studies. PMID- 22526530 TI - Cues predicting drug or food reward restore morphine-induced place conditioning in mice lacking delta opioid receptors. AB - RATIONALE: The exact role of delta opioid receptors in drug-induced conditioned place preference (CPP) remains debated. Under classical experimental conditions, morphine-induced CPP is decreased in mice lacking delta opioid receptors (Oprd1 ( /-)). Morphine self-administration, however, is maintained, suggesting that drug context association rather than drug reward is deficient in these animals. OBJECTIVES: This study further examined the role of delta opioid receptors in mediating drug-cue associations, which are necessary for the expression of morphine-induced CPP. METHODS: We first identified experimental conditions under which Oprd1 (-/-) mice are able to express CPP to morphine (5, 10 or 20 mg/kg) in a drug-free state and observed that, in this paradigm, CPP was dependent on circadian time conditions. We then took advantage of this particularity to assess the ability of various cues (internal or discrete), predicting either drug or food reward, to restore CPP induced by morphine (10 mg/kg) in Oprd1 (-/-) mice in conditions under which they normally fail to express CPP. RESULTS: We found that presentation of circadian, drug or auditory cues, predicting morphine or food reward, restored morphine CPP in Oprd1 (-/-) mice, which then performed as well as control mice. CONCLUSIONS: This study reveals that, in contrast to spatial cues, internal or discrete morphine-predicting stimuli permit full expression of morphine CPP in Oprd1 (-/-) mice. Delta receptors, therefore, appear to play a crucial role in modulating spatial contextual cue-related responses. This activity may be critical when context gains control over behavior, as is the case for context-induced relapse in drug abuse. PMID- 22526529 TI - High doses of dextromethorphan, an NMDA antagonist, produce effects similar to classic hallucinogens. AB - RATIONALE: Although reports of dextromethorphan (DXM) abuse have increased recently, few studies have examined the effects of high doses of DXM. OBJECTIVE: This study in humans evaluated the effects of supratherapeutic doses of DXM and triazolam. METHODS: Single, acute oral doses of DXM (100, 200, 300, 400, 500, 600, 700, and 800 mg/70 kg), triazolam (0.25 and 0.5 mg/70 kg), and placebo were administered to 12 healthy volunteers with histories of hallucinogen use, under double-blind conditions, using an ascending dose run-up design. Subjective, behavioral, and physiological effects were assessed repeatedly after drug administration for 6 h. RESULTS: Triazolam produced dose-related increases in subject-rated sedation, observer-rated sedation, and behavioral impairment. DXM produced a profile of dose-related physiological and subjective effects differing from triazolam. DXM effects included increases in blood pressure, heart rate, and emesis; increases in observer-rated effects typical of classic hallucinogens (e.g., distance from reality, visual effects with eyes open and closed, joy, anxiety); and participant ratings of stimulation (e.g., jittery, nervous), somatic effects (e.g., tingling, headache), perceptual changes, end-of-session drug liking, and mystical-type experience. After 400 mg/70 kg DXM, 11 of 12 participants indicated on a pharmacological class questionnaire that they thought they had received a classic hallucinogen (e.g., psilocybin). Drug effects resolved without significant adverse effects by the end of the session. In a 1 month follow-up, volunteers attributed increased spirituality and positive changes in attitudes, moods, and behavior to the session experiences. CONCLUSIONS: High doses of DXM produced effects distinct from triazolam and had characteristics that were similar to the classic hallucinogen psilocybin. PMID- 22526531 TI - The effects of varenicline on attention and inhibitory control among treatment seeking smokers. AB - RATIONALE: Varenicline represents a new class of smoking cessation aids that has different mechanisms of action that are unique from bupropion or nicotine replacement therapies. An improved understanding of these mechanisms may lead to greater treatment success in quitting smoking. OBJECTIVES: We examined the effects of steady-state varenicline on attention and inhibitory control among adult treatment-seeking smokers. METHODS: Adult smokers enrolled in a randomized clinical trial received either 4 weeks of pre-quit varenicline (n = 31) or 3 weeks of placebo (n = 26) followed by 1 week of standard varenicline treatment. Participants in the present work completed cognitive assessments at a baseline session (prior to treatment) and again 3 weeks later (during active treatment). At both sessions, participants completed the stop signal task to assess both lapses in attention and inhibitory control. RESULTS: Analyses indicated that varenicline improved lapses in attention compared to placebo. There were no significant differences observed between groups at either session for inhibitory control. CONCLUSIONS: The present study demonstrated that varenicline improves lapses in attention among treatment-seeking smokers preparing to make a quit attempt. These findings suggest that the domain of attention may be a good candidate for larger studies of the role of improved cognition in understanding the mechanisms of varenicline treatment for smoking cessation. PMID- 22526532 TI - Discriminative stimulus effects of pregnanolone in rats: role of training dose in determining mechanism of action. AB - RATIONALE: Positive gamma-aminobutyric acid(A) (GABA(A)) modulators acting at different binding sites often produce similar behavioral effects; however, their effects are not identical. Actions of neuroactive steroids at other receptors, in addition to GABA(A) receptors, might account for some differences between neuroactive steroids and other positive modulators, like benzodiazepines. OBJECTIVE: Multiple mechanisms of other drugs (e.g., ethanol) have been elucidated by comparing their discriminative stimulus effects across different training doses; the current study used that approach to examine the mechanisms of action of the neuroactive steroid pregnanolone. METHODS: Separate groups of rats (n = 6-8/group) discriminated pregnanolone from vehicle while responding under a fixed-ratio 10 schedule of food presentation. Two groups initially discriminated 3.2 mg/kg; once stimulus control was established, the training dose was systematically decreased to 1.33 mg/kg in one group and increased to 7.5 mg/kg in the other group. Other rats discriminated either 1.33 or 7.5 mg/kg without training at another dose. RESULTS: Stimulus control was established in 24-28 sessions in all groups. Positive GABA(A) modulators produced >=80 % pregnanolone lever responding, regardless of training dose; rank-order potency was flunitrazepam > midazolam > pregnanolone = pentobarbital. Ethanol produced some drug-lever responding (42 %) only in rats discriminating 1.33 mg/kg, whereas the N-methyl-D: -aspartate receptor antagonist ketamine and the serotonin receptor agonist 1-(m-chlorophenyl)-biguanide occasioned predominantly vehicle-lever responding in all rats. CONCLUSIONS: There was little difference in discriminative stimulus effects of pregnanolone across different training conditions, confirming a predominant, if not exclusive, role of GABA(A) receptors in these effects of pregnanolone. PMID- 22526533 TI - Central administration of oxytocin receptor ligands affects cued fear extinction in rats and mice in a timepoint-dependent manner. AB - RATIONALE: Oxytocin (OXT) has been proposed as a potential therapeutic agent for post-traumatic stress disorder (PTSD). OBJECTIVES: We aimed to verify whether pharmacological manipulation of the brain OXT system affects cued fear conditioning and fear extinction. METHODS: Male rats and mice were intracerebroventricularly administered synthetic OXT (rats, 0.1 or 1.0 MUg/5 MUl; mice, 0.1 or 0.5 MUg/2 MUl) and/or an OXT receptor antagonist (OXTR-A; rats, 0.75 MUg/5 MUl) either prior to fear conditioning or extinction training. RESULTS: Preconditioning administration of OXT did not affect fear conditioning in rats, but decreased fear expression and facilitated fear extinction. In contrast, preconditioning blockade of OXT neurotransmission by OXTR-A did not affect fear conditioning or fear expression, but impaired fear extinction. When administered before extinction training, OXT impaired fear extinction in both rats and mice, indicating that the effects of OXT on fear extinction are conserved across species. This impairment was OXTR-mediated, as the inhibitory effect of OXT on fear extinction was abolished by prior treatment with OXTR-A. The impaired fear extinction was not a result of reduced locomotion in rats, whereas an apparent decrease in fear expression and facilitation of fear extinction with the higher OXT dose in mice was the result of behavioral hyperactivity. CONCLUSIONS: These results suggest that increasing OXT neurotransmission during traumatic events is likely to prevent the formation of aversive memories. In contrast, OXT treatment before fear extinction training, which would be the comparable timepoint for psychotherapy in PTSD patients, rather delays fear extinction and, therefore, caution is needed before recommending OXT for the treatment of PTSD. PMID- 22526534 TI - Effects of the specific alpha4beta2 nAChR antagonist, 2-fluoro-3-(4-nitrophenyl) deschloroepibatidine, on nicotine reward-related behaviors in rats and mice. AB - RATIONALE: Alleviating addiction to tobacco products could prevent millions of deaths. Investigating novel compounds selectively targeting alpha4beta2 nAChRs hypothesized to have a key role in the rewarding effects of nicotine may be a useful approach for future treatment. OBJECTIVES: The present study was designed to evaluate 2-fluoro-3-(4-nitrophenyl) deschloroepibatidine (4-nitro-PFEB), a potent competitive antagonist of neuronal alpha4beta2 nAChRs, in several animal models related to nicotine reward: drug discrimination, intracranial self stimulation (ICSS), conditioned place preference, and limited access to self administration. METHODS: Long Evans rats were trained in a two-lever discrimination procedure to discriminate 0.4 mg/kg nicotine (s.c.) from saline. Male Sprague-Dawley rats were stereotaxically implanted with electrodes and trained to respond for direct electrical stimulation of the medial forebrain bundle. ICR mice were evaluated using an unbiased place preference paradigm, and finally, male Wistar rats were implanted with intrajugular catheters and tested for nicotine self-administration under limited access (1 h/day). RESULTS: 4-Nitro PFEB attenuated the discriminative stimulus effects of nicotine, but alone did not produce nicotine-like discriminative stimulus effects. Nicotine-induced facilitation of ICSS reward thresholds was reversed by 4-nitro-PFEB, which alone had no effect on thresholds. 4-Nitro-PFEB also blocked the conditioned place preference produced by nicotine, but alone had no effect on conditioned place preference. Finally, 4-nitro-PFEB dose-dependently decreased nicotine self administration. CONCLUSIONS: These results support the hypothesis that neuronal alpha4beta2 nAChRs play a key role in mediating the rewarding effects of nicotine and further suggest that targeting alpha4beta2 nAChRs may yield a potential candidate for the treatment of nicotine dependence. PMID- 22526536 TI - Histamine- and haloperidol-induced catalepsy in aged mice: differential responsiveness to L-DOPA. AB - RATIONALE: In rodents and dog, histamine induces catalepsy, a dopamine-dependent phenomenon that resembles the extrapyramidal signs of Parkinson's disease (PD). Histamine was also found to damage the dopaminergic neurons in rat substantia nigra. These facts, as well as an increase in brain histamine levels in Parkinsonian patients, suggest a pathogenic role for histamine in PD. As it seems, a comparison between pattern of experimental brain histamine toxicity and signs of PD would elucidate the role of histamine in PD pathogenesis. OBJECTIVE: This study aimed to examine whether mouse histamine-induced catalepsy shares such age-related traits of PD as disease aggravation and underresponsiveness to 3,4 dihydroxy-L: -phenylalanine (L: -DOPA) in aged patients. For comparison purposes, haloperidol-induced catalepsy was studied. METHODS: The intensity of catalepsy was measured as the time the mouse maintained an abnormal posture. The cataleptogens, histamine or haloperidol, were administered intracerebroventricularly and subcutaneously, respectively. RESULTS: The cataleptogenic activity of histamine was significantly higher in 18-19-month-old and 22-23-month-old mice than 3-4-month-old ones. Aging was found to decrease the responsiveness of the histamine-induced catalepsy to L: -DOPA. The intensity of the haloperidol-induced catalepsy and its sensitivity to L: -DOPA were found independent of the animal's age. CONCLUSIONS: The mouse histamine-induced catalepsy, unlike haloperidol-induced one, displays the same pattern of age dependency as PD. These findings support an involvement of histamine in the PD pathogenesis. PMID- 22526535 TI - Treatment of cocaine withdrawal anxiety with guanfacine: relationships to cocaine intake and reinstatement of cocaine seeking in rats. AB - RATIONALE: Successful treatment of cocaine addiction is severely impeded by the propensity of users to relapse. Withdrawal severity may serve as a key predictor of susceptibility to relapse. Therefore, the identification and treatment of cocaine withdrawal symptoms such as anxiety may improve addiction treatment outcome. OBJECTIVES: The current study examined the role of anxiety-like behavior during cocaine withdrawal and anxiolytic treatment in reinstatement of cocaine seeking in an animal model of relapse. METHODS: Male rats experienced daily IV cocaine self-administration. One group of animals received the norepinephrine alpha-2 agonist, guanfacine, or vehicle prior to anxiety testing 48 h after the last self-administration session. In the second group of rats, relationships between cocaine intake, anxiety-like behavior after withdrawal of cocaine, and reinstatement responding were investigated. The third and fourth groups of animals received guanfacine, yohimbine (norepinephrine alpha-2 antagonist), or vehicle once per day for 3 days 48 h after cessation of cocaine self administration, followed by extinction and subsequent reinstatement induced by cocaine injections, cocaine-paired cues, and yohimbine administration. RESULTS: Cocaine-withdrawn rats at 48 h demonstrated higher levels of anxiety-like behavior as measured on a defensive burying task when compared to yoked saline controls, an effect reversed by guanfacine treatment. Cocaine intake was positively correlated with measures of anxiety-like behavior during early withdrawal, and this anxiety-like behavior was significantly correlated with subsequent cocaine-primed reinstatement. Yohimbine treatment during early withdrawal increased reinstatement to conditioned cues, while guanfacine treatment reduced reinstatement to yohimbine. CONCLUSIONS: These studies suggest an important role for noradrenergic mediation of anxiety-like behavior that emerges after withdrawal of cocaine and potential risk of relapse as modeled by reinstatement, and suggest that treatment of anxiety symptoms during early abstinence may reduce the risk of relapse. PMID- 22526537 TI - Social rank, chronic ethanol self-administration, and diurnal pituitary-adrenal activity in cynomolgus monkeys. AB - RATIONALE: Dominance hierarchies affect ethanol self-administration, with greater intake among subordinate animals compared to dominant animals. Excessive ethanol intake disrupts circadian rhythms. Diurnal rhythms of the hypothalamic-pituitary adrenal axis have not been characterized in the context of ethanol self administration with regard to social rank. OBJECTIVE: This study aimed to determine whether diurnal pituitary-adrenal hormonal rhythms account for differences between social ranks in ethanol self-administration or are differentially affected by ethanol self-administration between social ranks. METHODS: During alternating individual (n = 11-12) and social (n = 3 groups) housing of male cynomolgus monkeys (Macaca fascicularis), diurnal measures of cortisol and adrenocorticotropic hormone (ACTH) were obtained from plasma samples three times per week. Social rank was determined, ethanol (4 %, w/v) self administration was induced, and then the monkeys were allowed a choice of water or ethanol for 22 h/day for 49 weeks. RESULTS: For all social ranks, plasma ACTH was elevated during social housing, but cortisol was stable, although greater among dominant monkeys. Ethanol self-administration blunted the effect of social housing, cortisol, and the diurnal rhythm for both hormones, regardless of daily ethanol intake (1.2-4.2 g/kg/day). Peak ACTH and cortisol were more likely to be observed in the morning during ethanol access. Ethanol, not vehicle, intake was lower during social housing across social ranks. Only dominant monkeys showed significantly lower blood-ethanol concentration during social housing. CONCLUSIONS: There was a low threshold for disruption of diurnal pituitary rhythms by ethanol drinking, but sustained adrenal corticosteroid rhythms. Protection against heavy drinking among dominant monkeys may have constrained ethanol intoxication, possibly to preserve dominance rank. PMID- 22526538 TI - Amphetamine as a social drug: effects of d-amphetamine on social processing and behavior. AB - RATIONALE: Drug users often report using drugs to enhance social situations, and empirical studies support the idea that drugs increase both social behavior and the value of social interactions. One way that drugs may affect social behavior is by altering social processing, for example by decreasing perceptions of negative emotion in others. OBJECTIVES: We examined effects of d-amphetamine on processing of emotional facial expressions and on the social behavior of talking. We predicted amphetamine would enhance attention, identification, and responsivity to positive expressions, and that this in turn would predict increased talkativeness. METHODS: Over three sessions, 36 healthy normal adults received placebo, 10, and 20 mg d-amphetamine under counterbalanced double-blind conditions. At each session, we measured processing of happy, fearful, sad, and angry expressions using an attentional visual probe task, a dynamic emotion identification task, and measures of facial muscle activity. We also measured talking. RESULTS: Amphetamine decreased the threshold for identifying all emotions, increased negative facial responses to sad expressions, and increased talkativeness. Contrary to our hypotheses, amphetamine did not alter attention to, identification of, or facial responses to positive emotions specifically. Interestingly, the drug decreased the threshold to identify all emotions, and this effect was uniquely related to increased talkativeness, even after controlling for overall sensitivity to amphetamine. CONCLUSIONS: The results suggest that amphetamine may encourage sociability by increasing sensitivity to subtle emotional expressions. These findings suggest novel social mechanisms that may contribute to the rewarding effects of amphetamine. PMID- 22526539 TI - Facilitation of extinction of operant behaviour in C57Bl/6 mice by chlordiazepoxide and D-cycloserine. AB - RATIONALE AND OBJECTIVE: Effects on the extinction of GABAergic drug, chlordiazepoxide (CDP), and glutamatergic drug, D: -cycloserine (DCS), in C57BL/6 mice were compared. MATERIALS AND METHODS: Following a palatability test (Experiment 1), Experiments 2-6 involved food-reinforced lever press training followed by extinction sessions at 1- or 4-day intervals. The effects of drugs were examined. Experiment 7 involved a two-lever task. RESULTS: CDP did not affect food palatability (Experiment 1), but facilitated extinction when administered prior to extinction sessions via intracerebral (Experiment 2) or peripheral administration at 1-day (Experiments 3-7) or 4-day intervals (Experiment 6). Reducing the amount of training prior to extinction reduced the delay in the effect of CDP typically seen, and CDP had a larger effect in early sessions on mice that had received less training (Experiment 3). There was some evidence that CDP could be blocked by flumazenil (Experiment 4), and CDP withdrawal reversed extinction facilitation (Experiments 5 and 7). With 4-day intervals, DCS administered immediately following extinction sessions, or pre session CDP, facilitated extinction with 48-trial sessions (experiment 6B). With six-trial sessions, the co-administration of post-session DCS enhanced facilitation produced by pre-session CDP (experiment 6A). Finally, CDP facilitated extinction in a dose-related fashion following training on a two lever food-reinforced task (Experiment 7). CONCLUSIONS: The findings are consistent with the hypotheses that two neurotransmitter systems have different roles in operant extinction and that glutamatergic systems are involved in extinction learning and GABAergic systems involved in the expression of that learning. This parallels findings with extinction following Pavlovian conditioning, which has been more extensively investigated. PMID- 22526540 TI - Effects of AZD3480, a neuronal nicotinic acetylcholine receptor agonist, and donepezil on dizocilpine-induced attentional impairment in rats. AB - BACKGROUND AND RATIONALE: Nicotinic acetylcholine systems play major roles in cognitive function. Nicotine and a variety of nicotinic agonists improve attention, and nicotinic antagonist exposure impairs it. This study was conducted to investigate the effect of a novel nicotinic receptor agonist at alpha4beta2 nicotinic receptors (AZD3480) on attention and reversal of pharmacologically induced attentional impairment produced by the NMDA glutamate antagonist dizocilpine (MK-801). METHODS: Adult female Sprague-Dawley rats were trained to perform an operant visual signal detection task to a stable baseline of accuracy. The rats were then injected subcutaneously following a repeated measures, counter balanced design with saline, AZD3480 (0.01, 0.1, and 1 mg/kg), dizocilpine (0.05 mg/kg), or their combinations 30 min before the test. The effect of donepezil on the same pharmacologically induced attentional impairment was also tested. A separate group of rats was injected with donepezil (0.01, 0.1, and 1 mg/kg), dizocilpine (0.05 mg/kg), or their combinations, and their attention were assessed. Saline was the vehicle control. RESULTS: Dizocilpine caused a significant (p < 0.0005) impairment in percent correct performance. This attentional impairment was significantly (p < 0.0005) reversed by 0.01 and 0.1 mg/kg of AZD3480. AZD3480 by itself did not alter the already high baseline control performance. Donepezil (0.01-1.0 mg/kg) also significantly (p < 0.005) attenuated the dizocilpine-induced attentional impairment. CONCLUSIONS: AZD3480, similar to donepezil, showed significant efficacy for counteracting the attentional impairment caused by the NMDA glutamate antagonist dizocilpine. Low doses of AZD3480 may provide therapeutic benefit for reversing attentional impairment in patients suffering from cognitive impairment due to glutamatergic dysregulation and likely other attentional disorders. PMID- 22526541 TI - Development of stereotyped behaviors during prolonged escalation of methamphetamine self-administration in rats. AB - RATIONALE: Experimental animal studies have shown that repeated administration of psychostimulants, such as methamphetamine (METH), results in an altered behavioral response profile, which includes the sensitization of both locomotor and stereotyped behaviors. Although sensitization of these behaviors has been characterized in detail during bolus, investigator-administered drug administration, little is known about the development or expression of stereotypies during psychostimulant self-administration. OBJECTIVE/METHODS: The present study investigated in rats the expression of focused stereotyped behaviors during an extended access, escalation procedure of METH self administration. Over several weeks during stepwise-extended daily access to METH (3, 6, and 12 h) followed by exposure to 24-h "binges," rats gradually increased daily drug intake. RESULTS: During the escalation procedure, the rats' behavioral response evolved from locomotor activation to progressively more focused stereotypies, culminating in continuous oral behaviors (licking, gnawing, and chewing), interrupted only by episodic lever presses. Sensitization of stereotyped behaviors was evident, particularly with regard to oral behaviors that exhibited a more rapid onset and intensification in the apparent absence of greater drug intake. CONCLUSIONS: Our data demonstrate that stepwise-extended daily access to METH (3, 6, 12, and 24 h) self-administration in rats closely approximates motivational, pharmacokinetic, as well as behavioral patterns of human METH abuse. The accompanied appearance of sensitization of intense focused stereotyped behaviors, which is probably a consequence of escalation of drug intake, resembles stereotypies associated with investigator-initiated METH administration and may parallel the development of stimulant-induced psychosis seen in human abusers. PMID- 22526542 TI - Role of nicotinic acetylcholine receptors in the effects of cocaine-paired contextual stimuli on impulsive decision making in rats. AB - RATIONALE: Chronic cocaine exposure produces unconditioned enhancement in impulsive decision making; however, little is known about the effects of cocaine paired conditioned stimuli on this behavior. Thus, this study explored the effects of cocaine-paired contextual stimuli on impulsive decision making and the contribution of nicotinic acetylcholine receptors (nAChRs) to this phenomenon. METHODS: Rats were trained to achieve stable performance on a delay discounting task, which involved lever press-based choice between a single food pellet (small reward) available immediately and three food pellets (large reward) available after a 10-, 20-, 40-, or 60-s time delay. Rats then received Pavlovian context cocaine (15 mg/kg, i.p.) and context-saline (1 ml/kg, i.p.) pairings in two other, distinct contexts. Subsequently, delay discounting task performance was assessed in the previously cocaine-paired or saline-paired context following pretreatment with saline or cocaine (15 mg/kg, Experiment 1) or with saline or the nAChR antagonist, mecamylamine (0.2 and 2 mg/kg, Experiment 2), using counterbalanced within-subjects testing designs. RESULTS: Independent of cocaine pretreatment, rats exhibited greater decrease in preference for the large reward as a function of delay duration in the cocaine-paired context, relative to the saline-paired context. Furthermore, systemic mecamylamine pretreatment dose dependently attenuated the decrease in preference for the large reward in the cocaine-paired context, but not in the saline-paired context, as compared to saline. CONCLUSION: Cocaine-paired contextual stimuli evoke a state of impulsive decision making, which requires nAChR stimulation. Drug context-induced impulsivity likely increases the propensity for drug relapse in cocaine users, making the nAChR an interesting target for drug relapse prevention. PMID- 22526543 TI - Effects of the kappa opioid receptor antagonist, norbinaltorphimine, on stress and drug-induced reinstatement of nicotine-conditioned place preference in mice. AB - RATIONALE: Several studies implicate stress as a risk factor for the development and maintenance of drug addictive behaviors and drug relapse. Kappa opioid receptor (KOR) antagonists have been shown to attenuate behavioral responses to stress and stress-induced reinstatement of cocaine and ethanol seeking and preference. OBJECTIVES: In the current study, we determined whether the selective KOR antagonist, norbinaltorphimine (nor-BNI), would block stress-induced reinstatement of nicotine preference. METHODS: Adult Institute of Cancer Research mice were conditioned with 0.5 mg/kg nicotine, injected subcutaneously (s.c.) for 3 days and tested in the nicotine-conditioned place preference (CPP) model. After 3 days extinction, nor-BNI (10 mg/kg, s.c.) was administered 16 h prior to a priming dose of nicotine (0.1 mg/kg, s.c.), and mice were tested in the CPP model for nicotine-induced reinstatement of CPP. A separate group of mice was subjected to a 2-day modified forced swim test (FST) paradigm to induce stress after 3 days extinction from CPP. Mice were given vehicle or nor-BNI (10 mg/kg, s.c.) 16 h prior to each FST session. RESULTS: Nor-BNI pretreatment significantly attenuated stress-induced reinstatement of nicotine-CPP, but had no effect on nicotine primed reinstatement. CONCLUSIONS: Blockade of KORs by selective antagonists attenuates stress-induced reinstatement of nicotine-CPP. Overall, the kappa opioid system may serve as a therapeutic target for suppressing multiple signaling processes which contribute to maintenance of smoking, smoking relapse, and drug abuse in general. PMID- 22526544 TI - Defensive effect of natrium diethyldithiocarbamate trihydrate (NDDCT) and lisinopril in DOCA-salt hypertension-induced vascular dementia in rats. AB - RATIONALE: Vascular dementia and hypertension are increasing day by day, with a high degree of co-occurrence. Tremendous amount of research work is required so that new pharmacological agents may be identified for their appropriate therapeutic utility to combat different dementing disorders. OBJECTIVES: This study investigates the effect of natrium diethyldithiocarbamate trihydrate (NDDCT), a nuclear factor kappa-B (NF-kappaB) inhibitor, as well as lisinopril, an angiotensin converting enzyme (ACE) inhibitor, on deoxycorticosterone acetate (DOCA) hypertension-induced vascular dementia in rats. METHODS: DOCA was used to induce hypertension and associated vascular dementia. Morris water maze (MWM) was used for testing learning and memory. Endothelial function was assessed by acetylcholine-induced endothelium-dependent relaxation of aortic strips. Different biochemical estimations were used to assess oxidative stress (aortic superoxide anion, serum and brain thiobarbituric acid reactive species, and brain glutathione), nitric oxide levels (serum nitrite/nitrate), and cholinergic activity (brain acetyl cholinesterase activity). RESULTS: DOCA treatment significantly raised the mean arterial blood pressure of rats, and these hypertensive rats performed poorly on MWM, reflecting impairment of learning and memory. DOCA treatment also impaired vascular endothelial function and different biochemical parameters. Treatments of NDDCT as well as lisinopril significantly attenuated DOCA hypertension-induced impairment of learning and memory, endothelial dysfunction, and changes in various biochemical levels. CONCLUSIONS: DOCA-salt hypertension induces vascular dementia in rats. NF-kappaB as well as ACE inhibitors may be considered as potential pharmacological agents for the management of hypertension-induced vascular dementia. PMID- 22526546 TI - Hirschsprung's disease and medullary thyroid carcinoma. PMID- 22526545 TI - Role of lymphoscintigraphy and sentinel lymph node biopsy in the management of pediatric melanoma and sarcoma. AB - PURPOSE: The purpose of this study was to describe the use of lymphoscintigraphy and sentinel lymph-node biopsy (SLNB) for the management of children with melanoma and sarcomas. We report the experience of two children's hospitals that utilize this technique to identify sentinel lymph nodes for lymph-node biopsy and dissection. METHODS: We identified 56 patients (median age 10.8 years) who underwent 58 lymphoscintigraphy procedures. There were 33 patients with melanoma and melanocytic lesions, and 23 with sarcomas. RESULTS: Of 58 lymphoscintigraphy procedures, sentinel lymph nodes were identified in 52 (90% success rate). Using the combination of intraoperative blue dye injection and lymphoscintigraphy, the success rate was 95% (55/58). Metastatic disease was found in 14 sentinel lymph nodes (13 patients with melanoma and melanocytic lesions, and 1 patient with rhabdomyosarcoma). CONCLUSION: We have found that lymphoscintigraphy with SLNB is an effective method to identify patients who may benefit from more extensive lymph-node dissection and to identify those patients who are unlikely to benefit from further lymph-node exploration. PMID- 22526547 TI - Infantile pulmonary tuberculosis: the great mimic. AB - PURPOSE: Infantile tuberculosis is common in developing countries and rarely presents as space occupying thoracic lesions mimicking congenital malformations. This case series reviews four such infants with varied presentations and their outcome. METHODS: Four cases of infantile pulmonary/mediastinal tuberculosis that presented like congenital thoracic lesions are described. Details of demography, symptomatology, contact history, immunization status, provisional diagnosis, tuberculin testing, imaging, histopathology, final diagnosis, management and outcome were retrospectively collated and analyzed. RESULTS: They were 4-6-month males, term-born and immunized. They presented with pneumonia/hyperactive airway disease since 2-12 weeks. One had a suspect and another a close tuberculous contact. The provisional diagnosis after imaging were infected congenital lung cyst, posterior mediastinal cyst and bronchopulmonary malformation. Two were tuberculin positive; none had gastric acid-fast bacilli. One underwent a pulmonary lobectomy for necrotic lung cyst; the second had a biopsy and drainage of a posterior mediastinal cyst that contained caseating material and was densely adherent to the esophagus. Surgical biopsy showed necrotizing granulomatous inflammation in both; one with acid-fast bacilli. Both succumbed to postoperative complications. The other two with tuberculous contacts who were managed with early antituberculous therapy, responded well and recovered uneventfully. CONCLUSIONS: Infantile pulmonary/mediastinal tuberculosis may mimic congenital thoracic malformations. A review of contact history, investigations and imaging help to establish the tuberculous etiology, avoids surgical misadventures and prompts early antituberculous therapy to achieve a favorable outcome. PMID- 22526548 TI - In vitro evaluation of the Aurora kinase inhibitor VX-680 for Hepatoblastoma. AB - PURPOSE: Hepatoblastoma (HB) has a poor prognosis in advanced stages. The aim of this study was to enhance effectiveness of chemotherapy with antineoplastic kinase inhibitors. METHODS: Viability was monitored in HB cells (HUH6, HepT1) in monolayer and spheroid cultures treated with kinase inhibitors VX-680, Wee1 InhibitorII, and SU11274 alone or in combination with cisplatin (CDDP) using MTT assays. Apoptosis was revealed by Caspase-3 assay. Western blot and immunohistochemical analyses were performed to determine histone H3 phosphorylation. RESULTS: Among the kinase inhibitors strongest anti proliferative effect on HB cells was documented for VX-680. HUH6 cells responded more sensitively to the Aurora kinase inhibitor as HepT1 cells (IC(50) 8 and 16.6 MUM, respectively). While VX-680 and CDDP showed no additive effects, the combination of VX-680 and histone deacetylase inhibitor SAHA had a synergistic effect on the proliferation of HUH6 cells. The inhibition with VX-680 led to reduced histone H3 phosphorylation, to an increase of apoptotic cells, and to morphological changes such as vacuolization and swelling of the cells and nuclei. CONCLUSION: The data provide evidence that VX-680 might improve treatment results in HB with increased Aurora kinase activity by inhibiting cell proliferation and induction of apoptosis. PMID- 22526549 TI - A new sternum elevator reduces severe complications during minimally invasive repair of the pectus excavatum. AB - INTRODUCTION: Although the Nuss procedure for pectus excavatum is widely employed, a variety of complications have been reported with relatively high frequency; those that involve cardiac and pericardial injuries can be life threatening. To reduce such dangers, we present here a newly developed sternal elevator. MATERIALS AND METHODS: The elevator is horseshoe shaped. Its elevator side has the same curvature as a Nuss introducer, so that interference between devices is minimal and no extra skin incision is needed for the elevator insertion. The elevator holds the sternum forward and enlarges the retrosternal space for safer passage of thoracoscopically guided introducer. RESULTS: The authors have used the elevator for 61 pectus excavatum cases between March 2004 and December 2009 without any major complications. The entire process of substernal tunneling was endoscopically observed, which eliminated any blunt and blind dissection, even in a significantly depressed funnel chest case. With the device, the sternum was effectively elevated again for the placement of the second plate in 30 cases. CONCLUSION: Our newly developed sternum elevator makes the Nuss procedure safer and more affordable without introducing any extra scarring. PMID- 22526550 TI - Intralobar pulmonary sequestration: an uncommon case with triple arterial supply and systemic venous drainage. AB - Pulmonary sequestration is a rare congenital pulmonary malformation. We report a case of a 10-month-old infant with intralobar pulmonary sequestration diagnosed in utero. The lesion had an uncommon blood supply consisting of three large arteries deriving from the thoracic aorta and venous drainage into the inferior vena cava. PMID- 22526551 TI - Concordance of imaging modalities and cost minimization in the diagnosis of pediatric choledochal cysts. AB - PURPOSE: Given evolving imaging technologies, we noted significant variation in the diagnostic evaluation of pediatric choledochal cysts (CDC). To streamline the diagnostic approach to CDC, and minimize associated expenses, we compared typing accuracy and costs of ultrasound (US), intraoperative cholangiography (IOC), and magnetic resonance cholangiopancreatography (MRCP). METHODS: Records of 30 consecutive pediatric CDC patients were reviewed. Blinded to all clinical data, two pediatric radiologists reviewed all US, MRCPs, and IOCs to type CDCs according to the Todani classification. When compared with pathologic findings, the concordance between and accuracy of each diagnostic test were determined. Inflation-adjusted procedure charges and collections for imaging modalities were analyzed. RESULTS: Mean typing accuracy overlapped for US, IOC, and MRCP. Inter rater reliability was 87 % for US (kappa = 0.77), 80 % for IOC (kappa = 0.62), and 60 % for MRCP (kappa = 0.37). MRCP procedure charges ($1204.69) and collections ($420.85) exceeded IOC and US combined ($264.80 charges, p = 0.0002; $93.40 collections, p = 0.0021). CONCLUSION: Our data support the use of US alone in the diagnosis of pediatric CDC when no intrahepatic biliary ductal dilatation is visualized. However, when dilated intrahepatic ducts are encountered on US, MRCP should be utilized to distinguish a type I from a type IV CDC, which may alter the operative approach. PMID- 22526552 TI - Colorectal carcinomas in children: an institutional experience. AB - PURPOSE: Colorectal carcinoma (CRC) is a rare malignancy in children. Due to its rarity this disease is seldom suspected in children and adolescents suffering from abdominal symptoms. Therefore, diagnosis is often delayed. The aim of the present study was to raise attention to this diagnosis and to present three very special cases of CRC in children treated at our department. METHODS: Patients' charts of all children treated at our department with colorectal carcinomas between 2000 and 2010 were analyzed. RESULTS: In the last 10 years three cases of CRC have been treated. The first patient was diagnosed a colon carcinoma following treatment of appendicitis, while the colon carcinoma could be resected without a recurrence. The genetic analysis demonstrated a high microsatellite instability. Subsequently, 4 years later, the patient developed an inoperable astrocytoma leading to the final diagnosis of a Turcot's syndrome. The second patient developed a colon carcinoma as a true second malignancy 10 years following an osteosarcoma. The third patient was diagnosed primarily with multiple metastases of a carcinoma of the descending colon. All three patients died 7, 8 and 11 years, respectively, following diagnosis. CONCLUSION: Albeit colon carcinomas in children are exceedingly rare, this diagnosis has to be considered in cases of unclear abdominal pain. Early recognition combined with radical surgery represents the mainstay of treatment of this disease in children. PMID- 22526553 TI - The timing of ostomy closure in infants with necrotizing enterocolitis: a systematic review. AB - PURPOSE: The optimal timing of ostomy closure is a matter of debate. We performed a systematic review of outcomes of early ostomy closure (EC, within 8 weeks) and late ostomy closure (LC, after 8 weeks) in infants with necrotizing enterocolitis. METHODS: PubMed, EMbase, Web-of-Science, and Cinahl were searched for studies that detailed time to ostomy closure, and time to full enteral nutrition (FEN) or complications after ostomy closure. Patients with Hirschsprung's disease or anorectal malformations were excluded. Analysis was performed using SPSS 17 and RevMan 5. RESULTS: Of 778 retrieved articles, 5 met the inclusion criteria. The median score for study quality was 9 [range 8-14 on a scale of 0 to 32 points (Downs and Black, J Epidemiol Community Health 52:377 384, 1998)]. One study described mean time to FEN: 19.1 days after EC (n = 13) versus 7.2 days after LC (n = 24; P = 0.027). Four studies reported complication rates after ostomy closure, complications occurred in 27% of the EC group versus 23% of the LC group. The combined odds ratio (LC vs. EC) was 1.1 [95% CI 0.5, 2.5]. CONCLUSION: Evidence that supports early or late closure is scarce and the published articles are of poor quality. There is no significant difference between EC versus LC in the complication rate. This systematic review supports neither early nor late ostomy closure. PMID- 22526554 TI - Primary anastomosis in necrotizing enterocolitis: the first option to consider. AB - INTRODUCTION: Necrotizing enterocolitis (NEC) is the most frequent gastrointestinal emergency in preterm newborns. Thirty percent of all cases will require surgical intervention. Following resection of the involved segment, most patients will undergo a diverting enterostomy. OBJECTIVE: To describe the safety and effectiveness of primary anastomosis in patients with complicated NEC. METHODS: This study was a retrospective chart review. The study participants were obtained from both public and private health systems between December 2004 and December 2009 in Santiago, Chile. The inclusion criteria were any patient who underwent a laparotomy for necrotizing enterocolitis. The following variables were evaluated: gestational age, birth weight, use of peritoneal drains, macroscopic features of the intestinal segment, number of anastomoses, parenteral nutrition requirements and post-surgical complications. RESULTS: Seventy patients were identified. Sixty patients (85%) underwent primary anastomosis. The remaining 10 patients underwent a resection with enterostomy. In the primary anastomosis group (n = 60), twelve percent weighed <1,000 g and 22% weighed 1,000 1,500 g. Two anastomoses were required in 18 patients. Post-surgical complications included infection of the surgical wound in three cases and anastomotic dehiscence in only one case. Seven percent developed short bowel syndrome. Overall mortality was 11.6%, all secondary to sepsis. CONCLUSION: In this series, primary anastomosis was a safe alternative in the management of complicated NEC, with low morbidity and mortality, independent of age, weight, intraperitoneal contamination or extent of disease. PMID- 22526555 TI - Proton-coupled hole hopping in nucleosomal and free DNA initiated by site specific hole injection. AB - Nucleosomes were reconstituted from recombinant histones and a 147-mer DNA sequence containing the damage reporter sequence 5' ...d([2AP]T[GGG](1)TT[GGG](2)TTT[GGG](3)TAT)... with 2-aminopurine (2AP) at position 27 from the dyad axis. Footprinting studies with OH radicals reflect the usual effects of "in" and "out" rotational settings, while, interestingly, the guanine oxidizing one-electron oxidant CO(3)(-) radical does not. Site-specific hole injection was achieved by 308 nm excimer laser pulses to produce 2AP(+) cations, and superoxide via the trapping of hydrated electrons. Rapid deprotonation (~100 ns) and proton coupled electron transfer generates neutral guanine radicals, G(-H) and hole hopping between the three groups of [GGG] on micro- to millisecond time scales. Hole transfer competes with hole trapping that involves the combination of O(2)(-) with G(-H) radicals to yield predominantly 2,5-diamino-4H-imidazolone (Iz) and minor 8-oxo-7,8-dihydroguanine (8-oxoG) end products in free DNA (Misiaszek et al., J. Biol. Chem. 2004, 279, 32106). Hole migration is less efficient in nucleosomal than in the identical protein-free DNA by a factor of 1.2-1.5. The Fpg/piperidine strand cleavage ratio is ~1.0 in free DNA at all three GGG sequences and at the "in" rotational settings [GGG](1,3) facing the histone core, and ~2.3 at the "out" setting at [GGG](2) facing away from the histone core. These results are interpreted in terms of competitive reaction pathways of O(2)(-) with G(-H) radicals at the C5 (yielding Iz) and C8 (yielding 8-oxoG) positions. These differences in product distributions are attributed to variations in the local nucleosomal B-DNA base pair structural parameters that are a function of surrounding sequence context and rotational setting. PMID- 22526556 TI - Selective effect of the anthelmintic bephenium on Haemonchus contortus levamisole sensitive acetylcholine receptors. AB - Acetylcholine receptors (AChRs) are pentameric ligand-gated ion channels involved in the neurotransmission of both vertebrates and invertebrates. A number of anthelmintic compounds like levamisole and pyrantel target the AChRs of nematodes producing spastic paralysis of the worms. The muscle AChRs of nematode parasites fall into three pharmacological classes that are preferentially activated by the cholinergic agonists levamisole (L-type), nicotine (N-type) and bephenium (B type), respectively. Despite a number of studies of the B-type AChR in parasitic species, this receptor remains to be characterized at the molecular level. Recently, we have reconstituted and functionally characterized two distinct L AChR subtypes of the gastro-intestinal parasitic nematode Haemonchus contortus in the Xenopus laevis oocyte expression system by providing the cRNAs encoding the receptor subunits and three ancillary proteins (Boulin et al. in Br J Pharmacol 164(5):1421-1432, 2011). In the present study, the effect of the bephenium drug on Hco-L-AChR1 and Hco-L-AChR2 subtypes was examined using the two-microelectrode voltage-clamp technique. We demonstrate that bephenium selectively activates the Hco-L-AChR1 subtype made of Hco-UNC-29.1, Hco-UNC-38, Hco-UNC-63, Hco-ACR-8 subunits that is more sensitive to levamisole than acetylcholine. Removing the Hco-ACR-8 subunit produced the Hco-L-AChR2 subtype that is more sensitive to pyrantel than acetylcholine and partially activated by levamisole, but which was bephenium-insensitive indicating that the bephenium-binding site involves Hco-ACR 8. Attempts were made to modify the subunit stoichiometry of the Hco-L-AChR1 subtype by injecting five fold more cRNA of individual subunits. Increased Hco unc-29.1 cRNA produced no functional receptor. Increasing Hco-unc-63, Hco-unc-38 or Hco-acr-8 cRNAs did not affect the pharmacological characteristics of Hco-L AChR1 but reduced the currents elicited by acetylcholine and the other agonists. Here, we provide the first description of the molecular composition and functional characteristics of any invertebrate bephenium-sensitive receptor. PMID- 22526559 TI - Iron and ER stress in neurodegenerative disease. AB - Neurodegenerative disease is a condition in which subpopulations of neuronal cells of the brain and spinal cord are selectively lost. A common event in many neurodegenerative diseases is the increased level of endoplasmic reticulum (ER) stress caused by accumulation and deposits of inclusion bodies that contain abnormal aggregated proteins. However, the basis of how ER stress contributes to the selective neuronal vulnerability and degeneration remain elusive. Iron accumulation in the central nerve system is consistently present in many neurodegenerative diseases. In the past 5 years we have begun to show a relationship between polymorphisms in the HFE (high iron) gene and the risk of neurodegenerative disorders. Recent findings have suggested a connection between ER stress and iron metabolism and neurodegeneration. Here we review how the different levels of chronic ER stress contribute to the different fates of neurons, namely the adaptive response and neuronal death. And, we discuss the roles of iron and HFE genotype in selective neuronal vulnerability and degeneration through modifying the ER stress level. PMID- 22526560 TI - Sub-lethal levels of amyloid beta-peptide oligomers decrease non-transferrin bound iron uptake and do not potentiate iron toxicity in primary hippocampal neurons. AB - Two major lesions are pathological hallmarks in Alzheimer's disease (AD): the presence of neurofibrillary tangles formed by intracellular aggregates of the hyperphosphorylated form of the cytoskeletal tau protein, and of senile plaques composed of extracellular aggregates of amyloid beta (Abeta) peptide. Current hypotheses regard soluble amyloid beta oligomers (AbetaOs) as pathological causative agents in AD. These aggregates cause significant calcium deregulation and mediate neurotoxicity by disrupting synaptic activity. Additionally, the presence of high concentrations of metal ions such as copper, zinc, aluminum and iron in neurofibrillary tangles and senile plaques, plus the fact that they accelerate the rate of formation of Abeta fibrils and AbetaOs in vitro, suggests that accumulation of these metals in the brain is relevant to AD pathology. A common cellular response to AbetaOs and transition metals such as copper and iron is the generation of oxidative stress, with the ensuing damage to cellular components. Using hippocampal neurons in primary culture, we report here the effects of treatment with AbetaOs on the (+)IRE and (-)IRE mRNA levels of the divalent metal transporter DMT1. We found that non-lethal AbetaOs concentrations decreased DMT1 (-)IRE without affecting DMT1 (+)IRE mRNA levels, and inhibited non-transferrin bound iron uptake. In addition, since both iron and AbetaOs induce oxidative damage, we studied whether their neurotoxic effects are synergistic. In the range of concentrations and times used in this study, AbetaOs did not potentiate iron-induced cell death while iron chelation did not decrease AbetaOs-induced cell death. The lack of synergism between iron and AbetaOs suggests that these two neurotoxic agents converge in a common target, which initiates signaling processes that promote neurodegeneration. PMID- 22526557 TI - Biogenic amines and the control of neuromuscular signaling in schistosomes. AB - Biogenic amines are small cationic monoamines that function broadly as neurotransmitters and/or neuromodulators in every animal phylum. They include such ubiquitous substances as serotonin, dopamine and invertebrate-specific phenolamines (tyramine, octopamine), among others. Biogenic amines are important neuroactive agents in all the flatworms, including blood flukes of the genus Schistosoma, the etiological agents of human schistosomiasis. A large body of evidence spanning nearly five decades identifies biogenic amines as major modulators of neuromuscular function in schistosomes, controlling movement, attachment to the host and other fundamental behaviors. Recent advances in schistosome genomics have made it possible to dissect the molecular mechanisms responsible for these effects and to identify the proteins involved. These efforts have already provided important new information about the mode of action of amine transmitters in the parasite. Moreover, these advances are continuing, as the field moves into a post-genomics era, and new molecular tools for gene and protein analysis are becoming available. Here, we review the current status of this research and discuss future prospects. In particular, we focus our attention on the receptors that mediate biogenic amine activity, their structural characteristics, functional properties and "druggability" potential. One of the themes that will emerge from this discussion is that schistosomes have a rich diversity of aminergic receptors, many of which share little sequence homology with those of the human host, making them ideally suited for selective drug targeting. Strategies for the characterization of these important parasite proteins will be discussed. PMID- 22526561 TI - Increased copper levels in in vitro and in vivo models of Niemann-Pick C disease. AB - Niemann-Pick type C disease (NPC) is a hereditary neurovisceral atypical lipid storage disorder produced by mutations in the NPC1 and NPC2 genes. The disease is characterized by unesterified cholesterol accumulation in late endosomal/lysosomal compartments and oxidative stress. The most affected tissues are the cerebellum and the liver. The lysotropic drug U18666A (U18) has been widely used as a pharmacological model to induce the NPC phenotype in several cell culture lines. It has already been reported that there is an increase in copper content in hepatoma Hu7 cells treated with U18. We confirmed this result with another human hepatoma cell line, HepG2, treated with U18 and supplemented with copper in the media. However, in mouse hippocampal primary cultures treated under similar conditions, we did not find alterations in copper content. We previously reported increased copper content in the liver of Npc1 (-/-) mice compared to control animals. Here, we extended the analysis to the copper content in the cerebella, the plasma and the bile of NPC1 deficient mice. We did not observe a significant change in copper content in the cerebella, whereas we found increased copper content in the plasma and decreased copper levels in the bile of Npc1(-/-) mice. Finally, we also evaluated the plasma content of ceruloplasmin, and we found an increase in this primary copper-binding protein in Npc1 (-/-) mice. These results indicate cell-type dependence of copper accumulation in NPC disease and suggest that copper transport imbalance may be relevant to the liver pathology observed in NPC disease. PMID- 22526562 TI - Spectroscopic and electrochemical characterization of gold(I) and gold(III) complexes with glyoxaldehyde bis(thiosemicarbazones): cytotoxicity against human tumor cell lines and inhibition of thioredoxin reductase activity. AB - Complexes [Au(2)(H(2)Gy3DH)(2)]Cl(2) (1), [Au(H(2)Gy3Me)]Cl(3) (2) and [Au(H(2)Gy3Et)]Cl(3) (3) were obtained with glyoxaldehyde bis(thiosemicarbazone) (H(2)Gy3DH) and its N(3)-methyl (H(2)Gy3Me) and N(3)-ethyl (H(2)Gy3Et) derivatives. The bis(thiosemicarbazones) and their gold(I) and gold(III) complexes exhibited anti-proliferative activity against HL-60, Jurkat (leukemia) and MCF-7 (breast cancer) cells at 10 MUmol L(-1). Complex (2) was able to in vitro inhibit thioredoxin reductase (TrxR) activity, which suggests that inhibition of TrxR could be part of its mechanism of action. PMID- 22526563 TI - Application of DFT methods to the study of the coordination environment of the VO2+ ion in V proteins. AB - Density functional theory (DFT) methods were used to simulate the environment of vanadium in several V proteins, such as vanadyl-substituted carboxypeptidase (sites A and B), vanadyl-substituted chloroplast F(1)-ATPase (CF(1); site 3), the reduced inactive form of vanadium bromoperoxidase (VBrPO; low- and high-pH sites), and vanadyl-substituted imidazole glycerol phosphate dehydratase (IGPD; sites alpha, beta, and gamma). Structural, electron paramagnetic resonance, and electron spin echo envelope modulation parameters were calculated and compared with the experimental values. All the simulations were performed in water within the framework of the polarizable continuum model. The angular dependence of [Formula: see text] and [Formula: see text] on the dihedral angle theta between the V=O and N-C bonds and on the angle phi between the V=O and V-N bonds, where N is the coordinated aromatic nitrogen atom, was also found. From the results it emerges that it is possible to model the active site of a vanadium protein through DFT methods and determine its structure through the comparison between the calculated and experimental spectroscopic parameters. The calculations confirm that the donor sets of sites B and A of vanadyl-substituted carboxypeptidase are [[Formula: see text], H(2)O, H(2)O, H(2)O] and [N(His)(||), N(His)(?), [Formula: see text], H(2)O], and that the donor set of site 3 of CF(1) ATPase is [[Formula: see text], OH(Thr), H(2)O, H(2)O, [Formula: see text]]. For VBrPO, the coordination modes [N(His)(||), N(His)(?), OH(Ser), H(2)O, H(2)O(ax)] for the low-pH site and [N(His)(||), N(His)(?), OH(Ser), OH(-), H(2)O(ax)] or [N(His)(||), N(His)(?), [Formula: see text], H(2)O] for the high-pH site, with an imidazole ring of histidine strongly displaced from the equatorial plane, can be proposed. Finally, for sites alpha, beta, and gamma of IGPD, the subsequent deprotonation of one, two, and three imidazole rings of histidine and the participation of a carboxylate group of a glutamate residue ([N(His)(||), [Formula: see text], H(2)O, H(2)O], [N(His)(||), N(His)(||), [Formula: see text], H(2)O], and [N(His)(||), N(His)(||), [Formula: see text], OH(-), [Formula: see text]], respectively) seems to be the most plausible hypothesis. PMID- 22526564 TI - Dke1--structure, dynamics, and function: a theoretical and experimental study elucidating the role of the binding site shape and the hydrogen-bonding network in catalysis. AB - This study elucidates the role of the protein structure in the catalysis of beta diketone cleavage at the three-histidine metal center of diketone cleaving enzyme (Dke1) by computational methods in correlation with kinetic and mutational analyses. Molecular dynamics simulations, using quantum mechanically deduced parameters for the nonheme Fe(II) cofactor, were performed and showed a distinct organization of the hydrophilic triad in the free and substrate-ligated wild-type enzyme. It is shown that in the free species, the Fe(II) center is coordinated to three histidines and one glutamate, whereas the substrate-ligated, catalytically competent enzyme-substrate complex has an Fe(II) center with three-histidine coordination, with a small fraction of three-histidine, one-glutamate coordination. The substrate binding modes and channels for the traffic of water and ligands (2,4-pentandionyl anion, methylglyoxal, and acetate) were identified. To characterize the impact of the hydrophobic protein environment around the metal center on catalysis, a set of hydrophobic residues close to the active site were targeted. The variations resulted in an up to tenfold decrease of the O(2) reduction rates for the mutants. Molecular dynamics studies revealed an impact of the hydrophobic residues on the substrate stabilization in the active site as well as on the orientations of Glu98 and Arg80, which have previously been shown to be crucial for catalysis. Consequently, the Glu98-His104 interaction in the variants is weaker than in the wild-type complex. The role of protein structure in stabilizing the primary O(2) reduction step in Dke1 is discussed on the basis of our results. PMID- 22526565 TI - The structure of the periplasmic nickel-binding protein NikA provides insights for artificial metalloenzyme design. AB - Understanding the interaction of a protein with a relevant ligand is crucial for the design of an artificial metalloenzyme. Our own interest is focused on the synthesis of artificial monooxygenases. In an initial effort, we have used the periplasmic nickel-binding protein NikA from Escherichia coli and iron complexes in which N(2)Py(2) ligands (where Py is pyridine) have been varied in terms of charge, aromaticity, and size. Six "NikA/iron complex" hybrids have been characterized by X-ray crystallography, and their interactions and solution properties have been studied. The hybrids are stable as indicated by their K (d) values, which are all in the micromolar range. The X-ray structures show that the ligands interact with NikA through salt bridges with arginine residues and pi stacking with a tryptophan residue. We have further characterized these interactions using quantum mechanical calculations and determined that weak CH/pi hydrogen bonds finely modulate the stability differences between hybrids. We emphasize the important role of the tryptophan residues. Thus, our study aims at the complete characterization of the factors that condition the interaction of an artificial ligand and a protein and their implications for catalysis. Besides its potential usefulness in the synthesis of artificial monooxygenases, our approach should be generally applicable in the field of artificial metalloenzymes. PMID- 22526566 TI - Electron transfer between periplasmic formate dehydrogenase and cytochromes c in Desulfovibrio desulfuricans ATCC 27774. AB - Desulfovibrio spp. are sulfate-reducing organisms characterized by having multiple periplasmic hydrogenases and formate dehydrogenases (FDHs). In contrast to enzymes in most bacteria, these enzymes do not reduce directly the quinone pool, but transfer electrons to soluble cytochromes c. Several studies have investigated electron transfer with hydrogenases, but comparatively less is known about FDHs. In this work we conducted experiments to assess potential electron transfer pathways resulting from formate oxidation in Desulfovibrio desulfuricans ATCC 27774. This organism can grow on sulfate and on nitrate, and contains a single soluble periplasmic FDH that includes a cytochrome c (3) like subunit (FdhABC(3)). It has also a unique cytochrome c composition, including two cytochromes c not yet isolated from other species, the split-Soret and nine-heme cytochromes, besides a tetraheme type I cytochrome c (3) (TpIc (3)). The FDH activity and cytochrome composition of cells grown with lactate or formate and nitrate or sulfate were determined, and the electron transfer between FDH and these cytochromes was investigated. We studied also the reduction of the Dsr complex and of the monoheme cytochrome c-553, previously proposed to be the physiological partner of FDH. FdhABC(3) was able to reduce the c-553, TpIc (3), and split-Soret cytochromes with a high rate. For comparison, the same experiments were performed with the [NiFe] hydrogenase from the same organism. This study shows that FdhABC(3) can directly reduce the periplasmic cytochrome c network, feeding electrons into several alternative metabolic pathways, which explains the advantage of not having an associated membrane subunit. PMID- 22526567 TI - Combined antibacterial activity of phage lytic proteins holin and lysin from Streptococcus suis bacteriophage SMP. AB - Development of novel antibacterial agents is required to control infection with multidrug-resistant Streptococcus suis. HolSMP and LySMP, the holin and lysin of S. suis serotype 2 bacteriophage, named SMP, are responsible for lysis of host cells and release of progeny phage. HolSMP and LySMP expressed in Escherichia coli BL21(DE3) exerted efficient activity at 37 degrees C, pH 5.2, with addition of 0.8 % beta-mercaptoethanol. Lytic spectra of purified HolSMP, LySMP or HolSMP + LySMP mixture were investigated. HolSMP, exhibiting a narrow lytic spectrum, was effective against Staphylococcus aureus and Bacillus subtilis, which were insensitive to LySMP. Moreover, HolSMP was identified as a promising antibacterial agent which was able to extend the spectrum of LySMP. The data suggest that combined use of holin and lysin could be a candidate strategy for resolution of drug resistance. PMID- 22526568 TI - Quantification of subgingival bacterial pathogens at different stages of periodontal diseases. AB - Anaerobic gram-negative oral bacteria such as Treponema denticola, Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, Campylobacter rectus, and Fusobacterium nucleatum are closely associated with periodontal diseases. We measured the relative population (bacterial levels) of these oral pathogens in subgingival tissues of patients at different stages of Korean chronic periodontal diseases. We divided the individuals into those with chronic gingivitis (G), moderate periodontitis (P1), severe periodontitis (P2), and normal individuals (N) (n = 20 for each group) and subgingival tissue samples were collected. We used real-time PCR with TaqMan probes to evaluate the change of periodontal pathogens among different stages of periodontitis. Bacterial levels of A. actinomycetemcomitans and C. rectus are significantly increased in individuals with chronic gingivitis and moderate periodontitis, but unchanged in severe periodontitis patients. These results suggest that analyzing certain bacterial levels among total oral pathogens may facilitate understanding of the role of periodontal bacteria in the early stages of periodontitis. PMID- 22526569 TI - Variability of RNA quality extracted from biofilms of foodborne pathogens using different kits impacts mRNA quantification by qPCR. AB - The biofilm formation by foodborne pathogens is known to increase the problem related with surface disinfection procedure in the food processing environment and consequent transmission of these pathogens into the population. Messenger RNA has been increasingly used to understand the action and the consequences of disinfectants in the virulence on such biofilms. RNA quality is an important requirement for any RNA-based analysis since the quality can impair the mRNA quantification. Therefore, we evaluated five different RNA extraction kits using biofilms of the foodborne pathogens Listeria monocytogenes, Escherichia coli, and Salmonella enterica. The five kits yielded RNA with different quantities and qualities. While for E. coli the variability of RNA quality did not affect the quantification of mRNA, the same was not true for L. monocytogenes or S. enterica. Therefore, our results indicate that not all kits are suitable for RNA extraction from bacterial biofilms, and thus, the selection of RNA extraction kit is crucial to obtain accurate and meaningful mRNA quantification. PMID- 22526570 TI - Carbon catabolite control is important for Listeria monocytogenes biofilm formation in response to nutrient availability. AB - The foodborne pathogen Listeria monocytogenes has the ability to develop biofilm in food-processing environment, which becomes a major concern for the food safety. The biofilm formation is strongly influenced by the availability of nutrients and environmental conditions, and particularly enhanced in poor minimal essential medium (MEM) containing glucose rather than in rich brain heart infusion (BHI) broth. To gain better insight into the conserved protein expression profile in these biofilms, the proteomes from biofilm- and planktonic grown cells from MEM with 50 mM glucose or BHI were compared using two dimensional polyacrylamide gel electrophoresis followed by MALDI-TOF/TOF analysis. 47 proteins were successfully identified to be either up (19 proteins) or down (28 proteins) regulated in the biofilm states. Most (30 proteins) of them were assigned to the metabolism functional category in cluster of orthologous groups of proteins. Among them, up-regulated proteins were mainly associated with the pentose phosphate pathway and glycolysis, whereas a key enzyme CitC involved in tricarboxylic acid cycle was down-regulated in biofilms compared to the planktonic states. These data implicate the importance of carbon catabolite control for L. monocytogenes biofilm formation in response to nutrient availability. PMID- 22526571 TI - Rapid and sensitive detection of major uropathogens in a single-pot multiplex PCR assay. AB - Urinary tract infection (UTI) is among the most common bacterial infections and poses a significant healthcare burden. Escherichia coli is the most common cause of UTI accounting for up to 70 % and a variable contribution from Proteus mirabilis, Pseudomonas aeruginosa and Klebsiella pneumoniae. To establish a complete diagnostic system, we have developed a single-tube multiplex PCR assay (mPCR) for the detection of the above-mentioned four major uropathogens. The sensitivity of the assay was found to be as low as 10(2) cfu/ml of cells. The mPCR evaluated on 280 clinical isolates detected 100 % of E. coli, P. aeruginosa, P. mirabilis and 95 % of K. pneumonia. The assay was performed on 50 urine samples and found to be specific and sensitive for clinical diagnosis. In addition, the mPCR was also validated on spiked urine samples using 40 clinical isolates to demonstrate its application under different strain used in this assay. In total, mPCR reported here is a rapid and simple screening tool that can compete with conventional biochemical-based screening assays that may require 2-3 days for detection. PMID- 22526572 TI - Acellular dermal (alloderm) grafts versus silastic sheets implants for management of empty nose syndrome. AB - The objective of the study is to conduct a prospective randomized blind clinical study comparing the efficacy and safety of use of acellular dermal (alloderm) grafts versus silastic sheets submucosal implants for management of empty nose syndrome (ENS). A total of 24 patients with a clinical diagnosis of ENS were randomly distributed in two equal groups: silastic implant group and alloderm implant group according to the type of implant used to rebuild the nose. This implant was inserted in submucoperichondrial and/or submucoperiosteal pockets fashioned along the septum, nasal floor, and lateral nasal wall. Subjective evaluation was done by reviewing the Sino-Nasal Outcome Test (SNOT-25), while objective evaluation was done by anterior rhinoscopy and nasal endoscopy. Both groups experienced a significant improvement after surgery (the mean SNOT-25 score before implantation was 61.4 compared to 33.6 after implantation in silastic implant group, while in alloderm implant group, it was 63.7 before surgery compared to 34.2 after implantation). There was no statistical evidence for a significant difference between the two groups. Objective evaluation showed rapid healing with no signs of implant infection, rejection, or allergic reaction in both groups. Both graft materials are well suited to this procedure with no statistical evidence for a significant difference between them. The silastic implant is inert and yet incorporated into the surrounding tissue because of the fashioned macropores. It is available and inexpensive. Acellular dermis graft is reliable, predictable, and readily shaped. Patients of both groups showed marked subjective and objective improvements. The surgical procedure is safe and relatively simple to perform. PMID- 22526573 TI - Swallowing, speech and quality of life in patients undergoing resection of soft palate. AB - The aim of this study was to evaluate swallowing, speech and quality of life in patients undergoing surgery for malignant tumors involving soft palate. We performed a cross sectional study of 23 patients (aged 32-80 years), submitted to soft palate resection, free of disease for at least 1 year. Primary closure of the surgical defect was performed in 5 patients (21.7 %), adaptation of a palatal obturator prosthesis in 2 (8.7 %), myocutaneous flap in 5 (21.7 %), local flap in 2 (8.7 %) and microsurgical free flap in 9 (39.1 %). All patients were submitted to fibreoptic endoscopic evaluation and completed functional and quality of life questionnaires. Functional evaluation of swallowing showed higher prevalence of pooling of food in the nasopharynx in patients submitted to regional flap reconstruction or primary closure (53.9 %). Swallowing difficulties were predominantly related to solid foods (54.5 %) and were associated with more extensive palatal resections. Most individuals submitted to reconstruction with microsurgical flaps had satisfactory velopharyngeal mobility (87 %). The presence of nasal air escape or velopharyngeal gap was minimal in most of the sample. Hypernasality contributed minimally to imprecisions in speech articulation or intelligibility. Vocal alteration did not impact patients' quality of life. Pharyngeal phase of swallowing was satisfactory in most patients. However, nasal reflux and penetration were present in a few patients. Most patients had minimal phono-articulatory alterations as a global outcome. Scores of swallowing and speech parameters regarding the questionnaires used were high, demonstrating minor impact on quality of life. PMID- 22526574 TI - DIY guide-needle-assisted conjunctivodacryocystorhinostomy (CDCR). AB - In this study, we introduce DIY guide-needle-assisted conjunctivodacryocystorhinostomy (CDCR), in which a guide needle helps in measuring the initial Jones tube length for insertion and reduces unnecessary handling for tube changes. Three CDCR procedures were conducted in which the length of the Jones tube was calculated using a 22-gauge DIY guide needle, and a prospective study of tube position change and migration, (a major cause of CDCR failure) was done. Wound healing was almost complete within 4 weeks postoperatively in the osteotomy site, but in cases of partial middle turbinectomy, a little more time was necessary. There was a slight change in Jones tube position in the nasal cavity compared with the expected position of original tube tip, but no tube migration from the caruncle fixation position had occurred by the final follow-up time. This guide-needle-assisted CDCR has multiple advantages, such as easy measurement of the proper initial tube size, utilization of the initial needle path, and easy replacement of tubes. Finally, this approach to CDCR can be readily applied because it uses materials ordinarily found in hospitals to create the devices needed for the procedure, so there is no additional cost. PMID- 22526575 TI - Imaging of ancient Egyptian mummies' temporal bones with digital volume tomography. AB - The radiographic imaging of ancient Egyptian mummies has always been of great interest. Computed tomography is the method of choice to demonstrate bony pathologies with high quality. As digital volume tomography (DVT) is an extension of panoramic tomography with a very high resolution, its qualities were evaluated by examination of temporal bones of Egyptian mummy skulls. Ten Egyptian mummy skulls from the Zoological Collection Marburg, estimated 1,700-5,000 years of age, from Abydos, Philae, Theben-West and Sakkarah, were examined by DVT (3D Accuitomo, Morita, Japan). Through a rotation 360 degrees of the X-ray source around the region of interest, a cylinder of 3 * 4 cm was captured as a three dimensional volume. The gained data were analyzed with the help of special software on a PC. The angles of the axial, coronal and sagittal sections were arbitrarily changed to represent single structures with high resolution of 0.125 mm to analyze specific anatomical structures. In all skulls, conditions of the temporal bone and its anatomical structures were evaluated and normal as well as pathological findings evaluated in detail. The analysis of special landmarks such as the ossicular chain, cochlea, external, and internal auditory canal, facial nerve canal, and semicircular canals showed an intact ossicular chain in six temporal bones, while only isolated and dislocated ossicles were found in eight temporal bones. Besides one dehiscence of the superior semicircular canal in one temporal bone which might have led to vertigo and deafness at lifetime, all other findings were normal. Fragments of foreign bodies additionally found in the labyrinth, external ear canal and intracranially were attributed to postmortem damage. Digital volume tomography extends the imaging possibilities of CT for paleoradiological evaluation of temporal bones. With its high resolution, geometric accuracy, reconstruction capabilities, rapidness, and comparably low costs, even small bony pathologies are precisely demonstrated in a limited area. Investigations of larger numbers of specimen might reveal further details of ancient history for further interdisciplinary investigation of anthropologists, Egyptiologists, otolaryngologists, and radiologists. PMID- 22526576 TI - Investigation of noise levels generated by otologic drills. AB - Drilling during temporal bone surgery may result in temporary or permanent noise induced hearing loss or tinnitus. This has practical implications for both the patient and the surgeon. Different surgical drill devices, routinely used in temporal bone surgery, are examined referring to their emitted sound levels and sound transport. Two surgical drills were used on a brass tubing and a steel wire to simulate sound generation during temporal bone surgery. Overview measurements were performed on human cadaver in a medical laboratory. A set-up in a silent chamber was chosen to exclude external sound sources. The noise emissions and the vibration generated by a silver diamond bur and a cutting drill (Rose bur) were registered when used on a brass tubing and a solid steel wire with sound level meter and a non-contact laser vibrometer. The highest sound rate generated by the diamond burr did not exceed 63 dB(A) when used on a solid steel wire, whereas the cutting burr emitted 76 dB(A). Both drills produced lower sound levels on the brass tubing. Again the cutting burr topped the diamond burr with 68 dB(A) against 56 dB(A). The sound emission did not exceed 76 dB(A) outside a radius 4 cm around the drill location. In conclusion, sound emission generated by different surgical burs routinely used in temporal bone surgery is lower than expected. Still, within a small radius around those burs high sound pressure levels may be induced into surrounding structures such as ossicles, labyrinth, and cochlear. Still damage is feasible when using surgical drills for a longer time period close to sensitive structures. PMID- 22526577 TI - Postoperative pain assessment after functional endoscopic sinus surgery (FESS) for chronic pansinusitis. AB - Postoperative pain after functional endoscopic sinus surgery (FESS) and its optimal management has not been described in detail. The objective was to evaluate pain, its influencing factors and its management on the first postoperative day following FESS. In a prospective case study, 101 FESS patients were examined after removal of the nasal packing within the Quality Improvement in Postoperative Pain Management (QUIPS) project allowing a standardized assessment of patients' characteristics, pain parameters, outcome and process parameters. The influence of these parameters on the patients' postoperative pain was estimated by univariate and multivariate statistic analysis. Pain during the first postoperative day after FESS was moderate. Younger patients reported significantly more pain than did older patients. Specific counseling about the possibilities of postoperative pain management reduced pain intensity highly significantly in univariate and multivariate analysis. Patients demanding for pain relief in the recovery room and on the ward predominantly received acetaminophen as non-opioid and piritramide as opioid. This pain management was obviously insufficient as these patients still reported significantly more from pain on the first postoperative day than patients not demanding for pain relief. We conclude that QUIPS could help to optimize the quality of postoperative pain management following FESS. PMID- 22526578 TI - Genomic differences in benign and malignant follicular thyroid tumours using 1-Mb array-comparative genomic hybridisation. AB - Currently there is a lack of objective markers that can reliably differentiate benign and malignant follicular thyroid tumours. Such markers are needed to avoid the morbidity and cost of diagnosing these lesions by a thyroid lobectomy and then a second operation to remove the remaining half of thyroid if cancer is found. The aim of this research was to look for genomic markers that might solve this important problem. Ethical approval for the project was obtained. DNA was extracted from formalin-fixed paraffin-embedded specimens and copy number analysed using an in-house produced 1-megabase genomic array by comparative genomic hybridization (1Mb-aCGH). Acceptable quality data were obtained in 25/26 (96 %) of adenomas and 17/28 (61 %) of carcinomas. Among the carcinomas, 11 were minimally invasive (MI), 5 widely invasive (WI) and there was one metastasis. Recurrent copy number changes distinguishing benign and malignant included +1p34.2-36.33, +1q, +13q12.11-14.3, +14q22.1-32.33, +20q and -22. +20q became more sensitive (36.4 %) for MI carcinomas, whereas +13q12.11-14.3 and +14q22.1 32.33 became more sensitive (66.7 %) for identifying WI cancers from adenomas. Only in the context of aneuploidy (3 adenomas, 3 MI, 3 WI) there were some specific copy number changes that could differentiate all aneuploid adenomas from carcinomas. This research is the first using 1Mb-aCGH to study benign and malignant follicular thyroid tumours. Overall, the incidence of any copy number changes is low, but there are a number of changes associated with different tumour types. Further research with a larger sample and better quality DNA will clarify these findings. PMID- 22526579 TI - Ocular vestibular evoked myogenic potentials in patients with acoustic neuroma. AB - To assess the usefulness of vestibular testing in patients with acoustic neuroma, considering two main aspects: to compare diagnostic sensitivity of the current vestibular tests, especially considering ocular vestibular evoked myogenic potentials (OVEMPs) and to identify pre-operative localization of the tumor (inferior vestibular nerve vs. superior vestibular nerve) only with the help of vestibular electrophysiological data. Twenty-six patients with unilateral acoustic neuroma (mainly intracanalicular type) were studied with a full audio vestibular test battery (pure tone and speech audiometry, caloric bithermal test, vibration-induced nystagmus test (VIN), cervical and OVEMPs). 18 patients (69 %) showed abnormal caloric responses. 12 patients (46.2 %) showed a pattern of VIN test suggestive of vestibular asymmetry. 16 patients (61.5 %) showed abnormal OVEMPs (12 only to AC, 4 both to AC and BC). 10 patients (38.5 %) showed abnormal cervical vestibular evoked myogenic potentials (5 both to AC and BC, 5 only to AC). In one case, results of vestibular evoked potentials and caloric test were confirmed by intra-operative and post-operative findings. Results of electrophysiological tests in AN patients could be helpful for planning the proper surgical approach, considering that sensitivity of every exam is quite low in intracanalicular lesion; clinical data allow a better interpretation of vestibular evoked myogenic potentials. PMID- 22526581 TI - Azathioprine induced liver injury: a case report. PMID- 22526580 TI - Vestibular rehabilitation strategies and factors that affect the outcome. AB - Ever since the introduction of Cawthorne-Cooksey exercises, vestibular rehabilitation (VR) has been gaining popularity in the treatment of the dizzy patient. Numerous studies support the effectiveness of VR in improving balance/walking skills, eye-head coordination and the quality of life of the patient. Different rehabilitation protocols have been used to treat patients with peripheral and central vestibular disorders. Assessment of the patients' progress is based on the patients' selfperception of dizziness and their functional skills. Factors such as age, medication, time of onset of vertigo and home based VR have been evaluated on their effect on the rehabilitation's outcome. The aim of this review is to evaluate rehabilitation strategies and discuss the factors that affect the outcome. PMID- 22526582 TI - Recurrent duodenal stricture secondary to untreated Crohn's disease. PMID- 22526583 TI - Bin1 attenuation suppresses experimental colitis by enforcing intestinal barrier function. AB - BACKGROUND: Inflammatory bowel disease (IBD) is associated with defects in intestinal barriers that rely upon cellular tight junctions. Thus, identifying genes that could be targeted to enforce tight junctions and improve barrier function may lead to new treatment strategies for IBD. AIMS: This preclinical study aimed to evaluate an hypothesized role for the tumor suppressor gene Bin1 as a modifier of the severity of experimental colitis. METHODS: We ablated the Bin1 gene in a mosaic mouse model to evaluate its effects on experimental colitis and intestinal barrier function. Gross pathology, histology and inflammatory cytokine expression patterns were characterized and ex vivo physiology determinations were conducted to evaluate barrier function in intact colon tissue. RESULTS: Bin1 attenuation limited experimental colitis in a sexually dimorphic manner with stronger protection in female subjects. Colitis suppression was associated with an increase in basal transepithelial electrical resistance (TER) and a decrease in paracellular transepithelial flux, compared to control wild-type animals. In contrast, Bin1 attenuation did not affect short circuit current, nor did it alter the epithelial barrier response to non-inflammatory permeability enhancers in the absence of inflammatory stimuli. CONCLUSIONS: Bin1 is a genetic modifier of experimental colitis that controls the paracellular pathway of transcellular ion transport regulated by cellular tight junctions. Our findings offer a preclinical validation of Bin1 as a novel therapeutic target for IBD treatment. PMID- 22526584 TI - DNA methyltransferases 1 and 3b expression in Huh-7 cells expressing HCV core protein of different genotypes. AB - BACKGROUND: Hepatitis C virus infects ~3% of the population and it is a risk factor for hepatocarcinogenesis. The epigenetic mechanisms of HCV-induced hepatocyte transformation towards malignancy in this context are unclear. AIMS: The purpose of this study was to evaluate the effect of HCV core proteins of different genotypes on DNA methyltransferases (DNMTs) induction. MATERIALS/METHODS: We investigated DNMT1, DNMT3b and E-Cadherin (CDH1) mRNA and protein expression levels in an in vitro model of Huh-7 cells expressing the HCV core protein of different genotypes: 1b, 2a, 3a, 4h and 5a. RESULTS: We found that both mRNA and protein expression levels of DNMT1 and 3b were upregulated in genotype 1b HCV core expressing cells as compared to control cells. DNMT3b mRNA levels did not change in genotypes 2a, 3a, 4h and 5a, but were upregulated at the protein level by genotype 1b, 2a, 3a. CDH1 mRNA expression was downregulated only in genotype 1b, whereas its protein expression resulted in downregulation by the HCV core of genotypes 1b, 2a and 3a. Conversely, no significant changes were observed for DNMTs and CDH1 investigated in Huh-7 cells expressing the genotypes 4h and 5a. Furthermore, we present evidence that HCV core 1b protein expression induces DNMTs overexpression through STAT3 protein as demonstrated by NSC74859 treatment. Moreover, SIRT1 inhibition affected DNMT1 and 3b expression only in HCV core protein genotype 1b expressing cells as demonstrated by treatment with its inhibitor sirtinol. CONCLUSIONS: Our findings suggest that HCV core protein could play a role in HCC development at least in part by altering DNMTs expression. PMID- 22526585 TI - PER1 modulates SGLT1 transcription in vitro independent of E-box status. AB - BACKGROUND AND AIMS: The intestine demonstrates profound circadian rhythmicity in glucose absorption in rodents, mediated entirely by rhythmicity in the transcription, translation, and function of the sodium glucose co-transporter SGLT1 (Slc5a1). Clock genes are rhythmic in the intestine and have been implicated in the regulation of rhythmicity of other intestinal genes; however, their role in the regulation of SGLT1 is unknown. We investigated the effects of one clock gene, PER1, on SGLT1 transcription in vitro. METHODS: Caco-2 cells were stably transfected with knockdown vectors for PER1 and mRNA expression of clock genes and SGLT1 determined using quantitative polymerase chain reaction (qPCR). Chinese hamster ovary (CHO) cells were transiently cotransfected with combinations of the PER1 expression vectors and the wild-type SGLT1-luciferase promoter construct or the promoter with mutated E-box sequences. RESULTS: Knockdown of PER1 increased native SGLT1 expression in Caco-2 enterocytes, while promoter studies confirmed that the inhibitory activity of PER1 on SGLT1 occurs via the proximal 1 kb of the SGLT1 promoter. E-box sites exerted a suppressive effect on the SGLT1 promoter; however, mutation of E-boxes had little effect on the inhibitory activity of PER1 on the SGLT1 promoter suggesting that the actions of PER1 on SGLT1 are independent of E-boxes. CONCLUSIONS: Our findings suggest that PER1 exerts an indirect suppressive effect on SGLT1, possibly acting via other clock-controlled genes binding to non-E-box sites on the SGLT1 promoter. Understanding the regulation of rhythmicity of SGLT1 may lead to new treatments for the modulation of SGLT1 expression in conditions such as malabsorption, diabetes, and obesity. PMID- 22526586 TI - Comparison of the influence of plastic and fully covered metal biliary stents on the accuracy of EUS-FNA for the diagnosis of pancreatic cancer. AB - BACKGROUND AND STUDY AIMS: Prior studies have reported that the presence of prior biliary stent may interfere with EUS visualization of pancreatic tumors. We aimed to compare the influence of the biliary plastic and fully covered self-expanding metal stents (CSEMS) on the accuracy of EUS-FNA cytology in patients with solid pancreatic masses. PATIENTS AND METHODS: We conducted a retrospective study evaluating 677 patients with solid pancreatic head/uncinate lesions and a previous biliary stent in whom EUS-FNA was performed. The patients were stratified into two groups: (1) those with a plastic stents and (2) those with CSEMS. Performance characteristics of EUS-FNA including the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were compared between the two groups. RESULTS: The frequency of obtaining an adequate cytology by EUS-FNA was similar in both the CSEMS group and the plastic stent group (97 vs. 97.1 % respectively; p = 1.0). The sensitivity, specificity, and accuracy of EUS-FNA was not significantly different between patients with CSEMS and plastic stents (96.8, 100, 100 % and 97.3, 98, 99.8 %, respectively). The negative predictive value for EUS-FNA was lower in the CSEMS group compared to the plastic stent group (66.6 vs. 78.1 % respectively; p = 0.42). There was one false-positive cytology in the plastic stent group compared to none in the CSEMS group. CONCLUSIONS: In a retrospective cohort trial, EUS-FNA was found to be highly accurate and safe in diagnosing patients with suspected pancreatic cancer, even in the presence of a plastic or metallic biliary stent. The presence of a stent did not contribute to a higher false-positive cytology rate. PMID- 22526587 TI - KRAS mutation and NF-kappaB activation indicates tolerance of chemotherapy and poor prognosis in colorectal cancer. AB - BACKGROUND: Evidence shows a strong relationship between KRAS mutations and the NF-kappaB signaling pathway. In colorectal cancer, however, the study of this subject has been very limited and results are inconsistent. AIMS: To examine the relationship between KRAS mutations and NF-kappaB activation and their effect on chemotherapy response and survival of colorectal cancer patients. MATERIALS AND METHODS: NF-kappaB activation was analyzed by immunohistochemistry in 167 primary colorectal cancer specimens in which the KRAS mutation status was confirmed. Clinical and pathologic data were extracted from the medical records and reviewed. RESULTS: Of 167 tumors screened, 63 (37.7 %) had NF-kappaB activation, 59 (35.3 %) had KRAS mutations, and 30 (18.0 %) had both NF-kappaB activation and KRAS mutations. The frequency of NF-kappaB activation in tumors with KRAS mutations was significantly higher than in tumors with wild type KRAS; 50.8 versus 30.6 %, P = 0.012. Patients with both KRAS mutations and NF-kappaB activation had a lower objective response to first-line chemotherapy than patients with other tumors, 23.8 versus 49.4 % (P = 0.035). Compared to patients with both KRAS mutations and NF-kappaB activation, overall survival of patients in other groups was significantly higher; median overall survival was 28.4 months (95 % CI 21.0-35.8) versus 46.3 months (95 % CI 39.4-53.2), hazard ratio 0.259 (95 % CI 0.125-0.538), P = 0.005. CONCLUSIONS: NF-kappaB activation was associated with KRAS mutation, and both KRAS mutation and NF-kappaB activation were indicative of high tolerance of chemotherapy and poor prognosis for colorectal cancer patients. Tumors with KRAS mutations and NF-kappaB activation may be a unique subtype of colorectal cancer. PMID- 22526588 TI - Tracheal aspiration of a capsule endoscope: not always a benign event. PMID- 22526589 TI - A comment on "Enteroendocrine and neuronal mechanisms in pathophysiology of acute infectious diarrhea" by Camilleri, Nullens and Nelsen. PMID- 22526590 TI - Efficacy, safety and pharmacokinetics of a novel subcutaneous immunoglobulin, Evogam(r), in primary immunodeficiency. AB - This phase III, open-label, multi-centre study investigated the efficacy, safety, pharmacokinetics and quality of life impact of Evogam((r)), a new chromatographically fractionated 16% subcutaneous immunoglobulin, utilising a 1:1 dose transition ratio from previous immunoglobulin therapy. Thirty-five previously treated patients with primary immunodeficiency received weekly Evogam over 36 weeks. Primary endpoints were rate of serious bacterial infections (SBIs) and steady-state serum immunoglobulin G (IgG) trough concentrations. No SBIs were reported during the study. Evogam produced significantly higher mean trough IgG concentrations with 1:1 dose conversion compared to previous immunoglobulin treatment (8.94 versus 8.27 g/L, p = 0.0063). Evogam was efficacious in the prevention of infections and maintenance of trough levels using a 1:1 dose conversion. It was well tolerated with no withdrawals due to adverse events and was preferred to IVIg by the majority of patients. PMID- 22526591 TI - The spectrum of disease manifestations in patients with common variable immunodeficiency disorders and partial antibody deficiency in a university hospital. AB - BACKGROUND: Common variable immunodeficiency disorders (CVIDs) represents a heterogeneous disease spectrum that includes recurrent infections and complications such as autoimmunity, inflammatory organ disease and an increased risk of cancer. A diagnostic delay is common in CVIDs patients. PURPOSE: To determine the spectrum of clinical manifestations, immunological characteristics, and the time to diagnosis of 61 adult CVIDs and 18 patients with a partial antibody deficiency (SADNI and IgG subclass deficiency). METHODS: A retrospective cohort study was performed in patients who met the ESID/PAGID for CVIDs, IgG subclass deficiency and SADNI. Medical records were reviewed to obtain patient demographics, clinical and laboratory data. RESULTS: Infections were the main presentation of all antibody deficient patients and the number of patients with infections declined during IgG therapy. The development of bronchiectasis continued despite IgG therapy, as well as the development of autoinflammatory conditions. Non-infectious disease complications were present in 30% of CVIDs patients at the time of diagnosis and this increased to 51% during follow up despite IgG therapy. The most common complications were autoimmunity or lymphoproliferative disease. The median time to diagnosis was 10 years and in the patients with non-infectious complications the time to diagnosis was considerably longer when compared to the group of patients without complications (17.6 vs. 10.2 years, p = 0.026). CONCLUSION: In contrast to the partial antibody deficiencies we found a considerable delay in the diagnosis of CVIDs, especially in those patients who were dominated by non-infectious complications, and thus increased awareness would be beneficial. Pulmonary and other complications may continue despite adequate IgG replacement therapy suggesting other causes responsible for these complications. PMID- 22526592 TI - Dual targeting of ErbB2 and MUC1 in breast cancer using chimeric antigen receptors engineered to provide complementary signaling. AB - PURPOSE: Chimeric antigen receptor (CAR) engineered T-cells occupy an increasing niche in cancer immunotherapy. In this context, CAR-mediated CD3zeta signaling is sufficient to elicit cytotoxicity and interferon-gamma production while the additional provision of CD28-mediated signal 2 promotes T-cell proliferation and interleukin (IL)-2 production. This compartmentalisation of signaling opens the possibility that complementary CARs could be used to focus T-cell activation within the tumor microenvironment. METHODS: Here, we have tested this principle by co-expressing an ErbB2- and MUC1-specific CAR that signal using CD3zeta and CD28 respectively. Stoichiometric co-expression of transgenes was achieved using the SFG retroviral vector containing an intervening Thosea asigna peptide. RESULTS: We found that "dual-targeted" T-cells kill ErbB2(+) tumor cells efficiently and proliferate in a manner that requires co-expression of MUC1 and ErbB2 by target cells. Notably, however, IL-2 production was modest when compared to control CAR-engineered T-cells in which signaling is delivered by a fused CD28 + CD3zeta endodomain. CONCLUSIONS: These findings demonstrate the principle that dual targeting may be achieved using genetically targeted T-cells and pave the way for testing of this strategy in vivo. PMID- 22526593 TI - Acquired C1-inhibitor deficiency: 7 patients treated with rituximab. AB - BACKGROUND: Acquired C1-inhibitor deficiency can occur secondary to excessive C1 inhibitor consumption (type I) and be associated with a lymphoid hemopathy, or linked to the presence of anti-C1-inhibitor autoantibodies (type II) in a context of an isolated monoclonal gammopathy, sometimes associated with lymphoproliferation. Efficacy of danazol, tranexamic acid and/or corticosteroids is inconstant. Rituximab efficacy against type II angioedema has been reported. METHODS: Description of 7 rituximab-treated patients, 6 with type II acquired angioedema and 1 with type I. RESULTS: Clinical efficacy (only for type II) was complete for 3, partial for 2 and 2 were therapeutic failures. Only 2 patients had improved biological parameters, with normalization of their C1-inhibitor levels and diminished anti-C1-inhibitor autoantibodies, observed 1-9 months after the last infusion of the second rituximab cycle. An associated lymphoproliferation did not affect the response to treatment. CONCLUSION: Rituximab efficacy in the treatment of acquired angioedema is inconstant and might require repeated cycles. PMID- 22526594 TI - Changes in proliferation kinetics of T cells: a new predictive cellular biomarkers for early rheumatoid arthritis? AB - OBJECTIVE: It has been demonstrated that early treatment of rheumatoid arthritis (RA) patients prevents further joint damage and disability, but biomarkers enabling early RA to be distinguished within the undifferentiated arthritis (UA) cohort are still being sought. PURPOSE: The aim of the research was to study the pathomechanism of initiation and progression of UA->RA and to find such new predictive biomarkers on the basis of functional studies of the immune system. METHODS: 55 patients with UA were enrolled into the study and followed up for 2 years. The dynamic parameters of proliferation of the peripheral blood CD4+ T cells were recorded at the UA stage. During the follow-up study, standard diagnostic procedures were performed to make the final diagnosis. Comparison of the CD4+ T cell proliferation parameters in the UA-RA and UA-non-RA patients was conducted after the final diagnosis was established. RESULTS: Our studies showed that the G0-G1 transition time, the cell cycle duration, the number of cell divisions per dividing CD4+ cells and the percentage of dividing CD4+ T cells differed significantly between UA-RA and UA-non-RA patients. Moreover, these proliferation parameters achieved higher specificity and sensitivity in the detection of early RA within UA patients compared to the routine serological tests available. CONCLUSION: The proliferation parameters of CD4+ T cells reflect central pathophysiological changes in RA and can be used as new biomarkers for early RA diagnosis, which would enable the international rheumatology recommendation to be achieved concerning the early diagnosis and treatment of RA patients. PMID- 22526595 TI - Immunological comorbity in coeliac disease: associations, risk factors and clinical implications. AB - PURPOSE: Coeliac disease is frequently associated with other immunomediated diseases. Our aim was to identify immunological comorbidities and possible risk factors for their development in coeliac patients. METHODS: We recruited a cohort of 1,015 coeliac patients followed from 0 to 46 years in a single tertiary referral centre. Data were collected from the yearly scheduled clinical and serological evaluations. Possible risk factors such as demographic parameters, type of symptomatic presentation, gluten exposure, gluten-free diet compliance and family history were all evaluated. Subjects (848,606) from the regional health registry were investigated as controls. RESULTS: The prevalence of immunomediated diseases was higher in patients with coeliac disease compared to the registry population (23 % vs 0.4 %, p < 0.001). Diagnosis during paediatric age represented a risk factor for the presence of at least an immunomediated disease (hazard ratio = 1.62, 95 % confidence interval 1.15-2.29, p = 0.0061). Type of presentation and dietetic compliance did not represent risk factors. Long standing gluten exposure reduced the risk of developing immunomediated diseases in coeliac subjects (hazard ratio for 1 year longer exposure 0.23, 95 % confidence interval 0.16-0.33, p < 0.0001). A familiar background characterized by the presence of immunological disorders was not a risk factor, although 419 (13 %) first degree relatives of coeliac patients out of 3,195 had an immunomediated disease. CONCLUSIONS: Our study suggests the need to investigate coeliac patients for other associated immunomediated diseases, independently of sex, gluten exposure and compliance to therapy; also subjects diagnosed in paediatric age should be carefully screened during follow up. PMID- 22526596 TI - Summary. PMID- 22526597 TI - Calcitriol decreases expression of importin alpha3 and attenuates RelA translocation in human bronchial smooth muscle cells. AB - PURPOSE: A potent immunomodulatory role of Vitamin D in both innate and adaptive immunity has recently been appreciated. In allergic asthma, activation of NF-kB induces transcription of various cytokines and chemokines involved in allergic airway inflammation. The nuclear import of activated NF-kB p50/RelA subunit is dependent on importin alpha3 (KPNA4) and importin alpha4 (KPNA3). In this study, we examined the role of importin alpha3 in immunomodulatory effect of calcitriol in human bronchial smooth muscle cells (HBSMCs). METHODS: Cultured HBSMCs were stimulated with calcitriol in the presence and absence of cytokines, TNF-alpha, IL-1beta, and IL-10. The mRNA transcripts of importin alpha3 and alpha4 were analyzed using qPCR while protein expression of importin alpha3, alpha4 and nuclear RelA was analyzed by immunoblotting. RESULTS: Calcitriol significantly decreased mRNA and protein expression of importin alpha3 as well as nuclear protein expression of NF-kB p65 (RelA). The decreased activation of RelA by calcitriol was confirmed by decreased release of RelA-inducible molecules, including IL-5, IL-6 and IL-8, by HBSMCs upon calcitriol treatment. Calcitriol attenuated the effect of TNF-alpha and IL-1beta to upregulate mRNA and protein expression of importin alpha3. IL-10 significantly decreased the TNF-alpha induced expression of importin alpha3 and this effect was further potentiated by calcitriol. CONCLUSIONS: These data suggest that under inflammatory conditions, calcitriol decreases the expression of importin alpha3 resulting in decreased nuclear import of activated RelA. This could be a novel mechanism by which calcitriol could exert its immunomodulatory effects to reduce allergic airway inflammation and thus may alleviate the symptoms in allergic asthma. PMID- 22526598 TI - 3D ultrasound DICOM data of the thyroid gland. First experiences in exporting, archiving, second reading and 3D processing. AB - PURPOSE: It has recently become possible to generate and archive three dimensional ultrasound (3D-US) volume data with the DICOM standard Enhanced Ultrasound Volume Storage (EUVS). The objective of this study was to examine the application of the EUVS standard based on the example of thyroid ultrasound. PATIENTS, METHODS: 32 patients, who were referred for thyroid diagnosis, were given a 3D-US examination of the thyroid gland (GE Voluson E8, convex 3D probe RAB4-8-D). The 3D data sets were exported to EUVS. Necessary additions to DICOM entries and transformation into an established DICOM standard were carried out. The visual assessment and volume measurements were performed by two experts on nuclear medicine using standard software in our hospital. RESULTS: In 24/32 (75%) of the patients, the whole organ was successfully recorded in a single 3D scan; in 8/32 (25%), only part of organ could be covered. In all cases, 3D-US data could be exported and archived. After supplementing the DICOM entry Patient Orientation and transformation into the DICOM PET format, 3D-US data could be displayed in the correct orientation and size at any viewing workstation and any web browser-based PACS viewer. Afterwards, 3D processing such as multiplanar reformation, volumetric measurements and image fusion with data of other cross sectional modalities could be performed. The intraclass correlation of the volume measurements was 0,94 and the interobserver variability was 5.7%. CONCLUSION: EUVS allows the generation, distribution and archiving of 3D-US data of the thyroid, facilitates a second reading by another physician and creates conditions for advanced 3D processing using routine software. PMID- 22526599 TI - Metal-free alpha-CH amination of ethers with hypervalent sulfonylimino-lambda3 bromane that acts as an active nitrenoid. AB - Hypervalent N-triflylimino-lambda(3)-bromane undergoes direct and regioselective alpha-C-H amination of ethers at room temperature under transition metal-free conditions. Kinetic results, substituent and deuterium isotope effects suggest an asynchronous concerted organonitrenoid transition state with some hydride transfer character, analogous to that for alkane C-H insertions. PMID- 22526600 TI - Domino cyclization-alkylation protocol for the synthesis of 2,3-functionalized indoles from o-alkynylanilines and allylic alcohols. AB - A practical and efficient protocol for the one-pot synthesis of 2,3-substituted indoles was developed via a palladacycle catalyzed domino cyclization-alkylation reaction involving 2-alkynylanilines and allylic alcohols under mild conditions without any additives. PMID- 22526601 TI - A combined DPA1~DPB1 amino acid epitope is the primary unit of selection on the HLA-DP heterodimer. AB - Here, we present results for DPA1 and DPB1 four-digit allele-level typing in a large (n = 5,944) sample of unrelated European American stem cell donors previously characterized for other class I and class II loci. Examination of genetic data for both chains of the DP heterodimer in the largest cohort to date, at the amino acid epitope, allele, genotype, and haplotype level, allows new insights into the functional units of selection and association for the DP heterodimer. The data in this study suggest that for the DPA1-DPB1 heterodimer, the unit of selection is the combined amino acid epitope contributed by both the DPA1 and DPB1 genes, rather than the allele, and that patterns of LD are driven primarily by dimer stability and conformation of the P1 pocket. This may help explain the differential pattern of allele frequency distribution observed for this locus relative to the other class II loci. These findings further support the notion that allele-level associations in disease and transplantation may not be the most important unit of analysis, and that they should be considered instead in the molecular context. PMID- 22526602 TI - Nomenclature report on the major histocompatibility complex genes and alleles of Great Ape, Old and New World monkey species. AB - The major histocompatibility complex (MHC) plays a central role in the adaptive immune response. The MHC region is characterised by a high gene density, and most of these genes display considerable polymorphism. Next to humans, non-human primates (NHP) are well studied for their MHC. The present nomenclature report provides the scientific community with the latest nomenclature guidelines/rules and current implemented nomenclature revisions for Great Ape, Old and New World monkey species. All the currently published MHC data for the different Great Ape, Old and New World monkey species are archived at the Immuno Polymorphism Database (IPD)-MHC NHP database. The curators of the IPD-MHC NHP database are, in addition, responsible for providing official designations for newly detected polymorphisms. PMID- 22526604 TI - Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). PMID- 22526603 TI - Physical activity reduces the risk of incident type 2 diabetes in general and in abdominally lean and obese men and women: the EPIC-InterAct Study. AB - AIMS/HYPOTHESIS: We examined the independent and combined associations of physical activity and obesity with incident type 2 diabetes in men and women. METHODS: The InterAct case-cohort study consists of 12,403 incident type 2 diabetes cases and a randomly selected subcohort of 16,154 individuals, drawn from a total cohort of 340,234 participants with 3.99 million person-years of follow-up. Physical activity was assessed by a four-category index. Obesity was measured by BMI and waist circumference (WC). Associations between physical activity, obesity and case-ascertained incident type 2 diabetes were analysed by Cox regression after adjusting for educational level, smoking status, alcohol consumption and energy intake. In combined analyses, individuals were stratified according to physical activity level, BMI and WC. RESULTS: A one-category difference in physical activity (equivalent to approximately 460 and 365 kJ/day in men and women, respectively) was independently associated with a 13% (HR 0.87, 95% CI 0.80, 0.94) and 7% (HR 0.93, 95% CI 0.89, 0.98) relative reduction in the risk of type 2 diabetes in men and women, respectively. Lower levels of physical activity were associated with an increased risk of diabetes across all strata of BMI. Comparing inactive with active individuals, the HRs were 1.44 (95% CI 1.11, 1.87) and 1.38 (95% CI 1.17, 1.62) in abdominally lean and obese inactive men, respectively, and 1.57 (95% CI 1.19, 2.07) and 1.19 (95% CI 1.01, 1.39) in abdominally lean and obese inactive women, respectively. CONCLUSIONS/INTERPRETATION: Physical activity is associated with a reduction in the risk of developing type 2 diabetes across BMI categories in men and women, as well as in abdominally lean and obese men and women. PMID- 22526605 TI - Genetic association of zinc transporter 8 (ZnT8) autoantibodies in type 1 diabetes cases. AB - AIMS/HYPOTHESIS: Autoantibodies to zinc transporter 8 (ZnT8A) are associated with risk of type 1 diabetes. Apart from the SLC30A8 gene itself, little is known about the genetic basis of ZnT8A. We hypothesise that other loci in addition to SLC30A8 are associated with ZnT8A. METHODS: The levels of ZnT8A were measured in 2,239 British type 1 diabetic individuals diagnosed before age 17 years, with a median duration of diabetes of 4 years. Cases were tested at over 775,000 loci genome wide (including 53 type 1 diabetes associated regions) for association with positivity for ZnT8A. ZnT8A were also measured in an independent dataset of 855 family members with type 1 diabetes. RESULTS: Only FCRL3 on chromosome 1q23.1 and the HLA class I region were associated with positivity for ZnT8A. rs7522061T>C was the most associated single nucleotide polymorphism (SNP) in the FCRL3 region (p = 1.13 * 10(-16)). The association was confirmed in the family dataset (p <= 9.20 * 10(-4)). rs9258750A>G was the most associated variant in the HLA region (p = 2.06 * 10(-9) and p = 0.0014 in family cases). The presence of ZnT8A was not associated with HLA-DRB1, HLA-DQB1, HLA-A, HLA-B or HLA-C (p > 0.05). Unexpectedly, the two loci associated with the presence of ZnT8A did not alter risk of having type 1 diabetes, and the 53 type 1 diabetes risk loci did not influence positivity for ZnT8A, despite them being disease specific. CONCLUSIONS/INTERPRETATION: ZnT8A are not primary pathogenic factors in type 1 diabetes. Nevertheless, ZnT8A testing in combination with other autoantibodies facilitates disease prediction, despite the biomarker not being under the same genetic control as the disease. PMID- 22526606 TI - Serine/threonine protein phosphatase 5 regulates glucose homeostasis in vivo and apoptosis signalling in mouse pancreatic islets and clonal MIN6 cells. AB - AIMS/HYPOTHESIS: During the development of type 2 diabetes mellitus, beta cells are often exposed to a high glucose/hyperlipidaemic environment, in which the levels of reactive oxygen species (ROS) are elevated. In turn, ROS can trigger an apoptotic response leading to beta cell death, by activating mitogen-activated protein kinase (MAPK) signalling cascades. Here we test the hypothesis that serine/threonine protein phosphatase 5 (PP5) acts to suppress proapoptotic c-Jun N-terminal kinase (JNK) signalling in beta cells. METHODS: Ppp5c(-/-) and Ppp5c(+/+) mice were subjected to intraperitoneal glucose (IPGTT) or insulin tolerance tests. Pancreatic islets from Ppp5c(-/-) and Ppp5c(+/+) mice or MIN6 cells treated with short-interfering RNA targeting PP5 were exposed to palmitate or H(2)O(2) to activate MAPK signalling. Changes in protein phosphorylation, mRNA expression, apoptosis and insulin secretion were detected by western blot analysis, quantitative RT-PCR or ELISA. RESULTS: Ppp5c(-/-) mice weighed less and exhibited reduced fasting glycaemia and improved glucose tolerance during IPGTT, but retained normal insulin sensitivity and islet volume. Comparison of MAPK signalling in islets from Ppp5c(-/-) mice and MIN6 cells revealed that the lack of PP5 was associated with enhanced H(2)O(2)-induced phosphorylation of JNK and c Jun. Cells with reduced PP5 also showed enhanced JNK phosphorylation and apoptosis after palmitate treatment. PP5 suppression in MIN6 cells correlated with hypersecretion of insulin in response to glucose. CONCLUSIONS/INTERPRETATION: PP5 deficiency in mice is associated with reduced weight gain, lower fasting glycaemia, and improved glucose tolerance during IPGTT. At a molecular level, PP5 helps suppress apoptosis in beta cells by a mechanism that involves regulation of JNK phosphorylation. PMID- 22526607 TI - Zinc transporter (ZnT)8(186-194) is an immunodominant CD8+ T cell epitope in HLA A2+ type 1 diabetic patients. AB - AIMS/HYPOTHESIS: Anti-zinc transporter (ZnT)8 autoantibodies are commonly detected in type 1 diabetic patients. We hypothesised that ZnT8 is also recognised by CD8(+) T cells and aimed to identify HLA-A2 (A*02:01)-restricted epitope targets. METHODS: Candidate epitopes were selected by ZnT8 plasmid DNA immunisation of HLA-A2/DQ8 transgenic mice and tested for T cell recognition in peripheral blood mononuclear cells of type 1 diabetic, type 2 diabetic and healthy participants by IFN-gamma enzyme-linked immunospot. RESULTS: White HLA A2(+) adults (83%) and children (60%) with type 1 diabetes displayed ZnT8 reactive CD8(+) T cells that recognised a single ZnT8(186-194) (VAANIVLTV) epitope. This ZnT8(186-194)-reactive fraction accounted for 50% to 53% of total ZnT8-specific CD8(+) T cells. Another sequence, ZnT8(153-161) (VVTGVLVYL), was recognised in 20% and 25% of type 1 diabetic adults and children, respectively. Both epitopes were type 1 diabetes-specific, being marginally recognised by type 2 diabetic and healthy participants (7-12% for ZnT8(186-194), 0% for ZnT8(153 161)). CONCLUSIONS/INTERPRETATION: ZnT8-reactive CD8(+) T cells are predominantly directed against the ZnT8(186-194) epitope and are detected in a majority of type 1 diabetic patients. The exceptional immunodominance of ZnT8(186-194) may point to common environmental triggers precipitating beta cell autoimmunity. PMID- 22526608 TI - Circulating 25-hydroxyvitamin D concentration and the risk of type 2 diabetes: results from the European Prospective Investigation into Cancer (EPIC)-Norfolk cohort and updated meta-analysis of prospective studies. AB - AIMS/HYPOTHESIS: Epidemiological evidence is suggestive, but limited, for an association between circulating 25-hydroxyvitamin D (25[OH]D) and risk of type 2 diabetes. We conducted a systematic review and meta-analysis that included new data from previously unpublished studies. METHODS: Using a nested case-cohort design in the European Prospective Investigation into Cancer (EPIC)-Norfolk study, we identified a random subcohort and incident type 2 diabetes cases occurring between baseline (1993-1997) and 2006. In the Ely prospective study we identified incident type 2 diabetes cases between 1990 and 2003. We conducted a systematic review of prospective studies on 25(OH)D and type 2 diabetes published in MEDLINE or EMBASE until 31 January 2012, and performed a random-effects meta analysis combining available evidence with results from the EPIC-Norfolk and Ely studies. RESULTS: In EPIC-Norfolk, baseline 25(OH)D was lower among incident type 2 diabetes cases (mean [SD] 61.6 [22.4] nmol/l; n=621) vs non-case subcohort participants (mean 65.3 [23.9] nmol/l; n=826). There was an inverse association between baseline 25(OH)D and incident type 2 diabetes in multivariable-adjusted analyses: HR (95% CI) 0.66 (0.45, 0.97), 0.53 (0.34, 0.82), 0.50 (0.32, 0.76), p trend <0.001, comparing consecutive increasing 25(OH)D quartiles with the lowest. In Ely, 37 incident type 2 diabetes cases were identified among 777 participants. In meta-analysis, the combined RR of type 2 diabetes comparing the highest with lowest quartile of 25(OH)D was 0.59 (0.52, 0.67), with little heterogeneity (I (2) =2.7%, p=0.42) between the 11 studies included (3,612 cases and 55,713 non cases). CONCLUSIONS/INTERPRETATION: These findings demonstrate an inverse association between circulating 25(OH)D and incident type 2 diabetes. However, causal inference should be addressed through adequately dosed randomised trials of vitamin D supplementation or genetic Mendelian randomisation experiments. PMID- 22526609 TI - Sex differences in the association between plasma copeptin and incident type 2 diabetes: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study. AB - AIMS/HYPOTHESIS: Vasopressin plays a role in osmoregulation, glucose homeostasis and inflammation. Therefore, plasma copeptin, the stable C-terminal portion of the precursor of vasopressin, has strong potential as a biomarker for the cardiometabolic syndrome and diabetes. Previous results were contradictory, which may be explained by differences between men and women in responsiveness of the vasopressin system. The aim of this study was to evaluate the usefulness of copeptin for prediction of future type 2 diabetes in men and women separately. METHODS: From the Prevention of Renal and Vascular Endstage Disease (PREVEND) study, 4,063 women and 3,909 men without diabetes at baseline were included. A total of 208 women and 288 men developed diabetes during a median follow-up of 7.7 years. RESULTS: In multivariable-adjusted models, we observed a stronger association of copeptin with risk of future diabetes in women (OR 1.49 [95% CI 1.24, 1.79]) than in men (OR 1.01 [95% CI 0.85, 1.19]) (p (interaction) < 0.01). The addition of copeptin to the Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) clinical model improved the discriminative value (C-statistic,+0.007, p = 0.02) and reclassification (integrated discrimination improvement [IDI] = 0.004, p < 0.01) in women. However, we observed no improvement in men. The additive value of copeptin in women was maintained when other independent predictors, such as glucose, high sensitivity C reactive protein (hs-CRP) and 24 h urinary albumin excretion (UAE), were included in the model. CONCLUSIONS/INTERPRETATION: The association of plasma copeptin with the risk of developing diabetes was stronger in women than in men. Plasma copeptin alone, and along with existing biomarkers (glucose, hs-CRP and UAE), significantly improved the risk prediction for diabetes in women. PMID- 22526610 TI - Delta cell secretory responses to insulin secretagogues are not mediated indirectly by insulin. AB - AIMS/HYPOTHESIS: Somatostatin from islet delta cells inhibits insulin and glucagon secretion, but knowledge of the regulation of pancreatic somatostatin release is limited. Some insulin secretagogues stimulate somatostatin secretion, and here we investigated whether delta cell secretory responses are indirectly regulated in a paracrine manner by insulin released from beta cells. METHODS: Hormone release from static incubations of primary mouse islets or somatostatin secreting TGP52 cells was measured by RIA. mRNA expression was assessed by RT PCR. RESULTS: Glucose and a range of other physiological and pharmacological agents stimulated insulin and somatostatin release, and insulin receptor mRNA was expressed in islets, MIN6 beta cells and TGP52 cells. However, exogenous insulin did not modulate basal or glucose-induced somatostatin secretion from islets, nor did pre-incubation with an antibody against the insulin receptor or with the insulin receptor tyrosine kinase inhibitor, HNMPA(AM)(3). Glucose and tolbutamide stimulated somatostatin release from TGP52 cells, whereas a range of receptor operating agents had no effect, the latter being consistent with a lack of corresponding receptor mRNA expression in these cells. Parasympathetic activation stimulated insulin, but inhibited somatostatin release from mouse islets in accordance with differences in muscarinic receptor mRNA expression in islets, MIN6 and TGP52 cells. The inhibitory effect on somatostatin secretion was reversed by pertussis toxin or the muscarinic receptor 2 antagonist, methoctramine. CONCLUSIONS/INTERPRETATIONS: A number of insulin secretagogues have analogous effects on insulin and somatostatin release, but this similarity of response is not mediated by an indirect, paracrine action of insulin on delta cells. PMID- 22526611 TI - Impact of gestational diabetes on the risk of diabetes following pregnancy among Chinese and South Asian women. AB - AIMS/HYPOTHESIS: Ethnicity and gestational diabetes mellitus (GDM) are both risk factors for the development of type 2 diabetes. However, it is uncertain whether ethnicity modifies the effect of GDM on diabetes risk. We aimed to determine the risk of diabetes following pregnancy with and without GDM for Chinese and South Asian women compared with white women. METHODS: Using healthcare databases, all 1,050,108 women aged 20-49 with live births between January 1995 and June 2008 in Ontario were identified. They were followed for up to 15 years for the diagnosis of diabetes. RESULTS: The age-standardised prevalences of GDM were 4.1%, 7.1% and 2.9% for Chinese, South Asian and white women, respectively. The cumulative incidence of diagnosed diabetes at the median follow-up time of 7.6 years was 16.5% and 1.8% for Chinese women with and without GDM, 31.8% and 3.6% for South Asian women with and without GDM, and 25.7% and 1.8% for white women with and without GDM. The presence of GDM conferred an increase in the risk for diabetes after pregnancy of more than 13-fold in white women, but only a nine- to tenfold increase among Chinese and South Asian women. CONCLUSIONS/INTERPRETATION: Although one-third of South Asian women with GDM were diagnosed with diabetes within 8 years postpartum, the incremental impact of GDM on diabetes risk was not as strong among Chinese and South Asian women as it was among white women. PMID- 22526613 TI - Exercise-induced albuminuria is associated with perivascular renal sinus fat in individuals at increased risk of type 2 diabetes. AB - AIMS/HYPOTHESIS: Microalbuminuria represents an established surrogate marker of early diabetic nephropathy and glomerular microangiopathy. Increasing evidence is emerging of a role of perivascular adipose tissue (PVAT) as an important link between obesity, insulin resistance and both macro- and microangiopathy. It is not known whether perivascular renal sinus fat (RSF) has an impact on microalbuminuria in the prediabetic stage. We investigated whether RSF quantified by MRI is associated with microalbuminuria before or after exercise. METHODS: Non diabetic individuals at increased risk of type 2 diabetes were recruited into the Tubingen Lifestyle Intervention Program (TULIP); 146 participants took part in the analysis. RSF was measured in axial MRI sections at the level of the renal artery. Urine was collected before and after exercise stress testing. RESULTS: Participants (age 47 +/- 12 years; mean +/- SD) reached a mean exercise load of 176 +/- 49 W, with a mean arterial peak pressure (MAPP) of 112 +/- 14 mmHg. After adjusting for sex, age, visceral adipose tissue (VAT) and MAPP during exercise, RSF was significantly associated with postexercise albumin/creatinine ratio (ACR; p = 0.006). No association between RSF and baseline BP could be observed after adjusting for confounders (p = 0.26), and there was no association between RSF and baseline ACR either (p = 0.2). CONCLUSIONS: RSF is associated with exercise induced albuminuria independently of sex, age, VAT and MAPP in a non-diabetic cohort at diabetic risk. We conclude that PVAT in the renal sinus may play a role in the pathogenesis of microalbuminuria. PMID- 22526612 TI - Dietary saturated fat and fibre and risk of cardiovascular disease and all-cause mortality among type 1 diabetic patients: the EURODIAB Prospective Complications Study. AB - AIMS/HYPOTHESIS: Low adherence to recommendations for dietary saturated fatty acid (SFA) and fibre intake in patients with type 1 diabetes mellitus may heighten their increased risk of cardiovascular disease (CVD) and mortality. We examined the relationship of SFA and total, soluble and insoluble fibre with incident CVD and all-cause mortality in type 1 diabetic patients. METHODS: A prospective cohort analysis was performed in 2,108 European type 1 diabetic patients aged 15-60 years who were free of CVD at baseline and enrolled in the EURODIAB Prospective Complications Study (51% male). Diet was assessed from a standardised 3 day dietary record. HR were calculated using Cox proportional hazards models. RESULTS: During a mean follow-up of 7.3 years, 148 incident cases of fatal and non-fatal CVD and 46 all-cause deaths were documented. No statistically significant association was found between SFA and CVD and all-cause mortality. Total dietary fibre, per 5 g/day, was associated with lower all-cause mortality risk (HR 0.72; 95% CI 0.55, 0.95). This association was stronger for soluble fibre (per 5 g/day, HR 0.34; 95% CI 0.14, 0.80) compared with insoluble fibre (per 5 g/day; HR 0.66; 95% CI 0.45, 0.97). Similar results were found for the association with CVD. CONCLUSIONS/INTERPRETATION: This study suggests that reported dietary SFA is not significantly associated with CVD and all-cause mortality in type 1 diabetic patients. On the contrary, higher dietary fibre consumption, especially soluble fibre, within the range commonly consumed by type 1 diabetic patients, may contribute to the prevention of CVD and all-cause mortality in type 1 diabetic patients. PMID- 22526614 TI - Is ARE/poly(U)-binding factor 1 (AUF1) a new player in cytokine-mediated beta cell apoptosis? AB - Type 1 diabetes is a chronic autoimmune disease involving the progressive loss of beta cell mass. Cytokines released by immune cells are early contributors to beta cell apoptosis. Thus, an understanding of the signal transduction mechanisms induced by cytokines in beta cells is necessary for the rational design of novel therapies to prevent or to cure this disease. Cytokine-mediated beta cell apoptosis is a complex phenomenon that includes activation of the transcription factors signal transducer and activator of transcription 1 and nuclear factor kappaB (NFkappaB), c-Jun N-terminal kinase, endoplasmic reticulum (ER) stress and the intrinsic mitochondrial apoptotic pathway. NFkappaB has both a pro inflammatory and a pro-apoptotic role in beta cells. One of the mechanisms by which NFkappaB contributes to beta cell apoptosis is via activation of ER stress. The role for ER stress in beta cell apoptosis is not completely clarified but involves production of C/EBP homologous protein and activation of the intrinsic mitochondrial apoptotic pathway. In this issue of Diabetologia, Roggli et al (DOI 10.1007/s00125-011-2399-7) report on a new player in this elaborate response, the RNA-binding protein ARE/poly(U)-binding factor 1. This commentary discusses these findings and their relevance to the field. PMID- 22526615 TI - Screening for diabetes: hope and despair. AB - This commentary discusses whether screening for type 2 diabetes or earlier normalisation of blood glucose levels or initiation of non-antihyperglycaemic agents or any other diabetes-specific treatment can help reduce the excess associated risks for macrovascular morbidity and mortality. The available data indicate that screening with the sole aim of decreasing the lead time between diagnosis and treatment is very unlikely to reduce these risks. In contrast to macrovascular complications, some microvascular events such as background retinopathy could theoretically be prevented by earlier diagnosis and better glycaemic control, particularly in relatively young type 2 diabetic patients. This, however, remains to be shown in controlled prospective intervention trials. PMID- 22526617 TI - Detection of visual field defects in pre-perimetric glaucoma using fundus oriented small-target perimetry. AB - PURPOSE: To evaluate the usefulness of automated fundus-oriented small-target perimetry in detecting glaucomatous visual field abnormalities. MATERIALS AND METHODS: One eye from each of 60 normal, 37 pre-perimetric glaucoma (PPG) and 29 early stage of primary open-angle glaucoma (POAG) persons were included. The new perimeter had two monitors, one for a campimeter and the other for the examiner's operation. A test area within the central 15 degrees was set in the fundus image. The target size was 2.9 min in diameter, and the distance between the two adjacent targets was 60 min. The rate of negative response (RNR) among the age matched controls, PPG and POAG were compared. The relationship between the RNR and age of the normal or standard automated perimetry (SAP) global indices in PPG and POAG was examined. The areas under the receiver-operating characteristic curve (AROC) to discriminate PPG or POAG versus normal were determined. RESULTS: The RNR increased significantly with age in normal and differed significantly (P < 0.001) among control (1.8 +/- 1.3 %), PPG (9.2 +/- 10.4 %) and POAG (21.2 +/- 14.3 %). Significant correlation was found between the RNR and SAP global indices. The AROC was 0.89 for PPG and 0.95 for POAG. CONCLUSION: Fundus-oriented small-target perimetry is useful in detecting visual field abnormalities in PPG. PMID- 22526616 TI - Disease-specific mortality among stage I-III colorectal cancer patients with diabetes: a large population-based analysis. AB - AIMS/HYPOTHESIS: The aim of our study was to investigate overall and disease specific mortality of colorectal cancer patients with diabetes. METHODS: In this population-based study, we included all colorectal cancer patients, newly diagnosed with stage I-III cancer, between 1997 and 2007 in the registration area of the Eindhoven Cancer Registry. Stage of cancer, cancer treatment and comorbidities were actively collected by reviewing hospital medical records. Data on patients with and without diabetes were linked to Statistics Netherlands to assess vitality, date of death and underlying cause of death. Follow-up of all patients was completed until 1 January 2009. RESULTS: We included 6,974 patients with colon cancer and 3,888 patients with rectal cancer, of whom 820 (12%) and 404 (10%), respectively, had diabetes at the time of cancer diagnosis. During follow-up, death occurred in 611 (50%) of 1,224 cancer patients with diabetes and 3,817 (40%) of 9,638 cancer patients without diabetes. Multivariate Cox regression analyses, adjusted for age, sex, socioeconomic status, stage, lymph nodes examined, adjuvant therapy and year of diagnosis, showed that overall mortality was significantly higher for colon (HR 1.12, 95% CI 1.01, 1.25) and rectal (HR 1.21, 95% CI 1.03, 1.41) cancer patients with diabetes than for those without. Disease-specific mortality was only significantly increased for rectal cancer patients (HR 1.30, 95% CI 1.06, 1.60). CONCLUSIONS/INTERPRETATION: Diabetes at the time of rectal cancer diagnosis was independently associated with an increased risk of colorectal cancer mortality compared with no diabetes, suggesting a specific interaction between diabetes and rectal cancer. Future in depth studies including detailed diabetes- and cancer-related variables should elucidate pathways. PMID- 22526618 TI - Intravitreal bevacizumab for iatrogenic choroidal neovascularization due to laser photocoagulation in central serous chorioretinopathy. AB - BACKGROUND: Choroidal neovascularization (CNV) is well recognized as a complication of laser photocoagulation for central serous chorioretinopathy (CSC). However, little is known about its management. PATIENTS: Two patients who developed iatrogenic CNV after laser photocoagulation for CSC. OBSERVATIONS: A single intravitreal bevacizumab (IVB) injection was given in both cases. The best corrected visual acuity (BCVA) of 1 of the patients improved from 0.3 to 0.5 on the following day and to 1.2 three months after the IVB, and the BCVA of the other patient improved from 0.5 to 1.0 two weeks after the IVB. In both cases, the CNV became inactive 1 month after IVB on fluorescein angiography and remained stable for over 1 year. CONCLUSION: IVB was beneficial for iatrogenic CNV that developed after laser photocoagulation for CSC. PMID- 22526619 TI - The role of Nrf2 and apoptotic signaling pathways in oroxylin A-mediated responses in HCT-116 colorectal adenocarcinoma cells and xenograft tumors. AB - Oroxylin A is a flavonoid found in the roots of Scutellaria baicalensis Georgi, a herbal medicine commonly used as an antipyretic, analgesic, antitumor, and anti inflammatory agent. It has recently been investigated for its anticancer activities in hepatoma, gastric, and breast tumors. Here, we investigated the antitumor effects of oroxylin A in human colon carcinoma HCT-116 cells in vitro and in vivo. We characterized the proapoptotic effect of oroxylin A using diamidino-phenyl-indole (DAPI) and annexin V/PI staining. We then found that both caspase-3 and caspase-9 were activated, the expression of Bcl-2 protein decreased, and the expression of Bax protein increased after treatment with oroxylin A. In addition, oroxylin A increased nuclear transcription factor erythroid-related factor 2 (Nrf2) expression and induced Nrf2 translocation into the nucleus. Furthermore, we found that oroxylin A treatment elevated intracellular reactive oxygen species levels and increased the protein expression level of two of the Nrf2 target genes heme oxygenase-1 and NADP(H):quinone oxidoreductase-1 in HCT-116 cells. Finally, our study demonstrated that oral administration of oroxylin A significantly decreased tumor volume and weight in immunodeficient mice that were inoculated with HCT-116 cells. The in-vivo chemopreventive efficacy of oroxylin A against HCT-116 human colon cancer was accompanied by its proapoptotic and Nrf2-inducing activities, which correlates with the in-vitro study. This is the first demonstration of oroxylin A-dependent chemoprevention in colon cancer and may offer a potential mechanism for its anticancer action in vivo. PMID- 22526620 TI - The effects of type 1 diabetes on the hypothalamic, pituitary and testes axis. AB - Type 1 diabetes is an autoimmune disorder characterized by a lack of insulin production by the beta cells of the pancreas. This lack of insulin causes a variety of systemic effects on whole-body metabolism. Poorly managed type 1 diabetes can lead to cardiovascular disease, diabetic neuropathy, and diabetic retinopathy. Increasingly, even well-managed type 1 diabetic patients show damage to peripheral organs related to complications from the disease. The central role of insulin in energy homeostasis also renders it an important signaling factor in the reproductive tract. type 1 diabetes has now been demonstrated to cause defects in sperm and testes. The aim of this review is to present the known effects of insulin's role in the function of the male reproductive tract. These effects might be mediated through hormonal alterations in the hypothalamic pituitary gonadal axis or through the direct interaction of insulin on the testes and sperm cells. Although fertility complications also occur in type 2 diabetic males, this review will focus on the defects specifically linked with the lack of insulin seen in type 1 diabetes. PMID- 22526623 TI - Transplantation of human umbilical cord blood cells mediated beneficial effects on apoptosis, angiogenesis and neuronal survival after hypoxic-ischemic brain injury in rats. AB - Transplantation of human umbilical cord blood (hucb) cells in a model of hypoxic ischemic brain injury led to the amelioration of lesion-impaired neurological and motor functions. However, the mechanisms by which transplanted cells mediate functional recovery after brain injury are largely unknown. In this study, the effects of hucb cell transplantation were investigated in this experimental paradigm at the cellular and molecular level. As the pathological cascade in hypoxic-ischemic brain injury includes inflammation, reduced blood flow, and neuronal cell death, we analyzed the effects of peripherally administered hucb cells on these detrimental processes, investigating the expression of characteristic marker proteins. Application of hucb cells after perinatal hypoxic ischemic brain injury correlated with an increased expression of the proteins Tie 2 and occludin, which are associated with angiogenesis. Lesion-induced apoptosis, determined by expression of cleaved caspase-3, decreased, whereas the number of vital neurons, identified by counting of NeuN-positive cells, increased. In addition, we observed an increase in the expression of neurotrophic and pro angiogenic growth factors, namely BDNF and VEGF, in the lesioned brain upon hucb cell transplantation. The release of neurotrophic factors mediated by transplanted hucb cells might cause a lower number of neurons to undergo apoptosis and result in a higher number of living neurons. In parallel, the increase of VEGF might cause growth of blood vessels. Thus, hucb transplantation might contribute to functional recovery after brain injury mediated by systemic or local effects. PMID- 22526622 TI - Cell-specific processing and release of the hormone-like precursor and candidate tumor suppressor gene product, Ecrg4. AB - The human open reading frame C2orf40 encodes esophageal cancer-related gene-4 (Ecrg4), a newly recognized neuropeptide-like precursor protein whose gene expression by cells in vitro, over-expression in mice in vivo, and knock-down in zebrafish affects cell proliferation, migration and senescence, progenitor cell survival and differentiation, and inflammatory function. Unlike traditionally secreted neuropeptide precursors, however, we find that Ecrg4 localizes to the epithelial cell surface and remains tethered after secretion. Here, we used cell surface biotinylation to establish that 14-kDa Ecrg4 localizes to the cell surface of prostate (PC3) or kidney (HEK) epithelial cells after transfection. Accordingly, this Ecrg4 is resistant to washing cells with neutral, high salt (2 M NaCl), acidic (50 mM glycine, pH 2.8), or basic (100 mM Na(2)CO(3), pH 11) buffers. Mutagenesis of Ecrg4 established that cell tethering was mediated by an NH(2)-terminus hydrophobic leader sequence that enabled both trafficking to the surface and tethering. Immunoblotting analyses, however, showed that different cells process Ecrg4 differently. Whereas PC3 cells release cell surface Ecrg4 to generate soluble Ecrg4 peptides of 6-14 kDa, HEK cells do neither, and the 14-kDa precursor resembles a sentinel attached to the cell surface. Because a phorbol ester treatment of PC3 cells stimulated Ecrg4 release from, and processing at, the cell surface, these data are consistent with a multifunctional role for Ecrg4 that is dependent on its cell of origin and the molecular form produced. PMID- 22526624 TI - Transdifferentiation: a cell and molecular reprogramming process. AB - Evidence has emerged recently indicating that differentiation is not entirely a one-way process, and that it is possible to convert one cell type to another, both in vitro and in vivo. This phenomenon is called transdifferentiation, and is generally defined as the stable switch of one cell type to another. Transdifferentiation plays critical roles during development and in regeneration pathways in nature. Although this phenomenon occurs rarely in nature, recent studies have been focused on transdifferentiation and the reprogramming ability of cells to produce specific cells with new phenotypes for use in cell therapy and regenerative medicine. Thus, understanding the principles and the mechanism of this process is important for producing desired cell types. Here some well documented examples of transdifferentiation, and their significance in development and regeneration are reviewed. In addition, transdifferentiation pathways are considered and their potential molecular mechanisms, especially the role of master switch genes, are considered. Finally, the significance of transdifferentiation in regenerative medicine is discussed. PMID- 22526621 TI - Neurotrophic factors in combinatorial approaches for spinal cord regeneration. AB - Axonal regeneration is inhibited by a plethora of different mechanisms in the adult central nervous system (CNS). While neurotrophic factors have been shown to stimulate axonal growth in numerous animal models of nervous system injury, a lack of suitable growth substrates, an insufficient activation of neuron intrinsic regenerative programs, and extracellular inhibitors of regeneration limit the efficacy of neurotrophic factor delivery for anatomical and functional recovery after spinal cord injury. Thus, growth-stimulating factors will likely have to be combined with other treatment approaches to tap into the full potential of growth factor therapy for axonal regeneration. In addition, the temporal and spatial distribution of growth factors have to be tightly controlled to achieve biologically active concentrations, to allow for the chemotropic guidance of axons, and to prevent adverse effects related to the widespread distribution of neurotrophic factors. Here, we will review the rationale for combinatorial treatments in axonal regeneration and summarize some recent progress in promoting axonal regeneration in the injured CNS using such approaches. PMID- 22526625 TI - Overexpression of ubiquitin carboxyl terminal hydrolase impairs multiple pathways during eye development in Drosophila melanogaster. AB - UCH-L1 (ubiquitin carboxyl terminal hydrolase L1) is well known as an enzyme that hydrolyzes polyubiquitin at its C-terminal to release ubiquitin monomers. Although the overexpression of UCH-L1 inhibits proteasome activity in cultured cells, its biological significance in living organisms has not been clarified in detail. Here, we utilized Drosophila as a model system to examine the effects of the overexpression of dUCH, a Drosophila homologue of UCH-L1, on development. Overexpression in the eye imaginal discs induced a rough eye phenotype in the adult, at least partly resulting from the induction of caspase-dependent apoptosis followed by compensatory proliferation. Genetic crosses with enhancer trap lines marking the photoreceptor cells also revealed that the overexpression of dUCH specifically impaired R7 photoreceptor cell differentiation with a reduction in activated extracellular-signal-regulated kinase signals. Furthermore, the dUCH-induced rough eye phenotype was rescued by co-expression of the sevenless gene or the Draf gene, a downstream component of the mitogen activated protein kinase (MAPK) cascade. These results indicate that the overexpression of dUCH impairs R7 photoreceptor cell differentiation by down regulating the MAPK pathway. Interestingly, this process appears to be independent of its pro-apoptotic function. PMID- 22526626 TI - The origin of IgG-containing cells in the bursa of Fabricius. AB - The bursa of Fabricius of the chicken is known as a primary lymphoid organ for B cell development. Morphologically, the origin of IgG-containing cells in the bursa has not been clear until now, because abundant maternal IgG (MIgG) is transported to the chick embryo and distributed to the bursal tissue around hatching. Thus, it has been difficult to find out whether these cells themselves biosynthesize IgG or if they acquire MIgG via attachment to their surface. Our present study employing in situ hybridization clarified that IgG-containing cells in the medulla of bursal follicles did not biosynthesize IgG. To study the role of MIgG in the development of those IgG-containing cells, MIgG-free chicks were established from surgically bursectomized hen (SBx-hen). We found that, on the one hand, deprivation of MIgG from chicks completely inhibited the development of IgG-containing cells in the medulla after hatching. On the other hand, administration of MIgG to MIgG-free chicks recovered the emergence of those cells. In addition, we observed that those cells did not bear a B-cell marker and possessed dendrites with aggregated IgG. These results demonstrate that IgG containing cells in the medulla are reticular cells that capture aggregated MIgG. Moreover, we show that the isolation of the bursa from environmental stimuli by bursal duct ligation (BDL) suppressed the development of IgG-containing cells after hatching. Thus, it is implied that environmental stimulations play a key role in MIgG aggregations and dendritic distributions of aggregated MIgG in the medulla after hatching. PMID- 22526627 TI - Arrivals and departures at the plasma membrane: direct and indirect transport routes. AB - Studies carried out during the last 2 decades have dramatically increased our knowledge of the pathways and mechanisms of intracellular membrane traffic, most recently due to the developments in light microscopy and in vivo imaging of fluorescent fusion proteins. These studies have also revealed that certain molecules do not behave according to the classical transportation rules first documented in cell biology textbooks in the 1980s and 1990s. Initially, unconventional mechanisms of secretion that do not involve passage of cargo through the stacked Golgi cisternae were thought to confer on cells the ability to discard excess amounts of protein products. With time, however, more physiological mechanisms and roles have been proposed for an increasing number of secretory processes that bypass the Golgi apparatus. PMID- 22526628 TI - Matrix metalloproteinases and epidermal wound repair. AB - Epidermal wound healing is a complex and highly coordinated process where several different cell types and molecules, such as growth factors and extracellular matrix (ECM) components, play an important role. Among the many proteins that are essential for the restoration of tissue integrity is the metalloproteinase (MMP) family. MMPs can act on ECM and non-ECM components affecting degradation and modulation of the ECM, growth-factor activation and cell-cell and cell-matrix signalling. MMPs are secreted by different cell types such as keratinocytes, fibroblasts and inflammatory cells at different stages and locations during wound healing, thereby regulating this process in a very coordinated and controlled way. In this article, we review the role of MMPs and their inhibitors (TIMPs), as well as the disintegrin and metalloproteinase with the thrombospondin motifs (ADAMs) family, in epithelial wound repair. PMID- 22526629 TI - Maternal adaptations and inheritance in the transgenerational programming of adult disease. AB - Adverse exposures in utero have long been linked with an increased susceptibility to adult cardio-renal and metabolic diseases. Clear gender differences exist, whereby growth-restricted females, although exhibiting some phenotypic modifications, are often protected from overt disease outcomes. One of the greatest physiological challenges facing the female gender, however, is that of pregnancy; yet little research has focused on the outcomes associated with this, as a potential 'second-hit' for those who were small at birth. We review the limited evidence suggesting that pregnancy may unmask cardio-renal and metabolic disease states and the consequences for long-term maternal health in females who were born small. Additionally, a growing area of research in this programming field is in the transgenerational transmission of low birth weight and disease susceptibility. Pathways for transmission might include an abnormal adaptation to pregnancy by the growth-restricted mother and/or inheritance via the parental germline. Strategies to optimise the pregnancy environment and/or prevent the consequences of inheritance of programmed deficits and dysfunction are of critical importance for future generations. PMID- 22526631 TI - Differential uptake of MRI contrast agents indicates charge-selective blood-brain interface in the crayfish. AB - This study provides a new perspective on the long-standing problem of the nature of the decapod crustacean blood-brain interface. Previous studies of crustacean blood-brain interface permeability have relied on invasive histological, immunohistochemical and electrophysiological techniques, indicating a leaky non selective blood-brain barrier. The present investigation involves the use of magnetic resonance imaging (MRI), a method for non-invasive longitudinal tracking of tracers in real-time. Differential uptake rates of two molecularly distinct MRI contrast agents, namely manganese (Mn(II)) and Magnevist(r) (Gd-DTPA), were observed and quantified in the crayfish, Cherax destructor. Contrast agents were injected into the pericardium and uptake was observed with longitudinal MRI for approximately 14.5 h. Mn(II) was taken up quickly into neural tissue (within 6.5 min), whereas Gd-DTPA was not taken up into neural tissue and was instead restricted to the intracerebral vasculature or excreted into nearby sinuses. Our results provide evidence for a charge-selective intracerebral blood-brain interface in the crustacean nervous system, a structural characteristic once considered too complex for a lower-order arthropod. PMID- 22526633 TI - Facile identification of photocleavable reactive metabolites and oxidative stress biomarkers in proteins via mass spectrometry. AB - Described herein is a method which combines bond selective fragmentation by photodissociation with online liquid chromatographic separation and mass spectrometric analysis. Photoexcitation of proteins or peptides with 266-nm light does not normally yield abundant fragmentation; however, incorporation of a suitable carbon-sulfur or carbon-halogen bond that is proximal to a chromophore allows access to direct dissociation pathways, resulting in homolytic cleavage of these bonds. Radicals generated through this process can cause further dissociation of the peptide backbone, which is useful for site specifically identifying the point of modification. Two specific applications of this technique for peptide analysis in model systems are presented: (1) identification of reactive metabolites which covalently modify cysteine residues, and (2) characterization of halogenated tyrosine residues which are biomarkers related to oxidative stress. In both cases, these naturally occurring post translational modifications create photocleavable bonds which can be fragmented by 266-nm light. The selectivity offered by photodissociation allows facile identification of the peptides of interest even in complex mixtures, and subsequent selective radical directed backbone fragmentation pinpoints the site of modification. This combination greatly simplifies data analysis and provides more confident assignments. PMID- 22526632 TI - Src-signaling interference impairs the dissemination of blood-borne tumor cells. AB - Although solid tumors continuously shed cells, only a small fraction of the neoplastic cells that enter the blood stream are capable of establishing metastases. In order to be successful, these cells must attach, extravasate, proliferate and induce angiogenesis. Preclinical studies have shown that small molecule ATP-competitive Src kinase inhibitors can effectively impair metastasis associated tumor cell functions in vitro. However, the impact of these agents on the metastatic cascade in vivo is less well understood. In the present studies, we have examined the ability of saracatinib, a dual-specific, orally available inhibitor of Src and Abl protein tyrosine kinases, to interfere with the establishment of lung metastases in mice by tumor cells introduced into the blood stream. The results demonstrate that Src inhibition most effectively interferes with the establishment of secondary tumor deposits when treatments are administered while tumor cells are in the initial phases of dissemination. PMID- 22526634 TI - A new analytical approach for the comprehensive characterization of polar xenobiotic organic compounds downgradient of old municipal solid waste (MSW) landfills. AB - Groundwater samples collected downgradient from a former municipal solid waste landfill near Berlin, Germany, were analyzed by GC-MS, HPLC-MS, and HPLC-NMR hyphenated techniques to comprehensively characterize the xenobiotic organic compounds (XOCs). The focus thereby was on the detection and identification of the polar XOCs which were analyzed in the extract obtained after separation of the unpolar components by pre-extraction. HPLC-NMR and HPLC-MS runs were used to identify polar XOCs on-line or to obtain preliminary structure information on the other XOCs. These compounds were then isolated by HPLC fractionation and their structures elucidated by off-line NMR and MS investigations. A variety of polar XOCs, products of the dye industry, degradation products of polyethylene glycol, and some heterocyclic compounds could be identified. Furthermore, a semi quantitative estimation of the identified polar compounds is given. PMID- 22526635 TI - Recent advances in sulfotransferase enzyme activity assays. AB - Sulfotransferases are enzymes that catalyze the transfer of sulfo groups from a donor, for example 3'-phosphoadenosine 5'-phosphosulfate, to an acceptor, for example the amino or hydroxyl groups of a small molecule, xenobiotic, carbohydrate, or peptide. These enzymes are important targets in the design of novel therapeutics for treatment of a variety of diseases. This review examines assays used for this important class of enzyme, paying particular attention to sulfotransferases acting on carbohydrates and peptides and the major challenges associated with their analysis. PMID- 22526636 TI - Microchip-based immunoassays with application of silicon dioxide nanoparticle film. AB - Highly sensitive detection of proteins offers the possibility of early and rapid diagnosis of various diseases. Microchip-based immunoassay integrates the benefits from both immunoassays (high specificity of target sample) and microfluidics (fast analysis and low sample consumption). However, direct capture of proteins on bare microchannel surface suffers from low sensitivity due to the low capacity of microsystem. In this study, we demonstrated a microchip-based heterogeneous immunoassay using functionalized SiO(2) nanoparticles which were covalently assembled on the surface of microchannels via a liquid-phase deposition technique. The formation of covalent bonds between SiO(2) nanoparticles and polydimethylsiloxane substrate offered sufficient stability of the microfluidic surface, and furthermore, substantially enhanced the protein capturing capability, mainly due to the increased surface-area-to-volume ratio. IgG antigen and FITC-labeled anti-IgG antibody conjugates were adopted to compare protein-enrichment effect, and the fluorescence signals were increased by ~75 fold after introduction of functionalized SiO(2) nanoparticles film. Finally, a proof-of-concept experiment was performed by highly efficient capture and detection of inactivated H1N1 influenza virus using a microfluidic chip comprising highly ordered SiO(2) nanoparticles coated micropillars array. The detection limit of H1N1 virus antigen was 0.5 ng mL(-1), with a linear range from 20 to 1,000 ng mL(-1) and mean coefficient of variance of 4.71%. PMID- 22526637 TI - A method to determine the kinetics of multiple proteins in human infants with respiratory distress syndrome. AB - We report a method to measure in vivo turnover of four proteins from sequential tracheal aspirates obtained from human newborn infants with respiratory distress syndrome using targeted proteomics. We detected enrichment for all targeted proteins approximately 3 h from the start of infusion of [5,5,5-(2)H(3)] leucine, secretion times that varied from 1.2 to 2.5 h, and half lives that ranged between 10 and 21 h. Complement factor B, a component of the alternative pathway of complement activation, had an approximately twofold-longer half-life than the other three proteins. In addition, the kinetics of mature and carboxy-terminal tryptic peptides from the same protein (surfactant protein B) were not statistically different (p = 0.49). PMID- 22526639 TI - Ultrasound-assisted emulsification microextraction coupled with gas chromatography-mass spectrometry using the Taguchi design method for bisphenol migration studies from thermal printer paper, toys and baby utensils. AB - The optimization of a clean procedure based on ultrasound-assisted emulsification liquid-liquid microextraction for the sensitive determination of four bisphenols is presented. The miniaturized technique was coupled with gas chromatography-mass spectrometry after derivatization by in situ acetylation. The Taguchi experimental method, an orthogonal array design, was applied to find the optimal combination of seven factors (each factor at three levels) influencing the emulsification, extraction and collection efficiency, namely acetic anhydride volume, sodium phosphate concentration, carbon tetrachloride volume, aqueous sample volume, sodium chloride concentration and ultrasound power and application time. A second factorial design was applied with four factors and five levels for each factor, 25 experiments being performed in this instance. The matrix effect was evaluated, and it was concluded that sample quantification can be done by calibration with aqueous standards. The detection limits ranged from 0.01 to 0.03 ng mL(-1) depending on the compound. The environmentally friendly sample pretreatment procedure was applied to study the migration of the bisphenols from different types of samples: thermal printer paper, compact discs, digital versatile discs, small tight-fitting waistcoats, baby's bottles, baby bottle nipples of different materials and children's toys. PMID- 22526638 TI - Rapid identification, by use of the LTQ Orbitrap hybrid FT mass spectrometer, of antifungal compounds produced by lactic acid bacteria. AB - Fungal contamination of food causes health and economic concerns. Several species of lactic acid bacteria (LAB) have antifungal activity which may inhibit food spoilage fungi. LAB have GRAS (generally recognised as safe) status, allowing them to be safely integrated into food systems as natural food preservatives. A method is described herein that enables rapid screening of LAB cultures for 25 known antifungal compounds associated with LAB. This is the first chromatographic method developed which enables the rapid identification of a wide range of antifungal compounds by a single method with a short analysis time (23 min). Chromatographic separation was achieved on a Phenomenex Gemini C18 100A column (150 mm * 2.0 mm; 5 MUm) by use of a mobile-phase gradient prepared from (A) water containing acetic acid (0.1%) and (B) acetonitrile containing acetic acid (0.1%), at a flow rate of 0.3 uL min(-1). The gradient involved a progressive ramp from 10-95% acetonitrile over 13 min. The LC was coupled to a hybrid LTQ Orbitrap XL fourier-transform mass spectrometer (FTMS) operated in negative ionisation mode. High mass accuracy data (<3 ppm) obtained by use of high resolution (30,000 K) enabled unequivocal identification of the target compounds. This method allows comprehensive profiling and comparison of different LAB strains and is also capable of the identification of additional compounds produced by these bacteria. PMID- 22526640 TI - Selective detection of alkaloids in MALDI-TOF: the introduction of a novel matrix molecule. AB - The current manuscript presents 3-[5'-(methylthio)-2,2'-bithiophen-5 ylthio]propanenitrile (MT3P), as a novel matrix molecule, which facilitates the selective ionization of alkaloids in matrix-assisted laser desorption/ionization mass spectrometry. Exhibiting strong ionizing properties at low levels of laser energy, MT3P was evaluated on 55 compounds belonging to various chemical families. The observed molecular ion yields induced by MT3P were compared with those obtained by commercially available matrices such as 1,8-dihydroxy-9,10 dihydroanthracen-9-one, alpha-cyano-4-hydroxycinnamic acid, 2,2':5',2" terthiophene and 2,5-dihydroxybenzoic acid. In conclusion, MT3P displayed excellent ionization properties for 23 out of 25 investigated alkaloids, while showing little to no interaction with compounds from different chemical origin. Further, in comparison to other tested matrices, MT3P generally facilitated better ionization of alkaloids. Eventually, levels of laser energy were adjusted to obtain spectra with significantly reduced matrix noise. PMID- 22526641 TI - Ecofriendly in-line process monitoring: a case study. Anthracene photodegradation in the presence of refuse-derived soluble bio-organics. AB - Photodegradation of anthracene has been studied in aqueous solutions containing soluble bio-organic substances isolated from urban refuse. To perform a preliminary rapid feasibility study of this process while reducing the amount of analytical effort and reagents, an experimental set-up was developed comprising a Teflon coil surrounding a UV-lamp and coupled with an in-line spectrofluorimeter. In this fashion only few millilitres of solution are needed to study the degradation process. Furthermore, the in-line spectroscopic approach enables monitoring of the process without consumption of reagents. Additional studies by liquid chromatography and use of toxicity tests clearly indicated that the apparent inhibition effect of bio-organic compounds on anthracene degradation is not relevant. The results imply that urban refuse may be used as an auxiliary in the recovery of polycyclic aromatic hydrocarbons from contaminated soil by washing, without deleterious effects on the photodegradation of anthracene and other aromatic pollutants. PMID- 22526642 TI - Nanostructured substrates for portable and miniature SPR biosensors. AB - Surface plasmon resonance (SPR) biosensing has matured into a valuable analytical technique for measurements related to biomolecules, environmental contaminants, and the food industry. Contemporary SPR instruments are mainly suitable for laboratory-based measurements. However, several point-of-measurement applications would benefit from simple, small, portable and inexpensive sensors to assess the health condition of a patient, potential environmental contamination, or food safety issues. This Trend article explores nanostructured substrates for improving the sensitivity of classical SPR instruments and nanoparticle (NP) based colorimetric substrates that may provide a solution to the development of point-of-measurement SPR techniques. Novel nanomaterials and methodology capable of enhancing the sensitivity of classical SPR sensors are destined to improve the limits of detection of miniature SPR instruments to the level required for most applications. In a different approach, paper or substrate-based SPR assays based on NPs, are a highly promising topic of research that may facilitate the widespread use of a novel class of miniature and portable SPR instruments. PMID- 22526643 TI - Substrate-dependent kinetics in tyrosinase-based biosensing: amperometry vs. spectrophotometry. AB - Despite the broad use of enzymes in electroanalytical biosensors, the influence of enzyme kinetics on the function of prototype sensors is often overlooked or neglected. In the present study, we employ amperometry as an alternative or complementary method to study the kinetics of tyrosinase, whose catalytic activity results in o-quinone products. We further compare our results for four monophenolic substrates with those obtained from ultraviolet-visible spectrophotometry and show that the results from both assays are in good agreement. We also observe large variations in the enzyme kinetics for different monophenolic substrates depending on the R-group at the para position. To further study this effect, we investigate the stability of quinone products in the enzymatic assay. This information can in principle be utilized to discriminate between different phenolic species by monitoring the reaction rate. PMID- 22526644 TI - Analytical tools for identification of non-intentionally added substances (NIAS) coming from polyurethane adhesives in multilayer packaging materials and their migration into food simulants. AB - Adhesives used in food packaging to glue different materials can provide several substances as potential migrants, and the identification of potential migrants and migration tests are required to assess safety in the use of adhesives. Solid phase microextraction in headspace mode and gas chromatography coupled to mass spectrometry (HS-SPME-GC-MS) and ChemSpider and SciFinder databases were used as powerful tools to identify the potential migrants in the polyurethane (PU) adhesives and also in the individual plastic films (polyethylene terephthalate, polyamide, polypropylene, polyethylene, and polyethylene/ethyl vinyl alcohol). Migration tests were carried out by using Tenax((r)) and isooctane as food simulants, and the migrants were analyzed by gas chromatography coupled to mass spectrometry. More than 63 volatile and semivolatile compounds considered as potential migrants were detected either in the adhesives or in the films. Migration tests showed two non-intentionally added substances (NIAS) coming from PU adhesives that migrated through the laminates into Tenax((r)) and into isooctane. Identification of these NIAS was achieved through their mass spectra, and 1,6-dioxacyclododecane-7,12-dione and 1,4,7-trioxacyclotridecane-8,13-dione were confirmed. Caprolactam migrated into isooctane, and its origin was the external plastic film in the multilayer, demonstrating real diffusion through the multilayer structure. Comparison of the migration values between the simulants and conditions will be shown and discussed. PMID- 22526645 TI - Selective LC-MS/MS method for the identification of BMAA from its isomers in biological samples. AB - Algal blooms are well-known sources of acute toxic agents that can be lethal to aquatic organisms. However, one such toxin, beta-N-methylamino-L-alanine (BMAA) is also believed to cause amyotrophic lateral sclerosis, also known as Lou Gehrig's disease. The detection and identification of BMAA in natural samples were challenging until the recent introduction of reliable methods. However, the issue of potential interference from unknown isomers of BMAA present in samples has not yet been thoroughly investigated. Based on a systematic database search, we generated a list of all theoretical BMAA structural isomers, which was subsequently narrowed down to seven possible interfering compounds for further consideration. The seven possible candidates satisfied the requirements of chemical stability and also shared important structural domains with BMAA. Two of the candidates, 2,4-diaminobutyric acid (DAB) and N-(2-aminoethyl) glycine (AEG) have recently been studied in the context of BMAA. A further isomer, beta-amino-N methyl-alanine (BAMA), has to be considered because it can potentially yield the fragment ion, which is diagnostic for BMAA. Here, we report the synthesis and analysis of BAMA, together with AEG, DAB, and other isomers that are of interest in the separation and detection of BMAA in biological samples by using either high-performance liquid chromatography or ultra-high-performance liquid chromatography coupled with tandem mass spectrometry. We detected for the first time BAMA in blue mussel and oyster samples. This work extends the previously developed liquid chromatography-tandem mass spectrometry platform Spacil et al. (Analyst 135:127, 2010) to allow BMAA isomers to be distinguished, improving the detection and identification of this important amino acid. PMID- 22526646 TI - Focused ultrasound solid-liquid extraction and gas chromatography tandem mass spectrometry determination of brominated flame retardants in indoor dust. AB - This study presents a focused ultrasound solid-liquid extraction (FUSLE) and gas chromatography tandem mass spectrometry method for the determination of brominated diphenyl ethers (BDEs), from mono- to hexa-congeners, in indoor dust. This approach provided a simple, fast, and economical method. After the solvent extraction selection, the FUSLE conditions were studied using a central composite design. Finally, the number of extraction cycles was studied. The selected conditions were 8 mL of 3:1 n-hexane-acetone mixture as extraction solvent, at a power of 65% for 20 s. The proposed method allowed accurate determination of BDEs, with recovery values around 100% and detection limits between 0.05 and 0.8 ng g(-1). It also has advantages over other existing methods in terms of simplicity, analysis time, and solvent consumption. The analysis of several indoor dust samples showed high concentration values of BDEs 47, 99, 100, 153, and 154 in some of the samples, moreover, BDEs 47 and 99 were found in all samples. PMID- 22526647 TI - Analysis of urinary oligosaccharides in lysosomal storage disorders by capillary high-performance anion-exchange chromatography-mass spectrometry. AB - Many lysosomal storage diseases are characterized by an increased urinary excretion of glycoconjugates and oligosaccharides that are characteristic for the underlying enzymatic defect. Here, we have used capillary high-performance anion exchange chromatography (HPAEC) hyphenated to mass spectrometry to analyze free oligosaccharides from urine samples of patients suffering from the lysosomal storage disorders fucosidosis, alpha-mannosidosis, G(M1)-gangliosidosis, G(M2) gangliosidosis, and sialidosis. Glycan fingerprints were registered, and the patterns of accumulated oligosaccharides were found to reflect the specific blockages of the catabolic pathway. Our analytical approach allowed structural analysis of the excreted oligosaccharides and revealed several previously unpublished oligosaccharides. In conclusion, using online coupling of HPAEC with mass spectrometric detection, our study provides characteristic urinary oligosaccharide fingerprints with diagnostic potential for lysosomal storage disorders. PMID- 22526648 TI - Development of sensitive direct and indirect enzyme-linked immunosorbent assays (ELISAs) for monitoring bisphenol-A in canned foods and beverages. AB - Enzyme-linked immunosorbent assays (ELISAs) are investigated in this work for the detection of bisphenol-A (BPA), a plastic monomer and a critical contaminant in food and environment. A series of polyclonal antibodies generated in vivo using BPA-butyrate-protein conjugate and BPA-valerate-protein conjugate were evaluated on direct and indirect competitive assay formats with five competing haptens (BPA butyrate, BPA-valerate, BPA-crotonate, BPA-acetate, and BPA-2-valerate). Two indirect ELISAs and one direct ELISA exhibiting high sensitivity and specificity for BPA were developed. The 50 % inhibition of antibody binding (IC(50)) values were 0.78 +/- 0.01-1.20 +/- 0.26 MUg L(-1), and the limits of detection as measured by the IC(20) values were 0.10 +/- 0.03-0.20 +/- 0.04 MUg L(-1). The assays were highly specific to BPA, only displaying low cross-reactivity (3-8 % for the indirect assays and 26 % for the direct assay) for 4-cumylphenol (4-CP), at pH 7.2. The degree of cross-reaction of 4-CP was influenced by the antibody/hapten conjugate combination, assay conditions, and the assay format. The assays were optimized for the analysis of BPA in canned vegetables, bottled water and carbonated drinks. The limits of quantification for these three evaluated sample types, based on the spike and recovery data, were 0.5, 2.5, and 100 MUg L(-1), respectively. PMID- 22526649 TI - An automated method for the measurement of a range of tyrosine kinase inhibitors in human plasma or serum using turbulent flow liquid chromatography-tandem mass spectrometry. AB - Tyrosine kinase inhibitors (TKIs) are used to treat a number of cancers, including chronic myeloid leukaemia and hepatocellular carcinoma. Therapeutic drug monitoring (TDM) may be indicated to (1) monitor adherence, (2) guide dosage, and (3) minimise the risk of drug-drug interactions and dose-related toxicity. On-line, automated sample preparation provided by TurboFlow technology (ThermoFisher Scientific) in conjunction with the sensitivity and selectivity of tandem mass spectrometry (MS/MS) detection may be applied to the analysis of single drugs and metabolites. We report the use of TurboFlow LC-MS/MS for the analysis of nine TKIs and metabolites (imatinib, N-desmethylimatinib, dasatinib, nilotinib, erlotinib, gefitinib, lapatinib, sorafenib, sunitinib) in human plasma or serum for TDM purposes. An Aria Transcend TLX-II system coupled with a TSQ Vantage was used. Samples (50 MUL) were vortex mixed with internal standard solution (150 MUL imatinib-D(8), gefitinib-D(8), sunitinib-D(10), and nilotinib (13)C (2) (15) N(2) in acetonitrile) and, after centrifugation 100 MUL supernatant were injected directly onto a 50 * 0.5-mm Cyclone TurboFlow column. Analytes were focussed onto a 50 * 2.1-mm (3 MUm) Hypersil GOLD analytical column and eluted with an acetonitrile/water gradient. Analytes were monitored in selected reaction monitoring mode (positive APCI). Total analysis time was 7 min without multiplexing. Calibration was linear (R(2) > 0.99) for all analytes. Inter- and intra-assay precision (in percent relative standard deviation, RSD) was <11 % and accuracy 89-117 % for all analytes. No matrix effects were observed. This method is suitable for high-throughput TDM in patients undergoing chronic therapy with TKIs and has been utilised in the analysis of clinical samples. PMID- 22526651 TI - Elemental imaging of MRI contrast agents: benchmarking of LA-ICP-MS to MRI. AB - Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) has been used to map the spatial distribution of magnetic resonance imaging (MRI) contrast agents (Gd-based) in histological sections in order to explore synergies with in vivo MRI. Images from respective techniques are presented for two separate studies namely (1) convection enhanced delivery of a Gd nanocomplex (developmental therapeutic) into rat brain and (2) convection enhanced delivery, with co-infusion of Magnevist (commercial Gd contrast agent) and Carboplatin (chemotherapy drug), into pig brain. The LA technique was shown to be a powerful compliment to MRI not only in offering improved sensitivity, spatial resolution and signal quantitation but also in giving added value regarding the fate of administered agents (Gd and Pt agents). Furthermore simultaneous measurement of Fe enabled assignment of an anomalous contrast enhancement region in rat brain to haemorrhage at the infusion site. PMID- 22526650 TI - Detection of recombinant human EPO administered to horses using MAIIA lateral flow isoform test. AB - Doping of horses with recombinant human erythropoietin (rHuEPO) to illegally enhance their endurance capacity in horseracing has been reported during the last years. This leads to increased blood viscosity which can result in sudden death and is of concern for the horse welfare. Additionally, the horse can start production of rHuEPO antibodies, which cross-reacts with endogenous equine EPO and can lead to severe anaemia and even death. In this study, a novel micro chromatographic method, EPO WGA MAIIA, has been tested for the capability in plasma and urine samples to detect administration of erythropoiesis-stimulating agents, like the rHuEPO glycoprotein varieties Eprex and Aranesp, to horses. After administration of 40 IU Eprex kg(-1) day(-1) to seven horses during 6 days, the presence of Eprex in horse plasma was detected up to 2-5 days after last injection. In urine samples collected from two horses, Eprex was detected up to 3 days. A single injection of Aranesp (0.39 MUg/kg) was detected up to 9 days in plasma and up to 8 days, the last day of testing, in the urine sample. The LC FAIMS-MS/MS system, with 1 day reporting time, confirmed the presence of Eprex up to 1 day after last injection for six out of seven horses and the presence of Aranesp up to 5 days after last injection in plasma samples. The MAIIA system showed to be a promising tool with high sensitivity and extremely short reporting time (1 h). PMID- 22526652 TI - Analytical methods for the detection of viruses in food by example of CCL-3 bioagents. AB - This critical review presents challenges and strategies in the detection of viral contaminants in food products. Adenovirus, caliciviruses, enteroviruses, and hepatitis A are emerging contaminant viruses. These viruses contaminate a variety of food products, including fruits, vegetables, shellfish, and ready-to-eat processed foods. The diversity of targets and sample matrices presents unique challenges to virus monitoring that have been addressed by a wide array of processing and detection methods. This review covers sample acquisition and handling, virus recovery/concentration, and the determination of targets using molecular biology and mass-spectrometric approaches. The concentration methods discussed include precipitation, antibody-based concentration, and filtration; the detection methods discussed include microscopy, polymerase chain reaction, nucleic acid sequence-based amplification, and mass spectrometry. PMID- 22526653 TI - Multiplexed paper test strip for quantitative bacterial detection. AB - Rapid, sensitive, on-site detection of bacteria without a need for sophisticated equipment or skilled personnel is extremely important in clinical settings and rapid response scenarios, as well as in resource-limited settings. Here, we report a novel approach for selective and ultra-sensitive multiplexed detection of Escherichia coli (non-pathogenic or pathogenic) using a lab-on-paper test strip (bioactive paper) based on intracellular enzyme (beta-galactosidase (B-GAL) or beta-glucuronidase (GUS)) activity. The test strip is composed of a paper support (0.5 * 8 cm), onto which either 5-bromo-4-chloro-3-indolyl-beta-D: glucuronide sodium salt (XG), chlorophenol red beta-galactopyranoside (CPRG) or both and FeCl(3) were entrapped using sol-gel-derived silica inks in different zones via an ink-jet printing technique. The sample was lysed and assayed via lateral flow through the FeCl(3) zone to the substrate area to initiate rapid enzyme hydrolysis of the substrate, causing a change from colorless-to-blue (XG hydrolyzed by GUS, indication of nonpathogenic E. coli) and/or yellow to red magenta (CPRG hydrolyzed by B-GAL, indication of total coliforms). Using immunomagnetic nanoparticles for selective preconcentration, the limit of detection was ~5 colony-forming units (cfu) per milliliter for E. coli O157:H7 and ~20 cfu/mL for E. coli BL21, within 30 min without cell culturing. Thus, these paper test strips could be suitable for detection of viable total coliforms and pathogens in bathing water samples. Moreover, inclusion of a culturing step allows detection of less than 1 cfu in 100 mL within 8 h, making the paper tests strips relevant for detection of multiple pathogens and total coliform bacteria in beverage and food samples. PMID- 22526654 TI - Enantiomeric determination of azole antifungals in wastewater and sludge by liquid chromatography-tandem mass spectrometry. AB - A sensitive and reliable liquid chromatographic-tandem mass spectrometric method for enantiomeric determination of five chiral azole antifungals (econazole, ketoconazole, miconazole, tebuconazole, and propiconazole) in wastewater and sludge has been established and validated. An isotope-labeled internal standard was used for quantification. Recovery of the individual enantiomers was usually in the range of 77-102 % for wastewater and 71-95 % for sludge, with relative standard deviations within 20 %. No significant difference (p>0.05) was observed between recovery of pairs of enantiomers of the chiral azole antifungals except for those of tebuconazole. Method quantification limits for individual enantiomers were 0.3-10 ng L(-1) and 3-29 ng g(-1) dry weight for wastewater and sludge, respectively. The method was used to investigate the enantiomeric composition of the azole pharmaceuticals in wastewater and sludge samples from a sewage treatment plant in China. Enantiomers of miconazole, ketoconazole, and econazole were widely detected. The results showed that the azole antifungals in wastewater and sludge were generally racemic or marginally non-racemic. The method is a useful tool for investigation of the enantiomeric occurrence, behavior, and fate of the chiral azole antifungals in the environment. PMID- 22526655 TI - Binding of the ionic liquid cation 1-alkyl-3-methylimidazolium to p tetranitrocalix[4]arene probed by fluorescent indicator displacement. AB - Acridine orange (AO) was used as a fluorescent probe molecule to study the encapsulation of an alkylimidazolium cation from a water-soluble ionic liquid (IL) within two cavitand species, p-tetranitrocalix[4]arene (1) and calix[4]resorcinarene (2), both in alkaline aqueous media. The addition of IL to the preformed [1.AO] adduct resulted in significantly increased fluorescence due to the expulsion of AO from the inclusion complex to the aqueous phase by competitive recognition of the 1-alkyl-3-methylimidazolium cation ([C(n)mim](+), n = 4 and 6) by 1. Conversely, the fluorescence signal dropped upon the addition of IL to the [2.AO] host-guest complex due to unfavorable binding between [C(n)mim](+) and 2. The formation of these postulated adducts is corroborated using ab initio calculations, which also provide evidence for the location of [bmim](+) at the lower external rim of [2.AO], providing an explanation for the observed luminescence quenching in the latter case. These results point to a number of different paths for exploration, ranging from the fluorescence monitoring of IL contamination in groundwater to the "daisy chaining" of macrocyles toward supramolecular ionic networks. They also broadly encourage the exploration of ILs in host-guest-based optical and mass spectrometric sensory systems. PMID- 22526656 TI - "In situ" extraction of essential oils by use of Dean-Stark glassware and a Vigreux column inside a microwave oven: a procedure for teaching green analytical chemistry. AB - One of the principal objectives of sustainable and green processing development remains the dissemination and teaching of green chemistry in colleges, high schools, and academic laboratories. This paper describes simple glassware that illustrates the phenomenon of extraction in a conventional microwave oven as energy source and a process for green analytical chemistry. Simple glassware comprising a Dean-Stark apparatus (for extraction of aromatic plant material and recovery of essential oils and distilled water) and a Vigreux column (as an air cooled condenser inside the microwave oven) was designed as an in-situ extraction vessel inside a microwave oven. The efficiency of this experiment was validated for extraction of essential oils from 30 g fresh orange peel, a by-product in the production of orange juice. Every laboratory throughout the world can use this equipment. The microwave power is 100 W and the irradiation time 15 min. The method is performed at atmospheric pressure without added solvent or water and furnishes essential oils similar to those obtained by conventional hydro or steam distillation. By use of GC-MS, 22 compounds in orange peel were separated and identified; the main compounds were limonene (72.1%), beta-pinene (8.4%), and gamma-terpinene (6.9%). This procedure is appropriate for the teaching laboratory, does not require any special microwave equipment, and enables the students to learn the skills of extraction, and chromatographic and spectroscopic analysis. They are also exposed to a dramatic visual example of rapid, sustainable, and green extraction of an essential oil, and are introduced to successful sustainable and green analytical chemistry. PMID- 22526657 TI - Comparative study of hollow-fiber liquid-phase micro-extraction and an aqueous two-phase system for determination of phytohormones in soil. AB - Two methods, hollow-fiber liquid-phase micro-extraction (HF-LPME) and an aqueous two-phase system (ATPS), have been systematically optimized and compared for extraction and determination of phytohormones in soil by high-performance liquid chromatography (HPLC). The effects on extraction of conditions including solvent type and volume, extraction time, temperature, and amount of salt were evaluated. It was shown that ATPS was superior to HF-LPME for determination of paclobutrazol and uniconazole under the optimum conditions. The limits of detection (LODs) of ATPS were 0.002 MUg g(-1) for uniconazole and 0.01 MUg g(-1) for paclobutrazol, whereas LODs of HF-LPME were 0.005 MUg g(-1) and 0.03 MUg g(-1), respectively. Relative standard deviations (RSDs, n=5) and recovery were in the range 1.7-5.3 % and 86-102 %, respectively, for ATPS and 6.7-7.9 % and 40-60 % for HF-LPME. In addition, the advantages of ATPS were shorter extraction time, suitable for simultaneous pretreatment of batches of samples, and higher extraction capacity. ATPS was therefore applied to the determination of paclobutrazol and uniconazole in real soil samples. Uniconazole was detected in all the samples analyzed whereas paclobutrazol was not found. PMID- 22526658 TI - Factors influencing the detection limit of the lateral-flow sandwich immunoassay: a case study with potato virus X. AB - Key factors influencing the analyte detection limit of the sandwich immunochromatographic assay (ICA), namely, the size of gold nanoparticles, the antibody concentration, the conjugation pH, and characteristics of membranes, are discussed. The impacts of these factors were quantitatively characterized and compared for the first time using the same antigen (potato virus X). The antibody colloidal gold conjugates synthesized at pH 9.0-9.5 (the pH was examined in the range from 7.5 to 10.0) and at an antibody concentration of 15 MUg/mL (the concentration was tested from 10 to 100 MUg/mL) demonstrated maximum binding with the analyte. The relationship between the size of gold nanoparticles and the ICA detection limit was determined. The detection limit decreases from 80 to 3 ng/mL (for antibodies with K (D) = 1.0 * 10(-9) M, data were obtained using a BIAcore X instrument) for a series of particles with a diameter from 6.4 to 33.4 nm (electron microscopy and dynamic light scattering data). In the case of larger particles (52 nm in diameter), the detection limit increases and reaches 9 ng/mL. A 10 mM phosphate buffer, pH 8, and a 50 mM phosphate buffer, pH 7, were the conditions of choice for the deposition of reactants. Taking into account these facts, we developed a lateral-flow test system for the rapid (10 min) detection of potato virus X in plant leaves. The ICA provided a visual detection limit of 3 ng/mL. In the case of the instrumental processing, potato virus X can be determined in the concentration range from 3 to 300 ng/mL with a detection limit 2 ng/mL. PMID- 22526659 TI - Reduction of matrix effects and improvement of sensitivity during determination of two chloridazon degradation products in aqueous matrices by using UPLC-ESI MS/MS. AB - The development and validation of a sensitive and reliable detection method for the determination of two polar degradation products, desphenyl-chloridazon (DPC) and methyl-desphenyl-chloridazon (MDPC) in surface water, ground water and drinking water is presented. The method is based on direct large volume injection ultra-performance liquid chromatography electrospray tandem mass spectrometry. This simple but powerful analytical method for polar substances in the aquatic environment is usually hampered by varying matrix effects, depending on the nature of different water bodies. For the two examined degradation products, the matrix effects are particularly strong compared with other polar degradation products of pesticides. Therefore, matrix effects were studied thoroughly with the aim of minimising them and improving sensitivity during determination by postcolumn addition of ammonia solution as a modifier. An internal standard was used in order to compensate for remaining matrix effects. The calibration curve shows very good coefficients of correlation (0.9994 for DPC and 0.9999 for MDPC). Intraday precision values were lower than 5 % for DPC, 3 % for MDPC and the limits of detection were 10 ng/L for both substances. The method was successfully used in a national round robin test with a deviation between 3 and 8 % from target values. Finally, about 1,000 samples from different water bodies have been examined with this method in the Rhine and Ruhr region of North-Rhine-Westphalia (Germany) and in the European Union. Approximately 76 % of analysed samples contained measurable amounts of DPC at concentrations up to 8 MUg/L while 53 % of the samples showed MDPC concentrations up to 2.3 MUg/L. PMID- 22526661 TI - Cell surface glycoprotein profiling of cancer cells based on bioorthogonal chemistry. AB - Bioorthogonal chemistry refers to chemical reactions that can occur within a living system without altering native biochemical processes. Applications of this concept extend to studies on a group of biomolecules that includes glycans, proteins, and lipids. In this study, a strategy for isolating cell surface glycoproteins and based on bioorthogonal chemistry was employed to identify new cancer-related glycoproteins. A novel alkyne reagent containing one disulfide bond was synthesized for the enrichment of glycoproteins metabolized with peracetylated N-azidoacetylmannosamine, which was applied on three different cancer cell lines, and all isolated proteins were analyzed by high-performance liquid chromatography-tandem mass spectrometry. The strategy of purifying cell surface glycoproteins introduced in this article was shown to be reliable, and a total of 56 cell surface glycoproteins were identified. Neuronal cell adhesion molecule was found uniquely expressed in A549 lung adenocarcinoma, and its expression in non-small-cell lung carcinomas was detected by immunohistochemistry. Furthermore, a significant increase of neuronal cell adhesion molecule expression was identified in non-small-cell lung adenocarcinoma compared with adjacent noncancerous tissues, and could be a novel potential target and marker in cancer treatment and detection. PMID- 22526660 TI - Visualization of acetylcholine distribution in central nervous system tissue sections by tandem imaging mass spectrometry. AB - Metabolite distribution imaging via imaging mass spectrometry (IMS) is an increasingly utilized tool in the field of neurochemistry. As most previous IMS studies analyzed the relative abundances of larger metabolite species, it is important to expand its application to smaller molecules, such as neurotransmitters. This study aimed to develop an IMS application to visualize neurotransmitter distribution in central nervous system tissue sections. Here, we raise two technical problems that must be resolved to achieve neurotransmitter imaging: (1) the lower concentrations of bioactive molecules, compared with those of membrane lipids, require higher sensitivity and/or signal-to-noise (S/N) ratios in signal detection, and (2) the molecular turnover of the neurotransmitters is rapid; thus, tissue preparation procedures should be performed carefully to minimize postmortem changes. We first evaluated intrinsic sensitivity and matrix interference using Matrix Assisted Laser Desorption/Ionization (MALDI) mass spectrometry (MS) to detect six neurotransmitters and chose acetylcholine (ACh) as a model for study. Next, we examined both single MS imaging and MS/MS imaging for ACh and found that via an ion transition from m/z 146 to m/z 87 in MS/MS imaging, ACh could be visualized with a high S/N ratio. Furthermore, we found that in situ freezing method of brain samples improved IMS data quality in terms of the number of effective pixels and the image contrast (i.e., the sensitivity and dynamic range). Therefore, by addressing the aforementioned problems, we demonstrated the tissue distribution of ACh, the most suitable molecular specimen for positive ion detection by IMS, to reveal its localization in central nervous system tissues. PMID- 22526662 TI - Quantification of steroids and endocrine disrupting chemicals in rat ovaries by LC-MS/MS for reproductive toxicology assessment. AB - Reproductive function is controlled by a finely tuned balance of androgens and estrogens. Environmental toxicants, notably endocrine disrupting chemicals (EDCs), appear to be involved in the disruption of hormonal balance in several studies. To further describe the effects of selected EDCs on steroid secretion in female rats, we aim to simultaneously investigate the EDC concentration and the sex hormone balance in the ovaries. Therefore, an effective method has been developed for the quantification of the sex steroid hormones (testosterone, androstenedione, estradiol, and estrone) and four endocrine disrupting chemicals (bisphenol A, atrazine, and the active metabolites of methoxychlor and vinclozolin) in rat ovaries. The sample preparation procedure is based on the so called "quick, easy, cheap, effective, rugged, and safe" approach, and an analytical method was developed to quantify these compounds with low detection limits by liquid chromatography coupled with a tandem mass spectrometer. This analytical method, applied to rat ovary samples following subacute EDC exposure, revealed some new findings for toxicological evaluation. In particular, we showed that EDCs with the same described in vitro mechanisms of action have different effects on the gonadal steroid balance. These results highlight the need to develop an integrative evaluation with the simultaneous measurement of EDCs and numerous steroids for good risk assessment. PMID- 22526663 TI - Development and validation of a direct competitive monoclonal antibody-based immunoassay for the sensitive and selective analysis of the phytoregulator forchlorfenuron. AB - Forchlorfenuron is a synthetic phytohormone with cytokinin-like activity used worldwide as a plant growth regulator to increase fruit size in a number of crops, mostly in kiwifruit and grape vines. A monoclonal antibody-based enzyme linked immunosorbent assay (ELISA) for the determination of forchlorfenuron has been characterized and optimized. The selected immunoreagents afforded a highly selective assay with a limit of detection of 10 ng L(-1) in buffer. This direct competitive ELISA was validated in terms of trueness, precision, and robustness using both commercial juice and whole fruit samples. Recoveries from fortified kiwifruit juices and white and red musts were between 97 % and 131 %, with relative standard deviations below 16 %. When homogenized whole fruits were analysed after acetonitrile extraction, recoveries between 96 % and 113 % were found, with a limit of quantification of 5 MUg kg(-1). The proposed immunoassay was validated by comparison with a reference chromatographic method using fruits from in-field treated grape and kiwifruit vines. Linear regression analysis of ELISA and HPLC-UV determinations showed an excellent correlation (r(2)=0.998), whereas analysis of the slope (0.99+/-0.01) and of the intercept (-1+/-3) clearly proved that the developed competitive immunoassay provided results that were statistically comparable to those obtained by the instrumental method for the analysis of forchlorfenuron in fruits at trace levels. PMID- 22526666 TI - Sampling of tar from sewage sludge gasification using solid phase adsorption. AB - Sewage sludge is a residue from wastewater treatment plants which is considered to be harmful to the environment and all living organisms. Gasification technology is a potential source of renewable energy that converts the sewage sludge into gases that can be used to generate energy or as raw material in chemical synthesis processes. But tar produced during gasification is one of the problems for the implementation of the gasification technology. Tar can condense on pipes and filters and may cause blockage and corrosion in the engines and turbines. Consequently, to minimize tar content in syngas, the ability to quantify tar levels in process streams is essential. The aim of this work was to develop an accurate tar sampling and analysis methodology using solid phase adsorption (SPA) in order to apply it to tar sampling from sewage sludge gasification gases. Four types of commercial SPA cartridges have been tested to determine the most suitable one for the sampling of individual tar compounds in such streams. Afterwards, the capacity, breakthrough volume and sample stability of the SupelcleanTM ENVI-Carb/NH(2), which is identified as the most suitable, have been determined. Basically, no significant influences from water, H(2)S or NH(3) were detected. The cartridge was used in sampling real samples, and comparable results were obtained with the present and traditional methods. PMID- 22526667 TI - The expanding field of SILAC. AB - Stable isotope labeling by amino acids (SILAC) metabolically encodes cell populations for protein quantification by mass spectrometry. SILAC was introduced in 2002 and the field of mass spectrometry based proteomics has changed dramatically over the last decade. Increased sensitivity and speed of mass spectrometry instruments coupled with significantly improved mass resolution and precision have led to much higher rates of peptide identification and deeper coverage of proteomic samples. Several proteomics approaches are now available for quantifying proteins and their post-translational modifications, each with their strengths and weaknesses. The simplicity and robustness of SILAC have led to its widespread adoption and new applications have emerged that play to its particular strengths as a metabolic labeling approach. PMID- 22526668 TI - Liquid chromatography-mass spectrometry for C60 fullerene analysis: optimisation and comparison of three ionisation techniques. AB - The increasing use and production of nanomaterials have led to growing concern over the release of new pollutants to the environment. Fullerenes have been a subject of intense research, both because of their unique chemistry and because of technological applications. The development of analytical methods to quantify the fullerenes in complex sample matrices is a crucial step in the study of their occurrence and exposure, and thus in risk assessment. This paper reports the development and optimisation of a method combining liquid chromatography with ion trap mass spectrometry (LC-ITMS) for analysis of the fullerene C(60). Under the optimised chromatogram conditions, a C(18) analytical column had good selectivity for fullerenes C(60) and C(70), with retention times of 3.0 and 4.1 min, respectively. Mass spectrometric detection was tested and optimised using three common ionisation techniques-atmospheric-pressure chemical ionisation (APCI), atmospheric-pressure photoionisation (APPI), and electrospray ionisation (ESI). The molecular ion was most abundant for C (60) (-) (m/z=720) in APCI and APPI, whereas adduct ions were formed with the molecular ion in ESI. Finally, the performance of the three ionisation techniques examined was compared by use of five validation criteria. The instrument detection limit (8 ng mL(-1)), quantification limit (27 ng mL(-1)), detection sensitivity (90.2 ng mL(-1)), linear range (8-1,000 ng mL(-1)), and repeatability (15 %) of APPI make it the most promising ionisation technique for fullerene C(60) analysis. PMID- 22526669 TI - Development and validation of an SPE HG-AAS method for determination of inorganic arsenic in samples of marine origin. AB - The present paper describes a novel method for the quantitative determination of inorganic arsenic (iAs) in food and feed of marine origin. The samples were subjected to microwave-assisted extraction using diluted hydrochloric acid and hydrogen peroxide, which solubilised the analytes and oxidised arsenite (As(III)) to arsenate (As(V)). Subsequently, a pH buffering of the sample extract at pH 6 enabled selective elution of As(V) from a strong anion exchange solid-phase extraction (SPE) cartridge. Hydride generation atomic absorption spectrometry (HG AAS) was applied to quantify the concentration of iAs (sum of As(III) and As(V)) as the total arsenic (As) in the SPE eluate. The results of the in-house validation showed that mean recoveries of 101-104% were achieved for samples spiked with iAs at 0.5, 1.0 and 1.5 mg.kg(-1), respectively. The limit of detection was 0.08 mg kg(-1), and the repeatability (RSD(r)) and intra-laboratory reproducibility (RSD(IR)) were less than 8% and 13%, respectively, for samples containing 0.2 to 1.5 mg kg(-1) iAs. The trueness of the SPE HG-AAS method was verified by confirming results obtained by parallel analysis using high performance liquid chromatography coupled to inductively coupled plasma mass spectrometry. It was demonstrated that the two sets of results were not significantly different (P < 0.05). The SPE HG-AAS method was applied to 20 marine food and feed samples, and concentrations of up to 0.14 mg kg(-1) of iAs were detected. PMID- 22526670 TI - 2-Nitro-6-monoacetylmorphine: potential marker for monitoring the presence of 6 monoacetylmorphine in urine adulterated with potassium nitrite. AB - 6-Monoacetylmorphine (6-MAM), being a unique metabolite of heroin, is routinely tested in urine samples to monitor heroin use. However, detection of 6-MAM related opiates such as morphine is known to be affected by in vitro urine adulteration using oxidizing adulterants such as potassium nitrite. This study aimed to investigate the fate of 6-MAM after exposure to nitrite and to identify any formed oxidation products that may potentially be used for monitoring heroin abuse despite nitrite adulteration. Potassium nitrite (0.05 M and 0.6 M) was reacted with 6-MAM (5-10,000 ng/mL) in both water and blank urine with pH adjusted to range from 3 to 8. Following reaction at room temperature for varying periods, the reaction mixtures were monitored by both the CEDIA(r) Heroin Metabolite (6-AM) immunoassay and liquid chromatography-mass spectrometry (LC-MS) methods. Structural elucidation of the isolated oxidation products was based on mass spectrometry and nuclear magnetic resonance spectroscopic evidence. Nitrite, under acidic environment (pH<7), was shown to be effective in masking the detection of 6-MAM by both the CEDIA(r) immunoassay and the LC-MS methods. 2 Nitro-6-monoacetylmorphine (2-nitro-MAM) was identified as the sole oxidation product, which remained detectable in urine for at least 11 days under the experimental conditions investigated. 2-Nitro-MAM was detectable in a urine sample of a heroin user after nitrite exposure. 2-Nitro-MAM has shown potential to serve as a marker for monitoring heroin abuse when urine is adulterated with nitrite. Certification of 2-nitro-MAM reference standard for further development of its quantitative testing methods is thus warranted. PMID- 22526671 TI - Non-aqueous capillary electrophoresis separation of fullerenes and C60 fullerene derivatives. AB - As the interest in the use of fullerene compounds in biomedical and cosmetic applications increases, so too does the need to develop methods for their determination and quantitation in such complex matrices. In this work, we studied the behavior of C60 and C70 fullerenes in non-aqueous capillary electrophoresis, as well as two C60 fullerene derivatives not previously reported by any electrophoretic method, N-methyl-fulleropyrrolidine and (1,2-methanofullerene C60)-61-carboxylic acid. The separation was performed using fused-silica capillaries with an I.D. of 50 MUm and tetraalkylammonium salts, namely tetra-n decylammonium bromide (200 mM) and tetraethylammonium bromide (40 mM), in a solvent mixture containing 6 % methanol and 10 % acetic acid in acetonitrile/chlorobenzene (1:1 v/v) as the background electrolyte. Detection limits, based on a signal-to-noise ratio of 3:1, were calculated, and values between 1 and 3.7 mg/L were obtained. Good run-to-run and day-to-day precisions on concentration were achieved with relative standard deviation lower than 15 %. For the first time, an electrophoretic technique has been applied for the analysis of C60 fullerene in a commercial cosmetic cream. A standard addition method was used for quantitation, and the result was compared with that obtained by analyzing the same cream by liquid chromatography coupled to mass spectrometry. PMID- 22526672 TI - CodY deletion enhances in vivo virulence of community-associated methicillin resistant Staphylococcus aureus clone USA300. AB - The Staphylococcus aureus global regulator CodY responds to nutrient availability by controlling the expression of target genes. In vitro, CodY represses the transcription of virulence genes, but it is not known if CodY also represses virulence in vivo. The dominant community-associated methicillin-resistant S. aureus (CA-MRSA) clone, USA300, is hypervirulent and has increased transcription of global regulators and virulence genes; these features are reminiscent of a strain defective in CodY. Sequence analysis revealed, however, that the codY genes of USA300 and other sequenced S. aureus isolates are not significantly different from the codY genes in strains known to have active CodY. codY was expressed in USA300, as well as in other pulsotypes assessed. Deletion of codY from a USA300 clinical isolate resulted in modestly increased expression of the global regulators agr and saeRS, as well as the gene encoding the toxin alpha hemolysin (hla). A substantial increase (>30-fold) in expression of the lukF-PV gene, encoding part of the Panton-Valentine leukocidin (PVL), was observed in the codY mutant. All of these expression differences were reversed by complementation with a functional codY gene. Moreover, purified CodY protein bound upstream of the lukSF-PV operon, indicating that CodY directly represses expression of lukSF PV. Deletion of codY increased the virulence of USA300 in necrotizing pneumonia and skin infection. Interestingly, deletion of lukSF-PV from the codY mutant did not attenuate virulence, indicating that the hypervirulence of the codY mutant was not explained by overexpression of PVL. These results demonstrate that CodY is active in USA300 and that CodY-mediated repression restrains the virulence of USA300. PMID- 22526673 TI - Expression of either lethal toxin or edema toxin by Bacillus anthracis is sufficient for virulence in a rabbit model of inhalational anthrax. AB - The development of therapeutics against biothreats requires that we understand the pathogenesis of the disease in relevant animal models. The rabbit model of inhalational anthrax is an important tool in the assessment of potential therapeutics against Bacillus anthracis. We investigated the roles of B. anthracis capsule and toxins in the pathogenesis of inhalational anthrax in rabbits by comparing infection with the Ames strain versus isogenic mutants with deletions of the genes for the capsule operon (capBCADE), lethal factor (lef), edema factor (cya), or protective antigen (pagA). The absence of capsule or protective antigen (PA) resulted in complete avirulence, while the presence of either edema toxin or lethal toxin plus capsule resulted in lethality. The absence of toxin did not influence the ability of B. anthracis to traffic to draining lymph nodes, but systemic dissemination required the presence of at least one of the toxins. Histopathology studies demonstrated minimal differences among lethal wild-type and single toxin mutant strains. When rabbits were coinfected with the Ames strain and the PA- mutant strain, the toxin produced by the Ames strain was not able to promote dissemination of the PA- mutant, suggesting that toxigenic action occurs in close proximity to secreting bacteria. Taken together, these findings suggest that a major role for toxins in the pathogenesis of anthrax is to enable the organism to overcome innate host effector mechanisms locally and that much of the damage during the later stages of infection is due to the interactions of the host with the massive bacterial burden. PMID- 22526674 TI - The A subunit of Escherichia coli heat-labile enterotoxin functions as a mucosal adjuvant and promotes IgG2a, IgA, and Th17 responses to vaccine antigens. AB - Enterotoxigenic Escherichia coli (ETEC) produces both heat-labile (LT) and heat stable (ST) enterotoxins and is a major cause of diarrhea in infants in developing countries and in travelers to those regions. In addition to inducing fluid secretion, LT is a powerful mucosal adjuvant capable of promoting immune responses to coadministered antigens. In this study, we examined purified A subunit to further understand the toxicity and adjuvanticity of LT. Purified A subunit was enzymatically active but sensitive to proteolytic degradation and unable to bind gangliosides, and even in the presence of admixed B subunit, it displayed low cyclic AMP (cAMP) induction and no enterotoxicity. Thus, the AB5 structure plays a key role in protecting the A subunit from proteolytic degradation and in delivering the enzymatic signals required for secretion. In contrast, the A subunit alone was capable of activating dendritic cells and enhanced immune responses to multiple antigens following intranasal immunization; therefore, unlike toxicity, LT adjuvanticity is not dependent on the AB5 holotoxin structure or the presence of the B subunit. However, immune responses were maximal when signals were received from both subunits either in an AB5 structure or with A and B admixed. Furthermore, the quality of the immune response (i.e., IgG1/IgG2 balance and mucosal IgA and IL-17 secretion) was determined by the presence of an A subunit, revealing for the first time induction of Th17 responses with the A subunit alone. These results have important implications for understanding ETEC pathogenesis, unraveling immunologic responses induced by LT-based adjuvants, and developing new mucosal vaccines. PMID- 22526675 TI - Enterohemorrhagic Escherichia coli O157:H7 Shiga toxins inhibit gamma interferon mediated cellular activation. AB - Enterohemorrhagic Escherichia coli (EHEC) serotype O157:H7 is a food-borne pathogen that causes significant morbidity and mortality in developing and industrialized nations. EHEC infection of host epithelial cells is capable of inhibiting the gamma interferon (IFN-gamma) proinflammatory pathway through the inhibition of Stat-1 phosphorylation, which is important for host defense against microbial pathogens. The aim of this study was to determine the bacterial factors involved in the inhibition of Stat-1 tyrosine phosphorylation. Human HEp-2 and Caco-2 epithelial cells were challenged directly with either EHEC or bacterial culture supernatants and stimulated with IFN-gamma, and then the protein extracts were analyzed by immunoblotting. The data showed that IFN-gamma-mediated Stat-1 tyrosine phosphorylation was inhibited by EHEC secreted proteins. Using two dimensional difference gel electrophoresis, EHEC Shiga toxins were identified as candidate inhibitory factors. EHEC Shiga toxin mutants were then generated and complemented in trans, and mutant culture supernatant was supplemented with purified Stx to confirm their ability to subvert IFN-gamma-mediated cell activation. We conclude that while other factors are likely involved in the suppression of IFN-gamma-mediated Stat-1 tyrosine phosphorylation, E. coli derived Shiga toxins represent a novel mechanism by which EHEC evades the host immune system. PMID- 22526676 TI - Fhb, a novel factor H-binding surface protein, contributes to the antiphagocytic ability and virulence of Streptococcus suis. AB - Streptococcus suis serotype 2 is a Gram-positive bacterium that causes sepsis and meningitis in piglets and humans. The mechanisms of S. suis serotype 2 invasive disease are not well understood. The surface proteins of pathogens usually play important roles in infection and bacterium-host interactions. Here, we identified a novel surface protein that contributed significantly to the virulence of S. suis serotype 2 in a piglet infection model. This protein showed little similarity to other reported proteins and exhibited strong binding activity to human factor H (hFH). It was designated Fhb (factor H-binding protein). The fhb genes found in S. suis serotypes 1, 2, 4, 7, and 9 exhibited molecular polymorphism. Fhb possessed two proline-rich repeat sequences and XPZ domains, and one repeat sequence exhibited a high homology to Bac, an IgA-binding protein of Streptococcus agalactiae. Evidence strongly indicated that fhb-deficient mutants had diminished phagocytosis resistance in bactericidal assays. In addition, Fhb plays important roles in complement-mediated immunity by interacting with hFH. These findings indicated that Fhb is a crucial surface protein contributing to the virulence of S. suis, with important functions in evading innate immune defenses by interaction with host complement regulatory factor hFH. PMID- 22526677 TI - Hierarchies of host factor dynamics at the entry site of Shigella flexneri during host cell invasion. AB - Shigella flexneri, the causative agent of bacillary dysentery, induces massive cytoskeletal rearrangement, resulting in its entry into nonphagocytic epithelial cells. The bacterium-engulfing membrane ruffles are formed by polymerizing actin, a process activated through injected bacterial effectors that target host small GTPases and tyrosine kinases. Once inside the host cell, S. flexneri escapes from the endocytic vacuole within minutes to move intra- and intercellularly. We quantified the fluorescence signals from fluorescently tagged host factors that are recruited to the site of pathogen entry and vacuolar escape. Quantitative time lapse fluorescence imaging revealed simultaneous recruitment of polymerizing actin, small GTPases of the Rho family, and tyrosine kinases. In contrast, we found that actin surrounding the vacuole containing bacteria dispersed first from the disassembling membranes, whereas other host factors remained colocalized with the membrane remnants. Furthermore, we found that the disassembly of the membrane remnants took place rapidly, within minutes after bacterial release into the cytoplasm. Superresolution visualization of galectin 3 through photoactivated localization microscopy characterized these remnants as small, specular, patchy structures between 30 and 300 nm in diameter. Using our experimental setup to track the time course of infection, we identified the S. flexneri effector IpgB1 as an accelerator of the infection pace, specifically targeting the entry step, but not vacuolar progression or escape. Together, our studies show that bacterial entry into host cells follows precise kinetics and that this time course can be targeted by the pathogen. PMID- 22526680 TI - Concentration-dependent cytotoxicity of copper ions on mouse fibroblasts in vitro: effects of copper ion release from TCu380A vs TCu220C intra-uterine devices. AB - Sustained release of copper (Cu) ions from Cu-containing intrauterine devices (CuIUD) is quite efficient for contraception. However, the tissue surrounding the CuIUD is exposed to toxic Cu ion levels. The objective for this study was to quantify the concentration dependent cytotoxic effects of Cu ions and correlate the toxicity due to Cu ion burst release for two popular T-shaped IUDs - TCu380A and TCu220C on L929 mouse fibroblasts. Fibroblasts were cultured in 98 well tissue culture plates and 3-(4,5-dimethylthiazol- 2-yl)-2,5-diphehyltetrazolium bromide (MTT) assay was used to determine their viability and proliferation as a function of time. For cell seeding numbers ranging from 10,000 to 100,000, a maximum culture time of 48 h was identified for fibroblasts without significant reduction in cell proliferation due to contact inhibition. Thus, for Cu cytotoxicity assays, a cell seeding density of 50,000 and a maximum culture time of 48 h in 96 well plates were used. 24 h after cell seeding, culture media were replaced with Cu ion containing media solutions of different concentrations, including 24 and 72 h extracts from TCuIUDs and incubated for a further 24 h. Cell viability decreased with increasing Cu ion concentration, with 30 % and 100 % reduction for 40 MUg/ml and 100 MUg/ml respectively at 24 h. The cytotoxic effects were further evaluated using light microscopy, apoptosis and cell cycle analysis assays. Fibroblasts became rounded and eventually detached from TCP surface due to Cu ion toxicity. A linear increase in apoptotic cell population with increasing Cu ion concentration was observed in the tested range of 0 to 50 MUg/ml. Cell cycle analysis indicated the arrest of cell division for the tested 25 to 50 MUg/ml Cu ion treatments. Among the TCuIUDs, TCu220C having 265 mm(2) Cu surface area released 9.08 +/- 0.16 and 26.02 +/- 0.25 MUg/ml, while TCu380A having 400 mm(2) released 96.7 +/- 0.11 and 159.3 +/- 0.15 MUg/ml respectively following 24 and 72 h extractions. The effects of TCuIUD extracts on viability, morphology, apoptosis and cell cycle assay on L929 mouse fibroblasts cells, were appropriate for their respective Cu ion concentrations. Thus, a concentration of about 46 MUg/ml (~29 MUM) was identified as the LD50 dose for L929 mouse fibroblasts when exposed for 24 h based on our MTT cell viability assay. The burst release of lethal concentration of Cu ions from TCu380A, especially at the implant site, is a cause of concern, and it is advisable to use TCuIUD designs that release Cu ions within cytotoxic limits yet therapeutic, similar to TCu220C. PMID- 22526681 TI - Multiparameter evaluation of the longevity in C. elegans under stress using an integrated microfluidic device. AB - Caenorhabditis elegans (C. elegans) is an excellent model organism for the study of aging and longevity. In this work, we presented a microfluidic approach for the evaluation of longevity in C. elegans under stress. The microfluidic device integrated multiple microvalves with parallel channels, which enabled the long term culture and flexible manipulation of C. elegans in real-time. The utility of the device was demonstrated by characterizing the lifespan, mobility behavior and fluorescence expression of oxidative stress in mutant strain CL2166 simultaneously at single animal resolution. A certain dose of polydatin was found to enable the extension of mean lifespan of CL2166 for the first time, and the prolonged longevity activity was possibly mediated by the protective response to oxidative stress, indicating the promising role of polydatin involved in aging process. The device is simple to operate, easy for real-time imaging and multiparatemer evaluations in parallel, providing the powerful platform for drug evaluation/screening in highthroughput format. PMID- 22526678 TI - Phenotypic, morphological, and functional heterogeneity of splenic immature myeloid cells in the host response to tularemia. AB - Recent studies have linked accumulation of the Gr-1+ CD11b+ cell phenotype with functional immunosuppression in diverse pathological conditions, including bacterial and parasitic infections and cancer. Gr-1+ CD11b+ cells were the largest population of cells present in the spleens of mice infected with sublethal doses of the Francisella tularensis live vaccine strain (LVS). In contrast, the number of T cells present in the spleens of these mice did not increase during early infection. There was a significant delay in the kinetics of accumulation of Gr-1+ CD11b+ cells in the spleens of B-cell-deficient mice, indicating that B cells play a role in recruitment and maintenance of this population in the spleens of mice infected with F. tularensis. The splenic Gr-1+ CD11b+ cells in tularemia were a heterogeneous population that could be further subdivided into monocytic (mononuclear) and granulocytic (polymorphonuclear) cells using the Ly6C and Ly6G markers and differentiated into antigen-presenting cells following ex vivo culture. Monocytic, CD11b+ Ly6C(hi) Ly6G- cells but not granulocytic, CD11b+ Ly6C(int) Ly6G+ cells purified from the spleens of mice infected with F. tularensis suppressed polyclonal T-cell proliferation via a nitric oxide-dependent pathway. Although the monocytic, CD11b+ Ly6C(hi) Ly6G- cells were able to suppress the proliferation of T cells, the large presence of Gr-1+ CD11b+ cells in mice that survived F. tularensis infection also suggests a potential role for these cells in the protective host response to tularemia. PMID- 22526679 TI - Microbicidal activity of vascular peroxidase 1 in human plasma via generation of hypochlorous acid. AB - Members of the heme peroxidase family play an important role in host defense. Myeloperoxidase (MPO) is expressed in phagocytes and is the only animal heme peroxidase previously reported to be capable of using chloride ion as a substrate to form the highly microbicidal species hypochlorous acid (HOCl) at neutral pH. Despite the potent bacterial killing activity of HOCl, individuals who fail to express MPO typically show only a modest increase in some fungal infections. This may point to the existence of redundant host defense mechanisms. Vascular peroxidase 1 (VPO1) is newly discovered member of the heme peroxidase family. VPO1 is expressed in cells of the cardiovascular system and is secreted into the bloodstream. In the present study, we investigate whether VPO1 is capable of generating HOCl and its role in host defense. Like MPO, VPO1 in the presence of H2O2 and chloride generates HOCl. VPO1-dependent HOCl generation was demonstrated by chlorination of taurine and tyrosine using mass spectrometry. In addition, the VPO1/H2O2/Cl- system can cause the chlorination of monochlorodimedone and the oxidation of 5-thio-2-nitrobenzoic acid. Purified VPO1 and VPO1 in plasma mediate bacterial killing that is dependent on chloride and H2O2; killing is inhibited by peroxidase inhibitors and by the H2O2 scavenger catalase. In the presence of erythrocytes, bacterial killing by VPO1 is slightly reduced. Thus, VPO1, in addition to MPO, is the second member of the heme peroxidase family capable of generating HOCl under physiological conditions. VPO1 is likely to participate in host defense, with bactericidal activity mediated through the generation of HOCl. PMID- 22526682 TI - Development of a microplate reader compatible microfluidic chip for ELISA. AB - We report a novel microfluidic device use for sandwich enzyme-linked immunoassay assay (ELISA). The related procedures including the introduction of reagents, dilution and distribution of samples, as well as immobilization of enzyme can be readily carried out on a poly (dimethylsiloxane) (PDMS) chip. Particularly, this microfluidic chip comprising of two distinct parallel units, and has an identical dimension as a conventional microtiter plate, which offers access to the directly quantitative detection by the microplate reader. Gradient-concentration reacting solutions at six different concentrations level generated by the microfluidic channel network are simultaneously transported to 24 reaction chambers to form enzymatic products. Alkaline phosphatase (ALP), 4-methylumbelliferyl phosphate (4 MUP) and KH(2)PO(4) are used as enzyme-substrate-inhibitor model, to demonstrate the utility of the developed microchip-based enzyme inhibitor assay. Various conditions such as the surface treatment of chip channels, fluids velocities, substrate concentration, and buffer pH are investigated. The present microfluidic device for ELISA holds several advantages, for instance frugal usage of samples and reagents, less of operating time, favorably integrated configuration, ease of manipulation, and could be explored to a variety of high throughput drug screening. PMID- 22526683 TI - Micromachined Coulter counter for dynamic impedance study of time sensitive cells. AB - This paper describes the design, modeling, fabrication and characterization MEMS Coulter counter that can detect and monitor the dynamic cell impedance changes in situ as a function of time after mixing isolated cell populations with different extracellular media within 0.3 s from the start of mixing. The novelty of this design is the use of multi-electrodes with vertical sidewalls to enable the measurements of time sensitive cells with significantly enhanced sensitivity as well as the integration of passive mixing, focusing of cells in line and impedance detection using the vertical electrodes on a single chip that is made mainly using multilayer of SU-8, which has not been reported before. The devices were tested with both fluidic and electrical functionality using yeast cells in cryoprotectant agent (diluted dimethyl sulfoxide), red blood cells, microbeads with different dimensions, and dyed fluids. The results demonstrate rapid changes of cell volume within the first 0.6 s after mixing followed by a stable and a fixed cell volume. The micromixer was initially simulated using COMSOL finite element tool. Image processing technique was used to quantitatively evaluate mixing efficiency by analyzing color intensities variation of captured images of 2 dyed fluids mixed in the channel at flow rates between 0.1-0.4 MUl/min, the mixing efficiencies were between 87 %-95 %, respectively. PMID- 22526685 TI - Minocycline benefits negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled clinical trial in patients on standard treatment. AB - The onset and early course of schizophrenia is associated with subtle loss of grey matter which may be responsible for the evolution and persistence of symptoms such as apathy, emotional blunting, and social withdrawal. Such 'negative' symptoms are unaffected by current antipsychotic therapies. There is evidence that the antibiotic minocycline has neuroprotective properties. We investigated whether the addition of minocycline to treatment as usual (TAU) for 1 year in early psychosis would reduce negative symptoms compared with placebo. In total, 144 participants within 5 years of first onset in Brazil and Pakistan were randomised to receive TAU plus placebo or minocycline. The primary outcome measures were the negative and positive syndrome ratings using the Positive and Negative Syndrome Scale. Some 94 patients completed the trial. The mean improvement in negative symptoms for the minocycline group was 9.2 and in the placebo group 4.7, an adjusted difference of 3.53 (s.e. 1.01) 95% CI: 1.55, 5.51; p < 0.001 in the intention-to-treat population. The effect was present in both countries. The addition of minocycline to TAU early in the course of schizophrenia predominantly improves negative symptoms. Whether this is mediated by neuroprotective, anti-inflammatory or others actions is under investigation. PMID- 22526684 TI - Delta9Tetrahydrocannabinol impairs visuo-spatial associative learning and spatial working memory in rhesus macaques. AB - Cannabis remains the most commonly abused illicit drug and is rapidly expanding in quasi-licit use in some jurisdictions under medical marijuana laws. Effects of the psychoactive constituent Delta9tetrahydrocannabinol (Delta9THC) on cognitive function remain of pressing concern. Prior studies in monkeys have not shown consistent evidence of memory-specific effects of Delta9THC on recognition tasks, and it remains unclear to what extent Delta9THC causes sedative versus specific cognitive effects. In this study, adult male rhesus monkeys were trained on tasks which assess spatial working memory, visuo-spatial associative memory and learning as well as motivation for food reward. Subjects were subsequently challenged with 0.1-0.3 mg/kg Delta9THC, i.m., in randomized order and evaluated on the behavioral measures. The performance of both vsPAL and SOSS tasks was impaired by Delta9THC in a dose and task-difficulty dependent manner. It is concluded that Delta9THC disrupts cognition in a way that is consistent with a direct effect on memory. There was evidence for interference with spatial working memory, visuo-spatial associative memory and incremental learning in the latter task. These results and the lack of specific effect of Delta9THC in prior visual recognition studies imply a sensitivity of spatial memory processing and/or working memory to endocannabinoid perturbation. PMID- 22526686 TI - Auditory contagious yawning in domestic dogs (Canis familiaris): first evidence for social modulation. AB - Dogs' capacity to 'catch' human yawns has recently attracted the attention of researchers in the field of animal cognition. Following recent studies suggesting that contagion yawning in humans, and some other primates, is empathy-related, some authors have considered the possibility that the same mechanism may underlie contagious yawning in dogs. To date, however, no positive evidence has been found, and more parsimonious hypotheses have been put forward. The present study explored the 'contagion-only' hypothesis by testing whether the mere sound of a human yawn can be sufficient to elicit yawning in dogs, in a way that is unaffected by social-emotional factors. Unexpectedly, results showed an interesting interplay between contagion and social effects. Not only were dogs found to catch human yawns, but they were also found to yawn more at familiar than unfamiliar yawns. Although not allowing for conclusive inferences about the mechanisms underlying contagious yawning in dogs, this study provides first data that renders plausible empathy-based, emotionally connected, contagious yawning in these animals. PMID- 22526687 TI - Cross-modal recognition of human individuals in domestic horses (Equus caballus). AB - This study has shown that domestic horses are capable of cross-modal recognition of familiar humans. It was demonstrated that horses are able to discriminate between the voices of a familiar and an unfamiliar human without seeing or smelling them at the same moment. Conversely, they were able to discriminate the same persons when only exposed to their visual and olfactory cues, without being stimulated by their voices. A cross-modal expectancy violation setup was employed; subjects were exposed both to trials with incongruent auditory and visual/olfactory identity cues and trials with congruent cues. It was found that subjects responded more quickly, longer and more often in incongruent trials, exhibiting heightened interest in unmatched cues of identity. This suggests that the equine brain is able to integrate multisensory identity cues from a familiar human into a person representation that allows the brain, when deprived of one or two senses, to maintain recognition of this person. PMID- 22526688 TI - One-trial spatial learning: wild hummingbirds relocate a reward after a single visit. AB - Beaconing to rewarded locations is typically achieved by visual recognition of the actual goal. Spatial recognition, on the other hand, can occur in the absence of the goal itself, relying instead on the landmarks surrounding the goal location. Although the duration or frequency of experiences that an animal needs to learn the landmarks surrounding a goal have been extensively studied with a variety of laboratory tasks, little is known about the way in which wild vertebrates use them in their natural environment. Here, we allowed hummingbirds to feed once only from a rewarding flower (goal) before it was removed. When we presented a similar flower at a different height in another location, birds frequently returned to the location the flower had previously occupied (spatial recognition) before flying to the flower itself (beaconing). After experiencing three rewarded flowers, each in a different location, they were more likely to beacon to the current visible flower than they were to return to previously rewarded locations (without a visible flower). These data show that hummingbirds can encode a rewarded location on the basis of the surrounding landmarks after a single visit. After multiple goal location manipulations, however, the birds changed their strategy to beaconing presumably because they had learned that the flower itself reliably signalled reward. PMID- 22526689 TI - How two word-trained dogs integrate pointing and naming. AB - Two word-trained dogs were presented with acts of reference in which a human pointed, named objects, or simultaneously did both. The question was whether these dogs would assume co-reference of pointing and naming and thus pick the pointed-to object. Results show that the dogs did indeed assume co-reference of pointing and naming in order to determine the reference of a spoken word, but they did so only when pointing was not in conflict with their previous word knowledge. When pointing and a spoken word conflicted, the dogs preferentially fetched the object by name. This is not surprising since they are trained to fetch objects by name. However, interestingly, in these conflict conditions, the dogs fetched the named objects only after they had initially approached the pointed-to object. We suggest that this shows that the word-trained dogs interpret pointing as a spatial directive, which they integrate into the fetching game, presumably assuming that pointing is relevant to finding the requested object. PMID- 22526691 TI - Biological relevance of acoustic signal affects discrimination performance in a songbird. AB - The fee-bee song of the black-capped chickadee (Poecile atricapillus) is a two note, tonal song that can be sung at different absolute pitches within an individual. However, these two notes are produced at a consistent relative pitch. Moreover, dominant birds more reliably produce songs with this species-typical interval, compared to subordinate birds. Therefore, we asked whether presenting the species-typical relative pitch interval would aid chickadees in solving pitch interval discriminations. We found that species-typical relative pitch intervals selectively facilitated discrimination performance using synthetic sine-wave stimuli. Using shifted fee-bee song notes from recordings of naturally produced songs, birds learned the discrimination in fewer trials overall compared to synthetic stimuli. These results may reflect greater generalization among stimuli that occur outside species-typical production parameters. In addition, although sex differences in performance are rarely observed in acoustic discriminations in chickadees, female chickadees performed more accurately compared to males. PMID- 22526690 TI - Place and direction learning in a spatial T-maze task by neonatal piglets. AB - Pigs are a valuable animal model for studying neurodevelopment in humans due to similarities in brain structure and growth. The development and validation of behavioral tests to assess learning and memory in neonatal piglets are needed. The present study evaluated the capability of 2-week old piglets to acquire a novel place and direction learning spatial T-maze task. Validity of the task was assessed by the administration of scopolamine, an anti-cholinergic drug that acts on the hippocampus and other related structures, to impair spatial memory. During acquisition, piglets were trained to locate a milk reward in a constant place in space, as well as direction (east or west), in a plus-shaped maze using extra maze visual cues. Following acquisition, reward location was reversed and piglets were re-tested to assess learning and working memory. The performance of control piglets in the maze improved over time (P < 0.0001), reaching performance criterion (80 % correct) on day 5 of acquisition. Correct choices decreased in the reversal phase (P < 0.0001), but improved over time. In a separate study, piglets were injected daily with either phosphate-buffered saline (PBS; control) or scopolamine prior to testing. Piglets administered scopolamine showed impaired performance in the maze compared to controls (P = 0.03), failing to reach performance criterion after 6 days of acquisition testing. Collectively, these data demonstrate that neonatal piglets can be tested in a spatial T-maze task to assess hippocampal-dependent learning and memory. PMID- 22526692 TI - Stereotypic head twirls, but not pacing, are related to a 'pessimistic'-like judgment bias among captive tufted capuchins (Cebus apella). AB - Abnormal stereotypic behaviour is widespread among captive non-human primates and is generally associated with jeopardized well-being. However, attributing the same significance to all of these repetitive, unvarying and apparently functionless behaviours may be misleading, as some behaviours may be better indicators of stress than others. Previous studies have demonstrated that the affective state of the individual can be inferred from its bias in appraising neutral stimuli in its environment. Therefore, in the present study, in order to assess the emotional state of stereotyping individuals, 16 captive tufted capuchins (Cebus apella) were tested on a judgment bias paradigm and their faecal corticoid levels were measured in order to assess the intensity of the emotional state. Capuchins with higher levels of stereotypic head twirls exhibited a negative bias while judging ambiguous stimuli and had higher levels of faecal corticoids compared to subjects with lower levels of head twirls. Levels of stereotypic pacing, however, were not correlated with the monkeys' emotional state. This study is the first to reveal a positive correlation between levels of stereotypic behaviour and a 'pessimistic'-like judgment bias in a non-human primate by employing a recently developed cognitive approach. Combining cognitive tests that evaluate the animals' affective valence (positive or negative) with hormonal measurements that provide information on the strength of the emotional state conduces to a better understanding of the animals' affective state and therefore to their well-being. PMID- 22526693 TI - The role of numerical competence in a specialized predatory strategy of an araneophagic spider. AB - Although a wide range of vertebrates have been considered in research on numerical competence, little is known about the role of number-related decisions in the predatory strategies of invertebrates. Here, we investigate how numerical competence is expressed in a highly specialized predatory strategy adopted by the small juveniles of Portia africana when practicing communal predation, with the prey being another spider, Oecobius amboseli. Two or more P. africana juveniles sometimes settle by the same oecobiid nest and then share the meal after one individual captures the oecobiid. Experiments were designed to clarify how these predators use number-related cues in conjunction with non-numerical cues when deciding whether to settle at a nest. We used lures (dead spiders positioned in lifelike posture) arranged in a series of 24 different scenes defined by the type, configuration and especially number of lures. On the whole, our findings suggest that P. africana juveniles base settling decisions on the specific number of already settled conspecific juveniles at the nest and express a preference for settling when the number is one instead of zero, two or three. By varying the size of the already settled juveniles and their positions around the nest, we show that factors related to continuous variables and stimulus configuration are unlikely explanations for our findings. PMID- 22526694 TI - Modularity of mind and the role of incentive motivation in representing novelty. AB - Animal and human brains contain a myriad of mental representations that have to be successfully tracked within fractions of a second in a large number of situations. This retrieval process is hard to explain without postulating the massive modularity of cognition. Assuming that the mind is massively modular, it is then necessary to understand how cognitive modules can efficiently represent dynamic environments-in which some modules may have to deal with change-induced novelty and uncertainty. Novelty of a stimulus is a problem for a module when unknown, significant stimuli do not satisfy the module's processing criteria-or domain specificity-and cannot therefore be included in its database. It is suggested that the brain mechanisms of incentive motivation, recruited when faced with novelty and uncertainty, induce transient variations in the domain specificity of cognitive modules in order to allow them to process information they were not prepared to learn. It is hypothesised that the behavioural transitions leading from exploratory activity to habit formation are correlated with (and possibly caused by) the organism's ability to counter novelty-induced uncertainty. PMID- 22526695 TI - Expert's comment concerning Grand Rounds case entitled "Temporary occipito cervical stabilization of an unilateral occipital condyle fracture" (by Klaus John Schnake, Andreas Pingel, Matti Scholz and Frank Kandziora). PMID- 22526696 TI - Empyema in spinal canal in thoracic region, abscesses in paravertebral space, spondylitis: in clinical course of zoonosis Erysipelothrix rhusiopathiae. AB - OBJECTIVES: Erysipelas is an animal disease caused by Gram-positive bacteria Erysipelothrix rhusiopathiae. Among the domestic animals, domestic pig (Sus scrofa f. domestica) suffers most frequently from the disease in human environment. This is a typical animal-borne disease observed mainly in occupational groups employed in agriculture, farming (of animals and birds), fishing and manufacturing industry. METHODS: We are presenting the clinical course of infection (E. rhusiopathiae) and discuss clinical forms. E. rhusiopathiae in humans may have the following clinical course: mild form of skin infection diagnosed as local erythema (erysipeloid), disseminated form of skin infection and the most serious form of infection of systemic course (endocarditis and sepsis). Mild skin infection and local erythema are the most common forms. Very rare case of animal-borne infection course has been presented in which after initial phase the disease was generalised to the abscesses formation in paravertebral space, spondylitis and empyema formation in spinal canal. In the presented clinical case, the patient was suffering from diabetes. It was probably an additional risk factor of the disease generalisation. Patient underwent drainage of empyema in spinal canal, after which his neurological status gradually improved. Antibiotic therapy was implemented and continued for 8 weeks. Such course of erysipelas was not previously described in the literature. RESULTS: After therapy neurological status was improved. In follow MRI control exam empyema and spondylitis was successfully eliminated. CONCLUSIONS: Various complications of the disease, such as endocarditis and heart valves disturbances, are well known and are the most severe complications of the generalised infection. Proper targeted and long-term antibiotic therapy is crucial. PMID- 22526698 TI - Ethnic differences in pedicle and bony spinal canal dimensions calculated from computed tomography of the cervical spine: a review of the English-language literature. AB - PURPOSE: The aims of this study were to review published data on pedicle dimensions and bony spinal canal diameters calculated from CT examinations of the cervical spine through the English-language literature and analyze these data for ethnic disparities and similarities. MATERIALS AND METHODS: The authors reviewed the literature on "pedicle" and "spinal canal" by conducting a bibliographic search using PubMed, Ovid MEDLINE, and Science Direct from January 1985 to December 2010. After evaluating all of the selected abstracts, we ultimately selected 19 studies involving living subjects: 12 studies on pedicle dimensions and 7 on spinal canal diameters. The four parameters, pedicle width (PW), pedicle transverse angle (PTA), anterior-posterior diameter of the spinal canal (APD), and transverse diameter of the spinal canal (TD), were analyzed at the relevant levels from C3 to C7. In addition, the values for pedicle dimensions and spinal canal diameters in the European/American populations were compared using the data from Asian populations as a baseline. RESULTS: The smallest mean PW was found at C4 in the male (5.1 mm) and female populations (4.1 mm); the largest mean PW was found at C7 in both male (7.7 mm) and female populations (7 mm). The PW in males was greater than in females at the majority of levels. The smallest mean PTA was found at C7 in both male (33.4 degrees ) and female populations (33 degrees ); the largest mean PTA was found at C4 in both male (53.2 degrees ) and female populations (52.1 degrees ). The overall PW, PTA, APD, and TD ratio of European/American to Asian populations was 91.4-98.8, 99.6-106.2, 110.7-122, and 100-108.3 %, respectively. CONCLUSION: Although our cervical spine CT data were suggestive of possible ethnic differences in spinal canal morphology, our analysis failed to identify significant ethnic disparity in pedicle dimensions despite potential differences in physique between populations. PMID- 22526697 TI - Quantitative MRI analysis of the surface area, signal intensity and MRI index of the central bright area for the evaluation of early adjacent disc degeneration after lumbar fusion. AB - PURPOSE: The aim of this study was to evaluate early ASD at short-term follow-up in fused and unoperated patients with degenerative disc disease, using quantitative magnetic resonance imaging (MRI) analysis of the area, signal intensity and their product, i.e., MRI index of the central bright area of the disc as well as measures of intervertebral disc height and Pfirrmann grading scale. The further purpose was to determine whether fusion accelerates ASD compared with non-surgical treatment in short-term follow-up. METHODS: One hundred and eight chronic low back patients diagnosed as L4/L5 degeneration undertook either one-level instrumented posterior lumbar interbody fusion or conservative treatment. They were followed up for about 1 year. Finally 46 fused and 45 conservatively treated patients with MRI follow-up were included. Pre- and post-treatment MRIs were compared to determine the progression of disc degeneration at the two cranial adjacent segments. RESULTS: The area, signal intensity and MRI index of the central bright area of the adjacent discs decreased in the operated and unoperated groups from pre-treatment to follow-up, except for an insignificant decrease of signal intensity at the second adjacent segment in the unoperated group. The changes in these parameters were statistically greater at the first than the second adjacent segment in the fused group, but not in the unoperated group. And the changes in the fused group were more pronounced than those at both neighbouring levels in the unoperated group. However, the Pfirrmann grading scale and intervertebral disc height did not detect any changes at adjacent discs in either group. CONCLUSIONS: Decrease in the parameters of quantitative MRI analysis indicated early degeneration at discs adjacent to lumbar spinal fusion. Fusion had an independent effect on the natural history of ASD during short-term follow-up. Continued longitudinal follow-up is required to determine whether these MRI changes lead to pathologic changes. PMID- 22526699 TI - Efficacy of multilevel anterior cervical discectomy and fusion versus corpectomy and fusion for multilevel cervical spondylotic myelopathy: a minimum 5-year follow-up study. AB - PURPOSE: We evaluated radiologic and clinical outcomes to compare the efficacy of anterior cervical discectomy and fusion (ACDF) and anterior corpectomy and fusion (ACCF) for multilevel cervical spondylotic myelopathy (CSM). METHODS: A total of 40 patients who underwent ACDF or ACCF for multilevel CSM were divided into two groups. Group A (n = 25) underwent ACDF and group B (n = 15) ACCF. Clinical outcomes (JOA and VAS scores), perioperative parameters (length of hospital stay, blood loss, operation time), radiological parameters (fusion rate, segmental height, cervical lordosis), and complications were compared. RESULTS: Both group A and group B demonstrated significant increases in JOA scores and significant decreases in VAS. Patients who underwent ACDF experienced significantly shorter hospital stays (p = 0.031), less blood loss (p = 0.001), and shorter operation times (p = 0.024). Both groups showed significant increases in postoperative cervical lordosis and achieved satisfactory fusion rates (88.0 and 93.3%, respectively). There were no significant differences in the incidence of complications among the groups. CONCLUSIONS: Both ACDF and ACCF provide satisfactory clinical outcomes and fusion rates for multilevel CSM. However, multilevel ACDF is associated with better radiologic parameters, shorter hospital stays, less blood loss, and shorter operative times. PMID- 22526700 TI - Perioperative mortality after lumbar spinal fusion surgery: an analysis of epidemiology and risk factors. AB - STUDY DESIGN: Analysis of the Nationwide Inpatient Sample (NIS) from 1998 to 2008. OBJECTIVE: To analyze the most recent available and nationally representative data for risk factors contributing to in-hospital mortality after primary lumbar spine fusion. SUMMARY OF BACKGROUND DATA: The total number of lumbar spine fusion surgeries has increased dramatically over the past decades. While the field of spine fusion surgery remains highly dynamic with changes in perioperative care constantly affecting patient care, recent data affecting rates and risk for perioperative mortality remain very limited. METHODS: We obtained the NIS from the Hospital cost and utilization project. The impact of patient and health care system related demographics, including various comorbidities as well as postoperative complications on the outcome of in-hospital mortality after spine fusion were studied. Furthermore, we analyzed the timing of in-hospital mortality. RESULTS: An estimated total of 1,288,496 primary posterior lumbar spine fusion procedures were performed in the US between 1998 and 2008. The average mortality rate for lumbar spine fusion surgery was 0.2%. Independent risk factors for in-hospital mortality included advanced age, male gender, large hospital size, and emergency admission. Comorbidities associated with the highest in-hospital mortality after lumbar spine fusion surgery were coagulopathy, metastatic cancer, congestive heart failure and renal disease. Most lethal complications were cerebrovascular events, sepsis and pulmonary embolism. Furthermore, we demonstrated that the timing of death occurred relatively early in the in-hospital period with over half of fatalities occurring by postoperative day 9. CONCLUSION: This study provides nationally representative information on risk factors for and timing of perioperative mortality after primary lumbar spine fusion surgery. These data can be used to assess risk for this event and to develop targeted intervention to decrease such risk. PMID- 22526701 TI - Remote intracranial parenchymal haematomas as complications of spinal surgery: presentation of three cases with minor or untypical symptoms. AB - INTRODUCTION: Intracranial haemorrhage is a rare complication of spinal surgery. Three cases of cerebral or cerebellar haemorrhages following spinal operations with CSF loss are reported, and the literature was reviewed. CASE PRESENTATIONS: One patient suffered from melancholy after the operation, one patient had moderate headache and nausea, and the third patient suffered from mental confusion and anxiety. The intracranial haemorrhages were treated conservatively. All patients recovered from the bleedings. RESULTS: The cases show that cerebral or cerebellar haemorrhage after spinal CSF loss may be accompanied by minor or rather untypical clinical symptoms. CONCLUSION: The dangerous complication of intracranial haemorrhage has to be kept in mind when patients have moderate cerebral symptoms after CSF loss due to spinal operations. PMID- 22526702 TI - The 100 most cited spine articles. AB - PURPOSE: Spine-related research has evolved dramatically during the last century. Significant contributions have been made by thousands of authors. A citation rank list has historically been used within a particular field to measure the importance of an article. The purpose of this article is to report on the 100 most cited articles in the field of spine. METHODS: Science Citation Index Expanded was searched for citations in 27 different journals (as of 30 November 2010) chosen based on the relevance for all cited spine publications. The top 100 most cited articles were identified. Important information such as journal, date, country of origin, author, subspecialty, and level of evidence (for clinical research) were compiled. RESULTS: The top 100 publications ranged from 1,695 to 240 citations. Fifty-three articles were of the lumbar, 17 were of the thoracolumbar, and 15 of the cervical spine. Eighty-one of the articles were clinical and 19 were basic science in nature. Level of evidence varied for the clinical papers, however, was most commonly level IV (34 of 81 articles). Notably, the 1990-1999 decade was the most productive period with 43 of the top 100 articles published during this time. CONCLUSIONS: Identification of the most cited articles within the field of spine recognizes some of the most important contributions in the peer-reviewed literature. Current investigators may utilize the aspects of their work to guide and direct future spine-related research. PMID- 22526703 TI - Is the development of Modic changes associated with clinical symptoms? A 14-month cohort study with MRI. AB - PURPOSE: Modic changes (MCs) have been suggested to be a diagnostic subgroup of low back pain (LBP). However, the clinical implications of MCs remain unclear. For this reason, the aims of this study were to investigate how MCs developed over a 14-month period and if changes in the size and/or the pathological type of MCs were associated with changes in clinical symptoms in a cohort of patients with persistent LBP and MCs. METHODS: Information on LBP intensity and detailed information from MRI on the presence, type and size of MCs was collected at baseline and follow-up. Changes in type (type I, II, III and mixed types) and size of MCs were quantified at both time points according to a standardised evaluation protocol. The associations between change in type, change in size and change in LBP intensity were calculated using odds ratios (ORs). RESULTS: Approximately 40% of the MCs followed the expected developmental path from type I (here type I or I/II) to type II (here type II or II/III) or type I to type I/II. In general, the bigger the size of the MC at baseline, the more likely it was that it remained unchanged in size after 14 months. Patients who had MC type I at both baseline and 14-month follow-up were less likely to experience an improvement in their LBP intensity as compared to patients who did not have type I changes at both time points (OR 7.2, CI 1.3-37). There was no association between change in size of MCs type I and change in LBP intensity. CONCLUSIONS: The presence of MCs type I at both baseline and follow-up is associated with a poor outcome in patients with persistent LBP and MCs. PMID- 22526704 TI - Currarino's triad diagnosed in an adult woman. AB - PURPOSE: To report on a female patient diagnosed with Currarino's triad in adulthood. CASE REPORT: This case presents an adult patient with a medical history of a congenital anal atresia, a partial sacral agenesis, and a surgically treated ectopic anus. After a coincidentally observed presacral mass by MRI, due to unexplained constipation later in adulthood, Currarino's triad was suspected in this patient. This triad consists of anorectal malformation(s), sacrococcygeal defects and a presacral mass of various origin. Further investigation confirmed the mass to be a meningocele, and showed a tethered cord and a syrinx. CONCLUSIONS: In (young) patients with anorectal malformations, although having no other symptoms, further examination might be required to exclude Currarino's triad. Importance of early diagnosis and multidisciplinary assessment is recommended to establish adequate treatment if needed. PMID- 22526705 TI - Comparison of the aorta impingement risks between thoracolumbar/lumbar curves with different convexities in adolescent idiopathic scoliosis: a computed tomography study. AB - PURPOSE: To compare the positions of the aorta relative to vertebral bodies and the potential risk of the aorta impingement for pedicle screw (PS) placement between right-sided and left-sided thoracolumbar/lumbar curves of adolescent idiopathic scoliosis (AIS). METHODS: Thirty-nine AIS patients with a main thoracolumbar or lumbar curve were recruited. The Lenke's classification was type 5C in all patients. According to the convexity of the thoracolumbar or lumbar curves, the patients were divided into either group R or Group L. The patients in Group R had a main right-sided thoracolumbar/lumbar curve, and the patients in Group L had a main left-sided thoracolumbar/lumbar curve. Axial CT images from T12 to L4 at the midvertebral body level were obtained to evaluate Aorta-vertebra angle (alpha), Vertebral rotation angle (beta), Lefty safety distance (LSD), and Right safety distance (RSD). The risks of the aorta impingement from T12 to L4 were calculated and then compared between the two groups. RESULTS: The alpha increased from T12 through L4 in Group R, increased from T12 through L1, and then decreased from L1 through L4 in Group L. The beta decreased from T12 through L4 in both groups. The LSD constantly increased from T12 through L4 in Group R, increased from T12 through L3, and then decreased from L3 through L4 in Group L. The RSD increased from T12 through L3 and then decreased from L3 through L4 in both groups. With the increment of the lengths of the simulated screws, the aorta impingement risks were constantly elevated at all levels in both groups. The aorta was at a high risk of impingement from left PS regardless of the diameters of the simulated screws in Group R (80-100 % at T12 and 53.3-100 % at L1). In Group L, the aorta was completely safe when using 35 mm (0 at all levels) PS and at high risks of the aorta impingement on the right side from 45 mm PSs (31.8 72.7 %). In all, the risks of the aorta impingement were mainly from left PS in Group R and from right PS in Group L, and the risk of the aorta impingement from PS placement was generally higher in right thoracolumbar or lumbar curves when compared with that of the left. CONCLUSIONS: The present study illustrated different changed positions of the aorta relative to vertebrae between thoracolumbar/lumbar curves with different convexities. In right-sided curve, the risks of the aorta impingement were mainly from left PS while in left-sided curves, from right PS. The aorta was more proximal to entry points in right-sided lumbar curve when compared with left-sided curve; thus placing PS carries more risks in right-sided thoracolumbar/lumbar curve. Surgeons should be more cautious when placing PSs on the concave sides of T12 and L1 vertebrae of right-sided thoracolumbar/lumbar curves. PMID- 22526707 TI - Etanercept treatment enhances clinical and neuroelectrophysiological recovery in partial spinal cord injury. AB - PURPOSE: To investigate the effect of an anti-TNF-alpha agent (etanercept) on recovery processes in a partial spinal cord injury (SCI) model using clinical and electrophysiological tests. METHODS: Twenty-four New Zealand rabbits were divided into three groups: group 1 [SCI + 2 ml saline intramuscular (i.m.), n = 8], group 2 (SCI + 2.5 mg/kg etanercept, i.m., 2-4 h after SCI, n = 8) and group 3 (SCI + 2.5 mg/kg etanercept, i.m., 12-24 h after SCI, n = 8). Rabbits were evaluated before SCI, immediately after SCI, 1 week after, and 2 weeks after SCI, clinically by Tarlov scale and electrophysiologically by SEP. RESULTS: Tarlov scores of groups 2 and 3 were significantly better than group 1, 2 weeks after SCI. SEP recovery was significantly better in groups 2 and 3 than group 1, 2 weeks after SCI. CONCLUSIONS: These results show that blocking TNF-alpha mediated inflammation pathway by an anti-TNF-alpha agent enhances clinical and electrophysiological recovery processes in partial SCI model. PMID- 22526708 TI - Lumbar instrumented posterolateral fusion in spondylolisthetic and failed back patients: a long-term follow-up study spanning 11-13 years. AB - INTRODUCTION AND MATERIALS: We examined lumbar transpedicular instrumented posterolateral fusion patients operated on between 1992 and 1997 presenting: degenerative spondylolisthesis with spinal stenosis; adult isthmic spondylolisthesis; failed back syndrome after one to five discectomies; and failed back syndrome after one to three laminectomy operations (groups 1-4, respectively). METHODS: They were examined by an independent orthopedic surgeon, completed the Oswestry Disability Index (ODI) and visual analog scale (VAS) questionnaires and their outcome was evaluated. RESULTS: The overall patient satisfaction at follow-up (mean 11.7 years) was 82.1%. The reoperation rate was 15.1% (7.5% due to adjacent segment disease). CONCLUSION: Group 1 showed the greatest improvements in ODI and VAS values, Group 2 the lowest and Group 3 the highest preoperative values, and Group 4 the second highest improvements. Patient satisfaction scores were 90.3, 69.7, 63.6 and 80.0%, respectively, and unplanned reoperation rates were 6.5, 9.1, 31.8 and 20.0%. Thus, long-term outcomes of lumbar instrumented posterolateral fusion (rarely previously studied) were satisfactory for >80% of patients, but varied among groups. PMID- 22526709 TI - Posterior lumbar spinal fusion and instrumentation in morbidly obese patients using the Synframe retractor system: technical note. AB - PURPOSE: Lumbar spine surgery in morbidly obese patients is a challenge to the operating surgeon. The aim of the study was to evaluate the surgical experience in this group of patients using the Synframe retractor system (Synthes, Paoli, PA, USA) as a tool for improved surgical access. METHODS: An Institutional Review Board approved retrospective study was conducted on 43 morbidly obese patients undergoing posterior lumbar decompression instrumentation and fusion. Patient selection was based on a BMI of >40. Information acquired included BMI, set up time, procedure time, ASA, intraoperative blood loss and the number of preoperative co-morbidities of each patient. Postoperative complications, length of stay, and pre-operative and postoperative Oswestry disability index (ODI) and visual analogue scale (VAS) were recorded at each postoperative visit. They were compared to 45 age matched controls from our spine database. RESULTS: The average set-up time (73.5 min), amount of blood loss (average 1,040 mL), length of incision (10.3-14.5 cm) and length of hospital stay (5.4 days) were recorded. The average surgical time was dependent on the procedure and number of levels fused and ranged from 164 to 245 min. These parameters were compared with normal weight patients and noted to be higher. CONCLUSION: The surgical experience determined that the Synframe retractor system provided a stable and well-illuminated operative field. It minimized the number of personnel required for assistance and improved surgical access. As may be expected, all the above recorded parameters were greater in the morbidly obese group. PMID- 22526710 TI - Locomotor dysfunction and risk of cardiovascular disease, quality of life, and medical costs: design of the Locomotive Syndrome and Health Outcome in Aizu Cohort Study (LOHAS) and baseline characteristics of the study population. AB - BACKGROUND: There is little evidence regarding long-term outcomes of locomotor dysfunction such as cardiovascular events, quality of life, and death. We are conducting a prospective cohort study to evaluate risk of cardiovascular disease, quality of life, medical costs, and mortality attributable to locomotor dysfunction. The present study determined baseline characteristics of participants in the Locomotive Syndrome and Health Outcome in Aizu Cohort Study (LOHAS). METHODS: Cohort participants were recruited from residents between 40 and 80 years old who received regular health check-ups conducted by local government each year between 2008 and 2010 in Minami-Aizu Town and Tadami Town in Fukushima Prefecture, Japan. Musculoskeletal examination included assessment of physical examination of the cervical and lumbar spine, and upper and lower extremities and of physical function, such as grasping power, one-leg standing time, and time for the 3-m timed up-and-go test. Cardiovascular risk factors, including blood pressure and biological parameters, were measured at annual health check-ups. We also conducted a self-administered questionnaire survey. RESULTS: LOHAS participants comprised 1,289 men (mean age 65.7 years) and 1,954 women (mean age 66.2 years) at the first year. The proportion of obese individuals (body mass index 25.0 kg/m(2)) was 31.9% in men and 34.3% in women, and 41.0% of participants reported being followed up for hypertension, 7.0% for diabetes, and 43.6% for hypercholesterolemia. Prevalence of lumbar spinal stenosis was 10.7% in men and 12.9% in women, while prevalence of low back pain was 15.8% in men and 17.6% in women. CONCLUSION: The LOHAS is a novel population based prospective cohort study that will provide an opportunity to estimate the risk of cardiovascular disease, quality of life, medical costs, and mortality attributable to locomotor dysfunction, and to provide the epidemiological information required to develop policies for detection of locomotor dysfunction. PMID- 22526711 TI - New bone formation in a true bone ceramic scaffold loaded with desferrioxamine in the treatment of segmental bone defect: a preliminary study. AB - BACKGROUND: Desferrioxamine (DFO), an iron chelator, can stimulate osteogenesis and angiogenesis by stabilizing hypoxia-inducible factor 1alpha. We postulate that a bone graft substitute combined with DFO is beneficial to the reconstruction of bone defects. METHODS: We implanted pure true bone ceramic (TBC) and DFO-loaded TBC (DFO/TBC) scaffolds into 15-mm rabbit radial defects for 8 weeks. The bone segments were examined with X-ray, micro-CT and histology. RESULTS: Radiographs showed that the DFO/TBC scaffold became radiopaque, and the gaps between the scaffold and radial cut ends were often invisible. Variables from micro-CT, including the bone volume fraction (BV/TV), trabecular thickness (Tb.Th) and trabecular number (Tb.N), were significantly increased in pure TBC and DFO/TBC scaffolds that had been implanted for 8 weeks compared to unimplanted TBC scaffolds (p values <0.05-0.001). Between the former two groups, BV/TV and Tb.Th were significantly increased in DFO/TBC scaffolds (p < 0.001), but Tb.N did not show significant differences. Histological examinations showed considerably increased new bone and decreased TBC trabecular remnants in DFO/TBC scaffolds compared to pure TBC scaffolds. Many cavities in the new bone area in DFO/TBC scaffolds were occupied by bone marrow elements and blood vessels. Percent of new bone with tetracycline labeling was significantly greater in DFO/TBC scaffolds than in pure TBC scaffolds (p < 0.001). CONCLUSION: This preliminary study reveals that DFO can effectively induce new bone growing into TBC scaffolds, suggesting that the DFO/TBC composite is a promising bone graft substitute for the treatment of bone defects. PMID- 22526712 TI - Dumbbell-type hemangiopericytoma in the cervical spine: a case report and review. PMID- 22526713 TI - Hyaluronan injection therapy for athletic patients with patellar tendinopathy. AB - BACKGROUND: Patellar tendinopathy produces activity-related pain and focal tenderness at the attachment of the patellar tendon at the lower pole of the patella. It frequently causes a reduction in athletic ability. An injection of hyaluronan was found to be useful for patellar tendinopathy, provided the indication is appropriate, based on the authors' pilot cases. The purpose of this study was to summarize the clinical experience of and to describe the appropriate indication for this injection therapy. METHODS: Fifty patients were treated from January 1999 to December 2006. The observation period averaged 25.7 months (range 6-88). All patients were graded stage 2 or 3 by Blazina's classification. Each treatment was counted separately for 9 patients (10 knees) who had more than one treatment period with 3 months or more between the injections. There were 4 bilaterally injected patients. Patellar tendinopathy was classified into 4 types according to the degree of tenderness and the regions that are tender. Hyaluronan was injected into the interface between the patellar tendon and the infrapatellar fat pad at the proximal insertion, or into the region of maximum tenderness. RESULTS: The total number of injections was 135, and there were an average of 2.0 injections per case (range 1-11). Following treatment, 54 % of the cases were rated in excellent condition, as they were able to return to their previous athletic activities with little difficulty, while 40 % of the cases were rated in good condition-these patients were able to return to their previous sporting activities with some degree of limitation. CONCLUSIONS: Hyaluronan injection therapy for athletic patients with patellar tendinopathy is an optional but effective treatment. PMID- 22526714 TI - Distal radial fracture arthroscopic intraarticular gap and step-off measurement after open reduction and internal fixation with a volar locked plate. AB - PURPOSE: A persistent articular gap and a step-off of >=1 mm after a distal radial fracture (DRF) may lead to post-traumatic arthritis of the radiocarpal joint. This study aims to arthroscopically assess the reduction in the articular surface in patients requiring volar locked-plate fixation for DRF via fluoroscopy guided open reduction and internal fixation (ORIF). METHODS: Seventy consecutive patients with DRF were prospectively enrolled. Posteroanterior and lateral radiographs and axial, coronal, and sagittal computed tomography (CT) scans were obtained before ORIF for DRF. The widest articular gap (pregap) and step-off (prestep-off) at the radiocarpal joint surface of the distal radius were measured on all radiographs and CT images. Total predisplacement was defined as the sum of all pregaps and prestep-offs. The DRF was reduced under fluoroscopic guidance, and a volar locked-plate was applied after fluoroscopic ORIF. The residual maximum articular gap and step-off (postgap and poststep-off) were measured arthroscopically with a calibrated probe. Total incongruity was defined as the sum of postgap and poststep-off. The receiver operating characteristic curve was applied within the pregaps, prestep-offs and total incongruity in order to identify the cutoff values of pregap and prestep-off beyond which total incongruity would exceed 1 mm. RESULTS: Of the 70 patients, 40 had a postgap of >=1 mm, and 15 had a poststep-off of >=1 mm. All pregap and prestep-off cutoff values were judged to be unsuitable as the screening criteria for arthroscopic reduction of DRF because of their low sensitivity and specificity. The cutoff value obtained from total predisplacement was 7.85 mm, and its sensitivity and specificity were 90 and 70 %, respectively. CONCLUSIONS: Since the cutoff value of 7.85 mm derived from total predisplacement is a good indicator of post-ORIF residual total incongruity of >=1 mm, it is also a good indicator of the need for arthroscopic reduction. PMID- 22526715 TI - The outcome of surgical treatment for recurrent giant cell tumor in the appendicular skeleton. AB - BACKGROUND: The treatment for recurrent giant cell tumor (GCT) remains controversial. In this study, we evaluated the outcome of surgical intervention for recurrent GCT. METHOD: Twenty-seven patients (14 males and 13 females) with recurrent GCT were recruited. Their primary GCTs were all treated with intralesional surgery. Among these recurrent GCTs, 9 grade III and 1 grade II tumors were treated with en bloc resection and endoprosthetic replacement, whereas 16 grade II and 1 grade III tumors were treated with intralesional curettage and PMMA bone cement filling. RESULTS: The mean interval between initial surgery and first recurrence was 28.8 months (range 7-97 months). About 70 % of first recurrences affected bones around the knee, 44 % in the proximal tibia and 26 % in the distal femur. Of 27 patients, 3 women treated with intralesional procedures suffered second recurrences in the proximal tibia. No second recurrence was found in patients with en bloc resection. Two grade III re recurrence GCTs were treated with en bloc resection, and 1 grade II was treated with an intralesional procedure. One patient with en bloc resection developed tumor metastasis in both lungs. Compared to patients with intralesional treatment, the functional score was significantly decreased in patients with en bloc resection (p < 0.01). CONCLUSION: The re-recurrence risk of grade III GCTs can be significantly decreased by wide en bloc resection and endoprosthetic replacement. However, intralesional treatment is a good option for less aggressive ( Cl((2)P) + NH(3)(v'), lead to a great number of populated vibrational states in the NH(3)(v') product, even starting from the NH(3)(v = 0) vibrational ground state at low energies, which is unphysical in a quantum world. This result is interpreted on the basis of non-conservation of the ZPE per mode. PMID- 22526718 TI - Response priming with apparent motion primes. AB - Response priming refers to the finding that a prime stimulus preceding a target stimulus influences the response to the following target stimulus. Typically, responses are faster and more accurate if the prime calls for the same response as the target (i.e., compatible trials), as compared with the situation where primes and targets trigger different responses (i.e., incompatible trials). However, the effect depends on presentational and temporal parameters such as the stimulus onset asynchrony (SOA) of prime and target, or prime duration. Until now, the special role of moving stimuli was largely ignored. In the present research, experiments were conducted using clearly visible moving dots as primes and static arrows as targets. Essentially, with short SOAs up to 200 ms, participants responded faster to compatible targets. In contrast, with SOAs above 200 ms, participants responded faster to incompatible targets. The results were compared with response priming with static primes. Here, a different pattern of results emerged, with faster responses to compatible than incompatible targets at a long SOA of 300 ms. Overall, the experiments provide evidence for the existence of an inhibitory mechanism in action control when (distracting) motion stimuli are present. Results could be explained with slight changes to different accounts of negative response priming effects, as well as theories of attention. PMID- 22526720 TI - [Postcolostral immunoglobulin G (IgG) levels in newborn piglets using three different ELISA detection systems]. AB - Objective of the study was to evaluate whether the Colostrum Quality Counter (CQC), a new test method for immunoglobulin G (IgG) levels in newborn piglets, is easy to handle and provides comparable results to established testing regimes. MATERIAL AND METHODS: Blood samples from 219 piglets from four different farms were tested for their IgG-concentrations using three different ELISA tests. Furthermore, double samples from 30 piglets were taken from both the anterior vena cava and from the tail to determine whether the collection site affects the results. The three tests used were the Colostrum Quality Counter (CQC; FarmulaONE, NL-Best), the internal IgG-ELISA from our laboratory (MUC) and a commercially-available IgG-ELISA (NAT; NatuTec, Frankfurt/Main, Germany). RESULTS: MUC and NAT showed a higher correlation to each other than to the CQC when referring to the individual results per single piglet. The results from the CQC were higher and the standard deviation was significantly greater. The sampling site had no significant effect on the IgG concentrations measured. CLINICAL RELEVANCE: The CQC is a straightforward and simple test, being very convenient for sampling a large number of piglets. CQC results were inhomogeneous with some unusually high IgG-concentrations. MUC and NAT provided comparable results to one another and the IgG-concentrations showed a good correlation. PMID- 22526721 TI - [Diagnostic assessment of peritoneal fluid cytology in horses with abdominal neoplasia]. AB - OBJECTIVE: To evaluate the diagnostic value of peritoneal fluid (PF) cytology for clinical diagnosis of abdominal neoplasia in horses. MATERIAL AND METHODS: Ten horses with histopathologically confirmed abdominal neoplasia, in which a PF analysis was performed, were included in this retrospective study. PF was analyzed for total protein concentration and a nucleated cell count was performed. Using cytological criteria of malignancy, the PF samples were evaluated regarding their probability of malignancy. RESULTS: Cytologic classification of cells according to criteria of malignancy allowed a positive cytologic diagnosis of neoplasia in 5 out of 10 peritoneal fluid samples. Malignant lymphoma was the most commonly diagnosed neoplasia (3/10) and could be identified by cytology in 2/3 cases. In 1/2 horses with plasma cell myeloma neoplastic cells were similarly found. Malignant melanoma (2/10) was diagnosed using cytology in one case (presence of melanin-containing cells). Cytological diagnosis of malignant neoplasia was established in the only horse with gastric squamous cell carcinoma, but the morphology of the identified tumour cells did not allow a specific diagnosis. Thus, a definitive diagnosis was achieved in 4/5 horses with proven abdominal neoplasia. The horses with adenocarcinoma (1/10) and haemangiosarcoma (1/10) had no evidence of neoplasia based on cytological findings. No relationship between total protein concentration or the nucleated cell count with the histolopathological diagnosis of abdominal neoplasia was found. Abnormal mitotic figures were considered of greater diagnostic value than the overall mitotic rate. CONCLUSION: The implementation of nuclear criteria of malignancy in the cytologic evaluation of PF samples allows the identification of neoplastic cells to an acceptable degree. For this purpose, the knowledge of the highly variable morphological features of mesothelial cells is essential. The absence of malignant cells does not rule out abdominal neoplasia. CLINICAL RELEVANCE: PF cytology should be considered as a valuable, minimally invasive, simple, and rapid diagnostic technique in horses with suspected abdominal neoplasia. PMID- 22526722 TI - [Relevance and diagnostics of selected bacterial pathogens of poultry]. AB - This paper provides an overview of diseases caused by Bordetella avium, Gallibacterium anatis, Ornithobacterium rhinotracheale, Riemerella anatipestifer and Enterococcus cecorum in poultry flocks. These bacterial species are almost exclusively found in birds. Their identification with biochemical methods is described and alternative molecular biological methods are discussed. PMID- 22526723 TI - Tick-borne fever caused by Anaplasma phagocytophilum in Germany: first laboratory confirmed case in a dairy cattle herd. AB - Four cows from North-West Germany have been diagnosed with tick-borne fever (TBF) based on the demonstration of morulae in neutrophilic granulocytes in their blood smears, positive signals in real-time PCR specific for Anaplasma phagocytophilum using DNA extracted from their buffy coats, and demonstration of specific antibodies in their sera using a commercially available immunofluorescence assay. Clinical findings included high fever, decreased milk production, lower limb edema with stiff walking, eye and nasal discharge, and depression. These signs developed about a week after the animals had been brought to the pasture for the first time in their life. All cows recovered after 5-15 days, although DNA of A.phagocytophilum could be detected by real-time PCR up to 6 weeks after onset of the disease. Considering the known prevalences of A.phagocytophilum in ticks in Germany and its detection in dogs and horses, we think that underdiagnosing of TBE in cattle is highly likely. Therefore TBF should be taken into account as differential diagnosis in case of high fever and/or a sudden decrease in milk production in pastured animals. PMID- 22526724 TI - [High perinatal mortality associated with triple anthelmintic resistance in a German sheep flock]. AB - High perinatal mortality, low milk yields and occasional ewe deaths were investigated in a Dorper sheep flock in Southern Germany. Parasitic gastroenteritis due to Trichostrongylus spp. associated with severe weight loss despite regular anthelmintic treatments of the flock was identified as the underlying cause. A faecal egg count reduction (FECR) test revealed zero reduction after treatment with ivermectin or albendazole, respectively, and a FECR of 57.9% following treatment with levamisole. These results indicate a lack of, or considerably reduced efficacy of substances from all three classical groups of anthelmintics and demonstrate that triple anthelmintic resistance is also present in Germany. The introduction of resistant worm populations with imported livestock, excessive use of anthelmintic drugs and under-dosing of goats have possibly led to the problem in the flock described. Veterinary advice on anthelmintic treatments and responsible parasite control programmes are therefore crucial in small ruminant flocks. PMID- 22526726 TI - [Legal aspects of the use of footbaths for cattle and sheep]. AB - Claw diseases pose a major problem for dairy and sheep farms. As well as systemic treatments of these illnesses by means of drug injection, veterinarians discuss the application of footbaths for the local treatment of dermatitis digitalis or foot rot. On farms footbaths are used with different substances and for various purposes. The author presents the requirements for veterinary medicinal products (marketing authorization and manufacturing authorization) and demonstrates the operation of the "cascade in case of a treatment crisis". In addition, the distinction between veterinary hygiene biocidal products and veterinary medicinal products and substances to care for claws is explained. PMID- 22526725 TI - [Clinical and pathological findings in an alpaca suffering from malignant catarrhal fever]. AB - Malignant catarrhal fever (MCF) is a worldwide occurring sporadic disease of cloven-hoofed animals. For the first time, this case report describes clinical and pathological as well as histopathological findings in an alpaca suffering from MCF caused by ovine herpesvirus 2. Clinical symptoms comprised apathy, dehydration, anorexia, and emaciation. These symptoms were unspecific and did not correspond to any known course of MCF in cattle. However, the findings of the pathological and histopathological examination showed broad analogies to the main findings in other ruminants infected with MCF. In this alpaca, infection with ovine herpesvirus 2 was confirmed by postmortal PCR of tissue samples of lung, trachea, oesophagus, larynx and tonsils as well as conjunctival swabs. PMID- 22526727 TI - Zinc or indium-mediated Barbier-type allylation of aldehydes with 3-bromomethyl 5H-furan-2-one in aqueous media: an efficient synthesis method for alpha methylene-gamma-butyrolactone. AB - A zinc or indium-mediated Barbier-type allylation of aldehydes with 3-bromomethyl 5H-furan-2-one in aqueous solvents was developed to provide an efficient route to alpha-methylene-gamma-butyrolactone, which is synthetically very useful. The desired products were obtained in moderate to high yields in aqueous solvents. Excellent drs were achieved, among which the best diastereomeric ratios of products were found when water was used in the indium-mediated reaction, and THF NH(4)Cl (sat, aq) (2 : 1) mixture in the zinc-mediated reaction. Furthermore, the allylation can be induced by chiral centers, especially those in the alpha position, as a substrate-controlled reaction to obtain the enantioselective homoallylation alcohols. PMID- 22526728 TI - Differences between unipolar and bipolar I depression in the quantitative analysis of glutamic acid decarboxylase-immunoreactive neuropil. AB - Alterations in GABAergic neurotransmission are assumed to play a crucial role in the pathophysiology of mood disorders. Glutamic acid decarboxylase (GAD) is the key enzyme in GABA synthesis. This study aimed to differentiate between unipolar and bipolar I depression using quantitative evaluation of GAD-immunoreactive (GAD ir) neuropil in several brain regions known to be involved in the pathophysiology of mood disorders. Immunohistochemical staining of GAD 65/67 was performed in the orbitofrontal, anterior cingulate and dorsolateral prefrontal cortex (DLPFC), the entorhinal cortex, the hippocampal formation and the medial dorsal and lateral dorsal (LD) thalamic nuclei, with a quantitative densitometric analysis of GAD-ir neuropil. The study was performed on paraffin-embedded brains from 9 unipolar and 12 bipolar I depressed patients (8 and 6 suicidal patients, respectively) and 18 matched controls. In unipolar patients, compared with controls, only the increased relative density of GAD-ir neuropil in the right LD was different from the previous results in depressed suicides from the same cohort (Gos et al. in J Affect Disord 113:45-55, 2009). On the other hand, the left DLPFC was the only area where a significant decrease was observed, specific for bipolar I depression. Significant differences between both diagnostic groups were found in these regions. By revealing abnormalities in the relative density of GAD-ir neuropil in brain structures, our study suggests a diathesis of the GABAergic system in mood disorders, which may differentiate the pathophysiology of unipolar from that of bipolar I depression. PMID- 22526729 TI - Effectiveness of antipsychotic maintenance therapy with quetiapine in comparison with risperidone and olanzapine in routine schizophrenia treatment: results of a prospective observational trial. AB - Objective of this observational trial is to examine the effects of quetiapine in comparison with olanzapine and risperidone on clinical outcomes and quality of life in patients with schizophrenia and schizoaffective disorder in routine care. 374 adult persons with schizophrenia or schizoaffective disorder prescribed antipsychotic maintenance therapy with quetiapine, olanzapine, or risperidone at discharge from inpatient treatment were included. Clinical and psychosocial outcomes were assessed before discharge and at 6, 12, 18, and 24 months. Statistical analyses were conducted by mixed-effects regression models for longitudinal data. The propensity score method was used to control for selection bias. Patients discharged on olanzapine had significantly lower hospital readmissions than those receiving quetiapine or risperidone. The average chlorpromazine equivalent dose of quetiapine was higher than in patients treated with olanzapine or risperidone. No further significant differences between treatment groups were found. Quetiapine and risperidone are less effective in preventing the need for psychiatric inpatient care than olanzapine, and higher chlorpromazine equivalent doses of quetiapine are needed to obtain clinical effects similar to those of olanzapine and risperidone. PMID- 22526730 TI - Long-term functional outcome in adult prison inmates with ADHD receiving OROS methylphenidate. AB - In a recent randomized, double-blind, placebo-controlled trial, we established a robust efficacy (Cohen's d = 2.17) of osmotic release oral system-methylphenidate (OROS-methylphenidate) delivered 72 mg daily for 5 weeks versus placebo on attention deficit hyperactivity disorder (ADHD) symptoms, global severity and global functioning in 30 adult male prison inmates with ADHD and coexisting disorders. Outcomes continued to improve during the subsequent 47-week open-label extension with OROS-methylphenidate delivered at a flexible daily dosage of up to 1.3 mg/kg body weight. In the present study, we evaluated long-term effectiveness and maintenance of improvement over the cumulated 52-week trial on cognition, motor activity, institutional behaviour and quality of life. Post hoc, we explored the associations between investigators' and self-ratings of ADHD symptoms and between ratings of symptoms and functioning, respectively. Outcomes, calculated by repeated measures ANOVA, improved from baseline until week 16, with maintenance or further improvement until week 52. Both verbal and visuospatial working memory, and abstract verbal reasoning improved significantly over time, as well as several cognition-related measures and motor activity. No substance abuse was detected and a majority of participants took part in psychosocial treatment programmes. The quality of life domains of Learning, and Goals and values improved over time; the latter domain was at open-label endpoint significantly related to improvements in attention. Investigators' and self ratings of ADHD symptoms, as well as global symptom severity related most significantly to global functioning at week 52. Finally, investigators' and self ratings of ADHD symptoms associated significantly at baseline with increasing convergence over time. PMID- 22526731 TI - Disturbed dreaming and sleep quality: altered sleep architecture in subjects with frequent nightmares. AB - Nightmares are intense, emotionally negative mental experiences that usually occur during late-night sleep and result in abrupt awakenings. Questionnaire based studies have shown that nightmares are related to impaired sleep quality; however, the polysomnographic profile of nightmare subjects has been only scarcely investigated. We investigated the sleep architecture of 17 individuals with frequent nightmares and 23 control subjects based on polysomnographic recordings of a second night spent in the laboratory after an adaptation night. Nightmare subjects in comparison with control subjects were characterized by impaired sleep architecture, as reflected by reduced sleep efficiency, increased wakefulness, a reduced amount of slow wave sleep, and increased nocturnal awakenings, especially from Stage 2 sleep. While these differences were independent of the effects of waking psychopathology, nightmare subjects also exhibited longer durations of REM sleep that was mediated by heightened negative affect. Our results support that nightmares are related to altered sleep architecture, showing impaired sleep continuity and emotion-related increase in REM propensity. PMID- 22526733 TI - New developments in understanding the mechanisms and function of spontaneous electrical activity in the developing mammalian auditory system. AB - In the mature mammalian auditory system, inner hair cells are responsible for converting sound-evoked vibrations into graded electrical responses, resulting in release of neurotransmitter and neuronal transmission via the VIIIth cranial nerve to auditory centres in the central nervous system. Before the cochlea can reliably respond to sound, inner hair cells are not merely immature quiescent pre hearing cells, but instead are capable of generating 'spontaneous' calcium-based action potentials. The resulting calcium signal promotes transmitter release that drives action potential firing in developing spiral ganglion neurones. These early signalling events that occur before sound-evoked activity are thought to be important in guiding and refining the initial phases of development of the auditory circuits. This review will summarise our current knowledge of the mechanisms that underlie spontaneous action potentials in developing inner hair cells and how these events are triggered and regulated. PMID- 22526734 TI - Subharmonic distortion in ear canal pressure and intracochlear pressure and motion. AB - When driven at sound pressure levels greater than ~110 dB stimulus pressure level, the mammalian middle ear is known to produce subharmonic distortion. In this study, we simultaneously measured subharmonics in the ear canal pressure, intracochlear pressure, and basilar membrane or round window membrane velocity, in gerbil. Our primary objective was to quantify the relationship between the subharmonics measured in the ear canal and their intracochlear counterparts. We had two primary findings: (1) The subharmonics emerged suddenly, with a substantial amplitude in the ear canal and the cochlea; (2) at the stimulus level for which subharmonics emerged, the pressure in scala vestibuli/pressure in the ear canal amplitude relationship was similar for the subharmonic and fundamental components. These findings are important for experiments and clinical conditions in which high sound pressure level stimuli are used and could lead to confounding subharmonic stimulation. PMID- 22526735 TI - Behavioral estimates of the contribution of inner and outer hair cell dysfunction to individualized audiometric loss. AB - Differentiating the relative importance of the various contributors to the audiometric loss (HL(TOTAL)) of a given hearing impaired listener and frequency region is becoming critical as more specific treatments are being developed. The aim of the present study was to assess the relative contribution of inner (IHC) and outer hair cell (OHC) dysfunction (HL(IHC) and HL(OHC), respectively) to the audiometric loss of patients with mild to moderate cochlear hearing loss. It was assumed that HL(TOTAL) = HL(OHC) + HL(IHC) (all in decibels) and that HL(OHC) may be estimated as the reduction in maximum cochlear gain. It is argued that the latter may be safely estimated from compression threshold shifts of cochlear input/output (I/O) curves relative to normal hearing references. I/O curves were inferred behaviorally using forward masking for 26 test frequencies in 18 hearing impaired listeners. Data suggested that the audiometric loss for six of these 26 test frequencies was consistent with pure OHC dysfunction, one was probably consistent with pure IHC dysfunction, 13 were indicative of mixed IHC and OHC dysfunction, and five were uncertain (one more was excluded from the analysis). HL(OHC) and HL(IHC) contributed on average 60 and 40 %, respectively, to the audiometric loss, but variability was large across cases. Indeed, in some cases, HL(IHC) was up to 63 % of HL(TOTAL), even for moderate losses. The repeatability of the results is assessed using Monte Carlo simulations and potential sources of bias are discussed. PMID- 22526732 TI - Conditional gene expression in the mouse inner ear using Cre-loxP. AB - In recent years, there has been significant progress in the use of Cre-loxP technology for conditional gene expression in the inner ear. Here, we introduce the basic concepts of this powerful technology, emphasizing the differences between Cre and CreER. We describe the creation and Cre expression pattern of each Cre and CreER mouse line that has been reported to have expression in auditory and vestibular organs. We compare the Cre expression patterns between Atoh1-CreER(TM) and Atoh1-CreER(T2) and report a new line, Fgfr3-iCreER(T2), which displays inducible Cre activity in cochlear supporting cells. We also explain how results can vary when transgenic vs. knock-in Cre/CreER alleles are used to alter gene expression. We discuss practical issues that arise when using the Cre-loxP system, such as the use of proper controls, Cre efficiency, reporter expression efficiency, and Cre leakiness. Finally, we introduce other methods for conditional gene expression, including Flp recombinase and the tetracycline inducible system, which can be combined with Cre-loxP mouse models to investigate conditional expression of more than one gene. PMID- 22526736 TI - The under-compensatory roll aVOR does not affect dynamic visual acuity. AB - Rotations of the head evoke compensatory reflexive eye rotations in the orbit to stabilize images onto the fovea. In normal humans, the angular vestibulo-ocular reflex (aVOR) gain (eye/head velocity) changes depending on the head rotation plane. For pitch and yaw head rotations, the gain is near unity, but during roll head rotations, the aVOR gain is ~ 0.7. The purpose of this study was to determine whether this physiological discrepancy affects dynamic visual acuity (DVA)--a functional measure of the aVOR that requires subjects to identify letters of varying acuities during head rotation. We used the scleral search coil technique to measure eye and head velocity during passive DVA testing in yaw, roll, and pitch head impulses in healthy controls and patients with unilateral vestibular hypofunction (UVH). For control subjects, the mean aVOR gain during roll impulses was significantly lower than the mean aVOR gain during yaw and pitch impulses; however, there was no difference in DVA between yaw, roll, or pitch. For subjects with UVH, only aVOR gain during head rotations toward the affected side (yaw) were asymmetric (ipsilesional, 0.32 +/- 0.17, vs. contralesional, 0.95 +/- 0.05), with no asymmetry during roll or pitch. Similarly, there was a large asymmetry for DVA only during yaw head rotations, with no asymmetry in roll or pitch. Interestingly, DVA during roll toward the affected ear was better than DVA during yaw toward the affected ear--even though the ipsilesional roll aVOR gain was 60 % lower. During roll, the axis of eye rotation remains nearly perpendicular to the fovea, resulting in minimal displacement between the fovea and fixation target image projected onto the back of the eye. For subjects with UVH, the DVA score during passive horizontal impulses is a better indicator of poor gaze stability than during passive roll or pitch. PMID- 22526738 TI - Changes in cardiac output and stroke volume as measured by non-invasive CO monitoring in infants with RSV bronchiolitis. AB - OBJECTIVES: The primary aim of the study was to determine the changes, if any, in cardiac output (CO) and stroke volume (SV) in normal infants with RSV bronchiolitis. The secondary aim was to determine whether changes in CO (DeltaCO) and SV (DeltaSV) are associated with changes in respiratory rate (DeltaRR). METHODS: Non-invasive CO recordings were obtained within 24 h of admission and discharge. Changes in CO, SV, and HR measurements were compared using paired t tests. The effect of fluid boluses during the first 24 h (<60 or >=60 cc/kg) on CO was assessed by 2 way ANOVA with time and group as main effect. The relationship between DeltaRR and DeltaCO or DeltaSV was assessed by linear regression. Data is presented as Mean +/- SEM and mean differences with 95 % confidence interval (p < 0.05 considered significant). RESULTS: 15 infants with RSV bronchiolitis were studied. CO (1.31 +/- 0.13 to 1.11 +/- 0.11 l/min (0.21 [0.04-0.37]) and SV (9.42 +/- 1.10 to 7.75 +/- 0.83 ml/beat (1.67 [0.21-3.12]) decreased significantly while HR (142.1 +/- 4.0 to 145.2 +/- 3.1 beats/min 3.0 [ 5.3 to 11.3]) was unchanged. SV (p = 0.02) and CO (p = 0.04) significantly decreased only in the 7 infants that received >=60 cc/kg. DeltaRR correlated significantly with DeltaCO (r (2) = 0.28, p = 0.04); but not with DeltaSV (r (2) = 0.20, p = 0.09). CONCLUSIONS: ?CO was related to DeltaSV and not Delta HR. The ?CO and DeltaSV were affected by fluid boluses. DeltaRR correlated with DeltaCO. Non-invasive CO monitoring can trend CO and SV in infants with bronchiolitis during hospitalization. PMID- 22526737 TI - Temporary suppression of tinnitus by modulated sounds. AB - Despite high prevalence of tinnitus and its impact on quality life, there is no cure for tinnitus at present. Here, we report an effective means to temporarily suppress tinnitus by amplitude- and frequency-modulated tones. We systematically explored the interaction between subjective tinnitus and 17 external sounds in 20 chronic tinnitus sufferers. The external sounds included traditionally used unmodulated stimuli such as pure tones and white noise and dynamically modulated stimuli known to produce sustained neural synchrony in the central auditory pathway. All external sounds were presented in a random order to all subjects and at a loudness level that was just below tinnitus loudness. We found some tinnitus suppression in terms of reduced loudness by at least one of the 17 stimuli in 90% of the subjects, with the greatest suppression by amplitude-modulated tones with carrier frequencies near the tinnitus pitch for tinnitus sufferers with relatively normal loudness growth. Our results suggest that, in addition to a traditional masking approach using unmodulated pure tones and white noise, modulated sounds should be used for tinnitus suppression because they may be more effective in reducing hyperactive neural activities associated with tinnitus. The long-term effects of the modulated sounds on tinnitus and the underlying mechanisms remain to be investigated. PMID- 22526739 TI - ["Men are from Mars, women are from Venus" : Gender medicine as a future must have in anesthesiology?]. PMID- 22526740 TI - [Gender aspects in anesthesia : modified approach in research and treatment?]. AB - Gender differences can have a relevant influence on the perioperative outcome as male and female patients are affected differently by adverse events, e.g. side effects of drugs. Furthermore, differences relating to specific drug effects, comorbidities and outcome after anesthesia or intensive care have been demonstrated. There seems to be a gender bias in diagnosis and therapy. While the knowledge regarding this field is still growing certain aspects have already been integrated into clinical practice: prevention of postoperative nausea and vomiting (PONV), target controlled infusion (TCI) model and male only policy with production of blood products. There is a need to study the influence of gender, age and race in order to optimize treatment towards a more individualized therapy. This article highlights already identified differences and discusses potential underlying mechanisms. PMID- 22526741 TI - [Hypoxemia after general anesthesia]. AB - BACKGROUND: Studies conducted shortly after the implementation of pulse oximetry (PO) into clinical practice 20-25 years ago revealed that many patients breathing room air during transfer from the operating room (OR) to the post-anesthesia care unit (PACU) directly after general anesthesia (GA) had a peripheral oxygen saturation (S(p)O(2)) below 90%. Moreover, it was shown that the detection of hypoxemia by clinical criteria is extremely unreliable. Meanwhile, the use of PO has become part of the obligatory standard monitoring during GA in Germany and many other countries. Likewise, the use of PO is standard care in the PACU although there are no official recommendations. However, for the time period in between, i.e. immediately after GA during transportation of patients from the OR to the PACU, monitoring of the S(p)O(2) in patients breathing room air is neither obligatory in Germany nor are there any official recommendations or guidelines in this respect. Given the introduction of shorter acting anesthetic agents within the last 25 years, the main goal of this study was to explore whether the incidence of hypoxemia in the immediate period after GA is still so high. Additional aims of this study were to examine whether the detection of hypoxemia based on clinical criteria can be confirmed to be very unreliable, what the risk factors for hypoxemia following GA are and how common it is in Germany to transport patients from the OR to the PACU without PO and supplemental oxygen. METHODS: In a prospective observational study 970 patients who underwent a broad spectrum of elective surgery under GA in a university hospital setting were included. The S(p)O(2) was measured at the end of the transfer from the OR to the PACU immediately after the anesthetist who had taken care of the patient during the operation had estimated the S(p)O(2). The association between biometric, surgical and anesthesiological variables on the one hand and hypoxemia as well as a decrease of S(p)O(2) on the other hand were studied using multivariate methods. Finally, a survey including all university hospitals was carried out to find out about the use of PO and oxygen during patient transfer from the OR to the PACU. RESULTS: Of the 959 patients who were eligible for analysis 17% had a S(p)O(2) < 90% and 6.6% a S(p)O(2) < 85%. Hypoxemia was not recognized in 82% of the patients in whom an assessment based on clinical grounds was carried out. Variables with an independent influence on hypoxemia and decrease of S(p)O(2) were as follows: saturation before induction of GA, body mass index, age, American Society of Anesthesiologists (ASA) physical status, difference between maximum and minimum inspiratory pressure, mode of ventilation, the choice of opioid and muscle relaxant as well as the use of nitrous oxide. Patient-dependent risk factors had the strongest impact on hypoxemia. In about 80% of the university hospitals neither PO nor supplemental oxygen is used during transportation of the patient from the OR to the PACU. CONCLUSIONS: The use of opioids and relaxants with short duration of action may have favorable effects on preventing hypoxemia and decreases of S(p)O(2). These measures will, however, not be sufficient to solve this problem because the highest risk factors for hypoxemia are patient-related. Despite knowing risk factors for oxygen desaturation, it is currently not possible to reliably predict which patients will become hypoxemic or have a decrease of S(p)O(2). Therefore, transportation of patients breathing room air from the OR to the PACU directly after GA without use of PO or supplemental oxygen seems to be questionable in terms of patient safety. PMID- 22526742 TI - [Comparison of ready-to-use devices for emergency cricothyrotomy : randomized and controlled feasibility study on a mannequin]. AB - BACKGROUND: According to various algorithms of airway management, emergency cricothyrotomy (coniotomy) represents the ultimate step for managing the difficult airway. As most physicians have limited experience with this technique several ready-to-use devices have emerged on the market with the aim of simplifying the procedure. However, they differ in details, such as configuration or the order of particular steps. Therefore, the intention of this randomized and controlled feasibility study was to test various sets and compare them to the classical surgical approach. METHODS: After obtaining informed consent German anesthesiologists who were also board-certified emergency physicians were asked to perform the cricothyrotomy procedure in a cervical mannequin (Frova Crico Trainer, VBM Medizintechnik) in a randomized order using a scalpel, peripheral intravenous cannula and the commercial devices TracheoQuick, Airfree, Portex Crico-Kit, Quicktrach I and Quicktrach II. Handling and duration of the procedures were analyzed utilizing the Wilcoxon signed-rank test. A p-value < 0.05 was considered significant. RESULTS: A total of 20 anesthesiologists (11 residents and 9 specialists) with a mean age of 34 years were included in this study and all had the additional qualification of emergency physician, which enabled them to work in prehospital emergency medicine in Germany. Participants had been working in this field for an average of 29.9 months (range 6-84 months) performing a mean of 1.9 24 h shifts per month (range 1-6 shifts/month). Of the participants only 2 (10%) had performed a coniotomy in reality before. In this study surgical coniotomy required a median time of 35.4 s (range 30.0-61.8 s). No significant differences were seen when the cuffed devices Quicktrach II (median: 29.9 s, range 25.0-50.5 s) and Portex-Crico-Kit (median: 46.7 s, range 37.0-67.3 s) were used. A significantly faster airway was established using the non-cuffed devices TracheoQuick (median: 20.2 s, range 11.4-44.7 s), Airfree (median: 22.8 s, range 14.3-33.2 s), Quicktrach I (median: 21.1 s, range 14.5-32.4 s) and the peripheral intravenous cannula (median: 19.2 s, range 10.8-27.8 s). Incorrect tube placements were not observed. CONCLUSION: This study allowed the comparison of surgical coniotomy to several ready-to-use devices in a standardized setting utilizing a reusable plastic mannequin. The interpretation for real emergency conditions is limited as individual anatomy, traumatic alterations of the neck or complications, such as bleeding or damage of important structures were not part of the study objectives. However, all participating emergency physicians successfully used the coniotomy sets provided at the first attempt. No device required significantly more time than the surgical approach. The procedures using cuffed devices lasted longer in comparison to procedures using uncuffed ones; however, this difference would only play a minor role in reality as effective ventilation with minute volumes greater than 7 l/min will only be achieved by a cuffed cannula with a minimum internal diameter of 4 mm. Devices with no cuff or with tube diameters smaller than 4 mm will only allow oxygenation of the patient, which in turn requires an inspiratory oxygen concentration of 100% and a relatively high ventilation frequency. PMID- 22526744 TI - [Positive end-expiratory pressure : adjustment in acute lung injury]. AB - Treatment of patients suffering from acute lung injury is a challenge for the treating physician. In recent years ventilation of patients with acute hypoxic lung injury has changed fundamentally. Besides the use of low tidal volumes, the most beneficial setting of positive end-expiratory pressure (PEEP) has been in the focus of researchers. The findings allow adaption of treatment to milder forms of acute lung injury and severe forms. Additionally computed tomography techniques to assess the pulmonary situation and recruitment potential as well as bed-side techniques to adjust PEEP on the ward have been modified and improved. This review gives an outline of recent developments in PEEP adjustment for patients suffering from acute hypoxic and hypercapnic lung injury and explains the fundamental pathophysiology necessary as a basis for correct treatment. PMID- 22526743 TI - [Intraoperative electrophysiological monitoring with evoked potentials]. AB - During the last 30 years intraoperative electrophysiological monitoring (IOEM) has gained increasing importance in monitoring the function of neuronal structures and the intraoperative detection of impending new neurological deficits. The use of IOEM could reduce the incidence of postoperative neurological deficits after various surgical procedures. Motor evoked potentials (MEP) seem to be superior to other methods for many indications regarding monitoring of the central nervous system. During the application of IOEM general anesthesia should be provided by total intravenous anesthesia with propofol with an emphasis on a continuous high opioid dosage. When intraoperative MEP or electromyography guidance is planned, muscle relaxation must be either completely omitted or maintained in a titrated dose range in a steady state. The IOEM can be performed by surgeons, neurologists and neurophysiologists or increasingly more by anesthesiologists. However, to guarantee a safe application and interpretation, sufficient knowledge of the effects of the surgical procedure and pharmacological and physiological influences on the neurophysiological findings are indispensable. PMID- 22526746 TI - [Age rationing : means of resource allocation in healthcare systems]. AB - The necessity of limiting resource in healthcare systems is becoming increasingly more evident. The population has requirements especially in the field of healthcare which are principally unlimited. However, there are only limited financial resources which can be used to satisfy the wishes of the population. For this reason rationing models are being discussed increasingly more often. One example of these models is called age rationing which means that defined services are only offered to patients up to a particular age. The aim of this article is to discuss the model of age rationing in the context of an optimized use of resources in the healthcare system. PMID- 22526745 TI - [Corticosteroid administration for acute respiratory distress syndrome : therapeutic option?]. AB - Despite a number of clinical trials there is still controversy about the role of corticosteroid therapy in acute respiratory distress syndrome (ARDS). In addition recent meta-analyses differed markedly in the conclusions. This review is intended to provide a short practical guide for the clinician. Based on the available literature, high-dose and pre-emptive administration of corticosteroids is hazardous and not indicated. A low-dose corticosteroid regime given for 4 weeks may potentially be helpful and can be considered in acute or unresolved ARDS in less than 14 days after onset of ARDS, if a close infection surveillance program is available, if neuromuscular blockade can be avoided and if a stepwise dose reduction of corticosteroids is performed. The total daily dose at the beginning of treatment should not exceed 2 mg/kg body weight (BW) methylprednisolone. PMID- 22526748 TI - Zoonotic transmission of tuberculosis between pastoralists and their livestock in South-East Ethiopia. AB - Despite huge global efforts in tuberculosis (TB) control, pastoral areas remain under-investigated. During two years sputum and fine needle aspirate (FNA) specimens were collected from 260 Ethiopian pastoralists of Oromia and Somali Regional States with suspected pulmonary TB and from 32 cases with suspected TB lymphadenitis. In parallel, 207 suspected tuberculous lesions were collected from cattle, camels and goats at abattoirs. All specimens were processed and cultured for mycobacteria; samples with acid-fast stained bacilli (AFB) were further characterized by molecular methods including genus and deletion typing as well as spoligotyping. Non-tuberculous mycobacteria (NTM) were sequenced at the 16S rDNA locus. Culturing of AFB from human sputum and FNA samples gave a yield of 174 (67%) and 9 (28%) isolates, respectively. Molecular typing was performed on 173 of these isolates and 160 were confirmed as Mycobacterium tuberculosis, three as M. bovis, and the remaining 10 were typed as NTMs. Similarly, 48 AFB isolates (23%) yielded from tuberculous lesions of livestock, of which 39 were molecular typed, including 24 M. bovis and 4 NTMs from cattle, 1 M. tuberculosis and 1 NTM from camels and 9 NTMs from goats. Isolation of M. bovis from humans and M. tuberculosis from livestock suggests transmission between livestock and humans in the pastoral areas of South-East Ethiopia. PMID- 22526747 TI - [Anesthesia for geriatric patients : Part 2: anesthetics, patient age and anesthesia management]. AB - Part 2 of this review on geriatric anesthesia primarily describes the multiple influences of age on the pharmacokinetics and pharmacodynamics of different anesthetic agents and their impact on clinical practice. In the elderly the demand for opioids is reduced by almost 50% and with total intravenous anesthesia the dosages of propofol and remifentanil as well as recovery times are more determined by patient age than by body weight. As a result depth of anesthesia monitoring is recommended for geriatric patients to individually adjust the dosing to patients needs. With muscle relaxants both delayed onset of action and prolonged duration of drug effects must be considered with increasing age and as this may lead to respiratory complications, neuromuscular monitoring is highly recommended. The following measures appear to be beneficial for geriatric patients: thorough preoperative assessment, extended hemodynamic monitoring, use of short-acting anesthetics in individually adjusted doses best tailored by depth of anesthesia monitoring, intraoperative normotension, normothermia and normocapnia, complete neuromuscular recovery at the end of the procedure and well planned postoperative pain management in order to reduce or avoid the use of opioids. PMID- 22526750 TI - Synanthropy of wild mammals as a determinant of emerging infectious diseases in the Asian-Australasian region. AB - Humans create ecologically simplified landscapes that favour some wildlife species, but not others. Here, we explore the possibility that those species that tolerate or do well in human-modified environments, or 'synanthropic' species, are predominantly the hosts of zoonotic emerging and re-emerging infectious diseases (EIDs). We do this using global wildlife conservation data and wildlife host information extracted from systematically reviewed emerging infectious disease literature. The evidence for this relationship is examined with special emphasis on the Australasian, South East Asian and East Asian regions. We find that synanthropic wildlife hosts are approximately 15 times more likely than other wildlife in this region to be the source of emerging infectious diseases, and this association is essentially independent of the taxonomy of the species. A significant positive association with EIDs is also evident for those wildlife species of low conservation risk. Since the increase and spread of native and introduced species able to adapt to human-induced landscape change is at the expense of those species most vulnerable to habitat loss, our findings suggest a mechanism linking land conversion, global decline in biodiversity and a rise in EIDs of wildlife origin. PMID- 22526749 TI - 'Changing climate, changing health, changing stories' profile: using an EcoHealth approach to explore impacts of climate change on inuit health. AB - Global climate change and its impact on public health exemplify the challenge of managing complexity and uncertainty in health research. The Canadian North is currently experiencing dramatic shifts in climate, resulting in environmental changes which impact Inuit livelihoods, cultural practices, and health. For researchers investigating potential climate change impacts on Inuit health, it has become clear that comprehensive and meaningful research outcomes depend on taking a systemic and transdisciplinary approach that engages local citizens in project design, data collection, and analysis. While it is increasingly recognised that using approaches that embrace complexity is a necessity in public health, mobilizing such approaches from theory into practice can be challenging. In 2009, the Rigolet Inuit Community Government in Rigolet, Nunatsiavut, Canada partnered with a transdisciplinary team of researchers, health practitioners, and community storytelling facilitators to create the Changing Climate, Changing Health, Changing Stories project, aimed at developing a multi-media participatory, community-run methodological strategy to gather locally appropriate and meaningful data to explore climate-health relationships. The goal of this profile paper is to describe how an EcoHealth approach guided by principles of transdisciplinarity, community participation, and social equity was used to plan and implement this climate-health research project. An overview of the project, including project development, research methods, project outcomes to date, and challenges encountered, is presented. Though introduced in this one case study, the processes, methods, and lessons learned are broadly applicable to researchers and communities interested in implementing EcoHealth approaches in community-based research. PMID- 22526753 TI - Duodenal gastrointestinal stroma tumours: difficulties of an individualized risk assessment and controversies in surgical therapy. PMID- 22526751 TI - The interplay of plant and animal disease in a changing landscape: the role of sudden aspen decline in moderating Sin Nombre virus prevalence in natural deer mouse populations. AB - We examined how climate-mediated forest dieback regulates zoonotic disease prevalence using the relationship between sudden aspen decline (SAD) and Sin Nombre virus (SNV) as a model system. We compared understory plant community structure, small mammal community composition, and SNV prevalence on 12 study sites within aspen forests experiencing levels of SAD ranging from <10.0% crown fade to >95.0% crown fade. Our results show that sites with the highest levels of SAD had reduced canopy cover, stand density, and basal area, and these differences were reflected by reductions in understory vegetation cover. Conversely, sites with the highest levels of SAD had greater understory standing biomass, suggesting that vegetation on these sites was highly clustered. Changes in forest and understory vegetation structure likely resulted in shifts in small mammal community composition across the SAD gradient, as we found reduced species diversity and higher densities of deer mice, the primary host for SNV, on sites with the highest levels of SAD. Sites with the highest levels of SAD also had significantly greater SNV prevalence compared to sites with lower levels of SAD, which is likely a result of their abundance of deer mice. Collectively, results of our research provide strong evidence to show SAD has considerable impacts on vegetation community structure, small mammal density and biodiversity and the prevalence of SNV. PMID- 22526755 TI - Synthesis and reactivity of electron poor allenes: formation of completely organic frustrated Lewis pairs. AB - The synthesis of several electron poor allenes bearing electron withdrawing substituents is described and their use as Lewis acids in the field of frustrated Lewis pair (FLP) chemistry reported. At room temperature the combination of N heterocyclic carbenes (NHC) with the allenes under study invariably afforded the corresponding Lewis adducts; however, at -78 degrees C this reaction is in most of the cases inhibited and kinetically induced organic FLPs are formed. Under these conditions the activation of S-S bonds in disulfides has been achieved in excellent yields. PMID- 22526754 TI - Assessment of the role of aptitude in the acquisition of advanced laparoscopic surgical skill sets: results from a virtual reality-based laparoscopic colectomy training programme. AB - PURPOSE: The surgeons of the future will need to have advanced laparoscopic skills. The current challenge in surgical education is to teach these skills and to identify factors that may have a positive influence on training curriculums. The primary aim of this study was to determine if fundamental aptitude impacts on ability to perform a laparoscopic colectomy. METHODS: A practical laparoscopic colectomy course was held by the National Surgical Training Centre at the Royal College of Surgeons in Ireland. The course consisted of didactics, warm-up and the performance of a laparoscopic sigmoid colectomy on thesimulator. Objective metrics such as time and motion analysis were recorded. Each candidate had their psychomotor and visual spatial aptitude assessed. The colectomy trays were assessed by blinded experts post procedure for errors. RESULTS: Ten trainee surgeons that were novices with respect to advanced laparoscopic procedures attended the course. A significant correlation was found between psychomotor and visual spatial aptitude and performance on both the warm-up session and laparoscopic colectomy (r > 0.7, p < 0.05). Performance on the warm-up session correlated with performance of the laparoscopic colectomy (r = 0.8, p = 0.04). There was also a significant correlation between the number of tray errors and time taken to perform the laparoscopic colectomy (r = 0.83, p = 0.001). CONCLUSION: The results have demonstrated that there is a relationship between aptitude and ability to perform both basic laparoscopic tasks and laparoscopic colectomy on a simulator. The findings suggest that there may be a role for the consideration of an individual's inherent baseline ability when trying to design and optimise technical teaching curricula for advanced laparoscopic procedures. PMID- 22526756 TI - Leptomeningeal carcinomatosis mimicking Creutzfeldt-Jakob disease: clinical features, laboratory tests, MRI images, EEG findings in an autopsy-proven case. AB - Leptomeningeal carcinomatosis (LC) refers to diffuse seeding of the leptomeninges by tumor metastases. The clinical presentation may differ and the diagnosis may be difficult especially when cancer has not yet been diagnosed. We report a case of LC, where the clinical picture and a specific change in cerebrospinal fluid suggested the diagnosis of a prion disease. PMID- 22526757 TI - Transient elevation of synaptosomal mitoenergetic proteins and Hsp70 early in a rat model of chronic cerebrovascular hypoperfusion. AB - Chronic cerebral hypoperfusion (CCH) might account for the cognitive deficits associated with vascular cognitive impairment, but the mechanisms of hypoperfusion insulting to the cognition remain obscure. In the present study, Wistar rats underwent permanent occlusion of bilateral common carotid arteries to induce CCH. 2D-DIGE combined with MALDI-TOF MS was applied to determine the proteins that were differentially expressed in synaptosomes of prefrontal cortex and hippocampus. ATPsynbeta, NDUFS1, UQCRC1 and Hsp70 were elevated both in synaptosomes of cortex and hippocampus at week 2 after operation, but subsided to baseline at week 4 except ATPsynbeta which was still upregulated in synaptosomes of hippocampus at week 4. IDH3A and PDC-E2 were increased, respectively, in synaptosomes of prefrontal cortex and hippocampus at week 2, and showed no difference when compared to control at week 4. Malate dehydrogenase showed no difference in synaptosomes of prefrontal cortex and hippocampus at week 2, but showed an elevation in synaptosomes of prefrontal cortex at week 4. Our results imply that metabolic reserve and anti-oxidative stress might transiently exist in the early stage of CCH, which probably help cognitive save. PMID- 22526758 TI - Electroacupuncture improves behavioral recovery and increases SCF/c-kit expression in a rat model of focal cerebral ischemia/reperfusion. AB - This study aims to investigate the mechanism of electroacupuncture (EA) in promoting behavioral recovery after focal cerebral ischemia/reperfusion. The SD rats received filament occlusion of the right middle cerebral artery for 2 h followed by reperfusion for 1, 3, 7, 14, and 21 days, respectively. Rats were randomly divided into sham group, model group and EA group. After 2 h of the reperfusion, EA was given at bilateral "Hegu" point (LI 4) in the EA group. Neurobehavioral evaluation, the expression of stem cell factor (SCF), its receptor c-kit and matrix metalloproteinase-9 (MMP-9) protein and mRNA in the cortical ischemic region were measured. EA treatment can improve behavioral recovery after ischemia/reperfusion. Compared with the sham group, the positive cells and mRNA expression of SCF, c-kit, MMP-9, the protein expression of SCF were increased significantly in the model and EA groups (P < 0.001). Compared with the model group, the positive cells, protein and mRNA expression of SCF were increased significantly in EA groups (P < 0.01). The positive cells and mRNA expression of c-kit were increased in EA groups beginning at 3 day and remained significantly high thereafter. The expression of MMP-9 positive cells and mRNA were deceased significantly in the 1 day subgroup in EA (P < 0.01), but increased significantly in the 3, 7 days subgroups (P < 0.01). We conclude that EA treatment up-regulates the positive cells and mRNA expression of SCF, c-kit and MMP-9 after cerebral ischemia/reperfusion. EA may promote neurobehavioral recovery by increasing the protein and mRNA expression of SCF, c-kit and MMP-9 after cerebral ischemia/reperfusion. PMID- 22526759 TI - Isolated pons variant of posterior reversible encephalopathy syndrome complicated with ischemic stroke in a young patient. PMID- 22526760 TI - Validity of the Italian version of the Pittsburgh Sleep Quality Index (PSQI). AB - The aim of this study is to validate the Italian version of the Pittsburgh Sleep Quality Index (PSQI), comparing five different groups of individuals (healthy young and elderly, sleep apnoea syndrome patients, depressed patients, individuals with dementia) by both questionnaire scores and polysomnographic measures. Fifty individuals (10 for each group) participated in the study. Each of them filled in the PSQI and slept for two consecutive nights in the sleep laboratory. The PSQI showed an overall reliability coefficient (Cronbach's alpha) of 0.835, indicating a high degree of internal consistency. The mean PSQI global score showed significant differences between groups, with an impaired overall quality of sleep in patients' groups with respect to both the healthy groups. Results also indicated that the best cut-off score (differentiating "good" from "bad" sleepers) is 5. Pittsburgh Sleep Quality Index is a useful, valid and reliable tool for the assessment of sleep quality, with an overall efficiency comparable to the mother language version and differentiate "good" from "bad" sleepers. The Italian version of the questionnaire provides a good and reliable differentiation between normal and pathological groups, with higher scores reported by people characterized by impaired objectively evaluated sleep quality. PMID- 22526762 TI - Early MRI findings in acquired hepatocerebral degeneration. PMID- 22526761 TI - Iowa Gambling Task in patients with early-onset Parkinson's disease: strategy analysis. AB - The aim of our study was to analyse decision making in early-onset Parkinson's disease (PD) patients performing the Iowa Gambling Task (IGT). We compared 19 patients with early-onset PD (<= 45 years) on dopaminergic medication (no evidence of depression, dementia, executive dysfunction according to the Tower of London test and the Stroop test, or pathological gambling) with 20 age-matched controls. A computer version of the IGT was employed. The PD patients achieved slightly lower IGT scores than the control group. A detailed analysis based on 'shift frequencies' between the individual decks showed that the patients tended to change their preferences for the decks more frequently, with a higher preference for the 'disadvantageous' deck B. Control subjects seemed to develop a more effective strategy. These differences could be caused by the poorer ability of the patients to develop any strategy at all. We observed changes in decision making during IGT performance in patients with early-onset PD, although they had no executive dysfunction as measured by established neuropsychological tests. The more detailed analysis employed in the present study could lead to a more accurate study of IGT performance and application of IGT in clinical practice. PMID- 22526763 TI - Natalizumab is effective in multiple sclerosis patients switching from other disease modifying therapies in clinical practice. AB - Natalizumab is one option for multiple sclerosis patients responding poorly to classical immunomodulators, but pilot studies did not point to its effectiveness as a second-line therapy. Aim of this study was to assess the efficacy of natalizumab as second-line therapy in patients switching from disease modifying therapies (DMTs) in a clinical setting. We retrospectively selected patients who had been treated with natalizumab for at least 12 months after switching from one or more DMTs. We collected clinical and neuroradiological data and we analysed the reduction in annualised relapse rate (ARR), the change of Expanded Disability Status Scale (EDSS) and the reduction of contrast-enhancing lesions (CELs) at magnetic resonance imaging (MRI) of the brain at 12 months of natalizumab and of previous DMT therapy. Fifty patients were included in the analysis (11 males, 39 females).We observed a reduction of ARR on natalizumab (p = 0.000) and a statistically significant different trend of relapse event between the two treatments (p = 0.0149). EDSS was stable during natalizumab therapy whilst it showed an increase on DMTs (p = 0.0244). The number of CELs decreased significantly (p = 0.006) during the 12 months of treatment with natalizumab, whilst it was stable on DMTs. Natalizumab showed to decrease ARR, stabilize EDSS, increase the percentage of CELs free patients and decrease the number of CELs in a group of 50 poor responders to classical DMT, after the first 12 months of therapy. PMID- 22526764 TI - Dropped head syndrome in early-onset Parkinson disease treated with bilateral subthalamic stimulation: clinical, imaging, EMG, and biopsy findings. PMID- 22526765 TI - Hypofractionated frameless stereotactic intensity-modulated radiotherapy with whole brain radiotherapy for the treatment of 1-3 brain metastases. AB - The aim of the study is to evaluate the efficacy and toxicity of hypofractionated frameless stereotactic radiotherapy (HSRT) with whole brain radiotherapy (WBRT) for the treatment of 1-3 brain metastases. 38 patients with a total of 58 brain metastases were treated at Ghent University Hospital with WBRT (10 * 3 Gy) followed by HSRT (5 * 6 Gy). Patients with RPA class I (n = 8) and II (n = 30) were eligible for HSRT. Acute toxicity was scored with the RTOG toxicity criteria. Response rates were scored every 3 months using the McDonald criteria. Overall survival (OS), brain-specific survival, local and distant brain control were calculated using the Kaplan-Meier method. Patient (age, Karnofsky performance score, KPS, RPA class) and tumor characteristics (number of lesions, extracranial metastases, brain tumor volume, primary cancer status, histology) were tested in univariate and multivariate analysis. Survival at 6 and 12 months was 65 and 35 %, respectively. On univariate analysis KPS < 90, number of lesions, a histologic diagnosis of adenocarcinoma and uncontrolled primary cancer status were statistic significant predictors for poor OS. Four patients (11 %) developed a grade 3 toxicity. Rates of complete remission, partial remission, no change and progressive disease were 30, 40, 23 and 5 %, respectively. Median survival was 7.6 months. The actuarial brain-specific survival was 97 % at 6 months and 91 % at 1 year of follow-up. The 1-year actuarial local and distant brain control was 66 and 75 %, respectively. WBRT + HSRT is an effective treatment for patients with up to three brain metastases. PMID- 22526766 TI - Elevated levels of S100B, tau and pNFH in cerebrospinal fluid are correlated with subtypes of Guillain-Barre syndrome. AB - Guillain-Barre syndrome (GBS) is an immune-mediated inflammatory disease in the peripheral nervous system. Specific biomarkers for the two most common clinical subtypes of GBS, i.e., acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN) are still missing. The distinctive pathological features of AIDP and AMAN may lead to release of such specific biomarkers including glial markers (calcium-binding astroglial protein, S100B) and axonal damage markers [axoskeletal protein, phosphorylated neurofilament heavy protein (pNFH); cytoskeletal protein, tau], etc. To explore the potentials of biochemical markers for differential diagnosis and evaluation of prognosis of clinical subtypes in GBS, we used ELISA to measure the levels of S100B, tau and pNFH in serum and cerebrospinal fluid (CSF) from the patients with AIDP, AMAN, viral encephalitis and other non-inflammatory neurological disorders (OND), respectively. The values of albumin quotient and IgG index in CSF are significantly higher in AIDP and AMAN than in OND. The levels of S100B, tau and pNFH in serum and CSF are elevated in the patients with AIDP and AMAN compared to OND. The concentrations of these proteins are all higher in CSF than in serum. Increased levels of S100B in CSF at the acute phase are positively correlated with the GBS disability scale scores (GDSs) in AIDP, whereas enhanced levels of tau and pNFH in CSF are positively correlated with the GDSs in AMAN. Increased CSF levels of S100B, tau and pNFH at the acute phase may predict a poor prognosis and evaluate the severity of AIDP or AMAN at plateau and the recovery phase. Elevated levels of pNFH in CSF may be used for differentiating between AMAN and AIDP. PMID- 22526767 TI - Relationship between thresholds to convulsions induced by a benzodiazepine inverse agonist and [3H]-L-glutamate binding in the membranes of brain regions. AB - Although some studies have investigated the influence of kindling model of epilepsy on the glutamatergic neurotransmission, the relation between glutamatergic receptors and seizure susceptibility remains unclear. The present study sought to determine if rats with high (HTR) and low (LTR) thresholds to clonic convulsions induced by the benzodiazepine inverse agonist DMCM differed in the [(3)H]-L-glutamate binding to membranes from discrete brain regions. Compared to the HTR subgroup, the LTR subgroup presented a lower binding of [(3)H]-L glutamate in the hippocampus, frontal cortex and amygdala plus limbic cortex, suggesting that glutamatergic receptors in these brain regions may underlie the susceptibility to DMCM-induced convulsions. PMID- 22526768 TI - Aneurysms of the medullary segments of the posterior-inferior cerebellar artery: considerations on treatment strategy and clinical outcome. AB - Proximal aneurysms of the medullary postero-inferior cerebellar artery (PICA) tract are peculiar due to critical anatomical location, small size and tortuosity of the parent vessel, close origin to brainstem perforators, and fragility of the sac wall. Moreover, most patients present after bleeding, increasing the challenges. Aim of this study is to evaluate the treatment modality and outcome of these patients during the last decade at the University Clinic of Torino. Databases of the Neurosurgical and Neuroradiological Department of the University of Torino were analyzed to retrieve patients treated for aneurysms of the medullary PICA tract. Charts and neuroradiological documentation were revised to complete the database. Of 621 patients treated for an intracranial aneurysm, 23 had PICA aneurysm, 18 located at the medullary tract. Only two were unruptured and 16 were ruptured aneurysms. Sixteen underwent endovascular treatment and two underwent surgery. In six cases the aneurysm was cured by parent vessel occlusion. At 6 months follow-up, the Glasgow outcome scale was high (5 and 4) in 16 patients; two patients had died in the acute phase, for reasons unrelated to the procedure. If not adequately compensated, parent vessel occlusion associates with high risks of ischemia and related brain swelling. In the present series sufficient collateral flow contributed to a good tolerance toward occlusion in all cases. Despite the small size of the present series, most treated cases presented a good outcome. Nevertheless, distal revascularization of the occluded artery would be indicated where collateral flow is insufficient. PMID- 22526769 TI - Hypoglycemia-induced hemichorea in a patient with Fahr's syndrome. AB - Non-ketotic hyperglycemia may be a cause of hemiballism-hemichorea. We present an elderly female type II diabetic patient with right-sided hemiballism-hemichorea of acute onset during hypoglycemia following insulin overtreatment of non-ketotic hyperglycemia. Brain computerized tomography and magnetic resonance imaging scans revealed characteristic hyperdensity and T1 hyperintensity, respectively, in the left basal ganglia, in addition to pallido-dentate calcifications, suggestive of Fahr's syndrome. Although extremely rare, hypoglycemia may be a cause of hemiballism-hemichorea especially in the presence of predisposing factors such as previous hyperglycemic episodes and Fahr's syndrome. PMID- 22526770 TI - Degeneration of peripheral nervous system in rats experimentally induced by methylmercury intoxication. AB - The objective of this study is to elucidate the primary action of methylmercury chloride (MMC) intoxication on peripheral nervous system. We chronologically observed the pathological changes of sciatic nerve, dorsal root ganglion (DRG) neurons, ventral and dorsal roots in rats given 4 mg/kg/day of MMC on consecutive days and killed on days 11, 15, 18 and 21. On day 11, an initial axonal degeneration of type B neuron occurred, predominantly in the distal portions of sciatic nerve. The DRG type A neuron was infiltrated by MRF-1-positive macrophages on day 11. Electron microscopy also demonstrated degenerated mitochondria in type A neuron. On day 21, most of type A neurons seemed to have disappeared. However, type B neurons were well preserved. Immunoblotting with monoclonal antibodies, P0 and neurofilament, demonstrated that both of proteins significantly decreases from day 15. In conclusion, these results indicate that the primary action on type A neuron is the neuron body that consequently results in an anterograde degeneration of nerve fibers, while the type B neuron degeneration occurs in a dying-back process in this subacute model. These findings suggest that the mechanisms involved in the degeneration induced by MMC vary and may depend on certain intrinsic factors peculiar to these neurons. PMID- 22526771 TI - Practice of yoga may cause damage of both sciatic nerves: a case report. AB - Sciatic nerve traumatic damage very rarely occurs bilaterally. We describe the case of a 67-year-old woman who reported a bilateral traumatic lesion of the sciatic nerve during practice of yoga. Nerve conduction studies showed a bilateral sciatic nerve neuropathy, mostly affecting the peroneal component. Lumbar plexus MRI documented regular anatomical features of the main principal nerve roots with bilateral T2 signal alteration of roots L4, L5 and S1 that extended into the sciatic nerves showing both increase in size, probably related to chronic injury of nerves, and an alteration in diffusion signal that suggested a recent acute overlapped process. PMID- 22526773 TI - Organosilicon-mediated regioselective acetylation of carbohydrates. AB - Organosilicon-mediated, regioselective acetylation of vicinal- and 1,3-diols is presented. Methyl trimethoxysilane or dimethyl dimethoxysilane was first used to form cyclic 1,3,2-dioxasilolane or 1,3,2-dioxasilinane intermediates, and subsequent acetate-catalyzed monoacylation was efficiently performed by addition of acetic anhydride or acetyl chloride under mild conditions. The reaction exhibited high regioselectivity, resulting in the same protection pattern as in organotin-mediated schemes. PMID- 22526774 TI - Modeling of permeabilization process in Pseudomonas putida G7 for enhanced limonin bioconversion. AB - A facile process of enhanced whole cell biotransformation to debitter the triterpenoid limonin in citrus juices was optimized in this work. To maximize bioconversion, permeabilization conditions were modeled using response surface methodology. A central composite rotatable design with four significant variables (concentration, temperature, pH, and treatment time) was employed. The second order polynomial equations with R2 values above 0.9 showed good correspondence between experimental and predicted values. The concentration, temperature, pH, and treatment time as well as their interactions had significant effects (p < 0.001) on limonin bioconversion. The optimum operating conditions for permeabilization were observed at a Na2EDTA concentration of 1.5 MUM, treatment time of 15 min, temperature of 28 degrees C, and pH 8. A maximum reduction of 76.71% in the limonin content was achieved within 150 min under selected conditions. The results are promising for refining permeabilization technique for whole cell biocatalysts thereby improving the debittering of citrus juices significantly. PMID- 22526775 TI - Effect of COD/N ratio on cultivation of aerobic granular sludge in a pilot-scale sequencing batch reactor. AB - Aerobic granular sludge was successfully cultivated with the effluent of internal circulation reactor in a pilot-scale sequencing batch reactor (SBR). Soy protein wastewater was used as an external carbon source for altering the influent chemical oxygen demand/nitrogen (COD/N) ratios of SBR. Initially, the phenomenon of partial nitrification was observed and depressed by increasing the influent COD/N ratios from 3.32 to 7.24 mg/mg. After 90 days of aerobic granulation, the mixed liquor suspended solids concentration of the reactor increased from 2.80 to 7.02 g/L, while the sludge volumetric index decreased from 105.51 to 42.99 mL/g. The diameters of mature aerobic granules vary in the range of 1.2 to 2.0 mm. The reactor showed excellent removal performances for COD and N4+--N after aerobic granulation, and average removal efficiencies were over 93% and 98%, respectively. The result of this study could provide further information on the development of aerobic granule-based system for full-scale applications. PMID- 22526776 TI - Expression analysis of the spi gene in the pock-forming plasmid pSA1.1 from Streptomyces azureus and localization of its product during differentiation. AB - The sporulation inhibitory gene spi in the pock-forming conjugative plasmid pSA1.1 of Streptomyces azureus was introduced into cells via a high or low copy number vector to examine the effect of gene dosage on the growth of Streptomyces lividans TK24 as a host. In transformants carrying a high spi copy number, nutrient mycelial growth was inhibited, as was morphological differentiation from substrate mycelium to aerial mycelium on solid media. The degree of inhibition depended on the spi gene dosage, but the presence of pSA1.1 imp genes, which encode negative repressor proteins for spi, relieved the inhibition. Confocal images of Spi tagged with enhanced green fluorescent protein in cells on solid media revealed that spi expression was initiated at the time of elongation of substrate mycelium, that its expression increased dramatically at septation in aerial hyphae, and that the expression was maximal during prespore formation. Expression of spi covered the whole of the hyphae, and the level of expression at the tip of the hyphae during prespore formation was about sixfold greater than during substrate mycelial growth and threefold greater than during aerial mycelial growth. Thus, localized expression of spi at particular times may inhibit sporulation until triggering imp expression to repress its inhibitory effects. PMID- 22526778 TI - Prokaryotic squalene-hopene cyclases can be converted to citronellal cyclases by single amino acid exchange. AB - Squalene-hopene cyclases (SHCs) are prokaryotic enzymes that catalyse the cyclisation of the linear precursor squalene to pentacyclic hopene. Recently, we discovered that a SHC cloned from Zymomonas mobilis (ZMO-1548 gene product) has the unique property to cyclise the monoterpenoid citronellal to isopulegol. In this study, we performed saturation mutagenesis of three amino acids of the catalytic centre of ZMO-1548 (F428, F486 and W555), which had been previously identified to interact with enzyme-bound substrate. Replacement of F428 by tyrosine increased hopene formation from squalene, but isopulegol-forming activity was strongly reduced or abolished in all muteins of position 428. W555 was essential for hopene formation; however, three muteins (W555Y, W428F or W555T) revealed enhanced cyclisation efficiency with citronellal. The residue at position 486 turned out to be the most important for isopulegol-forming activity. While the presence of phenylalanine or tyrosine favoured cyclisation activity with squalene, several small and/or hydrophobic residues such as cysteine, alanine or isoleucine and others reduced activity with squalene but greatly enhanced isopulegol formation from citronellal. Replacement of the conserved aromatic residue corresponding to F486 to cysteine in other SHCs cloned from Z. mobilis (ZMO-0872), Alicyclobacillus acidocaldarius (SHC(Aac)), Acetobacter pasteurianus (SHC(Apa)), Streptomyces coelicolor (SHC(Sco)) and Bradyrhizobium japonicum (SHC(Bja)) resulted in more or less strong isopulegol-forming activities from citronellal. In conclusion, many SHCs can be converted to citronellal cyclases by mutagenesis of the active centre thus broadening the applicability of this interesting class of biocatalyst. PMID- 22526779 TI - Bioenergetics for the growth of Staphylococcus lentus in biocompatible choline salts. AB - Choline-based biocompatible salts were used as "nutrients" for the growth of Staphylococcus lentus bacteria. Increase in the growth rate of bacteria was observed, compared to conventional carbon sources. In the case of the ionic liquid, choline lactate, the increase was pronounced. Bacterial growth was correlated with power-time curve in an investigation monitored online by reaction calorimetry. From the power-time curve, three phases of the growth can be distinctly seen. Heat yield coefficients estimated for the growth of S. lentus were found to match well with those reported hitherto. A comparative study of heat yields (catabolic) between glucose and choline lactate revealed significant information; the heat yield due to choline lactate (Y (Q/S)) consumption and oxygen (Y (Q/O)) were 23.4 kJ/g and 435 kJ/mol and whereas that for glucose with oxygen were 9.6 kJ/g and 427 kJ/mol, respectively, showing clearly the preferential affinity of choline lactate by the bacteria rather than glucose. This study also established that the use of ionic liquids as nutrients can be monitored using bioreaction calorimetry. PMID- 22526780 TI - Heterologous expression and structural characterization of two low pH laccases from a biopulping white-rot fungus Physisporinus rivulosus. AB - The lignin-degrading, biopulping white-rot fungus Physisporinus rivulosus secretes several laccases of distinct features such as thermostability, extremely low pH optima and thermal activation for oxidation of phenolic substrates. Here we describe the cloning, heterologous expression and structural and enzymatic characterisation of two previously undescribed P. rivulosus laccases. The laccase cDNAs were expressed in the methylotrophic yeast Pichia pastoris either with the native or with Saccharomyces cerevisiae alpha-factor signal peptide. The specific activity of rLac1 and rLac2 was 5 and 0.3 MUkat/MUg, respectively. However, mutation of the last amino acid in the rLac2 increased the specific laccase activity by over 50-fold. The recombinant rLac1 and rLac2 enzymes demonstrated low pH optima with both 2,6-dimethoxyphenol (2,6-DMP) and 2,2'-azino-bis(3 ethylbenzathiazoline-6-sulfonate). Both recombinant laccases showed moderate thermotolerance and thermal activation at +60 degrees C was detected with rLac1. By homology modelling, it was deduced that Lac1 and Lac2 enzymes demonstrate structural similarity with the Trametes versicolor and Trametes trogii laccase crystal structures. Comparison of the protein architecture at the reducing substrate-binding pocket near the T1-Cu site indicated the presence of five amino acid substitutions in the structural models of Lac1 and Lac2. These data add up to our previous reports on laccase production by P. rivulosus during biopulping and growth on Norway spruce. Heterologous expression of the novel Lac1 and Lac2 isoenzymes in P. pastoris enables the detailed study of their properties and the evaluation of their potential as oxidative biocatalysts for conversion of wood lignin, lignin-like compounds and soil-polluting xenobiotics. PMID- 22526781 TI - Antituberculars which target decaprenylphosphoryl-beta-D-ribofuranose 2'-oxidase DprE1: state of art. AB - Multidrug resistance is a major barrier in the battle against tuberculosis and still a leading cause of death worldwide. In order to fight this pathogen, two routes are practicable: vaccination or drug treatment. Vaccination against Mycobacterium tuberculosis with the current vaccine Mycobacterium bovis Bacillus Calmette-Guerin is partially successful, being its efficacy variable. A few new tuberculosis vaccines are now in various phases of clinical trials. The emergence of multidrug-resistant strains of M. tuberculosis gave the impulse to discover new effective antitubercular drugs, a few of which are in clinical development. Here we focus on three different classes of very promising antitubercular drugs recently discovered (benzothiazinones, dinitrobenzamides, and benzoquinoxalines) that share the same cellular target: a subunit of the heteromeric decaprenylphosphoryl-beta-D: -ribose 2'-epimerase, encoded by the dprE1 (or Rv3790) gene. This enzyme is involved in the biosynthesis of D: -arabinose which is crucial for the synthesis of the mycobacterial cell wall and essential for the pathogen's survival. PMID- 22526782 TI - Characterization of porcine circovirus type 2 (PCV2) capsid particle assembly and its application to virus-like particle vaccine development. AB - Porcine circovirus type 2 (PCV2) is the primary causative agent of porcine circovirus-associated diseases in pigs. The sole structural capsid protein of PCV2, Cap, consists of major antigenic domains, but little is known about the assembly of capsid particles. The purpose of this study is to produce a large amount of Cap protein using Escherichia coli expression system for further studying the essential sequences contributing to formation of particles. By using codon optimization of rare arginine codons near the 5'-end of the cap gene for E. coli, a full-length Cap without any fusion tag recombinant protein (Cap1-233) was expressed and proceeded to form virus-like particles (VLPs) in normal Cap appearance that resembled the authentic PCV2 capsid. The N-terminal deletion mutant (Cap51-233) deleted the nuclear localization signal (NLS) domain, while the internal deletion mutant (CapDelta51-103) deleted a likely dimerization domain that failed to form VLPs. The unique Cys108 substitution mutant (CapC/S) exhibited most irregular aggregates, and only few VLPs were formed. These results suggest that the N-terminal region within the residues 1 to 103 possessing the NLS and dimerization domains are essential for self-assembly of stable Cap VLPs, and the unique Cys108 plays an important role in the integrity of VLPs. The immunogenicity of PCV2 VLPs was further evaluated by immunization of pigs followed by challenge infection. The Cap1-233-immunized pigs demonstrated specific antibody immune responses and are prevented from PCV2 challenge, thus implying its potential use for a VLP-based PCV2 vaccine. PMID- 22526777 TI - General and rare bacterial taxa demonstrating different temporal dynamic patterns in an activated sludge bioreactor. AB - Temporal variation of general and rare bacterial taxa was investigated using pyrosequencing of 16S rRNA gene from activated sludge samples collected bimonthly for a two-year period. Most of operational taxonomic units (OTUs) were allocated to rare taxa (89.6%), but the rare taxa comprised a small portion of the community in terms of abundance of sequences analyzed (28.6%). Temporal variations in OTUs richness significantly differed between the two taxa groups in which the rare taxa showed a higher diversity and a more fluctuating pattern than the general taxa. Furthermore, the two taxa groups were constrained by different explanatory variables: influent BOD, effluent BOD, and DO were the significant (P < 0.05) parameters affecting the pattern of the general taxa, while temperature was the factor for the rare taxa. Over the test period, the general taxa persisted for a longer time (i.e., lower turnover rate) in the bioreactor than the rare taxa. In conclusion, this study demonstrated clear differences in temporal dynamic patterns for the general and rare bacterial taxa in an activated sludge bioreactor, which would be a foundation for better understanding the bacterial ecology of activated sludge. PMID- 22526783 TI - Molecular cloning, characterization, and engineering of xylitol dehydrogenase from Debaryomyces hansenii. AB - Because of its natural ability to utilize both xylose and arabinose, the halotolerant and osmotolerant yeast Debaryomyces hansenii is considered as a potential microbial platform for exploiting lignocellulosic biomass. To gain better understanding of the xylose metabolism in D. hansenii, we have cloned and characterized a xylitol dehydrogenase gene (DhXDH). The cloned gene appeared to be essential for xylose metabolism in D. hansenii as the deletion of this gene abolished the growth of the cells on xylose. The expression of DhXDH was strongly upregulated in the presence of xylose. Recombinant DhXdhp was expressed and purified from Escherichia coli. DhXdhp was highly active against xylitol and sorbitol as substrate. Our results showed that DhXdhp was thermo-sensitive, and except this, its biochemical properties were quite comparable with XDH from other yeast species. Furthermore, to make this enzyme suitable for metabolic engineering of D. hansenii, we have improved its thermotolerance and modified cofactor requirement through modelling and mutagenesis approach. PMID- 22526784 TI - Rhizocompetence and antagonistic activity towards genetically diverse Ralstonia solanacearum strains--an improved strategy for selecting biocontrol agents. AB - Bacterial wilt caused by Ralstonia solanacearum is a serious threat for agricultural production in China. Eight soil bacterial isolates with activity against R. solanacearum TM15 (biovar 3) were tested in this study for their in vitro activity towards ten genetically diverse R. solanacearum isolates from China. The results indicated that each antagonist showed remarkable differences in its ability to in vitro antagonize the ten different R. solanacearum strains. Strain XY21 (based on 16S rRNA gene sequencing affiliated to Serratia) was selected for further studies based on its in vitro antagonistic activity and its excellent rhizocompetence on tomato plants. Under greenhouse conditions XY21 mediated biocontrol of tomato wilt caused by seven different R. solanacearum strains ranged from 19 to 70 %. The establishment of XY21 and its effects on the bacterial community in the tomato rhizosphere were monitored by denaturing gradient gel electrophoresis of 16S rRNA gene fragments PCR-amplified from total community DNA. A positive correlation of the in vitro antagonistic activities of XY21 and the actual biocontrol efficacies towards seven genetically different R. solanacearum strains was found and further confirmed by the efficacy of XY21 in controlling bacterial wilt under field conditions. PMID- 22526785 TI - Agar degradation by microorganisms and agar-degrading enzymes. AB - Agar is a mixture of heterogeneous galactans, mainly composed of 3,6-anhydro-L galactoses (or L-galactose-6-sulfates) D-galactoses and L-galactoses (routinely in the forms of 3,6-anhydro-L-galactoses or L-galactose-6-sulfates) alternately linked by beta-(1,4) and alpha-(1,3) linkages. It is a major component of the cell walls of red algae and has been used in a variety of laboratory and industrial applications, owing to its jellifying properties. Many microorganisms that can hydrolyze and metabolize agar as a carbon and energy source have been identified in seawater and marine sediments. Agarolytic microorganisms commonly produce agarases, which catalyze the hydrolysis of agar. Numerous agarases have been identified in microorganisms of various genera. They are classified according to their cleavage pattern into three types-alpha-agarase, beta-agarase, and beta-porphyranase. Although, in a broad sense, many other agarases are involved in complete hydrolysis of agar, most of those identified are beta agarases. In this article we review agarolytic microorganisms and their agar hydrolyzing systems, covering beta-agarases as well as alpha-agarases, alpha neoagarobiose hydrolases, and beta-porphyranases, with emphasis on the recent discoveries. We also present an overview of the biochemical and structural characteristics of the various types of agarases. Further, we summarize and compare the agar-hydrolyzing systems of two specific microorganisms: Gram negative Saccharophagus degradans 2-40 and Gram-positive Streptomyces coelicolor A3(2). We conclude with a brief discussion of the importance of agarases and their possible future application in producing oligosaccharides with various nutraceutical activities and in sustainably generating stock chemicals for biorefinement and bioenergy. PMID- 22526787 TI - Cytochrome P450 reductase from Candida apicola: versatile redox partner for bacterial P450s. AB - Candida apicola belongs to a group of yeasts producing surface-active glycolipids consisting of sophorose and long-chain (omega)- or (omega-1)-hydroxy fatty acids. Hydroxylation of the fatty acids in this strain is likely catalyzed by cytochrome P450 monooxygenases (P450), which require reducing equivalents delivered via a cytochrome P450-diflavin reductase (CPR). We herein report cloning and characterization of the cpr gene from C. apicola ATCC 96134. The gene encoding a protein of 687 amino acids was cloned in Escherichia coli and the enzyme was expressed in functional form after truncation of its N-terminal putative membrane anchor. The truncated recombinant protein showed cytochrome c reducing activity (K (M) of 13.8 MUM and k (cat) of 1,915 per minute). Furthermore, we herein demonstrate to our best knowledge for the first time the use of a eukaryotic CPR to transfer electrons to bacterial P450s (namely CYP109B1 and CYP154E1). Cloning and characterization of this CPR therefore is not only an important step in the study of the P450 systems of C. apicola, but also provides a versatile redox partner for the characterization of other bacterial P450s with appealing biotechnological potential. The GenBank accession number of the sequence described in this article is JQ015264. PMID- 22526786 TI - Comparative analysis of bacterial community and antibiotic-resistant strains in different developmental stages of the housefly (Musca domestica). AB - The housefly (Musca domestica) is an important host for a variety of bacteria, including some pathogenic and antibiotic-resistant strains. To further investigate the relationship between the housefly and the bacteria it harbors, it is necessary to understand the fate of microorganisms during the larval metamorphosis. The major bacterial communities in three developmental stages of the housefly (maggot, pupa, and adult fly) were investigated by a culture independent method, polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) analysis of 16S rRNA genes. The bacteria that were identified using DGGE analysis spanned phyla Proteobacteria, Firmicutes, and Bacteroidetes. Changes in the predominant genera were observed during the housefly development. Bacteroides, Koukoulia, and Schineria were detected in maggots, Neisseria in pupae, and Macrococcus, Lactococcus, and Kurthia in adult flies. Antibiotic-resistant bacteria were screened using a selective medium and tested for antibiotic susceptibility. Most resistant isolates from maggots and pupae were classified as Proteus spp., while those from adult flies were much more diverse and spanned 12 genera. Among 20 tested strains across the three stages, 18 were resistant to at least two antibiotics. Overall, we demonstrated that there are changes in the major bacterial communities and antibiotic resistant strains as the housefly develops. PMID- 22526788 TI - The mitogen-activated protein kinase kinase kinase BcOs4 is required for vegetative differentiation and pathogenicity in Botrytis cinerea. AB - The high-osmolarity glycerol signal pathway plays an important role in the response of fungi to various environmental stresses. In this study, we characterized a mitogen-activated protein kinase kinase kinase gene BcOS4 in Botrytis cinerea, which is homologous to Saccharomyces cerevisiae SSK2/SSK22. The BcOS4 deletion mutant was significantly impaired in vegetative growth and conidial formation. The mutant exhibited increased sensitivity to the osmotic, oxidative stresses and to the fungicides iprodione and fludioxonil. Western blot analysis showed that BcSak1, a putative downstream component of BcOs4, was not phosphorylated in the mutant. In addition, the BcOS4 mutant was unable to infect leaves of rapeseed and cucumber, and grape fruits, although it can cause disease on apple fruits. All the defects were restored by genetic complementation of the BcOS4 deletion mutant with the wild-type BcOS4 gene. The data of this study indicate that BcOS4 is involved in vegetative differentiation, virulence, adaption to hyperosmotic and oxidative stresses, and to fungicides in B. cinerea. PMID- 22526789 TI - Characterization of Lactobacillus salivarius CECT 5713, a strain isolated from human milk: from genotype to phenotype. AB - Lactobacillus salivarius CECT 5713, isolated from human milk, has immunomodulatory, anti-inflammatory and antiinfectious properties, as revealed by several in vitro and in vivo assays, which suggests a strong potential as a probiotic strain. In this work, the relationships between several genetic features of L. salivarius CECT 5713 and the corresponding phenotypes were evaluated. Although it contains a plasmid-encoded bacteriocin cluster, no bacteriocin biosynthesis was observed, possibly due to a 4-bp deletion at the beginning of the histidine kinase determinant abpK. The genome of L. salivarius CECT 5713 harbours two apparently complete prophages of 39.6 and 48 kbp. Upon induction, the 48-kbp prophage became liberated from the bacterial genome, but no DNA replication took place, which resulted in lysis of the cultures but not in phage progeny generation. The strain was sensitive to most antibiotics tested and no transmissible genes potentially involved in antibiotic resistance were detected. Finally, the genome of L. salivarius CECT 5713 contained four ORFs potentially involved in human molecular mimetism. Among them, protein 1230 was considered of particular relevance because of its similarity with dendritic cell related proteins. Subsequently, in vitro assays revealed the ability of L. salivarius CECT 5713 to stimulate the maturation of immature dendritic cells and to inhibit the in vitro infectivity of HIV-1. PMID- 22526790 TI - Metabolic engineering of Rhizopus oryzae for the production of platform chemicals. AB - Rhizopus oryzae is a filamentous fungus belonging to the Zygomycetes. It is among others known for its ability to produce the sustainable platform chemicals L: (+)-lactic acid, fumaric acid, and ethanol. During glycolysis, all fermentable carbon sources are metabolized to pyruvate and subsequently distributed over the pathways leading to the formation of these products. These platform chemicals are produced in high yields on a wide range of carbon sources. The yields are in excess of 85 % of the theoretical yield for L: -(+)-lactic acid and ethanol and over 65 % for fumaric acid. The study and optimization of the metabolic pathways involved in the production of these compounds requires well-developed metabolic engineering tools and knowledge of the genetic makeup of this organism. This review focuses on the current metabolic engineering techniques available for R. oryzae and their application on the metabolic pathways of the main fermentation products. PMID- 22526791 TI - Impaired dendritic cell maturation and IL-10 production following H. pylori stimulation in gastric cancer patients. AB - The current study was to investigate the interaction between Helicobacter pylori and human dendritic cells (DCs). Whether impaired DC function can influence the outcome of H. pylori infections. Human monocyte-derived DCs (MDDCs) from five gastric cancer patients and nine healthy controls were stimulated with H. pylori. Maturation markers of MDDC were examined by flow cytometry. IL-10 and TNF-alpha released by MDDCs and IL-17 produced by T cells were measured by ELISA. Regulatory signaling pathways of IL-10 were examined by ELISA, western blotting, and chromatin immunoprecipitation assay. The results showed that as compared with healthy individuals, the maturation marker CD40 in MDDCs, IL-17A expression from T cells, and IL-10 expression from MDDCs were significantly lower in gastric cancer patients. Blocking DC-SIGN, TLR2, and TLR4 could reverse H. pylori associated IL-10 production. Activation of the p38 MAPK and NF-kB signaling pathways concomitant with decreased tri-methylated H3K9 and increased acetylated H3 accounted for the effect of H. pylori on IL-10 expression. Furthermore, upregulated IL-10 expression was significantly suppressed in H. pylori-pulsed MDDCs by histone acetyltransferase and methyltransferase inhibitors. Taken together, impaired DC function contributes to the less effective innate and adaptive immune responses against H. pylori seen in gastric cancer patients. H. pylori can regulate IL-10 production through Toll-like and DC-SIGN receptors, activates p-p38 MAPK signaling and the transcription factors NF-kB, and modulates histone modification. PMID- 22526792 TI - Engineering of LadA for enhanced hexadecane oxidation using random- and site directed mutagenesis. AB - LadA, a monooxygenase catalyzing the oxidation of n-alkanes to 1-alkanols, is the key enzyme for the degradation of long-chain alkanes (C(15)-C(36)) in Geobacillus thermodenitrificans NG80-2. In this study, random- and site-directed mutagenesis were performed to enhance the activity of the enzyme. By screening 7,500 clones from random-mutant libraries for enhanced hexadecane hydroxylation activity, three mutants were obtained: A102D, L320V, and F146C/N376I. By performing saturation site-directed mutagenesis at the 102, 320, 146, and 376 sites, six more mutants (A102E, L320A, F146Q/N376I, F146E/N376I, F146R/N376I, and F146N/N376I) were generated. Kinetic studies showed that the hydroxylation activity of purified LadA mutants on hexadecane was 2-3.4-fold higher than that of the wild-type enzyme, with the activity of F146N/N376I being the highest. Effects of the mutations on optimum temperature, pH, and heat stability of LadA were also investigated. A complementary study showed that Pseudomonas fluorescens KOB2Delta1 strains expressing the LadA mutants grew more rapidly with hexadecane than the strain expressing wild-type LadA, confirming the enhanced activity of LadA mutants in vivo. Structural changes resulting from the mutations were analyzed and the correlation between structural changes and enzyme activity was discussed. The mutants generated in this study are potentially useful for the treatment of environmental oil pollution and in other bioconversion processes. PMID- 22526794 TI - The metabolic burden of cellulase expression by recombinant Saccharomyces cerevisiae Y294 in aerobic batch culture. AB - Two recombinant strains of Saccharomyces cerevisiae Y294 producing cellulase using different expression strategies were compared to a reference strain in aerobic culture to evaluate the potential metabolic burden that cellulase expression imposed on the yeast metabolism. In a chemically defined mineral medium with glucose as carbon source, S. cerevisiae strain Y294[CEL5] with plasmid-borne cellulase genes produced endoglucanase and beta-glucosidase activities of 0.038 and 0.30 U mg dry cell weight(-1), respectively. Chromosomal expression of these two cellulases in strain Y294[Y118p] resulted in no detectable activity, although low levels of episomally co-expressed cellobiohydrolase (CBH) activity were detected. Whereas the biomass concentration of strain Y294[CEL5] was slightly greater than that of a reference strain, CBH expression by Y294[Y118p] resulted in a 1.4-fold lower maximum specific growth rate than that of the reference. Supplementation of the growth medium with amino acids significantly improved culture growth and enzyme production, but only partially mitigated the physiological effects and metabolic burden of cellulase expression. Glycerol production was decreased significantly, up to threefold, in amino acid-supplemented cultures, apparently due to redox balancing. Disproportionately higher levels of glycerol production by Y294[CEL5] indicated a potential correlation between the redox balance of anabolism and the physiological stress of cellulase production. With the reliance on cellulase expression in yeast for the development of consolidated bioprocesses for bioethanol production, this work demonstrates the need for development of yeasts that are physiologically robust in response to burdens imposed by heterologous enzyme production. PMID- 22526793 TI - Dominance of Candidatus Scalindua species in anammox community revealed in soils with different duration of rice paddy cultivation in Northeast China. AB - The anaerobic ammonium-oxidizing (anammox) bacteria play an important role in the oxygen-limited zone for nitrogen cycling, but their roles in agricultural ecosystems are still poorly understood. In this study, soil samples were taken from the rhizosphere and non-rhizosphere and from surface (0-5 cm) and subsurface (20-25 cm) layers with 1, 4, and 9 years of rice cultivation history on the typical albic soil of Northeast China to examine the diversity and distribution of anammox bacteria based on 16S rRNA gene and hydrazine oxidoreductase encoding gene (hzo). By comparing these soil samples, no obvious difference was observed in community composition between the rhizosphere and non-rhizosphere or the surface and subsurface layers. Surprisingly, anammox bacterial communities of these rice paddy soils were consisted of mainly Candidatus Scalindua species, which are best known to be dominant in marine and pristine environments. The highest diversity was revealed in the 4-year paddy soil based on clone library analysis. Phylogenetic analysis of 16S rRNA gene and deduced HZO from the corresponding encoding gene showed that most of the obtained clones are grouped together with Candidatus Scalindua sorokinii, Candidatus Scalindua brodae, and Candidatus Scalindua spp. of seawater. The obtained clone sequences from all samples are distributed in two subclusters that contain sequences from environmental samples only. Tentative new species were also discovered in this paddy soil. This study provides the first evidence on the existence of anammox bacteria with limited diversity in agricultural ecosystems in Northern China. PMID- 22526795 TI - Characterization and immobilization of a novel SGNH hydrolase (Est24) from Sinorhizobium meliloti. AB - A novel oligomeric SGNH hydrolase (Est24) from Sinorhizobium meliloti was identified, actively expressed in Escherichia coli, characterized, and immobilized for industrial application. Sequence analysis of Est24 revealed a putative catalytic triad (Ser13-Asp163-His169), with moderate homology to other SGNH hydrolases. Est24 was more active toward short-chain esters, such as p nitrophenyl acetate, butyrate, and valerate, while the S13A mutant completely lost its activity. Moreover, the activity of Est24 toward alpha- and beta naphthyl acetate, and enantioselectivity on (R)- and (S)-methyl-3-hydroxy-2 methylpropionate were tested. Est24 exhibited optimum activity at mesophilic temperature ranges (45-55 degrees C), and slightly alkaline pH (8.0). Structural and mutagenesis studies revealed critical residues involved in the formation of a catalytic triad and substrate-binding pocket. Cross-linked enzyme aggregates (CLEAs) of Est24 with and without amyloid fibrils were prepared, and amyloid fibril-linked Est24 with amyloid fibrils retained 83 % of its initial activity after 1 h of incubation at 60 degrees C. The high thermal stability of immobilized Est24 highlights its potential in the pharmaceutical and chemical industries. PMID- 22526797 TI - Generation of an actagardine A variant library through saturation mutagenesis. AB - The lantibiotic actagardine A is nineteen amino acids in length and comprises three intertwined C-terminal methyllanthionine-bridged rings and an N-terminal lanthionine-bridged ring. Produced by the actinomycete Actinoplanes garbadinensis ATCC 31049, actagardine A demonstrates antibacterial activity against important Gram-positive pathogens. This activity combined with its ribosomal synthesis makes it an attractive target for the generation of lantibiotic variants with improved biological activity. A variant generation system designed to allow the specific substitution of amino acids at targeted sites throughout the actagardine A peptide has been used to generate a comprehensive library by site-directed mutagenesis. With the exception of residues involved in bridge formation, each amino acid in the actagardine A peptide as well as the alanine (ala(0)) at position -1 relative to the mature peptide, has been systematically substituted with all remaining 19 amino acids. A total of 228 mutants have been engineered with 44 produced in good yield. The mutant V15F in particular demonstrates improved activity against a range of notable Gram-positive pathogens including Clostridium difficile, when evaluated alongside actagardine A. The scope of variants generated provides an insight into the flexibility of the actagardine A processing machinery and will undoubtedly assist in future mutational studies. PMID- 22526798 TI - Iodine from bacterial iodide oxidization by Roseovarius spp. inhibits the growth of other bacteria. AB - Microbial activities in brine, seawater, or estuarine mud are involved in iodine cycle. To investigate the effects of the microbiologically induced iodine on other bacteria in the environment, a total of 13 bacteria that potentially participated in the iodide-oxidizing process were isolated from water or biofilm at a location containing 131 MUg ml(-1) iodide. Three distinct strains were further identified as Roseovarius spp. based on 16 S rRNA gene sequences after being distinguished by restriction fragment length polymorphism analysis. Morphological characteristics of these three Roseovarius spp. varied considerably across and within strains. Iodine production increased with Roseovarius spp. growth when cultured in Marine Broth with 200 MUg ml(-1) iodide (I(-)). When 10(6) CFU/ml Escherichia coli, Pseudomonas aeruginosa, and Bacillus pumilus were exposed to various concentrations of molecular iodine (I(2)), the minimum inhibitory concentrations (MICs) were 0.5, 1.0, and 1.0 MUg ml(-1), respectively. However, fivefold increases in the MICs for Roseovarius spp. were obtained. In co cultured Roseovarius sp. IOB-7 and E. coli in Marine Broth containing iodide (I( )), the molecular iodine concentration was estimated to be 0.76 MUg ml(-1) after 24 h and less than 50 % of E. coli was viable compared to that co-cultured without iodide. The growth inhibition of E. coli was also observed in co-cultures with the two other Roseovarius spp. strains when the molecular iodine concentration was assumed to be 0.52 MUg ml(-1). PMID- 22526799 TI - Characterization of a S-layer protein from Lactobacillus crispatus K313 and the domains responsible for binding to cell wall and adherence to collagen. AB - It was previously shown that the surface (S)-layer proteins covering the cell surface of Lactobacillus crispatus K313 were involved in the adherence of this strain to human intestinal cell line HT-29. To further elucidate the structures and functions of S-layers, three putative S-layer protein genes (slpA, slpB, and slpC) of L. crispatus K313 were amplified by PCR, sequenced, and characterized in detail. Quantitative real-time PCR analysis reveals that slpA was silent under the tested conditions; whereas slpB and slpC, the putative amino acid sequences which exhibited minor similarities to the previously reported S-layer proteins in L. crispatus, were actively expressed. slpB, which was predominantly expressed in L. crispatus K313, was further investigated for its functional domains. Genetic truncation of the untranslated leader sequence (UTLS) of slpB results in a reduction in protein production, indicating that the UTLS contributed to the efficient S-layer protein expression. By producing a set of N- and C-terminally truncated recombinant SlpB proteins in Escherichia coli, the cell wall-binding region was mapped to the C terminus, where rSlpB(380-501) was sufficient for binding to isolated cell wall fragments. Moreover, the binding ability of the C terminus was variable among the Lactobacillus species (S-layer- and non-S-layer producing strains), and teichoic acid may be acting as the receptor of SlpB. To determine the adhesion region of SlpB to extracellular matrix proteins, ELISA was performed. Binding to immobilized types I and IV collagen was observed with the His-SlpB(1-379) peptides, suggesting that the extracellular matrix protein binding domain was located in the N terminus. PMID- 22526800 TI - Alternaria sp. MG1, a resveratrol-producing fungus: isolation, identification, and optimal cultivation conditions for resveratrol production. AB - Due to its potential in preventing or slowing the occurrence of many diseases, resveratrol (3,5,4'-trihydroxystilbene) has attracted great research interest. The objective of this study was to identify microorganisms from selected plants that produce resveratrol and to optimize the conditions for resveratrol production. Endophytes from Merlot wine grapes (Vitis vinifera L. cv. Merlot), wild Vitis (Vitis quinquangularis Rehd.), and Japanese knotweed (Polygonum cuspidatum Siebold & Zucc.) were isolated, and their abilities to produce resveratrol were evaluated. A total of 65 isolates were obtained and 21 produced resveratrol (6-123 MUg/L) in liquid culture. The resveratrol-producing isolates belonged to seven genera, Botryosphaeria, Penicillium, Cephalosporium, Aspergillus, Geotrichum, Mucor, and Alternaria. The resveratrol-producing capability decreased or was completely lost in most isolates after three rounds of subculture. It was found that only the strain Alternaria sp. MG1 (isolated from cob of Merlot using GA1 medium) had stable and high resveratrol-producing capability in all subcultures. During liquid cultivation of Alternaria sp. MG1 in potato dextrose medium, the synthesis of resveratrol began on the first day, increased to peak levels on day 7, and then decreased sharply thereafter. Cell growth increased during cultivation and reached a stable and high level of biomass after 5 days. The best fermentation conditions for resveratrol production in liquid cultures of Alternaria sp. MG1 were an inoculum size of 6 %, a medium volume of 125 mL in a 250-mL flask, a rotation speed of 101 rpm, and a temperature of 27 degrees C. PMID- 22526796 TI - Sialic acid metabolism and sialyltransferases: natural functions and applications. AB - Sialic acids are a family of negatively charged monosaccharides which are commonly presented as the terminal residues in glycans of the glycoconjugates on eukaryotic cell surface or as components of capsular polysaccharides or lipooligosaccharides of some pathogenic bacteria. Due to their important biological and pathological functions, the biosynthesis, activation, transfer, breaking down, and recycle of sialic acids are attracting increasing attention. The understanding of the sialic acid metabolism in eukaryotes and bacteria leads to the development of metabolic engineering approaches for elucidating the important functions of sialic acid in mammalian systems and for large-scale production of sialosides using engineered bacterial cells. As the key enzymes in biosynthesis of sialylated structures, sialyltransferases have been continuously identified from various sources and characterized. Protein crystal structures of seven sialyltransferases have been reported. Wild-type sialyltransferases and their mutants have been applied with or without other sialoside biosynthetic enzymes for producing complex sialic acid-containing oligosaccharides and glycoconjugates. This mini-review focuses on current understanding and applications of sialic acid metabolism and sialyltransferases. PMID- 22526801 TI - Differential proteomic analysis of an engineered Streptomyces coelicolor strain reveals metabolic pathways supporting growth on n-hexadecane. AB - The alkB gene, encoding an alkane monooxygenase in the actinomycete Gordonia sp. SoCg, was expressed in the non-alkane-degrading actinomycete Streptomyces coelicolor M145. The resulting engineered strain, M145-AH, can grow on n hexadecane as sole carbon source. To unravel proteins associated with growth on n alkanes, proteome of M145-AH after 6, 24, and 48 h of incubation in the Bushnell Haas (BH) mineral medium containing n-hexadecane as sole carbon source (H condition) and in BH without any carbon source (0 condition) were compared using 2D-differential gel electrophoresis. Proteome analysis revealed significant changes only at 48 h, showing 48 differentially abundant proteins identified by mass spectrometry procedures. To asses if these proteins were specifically related to n-hexadecane metabolism, their expression was investigated, comparing H proteome with that of M145-AH incubated in BH with glucose as sole carbon source (G condition). Thus, protein expression profiles at 6, 24, and 48 h under H, 0, and G conditions were combined, revealing that M145-AH regulates in a temporally- and carbon source-dependent manner the expression of proteins involved in regulatory events, central carbon metabolism, respiration, beta oxidation, membrane transport, and amino acid and protein metabolism. Interestingly, 21 % of them, mostly involved in membrane transport and protein metabolism, showed a n-hexadecane-dependent regulation with regulatory proteins such as CRP likely to have a key role in M145-AH n-hexadecane growth. These results, expanding the knowledge on n-alkane utilization in Gram-positive bacteria, reveal genes to be targeted to develop an efficient S. coelicolor M145 AH-based bioremediation system. PMID- 22526803 TI - Kinetic analysis of biodesulfurization of model oil containing multiple alkyl dibenzothiophenes. AB - Biodesulfurization is regarded as a promising alternative technology for desulfurization from diesel oil due to its mild operating conditions and its ability to remove sulfur from alky dibenzothiophenes (C(x)-DBTs). The diesel oil contains complex mixtures of C(x)-DBTs in which individual microbial biodesulfurization may be altered. In this work, interactions among three typical C(x)-DBTs such as dibenzothiophenes (DBT), 4-methyldibenzothiophene (4-MDBT), and 4,6-dimethyldibenzothiophene (4,6-DMDBT) were investigated using Mycobacterium sp. ZD-19 in an airlift reactor. The experimental results indicated that the desulfurization rates would decrease in the multiple C(x)-DBTs system compared to the single C(x)-DBT system. The extent of inhibition depended upon the substrate numbers, concentrations, and affinities of the co-existing substrates. For example, compared to individual desulfurization rate (100 %), DBT desulfurization rate decreased to 75.2 % (DBT + 4,6-DMDBT), 64.8 % (DBT + 4-MDBT), and 54.7 % (DBT + 4,6-DMDBT + 4-MDBT), respectively. This phenomenon was caused by an apparent competitive inhibition of substrates, which was well predicted by a Michaelis-Menten competitive inhibition model. PMID- 22526802 TI - Dynamics of specific ammonia-oxidizing bacterial populations and nitrification in response to controlled shifts of ammonium concentrations in wastewater. AB - Ammonia-oxidizing bacteria (AOB) are essential for the nitrification process in wastewater treatment. To retain these slow-growing bacteria in wastewater treatment plants (WWTPs), they are often grown as biofilms, e.g., on nitrifying trickling filters (NTFs) or on carriers in moving bed biofilm reactors (MBBRs). On NTFs, a decreasing ammonium gradient is formed because of the AOB activity, resulting in low ammonium concentrations at the bottom and reduced biomass with depth. To optimize the NTF process, different ammonium feed strategies may be designed. This, however, requires knowledge about AOB population dynamics. Using fluorescence in situ hybridization (FISH) and confocal laser scanning microscopy, we followed biomass changes during 6 months, of three AOB populations on biofilm carriers. These were immersed in aerated MBBR tanks in a pilot plant receiving full-scale wastewater. Tanks were arranged in series, forming a wastewater ammonium gradient mimicking an NTF ammonium gradient. The biomass of one of the dominating Nitrosomonas oligotropha-like populations increased after an ammonium upshift, reaching levels comparable to the high ammonium control in 28 days, whereas a Nitrosomonas europaea-like population increased relatively slowly. The MBBR results, together with competition studies in NTF systems fed with wastewater under controlled ammonium regimes, suggest a differentiation between the two N. oligotropha populations, which may be important for WWTP nitrification. PMID- 22526804 TI - Synthesis of highly water-soluble feruloyl diglycerols by esterification of an Aspergillus niger feruloyl esterase. AB - Ferulic acid (FA) is a component of plant cell walls that has applications in food, cosmetic, and health products, but its applications are limited by its high insolubility. We synthesized water-soluble FA derivatives by esterification of FA with diglycerol (DG) using feruloyl esterase purified from a commercial enzyme preparation produced by Aspergillus niger. The major reaction product, FA-DG1, was determined to be gamma-feruloyl-alpha,alpha'-DG by NMR and electrospray ionization mass spectrometry analyses. FA-DG1 is a sticky liquid whose water solubility (>980 mg/ml) is dramatically higher than that of FA (0.69 mg/ml). Suitable conditions for esterification of FA with DG were 100 mg of FA in the presence of 1 g of DG and 0.1 ml of 1 M phosphate buffer (pH 6.0) at 50 degrees C under reduced pressure. Under these conditions, 168 mg of feruloyl DGs (FA-DG1, 2, and 3) was obtained, corresponding to a 95 % conversion rate of FA. We also developed a batch method which resulted in synthesis of 729 mg of feruloyl DGs and 168 mg of diferuloyl DGs from 600 mg of FA and 1 g of DG (corresponding to conversion of 69 % of the FA to feruloyl DGs and 21 % of the FA to diferuloyl DGs). As an anti-oxidant, feruloyl DGs were essentially equal to FA and butyl hydroxytoluene in scavenging 1,1-diphenyl-2-picrylhydrazyl radicals. In contrast, the scavenging abilities of diferuloyl DGs were twice those of feruloyl DGs. PMID- 22526805 TI - Mining of unexplored habitats for novel chitinases--chiA as a helper gene proxy in metagenomics. AB - The main objective of this study was to assess the abundance and diversity of chitin-degrading microbial communities in ten terrestrial and aquatic habitats in order to provide guidance to the subsequent exploration of such environments for novel chitinolytic enzymes. A combined protocol which encompassed (1) classical overall enzymatic assays, (2) chiA gene abundance measurement by qPCR, (3) chiA gene pyrosequencing, and (4) chiA gene-based PCR-DGGE was used. The chiA gene pyrosequencing is unprecedented, as it is the first massive parallel sequencing of this gene. The data obtained showed the existence across habitats of core bacterial communities responsible for chitin assimilation irrespective of ecosystem origin. Conversely, there were habitat-specific differences. In addition, a suite of sequences were obtained that are as yet unregistered in the chitinase database. In terms of chiA gene abundance and diversity, typical low abundance/diversity versus high-abundance/diversity habitats was distinguished. From the combined data, we selected chitin-amended agricultural soil, the rhizosphere of the Arctic plant Oxyria digyna and the freshwater sponge Ephydatia fluviatilis as the most promising habitats for subsequent bioexploration. Thus, the screening strategy used is proposed as a guide for further metagenomics-based exploration of the selected habitats. PMID- 22526806 TI - Metabolic pathway analysis of Scheffersomyces (Pichia) stipitis: effect of oxygen availability on ethanol synthesis and flux distributions. AB - Elementary mode analysis (EMA) identifies all possible metabolic states of the cell metabolic network. Investigation of these states can provide a detailed insight into the underlying metabolism in the cell. In this study, the flux states of Scheffersomyces (Pichia) stipitis metabolism were examined. It was shown that increasing oxygen levels led to a decrease of ethanol synthesis. This trend was confirmed by experimental evaluation of S. stipitis in glucose-xylose fermentation. The oxygen transfer rate for an optimal ethanol production was 1.8 mmol/l/h, which gave the ethanol yield of 0.40 g/g and the ethanol productivity of 0.25 g/l/h. For a better understanding of the cell's regulatory mechanism in response to oxygenation levels, EMA was used to examine metabolic flux patterns under different oxygen levels. Up- and downregulation of enzymes in the network during the change of culturing condition from oxygen limitation to oxygen sufficiency were identified. The results indicated the flexibility of S. stipitis metabolism to cope with oxygen availability. In addition, relevant genetic targets towards improved ethanol-producing strains under all oxygenation levels were identified. These targeted genes limited the metabolic functionality of the cell to function according to the most efficient ethanol synthesis pathways. The presented approach is promising and can contribute to the development of culture optimization and strain engineers for improved lignocellulosic ethanol production by S. stipitis. PMID- 22526807 TI - Asymmetric bioreduction of activated alkenes by a novel isolate of Achromobacter species producing enoate reductase. AB - The strain Achromobacter sp. JA81, which produced enoate reductase, was applied in the asymmetric reduction of activated alkenes. The strain could catalyze the bioreduction of alkenes to form enantiopure (R)-beta-aryl-beta-cyano-propanoic acids, a precursor of (R)-gamma-amino butyric acids, including the pharmaceutically active enantiomer of the chiral drug (R)-baclofen with excellent enantioselectivity. It could catalyze as well the stereoselective bioreduction of other activated alkenes such as cyclic imides, beta-nitro acrylates, and nitro alkenes with up to >99 % ee and >99 % conversion. The draft genome sequencing of JA81 revealed six putative old yellow enzyme homologies, and the transcription of one of them, Achr-OYE3, was detected using reverse transcription polymerase chain reaction. The recombinant Escherichia coli expressing Achr-OYE3 displayed enoate reductase activity toward (Z)-3-cyano-3-phenyl-propenoic acid (2a). PMID- 22526808 TI - A comparison of two novel alcohol dehydrogenase enzymes (ADH1 and ADH2) from the extreme halophile Haloferax volcanii. AB - Haloarchaeal alcohol dehydrogenases are exciting biocatalysts with potential industrial applications. In this study, two alcohol dehydrogenase enzymes from the extremely halophilic archaeon Haloferax volcanii (HvADH1 and HvADH2) were homologously expressed and subsequently purified by immobilized metal-affinity chromatography. The proteins appeared to copurify with endogenous alcohol dehydrogenases, and a double Deltaadh2 Deltaadh1 gene deletion strain was constructed to prevent this occurrence. Purified HvADH1 and HvADH2 were compared in terms of stability and enzymatic activity over a range of pH values, salt concentrations, and temperatures. Both enzymes were haloalkaliphilic and thermoactive for the oxidative reaction and catalyzed the reductive reaction at a slightly acidic pH. While the NAD(+)-dependent HvADH1 showed a preference for short-chain alcohols and was inherently unstable, HvADH2 exhibited dual cofactor specificity, accepted a broad range of substrates, and, with respect to HvADH1, was remarkably stable. Furthermore, HvADH2 exhibited tolerance to organic solvents. HvADH2 therefore displays much greater potential as an industrially useful biocatalyst than HvADH1. PMID- 22526809 TI - Extracellular glutathione fermentation using engineered Saccharomyces cerevisiae expressing a novel glutathione exporter. AB - A novel extracellular glutathione fermentation method using engineered Saccharomyces cerevisiae was developed by following three steps. First, a platform host strain lacking the glutathione degradation protein and glutathione uptake protein was constructed. This strain improved the extracellular glutathione productivity by up to 3.2-fold compared to the parental strain. Second, the ATP-dependent permease Adp1 was identified as a novel glutathione export ABC protein (Gxa1) in S. cerevisiae based on the homology of the protein sequence with that of the known human glutathione export ABC protein (ABCG2). Overexpression of this GXA1 gene improved the extracellular glutathione production by up to 2.3-fold compared to the platform host strain. Finally, combinatorial overexpression of the GXA1 gene and the genes involved in glutathione synthesis in the platform host strain increased the extracellular glutathione production by up to 17.1-fold compared to the parental strain. Overall, the metabolic engineering of the glutathione synthesis, degradation, and transport increased the total (extracellular + intracellular) glutathione production. The extracellular glutathione fermentation method developed in this study has the potential to overcome the limitations of the present intracellular glutathione fermentation process in yeast. PMID- 22526810 TI - Benefit of Monascus-fermented products for hypertension prevention: a review. AB - gamma-Aminobutyric acid (GABA) has been reported to play a neurotransmitter in the central nervous system thereby exerting an inhibition in nerve impulse, in turn ameliorating depression; in addition, recent study also reveals the anti hypertensive effect of GABA in vivo. Edible fungi of the Monascus species have been used as traditional Chinese medicine in eastern Asia for several centuries. Monascus-fermented products possess a number of functional secondary metabolites, including anti-inflammatory pigments (such as monascin and ankaflavin), monacolins, dimerumic acid, and GABA. Several scientific studies have shown that these secondary metabolites have anti-inflammatory, anti-oxidative, and anti tumor activities. Moreover, many published reports have shown the efficacy of Monascus-fermented products in the prevention or amelioration of some diseases, including hypercholesterolemia, hyperlipidemia, hypertension, diabetes, obesity, Alzheimer's disease, and numerous types of cancer in recent studies. The current article discusses and provides evidence to elucidate the anti-hypertensive benefit of Monascus-fermented metabolites, including anti-inflammatory pigments and GABA. PMID- 22526811 TI - [Behaviour therapy in the practice management of a veterinary practice. Survey among practicing veterinarians and veterinarians specializing in behaviour therapy]. AB - OBJECTIVE: of the study was to investigate whether behaviour therapy may be an economic niche within practice management. MATERIAL AND METHODS: A questionnaire was used to analyze to what extent veterinarians have already applied behaviour therapy (BT) and how they evaluate economic efficiency and patient owners' attitude. The descriptive analysis included the data from 312 practicing veterinarians (167 randomly selected, interviewed and 145 signed on for training sessions, veterinarians) and of 23 veterinarians specialized in BT. RESULTS: Two thirds (67% of n=288) of the practicing veterinarians offered BT in their practices. The economic efficiency of BT was evaluated as positive by 64% (of n=281) of the practicing veterinarians and by 83% (of n=23) of specialists. 32% (of n = 146) of practitioners who offered behavioural therapy confirmed an increase in sales through the application of BT. Among the specialists, 84% (of n=19) confirmed this experience. In comparison to the specialists and literature data, most of the practicing veterinarians spent insufficient time (61% of n=180) for a behaviour consultation. Furthermore, most of them (86% of n=162) charged less for BT than the amounts fixed by the German Payment Regulations (Gebuhrenordnung fur Tierarzte), as compared to the specialists. CONCLUSION: The specialized veterinarians offered, in contrast to most practitioners, a consultation of BT with sufficiently calculated time and accurate payment planning to realise a therapeutic and commercial outcome. Therefore, the assessment of the economic efficiency of BT and their sales increase through BT were better than the estimation of the practicing veterinarians. Behaviour therapy cannot be managed by providing advice free of charge or charging less. Veterinarians have to become aware that BT is a veterinary area of specialization for which an adequate qualification is necessary. If the veterinarian is not specialized in BT he should refer to a qualified colleague. PMID- 22526812 TI - In-clinic laboratory diagnosis of canine babesiosis (Babesia canis canis) for veterinary practitioners in Central Europe. AB - OBJECTIVE: Haematological changes in dogs and climatic conditions favourable for the vector may assist in the quick in-house diagnosis of canine babesiosis. MATERIAL AND METHODS: Blood samples from 358 dogs suspected to have canine babesiosis were evaluated. The diagnosis was confirmed in 113 dogs by detection of Babesia canis by microscopic examination of a stained blood smear using the concentration line technique. RESULTS: Thrombocytopenia was present in all 113 dogs. Red blood cell count, packed cell volume and haemoglobin values were below the reference range in 62.8%, 61.1% and 46.0% of affected dogs, respectively. An increased reticulocyte count was apparent in five Babesia canis -positive dogs. Leukopenia, lymphopenia, neutropenia and monocytosis were present in 54.9%, 47.8%, 30.4% and 6.5% of the dogs, respectively. Evaluating haematological parameters by CART-analysis revealed a predictive model (accuracy= 93.5%) for canine babesiosis, when using the leucocyte, thrombocyte, and reticulocyte count. Climatic conditions present at the most probable time of Babesia canis- infection accounted for biseasonal occurrence. Changes of climatic factors during the year influence the vector activity and in conclusion should highlight babesiosis in the ranking of differentials for veterinarians. CONCLUSION: The results demonstrate that a tentative diagnosis of canine babesiosis can be made based on typical haematological changes. The results recorded match well with the seasonality of the tick vector and were confirmed here by the month of sample submission. PMID- 22526813 TI - [Epidemiological data of urinary stones in cats between 1981 and 2008]. AB - OBJECTIVE: Evaluation of urinary stones analysed between 1981 and 2008 in cats and comparison with data submitted, such as breed, age, sex and body weight. MATERIAL AND METHODS: Over the given years 5173 feline uroliths from cats in Germany and some neighbouring countries were analysed. From the forms submitted the following data was obtained for most cats: breed, age, sex, body weight, obesity status and location of the urinary stone(s). All uroliths were analysed by infrared spectroscopy. Uroliths containing at least 70% of a single mineral were classified as being of that type. RESULTS: The cats with urolithiasis belonged to 25 different breeds. The most common breed was the European shorthair (64.3%) followed by Persian (15.2%), British shorthair (3.9%), Chartreux (1.7%), Maine Coon (1.5%) and Siamese (1.1%). Most animals were neutered or castrated (81.8%). Tom cats were significantly more frequently affected than female cats. The mean age (7 years) was virtually identical between both sexes, but varied between different stone types. Cats with struvite stones were significantly younger than cats with calcium oxalate stones (6.6 versus 7.6 years). Most urinary stones were retrieved from the bladder and/or urethra (93%). Over the entire time period (1981-2008) struvite (51.2%) and calcium oxalate (38.7%) stones were the two most common urolith types. Percent calcium oxalate stones increased significantly over time and were seen more often in 2008 than struvite stones (48.6% versus 43.4%). Amongst other urinary stones, ammonium urate (1.7%), carbonate apatite (1.7%), cystine (0.5%) and xanthine (0.3%) uroliths were analysed. CONCLUSION AND CLINICAL RELEVANCE: While struvite and calcium oxalate stones are presently found at approximately equal frequency in cats, various different urinary stones types can also occur in this species. Epidemiological knowledge of urinary stones is crucial as a basis for adequate therapy and prevention. PMID- 22526814 TI - Comparison of conventional and sensor-based electronic stethoscopes in detecting cardiac murmurs of dogs. AB - BACKGROUND AND OBJECTIVE: Cardiac auscultation is one of the most important parts of the cardiological examination traditionally performed with acoustic stethoscopes. The aim of this study was to compare the sensitivities and the diagnostic capabilities of traditional and electronic stethoscopes in detecting canine heart murmurs. MATERIALS AND METHODS: The study was performed on 21 dogs referred for cardiologic examination with suspected heart murmurs. Six out of these dogs had cardiac murmurs bilaterally. Cardiac auscultation was performed independently by a final-year veterinary student (AB=I1) and by an experienced clinician (KV=I2), both using a traditional and a Welch Allyn Meditron electronic sensor-based stethoscope. Final diagnoses were established by echocardiography and by digital phonocardiography. RESULTS: Correct detection of a murmur was made by I1 with a traditional stethoscope in 20/27 (74.0%) of the suspected murmurs (p=0.30, kappa[kappa] =0.2) and with the electronic stethoscope in 26/27 (96.3%), respectively (p=0.0013, kappa=0.75). I2 correctly detected the murmurs with the traditional stethoscope in 25/27 (92.6%) cases (p=0.0013, kappa=0.75) and with the electronic stethoscope in all 27/27 (100%) cases (p=0.00012, kappa=1). Agreements of murmur intensity gradings between traditional and electronic stethoscopes were highly significant (I1: p=6.9'10-8; kappa=0.79), (I2: p=5.2'10 11; kappa=0.92). When grading the murmurs with the traditional stethoscope, there was a significant agreement between I1 and I2 (p=2.9'10-7; kappa=0.79), being even higher with the electronic stethoscope (p=1.1'10-11; kappa=0.92). CONCLUSION: The electronic stethoscope was more sensitive than the traditional one in detecting and grading cardiac murmurs being especially useful for I1 with less experience. However, it can be suggested to use a traditional and an electronic stethoscopes simultaneously to optimally utilize their advantages. PMID- 22526815 TI - [The use of fluoroquinolones in bacterial urinary tract infections in cats]. AB - Older cats (>10 years) with FLUTD (Feline Lower Urinary Tract Disease) symptoms are often affected by urinary tract infections. In most of these cats organ diseases (e.g. chronic renal failure, diabetes mellitus) or iatrogenic factors (immunosuppressive drugs, indwelling catheter) are found that clearly predispose cats to this kind of infection. From a diagnostic point of view, urinalysis and urine culture are the most important tools in detecting bacteriuria. The microbiological spectrum is thereby comparable to that found in dogs, revealing Escherichia ( E. ) coli but also Staphylococcus spp. and Enterococcus spp./ Streptococcus spp. Antibiotic therapy should be based on the results of susceptibility testing. If this kind of information is not available, drug selection has to be decided on an empirical basis unless it is a complicated urinary tract infection. Preferred antibiotics should have a high renal excretion rate and thus ensure therapeutically effective drug levels in the urine. In this respect, the fluoroquinolones belong to the group of appropriate drugs to be used in cats. The relevance of therapeutical drug concentrations achievable in the urine is discussed for the example of marbofloxacin, a third-generation fluoroquinolone. New pharmacokinetic data showed that marbofloxacin concentrations of >=2ug/ml are maintained in the urine of healthy cats for 72 and 103 hours after administration of 2 and 4mg/kg BW s.c., respectively. PMID- 22526816 TI - [Enterocutaneous fistula formation in a dog as a result of colonic foreign body perforation]. AB - A 5-year-old female Poodle was presented with a 3-month history of recurrent abscess and fistula formation on the right abdominal wall. Radiographic and ultrasonographic examinations demonstrated an enterocutaneous fistula formation secondary to foreign body perforation of the colon. Additionally, the diagnosis of a pyometra was made. Twenty-four hours after surgical therapy (ventral midline coeliotomy, foreign body removal, closure of the colon perforation, abdominal lavage and drainage, revision of the fistula) the patient was euthanized due to sepsis and incipient multiorgan dysfunction. PMID- 22526817 TI - Successful treatment of permethrin toxicosis in two cats with an intravenous lipid administration. AB - The present work describes successful treatment of permethrin toxicosis in two cats with a novel therapy of intravenous lipid administration. Two cats presented in lateral recumbency and with generalized tremor after they had been incidentally treated with permethrin for flea control by their owners. Initial therapy consisted of diazepam, propofol, bathing, and intravenous fluids. After an initial bolus of 2mg/kg BW pentobarbital a pentobarbital continuous rate infusion (CRI) was started. Both cats received an emulsion of 20% soybean oil and 80% olive oil, commonly used as fat component of total parenteral nutrition in humans, later in the course of therapy. A bolus of 2 ml/kg BW of the emulsion followed by a CRI of 4 ml/kg BW/h for 4 hours was administered via a jugular catheter as reported previously. One cat received two cycles of therapy with intravenous lipid whereas the other cat needed just one application. Both cats recovered completely without requiring any further treatment. In conclusion, administration of intravenous lipids for permethrin toxicosis in cats is a novel treatment approach which seems to be highly effective in shortening the recovery time for permethrin toxicosis and possibly other fat-soluble toxins. PMID- 22526818 TI - [Calcium deficiency: a problem in growing and adult dogs: two case reports]. AB - Two case reports demonstrate the consequences of a deficient calcium supply in dogs. The first case describes an adult dog with a history of food allergy. The dog had been fed with an unbalanced elimination diet (no minerals and vitamins supplemented) over many years and was referred with the diagnosis of osteomalacia (rubber jaw) for optimization of his ration. The second case refers to a puppy which was fed a homemade diet without supplementing the missing minerals and vitamins and suffered a femur fracture after moderate physical impact. In both cases, the computer-aided ration calculation showed a suboptimal to severely deficient supply for several minerals and vitamins, in particular calcium whereas serum calcium levels were normal. Both dogs recovered after being fed a complete and balanced diet. In conclusion, a survey of the feeding using ration calculation is essential especially in the case of potential nutrition-related skeletal disorders. Serum calcium levels cannot be used as a tool to diagnose nutritional calcium deficiency. PMID- 22526819 TI - [Castration of dogs from the standpoint of behaviour therapy]. AB - The castration of dogs is an amputation covered by Section 6 (1) of the Animal Protection Law in Germany. Apart from the general indications given by veterinary medicine, castration of an animal is a potential method of animal behaviour therapy. However, the highly variable, individual effects of castration on behaviour require detailed diagnosis by the veterinarian. Castration appears to exert its strongest influence on sexually dimorphic behaviour patterns in male dogs, e.g. status- related aggression, urine marking, mounting, house-soiling problems, and roaming. An indication to castrate a bitch is maternal aggression. When evaluating the effects of castration, one should always consider individual circumstances, such as learning experience (for example in the case of "experienced copulators"), age, and pack behaviour (if there is more than one dog in the household). Additional benefits of castration include a reduction in the dog's general activity level, decreased preparatory arousal and a decline in the dog's ability to focus its attention fully on the target of attack. As a result, it is much easier for the owner to disrupt and manage or control the dog's agonistic intentions. However, castration is not the ultimate remedy in dog handling. Any decision in this respect should be based on a precise behaviour- related indication. Otherwise, such surgery may well violate the Animal Protection Law. PMID- 22526821 TI - Fighting stigma of mental illness in midsize European countries. AB - PURPOSE: Stigma is the most powerful obstacle to the development of mental health care. Numerous activities aiming to reduce the stigma of mental illness and the consequent negative discrimination of the mentally ill and their families have been conducted in Europe. Descriptions of many of these activities are not easily available, either because there are no publications that describe them, or because descriptions exist only in local languages. This supplement aims to help in overcoming this imbalance by providing a description of anti-stigma activities in 14 countries in Europe regardless of the language in which they were published and regardless whether they were previously published. METHODS: The review was undertaken by experts who were invited to describe anti-stigma activities in the countries in which they reside. It was suggested that they use all the available evidence and that they consult others in their country to obtain a description of anti-stigma activities that is as complete as possible. RESULTS: The anti-stigma activities undertaken in the countries involved are presented in a tabular form. The texts contributed by the authors focus on their perception of the stigma of mental illness and of activities undertaken to combat it in their country. CONCLUSIONS: Although much has been done against the stigmatization and discrimination of the mentally ill, fighting stigma remains an essential task for mental health programs and for society. The descriptions summarized in this volume might serve as an inspiration for anti-stigma work and as an indication of potential collaborators in anti-stigma programs. PMID- 22526820 TI - Ontogeny of angiotensin type 2 and type 1 receptor expression in mice. AB - In the current experiment, we determined angiotensin type 2 receptor (AT2R) and angiotensin type 1 receptor (AT1R) protein expression by western blot analysis in developing normal mice. The results indicate that: (1) in all detected brain regions and in the spinal cord, adult mice exhibited significantly higher AT2R expression and lower AT1R expression in total protein extracts compared to fetuses and neonates; (2) other major organs, including heart, lung, liver and kidney, exhibited the same expression pattern as the brain and spinal cord; (3) reciprocal changes in AT2R and AT1R expression were found in the total protein extracts from the brainstems of mice from one-day prenatal to six weeks of age, and there was a negative correlation between AT2R and AT1R protein expression; (4) in both membrane and cytosolic fractions from the brainstem, adult mice exhibited higher AT2R and lower AT1R expression than did fetuses and neonates; and (5) in the brainstem, there were no significant differences in AT2R and AT1R messenger RNA (mRNA) levels among fetal, neonatal and adult mice. The above results reconfirmed our previous finding in rats that adult animals have higher AT2R and lower AT1R expression compared to fetuses and neonates. These data imply an involvement of AT1R in fetal development and of AT2R in adult function. PMID- 22526822 TI - DSM-IV psychiatric comorbidity according to symptoms of insomnia: a nationwide sample of Korean adults. AB - PURPOSE: The diagnosis of insomnia is based on the presence of four different symptoms: difficulty in initiating sleep (DIS), difficulty in maintaining sleep (DMS), early morning awakening (EMA), and non-restorative sleep (NRS). This study investigated the differences in sociodemographic correlates and psychiatric comorbidity between the four symptoms of insomnia in the general population of South Korea. METHODS: A sample of the population aged 18-64 (N = 6,510) was questioned using a face-to-face interview. Insomnia was defined as having at least one of the four following symptoms three or more times per week: DIS, DMS, EMA, and NRS. Psychiatric disorders were evaluated using the Korean version of Composite International Diagnostic Interview. Logistic regression analysis was used to test each of the sleep outcomes (DIS, DMS, EMA, or NRS) for an association with sociodemographic and clinical variables. RESULTS: The prevalence of DIS, DMS, EMA, and NRS were 7.9 % (95 % CI 6.6-9.5 %), 7.9 % (95 % CI 6.5-9.6 %), 4.9 % (95 % CI 3.9-6.0 %), and 14.8 % (95 % CI 12.6-17.4 %), respectively. The overall prevalence of insomnia was 19.0 % (95 % CI 16.1-22.2 %). Being separated, divorced, or widowed, being single, having a part-time job, having a psychiatric illness, and having a physical illness were all significantly related to insomnia. Older age also increased the risk of DMS and EMA, and younger age was a risk factor for NRS. The presence of most psychiatric disorders was significantly related to insomnia. However, the relationship between the psychiatric illness and each insomnia symptom varied and was dependent on the insomnia symptom. CONCLUSIONS: Most psychiatric disorders were significantly associated with each insomnia symptom in different ways. Differences in sociodemographic and clinical correlates between the four insomnia symptoms implied the heterogeneous characteristics of insomnia as defined by the current diagnostic criteria. PMID- 22526823 TI - US regional differences in death rates from depression. AB - BACKGROUND: Studies in a few countries (including the US) have reported that mortality rates in the population from psychiatric disorders are much higher when they are based on all causes of death ("multiple causes" or "mentions") coded on death certificates versus only the underlying cause. Studies appear to be lacking on geographic variation within the US in mortality rates from psychiatric disorders based on multiple causes of death. METHOD: The present study examined the US age-standardized rate (ASR) for death with depression using multiple causes versus underlying cause alone in each of the Census Bureau's four regions and nine divisions. ASRs for schizophrenia were also examined for comparison. RESULTS: For the entire US, the ratio of the ASR based on multiple causes to the ASR based on underlying cause was 20.9 for depression and 9.2 for schizophrenia; in analyses by region and division, these ratios showed limited variation. The most consistent finding for both depression and schizophrenia was that ASRs, whether based on multiple causes or only on underlying cause, were highest in the Midwest region (especially the East North Central division) and lowest in the South (and in each of its three divisions). For ASRs (using multiple causes of death) from depression, these regional differences were evident within each of several levels of urbanization. For deaths with depression coded as other than the underlying cause, ASRs for each of the three most common underlying causes (cardiovascular diseases, intentional injuries, and neoplasms) were highest in the Midwest and lowest in the South. CONCLUSION: Studies are needed to determine if these regional differences in mortality from depression are due to regional differences in: certifier practices (i.e., in assigning causes of death among persons with psychiatric conditions); the prevalence (among persons with psychiatric disorders) of lifestyle-related factors (e.g., tobacco use and obesity) that mediate mortality risks; and/or in unmet need for psychiatric treatment and medical care for other chronic diseases in persons with psychiatric conditions. Similar studies are needed of regional variation within other countries. PMID- 22526824 TI - Neighborhood social cohesion and posttraumatic stress disorder in a community based sample: findings from the Detroit Neighborhood Health Study. AB - PURPOSE: Posttraumatic stress disorder (PTSD) is common and debilitating. Although research has identified individual-level risk factors for PTSD, the role of macro-social factors in PTSD etiology remains unknown. This study tests whether perceived neighborhood social cohesion (NSC), measured at the both the individual and neighborhood levels, plays a role in determining past-year risk of PTSD among those exposed to trauma. METHODS: Data (n = 1,221) were obtained from an ongoing prospective epidemiologic study in the city of Detroit. Assessment of traumatic event exposure and PTSD was consistent with DSM-IV criteria. Generalized estimating equations (GEE) and logistic regression models were used to estimate the association of neighborhood-level perceived NSC with the risk of PTSD, adjusting for individual-level perceptions of NSC and other covariates. RESULTS: The odds of past-year PTSD were significantly higher among those residing in a neighborhood with low social cohesion compared to high (OR = 2.44, 95 % CI: 1.58, 3.78), independent of individual sociodemographic characteristics, number of traumas, and individual-level perceptions of NSC. The odds of past-year PTSD were not significantly associated with individual-level perceptions of NSC. CONCLUSIONS: These results demonstrate that social context shapes risk of PTSD and suggest that changing the social context may shift vulnerability to this disorder. PMID- 22526825 TI - Obsessive--compulsive disorder: prevalence, correlates, help-seeking and quality of life in a multiracial Asian population. AB - PURPOSE: Obsessive-compulsive disorder (OCD) is a particularly debilitating disorder characterized by early onset, chronic course, and significant comorbidity. People with OCD often delay or are unwilling to seek treatment. The aim of the study was to establish the prevalence and correlates of obsessive compulsive disorder in the Singapore population, to determine types of obsessive compulsive (O/C) symptoms, the comorbidity of the disorder and to examine the quality of life among those with OCD. METHODS: The Singapore Mental Health Study was a cross-sectional epidemiological survey of the adult, resident Singapore population. Face-to-face interviews were completed with 6,616 respondents between December 2009 and December 2010 giving a survey response rate of 75.9 %. The diagnoses of lifetime and 12-month mental disorders were established using Version 3.0 of the Composite International Diagnostic Interview (CIDI-3.0); clinical severity of cases in past 12-months was assessed using a fully structured version of the Yale-Brown Obsessive-Compulsive Scale and functional impairment was assessed by using the disease specific Sheehan Disability Scale, which are incorporated in the CIDI. Health-related quality of life was measured using the Euro-Quality of Life Scale. RESULTS: The lifetime and 12-month prevalence of OCD was 3.0 and 1.1 %, respectively. Younger age and marital status (divorced or separated) were significantly associated with OCD. About 40 % of respondents with lifetime OCD met criteria for other lifetime mental disorders, while 51.6 % of respondents with lifetime OCD had a comorbid physical disorder. The mean score of EQ-Index (0.89) and EQ-VAS (75.58) were lowest in OCD cases as compared with those with any other mental or physical disorders. The proportion of those with lifetime OCD who had sought treatment was 10.2 %. CONCLUSIONS: While OCD is not an extremely prevalent disorder, it has a profound impact on quality of life and daily activities of those suffering from the disorder. The large treatment gap among those with OCD and the significant delay in seeking treatment after the onset of the illness makes OCD a disorder of significant public health priority. PMID- 22526827 TI - A case of aseptic abscesses syndrome treated with corticosteroids and TNF-alpha blockade. AB - Aseptic abscesses syndrome (AA) is an emerging clinicopathological entity characterized by visceral sterile collections of mature neutrophils that do not respond to antibiotics but regress quickly when treated with corticosteroids. Although most previous case reports of AA have been restricted to Europe, we present here a Japanese woman with AA showing recurrence of splenic abscesses, ileocolitis, pyoderma gangrenosum, and arthritis. Although both steroid therapy and tumor necrosis factor (TNF)-alpha blockade were effective, relapses remained frequent. PMID- 22526826 TI - Determinants of ante-partum depression: a multicenter study. AB - INTRODUCTION: Ante-partum depression (APD) is usually defined as a non-psychotic depressive episode of mild to moderate severity, beginning in or extending into pregnancy. APD has received less attention than postpartum depression. This is a cross-sectional study carried out in the Obstetrics and Gynaecology (OG) departments of four different general hospitals in Italy. METHODS: Women attending consecutively the OG departments for their first ultrasound examination were asked to fill in the Edinburgh Postnatal Depression Scale (EPDS) in its Italian validated version. We used the total scores of the EPDS as a continuous variable for univariate and linear regression analyses; in accordance with the literature, the item analysis of EPDS was carried out by classifying the sample as women with "no depression" (scores 0-9), "possible depression" (scores 10-12), "probable depression" (scores 13+) and "probable APD" (scores 15+). RESULTS: The number of women recruited was 1,608. The EPDS assessment classified 10.9 % of the women as possibly depressed, 8.3 % as probably depressed and 4.7 % probably affected from an APD. EPDS score distribution was associated with nationality (higher scores for foreigners), cohabitation (higher scores for women living with friends or in a community), occupation (higher scores for housewives), past episodes of depression and use of herbal drugs. Non-depressed women had significantly lower values on all ten items as compared with depressed women, however, the pattern of item distribution on the EPDS scale remained similar across depression severity groups. In all four groups item 4 (anxious depression) attained the highest scores, while item 10 (suicidality) attained the lowest scores. PMID- 22526828 TI - HTLV-I virological and histopathological analysis in two cases of anti-centromere antibody-seropositive Sjogren's syndrome. AB - INTRODUCTION: The aim of this study was to show the clinical and pathological characteristics of anti-centromere-antibody (ACA)-seropositive Sjogren's syndrome (SS) in two anti-human T-cell leukemia virus type I (HTLV-I)-seropositive patients. METHODS: One patient was an HTLV-I carrier whereas the other was diagnosed with HTLV-I-associated myelopathy (HAM). Background data including serum HTLV-I titers, viral loads, and cytokine profiles were recorded. Azocarmine with aniline blue (Azan)-Mallory staining and immunohistochemistry of the labial salivary glands (LSGs) and a muscle biopsy specimen from the HAM patient were performed. RESULTS: Serum transforming growth factor beta (TGF-beta), tumor necrosis factor alpha (TNF-alpha), and HTLV-I viral load were high in the HAM-SS patient compared with the HTLV-I carrier. Fibrous change in LSG was prominent in the HAM-SS patient. Although TGF-beta expression was similar in the two patients, expression of HTLV-I-related proteins including p12, p28, group-specific antigen (GAG), and nuclear factor kappa-B (NF-kappaB) in the LSG were dominantly detected in the HAM-SS patient. Frequency of TGF-beta staining in HTLV-I-seropositive SS patients without ACA, HTLV-I-seronegative SS patients with ACA, and HTLV-I seronegative SS patients without ACA was lower than that of the previous two patients. CONCLUSION: A high HTLV-I viral load in situ is supposed to promote the production of cytokines, especially TGF-beta, resulting in the fibrous change of LSG in ACA-seropositive SS patients. PMID- 22526829 TI - Phospholipid scramblase 1 expression is enhanced in patients with antiphospholipid syndrome. AB - OBJECTIVE: Thrombus formation is the key event of vascular manifestations in antiphospholipid syndrome (APS). Phosphatidylserine (PS) is normally sequestered in the inner leaflet of cell membranes. Externalization of PS occurs during cell activation and is essential for promoting blood coagulation and for the binding of antiphospholipid antibodies (aPL) to cells. One of the molecules involved in PS externalization is phospholipid scramblase 1 (PLSCR1). We evaluated PLSCR1 expression on monocytes from APS patients and analyzed the in vitro effect of monoclonal aPL on PLSCR1 expression. PATIENTS AND METHODS: Forty patients with APS were investigated. In vitro experiments were performed in monocyte cell lines incubated with monoclonal aPL. PLSCR1 expression was determined by quantitative real-time polymerase chain reactions. PS exposure on CD14(+) cell surface was analyzed by flow cytometry. RESULTS: Levels of full-length PLSCR1 messenger RNA (mRNA) were significantly increased in APS patients compared with healthy controls (2.4 +/- 1.2 vs. 1.3 +/- 0.4, respectively, p < 0.001). In cultured monocytes, interferon alpha enhanced tissue-factor expression mediated by beta2 glycoprotein-I-dependent monoclonal anticardiolipin antibody. CONCLUSIONS: Monocytes in APS patients had increased PLSCR1 mRNA expression. PMID- 22526830 TI - Thrombotic thrombocytopenic purpura with an autoantibody to ADAMTS13 complicating Sjogren's syndrome: two cases and a literature review. AB - An association between thrombotic thrombocytopenic purpura (TTP) and Sjogren's syndrome (SS) is rare. This is the first report of two patients with TTP who had inhibitory autoantibodies to ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 repeats) complicating primary SS. A rapid diagnosis of TTP, which is a potentially lethal condition, made it possible to treat the two cases successfully. Only eight similar cases with TTP complicating SS have been reported in the literature. The possible presentation of primary SS without classic sicca symptoms, but with haematological abnormalities including TTP, should be recognised. Furthermore, it is important to measure ADAMTS13 activity and anti-ADAMTS13 antibodies, because TTP with SS seems to be a concurrent overlapping autoimmune disorder. We suggest that plasma exchanges in combination with corticosteroids should be administered as early as possible, since they appeared to be effective in treating TTP with SS, including in our cases. PMID- 22526831 TI - Efficacy of weekly mizoribine pulse therapy in refractory lupus nephritis. AB - OBJECTIVE: We investigated the efficacy of a high-dose intermittent dosing treatment method (weekly mizoribine pulse therapy) conceived in the hope of achieving better efficacy by increasing the peak blood levels of mizoribine in patients with refractory lupus nephritis. METHODS: Seventeen patients with lupus nephritis who had been resistant to corticosteroid and immunosuppressant therapy received weekly mizoribine pulse therapy. Mizoribine (350 mg) was administered three times at 12 h intervals over 2 consecutive days (700 mg for day 1 and 350 mg for day 2), followed by a washout period from day 3 to day 7. RESULTS: This therapeutic strategy enabled the peak blood levels of mizoribine to be increased to more than 3 MUg/mL in most of the patients. Although SLEDAI, anti-ds-DNA antibody titer, CH-50, and serum albumin level did not significantly improve, urinary protein levels decreased, and it was possible to taper the dose of concomitant steroids. Using our definition of clinical response, 10 of the 17 patients were responders and 4 of them were nonresponders. The average peak serum mizoribine concentration of the responders was as high as 3.5 MUg/mL. Elevation of serum liver enzymes was seen in 1 patient, and hyperuricemia occurred in 4 cases, but none of these adverse events were serious. CONCLUSION: Intermittent administration of mizoribine can increase blood levels and may be effective for refractory lupus nephritis. PMID- 22526832 TI - Clinical analysis of 50 children with juvenile dermatomyositis. AB - OBJECTIVE: We performed a retrospective review of medical records to assess the clinical characteristics of 50 Japanese children with juvenile dermatomyositis (JDM). METHODS: Fourteen boys and 36 girls who visited Yokohama City University Hospital between 1983 and 2008 were enrolled. Gender, age at disease onset and diagnosis, presenting clinical features, laboratory data at onset, complications, treatment, and outcome were reviewed. RESULTS: Mean age at disease onset was 6.9 years. Clinical manifestations at the first visit were muscle pain and/or weakness (90 %), malar rash (90 %), Gottron's papules (86 %), and heliotrope rash (80.0 %). Elevated serum levels of creatine kinase were found in 57.0 % of patients and aldolase in 95 %. T2-weighted magnetic resonance (MR) images with fat suppression demonstrated positive findings in 89.5 % of patients. Initial treatment was prednisolone (PSL) orally or pulsed methylprednisolone (mPSL) i.v. Pulsed mPSL therapy showed efficacy superior to PSL [flare in 8 of 19 (42 %) vs. 18 of 25 (72 %)]. Children refractory to initial treatment were given additional pulsed mPSL and/or cyclophosphamide (IVCY; n = 19) i.v.. Four patients with interstitial pneumonia responded well to IVCY. CONCLUSIONS: Our findings support the notion that JDM might be considered as both a systemic inflammatory and noninflammatory vasculopathy best treated by IVCY, as shown in previous literature. PMID- 22526833 TI - A review of tocilizumab treatment in 122 rheumatoid arthritis patients included in the Tsurumai Biologics Communication Registry (TBCR) Study. AB - OBJECTIVES: Biologics have transformed the treatment of rheumatoid arthritis. Clinical remission is now the goal. We sought to verify whether the administration of tocilizumab-a biologic-can help to achieve current treatment goals. METHODS: Using data from the Tsurumai Biologics Communication Registry for 122 patients treated with tocilizumab, we evaluated changes in DAS28-ESR at 12 months after initiation, and also evaluated remission rates defined using conventional and new Boolean-based remission criteria. We divided 50 patients who had received tocilizumab as a first-line treatment into two groups [disease duration at baseline of 12 months or less (<=12 M) and more than 12 months (>12 M)]. RESULTS: At 12 months after initiation, there was no difference in DAS28 ESR, and remission rates based on the conventional criterion were also comparable (50 % in both groups). However, under the new criterion, remission was 50.0 % in the <=12 M group against 12.5 % in the >12 M group (p = 0.0181). Among the individual components of the new remission criterion, the small proportion of patients in the >12 M group with a patient global assessment (PtGA) of <=1 had a particularly strong influence on the remission rate for that group, but this component was not as important for the <=12 M group. CONCLUSIONS: When used as a first-line biological drug for patients with early-stage RA (<=12 M), tocilizumab appears to provide high rates of remission under the Boolean-based remission criterion, which were strongly affected by the PtGA. PMID- 22526834 TI - Anti-leukemic effect of 2-pyrone derivatives via MAPK and PI3 kinase pathways. AB - Substituted 2-pyrones are important structural sub-units present in a number of natural products having broad range of biological activity. However, little is known about the anti-cancer effect of 2-pyrone derivatives including leukemia. Therefore, this present study was undertaken to investigate the effect of 2 pyrone derivatives in human acute myeloid leukemia (AML). Among 23 synthesized derivatives, 5-bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one (code name; pyrone 9) showed the most potent antileukemic activity with 5 * 10(-6) M to 5 * 10(-5) M of IC(50) in various AML cell lines as well as primary leukemic blasts from AML patients, while normal peripheral blood mononuclear cells was not affected by pyrone 9. Flow cytometric analysis indicated that pyrone 9 induced the G1 and G2 phase dual arrest of the cell cycle in HL-60 cells. To address the mechanism of the antileukemic effect of pyrone 9, we examined the effect of pyrone 9 on cell cycle-related proteins in HL-60 cell. The levels of CDK2, CDK4, CDK6, CDK1, cyclin B1 and cyclin E were decreased; in contrast, cyclin A was not altered. In addition, pyrone 9 not only increased the p27 level but also enhanced its binding to with CDK2, CDK4 and CDK6 which resulted in the reduction of CDK2-, CDK4- and CDK6-associated kinase activities. Pyrone 9 also induced the apoptosis in HL-60 cells. The apoptotic process of HL-60 cells was associated with increased Bax, decreased Bcl-2 and activation of caspase-8, -9, -3 and PARP. Antileukemic effect of pyrone 9 was associated with activation of mitogen-activated protein kinase (MAPK) pathway, as evidenced by activation of p-ERK and p38 MAPK. In addition, pyrone 9 was influenced PI3 kinase pathway. Expressions of p-Akt (ser473), p-Raf, and p-PDK were down-regulated; in contrast, those of PTEN and p-PTEN were up regulated. Furthermore, pyrone 9 suppressed NF-kappaB pathway signaling. To gain insights into the antileukemic activity of pyrone 9 in vivo, BALB/c mouse leukemic model was established using intraperitoneal inoculation of syngeneic WEHI-3BD(+) mouse leukemic cells. Pyrone 9 inhibited in vitro and in vivo the growth of WEHI-3BD(+) cells, and ultimately, prolonged the survival of pyrone 9 treated mice. These findings suggest that the pyrone 9 inhibits the cell proliferation of human AML cell line, HL-60, through MAPK and PI3 kinase pathway as well as induction of cell cycle arrest. In particular, pyrone 9 prolonged the survival of pyrone 9-treated leukemic mice. PMID- 22526835 TI - Inverse problems from biomedicine: inference of putative disease mechanisms and robust therapeutic strategies. AB - Many complex diseases that are difficult to treat cannot be mapped onto a single cause, but arise from the interplay of multiple contributing factors. In the study of such diseases, it is becoming apparent that therapeutic strategies targeting a single protein or metabolite are often not efficacious. Rather, a systems perspective describing the interaction of physiological components is needed. In this paper, we demonstrate via examples of disease models the kind of inverse problems that arise from the need to infer disease mechanisms and/or therapeutic strategies. We identify the challenges that arise, in particular the need to devise strategies that are robust against variable physiological states and parametric uncertainties. PMID- 22526836 TI - A mixture theory model of fluid and solute transport in the microvasculature of normal and malignant tissues. I. Theory. AB - In order to better understand the mechanisms governing transport of drugs, nanoparticle-based treatments, and therapeutic biomolecules, and the role of the various physiological parameters, a number of mathematical models have previously been proposed. The limitations of the existing transport models indicate the need for a comprehensive model that includes transport in the vessel lumen, the vessel wall, and the interstitial space and considers the effects of the solute concentration on fluid flow. In this study, a general model to describe the transient distribution of fluid and multiple solutes at the microvascular level was developed using mixture theory. The model captures the experimentally observed dependence of the hydraulic permeability coefficient of the capillary wall on the concentration of solutes present in the capillary wall and the surrounding tissue. Additionally, the model demonstrates that transport phenomena across the capillary wall and in the interstitium are related to the solute concentration as well as the hydrostatic pressure. The model is used in a companion paper to examine fluid and solute transport for the simplified case of an axisymmetric geometry with no solid deformation or interconversion of mass. PMID- 22526837 TI - Trail formation based on directed pheromone deposition. AB - We propose an Individual-Based Model of ant-trail formation. The ants are modeled as self-propelled particles which deposit directed pheromone particles and interact with them through alignment interaction. The directed pheromone particles intend to model pieces of trails, while the alignment interaction translates the tendency for an ant to follow a trail when it meets it. Thanks to adequate quantitative descriptors of the trail patterns, the existence of a phase transition as the ant-pheromone interaction frequency is increased can be evidenced. We propose both kinetic and fluid descriptions of this model and analyze the capabilities of the fluid model to develop trail patterns. We observe that the development of patterns by fluid models require extra trail amplification mechanisms that are not needed at the Individual-Based Model level. PMID- 22526839 TI - Helical swimming can provide robust upwards transport for gravitactic single-cell algae; a mechanistic model. AB - In still fluid, many phytoplankton swim in helical paths with an average upwards motion. A new mechanistic model for gravitactic algae subject to an intrinsic torque is developed here, based on Heterosigma akashiwo, which results in upwards helical trajectories in still fluid. The resultant upwards swimming speed is calculated as a function of the gravitactic and intrinsic torques. Helical swimmers have a reduced upwards speed in still fluid compared to cells which swim straight upwards. However a novel result is obtained when the effect of fluid shear is considered. For intermediate values of shear and intrinsic torque, a new stable equilibrium solution for swimming direction is obtained for helical swimmers. This results in positive upwards transport in vertical shear flow, in contrast to the stable equilibrium solution for straight swimmers which results in downwards transport in vertical shear flow. Furthermore, for strong intrinsic torque, when there is no longer a stable orientation equilibrium, we show that the average downwards transport of helical swimmers in vertical shear flow is greatly suppressed compared to straight swimmers. We hypothesise that helical swimming provides robustness for upwards transport in the presence of fluid shearing motions. PMID- 22526840 TI - Localized states in an unbounded neural field equation with smooth firing rate function: a multi-parameter analysis. AB - The existence of spatially localized solutions in neural networks is an important topic in neuroscience as these solutions are considered to characterize working (short-term) memory. We work with an unbounded neural network represented by the neural field equation with smooth firing rate function and a wizard hat spatial connectivity. Noting that stationary solutions of our neural field equation are equivalent to homoclinic orbits in a related fourth order ordinary differential equation, we apply normal form theory for a reversible Hopf bifurcation to prove the existence of localized solutions; further, we present results concerning their stability. Numerical continuation is used to compute branches of localized solution that exhibit snaking-type behaviour. We describe in terms of three parameters the exact regions for which localized solutions persist. PMID- 22526838 TI - A model of erythropoiesis in adults with sufficient iron availability. AB - In this paper we present a model for erythropoiesis under the basic assumption that sufficient iron availability is guaranteed. An extension of the model including a sub-model for the iron dynamics in the body is topic of present research efforts. The model gives excellent results for a number of important situations: recovery of the red blood cell mass after blood donation, adaptation of the number of red blood cells to changes in the altitude of residence and, most important, the reaction of the body to different administration regimens of erythropoiesis stimulating agents, as for instance in the case of pre-surgical administration of Epoetin-alpha. The simulation results concerning the last item show that choosing an appropriate administration regimen can reduce the total amount of the administered drug considerably. The core of the model consists of structured population equations for the different cell populations which are considered. A key feature of the model is the incorporation of neocytolysis. PMID- 22526841 TI - Spiky and transition layer steady states of chemotaxis systems via global bifurcation and Helly's compactness theorem. AB - The most important phenomenon in chemotaxis is cell aggregation. To model this phenomenon we use spiky or transition layer (step-function-like) steady states. In the case of one spatial dimension, we carry out global bifurcation analysis on the Keller-Segel model and several variants of it, showing that positive steady states exist if the chemotactic coefficient chi is larger than a bifurcation value chi1 which can be explicitly expressed in terms of the parameters in the models; then we use Helly's compactness theorem to obtain the profiles of these steady states when the ratio of the chemotactic coefficient and the cell diffusion rate is large, showing that they are either spiky or have the transition layer structure. Our results provide insights on how the biological parameters affect pattern formation, and reveal the similarities and differences of some popular chemotaxis models. PMID- 22526842 TI - Phase resetting reduces theta-gamma rhythmic interaction to a one-dimensional map. AB - Gamma and theta oscillations of the hippocampus are known to interact, but the mechanisms underlying such interaction are not well understood. We focus on a previously published computational model of hippocampal activity that shows the gamma rhythms nesting in the theta rhythms, and investigate the dynamical mechanisms underlying that interaction. There are three types of neurons in the model: pyramidal cells, fast-spiking interneurons, and "oriens lacunosum moelculare" (O-LM cells); the latter is an inhibitory cell whose inhibition has a longer time scale, and which has currents associated with intrinsic theta-rhythm behavior. We identify two main modes of interaction among the slow and the fast rhythms in the model, modulated by the strength of the excitatory synapse on the O-LM cells. Using resets of phases after each pyramidal cell and O-LM spike, we extend the use of the phase transition map (PTM) to encode the stability type of spiking patterns in networks where different frequencies interact. The tailored application of the PTM to the model network measures how the interaction between the shape of the phase response curves and the length of the gamma period determines the number of gamma spikes in theta cycles, and provides an explicit formula for the length of theta intervals in nesting regimes. Using the PTM, we also explain the covariance of the gamma and theta rhythms as drive is changed over some intervals. PMID- 22526843 TI - Determining a distributed parameter in a neural cable model via a boundary control method. AB - Dendrites of nerve cells have membranes with spatially distributed densities of ionic channels and hence non-uniform conductances. These conductances are usually represented as constant parameters in neural models because of the difficulty in experimentally estimating them locally. In this paper we investigate the inverse problem of recovering a single spatially distributed conductance parameter in a one-dimensional diffusion (cable) equation through a new use of a boundary control method. We also outline how our methodology can be extended to cable theory on finite tree graphs. The reconstruction is unique. PMID- 22526844 TI - Cell surface associated glycohydrolases in normal and Gaucher disease fibroblasts. AB - Gaucher disease (GD) is the most common lysosomal disorder and is caused by an inherited autosomal recessive deficiency in beta-glucocerebrosidase. This enzyme, like other glycohydrolases involved in glycosphingolipid (GSL) metabolism, is present in both plasma membrane (PM) and intracellular fractions. We analyzed the activities of CBE-sensitive beta-glucosidase (GBA1) and AMP-DNM-sensitive beta glucosidase (GBA2) in total cell lysates and PM of human fibroblast cell lines from control (normal) subjects and from patients with GD clinical types 1, 2, and 3. GBA1 activities in both total lysate and PM of GD fibroblasts were low, and their relative percentages were similar to those of control cells. In contrast, GBA2 activities were higher in GD cells than in control cells, and the degree of increase differed among the three GD types. The increase of GBA2 enzyme activity was correlated with increased expression of GBA2 protein as evaluated by QRT-PCR. Activities of beta-galactosidase and beta-hexosaminidase in PM were significantly higher for GD cells than for control cells and also showed significant differences among the three GD types, suggesting the occurrence of cross-talk among the enzymes involved in GSL metabolism. Our findings indicate that the profiles of glycohydrolase activities in PM may provide a valuable tool to refine the classification of GD into distinct clinical types. PMID- 22526847 TI - [Perspectives of health economics in Germany]. PMID- 22526846 TI - Prevalence of tetrahydrobiopterine (BH4)-responsive alleles among Austrian patients with PAH deficiency: comprehensive results from molecular analysis in 147 patients. AB - Phenylketonuria (PKU, MIM 261600) is an autosomal recessive disorder caused by mutations of the phenylalanine hydroxylase gene (PAH, GenBank U49897.1, RefSeq NM_000277). To date more than 560 variants of the PAH gene have been identified. In Europe there is regional distribution of specific mutations. Due to recent progress in chaperone therapy, the prevalence of BH4-responsive alleles gained therapeutic importance. Here we report the mutational spectrum of PAH deficiency in 147 unrelated Austrian families. Overall mutation detection rate was 98.6 %. There was a total of 62 disease-causing mutations, including five novel mutations IVS4 + 6T>A, p.H290Y, IVS8-2A>G, p.A322V and p.I421S. The five most prevalent mutations found in patients were p.R408W, IVS12 + 1G>A, p.R261Q, p.R158Q and IVS2 + 5G>C. Neonatal phenylalanine levels before treatment were available in 114/147 patients. Prediction of BH4-responsiveness in patients with full genotypes was exclusively made according to published data. Among the 133 patients needing dietary treatment, 28.4 % are expected to be BH4 "non-responsive", 4.5 % are highly likely BH4-responsive, 35.8 % are probably BH4-responsive while no interpretation was possible for 31.3 %. The mutation data reflect the population history of Austria and provide information on the likely proportion of Austrian PKU patients that may benefit from BH4-therapy. PMID- 22526845 TI - Mitochondrial proteomics--a tool for the study of metabolic disorders. AB - Mitochondria are important for a number of life and death processes, such as energy production, creation of reactive oxygen species, and elicitation of stress responses. These responses range from induction of protein quality control and antioxidant systems to mitochondria elimination and cell death. Mitochondrial dysfunctions are involved in pathologies associated with many diseases, for example metabolic disorders, diabetes, cancers, cardiovascular and neurodegenerative diseases as well as obesity and aging. Mitochondrial proteomics can be a powerful tool in the study of these diseases, especially since it can cover mitochondrial proteins from several metabolic pathways, such as the citric acid cycle, fatty acid oxidation, and respiratory chain, as well as protein networks involved in stress responses. The mitochondrial proteome can consist of more than 1,000 different proteins. However, it is difficult to define the precise number, since mitochondria are dynamic and difficult to purify, and because an unknown number of proteins possess dual or multiple localization, depending on cell type and physiological conditions. This review describes several quantitative studies of proteins from mitochondria isolated by centrifugation, separated by various methods (e.g., electrophoresis and nanoLC), and analyzed by advanced mass spectrometry. We illustrate the methods by showing that multiple pathways and networks are affected in cells from patients carrying gene variations affecting a mitochondrial protein. The study of cultured skin fibroblasts from patients with ethylmalonic aciduria associated with variations in the genes coding for short-chain acyl-CoA dehydrogenase (SCAD) or ETHE1 are two of the examples. The possibility of obtaining mitochondrial proteomics data from whole cell proteomics studies is also exemplified by the involvement of liver mitochondria in metabolic syndrome. PMID- 22526848 TI - [Fostering of health economics in Germany]. AB - Health economics is now well established in Germany with the aim to apply economic tools to answer problems in health and health care. After a short review of the international development of health economics and the development in Germany in particular, the article looks at selected recent topics of health economic analysis in Germany (economic evaluation, industrial economics, health and education). PMID- 22526849 TI - [Health care expenditures and the aging population]. AB - The impact of a longer life on future health care expenditures will be quite moderate because of the high costs of dying and the compression of mortality in old age. If not age per se but proximity to death determines the bulk of expenditures, a shift in the mortality risk to higher ages will not significantly affect lifetime health care expenditures, as death occurs only once in every life. A calculation of the demographic effect on health care expenditures in Germany up until 2050 that explicitly accounts for costs in the last years of life leads to a significantly lower demographic impact on per-capita expenditures than a calculation based on crude age-specific health expenditures. PMID- 22526850 TI - [Health-based risk adjustment. Effects and side effects]. AB - Numerous health systems have introduced competition between health plans while banning risk-rated premiums. Risk adjustment for health plans is introduced to reduce incentives for risk selection and to create incentives for health plans to permanently invest in care for the chronically ill. According to the international health economics state of the art, risk adjustment in the German social health insurance system has used information on health status (measured by diagnoses and drug prescriptions) on top of demographic information since 2009. In non-competitive health care systems similar mechanisms are sometimes established, e.g. to achieve an equitable distribution of resources between regions. An evaluation of the first year of health-based risk adjustment demonstrates a superior performance in comparison to the old, demographic risk adjustment. The old risk adjustment formula (without ex post high-cost pooling) showed R(2) of 5.8%, CPM of 10.4% and MAPE of 2,226 ?, in contrast to the new health status-based risk adjustment formula (without cash benefit for sick allowance) which reaches R(2) 20.2%, CPM 22.5% and MAPE 1,817 ?. However, to make competition between health plans functional for improvement of quality and efficiency of health care, health plans must be granted additional instruments to act as prudent buyers of health care. PMID- 22526851 TI - [DRG systems in Europe. Incentives, purposes and differences in 12 countries]. AB - DRG systems were introduced across Europe based on expected transparency and efficiency gains. However, European DRG systems have not been systematically analysed so far. As a consequence little is known about the relative strengths and weaknesses of different DRG systems. The EuroDRG project closed this research and knowledge gap by systematically analysing and comparing the DRG systems of 12 countries with different health systems (Austria, the UK, Estonia, Finland, France, Germany, Ireland, The Netherlands, Poland, Portugal, Spain and Sweden).This article summarizes the results of this analysis illustrating how DRG systems across Europe differ with regard to policy goals, patient classification, data collection, price setting and actual reimbursement. Moreover, it outlines which main challenges arise within and across the different types of DRG systems. The results show that the European DRG systems are very heterogeneous. Even if the basic DRG approach of grouping similar patients remains the same across countries, the design of the main building blocks differs to a great extent. PMID- 22526852 TI - [Economic aspects of integrated care]. AB - For more than 10 years integrated care has been an inherent part of the German healthcare system. The aims of selective contracts are to minimize interface problems between outpatient and inpatient sectors, generalist und specialist care as well as to intensify competition. Despite repeated efforts by the legislator, comprehensive integrated healthcare is still limited to a few flagship projects. This is mainly due to low incentives on the part of both suppliers and customers. Therefore, this article focuses on the economic aspects of integrated care. From a theoretical perspective, integrated care improves efficiency in the healthcare sector by reducing interface problems and asymmetric information as well as by intensifying competition. In practice, however, there are a number of obstacles to implementation. Particularly noteworthy are the financial difficulties in addition to problems regarding sectoral budgeting and the long-term nature of investments. However, the political environment and thus the financial arrangements within the statutory health insurance seem to be more important for further development of integrated care in Germany than the financing issues. PMID- 22526853 TI - [Implicit versus explicit rationing of health services]. AB - The common usage of the term "rationing" in health care as "withholding necessary services" is criticized and the relation between the concepts "rationing" and "prioritization" clarified. Furthermore, we distinguish among different types or rationing, in particular "hard" versus "soft" and "implicit" versus "explicit," and discuss their pros and cons. We then apply these concepts to the current situation in Germany, and discuss the contents and procedures of a possible explicit rationing within Social Health Insurance. In doing so, we attempt to make a contribution that may help to start the urgently needed open debate on scarcity and allocation of health care services in Germany. PMID- 22526854 TI - [Decision support through economic evaluation from the perspective of science in Germany]. AB - For decades, economic evaluation studies, or cost-benefit analyses (CBA), have been a tool for decision support in the use of public funds. Despite this, in the last few years, debates on the inclusion of CBAs in the German health care system have paid little attention to the findings and practical experiences of scientific research. CBAs - especially the QALY - were instead represented a priori as "unfair" and "discriminatory." Today they have virtually no meaning when it comes to allocation and pricing decisions about publicly funded health services. Of course, CBAs are based on value judgments, which have to be communicated. They can lead to allocations that violate the minimum standards of justice. Here, distributive requirements and criteria are needed and must be developed in an interdisciplinary discourse. However, a general waiver of CBA does not make decisions about the allocation of resources easier, especially since its involvement can contribute to more openness and transparency in the system. Accordingly, for Germany a dual approach is recommended: an interdisciplinary exploration of the methodological foundations of economic evaluation and a consistent application of these in healthcare decision-making. PMID- 22526855 TI - [Health economic evaluation based on administrative data from German health insurance]. AB - Although the quality of administrative data of German health insurance is relatively good, administrative data are rarely used for the purpose of health economic evaluations in Germany. Health economic evaluations in Germany have so far mainly been performed based on primary data while in other countries the use of secondary data is quite common. The objective of the article is to give an introduction into the possibilities of performing health economic evaluations based on administrative data. First, we show that German health insurance have data sets that allow the follow-up of patients across all sectors of health care. Subsequently, characteristics of primary data and administrative data of health insurance for the purpose of health economic evaluations are compared. Finally we present an overview of recently performed health economic evaluations based on administrative data in Germany and conclude with lessons from other countries on the use of administrative data and implications for Germany. PMID- 22526856 TI - [Costs of illness in dementia from a societal perspective. An overview]. AB - Dementias are one of the most expensive disease groups among the population aged 65 years and over. This is mainly due to the patients' deficits in activities of daily living which increase with the progression of dementia, leading to an increasing need for care. As a result, the costs of dementia may more than double over the course of the disease. The costs of medical care account for a relatively small share of total costs and are not greatly influenced by disease severity. By contrast, the costs of care make up at least three quarters of total costs in the majority of studies. When patients are cared for in the community, most of the care is often provided informally by relatives. Accordingly, up to 75 or 80% of the costs of illness in this setting, from a societal perspective, may be due to informal care. Additional professional home care accounts for a relatively small share of total costs. The costs of caring for patients who live in the community are directly related to the degree of functional impairment. By contrast, it can be difficult to estimate the costs which are specifically due to dementia in patients that are institutionalised. PMID- 22526857 TI - [Effects of multimorbidity on health care utilization and costs]. AB - Multiple chronic conditions (multimorbidity) are common among elderly patients; however, little is known about the specific effects of multimorbidity on health care utilization and health care costs. This article reviews empirical studies from the international literature that investigated the relationship between multiple chronic conditions and health care utilization (e.g. ambulatory care, stationary care, pharmacotherapy) and/or health care costs in elderly general populations. Although synthesis of studies was complicated, especially because of ambiguous definitions and measurements of multimorbidity, almost all studies observed a positive association of multimorbidity and utilization and costs. Many studies found that utilization and costs significantly increased with each additional chronic condition. In light of these findings coupled with the fear that current care arrangements may be inappropriate for many multimorbid patients, important implications for research and policy are presented and discussed. PMID- 22526858 TI - [Cardiovascular diseases in the focus of health economics. The example of drug eluting vascular stents in coronary heart disease]. AB - Coronary heart disease is an important disorder in Western industrialized societies, with regard to both the epidemiologic and economic burden of illness. A modern therapeutic strategy consists of coronary interventions and the implantation of drug-eluting vascular stents. The cost-effectiveness of such drug eluting stents has been an important subject of health-economic evaluation research in recent years. This article presents two examples of such studies and deals with the question whether existing study projects are able to provide sufficient evidence for allocation decisions in health care. On this basis we discuss important challenges for future health economic analysis. A key conclusion is the need for long-term and cross-sectoral evaluation strategies that could be based on routinely collected health care data. Supplemented by health economic results from clinical trials, the use of such data would lead to a broader data basis for allocation decisions in health care. PMID- 22526859 TI - [Using value of information analysis in decision making about applied research. The case of genetic screening for hemochromatosis in Germany]. AB - Public decision makers face demands to invest in applied research in order to accelerate the adoption of new genetic tests. However, such an investment is profitable only if the results gained from further investigations have a significant impact on health care practice. An upper limit for the value of additional information aimed at improving the basis for reimbursement decisions is given by the expected value of perfect information (EVPI). This study illustrates the significance of the concept of EVPI on the basis of a probabilistic cost-effectiveness model of screening for hereditary hemochromatosis among German men. In the present example, population-based screening can barely be recommended at threshold values of 50,000 or 100,000 Euro per life year gained and also the value of additional research which might cause this decision to be overturned is small: At the mentioned threshold values, the EVPI in the German public health care system was ca. 500,000 and 2,200,000 Euro, respectively. An analysis of EVPI by individual parameters or groups of parameters shows that additional research about adherence to preventive phlebotomy could potentially provide the highest benefit. The potential value of further research also depends on methodological assumptions regarding the decision maker's time horizon as well as on scenarios with an impact on the number of affected patients and the cost-effectiveness of screening. PMID- 22526860 TI - [Clinical and health economic challenges of personalized medicine]. AB - Healthcare systems across the globe are currently challenged by aging populations, increases in chronic diseases and the difficult task of managing a healthcare budget. In this health economic climate, personalized medicine promises not only an improvement in healthcare delivery but also the possibility of more cost-effective therapies. It is important to remember, however, that personalized medicine has the potential to both increase and decrease costs. Each targeted therapy must be evaluated individually. However, standard clinical trial design is not suitable for personalized therapies. Therefore, both scientists and regulatory authorities will need to accept innovative study designs in order to validate personalized therapies. Hence correct economic evaluations are difficult to carry out due to lack of clear clinical evidence, longitudinal accounting and experience with patient/clinician behavior in the context of personalized medicine. In terms of reimbursement, payers, pharmaceutical companies and companion diagnostic manufacturers will also need to explore creative risk sharing concepts. Germany is no exception to the challenges that face personalized medicine and for personalized medicine to really become the future of medicine many health economic challenges first need to be overcome. The health economic implications of personalized medicine remain unclear but it is certain that the expansion of targeted therapies in current healthcare systems will create a host of challenges. PMID- 22526861 TI - [Costs of intimate partner violence against women. A systematic review]. AB - About one in four women in Germany have experienced intimate partner violence at some point in their lives. Intimate partner violence against women is associated with a wide range of acute and long-term physical and psychological health problems. Partner violence also incurs huge costs to healthcare services, social care and the legal system with a subsequent loss in economic productivity. This systematic review will present existing studies on cost estimations with a particular focus on the types of costs and methodological problems in the studies which will provide information for the development of future surveys estimating the costs of partner violence. Electronic databases were searched in addition to manual searches. The database search for identification of such studies was only partially successful because administrative reports predominated. A total of nine cost estimates were identified which fulfilled the inclusion criteria and three studies considered direct, indirect and intangible costs. Due to the fragmentary data there is considerable heterogeneity in the cost categories and it can be assumed that the real costs are higher than those found in the studies. For reasons of international comparability, future data collection should be based on standard indicators which still need to be formulated. PMID- 22526862 TI - [Health promotion for long-term unemployed. Effects on motivation for a healthy lifestyle]. AB - Among the long-term unemployed ill health is often a hindrance to successful reintegration in the job market. In a quasi-experimental controlled study we examined the effects of a health promotion intervention program tailored to the specific needs of the long-term unemployed combining individual sessions based on motivational interviewing and participatory group sessions including physical activity. Over a period of 3 months the participants of the intervention group (n = 179) showed more improvement compared to the control group (n = 108) in terms of motivation for lifestyle changes towards more physical activity and healthier nutrition. Participants of the intervention group developed an intention to act significantly more often (active lifestyle: odds ratio 4.44; 95% CI: 2.00-9.83; healthy nutrition: odds ratio 3.94; 95% CI: 1.55-10.00) and actually implemented a behavior change significantly more often (active lifestyle: odds ratio 2.77; 95% CI: 1.35-5.71; healthy nutrition: odds ratio 4.34; 95% CI: 1.92-9.78). In terms of smoking and alcohol consumption no significant intervention effects were detected. The results of the study show the effectiveness of the described health promotion program regarding a lifestyle change towards more healthy nutrition and more physical activity. PMID- 22526863 TI - [Selected aspects of citizen and patient orientation in Germany. Assessment from the point of view of users]. AB - The growing citizen and patient orientation of the German healthcare system reflects a health policy process which aims to achieve more individual and social responsibility as well as more autonomy on the part of healthcare users. At the same time the process is regarded as an essential component of a future oriented quality development involving raising transparency, developing competence, strengthening patient rights and improving complaints management. Representative data on these parameters and on people's level of satisfaction with their most recent contact with the healthcare service were collected in the 2009 GEDA survey 'Information Behaviour and Self-determination of Citizens and Patients' by the Robert Koch Institute. It reveals knowledge deficits in the population relating to selected areas of the healthcare service and there are also deficits in people's knowledge and assertion of their rights and in the way complaints are handled. These deficits vary according to demographic and socio-economic criteria (age, sex, educational and social status, status vis a vis health insurance companies). It emerges that different population groups have different needs, which can be used for a target group orientation in the communication of knowledge and the development of competencies. PMID- 22526864 TI - beta2-adrenergic receptor haplotype may be associated with susceptibility to desensitization to long-acting beta2-agonists in COPD patients. AB - PURPOSE: Tauhat beta2-adrenergic receptor (beta2AR) haplotypes may play a key role in clinical response to beta2-agonists and haplotype Cys-19Gly16Gln27 (CysGlyGln) is reported to be associated with desensitization of beta2AR to beta agonists in lymphocytes isolated from patients with asthma and septic shock. We sought to determine whether haplotypic variation of the beta2AR affects the functional outcomes of long-acting beta2-agonist (LABA) treatment for chronic obstructive pulmonary disease (COPD) when used as monotherapy. METHODS: Treatment naive patients with COPD (n = 36) were prospectively treated with two kinds of LABA--inhaled salmeterol and transdermal tulobuterol patch--for 12 weeks in crossover study, and changes in pulmonary function data and 6-minute walk distance (6 MWD) were compared between groups stratified by the CysGlyGln. RESULTS: Frequencies of haplotype and diplotype for the CysGlyGln were 0.51 and 0.36, respectively. The individuals homozygous for CysGlyGln showed less improvement in FEV(1), %FEF(25-75 %), and IC/TLC than those with 0 or 1 copy of CysGlyGln after treatment with both LABAs despite initial bronchodilator responses to albuterol being similar in these groups. The response in these parameters was not significantly different between two types of LABA. Overall changes in 6 MWD in individuals with 2 copies of CysGlyGln versus 0 or 1 copy for salmeterol were 2.8 and 11 m, and for tulobuterol were -1.3 and 16 m, respectively. CONCLUSIONS: Homozygous haplotype for the CysGlyGln of beta2AR may be associated with susceptibility to desensitization to LABA in patients with COPD. PMID- 22526865 TI - The validity of static lung compliance in asbestos-induced diseases. AB - BACKGROUND: Pulmonary compliance can be viewed as an indicator of distensibility of the lungs, not only in asbestos-induced pulmonary disorders but also in visceral pleural fibrosis extending into the lung parenchyma. In this study we evaluated static compliance measurements in asbestos-derived diseases, especially in patients with parietal pleura plaques. Lung function analyses, especially static lung compliance, were correlated with high-resolution computer tomography examinations. METHODS: Sixty-three patients with parietal pleural plaques, 10 with visceral pleural fibrosis, 39 with parenchymal pulmonary asbestosis together with parietal pleural plaques, and 42 with parenchymal pulmonary asbestosis together with visceral pleural fibrosis were enrolled in the study. RESULTS: In comparison with patients having only parietal pleural plaques, those having asbestosis and visceral pleural fibrosis showed significant decreases in static lung compliance, diffusing capacity, and vital capacity. Visceral pleural thickening was also associated with significantly reduced FEV(1), MEF(50), and FEV(1)/FVC ratios. Multiple regression analyses indicated that the existence of visceral pleural fibrosis (p = 0.017) is the most important factor accounting for a decrease in static compliance. Reference values of static lung compliance differ notably. In comparison with mean reference values, the sensitivity of detecting reduced lung compliance was calculated to be between 9.7 and 45.5 %. Other respiratory function variables failed to show any significant differences. CONCLUSION: Our data indicate that the measurement of static compliance is not sufficient for early detection of pulmonary function impairment in patients with parietal pleural plaques. PMID- 22526867 TI - Stereo-selectivity in a cyclotriphosphazene derivative bearing an exocyclic P-O moiety. AB - Nucleophilic substitution reactions of N(3)P(3)Cl(4)[O(CH(2))(2)NCH(3)], (1) with the sodium salts of mono- and di-functional alcohols [methanol (2), phenol (3), tetraethyleneglycol (4) and 1,3-propanediol (5)] were carried out in order to investigate a possible directing effect of the spiro O-moiety on the formation of mono-substituted (2a, 3a), non-geminal di-substituted (2c, 3c) and ansa (4a, 5a) derivatives. Compounds isolated from the reactions were characterized by elemental analysis, mass spectrometry, (1)H and (31)P NMR spectroscopy and X-ray crystallographic analysis showed that the substituent OR in compounds (2a, 3a and 2c, 3c) and the ansa-ring in compounds (4a, 5a) formed cis to the P-O moiety of the exocyclic [O(CH(2))(2)NCH(3)] spiro ring. The formation of products (2a-d, 3a d, 4a, 5a and 5b) was quantified from the (31)P NMR spectra of the reaction mixtures, which showed an overwhelming preference for derivatives (2a, 3a, 2c, 3c, 4a, 5a) with the substituent cis to the P-O moiety of the exocyclic spiro ring (2a, 3a, 2c, 3c, 4a, 5a), except for reaction with 1,3-propanediol where the six-membered ring spiro derivative (5b) was about three times more abundant than the eight-membered ring ansa-derivative (5a). Overwhelming formation of products with the substituent cis to the exocyclic P-O moiety is proof that the cation assisted mechanism is responsible for the stereo-selectivity in the reactions with alkoxides. PMID- 22526866 TI - Relaxed genetic constraint is ancestral to the evolution of phenotypic plasticity. AB - Phenotypic plasticity--the capacity of a single genotype to produce different phenotypes in response to varying environmental conditions--is widespread. Yet, whether, and how, plasticity impacts evolutionary diversification is unclear. According to a widely discussed hypothesis, plasticity promotes rapid evolution because genes expressed differentially across different environments (i.e., genes with "biased" expression) experience relaxed genetic constraint and thereby accumulate variation faster than do genes with unbiased expression. Indeed, empirical studies confirm that biased genes evolve faster than unbiased genes in the same genome. An alternative hypothesis holds, however, that the relaxed constraint and faster evolutionary rates of biased genes may be a precondition for, rather than a consequence of, plasticity's evolution. Here, we evaluated these alternative hypotheses by characterizing evolutionary rates of biased and unbiased genes in two species of frogs that exhibit a striking form of phenotypic plasticity. We also characterized orthologs of these genes in four species of frogs that had diverged from the two plastic species before the plasticity evolved. We found that the faster evolutionary rates of biased genes predated the evolution of the plasticity. Furthermore, biased genes showed greater expression variance than did unbiased genes, suggesting that they may be more dispensable. Phenotypic plasticity may therefore evolve when dispensable genes are co-opted for novel function in environmentally induced phenotypes. Thus, relaxed genetic constraint may be a cause--not a consequence--of the evolution of phenotypic plasticity, and thereby contribute to the evolution of novel traits. PMID- 22526868 TI - Infectious diseases publications in leading medical journals--a comparative analysis. AB - The representation of medical disciplines in leading journals may provide valuable information on their respective importance for both researchers and funding agencies. We were interested in the scientific contribution of infectious diseases to leading medical journals and their ranking compared to other medical disciplines. Original articles and short communications in three leading medical journals from 2003 to 2009 were analyzed by contributing medical discipline and by nation: The New England Journal of Medicine (NEJM), The Lancet, and the Journal of the American Medical Association (JAMA). The medical disciplines were selected according to a standard textbook (Harrison's Principles of Internal Medicine). Each article was categorized into one to three medical disciplines. The most frequently represented disciplines in 3,953 articles were cardiology (19.5 %), infectious diseases (18.6 %), and hematology/oncology (15.9 %). Each of the journals had another leading discipline: cardiology in JAMA, hematology/oncology in NEJM, and infectious diseases in The Lancet. In the American journals, contributions from US researchers dominated the field (52.6 % in NEJM, 73.6 % in JAMA), while the majority of papers in The Lancet originated from non-US residents (76.5 %). This study underlines the importance of infectious diseases as a medical discipline in clinical research. PMID- 22526869 TI - Self-administration of outpatient parenteral antibiotic therapy and risk of catheter-related adverse events: a retrospective cohort study. AB - Despite increasing use, limited data has been published comparing safety of different outpatient parenteral antimicrobial therapy (OPAT) models. Potential risks of self-administration at home include venous access device infection and other line complications. This study aims to investigate rates and predictors of intravenous access device complications in a large OPAT cohort. This is a retrospective cohort study of all uses of midlines, peripherally inserted central catheters (PICCs) and tunnelled central venous catheters (TCVCs) with univariate and multivariate (logistic regression) analysis of factors associated with line infections (LIs) and with other line events (OLEs). On univariate analysis, line infections were associated with length of line use, female sex and TCVC lines (compared to midlines). Patients self-administering OPAT in the home had a non significantly lower rate of LIs. On multivariate analysis only duration of line use was a significant predictor of LIs-OR 1.012 (95%CI 1.001-1.023). For OLEs, multivariate analysis suggested that only line type and use of flucloxacillin were significant explanatory variables. In this cohort, there is no evidence that self-administration of OPAT is associated with higher rates of venous access device complications after controlling for confounding variables. PMID- 22526870 TI - Prospective evaluation of clinical scoring systems in infants with bronchiolitis admitted to the intensive care unit. AB - The objective of this investigation was to compare different scoring systems to assess the severity of illness in infants with bronchiolitis admitted to a tertiary paediatric intensive care unit (PICU). Over an 18-year period (1990 2007), infants with bronchiolitis aged up to 12 months and admitted to the PICU were prospectively scored using the Pediatric Risk of Mortality III (PRISM III) score, the Organ System Failure (OSF) score and the Acute Physiologic Score for Children (APSC) within 24 h. Infants were compared as to whether or not bronchiolitis was associated with respiratory syncytial virus (RSV). There was no difference between 113 RSV-positive and 80 RSV-negative infants regarding gestational age, birth weight, rate of premature delivery or bronchopulmonary dysplasia (BPD). The PRISM III score differed significantly between RSV-positive and RSV-negative cases (3.27 +/- 0.39 vs. 1.96 +/- 0.44, p = 0.006), as did the OSF score (0.56 +/- 0.05 vs. 0.35 +/- 0.06, p = 0.049) and the APSC (5.16 +/- 0.46 vs. 4.1 +/- 0.53, p = 0.048). All scores were significantly higher in the subgroup with mechanical ventilation (p < 0.0001). The mean time of ventilation was significantly higher in the RSV-positive group compared to the RSV-negative group (6.39 +/- 1.74 days vs. 2.4 +/- 0.47 days, p < 0.001). Infants suffering from RSV-positive bronchiolitis had higher clinical scores corresponding with the severity of bronchiolitis. PMID- 22526872 TI - 28S rDNA haplotypes of males are distinct from those of androgenetic hermaphrodites in the clam Corbicula leana. AB - The clam Corbicula leana exists in two forms, hermaphrodites and males. Our previous study on mitochondrial DNA suggested that the male nuclear DNA might have derived from hermaphrodite C. leana relatively recently. To clarify the origin of males in the clam, sequences of the nuclear 28S rDNA divergent domain (which is 441-444 bp long) in androgenetic hermaphrodites and males and dioecious (bisexual) species were analyzed. Unexpectedly, the nuclear 28S rDNA haplotypes of males and hermaphrodites were distinct. Haplotype network analysis indicated that males and hermaphrodites are reproductively isolated from each other without sharing the same nuclear haplotype. These results support a hypothesis that the egg nuclear genome of androgenetic hermaphrodites is replaced by the male sperm genome, and only males develop after fertilization by a male spermatozoon. PMID- 22526871 TI - Score to identify the severity of adult patients with influenza A (H1N1) 2009 virus infection at hospital admission. AB - The objective of this paper was to develop a prognostic index for severe complications among hospitalized patients with influenza A (H1N1) 2009 virus infection. We conducted a prospective observational cohort study of 618 inpatients with 2009 H1N1 virus infection admitted to 36 Spanish hospitals between July 2009 and February 2010. Risk factors evaluated included host-related factors and clinical data at admission. We developed a composite index of severe in-hospital complications (SIHC), which included: mortality, mechanical ventilation, septic shock, acute respiratory distress syndrome, and requirement for resuscitation maneuvers. Six factors were independently associated with SIHC: age >45 years, male sex, number of comorbidities, pneumonia, dyspnea, and confusion. From the beta parameter obtained in the multivariate model, a weight was assigned to each factor to compute the individual influenza risk score. The score shows an area under the receiver operating characteristic (ROC) curve of 0.77. The SIHC rate was 1.9 % in the low-risk group, 10.3 % in the intermediate risk group, and 29.6 % in the high-risk group. The odds ratio for complications was 21.8 for the high-risk group compared with the low-risk group. This easy-to score influenza A (H1N1) 2009 virus infection risk index accurately stratifies patients hospitalized for H1N1 virus infection into low-, intermediate-, and high risk groups for SIHC. PMID- 22526873 TI - Rananos expression pattern during oogenesis and early embryonic development in Rhynchosciara americana. AB - The Dipteran Rhynchosciara americana, a native Brazilian insect that has become a valuable model system for developmental biology research because it provides an interesting opportunity to study a different type of insect oogenesis. Sequences from a cDNA library that was constructed with poly A+RNA from the ovaries of R. americana larvae at different ages were analyzed. Molecular characterization confirmed interesting findings, such as the presence of Rananos. The nanos gene encodes a conserved RNA-binding protein that is required during early development for the maintenance and division of the primordial germ cells of Diptera. nanos plays an important role in specifying the posterior regions of insect embryos and is important for abdomen formation. In the present work, we showed the spatial and temporal expression profiles of this important gene, which is involved in oogenesis and early development. Data mining techniques were used to obtain the complete sequence of Rananos. Bioinformatic tools were used to determine the following: (1) the secondary structure of the 3'-untranslated region of the Rananos mRNA, (2) the encoded protein of the isolated Rananos gene, (3) the conserved zinc-finger domains of the RaNanos protein, and (4) phylogenetic analyses. Furthermore, RNA in situ hybridization and immunolocalization were used to determine mRNA and protein expression in the tissues that were studied and to define Rananos as a germ cell molecular marker. PMID- 22526874 TI - Islet1-expressing cardiac progenitor cells: a comparison across species. AB - Adult mammalian cardiac stem cells express the LIM-homeodomain transcription factor Islet1 (Isl1). They are considered remnants of Isl1-positive embryonic cardiac progenitor cells. During amniote heart development, Isl1-positive progenitor cells give rise mainly to the outflow tract, the right ventricle, and parts of the atria. This led to the hypothesis that the development of the right ventricle of the amniote heart depends on the recruitment of additional cells to the primary heart tube. The region from which these additional, Isl1-positive cells originate is called second heart field, as opposed to the first heart field whose cells form the primary heart tube. Here, we review the available data about Isl1 in different species, demonstrating that Isl1 is an important component of the core transcription factor network driving early cardiogenesis in animals of the two clades, deuterostomes, and protostomes. The data support the view of a single cardiac progenitor cell population that includes Isl1-expressing cells and which differentiates into the various cardiac lineages during embryonic development in vertebrates but not in other phyla of the animal kingdom. PMID- 22526876 TI - Prepatellar Morel-Lavallee effusion. PMID- 22526875 TI - Treatment of symptomatic para-articular intraosseous cysts by percutaneous injection of bone cement. AB - PURPOSE: To describe the technique and clinical outcome of percutaneous injection of bone cement in the treatment of symptomatic para-articular intraosseous cysts. MATERIALS AND METHODS: Five patients (three men, two women; mean age 35 years) with painful para-articular intraosseous cysts were treated by percutaneous injection of bone cement under combined fluoroscopic and computed tomography (CT) guidance. The lesions were all located in weight-bearing bones, involving the acetabulum, proximal tibia, distal tibia, talus, and calcaneus, respectively. RESULTS: The average amount of bone cement injected was 2.1 ml (range, 0.6-3.5 ml). Calcium phosphate cement was used in four cases and acrylic cement in one case. There were no immediate or delayed complications. Full pain relief was obtained between 1 and 4 weeks after treatment. All patients made a complete recovery and were pain-free at their last visit. CONCLUSIONS: Percutaneous injection of bone cement was a safe and efficient technique in the management of symptomatic para-articular intraosseous cysts in our population. PMID- 22526879 TI - Malignant degeneration of a lumbar osteochondroma into a chondrosarcoma which mimicked a large retropertioneal mass. AB - We report a case of a lumbar spinal osteochondroma that transformed into a large chondrosarcoma in a 39-year-old male who presented with an abdominal mass and back pain. This mass was also associated with a fracture of the stalk, which on cross-sectional imaging mimicked a mass of retroperitoneal origin. The diagnosis of chondrosarcoma transforming from a lumbar osteochondroma became apparent when comparison was made with previous studies. PMID- 22526880 TI - Osteoclast abnormalities in fractured bone during bisphosphonate treatment for osteoporosis: a case report. AB - Bisphosphonates have been widely used in the treatment of an array of bone disorders. Recent complications have included unusual femoral fractures in patients who have received long term bisphosphonate treatment for osteoporosis. Although it has been shown that bisphosphonates are effective by blunting osteoclast resorption, there has been little morphologic description of the local tissue activity at the site of these unusual fractures. To evaluate for local changes to bone morphology at the fracture site in patients presenting with a bisphosphonate-related femur fracture, a sample of cortical bone was obtained at the site of a bisphosphonate fracture and was processed in a nondecalcified manner. The specimen was evaluated for potential cellular changes consistent with bisphosphonate treatment. Significant osteoclast abnormalities at the fracture site were found in a 69-year-old woman treated for 2 years with Fosamax substantiating that bone remodeling at this site is distinctly abnormal. Addressing the osteoclast dysfunction should be a focus of future therapeutic attention and intervention. PMID- 22526881 TI - Fibrolipomatous hamartoma of the inferior calcaneal nerve (Baxter nerve). AB - Fibrolipomatous hamartoma (FLH) is a rare, benign lesion of the peripheral nerves most frequently involving the median nerve and its digital branches (80 %). Pathognomonic MR features of FLH such as coaxial-cable-like appearance on axial planes and a spaghetti-like appearance on coronal planes have been described by Marom and Helms, obviating the need for diagnostic biopsy. We present a case of fibrolipomatous hamartoma of the inferior calcaneal nerve (Baxter nerve) with associated subcutaneous fat proliferation. PMID- 22526882 TI - K+-Cl- cotransport mediates the bactericidal activity of neutrophils by regulating NADPH oxidase activation. AB - Neutrophilic phagocytosis is an essential component of innate immunity. During phagocytosis, the generation of bactericidal hypochlorous acid(HOCl) requires the substrates, Cl- and superoxide produced by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase to kill the internalized pathogens. Here we show that the neutrophilic K+-Cl- cotransporter (KCC) constitutes aCl- permeation pathway and mediates the bactericidal activity by regulating NADPH oxidase activation. Dihydroindenyloxy alkanoic acid (DIOA), a KCC inhibitor, suppressed the toxin- or chemical-induced efflux of 36Cl- or 86Rb+, and diminished the production of superoxide in human and murine neutrophils. Inhibition of KCC activity or knockdown of KCC expression, in particular KCC3, reduced the phosphorylation as well as the membrane recruitment of oxidase components. Activated neutrophils displayed a significant colocalization of KCC3 and early endosomal marker, indicating that KCC3 could be localized on the phagosomes once neutrophils are activated. The NADPH oxidase activity and the phosphorylation level of oxidase component were 50% lower in the neutrophils isolated from KCC3-/- mice than in the neutrophils isolated from KCC3+/+ mice.Mortality rate after intraperitoneal challenge with Staphylococcus aureus was higher in KCC3-/- mice, and the bacterial clearance was impaired in the survivors.We conclude that, in activated neutrophil, NADPH oxidase complexes are associated with KCC3 at the plasma membrane and are internalized to form phagosomes, where KCC activity and expression level affect the production of oxidants. PMID- 22526883 TI - Human responses to bright light of different durations. AB - Light exposure in the early night induces phase delays of the circadian rhythm in melatonin in humans. Previous studies have investigated the effect of timing, intensity, wavelength, history and pattern of light stimuli on the human circadian timing system. We present results from a study of the duration-response relationship to phase-delaying bright light. Thirty-nine young healthy participants (16 female; 22.18+/-3.62 years) completed a 9-day inpatient study. Following three baseline days, participants underwent an initial circadian phase assessment procedure in dim light (<3 lux), and were then randomized for exposure to a bright light pulse (~10,000 lux) of 0.2 h, 1.0 h, 2.5 h or 4.0 h duration during a 4.5 h controlled-posture episode centred in a 16 h wake episode. After another 8 h sleep episode, participants completed a second circadian phase assessment. Phase shifts were calculated from the difference in the clock time of the dim light melatonin onset (DLMO) between the initial and final phase assessments. Exposure to varying durations of bright light reset the circadian pacemaker in a dose-dependent, non-linear manner. Per minute of exposure, the 0.2 h duration was over 5 times more effective at phase delaying the circadian pacemaker (1.07+/-0.36 h) as compared with the 4.0 h duration (2.65+/-0.24 h). Acute melatonin suppression and subjective sleepiness also had a dose-dependent response to light exposure duration. These results provide strong evidence for a non-linear resetting response of the human circadian pacemaker to light duration. PMID- 22526884 TI - Differential blood flow responses to CO2 in human internal and external carotid and vertebral arteries. AB - Arterial CO2 serves as a mediator of cerebral blood flow(CBF), and its relative influence on the regulation of CBF is defined as cerebral CO2 reactivity. Our previous studies have demonstrated that there are differences in CBF responses to physiological stimuli (i.e. dynamic exercise and orthostatic stress) between arteries in humans. These findings suggest that dynamic CBF regulation and cerebral CO2 reactivity may be different in the anterior and posterior cerebral circulation. The aim of this study was to identify cerebral CO2 reactivity by measuring blood flow and examine potential differences in CO2 reactivity between the internal carotid artery (ICA), external carotid artery (ECA) and vertebral artery (VA). In 10 healthy young subjects, we evaluated the ICA, ECA, and VA blood flow responses by duplex ultrasonography (Vivid-e, GE Healthcare), and mean blood flow velocity in middle cerebral artery (MCA) and basilar artery (BA) by transcranial Doppler (Vivid-7, GE healthcare) during two levels of hypercapnia (3% and 6% CO2), normocapnia and hypocapnia to estimate CO2 reactivity. To characterize cerebrovascular reactivity to CO2,we used both exponential and linear regression analysis between CBF and estimated partial pressure of arterial CO2, calculated by end-tidal partial pressure of CO2. CO2 reactivity in VA was significantly lower than in ICA (coefficient of exponential regression 0.021 +/- 0.008 vs. 0.030 +/- 0.008; slope of linear regression 2.11 +/- 0.84 vs. 3.18 +/- 1.09% mmHg-1: VA vs. ICA, P <0.01). Lower CO2 reactivity in the posterior cerebral circulation was persistent in distal intracranial arteries (exponent 0.023 +/- 0.006 vs. 0.037 +/- 0.009; linear 2.29 +/- 0.56 vs. 3.31 +/- 0.87% mmHg 1: BA vs. MCA). In contrast, CO2 reactivity in ECA was markedly lower than in the intra-cerebral circulation (exponent 0.006 +/- 0.007; linear 0.63 +/- 0.64% mmHg 1, P <0.01). These findings indicate that vertebro-basilar circulation has lower CO2 reactivity than internal carotid circulation, and that CO2 reactivity of the external carotid circulation is markedly diminished compared to that of the cerebral circulation, which may explain different CBF responses to physiological stress. PMID- 22526885 TI - Two types of extracellular action potentials recorded with narrow-tipped pipettes in skeletal muscle of frog, Rana temporaria. AB - Two types of muscle fibre action potentials (APs) were recorded using narrow tipped extracellular pipettes in isolated sartorius muscles of frog, Rana temporaria. The waveform of type 1 responses (T1 AP, 75% of recordings) was biphasic, 'positive-negative.' The type 2 signals were tri-phasic, 'positive negative-positive' (T2 AP, 18%). The type of AP was preserved for up to 1 h of collecting data from the given site on the muscle fibre. However, a re positioning of the recording pipette by a few micrometres along the axis of the studied fibre resulted in a change of the type of AP in 73% of such attempts. In experiments with detubulated muscles, only T1 APs were observed. In experiments using 10 MUmol l(-1) Ba2+ filled pipettes, the characteristics of the T1 waveform did not change, but the amplitude of the third phase of T2 APs increased progressively during continuous recording. In experiments with 100 MUmol l(-1) Ba2+ filled pipettes, a decline and eventual inversion of the third phase of the T2 signal was observed. Amplitude and duration of the inverted third phase of T2 APs increased progressively with frequency of muscle stimulation. These results can be explained by suggesting that currents generated within the t-tubular system of muscle fibre form the third phase of extracellularly recorded APs. Measurement and analysis of T2 APs present a unique approach in determining the mechanisms controlling accumulation of t-tubular K+ and the role of these mechanisms in regulation of muscle contractility. PMID- 22526886 TI - Muscle sympathetic response to arousal predicts neurovascular reactivity during mental stress. AB - Mental stress often begins with a sudden sensory (or internal) stimulus causing a brief arousal reaction, and is followed by a more long lasting stress phase. Both arousal and stress regularly induce blood pressure (BP) increases whereas effects on muscle sympathetic nerve activity (MSNA) are variable. Here we have compared responses of MSNA and BP during arousal induced by an electrical skin stimulus and mental stress evoked by a 3 min paced auditory serial arithmetic test (PASAT) in 30 healthy males aged 33 +/- 10 years. In addition, recordings were made of ECG, respiratory movements, electrodermal activity and perceived stress. We also monitored corresponding effects of a cold test (CT: 2 min immersion of a hand in ice water). The arousal stimulus evoked significant inhibition of one or two MSNA bursts in 16 subjects, who were classified as responders; the remaining 14 subjects were non-responders. During mental stress responders showed a significant decrease of MSNA and a lesser BP increase compared to non-responders. In non-responders MSNA was unchanged or increased. Perceived stress was higher in non-responders (P = 0.056), but other measures were similar in the two groups. In non-responders mental stress and the cold test induced increases of BP that lasted throughout the subsequent rest period. During the cold test MSNA and BP increased equally in responders and non-responders. In the whole group of subjects, there was a significant correlation (r = 0.80, P < 0.001) between MSNA responses induced by arousal and by mental stress but not between responses evoked by arousal and the cold test (r < 0.1, P > 0.6). Additionally arousal induced MSNA change was positively correlated with blood pressure changes during MS (systolic BP: r = 0.48; P < 0.01; diastolic BP: r = 0.42; P < 0.05) but not with blood pressure changes during CT. We conclude that in males the MSNA response to arousal predicts the MSNA and BP responses to mental stress. PMID- 22526887 TI - C1 neurons excite locus coeruleus and A5 noradrenergic neurons along with sympathetic outflow in rats. AB - C1 neurons activate sympathetic tone and stimulate the hypothalamic-pituitary adrenal axis in circumstances such as pain, hypoxia or hypotension. They also innervate pontine noradrenergic cell groups, including the locus coeruleus (LC) and A5. Activation of C1 neurons reportedly inhibits LC neurons; however, because these neurons are glutamatergic and have excitatory effects elsewhere, we re examined the effect of C1 activation on pontine noradrenergic neurons (LC and A5) using a more selective method. Using a lentivirus that expresses channelrhodopsin2 (ChR2) under the control of the artificial promoter PRSx8, we restricted ChR2 expression to C1 neurons (67%), retrotrapezoid nucleus neurons (20%) and cholinergic neurons (13%). The LC contained ChR2-positive terminals that formed asymmetric synapses and were immunoreactive for vesicular glutamate transporter type 2. Low-frequency photostimulation of ChR2-expressing neurons activated LC (38 of 65; 58%) and A5 neurons (11 of 16; 69%) and sympathetic nerve discharge. Locus coeruleus and A5 inhibition was not seen unless preceded by excitation. Locus coeruleus activation was eliminated by intracerebroventricular kynurenic acid. Stimulation of ChR2-expressing neurons at 20 Hz produced modest increases in LC and A5 neuronal discharge. In additional rats, the retrotrapezoid nucleus region was destroyed with substance P-saporin prior to lentivirus injection into the rostral ventrolateral medulla, increasing the proportion of C1 ChR2-expressing neurons (83%). Photostimulation in these rats activated the same proportion of LC and A5 neurons as in control rats but produced no effect on sympathetic nerve discharge owing to the destruction of bulbospinal C1 neurons. In conclusion, low-frequency stimulation of C1 neurons activates pontine noradrenergic neurons and sympathetic nerve discharge, possibly via the release of glutamate from monosynaptic C1 inputs. PMID- 22526888 TI - Single motor unit activity in human extraocular muscles during the vestibulo ocular reflex. AB - Motor unit activity in human eye muscles during the vestibulo-ocular reflex (VOR) is not well understood, since the associated head and eye movements normally preclude single unit recordings. Therefore we recorded single motor unit activity following bursts of skull vibration and sound, two vestibular otolith stimuli that elicit only small head and eye movements. Inferior oblique (IO) and inferior rectus (IR) muscle activity was measured in healthy humans with concentric needle electrodes. Vibration elicited highly synchronous, short-latency bursts of motor unit activity in the IO (latency: 10.5 ms) and IR (14.5 ms) muscles. The activation patterns of the two muscles were similar, but reciprocal, with delayed activation of the IR muscle. Sound produced short-latency excitation of the IO muscle (13.3 ms) in the eye contralateral to the stimulus. Simultaneous needle and surface recordings identified the IO as the muscle of origin of the vestibular evoked myogenic potential (oVEMP) thus validating the physiological basis of this recently developed clinical test of otolith function. Single extraocular motor unit recordings provide a window into neural activity in humans that can normally only be examined using animal models and help identify the pathways of the translational VOR from otoliths to individual eye muscles. PMID- 22526889 TI - In vitro evaluation of surface roughness, adhesion of periodontal ligament fibroblasts, and Streptococcus gordonii following root instrumentation with Gracey curettes and subsequent polishing with diamond-coated curettes. AB - OBJECTIVES: The objective of the study was to evaluate the efficacy of an additional usage of a diamond-coated curette on surface roughness, adhesion of periodontal ligament (PDL) fibroblasts, and of Streptococcus gordonii in vitro. MATERIALS AND METHODS: Test specimens were prepared from extracted teeth and exposed to instrumentation with conventional Gracey curettes with or without additional use of diamond-coated curettes. Surface roughness (Ra and Rz) was measured before and following treatment. In addition, the adhesion of PDL fibroblasts for 72 h and adhesion of S. gordonii ATCC 10558 for 2 h have been determined. RESULTS: Instrumentation with conventional Gracey curettes reduced surface roughness (median Ra before: 0.36 MUm/after: 0.25 MUm; p < 0.001; median Rz before: 2.34 MUm/after: 1.61 MUm; p < 0.001). The subsequent instrumentation with the diamond-coated curettes resulted in a median Ra of 0.31 MUm/Rz of 2.06 MUm (no significance in comparison to controls). The number of attached PDL fibroblasts did not change following scaling with Gracey curettes. The additional instrumentation with the diamond-coated curettes resulted in a two-fold increase in the number of attached PDL fibroblasts but not in the numbers of adhered bacteria. CONCLUSIONS: Treatment of root surfaces with conventional Gracey curettes followed by subsequent polishing with diamond-coated curettes may result in a root surface which provides favorable conditions for the attachment of PDL fibroblasts without enhancing microbial adhesion. CLINICAL RELEVANCE: The improved attachment of PDL fibroblasts and the limited microbial adhesion on root surfaces treated with scaling with conventional Gracey curettes followed by subsequent polishing with diamond-coated curettes may favor periodontal wound healing. PMID- 22526890 TI - Salivary level of interleukin-8 in oral precancer and oral squamous cell carcinoma. AB - BACKGROUND: Interleukin 8 (IL-8) is a pro-angiogenic, pro-inflammatory mediator that belongs to the family of chemokines. Due to its pro-angiogenic characteristic, it may play a vital role in tumour angiogenesis and progression. OBJECTIVES: This study was designed to estimate the levels of salivary IL-8 in oral precancer and oral squamous cell carcinoma (OSCC) patients and compare them with healthy controls. The aim was to evaluate its efficacy as a potential biomarker for these diseases. MATERIALS AND METHODS: Each group comprised 25 individuals. The salivary IL-8 levels were determined by enzyme-linked immunosorbent assay. RESULTS: The levels of salivary IL-8 were found to be significantly elevated in patients with OSCC as compared to the precancer group (p < 0.0001) and healthy controls (p < 0.0001). However, the difference in salivary IL-8 concentrations among the precancer group and controls was statistically non-significant (p = 0.738). CONCLUSIONS: Our results suggested that salivary IL-8 can be utilised as a potential biomarker for OSCC. Salivary IL 8 was found to be non-conclusive for oral premalignancy in this preliminary study. Hence, its possible role in transition from premalignancy to malignancy needs further research with larger sample sizes. CLINICAL RELEVANCE: Saliva as a diagnostic biofluid offers a number of advantages over blood-based testing. The role of IL-8 in oral cancer if validated further by future research can provide an easy diagnostic test as well as a prognostic indicator for patients undergoing treatment. Therefore, if it's role in tumourigenesis can be sufficiently assessed, it could open up new avenues to find out novel treatment modalities for oral cancer. PMID- 22526891 TI - Efficacy and safety of intraseptal and periodontal ligament anesthesia achieved by computer-controlled articaine + epinephrine delivery: a dose-finding study. AB - OBJECTIVES: The main purpose of this study was to evaluate the dose-dependent anesthetic efficacy of the intraseptal anesthesia (ISA) and periodontal ligament anesthesia (PLA) obtained with different volumes of 4 % articaine and 1:100,000 epinephrine (Ar + Ep) in human mandibular premolars, using a computer-controlled local anesthetic delivery system (CCLADS). The safety profile of Ar + Ep was also studied by investigating the stability of cardiovascular parameters. MATERIAL AND METHODS: One hundred and eighty randomly selected healthy volunteers (ASA I) entered the single-blinded study to receive 16 mg + 4 MUg, 24 mg + 6 MUg, and 32 mg + 8 MUg of Ar + Ep, obtained with different volumes (0.4, 0.6, and 0.8 ml, respectively), for the ISA and PLA. Success rate, onset, and duration of profound pulpal anesthesia were evaluated by the electrical pulp tester, while the width of the anesthetic field and duration of soft tissue anesthesia were recorded using the pinprick testing. A monitor was used for the measurement of cardiovascular parameters. RESULTS: A dose-dependent duration of pulpal and soft tissue anesthesia was obtained only by the ISA. Success rate, duration of both pulpal and soft tissue anesthesia, and its width were significantly better in the ISA compared with the PLA. No significant cardiovascular changes were seen in both groups. CONCLUSIONS: It can be suggested that 0.6 and 0.8 ml of 4 % Ar + 1:100,000 Ep, delivered by CCLADS, offer high success rate and effective clinical parameters of ISA as a primary anesthesia. CLINICAL RELEVANCE: It seems that dental procedures requiring profound pulpal, bone, and soft tissue anesthesia could be effectively and safely obtained by mentioned anesthetic protocol. PMID- 22526892 TI - Microcomputed tomography analysis of particular autogenous bone graft in sinus augmentation at 5 months: differences on bone mineral density and 3D trabecular structure. AB - OBJECTIVES: This study investigated the effects of gender on the three dimensional (3D) bone mineral density (BMD) and micromorphology of the trabeculae of matured autogenous bone grafts after sinus floor augmentation, and compared them to those of adjacent native bone. MATERIALS AND METHODS: Ten bone biopsy samples were removed from the implant placement areas of patients who had received second-stage sinus floor augmentation, and analyzed by microcomputed tomography. BMD phantoms with two calcium hydroxyapatite densities (0.25 and 0.75 g/cm(3)) were used to determine the BMD of the grafted and native bone samples. The 3D structural parameters of the trabeculae, including percentage of bone volume (bone volume/tissue volume, BV/TV), trabecular thickness (Tb.Th), trabecular number, trabecular separation, trabecular pattern factor (Tb.Pf), and structure model index, were analyzed between males and females and between grafted bone and native bone. RESULTS: No significant gender-specific differences in BMD and 3D trabecular structure of either native or grafted bone were found (P > 0.05). Compared to the adjacent native bone, the autogenous grafted bone exhibited lower BV/TV and Tb.Th as well as a higher Tb.Pf (P < 0.05). Additionally, there was a weak positive correlation between the Tb.Th values of grafted and native bone (R (2) = 0.58). CONCLUSIONS: In the maxillary sinus, autogenous grafted bone exhibited lower BV/TV, Tb.Th, and trabecular connectivity than the adjacent native bone. No significant gender-specific differences were found for either the BMD or 3D trabecular structure of grafted bone. CLINICAL RELEVANCE: After bone remodeling, autogenous grafted bone revealed different 3D trabecular structure as compared to native bone. PMID- 22526893 TI - Influence of caries infiltrant contamination on shear bond strength of different adhesives to dentin. AB - OBJECTIVES: To analyze whether the contamination with a caries infiltrant system impairs the adhesive performance of etch-and-rinse and self-etching adhesives on dentin. MATERIALS AND METHODS: Dentin contamination with the caries infiltrant system (Icon, DMG) was simulated by applying either hydrochloric acid (15 % HCl, Icon Etch, 15 s), the resin infiltrant (Icon infiltrant, 4 min), or both prior to the application of the respective adhesives (each group n = 10). In the control groups, the etch-and-rinse adhesive (Optibond FL, Kerr) and the self-etching adhesive (iBOND Self Etch, Hereaus) were applied without former contamination with the infiltrant system. Additionally, the adhesive performance of the resin infiltrant alone was tested. Shear bond strength of a nano-hybrid composite was analyzed after thermocycling (5,000*, 5-55 degrees C) of the specimens and analyzed by ANOVA/Scheffe post hoc tests (p < 0.05) and Weibull statistics. Failure mode was inspected under a stereomicroscope at * 25 magnification. RESULTS: Contamination with the resin infiltrant alone did not impair shear bond strength, while contamination with hydrochloric acid or with hydrochloric acid and the resin infiltrant reduced shear bond strength (MPa) of the adhesives (Optibond FL: 20.5 +/- 3.6, iBOND Self Etch: 17.9 +/- 2.6) significantly. Hydrochloric acid contamination increased the number of adhesive failures. The adhesive performance of the caries infiltrant system alone was insufficient. CONCLUSION: The contamination with the caries infiltrant system impaired the shear bond strength of conventional dental adhesives. CLINICAL RELEVANCE: Contamination of the caries infiltrant system on dentin should be avoided due to the detrimental effect of hydrochloric acid etching. PMID- 22526894 TI - Dental erosion prevalence and associated risk indicators among preschool children in Athens, Greece. AB - OBJECTIVES: The aims of the study were to investigate dental erosion prevalence, distribution and severity in Greek preschool children attending public kindergartens in the prefecture of Attica, Greece and to determine the effect of dental caries, oral hygiene level, socio-economic factors, dental behavior, erosion related medication and chronic illness. MATERIAL AND METHODS: A random and stratified sample of 605 Greek preschool children was clinically examined for dental erosion using the Basic Erosive Wear Examination Index (BetaEpsilonWE). Dental caries (dmfs) and Simplified Debris Index were also recorded. The data concerning possible risk indicators were derived by a questionnaire. Zero inflated Poisson regression was generated to test the predictive effects of the independent variables on dental erosion. RESULTS: The prevalence of dental erosion was 78.8 %, and the mean and SE of BEWE index was 3.64 +/- 0.15. High monthly family income was positively related to BetaEpsilonWE cumulative scores [RR = 1.204 (1.016-1.427)], while high maternal education level [RR = 0.872 (0.771-0.986)] and poor oral hygiene level [DI-s, RR = 0.584 (0.450-0.756)] showed a negative association. CONCLUSIONS: Dental erosion is a common oral disease in Greek preschool children in Attica, related to oral hygiene and socio economic factors. CLINICAL RELEVANCE: Programs aimed at erosion prevention should begin at an early age for all children. PMID- 22526895 TI - Impact of laminar flow velocity of different acids on enamel calcium loss. AB - OBJECTIVE: The aim of the study was to evaluate the impact of flow velocity under laminar flow conditions of different acidic solutions on enamel erosion. MATERIAL AND METHODS: A total of 240 bovine enamel specimens were prepared and allocated to 30 groups (n = 8 each). Samples of 18 groups were superfused in a flow chamber system with laminar flow behavior using 1 ml of citric acid or hydrochloric acid (HCl) of pH 2.0, 2.6 or 3.0. Flow rates in the sample chamber were adjusted to 10, 60 or 100 MUl/min. To simulate turbulent flow behavior, samples of six groups were immersed in 1 ml of the respective solution, which was vortexed (15 min, 600 rpm). For simulating non-agitated conditions, specimens of the remaining six groups were immersed in 1 ml of the respective solution without stirring. Calcium in the solutions, released from the enamel samples, was determined using Arsenazo III method. RESULTS: For acidic solutions of pH 2.6 and 3.0, erosive potential of citric acid was equivalent to that of HCl at a flow of 100 MUl/min. The same observation was made for the samples subjected to turbulent conditions at pH 3. At all other conditions, citric acid induced a significantly higher calcium loss than HCl. CONCLUSION: It is concluded that under slow laminar flow conditions, flow rate variations lead to higher erosive impact of citric acid compared to hydrochloric acid at pH 2.0, but not at pH >= 2.6 and increasing laminar flow or turbulent conditions. CLINICAL RELEVANCE: Erosive enamel dissolution under laminar flow conditions is a complex issue influenced by flow rate and acidic substrate. PMID- 22526896 TI - Processing of coherent visual motion in topographically organized visual areas in human cerebral cortex. AB - Recent imaging studies in human subjects have demonstrated representations of global visual motion in medial parieto-occipital cortex (area V6) and posterior parietal cortex, the latter containing at least seven topographically organized areas along the intraparietal sulcus (IPS0-IPS5, SPL1). In this fMRI study we used topographic mapping procedures to delineate a total of 18 visual areas in human cerebral cortex and tested their responsiveness to coherent visual motion under conditions of controlled attention and fixation. Preferences for coherent visual motion as compared to motion noise as well as hemispheric asymmetries were assessed for contralateral, ipsilateral, and bilateral visual motion presentations. Except for areas V1-V4 and IPS3-5, all other areas showed stronger responses to coherent motion with the most significant activations found in V6, followed by MT/MST, V3A, IPS0-2 and SPL1. Hemispheric differences were negligible altogether suggesting that asymmetries in parietal cortex observed in cognitive tasks do not reflect differences in basic visual response properties. Interestingly, areas V6, MST, V3A, and areas along the intraparietal sulcus showed specific representations of coherent visual motion not only when presented in the hemifield primarily covered by the given visual representation but also when presented in the ipsilateral visual field. This finding suggests that coherent motion induces a switch in spatial representation in specialized motion areas from contralateral to full-field coding. PMID- 22526897 TI - Comparison of magnetic resonance imaging and histopathological response to chemoradiotherapy in locally advanced rectal cancer. AB - BACKGROUND: Magnetic resonance imaging (MRI) methods for chemoradiotherapy (CRT) response assessment of rectal cancer include posttreatment T staging (ymrT), tumor regression grading (mrTRG), volume reduction posttreatment, and modified RECIST measurement. We compared these methods in identifying good versus poor responders with the histopathological standards of T stage (ypT) and tumor regression grading (TRG). METHODS: A total of 86 patients underwent CRT in a prospective phase II trial for MRI-defined locally advanced rectal cancer. Two readers independently assessed MRIs for ymrT, mrTRG, volume change, and RECIST. Parameters for each case were categorized as good or poor response and analyzed against ypT and TRG by univariate logistic regression. RESULTS: A total of 83 patients had evaluable imaging, and 78 had final pathology (five did not undergo surgery). Of these, 34 patients had good response (ypT0-3a) and 44 had poor response (>ypT3a). Also, 27 patients had favorable pathologic TRG (predominant fibrosis) and 51 had unfavorable TRG (predominant tumor). Good mrTRG and ymr 80 % showed an OR of 3.23 (95 % CI: 1.14-9.17), 4.25 (95 % CI: 0.92 15.45), respectively, for a good ypT score (P = 0.028), but there was no association for histopathological TRG. CONCLUSION: Favorable and unfavorable histopathology are predicted by both ymrT and mrTRG, and we recommend these parameters for post-treatment assessment of rectal cancers treated with CRT. PMID- 22526898 TI - Is melphalan dose adjustment according to ideal body weight useful in isolated limb infusion for melanoma? AB - BACKGROUND: Isolated limb infusion (ILI), introduced in 1992, is a technique used to deliver regional chemotherapy to treat advanced melanoma confined to a limb. Adjusting melphalan dose according to ideal body weight (IBW) has been proposed as a method of decreasing limb toxicity without compromising outcome. The current study analyzed this proposed dose adjustment. METHODS: We reviewed 99 consecutive patients with lower extremity melanomas treated by ILI at our institution between May 1998 and February 2009. Toxicity and outcomes were tested for correlation with differences between administered dose and calculated adjusted dose, both in mg and mg/L, and with differences between actual limb volume and calculated adjusted limb volume. RESULTS: The median actual body weight was 71 kg, whereas the calculated median IBW was 57 kg (p < .001). Median administered melphalan dose was 7.7 mg/L. The median calculated adjusted dose was 6.5 mg/L (range 3.2 9.3 mg/L, p < .001). None of the three aforementioned parameters correlated with either Wieberdink toxicity grade or outcome. BMI did not correlate with toxicity either. Interestingly, a higher total melphalan dose did not only correlate with higher toxicity, but also with a lower response rate. CONCLUSIONS: Adjusting the melphalan dose for IBW does not appear to reduce toxicity following ILI for melanoma. The effect on outcome remains uncertain. More research is needed to optimize melphalan concentrations in individual patients during ILI to limit toxicity without compromising the response. PMID- 22526899 TI - Decreasing rates of lymph node dissection during radical nephrectomy for renal cell carcinoma. AB - BACKGROUND: The utility of lymph node dissection (LND) during radical nephrectomy for renal cell carcinoma (RCC) continues to be controversial, yet its use by urologists in the United States is unknown. We analyzed the incidence of and trends in LND from a large, nationally representative cancer registry. METHODS: Using the Surveillance, Epidemiology, and End Results registry we identified 37,279 patients with RCC who underwent radical nephrectomy from 1988 to 2005. LND was defined as a surgeon removing >=5 nodes; however, sensitivity tests were performed using cutoffs of >=3 and >=1 nodes. We analyzed changes in LND rates over time and used multivariable logistic regression to predict those who underwent LND. RESULTS: Of the 37,279 patients with RCC, 2,463 (6.6 %) received a LND. There was a gradual decline in LND beginning in 1988 that accelerated after 1997, with the period of 1998-2005 having significantly decreased odds of LND compared with the period 1988-1997 (odds ratio [OR]: 0.65; 95 % confidence interval [95 % CI]: 0.59-0.71). This decline was driven primarily by a 63 % reduction in LND rates among localized tumors (p < .001). CONCLUSIONS: There has been a significant decline in LND rates during radical nephrectomy for localized kidney cancer over the past 7 years. In contrast to prior estimates, very few urologists in the United States are removing >=5 nodes during lymph node dissection for RCC. PMID- 22526901 TI - FANCJ expression predicts the response to 5-fluorouracil-based chemotherapy in MLH1-proficient colorectal cancer. AB - PURPOSE: Fanconi anemia protein, FANCJ, directly interacts with MLH1, a key protein involved in DNA mismatch repair. Deficient mismatch repair, or microsatellite instability, is a potent marker for the ineffectiveness of 5 fluorouracil (5-FU) in colorectal cancer (CRC). We investigated the significance of FANCJ expression in CRC, focusing on the effects of 5-FU-based adjuvant chemotherapy. METHODS: Clinicopathologic features and immunohistochemical expression of FANCJ and MLH1 were studied in 219 patients with CRC. We also analyzed 5-FU sensitivity in CRC cell lines with varying levels of FANCJ expression. RESULTS: FANCJ expression was elevated in tumor tissues compared with normal epithelial tissue. High expression of FANCJ was significantly associated with 5-FU resistance measured by the SDI test (P < 0.05) and poor recurrence-free survival (RFS) (P < 0.05). Among patients with stage II/III tumors who received 5 FU, patients with tumors exhibiting high FANCJ expression had significantly worse RFS than did patients with tumors exhibiting low FANCJ expression (P < 0.01). Among patients who did not receive adjuvant chemotherapy, FANCJ expression was not correlated with RFS (P = 0.76). High FANCJ expression was correlated with 5 FU resistance in tumors with normal MLH1 expression (P < 0.05) but not in tumors not expressing MLH1 (P = 0.9). In vitro, FANCJ overexpression was correlated with 5-FU resistance in MLH1-proficient HCT116 3-6 cells but not in MLH1-deficient HCT116 cells. CONCLUSIONS: FANCJ could be a useful biomarker to predict the response to 5-FU and prognosis of CRC, particularly in tumors with normal MLH1 expression. PMID- 22526900 TI - A probabilistic analysis of completely excised high-grade soft tissue sarcomas of the extremity: an application of a Bayesian belief network. AB - BACKGROUND: It is important to understand the relative importance of prognostic variables in patients with soft tissue sarcomas. The purpose of this study was to describe the hierarchical relationships between features inherent to completely excised, localized high-grade soft tissue sarcomas of the extremity and compare the associations to those previously reported. METHODS: Data were collected from the Memorial Sloan-Kettering Cancer Center Sarcoma Database. All adult patients with high-grade extremity soft tissue sarcomas who underwent complete excision (R0 margins) at our institution between 1982 and 2010 were included in the analysis. Bayesian belief network (BBN) modeling software was used to develop a hierarchical network of features trained to estimate the likelihood of disease specific survival. Important relationships depicted by the BBN model were compared to those previously reported. RESULTS: The records of 1318 consecutive patients met the inclusion criteria, and all were included in the analysis. First degree associates of disease-specific survival were the primary tumor size; presence of and time to distant recurrence; and presence of and time to local recurrence. On cross-validation, the BBN model was sufficiently robust, with an area under the curve of 0.94 (95 % confidence interval 0.93-0.96). CONCLUSIONS: We successfully described the hierarchical relationships between features inherent to patients with completely excised high-grade soft tissue sarcomas of the extremity. The relationships defined by the BBN model were similar to those previously reported. Cross-validation results were encouraging, demonstrating that BBN modeling can be used to graphically illustrate the complex hierarchical relationships between prognostic features in this setting. PMID- 22526902 TI - A comparative study of the transperitoneal and posterior retroperitoneal approaches for laparoscopic adrenalectomy for adrenal tumors. AB - BACKGROUND: Laparoscopic adrenalectomy is considered the gold standard for the surgical treatment of small adrenal tumors. However, several approach routes, such as the transperitoneal (TP), lateral retroperitoneal, and the posterior retroperitoneal (PR) approaches are being used based on surgeon's preference. The PR approach has several benefits compared with the others. Recently, the authors used the PR approach to treat several adrenal tumors and here describe the methods used in detail and the preliminary results obtained. METHODS: From January 2009 to July 2010, 58 patients underwent adrenalectomy. Open adrenalectomy and robotic adrenalectomy were performed in 5 and 10 patients. Also, 43 patients underwent laparoscopic adrenalectomy, and the TP and PR approaches were used in 26 and 17 patients, respectively. Clinicopathologic data and surgical outcomes were evaluated and compared retrospectively. RESULTS: There were no significant differences between the TP and PR groups in terms of age, sex, BMI, lesion side, volume of blood loss, or tumor size (3.86 +/- 3.83 in TP approach, 2.64 +/- 1.61 in PR approach). Mean operative time and average oral intake time using the PR approach were shorter than for the TP approach. Less analgesia use was required in patients who underwent PR approach. CONCLUSIONS: This study shows that posterior retroperitoneoscopic adrenalectomy is a safe procedure and the operative time is comparable to transperitoneoscopic adrenalectomy. The use of the PR approach for small adrenal tumor can provide very favorable surgical outcomes compared with the TP approach. PMID- 22526903 TI - Outcome of patients with colorectal liver metastasis: analysis of 1,613 consecutive cases. AB - OBJECTIVE: This study was designed to evaluate the long-time outcome of patients with colorectal liver metastasis (CRLM) undergoing different types of therapy and identify prognosis factors. METHODS: From 2000 to 2010, 1,613 consecutive patients with CRLM were identified. Clinicopathological and outcome data were collected and analyzed by univariate and multivariate analyses. RESULTS: Synchronous liver metastasis (SLM), female, grade III-IV, T4 and N positive of primary tumor, bilobar disease, number of liver metastases >= 4, size of largest liver metastases >= 5 cm, serum CEA level >= 5 ng/ml, and CA19-9 level >= 37 u/ml were the predictors of adverse outcome using univariate analysis. The median survival and 5-year survival rate for patients after resection of liver metastases was 49.8 months and 47%, better than that for those after other therapy. In addition, patients without treatment had the poorest survival. Sixty four initially unresectable patients underwent surgery after conversion therapy with a median survival of 36.9 months and a 5-year survival of 30%. By multivariate analysis, SLM, poorly differentiated primary tumor, number of liver metastases >= 4, size of largest liver metastases >= 5 cm, and no surgical treatment of liver metastases were found to be independent predictors of poor survival. CONCLUSIONS: Patients with CRLM could get long-term survival benefit from different types of therapy, and resection of liver metastases was the optimal strategy. A predictive model using these above five factors may be of use in stratifying patients who may benefit from intensive surveillance and adjuvant therapy. PMID- 22526904 TI - Simultaneous medullary and differentiated thyroid cancer: a population-level analysis of an increasingly common entity. AB - BACKGROUND: Simultaneous medullary thyroid carcinoma (MTC) and differentiated thyroid carcinoma (DTC) is a rare entity. This is the first population-level analysis of the characteristics and outcomes of simultaneous MTC/DTC. METHODS: In the Surveillance, Epidemiology, and End Results (SEER) database (1988-2008), patients with simultaneous MTC/DTC were retrospectively compared with those with MTC alone using chi(2), ANOVA, log-rank tests, Cox multivariate regression, and Kaplan-Meier analyses. RESULTS: A total of 162 patients had simultaneous MTC/DTC; 1,699 had MTC alone. MTC was diagnosed first in 67.9 % of simultaneous MTC/DTC cases. Simultaneous MTC/DTC increased from 2.7 % of all MTCs in 1988-1997 to 12.3 % in 2003-2008. Compared with MTC alone, simultaneous MTC/DTC had smaller mean MTC tumor size (2.9 vs. 2.2 cm; p = 0.005) and lower rates of MTC extrathyroidal extension (25.4 vs. 16.8 %; p = 0.015) and distant metastases (15.7 vs. 9.3 %; p = 0.032). Patients diagnosed with DTC first had smaller mean MTC tumor sizes (p = 0.01), whereas patients diagnosed with MTC first had tumor sizes similar to those of MTC alone. Compared with MTC alone, patients with simultaneous MTC/DTC were more likely to receive thyroidectomy (84.7 vs. 93.2 %; p = 0.003) and radioisotopes (4.4 vs. 25 %; p < 0.001). On Kaplan-Meier analysis, disease specific survival rates were higher for simultaneous MTC/DTC than for MTC alone (10-year survival rates 87 vs. 81 %; p = 0.056). CONCLUSIONS: Simultaneous MTC/DTC is diagnosed earlier in tumor development than MTC alone, with a trend toward better prognosis. This entity likely represents a primary tumor with an incidental pathologic finding of a second malignancy. Each malignancy should be treated according to its respective stage and current guidelines. PMID- 22526905 TI - Resection of adrenocortical carcinoma liver metastasis: is it justified? AB - BACKGROUND: Adrenocortical carcinoma (ACC) liver metastases (LM) represent a therapeutic challenge, and it is unclear whether resection is justified. This study assesses long-term outcome and prognostic factors after liver resection for metastatic ACC. METHODS: Patients who underwent resection of ACC LM were identified from institutional databases. Recurrence, survival, and tumor characteristics, including beta-catenin and TP53 status based on immunohistochemistry and sequencing, were reviewed. The prognostic value of variables was assessed with log-rank test for univariate analysis and Cox proportional hazard models for multivariate analysis. RESULTS: From 1978 to 2009, 28 patients (20 females; median age, 45 years), including 11 with synchronous metastasis and 3 with extrahepatic metastasis, underwent resection for ACC LM (major hepatectomy in 61%). Postoperative mortality was nil and morbidity 55%. On pathological examination, tumors were multiple in 68%, with a median size of 43 mm, and resections were R0, 1, and 2 in 59%, 33%, and 7%, respectively. All 28 patients developed recurrent disease, which was treated surgically in 11, including repeat hepatectomy in 4. Of the 15 patients with adequate tissue for analysis, beta-catenin immunostaining was positive in 7, with 4 corresponding CTNNB1 mutations associated with decreased survival; p53 staining was positive in 5 (4 with corresponding TP53 mutations). The median disease-free and overall survival after hepatectomy was 7 and 31.5 months, respectively, with a 5-year survival of 39%. In multivariate analysis, nonfunctional tumor and surgical treatment of recurrence were independent predictors of good outcome. CONCLUSIONS: In selected patients with ACC LM, resection is associated with long-term survival and is, therefore, justified but rarely curative. PMID- 22526906 TI - A stepwise approach to transanal endoscopic microsurgery for rectal cancer using a single-incision laparoscopic port. AB - BACKGROUND: Radical rectal resection with total mesorectal excision is the current standard of care for the operative treatment of rectal cancer. Local excision is an acceptable alternative in selected patients with early disease (T(is)0-T(1)) and low-risk features, in whom radical resection may be associated with unacceptably high morbidity. With recent data demonstrating favorable results in well-selected patients, the role of local excision for rectal cancer is expanding.1 (,) 2 Transanal endoscopic microsurgery (TEM), which requires the use of an operating anoscope, has been used for the local excision of mid-upper rectal tumors. We describe an alternative approach to TEM for rectal cancer. METHODS: We present a stepwise technique for TEM using a single-incision laparoscopic (SILS) port. The patient is a 64 year-old male with a right anterolateral rectal polyp 7 cm from the anal verge, which on snare polypectomy demonstrated in-situ carcinoma with positive margins. Endoscopic ultrasound demonstrated uT(1) disease with no lymphadenopathy. He opted for local excision and underwent TEM. Our stepwise approach includes: (1) delineation of excision margins, (2) full thickness incision of the rectal wall, (3) circumferential dissection, and full thickness excision, and (4) suture repair. RESULTS: The procedure was performed without intraoperative or postoperative complications. Final pathology revealed in-situ carcinoma with widely negative margins. At 1- and 3-week follow-up visits, the patient was pain free with normal bowel activity and no rectal bleeding or genitourinary dysfunction. DISCUSSION: TEM using a SILS port is an effective technique for the local excision of mid-upper rectal cancer in well-selected patients. PMID- 22526907 TI - Laparoscopic hyperthermic intraperitoneal chemotherapy: indications, aims, and results: a systematic review of the literature. AB - PURPOSE: To evaluate laparoscopic hyperthermic intraperitoneal chemotherapy (HIPEC) with neoadjuvant, adjuvant, or palliative purpose in order to discuss potential clinical implications. METHODS: A systematic search of PubMed's Medline through August 2011 using the keywords laparoscopic, hyperthermic, and chemotherapy. RESULTS: Eight studies encompassing a total of 183 patients were considered. The indications for laparoscopic HIPEC was neoadjuvant in 5 patients, adjuvant in 102 patients, and palliative in 76 patients. There were 13 minor complications not requiring repeat operation, and no deaths related to procedure were recorded. When performed to treat refractory malignant ascites, the procedure was effective in 95 % of cases. CONCLUSIONS: Laparoscopic HIPEC appears to be a safe and effective procedure when performed to treat malignant ascites refractory to less aggressive treatments. The effectiveness of laparoscopy to perform HIPEC with neoadjuvant or adjuvant purpose needs to be confirmed by further studies. PMID- 22526908 TI - A multi-institutional study of pancreatic cancer in Harris County, Texas: race predicts treatment and survival. AB - BACKGROUND: Racial disparities exist for patients with pancreatic cancer. This observation has primarily been noted in the Surveillance, Epidemiology, and End Results database and has focused primarily on whites and African Americans. We sought to determine if these disparities exist in a local, racially diverse patient population. METHODS: Retrospective review of a pancreatic cancer tumor registry from two hospital systems from 1998 to 2010. Clinicopathologic parameters were recorded. Statistical analysis was performed by analysis of variance, Chi square test, Kaplan-Meier survival analysis, log rank test, and regression models. RESULTS: A total of 1039 patients were identified for this study. Hispanic and African American patients presented at an earlier age when compared to whites. There was no difference in gender or stage at presentation between racial groups. Adjusted for stage, race was predictive of chemotherapy administration. Independent predictors of increased mortality included male gender, African American race, stage at diagnosis, and older age. CONCLUSIONS: Despite adjusting for covariates, survival remains lowest for African American patients. Further investigation is needed to understand the effect of race and how it mediates treatment and survival in those with pancreatic cancer. PMID- 22526909 TI - Outcomes after total skin-sparing mastectomy and immediate reconstruction in 657 breasts. AB - BACKGROUND: Total skin-sparing mastectomy (TSSM), a technique comprising removal of all breast and nipple tissue while preserving the entire skin envelope, is increasingly offered to women for therapeutic and prophylactic indications. However, standard use of the procedure remains controversial as a result oft concerns regarding oncologic safety and risk of complications. METHODS: Outcomes from a prospectively maintained database of patients undergoing TSSM and immediate breast reconstruction from 2001 to 2010 were reviewed. Outcome measures included postoperative complications, tumor involvement of the nipple-areolar complex (NAC) on pathologic analysis, and cancer recurrence. RESULTS: TSSM was performed on 657 breasts in 428 patients. Indications included in situ cancer [111 breasts (16.9%)], invasive cancer [301 breasts (45.8%)], and prophylactic risk-reduction [245 breasts (37.3%)]. A total of 210 patients (49%) had neoadjuvant chemotherapy, 78 (18.2%) had adjuvant chemotherapy, and 114 (26.7%) had postmastectomy radiotherapy. Nipple tissue contained in situ cancer in 11 breasts (1.7%) and invasive cancer in 9 breasts (1.4%); management included repeat excision (7 cases), NAC removal (9 cases), or radiotherapy without further excision (4 cases). Ischemic complications included 13 cases (2%) of partial nipple loss, 10 cases (1.5%) of complete nipple loss, and 78 cases (11.9%) of skin flap necrosis. Overall locoregional recurrence rate was 2% (median follow-up 28 months), with a 2.4% rate observed in the subset of patients with at least 3 years' follow-up (median 45 months). No NAC skin recurrences were observed. CONCLUSIONS: In this large, high-risk cohort, TSSM was associated with low rates of NAC complications, nipple involvement, and locoregional recurrence. PMID- 22526910 TI - Relationship between the lymphatic drainage of the breast and the upper extremity: a postmortem study. AB - BACKGROUND: This anatomic study details the lymphatic drainage of the upper extremity (UE) and breast, as well as its course in the axilla and its relation to axillary reverse mapping. Two aspects important for breast cancer surgery were followed: connection between the lymphatics of the UE and breast, and the possible cause of lymphedema of the UE after sentinel node (SN) biopsy. METHODS: Patent blue dye was injected bilaterally in 23 cadavers with no history of breast carcinoma to simultaneously visualize the lymphatics of the UE and breast. After visualization and dissection of the lymphatic vessels and nodes, a record of their routes was made. A scheme of superficial UE and breast lymphatics was constructed. RESULTS: After application of color contrast to the UE, 2-4 main afferent collectors were shown. As opposed to cranial and medial collectors, caudal collectors diverged from the axillary vein and entered the caudal axilla. In five (10.8%) cases, the caudal collector entered a node, which was considered to be the SN of the breast. In six (13%) cases, the SN of the breast and SNs of the UE were found in close proximity (up to 1.5 cm). CONCLUSIONS: Lymphatic drainage of the UE and breast are closely related in the caudal part of the axilla. SN groups for the UE and breast share connections in 24% of cases, which could explain lymphedema after surgery if damaged. Additional studies are needed to further improve our understanding of the lymphatic drainage of the UE and breast. PMID- 22526911 TI - Missed opportunities: clinical antecedents in the diagnosis of advanced breast cancer. AB - BACKGROUND: Locally advanced breast cancer (LABC) often requires complex treatment, and the prognosis is typically poor. We hypothesize that LABC patients engage the healthcare system with a variant pattern as compared with patients diagnosed with early stage disease. METHODS: We identified all newly diagnosed breast cancer patients between 2005 and 2009 at Kings County Hospital (KCH), focusing upon established patients. All provider encounters during 2 years before diagnosis were retrieved from the medical record. Patients were stratified to two groups: early breast cancer (n = 87) and LABC (n = 44). Encounters were classified by type of clinic and whether a clinical breast examination or breast imaging study was performed. RESULTS: The early group made more total contacts with the healthcare system than LABC group, 10.4 and 7.4, respectively. Both groups demonstrated statistically equivalent rates of contact with subspecialty and acute providers. Early patients demonstrated greater usage of primary care services, 4.6 compared with 3.0 visits among LABC patients. The early cohort demonstrated increased rates of breast imaging and examinations overall as well as an increased rate of breast examination within primary care clinics. DISCUSSION: Delayed breast cancer diagnosis is influenced by patterns of healthcare utilization and the effectiveness of primary care services. LABC patients are less likely to visit primary care clinics despite frequent contacts with the healthcare system and as such are less likely to receive basic diagnostic procedures, including clinical breast examination and mammography. Renewed attention to these primary care activities should detect many LABC patients at an earlier stage. PMID- 22526912 TI - Sestamibi-negative patients: to operate or image? PMID- 22526913 TI - Reoperative lymph node dissection for recurrent papillary thyroid cancer and effect on serum thyroglobulin. AB - BACKGROUND: Papillary thyroid cancer (PTC) has an excellent prognosis with current treatment methods. However, the rates of locoregional recurrence after initial surgical management remain significant. This study evaluates the effect of reoperative neck dissection for locoregional recurrence of PTC after initial total thyroidectomy and radioiodine therapy on the incidence of cervical recurrence and postoperative serum thyroglobulin (Tg) levels. METHODS: This is a retrospective cohort study conducted in a single academic medical center of patients with recurrent or persistent PTC isolated to the neck after previous total thyroidectomy with or without lymph node dissection and adjuvant I(131) therapy who were treated with reoperative lymph node dissection. Outcomes including operative complications, pathologic findings, and effect of surgery on Tg levels and rates of recurrent disease were analyzed. RESULTS: From 2001 to 2010, a total of 61 patients had reoperative neck dissections for recurrent cervical PTC with a complication rate of 5 %. Seventy-two percent of patients were clinically free of detectable disease, and 28 % of patients had recurrent, persistent, or newly metastatic disease detected during the follow-up period. All patients had significant decreases in Tg levels, with a median 98 % reduction in preoperative levels. However, only 21 % of patients had an undetectable stimulated Tg (<0.5 ng/mL) during the follow-up period of 15.5 months. CONCLUSIONS: Reoperative treatment of recurrent or persistent PTC can be performed with low complication rates, and Tg levels greatly decrease in most patients; however, few achieve undetectable stimulated Tg. PMID- 22526914 TI - Treating prepartum depression to improve infant developmental outcomes: a study of diabetes in pregnancy. AB - Whether and how the co-occurrence of depression and diabetes in pregnancy may worsen infant development has not been reported. Pregnant women with diabetes and with (n = 34) or without (n = 34) major depressive disorder (MDD) were followed during pregnancy and 6-months postpartum. The MDD subset received randomly assigned treatment with cognitive behavior therapy (CBT) or supportive counseling (SC). Depression severity was measured with the Beck Depression Inventory (BDI); infant developmental outcomes were measured with the Bayley Scales of Infant Development (BSID) and its Behavior Rating Scale (BRS). Infants of women with MDD had lower BRS scores (p = .02). Reduction in depression scores was associated with better infant outcomes on the BSID and BRS (p values <.03). These preliminary findings suggest depression occurring in pregnant women with diabetes is associated with poorer infant development and improvement in prepartum depression is associated with improvement in measures of infant development. PMID- 22526915 TI - Taurine for EPR dosimetry. AB - EPR dosimetry is characterized by its non-destructive read-out and the possibility of dose archival. Here, taurine is proposed as a radiation dosimeter using EPR spectroscopy. The EPR spectrum of taurine was studied and assigned, and changes in the taurine EPR spectrum as a result of the change in both modulation amplitude and microwave power were quantified. For gamma radiation, the energy absorption coefficient and the collision mass stopping power of taurine were compared to the corresponding values of soft tissue and alanine, in addition to calculation of effective atomic numbers. The response of taurine to gamma radiation doses in the range from 0.1 to 50 kGy was investigated, as well as that in the range from 1.0 to 20.0 Gy using numerically enhanced EPR taurine spectra. Both response curves showed a linear behavior. In addition, the time dependence of radiation-induced radicals was studied for short (during the first 6 h after irradiation) and long (during about 3 months after irradiation) time periods, and a reasonable degree of stability of the taurine radicals was observed. It is concluded that taurine is a promising dosimeter, which is characterized by its simple spectrum, radical stability, and wide range of linear response to gamma radiation. PMID- 22526917 TI - Highly selective binding of naphthyridine with a trifluoromethyl group to cytosine opposite an abasic site in DNA duplexes. AB - We report on highly selective binding of a naphthyridine derivative with a trifluoromethyl group to cytosine opposite an abasic site in DNA duplexes; the binding-induced fluorescence quenching is applicable to the analysis of a C related single-base mutation in DNAs amplified by PCR. PMID- 22526916 TI - Micronuclei in human peripheral blood lymphocytes exposed to mixed beams of X rays and alpha particles. AB - The purpose of this study was to analyse the cytogenetic effect of exposing human peripheral blood lymphocytes (PBL) to a mixed beam of alpha particles and X-rays. Whole blood collected from one donor was exposed to different doses of alpha particles ((241)Am), X-rays and a combination of both. All exposures were carried out at 37 degrees C. Three independent experiments were performed. Micronuclei (MN) in binucleated PBL were scored as the endpoint. Moreover, the size of MN was measured. The results show that exposure of PBL to a mixed beam of high and low linear energy transfer radiation led to significantly higher than expected frequencies of MN. The measurement of MN size did not reveal any differences between the effect of alpha particles and mixed beam. In conclusion, a combined exposure of PBL to alpha particles and X-rays leads to a synergistic effect as measured by the frequency of MN. From the analysis of MN distributions, we conclude that the increase was due to an impaired repair of X-ray-induced DNA damage. PMID- 22526918 TI - High postoperative blood levels of macrophage migration inhibitory factor are associated with less organ dysfunction in patients after cardiac surgery. AB - Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine that exerts protective effects during myocardial ischemia/reperfusion injury. We hypothesized that elevated MIF levels in the early postoperative time course might be inversely associated with postoperative organ dysfunction as assessed by the simplified acute physiology score (SAPS) II and sequential organ failure assessment (SOFA) score in patients after cardiac surgery. A total of 52 cardiac surgical patients (mean age [+/- SD] 67 +/- 10 years; EuroScore: 7) were enrolled in this monocenter, prospective observational study. Serum levels of MIF and clinical data were obtained after induction of anesthesia, at admission to the intensive care unit (ICU), 4 h after admission and at the first and second postoperative day. To characterize the magnitude of MIF release, we compared blood levels of samples from cardiac surgical patients with those obtained from healthy volunteers. We assessed patient outcomes using the SAPS II at postoperative d 1 and SOFA score for the first 3 d of the eventual ICU stay. Compared to healthy volunteers, patients had already exhibited elevated MIF levels prior to surgery (64 +/- 50 versus 13 +/- 17 ng/mL; p < 0.05). At admission to the ICU, MIF levels reached peak values (107 +/- 95 ng/mL; p < 0.01 versus baseline) that decreased throughout the observation period and had already reached preoperative values 4 h later. Postoperative MIF values were inversely correlated with SAPS II and SOFA scores during the early postoperative stay. Moreover, MIF values on postoperative d 1 were related to the calculated cardiac power index (r = 0.420, p < 0.05). Elevated postoperative MIF levels are inversely correlated with organ dysfunction in patients after cardiac surgery. PMID- 22526920 TI - Is newer better?--evaluating the effects of data curation on integrated analyses in Saccharomyces cerevisiae. AB - Recent high-throughput experiments have produced a wealth of heterogeneous datasets, each of which provides information about different aspects of the cell. Consequently, integration of diverse data types is essential in order to address many biological questions. The quality of any integrated analysis system is dependent upon the quality of its component data, and upon the Gold Standard data used to evaluate it. It is commonly assumed that the quality of data improves as databases grow and change, particularly for manually curated databases. However, the validity of this assumption can be questioned, given the constant changes in the data coupled with the high level of noise associated with high-throughput experimental techniques. One of the most powerful approaches to data integration is the use of Probabilistic Functional Integrated Networks (PFINs). Here, we systematically analyse the changes in four highly-curated and widely-used online databases and evaluate the extent to which these changes affect the protein function prediction performance of PFINs in the yeast Saccharomyces cerevisiae. We find that the global trend in network performance improves over time. Where individual areas of biology are concerned, however, the most recent files do not always produce the best results. Individual datasets have unique biases towards different biological processes and by selecting and integrating relevant datasets performance can be improved. When using any type of integrated system to answer a specific biological question careful selection of raw data and Gold Standard is vital, since the most recent data may not be the most appropriate. PMID- 22526921 TI - Differential genotoxicity of Roundup((r)) formulation and its constituents in blood cells of fish (Anguilla anguilla): considerations on chemical interactions and DNA damaging mechanisms. AB - It has been widely recognized that pesticides represent a potential threat in aquatic ecosystems. However, the knowledge on the genotoxicity of pesticides to fish is still limited. Moreover, genotoxic studies have been almost exclusively focused on the active ingredients, whereas the effect of adjuvants is frequently ignored. Hence, the present study addressed the herbicide Roundup(r), evaluating the relative contribution of the active ingredient (glyphosate) and the surfactant (polyethoxylated amine; POEA) to the genotoxicity of the commercial formulation on Anguilla anguilla. Fish were exposed to equivalent concentrations of Roundup(r) (58, 116 MUg L-1), glyphosate (17.9, 35.7 MUg L-1) and POEA (9.3, 18.6 MUg L-1), during 1 and 3 days. The comet assay was applied to blood cells, either as the standard procedure, or with an extra step involving DNA lesion specific repair enzymes in an attempt to clarify DNA damaging mechanisms. The results confirmed the genotoxicity of Roundup(r), also demonstrating the genotoxic potential of glyphosate and POEA individually. Though both components contributed to the overall genotoxicity of the pesticide formulation, the sum of their individual effects was never observed, pointing out an antagonistic interaction. Although POEA is far from being considered biologically inert, it did not increase the risk associated to glyphosate when the two were combined. The analysis of oxidatively induced breaks suggested that oxidation of DNA bases was not a dominant mechanism of damage. The present findings highlighted the risk posed to fish populations by the assessed chemicals, jointly or individually, emphasizing the need to define regulatory thresholds for all the formulation components and recommending, in particular, the revision of the hazard classification of POEA. PMID- 22526919 TI - Mammalian DNA is an endogenous danger signal that stimulates local synthesis and release of complement factor B. AB - Complement factor B plays a critical role in ischemic tissue injury and autoimmunity. Factor B is dynamically synthesized and released by cells outside of the liver, but the molecules that trigger local factor B synthesis and release during endogenous tissue injury have not been identified. We determined that factor B is upregulated early after cold ischemia-reperfusion in mice, using a heterotopic heart transplant model. These data suggested upregulation of factor B by damage-associated molecular patterns (DAMPs), but multiple common DAMPs did not induce factor B in RAW264.7 mouse macrophages. However, exogenous DNA induced factor B mRNA and protein expression in RAW cells in vitro, as well as in peritoneal and alveolar macrophages in vivo. To determine the cellular mechanisms involved in DNA-induced factor B upregulation we then investigated the role of multiple known DNA receptors or binding partners. We stimulated peritoneal macrophages from wild-type (WT), toll-like receptor 9 (TLR9)-deficient, receptor for advanced glycation end products (RAGE)-/- and myeloid differentiation factor 88 (MyD88)-/- mice, or mouse macrophages deficient in high-mobility group box proteins (HMGBs), DNA-dependent activator of interferon-regulatory factors (DAI) or absent in melanoma 2 (AIM2), with DNA in the presence or absence of lipofection reagent. Reverse transcription-polymerase chain reaction, Western blotting and immunocytochemical analysis were employed for analysis. Synthesis of factor B was independent of TLR9, RAGE, DAI and AIM2, but was dependent on HMGBs, MyD88, p38 and NF-kappaB. Our data therefore show that mammalian DNA is an endogenous molecule that stimulates factor B synthesis and release from macrophages via HMGBs, MyD88, p38 and NF-kappaB signaling. This activation of the immune system likely contributes to damage following sterile injury such as hemorrhagic shock and ischemia-reperfusion. PMID- 22526922 TI - Are the toxic sediments deposited at Flix reservoir affecting the Ebro river biota? Purple heron eggs and nestlings as indicators. AB - The Flix reservoir, in the low course of the Ebro River, contains thousands of tons of polluted sediments, accumulated from the activities of a chemical factory. An ongoing project is working toward removing these pollutants. Piscivore birds like the purple heron (Ardea purpurea) may be useful bioindicators, so eggs and nestling feathers were sampled during the 2006-2008 breeding seasons at three localities: a reference site situated upstream and two potentially affected by the toxic muds; one at the focal area and one at a distal area, the Ebro Delta. The samples were analyzed for isotopic signatures of 15N and 13C and concentrations of heavy metals and selenium. Baseline nitrogen signatures were higher in riverine sites than in the delta. Nitrogen together with carbon signatures adequately discriminated riverine and deltaic ecosystems. Mercury levels are highly influenced by the polluted sediments at Flix and pose potential risks for the birds, as they are among the highest ever recorded in heron species. Selenium and copper concentrations probably derive from other sources. Except for mercury, heavy metals and selenium levels were below toxic levels. Purple heron eggs and nestling feathers have demonstrated their usefulness as bioindicators for pollution in the river biota; feathers in particular show pollutant impacts on a strict local basis. A long series of study years is necessary in dynamic ecosystems such as this, so continued monitoring of the heron population at Flix is advisable to trace the effects of the toxic muds, particularly during their removal, because of the high levels of mercury detected. PMID- 22526923 TI - Indicators of environmental stress: cellular biomarkers and reproductive responses in the Sydney rock oyster (Saccostrea glomerata). AB - We measured a suite of common biomarker responses for the first time in the Sydney rock oyster Saccostrea glomerata to evaluate their utility as biological effects measures for pollution monitoring. To examine the relationship between biomarker responses and population level effects, fertilisation and embryo development assays were also conducted. Adult oysters were deployed in two contaminated estuaries and a reference estuary in Sydney, Australia. The concentrations of various contaminants (metals and polycyclic aromatic hydrocarbon, PAHs) were quantified in oyster's tissue from each site and both metals and total PAHs were significantly elevated in contaminated estuaries relative to the reference estuary. Lysosomal membrane destabilisation, lipid peroxidation levels and glutathione (GSH) concentrations were measured in the digestive gland of oysters. Of all biomarkers measured, lysosomal membrane destabilisation proved to be the most useful indicator of oysters facing anthropogenic stress and we suggest this may be an especially useful biomarker for incorporation into local environmental monitoring programs. Moreover, lysosomal membrane destabilisation showed good correlations with fertilisation, normal embryo development and estuary status. GSH and lipid peroxidation were not as valuable for distinguishing between estuaries exposed to differing levels of anthropogenic stress, but did provide additional valuable information regarding overall health status of the oysters. PMID- 22526924 TI - Acute toxicity of three strobilurin fungicide formulations and their active ingredients to tadpoles. AB - Fungicide applications in the United States have increased tenfold in the last 5 years. Formulations and active ingredients (AIs) have been demonstrated to cause acute mortality to amphibian life stages. However, there has been little to no discrimination between the toxicity of fungicide formulations and their AIs. Therefore, we compared the acute toxicity of the active ingredients and formulations of the fungicides Headline(r), Stratego(r), and Quilt(r) using Bufo cognatus tadpoles exposed to four concentrations and a control. All fungicides, including AIs and formulations, demonstrated toxicity to tadpoles, with Headline(r) and Stratego(r) causing 100 % mortality at the highest concentrations. Exposure to Quilt(r) formulation and its AIs resulted in 50-60 % tadpole mortality. Overall, toxicity was comparable between AIs and formulations for all fungicides and concentrations, with the exception of Headline(r) at 5 MUg/L, where formulation exposure resulted in 79 % mortality versus no mortality from exposure to the AI. Results suggest the AIs are responsible for most mortality for Quilt(r) and Stratego(r). Results for Headline(r) however suggest that although the AI is toxic to tadpoles at environmentally relevant concentrations, adjuvant(s) in the Headline(r) formulation also contribute to mortality, making it the most toxic of the fungicides studied. PMID- 22526925 TI - Divergent teratogenicity of agonists of retinoid X receptors in embryos of zebrafish (Danio rerio). AB - Zebrafish (Danio rerio) embryos were comparably exposed to seven known agonists of retinoid X receptors (RXRs) including two endogenous compounds (9-cis-retinoic acid and docosahexaenoic acid), four man-made selective ligands (LGD1069, SR11237, fluorobexarotene and CD3254), and a biocide (triphenyltin). The dominant phenotypes of malformation were sharp mouths and small caudal fins in 1 mg/L SR11237-treated group after 5 days exposure. 9-cis-retinoic acid and LGD1069 induced multiple malformations including small eyes, bent notochords, reduced brain, enlarged proctodaems, absence of fins, short tails and edema after 5 days exposure. Fluorobexarotene and CD3254 induced similar phenotypes of malformations after 5 days exposure at low concentration (20 MUg/L) to those after the 1st d exposure at high concentrations (50 and 100 MUg/L). Triphenlytin induced multiple malformations including deformed eyes, bent notochords, bent tails, and edema in hearts after 5 days exposure at concentrations of 1-10 MUg Sn/L. In contrast, no discernible malformations were observed in triphenlytin-treated groups after each separate day exposure. These agonists not only showed different ability of teratogenicity but also induced different phenotypes of malformation in zebrafish embryos. In addition, the sensitive stages of zebrafish embryos were different in response to these agonists. Therefore, our results suggest that the agonists of RXRs had divergent teratogenicity in zebrafish embryos. PMID- 22526926 TI - Plants as models for chromium and nickel risk assessment. AB - The adverse effects of Cr(III), Cr(VI), and Ni(II) expressed as root and shoot growth inhibition, metal accumulation and translocation throughout plants, and genotoxicity study were examined. To examine phytoxicity and metal accumulation, Vicia sativa, Raphanus sativus, Zea mays and Sinapis alba plants were used. Except for S. alba root growth inhibition, Ni had the strongest inhibitory effect on root and shoot growth. The inhibitory rank order based on IC50 values was Ni(II) > Cr(VI) > Cr(III). Z. mays was the least sensitive to all metals. While the accumulation of Cr was higher in the roots than the upper plant parts, Ni transport to shoots was at least two times higher than that of Cr. The highest accumulation of Cr was found in Z. mays and that of Ni in V. sativa and Z. mays roots. For all plants, the translocation factor was higher for Cr(VI) than for Cr(III). The translocation factor for Ni was several times higher than those of Cr. For mutagenicity assay, root tips of V. sativa, R. sativus and Z. mays were used. All metals exerted a significant increase of chromosomal aberrations and the rank order of aberrations was: Cr(VI) > Ni(II) > Cr(III). Genotoxic effects of metals were also determined by analysis of micronuclei frequency in the pollen tetrads of Tradescantia plants. None of metals significantly stimulated micronuclei frequency and the genotoxic effect decreased in the following order: Cr(VI) >= Ni(II) > Cr(III). PMID- 22526927 TI - Effects of organic pollutants on Eobania vermiculata measured with five biomarkers. AB - In the present study, the effect of organic pollution on land snails Eobania vermiculata was investigated. Five pollution biomarkers (neutral red retention assay, morphometry of lysosomes and neutral lipids, acetylcholinesterase activity and metallothioneins content), were applied on tissues of the land snails. The results showed intense differentiations between the snails treated with organic pollutants and the control ones, as indicated by the results obtained. Statistically significant correlations among the results obtained emphasize the usefulness of these biomarkers. PMID- 22526929 TI - Decomposition analysis of LTREs may facilitate the design of short-term ecotoxicological tests. AB - This study compared two methods, based on re-analyzed data from a partly published life table response experiment (LTRE), to help determine the optimal approach for designing ecotoxicological assessments. The 36-day LTRE data recorded the toxic effects of cadmium (Cd) and imidacloprid, alone and in combination, on the reproduction and survivorship of aphids (Acyrthosiphon pisum Harris). We used this data to construct an age-classified matrix model (six age classes, each 6 days long) to estimate aphid population growth rate (lambda) under each treatment. For each treatment, an elasticity analysis and a demographic decomposition analysis were performed, and results were compared. Despite different results expected from the two toxicants, the elasticity values were very similar. The elasticity of lambda with respect to survival was highest in the first age class, and that with respect to fertility was highest in the second age class. The demographic decomposition analysis examined how changes in life-history traits contributed to differences in lambda between control and treated populations (Deltalambda). This indicated that the most important contributors to Deltalambda were the differences in survival (resulting from both demographic sensitivity and toxicity) in the first and the second age classes of aphids and differences in fertility in the third and the fourth age classes. Additionally, the toxicants acted differently. Cd reduced Deltalambda by impairing fertility at third age class and reducing survivorship from the second to the third age class. Imidacloprid mostly reduced survivorship at the first and second age classes. The elasticity and decomposition analyses showed different results, because these methods addressed different questions about the interaction of organism life history and sensitivity to toxicants. This study indicated that the LTRE may be useful for designing individual-level ecotoxicological experiments that account for both the effects of the toxicant and the demographic sensitivity of the organism. PMID- 22526928 TI - Cyanobacteria-blooming water samples from Lake Taihu induce endoplasmic reticulum stress in liver and kidney of mice. AB - To investigate whether endoplasmic reticulum (ER) stress was involved in apoptosis induced by cyanobacteria-blooming water, healthy male ICR mice were fed with water samples from cyanobacteria-blooming regions of Lake Taihu (China), including Meiliang Bay (M1 and M2), central lake region (H), macrophyte-dominated Xukou Bay (X), and tap water (control group) for three consecutive months. Hepatic and renal mRNA and protein expression of ER stress signaling molecules were measured with quantitative real-time PCR and western blotting. Compared to macrophyte-dominated and control water samples, cyanobacteria-blooming water changed hepatic ER stress signaling molecules. M1 water treatment increased the mRNA and protein levels of glucose regulation protein 78 (GRP78) and C/EBP homologous protein (CHOP), and decreased the mRNA levels of B-cell lymphoma 2 (Bcl-2). M2 water treatment up-regulated GRP78 mRNA and protein expression, whereas H water treatment up-regulated mRNA and protein expression of GRP78 and caspase-12. Cyanobacteria-blooming water exposure also changed mRNA and protein expression of ER stress signaling molecules in the kidneys. M1 water exposure up regulated GRP78 mRNA and protein expression and CHOP mRNA expression, whereas M2 water treatment up-regulated caspase-12 and Bcl-2 mRNA expression. M1 and M2 cyanobacteria-blooming water exposure significantly increased relative liver weights, and induced hepatic cell apoptosis. However, cyanobacteria-blooming water treatment did not change kidney weights, and did not induce renal apoptosis compared to macrophyte-dominated and control water samples. Hence, cyanobacteria blooming water induces hepatic apoptosis via ER stress, and ER stress may play an important role in the apparent anti-apoptotic effects on renal cells exposed to cyanobacteria-blooming water. PMID- 22526930 TI - Quantitative assays for anti-aquaporin-4 antibody with subclass analysis in neuromyelitis optica. AB - BACKGROUND: To clarify the clinical relevance of anti-aquaporin-4 (anti-AQP4) antibody titers and immunoglobulin (IgG) subclass. METHODS: Using a bridging enzyme-linked immunosorbent assay (ELISA), a flow cytometric assay (FCMA) and an immunofluorescence assay (IFA) for anti-AQP4 antibodies, sera from 142 patients with multiple sclerosis (MS) as defined by the McDonald criteria (2005), 29 with neuromyelitis optica (NMO) who fulfilled the 1999 criteria, 19 with recurrent and/or longitudinally extensive myelitis (RM/LM), 86 with other non-inflammatory neurological diseases (OND) and 28 healthy controls (HC) were studied. RESULTS: Anti-AQP4 antibody positivity rates by IFA, FCMA, and ELISA were 41.4%, 51.7% and 48.3%, respectively, in NMO (1999) patients, and 0% in the OND and HC groups. Twenty-six MS patients (18.3%) were positive for the antibody; 17 met the 2006 NMO criteria, including positivity for anti-AQP4 antibody, and five had longitudinally extensive myelitis (LM). Among the cases with anti-AQP4 antibody detected by FCMA, IgG1, 2, 3, and 4 anti-AQP4 antibodies were found in 97.8%, 37.0%, 6.5% and 6.5% respectively. There was no association of either antibody positivity or level of anti-AQP4 antibody IgG subclasses with clinical parameters after adjustment of p values for multiple comparisons. CONCLUSIONS: FCMA and bridging ELISA are useful for detecting and quantifying anti-AQP4 antibodies. PMID- 22526931 TI - Evaluation of the 2010 McDonald multiple sclerosis criteria in children with a clinically isolated syndrome. AB - BACKGROUND: Magnetic resonance imaging diagnostic criteria for paediatric multiple sclerosis have been established on the basis of brain imaging findings alone. The 2010 McDonald criteria for the diagnosis of multiple sclerosis, however, include spinal cord imaging for detection of lesion dissemination in space. The new criteria have been recommended in paediatric multiple sclerosis. OBJECTIVE: (1) To evaluate the 2010 McDonald multiple sclerosis criteria in children with a clinically isolated syndrome and to compare them with recently proposed magnetic resonance criteria for children; (2) to assess whether the inclusion of spinal cord imaging provided additional value to the 2010 McDonald criteria. METHODS: We performed a retrospective analysis of brain and spinal cord magnetic resonance imaging scans from 52 children with a clinically isolated syndrome. Sensitivity, specificity and accuracy of the magnetic resonance criteria were assessed. RESULTS AND CONCLUSION: The 2010 McDonald dissemination in space criteria were more sensitive (85% versus 74%) but less specific (80% versus 100%) compared to the 2005 McDonald criteria. The Callen criteria were more accurate (89%) compared to the 2010 McDonald (85%), the 2005 McDonald criteria for dissemination in space (81%), the KIDMUS criteria (46%) and the Canadian Pediatric Demyelinating Disease Network criteria (76%). The 2010 McDonald criteria for dissemination in time were more accurate (93%) than the dissemination in space criteria (85%). Inclusion of the spinal cord did not increase the accuracy of the McDonald criteria. PMID- 22526932 TI - [Staging of rectal cancer]. PMID- 22526933 TI - [The role of cross-sectional imaging in staging of rectal cancer]. AB - The ongoing diversification of treatment strategies for rectal cancer justifies the demand for highly specialized radiological imaging. Currently, numerous studies have underlined the ability of magnetic resonance imaging (MRI) to determine those parameters that are critical for therapeutic decision-making and prognosis in rectal cancer. Computed tomography (CT) does not meet the criteria of a first line diagnostic procedure with regard to local staging but will remain the workhorse in the search for distant metastases. The increasing acceptance of extended MRI-based concepts will, however, improve cost-effectiveness and simplify patient management. Response evaluation and detection of recurrent disease are the major indications for positron emission tomography (PET)/CT, which is currently not routinely recommended. PMID- 22526934 TI - Diborane(4)-metal bonding: between hydrogen bridges and frustrated oxidative addition. AB - The metal complexes [M{HB(hpp)}(2)(CO)(4)] (M = Cr, Mo or W) and [M(cod){HB(hpp)}(2)Cl] (M = Rh or Ir) of the doubly-base stabilized diborane(4) ligand [HB(hpp)](2) were fully characterized and their bonding nature was investigated in detail. While bonding in the group 6 complexes predominantly occurs through the hydrogen atoms, the metal-ligand interaction in the group 9 complexes can be regarded as an early stage oxidative addition of the boron-boron bond leading to diboryl compounds. PMID- 22526935 TI - Positive feedbacks to growth of an invasive grass through alteration of nitrogen cycling. AB - Understanding the mechanisms by which invasive plants maintain dominance is essential to achieving long-term restoration goals. While many reports have suggested invasive plants alter resource availability, experimental tests of feedbacks between invasive plants and soil resources are lacking. We used field observations and experimental manipulations to test if the invasive grass Microstegium vimineum both causes and benefits from altered soil nitrogen (N) cycling. To quantify M. vimineum effects on N dynamics, we compared inorganic N pools and nitrification rates in 20 naturally invaded and uninvaded plots across a range of mixed hardwood forests, and in experimentally invaded and uninvaded common garden plots. Potential nitrification rates were 142 and 63 % greater in invaded than uninvaded plots in forest and common garden soils, respectively. As a result, soil nitrate was the dominant form of inorganic N during peak M. vimineum productivity in both studies. To determine the response of M. vimineum to altered nitrogen availability, we manipulated the dominant N form (nitrate or ammonium) in greenhouse pots containing M. vimineum alone, M. vimineum with native species, and native species alone. M. vimineum productivity was highest in monocultures receiving nitrate; in contrast, uninvaded native communities showed no response to N form. Notably, the positive response of M. vimineum to nitrate was not apparent when grown in competition with natives, suggesting an invader density threshold is required before positive feedbacks occur. Collectively, our results demonstrate that persistence of invasive plants can be promoted by positive feedbacks with soil resources but that the magnitude of feedbacks may depend on interspecific interactions. PMID- 22526936 TI - Computing diversity from dated phylogenies and taxonomic hierarchies: does it make a difference to the conclusions? AB - Recently, dated phylogenies have been increasingly used for ecological studies on community structure and conservation planning. There is, however, a major impediment to a systematic application of phylogenetic methods in ecology: reliable phylogenies with time-calibrated branch lengths are lacking for a large number of taxonomic groups and this condition is likely to continue for a long time. A solution for this problem consists in using undated phylogenies or taxonomic hierarchies as proxies for dated phylogenies. Nonetheless, little is known on the potential loss of information of these approaches compared to studies using dated phylogenies with time-calibrated branch lengths. The aim of this study is to ask how the use of undated phylogenies and taxonomic hierarchies biases a very simple measure of diversity, the mean pairwise phylogenetic distance between community species, compared to the diversity of dated phylogenies derived from the freely available software Phylomatic. This is illustrated with three sets of data on plant species sampled at different scales. Our results show that: (1) surprisingly, the diversity computed from dated phylogenies derived from Phylomatic is more strongly related to the diversity computed from taxonomic hierarchies than to the diversity computed from undated phylogenies, while (2) less surprisingly, the strength of this relationship increases if we consider only angiosperm species. PMID- 22526937 TI - The nature of lemming cycles on Wrangel: an island without small mustelids. AB - Lemming cycles are a key process in the functioning of tundra ecosystems. Although it is agreed that trophic interactions are important in causing the cycles, the actual mechanism is disputed. Some researchers attribute a major role to predation by small mustelids such as stoats and least weasels. Here we present a 40-year time series of lemming dynamics from Wrangel Island and show statistically that lemmings do exhibit population cycles in the absence of small mustelids. The observed density fluctuations differed, however, from those observed elsewhere, with long cycles and possibly higher densities of lemmings during the low phase. These differences in the shape of the population cycles may be related to the unique species assemblage of Wrangel Island, where arctic foxes are the only year-round resident lemming predator, and to the high diversity of landscapes, microclimatic conditions, and plants on the island. Both spectral analysis and wavelet analysis show a change in period length from five years in the 1970s to nearly eight years in the 1990s and 2000s. This change in dynamics coincides with reports of dampening or fading out of lemming cycles that have been observed in several regions of the Arctic in recent decades. As in the other cases, the changed lemming dynamics on Wrangel Island may be related to ground icing in winter, which could delay peak years. PMID- 22526938 TI - Influence of summer marine fog and low cloud stratus on water relations of evergreen woody shrubs (Arctostaphylos: Ericaceae) in the chaparral of central California. AB - Mediterranean-type climate (MTC) regions around the world are notable for cool, wet winters and hot, dry summers. A dominant vegetation type in all five MTC regions is evergreen, sclerophyllous shrubland, called chaparral in California. The extreme summer dry season in California is moderated by a persistent low elevation layer of marine fog and cloud cover along the margin of the Pacific coast. We tested whether late dry season water potentials (Psi(min)) of chaparral shrubs, such as Arctostaphylos species in central California, are influenced by this coast-to-interior climate gradient. Lowland coastal (maritime) shrubs were found to have significantly less negative Psi(min) than upland interior shrubs (interior), and stable isotope (delta(13)C) values exhibited greater water use efficiency in the interior. Post-fire resprouter shrubs (resprouters) had significantly less negative Psi(min) than co-occurring obligate seeder shrubs (seeders) in interior and transitional chaparral, possibly because resprouters have deeper root systems with better access to subsurface water than shallow rooted seeders. Unexpectedly, maritime resprouters and seeders did not differ significantly in their Psi(min), possibly reflecting more favorable water availability for shrubs influenced by the summer marine layer. Microclimate and soil data also suggest that maritime habitats have more favorable water availability than the interior. While maritime seeders constitute the majority of local Arctostaphylos endemics, they exhibited significantly greater vulnerability to xylem cavitation than interior seeders. Because rare seeders in maritime chaparral are more vulnerable to xylem cavitation than interior seeders, the potential breakdown of the summer marine layer along the coast is of potential conservation concern. PMID- 22526939 TI - Virus infection decreases the attractiveness of white clover plants for a non vectoring herbivore. AB - Plant pathogens and insect herbivores are prone to share hosts under natural conditions. Consequently, pathogen-induced changes in the host plant can affect herbivory, and vice versa. Even though plant viruses are ubiquitous in the field, little is known about plant-mediated interactions between viruses and non vectoring herbivores. We investigated the effects of virus infection on subsequent infestation by a non-vectoring herbivore in a natural genotype of Trifolium repens (white clover). We tested whether infection with White clover mosaic virus (WClMV) alters (1) the effects of fungus gnat feeding on plant growth, (2) the attractiveness of white clover for adult fungus gnat females, and (3) the volatile emission of white clover plants. We observed only marginal effects of WClMV infection on the interaction between fungus gnat larvae and white clover. However, adult fungus gnat females clearly preferred non-infected over WClMV-infected plants. Non-infected and virus-infected plants could easily be discriminated based on their volatile blends, suggesting that the preference of fungus gnats for non-infected plants may be mediated by virus-induced changes in volatile emissions. The compound beta-caryophyllene was exclusively detected in the headspace of virus-infected plants and may hence be particularly important for the preference of fungus gnat females. Our results demonstrate that WClMV infection can decrease the attractiveness of white clover plants for fungus gnat females. This suggests that virus infections may contribute to protecting their hosts by decreasing herbivore infestation rates. Consequently, it is conceivable that viruses play a more beneficial role in plant-herbivore interactions than generally thought. PMID- 22526940 TI - Physical factors driving intertidal macroalgae distribution: physiological stress of a dominant fucoid at its southern limit. AB - Climate change is driving species range shifts worldwide. However, physiological responses related to distributional changes are not fully understood. Oceanographers have reported an increase in ocean temperature in the northwest Iberian Peninsula that is potentially related to the decline in some cold temperate intertidal macroalgae in the Cantabrian Sea, namely Fucus serratus. Low tide stress could also play a role in this decline. We performed one mensurative (in situ) and two manipulative (in culture) experiments designed to evaluate the interactive effects of some physical factors. The first experiment analysed field response to low tide stress in marginal (mid-Cantabrian Sea and northern Portugal) versus central (Galicia) populations of F. serratus. Then a second experiment was performed that utilized either harsh or mild summer conditions of atmospheric temperature, irradiance, humidity, and wind velocity to compare the responses of individuals from one marginal and one central population to low tide stress. Finally, the combined effect of sea temperature and the other factors was evaluated to detect interactive effects. Changes in frond growth, maximal photosynthetic quantum yield (F(v)/F(m)), temperature, and desiccation were found. Three additive factors (solar irradiation, ocean and air temperatures) were found to drive F. serratus distribution, except under mildly humid conditions that ameliorated atmospheric thermal stress (two additive factors). Mid-Cantabrian Sea temperatures have recently increased, reaching the inhibitory levels suggested in this study of F. serratus. We also expect an additive secondary contribution of low tide stress to this species decline. On the northern Portugal coast, ocean warming plus low tide stress has not reached this species' inhibition threshold. No significant differential responses attributed to the population of origin were found. Mechanistic approaches that are designed to analyse the interactive effects of physical stressors may improve the levels of confidence in predicted range shifts of species. PMID- 22526941 TI - Direct versus indirect effects of habitat fragmentation on community patterns in experimental landscapes. AB - Habitat area and fragmentation are confounded in many ecological studies investigating fragmentation effects. We thus devised an innovative experiment founded on fractal neutral landscape models to disentangle the relative effects of habitat area and fragmentation on arthropod community patterns in red clover (Trifolium pratense). The conventional approach in experimental fragmentation studies is to adjust patch size and isolation to create different landscape patterns. We instead use fractal distributions to adjust the overall amount and fragmentation of habitat independently at the scale of the entire landscape, producing different patch properties. Although habitat area ultimately had a greater effect on arthropod abundance and diversity in this system, we found that fragmentation had a significant effect in clover landscapes with <=40 % habitat. Landscapes at these lower habitat levels were dominated by edge cells, which had fewer arthropods and lower richness than interior cells. Fragmentation per se did not have a direct effect on local-scale diversity, however, as demonstrated by the lack of a broader landscape effect (in terms of total habitat area and fragmentation) on arthropods within habitat cells. Fragmentation-through the creation of edge habitat-thus had a strong indirect effect on morphospecies richness and abundance at the local scale. Although it has been suggested that fragmentation should be important at low habitat levels (<=20-30 %), we show that fragmentation per se is significant only at intermediate (40 %) levels of habitat, where edge effects were neither too great (as at lower levels of habitat) nor too weak (as at higher levels of habitat). PMID- 22526942 TI - Delayed induced silica defences in grasses and their potential for destabilising herbivore population dynamics. AB - Some grass species mount a defensive response to grazing by increasing their rate of uptake of silica from the soil and depositing it as abrasive granules in their leaves. Increased plant silica levels reduce food quality for herbivores that feed on these grasses. Here we provide empirical evidence that a principal food species of an herbivorous rodent exhibits a delayed defensive response to grazing by increasing silica concentrations, and present theoretical modelling that predicts that such a response alone could lead to the population cycles observed in some herbivore populations. Experiments performed under greenhouse conditions revealed that the rate of deposition of silica defences in the grass Deschampsia caespitosa is a time-lagged, nonlinear function of grazing intensity and that, upon cessation of grazing, these defences take around one year to decay to within 5 % of control levels. Simple coupled grass-herbivore population models incorporating this functional response, and parameterised with empirical data, consistently predict population cycles for a wide range of realistic parameter values for a (Microtus) vole-grass system. Our results support the hypothesis that induced silica defences have the potential to strongly affect the population dynamics of their herbivores. Specifically, the feedback response we observed could be a driving mechanism behind the observed population cycles in graminivorous herbivores in cases where grazing levels in the field become sufficiently large and sustained to trigger an induced silica defence response. PMID- 22526943 TI - One meadow for two sparrows: resource partitioning in a high elevation habitat. AB - Resource partitioning is the basis of the coexistence of sympatric species and has therefore received much attention in ecological studies. However, how variation in environmental conditions (and particularly natural variation in resource availability) can influence resource partitioning in free-ranging animals is not well understood. In the present study, we addressed the hypothesis that natural changes in the availability of food resources affect food partitioning between sympatric species. To do so, we examined temporal changes in the plasma isotopic signature (delta(15)N and delta(13)C) of syntopic Lincoln's sparrows Melospiza lincolnii and white-crowned sparrows Zonotrichia leucophrys, in parallel with seasonal changes in habitat maturity and food availability from spring to early summer. We found no apparent trophic segregation between Lincoln's and white-crowned sparrows when resources were scarce in spring. But, interestingly, as resource availability and the number of breeding birds increased, Lincoln's sparrows showed lower delta(15)N values than white-crowned sparrows, as they consumed more prey from lower trophic levels and less prey from higher trophic levels. This feeding divergence between sympatric species may be explained (1) by a change in foraging preferences and opportunities for Lincoln's sparrows and (2) by the abundance of competitors that increased faster than resources, thus promoting interspecific competition and trophic segregation. These results provide clear evidence that trophic segregation is dynamically tied to variation in environmental conditions, which are therefore fundamental to consider when examining resource partitioning between co-existing species. PMID- 22526944 TI - Ecosystem linkages revealed by experimental lake-derived isotope signal in heathland food webs. AB - Cross-ecosystem movement of nutrients and biomass can have important effects on recipient systems. Emerging aquatic insects are subsidies to terrestrial ecosystems and can influence foodweb interactions in riparian systems. In a 2 year field experiment, we simulated aquatic insect deposition by adding adult midge carcasses (150 g dry mass m(-2) year(-1)) to 1-m(2) heathland plots at a site with low natural midge deposition. We established four levels of midge addition treatments and measured stable isotopes (delta(13)C and delta(15)N) in plants and arthropods within each treatment. We used a multiple-source isotope Bayesian mixing model to estimate the terrestrial versus aquatic contribution to the diets of arthropods. Aquatic resources were incorporated into plant, detritivore, and predator biomass. Detritivorous Collembola showed the greatest difference in isotope values (+3 0/00 delta(15)N and +4 0/00 delta(13)C) between midge-addition and reference treatments. Isotope values of small spiders followed the same trend of enrichment as Collembola while other arthropods (mites and large spiders) were only enriched after 2 years of midge addition. Although predator diets did not change, they became isotopically enriched via their likely prey (Collembola). Plants also had elevated delta(15)N (+1 0/00) in midge addition treatments. The time required and amount of midge-derived C and N detected varied and depended on trophic position. Midge-derived nutrients were no longer present in arthropod biomass in the year following midge addition. Aquatic insect carcasses can be rapidly incorporated into terrestrial food webs in nearshore habitats, and repeated inputs can be detected at multiple trophic levels, thus highlighting the importance of the detrital pathway for aquatic to terrestrial cross-ecosystem subsidies. PMID- 22526945 TI - Seasonal climate manipulations have only minor effects on litter decomposition rates and N dynamics but strong effects on litter P dynamics of sub-arctic bog species. AB - Litter decomposition and nutrient mineralization in high-latitude peatlands are constrained by low temperatures. So far, little is known about the effects of seasonal components of climate change (higher spring and summer temperatures, more snow which leads to higher winter soil temperatures) on these processes. In a 4-year field experiment, we manipulated these seasonal components in a sub arctic bog and studied the effects on the decomposition and N and P dynamics of leaf litter of Calamagrostis lapponica, Betula nana, and Rubus chamaemorus, incubated both in a common ambient environment and in the treatment plots. Mass loss in the controls increased in the order Calamagrostis < Betula < Rubus. After 4 years, overall mass loss in the climate-treatment plots was 10 % higher compared to the ambient incubation environment. Litter chemistry showed within each incubation environment only a few and species-specific responses. Compared to the interspecific differences, they resulted in only moderate climate treatment effects on mass loss and these differed among seasons and species. Neither N nor P mineralization in the litter were affected by the incubation environment. Remarkably, for all species, no net N mineralization had occurred in any of the treatments during 4 years. Species differed in P-release patterns, and summer warming strongly stimulated P release for all species. Thus, moderate changes in summer temperatures and/or winter snow addition have limited effects on litter decomposition rates and N dynamics, but summer warming does stimulate litter P release. As a result, N-limitation of plant growth in this sub-arctic bog may be sustained or even further promoted. PMID- 22526946 TI - A field study on the influence of food and immune priming on a bumblebee-gut parasite system. AB - Laboratory experiments are often preferred over field experiments because they allow the control of confounding factors that would otherwise influence the causal effect of a particular focal experimental factor. These confounding factors can, however, significantly alter the response of an organism confronted with a particular situation, which can have great implications. In a field experiment with a bumblebee host-parasite system, we looked at the influence of additional food supply and immune challenge on various colony fitness values and parasite traits. We could confirm the importance of food on the colony fitness, but not on parasite infection probability or parasite genetic diversity. In contrast to the findings of laboratory experiments of this system, challenge of the immune system had no significant effect on colony fitness or parasite infections. These results likely reflect an overriding effect of environmental variation without disproving the concept of a cost of defence per se. But the results also demonstrate that confounding factors purposely controlled for in the laboratory have to be weighed against their ecological relevance, and stress the need for careful analysis before any direct transfer is made of laboratory results to field situations. PMID- 22526947 TI - Modulation of corticomuscular coherence by peripheral stimuli. AB - The purpose of this study was to investigate the effects of peripheral afferent stimuli on the synchrony between brain and muscle activity as estimated by corticomuscular coherence (CMC). Electroencephalogram (EEG) from sensorimotor cortex and electromyogram (EMG) from two intrinsic hand muscles were recorded during a key grip motor task, and the modulation of CMC caused by afferent electrical and mechanical stimulation was measured. The particular stimuli used were graded single-pulse electrical stimuli, above threshold for perception and activating cutaneous afferents, applied to the dominant or non-dominant index finger, and a pulsed mechanical displacement of the gripped object causing the subject to feel as if the object may be dropped. Following electrical stimulation of the dominant index finger, the level of beta-range (14-36 Hz) CMC was reduced in a stimulus intensity-dependent fashion for up to 400 ms post-stimulus, then returned with greater magnitude before falling to baseline levels over 2.5 s, outlasting the reflex and evoked changes in EMG and EEG. Subjects showing no baseline beta-range CMC nevertheless showed post-stimulus increases in beta-range CMC with the same time course as those with baseline beta-range CMC. The mechanical stimuli produced similar modulation of beta-range CMC. Electrical stimuli to the non-dominant index finger produced no significant increase in beta range CMC. The results suggest that both cutaneous and proprioceptive afferents have access to circuits generating CMC, but that only a functionally relevant stimulus produces significant modulation of the background beta-range CMC, providing further evidence that beta-range CMC has an important role in sensorimotor integration. PMID- 22526948 TI - Control of aperture closure initiation during trunk-assisted reach-to-grasp movements. AB - The present study investigated how the involvement and direction of trunk movement during reach-to-grasp movements affect the coordination between the transport and grasping components. Seated young adults made prehensile movements in which the involvement of the trunk was varied; the trunk was not involved, moved forward (flexion), or moved backward (extension) in the sagittal plane during the reach to the object. Each of the trunk movements was combined with an extension or flexion motion of the arm during the reach. Regarding the relationship between the trunk and arm motion for arm transport, the onset of wrist motion relative to that of the trunk was delayed to a greater extent for the trunk extension than for the trunk flexion. The variability of the time period from the peak of wrist velocity to the peak of trunk velocity was also significantly greater for trunk extension compared to trunk flexion. These findings indicate that trunk flexion was better integrated into the control of wrist transport than trunk extension. In terms of the temporal relationship between wrist transport and grip aperture, the relationship between the time of peak wrist velocity and the time of peak grip aperture did not change or become less steady across conditions. Therefore, the stability of temporal coordination between wrist transport and grip aperture was maintained despite the variation of the pattern of intersegmental coordination between the arm and the trunk during arm transport. The transport-aperture coordination was further assessed in terms of the control law according to which the initiation of aperture closure during the reach occurs when the hand crosses a hand-to-target distance threshold for grasp initiation, which is a function of peak aperture, wrist velocity and acceleration, trunk velocity and acceleration, and trunk-to-target distance at the time of aperture closure initiation. The participants increased the hand-to target distance threshold for grasp initiation in the conditions where the trunk was involved compared to the conditions where the trunk was not involved. An increase also occurred when the trunk was extended compared to when it was flexed. The increased distance threshold implies an increase in the hand-to target distance-related safety margin for grasping when the trunk is involved, especially when it is extended. These results suggest that the CNS significantly utilizes the parameters of trunk movement together with movement parameters related to the arm and the hand for controlling grasp initiation. PMID- 22526949 TI - Keeping the world at hand: rapid visuomotor processing for hand-object interactions. AB - The existence of hand-centred visual processing has long been established in the macaque premotor cortex. These hand-centred mechanisms have been thought to play some general role in the sensory guidance of movements towards objects, or, more recently, in the sensory guidance of object avoidance movements. We suggest that these hand-centred mechanisms play a specific and prominent role in the rapid selection and control of manual actions following sudden changes in the properties of the objects relevant for hand-object interactions. We discuss recent anatomical and physiological evidence from human and non-human primates, which indicates the existence of rapid processing of visual information for hand object interactions. This new evidence demonstrates how several stages of the hierarchical visual processing system may be bypassed, feeding the motor system with hand-related visual inputs within just 70 ms following a sudden event. This time window is early enough, and this processing rapid enough, to allow the generation and control of rapid hand-centred avoidance and acquisitive actions, for aversive and desired objects, respectively. PMID- 22526950 TI - Low-frequency galvanic vestibular stimulation evokes two peaks of modulation in skin sympathetic nerve activity. AB - We have previously shown that sinusoidal galvanic vestibular stimulation (sGVS), delivered bilaterally at 0.2-2.0 Hz, evokes a potent entrainment of sympathetic outflow to muscle and skin. Most recently, we showed that stimulation at 0.08 0.18 Hz generates two bursts of modulation of muscle sympathetic nerve activity (MSNA), more pronounced at 0.08 Hz, which we interpreted as reflecting bilateral projections from the vestibular nuclei to the medullary nuclei responsible for the generation of MSNA. Here, we test the hypothesis that these very low frequencies of sGVS modulate skin sympathetic nerve activity (SSNA) in a similar fashion. SSNA was recorded via tungsten microelectrodes inserted into the left common peroneal nerve in 11 awake-seated subjects. Bipolar binaural sGVS (+/-2 mA, 100 cycles) was applied to the mastoid processes at 0.08, 0.13 and 0.18 Hz. As with MSNA, cross-correlation analysis revealed two bursts of modulation of SSNA for each cycle of stimulation but, unlike MSNA, this modulation was equally pronounced at all frequencies. These results further support our conclusion that bilateral sGVS causes cyclical modulation of the left and right vestibular nerves and a resultant modulation of sympathetic outflow that reflects the summed activity of bilateral projections from the vestibular nuclei onto, in this case, the primary output nuclei responsible for SSNA-the medullary raphe. Furthermore, these findings emphasise the role of the vestibular system in the control of skin sympathetic outflow, and the cutaneous expression of motion sickness: pallor and sweat release. Indeed, vestibular modulation of SSNA was higher in those subjects reporting nausea than in those who did not report nausea during this low frequency sGVS. PMID- 22526951 TI - Emotive hemispheric differences measured in real-life portraits using pupil diameter and subjective aesthetic preferences. AB - The biased positioning of faces exposed to viewers of Western portraiture has suggested there may be fundamental differences in the lateralized expression and perception of emotion. The present study investigates whether there are differences in the perception of the left and right sides of the face in real life photographs of individuals. The study paired conscious aesthetic ratings of pleasantness with measurements of pupil size, which are thought to be a reliable unconscious measure of interest first tested by Hess. Images of 10 men and 10 women were taken from the left and right sides of the face. These images were also mirror-reversed. As expected, we found a strong preference for left-sided portraits (regardless of original or mirror-reversed orientation), such that left hemifaces elicited higher ratings and greater pupil dilation. Interestingly, this effect was true of both sexes. A positive linear relationship was also found between pupil size and aesthetic ratings such that pupil size increased with pleasantness ratings. These findings provide support for the notions of lateralized emotion, right-hemispheric dominance, pupillary dilation to pleasant images, and constriction to unpleasant images. PMID- 22526952 TI - Overcoming the guidance effect in motor skill learning: feedback all the time can be beneficial. AB - Extensive research has shown that augmented feedback presented too often can create a dependency on the feedback and hinder long-term memory formation of a motor skill. This dependency has been labeled the guidance effect, and one way to overcome the guidance effect is to reduce how often augmented feedback is presented during training. In two experiments, participants were presented with visual augmented feedback during every trial in a 5-min training interval. Participants were provided visual augmented feedback in the form of a Lissajous template of a 1:2 multi-frequency pattern and a cursor representing the coordination between the limbs. Some participants were trained with the cursor superimposed (behind group) on the Lissajous template, and others were trained with the cursor presented in a separate window (side group) from the Lissajous template. In experiment 1, motion of the end-effectors was constrained to the medial-lateral direction in the horizontal plane. In experiment 2, end-effector motion was possible in both the medial-lateral and anterior-posterior directions in the horizontal plane. The location of the cursor did not influence performance during the 5-min training interval in either experiment. After a 15-min break, a retention test performed without the visual feedback provided by the cursor revealed that the behind groups' performance was guided by the visual feedback in both experiments, whereas the side groups were able to perform without visual feedback. In experiment two, the side group's performance without feedback was influenced when anterior-posterior motion was not constrained; however, the extent of the guidance effect was significantly less compared to the behind trained group in both experiments. The results show that the emergence of guided motor performance depends on the format of the display that provides visually based augmented feedback, and not just on how often the feedback is provided. In conclusion, visually based augmented feedback leads to the simultaneous development of a spatial and motor representation of the task. The behind format led to a dependence on the spatial representation developed during training, while the side format facilitated the development of the motor representation as a means to overcome guidance. PMID- 22526954 TI - Nuclear medicine, scientific publishing and the era of cost containment: what factors hold the key? PMID- 22526953 TI - Preclinical evaluation of two 68Ga-siderophores as potential radiopharmaceuticals for Aspergillus fumigatus infection imaging. AB - PURPOSE: Invasive pulmonary aspergillosis is mainly caused by Aspergillus fumigatus, and is one of the major causes of morbidity and mortality in immunocompromised patients. The mortality associated with invasive pulmonary aspergillosis remains high, mainly due to the difficulties and limitations in diagnosis. We have shown that siderophores can be labelled with (68)Ga and can be used for PET imaging of A. fumigatus infection in rats. Here we report on the further evaluation of the most promising (68)Ga-siderophore candidates, triacetylfusarinine (TAFC) and ferrioxamine E (FOXE). METHODS: Siderophores were labelled with (68)Ga using acetate buffer. Log P, protein binding and stability values were determined. Uptake by A. fumigatus was studied in vitro in cultures with high and low iron loads. In vivo biodistribution was determined in normal mice and an infection model was established using neutropenic rats inoculated with A. fumigatus. Static and dynamic MUPET imaging was performed and correlated with CT images, and lung infection was evaluated ex vivo. RESULTS: (68)Ga siderophores were labelled with high radiochemical purity and specific activity. (68)Ga-TAFC and (68)Ga-FOXE showed high uptake by A. fumigatus in iron-deficient cultures. In normal mice, (68)Ga-TAFC and (68)Ga-FOXE showed rapid renal excretion with high metabolic stability. In the rat infection model focal lung uptake was detected by MUPET with both compounds and increased with severity of the infection, correlating with abnormal CT images. CONCLUSION: (68)Ga-TAFC and (68)Ga-FOXE displayed excellent in vitro stability and high uptake by A. fumigatus. Both compounds showed excellent pharmacokinetics, highly selective accumulation in infected lung tissue and good correlation with severity of disease in a rat infection model, which makes them promising agents for A. fumigatus infection imaging. PMID- 22526955 TI - PET/MR imaging of bone lesions--implications for PET quantification from imperfect attenuation correction. AB - PURPOSE: Accurate attenuation correction (AC) is essential for quantitative analysis of PET tracer distribution. In MR, the lack of cortical bone signal makes bone segmentation difficult and may require implementation of special sequences. The purpose of this study was to evaluate the need for accurate bone segmentation in MR-based AC for whole-body PET/MR imaging. METHODS: In 22 patients undergoing sequential PET/CT and 3-T MR imaging, modified CT AC maps were produced by replacing pixels with values of >100 HU, representing mostly bone structures, by pixels with a constant value of 36 HU corresponding to soft tissue, thereby simulating current MR-derived AC maps. A total of 141 FDG positive osseous lesions and 50 soft-tissue lesions adjacent to bones were evaluated. The mean standardized uptake value (SUVmean) was measured in each lesion in PET images reconstructed once using the standard AC maps and once using the modified AC maps. Subsequently, the errors in lesion tracer uptake for the modified PET images were calculated using the standard PET image as a reference. RESULTS: Substitution of bone by soft tissue values in AC maps resulted in an underestimation of tracer uptake in osseous and soft tissue lesions adjacent to bones of 11.2 +/- 5.4% (range 1.5-30.8%) and 3.2 +/- 1.7% (range 0.2-4%), respectively. Analysis of the spine and pelvic osseous lesions revealed a substantial dependence of the error on lesion composition. For predominantly sclerotic spine lesions, the mean underestimation was 15.9 +/- 3.4% (range 9.9 23.5%) and for osteolytic spine lesions, 7.2 +/- 1.7% (range 4.9-9.3%), respectively. CONCLUSION: CT data simulating treating bone as soft tissue as is currently done in MR maps for PET AC leads to a substantial underestimation of tracer uptake in bone lesions and depends on lesion composition, the largest error being seen in sclerotic lesions. Therefore, depiction of cortical bone and other calcified areas in MR AC maps is necessary for accurate quantification of tracer uptake values in PET/MR imaging. PMID- 22526956 TI - 18F-FDG PET uptake in the pre-Huntington disease caudate affects the time-to onset independently of CAG expansion size. AB - PURPOSE: To test in a longitudinal follow-up study whether basal glucose metabolism in subjects with a genetic risk of Huntington disease (HD) may influence the onset of manifest symptoms. METHODS: The study group comprised 43 presymptomatic (preHD) subjects carrying the HD mutation. They underwent a (18)F FDG PET scan and were prospectively followed-up for at least 5 years using the unified HD rating scale to detect clinical changes. Multiple regression analysis included subject's age, CAG mutation size and glucose uptake as variables in a model to predict age at onset. RESULTS: Of the 43 preHD subjects who manifested motor symptoms, suggestive of HD, after 5 years from the PET scan, 26 showed a mean brain glucose uptake below the cut-off of 1.0493 in the caudate, significantly lower than the 17 preHD subjects who remained symptom-free (P < 0.0001). This difference was independent of mutation size. Measurement of brain glucose uptake improved the CAG repeat number and age-based model for predicting age at onset by 37 %. CONCLUSION: A reduced level of glucose metabolism in the brain caudate may represent a predisposing factor that contributes to the age at onset of HD in preHD subjects, in addition to the mutation size. PMID- 22526957 TI - Tuberculous lymphadenitis: FDG PET and CT findings in responsive and nonresponsive disease. AB - PURPOSE: No data is available on the different FDG PET and CT findings in the lymph nodes (LN) of patients with HIV and tuberculosis (TB) who respond compared with those who do not respond to anti-TB treatment by 4 months after initiation of TB treatment. These findings were the focus of our study. METHODS: PET/CT scans performed at 4 months after initiation of TB treatment in 20 consecutive HIV patients were analysed. SUVmax values were obtained for all regions of LN involvement. The diameter of the LNs was measured and the CT enhancement (LNs showing peripheral rim enhancement with central low attenuation, PRECLO, in comparison with homogeneously involved LNs) and the calcification patterns of involved LNs assessed. The relationship between the PET and CT findings and the clinical outcome, response or nonresponse, was evaluated. RESULTS: FDG PET identified 91 sites of LN involvement, 20 of which were not identified by CT. SUVmax values were significantly higher in nonresponders (8 patients, SUVmax 11.2 +/- 4.0, mean +/- SD) when compared to responders (12 patients, SUVmax 2.6 +/- 2.3; p = 0.0001). In ROC analysis (AUC 0.952) a cut-off value of 4.5 for SUVmax yielded a sensitivity and specificity of 95% and 85% for discriminating nonresponding from responding LNs. LNs were significantly larger in nonresponders (1.9 +/- 0.4 cm) than in responders (1.4 +/- 0.4 cm; p = 0.0001); the AUC in the ROC analysis was 0.76. PRECLO LNs were significantly larger (2.2 +/- 0.3 cm) than homogeneous involved LN basins (1.5 +/- 0.4 cm) and LN basins with calcification (1.4 +/- 0.5 cm; p = 0.001). Using the presence of at least one LN basin with PRECLO as a criterion for nonresponse, responders could be separated from nonresponders with a sensitivity of 88% and a specificity of 66%. CONCLUSION: LNs responding to TB treatment could be differentiated from nonresponding LNs with a sensitivity and specificity of 95% and 85% using a SUVmax cut-off value of 4.5 and a sensitivity and specificity of 88% and 66% using the presence of at least one LN basin with PRECLO. PMID- 22526958 TI - Predictive value of pretreatment metabolic activity measured by fluorodeoxyglucose positron emission tomography in patients with metastatic advanced gastric cancer: the maximal SUV of the stomach is a prognostic factor. AB - PURPOSE: Few studies have evaluated metabolic activity by (18)F-FDG PET as a prognostic factor in advanced gastric cancer (AGC). We investigated its prognostic role in metastatic AGC. METHODS: We enrolled 82 patients with metastatic AGC, who were treatment-naive and underwent pretreatment (18)F-FDG PET/CT scanning. In each patient, the maximal standardized uptake value (SUVmax) was measured in each target lesion. Stomach(SUVmax) was defined as SUVmax in the stomach, while Total(SUVmax) was defined as the highest SUVmax among all the target lesions. RESULTS: The stomach was the organ most frequently displaying the highest SUVmax among all the target lesions (in 67.1% of patients). A Total(SUVmax) value of 11.5 was the value with the maximum sum of sensitivity and specificity from receiver-operating characteristic curves for progression-free survival (PFS). PFS was significantly longer in patients with a Total(SUVmax) value <11.5 than in those with a Total(SUVmax) value >=11.5 (P = 0.023); however, overall survival (OS) was not (P = 0.055). A Stomach(SUVmax) value of 6.0 was derived by similar methods. PFS and OS were significantly longer in those with a Stomach(SUVmax) value <6.0 than in those with a Stomach(SUVmax) value >=6.0 (P = 0.001 and P = 0.006, respectively). Furthermore, those with a low Total(SUVmax) and those with a low Stomach(SUVmax) showed better chemotherapeutic responses (P = 0.016 and P = 0.034, respectively). Among patients with histologically undifferentiated carcinomas, those with lower Total(SUVmax) and those with lower Stomach(SUVmax) showed longer median PFS (P = 0.027 and P = 0.005, respectively) and OS (P = 0.009 and P <0.001, respectively). Multivariate analysis demonstrated Stomach(SUVmax) as an independent predictor of PFS (P = 0.002) and OS (P = 0.038). CONCLUSION: Pretreatment metabolic activity may be a useful prognostic marker in patients with metastatic AGC undergoing palliative chemotherapy. Notably, Stomach(SUVmax) was the single, most robust factor predicting prognosis. PMID- 22526959 TI - Effects of type 2 diabetes mellitus on coronary microvascular function and myocardial perfusion in patients without obstructive coronary artery disease. AB - PURPOSE: We assessed the impact of type 2 diabetes, in the presence of other major cardiovascular risk factors, on coronary microvascular function and myocardial perfusion in patients without obstructive coronary artery disease (CAD). METHODS: In this prospective study, 23 patients with type 2 diabetes and 26 nondiabetic patients matched for age, sex and other cardiovascular risk factors underwent a cold pressure test (CPT) and dipyridamole transthoracic echocardiography to determine their coronary flow (CF) ratio. Within 2 weeks, all diabetic patients also underwent dipyridamole-rest myocardial perfusion single photon emission (MPS) CT. None of the patients with or without diabetes had significant CAD on invasive coronary angiography. RESULTS: The CPT-CF ratio was significantly lower in diabetic patients than in nondiabetic patients (1.46 +/- 0.26 vs. 1.71 +/- 0.32, p = 0.006) and was correlated significantly with fasting glycaemia (r = -0.35, p = 0.01), but not with glycated haemoglobin. The dipyridamole-CF ratio was also lower in diabetic patients than in nondiabetic patients (2.38 +/- 0.74 vs. 2.75 +/- 0.49, p = 0.04). On MPS imaging, 5 diabetic patients (22%) had stress-induced ischaemia and the remaining 18 (78%) had normal myocardial perfusion. The dipyridamole-CF ratio was not different in patients with and without reversible defects (2.3 +/- 1.1 vs. 2.4 +/- 0.6, p = 0.97). CONCLUSION: Coronary microvascular function is impaired in type 2 diabetic patients without significant CAD, compared to nondiabetic patients with similar other cardiovascular risk factors. In the majority of diabetic patients, microvascular dysfunction is associated with normal myocardial perfusion. PMID- 22526960 TI - Predictive value of early and late residual 18F-fluorodeoxyglucose and 18F fluorothymidine uptake using different SUV measurements in patients with non small-cell lung cancer treated with erlotinib. AB - PURPOSE: To evaluate the predictive value of early and late residual (18)F fluorodeoxyglucose (FDG) and (18)F-fluorothymidine (FLT) uptake using different SUV measurements in PET in patients with advanced non-small-cell lung cancer (NSCLC) treated with erlotinib. METHODS: We retrospectively reviewed data from 30 patients with untreated stage IV NSCLC who had undergone a combined FDG PET and FLT PET scan at 1 week (early) and 6 weeks (late) after the start of erlotinib treatment. Early and late residual FDG and FLT uptake were measured in up to five lesions per scan with different quantitative standardized uptake values (SUV(max), SUV(2Dpeak), SUV(3Dpeak), SUV(50), SUV(A50), SUV(A41)) and compared with short-term outcome (progression vs. nonprogression after 6 weeks of erlotinib treatment). Receiver-operating characteristics (ROC) curve analysis was used to determine the optimal cut-off value for detecting nonprogression after 6 weeks. Kaplan-Meier analysis and the log-rank test were used to evaluate the association between residual uptake and progression-free survival (PFS). RESULTS: Nonprogression after 6 weeks was associated with a significantly lower early and late residual FDG uptake, measured with different quantitative parameters. In contrast, nonprogression after 6 weeks was not associated with early and late residual FLT uptake. Furthermore, patients with a lower early residual FDG uptake measured in terms of SUV(max) and SUV(2Dpeak) had a significantly prolonged PFS (282 days vs. 118 days; p = 0.022) than patients with higher values. Similarly, lower late residual FDG uptake and early residual FLT uptake measured in terms of SUV(3Dpeak), SUV(A50) and SUV(A41), and late FLT uptake measured in terms of SUV(3Dpeak) and SUV(A50) was associated with an improved PFS. CONCLUSION: Early and late residual FDG uptake, measured using different quantitative SUV parameters, are predictive factors for short-term outcome in patients with advanced NSCLC treated with erlotinib. Additionally, low residual FDG and FLT uptake early and late in the course of erlotinib treatment is associated with improved PFS. PMID- 22526961 TI - A comparison of the performance of 68Ga-DOTATATE PET/CT and 123I-MIBG SPECT in the diagnosis and follow-up of phaeochromocytoma and paraganglioma. AB - PURPOSE: To compare the sensitivity of (123)I-metaiodobenzylguanidine (MIBG) SPECT and (68)Ga-DOTATATE PET/CT in detecting phaeochromocytomas (PCC) and paragangliomas (PGL) in the initial diagnosis and follow-up of patients with PCC and PGL disease. METHODS: Retrospective analysis of 15 patients with PCC/PGL who had contemporaneous (123)I-MIBG and (68)Ga-DOTATATE imaging. RESULTS: Of the 15 patients in the series, 8 were concordant with both modalities picking up clinically significant lesions. There were no patients in whom both modalities failed to pick up clinically significant lesions. There was discordance in seven patients: 5 had positive (68)Ga-DOTATATE and negative (123)I-MIBG, and 2 (12 and 14) had negative (68)Ga-DOTATATE and positive (123)I-MIBG. Utilizing (123)I-MIBG as the gold standard, (68)Ga-DOTATATE had a sensitivity of 80 % and a positive predictive value of 62 %. The greatest discordance was in head and neck lesions, with the lesions in 4 patients being picked up by (68)Ga-DOTATATE and missed by (123)I-MIBG. On a per-lesion analysis, cross-sectional (CT and MRI) and (68)Ga DOTATATE was superior to (123)I-MIBG in detecting lesions in all anatomical locations, and particularly bony lesions. CONCLUSION: First, (68)Ga-DOTATATE should be considered as a first-line investigation in patients at high risk of PGL and metastatic disease, such as in the screening of carriers for mutations associated with familial PGL syndromes. Second, if (123)I-MIBG does not detect lesions in patients with a high pretest probability of PCC or PGL, (68)Ga DOTATATE should be considered as the next investigation. Third, (68)Ga-DOTATATE hould be considered in preference to (123)I-MIBG in patients in whom metastatic spread, particularly to the bone, is suspected. PMID- 22526962 TI - Further considerations on adverse reactions to radiopharmaceuticals. PMID- 22526963 TI - Comparison of 68Ga-DOTATATE and 68Ga-DOTANOC PET/CT imaging in the same patient group with neuroendocrine tumours. AB - PURPOSE: Recent studies have suggested that positron emission tomography (PET) imaging with (68)Ga-labelled DOTA-somatostatin analogues (SST) like octreotide and octreotate is useful in diagnosing neuroendocrine tumours (NETs) and has superior value over both CT and planar and single photon emission computed tomography (SPECT) somatostatin receptor scintigraphy (SRS). The aim of the present study was to evaluate the role of (68)Ga-DOTA-1-NaI(3)-octreotide ((68)Ga DOTANOC) in patients with SST receptor-expressing tumours and to compare the results of (68)Ga-DOTA-D-Phe(1)-Tyr(3)-octreotate ((68)Ga-DOTATATE) in the same patient population. METHODS: Twenty SRS were included in the study. Patients' age (n = 20) ranged from 25 to 75 years (mean 55.4 +/- 12.7 years). There were eight patients with well-differentiated neuroendocrine tumour (WDNET) grade1, eight patients with WDNET grade 2, one patient with poorly differentiated neuroendocrine carcinoma (PDNEC) grade 3 and one patient with mixed adenoneuroendocrine tumour (MANEC). All patients had two consecutive PET studies with (68)Ga-DOTATATE and (68)Ga-DOTANOC. All images were evaluated visually and maximum standardized uptake values (SUV(max)) were also calculated for quantitative evaluation. RESULTS: On visual evaluation both tracers produced equally excellent image quality and similar body distribution. The physiological uptake sites of pituitary and salivary glands showed higher uptake in (68)Ga DOTATATE images. Liver and spleen uptake values were evaluated as equal. Both (68)Ga-DOTATATE and (68)Ga-DOTANOC were negative in 6 (30 %) patients and positive in 14 (70 %) patients. In (68)Ga-DOTANOC images only 116 of 130 (89 %) lesions could be defined and 14 lesions were missed because of lack of any uptake. SUV(max) values of lesions were significantly higher on (68)Ga-DOTATATE images. CONCLUSION: Our study demonstrated that the images obtained by (68)Ga DOTATATE and (68)Ga-DOTANOC have comparable diagnostic accuracy. However, (68)Ga DOTATATE seems to have a higher lesion uptake and may have a potential advantage. PMID- 22526964 TI - PET SUV correlates with radionuclide uptake in peptide receptor therapy in meningioma. AB - PURPOSE: To investigate whether the tumour uptake of radionuclide in peptide receptor radionuclide therapy (PRRT) of meningioma can be predicted by a PET scan with (68)Ga-labelled somatostatin analogue. METHODS: In this pilot trial, 11 meningioma patients with a PET scan indicating somatostatin receptor expression received PRRT with 7.4 GBq (177)Lu-DOTATOC or (177)Lu-DOTATATE, followed by external beam radiotherapy. A second PET scan was scheduled for 3 months after therapy. During PRRT, multiple whole-body scans and a SPECT/CT scan of the head and neck region were acquired and used to determine the kinetics and dose in the voxel with the highest radionuclide uptake within the tumour. Maximum voxel dose and retention of activity 1 h after administration in PRRT were compared to the maximum standardized uptake values (SUV(max)) in the meningiomas from the PET scans before and after therapy. RESULTS: The median SUV(max) in the meningiomas was 13.7 (range 4.3 to 68.7), and the maximum fractional radionuclide uptake in voxels of size 0.11 cm3 was a median of 23.4 * 10(-6) (range 0.4 * 10(-6) to 68.3 * 10(-6)). A strong correlation was observed between SUV(max) and the PRRT radionuclide tumour retention in the voxels with the highest uptake (Spearman's rank test, P < 0.01). Excluding one patient who showed large differences in biokinetics between PET and PRRT and another patient with incomplete data, linear regression analysis indicated significant correlations between SUV(max) and the therapeutic uptake (r = 0.95) and between SUV(max) and the maximum voxel dose from PRRT (r = 0.76). Observed absolute deviations from the values expected from regression were a median of 5.6 * 10(-6) (maximum 9.3 * 10(-6)) for the voxel fractional radionuclide uptake and 0.40 Gy per GBq (maximum 0.85 Gy per GBq) (177)Lu for the voxel dose from PRRT. CONCLUSION: PET with (68)Ga-labelled somatostatin analogues allows the pretherapeutic assessment of tumour radionuclide uptake in PRRT of meningioma and an estimate of the achievable dose. PMID- 22526965 TI - Relapsing polychondritis detected in PET/CT. PMID- 22526967 TI - Acute intramural haematoma of the ascending aorta. PMID- 22526966 TI - Concomitant radio- and fluorescence-guided sentinel lymph node biopsy in squamous cell carcinoma of the oral cavity using ICG-(99m)Tc-nanocolloid. AB - PURPOSE: For oral cavity malignancies, sentinel lymph node (SLN) mapping is performed by injecting a radiocolloid around the primary tumour followed by lymphoscintigraphy. Surgically, SLNs can then be localized using a handheld gamma ray detection probe. The aim of this study was to evaluate the added value of intraoperative fluorescence imaging to the conventional radioguided procedure. For this we used indocyanine green (ICG)-(99m)Tc-nanocolloid, a hybrid tracer that is both radioactive and fluorescent. METHODS: Fourteen patients with oral cavity squamous cell carcinoma were peritumourally injected with ICG-(99m)Tc nanocolloid. SLNs were preoperatively identified with lymphoscintigraphy followed by single photon emission computed tomography (SPECT)/CT for anatomical localization. During surgery, SLNs were detected with a handheld gamma ray detection probe and a handheld near-infrared fluorescence camera. Pre-incision and post-excision imaging with a portable gamma camera was performed to confirm complete removal of all SLNs. RESULTS: SLNs were preoperatively identified using the radioactive signature of ICG-(99m)Tc-nanocolloid. Intraoperatively, 43 SLNs could be localized and excised with combined radio- and fluorescence guidance. Additionally, in four patients, an SLN located close to the primary injection site (in three patients this SLN was located in level I) could only be intraoperatively localized using fluorescence imaging. Pathological analysis of the SLNs revealed a metastasis in one patient. CONCLUSION: Combined preoperative SLN identification and intraoperative radio- and fluorescence guidance during SLN biopsies for oral cavity cancer proved feasible using ICG-(99m)Tc-nanocolloid. The addition of fluorescence imaging was shown to be of particular value when SLNs were located in close proximity to the primary tumour. PMID- 22526968 TI - Lymphoscintigraphy and SPECT/CT in multicentric and multifocal breast cancer: does each tumour have a separate drainage pattern? Results of a Dutch multicentre study (MULTISENT). AB - PURPOSE: To investigate whether lymphoscintigraphy and SPECT/CT after intralesional injection of radiopharmaceutical into each tumour separately in patients with multiple malignancies in one breast yields additional sentinel nodes compared to intralesional injection of the largest tumour only. METHODS: Patients were included prospectively at four centres in The Netherlands. Lymphatic flow was studied using planar lymphoscintigraphy and SPECT/CT until 4 h after administration of (99m)Tc-nanocolloid in the largest tumour. Subsequently, the smaller tumour(s) was injected intratumorally followed by the same imaging sequence. Sentinel nodes were intraoperatively localized using a gamma ray detection probe and vital blue dye. RESULTS: Included in the study were 50 patients. Additional lymphatic drainage was depicted after the second and/or third injection in 32 patients (64%). Comparison of planar images and SPECT/CT images after consecutive injections enabled visualization of the number and location of additional sentinel nodes (32 axillary, 11 internal mammary chain, 2 intramammary, and 1 interpectoral. A sentinel node contained metastases in 17 patients (34%). In five patients with a tumour-positive node in the axilla that was visualized after the first injection, an additional involved axillary node was found after the second injection. In two patients, isolated tumour cells were found in sentinel nodes that were only visualized after the second injection, whilst the sentinel nodes identified after the first injection were tumour negative. CONCLUSION: Lymphoscintigraphy and SPECT/CT after consecutive intratumoral injections of tracer enable lymphatic mapping of each tumour separately in patients with multiple malignancies within one breast. The high incidence of additional sentinel nodes draining from tumours other than the largest one suggests that separate tumour-related tracer injections may be a more accurate approach to mapping and sampling of sentinel nodes in patients with multicentric or multifocal breast cancer. PMID- 22526969 TI - Comment on Heuveling et al.: Nanocolloidal albumin-IRDye 800CW: a near-infrared fluorescent tracer with optimal retention in the sentinel lymph node. PMID- 22526970 TI - Laser-assisted surgery with different wavelengths: a preliminary ex vivo study on thermal increase and histological evaluation. AB - Since the introduction of laser in clinical practice, different wavelengths have been used for oral surgery on the basis of the different characteristics and affinities of each one. The aim of this study was a comparison of different laser wavelengths in relation to both thermal increase and "histological quality" in a model of soft tissue surgery procedures. Thermal evaluation was realized, during laser-assisted surgery excision performed on a bovine tongue, by a thermal camera device to evaluate thermal increase on the surface of the sample and with four thermocouples to evaluate thermal increase on the depth of the specimen; temperature was recorded before starting surgical procedure and at the peak of every excision. The quality of excision, in terms of tissue damage and regularity, was realized by two blind examiners on the basis of established criteria. The highest superficial thermal increase was recorded for Superpulse 5 W CO2 laser, the lowest one for Er:YAG laser. The highest in depth thermal increase was recorded for 5 W Diode laser, the lowest one for Er:YAG laser. The best quality of incision was obtained with a 3-W CO2 laser and 3-W diode laser; epithelial, stromal, and vascular damages were evaluated with different degrees for all the used wavelengths with the best result, in terms of "tissue respect," for Er:YAG laser. In all the surgical procedures performed, thermal increase was evaluated until the end of the procedure; at remaining tissue level, thermal decrease was evaluable in the few seconds after surgery. The Er:YAG laser was the device with a lower influence on thermal increase; CO2 and diode lasers revealed a good histological quality. Further studies may be necessary to test the reliability of laser devices for the excision of all the types of specimens needing histological evaluation and diagnosis. PMID- 22526971 TI - The effect of Nd:YAG and Er,Cr:YSGG lasers on the microhardness of human dentin. AB - The current investigation determined the microhardness of dentin tissue irradiated with erbium, chromium-doped yttrium scandium gallium garnet (Er,Cr:YSGG) and neodymium-doped yttrium-aluminum garnet (Nd:YAG) lasers. Thirty non-carious human molars were used in this study. Dentin disks were prepared by horizontal sectioning of one third of the occlusal surface. Halves of dentin specimens were irradiated with 3.5- and 4.5-W Er,Cr:YSGG lasers and with a 2-W Nd:YAG laser. The remaining halves served as controls. The microhardness measurements were recorded with a Vickers surface microhardness tester. The results were statistically evaluated by paired t test and one-way ANOVA (p = 0.05). Laser irradiation has significantly reduced the microhardness of dentin within each group compared to its control. Moreover, statistically significant differences were observed among the different groups (p < 0.05). The 3.5-W Er,Cr:YSGG laser produced the greatest reduction in microhardness of dentin followed by 4.5 W and Nd:YAG laser. The differences between all the groups were statistically significant. It was concluded that both laser devices used in this study have resulted in significant thermal damage and subsequent reduction in dentin microhardness values. PMID- 22526973 TI - A prospective randomized trial comparing stapler and laser techniques for interlobar fissure completion during pulmonary lobectomy. AB - Alveolar air leaks, often resulting from lung tissue traumatization during dissection of fissures, still remain a challenging problem in lung surgery. Several tools and techniques have been used to reduce air leakage, but none was judged ideal. This prospective, randomized trial was designed to evaluate the feasibility, safety, and effectiveness of completion of fissures during pulmonary lobectomy by using a laser system. A standard stapler technique was used for comparison; the primary goal was to reach at least a comparable result. Forty four patients were enrolled, 22 were treated with standard technique by using staplers (S) and 22 underwent laser (L) dissection. Randomization to one of the two groups was intraoperative after evaluating the presence of incomplete fissure (grade 3-4 following Craig's classification). A Thulium laser 2010 nm (Cyber TM, Quanta System, Italy) was used at power of 40 W. Outcome primary measures were the evaluation and duration of intra- and postoperative air leaks, the rate of complications, and the hospital stay. Air leaks (2.1 +/- 4.2 vs 3.6 +/- 7.2 days; p = 0.98) and chest tube duration (6.4 +/- 4.2 vs 7.5 +/- 6.3 days, p = 0.44) were lower in L compared with S group even if these were not statistically significant. Complications (36.4 vs 77.3 %; p = 0.006), hospital stay (6.9 +/- 3.8 vs 9.9 +/- 6.9 days; p = 0.03), hospitalization costs (5,650 vs 8,147 euros; p = 0.01), and procedure costs (77 % of difference; p < 0.0001) were significantly lower for L group, while operative time was longer (197 +/- 34 vs 158 +/- 41 min; p = 0.004). The use of laser dissection to prevent postoperative air leaks is effective and comparable with stapler technique. Aero-haemostatic laser properties (by sealing of small blood vessels and checking air leaks) allow a safe application during pulmonary lobectomy in interlobar fissure completion avoiding stapler use. PMID- 22526972 TI - The efficacy of the use of IR laser phototherapy associated to biphasic ceramic graft and guided bone regeneration on surgical fractures treated with miniplates: a Raman spectral study on rabbits. AB - The aim of the present study was to assess, by Raman spectroscopy, the repair of surgical fractures fixed with internal rigid fixation (IRF) treated or not with IR laser (lambda780 nm, 50 mW, 4 * 4 J/cm(2) = 16 J/cm(2), phi = 0.5 cm(2), CW) associated or not to the use of hydroxyapatite and guided bone regeneration (GBR). Surgical tibial fractures were created under general anesthesia on 15 rabbits that were divided into five groups, maintained on individual cages, at day/night cycle, fed with solid laboratory pelted diet and had water ad libitum. The fractures in groups II, III, IV and V were fixed with miniplates. Animals in groups III and V were grafted with hydroxyapatite and GBR technique used. Animals in groups IV and V were irradiated at every other day during 2 weeks (4 * 4 J/cm(2), 16 J/cm(2) = 112 J/cm(2)). Observation time was that of 30 days. After animal death, specimens were taken and kept in liquid nitrogen and used for Raman spectroscopy. Raman spectroscopy showed significant differences between groups (p < 0.001). Basal readings showed mean value of 1,234 +/- 220.1. Group internal rigid fixation + biomaterial + laser showed higher readings (3,521 +/- 2,670) and group internal rigid fixation + biomaterial the lowest (212.2 +/- 119.8). In conclusion, the results of the present investigation are important clinically as spectral analysis of bone component evidenced increased levels of CHA on fractured sites by using the association of laser light to a ceramic graft. PMID- 22526975 TI - Early detection and intervention of psychosis in children and adolescents: urgent need for studies. PMID- 22526974 TI - Treatment of experimental periodontitis in rats using repeated adjunctive antimicrobial photodynamic therapy. AB - The aim of this study was to histologically and histometrically evaluate the influence of repeated adjunctive antimicrobial photodynamic therapy (aPDT) on bone loss (BL) in furcation areas in rats. Periodontitis was induced by placing a ligature around the mandibular molar in 75 rats. The animals were divided into five groups: the SS group was treated with saline solution (SS); the SRP group received scaling and root planing (SRP); the aPDT1 group received SRP as well as toluidine blue (TBO) and low-level laser therapy (LLLT; InGaAlP, 660 nm; 4.94 J/cm(2)/point) postoperatively at 0 h; the aPDT2 group received SRP as well as TBO and LLLT postoperatively at 0, 24, 28, and 72 h; and the aPDT3 group received SRP, TBO, and LLLT postoperatively at 0, 48, 96, and 144 h. The area of BL in the furcation region of the molar was histometrically analyzed. Data were analyzed statistically (P < 0.05). Animals treated with a single episode of aPDT showed less BL at days 7 and 30 than those who received only SRP treatment. No significant differences were found among the aPDT groups (P > 0.05). Repeated aPDT did not improve BL reduction when compared to a single episode of aPDT. PMID- 22526977 TI - Glass: Kohlrausch exponent, fragility, anharmonicity. AB - The thermodynamical and mechanical properties of (fragile and strong) glass are modeled based on a generalised activation energy relationship log( tau ) = DeltaG ( beta )/RTn(T') process of glass-forming liquids. This cooperative process involves 1/n(T') elementary beta motions of activation Gibbs energy DeltaG ( beta ) dependent on the equivalent temperature T', the temperature of the liquid in equilibrium having the volume of the glass, function of temperature and aging conditions. From this modified VFT law the relaxation of any properties (V , H , stress, creep) can be calculated and approximated by the Kohlrausch function. This model predicts consistency relationships for: a) the temperature (and aging time) variation of the Kohlrausch exponent; b) the temperature dependence of the stabilisation time domain of strong and fragile glass; c) the linear relation between the activation parameters (E (*) energy, S (*) entropy, V (*) volume) of the alpha and beta transition. The Lawson and Keyes (LK) relations are recalled and it is shown that these relations (somewhat equivalant to the compensation law or Meyer-Neldel rule) are observed generally in glass. Morever the (macroscopic) ratios DeltaH/DeltaV observed during aging or after a temperature jump and the (microscopic) ratio E (*)/V (*) are found equal to kappagamma (kappa compressibily, gamma Gruneisen parameter), in agreement with the LK predictions. From various experiments and in agreement with predictions of this model we conclude that the Gruneisen parameter gamma ( B ) (pressure derivative of the bulk modulus) and the Mean Square Displacement (MSD) characterising the anharmonicity of solids (and liquids) are the main parameters which govern the relaxation properties of the glass state. Linear relations between the parameters gamma ( B ), the fragility m, and the Kohlrausch exponent n ( g ) at T ( g ) are explained. These correlations underscore a strong relationship between the fragilty of glass formers and the extent of the anharmonicity in the interatomic interactions. PMID- 22526976 TI - Depression and anxiety disorders in children and adolescents with velo-cardio facial syndrome (VCFS). AB - Velo-cardio-facial syndrome (VCFS) is characterized by a high prevalence of depression and anxiety disorders in childhood and adolescence. These disorders are a source of great impairment in everyday functioning, as well as important risk factors for the emergence of later psychotic disorders. Impairment in daily and social functioning as well as loss of IQ throughout growth are also are well established correlates of the VCFS. This study aimed to confirm the high prevalence of depression and anxiety disorders. The second objective was to ascertain the correlation between anxious and depressive symptoms and the decline in adaptive and cognitive functioning. A total of 73 children and adolescents with VCFS (mean age 11.9 years) underwent psychiatric evaluation. Subjects were further divided into four age groups: ages 6-9, 9-12, 12-15 and 15-18 years. Assessments measuring intelligence, anxious and depressive symptoms, and adaptation skills reported by parents were submitted to a subsample of 62 children (mean age 12.2 years); 62.2 % of the sample showed an anxiety disorder, specific phobia being the most represented at all ages. Lifetime depression concerned 27 % of the sample, peaking at age 12-15 years. Anxious and depressive symptoms and low IQ were significantly associated with low adaptive functioning. Anxiety and depression are common disorders in children and adolescents with VCFS and have a great impact on adaptive functioning. Clinicians should pay great attention to diagnosis and treatment. PMID- 22526978 TI - The mechanism of antiparallel beta-sheet formation based on conditioned self avoiding walk. AB - By introducing an additional hydrogen bond to hydrogen bond interaction in the force field of the CSAW (Conditioned Self-Avoiding Walk) model, we investigate into the mechanism of antiparallel beta-sheet formation based on the folding of a short polyalanine in gas phase. Through our numerical simulation, we detect the possible presence of a transient helix during beta-sheet formation, whose presence is shown to have slowed the formation of beta-sheets by an order of magnitude. While we observe the mechanisms of nucleation, zipping and induction that drives the formation of a beta-sheet, we uncover a new mechanism that involves transient beta-turns and short beta-sheets during the formation of long beta-sheets. Our results have enabled us to provide an overview on the mechanisms of beta-sheet formation via two main folding pathways: slow folding through the intermediate state of transient helix, and fast folding from the nucleation of beta-turn. PMID- 22526979 TI - Theoretical model of the frequency and temperature dependence of the complex non linear dielectric effect in the isotropic phase above the isotropic-smectic-A phase transition. AB - Using the Landau model, the temperature and frequency dependence of the complex non-linear dielectric effect in the isotropic phase above the isotropic-smectic-A phase transition is calculated. Comparing the results of the calculations with existing data, we finally conclude that the model provides a description of the isotropic-smectic-A transition that takes all experimentally known features of the non-linear dielectric effect in the isotropic phase into account in a qualitatively correct way. PMID- 22526980 TI - Thermodynamic behaviour of two-dimensional vesicles revisited. AB - We study pressurised self-avoiding ring polymers in two dimensions using Monte Carlo simulations, scaling arguments and Flory-type theories, through models which generalise the model of Leibler, Singh and Fisher (Phys. Rev. Lett. 59, 1989 (1987)). We demonstrate the existence of a thermodynamic phase transition at a non-zero scaled pressure [Formula: see text] , where [Formula: see text] = Np/4[Formula: see text] , with the number of monomers N [Formula: see text] infinity and the pressure p [Formula: see text] 0 , keeping [Formula: see text] constant, in a class of such models. This transition is driven by bond energetics and can be either continuous or discontinuous. It can be interpreted as a shape transition in which the ring polymer takes the shape, above the critical pressure, of a regular N -gon whose sides scale smoothly with pressure, while staying unfaceted below this critical pressure. Away from these limits, we argue that the transition is replaced by a sharp crossover. The area, however, scales with N(2) for all positive p in all such models, consistent with earlier scaling theories. PMID- 22526982 TI - Capillary soft valves for microfluidics. AB - Capillary-driven microfluidics are simple to use and provide the opportunity to perform fast biological assays with nanogram quantities of reagents and microliters of sample. Here we describe capillary soft valves (CSVs) as a simple to-implement and -actuate approach for stopping liquids in capillary-driven microfluidics. CSVs are inserted between wettable microstructures and work to block liquids owing to a capillary pressure barrier of a few kPa. This barrier is suppressed by pressing down the soft cover of the CSV using, for example, the tip of a pen. CSVs comprise a hard layer (in silicon or polymer) with wettable microstructures and a soft cover made of poly(dimethylsiloxane) (PDMS) here. CSVs have a footprint as small as 0.6 mm(2). We illustrate how these valves work in the context of detecting DNA analytes. Specifically, a dsDNA target (997 bp PCR product, non-purified) was detected at concentrations of 20 and 200 nM in a sample volume of 0.7 MUL and within 10 min. The assay includes melting of the dsDNA at 95 degrees C, annealing of a 30-base biotinylated probe at 50 degrees C, and intercalation of a fluorescent dye into the re-hybridized dsDNA at 25 degrees C. Actuation of the CSV allows the DNA target-probe-dye complexes to flow over 100 MUm wide, streptavidin receptor lines. This work suggests that CSVs can fulfil the requirements set by complex assays, in which elevated temperatures and reaction with probes, dyes and capture species are needed. CSVs therefore greatly complement capillary-driven microfluidics without adding significant design, fabrication and actuation issues. PMID- 22526981 TI - Mechanical responses and stress fluctuations of a supercooled liquid in a sheared non-equilibrium state. AB - A steady shear flow can drive supercooled liquids into a non-equilibrium state. Using molecular dynamics simulations under steady shear flow superimposed with oscillatory shear strain for a probe, non-equilibrium mechanical responses are studied for a model supercooled liquid composed of binary soft spheres. We found that even in the strongly sheared situation, the supercooled liquid exhibits surprisingly isotropic responses to oscillating shear strains applied in three different components of the strain tensor. Based on this isotropic feature, we successfully constructed a simple two-mode Maxwell model that can capture the key features of the storage and loss moduli, even for highly non-equilibrium state. Furthermore, we examined the correlation functions of the shear stress fluctuations, which also exhibit isotropic relaxation behaviors in the sheared non-equilibrium situation. In contrast to the isotropic features, the supercooled liquid additionally demonstrates anisotropies in both its responses and its correlations to the shear stress fluctuations. Using the constitutive equation (a two-mode Maxwell model), we demonstrated that the anisotropic responses are caused by the coupling between the oscillating strain and the driving shear flow. Due to these anisotropic responses and fluctuations, the violation of the fluctuation-dissipation theorem (FDT) is distinct for different components. We measured the magnitude of this violation in terms of the effective temperature. It was demonstrated that the effective temperature is notably different between different components, which indicates that a simple scalar mapping, such as the concept of an effective temperature, oversimplifies the true nature of supercooled liquids under shear flow. An understanding of the mechanism of isotropies and anisotropies in the responses and fluctuations will lead to a better appreciation of these violations of the FDT, as well as certain consequent modifications to the concept of an effective temperature. PMID- 22526983 TI - Assessment of cadmium, copper, lead and zinc contamination using oysters (Saccostrea cucullata) as biomonitors on the coast of the Persian Gulf, Iran. AB - The levels of Cd, Cu, Pb and Zn in surface sediment, soft tissue and shell of the oyster Saccostrea cucullata collected from three locations, in the intertidal zones of Lengeh Port, northern part of Persian Gulf were measured. Results indicated that there were a positive correlation across Zn (r = 0.58, p = 0.025), Cd (r = 0.74, p < 0.01) and Cu (r = 0.80, p < 0.01) levels in the soft tissue of oyster and sediment which supported this fact that the soft tissue of S. cucullata can be considered as biomonitoring agent for Cd, Zn and Cu in the Lengeh Port. PMID- 22526984 TI - Oyster Saccostrea cucullata as a biomonitor for Hg contamination and the risk to humans on the coast of Qeshm Island, Persian Gulf, Iran. AB - A total of 174 individuals of rocky oysters (Saccostrea cucullata) and 35 surface sediment samples were collected from seven stations off the intertidal zones of Qeshm Island, Persian Gulf, in order to study the concentration of mercury in oysters' tissues, and to investigate whether mercury concentrations in the edible soft tissues are within the permissible limits for public health. The average mercury concentrations were found as 3.44, 50.66 and 2.29 MUg kg(-1) dw in the sediments, soft tissues and shells of the oysters, respectively. Results indicated that the levels of mercury in sediment differed significantly between the stations. In addition, results confirmed that the soft tissues of oysters could be a good indicator of mercury in the aquatic system. In comparison with food safety standards, mercury levels in oysters were well within the permissible limits for human consumption. PMID- 22526985 TI - Dissipation and residue of myclobutanil in lychee. AB - The dissipation and residue of myclobutanil in lychee under field conditions were studied. To determine myclobutanil residue in samples, an analytical method with a florisil column clean-up and detected by gas chromatography-electron capture detector (GC-ECD) was developed. Recoveries were found in the range of 83.24 % 89.00 % with relative standard deviations of 2.67 %-9.88 %. This method was successfully applied to analyze the dissipation and residue of myclobutanil in lychee in Guangdong and Guangxi Province, China. The half lives in lychee were from 2.2 to 3.4 days. The residues of myclobutanil in lychee flesh were all below the limit of quantification (LOQ) value (0.01 mg/kg), and most of the residues were concentrated in the peel. The terminal residues of myclobutanil were all bellow the maximum residue limit (MRL) value set by European Union (EU) (0.02 mg/kg). Hence it was safe for the use of this pesticide and the results also could give a reference for MRL setting of myclobutanil in lychee in China. PMID- 22526986 TI - A survey of aflatoxin M1 contamination in bulk milk samples from dairy bovine, ovine, and caprine herds in Iran. AB - A total of 150 bovine (60), ovine (42), and caprine (48) bulk milk samples were analyzed using a commercially available competitive ELISA kit. Overall, AFM1 was found in 46.7 % of the analyzed samples by an average concentration of 40.3 +/- 22.2 ng/L. The incidence rates of AFM1 contamination in bovine, ovine, and caprine bulk milk samples were 66.7, 31.0, and 35.4 %, respectively. The concentration of AFM1 in 37.5 % of AFM1-positive bovine milk samples and 5.9 % of AFM1-positive caprine milk samples were higher than 50 ng/L. PMID- 22526987 TI - Total mercury in liver and muscle tissue of two coastal sharks from the northwest of Mexico. AB - Total mercury (THg) in liver and muscle of three costal sharks from Mexico were evaluated. The highest concentrations of THg in muscle tissue of juveniles were found in Sphyrna lewini (0.82 +/- 0.33 mg kg(-1) wet basis). Rhizoprionodon longurio adults had the highest concentrations (0.92 +/- 1.03 mg kg(-1)). THg concentrations in liver were low compared to those found in muscle tissue; higher levels were found in liver of juvenile S. lewini (0.250 +/- 0.07 mg kg(-1)). Results showed that 35 % of muscle tissue samples are above the precautionary limit (0.50 mg kg(-1) of THg) and a 7 % exceeded the maximum limit for human consumption (1 mg kg(-1)). PMID- 22526988 TI - Cadmium-induced toxicity on larvae of the common Asian toad Duttaphrynus melanostictus (Schneider 1799): evidence from empirical trials. AB - This paper investigates the toxicity of cadmium (Cd) on young stages of the common Asian toad Duttaphrynus melanostictus (Schneider 1799). Signs of acute toxicity were evident in tadpoles repeatedly exposed to five concentrations ranging from 0.002 to 2 mg L(-1)of Cd which included environmentally relevant levels. Mortality at concentrations of 0.02 mg L(-1) and above was enhanced from 2 % at 0.02 mg L(-1) to 100 % at 1 mg L(-1), in a dose-dependent manner. Significant growth impairment was evident at 0.20 mg L(-1) with the larvae being markedly smaller. Delayed metamorphosis and retarded swimming were also observed. Therefore levels of Cd recorded in some freshwater bodies in Sri Lanka (e.g. 0.2 mg L(-1)) may be detrimental to the young stages of D. melanostictus. PMID- 22526989 TI - The acute and behavioral effects of a copper-nickel mixture on roach Rutilus rutilus. AB - Semi-static acute toxicity tests were conducted on adult roach, Rutilus rutilus, to estimate its sensitivity toward an equitoxic binary mixture (EBM) of copper and nickel. The sum of their individual LC50 values was considered to equal 100 %. The main endpoints of the study were mortality and behavioral responses: detection, locomotor activity, coughing rate and pectoral-fin activity. The 96-h LC50 of EBM was 14.4 (10.1 %-20.5 %), indicating a synergism of individual metals. The most meaningful behavioral results were obtained after 10-min, 1-h and 24-h exposures, and the most sensitive and informative behavioral response was found to be coughing rate. This bioassay response may be used successfully to evaluate wastewaters containing heavy metals for their toxicity toward fish. PMID- 22526990 TI - Comet assay to assess the genotoxicity of Persian walnut (Juglans regia L.) husks with statistical evaluation. AB - The aim of this study was to confirm the utility of the Comet assay as a genotoxicity screening test for evaluating the impact of walnut husk aqueous extract. Phytotoxicity assays using diluted and undiluted walnut husk aqueous extracts were performed on young roots of Raphanus sativus (radish), and the Comet assay was used to evaluate DNA integrity in isolated radish radicle nuclei. The results reveal a dose-dependent accumulation of DNA damage in radish radicles treated with walnut husks water extract and that the Kolmogorov-Smirnov test combined with Johnson SB distribution was the best approach for describing Comet assay data. PMID- 22526991 TI - Assessment of fluoride contamination in groundwater as precursor for electrocoagulation. AB - The Present study was conducted in January 2010, in order to assess the fluoride contamination in the Thirupathur Taluk. The major objective of this study was to locate the vulnerable areas in terms of fluoride contamination. The range of fluoride concentration varied between .26 and 2.75 mg/L. 60 % of the samples were above the permissible limit. Good correlation was observed between pH, Na, HCO(3), CO(3) TDS and NO(3). A negative correlation showed by Ca and K. The results show that Geochemistry of these ions controls the Fluoride concentration in the study area. All the samples exceeded the permissible limit of F was characterized by Na-HCO(3) type of water. A fairly good correlation between F and NO(3) suggest an anthropogenic input of F, mainly from the agricultural fields. Spatial distribution map of Fluoride shows very high concentration in the SW part of the study area. PMID- 22526992 TI - Spatial-based assessment of metal contamination in agricultural soils near an abandoned copper mine of eastern China. AB - An investigation about metal contamination on agricultural soils was carried out near an abandoned copper mine in eastern China. Results showed the average concentrations of Cu, Pb, Zn and Cd in the 155 soil samples were 147, 53.8, 158, 0.32 mg kg(-1) respectively, which were 4.6-, 2.2-, 2-, 1.7-fold of the corresponding background value. According to the Chinese Farmland Environmental Quality Evaluation Standards for Edible Agricultural Products, it was found 18.4 % of the soils belonged to heavily and moderately contaminated soils. PMID- 22526993 TI - Organochlorine pesticides and polychlorinated biphenyls in various tissues of waterbirds in Nalabana bird sanctuary, Chilika Lake, Orissa, India. AB - In order to understand whether organochlorine pesticides and polychlorinated biphenyls (PCBs) are responsible for the mortality of waterbirds in Nalaban bird sanctuary in Chilika Lake, the current investigation was carried out in tissues of 11 individuals comprising 7 species of birds. One or more residues were detected in all the tissues of birds analysed. Concentration of ?HCH, ?DDT, and ?PCBs were ranged from below detectable level (BDL)-811 ng/g, BDL-1,987 ng/g and BDL-1,027 ng/g respectively. PCBs levels were less than the food and drug administration's (FDA) action limits. Although varying levels of residues were detected among tissues, they do not appear to be responsible for the mass mortality of waterfowl. However, the need for additional research is heightened when considering that some of the birds are classified as a globally protected species by the international bodies. PMID- 22526994 TI - Occurrence of organophosphorus and carbamate pesticide residues in surface water samples from the Rangpur district of Bangladesh. AB - We report the presence of organophosphorus and carbamate residues in 24 surface water samples and five ground water samples from Pirgacha Thana, Rangpur district, Bangladesh using high-performance liquid chromatography. A number of samples of surface water from paddy fields were found to contain chlorpyriphos, carbofuran and carbaryl at concentrations ranging from 0-1.189, 0-3.395 and 0 0.163 MUg/L, respectively. Surface water from the lakes had chlorpyriphos, carbofuran and carbaryl at concentrations ranging from 0.544-0.895, 0.949-1.671 and 0-0.195 MUg/L, respectively. This result indicates that the general public living in the area of Rangpur is at high risk of pesticide exposure from contaminated waters in the environment. PMID- 22526995 TI - Microplastics in beaches of the East Frisian islands Spiekeroog and Kachelotplate. AB - Microplastic particles were quantified in beach transects of the East Frisian islands Spiekeroog and Kachelotplate and in two samples from a tidal flat. Both granules and fibres were present while fragments and polystyrene pellets were completely absent. On the Kachelotplate the highest number of granules (496/10 g sediment) was observed at the high water line while on Spiekeroog a sample from the dune area had the highest value (38/10 g sediment). The tidal flat samples hat 36 and 136 granules/10 g sediment with the higher number being associated with a blue mussel bank. Fibres were more homogeneously distributed and did not show any particular enrichment. In comparison with data from the Belgian coast the total numbers are higher which might be related to the exposure situation of the island beaches. PMID- 22526996 TI - Toxicity persistence in runoff water and soil in experimental soybean plots following chlorpyrifos application. AB - Toxicity persistence in runoff water and soil was studied in experimental soybean plots in successive runoff events produced by an irrigation system. Three chlorpyrifos applications throughout the growing period were assayed. Runoff and soil toxicity to the amphipod Hyalella curvispina and the fish Cnesterodon decemmaculatus was assessed. Toxicity persistence to H. curvispina was shorter in the early and midseason applications (23-28 and 21-69 days in runoff and soil, respectively) and longer in the late application (more than 140 days). The same trend was observed for C. decemmaculatus: 13 days for early and 56 for the late application. PMID- 22526997 TI - A comparative study on the persistence of imidacloprid and beta-cyfluthrin in vegetables. AB - In an effort to compare the persistence of imidacloprid and beta-cyfluthrin, when applied through a ready mix formulation, Solomon 300 OD @ 200 and 400 mL ha(-1) in the fruits of brinjal, tomato and okra, the present study has been made. The study indicated that the dissipation of these insecticides irrespective of fruits followed concentration dependent first order kinetics. The degradation constant and half live value of beta-cyfluthrin varies between -0.287 and -0.642 day(-1) and 1.07 and 2.41 days while that of imidacloprid between -0.21 and -0.34 day(-1) and 1.98 and 3.30 days respectively suggesting that the persistence of beta cyfluthrin is lower than that of imidacloprid in fruits of these vegetables. Moreover, the persistence of these insecticides when compared between different fruits, it is highest in brinjal followed by tomato and least in okra, a probable clue of which has been proposed based on the non-enzymatic antioxidant content of the fruits. PMID- 22526998 TI - Assessment of metal concentrations in two Cyprinid fish species (Leuciscus cephalus and Tinca tinca) captured from Yenicaga Lake, Turkey. AB - This study was performed to investigate certain major and toxic metal concentrations in muscle, gill and liver tissues of two Cyprinid species (Leuciscus cephalus, Tinca tinca). Generally liver and gill tissue exhibited higher metal concentrations than did muscle. The highest metal concentrations found in tench and chub muscle tissues were determined to be Al (59.01-108 mg kg( 1)), Zn (45.23-57.81 mg kg(-1)), Fe (9.23-16.03 mg kg(-1)) and Ba (3.50-2.69 mg kg(-1)) respectively. The level of metal accumulation is evaluated for potential risk to human health based on international standards. Zinc, lead and arsenic values of muscle tissues of the fishes were found to be above the allowed limits for human consumption. PMID- 22526999 TI - Chromium (VI) reduction by cell free extract of Ochrobactrum anthropi isolated from tannery effluent. AB - Chromium-resistant bacteria isolated from industrial wastes can be used to detoxify toxic chromium from contaminated sources. From effluent of Shafiq Tannery, Kasur, Pakistan, bacterial strain STCr-1 that could endure 40 mg mL(-1) of potassium chromate in nutrient agar medium was isolated. STCr-1, identified as Ochrobactrum anthropi by 16S rRNA gene sequence homology, demonstrated substantial Cr(VI) reduction at pH 7 and temperature 37 degrees C. It completely reduced 250 MUg mL(-1) of Cr(VI) and showed 71.2 % Cr(VI) reduction at Cr(VI) concentrations of 550 MUg mL(-1). Rate of Cr(VI) reduction increased with increase in cell and Cr(VI) concentration. The presence of Cu(2+), Co(2+) and Mn(2+) significantly stimulated Cr(VI) reduction. Assay with cell free extracts clearly indicated that Cr(VI) reduction was solely associated with the soluble fraction of the cell. PMID- 22527000 TI - Mercury bioaccumulation and prediction in terrestrial insects from soil in Huludao City, Northeast China. AB - Mercury accumulation was investigated by constructing and testing empirical equations based on mercury in soil (C(s)) and in 10 terrestrial insects (C(i)). C(s) ranged from 0.13 to 41.01 mg/kg. C(i) differed with species and the highest was found in dragonfly. C(s) and C(i) showed a good linear fit, and a simple equation was used in predicting C(i) when insects were classified into one Insecta group (r = 0.3399, p = 0.0037). The taxonomy can affect validities of empirical equations, which fit field data well when insects were grouped by feeding habits, and when grouped by species, empirical equations were suitable only for certain insects. PMID- 22527001 TI - Levels of Cd, Pb, As, Hg, and Se in hair of residents living in villages around Fenghuang polymetallic mine, southwestern China. AB - Heavy metal levels in hair of residents living in villages around Fenghuang mine were investigated. Samples belonging to mine areas showed the highest values, with mean concentrations (mg kg(-1)) of 0.17 for Cd, 8.67 for Pb, 0.11 for As, 2.19 for Hg, and 0.64 for Se. Significant correlations (p < 0.01) were found between Cd-Pb, Cd-As, Pb-As, and Se-Hg. There is no significant difference in any of the elements among age groups. However, significant differences in Cd and Pb levels were found between genders. Results revealed that children and females were more susceptible to Cd and Pb exposure. PMID- 22527002 TI - The role of catchment vegetation in reducing atmospheric inputs of pollutant aerosols in Ganga river. AB - The role of woody perennials in the Ganga river basin in modifying the run-off quality as influenced by atmospheric deposition of pollutant aerosols was investigated. The concentration of seven nutrients and eight metals were measured in atmospheric deposits as well as in run-off water under the influence of five woody perennials. Nutrient retention was recorded maximum for Bougainvillea spectabilis ranged from 4.30 % to 33.70 %. Metal retention was recorded highest for Ficus benghalensis ranged from 5.15 % to 36.98 %. Although some species showed nutrient enrichment, all the species considered in the study invariably contribute to reduce nutrients and metal concentration in run-off water. Reduction in run off was recorded maximum for B. spectabilis (nutrient 6.48 % 40.66 %; metal 7.86 %-22.85 %) and minimum for Ficus religiosa (nutrient 1.68 % 27.19 %; metal 6.55 %-31.55 %). The study forms the first report on the use of woody perennials in reducing input of atmospheric pollutants to Ganga river and has relevance in formulating strategies for river basin management. PMID- 22527003 TI - Temporal evolution of exposure to mercury in riverside communities in the Tapajos basin, from 1994 to 2010. AB - Our objective was to evaluate the temporal evolution of mercury exposure in two riverside communities, Barreiras and Sao Luiz do Tapajos, downstream of gold mining areas in the Tapajos basin, Brazilian Amazon. The quantification of mercury in hair sample was made by atomic absorption spectrophotometry in the period between 1994 and 2010. In Sao Luiz do Tapajos the mercury exposure varied, in log units, from the peak of 1.21 +/- 0.03 MUg/g in 1996 to 1.16 +/- 0.07 MUg/g in 2007. Mercury exposure in Barreiras varied, in log units, from 1.25 +/- 0.04 MUg/g in 1994 to 1 +/- 0.03 MUg/g in 2010, peaking in 1995 at 1.25 +/- 0.06 MUg/g. Total mercury concentration found in both communities had no statistical differences across the years (p > 0.05) and they were higher than non-mercury exposed communities in Brazil and in South America. We concluded that the mercury exposure in the Tapajos basin is more than regulatory levels or higher than the general population. PMID- 22527004 TI - Total and organic mercury in liver, kidney and muscle of waterbirds from wetlands of the Caspian Sea, Iran. AB - We measured and compared total and organic mercury in liver, kidney, and muscle of the Great Cormorant (Phalacrocorax carbo), mallard (Anas platyrhynchos), and coot (Fulica atra) from the Caspian Sea wetlands in Iran. For the Great Cormorant organic mercury in liver, kidney and muscle comprised 82 %, 79 % and 58 % of total mercury. In the mallard same values were 46 %, 54 %, and 64 %. For coot total mercury was: 0.1 +/- 0.0, 0.1 +/- 0.01, 0.03 +/- 0.01 in liver kidney and muscle respectively. We detected no organic mercury. In general older birds that feed on higher trophic levels can accumulate more mercury in their tissues. PMID- 22527005 TI - Multi-medium distributions of HCHs, DDTs, and PCBs in typical petrochemical industrial area and surrounding regions of Jilin Province, Northeast China. AB - The levels of DDTs, HCHs and PCBs in topsoil, cereal and irrigation water from typical industrial and agricultural areas of Jilin Province in Northeastern China were evaluated by using gas chromatography coupled with an electron capture detector. The amount of ?OCPs and ?(7)PCBs found in topsoils ranged from 24.7 to 98.0 and 17.2 to 98.7 ng g(-1), respectively. The geometric means of ?HCHs, ?DDTs and ?(7)PCBs in rice stem samples were 28.9, 32.4 and 49.0 ng g(-1), respectively. The average level of total OCPs concentration in rice field water in Meihekou area (0.849 ng g(-1)) is higher than that in Jilin area (0.178 ng g( 1)) and all OCPs concentrations in rice field water met the water quality standards for Grade I regulated by China's national environmental quality standard of surface water. PMID- 22527006 TI - Multiple in vitro bioassay approach in sediment toxicity evaluation: Masan Bay, Korea. AB - Extracts of 21 sediment samples from Masan Bay, Korea, used in an earlier chemical measurement, were screened for their ability to induce estrogen, - and dioxin - like gene expression using the E-Assay (+), DR-CALUX assay, respectively, and to inhibit acetylcholinesterase (AChE) activity using an in vitro AChE assay. Biological impact in the industry-rich inner bay is higher than outer bay. DDTs (0.65), coplanar PCBs (0.77), HCHs (0.64), PAHs (0.61) and APs (0.53) with good correlation to E-assay (+) are seen as environmental estrogens. The highest induction of DR-CALUX response was seen again at station M12 and 15 which received sewage effluents. PCDD/DFs gave the highest correlation (0.75). Interestingly, the M12 station at the sewage treatment outlet showed the highest activity. Among the targeted chemicals APs (0.66), PCBs (0.64), PAHs (0.61) and DDT (0.49) correlated well with the AChE bioassay. Spearman rank correlation on analytical and biochemical results affirmed the 'hot spots' and point sources (e.g., sewage treatment and industrial outfall) and suspected toxicants. Significant correlations between organo chlorine pesticides, PCBs, dioxins and alkylphenols and their biological effects were observed. PMID- 22527007 TI - Non-invasive estimation of cerebrospinal fluid pressure waveforms by means of retinal venous pulsatility and central aortic blood pressure. AB - Current techniques used for cerebrospinal fluid pressure (CSFp) measurements are invasive. They require a surgical procedure for placement of a pressure catheter in the brain ventricles or in the brain tissue. The human eye provides direct visualisation of its physiological structures and due to its anatomical connection with CSF via the retrolaminar optic nerve it may provide accessible information about CSFp. A total of 25 subjects were included in this study. 15 subjects were used to characterise the relationship between intraocular pressure (IOP), spontaneous retinal venous pulsatility (SRVP), and CSFp. IOP was manipulated and SRVP amplitudes recorded dynamically using the dynamic vessel analyzer (DVA). The relationship between IOP and SRVP amplitude was established to estimate CSFp. Additionally Doppler blood flow velocity of the middle cerebral artery and arterial blood pressure (ABP) were acquired for all subjects. This was to compare and validate our findings with an alternative approach (ICM+) which uses these values to estimate CSFp. A CSFp waveform was extracted from central blood pressure (CBP) waveform by removing its cardiac component frequency. Furthermore to calibrate the CSFp to CBP waveform ratio, invasive CSFp, and ABP was measured from 10 subjects with brain tumours who had a range of normal to elevated CSFp (i.e., 0-30 mmHg). Results show good agreement between the two methods (correlation r (2) = 0.55) Mean estimated CSFp for the two techniques did not show any significant difference (p > 0.05). A significant correlation between CBP pulse (CBPp) and invasive CSFp pulse (CSFpp) was observed (i.e., CSFpp = 0.0654CBBp + 3.91, p < 0.01). Estimated CSFpp was calibrated to CBPp according to this relation. In conclusion, the study demonstrated a good correlation between two different methods of estimating CSFp non-invasively and may provide a novel method to estimate CSF waveforms non-invasively. PMID- 22527008 TI - Polyelectrolyte complex membranes for prevention of post-surgical adhesions in neurosurgery. AB - Adhesions are bands of tissue that can form after the surgery and bind together the surrounding tissue in the vicinity of the surgical site. In this work, polyelectrolyte complex (PEC)-based membranes were developed and investigated for their potential application as anti-adhesion barriers after neurosurgery. The adhesion and migration behavior of fibroblast and mixed neuronal cells were also investigated. Fibroblasts cells neither adhered nor migrated onto the PEC material after 5 days in vitro. Similar behaviors were observed for neurons and astrocytes cells. Swelling experiments of these membranes showed that the membranes are extremely hygroscopic and absorb significant amount of water. Membranes containing 70% alginate absorbed the highest amount of water (442 +/- 24% of dry wet). PEC content was highest in 50% alginate containing membranes (87.1 +/- 6.7%). The membrane's mechanical properties were attributed to combined contribution of water absorption and PEC content. Drug release profiles were investigated using albumin as a model drug. Membranes containing 70% alginate showed highest initial drug release rate followed by membranes containing 60 and 50% alginate. Membranes were stable and did not dissolve for 1 month in phosphate buffer and lysozyme solutions. PMID- 22527009 TI - Toward computational identification of multiscale "tipping points" in acute inflammation and multiple organ failure. AB - Sepsis accounts annually for nearly 10% of total U.S. deaths, costing nearly $17 billion/year. Sepsis is a manifestation of disordered systemic inflammation. Properly regulated inflammation allows for timely recognition and effective reaction to injury or infection, but inadequate or overly robust inflammation can lead to Multiple Organ Dysfunction Syndrome (MODS). There is an incongruity between the systemic nature of disordered inflammation (as the target of inflammation-modulating therapies), and the regional manifestation of organ specific failure (as the subject of organ support), that presents a therapeutic dilemma: systemic interventions can interfere with an individual organ system's appropriate response, yet organ-specific interventions may not help the overall system reorient itself. Based on a decade of systems and computational approaches to deciphering acute inflammation, along with translationally-motivated experimental studies in both small and large animals, we propose that MODS evolves due to the feed-forward cycle of inflammation -> damage -> inflammation. We hypothesize that inflammation proceeds at a given, "nested" level or scale until positive feedback exceeds a "tipping point." Below this tipping point, inflammation is contained and manageable; when this threshold is crossed, inflammation becomes disordered, and dysfunction propagates to a higher biological scale (e.g., progressing from cellular, to tissue/organ, to multiple organs, to the organism). Finally, we suggest that a combination of computational biology approaches involving data-driven and mechanistic mathematical modeling, in close association with studies in clinically relevant paradigms of sepsis/MODS, are necessary in order to define scale-specific "tipping points" and to suggest novel therapies for sepsis. PMID- 22527010 TI - Modeling life. AB - We seek to construct physical and mathematical models of life. Such models allow us to test our understanding of how living systems function and how they respond to human imposed stimuli. One system is a genomically and chemically complete model of a minimal cell. This cell is a hypothetical bacterium with the fewest number of genes possible. Such a minimal cell provides a platform to ask about the essential features of a living cell and forms a platform to investigate "synthetic biology." A second system is "Body-on-a-Chip" which is a microfabricated microfluidic system with cells or tissue constructs representing various organs in the body. It can be constructed from human or animal cells and used in drug discovery development. That model is a physical representation of a physiologically based pharmacokinetic model. Both the computer and the physical models provide insight into the underlying biology and provide new tools to make use of that understanding to provide benefits to society. PMID- 22527011 TI - Mitochondrial dynamics and motility inside living vascular endothelial cells: role of bioenergetics. AB - The mitochondrial network is dynamic with conformations that vary between a tubular continuum and a fragmented state. The equilibrium between mitochondrial fusion/fission, as well as the organelle motility, determine network morphology and ultimately mitochondrial/cell function. Network morphology has been linked with the energy state in different cell types. In this study, we examined how bioenergetic factors affect mitochondrial dynamics/motility in cultured vascular endothelial cells (ECs). ECs were transduced with mitochondria-targeted green fluorescent protein (mito-GFP) and exposed to inhibitors of oxidative phosphorylation (OXPHOS) or ATP synthesis. Time-lapse fluorescence videos were acquired and a mathematical program that calculates size and speed of each mitochondrial object at each time frame was developed. Our data showed that inner mitochondrial membrane potential (DeltaPsi(m)), ATP produced by glycolysis, and, to a lesser degree, ATP produced by mitochondria are critical for maintaining the mitochondrial network, and different metabolic stresses induce distinct morphological patterns (e.g., mitochondrial depolarization is necessary for "donut" formation). Mitochondrial movement, characterized by Brownian diffusion with occasional bursts in displacement magnitude, was inhibited under the same conditions that resulted in increased fission. Hence, imaging/mathematical analysis shed light on the relationship between bioenergetics and mitochondrial network morphology; the latter may determine EC survival under metabolic stress. PMID- 22527012 TI - Flow field of a novel implantable valveless counterpulsation heart assist device. AB - Flow fields are one of the key factors associated with the life threatening formation of thrombi in artificial organs. Therefore, knowledge of flow field is crucial for the design and optimization of a long-term blood pump performance. The blood chamber flow of a novel counterpulsation heart assist device (CPD) has been investigated using laser Doppler velocimetry (LDV), particle image velocimetry (PIV), and near-wall PIV (wall-PIV). The wall-PIV is an in-house developed technique assessing wall shear rates (WSR). These experimental techniques analyzed complex transient three-dimensional (3D) flow fields including major and secondary structures during the whole CPD cycle (ejection, filling, and hold time). PIV measurements in the central plane investigated an evolution (development and destruction) of the blood chamber fully filling vortex as the major CPD flow structure. The wall-PIV measurements identified areas of blood stagnation (vortex center and jet impingements) and quantified WSR at the front housing. Maximal mean WSR of 2,045 +/- 605 s(-1) were found at the end of the filling. The LDV, which identified helical flow structure at the outer region of the pump, was used to complete 3D flow analysis and to combine PIV and wall PIV results. The results suggest good washing behavior of the CPD regarding thrombus formation. PMID- 22527013 TI - Effect of shear force on intervertebral disc (IVD) degeneration: an in vivo rat study. AB - Mechanical stress on the intervertebral disc (IVD) may contribute significantly to IVD degeneration, although its pathomechanism has not been fully understood. The purpose of this study was to test the hypothesis that sustained application of static shear force would result in IVD degeneration with minimum injury. We applied shear force on the rat lumbar spine (L5-L6) using a custom-designed loading device for 1 or 2 weeks. Degenerative changes such as nucleus pulposus cavity loss and border disruption were observed from the histology sections, indicating that the application of sustained dorsoventral shear force on the L6 vertebra induced degeneration of the IVDs in L5-L6 and adjacent levels of motion segment in 1 and 2 weeks. The findings of the present study could be useful for gaining a more relevant understanding of the biomechanical load factors of IVD degeneration not only for enabling better therapeutic interventions but also reducing the risk of low back injury. PMID- 22527014 TI - A numerical simulation approach to studying anterior cruciate ligament strains and internal forces among young recreational women performing valgus inducing stop-jump activities. AB - Anterior cruciate ligament (ACL) injuries are commonly incurred by recreational and professional women athletes during non-contact jumping maneuvers in sports like basketball and volleyball, where incidences of ACL injury is more frequent to females compared to males. What remains a numerical challenge is in vivo calculation of ACL strain and internal force. This study investigated effects of increasing stop-jump height on neuromuscular and bio-mechanical properties of knee and ACL, when performed by young female recreational athletes. The underlying hypothesis is increasing stop-jump (platform) height increases knee valgus angles and external moments which also increases ACL strain and internal force. Using numerical analysis tools comprised of Inverse Kinematics, Computed Muscle Control and Forward Dynamics, a novel approach is presented for computing ACL strain and internal force based on (1) knee joint kinematics and (2) optimization of muscle activation, with ACL insertion into musculoskeletal model. Results showed increases in knee valgus external moments and angles with increasing stop-jump height. Increase in stop-jump height from 30 to 50 cm lead to increase in average peak valgus external moment from 40.5 +/- 3.2 to 43.2 +/- 3.7 Nm which was co-incidental with increase in average peak ACL strain, from 9.3 +/- 3.1 to 13.7 +/- 1.1%, and average peak ACL internal force, from 1056.1 +/- 71.4 to 1165.4 +/- 123.8 N for the right side with comparable increases in the left. In effect this study demonstrates a technique for estimating dynamic changes to knee and ACL variables by conducting musculoskeletal simulation on motion analysis data, collected from actual stop-jump tasks performed by young recreational women athletes. PMID- 22527016 TI - o-Benzenedisulfonimide and its chiral derivative as Bronsted acids catalysts for one-pot three-component Strecker reaction. Synthetic and mechanistic aspects. AB - o-Benzenedisulfonimide (OBS) has efficiently catalysed the one-pot three component reaction of ketones and aromatic amines with trimethylsilyl cyanide (TMSCN) giving the corresponding alpha-amino nitriles in excellent yields (23 examples; average yield 85%). Reaction conditions were very simple, green and efficient. Theoretical calculations have allowed us to explain the mechanism of this reaction which has been found to take place in two phases; the first consists of the nucleophilic addition of the aniline to the ketone and the subsequent dehydration to an imine; the second one consists of the formal addition of cyanide anion to the protonated imine. OBS acts in all steps of this mechanism. Without an acid catalyst, the reaction mechanism is more simple but barriers are sensibly higher. A chiral derivative of OBS was also used and gave fairly good results. PMID- 22527015 TI - Diastolic ventricular support with cardiac support devices: an alternative approach to prevent adverse ventricular remodeling. AB - Heart failure is a global epidemic with limited therapy. Abnormal left ventricular wall stress in the diseased myocardium results in a biochemical positive feedback loop that results in global ventricular remodeling and further deterioration of myocardial function. Mechanical myocardial restraints such as the Acorn CorCap and Paracor HeartNet ventricular restraints have attempted to minimize diastolic ventricular wall stress and limit adverse ventricular remodeling. Unfortunately, these therapies have not yielded viable clinical therapies for heart failure. Cellular and novel biopolymer-based therapies aimed at stabilizing pathologic myocardium hold promise for translation to clinical therapy in the future. PMID- 22527017 TI - MDR3 immunostaining on frozen liver biopsy samples is not a sensitive diagnostic tool for the detection of heterozygous MDR3/ABCB4 gene mutations. PMID- 22527018 TI - An improved image analysis method for cell counting lends credibility to the prognostic significance of T cells in colorectal cancer. AB - Numerous immunohistochemically detectable proteins, such as immune cell surface (CD) proteins, vascular endothelial growth factor, and matrix metalloproteinases, have been proposed as potential prognostic markers in colorectal cancer (CRC) and other malignancies. However, the lack of reproducibility has been a major problem in validating the clinical use of such markers, and this has been attributed to insufficiently robust methods used in immunohistochemical staining or its assessment. In this study, we assessed how computer-assisted image analysis might contribute to the reliable assessment of positive area percentage and immune cell density in CRC specimens, and subsequently, we applied the computer-assisted cell counting method in assessing the prognostic value of T cell infiltration in CRC. The computer-assisted analysis methods were based on separating hematoxylin and diaminobenzidine color layers and then applying a brightness threshold using open source image analysis software ImageJ. We found that computer-based analysis results in a more reproducible assessment of the immune positive area percentage than visual semiquantitative estimation. Computer-assisted immune cell counting was rapid to perform and accurate (Pearson r > 0.96 with exact manual cell counts). Moreover, the computer-assisted determination of peritumoral and stromal T cell density had independent prognostic value. Our results suggest that computer-assisted image analysis, utilizing freely available image analysis software, provides a valuable alternative to semiquantitative assessment of immunohistochemical results in cancer research, as well as in clinical practice. The advantages of using computer-assisted analysis include objectivity, accuracy, reproducibility, and time efficiency. This study supports the prognostic value of assessing T cell infiltration in CRC. PMID- 22527020 TI - Case 1: hypertensive 58-year-old woman with hepatic nodules presented dyspnea and pleural effusion one week after an episode of pulmonary embolism. PMID- 22527021 TI - Dynamic myocardial perfusion imaging by dual-source computed tomography. AB - We report a dual-source computed tomography study of dynamic and quantitative myocardial perfusion in a 44-year-old patient with previous documented coronary artery disease. Quantitatively, the tomography showed myocardial perfusion deficit in the territories with significant coronary stenosis, confirmed by computed tomography angiography and conventional angiography. Dual-source computed tomography allowed dynamic perfusion and anatomic evaluation in a single study during the follow-up of this patient. PMID- 22527019 TI - TGF-beta/Smad pathway and BRAF mutation play different roles in circumscribed and infiltrative papillary thyroid carcinoma. AB - Poorly circumscribed growth pattern, extra-thyroid extension and high intratumoural lymph vessel density are significantly associated to nodal metastatization in papillary thyroid carcinoma (PTC). It was also shown that transforming growth factor beta (TGF-beta)/Smad-dependent pathway activity is associated with local invasion, nodal metastatization and BRAF-mutated PTCs. We analysed the immunoexpression of TGF-beta, Smad2/Smad3, Smad4 and Smad7 in a series of 42 cases of classic PTC and 33 cases of follicular variant of PTC with known clinico-pathological and follow-up data, as well as BRAF and RAS status. The 75 PTCs were divided into poorly circumscribed (PCPTC) (n = 53) and well circumscribed (WCPTC) (n = 22) according to their borders. Nodal metastases were not detected in any WCPTC regardless of the presence of immunoexpression for TGF beta, Smad2/Smad3, Smad4 and Smad7 and occurrence of BRAF mutation (in 20 % of WCPTCs). Increased cytoplasmatic expression of TGF-beta at the periphery of PCPTC was associated to morphological features of invasiveness, featuring the so-called epithelial-to-mesenchymal transition (EMT), and presence of nodal metastases, as well as to the occurrence of BRAF mutation which did not significantly alter, per se, the frequency of nodal metastases. The nuclear expression of Smad7 was more frequent in WCPTCs than in PCPTCs and was associated with unicentricity and absence of extra-thyroid extension, vascular invasion and nodal metastases. We conclude that nodal metastases are associated to poorly circumscribed, locally invasive PTCs that exhibit low levels of nuclear Smad7 and a peripheral EMT phenotype displaying TGF-beta overexpression, regardless of the occurrence of BRAF mutation. PMID- 22527022 TI - Papillary fibroelastoma: report of seven cases. AB - The papillary fibroelastoma (PFE) is a benign heart tumor, mainly found in the valves. Most tumors are asymptomatic, but when present, they are nonspecific or related to embolic phenomena. They are usually diagnosed at routine imaging studies or valve surgery and autopsies. Its treatment is controversial, due to its rarity. We describe seven PFE cases diagnosed and treated at our institution between 1989 and 2010, which constitutes the largest national case series study of this pathology to date. PMID- 22527023 TI - Why publish in national journals? AB - The reluctance of Brazilian authors to publish in Brazilian journals is historical and no longer justified. Currently, several Brazilian journals are indexed in international databases, of which English versions allow disclosure of our studies to foreign countries. The authors express their views on the importance of publishing in national journals and cite the example of the impact of publications from Instituto do Coracao - InCor-HCFMUSP in the past two years. PMID- 22527024 TI - Prognostic value of fasting glucose levels in elderly patients with acute coronary syndrome. AB - BACKGROUND: The fasting plasma glucose (FPG) test is a predictor of complications after Acute Coronary Syndrome (ACS). However, its prognostic value is not yet fully established in different age groups. OBJECTIVE: To evaluate the role of admission fasting plasma glucose (FPG) as a predictor of 30 days after ACS, and the association of hyperglycemia with major cardiovascular events (MACE): death, reinfarction and coronary artery bypass grafting, in two different age groups (<65 year and >=65 year-old patients). METHODS: Contemporary cohort of patients hospitalized for ACS in the Institute of Cardiology of Rio Grande do Sul (Southern Brazil). In the first 24 hours of admission, patients answered a questionnaire with clinical information and had peripheral blood collected for measurement of FPG. Patients were followed up during hospitalization and for 30 days for the presence of MACE. Statistical analyses were performed using the SPSS 15.0 with the chi-square or Fisher Exact test (categorical variables) and the Student t test (numerical variables). Multivariate analysis was performed. RESULTS: 580 patients were included in the study. Mean age was 61.2 (+/-12.3) years, with 38.6% of the patients (224) >=65 years old, and 67.7% (393) were male. Multivariable analysis showed that, after 30 days of follow-up, only FPG (OR= 1.01, 95% CI:1.00-1.01, P= 0.001) was associated with MACE in both age groups. CONCLUSION: Admission FPG was an independent predictor for MACE in the early phase of ACS. PMID- 22527025 TI - Tendency of mortality in acute myocardial infarction in Curitiba (PR) in the period of 1998 to 2009. AB - BACKGROUND: Acute Myocardial Infarction (AMI) is the single leading cause of death among non-transmitted chronic diseases in Brazil. The knowledge of mortality trends is necessary for planning prevention strategies. OBJECTIVE: To evaluate trends in mortality from myocardial infarction in the period from 1998 to 2009 in Curitiba (PR), their distribution by gender, age and their impact in reducing the absolute number of deaths from this disease in this period. METHODS: Demographic data were obtained from the Brazilian Institute of Geography and Statistics (IBGE) and death data were obtained from the Mortality Information System of the Ministry of Health, considering gender, age and residence. From the fit of a Poisson regression model we estimated mortality rates and expected number of deaths that were not observed. RESULTS: We found significant downward trend (p < 0.001) in the period. The estimated average reduction in death rate from AMI each year was 3.8% (95% CI: 3.2% - 4.5%). There was no significant difference between genders (p = 0.238), although the evolution of age-specific standard mortality rates differed significantly between the groups (p = 0.018). It is estimated that the annual reduction of 3.8% in the mortality rate has resulted in 2,168 deaths below the number expected given the mortality rate observed in 1998 and projecting that number on the population growth occurred during the study period. CONCLUSION: Although it remains an important cause of death, mortality from AMI decreased significantly during the evaluation period. PMID- 22527026 TI - Gastrointestinal changes associated to heart failure. AB - Over the last decade, several studies were conducted on the gastrointestinal changes associated to chronic heart failure. This article presents a literature review on the physiopathology and clinical consequences of pathological digestive changes of heart failure patients. Structural and functional abnormalities of the gastrointestinal tract, such as edema of absorptive mucosa and intestinal bacterial overgrowth, have been leading to serious clinical consequences. Some of these consequences are cardiac cachexia, systemic inflammatory activation and anemia. These conditions, alone or in combination, may lead to worsening of the pre-existing ventricular dysfunction. Although currently there is no therapy specifically earmarked for gastrointestinal changes associated to heart failure, the understanding of digestive abnormalities is germane for the prevention and management of systemic consequences. PMID- 22527027 TI - The polyvalence of C-reactive protein in coronary artery bypass grafting. PMID- 22527028 TI - [Pathology of the cardiovascular system]. PMID- 22527029 TI - [Hypofunctional thyroid tumor]. AB - Fine needle aspiration biopsy is considered to be the most valuable tool in the preoperative diagnosis of papillary thyroid carcinoma but the diagnostic criteria have to be strictly applied to avoid unnecessary surgery. In cases of cellular and encapsulated thyroid tumor serial sections from the tumor capsule should to be taken to exclude capsular and/or vascular invasion. PMID- 22527030 TI - Immobilized L-aspartate ammonia-lyase from Bacillus sp. YM55-1 as biocatalyst for highly concentrated L-aspartate synthesis. AB - L-aspartate ammonia-lyase from Bacillus sp. YM55-1 (AspB, EC 4.3.1.1) catalyzes the reversible conversion of L-aspartate (Asp) into fumarate and ammonia with a high specific activity toward the substrate. AspB was expressed in Escherichia coli and partially purified by heat precipitation and saturation with ammonium sulfate reaching purification factor of 7.7 and specific activity of 334 U/mg of protein. AspB was immobilized by covalent attachment on Eupergit(r) C (epoxy support) and MANA-agarose (amino support), and entrapment in LentiKats(r) (polyvinyl alcohol) with retained activities of 24, 85 and 63 %, respectively. Diffusional limitations were only observed for the enzyme immobilized in LentiKats(r) and were overcome by increasing substrate concentration. Free and immobilized AspB were used for the synthesis of aspartate achieving high product concentration (>=450 mM) after 24 h of reaction. Immobilized biocatalysts were efficiently reused in 5 cycles of Asp synthesis, keeping over 90 % of activity and reaching over 90 % of conversion in all the cases. PMID- 22527031 TI - Modeling of simultaneous growth and storage kinetics variation under unsteady feast conditions for aerobic heterotrophic biomass. AB - The heterotrophic biomass has the capacity of utilizing substrate predominantly for growth or storage processes under steady-state conditions. In this study, the short-term variations in growth and storage kinetics of activated sludge under disturbed feeding conditions were analyzed using a multi-component biodegradation model. The variations in growth and storage kinetics were investigated with the aid of multi-response modeling and identifiability analysis. It was found that the heterotrophic biomass is able to increase its direct growth activity together with reducing the substrate storage capability under the availability of external substrate. Reducing the sludge age (SRT) from 10 to 2 days increased the maximum specific growth rate, MU (OHO,Max) from 3.9 to 7.0 day(-1), but did not considerably affected the maximum storage rate, k (Stor,OHO). The alteration of sludge age also elevated the half-saturation constant for growth (K (S,OHO)) from 5 to 25 mg COD/L. The increase in primary growth metabolism together with reduced storage rate was validated by model for two different sludge ages in the availability of external substrate. Aside from having a lower storage capability, the biomass had fast adaptation ability to direct growth process at low SRTs. The alteration of feed conditions was found to have different impacts on storage and growth kinetics. These results are significant and advance the field of activated sludge modeling under dynamic conditions by incorporation of short-term effects. Appropriate modifications including short-term effects in model structure may also reduce dynamic model recalibration efforts in the future. PMID- 22527032 TI - Operating conditions optimization for (+)-terrein production in a stirred bioreactor by Aspergillus terreus strain PF-26 from marine sponge Phakellia fusca. AB - Terrein is a fungal metabolite with application values in the fields of medicine, cosmetology, and agriculture. However, mass production of single configuration terrein is still a big challenge. In this study, operating factors such as inoculation, agitation speed, aeration rate, pH control, and nutrient feeding were preliminarily optimized to improve the (+)-terrein production in the 5-L stirred bioreactor from the marine sponge-derived fungus Aspergillus terreus PF 26. Spore inoculation, low agitation speed, and aeration rate were proved to be suitable for A. terreus PF-26 to produce (+)-terrein in the stirred bioreactor. At 50 rpm agitation speed and 0.33 vvm aeration rate, 2.68 g/L (+)-terrein was achieved by feeding twofold concentrated maltose and glucose medium on the sixth day and controlling pH at 4.5 from the fourth day. This study lays foundation for the mass production of (+)-terrein by the marine filamentous A. terreus strain PF 26 in the stirred bioreactor. PMID- 22527033 TI - R583Q CACNA1A variant in SHM1 and ataxia: case report and literature update. AB - Familial hemiplegic migraine (FHM) type 1 is a rare monogenic dominant autosomal disease due to CACNA1A gene mutations. Besides the classical phenotype, mutations on CACNA1A gene are associated with a broader spectrum of clinical features including cerebellar ataxia, making FHM1 a complex channelopathy. We report the case of a patient carrying the p.Arg583Gln mutation affected by hemiplegic migraine and late onset ataxia and we performed a literature review about the clinical features of p.Arg583Gln. Although p.Arg583Gln mutations are associated with a heterogeneous phenotype, carriers present cerebellar signs which consisted generally in ataxia and dysmetria, with intention tremor appearing mostly in advanced age, often progressive and permanent. The heterogeneous spectrum of CACNA1A gene mutations probably causes sporadic hemiplegic migraine (SHM) to be misdiagnosed. Given the therapeutic opportunities, SHM/FHM1 should be considered in differential diagnosis of patients with cerebellar ataxia and migraine with aura. PMID- 22527034 TI - Comorbidity profiles of chronic migraine sufferers in a national database in Taiwan. AB - Chronic migraine (CM; >=15 headache days per month, >=3 months) is associated with a higher prevalence of comorbidities than episodic migraine (<15 headache days per month). However, it is unclear whether a similar pattern exists in Asian patients. To examine this, a retrospective matched cohort study was conducted using the Taiwan National Health Insurance Research Database. CM cases were defined as patients with at least one neurological outpatient visit with a primary or secondary ICD-9-CM (International Classification of Diseases, Ninth Revision, Clinical Modification) code of 346.11, diagnosed by neurologists at medical centers during 2007-2008. The study group was compared with patients suffering from other migraine subtypes and non-migraineurs in the general population. Both comparison groups were matched with CM sufferers at a 4:1 ratio by age, gender, urbanization level of the residence, income, and hospital setting. Relative risk (RR) was calculated using conditional logistic regression. Compared with patients with other migraines (n = 2,226), CM sufferers (n = 681) had a higher risk of hyperlipidemia (RR = 1.32; P = 0.041), asthma (RR = 1.77; P = 0.007), depression (RR = 1.88; P < 0.0001), bipolar disorder (RR = 1.81; P = 0.022) and anxiety disorders (RR = 1.48; P = <0.0001). Compared with the non migraineurs (n = 3,790), CM sufferers (n = 948) had significantly increased risks of cardiovascular disease, sinusitis, asthma, gastrointestinal ulcers, vertigo and psychiatric disorders by 1.6-3.9-fold. In conclusion, CM is associated with significant comorbidities in Asian patients. Differences in the comorbidity profiles of CM compared with other migraines have highlighted that patients with CM differ not just in terms of headache frequency but also in other important aspects. PMID- 22527035 TI - Serum levels of N-acetyl-aspartate in migraine and tension-type headache. AB - Serum levels of N-acetyl-aspartate (NAA) may be considered a useful marker of neuronal functioning. We aimed to measure serum NAA in cohorts of migraine and tension-type headache patients versus controls, performing correlations with main clinical features. A total of 147 migraine patients (including migraine without aura, with aura and chronic migraine), 65 tension-type headache (including chronic and frequent episodic tension-type headache) and 34 sex- and age-matched controls were selected. Serum was stored at -80 degrees C. Quantification of NAA was achieved by the standard addition approach and analysis was performed with liquid-chromatography-mass-spectrometry (LC/MS) technique. The NAA levels were significantly decreased in migraine group (0.065 +/- 0.019 mol/L), compared with both tension-type headache patients (0.078 +/- 0.016 mol/L) and controls (0.085 +/- 0.013 mol/L). Control subjects were significantly different from migraine with and without aura and chronic migraine, who differed significantly from episodic and chronic tension-type headache. Migraine with aura patients showed lower NAA levels when compared to all the other headache subtypes, including migraine without aura and chronic migraine. In the migraine group, no significant correlation was found between NAA serum levels, and headache frequency, allodynia and interval from the last and the next attack. The low NAA in the serum may be a sign of neuronal dysfunction predisposing to migraine, probably based on reduced mitochondria function. PMID- 22527036 TI - Pure menstrual migraine with sensory aura: a case report. AB - Hormonal changes related to the menstrual cycle have a great impact on migraines in women. Menstrual migraine attacks are almost invariably without aura. Categorizing migraines into menstrual or non-menstrual types is one way to stratify migraines without aura according to the appendix criteria of the International Classification of Headache Disorders. We report a peri-menopausal woman whose sensory aura exclusively heralded menstrual migraine. A 51-year-old woman had suffered from monthly episodic headaches since the age of 46. Before a headache, and within 1 h on the first day of her menstruation, she always experienced numbness in her entire left upper limb. After the sensory aura, migrainous headaches occurred with nausea and photophobia. In the postmenopausal period, she no longer had sensory aura, and her headache pattern changed and became less severe. Her physical and neurologic exams as well as electroencephalography, brain magnetic resonance imaging, and conventional angiography were all normal. She fulfilled the diagnosis of pure menstrual migraine with typical sensory aura. To our knowledge, this is the first formal case report of pure menstrual migraine with aura. PMID- 22527037 TI - Reply to Vera Osipova et al. PMID- 22527038 TI - Validation of housekeeping genes for gene expression studies in an ice alga Chlamydomonas during freezing acclimation. AB - Antarctic ice alga Chlamydomonas sp. ICE-L can endure extreme low temperature and high salinity stress under freezing conditions. To elucidate the molecular acclimation mechanisms using gene expression analysis, the expression stabilities of ten housekeeping genes of Chlamydomonas sp. ICE-L during freezing stress were analyzed. Some discrepancies were detected in the ranking of the candidate reference genes between geNorm and NormFinder programs, but there was substantial agreement between the groups of genes with the most and the least stable expression. RPL19 was ranked as the best candidate reference genes. Pairwise variation (V) analysis indicated the combination of two reference genes was sufficient for qRT-PCR data normalization under the experimental conditions. Considering the co-regulation between RPL19 and RPL32 (the most stable gene pairs given by geNorm program), we propose that the mean data rendered by RPL19 and GAPDH (the most stable gene pairs given by NormFinder program) be used to normalize gene expression values in Chlamydomonas sp. ICE-L more accurately. The example of FAD3 gene expression calculation demonstrated the importance of selecting an appropriate category and number of reference genes to achieve an accurate and reliable normalization of gene expression during freeze acclimation in Chlamydomonas sp. ICE-L. PMID- 22527039 TI - Hydroxybutyrate prevents protein aggregation in the halotolerant bacterium Pseudomonas sp. CT13 under abiotic stress. AB - Polyhydroxybutyrate (PHB), a typical carbon and energy storage compound, is widely found in Bacteria and Archae domains. This polymer is produced in response to conditions of physiological stress. PHB is composed of repeating units of beta hydroxybutyrate (R-3HB). It has been previously shown that R-3HB functions as an osmolyte in extremophile strains. In this study, Pseudomonas sp. CT13, a halotolerant bacterium, and its PHB synthase-minus mutant (phaC) were used to analyze the chaperone role of R-3HB. The production of this compound was found to be essential to salt stress resistance and positively correlated with salt concentration, suggesting that PHB monomer acts as a compatible solute in Pseudomonas sp. CT13. R-3HB accumulation was also associated with the prevention of protein aggregation under combined salt and thermal stresses in Pseudomonas sp. CT13. Physiological concentrations of R-3HB efficiently reduced citrate synthase (CS) aggregation and stabilized the enzymatic activities of CS during thermal stress. Docking analysis of the CS/R-3HB interaction predicted the stability of this complex under physiological concentrations of R-3HB. Thus, in vivo, in vitro and in silico analyses suggest that R-3HB can act as a chemical chaperone. PMID- 22527040 TI - Overexpression in a non-native halophilic host and biotechnological potential of NAD+-dependent glutamate dehydrogenase from Halobacterium salinarum strain NRC 36014. AB - Enzymes produced by halophilic archaea are generally heat resistant and organic solvent tolerant, and accordingly important for biocatalytic applications in 'green chemistry', frequently requiring a low-water environment. NAD(+)-dependent glutamate dehydrogenase from an extremely halophilic archaeon Halobacterium salinarum strain NRC-36014 was selected to explore the biotechnological potential of this enzyme and genetically engineered derivatives. Over-expression in a halophilic host Haloferax volcanii provided a soluble, active recombinant enzyme, not achievable in mesophilic Escherichia coli, and an efficient purification procedure was developed. pH and salt dependence, thermostability, organic solvent stability and kinetic parameters were explored. The enzyme is active up to 90 degrees C and fully stable up to 70 degrees C. It shows good tolerance of various miscible organic solvents. High concentrations of salt may be substituted with 30 % DMSO or betaine with good stability and activity. The robustness of this enzyme under a wide range of conditions offers a promising scaffold for protein engineering. PMID- 22527041 TI - Three nth homologs are all required for efficient repair of spontaneous DNA damage in Deinococcus radiodurans. AB - Deinococcus radiodurans is a bacterium that can survive extreme DNA damage. To understand the role of endonuclease III (Nth) in oxidative repair and mutagenesis, we constructed nth single, double and triple mutants. The nth mutants showed no significant difference with wild type in both IR resistance and H(2)O(2) resistance. We characterized these strains with regard to mutation rates and mutation spectrum using the rpoB/Rif(r) system. The Rif(r) frequency of mutant MK1 (?dr0289) was twofold higher than that of wild type. The triple mutant of nth (ME3)generated a mutation frequency 34.4-fold, and a mutation rate 13.8 fold higher than the wild type. All strains demonstrated specific mutational hotspots. Each single mutant had higher spontaneous mutation frequency than wild type at base substitution (G:C -> A:T). The mutational response was further increased in the double and triple mutants. The higher mutation rate and mutational response in ME3 suggested that the three nth homologs had non overlapped and overlapped substrate spectrum in endogenous oxidative DNA repair. PMID- 22527042 TI - Homogeneous incorporation of secondary cell wall polysaccharides to the cell wall of Thermus thermophilus HB27. AB - Regular surface protein layers (S-layers) from most Gram-positive bacteria and from the ancestral bacterium Thermus thermophilus attach to pyruvylated polysaccharides (SCWP) covalently bound to the peptidoglycan through their SLH domain. However, it is not known whether the synthesis of SCWP and S-layer is coordinated enough as to follow a similar pattern of incorporation to the cell wall during growth. In this work we analyse the localization of newly synthesized SCWP on the cell wall of T. thermophilus by immunoelectron microscopy. For this, we obtained mutants with a reduced amount of pyruvylated SCWP through mutation of the csaB gene encoding the SCWP-pyruvylating activity, and its upstream gene csaA, a putative sugar transporter. We hypothesized that CsaA would be required for the synthesis of the SCWP. However, we found that csaA mutants showed only a minor decrease in the amount of SCWP immunodetected on the cell walls in comparison with csaB mutants, revealing its irrelevance in the process. Complementation experiments of csaB mutants with CsaB expressed from inducible promoters revealed that newly synthesized SCWP was homogeneously distributed along the cell wall. Fusions with thermostable fluorescent protein revealed that CsaB was distributed also in homogeneous pattern associated with the membrane. These data support that synthesis of SCWP takes place in disperse and homogeneous form all over the cell surface, in contrast to the zonal incorporation at the cell centre recently demonstrated for SlpA. PMID- 22527043 TI - Sequence fingerprints of enzyme specificities from the glycoside hydrolase family GH57. AB - The glycoside hydrolase family 57 (GH57) contains five well-established enzyme specificities: alpha-amylase, amylopullulanase, branching enzyme, 4-alpha glucanotransferase and alpha-galactosidase. Around 700 GH57 members originate from Bacteria and Archaea, a substantial number being produced by thermophiles. An intriguing feature of family GH57 is that only slightly more than 2 % of its members (i.e., less than 20 enzymes) have already been biochemically characterized. The main goal of the present bioinformatics study was to retrieve from databases, and analyze in detail, sequences having clear features of the five GH57 enzyme specificities mentioned above. Of the 367 GH57 sequences, 56 were evaluated as alpha-amylases, 99 as amylopullulanases, 158 as branching enzymes, 46 as 4-alpha-glucanotransferases and 8 as alpha-galactosidases. Based on the analysis of collected sequences, sequence logos were created for each specificity and unique sequence features were identified within the logos. These features were proposed to define the so-called sequence fingerprints of GH57 enzyme specificities. Domain arrangements characteristic of the individual enzyme specificities as well as evolutionary relationships within the family GH57 are also discussed. The results of this study could find use in rational protein design of family GH57 amylolytic enzymes and also in the possibility of assigning a GH57 specificity to a hypothetical GH57 member prior to its biochemical characterization. PMID- 22527044 TI - Use of Raman spectroscopy for identification of compatible solutes in halophilic bacteria. AB - We explored the use of Raman spectroscopy to detect organic osmotic solutes as biomarkers in the moderately halophilic heterotrophic bacterium Halomonas elongata grown in complex medium (accumulation of glycine betaine) and in defined medium with glucose as carbon source (biosynthesis of ectoine), and in the anoxygenic phototrophic Ectothiorhodospira marismortui known to synthesize glycine betaine in combination with minor amounts of trehalose and N-alpha carbamoyl glutamineamide. We tested different methods of preparation of the material: lyophilization, two-phase extraction of water-soluble molecules, and perchlorate extraction. Raman signals of glycine betaine and ectoine were detected; perchlorate extraction followed by desalting the extract on an ion retardation column gave the best results. Lyophilized cells of E. marismortui showed strong signals of carotenoid pigments, and glycine betaine could be detected only after perchlorate extraction and desalting. The data presented show that Raman spectroscopy is a suitable tool to assess the mode of osmotic adaptation used by halophilic microorganisms. PMID- 22527045 TI - Cloning and expression of acidstable, high maltose-forming, Ca2+-independent alpha-amylase from an acidophile Bacillus acidicola and its applicability in starch hydrolysis. AB - The alpha-amylase encoding gene from acidophilic bacterium Bacillus acidicola was cloned into pET28a(+) vector and expressed in Escherichia coli BL21 (DE3). The recombinant E. coli produced a 15-fold higher alpha-amylase than B. acidicola strain. The recombinant alpha-amylase was purified to homogeneity by one-step nickel affinity chromatography using Ni(2+)-NTA resin with molecular mass of 62 KDa. It is active in the pH range between 3.0 and 7.0 and 30 and 100 degrees C with optimum at pH 4.0 and 60 degrees C. The enzyme is Ca(2+)-independent with K (m) and k (cat) values (on soluble starch) of 1.6 mg ml(-1) and 108.7 s(-1), respectively. The alpha-amylase of B. acidicola is acidstable, high maltose forming and Ca(2+)-independent, and therefore, is a suitable candidate for starch hydrolysis and baking. PMID- 22527046 TI - Properties of the endogenous components of the thioredoxin system in the psychrophilic eubacterium Pseudoalteromonas haloplanktis TAC 125. AB - The endogenous components of the thioredoxin system in the Antarctic eubacterium Pseudoalteromonas haloplanktis have been purified and characterised. The temperature dependence of the activities sustained by thioredoxin (PhTrx) and thioredoxin reductase (PhTrxR) pointed to their adaptation in the cold growth environment. PhTrxR was purified as a flavoenzyme and its activity was significantly enhanced in the presence of molar concentration of monovalent cations. The energetics of the partial reactions leading to the whole electron transfer from NADPH to the target protein substrate in the reconstituted thioredoxin system was also investigated. While the initial electron transfer from NADPH to PhTrxR was energetically favoured, the final passage to the heterologous protein substrate enhanced the energetic barrier of the whole process. The energy of activation of the heat inactivation process essentially reflected the psychrophilic origin of PhTrxR. Vice versa, PhTrx possessed an exceptional heat resistance (half-life, 4.4 h at 95 degrees C), ranking this protein among the most thermostable enzymes reported so far in psychrophiles. PhTrxR was covalently modified by glutathione, mainly by its oxidised or nitrosylated forms. A mutagenic analysis realised on three non catalytic cysteines of the flavoenzyme allowed the identification of C(303) as the target for the S-glutathionylation reaction. PMID- 22527048 TI - The amino acid composition of proteins from anaerobic halophilic bacteria of the order Halanaerobiales. AB - We performed a comparative analysis of the genome sequences of three anaerobic halophilic fermentative bacteria belonging to the order Halanaerobiales: Halanaerobium praevalens, the alkaliphilic "Halanaerobium hydrogeniformans", and the thermophilic Halothermothrix orenii to assess the amino acid composition of their proteins. Members of the Halanaerobiales were earlier shown to accumulate KCl rather than organic compatible solutes for osmotic balance, and therefore the presence of a dominantly acidic proteome was predicted. Past reports indeed showed a large excess of acidic over basic amino acids in whole-cell hydrolysates of selected members of the order. However, the genomic analysis did not show unusually high contents of acidic amino acids or low contents of basic amino acids. The apparent excess of acidic amino acids in these anaerobic halophiles reported earlier is due to the high content in their proteins of glutamine and asparagine, which yield glutamate and aspartate upon acid hydrolysis. It is thus suggested that the proteins of the Halanaerobiales, which are active in the presence of high intracellular KCl concentrations, do not possess the typical acidic signature of the 'halophilic' proteins of the Archaea of the order Halobacteriales or of the extremely halophilic bacterium Salinibacter. PMID- 22527049 TI - The effect of cartilaginous reinforcing sutures on initial tracheal anastomotic strength: a cadaver study. AB - OBJECTIVE: During tracheal resection with primary anastomosis, cartilaginous reinforcing sutures may be placed outside of the primary anastomosis with the goal of preventing early dehiscence. The direct effect of such reinforcing sutures on anastomotic strength has not been previously investigated. The goal of this study was to determine if the addition of cartilaginous reinforcing sutures adds to tracheal anastomosis stability. STUDY DESIGN: Prospective cadaver study. SETTING: This research was conducted at an anatomy lab at Indiana University School of Medicine. SUBJECTS AND METHODS: Twelve cadaver tracheas were harvested. Each trachea was bifurcated, with 1 segment of each trachea transected and anastomosed using circumferential sutures and the remaining tracheal segment undergoing the same procedure with the addition of cartilaginous reinforcing sutures. Segments (proximal versus distal) were alternated to control for potential anatomic-based strength differences. The force necessary for anastomotic rupture was measured, and a Wilcoxon signed-rank test was used to compare means. RESULTS: Analysis demonstrated the mean anastomotic rupture point for tracheas with reinforcing sutures was 297 N (95% confidence interval = 241.1 352.9), while the mean for trials without reinforcing sutures was 173 N (95% confidence interval = 142.63-203.37; P = .0054). The point of rupture occurred at the anastomosis in 1 case with reinforcing sutures and in 8 of 11 cases without reinforcing sutures. CONCLUSIONS: Cartilaginous reinforcing sutures were found to provide a higher force requirement for tracheal anastomotic rupture when compared with anastomoses without these sutures. This improved stability in tracheal anastomosis may result in a decreased risk of early tracheal rupture after anastomosis. PMID- 22527047 TI - Life at the hyperarid margin: novel bacterial diversity in arid soils of the Atacama Desert, Chile. AB - Nearly half the earth's surface is occupied by dryland ecosystems, regions susceptible to reduced states of biological productivity caused by climate fluctuations. Of these regions, arid zones located at the interface between vegetated semiarid regions and biologically unproductive hyperarid zones are considered most vulnerable. The objective of this study was to conduct a deep diversity analysis of bacterial communities in unvegetated arid soils of the Atacama Desert, to characterize community structure and infer the functional potential of these communities based on observed phylogenetic associations. A 454 pyrotag analysis was conducted of three unvegetated arid sites located at the hyperarid-arid margin. The analysis revealed communities with unique bacterial diversity marked by high abundances of novel Actinobacteria and Chloroflexi and low levels of Acidobacteria and Proteobacteria, phyla that are dominant in many biomes. A 16S rRNA gene library of one site revealed the presence of clones with phylogenetic associations to chemoautotrophic taxa able to obtain energy through oxidation of nitrite, carbon monoxide, iron, or sulfur. Thus, soils at the hyperarid margin were found to harbor a wealth of novel bacteria and to support potentially viable communities with phylogenetic associations to non-phototrophic primary producers and bacteria capable of biogeochemical cycling. PMID- 22527050 TI - Novel bioassay demonstrates attraction of the white potato cyst nematode Globodera pallida (Stone) to non-volatile and volatile host plant cues. AB - Potato cyst nematodes (PCNs) are a major pest of solanaceous crops such as potatoes, tomatoes, and eggplants and have been widely studied over the last 30 years, with the majority of earlier studies focusing on the identification of natural hatching factors. As a novel approach, we focused instead on chemicals involved in nematode orientation towards its host plant. A new dual choice sand bioassay was designed to study nematode responses to potato root exudates (PRE). This bioassay, conducted together with a traditional hatching bioassay, showed that biologically active compounds that induce both hatching and attraction of PCNs can be collected by water extraction of incised potato roots. Furthermore, our results demonstrated that PCN also were attracted by potato root volatiles. Further work is needed to fully understand how PCNs use host plant chemical cues to orientate towards hosts. Nevertheless, the simple attraction assay used in this study provides an important tool for the identification of host-emitted attractants. PMID- 22527051 TI - Foraging in the dark - chemically mediated host plant location by belowground insect herbivores. AB - Root-feeding insects are key components in many terrestrial ecosystems. Like shoot-feeding insect herbivores, they exploit a range of chemical cues to locate host plants. Respiratory emissions of carbon dioxide (CO(2)) from the roots is widely reported as the main attractant, however, there is conflicting evidence about its exact role. CO(2) may act as a 'search trigger' causing insects to search more intensively for more host specific signals, or the plant may 'mask' CO(2) emissions with other root volatiles thus avoiding detection. At least 74 other compounds elicit behavioral responses in root-feeding insects, with the majority (>80 %) causing attraction. Low molecular weight compounds (e.g., alcohols, esters, and aldehydes) underpin attraction, whereas hydrocarbons tend to have repellent properties. A range of compounds act as phagostimulants (e.g., sugars) once insects feed on roots, whereas secondary metabolites often deter feeding. In contrast, some secondary metabolites usually regarded as plant defenses (e.g., dihydroxy-7-methoxy-1,4-benzoxazin-3-one (DIMBOA)), can be exploited by some root-feeding insects for host location. Insects share several host location cues with plant parasitic nematodes (CO(2), DIMBOA, glutamic acid), but some compounds (e.g., cucurbitacin A) repel nematodes while acting as phagostimulants to insects. Moreover, insect and nematode herbivory can induce exudation of compounds that may be mutually beneficial, suggesting potentially significant interactions between the two groups of herbivores. While a range of plant-derived chemicals can affect the behavior of root-feeding insects, little attempt has been made to exploit these in pest management, though this may become a more viable option with diminishing control options. PMID- 22527053 TI - Sex-pairing pheromone in the Asian termite pest species Odontotermes formosanus. AB - The sex-pairing pheromone of the black winged subterranean termite, Odontotermes formosanus (Shiraki) (Isoptera, Termitidae), was investigated using headspace SPME, GC-MS, GC-EAD, and attraction bioassays. Females secrete the pheromone from their sternal gland to attract males. The sex-pairing pheromone is composed of (Z,Z)-dodeca-3,6-dien-1-ol and (Z)-dodec-3-en-1-ol, estimated at 9 to 16.64 ng and 0.2 to 0.54 ng, respectively. Both short- and long-distance sex attraction bioassays were employed to show that these compounds act in synergy at long distance, but only (Z,Z)-dodeca-3,6-dien-1-ol is active at short distance. The pheromone may be useful in efforts to control this pest, which is considered one of the most harmful termite species in Southeast Asia. PMID- 22527054 TI - Flavonoid metabolites in the hemolymph of European pine sawfly (Neodiprion sertifer) larvae. AB - Flavonoids in the hemolymph of European pine sawfly (Neodiprion sertifer) larvae that were feeding on Pinus sylvestris needles were identified. HPLC-ESI-MS analysis revealed that the main components in the hemolymph were flavonol di- and triglucosides and a catechin monoglucoside. These compounds were isolated from the larval hemolymph and their structures were established by HPLC-MS, GC-MS, and NMR spectroscopy. The isolated flavonoids were identified as (+)-catechin 7-O beta-glucoside, isorhamnetin 3,7,4'-tri-O-beta-glucoside, kaempferol 3,7,4'-tri-O beta-glucoside, and quercetin 3,7,4'-tri-O-beta-glucoside. The combined concentration of these four compounds in the hemolymph was 3.7 mg/ml. None of these compounds was present in the needles of P. sylvestris. Therefore, we propose that the flavonoid glucosides were produced by the larvae from flavonoid monoglucosides and (+)-catechin obtained from the pine needles. PMID- 22527052 TI - Induced immunity against belowground insect herbivores- activation of defenses in the absence of a jasmonate burst. AB - Roots respond dynamically to belowground herbivore attack. Yet, little is known about the mechanisms and ecological consequences of these responses. Do roots behave the same way as leaves, or do the paradigms derived from aboveground research need to be rewritten? This is the central question that we tackle in this article. To this end, we review the current literature on induced root defenses and present a number of experiments on the interaction between the root herbivore Diabrotica virgifera and its natural host, maize. Currently, the literature provides no clear evidence that plants can recognize root herbivores specifically. In maize, mild mechanical damage is sufficient to trigger a root volatile response comparable to D. virgifera induction. Interestingly, the jasmonate (JA) burst, a highly conserved signaling event following leaf attack, is consistently attenuated in the roots across plant species, from wild tobacco to Arabidopsis. In accordance, we found only a weak JA response in D. virgifera attacked maize roots. Despite this reduction in JA-signaling, roots of many plants start producing a distinct suite of secondary metabolites upon attack and reconfigure their primary metabolism. We, therefore, postulate the existence of additional, unknown signals that govern induced root responses in the absence of a jasmonate burst. Surprisingly, despite the high phenotypic plasticity of plant roots, evidence for herbivore-induced resistance below ground is virtually absent from the literature. We propose that other defensive mechanisms, including resource reallocation and compensatory growth, may be more important to improve plant immunity below ground. PMID- 22527055 TI - Occurrence of sarmentosin and other hydroxynitrile glucosides in Parnassius (papilionidae) butterflies and their food plants. AB - Sequestration of plant secondary metabolites is a widespread phenomenon among aposematic insects. Sarmentosin is an unsaturated gamma-hydroxynitrile glucoside known from plants and some Lepidoptera. It is structurally and biosynthetically closely related to cyanogenic glucosides, which are commonly sequestered from food plants and/or de novo synthesized by lepidopteran species. Sarmentosin was found previously in Parnassius (Papilionidae) butterflies, but it was not known how the occurrence was related to food plants or whether Parnassius species could biosynthesize the compound. Here, we report on the occurrence of sarmentosin and related compounds in four different Parnassius species belonging to two different clades, as well as their known and suspected food plants. There were dramatic differences between the two clades, with P. apollo and P. smintheus from the Apollo group containing high amounts of sarmentosin, and P. clodius and P. mnemosyne from the Mnemosyne group containing low or no detectable amounts. This was reflected in the larval food plants; P. apollo and P. smintheus larvae feed on Sedum species (Crassulaceae), which all contained considerable amounts of sarmentosin, while the known food plants of the two other species, Dicentra and Corydalis (Fumariaceae), had no detectable levels of sarmentosin. All insects and plants containing sarmentosin also contained other biosynthetically related hydroxynitrile glucosides in patterns previously reported for plants, but not for insects. Not all findings could be explained by sequestration alone and we therefore hypothesize that Parnassius species are able to de novo synthesize sarmentosin. PMID- 22527056 TI - Estimating insect flight densities from attractive trap catches and flight height distributions. AB - Methods and equations have not been developed previously to estimate insect flight densities, a key factor in decisions regarding trap and lure deployment in programs of monitoring, mass trapping, and mating disruption with semiochemicals. An equation to estimate densities of flying insects per hectare is presented that uses the standard deviation (SD) of the vertical flight distribution, trapping time, the trap's spherical effective radius (ER), catch at the mean flight height (as estimated from a best-fitting normal distribution with SD), and an estimated average flight speed. Data from previous reports were used to estimate flight densities with the equations. The same equations can use traps with pheromone lures or attractive colors with a measured effective attraction radius (EAR) instead of the ER. In practice, EAR is more useful than ER for flight density calculations since attractive traps catch higher numbers of insects and thus can measure lower populations more readily. Computer simulations in three dimensions with varying numbers of insects (density) and varying EAR were used to validate the equations for density estimates of insects in the field. Few studies have provided data to obtain EAR, SD, speed, and trapping time to estimate flight densities per hectare. However, the necessary parameters can be measured more precisely in future studies. PMID- 22527057 TI - Are leaf glandular trichomes of oregano hospitable habitats for bacterial growth? AB - Phyllospheric bacteria were isolated from microsites around essential-oil containing glands of two oregano (Origanum vulgare subsp. hirtum) lines. These bacteria, 20 isolates in total, were subjected to bioassays to examine their growth potential in the presence of essential oils at different concentrations. Although there were qualitative and quantitative differences in the essential oil composition between the two oregano lines, no differences were recorded in their antibacterial activity. In disk diffusion bioassays, four of the isolated strains could grow almost unrestrained in the presence of oregano oil, another five proved very sensitive, and the remaining 11 showed intermediate sensitivity. The strain least inhibited by oregano essential oil was further identified by complete16s rRNA gene sequencing as Pseudomonas putida. It was capable of forming biofilms even in the presence of oregano oil at high concentrations. Resistance of P. putida to oregano oil was further elaborated by microwell dilution bioassays, and its topology on oregano leaves was studied by electron microscopy. When inoculated on intact oregano plants, P. putida was able not only to colonize sites adjacent to essential oil-containing glands, but even to grow intracellularly. This is the first time that such prolific bacterial growth inside the glands has been visually observed. Results of this study further revealed that several bacteria can be established on oregano leaves, suggesting that these bacteria have attributes that allow them to tolerate or benefit from oregano secondary metabolites. PMID- 22527058 TI - Ecology and evolution of soil nematode chemotaxis. AB - Plants influence the behavior of and modify community composition of soil dwelling organisms through the exudation of organic molecules. Given the chemical complexity of the soil matrix, soil-dwelling organisms have evolved the ability to detect and respond to these cues for successful foraging. A key question is how specific these responses are and how they may evolve. Here, we review and discuss the ecology and evolution of chemotaxis of soil nematodes. Soil nematodes are a group of diverse functional and taxonomic types, which may reveal a variety of responses. We predicted that nematodes of different feeding guilds use host specific cues for chemotaxis. However, the examination of a comprehensive nematode phylogeny revealed that distantly related nematodes, and nematodes from different feeding guilds, can exploit the same signals for positive orientation. Carbon dioxide (CO(2)), which is ubiquitous in soil and indicates biological activity, is widely used as such a cue. The use of the same signals by a variety of species and species groups suggests that parts of the chemo-sensory machinery have remained highly conserved during the radiation of nematodes. However, besides CO(2), many other chemical compounds, belonging to different chemical classes, have been shown to induce chemotaxis in nematodes. Plants surrounded by a complex nematode community, including beneficial entomopathogenic nematodes, plant-parasitic nematodes, as well as microbial feeders, are thus under diffuse selection for producing specific molecules in the rhizosphere that maximize their fitness. However, it is largely unknown how selection may operate and how belowground signaling may evolve. Given the paucity of data for certain groups of nematodes, future work is needed to better understand the evolutionary mechanisms of communication between plant roots and soil biota. PMID- 22527059 TI - Chemical mediation of ternary interactions between marine holobionts and their environment as exemplified by the red alga Delisea pulchra. AB - The need for animals and plants to control microbial colonization is important in the marine environment with its high densities of microscopic propagules and seawater that provides an ideal medium for their dispersal. In contrast to the traditional emphasis on antagonistic interactions of marine organisms with microbes, emerging studies lend support to the notion that health and performance of many marine organisms are functionally regulated and assisted by associated microbes, an ecological concept defined as a holobiont. While antimicrobial activities of marine secondary metabolites have been studied in great depth ex situ, we are beginning to understand how some of these compounds function in an ecological context to maintain the performance of marine holobionts. The present article reviews two decades of our research on the red seaweed Delisea pulchra by addressing: the defense chemistry of this seaweed; chemically-mediated interactions between the seaweed and its natural enemies; and the negative influence of elevated seawater temperature on these interactions. Our understanding of these defense compounds and the functional roles they play for D. pulchra extends from molecular interactions with bacterial cell signaling molecules, to ecosystem-scale consequences of chemically-controlled disease and herbivory. Delisea pulchra produces halogenated furanones that antagonize the same receptor as acylated homoserine lactones (AHL)-a group of widespread intercellular communication signals among bacteria. Halogenated furanones compete with and inhibit bacterial cell-to-cell communication, and thus interfere with important bacterial communication-regulated processes, such as biofilm formation. In a predictable pattern that occurs at the ecological level of entire populations, environmental stress interferes with the production of halogenated furanones, causing downstream processes that ultimately result in disease of the algal holobiont. PMID- 22527061 TI - Comment on Grasso et al.: ECMO criteria for influenza A (H1N1)-associated ARDS: role of transpulmonary pressure. PMID- 22527060 TI - Adverse cardiac events during catecholamine vasopressor therapy: a prospective observational study. AB - PURPOSE: To determine the incidence of and risk factors for adverse cardiac events during catecholamine vasopressor therapy in surgical intensive care unit patients with cardiovascular failure. METHODS: The occurrence of any of seven predefined adverse cardiac events (prolonged elevated heart rate, tachyarrhythmia, myocardial cell damage, acute cardiac arrest or death, pulmonary hypertension-induced right heart dysfunction, reduction of systemic blood flow) was prospectively recorded during catecholamine vasopressor therapy lasting at least 12 h. RESULTS: Fifty-four of 112 study patients developed a total of 114 adverse cardiac events, an incidence of 48.2 % (95 % CI, 38.8-57.6 %). New-onset tachyarrhythmia (49.1 %), prolonged elevated heart rate (23.7 %), and myocardial cell damage (17.5 %) occurred most frequently. Aside from chronic liver diseases, factors independently associated with the occurrence of adverse cardiac events included need for renal replacement therapy, disease severity (assessed by the Simplified Acute Physiology Score II), number of catecholamine vasopressors (OR, 1.73; 95 % CI, 1.08-2.77; p = 0.02) and duration of catecholamine vasopressor therapy (OR, 1.01; 95 % CI, 1-1.01; p = 0.002). Patients developing adverse cardiac events were on catecholamine vasopressors (p < 0.001) and mechanical ventilation (p < 0.001) for longer and had longer intensive care unit stays (p < 0.001) and greater mortality (25.9 vs. 1.7 %; p < 0.001) than patients who did not. CONCLUSIONS: Adverse cardiac events occurred in 48.2 % of surgical intensive care unit patients with cardiovascular failure and were related to morbidity and mortality. The extent and duration of catecholamine vasopressor therapy were independently associated with and may contribute to the pathogenesis of adverse cardiac events. PMID- 22527062 TI - In-line filtration reduces severe complications and length of stay on pediatric intensive care unit: a prospective, randomized, controlled trial. AB - PURPOSE: Particulate contamination due to infusion therapy carries a potential health risk for intensive care patients. METHODS: This single-centre, prospective, randomized controlled trial assessed the effects of filtration of intravenous fluids on the reduction of complications in critically ill children admitted to a pediatric intensive care unit (PICU). A total of 807 subjects were randomly assigned to either a control (n = 406) or filter group (n = 401), with the latter receiving in-line filtration. The primary endpoint was reduction in the rate of overall complications, which included the occurrence of systemic inflammatory response syndrome (SIRS), sepsis, organ failure (circulation, lung, liver, kidney) and thrombosis. Secondary objectives were a reduction in the length of stay on the PICU and overall hospital stay. Duration of mechanical ventilation and mortality were also analyzed. FINDINGS: Analysis demonstrated a significant reduction in the overall complication rate (n = 166 [40.9 %] vs. n = 124 [30.9 %]; P = 0.003) for the filter group. In particular, the incidence of SIRS was significantly lower (n = 123 [30.3 %] vs. n = 90 [22.4 %]; P = 0.01). Moreover the length of stay on PICU (3.89 [95 % confidence interval 2.97-4.82] vs. 2.98 [2.33-3.64]; P = 0.025) and duration of mechanical ventilation (14.0 [5.6-22.4] vs. 11.0 [7.1-14.9] h; P = 0.028) were significantly reduced. CONCLUSION: In-line filtration is able to avert severe complications in critically ill patients. The overall complication rate during the PICU stay among the filter group was significantly reduced. In-line filtration was effective in reducing the occurrence of SIRS. We therefore conclude that in-line filtration improves the safety of intensive care therapy and represents a preventive strategy that results in a significant reduction of the length of stay in the PICU and duration of mechanical ventilation (ClinicalTrials.gov number: NCT00209768). PMID- 22527063 TI - Propofol and remifentanil versus midazolam and fentanyl for sedation during therapeutic hypothermia after cardiac arrest: a randomised trial. AB - PURPOSE: To compare two protocols for sedation and analgesia during therapeutic hypothermia: midazolam and fentanyl versus propofol and remifentanil. The primary outcome was the time from discontinuation of infusions to extubation or decision not to extubate (offset time). Secondary outcomes were blood pressure, heart rate, use of vasopressors and inotropic drugs, pneumonia and neurological outcome. METHODS: This was an open, randomised, controlled trial on 59 patients treated with therapeutic hypothermia (33-34 degrees C for 24 h) after cardiac arrest in two Norwegian university hospitals between April 2008 and May 2009. The intervention was random allocation to sedation and analgesia with propofol/remifentanil or midazolam/fentanyl. RESULTS: Twenty-nine patients received propofol and remifentanil, and 30 midazolam and fentanyl. Baseline characteristics were similar. Sedation and analgesia were stopped in 35 patients, and extubation was performed in 17 of these. Sedation had to be continued for 24 patients. Time to offset was significantly lower in patients given propofol and remifentanil [mean (95 % confidence intervals) 13.2 (2.3-24) vs. 36.8 (28.5-45.1) h, respectively, p < 0.001]. Patients given propofol and remifentanil needed norepinephrine infusions twice as often (23 vs. 12 patients, p = 0.003). Incidence of pneumonia and 3-month neurological outcome were similar in the two groups. CONCLUSIONS: Time to offset was significantly shorter in patients treated with propofol and remifentanil. However, the clinical course in 40 % of patients prevented discontinuation of sedation and potential benefits from a faster recovery. The propofol and remifentanil group required norepinephrine twice as often, but both protocols were tolerated in most patients. PMID- 22527065 TI - Chlorhexidine body washing to control antimicrobial-resistant bacteria in intensive care units: a systematic review. AB - PURPOSE: Infections caused by antimicrobial-resistant bacteria (AMRB) are increasing worldwide, especially in intensive care units (ICUs). Chlorhexidine body washing (CHG-BW) has been proposed as a measure to limit the spread of AMRB. We have systematically assessed the evidence on the effectiveness of CHG-BW in reducing colonization and infection with AMRB in adult ICU patients. METHODS: PubMed, Embase, CINAHL, and OpenSigle databases were searched using synonyms for "intensive care unit," "hospital," and "chlorhexidine." All potentially relevant articles were examined by two independent reviewers. Inclusion was limited to studies with ICU patients as domain, providing outcomes related to colonization or infection with AMRB. Data from 16 studies were extracted; 9 were excluded because of assessed high risk of bias or inadequate analyses. The remaining studies differed markedly in (co-)interventions and case mix, which precluded pooling of data in a formal meta-analysis. RESULTS: Incidences of MRSA acquisition were reduced significantly in three studies in which this was the primary endpoint. Significant reduction in MRSA infection rates was observed in only one of five studies. Carriage and bacteremia rates of VRE were assessed in one study, and both significantly declined. There were hardly any data on the effects of CHG-BW on antibiotic-resistant gram-negative bacteria (ARGNB). CONCLUSIONS: CHG-BW may be effective in preventing carriage, and possibly bloodstream infections, with MRSA and VRE in different ICU settings. As CHG-BW protocols, co-interventions and case mix varied widely, attribution of these effects to CHG-BW alone should be done with care. Evidence that CHG-BW reduces carriage of or infections with ARGNB is lacking. PMID- 22527064 TI - An overview of anthrax infection including the recently identified form of disease in injection drug users. AB - PURPOSE: Bacillus anthracis infection (anthrax) can be highly lethal. Two recent outbreaks related to contaminated mail in the USA and heroin in the UK and Europe and its potential as a bioterrorist weapon have greatly increased concerns over anthrax in the developed world. METHODS: This review summarizes the microbiology, pathogenesis, diagnosis, and management of anthrax. RESULTS AND CONCLUSIONS: Anthrax, a gram-positive bacterium, has typically been associated with three forms of infection: cutaneous, gastrointestinal, and inhalational. However, the anthrax outbreak among injection drug users has emphasized the importance of what is now considered a fourth disease form (i.e., injectional anthrax) that is characterized by severe soft tissue infection. While cutaneous anthrax is most common, its early stages are distinct and prompt appropriate treatment commonly produces a good outcome. However, early symptoms with the other three disease forms can be nonspecific and mistaken for less lethal conditions. As a result, patients with gastrointestinal, inhalational, or injectional anthrax may have advanced infection at presentation that can be highly lethal. Once anthrax is suspected, the diagnosis can usually be made with gram stain and culture from blood or tissue followed by confirmatory testing (e.g., PCR). While antibiotics are the mainstay of anthrax treatment, use of adjunctive therapies such as anthrax toxin antagonists are a consideration. Prompt surgical therapy appears to be important for successful management of injectional anthrax. PMID- 22527066 TI - Cough-induced rupture of the right diaphragm and abdominal herniation. PMID- 22527067 TI - Prospective validation of the vasoactive-inotropic score and correlation to short term outcomes in neonates and infants after cardiothoracic surgery. AB - PURPOSE: Prospective validation of the vasoactive-inotropic score (VIS) and inotrope score (IS) in infants after cardiovascular surgery. METHODS: Prospective observational study of 70 infants (<=90 days of age) undergoing cardiothoracic surgery. VIS and IS were assessed at 24 (VIS24, IS24), 48 (VIS48, IS48), and 72 (VIS72, IS72) h after surgery. Maximum VIS and IS scores in the first 48 h were also calculated (VIS48max and IS48max). The primary outcome was length of intubation. Additional outcomes included length of intensive care (ICU) stay and hospitalization, cardiac arrest, mortality, time to negative fluid balance, peak lactate, and change in creatinine. RESULTS: Based on receiver-operating characteristic (ROC) analysis, the area under the curve (AUC) was highest for VIS48 to identify prolonged intubation time. AUC for the primary outcome was higher for VIS than IS at all time points assessed. On multivariate analysis VIS48 was independently associated with prolonged intubation (OR 22.3, p = 0.002), prolonged ICU stay (OR 8.1, p = 0.017), and prolonged hospitalization (OR 11.3, p = 0.011). VIS48max, IS48max, and IS48 were also associated with prolonged intubation, but not prolonged ICU or hospital stay. None of the scores were associated with time to negative fluid balance, peak lactate, or change in creatinine. CONCLUSION: In neonates and infants, a higher VIS at 48 h after cardiothoracic surgery is strongly associated with increased length of ventilation, and prolonged ICU and total hospital stay. At all time points assessed, VIS is more predictive of poor short-term outcome than IS. VIS may be useful as an independent predictor of outcomes. PMID- 22527068 TI - Incidence and risk factors for mortality in paediatric severe sepsis: results from the national paediatric intensive care registry in Japan. AB - PURPOSE: To assess the incidence, background, outcome and risk factors for death of severe sepsis in Japanese paediatric intensive care units (PICUs). METHODS: A data analysis of a prospective, multicentre, 3-year case registry from nine medical-surgical Japanese PICUs. Children with severe sepsis, aged 0-15 years, who were consecutively admitted to the participating PICUs from 1 January 2007 to 31 December 2009 were enrolled. The incidence, background, causative pathogens or infective foci, outcome and risk factors for death caused by severe sepsis were analysed. RESULTS: One hundred forty-one cases were registered. After the exclusion of 14 patients because of incomplete data or inappropriate entry, 127 patients were eligible for the analysis. There were 60 boys and 67 girls, aged 23 [5-68] (median [IQR]) months and weighed 10 [5.5-16.5] kg. The incidence was 1.4 % of total PICU admissions. Sepsis was community-acquired in 35 %, PICU-acquired in 37 % and acquired in hospital general wards in 28 %. Methicillin-resistant Staphylococcus aureus was the most frequent pathogen. The crude 28-day mortality was 18.9 %, comparable to the mean PIM-2 predicted mortality (17.7 %). The mortality rate in patients with shock was significantly increased to 28 % compared to those without shock (5 %). The presences of existing haematological disorders (OR 8.97, 95 % CI, 1.56-51.60) and shock (OR 5.35, 1.04-27.44) were significant factors associated with mortality by multivariate analysis. CONCLUSIONS: The mortality from severe sepsis/septic shock in Japanese PICUs was ~19 %. Haematological disorders and presence of shock were associated with death. PMID- 22527069 TI - Outcome of critically ill lung transplant candidates on invasive respiratory support. AB - PURPOSE: Lung transplantation (LTx) of patients on mechanical ventilation (MV) or extracorporeal support (ECS) is controversial because of impaired survival. Prognostic factors to predict survival should be identified. METHODS: A retrospective analysis was performed in a single centre of all ventilated LTx candidates awarded an Eurotransplant (ET) high-urgency (HU) status between November 2004 and July 2009. Clinical data were collected on the first day of HU status from intubated patients with an approved HU status. Single parameters as well as the lung allocation score (LAS), the Sequential Organ Failure Assessment score (SOFA) and the Simplified Acute Physiology Score (SAPS 2) were calculated. The association of these variables with survival was evaluated. RESULTS: A total of 100 intubated patients (median age 38 years, 56 % female) fulfilled the inclusion criteria, of whom 60 also required ECS. The main indications were cystic fibrosis (25 %) and idiopathic pulmonary fibrosis (24 %). Median time with HU status was 12 days [interquartile range (IQR) 6-21 days]. Sixty patients were transplanted, five were weaned from mechanical ventilation and 38 died while on the wait list. One-year-survival rates were 57, 36 and 5 % for transplanted patients, all candidates and non-transplanted candidates, respectively (p < 0.001). A SAPS score >24 (median 30, IQR 27-35), a procalcitonin level of >0.5 ug/l (median 0.4, IQR 0.1-1.4 ug/l) and any escalation of bridging strategy were independently associated with mortality (p = 0.021, = 0.003, and < 0.001, respectively). The LAS (median 88, IQR 8-90) did not predict survival (p = 0.92). CONCLUSIONS: High-urgency LTx improves survival in critically ill intubated candidates. Higher SAPS scores, escalating therapy and an abnormal procalcitonin level were associated with a poor outcome. PMID- 22527070 TI - Are religion and religiosity important to end-of-life decisions and patient autonomy in the ICU? The Ethicatt study. AB - PURPOSE: This study explored differences in end-of-life (EOL) decisions and respect for patient autonomy of religious members versus those only affiliated to that particular religion (affiliated is a member without strong religious feelings). METHODS: In 2005 structured questionnaires regarding EOL decisions were distributed in six European countries to ICUs in 142 hospital ICUs. This sub study of the original data analyzed answers from Protestants, Catholics and Jews. RESULTS: A total of 304 physicians, 386 nurses, 248 patients and 330 family members were included in the study. Professionals wanted less treatment (ICU admission, CPR, ventilator treatment) than patients and family members. Religious respondents wanted more treatment and were more in favor of life prolongation, and they were less likely to want active euthanasia than those affiliated. Southern nurses and doctors favored euthanasia more than their Northern colleagues. Three quarters of doctors and nurses would respect a competent patient's refusal of a potentially life-saving treatment. No differences were found between religious and affiliated professionals regarding patient's autonomy. Inter-religious differences were detected, with Protestants most likely to follow competent patients' wishes and the Jewish respondents least likely to do so, and Jewish professionals more frequently accepting patients' wishes for futile treatment. However, these findings on autonomy were due to regional differences, not religious ones. CONCLUSIONS: Health-care professionals, families and patients who are religious will frequently want more extensive treatment than affiliated individuals. Views on active euthanasia are influenced by both religion and region, whereas views on patient autonomy are apparently more influenced by region. PMID- 22527071 TI - Knee area tissue oxygen saturation is predictive of 14-day mortality in septic shock. AB - PURPOSE: Thenar eminence tissue oxygen saturation (StO(2)) was developed to assess organ perfusion. However, mottling, a strong predictor of mortality in septic shock, develops preferentially around the knee. We aimed to evaluate the prognostic value of StO(2) measured around the knee in septic shock patients and compare it to thenar StO(2). METHODS: This was a prospective observational study in a tertiary teaching hospital. All consecutive patients with septic shock were included. Parameters were recorded when vasopressors were started (H0) and every 6 h during 24 h. Their predictive value was assessed on 14-day mortality. RESULTS: Fifty-two patients were included. SOFA score was 11 (9-15) and SAPS II was 56 (40-72). At 6 h after ICU admission (H6), mean arterial pressure, cardiac index, and central venous pressure were not different between non-survivors and survivors; but non-survivors had higher arterial lactate level (8.8 +/- 5.0 vs. 2.2 +/- 1.5 mmol/l, P < 0.001), lower urinary output (0.22 +/- 0.45 vs. 0.70 +/- 0.50 ml/kg/h, P < 0.001) and ScvO(2) (62 +/- 20 vs. 72 +/- 9 %, P = 0.03). At H6, StO(2) was lower in non-survivors; this difference was not significant for thenar StO(2) (70 +/- 15 vs. 77 +/- 12 %, P = 0.10) but was very pronounced for knee StO(2) (39 +/- 23 vs. 71 +/- 12 %, P < 0.001). At H6, a low knee StO(2) was associated with a higher mottling score (P < 0.01), a higher lactate level (P < 0.002, R (2) = 0.2), and a lower urinary output (P = 0.02, R (2) = 0.12). CONCLUSION: After initial septic shock resuscitation, StO(2) measured around the knee is a strong predictive factor of 14-day mortality. PMID- 22527072 TI - Random errors in insulin infusion concentrations. PMID- 22527073 TI - Religion and end-of-life decisions in critical care: where the word meets deed. PMID- 22527074 TI - Hyperbaric oxygen therapy in necrotising soft tissue infections: a study of patients in the United States Nationwide Inpatient Sample. AB - PURPOSE: Necrotising soft tissue infection (NSTI) is a deadly disease associated with a significant risk of mortality and long-term disability from limb and tissue loss. The aim of this study was to determine the effect of hyperbaric oxygen (HBO(2)) therapy on mortality, complication rate, discharge status/location, hospital length of stay and inflation-adjusted hospitalisation cost in patients with NSTI. METHODS: This was a retrospective study of 45,913 patients in the Nationwide Inpatient Sample (NIS) from 1988 to 2009. RESULTS: A total of 405 patients received HBO(2) therapy. The patients with NSTI who received HBO(2) therapy had a lower mortality (4.5 vs. 9.4 %, p = 0.001). After adjusting for predictors and confounders, patients who received HBO(2) therapy had a statistically significantly lower risk of dying (odds ratio (OR) 0.49, 95 % confidence interval (CI) 0.29-0.83), higher hospitalisation cost (US$52,205 vs. US$45,464, p = 0.02) and longer length of stay (LOS) (14.3 days vs. 10.7 days, p < 0.001). CONCLUSIONS: This retrospective analysis of HBO(2) therapy in NSTI showed that despite the higher hospitalisation cost and longer length of stay, the statistically significant reduction in mortality supports the use of HBO(2) therapy in NSTI. PMID- 22527075 TI - Azithromycin to prevent Pseudomonas aeruginosa ventilator-associated pneumonia by inhibition of quorum sensing: a randomized controlled trial. AB - PURPOSE: Anti-virulence strategies have not been evaluated for the prevention of bacterial infections. Prolonged colonization of intubated patients with Pseudomonas aeruginosa isolates producing high-levels of the quorum sensing (QS) regulated virulence factor rhamnolipids has been associated with ventilator associated pneumonia (VAP). In this pathogen, azithromycin reduces QS-regulated virulence. We aimed to assess whether azithromycin could prevent VAP in patients colonized by rhamnolipids producing isolates. METHODS: In a randomized, double blind, multicenter trial, intubated colonized patients received either 300 mg/day azithromycin or placebo. Primary endpoint was the occurrence of P. aeruginosa VAP. We further identified those patients persistently colonized by isolates producing high-levels of rhamnolipids and therefore at the highest risk to develop VAP linked to this QS-dependent virulence factor. RESULTS: Ninety-two patients were enrolled; 43 azithromycin-treated and 42 placebo patients were eligible for the per-protocol analysis. In the per-protocol population, the occurrence of P. aeruginosa VAP was reduced in the azithromycin group but without reaching statistical significance (4.7 vs. 14.3 % VAP, p = 0.156). QS-dependent virulence of colonizing isolates was similarly low in both study groups, and only five patients in each arm were persistently colonized by high-level rhamnolipids producing isolates. In this high-risk subgroup, the incidence of VAP was reduced fivefold in azithromycin versus placebo patients (1/5 vs. 5/5 VAP, p = 0.048). CONCLUSIONS: There was a trend towards reduced incidence of VAP in colonized azithromycin-treated patients. In addition, azithromycin significantly prevented VAP in those patients at high risk of rhamnolipid-dependent VAP, suggesting that virulence inhibition is a promising anti-microbial strategy. PMID- 22527076 TI - Safety of gelatin for volume resuscitation--a systematic review and meta analysis. AB - PURPOSE: Gelatin is frequently used as a volume expander in critical care. Our goal was to investigate its safety. METHODS: Systematic review of randomized controlled trials (RCT) in patients receiving gelatin for resuscitation in comparison to albumin or crystalloids. RESULTS: We identified 40 RCTs published between 1976 and 2010 with 3,275 patients. Median sample size in the gelatin groups was 15 patients (range 10-249). Median gelatin dose was 17 ml/kg (range 6 57 ml/kg). In 32 RCTs (n = 1,946/3,275, 59 % of all patients), the study period was <=24.0 h. Twenty-nine RCTs (n = 2,001) investigated elective surgical patients, mostly undergoing cardiac surgery (18 RCTs, n = 819). Three RCTs (n = 723) investigated critically ill adults. Two RCTs (n = 59) were performed in emergency room patients, and six RCTs (n = 492) were performed in neonates or children. No study was adequately powered to investigate the frequency of patient important outcomes. Risks were not statistically significantly different for mortality (RR 1.12, 95 % confidence interval, 0.87-1.44) and exposure to allogeneic transfusion (RR 1.28, 0.89-1.83). On account of only few included studies and the small number of patients, subgroup analyses (high vs. low dose, >24 h vs. shorter periods, and critically ill patients vs. others) were uninformative. Only three RCTs reported the occurrence of acute renal failure. CONCLUSION: Despite over 60 years of clinical practice, the safety and efficacy of gelatin cannot be reliably assessed in at least some settings in which it is currently used. We suggest the need to investigate and establish such safety. PMID- 22527077 TI - Treating bacterial virulence systems: we are not there yet. PMID- 22527078 TI - Does "treatment failure bias" impact comparisons of ICUs? PMID- 22527079 TI - Levosimendan infusion in newborns after corrective surgery for congenital heart disease: randomized controlled trial. AB - PURPOSE: To evaluate the safety and efficacy of levosimendan in neonates with congenital heart disease undergoing cardiac surgery with cardiopulmonary bypass (CPB). METHODS: Neonates undergoing risk-adjusted classification for congenital heart surgery (RACHS) 3 and 4 procedures were randomized to receive either a 72 h continuous infusion of 0.1 MUg/kg/min levosimendan or standard post-CPB inotrope infusion. RESULTS: Sixty-three patients (32 cases and 31 controls) were recruited. There were no differences between groups regarding demographic and baseline clinical data. No side effects were observed. There were no significant differences in mortality (1 vs. 3 patients, p = 0.35), length of mechanical ventilation (5.9 +/- 5 vs. 6.9 +/- 8 days, p = 0.54), and pediatric cardiac intensive care unit (PCICU) stay (11 +/- 8 vs. 14 +/- 14 days, p = 0.26). Low cardiac output syndrome occurred in 37 % of levosimendan patients and in 61 % of controls (p = 0.059, OR 0.38, 95 % CI 0.14-1.0). Postoperative heart rate, with a significant difference at 6 (p = 0.008), 12 (p = 0.037), and 24 h (p = 0.046), and lactate levels, with a significant difference at PCICU admission (p = 0.015) and after 6 h (p = 0.048), were lower in the levosimendan group. Inotropic score was significantly lower in the levosimendan group at PCICU admission, after 6 h and after 12 h, (p < 0.0001). According to multivariate analysis, a lower lactate level 6 h after PCICU admission was independently associated with levosimendan administration after correction for CPB time and the need for deep hypothermic circulatory arrest. CONCLUSIONS: Levosimendan infused in neonates undergoing cardiac surgery was well tolerated with a potential benefit of levosimendan on postoperative hemodynamic and metabolic parameters of RACHS 3-4 neonates. PMID- 22527080 TI - Elevation of creatine kinase is associated with worse outcomes in 2009 pH1N1 influenza A infection. AB - BACKGROUND: Current medical knowledge lacks specific information regarding creatine kinase (CK) elevation in influenza A pH1N1 (2009) infection. OBJECTIVES: Primary endpoints were correlation between CK at intensive care unit (ICU) admission and ICU mortality. Secondary endpoints were ICU length of stay (LOS), mechanical ventilation (MV), and requirement of renal replacement techniques (RRT). MATERIALS AND METHODS: A prospective multicenter register included all adults admitted for severe acute respiratory insufficiency (SARI) with confirmed pH1N1 in 148 ICUs. Clinical data including demographics, comorbidities, laboratory information, organ involvement, and prognostic data were registered. Post hoc classification of subjects was determined according to CK level. Data are expressed as median (interquartile range). RESULTS: Five hundred and five (505) patients were evaluable. Global ICU mortality was 17.8 % without documented differences between breakpoints. CK >=500 UI/L was documented in 23.8 % of ICU admissions, being associated with greater renal dysfunction: acute kidney injury (AKI) was more frequent (26.1 versus 17.1 %, p < 0.05) and twofold requirement of RRT [11 versus 5.6 %, p < 0.05; odds ratio (OR) = 2.09 (95 % confidence interval [CI] 1.01-4.32)]. Increase of CK >=1,000 UI/L was associated with two or more quadrant involvement on chest X-ray (63.2 versus 40.2 %, p < 0.01) and increased intubation risk (73.9 versus 56.7 %, p = 0.07) and duration of mechanical ventilation (median 15 days versus 11 days, p < 0.01). As a result, CK >=1,000 UI/L was associated with 5 extra days of ICU and hospital LOS. CONCLUSIONS: CK is a biomarker of severity in pH1N1 infection. Elevation of CK was associated with more complications and increased ICU LOS and healthcare resources. PMID- 22527081 TI - Increase in use of non-invasive ventilation for infants with severe bronchiolitis is associated with decline in intubation rates over a decade. AB - PURPOSE: To redress the paucity of studies evaluating non-invasive respiratory support in bronchiolitis patients. METHODS: Following ethics committee approval, the clinical database of a tertiary 23-bed paediatric intensive care unit (PICU) was reviewed for bronchiolitis admissions from January 2000 to December 2009. Length of stay (LOS), ventilatory requirements and risk factors, including prematurity, respiratory syncytial virus (RSV) status, chronic lung, neuromuscular, immune and congenital heart disease, were analysed. RESULTS: Of 8,288 admissions, 520 (6.27 %) had bronchiolitis with 343 (65.9 %) having RSV. Median (+/-SD) age and LOS were 2.78 months and 2.68 (+/-4.32) days. One (0.2 %) patient died. Assisted ventilation was required for 399 (76.7 %) patients. A total of 114 (28.6 %) patients were intubated directly and 285 (71.4 %) had a trial of non-invasive ventilation (NIV). Significant increase in the use of NIV was seen (2.8 %/year) with decline in intubation rates (1.9 %/ year) (p = 0.002). Of NIV patients, 237 (83.2 %) needed only NIV and 48 (16.8 %) failed and therefore needed intubation. The median LOS was shorter in those who succeeded NIV (2.38 +/- 2.43 days) compared to those with invasive ventilation (5.19 +/- 6.34 days) and those who failed NIV (8.41 +/- 3.44 days). Presence of a risk factor increased the chances of failing NIV from 6 to 10 %. CONCLUSION: NIV was successful in the vast majority of patients, particularly in those without risk factors and halved the LOS in intensive care. Failure of NIV was associated with increased duration of invasive ventilation and PICU LOS. A prospective study comparing different techniques of NIV will be helpful in defining the risks of failure of NIV. PMID- 22527082 TI - Development and preliminary evaluation of a telephone-based coping skills training intervention for survivors of acute lung injury and their informal caregivers. AB - PURPOSE: Survivors of acute lung injury (ALI) and their informal caregivers have difficulty coping with the physical and emotional challenges of recovery from critical illness. We aimed to develop and pilot test a telephone-based coping skills training intervention for this population. METHODS: Fifty-eight participants were enrolled overall. A total of 21 patients and 23 caregivers participated in a cross-sectional study to assess coping and its association with psychological distress. This also informed the development of an ALI coping skills training intervention in an iterative process involving content and methodological experts. The intervention was then evaluated in seven patients and seven caregivers in an uncontrolled, prospective, pre-post study. Outcomes included acceptability, feasibility, and symptoms of psychological distress measured with the Hospital Anxiety and Depression Scale (HADS) and Post-Traumatic Symptom Scale (PTSS). RESULTS: Survivors and their caregivers used adaptive coping infrequently, a pattern that was strongly associated with psychological distress. These findings informed the development of a 12-session intervention for acquiring, applying, and maintaining coping skills. In the evaluation phase, participants completed 77 (92 %) of a possible 84 telephone sessions and all (100 %) reported the intervention's usefulness in their daily routine. Mean change scores reflecting improvements in the HADS (7.8 U) and PTSS (10.3 U) were associated with adaptive coping (r = 0.50-0.70) and high self-efficacy (r = 0.67 0.79). CONCLUSIONS: A novel telephone-based coping skills training intervention was acceptable, feasible, and may have been associated with a reduction in psychological distress among survivors of ALI and their informal caregivers. A randomized trial is needed to evaluate the intervention. PMID- 22527083 TI - Prolonged but reversible coma: an unusual complication of severe heatstroke. PMID- 22527084 TI - Standardised drug labelling in intensive care: results of an international survey among ESICM members. AB - PURPOSE: Standardised coloured drug labels may increase patient safety in the intensive care unit (ICU). The rates of adherence to standardised drug syringe labelling (DSL) in European and non-European ICUs, and the standards applied are not known. The aim of this survey among ESICM members was to assess if and what standardised drug syringe labelling is used, if the standards for drug syringe labelling are similar internationally and if intensivists expect that standardised DSL should be delivered by the pharmaceutical industry. METHODS: A structured, web-based, anonymised survey on standardised DSL, performed among ESICM members (March-May 2011; Clinicaltrials.gov NCT01232088). Descriptive data analysis was performed and Fisher's exact test was applied where applicable. RESULTS: Four hundred eighty-two submissions were analysed (20 % non-European). Thirty-five percent of the respondents reported that standardised drug labelling was used hospital-wide, and 39 % reported that standardised DSL was used in their ICU (Europe: Northern 53 %, Western 52 %, Eastern 17 %, Southern 22 %). The International Organization of Standardization (ISO) 26825 norm in its original form was used by 30 %, an adapted version by 19 % and local versions by 45 %; 6 % used labels that were included in the drug's packaging. Eighty percent wished that the pharmaceutical industry supplied ISO 26825 norm labelling together with the drugs. CONCLUSIONS: Standardised DSL is not widely applied in European and non-European ICUs and mostly does not adhere strictly to the ISO norm. The frequency and quality of DSL differs to a great extent among European regions. This leaves much room for improvement. PMID- 22527085 TI - An evaluation of three measures of intracranial compliance in traumatic brain injury patients. AB - PURPOSE: To compare intracranial pressure (ICP) amplitude, ICP slope, and the correlation of ICP amplitude and ICP mean (RAP index) as measures of compliance in a cohort of traumatic brain injury (TBI) patients. METHODS: Mean values of the three measures were calculated in the 2-h periods before and after surgery (craniectomies and evacuations), and in the 12-h periods preceding and following thiopental treatment, and during periods of thiopental coma. The changes in the metrics were evaluated using the Wilcoxon test. The correlations of 10-day mean values for the three metrics with age, admission Glasgow Motor Score (GMS), and Extended Glasgow Outcome Score (GOSe) were evaluated. Patients under and over 60 years old were also compared using the Student t test. The correlation of ICP amplitude with systemic pulse amplitude was analyzed. RESULTS: ICP amplitude was significantly correlated with GMS, and also with age for patients 35 years old and older. The correlations of ICP slope and the RAP index with GMS and with age were not significant. All three metrics indicated significant improvements in compliance following surgery and during thiopental coma. None of the metrics were significantly correlated with outcome, possibly due to confounding effects of treatment factors. The correlation of systemic pulse amplitude with ICP amplitude was low (R = 0.18), only explaining 3 % of the variance. CONCLUSIONS: This study provides further validation for all three of these features of the ICP waveform as measures of compliance. ICP amplitude had the best performance in these tests. PMID- 22527086 TI - Brain compliance: the old story with a new 'et cetera'. PMID- 22527087 TI - Left tilt position for easy extracorporeal membrane oxygenation cannula insertion in late pregnancy patients. AB - The aim was to describe how to avoid technical difficulties during venous femoral cannula insertion for extracorporeal membrane oxygenation (ECMO) in a woman in late pregnancy. A 28-year old pregnant woman presented at 32 weeks of gestation after developing an acute respiratory distress syndrome (ARDS) of an unknown origin that required venovenous ECMO insertion via the femoral vein. A cannula insertion by the Seldinger visual control technique was impossible in the supine position. A left lateral tilt between 15 degrees and 30 degrees was performed by placing a wedge-shaped cushion under the right hip permitting the cannula insertion. We proposed a systematic 15 degrees -30 degrees left lateral tilt position during the ECMO femoral cannula insertion in late pregnancy cases needing ECMO. This precaution should avoid an injury to the vessels due to multiple insertion attempts. PMID- 22527088 TI - What is the optimum strategy for thromboembolic prophylaxis following extrapleural pneumonectomy in patients with malignant pleural mesothelioma? AB - Malignant pleural mesothelioma (MPM) increases the risk of venous thromboembolic (VTE) events. This risk is higher following extrapleural pneumonectomy (EPP) as part of trimodality therapy, where VTE can be catastrophic. In our series, the impact of warfarin in preventing a pulmonary embolus (PE) after neoadjuvant chemotherapy and EPP for MPM was analysed. A retrospective analysis of 21 consecutive patients undergoing EPP for MPM was conducted. The first 10 patients (Group A) had VTE prophylaxis by subcutaneous enoxaparin and compression stockings commenced a day prior to surgery, intraoperative pneumatic calf compression and early post-operative mobilization. Enoxaparin was continued for 30 days postoperatively. The following 11 patients (Group B) had the same VTE prophylaxis, together with warfarin, started prior to hospital discharge and continued for 6 months postoperatively. All patients had a computed tomography pulmonary angiogram within 8 weeks after surgery and a full examination at 1, 3, 6 and 12 months. Both groups were comparable for characteristics. Three patients in Group A suffered a PE at 4, 6 and 16 weeks postoperatively. One PE was fatal. No patient in Group B suffered VTE (P = 0.05, chi(2) test) or haemorrhagic complications. Warfarin anticoagulation following EPP is feasible and safe, and is associated with a significant reduction in VTE complications. PMID- 22527089 TI - Local anaesthetic thoracoscopy for intractable pneumothorax in a high-risk patient. AB - The management of high-operative-risk patients with a pneumothorax is complicated. The case of a 79-year old man with an intractable secondary pneumothorax, who had taken oral steroids to control asthma, is presented. Since the patient could not tolerate general anaesthesia because of poor cardiac function, thoracoscopic surgery was performed under local anaesthesia. A successful lung fistula closure was achieved and the continuous air leakage disappeared immediately after the surgery. PMID- 22527090 TI - Case report: acute coronary artery spasm in a patient in the setting of non cardiac surgery. PMID- 22527091 TI - Gender-specific predictors of early mortality after coronary artery bypass graft surgery. AB - BACKGROUND: Female gender is a risk factor for early mortality after coronary artery bypass graft surgery (CABG). Yet, the causes for this excess mortality in women have not been fully explained. OBJECTIVES: To analyse gender differences in early mortality (30 days post surgery) after CABG and to identify variables explaining the association between female gender and excess mortality, taking into account preoperative clinical and psychosocial, surgical and postoperative risk factors. METHODS: A total of 1,559 consecutive patients admitted to the German Heart Institute Berlin (2005-2008) for CABG were included in this prospective study. A comprehensive set of prespecified preoperative, surgical and postoperative risk factors were examined for their ability to explain the gender difference in early mortality. RESULTS: Early mortality after CABG was higher in women than in men (6.9 vs. 2.4 %, HR 2.91, 95 % CI 1.70-4.96, P < 0.001). Women were older than men (+4.7 years, P < 0.001), had lower self-assessed preoperative physical functioning (-16 points on a scale from 0 to 100, P < 0.001), and had higher rates of postoperative low cardiac output syndromes (6.6 vs. 3.3 %, P = 0.01), respiratory insufficiency (9.4 vs. 5.3 %, P = 0.006) and resuscitation (5.2 vs. 1.8 %, P = 0.001). The combination of these factors explained 71 % of the gender difference in early mortality; age and physical functioning alone accounted for 61 %. Adjusting for these variables, HR for female gender was 1.36 (95 % CI 0.77-2.41, P = 0.29). CONCLUSIONS: Age, physical function and postoperative complications are key mediators of the overmortality of women after aortocoronary bypass surgery. Self-assessed physical functioning should be more seriously considered in preoperative risk assessment particularly in women. PMID- 22527092 TI - Evaluation of cardiac autonomic function by various indices in patients with primary premature ovarian failure. AB - BACKGROUND: The association between premature ovarian failure (POF) and cardiovascular diseases (CVD) was investigated previously, but none of the studies have looked at cardiac autonomic functions in these patients. In this study, we aimed to evaluate cardiac autonomic functions in patients with POF. METHODS: We enrolled 26 female patients (mean age 37.5 +/- 10.1 years) with primary POF and 31 healthy subjects (mean age 37.5 +/- 9.0 years). All participants underwent 24-h Holter recording. Heart rate recovery (HRR) indices were calculated by subtracting 1st-, 2nd- and 3rd-min heart rates from maximal heart rate. Heart rate variability (HRV) and heart rate turbulence (HRT) parameters were analyzed in all patients. RESULTS: Both groups were similar with regard to age, gender, body mass index and left ventricular ejection fraction. Mean HRR1 (p = 0.018), HRR2 (p = 0.021) and HRR3 (p = 0.027) values were significantly higher in the control group. When HRV considered SDNN, SDANN, RMSSD, PNN50 and HF were significantly decreased in patients with POF compared to healthy controls, but LF and LF/HF were significantly higher in POF patients. Both HRT onset and slope were more abnormal in POF patients. Also, there was a significant correlation between HRR, HRV and HRT parameters and FSH, LH and estradiol levels. CONCLUSION: Our study results suggest that cardiac autonomic function is impaired in patients with POF despite the absence of overt cardiac involvement and symptoms. Further studies are needed to elucidate the prognostic significance and clinical implications of impaired autonomic functions in patients with POF. PMID- 22527093 TI - Serum vitamin D concentration status and its correlation with early biomarkers of remodeling following acute myocardial infarction. PMID- 22527094 TI - Human pericyte-endothelial cell interactions in co-culture models mimicking the diabetic retinal microvascular environment. AB - Pericytes regulate vascular tone, perfusion pressure and endothelial cell (EC) proliferation in capillaries. Thiamine and benfotiamine counteract high glucose induced damage in vascular cells. We standardized two human retinal pericyte (HRP)/EC co-culture models to mimic the diabetic retinal microvascular environment. We aimed at evaluating the interactions between co-cultured HRP and EC in terms of proliferation/apoptosis and the possible protective role of thiamine and benfotiamine against high glucose-induced damage. EC and HRP were co cultured in physiological glucose and stable or intermittent high glucose, with or without thiamine/benfotiamine. No-contact model: EC were plated on a porous membrane suspended into the medium and HRP on the bottom of the same well. Cell to-cell contact model: EC and HRP were plated on the opposite sides of the same membrane. Proliferation (cell counts and DNA synthesis), apoptosis and tubule formation in Matrigel were assessed. In the no-contact model, stable high glucose reduced proliferation of co-cultured EC/HRP and EC alone and increased co cultured EC/HRP apoptosis. In the contact model, both stable and intermittent high glucose reduced co-cultured EC/HRP proliferation and increased apoptosis. Stable high glucose had no effects on HRP in separate cultures. Both EC and HRP proliferated better when co-cultured. Thiamine and benfotiamine reversed high glucose-induced damage in all cases. HRP are sensitive to soluble factors released by EC when cultured in high glucose conditions, as suggested by conditioned media assays. In the Matrigel models, addition of thiamine and benfotiamine re-established the high glucose-damaged interactions between EC/HRP and stabilized microtubules. PMID- 22527095 TI - Prevalence of phonatory symptoms in patients with type 2 diabetes mellitus. AB - To look at the prevalence of phonatory symptoms in patients with type 2 diabetes mellitus. The correlation between these symptoms with duration of the disease, glycemic control, and neuropathy will be described. A total of 105 consecutive patients diagnosed with type 2 diabetes mellitus by their primary endocrinologist were evaluated. A control group consisting of 33 healthy subjects was recruited for this study. Demographic data included: age, gender, allergy, smoking, duration of the disease, glycemic control, and presence or absence of neuropathy. Subjects were also asked about the presence or absence of the following symptoms: hoarseness, vocal tiring or fatigue, vocal straining, and aphonia or complete loss of voice. Patients were also asked to fill out the Voice Handicap Index 10. The mean age of patients with diabetes was 53.21 + 9.68 years with male-to-female ratio of 2/3. The most common phonatory symptoms were vocal tiring or fatigue and hoarseness (34.3 and 33.3 %). There was a significant difference in the prevalence of hoarseness and vocal straining (p value 0.045 and 0.015, respectively) compared to controls. There was a significant correlation between glycemic control, neuropathy, and hoarseness (p value 0.030 and 0.001, respectively). Vocal straining and aphonia also correlated significantly with the presence of neuropathy. Close to 16 % of diabetic patients had a VHI-10 above or equal to 7. Diabetic patients are more likely to have phonatory symptoms compared to controls, namely straining and hoarseness. One out of seven patients with diabetes has reported that phonatory symptoms had a significant impact on their quality of life. The presence of neuropathy and poor glycemic control should alert the treating physician to these vocal complaints. PMID- 22527096 TI - Comparison of arterial and mixed venous blood glucose levels in hemodynamically unstable pigs: implications for location of a continuous glucose sensor. AB - One of several unsolved challenges in the construction of an artificial endocrine pancreas (a system for automatically adjusting the blood glucose level) is the positioning of the glucose sensor. We believe the best positioning to be either intraarterial or in a central vein. It is therefore important to know whether the glucose content in these blood locations is the same. We conducted a post hoc analysis of previously collected data from pigs exposed to gross inflammatory and circulatory stress. Paired arterial and mixed venous glucose values were compared with a mixed effects model. We found the blood glucose values from the arterial and mixed venous blood to be the same. PMID- 22527097 TI - Comments on the use of a single or multiple probeset approach for microarray based analyses of routine molecular markers in breast cancer. PMID- 22527098 TI - Oncogene amplification in male breast cancer: analysis by multiplex ligation dependent probe amplification. AB - Gene amplification is an important mechanism for oncogene activation, a crucial step in carcinogenesis. Compared to female breast cancer, little is known on the genetic makeup of male breast cancer, because large series are lacking. Copy number changes of 21 breast cancer related genes were studied in 110 male breast cancers using multiplex ligation-dependent probe amplification. A ratio of >1.3 was regarded indicative for gene copy number gain and a ratio >2.0 for gene amplification. Data were correlated with clinicopathological features, prognosis and 17 genes were compared with a group of female breast cancers. Gene copy number gain of CCND1, TRAF4, CDC6 and MTDH was seen in >40 % of the male breast cancer cases, with also frequent amplification. The number of genes with copy number gain and several single genes were associated with high grade, but only CCND1 amplification was an independent predictor of adverse survival in Cox regression (p = 0.015; hazard ratio 3.0). In unsupervised hierarchical clustering a distinctive group of male breast cancer with poor prognosis (p = 0.009; hazard ratio 3.4) was identified, characterized by frequent CCND1, MTDH, CDC6, ADAM9, TRAF4 and MYC copy number gain. Compared to female breast cancers, EGFR (p = 0.005) and CCND1 (p = 0.041) copy number gain was more often seen in male breast cancer, while copy number gain of EMSY (p = 0.004) and CPD (p = 0.001) and amplification in general was less frequent. In conclusion, several female breast cancer genes also seem to be important in male breast carcinogenesis. However, there are also clear differences in copy number changes between male and female breast cancers, pointing toward differences in carcinogenesis between male and female breast cancer and emphasizing the importance of identifying biomarkers and therapeutic agents based on research in male breast cancer. In addition CCND1 amplification seems to be an independent prognosticator in male breast cancer. PMID- 22527099 TI - Collective evidence supports neutrality of BRCA1 V1687I, a novel sequence variant in the conserved THV motif of the first BRCT repeat. AB - Unambiguous classification of BRCA1 and BRCA2 variants of uncertain significance (VUS) is a challenging task that vexes health care providers and has profound implications for patients and their family members. Numerous VUS have been described to date, which await assessment of their functional, hence clinical, impact. As a result of a routine BRCA1/BRCA2 mutational screening, we identified a previously unreported BRCA1 sequence alteration [c.5178G>A (V1687I)] in a patient diagnosed with early onset triple negative breast cancer. The sequence alteration falls in the invariant THV motif of the BRCT domain. To investigate its significance, we applied an integrated approach that, in addition to genetic and histopathological data, included in silico analyses, comparative structural modeling and verification of BRCT-mediated interactions. In line with web-based algorithms that predicted the benign nature of BRCA1 V1687I, the three dimensional model of the BRCA1 V1687I BRCT domain did not reveal any major structural changes relative to its wild-type counterpart, thus suggesting that BRCA1 V1687I has a negligible impact on both the local architecture and the overall stability of the protein. Consistently, the BRCA1 V1687I protein was properly expressed and localized to the nucleus, and it was still capable of binding three BRCT-interacting, DNA damage response, and repair partner proteins, namely BRIP1/FANCJ, CtIP, and Abraxas. Our collected evidence suggests that, although occurring in a highly conserved region, the BRCA1 V1687I variant is likely a benign sequence alteration. PMID- 22527100 TI - NFkappaB signaling is important for growth of antiestrogen resistant breast cancer cells. AB - Resistance to endocrine therapy is a major clinical challenge in current treatment of estrogen receptor-positive breast cancer. The molecular mechanisms underlying resistance are yet not fully clarified. In this study, we investigated whether NFkappaB signaling is causally involved in antiestrogen resistant cell growth and a potential target for re-sensitizing resistant cells to endocrine therapy. We used an MCF-7-derived cell model for antiestrogen resistant breast cancer to investigate dependence on NFkappaB signaling for antiestrogen resistant cell growth. We found that targeting NFkappaB preferentially inhibited resistant cell growth. Antiestrogen resistant cells expressed increased p50 and RelB, and displayed increased phosphorylation of p65 at Ser529 and Ser536. Moreover, transcriptional activity of NFkappaB after stimulation with tumor necrosis factor alpha was enhanced in antiestrogen resistant cell lines compared to the parental cell line. Inhibition of NFkappaB signaling sensitized tamoxifen resistant cells to the growth inhibitory effects of tamoxifen but was not sufficient to fully restore sensitivity of fulvestrant resistant cells to fulvestrant. In support of this, depletion of p65 with siRNA in tamoxifen resistant cells increased sensitivity to tamoxifen treatment. Our data provide evidence that NFkappaB signaling is enhanced in antiestrogen resistant breast cancer cells and plays an important role for antiestrogen resistant cell growth and for sensitivity to tamoxifen treatment in resistant cells. Our results imply that targeting NFkappaB might serve as a potential novel treatment strategy for breast cancer patients with resistance toward antiestrogen. PMID- 22527101 TI - CYP2C8*3 predicts benefit/risk profile in breast cancer patients receiving neoadjuvant paclitaxel. AB - Paclitaxel is one of the most frequently used chemotherapeutic agents for the treatment of breast cancer patients. Using a candidate gene approach, we hypothesized that polymorphisms in genes relevant to the metabolism and transport of paclitaxel are associated with treatment efficacy and toxicity. Patient and tumor characteristics and treatment outcomes were collected prospectively for breast cancer patients treated with paclitaxel-containing regimens in the neoadjuvant setting. Treatment response was measured before and after each phase of treatment by clinical tumor measurement and categorized according to RECIST criteria, while toxicity data were collected from physician notes. The primary endpoint was achievement of clinical complete response (cCR) and secondary endpoints included clinical response rate (complete response+partial response) and grade 3+ peripheral neuropathy. The genotypes and haplotypes assessed were CYP1B1*3, CYP2C8*3, CYP3A4*1B/CYP3A5*3C, and ABCB1*2. A total of 111 patients were included in this study. Overall, cCR was 30.1% to the paclitaxel component. CYP2C8*3 carriers (23/111, 20.7%) had higher rates of cCR (55% vs. 23%; OR=3.92 [95% CI: 1.46-10.48], corrected p=0.046). In the secondary toxicity analysis, we observed a trend toward greater risk of severe neuropathy (22% vs. 8%; OR=3.13 [95% CI: 0.89-11.01], uncorrected p=0.075) in subjects carrying the CYP2C8*3 variant. Other polymorphisms interrogated were not significantly associated with response or toxicity. Patients carrying CYP2C8*3 are more likely to achieve clinical complete response from neoadjuvant paclitaxel treatment, but may also be at increased risk of experiencing severe peripheral neurotoxicity. PMID- 22527102 TI - Invasive breast carcinomas in Ghana: high frequency of high grade, basal-like histology and high EZH2 expression. AB - Breast cancer in African-American women has a worse outcome than in Caucasian women. The ancestors of most African-American women come from West Africa, including Ghana. The Polycomb group protein EZH2 is a marker of poor outcome in breast cancers from Caucasian women. The histopathological features and biomarker expression of African breast cancers remain obscure. Here, we investigated a cohort of Ghanaian breast cancers to better define the prevalent tumor types and to test if EZH2 protein may identify aggressive tumors. A group of 169 breast tissues (100 invasive carcinomas and 69 benign) from women treated at Komfo Anoyke Teaching Hospital between 2006 and 2011 were histologically classified and investigated for EZH2 expression. EZH2 nuclear expression we defined as high or low following previously published criteria. Of the 100 invasive carcinomas, 89 % were ductal, 2 % were lobular, and 9 % were metaplastic. Basal-like pathological features were present in 30 % of the tumors. Of the invasive carcinomas, 7 % were grade 1, 41 % grade 2, and 52 % grade 3. EZH2 protein was overexpressed in invasive carcinomas compared to benign breast (p < 0.0001). In invasive carcinomas nuclear EZH2 overexpression was significantly associated with basal like subtype (p = 0.03) and high histologic grade (p < 0.05). Cytoplasmic EZH2, which has not been previously reported, was present in 16 % of invasive carcinomas and it was associated with triple negative status (p = 0.02). Our results provide the first comprehensive histopathological study of this patient population and uncover the association of EZH2 with high grade and basal-like tumors. We provide the basis for further detailed investigations on this cohort to advance diagnosis and treatment of African and African-American women. PMID- 22527103 TI - Risk factors for uncommon histologic subtypes of breast cancer using centralized pathology review in the Breast Cancer Family Registry. AB - Epidemiologic studies of histologic types of breast cancer including mucinous, medullary, and tubular carcinomas have primarily relied on International Classification of Diseases-Oncology (ICD-O) codes assigned by local pathologists to define histology. Using data from the Breast Cancer Family Registry (BCFR), we compared histologic agreement between centralized BCFR pathology review and ICD-O codes available from local tumor registries among 3,260 breast cancer cases. Agreement was low to moderate for less common histologies; for example, only 55 and 26 % of cases classified as mucinous and medullary, respectively, by centralized review were similarly classified using ICD-O coding. We then evaluated risk factors for each histologic subtype by comparing each histologic case group defined by centralized review with a common set of 2,997 population based controls using polytomous logistic regression. Parity [odds ratio (OR) = 0.4, 95 % confidence interval (95 % CI): 0.2-0.9, for parous vs. nulliparous], age at menarche (OR = 0.5, 95 % CI: 0.3-0.9, for age >=13 vs. <=11), and use of oral contraceptives (OCs) (OR = 0.5, 95 % CI: 0.2-0.8, OC use >5 years vs. never) were associated with mucinous carcinoma (N = 92 cases). Body mass index (BMI) (OR = 1.05, 95 % CI: 1.0-1.1, per unit of BMI) and high parity (OR = 2.6, 95 % CI: 1.1-6.0 for >=3 live births vs. nulliparous) were associated with medullary carcinoma (N = 90 cases). We did not find any associations between breast cancer risk factors and tubular carcinoma (N = 86 cases). Relative risk estimates from analyses using ICD-O classifications of histology, rather than centralized review, resulted in attenuated, and/or more imprecise, associations. These findings suggest risk factor heterogeneity across breast cancer tumor histologies, and demonstrate the value of centralized pathology review for classifying rarer tumor types. PMID- 22527104 TI - Predisposition gene identification in common cancers by exome sequencing: insights from familial breast cancer. AB - The genetic component of breast cancer predisposition remains largely unexplained. Candidate gene case-control resequencing has identified predisposition genes characterised by rare, protein truncating mutations that confer moderate risks of disease. In theory, exome sequencing should yield additional genes of this class. Here, we explore the feasibility and design considerations of this approach. We performed exome sequencing in 50 individuals with familial breast cancer, applying frequency and protein function filters to identify variants most likely to be pathogenic. We identified 867,378 variants that passed the call quality filters of which 1,296 variants passed the frequency and protein truncation filters. The median number of validated, rare, protein truncating variants was 10 in individuals with, and without, mutations in known genes. The functional candidacy of mutated genes was similar in both groups. Without prior knowledge, the known genes would not have been recognisable as breast cancer predisposition genes. Everyone carries multiple rare mutations that are plausibly related to disease. Exome sequencing in common conditions will therefore require intelligent sample and variant prioritisation strategies in large case-control studies to deliver robust genetic evidence of disease association. PMID- 22527105 TI - Genetic polymorphisms in telomere pathway genes, telomere length, and breast cancer survival. AB - The impact of genetic variants in telomere pathway genes on telomere length and breast cancer survival remains unclear. We hypothesized that telomere length and genetic variants of telomere pathway genes are associated with survival among breast cancer patients. A population-based cohort study of 1,026 women diagnosed with a first primary breast cancer was conducted to examine telomere length and 52 genetic variants of 9 telomere pathway genes. Adjusted Cox regression analysis was employed to examine associations between telomere length, genetic variants and all-cause and breast cancer-specific mortality. Longer telomere length was significantly correlated with all-cause mortality in the subgroup with HER-2/neu negative tumors (HR=1.90, 95% CI: 1.12-3.22). Carrying the PINX1-33 (rs2277130) G allele was significantly associated with increased all-cause mortality (HR=1.45, 95% CI: 1.06-1.98). Three SNPs (TERF2-03 rs35439397, TERT-14 rs2853677, and TERT 67 rs2853669) were significantly associated with reduced all-cause mortality. A similar reduced trend for breast cancer-specific mortality was observed for carrying the TERT-14 (rs2853677) T-allele (HR=0.57, 95% CI: 0.39-0.84), while carrying the POT1-18 (rs1034794) T-allele significantly increased breast cancer specific mortality (HR=1.48, 95% CI: 1.00-2.19). However, none of the associations remained significant after correction for multiple tests. A significant dose-response effect was observed with increased number of unfavorable alleles/genotypes (PINX1-33 G-allele, POT1-18 T-allele, TERF2-03 GG, TERT-14 CC, and TERT-67 TT genotypes) and decreased survival. These data suggest that unfavorable genetic variants in telomere pathway genes may help to predict breast cancer survival. PMID- 22527107 TI - Predictors of functional shoulder recovery at 1 and 12 months after breast cancer surgery. AB - The objective of this study are (1) to determine if upper extremity function, as represented by shoulder ROM, self-reported symptoms and upper extremity functional limitations in activities of daily living could be predictively related to demographic and cancer characteristics post-surgery for breast cancer. And (2) to examine if variables related to early onset impairment contribute to late onset impairments in women after breast cancer surgery. Subjects were assessed preoperatively and 1, 3, 6, 9, and 12+ months post breast cancer surgery for impairments and symptoms and at 12+ months for shoulder functional limitations using a physical therapy surveillance model. Body weight, shoulder ROM, manual muscle testing, and upper limb volume were recorded. At 12+ months, the Harvard Alumni Health Study Physical Activity Questionnaire, and an Upper Limb Disability Questionnaire were administered. Symptoms and ROM impairments were compared by functional limitations. Characteristics significantly associated with early ROM impairment (but not later impairment) were axillary lymph node dissection, removal of >=15 nodes, mastectomy surgery and stage II breast cancer. Positive nodes, older age, and BMI>=25 were significantly associated with reduced shoulder ROM at 12+ months. At 12+ months, only 10 % of the patients experienced ROM impairments while rates of self-reported symptoms in the affected upper extremity at 12+ months were as follows: pain-49%, weakness-47.1%, numbness 55.9%, feeling tired-42.5%. The majority of patients used the affected upper extremity for reaching without limitation, but >=35% reported limitation with household chores, carrying and lifting. Difficulty carrying and lifting could be predicted by BMI>=25 and use of the dominant affected upper limb. Different factors are associated with early versus later ROM loss. Symptoms reported by breast cancer survivors are frequently associated with functional limitations in upper extremity tasks and warrant intervention. Physical therapy using a prospective surveillance model of care may reduce severity of ROM loss, symptoms and functional upper extremity limitations 1 year after breast cancer surgery. PMID- 22527106 TI - A prospective, multicenter, controlled, observational study to evaluate the efficacy of a patient support program in improving patients' persistence to adjuvant aromatase inhibitor medication for postmenopausal, early stage breast cancer. AB - Since the rate of persistence to adjuvant endocrine therapy such as 5-year aromatase inhibitors (AI) would decrease over time in patients with hormone sensitive breast cancer, it is necessary to investigate if a patient support program could modify patients' beliefs and improve their persistence to AI treatment. This was a prospective, multicenter, controlled, observational study to evaluate the efficacy of a patient support program in improving postmenopausal patients' persistence to adjuvant AI medication for early stage breast cancer (NCT00769080). The primary objective was to compare the rates of 1-year persistence to upfront adjuvant AI for patients in the two observational arms (standard treatment group and standard treatment plus patient support program group). In this study, 262 patients were enrolled in the standard treatment group and 241 patients in the standard treatment plus patient support program group. The mean 1-year persistence rates were 95.9 and 95.8% for the standard treatment group and the standard treatment plus patient support program group, respectively (P=0.95). The mean times to treatment discontinuation were 231.2 days in the standard treatment group and 227.8 days in the standard treatment plus patient support program group, with no statistically significant difference between the two groups (P=0.96). There was also no statistically significant difference in the reason for treatment discontinuation (P=0.32). There was a significant relationship between the patient centered care questionnaire and poor persistence (odds ratio=3.9; 95% CI, 1.1-13.7; P=0.035), suggesting that the persistence rate of patients with whom the doctor always or usually spends time is greater than that of patients with whom the doctor sometimes or never spends time. Patients' persistence to adjuvant AI medication for postmenopausal, early stage breast cancer is relatively high in the first year and is not significantly increased by adding a patient support program to standard treatment. PMID- 22527108 TI - Clinical and pathologic characteristics of BRCA-positive and BRCA-negative male breast cancer patients: results from a collaborative multicenter study in Italy. AB - Recently, the number of studies on male breast cancer (MBC) has been increasing. However, as MBC is a rare disease there are difficulties to undertake studies to identify specific MBC subgroups. At present, it is still largely unknown whether BRCA-related breast cancer (BC) in men may display specific characteristics as it is for BRCA-related BC in women. To investigate the clinical-pathologic features of MBC in association with BRCA mutations we established a collaborative Italian Multicenter Study on MBC with the aim to recruit a large series of MBCs. A total of 382 MBCs, including 50 BRCA carriers, were collected from ten Italian Investigation Centres covering the whole country. In MBC patients, BRCA2 mutations were associated with family history of breast/ovarian cancer (p<0.0001), personal history of other cancers (p=0.044) and contralateral BC (p=0.001). BRCA2-associated MBCs presented with high tumor grade (p=0.001), PR (p=0.026) and HER2+ (p=0.001) status. In a multivariate logistic model BRCA2 mutations showed positive association with personal history of other cancers (OR 11.42, 95% CI 1.79-73.08) and high tumor grade (OR 4.93, 95% CI 1.02-23.88) and inverse association with PR+ status (OR 0.19, 95% CI 0.04-0.92). Based on immunohistochemical (IHC) profile, four molecular subtypes of MBC were identified. Luminal A was the most common subtype (67.7%), luminal B was observed in 26.5% of the cases and HER2 positive and triple negative were represented by 2.1% and 3.7% of tumors, respectively. Intriguingly, we found that both luminal B and HER2 positive subtypes were associated with high tumor grade (p=0.003 and 0.006, respectively) and with BRCA2 mutations (p=0.016 and 0.001, respectively). In conclusion, our findings indicate that BRCA2-related MBCs represent a subgroup of tumors with a peculiar phenotype characterized by aggressive behavior. The identification of a BRCA2-associated phenotype might define a subset of MBC patients eligible for personalized clinical management. PMID- 22527109 TI - Assessment accuracy of core needle biopsy for hormone receptors in breast cancer: a meta-analysis. AB - The concordance of hormone receptors (HR) status identified by core needle biopsy (CNB) compared with excisional biopsy (EB) has been widely reported, but results were extremely variable and underpowered. To derive a more precise estimation of assessment accuracy of CNB for HR in breast cancer, we conducted a meta-analysis of all eligible studies comparing concordance or disconcordance between CNB and EB for HR status. Eligible articles were identified by search of databases including PubMed, Web of Science, EMBASE, and Chinese Biomedical Literature database for the period up to November 2011, and the reference lists of identified studies, relevant reviews, meta-analyses, and abstracts from recent conference proceedings were reviewed as a augmented searching. Finally, a total of 21 articles involving 2,450 patients for estrogen receptor (ER) and 2,448 patients for progesterone receptor (PR) were included and analyzed in this analysis. Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies checklist. The overall aggrement between CNB and EB were 92.8 % for ER (kappa = 0.78) and 85.2 % for PR (kappa = 0.66), indicating a good agreement in PR and a better result in ER. The pooled sensitivity and specificity were 97.3 % (95 % CI 96.0-98.2) and 82.0 % (95 % CI 68.2-90.6) for ER, and the corresponding values for PR were 92.3 % (95 % CI 88.2-95.1) and 76.5 % (95 % CI 64.6-85.3), respectively. The pooled positive likelihood ratios was 5.39 % (95 % CI 2.92-9.97) and the negative likelihood ratios was 0.03 % (95 % CI 0.02-0.05) for ER, the corresponding values for PR were 3.93 % (95 % CI 2.53-6.11) and 0.10 % (95 % CI 0.07-0.16), respectively. In summary, although a good agreement was observed between CNB and EB for both ER and PR, we still suggest that negative HR testing results should be interpreted with caution or repeated on EB. PMID- 22527110 TI - Letter in response: the value of mammography screening. PMID- 22527112 TI - Therapeutic implications of estrogen receptor signaling in HER2-positive breast cancers. AB - There is considerable pre-clinical and clinical evidence demonstrating that HER2 positive breast cancers that express estrogen receptor (ER) exhibit intrinsic resistance to endocrine therapy. Therefore, in general, chemotherapy in combination with HER2-directed agents is recommended for all but the smallest HER2-positive early stage breast cancers regardless of ER status. This paradigm has recently come into question when responses to neo-adjuvant HER2-directed regimens were noted to vary based on ER expression, and pathologic complete response was noted not to be prognostic for ER-positive, HER2-positive breast cancers. These and other data suggest the possibility that a subset of HER2 positive, ER-positive breast cancers are driven primarily by ER, and biologically behave more like HER2-negative, ER-positive breast cancers. Identification of this subset of HER2-positive breast cancers is essential to avoid over-treatment of patients with small HER2-positive, ER-positive breast cancers, who may be optimally treated with endocrine therapy alone, or in combination with a HER2 directed agent, thereby avoiding the use of chemotherapy. Crosstalk between the ER and HER2 pathways has been established as playing a role in both intrinsic and acquired resistance to endocrine agents. Emerging data suggests that crosstalk between these pathways is also involved in resistance to HER2-directed agents. Unraveling the role of the ER pathway in resistance to HER2-directed agents could potentially result in therapeutic approaches that can improve outcome for patients with ER-positive, HER2-positive breast cancer. PMID- 22527111 TI - Non-initiation of adjuvant hormonal therapy in women with hormone receptor positive breast cancer: The Breast Cancer Quality of Care Study (BQUAL). AB - Adjuvant hormonal therapy for non-metastatic hormone receptor (HR)-positive breast cancer decreases risk of breast cancer recurrence and increases survival. However, some women do not initiate this life-saving treatment. We used a prospective cohort design to investigate factors related to non-initiation of hormonal therapy among women with newly diagnosed, non-metastatic HR-positive breast cancer recruited from three U.S. sites. Serial interviews were conducted at baseline and during treatment to examine sociodemographic factors, tumor characteristics, and treatment decision-making factors. Multivariate modeling assessed associations between variables of interest and hormonal therapy initiation. Of 1,050 breast cancer patients recruited, 725 (69%) had HR-positive breast cancer, of whom 87 (12.0%) based on self-report and 122 (16.8%) based on medical record/pharmacy fill rates did not initiate hormonal therapy. In a multivariable analysis, non-initiation of hormonal therapy, defined by medical record/pharmacy, was associated with having greater negative beliefs about efficacy of treatment (OR 1.42, 95% CI 1.18-1.70). Non-initiation was less likely in those who found the quality of patient/physician communication to be higher (OR 0.96, 95% CI 0.93-0.99), the hormonal therapy treatment decision an easy one to make (OR 0.45, 95% CI 0.23-0.90) or neither easy nor difficult (OR 0.34, 95% CI 0.20-0.58); and had more positive beliefs about hormonal therapy efficacy (OR 0.40, 95% CI 0.34-0.62). Factors influencing non-initiation of adjuvant hormonal therapy are complex and influenced by patient beliefs regarding treatment efficacy and side effects. Educational interventions to women about the benefits of hormonal therapy may decrease negative beliefs and increase hormone therapy initiation. PMID- 22527113 TI - Plant rDNA database: ribosomal DNA loci information goes online. AB - Number, position and structure of the 5S and 18S-5.8S-26S ribosomal DNA (rDNA) loci are important species characteristics. In recent decades, we have witnessed accumulation of rDNA data, and there is a need to compile, store and analyse this information, and to make it accessible to a broader scientific community. An online resource, accessible at www.plantrdnadatabase.com , has been developed to accomplish these goals. Current knowledge regarding chromosomal rDNA sites is provided for more than 1,000 plant species (including more than 1,400 different accessions). The data comes from fluorescent in situ hybridisation experiments (FISH) from more than 300 publications. Additional information is also displayed, such as ploidy level, mutual arrangement of rRNA genes, genome size and life cycle. The webpage is intuitive and user-friendly, including different search options, and currently holds information published (or in press) up until January 2011; frequent updates are planned. We expect this database to be used for data mining, analysing rDNAs from different angles, unit organisation, distribution, evolution and linkage of rDNA patterns with phylogenetic relationships. PMID- 22527116 TI - Spatial distribution and controlling factors of heavy metals contents in paddy soil and crop grains of rice-wheat cropping system along highway in East China. AB - There is consensus concerning the heavy metal pollution from traffic emission on roadside agricultural land. However, few efforts have been paid on examining the contamination characteristics of heavy metals in roadside paddy-upland rotation field, and especially in combination with detailed quantitative analysis. In this study, we investigated the concentrations of heavy metals (Pb, Cd, Cr and Zn) in soil and crop grains of the rice-wheat cropping system along a major highway in East China in 2008 and analyzed the spatial distribution characteristics of heavy metals and their influencing factors with GIS and Classification and Regression Trees (CART). Significantly elevated levels of heavy metals in soil, rice and wheat grains indicated the heavy metals contamination of traffic emission in roadside rice-wheat rotation field. The contamination levels of Cd, Cr and Zn in wheat grain were higher than rice grain, while that of Pb showed an opposite trend. Obvious dissimilarities in the spatial distributions of heavy metals contents were found between in the soil, rice and wheat grains, indicating that the heavy metals contents in the roadside crop grains were not only determined by the concentrations of heavy metals in the paddy soil. Results of CART analysis showed that the spatial variation of the heavy metals contents in crop grains was mainly affected by the soil organic matter or soil pH, followed by the distance from highway and wind direction. Our findings have important implications for the environmental assessment and crop planning for food security along the highway. PMID- 22527114 TI - The evolutionary life cycle of the resilient centromere. AB - The centromere is a chromosomal structure that is essential for the accurate segregation of replicated eukaryotic chromosomes to daughter cells. In most centromeres, the underlying DNA is principally made up of repetitive DNA elements, such as tandemly repeated satellite DNA and retrotransposable elements. Paradoxically, for such an essential genomic region, the DNA is rapidly evolving both within and between species. In this review, we show that the centromere locus is a resilient structure that can undergo evolutionary cycles of birth, growth, maturity, death and resurrection. The birth phase is highlighted by examples in humans and other organisms where centromere DNA deletions or chromosome rearrangements can trigger the epigenetic assembly of neocentromeres onto genomic sites without typical features of centromere DNA. In addition, functional centromeres can be generated in the laboratory using various methodologies. Recent mapping of the foundation centromere mark, the histone H3 variant CENP-A, onto near-complete genomes has uncovered examples of new centromeres which have not accumulated centromere repeat DNA. During the growth period of the centromere, repeat DNA begins to appear at some, but not all, loci. The maturity stage is characterised by centromere repeat accumulation, expansions and contractions and the rapid evolution of the centromere DNA between chromosomes of the same species and between species. This stage provides inherent centromere stability, facilitated by repression of gene activity and meiotic recombination at and around the centromeres. Death to a centromere can result from genomic instability precipitating rearrangements, deletions, accumulation of mutations and the loss of essential centromere binding proteins. Surprisingly, ancestral centromeres can undergo resurrection either in the field or in the laboratory, via as yet poorly understood mechanisms. The underlying principle for the preservation of a centromeric evolutionary life cycle is to provide resilience and perpetuity for the all-important structure and function of the centromere. PMID- 22527115 TI - On the regulation, function, and localization of the DNA-dependent ATPase PICH. AB - The putative chromatin remodeling enzyme Plk1-interacting checkpoint helicase (PICH) was discovered as an interaction partner and substrate of the mitotic kinase Plk1. During mitosis PICH associates with centromeres and kinetochores and, most interestingly, constitutes a robust marker for ultrafine DNA bridges (UFBs) that connect separating chromatids in anaphase cells. The precise roles of PICH remain to be clarified. Here, we have used antibody microinjection and siRNA rescue experiments to study PICH function and localization during M phase progression, with particular emphasis on the role of the predicted ATPase domain and the regulation of PICH localization by Plk1. We show that interference with PICH function results in chromatin bridge formation and micronucleation and that ATPase activity is critical for PICH function. Interestingly, an intact ATPase domain of PICH is required for prevention of chromatin bridge formation but not for UFB resolution, and quantitative analyses of UFB and chromatin bridge frequencies suggest that these structures are of different etiologies. We also show that the ATPase activity of PICH is required for temporal and spatial control of PICH localization to chromatin and that Plk1 likely controls PICH localization through phosphorylation of proteins distinct from PICH itself. This work strengthens the view that PICH is an important, Plk1-regulated enzyme, whose ATPase activity is essential for maintenance of genome integrity. Although not required for the spindle assembly checkpoint, PICH is clearly important for faithful chromosome segregation. PMID- 22527117 TI - PAHs in indoor dust samples in Shanghai's universities: levels, sources and human exposure. AB - Given the significant amount of time people spend indoors, the occurrence of polycyclic aromatic hydrocarbons (PAHs) in indoor dust and their potential risks are of great concern. In the present study, ten dust samples from lecture theatres and twelve samples from dining halls were collected from university campuses in Shanghai to investigate the PAH levels, possible sources and human exposure. The total concentrations of 18 PAHs ranged from 9.84 to 21.44 MUg/g for dust samples from lecture theatres, and 9.63-44.13 MUg/g for samples from dining halls. Total PAH concentrations in indoor dust samples showed a better correlation to black carbon compared to total organic carbon contents. PAHs in dining halls samples showed a similar distribution pattern with that of commercial kitchen air, which indicated that cooking activities could contribute most of the PAHs found in dining halls. Principal component analysis revealed both petrogenic and pyrogenic sources. The potential health risk for PAHs was assessed in terms of BaP equivalent carcinogenic power and estimated daily intake (EDI). Relatively high EDI values compared to other studies suggested that PAHs posed a potential threat to human health in indoor environments at Shanghai's universities. PMID- 22527119 TI - fMRI and corpus callosum relationships in monozygotic twins discordant for handedness. AB - To further investigate brain structure and function in 26 handedness discordant monozygotic twin pairs (MzHd), MRI and behavioural assessments were carried out. These showed significant correlation between language-specific functional laterality in inferior and middle frontal gyri, and anterior corpus callosum. Previous studies of handedness discordant monozygotic twins failed to resolve the issue concerning handedness and hemispheric laterality for language due to methodological disparities. The results would be relevant to genetic theories as well as to brain structure:function explanations. MzHd twins underwent MRI and fMRI scanning as well as behavioural assessment of motor performance and cognition. There were significant differences on MRI and fMRI laterality measures, as well as a significant correlation between anterior callosal widths and functional laterality. LH twins showed higher frequencies of atypical functional laterality. There was no significant within-twin pair correlation on fMRI verbal laterality, nor did results show within-twin pair differences on verbal fluency or IQ. Implications for the field of laterality research pertain to frontal hemispheric equipotentiality for verbal processes in healthy individuals. In particular, there can be an apparent lack of cognitive 'cost' to atypical laterality. An fMRI verbal laterality index correlated significantly with corpus callosum widths near Broca's area. PMID- 22527120 TI - The sea lamprey tryptophan hydroxylase: new insight into the evolution of the serotonergic system of vertebrates. AB - Recent research has shown that at least two tryptophan hydroxylase (Tph) genes are present in gnathostome vertebrates, but it is not known when the duplication of the ancestral Tph gene took place during evolution. By their position as an out-group of gnathostomes, lampreys (agnathans) are key models to understand molecular evolution in vertebrates. Here, we report the cloning of a Tph cDNA of the sea lamprey and the pattern of Tph mRNA expression in larval and postmetamorphic (young adult) sea lampreys using in situ hybridization. Phylogenetic analysis indicated that the lamprey Tph is an orthologue of Tphs of other vertebrates and suggested that the duplication of the ancestral Tph gene occurred before the separation of agnathans and gnathostomes, although alternative hypothesis are also discussed in the present study. In the sea lamprey brain, the Tph transcript was expressed in perikarya of the pineal organ, the retina, the diencephalic and rhombencephalic nuclei reported previously with serotonin immunohistochemistry and in small cells of the spinal cord, with a pattern similar to that observed with anti-serotonin antibodies. This suggests that expression of this Tph gene is shared by all lamprey serotonergic brain populations, unlike that reported in zebrafish and mammals for their different Tph genes. However, no Tph expression was observed in peripheral serotonergic cells, which, unlike in other vertebrates, are widely distributed in lampreys. Our results suggest that the selection of Tph2 to be expressed in raphe neurons may have occurred along the line leading to gnathostomes. PMID- 22527118 TI - Serotonergic innervation and serotonin receptor expression of NPY-producing neurons in the rat lateral and basolateral amygdaloid nuclei. AB - Pharmacobehavioral studies in experimental animals, and imaging studies in humans, indicate that serotonergic transmission in the amygdala plays a key role in emotional processing, especially for anxiety-related stimuli. The lateral and basolateral amygdaloid nuclei receive a dense serotonergic innervation in all species studied to date. We investigated interrelations between serotonergic afferents and neuropeptide Y (NPY)-producing neurons, which are a subpopulation of inhibitory interneurons in the rat lateral and basolateral nuclei with particularly strong anxiolytic properties. Dual light microscopic immunolabeling showed numerous appositions of serotonergic afferents on NPY-immunoreactive somata. Using electron microscopy, direct membrane appositions and synaptic contacts between serotonin-containing axon terminals and NPY-immunoreactive cellular profiles were unequivocally established. Double in situ hybridization documented that more than 50 %, and about 30-40 % of NPY mRNA-producing neurons, co-expressed inhibitory 5-HT1A and excitatory 5-HT2C mRNA receptor subtype mRNA, respectively, in both nuclei with no gender differences. Triple in situ hybridization showed that individual NPY mRNA-producing interneurons co-express both 5-HT1A and 5-HT2C mRNAs. Co-expression of NPY and 5-HT3 mRNA was not observed. The results demonstrate that serotonergic afferents provide substantial innervation of NPY-producing neurons in the rat lateral and basolateral amygdaloid nuclei. Studies of serotonin receptor subtype co-expression indicate a differential impact of the serotonergic innervation on this small, but important, population of anxiolytic interneurons, and provide the basis for future studies of the circuitry underlying serotonergic modulation of emotional stimulus processing in the amygdala. PMID- 22527122 TI - Immunocytochemical characterization of olfactory ensheathing cells in fish. AB - In the olfactory system of vertebrates, neurogenesis occurs throughout life. The regenerating activities of the olfactory receptor neurons are connected to particular glial cells in the olfactory pathway: the olfactory ensheathing cells. A considerable number of studies are available in literature regarding mammalian olfactory ensheathing cells; this is due to their potential role in cell-based therapy for spinal cord injury repair. But very little is known about these cells in non-mammalian vertebrates. In this study we examined the immunocytochemical characteristics of the olfactory ensheathing cells in fish, which provide a good model for the study of glial cells in the olfactory pathway of non-mammalian vertebrates. Paraffin sections from decalcified heads of Poecilia reticulata (microsmatic fish) and Carassius auratus (macrosmatic fish) were processed to immunocytochemically detect ensheathing cell markers used in research on mammals: GFAP, S100, NCAM, PSA-NCAM, vimentin, p75NTR and galectin-1. GFAP, S100 and NCAM were clearly detected in both fish, though the intracranial tract of the primary olfactory pathway of Carassius appears more S100 stained than the extracranial tract. P75NTR staining is more evident in Poecilia, PSA-NCAM positivity in Carassius. A slight vimentin immunostaining was detected only in Carassius. No galectin-1 staining appeared in the olfactory pathways of either fish. This study shows that some markers for mammalian olfactory ensheathing cells also stain the olfactory pathway in fish. Immunocytochemical staining differs in the two fish under examination, even along the various tracts of the olfactory pathway in the same species. PMID- 22527121 TI - Mapping of the mouse olfactory system with manganese-enhanced magnetic resonance imaging and diffusion tensor imaging. AB - As the power of studying mouse genetics and behavior advances, research tools to examine systems level connectivity in the mouse are critically needed. In this study, we compared statistical mapping of the olfactory system in adult mice using manganese-enhanced MRI (MEMRI) and diffusion tensor imaging (DTI) with probabilistic tractography. The primary goal was to determine whether these complementary techniques can determine mouse olfactory bulb (OB) connectivity consistent with known anatomical connections. For MEMRI, 3D T1-weighted images were acquired before and after bilateral nasal administration of MnCl(2) solution. Concomitantly, high-resolution diffusion-tensor images were obtained ex vivo from a second group of mice and processed with a probabilistic tractography algorithm originating in the OB. Incidence maps were created by co-registering and overlaying data from the two scan modalities. The resulting maps clearly show pathways between the OB and amygdala, piriform cortex, caudate putamen, and olfactory cortex in both the DTI and MEMRI techniques that are consistent with the known anatomical connections. These data demonstrate that MEMRI and DTI are complementary, high-resolution neuroimaging tools that can be applied to mouse genetic models of olfactory and limbic system connectivity. PMID- 22527123 TI - Circadian clock components in the rat neocortex: daily dynamics, localization and regulation. AB - The circadian master clock of the mammalian brain resides in the suprachiasmatic nucleus (SCN) of the hypothalamus. At the molecular level, the clock of the SCN is driven by a transcriptional/posttranslational autoregulatory network with clock gene products as core elements. Recent investigations have shown the presence of peripheral clocks in extra-hypothalamic areas of the central nervous system. However, knowledge on the clock gene network in the cerebral cortex is limited. We here show that the mammalian clock genes Per1, Per2, Per3, Cry1, Cry2, Bmal1, Clock, Nr1d1 and Dbp are expressed in the rat neocortex. Among these, Per1, Per2, Per3, Cry1, Bmal1, Nr1d1 and Dbp were found to exhibit daily rhythms. The amplitude of circadian oscillation in neocortical clock gene expression was damped and the peak delayed as compared with the SCN. Lesions of the SCN revealed that rhythmic clock gene expression in the neocortex is dependent on the SCN. In situ hybridization and immunohistochemistry showed that products of the canonical clock gene Per2 are located in perikarya throughout all areas of the neocortex. These findings show that local circadian oscillators driven by the SCN reside within neurons of the neocortex. PMID- 22527124 TI - Co-culture of apoptotic breast cancer cells with immature dendritic cells: a novel approach for DC-based vaccination in breast cancer. AB - A dendritic cell (DC)-based vaccine strategy could reduce the risk of recurrence and improve the survival of breast cancer patients. However, while therapy induced apoptosis of hepatocellular and colorectal carcinoma cells can enhance maturation and antigen presentation of DCs, whether this effect occurs in breast cancer is currently unknown. In the present study, we investigated the effect of doxorubicin (ADM)-induced apoptotic MCF-7 breast cancer cells on the activation of DCs. ADM-induced apoptotic MCF-7 cells could effectively induce immature DC (iDC) maturation. The mean fluorescence intensity (MFI) of DC maturity marker CD83 was 23.3 in the ADM-induced apoptotic MCF-7 cell group compared with 8.5 in the MCF-7 cell group. The MFI of DC co-stimulatory marker CD86 and HLA-DR were also increased after iDCs were treated with ADM-induced apoptotic MCF-7 cells. Furthermore, the proliferating autologous T-lymphocytes increased from 14.2 to 40.3% after incubated with DCs induced by apoptotic MCF-7 cells. The secretion of interferon-gamma by these T-lymphocytes was also increased. In addition, cell cell interaction between apoptotic MCF-7 cells and iDCs, but not soluble factors released by apoptotic MCF-7 cells, was crucial for the maturation of iDCs. These findings constitute a novel in vitro DC-based vaccine strategy for the treatment of breast cancer by ADM-induced apoptotic MCF-7 cells. PMID- 22527125 TI - Correlations of circulating peptide YY and ghrelin with body weight, rate of weight gain, and time required to achieve the recommended daily intake in preterm infants. AB - The objective was to elucidate the relationships between serum concentrations of the gut hormone peptide YY (PYY) and ghrelin and growth development in infants for potential application to the clinical observation index. Serum concentrations of PYY and ghrelin were measured using radioimmunoassay from samples collected at the clinic. For each patient, gestational age, birth weight, time required to return to birth weight, rate of weight gain, time required to achieve recommended daily intake (RDI) standards, time required for full-gastric feeding, duration of hospitalization, and time of administration of total parenteral nutrition were recorded. Serum PYY and ghrelin concentrations were significantly higher in the preterm group (N = 20) than in the full-term group (N = 20; P < 0.01). Within the preterm infant group, the serum concentrations of PYY and ghrelin on postnatal day (PND) 7 (ghrelin = 1485.38 +/- 409.24; PYY = 812.37 +/- 153.77 ng/L) were significantly higher than on PND 1 (ghrelin = 956.85 +/- 223.09; PYY = 545.27 +/- 204.51 ng/L) or PND 3 (ghrelin = 1108.44 +/- 351.36; PYY = 628.96 +/- 235.63 ng/L; P < 0.01). Both serum PYY and ghrelin concentrations were negatively correlated with body weight, and the degree of correlation varied with age. Serum ghrelin concentration correlated negatively with birth weight and positively with the time required to achieve RDI (P < 0.05). In conclusion, serum PYY and ghrelin concentrations reflect a negative energy balance, predict postnatal growth, and enable compensation. Further studies are required to elucidate the precise concentration and roles of PYY and ghrelin in newborns and to determine the usefulness of measuring these hormones in clinical practice. PMID- 22527126 TI - Micronucleated lymphocytes in parents of Down syndrome children. AB - Down syndrome (DS) is the most common disease due to an autosomal aneuploidy in live born children and also the major known genetic cause of mental retardation. The risk of a DS pregnancy increases substantially with increasing maternal age. However, several women aged less than 35 years at conception have a child with DS. The micronucleus (MN) assay can identify chromosome breakage or chromosome malsegregation and is an ideal biomarker to investigate genomic instability. The aim of the present study was to determine the frequency of peripheral lymphocytes with MN in the parents of DS individuals. The subjects were 17 couples, 1 father and 9 mothers, and 24 couples who had at least one healthy child formed the control group. For each individual we evaluated the frequency of binucleated micronucleated lymphocytes (BNMN%) as number of binucleated lymphocytes containing one or more MN per 1000 binucleated cells. The mean age of DS parents and controls was 32.6 and 29.8 years, respectively. The frequency of MN in DS parents was significantly higher compared to controls. The higher frequency of MN in DS parents suggests a higher predisposition of DS parents to aneuploidy events in this sample. PMID- 22527127 TI - Pain pressure threshold algometry of the abdominal wall in healthy women. AB - The objective of this study was to determine the inter- and intra-examiner reliability of pain pressure threshold algometry at various points of the abdominal wall of healthy women. Twenty-one healthy women in menacme with a mean age of 28 +/- 5.4 years (range: 19-39 years) were included. All volunteers had regular menstrual cycles (27-33 days) and were right-handed and, to the best of our knowledge, none were taking medications at the time of testing. Women with a diagnosis of depression, anxiety or other mood disturbances were excluded. Women with previous abdominal surgery, any pain condition or any evidence of inflammation, hypertension, smoking, alcoholism, or inflammatory disease were also excluded. Pain perception thresholds were assessed with a pressure algometer with digital traction and compression and a measuring capacity for 5 kg. All points were localized by palpation and marked with a felt-tipped pen and each individual was evaluated over a period of 2 days in two consecutive sessions, each session consisting of a set of 14 point measurements repeated twice by two examiners in random sequence. There was no statistically significant difference in the mean pain threshold obtained by the two examiners on 2 different days (examiner A: P = 1.00; examiner B: P = 0.75; Wilcoxon matched pairs test). There was excellent/good agreement between examiners for all days and all points. Our results have established baseline values to which future researchers will be able to refer. They show that pressure algometry is a reliable measure for pain perception in the abdominal wall of healthy women. PMID- 22527128 TI - Emergence of clonal complex 5 (CC5) methicillin-resistant Staphylococcus aureus (MRSA) isolates susceptible to trimethoprim-sulfamethoxazole in a Brazilian hospital. AB - In this study, genotyping techniques including staphylococcal chromosomal cassette mec (SCCmec) typing, pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST) and restriction-modification tests were used to compare the molecular characteristics of methicillin-resistant Staphylococcus aureus (MRSA) isolates recovered at two times within a 10-year interval (1998 and 2008) from a tertiary Brazilian hospital. In addition, the antimicrobial susceptibility profiles were analyzed. All 48 MRSA isolates from 1998 and 85.7% from 2008 (48/56 isolates) displayed multidrug-resistance phenotypes and SCCmec III. All but one of the 13 representative SCCmec III isolates belonged to CC8 and had PFGE patterns similar to that of the BMB9393 strain (Brazilian epidemic clone of MRSA; BEC). In 2008, we found an increased susceptibility to rifampicin and chloramphenicol among the SCCmec III isolates. In addition, we detected the entrance of diverse international MRSA lineages susceptible to trimethoprim sulfamethoxazole (SXT), almost all belonging to CC5. These non-SCCmec III isolates were related to the USA 300 (ST8-SCCmec IV; PFGE-type B), USA 800 (ST5 SCCmec IV; subtype D1), USA 100 (ST5-SCCmec II; subtype D2), and EMRSA-3/Cordobes (ST5-SCCmec I, type C) clones. To the best of our knowledge, this is the first report of the emergence of isolates genetically related to the EMRSA-3/Cordobes clone in southeast Brazil. In this regard, these isolates were the most common non-SCCmec III MRSA in our institution, accounting for 8.9% of all isolates recovered in 2008. Thus, despite the supremacy of BEC isolates in our country, significant changes may occur in local MRSA epidemiology, with possible consequences for the rationality of MRSA empiric therapy. PMID- 22527129 TI - Vascular dysfunction by myofibroblast activation in patients with idiopathic pulmonary fibrosis and prognostic significance. AB - In this study, we demonstrated the importance of telomerase protein expression and determined the relationships among telomerase, endothelin-1 (ET-1) and myofibroblasts during early and late remodeling of parenchymal and vascular areas in usual interstitial pneumonia (UIP) using 27 surgical lung biopsies from patients with idiopathic pulmonary fibrosis (IPF). Telomerase+, myofibroblasts alpha-SMA+, smooth muscle cells caldesmon+, endothelium ET-1+ cellularity, and fibrosis severity were evaluated in 30 fields covering normal lung parenchyma, minimal fibrosis (fibroblastic foci), severe (mural) fibrosis, and vascular areas of UIP by the point-counting technique and a semiquantitative score. The impact of these markers was determined in pulmonary functional tests and follow-up until death from IPF. Telomerase and ET-1 expression was significantly increased in normal and vascular areas compared to areas of fibroblast foci. Telomerase and ET 1 expression was inversely correlated with minimal fibrosis in areas of fibroblast foci and directly associated with severe fibrosis in vascular areas. Telomerase activity in minimal fibrosis areas was directly associated with diffusing capacity of the lung for oxygen/alveolar volume and ET-1 expression and indirectly associated with diffusing capacity of the lungs for carbon monoxide and severe fibrosis in vascular areas. Cox proportional hazards regression revealed a low risk of death for females with minimal fibrosis displaying high telomerase and ET-1 expression in normal areas. Vascular dysfunction by telomerase/ET-1 expression was found earlier than vascular remodeling by myofibroblast activation in UIP with impact on IPF evolution, suggesting that strategies aimed at preventing the effect of these mediators may have a greater impact on patient outcome. PMID- 22527131 TI - Tissue transglutaminase (TG2) activity regulates osteoblast differentiation and mineralization in the SAOS-2 cell line. AB - Tissue transglutaminase (type II, TG2) has long been postulated to directly promote skeletal matrix calcification and play an important role in ossification. However, limited information is available on the expression, function and modulating mechanism of TG2 during osteoblast differentiation and mineralization. To address these issues, we cultured the well-established human osteosarcoma cell line SAOS-2 with osteo-inductive conditioned medium and set up three time points (culture days 4, 7, and 14) to represent different stages of SAOS-2 differentiation. Osteoblast markers, mineralization, as well as TG2 expression and activity, were then assayed in each stage. Furthermore, we inhibited TG activity with cystamine and then checked SAOS-2 differentiation and mineralization in each stage. The results showed that during the progression of osteoblast differentiation SAOS-2 cells presented significantly high levels of osteocalcin (OC) mRNA, bone morphogenetic protein-2 (BMP-2) and collagen I, significantly high alkaline phosphatase (ALP) activity, and the increased formation of calcified matrix. With the same tendency, TG2 expression and activity were up-regulated. Furthermore, inhibition of TG activity resulted in a significant decrease of OC, collagen I, and BMP-2 mRNA and of ALP activity and mineralization. This study demonstrated that TG2 is involved in osteoblast differentiation and may play a role in the initiation and regulation of the mineralization processes. Moreover, the modulating effects of TG2 on osteoblasts may be related to BMP-2. PMID- 22527130 TI - Human prophylactic vaccine adjuvants and their determinant role in new vaccine formulations. AB - Adjuvants have been considered for a long time to be an accessory and empirical component of vaccine formulations. However, accumulating evidence of their crucial role in initiating and directing the immune response has increased our awareness of the importance of adjuvant research in the past decade. Nevertheless, the importance of adjuvants still is not fully realized by many researchers working in the vaccine field, who are involved mostly in the search for better target antigens. The choice of a proper adjuvant can be determinant for obtaining the best results for a given vaccine candidate, but it is restricted due to intellectual property and know-how issues. Consequently, in most cases the selected adjuvant continues to be the aluminum salt, which has a record of safety, but predominantly constitutes a delivery system (DS). Ideally, new strategies should combine immune potentiators (IP) and DS by mixing both compounds or by obtaining structures that contain both IP and DS. In addition, the term immune polarizer has been introduced as an essential concept in the vaccine design strategies. Here, we review the theme, with emphasis on the discussion of the few licensed new adjuvants, the need for safe mucosal adjuvants and the adjuvant/immunopotentiating activity of conjugation. A summary of toxicology and regulatory issues will also be discussed, and the Finlay Adjuvant Platform is briefly summarized. PMID- 22527133 TI - Behcet's disease seen in China: analysis of 334 cases. AB - For the purpose of investigating Behcet's disease in China, all the patients diagnosed as Behcet's disease in our hospital during the past 2 years were recruited into the study. The clinical and laboratory data of the patients were recorded and further analyzed; 334 patients were included with 195 males and 139 females. The mean age at onset was 35.8 +/- 11.1 years. The most frequent initial manifestations were oral aphthae and genital ulceration. The common manifestations observed throughout the disease course were oral aphthae, genital ulceration and various cutaneous lesions. Besides these, many organs/systems including joint, eye, vessel, gastrointestine, nervous system, cardiovascular system, and pulmonary system were also involved in 28.4, 26.1, 17.4, 16.8, 9.6, 8.1, and 4.8 % of our patients, respectively. Involvement of ocular and vascular was more common in males than in females. Behcet' disease most frequently affects the Chinese patients aged 30-39 and displays a wide clinical spectrum with varieties of severe internal organ involvement. The disease is more common and severe in males than in females in Chinese populations. PMID- 22527134 TI - IL-32 aggravates synovial inflammation and bone destruction and increases synovial natural killer cells in experimental arthritis models. AB - This study was performed to investigate the effects of IL-32 on joint inflammation, bone destruction, and synovial cytokine expressions, and on synovial natural killer (NK) cell expressions in collagen-induced arthritis (CIA). CIA was induced by type II collagen in DBA1 mice, and phosphate-buffered saline (PBS group) or IL-32 (IL-32 group) were injected into both knee joints at day 28 and 32, then mice were killed at day 35. Severity of synovial inflammation and bone destruction was determined by histological scoring method, and synovial cytokine expressions such as IL-1beta, TNF-alpha, IL-17, IL-18, IFN-gamma, IL-21, and IL-23 were measured by real-time RT-PCR and western blot. Synovial NK cell expressions were determined by real-time RT-PCR, western blot and immunohistochemistry, and chemokines and chemokine receptors expressions that are associated with NK cell migration were determined by real-time RT-PCR. Scores of synovial inflammation and bone destruction, synovial expressions of IL-1beta, TNF alpha, IL-18, and IFN-gamma were significantly increased in IL-32 group compared with PBS group. Synovial expressions of NK cell, and chemokines (CCL2 and CXCL9) and chemokine receptors (CCR2 and CCR5) that are associated with NK cell migration were significantly increased in IL-32 group compared with PBS group. IL 32 aggravated joint inflammation and bone destruction and increased synovial expressions of inflammatory cytokine and NK cells in CIA. These results suggest that IL-32 play a role in joint inflammation and bone destruction, and IL-32 might be a new target for treatment of rheumatoid arthritis. PMID- 22527135 TI - Efficacy of supervised exercise combined with transcutaneous electrical nerve stimulation in women with fibromyalgia: a prospective controlled study. AB - The aim of this study was to investigate the results of a supervised exercise with transcutaneous electrical nerve stimulation (TENS) in an exercise controlled study in women with fibromyalgia. Sixty-six women with fibromyalgia who admitted to the outpatient clinic of our hospital were randomized into two treatment groups. The patients in both groups participated in a supervised combined exercise program for 12 weeks. The women in first group had additional TENS in the first 3 weeks of the study. All subjects were analyzed at the baseline, at the end of the 3rd and 12th weeks. Outcome measures were tender point count (TPC), myalgic pain score (MPS), Fibromyalgia Impact Questionnaire (FIQ) and Short Form-36 (SF-36) Health Survey. Sixty women with fibromyalgia completed the study. The patients in both groups showed improvement in terms of TPC, MPS, FIQ, physical and mental summary scores and total scores of SF-36 at the end of the 3rd and 12th weeks. The improvement in MPS at the third week was higher in the first group (p = 0.01). But there was no difference in terms of the improvement in MPS between the groups at the end of the 12th week control (p = 0.87). There was no significant difference between the improvement in the other outcome parameters of the two groups. As a result, supervised exercise program was successful to improve the myalgic pain, functional status and quality of life in women with fibromyalgia. Exercises combined with TENS might be useful due to quick myalgic pain relief in the treatment of fibromyalgia in everyday practice. PMID- 22527136 TI - Excess weight and associated risk factors in patients with systemic lupus erythematosus. AB - The objective of this study is to determine the socio-demographic, clinical and laboratory characteristics of outpatients with SLE who present with excess weight as well as to assess the immunosuppressive therapy used. One hundred and seventy women with SLE were evaluated consecutively in a transversal study. The relationship between excess weight and the patients' characteristics was evaluated using univariate and multivariate Poisson regression analysis. Of the 170 patients evaluated, 109 presented with excess weight, two were malnourished and 59 were classified as eutrophic. Age and disease duration of those with excess weight were 42.4 +/- 8.7 and 10.4 +/- 6.2 years, respectively. Risk factors associated with excess weight were the following: age >=40 years, <8 years of education, lack of occupation, damage index >=1, systemic high blood pressure, diabetes mellitus and triglycerides >=150 mg/dL levels. The use of antimalarial therapy and steroids was associated with a lower frequency of excess weight. Age >=40 years and the non-usage of methotrexate were the variables independently associated with excess weight in the multivariate analysis. Patients with SLE who have excess weight present distinct clinical-laboratory findings, socio-demographic characteristics and treatment options when compared to normal weight patients. Prospective studies should assess whether these characteristics will interfere with the outcome or prognosis of lupus. PMID- 22527137 TI - A CCR6 variant strongly associated with rheumatoid arthritis in two populations is not associated with ankylosing spondylitis. PMID- 22527138 TI - Alfacalcidol in men with osteoporosis: a prospective, observational, 2-year trial on 214 patients. AB - Due to pleiotropic-synergistic actions on bone, muscle, gut, brain and different other non-skeletal tissues, alfacalcidol is an interesting drug for treating osteoporosis. In studies on glucocorticoid-induced osteoporosis, men have always been treated with calcitriol or this active D-hormone prodrug, but there is no study of male patients only in the literature. The AIM-Trial (Alfacalcidol In Men) is an extension of the control group (n = 158) of our former risedronate study in male osteoporosis (Ringe et al. in Rheumatol Int 29:311-315, 2009). In that study, we treated daily those controls with prevalent vertebral fractures with 1 MUg alfacalcidol + 500 mg calcium (group A) and those without prevalent vertebral fractures with 1,000 IU plain vitamin D (Vit. D) + 1,000 mg calcium (group B). Subsequently, we added an additional 56 pairs of patients to these two groups: 28 with and 28 without prevalent vertebral fractures, reaching a total of 214 cases. That means with this design, we are comparing two groups with a different risk at onset. Due to the prevalent vertebral fractures and lower average bone mineral density (BMD) values, there was a higher risk of incident fractures in group A. After 2 years, we found significantly higher increases in lumbar spine BMD (+3.2 vs. +0.8 %) and total hip BMD (+1.9 vs. -0.9 %) in group A and B, respectively. Eighteen incident falls were recorded in the alfacalcidol group and 38 in the group treated with Vit. D (p = 0.041). There were significantly lower rates of patients with new vertebral and non-vertebral fractures in group A than in group B. Back pain was significantly reduced only with alfacalcidol. Concerning the incidence of new non-vertebral fractures, we found that there was a relation to renal function in the two groups. The advantage for alfacalcidol was mainly due to a higher non-vertebral fracture reducing potency in patients with a creatinine clearance (CrCl) below 60 ml/min (p = 0.0019). There were no serious adverse events (SAE), and the numbers of mild to-moderate adverse events (AE) were not different between groups. Despite the higher initial fracture risk in the alfacalcidol group, 2-year treatment with this active D-hormone prodrug showed a higher therapeutic efficacy in terms of BMD, falls and fractures. One important advantage of alfacalcidol may be that it is effective even in patients with mild-to-moderate renal insufficiency. PMID- 22527139 TI - Hesperidin inhibits collagen-induced arthritis possibly through suppression of free radical load and reduction in neutrophil activation and infiltration. AB - Rheumatoid arthritis is a chronic inflammatory disease characterized by the destruction of articular cartilage and bone in a chronic phase. Pathology of rheumatoid arthritis suggests autoimmunity linked to inflammation. In our study, rheumatoid arthritis was induced in Wistar rats by intradermal injections of 100 MUl of emulsion containing bovine type II collagen in complete Freund's adjuvant at the base of the tail. Disease developed about 13 +/- 1 days after immunization and treatment with hesperidin (HES) at a dose of 160 mg kg(-1) body weight was given after onset of disease daily until 20th day. The effect of treatment in the rats was monitored by clinical scoring, biochemical parameters and histological evaluations in joints. A steady increase in the articular elastase, nitric oxide and lipid peroxidation was observed in joints of arthritic rats as compared to control, whereas a significant decrease in reduced glutathione, superoxide dismutase activity and catalase was observed in collagen-induced arthritis rats as compared to control group. The results from the present work indicate that the treatment with hesperidin was effective in bringing about significant changes on all the parameters studied in collagen-induced arthritis rats. These data confirm that erosive destruction of the joint cartilage in collagen-induced arthritis is due free radicals released by activated neutrophils and produced by other biochemical pathways. In the present study, an attempt has been made to amelioration of the disease process by a natural product. These results suggest that oral administration of HES could be effective for treating human RA patients. PMID- 22527140 TI - Anti-Saccharomyces cerevisiae antibodies in patients with systemic lupus erythematosus. AB - Anti-Saccharomyces cerevisiae antibodies (ASCA) had been known to be specific for Crohn's disease but it has been found in many other autoimmune diseases like systemic lupus erythematosus (SLE). Furthermore, cross-reactive epitopes on beta2 glycoprotein I (beta2GPI) and Saccharomyces cerevisiae were found in SLE patients. The aims of this study were to evaluate the frequency of ASCA in patients with SLE and to compare it with that of anti-beta2GPI antibodies (abeta2GPI). Sera of 116 patients with SLE were analyzed in this retrospective study. All patients fulfilled at least 4 criteria of the 1997 American College of Rheumatology updated criteria for the classification of SLE. Sera of 160 blood donors were included as normal controls. ASCA IgA and IgG and abeta2GPI antibodies were determined by enzyme-linked immunosorbent assays. The frequency of ASCA (IgG and/or IgA) was significantly higher in SLE patients than in control group (31.9 vs. 3.7 %, p < 10(-6)). ASCA IgG and ASCA IgA were more frequent in SLE patients than in control group (29.3 vs. 3.1 %, p < 10(-6) and 12.1 vs. 0.6 %, p = 10(-4), respectively). The mean level of ASCA IgG was higher than that of ASCA IgA (9.5 vs. 6.4 U/ml) but the difference was not statistically significant. The frequencies of abeta2GPI (IgG and/or IgA) and abeta2GPI IgA were significantly higher than those of ASCA (IgG and/or IgA) and ASCA IgA (54.3 vs. 31.9 %, p = 5 * 10(-4) and 50.9 vs. 12.1 %, p < 10(-6), respectively). Increased ASCA IgG was observed in patients with SLE, suggesting a role of environmental stimuli in its pathogenesis. PMID- 22527141 TI - Successful childbearing in two women with rheumatoid arthritis and a history of miscarriage after etanercept treatment. AB - Two women with rheumatoid arthritis who had experienced miscarriages became pregnant while they were under etanercept treatment. One stopped etanercept after 3 weeks with increased doses of prednisolone, and the other restarted etanercept at a half doses 3 months later. They delivered a healthy baby at full term, and no problems in both expecting mothers and babies were observed. The use of etanercept in patients with rheumatoid arthritis seemed safe for pregnant mothers and their fetuses. PMID- 22527142 TI - Capillaroscopic pattern in systemic lupus erythematosus and undifferentiated connective tissue disease: what we still have to learn? AB - In rheumatology, specific is the capillaroscopic pattern in systemic sclerosis (SSc), the so-called "scleroderma type". Capillaroscopic pattern in systemic lupus erythematosus (SLE) is less specific and includes a wide range of microvascular changes-"SLE-type" capillaroscopic pattern, non-specific findings and in a small percentage "scleroderma-like" pattern. The latter finding is currently associated with a potential subclinical overlap with SSc. Various microvascular changes have been observed in a different proportion of patients with undifferentiated connective tissue disease (UCTD). The aim of the study was to evaluate the capillaroscopic changes in SLE and UCTD. Patients from the following groups were included in the study: 30 female patients with SLE (mean age, 49 +/- 15.4 years), 31 patients with UCTD (mean age, 50 +/- 17 years; 30 females and 1 male); 34 age- and sex-matched healthy volunteers were examined as a control group. Nailfold capillaroscopy was performed using videocapillaroscope Videocap 3.0 (DS Medica). Capillaroscopic findings were compared with clinical and laboratory data of the patients. At capillaroscopic examination, the most frequent capillaroscopic changes in SLE patients were the presence of elongated capillaries in 43 % (13/30), an increased tortuosity in 70 % (21/30) and a prominent subpapillary plexus in 60 % (18/30) of the cases. In 80 % (24/30) of the patients, dilated capillaries were found; in 6.6 % (2/30), giant capillary loops; and in 16.6 % (5/30), haemorrhages. In 50 % of the patients, an "SLE-type" capillaroscopic pattern was found. In 30 % (9/30) of the cases the capillaroscopic examination revealed "non-specific changes", in 6.6 % (2/30) of the patients it was found a normal capillaroscopic pattern and in 13.3 % (4/30) a "scleroderma-like" pattern. Positive tests for ANA were detected in 73.3 % (11/15) of the patients with "SLE-type" capillaroscopic pattern. In all the patients with "scleroderma-like" capillaroscopic finding, positive autoantibodies with a high titre were found, without signs for overlap with other connective tissue disease (CTD). In two out of four patients with such capillaroscopic findings, a vasculitis of peripheral vessels was evident and in the other two secondary RP and high immunologic activity. A "scleroderma-like" pattern was found in 38 % (12/31) of the patients with UCTD. In 51 % (16/31) of the patients from this group, "non-specific" capillaroscopic findings were observed. For the evaluation of the predictive value of capillaroscopic pattern for the development of a distinct rheumatic disorder in patients with UCTD, a longer period of follow up is necessary. In SLE patients, it has been found that capillaroscopic examination reveals microvascular changes also in the absence of RP. Here, the results from the study illustrate the correlation between capillaroscopic changes and immunological profile. "Scleroderma-like" capillaroscopic pattern may be observed in the context of active vasculitis of peripheral vessels as well as in patients with secondary RP and high immunologic activity. It does not have an obligatory association with an overlap syndrome with other CTD. Capillaroscopic findings in UCTD are heterogeneous. The potential of capillaroscopic examination in UCTD for evaluating the prognosis of the disease needs to be revealed through long-term follow-up. PMID- 22527143 TI - The functional interaction between CDK11p58 and beta-1,4-galactosyltransferase I involved in astrocyte activation caused by lipopolysaccharide. AB - Glial cells are mediating the main activation of the central nervous system (CNS), being astrocytes the mayor glial cells in the brain. Glial activation may result beneficial since it could promote tissue repair and pathogen elimination. However, excessive glial activation mechanism can also have do harm to the tissue. beta-1,4-Galactosyltransferase I (beta-1,4-GalT-I) is a key inflammatory mediator that participates in the initiation and maintenance of inflammatory reaction in some diseases. Moreover, CDK11(p58) has been reported to be associated with beta-1,4-GalT-I. We have found that CDK11(p58) and beta-1,4-GalT I are induced in lipopolysaccharide (LPS)-challenged rat primary astrocytes in a affinis dose- and time-dependent manner. CDK11(p58) regulates the expression of beta-1,4-GalT-I by interacting with it. After the knockdown of CDK11(p58) expression, the expression of beta-1,4-GalT-I decreases, and astrocyte activation downregulates. Inversely, the expression of beta-1,4-GalT-I increases, and astrocyte activation enhances due to the overexpression of CDK11(p58). Knockdown of beta-1,4-GalT-I reduces the activation potentiation caused by the overexpression of CDK11(p58), illustrating the function of CDK11(p58) to promote astrocyte activation depends on beta-1,4-GalT-I. The interaction between CDK11(p58) and beta-1,4-GalT-I to upregulate astrocyte activation is related to activating p38 and JNK pathways. These findings indicated that the functional interaction between CDK11(p58) and beta-1,4-GalT-I may play an important role during astrocyte activation after LPS administration. PMID- 22527144 TI - Apigenin inhibits the expression of IL-6, IL-8, and ICAM-1 in DEHP-stimulated human umbilical vein endothelial cells and in vivo. AB - Di-(2-ethylhexyl) phthalate (DEHP) in house dust is associated with asthma and allergic inflammatory symptoms in children. This study aimed to examine an inhibitory effect of a flavonoid apigenin on DEHP-stimulated inflammatory responses in human umbilical vein endothelial cells (HUVECs). We found that apigenin significantly suppressed DEHP-stimulated expression of intercellular adhesion molecule-1 (ICAM-1) at the mRNA and protein levels and subsequently inhibited the adhesion of THP-1 monocytic cells to HUVECs. Treatment with apigenin also led to a dose-dependent inhibition of mRNA and protein expression of interleukin (IL)-6 and IL-8 in DEHP-stimulated HUVECs. Moreover, pretreatment with apigenin partially inhibited the DEHP-induced activation of c-Jun N-terminal kinase (JNK) but not the degradation of IkappaBalpha or the phosphorylation of extracellular-regulated kinase (ERK)1/2, indicating that the inhibitory effect of apigenin on the expression of IL-6, IL-8, and ICAM-1 may be mediated by JNK pathway but not IkappaBalpha/nuclear factor-kappaB or ERK/mitogen-activated protein kinase pathway. Furthermore, apigenin reduced the release of IL-6, IL-8, and ICAM-1 and inhibited compound 48/80-induced systemic anaphylaxis in vivo. These results suggest that apigenin can be used as a therapeutic means for the treatment of DEHP-associated allergic disorders. PMID- 22527145 TI - High levels of inflammation and insulin resistance in obstructive sleep apnea patients with hypertension. AB - Hypertension induced by obstructive sleep apnea (OSA) may be multifactorial in origin, and systemic inflammation is one of the major factors. However, OSA patients do not always have the identical probability with hypertension even in patients with the same history and degree of OSA. The aim of this study was to compare the levels of inflammation and insulin resistance in two groups of patients who had the same degree as well as the same long history of OSA, but with/without hypertension. OSA patients (Apnea Hyponea Index, AHI >= 40/h, n = 70) were examined by polysomnography and blood analysis for the measurements of fasting plasma glucose, serum insulin (FINS), high-sensitivity C-reactive protein (CRP), peptide C,TNF-alpha, IL-6, and IL-10. Patients with hypertension (n = 40) had higher level of LDL-C and lower HDL-C levels than patients without hypertension. Almost half (16/40) of OSA patients with hypertension had family history of hypertension. Moreover in OSA patients with hypertension, the levels of TNF-alpha, IL-6, and CRP were higher, but IL-10 was lower than those without hypertension. FINS, peptide C, HOMA-IR, and HOMA-islet were also higher in OSA patients with hypertension. OSA patients with hypertension have higher level of inflammation and insulin resistance. Systemic inflammation and insulin resistance are both important factors for the development of hypertension in OSA patients. PMID- 22527146 TI - Effects of rifaximin on bacterial translocation in thioacetamide-induced liver injury in rats. AB - Intestinal bacterial overgrowth (IBO) and increased mucosal permeability are suggested to increase bacterial translocation (BT) in liver injury. Rifaximin (RIF) is a minimally absorbed oral antimicrobial agent that restores gut microflora imbalance. The aim of the present study was to investigate the effects of RIF on BT frequency in thioacetamide (TAA)-induced liver injury. Group 1 was the control. In group 2 (TAA), rats received TAA daily for 3 days. In group 3 (TAA + RIF), RIF was commenced on the same day as the first dose of TAA. In group 4 (RIF), rats received only RIF. Ileal aspirate Escherichia coli counts were significantly lower in the TAA + RIF group than in TAA group. There was no difference in BT frequency between the TAA and TAA + RIF groups. Our results suggest that factors such as intestinal barrier dysfunction and impaired host immune shield, apart from IBO, play an important role in BT in this model. PMID- 22527147 TI - Clinical and functional outcomes of the saddle prosthesis. AB - BACKGROUND: The implantation of a saddle prosthesis after resection of a pelvic tumor has been proposed as a simple method of reconstruction that provides good stability and reduces the surgical time, thus limits the onset of intraoperative complications. There are no studies in the literature of patients evaluated using gait analysis after being implanted with a saddle prosthesis. The present study is a retrospective case review aimed at illustrating long-term clinical and functional findings in tumor patients reconstructed with a saddle prosthesis. MATERIALS AND METHODS: A series of 15 patients who received pelvic reconstruction with a saddle prosthesis were retrospectively reviewed in terms of clinical, radiographic, and functional evaluations. Two patients were additionally assessed by gait analysis. RESULTS: Long-term functional follow-up was achieved in only 6 patients, and ranged from 97 to 167 months. Function was found to be rather impaired, as a mean of only 57 % of normal activity was restored. Gait analysis demonstrated that the implant had poor biomechanics, as characterized by very limited hip motion. CONCLUSIONS: Though the saddle prosthesis was proposed as advance in tumor-related pelvic surgery, the present study indicates that it yields unsatisfactory clinical and functional results due to both clinical complications and the poor biomechanics of the device. The use of a saddle prosthesis in tumor surgery did not provide satisfactory results in long-term follow-up. It is no longer implanted at our institute, and is currently considered a "salvage technique." PMID- 22527149 TI - Loose body following cross-pin fixation for anterior cruciate ligament reconstruction. AB - We report a case of loosening of a bioabsorbable cross-pin fixation device for anterior cruciate ligament reconstruction. Forty-two months following a bone tendon bone reconstruction of the anterior cruciate ligament, the patient presented with a subcutaneous collection in the medial side of the knee. At subsequent surgery, a RIGIDFIX cross-pin fixator (Mitek, Westwood, MA, USA) was retrieved, intact, from the sterile fluctuant mass around the superomedial aspect of the knee. The graft was stable both radiologically and clinically, and the patient remains symptom free. This case raises concern about the use of this smooth cross-pin fixator and the consequences of backing out and the resultant intraarticular loose body. We suggest consideration of a loose body if the patient becomes symptomatic postoperatively, and early intervention to prevent chondral damage is recommended. PMID- 22527150 TI - Bedside fasciotomy under local anesthesia for acute compartment syndrome: a feasible and reliable procedure in selected cases. AB - BACKGROUND: Fasciotomy for compartment syndrome is an emergent procedure that is usually done in the operating theater under general anesthesia. Delay in performing the procedure can lead to worse outcome. Various reasons can cause delay in performing the surgery. Bedside fasciotomy under local anesthesia can be done in these cases to avoid delay in compartment release. MATERIALS AND METHODS: This was a retrospective study of 34 cases of acute compartment syndrome for which fasciotomy was done at the bedside under local anesthesia. The minimum follow-up period was 6 months. RESULTS: All patients had immediate and marked improvement in pain. Thirty-three patients regained their normal muscle strength. Thirty-two patients regained normal range of motion of adjacent joints. One patient developed flexion contracture of the great toe. There was no deep infection, chronic osteomyelitis, or amputation. Superficial wound infection was noted in three patients; one patient had persistent foot drop. CONCLUSION: Bedside fasciotomy under local anesthesia is a feasible, safe, and effective choice for treating compartment syndrome in patients with delayed presentation or those with anticipated delay to undergo surgery in the operating theater under general or regional anesthesia. The results of this study are encouraging, as all wounds healed satisfactory and there were no cases of deep infections. The formal release of compartments in the operating room under general anesthesia continues to be the standard of care. This is the first description in the literature for bedside fasciotomy under local anesthesia with a relatively large number of patients. PMID- 22527151 TI - The trivector approach for minimally invasive total knee arthroplasty: a technical note. AB - One of the main criticisms of minimally invasive approaches in total knee arthroplasty has been their poor adaptability in cases of major deformity or stiffness of the knee joint. When they are used in such cases, excessive soft tissue tension is needed to provide appropriate joint exposure. Here, we describe the "mini trivector approach," which has become our standard approach for total knee replacement because it permits us to enlarge the indication for minimally or less invasive total knee replacement to many knees where quad sparing, a subvastus approach, or a mini quad or mini midvastus snip may not be sufficient to achieve correct exposure. It consists of a limited double snip of the VMO and the quadriceps tendon that reduces tension on the extensor mechanism and allows easier verticalization of the patella as well as good joint exposure. PMID- 22527152 TI - Clinical applications of (18)F-FDG PET in the management of hepatobiliary and pancreatic tumors. AB - The assessment of hepatobiliary and pancreatic tumors is commonly achieved by ultrasound, computed tomography (CT), and magnetic resonance. The 2-[fluorine 18]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) detects increased glucose metabolism associated with neoplastic lesions, provides high accuracy in most cancer imaging applications and is now widely used in clinical practice. However, PET is not always useful and accurate knowledge of appropriate indications is essential for a proper clinical management. (18)F-FDG is transported into cells and phosphorylated by the enzyme hexokinase to (18)F-FDG-6 phosphate, which cannot proceed down the glycolytic pathway and therefore is accumulated in the malignant tissue. PET allows accurate quantification of FDG uptake in tissue, and previous studies have demonstrated that standardized uptake values provide highly reproducible parameters of tumor glucose use (Weber et al., J Nucl Med 40:1771-1777, 1999). The recent development and diffusion of hybrid PET-CT scanners allows functional and anatomic data to be obtained in a single examination, improving lesion localization and resulting in significant diagnostic improvement (Wahl, J Nucl Med 45:82S-95S, 2004). Moreover, CT can be performed diagnostically with the use of intravenous and oral contrast and simultaneous PET-contrast-enhanced CT scanning appears to be an efficient method in cancer evaluation. However, in most centers, a low-dose CT is routinely performed without contrast media infusion.Proper patient preparation, scanning protocol, combined assessment of PET and CT data, and the evaluation of conventional imaging findings are essential to define disease and to avoid diagnostic pitfalls. The role of PET and PET-CT in malignancies of the liver, biliary tract, and pancreas is here reviewed; normal patterns, representative cases, and common pitfalls are also presented. PMID- 22527153 TI - Imaging following bariatric procedures: Roux-en-Y gastric bypass, gastric sleeve, and biliopancreatic diversion. AB - Morbid obesity remains as a common and increasing health problem. Due to limited long-term success with nonsurgical weight loss measures for morbid obesity, bariatric surgery is being performed more and more often in both academic and private practice settings and has proven to be an effective treatment option with sustained weight loss, decreased morbidity, reversal of comorbidities, and prolonged life expectancies [Am J Clin Nutr 55:615S-619S, 1992; Brolin, Nutrition 12:403-404, 1996; Fisher and Schauer, Am J Surg 184:9S-16S 2002]. The Roux-en-Y gastric bypass, biliopancreatic diversion, and gastric sleeve will be discussed in terms of their expected imaging appearance and potential complications. PMID- 22527154 TI - Introduction to the feature section on "Crohn's disease activity: MRI assessment and clinical implications". PMID- 22527155 TI - Comparison of MR enteroclysis with video capsule endoscopy in the investigation of small-intestinal disease. AB - PURPOSE: To evaluate the diagnostic accuracy of MR enteroclysis and to compare it to video capsule endoscopy (VCE) in the analysis of suspected small-bowel disease. METHODS: We performed a retrospective analysis of 77 patients who underwent both MR enteroclysis and VCE and compared the findings of these studies with the findings of enteroscopy, surgery, or with the results of clinical follow up lasting >=2 years. RESULTS: Findings included malignant neoplasms (n = 13), benign neoplasms (n = 10), refractory celiac disease (n = 4), Crohn's disease (n = 2) and miscellaneous conditions (n = 10). Specificity of MR enteroclysis was higher than that of VCE (0.97 vs. 0.84, P = 0.047), whereas sensitivity was similar (0.79 vs. 0.74, P = 0.591). In 2/32 (6.3%) patients with both negative VCE and negative MR enteroclysis a positive diagnosis was established, compared to 5/11 (45.5%) patients in whom VCE was positive and MR enteroclysis was negative (likelihood ratio 8.1; P = 0.004), 9/11 (81.8%) patients in whom MR enteroclysis was positive and VCE was negative (likelihood ratio 23.5; P < 0.0001), and all 23 patients in whom both VCE and MR enteroclysis showed abnormalities (likelihood ratio 60.8; P < 0.0001). CONCLUSIONS: VCE and MR enteroclysis are complementary modalities. In our study-population, MR enteroclysis was more specific than VCE, while both produced the same sensitivity. PMID- 22527156 TI - Lower gastrointestinal bleeding due to primary ilioenteric fistula. PMID- 22527157 TI - Percutaneous transsplenic embolization of jejunal varices in a patient with liver cirrhosis: a case report. AB - Bleeding jejunal varices are rare and could be life threatening. They are usually found in the presence of portal hypertension and prior history of gastrointestinal surgery. They can be effectively managed by radiological interventions such as transjugular intrahepatic portosystemic shunt or transhepatic embolization of varices. However, in patients with portal vein obstruction, an alternative access is necessary. We report a case of bleeding jejunal varices associated with postoperative adhesion in a patient with portal vein thrombosis which was successfully managed by percutaneous transsplenic embolization. PMID- 22527158 TI - Self-expanding covered metallic stent treatment of esophagojejunostomy fistulas. AB - PURPOSE: The purpose of this study is to analyze the outcomes of the self expanding covered metallic stent (SECMS) therapy in the management of the postoperative anastomotic leaks that seen after total gastrectomy esophagojejunostomy (EJ) operations. MATERIALS AND METHODS: Contrast radiography and endoscopy revealed EJ fistulas in 14 patients. SECMSs were implanted both fluoroscopically and endoscopically to seal fistulas. Postoperative fistula diagnosis times, postoperative covered stent implantation times, primary success rates, clinical success rates, postinterventional oral feeding beginning times, reduction of the drainage from the surgical drains, procedure-related mortality morbidity, and mortality related with factors other than the procedure were noted. RESULTS: Technical success rate was 100 %. Clinical success rate was 79 %. Reduction of the fluid from surgical drains was observed in all patients. There were no procedure-related mortality. Recurrent fistula was observed in two patients (14 %) at the third and fifth day after the intervention. In one patient (7 %), stent dislocation was observed at the 10th day after the intervention. Non procedure-related mortality was 21 %. No anastomotic stricture, no in-stent stenosis was observed during the follow up period(11.09 +/- 3.21 months). CONCLUSION: From the above results we concluded that SECMS treatment for EJ fistulas is a safe, effective and technically easy procedure. PMID- 22527159 TI - Pelvic inflammatory disease: evaluation of diagnostic accuracy with conventional MR with added diffusion-weighted imaging. AB - PURPOSE: To determine the incremental value of magnetic resonance (MR) diffusion weighted (DW) imaging for the diagnosis of pelvic inflammatory diseases (PID). MATERIALS AND METHODS: We added DW sequences to conventional MR imaging in 187 patients with clinically suspected PID. The imaging findings included shape, signal intensity on T1-weighted, T2-weighted, and DW imaging, shade in the peripheral lesions, free pelvic fluid, and lymphadenopathy. RESULTS: Laparoscopic and pathological findings confirmed the diagnosis in all patients. Conventional MR findings were consistent with a diagnosis of PID in 90.7% (117/129) and of non PID in 93.3% (28/30) of the 159 patients. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of conventional MR imaging findings vs. the addition of DW imaging to conventional MR protocols for predicting PID were 90.7%, 93.3%, 98.3%, 70.0%, and 91.2% and 98.4%, 93.3%, 98.4%, 93.3%, and 97.5%, respectively. CONCLUSION: The addition of DW sequences to conventional MR imaging can improve the accuracy of diagnosis in PID. PMID- 22527160 TI - Methyl bromide exposure and cancer risk in the Agricultural Health Study. AB - PURPOSE: Methyl bromide is a genotoxic soil fumigant with high acute toxicity, but unknown human carcinogenicity. Although many countries have reduced methyl bromide use because of its ozone depleting properties, some uses remain in the United States and other countries, warranting further investigation of human health effects. METHODS: We used Poisson regression to calculate rate ratios (RR) and 95 % confidence intervals (CI) for associations between methyl bromide use and all cancers combined, as well as 12 specific sites, among 53,588 Agricultural Health Study pesticide applicators with follow-up from 1993 to 2007. We also evaluated interactions with a family history for four common cancers (prostate, lung, colon, and lymphohematopoietic). We categorized methyl bromide exposure based on lifetime days applied weighted by an intensity score. RESULTS: A total of 7,814 applicators (14.6 %) used methyl bromide, predominantly before enrollment. Based on 15 exposed cases, stomach cancer risk increased monotonically with increasing methyl bromide use (RR = 1.42; 95 % CI, 0.51-3.95 and RR = 3.13; 95 % CI, 1.25-7.80 for low and high use compared with no use; p (trend) = 0.02). No other sites displayed a significant monotonic pattern. Although we previously observed an association with prostate cancer (follow-up through 1999), the association did not persist with longer follow-up. We observed a nonsignificant elevated risk of prostate cancer with methyl bromide use among those with a family history of prostate cancer, but the interaction with a family history did not achieve statistical significance. CONCLUSIONS: Our results provide little evidence of methyl bromide associations with cancer risk for most sites examined; however, we observed a significant exposure-dependent increase in stomach cancer risk. Small numbers of exposed cases and declining methyl bromide use might have influenced our findings. Further study is needed in more recently exposed populations to expand on these results. PMID- 22527161 TI - Dietary intake of lignans and risk of adenocarcinoma of the esophagus and gastroesophageal junction. AB - PURPOSE: The strong male predominance in esophageal and gastroesophageal junctional adenocarcinoma remains unexplained. Sex hormonal influence has been suggested, but not proven. A protective role of dietary phytoestrogen lignans was hypothesized. METHODS: A Swedish nationwide population-based case-control study was conducted in 1995-1997, including 181 cases of esophageal adenocarcinoma, 255 cases of gastroesophageal junctional adenocarcinoma, 158 cases of esophageal squamous cell carcinoma, and 806 control subjects. Data on various exposures, including dietary data, were collected through personal interviews and questionnaires. Dietary intake of lignans was assessed using a food frequency questionnaire and categorized into quartiles based on the consumption among the control participants. Unconditional logistic regression was used to calculate odds ratios (ORs) with 95 % confidence intervals (CIs), including adjustment for all established risk factors. RESULTS: Participants in the highest quartile of intake of lignans compared with the lowest quartile were at a decreased risk of esophageal adenocarcinoma (OR, 0.65; 95 % CI, 0.38-1.12; p for trend =0.03), gastroesophageal junctional adenocarcinoma (OR, 0.37; 95 % CI, 0.23-0.58; p for trend <0.0001), and these adenocarcinomas combined (OR, 0.45; 95 % CI, 0.31-0.67; p for trend <0.0001). No clear associations were found between lignan intake and risk of esophageal squamous cell carcinoma. CONCLUSIONS: This population-based study indicates that a high dietary intake of lignans decreases the risk of adenocarcinoma of the esophagus and gastroesophageal junction. PMID- 22527162 TI - Dietary cadmium and risk of invasive postmenopausal breast cancer in the VITAL cohort. AB - PURPOSE: The aim of the study was to estimate the association between dietary intake of cadmium, a carcinogenic heavy metal, and risk of invasive postmenopausal breast cancer. METHODS: Study subjects were 30,543 postmenopausal women in the VITamins And Lifestyle (VITAL) cohort who completed a food frequency questionnaire (FFQ) at baseline (2000-2002). Dietary cadmium consumption was estimated by combining FFQ responses with US Food and Drug Administration data on food cadmium content. Incidence of invasive breast cancer was ascertained through linkage of the cohort to the western Washington Surveillance, Epidemiology, and End Results cancer registry through 31 December 2009. Cox regression was applied to estimate adjusted hazard ratios (aHRs) and 95 % confidence intervals (CIs) for breast cancer with increasing dietary cadmium intake, adjusted for total energy intake, smoking history, consumption of vegetables, potatoes, and whole grains, multivitamin use, education, race, body mass index, physical activity, age at first birth, postmenopausal hormone use, and mammography. RESULTS: Vegetables and grains together contributed an average of 66 % of estimated dietary cadmium. During a mean of 7.5 years of follow-up, 1,026 invasive postmenopausal breast cancers were identified. Among 899 cases with complete covariate information, no evidence of an association between dietary cadmium intake and breast cancer risk was observed (aHR (95 % CI), highest to lowest quartile cadmium: 1.00 (0.72 1.41), p (trend) = 0.95). No evidence was found for interactions between dietary cadmium and breast cancer risk factors, smoking habits, or total intake of calcium, iron, or zinc from diet, supplements, and multivitamins. CONCLUSIONS: This study does not support the hypothesis that dietary cadmium intake is a risk factor for breast cancer. However, non-differential measurement error in the estimate of cadmium intake is likely the most important factor that could have obscured an association. PMID- 22527164 TI - Hypomethylation of Alu repetitive elements in esophageal mucosa, and its potential contribution to the epigenetic field for cancerization. AB - BACKGROUND: Aberrant hypermethylation of specific genes is present in esophageal squamous cell carcinomas (ESCCs). Such hypermethylation is also present in normal appearing esophageal mucosae of ESCC patients and is considered to contribute to the formation of a field for cancerization. On the other hand, the presence of global hypomethylation in ESCCs or in their background esophageal mucosae is unknown. METHOD: We collected 184 samples of esophageal mucosae (95 normal mucosae from healthy subjects, and 89 non-cancerous background mucosae from ESCC patients) and 93 samples of ESCCs. Methylation levels of repetitive elements (Alu, LINE1) and cancer/testis antigen genes (NY-ESO-1, MAGE-C1) were measured by bisulfite pyrosequencing and quantitative methylation-specific PCR, respectively. RESULTS: Methylation levels of Alu, LINE1, NY-ESO-1, and MAGE-C1 were significantly lower in ESCCs than in their background and normal mucosae. Also, in the background mucosae, a significant decrease of the Alu methylation level compared with the normal mucosae was present. In ESCCs, methylation levels of the two repetitive elements and the two cancer/testis antigen genes were correlated with each other. CONCLUSION: This is the first study to show the presence of global hypomethylation in ESCCs, and even in their non-cancerous background mucosae. Alu hypomethylation might reflect the severity of an epigenetic field for cancerization. PMID- 22527163 TI - Dietary intake of B vitamins and methionine and prostate cancer incidence and mortality. AB - PURPOSE: We investigated prospectively the relationship between dietary intakes of methionine, B vitamins associated with one-carbon metabolism, and risk of incident and fatal prostate cancer. METHODS: The Melbourne Collaborative Cohort Study recruited 41,514 people aged 40-69 years between 1990 and 1994. During follow-up of 14,620 men for 15 years on average, we ascertained 1,230 incident prostate cancers and 114 prostate cancer deaths. Dietary intakes were estimated using a 121-item food frequency questionnaire. Hazard ratios (HR) and 95 % confidence intervals were estimated using Cox regression. RESULTS: For overall prostate cancer incidence, HRs for riboflavin intake were significantly increased relative to quintile 1 (except quintile 5), with a peak for quintile 3, HR 1.29 (1.07, 1.57). A similar but non-statistically significant pattern existed between riboflavin intake and prostate cancer mortality. The HR for folate intake and overall incidence was significantly increased for quintile 4, HR 1.21 (1.01, 1.46). No association was observed between prostate cancer mortality and the intake of either folate or any other B vitamin or methionine, and no observed association varied by tumor aggressiveness (all P(homogeneity) > 0.1). CONCLUSIONS: We found little evidence of association between dietary intakes of B vitamins or methionine and prostate cancer risk. Weak associations between prostate cancer incidence and dietary intake of riboflavin and folate, and between riboflavin intake and prostate cancer mortality, need corroboration by other studies. PMID- 22527165 TI - High rates of endometrial cancer among Pacific women in New Zealand: the role of diabetes, physical inactivity, and obesity. AB - PURPOSE: To determine the endometrial cancer rates, and the proportion attributable to diabetes mellitus (DM), physical inactivity, and overweight/obesity, by ethnicity with a focus on Pacific women in New Zealand. METHODS: Linked census-cancer records (1981-2004) were used to determine incidence rates of endometrial cancer by ethnicity. Health survey data (2006 2007) were used to determine risk factor prevalence by ethnicity. Relative risks for the association between diabetes, obesity, physical inactivity and endometrial cancer were sourced from published studies. Population attributable risk (PAR) methods, with Monte Carlo simulation, were used to estimate the PAR% by ethnicity and applied to 2001-2004 cancer rates. RESULTS: Pacific women had 2.61 (95 % confidence interval 2.22-3.05) times the endometrial cancer rate of European/Other women pooled over time, and the most rapidly increasing rates over time with the rate ratio increasing from 1.96 (1.14-3.37) in 1981/1986 to 3.78 (3.03-4.71) in 2001/2004 (p for trend = 0.14). Pacific women had the highest PAR% for DM, physical inactivity, and overweight/obesity (63.1 %), followed by Maori (58.6 %) and European/Other (48.6 %). Applying these PAR% to 2001-2004 endometrial cancer rates, the rate ratio comparing Pacific to European/Other endometrial cancer reduced from 3.8 for total cancer (attributable plus non attributable) to 2.3 for non-attributable cancer, and the rate difference reduced by 79 % from 51 to 11 per 100,000. CONCLUSIONS: Pacific women have high endometrial cancer rates in New Zealand. Some, but not all, of the ethnic inequalities were explained by measured differences in obesity/overweight, DM, and physical inactivity. PMID- 22527166 TI - Total and individual antioxidant intake and endometrial cancer risk: results from a population-based case-control study in New Jersey. AB - We evaluated the role of total dietary antioxidant capacity and of individual antioxidants on endometrial cancer risk in a population-based case-control study in New Jersey, including 417 cases and 395 controls. Dietary intake was ascertained using a food-frequency questionnaire (FFQ), and total antioxidant capacity (TAC) intake was estimated using the USDA Oxygen Radical Absorbance Capacity (ORAC) database and the University of Oslo's Antioxidant Food Database (AFD) and FFQ-derived estimates of intake. Odds ratios and 95 % confidence intervals were derived using multivariate logistic regression controlling for major endometrial cancer risk factors. Using the ORAC database, after adjusting for major covariates, we found decreased risks for the highest tertile of total phenolic intake compared with the lowest (OR: 0.62; 95 % CI: 0.39-0.98). There was no association for TAC intake based on the AFD, which utilized the ferric reducing ability of plasma (FRAP) assay to assess antioxidant capacity. There was no strong evidence for an association with intake of any of the individual antioxidants. Our findings suggest that total phenolic consumption may decrease endometrial cancer risk. PMID- 22527168 TI - A cross-sectional analysis of the association between diet and insulin-like growth factor (IGF)-I, IGF-II, IGF-binding protein (IGFBP)-2, and IGFBP-3 in men in the United Kingdom. AB - BACKGROUND: There is evidence of associations between insulin-like growth factor I (IGF-I), IGF-II, insulin-like binding protein-2 (IGFBP-2), IGFBP-3, and prostate cancer risk. This study examines the association between dietary factors associated with prostate cancer and serum levels of these peptides. METHODS: A cross-sectional analysis of self-reported 12-month dietary intake with serum IGF and IGFBP levels was performed using data from 1,798 subjects screened negative for prostate cancer as part of a UK multicenter trial comparing treatments for this condition. Multivariable linear regression models tested associations of diet with IGFs and IGFBPs. RESULTS: For a one standard deviation (SD) increase in dairy product and dairy protein intake, IGF-I increased by 5.28 ng/mL (95 % confidence interval: 2.64, 7.92 ng/mL) and 6.02 ng/mL (3.34, 8.71 ng/mL), respectively. A 25 % increase in calcium and selenium intake was associated with an increase in IGF-I of 5.92 ng/mL (3.77, 8.07 ng/mL) and 2.61 ng/mL (1.10, 4.13 ng/mL), respectively. A one SD increase in animal protein was associated with a decrease in IGFBP-2 of 6.20 % (-8.91, -3.41 %), and there was some evidence of an inverse association with dairy protein and calcium. There was no evidence of any dietary associations with IGFBP-3 or IGF-II. CONCLUSIONS: Diet is associated with IGF-I and IGFBP-2 levels in men in the UK, and these peptides warrant further investigation as part of randomized trials of dietary interventions to reduce the risk or progression of prostate cancer. There is no evidence that IGF-II or IGFBP 3 are mediators of dietary associations with prostate cancer. PMID- 22527167 TI - Neighborhood socio-economic characteristics, African ancestry, and Helicobacter pylori sero-prevalence. AB - PURPOSE: The authors recently reported high Helicobacter pylori sero-prevalence among African-Americans of high African ancestry. We sought to determine whether neighborhood-level socio-economic characteristics are associated with H. pylori prevalence and whether this helps explain the link between African ancestry and H. pylori. METHODS: Antibodies to H. pylori proteins were assessed in the serum of 336 African-American and 329 white Southern Community Cohort Study participants. Prevalence odds ratios (ORs) and 95 % confidence intervals (CIs) for CagA+ and CagA- H. pylori were calculated using polytomous logistic regression in relation to 10 Census block group-level measures of socio-economic status. RESULTS: After adjusting for individual-level characteristics, three neighborhood-level factors were significantly inversely related to CagA+ H. pylori: percent completed high school; median house values; and percent employed (comparing highest to lowest tertile, OR, 0.47, 95 % CI, 0.26-0.85; OR, 0.56, 95 % CI, 0.32-0.99; and OR, 0.59, 95 % CI, 0.34-1.03, respectively). However, accounting for these measures did not attenuate the association between African ancestry and CagA+ H. pylori, with African-Americans of low, medium, and high African ancestry maintaining two-, seven-, and ninefold increased odds, respectively, compared to whites. CONCLUSIONS: Neighborhood-level measures of education, employment, and house values are associated with CagA+ H. pylori sero prevalence, but do not explain the persistent strong relationship between African ancestry level and CagA+ H. pylori. The findings suggest that neighborhood socio economic status can help to highlight high-risk areas for prevention and screening efforts and that the link between African ancestry and H. pylori may have a biological basis. PMID- 22527169 TI - Challenges and opportunities in research on early-life events/exposures and cancer development later in life. AB - It is becoming increasingly evident that early-life events and exposures have important consequences for cancer development later in life. However, epidemiological studies of early-life factors and cancer development later in life have had significant methodological challenges such as the long latency period, the distinctiveness of each cancer, and large number of subjects that must be studied, all likely to increase costs. These traditional hurdles might be mitigated by leveraging several existing large-scale prospective studies in the United States (US) and globally, as well as birth databases and birth cohorts, in order to launch both association and mechanistic studies of early-life exposures and cancer development later in life. Dedicated research funding will be needed to advance this paradigm shift in cancer research, and it seems justified by its potential to produce transformative understanding of how cancer develops over the life-course. This in turn has the potential to transform cancer prevention strategies through interventions in early-life rather than later in life, as is the current practice, where it is perhaps less effective. PMID- 22527170 TI - Breast-feeding and risk of epithelial ovarian cancer. AB - PURPOSE: Evidence suggests that breast-feeding may decrease the risk of epithelial ovarian cancer but it is not clear whether there is a relationship with duration of breast-feeding, patterns of breast-feeding, or particular histological subtypes of ovarian cancer. We sought to investigate these issues in detail. METHODS: Data from participants in a population-based study of ovarian cancer in western Washington State, USA (2002-2007) who had had at least one birth (881 cases and 1,345 controls) were used to assess relations between patterns of breast-feeding and ovarian cancer. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Women who ever breast-fed had a 22 % reduction in risk of ovarian cancer compared with those who never breast-fed (OR = 0.78, 95% CI 0.64-0.96) and risk reduction appeared greater with longer durations of feeding per child breast-fed (OR = 0.56, 95% CI 0.32-0.98 for 18 months average duration breast-feeding versus none). Introduction of supplementary feeds did not substantially alter these effects. The overall risk reduction appeared greatest for the endometrioid and clear cell subtypes (OR per month of average breast-feeding per child breast-fed = 0.944, 95% CI 0.903-0.987). CONCLUSIONS: Among women who have had the opportunity to breast-feed, ever breast-feeding and increasing durations of episodes of breast-feeding for each breast-fed child are associated with a decrease in the risk of ovarian cancer independent of numbers of births, which may be strongest for the endometrioid subtype. PMID- 22527171 TI - Modeling the effect of disseminating brief intervention for smoking cessation at medical facilities in Japan: a simulation study. AB - PURPOSE: The Japanese male smoking prevalence is still high. Underlying causes are the low quit attempt rate (QAR) and lack of pharmacotherapy (PT) use. Though health checkups are widely and systematically performed in Japan, this setting has not been utilized for intervention to smokers. We aimed to estimate the population effect of disseminating brief intervention (BI) at health checkup facilities combined with encouraging PT utilization. METHODS: The annual population quit rate (PQR) was modeled as a product of three components: the QAR, utilization of PT, and effectiveness of PT. A policy to disseminate effective BI at health checkup facilities was then incorporated into the PQR model as means to increase the QAR and/or PT utilization. Japanese male smokers aged 40-74 years were the target population, and the baseline year was set at 2005. The PQR and the number of smokers who successfully quit were compared with the baseline to evaluate the BI policy. RESULTS: The BI policy was estimated to increase the PQR from 4.3 to 5.7 % (rate ratio: 1.34) in a scenario where 75 % of smokers having an annual health checkup received BI and 60 % of BI-induced quit attempts were supported by PT, resulting in 177,000 new successful quitters on an annual basis and 3,000 avoidable cancer deaths in 10 years. Comparisons of different scenarios revealed that increasing QAR and encouraging PT were both essential to maximize the effect of BI policy. CONCLUSION: The dissemination of BI at health checkup facilities encouraging PT utilization is an effective tobacco control policy in Japan. PMID- 22527173 TI - Socioeconomic disparities and breast cancer hormone receptor status. AB - PURPOSE: Recent research, although inconsistent, indicates that socioeconomic status (SES) may be associated with hormone receptor (HR) status. This study aims to examine the association between SES and breast cancer HR status within and across racial/ethnic groups stratified by age at diagnosis and tumor stage. METHODS: The study subjects were 184,602 women with incident breast cancer diagnosed during 2004-2007 and identified from the National Cancer Institute's Surveillance, Epidemiology and End Results program. Log-binomial regression assessed the risk of having breast tumors that were (1) HR-negative versus HR positive and (2) HR-unknown versus HR-known between women who, at the time of diagnosis, were residing in high or medium poverty areas compared to low poverty areas. RESULTS: High poverty areas tended to have a greater prevalence of HR negative tumors compared to more affluent areas. Although not always significant, this was observed among non-Hispanic white and Hispanic women regardless of age tumor stage category, and only among young, non-Hispanic black women and non Hispanic Asian/Pacific Islander women with regional and distant stage. High poverty areas also tended to have a greater prevalence of HR-unknown tumors compared to more affluent areas. Furthermore, significant trends between HR status and poverty level varied by race/ethnicity, age, and tumor stage. CONCLUSIONS: Poverty may be related to breast cancer negative and unknown HR status. These findings suggest the effects of non-genetic factors on biochemical features of breast cancer, as well as imply a clinical importance to improve HR measurement or recording for low socioeconomic breast cancer patients. PMID- 22527172 TI - Rye bread consumption in early life and reduced risk of advanced prostate cancer. AB - OBJECTIVE: To determine whether consumption of whole-grain rye bread, oatmeal, and whole-wheat bread, during different periods of life, is associated with risk of prostate cancer (PCa). METHODS: From 2002 to 2006, 2,268 men, aged 67-96 years, reported their dietary habits in the AGES-Reykjavik cohort study. Dietary habits were assessed for early life, midlife, and current life using a validated food frequency questionnaire. Through linkage to cancer and mortality registers, we retrieved information on PCa diagnosis and mortality through 2009. We used regression models to estimate odds ratios (ORs) and hazard ratios (HRs) for PCa according to whole-grain consumption, adjusted for possible confounding factors including fish, fish liver oil, meat, and milk intake. RESULTS: Of the 2,268 men, 347 had or were diagnosed with PCa during follow-up, 63 with advanced disease (stage 3+ or died of PCa). Daily rye bread consumption in adolescence (vs. less than daily) was associated with a decreased risk of PCa diagnosis (OR = 0.76, 95 % confidence interval (CI): 0.59-0.98) and of advanced PCa (OR = 0.47, 95 % CI: 0.27-0.84). High intake of oatmeal in adolescence (>=5 vs. <=4 times/week) was not significantly associated with risk of PCa diagnosis (OR = 0.99, 95 % CI: 0.77 1.27) nor advanced PCa (OR = 0.67, 95 % CI: 0.37-1.20). Midlife and late life consumption of rye bread, oatmeal, or whole-wheat bread was not associated with PCa risk. CONCLUSION: Our results suggest that rye bread consumption in adolescence may be associated with reduced risk of PCa, particularly advanced disease. PMID- 22527176 TI - Production of recombinant antigens and antibodies in Nicotiana benthamiana using 'magnifection' technology: GMP-compliant facilities for small- and large-scale manufacturing. AB - This review describes the adaptation of the plant virus-based transient expression system, magnICON((r)) for the at-scale manufacturing of pharmaceutical proteins. The system utilizes so-called "deconstructed" viral vectors that rely on Agrobacterium-mediated systemic delivery into the plant cells for recombinant protein production. The system is also suitable for production of hetero oligomeric proteins like immunoglobulins. By taking advantage of well established R&D tools for optimizing the expression of protein of interest using this system, product concepts can reach the manufacturing stage in highly competitive time periods. At the manufacturing stage, the system offers many remarkable features including rapid production cycles, high product yield, virtually unlimited scale up potential, and flexibility for different manufacturing schemes. The magnICON system has been successfully adaptated to very different logistical manufacturing formats: (1) speedy production of multiple small batches of individualized pharmaceuticals proteins (e.g. antigens comprising individualized vaccines to treat NonHodgkin's Lymphoma patients) and (2) large-scale production of other pharmaceutical proteins such as therapeutic antibodies. General descriptions of the prototype GMP-compliant manufacturing processes and facilities for the product formats that are in preclinical and clinical testing are provided. PMID- 22527177 TI - One Health: its origins and future. AB - One Health is an emerging concept that aims to bring together human, animal, and environmental health. Achieving harmonized approaches for disease detection and prevention is difficult because traditional boundaries of medical and veterinary practice must be crossed. In the nineteenth and early twentieth centuries, this was not the case-then researchers like Louis Pasteur and Robert Koch and physicians like William Osler and Rudolph Virchow crossed the boundaries between animal and human health. More recently, Calvin Schwabe revived the concept of One Medicine. This was critical for the advancement of the field of epidemiology, especially as applied to zoonotic diseases. The future of One Health is at a crossroad with the need to more clearly define its boundaries and demonstrate its benefits. Interestingly, the greatest acceptance of One Health is seen in the developing world where it is having significant impacts on control of infectious diseases. PMID- 22527174 TI - Diabetes and cancer II: role of diabetes medications and influence of shared risk factors. AB - An association between type 2 diabetes mellitus (DM) and cancer has long been postulated, but the biological mechanism responsible for this association has not been defined. In part one of this review, we discussed the epidemiological evidence for increased risk of cancer, decreased cancer survival, and decreased rates of cancer screening in diabetic patients. Here we review the risk factors shared by cancer and DM and how DM medications play a role in altering cancer risk. Hyperinsulinemia stands out as a major factor contributing to the association between DM and cancer, and modulation of circulating insulin levels by DM medications appears to play an important role in altering cancer risk. Drugs that increase circulating insulin, including exogenous insulin, insulin analogs, and insulin secretagogues, are generally associated with an increased cancer risk. In contrast, drugs that regulate insulin signaling without increasing levels, especially metformin, appear to be associated with a decreased cancer risk. In addition to hyperinsulinemia, the effect of DM medications on other shared risk factors including hyperglycemia, obesity, and oxidative stress as well as demographic factors that may influence the use of certain DM drugs in different populations are described. Further elucidation of the mechanisms behind the association between DM, cancer, and the role of DM medications in modulating cancer risk may aid in the development of better prevention and treatment options for both DM and cancer. Additionally, incorporation of DM medication use into cancer prediction models may lead to the development of improved risk assessment tools for diabetic patients. PMID- 22527178 TI - Hybrid treatment of a ruptured aneurysm in the distal aortic arch: report of a case. AB - An 80-year-old man was transferred to our hospital for surgical treatment of a ruptured aortic arch aneurysm. Based on a history of severe heart failure and coronary artery bypass, we considered him unsuitable for conventional open repair. He underwent a hybrid repair, in the form of supra-aortic vessel debranching followed by endoluminal aortic repair. Although the ostia of the left carotid and left subclavian arteries were occluded by the stent-graft, the left supra-aortic vessels and the left internal thoracic artery attached to the coronary artery were perfused through an extra-anatomic bypass from the right axillary artery to the left carotid artery and the left axillary artery. After additional endovascular repair for recurrent hemosputum, the patient recovered without complications. Although continued follow-up is necessary, acute hybrid arch repair seems feasible for treating ruptured aortic arch aneurysms, even in the setting of severe heart failure and a previous coronary artery bypass. PMID- 22527180 TI - Analysis of the impact of the body mass index in patients with gastric carcinoma. AB - BACKGROUND: Body mass index (BMI) has been suggested to provide clinicopathological information in tumor development and progression in patients with gastric carcinoma. METHODS: The correlation of BMI with clinicopathological features and operation-related factors was analyzed in 308 patients with gastric carcinoma who had undergone distal or total gastrectomy. RESULTS: There was no significant correlation of obesity, indicated by a high value of BMI, with tumor related factors including survival, or with operation-related factors. On the other hand, more advanced tumors and worse preoperative nutritional and immunological conditions were found in patients with a lower value of BMI. CONCLUSIONS: BMI might be a representation of the physical condition brought about by the extent of tumor progression rather than a factor influencing the factors related to gastric carcinoma. PMID- 22527179 TI - Quality of life after laparoscopy-assisted pylorus-preserving gastrectomy: an evaluation using a questionnaire mailed to the patients. AB - PURPOSE: This study investigated the postoperative quality of life (QOL) after laparoscopy-assisted pylorus-preserving gastrectomy (LAPPG) in comparison to laparoscopy-assisted distal gastrectomy (LADG). METHODS: Twenty-one patients with early-stage gastric cancer underwent minimally invasive LADG (n = 12) or LAPPG (n = 9). Demographic and cancer-related data were obtained retrospectively from medical records. QOL was assessed using a 13-item questionnaire and the Japanese edition of the Gastrointestinal Symptom Rating Scale, which were mailed to patients twice postoperatively. Body weight and hemoglobin levels were measured at the same time. RESULTS: Early upper abdominal pain was rated as significantly worse with LAPPG than with LADG at the first checkup (1.4 vs. 1.0, P = 0.02) but not at the second checkup (1.3 vs. 1.0, P = 0.07). There was a trend toward less body weight loss in the LAPPG patients in comparison to the LADG patients. The serum hemoglobin levels of LAPPG patients at the second checkup showed significantly higher than LADG patients (13.3 vs. 11.6 g/dL, P < 0.05). CONCLUSIONS: LAPPG and LADG produce similar QOL in patients. Trends toward less body weight loss and improved anemia in LAPPG patients may therefore become more pronounced in future studies that have adequate number of the patients and longer follow-up periods. PMID- 22527181 TI - Depressed type of intramucosal differentiated-type gastric cancer has high cell proliferation and reduced apoptosis compared with the elevated type. AB - BACKGROUND: The depressed type of early gastric cancer, in comparison to the elevated type, tends to invade the submucosal layer and metastasize to the lymph nodes. This study compared the differences in tumor cell proliferation and apoptosis between the elevated and depressed types of intramucosal differentiated gastric cancer. METHODS: A total of 57 intramucosal differentiated gastric cancers were studied. Twenty samples were the elevated type and 37 were the depressed type. The tumor cells were analyzed by immunohistochemistry for Ki-67, Bcl-2, and Bax, and terminal deoxynucleotidyl transferase 2'-deoxyuridine, 5' triphosphate (dUTP)-biotin nick end labeling was carried out to detect apoptotic cells. RESULTS: (1) The Ki-67 labeling index (KI) was higher in the depressed type (median: 38.6) than in the elevated type (median: 21.2). (2) Immunopositivity for Bax and the apoptosis index (AI) were lower in the depressed type (median AI: 0.20) than the elevated type (median AI: 1.05). (3) The AI/KI was lower in the depressed type (median: 0.17) than in the elevated type (median: 5.57). (4) The AI in the tumors with a Bcl-2-negative and Bax-positive pattern (median: 2.0) was higher than that in the tumors with a Bcl-2-positive and Bax negative pattern (median: 0.2). CONCLUSION: These results show that, regarding cell proliferation and apoptosis, the depressed type of intramucosal differentiated-type gastric cancer has high malignant potential in comparison to the elevated type. PMID- 22527182 TI - Suppression of myeloid cell leukemia-1 (Mcl-1) enhances chemotherapy-associated apoptosis in gastric cancer cells. AB - BACKGROUND: Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic protein that regulates apoptosis sensitivity in a variety of cell types. Here we evaluate the roles of Mcl-1 in chemotherapy-associated apoptosis in gastric cancer cells. In addition, our study examined whether Mcl-1 contributed to apoptosis resistance in so-called cancer stem cell (CSC)-like populations in gastric cancer. METHODS: Seven gastric cancer cell lines were used. The expression of Mcl-1 was assessed by either real-time polymerase chain reaction or Western blot analysis. Apoptosis was quantitated by morphological observation and caspase activity measurement. Adenovirus-mediated RNA interference (RNAi) technology was used to knockdown the expression of Mcl-1. The release of cytochrome c was evaluated by subcellular fractionation and immunoblot analysis. To identify and isolate the CSC-like populations, we used the CSC-associated cell surface marker CD44 and flow cytometry. RESULTS: Six out of the 7 gastric cancer cell lines overexpressed Mcl 1 protein. These Mcl-1-expressing cell lines were relatively resistant to chemotherapeutic agents such as 5-fluorouracil (5-FU) and cisplatin (CDDP). Depletion of Mcl-1 protein by RNAi technology effectively sensitized the cells to anticancer drug-induced mitochondrial cytochrome c release, caspase activation, and apoptosis. In addition, vast amounts of Mcl-1 mRNA were expressed in CD44 positive CSC-like cells. Mcl-1 suppression enhanced the apoptosis in CD44 positive cells to a level equivalent to that in CD44-negative cells, suggesting that Mcl-1 mediates chemotherapy resistance in CSC-like populations. CONCLUSION: These results suggest that Mcl-1 mediates the resistance to apoptosis in gastric cancer cells by blocking the mitochondrial pathway of cell death. Mcl-1 depletion appears to be an attractive strategy to overcome chemotherapy resistance in gastric cancer cells. PMID- 22527183 TI - Incidence trends and mortality rates of gastric cancer in Israel. AB - BACKGROUND: Gastric cancer is the fourth most common malignancy worldwide. The incidence trends and mortality rates of gastric cancer in Israel have not been studied in depth. The aim of our study was to try and investigate the aforementioned issues in Israel in different ethnic groups. METHODS: This retrospective study is based on the data of The Israel National Cancer Registry and The Central Bureau of Statistics. Published data from these two institutes were collected, summarized, and analyzed in this study. RESULTS: Around 650 new cases of gastric cancer are diagnosed yearly in Israel. While we noticed a decline during the period 1990-2007 in the incidence in the Jewish population (13.6-8.9 and 6.75-5.42 cases per 100,000 in Jewish men and women, respectively), an increase in the Arab population was noticed (7.7-10.2 and 3.7-4.2 cases per 100,000 in men and women, respectively). Age-adjusted mortality rates per 10,000 cases of gastric cancer decreased significantly, from 7.21 in 1990 to 5.46 in 2007, in the total population. The 5-year relative survival showed a slight increase for both men and women. CONCLUSION: There is a difference in the incidence and outcome of gastric cancer between the Jewish and Arab populations in Israel. The grim prognosis of gastric cancer patients in Israel is probably due to the advanced stage at which gastric cancer is diagnosed in Israel. PMID- 22527184 TI - Long-term follow up of patients who were positive for peritoneal lavage cytology: final report from the CCOG0301 study. AB - BACKGROUND: In gastric cancer patients who have positive results for peritoneal lavage cytology the disease is defined as CY1, and classified as stage IV, and this population has generally suffered a dismal outcome. For this population, we had conducted a phase II trial, with the 2-year survival rate as the primary endpoint, to test the strategy of D2 dissection followed by chemotherapy with single-agent S-1 (1 M tegafur-0.4 M gimestat-1 M otastat potassium). Forty-eight patients were enrolled, of whom 47 were found to have been eligible for analysis. The 2-year survival rate of 46 % exceeded our expectations. METHODS: Further follow up was conducted to confirm whether radical surgery could be recommended for the CY1 population. RESULTS: The 5-year overall and relapse-free survival rates were 26 and 21 %, respectively. CONCLUSIONS: Gastrectomy with curative intent could be considered for patients with CY1 disease provided they are scheduled to receive effective postoperative chemotherapy. PMID- 22527185 TI - A prospective feasibility and safety study of laparoscopy-assisted distal gastrectomy for clinical stage I gastric cancer initiated by surgeons with much experience of open gastrectomy and laparoscopic surgery. AB - BACKGROUND: The aim of this prospective study was to evaluate the feasibility and safety of laparoscopy-assisted distal gastrectomy (LADG) initiated by surgeons with much experience of open gastrectomy and laparoscopic surgery. METHODS: Three surgeons who each had experience with more than 300 cases of open gastrectomy, more than 100 cases of laparoscopic cholecystectomy, more than 5 cases of laparoscopic colectomy, and more than 5 cases of laparoscopic partial gastrectomy were nominated as LADG operators. All three operators received training for LADG with study materials including videotapes, a box simulator, and an animal laboratory, with lectures and assistance from LADG instructors who each had experience of more than 50 LADG operations. Then the nominated LADG operators performed LADG with the instructors, in which their skills were evaluated and certified. Thereafter, they performed LADG without assistance from the instructors. The target of this study was clinical stage I gastric cancer that was resectable by distal gastrectomy. D1 + alpha, D1 + beta, or D2 dissection was performed laparoscopically. Basically reconstruction was done extracorporeally with a Billroth-I gastroduodenostomy. An extramural review board checked the surgical quality of the operations performed by the three surgeons. The primary endpoint was morbidity and mortality. RESULTS: A total of 193 patients were enrolled in this study between August 2004 and July 2009. The median blood loss was 35 ml and the median operation time was 250 min. Conversion to open surgery was seen in 6 patients; 4 due to bleeding and 2 due to advanced disease. Overall morbidity was 1.6 %, including grade 2 anastomotic leakage in 0.5 % and grade 2 pancreatic fistula in 0.5 %. No mortality was observed. The number of cases required until the LADG operators acted as LADG surgeons without an instructor was 3 for each of the three surgeons. When comparing the data between that in the training period (n = 9) and the operators' data (n = 174), the median operation time was significantly longer in the training period (355 min) than in the latter period (247.5 min) (p = 0.015). Median blood loss was also greater in the training period (150 ml) than the latter period (32.5 ml), but the difference did not reach statistical significance (p = 0.084). During the training period, no patient developed any complications of >= grade 2. CONCLUSION: These results suggested that LADG could be initiated and performed feasibly and safely if surgeons with much experience of open gastrectomy and laparoscopic surgery received adequate training for LADG. PMID- 22527187 TI - Population data of 30 insertion/delection polymorphisms from a sample taken in the North of Portugal. PMID- 22527186 TI - Risk factors for 6-month continuation of S-1 adjuvant chemotherapy for gastric cancer. AB - BACKGROUND: The factors that affect the 6-month continuation of adjuvant chemotherapy with S-1 have not been fully evaluated. The objective of this retrospective study was to clarify the risk factors for 6-month continuation of S 1 adjuvant chemotherapy. METHODS: The study selected patients who underwent curative D2 surgery for gastric cancer, were diagnosed with stage 2 or 3 disease, had a serum creatinine level of <= 1.2 mg/dl, and received adjuvant S-1 between June 2002 and March 2011. RESULTS: One hundred of these patients were eligible for the present study. A comparison of 6-month continuation of S-1 stratified by various clinical factors, using the log-rank test, revealed a marginally significant difference in creatinine clearance (CCr) between those patients who continued for 6 months and those who did not. A CCr of 60 ml/min was regarded as the critical point. Uni- and multivariate Cox's proportional hazard analyses demonstrated that CCr was the only significant independent factor for the prediction of 6-month continuation. The 6-month continuation rate was 72.9 % in the patients with CCr >= 60 ml/min, and 40.0 % in patients with CCr <60 ml/min (P = 0.015). Adverse events occurred more frequently and earlier in the patients with CCr <60 ml/min than in those with CCr >= 60 ml/min. CONCLUSIONS: CCr <60 ml/min was a significant risk factor for 6-month continuation of S-1 adjuvant chemotherapy, even though the renal function was judged as normal by the serum creatinine level. Careful attention is therefore required for S-1 continuation in patients with CCr <60 ml/min. PMID- 22527188 TI - Forensic and phylogeographic characterisation of mtDNA lineages from Somalia. AB - The African mitochondrial (mt) phylogeny is coarsely resolved but the majority of population data generated so far is limited to the analysis of the first hypervariable segment (HVS-1) of the control region (CR). Therefore, this study aimed on the investigation of the entire CR of 190 unrelated Somali individuals to enrich the severely underrepresented African mtDNA pool. The majority (60.5 %) of the haplotypes were of sub-Saharan origin with L0a1d, L2a1h and L3f being the most frequently observed haplogroups. This is in sharp contrast to previous data reported from the Y-chromosome, where only about 5 % of the observed haplogroups were of sub-Saharan provenance. We compared the genetic distances based on population pairwise F (st) values between 11 published East, Central and North African as well as western Asian populations and the Somali sequences and displayed them in a multi-dimensional scaling plot. Genetic proximity evidenced by clustering roughly reflected the relative geographic location of the populations. The sequences will be included in the EMPOP database ( www.empop.org ) under accession number EMP00397 upon publication (Parson and Dur Forensic Sci Int Genet 1:88-92, 2007). PMID- 22527189 TI - Representations of workplace psychological harassment in print news media. AB - OBJECTIVE: To analyze discourses on workplace psychological harassment in print media. METHODOLOGICAL PROCEDURES: Documental study on workplace psychological harassment that analyzed news stories published in three major newspapers of the State of Sao Paulo (southeastern Brazil) between 1990 and 2008. Discourse analysis was performed to identify discursive practices that reflect the phenomenon of psychological harassment in today's society, explanations for its occurrence and impact on workers' health. RESULT ANALYSIS: This theme emerged in the media through the dissemination of books, academic research production and laws. It was initially published in general news then in jobs and/or business sections. Discourses on compensation and precautionary business practices and coping strategies are widespread. Health-related aspects are foregone under the prevailing money-based rationale. Corporate cultures are permissive regarding psychological harassment and conflicts are escalated while working to achieve goals and results. Indifference, embarrassment, ridicule and demean were common in the news stories analyzed. CONCLUSIONS: The causal explanations of workplace harassment tend to have a psychological interpretation with emphasis on individual and behavioral characteristics, and minimizing a collective approach. The discourses analyzed trivialized harassment by creating caricatures of the actors involved. People apprehend its psychological content and stigmatization which contributes to making workplace harassment an accepted practice and trivializing work-related violence. PMID- 22527190 TI - Composite indicator to evaluate quality of municipal management of primary health care. AB - OBJECTIVE: To develop a composite indicator to evaluate the quality of municipal management of primary health care. METHODS: The evaluation model focuses on aspects of health system management. Fifty-five performance indicators were used and classified according to the criteria of relevance, effectiveness, efficacy and efficiency. The measures were aggregated through an additive data envelopment analysis model for measures of value, merit and quality. Data was utilized from 36 municipalities in Santa Catarina State (Southern Brazil), with populations between 10 thousand and 50 thousand residents in 2006. RESULTS: The results are presented as monotonic measures over the interval [0, 1] (score = 1: efficient; other values: inefficient). Five municipalities had a score of 1 in the quality of management for actions promoting access, while eight municipalities received a score of 1 in the quality of management of actions for service provision; the other municipalities were classified as inefficient (score < 1) for both dimensions. CONCLUSIONS: The quality of municipal management in primary health care can be evaluated with a composite indicator, constructed through linear programming techniques, which simultaneously considers the criteria of relevance, effectiveness, efficacy and efficiency and expresses them as measures of value, merit and quality. PMID- 22527191 TI - Drug use in college students: a 13-year trend. AB - OBJECTIVE: To analyze drug use trends among college students in 1996, 2001 and 2009. METHODS: A cross-sectional epidemiological study with a multistage stratified cluster sample with 9,974 college students was conducted in the city of Sao Paulo, southeastern Brazil. An anonymous self-administered questionnaire was used to collect information on drug use assessed in lifetime, the preceding 12 months and the preceding 30 days. The Bonferroni correction was used for multiple comparisons of drug use rates between surveys. RESULTS: There were changes in the lifetime use of tobacco and some other drugs (hallucinogens [6.1% to 8.8%], amphetamines [4.6% to 8.7%], and tranquilizers [5.7% to 8.2%]) from 1996 to 2009. Differences in the use of other drugs over the 12 months preceding the survey were also seen: reduced use of inhalants [9.0% to 4.8%] and increased use of amphetamines [2.4% to 4.8%]. There was a reduction in alcohol [72.9% to 62.1%], tobacco [21.3% to 17.2%] and marijuana [15.0% to 11.5%] use and an increase in amphetamine use [1.9% to 3.3%] in the preceeding 30 days. CONCLUSIONS: Over the 13-year study period, there was an increase in lifetime use of tobacco, hallucinogens, amphetamines, and tranquilizers. There was an increase in amphetamine use and a reduction in alcohol use during the preceding 12 months. There was an increase in amphetamine use during the preceding 30 days. PMID- 22527192 TI - Payment for performance in the Family Health Programme: lessons from the UK Quality and Outcomes Framework. AB - OBJECTIVE: Payment for performance financial incentive schemes reward doctors based on the quality and the outcomes of their treatment. In Brazil, the Ministry of Health is looking to scale up its use in public hospitals and some municipalities are developing payment for performance schemes even for the Family Health Programme. In this article the Quality and Outcomes Framework used in the UK since 2004 is discussed, as well as its experience to elaborate some important lessons that Brazilian municipalities should consider before embarking on payment for performance scheme in primary care settings. PMID- 22527193 TI - Effect of interventions on the body mass index of school-age students. AB - OBJECTIVE: To evaluate the effect of intervention programs using nutritional education, physical activity or both on the reduction of body mass index in school-age students. METHODS: The systematic review with meta-analysis included randomized controlled studies available from the following electronic databases for the years 1998 to 2010: PubMed, Lilacs, Embase, Scopus, Web of Science and Cochrane Library. The descriptors were: randomized controlled trial, overweight, obesity, body mass index, child, adolescent, physical activity, nutrition education and Schools. A weighted average was based on the standardized means difference and used a 95% confidence interval. The inconsistency test was utilized to evaluate the heterogeneity of studies. RESULTS: Initially, 995 studies were identified, of which 23 were included, and 3 meta-analyses were performed. Isolated physical activity interventions did not present a significant reduction in BMI, with a standardized mean difference of -0.02 (95%CI: -0.08; 0.04). A similar result (n= 3,524) was observed in the isolated interventions of nutritional education, with a standardized mean difference of -0.03 (95%CI: 0.10; 0.04).When the interventions with physical activity and nutritional education were combined, the result of the meta-analysis (n= 9,997) presented a statistically significant effect in the reduction of body mass index in school age students, with a standardized mean difference: -0.37 (95%CI: -0.63; -0.12). CONCLUSIONS: The interventions that combined physical activity and nutritional education had more positive effects in the reduction of body mass index among school-age students than when they were applied individually. PMID- 22527194 TI - A new isoform of thioredoxin h group in potato, SbTRXh1, regulates cold-induced sweetening of potato tubers by adjusting sucrose content. AB - In order to study the molecular mechanism of the cold-induced sweetening (CIS) of potato tubers, a novel isoform of thioredoxin h group, SbTRXh1, which was up regulated early in the 4 degrees C storage of CIS-resistant potato (Solanum berthaultii) tubers, was cloned in present research. The genetic transformation of over-expression (OE) and RNA interference (RNAi) of SbTRXh1 into potato cv. E Potato 3 (E3) was carried out to clarify its function in CIS regulation. The results showed that the transcripts of SbTRXh1 in either OE- or RNAi-tubers were strongly induced in 4 degrees C storage and quantitatively related to the reducing sugar (RS) accumulation, indicating that SbTRXh1 is involved in the CIS process of potato tubers. Regression analysis between the transcripts and protein contents of SbTRXh1 showed a very significant logarithmic relationship implying that the expression of SbTRXh1 may be mainly regulated at transcriptional level. Further monitoring the variation of the sugar contents in cold-stored tubers demonstrated a linear relationship between RS and sucrose (Suc). Thus, it can be inferred that SbTRXh1 may function in the Suc-RS pathway for CIS regulation of potato tubers. KEY MESSAGE: SbTRXh1 is primarily demonstrated to be involved in the regulation of cold-induced sweetening (CIS) of potato tubers, and it may function in the Suc-RS pathway for CIS regulation. PMID- 22527195 TI - Expression profiles of a banana fruit linker histone H1 gene MaHIS1 and its interaction with a WRKY transcription factor. AB - Chromatin remodeling-related proteins, such as linker histone H1, involving in fruit ripening and stress responses are poorly understood. In the present study, a novel cDNA encoding linker histone H1 gene, designated as MaHIS1 was isolated and characterized from banana fruit. The full-length cDNA sequence was 1,253 bp with an open-reading frame (ORF) of 948 bp, encoding 315 amino acids with a molecular weight of 31.98 kDa and a theoretical isoelectric point of 10.67. Subcellular localization analysis showed that MaHIS1 was a nucleus-localized protein. Real-time PCR analysis indicated that expression of MaHIS1 gene is induced by external and internal ethylene during fruit postharvest ripening. Accumulation of MaHIS1 transcript was also obviously enhanced by exogenous hormones, including methyl jasmonate, abscisic acid, and hydrogen peroxide (H2O2), as well as stresses, such as chilling and pathogen Colletotrichum musae infection. Moreover, yeast two-hybrid and bimolecular fluorescence complementation assays showed that MaHIS1 could interact with a transcription factor (TF) MaWRKY1. Taken together, our results suggest that MaHIS1 may be related to ripening and stress responses of banana fruit, and be likely functionally coordinating with MaWRKY1 in these physiological processes. KEY MESSAGE: MaHIS1 may be related to ripening and stress responses of banana fruit, and it also could interact with WRKY TF, which expands the very limited information regarding the functions of linker histone H1 in fruits. PMID- 22527196 TI - Genetic engineering and sustainable production of ornamentals: current status and future directions. AB - Through the last decades, environmentally and health-friendly production methods and conscientious use of resources have become crucial for reaching the goal of a more sustainable plant production. Protection of the environment requires careful consumption of limited resources and reduction of chemicals applied during production of ornamental plants. Numerous chemicals used in modern plant production have negative impacts on human health and are hazardous to the environment. In Europe, several compounds have lost their approval and further legal restrictions can be expected. This review presents the more recent progress of genetic engineering in ornamental breeding, delivers an overview of the biological background of the used technologies and critically evaluates the usefulness of the strategies to obtain improved ornamental plants. First, genetic engineering is addressed as alternative to growth retardants, comprising recombinant DNA approaches targeting relevant hormone pathways, e.g. the gibberellic acid (GA) pathway. A reduced content of active GAs causes compact growth and can be facilitated by either decreased anabolism, increased catabolism or altered perception. Moreover, compactness can be accomplished by using a natural transformation approach without recombinant DNA technology. Secondly, metabolic engineering approaches targeting elements of the ethylene signal transduction pathway are summarized as a possible alternative to avoid the use of chemical ethylene inhibitors. In conclusion, molecular breeding approaches are dealt with in a way allowing a critical biological assessment and enabling the scientific community and public to put genetic engineering of ornamental plants into a perspective regarding their usefulness in plant breeding. PMID- 22527198 TI - Salt tolerance in soybean WF-7 is partially regulated by ABA and ROS signaling and involves withholding toxic Cl- ions from aerial tissues. AB - Salt tolerance in plants is a complex trait involving multiple mechanisms. Understanding these mechanisms and their regulation will assist in developing novel strategies to engineer salt-tolerant crops. In the current study, we investigated salt-tolerant mechanisms in soybean (Glycine max) cultivar WF-7 in comparison to salt-sensitive Union. In vivo and in vitro salt assays demonstrated the salt tolerance of WF-7 at the seedling stage and during germination. After a 10-day 200 mM NaCl treatment, chlorophyll content in Union was reduced by 50 % compared to a 17 % reduction in WF-7. WF-7 was also less affected by abscisic acid (ABA) and NaCl during germination than Union. Upon ABA and NaCl treatment, the ABA-responsive genes SCOF1, ASN1, bZIP44, and AAPK1 are differentially expressed in WF-7 and Union seedlings. These results suggest that salt tolerance in WF-7 is in part regulated through an ABA-dependent pathway. In addition, following a 4-day 200 mM NaCl treatment, WF-7 produced more H2O2 than Union indicating the involvement of reactive oxygen species (ROS) in regulating salt tolerance in WF-7. Yet another mechanism WF-7 employs is withholding toxic chloride (Cl-) ions from aerial tissues. Following 200 mM NaCl treatment, Cl- accumulation was mostly localized to the roots of WF-7. In contrast, most of the Cl- in Union was transported into the stems and leaves. Taken together, our results demonstrated a role of ABA and ROS in regulating salt tolerance in WF-7, and the critical role of Cl- in NaCl-induced mortality in soybean. Key message Withholding toxic Cl- ions from leaves and, to a lesser extent, stems, confers salt tolerance to soybean WF-7. In addition, ABA and ROS may be involved in salt stress signal transduction. PMID- 22527200 TI - Does the US health care safety net discourage private insurance coverage? AB - The large and growing uninsured population poses an alarming threat to the US health care system, and is a major target of the Obama health reform. This paper investigates analytically and empirically the degree to which the absence of health insurance in the US reflects the availability of the health care safety net, such as the guaranteed or charitable care provided by emergency rooms, community health centers and physicians. Our theoretical model demonstrates that the safety net can be a real alternative to health insurance, thus discouraging private insurance purchase in the market setting. In particular, when the community premium rate fails to reflect the value of such resources, not purchasing insurance becomes a rational decision for a sizeable portion of the population. The calibrated simulation based on US statistics indicates about 15.75% of the uninsured population, or 7.2 million people in US, are attributable to the existing safety net system. Further empirical analysis using nationally representative data shows consistently that the presence of local safety net resources may reduce the probability of individual insurance purchase by as much as 45.9%. PMID- 22527199 TI - Equal modulation of endothelial cell function by four distinct tissue-specific mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) can generate multiple end-stage mesenchymal cell types and constitute a promising population of cells for regenerative therapies. Additionally, there is increasing evidence supporting other trophic activities of MSCs, including the ability to enable formation of vasculature in vivo. Although MSCs were originally isolated from the bone marrow, the presence of these cells in the stromal vascular fraction of multiple adult tissues has been recently recognized. However, it is unknown whether the capacity to modulate vasculogenesis is ubiquitous to all MSCs regardless of their tissue of origin. Here, we demonstrated that tissue-resident MSCs isolated from four distinct tissues have equal capacity to modulate endothelial cell function, including formation of vascular networks in vivo. MSCs were isolated from four murine tissues, including bone marrow, white adipose tissue, skeletal muscle, and myocardium. In culture, all four MSC populations secreted a plethora of pro angiogenic factors that unequivocally induced proliferation, migration, and tube formation of endothelial colony-forming cells (ECFCs). In vivo, co-implantation of MSCs with ECFCs into mice generated an extensive network of blood vessels with ECFCs specifically lining the lumens and MSCs occupying perivascular positions. Importantly, there were no differences among all four MSCs evaluated. Our studies suggest that the capacity to modulate the formation of vasculature is a ubiquitous property of all MSCs, irrespective of their original anatomical location. These results validate multiple tissues as potential sources of MSCs for future cell-based vascular therapies. PMID- 22527201 TI - Heritable and environmental factors in the causation of clinical vertebral fractures. AB - Vertebral fractures are common osteoporotic fractures, and their incidence is greater in Scandinavia than in other European regions. Vertebral fractures are strongly associated with low bone mineral density, which has a predominant genetic etiology. The heritability of radiological vertebral deformities has been estimated in one recent family study. The objective of our study was to determine the genetic liability to clinical vertebral fractures and to what extent individual-specific environmental factors can explain the variance of these fractures. Participants were ascertained from the Swedish Twin Registry. Twin pairs born 1896-1944 formed the study base, a total of 33,432 subjects. Vertebral fractures after the age of 50 years were identified in the National Patient Register (n = 1,037) or by self-report (n = 35). The age-adjusted heritability for all vertebral fractures was 0.17 (95 % CI 0.00-0.40). Restricting the fracture cases to low-energy causes of injury, the heritability was 0.24 (95 % CI 0.00-0.47). Individual-specific environmental influences were found to explain one-third of the variance in vertebral fracture occurrence before the age of 70 years (0.33, 95 % CI 0.16-0.56), whereas they explained most of the variance among those 80 years of age or older (0.83, 95 % CI 0.61-1.00). We conclude that the occurrence of clinical vertebral fractures is largely explained by environmental influences and not by genetic factors. Individual-specific environmental influences such as lifestyle become more important with increasing age, and it is of importance to identify those environmental factors that cause more fracture cases in Scandinavia than in other European settings. PMID- 22527203 TI - The effect of socioeconomic position on bone health among Koreans by gender and menopausal status. AB - While studies suggest that socioeconomic position (SEP) influences bone health and risk of osteoporotic fracture in postmenopausal women, few studies have simultaneously examined gender and menopause differences as they relate to SEP and bone health. Here, we investigated the relationship between SEP and bone mineral density (BMD) among Korean men, premenopausal women, and postmenopausal women using the BMD data set (n = 9,995) of the Korean National Health and Nutrition Examination Survey IV. The relationship between SEP and BMD was estimated using analysis of covariance (ANCOVA); adjustments were made for age and body mass index (BMI) in the multivariate models. The relationship between SEP and osteoporosis prevalence was estimated using logistic regression. Relative index of inequality (RII) in osteoporosis was estimated using log-binomial regression. ANCOVA (adjusted for age and for age plus BMI) showed a significant positive association between SEP and BMD among men and postmenopausal women. Logistic regression showed a significant negative association between SEP and osteoporosis prevalence among men and postmenopausal women but not in premenopausal women. The RII, estimated by log-binomial regression, showed the impact of SEP on osteoporosis to be significant in men and postmenopausal women (p < 0.05) but not in premenopausal women. Overall, low SEP was associated with both low BMD and high risk of osteoporosis among men and postmenopausal women. Efforts to reduce the economic burden of morbidity and mortality from osteoporosis should target men and postmenopausal women with low SEP. PMID- 22527202 TI - Circulating sclerostin and Dickkopf-1 (DKK1) in predialysis chronic kidney disease (CKD): relationship with bone density and arterial stiffness. AB - Abnormalities of bone metabolism and increased vascular calcification are common in chronic kidney disease (CKD) and important causes of morbidity and mortality. The Wnt signaling pathway may play a role in the bone and vascular disturbances seen in CKD, termed collectively "CKD-MBD." The aim of the study was to investigate the possible association of circulating concentrations of the secreted Wnt signaling inhibitors DKK1 and sclerostin with BMD and arterial stiffness in predialysis CKD. Seventy-seven patients (48 M, 29 F), mean age 57 (SD = 14) years with CKD stages 3B (n = 32) and 4 (n = 45) were studied. Sclerostin, DKK1, PTH, and 1,25(OH)(2)D were analyzed. BMD was measured at the lumbar spine (LS), femoral neck (FN), total hip (TH), and forearm (FARM). Arterial stiffness index was determined by contour analysis of digital volume pulse (SI(DVP)). There was a positive correlation between sclerostin and age (r = 0.47, p < 0.000). Sclerostin was higher in men than women (p = 0.013). Following correction for age and gender, there was a negative association between GFR and sclerostin (p = 0.002). We observed a positive association between sclerostin and BMD at the LS (p = 0.0001), FN (p = 0.004), and TH (p = 0.002). In contrast, DKK1 was negatively associated with BMD at the FN (p = 0.038). A negative association was seen between DKK1 and SI(DVP) (p = 0.027). Our data suggest that the Wnt pathway may play a role in CKD-MBD. Prospective studies are required to establish the clinical relevance of sclerostin and DKK1 as serological markers in CKD. PMID- 22527204 TI - Poor trabecular microarchitecture at the distal radius in older men with increased concentration of high-sensitivity C-reactive protein--the STRAMBO study. AB - Low-grade inflammation, assessed by serum high-sensitivity C-reactive protein (hsCRP) concentration, is associated with higher fracture risk irrespective of areal bone mineral density (aBMD). We assessed the association of hsCRP with bone microarchitecture (measured by high-resolution pQCT) at the distal radius and tibia in 1,149 men, aged 19-87 years. hsCRP concentration increased with age until the age of 72, then remained stable. aBMD was not correlated with hsCRP level. After adjustment for confounders, bone microarchitecture was not associated with hsCRP level in men aged <72. After the age of 72, hsCRP >5 mg/L was associated with lower trabecular density, lower trabecular number, higher trabecular spacing, and more heterogeneous trabecular distribution (p < 0.05 0.005) at the distal radius versus hsCRP <= 5 mg/L. Similar differences were found for the fourth hsCRP quartile (>3.69 mg/L) versus the three lower quartiles combined. Cortical parameters of distal radius and microarchitectural parameters of distal tibia did not vary according to hsCRP concentration in men aged >= 72. Fracture prevalence increased with increasing hsCRP level. After adjustment for confounders (including aBMD), odds for fracture were higher in men with hsCRP >5 mg/L compared to hsCRP <1 mg/L (OR = 2.22, 95 % CI 1.29-3.82) and did not change after additional adjustment for microarchitectural parameters. The association between hsCRP level and bone microarchitecture was observed only for trabecular parameters at the radius in men aged >=72. Impaired bone microarchitecture does not seem to explain the association between elevated CRP level and higher risk of fracture. PMID- 22527205 TI - Osteoclast fusion and fission. AB - Osteoclasts are specialized multinucleated cells with the unique capacity to resorb bone. Despite insight into the various steps of the interaction of osteoclast precursors leading to osteoclast formation, surprisingly little is known about what happens with the multinucleated cell itself after it has been formed. Is fusion limited to the short period of its formation, or do osteoclasts have the capacity to change their size and number of nuclei at a later stage? To visualize these processes we analyzed osteoclasts generated in vitro with M-CSF and RANKL from mouse bone marrow and native osteoclasts isolated from rabbit bones by live cell microscopy. We show that osteoclasts fuse not only with mononuclear cells but also with other multinucleated cells. The most intriguing finding was fission of the osteoclasts. Osteoclasts were shown to have the capacity to generate functional multinucleated compartments as well as compartments that contained apoptotic nuclei. These compartments were separated from each other, each giving rise to a novel functional osteoclast or to a compartment that contained apoptotic nuclei. Our findings suggest that osteoclasts have the capacity to regulate their own population in number and function, probably to adapt quickly to changing situations. PMID- 22527206 TI - Pantoprazole, a proton pump inhibitor, delays fracture healing in mice. AB - Proton pump inhibitors (PPIs), which are widely used in the treatment of dyspeptic problems, have been shown to reduce osteoclast activity. There is no information, however, on whether PPIs affect fracture healing. We therefore studied the effect of the PPI pantoprazole on callus formation and biomechanics during fracture repair. Bone healing was analyzed in a murine fracture model using radiological, biomechanical, histomorphometric, and protein biochemical analyses at 2 and 5 weeks after fracture. Twenty-one mice received 100 mg/kg body weight pantoprazole i.p. daily. Controls (n = 21) received equivalent amounts of vehicle. In pantoprazole-treated animals biomechanical analysis revealed a significantly reduced bending stiffness at 5 weeks after fracture compared to controls. This was associated with a significantly lower amount of bony tissue within the callus and higher amounts of cartilaginous and fibrous tissue. Western blot analysis showed reduced expression of the bone formation markers bone morphogenetic protein (BMP)-2, BMP-4, and cysteine-rich protein (CYR61). In addition, significantly lower expression of proliferating cell nuclear antigen indicated reduced cell proliferation after pantoprazole treatment. Of interest, the reduced expression of bone formation markers was associated with a significantly diminished expression of RANKL, indicating osteoclast inhibition. Pantoprazole delays fracture healing by affecting both bone formation and bone remodeling. PMID- 22527208 TI - An unprecedented ring-opening reaction of N-(aziridin-2-ylmethylene)hydrazines to facile synthesis of functionalized enamines catalysed by Lewis acid. AB - An interesting Lewis acid-catalysed ring-opening reaction of N-(aziridin-2 ylmethylene)hydrazines has been described in this context. A variety of functionalized enamines could be obtained in good yields through a highly regioselective cleavage of a carbon-nitrogen single bond in the aziridines along with a 1,2-migration of the substituent. PMID- 22527209 TI - Type 2 diabetes mellitus and gender-specific risk for colorectal neoplasia. AB - Although a positive association between type 2 diabetes mellitus (T2DM) and colorectal cancer is well established, uncertainty exists about risk differences in diabetic men and women when considering colorectal neoplasia (CN). The main objective was to examine gender-specific associations of T2DM with CN in a population-based cohort study of adults in Germany. This analysis is based on participants of the ESTHER-study, a population-based cohort study. Participants were 50-74 years old at baseline and underwent colonoscopy during 5 year follow up. CN detected at colonoscopy were validated by medical records review. Total and gender-specific associations of T2DM at baseline and CN were estimated using log-binomial regression. Overall, 55 cases of CN were detected in 166 participants with T2DM and 328 cases in 1,360 participants without T2DM. In women, CN was found in 32 % of participants with T2DM and in 18 % without T2DM (adjusted prevalence ratio (PR): 1.66 95 % CI 1.04-2.64). In men, prevalence for CN was 35 % for those with T2DM and 33 % for those without T2DM (adjusted PR = 1.01; 95 % CI 0.71-1.43). T2DM might have a stronger impact on CN among women than among men. Further research should examine possible reasons for these differences. PMID- 22527210 TI - [Autoinflammatory disease]. PMID- 22527211 TI - [Adult onset Still's disease, fever, diagnosis and therapy]. AB - Adult onset Still's disease (AOSD) with an incidence of 1-3 cases per 1 million belongs to the most difficult diagnosis of febrile diseases. The lack of biomarkers and its similarity to infectious and malignant and rheumatic diseases lead to a prolongation of its diagnosis. The following report focuses on providing an overview of the current knowledge of relevant symptoms and laboratory parameters for the diagnosis of AOSD and new treatment possibilities. PMID- 22527212 TI - [Schnitzler syndrome]. AB - Schnitzler syndrome is a rare systemic inflammatory disease characterized by the presence of chronic urticarial skin rash and a monoclonal immunoglobulin M (IgM) gammopathy, combined with further, variable disease symptoms. The term refers to a young disease entity which has recently gained increasing acknowledgement and attention, also due to the availability of interleukin-1 (IL-1) blockade as an effective therapeutic option. Insights into the pathophysiology of the disease have resulted in the assumption of Schnitzler syndrome being a special form of an autoinflammatory disease with late onset or an acquired genesis. This article provides an overview on the clinical appearance, current knowledge of pathophysiology and available therapeutic options. PMID- 22527214 TI - [Cryopyrin-associated periodic syndrome]. AB - The cryopyrin-associated periodic syndrome is a very rare disease. It is estimated that there are 1-2 cases out of 1 million inhabitants in the USA and 1/360,000 in France. However, many patients are diagnosed very late or not at all. Therefore the real prevalence is likely to be higher. CAPS encompasses the three entities familial cold autoinflammatory syndrome (FCAS), the Muckle-Wells syndrome and the neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic cutaneous and articular (CINCA) syndrome. They have in common a causative mutation in the NLRP3-gene. The altered gene product cryopyrin leads to activation of the inflammasome which in turn is responsible for excessive production of IL-1beta. IL-1beta causes the inflammatory manifestations in CAPS. These appear as systemic inflammation including fever, headache or fatigue, rash, eye disease, progressive sensorineural hearing loss, musculoskeletal manifestations and CNS symptoms (NOMID/CINCA only). With the advent of the IL-1 inhibitors anakinra, rilonacept and canakinumab for the first time safe and effective therapeutic options are available for this devastating disease. To prevent severe and possible life-threatening disease sequelae, early and correct diagnosis and immediate initiation of therapy are mandatory. PMID- 22527215 TI - [Drug-drug interactions in antirheumatic treatment]. AB - Clinically relevant drug-drug interactions contribute considerably to potentially dangerous drug side-effects and are frequently the reason for hospitalization. Nevertheless they are often overlooked in daily practice. For most antirheumatic drugs a vast number of interactions have been described but only a minority with clinical relevance. Several potentially important drug interactions exist for non steroidal anti-inflammatory drugs (NSAIDs), methotrexate, azathioprine, mycophenolate-mofetil and especially for cyclosporin A. Most importantly co medication with methotrexate and sulfmethoxazole trimethoprim as well as azathioprine and allopurinol carries the risk of severe, sometimes life threatening consequences. Nevertheless, besides these well-known high-risk combinations in each case of polypharmacy with antirheumatic drugs it is necessary to bear in mind the possibility of drug interactions. As polypharmacy is a common therapeutic practice in older patients with rheumatic diseases, they are at special risk. PMID- 22527216 TI - [Clinical symptoms and pathophysiology of osteophyte formation and ankylosis]. AB - The interdisciplinary combined project ANCYLOSS is investigating in six subprojects molecular factors which play an essential role in the formation of osteophytes. These bony projections are designed to counteract bone degeneration but, however, in certain rheumatic diseases lead to an excessive reaction with uncontrolled bone spur formation. It could be shown that low levels of Dickkopf-1 protein, which is stimulated by TNF-alpha, promote the formation of bone spurs. PMID- 22527213 TI - [Immune reconstitution syndrome]. AB - The immune reconstitution inflammatory syndrome (IRIS) represents a heterogeneous group of conditions. Whilst they typically present in HIV-infected patients with advanced immunodeficiency, IRIS have also been described in HIV-negative patients with immune reconstitution due to other causes of immunosuppression. Frequently IRIS results from an immune response against underlying infection (pathogen associated IRIS). However, IRIS might become evident during immune reconstitution without an underlying pathogen such as a sarcoid-like illness or an autoimmune thyropathy. Here we report on the epidemiology and risk factors of IRIS along with diagnosis and management of this clinically important inflammatory syndrome. PMID- 22527217 TI - [Hospital financing in 2012 - Relevant changes for rheumatology]. AB - The following article presents the major general and specific changes for the financing of rheumatology in Germany for 2012. Besides relevant changes in the German diagnosis-related groups (G-DRG) classification system and for the coding, the new legislation and the resulting incentives are covered. The consequences for hospitals specialized in rheumatology are discussed. PMID- 22527220 TI - Manofluorography in the evaluation of oropharyngeal dysphagia. AB - Manofluorography, that is, the concurrent use of manometry and videofluorography for the evaluation of pharyngeal dysphagia, has not been widely used clinically, partially because of various limitations of conventional manometry. Technological advancements in recent years have led to substantial improvements in manometric devises, which can now overcome many of the shortcomings of standard manometry. In parallel with this, studies examining the utility of high-resolution manometry for the evaluation of pharyngeal disorders of swallowing have begun to emerge. This review summarizes the technological developments in manometry and the existing literature on pharyngeal high-resolution manofluorography with pressure topography. The article also discusses the potential clinical value of high resolution pharyngeal-esophageal pressure topography and suggests directions for future investigations. Studies conducted so far have shown heterogeneous approaches to utilizing high-resolution manofluorography. These studies have revealed important information regarding its diagnostic potential and researchers have devised innovative methods of measurements. However, substantial research is required to transform manofluorography into a clinically useful tool. There is a need to conduct validation studies, correlating manometric measures with structural changes in the swallow seen on videofluorography and devise diagnostic methods that utilize the advantages of both tools. Furthermore, studies comparing healthy and clinical populations are needed to identify measures most clinically significant in order to develop diagnostic paradigms. PMID- 22527221 TI - Dementia and behavioral neurology: recent advances. AB - In this review, progress in dementia and behavioral neurology research published in the Journal of Neurology during the past year is summarized. PMID- 22527222 TI - Promotor polymorphisms of plasminogen activator inhibitor-1 and other thrombophilic genotypes in cerebral venous thrombosis: a case-control study in adults. AB - Plasminogen activator inhibitor 1 (PAI-1) is the main inhibitor of tissue-type and urokinase-type plasminogen activator. A 4G/5G polymorphism in the promoter region of the PAI-1 gene has been reported to enhance the plasma levels of PAI-1. In particular, the 4G allele (guanosine deletion) has been linked with increased plasma PAI-1 levels, which may lead to impaired activity of the fibrinolytic system, thus increasing the incidence of thrombotic events. The aim of this case control study was to analyze whether variants of the PAI-1 promotor genotype 4G/4G, 4G/5G and 5G/5G, in particular the 4G/5G-variant, constitute an independent risk factor of cerebral venous thrombosis (CVT). A total of 136 consecutive patients with proven CVT were compared to 1,054 DNA specimens of healthy controls from a population-based cohort. PAI-1 promotor polymorphisms were evaluated using polymerase chain reaction. No significant association of CVT with PAI-1 4G/5G was found in either the additive (OR 1.04; 95 % CI 0.78-1.38) or in the dominant model (OR 1.24; 95 % CI 0.72-2.13). Also, the prevalence of the other genotypes (4G/4G and 5G/5G) in patients was not significantly different from controls. When considering the variants of the PAI-1 promoter genotype in combination with known genetical thrombophilias, no differences were found either. As was expected, the prothrombin (G20210A) genotype was confirmed as an independent risk factor for CVT. We conclude that the 4G allele of the PAI-1 polymorphism does not increase the risk of CVT in adults. PMID- 22527223 TI - Neurological disorder screening in the elderly in low-income countries. AB - There are few data on neurological disorder prevalence from developing countries, particularly in the elderly in sub-Saharan Africa (SSA). This is in part due to the lack of a feasible and valid screening instrument. We aimed to develop (and pilot) a brief screening instrument for neurological disorders in an elderly population in SSA. Our study population of 2,232 was selected at random from the entire 70 years and over population of a demographic surveillance site in rural Tanzania. One village, with a population of 277, was randomly selected as a pilot site prior to screening the rest of the study population. We designed a screening questionnaire based on the neurological section of the WHO International Statistical Classification of Diseases and Related Health Problems 10th Revision for use by non-medical interviewers (NMI). Of the 277 participants aged 70 years and over in the pilot village, 82 had neurological disorders, with a further 267 identified as having neurological disorders during the study extension to the remaining study population of 1955. The questionnaire was practical, acceptable to recipients, and easily performed by an NMI. The sensitivity and specificity of the questionnaire were 87.8 and 94.9 %, respectively, in the pilot and 97.0 and 90.4 %, respectively, in the extension. This is the first published screening instrument for measuring the prevalence of neurological disorders in a developing country, which is dedicated to the elderly population. It is feasible to use and has high sensitivity and specificity. PMID- 22527224 TI - Clinical assessment of deficits after SAH: hasty neurosurgeons and accurate neurologists. AB - For survivors of aneurysmal subarachnoid hemorrhage (SAH), somatic and cognitive deficits can affect long-term outcomes. We were interested in comparing the deficits identified in SAH patients, including cognitive deficits, at discharge by neurosurgeons and deficits identified by neurologists upon admission to the rehabilitation unit on the same day. The assessment of deficits might have an impact on referring patients to rehabilitation. This retrospective study included 494 SAH patients treated between 2005 and 2010. Of these, 50 patients were discharged to an affiliated rehabilitation unit. Deficits were grouped into 18 categories and summarized into three groups: major somatic, minor somatic, and cognitive deficits. Major somatic deficits were identified in 16 and 20 patients (p = 0.53), minor somatic deficits in 16 and 44 (p < 0.0001) patients, and cognitive deficits in 36 and 45 (p < 0.04) patients by neurosurgeons and neurologists, respectively. The absolute number of deficits in daily activities identified by the neurosurgeon and neurologist were 21 and 31 major somatic deficits (p = 0.2), 18 and 97 minor somatic deficits (p < 0.0001), and 61 and 147 cognitive deficits (p < 0.0001), respectively. Significant differences in assessment of cognitive and minor somatic deficits between neurosurgeons and neurologists exist. Based on these findings, it is evident that for the neurosurgeon, there needs to be an increased awareness of the assessment of cognitive deficits and a more routine interdisciplinary approach, including the use of neuropsychological evaluations, to ensure a better triage of patients to rehabilitation or for discharge home. PMID- 22527225 TI - Age-dependent differences in cervical artery dissection. AB - The goal of this work was to explore age-dependent differences in cervical artery dissection (CeAD). This study is based on the Cervical Artery Dissection and Ischemic Stroke Patients population comprising 983 consecutive CeAD patients and 658 control patients with a non-CeAD ischemic stroke (IS), frequency-matched for age and gender. Patients were divided into three age categories: <=33 (for CeAD, n = 150), 34-54 (n = 688), and >=55 (n = 145) years, and the youngest and oldest groups were compared. The youngest patients were mostly women and the oldest men. The frequency of internal carotid artery dissection (ICAD) versus vertebral artery dissection (VAD) increased with age from 44 to 75 %. This age-related shift remained significant after adjustment for sex. The frequency of a transient ischemic event as the CeAD symptom declined from 33 % in the youngest age group, to 19 % in the oldest. Vascular risk factors increased in frequency with advancing age in both groups, but for hypertension the increase was steeper for non-CeAD IS patients. For CeAD patients, but not for patients with non-CeAD IS, preceding infection was more common in the oldest group. The youngest non-CeAD IS patients had better functional outcome (modified Rankin Scale 0-1) than the oldest, while the similar trend was not statistically significant among CeAD patients. Younger age seems to be associated with VAD and female gender, and older age with ICAD and male gender. Age-related changes in the frequencies of hypertension and recent infection were different between the CeAD and non-CeAD IS groups. Age does not seem to be an important outcome predictor in CeAD strokes. PMID- 22527226 TI - Adolf von Strumpell: a key yet neglected protagonist of neurology. AB - German internist and neurologist Adolf von Strumpell (1853-1925) was a leading figure in German neurosciences around 1900 and helped to establish neurology as a discipline in its own right. He made contributions that were crucial to the development of the subject and in many cases his were the first descriptions of complex diseases such as Bechterew disease (ankylosing spondylitis), primary lateral sclerosis, hereditary spastic paraplegia, and syphilis. His Textbook of Special Pathology and Therapy of Internal Diseases, published in English as Text book of Medicine for Students and Practitioners, and in particular the subvolume on neurological diseases, were the guiding manuals for the training in neurology for decades. However, despite his pioneering achievements, his name has almost become unknown within medical terminology. This article, therefore, wishes to revive an awareness not only of the most important stages in Strumpell's life in Erlangen, Leipzig, Breslau (Wroclaw), and Vienna, but also of his scientific achievements, focusing primarily on his neurological studies. To this end, the article reviews his most important publications on the subject and seeks to evaluate their and hence Strumpell's impact on the understanding of certain illnesses. PMID- 22527228 TI - Clinical and radiological response of leptomeningeal melanoma after whole brain radiotherapy and ipilimumab. PMID- 22527227 TI - Anti-JCV antibody prevalence in a French cohort of MS patients under natalizumab therapy. AB - To measure the prevalence of JCV-specific antibodies in a French cohort of MS patients treated with natalizumab and to identify risk factor(s) of JCV seropositivity. Progressive multifocal leukoencephalopathy (PML) risk may be stratified by anti-JCV antibody status, duration of natalizumab therapy (>=24 months) and prior exposure to immunosuppressive (IS) drugs. No data are available in France on the prevalence of anti-JCV antibodies and distribution of PML risk factors in patients treated with natalizumab. Sera of 361 patients under natalizumab therapy in two MS centers were analyzed using a previously validated ELISA test. We studied different characteristics: demographic, ethnic, radiological, clinical, prior use of immunomodulatory (IM) or IS drugs and natalizumab exposure duration. The JCV seropositivity rate was 51 % for the whole cohort. Mean natalizumab exposure duration was 27.27 months +/- 15.57 (mean +/- SD), and prior use of IS drugs was observed in 15.24 % of patients. Twenty-three patients (6.4 %) presented the three PML risk factors. By multivariate analysis, presence of anti-JCV antibodies was significantly linked to age, North African origin and natalizumab exposure duration. Anti-JCV antibody prevalence was similar to previously published data. Anti-JCV antibody status was linked to age. We also suggested that anti-JCV antibody status could be linked to natalizumab exposure duration and ethnic characteristics. PMID- 22527229 TI - NMDA receptor autoantibodies in sporadic Creutzfeldt-Jakob disease. PMID- 22527230 TI - A short scale for evaluation of neuropsychiatric disorders in Parkinson's disease: first psychometric approach. AB - The neuropsychiatric symptoms and behavioral disorders affecting Parkinson's disease (PD) patients are common and disabling. A PD-specific interview-based 12 item scale, the Scale for Evaluation of Neuropsychiatric Disorders in Parkinson's Disease (SEND-PD), has been developed to assess the severity of neuropsychiatric manifestations. The present study is aimed at testing some basic psychometric attributes of this scale. A total of 633 consecutive patients and their caregivers were included in this cross-sectional, multicenter, observational study. In addition to the tested scale, the following assessments were applied: Hoehn and Yahr staging, Scales for Outcomes in Parkinson's Disease Motor and Psychiatric complications, MiniMental State Examination, Clinical Impression of Severity Index, and the Zarit Caregiver Burden Inventory. Patients in all stages of disease were included and 18.38 % were demented. The SEND-PD was responded by patients (86.16 %), caregivers (13.15 %), or both (0.69 %). Three factors (accounting for 66.63 % of the variance) were identified and considered as subscales: Psychotic symptoms, Mood/Apathy, and Impulse control disorders. The subscales showed satisfactory scaling assumptions (multitrait-item success rate 100 %) and internal consistency (alpha indices >0.70). The convergent validity with other measures of psychiatric symptoms and the discriminant validity to distinguish between categories of patients' age, duration and severity of disease, and dopaminergic treatment were satisfactory. The precision of the scale dimensions was acceptable. The SEND-PD performed as an acceptable, consistent, valid, and precise scale for evaluation of neuropsychiatric symptoms in Parkinson's disease. PMID- 22527231 TI - Age-dependent effects of carotid endarterectomy or stenting on cognitive performance. AB - Although evidence is accumulating that age modifies the risk of carotid angioplasty and stenting (CAS) versus endarterectomy (CEA) for patients with significant carotid stenosis, the impact of age on cognition after either CEA or CAS remains unclear. In this study, we analyzed the effects of age on cognitive performance after either CEA or CAS using a comprehensive neuropsychological test battery with parallel test forms and a control group to exclude a learning effect. The neuropsychological outcomes after revascularization were determined in 19 CAS and 27 CEA patients with severe carotid stenosis. The patients were subdivided according to their median age (<68 years and >=68 years); 27 healthy subjects served as a control group. In all patients clinical examinations, MRI scans and a neuropsychological test battery that assessed four major cognitive domains were performed immediately before, within 72 h, and 3 months after CEA or CAS. While patients <68 years of age showed no significant cognitive alteration after either CEA or CAS, a significant cognitive decline was observed in patients >=68 years in both treatment groups (p = 0.001). Notably, this cognitive deterioration persisted in patients after CEA, whereas it was only transient in patients treated with CAS. These results demonstrate an age-dependent effect of CEA and CAS on cognitive functions. In contrast to the recently observed increased clinical complication rates in older subjects after CAS compared with CEA, CEA appears to be associated with a greater, persistent decline in cognitive performance than CAS in this subgroup of patients. PMID- 22527232 TI - Quality of life and depression in multiple sclerosis patients: longitudinal results of the BetaPlus study. AB - Enhancing quality of life (QoL) is an important objective of disease-modifying therapies in multiple sclerosis (MS). Strategies to substantiate the effect on QoL and depression have been suggested, including injection devices and nursing support. This study assesses QoL and depression in MS patients treated with interferon beta-1b (IFNB-1b) and evaluates the impact of different elements of a patient support programme and of coping strategies on QoL and depression. A prospective, observational, 2-year cohort study was conducted. MS patients were eligible if they had previously switched to IFNB-1b. Data were collected every 6 months. For the measurement of QoL the Functional Assessment of MS (FAMS) was used. Depression symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D); coping strategies were assessed using the 66 item version of Ways of Coping Questionnaire. A total of 1,077 patients were recruited into the study. Seven hundred (65 %) patients completed the study. Within the subgroup completing questionnaires on QoL (N = 472) and depression (N = 363), QoL increased (110.4 vs. 115.8, p < 0.001), and the proportion of depressed patients decreased from 53.7 to 43.3 % (p < 0.001). Modelling QoL and depressions, the use of the autoinjector Betaject((r)) over time showed a positive association with QoL (p = 0.049). The support from a nurse was positively associated with lower depressive symptoms (p = 0.039). The coping strategies 'planful problem-solving' and 'positive reappraisal' were associated with higher QoL and lower depressive symptoms. Patients on IFNB-1b treatment who were included in the patient support programme and completed the study showed an improvement in QoL. Moreover, compared to baseline the proportion of depressive patients decreased. Coping strategies as well as supportive elements such as autoinjectors and nurses had a significant impact on QoL and depression. However, the study had the general limitations of a non-controlled design. PMID- 22527233 TI - Importance of CAG repeat length in childhood-onset dentatorubral-pallidoluysian atrophy. AB - To elucidate a relationship between CAG repeat expansion length and disease progression history in patients with childhood-onset dentatorubral-pallidoluysian atrophy (DRPLA). We retrospectively evaluated information from nine Japanese patients with disease onset reported as between 6 months and 12 years of age. CAG repeat length in these patients ranged from 62 to 93. A strong correlation was confirmed for the age of disease onset, with the onset of epilepsy and involuntary movements, emergence of regression, and autonomic symptoms. The age at becoming wheelchair-bound and initiation of tube feeding also showed a significant correlation with CAG repeat length. This is the first report detailing this aspect of DRPLA focusing on the childhood-onset population. Earlier disease milestones were revealed compared to the expected age based upon a previous report that contained data from the entire patient population, including adult-onset cases (Hasegawa et al. in Mov Disord 25:1694-1700, 2010). These results provide a basis for predicting the outcome of patients in this particular age group, as well as for assessing the results of future clinical therapeutic trials. PMID- 22527235 TI - Subacute progressive ophthalmoplegia associated with dermatomyositis. PMID- 22527234 TI - Seizures and epilepsy in herpes simplex virus encephalitis: current concepts and future directions of pathogenesis and management. AB - Mortality related to herpes simplex virus encephalitis (HSE) dropped dramatically with the systematic initiation of antiviral treatment in encephalitic syndromes. Further efforts need to be taken to reduce long-term morbidity in the survivors. In this regard, the high rate of postencephalitic epilepsy, which is frequently refractory to medical treatment, contributes significantly to the unfavorable clinical outcome of the disease. Seizures during the acute phase of HSE are the main risk for the development of postencephalitic epilepsy. Yet, there are no randomized controlled trials for the management of acute seizures, preventive measures or the ideal duration of antiepileptic treatment. Hence, concepts for the medical treatment of seizures during the acute phase of HSE and postencephalitic epilepsy are eagerly awaited. Epilepsy surgery is a potential treatment option for the latter, but only promising in a subgroup of patients suffering from unilateral mesio-temporal lobe epilepsy and congruent neuropsychological impairment. Relapsing HSE and post-infectious autoimmune conditions can lead to seizures in the aftermath of acute HSE. These conditions need to be kept in mind in order to promptly assure the initiation of accurate diagnostic steps and respective treatment. The purpose of this review is to summarize the current pathogenetical understanding, clinical and diagnostic considerations, and treatment options of seizures in acute HSE and postencephalitic epilepsy. PMID- 22527236 TI - Outcomes of basilar artery occlusion in patients aged 75 years or older in the Basilar Artery International Cooperation Study. AB - Patients with an acute basilar artery occlusion (BAO) have a high risk of long lasting disability and death. Only limited data are available on functional outcome in elderly patients with BAO. Using data from the Basilar Artery International Cooperation Study, we aimed to determine outcomes in patients >=75 years. Primary outcome measure was poor functional outcome (modified Rankin scale score 4-6). Secondary outcomes were death, insufficient vessel recanalization (defined as thrombolysis in myocardial infarction score 0-1) and symptomatic intracranial hemorrhage (SICH). Patients were divided into four age-groups, based on quartiles: 18-54, 55-64, 65-74, and >=75 years. Outcomes were compared between patients >=75 years and patients aged 18-54 years. Risk ratios with corresponding 95 % confidence intervals (CI) were calculated and Poisson regression analyses were performed to calculate adjusted risk ratios (aRR). We included 619 patients [18-54 years n = 153 (25 %), 55-64 years n = 133 (21 %), 65-74 years n = 171 (28 %), and >=75 years n = 162 (26 %)]. Compared with patients aged 18-54 years, patients >=75 years were at increased risk of poor functional outcome [aRR 1.33 (1.14-1.55)] and death [aRR 2.47 (1.75-3.51)]. Nevertheless, 35/162 (22 %, 95 % CI 15-28 %) of patients >=75 years had good functional outcome. No significant differences between age groups were observed for recanalization rate and incidence of SICH. Although patients >=75 years with BAO have an increased risk of poor outcome compared with younger patients, a substantial group of patients >=75 years survives with a good functional outcome. PMID- 22527237 TI - Background information on multiple sclerosis patients stopping ongoing immunomodulatory therapy: a multicenter study in a community-based environment. AB - Adherence to an immunomodulatory therapy still needs to be improved in MS patients. We analyzed the data of 396 MS patients of 40 German MS outpatient centers who had stopped an ongoing immunomodulatory treatment. Items analyzed were among others adherence data, reasons for the interruption and willingness to start a new therapy. It became obvious that 74.6 % of the patients made the decision to withdraw from therapy on their own. The most commonly mentioned reasons for the withdrawal were proven or putative lack of efficacy (51.4 %), side effects (58.1 %), and complaints of fatigue and depression. There was no difference concerning sex, duration of the treatment and medication taken. The expectations correlated with the empathy of the treating physician and the setting with MS nurses taking care of the patient. A total of 199 patients (51.8 % of the females, 48.9 % of the males) wanted to restart another IMT. Reasons for not wanting to restart were lack of conviction that a therapy may influence the disease (29.4 %), fear of injection (18.7 %), fear of bringing the disease to mind regularly (17.9 %) and doubt about the diagnosis (11.2 %). The results suggest that adherence is most effectively promoted by cultivating an appropriate and individual therapeutic setting for each MS patient on a medical, organizational and last but not least psychological level. PMID- 22527238 TI - A novel prognostic marker in acute ischemic stroke: small pericardial effusion. AB - The study aimed to evaluate the prognostic importance of small pericardial effusion (SPE) found on echocardiography in a cohort of patients hospitalized for acute ischemic stroke. We prospectively followed a series of 408 consecutive first-ever acute ischemic stroke patients aged >=50 years who were admitted to the hospital within 24 h of the onset of stroke symptoms. All of the patients underwent transthoracic echocardiography within the first 48 h. Exclusion criteria were cardiothoracic surgery or acute myocardial infarction within the previous 6 months, a moderate or greater pericardial effusion (>1 cm if circumferential), and inadequate visualization of the pericardial space. The patients were followed for 1 year or until death, whichever came first. SPE was noted in 64 (15.7 %) of the patients. Mortality at 1 year was greater for patients with a small effusion (n = 21, 32.8 %) compared to those without an effusion (n = 40, 11.6 %, p < 0.001). After adjustment for age, demographics, medical history, and other echocardiographic findings, SPE remained associated with higher mortality (OR 2.515; 95 % CI 1.188-5.477; p = 0.008). This study is the first to demonstrate that the presence of SPE is associated with increased mortality in patients with first-ever acute ischemic stroke. PMID- 22527239 TI - Myopathy caused by anoctamin 5 mutations and necrotizing vasculitis. PMID- 22527240 TI - Prognostic value of decreased tongue strength on survival time in patients with amyotrophic lateral sclerosis. AB - Decreased tongue strength (TS) might herald bulbar involvement in patients with amyotrophic lateral sclerosis (ALS) well before dysarthria or dysphagia occur, and as such might be prognostic of short survival. The purpose of this study was to investigate the prognostic value of a decreased TS, in addition to other prognostic factors, such as site of onset, bulbar symptoms, bulbar signs, age, sex, maximum phonation time, time from symptoms to diagnosis, and gastrostomy, for survival time in patients with ALS. TS was measured in four directions in 111 patients who attended the diagnostic outpatient motor neuron clinic of our university hospital. Of these patients, 54 were diagnosed with ALS. TS was considered abnormal if the strength in minimally one direction was at least two standard deviations below the reference values obtained from comparable age category and sex-groups of healthy controls (n = 119). Twenty of the patients with ALS had a decreased TS. Multivariable analysis showed that, in addition to age, TS was an independent prognostic factor for survival time in patients with ALS. PMID- 22527241 TI - New and old: notable drug developments for clinical practice. PMID- 22527243 TI - Increased intratumoral IL-22-producing CD4(+) T cells and Th22 cells correlate with gastric cancer progression and predict poor patient survival. AB - IL-22-producing CD4(+) T cells (IL-22(+)CD4(+) T cells) and Th22 cells (IL 22(+)IL-17(-)IFN-gamma(-)CD4(+) T cells) represent newly discovered T-cell subsets, but their nature, regulation, and clinical relevance in gastric cancer (GC) are presently unknown. In our study, the frequency of IL-22(+)CD4(+) T cells in tumor tissues from 76 GC patients was significantly higher than that in tumor draining lymph nodes, non-tumor, and peritumoral tissues. Most intratumoral IL 22(+)CD4(+) T cells co-expressed IL-17 and IFN-gamma and showed a memory phenotype. Locally enriched IL-22(+)CD4(+) T cells positively correlated with increased CD14(+) monocytes and IL-6 and IL-23 detection ex vivo, and in vitro IL 6 and IL-23 induced the polarization of IL-22(+)CD4(+) T cells in a dose dependent manner and the polarized IL-22(+)CD4(+) T cells co-expressed of IL-17 and IFN-gamma. Moreover, IL-22(+)CD4(+) T-cell subsets (IL-22(+)IL-17(+)CD4(+), IL-22(+)IL-17(-)CD4(+), IL-22(+)IFN-gamma(+)CD4(+), IL-22(+)IFN-gamma(-)CD4(+), and IL-22(+)IL-17(+)IFN-gamma(+)CD4(+) T cells), and Th22 cells were also increased in tumors. Furthermore, higher intratumoral IL-22(+)CD4(+) T-cell percentage and Th22-cell percentage were found in patients with tumor-node metastasis stage advanced and predicted reduced overall survival. In conclusion, our data indicate that IL-22(+)CD4(+) T cells and Th22 cells are likely important in establishing the tumor microenvironment for GC; increased intratumoral IL 22(+)CD4(+) T cells and Th22 cells are associated with tumor progression and predict poorer patient survival, suggesting that tumor-infiltrating IL 22(+)CD4(+) T cells and Th22 cells may be suitable therapeutic targets in patients with GC. PMID- 22527244 TI - The roles of mast cells in anticancer immunity. AB - The tumor microenvironment (TME), which is composed of stromal cells such as endothelial cells, fibroblasts, and immune cells, provides a supportive niche promoting the growth and invasion of tumors. The TME also raises an immunosuppressive barrier to effective antitumor immune responses and is therefore emerging as a target for cancer immunotherapies. Mast cells (MCs) accumulate in the TME at early stages, and their presence in the TME is associated with poor prognosis in many aggressive human cancers. Some well established roles of MCs in cancer are promoting angiogenesis and tumor invasion into surrounding tissues. Several mouse models of inducible and spontaneous cancer show that MCs are among the first immune cells to accumulate within and shape the TME. Although MCs and other suppressive myeloid cells are associated with poor prognosis in human cancers, high densities of intratumoral T effector (T(eff)) cells are associated with a favorable prognosis. The latter finding has stimulated interest in developing therapies to increase intratumoral T cell density. However, cellular and molecular mechanisms promoting high densities of intratumoral T(eff) cells within the TME are poorly understood. New evidence suggests that MCs are essential for shaping the immune-suppressive TME and impairing both antitumor T(eff) cell responses and intratumoral T cell accumulation. These roles for MCs warrant further elucidation in order to improve antitumor immunity. Here, we will summarize clinical studies of the prognostic significance of MCs within the TME in human cancers, as well as studies in mouse models of cancer that reveal how MCs are recruited to the TME and how MCs facilitate tumor growth. Also, we will summarize our recent studies indicating that MCs impair generation of protective antitumor T cell responses and accumulation of intratumoral T(eff) cells. We will also highlight some approaches to target MCs in the TME in order to unleash antitumor cytotoxicity. PMID- 22527245 TI - Targeted immunotherapy of cancer with CAR T cells: achievements and challenges. AB - The adoptive transfer of chimeric antigen receptor (CAR)-expressing T cells is a relatively new but promising approach in the field of cancer immunotherapy. This therapeutic strategy is based on the genetic reprogramming of T cells with an artificial immune receptor that redirects them against targets on malignant cells and enables their destruction by exerting T cell effector functions. There has been an explosion of interest in the use of CAR T cells as an immunotherapy for cancer. In the pre-clinical setting, there has been a considerable focus upon optimizing the structural and signaling potency of the CAR while advances in bio processing technology now mean that the clinical testing of these gene-modified T cells has become a reality. This review will summarize the concept of CAR-based immunotherapy and recent clinical trial activity and will further discuss some of the likely future challenges facing CAR-modified T cell therapies. PMID- 22527247 TI - Antitumor effects of Stat3-siRNA and endostatin combined therapies, delivered by attenuated Salmonella, on orthotopically implanted hepatocarcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most aggressive carcinomas. Limited therapeutic options, mainly due to a fragmented genetic understanding of HCC, and major HCC resistance to conventional chemotherapy are the key reasons for a poor prognosis. Thus, new effective treatments are urgent and gene therapy may be a novel option. Signal transducer and activator of transcription 3 (Stat3) is a highly studied member of the STAT family. Inhibition of Stat3 signaling has been found to suppress tumor growth and improve survival, providing a molecular target for cancer therapy. Furthermore, HCC is a hypervascular tumor and angiogenesis plays a crucial role in tumor growth and metastasis. Thus, anti-angiogenic therapy, combined with inhibition of Stat3, may be an effective approach to combat HCC. We tested the effect that the combination therapy consisting of endostatin (a powerful angiogenesis inhibitor) and Stat3-specific small interfering RNA, using a DNA vector delivered by attenuated S. typhimurium, on an orthotopic HCC model in C57BL/6 mice. Although antitumor effects were observed with either single therapeutic treatment, the combination therapy provided superior antitumor effects. Correlated with this finding, the combination treatment resulted in significant alteration of Stat3 and endostatin levels and that of the downstream gene VEGF, decreased cell proliferation, induced cell apoptosis and inhibited angiogenesis. Importantly, combined treatment also elicited immune system regulation of various immune cells and cytokines. This study has provided a novel cancer gene therapeutic approach. PMID- 22527248 TI - Shikonin induces immunogenic cell death in tumor cells and enhances dendritic cell-based cancer vaccine. AB - Immunogenic cell death is characterized by damage-associated molecular patterns, which can enhance the maturation and antigen uptake of dendritic cells. Shikonin, an anti-inflammatory and antitumor phytochemical, was exploited here as an adjuvant for dendritic cell-based cancer vaccines via induction of immunogenic cell death. Shikonin can effectively activate both receptor- and mitochondria mediated apoptosis and increase the expression of all five tested damage associated molecular patterns in the resultant tumor cell lysates. The combination treatment with damage-associated molecular patterns and LPS activates dendritic cells to a high maturation status and enhances the priming of Th1/Th17 effector cells. Shikonin-tumor cell lysate-loaded mature dendritic cells exhibit a high level of CD86 and MHC class II and activate Th1 cells. The shikonin-tumor cell lysate-loaded dendritic cell vaccines result in a strong induction of cytotoxic activity of splenocytes against target tumor cells, a retardation in tumor growth, and an increase in the survival of test mice. The much enhanced immunogenicity and efficacy of the current cancer vaccine formulation, that is, the use of shikonin-treated tumor cells as cell lysates for the pulse of dendritic cells in culture, may suggest a new ex vivo approach for developing individualized, dendritic cells-based anticancer vaccines. PMID- 22527246 TI - Activation-induced cytidine deaminase (AID) linking immunity, chronic inflammation, and cancer. AB - Activation-induced cytidine deaminase (AID) is critically involved in class switch recombination and somatic hypermutation of Ig loci resulting in diversification of antibodies repertoire and production of high-affinity antibodies and as such represents a physiological tool to introduce DNA alterations. These processes take place within germinal centers of secondary lymphoid organs. Under physiological conditions, AID is expressed predominantly in activated B lymphocytes. Because of the mutagenic and recombinogenic potential of AID, its expression and activity is tightly regulated on different levels to minimize the risk of unwanted DNA damage. However, chronic inflammation and, probably, combination of other not-yet-identified factors are able to create a microenvironment sufficient for triggering an aberrant AID expression in B cells and, importantly, in non-B-cell background. Under these circumstances, AID may target also non-Ig genes, including cancer-related genes as oncogenes, tumor suppressor genes, and genomic stability genes, and modulate both genetic and epigenetic information. Despite ongoing progress, the complete understanding of fundamental aspects is still lacking as (1) what are the crucial factors triggering an aberrant AID expression/activity including the impact of Th2-driven inflammation and (2) to what extent may aberrant AID in human non-B cells lead to abnormal cell state associated with an increased rate of genomic alterations as point mutations, small insertions or deletions, and/or recurrent chromosomal translocations during solid tumor development and progression. PMID- 22527249 TI - TriVax-HPV: an improved peptide-based therapeutic vaccination strategy against human papillomavirus-induced cancers. AB - BACKGROUND: Therapeutic vaccines for cancer are an attractive alternative to conventional therapies, since the later result in serious adverse effects and in most cases are not effective against advanced disease. Human papillomavirus (HPV) is responsible for several malignancies such as cervical carcinoma. Vaccines targeting oncogenic viral proteins like HPV16-E6 and HPV16-E7 are ideal candidates to elicit strong immune responses without generating autoimmunity because: (1) these products are not expressed in normal cells and (2) their expression is required to maintain the malignant phenotype. Our group has developed peptide vaccination strategy called TriVax, which is effective in generating vast numbers of antigen-specific T cells in mice capable of persisting for long time periods. MATERIALS AND METHODS: We have used two HPV-induced mouse cancer models (TC-1 and C3.43) to evaluate the immunogenicity and therapeutic efficacy of TriVax prepared with the immunodominant CD8 T-cell epitope HPV16 E7(49-57), mixed with poly-IC adjuvant and costimulatory anti-CD40 antibodies. RESULTS: TriVax using HPV16-E7(49-57) induced large and persistent T-cell responses that were therapeutically effective against established HPV16-E7 expressing tumors. In most cases, TriVax was successful in attaining complete rejections of 6-11-day established tumors. In addition, TriVax induced long-term immunological memory, which prevented tumor recurrences. The anti-tumor effects of TriVax were independent of NK and CD4 T cells and, surprisingly, did not rely to a great extent on type-I or type-II interferon. CONCLUSIONS: These findings indicate that the TriVax strategy is an appealing immunotherapeutic approach for the treatment of established viral-induced tumors. We believe that these studies may help to launch more effective and less invasive therapeutic vaccines for HPV mediated malignancies. PMID- 22527250 TI - Integration of autologous dendritic cell-based immunotherapy in the standard of care treatment for patients with newly diagnosed glioblastoma: results of the HGG 2006 phase I/II trial. AB - PURPOSE: Dendritic cell (DC)-based tumor vaccination has rendered promising results in relapsed high-grade glioma patients. In the HGG-2006 trial (EudraCT 2006-002881-20), feasibility, toxicity, and clinical efficacy of the full integration of DC-based tumor vaccination into standard postoperative radiochemotherapy are studied in 77 patients with newly diagnosed glioblastoma. PATIENTS AND METHODS: Autologous DC are generated after leukapheresis, which is performed before the start of radiochemotherapy. Four weekly induction vaccines are administered after the 6-week course of concomitant radiochemotherapy. During maintenance chemotherapy, 4 boost vaccines are given. Feasibility and progression free survival (PFS) at 6 months (6mo-PFS) are the primary end points. Overall survival (OS) and immune profiling, rather than monitoring, as assessed in patients' blood samples, are the secondary end points. Analysis has been done on intent-to-treat basis. RESULTS: The treatment was feasible without major toxicity. The 6mo-PFS was 70.1 % from inclusion. Median OS was 18.3 months. Outcome improved significantly with lower EORTC RPA classification. Median OS was 39.7, 18.3, and 10.7 months for RPA classes III, IV, and V, respectively. Patients with a methylated MGMT promoter had significantly better PFS (p = 0.0027) and OS (p = 0.0082) as compared to patients with an unmethylated status. Exploratory "immunological profiles" were built to compare to clinical outcome, but no statistical significant evidence was found for these profiles to predict clinical outcome. CONCLUSION: Full integration of autologous DC-based tumor vaccination into standard postoperative radiochemotherapy for newly diagnosed glioblastoma seems safe and possibly beneficial. These results were used to power the currently running phase IIb randomized clinical trial. PMID- 22527251 TI - Controlled-rate freezer cryopreservation of highly concentrated peripheral blood mononuclear cells results in higher cell yields and superior autologous T-cell stimulation for dendritic cell-based immunotherapy. AB - Availability of large quantities of functionally effective dendritic cells (DC) represents one of the major challenges for immunotherapeutic trials against infectious or malignant diseases. Low numbers or insufficient T-cell activation of DC may result in premature termination of treatment and unsatisfying immune responses in clinical trials. Based on the notion that cryopreservation of monocytes is superior to cryopreservation of immature or mature DC in terms of resulting DC quantity and immuno-stimulatory capacity, we aimed to establish an optimized protocol for the cryopreservation of highly concentrated peripheral blood mononuclear cells (PBMC) for DC-based immunotherapy. Cryopreserved cell preparations were analyzed regarding quantitative recovery, viability, phenotype, and functional properties. In contrast to standard isopropyl alcohol (IPA) freezing, PBMC cryopreservation in an automated controlled-rate freezer (CRF) with subsequent thawing and differentiation resulted in significantly higher cell yields of immature and mature DC. Immature DC yields and total protein content after using CRF were comparable with results obtained with freshly prepared PBMC and exceeded results of standard IPA freezing by approximately 50 %. While differentiation markers, allogeneic T-cell stimulation, viability, and cytokine profiles were similar to DC from standard freezing procedures, DC generated from CRF-cryopreserved PBMC induced a significantly higher antigen-specific IFN-gamma release from autologous effector T cells. In summary, automated controlled-rate freezing of highly concentrated PBMC represents an improved method for increasing DC yields and autologous T-cell stimulation. PMID- 22527253 TI - Effects of 1-methyltryptophan stereoisomers on IDO2 enzyme activity and IDO2 mediated arrest of human T cell proliferation. AB - IDO2 is a newly discovered enzyme with 43 % similarity to classical IDO (IDO1) protein and shares the same critical catalytic residues. IDO1 catalyzes the initial and rate-limiting step in the degradation of tryptophan and is a key enzyme in mediating tumor immune tolerance via arrest of T cell proliferation. The role of IDO2 in human T cell immunity remains controversial. Here, we demonstrate that similar to IDO1, IDO2 also degrades tryptophan into kynurenine and is inhibited more efficiently by Levo-1-methyl tryptophan (L-1MT), an IDO1 competitive inhibitor, than by dextro-methyl tryptophan (D-1MT). Although IDO2 enzyme activity is weaker than IDO1, it is less sensitive to 1-MT inhibition than IDO1. Moreover, our results indicate that human CD4(+) and CD8(+) T cell proliferation was inhibited by IDO2, but both L-1MT and D-1MT could not reverse IDO2-mediated arrest of cell proliferation, even at high concentrations. These data indicate that IDO2 is an inhibitory mechanism in human T cell proliferation and support efforts to develop more effective IDO1 and IDO2 inhibitors in order to overcome IDO-mediated immune tolerance. PMID- 22527254 TI - Differences between non-profit and for-profit hospices: patient selection and quality. AB - This research compares the behavior of non-profit organizations and private for profit firms in the hospice industry, where there are financial incentives created by the Medicare benefit. Medicare reimburses hospices on a fixed per diem basis, regardless of patient diagnosis. Because under this system patients with lower expected costs are more profitable, hospices can selectively enroll patients with longer lengths of stay. While it is illegal for hospices to reject potential patients explicitly, they can influence their patient mix through referral networks. A fixed per diem rate also creates an incentive shirk on quality and to substitute lower skilled for higher skilled labor, which has implications for quality of care. By using within-market variation in hospice characteristics, the empirical evidence suggests that for-profit hospices differentially take advantage of these incentives. The results show that for profit hospices engage in patient selection through significantly different referral networks than non-profits. They receive more patients from long-term care facilities and fewer patients through more traditional paths, such as physician referrals. This mechanism of patient selection is supported by the result that for-profits have fewer cancer patients and more patients with longer lengths of stay. While non-profit and for-profit hospices report similar numbers of staff visits per patient, for-profit firms make significantly less use of skilled nursing providers. We also find some weak evidence of lower levels of quality in for-profit hospices. PMID- 22527252 TI - Humoral anti-KLH responses in cancer patients treated with dendritic cell-based immunotherapy are dictated by different vaccination parameters. AB - PURPOSE: Keyhole limpet hemocyanin (KLH) attracts biomedical interest because of its remarkable immunostimulatory properties. Currently, KLH is used as vaccine adjuvant, carrier protein for haptens and as local treatment for bladder cancer. Since a quantitative human anti-KLH assay is lacking, it has not been possible to monitor the dynamics of KLH-specific antibody (Ab) responses after in vivo KLH exposure. We designed a quantitative assay to measure KLH-specific Abs in humans and retrospectively studied the relation between vaccination parameters and the vaccine-induced anti-KLH Ab responses. EXPERIMENTAL DESIGN: Anti-KLH Abs were purified from pooled serum of melanoma patients who have responded to KLH as a vaccine adjuvant. Standard isotype-specific calibration curves were generated to measure KLH-specific Ab responses in individual serum samples using ELISA. RESULTS: KLH-specific IgM, IgA, IgG and all IgG-subclasses were accurately measured at concentrations as low as 20 MUg/ml. The intra- and inter-assay coefficients of variation of this ELISA were below 6.7 and 9.9 %, respectively. Analyses of 128 patients demonstrated that mature DC induced higher levels of KLH specific IgG compared to immature DC, prior infusion with anti-CD25 abolished IgG and IgM production and patients with locoregional disease developed more robust IgG responses than advanced metastatic melanoma patients. CONCLUSIONS: We present the first quantitative assay to measure KLH-specific Abs in human serum, which now enables monitoring both the dynamics and absolute concentrations of humoral immune responses in individuals exposed to KLH. This assay may provide a valuable biomarker for the immunogenicity and clinical effectiveness of KLH-containing vaccines and therapies. PMID- 22527255 TI - Utility of the inversion scout sequence (TI scout) in diagnosing myocardial amyloid infiltration. AB - To evaluate the utility of inversion scout (TI-scout) obtained during cardiac magnetic resonance imaging (CMR) in diagnosing myocardial amyloid infiltration. A retrospective analysis of CMR exams in 39 patients (24 males, age range 29-77 years) was performed. Imaging was performed on a 1.5T system, and included steady state cine, post contrast TI-scout and delayed enhancement images. Evaluations included studies in 13 patients with myocardial amyloidosis and 26 patients without myocardial amyloidosis. To characterize abnormal nulling, the time to myocardial nulling on the TI scout was compared to the null times of the blood pool and spleen for each scan. The sensitivity and specificity of different tissue nulling abnormalities for myocardial amyloidosis were computed. The null times of tissues in 18/26 (69%) patients in the non-amyloid group followed a consistent order with the blood pool null time preceding the myocardial nulling which was equal to that of splenic nulling (Type 1 pattern). This order differed in all 13 patients with myocardial amyloidosis described as three non-mutually exclusive nulling categories: 10 patients had myocardial null time preceding or coincident with blood pool (Type 2 pattern); in 11 patients myocardial null time was non-coincident with splenic nulling (Type 3 pattern); and in 8 patients myocardial null time was non-coincident with both blood pool AND splenic nulling (Type 4 pattern). While no patient exhibited Type 4 nulling pattern in the non amyloid group, 1/26 patient had a Type 2 and 7/26 patients had a Type 3 nulling pattern. A sensitivity of 100% was obtained when either Type 2 OR Type 3 nulling was present while a specificity of 100% was obtained when both Type 2 AND Type 3 nulling were present together (Type 4 pattern). Our study demonstrates that the pattern of nulling on the TI scout sequence CMR has potential diagnostic utility for the presence of myocardial amyloidosis. The temporal pattern of myocardial, blood pool and splenic nulling needs to be carefully evaluated on the TI scout sequence and could prove useful in other infiltrative cardiomyopathies. PMID- 22527256 TI - Morphological characteristics of culprit coronary lesions according to clinical presentation: insights from a multimodality imaging approach. AB - The aim of this study was to prospectively evaluate the morphological characteristics of culprit coronary lesions according to clinical presentation. A combined, comprehensive, multi-imaging modality protocol was systematically used. A total of 46 consecutive patients with stable angina (n = 24) or acute coronary syndromes (n = 22) were included. Culprit lesions were prospectively studied with angiography, multislice computed tomography (MSCT), intravascular ultrasound and virtual histology. MSCT showed a lower radiographic density and a higher remodeling index in culprit lesions of patients with acute coronary syndromes. Intravascular ultrasound examination demonstrated a larger remodeling index, a lower degree of calcification and a higher prevalence of soft lesions in unstable patients. Virtual histology analysis showed a lower percentage of calcium in the area of greatest stenosis and a higher prevalence of lesions with vulnerable characteristics in unstable patients. In multivariable logistic regression analysis, remodeling index by intravascular ultrasound and radiographic density in MSCT were the only independent predictors for identifying unstable culprit lesions. Our study adds further evidence on the best morphological criteria of instability in culprit lesions. Remodeling index by IVUS and low radiographic density by MSTC were the only independent predictors of unstable lesions. PMID- 22527257 TI - Shorter delay time reduces interpatient variability in coronary enhancement in coronary CT angiography using the bolus tracking method with 320-row CT. AB - The purpose was to investigate the influence of shorter delay time on the interpatient variability in coronary enhancement and appropriateness of scan timing in coronary CT angiography (CTA) using bolus tracking method with 320-row CT. The bolus tracking scan was performed at the level of the bifurcation of the trachea for first 50 patients (group 1) and at the center level of the diagnostic scan for the last 50 patients (group 2). The CT number of the proximal coronary arteries was measured in the right coronary artery (RCA) and the left main trunk (LMT). The CT numbers of the right ventricle, left ventricle, ascending aorta, and descending aorta were also measured to consider the appropriateness of the scan timing. The delay time was longer in group 1 than in group 2 (7.0 vs. 2.6 s; p < 0.0001). The CT number within the RCA was 390 +/- 75 HU for group 1 and 419 +/- 42 HU for group 2. The CT number within the LMT was 396 +/- 72 HU for group 1 and 420 +/- 40 HU for group 2. The difference of average (p = 0.02 and 0.04) and standard deviation (p = 0.03 and 0.02) was statistically significant. The scan timing was early or late in 15 patients for group 1, but only 2 patients for group 2 (p = 0.0002). Shortening the delay time could reduce the interpatient variability in coronary enhancement with appropriate scan timing in coronary CTA. PMID- 22527258 TI - Effect of protocol choice on phase contrast cardiac magnetic resonance flow measurement in the ascending aorta: breath-hold and non-breath-hold. AB - Flow assessment with phase contrast magnetic resonance imaging (PC-MRI) protocols is an important component of a comprehensive cardiovascular MR (CMR) assessment. Breath-hold (BH) and non-breath-hold (NBH) PC-MRI protocols are widely available for this imaging modality. Because flow in the great vessels is known to vary with the respiratory cycle, we hypothesized that these 2 approaches might yield different results in the clinical assessment of forward and regurgitant flow in the ascending aorta. Further, given renewed awareness of the possible effect of velocity offsets in PC-MRI, we also sought to evaluate the impact of BH and NBH protocols on this potential source of error. A prospective observational study was performed in 55 consecutive patients referred for clinical CMR of the thoracic aorta. Both BH and NBH protocols were performed at the sinotubular junction and at the mid ascending aorta. Ten additional patients underwent repeated scanning at the mid ascending aorta with both BH and NBH protocols so that protocol variability could be assessed. Finally, ten patients were scanned with both BH and NBH protocols, and phantoms were then imaged with identical imaging parameters so that offset errors associated with each protocol could be evaluated. Forward flow was generally greater with the NBH protocol than with the BH protocol (mean values 102.1 mL vs. 97.9 mL; P = 0.0004). The Bland-Altman limits of agreement were quite wide for all indices (e.g, forward flow, -26.7 mL, +18.2 mL), which suggests that results from BH and NBH protocols cannot be interchanged with confidence. Estimated phase offset errors were similar for both protocols and were generally within acceptable ranges at the mid ascending level, with slightly higher values observed at the sinotubular junction for the BH technique. We observed differences in flow values with BH and NBH protocols for PC-MRI. This finding is relevant to patients imaged serially for the evaluation of cardiac output or valve (aortic or mitral) insufficiency, for whom adherence to one PC-MRI breathing protocol is likely most effective. PMID- 22527259 TI - Cardiac computed tomographic imaging to evaluate myocardial scarring/fibrosis in patients with hypertrophic cardiomyopathy: a comparison with cardiac magnetic resonance imaging. AB - Contrast enhanced magnetic resonance imaging (CeMRI) reliably identifies myocardial fibrosis in patients with hypertrophic cardiomyopathy (HCM). However, many patients have contraindications to ceMRI. Previous studies have shown that contrast enhanced multi-detector computed tomography (ceMDCT) can visualize focal scars following myocardial infarction in experimental animals and patients. The purpose of this manuscript is to assess the ability of ceMDCT to detect focal myocardial scars in patients with HCM. Twelve HCM patients underwent ceMRI and ceMDCT. Fibrotic areas of myocardium were defined as focal or diffuse areas of fibrosis. The mean signal intensity in ceMRI and attenuation values in ceMDCT of the fibrotic regions, normal myocardium and left ventricle blood pool contrast were measured using qualitative and quantitative analysis. Focal scar mass was calculated using both techniques. Focal scars were detected in 9 patients and diffuse fibrosis was visualized in all patients by ceMRI. Differences between normalized SI of normal myocardium and focal scars, normal and diffuse areas of fibrosis, and diffuse fibrosis and focal scars were significant for both ceMRI and ceMDCT (p < 0.05). Diffuse fibrosis was poorly visualized by ceMDCT but was detectable using quantitative measurements. CeMDCT has potential to detect focal myocardial scars in patients with HCM who have contraindications to ceMRI study. However, ceMDCT does not enable adequate visualization of diffuse myocardial fibrosis, and thus is less well suited than ceMRI for assessment of total burden of fibrosis. This limitation may be overcome using quantitative methodology. PMID- 22527260 TI - Failed heart rate control with oral metoprolol prior to coronary CT angiography: effect of additional intravenous metoprolol on heart rate, image quality and radiation dose. AB - The purpose of this study was to evaluate the effect of intravenous (i.v.) metoprolol after a suboptimal heart rate (HR) response to oral metoprolol (75-150 mg) on HR control, image quality (IQ) and radiation dose during coronary CTA using 320-MDCT. Fifty-three consecutive patients who failed to achieve a target HR of < 60 bpm after an oral dose of metoprolol and required supplementary i.v. metoprolol (5-20 mg) prior to coronary CTA were evaluated. Patients with HR < 60 bpm during image acquisition were defined as responders (R) and those with HR >= 60 bpm as non-responders (NR). Two observers assessed IQ using a 3-point scale (1 2, diagnostic and 3, non-diagnostic). Effective dose (ED) was estimated using dose-length product and a 0.014 mSV/mGy.cm conversion factor. Baseline characteristics and HR on arrival were similar in the two groups. 58% of patients didn't achieve the target HR after receiving i.v. metoprolol (NR). R had a significantly higher HR reduction after oral (mean HR 63.9 +/- 4.5 bpm vs. 69.6 +/- 5.6 bpm) (p < 0.005) and i.v. (mean HR 55.4 +/- 3.9 bpm vs. 67.4 +/- 5.3 bpm) (p < 0.005) doses of metoprolol. Studies from NR showed a significantly higher ED in comparison to R (8.0 +/- 2.9 vs. 6.1 +/- 2.2 mSv) (p = 0.016) and a significantly higher proportion of non-diagnostic coronary segments (9.2 vs. 2.5%) (p < 0.001). 58% of patients who do not achieve a HR of <60 bpm prior to coronary CTA with oral fail to respond to additional i.v. metoprolol and have studies with higher radiation dose and worse image quality. PMID- 22527261 TI - Differentiation of transmural and nontransmural infarction using speckle tracking imaging to assess endocardial and epicardial torsion after revascularization. AB - Assessment of transmural extent (TME) of necrosis after acute myocardial infarction (MI) remains a major problem in clinical practice. The study sought to determine whether speckle tracking imaging (STI) could differentiate transmural from nontransmural acute MI by assessment of endocardial and epicardial torsion. TME of infarct was measured by contrast-enhanced magnetic resonance imaging. Patients were divided into two groups according to TME (transmural MI group [TME >= 50%, n = 36] and nontransmural MI group [TME < 50%, n = 35]). As a control group, 30 subjects without evidence of structural heart disease were included. Conventional echocardiography and STI were done in controls and patients before and 1 month after percutaneous coronary intervention. Compared with control subjects, endocardial and epicardial torsion in patients with transmural and nontransmural MI were all extremely decreased (all P < 0.01). One month after percutaneous coronary intervention, there was no significant increase in endocardial and epicardial torsion in transmural MI patients. However, apical rotation and left ventricular torsion resumed slightly but significantly in the epicardium (but not endocardium) in patient with nontransmural MI (3.11 +/- 0.81 vs. 4.37 +/- 1.15 degrees , P < 0.01; 3.69 +/- 1.07 vs. 5.52 +/- 1.89 degrees , P < 0.01, respectively). The combined evaluation of endocardial and epicardial torsion by STI may be used to differentiate transmural from nontransmural MI after revascularization. PMID- 22527262 TI - Prevalence of thoracic aortic calcification and its relationship to cardiovascular risk factors and coronary calcification in an unselected population-based cohort: the Heinz Nixdorf Recall Study. AB - Thoracic aortic calcification (TAC) and coronary artery calcium (CAC) have been proposed for risk assessment of coronary artery and cardiovascular disease events. The aim of this analysis is to assess the prevalence of TAC and to determine its relationship with cardiovascular risk factors and CAC in a general unselected population. TAC was measured from electron beam computed tomography scans and quantified by Agatston-Score in 4,025 participants aged 45-75 years (mean age 59.4 +/- 7.8 years, 53% female) from the Heinz Nixdorf Recall Study. Multivariable generalized linear regression was used to evaluate relationships between TAC and cardiovascular risk factors and CAC. Overall 2,538/4,025 (63.1%) participants revealed TAC. Prevalence of TAC was greater in men than in women (65.2 vs. 61.7%, p = 0.009). TAC was most strongly associated with age, systolic blood pressure, smoking and high levels of LDL-cholesterol. Prevalence of CAC was significantly higher in participants with TAC than without (74.0 vs. 57.6%, p < 0.0001) demonstrating an increased risk of having CAC in the presence of TAC (prevalence ratio (PR) 1.29 [95% CI: 1.22-1.35], p < 0.0001, PR adjusted for risk factors 1.14 [1.09-1.20], p < 0.0001). In general population, TAC has high prevalence and largely shares cardiovascular risk factors with CAD while being independently associated with present CAC. PMID- 22527263 TI - Is there a role for thoracic aortic calcium to fine-tune cardiovascular risk prediction? AB - Screening asymptomatic subjects to streamline measures for the prevention of cardiovascular events remains a major challenge. The established primary prevention risk-scoring methods use equations derived from large prospective cohort studies, but further fine-tuning of cardiovascular risk assessment remains important as 25% of individuals with low estimated risk may experience cardiac events. Independent studies provided evidence that extended risk assessment using coronary artery calcium quantification may improve risk stratification as it can lead to reclassification of persons at increased risk. Particularly in intermediate-risk subjects, coronary artery calcium scoring can help to correctly identify individuals at highest risk. Data on the extent of calcification of the ascending and descending thoracic aorta might be useful for additional cardiovascular risk stratification. Future analyses and studies will be required to answer the question of whether the implementation of such data may allow further fine-tuning of cardiovascular risk prediction in specific subpopulations- for instance in women or men with an increased risk of stroke and/or symptomatic peripheral vascular disease. PMID- 22527264 TI - Exploring ART intake scenes in a human rights-based intervention to improve adherence: a randomized controlled trial. AB - To assess the effectiveness of a psychosocial individual intervention to improve adherence to ART in a Brazilian reference-center, consenting PLHIV with viral load >50 copies/ml were selected. After 4 weeks of MEMS cap use, participants were randomized into an intervention group (IG) (n = 64) or control group (CG) (n = 57). CG received usual care only. The IG participated in a human rights-based intervention approach entailing four dialogical meetings focused on medication intake scenes. Comparison between IG and CG revealed no statistically significant difference in adherence measured at weeks 8, 12, 16, 20 and 24. Viral load (VL) decreased in both groups (p < 0.0001) with no significant difference between study groups. The lower number of eligible patients than expected underpowered the study. Ongoing qualitative analysis should provide deeper understanding of the trial results. NIH Clinical Trials: NCT00716040. PMID- 22527265 TI - Treatment with algae extracts promotes flocculation, and enhances growth and neutral lipid content in Nannochloropsis oculata--a candidate for biofuel production. AB - Marine microalgae represent a potentially valuable feedstock for biofuel production; however, large-scale production is not yet economically viable. Optimisation of productivity and lipid yields is required and the cost of biomass harvesting and dewatering must be significantly reduced. Microalgae produce a wide variety of biologically active metabolites, many of which are involved in inter- and intra-specific interactions (the so-called infochemicals). The majority of infochemicals remain unidentified or uncharacterised. Here, we apply known and candidate (undefined extracts) infochemicals as a potential means to manipulate the growth and lipid content of Nannochloropsis oculata-a prospective species for biofuel production. Five known infochemicals (beta-cyclocitral, trans,trans-2,4-decadienal, hydrogen peroxide, norharman and tryptamine) and crude extracts prepared from Skeletonema marinoi and Dunaliella salina cultures at different growth stages were assayed for impacts on N. oculata over 24 h. The neutral lipid content of N. oculata increased significantly with exposure to three infochemicals (beta-cyclocitral, decadienal and norharman); however the effective concentrations affected a significant decrease in growth. Exposure to particular crude extracts significantly increased both growth and neutral lipid levels. In addition, water-soluble extracts of senescent S. marinoi cultures induced a degree of flocculation in the N. oculata. These preliminary results indicate that artificial manipulation of N. oculata cultures by application of algae infochemicals could provide a valuable tool towards achieving economically viable large-scale algae biofuel production. PMID- 22527266 TI - The bacterial community of the lithistid sponge Discodermia spp. as determined by cultivation and culture-independent methods. AB - The marine lithistid sponge Discodermia spp. (Family Theonellidae) contains many types of associated bacteria visible in the mesohyl while biofilms cover the pinacoderm. This study determined the identity of bacteria associated with members of the genus Discodermia using microbial culture, 16S rRNA gene clone libraries and fluorescence in situ hybridization. Four samples of Discodermia spp. were collected at depths between 24-161 m near Grand Bahama Island and Cay Sal Bank, Bahamas. A total of 80 unique isolates and 94 different clone sequences from at least eight bacterial classes were obtained. It appeared that Discodermia spp. may have a core community of bacteria that is common to all sponges of this genus. Species of at least six different classes of bacteria were regularly found in most of the sponge specimens collected, irrespective of collection depth or location. This indicates that a diverse spectrum of bacteria is associated with lithistid sponges irrespective of the transient seawater community that enters the sponge. PMID- 22527267 TI - Genomics in eels--towards aquaculture and biology. AB - Freshwater eels (genus Anguilla), especially the species inhabiting the temperate areas such as the European, American and Japanese eels, are important aquaculture species. Although artificial reproduction has been attempted since the 1930s and large numbers of studies have been conducted, it has not yet fully succeeded. Problems in eel artificial breeding are highly diverse, for instance, lack of basic information about reproduction in nature, no appropriate food for larvae, high mortality, and high individual variation in adults in response to maturation induction. Over the last decade, genomic data have been obtained for a variety of aquatic organisms. Recent technological advances in sequencing and computation now enable the accumulation of genomic information even for non-model species. The draft genome of the European eel Anguilla anguilla has been recently determined using Illumina technology and transcriptomic data based on next generation sequencing have been emerging. Extensive genomic information will facilitate many aspects of the artificial reproduction of eels. Here, we review the progress in genome-wide studies of eels, including additional analysis of the European eel genome data, and discuss future directions and implications of genomic data for aquaculture. PMID- 22527268 TI - Exploring the transcriptome of Atlantic salmon (Salmo salar) skin, a major defense organ. AB - The skin of fish is the first line of defense against pathogens and parasites. The skin transcriptome of the Atlantic salmon is poorly characterized, and currently only 2,089 expressed sequence tags (ESTs) out of a total of half a million sequences are generated from skin-derived cDNA libraries. The primary aim of this study was to enhance the transcriptomic knowledge of salmon skin by using next-generation sequencing (NGS) technology, namely the Roche-454 platform. An equimolar mixture of high-quality RNA from skin and epidermal samples of salmon reared in either freshwater or seawater was used for 454-sequencing. This technique yielded over 600,000 reads, which were assembled into 34,696 isotigs using Newbler. Of these isotigs, 12 % had not been sequenced in Atlantic salmon, hence representing previously unreported salmon mRNAs that can potentially be skin-specific. Many full-length genes have been acquired, representing numerous biological processes. Mucin proteins are the main structural component of mucus and we examined in greater detail the sequences we obtained for these genes. Several isotigs exhibited homology to mammalian mucins (MUC2, MUC5AC and MUC5B). Mucin mRNAs are generally >10 kbp and contain large repetitive units, which pose a challenge towards full-length sequence discovery. To date, we have not unearthed any full-length salmon mucin genes with this dataset, but have both N- and C-terminal regions of a mucin type 5. This highlights the fact that, while NGS is indeed a formidable tool for sequence data mining of non-model species, it must be complemented with additional experimental and bioinformatic work to characterize some mRNA sequences with complex features. PMID- 22527269 TI - RNA aptamers inhibit the growth of the fish pathogen viral hemorrhagic septicemia virus (VHSV). AB - Viral hemorrhagic septicemia virus (VHSV) is a serious disease impacting wild and cultured fish worldwide. Hence, an effective therapeutic method against VHSV infection needs to be developed. Aptamer technology is a new and promising method for diagnostics and therapeutics. It revolves around the use of an aptamer molecule, an artificial ligand (nucleic acid or protein), which has the capacity to recognize target molecules with high affinity and specificity. Here, we aimed at selecting RNA aptamers that can specifically bind to and inhibit the growth of a strain of fish VHSV both in vitro and in vivo. Three VHSV-specific RNA aptamers (F1, F2, and C6) were selected from a pool of artificially and randomly produced oligonucleotides using systematic evolution of ligands by exponential enrichment. The three RNA aptamers showed obvious binding to VHSV in an electrophoretic mobility shift assay but not to other tested viruses. The RNA aptamers were tested for their ability to inhibit VHSV in vitro using hirame natural embryo (HINAE) cells. Cytopathic effect and plaque assays showed that all aptamers inhibited the growth of VHSV in HINAE cells. In vivo tests using RNA aptamers produced by Rhodovulum sulfidophilum showed that extracellular RNA aptamers inhibited VHSV infection in Japanese flounder. These results suggest that the RNA aptamers are a useful tool for protection against VHSV infection in Japanese flounder. PMID- 22527270 TI - Use of comparative genomics to develop EST-SSRs for red drum (Sciaenops ocellatus). AB - Microsatellites physically linked to expressed sequence tags (EST-SSRs) are an important resource for linkage mapping and comparative genomics, and data mining in publicly available EST databases is a common strategy for EST-SSR discovery. At present, many species lack species-specific EST sequence data needed for the efficient characterization of EST-SSRs. This paper describes the discovery and development of EST-SSRs for red drum (Sciaenops ocellatus), an estuarine dependent sciaenid species of economic importance in the USA and elsewhere, using a phylogenetically informed, comparative genomics approach to primer design. The approach entailed comparing existing genomic resources from species closely allied phylogenetically to red drum, with resources from more distantly related outgroup species. By taking into account the degree to which flanking regions are conserved across taxa, the efficiency of PCR primer design was increased greatly. The amplification success rate for primers designed for red drum was 100 % when using EST libraries from confamilial species and 92 % when using an EST library from a species in the same suborder. The primers developed also amplified EST SSRs in a wide range of perciform fishes, suggesting potential use in comparative genomics. This study demonstrates that EST-SSRs can be efficiently developed for an organism when limited species-specific data are available by exploiting genomic resources from well-studied species, even those at extended phylogenetic distances. PMID- 22527271 TI - In silico identification and characterization of 1-aminocyclopropane-1 carboxylate deaminase from Phytophthora sojae. AB - As part of an effort to obtain a fungal 1-aminocyclopropane-1-carboxylate deaminase encoding gene from Phytophthora sojae expressed sequence Tag database, we identify and characterize the ACCD from P. sojae using bioinformatics data mining tools and techniques. Computed structural model of P. sojae ACCD was found to consist of mixed alpha/beta motifs and probable loops. The predicted model resembles the structure of Pseudomonas ACCD (RMSD-0.44 A). The main differences observed between them are the presence of partial length of domain one, and longer helix alpha4. Ramachandran plot analysis revealed that portion of all residues falling into the most favorable regions was 95.0%. The substrate - and geometrical- docking of developed structure postulated functional capability of ACCD to carry out ACC cleavage reaction. The catalytic site in homo-tetrameric structure open to opposite directions separated by ~37.97 A distance arranged around central axis. This study provides a comprehensive identification and characterization of the ACCD in P. sojae and it may be helpful in the transcriptional and expression based study of P. sojae pathogenesis. PMID- 22527272 TI - The basic antioxidant structure for flavonoid derivatives. AB - An antioxidant structure-activity study is carried out in this work with ten flavonoid compounds using quantum chemistry calculations with the functional of density theory method. According to the geometry obtained by using the B3LYP/6 31G(d) method, the HOMO, ionization potential, stabilization energies, and spin density distribution showed that the flavonol is the more antioxidant nucleus. The spin density contribution is determinant for the stability of the free radical. The number of resonance structures is related to the pi-type electron system. 3-hydroxyflavone is the basic antioxidant structure for the simplified flavonoids studied here. The electron abstraction is more favored in the molecules where ether group and 3-hydroxyl are present, nonetheless 2,3-double bond and carbonyl moiety are facultative. PMID- 22527273 TI - CoMFA/CoMSIA 3D-QSAR of pyrimidine inhibitors of Pneumocystis carinii dihydrofolate reductase. AB - Pneumocystis carinii is typically a non-pathogenic fungus found in the respiratory tract of healthy humans. However, it may cause P. carinii pneumonia (PCP) in people with immune deficiency, affecting mainly premature babies, cancer patients and transplant recipients, and people with acquired immunodeficiency syndrome (AIDS). In the latter group, PCP occurs in approximately 80% of patients, a major cause of death. Currently, there are many available therapies to treat PCP patients, including P. carinii dihydrofolate reductase (PcDHFR) inhibitors, such as trimetrexate (TMX), piritrexim (PTX), trimethoprim (TMP), and pyrimethamine (PMT). Nevertheless, the high percentage of adverse side effects and the limited therapeutic success of the current drug therapy justify the search for new drugs rationally planned against PCP. This work focuses on the study of pyrimidine inhibitors of PcDHFR, using both CoMFA and CoMSIA 3D-QSAR methods. PMID- 22527274 TI - Molecular modeling of two-photon absorption and third-order nonlinearities of polymethine dyes for all-optical switching. AB - Stimulated by a recent experimental report [Hales JM et al. (2010) Science 327:1485-1488], two-photon absorption and third-order optical nonlinearities of selenopyrylium- and bis(dioxaborine)-terminated polymethine dyes (called SE-7C and DOB-9C) used for all-optical switching were investigated theoretically with time-dependent DFT (TD-DFT) and response theory as well as visualized real-space analysis. The calculated results for the first hyperpolarizability and second hyperpolarizability demonstrated that the two molecules both have large third order optical nonlinearities. Using real-space analysis, we were able to visually determine that in the one-photon absorption (OPA) process, the first singlet excited state of SE-7C and DOB-9C is an intramolecular charge transfer (ICT) excited state with strong absorption, while the second excited state of these dyes (also termed the "ICT state") shows weak absorption. However, in the two photon absorption (TPA) process, a larger TPA absorption cross-section was predicted for the second excited state. In this paper, we describe the properties of the S2 excited state, incorporating charge transfer and the transition moment, via real-space analysis, which was very important for understanding the TPA characteristics of the S(2) state. PMID- 22527275 TI - XZP + 1d and XZP + 1d-DKH basis sets for second-row elements: application to CCSD(T) zero-point vibrational energy and atomization energy calculations. AB - Recently, segmented all-electron contracted double, triple, quadruple, quintuple, and sextuple zeta valence plus polarization function (XZP, X = D, T, Q, 5, and 6) basis sets for the elements from H to Ar were constructed for use in conjunction with nonrelativistic and Douglas-Kroll-Hess Hamiltonians. In this work, in order to obtain a better description of some molecular properties, the XZP sets for the second-row elements were augmented with high-exponent d "inner polarization functions," which were optimized in the molecular environment at the second-order Moller-Plesset level. At the coupled cluster level of theory, the inclusion of tight d functions for these elements was found to be essential to improve the agreement between theoretical and experimental zero-point vibrational energies (ZPVEs) and atomization energies. For all of the molecules studied, the ZPVE errors were always smaller than 0.5 %. The atomization energies were also improved by applying corrections due to core/valence correlation and atomic spin orbit effects. This led to estimates for the atomization energies of various compounds in the gaseous phase. The largest error (1.2 kcal mol(-1)) was found for SiH(4). PMID- 22527277 TI - DFT study of the interaction between the conjugated fluorescein and dabcyl system, using fluorescene quenching method. AB - Molecular beacon is a DNA probe containing a sequence complementary to the target that is flanked by self-complementary termini, and carries a fluorophore and a quencher at the ends. We used the fluorescein and dabcyl as fluorophore and quencher respectively, and studied with DFT calculations at the GGA/DNP level, and taking into account DFT dispersion corrections by the Grimme and Tkatchenko Scheffler (TS) schemes, the distance, where the most favorable energetic interaction between the fluorophore and quencher in conjugated form occurs. This distance occurs at a separation distance of 29.451 A between the centers of Dabcyl and fluorescein employing the TS DFT dispersion correction scheme, indicating FRET efficiency around 94.28 %. The calculated emission spectra of the conjugated pair in water indicated that the emission and absorption spectrum overlap completely and thus no fluorescence can be observed due to the fluorescence resonance energy transfer (FRET) effect. The DFT results confirmed the experimentally observing fluorescence quenching of the fluorescein-dabcyl conjugated system by FRET. PMID- 22527276 TI - Probing the structure of Leishmania major DHFR TS and structure based virtual screening of peptide library for the identification of anti-leishmanial leads. AB - Leishmaniasis, a multi-faceted ethereal disease is considered to be one of the World's major communicable diseases that demands exhaustive research and control measures. The substantial data on these protozoan parasites has not been utilized completely to develop potential therapeutic strategies against Leishmaniasis. Dihydrofolate reductase thymidylate synthase (DHFR-TS) plays a major role in the infective state of the parasite and hence the DHFR-TS based drugs remains of much interest to researchers working on Leishmaniasis. Although, crystal structures of DHFR-TS from different species including Plasmodium falciparum and Trypanosoma cruzi are available, the experimentally determined structure of the Leishmania major DHFR-TS has not yet been reported in the Protein Data Bank. A high quality three dimensional structure of L.major DHFR-TS has been modeled through the homology modeling approach. Carefully refined and the energy minimized structure of the modeled protein was validated using a number of structure validation programs to confirm its structure quality. The modeled protein structure was used in the process of structure based virtual screening to figure out a potential lead structure against DHFR TS. The lead molecule identified has a binding affinity of 0.51 nM and clearly follows drug like properties. PMID- 22527278 TI - Analyzing of expression of novel polypeptide complexes consisting of Shiga toxin B subunit and Adherence Fimbriae of Escherichia coli based on in silico modeling. AB - Enterohemorrhagic (EHEC) and enteroaggregative (EAEC) are two pathotypes of diarrheagenic Escherichia coli. EAEC strains express adhesins called aggregate adherence fimbriae (AAFs) which the bacteria use to adhere to intestinal mucosa. EHEC virulence factor is Shiga toxin which belongs to the AB5 toxin family. B subunit, the nontoxic part of Shiga toxin (StxB), forms a homo pentamer and is responsible for binding to target cells. StxB has recently been proven to have adjuvant activity. In the current study we fused StxB encoding gene to 3' end of genes encoding two variants of AAFs, i.e., AAF/I and AAF/II. The in silico studies on tertiary structure and biochemical characteristics of Shiga toxin A subunit (StxA) revealed more resemblance to AAF/II than AAF/I. The constructs were prepared in a way that StxB could imitate its natural structure (pentamer formation) and its position (C-terminus) in the native toxin complex. The expression of these constructs showed the formation of AAF/II-B as a protein complex but with lower molecular mass than its expected size. In contrast, the AAF/I-B complex was not formed. Overall, the results of in silico studies and expression experiments together revealed that despite AAF/II-B expression, StxB failed to form pentamer. Therefore the observed protein complex has lower molecular mass. Since StxB is bound to AAF/II through disulfide bond, this bond prevents pentamer formation of StxB. However, due to the lack of disulfide bond between AAF/I and StxB, no protein complex is formed, thus StxB maintains its pentamer structure. PMID- 22527279 TI - The use of quantum-chemical descriptors for predicting the photoinduced toxicity of PAHs. AB - The geometries of 19 polyaromatic hydrocarbons (PAHs) were fully optimized and calculated by a density functional method (B3LYP) with the 3-21G basis set. Various quantum chemical descriptors such as the energy of the highest occupied molecular orbital (E (HOMO)), the energy of the lowest unoccupied molecular orbital (E (LUMO)), the difference in energy between those orbitals (E (GAP)), electronegativity (chi), chemical potential (MU), chemical hardness (eta), softness index (S), electrophilicity (omega), and polarizability (alpha) were employed along with physicochemical descriptors to construct useful quantitative structure-activity relationship (QSAR) models for the photoinduced toxicity of PAHs toward two aquatic species (Daphnia magna and Scenedesmus vacuolatus). E (LUMO), E (HOMO), E (GAP), S, chi, the molar refractivity (MR), and the molecular weight provide valuable information and play a significant role in the assessment of PAH phototoxicity. The resulting models are not expected to be useful per se for making genuine predictions for much larger test sets, but the various results do demonstrate the potential benefits of incorporating quantum-chemical descriptors into QSAR models for predicting the phototoxicity of PAHs. PMID- 22527280 TI - The quantum chemical study of the electronic states of S2Cl and its monovalent ions. AB - High-level quantum chemical techniques have been utilized to accurately describe the geometrical parameters, vibrational frequencies and dissociation pathways of the X (2)A", 1 (2)A', 2 (2)A', 2 (2)A" states of S(2)Cl; X (1)A', 1 (3)A", 1 (1)A", 1 (3)A' states of S(2)Cl(+); X (1)A', 1 (3)A', (1)A" states of S(2)Cl(-), and the corresponding excitation energies have been obtained from the energies extrapolated to their complete basis set limits. It has been established that the 2 (2)A' and 2 (2)A" terms of S(2)Cl exhibit a strong multi-reference character, while all the remaining excited states are dominated by the single replacements from the reference determinants. The enthalpies of the decomposition reactions have been obtained to aid in the investigations into the photolysis of S(2)Cl(2) and related systems. The value of the ionization potential of S(2)Cl has been found within the error bars of the experiment, and a reliable estimate of its electron affinity, EA (0) = -2.352 eV, has been proposed. PMID- 22527281 TI - Long-term effects of biomechanical exposure on severe shoulder pain in the Gazel cohort. AB - OBJECTIVE: We aimed to assess whether the risk factors for severe shoulder pain, especially exposure to arm elevation, were still relevant after a 12-year follow up, even following retirement. METHODS: All men participating in the ARPEGE ancillary study of the GAZEL cohort (followed-up since 1989) and who answered the 1994 or 1995 general GAZEL self-administered questionnaire were included. Weight and self-reported exposure (arm elevation >90 degrees with and without carrying loads) over the entire working life were collected at baseline (1994-1995). Shoulder pain and its intensity were recorded in 1994-1995 and again in 2006. Shoulder pain was measured on an intensity or discomfort 6-point scale in 1994 1995 and on an 8-point scale in 2006. Severe shoulder pain was defined as point rated higher than the mid-points (>3/6 in 1994-1995 and >4/8 in 2006) while moderate pain was lower or equal to these thresholds. RESULTS: At baseline, 1786 47-51-year-old men were included. In 1994-1995, moderate pain was observed among 8.5% (N=151) of men and severe shoulder pain among 14.6% (N=261). Exposure to arm elevation >90 degrees while carrying loads was significantly associated with severe shoulder pain with >25 years of exposure [adjusted odds ratio (OR (adj)) 4.2, 95% confidence interval (95% CI) 1.7-10.5], taking into account age, sports, smoking habits, history of shoulder trauma, and body mass index. In 2006, when most of the subjects had retired, 1482 men (83.0%) answered the questionnaire, 17.3% of them with severe shoulder pain; the association between exposure to arm elevation >90 degrees while carrying loads and severe shoulder pain was still significant (ORadj 3.3, 95% CI 1.3-8.0), and remained so when subjects with shoulder pain at baseline were excluded. CONCLUSIONS: Among men, the effect of high shoulder exposure (arm elevation >90 degrees while carrying loads) during working life on severe shoulder pain remains even after retirement. Extended surveillance and prevention should be offered to these workers. PMID- 22527282 TI - Regulation of nucleocytoplasmic shuttling of Bruton's tyrosine kinase (Btk) through a novel SH3-dependent interaction with ankyrin repeat domain 54 (ANKRD54). AB - Bruton's tyrosine kinase (Btk), belonging to the Tec family of tyrosine kinases (TFKs), is essential for B-lymphocyte development. Abrogation of Btk signaling causes human X-linked agammaglobulinemia (XLA) and murine X-linked immunodeficiency (Xid). We employed affinity purification of Flag-tagged Btk, combined with tandem mass spectrometry, to capture and identify novel interacting proteins. We here characterize the interaction with ankryin repeat domain 54 protein (ANKRD54), also known as Lyn-interacting ankyrin repeat protein (Liar). While Btk is a nucleocytoplasmic protein, the Liar pool was found to shuttle at a higher rate than Btk. Importantly, our results suggest that Liar mediates nuclear export of both Btk and another TFK, Txk/Rlk. Liar-mediated Btk shuttling was enriched for activation loop, nonphosphorylated Btk and entirely dependent on Btk's SH3 domain. Liar also showed reduced binding to an aspartic acid phosphomimetic SH3 mutant. Three other investigated nucleus-located proteins, Abl, estrogen receptor beta (ERbeta), and transcription factor T-bet, were all unaffected by Liar. We mapped the interaction site to the C terminus of the Btk SH3 domain. A biotinylated, synthetic Btk peptide, ARDKNGQEGYIPSNYVTEAEDS, was sufficient for this interaction. Liar is the first protein identified that specifically influences the nucleocytoplasmic shuttling of Btk and Txk and belongs to a rare group of known proteins carrying out this activity in a Crm1 dependent manner. PMID- 22527283 TI - An enhanced H/ACA RNP assembly mechanism for human telomerase RNA. AB - The integral telomerase RNA subunit templates the synthesis of telomeric repeats. The biological accumulation of human telomerase RNA (hTR) requires hTR H/ACA domain assembly with the same proteins that assemble on other human H/ACA RNAs. Despite this shared RNP composition, hTR accumulation is particularly sensitized to disruption by disease-linked H/ACA protein variants. We show that contrary to expectation, hTR-specific sequence requirements for biological accumulation do not act at an hTR-specific step of H/ACA RNP biogenesis; instead, they enhance hTR binding to the shared, chaperone-bound scaffold of H/ACA core proteins that mediates initial RNP assembly. We recapitulate physiological H/ACA RNP assembly with a preassembled NAF1/dyskerin/NOP10/NHP2 scaffold purified from cell extract and demonstrate that distributed sequence features of the hTR 3' hairpin synergize to improve scaffold binding. Our findings reveal that the hTR H/ACA domain is distinguished from other human H/ACA RNAs not by a distinct set of RNA protein interactions but by an increased efficiency of RNP assembly. Our findings suggest a unifying mechanism for human telomerase deficiencies associated with H/ACA protein variants. PMID- 22527284 TI - Oil palm phenolics attenuate changes caused by an atherogenic diet in mice. AB - BACKGROUND: Water-soluble phenolics from the oil palm possess significant biological properties. PURPOSE: In this study, we aimed to discover the role of oil palm phenolics (OPP) in influencing the gene expression changes caused by an atherogenic diet in mice. METHODS: We fed mice with either a low-fat normal diet (14.6 % kcal/kcal fat) with distilled water, or a high-fat atherogenic diet (40.5 % kcal/kcal fat) containing cholesterol. The latter group was given either distilled water or OPP. We harvested major organs such as livers, spleens and hearts for microarray gene expression profiling analysis. We determined how OPP changed the gene expression profiles caused by the atherogenic diet. In addition to gene expression studies, we carried out physiological observations, blood hematology as well as clinical biochemistry, cytokine profiling and antioxidant assays on their blood sera. RESULTS: Using Illumina microarrays, we found that the atherogenic diet caused oxidative stress, inflammation and increased turnover of metabolites and cells in the liver, spleen and heart. In contrast, OPP showed signs of attenuating these effects. The extract increased unfolded protein response in the liver, attenuated antigen presentation and processing in the spleen and up-regulated antioxidant genes in the heart. Real-time quantitative reverse transcription-polymerase chain reaction validated the microarray gene expression fold changes observed. Serum cytokine profiling showed that OPP attenuated inflammation by modulating the Th1/Th2 axis toward the latter. OPP also increased serum antioxidant activity to normal levels. CONCLUSION: This study suggests that OPP may possibly attenuate atherosclerosis and other forms of cardiovascular disease. PMID- 22527285 TI - Factors affecting the distribution of folate forms in the serum of elderly German adults. AB - PURPOSE: We investigated the roles of age, vitamin B(12) markers, and the 5,10 methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism as determinants of folate forms in serum. METHODS: We measured the serum concentrations of (6S)-5 CH(3)-H(4)folate, (6S)-H(4)folate, (6S)-5-HCO-H(4)folate, (6R)-5,10-CH(+) H(4)folate, and folic acid in 146 non-supplemented older participants (median age 74 years). The concentrations of total vitamin B(12), holotranscobalamin (holoTC), methylmalonic acid (MMA), and total homocysteine (tHcy) were also measured. RESULTS: Elevated metabolites (MMA > 271 nmol/L and tHcy > 12.0 MUmol/L) were found in 24.0 and 63.0 % of the participants, respectively. We found a significant age-dependent decrease (participants with a median age of 87 years compared with participants with a median age of 60 years) in the sum of serum folate levels, the (6S)-5-CH(3)-H(4)folate concentration, and the (6S)-5 CH(3)-H(4)folate proportion. In addition, participants with elevated metabolite levels were older, had lower concentrations of the sum of folates and (6S)-5 CH(3)-H(4)folate, and had higher concentrations of (6S)-5-CHO-H(4)folate and creatinine but had a comparable holoTC/total vitamin B(12) ratio. No association was found between the MTHFR C677T genotype and serum folate forms. CONCLUSION: Low serum (6S)-5-CH(3)-H(4)folate concentrations and the proportion of (6S)-5 CH(3)-H(4)folate (percentage of the sum of folate forms) are related to older age and elevated MMA and tHcy levels. PMID- 22527286 TI - Combined arginine and glutamine decrease release of de novo synthesized leukotrienes and expression of proinflammatory cytokines in activated human intestinal mast cells. AB - PURPOSE: Glutamine and arginine modulate inflammatory responses of epithelial cells and monocytes. Here, we studied the response of human mast cells to pharmacological doses of arginine and glutamine. METHODS: Mast cells isolated from intestinal tissue were incubated with physiological doses of arginine (0.1 mmol/L) and glutamine (0.6 mmol/L) or with pharmacological doses of arginine (2 mmol/L) and glutamine (10 mmol/L) for 18 h. Following stimulation by IgE receptor crosslinking mast cell mediators were measured by enzymatic assay, ELISA, multiplex bead immunoassay, or real-time RT-PCR, and activation of intracellular signaling molecules was determined using proteome profiler array or immunoblotting. RESULTS: We found that the combined challenge of mast cells with pharmacological doses of arginine and glutamine caused a decrease in induced release of de novo synthesized leukotriene C(4) but not of pre-stored beta hexosaminidase. Moreover, we found reduced expression of chemokines monocyte chemoattractant protein-1 (CCL2), macrophage inflammatory protein-1beta (CCL4), IL-8 (CXCL8), and TNF in response to high doses of both amino acids. The anti inflammatory effects of arginine and glutamine were associated with decreased activation levels of signaling molecules known to be involved in mast cell cytokine expression such as MAPK family members extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38, and the protein kinase B (Akt). CONCLUSION: Arginine and glutamine attenuate IgE-dependent human mast cell activation by decreasing lipid mediator release and expression of proinflammatory cytokines. PMID- 22527288 TI - Vitamin C-related nutrient-nutrient and nutrient-gene interactions that modify folate status. AB - PURPOSE: Folate-related nutrient-nutrient and nutrient-gene interactions modify disease risk; we therefore examined synergistic relationships between dietary folic acid, vitamin C and variant folate genes with respect to red cell folate status. METHODS: Two hundred and twelve subjects were examined using chemiluminescent immunoassay, PCR and food frequency questionnaire to determine red cell and serum folate, 14 folate gene polymorphisms, dietary folate (natural and synthetic) and vitamin C. RESULTS: When examined independently, synthetic PteGlu correlates best with red cell folate at higher levels of intake (p = 0.0102), while natural 5CH(3)-H(4)-PteGlu(n) correlates best with red cell folate at lower levels of intake (p = 0.0035). However, dietary vitamin C and 5CH(3) H(4)-PteGlu(n) interact synergistically to correlate with red cell folate at higher levels of intake (p = 0.0005). No interaction between dietary vitamin C and PteGlu was observed. This 'natural' nutrient-nutrient interaction may provide an alternative to synthetic PteGlu supplementation that is now linked to adverse phenomena/health outcomes. On its own, vitamin C also correlates with red cell folate (p = 0.0150) and is strongly influenced by genetic variation in TS, MTHFR and MSR, genes critical for DNA and methionine biosynthesis that underpin erythropoiesis. Similarly, dietary vitamin C and 5CH(3)-H(4)-PteGlu(n) act synergistically to modify red cell folate status according to variation in folate genes: of note, heterozygosity for 2R3R-TS (p = 0.0181), SHMT (p = 0.0046) and all three MTHFR SNPs (p = 0.0023, 0.0015 and 0.0239 for G1793A, C677T and A1298C variants, respectively) promote a significant association with red cell folate. Again, all these genes are critical for nucleic acid biosynthesis. Folate variants with the strongest independent effect on folate status were C677T-MTHFR (p = 0.0004) and G1793A-MTHFR (p = 0.0173). CONCLUSIONS: 5CH(3)-H(4)-PteGlu(n) assimilation and variant folate gene expression products may be critically dependent on dietary vitamin C. PMID- 22527289 TI - Direct demonstration of CD4 T cell cooperation in the primary in vivo generation of CD4 effector T cells. AB - Many observations bear upon the cellular and molecular requirements for CD4 T cell activation. The interaction of CD4 T cells with dendritic cells (DC), central to the induction of most immune responses, is the most studied. However, leukocytes other than DC can dramatically affect the induction and differentiation of CD4 T cells into effector cells. We recently provided indirect evidence that in vivo CD4 T cooperation facilitates the activation of CD4 T cells. Here, we demonstrate that the activation of CD4 T cells, specific for the hen egg lysozyme (HEL)(105) (-120) peptide, is optimally achieved when BALB/c mice are immunized with additional MHC class II-binding HEL peptides in incomplete Freund's adjuvant. This cooperation cannot be mimicked by the coadministration of LPS or of an agonistic antibody to CD40, at the time of immunization. In contrast, OX40-OX40L interactions are necessary for CD4 T cell cooperation in that an OX40 agonistic antibody can replace, and an OX40L-blocking antibody can abrogate, CD4 T cell cooperation in situations where such cooperation would otherwise enhance the activation of CD4 T cells. PMID- 22527287 TI - LDL-cholesterol-lowering effect of a dietary supplement with plant extracts in subjects with moderate hypercholesterolemia. AB - PURPOSE: Red yeast rice (RYR), sugar cane-derived policosanols (SCdP) and artichoke leaf extracts (ALEs) are currently incorporated alone or in combination into dietary supplements for their potential low-density-lipoprotein cholesterol (LDL-cholesterol)-lowering effects. Yet, there is no information supporting the efficacy of this association on the reduction in LDL-cholesterol. The main objective of this study was to investigate the effects of a new dietary supplement (DS) with RYR, SCdP and ALEs on LDL-cholesterol. METHODS: In a double blind, randomized, parallel controlled study, 39 subjects from 21 to 55 years with moderate hypercholesterolemia without drug treatment were assigned to 2 groups and then consumed either a DS containing RYR, SCdP and ALEs or a placebo over a 16-week period. Plasma concentrations of lipids [LDL-cholesterol, total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-cholesterol), triacylglycerols (TG)] and plasma levels of vitamins C and E, total polyphenols and malondialdehyde were determined at baseline and after 4, 8, 12 and 16 weeks. RESULTS: LDL-cholesterol and TC were reduced by, respectively, 21.4 % (95 % CI, 13.3 to -24.9 %, p < 0.001) and 14.1 % (95 % CI, -10.1 to -18.0 %, p < 0.001) at week 16 in the DS group compared with baseline. Similar results were obtained at weeks 4, 8 and 12. TG decreased by 12.2 % after 16 weeks in the DS group (95 % CI: -24.4 to -0.1 %, p < 0.05). For the vitamin E/TC ratio, a difference was observed between groups at week 16 (p < 0.05). Other parameters were not modified. CONCLUSIONS: Daily consumption of this new DS decreased LDL-cholesterol and TC and is therefore an interesting, convenient aid in managing mild to moderate hypercholesterolemia. PMID- 22527290 TI - Recombinant factor VIIa treatment for asymptomatic factor VII deficient patients going through major surgery. AB - Factor VII deficiency is the most common among the rare autosomal recessive coagulation disorders worldwide. In factor VII deficient patients, the severity and clinical manifestations cannot be reliably determined by factor VII levels. Severe bleeding tends to occur in individuals with factor VII activity levels of 2% or less of normal. Patients with 2-10% factor VII vary between asymptomatic to severe life threatening haemorrhages behaviour. Recombinant factor VIIa (rFVIIa) is the most common replacement therapy for congenital factor VII deficiency. However, unlike haemophilia patients for whom treatment protocols are straight forward, in asymptomatic factor VII deficiency patients it is still debatable. In this study, we demonstrate that a single and very low dose of recombinant factor VIIa enabled asymptomatic patients with factor VII deficiency to go through major surgery safely. This suggestion was also supported by thrombin generation, as well as by thromboelastometry. PMID- 22527291 TI - Negative correlation between D-dimer and plasminogen activator inhibitor-1 levels is absent in obese women. AB - Obesity is characterized by alterations in haemostatic processes that lead to a prothrombotic state. D-dimer (D-Di) is the last product of the fibrinolysis and may reflect the haemostatic balance. As the plasminogen activator inhibitor (PAI) 1 is the main inhibitor of fibrinolysis and it is elevated in obese, we hypothesize that negative correlation exists between PAI-1 and D-Di. In addition, we evaluated if plasma levels of PAI-1 and D-Di may be correlated with clinical parameters of adiposity [waist circumference and waist-to-hip ratio (WHR)]. We measured plasma PAI-1 and D-Di concentrations using ELISA in 60 women: 21 lean women without comorbidities and 39 obese women. We found higher levels of D-Di and PAI-1 in obese groups compared to control group (P < 0.05). No differences were observed between obese and obese untreated hypertensives. PAI-1 levels, but not of D-Di, are positively correlated with BMI (control, r = 0.44) and WHR (all obese, r = 0.40). Negative correlation was found between PAI-1 and D-Di in control (r = -0.56), no association was observed in obese, signalizing to a particular attention regarding the clinical use of D-Di. Our results indicate the magnitude of central obesity as a risk factor for development of disorders related to prothrombotic states. PMID- 22527292 TI - A surgical case of cerebral hemorrhage in a patient with factor XI deficiency. AB - A 63-year-old man suddenly presented with right hemiplegia and was taken to our hospital. Computed tomography (CT) scan revealed subcortical hemorrhage of the left parietal lobe. He had no medical history except hypertension; thus, it initially appeared to be a typical hypertensive hemorrhage. However, blood analysis showed an abnormally elevated activated partial thromboplastin time. One hour after admission, his Glasgow Coma Scale fell from 14 to 11. We performed an echo-guided stereotaxic removal of the hematoma. He improved immediately and was diagnosed with congenital factor XI (FXI) deficiency a few days after surgery. FXI deficiency, described as hemophilic syndrome C, rarely manifests as spontaneous bleeding, but surgical intervention has been known to manifest as bleeding. This case highlights the importance of evaluation of coagulopathies in patients with intracerebral hemorrhage before surgery, and, in cases wherein blood analysis results suggest coexisting coagulation disorders, less invasive surgical methods would likely lead to good outcomes. PMID- 22527293 TI - Thrombophilic disorders: a real threat to patients with end-stage renal disease on hemodialysis and at the time of renal transplantation. AB - Management of end-stage renal disease is the mainstay of prevention of renal vascular complications and kidney rejection. We sought to describe the association of some disorders such as diabetic nephropathy, polycystic renal disease, hypertension, and thrombophilia with renal failure and discuss possible mechanisms explaining the implication of the thrombophilic states in kidney allograft thrombosis and renal rejection. Five hundred and sixty-eight patients were included in this case-control study and multivariate analysis was applied. Cases and controls were tested for all major types of thrombophilia. Diabetic nephropathy, autosomal dominant polycystic kidney disease, hypertension, and smoking are the strongest causal agents of end-stage renal disease in Tunisia. It should also be noted that the prevalence of factor V Leiden (P = 0.05) and protein C deficiency (P = 0.005) were significantly higher in ESRD patients awaiting renal transplantation than controls. The present study has raised the possibility that thrombophilic factors may play a pathophysiological role in renal failure. These results will serve as a basis for anticoagulant prophylaxis aimed at preventing kidney rejection and renal allograft thrombosis. PMID- 22527294 TI - An uncommon cause of elbow synovitis in an adult haemophilia patient. AB - We present the case of an adult haemophilia patient that at clinical examination showed intense painless synovitis in his left elbow, with full range of movement, which was unresponsive to 1 month of on-demand haematologic treatment at home. Radiological examination demonstrated a spontaneous displaced fracture of the olecranon secondary to severe osteolysis, due to advanced haemophilic arthropathy. Then, the patient was treated with a posterior plaster splint to immobilize the joint for 3 weeks together with secondary prophylaxis (3000 IU twice a week for 3 months). One month later the patient was better, with full range of movement, and the amount of swelling had improved. Regarding the outcome of the fracture, 6 months later there was no healing of the fracture, and the patient developed a painless nonunion that allowed him to return to his preinjury activities of daily living. As far as we know, this rare combination of problems (unresponsive synovitis, severe haemophilic arthropathy, spontaneous elbow fracture) has not been previously published in the literature. PMID- 22527295 TI - [Laudation for Ney Romiti on his 80th birthday]. PMID- 22527296 TI - [Disseminated cutaneous leiomyomas]. AB - Cutaneous leiomyomas are benign smooth muscle tumors. Depending on the site of origin, one distinguishes three different types--piloleiomyoma, angioleiomyoma and genital leiomyoma. They appear between the first and third decades of life. A 56-year-old woman presented with painful red - brown papules and nodules on her trunk. Based on clinical and histological criteria the diagnosis of disseminated cutaneous leiomyomas was made. Because of the widespread cutaneous involvement, surgical treatment was not possible. Therefore we decided to employ a pharmacologic anti-depressive treatment. With this approach, the patient experienced considerable pain reduction. PMID- 22527297 TI - [Pemphigus erythematosus]. AB - Pemphigus erythematosus, also known as Senear-Usher syndrome, was originally described as a variant of pemphigus with features of lupus erythematosus but regarded today as a localized form of pemphigus foliaceus and considered an autoimmune bullous disease. The autoantigen is desmoglein 1, a desmosomal adhesion protein in keratinocytes. A 69-year-old man presented with a 3-month history of erosions and blisters on the cheeks, which then also appeared on the trunk. Clinical and histopathologic criteria as well as immunofluorescence studies lead to the diagnosis of pemphigus erythematosus with transition to pemphigus foliaceus. PMID- 22527298 TI - [Keratosis palmoplantaris papulosa]. AB - Keratosis palmoplantaris punctata (KPPP) is a rare genodermatosis inherited in autosomal dominant fashion. Clinical findings are multiple, hyperkeratotic, mostly asymptomatic, pinhead-sized papules localized on the palms and soles with progression to hyperkeratotic plaques at pressure sites. A 79-year-old woman presented with a history of hyperkeratotic papules on the palms and soles. Clinical and histopathologic criteria led to the diagnosis KPPP. Identification of causative genes is necessary to permit a better classification and estimation of associated disorders. PMID- 22527299 TI - [Cutaneous malignant lymphomas. Update on diagnosis and therapy of cutaneous T cell lymphomas]. AB - Cutaneous T-cell lymphomas represent extranodal non-Hodgkin lymphomas of mature T cells, which accumulate in the skin. They have been recognized as a heterogeneous group with distinct variability in clinical presentation and histopathology, with divergent biological behaviour and prognosis. Therefore the exact diagnosis is an important prerequisite for an adequate and stage-adapted treatment. PMID- 22527300 TI - Workload assessment of surgeons: correlation between NASA TLX and blinks. AB - BACKGROUND: Blinks are known as an indicator of visual attention and mental stress. In this study, surgeons' mental workload was evaluated utilizing a paper assessment instrument (National Aeronautics and Space Administration Task Load Index, NASA TLX) and by examining their eye blinks. Correlation between these two assessments was reported. METHODS: Surgeons' eye motions were video-recorded using a head-mounted eye-tracker while the surgeons performed a laparoscopic procedure on a virtual reality trainer. Blink frequency and duration were computed using computer vision technology. The level of workload experienced during the procedure was reported by surgeons using the NASA TLX. RESULTS: A total of 42 valid videos were recorded from 23 surgeons. After blinks were computed, videos were divided into two groups based on the blink frequency: infrequent group (<= 6 blinks/min) and frequent group (more than 6 blinks/min). Surgical performance (measured by task time and trajectories of tool tips) was not significantly different between these two groups, but NASA TLX scores were significantly different. Surgeons who blinked infrequently reported a higher level of frustration (46 vs. 34, P = 0.047) and higher overall level of workload (57 vs. 47, P = 0.045) than those who blinked more frequently. The correlation coefficients (Pearson test) between NASA TLX and the blink frequency and duration were -0.17 and 0.446. CONCLUSION: Reduction of blink frequency and shorter blink duration matched the increasing level of mental workload reported by surgeons. The value of using eye-tracking technology for assessment of surgeon mental workload was shown. PMID- 22527301 TI - Highly sensitive detection of residual chlorpromazine hydrochloride with solid substrate room temperature phosphorimetry. AB - Under the condition of 60 degrees C and 20 min at pH 6.12, chlorpromazine hydrochloride (CPZ) could react with fluorescein isothiocyanate (FITC) to produce FITC-CPZ, which increased the pi-electron density (delta) of carbon atom in FITC conjugated system and the room temperature phosphorescence (RTP) intensity of FITC. Thus, a new solid substrate room temperature phosphorimetry (SSRTP) for the determination of residual CPZ was established. The regression equation of working curve was DeltaI (p) = 4.254 + 7.906 m(CPZ) (ag spot(-1)) with the correlation coefficient (r) of 0.9990 in the range of 0.036-9.6 ag spot(-1) (corresponding concentration: 0.090-24 fg ml(-1), sample volume: 0.40 MUl spot(-1)), and the detection limit (LD) was 0.018 ag spot(-1) (corresponding concentration: 4.5 * 10(-17) g ml(-1)). This method with wide linear range and high sensitivity was not only used to diagnose human disease based on the correlation between the residual quantity and lethal dose of CPZ in human serum, but also used to determine residual CPZ in biological samples with the results consisting with those obtained by gas chromatography (GC), showing good accuracy. The constituent of FITC-CPZ was analyzed by GC-MS (mass spectrometry) and the reaction mechanism of SSRTP for the determination of trace CPZ was also discussed. PMID- 22527302 TI - Fluorescence characteristics and inclusion of ICT fluorescent probe in organized assemblies. AB - The inclusion behavior of an intramolecular charge transfer (ICT) fluorescent probe namely; 2-[3-(4-dimethylamino-phenyl)-allylidene]-tetralone (DMAPT) in organized assemblies of aqueous micellar, alpha- and beta-cyclodextrins (CDs) and bovine serum albumin (BSA) pockets have been studied using steady-state absorption and fluorescence spectroscopy. The fluorescence characteristics (energy and intensity) of DMAPT are highly sensitive to the properties of the medium. The ICT maximum is strongly blue-shifted with a great enhancement of the fluorescence intensity upon addition of different surfactants, confirming the solubilization of DMAPT in the hydrophobic micellar assembly. In addition, the fluorescence of DMAPT is more sensitive to the nature and concentration of the added CDs. In alpha- or beta-CD solutions, the fluorescence intensity increases strongly (by 6 and 23 orders of magnitude, respectively). Upon encapsulation in the CD cavity, the molecular flexibility decreases due to the geometrical restrictions of the CD nanocavity which decreases the non radiative transition via the free rotation around the single and/or double bonds of the butadiene bridge. This was supported by finding that the fluorescence quantum yield of DMAPT increases with increasing the viscosity of the medium. The binding constants of DMAPT with micelles, alpha- and beta-CD solutions have been calculated and were found to be highly dependent on the nature of the used surfactants or CDs. The thermodynamic parameters have been also determined and the difference in magnitude between the formed alpha- and beta-CD-DMAPT inclusion complexes is discussed on the basis of the cavity size. Finally, the binding constant of DMAPT with bovine serum albumin was calculated, indicating the relative stability of the DMAPT-BSA complex. The energy transfer distance between BSA as a donor and DMAPT as an acceptor was obtained following the fluorescence quenching of BSA by DMAPT, via resonance mechanism as a quencher. PMID- 22527303 TI - Spectral properties of Y-shaped donor-acceptor push-pull imidazole-based fluorophores: comparison between solution and polymer matrices. AB - The spectral properties of a novel type of Y-shaped fluorophores consisting of an imidazole ring end-capped with two electron-donating N,N-dimethylaminophenyl groups at positions C4 and C5 and one electron-withdrawing cyano group on the imidazole moiety at position C2 were examined. The pi-linker separating the 4,5 bis[4-(N,N-dimethylamino)phenyl]-1H-imidazole donor moiety and the cyano group comprises 1,4-phenylene (1), (E)-phenylethenyl (2), (E)-phenylbuta-1,3-dienyl (3), biphenyl (4), (E)-phenylethenylphenyl (5) and phenylethynylphenyl (6) conjugated paths. The absorption and fluorescence spectra were obtained in toluene, dichloromethane, acetonitrile and methanol and in polymer matrices such as polystyrene (PS), poly(methyl methacrylate) (PMMA) and poly(vinylchloride) (PVC). The most intense absorption bands of fluorophores 1-6 were observed within the range of 283 to 330 nm. Less intense but longer-wavelength absorption bands designated as charge-transfer bands were observed at approximately 380-430 nm depending on the medium. The fluorophores exhibited strong fluorescence in the visible region with a Stokes shift of approximately 4300-5800 cm(-1) in non-polar toluene and polystyrene, whereas very low intensity of fluorescence was observed with a Stokes shift in the 6500-7800 cm(-1) region in polar methanol and acetonitrile. The large Stokes shift indicates a large difference in the spatial arrangement of the chromophore in the absorbing and emitting states. A relatively intense fluorescence (quantum yields of 0.12-0.69) was observed only for derivative 1 in all media except methanol. The fluorophores doped in matrices yielded more intense fluorescence compared with the fluorescence in liquid media. The use of solid polymer matrices lowers the probability of forming non-emissive excited states. The fluorescence lifetimes were short (1-4 ns) for all of the fluorophores in solvents and in polymer matrices. PMID- 22527304 TI - Introducing dichlorocarbene in graphene. AB - The functionalization of graphene with dichlorocarbene has been successfully attained based on a conventional method for the generation of dichlorocarbenes. The obtained material was fully characterized using high resolution X-ray photoelectron spectroscopy, transmission electron microscopy, infrared and Raman spectroscopies. PMID- 22527305 TI - Chemical and semisynthesis of posttranslationally modified proteins. AB - Posttranslational modifications of proteins play crucial roles in health and disease by affecting numerous aspects of protein structure, function, stability and sub cellular localization. Yet understanding the effects of these modifications on several of these processes at the molecular level has been hindered by the lack of homogeneously modified proteins obtained via traditional biochemical and molecular biology approaches. Moreover, the preparation of such bioconjugates at a workable level is highly demanding. Recent advances in protein chemistry applying chemical and semisynthetic approaches are becoming increasingly beneficial to overcome these challenges. These methods allow site specific modifications of a desired protein and afford the product in large quantities for biochemical and structural analyses. In this review, we survey these efforts and their importance in dissecting the role of several posttranslational modifications in various proteins. Several examples are presented where glycosylated, phosphorylated, ubiquitinated, lipidated, acetylated and methylated proteins were prepared. PMID- 22527307 TI - Growth inhibition of human lens epithelial cells by short hairpin RNA in transcription factor forkhead box E3 (FOXE3). AB - BACKGROUND: Posterior capsule opacification occurs mainly due to the remnant lens epithelial cell proliferation and migration after cataract surgery. The purpose of this study was to investigate whether small hairpin RNA (shRNA)-mediated gene silencing of transcription factor forkhead box E3 (FOXE3) can be employed to inhibit the expression of FOXE3 and suppress the growth in lens epithelial cells. METHODS: FOXE3-targeted shRNA was transfected into a human lens epithelial cell line (HLEB-3) using Lipofectamine 2000 reagent. Quantitative PCR was used to confirm the downregulation of FOXE3 mRNA expression following infection of lens epithelial cells, and FOXE3 protein expression levels were evaluated by Western blot analysis and immunofluorescence staining. HLEB-3 cell growth after the transduction was analyzed by cell counting and MTT colorimetric assay. Cell cycle of the HLEB-3 cells was examined by flowcytometric analysis. RESULTS: Compared with the control groups, both mRNA and protein levels of FOXE3 expression were significantly decreased in shRNA-treated groups, and cytostatic effects were obvious within 48 h after transfection. An increased incidence of G1-phase arrest was identified in FOXE3-shRNA transfected HLEB-3 cells. CONCLUSIONS: shRNA mediated gene silencing of FOXE3 could significantly inhibit cell growth and induce the G1-phase arrest in HLEB-3 cells. Formation of posterior capsular opacification might be repressed if lens epithelial cell growth ceases after the FOXE3 gene is silenced with molecular biology technology. PMID- 22527308 TI - Successful treatment of blepharitis with bibrocathol (Posiformin(r) 2 %). AB - BACKGROUND: Bibrocathol is a well-established antiseptic drug for the treatment of acute eyelid diseases like blepharitis. Despite its frequent use in clinical practice, no controlled clinical trial on the efficacy of bibrocathol 2% eye ointment has been performed until now. The aim of the study was to investigate efficacy, safety and tolerability of bibrocathol (Posiformin(r) 2 %) eye ointment in patients diagnosed with blepharitis. METHODS: In this multi-center, randomized, double-masked, placebo-controlled parallel-group comparison, the change of signs and symptoms (sum score) of blepharitis in 197 patients (ITT (intention-to-treat-group); mean age 56 +/- 18 years, 56 % female, active drug:vehicle = 97:100) over 2 weeks treatment with bibrocathol 2 % eye ointment was evaluated. RESULTS: Patients receiving bibrocathol 2 % showed greater improvement in the sum score than the placebo patients (p < 0.0001, Cohen's effect size d = 0.73). Also, the results from further efficacy assessments improvement of single symptoms and ocular discomfort measured by a VAS (visual analogue scale) supported treatment with bibrocathol. Patients and investigators provided favorable tolerability ratings preferring bibrocathol over placebo. No safety issues were observed with regard to intraocular pressure, visual acuity, or occurrence of adverse events. CONCLUSIONS: Blepharitis therapy with the antiseptic bibrocathol 2 % in this trial was highly efficacious and safe. PMID- 22527309 TI - Complication rate and risk factors for intraoperative complications in resident performed phacoemulsification surgery. AB - BACKGROUND/AIM: To determine the complication rate and risk factors for intraoperative complications in resident-performed phacoemulsification surgery at a tertiary care center during the first 100 surgeries. METHODS: Retrospective chart review of the first 100 performed phacoemulsification cases of six consecutive residents. Posterior capsule tear, vitreous loss, and dislocation of lenticular fragments into the vitreous were defined as intraoperative complications. Patient characteristics considered risk factors for surgery were identified and correlated with the occurrence of intraoperative complications. RESULTS: Complications occurred in 23 of 600 operations (3.8 %). Surgery was complicated by posterior capsular tear in 23 eyes (3.8 %) with vitreous loss in 17 eyes (2.8 %) and loss of lenticular fragments into the vitreous in seven eyes (1.2 %). Eyes with dense nuclear sclerosis (p = 0.002) and white cataracts (p = 0.019) were associated with a statistically significantly greater incidence of posterior capsular tears and vitreous loss (p = 0.007 and p = 0.027 respectively). An intraocular lens was implanted in 591 eyes as intended. CONCLUSIONS: Residents achieve an acceptable complication rate during their initial 100 phacoemulsification cases. PMID- 22527310 TI - Eye injuries in the elderly from consumer products in the United States: 2001 2007. AB - PURPOSE: To quantify and characterize eye injuries related to consumer products in elderly patients (>= 65) treated in United States (US) hospital emergency departments (EDs) in 2001-2007. DESIGN: Retrospective study. PARTICIPANTS: The study comprised 1,455 patient cases. METHODS: Descriptive analysis of consumer product (CP)-related eye injury data derived from the National Electronic Injury Surveillance System, a probability sample of 100 hospitals nationwide with 24 hour EDs. Narrative data was used to assign each case with the CP causing the eye injury, correcting for cases with misclassified CP codes. The proportions of eye injury visits were calculated by age, gender, diagnosis, disposition, locale of incident, and CP categories. The patient population included ocular injuries of all severity levels. We examined data for all non-fatal eye injuries in elderly patients (>= 65) treated in US EDs in 2001-2007. MAIN OUTCOME MEASURES: Age, gender, diagnosis, case disposition, locale of incident, CP causing the injury. RESULTS: There were an estimated 67,864 visits to United States EDs by patients >65 years for CP-related eye injuries during the study period, of which 64 % (43,105; 95 % confidence interval [CI], 40,739-45,472) were by males; 70 % (CI, 44,837-49,496) occurred at home. Chemicals (22 %; 15,236; CI, 13,482-16,989), followed by cutting tools/construction (21 %; 14,524; CI, 12,777-16,272), furniture (15 %; 10,145; CI, 8,724-11,566), and gardening (14 %; 9,467; CI, 8,021 10,912) were the most common causes of eye injury. The CP categories with the greatest proportion of preventable injuries were cutting tools/construction (90 %), gardening (88 %), and household tools (71 %). Contusions or abrasions (39 %; 26,968; CI, 24,850-29,086) were the most common diagnoses. CONCLUSIONS: This study suggests that most CP-related elderly eye injuries in the U.S. occur at home and in men. Chemicals are the most common cause of injury. Further research is needed to determine effective strategies to minimize CP-related eye injuries in the elderly. PMID- 22527311 TI - The effect of test variability on the structure-function relationship in early glaucoma. AB - PURPOSE: To determine whether the weakness of the structure-function relationship could be produced by test variability alone, without implying underlying dissociation between the true rates of structural and functional change. METHODS: Perimetric mean deviation (MD), and rim area (RA) and cup volume (CV) from confocal scanning laser ophthalmoscopy, over six visits, were taken from 166 eyes of 92 participants with high-risk ocular hypertension or suspected/early glaucoma in the Portland Progression Project. Models were created of each measure's variability. A further model predicted the rate of functional change from the rate of structural change. These were used to generate realistic simulated sequences of both functional and structural data with different standard deviations sigma between the underlying rates of change. 'Observed' structure function relationships were calculated. An empirical p-value was derived, equaling the proportion of simulated series for which the 'observed' structure function dissociation was greater than that seen in patient data. RESULTS: The correlation between the rates of structural (RA) and functional (MD) change was 0.171, consistent with sigma < 0.02 dB/yr. Using CV, the correlation was -0.091, consistent with sigma < 0.01 dB/yr. By comparison, the models predicted that the standard deviation of the rate of functional change for a healthy eye due to test variability would be 0.18 dB/yr. CONCLUSION: Test variability is sufficiently large that realistic patient data can be simulated without requiring a large variability between the underlying rates of structural and functional change. This absence of implied dissociation is a necessary condition for it to be valid to combine structural and functional measures to improve estimates of functional change and/or to reduce perimetric variability. PMID- 22527312 TI - Iris color and visual functions. AB - BACKGROUND: The aim of this study was to evaluate if iris color is associated with differences in visual functions such as intraocular straylight (IOSL), contrast sensitivity (CS), or best-corrected visual acuity (BCVA). METHODS: In this retrospective cohort study, which is a subgroup analysis of a large prospective trial about visual impairments in European car drivers, we included 853 persons between 20 and 80 years of age and without a history of ocular surgery or any eye disease including cataract. Subjects participated in an ophthalmological examination, grading of lens opacity, and the measurement of visual functions such as IOSL, CS, and BCVA. Dependent on iris color, participants were divided into four groups: light-blue, blue-grey, green-hazel, and brown. RESULTS: Independent of age, IOSL was significantly (all p values < 0.0001, Fisher's LSD test) higher in participants with light-blue colored iris (1.14 log(IOSL) [95 % CI: 1.11-1.17]) compared to participants with blue-grey (1.07 log(IOSL) [95 % CI: 1.05-1.09]), green-hazel (1.06 log(IOSL) [95 % CI: 1.04 1.08]) or brown (1.06 log(IOSL) [95 % CI: 1.04-1.08]) iris color. CS was also lower in participants with light-blue pigmented irises (1.60 log(CS) [95 % CI: 1.58-1.62]) than in the other groups, but statistically significant (p = 0.013, Fisher's LSD test) only compared to brown iris color. For BCVA we could not found any difference between the four groups. CONCLUSIONS: We could show in this study that iris color has a significant impact on IOSL and to a lower degree on CS, but not on BCVA. Persons with light-blue iris color who showed significantly higher IOSL values therefore may experience disability glare in daily situations such as driving at night more often than others. PMID- 22527313 TI - The subconjunctival use of cetuximab and bevacizumab in inhibition of corneal angiogenesis. AB - PURPOSE: To investigate the effects of cetuximab and bevacizumab on experimental rat model of corneal angiogenesis. METHODS: The right eyes of 28 male Sprague Dawley rats were included in silver nitrate cauterization-induced corneal angiogenesis model. They were divided into four groups: (1) silver nitrate cauterization-induced and 0.15 ml serum physiologic was given to the angiogenesis group, (2) bevacizumab was given 1.25 mg to the bevacizumab group, (3) cetuximab was given 5 mg to the cetuximab group, and (4) 1.25 mg bevacizumab plus 5 mg cetuximab were given to the bevacizumab + cetuximab group. All eyes were exposed to the treatment on days 1, 4, and 7 of the experiment, and drugs were given subconjunctivally. The left eyes were untreated and used as sham. On day 8, the treated eyes were evaluated biomicroscopically. Then, the rats were sacrificed, and corneal specimens were prepared for histopathologic examinations. RESULTS: The degree of angiogenesis inhibition was observed as 50.8% in bevacizumab, 54.3% in cetuximab, and 15.8% in bevacizumab + cetuximab groups by biomicroscopic evaluation. According to the histopathological and immunohistochemical findings obtained from the present study, the amount of angiogenesis was determined to have decreased considerably in both the bevacizumab and cetuximab groups; also, relatively less inhibiton was observed in the bevacizumab + cetuximab group. CONCLUSION: Subconjunctival injection of cetuximab and bevacizumab is effective in reducing corneal angiogenesis in silver nitrate cauterization induced angiogenesis model of rats. Further investigation is needed to assess the potential side-effects of the drugs, especially cetuximab. PMID- 22527314 TI - FUSION regimen: ranibizumab in treatment-naive patients with exudative age related macular degeneration and relatively good baseline visual acuity. AB - BACKGROUND: To investigate the safety and efficacy of a combined fixed-interval and pro re nata regimen of ranibizumab (FUSION regimen) for treatment of exudative age-related macular degeneration in patients with good visual acuity at baseline. To establish whether similar efficacy to monthly regimens can be achieved with fewer injections, even in patients with good visual acuity. METHODS: This was a prospective, open-label, consecutive interventional case series in treatment-naive patients with exudative age-related macular degeneration. The FUSION regimen consists of three phases: 1) a loading phase of two or three injections, depending on presence or absence of choroidal neovascularization activity at first follow-up, 2) administration of one injection on disappearance of exudation, and 3) subsequent administration of two separate injections at intervals 2 months apart, and then an injection every 3 months. Endpoints included visual acuity, presence of fluid, adverse events and number of injections administered. RESULTS: Seventeen eyes of 17 Caucasian patients were included. Mean patient age was 76 years, and 15 patients were female. Mean baseline visual acuity was 67.5 letters (median 67), with Snellen equivalent 20/50++, ranged between 45 (20/125) and 83 (20/20--). At 3 months, mean change in best-corrected visual acuity (BCVA) was +2.3 letters (median +9) compared with baseline (p = 0.3). At 6 months, mean change in BCVA was +4.2 letters (median +9) compared with baseline (p = 0.02). At 12 months, one patient had discontinued the study. Mean change in BCVA was 5.6 (median +10) compared with baseline (p = 0.04). No patient lost >=15 letters, and 14 patients (87.5%) lost <5 letters. The mean number of injections was 6.9. One patient experienced a retinal pigment epithelium tear; no other complications were observed. CONCLUSIONS: The FUSION regimen for ranibizumab has the potential to maintain visual gains achieved during the loading phase, as reported in studies with monthly injections, even in eyes with a relatively good visual acuity at baseline. These 12-month results warrant validation in a larger, randomized controlled trial. PMID- 22527315 TI - Early local functional changes in the human diabetic retina: a global flash multifocal electroretinogram study. AB - PURPOSE: To investigate early functional changes of local retinal defects in type II diabetic patients using the global flash multifocal electroretinogram (MOFO mfERG). METHODS: Thirty-eight diabetic patients and 14 age-matched controls were recruited. Nine of the diabetics were free from diabetic retinopathy (DR), while the remainder had mild to moderate non-proliferative diabetic retinopathy. The MOFO mfERG was performed at high (98 %) and low (46 %) contrast levels. MfERG responses were grouped into 35 regions for comparison with DR classification at those locations. Z-scores of the regional mfERG responses were compared across different types of DR defects. RESULTS: The mfERG waveform consisted of the direct component (DC) and the induced component (IC). Local reduction in DC and IC amplitudes were found in diabetic patients with and without DR. With increasing severity of retinopathy, there was a further deterioration in amplitude of both components. Under MOFO mfERG paradigm, amplitude was a useful screening parameter. CONCLUSION: The MOFO mfERG can help in detecting early functional anomalies before the appearance of visible signs, and may assist in monitoring further functional deterioration in diabetic patients. PMID- 22527316 TI - Increased lens vault as a risk factor for angle closure: confirmation in a Japanese population. AB - PURPOSE: A thicker lens vault (LV), measured by anterior segment optical coherence tomography (ASOCT), was recently identified as a novel risk factor for angle closure in Chinese Singaporeans. The purpose of our study was to investigate the association of LV with angle closure in Japanese subjects. DESIGN: Case-control study METHODS: One hundred and twenty-four subjects with primary angle-closure disease and 80 controls were recruited. All participants underwent ASOCT, and customized software was used to measure LV, defined as the perpendicular distance between the anterior pole of the lens and a horizontal line joining the two scleral spurs. A-scan biometry was used to measure lens thickness (LT) and to calculate lens position (LP) and relative lens position (RLP). RESULTS: Eyes with angle closure had significantly shallower anterior chamber depth (ACD), shorter axial length, greater LV and LT (p <0.001 for all), and anteriorly positioned lenses (LP, p < 0.001; RLP, p = 0.019). After multivariate analysis adjusted for age, gender, ACD, LT, and RLP, increased LV was significantly associated with angle closure (odds ratio [OR] 24.2; 95 % confidence interval [CI], 2.3-250.5, comparing lowest with highest quartile), but no association was found for LT (OR 2.59; 95 %CI, 0.48-13.85). In a sub-analysis evaluating the effect of LT on LV, LV was significantly greater in both the angle closure group with thinner lens (LT <= 4.91 mm) and angle-closure group with thicker lens (LT > 4.91 mm) compared to normal controls (p < 0.001 for both). CONCLUSIONS: In Japanese eyes, LV was independently associated with angle closure. These results corroborate the recent findings from Singapore on LV as a risk factor for angle closure. PMID- 22527317 TI - Prevalence and associations of cataract in a rural Chinese adult population: the Handan Eye Study. AB - BACKGROUND: Cataract remains the leading cause of blindness and visual impairment in the world and in China. However, data on the prevalence of cataract based on standardized lens grading protocols from mainland China are limited. This paper estimated the age- and gender-specific prevalence and risk factor for cataract METHODS: In a population-based Chinese sample, participants underwent a comprehensive ophthalmic examination, including assessment of cortical, nuclear, posterior subcapsular (PSC) and mixed lens opacities from slit-lamp grading using the Lens Opacities Classification System III. RESULTS: Of the 7,557 eligible subjects, 6,830 took part in the study (90.4% response rate), and 6,544 participants (95.8%, mean age 52.0 +/- 11.8 years) had lens data for analyses. The prevalence of any cataract surgery in at least one eye was 0.8% (95% confidence interval [CI], 0.62, 1.06), with similar rates between men and women. The overall prevalence of any cataract or cataract surgery was 20.8% (95% CI, 19.8, 21.8), higher in women than in men after adjusting for age (23.6% vs 17.6%; OR: 1.78; 95% CI: 1.54-2.07). When distinct lens opacity was categorized in each eye as cortical, nuclear, PSC or mixed, based on one randomly selected eye, cortical cataract was the most common distinct subtype (12.3%), followed by mixed (3.2%), nuclear (1.7%), and PSC (0.2%) cataract. The prevalence of all lens opacities increased with age (P < 0.001). After excluding other causes for visual impairment, the proportion of people with best corrected visual acuity <20/60 was 21% among those with PSC, and 12% among those with mixed opacities in the better seeing eye. In multivariable logistic regression models, myopia was associated with all cataract types, while higher fasting plasma glucose and diabetes were only associated with PSC cataract. CONCLUSIONS: Cataract affects 20% of the population aged 30 years and older living in rural China, with cortical cataract the most common subtype. Risk factors for cataract include myopia and diabetes. PMID- 22527318 TI - Comparison of intraocular lens power prediction using immersion ultrasound and optical biometry with and without formula optimization. AB - PURPOSE: Comparison of postoperative refraction results using ultrasound biometry with closed immersion shell and optical biometry. PATIENTS AND METHOD: Three hundred and sixty-four eyes of 306 patients (age: 70.6 +/- 12.8 years) underwent cataract surgery where intraocular lenses calculated by SRK/T formula were implanted. In 159 cases immersion ultrasonic biometry, in 205 eyes optical biometry was used. Differences between predicted and actual postoperative refractions were calculated both prior to and after optimization with the SRK/T formula, after which we analysed the similar data in the case of Holladay, Haigis, and Hoffer-Q formulas. Mean absolute error (MAE) and the percentage rate of patients within +/-0.5 and +/-1.0 D difference in the predicted error were calculated with these four formulas. RESULTS: MAE was 0.5-0.7 D in cases of both methods with SRK/T, Holladay, and Hoffer-Q formula, but higher with Haigis formula. With no optimization, 60-65 % of the patients were under 0.5 D error in the immersion group (except for Haigis formula). Using the optical method, this value was slightly higher (62-67 %), however, in this case, Haigis formula also did not perform so well (45 %). Refraction results significantly improved with Holladay, Hoffer-Q, and Haigis formulas in both groups. The rate of patients under 0.5 D error increased to 65 % by the immersion technique, and up to 80 % by the optical one. CONCLUSIONS: According to our results, optical biometry offers only slightly better outcomes compared to those of immersion shell with no optimized formulas. However, in case of new generation formulas with both methods, the optimization of IOL-constants give significantly better results. PMID- 22527319 TI - Descemet's stripping endothelial keratoplasty (DSEK) for children with congenital hereditary endothelial dystrophy: surgical challenges and 1-year outcomes. AB - PURPOSE: To evaluate the outcomes of Descemet's stripping endothelial keratoplasty (DSEK) in patients with congenital hereditary endothelial dystrophy (CHED). METHODS: Retrospective, interventional case series of five eyes of five patients with congenital hereditary endothelial dystrophy (CHED) undergoing Descemet's stripping endothelial keratoplasty (DSEK) from June 2009 to June 2010 by a single surgeon. Patients were evaluated during the postoperative period for visual acuity, refraction, corneal clarity, lenticule status, and intraocular pressure. Anterior segment ocular coherence tomography (OCT) and confocal microscopy were performed when possible. RESULTS: Three male and two female children with an average age of 7.8 years (range 5-12 years) with CHED underwent DSEK. Surgery was uneventful in all patients and the lenticules stayed attached during the postoperative period. All the patients had 1-year follow-up. Corneal clarity improved in all the patients over the period of follow-up. Anterior segment OCT showed a gradual reduction in the thickness of the central corneal thickness and the graft over a period of time. CONCLUSIONS: DSEK is a viable alternative to penetrating keratoplasty in patients with CHED with distinct advantages of reduced postoperative astigmatism and potential reduction of postoperative complications. PMID- 22527320 TI - Novel diagnosis of fungal endophthalmitis by broad-range real-time PCR detection of fungal 28S ribosomal DNA. AB - AIM: To detect the fungal genome in the ocular fluids of patients with fungal endophthalmitis by using a novel broad-range polymerase chain reaction (PCR) system. METHODS: After informed consent was obtained, ocular fluid samples (aqueous humor or vitreous fluids) were collected from 497 patients (76 patients with infectious endophthalmitis including clinically suspected bacterial and fungal endophthalmitis and 421 patients with infectious or non-infectious uveitis). Forty ocular samples from non-infectious patients without ocular inflammation were collected as controls. Fungal ribosomal DNA (28 S rDNA) was measured by a quantitative real-time PCR assay. RESULTS: Fungal 28 S rDNA of the major fungal species, such as Candida, Aspergillus, and Cryptococcus, were detected by novel broad-range real-time PCR examination (>10(1) copies/ml). Fungal 28 S rDNA was detected in the ocular fluids of 11 patients with endophthalmitis or uveitis (11/497, 2.2%). All 11 positive samples were detected in the infectious endophthalmitis patients (11/76, 14.5%). These PCR-positive ocular fluids had high copy numbers of fungal 28 S rDNA (range, 1.7 * 10(3) to 7.9 * 10(6) copies/ml), which indicated the presence of fungal infection. Of the 11 patients who were PCR positive, further examinations led to a diagnosis of fungal endophthalmitis in ten patients. The fungal 28 S rDNA was detected in one non-infectious case (a false-positive case). In addition, there were two PCR false-negative cases that were clinically suspected of having fungal endophthalmitis. CONCLUSIONS: This novel quantitative broad-range PCR of fungal 28 S rDNA is a useful tool for diagnosing endophthalmitis related to fungal infections. PMID- 22527321 TI - Corneal biomechanical properties in exfoliation syndrome and exfoliation glaucoma. PMID- 22527322 TI - Ranibizumab is not bevacizumab for retinal vein occlusions. PMID- 22527323 TI - Response to the comments of Gatzioufas Z. & Seitz B. on the article entitled: "Ocular response analyser to assess corneal biomechanical properties in exfoliation syndrome and exfoliative glaucoma". PMID- 22527324 TI - Position-dependent accommodative shift of retropupillary fixated iris-claw lenses. AB - PURPOSE: After implantation of retropupillary fixated iris-claw lenses, changes of the objective refraction can occur depending on the patients' position. The purpose of this study was to evaluate and quantify these changes as well as the influencing factors. METHODS: Within a retrospective study, postoperative refraction visual, acuity and anterior chamber depth after implantation of a retropupillary fixated iris-claw lens (Artisan(r) / Verisyse(r)) were measured in 51 eyes (49 patients) depending on their head position. These parameters were determined with the assistance of a mobile auto-refractometer, acoustic biometry, IOL-Master, chart projector and accommodometer in primary position, as well as in forward- and backward-tilted head position. RESULTS: The data analysis indicated a position-dependent change of the anterior chamber depth, which was largest in the backward-tilted head position (median: 4.25 mm/min.: 3.39 mm/max.: 5.37 mm). In comparison to the primary position (4.15 mm), it decreased in a forward-tilted position of the head (4.08 mm). A significant difference in anterior chamber depth was verified for backward- and forward-tilted heads (median: 0.155 mm). Refraction showed a significant difference (0.37 D) between forward- and backward tilted head position. In comparison to the back-tilted head position (mean: 0.065 D), a smaller spherical equivalent could be demonstrated by bending the head forward (mean: -0.438 D). In addition, no correlation was found between lens movement and other continuous attributes. CONCLUSIONS: Significant changes in anterior chamber depth and refraction due to the iris-claw lens shift were found, depending on head position. The phenomenon of pseudophakic accommodation is explained by pseudo-myopia and pseudo-hyperopia. A considerable influence on visual acuity depending on patients' head position could not be verified. PMID- 22527325 TI - Adhesion/growth-regulatory galectins in the human eye: localization profiles and tissue reactivities as a standard to detect disease-associated alterations. AB - OBJECTIVES: To characterize the localization profiles of seven adhesion/growth regulatory galectins in the normal human eye using immunodetection of endogenous galectins and binding of labeled galectins to sections, useful as a basis to detect disease-associated alterations. METHODS: Non-cross-reactive anti-galectin antibodies and biotinylated galectins were tested on acetone-fixed cryosections of normal human donor eyes. Controls included omission of first-step reagent, testing of an antibody against a galectin specific for rat (galectin-5), and blocking of galectin binding with lactose. RESULTS: Galectin presence was not restricted to one or few members of this family. Signal occurrence can even include all tested or most proteins (conjunctival or corneal epithelium), whereas choroid positivity is fully accounted for by galectin-9. Regional specificity and characteristic profiles for each protein, immuno- and galectin histochemically, were determined. Differences in tissue reactivity among the galectins were detected. CONCLUSIONS: That the galectins have characteristic localization/reactivity profiles supports the concept of a network with potential for non-overlapping functions. The reported data thus prompt to proceed to the respective analysis of specimens from ocular diseases. PMID- 22527326 TI - Long-term effect of intravitreal injection of anti-VEGF agent for visual acuity and chorioretinal atrophy progression in myopic choroidal neovascularization. AB - PURPOSE: To investigate the long-term visual prognosis and progression of chorioretinal atrophy in patients with myopic choroidal neovascularization (mCNV) treated with intravitreal injections of bevacizumab. METHODS: Hospital-based, retrospective, cross-sectional study. In total, 22 patients (22 eyes) with treatment-naive mCNV who underwent intravitreal injection of bevacizumab and were followed up for more than 48 months were investigated. Visual acuity and fundus photographs before and 1, 2, 3, and 4 years after initial treatment in the clinics were compared and judged if chorioretinal atrophy (CRA) developed/enlarged or remained unchanged. The influence of clinical characteristics including age, sex, axial length, baseline visual acuity, CNV area, CNV location, and number of injections were investigated with logistic regression analysis. RESULTS: Mean logarithm of the minimum angle of resolution (logMAR) improved from 0.76 to 0.52 (P < .01), 0.48 (P < .01), and 0.54 (P < .05) after 1, 2, and 3 years, respectively. The effect slightly declined to marginally non-significant levels after 4 years (logMAR, 0.59; P = .07). CRA developed or enlarged in nine cases (41 %) in 1 year, reaching 16 cases (73 %) at the final visit. Those without CRA enlargement achieved better visual improvement. None of the aforementioned patient characteristics significantly affected CRA. CONCLUSIONS: Anti-VEGF therapy for mCNV is effective for vision improvement in the long term. On the other hand, development or enlargement of CRA frequently occurred, and affected visual improvement. Strategies to manage atrophy should be the next step in achieving better visual outcome upon mCNV treatment. PMID- 22527327 TI - Ranibizumab for serous macular detachment in branch retinal vein occlusions. AB - BACKGROUND: The purpose of this study was to compare the efficacy of intravitreal ranibizumab in the treatment of macular edema due to branch retinal vein occlusions (BRVO) with and without serous macular neuroretinal detachment (SMD). METHODS: Forty-nine eyes of 49 patients with macular edema due to branch retinal vein occlusion (22 with SMD and 27 without SMD) were included in this prospective, parallel-group, comparative study. Intravitreal injection of ranibizumab was administered at baseline. Thereafter patients were followed monthly and further injections were performed in the presence of persistence or recurrence of macular thickening. Flattening of the macula was considered success. At the last visit, best-corrected visual acuity (BCVA), and spectral domain optical coherence tomography (SD-OCT) quantitative parameters (central subfield thickness, cube volume, average cube thickness) were compared between groups. RESULTS: In patients with SMD, BCVA and all the SD-OCT quantitative parameters improved significantly after a mean number of 5.0 ranibizumab intravitreal injections through a median follow-up of 12.5 months (range, 7-34). In patients without SMD, all the variables analyzed improved significantly except for the cube volume, after a mean number of 4.3 ranibizumab intravitreal injections through a median follow-up of 10.4 months (range, 6.5-40.2). The numbers of injections were similar in both groups. The final BCVA was better in patients without SMD at baseline but without significant differences in the SD OCT parameters between groups. CONCLUSIONS: The presence of SMD may be a baseline predictive factor for ranibizumab treatment outcomes in BRVO patients, with no influence in the number of treatments needed between patients with or without SMD at baseline. Further studies are needed in order to confirm the role of SMD as an independent predicitive factor in cases of BRVO. PMID- 22527328 TI - Correlation of complement fragment C5a with inflammatory cytokines in the vitreous of patients with proliferative diabetic retinopathy. AB - PURPOSE: To determine the vitreous concentration of complement fragment C5a in patients with proliferative diabetic retinopathy (PDR) and the relation between C5a and inflammatory cytokines including vascular endothelial growth factor (VEGF) and monocyte chemotactic protein-1 (MCP-1). METHODS: Vitreous samples were obtained at the time of vitrectomy from 12 eyes of 11 PDR patients and from 11 eyes of 11 patients without diabetes with macular disease (controls). Vitreous and serum concentrations of human C5a, VEGF, and MCP-1 were quantified using FACS Caliber flow cytometer. RESULTS: Vitreous concentration of C5a increased significantly in patients with PDR [median (range): 928.7 (46.6 to 3,319.4) pg/ml] compared with controls [58.7 (22.2 to 1,432.4) pg/ml; p < 0.01]. In PDR patients, vitreous concentration of C5a correlated significantly with those of VEGF (p < 0.05) and MCP-1 (p < 0.05). CONCLUSIONS: Our results suggest that C5a may play an important role in the pathogenesis of PDR and work in concert with inflammatory cytokines such as VEGF and MCP-1 in pathological angiogenesis. PMID- 22527329 TI - Non-arteritic anterior ischemic optic neuropathy versus cerebral ischemic stroke. PMID- 22527330 TI - Bordetella Pertussis Toxin does not induce the release of pro-inflammatory cytokines in human whole blood. AB - Pertussis Toxin (PTx) is one of the most important virulence factors of Bordetella pertussis, the cause of whooping cough. Therefore, the inactivated toxin is an obligatory constituent of acellular pertussis vaccines. It is described in the literature that both native PTx and recombinant Pertussis Toxin (PTg) activate human monocytes whereas others report an inhibition of mammalian monocytes during pertussis infection. B. pertussis, as a Gram-negative bacterium, harbours naturally lipopolysaccharide (LPS, also known as endotoxin), one of the strongest stimulators of monocytes. The latter is triggered via the interaction of endotoxin with inter alia the surface receptor CD14. Consequently, it is necessary to consider a potential contamination of Pertussis Toxin preparations with LPS. First, we determined the LPS content in different preparations of PTx and PTg. All preparations examined were contaminated with LPS; therefore, possible PTx- and PTg-driven monocyte activation independently of LPS was investigated. To meet these aims, we examined monocyte response to PTx and PTg while blocking the LPS receptor CD14 with a specific monoclonal antibody (anti CD14 mAb). In addition, all toxin preparations examined underwent an LPS depletion. Our results show that it is contaminating LPS, not Pertussis Toxin, which activates human monocytes. Blocking the CD14 receptor prevents Pertussis Toxin-mediated induction of pro-inflammatory cytokines in human monocytes. The depletion of LPS from Pertussis Toxin leads to the same effect. Additionally, the PTx toxicity after LPS depletion procedure was confirmed by animal tests. In contrast, the original Pertussis Toxin preparations not treated as mentioned above generate strong monocyte activation. The results in this publication allow the conclusion that purified Pertussis Toxin preparations do not induce the release of pro-inflammatory cytokines in human whole blood. PMID- 22527331 TI - Leadership initiatives to disseminate the institute of medicine's future of nursing report. AB - This article discusses the critical role professional nurses will play and the tremendous impact nursing education and leadership development will have on the future of health care, as outlined in the recommendations of the Institute of Medicine's report, "The future of nursing: Leading change, and advancing health." Six doctorate of nursing practice students from Case Western Reserve University analyzed the Institute of Medicine (IOM) report and developed projects to disseminate key components to selected organizations. The students developed two primary initiatives. One initiative involved presenting the report to various professional organizations, including a local chapter of an international honor society, a specialty organization, and a health care organization. The second initiative included interviewing several nurse leaders within a large multihospital health system, and a nursing leader in academia to determine (a) the level of awareness about the IOM report and (b) strategies these leaders have implemented or envisioned to address the report recommendations. PMID- 22527332 TI - Joint commission accreditation and quality measures in U.S. nursing homes. AB - This study examines the association between accreditation and select measures of quality in U.S. nursing homes, both cross-sectionally and over time. Data analyzed in this research originated from a web-based search of The Joint Commission (TJC) accredited facilities and the Nursing Home Compare set of Quality Measures relating to physical restraint use, pain management, urinary catheter use, and pressure sores. Five-Star Nursing Home Quality Rating System information was also used to calculate overall quality measure and health inspection scores. Data were analyzed using negative binomial regression. Comparing quality in the year before accreditation with the 1st year after accreditation, all five Quality Measures and both Five-Star categories demonstrated improvement. In comparing quality after 8 years of accreditation, three of the Quality Measures examined continued to improve. There were no cases where accreditation was associated with decreased quality. These results indicate that TJC accredited nursing homes improve their quality immediately after accreditation but do not continue to improve in all areas over time. PMID- 22527333 TI - The fate of acutely inflamed joints with a negative synovial fluid culture. AB - PURPOSE: The purpose of this study was to evaluate the management and fate of acutely inflamed joints with a negative synovial fluid culture. METHODS: Between January and December 2009, all the patients who presented to our institution with an acutely inflamed joint and were subjected to microbiological assessment of their synovial fluid, were included in the study. Patients with a positive synovial fluid culture, a prosthetic joint replacement in situ and where an aspirate was obtained for a rheumatological diagnosis were excluded. This cohort was then divided into two groups depending on whether a diagnosis could be established through the course of their treatment. Group I included patients in whom a diagnosis could be established and group II included patients in whom a diagnosis could not be established. A thorough review of the patients' medical records and the hospital database was performed. Following this, a database consisting of the patient demographics, clinical features, investigations, treatment and outcome was created. RESULTS: A total of 144 patients met the inclusion criteria (group I: 95, group II: 49). The most commonly affected joint in both the groups was the knee. The average time to presentation was shorter in group II. Clinical findings at presentation were comparable in both groups. However, inflammatory markers were more likely to be raised in group II in comparison with group I. Eighty-two percent of group II required antibiotic treatment compared with 15% of group I. The mean duration of antibiotic treatment in group I was ten days and in group II was 26 days. Mean hospital stay differed significantly between the two groups, with group II being more than twice as long as compared with group I (p=0.001). The rate of mortality was also higher in group II (8.2%, p=0.03). CONCLUSION: Our study shows that patients presenting with an acutely inflamed joint and a negative synovial fluid culture in whom a diagnosis cannot be established during their hospital stay have a longer hospital stay and an increased rate of mortality as compared with patients in whom a diagnosis can be established. PMID- 22527334 TI - Quantitative CT with finite element analysis: towards a predictive tool for bone remodelling around an uncemented tapered stem. AB - PURPOSE: We used quantitative CT in conjunction with finite element analysis to provide a new tool for assessment of bone quality after total hip arthroplasty in vivo. The hypothesis of this prospective five-year study is that the combination of the two modalities allows 3D patient-specific imaging of cortical and cancellous bone changes and stress shielding. METHOD: We tested quantitative CT in conjunction with finite elements on a cohort of 29 patients (31 hips) who have been scanned postoperatively and at one year, two years and five years follow-up. The method uses cubic Hermite finite element interpolation for efficient mesh generation directly from qCT datasets. The element Gauss points that are used for the geometric interpolation functions are also used for interpolation of osteodensitometry data. RESULTS: The study showed changes of bone density suggestive of proximal femur diaphysis load transfer with osteointegration and moderate metaphyseal stress shielding. Our model revealed that cortical bone initially became porous in the greater trochanter, but this phenomenon progressed to the cortex of the lesser trochanter and the posterior aspect of the metaphysis. The diaphyseal area did not experience major change in bone density for either cortical or cancellous bone. CONCLUSION: The combination of quantitative CT with finite element analysis allows visualization of changes to bone density and architecture. It also provides correlation of bone density/architectural changes with stress patterns enabling the study of the effects of stress shielding on bone remodelling in vivo. This technology can be useful in predicting bone remodeling and the quality of implant fixation using prostheses with different design and/or biomaterials. PMID- 22527335 TI - The direct anterior approach in hemiarthroplasty for displaced femoral neck fractures. AB - PURPOSE: Hip replacement is the most common treatment for displaced femoral neck fractures in the elderly, and minimally invasive surgery is popular in the field of orthopaedic surgery. This study evaluated the outcome of monopolar hemiarthroplasty by the direct anterior approach over a postoperative period up to 2.5 years. METHODS: A total of 86 patients with displaced femoral neck fractures were included (mean age of 86.5 years). Surviving patients were reviewed three months (retrospectively) and one to 2.5 years (prospectively) after surgery. One-year mortality was 36 %. RESULTS: For all stems, implant positioning with respect to stem alignment, restoration of leg length and femoral offset was correct. Acetabular protrusion was observed in 55 % of the patients one to 2.5 years postoperatively. Subsidence and intraoperative periprosthetic fractures occurred in three patients (3 %) each. All revision stems for postoperative periprosthetic fractures could be implanted using the initial surgical technique without extension of the previous approach. The mean Harris hip score was 85 points at the one to 2.5-year follow-up; 85 % of the patients were satisfied with their hip and 57 % returned to their preoperative level of mobility. CONCLUSION: Based on these findings, hemiarthroplasty for hip fractures can be performed safely and effectively via the direct anterior approach with good functional outcome and high patient satisfaction. PMID- 22527336 TI - Clinical management and surgical treatment of distal fibular tumours: a case series and review of the literature. AB - PURPOSE: Study reports clinical and functional outcomes of surgical treatment in a case series of nine patients with distal fibular tumours. METHODS: Nine patients with distal fibular tumours were observed between 2005 and 2010. A PubMed search was performed using the terms "fibula", "lower limb tumour [cancer]", "sarcoma", "Ewing", "peroneal", "fibular metastasis", and "limb salvage surgery". RESULTS: In all our patients, lesions were unilateral. All patients complained of pain; limping was present in 5 of 9 tumours. Patients were managed surgically, except one who underwent local radiotherapy. In six patients, a benign or tumor-like lesion was detected. Malignancies consisted of metastatic lung adenocarcinoma (two cases) or multifocal mesenchymal cancer (one case). Non malignant lesions were treated by curettage and filling, followed by internal fixation when needed. In malignant or locally aggressive lesions, metadiaphyseal fibular resection was performed. The literature search retrieved either case reports or small case series, reflecting the rarity of distal fibular tumours. Surgical treatment was successful in all patients with benign lesions, whereas the rate of success was 40-100 % in case of malignancies. CONCLUSIONS: Given the low incidence of distal fibular tumours, controversies exist about the optimal surgical management. Clinical observation and imaging should be reserved to asymptomatic benign lesions. In non-malignant tumours causing pain, limping, and pathological fractures; in malignancies, surgery is recommended. Finally, in patients with asymptomatic lesions of uncertain nature, biopsy and histological examination should be performed to plan appropriate management. PMID- 22527337 TI - Secondary cement injection technique reduces pulmonary embolism in total hip arthroplasty. AB - PURPOSE: Cardio-pulmonary damage due to embolism is a feared complication of cemented hip arthroplasty and can be fatal. Embolic events result from an increased intramedullary pressure during cement and stem insertion and can lead to extrusion of bone-marrow elements into the circulation. To reduce embolism and at the same time achieve an ideal cement mantle, the cement injection stem has been designed. In contrast to conventional stems where cement applied before stem insertion (primary cementing technique), the cement injection stem is positioned first and only then is the cement injected via the stem in a volume- and pressure controlled fashion (secondary cementing technique). METHODS: A randomised trial with 30 patients was performed to evaluate whether this technique is able to reduce embolic events. Patients either received a conventional cemented stem (primary cementing technique) or a cement injection stem (secondary cementing technique). Embolic events were recorded by transesophageal echocardiography at six specific points during the operation and classified from grade 0 to grade 3. RESULTS: Significantly fewer grade 2 and 3 embolic events were observed in patients receiving the cement injection stem using the secondary cementing technique. Moreover, in the conventional group all patients (100 %) had at least one grade 3 embolus whereas only 20 % with the secondary cementing technique had an embolic event of grade 3. CONCLUSION: Secondary cement insertion via the cement injection stem is able to reduce severe embolic events significantly. The technique offers a more gentle cementing technique and therefore appears especially beneficial for patients of advanced age and/or with pre-existing cardio-pulmonary comorbidities. PMID- 22527338 TI - Factors associated with prolonged length of stay following a total knee replacement in patients aged over 75. AB - PURPOSE: The aim of this study was to examine factors associated with a prolonged length of stay (LOS) in patients over 75 undergoing a total knee replacement (TKR). METHODS: Patients over 75 undergoing a TKR at our institution from January 2008 to February 2009 were identified (n = 112). Patient and operative factors previously shown to affect length of stay were identified. Patient notes were reviewed for details on each of these and data analysed for their effect on length of stay. Discrete data were analysed for their effect on post-operative length of stay using either the Mann-Whitney U test or the Kruskall-Wallis test and continuous data analysed with the Spearman's rank correlation coefficient. RESULTS: The following factors were associated with length of stay at the 95 % confidence level: patient age, pre-operative mobility and the use of walking aids, BMI, whether the patient was able to mobilise within 24 or 48 hours of the surgery, the day on which the patient first walked ten metres and achieved 90 degrees active knee flexion, pre and post-operative haemoglobin and the need for a blood transfusion. CONCLUSIONS: Pre-operative use of walking aids, peri operative haemoglobin concentration, failure to mobilise early following the operation and post-operative complications (including the need for a blood transfusion) seem to be the significant factors associated with a prolonged stay in hospital in the over 75 year olds. PMID- 22527339 TI - Applying the interactive systems framework to the dissemination and adoption of national and state recommendations for hypertension. AB - The Centers for Disease Control and Prevention (CDC), Division for Heart Disease and Stroke Prevention (DHDSP), commissioned an Institute of Medicine (IOM) report to identify the highest priority action areas for CDC, state health departments, and other public health partners in their efforts to reduce and control hypertension. To assess the dissemination and adoption of the IOM report recommendations, DHDSP developed an evaluation based on the Interactive Systems Framework for Dissemination and Implementation (ISF). The evaluation incorporates data collection at critical points across 3 years. In this article, we focus on the ISF systems to describe the role of funded state partners and their relationship with CDC in implementing public health recommendations. We describe baseline results for three data collection activities: (1) key informant interviews, (2) a Web-based survey, and (3) content analysis of state workplans to determine the degree of alignment with IOM recommendations. For example, currently 30 % of surveyed programs are implementing most (or all) of the recommendations in the IOM report, however 76 % intend to change hypertension program priorities based on the recommendations of the IOM report. Qualitative data suggest that there are several facilitators and barriers in implementing public health policy recommendations. DHDSP will use these baseline results to provide additional technical assistance and support to state health departments in their efforts to implement the IOM report's recommendations. PMID- 22527340 TI - Moving forward with systems of care: needs and new directions. AB - The articles in this Special Issue on system change within systems of care (SOCs) provide guidance regarding strategies for modifying SOCs to address the needs of different populations, and ways for changing systems to support more positive child and family outcomes. This paper frames central needs, unanswered questions, and issues that remain for those working to implement SOCs. Specific needs and new directions considered include: (1) rigorous implementation-focused research to identify the necessary and sufficient elements of SOCs and the primary practice approach currently used in SOCs, wraparound; (2) applied research to assess SOCs and document their effectiveness in non-standard or non-traditional settings (i.e., non-mental health settings, including child welfare, juvenile justice, local housing authorities); (3) controlled outcome studies for school based wraparound initiatives; (4) research to document the effectiveness of the family support efforts that are part of most SOCs; and (5) attention to context, for families, service providers, and collaborative implementation efforts, by researchers and providers alike. Progress in these areas can inform well-targeted system change efforts in the context of SOCs, a critical need given changes in federal funding for these initiatives. PMID- 22527341 TI - Bleeding adverse drug reactions (ADRs) in patients exposed to antiplatelet plus serotonin reuptake inhibitor drugs: analysis of the French Spontaneous Reporting Database for a controversial ADR. AB - AIM: The aim of the present study was to investigate bleeding adverse drug reactions (ADRs) in patients exposed to serotonin reuptake inhibitors (SRI) plus antiplatelet agents using the French Pharmacovigilance Database (FPVDB) regarding the controversial data in the literature. METHODS: The case/non-case method was used to measure the association between bleedings and exposure to SRIs plus antiplatelet agents versus antiplatelet drugs alone. RESULTS: Over 3 years, a total of 1,977 spontaneous reports of ADRs were collected with antiplatelet drugs, and antiplatelet agents plus SRIs in patients aged over 50 years, of which 1,331 (67.3 %) concerned bleeding. Multivariate logistic regression analysis failed to show any significant association [adjusted ROR = 0.8 (0.5-1.2)]. CONCLUSION: The data did not demonstrate any significant association between bleeding ADRs and exposure to SRI + antiplatelet agents versus antiplatelets alone. Considering other conflicting results, this risk should be kept in mind by physicians when treating patients with several risk factors. PMID- 22527342 TI - Pharmacokinetics of the novel PAR-1 antagonist vorapaxar in patients with hepatic impairment. AB - PURPOSE: To determine whether hepatic impairment has an effect on the pharmacokinetics (PK) of vorapaxar or M20, its main pharmacologically active metabolite. METHODS: This was an open-label study in which a single 40-mg oral dose of vorapaxar was administered to patients with mild (n = 6), moderate (n = 6), and severe (n = 4) hepatic impairment and healthy controls (n = 16) matched for age, gender, weight, and height. Blood samples for vorapaxar and M20 assay were collected predose and at frequent intervals up to 8 weeks postdose. RESULTS: Plasma vorapaxar and M20 PK profiles were similar between patients with impaired liver function and healthy controls. Group mean values for vorapaxar C(max) and AUC(tf) were 206-279 ng/mL and 14,200-18,200 ng.h/mL, respectively, with the lowest values observed in patients with severe impairment. Vorapaxar median T(max) and mean t(1/2) values were 1.00-1.75 h and 298-366 h, respectively. There was no apparent correlation between vorapaxar or M20 exposure or t(1/2) values and disease severity. Vorapaxar was generally well tolerated; one serious adverse event (gastrointestinal bleeding secondary to ruptured esophageal varices) was reported in a patient with severe hepatic impairment. CONCLUSIONS: Hepatic impairment had no clinically relevant effect on the PK of vorapaxar and M20. No dose or dosage adjustment of vorapaxar will be required in patients with mild to moderate hepatic impairment. Although systemic exposure to vorapaxar does not appear to increase in patients with severe hepatic impairment, administration of vorapaxar to such patients is not recommended given their bleeding diathesis. PMID- 22527343 TI - Exposure to medicines among patients admitted for hip fracture and the case fatality rate at 1 year: a longitudinal study. AB - PURPOSE: To describe the demographic and clinical characteristics and the pre fracture exposure to medicines of patients admitted for a hip fracture, and to explore their association with fatal outcome 1 year after the fracture. METHODS: All patients >= 65 years old admitted for a hip fracture in a tertiary hospital in Barcelona between January 1 and December 31 2007 were included. Data on the patients' clinical characteristics before and during hospital admission and on pre-fracture exposures to medicines were collected from the clinical records. One year mortality was checked by approaching the patients and their families and was cross-checked with the national mortality statistics database. A Cox proportional hazards analysis was carried out. RESULTS: Four hundred and fifty-six patients [mean age (SD) 82.9 (7.2) years, 73.5 % female], were admitted with hip fracture during the study period. Almost 80 % of the patients (363, 79.6 %) had three or more associated conditions, and 41.7 % received pre-fracture treatment with five or more drugs. The case-fatality rate during hospital admission was 4.6 % (21 patients). One hundred and seven patients died within 1 year (23.5 %). Advanced age, male gender, two or more associated chronic conditions, cancer, severe cognitive impairment, and treatment with opiates before fracture were significantly associated with the risk of dying. An inverse association was recorded between mortality and pre-hospital exposure to medicines for osteoporosis. CONCLUSIONS: One-quarter of patients admitted for hip fracture died within 1 year after the fracture. Exposure to opiates before hip fracture was associated with an increased 1-year death rate, whereas treatment with drugs for osteoporosis was associated with a decrease in death rate. These results should be confirmed in studies with detailed prospective collection of information on exposure to medicines. PMID- 22527344 TI - Population pharmacokinetics and Bayesian estimation of cyclosporine in a Tunisian population of hematopoietic stem cell transplant recipient. AB - PURPOSE: Therapeutic drug monitoring of cyclosporine minimizes the risk of toxicity and acute rejection after transplantation. Areas under the curve (AUCs) rather than trough concentration-based monitoring are recommended. Population pharmacokinetics (PopPK) modeling and Bayesian estimation seem to be the best way to predict cyclosporine disposition and dose requirements to achieve the therapeutic target in an individual patient because of the possibility of predicting cyclosporine AUC using only a few blood samples. Our objectives were to build a PopPk model for cyclosporine in a Tunisian population of HSCT patients and to develop a Bayesian method for the estimation of individual cyclosporine AUC. PATIENTS AND METHODS: The PopPk of cyclosporine was studied using nonlinear mixed effects modeling (NONMEM) in 30 patients (index group) receiving cyclosporine on a twice-daily basis. Ten blood samples were collected after steady-state morning cyclosporine dose. Bayesian estimation of individual AUC was made on the basis of three blood concentration measurements in an independent group of 30 patients (test group). RESULTS: A two-compartment model with first order absorption and a lag time provided the best fitting. The population mean estimate and interindividual variability from the final model for CL, Ka, Tlag, V1, V2, and Q were 25.4 L/h (CV = 38.72 %), 0.214 h(-1)(CV = 28.5 %), 0.382 h, 10.9 L (85.73 %), 496 L, and 5 L/h, respectively. Covariates had no discernible effects on cyclosporine pharmacokinetics in our population. Bayesian estimation provided an accurate estimation of AUC, although a bias was observed leading to slight underprediction of AUC (bias -1.03 %). A very satisfactory precision was observed (RMSE 12.07 %). CONCLUSION: We report a PopPK model for cyclosporine in Tunisian HSCT patients. Bayesian estimation using only three concentrations provides good prediction of cyclosporine exposure. These tools allow us to routinely estimate cyclosporine AUC in a clinical setting. PMID- 22527345 TI - CYP2C19 genetics in fatal carisoprodol intoxications. AB - INTRODUCTION: Carisoprodol, a frequently used muscle relaxant, can cause potentially fatal intoxications. Conversion to its active metabolite meprobamate is almost solely mediated by cytochrome P450 2C19 (CYP2C19), and mutations in this enzyme could have significant effects on serum concentrations. The objective of this study was to investigate the role of CYP2C19 genetics in mortalities due to carisoprodol intoxication. METHODS: The frequencies of CYP2C19 variant alleles were compared between the study group (n = 75) and two control groups, i.e. (1) deaths where carisoprodol was detected in the blood of the deceased, but intoxication was not the cause of death (control group A, n = 38), and (2) a healthy population not using carisoprodol (control group B, n = 185). In the study group and control A, the concentrations of carisoprodol and meprobamate were compared between the different genotype subgroups. RESULTS: The variant allele frequencies of CYP2C19 did not differ significantly between the study group and control groups. Moreover, no statistically significant difference in the concentrations of carisoprodol and meprobamate between the different genotype subgroups was found. CONCLUSIONS: This study finds no evidence for an important association between CYP2C19 genetics and mortality risk of carisoprodol. Other factors, such as co-administration with other drugs, likely play a more important role. PMID- 22527347 TI - Bile acid is important for gastrointestinal absorption of nilotinib. PMID- 22527346 TI - Association of UDP-glucuronosyltransferase 1A9 polymorphisms with adverse reactions to catechol-O-methyltransferase inhibitors in Parkinson's disease patients. AB - PURPOSE: To investigate the association between adverse reactions to catechol-O methyltransferase (COMT) inhibitors and the UDP-glucuronosyltransferase 1A9 genotypes UGT1A9*1b and UGT1A9*3a, which were previously identified in individual cases of COMT inhibitor-induced toxicity. METHODS: The study included 52 Parkinson's disease (PD) patients on COMT inhibitors without evidence of adverse reactions and 11 PD patients who had been withdrawn from COMT inhibitors due to adverse reactions. UGT1A9*1b was identified by direct sequencing of the PCR amplification of the gene and UGT1A9*3a was assayed by real-time PCR. RESULTS: The frequency of the *3a/*3a and *1/*3a genotype variants was 45.5 % in subjects with adverse reactions and 21.1 % in subjects without adverse reactions [overall UGT1A9*3a allele frequency 27.3 vs. 11.5 %, P = 0.087; odds ratio (OR) 2.87, 95 % confidence interval (CI) 0.94-8.77]. The frequency of genotype combinations leading to low glucuronosyltransferase activity (*3a/*3a irrespective of *1b or *1/*3a and *1/*1b) was 5.8 % in subjects without adverse reactions and 36.4 % in subjects with adverse reactions (P = 0.014; OR 9.33, 95 % CI 1.71-50.78). CONCLUSIONS: In PD patients UDP-glucuronosyltransferase 1A9 genotypes are associated with adverse reactions to COMT inhibitors, leading to treatment withdrawal. UDP-glucuronosyltransferase 1A9 genotyping may be a screening and/or diagnostic test to assist individualized treatments with COMT inhibitors. PMID- 22527348 TI - Non-steroidal anti-inflammatory drugs (NSAIDs) and hypertension treatment intensification: a population-based cohort study. AB - PURPOSE: Non-steroidal anti-inflammatory drugs (NSAIDs) are known to antagonize the effects of antihypertensive drugs, and these associations can lead to an increase in arterial blood pressure. However, the impact of NSAIDs on hypertension treatment management in large-scale populations remains poorly evaluated. We examined whether the introduction of NSAID into the treatment regimen would induce an intensification of hypertension treatment (defined as the introduction of a new antihypertensive drug). METHODS: We conducted a cohort study involving 5,710 hypertensive subjects included in the French health insurance system database who had been treated and stabilized with their antihypertensive therapy and not exposed to any NSAID between 1 April 2005 and 1 April 2006. The maximum follow-up duration was 4 years. RESULTS: Adjusted hazard ratios (HR) for hypertension treatment intensification were 1.34 [95 % confidence interval (CI) 1.05-1.71] for NSAIDs in general, 1.79 (95 % CI 1.15-2.78) for diclofenac and 2.02 (95 % CI:1.09-3.77) for piroxicam. There were significant interactions between NSAIDs and angiotensin converting enzyme inhibitors (ACEIs; HR 4.09, 95 % CI 2.02-8.27) or angiotensin receptor blockers (ARBs; HR 3.62, 95 % CI 1.80-7.31), but not with other antihypertensive drugs. CONCLUSIONS: Exposure to NSAIDs leads to an intensification of hypertension treatment, especially in patients treated with ACEIs or ARBs. Renin-angiotensin system blockers should be avoided whenever NSAIDs are prescribed. PMID- 22527349 TI - Paracetamol toxicity: What would be the implications of a change in UK treatment guidelines? AB - BACKGROUND: Treatment of single-time-point ingestion acute paracetamol (acetaminophen) poisoning with N-acetylcysteine (NAC) is guided by plotting a timed plasma paracetamol concentration on established nomograms. Guidelines in the UK differ from those in the U.S. and Australasia by having two treatment lines on the nomogram. Patients deemed to be at 'normal' risk of hepatotoxicity are treated using the treatment line starting at 200 mg/L at 4 h post-ingestion; those at higher risk are treated using the 'high risk' treatment line starting at 100 mg/L at 4 h post-ingestion. AIM: To examine the effect on treatment numbers if UK guidelines were to adopt a single treatment line nomogram or lower, risk stratified treatment lines. METHODS: We undertook a retrospective analysis of a series of acute single-time-point paracetamol poisonings presenting to our inner city emergency department. Treatment numbers and effect on treatment costs were modelled for three alternative scenarios: a 150 line-a combined single treatment line starting at a 4 h concentration of 150 mg/L, a 100 line-a combined single treatment line starting at a 4 h concentration of 100 mg/L, and a 150/75 line-a double treatment line at the lower concentrations of 150 mg/L for normal risk and 75 mg/L for high risk patients. RESULTS: A total of 1,214 cases were identified. Under current UK guidance, 133 (11.0%) high risk cases and 98 (8.1%) normal risk cases needed treatment (total 231, 19.0%). A 150 line would result in 87 (7.2%) high risk cases and 155 (12.8%) normal risk cases needing treatment (total 242, 19.9%). A 100 line would result in 133 (11.0%) high risk and 251 (20.7%) normal risk cases needing treatment (total 384, 31.6%). A 150/75 line would result in 153 (12.6%) high risk and 155 (12.8%) normal risk cases needing treatment (total 308, 25.4%). CONCLUSIONS: Both a 100 line and a 150/75 line would result in a large increase in the number of patients being treated and an associated increase in the costs of treatment. A single 150 mg/L treatment line would simplify treatment algorithms and lead to a similar number of patients being treated with NAC overall. A potential concern however is whether any of the high risk cases that would no longer be treated might develop significant hepatotoxicity. After consideration of the evidence for dual treatment lines, we feel that these risks are small and that it is worth reconsidering a change of treatment recommendations to a single 150 line. PMID- 22527350 TI - Relative bioavailability and pharmacodynamic effects of methantheline compared with atropine in healthy subjects. AB - OBJECTIVES: Methantheline is a strong muscarinic receptor blocking drug used in the treatment of overactive bladder syndrome, hypersalivation and hyperhidrosis. To provide basic information on the pharmacokinetics, magnitude of pharmacodynamic (PD) effects and their correlations with plasma concentrations, we performed a clinical study in 12 healthy subjects receiving methantheline as immediate-release coated tablets (IR) or in watery solution (SOL) in comparison with atropine and placebo tablets. METHODS: The pharmacokinetics and influence of methantheline, atropine and placebo on salivation and accommodation and pupil function (pupillometry: diameter, response to light flash) were studied in a randomized, controlled study after the administration of 100 mg methantheline bromide as IR and in SOL (phase 1) and 1.0 mg atropine sulphate and placebo (phase 2). RESULTS: Methantheline reached maximum plasma concentrations of approximately 25 ng/ml after 2.5-3 h and was eliminated at an apparent half-life of approximately 2 h. There was no pharmacokinetic (PK) bioequivalence of methantheline IR and SOL. The ratio IR/SOL (90 % confidence interval) were 0.892 (0.532-1.493) for AUC(0-infinity) and 0.905 (0.516-1.584) for maximum plasma concentration. The PD effects of both forms were nearly equivalent with a IR/SOL ratio of 1.015 (0.815-1.262) for salivation, which is the most susceptible characteristic. Methantheline reduced salivation at a potency (methantheline concentration at half maximum effects, EC50) of 5.5 ng/ml in accordance with it plasma concentration. The antimuscarinic effects observed after methantheline administration were stronger and persisted longer than those following the administration of atropine. CONCLUSIONS: Methantheline is slowly absorbed but rapidly eliminated in humans, and it exerts a strong effect on salivation which is closely associated with its plasma concentrations following a standard sigmoid PD model. Immediate-release tablets and a watery solution of methantheline are equivalent in terms of major PD effects (salivation, pupil function, heart rate) despite its high PK variability. PMID- 22527351 TI - The effect of lersivirine, a next-generation NNRTI, on the pharmacokinetics of midazolam and oral contraceptives in healthy subjects. AB - PURPOSE: Lersivirine is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with a unique resistance profile that exhibits potent antiretroviral activity against wild-type human immunodeficiency virus and clinically relevant NNRTI-resistant strains. Results from in vitro and in vivo investigations suggest that lersivirine is a cytochrome P450 (CYP3A4) inducer that is metabolized by CYP3A4 and uridine diphosphate glucuronosyltransferase (UGT) 2B7. In order to formally assess the effects of lersivirine on CYP3A4 metabolism and/or glucuronidation, we performed studies aimed at investigating the effects of lersivirine co-administration on the pharmacokinetics (PK) of midazolam, ethinylestradiol and levonorgestrel. METHODS: Two drug-drug interaction studies were performed. Healthy subjects were co-administered (1) single dose midazolam, a prototypical CYP3A4 substrate, followed by 14 days of lersivirine twice daily with single dose midazolam on the final day of lersivirine dosing or (2) 10 days of once-daily (QD) lersivirine and QD oral contraceptives (OCs; ethinylestradiol and levonorgestrel), substrates for CYP3A4, UGT2B7, and/or P-glycoprotein. The effects of co-administration on the PK parameters of midazolam and OCs were assessed. RESULTS: At clinically relevant lersivirine doses (500-1,000 mg total daily dose), the mean plasma exposure of midazolam was reduced in a dose-dependent manner by 20-36 %. Co-administration of lersivirine 1,000 mg QD with OCs had minor PK effects, increasing ethinylestradiol exposure by 10 % and reducing levonorgestrel exposure by 13 %. CONCLUSIONS: These data further support previous observations that lersivirine is a weak CYP3A4 inducer, a weak inhibitor of glucuronidation, and a P-glycoprotein inhibitor. In both studies, lersivirine appeared to have a good safety and tolerability profile. PMID- 22527352 TI - Evaluation of antinociceptive and anti-inflammatory activity of hydromethanol extract of Cocos nucifera L. AB - Cocos nucifera L. (family: arecaceae) is generally straight unbranched plant, traditionally cultivated for its fruit (coconut) in home gardens. In the present study, anti-inflammatory and antinociceptive (analgesic) activity of hydromethanol extract of Cocos nucifera L. (HECN) was evaluated in animal models. HECN showed significant (p < 0.05) and dosedependent anti-inflammatory activity in carrageenan induced paw oedema models of inflammation and the result was comparable with the standard drug diclofenac. In addition, the extract also showed highly significant (p < 0.01) antinociceptive activity. HECN treated group showed increase in the reaction time in hot plate method and decrease the writhing induced by acetic acid in mice when compared with control group animal. The anti-inflammatory and antinociceptive activity observed in the present study could be attributed largely to the presence of its antioxidant phytoconstituents such as flavonoid, saponin and polyphenols. PMID- 22527353 TI - The kinin system in hypertensive pathophysiology. AB - Cardiovascular diseases are the prime cause of death in the world. The kallikrein kinin system has been implicated in the pathophysiology of the vascular smooth muscle and cardiac dysfunctions. In recent years, numerous observations obtained from clinical and experimental models of diabetes, hypertension, cardiac failure, ischemia, myocardial infarction and left ventricular hypertrophy, have suggested that the reduced activity of the local kallikrein-kinin system may be instrumental for the induction of cardiovascular-related diseases. The cardioprotective actions of the angiotensin-converting enzyme inhibitors are primarily dependent on protecting the kinin-forming components, which may cause regression of the left ventricular hypertrophy in hypertensive situations. The ability of kallikrein gene delivery to produce a wide spectrum of beneficial effects makes it an excellent candidate in treating hypertension, cardiovascular and renal diseases. In addition, stable kinin agonists may also be available in the future as therapeutic agents for cardiovascular and renal disorders. PMID- 22527355 TI - Optimizing the European regulatory framework for sustainable bacteriophage therapy in human medicine. AB - For practitioners at hospitals seeking to use natural (not genetically modified, as appearing in nature) bacteriophages for treatment of antibiotic-resistant bacterial infections (bacteriophage therapy), Europe's current regulatory framework for medicinal products hinders more than it facilitates. Although many experts consider bacteriophage therapy to be a promising complementary (or alternative) treatment to antibiotic therapy, no bacteriophage-specific framework for documentation exists to date. Decades worth of historical clinical data on bacteriophage therapy (from Eastern Europe, particularly Poland, and the former Soviet republics, particularly Georgia and Russia, as well as from today's 27 EU member states and the US) have not been taken into account by European regulators because these data have not been validated under current Western regulatory standards. Consequently, applicants carrying out standard clinical trials on bacteriophages in Europe are obliged to initiate clinical work from scratch. This paper argues for a reduced documentation threshold for Phase 1 clinical trials of bacteriophages and maintains that bacteriophages should not be categorized as classical medicinal products for at least two reasons: (1) such a categorization is scientifically inappropriate for this specific therapy and (2) such a categorization limits the marketing authorization process to industry, the only stakeholder with sufficient financial resources to prepare a complete dossier for the competent authorities. This paper reflects on the current regulatory framework for medicines in Europe and assesses possible regulatory pathways for the (re-)introduction of bacteriophage therapy in a way that maintains its effectiveness and safety as well as its inherent characteristics of sustainability and in situ self-amplification and limitation. PMID- 22527354 TI - Matched sibling versus matched unrelated allogeneic hematopoietic stem cell transplantation in children with severe acquired aplastic anemia: experience of the polish pediatric group for hematopoietic stem cell transplantation. AB - In the study, 48 children with severe acquired aplastic anemia (SAA) transplanted from matched sibling donor (MSD) between 1991 and 2009, and 38 children with SAA transplanted from matched unrelated donor (MUD) between 2000 and 2009 were evaluated. Engraftment was achieved in 45 (93.75 %) patients after MSD hematopoietic stem cell transplantation (HSCT) and in 33 (86.8 %) after MUD-HSCT. Transplant-related mortality rate after MSD-HSCT was 8 %, while 37 % after MUD HSCT. After MSD-HSCT 44 (91.7 %) patients are alive for 1-216 months (median: 85 months), while after MUD-HSCT 24 (63.2 %) patients for 1-84 months (median: 16 months). The 5-year probability of event-free survival after MSD-HSCT and MUD HSCT was 87 and 53 %, respectively, while 5 years of overall survival was 91 and 64 %, respectively. It was concluded that MSD-HSCT as the first line treatment for children with SAA is a safe therapeutic approach with a low rate of treatment failures and excellent outcome. Results of MUD-HSCT in pediatric patients with SAA who failed to respond to immunosuppressive therapy are still inferior than those of MSD-HSCT. Treatment failures of MUD-HSCT are mainly related to infectious complications and graft failure. It seems, however, that HLA-matching of unrelated donors at allelic level along with early MUD-HSCT after FCA (FLUDA, low-dose cyclophosphamide, and anti-thymocyte globulin) conditioning, perhaps using lower Thymoglobulin dose could enable further improvement of long-term results in children with SAA who lack MSD. PMID- 22527356 TI - Retained products of conception through a perforated uterine wall following elective abortion: a unique case report. PMID- 22527357 TI - Bone in the belly: traumatic heterotopic mesenteric ossification. AB - Heterotopic mesenteric ossification is an unusual but important complication in patients who sustain blunt and penetrating abdominal trauma. In this condition, bone formation occurs in the mesenteric and omental fat in response to injury and may result in serious complications such as bowel obstruction and fistula formation. Although a few case reports exist, the radiology literature on this topic is scant. Based on our experience, this entity is under-recognized on imaging studies and often results in diagnostic confusion due to its resemblance to other pathologies such as barium leak and extraskeletal bone-forming neoplasms. This review highlights the imaging features of heterotopic mesenteric ossification with an emphasis on computed tomographic findings. Radiologist awareness of this condition is crucial to avoid misdiagnosis as well as to direct appropriate and timely management. PMID- 22527358 TI - Transient cytotoxic edema caused by hypoglycemia: follow-up diffusion-weighted imaging features. PMID- 22527359 TI - Aortic dissection in osteogenesis imperfecta: case report and review of the literature. PMID- 22527360 TI - Dural metastases from prostate cancer mimicking acute sub-dural hematoma. AB - Metastases of prostate carcinoma to the central nervous system are rare, while dural metastases are even rarer. Patients are often clinically asymptomatic or present with non-specific symptoms, rendering the condition unsuspected. The imaging findings could resemble benign conditions and be misdiagnosed as such when the diagnosis is not considered. We present an unusual case of dural metastasis from carcinoma of the prostate mimicking acute sub-dural hematoma as shown on non-contrast-enhanced CT. The radiological features are analyzed, and clues to differentiating the two conditions are discussed. PMID- 22527361 TI - Effects of patient size on radiation dose reduction and image quality in low-kVp CT pulmonary angiography performed with reduced IV contrast dose. AB - The purpose of the study is to evaluate image quality and radiation exposure as a function of patient size for CT pulmonary angiography (CTPA) performed at reduced tube voltage and reduced intravenous (IV) contrast dose. We reviewed consecutive CTPAs performed between 9/1/2010 and 10/31/2010 on a 128-slice Siemens AS+ scanner using automated tube current modulation with quality reference mAs 200 and IV contrast concentration 370 mg I/ml followed by a saline flush: 99 scans at 120 kVp using 75 ml of contrast at 5 ml/s and 53 scans on patients lighter than 175 lbs at 100 kVp using 50 ml of contrast at 4 ml/s. We measured patient size (mean water-equivalent diameter) using a topogram analysis tool, signal (mean CT density) and noise (standard deviation) in the main pulmonary artery (MPA) on axial images, and calculated local CTDI(vol) from the kVp and mAs. Linear regression models were created for dependent variables ln(CTDI(vol)), signal, noise, and signal to noise ratio (SNR) as a function of independent variables size, age, gender, and kVp. After controlling for other variables, scanning at 100 kVp yielded CTDI(vol) reduction of 33 % (p < 0.0001), signal increase of 96 HU (p < 0.0001), and increased image noise (p < 0.0001), but without significant difference in SNR (p = 0.99). Relative to 120 kVp, 100-kVp CTPA allows simultaneous reduction of radiation exposure by 33 % and IV contrast dose by 33 % while maintaining image quality. Scanning at 100 kVp is recommended in all patients for whom the required mAs does not exceed maximum X-ray tube output. PMID- 22527362 TI - Transfer patient imaging: a survey of members of the American Society of Emergency Radiology. AB - When trauma patients are transferred from outside hospitals, the receiving clinicians often consult their local radiologists for definitive interpretations of outside examinations (IOE). Such requests introduce a host of logistical, medicolegal, and financial concerns related to quality control and resource utilization. We surveyed 701 members of the American Society of Emergency Radiology to elucidate these concerns. We found that the majority of emergency departments still rely on compact disks for conveyance of outside images; hard film and network transfers were minor mechanisms for most respondents. Sixty-nine percent of the respondents indicated that radiologist reports accompany fewer than 25 % of all transferred imaging studies; of the reports that do arrive, most are unverified preliminary reads. There is considerable variability in billing practices and reimbursement patterns for radiologic second opinions; 68 % of the respondents do not know how often their IOEs are reimbursed. Suboptimal communication between community hospitals and referral centers may result in duplicated efforts and inconsistent quality of medical imaging studies. Further investigation into the role of radiology trainees in the handling of outside studies is also highly recommended. PMID- 22527363 TI - Analytical and numerical analyses of the micromechanics of soft fibrous connective tissues. AB - State of the art research and treatment of biological tissues require accurate and efficient methods for describing their mechanical properties. Indeed, micromechanics-motivated approaches provide a systematic method for elevating relevant data from the microscopic level to the macroscopic one. In this work, the mechanical responses of hyperelastic tissues with one and two families of collagen fibers are analyzed by application of a new variational estimate accounting for their histology and the behaviors of their constituents. The resulting close-form expressions are used to determine the overall response of the wall of a healthy human coronary artery. To demonstrate the accuracy of the proposed method, these predictions are compared with corresponding 3D finite element simulations of a periodic unit cell of the tissue with two families of fibers. Throughout, the analytical predictions for the highly nonlinear and anisotropic tissue are in agreement with the numerical simulations. PMID- 22527364 TI - Computational model for the cell-mechanical response of the osteocyte cytoskeleton based on self-stabilizing tensegrity structures. AB - The mechanism by which mechanical stimulation on osteocytes results in biochemical signals that initiate the remodeling process inside living bone tissue is largely unknown. Even the type of stimulation acting on these cells is not yet clearly identified. However, the cytoskeleton of osteocytes is suggested to play a major role in the mechanosensory process due to the direct connection to the nucleus. In this paper, a computational approach to model and simulate the cell structure of osteocytes based on self-stabilizing tensegrity structures is suggested. The computational model of the cell consists of the major components with respect to mechanical aspects: the integrins that connect the cell with the extracellular bone matrix, and different types of protein fibers (microtubules and intermediate filaments) that form the cytoskeleton, the membrane-cytoskeleton (microfilaments), the nucleus and the centrosome. The proposed geometrical cell models represent the cell in its physiological environment which is necessary in order to give a statement on the cell behavior in vivo. Studies on the mechanical response of osteocytes after physiological loading and in particular the mechanical response of the nucleus show that the load acting on the nucleus is rising with increasing deformation applied to the integrins. PMID- 22527365 TI - An anisotropic elastic-viscoplastic damage model for bone tissue. AB - A new anisotropic elastic-viscoplastic damage constitutive model for bone is proposed using an eccentric elliptical yield criterion and nonlinear isotropic hardening. A micromechanics-based multiscale homogenization scheme proposed by Reisinger et al. is used to obtain the effective elastic properties of lamellar bone. The dissipative process in bone is modeled as viscoplastic deformation coupled to damage. The model is based on an orthotropic ecuntric elliptical criterion in stress space. In order to simplify material identification, an eccentric elliptical isotropic yield surface was defined in strain space, which is transformed to a stress-based criterion by means of the damaged compliance tensor. Viscoplasticity is implemented by means of the continuous Perzyna formulation. Damage is modeled by a scalar function of the accumulated plastic strain [Formula: see text] , reducing all element s of the stiffness matrix. A polynomial flow rule is proposed in order to capture the rate-dependent post yield behavior of lamellar bone. A numerical algorithm to perform the back projection on the rate-dependent yield surface has been developed and implemented in the commercial finite element solver Abaqus/Standard as a user subroutine UMAT. A consistent tangent operator has been derived and implemented in order to ensure quadratic convergence. Correct implementation of the algorithm, convergence, and accuracy of the tangent operator was tested by means of strain- and stress-based single element tests. A finite element simulation of nano- indentation in lamellar bone was finally performed in order to show the abilities of the newly developed constitutive model. PMID- 22527366 TI - Physical invariant strain energy function for passive myocardium. AB - Principal axis formulations are regularly used in isotropic elasticity, but they are not often used in dealing with anisotropic problems. In this paper, based on a principal axis technique, we develop a physical invariant orthotropic constitutive equation for incompressible solids, where it contains only a one variable (general) function. The corresponding strain energy function depends on six invariants that have immediate physical interpretation. These invariants are useful in facilitating an experiment to obtain a specific constitutive equation for a particular type of materials. The explicit appearance of the classical ground-state constants in the constitutive equation simplifies the calculation for their admissible values. A specific constitutive model is proposed for passive myocardium, and the model fits reasonably well with existing simple shear and biaxial experimental data. It is also able to predict a set of data from a simple shear experiment. PMID- 22527367 TI - Failure modelling of trabecular bone using a non-linear combined damage and fracture voxel finite element approach. AB - Trabecular bone tissue failure can be considered as consisting of two stages: damage and fracture; however, most failure analyses of 3D high-resolution trabecular bone samples are confined to damage mechanisms only, that is, without fracture. This study aims to develop a computational model of trabecular bone consisting of an explicit representation of complete failure, incorporating damage criteria, fracture criteria, cohesive forces, asymmetry and large deformation capabilities. Following parameter studies on a test specimen, and experimental testing of bone sample to complete failure, the asymmetric critical tissue damage and fracture strains of ovine vertebral trabecular bone were calibrated and validated to be compression damage -1.16 %, tension damage 0.69 %, compression fracture -2.91 % and tension fracture 1.98 %. Ultimate strength and post-ultimate strength softening were captured by the computational model, and the failure of individual struts in bending and shear was also predicted. This modelling approach incorporated a cohesive parameter that provided a facility to calibrate ductile-brittle behaviour of bone tissue in this non-linear geometric and non-linear constitutive property analyses tool. Finally, the full accumulation of tissue damage and tissue fracture has been monitored from range of small magnitude (normal daily loading) through to specimen yielding, ultimate strength and post-ultimate strength softening. PMID- 22527368 TI - Double-network acrylamide hydrogel compositions adapted to achieve cartilage-like dynamic stiffness. AB - Since articular cartilage has a limited potential for spontaneous healing, various techniques are employed to repair cartilage lesions. Acrylate-based double-network (DN) hydrogels containing ~90% water have shown promising properties as repair materials for skeletal system soft tissues. Although their mechanical properties approach those of native cartilage, the critical factor stiffness-of DN-gels does not equal the stiffness of articular cartilage. This study investigated whether revised PAMPS/PAAm compositions with lower water content result in stiffness parameters closer to cartilage. DN-gels containing 61, 86 and 90% water were evaluated using two non-destructive, mm-scale indentation test modes: fast-impact (FI) and slow-sinusoidal (SS) deformation. Deformation resistance (dynamic modulus) and energy handling (loss angle) were determined. The dynamic modulus increased with decreasing water content in both testing modes. In the 61% water DN-gel, the modulus resembled that of cartilage (FI-mode: DN-gel = 12, cartilage = 17; SS-mode: DN-gel = 4, cartilage = 1.7 MPa). Loss angle increased with decreasing water content in fast-impact, but not in slow-sinusoidal deformation. However, loss angle was still much lower than cartilage (FI: DN-gel = 5, cartilage = 11; SS: DN-gel = 10, cartilage = 32 degrees ), indicating somewhat less ability to dissipate energy. Overall, results show that it is possible to adapt DN-gel composition to produce dynamic stiffness properties close to normal articular cartilage. PMID- 22527369 TI - Assessment of the metabolic flow phenotype of primary colorectal cancer: correlations with microvessel density are influenced by the histological scoring method. AB - OBJECTIVES: To investigate how the histological scoring of microvessel density affects correlations between integrated (18)F-FDG-PET/perfusion CT parameters and CD105 microvessel density. METHODS: A total of 53 patients were enrolled from 2007 to 2010. Integrated (18)F-FDG-PET/perfusion CT was successful in 45 patients, 35 of whom underwent surgery without intervening treatment. Tumour SUV(max), SUV(mean) and regional blood flow (BF) were derived. Immunohistochemical staining for CD105 expression and analysis were performed for two hot spots, four hot spots and the Chalkley method. Correlations between metabolic flow parameters and CD105 expression were assessed using Spearman's rank correlation. RESULTS: Mean (SD) for tumour size was 38.5 (20.5) mm, for SUV(max), SUV(mean) and BF it was 19.1 (4.5), 11.6 (2.5) and 85.4 (40.3) mL/min/100 g tissue, and for CD105 microvessel density it was 71.4 (23.6), 66.8 (22.9) and 6.18 (2.07) for two hot spots, four hot spots and the Chalkley method, respectively. Positive correlation between BF and CD105 expression was modest but higher for Chalkley than for four hot spots analysis (r = 0.38, P = 0.03; r = 0.33, P = 0.05, respectively). There were no significant correlations between metabolic parameters (SUV(max) or SUV(mean)) and CD105 expression (r = 0.08-0.22, P = 0.21-0.63). CONCLUSIONS: The histological analysis method affects correlations between tumour CD105 expression and BF but not SUV(max) or SUV(mean). KEY POINTS: * FDG-PET/perfusion CT offers new surrogate biomarkers of angiogenesis. * Microvessel density scoring influences histopathological correlations with CT blood flow. * Highest correlations were found with the Chalkley analysis method. * Correlations between SUV and CD105 are not affected by the scoring method. PMID- 22527370 TI - Impact of iterative reconstruction on image quality and radiation dose in multidetector CT of large body size adults. AB - OBJECTIVE: To compare image quality and radiation dose using Adaptive Statistical Iterative Reconstruction (ASiR) and Filtered Back Projection (FBP) in patients weighing >= 91 kg. METHODS: In this Institution Review Board-approved retrospective study, single-phase contrast-enhanced abdominopelvic CT examinations of 100 adults weighing >= 91 kg (mean body weight: 107.6 +/- 17.4 kg range: 91-181.9 kg) with (1) ASiR and (2) FBP were reviewed by two readers in a blinded fashion for subjective measures of image quality (using a subjective standardized numerical scale and objective noise) and for radiation exposure. Imaging parameters and radiation dose results of the two techniques were compared within weight and BMI sub-categories. RESULTS: All examinations were found to be of adequate quality. Both subjective (mean = 1.4 +/- 0.5 vs. 1.6 +/- 0.6, P < 0.05) and objective noise (13.0 +/- 3.2 vs.19.5 +/- 5.7, P < 0.0001) were lower with ASiR. Average radiation dose reduction of 31.5 % was achieved using ASiR (mean CTDIvol. ASiR: 13.5 +/- 7.3 mGy; FBP: 19.7 +/- 9.0 mGy, P < 0.0001). Other measures of image quality were comparable between the two techniques. Trends for all parameters were similar in patients across weight and BMI sub-categories. CONCLUSION: In obese individuals, abdominal CT images reconstructed using ASiR provide diagnostic images with reduced image noise at lower radiation dose. KEY POINTS: * CT images in obese adults are noisy, even with high radiation dose. * Newer iterative reconstruction techniques have theoretical advantages in obese patients. * Adaptive statistical iterative reconstruction should reduce image noise and radiation dose. * This has been proven in abdominopelvic CT images of obese patients. PMID- 22527371 TI - Triple-negative invasive breast cancer on dynamic contrast-enhanced and diffusion weighted MR imaging: comparison with other breast cancer subtypes. AB - OBJECTIVES: To determine the MRI features of triple-negative invasive breast cancer (TNBC) on dynamic contrast-enhanced MR imaging (DCE-MRI) and diffusion weighted MR imaging (DWI) in comparison with ER-positive/HER2-negative (ER+) and HER2-positive cancer (HER2+). METHODS: A total of 271 invasive cancers in 269 patients undergoing preoperative MRI and surgery were included. Two radiologists retrospectively assessed morphological and kinetic characteristics on DCE-MRI and tumour detectability on DWI. Apparent diffusion coefficient (ADC) values of lesions were measured. Clinical and MRI features of the three subtypes were compared. RESULTS: Compared with ER+ (n = 119) and HER2+ (n = 94), larger size, round/oval mass shape, smooth mass margin, and rim enhancement on DCE-MRI were significantly associated with TNBC (n = 58; P < 0.0001). On DWI, mean ADC value (* 10(-3) mm(2)/s) of TNBC (1.03) was higher than the mean ADC values for ER+ and HER2+ (0.89 and 0.84; P < 0.0001). There was no difference in tumour detectability (P = 0.099). Tumour size (P = 0.009), mass margin (smooth, P < 0.0001; irregular, P = 0.020), and ADC values (P = 0.002) on DCE-MRI and DWI were independent features of TNBC. CONCLUSIONS: In addition to the morphological features, higher ADC values on DWI were independently associated with TNBC and could be useful in differentiating TNBC from ER+ and HER2+. KEY POINTS: * Triple negative breast cancers (TNBC) lack oestrogen/progesterone receptors and HER2 expression/amplification. * TNBCs are larger, better defined and more necrotic than conventional cancers. * On MRI, necrosis yields high T2-weighted signal intensity and ADCs. * High ADC values can be useful in diagnosing TNBC. PMID- 22527372 TI - DNA double-strand breaks as potential indicators for the biological effects of ionising radiation exposure from cardiac CT and conventional coronary angiography: a randomised, controlled study. AB - OBJECTIVES: To prospectively compare induced DNA double-strand breaks by cardiac computed tomography (CT) and conventional coronary angiography (CCA). METHODS: 56 patients with suspected coronary artery disease were randomised to undergo either CCA or cardiac CT. DNA double-strand breaks were assessed in fluorescence microscopy of blood lymphocytes as indicators of the biological effects of radiation exposure. Radiation doses were estimated using dose-length product (DLP) and dose-area product (DAP) with conversion factors for CT and CCA, respectively. RESULTS: On average there were 0.12 +/- 0.06 induced double-strand breaks per lymphocyte for CT and 0.29 +/- 0.18 for diagnostic CCA (P < 0.001). This relative biological effect of ionising radiation from CCA was 1.9 times higher (P < 0.001) than the effective dose estimated by conversion factors would have suggested. The correlation between the biological effects and the estimated radiation doses was excellent for CT (r = 0.951, P < 0.001) and moderate to good for CCA (r = 0.862, P < 0.001). One day after radiation, a complete repair of double-strand breaks to background levels was found in both groups. CONCLUSIONS: Conversion factors may underestimate the relative biological effects of ionising radiation from CCA. DNA double-strand break assessment may provide a strategy for individualised assessments of radiation. KEY POINTS: * Radiation dose causes concern for both conventional coronary angiography and cardiac CT. * Estimations of the biological effects of ionising radiation may become feasible. * Fewer DNA double-strand breaks are induced by cardiac CT than CCA. * Conversion factors may underestimate the relative effects of ionising radiation from CCA. PMID- 22527373 TI - Diagnostic value of ADC in patients with prostate cancer: influence of the choice of b values. AB - OBJECTIVES: To evaluate the influence of the choice of b values on the diagnostic value of the apparent diffusion coefficient (ADC) for detection and grading of prostate cancer (PCa). METHODS: Forty-one patients with biopsy-proven PCa underwent endorectal 3-T MRI before prostatectomy. Different combinations of b values (0-800 s/mm(2)) were used to calculate four representative ADC maps. Mean ADCs of tumours and non-malignant tissue were determined. Tumour appearance on different ADC maps was rated by three radiologists as good, fair or poor by assigning a visual score (VS) of 2, 1 or 0, respectively. Differences in the ADC values with the choice of b values were analysed using one-way ANOVA. RESULTS: Choice of b values had a highly (P < 0.001) significant influence on the absolute ADC in each tissue. Maps using b = [50, 800] and [0, 800] were rated best (VS= 1.6 +/- 0.3) and second best (1.1 +/- 0.3, P < 0.001), respectively. For low grade carcinomas (Gleason score <= 6, 13/41 patients), only the former choice received scores better than fair (VS = 1.4 +/- 0.3). Mean tumour ADCs showed significant negative correlation (Spearman's rho -0.38 to -0.46, P < 0.05) with Gleason score. CONCLUSIONS: Absolute ADC values strongly depend on the choice of b values and therefore should be used with caution for diagnostic purposes. A minimum b value greater than zero is recommended for ADC calculation to improve the visual assessment of PCa in ADC maps. KEY POINTS: * Absolute ADC values are highly dependent on the choice of b values. * Absolute ADC thresholds should be used carefully to predict tumour aggressiveness. * Subjective ratings of ADC maps involving b = 0 s/mm ( 2 ) are poor to fair. * Minimum b value greater than 0 s/mm ( 2 ) is recommended for ADC calculation. PMID- 22527374 TI - Predicting response to neoadjuvant chemotherapy in primary breast cancer using volumetric helical perfusion computed tomography: a preliminary study. AB - OBJECTIVES: To investigate whether CT-derived vascular parameters in primary breast cancer predict complete pathological response (pCR) to neoadjuvant chemotherapy (NAC). METHODS: Twenty prospective patients with primary breast cancer due for NAC underwent volumetric helical perfusion CT to derive whole tumour regional blood flow (BF), blood volume (BV) and flow extraction product (FE) by deconvolution analysis. A pCR was achieved if no residual invasive cancer was detectable on pathological examination. Relationships between baseline BF, BV, FE, tumour size and volume, and pCR were examined using the Mann-Whitney U test. Receiver operating characteristic (ROC) curve analysis was performed to assess the parameter best able to predict response. Intra- and inter-observer variability was assessed using Bland-Altman statistics. RESULTS: Seventeen out of 20 patients completed NAC with four achieving a pCR. Baseline BF and FE were higher in patients who achieved a pCR compared with those who did not (P = 0.032); tumour size and volume were not significantly different (P > 0.05). ROC analysis revealed that BF and FE were able to identify responders effectively (AUC = 0.87; P = 0.03). There was good intra- and inter-observer agreement. CONCLUSIONS: Primary breast cancers which exhibited higher levels of perfusion before treatment were more likely to achieve a pCR to NAC. PMID- 22527375 TI - Diagnostic performance of stress myocardial perfusion imaging for coronary artery disease: a systematic review and meta-analysis. AB - OBJECTIVES: To determine and compare the diagnostic performance of stress myocardial perfusion imaging (MPI) for the diagnosis of obstructive coronary artery disease (CAD), using conventional coronary angiography (CCA) as the reference standard. METHODS: We searched Medline and Embase for literature that evaluated stress MPI for the diagnosis of obstructive CAD using magnetic resonance imaging (MRI), contrast-enhanced echocardiography (ECHO), single-photon emission computed tomography (SPECT) and positron emission tomography (PET). RESULTS: All pooled analyses were based on random effects models. Articles on MRI yielded a total of 2,970 patients from 28 studies, articles on ECHO yielded a sample size of 795 from 10 studies, articles on SPECT yielded 1,323 from 13 studies. For CAD defined as either at least 50 %, at least 70 % or at least 75 % lumen diameter reduction on CCA, the natural logarithms of the diagnostic odds ratio (lnDOR) for MRI (3.63; 95 % CI 3.26-4.00) was significantly higher compared to that of SPECT (2.76; 95 % CI 2.28-3.25; P = 0.006) and that of ECHO (2.83; 95 % CI 2.29-3.37; P = 0.02). There was no significant difference between the lnDOR of SPECT and ECHO (P = 0.52). CONCLUSION: Our results suggest that MRI is superior for the diagnosis of obstructive CAD compared with ECHO and SPECT. ECHO and SPECT demonstrated similar diagnostic performance. PMID- 22527376 TI - Prediction of early response to uterine arterial embolisation of adenomyosis: value of T2 signal intensity ratio of adenomyosis. AB - OBJECTIVES: To identify imaging predictors for complete necrosis after uterine artery embolisation (UAE) via quantitative measurement of the signal intensity obtained from magnetic resonance imaging (MRI) of a patient with adenomyosis. METHODS: The MRIs of 119 patients with uterine adenomyosis, who underwent UAE, were retrospectively evaluated. Each lesion was classified based on its location and morphology on MRI. Thickness and signal intensity were measured in each adenomyosis and in the rectus muscle on the T2-weighted sagittal plane, and the T2-weighted signal intensity ratio (T2SR) was calculated. MR parameters were then compared in patients showing complete response that achieved complete necrosis and incomplete response after UAE via univariate and multivariate analysis. Receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic performance of the predictor using MR parameters for differentiating the complete from the incomplete response. RESULTS: The complete necrosis rate was 66.4 % (79/119) after UAE for adenomyosis. Univariate and multivariate analysis results indicated that T2SR was associated significantly with complete necrosis (P = 0.012). Symptomatic adenomyosis with T2SR above 0.475 was associated with complete necrosis after UAE (sensitivity = 57.0, specificity = 70.0, area under the ROC curve [AUC] = 0.643). CONCLUSION: T2SR of adenomyosis on pre-procedural MRI can be utilised as a predictor for early therapeutic response of UAE in adenomyosis. PMID- 22527379 TI - [Exciting and clinically relevant advances in the diagnosis of food allergies]. PMID- 22527377 TI - MR-guided radiofrequency ablation using a wide-bore 1.5-T MR system: clinical results of 213 treated liver lesions. AB - OBJECTIVE: To evaluate the technical effectiveness, technical success and patient safety of MR-guided radiofrequency (RF) ablation of liver malignancies using a wide-bore 1.5-T MR system. METHODS: In 110 patients, 56 primary liver lesions and 157 liver metastases were treated in 157 sessions using percutaneous RF ablation. Mean lesion diameter was 20 mm (range 4-54 mm). All planning, procedural and post interventional control MR investigations were carried out using a wide-bore 1.5-T MR system. Technical success was assessed by a contrast-enhanced MR liver examination immediately after the intervention. Technique effectiveness was assessed by dynamic hepatic MR study 1 month post ablation; mean follow-up period was 24.2 months (range 5-44). RESULTS: Technical success and technique effectiveness were achieved in 210/213 lesions (98.6 %). In 18/210 lesions (8.6 %), local tumour progression occurred 4-28 months after therapy. Seven of these 18 lesions were treated in a second session achieving complete ablation, 6 other lesions were referred to surgery. Overall RF effectiveness rate was 199/213 (93.4 %); overall therapy success (including surgery) was 205/213 (96.2 %). Two major complications (1.3 %) (bleeding and infected biloma) and 14 (8.9 %) minor complications occurred subsequent to 157 interventions. CONCLUSION: Wide-bore MR guided RF ablation is a safe and effective treatment option for liver lesions. PMID- 22527380 TI - [Severe soy allergy in adults. Is there a role for specific immunotherapy?]. AB - An increasing number of immediate type allergies after consumption of soy products have been reported during the last years. Due to cross reactions between the main birch pollen allergen Bet v 1 and soy allergen Gly m 4, patients sensitized to birch are at special risk for soy allergy. Severe immediate type reactions to soy have also been associated with sensitizations to storage proteins Gly m 5 and Gly m 6. Therapy should include avoidance of soy products with high protein content (i.e. drinks). A limited number of studies has investigated specific immunotherapy (SIT) against birch in patients with birch associated food allergy, namely to apple or hazel. A therapeutic effect on birch- associated food allergy was shown in some of these trials. Results are discussed controversially with regard to number of patients, study design and investigational products. A multicenter trial (BASALIT) is currently investigating the effect of SIT with 80 ug of the folded variant of recombinant Bet v 1 on birch-associated soy allergy. PMID- 22527381 TI - [Food allergy in atopic dermatitis]. AB - Food allergy predominantly affects children rather than adult patients with atopic dermatitis (AD). Early sensitization to foods has been found to be significantly associated with AD. Three different patterns of clinical reactions to food allergens in AD patients exist: i. immediate-type reaction, ii. isolated late-type reaction, iii. combined reaction (i. + ii.). While in children allergens from cow's milk, hen's egg, soy, wheat, fish, peanut or tree nuts are mostly responsible for allergic reactions, birch-pollen related food allergens seem to play a major role in adolescent and adults with AD in Central and Northern Europe. Defects of the epidermal barrier function seem to facilitate the development of sensitization to allergens following epicutaneous exposure. The relevance of defects of the gut barrier as well as genetic characteristics associated with an increased risk for food allergy remain to be further investigated. Numerous studies focus on prevention strategies which include breast-feeding or feeding with hydrolyzed milk substitute formula during the first 4 months of life. PMID- 22527382 TI - [Medical emergencies in daily dermatological practice]. AB - Many patients and their companions who present daily in dermatological clinics and private practices may have numerous non-dermatological comorbidities, which can cause medical emergencies. Additionally several dermatologic diagnostic or therapeutic procedures which are commonly performed can cause life-threatening complications. Therefore dermatologists can be confronted with acute medical emergencies at any time. Mostly these are internal medicine emergencies. Therefore dermatologists must have the basic emergency medical knowledge; emergency situations should be practiced regularly and this training documented for quality control measures. Every practice must be able to deliver life-saving care until trained emergency medical personnel arrive. The general emergency procedures are presented below and the practical approach is illustrated at different cardinal symptoms such as impaired consciousness, respiratory disorders or cardiocirculatory disorders. PMID- 22527383 TI - [Onychomycosis with onychodystrophy or acrolentiginous melanoma with onychomycosis and onychodystrophy?]. AB - A 68-year-old female patient had been treated locally and systemically for onychomycosis of the left thumbnail for 1 year. During the course of treatment there was increasing destruction of approximately 50% of the nail without Hutchinson's sign. Dermoscopically there were yellow to brown vertical stripes of varying width in the remaining parts of the nail. In the visible nail matrix reddish, brownish and grey-black colored components with varying differential structures could be detected. An acrolentiginous melanoma with a diameter of 1.04 mm could be identified histologically and the associated onychomycosis was confirmed by culturing. PMID- 22527385 TI - Prognostic impact of significant non-infarct-related left main coronary artery disease in patients with acute myocardial infarction who receive a culprit-lesion percutaneous coronary intervention. AB - BACKGROUND: Infarct-related left main coronary artery disease (LMCAD) is associated with an increased cardiac mortality in the setting of acute myocardial infarction (AMI). However, the prevalence and prognostic impact of significant (>=50% stenosis) non-infarct-related LMCAD in patients with AMI have not yet been elucidated. METHODS: We prospectively analyzed 7655 AMI patients who had undergone a percutaneous coronary intervention (PCI) in the Korea Acute Myocardial Infarction Registry from November 2005 to January 2008. We compared major adverse cardiac events (MACEs) in AMI patients with non-infarct-related LMCAD and those without LMCAD. RESULTS: Of 99 (1.3%) non-infarct-related LMCAD patients, 40 patients had undergone PCI due to their lesions on the left main coronary artery. The incidences of all-cause death, cardiac death, recurrent myocardial infarction, and composite of MACE except repeat revascularization were higher in patients with non-infarct-related LMCAD at 12 months. In Cox proportional hazard analysis for the prediction of MACE at 12 months, the hazard ratio of LMCAD was 2.189 (95% confidence interval 1.230-3.896, P=0.008). In subgroup analysis, there was no significant cumulative difference between patients who had undergone non-infarct-related left main coronary artery PCI and those who did not undergo PCI at 1 and 12 months. CONCLUSION: The significant, non-infarct-related LMCAD in patients with AMI remains a major adverse prognostic indicator even after receiving optimal culprit-lesion PCI. PMID- 22527386 TI - Root system architecture: insights from Arabidopsis and cereal crops. AB - Roots are important to plants for a wide variety of processes, including nutrient and water uptake, anchoring and mechanical support, storage functions, and as the major interface between the plant and various biotic and abiotic factors in the soil environment. Understanding the development and architecture of roots holds potential for the exploitation and manipulation of root characteristics to both increase food plant yield and optimize agricultural land use. This theme issue highlights the importance of investigating specific aspects of root architecture in both the model plant Arabidopsis thaliana and (cereal) crops, presents novel insights into elements that are currently hardly addressed and provides new tools and technologies to study various aspects of root system architecture. This introduction gives a broad overview of the importance of the root system and provides a snapshot of the molecular control mechanisms associated with root branching and responses to the environment in A. thaliana and cereal crops. PMID- 22527387 TI - Peptides and receptors controlling root development. AB - The growth of a plant's root system depends on the continued activity of the root meristem, and the generation of new meristems when lateral roots are initiated. Plants have developed intricate signalling systems that employ secreted peptides and plasma membrane-localized receptor kinases for short- and long-range communication. Studies on growth of the vascular system, the generation of lateral roots, the control of cell differentiation in the root meristem and the interaction with invading pathogens or symbionts has unravelled a network of peptides and receptor systems with occasionally shared functions. A common theme is the employment of conserved modules, consisting of a short signalling peptide, a receptor-like kinase and a target transcription factor, that control the fate and proliferation of stem cells during root development. This review intends to give an overview of the recent advances in receptor and peptide ligand-mediated signalling involved in root development. PMID- 22527388 TI - Multiple AUX/IAA-ARF modules regulate lateral root formation: the role of Arabidopsis SHY2/IAA3-mediated auxin signalling. AB - In Arabidopsis thaliana, lateral root (LR) formation is regulated by multiple auxin/indole-3-acetic acid (Aux/IAA)-AUXIN RESPONSE FACTOR (ARF) modules: (i) the IAA28-ARFs module regulates LR founder cell specification; (ii) the SOLITARY-ROOT (SLR)/IAA14-ARF7-ARF19 module regulates nuclear migration and asymmetric cell divisions of the LR founder cells for LR initiation; and (iii) the BODENLOS/IAA12 MONOPTEROS/ARF5 module also regulates LR initiation and organogenesis. The number of Aux/IAA-ARF modules involved in LR formation remains unknown. In this study, we isolated the shy2-101 mutant, a gain-of-function allele of short hypocotyl2/suppressor of hy2 (shy2)/iaa3 in the Columbia accession. We demonstrated that the shy2-101 mutation not only strongly inhibits LR primordium development and emergence but also significantly increases the number of LR initiation sites with the activation of LATERAL ORGAN BOUNDARIES DOMAIN16/ASYMMETRIC LEAVES2-LIKE18, a target gene of the SLR/IAA14-ARF7-ARF19 module. Genetic analysis revealed that enhanced LR initiation in shy2-101 depended on the SLR/IAA14-ARF7-ARF19 module. We also showed that the shy2 roots contain higher levels of endogenous IAA. These observations indicate that the SHY2/IAA3-ARF-signalling module regulates not only LR primordium development and emergence after SLR/IAA14-ARF7-ARF19 module-dependent LR initiation but also inhibits LR initiation by affecting auxin homeostasis, suggesting that multiple Aux/IAA-ARF modules cooperatively regulate the developmental steps during LR formation. PMID- 22527389 TI - Genetic approach towards the identification of auxin-cytokinin crosstalk components involved in root development. AB - Phytohormones are important plant growth regulators that control many developmental processes, such as cell division, cell differentiation, organogenesis and morphogenesis. They regulate a multitude of apparently unrelated physiological processes, often with overlapping roles, and they mutually modulate their effects. These features imply important synergistic and antagonistic interactions between the various plant hormones. Auxin and cytokinin are central hormones involved in the regulation of plant growth and development, including processes determining root architecture, such as root pole establishment during early embryogenesis, root meristem maintenance and lateral root organogenesis. Thus, to control root development both pathways put special demands on the mechanisms that balance their activities and mediate their interactions. Here, we summarize recent knowledge on the role of auxin and cytokinin in the regulation of root architecture with special focus on lateral root organogenesis, discuss the latest findings on the molecular mechanisms of their interactions, and present forward genetic screen as a tool to identify novel molecular components of the auxin and cytokinin crosstalk. PMID- 22527390 TI - In silico analyses of pericycle cell populations reinforce their relation with associated vasculature in Arabidopsis. AB - In Arabidopsis, lateral root initiation occurs in a subset of pericycle cells at the xylem pole that will divide asymmetrically to give rise to a new lateral root organ. While lateral roots never develop at the phloem pole, it is unclear how the interaction with xylem and phloem poles determines the distinct pericycle identities with different competences. Nevertheless, pericycle cells at these poles are marked by differences in size, by ultrastructural features and by specific proteins and gene expression. Here, we provide transcriptional evidence that pericycle cells are intimately associated with their vascular tissue instead of being a separate concentric layer. This has implications for the identification of cell- and tissue-specific promoters that are necessary to drive and/or alter gene expression locally, avoiding pleiotropic effects. We were able to identify a small set of genes that display specific expression in the phloem or xylem pole pericycle cells, and we were able to identify motifs that are likely to drive expression in either one of those tissues. PMID- 22527392 TI - Development of real-time radioisotope imaging systems for plant nutrient uptake studies. AB - Ionic nutrition is essential for plant development. Many techniques have been developed to image and (or) measure ionic movement in plants. Nevertheless, most of them are destructive and limit the analysis. Here, we present the development of radioisotope imaging techniques that overcome such restrictions and allow for real-time imaging of ionic movement. The first system, called macroimaging, was developed to visualize and measure ion uptake and translocation between organs at a whole-plant scale. Such a device is fully compatible with illumination of the sample. We also modified fluorescent microscopes to set up various solutions for ion uptake analysis at the microscopic level. Both systems allow numerical analysis of images and possess a wide dynamic range of detection because they are based on radioactivity. PMID- 22527391 TI - Dissecting the effects of nitrate, sucrose and osmotic potential on Arabidopsis root and shoot system growth in laboratory assays. AB - Studying the specific effects of water and nutrients on plant development is difficult because changes in a single component can often trigger multiple response pathways. Such confounding issues are prevalent in commonly used laboratory assays. For example, increasing the nitrate concentration in growth media alters both nitrate availability and osmotic potential. In addition, it was recently shown that a change in the osmotic potential of media alters the plant's ability to take up other nutrients such as sucrose. It can also be difficult to identify the initial target tissue of a particular environmental cue because there are correlated changes in development of many organs. These growth changes may be coordinately regulated, or changes in development of one organ may trigger changes in development of another organ as a secondary effect. All these complexities make analyses of plant responses to environmental factors difficult to interpret. Here, we review the literature on the effects of nitrate, sucrose and water availability on root system growth and discuss the mechanisms underlying these effects. We then present experiments that examine the impact of nitrate, sucrose and water on root and shoot system growth in culture using an approach that holds all variables constant except the one under analysis. We found that while all three factors also alter root system size, changes in sucrose and osmotic potential also altered shoot system size. In contrast, we found that, when osmotic effects are controlled, nitrate specifically inhibits root system growth while having no effect on shoot system growth. This effectively decreases the root : shoot ratio. Alterations in root : shoot ratio have been widely observed in response to nitrogen starvation, where root growth is selectively increased, but the present results suggest that alterations in this ratio can be triggered across a wide spectrum of nitrate concentrations. PMID- 22527393 TI - Early development and gravitropic response of lateral roots in Arabidopsis thaliana. AB - Root system architecture plays an important role in determining nutrient and water acquisition and is modulated by endogenous and environmental factors, resulting in considerable developmental plasticity. The orientation of primary root growth in response to gravity (gravitropism) has been studied extensively, but little is known about the behaviour of lateral roots in response to this signal. Here, we analysed the response of lateral roots to gravity and, consistently with previous observations, we showed that gravitropism was acquired slowly after emergence. Using a lateral root induction system, we studied the kinetics for the appearance of statoliths, phloem connections and auxin transporter gene expression patterns. We found that statoliths could not be detected until 1 day after emergence, whereas the gravitropic curvature of the lateral root started earlier. Auxin transporters modulate auxin distribution in primary root gravitropism. We found differences regarding PIN3 and AUX1 expression patterns between the lateral root and the primary root apices. Especially PIN3, which is involved in primary root gravitropism, was not expressed in the lateral root columella. Our work revealed new developmental transitions occurring in lateral roots after emergence, and auxin transporter expression patterns that might explain the specific response of lateral roots to gravity. PMID- 22527394 TI - Recovering the dynamics of root growth and development using novel image acquisition and analysis methods. AB - Roots are highly responsive to environmental signals encountered in the rhizosphere, such as nutrients, mechanical resistance and gravity. As a result, root growth and development is very plastic. If this complex and vital process is to be understood, methods and tools are required to capture the dynamics of root responses. Tools are needed which are high-throughput, supporting large-scale experimental work, and provide accurate, high-resolution, quantitative data. We describe and demonstrate the efficacy of the high-throughput and high-resolution root imaging systems recently developed within the Centre for Plant Integrative Biology (CPIB). This toolset includes (i) robotic imaging hardware to generate time-lapse datasets from standard cameras under infrared illumination and (ii) automated image analysis methods and software to extract quantitative information about root growth and development both from these images and via high-resolution light microscopy. These methods are demonstrated using data gathered during an experimental study of the gravitropic response of Arabidopsis thaliana. PMID- 22527395 TI - Phloem-associated auxin response maxima determine radial positioning of lateral roots in maize. AB - In Arabidopsis thaliana, lateral-root-forming competence of pericycle cells is associated with their position at the xylem poles and depends on the establishment of protoxylem-localized auxin response maxima. In maize, our histological analyses revealed an interruption of the pericycle at the xylem poles, and confirmed the earlier reported proto-phloem-specific lateral root initiation. Phloem-pole pericycle cells were larger and had thinner cell walls compared with the other pericycle cells, highlighting the heterogeneous character of the maize root pericycle. A maize DR5::RFP marker line demonstrated the presence of auxin response maxima in differentiating xylem cells at the root tip and in cells surrounding the proto-phloem vessels. Chemical inhibition of auxin transport indicated that the establishment of the phloem-localized auxin response maxima is crucial for lateral root formation in maize, because in their absence, random divisions of pericycle and endodermis cells occurred, not resulting in organogenesis. These data hint at an evolutionarily conserved mechanism, in which the establishment of vascular auxin response maxima is required to trigger cells in the flanking outer tissue layer for lateral root initiation. It further indicates that lateral root initiation is not dependent on cellular specification or differentiation of the type of vascular tissue. PMID- 22527396 TI - Repression of early lateral root initiation events by transient water deficit in barley and maize. AB - The formation of lateral roots (LRs) is a key driver of root system architecture and developmental plasticity. The first stage of LR formation, which leads to the acquisition of founder cell identity in the pericycle, is the primary determinant of root branching patterns. The fact that initiation events occur asynchronously in a very small number of cells inside the parent root has been a major difficulty in the study of the molecular regulation of branching patterns. Inducible systems that trigger synchronous lateral formation at predictable sites have proven extremely valuable in Arabidopsis to decipher the first steps of LR formation. Here, we present a LR repression system for cereals that relies on a transient water-deficit treatment, which blocks LR initiation before the first formative divisions. Using a time-lapse approach, we analysed the dynamics of this repression along growing roots and were able to show that it targets a very narrow developmental window of the initiation process. Interestingly, the repression can be exploited to obtain negative control root samples where LR initiation is absent. This system could be instrumental in the analysis of the molecular basis of drought-responsive as well as intrinsic pathways of LR formation in cereals. PMID- 22527397 TI - Molecular interactions of ROOTLESS CONCERNING CROWN AND SEMINAL ROOTS, a LOB domain protein regulating shoot-borne root initiation in maize (Zea mays L.). AB - Rootless concerning crown and seminal roots (Rtcs) encodes a LATERAL ORGAN BOUNDARIES domain (LBD) protein that regulates shoot-borne root initiation in maize (Zea mays L.). GREEN FLUORESCENT PROTEIN (GFP)-fusions revealed RTCS localization in the nucleus while its paralogue RTCS-LIKE (RTCL) was detected in the nucleus and cytoplasm probably owing to an amino acid exchange in a nuclear localization signal. Moreover, enzyme-linked immunosorbent assay (ELISA) experiments demonstrated that RTCS primarily binds to LBD DNA motifs. RTCS binding to an LBD motif in the promoter of the auxin response factor (ARF) ZmArf34 and reciprocally, reciprocal ZmARF34 binding to an auxin responsive element motif in the promoter of Rtcs was shown by electrophoretic mobility shift assay experiments. In addition, comparative qRT-PCR of wild-type versus rtcs coleoptilar nodes suggested RTCS-dependent activation of ZmArf34 expression. Consistently, luciferase reporter assays illustrated the capacity of RTCS, RTCL and ZmARF34 to activate downstream gene expression. Finally, RTCL homo- and RTCS/RTCL hetero-interaction were demonstrated in yeast-two-hybrid and bimolecular fluorescence complementation experiments, suggesting a role of these complexes in downstream gene regulation. In summary, the data provide novel insights into the molecular interactions resulting in crown root initiation in maize. PMID- 22527398 TI - Natural genetic variation of root system architecture from Arabidopsis to Brachypodium: towards adaptive value. AB - Root system architecture is a trait that displays considerable plasticity because of its sensitivity to environmental stimuli. Nevertheless, to a significant degree it is genetically constrained as suggested by surveys of its natural genetic variation. A few regulators of root system architecture have been isolated as quantitative trait loci through the natural variation approach in the dicotyledon model, Arabidopsis. This provides proof of principle that allelic variation for root system architecture traits exists, is genetically tractable, and might be exploited for crop breeding. Beyond Arabidopsis, Brachypodium could serve as both a credible and experimentally accessible model for root system architecture variation in monocotyledons, as suggested by first glimpses of the different root morphologies of Brachypodium accessions. Whether a direct knowledge transfer gained from molecular model system studies will work in practice remains unclear however, because of a lack of comprehensive understanding of root system physiology in the native context. For instance, apart from a few notable exceptions, the adaptive value of genetic variation in root system modulators is unknown. Future studies should thus aim at comprehensive characterization of the role of genetic players in root system architecture variation by taking into account the native environmental conditions, in particular soil characteristics. PMID- 22527399 TI - High-throughput imaging and analysis of root system architecture in Brachypodium distachyon under differential nutrient availability. AB - Nitrogen (N) and phosphorus (P) deficiency are primary constraints for plant productivity, and root system architecture (RSA) plays a vital role in the acquisition of these nutrients. The genetic determinants of RSA are poorly understood, primarily owing to the complexity of crop genomes and the lack of sufficient RSA phenotyping methods. The objective of this study was to characterize the RSA of two Brachypodium distachyon accessions under different nutrient availability. To do so, we used a high-throughput plant growth and imaging platform, and developed software that quantified 19 different RSA traits. We found significant differences in RSA between two Brachypodium accessions grown on nutrient-rich, low-N and low-P conditions. More specifically, one accession maintained axile root growth under low N, while the other accession maintained lateral root growth under low P. These traits resemble the RSA of crops adapted to low-N and -P conditions, respectively. Furthermore, we found that a number of these traits were highly heritable. This work lays the foundation for future identification of important genetic components of RSA traits under nutrient limitation using a mapping population derived from these two accessions. PMID- 22527400 TI - Complexity of miRNA-dependent regulation in root symbiosis. AB - The development of root systems may be strongly affected by the symbiotic interactions that plants establish with soil organisms. Legumes are able to develop symbiotic relationships with both rhizobial bacteria and arbuscular mycorrhizal fungi leading to the formation of nitrogen-fixing nodules and mycorrhizal arbuscules, respectively. Both of these symbiotic interactions involve complex cellular reprogramming and profound morphological and physiological changes in specific root cells. In addition, the repression of pathogenic defence responses seems to be required for successful symbiotic interactions. Apart from typical regulatory genes, such as transcription factors, microRNAs (miRNAs) are emerging as riboregulators that control gene networks in eukaryotic cells through interactions with specific target mRNAs. In recent years, the availability of deep-sequencing technologies and the development of in silico approaches have allowed for the identification of large sets of miRNAs and their targets in legumes. A number of conserved and legume-specific miRNAs were found to be associated with symbiotic interactions as shown by their expression patterns or actions on symbiosis-related targets. In this review, we combine data from recent literature and genomic and deep-sequencing data on miRNAs controlling nodule development or restricting defence reactions to address the diversity and specificity of miRNA-dependent regulation in legume root symbiosis. Phylogenetic analysis of miRNA isoforms and their potential targets suggests a role for miRNAs in the repression of plant defence during symbiosis and revealed the evolution of miRNA-dependent regulation in legumes to allow for the modification of root cell specification, such as the formation of mycorrhized roots and nitrogen-fixing nodules. PMID- 22527401 TI - Can we improve heterosis for root growth of maize by selecting parental inbred lines with different temperature behaviour? AB - Tolerance to high and low temperature is an important breeding aim for Central and Northern Europe, where temperature fluctuations are predicted to increase. However, the extent to which genotypes differ in their response to the whole range of possible temperatures is not well understood. We tested the hypothesis that the combination of maize (Zea mays L.) inbred lines with differing temperature optima for root growth would lead to superior hybrids. This hypothesis is based on the concept of 'marginal overdominance' in which the hybrid expresses higher relative fitness than its parents, summed over all situations. The elongation rates of axile and lateral roots of the reciprocal cross between two flint and two dent inbred lines were assessed at temperatures between 15 degrees C and 40 degrees C. Indeed, the cross between UH005 and UH250 with lateral root growth temperature optima at 34 degrees C and 28 degrees C, respectively, resulted in intermediate hybrids. At temperatures below and above 31 degrees C, the hybrids' root growth was comparable to the better parent, respectively, thereby increasing temperature tolerance of the hybrid compared with its parents. The implications of and reasons for this heterosis effect are discussed in the context of breeding for abiotic stress tolerance and of putatively underlying molecular mechanisms. This finding paves the way for more detailed investigations of this phenomenon in future studies. PMID- 22527402 TI - Large-scale sequestration of atmospheric carbon via plant roots in natural and agricultural ecosystems: why and how. AB - The soil holds twice as much carbon as does the atmosphere, and most soil carbon is derived from recent photosynthesis that takes carbon into root structures and further into below-ground storage via exudates therefrom. Nonetheless, many natural and most agricultural crops have roots that extend only to about 1 m below ground. What determines the lifetime of below-ground C in various forms is not well understood, and understanding these processes is therefore key to optimising them for enhanced C sequestration. Most soils (and especially subsoils) are very far from being saturated with organic carbon, and calculations show that the amounts of C that might further be sequestered (http://dbkgroup.org/carbonsequestration/rootsystem.html) are actually very great. Breeding crops with desirable below-ground C sequestration traits, and exploiting attendant agronomic practices optimised for individual species in their relevant environments, are therefore important goals. These bring additional benefits related to improvements in soil structure and in the usage of other nutrients and water. PMID- 22527403 TI - New roots for agriculture: exploiting the root phenome. AB - Recent advances in root biology are making it possible to genetically design root systems with enhanced soil exploration and resource capture. These cultivars would have substantial value for improving food security in developing nations, where yields are limited by drought and low soil fertility, and would enhance the sustainability of intensive agriculture. Many of the phenes controlling soil resource capture are related to root architecture. We propose that a better understanding of the root phenome is needed to effectively translate genetic advances into improved crop cultivars. Elementary, unique root phenes need to be identified. We need to understand the 'fitness landscape' for these phenes: how they affect crop performance in an array of environments and phenotypes. Finally, we need to develop methods to measure phene expression rapidly and economically without artefacts. These challenges, especially mapping the fitness landscape, are non-trivial, and may warrant new research and training modalities. PMID- 22527404 TI - Stereoselective synthesis of mono-fluoroalkenes. AB - Recent developments in the stereoselective synthesis of fluoroalkenes, which include hydrofluorination of alkyne, fluorination of alkenylmetal, condensation methods, dehydrofluorination of gem-difluoro compounds, and a cross-coupling reaction using fluorohaloalkenes or fluoroalkenylmetal, are described in this chapter. PMID- 22527405 TI - Selective alkene metathesis in the total synthesis of complex natural product. AB - Alkene metathesis has had a significant impact on the selective and efficient formation of carbon-carbon bonds and the advances of complex natural product total synthesis over the last two decades. In this chapter we highlight a number of recent examples of total syntheses in which selective alkene metathesis plays a vital role in the design and implementation for efficient synthesis. In this regard, we expect the influence of this transformation will continue to shape the landscape of the state of the art and science of natural product total synthesis. PMID- 22527406 TI - Selective olefination of carbonyl compounds via metal-catalyzed carbene transfer from diazo reagents. AB - A number of transition metal complexes are capable of catalyzing selective olefination of carbonyl compounds, including aldehydes, activated and unactivated ketones, with diazo reagents in the presence of triphenylphosphine or related tertiary phosphines. These catalytic olefination reactions can be carried out in a one-pot fashion under neutral conditions with the use of different diazo reagents as carbene sources, typically affording olefins in high yields and high stereoselectivity. PMID- 22527407 TI - Recent advances in stereoselective synthesis of 1,3-dienes. AB - The aim of this review is to present the latest developments in the stereoselective synthesis of conjugated dienes, covering the period 2005-2010. Since the use of this class of compounds is linked to the nature of their appendages (aryls, alkyls, electron-withdrawing, and heterosubstituted groups), the review has been categorized accordingly and illustrates the most representative strategies and mechanisms to access these targets. PMID- 22527408 TI - Development of an evidence-based information booklet to support parents of children without a diagnosis. AB - The aim of this study was to develop an evidence-based psychosocial information booklet for parents of children without a specific diagnosis, many of whom are seen through the genetic clinic. A mixed methods approach was adopted involving four phases. The first two phases involving a systematic review and in-depth interviews are summarised briefly but reported in detail elsewhere. Phase 3 comprised: (1) a grey literature search to identify relevant literature and resources from other patient organizations; (2) drafting the booklet using themes identified through the previous phases; (3) piloting the booklet with eight professional and support group stakeholders and (4) piloting the booklet with 14 parents (from Phase 2) to ensure the information reflected their experiences. In Phase 4, we assessed satisfaction with the booklet through a questionnaire completed by 38 parents. The booklet was well accepted. The importance of providing the booklet at the beginning of the parental 'journey' was identified. We have developed an evidence-based information booklet to support parents via a rigorous mixed methods approach. This booklet meets a largely unmet psychosocial need and could be used in practice to support parents of children without a diagnosis. PMID- 22527409 TI - The efficacy comparison of on-demand boluses with and without basal infusion of 0.1 % bupivacaine via perineural femoral catheter after arthroscopic ACL reconstruction. AB - PURPOSE: Optimal postoperative analgesia after anterior cruciate ligament repair remains challenging. The objective of this prospective experimental clinical study was to compare the postoperative analgesic efficacy of two infusion regimens of 0.1 % bupivacaine administered via perineural femoral catheter. METHODS: Forty adult ASA I and II patients undergoing anterior cruciate ligament reconstruction were enrolled. Surgery was performed under spinal anesthesia combined with femoral nerve block. A perineural femoral catheter was connected to the patient controlled analgesia infusion pump filled with 0.1 % bupivacaine for postoperative pain control. Subjects were assigned to one of two groups according to the bupivacaine infusion regimen: (1) 5 mL/h basal infusion with on-demand 5 mL boluses and 30-min refractive periods, and (2) only on-demand 5 mL boluses and 15-min refractive periods. Quality of postoperative analgesia, adjunctive analgesic consumption, and overall patient satisfaction were recorded for 48 h. RESULTS: Pain control was better in Group I on the day of surgery (P = 0.001) and on the first postoperative day at rest and during mobilization (P = 0.02 and P = 0.009). On the second postoperative day, only pain control during mobilization was better in Group I (P = 0.047). Adjunctive analgesic consumption and patient satisfaction were similar. CONCLUSION: Perineural femoral infusion of on-demand 5 mL boluses of 0.1 % bupivacaine combined with 5 mL/h basal infusion was more efficient than on-demand regimen alone for postoperative pain management after reconstruction of anterior cruciate ligament of the knee. LEVEL OF EVIDENCE: II. PMID- 22527410 TI - Comparison of tunnel placements and clinical results of single-bundle anterior cruciate ligament reconstruction before and after starting the use of double bundle technique. AB - PURPOSE: To investigate whether the locations of the grafts in single-bundle (SB) anterior cruciate ligament (ACL) reconstruction have changed to more anatomical as the double-bundle (DB) method has become more familiar. METHODS: Operation using anteromedial (not transtibial) portal and freehand technique [Group A (N = 25) in 2003, Group B (N = 25) in 2007]. The evaluation methods preoperatively and at the 2-year follow-up (two blinded examiners): clinical examination, stability measurement (KT-1000 arthrometer), the International Knee Documentation Committee (IKDC), and the Lysholm knee scores. A musculoskeletal radiologist made tunnel measurements from the magnetic resonance imaging (MRI). RESULTS: The average tunnel placement in the femoral side: from Blumensaat's line 27 % (Group A) and 26 % (Group B), from the posterior edge of the femur 32 % (Group A) and 29 % (Group B). The average tunnel placement in the tibial side: from the anterior edge 45 % (Group A) and 45 % (Group B), from the lateral side 57 % (Group A) and 54 % (Group B) (P = 0.024). Graft failures ending up to revision ACL surgery: 4 (Group A) and 0 (Group B) (P = 0.045). Operation time reduced 19 min (P = 0.001). CONCLUSION: Tunnel placement at the femoral side was already very low (anatomical) in patients operated in 2003. No significant difference was found when comparing to the patients operated in 2007. There were significantly more graft failures in the Group A, suggesting that the use of the DB method in ACL surgery in 2007 may have also improved the technique and results of the SB ACL reconstruction. LEVEL OF EVIDENCE: Prospective comparative study, Level II. PMID- 22527411 TI - Symptomatic mucoid degeneration of the anterior cruciate ligament. AB - PURPOSE: Mucoid degeneration of the anterior cruciate ligament (ACL) is a little known entity. The aim of this study was to detail the clinical, radiological, arthroscopic and pathological findings of this condition and to report clinical outcomes following arthroscopic partial excision of the ACL. METHODS: Between 1999 and 2009, 80 knees in 78 patients were diagnosed as having mucoid degeneration of the ACL based on MRI and clinical findings, and subsequently underwent arthroscopic treatment. Of these, 68 knees in 66 patients, with a median age of 51 years (range, 35-75 years), were followed-up for at least one year. RESULTS: All patients had insidious onset of knee pain, while 56 knees (82 %) had associated extension deficits and 36 knees (53 %) had restricted flexion. MRI findings typically showed diffuse thickening and increased signal intensity of the ACL. Arthroscopic examination revealed notch impingement and bulging of hypertrophied ACL into lateral compartments. Associated lesions included meniscal tears in 33 knees and chondral lesions of at least Outerbridge grade 2 in 56 knees. All knees underwent arthroscopic partial excision of the hypertrophied ACL, with three undergoing preoperative and 30 undergoing concomitant meniscectomies. Pain relief was achieved in 58 of 62 knees (94 %) following partial excision of the ACL. Extension deficits were normalized in 49 of 56 knees (88 %), and restricted flexion was normalized in 33 of 36 affected knees (92 %). Four knees of four patients had postoperative symptoms of anterior instability. CONCLUSIONS: Pain and limitation of motion due to mucoid degeneration of the ACL can be improved by arthroscopic partial excision of the ACL with or without notchplasty. However, one potential complication is the development of postoperative symptoms of anterior instability. LEVEL OF EVIDENCE: Retrospective study, Level IV. PMID- 22527412 TI - Meniscus root refixation technique using a modified Mason-Allen stitch. AB - A complete posterior medial meniscus root tear results in the inability to withstand hoop stress and requires the repair of the posterior medial meniscus root. Several techniques to repair the posterior medial meniscus root have been proposed, but most techniques are based on simple stitching. A modified Mason Allen technique, recognized as a superior stitching method to repair rotator cuff in shoulder surgery, was applied to overcome the potential weakness of those simple stitching techniques. This newly modified Mason-Allen technique reproduces the locking effect of a conventional modified Mason-Allen stitch allowing the physiological meniscal extrusion. The purpose of this article is to describe a posterior root repair technique using a modified Mason-Allen stitch with two strands consisting of a simple horizontal and a simple vertical stitch. Level of evidence V. PMID- 22527413 TI - Partial resection of the PCL insertion site during tibial preparation in cruciate retaining TKA. AB - PURPOSE: Based on the anatomy of the tibial PCL insertion site, we hypothesized that at least part of it is damaged while performing a standard tibial cut in a PCL-retaining total knee replacement. The purpose of this study was to determine and quantify the amount of resection of the tibial PCL attachment with a 9 mm tibial cut with 3 degrees of posterior slope. METHODS: Twenty cadaver tibias were used. The borders of the PCL footprint were demarcated, and calibrated digital pictures were taken in order to determine the surface area. A standard tibial intramedullary guide was used to prepare and perform a tibial cut at a depth of 9 mm with 3 degrees posterior slope. After the tibial cut was made, a second digital picture was taken using the same methodology to measure the surface area of the remaining PCL insertion. RESULTS: The mean surface area of the intact tibial PCL footprint before the cut was 148.9 +/- 25.8 mm(2) and after the tibial cut 47.1 +/- 28.0 mm(2). On average, 68.8 +/- 15.3 % of the surface area of the PCL insertion was removed. CONCLUSION: The results of this study, therefore, indicate that the conventional technique for tibial preparation in cruciate retaining total knee arthroplasty can result in damage or removal of a significant part of the tibial PCL insertion. PMID- 22527414 TI - The effects of plasma rich in growth factors (PRGF-Endoret) on healing of medial collateral ligament of the knee. AB - PURPOSE: Platelet-rich plasma (PRP) has been increasingly used in sports-related injuries for therapeutic applications. However, there are numerous manufacturing procedures and treatment protocols of PRP use, which make difficult to assess its real efficacy for tissue healing. This study addressed to evaluate the therapeutic effects of locally delivered plasma rich in growth factors (PRGF Endoret) on the early healing of medial collateral ligament (MCL) in rabbit knees. METHODS: Thirty-one Japanese white rabbits were subjected to a mop-end tear in the MCL of the left knee. PRGF-Endoret was prepared using Anitua's technique. Two groups were set up. In 17 knees, prepared 1.0 ml of PRGF-Endoret after clotting was applied on the tear site, while in 14 knees the tear site was untreated serving as a control. Quantitative aspects of PRGF-Endoret, the concentration of platelets, leukocytes and erythrocytes and therapeutic growth factors such as PDGF-BB and TGF-beta1 were measured. Rabbits were sacrificed at 3 and 6 weeks after the operation and histological and biomechanical evaluation were performed. RESULTS: No leukocytes were measured and certain amount of growth factors such as PDGF-BB and TGF-beta1 were confirmed in the PRGF-Endoret. PRGF Endoret stimulated proliferation of fibroblasts and neovascularization, and induced statistically better structural properties in repaired MCL. CONCLUSIONS: Our findings provide evidence that local administration of PRGF-Endoret promotes early steps in ligament healing and the repair of structural properties in a rabbit model. PRGF-Endoret would be a useful product in clinical treatment of ligament injuries. PMID- 22527415 TI - Effect of ACL reconstruction tunnels on stress in the distal femur. AB - PURPOSE: This study examined the change in femoral stress caused by graft tunnels drilled for anterior cruciate ligament (ACL) reconstruction. Using a computational model, the number, geometry and position of the graft tunnels exits were varied to determine the effect on bone stress. METHODS: A finite element model of the distal femur was developed from a CT scan of a cadaveric knee. To assess the model, the strain calculated computationally was compared to experimentally measured strains in eleven unpaired human cadaver femurs. Using the computational model, the number, geometry and position of the graft tunnel exits were varied to determine the effect on bone stress based on the stress concentration factor: the ratio of bone stress with tunnels to intact bone stress. RESULTS: The results indicated that the second tunnel in double-bundle ACL reconstruction results in approximately a 20 % increase in the maximum femoral stress as compared to single-bundle reconstruction. The highest stresses occur at the tunnel exits. The position of the tunnel exits effects femoral stress with the stress increasing slightly (AM SCR from 0.7 to 1 and PL SCR from 1.2 to 1.3) when the AM tunnel exit is moved anteriorly and having greater increases as the posterior lateral (PL) tunnel exit is moved laterally (PL SCR from 1.2 to 1.7) or posteriorly (PL SCR from 1.2 to 2). CONCLUSION: In anatomical ACL reconstruction, the tunnel entrances are dictated by anatomy; however, there can be variations in tunnel exit positions. Consideration should be given when positioning tunnel exits on the effect on stress in the femur. Moving the PL tunnel exit laterally or posteriorly increases in the stress at the PL tunnel exit. PMID- 22527416 TI - Accuracy of manual instrumentation of tibial cutting guide in total knee arthroplasty. AB - PURPOSE: The aim of this study was to evaluate the accuracy of conventional instrumentation for tibial resection in total knee arthroplasty (TKA) as assessed by a computer-based navigation system during each phase of the surgical procedure. The hypothesis is that conventional instrumentation fails to achieve optimal accuracy in final implant positioning, thus leading to surgical errors. METHODS: Forty primary TKAs were performed. The resection guide was placed using an extramedullary guide. Accurate guide positioning was assessed by the navigation system prior to the osteotomy. The alignment measurement was repeated after resection and after component implantation in order to quantify the deviation caused by the manual positioning of the prosthetic components. A deviation >=2 degrees was considered unsatisfactory. RESULTS: In the frontal plane, unsatisfactory results observed were as follows: 15 % with reference to manual positioning of the resection guide and 10 % with reference to definition of the resection plane with a tendency towards varus malalignment. In the sagittal plane, unsatisfactory results were as follows: 45 % with reference to manual positioning of the resection guide and 40 % with reference to definition of the resection plane with a trend of decreased tibial slope angle. The deviation between bone resection and subsequent implant placement was >=2 degrees in none of the cases. CONCLUSIONS: The study confirms the hypothesis that conventional instrumentation fails to achieve optimal accuracy in the positioning of the tibial component. During each phase of the surgical procedure, a tendency towards varus malalignment and a decreased tibial slope angle were observed. LEVELS OF EVIDENCE: II. PMID- 22527417 TI - Proprioception level after endoscopically guided percutaneous Achilles tendon. AB - PURPOSE: To evaluate ankle function following endoscopically guided percutaneous Achilles tendon repair. The hypothesis of this study was that patients with percutaneous repair of the Achilles tendon would still display impaired involved side ankle proprioception. METHODS: Nineteen male patients with percutaneous Achilles tendon surgery were tested for bilateral ankle active angle reproduction at 10 degrees dorsiflexion and 15 degrees plantar flexion, peak concentric isokinetic ankle dorsiflexor and plantar flexor torque, one-leg hop for distance, and single-leg vertical jump height. Dominant sides of age- and sex-matched 19 healthy controls were evaluated for ankle active angle reproduction at 10 degrees dorsiflexion and 15 degrees plantar flexion, peak concentric isokinetic ankle dorsiflexor and plantar flexor torque. RESULTS: Peak isokinetic torque, one-leg hop for distance, single-leg vertical jump for height and ankle joint position sense at 10 degrees dorsiflexion did not differ between the affected and unaffected side. Ankle joint position sense for active angle replication at 15 degrees plantar flexion revealed a significant side-to-side difference. Joint position sense at 10 degrees dorsiflexion and at 15 degrees plantar flexion at affected side was poor in patients compared with the controls, while joint position sense at 10 degrees dorsiflexion and at 15 degrees plantar flexion at unaffected side was same in patients compared with the controls. CONCLUSIONS: It has revealed a significant difference in joint position sense at plantar flexion of the patients at least 1 year after percutaneous Achilles tendon surgery compared to their unaffected limb. Large prospective longitudinal studies are needed to evaluate therapeutic interventions designed to improve proprioception. PMID- 22527419 TI - Graft impingement in anterior cruciate ligament reconstruction. AB - Anterior cruciate ligament (ACL) graft impingement is one of the most troubling complications in ACL reconstruction. In the previous strategy of isometric "non anatomical" ACL reconstruction, posterior tibial tunnel placement and notchplasty were recommended to avoid graft impingement. Recently, the strategy of ACL reconstruction is shifting towards "anatomical" reconstruction. In anatomical ACL reconstruction, the potential risk of graft impingement is higher than in non anatomical reconstruction because the tibial tunnel is placed at a more anterior portion on the tibia. However, there have been few studies reporting on graft impingement in anatomical ACL reconstruction. This study will provide a review of graft impingement status in both non-anatomical and the more recent anatomical ACL reconstruction techniques. In conclusion, with the accurate creation of bone tunnels within ACL native footprint, the graft impingement might not happen in anatomical ACL reconstruction. For the clinical relevance, to prevent graft impingement, surgeons should pay attention of creating correct anatomical tunnels when they perform ACL reconstruction. Level of evidence IV. PMID- 22527418 TI - Coracoid impingement: current concepts. AB - For many years, coracoid impingement has been a well-recognized cause of anterior shoulder pain. However, a precise diagnosis of coracoid impingement remains difficult in some cases due to the presence of multifactorial pathologies and a paucity of supporting evidence in the literature. This review provides an update on the current anatomical and biomechanical knowledge regarding this pathology, describes the diagnostic process, and discusses the possible treatment options, based on a systematic review of the literature. Level of evidence V. PMID- 22527420 TI - Origin of the synchronicity in bond formation in polar Diels-Alder reactions: an ELF analysis of the reaction between cyclopentadiene and tetracyanoethylene. AB - The origin of the synchronicity in C-C bond formation in polar Diels-Alder (P-DA) reactions involving symmetrically substituted electrophilic ethylenes has been studied by an ELF analysis of the electron reorganization along the P-DA reaction of cyclopentadiene (Cp) with tetracyanoethylene (TCE) at the B3LYP/6-31G* level. The present study makes it possible to establish that the synchronicity in C-C bond formation in P-DA reactions is controlled by the symmetric distribution of the electron-density excess reached in the electrophile through the charge transfer process, which can be anticipated by an analysis of the spin electron density at the corresponding radical anion. The ELF comparative analysis of bonding along the DA reactions of Cp with ethylene and with TCE asserts that these DA reactions, which have a symmetric electron reorganization, do not have a cyclic electron reorganization as the pericyclic mechanism states. Due to the very limited number of cases of symmetrically substituted ethylenes, we can conclude that the synchronous mechanism is an exception of DA reactions. PMID- 22527423 TI - Skin cancer: prevention and latest treatments. PMID- 22527424 TI - Treatment of actinic keratoses with 5% topical imiquimod: a multicenter prospective observational study from 93 Austrian office-based dermatologists. AB - BACKGROUND: While randomized, controlled trials have generated information about the safety and efficacy of imiquimod 5% cream in the treatment of actinic keratosis, still very little is known about the challenges and pitfalls of this therapy in the daily clinical routine. OBJECTIVE: To mirror the full picture of the actinic keratosis imiquimod routine therapy, ie, patient profile, in-therapy decisions, tolerability, and satisfaction. METHODS: The present observational, multicenter study included 463 patients from the offices of 93 non-hospital based Austrian dermatologists. Inclusion was solely based on the treatment decision of the dermatologist and the patient's will to participate. There were no specific interventions except suggested time points of visits with pre-defined documentation forms. RESULTS: The typical actinic keratosis patient was a male, aged 74 years, with a disease history of 5.7+/-5.3 years, who presented with 8.4+/-8.0 multiple pre-treated lesions at the face. More than 95% of the patients developed therapeutic skin responses (dominated by erythema and crusting), which led to a significant reduction of lesions from baseline to the end of the therapy. Notably, one-third of those patients prone to a second therapeutic course were submitted to another form of treatment. Post-imiquimod therapy comprised of antibiotic creams, topical steroids, and numerous emollients. Patients and dermatologists reported high satisfaction with the therapy including the cosmetic outcome. CONCLUSION: Our data show the high need for experience at the dermatologist side and information at the patient side. Moreover, the method of treatment for imiquimod-related skin reactions definitively asks for standardization. The study was registered at ClinicalTrials.gov (NCT01151956). Decision by ClinicalTrials.gov: Federal University Teaching Hospital, Feldkirch, Austria Protocol Record OBIMQ465-AK-08, Imiquimod and actinic keratoses: an observational study. PMID- 22527425 TI - Trends in primary skin cancer prevention among US Hispanics: a systematic review. AB - OBJECTIVE: To evaluate trends and identify deficiencies and disparities in primary skin cancer prevention efforts among Hispanics in the US. METHODS: PubMed/MEDLINE and SCOPUS were searched using the following keywords: awareness, knowledge, behavior, sunscreen, hat, clothing, minorities, ethnic skin, Hispanic, Latino, and skin. Reference lists of selected studies were checked for additional studies. Studies that quantitatively evaluated primary skin cancer prevention efforts among US Hispanics were selected. Primary outcome measures included 1) use of sunscreen or sunblock, 2) use of sun-protective clothing and/or hats, and 3) shade seeking behavior. Selected studies were reviewed and quantitative data for each primary outcome measure were extracted. Additionally, we examined survey methodology and demographics of the studied populations. RESULTS: Studies evaluating primary prevention of skin cancer among US Hispanics are limited in number and study populations. Overall, 9.5-29.9% of the Hispanics evaluated reported wearing sunscreen either most of the time or always compared to 16.5 35.9% of NHW. Hispanics reported slightly higher rates of wearing hats compared to NHW, with 23.9-25.0% of Hispanics reporting wearing hats either most of the time or always compared to 20-20.7% of NHW. Trends in wearing sun protective clothing and shade seeking varied between different Hispanic populations evaluated, but overall prevalence of these practices remained low. CONCLUSION: The limited studies suggest that improvements are needed in primary skin cancer prevention practiced by Hispanics. Future studies and interventions need to account for heterogeneity in socio-cultural backgrounds, degree of acculturation, and occupation among US Hispanics. PMID- 22527426 TI - In vitro PLK1 inhibition by BI 2536 decreases proliferation and induces cell cycle arrest in melanoma cells. AB - Melanoma is one of the most treatment-resistant malignancies and regardless of new therapeutic tactics the outcome remains dismal. Polo-like kinase 1 (PLK1) has been shown to be over-expressed in a variety of tumors, becoming an attractive target for cancer management. In the present study we tested the in vitro antitumor activities of BI 2536, a selective inhibitor of PLK1, against two melanoma cell lines. Our results showed that nanomolar concentrations (10-150 nmol/L) of the drug significantly decreased cell proliferation and clonogenicity, promoting cell cycle arrest in G2/M. Targeting the cell cycle offers an attractive potential cancer-treatment option. Herein we show that PLK1 inhibition may be a feasible approach for the impairment of tumor progression and dissemination. This in vitro profile of melanoma cell growth inhibition by PLK1 modulation may be an interesting model to be tested in association with first line antineoplasic agents in melanomas. PMID- 22527427 TI - Evaluation of the chemopreventative effects of ALA PDT in patients with multiple actinic keratoses and a history of skin cancer. AB - BACKGROUND: Actinic keratoses (AKs) are in situ epidermal tumors that may progress to invasive squamous cell carcinomas (SCCs). Aminolevulinic acid with photodynamic therapy (ALA PDT) is a field treatment for AK. OBJECTIVE: To evaluate the time to development of new non-melanoma skin cancers (NMSC) within one year of ALA-PDT treatment in immunocompetent patients with AK and a history of skin cancer. METHODS AND MATERIALS: One hundred forty anatomic sites in 114 patients were treated with topical ALA for a 1 to 3 hour incubation period followed by photodynamic therapy (PDT) with a blue light. All new NMSCs within the treatment areas were recorded over a 1-year observational period. RESULTS: Eighty-three anatomic sites (59%) did not develop new skin cancers within 1 year. Additionally, 92%, 78%, and 64% of anatomic sites were free of new skin cancers at 3, 6, and 9 months after treatment was initiated. Although approximately 41% of patients treated on both the scalp and face developed new skin cancers within 1 year of treatment, the average time to develop skin cancer was longer for the face (7.09 months) than for the scalp (5.34 months). CONCLUSION: In patients with a history of NMSC and multiple AKs, ALA PDT may be a valuable option for the prevention and delay of new NMSCs. PMID- 22527428 TI - Diclofenac sodium 3% gel for the management of actinic keratosis: 10+ years of cumulative evidence of efficacy and safety. AB - BACKGROUND: Diclofenac sodium 3% gel (Solaraze(r)) gained US approval for the treatment of actinic keratosis (AK) more than 10 years ago. Since the publication of the pivotal phase 3 studies, numerous clinical studies have assessed use of this therapy in a variety of body areas, special populations, and novel combinations. OBJECTIVE: To provide a comprehensive update on clinical data and research on the use of diclofenac sodium 3% gel in AK. METHODS: Review of the literature. RESULTS: Accumulating evidence from preclinical research supports that the proposed mechanism of diclofenac sodium 3% gel may include cyclo oxgenase 2 (COX-2) inhibition, inhibition of angiogenesis, and induction of apoptosis. A literature review identified 17 publications (beyond the 2 pivotal studies) on the use of diclofenac sodium 3% gel for AK. A phase 4 open-label study reported that 58 percent of patients achieved complete clearance of target lesions at the 30-day post-treatment assessment; among patients who were evaluable at 1-year post-treatment, sustained long-term clearance of AK lesions was observed. Active comparator studies demonstrated comparable efficacy of diclofenac sodium 3% gel with 5-fluorouracil 5% and imiquimod 5%. Publications on the efficacy of diclofenac sodium 3% gel for AK of the lip report complete clearance rates comparable to those reported for other body areas. Diclofenac sodium 3% gel has also demonstrated efficacy for clearing AK lesions in immunosuppressed populations. Sequential use of diclofenac sodium 3% gel with cryosurgery or photodynamic therapy has been investigated and may emerge as a useful approach for some patients. CONCLUSIONS: Diclofenac sodium 3% gel has a unique proposed mechanism of action in AK that may involve COX-2 inhibition, inhibition of angiogenesis, and induction of apoptosis. In the past decade, numerous clinical studies have demonstrated this topical therapy to be effective and well tolerated for the treatment of AK. PMID- 22527429 TI - Sarcoidosis as an adverse effect of tumor necrosis factor inhibitors. AB - BACKGROUND: Tumor necrosis factor inhibitors are valuable tools for dermatologists. As their use increases, rare adverse events are more likely to be encountered. OBJECTIVE: We describe one patient who developed sarcoidosis while being treated for psoriasis with etanercept. We sought to review to previously reported cases and further characterize the nature of this reaction. METHODS: A literature search was performed with the key words "sarcoidosis, sarcoid, etanercept, infliximab, adalimumab, granulomatous, and drug reaction." All relevant cases in the English language were included and evaluated for demographic data, duration of therapy prior to developing sarcoid, duration of sarcoid signs/symptoms, treatments used and time to resolution after discontinuation of the drug. RESULTS: Including the present case, there are 34 cases of sarcoidosis developing during anti-tumor necrosis factor therapy. All previously reported cases were patients with a primarily rheumatologic diagnosis. In all but one case, discontinuation of the drug resulted in complete resolution of symptoms. The lung and surrounding lymph nodes were the areas most commonly affected. The average amount of time between initiation of therapy and onset of symptoms was 22 months. The average time to resolution of symptoms after discontinuation of the drug was 5.2 months. LIMITATIONS: This is a retrospective case review. CONCLUSIONS: These data indicated that sarcoid is a possible adverse effect of tumor necrosis factor inhibitor therapy that should be noted by dermatologists using these drugs. While it has been reported in the rheumatology literature, it may be under-recognized by dermatologists. PMID- 22527430 TI - Improved texture and appearance of human facial skin after daily topical application of barley produced, synthetic, human-like epidermal growth factor (EGF) serum. AB - A three month, open-label, single center study was conducted to determine whether a uniquely derived serum containing barley bioengineered, human-like epidermal growth factor protein could improve visible signs of photodamage and aging in facial skin. Twenty-nine females, aged 39 to 75 years, with mild to severe, fine and course rhytids, photodamage, and pigmentation were enrolled. Subjects then applied the treatment serum per the prescribed protocol twice-daily for 3 months, in addition to the use of a basic sunscreen and facial cleanser. In-person clinical evaluations and subject self-assessment questionnaires were administered at each follow up visit. In addition, clinical photography was completed at baseline, and each subsequent visit. Clinical evaluations showed statistically significant improvement in the appearance of fine lines and rhytids, skin texture, pore size, and various dyschromatic conditions apparent within the first month of use, and continuing improvement trends for the duration of the study. The treatment serum was well tolerated with minimal treatment-related complications reported throughout. Efficacy of this novel serum and treatment protocol resulted in meaningful improvements in photodamage and visible signs of aging. PMID- 22527431 TI - Where does rituximab fit in the treatment of autoimmune mucocutaneous blistering skin disease? AB - We propose rituximab as a first-line therapy for pemphigus vulgaris and steroid dependent bullous pemphigoid with or without systemic steroids. A brief review of the literature substantiates the significant risk associated with the use of long term, high-dose prednisone, mycophenolate mofetil (MMF), and azathioprine. No head-to-head studies are available with respect to safety and efficacy of rituximab versus these therapies. When comparing the side effects of rituximab to MMF, both are found to be mild when used as monotherapy in dermatologic patients. The most severe side effects of rituximab include fatal infusion reactions and hypersensitivity, pancytopenia, infection and organ dysfunction. With MMF, malignancy, pancytopenia, infection, and organ dysfunction are the most concerning side effects. The frequencies of these observed adverse events are difficult to compare, but the side effect profiles of rituximab and MMF are clearly similar. Therefore, there is equipoise whether to use rituximab before rather than after MMF and/or systemic corticosteroids. PMID- 22527432 TI - Lessons of leprosy: the emergence of TH17 cytokines during type II reactions (ENL) is teaching us about T-cell plasticity. AB - BACKGROUND: Leprosy was the first disease classified according to the thymus derived T-cell in the 1960s and the first disease classified by the cytokine profile as intact interferon-gamma (IFN-gamma) and interleukin-2 (IL2) or TH1 (tuberculoid) and deficient IFN-gamma and IL2 or TH2 (lepromatous), in the 1980s. OBJECTIVE: In the present study, we set out to explore the T helper 17 (TH17) lymphocyte subset, the hallmark of T-cell plasticity, in skin biopsies from patients with erythema nodosum leprosum (ENL) who were treated with thalidomide. METHOD: RNA was extracted from paraffin embedded tissue before and after thalidomide treatment of ENL and RT-PCR was performed. RESULTS: IL17A, the hallmark of TH17, was consistently seen before and after thalidomide treatment, confirming the TH17 subset to be involved in ENL and potentially up-regulated by thalidomide. CONCLUSION: A reduction in CD70, GARP, IDO, IL17B (IL-20), and IL17E (IL-25), coupled with increases in RORgammaT, ARNT, FoxP3, and IL17C (IL-21) following thalidomide treatment, opens the door to understanding the complexity of the immunomodulatory drug thalidomide, which can operate as an anti inflammatory while simultaneously stimulating cell-mediated immunity (CMI). We conclude that TH17 is involved in the immunopathogenesis of ENL and that thalidomide suppresses inflammatory components of TH17, while enhancing other components of TH17 that are potentially involved in CMI. PMID- 22527433 TI - A comparison of physicochemical properties of a selection of modern moisturizers: hydrophilic index and pH. AB - OBJECTIVE: To quantify and compare the physiochemical properties of various topical emollients and to correlate these findings with the products' potential to maintain the stratum corneum (SC) acid milieu, while possessing the appropriate water content for skin rehydration, user adherence, and comfort. MATERIAL AND METHODS: The pH and hydrophilic fraction of 31 skin moisturizers sold in the US were measured. Hydrophilic Index (HI) was calculated using the "HI equation." The two parameters were charted using a scatter plot with quadrant divisions. Products with lower hydrophilicity were considered "more greasy" and assigned a lower HI as compared to their counterparts with a higher hydrophilicity. RESULTS: Our findings are in good accordance with common clinical impressions: lotions generally have higher HI, while ointments have lower HI. The majority of the products tested fall into low HI, suggesting that a large percentage of the products may be rich in overall lipid content. The pH values range widely, from 3.7 to 8.2, with the majority of the products close to the physiologic skin pH of 4 to 6. CONCLUSION: This study introduces HI as a novel method of quantifying the aqueous content of topical emollients. When considered together with pH, the two indices can guide providers in choosing the most suitable emollients for patients with skin diseases involving altered acid mantle and barrier disruption, such as atopic dermatitis, irritant contact dermatitis, and ichthyosis vulgaris. PMID- 22527434 TI - Biophysical evaluation of fractional laser skin resurfacing with an Er:YSGG laser device in Japanese skin. AB - BACKGROUND: Ablative fractional laser skin resurfacing (FLSR) has recently been used for the amelioration of acne scars, and previous studies have shown clinical effectiveness. Despite its extensive use, few studies have focused on the associated changes in biophysical properties of the epidermis. Herein, we evaluate transepidermal water loss, sebum levels, skin hydration, and skin elasticity, following FLSR treatments with an Er:YSGG laser device (Pearl FractionalTM, Cutera Inc., Brisbane, CA), employing non-invasive measurements. METHODS: Five Japanese patients with facial acne scars underwent one FLSR session. Some acne scars appeared to become less obvious as a consequence of the treatment. All patients were aware of a feeling of skin tightness in treated areas. RESULTS: Objective measurements on the lower lateral angle of the eye and on the inner cheeks were evaluated at baseline and at 3 days, 1 week, and 4 weeks after FLSR. Transepidermal water loss showed a significant two-fold (100%) increase at day 3, but had returned to almost the baseline level at week 4 in both areas. Sebum secretion showed a 50% increase at day 3, but had returned to the baseline level after day 7. Skin hydration showed a significant decrease at day 3, but had returned to the baseline level by day 7, and showed significant improvement at the end of the study. Skin elasticity (R2) was still at baseline on day 3, but showed some improvement--an increase of at least 30%--at the end of the study. CONCLUSIONS: Based on our findings, we believe that FLSR should be performed no more than once a month to allow sufficient time for the damaged skin to recover its barrier function in most areas of the face. PMID- 22527435 TI - Fitzpatrick skin types and clindamycin phosphate 1.2%/benzoyl peroxide gel: efficacy and tolerability of treatment in moderate to severe acne. AB - BACKGROUND: Acne in skin of color is an increasing problem, presenting unique challenges. Although combination therapy is now standard of care in acne, concerns exist with the increased potential irritation and dryness in skin of color. Although individual medications can be titrated or applied at different times of the day to minimize irritation, this is not always practical or desirable. There is a paucity of clinical studies that evaluate the safety and efficacy of acne medications in skin of color. METHODS: A post-hoc analysis of efficacy and cutaneous tolerability in 797 subjects receiving clindamycin phosphate 1.2% benzoyl peroxide (BPO) 2.5% gel from two 12-week, multi-center, double-blind studies that enrolled 2,813 subjects with moderate to severe acne. Efficacy, tolerability, and subject satisfaction in Fitzpatrick skin types I-III subjects were compared to subjects with Fitzpatrick skin types IV-VI. RESULTS: Median reductions in inflammatory lesions were comparable between the two groups. There was a small difference in noninflammatory and total lesions in favor of those patients with Fitzpatrick skin types I-III (P=0.013 and P=0.024, respectively). Median reductions in inflammatory, noninflammatory, and total lesions at week 12 were 63%, 50%, and 52.4%, respectively for Fitzpatrick skin types I-III and 65%, 47%, and 51.4%, respectively for Fitzpatrick skin types IV VI. Treatment success was comparable between the two groups and both groups had a high level of subject satisfaction at week 12. Cutaneous tolerability was excellent, with all mean scores less than or equal to 0.2 at week 12 (where 1=mild). Results in the two groups were comparable, although there was slightly more erythema reported in the Fitzpatrick skin types I-III subjects (0.2 versus 0.1). This could be due to the difficulty in visualizing erythema in subjects with darker skin. CONCLUSIONS: Acne subjects with Fitzpatrick skin types IV-VI were not found to be more susceptible to cutaneous irritation from treatment with clindamycin phosphate 1.2%/BPO 2.5% gel and both efficacy and tolerability was comparable across the two treatment groups. PMID- 22527436 TI - A new simple, safe, and easy solution for upper lip dermabrasion. AB - BACKGROUND: Upper lip wrinkling is a common complaint of patients seeking perioral rejuvenation. Lately, manual dermabrasion has become more popular due to its safety, minimal cost, and favorable results. In several hospitals, the ability to efficiently sterilize sand paper has been questioned. METHODS: Between 2007 and 2010, 29 patients underwent manual dermabrasion of the skin of the upper lip using an electric cautery scratch pad during their surgeries. RESULTS: The average patient was aged 60.2 years. The average healing period was 5.8 days. Patient satisfaction from the procedure ranged from very good to excellent. No serious or long lasting complications have been encountered during our follow-up period. PMID- 22527438 TI - Infliximab (Remicade) and increased incidence of development of basal cell carcinoma. AB - Immunosuppression is a known risk factor for the development of non-melanoma skin cancers (NMSC). Certain medications that induce immunosuppression, such as tumor necrosis factor-alpha (TNF-alpha) inhibitors, are being used more frequently. We report a case of a young, pregnant woman who was treated with infliximab for Crohn's disease, and subsequently experienced a rapid growth of two pre-existing basal cell carcinomas. As use of TNF-alpha inhibitors increases, it is important to closely monitor patients for the development of NMSC. PMID- 22527440 TI - Treatment of mild to moderate facial melasma with the Lumixyl topical brightening system. AB - BACKGROUND: Melasma is a cutaneous disorder associated with an overproduction of melanin by the tyrosinase enzyme. A proprietary oligopeptide (LumixylTM) was previously shown to competitively inhibit mushroom and human tyrosinase in vitro without the associated cytotoxicity of hydroquinone and to diminish the appearance of facial melasma. OBJECTIVE: The aim of this case study was to determine if the Lumixyl Topical Brightening System (0.01% oligopeptide cream, an antioxidant cleanser, 20% glycolic acid lotion and physical sunscreen) accelerates clearance of mild-to-moderate melasma. RESULTS: All patients showed improvement in their facial melasma with 1 of 4 patients showing complete clearance after just 6 weeks. CONCLUSIONS: Results suggest that this regimen may be a useful new tool to treat mild to moderate melasma. PMID- 22527441 TI - Lymphoepithelioma-like carcinoma in a patient with mycosis fungoides. PMID- 22527442 TI - Home laser treatments: acne, aging, and unwanted hair. PMID- 22527445 TI - Pretreatment with anti-flagellin serum delays acute lung injury in rats with sepsis. AB - OBJECTIVE: This study examined the reduction of sepsis-induced ALI by inhibition of flagellin-stimulated TLR5 signaling. METHODS: Rats were randomly divided into three groups: one group served as the sham-operated group (control group), and the other two groups received the induction of sepsis (sepsis and treatment groups). The treatment group was injected with anti-flagellin serum before induction of sepsis. At 2, 4, 6, 12, 24, and 48 h following induction of sepsis (six time-point subgroups, n = 10 per subgroup), arterial PaO(2), wet/dry (W/D) lung weight ratios, levels of serum and BALF flagellin and TNF-alpha, pulmonary pathological alterations, and TLR5 mRNA expression in the lungs were examined. RESULTS: Compared to sham-operated rats, septic rats had: increased levels of serum and BALF flagellin at 6, 12, 24, and 48 h; reduced arterial PaO(2); elevated W/D lung weight ratio; increased serum and BALF TNF-alpha levels; and up regulated TLR5 mRNA expression at 12, 24, and 48 h (P < 0.01). Pretreatment with anti-flagellin serum, however, significantly inhibited sepsis-associated declines in arterial PaO(2), increased W/D lung weight ratios, elevated serum and BALF TNF alpha levels, and up-regulated TLR5 mRNA expression at 24 and 48 h (P < 0.01). CONCLUSION: Neutralizing the actions of circulating flagellin with anti-flagellin serum delayed the development of ALI in rats with sepsis. PMID- 22527446 TI - Local and systemic pro-inflammatory and anti-inflammatory cytokine patterns in patients with chronic subdural hematoma: a prospective study. AB - OBJECTIVE AND DESIGN: Innate immune pro- and anti-inflammatory responses in patients with chronic subdural hematoma (CSDH) were investigated by measuring and comparing the systemic and subdural fluid levels of cytokines. MATERIALS AND METHOD: Cytokine values were analyzed in samples obtained during surgery of 56 adult patients who were operated on for unilateral CSDHs using a Multiplex antibody bead kit. RESULTS: There were significantly higher levels of the pro inflammatory IL-2R (p = 0.004), IL-5 (p < 0.001), IL-6 (p < 0.001), and IL-7 (p < 0.001), and anti-inflammatory mediators IL-10 (p < 0.001) and IL-13 (p = 0.002) in CSDH fluid compared with systemic levels. The pro-inflammatory TNF-alpha (p < 0.001), IL-1beta (p < 0.001), IL-2 (p = 0.007) and IL-4 (p < 0.001) were significantly lower in hematoma fluid compared with systemic levels. The ratios between pro- versus anti-inflammatory cytokines were statistically significant higher in CSDH (7.8) compared with systemic levels (1.3). CONCLUSIONS: The innate immune responses occur both locally at the site of CSDH, as well as systematically in patients with CSDH. The local hyper-inflammatory and low anti inflammatory responses exist simultaneously. The findings suggest poorly coordinated innate immune responses at the site of CSDH that may lead to propagating of local inflammatory process and basically contribute to formation and progression of CSDH. PMID- 22527447 TI - Utility of QuantiFERON(r)-TB Gold test in diagnosis and management of suspected tubercular uveitis in India. AB - The tuberculin skin test, used to detect latent systemic tuberculosis (TB), has its limitations. The utility of interferon-gamma assays, found useful in the diagnosis of latent TB, is still unestablished in tubercular uveitis. We present the results of QuantiFERON((r))-TB Gold (QFT-G) test and its relevance in the diagnosis and management of suspected tubercular uveitis in India. All suspected tubercular uveitis patients seen at our uveitis clinic between October 2006 and June 2008 who underwent relevant blood investigations, chest X-rays, Mantoux tests and QFT-G tests were included. Clinical profile, systemic correlation and outcome with treatment were analysed. Fifty suspected tubercular uveitis patients underwent QFT-G testing. The age range of the patients was 6-55 years (mean 32.66 years). Seven patients presented with active and three with a past history of systemic TB. The QFT-G test was positive in 29 patients. Radiological findings of TB were seen in four patients with a positive QFT-G and one patient with a negative QFT-G test. In 11 patients both QFT-G and Mantoux tests were positive. Eighteen Mantoux-negative patients were QFT-G-positive. Significantly, no patient with a positive Mantoux had a negative QFT-G test. Of the 32 patients with posterior uveitis, 17 patients had serpiginous choroiditis, four patients had a choroidal granuloma, six patients had multifocal choroiditis, four patients had retinal vasculitis, and one patient had a subretinal abscess. All QFT-G-positive patients were treated with anti-tuberculosis therapy as well as systemic steroids with a favorable clinical outcome. Our study shows that the QFT-G test is very useful in the diagnosis and management of suspected ocular TB. It was found to be very sensitive in identifying latent TB patients who, upon treatment, had a significantly reduced frequency of recurrences. It was more sensitive than the Mantoux test and is not significantly affected by previous treatment with systemic steroids or immunosuppressives. A negative QFT-G test can also be used as an adjunct before initiation of systemic steroids or immunosuppressives in uveitic patients particularly in an endemic setting like India. PMID- 22527448 TI - Visual and morphological outcomes of bevacizumab (Avastin(r)) versus ranibizumab (Lucentis(r)) treatment for retinal angiomatous proliferation. AB - Retinal angiomatous proliferation (RAP) is a variant of exudative age-related macular degeneration with particularly bad prognosis. The purpose of this work is to describe the long-term functional and morphological outcome of patients treated with intravitreal bevacizumab and ranibizumab. Retrospective case series of 16 eyes treated with bevacizumab and 19 eyes treated with ranibizumab. All patients received initially three intravitreal injections of bevacizumab (1.25 mg/0.05 ml) or ranibizumab (0.5 mg/0.05 ml) every 4 weeks. Follow-up ranged from 1 to 7 months after the third injection. Complete ophthalmologic examination including best-corrected visual acuity (VA), optical coherence tomography, fluorescein angiography, and in selected cases, indocyanine green angiography was performed. Triple intravitreal injections resulted in improvement of VA in bevacizumab-treated as well as in ranibizumab-treated patients; logarithm of the minimal angle of resolution (logMAR) 0.84 before treatment and 0.67 at month 9, and logMAR 0.75 before treatment and 0.59 at month 9, respectively. Central macular thickness (CMT) in the bevacizumab group improved from 363.67 +/- 47.4 MUm at baseline to 328 +/- 49.77 MUm at month 6 (p = 0.03) and 301 +/- 129.69 at month 9 (p = 0.35). CMT in the ranibizumab group improved from 545.62 +/- 167.39 MUm at baseline to 395.88 +/- 169.37 MUm at month 6 and 411.83 +/- 212.41 MUm at month 9 (p = 0.03, p = 0.05, respectively). Patients with RAP might benefit from both intravitreal bevacizumab and ranibizumab treatments with stabilization of VA over a longer period of time. Close follow-up should nevertheless be performed in this special subgroup because of the high recurrence rate. PMID- 22527449 TI - First contact diagnosis and management of contact lens-related complications. AB - To describe the spectrum of contact lens-related problems in cases presenting to a tertiary referral eye hospital. A retrospective case record analysis of 111 eyes of 97 consecutive patients was undertaken over a period of five months at the Royal Victorian Eye and Ear Hospital, Melbourne, Australia. Contact lens related complications (CLRC) were classified into microbial keratitis, sterile corneal infiltrates, corneal epitheliopathy and contact lens-related red eye (CLARE). Main parameters examined were nature of the first contact, clinical diagnosis, and management pattern. Forty-two percent of the initial presentations were to health care practitioners (HCPs) other than ophthalmologists. Mean duration from the onset of symptoms to presentation was 6.3 +/- 10.9 days. Forty nine percent (n = 54) of patients had an associated risk factor, most commonly overnight use of contact lenses (n = 14, 13 %). Most common diagnosis at presentation was corneal epitheliopathy (68 %) followed by sterile infiltrates (10 %), CLARE (8 %) and microbial keratitis (6 %). No significant differences were found in the pattern of treatment modalities administered by ophthalmologists and other HCPs. HCPs other than ophthalmologists are the first contact for contact lens-related problems in a significant proportion of patients. These HCPs manage the majority of CLRC by direct treatment or immediate referral. PMID- 22527450 TI - Presumed melanoma-associated retinopathy (MAR): a presenting sign of primary small intestinal melanoma? AB - Melanoma-associated retinopathy is a paraneoplastic retinopathy associated mostly with cutaneous melanoma. In most cases it presents months to years after diagnosis of primary cutaneous melanoma was made or after recurrence. We describe a 55-year-old male patient who presented with symptoms of decreased vision and photopsia. Diagnosis of melanoma-associated retinopathy was made, but no primary cutaneous melanoma was found. 3 months later he developed intestinal perforation due to small intestinal melanoma. PMID- 22527453 TI - Deterioration of coastal groundwater quality in Island and mainland regions of Ramanathapuram District, Southern India. AB - A study was carried out in the Island and mainland regions of Ramanathapuram District to characterize the physico-chemical characteristics of 87 groundwater samples in Island and 112 groundwater samples in mainland which include pH, EC, TDS, salinity, total alkalinity, calcium hardness, magnesium hardness, total hardness, chloride and fluoride. Heavy inorganic load in majority of the groundwater samples has been estimated due to the salinity, TDS, TH and chloride beyond the threshold level which substantiates the percolation of sea water into the freshwater confined zones. Although the groundwater sources are available in plenty, the scarcity of potable water is most prevalent in this coastal area. The Water Quality Index (WQI) and Langeleir Saturation Index (LSI) have also been calculated to know the potable and corrosive/incrusting nature of the water samples. The statistical tools such as principal component analysis, box plots and correlation matrix have also been used to explain the influence of different physico-chemical parameters with respect to one another among the groundwater samples. The percentage of groundwater samples in mainland was more than that in Island with respect to the acceptable limit of WHO drinking standard, especially in TDS, CH, TH and chloride but the converse is observed in the case of fluoride. About 8% of the mainland aquifers and 42% of Island aquifers were identified to have fluoride greater than 1.5 mg/l. The signature of salt-water intrusion is observed from the ratio of Cl/CO(3)(2-) + HCO(3) and TA/TH. A proper management plan to cater potable water to the immediate needs of the people is to be envisaged. PMID- 22527454 TI - Spatial distribution and temporal trends of polycyclic aromatic hydrocarbons in Mytilus galloprovincialis from the Iberian Mediterranean coast. AB - Polycyclic aromatic hydrocarbons (PAHs) have been determined in blue mussels (Mytilus galloprovincialis) from several Iberian Mediterranean coastal areas through the implementation of a monitoring programme from Spain in the framework of the Mediterranean Pollution Programme (MED POL). The selected areas correspond to sites with differing degrees of exposure to the main pollution sources (hot spots, coastal and reference areas). The sampling campaigns were performed from 2004 to 2009, with samples being taken from May to June, the non-spawning period for mussels in this area. Thirteen PAHs were determined by high-performance liquid chromatography with specific fluorescence detection. In general, total PAHs concentration was lower than 50 MUg kg(-1) d.w., except in areas close to the principal ports and cities (Barcelona, Tarragona, Valencia and Algeciras) where it varies from 75 to 390 MUg kg(-1) d.w. Background concentrations have been proposed for PAHs in mussels (23.8 MUg kg(-1) d.w.) from Western Mediterranean area. Temporal trends were not statistically significant for PAHs concentrations from 2004 to 2009. Longer monitoring periods would be required to detect a continuous tendency, especially for PAHs because although the efficiency of combustion engines has reduced PAHs emissions, their increasing use could alter this potential reduction. The predominant PAHs were three and four ring congeners in all cases, with the predominance of phenanthrene in mussels sited far from the main PAHs sources. The phenanthrene/anthracene (lower than 10) and fluoranthene/pyrene (higher than 1) ratios indicate that PAHs detected in Spanish Mediterranean coastal mussels are mainly of pyrolytic origin. PMID- 22527451 TI - Cell-cell and cell-matrix dynamics in intraperitoneal cancer metastasis. AB - The peritoneal metastatic route of cancer dissemination is shared by cancers of the ovary and gastrointestinal tract. Once initiated, peritoneal metastasis typically proceeds rapidly in a feed-forward manner. Several factors contribute to this efficient progression. In peritoneal metastasis, cancer cells exfoliate into the peritoneal fluid and spread locally, transported by peritoneal fluid. Inflammatory cytokines released by tumor and immune cells compromise the protective, anti-adhesive mesothelial cell layer that lines the peritoneal cavity, exposing the underlying extracellular matrix to which cancer cells readily attach. The peritoneum is further rendered receptive to metastatic implantation and growth by myofibroblastic cell behaviors also stimulated by inflammatory cytokines. Individual cancer cells suspended in peritoneal fluid can aggregate to form multicellular spheroids. This cellular arrangement imparts resistance to anoikis, apoptosis, and chemotherapeutics. Emerging evidence indicates that compact spheroid formation is preferentially accomplished by cancer cells with high invasive capacity and contractile behaviors. This review focuses on the pathological alterations to the peritoneum and the properties of cancer cells that in combination drive peritoneal metastasis. PMID- 22527455 TI - Comparative bioaccumulation of trace metals using six filter feeder organisms in a coastal lagoon ecosystem (of the central-east Gulf of California). AB - The Tobari Lagoon, located in the central-east coast of the Gulf of California, receives effluents from the Yaqui Valley, one of the most extensive agricultural areas of Mexico. The Tobari Lagoon also receives effluents from nearby shrimp farms and untreated municipal sewage. Surface sediment samples and six different species of filter feeders (Crassostrea corteziensis, Crassostrea gigas, Chione gnidia, Anadara tuberculosa, Chione fluctifraga, and Fistulobalanus dentivarians) were collected during the dry and the rainy seasons and analyzed to determine concentrations of cadmium (Cd), copper (Cu), mercury (Hg), lead (Pb), and zinc (Zn). Seasonal variations in metal concentrations in sediment were evident, especially for Cd, Cu, Hg, and Zn. The total and bioavailable concentrations of the five metals are not elevated in comparison to other areas around the world. The percentages of bioavailable respect to total concentrations of the metals varied from 0.6 % in Hg to 50.2 % for Cu. In the organisms, Hg showed the lowest concentrations (ranged from 0.22 to 0.65 MUg/g) while Zn showed the highest (ranged from 36.6 to 1,702 MUg/g). Linear correlations between the levels of Cu, Pb, and Zn in the soft tissues of C. fluctifraga and C. gnidia, and A. tuberculosa and C. gnidia were found. Seasonal and interspecies variations in the metal levels in filter feeders were found; F. dentivarians, C. corteziensis, and C. gigas exhibited the highest levels, could be used as biomonitors of metals contamination in this area. PMID- 22527456 TI - Determination of Pb(II), Zn(II), Cd(II), and Co(II) ions by flame atomic absorption spectrometry in food and water samples after preconcentration by coprecipitation with Mo(VI)-diethyldithiocarbamate. AB - A new, simple, and rapid separation and preconcentration procedure, for determination of Pb(II), Cd(II), Zn(II), and Co(II) ions in environmental real samples, has been developed. The method is based on the combination of coprecipitation of analyte ions by the aid of the Mo(VI)-diethyldithiocarbamate (Mo(VI)-DDTC) precipitate and flame atomic absorption spectrometric determinations. The effects of experimental conditions like pH of the aqueous solution, amounts of DDTC and Mo(VI), standing time, centrifugation rate and time, sample volume, etc. and also the influences of some foreign ions were investigated in detail on the quantitative recoveries of the analyte ions. The preconcentration factors were found to be 150 for Pb(II), Zn(II) and Co(II), and 200 for Cd(II) ions. The detection limits were in the range of 0.1-2.2 MUg L(-1) while the relative standard deviations were found to be lower than 5 % for the studied analyte ions. The accuracy of the method was checked by spiked/recovery tests and the analysis of certified reference material (CRM TMDW-500 Drinking Water). The procedure was successfully applied to seawater and stream water as liquid samples and baby food and dried eggplant as solid samples in order to determine the levels of Pb(II), Cd(II), Zn(II), and Co(II) ions. PMID- 22527457 TI - Water quality of the Ribeirao Preto Stream, a watercourse under anthropogenic influence in the southeast of Brazil. AB - It is known that Brazil still has a privileged position of water quantity and quality, but water use has not proceeded in a responsible manner and often results in impairment of quality. This study aims to evaluate limnological parameters, parasites and bacteria, and concentrations of heavy metals (Cd, Pb, Cu, Cr, Mn, Hg, and Zn) in surface water of Ribeirao Preto Stream. The Ribeirao Preto Stream is located in urban areas under anthropogenic influence. The results showed that the levels of dissolved oxygen values were lower than those established by the National Environmental Council (CONAMA Resolution No 357/2005). The reading of electrical conductivity showed values typical of impacted environments. The parasitological analysis revealed the presence of nematode larvae. The bacteriological analysis showed higher values for total coliform and Escherichia coli than those set by the Brazilian National Environment Council (CONAMA). The heavy metals Cd, Pb, Cu, Cr, Mn, Hg, and Zn showed concentrations in accordance with the guidelines established by CONAMA. The results provide data on the quality of these waters and showed the necessity to protect the watercourse from point sources of contamination, recommending their continued monitoring. PMID- 22527458 TI - Heavy metals in the habitat and throughout the food chain of the Neotropical otter, Lontra longicaudis, in protected Mexican wetlands. AB - Top predators like the Neotropical otter, Lontra longicaudis annectens, are usually considered good bioindicators of habitat quality. In this study, we evaluated heavy metal contamination (Hg(tot), Pb, Cd) in the riverine habitat, prey (crustaceans and fish), and otter feces in two Ramsar wetlands with contrasting upstream contamination discharges: Rio Blanco and Rio Cano Grande in Veracruz, Mexico, during the dry, the wet, and the nortes seasons. Most comparisons revealed no differences between sites while seasonal differences were repeatedly detected for all of the compartments. Higher concentrations of Pb during the dry season and of Cd during the wet season in otter feces mirrored differences detected in the most seasonally consumed prey. Compared with fecal methylmercury values reported for the European otter (0.25-0.75 mg kg(-1)) in unprotected areas, the Hg(tot) levels that we measured were lower (0.02-0.17 mg kg(-1)). However, Pb (117.87 mg kg(-1)) and Cd (9.14 mg kg(-1)) concentrations were higher (Pb, 38.15 mg kg(-1) and Cd, 4.72 mg kg(-1)) in the two Ramsar wetlands. Protected areas may shelter species, but those with water-linked diets may suffer the effect of chemicals used upstream. PMID- 22527459 TI - Levels and distribution of PCDD/Fs, dl-PCBs, and organochlorine pesticides in sediments from the lower reaches of the Haihe River basin, China. AB - The concentrations of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), dioxin-like polychlorinated biphenyls (dl-PCBs), and organochlorine pesticides (OCPs) in surface sediments from the lower reaches of the Haihe River basin, northern China, were determined by high-resolution gas chromatograph-high resolution mass spectrometer. The concentrations of 2,3,7,8-substituted PCDD/Fs, dl-PCBs, and total OCPs [sum of hexachlorobenzene, hexachlorocyclohexanes, and dichlorodiphenyltrichloroethane (DDTs)] in 17 sediment samples were in the ranges of 11.6-1,180,924 pg/g dry weight (dw), 18.7-50,017 pg/g dw, and 1.7-35,280 ng/g dw, respectively. The contamination levels in the samples varied significantly between the different sites. Abnormally high concentrations of PCDD/Fs, dl-PCBs, and some OCPs were found in sediments from the lower reaches of the main channel of the Haihe River and the Dagu Drainage River, which were attributed to the historical production of pentachlorophenol and other pesticides near these locations. High levels of DDTs were detected in the Yongding New River sediment, which were likely to have originated from the discharge of wastewater from a dicofol factory upstream. In samples taken from other sites, the concentrations of these pollutants were at levels comparable to those documented in other areas of China. This preliminary investigation suggests that historical pesticide production in the Haihe River basin has contributed significantly to the contamination of this aquatic ecosystem and that further attention to this issue is warranted. PMID- 22527460 TI - Biomonitoring of heavy metals in fish from the Danube River. AB - The Croatian part of the Danube River extends over 188 km and comprises 58 % of the country's overall area used for commercial freshwater fishing. To date, the heavy metal contamination of fish in the Croatian part of the Danube has not been studied. The main purpose of this study was to determine heavy metal levels in muscle tissue of sampled fish species and to analyze the measured values according to feeding habits of particular groups. Lead ranged from 0.015 MUg(-1) dry weight in planktivorous to 0.039 MUg(-1) dry weight in herbivorous fish, cadmium from 0.013 MUg(-1) dry weight in herbivorous to 0.018 MUg(-1) dry weight in piscivorous fish, mercury from 0.191 MUg(-1) dry weight in omnivorous to 0.441 MUg(-1) dry weight in planktivorous fish and arsenic from 0.018 MUg(-1) dry weight in planktivorous to 0.039 MUg(-1) dry weight in omnivorous fish. Among the analyzed metals in muscle tissue of sampled fish, only mercury exceeded the maximal level (0.5 mg kg(-1)) permitted according to the national and EU regulations determining maximum levels for certain contaminants in foodstuffs, indicating a hazard for consumers of fish from the Danube River. PMID- 22527462 TI - A new multiscale approach for monitoring vegetation using remote sensing-based indicators in laboratory, field, and landscape. AB - Remote sensing is an important tool for studying patterns in surface processes on different spatiotemporal scales. However, differences in the spatiospectral and temporal resolution of remote sensing data as well as sensor-specific surveying characteristics very often hinder comparative analyses and effective up- and downscaling analyses. This paper presents a new methodical framework for combining hyperspectral remote sensing data on different spatial and temporal scales. We demonstrate the potential of using the "One Sensor at Different Scales" (OSADIS) approach for the laboratory (plot), field (local), and landscape (regional) scales. By implementing the OSADIS approach, we are able (1) to develop suitable stress-controlled vegetation indices for selected variables such as the Leaf Area Index (LAI), chlorophyll, photosynthesis, water content, nutrient content, etc. over a whole vegetation period. Focused laboratory monitoring can help to document additive and counteractive factors and processes of the vegetation and to correctly interpret their spectral response; (2) to transfer the models obtained to the landscape level; (3) to record imaging hyperspectral information on different spatial scales, achieving a true comparison of the structure and process results; (4) to minimize existing errors from geometrical, spectral, and temporal effects due to sensor- and time-specific differences; and (5) to carry out a realistic top- and downscaling by determining scale-dependent correction factors and transfer functions. The first results of OSADIS experiments are provided by controlled whole vegetation experiments on barley under water stress on the plot scale to model LAI using the vegetation indices Normalized Difference Vegetation Index (NDVI) and green NDVI (GNDVI). The regression model ascertained from imaging hyperspectral AISA-EAGLE/HAWK (DUAL) data was used to model LAI. This was done by using the vegetation index GNDVI with an R (2) of 0.83, which was transferred to airborne hyperspectral data on the local and regional scales. For this purpose, hyperspectral imagery was collected at three altitudes over a land cover gradient of 25 km within a timeframe of a few minutes, yielding a spatial resolution from 1 to 3 m. For all recorded spatial scales, both the LAI and the NDVI were determined. The spatial properties of LAI and NDVI of all recorded hyperspectral images were compared using semivariance metrics derived from the variogram. The first results show spatial differences in the heterogeneity of LAI and NDVI from 1 to 3 m with the recorded hyperspectral data. That means that differently recorded data on different scales might not sufficiently maintain the spatial properties of high spatial resolution hyperspectral images. PMID- 22527461 TI - Profile of PAHs in the inhalable particulate fraction: source apportionment and associated health risks in a tropical megacity. AB - The present study proposed to investigate the atmospheric distribution, sources, and inhalation health risks of polycyclic aromatic hydrocarbons (PAHs) in a tropical megacity (Delhi, India). To this end, 16 US EPA priority PAHs were measured in the inhalable fraction of atmospheric particles (PM(10); aerodynamic diameter, <= 10 MUm) collected weekly at three residential areas in Delhi from December 2008 to November 2009. Mean annual 24 h PM(10) levels at the sites (166.5-192.3 MUg m(-3)) were eight to ten times the WHO limit. Weekday/weekend effects on PM(10) and associated PAHs were investigated. Sigma(16)PAH concentrations (sum of 16 PAHs analyzed; overall annual mean, 105.3 ng m(-3); overall range, 10.5-511.9 ng m(-3)) observed were at least an order of magnitude greater than values reported from European and US cities. Spatial variations in PAHs were influenced by nearness to traffic and thermal power plants while seasonal variation trends showed highest concentrations in winter. Associations between Sigma(16)PAHs and various meteorological parameters were investigated. The overall PAH profile was dominated by combustion-derived large-ring species (85-87 %) that were essentially local in origin. Carcinogenic PAHs contributed 58 62 % to Sigma(16)PAH loads at the sites. Molecular diagnostic ratios were used for preliminary assessment of PAH sources. Principal component analysis coupled with multiple linear regression-identified vehicular emissions as the predominant source (62-83 %), followed by coal combustion (18-19 %), residential fuel use (19 %), and industrial emissions (16 %). Spatio-temporal variations and time evolution of source contributions were studied. Inhalation cancer risk assessment showed that a maximum of 39,780 excess cancer cases might occur due to lifetime inhalation exposure to the analyzed PAH concentrations. PMID- 22527463 TI - Environmental fate of chlorantraniliprole residues on cauliflower using QuEChERS technique. AB - Chlorantraniliprole, an anthranilic diamide insecticide with novel mode of action is found effective against several lepidopteran as well as coleopteran, dipteran, and hemipteran pests. The present studies were carried out to study the dissipation pattern of chlorantraniliprole on cauliflower and to suggest suitable waiting period for the safety of consumers. Quick, easy, cheap, effective, rugged, and safe method was used for the extraction and cleanup of samples and the residues of chlorantraniliprole were estimated using high-performance liquid chromatograph (HPLC) and confirmed by liquid chromatograph-mass spectrometer and high-performance thin layer chromatograph. Following three applications of chlorantraniliprole (Coragen 18.5 SC) at recommended dose (9.25 g a.i. ha(-1)) and double the recommended dose (18.50 g a.i. ha(-1)), the average initial deposits of chlorantraniliprole were observed to be 0.18 and 0.29 mg kg(-1), respectively. These deposits were found to be less than the maximum residue limit of 2.0 mg kg(-1) prescribed by the Codex Alimentarius Commission. These residues dissipated below the limit of quantification of 0.10 mg kg(-1) after 3 and 5 days at recommended and double the recommended dosages, respectively. The half-life value (T (1/2)) of chlorantraniliprole was worked out to be 1.36 days following its application at recommended dosages. Hence, the use of this pesticide at recommended dosages does not seem to pose any risk, and a waiting period of 1 day is suggested for safe consumption of cauliflower curds. PMID- 22527464 TI - Particulate matter concentration in ambient air and its effects on lung functions among residents in the National Capital Region, India. AB - The World Health Organization has estimated that air pollution is responsible for 1.4 % of all deaths and 0.8 % of disability-adjusted life years. NOIDA, located at the National Capital Region, India, was declared as one of the critically air polluted areas by the Central Pollution Control Board of the Government of India. Studies on the relationship of reduction in lung functions of residents living in areas with higher concentrations of particulate matter (PM) in ambient air were inconclusive since the subjects of most of the studies are hospital admission cases. Very few studies, including one from India, have shown the relationship of PM concentration and its effects of lung functions in the same location. Hence, a cross-sectional study was undertaken to study the effect of particulate matter concentration in ambient air on the lung functions of residents living in a critically air-polluted area in India. PM concentrations in ambient air (PM(1,) PM(2.5)) were monitored at residential locations and identified locations with higher (NOIDA) and lower concentrations (Gurgaon). Lung function tests (FEV(1), PEFR) were conducted using a spirometer in 757 residents. Both air monitoring and lung function tests were conducted on the same day. Significant negative linear relationship exists between higher concentrations of PM(1) with reduced FEV(1) and increased concentrations of PM(2.5) with reduced PEFR and FEV(1). The study shows that reductions in lung functions (PEFR and FEV(1)) can be attributed to higher particulate matter concentrations in ambient air. Decline in airflow obstruction in subjects exposed to high PM concentrations can be attributed to the fibrogenic response and associated airway wall remodeling. The study suggests the intervention of policy makers and stake holders to take necessary steps to reduce the emissions of PM concentrations, especially PM(1,) PM(2.5), which can lead to serious respiratory health concerns in residents. PMID- 22527465 TI - Heavy metals partitioning in sediments of the Kabini River in South India. AB - Cu, Cr, Fe, Mn, Ni, Pb, and Zn in the sediments of the Kabini River, Karnataka, India was studied to determine the association of metal with various geochemical phases by sequential extraction. The variations of heavy metal concentration depend on the lithology of the river basin and partly on anthropogenic activities. The Kabini River sediments are dominated by Sargur supracrustals with amphibolites, gneisses, carbonates, and ultrabasic rocks weathering into gneissic and serpentine soils carrying a natural load of cationic heavy metals. The source of heavy metals in the Kabini riverbed sediments is normally envisaged as additional inputs from anthropogenic over and above natural and lithogenic sources. Geochemical study indicates the metals under study were present mostly in the least mobilizable fraction in the overlying water and it is concluded that heavy metals in these sediments are to a great extent derived from multisource anthropogenic inputs besides geochemical background contributions The results show that lead and chromium have higher potential for mobilization from the sediment due to higher concentration at the exchangeable ion and sulfide ion bounded, also Cu and Pb have the greatest percentage of carbonate fraction, it means that the study area received inputs from urban and industrial effluents. Association of the Fe with organic matter fraction can be explained by the high affinity of these elements for the humic substances. Further, Zn and Ni reveal a significant enrichment in sediment and it is due to release of industrial wastewater into the river. These trace metals are possible contaminants to enter into aquatic and food chain. PMID- 22527466 TI - Influences of urban wastewaters on the stream water quality: a case study from Gumushane Province, Turkey. AB - Urban wastewater in Turkey is primarily discharged without treatment to marine environments, streams and rivers, and natural and artificial lakes. Since it has been well established that untreated effluent in multi-use waters can have acute and chronic impacts to both the environment and human health, it is important to evaluate the consequences of organic enrichment relative to the structure and function of aquatic environment. We investigated the impacts of untreated municipal wastewater discharge from the city of Gumushane in the Eastern Black Sea Region of Turkey on the surface water quality of the stream Harsit. Several key water-quality indicators were measured: chemical oxygen demand (COD), ammonium nitrogen (NH (4)(+)-N), nitrite nitrogen (NO(2)(-)-N), nitrate nitrogen (NO(3)(-)-N), total Kjeldahl nitrogen (TKN), total nitrogen (TN), orthophosphate phosphorus (PO(4)(3-)-P), methylene blue active substances (MBAS), water temperature (t), pH, dissolved oxygen (DO), and electrical conductivity (EC). The monitoring and sampling studies were conducted every 15 days from March 2009 to February 2010 at three longitudinally distributed stations. While t, pH, DO, and EC demonstrated relatively little variability over the course of the study, other parameters showed substantial temporal and spatial variations. The most dramatic differences were noted in COD, NH(4)(+)-N, NO(2)(-)-N, TKN, TN, PO(4)(3-) P, and MBAS immediately downstream of the wastewater discharge. Concentration increases of 309 and 418 % for COD, 5,635 and 2,162 % for NH (4)(+)-N, 2,225 and 674 % for NO(2)(-)-N, 283 and 478 % for TKN, 208 and 213 % for PO(4)(3-)-P, and 535 and 1,260 % for MBAS were observed in the summer and autumn, respectively. These changes were associated with greatly diminished seasonal stream flows. Based on NO(2)(-)-N, TKN, PO(4)(3-) P, and MBAS concentrations, it was concluded that Harsit stream water was correctly classified as polluted. The most telling parameter, however, was NH (4) (+) -N, which indicated highly polluted waters in both the summer and autumn. The elevated concentrations of both P and N in the downstream segment of the stream triggered aggressive growth of submerged algae. This eutrophication of river systems is highly representative of many urban corridors and is symptomatic of ongoing organic enrichment that must be addressed through improved water treatment facilities. PMID- 22527467 TI - Distribution of natural radionuclides in surface soils in the vicinity of abandoned uranium mines in Serbia. AB - The activity concentrations of natural radionuclides in soils from the area affected by uranium mining at Stara Planina Mountain in Serbia were studied and compared with the results obtained from an area with no mining activities (background area). In the affected area, the activity concentrations ranged from 1.75 to 19.2 mg kg(-1) for uranium and from 1.57 to 26.9 mg kg(-1) for thorium which is several-fold higher than those in the background area. The Th/U, K/U, and K/Th activity ratios were also determined and compared with data from similar studies worldwide. External gamma dose rate in the air due to uranium, thorium, and potassium at 1 m above ground level in the area affected by uranium mining was found to be 91.3 nGy h(-1), i.e., about two-fold higher than that in background area. The results of this preliminary study indicate the importance of radiological evaluation of the area and implementation of remedial measures in order to prevent further dispersion of radionuclides in the environment. PMID- 22527468 TI - Depurated fish as an alternative reference for field-based biomarker monitoring. AB - The whole of the Swan-Canning Estuary, in the south-west of Australia, is impacted by human activity, and the selection of a local reference site to assess the impact of environmental contamination on the health of biota is not possible. To determine whether fish depurated under laboratory conditions could be used as an alternative to a reference site; adult black bream (Acanthopagrus butcheri) were collected from the estuary and maintained in clean water (S24) for 3 months. A suite of biomarkers of fish health were assessed, and the results were compared with field-captured black bream from three sites within the estuary (Ascot, Claisebrook, and Riverton). Comparisons of a subset of biomarkers were also made between hatchery-bred juvenile fish and the depurated fish. Biomarker levels were up to 3.8 times higher in field captured fish compared with depurated fish, while DNA integrity was lower. EROD activity was comparable in the hatchery-bred black bream to the depurated fish while s-SDH levels were two times higher in the hatchery fish. From the results obtained, field-captured black bream depurated for 3 months are suitable to determine reference/baseline levels for biomarker of health studies in estuarine environments. PMID- 22527469 TI - Determination of an acceptable assimilable organic carbon (AOC) level for biological stability in water distribution systems with minimized chlorine residual. AB - There is considerable interest in minimizing the chlorine residual in Japan because of increasing complaints about a chlorinous odor in drinking water. However, minimizing the chlorine residual causes the microbiological water quality to deteriorate, and stricter control of biodegradable organics in finished water is thus needed to maintain biological stability during water distribution. In this investigation, an acceptable level of assimilable organic carbon (AOC) for biologically stable water with minimized chlorine residual was determined based on the relationship between AOC, the chlorine residual, and bacterial regrowth. In order to prepare water samples containing lower AOC, the fractions of AOC and biodegradable organic matter (BOM) in tap water samples were reduced by converting into biomass after thermal hydrolysis of BOM at alkaline conditions. The batch-mode incubations at different conditions of AOC and chlorine residual were carried out at 20 degrees C, and the presence or absence of bacterial regrowth was determined. The determined curve for biologically stable water indicated that the acceptable AOC was 10.9 MUg C/L at a minimized chlorine residual (0.05 mg Cl(2)/L). This result indicated that AOC removal during current water treatment processes in Japan should be significantly enhanced prior to minimization of the chlorine residual in water distribution. PMID- 22527470 TI - Impact of urbanization on the concentrations and distribution of organic contaminants in boreal lake sediments. AB - The main goal of this study was to evaluate the impacts of a middle-sized Finnish urban area on the quality of sediments in an adjacent boreal lake. We investigated the sources and distribution of organic pollutants (polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs)) in the sediments from urban stormwater traps and from Lake Vesijarvi. Grab surface sediment samples were taken from Lake Vesijarvi at various distances (25-2,000 m) from four major stormwater drainage outlets and at 15 urban stormwater traps in areas with different degrees of urbanization. These samples were analysed for 16 PAHs and 28 PCBs with gas chromatography-mass spectrometry. The concentrations of pollutants in the lake sediments were elevated in the vicinity of the urban shore (?PAH 3-16, ?PCB up to 0.02-0.3 mg/kg dw) and decreased as a function of distance (?PAH 0.1-2.5, ?PCB 0.01-0.3 mg/kg dw at a distance of more than 500 m from the shore), whereas contamination levels in suburban areas were notably lower (?PAH 0.1-3, ?PCB < LOQ-0.03 mg/kg dw; did not decline with distance). Possible sources and pathways of contamination were also investigated. The majority of stormwater trap sediments contained predominantly asphalt-derived PAHs due to pulverized pavement. PAHs in lake sediments were of pyrogenic origin, including the combustion of gasoline, diesel and coal. Suggested pathways of lake contamination are urban runoff discharge, boat traffic and atmospheric deposition. PMID- 22527471 TI - Spatial distribution and seasonal variation of polycyclic aromatic hydrocarbons (PAHs) contaminations in surface water from the Hun River, Northeast China. AB - The objectives of this study were to investigate the levels, dispersion patterns, seasonal variation, and sources of 16 priority polycyclic aromatic hydrocarbons (16 EPA-PAHs) in the Hun River of Liaoning Province, China. Samples of surface water were collected from upstream to downstream locations, and also from the main tributaries of the Hun River in dry period, flood period, and level period, respectively. After appropriate preparation, all samples were analyzed for 16 EPA PAHs. Total PAHs concentrations varied from 124.55 to 439.27 ng l(-1) in surface water in dry period, 1,615.75 to 5,270.04 ng l(-1) in flood period, and 2,247.42 to 7,767.9 ng l(-1) in level period. The 16 EPA-PAHs concentrations were significantly increased in the order of level period > flood period > dry period. The composition pattern of PAHs in surface water was dominated by low molecular weight PAHs, in particular two- to three-ring PAHs. In addition, two-ring PAH accounted for 39.33 to 88.27 % of the total PAHs in level period. Low molecular weight PAHs predomination together with higher levels of PAHs in flood and level period suggested a relatively recent local source of PAHs. Special PAHs ratios such as phenanthrene/anthracene and fluoranthene/pyrene indicated that under dry weather season conditions, the PAHs found in surface water were primarily from petrogenic source, while under wet weather season conditions they were from mixed source of both petrogenic inputs and combustion sources. The comparison of PAHs contamination among different types of areas in China suggested that atmospheric depositions might be the most important approaches of PAHs into water system. Although the Hun River exists low PAHs ecological risk now, potential toxic effects will be existed in the future especially in flood and level period. PMID- 22527472 TI - Heavy metals in urban ambient PM10 and soil background in eight cities around China. AB - The ambient PM(10) and background soil samples were collected and analyzed with ICP-AES in eight cities around China to investigate the levels of ten heavy metals (Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, and Pb). The mean concentrations of ten heavy metals in PM(10) of the eight cities of China followed the order of Zn > Pb > Mn > Cu > Ni > Cr > Co > V. The metals in the ambient PM(10) and soil were compared in each city to evaluate the heavy metal mass fraction from anthropogenic sources in ambient air. The CD values in these cities were all above 0.2, indicating that the ingredients spectrums of PM(10) and soil vary markedly. Most heavy metals were enriched in PM(10), except Fe and Ti. The results showed that almost all the cities suffer important heavy metal pollution from anthropogenic sources. The eight cities were also grouped according to their similarity in heavy metals of ambient PM(10) by cluster analysis to investigate the relationship between the heavy metals and the pollution sources of each city. The conclusion was that the eight cities were divided into three clusters which had similar industrial type and economy scale: the first cluster consisted of Shenzhen, Wuxi, and Guiyang; followed by Jinan and Zhengzhou as the second grouping; and the third group had Taiyuan, Urumqi, and Luoyang. PMID- 22527473 TI - Dissipation of flubendiamide residues in/on cabbage (Brassica oleracea L.). AB - Residues of fubendiamide and its metabolite desiodo flubendiamide were estimated in cabbage and soil using high-performance liquid chromatography with UV-vis detector. The initial deposits of flubendiamide residues on cabbage were found to be 0.16 and 0.31 MUg g(-1) following two applications of flubendiamide 20 WG at 12.5 (standard dose) and 25 (double dose) g a.i. ha(-1) respectively at 10-days interval. The half-life values (t(1/2)) of flubendiamide on cabbage ranged from 3.4 to 3.6 days. When flubendiamide applied at both the standard and double dose, no detectable residues were found in cabbage and soil at harvest. Thus, a waiting period of 1.63 days was suggested for the safe consumption of flubendiamide treated cabbage. These data could provide guidance for the proper and safe use of this pesticide on cabbage crops in India. PMID- 22527474 TI - Preventable drug-related morbidity in community pharmacy: development and piloting of a complex intervention. AB - BACKGROUND: Preventable drug-related morbidity (PDRM) arising in the community is a problem of unacceptable magnitude. Effective interventions to reduce this problem will avoid unnecessary patient harm and waste of resources for the health care system. OBJECTIVE: To develop and pilot an intervention to manage the risk of PDRM in community pharmacy, underpinned by validated PDRM indicators. Setting Portuguese community pharmacy. METHOD: Our work was informed by the Medical Research Council framework for the development and evaluation of complex interventions. Human error theory was considered as a theoretical framework for developing the intervention. Additionally, this stage consisted of a literature review, followed by two focus groups (17 community pharmacists) and interviews with 8 professional leaders. A 4-component intervention, was developed: (1) operationalisation of 4 validated PDRM indicators in dispensing encounters ('dispensing' indicators), and operationalisation of 25 validated indicators in patients enrolled in pharmaceutical care programmes ('follow-up' indicators), (2) pharmacist resource pack, (3) pharmacists' training and (4) support scheme. Piloting consisted of a feasibility study in 15 community pharmacies and an acceptability study with participating pharmacists (n = 16). Main outcome measures Proportion of cases with counselling (dispensing indicators); proportion of cases assessable, proportion of cases at risk and proportion of cases with risk minimisation actions (follow-up indicators). RESULTS: Operationalization of dispensing indicators resulted in counselling in 44.1 % of cases (n = 666). Factors influencing acceptability included pharmacists' perceptions of patients' characteristics, interest and informational needs, as well as perceptions on the relevance of safety information. For follow-up indicators, data were available to assess most cases (93/105, 88.6 %). About half of the assessable cases were at risk of a PDRM event (n = 49; 51.6 %); pharmacists undertook risk minimization actions in 23 cases (46.9 %). Lack of time and inter-professional issues emerged as important factors influencing acceptability. CONCLUSIONS: A novel risk management intervention was developed. Feasibility and acceptability of the 4 component intervention in Portuguese community pharmacy provided 'proof of concept', whilst highlighting aspects that need further refinement to better measure and maximise efficacy in future evaluative research. PMID- 22527475 TI - Acute myocardial infarction and subacute stent thrombosis associated with cabazitaxel: a case report. AB - CASE: Although newer cancer treatments and supportive care treatments have led to vast improvements in the management of complications associated with cancer treatment, sometimes they might cause serious side effects such as coronary artery disease, myocardial infarction and heart failure. These complications may occur any time during or after chemotherapeutics. In this report we present a patient with prostate cancer who experienced myocardial infarction and stent thrombosis probably caused by cabazitaxel -a new chemotherapeutic agent- administration. CONCLUSION: Cardiologists and oncologists should take into consideration the cardiac side effects of new chemotherapeutic agents with the aim of maximizing both quality of life and survival. PMID- 22527476 TI - Impact of an interactive workshop on community pharmacists' beliefs toward patient care. AB - BACKGROUND: Patient assessment and documentation are less than optimal in pharmacy practice as preparing and dispensing medications is still a major part of community pharmacy practice. Pharmacists' attitudes, specifically self efficacy and role beliefs, toward practice have been shown to predict practice change. OBJECTIVE: This study will determine the impact of an interactive workshop on pharmacists' attitudes toward assessment and documentation in routine pharmacy practice. Specific objectives included how (1) pharmacists' role beliefs and self-efficacy toward assessment and documentation change after training and rehearsal and (2) frequently do pharmacists assess patient therapy and document patient care? SETTING: "Chat, Check and Chart: patient assessment and documentation demystified" workshop Alberta College of Pharmacists Annual General Meeting in Calgary, Canada. METHODS: This study is pre-post evaluation. Quantitative data on self-efficacy and role beliefs toward assessment and documentation was gathered from a validated written survey. Surveys were completed before and after the intervention. The intervention, an interactive workshop, focused on the use of three tools practice and was designed to support pharmacists in achieving the assessment and documentation required by the Alberta College of Pharmacists Standards for Practice. MAIN OUTCOME MEASURE: Pharmacists' role beliefs and self-efficacy toward assessment and documentation in patient care. RESULTS: Of the 61 eligible pharmacists, the response rate was 61 % (37 pharmacists) with complete data. In the past 2 weeks, 54 % of pharmacists were assessing patients and 32.6 % of pharmacists were documenting greater than half the time. Prior to the workshop, pharmacists "agreed" (5.42 +/- 1.41) with their role in patient assessment and they were "quite sure" (4.75 +/- 1.10) they could assess patients. Pharmacists "agreed" (5.13 +/- 0.890) with their overall role in documentation of patient interactions and reported lower self-efficacy (3.88 +/- 1.32) for their ability to document patient interactions. After the interactive workshop, there were statistically significant increases in pharmacists' self efficacy and role beliefs in regards to both patient assessment and documentation (p < 0.05). CONCLUSION: This brief interactive workshop increased both self efficacy and role beliefs towards assessment and documentation, indicating these pharmacists are likely to change future practice. Future research will assess practice uptake and implementation. PMID- 22527477 TI - Physicians and pharmacists: collaboration to improve the quality of prescriptions in primary care in Mexico. AB - BACKGROUND: Inappropriate prescription is a relevant problem in primary health care settings in Mexico, with potentially harmful consequences for patients. OBJECTIVE: To evaluate the effectiveness of incorporating a pharmacist into primary care health team to reduce prescription errors for patients with diabetes and/or hypertension. SETTING: One Family Medicine Clinic from the Mexican Institute of Social Security in Mexico City. METHOD: A "pharmacotherapy intervention" provided by pharmacists through a quasi experimental (before-after) design was carried out. Physicians who allowed access to their diabetes and/or hypertensive patients' medical records and prescriptions were included in the study. Prescription errors were classified as "filling", "clinical" or "both". Descriptive analysis, identification of potential drug-drug interactions (pD-DI), and comparison of the proportion of patients with prescriptions with errors detected "before" and "after" intervention were performed. MAIN OUTCOME MEASURE: Decrease in the proportion of patients who received prescriptions with errors after the intervention. RESULTS: Pharmacists detected at least one type of error in 79 out of 160 patients. Errors were "clinical", "both" and "filling" in 47, 21 and 11 of these patient's prescriptions respectively. Predominant errors were, in the subgroup of patient's prescriptions with "clinical" errors, pD-DI; in the subgroup of "both" errors, lack of information on dosing interval and pD-DI; and in the "filling" subgroup, lack of information on dosing interval. The pD-DI caused 50 % of the errors detected, from which 19 % were of major severity. The impact of the correction of errors post-intervention was observed in 19 % of patients who had erroneous prescriptions before the intervention of the pharmacist (49.3-30.3 %, p < 0.05). CONCLUSION: The impact of the intervention was relevant from a clinical point of view for the public health services in Mexico. The implementation of early warning systems of the most widely prescribed drugs is an alternative for reducing prescription errors and consequently the risks they may cause. PMID- 22527478 TI - Telbivudine myopathy in a patient with chronic hepatitis B. AB - CASE: A 25-year-old man with hepatitis B virus (HBV) infection received antiviral treatment with telbivudine 600 mg daily. Six months after starting treatment, the patient developed progressive weakness and myalgia. Physical examination showed symmetrical proximal weakness. Blood tests at admission revealed positive hepatitis b surface antigen (HBs Ag), and, elevated creatine kinase (CK) level (1,614 U/L, normal range: 38-174 U/L). Aspartate aminotransferase was 64.7 U/L (normal range: 8-40 U/L), and LDH was 293 U/L (normal range: 80-285 U/L). Electrodiagnostic studies indicated myopathic changes. A muscle biopsy revealed myositis and no mitochondrial changes were found. Drug-induced myopathy was suspected and telbivudine was changed to entecavir. The muscle weakness and laboratory findings improved. CONCLUSION: A patient developed drug-induced myopathy during long-term treatment with telbivudine for chronic HBV. To promptly detect this reversible adverse event, monitoring of serum CK level and recognition of myopathic signs and symptoms are necessary. Further investigations are needed to clarify the possible mechanism of telbivudine-induced myopathy. PMID- 22527479 TI - Review of services provided by pharmacies that promote healthy living. AB - BACKGROUND: The recognition that community pharmacies have the potential to make a greater contribution to promoting public health has led to a new concept, called the Healthy Living Pharmacy (HLP). These are designed to meet public health needs through a tiered commissioning framework delivering health and well being services through community pharmacy, tailored to local requirements for tackling health inequalities. AIM: To search the literature for quality evidence to support the inclusion of services in the HLP portfolio and suggest areas where more evidence is required. METHOD: A systematic review of the research literature covering the period January 1990-August 2011 inclusive, using MEDLINE, EMBASE, Pharmline, NHS Evidence and the Cochrane databases. On-line searching of the grey literature (e.g. conference proceedings) was also carried out. Standard methods of assessing quality were employed. RESULTS: A total of 377 papers were included. Over time, there was a marked increase in frequency of publications reflecting a growing pharmacy interest in the public healthcare agenda; over a third (35 %) of papers appeared in the last three-year study period. The body of research had a wide geographical basis; contributions were as follows: UK (51.5 %), US (20.4 %), Australia/New Zealand (9.8 %), Europe (7.7 %) and Canada (7.2 %). The topics of contraception, cardiovascular disease prevention, diabetes and smoking cessation accounted for 40 % of included papers. The literature supports the introduction of specific community pharmacy services, targeted at customer groups, both with and without pre-existing diseases. Good evidence exists for smoking cessation, cardiovascular disease prevention, hypertension and diabetes. Some good evidence exists for interventions on asthma and heart failure. The evidence supporting weight management, sexual health, osteoporosis detection, substance abuse and chronic obstructive pulmonary disease is weak and needs development. CONCLUSION: There is strong evidence for the role of community pharmacy in a range of services, not only aimed at improving general health, but also maintaining the health of those with existing disease. In other areas, the evidence is less strong and further research is required to justify their inclusion in a HLP portfolio. PMID- 22527480 TI - Prescribing omissions in elderly patients admitted to a stroke unit: descriptive study using START criteria. AB - BACKGROUND: Underuse of medication considered beneficial is particularly common in elderly patients. A new Screening Tool to Alert Doctors to the Right Treatment (START) has been published to identify potential prescribing omissions. OBJECTIVE: To quantify and characterize potential prescribing omissions of cardiovascular risk management therapy using START criteria. SETTING: This study was conducted in the Stroke Unit of the university teaching hospital of Cova da Beira Hospital Centre, Covilha, located in the Eastern Central Region of Portugal. METHOD: During 6 months, the medical files of all elderly patients (age >= 65 years) admitted with acute cardiovascular disease were reviewed and the START criteria applied to the information of medication, at admission and at the time of discharge from the hospital Stroke Unit. MAIN OUTCOME MEASURE: Potential prescribing omissions of cardiovascular and endocrine pharmacological therapy were identified and the difference in the potential prescribing omissions between admission and discharge from hospital Stroke Unit was also evaluated. RESULTS: At the time of admission to the Stroke Unit, 101 potential prescribing omissions were found in 68.1 % (n = 91) of elderly (average 1.11 omissions per patient), of which 84.2 % (n = 85) were corrected at the time of discharge. In 14 patients, 16 omissions found at admission were not corrected during hospitalization, and in 5 patients 5 new omissions were detected. CONCLUSION: Prescribing omissions of beneficial drugs are highly prevalent in acutely ill admitted to a Stroke Unit. START criteria represent a simple, evidence-based and easy-to-use tool to screen underuse of cardiovascular risk management therapy in elderly patients. PMID- 22527481 TI - Evaluation of educational needs in patients with diabetes mellitus in respect of medication use in Austria. AB - BACKGROUND: Effective control of diabetes mellitus type 1 (DM1) and type 2 (DM2) can reduce the development and progression of diabetic complications. Therefore, patient education should be considered as an integral part of diabetes management. OBJECTIVE: The aim of the study was to assess DM patients' perception of knowledge for their medication and attitude towards self-management and pharmacist's role. SETTING: The study was conducted at the diabetes out-patient clinic at the Vienna General Hospital (AKH), Division of Endocrinology and Metabolism, Department of Internal Medicine III, Austria. METHOD: The study was a cross sectional survey using patient data from a validated patient questionnaire and medical records. Medical records were evaluated by applying a medication assessment tool. MAIN OUTCOME MEASURE: To assess the quality of diabetes self management the following outcome measures are considered: HbA1c levels, pre- and post-prandial blood glucose levels, prevention of acute episodes of hypo- and hyperglycaemia, reduction of macrovascular risk factors, short term quality of life, adverse effects and treatment tolerance. RESULTS: The present study comprised 225 patients with DM1 and 201 patients with DM2, respectively. In comparison to DM2 patients, cardio- and cerebrovascular diseases were diagnosed very rarely in patients with DM1. The risk for these diseases was higher in patients with other factors of the metabolic syndrome, in addition. Overall, 118 of these patients participated in the questionnaire. The level of positive response on diabetes self-care and knowledge with respect to medication for the prevention of diabetes complications, glycaemic control, and treatment goals in diabetes was 81.8 %. The comparison of patients' perceptions of diabetes self care and knowledge showed differences among subgroups. Higher perceived knowledge and self-care apparently was associated with DM1. Additional findings of this study indicate that patients do not expect community pharmacists to be integrated in a multidisciplinary diabetes care team. CONCLUSION: Although the level of positive response was found to be high there is still a minority of patients whose level of comprehension appears to be insufficient. Intense pharmaceutical care including patients' education within a multidisciplinary team could contribute to improvements in those patients. PMID- 22527483 TI - Characteristics of HIV patients referred to a medication adherence program in Switzerland. AB - BACKGROUND: Since August 2004, HIV patients who encounter -or are at risk of problems with their antiretroviral treatment (ART) are referred by their physician to a medication adherence program at the community pharmacy of the Department of Ambulatory Care and Community Medicine in Lausanne (Switzerland). The program combines motivational interviewing and electronic drug monitoring. OBJECTIVE: To compare the demographic and clinical characteristics as well as ART of HIV patients referred to the adherence program versus those of the entire HIV population followed in the same infection disease department in the same time frame. METHOD: Retrospective descriptive cross-sectional study. Study time frame was defined according to the period with the highest number of HIV patients visiting the adherence program. RESULTS: Subjects included in the adherence program had more often a protease inhibitor-based regimen (64 %; 95 % CI [52-75 %] vs. 37 %) and lower CD4 cell counts (419 (252.0, 521.0); 95 % CI [305-472] vs. 500 (351.0, 720.0)) than the entire HIV population. A majority of women were included in the adherence program (66 %; 95 % CI [54-76 %] vs. 39% in the entire HIV population). CONCLUSION: Subjects referred to the adherence program were different from the entire HIV population and showed worse clinical outcomes and were more often under salvage therapy. More women than men were included. Reasons for such a difference need to be further explored. PMID- 22527482 TI - Outpatient parenteral antimicrobial therapy with ceftriaxone, a review. AB - BACKGROUND: More than 30 years since it was developed for clinical use, the third generation cephalosporin ceftriaxone remains the most commonly used agent for outpatient parental antimicrobial therapy (OPAT). Recent antimicrobial stewardship programmes have tended to restrict ceftriaxone use in hospitals to control antibiotic resistance and outbreaks of Clostridium difficle infection (CDI). Considering the expansion of OPAT programmes both in the UK and worldwide, revisiting the role of ceftriaxone in OPAT in the context of changing antimicrobial prescribing practices is timely. AIM OF THE REVIEW: To identify the evidence base for OPAT, review current and historical data on indications for, and safety of ceftriaxone within the OPAT setting, and to provide some perspectives on the future role of ceftriaxone. METHOD: We searched PubMed and Scopus for articles published in English, and hand searched reference lists. We also conducted a complementary descriptive analysis of prospectively acquired data on the use of ceftriaxone in more than 1,300 OPAT episodes over a 10-year period in our UK centre. RESULTS: Ceftriaxone has an excellent safety profile in the OPAT setting, and its broad spectrum of activity makes it an established agent in a wide range of clinical infection syndromes, such as skin and soft tissue infection, bone and joint infection, streptococcal endocarditis and several others. Intriguingly, in contrast to the inpatient setting, liberal use of ceftriaxone in OPAT has not been strongly linked to CDI, suggesting additional patient and environmental factors may be important in mediating CDI risk. PMID- 22527484 TI - Turkish pharmacists' counseling practices and attitudes regarding emergency contraceptive pills. AB - OBJECTIVE: The aim of this study is to assess Turkish pharmacists' counseling practices and attitudes regarding emergency contraception pills (ECPs). SETTING: This cross-sectional observational study was conducted via a web-based survey in Turkey. METHODS: Pharmacists registered at a professional web site (n = 822) were invited to fill in the study questionnaire; 624 questionnaires were completed and further analyzed. Pharmacists who agreed to participate in the study completed the questionnaire which was structured to elicit their demography, professional experience, counseling practices and attitudes regarding ECP. Attitudes were measured by 18 items under four domains: "reproductive health; information and availability; risk behavior and regulatory restrictions". The answer choices consisted of five items as: "totally agree, agree, neither agree nor disagree, disagree and totally disagree". MAIN OUTCOME MEASURES: The rate of counseling on various aspects of the ECPs and the rate of negative/positive attitudes. RESULTS: The aspects most frequently counseled on by the pharmacists were dosage, timeframes, efficacy and pregnancy testing. Less frequently counseled aspects were mechanism of action, methods of contraception and side-effects. In general, the pharmacists displayed positive attitudes towards all domains of the survey; while they were negative to the items suggesting that ECP should be sold only to women and only on prescription. Another interesting finding is that 58 % of the pharmacists agreed with the item suggesting limiting the ECP sales to those over 18 years of age. CONCLUSIONS: Our results showed that the pharmacists served the clients in need of emergency contraception more frequently than the other health care providers and in general had favorable attitudes towards ECP. Some aspects of their counseling practices need to be improved. This can be accomplished through continuous education programs that would equip them with the competence to provide counseling on emergency contraception which will in turn help prevent unintended pregnancies and reduce abortion rates. PMID- 22527486 TI - Identification of polymorphisms in genes of the immune system in cynomolgus macaques. AB - Cynomolgus macaques are a standard species used preclinically for evaluating efficacy and toxicity of therapeutic drug candidates and vaccines. However, findings from preclinical studies conducted in cynomolgus macaques are often highly variable, which may in part be attributed to genetic diversity. In this study, genetic polymorphisms were identified in 49 genes of the immune system using DNA isolated from 40 cynomolgus macaques. Of these, 20 originated from a breeding center in China and 20 were of Mauritian origin. A total of 580 polymorphisms were identified, including 561 SNPs, 9 deletions, and 10 insertions with minor allele frequencies ranging from 0.03 to 0.5. Of these genes, 92 % had a SNP distribution frequency >1 per 1,000 bp, illustrating that genes of the immune system in cynomolgus macaques are highly polymorphic. There were 551 common SNPs between the Chinese and Mauritian populations, demonstrating a surprisingly high level of conservation. In silico tools were employed to predict the functional consequences for 264 nonintronic polymorphisms identified. Five polymorphisms were predicted to alter binding of one or more transcription factors, and four were predicted to interfere with miRNA target sites. Additionally, 107 were identified to be nonsynonymous polymorphisms with one causing a frameshift in protein sequence (20,787C deletion in TGF-beta1) and three generating premature stop codons (11,990 C>T in IFN-gammaR2, 11174 C>T in CR1, and 3477 G>T in CTLA-4). Understanding polymorphisms present in cynomolgus macaque genes and their functional consequences will enhance understanding and interpretation of data from preclinical studies conducted in this species. PMID- 22527487 TI - Co-expression of soybean Dicer-like genes in response to stress and development. AB - Regulation of gene transcription and post-transcriptional processes is critical for proper development, genome integrity, and stress responses in plants. Many genes involved in the key processes of transcriptional and post-transcriptional regulation have been well studied in model diploid organisms. However, gene and genome duplication may alter the function of the genes involved in these processes. To address this question, we assayed the stress-induced transcription patterns of duplicated gene pairs involved in RNAi and DNA methylation processes in the paleopolyploid soybean. Real-time quantitative PCR and Sequenom MassARRAY expression assays were used to profile the relative expression ratios of eight gene pairs across eight different biotic and abiotic stress conditions. The transcriptional responses to stress for genes involved in DNA methylation, RNAi processing, and miRNA processing were compared. The strongest evidence for pairwise co-expression in response to stresses was exhibited by non-paralogous Dicer-like (DCL) genes GmDCL2a-GmDCL3a and GmDCL1b-GmDCL2b, most profoundly in root tissues. Among homoeologous or paralogous DCL genes, the Dicer-like 2 (DCL2) gene pair exhibited the strongest response to stress and most conserved co expression pattern. This was surprising because the DCL2 duplication event is more ancient than the other DCL duplications. Possible mechanisms that may be driving the DCL2 co-expression are discussed. PMID- 22527485 TI - New mouse models for metabolic bone diseases generated by genome-wide ENU mutagenesis. AB - Metabolic bone disorders arise as primary diseases or may be secondary due to a multitude of organ malfunctions. Animal models are required to understand the molecular mechanisms responsible for the imbalances of bone metabolism in disturbed bone mineralization diseases. Here we present the isolation of mutant mouse models for metabolic bone diseases by phenotyping blood parameters that target bone turnover within the large-scale genome-wide Munich ENU Mutagenesis Project. A screening panel of three clinical parameters, also commonly used as biochemical markers in patients with metabolic bone diseases, was chosen. Total alkaline phosphatase activity and total calcium and inorganic phosphate levels in plasma samples of F1 offspring produced from ENU-mutagenized C3HeB/FeJ male mice were measured. Screening of 9,540 mice led to the identification of 257 phenodeviants of which 190 were tested by genetic confirmation crosses. Seventy one new dominant mutant lines showing alterations of at least one of the biochemical parameters of interest were confirmed. Fifteen mutations among three genes (Phex, Casr, and Alpl) have been identified by positional-candidate gene approaches and one mutation of the Asgr1 gene, which was identified by next generation sequencing. All new mutant mouse lines are offered as a resource for the scientific community. PMID- 22527488 TI - The correlations of work conditions with unhealthy lifestyles and occupational health problems of casino croupiers in Macau. AB - The Macau economy and employment of residents rely heavily on the gaming industry. It is important that the working conditions in casinos are not harmful to the health of the casino employees. This study examines the correlations between work conditions, unhealthy lifestyles and occupational health problems amongst casino croupiers in Macau. Its findings will provide casino managers and policy makers with evidence and awareness of the workplace health risks for the casino workers. The data were gathered by a questionnaire survey of 1,042 croupiers, which represents roughly 5 % of the croupier population in Macau. Work conditions were measured by worker satisfaction towards the biological, chemical and physical elements in their work environments. Unhealthy lifestyles were measured by practices of excessive drinking, smoking, electronic game playing and addictive substance use as well as gambling. Occupational health problems were measured by experiences of work related illnesses or symptoms. Results showed that high percentages of respondents were dissatisfied with the work conditions. On average each croupier experienced 10 work related health problems in the past 7 days. Over 5 % of the respondents drank more than three glasses of alcohol a day, 24 % smoked cigarettes, 12 % took addictive substances, 14 % gambled in the past 7 days. The analysis showed that dissatisfaction with work conditions did not correlate with unhealthy lifestyles but were strongly and significantly correlated with stress-related occupational health problems (R = 0.377-0.479, P < 0.001) and other occupational health problems (R = 0.348-0.461, P < 0.001). Casino workers in Macau experience a variety of problems associated with their work conditions that can be hazardous to their health. The working conditions in casinos need to be regularly monitored and improvements such as occupational health training and enhanced health related policies can be introduced. PMID- 22527489 TI - Social density of gambling and its association with gambling problems: an initial investigation. AB - The role of social factors in pathological gambling has received relatively little systematic research. The goal of the current study was to examine the relationship between a target individual's gambling behavior and the gambling behavior among that individual's parents, siblings and five closest friends. The specific aims were, first, to apply a novel brief assessment to study the social density of factors relating to pathological gambling; second, to replicate previously observed findings involving the social aggregation of alcohol and tobacco use; and third, to examine social density findings among the three domains. Participants were 128 frequent gamblers from the Athens, Georgia area, 79.7 % male with a mean age of 34.2 (SD = 11.7). Participants were assessed using the Diagnostic Interview for Gambling Severity for gambling severity, the Alcohol Use Disorders Identification Test for alcohol abuse, the Fagerstrom Test of Nicotine Dependence for tobacco use, and the novel Brief Social Density of Gambling, Alcohol, and Tobacco Assessment. Significant relationships were observed between participants' and friends' activity within all domains: gambling (ps = .001), alcohol use (p < .001) and tobacco use (p < .001). Relationships with friends' activity across domains were less strong. Distinct patterns of associations with parents and siblings were not observed. Thus, social aggregation was observed across the three domains of potentially addictive behaviors, generally with specificity within domains and with friends, not biological relatives. Methodological considerations and potential applications of these findings are discussed. PMID- 22527490 TI - Minimal residual disease and circulating tumor cells in breast cancer: open questions for research. PMID- 22527491 TI - Self-seeding in cancer. AB - Despite significant progress in our understanding and treatment of metastatic cancer, nearly all metastatic cancers are incurable. In this Review, we use breast cancer as a model to highlight the limitations and inconsistencies of our existing treatment paradigms for metastatic disease. In turn, we offer a new theory of metastasis, termed "self-seeding. " The self-seeding paradigm, well validated in mathematical, experimental and animal models, challenges the notion that cancers cells that leave a primary tumor cell, unidirectionally seed metastases in regional lymph nodes and/or distant sites. In contrast, there is mounting evidence that circulating tumor cells can move multi-directionally, seeding not only distant sites but also their tumors of origin. Here, we show that the self-seeding model may answer many of the quandaries intrinsic to understanding how cancer spreads and ultimately kills. Indeed, redirecting our research and treatment efforts within the self-seeding model may offer new possibilities for eradicating metastatic cancer. PMID- 22527493 TI - Immunomagnetic separation technologies. AB - The largest difficulty one faces in the development of technology for detection of circulating tumor cells (CTCs) is whether or not tumor cells are present in the blood and at what frequency. Although the introduction of the validated CellSearch system for CTC enumeration has facilitated CTC research the question remains whether CTC are missed or whether the CTC that are reported are indeed clinically relevant. To fulfill the promise of CTC as a real-time liquid biopsy they will need to be present in the blood volume tested and need to be isolated without losing the ability to test the presence of treatment targets. To characterize a sufficiently large number of CTCs in the majority of cancer patients the volume of blood needed is simply too large to process without enrichment prior to detection. Here, we review the detection of CTCs by flow cytometry and fluorescence microscopy with and without immunomagnetic enrichment. PMID- 22527494 TI - Microfluidic technologies. AB - Presence of circulating tumor cells (CTCs) in blood is an important intermediate step in cancer metastasis, a mortal consequence of cancer. However, CTCs are extremely rare in blood with highly heterogeneous morphologies and molecular signatures, thus making their isolation technically very challenging. In the past decade, a flurry of new microfluidic-based technologies has emerged to address this compelling problem. This chapter highlights the current state of the art in microfluidic systems developed for CTCs separation and isolation. The techniques presented are broadly classified as physical- or affinity-based isolation depending on the separation principle. The performance of these techniques is evaluated based on accepted separation metrics including sensitivity, purity and processing/analysis time. Finally, further insights associated with realizing an integrated microfluidic CTC lab-on-chip system as an onco-diagnostic tool will be discussed. PMID- 22527492 TI - Microenvironments dictating tumor cell dormancy. AB - The mechanisms driving dormancy of disseminated tumor cells (DTCs) remain largely unknown. Here, we discuss experimental evidence and theoretical frameworks that support three potential scenarios contributing to tumor cell dormancy. The first scenario proposes that DTCs from invasive cancers activate stress signals in response to the dissemination process and/or a growth suppressive target organ microenvironment inducing dormancy. The second scenario asks whether therapy and/or micro-environmental stress conditions (e.g. hypoxia) acting on primary tumor cells carrying specific gene signatures prime new DTCs to enter dormancy in a matching target organ microenvironment that can also control the timing of DTC dormancy. The third and final scenario proposes that early dissemination contributes a population of DTCs that are unfit for immediate expansion and survive mostly in an arrested state well after primary tumor surgery, until genetic and/or epigenetic mechanisms activate their proliferation. We propose that DTC dormancy is ultimately a survival strategy that when targeted will eradicate dormant DTCs preventing metastasis. For these non-mutually exclusive scenarios we review experimental and clinical evidence in their support. PMID- 22527495 TI - EPISPOT assay: detection of viable DTCs/CTCs in solid tumor patients. AB - The enumeration and characterization of circulating tumor cells (CTCs) in the peripheral blood and disseminated tumor cells (DTCs) in bone marrow may provide important prognostic information and might help to monitor efficacy of therapy. Since current assays cannot distinguish between apoptotic and viable DTCs/CTCs, it is now possible to apply a novel ELISPOT assay (designated 'EPISPOT') that detects proteins secreted/released/shed from single epithelial cancer cells. Cells are cultured for a short time on a membrane coated with antibodies that capture the secreted/released/shed proteins which are subsequently detected by secondary antibodies labeled with fluorochromes. In breast cancer, we measured the release of cytokeratin-19 (CK19) and mucin-1 (MUC1) and demonstrated that many patients harbored viable DTCs, even in patients with apparently localized tumors (stage M(0): 54%). Preliminary clinical data showed that patients with DTC releasing CK19 have an unfavorable outcome. We also studied CTCs or CK19 secreting cells in the peripheral blood of M1 breast cancer patients and showed that patients with CK19-SC had a worse clinical outcome. In prostate cancer, we used prostate-specific antigen (PSA) secretion as marker and found that a significant fraction of CTCs secreted fibroblast growth factor-2 (FGF2), a known stem cell growth factor. In conclusion, the EPISPOT assay offers a new opportunity to detect and characterize viable DTCs/CTCs in cancer patients and it can be extended to a multi-parameter analysis revealing a CTC/DTC protein fingerprint. PMID- 22527496 TI - Advances in optical technologies for rare cell detection and characterization. AB - Scanning cytometry enables detection of circulating tumor cells without enrichment, minimizing potential loss of sensitivity due to variable expression of enrichment targets; however, some approaches lack specificity without imaging to identify false positives. High fidelity imaging enables identification of CTCs using morphological considerations and semi-quantitative measurement of biomarker expression for predicting targeted therapy but often lacks speed needed for the large number of mononuclear blood cells. A hybrid approach of first scanning a sample at high speed and high numerical aperture to locate CTCs followed by high resolution imaging of a small number of objects reduces the time needed for high resolution imaging without loss of detection sensitivity. PMID- 22527497 TI - Size-based enrichment technologies for CTC detection and characterization. AB - The degree of metastatic outspread in malignant disease is one of the leading factors in determining the appropriate course treatment. Circulating tumor cells (CTCs) represent the population of cells that have acquired the means to gain access to the circulatory system, and the cell population ultimately responsible for the development of metastases at distant sites in the body. While promising as a biomarker for metastatic disease, the widespread study of CTCs has been limited by their rarity, as CTCs are reported to occur as infrequently as 1/mL of whole blood. In this text, we will discuss current and emerging technologies for the size-based enrichment of CTCs from whole blood, and compare some of the advantages and disadvantages of using a size-based approach to CTC enrichment versus affinity-based CTC enrichment platforms. PMID- 22527498 TI - Emerging technologies for CTC detection based on depletion of normal cells. AB - Properly conducted, an enrichment step can improve selectivity, sensitivity, yield, and most importantly, significantly reduce the time needed to isolate rare circulating tumor cells (CTCs). The enrichment process can be broadly categorized as positive selection versus negative depletion, or in some cases, a combination of both. We have developed a negative depletion CTC enrichment strategy that relies on the removal of normal cells using immunomagnetic separation in the blood of cancer patients. This method is based on the combination of magnetic and fluid forces in an axial, laminar flow in long cylinders placed in quadrupole magnets. Using this technology, we have successfully isolated CTCs from patients with breast carcinoma and squamous cell carcinoma of the head and neck. In contrast to a positive selection methodology, this approach provides an unbiased characterization of these cells, including markers associated with epithelial mesenchymal transition. PMID- 22527499 TI - Molecular assays for the detection and characterization of CTCs. AB - Molecular characterization for circulating tumor cells (CTCs) can be used to better understand the biology of metastasis, to improve patient management and help to identify novel targets for biological therapies aimed to prevent metastatic relapse. New areas of research are directed towards developing novel sensitive assays for CTC molecular characterization. Towards this direction, molecular detection technologies that take advantage of the extreme sensitivity and specificity of PCR, offer many advantages, such as high sensitivity, specificity, and significant flexibility in the clinical lab setting, in terms of high-throughput analysis, multiplexing, and quality control issues. Using molecular assays, a variety of molecular markers such as multiple gene expression, DNA methylation markers, DNA mutations, and miRNAs have been detected and quantified in CTCs in various cancer types, enabling their molecular characterization. Here, we present the main molecular detection technologies currently used for CTC analysis and molecular characterization. PMID- 22527500 TI - Multiplex molecular analysis of CTCs. AB - Beyond enumeration, CTC characterization is expected to help guide therapeutic selection for personalized care of cancer patients. Different approaches may be used to simultaneously identify multiple CTC-specific markers for biological characterization; yet awareness of associated pitfalls is also important. We have focused this chapter on molecular profiling of CTCs following enrichment. We describe the MagSweeper technology that was specifically developed to isolate live and highly purified CTCs for pooled or single cell or pooled cell molecular analyses or for CTC growth in vitro or in vivo. However, most of what is discussed will apply to any multiplex analysis of CTCs, irrespective of the enrichment method. PMID- 22527501 TI - Circulating DNA and next-generation sequencing. AB - Personalising cancer medicine depends upon the implementation of personalised diagnostics and therapeutics. Detailed genomic screening is likely to play a central role in this. As the range of drugs and other therapies for cancer continues to increase, there is an increasingly urgent need for sensitive and specific measures of disease burden to guide treatment regimens. The ability to quantify disease burden with high accuracy and sensitivity in patients with cancer would open many potential routes to personalising therapeutic choices. For example, the intensity of therapy could be guided by the amount of disease at diagnosis; monitoring the response of patients to drugs could allow extension of the period of treatment in responders or early changeover of therapy in nonresponders; and early prediction of recurrence could allow salvage therapy to be instituted before complications of relapse develop. The detection of tumour specific rearrangements in DNA free in the serum or plasma may provide a substantial advance in the accuracy of monitoring disease burden in patients with solid tumours. PMID- 22527502 TI - Circulating microRNAs as noninvasive biomarkers in breast cancer. AB - MicroRNAs (miRNAs) are master regulators of gene expression. By degrading or blocking translation of messenger RNA targets, these non-coding RNAs can modulate the expression of more than half the protein-coding genes in mammalian genomes. MiRNAs play important regulatory roles in a variety of cellular functions and in several diseases, including cancer. Aberrant miRNA expression has been well characterized in cancer, with implications for progression and prognosis. Recently, the discovery of miRNAs in body fluids, such as serum and plasma, opens up the possibility of using them as noninvasive biomarkers of disease and therapy response. In this chapter, we discuss the use of circulating miRNAs as biomarkers of disease and therapy response and as diagnostic and prognostic markers in breast cancer. We also discuss the main issues related to establishing circulating miRNAs as biomarkers in cancer. PMID- 22527503 TI - Circulating endothelial cells and circulating endothelial progenitors. AB - The roles of circulating endothelial cells (CECs) and circulating endothelial progenitors (CEPs) are currently being investigated in several diseases including cancer and metastases development. Preclinical and clinical data suggest that CEC enumeration might be useful to identify patients who might benefit from anti angiogenic treatments while CEPs seem to have a "catalytic" role in different steps of cancer progression and recurrence after therapy. The definition of CEC and CEP phenotypes and the standardization of CEC and CEP enumeration procedures are highly warranted to use these cells as biomarkers in clinical trials in oncology, and to compare results from different studies. PMID- 22527504 TI - DTCs in breast cancer: clinical research and practice. AB - Minimal residual disease (MRD), i.e., isolated tumor cells (ITC) in bone marrow, may be the source of potentially fatal overt distant metastases in solid tumors even years after primary treatment. MRD can be detected by immunohistochemical methods using antibodies directed against cytokeratins, cell-surface markers, or molecular PCR-based techniques. Among solid tumors, the clinical relevance of MRD has been most extensively studied in breast cancer patients. The highest level of evidence for the prognostic impact of MRD in primary breast cancer was reached by a pooled analysis comprising more than 4,000 patients, showing poor outcome in patients with MRD at primary therapy. Yet, clinical application of MRD detection is hampered by the lack of a standardized detection assay. Moreover, clinical trial results demonstrating the benefit of a therapeutic interference derived from bone marrow status are still missing. Recent results suggest that in addition to its prognostic impact, MRD can be used for therapy monitoring or as a potential therapeutic target after phenotyping of the tumor cells. Persisting MRD after primary treatment may lead to an indication for extended adjuvant therapy. In a pooled analysis bone marrow aspirates of 726 patients from academic breast cancer units in Oslo (n=356), Munich (n=228), and Tuebingen (n=142) were analyzed during recurrence-free follow-up at a mean interval of 31.7 months after primary diagnosis of breast cancer pT1-4, pN0-3 pM0. Persistent ITC was detected in 15.4% of the patients (n=112). The Kaplan-Meier estimate for mean distant relapse-free survival estimate was 163.6 months in patients with negative and 105.2 months in patients with positive BM status. Patients without evidence of persistent ITC had a significantly longer overall survival (165.6), than patients with positive bone marrow status (103.3 months, p < .0001). Given these inspiring results on ITC in the bone marrow, several trials currently analyze the prognostic relecance of circulating tumor cells (CTC) in peripheral blood in the adjuvant setting. Persisting MRD after primary treatment may lead to an indication for extended adjuvant therapy. However, until clinical consequences of MRD detection in solid tumors and particularly in breast cancer have been validated, the detection of isolated tumor cells in bone marrow should be performed mainly in clinical trials. PMID- 22527505 TI - CTCs in primary breast cancer (I). AB - The prognostic and predictive value of circulating tumor cells (CTCs) in primary breast cancer patients is subject of several recent publications. In the context of neoadjuvant chemotherapy CTCs were detected in 22-23% of patients before and in 10-17% after systemic treatment. These findings did not correlate with primary tumor characteristics or tumor response rates. One major trial evaluated the prognostic value of CTCs in 2.026 primary breast cancer patients after tumor resection but before adjuvant chemotherapy. The prevalence of CTCs was 22%. In multivariate analysis, the presence of CTCs before treatment was shown to be an independent predictor for both disease-free (hazard ratio; HR 1.88) and overall survival (HR 1.91). Results demonstrate that not only the mere presence but also the quantity of CTCs is associated with worse outcome. The risk for recurrence or tumor-related death increased with higher numbers of CTCs detected (>=5 CTCs: HR 4.04 for DFS and 3.05 for OAS; p < 0.05). In subsequent analyses of smaller subgroups within this trial, using a cutoff for positivity of >1 CTC, 10% of patients with the detection of CTCs before chemotherapy remained CTC-positive after completion of chemotherapy. Eight percentage of initially negative patients showed CTCs immediately after chemotherapy. Early data demonstrate that persisting CTCs after cytostatic treatment correlate with a decreased disease free survival (p = 0.0623). Increasing evidence confirms the prognostic relevance of CTCs in primary breast cancer. CTC detection could help to identify patients with increased risk for relapse. Present trials will show whether CTCs can also be used as a valid tool for treatment monitoring or direct treatment target. PMID- 22527506 TI - CTCs in primary breast cancer (II). AB - CTCs can be detected by real-time RT-PCR for CK19 mRNA in the blood of early breast cancer patients before the start and after the completion of adjuvant chemotherapy and during adjuvant hormonal therapy and the follow-up. Patients with CK19 mRNA-positive cells both before and after chemotherapy have the worst prognosis with shorter disease-free and overall survival. The same is true for patients who have detectable CK19 mRNA-positive cells despite adjuvant tamoxifen while persistent detection during the follow-up predicts for late disease relapse. Thus CTC monitoring offers the opportunity to evaluate the efficacy of adjuvant therapy and identify those patients who are more likely to benefit from secondary adjuvant treatments. PMID- 22527507 TI - CTCs in metastatic breast cancer. AB - Circulating tumor cells (CTCs), enumerated by the Food and Drugs Administration cleared CellSearch((r)) system, are an independent prognostic factor of progression-free survival (PFS) and overall survival (OS) in metastatic breast cancer (MBC) patients. Several published papers demonstrated the poor prognosis for MBC patients who presented basal CTC count >=5 in 7.5 mL of blood. Therefore, the enumeration of CTCs during treatment for MBC provides a tool with the ability to predict progression of disease earlier than standard timing of anatomical assessment using conventional radiological tests. Randomized clinical trials are ongoing to demonstrate whether CTCs detected by CellSearch((r)) may help to guide treatments in MBC patients and improve prognosis. Moreover, the ability to perform molecular characterization of CTCs might identify a new druggable target in MBC patients. For example, the RT-PCR-based approach AdnaTest BreastCancerSelect(TM) showed a high discordance rate in receptor expression between the primary tumors and CTCs. Theoretically, the phenotypic analysis of CTCs can represent a "liquid" biopsy of breast tumor that is able to identify a new potential target against the metastatic disease. PMID- 22527508 TI - HER2-positive DTCs/CTCs in breast cancer. AB - The presence of circulating tumor cells (CTCs) in the blood as well as disseminated tumor cells (DTCs) in the bone marrow of breast cancer patients is associated with a worsened prognosis in the primary as well as in the metastatic situation. Next to their detection, evaluation of human epidermal growth factor receptor (HER2) expression is a valuable feature of CTCs/DTCs. As the HER2 status may change during disease progression CTCs/DTCs might (1) characterize the phenotype of minimal residual disease in the adjuvant setting and (2) serve as a "real time biopsy" of metastatic breast cancer. Phenotyping of CTCs/DTCs will thus help to understand mechanism of resistance to HER2-directed therapy. Moreover, patients that are likely to benefit from HER2-directed therapy despite a HER2-negative primary tumor might be identified. PMID- 22527509 TI - DTCs/CTCs in breast cancer: five decades later. AB - Since circulating tumor cells were first reported in 1955, the field has seen major advances in their detection and has established their prognostic impact. Here we review the current evidence for the prognostic and predictive value of circulating tumor cells in metastatic breast cancer. We then evaluate the role of CTCs and DTCs in early stage breast cancer. The weight of the evidence supports the role of CTCs and DTCs as prognostic indicators, however their role in therapy prediction remains unclear. Ongoing trials may provide answers and newer detection methods which improve sensitivity and specificity may have greater impact. At this point, the data does not support incorporation into clinical practice for early breast cancer patients. PMID- 22527510 TI - Challenges in drug and biomarker co-development. AB - Co-development of drugs and biomarkers should be considered when the biomarker is intricately related to the use of the drug. There are risks and benefits to co development and these need to be considered carefully early in the process. The current chapter attempts to delineate when it is appropriate to plan for co development and to discuss a range of issues. Challenges include the determination of the type of assay (laboratory-developed test vs. reference laboratory vs. kit), the designs of trials for evaluation of clinical utility, and the regulatory pathway. Successful co-development requires planning very early in the process and assembling the appropriate multi-disciplinary team. PMID- 22527511 TI - Challenges and opportunities in the use of CTCs for companion diagnostic development. AB - Circulating tumor cells offer promise as a surrogate source of cancer cells that can be obtained in real time and may provide opportunities to evaluate predictive biomarkers that can guide treatment decisions. In this review, we consider some of the technical hurdles around CTC numbers and suitability of various CTC capture and analysis platforms for biomarker evaluation. In addition, we consider the potential regulatory hurdles to development of CTC-based diagnostics. Finally, we suggest a path for co-development of anticancer therapeutics with CTC based diagnostics that could enable clinical validation and qualification of CTC based assays as companion diagnostics. PMID- 22527512 TI - Combining ultracentrifugation and peptide termini group-specific immunoprecipitation for multiplex plasma protein analysis. AB - Blood plasma is a valuable source of potential biomarkers. However, its complexity and the huge dynamic concentration range of its constituents complicate its analysis. To tackle this problem, an immunoprecipitation strategy was employed using antibodies directed against short terminal epitope tags (triple X proteomics antibodies), which allow the enrichment of groups of signature peptides derived from trypsin-digested plasma. Isolated signature peptides are subsequently detected using MALDI-TOF/TOF mass spectrometry. Sensitivity of the immunoaffinity approach was, however, compromised by the presence of contaminant peaks derived from the peptides of nontargeted high abundant proteins. A closer analysis of the enrichment strategy revealed nonspecific peptide binding to the solid phase affinity matrix as the major source of the contaminating peptides. We therefore implemented a sucrose density gradient ultracentrifugation separation step into the procedure. This yielded a 99% depletion of contaminating peptides from a sucrose fraction containing 70% of the peptide-antibody complexes and enabled the detection of the previously undetected low abundance protein filamin-A. Assessment of this novel approach using 15 different triple X proteomics antibodies demonstrated a more consistent detection of a greater number of targeted peptides and a significant reduction in the intensity of nonspecific peptides. Ultracentrifugation coupled with immunoaffinity MS approaches presents a powerful tool for multiplexed plasma protein analysis without the requirement for demanding liquid chromatography separation techniques. PMID- 22527513 TI - Development of a pharmaceutical hepatotoxicity biomarker panel using a discovery to targeted proteomics approach. AB - There is a pressing and continued need for improved predictive power in preclinical pharmaceutical toxicology assessment as substantial numbers of drugs are still removed from the market, or from late-stage development, because of unanticipated issues of toxicity. In recent years a number of consortia have been formed with a view to integrating -omics molecular profiling strategies to increase the sensitivity and predictive power of preclinical toxicology evaluation. In this study we report on the LC-MS based proteomic analysis of the effects of the hepatotoxic compound EMD 335823 on liver from rats using an integrated discovery to targeted proteomics approach. This compound was one of a larger panel studied by a variety of molecular profiling techniques as part of the InnoMed PredTox Consortium. Label-free LC-MS analysis of hepatotoxicant EMD 335823 treated animals revealed only moderate correlation of individual protein expression with changes in mRNA expression observed by transcriptomic analysis of the same liver samples. Significantly however, analysis of the protein and transcript changes at the pathway level revealed they were in good agreement. This higher level analysis was also consistent with the previously suspected PPARalpha activity of the compound. Subsequently, a panel of potential biomarkers of liver toxicity was assembled from the label-free LC-MS proteomics discovery data, the previously acquired transcriptomics data and selected candidates identified from the literature. We developed and then deployed optimized selected reaction monitoring assays to undertake multiplexed measurement of 48 putative toxicity biomarkers in liver tissue. The development of the selected reaction monitoring assays was facilitated by the construction of a peptide MS/MS spectral library from pooled control and treated rat liver lysate using peptide fractionation by strong cation exchange and off-gel electrophoresis coupled to LC MS/MS. After iterative optimization and quality control of the selected reaction monitoring assay panel, quantitative measurements of 48 putative biomarkers in the liver of EMD 335823 treated rats were carried out and this revealed that the panel is highly enriched for proteins modulated significantly on drug treatment/hepatotoxic insult. This proof-of-principle study provides a roadmap for future large scale pre-clinical toxicology biomarker verification studies whereby putative toxicity biomarkers assembled from multiple disparate sources can be evaluated at medium-high throughput by targeted MS. PMID- 22527514 TI - The Protein Structure Initiative Structural Biology Knowledgebase Technology Portal: a structural biology web resource. AB - The Technology Portal of the Protein Structure Initiative Structural Biology Knowledgebase (PSI SBKB; http://technology.sbkb.org/portal/ ) is a web resource providing information about methods and tools that can be used to relieve bottlenecks in many areas of protein production and structural biology research. Several useful features are available on the web site, including multiple ways to search the database of over 250 technological advances, a link to videos of methods on YouTube, and access to a technology forum where scientists can connect, ask questions, get news, and develop collaborations. The Technology Portal is a component of the PSI SBKB ( http://sbkb.org ), which presents integrated genomic, structural, and functional information for all protein sequence targets selected by the Protein Structure Initiative. Created in collaboration with the Nature Publishing Group, the SBKB offers an array of resources for structural biologists, such as a research library, editorials about new research advances, a featured biological system each month, and a functional sleuth for searching protein structures of unknown function. An overview of the various features and examples of user searches highlight the information, tools, and avenues for scientific interaction available through the Technology Portal. PMID- 22527515 TI - Immunocamouflage of latex surfaces by grafted methoxypoly(ethylene glycol) (mPEG): proteomic analysis of plasma protein adsorption. AB - Grafting of methoxypoly(ethylene glycol) (mPEG) to cells and biomaterials is a promising non-pharmacological immunomodulation technology. However, due to the labile nature of cells, surface-plasma interactions are poorly understood; hence, a latex bead model was studied. PEGylation of beads resulted in a density and molecular weight dependent decrease in total adsorbed protein with a net reduction from (159.9+/-6.4) ng cm(-2) on bare latex to (18.4+/-0.8) and (52.3+/ 5.3) ng cm(-2) on PEGylated beads (1 mmol L(-1) of 2 or 20 kD SCmPEG, respectively). SDS-PAGE and iTRAQ-MS analysis revealed differential compositions of the adsorbed protein layer on the PEGylated latex with a significant reduction in the compositional abundance of proteins involved in immune system activation. Thus, the biological efficacy of immunocamouflaged cells and materials is mediated by both biophysical obfuscation of antigens and reduced surface macromolecule interactions. PMID- 22527516 TI - Cell orientation of swimming bacteria: from theoretical simulation to experimental evaluation. AB - The motion of small bacteria consists of two phases: relatively long runs alternate with intermittent stops, back-ups, or tumbles, depending on the species. In polar monotrichous bacteria, the flagellum is anchored at the cell pole inherited from the parent generation (old pole) and is surrounded by a chemoreceptor cluster. During forward swimming, the leading pole is always the pole recently formed in cell division (new pole). The flagella of the peritrichous bacterium Escherichia coli often form a bundle behind the old pole. Its cell orientation and receptor positioning during runs generally mimic that of monotrichous bacteria. When encountering a solid surface, peritrichous bacteria exhibit a circular motion with the leading pole dipping downward. Some polar monotrichous bacteria also perform circular motion near solid boundaries, but during back-ups. In this case, the leading pole points upward. Very little is known about behavior near milieu-air interfaces. Biophysical simulations have revealed some of the mechanisms underlying these phenomena, but leave many questions unanswered. Combining biophysics with molecular techniques will certainly advance our understanding of bacterial locomotion. PMID- 22527517 TI - Characterizing the induction of diabetes in juvenile cynomolgus monkeys with different doses of streptozotocin. AB - Juvenile (2-23 years old) cynomolgus monkeys are frequently used as recipients in non-human primate islet transplantation studies. The aim of this study was to examine the effects of different doses of streptozotocin (STZ), and find the optimal dose for inducing diabetes in these monkeys. Fifteen juvenile (2-3 years old) cynomolgus monkeys were separated into three groups and administered with different doses of STZ (100, 68 or 60 mg kg(-1)). Basal and glucose-stimulated blood glucose, insulin, and C-peptide levels, as well as body weights were monitored. Hepatic and renal function tests and pancreatic immunohistochemistry were performed before and after STZ treatment. Monkeys treated with both 100 and 68 mg kg(-1) of STZ exhibited continuous hyperglycemia, which coincided with a nearly complete loss of islet beta-cells. Two monkeys received 60 mg kg(-1) of STZ, but only one became completely diabetic. During the first week following STZ treatment, hepatic and renal function slightly increased in these three groups. However, 24 hours post-STZ, serum total bile acid levels were significantly increased in monkeys treated with 100 mg kg(-1) than those treated with 68 mg kg( 1) of STZ (P<0.05). These data suggest that 100 mg kg(-1) and 68 mg kg(-1) of STZ can safely induce diabetes in cynomolgus monkeys aged 2-3 years, but 68 mg kg(-1) of STZ, rather than 100 mg kg(-1) of STZ, may be more appropriate for inducing diabetes in these monkeys. Furthermore, body surface area, rather than body weight, was a more reliable determinant of dosage, where 700 mg m(-2) of STZ should be the lower limit for inducing diabetes in juvenile monkeys. PMID- 22527518 TI - Establishment of a transgenic mouse model with liver-specific expression of secretory immunoglobulin D. AB - Mutation of mevalonate kinase (MVK) is thought to account for most cases of hyperimmunoglobulinemia D syndrome (HIDS) with recurrent fever. However, its mechanism and the relationship between elevated serum immunoglobulin D (IgD) and the clinical features of HIDS are unclear. In this study, we generated by fusion PCR a vector to express high levels of chimeric secretory IgD (csIgD) specifically in the liver. We then generated seven founder lines of transgenic mice by co-microinjection, and verified them using genomic PCR and Southern blotting. We detected the expression of csIgD by reverse transcription PCR, quantitative PCR, western blotting, and enzyme-linked immunosorbent assays. We demonstrated that csIgD could be specifically and stably expressed in the liver. We used flow cytometry to show that overexpression of csIgD in the bone marrow and spleen cells had no effect on B cell development. Morphologic and anatomical observation of the transgenic mice revealed skin damage, hepatosplenomegaly, and nephromegaly in some transgenic mice; in these mice, pathological sections showed high levels of cell necrosis and protein-like sediments in the liver, spleen, and kidney. We demonstrated that the genomic insertion sites of the transgenes did not disrupt the MVK gene on mouse chromosome 5. This transgenic mouse will be useful to explore the pathogenesis of HIDS. PMID- 22527519 TI - RAB-27 and its effector RBF-1 regulate the tethering and docking steps of DCV exocytosis in C. elegans. AB - The molecular mechanisms by which dense core vesicles (DCVs) translocate, tether, dock and prime are poorly understood. In this study, Caenorhabditis elegans was used as a model organism to study the function of Rab proteins and their effectors in DCV exocytosis. RAB-27/AEX-6, but not RAB-3, was found to be required for peptide release from neurons. By analyzing the movement of DCVs approaching the plasma membrane using total internal reflection fluorescence microscopy, we demonstrated that RAB-27/AEX-6 is involved in the tethering of DCVs and that its effector rabphilin/RBF-1 is required for the initial tethering and subsequent stabilization by docking. PMID- 22527520 TI - Mineralization regulation and biological influence of bioactive glass-collagen phosphatidylserine composite scaffolds. AB - Biomimetic scaffolds are appealing products for the repair of bone defects using tissue engineering strategies. In the present study, novel biomimetic composite scaffolds, with similar properties to natural bone, were prepared, blended and cross-linked with bioactive glass, type I collagen and phosphatidylserine. When exposed to cell culture solution in the absence of a cellular source, the composite scaffolds form crystals with octahedral structure. These crystals are similar to the products derived from MC3T3-E1 cell mineralization within the composite scaffolds, with respect to both composition and morphology. Furthermore, crystals with octahedral structure were observed to develop into plate-like hydroxyapatite. The bio-mineralization behavior of the composite scaffolds is likely influenced by inorganic components. Finally, a rabbit tibia defect model shows that the highly bioactive properties of the investigated composites result in excellent bone repair. PMID- 22527521 TI - Interaction between temperature and photoperiod in regulation of flowering time in rice. AB - Photoperiod and temperature are two pivotal regulatory factors of plant flowering. The floral transition of plants depends on accurate measurement of changes in photoperiod and temperature. The flowering time of rice (Oryza sativa) as a facultative short-day (SD) plant is delayed under long-day (LD) and/or low temperature conditions. To elucidate the regulatory functions of photoperiod and temperature on flowering time in rice, we systematically analyzed the expression and regulation of several key genes (Hd3a, RFT1, Ehd1, Ghd7, RID1/Ehd2/OsId1, Se5) involved in the photoperiodic flowering regulatory pathway under different temperature and photoperiod treatments using a photoperiod-insensitive mutant and wild type plants. Our results indicate that the Ehd1-Hd3a/RFT1 pathway is common to and conserved in both the photoperiodic and temperature flowering regulatory pathways. Expression of Ehd1, Hd3a and RFT1 is dramatically reduced at low temperature (23 degrees C), suggesting that suppression of Ehd1, Hd3a and RFT1 transcription is an essential cause of delayed flowering under low temperature condition. Under LD condition, Ghd7 mRNA levels are promoted at low temperature (23 degrees C) compared with normal temperature condition (28 degrees C), suggesting low temperature and LD treatment have a synergistic role in the expression of Ghd7. Therefore, upregulation of Ghd7 might be a crucial cause of delayed flowering under low temperature condition. We also analyzed Hd1 regulatory relationships in the photoperiodic flowering pathway, and found that Hd1 can negatively regulate Ehd1 transcription under LD condition. In addition, Hd1 can also positively regulate Ghd7 transcription under LD condition, suggesting that the heading-date of rice under LD condition is also regulated by the Hd1-Ghd7-Ehd1-RFT1 pathway. PMID- 22527522 TI - Induction of seed germination in Orobanche spp. by extracts of traditional Chinese medicinal herbs. AB - The co-evolution of Orobanche spp. and their hosts within the same environment has resulted in a high degree of adaptation and effective parasitism whereby the host releases parasite germination stimulants, which are likely to be unstable in the soil. Our objective was to investigate whether extracts from non-host plants, specifically, Chinese medicinal plants, could stimulate germination of Orobanche spp. Samples of 606 Chinese medicinal herb species were extracted with deionized water and methanol. The extracts were used to induce germination of three Orobanche species; Orobanche minor, Orobanche cumana, and Orobanche aegyptiaca. O. minor exhibited a wide range of germination responses to the various herbal extracts. O. cumana and O. aegyptiaca exhibited an intermediate germination response to the herbal extracts. O. minor, which has a narrow host spectrum, showed higher germination rates in response to different herbal extracts compared with those of O. cumana and O. aegyptiaca, which have a broader host spectrum. Methanolic extracts of many Chinese herbal species effectively stimulated seed germination among the Orobanche spp., even though they were not the typical hosts. The effective herbs represent interesting examples of potential trap crops. Different countries can also screen extracts from indigenous herbaceous plants for their ability to induce germination of Orobanche spp. seeds. The use of such species as trap plants could diminish the global soil seed bank of Orobanche. PMID- 22527523 TI - Literature and patent analysis of the cloning and identification of human functional genes in China. AB - The Human Genome Project was launched at the end of the 1980s. Since then, the cloning and identification of functional genes has been a major focus of research across the world. In China too, the potentially profound impact of such studies on the life sciences and on human health was realized, and relevant studies were initiated in the 1990s. To advance China's involvement in the Human Genome Project, in the mid-1990s, Committee of Experts in Biology from National High Technology Research and Development Program of China (863 Program) proposed the "two 1%" goal. This goal envisaged China contributing 1% of the total sequencing work, and cloning and identifying 1% of the total human functional genes. Over the past 20 years, tremendous achievement has been accomplished by Chinese scientists. It is well known that scientists in China finished the 1% of sequencing work of the Human Genome Project, whereas, there is no comprehensive report about "whether China had finished cloning and identifying 1% of human functional genes". In the present study, the GenBank database at the National Center of Biotechnology Information, the PubMed search tool, and the patent database of the State Intellectual Property Office, China, were used to retrieve entries based on two screening standards: (i) Were the newly cloned and identified genes first reported by Chinese scientists? (ii) Were the Chinese scientists awarded the gene sequence patent? Entries were retrieved from the databases up to the cut-off date of 30 June 2011 and the obtained data were analyzed further. The results showed that 589 new human functional genes were first reported by Chinese scientists and 159 gene sequences were patented (http://gene.fudan.sh.cn/introduction/database/chinagene/chinagene.html). This study systematically summarizes China's contributions to human functional genomics research and answers the question "has China finished cloning and identifying 1% of human functional genes?" in the affirmative. PMID- 22527524 TI - [Vestibular disorders. Effects of sensorimotor training on postural regulation and on recovery process]. AB - Complex sensorimotor training can improve the postural stability of patients with vestibular neuropathy. Particularly the efficiency of the cerebellar system was significantly improved. In addition, the results show that the affected peripheral vestibular system cannot be influenced directly, regardless of the kind of rehabilitation measure used. PMID- 22527525 TI - [The Acoustic Voice Quality Index. Toward expanded measurement of dysphonia severity in German subjects]. AB - BACKGROUND: The purpose of this study was first to explore the cross-linguistic robustness of the Acoustic Voice Quality Index (i.e., AVQI) when administered to German continuous speech segments instead of Dutch sentences. The second aim was to define a normative AVQI threshold for distinguishing between normophonia and dysphonia in German speakers. METHODS: Sixty-one German subjects with diverse voice disorders were asked to sustain the vowel [a] and to read aloud a common text. A 3-s mid-vowel segment and the first two sentences of the text "The northwind and the sun" were edited, concatenated and analyzed according to methods described elsewhere. The voice recordings from all 61 participants were (1) auditory-perceptually rated with 'H' from the RBH system by five experienced clinicians and (2) acoustically analyzed to yield the AVQI scores. RESULTS: First, a reasonable correlation was found between the AVQI and H (i.e., r(s) = 0.79). Second, the AVQI revealed an acceptable diagnostic differentiation between normal and dysphonic voices (i.e., AUC = 0.888). These results on German material accord with the results from previous studies on Dutch material. Furthermore, in the German version, the AVQI's cutoff score of 2.70 is accompanied by sensitivity = 79% and specificity = 92%. This indicates minimal normative deviation from the AVQI's cutoff score of 2.95 in Dutch. CONCLUSION: The present and the previous studies yielded almost identical results, denoting the AVQI's cross-linguistic robustness and its feasibility to clinically measure voice quality in German. PMID- 22527526 TI - Human visual short-term memory precision can be varied at will when the number of retained items is low. AB - It has been debated whether human visual working memory is limited by the number of items or the precision with which they are represented. In the research reported here, we show that the precision of working memory can be flexibly and willfully controlled, but only if the number of retained items is low. Electroencephalographic recordings revealed that a neural marker for visual working memory (contralateral delay activity, or CDA) that is known to increase in amplitude with the number of retained items was also affected by the precision with which items were retained. However, willfully enhanced precision increased CDA amplitude only when the number of retained items was low. These results show that both the number and the (willfully controlled) precision of retained items constrain visual working memory: People can enhance the precision of their visual working memory, but only for a few items. PMID- 22527527 TI - A power-law model of psychological memory strength in short- and long-term recognition. AB - A classic law of cognition is that forgetting curves are closely approximated by power functions. This law describes relations between different empirical dependent variables and the retention interval, and the precise form of the functional relation depends on the scale used to measure each variable. In the research reported here, we conducted a recognition task involving both short- and long-term probes. We discovered that formal memory-strength parameters from an exemplar-recognition model closely followed a power function of the lag between studied items and a test probe. The model accounted for rich sets of response time (RT) data at both individual-subject and individual-lag levels. Because memory strengths were derived from model fits to choices and RTs from individual trials, the psychological power law was independent of the scale used to summarize the forgetting functions. Alternative models that assumed different functional relations or posited a separate fixed-strength working memory store fared considerably worse than the power-law model did in predicting the data. PMID- 22527528 TI - Urinary endothelin-1-like immunoreactivity excretion in Wilms' tumor survivors. AB - BACKGROUND: We evaluated urinary endothelin (ET)-1-like Immunoreactivity (uET-1 L) excretion in Wilms tumor (WT) survivors and investigated its relationships with glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). Glomerular hemodynamics were also assessed by Gomez formulae. METHODS: Seventeen WT survivors underwent renal sequential scintigraphy for residual kidney function determination including ERPF and GFR. Forty-five healthy individuals were selected as the control group. uET-1 L was measured by radioimmunoassay from the 24-h urine collection. RESULTS: In WT survivors, uET-1 L excretion was significantly higher than in controls. Significant correlations were found between uET-1 L and ERPF and GFR. Cluster analysis, applied on uET-1 L, identified two different patient groups. Between them, GFR and ERPF were significantly different. No significant difference existed between the two clusters for age and sex, elapsed time from nephrectomy, treatment, or nephrectomy side. Applying Gomez formulae, significant difference was found for afferent and total renal resistance. CONCLUSIONS: According to our results, uET-1 L seems to be a marker of glomerular injury in patients with renal mass loss revealing renal overload condition. The uET-1 L role in renal damage progression and hemodynamic glomerular worsening in nephrectomized patients should be proven by prospective long-term follow-up studies, even for potential ET-1 receptor antagonist therapeutic use. PMID- 22527529 TI - High prevalence of elevated lead levels in pediatric dialysis patients. AB - BACKGROUND: After parents raised concerns about potential lead (Pb) contamination of calcium carbonate for treatment of hyperphosphatemia in chronic kidney disease (CKD), we measured blood Pb using high-resolution sector field inductively coupled mass spectrometry in a quality-assurance investigation of ten pediatric dialysis patients (nine on hemodialysis) and six patients before dialysis. METHODS: We assessed the kidney function as cystatin C estimated glomerular filtration rate (eGFR), blood Pb levels, calcium carbonate dose, and standard laboratory parameters, as well as Pb levels in the dialysis feed water. RESULTS: Mean blood Pb concentration in the 16 pediatric CKD patients was 21.1 +/- 15.8 ug/l with a maximum of 58 ug/l, which was significantly higher than that of 467 apparently healthy controls (median 6.35 ug/l, interquartile range 4.47, 8.71) and comparable to that of ten adult peritoneal dialysis (PD) patients. Lead levels correlated with red blood cell distribution width, eGFR, and calcium carbonate dose. Pb in dialysate feed water was always <0.00018 mg/l, which is below the accepted limit for water for dialysis of 0.005 mg/l. CONCLUSIONS: We found a high prevalence of elevated Pb levels in pediatric CKD patients that correlated with the calcium carbonate dose and GFR. Lead levels should be monitored in these patients. PMID- 22527530 TI - Interleukin-6 and interleukin-8 levels in the urine of children with renal scarring. AB - BACKGROUND: Acute pyelonephritis (APN) is one of the most significant bacterial infections in infancy and early childhood, and can lead to permanent kidney damage and chronic renal failure. OBJECTIVE: To evaluate interleukin-6 (IL-6) and interleukin-8 (IL-8) levels in the urine of children with renal scarring (RS), searching for clinical information about the immuno-inflammatory process that contributes to RS. METHODS: Urine concentrations of IL-6 and IL-8 were evaluated in 50 children, 33 with RS detected after an episode of acute pyelonephritis (group A) and 17 children with a history of acute pyelonephritis, but without RS (group B). These children were divided into four groups: group A(1), 23 children with RS and vesicoureteral reflux (VUR); group A(2), 10 children with RS without VUR; group B(1), 13 children without RS and without VUR; group B(2), 4 children without RS, but with VUR. None of them had had urinary tract infection for a minimum of 6 months. To avoid dilution effects, urinary levels of IL-6 and IL-8 were expressed as the ratio of cytokine to urinary creatinine (pg/mg). RESULTS: Urinary IL-8 levels were below the lower detection limit in all samples. IL-6 was detectable in the majority of children with RS and below the detection limits in the urine samples of children without RS. There were no statistically significant differences between urinary interleukin-6 levels in children with and those without VUR. There was a significant relationship between the grade of renal scars, the time passed since the last episode of acute pyelonephritis and the urinary levels of IL-6 (p < 0.0001 and p < 0.04 respectively). CONCLUSION: Further experimental studies are required to demonstrate the correlation between histopathology and urinary cytokine levels. PMID- 22527531 TI - Does thiazide treatment improve bone mineral density in hypercalciuric children? PMID- 22527532 TI - Left ventricular function in children and adults after renal transplantation in childhood. AB - BACKGROUND: Renal transplantation improves left ventricular (LV) function, but cardiovascular mortality remains elevated. The aim of this cross-sectional study was to determine whether subclinical abnormalities of LV longitudinal function also persist in patients who underwent renal transplant in childhood. METHODS: Conventional and speckle tracking echocardiography was performed in 68 renal transplant recipients (34 children and 34 adults, median 9.8 years (range 2.0 28.4 years) after first transplantation and 68 age- and sex-matched healthy controls. RESULTS: Mean age at first transplantation was 8.8 +/- 4.8 years. Forty three percent had a pre-emptive transplant. Of the remaining, 70% received haemodialysis and 30% peritoneal dialysis on average for 6.9 months. Thirty-one percent of paediatric and 35% of adult patients had hypertension. LV mass index was increased in adult patients (92 +/- 24 vs 75 +/- 11 g/m(2), P< 0.01). LV diastolic function and exercise capacity were impaired in both paediatric and adult patients. LV longitudinal peak systolic strain and strain rate were comparable in patients and controls. In multivariate analysis, systolic blood pressure and LV diastolic relaxation were the main covariates of LV peak systolic strain and strain rate (all P < 0.01). CONCLUSIONS: Patients who underwent renal transplantation in childhood have abnormal LV diastolic function and impaired exercise capacity, despite preserved LV longitudinal systolic deformation. PMID- 22527533 TI - Deferasirox-induced renal impairment in children: an increasing concern for pediatricians. AB - BACKGROUND: Deferasirox (DFX) is an oral iron chelator with an established dose dependent efficacy in transfusion-related iron overload. Whereas emerging long term data confirm the safety of the drug, with transient moderate elevation of serum creatinine level, several authors have reported renal tubular dysfunction. The aim of this study was to evaluate tubular and glomerular function before and after the initiation of DFX therapy in a pediatric patient population. METHODS: Ten children (4 girls, mean age 12.4 +/- 3.9 years) enrolled in a routine blood transfusion program were treated with 24.8 +/- 9.6 mg/kg per day of DFX, and renal function was assessed before and 17.2 +/- 8.9 months after the initiation of DFX therapy. RESULTS: Prior to treatment with DFX, all patients had a normal glomerular function rate (GFR) (125 +/- 15 ml/min per 1.73 m(2)) and normal tubular function. Following the initiation of DFX therapy, the GFR decreased by approximately 20 % with one patient with a GFR of <80 mL/min per 1.73 m(2) and seven patients with a GFR of <100 mL/min per 1.73 m(2). Two patients experienced a generalized proximal tubular dysfunction whereas nine patients presented at least one sign of proximal tubular dysfunction. CONCLUSIONS: Renal toxicity is a frequent adverse event of DFX treatment, presenting as both glomerular and proximal dysfunction. A routine renal assessment is therefore required to prevent chronic kidney disease that may result from prolonged tubular injury. PMID- 22527534 TI - Nephrotic syndrome in Kawasaki disease: a report of three cases. AB - BACKGROUND: Renal manifestations are rare in Kawasaki disease (KD). Acute renal failure with tubular necrosis, tubulointerstitial nephritis and renovascular hypertension have been reported in KD, but only one case of a patient with KD associated with nephrotic syndrome (NS) has been reported to date, with the patient improving on steroid therapy but dying from coronary aneurysm. METHODS: We report the cases of three children, aged 4, 4.5 and 8 years, respectively, who presented with typical KD symptoms (high fever, diffuse maculopapular rash, conjunctivitis, peripheral oedema, cervical adenopathies and high C reactive protein levels) and developed NS. RESULTS: Patient 1 had a haemodynamic shock due to cardiac dysfunction and transient renal failure. Ten days later, he developed a NS which spontaneously disappeared 1 week later. Patient 2 had a NS on admission with normal plasma creatinine and no haematuria. Proteinuria disappeared within 10 days. Patient 3 developed NS 5 days after onset with a moderate increase in plasma creatinine. Proteinuria disappeared within 2 weeks. All three patients were treated with intravenous immunoglobulins, antibiotic therapy and aspirin, but none of them received steroid therapy. To date, all three patients have maintained long-term remission. CONCLUSIONS: In conclusion, proteinuria with NS may develop during the acute phase of KD with persistent remission occurring without steroid therapy. PMID- 22527535 TI - Acute kidney injury in two children caused by renal hypouricaemia type 2. AB - BACKGROUND: Renal hypouricaemia is a heterogeneous inherited disorder characterized by impaired tubular uric acid transport with severe complications, such as acute kidney injury and nephrolithiasis. Type 1 is caused by a loss-of function mutation in the SLC22A12 gene (OMIM #220150), while type 2 is caused by defects in the SLC2A9 gene (OMIM #612076). CASE-DIAGNOSIS/TREATMENT: The cases of two children, a 12- and a 14-year-old boy with acute kidney injury (proband 1: urea 9.4 mmol/l, creatinine 226 MUmol/l; proband 2: urea 11.7 mmol/l, creatinine 202 MUmol/l) are described. Both are offspring of nonconsanguineous couples in the UK. The concentrations of serum uric acid were consistently below the normal range (0.03 and 0.04 mmol/l) and expressed as an increase in the fractional excretion of uric acid (46 and 93 %). CONCLUSIONS: A sequencing analysis of the coding region of uric acid transporters SLC22A12 and SLC2A9 was performed. Analysis of genomic DNA revealed two unpublished missense transitions, p.G216R and p.N333S in the SLC2A9 gene. No sequence variants in SLC22A12 were found. Our findings suggest that homozygous and/or compound heterozygous loss-of-function mutations p.G216R and p.N333S cause renal hypouricaemia via loss of uric acid absorption and do lead to acute kidney injury. PMID- 22527536 TI - Post-transplantation encapsulating peritoneal sclerosis in a pediatric patient. AB - BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is a serious complication of long-term peritoneal dialysis (PD), but only a few cases have been described in the pediatric patient population. There is no established medical treatment, and surgery has been reported with variable success. The number of reports of EPS being successfully treated with tamoxifen, based on its anti-fibrotic effects, are increasing. The role of sirolimus, an mTOR inhibitor with immunomodulatory and anti-proliferative properties, has been less well-defined. CASE DIAGNOSIS/TREATMENT: A 17-year-old kidney transplant recipient, with a previous cumulative time on PD of 8 years and 3 months, developed severe bowel obstruction 8 months after undergoing a second kidney graft. Her immunosuppressive regimen consisted of tacrolimus, mycophenolate mofetil, and prednisolone. The patient underwent laparotomy, which revealed multiple thick leathery adhesions with an encapsulated small bowel. Enterolysis was performed, and total parenteral nutrition was commenced after surgery to provide an adequate food intake. Treatment with tamoxifen was initiated, but the patient developed significant liver toxicity 2 weeks later, and the drug was withdrawn. The immunosuppressive regimen was changed to an increased dose of prednisolone, and tacrolimus was replaced with sirolimos. At 20 months of follow-up, the patient remains symptom free, with a functioning kidney transplant. CONCLUSION: Although EPS is a very rare condition in the pediatric population, it should be considered when a child or adolescent with a long-term history of PD presents with nonspecific gastrointestinal symptoms or with signs of bowel obstruction. There is an urgent need for alternative immunosuppressive protocols. The use of sirolimus in this group of patients remains controversial. PMID- 22527537 TI - Direct percutaneous embolization of an iatrogenic lumbar artery pseudoaneurysm following unsuccessful coil embolization. AB - A 56-year-old man with acute myeloleukemia was hospitalized for lumbar pain. Treatment with antibiotics failed to improve the symptoms. For the diagnosis of infiltration by leukemia we performed CT-guided percutaneous needle biopsy of the L2-L3 disc and the L3 vertebral body using a left posterolateral approach. His symptoms were improved by treatment with antibiotics and he was discharged 4 days later. He again experienced lumbar pain 4 days post-discharge and was readmitted. Unenhanced CT scans of the abdomen and pelvis revealed a giant hematoma in the left psoas muscle and we suspected lumbar arterial injury. A preoperative aortography and transcatheter arterial coil embolization was then performed for the diagnosis and treatment of a lumbar artery pseudoaneurysm. On the preoperative angiography, pseudoaneurysm arising from the left lumbar artery was shown. All feeders were shown by the selective catheterization of the lumbar arteries and they were completely embolized using coils. However, contrast enhanced CT obtained on the next day still demonstrated a pseudoaneurysm in the left psoas muscle. Thus, additional percutaneous embolization using N-butyl-2 cyanoacrylate was performed. After this procedure, complete embolization of the pseudoaneurysm was obtained and his lumbar pain was relieved. PMID- 22527538 TI - Increased microRNA-221/222 and decreased estrogen receptor alpha in the cervical portion of the uterosacral ligaments from women with pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to compare the expression of microRNA (miR)-221, miR-222, and estrogen receptor alpha (ERalpha) in the uterosacral ligaments of women with and without pelvic organ prolapse (POP). METHODS: Histologically confirmed full-thickness uterosacral ligament biopsies were procured during hysterectomies from 40 POP patients and 40 postmenopausal women without prolapse. Expression of miR-221/222 was determined by quantitative real-time polymerase chain reaction (PCR), and ERalpha protein expression was analyzed by Western blotting and immunohistochemistry. RESULTS: The mean expression levels of miR-221/222 both increased by approximately twofold in women with POP relative to controls, while ERalpha protein levels in POP patients were significantly lower than controls. Negative correlations were observed between ERalpha protein expression and both miR-221 (r = -0.8542) and miR-222 (r = 0.861) in POP patients. CONCLUSIONS: Elevated miR-221/222 expression levels are associated with, and may be responsible for, reduced ERalpha expression in the cervical portion of uterosacral ligaments of patients with POP. MiR-221/222 may serve as potential therapeutic targets for POP. PMID- 22527539 TI - Reproducibility of a cough and jump stress test for the evaluation of urinary incontinence. AB - INTRODUCTION AND HYPOTHESIS: The study seeks to determine whether a urinary cough and jump stress test is reproducible and whether there is a relationship between a stress test and a 24-h pad test and our subjective Stress Incontinence Index. METHODS: Multicenter prospective cohort study of women with subjective stress incontinence. Each patient completed a validated Stress and Urge Incontinence Questionnaire and a 24-h pad test and performed two standardized cough and jump stress tests. RESULTS: All 108 women were incontinent during both the first and second stress tests. There was a large variation in leakage and the leakage was significantly larger during stress test 2 than during stress test 1 (P < 0.02). Correlations found between the stress test and the 24 hour pad test and between the stress test and the Stress Incontinence Index were poor. CONCLUSION: The cough and jump stress test is reproducible and able to document stress leakage. PMID- 22527540 TI - Miniarc single-incision sling for treatment of stress urinary incontinence: 2 year clinical outcomes. AB - INTRODUCTION AND HYPOTHESIS: We report 2-year data on the effectiveness and safety of the MiniArc single-incision sling in women with stress urinary incontinence. METHODS: This multi-center, prospective, single-arm, industry sponsored study measured the effectiveness of the MiniArc sling via quantitative (cough stress test and 1-h pad weight test) and qualitative (Urogenital Distress Inventory-Short Form and Incontinence Impact Questionnaire-Short Form) measurements. The objective efficacy rate was defined as the number of patients with a negative cough stress test or 1-h pad weight test <= 1 g at 2 years. The subjective efficacy rate was determined by patient responses to the UDI-6 question # 3, "Do you experience, and if so, how much are you bothered by urine leakage related to physical activity, coughing, or sneezing?" Secondary objectives were to evaluate procedural variables of implantation and long-term safety. RESULTS: One hundred and eighty women with a mean age of 51.1 years were implanted in the study. Mean procedure time, blood loss, and length of stay were 11.0 min, 41.7 mL and 9.5 h respectively. At 2 years, 142 patients were available for analysis. The objective efficacy rates for the cough stress test (CST) and pad weight test (PWT) were 84.5 % and 80.1 % respectively and the subjective efficacy rate was 92.9 %. Median Urogenital Distress Inventory-Short Form and Incontinence Impact Questionnaire-Short Form scores showed statistically significant improvement (p < .001). The most common adverse events included UTI (4.8 %), constipation (3.7 %), and temporary urinary retention (3.2 %). CONCLUSION: MiniArc is a safe and effective surgical procedure for the treatment of SUI in women with follow-up through 2 years. PMID- 22527541 TI - Management of recurrent stress urinary incontinence after failed midurethral sling: tape tightening or repeat sling? AB - INTRODUCTION AND HYPOTHESIS: This study was performed to compare surgical outcomes of repeat midurethral sling (MUS) with those of tape shortening in patients who underwent failed initial MUS. METHODS: We assessed 66 patients who underwent failed initial MUS and a second surgical procedure because of recurrent or persistent stress urinary incontinence (SUI), including 36 who underwent repeat MUS and 30 who underwent tape shortening. All patients were followed up for at least 12 months after second surgery. Efficacy was measured by cure rates on the Sandvik questionnaire. Safety was evaluated by assessing maximal urine flow rate, postvoid residual urine volume, and procedure-related complications. RESULTS: The cure rate was significantly higher in patients who underwent repeat MUS (72.2 % vs. 46.7 %, p = 0.034). Among patients with a Valsalva leak point pressure (VLPP) of <60 cmH(2)O or SUI severity of at least moderate, the cure rate was significantly higher in those who underwent repeat MUS than in those who underwent tape shortening (76.5 % vs. 40.0 % and 79.2 % vs. 43.8 %, respectively). Univariate analysis of preoperative factors demonstrated that there were no risk factors associated with the cure rates in either group. One patient who underwent repeat MUS required tape cutting, and one who underwent tape shortening experienced mesh erosion. A limitation of this study is that it was not a randomized, controlled study. CONCLUSIONS: Repeat MUS has a higher cure rate than does tape shortening in surgical treatment of patient with persistent or recurrent SUI, especially those with low VLPP or high SUI grade. PMID- 22527542 TI - Biomechanical effects of polyglecaprone fibers in a polypropylene mesh after abdominal and rectovaginal implantation in a rabbit. AB - INTRODUCTION AND HYPOTHESIS: To investigate the biomechanical effects of polyglecaprone fibers in lightweight meshes implanted into the vaginal and abdominal wall of parous rabbits. METHODS: New Zealand White rabbits (n = 24) were implanted with polypropylene meshes (32 g/m(2)), with (Prolift plus M, n = 12) or without (Prolift minus M, n = 12) polyglecaprone fibers. Following implantation in the posterior vaginal and abdominal wall, local side effects were evaluated and explants underwent uniaxial tensiometry after 120 and 180 days. RESULTS: The vaginal extrusion rate was at least 50 %, coinciding with a minimum of 20 % of contraction. There were no measurable effects of the addition of polyglecaprone on tensiometric strength and compliance in abdominal explants. CONCLUSIONS: The addition of polyglecaprone fibers did not compromise the biomechanical properties nor did it prevent vaginal extrusion and contraction. The latter as well as some other limitations preclude the rabbit vagina to be a suitable model for biomechanical testing. PMID- 22527543 TI - Long-term follow-up of persistent vaginal polypropylene mesh exposure for transvaginally placed mesh procedures. AB - INTRODUCTION AND HYPOTHESIS: The surgical treatment of a cystocele via the vaginal route may require the placement of a synthetic mesh below the bladder. However, the placement of a synthetic mesh via the vaginal route can be associated with specific complications, such as vaginal mesh exposure. There is a lack of data concerning the long-term follow-up of asymptomatic persistent vaginal polypropylene mesh exposure. METHODS: This was a retrospective case series of nine patients presenting with persistent vaginal mesh exposure following the placement of a macroporous monofilament polypropylene mesh for cystocele treatment. Expectant management has been proposed since the patients were asymptomatic. RESULTS: The median follow-up duration was 121 months [interquartile range (IQR) 119-132]. The median surface area of vaginal mesh exposure (1 cm(2); IQR 1-1) did not change significantly during the follow-up. No pelvic or perineal abscess occurred during the follow-up. Only one of them was sexually active; she complained of dyspareunia at the last follow-up, but refused renewed surgery since she had sexual intercourse on only a small number of occasions per year. Clinical examination using the International Continence Society Pelvic Organ Prolapse Quantification system: Ba -3 to -2 (n = 7; 88 %), Ba -1 (n = 1; 12 %), Ba 0 or greater (n = 0). CONCLUSIONS: Persistent asymptomatic vaginal polypropylene mesh exposure is associated with few complications at long-term follow-up. PMID- 22527545 TI - Beyond the complications: medium-term anatomical, sexual and functional outcomes following removal of trocar-guided transvaginal mesh. A retrospective cohort study. AB - INTRODUCTION AND HYPOTHESIS: The aims of this study were to assess the anatomical, sexual and functional outcomes of women undergoing surgical intervention for complications of the trocar-guided transvaginal mesh (TVM) procedure. METHODS: This was a retrospective analysis of a clinical database of women who had developed a complication following a TVM procedure. This included dyspareunia, mesh erosion, urinary symptoms, mesh contraction and prolapse recurrence. Pre- and post-operatively, we assessed the women for prolapse, stress incontinence, urgency, defecatory difficulty, digitation, pain, dyspareunia and apareunia. We also recorded the Pelvic Organ Prolapse Quantification (POP-Q) score. The TVM was removed and a Biodesign graft was used in the majority of cases to prevent further prolapse. Follow-up was at 6 weeks, 6 months, 1 and 2 years. RESULTS: In our cohort of 21 women, 18 required surgery for pain and/or dyspareunia; 20 women had reached the 6-week follow-up at the time of analysis. At 6 weeks, two women still had pain and required a second intervention. Fifteen women had reached a 6-month follow-up and only one woman had persistent pain requiring repeat surgery. Of the 15 women, 7 were sexually active and in 6 cases the dyspareunia had resolved completely with 1 woman retaining an element of pain at intercourse. Six women had been seen at 12 months and all four of the sexually active women had no dyspareunia. There were no symptoms relating to prolapse in any of the women at 6 weeks, 6, 12 or 24 months. CONCLUSIONS: We report satisfactory outcomes following removal of a complicated TVM kit. PMID- 22527544 TI - The iceberg of health care utilization in women with urinary incontinence. AB - INTRODUCTION AND HYPOTHESIS: The objective of the study was to estimate prevalence of urinary incontinence (UI) health care utilization in women from the population up to specialty care. METHODS: The General Longitudinal Overactive Bladder Evaluation-UI (GLOBE-UI) is a population-based study on the natural history of UI in women >= 40 years of age. Prevalence of UI was estimated by using the Bladder Health Survey (BHS). Survey data were linked with electronic health records to build the different steps of the iceberg of disease. Descriptive statistics were used to estimate the prevalence estimates at all levels of the iceberg. RESULTS: A total sample of 7,059 women received the BHS. Of those, 3,316 (47 %) responded. Prevalence of UI was 1,366 (41 %). Women with or without UI did not differ by age or marital status. However, women with versus without UI were more parous (91 vs 87 %), significantly more overweight or obese (74 vs 61 %), and more likely to have a college education or higher (54 vs 46 %), P < 0.01. Nine hundred fifty-eight (73 %) women with UI reported duration of more than 2 years and 72 % reported moderate to severe UI symptoms. Of all 1,366 women with BHS UI diagnosis, only 339 (25 %) sought care, 313 (23 %) received some care, and 164 (12 %) received subspecialty care. CONCLUSIONS: UI is a highly prevalent disease. Only a minority with UI appears to seek care and a fraction sees a pelvic floor specialist. It is important not only to educate women, but also primary care providers about this highly prevalent yet treatable condition. PMID- 22527546 TI - Is cervical elongation associated with pelvic organ prolapse? AB - INTRODUCTION AND HYPOTHESIS: It is commonly believed that pelvic organ prolapse (POP) is associated with cervical elongation. However, cervical lengths have not been formally compared between women with prolapse and those with normal support. METHODS: Cervix and uterine corpus lengths were measured on magnetic resonance images in a case-control study of 51 women with prolapse and 46 women with normal support determined by the Pelvic Organ Prolapse Quantification (POP-Q) examination. Group matching ensured similar demographics in both groups. Ranges for normal cervical lengths were determined from the values in the control group in order to evaluate for cervical elongation amongst women with prolapse. RESULTS: The cervix is 36.4 % (8.6 mm) longer in women with prolapse than in women with normal pelvic support (p < 0.001). Linear regression modeling suggests the feature most highly associated with cervical length is the degree of uterine descent (POP-Q point C). Approximately 40 % of women with prolapse have cervical elongation; 57 % of cervical elongation in prolapse can be explained by a logistic regression-based model including POP-Q point C, body mass index, and menopausal status. CONCLUSIONS: Cervical elongation is found in one third of women with POP, with the extent of elongation increasing with greater degrees of uterine descent. PMID- 22527547 TI - Uretero-vesico-cervical fistula following a caesarean section: a unique case report. AB - A unique combined fistula involving simultaneously the bladder, ureter, and cervix following cesarean section is described. Evaluation, management, and review of the literature regarding this rare and challenging case are reported. This unique case report emphasizes the potential complexity of iatrogenic genitourinary fistulae, suggesting that these might have unexpected morphology and present with multiple fistulous components. It has been demonstrated that concomitant ureteral involvement is estimated to complicate at least 10 % of vesico-vaginal fistulae. Thus, increased awareness of the possibility of complex iatrogenic fistulae and precise evaluation of the upper urinary tract are necessary to accurately define the extent of all fistulous tracts during the initial evaluation. This in turn may enable tailored management of these challenging cases. Moreover, in the case of surgical treatment, an accurate initial definition of fistula morphology may enable a single-stage reconstructive procedure sparing additional interventions and avoiding any potential complications. PMID- 22527548 TI - Surgical management of apical pelvic support defects: the impact of robotic technology. AB - INTRODUCTION AND HYPOTHESIS: Our aim was to determine what effect access to robotic technology had on our approach to managing apical pelvic support defects. METHODS: This was a retrospective chart review of 187 pelvic floor reconstructive surgeries performed for the 18 months prior to (time period 1: January 2007 to July 2008) and following (time period 2: July 2009 to December 2009) the introduction of the robot. Chi-square was used to compare percentages, and analysis of variance (ANOVA) was used to compare demographic data among groups. RESULTS: Overall, 187 procedures were performed for apical prolapse during the study period: 61 in time period 1 and 126 in time period 2. Following the introduction of robotic technology, a significant change from vaginal to abdominal reconstruction occurred. Uterosacral ligament suspension declined from 67 % to 22 % (p < 0.0001), whereas sacrocolpopexy increased from 25 % (15/61) to 66 % (83/126) (p < 0.0001). The rate of abdominal sacrocolpopexy, however, declined from 25 % (15/61) to 2 % (2/126) over the two time periods (p < 0.0001). CONCLUSION: The introduction of robotic technology significantly affected the surgical procedure and mode of surgical access for repair of apical pelvic support defects. PMID- 22527549 TI - Periurethral angioleiomyoma in a female patient. AB - A 51-year-old white woman, gravida 4, para 3-0-1-3 referred to our urogynecology clinic for evaluation of questionable symptomatic pelvic organ prolapse was found to have a periurethral mass with associated urinary urgency. She underwent transvaginal excision of this mass, and pathology revealed angioleiomyoma. Her urinary urgency has resolved after surgery. No prior periurethral angioleiomyoma has been reported in female patients. PMID- 22527550 TI - Female urinary incontinence: patient-reported outcomes 1 year after midurethral sling operations. AB - INTRODUCTION AND HYPOTHESIS: Although midurethral slings have become standard surgical methods to treat stress urinary incontinence (SUI), little is known about women who still have urinary incontinence (UI) after surgery. This study assesses and compares the patient-reported outcome 12 months after tension-free vaginal tape (TVT), tension-free vaginal tape-obturator (TVT-O), and transobturator tape (TOT), with a special focus on women who still have urinary leakage postoperatively. METHODS: This study analyzed preoperative and 12-month postoperative data from 3,334 women registered in the Swedish National Quality Register for Gynecological Surgery. RESULTS: Among the women operated with TVT (n = 2,059), TVT-O (n = 797), and TOT (n = 478), 67 %, 62 %, and 61 %, respectively, were very satisfied with the result at the 1-year follow-up. There was a significantly higher chance of becoming continent after TVT compared with TOT. In total, 977 women (29 %) still had some form of urinary leakage postoperatively. Among the postoperatively incontinent women who expressed a negative impact of UI on family, social, work, and sexual life preoperatively, considerably fewer reported a negative impact in all domains after surgery. Of those in the postoperatively incontinent group who had coital incontinence preoperatively, 63 % reported a cure of coital incontinence. CONCLUSIONS: The proportion of women very satisfied with the result of the operation did not differ between the three groups. TVT had a higher SUI cure rate than did TOT. Despite urinary leakage 1 year postoperatively, half of the women were satisfied with the result of the operation. PMID- 22527551 TI - Full-thickness rectal prolapse following posterior vaginal repair: something to worry about? PMID- 22527552 TI - Failed labor induction in nulliparous women at term: the role of pelvic floor muscle strength. AB - INTRODUCTION AND HYPOTHESIS: The prolongation, protraction or complete cessation of labor is called failed labor. It is one of the leading indications for cesarean delivery. The goal of this study was to measure pelvic floor muscle strength and investigate its effect on labor in nulliparous pregnant women. METHODS: A total of 88 patients were included in the study. The study was conducted in nulliparous pregnant women with a low Bishop score (<= 7). A low dose intravenous oxytocin protocol was used for labor induction in all patients. Evaluation of pelvic floor muscle (PFM) strength was performed using a vaginal pressure measurement device just before labor induction. The duration of labor stages and the rate of failed labor were considered the main outcomes. The study group consisted of patients whose labor failed and who subsequently underwent cesarean delivery. The control group consisted of patients who delivered vaginally. The pelvic floor muscle strength and main outcome measures of the two groups were compared. RESULTS: No differences were found in age, weight, height, body mass index (BMI), and neonatal birth weight between the study and control groups. The mean resting and maximum squeeze pressures in the study group were 29.6 +/- 9.8 and 56.4 +/- 12.1 cm H(2)O respectively, significantly higher than in the control group. The best predictor of failed labor was a maximum squeeze pressure value of 59 cm H(2)0 (51.6% sensitivity and 87.7% specificity). CONCLUSIONS: Pelvic floor muscle strength appears to play a role in predicting failed labor. PMID- 22527553 TI - Vault prolapse of sigmoid neovagina 26 years after vaginoplasty in Mayer Rokitansky-Kuster-Hauser syndrome: a case report. AB - Various operative methods have been devised to create a neovagina for patients with Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. Sigmoid vaginoplasty, a common modality for vaginal reconstruction, is believed to have satisfactory long term anatomical and functional results. We herein report a patient with MRKH syndrome and vault prolapse of a sigmoid neovagina 26 years after vaginoplasty. Biopsies from the neovagina revealed colonic mucosa. Bilateral iliococcygeus fascia fixation of the neovaginal vault was performed vaginally. The patient had a low Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire-12 (PISQ 12) score preoperatively, which further decreased postoperatively. Therefore, the surgery failed to achieve a good functional result. No recurrence of the prolapse was observed 2 years postoperatively. PMID- 22527554 TI - Impact of surgically induced weight loss on pelvic floor disorders. AB - INTRODUCTION AND HYPOTHESIS: Given the increased prevalence of obesity and pelvic floor disorders (PFDs), we estimated changes in prevalence, bother, and quality of life (QOL) for PFDs in obese women undergoing bariatric surgery. We hypothesized PFDs would improve after surgical weight loss. METHODS: The prevalence, bother, and QOL impact of PFDs were estimated using validated measures. McNemar's and paired t tests were used to compare pre- and postprocedural outcomes. Power calculations deemed that 90 individuals would achieve at least 80 % power to detect a decrease in prevalence of 12 %. RESULTS: The baseline mean (+/- standard deviation) age and body mass index (BMI) of the 98 women were 43.3 +/- 11.8 years and 39.7 +/- 6.2 kg/m.(2) BMI decreased to 34.4 +/- 5.8 at 6 months and 34.0 +/- 5.6 at 12 months. Whereas the overall prevalence of stress urinary incontinence (SUI) decreased from 22/69 (32 %) at baseline to 10/69 (15 %) at 6 months (p = 0.006) and 14/69 (20 %) at 12 months (p = 0.027), there were no significant decreases in overall prevalence of other PFDs. However, for women with SUI, overactive bladder (OAB), and anal incontinence at baseline, 11/23 (48 %), 8/11 (73 %) and 4/20 (20 %) resolved at 12 months, respectively. Pelvic Floor Impact Questionnaire scores decreased from baseline to 12 months (p < 0.001). Mean visual analog scores for women with SUI, OAB, and anal incontinence decreased at 12 months. CONCLUSIONS: Surgical weight loss resulted in resolution of symptoms in nearly half of women with SUI and three quarters of women with OAB and was associated with significant improvement in QOL. PMID- 22527555 TI - Effects of a modified technique for TVT-O positioning on postoperative pain: single-blind randomized study. AB - INTRODUCTION AND HYPOTHESIS: One of the most frequent and distressing complications of the tension-free vaginal tape obturator (TVT-O) procedure for stress urinary incontinence (SUI) is groin pain, which may be related to the surgical technique or to the tape. The aim of this study was to evaluate the impact of a more limited dissection and a more medial trocar trajectory in TVT-O positioning on postoperative pain. METHODS: Seventy-two SUI patients were randomized to undergo TVT-O either with the traditional technique (group A) or a modified procedure (reduced paraurethral dissection and a more medial trocar trajectory) (group B). Visual analog scale pain scores 12 h, 24 h, and 1 month after the procedure, number of analgesic vials, objective cure rate, and patient functional and quality of life scores 6 months after the procedure were evaluated. Data were analyzed by the Student's t test for parametric variables, the Mann-Whitney U and Wilcoxon tests for nonparametric variables, and Fisher's exact test for categorical variables. RESULTS: Pain scores were significantly lower in group B compared with group A 24 h after surgery (P = 0.01). Pain scores significantly decreased from 12-24 h postoperatively to 1 month follow-up in both groups (P < 0.001). No significant differences were observed in the number of analgesic vials administered, cure rates, and questionnaire scores between the two groups. CONCLUSIONS: More limited dissection and a more medial trocar trajectory of TVT-O seem to reduce postoperative groin pain at 24 h after the procedure, but not the analgesic requirement. PMID- 22527556 TI - Posterior vaginal prolapse shape and position changes at maximal Valsalva seen in 3-D MRI-based models. AB - INTRODUCTION AND HYPOTHESIS: Two-dimensional magnetic resonance imaging (MRI) of posterior vaginal prolapse has been studied. However, the three-dimensional (3-D) mechanisms causing such prolapse remain poorly understood. This discovery project was undertaken to identify the different 3-D characteristics of models of rectocele-type posterior vaginal prolapse (PVP(R)) in women. METHODS: Ten women with (cases) and ten without (controls) PVP(R) were selected from an ongoing case control study. Supine, multiplanar MR imaging was performed at rest and maximal Valsalva. Three-dimensional reconstructions of the posterior vaginal wall and pelvic bones were created using 3D Slicer v. 3.4.1. In each slice the posterior vaginal wall and perineal skin were outlined to the anterior margin of the external anal sphincter to include the area of the perineal body. Women with predominant enteroceles or anterior vaginal prolapse were excluded. RESULTS: The case and control groups had similar demographics. In women with PVP(R) two characteristics were consistently visible (10/10): (1) the posterior vaginal wall displayed a folding phenomenon similar to a person beginning to kneel ("kneeling" shape) and (2) a downward displacement in the upper two thirds of the vagina. Also seen in some, but not all of the scans were: (3) forward protrusion of the distal vagina (6/10), (4) perineal descent (5/10), and (5) distal widening in the lower third of the vagina (3/10). CONCLUSIONS: Increased folding (kneeling) of the vagina and an overall downward displacement are consistently present in rectocele. Forward protrusion, perineal descent, and distal widening are sometimes seen as well. PMID- 22527557 TI - A novel transvaginal approach to correct recurrent apical prolapse after failed sacral colpopexy: case series. AB - INTRODUCTION AND HYPOTHESIS: The objective of the study was to describe the transvaginal approach utilizing the existing sacral colpopexy (SC) graft for recurrent apical prolapse following failed SC. METHODS: Twenty-two patients with recurrent vaginal vault prolapse following a prior SC were treated between January 2000 and December 2009. Twelve patients had a standard uterosacral ligament cuff suspension (USLS) performed. In ten patients, the vaginal cuff was suspended to the left uterosacral ligament and reattached to the graft material from the prior SC. One of these ten subsequently failed and a standard USLS was performed. Patient characteristics, preoperative pelvic floor assessment, operative information, and postoperative follow-up were collected. Cases in which the graft material was used were compared with those undergoing standard USLS. RESULTS: Demographic characteristics and preoperative Baden-Walker scores were similar. Of 23 cases, 21 (91 %) were a consequence of graft separation from the vagina and not the sacrum. Two of nine patients with follow-up where the SC graft was utilized transvaginally had recurrent prolapse. One required reoperation. Of 13 patients in the group that underwent traditional USLS, 2 had asymptomatic recurrent anterior prolapse; neither required additional surgery. CONCLUSIONS: A transvaginal surgical approach for recurrent vaginal prolapse after a history of failed abdominal SC should be considered. If feasible, the SC graft material can be used when performing USLS instead of the right uterosacral ligament for these patients with a prior history of abdominal SC. PMID- 22527558 TI - Occult incontinence as predictor for postoperative stress urinary incontinence following pelvic organ prolapse surgery. AB - INTRODUCTION AND HYPOTHESIS: Recommending prophylactic anti-incontinence procedures to continent women undergoing surgery for pelvic organ prolapse (POP) is controversial. We hypothesized that testing for occult incontinence before surgery using four different tests and three defined test combinations would identify individual women at risk for postoperative stress urinary incontinence (POSUI). The diagnostic accuracy of these tests and test combinations were evaluated. METHODS: We tested 137 women before and after surgery. Fisher's exact test was used when evaluating associations between test results and outcomes. The validity of each test and test combinations was calculated. RESULTS: We found a statistically significant association between occult incontinence and POSUI in two tests and all test combinations. However, all tests and test combinations displayed poor performance when predicting at individual levels. CONCLUSIONS: This study confirms a positive association between occult incontinence and POSUI. Occult incontinence does not, however, adequately identify individual women in need of prophylactic anti-incontinence surgery when undergoing POP repair. PMID- 22527559 TI - Patient goal attainment in vaginal prolapse repair with and without mesh. AB - INTRODUCTION AND HYPOTHESIS: The objective of this study was to describe patient centered goals and their attainment in vaginal prolapse repair, with and without mesh. METHODS: A secondary analysis of a multicenter randomized controlled trial of prolapse repair with or without vaginal mesh was performed. Participants (n = 65) selected three preoperative goals ranked by importance. At 3 and 12 months postoperatively, patients graded their goal attainment on a scale of 1 (not at all) to 5 (100 % attainment). Goal attainment was compared with anatomical outcome, symptoms, quality of life, and satisfaction scores. Nonparametric tests and the log-rank test were used to determine statistical significance (p < 0.05). RESULTS: A total of 176 goals were selected. The first goal in 37 women (57 %) was improving prolapse symptoms, in 15 (23 %) urinary symptoms, in 7 (11 %) appearance, activity, and self-image, in 2 (3.1 %) bowel symptoms, and in 2 (3.1 %) sexual function. At 3 and 12 months postoperatively, goal achievement for prolapse symptoms was 96.1 and 93.6 %, for urinary symptoms 75.6 and 70.0 %, and for appearance, activity, and self-image 90.5 and 94.7 %, respectively. The effect of anatomical outcome, mesh use, or the presence of mesh erosion on goal attainment could not be demonstrated. Women who achieved their first goal had significantly better symptoms, quality of life, and satisfaction scores than women who did not. CONCLUSIONS: Patient goal attainment after vaginal prolapse repair was high and not consistently related to objective anatomical outcome or mesh use. It persisted between 3 and 12 months postoperatively and was associated with better satisfaction, quality of life, and symptom scores. PMID- 22527560 TI - Periurethral abscess following polyacrylamide hydrogel (Bulkamid) for stress urinary incontinence. AB - Bulkamid is a periurethral bulking agent used to treat stress urinary incontinence (SUI). Manufacturers describe it as nontoxic, nonbiodegradable and biocompatible. Periurethral abscesses are one of the known complications of bulking agents. We present the first reported case of periurethral abscess following Bulkamid injection. The woman had previously had a transobturator tape (TOT) and total vaginal mesh repair. At 6 weeks after injection of the bulking agent, she reported 100 % cure of her SUI. Transperineal ultrasound was used to diagnose and monitor an abscess that developed anterior and lateral to the urethra and separate from the TOT. Magnetic resonance imaging was helpful in delineating the extent of the abscess into the retropubic space but was not able to identify the urethra or the TOT. Surgical drainage of the abscess was performed vaginally, resulting in successful resolution of pain but recurrence of incontinence. PMID- 22527562 TI - Fluid intake and voiding parameters in asymptomatic Turkish women. AB - INTRODUCTION AND HYPOTHESIS: For an accurate evaluation of bladder diaries, we aim to investigate normal urinary habits and determining factors on functional bladder capacity, frequency, and 24-h volume in the bladder diaries of asymptomatic women. METHODS: One-hundred and fifteen asymptomatic women who recorded a 24-h bladder diary were included in the study. Linear regression analyses were used to explore associations between diary values and patient characteristics. RESULTS: Total number of voids was related to age, body mass index, total voided volume, total fluid intake, total diuresis rate, and maximum fluid intake in one go. Maximum, average, and minimum volumes per void were found to be related to body mass index, total voided volume, total fluid intake, total diuresis rate, and maximum fluid intake. When we used multiple regression analysis, only maximum fluid intake was found to be related to the total number of voids, maximum, average, and minimum volumes per void. CONCLUSIONS: Maximum fluid intake rather than total voided volume seems to be an important determinant factor for total number of voids and functional bladder capacity. PMID- 22527561 TI - Determination of urinary hexosamines for diagnosis of bladder pain syndrome. AB - INTRODUCTION AND HYPOTHESIS: Bladder pain syndrome (BPS) is a chronic disease characterized by urgency, bladder pain, and frequency, and urinary glycosaminoglycans are thought to reflect bladder epithelial deficiency in BPS. Sensitive and specific evaluation of total urinary glycosaminoglycans may be useful for the clinical diagnosis of BPS and its treatment. METHODS: A procedure for the simultaneous determination of glucosamine and galactosamine produced from urinary glycosaminoglycans has been performed in BPS patients and healthy subjects. RESULTS: The total content of urinary hexosamines in BPS patients significantly increased by ~130% with the increase in glucosamine greater than galactosamine. CONCLUSIONS: A significant increase in total hexosamines content and in particular in glucosamine belonging to urinary heparan sulfate was determined in BPS patients compared with controls. We propose HS and in particular its low-molecular mass fragments and glucosamine assay as useful markers for a biochemical diagnosis of BPS and for monitoring this syndrome. PMID- 22527563 TI - B16-F10 melanoma cells contribute to the new formation of blood vessels in the chick embryo chorioallantoic membrane through vasculogenic mimicry. AB - Grafting of mammalian cells and tissues to the chick embryo chorioallantoic membrane (CAM) is a well-established experimental system to evaluate many different parameters of tumor growth, and B16-F10 murine melanoma cell line has been successfully used to study metastatic process in the CAM assay. The aim of this study was to demonstrate the capability of B16-F10 melanoma cells to contribute to the new formation of host blood vessels through a vasculogenic mimicry mode. Results have shown that B16-F10 melanoma cells are able to form in 4 days macroscopic tumor masses and induce a strong angiogenic response comparable to that of a well-known angiogenic cytokine, namely fibroblast growth factor-2. Moreover, tumor cells are able to cross the chorionic epithelium, and to move beneath in the mesenchyme to form tumor masses immunoreactive to specific antibodies anti-S100 and anti-MART-1/Melan-A. Finally, we have shown that CAMs new-formed blood vessels are lined by both pigmented melanoma cells and cells immunoreactive to MART-1/Melan-A and PAS, suggesting the occurrence of a vasculogenic mimicry process. PMID- 22527564 TI - A case-control study of risk factors for severe hand-foot-mouth disease among children in Ningbo, China, 2010-2011. AB - BACKGROUND: A small fraction of hand-foot-mouth disease (HFMD) progression from the onset of severity to fatality may be remarkably rapid. Early recognition of children at risk of severity is critical to increase treatment effectiveness and reduce acute mortality. METHODS: A frequency-matched case-control study was conducted between January 2010 and June 2011 in Ningbo to identify risk factors associated with the occurrence of severity in children with HFMD. Data including demographic characteristics, clinical features, and laboratory test results were collected by trained interviewers through retrospective medical record review and/or face-to-face interviews with children's parents using a standardized questionnaire. RESULTS: Eighty-nine cases with severe HFMD and 267 controls with mild HFMD were recruited in this study. Palm rashes (OR = 0.004, 95%CI = 0.000 0.039, p < 0.001), oral ulcers or herpes (OR = 0.001, 95%CI = 0.000-0.009, p < 0.001) were significantly associated with protection against severity, and an increased risk of severity was significantly associated with the presence of, e.g., a high fever of over 39 degrees C for more than 3 days (OR = 2.217, 95%CI = 1.082-4.541, p = 0.030), leg trembling (OR = 29.008, 95%CI = 1.535-548.178, p = 0.025), papule rash (OR = 4.622, 95%CI = 1.110-19.252, p = 0.035), a raised WBC count > 10.8 * 10(9)/L (OR = 4.495, 95%CI = 1.311-15.415, p = 0.017), and human enterovirus 71 infection (OR = 39.172, 95%CI = 9.803-156.522, p < 0.001). CONCLUSION: Clinicians should pay increased attention to children diagnosed as HFMD with the independent risk factors above. PMID- 22527565 TI - Medical management of moyamoya disease and recurrent stroke in an infant with Majewski osteodysplastic primordial dwarfism type II (MOPD II). AB - We report an infant diagnosed with Majewski osteodysplastic primordial dwarfism type II at age 8 months, who experienced cerebrovascular morbidities related to this entity. Molecular analysis identified c.2609+1 G>A, intron 14, homozygous splice site mutation in the pericentrin gene. At age 18 months, she developed recurrent strokes and hemiparesis. Brain magnetic resonance imaging and magnetic resonance angiography showed abnormal gyral pattern, cortical acute infarcts, bilateral stenosis of the internal carotid arteries and reduced flow on the cerebral arteries, consistent with moyamoya disease. In Majewski osteodysplastic primordial dwarfism type II, life expectancy is reduced because of high risk of stroke secondary to cerebral vascular anomalies (aneurysms, moyamoya disease). Periodic screening for vascular events is recommended in individuals with Majewski osteodysplastic primordial dwarfism type II every 12-18 months following diagnosis. Our patient was medically managed with low molecular weight heparin followed with aspirin prophylaxis, in addition to carbamazepine and physical rehabilitation. CONCLUSION: We report an infant with moyamoya disease and recurrent stroke presenting 10 months after diagnosis (at age 18 months), and discuss the outcome of nonsurgical medical management. The presented case is the second youngest case developing stroke and moyamoya disease. PMID- 22527566 TI - Factors influencing neurological outcome of children with bacterial meningitis at the emergency department. AB - We performed a cohort study of children who survived bacterial meningitis after the neonatal period at a single pediatric center in France over a 10-year period (1995-2004) to identify predictors of death and long-term neurological deficits in children with bacterial meningitis. We performed multivariate regression to determine independent predictors of death and neurologic deficits. We identified 101 children with bacterial meningitis of which 19 died during initial hospitalization. Need for mechanical ventilation [hazard ratio (HR) 11.5, 95 % confidence interval (CI) 2.4-55.5)] and thrombocytopenia defined as a platelet count <150 * 10(9) per liter (HR 0.6, 95 % CI 0.4-0.9) at presentation were associated with death during initial hospitalization. At final assessment, 42 of the 70 survivors had no neurologic deficits identified; 20 had a single deficit, and eight had multiple deficits. A delay in initiation of antibiotics (HR 1.3, 95 % CI 1.1-1.7) and hydrocephalus on computed tomographic scan (HR 2.6, 95 % CI 1.1 6.0) were associated with having one or more long-term neurologic deficits. Identification of children at risk of death or long-term neurologic sequelae may allow therapeutic interventions to be directed to children at the highest risk. PMID- 22527567 TI - Correlation of blood pressure, obesity, and adherence to the Mediterranean diet with indices of arterial stiffness in children. AB - The aim of the study was to assess the hypothesis that obesity, blood pressure (BP), and dietary habits (adherence to the Mediterranean diet) are related to indices of arterial stiffness (AS) in childhood. Two hundred and seventy-seven children aged 12 years were measured with the R6.5 Pulsecor(r) monitor, which performs measurements using an upper arm BP cuff held at above systolic pressure for a short time. The augmentation index (AI) in the brachial artery, the peripheral pulse pressure to central pulse pressure (PPP/CPP) ratio, and the reflected wave transit time to height ratio were used as indices of AS. The degree of adherence to the Mediterranean diet was assessed by the KIDMED index which includes 16 questions on specific dietary habits. Forty-three percent of the children were overweight and obese. Overweight and obese children had significantly lower PPP/CPP and KIDMED score in comparison to children with normal body mass index (BMI). In multivariate regression models, indices of AS were related to mean peripheral BP, heart rate, and height, while BMI had an independent correlation to PPP/CPP. The KIDMED index also had a negative correlation with AI independently of obesity. CONCLUSION: Obesity and adherence to the Mediterranean diet patterns are factors related independently to indices of AS even in 12-year-old children. PMID- 22527568 TI - Lupus anticoagulants in two children--bleeding due to nonphospholipid-dependent antiprothrombin antibodies. AB - We describe two children with significant bleeding: one with multiple ecchymoses and the other with scrotal bleeding. In both patients, the activated partial thromboplastin time (APTT) was prolonged, with positivity for lupus anticoagulants (LA). However, the Owren prothrombin time (PT), usually insensitive for LA, was also prolonged. The presence of LA is associated with diverse clinical manifestations, with most patients being asymptomatic while others present venous or arterial thrombosis. Bleeding in conjunction with LA is rare and it is unusual to see prolongation of the Owren PT assay due to LA. An extended laboratory investigation of one of the patient's plasma revealed not only LA but also a specific nonphospholipid-dependent antiprothrombin antibody causing an acquired hypoprothrombinemia. CONCLUSION: It is likely that the low prothrombin activity and not the LA caused the bleeding. The bleeding signs and symptoms in both patients subsided when the PT was normalized, although the prolonged APTT and the LA remained. PMID- 22527569 TI - Pressure-induced angioedema associated with endotracheal tube: successful treatment with epinephrine in two cases. AB - Pressure-induced urticaria is a non-immunoglobulin E-mediated type of urticaria. Some patients only have angioedema, and the term pressure-induced angioedema (PIA) is more appropriate for them. PIA has not previously been reported in association with endotracheal tube. Here we describe two patients who developed PIA after endotracheal intubation. There were no histories of angioedema, drug and food allergy in both patients. Tests for specific aero-allergens and latex were negative. Serum total immunoglobulin E and C4 levels were in normal ranges. Antihistamines and intravenous steroid therapy were ineffective. Angioedema regressed with intravenous epinephrine infusion and did not relapse after extubation. CONCLUSION: We suggest that endotracheal tubes can cause PIA. Epinephrine therapy should be used early at treatment, especially in the patients who are at great risk for life-threatening airway problems. PMID- 22527570 TI - The controversy regarding the need for hormonal treatment in boys with unilateral cryptorchidism goes on: a review of the literature by B. Ludwikowski and R. Gonzalez. PMID- 22527571 TI - Cauda equina compression post lumbar discography. AB - Discography is used as an aid in the diagnosis of back pain related to intervertebral disc pathology. It involves attempting to elicit the patient's pain symptoms by injecting contrast into the suspected pathological disc. The overall complication rate of discography is low, with discitis being the most common complication and acute disc herniation post lumbar discography being reported in a small number of cases. We describe the case of a patient who developed cauda equina compression post lumbar discography. PMID- 22527572 TI - Anatomy of the supraventricular portion of the pyramidal tract. AB - BACKGROUND: The anatomy and somatotopy of the pyramidal tract during its course in the internal capsule has recently been discussed by many publications. However, the reports on the anatomy of the clinically more important supraventricular portion of the tract are scarce. The objective of this study is to investigate the anatomy and somatotopy of the supraventricular portion of the pyramidal tract. METHODS: In 13 patients undergoing surgery with subcortical electric stimulation for tumors located in the supraventricular white matter close to the pyramidal tract (as depicted by diffusion tensor tracking [DTT]), the relationship between the position of the stimulation point and the motor response in the arm or leg was analyzed. Additionally, the somatotopic organization of the tract was studied using separate tracking of arm and leg fibers in 20 healthy hemispheres. Finally, the course of the tract was studied by dissecting 15 previously frozen human hemispheres. RESULTS: In most cases, subcortical stimulation during the resection of tumors located behind and in front of the pyramidal tract elicited leg and arm movement, respectively. This association of stimulation point position with motor response type was significant. A DTT study of the somatotopy demonstrated a varying degree of rotation of the leg and arm fibers from mediolateral to posteroanterior configuration. Anatomic dissections demonstrated a folding-fan like structure of the pyramidal tract with a similar rotation pattern. CONCLUSION: The pyramidal tract undergoes a large part of its rotation from mediolateral to posteroanterior configuration during its course in the supraventricular white matter, although interindividual differences exist. PMID- 22527573 TI - Additional competence training in neurosurgical (Stereotactic) radiosurgery. PMID- 22527574 TI - The impact of timing of cranioplasty in patients with large cranial defects after decompressive hemicraniectomy. AB - BACKGROUND: It is unclear how soon after a decompressive hemicraniectomy that cranioplasty be safely performed in a patient in whom the ICP has been normalized. Early surgery has been associated with infection, intracerebral hematoma, and complications due to persistent or recurrent brain edema. Delayed cranioplasty of large cranial defects exposes the patient to different conditions known in the literature as the syndrome of the sinking skin flap. The purpose of this study was to investigate the hypothesis that timing of cranioplasty after decompressive hemicraniectomy influences outcome and complications. METHODS: We retrospectively examined outcome after cranioplasty performed at <7 weeks, 7-12 weeks, and >13 weeks after craniectomy in patients with large cranial defects after decompressive hemicraniectomy in our institution between 1997 and 2008. RESULTS: The time between craniectomy and cranioplasty ranged from 17 days to 4 months depending on several factors such as: the cause of decompression, infection before or after craniectomy, and skin flap concavity. The analysis of the registered postoperative complications revealed that there were no significant differences between the examined groups. The cranioplasty at <7 weeks, in the form of reimplantation of the own skull flap, led to a GOS improvement of 78 %, at 7-12 weeks 46 % and at >13 weeks 12 %, respectively. Pairwise comparisons showed that the difference between cranioplasty at <7 weeks versus 7-12 weeks or >13 weeks cranioplasty groups was statistically significant (p = 0.05 and p < 0.001, respectively). CONCLUSIONS: Our study suggests that many patients with large cranial defects after decompressive craniectomy can safely undergo cranioplasty in an early stage; direct answers to these questions of timing of cranioplasty are best addressed by prospective studies. Nevertheless, the present study provides a basis for decision-making in certain patients and for the design of future investigations. PMID- 22527575 TI - Accreditation of neurosurgical training programmes in Europe: report of JRAAC. PMID- 22527576 TI - A review of the role of stem cells in the development and treatment of glioma. AB - The neurosurgical management of patients with intrinsic glial cancers is one of the most rapidly evolving areas of practice. This has been fuelled by advances in surgical technique not only in cytoreduction but also in drug delivery. Further innovation will depend on a deeper understanding of the biology of the disease and an appreciation of the limitations of current knowledge. Here we review the controversial topic of cancer stem cells applied to glioma to provide neurosurgeons with a working overview. It is now recognised that the adult human brain contains regionally specified cell populations capable of self-renewal that may contribute to tumour growth and maintenance following accumulated mutational change. Tumour cells adapted to maintain growth demonstrate some stem-like characteristics and as such constitute a legitimate therapeutic target. Cellular reprogramming technologies raise the potential of developing stem cells as novel surgical tools to target disease and possibly ameliorate some of the consequences of treatment. Achieving these goals remains a significant challenge to neurosurgical oncologists, not least in challenging how we think about treating brain cancer. This review will briefly examine our understanding of adult stem cells within the brain, the evidence that they contribute to the development of brain tumours as tumour-initiating cells, and the potential implications for therapy. It will also look at the role stem cells may play in the future management of glioma. PMID- 22527577 TI - Aneurysm treatment in Europe 2010: an internet survey. AB - BACKGROUND: Aneurysm (AN) treatment appears to differ from country to country and even from centre to centre. Therefore we decided to conduct a survey in order to better understand the "state of the art" in aneurysm treatment in Europe. The primary aim was to understand the roles of clipping and coiling in aneurysm treatment. METHODS: An interactive form was sent to major European neurosurgical centres. The responses relating to AN location, status (ruptured/unruptured) and treatment modality were divided with regard to the volume of cases and the centre's geographical location. RESULTS: Responses were received from 96 European centres. The main finding was that clipping was used significantly more often in Eastern Europe than in the rest of Europe to treat ruptured ANs of the anterior circulation. Almost all ruptured ANs across all locations are treated actively. The treatment of unruptured aneurysms of the anterior circulation is similar. The median relating to observed unruptured ANs across the Europe was 10 %. Posterior circulation ANs are treated predominantly by coiling, regardless of aneurysm status or geographical location. The average number of coilers versus surgeons per centre was 2.5:3.0 in Western, 1.9:3.6 in Southern, 1.9:4.3 in Eastern and 2.7:3.1 in Northern Europe. CONCLUSIONS: The way in which intracranial aneurysms are treated appears to correlate with the economic development of European countries. It is probably also affected by the lack of experienced coilers in Eastern Europe. PMID- 22527578 TI - Pituitary tumorous hyperplasia due to primary hypothyroidism. AB - BACKGROUND: To study the diagnostic and therapeutic features of pituitary tumorous hyperplasia due to primary hypothyroidism. METHODS: Fifteen patients with pituitary tumorous hyperplasia were studied in clinical manifestation, pathologic, endocrinological, radiographic and therapeutic features retrospectively. RESULTS: All of these patients suffered from primary hypothyroidism. Magnetic resonance imaging (MRI) scanning found that there were masses in the sellar region with equal T1 and little longer T2 signal, and which could be obviously enhanced by gadolinium EDTA injection. Diameters of these masses were between 1.1 and 2.5 cm. Thyroxine substitution therapy was ordered. Four months later, MRI scanning found that the masses disappeared and only normal pituitary gland left. Plasma thyroxine, thyroid-stimulating hormone (TSH), and prolactin (PRL) levels dropped to their normal ranges. CONCLUSIONS: Thyroxine substitution therapy was the first choice of pituitary tumorous hyperplasia due to primary hypothyroidism. If they are followed by TSH adenoma, or the optic chiasma was pressed by the enlarged pituitary, transsphenoidal microsurgery could be applied. PMID- 22527579 TI - Is C-reactive protein useful as a predictor for poor outcome after aneurysmal subarachnoid hemorrhage? PMID- 22527581 TI - Primary decompressive craniectomy for acute subdural haematomas: results of an international survey. PMID- 22527582 TI - Ultrasonically assisted face-lift. AB - BACKGROUND: The face-lift procedure is one of the most skillful interventions performed by plastic surgeons. Ultrasonic energy is used to elevate the facial skin flap, which allows for preservation of vascular, lymphatic, and nervous structures, thereby decreasing the morbidity associated with this procedure. METHODS: A retrospective study to compare the outcomes of ultrasound and non ultrasound-assisted face-lifts is reported. All the procedures were performed at the Institute for Plastic Surgery. Each group consisted of 104 patients. Statistical analysis was performed to determine differences between the groups. RESULTS: The mean operating time was 4 h in the treatment group versus 4.2 h in the control group (p>0.05). The incidence of hematoma formation was 0.96% in the treatment group versus 2.4% in the control group (p<0.05). The incidence of flap necrosis was 0% in both groups. The duration of ecchymosis was 13 days in the experimental group versus 17.2 days in the control group (p<0.05). The duration of postoperative swelling was 17.4 days in the treatment group versus 20.4 days in the control group (p<0.05). As reported, 85% of patients in the treatment group were very satisfied, 14.42% were satisfied, 0% were mildly satisfied, and 0% were not satisfied. In the control group, 80.7% were very satisfied, 18.26% were satisfied, 0.96% were mildly satisfied, and 0% were not satisfied. According to Fisher's exact test, the p value for patient satisfaction exceeded 0.05%. CONCLUSIONS: The preservation of the blood and lymphatic vessels diminishes postoperative swelling and shortens the duration of ecchymosis considerably. The incidence of hematoma formation is lower than with a non-ultrasonic face-lift. This study failed to prove any statistically significant difference in operating time or patient satisfaction between the two groups. PMID- 22527583 TI - Pseudoaneurysm of the superficial temporal artery: a complication of botulinum toxin injection. AB - Pseudoaneurysms of the superficial temporal artery (STA) must be considered in the differential diagnosis of masses of the lateral forehead and temporal fossa. Although the first reported case of a temporal artery aneurysm was by Thomas Bartholin in 1740, this lesion receives scant mention in the plastic and maxillofacial surgical literature. A history of recent blunt trauma or surgery to the forehead combined with a pulsatile bruit should direct the physician to this diagnosis. A case of pseudoaneurysm arising from the frontal branch of the left STA 2 months after Botox injection is presented. The patient underwent embolization of the STA with Onnix. A similar case was previously reported once in the world literature. PMID- 22527584 TI - A prospective, noninterventional study of the treatment of the aging hand with Juvederm Ultra(r) 3 and Juvederm (r) Hydrate. AB - BACKGROUND: Hand rejuvenation aims to restore volume and produce smooth, elastic skin. A combined treatment has been proposed: Juvederm Ultra(r) 3 for filling and smoothing the skin and Juvederm(r) Hydrate to rehydrate and restore skin quality. METHODS: Twenty physicians enrolled 99 subjects (i.e., 198 hands). At the first visit, hands were injected with Juvederm Ultra(r) 3. At the second visit (day 15) hands were treated with Juvederm(r) Hydrate. A final assessment was made at day 30. RESULTS: Ninety-eight percent of subjects were female (mean age=60.3 years). Mean volumes injected were 1.02 ml Juvederm Ultra(r) 3 per hand at day 0 and 0.91 ml Juvederm(r) Hydrate per hand at day 15. Mean grading on the Hand Aging Scale was 3.18 preinjection, which decreased to 1.73 on study completion (p<0.0001). Injections were rated as "very easy/easy" in 99.4 and 98.9% of cases for Juvederm Ultra(r) 3 and Juvederm(r) Hydrate, respectively. Most physicians found both products "very easy/easy" to massage. Physician evaluation based on the Global Aesthetic Improvement Scale (GAIS) showed that the proportion of "very much/much improved" was significantly higher at days 15 and 30 compared to baseline (63.7 and 70.3 vs. 41.8%). Patient GAIS scores showed that the proportion of "much improved" was significantly higher at day 30 than at day 15 (53.1 vs. 43.9%). Over 94% of physicians and approximately 90% of subjects would recommend treatment. The adverse event rate was 8.2 %, including edema, hematoma, redness, and pain. CONCLUSION: Combined Juvederm Ultra(r) 3 and Juvederm(r) Hydrate treatment is effective and safe for rejuvenating the aging hand. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266. PMID- 22527585 TI - Efficacy and safety of penile girth enhancement by autologous fat injection for patients with thin penises. AB - BACKGROUND: This study aimed to investigate the efficacy and safety of autologous fat injection (AFI) for penile girth enhancement (PGE) in patients with thin penises. METHODS: This study investigated 52 patients with a small penile circumference who underwent AFI for PGE and were followed up for more than 6 months. The patients whose proximal one third (G1) and distal one third of their penis (G2) had a mean thickness of 7.4 cm or less were selected as subjects. After fat suction using a liposuction device, fat was evenly injected into the superficial, middle, and deep layers of the Colles' fascia. Patient age and operative time were analyzed. The G1, G2, flaccid (L1), stretched length (L2), and five-item version of the International Index of Erectile Function-5 (IIEF-5) before and 6 months after the surgery were compared. Postoperative complications were surveyed. RESULTS: The patient mean age was 42.15 years (range, 22-56) years, and the operative time was 44.44 min (range, 37-49 min). The injected fat volume was 38.54 ml (range, 25-49 ml). Preoperatively, G1 was 7.01+/-0.39 cm, and G2 was 7.06+/-0.37 cm. Postoperatively, G1 was 9.29+/-0.82 cm (P<0.001), and G2 was 9.34+/-0.86 (P<0.001) cm 6 months after the surgery. The difference between L1 and L2 before and after the surgery was not significant. The IIEF-5 was 19.10+/-3.22 before the surgery and 19.90+/-3.05 after the surgery (P=0.001). The only complication was nodular fat observed in one case (1.92%). CONCLUSION: The use of AFI for PGE in men with thin penises was effective and safe without major complications. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266. PMID- 22527586 TI - Treatment of hyperdynamic nasal tip ptosis in open rhinoplasty: using the anatomic relationship between the depressor septi nasi muscle and the dermocartilaginous ligament. AB - BACKGROUND: Smiling causes a deformity in some rhinoplasty patients that includes drooping of the nasal tip, elevation and shortening of the upper lip, and increased maxillary gingival show. The depressor septi muscle leads this deformity. The dermocartilaginous ligament originates from the fascia of the upper third of the nose and extends down to the medial crus, merging into the depressor septi muscle. METHODS: In this study, 100 primary rhinoplasty patients were studied for hyperdynamic nasal tip ptosis. Of these patients, 36 had hyperdynamic nasal tip ptosis due to hyperactive depressor septi nasi muscle. The dermocartilaginous ligament was used as a guide to reach the depressor septi muscle in open rhinoplasty. Muscle excision was performed just below the footplates of the medial crura. A strong columellar strut graft was placed between the medial crura to avoid narrowing of the columellar width resulting from tissue excision and to withstand activation of depressor septi muscle remnants. RESULTS: No complications such as infection or hematoma occurred in the early postoperative period. The technique corrected the hyperdynamic nasal tip ptosis, increased upper lip length, and decreased gingival show when patients smiled. There was no narrowing of the columellar width. No depression in the columellar-labial junction due to distal resection of the depressor septi muscle was observed. CONCLUSION: The dermocartilaginous ligament can be used as a reliable guide to reach the depressor septi muscle in open rhinoplasty. Therefore, the hyperactive depressor septi muscle can be definitively identified and treated without an intraoral approach. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266. PMID- 22527587 TI - Assessing nonacceptance of the facial appearance in adult patients after complete treatment of their rare facial cleft. AB - BACKGROUND: Treatment of patients with severe congenital facial disfigurements is aimed at restoring an aesthetic and functional balance. Besides an adequate level of satisfaction, an individual's acceptance of facial appearance is important to achieve because nonacceptance is thought to lead to daily psychological struggles. This study objectified the prevalence of nonacceptance among adult patients treated for their severe facial clefts, evaluated risk factors, and developed a screening tool. METHODS: The study included 59 adults with completed treatment for their severe facial cleft. All the patients underwent a semistructured in-depth interview and filled out the Body Cathexis Scale. RESULTS: Nonacceptance of facial appearance was experienced by 44% of the patients. Of the nonaccepting patients, 72% experienced difficulties in everyday activities related to their appearance versus 35% of the accepting patients. Acceptance did not correlate with objective severity or bullying in the past. Risk factors for nonacceptance were high self-perceived visibility, a troublesome puberty period, and an emotion-focused coping strategy. Also, the presence of functional problems was shown to be highly associated. CONCLUSIONS: The objective severity of the residual deformity did not correlate with the patients' acceptance of their facial appearance, but the self-perceived visibility did correlate. The process of nonacceptance resembles the process seen in patients with body dysmorphic disorders. Surgical treatment is no guarantee for an improvement in acceptance and is therefore discouraged for patients who match the risk factors for nonacceptance unless it solves a functional problem. The authors therefore recommend screening patients for nonacceptance and considering psychological treatment before surgery is performed. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266. PMID- 22527588 TI - An innovative method for intraoperative shaping and positioning of the nipple areola complex in reduction mammaplasty and mastopexy. AB - Issues of hypertrophic circumareolar scars and malpositioning or irregularity of the nipple-areola complex (NAC) are frequently associated with breast reduction or mastopexy techniques that rely on an ample excision of skin around the areola, either alone or associated with a vertical incision. To avoid such problems, many efforts have been made to improve the accuracy of preoperative marking for the future NAC. However, the correct design and position of the NAC may be difficult to achieve for the patient at the end of the procedure after closure of the skin incisions. This article describes a novel, simple, and effective method for intraoperative shaping and positioning of the NAC. The described method is based on using a specially designed surgical instrument to determine the best position, diameter, shape, and configuration of a new NAC. This study aimed to demonstrate the efficacy of this method to reduce the common complications of the periareolar region in reduction mammaplasty and mastopexy. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266. PMID- 22527589 TI - Preauricular incision outlining during a face-lift: a step-by-step description. AB - The data on the proper way to establish the preauricular incision (PAI) line and manage skin tension during lifting are limited. Undoubtedly, proper tissue handling represents a true challenge during a lifting procedure and is a crucial step in avoiding disfiguration. The authors describe their approach to PAI demarcation and local skin tension management performed in 165 cases since 2007. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266. PMID- 22527590 TI - Sleeve gastrectomy plus side-to-side jejunoileal anastomosis for the treatment of morbid obesity and metabolic diseases: a promising operation. AB - BACKGROUND: The continuing need for simple, safe, and effective procedures led us to design a new operation for treating morbid obesity. METHODS: Thirty-two patients underwent our novel procedure, sleeve gastrectomy plus side-to-side jejunoileal anastomosis (SG plus), and were followed for 6 to 24 months. A matched cohort of 32 patients underwent sleeve gastrectomy over the same period and was used as the control group. Weight loss, comorbidity outcomes, and the duodenum to cecum transit time after a gastrografin swallow, performed at postoperative day 4, were compared. RESULTS: There were no deaths and no major perioperative complications. Three patients developed long-term complications requiring surgical intervention (intestinal obstruction, nausea-vomiting, and hypoalbuminemia). In the SG plus group, a 77.8 % excess weight loss was achieved at 12 months postoperatively, which was significantly better (p < 0.01) than the 67 % observed in the control group. The comorbidity outcomes, particularly diabetes resolution, were also significantly superior in the SG plus patients. The duodenum to cecum transit time of 11 min in the SG plus group was significantly shorter (p < 0.01) than the 31 min observed in the control group. CONCLUSIONS: Sleeve gastrectomy plus side-to-side jejunoileal anastomosis appears to be a simple, considerably safe, and effective procedure for treating obesity and its metabolic comorbidities. PMID- 22527591 TI - The impact of hospital and surgeon volume on clinical outcome following bariatric surgery. AB - The dramatic rise in the prevalence of obesity worldwide has led to the rapid growth of bariatric surgery. The aim of this pooled analysis is to evaluate the relationship between institutional and surgeon volume and outcomes following bariatric surgery. Medical, Embase, trial registries, conference proceedings and reference lists were searched for trials comparing clinical outcome following bariatric surgery at high and low volume hospitals and by high and low volume surgeons. Outcomes analysed were mortality, morbidity and length of hospital stay. Fifteen publications were included in this analysis. In total, 289,732 bariatric procedures were included in the institutional volume analysis, and 32,920 bariatric operations were included in the surgeon volume analysis. Mortality was reduced following surgery at high volume institutions (0.24 vs. 2.18 %; pooled odds ratio = 0.26; P = 0.004) and by high volume surgeons (0.41 vs. 2.77 %; pooled odds ratio = 0.21; P < 0.001). Similarly, morbidity was reduced in high volume institutions (7.84 vs. 8.85 %; pooled odds ratio = 0.52; P < 0.001) and with high volume surgeons (6.92 vs. 7.29 %; pooled odds ratio = 0.47; P < 0.001). There were insufficient data for conclusive statistical analysis of length of hospital stay. This pooled analysis does suggest a benefit in the centralisation of bariatric surgery to high volume institutions and surgeons with respect to mortality and morbidity. Future high-powered studies with adjustment for procedural and patient case mix are required to further define the volume-outcome relationship in bariatric surgery. PMID- 22527593 TI - A call for maintaining ethical behavior in bariatric surgery. PMID- 22527592 TI - Obesity and inflammation: change in adiponectin, C-reactive protein, tumour necrosis factor-alpha and interleukin-6 after bariatric surgery. AB - BACKGROUND: Obesity is associated with a low-grade inflammatory state. A causal association between inflammation and atherosclerosis has been suggested. The aim of this study was to evaluate changes in the proinflammatory profile of morbidly obese patients after weight loss following bariatric surgery. METHODS: In this study, we measured levels of adiponectin, high-sensitivity C-reactive protein (hs CRP), tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) and their relation to insulin resistance and lipid parameters in 60 morbidly obese women at baseline and 3, 6 and 12 months after gastric bypass. RESULTS: Twelve months after surgery, there was a significant increase in plasma levels of adiponectin (p < 0.001) and high-density lipoprotein cholesterol (p < 0.01) and a significant decrease in levels of IL-6 (p < 0.001), hs-CRP (p < 0.001), cholesterol (p < 0.001), triglycerides (p < 0.001), low-density lipoprotein cholesterol (p < 0.001), glucose (p < 0.001), insulin (p < 0.001) and homeostasis model assessment (HOMA; p < 0.001). At 12 months, correlations were seen between IL-6 levels and the following: body mass index (BMI) (r = 0.53, p < 0.001), insulin (r = 0.51, p < 0.001) and HOMA (r = 0.55, p < 0.001). Also, hs-CRP levels correlated with BMI (r = 0.40, p = 0. 004), triglycerides (r = 0.34, p = 0.017), insulin (r = 0.50, p = 0.001) and HOMA (r = 0.46, p = 0.002). CONCLUSIONS: In patients with morbid obesity, significant weight loss is followed by a significant improvement in the inflammatory state, insulin sensitivity and lipid profile. A relationship exists between improved inflammatory profile and insulin sensitivity. PMID- 22527594 TI - Eating behaviors post-bariatric surgery: a qualitative study of grazing. AB - BACKGROUND: Eating behaviors after bariatric surgery play an important role in postoperative outcomes. The purpose of this study was to explore eating behaviors among post-bariatric surgery patients, including developing a better understanding of the term "grazing", as interpreted by patients. METHODS: This study was conducted at a research institute with a community-based sample. Structured focus groups using the nominal group technique were conducted with five groups of post-bariatric patients (n = 29). All patients were over 18 years old and reported having bariatric surgery at least 1 year prior to participation. Participants were asked to produce responses to the question: "What does grazing mean to you?" Then, they were instructed to rank their responses to the questions: "What is grazing?" and "How does grazing affect you?" RESULTS: The mean age of the sample was 47, mean body mass index was 29.0 kg/m(2), and the majority of the participants were women (93 %). The group members generated a total of 105 responses, which were categorized into 17 themes. Common responses included eating frequently all through the day, out of control eating, and eating due to boredom, not hunger. Results suggest that grazing has a number of unique interpretations, including mindful and mindless behaviors. CONCLUSIONS: Post bariatric surgery patients seem to view grazing as a healthy eating behavior characterized by mindful food choices that are consumed in small amounts frequently throughout the day. However, grazing may also be viewed as an unhealthy eating pattern when it is perceived as unplanned, mindless, continuous food consumption. PMID- 22527595 TI - Metabolic profile of clinically severe obese patients. AB - BACKGROUND: Since low basal metabolic rate (BMR) is a risk factor for weight regain, it is important to measure BMR before bariatric surgery. We aimed to evaluate the BMR among clinically severe obese patients preoperatively. We compared it with that of the control group, with predictive formulas and correlated it with body composition. METHODS: We used indirect calorimetry (IC) to collect BMR data and multifrequency bioelectrical impedance to collect body composition data. Our sample population consisted of 193 patients of whom 130 were clinically severe obese and 63 were normal/overweight individuals. BMR results were compared with the following predictive formulas: Harris-Benedict (HBE), Bobbioni-Harsch (BH), Cunningham (CUN), Mifflin-St. Jeor (MSJE), and Horie Waitzberg & Gonzalez (HW & G). This study was approved by the Ethics Committee for Research of the University of Brasilia. Statistical analysis was used to compare and correlate variables. RESULTS: Clinically severe obese patients had higher absolute BMR values and lower adjusted BMR values (p < 0.0001). A positive correlation between fat-free mass and a negative correlation between body fat percentage and BMR were found in both groups. Among the clinically severe obese patients, the formulas of HW & G and HBE overestimated BMR values (p = 0.0002 and p = 0.0193, respectively), while the BH and CUN underestimated this value; only the MSJE formulas showed similar results to those of IC. CONCLUSIONS: The clinically severe obese patients showed low BMR levels when adjusted per kilogram per body weight. Body composition may influence BMR. The use of the MSJE formula may be helpful in those cases where it is impossible to use IC. PMID- 22527596 TI - Sleeve gastrectomy with jejunal bypass for the treatment of type 2 diabetes mellitus in patients with body mass index <35 kg/m2. A cohort study. AB - The objective of this study was to evaluate sleeve gastrectomy with jejunal bypass (SGJB) as a surgical treatment for type 2 diabetes mellitus (T2DM) in patients with a body mass index (BMI) <35 kg/m(2). This is a prospective cohort study. Patients with T2DM and BMI <35 kg/m(2) who underwent SGJB between January 2009 and June 2011 at DIPRECA Hospital, in Santiago, and Hospital Base, Osorno, Chile were included. SGJB consists of creating a gastric tube, which preserves the pylorus, and performing a jejunoileal anastomosis 300 cm distal to the angle of Treitz. Excess weight loss (EWL) and complete or partial remission of T2DM were reported. Forty-nine patients met the inclusion criteria. The mean age was 49 years (36-62), and 53 % of patients were female. Mean preoperative BMI was 31.6 kg/m(2) (25-34.9 kg/m(2)). Operation time was 123 +/- 14 min, with 94.7 % of operations performed laparoscopically. Mean postoperative hospital stay was 2 days. Mean postoperative follow-up was 12 months. Median EWL at 1, 3, 6, 12, and 18 months postoperatively was 31.9 %, 56.9 %, 76.1 %, 81.5 %, and 76.1 %, respectively. Complete T2DM remission was achieved in 81.6 % of patients (40/49) and partial remission in 18.4 % (9/49). Forty of 41 patients (97.6 %) on oral hypoglycemic agents achieved complete T2DM remission, and 100 % of insulin dependent patients stopped using insulin but were still being treated for T2DM. One patient experienced postoperative gastrointestinal bleeding. There were no deaths. SGJB is an effective treatment for T2DM in patients with BMI <35 kg/m(2). PMID- 22527597 TI - Perioperative morbi-mortality associated with bariatric surgery: from systematic biliopancreatic diversion to a tailored laparoscopic gastric bypass or sleeve gastrectomy approach. AB - BACKGROUND: The effectiveness and safety of the different bariatric surgical procedures currently available depend, partly, on the characteristics of the populations under study, the technical approach, the expertise of surgical teams, and on institutional factors. To evaluate the effectiveness and safety of these procedures, we compared the surgical results for biliopancreatic diversion surgery versus laparoscopic gastric bypass and sleeve gastrectomies performed in our institution. METHODS: This was a retrospective observational study of 296 patients undergoing bariatric surgery from January 2005 through October 2010. We analyzed mortality rate, cardiocirculatory and pulmonary perioperative complications, duration of surgery, intensive care unit admissions, and length of stay. We describe the changes in the choice of the surgical procedures throughout the study period. RESULTS: We observed a rate of pulmonary complications of 2.3 % and a mortality rate 3 months after discharge of 2.36 % with sepsis secondary to anastomotic leak as the main cause of death. Biliopancreatic diversion surgery was associated with higher mortality rates (p value = 0.014) and longer hospital stay (median of 9 versus 6 days for laparoscopic gastric bypass and sleeve gastrectomy, p value <0.001). Body mass index >= 50 was also related to higher mortality (p value = 0.023). We confirmed a progressive increase in laparoscopic restrictive and mixed techniques in our institution (from 0 % in 2005 to 87 % of all procedures in 2010). CONCLUSIONS: Bariatric surgery in our institution has dramatically shifted from systematic biliopancreatic diversion to a tailored laparoscopic gastric bypass or sleeve gastrectomy approach, which has made it possible to reduce hospital stay and mortality rates. PMID- 22527598 TI - Hyperuricemia: a reality in the Indian obese. AB - Hyperuricemia is known to be associated with obesity and metabolic syndrome. The aims of this study were to evaluate the prevalence of hyperuricemia in the Indian obese population and to determine if a correlation exists between hyperuricemia, body mass index, waist circumference and components of metabolic syndrome. This was a retrospective observational study. Four hundred nine obese patients were included. Anthropometric parameters were recorded. Prevalence of type 2 diabetes mellitus (T2DM), hypertension and dyslipidemia were recorded. Uric acid levels were measured in all patients. Hyperuricemia was defined as serum uric acid levels greater than 6 mg/dl. The population studied had a median body mass index (BMI) of 44.14 kg/m(2) (range 28.1-88.2 kg/m(2)) and a median age of 41 years (range 18 to 75 years). Overall prevalence of hyperuricemia was 44.6 %. Thirty four percent in the BMI range of 28-35 kg/m(2) and 47 % of patients with a BMI of >35 kg/m(2) had hyperuricemia. The incidence of hyperuricemia in males was 50 vs 21.7 % in females. Of patients in the hyperuricemia group, 47.3 % had hypertension as compared to 37 % in the normouricemic group. Dyslipidemia was seen in 7.3 % of hyperuricemic patients as compared to 5.8 % of the normouricemic subjects. The prevalence of T2DM was comparable in both the groups. The Indian obese population has a significant high prevalence of hyperuricemia; the incidence of hyperuricemia in male patients was greater than in female patients. Central obesity had no direct link to hyperuricemia. There was no significant correlation between the occurrence of T2DM and dyslipidemia and hyperuricemia. Hypertension was the only comorbidity seen to occur in conjunction with hyperuricemia. PMID- 22527599 TI - Accelerated gastric emptying but no carbohydrate malabsorption 1 year after gastric bypass surgery (GBP). AB - BACKGROUND: Following gastric bypass surgery (GBP), there is a post-prandial rise of incretin and satiety gut peptides. The mechanisms of enhanced incretin release in response to nutrients after GBP is not elucidated and may be in relation to altered nutrient transit time and/or malabsorption. METHODS: Seven morbidly obese subjects (BMI = 44.5 +/- 2.8 kg/m(2)) were studied before and 1 year after GBP with a D: -xylose test. After ingestion of 25 g of D: -xylose in 200 mL of non carbonated water, blood samples were collected at frequent time intervals to determine gastric emptying (time to appearance of D: -xylose) and carbohydrate absorption using standard criteria. RESULTS: One year after GBP, subjects lost 45.0 +/- 9.7 kg and had a BMI of 27.1 +/- 4.7 kg/m(2). Gastric emptying was more rapid after GBP. The mean time to appearance of D: -xylose in serum decreased from 18.6 +/- 6.9 min prior to GBP to 7.9 +/- 2.7 min after GBP (p = 0.006). There was no significant difference in absorption before (serum D: -xylose concentrations = 35.6 +/- 12.6 mg/dL at 60 min and 33.9 +/- 9.1 mg/dL at 180 min) or 1 year after GBP (serum D: -xylose = 31.5 +/- 18.1 mg/dL at 60 min and 27.2 +/ 11.9 mg/dL at 180 min). CONCLUSIONS: These data confirm the acceleration of gastric emptying for liquid and the absence of carbohydrate malabsorption 1 year after GBP. Rapid gastric emptying may play a role in incretin response after GBP and the resulting improved glucose homeostasis. PMID- 22527600 TI - Upper gastrointestinal swallow study following bariatric surgery: institutional review and review of the literature. AB - BACKGROUND: The aim of this study was to determine the efficacy of routine upper gastrointestinal imaging following the three forms of laparoscopic bariatric surgery completed at our institution (laparoscopic Roux en Y gastric bypass (LRYGB), laparoscopic sleeve gastrectomy (LS), and laparoscopic adjustable gastric banding (LAGB)). METHODS: Radiograph reports were reviewed from the period of January 2005 to July 2010. During that time, 129 patients underwent LRYGB, 209 underwent LS, and 12 patients underwent LAGB. Of those patients, 120 LRYGB patients, 188 LS patients, and 11 LAGB patients underwent upper gastrointestinal studies on postoperative days (POD) 1 or 2. RESULTS: Of the 319 total patients who underwent UGI, no contrast leaks were found. One LRYGB patient was found to have stenosis of the jejunojejunal anastomosis and was taken to the operating room for revision. A total of ten patients went on to develop leaks: four LRYGB patients, six LS patients, and zero LAGB patients. CONCLUSIONS: The results of our study show that a positive UGI study for stricture has a specificity of 100 %. In terms of leak, which offers a much higher risk of significant morbidity and mortality, UGI was unable to find any on postoperative days 1 or 2. Based on the results of this study, our institution has stopped completing routine UGI on POD 1 following bariatric surgery. PMID- 22527601 TI - Roux-en-Y gastric bypass in mice--surgical technique and characterisation. AB - BACKGROUND: A reproducible Roux-en-Y gastric bypass (RYGB) model in mice is needed to study the physiological alterations after surgery. METHODS: Male C57BL6 mice weighing 29.0 +/- 0.8 g underwent either RYGB (n = 14) or sham operations (n = 6). RYGB surgery consisted of a small gastric pouch (~2 % of the initial stomach size), a biliopancreatic and alimentary limb of 10 cm each and a common channel of 15 cm. Animals had free access to standard chow in the postoperative period. Body mass and food intake were recorded for 60 days. Bomb calorimetry was used for faecal analysis. Anatomical rearrangement was assessed using planar X ray fluoroscopy and computed tomography (CT) after oral Gastrografin(r) injection. RESULTS: RYGB surgery led to a sustained reduction in body weight compared to sham-operated mice (postoperative week 1: sham 27.8 +/- 0.7 g vs. RYGB 26.5 +/- 1.0 g, p = 0.008; postoperative week 8: sham 30.7 +/- 0.8 g vs. RYGB 28.4 +/- 1.1 g, p = 0.003). RYGB mice ate less compared to shams (sham 4.6 +/- 0.2 g/day vs. RYGB 4.3 +/- 0.4 g/day, p < 0.001). There were no differences in faecal mass (p = 0.13) and faecal energy content (p = 0.44) between RYGB and shams. CT scan demonstrated the expected anatomical rearrangement without leakage or stenosis. Fluoroscopy revealed rapid pouch emptying. CONCLUSIONS: RYGB with a small gastric pouch is technically feasible in mice. With this model in place, genetically manipulated mouse models could be used to study the physiological mechanisms involved with metabolic changes after gastric bypass. PMID- 22527602 TI - Unsaturation of mitochondrial membrane lipids is related to palmitate oxidation in subsarcolemmal and intermyofibrillar mitochondria. AB - Membrane lipid composition is thought to influence the function of integral membrane proteins; however, the potential for lipid composition to influence overall mitochondrial long-chain fatty acids (LCFA) oxidation is currently unknown. Therefore, the naturally occurring variability of LCFA oxidation rates within subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria in muscles with varying oxidative potentials (heart -> red -> white) was utilized to examine this relationship. To this end, SS and IMF mitochondria were isolated and palmitate oxidation rates were compared to membrane phospholipid composition. Among tissues, rates of palmitate oxidation in mitochondria displayed a 2.5-fold range, creating the required range to determine potential relationships with membrane lipid composition. In general, the percent mole fraction of phospholipid head groups and major fatty acid subclasses were similar in all mitochondria studied. However, rates of palmitate oxidation were positively correlated with both the unsaturation index and relative abundance of cardiolipin within mitochondria (r = 0.57 and 0.49, respectively; p < 0.05). Thus, these results suggest that mitochondrial LCFA oxidation may be significantly influenced by the total unsaturation and percent mole fraction of cardiolipin of the mitochondrial membrane, whereas other indices of membrane structure (e.g., percent mole fraction of other predominant membrane phospholipids, chain length, and ratio of phosphatidylcholine to phosphatidylethanolamine) were not significantly correlated. PMID- 22527603 TI - Expression of transcriptional factor genes (Oct-4, Nanog, and Sox-2) and embryonic stem cell-like characters in placental membrane of Buffalo (Bubalus bubalis). AB - The aim of the study was to assess the expression of transcriptional factor genes and embryonic stem cell-like characters in the placental membrane of buffalo (Bubalus bubalis). Along with the placenta, amniotic fluid, maternal peripheral blood, and umbilical cord blood samples were taken for the future study. The isolation and culture of cells from the placental membrane was followed by the determination of RT-PCR-based markers (Oct-4, Nanog, Sox-2, alkaline phosphatase, stem cell factor, and Nestin) of these cells. Placental membrane cells also positively expressed alkaline phosphatase staining. We isolated adherent cells from trypsin-EDTA-digested placentas and examined these cells for morphology, surface markers, and differentiation potential and found that they expressed several stem cell markers. They also showed neurogenic and adipogenic differentiation potentials under appropriate guided conditions. We suggest that placenta-derived cells have multilineage differentiation potential similar to mesenchymal stem cells in terms of morphology and cell-surface antigen expression. The placenta may prove to be a useful source of mesenchymal stem cells. PMID- 22527604 TI - Changes in surface-charge density of blood cells after sudden unexpected death. AB - The objective of the investigation was evaluation of postmortem changes of electric charge of human erythrocyte and thrombocyte membranes after sudden unexpected death. The surface charge density values were determined on the basis of the electrophoretic mobility measurements of the cells carried out at various pHs of electrolyte solution. The interactions between both erythrocyte and thrombocyte membranes and electrolyte ions were studied. Values of parameters characterizing the membrane--that is, the total surface concentrations of both acidic and basic groups and their association constants with solution ions--were calculated on the basis of a four-equilibria mathematical model. The model was validated by comparison of these values to experimental data. We established that examined electric properties of the cell membranes are affected by sudden unexpected death. Postmortem processes occurring in the cell membranes can lead to disorders of existing equilibria, which in turn result in changes in values of all the above-mentioned parameters. PMID- 22527606 TI - RETRACTED ARTICLE: Deprotonation of arginines in S4 is involved in NaChBac gating. PMID- 22527605 TI - Protective effect of blackcurrant on liver cell membrane of rats intoxicated with ethanol. AB - Chronic ethanol intoxication oxidative stress participates in the development of many diseases. Nutrition and the interaction of food nutrients with ethanol metabolism may modulate alcohol toxicity. One such compound is blackcurrant, which also has antioxidant abilities. We investigated the effect of blackcurrant as an antioxidant on the composition and electrical charge of liver cell membranes in ethanol-intoxicated rats. Qualitative and quantitative phospholipid composition and the presence of integral membrane proteins were determined by high-performance liquid chromatography. Electrophoresis was used to determine the surface charge density of the rat liver cell membranes. Ethanol intoxication is characterized by changes in cell metabolism that alter the structure and function of cell membrane components. Ethanol increased phospholipid levels and altered the level of integral proteins as determined by decreased phenylalanine, cysteine, and lysine. Ethanol significantly enhanced changes in the surface charge density of the liver cell membranes. Administration of blackcurrant to rats intoxicated with ethanol significantly protected lipids and proteins against oxidative modifications. It is possible that the beneficial effect of blackcurrant is connected with its abilities to scavenge free radicals and to chelate metal ions. PMID- 22527607 TI - Substance use progression from adolescence to early adulthood: effortful control in the context of friendship influence and early-onset use. AB - In a sample of 998 ethnically diverse adolescents, a multiagent, multimethod approach to the measurement of adolescent effortful control, adolescent substance use, and friendship influence was used to predict escalations to early-adult tobacco, alcohol, and marijuana use by ages 22-23. Structural equation modeling revealed that adolescent substance use and friends' substance use tended to be highly correlated and together were robust predictors of a problematic pattern of usage for all substances in early adulthood. In addition, the adolescent effortful control construct directly predicted progressions to problematic use of tobacco and marijuana, but not for alcohol. In the alcohol model, effortful control interacted with the construct of substance use lifestyle (based on adolescent alcohol use and friends' substance use) when predicting problematic alcohol use in early adulthood. Results held when comparing across genders and across ethnic groups. These findings emphasize the importance of addressing adolescent self-regulation in interventions designed to treat and prevent early adult substance abuse. PMID- 22527608 TI - A prospective longitudinal study of shyness from infancy to adolescence: stability, age-related changes, and prediction of socio-emotional functioning. AB - This longitudinal, population-based and prospective study investigated the stability, age-related changes, and socio-emotional outcomes of shyness from infancy to early adolescence. A sample of 921 children was followed from ages 1.5 to 12.5 years. Parent-reported shyness was assessed at five time points and maternal- and self-reported social skills and symptoms of anxiety and depression were assessed at age 12.5 years. Piecewise latent growth curve analysis was applied, with outcomes regressed on latent shyness intercept and slope factors. Results showed moderate stability and increasing levels of shyness across time, with more variance and a steeper increase in early as compared to mid-to-late childhood. Both stable shyness and increased shyness in mid-to-late (but not early) childhood predicted poorer social skills and higher levels of anxiety and depression symptoms in early adolescence. The implications of the evidence for two developmental periods in shyness trajectories with differential impact on later socio-emotional functioning are discussed. PMID- 22527609 TI - Getting out of rumination: comparison of three brief interventions in a sample of youth. AB - Rumination, passively and repetitively dwelling on and questioning negative feelings in response to distress, is a risk factor for the development of psychopathology, especially depression. The ruminative process is difficult to stop once it has begun. The present studies focused on strategies that may help youth disengage from ruminative states. In Study 1, we validated a technique for inducing distress and measuring state rumination. Twenty-six participants (mean age = 12.21; 62 % girls) underwent a negative mood induction followed by either a rumination or distraction induction. In Study 2, we examined the utility of three different brief interventions for stopping the ruminative process. One hundred two youth (mean age = 11.51; 64 % girls) underwent a negative mood induction followed by a rumination induction. Following this, participants were randomly assigned to one of three conditions designed to help them out of the ruminative state (distraction, problem-solving, or mindfulness). In Study 1, participants in the rumination condition reported significantly higher levels of state rumination compared to those in the distraction condition. In Study 2, both distraction and mindfulness helped reduced state rumination compared to problem-solving. Taken together, these data suggest that even a brief period of distraction or mindfulness is helpful in getting youth out of a ruminative state. Clinical implications might include the potential use of mobile device applications to help alleviate rumination. PMID- 22527610 TI - Longitudinal predictors of school-age academic achievement: unique contributions of toddler-age aggression, oppositionality, inattention, and hyperactivity. AB - This project examined the unique predictive validity of parent ratings of toddler age aggression, oppositionality, inattention, and hyperactivity-impulsivity to academic achievement at school-age in a sample of 566 high-risk children and families. The study also investigated potential indirect effects of the Family Check-Up on school-age academic achievement through changes in child behavior problems. The results demonstrated that toddler-age aggression was most consistently associated with school-age academic achievement, albeit modestly. Moreover, findings showed that the intervention predicted greater decreases in aggression from ages 2-3 to 4-5 compared to controls. The results suggest that in high-risk toddler-aged children, aggression may be a more consistent predictor of school-age academic achievement than other externalizing dimensions, which has implications for early identification and efforts to promote children's adaptation. PMID- 22527611 TI - Screening and characterization of sex-specific DNA fragments in the freshwater fish matrincha, Brycon amazonicus (Teleostei: Characiformes: Characidae). AB - The matrincha Brycon amazonicus, a commercially important freshwater fish resource, has no heteromorphic sex chromosomes so far described. In the present study, we performed a screening of sex-associated DNA markers in this species, through the use of a random amplified polymorphic DNA (RAPD) assay and a genomic DNA restriction digestion analysis. DNA digestions evidenced no differences between sexes. Sixty-six random primers were used in pooled and individual DNA samples of males and females, and the analysis of the RAPD fingerprints revealed one female sex-associated band. Cloning and sequencing of this band led to the identification of two distinct DNA segments. While one of the isolated fragments showed a significant identity with a described protein gene (phosphatidylinositol glycan anchor biosynthesis, class W), the other fragment, composed of 535 bp, corresponds to a novel DNA marker. Further experiments were performed with this second DNA fragment in order to verify its sex-specificity. Data on dot blot hybridization, using total DNA of both sexes, confirmed its female-specificity in B. amazonicus. A primer set was designed based on its sequence data and used in PCR with DNA samples of this species, leading to diagnose the animals' sexes with a 100 % overall accuracy through a sequence characterized amplified region approach. No amplification results were found for two other species of the genus- B. orbignyanus and B. lundii. The obtained data can lead to the hypothesis that B. amazonicus may present heteromorphic sex chromosomes that should be in an early phase of differentiation. PMID- 22527612 TI - Effects of temperature on power output and contraction kinetics in the locomotor muscle of the regionally endothermic common thresher shark (Alopias vulpinus). AB - The common thresher shark (Alopias vulpinus) is a pelagic species with medially positioned red aerobic swimming musculature (RM) and regional RM endothermy. This study tested whether the contractile characteristics of the RM are functionally similar along the length of the body and assessed how the contractile properties of the common thresher shark compare with those of other sharks. Contractile properties of the RM were examined at 8, 16 and 24 degrees C from anterior and posterior axial positions (0.4 and 0.6 fork length, respectively) using the work loop technique. Experiments were performed to determine whether the contractile properties of the RM are similar along the body of the common thresher shark and to document the effects of temperature on muscle power. Axial differences in contractile properties of RM were found to be small or absent. Isometric twitch kinetics of RM were ~fivefold slower than those of white muscle, with RM twitch durations of about 1 s at 24 degrees C and exceeding 5 s at 8 degrees C, a Q(10) of nearly 2.5. Power increased approximately tenfold with the 16 degrees C increase in temperature, while the cycle frequency for maximal power only increased from about 0.5-1.0 Hz over this temperature range. These data support the hypothesis that the RM is functionally similar along the body of the common thresher shark and corroborate previous findings from shark species both with and without medial RM. While twitch kinetics suggest the endothermic RM is not unusually temperature sensitive, measures of power suggest that the RM is not well suited to function at cool temperatures. The cycle frequency at which power is maximized appeared relatively insensitive to temperature in RM, which may reflect the relatively cooler temperature of the thresher RM compared to that observed in lamnid sharks as well as the relatively slow RM phenotype in these large fish. PMID- 22527613 TI - In silico analysis of the regulatory region of the Yellowtail Kingfish and Zebrafish Kiss and Kiss receptor genes. AB - We have cloned and analysed the partial putative promoter sequences of the Yellowtail Kingfish (Seriola lalandi) Kiss2 and Kiss2r genes (380 and 420 bp, respectively). We obtained in silico 1.5 kb of the zebrafish (Danio rerio) Kiss1, Kiss2, Kiss1r and zfKiss2r sequences upstream of the putative transcriptional initiation site. Bioinformatic analysis revealed promoter regulatory elements including AP-1, Sp1, GR, ER, PR, AR, GATA-1, TTF-1, YY1 and C/EBP. These regulatory elements may mediate novel roles of the Kiss genes and their receptors in addition to their established role in reproductive function. PMID- 22527614 TI - Stress-induced inhibition of recruitment of ovarian follicles for vitellogenic growth and interruption of spawning cycle in the fish Oreochromis mossambicus. AB - The tilapia, Oreochromis mossambicus, shows a short ovarian cycle of 24-26 days in nonmouthbrooding condition. In this study, the stripped female O. mossambicus were exposed to repeated mild acute stressors such as handling, chasing, frequent netting and low water levels daily for a period of 26 days. The follicular dynamics did not show significant difference during previtellogenic phase (day 12), whereas the mean number of stage IV (vitellogenic) follicles remained significantly lower compared with controls at the end of vitellogenic phase (day 18). The stage V (vitellogenic, preovulatory) follicles were completely absent in contrast to their presence in controls prior to spawning (day 23). The control fish spawned spontaneously after 24 days and entered mouthbrooding phase, whereas those exposed to stressors did not spawn. Furthermore, the serum levels of estradiol (E(2)) remained significantly lower concomitant with a significant increase in the serum cortisol concentration during vitellogenic and prespawning phase compared with those of the controls. The LH cells in the PPD of the pituitary gland showed weak immunoreactivity through vitellogenic and prespawning phase in fish exposed to stressors indicating the diminished secretory activity in contrast to the intensely stained ir-material in controls. The study reveals the disruptive effects of aquacultural stressors on the spawning cycle through suppression of LH and E(2) secretion along the pituitary-ovary axis. The results suggest that the ovarian stress response depends on the phase of the cycle and that the interruption of the spawning cycle is due to inhibition of recruitment of preovulatory follicles in O. mossambicus. PMID- 22527615 TI - Thyroid cancer in patients with acromegaly: a case-control study. AB - Several studies have associated acromegaly with an increased risk of benign and malignant tumors. While simple and multinodular goiters are common findings in acromegaly, the prevalence of thyroid cancer is uncertain. The objective of this study was to estimate the prevalence of thyroid cancer in a series of acromegalic patients from three hospitals in northeast of Brazil. The methodology used included morphological, cytological and histological thyroid analysis of acromegalic patients and volunteers over 18 years, matched for age and sex and with nodule (s) >=1 cm. The subjects of this study were 124 acromegalic patients, including 76 females (61.3%) and 48 men (38.7%), with a mean age 45.1 years. Results of the study showed that thyroid ultrasonography was normal in 31 cases (25%), 25 had diffuse goiter (20.1%), 67 had nodules (54%) and one agenesis of the right lobe (0.8%). Thirty-six patients underwent fine needle aspiration biopsy (FNAB) of their nodules and 9 cases of papillary cancer were found (7.2%). The control group consisted of 263 subjects, 156 females (59.3%) and 107 males (40.7%), mean age 44.7 years. In ultrasound assessment, 96 had nodules (36.5%). Of these, 13 were punctured and 2 cases of papillary carcinoma were found (0.7%). These results gave an odds ratio of 10.21 (p = 0.0011, 95% CI 2.17 to 48.01). These findings demonstrate an increased prevalence of thyroid cancer, statistically significant when compared to our control group. Thus, it is suggested that acromegalic patients should be routinely submitted to thyroid ultrasound evaluation, followed by FNAB of nodules when indicated. PMID- 22527616 TI - Genetic analysis in a patient presenting with meningioma and familial isolated pituitary adenoma (FIPA) reveals selective involvement of the R81X mutation of the AIP gene in the pathogenesis of the pituitary tumor. AB - Familial isolated pituitary adenoma (FIPA), defined as the occurrence of at least two cases of pituitary adenoma in a family that does not exhibit features of syndromic diseases, such as Carney complex or Multiple Endocrine Neoplasia type 1 or 4, is a rare autosomal dominant disease with low penetrance. About 20 % of the families with FIPA harbor inactivating mutation in aryl hydrocarbon receptor interacting protein gene (AIP) associated with loss of heterozygosity of the same genetic locus (11q13) in the tumor. Rarely different types of extra-pituitary tumors have been described in the setting of AIP mutation-positive FIPA. We present the case of a patient who was diagnosed with acromegaly due to the AIP mutation c.241C>T (p.R81X) at the age of 34 years, and treated by transsphenoidal surgery. At the age of 43 years she was diagnosed with a meningioma, and at age 46 had recurrence of the somatotropinoma. Genetic studies demonstrated loss of the normal allele (by sequencing and microsatellite analysis) in DNA from the pituitary adenoma but not from the meningioma, suggesting a selective involvement of AIP mutation in the pathogenesis of the pituitary adenoma, and a casual association with the meningioma. Further investigations are required to define the exact role of AIP in non-pituitary tumorigenesis. PMID- 22527617 TI - Clinical consequences of Cushing's syndrome. AB - Recent evidence suggests that correction of hypercortisolism in Cushing's syndrome (CS) may not lead to complete remission of the clinical abnormalities associated with this condition. In particular, elevated cardiovascular risk may persist in "cured" CS patients long-term after eucortisolism has been reached. This is believed to be related with the maintenance of visceral obesity and altered adipokine secretory pattern which perpetuate features of metabolic syndrome, including impaired glucose tolerance, hypertension, dyslipidemia, atherosclerosis and hypercoagulability. Nephrolithiasis and incomplete recovery of bone mineral density have also been described in "cured" CS patients. Moreover, previous exposure to excess cortisol may have irreversible effects on the structures of the central nervous system controlling cognitive function and mood. Thus, sustained deterioration of the cardiovascular system, bone remodelling and cognitive function may be associated with high morbidity and poor quality of life in CS patients in remission for many years. Although mortality in "cured" CS patients may not differ from that in the general population, data beyond 20 years follow-up are very scarce, so further studies evaluating larger cohorts for longer follow-up periods are needed to draw definitive conclusions on longevity. Life-long monitoring is mandatory in CS patients in order to control long term complications of previous cortisol excess and, possibly, normalize life expectancy. PMID- 22527618 TI - H(2) mediates cardioprotection via involvements of K(ATP) channels and permeability transition pores of mitochondria in dogs. AB - PURPOSE: Inhalation of hydrogen (H(2)) gas has been shown to limit infarct size following ischemia-reperfusion injury in rat hearts. However, H(2) gas-induced cardioprotection has not been tested in large animals and the precise cellular mechanism of protection has not been elucidated. We investigated whether opening of mitochondrial ATP-sensitive K+ channels (mK(ATP)) and subsequent inhibition of mitochondrial permeability transition pores (mPTP) mediates the infarct size limiting effect of H(2) gas in canine hearts. METHODS: The left anterior descending coronary artery of beagle dogs was occluded for 90 min followed by reperfusion for 6 h. Either 1.3% H(2) or control gas was inhaled from 10 min prior to start of reperfusion until 1 h of reperfusion, in the presence or absence of either 5-hydroxydecanoate (5-HD; a selective mK(ATP) blocker), or atractyloside (Atr; a mPTP opener). RESULTS: Systemic hemodynamic parameters did not differ among the groups. Nevertheless, H(2) gas inhalation reduced infarct size normalized by risk area (20.6+/-2.8% vs. control gas 44.0+/-2.0%; p<0.001), and administration of either 5-HD or Atr abolished the infarct size-limiting effect of H(2) gas (42.0+/-2.2% with 5-HD and 45.1+/-2.7% with Atr; both p<0.001 vs. H(2) group). Neither Atr nor 5-HD affected infarct size per se. Among all groups, NAD content and the number of apoptotic and 8-OHdG positive cells was not significantly different, indicating that the cardioprotection afforded by H(2) was not due to anti-oxidative actions or effects on the NADH dehydrogenase pathway. CONCLUSIONS: Inhalation of H(2) gas reduces infarct size in canine hearts via opening of mitochondrial K(ATP) channels followed by inhibition of mPTP. H(2) gas may provide an effective adjunct strategy in patients with acute myocardial infarction receiving reperfusion therapy. PMID- 22527619 TI - Impact of statins on the coagulation status of type 2 diabetes patients evaluated by a novel thrombin-generation assay. AB - PURPOSE: Dyslipidemia is common in type 2 diabetes (T2D) and contributes to cardiovascular disease (CVD) by exacerbating atherosclerosis and hypercoagulability. Statins can stabilize atherosclerotic plaque and reduce prothrombotic status. In the present study we aimed to evaluate the coagulation activity and the effect of statins on procoagulant state of T2D patients using a novel activated protein C (APC)-dependent thrombin-generation assay. METHODS: Procoagulant status (by HemosIL ThromboPath (ThP) assay) and in vivo platelet activation (by plasma soluble (s)CD40L levels) were analyzed in a retrospective, cross-sectional study of 198 patients with long-standing T2D and 198 controls. RESULTS: Procoagulant status of T2D patients was enhanced when compared to control subjects (p < 0.0001). Similarly, sCD40L levels were increased in T2D (p < 0.0001). When testing ThP as the dependent variable in a multivariate regression model, sCD40L (p < 0.0001) and statin treatment (p = 0.019) were independent predictors of the procoagulant state of T2D patients. Subgroup analysis showed a significant improvement of coagulability in T2D patients on statins (p = 0.012). CONCLUSIONS: The use of a standardized, easy-to-run, and commercially available APC-dependent thrombin-generation assay detected the presence of a procoagulant status in a large series of patients with long standing T2D and demonstrated a significant impact of statins in the coagulation status of patients with T2D. PMID- 22527620 TI - Recombinant human interleukin-1 receptor antagonist provides cardioprotection during myocardial ischemia reperfusion in the mouse. AB - PURPOSE: Acute myocardial infarction (AMI) drives an intense inflammatory response that contributes to infarct healing and cardiac remodeling. Recently, different studies have identified a role of interleukin-1 (IL-1) in the development of adverse cardiac remodeling. However, in animal models of AMI IL-1 has been shown to be cardioprotective in preconditioning, raising the question of clinical safety of therapeutic IL-1 blockade for autoinflammatory diseases or for the prevention or the treatment of AMI. In this study we proposed to evaluate the effects of pretreatment with recombinant human interleukin-1 receptor antagonist (rhIL-1Ra) on ischemia reperfusion (I/R) injury to the heart. METHODS: RhIL-1Ra was given 4 h or 30 min before the surgical induction of I/R. Left ventricular ejection fraction(LVEF) and infarct size were assessed to determine the effects of the drug pretreatment compared to vehicle treated mice. RESULTS: RhIL-1Ra, given 4 h or 30 min before the onset of the ischemia, showed marked cardioprotection though preservation of the LVEF (no change vs sham operated mice) and the reduction of the infarct size (-40 % vs vehicle-treated mice). No differences were observed between the two groups of rhIL-1Ra treatment. CONCLUSIONS: IL-1 blockade therapies using rhIL-1Ra prior the onset of AMI protects the myocardium and preserves cardiac function. PMID- 22527621 TI - A thermostable alpha-galactosidase from Lenzites elegans (Spreng.) ex Pat. MB445947: purification and properties. AB - An alpha-galactosidase was isolated from a culture filtrate of Lenzites elegans (Spreng.) ex Pat. MB445947 grown on citric pectin as carbon source. It was purified to electrophoretic homogeneity by ammonium sulfate precipitation, gel filtration chromatography and anion-exchange chromatography. The relative molecular mass of the native purified enzyme was 158 kDa determined by gel filtration and it is a homodimer (Mr subunits = 61 kDa). The optimal temperature for enzyme activity was in the range 60-80 degrees C. This alpha-galactosidase showed a high thermostability, retaining 94 % of its activity after preincubation at 60 degrees C for 2 h. The optimal pH for the enzyme was 4.5 and it was stable from pH 3 to 7.5 when the preincubation took place at 60 degrees C for 2 h. It was active against several alpha-galactosides such as p-nitrophenyl-alpha-D galactopyranoside, alpha-D-melibiose, raffinose and stachyose. The alpha galactosidase is a glycoprotein with 26 % of structural sugars. Galactose was a non-competitive inhibitor with a Ki = 22 mM versus p-nitrophenyl-alpha-D galactoside and 12 mM versus alpha-D-melibiose as substrates. Glucose was a simple competitive inhibitor with a Ki = 10 mM. Cations such as Hg(2+) and p chloromercuribenzoate were also inhibitors of this activity, suggesting the presence of -SH groups in the active site of the enzyme. On the basis of the sequence of the N-terminus (SPDTIVLDGTNFALN) the studied alpha-galactosidase would be a member of glycosyl hydrolase family 36 (GH 36). Given the high optimum temperature and heat stability of L. elegans alpha-galactosidase, this fungus may become a useful source of alpha-galactosidase production for multiple applications. PMID- 22527622 TI - Streptosporangium anatoliense sp. nov., isolated from soil in Turkey. AB - A novel actinobacterium, strain N9999(T), was isolated from soil and its taxonomic position determined using a polyphasic approach. The organism formed abundant aerial hyphae that differentiated into spherical spore vesicles. The cell wall contained meso-diaminopimelic acid; the whole-cell sugars were galactose, glucose, mannose, madurose and ribose; the predominant menaquinones MK 9 (H(2)) and MK-9 (H(4)); the major phospholipids phosphatidylethanolamine, diphosphatidylglycerol, a phosphaglycolipid and phosphatidylinositol mannosides; while the cellular fatty acids were rich in iso-C(14:0), C(15:0), cis-9-C(17:1), iso-C(16:0) and 10-methyl C(17:0) components. Phylogenetic analyses based on an almost complete 16S rRNA gene sequence indicated that strain N9999(T) was closely related to a group that consisted of Streptosporangium pseudovulgare DSM 43181(T) and Streptosporangium nondiastaticum DSM 43848(T). However, DNA-DNA relatedness and phenotypic data demonstrated that strain N9999(T) was clearly distinguished from all closely related Streptosporangium species. The combined genotypic and phenotypic data demonstrate conclusively that the isolate should be classified as a new species of Streptosporangium. PMID- 22527623 TI - The impact of pH and nutrient stress on the growth and survival of Streptococcus agalactiae. AB - Streptococcus agalactiae is a major neonatal pathogen that is able to colonise various host environments and is associated with both gastrointestinal and vaginal maternal carriage. Maternal vaginal carriage represents the major source for transmission of S. agalactiae to the foetus/neonate and thus is a significant risk factor for neonatal disease. In order to understand factors influencing maternal carriage we have investigated growth and long term survival of S. agalactiae under conditions of low pH and nutrient stress in vitro. Surprisingly, given that vaginal pH is normally <4.5, S. agalactiae was found to survive poorly at low pH and failed to grow at pH 4.3. However, biofilm growth, although also reduced at low pH, was shown to enhance survival of S. agalactiae. Proteomic analysis identified 26 proteins that were more abundant under nutrient stress conditions (extended stationary phase), including a RelE family protein, a universal stress protein family member and four proteins that belong to the Gls24 (PF03780) stress protein family. Cumulatively, these data indicate that novel mechanisms are likely to operate that allow S. agalactiae survival at low pH and under nutrient stress during maternal vaginal colonisation and/or that the bacteria may access a more favourable microenvironment at the vaginal mucosa. As current in vitro models for S. agalactiae growth appear unsatisfactory, novel methods need to be developed to study streptococcal colonisation under physiologically-relevant conditions. PMID- 22527624 TI - Streptomyces phytohabitans sp. nov., a novel endophytic actinomycete isolated from medicinal plant Curcuma phaeocaulis. AB - A novel actinomycete, designated strain KLBMP 4601(T), was isolated from the root of the medicinal plant Curcuma phaeocaulis collected from Sichuan Province, south west China. The strain produced extensively branched substrate and aerial hyphae that carried straight to flexuous spore chains. Chemotaxonomic properties of this strain were consistent with those of members of the genus Streptomyces. The cell wall of strain KLBMP 4601(T) contained LL-diaminopimelic acid as the characteristic diamino acid. The major menaquinone was MK-9(H(4)), with minor amounts of MK-9(H(6)), MK-9(H(8)) and MK-10(H(2)). The major fatty acids were C(16:0), iso-C(16:0), C(18:1)omega9c and C(16:1), iso G. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain KLBMP 4601(T) belongs to the genus Streptomyces and is most closely related to Streptomyces armeniacus JCM 3070(T) (97.9 %), Streptomyces pharmamarensis PM267(T) (97.6 %) and Streptomyces artemisiae YIM 63135(T) (97.5 %). The 16S rRNA gene sequence similarity between strain KLBMP 4601(T) and other members of this genus were lower than 97.5 %. DNA DNA hybridization studies of strain KLBMP 4601(T) with the three closest species showed relatedness values of 36.3 +/- 4.2 %, 27.3 +/- 0.6 %, and 30.9 +/- 2.5 %, respectively. On the basis of chemotaxonomic, phenotypic and genotypic characteristics, it is evident that strain KLBMP 4601(T) represents a novel species of the genus Streptomyces, for which the name Streptomyces phytohabitans sp. nov. is proposed. The type strain is KLBMP 4601(T) (=KCTC 19892(T) = NBRC 108772(T)). PMID- 22527625 TI - Description of Fimbriimonas ginsengisoli gen. nov., sp. nov. within the Fimbriimonadia class nov., of the phylum Armatimonadetes. AB - Strain Gsoil 348(T) was isolated from a ginseng field soil sample by selecting micro-colonies from one-fifth strength modified R2A agar medium after a long incubation period. 16S rRNA gene sequence analysis indicated that the strain is related to members of the phylum Armatimonadetes (formerly called candidate phylum OP10). Strain Gsoil 348(T) is mesophilic, strictly aerobic, non-motile and rod-shaped. It only grows in low nutrient media. The major respiratory quinones are menaquinones MK-11 and MK-10, and the main fatty acids are iso-C(15:0), iso C(17:0), C(16:0) and C(16:1) omega11c. The G+C content is 61.4 mol%. The 16S rRNA gene sequences in public databases belonging to the phylum Armatimonadetes were clustered here into 6 groups. Five of these groups constituted a coherent cluster distinct from the sequences of other phyla in phylogenetic trees that were constructed using multiple-outgroup sequences from 49 different phyla. On the basis of polyphasic taxonomic analyses, it is proposed that strain Gsoil 348(T) (= KACC 14959(T) = JCM 17079(T)) should be placed in Fimbriimonas ginsengisoli gen. nov., sp. nov., as the cultured representative of the Fimbriimonadia class. nov., corresponding with Group 4 of the phylum Armatimonadetes. PMID- 22527626 TI - Exposure of the wide interior of the fourth ventricle without splitting the vermis: importance of cutting procedures for the tela choroidea. AB - In recent years, new procedures for fourth ventricular surgeries have been developed with good results. In particular, the trans-cerebellomedullary fissure approach, which exposes the fourth ventricle without splitting the inferior vermis, has proven successful. For optimum results, specialized techniques should be employed in order to effectively open the roof of the fourth ventricle and obtain a wide exposure of its interior. These techniques include the following steps: (1) placement of an incision over the teania extending from the foramen of Magendie to the ventricular entrance of the lateral recess; (2) lateral extension of the incision to the roof of the lateral recess to facilitate its exposure; (3) implementation of the same procedure on the contralateral side. Upon completion of these steps, the bilateral cerebellar tonsils can be easily retracted superolaterally; this eventually exposes a wide interior of the ventricle. In order to ensure successful surgeries, explicit and accurate descriptions of technique are vital. In this article, we employ detailed illustrations to precisely demonstrate the operative procedures and techniques for fourth ventricular surgeries. PMID- 22527627 TI - Parkinsonism secondary to subdural haematoma. AB - Parkinsonism consists of several extrapyramidal signs, characterized by tremor, muscle rigidity, and loss of postural reflexes. The most common cause of parkinsonism is idiopathic Parkinson's disease, whereas the secondary forms include drug exposure, trauma, infection, and chronic subdural haematomas. Four patients with parkinsonism out of 1,289 chronic subdural haematomas were admitted to our hospital between 1985 and 2010. Nineteen patients identified in the literature were also included in this revision. Of the 23 cases reviewed (19 men and 4 women; age at diagnosis ranged between 38 and 83 years; mean, 68.8), the interval between initial symptoms and haematoma diagnosis ranged between 1 week and 1 year (mean interval, 8 weeks). The haematoma was unilateral in 13 cases and bilateral in 10 cases. All chronic subdural haematomas were resolved using different surgical techniques with marked improvement following surgery. Parkinsonism is a rare presentation of chronic subdural haematoma. However, the sudden onset of parkinsonisms requires prompt neuroimaging to rule out this potentially reversible aetiology. The prognosis of chronic subdural haematoma related parkinsonism is favourable after surgical evacuation. PMID- 22527628 TI - Long-term outcome of surgical management of adult Chiari I malformation. AB - Chiari I malformation continues to inspire controversy. Debate still exists about surgical options. The aim of this study is to evaluate the long-term outcome of posterior fossa decompression procedure (PFD) in the treatment of adult Chiari I malformation, focusing on some factors or technical aspects which might influence the outcome. Forty-six adult patients with Chiari I malformation operated by PFD are the subject of this study. The group included 21 males and 25 females, with mean age of 37.4 years. Patients were divided into two groups: group I (32 cases) with syringomyelia and group II (14 cases) without syringomyelia. Group I was further subdivided into three subgroups according to the surgical procedure adopted: group Ia (12 cases) operated by PFD only, group Ib (14 cases) operated by PFD with fourth ventricular shunt, and group Ic (six cases) operated by PFD and syringosubarachnoid shunt. All cases included in group II were operated by PFD only. In group I, symptoms improved in 14 cases (43.8 %) and stabilized in 18 cases (56.3 %), whereas in group II, symptoms resolved in ten cases (71.4 %) and improved in four cases (28.6 %). Postoperative magnetic resonance imaging showed that the syrinx was resolved in 21 cases (65.6 %), improved in seven cases (21.9 %), and unchanged in four cases (12.5 %). Among the mean follow-up period (5.8 years), recurrence of symptoms occurred in five cases (10.9 %), all of them are included in group I, and were reoperated again. Posterior fossa decompression is recommended as the treatment of choice in adult Chiari I malformation with or without syringomyelia. The presence of syringomyelia predicts a less favorable response to surgical intervention. Syringosubarachnoid shunting did not improve the long-term outcome either clinically or radiologically. Implanting a fourth ventricular shunt in cases of syringomyelia associated with adhesions at the foramen of Magendie decreases the long-term incidence of recurrence significantly. For recurrent cases, re-exploration of the initial posterior fossa decompression is recommended before any consideration is given for direct management of the syrinx. PMID- 22527629 TI - Preauricular transzygomatic anterior infratemporal fossa approach for tumors in or around infratemporal fossa lesions. AB - Various surgical approaches to the infratemporal fossa (ITF) have been reported. Among them, the preauricular transzygomatic anterior ITF approach (anterior ITF approach) has been used for exposure of the antero-superior part of the ITF. The purpose of this article is to show anatomical dissections using the anterior ITF approach and to evaluate our surgical experience using this approach. An anatomical study of the anterior ITF approach was performed using six sides of three cadaveric heads. Clinical course was retrospectively reviewed for 34 patients who underwent microsurgical resection of tumor in or around the ITF using this approach. Medical, surgical, and neuroimaging records of these patients were evaluated. The key point of this approach was mobilization of the second and third divisions of the trigeminal nerve after drilling of the lateral loop between the foramina rotundum and ovale. After mobilization of the trigeminal nerve, the auditory tube, tensor veli palatini muscle, and pharyngobasilar membrane could be seen. Removal of the pterygoid muscles and plates allowed surgical access to the ITF, orbit, maxillary sinus, pterygopalatine fossa, and parapharyngeal space. We used this approach in 31 patients with skull base tumors between 1994 and 2007. Gross total removal was achieved in 27 of the 31 patients. No mortality or severe morbidity was encountered. Therefore, the anterior ITF approach provides easy access to the ITF and adjacent regions without destruction of important organs. PMID- 22527630 TI - Abrupt clinical onset of Chiari type I/syringomyelia complex: clinical and physiopathological implications. AB - Chiari I malformation (CI) continues to raise great interest among physicians due to the larger and larger number of newly diagnosed cases. The clinical and radiological picture and the management options of such a chronic disease are well acknowledged as well as those of the associated syringomyelia. Little is known, on the other hand, about abrupt clinical onset following decompensation of CI/syringomyelia complex. This review on the sudden onset of these two conditions shows that this is a very rare phenomenon; only 41 cases are being reported in the last three decades. In all these cases, acute onset was referable to CI/syringomyelia and the clinical course quickly precipitated. Motor deficits (36.5 %), respiratory failure (29 %), cranial nerve palsy (17 %), and cardiac arrest (14.5 %) were the most common findings, thus confirming that abrupt onset may have severe and life-threatening consequences. Indeed, sudden or early mortality accounted for 19.5 % of cases. In spite of that, most of the surviving subjects had an excellent outcome following either surgical or medical/rehabilitation treatment. Physiopathology of abrupt onset is attributed to the acute compression of the brainstem/upper cervical spinal cord by ectopic tonsils and syringobulbia/syringomyelia, frequently precipitated by a minor injury, followed by impairment of medullary baroreceptors and midbrain reticular substance (cardiac arrest, syncope), medullary chemoreceptors and phrenic nerve nuclei (respiratory failure), lower cranial nerve nuclei (cardiac arrest, cranial nerve palsy), and pyramidal tracts (motor deficits). About 87 % of patients of this review were asymptomatic prior to their acute onset. The problem of the management of asymptomatic subjects is still open. PMID- 22527631 TI - Transcranial superior orbitotomy for the treatment of intraorbital intraconal tumors: surgical technique and long-term results in single institute. AB - In this article, the authors are presenting their experience and the results with the surgical treatment of intraorbital intraconal tumors based on a review of 33 constitutive cases. Our data were evaluated in comparison to other major series, and possible factors that might influence surgical outcome and survival are discussed. Thirty-three patients diagnosed with intraorbital intraconal tumors between 1998 and 2009 were treated by transcranial approach. Of these patients, there were 14 males (42.4 %) and 19 females (57.8 %). The age ranged between 2 and 70 years (mean = 36 +/- 16.6 years). The follow-up period ranged between 2 and 13 years (mean = 7.3 +/- 3.2 years). The most common presenting symptoms were exophthalmus and decreased visual acuity, which was seen in 21 (63.6 %) and 19 patients (57.6 %), respectively. Total resection was achieved in 23 patients (69.7 %) while subtotal resection was done in ten patients (30.3 %). Cavernoma and optic nerve sheath meningioma were the most common histologic variants, which were found in 11 (33.3 %) and 10 (30.3 %) patients, respectively. In the long term follow-up, 54.5 % of the patients showed total ophthalmologic improvement, 9.1 % showed partial improvement, 21.2 % demonstrated unchanged ophthalmologic status, and 15.2 % showed worse ophthalmologic outcome. Transcranial approach for the treatment of intraorbital intraconal tumors is an effective approach for the management of these pathologies. The effectiveness is clearly demonstrated by the clinical results and outcomes of these patients' groups. PMID- 22527633 TI - Do opioids activate latent HIV-1 by down-regulating anti-HIV microRNAs? AB - Researchers have recently demonstrated the presence of anti-HIV-1 microRNAs (miR 28, miR-125b, miR-150, miR-223, and miR-382) in monocytes, macrophages, and CD4+ T cells, which are the primary targets of HIV infection. These miRNAs appear to regulate the level of infectivity of HIV-1 in the target cells, and thus have an impact on HIV-1 latency. The levels of these miRNAs are significantly higher in resting CD4+ T cells than those in active CD4+ T cells, whereas HIV-1 infectivity is greater in active than in resting CD4+ T cells. Similarly, the levels of these miRNAs are significantly higher in monocytes than in macrophages, whereas HIV-1 infectivity is greater in macrophages than in monocytes. Down-regulation or inhibition of the activity of these miRNAs can promote replication of latent HIV 1 in resting CD4+ T cells and in monocytes. Recently, morphine was shown to down regulate the expression of anti-HIV miRNAs (miRNA-28, 125b, 150, and 382) in cultured human monocytes and this effect of morphine was mediated via activation of mu opioid receptors (MOR). In addition, levels of these anti-HIV miRNAs were significantly lower in the peripheral blood mononuclear cells (PBMCs) isolated from heroin-dependent subjects than those from control subjects. These findings raise an important question: Does morphine have potential to activate latent HIV 1 in resting CD4+ T cells and macrophages, including microglia of human subjects maintained on highly active antiretroviral therapy (HAART)? Further research is required to answer this question. PMID- 22527634 TI - Neuroprotective effect of curcuminoids against inflammation-mediated dopaminergic neurodegeneration in the MPTP model of Parkinson's disease. AB - The present study investigated the neuroprotective effect of curcuminoids, the active polyphenols of Curcuma longa (L.) rhizomes against inflammation-mediated dopaminergic neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) model of Parkinson's disease (PD). Male C57BL/6 mice were pre-treated with curcuminoids (150 mg/kg/day) for 1 week, followed by four intra-peritoneal (i.p.) injections of MPTP (20 mg/kg) at 2 h intervals with further administration of curcuminoids or deprenyl (3 mg/kg/day) for 2 weeks. Our results show that oral administration of curcuminoids significantly prevented MPTP-mediated depletion of dopamine and tyrosine hydroxylase (TH) immunoreactivity. In-addition, pre-treatment with curcuminoids reversed glial fibrillary acidic protein (GFAP) and inducible nitric oxide synthase (iNOS) protein expression, as well as, reduced pro-inflammatory cytokine and total nitrite generation in the striatum of MPTP-intoxicated mice. Significant improvement in motor performance and gross behavioural activity, as determined by rota-rod and open field tests were also observed. Taken together, our findings suggest that curcuminoids exert a neuroprotective effect against MPTP-induced dopaminergic neurodegeneration through its anti-inflammatory action and thus holds immense potential as a therapeutic candidate for the prevention and management of PD. PMID- 22527632 TI - When human immunodeficiency virus meets chemokines and microglia: neuroprotection or neurodegeneration? AB - Chemokines are chemotactic cytokines that were originally discovered as promoters of leukocyte proliferation and mobility. In recent years, however, evidence has demonstrated constitutive expression of chemokines and chemokine receptors in a variety of cells in the central and peripheral nervous system and has proposed a role for chemokines in neurodegenerative diseases characterized by inflammation and microglia proliferation. In addition, chemokine receptors, and in particular CXCR4 and CCR5, mediate human immunodeficiency virus type 1 (HIV) infection of immunocompetent cells as well as microglia. Subsequently, HIV, through a variety of mechanisms, promotes synapto-dendritic alterations and neuronal loss that ultimately lead to motor and cognitive impairments. These events are accompanied by microglia activation. Nevertheless, a microglia-mediated mechanism of neuronal degeneration alone cannot fully explain some of the pathological features of HIV infected brain such as synaptic simplification. In this article, we present evidence that some of the microglia responses to HIV are beneficial and neuroprotective. These include the ability of microglia to release anti inflammatory cytokines, to remove dying cells and to promote axonal sprouting. PMID- 22527635 TI - Mitochondrial glutaminase release contributes to glutamate-mediated neurotoxicity during human immunodeficiency virus-1 infection. AB - Human immunodeficiency virus (HIV) induces a neurological disease culminating in frank dementia referred to as HIV-associated dementia (HAD). Neurotoxins from HIV 1-infected and activated mononuclear phagocytes contribute to the neuropathogenesis of HAD. Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system (CNS) and functions through activation of multiple receptors. Excessive glutamate production by HIV infected macrophages in HAD may contribute to neuronal injury. Our previous studies have suggested that mitochondrial glutaminase is responsible for the excessive production of glutamate. However, how HIV-1 infection regulates glutamate over-production remains unclear. In this study, we propose that HIV infection-induced oxidative stress contributes to mitochondrial glutaminase release, which results in the excessive production of glutamate and subsequent neuronal injury. We collected conditioned media from HIV-1 infected macrophages and analyzed glutamate concentration in the media by RP-HPLC, and found that the cyclosporine A (CsA), an inhibitor of HIV-1 replication and mitochondrial permeability transition pore, and N-acetylcysteine (NAC), a remover of reactive oxygen species (ROS), not only blocked the excessive glutamate production, but also decreased the glutamate-mediated neurotoxicity. In addition, HIV-infection induced ROS generation was accompanied with the excessive glutamate production, suggesting that oxidative stress was involved in glutamate regulation. Using the isolated rat brain mitochondria as an ex vivo model and over-expressing GFP glutaminase fusion protein in mammalian cells as a cell model, we confirm oxidative stress-mediated mitochondrial glutaminase release during HIV-1 infection contributes to glutamate over-production and the subsequent neurotoxicity. These results may provide insight into HAD pathogenesis and a therapeutic strategy for HAD treatment. PMID- 22527636 TI - Microglial SK3 and SK4 currents and activation state are modulated by the neuroprotective drug, riluzole. AB - Microglia monitor the CNS for 'danger' signals after acute injury, such as stroke and trauma, and then undergo complex activation processes. Classical activation of microglia can produce neurotoxic levels of glutamate and immune mediators (e.g., pro-inflammatory cytokines, reactive oxygen and nitrogen species), while alternative activation up-regulates anti-inflammatory molecules and is thought to resolve inflammation and protect the brain. Thus, pharmacological strategies to decrease classical- and/or promote alternative activation are of interest. Here, we assessed actions of the neuroprotective drug, riluzole, on two Ca(2+)- activated K channels in microglia - SK3 (KCa2.3, KCNN3) and SK4 (KCa3.1, KCNN4) - and on classical versus alternative microglial activation. Riluzole is used to treat amyotrophic lateral sclerosis, and is in clinical trials for several other CNS disorders, where it has been presumed to target neurons and reduce glutamate mediated toxicity. We show that simply elevating intracellular Ca(2+) to micromolar levels in whole-cell recordings does not activate SK channels in a cell line derived from primary rat microglia (MLS-9). In intact cells, riluzole raised cytoplasmic Ca(2+), but it was marginal (~200 nM) and transient (2 min). Surprisingly then, in whole cell recordings, riluzole rapidly activated SK3 and SK4 channels for as long as it was present, and did not require elevated intracellular Ca(2+). We then used primary rat microglia to analyze expression of several activation markers and inflammatory mediators. Riluzole decreased classical LPS-induced activation, and increased some aspects of IL-4-induced alternative activation. These actions on microglia suggest an additional mechanism underlying the neuroprotective actions of riluzole. PMID- 22527637 TI - Structure, interactions and function of the N-terminus of cardiac myosin binding protein C (MyBP-C): who does what, with what, and to whom? AB - The thick filament protein myosin-binding protein-C shows a highly modular architecture, with the C-terminal region responsible for tethering to the myosin and titin backbone of the thick filament. The N-terminal region shows the most significant differences between cardiac and skeletal muscle isogenes: an entire Ig-domain (C0) is added, together with highly regulated phosphorylation sites between Ig domains C1 and C2. These structural and functional differences at the N-terminus reflect important functions in cardiac muscle regulation in health and disease. Alternative interactions of this part of MyBP-C with the head-tail (S1 S2) junction of myosin or to actin filaments have been proposed, but with conflicting experimental evidence. The regulation of myosin or actin interaction by phosphorylation of the cardiac MyBP-C N-terminus may play an additional role in length-dependent contraction regulation. We discuss here the evidence for these proposed interactions, considering the required properties of MyBP-C, the way in which they may be regulated in muscle contraction and the way they might be related to heart disease. We also attempt to shed some light on experimental pitfalls and future strategies. PMID- 22527639 TI - A study of store dependent Ca2+ influx in frog skeletal muscle. AB - Ca2+ influx across the plasma membrane upon drastic reduction of the sarcoplasmic reticulum Ca2+ content was studied in voltage clamped frog skeletal muscle fibers. Depletion was produced by the application of 30 MUM cyclopiazonic acid (CPA) in Ca2+-free, [Mg2+] = 8 mM external salines and produced an increase in resting free myoplasmic [Ca2+]. Once depletion was attained the external solution was changed to one containing the same concentration of the drug but with Ca2+ instead of Mg2+. Of 27 fibers studied only nine showed a secondary increase in free myoplasmic [Ca2+] upon readmitting Ca2+ in the external perfusate. In the presence of CPA the resting myoplasmic [Ca2+] in Ca2+-free external saline was 0.08 +/- 0.01 MUM (Mean +/- SEM), and in Ca2+-containing external saline 0.10 +/- 0.02 MUM when the intracellular solution contained [EGTA] = 5 mM (n = 18). In cells with lower (0.5 mM) intracellular [EGTA] resting [Ca2+] went from 0.35 +/- 0.08 MUM in Ca2+-free external solution to 0.42 +/- 0.12 MUM upon reapplication of Ca2+(n = 9). In both cases the differences between means were not statistically significant (paired t test, p = 0.13 in high EGTA and p = 0.25 in low EGTA). In the nine fibers that showed a secondary increase of resting [Ca2+] the holding current measured at -90 mV did not significantly change. These results suggest the Ca2+ entry secondary to store depletion is a labile mechanism in frog skeletal muscle and when present does not have an obvious electrical manifestation. PMID- 22527638 TI - Pathogenic properties of the N-terminal region of cardiac myosin binding protein C in vitro. AB - Cardiac myosin binding protein-C (cMyBP-C) plays a role in sarcomeric structure and stability, as well as modulating heart muscle contraction. The 150 kDa full length (FL) cMyBP-C has been shown to undergo proteolytic cleavage during ischemia-reperfusion injury, producing an N-terminal 40 kDa fragment (mass 29 kDa) that is predominantly associated with post-ischemic contractile dysfunction. Thus far, the pathogenic properties of such truncated cMyBP-C proteins have not been elucidated. In the present study, we hypothesized that the presence of these 40 kDa fragments is toxic to cardiomyocytes, compared to the 110 kDa C-terminal fragment and FL cMyBP-C. To test this hypothesis, we infected neonatal rat ventricular cardiomyocytes and adult rabbit ventricular cardiomyocytes with adenoviruses expressing the FL, 110 and 40 kDa fragments of cMyBP-C, and measured cytotoxicity, Ca(2+) transients, contractility, and protein-protein interactions. Here we show that expression of 40 kDa fragments in neonatal rat ventricular cardiomyocytes significantly increases LDH release and caspase 3 activity, significantly reduces cell viability, and impairs Ca(2+) handling. Adult cardiomyocytes expressing 40 kDa fragments exhibited similar impairment of Ca(2+) handling along with a significant reduction of sarcomere length shortening, relaxation velocity, and contraction velocity. Pull-down assays using recombinant proteins showed that the 40 kDa fragment binds significantly to sarcomeric actin, comparable to C0-C2 domains. In addition, we discovered several acetylation sites within the 40 kDa fragment that could potentially affect actomyosin function. Altogether, our data demonstrate that the 40 kDa cleavage fragments of cMyBP-C are toxic to cardiomyocytes and significantly impair contractility and Ca(2+) handling via inhibition of actomyosin function. By elucidating the deleterious effects of endogenously expressed cMyBP-C N-terminal fragments on sarcomere function, these data contribute to the understanding of contractile dysfunction following myocardial injury. PMID- 22527641 TI - [Benefits and disadvantages of therapy for fibromyalgia syndrome: new insights and decision aids from consumer reports?]. PMID- 22527640 TI - Protein kinase C depresses cardiac myocyte power output and attenuates myofilament responses induced by protein kinase A. AB - Following activation by G-protein-coupled receptor agonists, protein kinase C (PKC) modulates cardiac myocyte function by phosphorylation of intracellular targets including myofilament proteins cardiac troponin I (cTnI) and cardiac myosin binding protein C (cMyBP-C). Since PKC phosphorylation has been shown to decrease myofibril ATPase activity, we hypothesized that PKC phosphorylation of cTnI and cMyBP-C will lower myocyte power output and, in addition, attenuate the elevation in power in response to protein kinase A (PKA)-mediated phosphorylation. We compared isometric force and power generating capacity of rat skinned cardiac myocytes before and after treatment with the catalytic subunit of PKC. PKC increased phosphorylation levels of cMyBP-C and cTnI and decreased both maximal Ca(2+) activated force and Ca(2+) sensitivity of force. Moreover, during submaximal Ca(2+) activations PKC decreased power output by 62 %, which arose from both the fall in force and slower loaded shortening velocities since depressed power persisted even when force levels were matched before and after PKC. In addition, PKC blunted the phosphorylation of cTnI by PKA, reduced PKA induced spontaneous oscillatory contractions, and diminished PKA-mediated elevations in myocyte power. To test whether altered thin filament function plays an essential role in these contractile changes we investigated the effects of chronic cTnI pseudo-phosphorylation on myofilament function using myocyte preparations from transgenic animals in which either only PKA phosphorylation sites (Ser-23/Ser-24) (PP) or both PKA and PKC phosphorylation sites (Ser-23/Ser 24/Ser-43/Ser-45/T-144) (All-P) were replaced with aspartic acid. Cardiac myocytes from All-P transgenic mice exhibited reductions in maximal force, Ca(2+) sensitivity of force, and power. Similarly diminished power generating capacity was observed in hearts from All-P mice as determined by in situ pressure-volume measurements. These results imply that PKC-mediated phosphorylation of cTnI plays a dominant role in depressing contractility, and, thus, increased PKC isozyme activity may contribute to maladaptive behavior exhibited during the progression to heart failure. PMID- 22527642 TI - [Development of an internet-based clinical pathway exemplified by the fibromyalgia syndrome]. AB - Clinical pathways (CP) are considered to be a tool of clinical process management describing the optimal route for diagnostic and therapeutic medical treatment of a specified patient. Apart from economic aspects CPs can make a contribution to optimization of health quality management as well as to improvement of medical staff and both patient satisfaction and patient safety whereas the feasibility and acceptance of evidence-based medicine guidelines are often found to be low. In order to stimulate critical discussion by offering the opportunity to easily gain first practical experience, a free web-based clinical pathway system for diagnosis and treatment for patients with fibromyalgia syndrome (FMS) will be presented. PMID- 22527643 TI - [Efficacy, utility and cost-effectiveness of multidisciplinary treatment for chronic low back pain]. AB - BACKGROUND: Qualitative criteria, such as efficacy, utility and cost effectiveness are essential for insurance and reimbursement companies to meet the costs for a multidisciplinary treatment (MDT) for persons with chronic low back pain (CLBP). METHOD: A systematic search concerning the qualitative criteria of MDT for CLBP presents an overview of the current literature. RESULTS: The search revealed 8 systematic reviews which document a moderate efficacy of MDT as a treatment for persons with CLBP although some reported restrictions. Analysis of 6 studies that have not yet been included in previous reviews confirmed the findings from these reviews. The comparison of conservative and surgical treatment for CLBP revealed that long-term outcomes hardly differed in quality, whereas surgical treatment was more expensive and contained more and higher risks. References on moderate to high cost-effectiveness of MDT are represented in 3 original studies. CONCLUSION: The MDT of CLBP is moderately efficient, purposeful, cost-effective and demonstrate an alternative treatment form to surgical treatment. PMID- 22527644 TI - [German fibromyalgia consumer reports. Benefits and harms of fibromyalgia syndrome therapies]. AB - BACKGROUND: Consumer reports provide information on benefits and harms in routine clinical care. We report the first fibromyalgia syndrome (FMS) consumer reports in Europe. MATERIAL AND METHODS: The study was carried out from November 2010 to April 2011. The benefits and harms of pharmacological and non-pharmacological therapies experienced by the patient were assessed in an 11-point Likert scale (0=no, 10=very high benefit or harm) by a questionnaire. The questionnaire was distributed by the German League against Rheumatism and the German Fibromyalgia Association to their members and to all consecutive FMS patients of nine clinical centers of different levels of care. RESULTS: A total of 1,661 questionnaires (95% women, mean age 54 years) were analyzed. Self-management strategies (distraction, resting, aerobic exercise), physical therapies (warm and pool therapies), psychological therapies (education, psychotherapy), and inpatient multicomponent therapies were judged to be more efficacious and less harmful than all types of pharmacological therapies. CONCLUSION: The German fibromyalgia consumer reports highlight the importance of non-pharmcological therapies in the long-term management of FMS. PMID- 22527645 TI - [Therapy of functional abdominal pain in childhood. Concept, acceptance and preliminary results of a short hypnotherapeutic-behavioural intervention]. AB - OBJECTIVE: Recurrent abdominal pain is one of the most frequent pain syndromes in childhood and is accompanied by notable functional impairment and unfavourable long-term outcome. Psychotherapeutic approaches are promising, but not widely used in Germany. The concept of a multimodal short-term intervention and its acceptance are described and preliminary results are reported. METHOD: A total of 21 children aged 6-12 years and their parents participated in a hypnotherapeutic behavioural short intervention program. Preliminary results on efficacy up to 3 months are reported. RESULTS: Participating children showed a decrease in pain frequency and daily impairment. Health-related quality of life also increased and associated mental problems could be reduced. Content and conditions of the intervention were rated as helpful by children and parents. CONCLUSION: Preliminary results indicate that even short psychotherapeutic interventions might help affected children effectively and lower the burden felt by parents. Further investigations using a randomized controlled trial design and focussing on children suffering more severely should follow to allow major conclusions. PMID- 22527646 TI - [German pain questionnaire and standardised documentation with the KEDOQ-Schmerz. A way for quality management in pain therapy]. AB - KEDOQ-Schmerz was developed by the German Pain Society (formerly DGSS) as a basic tool for documentation and quality management of pain therapy. It is planned to use KEDOQ-Schmerz as the data basis for nationwide, cross-sectional and independent scientific research in health services in Germany. With comparatively little effort, each participating institution (practices, pain clinics) will be able to provide quality control of their own diagnostic procedures and therapeutic effects by using benchmarking. In future KEDOQ-Schmerz will also be used as a method for external quality management in pain therapy in Germany. PMID- 22527648 TI - [Long-term effects of interventional treatment on chronic pain of the musculoskeletal system. Retrospective outcome study of repeated in-patient treatment]. AB - INTRODUCTION: Interventional procedures are frequently used for treatment of musculoskeletal pain syndromes but current scientific evidence does not show successful outcome in chronic cases. In this study the effect of repeated interventional treatment on the long-term outcome of patients with chronic musculoskeletal pain was examined. MATERIALS AND METHODS: In order to prepare for a retrospective outcome study (RCT) on proliferation therapy the clinical records of 38 patients who had been repeatedly treated (minimum 5 times) with an interventional treatment concept were examined. RESULTS: Patients were treated on average 10 times with approximately 107 single injections during each treatment cycle. In the long term the chronic pain syndrome showed a statistically significant deterioration with a generalization of the pain as well as an increase in pain medication, surgery and psychosocial impairment.. DISCUSSION: Repeated treatment cycles of interventional pain therapy did not lead to an improvement in the treated pain syndromes and in the long term the pain syndromes deteriorated further. It seems likely that the interventional approach promoted this adverse development but the data of this study are not sufficient to conclusively prove this thesis. PMID- 22527647 TI - [Effect of botulinum toxin type B on residual limb sweating and pain. Is there a chance for indirect phantom pain reduction by improved prosthesis use?]. AB - OBJECTIVES: Hyperhidrosis of a residual limb after amputation is one of the most common reasons for impaired prosthesis use and quality of life and affects 30-50% of all amputees causing skin irritation in about 25%. Thus the probability of residual limb pain increases in addition to an increased likelihood of phantom pain due to shorter duration of prothesis use. Development of both types of pain was studied following treatment of hyperhidrosis in 9 amputees. DESIGN: A total of 9 lower limb amputees received injections of 1750 units of botulinum toxin type B (BTX-B) for the treatment of hyperhidrosis of a residual limb (20 intracutaneous injections each). Prior to injections and 4 weeks and 3 months afterwards, patients rated the impairments regarding residual limb pain, phantom pain and sweating of the residual limb. Furthermore the duration of use of the prosthetic device and quality of life were rated on a numeric rating scale (NRS 0 10). RESULTS: Stump pain (n=9) was highly significantly reduced after 3 months (baseline: NRS 5; 4 weeks: NRS 4, p=0.109; 3 months: NRS 3, p=0.008) and also a tendency for phantom pain after 3 months (baseline NRS 5; 3 months: NRS 3; p=0.109). Sweating of the residual limb prior to BTX-B application was rated as a median 7 on the NRS scale with significant improvements after 4 weeks (NRS 3, p=0.027) and 3 months (NRS 3, p=0.020). Impaired duration of prothesis use improved from NRS 8 to NRS 2 (4 weeks; p=0.023) and NRS 3 (3 months; p=0.023) as well as the quality of life (p=0.016, p=0.023, respectively). CONCLUSIONS: Residual limb pain improved 3 months after intracutaneous, low-dose BTX-B in a trial with 9 patients and also phantom pain by tendency. Sweating of the residual limb was significantly reduced, probably thereby improving the duration of prothesis use. Larger studies should confirm these findings and conclusions. PMID- 22527649 TI - [Prevalence and predictors of urogenital pain in men. Results from a survey of a representative German population sample]. AB - BACKGROUND: In Germany no data are available on the prevalence and predictors of urogenital pain in men from representative population samples. MATERIALS AND METHODS: Persons older than 14 years of age from a representative sample of the German population were examined by standardized questionnaires within a cross sectional survey. Urogenital pain was assessed by the German version of the National Institutes of Health Chronic Prostatitis Symptoms Index (NIH-CPSI), depression by the patient health questionnaire PHQ-9 and health-related quality of life by the short form health survey SF-36. RESULTS: A total of 2,043 persons (66.5%s) took part in the study and 960 men with a mean age of 47.2 years were analyzed. The 1-week prevalence of urogenital pain was 9.6% whereby 2.4% met the criteria of mild and 1.9% the criteria of severe prostatitis-like symptoms. The total pain score of the NIH-CPSI was predicted by old age, high income and high depression scores. Men with mild and severe prostatitis-like symptoms reported higher depression and lower health-related quality of life than men without prostatitis-like symptoms CONCLUSIONS: Prostatitis-like symptoms are associated with depression and reduced health-related quality of life in the general population. PMID- 22527650 TI - [Pain management in international curricula for undergraduate education in palliative medicine. A palliative education assessment tool (PEAT) analysis]. AB - BACKGROUND: In the context of undergraduate medical education, there is the question of overlap between palliative medicine and pain management. International curricula for palliative medicine were analyzed with regard to the content concerning pain management. METHODS: Available international curricula were sought through general search engines (Google, Medline/Pubmed) in the German and English languages. The palliative care education assessment tool (PEAT), a validated instrument for curricula mapping, was used for detection of pain management content. The PEAT comprises 7 domains and 83 objectives. Domain II (pain) contains 12 items (15%). Additional pain management content was analyzed qualitatively. RESULTS: Between 1993 and 2011 16 international curricula for undergraduate education in palliative medicine were identified and every curriculum contained PEAT-domain II (pain). Altogether, 2-65 out of 83 PEAT objectives and 0-11 specific pain-related PEAT objectives were included as learning content. Hence, the latter define 0-21% of the contents of the analyzed curricula. The only additional topic was "breakthrough pain" which was mentioned in 4 out of 16 curricula. CONCLUSIONS: Pain-related objectives are regularly mentioned in international undergraduate palliative medicine curricula. The extent is limited and therefore the concordance to general pain management is low. PMID- 22527651 TI - [National standard for acute pain management in nursing. First update]. PMID- 22527652 TI - [Placebo for fibromyalgia--but how?]. PMID- 22527653 TI - [President's corner]. PMID- 22527654 TI - Multiple primary enoral soft tissue manifestations of a Hodgkin lymphoma--case report and literature review. AB - BACKGROUND: Hodgkin lymphoma (HL) are lymphoproliferative neoplasms, histologically comprising of mononuclear and multinucleated Hodgkin and Reed Sternberg cells (HRS). About 4 % of all lymphatic malignancies of the head and neck are HL. The typical disease presents itself as a nodal lesion. Extranodal, enoral soft tissue involvement by HL is very rare. CASE REPORT: A 73-year-old man with a suspect, ulcerating lesion in the left retromolar region of the mandible was assigned to our hospital. Prior anti-inflammatory therapy has been without success. Subsequently, three biopsies were taken which could only show inflammation. Finally, two biopsies from the left retromolar region and the left inner cheek showed HRS cells with positive expressions of CD15 and CD30 corresponding to a Hodgkin lymphoma. No lymphatic node or bone involvement could be detected. The patient was designated to receive radio-chemotherapy, but died 3 weeks after diagnosis of multiple organ failure. In a literature review, together with this report, nine cases were found concerning primary HL of the oral mucosa. Accordingly, this is the first case of primary multiple extranodal HL in the oral mucosa in absence of lymphatic node involvement. DISCUSSION: Neither clinical features nor radiological appearances of HL presenting as primary enoral lesions are pathognomonic. Especially when only small biopsy specimens are available, histological diagnosis remains challenging, may lead to a delay in therapy and may result in a significant worse prognosis. PMID- 22527655 TI - Rare case of superolateral dislocation of the condyle. AB - BACKGROUND: Dislocation of the mandibular condyle occurs most commonly in the anterior direction. When there is an intracranial displacement of the condyle, it is often associated with CSF leak. Superolateral dislocation of the condyle from the glenoid fossa is a rare condition which commonly occurs following traumatic insult to the mandible. When there is a superlolateral displacement, the condyle is often lodged in the temporal fossa. CASE REPORT: We report an unusual case of a 50-year-old male with a superolateral dislocation of the left mandibular condyle into the zygomatic arch along with a fracture of the right mandible following road traffic accident. Manual reduction of the condyle was first attempted under general anaesthesia which was futile, following which the displaced condyle was reduced by a combination of open traction and manual reduction using Keen's approach in left maxillary vestibule. After reduction of the condyle, intermaxillary fixation (IMF) was done and X plate was used to fix the mandible fracture on the right body. Postoperatively, patient was placed on IMF for a period of 2 weeks. DISCUSSION: Superolateral dislocations of the condyle can be unilateral or bilateral. These types of dislocations generally occur following traumatic injury to the mandible when the mouth is open. Early diagnosis and reduction of the condyle is required to achieve satisfactory occlusion which should be followed by physiotherapy to prevent ankylosis. PMID- 22527656 TI - Epithelioid myoepithelioma of the hard palate. AB - BACKGROUND: Myoepithelioma, a generally benign tumor comprised of myoepithelial cells, is an uncommon salivary gland tumor. Among four morphologic variants of myoepithelioma, epithelioid type has not been reported in the oral and maxillofacial region. CASE REPORT: A 61-year-old man first noticed the mass 3 years previously. The oral examination revealed a firm, non-tender, and well circumscribed mass in the middle of the hard palate. A magnetic resonance imaging scan showed a well-circumscribed mass with low signal intensity (T(1)-weighted image) or increased signal intensity (T(2)-weighted image). DISCUSSION: Immunohistochemically, the tumor cells in the present case reacted to the epithelial (CK HMW and CAM5.2) and the mesenchymal (vimentin) markers. However, myoepithelial markers (S-100 protein, alpha-smooth muscle actin, glial fibrillary acidic protein, and calponin), except p63, were not expressed in the tumor cells. These results indicated that the epithelial myoepithelioma cells differentiated into epithelial cells rather than myoepithelial cells. We believe that epithelioid myoepithelioma of the palate is a distinctive subtype of myoepithelioma that should be included in the differential diagnosis of tumors of the palate. PMID- 22527657 TI - Role of HMGB1 in doxorubicin-induced myocardial apoptosis and its regulation pathway. AB - Doxorubicin (DOX) is a widely used anti-tumor agent. The clinical application of the medication is limited by its side effect which can elicit myocardial apoptosis and cardiac dysfunction. However, the underlying mechanism by which DOX causes cardiomyocyte apoptosis is not clear. The aim of present study is to investigate the role of high-mobility group box 1 (HMGB1) in DOX-induced myocardial injury, and signal pathway involved in regulation of HMGB1 expression in cardiomyocytes with DOX. We found treatment of isolated cardiomyocytes and naive mice with the DOX resulted in an increased HMGB1 expression which was associated with increased myocardial cell apoptosis. Pharmacological (A-box) or genetic blockade (TLR4 deficiency, TLR4(-/-)) of HMGB1 attenuated the DOX-induced myocardial apoptosis and cardiac dysfunction. In addition, our study showed that DOX resulted in an increment in the generation of peroxynitrite (ONOO(-)) and an elevation in phosphorylation of c-Jun N terminal kinase (JNK). Pretreatment of myocytes with FeTPPS, a peroxynitrite decomposition catalyst, prevented DOX induced JNK phosphorylation, HMGB1 expression, myocardial apoptosis and cardiac dysfunction. Genetic (JNK(-/-)) or pharmacological (SP600125) inhibition of JNK ameliorated the DOX-induced HMGB1 expression and diminished myocardial apoptosis and cardiac dysfunction. Taken together, our results indicate that HMGB1 mediates the myocardial injury induced by DOX and ONOO(-)/JNK is a key regulatory pathway of myocardial HMGB1 expression induced by DOX. PMID- 22527658 TI - Demographic characteristics and physical activity behavior of park-visitors versus non-visitors. AB - To examine physical activity (PA) behaviors among park visitors versus non visitors by select demographic variables of a large city park. A sample of 251 respondents participated in a random digit dial survey. PA was measured using the Behavioral Risk Factor Surveillance System (BRFSS) PA module. The majority of respondents reported meeting PA recommendations (70.5 %) and being park visitors (60.2 %). A greater proportion of adults were park visitors (65.6 %) compared to the proportion of older adults who were park visitors (49.2 %). All persons who identified as being a race other than white and reported meeting the national PA recommendations through vigorous PA were park visitors. Environmental interventions that increase the availability of city parks may impact PA behavior among racial minority groups. There is also an opportunity to promote park usage among older adults. PMID- 22527659 TI - Appalachian residents' perspectives on new U.S. cigarette warning labels. AB - The U.S. Food and Drug Administration revealed new pictorial warning labels in June 2011 for cigarette packages, yet little is known about how these labels are perceived by U.S. residents. We examined the reactions to and attitudes about the new labels among residents of Appalachian Ohio, a region with a high smoking prevalence. We conducted focus groups with Appalachian Ohio residents between July and October 2011. Participants included healthcare providers (n = 30), community leaders (n = 26), parents (n = 28), and young adult men ages 18-26 (n = 18). Most participants supported the addition of the new labels to U.S. cigarette packages, though many were unaware of the labels prior to the focus groups. Participants did not think the labels would be effective in promoting smoking cessation among smokers in their communities, but they were more positive about the potential of the labels to reduce smoking initiation. Participants reported positive feedback about the more graphic labels, particularly those showing a man with a tracheal stoma or a person with severe oral disease. The labels that include a cartoon image of an ill infant and a man who quit smoking received the most negative feedback. Participants generally supported adding pictorial warning labels to U.S. cigarette packages, but only a few of labels received mostly positive feedback. Results offer early insight into how the new labels may be received if they are put into practice. PMID- 22527660 TI - [Pneumological intensive care medicine]. PMID- 22527661 TI - [Acute hepatic failure after ingestion of mushrooms]. AB - This report is about a married couple who were admitted to hospital suffering from gastrointestinal complaints after eating mushrooms. With the suspicion of poisoning with Amanita phalloides treatment started with elimination of the toxins, symptomatic therapy and specific therapy with silibinin. After quantitative determination of the Amanita toxins the patients were immediately transferred to a university hospital.Poisoning by the death cap mushroom is responsible for acute hepatic and often also renal failure and is accompanied by a high mortality. Clinical symptoms follow a three-phase course with gastrointestinal complaints, an asymptomatic interval and finally the hepatorenal phase. Even in suspected cases of intoxication, treatment should be started by antidote therapy with silibinin. PMID- 22527662 TI - [Respiratory pump failure. Clinical symptoms, diagnostics and therapy]. AB - The total anatomical and functional apparatus which allows normal ventilation of the lungs is known as the respiratory pump. An insufficiency of this system, which can be caused by a multitude of reasons, primarily affects the inspiratory musculature and especially the diaphragm. One of the essential clinical characteristics is rapid shallow breathing. Exhaustion of the repiratory musculature due to acute respiratory insufficiency is normally clinically registered but can also be functionally determined in particular by the maximum static inspiratory closed mouth pressure. A further option is invasive measurement of the transdiaphragmal pressure, which however is not suitable as a routine procedure. Mechanical ventilation is used as treatment of respiratory pump insufficiency independent of the cause. This is initially a non-invasive procedure but if unsuccessful intubation and invasive ventilation are indicated. The technical developments in the field of extracorporeal gas exchange systems are very promising. However, in view of the insufficient data, ventilation procedures using masks and tubes still remain the first choice methods. PMID- 22527663 TI - [Right heart failure in chronic pulmonary hypertension and acute pulmonary embolism]. AB - Right-sided heart failure is a severe and often life-threatening complication of chronic pulmonary hypertension. The detection of trigger factors that induce right heart failure in previously stable patients is important to initiate a causal therapeutic strategy. Pulmonary embolism (PE) is a frequent cause of acute right heart failure and therapeutic strategies for PE are well documented in the current guidelines. Treatment of choice for chronic thromboembolic pulmonary hypertension (CTEPH) is surgical pulmonary endarterectomy (PEA) and patients with possible CTEPH should be referred to an experienced PEA surgeon without delay. Intensive care management for overt right heart failure is complex and includes the use of pulmonary vasodilators, individual adjustment of diuretic or volume therapy, augmentation of myocardial contractility and left ventricular afterload. Therapeutic regimens aim at optimized filling of the right ventricle, improvement of myocardial perfusion by avoiding tachycardia, elevating systemic pressure and reducing right ventricular afterload. Early communication with a specialized center for pulmonary hypertension is recommended. PMID- 22527664 TI - [Acute respiratory distress syndrome]. AB - Acute respiratory distress syndrome (ARDS) is the clinical manifestation of an acute lung injury caused by a variety of direct and indirect injuries to the lung. The cardinal clinical feature of ARDS, refractory arterial hypoxemia, is the result of protein-rich alveolar edema with impaired surfactant function, due to vascular leakage and dysfunction with consequently impaired matching of ventilation to perfusion. Better understanding of the pathophysiology of ARDS has led to the development of novel therapies, pharmacological strategies, and advances in mechanical ventilation. However, protective ventilation is the only confirmed option in ARDS management improving survival, and few other therapies have translated into improved oxygenation or reduced ventilation time. The development of innovative therapy options, such as extracorporeal membrane oxygenation, have the potential to further improve survival of this devastating disease. PMID- 22527665 TI - [Emergencies in adult mucoviscidosis patients]. AB - Cystic fibrosis is an inherited autosomal recessive metabolic disease caused by mutations on the CFTR gene. This leads to defective chloride channels on epithelial cell membranes and causes various disorders of the respiratory, gastrointestinal, and urogenital tracts.As a result, all exocrine glands produce a viscous secretion, leading to pulmonary symptoms such as chronic cough, secretion retention, recurring infections as well as bronchiectasis and obstructive lung emphysema. Gastrointestinal effects include exocrine and often also endocrine pancreatic insufficiency with chronic diarrhea and maldigestion syndrome as well as pancreoprivic diabetes mellitus; biliary cirrhosis occurs in 10% of cases. Additional effects include reduced fertility in women and infertility in men.Life-threatening complications include bleeding from the bronchial arteries, pneumothorax, and distal intestinal obstruction syndrome (DIOS), previously known as meconium ileus equivalent. Treatment requires rapid diagnosis and should be carried out in experienced centres, since the mortality rate can otherwise be up to 50%. PMID- 22527666 TI - [Lung transplantation]. AB - Since the early days of lung transplantation the demand for donor organs has outstripped donor organ availability. Consequently waiting times continue to increase with patients of highest priority often waiting several weeks or even months until a suitable donor organ becomes available resulting in considerable mortality on the waiting list. These issues have led to renewed interest in bridging strategies for patients with end-stage lung disease. The use of endotracheal intubation and mechanical ventilation (MV) has been viewed as a last resort as the majority of intubated patients fail to reach transplantation and those who do tend to have a poor postoperative outcome. New bridging strategies with awake extracorporeal membrane oxygenation (ECMO) seem to be hopeful alternatives in some patients. In the early intensive care unit (ICU) phase primary graft dysfunction, acute rejection, infections and surgical complications are common problems. Later, rejection, infection and sepsis, special airway complications and pulmonary bleeding may be reasons for ICU treatment. PMID- 22527667 TI - [Endoscopic and percutaneous intervention in the long-term treatment of benign biliary stenosis. A 71-year-old patient with cholestasis following radiotherapy]. AB - Benign biliary stenosis can have various causes and requires differentiation from disorders caused by malignant disease. Treatment of benign stenosis is often difficult and includes treatment modalities such as endoscopic, percutaneous or surgical interventions. Exact knowledge of the etiology and localization of the stenosis is essential when selecting the appropriate method of treatment. Here we present the case of a 71-year-old patient admitted to our hospital with cholangitis 13 years after undergoing radiotherapy of the renal bed due to hypernephroma of the right kidney. The patient was diagnosed with common bile duct stenosis due to the secondary effects of radiation, which is rarely reported in the literature. Our case covers a total treatment period of 15 years, enabling us to also discuss a viable sequence of treatment modalities in the treatment of benign bile duct stenosis. PMID- 22527668 TI - [Chemotherapy in elderly frail patients with advanced colorectal cancer. MRC FOCUS 2 (UK Medical Research Council Fluorouracil, Oxaliplatin, and Capecitabine: Use and Sequencing)]. PMID- 22527669 TI - A switch from GnRH agonist to GnRH antagonist in castration-resistant prostate cancer patients leads to a low response rate on PSA. AB - PURPOSE: At the time of castration resistance, it is recommended to realize hormonal manipulations before chemotherapy. We evaluated the impact of a switch from GnRH agonist to antagonist in patients with castration-resistant prostate cancer on PSA and testosterone levels at 3 months. METHODS: Retrospectively, 17 patients from 5 different centers undergoing androgen deprivation therapy and presenting rising PSA confirmed on 3 blood samples 2 weeks apart and despite a castrate testosterone level (<0.5 ng/ml) were reviewed. Antiandrogen withdrawal syndrome had been tested before the switch. Degarelix was administered as followed: 240 mg for the first injection and then 80 mg every month, subcutaneously. We evaluated the PSA and testosterone level variation 3 months after the switch. Patients who experienced a variation in PSA of less than 10% compared to the baseline or who had a more than 10% PSA decrease were defined as responders. RESULTS: Mean PSA level at the switch was 34.3 +/- 50.3 ng/ml, with a mean testosterone level of 0.21 +/- 0.13 ng/ml. Three months after the switch, mean PSA level was 59.9 +/- 81.6 ng/ml (P = 0.061), with a mean testosterone level of 0.19 +/- 0.08 ng/ml (P = 0.086). At 3 months, 4 patients (23%) responded to therapy. Thirteen patients (77%) experienced a rise in PSA of more than 10% compared to baseline; 41% of patients decreased their testosterone level. The limitations of this study are its retrospective nature and the limited number of patients. CONCLUSION: Switch from an agonist to an antagonist of GnRH has a limited impact on PSA at 3 months in castration-resistant prostate cancer patients. PMID- 22527670 TI - Orchialgia after laproscopic renal surgery: a common problem with questionable etiology. Are there any predictors? AB - PURPOSE: Orchialgia after laproscopic renal surgery has been rarely reported in literature, and gonadal vein ligation is considered the main etiology. Our objective was to study the incidence, intensity and to find out any specific factors that could lead to orchialgia. MATERIALS AND METHODS: All patients planned for laproscopic renal surgery between Jan 2009 and July 2011 had a history and physical examination before surgery, in postoperative period, and after discharge. Pain was scored on a standard 10-point scale approved by the NIH. Baseline, perioperative, and postoperative data were collected prospectively. RESULTS: A total of 460 laproscopic renal surgeries were performed on males out of which 440 met our criteria of evaluation. A total of 38 patients had ipsilateral orchialgia (8.52 %). The pain was more common for left-sided procedures. Mean pain intensity was 3.2. On statistical analysis, there was no difference in the operative parameters between patients of pain and those without pain except that the level of ligation of ureter and that of gonadal vein were significantly associated with orchialgia (p value <0.001 and 0.003, respectively) with the odds ratio for ligating them below the crossing of iliac vessels being 6.443 (3.098-13.397) and 4.457 (2.165-9.176), respectively. CONCLUSION: Ipsilateral orchialgia is common in patients undergoing laproscopic renal surgery specially after radical nephroureterectomy and nephrectomy specially when the ureter and gonadal vein are taken down at or below their crossing of iliac vessels. Taking down ureter above, rather than below, the iliac vessels whenever possible may be preventive as is the preservation of gonadal vein. PMID- 22527671 TI - Transperitoneal laparoscopic nephroureterectomy for native upper tract urothelial carcinoma in renal transplant recipients. AB - PURPOSE: To analyze the safety and clinical outcome of laparoscopic nephroureterectomy (LNUT) for native upper tract urothelial carcinoma (UC) in renal transplant (RT) recipients. METHODS: We conducted a retrospective analysis of 956 RT recipients from January 2003 to December 2010 to evaluate the benefit of LNUT for patients who were diagnosed with de novo UC after renal transplantation. RESULTS: Women predominated (10/11, 91 %) in the 11 patients with upper tract UC who underwent LNUT. Five patients underwent LNUT ipsilateral to the transplanted kidney, 4 patients underwent contralateral LNUT, and 2 patients underwent bilateral LNUT. Nine were operated with LNUT combining resection of bladder cuff, 2 with right ureteral cancer underwent open ureterectomy with bladder cuff due to severe adhesions attached to the lesion. The mean surgical duration was 184.2 min (105-305), the mean blood loss was 182.3 ml (20-500), and the mean hospitalization time was 6.7 days (5-9). The mean levels of preoperative and postoperative serum creatinine were 0.99 mg/dl (0.78 1.16) and 1.01 mg/dl (0.89-1.18), respectively. No intraoperative complications occurred. One patient died of multiple metastases at 13 months after LNUT. The mean follow-up of the remaining 10 patients after diagnosis was 21.7 months (3 48). Two patients had recurrent bladder cancer and underwent transurethral resection of the tumor. Eight patients showed no evidence of disease during the follow-up. CONCLUSIONS: LNUT is a safe and effective approach with low morbidity in transplant recipients, and this therapy provides less trauma, quicker recovery, and acceptable oncological outcomes. PMID- 22527672 TI - Correlation of the RENAL nephrometry score with warm ischemia time after robotic partial nephrectomy. AB - PURPOSE: The RENAL nephrometry score (RNS) was developed to quantify complexity of renal tumors in a reproducible manner. We aim to determine whether individual categories of the RNS have different impact on the warm ischemia time (WIT) for patients undergoing robotic partial nephrectomy (RPN). METHODS: In a retrospective analysis of a prospectively maintained database, we identified 251 consecutive patients who underwent RPN between January 2007 and June 2010. RNS was determined in 187 with available imaging. Univariable analysis and multivariable linear regression analysis were performed to identify which factors were more significantly associated with WIT. RESULTS: Overall RNS was of low (4 6), moderate (7-9), and high complexity (10-12) in 84 (45 %), 80 (43 %), and 23 (12 %) patients, respectively. There was no association between gender (p = 0.6), BMI (p = 0.3), or anterior/posterior location (A) (p = 0.8), and WIT. On univariable analysis, longer WIT was associated with size (R) >4 cm (p < 0.0001), entirely endophytic properties (E) (p = 0.005), tumor <4 mm from the collecting system/sinus (N) (p < 0.0001), and location between the polar lines (L) (p = 0.004). Total RNS and WIT were highly correlated (Spearman correlation coefficient = 0.54, p < 0.0001). There was a significant trend of higher WIT with increased tumor complexity (p for trend <0.0001). After multivariable analysis, only R (p = 0.0003), E (p = 0.003), and N (p = 0.00002) components of the RNS were significantly associated with WIT. CONCLUSIONS: The A and L subcategories of the RNS have no significant impact on the WIT of patients undergoing RPN. WIT is significantly dependent upon the other subcategories, as well as the overall RNS. These findings can be used to preoperatively predict which tumor characteristics will likely affect WIT and may be useful in preoperative counseling as well as planning of approach. PMID- 22527673 TI - The impact of location and number of cores on the diagnostic accuracy of renal mass biopsy: an ex vivo study. AB - OBJECTIVE: To evaluate whether renal mass biopsy (RMB) biopsy location or number affected diagnostic accuracy in a prospective ex vivo study. METHODS: Three cores (1 central and 2 peripheral) were obtained for histologic processing from each of 48 renal masses after nephrectomy. Individual biopsy cores were evaluated independently for tumor subtype and grade by a single, blinded GU pathologist. RESULTS: Although individual biopsy cores were informative and confirmed accurate in only 59 % of samples, accuracy increased to 85 % with three-core biopsy (p < 0.01). Cancer identification with a single peripheral core increased to 77 % by adding a central core (p = 0.005), to 80 % with a second peripheral core (p = 0.008), and to 85 % with three cores (p = 0.001). Similarly, diagnostic yield for histologic subtyping increased from 44 % for 1-core biopsy to 59-63 % with 2-core biopsy (p = 0.03) and to 67 % with 3-core biopsy (p = 0.02). The correct subtype was confirmed at nephrectomy for 63 % of clear cell RCC, 60 % of papillary RCC, 100 % of chromophobe RCC and 75 % of oncocytomas. When recorded, nuclear grade corresponded to final grade assignment in 56 % and was within 1 grade in an additional 37 %. CONCLUSIONS: RMB has not been used routinely in the evaluation of renal cortical neoplasms because of reportedly high rates of indeterminate or inaccurate diagnoses. In this prospective, ex vivo study, single-core RMB results in a low diagnostic yield. Obtaining multiple cores significantly improved diagnostic yield, with similar results with two-core and three-core RMB. We therefore recommend that RMB for suspicion of cancer include at least two peripheral cores. PMID- 22527674 TI - Evaluating the Prostate Cancer Prevention Trial High Grade Prostate Cancer Risk Calculator in 10 international biopsy cohorts: results from the Prostate Biopsy Collaborative Group. AB - OBJECTIVES: To assess the applicability of the Prostate Cancer Prevention Trial High Grade (Gleason grade >= 7) Risk Calculator (PCPTHG) in ten international cohorts, representing a range of populations. METHODS: A total of 25,512 biopsies from 10 cohorts (6 European, 1 UK and 3 US) were included; 4 implemented 6-core biopsies, and the remaining had 10 or higher schemes; 8 were screening cohorts, and 2 were clinical. PCPTHG risks were calculated using prostate-specific antigen, digital rectal examination, age, African origin and history of prior biopsy and evaluated in terms of calibration plots, areas underneath the receiver operating characteristic curve (AUC) and net benefit curves. RESULTS: The median AUC of the PCPTHG for high-grade disease detection in the 10- and higher-core cohorts was 73.5% (range, 63.9-76.7%) compared with a median of 78.1% (range, 72.0-87.6%) among the four 6-core cohorts. Only the 10-core Cleveland Clinic cohort showed clear evidence of under-prediction by the PCPTHG, and this was restricted to risk ranges less than 15%. The PCPTHG demonstrated higher clinical net benefit in higher-core compared with 6-core biopsy cohorts, and among the former, there were no notable differences observed between clinical and screening cohorts, nor between European and US cohorts. CONCLUSIONS: The PCPTHG requires minimal patient information and can be applied across a range of populations. PCPTHG risk thresholds ranging from 5 to 20%, depending on patient risk averseness, are recommended for clinical prostate biopsy decision-making. PMID- 22527675 TI - Three-tesla MRI biphasic angiography: a method for preoperative assessment of the vascular supply in renal tumours: a surgical perspective. AB - PURPOSE: The new generation of 3TMRI has improved spatial and time resolutions, which are favourable in imaging of the renal vasculature. In this study, we have compared the imaging findings of the renal blood vessels using 3TMRI and CT with intraoperative assessment of the renal vasculature as gold standard. METHODS: This prospective study was approved by the local ethical committee. Between 4/2011 and 12/2011, 80 patients with renal tumours underwent 3TMRA (angiography) (Magnetom SKYRA 3T, Siemens). Twenty of the patients were also examined with CT AG. The results of the CTA- and MRA-imaging studies were correlated with the intraoperative assessment of the renal vessels. RESULTS: Seventy patients (87.5 %) had a detailed intraoperative assessment of the renal vessels. The sensitivities for CTA and MRA were 88.2 and 88.6 %, respectively. All discrepancies between imaging studies and intraoperative findings were due to inability to identify small polar vessels. The results of MRA were concordant with CTA in 85.0 % of cases. The (three) discrepancies between MRI and CT were due to failure of MRI in identifying small polar vessels. CONCLUSIONS: (1) 3TMRA gives detailed information about the renal vasculature including its topographical anatomy. (2) With MRI, small aberrant vessels are more frequently missed than with CTA. (3) CTA remains the gold standard. However, MRA may be used for planning of laparoscopic operations. (4) The quality of the 3D reconstruction is highly depending on the skills of the radiologist. PMID- 22527676 TI - Thrombotic complications during overt hyperthyroidism. PMID- 22527677 TI - Chest ultrasonography to detect lung involvement in Von Recklinghausen's disease. PMID- 22527679 TI - The heart seems to be the primary site and the target of anaphylaxis resulting in the development of Kounis syndrome. PMID- 22527680 TI - Estimation of treatment effects based on possibly misspecified Cox regression. AB - In randomized clinical trials, a treatment effect on a time-to-event endpoint is often estimated by the Cox proportional hazards model. The maximum partial likelihood estimator does not make sense if the proportional hazard assumption is violated. Xu and O'Quigley (Biostatistics 1:423-439, 2000) proposed an estimating equation, which provides an interpretable estimator for the treatment effect under model misspecification. Namely it provides a consistent estimator for the log-hazard ratio among the treatment groups if the model is correctly specified, and it is interpreted as an average log-hazard ratio over time even if misspecified. However, the method requires the assumption that censoring is independent of treatment group, which is more restricted than that for the maximum partial likelihood estimator and is often violated in practice. In this paper, we propose an alternative estimating equation. Our method provides an estimator of the same property as that of Xu and O'Quigley under the usual assumption for the maximum partial likelihood estimation. We show that our estimator is consistent and asymptotically normal, and derive a consistent estimator of the asymptotic variance. If the proportional hazards assumption holds, the efficiency of the estimator can be improved by applying the covariate adjustment method based on the semiparametric theory proposed by Lu and Tsiatis (Biometrika 95:679-694, 2008). PMID- 22527681 TI - Recent advances in the genetics of cerebellar ataxias. AB - The hereditary cerebellar ataxias are a clinically and genetically heterogeneous group of disorders that primarily affect the cerebellum; often there are additional features such as neuropathy, cognitive decline, or maculopathy that help define the clinical subtype of ataxia. They are commonly classified according to their mode of inheritance into autosomal dominant, autosomal recessive, X-linked, and mitochondrial forms. Great advances have been made in understanding the genetics of cerebellar ataxias in the last 15 years. At least 36 different forms of ADCA are known, 20 autosomal-recessive, two X-linked, and several forms of ataxia associated with mitochondrial defects are known to date. However, in about 40 % of suspected genetically determined ataxia cases, the underlying genetic defect remains undetermined. Although the majority of disease genes have been found in the last two decades, over the last 2 years the genetics has undergone a methodological revolution. New DNA sequencing technologies are enabling us to investigate the whole or large targeted proportions of the genome in a rapid, affordable, and comprehensive way. Exome and targeted sequencing has recently identified four new genes causing ataxia: TGM6, ANO10, SYT14, and rundataxin. This approach is likely to continue to discover new ataxia genes and make screening of existing genes more effective. Translating the genetic findings into isolated and overlapping disease pathways will help stratify patient groups and identify therapeutic targets for ataxia that have so far remained undiscovered. PMID- 22527682 TI - Update on multimodality monitoring. AB - Brain injury is a dynamic process marked by an initial damaging insult followed by a cascade of physical, electrical, and metabolic changes capable of resulting in further patient disability. These subclinical changes should be detected at a time when therapeutic intervention is most efficacious and preemptive. Multimodality monitoring is the practice by which a variety of brain monitors are utilized to deliver care, specific to the needs of the individual patient, in an attempt to minimize secondary injury and long-term disability. Intracranial pressure, continuous electroencephalography, brain tissue oxygen, cerebral microdialysis, cerebral blood flow, and jugular oximetry monitoring have been utilized to direct treatment of the critical ill neurologic and neurosurgical patient. Optimization of monitoring technique and protocol is an ongoing effort of intensivists in the field of neurocritical care. PMID- 22527683 TI - Continuous electroencephalography monitoring in neonates. AB - As more critically ill term and premature neonates are surviving their acute illness, their long-term neurodevelopmental morbidity is being recognized. Continuous monitoring of cerebral function, with electroencephalography or derived digital trends, can provide key information regarding seizures and background patterns, with direct treatment and prognostic implications. Conventional video-electroencephalography remains the gold standard for neonatal seizure diagnosis and quantification, but can be supplemented by digital trending modalities. Both conventional and amplitude-integrated electroencephalography can provide valuable data regarding the background trends. This review describes indications and methods for continuous electroencephalography monitoring in high risk neonates. PMID- 22527685 TI - Lateralized petrous internal carotid artery: imaging features and distinction from the aberrant internal carotid artery. AB - INTRODUCTION: This study aimed to describe the lateralized petrous internal carotid artery (ICA), a rare variant of the intratemporal course of the ICA, and distinguish it from aberrant ICA. METHODS: A retrospective multi-institutional review of all patients diagnosed over a 10-year period with lateralized ICA was completed. Medical records were reviewed for demographic data as well as clinical information in all patients. Computerized tomography (CT) studies were reviewed in all patients. Magnetic resonance studies in this patient group were reviewed when available. In order to obtain normative data for the ICA, the intratemporal course of the ICA was evaluated on 50 consecutive high-resolution sinus CT scans. RESULTS: Sixteen cases of lateralized ICA were identified on CT scans in 12 patients. In each of these, the ICA entered the skull base in a position more lateral to the cochlea than normal and protruded into the anterior mesotympanum with dehiscent or thinned overlying bone. Magnetic resonance angiography was available in 5 of 12 patients and catheter angiography in 1 of 12. CONCLUSION: Lateralized petrous ICA can be identified on CT by its more posterolateral entrance to the skull base and protrusion into the anterior mesotympanum. It can be distinguished from the aberrant ICA which enters the posterior hypotympanum through an enlarged inferior tympanic canaliculus, then courses across the inferior cochlear promontory to connect with the normal horizontal petrous ICA. Lateralized ICA is best considered an incidental petrous ICA variant. Awareness of this entity is important in the presurgical evaluation of the temporal bone to avoid vascular injury and confusion with the congenital diagnosis of aberrant ICA. PMID- 22527684 TI - Factors affecting long-term restenosis after carotid stenting for carotid atherosclerotic disease. AB - INTRODUCTION: The most significant factors leading to restenosis are yet to be described in the literature. The purpose of our study was to identify the incidence of restenosis in our patients with carotid artery stenting (CAS) for carotid atherosclerotic disease and to identify risk factors that are significantly responsible or related to the restenosis. METHODS: In this retrospective analysis of patients who underwent CAS for atherosclerotic disease between years 2002 and 2006, we studied various demographic, clinical, and medical factors, plaque characteristics, and technical aspects of CAS. All patients were followed up with carotid Doppler ultrasound at baseline (after 2 to 4 weeks of CAS) and then with Doppler ultrasound and clinically for various intervals of time. The restenosis was classified based on carotid Doppler ultrasound results. Clinically, restenosis was classified as symptomatic or asymptomatic. Pearson correlation coefficient was used to assess the statistical correlation of the different factors with the incidence of restenosis. RESULTS: We had a total of 105 patients, with a total of 204.6 patient-year follow-up (mean, 1.95 years; range, 0-7.3 years). The overall incidence of restenosis was 26.7 % (n = 28): mild, 7.6 % (n = 8); moderate, 10.5 % (asymptomatic, 11; symptomatic, 0); and severe, 8.6 % (asymptomatic, 5; symptomatic, 4). Overall, 14.3 % (n = 4) patients with restenosis were symptomatic and 7.1 % (n = 2) underwent retreatment. Post-stenting residual stenosis greater than either 30 % (p = 0.016) or 50 % (p = 0.05) were significant for long-term restenosis. Plaques longer than 20 mm were significantly related to restenosis (p < 0.001). CONCLUSION: The most important factor to explain restenosis was the immediate post-CAS residual stenosis and length of the plaque. PMID- 22527686 TI - CT volumetry of lumbar vertebral bodies in patients with hypoplasia L5 and bilateral spondylolysis and in normal controls. AB - INTRODUCTION: To examine the feasibility and results of calculating the volume of lumbar vertebral bodies in normal patients and patients with suspected hypoplasia of L5. METHODS: Lumbar multi-detector CT was performed in 38 patients with bilateral spondylolysis and hypoplasia of L5 and in 38 normal patients. Lumbar vertebral body volume of L3, L4 and L5 was measured by CT volumetry with a semi automated program, created with MeVisLab. RESULTS: In the control group, the average vertebral body volume (in cubic centimeters) of L3 was 35.93 (+/-7.33), 36.34 (+/-7.13) for L4 and 34.63 (+/-6.88) for L5. In patients with suspected hypoplasia L5 the average body volume (in cubic centimeters) of L3 was 36.85 (+/ 7.37), 36.90 (+/-6.99) for L4 and 33.14 (+/-6.57) for L5. The difference in mean vertebral body volume for L3, L4 and L5 between both groups was statistically not significant. However, there was a statistically significant difference of the ratio L5/L4 (P < 0.001) between both groups: the mean ratio L5/L4 in the control group was 95.3 +/- 3.9%, the ratio for the hypoplastic L5 group was 89.9 +/- 6.3%. CONCLUSIONS: There was no significant difference in the vertebral body volume for L3, L4 and L5 between both groups due to inter-patient variability. However, the relation between the body volume of L5 and L4 is significantly different between both groups. The volume of the vertebral body of L5 proved to be on average 10.2% smaller than the volume of L4 in the group with hypoplasia L5 versus 4.7% in the control group. PMID- 22527687 TI - Altered default-mode network activation in mild cognitive impairment compared with healthy aging. AB - INTRODUCTION: Rapidly increasing aging of the world's population is causing a heightened prevalence of Alzheimer's disease (AD) and mild cognitive impairment (MCI). The global burden, caused by this, is tremendous. In order to slow down the progression of the disease and preserve quality of life as much as possible, early identification of subjects at risk is indispensable within this framework. METHODS: In the present study, we combined independent component analysis and statistical parametric analysis to identify and compare the default-mode network (DMN) in healthy elderly and patients with MCI, with a special interest for hippocampal and lateral temporal involvement. RESULTS: Functional results indicated reduced cortical activation in the DMN for MCI patients, compared with age- and education-matched healthy elderly controls, mainly in the retrosplenial region/posterior cingulate cortex, left hippocampus, and bilateral inferior and middle frontal areas. Increased activation for patients was observed in the medial prefrontal and bilateral middle temporal/angular cortex. Lateral temporal involvement in the DMN was in both the elderly control samples, and the patient group detected and suggested a slightly increased activation, more right than left, in middle temporal areas in the MCI patients, compared with healthy elderly. CONCLUSION: Results are discussed with reference to the existing literature on early pathological changes in MCI and AD and subsequent compensation mechanisms in resting state and memory circuits. PMID- 22527688 TI - Global and New Caledonian patterns of population genetic variation in the deep sea splendid alfonsino, Beryx splendens, inferred from mtDNA. AB - Splendid alfonsino Beryx splendens is a commercial species in several countries, but is not currently exploited in New Caledonia. Information on species biology and genetics can influence the development of fisheries and assist in their management, but the genetic structuring and diversity of B. splendens populations remain largely unknown. To improve knowledge of genetic parameters, we used mitochondrial DNA sequences to conduct a comparative study of populations from throughout the world. Fragments of 815 bp of cytochrome b gene were sequenced and used to interpret the species history. We analyzed 204 individuals representing 14 geographical populations worldwide. A special focus was put on populations from New Caledonia. Analysis of variation between sequences, based on pairwise F statistics and AMOVA, demonstrated a population subdivision between the Atlantic and Indo-Pacific Oceans (Fst = 0.11-0.32; P < 0.05). Minimum-spanning network analysis revealed a mainly star-shaped pattern, with two lineages that may represent population expansion following a bottleneck/founder event and/or suggest colonization by migratory events over large distances. Our observations demonstrated that the species seems to follow the oceanic currents. Analysis of the nucleotide sequences revealed 122 variable sites, which defined numerous haplotypes, some associated with particular geographical regions. These data suggest an extremely high intra-specific genetic diversity, even at small scales. Focusing on the New Caledonia area, statistical analysis did not reveal sub structuring among samples, suggesting again that at least a fraction of individuals migrate. No significant isolation by distance pattern was observed in this species (R = -0.22; P = 0.79) among seamount populations in the EEZ. PMID- 22527690 TI - Differentiation of repetitive DNA sites and sex chromosome systems reveal closely related group in Parodontidae (Actinopterygii: Characiformes). AB - Parodon and Apareiodon lack sufficiently consistent morphological traits to be considered a monophyletic group in Parodontidae. Species within this family are either sex-homomorphic or sex-heteromorphic (i.e., lacking a differentiated sex chromosome system, ZZ/ZW or ZZ/ZW(1)W(2)). In this study, a DNA fragment from the heterochromatin segment of the W chromosome of Apareiodon ibitiensis (named WAp) was microdissected and used for in situ mapping of nine Parodontidae species. The species were also characterized using a satellite DNA probe (pPh2004). The species were phylogenetically clustered according to 17 characters, which were examined by both classical and molecular cytogenetic techniques. Given the present results, the single ZZ/ZW sex chromosome system seems to have been derived from a paracentric inversion of a terminal WAp site onto the proximal regions of the short arms of a metacentric chromosome pair, followed by WAp site amplification. We reason that these events restrained recombination and favored differentiation of the W chromosome in some species. Moreover, co-hybridization experiments targeting the WAp and pPh2004 repetitive DNA sites of A. affinis suggest that the ZZ/ZW(1)W(2) sex chromosomes of this species may have arisen from a translocation between the proto-sex chromosome and an autosome. Our phylogenetic analysis corroborates the hypothesis of sex chromosome differentiation and establishes groups of closely related species. The phylogenetic reorganization in response to these new data supports the presence of internal monophyletic groups within Parodontidae. PMID- 22527689 TI - The role of vertical and horizontal transfer in the evolution of Paris-like elements in drosophilid species. AB - The transposable element (TE) Paris was described in a Drosophila virilis strain (virilis species group) as causing a hybrid dysgenesis with other mobile genetic elements. Since then, the element Paris has only been found in D. buzzatii, a species from the repleta group. In this study, we performed a search for Paris like elements in 56 species of drosophilids to improve the knowledge about the distribution and evolution of this element. Paris-like elements were found in 30 species from the Drosophila genus, 15 species from the Drosophila subgenus and 15 species from the Sophophora subgenus. Analysis of the complete sequences obtained from the complete available Drosophila genomes has shown that there are putative active elements in five species (D. elegans, D. kikkawai, D. ananassae, D. pseudoobscura and D. mojavensis). The Paris-like elements showed an approximately 242-bp-long terminal inverted repeats in the 5' and 3' boundaries (called LIR: long inverted repeat), with two 28-bp-long direct repeats in each LIR. All potentially active elements presented degeneration in the internal region of terminal inverted repeat. Despite the degeneration of the LIR, the distance of 185 bp between the direct repeats was always maintained. This conservation suggests that the spacing between direct repeats is important for transposase binding. The distribution analysis showed that these elements are widely distributed in other Drosophila groups beyond the virilis and repleta groups. The evolutionary analysis of Paris-like elements suggests that they were present as two subfamilies with the common ancestor of the Drosophila genus. Since then, these TEs have been primarily maintained by vertical transmission with some events of stochastic loss and horizontal transfer. PMID- 22527692 TI - Towards a flexible middleware for context-aware pervasive and wearable systems. AB - Ambient intelligence and wearable computing call for innovative hardware and software technologies, including a highly capable, flexible and efficient middleware, allowing for the reuse of existing pervasive applications when developing new ones. In the considered application domain, middleware should also support self-management, interoperability among different platforms, efficient communications, and context awareness. In the on-going "everything is networked" scenario scalability appears as a very important issue, for which the peer-to peer (P2P) paradigm emerges as an appealing solution for connecting software components in an overlay network, allowing for efficient and balanced data distribution mechanisms. In this paper, we illustrate how all these concepts can be placed into a theoretical tool, called networked autonomic machine (NAM), implemented into a NAM-based middleware, and evaluated against practical problems of pervasive computing. PMID- 22527693 TI - 3D organization and function of the cell: Golgi budding and vesicle biogenesis to docking at the porosome complex. AB - Insights into the three-dimensional (3D) organization and function of intracellular structures at nanometer resolution, holds the key to our understanding of the molecular underpinnings of cellular structure-function. Besides this fundamental understanding of the cell at the molecular level, such insights hold great promise in identifying the disease processes by their altered molecular profiles, and help determine precise therapeutic treatments. To achieve this objective, previous studies have employed electron microscopy (EM) tomography with reasonable success. However, a major hurdle in the use of EM tomography is the tedious procedures involved in fixing, high-pressure freezing, staining, serial sectioning, imaging, and finally compiling the EM images to obtain a 3D profile of sub-cellular structures. In contrast, the resolution limit of EM tomography is several nanometers, as compared to just a single or even sub nanometer using the atomic force microscope (AFM). Although AFM has been hugely successful in 3D imaging studies at nanometer resolution and in real time involving isolated live cellular and isolated organelles, it has had limited success in similar studies involving 3D imaging at nm resolution of intracellular structure-function in situ. In the current study, using both AFM and EM on aldehyde-fixed and semi-dry mouse pancreatic acinar cells, new insights on a number of intracellular structure-function relationships and interactions were achieved. Golgi complexes, some exhibiting vesicles in the process of budding were observed, and small vesicles were caught in the act of fusing with larger vesicles, possibly representing either secretory vesicle biogenesis or vesicle refilling following discharge, or both. These results demonstrate the power and scope of the combined engagement of EM and AFM imaging of fixed semi-dry cells, capable of providing a wealth of new information on cellular structure-function and interactions. PMID- 22527694 TI - Effects of leptin and adiponectin on proliferation and protein metabolism of porcine myoblasts. AB - The aim of this study was to show the abundance of leptin and adiponectin receptors (LEPR, ADIPOR1, ADIPOR2) and to determine the direct effects of leptin and adiponectin on the in vitro growth of porcine skeletal muscle cells. ADIPOR1 and ADIPOR2 were abundant at mRNA and protein level in proliferating and differentiating myoblast cultures derived from semimembranosus and semitendinosus muscles of newborn piglets, whereas LEPR expression was close to the detection limit. Adiponectin (10, 20, 40 MUg/ml) attenuated the proliferation of porcine myoblasts, measured as [(3)H]-thymidine incorporation and real-time monitoring of the cells in response to 24- and 48-h exposure, in a dose-dependent manner. This effect resulted from suppressed basic fibroblast growth factor (bFGF)-mediated stimulation of DNA synthesis in serum-free medium (SFM) containing bFGF. No effects of leptin (5, 10, 20, 40, 80 ng/ml) on myoblast proliferation in SFM were detectable. Neither leptin nor adiponectin altered protein synthesis and degradation in differentiating porcine myoblasts cultured in SFM. The results on receptor abundance suggest that porcine skeletal muscle cells may be sensitive to adiponectin and leptin. However, except via inhibitory interaction of adiponectin with bFGF, these adipokines appear not to affect in vitro proliferation and protein metabolism of porcine muscle cells directly under serum-free culture conditions. PMID- 22527695 TI - Dissection of the role of Pinin in the development of zebrafish posterior pharyngeal cartilages. AB - Pinin (pnn), a nuclear and desmosome-associated SR-like protein, has been shown to play multiple roles in cell adhesion, transcriptional regulation, pre-mRNA splicing and mRNA export. Because of the embryonic lethality of pnn-deficient mice, here we used the zebrafish system to investigate the functions of pnn. Injection of morpholinos into zebrafish to knockdown pnn resulted in several obvious defective phenotypes, such as short body, bent tail, and an abnormal pigment distribution pattern. Moreover, aberrant blood vessels were formed, and most of the cartilages of pharyngeal arches 3-7 were reduced or absent in pnn morphants. Because most of the defects manifested by pnn morphants were reminiscent of those caused by neural crest-derived malformation, we investigated the effects of pnn deficiency in the development of neural crest cells. Neural crest induction and specification were not hindered in pnn morphants, as revealed by normal expression of early crest gene, sox10. However, the morphants failed to express the pre-chondrogenic gene, sox9a, in cells populating the posterior pharyngeal arches. The reduction of chondrogenic precursors resulted from inhibition of proliferation of neural crest cells, but not from cellular apoptosis or premature differentiation in pnn morphants. These data demonstrate that pnn is essential for the maintenance of subsets of neural crest cells, and that in zebrafish proper cranial neural crest proliferation and differentiation are dependent on pnn expression. PMID- 22527696 TI - Endometrial epithelial cell modifications in response to embryonic signals in bonnet monkeys (Macaca radiata). AB - The present investigation reports embryo-induced modifications in the epithelial cells of the endometrium in a primate species. In vivo, epithelial cell response to the embryonic signals was assessed at the embryo attachment stage in the gestational uterus of bonnet monkeys (Macaca radiata) and in vitro response was investigated by treating human endometrial epithelial cell line (Ishikawa) with human embryo conditioned media (CM). Endometrial epithelial (EE) cells at the embryo attachment stage in bonnet monkeys revealed higher proliferation accompanied by significant up regulation (p < 0.05) in the expression of estrogen receptor (ER)alpha and down regulation (p < 0.05) in ERbeta expression. Further gestational EE cells showed higher (p < 0.001) expression of mucin-1, except in the embryo attachment site. Also, observed were significantly higher expression (p < 0.05) and altered cytoplasmic distribution of alpha(v) and beta(3) integrins, when compared to non-pregnant animals. In pregnant animals, the embryo attachment zone showed differential expression of immunoreactive integrins as compared to the non-attachment zone. This suggested the role of embryo secreted factors in modulation of the epithelial cell profile. In vitro studies partially supported this assumption. Significantly higher proliferation (p < 0.05), as well as increased expression of ERalpha, integrin beta(3) and mucin-1 (p < 0.05) were observed in Ishikawa cells, on stimulation with CM. Taken together, these results indicated the proliferation and modulation in the expression of estrogen receptors and cell adhesion molecules in the EE cells; at the embryo attachment stage in bonnet monkeys. Further it is likely that embryo secreted factors contribute to some of these modifications in EE cells. This report is the first account of discrete cellular events, which occur in the uterine epithelium, at the embryo attachment stage in a primate species. PMID- 22527697 TI - Expression and distribution of grp-78/bip in mineralizing tissues and mesenchymal cells. AB - Glucose-regulated protein 78 (GRP-78) is one of the many endoplasmic reticulum chaperone proteins that have been shown to possess multifunctional roles. We have previously demonstrated that GRP-78 functions as a receptor for dentin matrix protein 1 (DMP1) and is required for DMP1-mediated calcium release; that it is a secreted protein and can bind to type I collagen and DMP1 extracellularly and aid in the nucleation of calcium phosphate. We provide evidence in this study that tyrosine phosphorylation is required for DMP1/GRP-78-mediated calcium release in mesenchymal cells. We further demonstrate that GRP-78 is localized in the nucleus of mesenchymal cells and that the cell surface GRP-78 is not associated with the G-protein Galphaq in mesenchymal cells. Results from this study show that during development of mineralized tissues, increased expression of GRP-78 can be observed in condensing cartilage and mesenchymal cells of the alveolar bone, endochondral bone and dental pulp. Additionally, we show that GRP-78 is present in the mineralizing matrices of teeth, bone and in the extracellular matrix of differentiating human marrow stromal cells and dental pulp stem cells. Collectively, our observations provide a new perspective on GRP-78 with respect to mineralized matrix formation. PMID- 22527698 TI - Gastrointestinal chemosensation: chemosensory cells in the alimentary tract. AB - Sensing potentially beneficial or harmful constituents in the luminal content by specialized cells in the gastrointestinal mucosa is an essential prerequisite for governing digestive processes, initiating protective responses and regulating food intake. Until recently, it was poorly understood how the gastrointestinal tract senses and responds to nutrients and non-nutrients in the diet; however, the enormous progress in unraveling the molecular machinery underlying the responsiveness of gustatory cells in the lingual taste buds to these compounds has been an important starting point for studying intestinal chemosensation. Currently, the field of nutrient sensing in the gastrointestinal tract is evolving rapidly and is benefiting from the deorphanization of previously unliganded G-protein-coupled receptors which respond to important nutrients, such as protein degradation products and free fatty acids as well as from the FACS assisted isolation of distinct cell populations. This review focuses on mechanisms and principles underlying the chemosensory responsiveness of the alimentary tract. It describes the cell types which might potentially contribute to chemosensation within the gut: cells that can operate as specialized sensors and transducers for luminal factors and which communicate information from the gut lumen by releasing paracrine or endocrine acting messenger molecules. Furthermore, it addresses the current knowledge regarding the expression and localization of molecular elements that may be part of the chemosensory machinery which render some of the mucosal cells responsive to constituents of the luminal content, concentrating on candidate receptors and transporters for sensing nutrients. PMID- 22527699 TI - Gonocyte development in rats: proliferation, distribution and death revisited. AB - Spermatogonial stem cells are responsible for the constant production of spermatozoa. These cells differentiate from the gonocytes, but little is known about these cells and their differentiation into spermatogonia. This study analyzed rat gonocyte proliferation, death and distribution as well as their differentiation into spermatogonia. Rat testes were collected at 19 dpc and at 1, 3, 5, 8, 11 and 15 dpp and submitted to apoptosis investigation through morphological analysis and TUNEL, p53 and cleaved caspase 3 labeling. Ki67 and MVH labeling was used to check gonocyte proliferation and quantification, respectively. OCT4 and DBA labeling were used to check gonocyte differentiation. Seminiferous cord length and gonocyte numerical density were measured to check gonocyte distribution along the seminiferous cords. Although a reduction of gonocyte number per testicular section has been observed from 1 to 5 dpp, the total number of these cells did not change. Apoptotic gonocytes were not detected at these ages, suggesting that the reduction in gonocyte number per testicular section was due to their redistribution along the seminiferous cords, which showed continuous growth from 19 dpc to 5 dpp. The first proliferating germ cells were observed at 8 dpp, coinciding with OCT4 upregulation and with the emergence of the first spermatogonia. In conclusion, this study suggests that (a) gonocytes do not die in the first week after birth, but are rather redistributed along the seminiferous cords just before their differentiation into spermatogonia; (b) mitosis resumption and the emergence of the first spermatogonia are coincident with OCT4 upregulation. PMID- 22527700 TI - Left visual field biases when infants process faces: a comparison of infants at high- and low-risk for autism spectrum disorder. AB - While it is well-known that individuals with autism spectrum disorder (ASD) have difficulties processing faces, very little is known about the origins of these deficits. The current study focused on 6- and 11-month-old infants who were at either high-risk (n = 43) or low-risk (n = 31) for developing ASD based on having a sibling already diagnosed with the disorder. Eye-tracking data were collected while the infants viewed color photographs of faces. Similar to previous studies with both typically developing adults and infants, low-risk infants demonstrated a preference for looking at the left side of the face (known as a left visual field bias) that emerged by 11 months of age. In contrast, high-risk infants did not demonstrate a left visual field bias at either age. Comparisons of the amount of attention given to the eye versus mouth regions indicated no differences between the two risk groups. PMID- 22527701 TI - Dialogic linkage and resonance in autism. AB - We evaluated how children with autism make linguistic adjustments when talking with someone else. We devised two novel measures to assess (a) overall conversational linkage and (b) utterance-by-utterance resonance within dialogue between an adult and matched participants with and without autism (n = 12 per group). Participants with autism were less able to establish 'cognitive linkage' with an interlocutor. As predicted, only among children with autism was there a positive correlation between the ability to link in with speaker's meanings and ratings of emotional connectedness with the conversational partner. Participants with autism were not less likely to show a basic form of dialogic resonance across successive utterances (the 'frame grab'), but more often elaborated their responses in an atypical manner. PMID- 22527702 TI - 'History and first descriptions' of autism: a response to Michael Fitzgerald. AB - Letter to the editor in response to Michael Fitzgerald's controversial allegation that one of the two pioneers of autism--Leo Kanner--may have been influenced by an earlier paper by the other autism pioneer--Hans Asperger--without acknowledging the debt, and that Kanner may even have been guilty of plagiarising Asperger. In correspondence, Professor Fitzgerald has suggested that I "consider doing my take on the matter". This is it. PMID- 22527703 TI - From interdisciplinary to integrated care of the child with autism: the essential role for a code of ethics. AB - To address the developmental deficits of children with autism, several disciplines have come to the forefront within intervention programs. These are speech-pathologists, psychologists/counselors, occupational-therapists/physical therapists, special-education consultants, behavior analysts, and physicians/medical personnel. As the field of autism therapy moves toward a more comprehensive, holistic and interdisciplinary model, the complexity of an interdisciplinary service delivery model could pose significant challenges. The difficulty of carrying out this approach could lead to sub-par programs being established. With integration among the disciplines a necessity, the ethical principles and language common to all the contributing disciplines is argued as the appropriate integrating force. An outline of these principles and a draft code of ethics are offered to introduce high standards and expectations for all participating in such a program. PMID- 22527704 TI - The relationship between anxiety and repetitive behaviours in autism spectrum disorder. AB - Children with Autism Spectrum Disorder are vulnerable to anxiety. Repetitive behaviours are a core feature of Autism Spectrum Disorder (ASD) and have been associated anxiety. This study examined repetitive behaviours and anxiety in two groups of children with autism spectrum disorder, those with high anxiety and those with lower levels of anxiety. Children with high anxiety had more repetitive behaviours than those without anxiety. Within the anxiety sample, higher levels of insistence on sameness were associated with more anxiety. No association was found between sensory motor repetitive behaviours and anxiety in this group. In the non-anxious sample, anxiety was associated with sensory motor repetitive behaviours. These findings indicate a differential relationship for repetitive behaviours in relation to anxious and non-anxious children with ASD. PMID- 22527705 TI - Brief report: Insight into illness and social attributional style in Asperger's syndrome. AB - A number of psychiatric illnesses have been recognized to have some level of insight deficits, including developmental disorders, such as Asperger's Syndrome (ASP). However insight into illness has not been empirically investigated in ASP and little research has examined how individuals with ASP view their deficits. This is the first study to assess insight and the relationship between insight and externalizing bias (EB) in ASP. Participants with ASP (n = 21) and healthy controls (n = 24) were recruited. Attributional style was assessed with the internal, personal, and situational attribution questionnaire. Insight was assessed with both a clinician-administered and a self-administered measure. Results revealed that EB was negatively correlated with insight as assessed with the clinician-administered but not the self-administered measure of insight. PMID- 22527706 TI - Is talent in autism spectrum disorders associated with a specific cognitive and behavioural phenotype? AB - Parents of 125 children, adolescents and young adults with autism spectrum disorders completed a newly developed questionnaire aimed at identifying cognitive and behavioural characteristics associated with savant skills in this group. Factors distinguishing skilled individuals were then further investigated in case studies of three individuals with exceptional skills for music, art and mathematics. The findings from the case studies largely confirmed the results from the questionnaire study in showing that special skills are associated with superior working memory and highly focused attention that is not associated with increased obsessesionality. Although intellectual impairment and a local bias have been widely associated with special skills in the savant literature, neither the screening nor case studies provided strong evidence for such associations. PMID- 22527707 TI - Brief report: The relationship between language skills, adaptive behavior, and emotional and behavior problems in pre-schoolers with autism. AB - This study investigated the relationship between structural language skills, and communication skills, adaptive behavior, and emotional and behavior problems in pre-school children with autism. Participants were aged 3-5 years with autism (n = 27), and two comparison groups of children with developmental delay without autism (n = 12) and typically developing children (n = 20). The participants were administered standardised tests of structural language skills, and parents completed the Vineland Adaptive Behavior Scales and the Developmental Behaviour Checklist. Results indicated that for children with autism, communication skills, and in particular receptive communication skills, were associated with social and daily living skills, and behavior problems. Receptive structural language skills were associated with expressive communication skills. There were no associations found between structural language skills and social or daily living skills, nor behavior problems. The results of this study suggest that communication skills are more closely linked to functional and behavioral outcomes in autism than structural language skills. PMID- 22527708 TI - An early social engagement intervention for young children with autism and their parents. AB - The social vulnerabilities associated with young children with autism are recognized as important intervention targets due to their influence on subsequent development. Current research suggests that interventions that combine motivational and social components can create meaningful changes in social functioning. Simultaneously, it is hypothesized that parent delivery of such strategies can invoke increases in these core social behaviors and parent engagement. This study examined the effects of teaching parents to implement a social engagement intervention with their children. The results indicated that the use of this parent-delivered social intervention led to (a) increases in their children's use of eye contact, directed positive affect, and verbal initiations, (b) increases in parent positive affect and synchronous engagement, and (c) generalized increases in parent and child behaviors. PMID- 22527709 TI - A collaborative care model to improve access to pediatric mental health services. AB - To examine if an innovative collaborative care model known as Targeted Child Psychiatric Services designed for primary care pediatricians (PCPs) and child psychiatrists (1) was associated with improved access to child psychiatry services, (2) had the potential to identify optimal care settings for pediatric mental health care and (3) examined if pediatricians appeared as likely to accept children back into their practices at discharge from TCPS depending upon diagnostic category, controlling for severity of illness and function. The diagnostic classes examined were ADHD (39%), depression (31%) and anxiety (13%). This prospective cohort design study collected medical records of 329 children referred to TCPS by 139 PCPs. To detect the likelihood of return to referring pediatricians for follow-up care at discharge from TCPS, we employed logistic regression models. Mean age was 12.3 (SD = 4.0); 43% were female. Ninety-three percent of parents complied with pediatricians' recommendations to have their child assessed by a child psychiatrist. A total of 28.0% of referrals returned to PCPs for follow-up care; the remainder were followed in mental health. Regression findings indicated that children with major depression (OR = 7.5) or anxiety disorders (OR = 5.1) were less likely to return to PCPs compared to ADHD even though severity of psychiatric illness and functional levels did not differ across diagnostic groups. Families widely accepted pediatricians' recommendations for referral to child psychiatrists. Depression and anxiety were strong correlates of retention in mental health settings at discharge from TCPS though children with these disorders appeared to be no more severely ill or functionally limited than peers with ADHD. These children possibly could be managed in a less intensive and expensive primary care treatment setting that could access mental health specialty services as needed in a collaborative model of care. TCPS is contrasted with the well-known collaborative model for adult depression in primary care. TCPS could serve as a feasible model of care that addresses the daunting barriers in accessing pediatric mental health services. PMID- 22527710 TI - The use of a participatory approach to develop a framework for assessing quality of care in children's mental health services. AB - The purpose of this study was to develop a framework for assessing the quality of children's mental health services that reflects the primary concerns and perspectives of diverse stakeholders. A participatory research approach was adopted in order to incorporate caregivers of children with mental health problems, mental health service providers, and managed care administrators in identifying and developing quality of care indicators and methods for assessment. This research occurred in three phases that moved from very qualitative and exploratory to more quantitative as we sought to refine and verify the resulting Quality of Care Framework. We found that the use of a participatory approach was beneficial in ensuring the validity of research tools and utility of the framework, and also greatly increased the sense of ownership of research findings among participants. PMID- 22527711 TI - Substance use disorder counselors' job performance and turnover after 1 year: linear or curvilinear relationship? AB - The main goals of the current study were to investigate whether there are linear or curvilinear relationships between substance use disorder counselors' job performance and actual turnover after 1 year utilizing four indicators of job performance and three turnover statuses (voluntary, involuntary, and no turnover as the reference group). Using longitudinal data from 440 matched counselor clinical supervisor dyads, results indicate that overall, counselors with lower job performance are more likely to turn over voluntarily and involuntarily than not to turn over. Further, one of the job performance measures shows a significant curvilinear effect. We conclude that the negative consequences often assumed to be "caused" by counselor turnover may be overstated because those who leave both voluntarily and involuntarily demonstrate generally lower performance than those who remain employed at their treatment program. PMID- 22527712 TI - TCR signaling requirements for activating T cells and for generating memory. AB - Over the last two decades the molecular and cellular mechanisms underlying T cell activation, expansion, differentiation, and memory formation have been intensively investigated. These studies revealed that the generation of memory T cells is critically impacted by a number of factors, including the magnitude of the inflammatory response and cytokine production, the type of dendritic cell [DC] that presents the pathogen derived antigen, their maturation status, and the concomitant provision of costimulation. Nevertheless, the primary stimulus leading to T cell activation is generated through the T cell receptor [TCR] following its engagement with a peptide MHC ligand [pMHC]. The purpose of this review is to highlight classical and recent findings on how antigen recognition, the degree of TCR stimulation, and intracellular signal transduction pathways impact the formation of effector and memory T cells. PMID- 22527713 TI - Regulation of Parkin E3 ubiquitin ligase activity. AB - Parkin is an E3 ubiquitin ligase mutated in autosomal recessive juvenile Parkinson's disease. In addition, it is a putative tumour suppressor, and has roles outside its enzymatic activity. It is critical for mitochondrial clearance through mitophagy, and is an essential protein in most eukaryotes. As such, it is a tightly controlled protein, regulated through an array of external interactions with multiple proteins, posttranslational modifications including phosphorylation and S-nitrosylation, and self-regulation through internal associations. In this review, we highlight some of the recent studies into Parkin regulation and discuss future challenges for gaining a full molecular understanding of the regulation of Parkin E3 ligase activity. PMID- 22527714 TI - Bioportide: an emergent concept of bioactive cell-penetrating peptides. AB - Cell-penetrating peptides (CPPs) have proven utility for the highly efficient intracellular delivery of bioactive cargoes that include peptides, proteins, and oligonucleotides. The many strategies developed to utilize CPPs solely as pharmacokinetic modifiers necessarily requires them to be relatively inert. Moreover, it is feasible to combine one or multiple CPPs with bioactive cargoes either by direct chemical conjugation or, more rarely, as non-covalent complexes. In terms of the message-address hypothesis, this combination of cargo (message) linked to a CPP (address) as a tandem construct conforms to the sychnological organization. More recently, we have introduced the term bioportide to describe monomeric CPPs that are intrinsically bioactive. Herein, we describe the design and biochemical properties of two rhegnylogically organized monometic CPPs that collectively modulate a variety of biological and pathophysiological phenomena. Thus, camptide, a cell-penetrant sequence located within the first intracellular loop of a human calcitonin receptor, regulates cAMP-dependent processes to modulate insulin secretion and viral infectivity. Nosangiotide, a bioportide derived from endothelial nitric oxide synthase, potently inhibits many aspects of the endothelial cell morphology and movement and displays potent anti-angiogenic activity in vivo. We conclude that, due to their capacity to translocate and target intracellular signaling events, bioportides represent an innovative generic class of bioactive agents. PMID- 22527715 TI - CCN1: a novel inflammation-regulated biphasic immune cell migration modulator. AB - In this study, we performed a comprehensive analysis of the effect of CCN1 on the migration of human immune cells. The molecule CCN1, produced by fibroblasts and endothelial cells, is considered as an important matrix protein promoting tissue repair and immune cell adhesion by binding various integrins. We recently reported that CCN1 therapy is able to suppress acute inflammation in vivo. Here, we show that CCN1 binds to various immune cells including T cells, B cells, NK cells, and monocytes. The addition of CCN1 in vitro enhances both actin polymerization and transwell migration. Prolonged incubation with CCN1, however, results in the inhibition of migration of immune cells by a mechanism that involves downregulation of PI3Kgamma, p38, and Akt activation. Furthermore, we observed that immune cells themselves produce constitutively CCN1 and secretion is induced by pro-inflammatory stimuli. In line with this finding, patients suffering from acute inflammation had enhanced serum levels of CCN1. These findings extend the classical concept of CCN1 as a locally produced cell matrix adhesion molecule and suggest that CCN1 plays an important role in regulating immune cell trafficking by attracting and locally immobilizing immune cells. PMID- 22527716 TI - The p38alpha MAPK positively regulates osteoblast function and postnatal bone acquisition. AB - Bone continuously remodels throughout life by coordinated actions of osteoclasts and osteoblasts. Abnormalities in either osteoclast or osteoblast functions lead to bone disorders. The p38 MAPK pathway has been shown to be essential in controlling osteoblast differentiation and skeletogenesis. Although p38alpha is the most abundant p38 member in osteoblasts, its specific individual contribution in regulating postnatal osteoblast activity and bone metabolism is unknown. To elucidate the specific role of p38alpha in regulating osteoblast function and bone homeostasis, we generated mice lacking p38alpha in differentiated osteoblasts. Osteoblast-specific p38a knockout mice were of normal weight and size. Despite non-significant bone alterations until 5 weeks of age, mutant mice demonstrated significant and progressive decrease in bone mineral density from that age. Adult mice deficient in p38a in osteoblasts displayed a striking reduction in cancellous bone volume at both axial and appendicular skeletal sites. At 6 months of age, trabecular bone volume was reduced by 62% in those mice. Mutant mice also exhibited progressive decrease in cortical thickness of long bones. These abnormalities correlated with decreased endocortical and trabecular bone formation rate and reduced expressions of type 1 collagen, alkaline phosphatase, osteopontin and osteocalcin whereas bone resorption and osteoclasts remained unaffected. Finally, osteoblasts lacking p38alpha showed impaired marker gene expressions and defective mineralization in vitro. These findings indicate that p38alpha is an essential positive regulator of osteoblast function and postnatal bone formation in vivo. PMID- 22527717 TI - The intestinal epithelium tuft cells: specification and function. AB - The intestinal epithelium, composed of at least seven differentiated cell types, represents an extraordinary model to understand the details of multi-lineage differentiation, a question that is highly relevant in developmental biology as well as for clinical applications. This review focuses on intestinal epithelial tuft cells that have been acknowledged as a separate entity for more than 60 years but whose function remains a mystery. We discuss what is currently known about the molecular basis of tuft cell fate and differentiation and why elucidating tuft cell function has been so difficult. Finally, we summarize the current hypotheses on their potential involvement in diseases of the gastro intestinal tract. PMID- 22527718 TI - Left-right asymmetry in zebrafish. AB - In vertebrates, internal organs are positioned asymmetrically across the left right (LR) axis, placing them in a defined area within the body. This LR asymmetric placement is a conserved feature of the vertebrate body plan. Events determining LR asymmetry occur during embryonic development, and are regulated by the coordinated action of genetic mechanisms that are evolutionarily conserved among vertebrates. Recent studies using zebrafish have provided new insights into how the Kupffer's vesicle organizer region is generated, and how it relays LR asymmetry information to the lateral plate mesoderm. In this review, we summarize recent advances in zebrafish and describe our current understanding of the mechanisms underlying these processes. PMID- 22527719 TI - Targeting transcription factor corepressors in tumor cells. AB - By being the "integration" center of transcriptional control as they move and target transcription factors, corepressors fine-tune the epigenetic status of the nucleus. Many of them utilize enzymatic activities to modulate chromatin through histone modification or chromatin remodeling. The clinical and etiological relevance of the corepressors to neoplastic growth is increasingly being recognized. Aberrant expression or function (both loss and gain of) of corepressors has been associated with malignancy and contribute to the generation of transcriptional "inflexibility" manifested as distorted signaling along certain axes. Understanding and predicting the consequences of corepressor alterations in tumor cells has diagnostic and prognostic value, and also have the capacity to be targeted through selective epigenetic regimens. Here, we evaluate corepressors with the most promising therapeutic potential based on their physiological roles and involvement in malignant development, and also highlight areas that can be exploited for molecular targeting of a large proportion of clinical cancers and their complications. PMID- 22527720 TI - gamma-Glutamyltranspeptidases: sequence, structure, biochemical properties, and biotechnological applications. AB - gamma-Glutamyltranspeptidases (gamma-GTs) are ubiquitous enzymes that catalyze the hydrolysis of gamma-glutamyl bonds in glutathione and glutamine and the transfer of the released gamma-glutamyl group to amino acids or short peptides. These enzymes are involved in glutathione metabolism and play critical roles in antioxidant defense, detoxification, and inflammation processes. Moreover, gamma GTs have been recently found to be involved in many physiological disorders, such as Parkinson's disease and diabetes. In this review, the main biochemical and structural properties of gamma-GTs isolated from different sources, as well as their conformational stability and mechanism of catalysis, are described and examined with the aim of contributing to the discussion on their structure function relationships. Possible applications of gamma-glutamyltranspeptidases in different fields of biotechnology and medicine are also discussed. PMID- 22527723 TI - Muse cells and induced pluripotent stem cell: implication of the elite model. AB - Induced pluripotent stem (iPS) cells have attracted a great deal attention as a new pluripotent stem cell type that can be generated from somatic cells, such as fibroblasts, by introducing the transcription factors Oct3/4, Sox2, Klf4, and c Myc. The mechanism of generation, however, is not fully understood. Two mechanistic theories have been proposed; the stochastic model purports that every cell type has the potential to be reprogrammed to become an iPS cell and the elite model proposes that iPS cell generation occurs only from a subset of cells. Some reports have provided theoretical support for the stochastic model, but a recent publication demonstrated findings that support the elite model, and thus the mechanism of iPS cell generation remains under debate. To enhance our understanding of iPS cells, it is necessary to clarify the properties of the original cell source, i.e., the components of the original populations and the potential of each population to become iPS cells. In this review, we discuss the two theories and their implications in iPS cell research. PMID- 22527722 TI - Immunoregulation by the gut microbiota. AB - The human intestinal mucosa is constantly exposed to commensal microbiota. Since the gut microbiota is beneficial to the host, hosts have evolved intestine specific immune systems to co-exist with the microbiota. On the other hand, the intestinal microbiota actively regulates the host's immune system, and recent studies have revealed that specific commensal bacterial species induce the accumulation of specific immune cell populations. For instance, segmented filamentous bacteria and Clostridium species belonging to clusters XIVa and IV induce the accumulation of Th17 cells in the small intestine and Foxp3(+) regulatory T cells in the large intestine, respectively. The immune cells induced by the gut microbiota likely contribute to intestinal homeostasis and influence systemic immunity in the host. PMID- 22527724 TI - Pluripotent stem cells reveal the developmental biology of human megakaryocytes and provide a source of platelets for clinical application. AB - Human pluripotent stem cells [PSCs; including human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs)] can infinitely proliferate in vitro and are easily accessible for gene manipulation. Megakaryocytes (MKs) and platelets can be created from human ESCs and iPSCs in vitro and represent a potential source of blood cells for transfusion and a promising tool for studying the human thrombopoiesis. Moreover, disease-specific iPSCs are a powerful tool for elucidating the pathogenesis of hematological diseases and for drug screening. In that context, we and other groups have developed in vitro MK and platelet differentiation systems from human pluripotent stem cells (PSCs). Combining this co-culture system with a drug-inducible gene expression system enabled us to clarify the novel role played by c-MYC during human thrombopoiesis. In the next decade, technical advances (e.g., high-throughput genomic sequencing) will likely enable the identification of numerous gene mutations associated with abnormal thrombopoiesis. Combined with such technology, an in vitro system for differentiating human PSCs into MKs and platelets could provide a novel platform for studying human gene function associated with thrombopoiesis. PMID- 22527725 TI - The contribution of the extracellular matrix to the fracture resistance of bone. AB - The likelihood of suffering a bone fracture is not solely predicated on areal bone mineral density. As people age, there are numerous changes to the skeleton occurring at multiple length scales (from millimeters to submicron scales) that reduce the ability of bone to resist fracture. Herein is a review of the current knowledge about the role of the extracellular matrix (ECM) in this resistance, with emphasis on engineering principles that characterize fracture resistance beyond bone strength to include bone toughness and fracture toughness. These measurements of the capacity to dissipate energy and to resist crack propagation during failure precipitously decline with age. An age-related loss in collagen integrity is strongly associated with decreases in these mechanical properties. One potential cause for this deleterious change in the ECM is an increase in advanced glycation end products, which accumulate with aging through nonenzymatic collagen crosslinking. Potential regulators and diagnostic tools of the ECM with respect to fracture resistance are also discussed. PMID- 22527727 TI - [Functional glaucoma diagnostics. An essential criterion for estimating visual impairment and its progression]. PMID- 22527721 TI - Type I IFN-mediated regulation of IL-1 production in inflammatory disorders. AB - Although contributing to inflammatory responses and to the development of certain autoimmune pathologies, type I interferons (IFNs) are used for the treatment of viral, malignant, and even inflammatory diseases. Interleukin-1 (IL-1) is a strongly pyrogenic cytokine and its importance in the development of several inflammatory diseases is clearly established. While the therapeutic use of IL-1 blocking agents is particularly successful in the treatment of innate-driven inflammatory disorders, IFN treatment has mostly been appreciated in the management of multiple sclerosis. Interestingly, type I IFNs exert multifaceted immunomodulatory effects, including the reduction of IL-1 production, an outcome that could contribute to its efficacy in the treatment of inflammatory diseases. In this review, we summarize the current knowledge on IL-1 and IFN effects in different inflammatory disorders, the influence of IFNs on IL-1 production, and discuss possible therapeutic avenues based on these observations. PMID- 22527726 TI - Pathways for bone loss in inflammatory disease. AB - Chronic inflammation including autoimmune disease is an important risk factor for the development of osteoporosis. Receptor activator of nuclear factor-kappaB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) play a central role in osteoclast differentiation and function, and the molecular pathways by which M-CSF and RANKL induce osteoclast differentiation have been analyzed in detail. Proinflammatory cytokines directly or indirectly regulate osteoclastogenesis and bone resorption providing a link between inflammation and osteoporosis. Tumor necrosis factor-alpha, interleukin (IL)-1, IL-6, and IL-17 are the most important proinflammatory cytokines triggering inflammatory bone loss. Inhibition of these cytokines has provided potent therapeutic effects in the treatment of diseases such as rheumatoid arthritis. Further investigation is needed to understand the pathophysiology and to develop new strategies to treat inflammatory bone loss. This review summarizes new data on inflammatory bone loss obtained in 2011. PMID- 22527728 TI - [Importance of flicker contrast tests in functional glaucoma diagnostics]. AB - One of the many unsolved problems concerning glaucoma is early detection and many different methodologies have been developed. This article concentrates on methodologies belonging to the class of flicker contrast tests which present dynamic stimuli (with temporal frequencies generally above 10 Hz) and assess the perceptual thresholds for contrast, be it global or locally resolved. The tests include global flicker sensitivity, flicker perimetry (current embodiment: Pulsar), Rauschfeld campimetry, frequency doubling perimetry and flicker-defined edge perimetry. These different approaches are placed into historical perspective and are critically assessed. PMID- 22527729 TI - [Conventional perimetry. Antiquated or indispensable for functional glaucoma diagnostics?]. AB - Despite its relatively long history conventional perimetry has preserved its role in (glaucoma) diagnostics by the continuous advancement of technical equipment, examination strategies and new methods for analysis and visualization of progression. A high standardization in execution and evaluation of visual field examination can now be obtained by the increasing use of computer technology. Standardized protocols become increasingly more useful especially in cases of chronic diseases, such as glaucoma where several suitable diagnostic methods must be applied over a long time period. For the assessment of functional deterioration several (numeric) perimetric indices are available in addition to clinical evaluation. The use of fast threshold estimating strategies and locally condensed grids are promising tools for early detection of the functional manifestation or progression of (glaucomatous) loss of visual field. In cases of advanced (glaucomatous) visual field loss, perimetry with (computer generated) moving stimuli (semi-automated kinetic perimetry) allows an efficient, standardized and patient-friendly edge detection of scotoma borders. This method is also very well suited for expert opinions and ability testing. The assessment by morphological or morphometric, hydrodynamic and other functional parameters serve as complementary diagnostic aids or as elementary tools for plausibility control. PMID- 22527730 TI - [Functional diagnostic options for advanced and end stage glaucoma]. AB - The visual functional diagnostics for patients with advanced glaucomatous optic neuropathy are subject to challenge. Reduced visual acuity, instable fixation and extensive scotomata frequently lead to incorrect results within the central 30 degrees or 24 degrees field. Static automatic perimetry (SAP) in particular is often hampered by extended examination time and fatigue especially in older patients. Focusing of the examination towards the central 10 degrees field using a dense test grid (2 degrees distance between stimulus locations) allows a more exact assessment of the small remaining central island. Tailoring the examination area towards the central 10 degrees field may be useful even in cases with a mean deviation (MD) of 15 dB. In cases of advanced visual field loss kinetic perimetry is superior to static perimetry for various reasons: sharply demarcated visual field defects can be comparatively easily delineated (edge detection); the results are more reliable because fixation can be easily controlled and fatigue is much less pronounced in this interactive examination procedure. However, manual kinetic visual field testing within the central 5 degrees using the conventional Goldmann perimeter is almost impossible due to technical reasons. Semi-automated kinetic perimetry, presenting moving stimuli along interactively defined vectors is a useful tool under these circumstances. The standardized presentation of kinetic stimuli is also feasible within the pericentral region and has particular advantages also with regard to follow-up examinations. On the other hand, detection and delineation of small visual field remnants are comparatively difficult to handle with this kind of vector-based kinetic perimetry. PMID- 22527731 TI - [Fundus perimetry in functional diagnostics of glaucoma. Applicable in the practice?]. AB - Examination of the visual field using static automated perimetry (SAP) is the method of choice for the detection of functional damage secondary to glaucoma. However, with SAP early visual field defects might be missed even if there is already visible damage of the retinal nerve fibre. The microperimetry or beter fundus perimetry provides a detailed examination of the differential luminance threshold within defined retinal areas. However, in contrast to lesions of the retinal receptors, in cases of glaucomatous damage the retinal fibre course has to be considered resulting in a displacement between the structural lesion and the location of the related functional defect. The functional damage may be detected at earlier stages and with enhanced spatial resolution compared to conventional SAP. The extra costs and time associated with the application of fundus perimetry have prevented its widespread use. Current developments are leading to new options. PMID- 22527732 TI - [Current state of pupil-based diagnostics for glaucomatous optic neuropathy]. AB - There are considerable differences between pupillary reactions to light in glaucoma patients and healthy subjects which can be identified by various techniques. These methods are based on the early asymmetry of the afferent conduction in the visual pathway, on the examination of the visual field by focal light stimuli or on visual stimuli in analogy with multifocal electrophysiological tests. Latest findings in pupillary research also suggest a possible use of the intrinsically photosensitive (melanopsin expressing) retinal ganglion cells in glaucoma diagnostics. The current results of pupillary experiments in glaucoma patients are encouraging for further research in this field because suitable objective screening methods for glaucoma are continually being sought. PMID- 22527733 TI - [Electrophysiological examination methods in glaucoma diagnostics]. AB - The two currently used most successful techniques for early detection of glaucoma are described. (1) The pattern electroretinogram (PERG) allows detection of incipient glaucomatous damage in eyes with ocular hypertension up to 4 years ahead of manifest glaucoma with a sensitivity and specificity of approximately 75%. This is achieved by selecting optimized stimulation (check size and stimulation frequency) and analysis protocols (amplitude ratio to different check sizes). The major disadvantage is the requirement for best corrected visual acuity to be at least 0.8(decimal) to avoid false positive results. (2) The photopic negative response (PhNR), a component of the Ganzfeld ERG, does not suffer from optical factors reducing visual acuity. It is also affected in early glaucoma but so far has not achieved the same sensitivity and specificity as the PERG. PMID- 22527734 TI - [Is choroidal thickness of importance in idiopathic macular hole?]. AB - BACKGROUND: The pathogenesis of idiopathic macular hole (MH) formation is not fully understood and the choroid might be involved in its etiology. Recently published data reported choroidal thickness (CT) to be significantly thinner in eyes with idiopathic MH and in fellow eyes compared to age-matched healthy controls [24]. METHODS: The enhanced depth imaging (EDI) modus of the Spectralis OCT (Heidelberg Engineering, Heidelberg) was used to measure subfoveal CT in 12 patients with MH of which 2 suffered from bilateral MH. Measurements were manually acquired preoperatively using the horizontal foveal scan of the 7-line scan (5 * 30 perifoveal) with 100 averaged scans per scan, between the outer border of the retinal pigment epithelium and the inner scleral border. Additional CT measurements were obtained 8 weeks and 6 months postoperatively. RESULTS: Subfoveal CT of the 12 patients with MH (10 ?, 2 ?; 68 +/- 7 years) was 274 +/- 65 um. The CT of the 10 patients with healthy fellow eyes measured 268 +/- 75 um and CT of the 2 patients with bilateral MH measured 309 +/- 34 um in the non operated eye. The mean axial length (AL) in eyes with MH was 23.64 +/- 0.59 mm and in healthy fellow eyes 23.68 +/- 0.54 mm. After surgery MH closure was obvious in all eyes, the postoperative CT at 8 weeks measured 284 +/- 77 um and at 6 months 276 +/- 73 um. CONCLUSIONS: The EDI-OCT procedure enables measurements of CT. In the patients studied a reduced CT could not be found neither in patients with macular holes nor in the fellow eyes. There was no significant change in CT comparing preoperative with postoperative measurements. In contrast to recently published data [24] no reduction in CT in idiopathic macular hole could be demonstrated. PMID- 22527735 TI - [Blindness in Germany - comparison between retrospective data and predictions for the future]. AB - AIM: There are no exact figures on the number of blind and visually impaired persons in Germany. The purpose of this study was to compare the development over the last years with earlier predictions and an outlook into the future. METHODS: Data from scientific publications as well as the Federal Statistical Office and from organizations for the blind on the frequency of blindness was compared to the forecast development of blindness. In addition the development of the frequency of age-related macular degeneration (ARMD) was taken into consideration. RESULTS: While the proportion of over 60-year-olds has steadily increased from 21% in 1993 to 25.9% in 2009, the ratio of blind people has risen from 8.9 per 10,000 inhabitants in 1993 to 10.6 per 10,000 inhabitants in 2003. However, up to 2009 decreased every year to 9.7 which is approximately the same as 1995, although ARMD has also become much more frequent as the main cause. Additionally there are considerable differences up to a factor two between the various studies on the number of blind people in different regions of Germany. DISCUSSION: At present there are approximately 150,000 blind and about 500,000 visually impaired persons in Germany. However, these numbers are only on the basis of estimates and according to studies in other European nations. Similar uncertainty exists concerning the diseases causing blindness. A transfer from epidemiological studies is limited especially because of the different definition of blindness. The expected increase of visually impaired and blind persons for the last 20 years as a result of the increasing age cannot be confirmed from the present data. It would be desirable to extensively register the specifications to prevalence and incidence of visual impairment and blindness including valid information on the corresponding cause to confirm the rising importance of visual impairment. PMID- 22527736 TI - [Possible correlation between prostate cancer and temporary increase in eye pressure]. AB - It is presumed that there is a correlation between a temporary increase in eye pressure and the presence of histologically confirmed prostate cancer. This is supported by the normalization of the eye pressure following successful radical prostatectomy. Therefore, increased PSA (prostate-specific antigen) values should be specifically targeted when newly diagnosed increased eye pressure occurs. PMID- 22527737 TI - [Bilateral recurrent blurred vision associated with halos around sources of light and headache]. AB - A 21-year-old male presented with headache and blurred vision associated with halos around sources of light. The visual acuity was slightly reduced and the intraocular pressure in the left eye was elevated to 44 mmHg and in the right eye to 49 mmHg. Slit lamp examination of the anterior segment revealed bilateral cells and a Tyndall phenomenon 2 +, several cell clumps adherent to the corneal endothelium, known as mutton-fat keratic precipitates and a circumscribed inflammatory infiltration of the right iris. The posterior segment of both eyes was normal. The cause of the presumed clinical diagnosis secondary open angle glaucoma due to anterior granulomatous uveitis was sarcoidosis, confirmed by elevated serological markers of angiotensin-converting enzyme (ACE), soluble interleukin-2 receptor (sIL-2R) and by pulmonary hilar lymphadenopathy. The local and systemic corticosteroid therapy was successful and also normalized the intraocular pressure. PMID- 22527738 TI - [Salzmann's nodular degeneration. Mostly an epithelial corneal dystrophy]. AB - So-called Salzmann's nodular degeneration has been given a misleading position in the systematics of ophthalmology. The majority of cases of Salzmann's nodular degeneration are in fact a clinical entity fulfilling the criteria of epithelial corneal dystrophy involving Bowman's layer. As with all epithelial dystrophies Salzmann's nodular degeneration recurs after surgical removal. An analysis of Salzmann's original paper discloses that the etiological postulates (severe preceding keratitis, especially phlyctenular keratitis) have never been substantiated by direct observation but only suspected by indirect histopathological circumstantial evidence. This has long lost credibility and should never have been taken for real evidence. However, degenerative types of Salzmann's nodular degeneration besides the dystrophic type still exist but the etiology and pathogenesis of these degenerative types have not yet been sufficiently described. No distinction has been made in studies of Salzmann's nodular degeneration up to now between dystrophic and degenerative types which could render such publications worthless on re-evaluation. While therapy of Salzmann's dystrophy is usually simple even after recurrence this may be different with the degenerative forms. The many questions and inconsistencies which have long been noted with "Salzmann's degeneration" as it has been misunderstood, can only be answered and solved if dystrophy and degeneration are investigated separately in future studies. PMID- 22527740 TI - Neighborhood context and hypertension outcomes among Latinos in Chicago. AB - Although a health advantage in hypertension has been documented among Latinos, this advantage appears to be eroding. Of particular concern is the observation that Latinos are less likely to be screened and treated for hypertension and to having it controlled. Scholars have suggested that, above and beyond individual level factors, neighborhood characteristics may be important predictors of health and health care. We analyzed 2001-2003 data from the Chicago Community Adult Health Study to examine (a) the relationship between the Latino and immigrant composition of neighborhoods in Chicago and several outcomes among Latinos: having hypertension, utilizing hypertension-related health care, and being treated for hypertension; and (b) whether there was a differential effect of neighborhood Latino/immigrant concentration by language of interview and nativity status. We controlled for additional neighborhood characteristics relevant to hypertension and to the availability and accessibility of health care resources. Neighborhoods with higher concentrations of immigrants and Latinos were associated with Latinos having lower odds of hypertension (OR = 0.60, p = 0.03). However, among those with hypertension, our results point to deleterious effects on hypertension care (OR = 0.55, p = 0.06) and treatment (OR = 0.54, p = 0.04) associated with living in neighborhoods with higher concentrations of immigrants and Latinos. We detected no significant interaction effects between immigrant/Latino neighborhood composition and language of interview or being an immigrant in this sample. These results suggest that improving access to care for Latinos with hypertension requires enhanced placement of community clinics and other safety-net health centers in neighborhoods with higher proportions of immigrants and Latinos. PMID- 22527741 TI - Prevalence of chronic disease and insurance coverage among refugees in the United States. AB - Little is known about the health status of refugees beyond the immediate post arrival period in the US. Using data from the 2003 New Immigrant Survey, a nationally representative survey of immigrants who had recently become legal permanent residents, we determined the prevalence of chronic conditions and health insurance coverage among adult refugees who had lived in the US for at least 1 year (n = 490). We compared their health status with that of other immigrants (n = 3,715) using multivariable logistic regression. The median duration of US residency was 5.6 and 8.0 years among refugees and other immigrants, respectively. Refugees were more likely than other immigrants to report at least one chronic condition (24.7 vs. 15.6 %, P < 0.001). After adjusting for sociodemographic differences, the odds of the following conditions remained significantly higher among refugees: arthritis (adjusted odds ratio [AOR] = 1.67, 95 % confidence interval [CI] = 1.07, 2.61), heart disease (AOR = 2.49, 95 % CI = 1.30, 4.74), stroke (AOR = 5.87, 95 % CI = 1.27, 27.25), activity limitation due to pain (AOR = 1.96, 95 % CI = 1.31, 2.93), and any chronic condition (AOR = 1.37, 95 % CI = 1.03, 1.81). Although similar percentages of refugees (49.0 %) and other immigrants (47.4 %) were uninsured, 46.5 % of refugees with chronic conditions lacked health insurance. Refugees have a high burden of chronic disease and would benefit from expanded insurance coverage for adults with preexisting conditions. PMID- 22527742 TI - Validation of a temperature prediction model for heat deaths in undocumented border crossers. AB - Heat exposure is a leading cause of death in undocumented border crossers along the Arizona-Mexico border. We performed a validation study of a weather prediction model that predicts the probability of heat related deaths among undocumented border crossers. We analyzed a medical examiner registry cohort of undocumented border crosser heat- related deaths from January 1, 2002 to August 31, 2009 and used logistic regression to model the probability of one or more heat deaths on a given day using daily high temperature (DHT) as the predictor. At a critical threshold DHT of 40 degrees C, the probability of at least one heat death was 50 %. The probability of a heat death along the Arizona-Mexico border for suspected undocumented border crossers is strongly associated with ambient temperature. These results can be used in prevention and response efforts to assess the daily risk of deaths among undocumented border crossers in the region. PMID- 22527743 TI - Health behaviors among Cambodian adults in Lowell, Massachusetts. AB - Physical activity, maintaining healthy weight, eating fruits and vegetables, and non-smoking are health behaviors that reduce risk for a variety of poor health outcomes. This analysis reports frequencies and socio-demographic correlates of these behaviors among 381 Cambodians aged 25 and older surveyed in Lowell, MA. The majority reported some physical activity (72 %), healthy weight (62 %), and not smoking (77 %). Only 28 % reported adequate fruit and vegetable consumption. Four multivariable models indicate that (1) physical activity was associated with higher income, lower levels of US education, reading English, and living in the US 11-19 years; (2) healthy weight with living in the US 20 or more years; (3) not smoking with being female and living in the US less than 11 years; and (4) adequate fruit and vegetable consumption with lower levels of US education and reading English. These results inform public health planning for Cambodians. PMID- 22527744 TI - The role of maternal perceptions and ethnic background in the mental health help seeking pathway of adolescent girls. AB - Mothers play a crucial role in the help-seeking pathway of adolescents. This study examined how mothers with different ethnic backgrounds perceive the issue of help-seeking for internalizing problems (e.g. depression) in adolescent girls. Seven focus group discussions were conducted with 41 Dutch, Moroccan and Turkish mothers with a teenage daughter. Discussions were conceptually framed within a model of help-seeking and facilitated by a vignette. The internalizing problems sketched in the vignette were recognized as severe nonetheless; identified long term consequences varied per ethnic group. Negative attitudes towards General Practitioners, inaccessible mental health services and denial by daughters would hamper help-seeking. Fear of negative judgments/gossiping was considered a barrier by Turkish and Moroccan participants. Participants identified themselves and schools as primary sources of help. Turkish participants also named chaplains. To enhance utilization of mental health services by (minority) youth it is important to also address maternal barriers. PMID- 22527745 TI - Intimate partner violence among Asian Americans and their use of mental health services: comparisons with white, black, and Latino victims. AB - Studies have been conducted on intimate partner violence (IPV) among Asian Americans, but knowledge on their use of mental health services is limited. This study seeks to fill this gap by using a national sample to examine Asian victims' use of mental health services. We analyzed data from the Collaborative Psychiatric Epidemiology Surveys. The dependent variable was use of mental health services. The independent variables included race, employment, and the type of IPV. Results showed that Asian victims used the service less than other racial groups. The rates of use of mental health services were lower among older people and men. The lowest rate of mental health service use among Asian victims indicates a possible gap between their needs to be met and mental health services available to them. It is crucial to increase access to mental health services for ethnic minorities. PMID- 22527746 TI - Hispanic health disparities after a flood disaster: results of a population-based survey of individuals experiencing home site damage in El Paso (Texas, USA). AB - In 2006, El Paso County, a predominantly Hispanic urban area, was affected by a flood disaster; 1,500 homes were damaged. We assessed the health impacts of the disaster upon 475 individuals whose homes were flood-damaged using mail survey data and logistic regression. Substantial proportions of individuals had one or more physical (43 %) or mental (18 %) health problem in the four months following the floods; 28 % had one or more injury or acute effect related to post-flood cleanup. Adverse event experiences, older age, and lower socioeconomic status were significantly associated with negative post-flood health outcomes in all three logistic regression models. A lack of access to healthcare, non-US citizenship, and English proficiency were significant predictors of negative outcomes in both the physical and mental health models, while Hispanic ethnicity (physical), native-birth (mental), and more serious home damage (cleanup) were significant predictors in one model each. The disaster had disproportionate negative health impacts on those who were more exposed, poorer, older, and with constrained resource-access. While a lack of US citizenship and Hispanic ethnicity were associated with higher risks, being less acculturated (i.e., English-deficient, foreign-born) may have protected against health impacts. PMID- 22527747 TI - Adapting large batteries of research measures for immigrants. AB - A four-step, streamlined process to adapt a large battery of measures for a study of mother-child adjustment in Arab Muslim immigrants and the lessons learned are described. The streamlined process includes adapting content, translation, pilot testing, and extensive psychometric evaluation but omits in-depth qualitative inquiry to identify the full content domain of the constructs of interest and cognitive interviews to assess how respondents interpret items. Lessons learned suggest that the streamlined process is not sufficient for certain measures, particularly when there is little published information about how the measure performs with different groups, the measure requires substantial item revision to achieve content equivalence, and the measure is both challenging to translate and has little to no redundancy. When these conditions are present, condition specific procedures need to be added to the streamlined process. PMID- 22527748 TI - An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint terminology and classification of the complications related to native tissue female pelvic floor surgery. AB - INTRODUCTION AND HYPOTHESIS: A terminology and standardized classification has yet to be developed for those complications related to native tissue female pelvic floor surgery. METHODS: This report on the terminology and classification combines the input of members of the Standardization and Terminology Committees of two International Organizations, the International Urogynecological Association (IUGA) and the International Continence Society (ICS) and a Joint IUGA/ICS Working Group on Complications Terminology, assisted at intervals by many external referees. A process of rounds of internal and external review took place with decision making by collective opinion (consensus). RESULTS: A terminology and classification of complications related to native tissue female pelvic floor surgery has been developed, with the classification based on category (C), time (T), and site (S) classes and divisions that should encompass all conceivable scenarios for describing operative complications and healing abnormalities. The CTS code for each complication, involving three (or four) letters and three numerals, is likely to be very suitable for any surgical audit or registry, particularly one that is procedure-specific. Users of the classification have been assisted by case examples, colour charts and online aids ( www.icsoffice.org/ntcomplication ). CONCLUSIONS: A consensus-based terminology and classification report for complications in native tissue female pelvic floor surgery has been produced. It is aimed at being a significant aid to clinical practice and particularly to research. PMID- 22527749 TI - Glioblastoma with oligodendroglial components: glioblastoma or anaplastic oligodendroglial tumors. AB - There have been some recent reports about glioblastoma with oligodendroglial (OG) components and malignant glioma with primitive neuroectodermal tumor (PNET)-like components. We investigated whether the presence and extent of OG components and PNET-like components influenced the prognosis in patients with glioblastoma. Eighty-six patients with glioblastoma were divided into an OG group (28 %), which revealed areas with a honeycomb appearance, and a non-OG group (72 %) without a honeycomb appearance. Patients with glioblastoma were also divided into a PNET group (27 %), which revealed areas with PNET-like features defined as neoplastic cells with high N/C ratios and hyperchromatic oval-carrot-shaped nuclei, and lacked the typical honeycomb appearance, and a non-PNET group (73 %) without PNET features. There were no significant differences in overall survival among the OG, the non-OG, the PNET, and the non-PNET groups. Two patients who survived longer than 36 months had both OG and PNET components with 1p or 19q loss of heterozygosity. Perinuclear halo, which is a characteristic feature of oligodendrogliomas, is an artifact of tissue fixation. Therefore, we should not readily use the term glioblastoma with OG components. PNET-like components, which are considered rare in malignant gliomas, may be frequently identified in glioblastomas. PMID- 22527750 TI - Deep EST profiling of developing fenugreek endosperm to investigate galactomannan biosynthesis and its regulation. AB - Galactomannans are hemicellulosic polysaccharides composed of a (1 -> 4)-linked beta-D-mannan backbone substituted with single-unit (1 -> 6)-alpha-linked D galactosyl residues. Developing fenugreek (Trigonella foenum-graecum) seeds are known to accumulate large quantities of galactomannans in the endosperm, and were thus used here as a model system to better understand galactomannan biosynthesis and its regulation. We first verified the specific deposition of galactomannans in developing endosperms and determined that active accumulation occurred from 25 to 38 days post anthesis (DPA) under our growth conditions. We then examined the expression levels during seed development of ManS and GMGT, two genes encoding backbone and side chain synthetic enzymes. Based on transcript accumulation dynamics for ManS and GMGT, cDNA libraries were constructed using RNA isolated from endosperms at four ages corresponding to before, at the beginning of, and during active galactomannan deposition. DNA from these libraries was sequenced using the 454 sequencing technology to yield a total of 1.5 million expressed sequence tags (ESTs). Through analysis of the EST profiling data, we identified genes known to be involved in galactomannan biosynthesis, as well as new genes that may be involved in this process, and proposed a model for the flow of carbon from sucrose to galactomannans. Measurement of in vitro ManS and GMGT activities and analysis of sugar phosphate and nucleotide sugar levels in the endosperms of developing fenugreek seeds provided data consistent with this model. In vitro enzymatic assays also revealed that the ManS enzyme from fenugreek endosperm preferentially used GDP-mannose as the substrate for the backbone synthesis. PMID- 22527751 TI - Transcriptional organization of the large and the small ATP synthase operons, atpI/H/F/A and atpB/E, in Arabidopsis thaliana chloroplasts. AB - The ATP synthase is a ubiquitous enzyme which is found in bacteria and eukaryotic organelles. It is essential in the photosynthetic and respiratory processes, by transforming the electrochemical proton gradient into ATP energy via proton transport across the membranes. In Escherichia coli, the atp genes coding for the subunits of the ATP synthase enzyme are grouped in the same transcriptional unit, while in higher plants the plastid atp genes are organized into a large (atpI/H/F/A) and a small (atpB/E) atp operon. By using the model plant Arabidopsis thaliana, we have investigated the strategy evolved in chloroplasts to overcome the physical separation of the atp gene clusters and to coordinate their transcription. We show that all the identified promoters in the two atp operons are PEP dependent and require sigma factors for specific recognition. Our results indicate that transcription of the two atp operons is initiated by at least one common factor, the essential SIG2 factor. Our data show that SIG3 and SIG6 also participate in transcription initiation of the large and the small atp operon, respectively. We propose that SIG2 might be the factor responsible for coordinating the basal transcription of the plastid atp genes and that SIG3 and SIG6 might serve to modulate plastid atp expression with respect to physiological and environmental conditions. However, we observe that in the sigma mutants (sig2, sig3 and sig6) the deficiency in the recognition of specific atp promoters is largely balanced by mRNA stabilization and/or by activation of otherwise silent promoters, indicating that the rate-limiting step for expression of the atp operons is mostly post-transcriptional. PMID- 22527752 TI - Complex I-complex II ratio strongly differs in various organs of Arabidopsis thaliana. AB - In most studies, amounts of protein complexes of the oxidative phosphorylation (OXPHOS) system in different organs or tissues are quantified on the basis of isolated mitochondrial fractions. However, yield of mitochondrial isolations might differ with respect to tissue type due to varying efficiencies of cell disruption during organelle isolation procedures or due to tissue-specific properties of organelles. Here we report an immunological investigation on the ratio of the OXPHOS complexes in different tissues of Arabidopsis thaliana which is based on total protein fractions isolated from five Arabidopsis organs (leaves, stems, flowers, roots and seeds) and from callus. Antibodies were generated against one surface exposed subunit of each of the five OXPHOS complexes and used for systematic immunoblotting experiments. Amounts of all complexes are highest in flowers (likewise with respect to organ fresh weight or total protein content of the flower fraction). Relative amounts of protein complexes in all other fractions were determined with respect to their amounts in flowers. Our investigation reveals high relative amounts of complex I in green organs (leaves and stems) but much lower amounts in non-green organs (roots, callus tissue). In contrast, complex II only is represented by low relative amounts in green organs but by significantly higher amounts in non-green organs, especially in seeds. In fact, the complex I-complex II ratio differs by factor 37 between callus and leaf, indicating drastic differences in electron entry into the respiratory chain in these two fractions. Variation in amounts concerning complexes III, IV and V was less pronounced in different Arabidopsis tissues (quantification of complex V in leaves was not meaningful due to a cross-reaction of the antibody with the chloroplast form of this enzyme). Analyses were complemented by in gel activity measurements for the protein complexes of the OXPHOS system and comparative 2D blue native/SDS PAGE analyses using isolated mitochondria. We suggest that complex I has an especially important role in the context of photosynthesis which might be due to its indirect involvement in photorespiration and its numerous enzymatic side activities in plants. PMID- 22527753 TI - ABA-mediated inhibition of seed germination is associated with ribosomal DNA chromatin condensation, decreased transcription, and ribosomal RNA gene hypoacetylation. AB - Seed germination is a highly organized biological process accompanied by many cellular and metabolic changes. The ribosomal RNA (rRNA) gene, which forms the nucleolus at interphase and is transcribed for ribosome production and protein synthesis, has an important role during seed germination. In this study, we report that there is a decondensation of ribosomal DNA (rDNA) chromatin during seed germination accompanied with increased rRNA gene expression and overall genomic hyperacetylation. Analysis of the rRNA gene promoter region by using chromatin immunoprecipitation (ChIP) shows that there is an increase in acetylation levels at the rRNA gene promoter region. Application of seed germination inhibitor abscisic acid (ABA) suppresses rDNA chromatin decondensation, the expression of rRNA genes and global genomic acetylation. The further ChIP experiments show that ABA treatment hinders the elevation of acetylation levels in the promoter region of the rRNA gene. The data together indicate that ABA treatment inhibits seed germination, which is associated with rDNA chromatin condensation, decreased transcription and rRNA gene hypoacetylation. PMID- 22527755 TI - P-wave locking in the postventricular atrial refractory period of cardiac resynchronization devices. Management with the Biotronik system. AB - Electrical desynchronization in cardiac resynchronization therapy (CRT) occurs when sinus P waves are continually locked in the postventricular atrial refractory period (PVARP). This process is characterized by sequences of a P wave as an atrial event in the PVARP followed by a conducted and sensed ventricular event. Such sequences are more common in patients with a prolonged PR interval, often initiated by premature ventricular complexes (PVC) and terminated by PVCs or slowing of the sinus rate. Specific algorithms automatically identify a recurring pattern of P wave locking in the PVARP, whereupon they shorten the PVARP temporarily until atrial tracking is restored with the programmed sensed AV interval. The Biotronik family of Lumax CRT devices use an AV control window which is not an algorithm that "unlocks" P waves trapped in the PVARP. Rather, it prevents P waves from becoming trapped in the PVARP. A ventricular sensed event occurring within the AV control interval does not start a PVARP so that P wave locking cannot occur when the AV conduction time is shorter than the AV control interval. PMID- 22527754 TI - Integration of deep transcript and targeted metabolite profiles for eight cultivars of opium poppy. AB - Recent advances in DNA sequencing technology and analytical mass spectrometry are providing unprecedented opportunities to develop the functional genomics resources required to investigate complex biological processes in non-model plants. Opium poppy produces a wide variety of benzylisoquinoline alkaloids (BIAs), including the pharmaceutical compounds codeine, morphine, noscapine and papaverine. A functional genomics platform to identify novel BIA biosynthetic and regulatory genes in opium poppy has been established based on the differential metabolite profile of eight selected cultivars. Stem cDNA libraries from each of the eight opium poppy cultivars were subjected to 454 pyrosequencing and searchable expressed sequence tag databases were created from the assembled reads. These deep and integrated metabolite and transcript databases provide a nearly complete representation of the genetic and metabolic variances responsible for the differential occurrence of specific BIAs in each cultivar as demonstrated using the biochemically well characterized pathway from tyrosine to morphine. Similar correlations between the occurrence of specific transcripts and alkaloids effectively reveals candidate genes encoding uncharacterized biosynthetic enzymes as shown using cytochromes P450 potentially involved in the formation of papaverine and noscapine. PMID- 22527756 TI - Conformational mapping and energetics of saccharide-aromatic residue interactions: implications for the discrimination of anomers and epimers and in protein engineering. AB - Aromatic residues play a key role in saccharide-binding sites. Experimental studies have given an estimate of the energetics of saccharide-aromatic residue interactions. In this study, dependence of the energetics on the mutual position orientation (PO) of saccharide and aromatic residue has been investigated by geometry optimization of a very large number (164) of complexes at MP2/6-31G(d,p) level of theory. The complexes are of Tyr and Phe analogs with alpha/beta-D-Glc, beta-D-Gal, alpha-D-Man and alpha/beta-L-Fuc. A number of iso-energy POs are found for the complexes of all six saccharides. Stacking and non-stacking modes of binding are found to be of comparable strengths. In general, complexes of p OHTol are stronger than those of Tol, and those dominated by OH...O interactions are more stable than ones dominated by CH...pi interactions. The strengths of OH...O/pi interactions, but not those of CH...pi, show large variations. Even though an aromatic residue has a large variety of POs to interact with a saccharide, distinct preferences are found due to anomeric and epimeric differences. An aromatic residue can interact from either the a- or b-face of Glc, but only through the b-face with Gal, its C4-epimer. In contrast, stacking interaction with Man (C2-epimer of Glc) requires the participation of the CH(2)OH group and free rotation of this group, as is observed in solution, precludes all modes of stacking interactions. It is also found that an aromatic residue can be strategically placed either to discriminate or to accommodate (i) anomers of Glc and of Fuc and (ii) Gal/Fuc. Thus, analysis of the optimized geometries of by far the largest number of complexes, and with six different saccharides, at this level of theory has given insights into how Nature cleverly uses aromatic residues to fine tune saccharide specificities of proteins. These are of immense utility for protein engineering and protein design studies. PMID- 22527757 TI - Variation in mortality of ischemic and hemorrhagic strokes in relation to high temperature. AB - Outdoor temperature has been reported to have a significant influence on the seasonal variations of stroke mortality, but few studies have investigated the effect of high temperature on the mortality of ischemic and hemorrhagic strokes. The main study goal was to examine the effect of temperature, particularly high temperature, on ischemic and hemorrhagic strokes. We investigated the association between outdoor temperature and stroke mortality in four metropolitan cities in Korea during 1992-2007. We used time series analysis of the age-adjusted mortality rate for ischemic and hemorrhagic stroke deaths by using generalized additive and generalized linear models, and estimated the percentage change of mortality rate associated with a 1 degrees C increase of mean temperature. The temperature-responses for the hemorrhagic and ischemic stroke mortality differed, particularly in the range of high temperature. The estimated percentage change of ischemic stroke mortality above a threshold temperature was 5.4 % (95 % CI, 3.9 6.9 %) in Seoul, 4.1 % (95 % CI, 1.6-6.6 %) in Incheon, 2.3 % (-0.2 to 5.0 %) in Daegu and 3.6 % (0.7-6.6 %) in Busan, after controlling for daily mean humidity, mean air pressure, day of the week, season, and year. Additional adjustment of air pollution concentrations in the model did not change the effects. Hemorrhagic stroke mortality risk significantly decreased with increasing temperature without a threshold in the four cities after adjusting for confounders. These findings suggest that the mortality of hemorrhagic and ischemic strokes show different patterns in relation to outdoor temperature. High temperature was harmful for ischemic stroke but not for hemorrhagic stroke. The risk of high temperature to ischemic stroke did not differ by age or gender. PMID- 22527758 TI - Droughts and broad-scale climate variability reflected by temperature-sensitive tree growth in the Qinling Mountains, central China. AB - The relationship between temperature and drought was investigated using the temperature-sensitive growth of Larix chinensis Beissn in the Qinling Mountains, central China. Extremely high tree-ring width index values (TRWI) agreed well with dry conditions defined by the dryness-wetness index (DWI) obtained from data in Chinese historical documents and climate-related papers between 1814 and 1956 (before the short of instrumental measurements); the reverse applied to extremely low TRWI values. The main severe drought epochs occurred from the late 1850s to the 1870s, the 1920s to 1930s and in the 2000s, whereas wet spells occurred from 1817-1827 and 1881-1886. The droughts in the 2000s exhibited a similar pattern as the ones from the 1920s to 1930s, with obviously an increasing temperature. The variation of tree growth agreed well with other reconstructed temperature series from nearby and remote regions, suggesting that Larix chinensis could respond to broad-scale climate variability. The longest cold interval, 1817-1827, could be associated with the influence of the Tambora eruption in 1815. PMID- 22527759 TI - The impact of the 2008 cold spell on mortality in Shanghai, China. AB - No prior studies in China have investigated the health impact of cold spell. In Shanghai, we defined the cold spell as a period of at least seven consecutive days with daily temperature below the third percentile during the study period (2001-2009). Between January 2001 and December 2009, we identified a cold spell between January 27 and February 3, 2008 in Shanghai. We investigated the impact of cold spell on mortality of the residents living in the nine urban districts of Shanghai. We calculated the excess deaths and rate ratios (RRs) during the cold spell and compared these data with a winter reference period (January 6-9, and February 28 to March 2). The number of excess deaths during the cold spell period was 153 in our study population. The cold spell caused a short-term increase in total mortality of 13 % (95 % CI: 7-19 %). The impact was statistically significant for cardiovascular mortality (RR = 1.21, 95 % CI: 1.12-1.31), but not for respiratory mortality (RR = 1.14, 95 % CI: 0.98-1.32). For total mortality, gender did not make a statistically significant difference for the cold spell impact. Cold spell had a significant impact on mortality in elderly people (over 65 years), but not in other age groups. Conclusively, our analysis showed that the 2008 cold spell had a substantial effect on mortality in Shanghai. Public health programs should be tailored to prevent cold-spell-related health problems in the city. PMID- 22527760 TI - Special issue: Universal Thermal Comfort Index (UTCI). PMID- 22527761 TI - State school policies and youth obesity. AB - The objective of this study was to examine relations between state-level school policies and childhood obesity for youth ages 10-17 years. Secondary analysis of the 2003-2006 School Nutrition Environment State Policy Classification System, 2003-2007 Physical Education Related State Policy Classification System, and 2003 and 2007 National Surveys of Children's Health was performed. Eleven nutrition and 5 physical education (PE) domains were examined for elementary (ES), middle (MS), and high school (HS) children. Logistic regression models examined the association of policies on obesity prevalence in 2007 as well as change scores for the policy assessments. Scores for 5 of 11 nutrition domains and 4 of 5 PE domains increased between 2003 and 2006-2007. Controlling for individual, family and neighborhood factors, nutrition policies were positively associated with the odds of 2007 obesity in 3 ES and 2 MS domains and negatively associated with 1 HS domain. Adjusted positive associations also were observed between 2 ES and 1 MS PE policy domains and 2007 obesity. Controlling for covariates, nutrition policy change scores showed positive associations between increases in 1 ES and 1MS domain, and negative associations with 1 ES and 1 HS domain and 2007 obesity. PE policy change scores showed positive adjusted associations between increases in 2 ES, 2 MS and 1 HS domains and 2007 obesity. The findings indicate that state level school health policies are associated with childhood obesity after adjusting for related factors, suggesting that states with higher obesity levels have responded with greater institution of policies. PMID- 22527762 TI - A qualitative study of factors affecting pregnancy weight gain in African American women. AB - African Americans and overweight or obese women are at increased risk for excessive gestational weight gain (GWG) and postpartum weight retention. Interventions are needed to promote healthy GWG in this population; however, research on exercise and nutritional barriers during pregnancy in African American women is limited. The objective of this qualitative study is to better inform intervention messages by eliciting information on perceptions of appropriate weight gain, barriers to and enablers of exercise and healthy eating, and other influences on healthy weight gain during pregnancy in overweight or obese African American women. In-depth interviews were conducted with 33 overweight or obese African American women in Columbia, South Carolina. Women were recruited in early to mid-pregnancy (8-23 weeks gestation, n = 10), mid to late pregnancy (24-36 weeks, n = 15), and early postpartum (6-12 weeks postpartum, n = 8). Interview questions and data analysis were informed using a social ecological framework. Over 50 % of women thought they should gain weight in excess of the range recommended by the Institute of Medicine. Participants were motivated to exercise for personal health benefits; however they also cited many barriers to exercise, including safety concerns for the fetus. Awareness of the maternal and fetal benefits of healthy eating was high. Commonly cited barriers to healthy eating include cravings and availability of unhealthy foods. The majority of women were motivated to engage in healthy behaviors during pregnancy. However, the interviews also uncovered a number of misconceptions and barriers that can serve as future intervention messages and strategies. PMID- 22527763 TI - Risk of spontaneous preterm birth in relation to maternal exposure to intimate partner violence during pregnancy in Peru. AB - Intimate partner violence (IPV) is increasingly recognized as an important cause of maternal and perinatal morbidity. We assessed the relation between IPV and risk of spontaneous preterm birth (PTB) among Peruvian women. The study was conducted among 479 pregnant women who delivered a preterm singleton infant (<37 weeks gestation) and 480 controls (>=37 weeks gestation). Participants' exposure to physical and emotional violence during pregnancy was collected during in person interviews conducted after delivery and while patients were in hospital. Odds ratios (aOR) and 95 % confidence intervals (CI) were estimated from logistic regression models. The prevalence of any IPV during pregnancy was 52.2 % among cases and 34.6 % among controls. Compared with those reporting no exposure to IPV during pregnancy, women reporting any exposure had a 2.1-fold increased risk of PTB (95 % CI 1.59-2.68). The association was attenuated slightly after adjusting for maternal age, pre-pregnancy weight, and other covariates (OR = 1.99; 95 % CI 1.52-2.61). Emotional abuse in the absence of physical violence was associated with a 1.6-fold (95 % CI 1.21-2.15) increased risk of PTB. Emotional and physical abuse during pregnancy was associated with a 4.7-fold increased risk of PTB (95 % CI 2.74-7.92). Associations of similar directions and magnitudes were observed when PTB were sub-categorized according to clinical presentation or severity. IPV among pregnant women is common and is associated with an increased risk of PTB. Our findings and those of others support recent calls for coordinated global health efforts to prevent violence against women. PMID- 22527765 TI - Multiple childcare arrangements and health outcomes in early childhood. AB - This study examined the associations between multiple childcare arrangements and young children's health problems. This study used three waves of the Early Childhood Longitudinal Study-Birth Cohort, collected from a nationally representative sample of children when they were 9 months old, 2 years old, and 4 years old (N = 7,150). 'Multiple childcare arrangements' was defined and measured by the number of non-parental childcare arrangements that occurred on a regular basis. During each wave of the data collection, the mother reported the number of regular childcare arrangements by three types: relative care, non-relative care, and center-based care. These numbers were summed to calculate the total number of arrangements. The mother also reported the incidence of ear infections, gastrointestinal illnesses, asthma diagnosis, and unintentional injuries of the child. Random effects and fixed effects regression models were used to estimate the association between the number of childcare arrangements and measures of early childhood health problems. Increases in the total number of childcare arrangements were associated with an elevated risk of ear infections, gastrointestinal illnesses, and diagnosed asthma in children. Further analysis indicates that increases in both the number of center-based care and non-relative care (but not relative care) arrangements can lead to a greater chance of health problems in young children. Multiple childcare arrangements are associated with communicable illness and diagnosed asthma in early childhood and appear to be a risk factor for health problems in early childhood. PMID- 22527766 TI - Survey of Minnesota parent attitudes regarding school-based depression and suicide screening and education. AB - School-based depression screening and education programs are recommended for addressing the high rates of children's mental illness. The objectives of this study were to (1) identify Minnesota parent attitudes regarding the provision of school-based depression and suicide screening and education and (2) identify predictors of parent support for these school-based programs. A random sample of 1,300 Minnesota households with children ages 5-18 years was surveyed by mail. Chi-square tests and regression analyses were used to detect differences in parent support for depression and suicide screening and education across demographic categories, and parent beliefs and knowledge about depression and suicide. The response rate of eligible households was 43 % (N = 511). Overall, 84 89 % of parents supported school-based depression and suicide screening and education. After adjusting for all variables, parent support for depression screening was associated with greater knowledge [OR 8.48, CI(1.30-55.21)] and fewer stigmatizing beliefs [OR 0.03, CI(0.01-0.12)]. Support for suicide screening was associated with fewer stigmatizing beliefs [OR 0.03, CI(0.01 0.10)]. Support for depression education was associated with fewer stigmatizing beliefs [OR 0.32, CI(0.10-1.00)] and lower educational attainment [OR 0.59, CI(0.40-0.89)]. Support for suicide education was associated with greater knowledge [OR 7.99, CI(1.02-62.68)], fewer stigmatizing beliefs [OR 0.26, CI(0.07 0.92)], and lower educational attainment [OR 0.60, CI(0.38-0.94)]. Parent support for school-based depression and suicide screening and education was high. Parent education to decrease stigmatizing beliefs and increase knowledge about depression and suicide may increase support among the minority of parents who do not endorse such programs. PMID- 22527767 TI - "They told me to come back": women's antenatal care booking experience in inner city Johannesburg. AB - To assess women's experience of public antenatal care (ANC) services and reasons for late antenatal care attendance in inner-city Johannesburg, South Africa. This cross-sectional study was conducted at three public labour wards in Johannesburg. Interviews were conducted with 208 women who had a live-birth in October 2009. Women were interviewed in the labour wards post-delivery about their ANC experience. Gestational age at first clinic visit was compared to gestational age at booking (ANC service provided). ANC attendance was high (97.0 %) with 46.0 % seeking care before 20 weeks gestation (early). Among the 198 women who sought care, 19.2 % were asked to return more than a month later, resulting in a 3-month delay in being booked into the clinic for these women. Additionally 49.0 % of women reported no antenatal screening being conducted when they first sought care at the clinic. Delay in recognizing pregnancy (21.7 %) and lack of time (20.8 %) were among the reasons women gave for late attendance. Clinic booking procedures and delays in diagnosing pregnancy are important factors causing women to access antenatal care late. In a country where a third of pregnant women are HIV infected, early ANC is vital in order to optimise ART initiation and thereby reduce maternal mortality and paediatric HIV infection. It is therefore imperative that existing antenatal care policies are implemented and reinforced and that women are empowered to demand better services. PMID- 22527769 TI - Recognizing excellence in Maternal and Child Health (MCH) Epidemiology: the 2011 MCH Epidemiology Awards. PMID- 22527768 TI - Characteristics of sexually active teenage girls who would be pleased with becoming pregnant. AB - To investigate factors associated with favorable pregnancy attitudes among teenage girls. Participants were sexually active teenage girls aged 15-18 years old (n = 965) who took part in the 2002 or 2006-2010 National Survey of Family Growth (NSFG). Multinomial multivariable logistic regression was used to assess the likelihood of being pleased with a teenage pregnancy. Sixteen percent of sexually active teenage girls (n = 164) would be pleased (11 % a little pleased, 5 % very pleased) if they became pregnant. In a multivariable model, participants who had not yet discussed sexual health topics (i.e., how to say no to sexual intercourse or birth control) or had only discussed birth control with a parent were more likely to be very pleased with a teenage pregnancy than participants who had discussed both topics with a parent. Prior pregnancy, racial/ethnic group status, older age, and having parents with a high school education or less also increased the odds of being pleased with a teenage pregnancy. Being pleased with a teenage pregnancy was correlated with a lack of discussion of sexual health topics with parents, prior pregnancy, and sociodemographic factors (having less educated parents, racial/ethnic group status). Pregnancy prevention efforts can be improved by acknowledging the structural and cultural factors that shape teenage pregnancy attitudes. PMID- 22527770 TI - The consequences of unintended pregnancy for maternal and child health in rural India: evidence from prospective data. AB - To investigate the relationship between pregnancy intendedness and utilization of recommended prenatal care for mothers and vaccinations for children against six vaccine preventable diseases in rural India using a prospective dataset. To examine the association between pregnancy intention and neonatal and infant mortality in rural India. The study is based upon a prospective follow-up survey of a cohort selected from the National Family Health Survey 1998-1999, carried out in 2002-2003 in rural areas of four Indian states of Bihar, Jharkhand, Maharashtra and Tamil Nadu. Data for 2108 births for which pregnancy intendedness was assessed prospectively was analyzed using bivariate analysis, logistic regressions and discrete-time survival analysis. Mothers reporting unwanted births were 2.32 (95 % CI: 1.54-3.48) times as likely as mothers reporting wanted births to receive inadequate prenatal care. Moreover, unwanted births were 1.38 (95 % CI: 1.01-1.87) times as likely as wanted births to receive inadequate childhood vaccinations. Likewise, births that were identified as mistimed/unwanted had 83 % higher risk of neonatal mortality compared to wanted births. The association between pregnancy intendedness and infant mortality was only marginally significant. This is the first study of its kind which has investigated the relationship between prospectively assessed pregnancy intendedness and early childhood mortality in rural India. The study provides additional and more conclusive evidence that unwanted births are disadvantaged in terms of maternal and child health outcomes. Findings argue for enhanced focus on family planning to reduce the high prevalence of unintended pregnancy in rural India. PMID- 22527771 TI - Early predictors of obesity and cardiovascular risk among American Indian children. AB - American Indian (AI) children have the highest rates of obesity among ethnic groups in the United States, and rates continue to increase. This study was designed to examine the effects of prenatal and early postnatal factors on AI children's body mass index (BMI) trajectories, adiposity, and cardiovascular risk markers during early childhood. We screened 471 AI children (ages 5-8) from three Wisconsin tribes. Screenings included anthropometric and body fat measures and non-fasting lipid and glucose via fingerstick blood samples. Tribal records from Women Infants and Children (WIC) programs and clinic charts provided data on children's BMI trajectories, maternal prenatal factors, and the early postnatal feeding environment. Forty-seven percent of children were overweight or obese. Analysis of growth trajectories showed that children's BMI category was largely determined within the 1 year of life. Significant predictors of children's BMI category at age 1 included macrosomia (OR 4.38), excess gestational weight gain (OR 1.64) and early termination of breastfeeding (OR 1.66). Children who were overweight/obese at age 1 had greater odds of being overweight (OR 3.42) or obese (OR 3.36), and having unhealthy levels of body fat (OR 2.95) and LDL cholesterol (OR 1.64) at ages 5-8. Children's BMI category is determined in the early post natal environment, within the 1 year of life, by factors including excess gestational weight gain and early termination of breastfeeding. In turn, children's BMI category at age 1 predicts the emergence of cardiovascular risk markers in early childhood. PMID- 22527772 TI - Tobacco use among married women in Nepal: the role of women's empowerment. AB - This study documented the prevalence and correlates of tobacco use among women of reproductive age in Nepal using nationally representative data. We utilized the 2006 Nepal Demographic and Health Survey that interviewed 10,793 women and 4,397 men. We analyzed the couple's data or households (N = 2,600) in which both husband and wife were interviewed. We examined the effects of women's empowerment measured by education, employment, intra-household decisions, and age-on their tobacco use controlling for other individual and household characteristics. Women's empowerment had mixed effects on tobacco use. While women's education was inversely associated with their tobacco use, their age, employment and ability to make intra-household mobility decisions were positively associated with smoking. Women with primary and beyond primary education were 48 and 92 % less likely to smoke compared to women with no education, respectively. Tobacco use among women increased dramatically with age from 8 % in teen years to 42 % in their forties. A 1 year increase in age increased the odds of tobacco use by 6 %. Women whose husbands smoked were twice as likely to smoke. Nepal should not only restrict tobacco use in public places by implementing its Tobacco Control and Regulatory Act of 2010 but also focus on encouraging smoke-free homes by increasing awareness about the health consequences of tobacco use and secondhand smoke among populations most likely to smoke that include nearly all men, employed women, women with low levels of education, women whose spouses smoke and those who are 30 and above in age. Additionally, a long term goal should be to ensure at least 5th grade of education for all girls. PMID- 22527773 TI - Changes in LDL and HDL subclasses in normal pregnancy and associations with birth weight, birth length and head circumference. AB - Pregnancy is associated with alterations in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) subclasses, but the exact pattern of these variations remains controversial. This study investigates longitudinal changes of plasma LDL and HDL particles distributions during the course of normal pregnancy, as well as associations of maternal LDL and HDL subclasses distributions before delivery with parameters of newborn size. Blood samples were collected from 41 healthy pregnant women throughout entire pregnancy, before delivery and 7 weeks postpartum. LDL and HDL subclasses were determined by gradient gel electrophoresis, while other biochemical parameters were measured by standard laboratory methods. During gestation LDL size significantly decreased (P < 0.001), due to reduction in relative proportion of LDL I (P < 0.01) and increase of LDL II (P < 0.001) and IIIA (P < 0.05) subclasses. In the same time, HDL size and proportions of HDL 2a particles significantly decreased (P < 0.001), with concomitant increase of HDL 3b and 3c subclasses (P < 0.05). Observed alterations were associated with changes in serum triglyceride levels. Rearrangement in LDL subclasses distribution during gestation was transient, while postpartum HDL subclasses distribution remained shifted toward smaller particles. Higher proportion of LDL IVB in maternal plasma before delivery was an independent predictor of smaller birth weights and lengths, while higher proportions of LDL IVB and HDL 2a subclasses were independent determinants of newborns' smaller head circumferences. Routine gestational and prenatal care in otherwise normal pregnancy could be complemented with evaluation of LDL and HDL particles distribution in order to ensure an adequate size of the newborn. PMID- 22527774 TI - Association of residential mobility with child health: an analysis of the 2007 National Survey of Children's Health. AB - To describe the association of residential mobility with child health. We conducted descriptive, bivariate, and multivariable analyses of data from 63,131 children, 6-17 years, from the 2007 National Survey of Children's Health. Logistic regression was used to explore the association of residential mobility with child health and measures of well-being. Analyses were carried out using SAS callable SUDAAN to appropriately weight estimates and adjust for the complex sampling design. After adjusting for age, race/ethnicity, presence of a special health care need, family structure, parental education, poverty level, and health insurance status, children who moved >= 3 times were more likely to have poorer reported overall physical (AOR 1.21 [95 %CI: 1.01-1.46]) and oral health status (AOR 1.31 [95 % CI: 1.15-1.49]), and >= 1 moderate/severe chronic conditions (AOR 1.40 [95 % CI: 1.19-1.65]) than children who had no lifetime moves. When compared to children who had never moved, children who moved >= 3 times were more likely to be uninsured/have periods of no coverage (AOR 1.35; 95 % CI: 0.98-1.87) and lack a medical home (AOR 1.16, 95 % CI: 1.04-1.31). None of the outcomes were statistically significant for children who moved fewer than 3 times. Clinicians need to be aware that children who move frequently may lack stable medical homes and consistent coverage increasing their risk of poor health outcomes and aggravation of mild or underlying chronic conditions. Public health systems could provide the necessary link between parents and clinicians to ensure that continuous, coordinated care is established for children who move frequently. PMID- 22527775 TI - Health-related quality of life in children and adolescents following traumatic injury: a review. AB - This paper comprehensively reviews the published literature investigating health related quality of life (HRQOL) following general traumatic injury in individuals between birth and 18 years. Studies were not considered if they primarily compared medical treatment options, evaluated physical function but not other aspects of HRQOL, or focused on non-traumatic wounds. Specific injury types (e.g., burn injury) were also not included. A total of 16 studies met criteria. Participants were age 1-18 years, with 12 studies considering children 5 years of age or older. Males were overrepresented. Injury severity averaged mostly in the moderate range. HRQOL deficits were noted in injured samples in all studies except the two with the longest time to follow-up (6-11 years). Some improvement was seen 6 months to 2 years after injury. Factors associated with HRQOL deficits were investigated, with acute and posttraumatic stress disorder symptoms showing the strongest relationship. Research to date in this area is impressive, particularly the number of studies using prospective longitudinal investigations and validated measures. Challenges remain regarding methodologic differences, assessment of preinjury status, retention of participants, and management of missing data. Suggested future directions include extension of follow-up duration, utilization of pediatric self-report when possible, inclusion of younger children, and development of intervention programs. PMID- 22527776 TI - Cerebrospinal fluid amyloid-beta 2-42 is decreased in Alzheimer's, but not in frontotemporal dementia. AB - Alzheimer's dementia (AD) and frontotemporal dementias (FTD) are common and their clinical differential diagnosis may be complicated by overlapping symptoms, which is why biomarkers may have an important role to play. Cerebrospinal fluids (CSF) Abeta2-42 and 1-42 have been shown to be similarly decreased in AD, but 1-42 did not display sufficient specificity for exclusion of other dementias from AD. The objective of the present study was to clarify the diagnostic value of Abeta2-42 peptides for the differential diagnosis of AD from FTD. For this purpose, 20 non demented disease controls (NDC), 22 patients with AD and 17 with FTD were comparatively analysed by a novel sequential aminoterminally and carboxyterminally specific immunoprecipitation protocol with subsequent Abeta-SDS PAGE/immunoblot, allowing the quantification of peptides 1-38(ox), 2-40 and 2-42 along with Abeta 1-37, 1-38, 1-39, 1-40, 1-40(ox) and 1-42. CSF Abeta1-42 was decreased in AD as compared to NDC, but not to FTD. In a subgroup of the patients analyzed, the decrease of Abeta2-42 in AD was evident as compared to both NDC and FTD. Abeta1-38 was decreased in FTD as compared to NDC and AD. For differentiating AD from FTD, Abeta1-42 demonstrated sufficient diagnostic accuracies only when combined with Abeta1-38. Abeta2-42 yielded diagnostic accuracies of over 85 % as a single marker. These accuracy figures could be improved by combining Abeta2-42 to Abeta1-38. Abeta2-42 seems to be a promising biomarker for differentiating AD from other degenerative dementias, such as FTD. PMID- 22527777 TI - Changes in insulin-signaling transduction pathway underlie learning/memory deficits in an Alzheimer's disease rat model. AB - Brain metabolic dysregulation is a hallmark pathological change in Alzheimer's disease (AD). Although detailed mechanisms are still not fully elucidated, recent studies suggest alterations of insulin-signaling transduction cascades underlie neuronal stresses in AD brains. In this study, we performed in vivo experiments to determine the impact of soluble Abeta oligomers on insulin-signaling transduction in rat hippocampi by utilizing lateral ventricular injection of amyloid beta (Abeta) oligomers on male Wistar rats (225 +/- 25 g, 3-4 months old) as an AD rat model. The Abeta-infused rats manifested remarkably increased escape latency and significantly decreased proportions of time and pathway crossing the hidden platform as compared to the rats in the pseudo-injection group and the non injection group in Morris water maze test implicating the damaging effect of soluble Abeta oligomers on rat learning and memory functions. Accordingly, our subsequent results demonstrated that the infusion of soluble Abeta oligomers significantly decreased the expressions of insulin receptor, insulin receptor substrate-I, B cell lymphoma/leukemia-2 and serine/threonine protein kinase B in rat hippocampal neurons, whereas the expression level of total cAMP response element-binding protein was not changed. This study suggests that soluble Abeta oligomers instigated insulin-signaling disturbances which are potentially associated with learning and memory deficits in the AD rat model. PMID- 22527779 TI - Peroneal tendoscopy. AB - Peroneal tendoscopy is an innovative technique that allows visualization of the tendons from the myotendinous junction to the peroneal tubercle, together with adjacent anatomic structures such as the recently unveiled vincula. Through a minimally invasive approach, it is possible to diagnose and treat several disorders, such as common tenosynovitis, accessory muscles, hypertrophic bony prominences, and thickened vincula, that can cause pain and tendon catching. Surgical morbidity and postoperative pain are significantly reduced when compared with open procedures. In this paper, the main indications for peroneal tendoscopy are discussed, the available literature is reviewed, and the surgical technique is described. Advantages of this procedure and current limitations are also presented. Anatomic and histological studies were also performed in order to verify: 1) the feasibility of peroneal tendoscopy for evaluation of peroneal tendons, using cadaver specimens; 2) the presence of nervous tissue in cadaver peroneal vincula as well as in tendoscopic vincula biopsies from patients undergoing surgery for chronic lateral ankle pain. PMID- 22527778 TI - Clinical phenotypes and genetic biomarkers of FTLD. AB - Frontotemporal lobar degeneration (FTLD) is the most frequent neurodegenerative disorder with a presenile onset. It presents with a spectrum of clinical manifestations, ranging from behavioural and executive impairment to language disorders and motor dysfunction. New diagnostic criteria identified two main cognitive syndromes: behavioural variant frontotemporal dementia (bvFTD) and primary progressive aphasia (PPA). Regarding bvFTD, new criteria that include the use of biomarkers have been proposed. According to them, bvFTD can be classified in "possible" (clinical features only), "probable" (inclusion of imaging biomarkers) and "definite" (in the presence o f a known causal mutation or at autopsy). Concerning autosomal dominant mutations, microtubule associated protein tau gene mutations have been the first ones identified and are generally associated with early onset bvFTD phenotype. More recently, progranulin gene mutations were recognized in association with familial form of FTLD. In addition, other genes are linked to rare cases of familial FTLD, primarily the newly discovered C9ORF72 hexanucleotide expansion repeats. As regards PPA, new consensus criteria identify three syndromes: primary non-fluent aphasia, semantic variant of PPA and logopenic aphasia, which seems to be associated, in the majority of cases, with underlying Alzheimer's disease pathology. In this review, new criteria, including MRI, cerebrospinal fluid and genetic biomarkers, will be presented and discussed. PMID- 22527780 TI - COSARA: integrated service platform for infection surveillance and antibiotic management in the ICU. AB - The Intensive Care Unit is a data intensive environment where large volumes of patient monitoring and observational data are daily generated. Today, there is a lack of an integrated clinical platform for automated decision support and analysis. Despite the potential of electronic records for infection surveillance and antibiotic management, different parts of the clinical data are stored across databases in their own formats with specific parameters, making access to all data a complex and time-consuming challenge. Moreover, the motivation behind physicians' therapy decisions is currently not captured in existing information systems. The COSARA research project offers automated data integration and services for infection control and antibiotic management for Ghent University Hospital. The platform not only gathers and integrates all relevant data, it also presents the information visually at the point of care. In this paper, we describe the design and value of COSARA for clinical treatment and infectious diseases monitoring. On the one hand, this platform can facilitate daily bedside follow-up of infections, antibiotic therapies and clinical decisions for the individual patient, while on the other hand, the platform serves as management view for infection surveillance and care quality improvement within the complete ICU ward. It is shown that COSARA is valuable for registration, real-time presentation and management of infection-related and antibiotics data. PMID- 22527781 TI - The differing privacy concerns regarding exchanging electronic medical records of internet users in Taiwan. AB - This study explores whether Internet users have different privacy concerns regarding the information contained in electronic medical records (EMRs) according to gender, age, occupation, education, and EMR awareness. Based on the Concern for Information Privacy (CFIP) scale developed by Smith and colleagues in 1996, we conducted an online survey using 15 items in four dimensions, namely, collection, unauthorized access, secondary use, and errors, to investigate Internet users' concerns regarding the privacy of EMRs under health information exchanges (HIE). We retrieved 213 valid questionnaires. The results indicate that the respondents had substantial privacy concerns regarding EMRs and their educational level and EMR awareness significantly influenced their privacy concerns regarding unauthorized access and secondary use of EMRs. This study recommends that the Taiwanese government organizes a comprehensive EMR awareness campaign, emphasizing unauthorized access and secondary use of EMRs. Additionally, to cultivate the public's understanding of EMRs, the government should employ various media, especially Internet channels, to promote EMR awareness, thereby enabling the public to accept the concept and use of EMRs. People who are highly educated and have superior EMR awareness should be given a comprehensive explanation of how hospitals protect patients' EMRs from unauthorized access and secondary use to address their concerns. Thus, the public can comprehend, trust, and accept the use of EMRs, reducing their privacy concerns, which should facilitate the future implementation of HIE. PMID- 22527782 TI - Using electronic medical record systems for admission decisions in emergency departments: examining the crowdedness effect. AB - Many medical organizations have deployed electronic medical record (EMR) information systems (IS) to improve medical decision-making and increase efficiency. Despite their advantages, however, EMR IS may make less of a contribution in the stressful environment of an emergency department (ED) that operates under tight time constraints. The high level of crowdedness in the EDs itself can cause physicians to make medical decisions resulting in more unnecessary admissions and fewer necessary admissions. Thus this study evaluated the contribution of an EMR IS to physicians by investigating whether EMR IS leads to improved medical outcomes in points of care in EDs under different levels of crowdedness. For this purpose a track log-file analysis of a database containing 3.2 million ED referrals in seven main hospitals in Israel (the whole population in these hospitals) was conducted. The findings suggest that viewing medical history via the EMR IS leads to better admission decisions, and reduces the number of possibly avoidable single-day admissions. Furthermore, although the ED can be very stressful especially on crowded days, physicians used EMR IS more on crowded days than on non-crowded days. These results have implications as regards the viability of EMR IS in complex, fast-paced environments. PMID- 22527783 TI - Mitigating error vulnerability at the transition of care through the use of health IT applications. AB - Adverse drug events are largely considered to be errors in which the severity of effects could be lessened or even prevented through more effective medication reconciliation practices. Transitions of care, particularly at the time of discharge from the hospital, represent a time of heightened error vulnerability that contributes to medication discrepancy occurrences. The observed vulnerability can be attributed to communication and care continuity gaps across health care settings and can often lead to preventable errors. Health IT tools developed through research can identify factors which increase the risk of medication discrepancies. Additionally, the implementations of optimized clinical workflow processes to form effective transitions of care are approaches to decreasing medication discrepancies which may lead to adverse drug events. While federal policies and certifying organizations have implemented quality initiatives to increase focus on medication reconciliation practices in the hospital and primary care settings, the same practices must be implemented after a patient is discharged to their homes or another health care facility in order to mitigate error vulnerabilities that occur at the transition of care. This paper provides an overview of health IT system capabilities and their applications within and across health care delivery settings to facilitate care coordination to ensure continuity of care. PMID- 22527784 TI - An efficient authentication scheme for telecare medicine information systems. AB - To ensure patients' privacy, such as telephone number, medical record number, health information, etc., authentication schemes for telecare medicine information systems (TMIS) have been studied widely. Recently, Wei et al. proposed an efficient authentication scheme for TMIS. They claimed their scheme could resist various attacks. However, in this paper, we will show their scheme is vulnerable to an off-line password guessing attack when user's smart card is lost. To improve the security, we propose a new authentication scheme for TMIS. The analysis shows our scheme could overcome the weaknesses in Wei et al.'s scheme and has better performance than their scheme. PMID- 22527785 TI - Cerebrotendinous xanthomatosis presenting with asymmetric parkinsonism: a case with I-123-FP-CIT SPECT imaging. AB - Cerebrotendinous xanthomatosis (CTX) is a rare inherited neurometabolic disease. Clinical symptoms are caused by increased deposition of cholestanol and cholesterol in various tissues. Progressive neurological symptoms are one of the principal manifestations. We report the case of a 44-year-old man who presented with asymmetric parkinsonism. In addition, there were mild bilateral pyramidal signs and a mild polyneuropathy. Brain MRI showed bilateral lesions in the dentate nucleus of the cerebellum and in the substantia nigra. Nuclear brain imaging using I-123-FP-CIT demonstrated an asymmetric reduced presynaptic dopaminergic function of the putamen and caudate nucleus, correlating well with his lateralized bradykinetic-rigid syndrome. CTX was diagnosed based on an increased plasma level of cholestanol, typical cerebellar brain lesions and the causative genetic mutation. CTX presenting with parkinsonism is considered rare and data on the neuroimaging of the dopaminergic deficit are limited. PMID- 22527786 TI - Effect of dexamethasone on the frequency of postdural puncture headache after spinal anesthesia for cesarean section: a double-blind randomized clinical trial. AB - In this study, we evaluated the effect of dexamethasone used as a prophylaxis for nausea and vomiting on the incidence of postdural puncture headache (PDPH) in pregnant women receiving spinal anesthesia for cesarean section. In a prospective, randomized, double-blind, placebo-controlled study, 372 women under spinal anesthesia received 8 mg of dexamethasone or placebo intravenously just after the umbilical cord was clamped. The rate of PDPH and correlated risk factors were evaluated. The prevalence of nausea and vomiting in the dexamethasone and placebo groups was 54.4 and 51.7%, respectively. There was no statistically meaningful difference between the results (P value = 0.673). The overall incidence rate of PDPH was 10.8%, with 28 cases from the dexamethasone group compared with 11 subjects from the placebo group (P value = 0.006). This effect was most prominent on the first day (P value = 0.046) and disappeared on the second day after spinal anesthesia (P value = 0.678). Prophylactic treatment with 8 mg of dexamethasone not only increases the severity and incidence of PDPH, but is also ineffective in decreasing the prevalence of intra-operative nausea and vomiting during cesarean section. The treatment is a significant risk factor for the development of PDPH. PMID- 22527787 TI - Chiari malformation presenting with pseudotumor cerebri: what is the best treatment? PMID- 22527788 TI - Neurocysticercosis in Western Europe: a re-emerging disease? AB - The objective of the study was to estimate the magnitude of neurocysticercosis in Western Europe and to determine the pattern of disease expression in the region. Review of patients with neurocysticercosis diagnosed in Western Europe from 1970 to 2011. Abstracted data included: demographic profile, clinical manifestations, form of neurocysticercosis, and whether the disease occurred in immigrants, European international travelers, or Europeans who had never been abroad. A total of 779 patients were found. Of these, only 28 were diagnosed before 1985. Countries with more reported patients were Portugal (n = 384), Spain (n = 228), France (n = 80), The United Kingdom (n = 26), and Italy (n = 21). Information on citizenship status, clinical manifestations, and forms of the disease was available in only 30-40% of patients. Immigrants accounted for 53% of cases, European travelers for 8%, and non-traveler Europeans for 39%. Immigrants/European travelers were most often diagnosed during the new Millennium, presented most often with seizures, and had less frequently inactive (calcified) neurocysticercosis than non-traveler Europeans. The prevalence of neurocysticercosis in Western Europe may be on the rise. The pattern of disease expression is different among immigrants/European travelers than among non traveler Europeans. It is possible that some patients had acquired the disease as the result of contact with Taenia solium carriers coming from endemic countries. Much remains to be learned on the prevalence of neurocysticercosis in this region. PMID- 22527789 TI - Experiences of the patients and their caregivers regarding the disclosure of the diagnosis of Alzheimer's disease: a Belgian retrospective survey. AB - Although the disclosure of the diagnosis of Alzheimer's disease (AD) is recommended by several guidelines, many clinicians do not announce the diagnosis to their patient. One of the main arguments against disclosure is the fear of a depressive reaction. Our aim was to report the experience and agreement of patients and their caregivers regarding the disclosure of the diagnosis of AD. All the patients with a diagnosis of AD attending our memory clinic were screened during 1 year. The patients and their caregivers were interviewed with a structured questionnaire. We included 108 patients (mean age = 77; Mini-Mental State Examination = 21) and matched caregivers (mean age 65). Twenty-nine percent of patients said they had suffered when the diagnosis was disclosed and 5% wished they had not been informed. Four percent felt more sad or depressed and 14% more anxious since the disclosure. The caregivers reported that 32% of patients had suffered from the disclosure, but only 15% were still suffering. In 85% of cases, the caregivers thought that the disclosure was useful. If they could go back in time and decide whether to disclose or not the diagnosis, only 4% of caregivers would retrospectively disagree to disclose the diagnosis to the patient. The disclosure of AD can induce anxiety and sadness. However, these negative feelings seem to persist only in a minority of patients. The vast majority of patients and caregivers agrees with the disclosure. PMID- 22527790 TI - Migrainous infarction: aspects on risk factors and therapy. AB - Migraine and stroke are related in more than one way. Migraine with aura is a risk factor for ischemic stroke in women under age 45 years, particularly when combined with other risk factors such as smoking and oral contraceptives. Further, individuals with migraine with aura seem to have more white matter lesions and ischemic infarctions than control patients. Migraine has been correlated to cervical artery dissection, the symptoms of which can mimic migraine. Correspondingly, migraine with aura sometimes is mistaken for stroke. Migrainous infarction is a rare but specific type of ischemic stroke developing during an attack of migraine with aura. It is important to recognize this unusual complication of migraine because the management probably is important. In this review, we will discuss the present knowledge of migrainous infarction, the clinical picture, possible mechanisms, and potential prevention and treatment. PMID- 22527791 TI - Axon myelination and electrical stimulation in a microfluidic, compartmentalized cell culture platform. AB - Axon demyelination contributes to the loss of sensory and motor function following injury or disease in the central nervous system. Numerous reports have demonstrated that myelination can be achieved in neuron/oligodendrocyte co cultures. However, the ability to selectively treat neuron or oligodendrocyte (OL) cell bodies in co-cultures improves the value of these systems when designing mechanism-based therapeutics. We have developed a microfluidic-based compartmentalized culture system to achieve segregation of neuron and OL cell bodies while simultaneously allowing the formation of myelin sheaths. Our microfluidic platform allows for a high replicate number, minimal leakage, and high flexibility. Using a custom built lid, fit with platinum electrodes for electrical stimulation (10-Hz pulses at a constant 3 V with ~190 kOmega impedance), we employed the microfluidic platform to achieve activity-dependent myelin segment formation. Electrical stimulation of dorsal root ganglia resulted in a fivefold increase in the number of myelinated segments/mm2 when compared to unstimulated controls (19.6 +/- 3.0 vs. 3.6 +/- 2.3 MBP+ segments/mm2). This work describes the modification of a microfluidic, multi-chamber system so that electrical stimulation can be used to achieve increased levels of myelination while maintaining control of the cell culture microenvironment. PMID- 22527793 TI - Opioid system and Alzheimer's disease. AB - The opioid system may be involved in the pathogenesis of AD, including cognitive impairment, hyperphosphorylated tau, Abeta production, and neuroinflammation. Opioid receptors influence the regulation of neurotransmitters such as acetylcholine, norepinephrine, GABA, glutamate, and serotonin which have been implicated in the pathogenesis of AD. Opioid system has a close relation with Abeta generation since dysfunction of opioid receptors retards the endocytosis and degradation of BACE1 and gamma-secretase and upregulates BACE1 and gamma secretase, and subsequently, the production of Abeta. Conversely, activation of opioid receptors increases the endocytosis of BACE1 and gamma-secretase and downregulates BACE1 and gamma-secretase, limiting the production of Abeta. The dysfunction of opioid system (opioid receptors and opioid peptides) may contribute to hyperphosphorylation of tau and neuroinflammation, and accounts for the degeneration of cholinergic neurons and cognitive impairment. Thus, the opioid system is potentially related to AD pathology and may be a very attractive drug target for novel pharmacotherapies of AD. PMID- 22527792 TI - Roles of endoplasmic reticulum and energetic stress in disturbed sleep. AB - Sleep disturbances are contributing factors to health risk for several diseases including hypertension, diabetes, obesity, depression, and stroke. On a molecular level, sleep disturbances that incur sleep loss and sleep fragmentation result in cellular stress, inflammation, and an impaired immune system. It has been hypothesized that sleep deprivation or prolonged waking leads to increased energy demand and thus energetic stress. Sleep loss and sleep fragmentation are also known to lead to cellular stress specifically endoplasmic reticulum (ER) stress. This review will summarize the current knowledge of the roles of ER and energetic stress during sleep loss and fragmentation that are characteristics of many sleep disturbances. Sleep research pertinent to these specific pathways will be discussed. PMID- 22527794 TI - Impact of left ventricular function and the extent of ischemia and scar by stress myocardial perfusion imaging on prognosis and therapeutic risk reduction in diabetic patients with coronary artery disease: results from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. AB - BACKGROUND: The Bypass Angioplasty Revascularization Investigation 2 Diabetes trial demonstrated similar long-term clinical effectiveness of revascularization (REV) and intensive medical (MED) therapy. Comparisons of post-intervention ischemic burden have not been explored but are relevant to treatment decisions. This study examined differences in 1-year stress myocardial perfusion SPECT (MPS) abnormalities by randomized treatment. METHODS: MPS was performed in 1,505 patients at 1-year following randomization. MPS images were analyzed (masked to treatment) by a Nuclear Core Laboratory using a quantitative percent (%) of total, ischemic, and scarred myocardium. Cox proportional hazards models were used to estimate the relationship between MPS variables and trial endpoints. RESULTS: At 1-year, nearly all REV patients underwent the assigned procedure; while 16% of those randomized to MED received coronary REV. Patients randomized to REV exhibited fewer stress perfusion abnormalities than MED patients (P < .001). CABG patients had more frequent ischemic and scarred myocardium encumbering >= 5% of the myocardium when compared to those receiving PCI. Patients randomized to MED had more extensive ischemia and the median % of the myocardium with perfusion abnormalities was lower following REV (3% vs 9%, P = .01). A total of 59% of REV patients had no inducible ischemia at 1-year compared to 49% of MED patients (P < .001). Within the CABG stratum, those randomized to MED had the greatest rate of ischemic (P = .032) and scarred (P = .017) perfusion abnormalities. At 1-year, more extensive and severe stress myocardial perfusion abnormalities were associated with higher 5-year rates of death and a combined endpoint of cardiac death or myocardial infarction (MI) rates (11.3%, 8.1%, 6.8%, for >= 10%, 5%-9.9%, and 1-4.9% abnormal myocardium at stress, respectively, P < .001). In adjusted models, selected MPS variables were significantly associated with an increased hazard of cardiac death or MI (hazard ratio = 1.11 per 5% increase in abnormal myocardium at stress, P = .004). CONCLUSIONS: Patient management strategies that focus on ischemia resolution can be useful to guide the efficacy of near-term therapeutic approaches. A 1-year post-therapeutic intervention myocardial perfusion scan provides important information regarding prognosis in stable CAD patients with diabetes. PMID- 22527795 TI - Feasibility of myocardial perfusion imaging with half the radiation dose using ordered-subset expectation maximization with resolution recovery software. AB - OBJECTIVE: This study sought to assess the feasibility of performing myocardial perfusion imaging (MPI) with half the technetium activity using ordered-subset expectation maximization with resolution recovery (OSEM-RR), an iterative reconstruction software developed to improve count statistics and acquisition time. METHODS: Two hundred eighteen patients referred for MPI were randomly allocated to undergo stress-rest or rest-stress protocols with standard full-dose (FD) injections of technetium (Tc)-99m sestamibi or half-dose (HD) injections and OSEM-RR processing. Dose activities were adjusted individually by weight. The groups were compared for image quality and clinical results. RESULTS: The groups were similar for mean patient age, weight, and body mass index, sex distribution, pre-test probability of CAD and CAD prevalence. Mean Tc-99m activities for the low-dose and high-dose stages were as follows: FD group: 429 +/- 85 MBq and 1132 +/- 200 MBq; HD group: 263 +/- 129 MBq and 629 +/- 85 MBq (P < .0001 for both). Mean effective dose per study was 13.6 +/- 1.4 mSv in the FD group and 7.7 +/- 1.0 mSv in the HD group (P < .001). Over all image quality was good-to-excellent in 98% and 95% of the groups, respectively. However, when we analyzed the low dose stage separately, image quality was slightly worse in the HD than the FD, though still within the good-to excellent range. CONCLUSIONS: MPI with nearly half the radiation dose is feasible with good image quality. PMID- 22527796 TI - Diet intervention reduces uptake of alphavbeta3 integrin-targeted PET tracer 18F galacto-RGD in mouse atherosclerotic plaques. AB - BACKGROUND: Expression of alpha(v)beta(3) integrin has been proposed as a marker for atherosclerotic lesion inflammation. We studied whether diet intervention reduces uptake of alpha(v)beta(3) integrin-targeted positron emission tomography tracer (18)F-galacto-RGD in mouse atherosclerotic plaques. METHODS AND RESULTS: Hypercholesterolemic LDLR(-/-) ApoB(100/100) mice on high-fat diet for 4 months were randomized to further 3 months on high-fat diet (high-fat group, n = 8) or regular mouse chow (intervention group, n = 7). Intima-media ratio describing plaque burden was comparable between intervention and high-fat groups (2.0 +/- 0.5 vs 2.3 +/- 0.8, P = .5). Uptake of (18)F-galacto-RGD in the aorta was lower in the intervention than high-fat group (%ID/g 0.16 vs 0.23, P < .01). Autoradiography showed 35% lower uptake of (18)F-galacto-RGD in the atherosclerotic plaques in the intervention than high-fat group (P = .007). Uptake of (18)F-galacto-RGD in plaques correlated with uptake of (3)H deoxyglucose and nuclear density, which was lower in the intervention than high fat group (P = .01). Flow cytometry demonstrated macrophages expressing alpha(v) and beta(3) integrins in the aorta. CONCLUSIONS: Uptake of (18)F-galacto-RGD in mouse atherosclerotic lesions was reduced by lipid-lowering diet intervention. Expression of alpha(v)beta(3) integrin is a potential target for evaluation of therapy response in atherosclerosis. PMID- 22527797 TI - Comparing slow- versus high-speed CT for attenuation correction of cardiac SPECT perfusion studies. AB - BACKGROUND: For SPECT, CT-based attenuation correction is preferred. Many different models of CT are available with SPECT/CT systems. Our study compares clinical cardiac SPECT images that were attenuation corrected using slow-rotation CT and high-speed CT transmission scans. METHODS: We evaluated 59 rest/stress perfusion studies from patients who had undergone both a SPECT/CT with a slow rotation CT and a perfusion study on a PET/CT camera equipped with a high-speed CT scanner. Each SPECT study was reconstructed with transmission maps from both CT scans and the relative perfusion was assessed using semi-automated software. The summed stress/rest/and difference scores (SSS/SRS/SDS) were compared as well as the test classification. RESULTS: The intraclass correlation coefficients for the SSS, SRS, and SDS were 0.97, 0.96, and 0.80 respectively. There were no significant differences in the mean SSS, SRS, or SDS with the use of either CT for attenuation corrections. Classifying SSS > 3 as abnormal, there was 97% concordance (kappa = 0.88). Classifying SDS > 1 as abnormal, there was 95% concordance (kappa = 0.54). A McNemar's test showed no significant differences. CONCLUSIONS: There were no significant differences between using a high-speed CT and using a slow-rotation CT for attenuation correction of SPECT myocardial perfusion images. PMID- 22527799 TI - Photopenic mediastinum due to enlarged atria. PMID- 22527800 TI - Quantification of regional myocardial blood flow estimation with three dimensional dynamic rubidium-82 PET and modified spillover correction model. AB - PURPOSE: Myocardial blood flow (MBF) estimation with (82)Rubidium ((82)Rb) positron emission tomography (PET) is technically difficult because of the high spillover between regions of interest, especially due to the long positron range. We sought to develop a new algorithm to reduce the spillover in image-derived blood activity curves, using non-uniform weighted least-squares fitting. METHODS: Fourteen volunteers underwent imaging with both 3-dimensional (3D) (82)Rb and (15)O-water PET at rest and during pharmacological stress. Whole left ventricular (LV) (82)Rb MBF was estimated using a one-compartment model, including a myocardium-to-blood spillover correction to estimate the corresponding blood input function Ca(t)(whole). Regional K1 values were calculated using this uniform global input function, which simplifies equations and enables robust estimation of MBF. To assess the robustness of the modified algorithm, inter operator repeatability of 3D (82)Rb MBF was compared with a previously established method. RESULTS: Whole LV correlation of (82)Rb MBF with (15)O-water MBF was better (P < .01) with the modified spillover correction method (r = 0.92 vs r = 0.60). The modified method also yielded significantly improved inter operator repeatability of regional MBF quantification (r = 0.89) versus the established method (r = 0.82) (P < .01). CONCLUSION: A uniform global input function can suppress LV spillover into the image-derived blood input function, resulting in improved precision for MBF quantification with 3D (82)Rb PET. PMID- 22527798 TI - Assessment of coronary heart disease by CT angiography: current and evolving applications. AB - Computed tomography angiography (CTA) of the heart is a rapidly evolving application for comprehensive assessment of coronary arterial anatomy, myocardial function, perfusion, and myocardial viability. Thus, cardiac CTA is capable of retrieving the most critical information for guiding the management of patients with suspected coronary heart disease (CHD). Ongoing technologic advancements have allowed acquiring such information within minutes, at radiation doses that are lower than those from conventional computed tomography imaging or common nuclear imaging techniques. Cardiac CTA has positioned itself as an imaging modality that may be well suited to fulfill central needs of cardiovascular medicine. This article reviews the evidence for the clinical utility of cardiac CTA in patients with suspected CHD. PMID- 22527801 TI - Assessment of transient ischemic dilation (TID) ratio in gated SPECT myocardial perfusion imaging (MPI) using regadenoson, a new agent for pharmacologic stress testing. AB - BACKGROUND: Abnormal values of the transient ischemic dilation (TID) ratio are associated with severe and extensive coronary artery disease (CAD). The objective of this study was to determine the relationship between TID, determined from stress and rest ventricular volumes during regadenoson gated single-photon emission computed tomography myocardial perfusion imaging (MPI) dual isotope studies, and the extent of CAD found during coronary angiography. METHODS: 195 patients who underwent dual isotope MPI with regadenoson and cardiac angiography between March 2009 and February 2010 were analyzed. TID was calculated using commercially available software, Emory Cardiac Toolbox. Mean TID values were compared across disease types. A threshold for abnormal TID was determined by adding two standard deviations (SDs) to the mean TID of the "non-obstructive CAD" subgroup. RESULTS: In the 195-patient group analyzed, the mean TID ratio for non obstructive CAD (n = 104) was found to be 1.09 with a SD of 0.15. In a subgroup of patients whose angiogram was within 3 months of MPI (n = 155), the mean TIDs for non-obstructive disease (n = 81), single-vessel disease (n = 35), and multi vessel disease (n = 39) were 1.09, 1.15, and 1.19 with SDs of 0.16, 0.19, and 0.26, respectively. Those with an abnormal TID had a crude and adjusted odds ratio of 3.4 for multi-vessel disease which was statistically significant. History of diabetes was not found to be a significant confounder, effect modifier, or mediator of the relationship between the TID and the vessel disease. CONCLUSION: The mean TID ratio in patients with multi-vessel disease was 1.19. The threshold for an abnormal TID was 1.39 with specificity of 95% and sensitivity of 15% for determining multi-vessel CAD status. We conclude that the level of TID in gated SPECT MPI using regadenoson is associated with the degree of CAD on angiography. PMID- 22527802 TI - Preload dependence of gated cardiac SPECT-derived ventricular volumes in hemodialysis patients. AB - BACKGROUND: In hemodialysis (HD) patients, the intravascular volume expansion of the pre-HD state leads to a high preload. We aim to examine its effect on myocardial perfusion gated SPECT (MPGS)-derived left ventricular (LV) volumes. METHODS: The study comprised 50 end-stage renal disease (ESRD) patients on HD with normal 2-day stress/rest MPGS performed for kidney transplantation risk assessment. Patients (pts) comprised 23 men/27 women, with mean age of 59.4 +/- 7.1 years. The time elapsed from the last HD session in hours was calculated on both days, and patients were classified according to whether it was higher (group A: 19 pts), lower (group B: 27 pts), or equal (group C: 4 pts) on the stress vs the rest day. End-diastolic, end-systolic volumes (EDV, ESV), and left ventricular ejection fraction (LVEF) were determined using QGSTM software. Transient ischemic dilation (TID) ratios were derived from the nongated images using QPSTM software. RESULTS: Volumes were significantly higher at stress in group A, at rest in group B, and similar in group C. TID ratios were significantly higher in group A vs groups B and C. CONCLUSIONS: MPGS-derived ventricular volumes are preload dependent. The high preload of the pre-HD state may mimic ischemic TID if occurring on the stress day and create confusion if coinciding with the rest day. PMID- 22527806 TI - [Abstracts of the 118th Congress of the DGIM (German Society for Internal Medicine). April 14-17, 2012. Rhein-Main-Halle, Germany]. PMID- 22527804 TI - Regadenoson stress in patients with asthma and COPD: a breath of fresh air. PMID- 22527807 TI - Preparation of nanoemulsions and solid lipid nanoparticles by premix membrane emulsification. AB - In an attempt to overcome problems of conventional high-energy preparation processes for colloidal drug carrier systems, premix membrane emulsification was investigated for the first time as an alternative low-energy input process for the preparation of pharmaceutical nanoemulsions and solid lipid nanoparticles. The effect of process parameters on dispersions based on nonpolar lipids (medium chain triglycerides, soybean oil, and trimyristin) and different emulsifiers (sodium dodecyl sulfate, poloxamer 188, polyglyceryl-10-laurate, and sucrose laurate) was studied in a small-volume device and a larger scale-up approach. For emulsions and suspensions, mean particle sizes in a range from about 100 to 200 nm were observed for monomodal to monodisperse particle size distributions after 21 cycles of extrusion through polycarbonate membrane filters. As the mass ratio of matrix lipid to emulsifier (4:3, w/w concentrations) usually applied for the preparation of stable colloidal lipid particles was quite high, the amount of emulsifier in the dispersions was minimized. It was observed that the minimal concentration of emulsifier increased with decreasing membrane pore size. The possibility to prepare colloidal drug carrier systems with a high concentration of matrix lipid (up to 20%) by an optimized membrane extrusion process offers new opportunities for the processing of sensitive substances. PMID- 22527808 TI - Efficacy of two different surgical techniques combined in the treatment of rectocele. AB - Rectocele is defined as the herniation of rectal wall due to a rectovaginal septum defect in direction of the vagina. In most of cases it is a result of vaginal delivery or repeated increases of intra-abdominal pressure due to chronic constipation. Some patients can develop rectocele as a consequence of congenital or inherited weakness of the pelvic support system. The rectopexy procedure by a single mechanical stapler allows to ablate the exceeding tissue. This surgery is performed through transanal access without laparotomy, by means of a circular stapler which simultaneously resects portion of the rectal wall and re anastomizes it. Also the technique of sequential transfixed stitches (TSTS) represents a minimally invasive procedure for the rectocele treatment, allowing the performance of a complete plasty of rectal wall through transanal access. Hence, starting from a more effective stadiation of rectocele, the authors of this study will show the advantages of an endorectal approach for the treatment of the above-mentioned disease using both methods. A total of 25 female patients attending our colonproctology outpatient department, with an age ranging between 38 and 63 years, have been selected for our study; following a careful assessment of stadiation, they have undergone rectopexy with circular stapler first, thereafter fulfilling the surgery with TSTS. the mean duration of hospital stay was 2.5 days (range 2-3). Twelve patients out of 25 have shown early complications, and 11 patients late ones. Among the early complications, 3 patients reported pain (12 %), 3 patients urinary retention (12 %), and 2 patients bleeding (8 %). Among late complications, 5 cases of urgency defecation disorders (>4 months) (20 %), 1 intestinal flatus incontinence (4 %), 1 stenosis (4 %), 2 prolonged pain and 2 cases of persistent obstructive defecation syndrome were reported. No cases of life-threatening local or pelvic sepsis as well as of rectovaginal fistulae were reported. At the 6 months post-surgery evaluation, neither rectocele recurrence nor prolapse was observed. The association of circular stapler and TSTS in the rectopexy treatment of rectocele showed its short-term efficacy, producing an improvement of patient's clinical conditions, without inducing further alterations of pelvic statics, of the sphincteric tone as well as of rectum emptiness deficit. PMID- 22527809 TI - Synchronous medullary, papillary and follicular carcinomas in the same thyroid: case report and review of literature. PMID- 22527811 TI - Comparison of ventilation and cardiovascular parameters between prone thoracoscopic and Ivor Lewis esophagectomy. AB - Thoracoscopic esophagectomy in the prone position is associated with better surgical ergonomics compared to the left lateral decubitus position due to the effects of gravity pooling blood outside the operative field and the reduced need for lung retraction. The aim of this study was to evaluate the physiological effects of prone thoracoscopic esophagectomy with single-lumen intubation on ventilation, respiratory gas exchange, and cardiovascular parameters. Thirty-two consecutive patients underwent esophagectomy either through a prone thoracoscopic approach or through a right thoracotomic approach. Samples of arterial and central venous blood, as well as ventilation and cardiovascular parameters were obtained at baseline, during induction of anesthesia, throughout the operation, and after extubation. Patients undergoing prone thoracoscopic esophagectomy showed higher oxygenation levels (p < 0.001), and a significantly lower mean pulmonary shunt fraction (p = 0.001). Perioperative hemodynamics remained stable throughout the surgical procedures. Thoracoscopic esophagectomy in the prone position with two-lung ventilation was associated with a significant improvement of global oxygen delivery and a significant reduction of the pulmonary shunt when compared to the Ivor Lewis operation. PMID- 22527810 TI - "Fast track surgery" in the north-west of Italy: influence on the orientation of surgical practice. AB - Fast track surgery is a peri-operative management model, including different strategies to improve patients' convalescence, avoid metabolic alterations, reduce complications, and shorten hospital stay. Prerequisite is coordination between different practitioners (surgeon, anaesthetist, nurse, nutritionist, physiotherapist). The purpose of our investigation is to understand the level of fast track surgery application in Piedmont and to evidence analogies and differences among departments. We projected an investigation proposing, to every surgery department in Piedmont, a multiple-choice questionnaire evaluating the level of fast track surgery peri-operative interventions' application. Data analysis was conducted in two points of view: the transversal one with an overview of answer's percentages, the longitudinal one correlating data through Pearson's index (r). We collected answers by 78 % of balloted departments (38 on 49). Transversal analysis, including the evaluation of percentages of each question, shows that intra-operative period is the most influenced by fast track principles, and that only 12 departments of 38 apply complete protocols. Longitudinal analysis, estimating the whole of each department's answers, demonstrates the absence of statistical significance in the correlation between fast track surgery application and territorial (r = 0.18), economic (r = 0.31), or age (r = 0.06) variables. Influence of fast track surgery is significantly present in our territory, even though it is not fully concretized in protocols. The choice of fast track depends on the instruction, the environment and the sensibility of each surgeon. Knowledge of geographic distribution of departments applying this model can be useful to organize common protocols, starting from more experienced hospitals. PMID- 22527812 TI - Healthy Cities indicators--a suitable instrument to measure health? AB - The evidence-base for a health strategy should include information on the determinants of health and how they link together if it is to influence the health of the population. The WHO European Healthy Cities Network developed a set of 53 healthy city indicators (HCIs), to describe the health of its citizens and capture a range of local initiatives addressing the wider dimensions of health. This was the first systematic effort to collect and analyze a range of data from European cities. The analysis provided important insights into the interpretation, availability, and feasibility of collecting data, resulting in the development of a revised set of 32 indicators with improved definitions. An analysis of the revised indicators showed that this data was more complete and feasible to collect. It provided useful information to cities contributing to developing a description of health and thus helping to identify health problems. It also highlighted issues about the importance of collecting qualitative as well as quantitative data, the number of indicators and the appropriateness of using the indicators to compare different cities. HCIs facilitated the collection of routinely available health data in a systematic manner. The introduction of HCIs has encouraged cities to adopt a structured process of collecting information on the health of their citizens and build on this information by collecting appropriate local data for developing a city health profile to underpin a city health plan that would set out strategies and interventions to improve health and provide the evidence-base for health plans. PMID- 22527813 TI - Effects of Helicobacter pylori eradication on proteinuria: a prospective study. AB - BACKGROUND: Helicobacter pylori is one of the most common bacterial infections, seen in humans worldwide and its possible relationship to different diseases is a focus of attention nowadays. The aim of this study was to analyse the effects of H. Pylori eradication on proteinuria. METHODS: Ninety-nine patients suffering from dyspeptic complaints were recruited in this prospective study. The patients were divided into two groups according to the presence of H. pylori infection. Thus, a total of 67 H. pylori positive and 32 H. pylori negative patients were studied. The H. pylori positive patients' group was divided into two groups according to response toH. pylori eradication treatment. A total of three groups were formed, viz; group 1 comprises of patients who are H. pylori positive and responds positively toH. pylori eradication therapy, group 2 comprises of patients who are H. pylori positive and responds negatively toH. pylori eradication therapy and group 3 is the control group and comprises of patients that are H. pylori negative. Urine samples to obtain the protein/creatinine ratio were collected initially and at the end of the study from all patients. RESULTS: Mean difference levels (pre- and post-treatment difference) of urine protein/creatinine ratio was 0.055 +/- 0.13 in group 1. The ratio was - 0.0007 +/ 0.0067 in group 2 and - 0.0022 +/- 0.008 in group 3. A statistically significant difference was found in group 1 compared to the other groups in terms of mean difference levels of protein/creatinine ratios (p < 0.001). CONCLUSION: As a result of our study, treatment of H. pylori eradication significantly reduced the proteinuria within the normal limits. PMID- 22527814 TI - Acquired rhinophyma as a paraneoplastic manifestation of non-small cell lung cancer. AB - We report a case of a 58-year-old man who developed rhinophyma caused by non small cell lung cancer. To the best of our knowledge, rhinophyma as paraneoplastic syndrome associated with non-small cell lung cancer has not been previously reported. PMID- 22527815 TI - Transient ST segment elevation and left bundle branch block caused by mad-honey poisoning. AB - We herein present a case of a 76-year-old male patient presented with transient ST segment elevation and left bundle branch block caused by mad-honey poisoning. PMID- 22527816 TI - Meckel's diverticulitis in Amyand's hernia. PMID- 22527817 TI - Sarcoidosis and molecular mimicry--important etiopathogenetic aspects: current state and future directions. AB - Sarcoidosis is a disease of uncertainty in terms of its cause, presentation, and clinical course. The disease has a worldwide distribution and affects all ages, races, and both sex. Sarcoidosis of the skin may have an extremely heterogeneous clinical presentation, so that the definitions of 'great imitator' and 'clinical chameleon' have long been used. The factors that influence clinical picture and severity of the disease are probably linked to the etiopathogenesis of sarcoidosis, which continues to be shrouded in mystery. The current state of the art on the pathogenesis of sarcoidosis is that it is an immunological response in a genetically susceptible individual to an as-yet undefined antigenic stimulus. How exposure occurs in genetically predisposed patients is not completely clear, but the most likely explanation is that these agents or antigens are either inhaled into the lungs or enter through contact with the skin, as these are the common target organs that are constantly in contact with the environment. An autoimmune etiology of sarcoidosis could possibly occur through a process of molecular mimicry of infectious or other environmental antigens to host antigens. This could lead to a cross-mediated immune response and induction of autoimmune disease. This molecular mimicry may probably be responsible for the heterogeneous clinical presentations of the disease. Several investigations and studies have provided valuable evidence on the etiopathogenesis of sarcoidosis, which may lead to the future development of targeted and innovative treatment strategies. Nevertheless, we are still a long way from unravelling the underlying cause of this mysterious disease. PMID- 22527819 TI - Molecular epidemiology of Pseudomonas aeruginosa in cystic fibrosis patients from Southeast Austria. AB - Pseudomonas aeruginosa is the major pathogen in the cystic fibrosis (CF) lung, the predominant source of its acquisition, however, is under discussion. In order to study the molecular epidemiology, we evaluated 86 P. aeruginosa isolates from 43 CF patients from southeast Austria. The DiversiLab system was used to identify genetic relationships among the isolates. Antibiotic susceptibilities were tested with a broth microdilution method (Micronaut Merlin). A total of 39 unrelated P. aeruginosa genotypes were found of which 34 were unique to a single patient and one was unique to a sibling pair. We found low rates of resistance for beta lactams with resistance to piperacillin/tazobactam and ceftazidime ranging from 4 to 6%. Resistance rates for meropenem and ciprofloxacin were 11% and 15%, respectively. The prevalence of multidrug-resistant isolates was 2%. We conclude that the majority of P. aeruginosa isolates from CF patients originate from environmental sources and patient-to-patient spread is very uncommon in our centre. PMID- 22527820 TI - Leriche syndrome, a rare case of intractable hypertension. PMID- 22527818 TI - CK/CK-MB ratio as an indirect predictor for survival in polytraumatized patients. AB - BACKGROUND: Accurate assessment of injury severity is critical for decision making related to the prevention, triage, and treatment of several injured patients. Early estimation of mortality risk of critically injured patients is mandatory for adequate therapeutic strategies. Current risk stratification relies on clinical diagnosis and scoring systems. In our study, we hypothesized whether a simple laboratory test, the CK/CK-MB ratio, could help improving risk prediction in severely traumatized patients. METHODS: In a 9-year period, 328 nonselected trauma patients were included in our retrospective study at a Level I Trauma Center up to September 2002. Data for this study were obtained from our computerized trauma database, established in September 1992. RESULTS: In our study population, we could show a negative correlation between Injury Severity Score (ISS) and leukocytes. A positive correlation was detected for liver enzymes and CK-MB. The correlation between ISS and Na(+) was significant. No correlation between ISS, K(+), and Hb/Ht could be observed. Exitus was associated with ISS, alteration in thrombocytes, CK, CK-MB, CRP, Crea, and Na(+). CONCLUSION: In our study population, CK-MB levels showed a significant correlation with overall surveillance in polytraumatized patients. In our opinion, this might suggest that CK-MB levels could be taken as an indirect predictor for survival. Our findings need to be proven in further prospective clinical trials. PMID- 22527821 TI - Splenic decapsulation after gastroscopy. AB - Sanguineous splenic complications in elective treatment procedures remain a potentially life-threatening complication in patients of all age groups. In this case, the patient, as per her past medical history, underwent a laparoscopic appendectomy when she was admitted to the clinic. One of the diagnostic procedures to find the reason for the epigastric pain, a gastroscopy, can retrospectively be held responsible for decapsulation of the spleen. PMID- 22527822 TI - Rapid detection of bloodstream pathogens by real-time PCR in patients with sepsis. AB - Rapid detection of bloodstream infections is an important issue for a better patient outcome. The aim of our study was thus to evaluate the LightCycler SeptiFast assay for diagnosis of bloodstream pathogens in a tertiary hospital in Western Austria. The 71 blood samples of 61 patients with presumed sepsis were investigated and compared with conventional blood culture system results. In both assays, 51 samples (71.8 %) were negative. In 20 positive samples (28.2 %), 10 different pathogens were detected by either blood culture system or SeptiFast assay or by both methods. Five samples were positive in both assays. The agreement rate of blood culture system and SeptiFast assay was 78.9 %, the negative predictive value of SeptiFast assay versus blood culture system was 0.94, sensitivity was 0.63, and specificity 0.81. In 12 samples where a positive SeptiFast assay and a negative blood culture system result were obtained, the same pathogens as identified by SeptiFast assay were detected in samples from other body sites suggesting a correct positive detection. In 11.3 % of cases, the SeptiFast assay resulted in an adjustment of the patients' therapy. In 3 samples, the blood culture assay was positive whereas the SeptiFast assay yielded negative results. In two of these cases, the pathogens involved were not included in the SeptiFast detection list, in the third case SeptiFast assay failed to detect Candida glabrata.Thus we recommend the SeptiFast assay as a valuable tool for rapid diagnosis of bloodstream infections in addition to, but not as replacement for, the blood culture test. PMID- 22527823 TI - Self-perceived health, quality of life, and health-related behavior in obesity: is social status a mediator? AB - BACKGROUND: Obesity prevalence is increasing worldwide and is associated with a high health risk. Unfavorable psychological factors, lower self-ratings of health, and worse health-related behavior can be found in individuals with a low socioeconomic status (SES). Therefore, the aim of this study is to investigate whether obese subjects with a high SES differ from those with a low SES depending on these outcomes. METHODS: Data of the Austrian Health Interview Survey (ATHIS) 2006/2007-precisely of 760 obese subjects with a low SES and 851 with a high SES were analyzed stratified by sex and adjusted by age with regard to differences in self-perceived health, quality of life (regarding physical and psychological health, environment, and social relationships), and health-related behavior (smoking, alcohol consumption, eating behavior, physical exercise). RESULTS: The results have shown that obese subjects with a low SES differ significantly from those with a high SES in terms of self-perceived health, quality of life, and intensity of physical activities. Furthermore, differences were found in obese women as to smoking behavior, alcohol consumption, and continuance of physical exercise. CONCLUSION: It seems that not only obesity but also the socioeconomic status plays a role in health, and the risk assessment of obese individuals in the primary health care setting should include socioeconomic factors. Furthermore, public health programs which focus on obese subjects with a low SES are urgently needed. PMID- 22527824 TI - Can subacute thyroiditis be associated with acute hepatitis B virus infection? PMID- 22527825 TI - A case of acute myocardial infarction due to the use of cayenne pepper pills. AB - The use of weight loss pills containing cayenne pepper has ever been increasing. The main component of cayenne pepper pills is capsaicin. There are conflicting data about the effects of capsaicin on the cardiovascular system. In this paper, we present the case of a 41 year old male patient with no cardiovascular risk factors who took cayenne pepper pills to lose weight and developed acute myocardial infarction. PMID- 22527826 TI - Social inequalities regarding health and health behaviour in Austrian adults. AB - Studies have shown that people of a low socioeconomic status (SES) show worse health and health behaviour as well as a higher mortality rate than subjects with a high SES. Studies concerning the association between mortality and SES in Austrian adults have been conducted before, but not regarding specific variables which have an influence on mortality. Therefore the aim of our study was to investigate whether Austrian adults with a high versus low SES differ concerning ill health, health-related behaviour, quality of life as well as use of medical care. Data of 12,892 subjects from the Austrian Health Interview Survey (ATHIS) 2006/2007 were analysed concerning these outcomes. Subjects with low SES differ significantly from those with high SES in terms of health behaviour (e.g. eating behaviour, physical activity) and quality of life. They report significantly more diseases (e.g. cardiac infarction) and use health services more often. Low SES has a strong negative impact on health in Austrian adults. Therefore, in Austria a continued strong public health programme is required with absolute priority on low-SES groups. PMID- 22527828 TI - Adjacent level fracture after osteoporotic vertebral compression fracture: a nonrandomized prospective study comparing balloon kyphoplasty with conservative therapy. AB - BACKGROUND: In literature, there are conflicting clinical data regarding the incidence of subsequent fracture after balloon kyphoplasty (BK); moreover, the risk of adjacent vertebral fractures has not been well established because there are limited comparative data available with conservatively treated control groups. PURPOSE: The purpose of this prospective nonrandomized comparative study was to analyze the incidence and possible risk factors of adjacent level fracture comparing BK with conservative therapy. METHODS: Consecutive patients satisfying the inclusion criteria of acute vertebral fracture pain (occurring within 1-6 weeks of the event and not relieved by oral analgesia) and imaging criteria of acute fracture activity were enrolled. All patients meeting the inclusion criteria were offered BK. The patients who declined BK and agreed to longitudinal evaluation were treated conservatively and constituted the control group. RESULTS: In 3 out of 46 patients (6.5 %) treated with BK and in 10 out of 61 patients treated conservatively (16.4 %), the adjacent level fracture occurred within 1 year. The degree of local kyphosis and bone mineral density (BMD) were identified as important predictive factors for adjacent level fracture. CONCLUSION: These results indicated that BK carries a low risk of adjacent level fractures. Lower BMD values and altered biomechanics in the treated area of the spine due to resistant kyphosis are possible predictive factors for adjacent level fractures. A positive effect of BK over conventional treatment was observed upon reduction of the incidence of adjacent level fracture, vertebral morphology, and pain reduction. PMID- 22527829 TI - Efficacy of vitamin E and N-acetylcysteine in the prevention of contrast induced kidney injury in patients with chronic kidney disease: a double blind, randomized controlled trial. AB - BACKGROUND: Contrast induced acute kidney injury is one of the most frequent causes of hospital acquired acute kidney injury. The present study aims to investigate the efficacy of vitamin E or N-acetylcysteine as an adjunct to current standard therapy in the prevention of this clinical predicament. We tested the hypothesis that vitamin E or N-acetylcysteine added to standard therapy with 0.45 % saline is superior in preserving renal function in patients with chronic kidney disease stage 1-4 undergoing elective computer-assisted tomography with nonionic radiocontrast agents when compared to 0.45 % saline alone. DESIGN: Prospective, randomized, single-center, double-masked, double dummy, placebo-controlled, parallel clinical trial. METHODS: The patients were randomized to either vitamin E (total dose 2160 mg i.v.) or N-acetylcysteine (total dose 4800 mg p.o.) in addition to 0.45 % saline (1 mL/kg/h over 24 h) or saline alone. Serum creatinine change between baseline and 24 h after radiocontrast was the primary outcome. Contrast induced acute kidney injury was defined as a rise in serum creatinine > 25 % over the baseline value within 48 h. RESULTS: Thirty patients (mean age 74.6 years; 17 females; 9 diabetics; all Caucasians; mean serum creatinine 1.35 mg/dL; mean creatinine clearance 56 mL/min) were enrolled. No patient developed contrast induced acute kidney injury. There was no significant difference in serum creatinine change between the three study arms. CONCLUSION: Following radiocontrast administration, neither vitamin E nor N-acetylcystein in addition to saline demonstrated an additional beneficial effect on kidney function when compared to saline alone. PMID- 22527830 TI - Developmental diseases caused by impaired nucleotide sugar transporters. AB - Nucleotide sugar transporters play critical roles in glycosylation of proteins, lipids and proteoglycans, which are essential for organogenesis, development, mammalian cellular immunity and pathogenicity of human pathogenic agents. Functional deficiencies of these transporters result in global defects of glycoconjugates, which in turn lead to a diversity of biochemical, physiological and pathological phenotypes. In this short review, we will highlight human and bovine diseases caused by mutations of these transporters. PMID- 22527831 TI - Molecular discrimination of phytoseiids associated with the red palm mite Raoiella indica (Acari: Tenuipalpidae) from Mauritius and South Florida. AB - Phytoseiid populations imported from Mauritius for evaluation for a classical biological control program in Florida, USA, were morphologically identified as Amblyseius largoensis Muma, a species associated with the red palm mite in south Florida and the Caribbean. Bayesian analysis and sequence divergences of the mitochondrial 12S rRNA and nuclear Elongation factor--I alpha (EF-Ialpha) genes and Neighbor-Joining analysis of High-fidelity-RAPD-PCR markers were used to discriminate between the south Florida and Mauritius populations. High-fidelity RAPD-PCR markers in addition to Bayesian and sequence divergence analyses of the 12S rRNA sequences suggest that the Mauritius and south Florida populations are genetically different but whether these are species or population differences is unknown. The degenerate EF-Ialpha primers used to survey the phytoseiids amplified two different elongation factor sequences with distinct amino acid translations, the putative EF-Ialpha and an unknown elongation factor. Variability within the 12S gene was used to develop population-specific primers for identifying the Mauritius phytoseiids in the event they are released in south Florida. PMID- 22527832 TI - Changes in leaf physiology caused by Calacarus heveae (Acari, Eriophyidae) on rubber tree. AB - The influence of Calacarus heveae Feres on physiological processes was evaluated in two rubber tree clones. Experiments were conducted in a greenhouse with 5 month-old potted seedlings of RRIM 600 and GT 1 clones, that were either infested with C. heveae or not (non-infested control). The level of photosynthetic pigments, net photosynthetic rate, stomatal conductance, transpiration rate, changes in relative humidity between leaf surface and ambient air (Deltaw) and intercellular CO(2) concentration (Ci CO(2)) were evaluated. Infested plants showed significant reductions in the rate of transpiration, the rate of photosynthesis, stomatal conductance and Deltaw. RRIM 600 seedlings showed more pronounced physiological damage than GT 1 seedlings, indicating a lower physiological tolerance of the former clone to the mite. However, carotenoid levels were reduced only in GT 1 seedlings. Photosynthesis was probably reduced due to a decrease in stomatal opening, as indicated by reductions in transpiration rate and stomatal conductance and by the absence of differences in chlorophyll levels between treatments. Our results indicate that populations of C. heveae reduce the productivity of rubber trees. Thus, farmers must to be aware to control this mite pest in rubber tree plantations. PMID- 22527833 TI - The efficacy of four avermectins on the synanthropic mite Lepidoglyphus destructor under laboratory conditions. AB - The effect of four avermectins on the population growth of pest mite Lepidoglyphus destructor was tested in laboratory experiments. The avermectins (abamectin, doramectin, emamectin-benzoate and ivermectin) of analytical purity were incorporated into an experimental diet at the same molar concentrations, ranging from 0.16 to 8 nmol/3 g of diet. Using an initial population of 50 mites, the population growth was recorded after 21 days at 85 % relative humidity and 25 degrees C; 12 repeats were performed per avermectin concentration and control. The diets containing the avermectins successfully suppressed the population growth of L. destructor. The EC(50) recalculated to ng of substance per g of diet showed different suppressive effects of the avermectins: doramectin (181 ng/g diet), abamectin (299 ng/g diet), emamectin-benzoate (812 ng/g diet) and ivermectin (992 ng/g diet). Of the tested avermectins, abamectin is registered for the control of phytophagous mites and ivermectin against parasitic mites, i.e., Psoroptes ovis. Although emamectin-benzoate and ivermectin were less effective on L. destructor, all of the tested avermectins are highly suitable compounds for the control of synanthropic mites. PMID- 22527834 TI - Evaluation of the predatory mite Amblyseius hainanensis (Acari: Phytoseiidae) and artificial rainfall for the management of Brevipalpus obovatus (Acari: Tenuipalpidae). AB - Brevipalpus obovatus Donnadieu is an important pest mite on tea plants in South China. In the current study, predatory mites of B. obovatus in the tea gardens of Guangzhou were extensively surveyed. In total, 13 species of predatory mites (four families with seven genera) were recorded. The population proportion of Amblyseius hainanensis Wu et Qian was the highest (68.6 %), followed by that of Anystis baccarum (L.) (8.4 %) and A. theae Wu (6.3 %). The effects of starvation time, habitat size and pest population density on the predatory efficiency of the most dominant species, A. hainanensis, feeding on B. obovatus were assessed. In addition, the effectiveness of artificial rainfall in reducing B. obovatus populations was evaluated. After starvation for 48 h, the predatory efficiency of A. hainanensis was significantly higher than those that had been starved for 24 or 72 h when 30-50 B. obovatus eggs were made available. The predation of A. hainanensis on B. obovatus also increased with increasing prey density. The number of prey attacked by A. hainanensis in a 3.2 cm(2) habitat was significantly higher than in a 6.3 cm(2) habitat. The average predation of A. hainanensis was 31.7 eggs per day when offered 100 B. obovatus eggs on a tea leaf. This decreased to 17.8 eggs per day when four A. hainanensis shared 100 B. obovatus eggs. B. obovatus populations can be reduced by artificial rainfall, with the reduction affected by rainfall intensity. With an intensity of 40 mm in 15 min, 90.2 % mortality of B. obovatus occurred; lower mortalities were recorded (13.3 and 29.8 %) when the intensity was 2 or 4 mm in 15 min. Combination of the predatory mite A. hainanensis and artificial rainfall for the integrated pest management of B. obovatus is discussed. PMID- 22527835 TI - Effects of air temperature and water vapor pressure deficit on storage of the predatory mite Neoseiulus californicus (Acari: Phytoseiidae). AB - To determine the optimum air temperature and water vapor pressure deficit (VPD) for the storage of the predatory mite, Neoseiulus californicus, 3-day-old mated females were stored at air temperatures of 0, 5, 10, or 15 degrees C and VPDs of 0.1, 0.3, or 0.5 kPa for 10, 20, or 30 days. At 10 degrees C and 0.1 kPa, 83 % of females survived after 30 days of storage; this percentage was the highest among all conditions. VPDs of 0.3 and 0.5 kPa regardless of air temperature, and an air temperature of 0 degrees C regardless of VPD were detrimental to the survival of the females during storage. Since the highest survival was observed at 10 degrees C and 0.1 kPa, the effect of the storage duration on the post storage quality of the stored females and their progeny was investigated at 25 degrees C to evaluate the effectiveness of the storage condition. The oviposition ability of the stored females, hatchability, and sex ratio of their progeny were not affected even when the storage duration was extended to 30 days. Although a slight decrease in the survival during the immature stages of progeny was observed when the storage duration was >=20 days, the population growth of N. californicus may not be affected when individuals stored in these conditions are applied to greenhouses and agricultural fields. The results indicate that mated N. californicus females can be stored at 10 degrees C and 0.1 kPa VPD for at least 30 days. PMID- 22527836 TI - Consumption rate, functional response and preference of the predaceous mite Iphiseius degenerans to Tetranychus urticae and Eutetranychus orientalis. AB - The functional response of females of the phytoseiid mite, Iphiseius degenerans (Berlese), to increasing densities of females of its prey, Tetranychus urticae Koch and Eutetranychus orientalis Klein, on bean leaves, were studied under laboratory conditions. Our results indicated that the predator consumed significantly more items of E. orientalis than of T. urticae at all densities treatments. Daily consumption of the predator increased with increasing prey density until a plateau was reached-maximum number of prey consumed was ca. 4 for T. urticae and ca. 12 for E. orientalis. A Type II functional response was determined by a logistic regression model. The highest estimated value a (instantaneous rate of attack) and the lowest value of T ( h ) (handling time) were found for the predator feeding on E. orientalis. Prey selection was evaluated by simultaneously presenting both prey species to the predator in various ratios and at increasing densities. I. degenerans showed a higher predation rate and higher preference for E. orientalis at all the ratios and prey densities tested. This may be due to the smaller size or the inactivity of E. orientalis and the inability of the predator to cope with the webbing of T. urticae. Our results suggest that I. degenerans can be considered a suitable biological control candidate based on its preference for E. orientalis in the Mediterranean region. PMID- 22527837 TI - Can climate change jeopardize predator control of invasive herbivore species? A case study in avocado agro-ecosystems in Spain. AB - Climate change is one of the most important factors affecting the phenology, distribution, composition and diversity of organisms. In agricultural systems many pests and natural enemies are arthropods. As poikilotherm organisms, their body temperature is highly dependent on environmental conditions. Because higher trophic levels typically have lower tolerance to high temperatures than lower trophic levels, trends towards increasing local or regional temperatures may affect the strength of predator/prey interactions and disrupt pest control. Furthermore, increasing temperatures may create climate corridors that could facilitate the invasion and establishment of invasive species originating from warmer areas. In this study we examined the effect of environmental conditions on the dynamics of an agro-ecosystem community located in southern Spain, using field data on predator/prey dynamics and climate gathered during four consecutive years. The study system was composed of an ever-green tree species (avocado), an exotic tetranychid mite, and two native species of phytoseiid mites found in association with this new pest. We also present a climatological analysis of the temperature trend in the area of study during the last 28 years, as evidence of temperature warming occurring in the area. We found that the range of temperatures with positive per capita growth rates was much wider in prey than in predators, and that relative humidity contributed to explain the growth rate variation in predators, but not in prey. Predator and prey differences in thermal performance curves could explain why natural enemies did not respond numerically to the pest when environmental conditions were harsh. PMID- 22527839 TI - Temperature-related development and population parameters for Typhlodromus pyri (Acari: Phytoseiidae) found in Oregon vineyards. AB - The beneficial mite Typhlodromus pyri is a key predator of grapevine rust mite Calepitrimerus vitis in Pacific coastal vineyards. Rust mite feeding has been associated with damage such as stunted, deformed shoot growth and reductions in fruit yield. The life history traits of T. pyri were assessed at seven constant temperatures (12.5, 15, 17.5, 20, 25, 30 and 35 degrees C) to determine population parameters providing data to better predict biological control of C. vitis populations by T. pyri in vineyards. Successful development from the egg to adult stage was observed at temperatures ranging from 15 to 30 degrees C. Constant exposure to 12.5 and 35 degrees C resulted in 100 % mortality in immature T. pyri. Developmental times, fecundity and longevity were highest at 25 degrees C. The estimated minimum and maximum developmental thresholds were 7.24 and 42.56 degrees C, respectively. Intrinsic rate of increase (r ( m )) was positive from 15 to 30 degrees C indicating population growth within this range of temperatures. Net reproductive rate and intrinsic rate of increase were greatest at 25 degrees C. These developmental parameters can be used to estimate population growth, determine seasonal phenology and aid in conservation management of T. pyri. Results presented in this study will aid in evaluating the effectiveness of T. pyri as a key biological control agent of C. vitis during different periods of the growing season in Pacific Northwest vineyards. PMID- 22527838 TI - Crossbreeding between different geographical populations of the brown dog tick, Rhipicephalus sanguineus (Acari: Ixodidae). AB - Brown dog ticks are distributed world-wide, and their systematics and phylogeny are the subject of an ongoing debate. The present study evaluates the reproductive compatibility between Rhipicephalus sanguineus ticks from North America, Israel, and Africa. Female ticks of the parent generation were mated with males from the same and alternate colonies. Every pure and hybrid cohort was maintained separately into the F2 generation with F1 females being allowed to mate only with males from the same cohort. The following survival parameters were measured and recorded for every developmental stage: feeding duration and success; engorgement weight, fertility, and fecundity of females; molting and hatching success. Ticks from North American and Mediterranean populations hybridized successfully. The survival parameters of all their hybrid lines were similar to those in pure lines throughout the F1 generation, and F1 adults were fully fertile. Parent adult ticks from the African population hybridized with either North American or Mediterranean ticks and produced viable progenies whose survival parameters were also similar to those in pure lines throughout the F1 generation. However, F1 adults in the four hybrid lines that included African ancestry were infertile. No parthenogenesis was observed in any pure or hybrid lines as proportion of males in F1 generation ranged from 40 to 60 %. Phylogenetic analysis of the 12S rDNA gene sequences placed African ticks into a separate clade from those of the North American or Mediterranean origins. Our results demonstrate that Rh. sanguineus ticks from North America and Israel represent the same species, whereas the African population used in this study is significantly distant and probably represents a different taxon. PMID- 22527840 TI - Variable clinical responses of a scrub typhus outbred mouse model to feeding by Orientia tsutsugamushi infected mites. AB - Rodents are the natural hosts for Leptotrombidium mites that transmit Orientia tsutsugamushi, the causative agent of scrub typhus, a potentially fatal febrile human disease. Utilizing mite lines that included O. tsutsugamushi infected and non-infected Leptotrombidium species we investigated the varied infection response of outbred mice (ICR) exposed to L. chiangraiensis (Lc), L. imphalum (Li) and L. deliense (Ld). Each of six mite lines (Lc1, Lc5, Li3, Li4, Li7 and Ld) was separately placed in the inner ears of ICR mice either as a single individual (individual feeding, IF) or as a group of 2-4 individuals (pool feeding, PF). The species of infected chigger feeding on mice significantly affected mortality rates of the mice, with mite lines of Lc causing higher mean (+/-SE) mortality (90.7 +/- 3.6 %) than mite lines of Li (62.9 +/- 5.6 %) or Ld (53.6 +/- 5.8 %). Mouse responses which included time to death, food consumption and total mice weight change depended on mite species and their O. tsutsugamushi genotype, more than on feeding procedure (IF vs. PF) except for mite lines within the Lc. Infected mite lines of Lc were the most virulent infected mites assessed whereas the infected Ld species was the least virulent for the ICR. Mice killed by various mite lines showed enlarged spleens and produced ascites. The results of this investigation of the clinical responses of ICR mice to feeding by various infected mite lines indicated that the different species of infected mites and their O. tsutsugamushi genotype produced different clinical presentations in ICR mice, a scrub typhus mouse model which mimics the natural transmission of O. tsutsugamushi that is critical for understanding scrub typhus disease in terms of natural transmission, host-pathogen-vector interaction and vaccine development. PMID- 22527841 TI - A high-performance humidity control system for tiny animals: demonstration of its usefulness in testing egg hatchability of the two-spotted spider mite, Tetranychus urticae. AB - We developed a computer-based system for controlling water vapor conditions (i.e., humidity) using a two-flow method in which streams of humidified and dehumidified air were combined in an acrylic container. The flow rate of each stream was independently controlled to adjust relative humidity (RH). In this system, humidification from 15 to 90 % RH and dehumidification from 90 to 15 % RH at an air temperature (AT) of 25 degrees C were properly operated with short time constants of 4.3 and 10 min, respectively. Tetranychus urticae egg hatchability was then examined at 20-95 % RH and 25 degrees C AT. The coefficients of variation of RH were low (0.3-1.5 %). Egg hatchability in a polystyrene Petri dish was lower at 20 % RH than at 70-95 % RH. A delay in hatching was also observed at 70 % RH for eggs tested on a leaf disk placed on water-soaked cotton; this delay was attributed to the AT being 1.4 degrees C lower on the leaf surface than on the inner surface of the dish. Our system is expected to be useful for further examination of ecological and behavioral responses in pest mites and for developing novel physical control measures using water vapor. PMID- 22527842 TI - Effect of silicon deficiency on secondary cell wall synthesis in rice leaf. AB - Rice (Oryza sativa L.) is a typical Si-accumulating plant and is able to accumulate Si up to >10 % of shoot dry weight. The cell wall has been reported to become thicker under Si-deficient condition. To clarify the relationship between Si accumulation and cell wall components, the physical properties of, and macromolecular components and Si content in, the pectic, hemicellulosic, and cellulosic fractions prepared from rice seedlings grown in hydroponics with or without 1.5 mM silicic acid were analyzed. In the absence of Si (the -Si condition), leaf blades drooped, but physical properties were enhanced. Sugar content in the cellulosic fraction and lignin content in the total cell wall increased under -Si condition. After histochemical staining, there was an increase in cellulose deposition in short cells and the cell layer just beneath the epidermis in the -Si condition, but no significant change in the pattern of lignin deposition. Expression of the genes involved in secondary cell wall synthesis, OsCesA4, OsCesA7, OsPAL, OsCCR1 and OsCAD6 was up-regulated under -Si condition, but expression of OsCesA1, involved in primary cell wall synthesis, did not increase. These results suggest that an increase in secondary cell wall components occurs in rice leaves to compensate for Si deficiency. PMID- 22527843 TI - Pyridine metabolism in tea plants: salvage, conjugate formation and catabolism. AB - Pyridine compounds, including nicotinic acid and nicotinamide, are key metabolites of both the salvage pathway for NAD and the biosynthesis of related secondary compounds. We examined the in situ metabolic fate of [carbonyl (14)C]nicotinamide, [2-(14)C]nicotinic acid and [carboxyl-(14)C]nicotinic acid riboside in tissue segments of tea (Camellia sinensis) plants, and determined the activity of enzymes involved in pyridine metabolism in protein extracts from young tea leaves. Exogenously supplied (14)C-labelled nicotinamide was readily converted to nicotinic acid, and some nicotinic acid was salvaged to nicotinic acid mononucleotide and then utilized for the synthesis of NAD and NADP. The nicotinic acid riboside salvage pathway discovered recently in mungbean cotyledons is also operative in tea leaves. Nicotinic acid was converted to nicotinic acid N-glucoside, but not to trigonelline (N-methylnicotinic acid), in any part of tea seedlings. Active catabolism of nicotinic acid was observed in tea leaves. The fate of [2-(14)C]nicotinic acid indicates that glutaric acid is a major catabolite of nicotinic acid; it was further metabolised, and carbon atoms were finally released as CO(2). The catabolic pathway observed in tea leaves appears to start with the nicotinic acid N-glucoside formation; this pathway differs from catabolic pathways observed in microorganisms. Profiles of pyridine metabolism in tea plants are discussed. PMID- 22527844 TI - Lipid class and fatty acid content of the leptocephalus larva of tropical eels. AB - The leptocephalus larva of eels distinguishes the elopomorph fishes from all other bony fishes. The leptocephalus is long lived and increases in size primarily through the synthesis and deposition of glycosaminoglycans. Energy stored during the larval stage, in the form of glycosaminoglycan and lipids, is required to fuel migration, metamorphosis and metabolism of the subsequent glass eel stage. Despite the importance of energy storage by leptocephali for survival and recruitment, their diet, condition and lipid content and composition is essentially unknown. To gain further insight into energy storage and condition of leptocephali, we determined the lipid class and fatty acid concentration of larvae collected on a cross-shelf transect off Broome, northwestern Australia. The total lipid concentration of two families and four sub-families of leptocephali ranged from 2.7 to 7.0 mg g wet weight(-1), at the low end of the few published values. Phospholipid and triacylglycerol made up ca. 63 % of the total lipid pool. The triacylglycerol:sterol ratio, an index of nutritional condition, ranged from 0.9 to 3.7, indicating that the leptocephali were in good condition. The predominant fatty acids were 16:0 (23 mol%), 22:6n-3 (docosahexaenoic acid, DHA, 16 mol%), 18:0 (8.2 mol%), 20:5n-3 (eicosapentaenoic acid, EPA, 6.7 mol%), 18:1n-9 (6.4 mol%) and 16:1n-7 (6.3 mol%). The DHA:EPA ratio ranged from 2.4 to 2.9, sufficient for normal growth and development of fish larvae generally. The leptocephali had proportions of bacterial markers >4.4 %, consistent with the possibility that they consume appendicularian houses or other marine snow that is bacteria rich. PMID- 22527845 TI - Low docosahexaenoic acid content in plasma phospholipids is associated with increased non-alcoholic fatty liver disease in China. AB - A large proportion of the Chinese population is now at risk of non-alcoholic fatty liver disease (NAFLD). We aimed to investigate the relationship between plasma phospholipids (PL) fatty acids and the risk of NAFLD. One hundred NAFLD patients and 100 healthy subjects were recruited in Hangzhou, China. Plasma PL and selected biochemical and hematological parameters were analyzed by using standard methods. Stepwise logistic regression was used to identify independent risk factors of NAFLD. Plasma PL total saturated fatty acid (SFA), C20:3n-6, serum alanine aminotransferase, high-density lipoprotein cholesterol, and body mass index were independent risk factors of NAFLD. The risk of NAFLD was significantly increased with higher quartiles of plasma PL total SFA (P for trend = 0.028) and C20:3n-6 (P for trend <0.001); plasma PL docosahexaenoic acid (C22:6n-3) was significantly lower in NAFLD patients than in controls (P = 0.032) and the OR of NAFLD in the highest quartile of C22:6n-3 was 0.41 (95 % CI = 0.17 0.97) compared with the lowest quartile. In conclusion, plasma PL total SFA and C20:3n-6 are positively correlated with the risk of NAFLD, while C22:6n-3 is negatively correlated with the risk of NAFLD. PMID- 22527846 TI - Experience with combination of docetaxel, cisplatin plus 5-fluorouracil chemotherapy, and intensity-modulated radiotherapy for locoregionally advanced nasopharyngeal carcinoma. AB - BACKGROUND: Our aim was to evaluate the efficacy and toxicity of cisplatin, fluorouracil, and docetaxel chemotherapy plus intensity-modulated radiotherapy (IMRT) for locoregionally advanced nasopharyngeal carcinoma (NPC). METHODS: Sixty patients with locoregionally advanced NPC were enrolled. Patients received IMRT plus three courses of neoadjuvant chemotherapy and two courses of adjuvant chemotherapy consisting of docetaxel (60 mg/m(2)/day on day 1), cisplatin (25 mg/m(2)/day on days 1-3), and 5-fluorouracil (500 mg/m(2)/day on days 1-3). RESULTS: The overall response rate to neoadjuvant chemotherapy was 89 %. Three months after the completion of radiotherapy, 53 (93 %) patients achieved complete regression, 3 (5 %) achieved partial response (PR), and 1 experienced liver metastasis. However, among the 3 PR patients, 2 patients had no evidence of relapse in the follow-up. With a median follow-up of 27 months (range, 6-43), the 2-year estimated locoregional failure-free survival, distant failure-free survival, progression-free survival, and overall survival were 96.6, 93.3, 89.9, and 98.3 %, respectively. Leukopenia was the main adverse effect in chemotherapy; 14 patients experienced grade 3 or grade 4 neutropenia, and 1 patient developed febrile neutropenia. The nonhematological adverse events included alopecia, nausea, vomiting, anorexia, and diarrhea. The incidence of grade 3 acute radiotherapy-related mucositis was 28.3 %; no grade 4 acute mucositis was observed. No grade 3 or grade 4 hematological toxicity occurred during radiotherapy. None of the patients had interrupted radiotherapy. The common late adverse effects included xerostomia and hearing impairment. CONCLUSIONS: Neoadjuvant-adjuvant chemotherapy using cisplatin, fluorouracil, plus docetaxel combined with IMRT was an effective and well-tolerated alternative for advanced NPC. PMID- 22527847 TI - Circulating cell-free human telomerase reverse transcriptase mRNA in plasma and its potential diagnostic and prognostic value for gastric cancer. AB - BACKGROUND: Our aims were to detect circulating cell-free human telomerase reverse transcriptase (hTERT) mRNA in the plasma of gastric cancer patients and evaluate its potential diagnostic and prognostic value. METHODS: Real-time quantitative reverse transcription-polymerase chain reaction was employed to detect circulating cell-free hTERT mRNA from 118 gastric cancer patients, 40 chronic atrophic gastritis (CAG) patients, and 58 healthy controls. RESULTS: Circulating cell-free hTERT mRNA was detected in all gastric cancer patients, 39 (97.5 %) CAG patients and 56 (96.6 %) healthy control individuals, respectively. However, it was higher in gastric cancer than in CAG and healthy controls (all at P < 0.05). Moreover, its high level was significantly correlated with clinical stages (P < 0.001) and lymph nodes metastasis (P < 0.001). There was no difference between circulating cell-free mRNA and other parameters. The area under the receiver operating characteristic (ROC) curve was 0.891, and the optimal cut-off point was 0.18, providing a sensitivity of 66 % and a specificity of 87 %. The ROC analysis showed that the diagnosis capability of circulating cell-free mRNA was statistically significantly higher than that of carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA19-9), alone [CEA (0.656); CA19-9 (0.722)] or in combination (0.756). Kaplan-Meier analysis demonstrated a correlation between increased circulating cell-free hTERT mRNA and reduced disease-free survival (P < 0.001) and overall survival (P < 0.001). Cox analysis indicated that it was an independent prognostic factor for disease-free survival and overall survival. CONCLUSIONS: We concluded that circulating cell free hTERT mRNA might serve as a potential and useful noninvasive tumor marker for gastric cancer. PMID- 22527848 TI - The relationship between urinary bisphenol A levels and meningioma in Chinese adults. AB - BACKGROUND: Estrogen has been implicated as a risk factor for meningioma. Bisphenol A (BPA), a widely used synthetic xenoestrogen, has already been reported to be associated with several estrogen-sensitive tumors. METHOD: An exploratory association study of 243 meningioma cases and 258 frequency-matched healthy controls was conducted, using subjects from a hospital-based study to demonstrate the association of urine BPA concentration and the risk of meningioma. The specimens and data of patients were collected at Union Hospital, Wuhan, China, from 2009 to 2010. RESULTS: A positive association between increasing levels of urinary BPA and meningioma was observed, independent of confounding factors such as gender, age, race, body mass index, HRT use, BMI, and family history of cancer. Compared to quartile 1 (referent), the multivariate adjusted odds ratio of meningioma associated with quartile 4 was 1.45 (95 % CI, 1.02-1.98) (P trend = 0.03). CONCLUSION: In this case-control study from China, a clear association between urinary BPA concentrations and diagnosis of meningioma was detected. PMID- 22527849 TI - Proliferation and chondrogenic differentiation potential of menstrual blood- and bone marrow-derived stem cells in two-dimensional culture. AB - Menstrual blood is easily accessible, renewable, and inexpensive source of stem cells. In this study, we investigated the chondrogenic differentiation potential of menstrual blood-derived stem cells (MenSCs) compared with that of bone marrow derived stem cells (BMSCs) in two-dimensional culture. Following characterization of isolated cells, the potential for chondrogenic differentiation of MenSCs and BMSCs was evaluated by immunocytochemical and molecular experiments. MenSCs were strongly positive for mesenchymal stem cell markers in a manner similar to that of BMSCs. In contrast to BMSCs, MenSCs exhibited marked expression of OCT4, and higher proliferative capacity. Differentiated MenSCs showed strong immunoreactivity to a monoclonal antibody against Collagen type 2, in a pattern similar to BMSCs. Accumulation of proteoglycans in differentiated MenSCs was also comparable with that in differentiated BMSCs. However, the mRNA expression patterns as judged by RT-PCR of chondrogenic markers such as Collagen 2A1, Collagen 9A1 and SOX9 in MenSCs were different from those in BMSCs. Given these findings, MenSCs appear to be a unique stem cell population with higher proliferation than and comparable chondrogenic differentiation ability to BMSCs in two-dimensional culture. Much quantitative studies at the molecular level may elucidate the reasons for the observed differences in MenSCs and BMSCs. PMID- 22527850 TI - Chronic myeloid leukaemia and human immunodeficiency virus (HIV) infection. AB - The occurrence of chronic myeloid leukaemia (CML) in patients infected with the human immunodeficiency virus (HIV) has rarely been reported in the literature. In this report, we describe the experience of a single centre in the management of 10 such patients, including demographic information, disease characteristics and response to therapy. We had a black female predominance in our series, with only a minority of patients achieving a complete cytogenetic response. The main reason for this appears to be compliance, which was influenced by distance to the treating centre. The side-effect profile was similar to that expected, with the exception of one patient who developed a drug rash with eosinophilia and systemic symptoms. Although CML patients co-morbid for HIV face certain unique challenges when compared to non-infected patients, their long-term outcome can be positive when appropriately managed. PMID- 22527851 TI - Vascular endothelial growth factor corrected for platelet count and hematocrit is associated with the clinical course of aplastic anemia in children. AB - The wide variety of clinical courses that lead to the development of severe aplastic anemia (AA) makes it difficult to speculate whether treatment for AA is required in the early phase. The objective of this study was to identify a method for predicting the clinical course of AA at the onset of the disease. First, in healthy adults, vascular endothelial growth factor (VEGF) released per platelet was measured by the activation of platelet-rich plasma (PRP) and platelet-poor plasma (PPP). Serum concentration of VEGF, serum concentration of VEGF corrected for platelet count, and serum concentration of VEGF corrected for both platelet count and hematocrit (corrected VEGF) were then compared to VEGF released per platelet. Corrected VEGF showed the best correlation with VEGF released per platelet by the activation of PRP in healthy subjects (R (2) = in a single 0.806, p = 0.001). Next, corrected VEGF was assayed in 11 pediatric patients with AA at the time of diagnosis. Corrected VEGF in AA patients was significantly greater than that in age-matched control subjects [1.32 * 10(-6) pg (range 0.36-1.85) vs. 0.18 * 10(-6) pg (range 0.12-0.94)] (p = 0.002). Moreover, corrected VEGF in AA patients who did not require treatment for more than 2 years was significantly greater than that in AA patients who required earlier treatment [1.67 * 10(-6) pg (range 1.32-1.85) vs. 0.87 * 10(-6) pg (0.36-1.34)] (p = 0.011). These data indicate that a compensatory mechanism for increasing VEGF and preventing disease progression might play a role in AA. Corrected VEGF may be useful for predicting the clinical course of AA. PMID- 22527852 TI - Pituitary lymphoma developing within pituitary adenoma. AB - Lymphoma occurring in the pituitary gland is an exceedingly infrequent event. Here, we describe a case of pituitary lymphoma complicating recurrent pituitary adenoma. A 56-year-old male with a history of pituitary adenoma was diagnosed with diffuse large B-cell lymphoma (DLBCL) of the left ocular adnexa, which was successfully treated by standard chemotherapy and local radiotherapy. Eight months later, he complained of diplopia and bitemporal hemianopia. Brain magnetic resonance imaging detected a suprasellar tumor. Transsphenoidal biopsy of the mass was performed, and histopathological examination revealed DLBCL admixed with pituitary adenoma. On a review of the literature, we found that pituitary lymphoma developing within adenoma is a recurrent phenomenon. The composite tumor is likely to be characterized by suprasellar involvement and presentation of visual disturbances. Moreover, in the present case, the suprasellar tumor remained visible after autologous peripheral stem cell transplant, likely due to the residual pituitary adenoma. We therefore recommend that refractory pituitary lymphoma should be vigorously biopsied in search of possibly underlying adenoma. PMID- 22527853 TI - T-cell prolymphocytic leukemia in Japan: is it a variant? AB - T-cell prolymphocytic leukemia (T-PLL) is characterized by a post-thymic immunophenotype, salient chromosome abnormalities, and an aggressive clinical course. However, cases in which these features are absent have been occasionally reported in Japan. Here, clinical and biological features of 13 T-PLL cases, diagnosed between 1992 and 2009 in the Tohoku region of Japan, were compared with three Western series. Median age was 64 (range 40-78) years old, and the male to female ratio (12:1) was higher than that of the Western series (P < 0.04). Presented manifestations were similar to those of Western cases, but central nervous system involvement, which is rare in Western cases, was observed in 3 of 13 cases (23 %) (P < 0.04). Immunophenotypic patterns were similar to those of Western cases, but HLA-DR was positive in 6 of 9 cases (67 %), which is distinct from Western cases (0-9 %) (P < 0.002). By chromosome analyses, 14q11 abnormality and trisomy 8q, which are common among Western cases (70-80 %), were not observed in any cases (P < 0.002). Morphologically, seven were classified as typical type, five as a small-cell variant, and one as a cerebriform variant. Seven cases experienced an aggressive course, whereas six experienced an indolent course over a median follow-up of 50 months. In contrast to Western cases, clinical courses were closely correlated with morphological types; 86 % of typical types were aggressive, whereas 83 % of small-cell types were indolent (P = 0.025). On the basis of these observations, together with previous Japanese cases in the literature, we propose that Japanese cases of T-PLL may constitute a variant. PMID- 22527854 TI - Excellent outcome of allogeneic bone marrow transplantation for Fanconi anemia using fludarabine-based reduced-intensity conditioning regimen. AB - Fanconi anemia (FA) is a disorder characterized by developmental anomalies, bone marrow failure and a predisposition to malignancy. It has recently been shown that hematopoietic stem cell transplantation using fludarabine (FLU)-based reduced-intensity conditioning is an efficient and quite safe therapeutic modality. We retrospectively analyzed the outcome of bone marrow transplantation (BMT) in eight patients with FA performed in two institutes between 2001 and 2011. There were seven females and one male with a median age at diagnosis = 4.5 years (range 2-12 years). The constitutional characteristics associated with FA, such as developmental anomalies, short stature and skin pigmentation, were absent in three of the patients. One patient showed myelodysplastic features at the time of BMT. All patients received BMT using FLU, cyclophosphamide (CY) and rabbit anti-thymocyte globulin (ATG) either from a related donor (n = 4) or an unrelated donor (n = 4). Acute graft-versus-host disease (GVHD) of grade I developed in one patient, while chronic GVHD was not observed in any patient. All patients are alive and achieved hematopoietic recovery at a median follow-up of 72 months (range 4-117 months). BMT using FLU/low-dose CY/ATG -based regimens regardless to the donor is a beneficial therapeutic approach for FA patients. PMID- 22527855 TI - Hepatosplenic alphabeta T-cell lymphoma associated with azathioprine therapy. PMID- 22527856 TI - Persistent thrombocytosis in elderly patients with rare hyposplenias that mimic essential thrombocythemia. AB - When elderly patients present with persistent thrombocytosis, myeloproliferative disease, iron-deficiency anemia or post-splenectomy status are suspected along with autoimmune diseases. Reported here are the cases of two elderly patients with persistent thrombocytosis due to hyposplenia, which is very rarely diagnosed in old age. Case 1 was a 72-year-old man whose thrombocytosis was due to non familial type isolated congenital asplenia. Case 2 was a 74-year-old man whose thrombocytosis was caused by an atrophied spleen resulting from perforated stomach ulcer-related panperitonitis that had been treated 20 years previously. Both patients had thrombocyte counts exceeding >500,000/MUl in association with small vestigial spleen tissue on a computed tomography scan and positive Howell Jolly bodies on the blood smear. A correct diagnosis is essential for the management of persistent thrombocytosis. PMID- 22527857 TI - Alcoholic extract of Bacopa monniera Linn. protects against 6-hydroxydopamine induced changes in behavioral and biochemical aspects: a pilot study. AB - Parkinson's disease is one of the commonest neurodegenerative diseases, and oxidative stress has been evidenced to play a vital role in its causation. In this study, we evaluated whether alcoholic extract of Bacopa monniera (AEBM), an antioxidant and memory enhancer can slow the neuronal injury in a 6-OHDA-rat model of Parkinson's. Rats were treated with 20 and 40 mg/kg bodyweight of AEBM for 3 weeks. On Day 21, 2 MUl of 6-OHDA (12 MUg in 0.01 % in ascorbic acid saline) was infused into the right striatum, while the control group received 2 MUl of vehicle. Three weeks after the 6-OHDA injection, the rats were tested for neurobehavioral activity (rotarod, locomotor activity, grip test, forced swim test, radial arm maze) and were killed after 6 weeks for the estimation of lipid peroxidation, reduced glutathione (GSH) content, activities of glutathione-S transferase, glutathione reductase, glutathione peroxidase, superoxide dismutase (SOD), and catalase (CAT). The deficits in behavioral activity due to 6-OHDA lesioning were significantly and dose dependently restored by AEBM. Lesioning was followed by an increased lipid peroxidation and significant depletion of reduced GSH content in the substantia nigra, which was prevented with AEBM pretreatment. The activities of GSH-dependent enzymes, CAT and SOD in striatum were reduced significantly by lesioning, which were restored significantly and dose dependently by AEBM. This study indicates that the extract of B. monniera might be helpful in attenuating 6-OHDA-induced lesioning in rats. PMID- 22527858 TI - The vasopressin-deficient Brattleboro rat: lessons for the hypothalamo-pituitary adrenal axis regulation. AB - Adaptation to stress is indispensable to life and the hypothalamo-pituitary adrenocortical axis is one of the major components of the adaptation. The hypothalamic component consists of corticotropin-releasing hormone and arginine vasopressin, with a questionable contribution of the latter. Vasopressin was more important in the regulation of the adrenocorticotropin secretion in the perinatal vasopressin-deficient Brattleboro rats than in adulthood, where its role depended on the nature of the stressor encountered. In adults, the vasopressin deficiency did not influence the development of chronic stress response. In the neonatal rats, the role of vasopressin was supported by the inhibitory action of a V1b antagonist and vasopressin antiserum. As the corticosterone response to stress did not follow the adrenocorticotropin levels, we assume the presence of an adrenocorticotropin independent adrenal gland regulation in the neonates. We have shown that the apparent dissociation of the corticosterone and adrenocorticotropin responses is not due to the different time course of the two hormone responses, to different level of the corticosterone binding globulin or to changes in the adrenal gland sensitivity. In vitro experiments point to the contribution of beta-adrenoceptors in the process. It was also confirmed by in vivo tests using the vasopressin-deficient Brattleboro pup as a model organism, where corticosterone levels may rise without adrenocorticotropin level changes. Another important question is the role of adrenocorticotropin beyond the corticosterone secretion regulation, which could be supposed, e.g., in cardiovascular events, immunological processes, and metabolism. We can conclude that Brattleboro rats gave us much information about the stress-axis regulation far beyond the role of vasopressin itself. PMID- 22527859 TI - Time-course of hypothalamic-pituitary-adrenal axis activity and inflammation in juvenile rat brain after cranial irradiation. AB - Recent studies reported that exposure of juvenile rats to cranial irradiation affects hypothalamic-pituitary-adrenal (HPA) axis stability, leading to its activation along with radiation-induced inflammation. In the present study, we hypothesized whether inflammatory reaction in the CNS could be a mediator of HPA axis response to cranial irradiation (CI). Therefore, we analyzed time-course changes of serum corticosterone level, as well IL-1beta and TNF-alpha level in the serum and hypothalamus of juvenile rats after CI. Protein and gene expression of the glucocorticoid receptor (GR) and nuclear factor kappaB (NFkappaB) were examined in the hippocampus within 24 h postirradiation interval. Cranial irradiation led to rapid induction of both GR and NFkappaB mRNA and protein in the hippocampus at 1 h. The increment in NFkappaB protein persisted for 2 h, therefore NFkappaB/GR protein ratio was turned in favor of NFkappaB. Central inflammation was characterized by increased IL-1beta in the hypothalamus, with maximum levels at 2 and 4 h after irradiation, while both IL-1beta and TNF-alpha were undetectable in the serum. Enhanced hypothalamic IL-1beta probably induced the relocation of hippocampal NFkappaB to the nucleus and decreased NFkappaB mRNA at 6 h, indicating promotion of inflammation in the key tissue for HPA axis regulation. Concomitant increase of corticosterone level and enhanced GR nuclear translocation in the hippocampus at 6 h might represent a compensatory mechanism for observed inflammation. Our results indicate that acute radiation response is characterized by increased central inflammation and concomitant HPA axis activation, most likely having a role in protection of the organism from overwhelming inflammatory reaction. PMID- 22527861 TI - Construction of an infectious clone of human adenovirus type 41. AB - Human adenovirus type 41 (HAdV-41) is well known for its fastidiousness in cell culture. To construct an infectious clone of HAdV-41, a DNA fragment containing the left and right ends of HAdV-41 as well as a kanamycin resistance gene and a pBR322 replication origin was excised from the previously constructed plasmid pAd41-GFP. Using homologous recombination, the plasmid pKAd41 was generated by co transformation of the E. coli BJ5183 strain with this fragment and HAdV-41 genomic DNA. Virus was rescued from pKAd41-transfected 293TE7 cells, a HAdV-41 E1B55K-expressing cell line. The genomic integrity of the rescued virus was verified by restriction analysis and sequencing. Two fibers on the virion were confirmed by western blot. Immunofluorescence showed that more expression of the hexon protein could be found in 293TE7 cells than in 293 cells after HAdV-41 infection. The feature of non-lytic replication was preserved in 293TE7 cells, since very few progeny HAdV-41 viruses were released to the culture medium. These results show that pKAd41 is an effective infectious clone and suggest that the combination of pKAd41 and 293TE7 cells is an ideal system for virological study of HAdV-41. PMID- 22527862 TI - Mesoniviridae: a proposed new family in the order Nidovirales formed by a single species of mosquito-borne viruses. AB - Recently, two independent surveillance studies in Cote d'Ivoire and Vietnam, respectively, led to the discovery of two mosquito-borne viruses, Cavally virus and Nam Dinh virus, with genome and proteome properties typical for viruses of the order Nidovirales. Using a state-of-the-art approach, we show that the two insect nidoviruses are (i) sufficiently different from other nidoviruses to represent a new virus family, and (ii) related to each other closely enough to be placed in the same virus species. We propose to name this new family Mesoniviridae. Meso is derived from the Greek word "mesos" (in English "in the middle") and refers to the distinctive genome size of these insect nidoviruses, which is intermediate between that of the families Arteriviridae and Coronaviridae, while ni is an abbreviation for "nido". A taxonomic proposal to establish the new family Mesoniviridae, genus Alphamesonivirus, and species Alphamesonivirus 1 has been approved for consideration by the Executive Committee of the ICTV. PMID- 22527863 TI - Inhibition of HSV-1 by chemoattracted neutrophils: supernatants of corneal epithelial cells (HCE) and macrophages (THP-1) treated with virus components chemoattract neutrophils (PMN), and supernatants of PMN treated with these conditioned media inhibit viral growth. AB - The role of PMNs (neutrophils) in corneal herpes was studied using an in vitro system. Human corneal cells (HCE) and macrophages (THP-1) infected with HSV-1 or treated with virus components (DNA or virus immune complexes) released chemokines, which attracted PMNs. Highly reactive oxygen species were detected in PMNs. PMNs inhibited HSV when overlaid onto infected HCE cells (50:1). PMNs incubated with the supernatants of HCE cells treated with virus components released H(2)O(2) and myeloperoxidase. These inhibited virus growth. PMNs released NO and MIG, which may differentiate CD4 T cells to Th1. PMNs participate in innate immune responses, limit virus growth, and initiate immunopathology. PMID- 22527864 TI - The genome sequence of lettuce necrotic stunt virus indicates a close relationship to Moroccan pepper virus. AB - Lettuce necrotic stunt virus (LNSV) causes severe losses to lettuce production in the western United States, which results in stunting, necrosis and death on all non-crisphead lettuces, as well as flower abortion and yield losses in greenhouse tomato production. The genome of LNSV was sequenced and has an organization typical of viruses of the genus Tombusvirus. Sequence comparisons indicated that much of the genome is relatively closely related to tomato bushy stunt virus; however, the coat protein is very closely related to that of isolates of Moroccan pepper virus (MPV). PMID- 22527865 TI - Live cell imaging fails to support viral-protein-mediated intercellular trafficking. AB - The herpes simplex virus type I protein VP22 has been reported to have the property of intercellular trafficking. However, there is little direct evidence to demonstrate that VP22 can shuttle freely between living cells. Here, we employ a novel and simple assay using live cell fluorescence microscopy to investigate the intercellular transport property. Our results demonstrated that VP22, bovine herpesvirus-1 VP22, HSV-1 US11 and HIV Tat could not shuttle into neighboring cells via direct contact. PMID- 22527866 TI - Resistance to Bombyx mori nucleopolyhedrovirus via overexpression of an endogenous antiviral gene in transgenic silkworms. AB - Transgenic technology is a powerful tool for improving disease-resistant species. Bmlipase-1, purified from the midgut juice of Bombyx mori, showed strong antiviral activity against B. mori nucleopolyhedrovirus (BmNPV). In an attempt to create an antiviral silkworm strain for sericulture, a transgenic vector overexpressing the Bmlipase-1 gene was constructed under the control of a baculoviral immediate early-1 (IE1) promoter. Transgenic lines were generated via embryo microinjection. The mRNA level of Bmlipase-1 in the midguts of the transgenic line was 27.3 % higher than that of the non-transgenic line. After feeding the silkworm with different amounts of BmNPV, the mortality of the transgenic line decreased to approximately 33 % compared with the non-transgenic line when the virus dose was 10(6) OB/larva. These results imply that overexpressing endogenous antiviral genes can enhance the antiviral resistance of silkworms. PMID- 22527867 TI - Genetic characterization of astroviruses detected in guinea fowl (Numida meleagris) reveals a distinct genotype and suggests cross-species transmission between turkey and guinea fowl. AB - Astroviruses can infect mammalian and avian species and are often responsible for gastroenteric disease symptoms. In this study, the complete open reading frame (ORF) 2, the 3' end of ORF1b and the corresponding intergenic region of astroviruses identified in farmed guinea fowl (Numida meleagris) were sequenced and genetically analysed. Overall, the genetic sequence of guinea fowl astroviruses was related to turkey astrovirus type 2 (TastV2), although a marked genetic distance was revealed based on ORF2, which might indicate the circulation of a distinct virus genotype and serotype in guinea fowl. Furthermore, the genetic data presented herein suggest that either recombination between different astroviruses infecting distinct hosts or adaptation of a given astrovirus to a new host had occurred. In either case, direct or indirect interspecies transmission of astroviruses is likely to have occurred between turkey and guinea fowl, indicating the ability of viruses belonging to the family Astroviridae to cross species barriers. PMID- 22527868 TI - Complete genome organization of American hop latent virus and its relationship to carlaviruses. AB - The complete genomic sequence of American hop latent virus (AHLV; genus Carlavirus) was determined. The genome consists of 8,601 nucleotides plus a 3' polyadenylate tail. The genome encompasses six potential open reading frames (ORF) in the positive sense, and their organization is typical of other carlaviruses. Analysis of the coat protein coding sequence at both the nucleic acid level and the amino acid level indicates that AHLV is only remotely related to the other carlaviruses known to infect common hop. Polyclonal antibodies were produced against the bacterially expressed coat protein of AHLV. These antibodies differentiated between AHLV and other carlaviruses of hop. PMID- 22527869 TI - Complete genome sequence of pepper yellow mosaic virus, a potyvirus, occurring in Brazil. AB - The complete genomic sequence of pepper yellow mosaic virus (PepYMV), a member of the genus Potyvirus, was determined. The sequence was 9745 nucleotides long, excluding the 3' poly(A) tail. The genome contained a large open reading frame encoding a polyprotein of 3085 amino acids, which contained the typically conserved motifs found in members of the genus Potyvirus and an additional P3 PIPO (pretty interesting potyvirus ORF). In a pairwise comparison with other potyvirus sequences, the full genome of PepYMV shared a maximum of 63.84 % nucleotide sequence identity with pepper mottle virus (PepMoV), followed by verbena virus Y (VVY, 62.11 %), potato virus Y (PVY, 62.07 %) and Peru tomato mosaic virus (PTV, 62.00 %). Based upon a phylogenetic analysis, PepYMV was most closely related to PepMoV and PTV, within the PVY subgroup cluster, like most potyviruses isolated in solanaceous hosts in South America. PMID- 22527870 TI - Phylogeny and evolution of porcine teschovirus 8 isolated from pigs in China with reproductive failure. AB - A porcine teschovirus (PTV) was isolated from a dead piglet from a herd of 200 sows showing reproductive failure in Fuyu, Heilongjiang Province, China. Sequencing of most of the genome of this isolate, designated Fuyu/2009, revealed that is was a PTV-8 isolate, closely related to a previously identified Chinese PTV-8 strain (Jilin/2003). Both Chinese strains vary from the European PTV-8 strains by different clustering of the 3CD sequences. Infection with these viruses may be associated with pronounced diseases. PMID- 22527871 TI - Exploring the comorbidity of anxiety and substance use disorders. AB - Anxiety disorders and substance use disorders are highly comorbid, and such comorbidity complicates treatment and worsens prognosis. The mechanisms underlying the relationship between anxiety and substance use disorders are poorly understood. This paper reviews recent research attempting to explain these associations. Cognitive factors, such as attentional bias, expectancies, and anxiety sensitivity, appear to impact on the relation between anxiety and substance misuse. Temporality of the anxiety and substance use disorder may also indicate whether the substance use disorder is primary (anxiety may be a result of use) or secondary (substances may be used to self-medicate). Social phobia has been predominantly identified as a primary disorder preceding substance use, while the temporality of other anxiety and substance use disorders is less clear. The efficacy of concurrent treatment compared with separate treatment of either anxiety or substance use disorder is unclear and requires further research. PMID- 22527872 TI - A 2012 evidence-based algorithm for the pharmacotherapy for obsessive-compulsive disorder. AB - There is a need to synthesize the growing body of literature on the pharmacotherapeutic management of patients with obsessive-compulsive disorder for clinicians working at a primary care level. We have aimed to generate a simple, easy-to-follow algorithm for the primary care practitioner. This seven-step algorithm addresses diagnosis of obsessive-compulsive disorder, initiation of pharmacotherapy, monitoring and maintenance treatment, and guidelines for the management of patients who are resistant to initial therapy. In creating this algorithm, we have drawn on the body of published evidence, as well as on expert opinion. PMID- 22527873 TI - Deinstitutionalization? Where have all the people gone? AB - Although there is broad consensus that the state psychiatric hospital population drastically declined over the past five decades, the destination and well-being of people with serious mental illness (SMI) have been in greater doubt. In this article, we examine the aftermath of the deinstitutionalization movement. We begin with a brief historical overview of the move away from state hospitals, followed by an examination of where people with SMI currently reside and receive treatment. Next, we review recent trends reflecting access to treatment and level of community integration among this population. Evidence suggests the current decentralized mental health care system has generally benefited middle-class individuals with less severe disorders; those with serious and persistent mental illness, with the greatest need, often fare the worst. We conclude with several questions warranting further attention, including how deinstitutionalization can be defined and how barriers to community integration may be addressed. PMID- 22527874 TI - Enterprise size and return to work after stroke. AB - INTRODUCTION: It has been hypothesised that return to work rates among sick listed workers increases with enterprise size. The aim of the present study was to estimate the effect of enterprise size on the odds of returning to work among previously employed stroke patients in Denmark, 2000-2006. METHODS: We used a prospective design with a 2 year follow-up period. The study population consisted of 13,178 stroke patients divided into four enterprise sizes categories, according to the place of their employment prior to the stroke: micro (1-9 employees), small (10-49 employees), medium (50-249 employees) and large (>250 employees). The analysis was based on nationwide data on enterprise size from Statistics Denmark merged with data from the Danish occupational hospitalisation register. RESULTS: We found a statistically significant association (p = 0.034); each increase in enterprise size category was followed by an increase in the estimated odds of returning to work. CONCLUSIONS: The chances of returning to work after stroke increases as the size of enterprise increases. Preventive efforts and research aimed at finding ways of mitigating the effect are warranted. PMID- 22527875 TI - Predictors of functional disability in disability welfare claimants. AB - BACKGROUND: People unemployed and claiming welfare due to poor health are by definition functionally disabled. Understanding the factors associated with such disability is crucial in the development of biopsychosocial formulations and associated occupational rehabilitation. METHOD: A cross-sectional design in a sample of claimants (n = 4,119) of health-related welfare, unemployed due to mental or physical health problems. Participants provided socio-demographic information and completed validated measures of psychological distress, self efficacy and disability. Hierarchical multiple regression analyses then tested which psychological and socio-demographic factors were associated with disability. RESULTS: Despite equal rates of functional disability across health condition groups, differing variables were associated with disability for mental and physical health conditions. Psychological distress was the strongest predictor of disability across all health conditions. For physical conditions, lack of previous employment was the only additional variable associated with current disability and for mental health conditions age and self-efficacy were additional factors. CONCLUSION: Results are discussed in terms of biopsychosocial formulations of health-related unemployment, the potential mechanisms by which psychological distress can influence disability, the methodological limitations of cross sectional regression analyses and the implications for condition specific occupational rehabilitation. PMID- 22527876 TI - A prospective cohort study on hospital mortality due to Clostridium difficile infection. AB - PURPOSE: Although an increase in burden of disease has frequently been reported for Clostridium difficile infection (CDI), specific data on the effect of CDI on a patient's risk of death or overall hospital mortality are scarce. Therefore, we performed a prospective cohort study to analyse the effect of CDI on the risk of pre-discharge all-cause death in all inpatients with CDI compared to all inpatients without CDI during 2009 in a single hospital. METHODS: Clostridium difficile infection was defined as by the European Society of Clinical Microbiology and Infectious Diseases. Data were collected from the medical charts of CDI patients and from the hospital discharge data of non-CDI and CDI patients. The effect measures of CDI used to compute the risk of pre-discharge all-cause death were risk ratio, attributable risk, mortality fraction (%) and population attributable risk percentage. Co-morbidity was categorized using the Charlson co morbidity score in which a value of <=2 was defined as low co-morbidity and that of >2 as moderate/severe co-morbidity. A stratified analysis and a Poisson regression model were applied to adjust for the effects of the risk factors sex, age and severity of co-morbidity. RESULTS: A total of 185 hospitalized patients with CDI were compared to 38,644 other hospitalized patients without CDI admitted between 1 January 2009 and 31 December 2009. The mean age of the CDI and non-CDI patients was 74.3 (range 72.3-76.4) and 51.9 (range 51.6-52.1) years, respectively. Of the 185 CDI, 136 (73.5%) and 49 (26.5%) were categorized with low and high co-morbidity, respectively, versus 32,107 (83.4%) and 6,352 (16.5%), respectively, in non-CDI patients. Overall, 24 of the 185 CDI patients (13%) versus 1,021 of the 38,459 non-CDI patients (2.7%) died during their hospital stay, resulting in a relative risk of pre-discharge death of 4.89 [95% confidence interval (CI) 3.35-7.13] for CDI patients, a CDI attributable risk of death of 10.3 per 100 patients and a CDI attributable fraction of 79.5 % (95% CI 70.1-86 %). After adjustment for age, sex and co-morbidity the relative risk of pre discharge death was 2.74 (95% CI 1.82-4.10; p < 0.0001) for patients with CDI, and the proportion of hospital deaths due to CDI was 1.72 (95% CI 1.22-2.05). CONCLUSION: The results of this study lead to the conclusion that hospitalized patients with CDI are--independent of age, sex and co-morbidity severity--2.74 fold more likely to die during their hospital stay than all other hospitalized patients. The eradication of CDI in the hospital could have prevented 1.72% of in hospital deaths in our study population during the 1 year of the study. PMID- 22527877 TI - Lemierre's syndrome in the liver. PMID- 22527878 TI - Dengue virus identification by transmission electron microscopy and molecular methods in fatal dengue hemorrhagic fever. AB - Dengue virus is the most significant virus transmitted by arthropods worldwide and may cause a potentially fatal systemic disease named dengue hemorrhagic fever. In this work, dengue virus serotype 4 was detected in the tissues of one fatal dengue hemorrhagic fever case using electron immunomicroscopy and molecular methods. This is the first report of dengue virus polypeptides findings by electron immunomicroscopy in human samples. In addition, not-previously documented virus-like particles visualized in spleen, hepatic, brain, and pulmonary tissues from a dengue case are discussed. PMID- 22527879 TI - Monitoring of Epstein-Barr virus load in patients after allogeneic hematopoietic stem cell transplantation. PMID- 22527880 TI - Emergence and evolution of the renin-angiotensin-aldosterone system. AB - The renin-angiotensin-aldosterone system (RAAS) is not the sole, but perhaps the most important volume regulator in vertebrates. To gain insights into the function and evolution of its components, we conducted a phylogenetic analysis of its main related genes. We found that important parts of the system began to appear with primitive chordates and tunicates and that all major components were present at the divergence of bony fish, with the exception of the Mas receptor. The Mas receptor first appears after the bony-fish/tetrapod divergence. This phase of evolutionary innovation happened about 400 million years ago. We found solid evidence that angiotensinogen made its appearance in cartilage fish. The presence of several RAAS genes in organisms that lack all the components shows that these genes have had other ancestral functions outside of their current role. Our analysis underscores the utility of sequence comparisons in the study of evolution. Such analyses may provide new hypotheses as to how and why in today's population an increased activity of the RAAS frequently leads to faulty salt and volume regulation, hypertension, and cardiovascular diseases, opening up new and clinically important research areas for evolutionary medicine. PMID- 22527881 TI - Regulation of H19 and its encoded microRNA-675 in osteoarthritis and under anabolic and catabolic in vitro conditions. AB - Cartilage degeneration in the course of osteoarthritis (OA) is associated with an alteration in chondrocyte metabolism. In order to identify molecules representing putative key regulators for diagnosis and therapeutic intervention, we analyzed gene expression and microRNA (miR) levels in OA and normal knee cartilage using a customized cartilage cDNA array and quantitative RT-PCR. Among newly identified candidate molecules, H19, IGF2, and ITM2A were significantly elevated in OA compared to normal cartilage. H19 is an imprinted maternally expressed gene influencing IGF2 expression, whose transcript is a long noncoding (lnc) RNA of unknown biological function harboring the miR-675. H19 and IGF2 mRNA levels did not correlate significantly within cartilage samples suggesting that deregulation by imprinting effects are unlikely. A significant correlation was, however, observed for H19, COL2A1, and miR-675 expression levels in OA tissue, and functional regulation of these candidate molecules was assessed under anabolic and catabolic conditions. Culture of chondrocytes under hypoxic signaling showed co-upregulation of H19, COL2A1, and miRNA-675 levels in close correlation. Proinflammatory cytokines IL-1beta and TNF-alpha downregulated COL2A1, H19, and miR-675 significantly without close statistical correlation. In conclusion, this is the first report demonstrating deregulation of an lncRNA and its encoded miR in the context of OA-affected cartilage. Stress-induced regulation of H19 expression by hypoxic signaling and inflammation suggests that lncRNA H19 acts as a metabolic correlate in cartilage and cultured chondrocytes, while the miR-675 may indirectly influence COL2A1 levels. H19 may not only be an attractive marker for cell anabolism but also a potential target to stimulate cartilage recovery. PMID- 22527883 TI - Conserved anchorless surface proteins as group A streptococcal vaccine candidates. AB - Streptococcus pyogenes (group A Streptococcus (GAS)) causes ~700 million human infections each year, resulting in over 500,000 deaths. The development of a commercial GAS vaccine is hampered by the occurrence of many unique GAS serotypes, antigenic variation within the same serotype, differences in serotype geographical distribution, and the production of antibodies cross-reactive with human tissue that may lead to autoimmune disease. Several independent studies have documented a number of GAS cell wall-associated or secreted metabolic enzymes that contain neither N-terminal leader sequences nor C-terminal cell wall anchors. Here, we applied a proteomic analysis of serotype M1T1 GAS cell wall extracts for the purpose of vaccine development. This approach catalogued several anchorless proteins and identified two protective vaccine candidates, arginine deiminase and trigger factor. These surface-exposed enzymes are expressed across multiple GAS serotypes exhibiting >=99% amino acid sequence identity. Vaccine safety concerns are alleviated by the observation that these vaccine candidates lack human homologs, while sera from human populations suffering repeated GAS infections and high levels of autoimmune complications do not recognize these enzymes. Our study demonstrates anchorless cell surface antigens as promising vaccine candidates for the prevention of GAS disease. PMID- 22527882 TI - Selenoprotein N in skeletal muscle: from diseases to function. AB - Selenoprotein N (SelN) deficiency causes several inherited neuromuscular disorders collectively termed SEPN1-related myopathies, characterized by early onset, generalized muscle atrophy, and muscle weakness affecting especially axial muscles and leading to spine rigidity, severe scoliosis, and respiratory insufficiency. SelN is ubiquitously expressed and is located in the membrane of the endoplasmic reticulum; however, its function remains elusive. The predominant expression of SelN in human fetal tissues and the embryonic muscle phenotype reported in mutant zebrafish suggest that it is involved in myogenesis. In mice, SelN is also mostly expressed during embryogenesis and especially in the myotome, but no defect was detected in muscle development and growth in the Sepn1 knock out mouse model. By contrast, we recently demonstrated that SelN is essential for muscle regeneration and satellite cell maintenance in mice and humans, hence opening new avenues regarding the pathomechanism(s) leading to SEPN1-related myopathies. At the cellular level, recent data suggested that SelN participates in oxidative and calcium homeostasis, with a potential role in the regulation of the ryanodine receptor activity. Despite the recent and exciting progress regarding the physiological function(s) of SelN in muscle tissue, the pathogenesis leading to SEPN1-related myopathies remains largely unknown, with several unsolved questions, and no treatment available. In this review, we introduce SelN, its properties and expression pattern in zebrafish, mice, and humans, and we discuss its potential roles in muscle tissue and the ensuing clues for the development of therapeutic options. PMID- 22527884 TI - Genetic variation in the carbonyl reductase 3 gene confers risk of type 2 diabetes and insulin resistance: a potential regulator of adipogenesis. AB - Prostaglandins are potent modulators of insulin sensitivity. We systemically evaluated the association of 61 tag single-nucleotide polymorphisms (SNP) in 14 genes involved in prostaglandin metabolism with type 2 diabetes. Among all genotyped SNPs, rs10483032 in the CBR3 (carbonyl reductase 3) gene, which encodes for an enzyme converting prostaglandin E(2) to prostaglandin F2(alpha), was associated with type 2 diabetes in 760 type 2 diabetic cases and 760 controls (stage-1 study) (P = 2.0 * 10(-4)). The association was validated in 1,615 cases and 1,162 controls (stage-2 study) (P = 0.009). The A allele at rs10483032 was associated with increased risk of type 2 diabetes (odds ratio = 1.29; 95% confidence interval = 1.14-1.47; combined P < 0.0001). The association was externally validated in the Finland-United States Investigation of NIDDM Genetics (FUSION) study (P = 3.7 * 10(-4)). The risk A allele was associated with higher homeostasis model assessment of insulin resistance (HOMA-IR) in 1,012 non diabetic controls and 1,138 non-diabetic subjects from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) family study. CBR3 gene expression in human abdominal adipose tissue was negatively associated with fasting insulin and HOMA-IR. CBR3 gene expression increased during differentiation of 3T3-L1 preadipocytes into adipocytes. Knockdown of CBR3 in 3T3 L1 preadipocytes enhanced adipogenesis and peroxisome proliferator-activator receptor-gamma response element reporter activity. Our results indicated that genetic polymorphism in the CBR3 gene conferred risk of type 2 diabetes and insulin resistance in Chinese. The association was probably mediated through modulation of adipogenesis. PMID- 22527885 TI - Siderophore-mediated iron trafficking in humans is regulated by iron. AB - Siderophores are best known as small iron binding molecules that facilitate microbial iron transport. In our previous study we identified a siderophore-like molecule in mammalian cells and found that its biogenesis is evolutionarily conserved. A member of the short chain dehydrogenase family of reductases, 3 hydroxy butyrate dehydrogenase (BDH2) catalyzes a rate-limiting step in the biogenesis of the mammalian siderophore. We have shown that depletion of the mammalian siderophore by inhibiting expression of bdh2 results in abnormal accumulation of cellular iron and mitochondrial iron deficiency. These observations suggest that the mammalian siderophore is a critical regulator of cellular iron homeostasis and facilitates mitochondrial iron import. By utilizing bioinformatics, we identified an iron-responsive element (IRE; a stem-loop structure that regulates genes expression post-transcriptionally upon binding to iron regulatory proteins or IRPs) in the 3'-untranslated region of the human BDH2 (hBDH2) gene. In cultured cells as well as in patient samples we now demonstrate that the IRE confers iron-dependent regulation on hBDH2 and binds IRPs in RNA electrophoretic mobility shift assays. In addition, we show that the hBDH2 IRE associates with IRPs in cells and that abrogation of IRPs by RNAi eliminates the iron-dependent regulation of hBDH2 mRNA. The key physiologic implication is that iron-mediated post-transcriptional regulation of hBDH2 controls mitochondrial iron homeostasis in human cells. These observations provide a new and an unanticipated mechanism by which iron regulates its intracellular trafficking. PMID- 22527886 TI - Cysteinyl leukotriene signaling through perinuclear CysLT(1) receptors on vascular smooth muscle cells transduces nuclear calcium signaling and alterations of gene expression. AB - Leukotrienes are pro-inflammatory mediators that are locally produced in coronary atherosclerotic plaques. The response induced by cysteinyl leukotrienes (CysLT) in human coronary arteries may be altered under pathological conditions, such as atherosclerosis. The aim of the present study was to elucidate cysteinyl leukotriene signaling in vascular smooth muscle cells (SMCs) and the effects of inflammation on this process. Immunohistochemical analysis of human carotid endarterectomy samples revealed that the CysLT(1) leukotriene receptor was expressed in areas that also stained positive for alpha-smooth muscle actin. In human coronary artery smooth muscle cells, lipopolysaccharide significantly upregulated the CysLT(1) receptor and significantly enhanced the changes in intracellular calcium induced by leukotriene C(4) (LTC(4)). In these cells, the CysLT(1) receptor exhibited a perinuclear expression, and LTC(4) stimulation predominantly enhanced nuclear calcium increase, which was significantly inhibited by the CysLT(1) receptor antagonist MK-571. Microarray analysis revealed, among a number of significantly upregulated genes after 24 h stimulation of human coronary artery smooth muscle cells with LTC(4), a 5-fold increase in mRNA levels for plasminogen activator inhibitor (PAI)-2. The LTC(4) induced increase in PAI-2 expression was confirmed by real-time quantitative PCR and ELISA and was inhibited by the CysLT(1) receptor antagonist MK-571 and by calcium chelators. In summary, pro-inflammatory stimulation of vascular SMCs upregulated a perinuclear CysLT(1) receptor expression coupled to nuclear calcium signaling and changes in gene expression, such as upregulation of PAI-2. Taken together, these findings suggest a role of nuclear CysLT(1) receptor signaling in vascular SMCs inducing gene expression patterns associated with atherosclerosis. PMID- 22527887 TI - Multiple once-daily subcutaneous doses of pasireotide were well tolerated in healthy male volunteers: a randomized, double-blind, placebo-controlled, cross over, Phase I study. AB - A randomized, double-blind, placebo-controlled, cross-over, dose-escalating, single-center study was conducted to evaluate the safety, tolerability, and pharmacokinetic (PK) profile of multiple once-daily (qd) subcutaneous (sc) doses of pasireotide in healthy male subjects. Subjects received pasireotide 50, 200, or 600 MUg sc qd for 14 days and placebo in separate sequences. Thirty-three subjects were randomized. The most frequently reported drug-related adverse events were injection-site reactions (n = 18), diarrhea (n = 14) and nausea (n = 10), which were mostly mild or moderate in intensity. Pasireotide 600 MUg sc was associated with pre- and post-prandial elevations in glucose levels relative to placebo; however, this effect was less pronounced on day 14 compared with day 1. PK steady state appeared to be achieved after 3 days of dosing and PK exposures had a moderate accumulation of 20-40 % across doses. Pasireotide demonstrated fast absorption (T(max,ss): 0.25-0.5 h), low clearance (CL/F(ss): 8.10-9.03 L/h), long effective half-life (T(1/2,eff): ~12 h, on average between 9.7 and 13.1 h for 50, 200, and 600 MUg sc qd), and large volume of distribution (V(z)/F(ss): 251-1,091 L) at steady state. Dose proportionality was confirmed for C(max,ss); other PK parameters (C(max), AUC(0-24 h) and AUC(tau)) were approximately dose proportional. Growth hormone inhibition was observed with pasireotide 200 and 600 MUg sc qd. Gallbladder volume increased post-prandially with pasireotide 200 and 600 MUg sc qd, which appeared to correlate with reduced levels of cholecystokinin at these doses. Pasireotide was generally well tolerated up to the tested dose of 600 MUg qd, with a linear and time-independent PK profile after sc qd dosing in healthy subjects. PMID- 22527888 TI - Radix Astragali lowers kidney oxidative stress in diabetic rats treated with insulin. AB - Fluctuations in glucose levels in diabetic patients can result in oxidative stress, resulting in an increased risk for diabetic complications. We investigated whether antioxidation would protect the kidney from oxidative stress in diabetic rats treated with insulin and provide evidence for the efficacy of antioxidant treatment in diabetes management. Diabetes was induced by injection of Streptozotocin intraperitoneally in male Wistar rats. Diabetic rats received either insulin, both insulin and Radix Astragali (RA), RA, or no treatment. The levels of malondialdehyde (MDA), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha) and activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) in kidney were determined. The changes of blood glucose levels and body weight were monitored. The levels of serum creatinine (Scr) were determined. The expression of PKCalpha was determined by western blot. NF-kappaB activation in kidney was assessed using EMSA. Compared to diabetic rats treated with insulin alone, the diabetic rats treated with combination of insulin and RA showed: (1) significantly lower levels of MDA, IL-6, TNF-alpha, and Scr (p < 0.05); (2) significantly higher SOD and GSH-Px activities (p < 0.05); (3) significantly lower NF-kappaB activation and lower expression levels of PKCalpha (p < 0.05); (4) significantly smaller kidney-to-body weight ratio (p < 0.05). RA is an effective agent in lowering oxidative stress in diabetic rats treated with insulin. Antioxidation is beneficial in reducing the risk of kidney damage due to oxidative stress in diabetic patients. PMID- 22527889 TI - Detection rate of recurrent medullary thyroid carcinoma using fluorine-18 fluorodeoxyglucose positron emission tomography: a meta-analysis. AB - Several studies evaluated the diagnostic performance of fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET), and positron emission tomography/computed tomography (PET/CT) in detecting recurrent medullary thyroid carcinoma (MTC) with conflicting results. Aim of our study is to meta analyze published data about this topic. A comprehensive computer literature search of studies published in PubMed/MEDLINE, Scopus, and Embase databases through December 2011 and regarding FDG PET or PET/CT in patients with suspected recurrent MTC was carried out. Pooled detection rate (DR) on a per patient-based analysis was calculated to measure the diagnostic performance of FDG PET and PET/CT in this setting. A sub-analysis considering PET device used, serum calcitonin, carcino-embryonic antigen (CEA), calcitonin doubling time (CTDT), and CEA doubling time (CEADT) values was also performed. Twenty-four studies comprising 538 patients with suspected recurrent MTC were included. DR of FDG PET or PET/CT in suspected recurrent MTC on a per patient-based analysis was 59 % (95 % confidence interval: 54-63 %). Heterogeneity between the studies was revealed. DR increased in patients with serum calcitonin >= 1,000 ng/L (75 %), CEA >= 5 ng/ml (69 %), CTDT <12 months (76 %), and CEADT <24 months (91 %). In patients with suspected recurrent MTC FDG PET and PET/CT are associated with a non-optimal DR since about 40 % of suspected recurrent MTC remain usually unidentified. However, FDG PET and PET/CT could modify the patient management in a certain number of recurrent MTC because these methods are often performed after negative conventional imaging studies. DR of FDG PET and PET/CT increases in patients with higher calcitonin and CEA values and lower CTDT and CEADT values, suggesting that these imaging methods could be very helpful in patients with more aggressive disease. PMID- 22527890 TI - Study of the role of novel RF-amide neuropeptides in affecting growth hormone secretion in a representative non-human primate (Macaca mulatta). AB - RF amide peptide family with distinctive terminal -Arg-Phe-NH(2) signature is evolutionarily conserved from invertebrates to mammals. These neuropeptides have been shown to affect diverse functions in invertebrates and vertebrates including influencing pituitary hormone secretion. More recently, two members of this family 26-amino acid and 43-amino acid RF amide peptide (26RFa and 43RFa, respectively) originally isolated from frog have been cloned in rats and humans. Actions of these peptides on hormone secretion have not been studied in primates. In the present study, effect of iv administration of three different doses of human 26RFa and 43RFa on GH secretion was studied in a representative higher primate, the rhesus monkey. As control against these two peptides, normal saline and a scrambled sequence of 26RFa was administered. A set of four intact adult male monkeys received the administration in a random order. Peripheral blood samples were obtained from the chairrestrained but fully conscious animals for a period of 30 min before and 240 min after the administration at 15-min intervals. For quantitative measurement of GH concentration, a human GH chemiluminescent immunometric assay was used. Peripheral administration of 38 and 76 nmol doses of 26RFa significantly (P < 0.05) stimulated GH AUC during a 0-120 min period after injection of 26RFa. In contrast to 26RFa, administration of 43RFa appeared to suppress GH levels during the later stages of the sampling i.e. from 120 to 240 min period. Mean AUC during the period was significantly (P < 0.05) reduced by 76 nmol dose of 43RFa, while 38 nmol dose of 43RFa also had similar effect but lacked full statistical significance (P = 0.058). To our knowledge present study reports for the first time-specific stimulatory effect of 26RFa on the GH secretion and a novel inhibitory and delayed effect of 43RFa on the GH secretion in higher primates. In conclusion, present findings extend evidence for endocrine actions of RF amides in primates and suggest differential effect of these peptides on GH secretion in primates. PMID- 22527892 TI - Anti-oxidant therapy in non-alcoholic fatty liver disease: the role of silymarin. PMID- 22527891 TI - Exercise and nutritional interventions for improving aging muscle health. AB - Skeletal muscle mass declines with age (i.e., sarcopenia) resulting in muscle weakness and functional limitations. Sarcopenia has been associated with physiological changes in muscle morphology, protein and hormonal kinetics, insulin resistance, inflammation, and oxidative stress. The purpose of this review is to highlight how exercise and nutritional intervention strategies may benefit aging muscle. It is well known that resistance exercise training increases muscle strength and size and evidence also suggests that resistance training can increase mitochondrial content and decrease oxidative stress in older adults. Recent findings suggest that fast-velocity resistance exercise may be an effective intervention for older adults to enhance muscle power and functional capacity. Aerobic exercise training may also benefit aging skeletal muscle by enhancing mitochondrial bioenergetics, improving insulin sensitivity, and/or decreasing oxidative stress. In addition to exercise, creatine monohydrate, milk-based proteins, and essential fatty acids all have biological effects which could enhance some of the physiological adaptations from exercise training in older adults. Additional research is needed to determine whether skeletal muscle adaptations to increased activity in older adults are further enhanced with effective nutritional interventions and whether this is due to enhanced muscle protein synthesis, improved mitochondrial function, and/or a reduced inflammatory response. PMID- 22527893 TI - Spontaneous bilateral adrenal hemorrhage. PMID- 22527894 TI - Hyaluronan-enriched transfer medium improves outcome in patients with multiple embryo transfer failures. AB - PURPOSE: To ascertain whether the use of hyaluronan-enriched transfer medium (HETM) improves pregnancy and implantation rates among embryo transfer patients with a history of multiple implantation failures. METHODS: Patients (n = 314) under the age of 40 and with a history of multiple unsuccessful embryo transfers were enrolled. There were three groups of patients: those undergoing fresh embryo transfer (fresh ET [n = 111]), those undergoing vitrified-warmed ET in the natural cycle (WET-N [n = 101]) and those undergoing WET in a hormone replacement cycle (WET-H [n = 102]). On the day of ET, patients were randomized to HETM (0.5 mg/ml hyaluronan) or control medium containing no hyaluronan. Only patients with good quality embryos on day 3 were included. RESULTS: For all three patients groups (fresh ET, WET-N and WET-H) pregnancy rates (37.5 %, 31.4 % and 41.2 %, respectively) were significantly higher when using HETM compared with control medium (10.9 %, 10.0 % and 15.7 %, respectively; p < 0.05), and implantation rates when using HETM were also significantly higher compared with control medium (p < 0.05). Miscarriage rates were similar in both groups. CONCLUSION: HETM significantly increased pregnancy and implantation rates among embryo transfer patients with a history of multiple unsuccessful implantations-regardless of method used to prepare the endometrium. PMID- 22527895 TI - Supplementation of biotin to sperm preparation medium increases the motility and longevity in cryopreserved human spermatozoa. AB - PURPOSE: To study the effect of supplementing biotin to sperm preparation medium on the motility of frozen-thawed spermatozoa. METHODS: Semen samples of men attending the University infertility clinic (n = 105) were cryopreserved using glycerol-egg yolk-citrate buffered cryoprotective medium in liquid nitrogen. After a period of two weeks, the semen samples were thawed and the motile spermatozoa were extracted by swim-up technique using Earle's balanced salt solution (EBSS) medium supplemented with either biotin (10 nM) or pentoxifylline (1 mM). The post-wash motility was observed up to 4 h after incubation. RESULTS: Both biotin and pentoxifylline supplementation resulted in significant increase in total motility (p < 0.05), progressive motility (p < 0.001) and rapid progressive motility (p < 0.05 v/s biotin and p < 0.01 v/s pentoxifylline) compared to the control at 1 h post-incubation period. Significantly higher percentage of total (p < 0.01, p < 0.05 in biotin and pentoxifylline respectively), progressive (p < 0.001) and rapid progressive motilities (p < 0.01) were observed in these two groups even at 2 h compared to the control. In the control group at 4 h after incubation, ~11% decline in total motility and ~8% decline in progressive motility was observed. However, in both biotin and pentoxifylline group the motility was significantly higher than control (p < 0.001). No significant difference in the motility was observed between biotin and pentoxifylline groups at any of the time intervals studied. CONCLUSIONS: Biotin can enhance the sperm motility and prolong the survival of frozen-thawed semen samples which may have potential benefit in assisted reproductive technology field. PMID- 22527897 TI - Triploid and diploid embryonic stem cell lines derived from tripronuclear human zygotes. AB - PURPOSE: Human embryonic stem cells (hESCs) are self-renewing, pluripotent cells that are valuable research tools and hold promise for use in regenerative medicine. The need for new hESC lines motivated our attempts to find a new resource for the derivation of hESC lines. The aim of this work was to establish more hESC lines from abnormal fertilized zygotes and to meet the emerging requirements for their use in cell replacement therapies, disease modeling, and basic research. METHODS: A total of 130 tripronuclear human zygotes was collected 18-20 h post-insemination and cultured in a modified culture medium. The inner cell mass of 12 blastocysts were isolated by a mechanical method in order to establish embryonic stem cell lines. RESULTS: We established four hESC lines derived from 130 trinuclear zygotes, one of which was triploid and the others were diploid. The efficiency of deriving hESC lines is 3.08 %. The ratio of deriving triploid and diploid hESC lines is 1:3. All of these hESC lines exhibited similar markers of undifferentiated hESCs and had the typical morphology of hESCs, a capacity for long-term proliferation, and pluripotent differentiation potential both in vivo and in vitro. CONCLUSIONS: These abnormal zygotes, which otherwise would have been discarded, can serve as an alternative source for normal euploid hESC lines. PMID- 22527896 TI - Frequent polymorphisms of FSH receptor do not influence antral follicle responsiveness to follicle-stimulating hormone administration as assessed by the Follicular Output RaTe (FORT). AB - PURPOSE: To verify whether carriers of common single-nucleotide polymorphisms (SNPs) of the FSH receptor (FSHR) show reduced responsiveness of antral follicles to FSH administration as assessed by the FORT. METHODS: We performed a prospective study in a university hospital. Study population consisted of 124 Caucasian IVF-ET candidates. FSHR 307Ala and 680Ser variants were analyzed in haplotypes and as separated genes. Serum FSH, estradiol (E(2)), and anti Mullerian hormone (AMH) were measured on cycle-day 3. Antral follicle (3-8 mm) count (AFC) and preovulatory follicle (16-22 mm) count (PFC) were performed, respectively, at the achievement of pituitary suppression (before FSH administration) and on the day of hCG administration. Antral follicle responsiveness to FSH administration assessed by the FORT (PFCx100/AFC). RESULTS: Data concerning baseline and IVF-ET parameters were similar between SNPs carriers and controls. Moreover, FORT was similar for different haplotypes Thr307-Asn680 (45.9%) and Ala307-Ser680 (39.4%) and 307Thr/Ala-Ala/Ala (41.1%; 5.0-91.6%) versus 307Thr/Thr (44.4%; 17.3-83.3%) and in 680Asn/Ser-Ser/Ser (40.0%; 5.0 91.6%) versus 680Asn/Asn (42.2%; 8.3-90.0%) carriers. CONCLUSIONS: Antral follicle responsiveness to FSH, as far as measured by the FORT, is not influenced by the presence of SNPs of FSHR 307Ala and 680Ser. PMID- 22527898 TI - Severe combined immunodeficiency (SCID): from the detection of a new mutation to preimplantation genetic diagnosis. AB - PURPOSE: To describe the identification of a new mutation responsible for causing human severe combined immunodeficiency syndrome (SCID). In a large consanguineous Israeli Arab family, this served as a diagnostic tool and enabled us to carry out preimplantation genetic diagnosis (PGD). We also demonstrated that PGD for homozygosity alleles is feasible. METHODS: We carried out genome-wide screening followed by fine mapping and linkage analysis in order to identify the candidate genes. We then sequenced DCLRE1C in order to find the familial mutation. The family was anxious to avoid the birth of an affected child, and therefore, because of their religious beliefs, PGD was the only option open to them. The embryos were biopsied at day 3, and a single blastomere from each embryo was analyzed by multiplex polymerase chain reaction for the SCID mutation and 5 additional polymorphic markers flanking DCLRE1C. RESULTS: Linkage analysis revealed linkage to chromosome 10p13, which harbors the DNA Cross-Link Repair Protein 1 C (DCLRE1C) ARTEMIS gene. Sequencing identified an 8 bp insertion in exon 14 (1306ins8) of DCLRE1C in all the affected patients; this causes an alteration in amino acid 330 of the protein from cysteine to a stop codon (p.C330X). One cycle of PGD was performed and two embryos were transferred, one homozygous wild-type and one a heterozygous carrier, and healthy twins were born. CONCLUSIONS: Identifying the familial mutation enabled us to design a reliable and accurate PGD protocol, even in this case of a consanguineous family. PMID- 22527899 TI - Cumulus cell-oocyte complexes retrieved from antral follicles in IVM cycles: relationship between COCs morphology, gonadotropin priming and clinical outcome. AB - PURPOSE: To assess retrospectively the developmental potential of different types of cumulus cell-oocyte complexes (COCs) derived from IVM cycles. METHODS: IVM cycles were performed in natural cycles or after HCG, FSH, or FSH/HCG priming. COCs recovered were morphologically characterized in different types: compact (CC) or expanded (EC) cumulus mass but including an immature oocyte, and expanded cumulus mass enclosing a mature oocyte (EC-MII). Embryo developmental competence was investigated analysing exclusively cycles in which all transferred embryos derived from the same COC category. RESULTS: Fertilization rates did not differ significantly. Significant differences in pregnancy rates (14.5%, 10.0% and 27.6 % in the CC, EC, and EC-MII categories, respectively) were observed. Likewise, significant differences in implantation rates (8.9%, 6.3% and 19.1% in the CC, EC, and EC-MII categories, respectively) were found. Overall, priming with FSH/HCG had a beneficial effect on pregnancy and implantation rates, while no priming or HCG alone generated oocytes with poor competence. CONCLUSIONS: In IVM cycles, morphological evaluation at the time of collection can predict the developmental ability of different COCs. FSH/HGC priming has a positive effect on oocyte competence. PMID- 22527900 TI - Sperm meiotic segregation, aneuploidy and high risk of delivering an affected offspring in carriers of non-Robertsonian translocation t(13;15). AB - PURPOSE: To determine the percentage of unbalanced spermatozoa and an interchromosomal effect in two carriers of balanced translocations t(13;15)(q32;q26) and t(13;15)(q32;p11.2). METHODS: Sperm nuclei analysis by fluorescent in situ hybridization for detection of percentage of unbalanced spermatozoa and sperm with disomy of chromosomes X, Y, 8, 18, 21 and diploidy. RESULTS: The incidence of unbalanced spermatozoa was 50.5 % and 44.6 % in patient 1 (P1) and patient 2 (P2), respectively. Partial disomy of chromosome 13 was detected in 13.4 % and 21.3 % of sperm in P1 and P2, respectively. The unbalanced karyotype der(15)t(13;15) was found previously in a son of P1 and in two adult relatives, and prenatally in the family of P2. This demonstrates a high risk of delivering an affected offspring. Significantly increased frequencies of chromosomes 8, 18, X and XY disomy and diploidy were observed in P2, which might either indicate an interchromosomal effect or be related to his asthenoteratozoospermia. CONCLUSIONS: Since the proportions of unbalanced spermatozoa and the risk of delivering an affected offspring are high, prenatal or preimplantation genetic diagnosis is recommended for such patients. PMID- 22527901 TI - Embryo transfer following in vitro maturation and cryopreservation of oocytes recovered from antral follicles during conservative surgery for ovarian cancer. PMID- 22527902 TI - Reproductive aging is associated with decreased mitochondrial abundance and altered structure in murine oocytes. AB - PURPOSE: To establish the phenotype of reproductive aging in our mouse model. To test the hypotheses that reproductive aging is associated with a decrease in mitochondrial abundance that could ultimately reflect dysfunction in oocytes. METHODS: Breeding studies were performed in young and aged female virgin wild type C57BL6J mice to establish their reproductive phenotype by measuring time to conception, litter size, and live birth per dam. Individual oocytes were analyzed for mtDNA content. Transmission electron microscopy was used to study ultrastructure of mitochondria in oocytes. RESULTS: Old females were found to have significantly prolonged time to conception and fewer surviving pups in their litters. Oocytes from old mice had 2.7-fold less mtDNA compared to younger controls (p < 0.001; 95 % CI 2.1-3.5). Decrease in mitochondrial organelle abundance in old animal's oocytes was confirmed with transmission electron microscopy. Distinct morphological changes were noted in mitochondria, suggesting altered mitochondrial biogenesis in the old animals' oocytes. CONCLUSIONS: Reproductive aging in mice is associated with reduced reproductive competence. Aging is associated with a significant decrease in number of mitochondria in oocytes. Our data support mitochondrial organelle loss and dysfunction in oocytes as a potential etiology for reproductive senescence. PMID- 22527904 TI - The impact of ART on major malformations is not known at this time. PMID- 22527903 TI - A meta-analysis on the association between PPAR-gamma Pro12Ala polymorphism and polycystic ovary syndrome. AB - PURPOSE: To investigate the influence of the peroxisome proliferator activated receptor gamma (PPAR-gamma) Pro12Ala polymorphism on the susceptibility of polycystic ovary syndrome (PCOS) and body mass index (BMI), fast insulin levels, homeostasis model assessment of insulin resistance (HOMA-IR) in PCOS patients. METHODS: PubMed, EMBASE, MEDLINE and CENTRAL databases were searched to identify eligible studies. We then conducted a meta-analysis to examine the association between Pro12Ala polymorphism and PCOS. RESULTS: Seventeen eligible studies, including 2,149 patients and 2,124 controls were enrolled in this meta-analysis. Pro12Ala polymorphism was significantly associated with the susceptibility of PCOS (odds ratio [OR] 0.74, 95 % confidence interval [CI] [0.61, 0.90] for allele; OR 0.70, 95 % CI [0.57, 0.86] for genotype). In the European subgroup of PCOS, the X/Ala genotype was associated with lower BMI (mean difference [MD] 1.08, 95 % CI [-2.08, -0.09]) and fast insulin levels (MD -19.82, 95 % CI [ 34.07, -5.58]). However, this polymorphism did not display an impact on HOMA-IR in PCOS patients. CONCLUSIONS: Ala variant would decrease the risk of PCOS and result in lower BMI and fast insulin levels in a European population, but had no impact on HOMA-IR in PCOS patients. Further studies are required to elucidate these associations more clear. PMID- 22527905 TI - The sensitivity and specificity of hyperglycosylated hCG (hhCG) levels to reliably diagnose clinical IVF pregnancies at 6 days following embryo transfer. AB - OBJECTIVE: To determine the sensitivity and specificity of hyperglycosylated hCG (hhCG) measurements for the diagnosis of clinical pregnancies in the IVF setting and how soon post embryo transfer (ET) a pregnancy can be detected using an ultrasensitive (hhCG) assay. To determine if a single, early hhCG measurement can discriminate between biochemical and clinical pregnancies. DESIGN: A 4 center prospective blinded clinical trial was performed with patients undergoing IVF-ET. Patients had blood drawn and submitted for hhCG analysis on the day of ET and at days 4, 6, 8, and 12 thereafter. First morning urines were collected and submitted for hhCG analysis on days 0, 4, 6, 8, 10 and 12. SETTING: Fertility Centers OUTCOME MEASURES: Clinical pregnancies were defined as an ultrasound study demonstrating a gestational sac and/or heart beat at appropriate gestational ages. RESULTS: Fifty-six of 58 enrolled patients completed the study. There were 25 clinical and 6 biochemical pregnancies. For blastocyst transfers, a single serum or urine hhCG measurement identified pregnancies (both biochemical and clinical) at 6 days post ET with 100% sensitivity and specificity. There were 6 biochemical pregnancies, all following blastocyst transfers. All of these pregnancies were identified by lower values. PMID- 22527906 TI - Competition between transposable elements and mutator genes in bacteria. AB - Although both genotypes with elevated mutation rate (mutators) and mobilization of insertion sequence (IS) elements have substantial impact on genome diversification, their potential interactions are unknown. Moreover, the evolutionary forces driving gradual accumulation of these elements are unclear: Do these elements spread in an initially transposon-free bacterial genome as they enable rapid adaptive evolution? To address these issues, we inserted an active IS1 element into a reduced Escherichia coli genome devoid of all other mobile DNA. Evolutionary laboratory experiments revealed that IS elements increase mutational supply and occasionally generate variants with especially large phenotypic effects. However, their impact on adaptive evolution is small compared with mismatch repair mutator alleles, and hence, the latter impede the spread of IS-carrying strains. Given their ubiquity in natural populations, such mutator alleles could limit early phase of IS element evolution in a new bacterial host. More generally, our work demonstrates the existence of an evolutionary conflict between mutation-promoting mechanisms. PMID- 22527907 TI - Fluctuating asymmetry of the permanent mandibular molars in a Japanese population. AB - The purpose of the present study is to investigate the pattern of fluctuating odontometric asymmetry of permanent mandibular first and second molars in a Japanese population. Dental plaster casts of 112 (57 males and 55 females) Japanese undergraduate dental students were used. The mesiodistal and buccolingual diameters of the whole crown and trigonid and talonid crown components were taken on the left and right sides of the mandibular permanent first and second molars. Crown areas were also calculated. The fluctuating asymmetry (FA) value was obtained by dividing the absolute side difference by the absolute mean size of the left and right teeth: FA = abs (R-L)/((R + L)/2). Fluctuating asymmetry between mandibular first and second molars was significantly different with the mandibular second molar showing higher asymmetry in both males and females. Meanwhile, fluctuating asymmetry between males and females in the first and second molars was not significantly different in all measured dimensions. With regard to trigonid and talonid components, fluctuating asymmetry of the distal talonid area was significantly larger than the mesial trigonid area in the mandibular permanent first molar of males (P < 0.01), and asymmetry of buccolingual diameter of the talonid was also larger than that of the trigonid in the mandibular permanent second molar of males (P < 0.05). In conclusion, these findings suggest that the crown dimensions of later developing teeth in the mandibular molar tooth class and crown component in the same molar tooth show more asymmetry and, therefore, are more affected by external factors. PMID- 22527908 TI - Influence of third molar space on angulation and dental arch crowding. AB - The influence of the third molars on mandibular incisor crowding has been extensively studied but remains controversial. The purpose of this study was to ascertain whether, in Mongolian subjects, the lower third molar can affect anterior crowding and/or the inclination of teeth in the lower lateral segments. Panoramic radiographs, 45 degrees oblique cephalograms, and dental casts were taken from Mongolian subjects (age range 18.3-24.1 years, mean 21.0 years) exhibiting impaction of all four third molars and an Angle Class I molar relationship. The Ganss ratio was calculated using panoramic radiographs, whereas the gonial angle and angulation of lower canines, premolars and molars were measured using 45 degrees oblique cephalograms. Little's index of irregularity was calculated using dental casts. Significant relationships between the angulation of the third and second molars and between the first molars and second premolars were found. Conversely, there was no significant correlation between the angulation of third molars, first premolars and canines. The Ganss ratio calculations showed that the lower first and second molars and the second premolars inclined mesially if there was insufficient space for the lower third molars. However, there was no significant correlation between Little's index of irregularity and third molar angulation. Furthermore, although the third molar influences the lateral segments, no obvious relationship between the third molar and anterior crowding was observed. Therefore, the angulation of the third molar appears not to cause anterior crowding. PMID- 22527910 TI - Absolute configurations of C34 and C35 of antibiotic niphimycin A. AB - The relative configurations of four stereogenic centers of the C33-C42 fragment of niphimycin A were assigned as 2S*, 3R*, 4S* and 6S*, based upon (1)H NMR analysis with double-quantum filtered COSY and nuclear Overhauser spectroscopy experiments. These data were then correlated with absolute configurations at C36 and C38 of niphimycin A, which were declared previously as 36S and 38S [3]. This allowed for the assignment of the absolute configurations at C34 and C35 of niphimycin A as 34S and 35R. PMID- 22527909 TI - Impact of nickel-titanium instrumentation of the root canal on clinical outcomes: a focused review. AB - Nickel-titanium (NiTi) root canal instruments have improved the technical quality of enlarging and shaping. These instruments have been shown to prepare even severely curved root canal with fewer procedural errors than traditional stainless steel hand instruments. While it would appear that these instruments might enhance clinical outcomes, very few studies have assessed their impact when used in primary root canal treatment. Clinical studies investigating the outcome of primary root canal treatment using nickel-titanium hand or rotary instruments were identified (MEDLINE database) using appropriate key words in an attempt to determine if there have been enhanced outcomes with these instruments. Evidence from one clinical trial suggests that (i) better maintenance of the original canal curvature and shape results in increased success rates and (ii) that ledging of root canals results in reduced success rates. Evidence from two studies indicates that the use of NiTi-either hand or rotary-instruments significantly increases success rates of primary nonsurgical root canal treatment compared with the use of stainless steel hand instruments, while three investigations failed to show any significant differences. PMID- 22527911 TI - Orthoamides and iminium salts LXXII: N,N,N',N',N'',N'',N''',N'''-octamethyl-(but 2-yne)-bis(amidinium) tetrafluoroborate: the first bis-amidinium salt of acetylenedicarboxyclic acid. A new superelectrophile? AB - A method for the preparation of the first acetylenedicarboxamidinium salt from a bis-orthoamide derivative of acetylenedicarboxyclic acid has been established. The salt reacted with cyclopentadiene and furan at room temperature to give bicyclic [4+2]-cycloaddition products. The solid compounds were characterized by solution NMR spectroscopy and by single-crystal X-ray diffraction. Quantum chemical calculations of the isolated N,N,N',N',N'',N'',N''',N'''-octamethyl acetylene-bis(carboxamidinium) ion showed very good agreement with the spectroscopic and diffraction data. PMID- 22527912 TI - Geographical distribution of plakophilin-2 mutation prevalence in patients with arrhythmogenic cardiomyopathy. AB - Arrhythmogenic cardiomyopathy (AC) is characterised by myocardial fibrofatty tissue infiltration and presents with palpitations, ventricular arrhythmias, syncope and sudden cardiac death. AC is associated with mutations in genes encoding the desmosomal proteins plakophilin-2 (PKP2), desmoplakin (DSP), desmoglein-2 (DSG2), desmocollin-2 (DSC2) and junctional plakoglobin (JUP). In the present study we compared 28 studies (2004-2011) on the prevalence of mutations in desmosomal protein encoding genes in relation to geographic distribution of the study population. In most populations, mutations in PKP2 showed the highest prevalence. Mutation prevalence in DSP, DSG2 and DSC2 varied among the different geographic regions. Mutations in JUP were rarely found, except in Denmark and the Greece/Cyprus region. PMID- 22527913 TI - Amor and Psyche; a growing relationship? PMID- 22527914 TI - An unusual fistula closed by percutaneous coil embolisation. PMID- 22527915 TI - Self-reported versus 'true' adherence in heart failure patients: a study using the Medication Event Monitoring System. AB - BACKGROUND: Adherence to (non)pharmacological treatment is important in heart failure (HF) patients, since it leads to better clinical outcome. Although self reported and objectively measured medication adherence in HF patients have been compared in previous studies, none of these studies have used an evidence-based cutpoint to differentiate between adherence and non-adherence. METHODS: In 37 HF patients (mean age 68 +/- 10 years, 27 % female, 40 % NYHA functional class III IV), medication (ACEi/ARB) adherence was objectively measured using the Medication Event Monitoring System (MEMS). Adherence to and importance of taking medication was also assessed by self-report using the Revised HF Compliance Questionnaire. RESULTS: All patients reported that adherence was (highly) important to them and that they 'always' took their medication as prescribed (i.e. 100 % adherence). However, when measured by the MEMS, only 76 % of all patients were adherent. Non-adherent patients more often had a complex medication regimen (78 % vs. 21 %, P < .01), more often depressive symptoms (75 % vs. 29 %, P = .04) and a shorter history of HF (8 vs. 41 months, P = .04), compared with adherent patients. CONCLUSIONS: Medication adherence measured by the MEMS was remarkably lower than self-reported adherence. Given the evidence of its importance, further efforts are needed to improve adherence to the pharmacological regimen in HF patients. PMID- 22527916 TI - Design and methodology of the COACH-2 (Comparative study on guideline adherence and patient compliance in heart failure patients) study: HF clinics versus primary care in stable patients on optimal therapy. AB - BACKGROUND: Since the number of heart failure (HF) patients is still growing and long-term treatment of HF patients is necessary, it is important to initiate effective ways for structural involvement of primary care services in HF management programs. However, evidence on whether and when patients can be referred back to be managed in primary care is lacking. AIM: To determine whether long-term patient management in primary care, after initial optimisation of pharmacological and non-pharmacological treatment in a specialised HF clinic, is equally effective as long-term management in a specialised HF clinic in terms of guideline adherence and patient compliance. METHOD: The study is designed as a randomised, controlled, non-inferiority trial. Two-hundred patients will be randomly assigned to be managed and followed in primary care or in a HFclinic. Patients are eligible to participate if they are (1) clinically stable, (2) optimally up-titrated on medication (according to ESC guidelines) and, (3) have received optimal education and counselling on pre-specified issues regarding HF and its treatment. Furthermore, close cooperation between secondary and primary care in terms of back referral to or consultation of the HF clinic will be provided.The primary outcome will be prescriber adherence and patient compliance with medication after 12 months. Secondary outcomes measures will be readmission rate, mortality, quality of life and patient compliance with other lifestyle changes. EXPECTED RESULTS: The results of the study will add to the understanding of the role of primary care and HF clinics in the long-term follow-up of HF patients. PMID- 22527917 TI - Initial experience of treating anal fistula with the Surgisis anal fistula plug. AB - BACKGROUND: Complex anal fistulas remain a challenge for the colorectal surgeon. The anal fistula plug has been developed as a simple treatment for fistula-in ano. We present and evaluate our experience with the Surgisis anal fistula plug from two centres. METHODS: Data were prospectively collected and analysed from consecutive patients undergoing insertion of a fistula plug between January 2007 and October 2009. Fistula plugs were inserted according to a standard protocol. Data collected included patient demographics, fistula characteristics and postoperative outcome. RESULTS: Forty-four patients underwent insertion of 62 plugs (27 males, mean age 45.6 years), 25 of whom had prior fistula surgery. Mean follow-up was 10.5 months Twenty-two patients (50%) had successful healing following the insertion of plug with an overall success rate of 23 out of 62 plugs inserted (35%). Nineteen out of 29 patients healed following first-time plug placement, whereas repeated plug placement was successful in 3 out of 15 patients (20%; p = 0.0097). There was a statistically significant difference in the healing rate between patients who had one or less operations prior to plug insertion (i.e. simple fistulas) compared with patients who needed multiple operations (18 out of 24 patients vs. 4 out of 20 patients; p = 0.0007). CONCLUSIONS: Success of treatment with the Surgisis anal fistula plug relies on the eradication of sepsis prior to plug placement. Plugs inserted into simple tracts have a higher success rate, and recurrent insertion of plugs following previous plug failure is less likely to be successful. We suggest the fistula plug should remain a first-line treatment for primary surgery and simple tracts. PMID- 22527918 TI - 3D intrastomal ultrasonography, an instrument for detecting stoma-related fistula. AB - BACKGROUND: The aim of the present study was to evaluate the recently developed 3D intrastomal ultrasonography in diagnosing stoma-associated complaints and suspected complications after parastomal hernia repair such as peristomal fistula and abscesses. METHODS: 3D intrastomal ultrasonography was used to image peristomal tissue in two patients with complaints after parastomal hernia repair performed with IPOM (intraperitoneal onlay mesh). One patient had ulcerative colitis and one Crohn's disease. Both patients were investigated because of pain and in one case also signs of a subcutaneous abscess. RESULTS: Intrastomal ultrasonography revealed fistulas connected to the intestinal segment leading to the stoma in both cases. Both cases also showed signs of a fistula descending to the abdominal cavity. In one case, a subcutaneous abscess was identified and in the other a small abscess adjacent to the fistula and the edge of the fascia. CONCLUSIONS: Stoma complaints after surgery for parastomal hernia with implantation of IPOM mesh can be diagnosed using 3D intrastomal ultrasonography. This new 3D technique for imaging intrastomal hernia can be used to complement traditional methods in the detection of stoma-associated abscesses and fistulas with or without foreign material such as mesh. PMID- 22527919 TI - Sacral nerve stimulation in patients with severe fecal incontinence after rectal resection. PMID- 22527920 TI - A novel device reduces anal pain after rubber band ligation: a randomized controlled trial. AB - BACKGROUND: Anal pain is a well-known sequel of rubber band ligation (RBL). A plastic device, the anal cooler which can be frozen in a freezer, has been developed to reduce anal pain. It contains a mixture of glycols and has a minimum temperature of 4 degrees C. This study was designed to investigate the efficacy of the anal cooler in pain relief after RBL. METHODS: Between 2009 and 2010, 100 patients who underwent RBL were prospectively randomized into an anal cooler group (n = 50) or a control group (n = 50). The anal cooler group was instructed to use the cooler when they had pain. All patients were asked to keep a pain diary (0 = no pain; 10 = extreme pain), and follow-up was performed after 3-6 weeks. RESULTS: It was found that 24/50 patients (48 %) in the anal cooler group and 31/50 (62 %) in the control group needed oral analgesics (NS). In total, 36/50 patients (72 %) used the anal cooler. Of these, 9/36 patients (25 %) noticed improvement. Of the remaining 27/36 patients (75 %) who did not notice improvement, 5/36 patients (14 %) found the insertion of the cooler uncomfortable and 1/36 patients (3 %) experienced nausea. No complications occurred during or after the use of the cooler. The 14/50 patients (28 %), who did not use the cooler, had a lower post-banding pain score compared with patients who used the cooler (1.4 vs 6.4; P < 0.001). CONCLUSIONS: Although post-banding pain after RBL is usually mild, the anal cooler seems to relieve anal pain in 25 % of the patients who used the device. PMID- 22527921 TI - Tarlov cysts: an unusual case of perianal pain. PMID- 22527922 TI - More advanced or aggressive colorectal cancer is associated with a higher incidence of "high-grade intraepithelial neoplasia" on biopsy-based pathological examination. AB - BACKGROUND: Invasion of submucosa (ISM) is required for the pathological diagnosis of colorectal cancer according to the WHO criteria. A large proportion of colorectal cancers may be underdiagnosed as high-grade intraepithelial neoplasia (HGIN) because ISM is not identified in the preoperative biopsy. The aim of this study was to investigate the clinicopathologic features that are associated with missing the diagnosis of ISM in biopsy specimens of invasive colorectal cancer. METHODS: Three hundred and sixteen patients diagnosed with colorectal cancer between January 2007 and December 2008 with well-preserved preoperative biopsy specimens were enrolled in the study. Three hundred and eleven patients had an isolated lesion, and five had two lesions. Biopsy specimens were reevaluated by two senior pathologists. Clinicopathologic features, biopsy pathology and surgical pathology results of all patients were analyzed by univariate and multivariate analyses. RESULTS: ISM was identified in 216 cases (67.3 %) by biopsy-based pathological examination, and missed in 105 (32.7 %) cases, 72 of which were diagnosed as HGIN. Univariate analysis indicated that in colorectal cancer patients with smaller biopsy specimens (P = 0.042), mucinous or signet-ring cell carcinoma (P = 0.003), higher WHO tumor grade (P = 0.001) and positive lymph nodes (P = 0.011), ISM was more likely to be missed. There was a trend toward an increased diagnosis of ISM with the increase in the number of biopsy specimens (P = 0.105). On multivariate logistic regression analysis, smaller biopsy specimens (OR, 1.810; 95 % CI, 1.081-3.032; P = 0.024) and higher WHO tumor grade (OR, 2.073; 95 % CI, 1.046-4.107; P = 0.037) were the only factors associated with failure to identify ISM. CONCLUSIONS: A large number of invasive colorectal cancers are at risk of being underdiagnosed as HGIN by biopsy-based pathology. The smaller the biopsy size, the less likely it is that the muscularis mucosae is included in the specimen. Also, in the more advanced or aggressive colorectal cancers, ISM is more likely to be missed on biopsy, which may be due to the destruction of the muscularis mucosae by more aggressive cancers. PMID- 22527923 TI - Laparoscopic Hartmann's procedure for fecal peritonitis resulting from perforation of the left-sided colon in elderly and severely ill patients. AB - BACKGROUND: Traditional treatment for fecal peritonitis resulting from perforation of the left-sided colon has been performed using Hartmann's procedure to reduce the high mortality caused by anastomotic leakage. However, the morbidity rates associated with abdominal incision (due in great part to wound infection, and dehiscence of abdominal fascia) are high. Therefore, we propose using laparoscopic Hartmann's procedure with abdominal incisions only for the port site to reduce the high morbidity associated with the laparoscopic procedure as compared to open surgery. METHODS: Between April 2008 and July 2011, we treated 16 consecutive patients (median age, 83 years) with fecal peritonitis resulting from perforations in the left-sided colon due to various causes. The American Society of Anesthesiologists score of each patient was either IV or V. Patients underwent a four-port laparoscopic Hartmann's procedure. Specimens were extracted through the stoma site. Irrigation of the abdominal cavity with more than 10 L of saline was performed in every case, as was insertion of three 10-mm silicon drains via the port site into the left- and right subphrenic spaces or the pouch of Douglas. RESULTS: The median total surgical time was 166 min (range, 123-250 min). There were no intraoperative complications, and there was no need to convert to open surgery. Fourteen patients survived. There was no wound infection or dehiscence of abdominal fascia. Successful laparoscopic reversals of the laparoscopic Hartmann's procedure were performed in all 14 survivors. CONCLUSIONS: This laparoscopic Hartmann's procedure is a promising surgical strategy for treating fecal peritonitis arising from perforation of the left sided colon. PMID- 22527924 TI - A simple technique for repair of distal limb prolapse of a loop colostomy. AB - Several procedures have been proposed for the prolapse of a loop colostomy. However, most are associated with a high recurrence rate or are rather expensive. We have newly developed a simple, safe, and inexpensive method, which is a modification of Thiersch's method, for repair of distal limb prolapse of a loop colostomy. PMID- 22527925 TI - Avoiding extraction site herniation after laparoscopic right colectomy. AB - Transverse abdominal wall incisions are favoured as part of enhanced recovery programmes. We explored the use of rectus-preserving extraction site incisions in laparoscopic right colectomy. The approach involved minimal anterior abdominal wall disruption with preservation of the rectus abdominis muscle: the rectus abdominis muscle extraction site (RAMES). In 15 patients, a RAMES was used electively in right colectomy for malignancy. The median wound length was 6 cms. There was no clinical or radiological evidence of incisional herniation in the 15 patients at 12-month and in the 12 survivors at 24-month follow-up. An anatomical dissection at specimen extraction site reduces early incisional herniation rates and should be of benefit in the longer term. PMID- 22527927 TI - Saving time stitching thick biological mesh during laparoscopic ventral rectopexy. AB - We present a trick to save time at stitching of thick biological mesh during laparoscopic ventral mesh rectopexy by the use of a belt hole puncher. PMID- 22527926 TI - The influence of age on posterior pelvic floor dysfunction in women with obstructed defecation syndrome. AB - BACKGROUND: Knowledge of risk factors is particularly useful to prevent or manage pelvic floor dysfunction but although a number of such factors have been proposed, results remain inconsistent. The purpose of this study was to evaluate the impact of aging on the incidence of posterior pelvic floor disorders in women with obstructed defecation syndrome evaluated using echodefecography. METHODS: A total of 334 patients with obstructed defecation were evaluated using echodefecography in order to quantify posterior pelvic floor dysfunction (rectocele, intussusception, mucosal prolapse, paradoxical contraction or non relaxation of the puborectalis muscle, and grade III enterocele/sigmoidocele). Patients were grouped according to the age (Group I = patients up to 50 years of age; Group II = patients over 50 years of age) to evaluate the isolated and associated incidence of dysfunctions. To evaluate the relationship between dysfunction and age-related changes, patients were also stratified into decades. RESULTS: Group I included 196 patients and Group II included 138. The incidence of significant rectocele, intussusception, rectocele associated with intussusception, rectocele associated with mucosal prolapse and 3 associated disorders was higher in Group II, whereas anismus was more prevalent in Group I. The incidence of significant rectocele, intussusception, mucosal prolapse and grade III enterocele/sigmoidocele was found to increase with age. Conversely, anismus decreased with age. CONCLUSIONS: Aging was shown to influence the incidence of posterior pelvic floor disorders (rectocele, intussusception, mucosa prolapse and enterocele/sigmoidocele), but not the incidence of anismus, in women with obstructed defecation syndrome. PMID- 22527928 TI - Laparoscopic diagnosis and management of a novel inguino-pelvic hernia. AB - Inguinal hernias can typically be diagnosed with a proper history and thorough physical exam. However, patients with chronic groin pain, normal physical exam and no radiologic findings present a diagnostic/therapeutic dilemma [1]. We present a case of a female patient with obscure chronic groin pain. Upon laparoscopic exploration, she was found to have a hernia in a previously non described location. Reduction of a chronically incarcerated preperitoneal fat and subsequent repair using traditional transabdominal preperitoneal repair resulted in a complete resolution of her pain. PMID- 22527929 TI - A new classification for seroma after laparoscopic ventral hernia repair. AB - INTRODUCTION: Laparoscopic techniques are being used increasingly in the repair of ventral hernias, but different incidences and complications have been described as potential risks of this approach. Seroma formation has been documented as one of the most common complication, although most of the time remains asymptomatic and it can be considered just an incident. The incidence of seroma after laparoscopic ventral hernia repair has not been properly documented and analyzed since the definition used by different authors is not the same from one series to another. We present a new classification of clinical seroma in order to try to establish the real incidence of this potential complication. CLINICAL CLASSIFICATION: Clinical seromas could be detected during physical examination in many patients after LVHR, but in most of the cases they do not cause any problem or just a minimum discomfort that allows normal activity. Based on this fact and on the need of carrying out a medical or an invasive therapy to treat them, five groups can be established in order to classified this entity: Type 0, no clinical seroma (being 0a no seroma after clinical examination and radiological examinations and 0b those detected radiologically but not detected clinically); Type I, clinical seroma lasting less than 1 month; Type II (seroma with excessive duration), clinical seroma lasting more than 1 month (being IIa between 1 and 3 months and IIb between 3 and 6 months); Type III (symptomatic seromas that may need medical treatment), minor seroma-related complications (seroma lasting more than 6 month, esthetic complaints of the patient due to seroma, discomfort related to the seroma that does not allow normal activity to the patient, pain, superficial infection with cellulites); and Type IV (seroma that need to be treated), mayor seroma-related complications (need to puncture the seroma, seroma drained spontaneously, applicable to open approach, deep infection, recurrence and mesh rejection). It is important to differentiate between a complication and an incident, being considered seroma as an incident if it is classified as seroma Type I or II, and a complication if it is included in group III and IV. The highest classification is the one that should be used in order to describe the type of seroma. CONCLUSIONS: Seroma is one of the most common complications after laparoscopic ventral hernia repair although its real clinical incidence is variable since it has been described in the literature following different parameters. It is observed in almost all cases by radiological examinations, but it is not determined if must be considered an incident or a complication. For these reasons, a new classification of seroma has been proposed in order to unify criteria among surgeons when describing their experience. This classification could be also used in the future to measure the effect of new methods proposed to reduce seroma formation to evaluate the incidence of seroma depending on the mesh used, and it could be also proposed to be used to describe the incidence of seroma after open ventral hernia repair. PMID- 22527930 TI - EuraHS: the development of an international online platform for registration and outcome measurement of ventral abdominal wall hernia repair. AB - BACKGROUND: Although the repair of ventral abdominal wall hernias is one of the most commonly performed operations, many aspects of their treatment are still under debate or poorly studied. In addition, there is a lack of good definitions and classifications that make the evaluation of studies and meta-analyses in this field of surgery difficult. MATERIALS AND METHODS: Under the auspices of the board of the European Hernia Society and following the previously published classifications on inguinal and on ventral hernias, a working group was formed to create an online platform for registration and outcome measurement of operations for ventral abdominal wall hernias. Development of such a registry involved reaching agreement about clear definitions and classifications on patient variables, surgical procedures and mesh materials used, as well as outcome parameters. The EuraHS working group (European registry for abdominal wall hernias) comprised of a multinational European expert panel with specific interest in abdominal wall hernias. Over five working group meetings, consensus was reached on definitions for the data to be recorded in the registry. RESULTS: A set of well-described definitions was made. The previously reported EHS classifications of hernias will be used. Risk factors for recurrences and co morbidities of patients were listed. A new severity of comorbidity score was defined. Post-operative complications were classified according to existing classifications as described for other fields of surgery. A new 3-dimensional numerical quality-of-life score, EuraHS-QoL score, was defined. An online platform is created based on the definitions and classifications, which can be used by individual surgeons, surgical teams or for multicentre studies. A EuraHS website is constructed with easy access to all the definitions, classifications and results from the database. CONCLUSION: An online platform for registration and outcome measurement of abdominal wall hernia repairs with clear definitions and classifications is offered to the surgical community. It is hoped that this registry could lead to better evidence-based guidelines for treatment of abdominal wall hernias based on hernia variables, patient variables, available hernia repair materials and techniques. PMID- 22527933 TI - Oxidatively modified high density lipoprotein promotes inflammatory response in human monocytes-macrophages by enhanced production of ROS, TNF-alpha, MMP-9, and MMP-2. AB - It has been proposed that high-density lipoprotein (HDL) loses its cardioprotective ability through oxidative modifications by reactive oxygen species (ROS) and promote atherogenesis. However, the pro-atherogenic pathways undergone by oxidized HDL remain poorly understood. Since monocytes play a crucial role in atherogenesis, this study was aimed to investigate the influence of both native and oxidized HDL (oxHDL) on monocytes-macrophages functions relevant to atherogenesis. HDL particles were isolated from human blood samples by ultracentrifugation and subjected to in vitro oxidation with CuSO(4). The extent of oxidation was quantitated by measurement of lipid peroxides. Human peripheral blood mononuclear cells were isolated and cultured under standard conditions. Cells were treated with native and oxHDL at varying concentrations for different time intervals and used for several analyses. Intracellular ROS production was assessed based on ROS-mediated DCFH fluorescence of the cells. The release of TNF-alpha and matrix metalloproteinases (MMPs) was quantitated using ELISA kit and gelatine zymography, respectively. Treatment of cells with oxidized HDL enhanced the production of ROS in a concentration-dependent way, while native HDL had no such effect. Further, the release of TNF-alpha, MMP-9, and MMP-2 was found to be remarkably higher in cells incubated with oxHDL than that of native HDL. Results demonstrate that oxidative modification of HDL induces pro inflammatory response and oxidative stress in human monocytes-macrophages. PMID- 22527932 TI - Clinical relevance of cyclooxygenase-2 and matrix metalloproteinases (MMP-2 and MT1-MMP) in human breast cancer tissue. AB - Breast cancer (BC) is the most common neoplasm among women in most developed countries, including Egypt. Elevated levels of certain proteins in human BC are associated with unfavorable prognosis and progressive stages of the disease. The aim of our study was to evaluate the protein expression profile and prognostic significance of cyclooxygenase-2 (COX-2), matrix metalloproteinase-2 (MMP-2), MMP 9 and membrane type 1-MMP (MT1-MMP) and their interaction in operable BC patients. The protein expression of COX-2, MMP-2 and MT1-MMP were evaluated by western blot technique, whereas enzymatic activity of MMP-2 and MMP-9 was determined by zymography in 47 breast cancer patients as well as normal adjacent tissues. Also, the correlation between these proteins and age, tumor size, LN stage, TNM stage, estrogen receptor, progesterone receptor, disease-free survival, and overall survival (OS) has been investigated. As compared to adjacent normal tissues, COX-2, MMP-2 and MT1-MMP were over-expressed in 43, 64, and 60 % of tumor tissues, respectively. In the same pattern, the activity of MMP 2 (62 %) and MMP-9 (45 %) was elevated in BC tissues. Multivariate analysis showed a positive correlation between the protein expression of COX-2, MMP-2, and MT1-MMP and the activity of MMP-2 and MMP-9 in BC patients. However, the enzymatic activity showed no correlation with clinicopathological features. This study confirms the preclinical evidence that COX-2 increased the expression of MT1-MMP, which in turn activates MMP-2. The lack of correlation with clinicopathological features, OS or disease-free survival ascertains the complexity of tumor progression and metastasis with many pro- and counter regulatory factors. PMID- 22527935 TI - Cyclic stretch stimulates recruitment of active Na+/K+-ATPase subunits to the plasma membrane of skeletal muscle cells. AB - Cyclic stretch increases Na(+)/K(+)-ATPase activity and abundance in several tissues, including skeletal muscle cells. The present study was undertaken to investigate whether Na(+)/K(+)-ATPase undergoes acute changes in its catalytic activity in response to cyclic stretch. Na(+)/K(+)-ATPase activity increased after continuously stretched for 6 h, and reached the maximum at 24 h. The inhibition of gene transcription (actinomycin D) had no effect on stretch-induced Na(+)/K(+)-ATPase activity. Cyclic stretch also increases the plasma membrane content of alpha(1)- and alpha(2)-subunit of Na(+)/K(+)-ATPase. Brefeldin A could completely abolished the stretch-induced recruitment of alpha-subunits to the plasma membrane and Na(+)/K(+)-ATPase activity. In conclusion, cyclic stretch directly stimulates Na(+)/K(+)-ATPase activity in skeletal muscle cells through post-transcriptional activation, likely by increasing translocation of Na(+)/K(+) ATPase molecules to plasma membrane. PMID- 22527934 TI - Role of NF-kappaB and p38 MAPK activation in mediating angiotensin II and endothelin-1-induced stimulation in leptin production and cardiomyocyte hypertrophy. AB - We recently identified leptin as a downstream factor mediating the hypertrophic effects of both angiotensin II and endothelin-1 in cardiomyocytes, an effect dependent on increased leptin biosynthesis, however, the mechanism for such increased leptin production is not known. This study was designed to elucidate the mechanisms underlying angiotensin II- and endothelin-1-stimulated synthesis in cultured ventricular myocytes. The hypertrophic effects of both angiotensin II (100 nM) and endothelin-1 (10 nM) were associated with increased leptin secretion and gene expression by 40 and 50 %, and 86 and 68 %, respectively. These effects were associated with significantly increased nuclear factor kappa-light-chain enhancer of activated B cells (NF-kappaB) phosphorylation by 34 and 52 %, as well as enhanced translocation of NF-kappaB into nuclei and also the NF-kappaB-DNA binding activity by 35 and 31 % induced by angiotensin II and endothelin-1, respectively. On their own, 24 h treatment with either angiotensin II or endothelin-1 increased cell surface area by 30 and 40 %, protein synthesis by 30 % and the alpha-skeletal actin gene by 53 and 68 %, respectively, indicating a robust hypertrophic effect whereas this was completely prevented by NF-kappaB inhibition. In addition, NF-kappaB inhibition significantly attenuated angiotensin II and endothelin-1-induced p38 MAPK activation whereas inhibition of p38 MAPK blocked both angiotensin II- and endothelin-1-induced increases in leptin secretion. The ability of both angiotensin II- and endothelin-1 to increase leptin production in cardiomyocytes and the resultant hypertrophic response are mediated by NF-kappaB and dependent on p38 MAPK activation. PMID- 22527936 TI - Endothelin-induced differentiation of Nkx2.5+ cardiac progenitor cells into pacemaking cells. AB - The mechanisms governing the development of cardiac pacemaking and conduction system are not well understood. In order to provide evidence for the derivation of pacemaking cells and the signal that induce and maintain the cells in the developing heart, Nkx2.5(+) cardiac progenitor cells (CPCs) were isolated from embryonic heart tubes of rats. Endothelin-1 was subsequently added to the CPCs to induce differentiation of them towards cardiac pacemaking cells. After the treatment, Nkx2.5(+) CPCs displayed spontaneous beating and spontaneously electrical activity as what we have previously described. Furthermore, RT-PCR and immunofluorescence staining demonstrated that Tbx3 expression was increased and Nkx2.5 expression was decreased in the induced cells 4 days after ET-1 treatment. And the significantly increased expression of Hcn4 and connexin-45 were detected in the induced cells 10 days after the treatment. In addition, Nkx2.5(+) CPCs were transfected with pGCsi-Tbx3 4 days after ET-1 treatment in an attempt to determine the transcription regulatory factor governing the differentiation of the cells into cardiac pacemaking cells. The results showed that silencing of Tbx3 decreased the pacemaking activity and led to down-regulation of pacemaker genes in the induced cells. These results confirmed that Nkx2.5(+) CPCs differentiated into cardiac pacemaking cells after being treated with ET-1 and suggested that an ET-1-Tbx3 molecular pathway govern/mediate this process. In conclusion, our study support the notion that pacemaking cells originate from Nkx2.5(+) CPCs present in embryonic heart tubes and endothelin-1 might be involved in diversification of cardiomyogenic progenitors toward the cells. PMID- 22527937 TI - Apigenin induces apoptosis via extrinsic pathway, inducing p53 and inhibiting STAT3 and NFkappaB signaling in HER2-overexpressing breast cancer cells. AB - Phytoestrogens are known to prevent tumor induction. But their molecular mechanisms of action are still unknown. This study aimed to examine the effect of apigenin on proliferation and apoptosis in HER2-expressing breast cancer cells. In our experiments, apigenin inhibited the proliferation of MCF-7 vec and MCF-7 HER2 cells. This growth inhibition was accompanied with an increase of sub G(0)/G(1) apoptotic fractions. Overexpression of HER2 did not confer resistance to apigenin in MCF-7 cells. Apigenin-induced extrinsic apoptosis pathway up regulating the levels of cleaved caspase-8, and inducing the cleavage of poly (ADP-ribose) polymerase, whereas apigenin did not induce apoptosis via intrinsic mitochondrial apoptosis pathway since this compound did not decrease mitochondrial membrane potential maintaining red fluorescence and did not affect the levels of B-cell lymphoma 2 (BCL2) and Bcl-2-associated X protein. Moreover, apigenin reduced the tyrosine phosphorylation of HER2 (phospho-HER2 level) in MCF 7 HER2 cells, and up-regulated the levels of p53, phospho-p53 and p21 in MCF-7 vec and MCF-7 HER2 cells. This suggests that apigenin induces apoptosis through p53-dependent pathway. Apigenin also reduced the expression of phospho-JAK1 and phospho-STAT3 and decreased STAT3-dependent luciferase reporter gene activity in MCF-7 vec and MCF-7 HER2 cells. Apigenin decreased the phosphorylation level of IkappaBalpha in the cytosol, and abrogated the nuclear translocation of p65 within the nucleus suggesting that it blocks the activation of NFkappaB signaling pathway in MCF-7 vec and MCF-7 HER2 cells. Our study indicates that apigenin could be a potential useful compound to prevent or treat HER2-overexpressing breast cancer. PMID- 22527939 TI - Increased expression of calcium-sensing receptors in atherosclerosis confers hypersensitivity to acute myocardial infarction in rats. AB - Acute myocardial infarction (AMI) is a leading cause of death worldwide. Most cases of AMI result from coronary atherosclerosis (AS). The pathogenic mechanisms underlying AS lesions and AMI are incompletely understood. Calcium-sensing receptors (CaSR) belong to a family of G-protein-coupled receptors. We previously discovered that CaSR was expressed in the heart tissue of adult rats. CaSR may contribute to AMI in AS. We initially established a rat model of AS by injection of vitamin D(3) and feeding with a high-fat diet. Isoproterenol (ISO) was used to induce AMI. The MB isoenzyme of creatine kinase (CK-MB), lactate dehydrogenase (LDH), cardiac troponin T (cTnT), tetrazolium chloride staining, and cardiac function parameters were selected as indicators of myocardial damage or necrosis. Cardiac apoptosis was analyzed by transferase dUTP nick-end labeling (TUNEL) assay. Expression of CaSR, Bcl-2, Bax, caspase-3, p-ERK1/2, p-JNK, and p-p38 were determined by Western blot analysis. Compared with the control group, levels of cTnT, CK-MB, and LDH; number of TUNEL-positive cells; and expression of CaSR, Bax, caspase-3, p-ERK1/2, p-JNK and p-p38, were significantly increased, whereas cardiac function and expression of Bcl-2 were decreased markedly in isoproterenol (ISO)-treated group (C/ISO) and AS groups. These changes were significant in the AS/ISO group than in the C/ISO group or AS group. The upregulation of CaSR during AS formation renders hypersensitivity to AMI. Activation of the pro-apoptotic mitochondria pathway and JNK-p38 MAPK pathway triggered by increased expression of CaSR may be one of molecular mechanisms underlying AMI in AS. PMID- 22527938 TI - Phytanic acid disturbs mitochondrial homeostasis in heart of young rats: a possible pathomechanism of cardiomyopathy in Refsum disease. AB - Phytanic acid (Phyt) accumulates in tissues and biological fluids of patients affected by Refsum disease. Although cardiomyopathy is an important clinical manifestation of this disorder, the mechanisms of heart damage are poorly known. In the present study, we investigated the in vitro effects of Phyt on important parameters of oxidative stress in heart of young rats. Phyt significantly increased thiobarbituric acid-reactive substances levels (P < 0.001) and carbonyl formation (P < 0.01), indicating that this fatty acid induces lipid and protein oxidative damage, respectively. In contrast, Phyt did not alter sulfhydryl oxidation. Phyt also decreased glutathione (GSH) concentrations (P < 0.05), an important non-enzymatic antioxidant defense. Moreover, Phyt increased 2',7' dichlorofluorescin oxidation (DCFH) (P < 0.01), reflecting increased reactive species generation. We also found that the induced lipid and protein oxidative damage, as well as the decreased GSH levels and increased DCFH oxidation provoked by this fatty acid were prevented or attenuated by the reactive oxygen species scavengers melatonin, trolox, and GSH, but not by the nitric oxide inhibitor N: (omega)-nitro-L: -arginine methyl ester, suggesting that reactive oxygen species were involved in these effects. Next, we verified that Phyt strongly inhibited NADH-cytochrome c oxidoreductase (complex I-III) activity (P < 0.001) in heart supernatants, and decreased membrane potential and the NAD(P)H pool in heart mitochondria, indicating that Phyt acts as a metabolic inhibitor and as an uncoupler of the electron transport chain. Therefore, it can be presumed that disturbance of cellular energy and redox homeostasis induced by Phyt may possibly contribute to the cardiomyopathy found in patients affected by Refsum disease. PMID- 22527940 TI - The key role of PGC-1alpha in mitochondrial biogenesis and the proliferation of pulmonary artery vascular smooth muscle cells at an early stage of hypoxic exposure. AB - Peroxisome proliferator activated receptor gamma coactivator 1alpha (PGC-1alpha) induced by hypoxia regulates mitochondrial biogenesis and oxidative stress. However, the potential role of PGC-1alpha in hypoxia-promoted proliferation of pulmonary arterial vascular smooth muscle cells (PASMCs) is completely unknown. In this study, we found that hypoxia significantly induced the expression of PGC 1alpha in cultured PASMCs and activated mitochondrial biogenesis through upregulation of nuclear respiratory factor-1 and mitochondria transcription factor A in a time-dependent manner. Knockdown of PGC-1alpha by siRNA abrogated hypoxia-induced PASMCs proliferation via the downregulation of PCNA, cyclinA, and cyclinE. Furthermore, we observed that PI3K/Akt signaling pathway was involved in hypoxia induced PGC-1alpha expression and PASMCs proliferation. Taken together, these datas reveal PGC-1alpha as the key regulator to mediate mitochondrial biogenesis and the proliferation of PASMCs at an early stage of hypoxic exposure. This process might bring to light a potential adaptive mechanism for PASMCs to minimize hypoxic damage and our novel findings provide new insight into the development of hypoxic pulmonary hypertension. PMID- 22527941 TI - Isothiocyanate-drug interactions in the human adenocarcinoma cell line Caco-2. AB - Isothiocyanates, among which alyssin is counted, are the compounds that have proved chemopreventive properties and the ability to induce the 2 and the 3 detoxification phase by affecting the transcription factor nuclear erythroid 2 related factor (Nrf2). Having a positive effect on the human body, these compounds are used as dietary supplements. Because of the observed increase in the consumption of dietary supplements taken along with the drugs routinely used in medical practice, this study examined the possibility of interactions between alyssin and drugs, which could have an impact on cell metabolism. We have determined the effects of the tested substances and their interactions on the expression and activity of the phase 2 genes, as well as on the drug transport, which could be influenced by affecting the expression of transport proteins that belong to the 3 phase of metabolism. It was also studied whether the transcription factor Nrf2 is responsible for the interactions that occurred. The results showed that the interactions between alyssin and the tested drugs strengthen or weaken the effect of the drugs given separately depending on the concentration of alyssin and the type of drug. Even though Nrf2 is involved in the interaction, it seems that it is not the only factor regulating the interactions between the tested medications. PMID- 22527942 TI - Monocyte chemoattractant protein-1 mediates angiotensin II-induced vascular smooth muscle cell proliferation via SAPK/JNK and ERK1/2. AB - Abnormal vascular smooth muscle cells proliferation is the pathophysiological basis of cardiovascular diseases, such as hypertension, atherosclerosis, and restenosis after angioplasty. Angiotensin II can induce abnormal proliferation of vascular smooth muscle cells, but the molecular mechanisms of this process remain unclear. Here, we explored the role and molecular mechanism of monocyte chemotactic protein-1, which mediated angiotensin II-induced proliferation of rat aortic smooth muscle cells. 1,000 nM angiotensin II could stimulate rat aortic smooth muscle cells' proliferation by angiotensin II type 1 receptor (AT(1)R). Simultaneously, angiotensin II increased monocyte chemotactic protein-1 expression and secretion in a dose-and time-dependent manner through activation of its receptor AT(1)R. Then, monocyte chemotactic protein-1 contributed to angiotensin II-induced cells proliferation by CCR2. Furthermore, we found that intracellular ERK and JNK signaling molecules were implicated in angiotensin II stimulated monocyte chemotactic protein-1 expression and proliferation mediated by monocyte chemotactic protein-1. These results contribute to a better understanding effect on angiotensin II-induced proliferation of rat smooth muscle cells. PMID- 22527943 TI - Analytical optimal controls for the state constrained addition and removal of cryoprotective agents. AB - Cryobiology is a field with enormous scientific, financial, and even cultural impact. Successful cryopreservation of cells and tissues depends on the equilibration of these materials with high concentrations of permeating chemicals (CPAs) such as glycerol or 1,2 propylene glycol. Because cells and tissues are exposed to highly anisosmotic conditions, the resulting gradients cause large volume fluctuations that have been shown to damage cells and tissues. On the other hand, there is evidence that toxicity to these high levels of chemicals is time dependent, and therefore it is ideal to minimize exposure time as well. Because solute and solvent flux is governed by a system of ordinary differential equations, CPA addition and removal from cells is an ideal context for the application of optimal control theory. Recently, we presented a mathematical synthesis of the optimal controls for the ODE system commonly used in cryobiology in the absence of state constraints and showed that controls defined by this synthesis were optimal. Here we define the appropriate model, analytically extend the previous theory to one encompassing state constraints, and as an example apply this to the critical and clinically important cell type of human oocytes, where current methodologies are either difficult to implement or have very limited success rates. We show that an enormous increase in equilibration efficiency can be achieved under the new protocols when compared to classic protocols, potentially allowing a greatly increased survival rate for human oocytes and pointing to a direction for the cryopreservation of many other cell types. PMID- 22527944 TI - Influence of the nuclear membrane, active transport, and cell shape on the Hes1 and p53-Mdm2 pathways: insights from spatio-temporal modelling. AB - There are many intracellular signalling pathways where the spatial distribution of the molecular species cannot be neglected. These pathways often contain negative feedback loops and can exhibit oscillatory dynamics in space and time. Two such pathways are those involving Hes1 and p53-Mdm2, both of which are implicated in cancer. In this paper we further develop the partial differential equation (PDE) models of Sturrock et al. (J. Theor. Biol., 273:15-31, 2011) which were used to study these dynamics. We extend these PDE models by including a nuclear membrane and active transport, assuming that proteins are convected in the cytoplasm towards the nucleus in order to model transport along microtubules. We also account for Mdm2 inhibition of p53 transcriptional activity. Through numerical simulations we find ranges of values for the model parameters such that sustained oscillatory dynamics occur, consistent with available experimental measurements. We also find that our model extensions act to broaden the parameter ranges that yield oscillations. Hence oscillatory behaviour is made more robust by the inclusion of both the nuclear membrane and active transport. In order to bridge the gap between in vivo and in silico experiments, we investigate more realistic cell geometries by using an imported image of a real cell as our computational domain. For the extended p53-Mdm2 model, we consider the effect of microtubule-disrupting drugs and proteasome inhibitor drugs, obtaining results that are in agreement with experimental studies. PMID- 22527945 TI - Persistence probabilities for stream populations. AB - Individuals in streams and rivers are constantly at risk of being washed downstream and thereby lost to their population. The possibility of diffusion mediated persistence of populations in advective environments has been the focus of a multitude of recent modeling efforts. Most of these recent models are deterministic, and they predict the existence of a critical advection velocity, above which a population cannot persist. In this work, we present a stochastic approach to the persistence problem in streams and rivers. We use the dominant eigenvalue of the advection-diffusion operator to transition from a spatially explicit description to a spatially implicit birth-death process, in which individual washout from the domain appears as an additional death term. We find that the deterministic persistence threshold is replaced by a smooth transition from almost sure persistence to extinction as advection velocity increases. More interestingly, we explore how temporal variation in flow rate and other parameters affect the persistence probability. In line with general expectations, we find that temporal variation often decreases the persistence probability, and we focus on a few examples of how variation can increase population persistence. PMID- 22527946 TI - Relapse of acute myeloid leukemia at the pituitary gland: a case report and review of literature. PMID- 22527947 TI - Cell-type-specific expression of STAT transcription factors in tissue samples from patients with lymphocytic thyroiditis. AB - Expression of cytokine-regulated signal transducer and activator of transcription (STAT) proteins was histochemically assessed in patients diagnosed as having Hashimoto's disease or focal lymphocytic thyroiditis (n = 10). All surgical specimens showed histological features of lymphocytic thyroiditis, including a diffuse infiltration with mononuclear cells and an incomplete loss of thyroid follicles, resulting in the destruction of glandular tissue architecture. Immunohistochemical analysis demonstrated differential expression patterns of the various members of the STAT transcription factors examined, indicating that each member of this conserved protein family has its distinct functions in the development of the disease. Using an antibody that specifically recognized the phosphorylated tyrosine residue in position 701, we detected activated STAT1 dimers in numerous germinal macrophages and infiltrating lymphocytes as well as in oncocytes. In contrast, STAT3 expression was restricted to epithelial cells and showed a clear colocalization with the antiapoptotic protein Bcl-2. Moreover, expression of phospho-STAT3 was associated with low levels of stromal fibrosis, suggesting that STAT3 serves as a protective factor in the remodeling of the inflamed thyroid gland. Phospho-STAT5 immunoreactivity was detected in numerous infiltrating cells of hematopoietic origin and, additionally, in hyperplastic follicular epithelia. This tissue distribution demonstrated that activated STAT5 molecules participate in both lymphocytopoiesis and possibly also in the buildup of regenerating thyroid follicles. Taken together, the cell-type-specific expression patterns of STAT proteins in human lymphocytic thyroiditis reflect their distinct and partially antagonistic roles in orchestrating the balance between degenerating and regenerating processes within a changing cytokine environment. PMID- 22527948 TI - Fine needle aspiration biopsy of an unusual follicular adenoma with sebaceous like features. PMID- 22527949 TI - Delineation of the effects of angiotensin type 1 and 2 receptors on HL-1 cardiomyocyte apoptosis. AB - Angiotensin II (Ang II) exerts its effects by activating its receptors, primarily type 1 (AT1R) and type 2 (AT2R). While the role of AT1R activation in cardiomyocyte physiology is well known, the role of AT2R in cardiomyocyte apoptosis remains controversial. To define the precise role of AT1R and AT2R in this process, we transfected HL-1 cardiomyocytes with AT1R or AT2R cDNA, and examined markers of apoptosis. We found that AT1R overexpression was associated with upregulation of endogenous AT2R expression, but AT2R overexpression did not affect endogenous AT1R expression. Caspase-3 staining indicated that overexpression of AT1R as well as AT2R resulted in cardiomyocyte apoptosis with appropriate alterations in annexin V, Bax and Bcl2 expression. Overexpression of AT1R and AT2R markedly increased IL-1beta (AT2R>AT1R), iNOS (AT2R>AT1R) and eNOS expression. AT2R-induced cell apoptosis could be blocked by the iNOS selective inhibitor 1,400 W, and did not require exogenous Ang II. These findings suggest that AT2R overexpression induces cardiomyocyte apoptosis, most likely via iNOS upregulation. AT1R-mediated cardiomyocyte apoptosis may be partially mediated by upregulation of endogenous AT2R. PMID- 22527950 TI - Bone loss in rheumatoid arthritis: systemic, periarticular, and focal. AB - Rheumatoid arthritis is a chronic inflammatory disease that results in generalized bone loss and increased fracture risk. Characteristic radiologic features of rheumatoid arthritis include periarticular osteopenia and marginal erosions. An emerging literature highlights the importance of osteoclasts as mediators of the erosive process, with an impairment of bone formation by inhibition of the Wnt signaling pathway as a cause of lack of repair of erosions. MRI has demonstrated the importance of inflammation in the bone marrow compartment as a cause of periarticular osteopenia. The term osteoimmunology has evolved to highlight the association between cells and cytokines of the immune system and their relationship to bone metabolism in rheumatoid arthritis and other forms of chronic inflammatory arthritis. PMID- 22527951 TI - Is psoriatic arthritis a result of abnormalities in acquired or innate immunity? AB - Psoriatic arthritis is a common chronic inflammatory joint disease in which both inflammation and tissue damage contribute to the patient's outcome. Abnormal activation of the innate and the adaptive immune system contributes to the chronic disease process. Novel insights into these immune pathways are further corroborated by genetic evidence. In this review, we compare the current paradigm of psoriasis to mechanisms that likely play a role in psoriatic arthritis and provide an overview of the role of immune mechanisms in the different features of the disease. PMID- 22527952 TI - Ultrastructural alterations in colon absorptive cells of alloxan-induced diabetic rats submitted to long-term physical training. AB - Absorptive cells have notable importance for proper function of the colon, absorbing water and nutrients. In type I diabetes, hyperglycemia leads to remarkable alterations in cell structure. In absorptive cells, such changes may impair the function of the organ as a whole. Also, the effects of physical training, which plays crucial role in the treatment of diabetes, are not yet known in these cells. For this reason, to analyze the changes in colon epithelial absorptive cells of diabetic rats and the effects of physical training, Wistar rats were divided into four groups: sedentary control (SC), trained control (TC), sedentary diabetic (SD), and trained diabetic (TD). The training protocol consisted of swimming for 60 min a day, 5 days per week, during 8 weeks. Colon samples were collected, processed, and evaluated by histochemical and ultrastructural techniques. Although histochemical analysis did not reveal major differences, significant morphological differences were ultrastructurally observed among groups, especially related to the structure of tight junctions, interdigitations, and microvilli, which became longer in diabetics, and whose length was reduced after physical training, as proved by statistical analysis. There were no relevant changes in organelles. Thus, the development of type I diabetes can lead to changes at ultrastructural level that, even subtle, may cause important alterations in cell function. The practice of physical training, in turn, proved to be an important ally in the treatment of such changes. However, it cannot be used singly for treating this disease, requiring the combined practice of other methods. PMID- 22527953 TI - [Intercultural differences in the treatment of severely injured patients with poor prognosis. Using the example of a 23-year-old Chinese patient]. AB - Because of globalization, we are increasingly confronted with the treatment of patients from other cultures. Using the example of a 23-year-old Chinese patient, we explain the origin of the intercultural differences which developed into a conflict.Due to a bicycle accident the patient incurred an extremely severe traumatic brain injury with multiple midface fractures. The prognosis was unfavorable. Despite extensive information the family insisted on maximum therapy. This resulted in a misunderstanding among the medical team involved, because they believed that this was not in the interests of the patient. The position of the family is rooted in Chinese culture. An intensive examination might have avoided, or at least mitigated, a conflict. To summarize, it could be useful to address cultural peculiarities at an early stage when treating patients from different cultures to prevent conflicts or to be better prepared for them. Also, an Ethics Commission may be involved early for preventing or resolving a potential conflict. PMID- 22527954 TI - [Patients with periprosthetic femur fractures and consecutive stem replacement. Analysis of survival, complications, and quality of life]. AB - BACKGROUND: The goal of treating proximal periprosthetic femur fractures in geriatric patients is a timely postoperative mobilization. The purpose of this study is to analyze the results after treating our patients by femoral stem exchange irrespective of fixation status. The study included 32 patients (2001 2009; mean age 82 years; Vancouver classification: 12 type B1, 16 type B2, and 4 type C). METHOD: Ambulatory status and activities of daily living pre- and postoperatively were compared. Retrospective data collection was performed by reviewing patients' charts. By interviewing patients, family members, and family physicians missing information was collected. RESULTS: A total of 22 patients (69%) achieved their pre-traumatic mobilization level; 22 of 26 patients (85%) were reintegrated into their pre-traumatic environment. A 16% (n=5) complication rate and an 87% 12-month survival rate were calculated. CONCLUSION: The concept of primary stable periprosthetic fracture care by using a revision prosthetic device potentially reduces complications related to postoperative non-weight bearing without increasing the complication rate related to a more complex surgical procedure. PMID- 22527955 TI - [Evidence-based treatment protocol to manage patellar dislocation]. AB - Patellar dislocation is a common knee injury with mainly lateral dislocations, leading to ruptures of the medial patellofemoral ligament in most of the cases. Reliable data and prognostic factors for stability of the patellofemoral joint and satisfaction of the patient after either conservative or operative treatment have not been established yet. Until now, there are no randomized controlled trials for recurrent patellar dislocation at all. As a synopsis of the randomized controlled trials about first-time patellar dislocation, no significant difference between operative and conservative management is evident. This applies to both children and adolescents as well as to adults. There is a clear tendency towards first-line conservative therapy after traumatic patellar dislocation. Operative treatment is only required in case of accompanying injuries like osteochondral fractures or in case of recurrent dislocations. Further prospective randomized controlled trials with standardized operative and conservative treatment and patient cohorts of sufficient size are necessary in the future. PMID- 22527956 TI - [Femoral osteotomy for patellofemoral instability]. AB - Axis and torsion malalignment of the femur has been widely recognized as a primary reason for patellofemoral instability and pain. In this article we explain the current concepts of biomechanics and describe the radiological findings in computed tomography (CT) examination. We describe the technique of a biplanar varus and/or external rotation distal femoral osteotomy in detail. Existing clinical studies describe this technique as part of a multimodal treatment concept with good to excellent results. We present our current technique and clinical results. PMID- 22527958 TI - [Easier documentation for certified trauma centers oft (corrected) the German Society for accident surgery (corrected)]. PMID- 22527957 TI - [Standardized documentation in emergency departments with the core dataset of the DIVI]. AB - In Germany the documentation of every prehospital emergency medical treatment has been standardized since 1997 based on the core data-set MIND (minimal emergency physician data-set). Against this background it is very surprising that there is still no standardized data-set implemented for the documentation of early inhospital emergency care. In order to create such a data-set the current state of documentation in many different hospitals all over the country was scrutinized. In addition existing registries and international requirements were taken into consideration. Finally, a modular data-set was created using a Delphi process. This data-set was tested, clinically validated and finally ratified by the executive committee of the DIVI (German Interdisciplinary Association of Critical Care Medicine). The modular data-set was designed in such a way that a basic module forms the foundation for every patient. Process-oriented modules (e.g. surveillance) and symptom-oriented modules (e.g. trauma, neurology) were added if necessary. Along with this data-set a set of six modules was created for graphical representation when required. This high level of standardization not only allows an internal and external quality assessment but also provides a sophisticated documentation system especially to the trauma team in the emergency department. In terms of content major parameters of interhospital quality management are recorded and important factors of process management, such as MTS (Manchester triage system), ATLS (advanced trauma life support) and EWS (early warning score) have been implemented. The data-set includes all necessary information for transfers between physicians and non-academic staff as well as between physicians and could also be used as a fundamental discharge letter. Moreover, this new core data-set is the implementation of items required by existing registries into the daily routine documentation in order to reduce unnecessarily time-consuming and error-prone secondary data acquisition. For example, all items of the preclinical and emergency room documentation for the TraumaRegister DGU(r) (documentation phase S, A and B of the standard and QM form) have been included. This is sufficient for participation as a TraumaNetzwerk DGU(r) member as far as the early clinical treatment of multiple injured patients is concerned. PMID- 22527959 TI - The state of the guanosine nucleotide allosterically affects the interfaces of tubulin in protofilament. AB - The dynamics of microtubules is essential for many microtubule-dependent cellular functions such as the mitosis. It has been recognized for a long time that GTP hydrolysis in alphabeta-tubulin polymers plays a critical role in this dynamics. However, the effects of the changes in the nature of the guanosine nucleotide at the E-site in beta-tubulin on microtubule structure and stability are still not well understood. In the present work, we performed all-atom molecular dynamics simulations of a alphabetaalpha-tubulin heterotrimer harboring a guanosine nucleotide in three different states at the E-site: GTP, GDP-Pi and GDP. We found that changes in the nucleotide state is associated with significant conformational variations at the alpha-tubulin N- and beta-tubulin M-loops which impact the interactions between tubulin protofilaments. The results also show that GTP hydrolysis reduces alphabeta-tubulin interdimer contacts in favor of intradimer interface. From an atomistic point view, we propose a role for alpha tubulin glutamate residue 254 in catalytic magnesium coordination and identified a water molecule in the nucleotide binding pocket which is most probably required for nucleotide hydrolysis. Finally, the results are discussed with reference to the role of taxol in microtubule stability and the recent tubulin-sT2R crystal structures. PMID- 22527960 TI - Virtual screening using a conformationally flexible target protein: models for ligand binding to p38alpha MAPK. AB - We have used virtual screening to develop models for the binding of aryl substituted heterocycles to p38alpha MAPK. Virtual screening was conducted on a number of p38alpha MAPK crystal structures using a library of 46 known p38alpha MAPK inhibitors containing a heterocyclic core substituted by pyridine and fluorophenyl rings (structurally related to SB203580) and a set of decoy compounds. Multiple protonation states and tautomers of active and decoy compounds were considered. Each docking model was evaluated using receiver operating characteristic (ROC) curves and enrichment factors. The two best performing single crystal structures were found to be 1BL7 and 2EWA, with enrichment factors of 14.1 and 13.0 at 2% of the virtual screen respectively. Ensembles of up to four receptors of similar conformations were generated, generally giving good or very good performances with high ROC AUCs and good enrichment. The 1BL7-2EWA ensemble was able to outperform each of its constituent receptors and gave high enrichment factors of 17.3, 12.0, 8.0 at 2, 5 and 10% respectively, of the virtual screen. A ROC AUC of 0.94 was obtained for this ensemble. This method may be applied to other proteins where there are a large number of inhibitor classes with different binding site conformations. PMID- 22527963 TI - Photo quiz. Painful arthritis and extremity rash in an 8-year-old boy. PMID- 22527961 TI - Structure-based design of oxygen-linked macrocyclic kinase inhibitors: discovery of SB1518 and SB1578, potent inhibitors of Janus kinase 2 (JAK2) and Fms-like tyrosine kinase-3 (FLT3). AB - Macrocycles from our Aurora project were screened in a kinase panel and were found to be active on other kinase targets, mainly JAKs, FLT3 and CDKs. Subsequently these compounds became leads in our JAK2 project. Macrocycles with a basic nitrogen in the linker form a salt bridge with Asp86 in CDK2 and Asp698 in FLT3. This residue is conserved in most CDKs resulting in potent pan CDK inhibition. One of the main project objectives was to achieve JAK2 potency with 100-fold selectivity against CDKs. Macrocycles with an ether linker have potent JAK2 activity with the ether oxygen forming a hydrogen bond to Ser936. A hydrogen bond to the equivalent residues of JAK3 and most CDKs cannot be formed resulting in good selectivity for JAK2 over JAK3 and CDKs. Further optimization of the macrocyclic linker and side chain increased JAK2 and FLT3 activity as well as improving DMPK properties. The selective JAK2/FLT3 inhibitor 11 (Pacritinib, SB1518) has successfully finished phase 2 clinical trials for myelofibrosis and lymphoma. Another selective JAK2/FLT3 inhibitor, 33 (SB1578), has entered phase 1 clinical development for the non-oncology indication rheumatoid arthritis. PMID- 22527972 TI - Effect of fullerenol C(60)(OH) (24) on lipid peroxidation of kidneys, testes and lungs in rats treated with doxorubicine. AB - The aim of this study is to investigate the protective effect of fullerenol C60(OH)24 in various doses, on lipid peroxidation of rat's kidneys, testes and lungs after application of doxorubicin. The experiment was performed on healthy male Wistar rats. The animals were randomly divided into five experimental groups and treated with saline (0.9 % NaCl i.v.), doxorubicin alone (10 mg/kg i.v.), combination of doxorubicin/fullerenol (50 and 100 mg/kg fullerenol, respectively, 30 min before the introduction of doxorubicin) and fullerenol alone (100 mg/kg), respectively. Animals were killed on the 2nd and 14th day after treatment. Products of lipid peroxidation and thiobarbituric acid are determined spectrophotometrically from the crude homogenate fraction of the kidney, testis and lung tissues of the rats. Fullerenol, applied as a pre-treatment of doxorubicin, significantly reduced or completely prevented the appearance of doxorubicin toxicity in kidneys and testes, in both tested doses. A dose of 100 mg/kg i.p. exhibited a better protective effect. When fullerenol was applied alone, at a dose of 100 mg/kg i.p, it did not significantly affect the intensity of lipid peroxidation in all tested organs. PMID- 22527973 TI - Electrodeless electrohydrodynamic drop-on-demand encapsulation of drugs into porous polymer films for fabrication of personalized dosage units. AB - Noncontact drop-on-demand (DOD) dosing is a promising strategy for manufacturing of personalized dosage units. However, current DOD methods developed for printing chemically and thermally stable, low-viscosity inks are of limited use for pharmaceuticals due to fundamentally different functional requirements. To overcome their deficiency, we developed a novel electrohydrodynamic (EHD) DOD (Appl, Phys, Lett. 97, 233501, 2010) that operates on fluids of up to 30 Pa.s in viscosity over a wide range of droplet sizes and provides a precise control over the droplet volume. We now evaluate the EHD DOD as a method for fabrication of dosage units by printing drug solutions on porous polymer films prepared by freeze-drying. Experiments were carried out on ibuprofen and griseofulvin, as model poorly water-soluble drugs, polyethylene glycol 400, as a drug carrier, and hydroxypropyl methylcellulose films. The similarities between drug release profiles from different dosage units were assessed by model-independent difference, f(1) , and similarity, f(2) , factors. The results presented show that EHD DOD offers a powerful tool for the evolving field of small-scale pharmaceutical technologies for tailoring medicines to individual patient's needs by printing a vast array of predefined amounts of therapeutics arranged in a specific pattern on a porous film. PMID- 22527974 TI - Conservation and dissipation of light energy in desiccation-tolerant photoautotrophs, two sides of the same coin. AB - Conservation of light energy in photosynthesis is possible only in hydrated photoautotrophs. It requires complex biochemistry and is limited in capacity. Charge separation in reaction centres of photosystem II initiates energy conservation but opens also the path to photooxidative damage. A main mechanism of photoprotection active in hydrated photoautotrophs is controlled by light. This is achieved by coupling light flux to the protonation of a special thylakoid protein which activates thermal energy dissipation. This mechanism facilitates the simultaneous occurrence of energy conservation and energy dissipation but cannot completely prevent damage by light. Continuous metabolic repair is required to compensate damage. More efficient photoprotection is needed by desiccation-tolerant photoautotrophs. Loss of water during desiccation activates ultra-fast energy dissipation in mosses and lichens. Desiccation-induced energy dissipation neither requires a protonation reaction nor light but photoprotection often increases when light is present during desiccation. Two different mechanisms contribute to photoprotection of desiccated photoautotrophs. One facilitates energy dissipation in the antenna of photosystem II which is faster than energy capture by functional reaction centres. When this is insufficient for full photoprotection, the other one permits energy dissipation in the reaction centres themselves. PMID- 22527975 TI - A 44-year experience of prosthetic heart valve implantation at Niigata University Hospital. AB - Based on a single hospital experience of heart valve implantation from 1965 to 2009, the superiority of prosthetic heart valves including Starr-Edwards caged ball valves, Omniscience aortic tilting disc valves, and St. Jude Medical bileaflet valves are reviewed. This review discusses the prominent antithrombogenicity of the Starr-Edwards model 1200 aortic prosthesis under selected conditions, the relatively rarely thrombosed (despite its decreased opening angle) Omniscience aortic valve, the long-term outcomes 10 as well as 30 years after St. Jude Medical valve replacement, and finally the latest results on the significance of patient-aortic prosthesis mismatch in relation to myocardial hypertrophy. The findings described here should be considered in further investigations of cardiac valve prostheses. PMID- 22527976 TI - Long-term durability of Starr-Edwards ball valve. PMID- 22527977 TI - The effect of combined treatment with Impella((r)) and landiolol in a swine model of acute myocardial infarction. AB - Cardiogenic shock is associated with a high mortality rate in patients with acute myocardial infarction (AMI). We developed a new treatment approach named heart rest therapy (HRT) for complete revascularization in the early stage of AMI using an ultra-short-acting beta-blocker (landiolol) and an Impella((r)) left ventricular assist device and verified the effect of this therapy in a swine model. In 18 male pigs, AMI was induced by left anterior descending coronary artery occlusion at the level of the second diagonal branch for 120 min, followed by 240 min of reperfusion. The animals were divided into three groups: group A had no support, group B was supported with the Impella((r)), and group C was treated with HRT from 90 min after ischemia to 240 min after reperfusion. Infarct ratio (percentage of the infarct area relative to the area at infarct risk) was significantly reduced in group C (group A 65.38 +/- 6.07, group B 39.66 +/- 11.16, group C 21.78 +/- 7.29), with a significant difference between groups A and B (P < 0.001), A and C (P < 0.001), and B and C (P = 0.006). Heart rates were significantly lower in group C at 30 min (P = 0.01), 60 min (P = 0.022), and 240 min (P = 0.032) after reperfusion compared with group B, without development of hypotension. HRT at the early stage in AMI stabilized the hemodynamic conditions and reduced infarct size and complications in a swine model. These results suggest that HRT can improve the prognosis of patients with AMI. PMID- 22527979 TI - Early decision for a left ventricular assist device implantation is necessary for patients with modifier A. AB - Refractory ventricular tachyarrhythmias are life threatening, especially in patients with stage D heart failure, and left ventricular assist device therapy is virtually the sole option to resolve the fatal conditions in many cases. The Interagency Registry for Mechanically Assisted Circulatory Support defines modifier A as complicating recurrent ventricular tachyarrhythmias. However, the optimal timing to implant a left ventricular assist device remains to be determined in less sick patients with modifier A. We experienced three patients with stage D heart failure with revised modifier A, i.e., at least two appropriate operations of implantable cardiac defibrillators within 2 weeks. Two of them were rescued by extracorporeal left ventricular assist device implantation, but one died because of an electrical storm before left ventricular assist device support was available. We would like to emphasize that we should consider implantable left ventricular assist device therapy as soon as possible for those who are assigned modifier A to prevent sudden arrhythmic death. PMID- 22527978 TI - Bioactive polymer scaffold for fabrication of vascularized engineering tissue. AB - Tissue engineering seeks strategies to design polymeric scaffolds that allow high cell-density cultures with signaling molecules and suitable vascular supply. One major obstacle in tissue engineering is the inability to create thick engineered tissue constructs. A pre-vascularized tissue scaffold appears to be the most favorable approach to avoid nutrient and oxygen supply limitations as well as to allow waste removal, factors that are often hurdles in developing thick engineered tissues. Vascularization can be achieved using strategies in which cells are cultured in bioactive polymer scaffolds that can mimic extracellular matrix environments. This review addresses recent advances and future challenges in developing and using bioactive polymer scaffolds to promote tissue construct vascularization. PMID- 22527980 TI - Terumo-Triplex grafts for total arch replacement: analysis of postoperative graft performance. AB - We evaluated the performance of Terumo-Triplex (TRP) with a large-diameter vascular graft sealed with non-biodegradable material in 48 patients who underwent total arch replacement under selective cerebral perfusion between 2004 and 2009. TRP grafts were used in 13 patients (T group), Gelseal graft in 15 (G group), Hemashield graft in 10 (H group) and Intergard graft in 10 (I group). The total tube drainage, time to tube removal, graft dilation ratio and inflammation were evaluated postoperatively. Cardiopulmonary bypass and selective cerebral perfusion times did not differ between groups. Two patients died in hospital. The total drain drainage was significantly lower in the T group (956 +/- 156 ml) than in the H (2058 +/- 403 ml, p = 0.001) or I (5959 +/- 1027 ml, p = 0.01) groups. The time to tube removal was significantly lower in T group and G group than H and I group (T: 3.7 +/- 0.4, G: 4.1 +/- 0.4, H: 8.3 +/- 1.6, I: 18.6 +/- 3.6 days, T vs. H, I: p = 0.07, 0.0002, G vs. H, I: p = 0.004, <0.0001). The graft dilation ratio was significantly lower in T group than G group (T: 104 +/- 4 vs. 130 +/- 7 %, p = 0.001). The max C-reactive protein level was significantly lower in T group (16.2 +/- 4.5 mg/dl) than in the G group (19.4 +/- 3.2 mg/dl, p = 0.047), H (20.4 +/- 4.1 mg/dl, p = 0.048), or I (20.5 +/- 4.5 mg/dl, p = 0.013) groups. Maximum body temperature was also lower in the T group (38.2 +/- 0.5 degrees C) than in the G (38.7 +/- 0.4 degrees C, p = 0.011), H (38.9 +/- 0.6 degrees C, p = 0.0087), and I (39.3 +/- 0.7 degrees C, p = 0.0005). Thus, TRP graft might attenuate inflammatory response compared to the other sealed grafts for total arch replacement in patients with aortic arch aneurysm or dissection. PMID- 22527981 TI - Supramolecular assembly of conjugated polymers containing polyoxometalate terminal side chains in polar and nonpolar solvents. PMID- 22527983 TI - Single-nucleotide polymorphisms and haplotypes of membrane type 1-matrix metalloproteinase in susceptibility and clinical significance of squamous cell neoplasia of uterine cervix in Taiwan women. AB - Membrane type 1-matrix metalloproteinase (MT1-MMP) participates in the activity of MMP-2, which correlates with cancer of uterine cervix. Single-nucleotide polymorphisms (SNPs) in promoter and exon of MT1-MMP may influence their binding with transcription factors and gene transcription. To date, no study reports the association of the MT1-MMP polymorphisms with cervical neoplasia. Therefore, we investigated the influence of the MT1-MMP gene polymorphisms on the susceptibility and clinicopathological variables of cervical neoplasia for women in Taiwan. We recruited 72 patients with cervical squamous cell carcinoma and 63 with high-grade dysplasia as 1 subgroup. Meanwhile, 280 control women were included as another subgroup. The SNPs rs1003349 (site -165), rs2236307 (+7096), and rs3751489 (+8153) as well as rs2236302 (site +6727) of MT1-MMP gene were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism and real-time PCR genotyping, respectively. Then, we correlated these SNPs and haplotypes with the development of cervical neoplasia and cancer clinicopathological variables. We found that women with CC genotype in rs2236307 SNP exhibited a more risk to develop cervical neoplasia as compared with those with wild genotype TT. Haplotypes -165 T, +6727 C, +7096 C, +8153 G or -165 G, +6727 G, +7096 T, and +8153 G and diplotypes including at least 1 type of these haplotypes of MT1-MMP gene showed a higher risk of cervical neoplasia. However, both haplotypes were not significantly correlated with the clinicopathological characteristics of cervical cancer. In conclusion, Taiwan women with variant homozygote CC (+7096) and haplotypes, TCCG and GGTG, of MT1-MMP exhibit more risk in developing cervical neoplasia. PMID- 22527982 TI - Stress exacerbates endometriosis manifestations and inflammatory parameters in an animal model. AB - Women with endometriosis have significant emotional distress; however, the contribution of stress to the pathophysiology of this disease is unclear. We used a rat model of endometriosis to examine the effects of stress on the development of this condition and its influence on inflammatory parameters. Female Sprague Dawley rats were subjected to swim stress for 10 consecutive days prior to the surgical induction of endometriosis by suturing uterine horn implants next to the intestinal mesentery (endo-stress). Sham-stress animals had sutures only, and an endo-no stress group was not subjected to the stress protocol. At the time of sacrifice on day 60, endometriotic vesicles were measured and colons assessed for macroscopic and microscopic damage. Colonic tissue and peritoneal fluid were collected for inflammatory cell analysis. Endometriosis, regardless of stress, produced a decrease in central corticotropin-releasing factor immunoreactivity, specifically in the CA3 subregion of the hippocampus. Prior exposure to stress increased both the number and severity of vesicles found in animals with endometriosis. Stress also increased colonic inflammation, motility, myeloperoxidase levels, and numbers of mast cells. In summary, prior stress may contribute to the development and severity of endometriosis in this animal model through mechanisms involving cell recruitment (eg, mast cells), release of inflammatory mediators, and deregulation of hypothalamic-pituitary axis responses in the hippocampus. PMID- 22527985 TI - The A118G single-nucleotide polymorphism of human MU-opioid receptor gene and use of labor analgesia. AB - The human u-opioid receptor (MOR) is the major site of action of endogenous opioids and most of the clinically used opioid analgesics. The single-nucleotide polymorphism (SNP), A118G of the MOR 1 gene (OPRM1), has been associated with altered pain perception. The aim of this study was to investigate whether this polymorphism of OPRM1 is associated with a number of pain-related behaviors during labor. In this observational retrospective population-based study, pregnant women (n = 814) were recruited at gestational week 18. A plasma sample was collected from each participant and an SNP genotyping assay was performed. No differences in sociodemographic variables or labor pain-related outcomes, such as stage of cervical dilation on arrival at the delivery unit or use of any type of second-line analgesia during spontaneous labor, were found between noncarriers and G-allele carriers of OPRM1. We conclude that there is no association between the A118G polymorphism of OPRM1 regarding pain-related behavior during labor. PMID- 22527984 TI - Maternal micronutrient status and preterm versus term birth for black and white US women. AB - OBJECTIVE: Micronutrient deficiencies are hypothesized to play a role in spontaneous preterm birth (PTB; <37 weeks of gestation) and possibly the racial disparity in rates of PTB between black and white women. Yet relatively few studies have addressed the role of micronutrient deficiencies in spontaneous PTB among black and white women in the United States. The purpose of this study was to investigate whether 25-hydroxy vitamin D (25-OH-D), folate, and omega-6/omega 3 fatty acid status are associated with spontaneous PTB among black and white women in the United States. METHODS: Biospecimens and medical record data for this study were derived from a subsample of the 1547 women enrolled into the Nashville Birth Cohort during 2003-2006. We randomly selected 80 nulliparous and primiparous women for whom stored plasma samples from the delivery admission were available and analyzed the stored plasma for 25-OH-D, folate, and total omega 6/omega-3 fatty acids. We used multivariate logistic regression to assess the odds of spontaneous PTB among women with 25-OH-D <20 ng/mL, folate <5 ug/L, and omega-6/omega-3 >15. RESULTS: An omega-6/omega-3 ratio >15 was significantly associated with spontaneous PTB for white (adjusted odds ratio [aOR] 4.25, 95% confidence interval [CI] 1.25-14.49) but not black women (aOR 1.90, 95% CI: 0.69 5.40), whereas no significant relationships were observed for folate and 25-OH-D status and PTB for black or white women. CONCLUSION: Maternal plasma total omega 6/omega-3 fatty acid ratio >15 at delivery was significantly associated with spontaneous PTB for white, but not black, women. PMID- 22527986 TI - Concomitant use of contraceptives and potentially teratogenic medicinal products- results from a study using pharmacy dispensing data in the Netherlands. AB - The objective of this study was to analyze to what extent potentially teratogenic medicinal products are dispensed concomitantly with contraceptives. Data on dispensed medicinal products in this population-based study were obtained from the Dutch Foundation for Pharmaceutical Statistics. For over 178 potentially teratogenic medicinal products, concomitant use of contraceptives was assessed. The proportion of potentially teratogenic medicinal products dispensed concomitantly with a contraceptive varied significantly from 40.9% (95% CI 40.7 41.2) in 2005 to 43.4% in 2009 (95% CI 44.2-43.7). Significant differences existed as well between age categories with the lowest proportions of concomitant use of contraceptives for any potentially teratogenic drug in women aged 36 through 45 years (35.0%, 95% CI 34.9-35.1) in comparison to those aged 26 through 35 years (47.1%, 95% CI 46.9-47.3) and 15 through 25 years (53.6%, 95% CI 53.4 53.8). Although our data retrieval did not cover the use of nonpharmacological forms of contraception such as condoms and sterilization and as situations may occur during which the use of drugs with (low) teratogenic potential is a balanced decision, our results raise doubts about the safe use of medicinal products with teratogenic potential. PMID- 22527987 TI - REDD1 expression in placenta during human gestation. AB - The aim of the study was to detect the regulated in development and DNA responses (REDD1) in human placentas throughout different gestational ages (GAs) and to correlate REDD1 with preeclampsia (PE). In experiments, REDD1 messenger RNA and protein expression levels throughout the gestation were determined using immunohistochemistry, quantitative reverse transcriptase polymerase chain reaction, and Western blot. Furthermore, REDD1 protein levels in placenta were also compared between normal outcome pregnancies (n = 20, GA >37 weeks) and PE pregnancies (n = 29), which includes early onset PE; n = 15, GA: 24-33 weeks) and late onset PE (n = 14, GA: 34-39 weeks) by Western blot. As a result, REDD1 protein was predominantly observed in the cytoplasm of trophoblasts. Moreover, higher levels of REDD1 were found not only at earlier gestational stage but also in the PE groups (P < .05). In conclusion, REDD1 may play an important role in maintaining the normal function of placenta during various stages of gestation and predicted that the increase in REDD1 is related to the pathogenesis of PE. PMID- 22527988 TI - USRC: a new strategy for adding digital images to the medical school curriculum. AB - Many medical schools use learning management systems (LMSs) to give students access to online lecture notes, assignments, quizzes, and other learning resources. LMSs can also be used to provide access to digital radiology images, potentially improving preclinical teaching in anatomy, physiology, and pathology while also allowing students to develop interpretation skills that are important in clinical practice. However, it is unclear how radiology images can best be stored, imported, and displayed in an LMS. We developed University of Saskatchewan Radiology Courseware (USRC), a new web application that allows course designers to import images into pages linked to BlackBoard Learn, a popular LMS. Page content, including images, annotations, captions, and supporting text, are stored as teaching cases on a MIRC (Medical Imaging Resource Center) server. Course designers create cases in MIRC, and then create a corresponding page in BlackBoard by modifying an HTML template so that it holds the URL of a MIRC case. When a user visits the page in BlackBoard, the page requests content from the MIRC case, reformats the text for display in BlackBoard, and loads an image viewer plug-in that allows students to view and interact with the images stored in the case. The USRC technology can be used to reformat MIRC cases for presentation in any website or in any learning management system that supports custom pages written in HTML with embedded JavaScript. PMID- 22527989 TI - A study on image quality management in PACS used by Korean hospitals. AB - This study evaluated a method to maintain the optimal image quality in clinical practice for image quality management in a picture archiving and communication system (PACS) that uses typical technology for digital medical images. This study conducted a survey of 25 hospitals in Seoul and metropolitan areas that had installed PACS to examine the reality of image quality management. Sixteen diagnostic monitors were used as calibration tools to compare and analyze the external illuminance uniformity and grayscale standard display function (GSDF) values at each frequency. According to the survey results, most of the hospitals did not have any particular rules or standardized methods for image quality control. In a PACS, the calibration frequency was examined within the allowable limits of error for each week and month. The calibration was not affected by the difference in brightness of the environment for reading an image. The GSDF measurement values were quite different from the standard values. In conclusion, to improve the image quality of the digital system, it is important to make good use of the system and maintain the image quality. Therefore, it is critical to capitalize on the method suggested in this study and maintain the optimal image quality to guarantee a high level of observer satisfaction. PMID- 22527990 TI - The morphology and origin of the skeletal muscle bundles associated with the human mustache. AB - The arrector pili muscle is a smooth muscle bundle that attaches to the bulge region of the hair follicle and extends to its superior attachment in the upper dermis or epidermis. However, the morphology and origin of the muscle associated with the human mustache is different, having a general smooth arrector pili muscle. The purpose of the present study was to identify the morphology of the muscle associated with the human mustache using three-dimensional reconstruction. The skin of the superior part of the upper lip region from human cadavers were fixed, processed using routine histological methods, serially sectioned at a thickness of 10 MUm, and then stained with Masson's trichrome. The serial sections were reconstructed three-dimensionally using 'Reconstruct' software. The present study confirmed skeletal muscle fibers in this area, but they did not attach to the follicle of the human mustache. Although the follicle of the mustache was surrounded with some muscle fibers, they just ran obliquely to the skin surface from the deeper orbicularis oris muscle regardless of the follicle. There was no muscle associated with the human mustache. The voluntary or involuntary mobility of the human mustache has been lost evolutionally forever. PMID- 22527991 TI - Newly identified thin membranous tissue in the deep infratemporal region. AB - Recently, the importance of deglutition has attracted attention due to its role in the prevention of aspiration pneumonia. We therefore observed the anatomy of the pharynx of 57 hemi-sections of adult Japanese cadavers (male 32 sides, female 25 sides). A previously unidentified tissue was observed in the infratemporal fossa. This unidentified tissue was a thin membranous tissue that existed between the medial pterygoid and the superior constrictor in all of the cadavers examined. The previously unknown membranous tissue consisted of collagenous and muscular fibers and was innervated mainly by a branch of the mandibular nerve. PMID- 22527992 TI - Grey matter abnormalities in social anxiety disorder: a pilot study. AB - While a number of studies have explored the functional neuroanatomy of social anxiety disorder (SAD), data on grey matter integrity are lacking. We conducted structural MRI scans to examine the cortical thickness of grey matter in individuals with SAD. 13 unmedicated adult patients with a primary diagnosis of generalized social anxiety disorder and 13 demographically (age, gender and education) matched healthy controls underwent 3T structural magnetic resonance imaging. Cortical thickness and subcortical volumes were estimated using an automated algorithm (Freesurfer Version 4.5). Compared to controls, social anxiety disorder patients showed significant bilateral cortical thinning in the fusiform and post central regions. Additionally, right hemisphere specific thinning was found in the frontal, temporal, parietal and insular cortices of individuals with social anxiety disorder. Although uncorrected cortical grey matter volumes were significantly lower in individuals with SAD, we did not detect volumetric differences in corrected amygdala, hippocampal or cortical grey matter volumes across study groups. Structural differences in grey matter thickness between SAD patients and controls highlight the diffuse neuroanatomical networks involved in both social anxiety and social behavior. Additional work is needed to investigate the causal mechanisms involved in such structural abnormalities in SAD. PMID- 22527993 TI - Exposure to prenatal stress enhances the development of seizures in young rats. AB - A febrile seizure is a neurological disorder that occurs following an infection that results in a rapid rise in body temperature. It commonly affects 3-5% of children between the ages of 3 months and 5 years. Interleukin-1 beta IL-1beta a pro-inflammatory cytokine has been suggested to play a role in the manifestation of febrile seizures. There is evidence suggesting that neurological disorders can be exacerbated in an offspring that was exposed to stress prenatally. The aim of our study was therefore to investigate whether febrile seizures are exacerbated in the offspring of rats that were prenatally stressed. The offspring of pregnant Sprague-Dawley dams were used in the study. Prenatal stress consisted of exposing the pregnant dams to 45 min of restraint, 3 times per day with 3 h intervals in between, for 7 days starting on gestational day 14 (GND14). On postnatal day (PND) 14, the pups were injected with lipopolysaccharide (LPS, 200 MUg/kg, i.p.) followed 2.5 h later by an i.p. injection of kainic acid (KA, 1.75 mg/kg). All the animals were decapitated on PND 21. Trunk blood was collected to detect plasma interleukin-1beta (IL-1beta) levels in the various groups. Our data showed that i.p. injections of LPS followed by KA led to the development of seizure activity that was associated with increased plasma IL-1beta levels. Prior exposure to prenatal stress resulted in the development of advanced stages of seizure development, leading to an exaggerated seizure response. Prenatal stress alone also led to elevated plasma IL-1beta levels, while previously stressed animals receiving LPS and KA yielded the highest plasma levels of IL-1beta levels. Our data therefore shows that IL-1beta levels may play an important role in the development of febrile seizures. PMID- 22527994 TI - Mucopolysaccharidosis type I: current knowledge on its pathophysiological mechanisms. AB - Mucopolysaccharidosis type I is one of the most frequent lysosomal storage diseases. It has a high morbidity and mortality, causing in many cases severe neurological and somatic damage in the first years of life. Although the clinical phenotypes have been described for decades, and the enzymatic deficiency and many of the mutations that cause this disease are well known, the underlying pathophysiological mechanisms that lead to its development are not completely understood. In this review we describe and discuss the different pathogenic mechanisms currently proposed for this disease regarding its neurological damage. Deficiency in the lysosomal degradation of heparan sulfate and dermatan sulfate, as well as its primary accumulation, may disrupt a variety of physiological and biochemical processes: the intracellular and extracellular homeostasis of these macromolecules, the pathways related to gangliosides metabolism, mechanisms related to the activation of inflammation, receptor-mediated signaling, oxidative stress and permeability of the lysosomal membrane, as well as alterations in intracellular ionic homeostasis and the endosomal pathway. Many of the pathogenic mechanisms proposed for mucopolysaccharidosis type I are also present in other lysosomal storage diseases with neurological implications. Results from the use of methods that allow the analysis of multiple genes and proteins, in both patients and animal models, will shed light on the role of each of these mechanisms and their combination in the development of different phenotypes due to the same deficiency. PMID- 22527996 TI - Early maternal separation leads to down-regulation of cytokine gene expression. AB - Exposure to stressors may lead to subsequent alterations in the immune response. The precise mechanisms underlying such vulnerability are poorly understood, but may be hypothesized to include changes in cytokine systems. Maternal separation was used as a model of exposure to early life stressors. Subsequent cytokine gene expression was studied using a cytokine gene expression array. Maternal separation resulted in significant down-regulation of the expression of 6 cytokine genes; chemokine ligand 7, chemokine receptor 4, interleukin 10, interleukin-1beta, interleukin 5 receptor alpha and integrin alpha M. Specific cytokines may be involved in mediating the effects of early adversity on subsequent immunosuppression. Further work is needed to delineate fully the relationship between early adversity, immune alterations, and behavioural changes. PMID- 22527995 TI - A longitudinal systems biology analysis of lactulose withdrawal in hepatic encephalopathy. AB - The pathogenesis of hepatic encephalopathy(HE) is unclear. However gut flora changes, inflammation and neuro-glial injury have been implicated. The aim was to evaluate factors that were associated with HE recurrence after lactulose withdrawal by analyzing the clinical phenotype, stool microbiome and systemic metabolome longitudinally. HE patients on a standard diet who were adherent on lactulose underwent characterization of their phenotype [cognition, inflammatory cytokines, in-vivo brain MR spectroscopy(MRS)], gut microbiome (stool Multitag Pyrosequencing) and metabolome (urine/serum ex-vivo MRS) analysis while on lactulose and on days 2, 14 and 30 post-withdrawal. Patients whose HE recurred post-withdrawal were compared to those without recurrence. We included seven men (53 +/- 8 years) who were adherent on lactulose after a precipitated HE episode were included. HE recurred in three men 32 +/- 6 days post-withdrawal. In-vivo brain MRS showed increased glutamine+glutamate (Glx) and decreased myoinositol with a reduction in stool Faecalibacterium spp., post-withdrawal. HE recurrence was predicted by poor baseline inhibitory control and block design performance and was associated with a shift of choline metabolism from tri-methylamine oxide formation towards the development of di-methylglycine, glycine and creatinine. This was accompanied by a mixed effect on the immune response (suppressed IL-10 and Th1/Th2/Th17 response). The correlation network showed Prevotella to be linked to improved cognition and decreased inflammation in patients without HE recurrence. We conclude that lactulose withdrawal results in worsening cognition, mixed inflammatory response effect, lowered stool Faecalibacterium and increase in MR-measurable brain Glx. HE recurrence post-lactulose withdrawal can be predicted by baseline cognitive performance and is accompanied by disrupted choline metabolism. PMID- 22527997 TI - Effect of maternal separation on mitochondrial function and role of exercise in a rat model of Parkinson's disease. AB - Early life stress, such as maternal separation, causes adaptive changes in neural mechanisms that have adverse effects on the neuroplasticity of the brain in adulthood. As a consequence, children who are exposed to stress during development may be predisposed to neurodegenerative disorders in adulthood. A possible mechanism for increased vulnerability to neurodegeneration may be dysfunctional mitochondria. Protection from neurotoxins, such as 6 hydroxydopamine (6-OHDA), has been observed following voluntary exercise. The mechanism of this neuroprotection is not understood and mitochondria may play a role. The purpose of this study was to determine the effects of maternal separation and exercise on mitochondrial function in a rat model of Parkinson's disease. Maternally separated (pups separated from the dam for 3 h per day from postnatal day (P) 2-14) and non-separated rats were placed in individual cages with or without attached running wheels for 1 week prior to unilateral infusion of 6-OHDA (5 MUg/4 MUl, 0.5 MUl/min) into the left medial forebrain bundle at P60. After 2 h recovery, rats were returned to their cages and wheel revolutions recorded for a further 2 weeks. On P72, the rats' motor function was assessed using the forelimb akinesia test. On P74, rats were sacrificed for measurement of mitochondrial function. Exercise increased the respiratory control index (RCI) in the non-lesioned hemisphere of 6-OHDA-lesioned rats. This effect was evident in the striatum of non-separated rats and the prefrontal cortex of maternally separated rats. These results suggest that early life stress may reduce the adaptive response to exercise in the striatum, a major target of dopamine neurons, but not the prefrontal cortex in this model of Parkinson's disease. PMID- 22528020 TI - The symmetry of self mutilation and the chess board pattern. PMID- 22527999 TI - Developmental traumatic brain injury decreased brain derived neurotrophic factor expression late after injury. AB - Pediatric traumatic brain injury (TBI) is a major cause of acquired cognitive dysfunction in children. Hippocampal Brain Derived Neurotrophic Factor (BDNF) is important for normal cognition. Little is known about the effects of TBI on BDNF levels in the developing hippocampus. We used controlled cortical impact (CCI) in the 17 day old rat pup to test the hypothesis that CCI would first increase rat hippocampal BDNF mRNA/protein levels relative to SHAM and Naive rats by post injury day (PID) 2 and then decrease BDNF mRNA/protein by PID14. Relative to SHAM, CCI did not change BDNF mRNA/protein levels in the injured hippocampus in the first 2 days after injury but did decrease BDNF protein at PID14. Surprisingly, BDNF mRNA decreased at PID 1, 3, 7 and 14, and BDNF protein decreased at PID 2, in SHAM and CCI hippocampi relative to Naive. In conclusion, TBI decreased BDNF protein in the injured rat pup hippocampus 14 days after injury. BDNF mRNA levels decreased in both CCI and SHAM hippocampi relative to Naive, suggesting that certain aspects of the experimental paradigm (such as craniotomy, anesthesia, and/or maternal separation) may decrease the expression of BDNF in the developing hippocampus. While BDNF is important for normal cognition, no inferences can be made regarding the cognitive impact of any of these factors. Such findings, however, suggest that meticulous attention to the experimental paradigm, and possible inclusion of a Naive group, is warranted in studies of BDNF expression in the developing brain after TBI. PMID- 22527998 TI - Melatonin: an overlooked factor in schizophrenia and in the inhibition of anti psychotic side effects. AB - This paper reviews melatonin as an overlooked factor in the developmental etiology and maintenance of schizophrenia; the neuroimmune and oxidative pathophysiology of schizophrenia; specific symptoms in schizophrenia, including sleep disturbance; circadian rhythms; and side effects of antipsychotics, including tardive dyskinesia and metabolic syndrome. Electronic databases, i.e. PUBMED, Scopus and Google Scholar were used as sources for this review using keywords: schizophrenia, psychosis, tardive dyskinesia, antipsychotics, metabolic syndrome, drug side effects and melatonin. Articles were selected on the basis of relevance to the etiology, course and treatment of schizophrenia. Melatonin levels and melatonin circadian rhythm are significantly decreased in schizophrenic patients. The adjunctive use of melatonin in schizophrenia may augment the efficacy of antipsychotics through its anti-inflammatory and antioxidative effects. Further, melatonin would be expected to improve sleep disorders in schizophrenia and side effects of anti-psychotics, such as tardive dyskinesia, metaboilic syndrome and hypertension. It is proposed that melatonin also impacts on the tryptophan catabolic pathway via its effect on stress response and cortisol secretion, thereby impacting on cortex associated cognition, amygdala associated affect and striatal motivational processing. The secretion of melatonin is decreased in schizophrenia, contributing to its etiology, pathophysiology and management. Melatonin is likely to have impacts on the metabolic side effects of anti-psychotics that contribute to subsequent decreases in life-expectancy. PMID- 22528021 TI - The first definitive Asian spinosaurid (Dinosauria: Theropoda) from the Early Cretaceous of Laos. AB - Spinosaurids are among the largest and most specialized carnivorous dinosaurs. The morphology of their crocodile-like skull, stomach contents, and oxygen isotopic composition of the bones suggest they had a predominantly piscivorous diet. Even if close relationships between spinosaurids and Middle Jurassic megalosaurs seem well established, very little is known about the transition from a generalized large basal tetanuran to the specialized morphology of spinosaurids. Spinosaurid remains were previously known from the Early to Late Cretaceous of North Africa, Europe, and South America. Here, we report the discovery of a new spinosaurid theropod from the late Early Cretaceous Savannakhet Basin in Laos, which is distinguished by an autapomorphic sinusoidal dorsosacral sail. This new taxon, Ichthyovenator laosensis gen. et sp. nov., includes well-preserved and partially articulated postcranial remains. Although possible spinosaurid teeth have been reported from various Early Cretaceous localities in Asia, the new taxon I. laosensis is the first definite record of Spinosauridae from Asia. Cladistic analysis identifies Ichthyovenator as a member of the sub-clade Baryonychinae and suggests a widespread distribution of this clade at the end of the Early Cretaceous. Chilantaisaurus tashouikensis from the Cretaceous of Inner Mongolia, and an ungual phalanx from the Upper Jurassic of Colorado are also referred to spinosaurids, extending both the stratigraphical and geographical range of this clade. PMID- 22528022 TI - A long-bodied centriscoid fish from the basal Eocene of Kabardino-Balkaria, northern Caucasus, Russia. AB - The Paleocene-Eocene transition is of crucial interest for interpreting the Cenozoic evolutionary radiation of vertebrates. A substantial increase of the number of vertebrate families occurred between the Late Paleocene and Early Eocene, with the appearance of most of the representatives of extant lineages. Basal Eocene marine fish diversity is currently poorly known, exclusively restricted to two assemblages from Denmark and Turkmenistan, respectively. Exceptionally well-preserved articulated skeletal remains of fishes have recently been discovered from a basal Eocene sapropelitic layer exposed along the Kheu River in the Republic of Kabardino-Balkaria, northern Caucasus, Russia. Here, we report on Gerpegezhus paviai gen. et sp. nov., a new peculiar syngnathoid fish from this new Ciscaucasian locality. The morphological structure of the single available specimen suggests that it is the first long-bodied member of the superfamily Centriscoidea, representing the sole member of the new family Gerpegezhidae, which forms a sister pair with the extant family Centriscidae. PMID- 22528023 TI - Inverse Rensch's rule in a frog with female-biased sexual size dimorphism. AB - Rensch's rule claims that sexual size dimorphism (SSD) increases with body size when males are larger but decreases with body size when males are smaller. Chinese wood frog Rana chensinensis is a medium-sized species with female-biased size dimorphism. Using data on body size and age in 27 populations covering the full known size range of the species, we tested the consistency of allometric relationships between the sexes with Rensch's rule and evaluated the hypothesis that SSD is largely a function of age differences between the sexes. The results showed that level of female-biased SSD increased with increasing mean size, supporting the inverse of Rensch's rule. Moreover, most of the variation in SSD can be explained in terms of differences in age between the sexes in populations. PMID- 22528024 TI - Condition-dependent expression of melanin-based coloration in the Eurasian kestrel. AB - Melanin is the most common pigment in animal integuments and is responsible for some of the most striking ornaments. A central tenet of sexual selection theory states that melanin-based traits can signal absolute individual quality in any environment only if their expression is condition-dependent. Significant costs imposed by an ornament would ensure that only the highest quality individuals display the most exaggerated forms of the signal. Firm evidence that melanin based traits can be condition-dependent is still rare in birds. In an experimental test of this central assumption, we report condition-dependent expression of a melanin-based trait in the Eurasian kestrel (Falco tinnunculus). We manipulated nestling body condition by reducing or increasing the number of nestlings soon after hatching. A few days before fledging, we measured the width of sub-terminal black bands on the tail feathers. Compared to nestlings from enlarged broods, individuals raised in reduced broods were in better condition and thereby developed larger sub-terminal bands. Furthermore, in 2 years, first born nestlings also developed larger sub-terminal bands than their younger siblings that are in poorer condition. This demonstrates that expression of melanin-based traits can be condition-dependent. PMID- 22528026 TI - Inadequate treatment for elderly patients: professional norms and tight budgets could cause "ageism" in hospitals. AB - We have studied ethical considerations of care among health professionals when treating and setting priorities for elderly patients in Norway. The views of medical doctors and nurses were analysed using qualitative methods. We conducted 21 in depth interviews and 3 focus group interviews in hospitals and general practices. Both doctors and nurses said they treated elderly patients different from younger patients, and often they were given lower priorities. Too little or too much treatment, in the sense of too many interventions and too much drugs, combined with too little care and comfort, was admitted as a relatively frequent yet unwanted consequence of the way clinical priorities were set for elderly patients. This was explained in terms of elderly patients not tolerating the same treatment as younger patients, and questions were raised about the quality of life of many elderly patients after treatment. These explanations were frequently referred to as medically sound decision making. Other explanations had little to do with medically sound decisions. These often included deep frustration with executive guidelines and budget constraints. PMID- 22528025 TI - Representation of motion onset and offset in an augmented Barlow-Levick model of motion detection. AB - Kinetic occlusion produces discontinuities in the optic flow field, whose perception requires the detection of an unexpected onset or offset of otherwise predictably moving or stationary contrast patches. Many cells in primate visual cortex are directionally selective for moving contrasts, and recent reports suggest that this selectivity arises through the inhibition of contrast signals moving in the cells' null direction, as in the rabbit retina. This nulling inhibition circuit (Barlow-Levick) is here extended to also detect motion onsets and offsets. The selectivity of extended circuit units, measured as a peak evidence accumulation response to motion onset/offset compared to the peak response to constant motion, is analyzed as a function of stimulus speed. Model onset cells are quiet during constant motion, but model offset cells activate during constant motion at slow speeds. Consequently, model offset cell speed tuning is biased towards higher speeds than onset cell tuning, similarly to the speed tuning of cells in the middle temporal area when exposed to speed ramps. Given a population of neurons with different preferred speeds, this asymmetry addresses a behavioral paradox-why human subjects in a simple reaction time task respond more slowly to motion offsets than onsets for low speeds, even though monkey neuron firing rates react more quickly to the offset of a preferred stimulus than to its onset. PMID- 22528027 TI - Selective COSY-J-resolved-HMBC, a new method for improving sensitivity of cross peaks of methine proton signals attached to a methyl group. AB - Improved pulse sequences for measuring long-range C-H coupling constants ((n)J(C H)), named selective COSY-J-resolved HMBC-1 and -2, have been developed. In the spin systems, such as -CH(C)-CH(A)(CH(3))-CH(B)-, a methine proton H(A) splits into a multiplet owing to several vicinal couplings with protons, resulting in attenuation of its cross-peak intensity. Therefore, the measurements of (n)J(C-H) with H(A) are generally difficult in the J-resolved HMBC or selective J-resolved HMBC spectrum. With the aim of accurate measurements of (n)J(C-H) in such a spin system, we have developed new pulse sequences, which transfer the magnetization of a methyl group to its adjacent methine proton. The proposed pulse sequences successfully enable to enhance the sensitivity of H(A) cross peak in comparison with the selective J-resolved HMBC pulse sequence. PMID- 22528028 TI - Facial emotion recognition in children with high functioning autism and children with social phobia. AB - Recognizing facial affect is essential for effective social functioning. This study examines emotion recognition abilities in children aged 7-13 years with High Functioning Autism (HFA = 19), Social Phobia (SP = 17), or typical development (TD = 21). Findings indicate that all children identified certain emotions more quickly (e.g., happy < anger, disgust, sad < fear) and more accurately (happy) than other emotions (disgust). No evidence was found for negative interpretation biases in children with HFA or SP (i.e., all groups showed similar ability to discriminate neutral from non-neutral facial expressions). However, distinct between-group differences emerged when considering facial expression intensity. Specifically, children with HFA detected mild affective expressions less accurately than TD peers. Behavioral ratings of social effectiveness or social anxiety were uncorrelated with facial affect recognition abilities across children. Findings have implications for social skills treatment programs targeting youth with skill deficits. PMID- 22528029 TI - Longitudinal developmental courses in Japanese children with autism spectrum disorder. AB - We followed up 67 children with autistic disorder (AD) and 31 children with pervasive developmental disorder not otherwise specified (PDDNOS) for more than 10 years by reviewing medical records at a clinic for children with developmental disabilities. The participants' data were collected between their first visit to the clinic and the visit at which they applied for basic disability benefits. The standardized IQ scores and autistic symptoms were examined as measures of the children's personal functioning. For environmental factors, we examined the participants' educational placements and work and residential status. Using structural equation modeling, we examined the longitudinal developmental courses of AD and PDDNOS. Participants diagnosed with AD consistently showed lower IQ and more severe autistic symptoms than those diagnosed with PDDNOS. Relationships between personal functioning and environmental factors differed between the two groups. AD and PDDNOS are heterogeneous, so they must be treated differently to improve children's prognoses. PMID- 22528030 TI - Relations between behavioral inhibition, big five personality factors, and anxiety disorder symptoms in non-clinical and clinically anxious children. AB - This study examined the relations between behavioral inhibition, Big Five personality traits, and anxiety disorder symptoms in non-clinical children (n = 147) and clinically anxious children (n = 45) aged 6-13 years. Parents completed the Behavioral Inhibition Questionnaire-Short Form, the Big Five Questionnaire for Children, and the Screen for Child Anxiety Related Emotional Disorders Revised. Results indicated that, compared to parents of non-clinical children, parents of clinically anxious children rated their offspring higher on neuroticism and behavioral inhibition, but lower on extraversion, conscientiousness, and intellect/openness. Further, extraversion emerged as the strongest correlate of an inhibited temperament, and this appeared true for the clinically anxious as well as the non-clinical children. Finally, in both the clinical and non-clinical samples, higher levels of behavioral inhibition and neuroticism were unique and significant predictors of anxiety disorders symptoms. PMID- 22528031 TI - Emotion regulation and childhood aggression: longitudinal associations. AB - Accumulating evidence suggests that emotion dysregulation is associated with psychopathology. This paper provides a review of recent longitudinal studies that investigate the relationship between emotion regulation and aggressive behavior in childhood age. While there is substantial evidence for assuming a close relation of emotion regulation and aggressive behavior, moderating and mediating factors like gender and peer rejection have been established. Furthermore, results suggest emotion dysregulation as an important risk factor of aggressive behavior. Several directions for future research are pointed out to further validate and refine the reviewed relationships. PMID- 22528032 TI - Understanding the relation of low income to HPA-axis functioning in preschool children: cumulative family risk and parenting as pathways to disruptions in cortisol. AB - This study examined the relation of low income and poverty to cortisol levels, and tested potential pathways from low income to disruptions in cortisol through cumulative family risk and parenting. The sample of 306 mothers and their preschool children included 29 % families at or near poverty, 27 % families below the median income, and the remaining families at middle and upper income. Lower income was related to lower morning cortisol levels, and cumulative risk predicted a flatter diurnal slope, with a significant indirect effect through maternal negativity, suggesting that parenting practices might mediate an allostatic effect on stress physiology. PMID- 22528033 TI - Comparison of the intestinal absorption and bioavailability of gamma-tocotrienol and alpha-tocopherol: in vitro, in situ and in vivo studies. AB - The aim of this work was to compare the intestinal absorption kinetics and the bioavailability of gamma-tocotrienol (gamma-T3) and alpha-tocopherol (alpha-Tph) administered separately as oil solutions to rats in vivo. Also, to explain the significant difference in the oral bioavailability of the compounds: (1) the release profiles using the dynamic in vitro lipolysis model, (2) the intestinal permeability and (3) carrier-mediated uptake by Niemann-Pick C1-like 1 (NPC1L1) transporter were examined. Absolute bioavailability studies were conducted after oral administration of gamma-T3 or alpha-Tph prepared in corn oil to rats. In situ rat intestinal perfusion with ezetimibe (a NPC1L1 inhibitor) was performed to compare intestinal permeability. The in vitro interaction kinetics with NPC1L1 was examined in NPC1L1 transfected cells. While the in vitro release studies demonstrated a significantly higher release rate of gamma-T3 in the aqueous phase, the oral bioavailability of alpha-Tph (36%) was significantly higher than gamma-T3 (9%). Consequent in situ studies revealed significantly higher intestinal permeability for alpha-Tph compared with gamma-T3 in rats. Moreover, the NPC1L1 kinetic studies demonstrated higher Vmax and Km values for alpha-Tph compared with gamma-T3. Collectively, these results indicate that intestinal permeability is the main contributing factor for the higher bioavailability of alpha-Tph. Also, these results emphasize the potentially important role of intestinal permeability in the bioavailability of gamma-T3, suggesting that enhancing its permeability would increase its oral bioavailability. PMID- 22528034 TI - Fostering partnerships in survivorship care: report of the 2011 Canadian genitourinary cancers survivorship conference. AB - PURPOSE: New models of survivorship care are required to address the needs of genitourinary (GU) cancer survivors. Current approaches do not effectively engage cancer survivors or advocacy groups. A group of clinicians in collaboration with the Canadian Urologic Association held a forum for GU cancer survivors, advocacy groups, and health professionals to explore ways to collaboratively enhance survivorship care. METHODS: Participants attended a 2-day conference that included presentations, breakout groups, and a postconference survey. Discussions by breakout groups were recorded and analyzed alongside open-ended survey responses for common themes. Basic statistics were calculated. RESULTS: Conference participants (n = 42) included 18 cancer survivors/caregivers, 21 health professionals, and 3 researchers representing bladder, kidney, prostate, and testis cancer groups. Breakout group discussions and responses to the postconference survey (83.3 % response rate) showed strong support for greater collaboration among all parties. Strategies to facilitate collaboration reflected a need to: (1) raise awareness of the shared and unique needs of GU cancer survivors and the expertise of cancer advocacy groups, (2) facilitate communication and collaborative opportunities among clinicians/researchers and cancer survivors/advocacy groups, (3) facilitate collaborative programming and fund-raising among GU advocacy groups, and (4) synthesize and facilitate access to GU cancer survivorship resources and services. CONCLUSIONS: There is strong support for formal collaboration to enhance survivorship care among a critical mass of GU cancer survivors, advocacy groups, clinicians, and researchers. Responsibility for collaboration lies with all stakeholder groups. Strategies to foster such partnerships should employ integrated knowledge translation approaches that actively engage all parties throughout the entire research to practice process. IMPLICATIONS FOR CANCER SURVIVORS: Successful partnerships between cancer survivors, advocacy groups, clinicians, and researchers require familiarity with each other's expertise, along with sufficient resources and organizational structures. GU survivorship advocacy groups need to work more closely together to ensure a strong, unified voice when interacting with clinicians and researchers. PMID- 22528035 TI - A pharmacokinetic model for the glycation of albumin. AB - Glycated haemoglobin (HbA1c) concentrations can be falsely lowered in circumstances when red blood cell (RBC) survival is reduced, e.g. in patients with chronic kidney disease (CKD). Glycated albumin (GA) has been suggested as an alternative marker of glycaemic control in these patients since it is independent of the RBC life span. The primary aim of this work was to develop a pharmacokinetic model that describes the time course of GA. The secondary aim was to assess the performance of GA as marker for glycaemic control in comparison to HbA1c based on simulations. For the second aim, three different scenarios were considered in the simulations: 1) assessment of the effect of large intra-day fluctuations in mean blood glucose on GA concentrations, 2) initiation of antidiabetic treatment on the GA profile, and 3) a hypothetical phase II study for a new antidiabetic compound. The GA model, as well as a previously developed HbA1c model described literature data well. GA concentrations appear to be stable even in the presence of high intra-day fluctuations in mean blood glucose concentrations. Simulation of a decrease in mean blood glucose concentrations resulted in a faster change in GA compared to HbA1c. GA also provided a time to 90 % power of the effect of a hypothetical antidiabetic drug that was 16 days shorter than when using HbA1c. These results indicate that GA could be used as alternative marker to assess blood glucose control in diabetic patients with CKD and also to follow an individual patient over time. PMID- 22528036 TI - Sexual assaulters in the United States: prevalence and psychiatric correlates in a national sample. AB - This study presents sociodemographic characteristics and psychiatric correlates of a representative sample of sexual assaulters in the United States. Data were drawn from a nationally representative survey, the National Epidemiologic Survey on Alcohol and Related Conditions. Face-to-face interviews of more than 43,000 adults were conducted between the 2001-2002 period, based on the Alcohol Use Disorder and Associated Disabilities Interview Schedule-DSM-IV Version. The prevalence of committing sexual assault in the U.S. was 0.15 %. Sexual assaulters had significantly lower education than their counterparts. Sexual assaulters were significantly more likely to report a wide range of antisocial behaviors. Multivariate logistic regression analyses indicated strong associations between sexual assault and lifetime psychiatric disorders often associated with impaired impulse control, such as antisocial personality disorder, conduct disorder, and cocaine use disorder. In addition, psychotic disorders were consistently associated with sexual assault. Our findings indicate that sexual assault could represent a behavioral manifestation of a broader spectrum, including impairment of impulse control and psychotic disorders. PMID- 22528038 TI - Masturbation is related to psychopathology and prostate dysfunction: comment on Quinsey (2012). PMID- 22528037 TI - Preschool children with gender normative and gender non-normative peer preferences: psychosocial and environmental correlates. AB - We addressed several issues concerning children who show gender non-normative (GNN) patterns of peer play. First, do young children with GNN peer preferences differ from children with gender normative (GN) peer preferences in problem behaviors? Second, do GNN and GN children differ in sociability and isolation and do they have differential socialization opportunities with externalizing, internalizing, and socially competent peers? We employed a Bayesian approach for classifying children as GNN based on their peer preferences as compared to their peers using a sample of Head Start preschool children from a large Southwestern city (N = 257; 53 % boys; M age = 51 months; 66 % Mexican American). To calculate socialization opportunities, we assessed affiliation to each child in the class and weighted that by each peer's characteristics to determine the exposure that each child had to different kinds of peers. GN children of both sexes interacted more with same-sex peers, which may limit learning of different styles of interaction. As compared to GN children, GNN children exhibited more engagement in other-sex activities and with other-sex play partners and GNN children experienced somewhat fewer peer interactions, but did not differ on problem behaviors or social competence. Boys with GNN peer preferences had increased exposure to peers with problem behaviors. GNN girls experienced little exposure to peers with problem behaviors, but they also had little exposure to socially competent peers, which may reduce learning social skills from peers. Implications of these findings for future socialization and development will be discussed. PMID- 22528040 TI - Interaction among alliance, psychodynamic-interpersonal and cognitive-behavioural techniques in the prediction of post-session change. AB - The current study examined the interaction of clients' perceptions of the psychodynamic-interpersonal (PI) and cognitive-behavioural (CB) techniques that their therapist utilized in their most recent therapy session and working alliance in the prediction of post-session changes. Seventy-five clients were treated by 25 therapists at a counselling centre in the USA. We posited that alliance would interact with clients' perceptions of their therapists' use of PI and CB techniques in the prediction of post-session changes. The results revealed a three-way interaction between clients' perceptions of the alliance, PI techniques and CB techniques in the prediction of post-session changes. More PI and more CB techniques and more PI but fewer CB techniques were associated with better post-sessions changes in the context of higher alliances. More CB techniques but fewer PI techniques and fewer PI and fewer CB techniques were not significantly associated with post-session changes in the context of higher (or lower) alliances. KEY PRACTITIONER MESSAGE: Clients' perceptions of PI techniques in the context of stronger alliances were most beneficial for post-session outcomes. Thus, a high alliance will likely maximize the impact of PI techniques. Clients who rated their therapist as being relatively inactive reported fewer positive post-session outcomes, suggesting that an idle therapeutic approach is not advantageous. Therapist differences explained two to three times more variation in session outcomes than client ratings of alliance or techniques. Some therapists are better at facilitating positive session outcomes as compared with others, suggesting that a potential key barometer of therapists' effectiveness may be captured by session outcomes. PMID- 22528041 TI - Synthesis of PCP-supported nickel complexes and their reactivity with carbon dioxide. AB - The Ni amide and hydroxide complexes [(PCP)Ni(NH(2))] (2; PCP=bis-2,6-di-tert butylphosphinomethylbenzene) and [(PCP)Ni(OH)] (3) were prepared by treatment of [(PCP)NiCl] (1) with NaNH(2) or NaOH, respectively. The conditions for the formation of 3 from 1 and NaOH were harsh (2 weeks in THF at reflux) and a more facile synthetic route involved protonation of 2 with H(2)O, to generate 3 and ammonia. Similarly the basic amide in 2 was protonated with a variety of other weak acids to form the complexes [(PCP)Ni(2-Me-imidazole)] (4), [(PCP)Ni(dimethylmalonate)] (5), [(PCP)Ni(oxazole)] (6), and [(PCP)Ni(CCPh)] (7), respectively. The hydroxide compound 3, could also be used as a Ni precursor and treatment of 3 with TMSCN (TMS=trimethylsilyl) or TMSN(3) generated [(PCP)Ni(CN)] (8) or [(PCP)Ni(N(3))] (9), respectively. Compounds 3-7, and 9 were characterized by X-ray crystallography. Although 3, 4, 6, 7, and 9 are all four-coordinate complexes with a square-planar geometry around Ni, 5 is a pseudo-five-coordinate complex, with the dimethylmalonate ligand coordinated in an X-type fashion through one oxygen atom, and weakly as an L-type ligand through another oxygen atom. Complexes 2-9 were all reacted with carbon dioxide. Compounds 2-4 underwent facile reaction at low temperature to form the kappa(1)-O carboxylate products [(PCP)Ni{OC(O)NH(2)}] (10), [(PCP)Ni{OC(O)OH}] (11), and [(PCP)Ni{OC(O)-2-Me imidazole}] (12), respectively. Compounds 10 and 11 were characterized by X-ray crystallography. No reaction was observed between 5-9 and carbon dioxide, even at elevated temperatures. DFT calculations were performed to model the thermodynamics for the insertion of carbon dioxide into 2-9 to form a kappa(1)-O carboxylate product and understand the pathways for carbon dioxide insertion into 2, 3, 6, and 7. The computed free energies indicate that carbon dioxide insertion into 2 and 3 is thermodynamically favorable, insertion into 8 and 9 is significantly uphill, insertion into 5 and 7 is slightly uphill, and insertion into 4 and 6 is close to thermoneutral. The pathway for insertion into 2 and 3 has a low barrier and involves nucleophilic attack of the nitrogen or oxygen lone pair on electrophilic carbon dioxide. A related stepwise pathway is calculated for 7, but in this case the carbon of the alkyne is significantly less nucleophilic and as a result, the barrier for carbon dioxide insertion is high. In contrast, carbon dioxide insertion into 6 involves a single concerted step that has a high barrier. PMID- 22528042 TI - Trichoderma biodiversity in China. AB - In the present study, we made further investigation into the diversity of Trichoderma in China than previous ones utilizing comprehensive approaches of morphological microscopic observation and phylogenetic analysis by detecting molecular markers. One thousand nine hundred ten Trichoderma strains were isolated from soil or other materials in China: East (Anhui, Fujian, Jiangsu, Jiangxi, Shandong, Zhejiang province and Shanghai municipality), South-West (Guizhou, Qinghai, Shanxi, Sichuan and Yunnan province, Tibet Autonomous Region and Chongqing municipality), South-East (Guangdong, Guangxi, Hainan province), and Middle China (Henan, Hubei and Hunan province). Representative isolates were verified at the species level by morphological characters and the oligonucleotide barcode program TrichoOKey v.10 and the custom BLAST server TrichoBLAST, using sequence of the ITS 1 and 2 region of the rDNA cluster and partial sequences of translation elongation factor 1-alpha(tef1-alpha). A total of 23 Trichoderma species were identified : T.asperellum, T.atrioviride, T.aureovriride, T.brevicompactum, T.citrioviride, T.erinaceum, T.gamsii, T.hamatum, T.harzianum (H.1ixii), T.intricatum, T.koningii (H.koningii), T.koningiopsis, T.longibranchiatum, T.pleuroticola, T.reeseii (H.jecorina), T.sinensis, T.spirale, T.stromaticum, T.tomentosum, T.velutinum, T.vermipilum, T.virens (H.virens), T.viride. Among them, 3 species: T.intricatum, T.stromaticum, T.vermipilum were first reported in China; T.harzianum (H,1ixii) was the most widely distributed species in China. This study further shows that, the highest biodiversity of Trichoderma population appeared in South-West China. PMID- 22528043 TI - A new form or a variant of SMD type A4. PMID- 22528044 TI - Theoretical evidence of the stabilization of an unusual four-membered metallacycloallene by a transition-metal fragment. PMID- 22528046 TI - Demographic and behavioral correlates of HIV risk among men and transgender women recruited from gay entertainment venues and community-based organizations in Thailand: implications for HIV prevention. AB - High HIV prevalence among men who have sex with men (MSM) and transgender women in Thailand suggest a vital need for targeted interventions. We conducted a cross sectional survey to examine and compare sexual risk behaviors, and demographic and behavioral correlates of risk, among MSM and transgender women recruited from gay entertainment venue staff and community-based organization (CBO) participants. We used venue-based sampling across nine sites in Bangkok and Chiang Mai. Among 260 participants (57.3% gay-identified, 26.9% heterosexual/bisexual-identified, 15.8% transgender; mean age = 26.7 years), nearly one-fifth (18.5%) reported unprotected anal sex (UAS), half (50.4%) sex in exchange for money, and one-fifth (20.0%) STI diagnosis (past year). Nearly one fourth (23.1%) reported oral erectile dysfunction medication use and nearly one fifth (19.2%) illicit drug use (past 3 months). Overall, 43.1% indicated that healthcare providers exhibited hostility towards them. Gay entertainment venue staff were significantly more likely to self-identify as heterosexual/bisexual (versus gay or transgender female), and to have less than high school degree education, higher monthly income, to have engaged in sex in exchange for money, sex with women and unprotected vaginal sex, but were significantly less likely to have engaged in UAS than CBO participants. Targeted interventions for younger MSM and transgender women, for non gay-identified men, and strategies to address structural determinants of risk, including low education and discrimination from healthcare providers, may support HIV prevention among MSM and transgender women, and serve broader national HIV prevention efforts in Thailand. PMID- 22528045 TI - Latent class analysis of stages of change for multiple health behaviors: results from the Special Diabetes Program for Indians Diabetes Prevention Program. AB - This study sought to identify latent subgroups among American Indian and Alaska Native (AI/AN) patients with pre-diabetes based on their stages of change for multiple health behaviors. We analyzed baseline data from participants of the Special Diabetes Program for Indians Diabetes Prevention (SDPI-DP) Program, a lifestyle intervention program to prevent diabetes among AI/ANs. A total of 3,135 participants completed baseline questionnaires assessing stages of change for multiple health behaviors, specifically exercise, healthy eating, and weight loss. Latent class analysis was used to identify subgroups of people based on their answers to stages of change questions. Covariates were added to the latent class analyses to investigate how class membership was related to sociodemographic, behavioral, and psychosocial factors. Three classes were identified based on the distributions of the stages of change variables: Contemplation, Preparation, and Action/Maintenance classes. Male and retired participants were more likely to be in more advanced stages. Those who exercised more, ate healthier diets, and weighed less were significantly more likely to be in the Action/Maintenance class. Further, the participants who had higher self efficacy, stronger family support, and better health-related quality of life had higher odds of being in the Action/Maintenance class. In conclusion, we found that stages of change for multiple behaviors can be summarized by a three-class model in this sample. Investigating the relationships between latent classes and intervention outcomes represents important next steps to extend the findings of the current study. PMID- 22528047 TI - Atrial fibrillation inducibility in the absence of structural heart disease or clinical atrial fibrillation: critical dependence on induction protocol, inducibility definition, and number of inductions. AB - BACKGROUND: Inducibility of atrial fibrillation (AF) after pulmonary vein isolation has been used to guide additional left atrial ablation in paroxysmal AF. The sensitivity and specificity of AF induction in this setting remains uncertain. We examined the incidence and characteristics of inducible AF in patients without structural heart disease or clinical AF and the effect of different induction protocols on AF inducibility. METHODS AND RESULTS: In 44 patients with supraventricular tachycardia with no history of AF or risk factors for AF, atrial refractoriness and conduction were measured, followed by AF induction attempts (10/patient). Each induction was performed after a waiting time that exceeded twice the duration of induced AF from the preceding induction. AF>=1 minute was considered inducible, and >=5 minutes as sustained. Burst pacing (at 200 ms for 10 seconds) was compared to decremental pacing (from 200 ms to shortest cycle length, resulting in 1:1 atrial capture for 10 seconds). After 10 inductions, AF was inducible in 49.5%, and sustained in 29.5% of patients. The incidence of both inducible and sustained AF increased with each induction. Apart from male gender, no clinical or electrophysiological features were associated with sustained AF. Decremental pacing was associated with a higher incidence of sustained AF (41.2% versus 14.8%, P=0.049), longer duration of AF (P=0.006), and shorter mean AF cycle length (P<0.001) compared with burst pacing. CONCLUSIONS: Inducible and sustained AF is common in patients in the absence of structural heart disease or clinical AF, and its incidence varies according to gender, method of induction, and number of inductions. There is a direct relationship between AF persistence and number of inductions, which has not reached a plateau after 10 inductions. PMID- 22528048 TI - Mitochondrial K+ channels are involved in ischemic postconditioning in rat hearts. AB - The mitochondrial calcium-activated potassium channel (mitoK(Ca)) and the mitochondrial ATP-sensitive potassium channel (mitoK(ATP)) are both involved in cardiac preconditioning. Here, we examined whether these two channels are also involved in ischemic or pharmacological postconditioning. Using Langendorff perfusion, rat hearts were made hypoxic for 45 min and then reoxygenated for 30 min. Ischemic postconditioning (IPT) was achieved through application of 3 cycles of 10 s of reperfusion and 10 s of ischemia before reoxygenation, with and without paxilline (Pax; a mitoK(Ca) blocker) or 5-hydroxydecanoate (5-HD; a mitoK(ATP) blocker). Pharmacological postconditioning was carried out for 5 min at the onset of reoxygenation using NS1619 (a mitoK(Ca) opener) or diazoxide (Dia; a mitoK(ATP) opener). Pax and 5-HD abolished IPT-induced cardioprotection from reoxygenation injury, whereas administration of NS1619 or Dia significantly improved cardiac contractile activity and reduced aspartate aminotransferase (an index of myocyte injury) release following reoxygenation. In addition, isolated rat myocytes were loaded with tetramethylrhodamine methyl ester (TMRE; fluorescent mitochondrial membrane potential indicator) and 2',7' dichlorofluorescein [DCFH; fluorescent reactive oxygen species (ROS) indicator] or Fluo-4-acetoxymethyl ester (Fluo-4-AM; fluorescent calcium indicator). When TMRE-loaded myocytes were laser illuminated, the DCFH and Fluo-4 fluorescence increased, and TMRE fluorescence decreased. These effects were significantly inhibited by NS1619 and Dia. We therefore conclude that IPT may protect the heart through activation of mitoK(ATP) and mitoK(Ca) channels, and that opening of these channels at the onset of reoxygenation protects the heart from reoxygenation injury, most likely by reducing excess generation of ROS and the resultant Ca(2+) overload. PMID- 22528049 TI - Zebrafish HSF4: a novel protein that shares features of both HSF1 and HSF4 of mammals. AB - Heat-shock proteins (hsps) have important roles in the development of the eye lens. We previously demonstrated that knockdown of hsp70 gene expression using morpholino antisense technology resulted in an altered lens phenotype in zebrafish embryos. A less severe phenotype was seen with knockdown of heat-shock factor 1 (HSF1), suggesting that, while it likely plays a role in hsp70 regulation during lens formation, other regulatory factors are also involved. Heat-shock factor 4 plays an important role in mammalian lens development, and an expressed sequence tag encoding zebrafish HSF4 has been identified. The deduced amino acid sequence shares structural similarities with mammalian HSF4 including the lack of an HR-C domain. However, the HR-C domain is absent due to a severe C terminal truncation within zebrafish HSF4 (zHSF4) relative to the mammalian protein. Surprisingly, the amino acid composition of the zHSF4 DNA binding domain shares a greater degree of identity with HSF1 proteins than it does with mammalian HSF4 proteins. Consistent with this, the binding affinity of in vitro synthesized zHSF4 for discontinuous heat-shock response element sequences is more limited, similar to what has been previously observed for HSF1 proteins. Hsf4 mRNA is expressed in zebrafish adult eye tissue but is only observed in developing embryonic tissue at 60 h post-fertilization or later. This, together with the lack of an observable phenotype following morpholino-based antisense knockdown of hsf4, suggests that zHSF4 is unlikely to play a role in regulating early embryonic lens development. PMID- 22528050 TI - The interaction of HspA1A with TLR2 and TLR4 in the response of neutrophils induced by ovarian cancer cells in vitro. AB - Inducible heat shock protein (HspA1A) promotes tumor cell growth and survival. It also interacts with effector cells of the innate immune system and affects their activity. Recently, we showed that the direct contact of ovarian cancer cells, isolated from tumor specimens, with neutrophils intensified their biological functions. Our current experiments demonstrate that the activation of neutrophils, followed by an increased production of reactive oxygen species, by cancer cells involves the interaction of HspA1A from cancer cells with Toll-like receptors 2 and 4 expressed on the neutrophils' surface. Our data may have a practical implication for targeted anticancer therapies based, among other factors, on the inhibition of HspA1A expression in the cancer cells. PMID- 22528051 TI - Hsp27 as a marker of cell damage in children on chronic dialysis. AB - Intracellular heat shock protein (Hsp) 27 is a potent anti-apoptotic factor that, among other activities, prevents the binding of membrane receptor Fas to its ligand FasL. However, the potential role of extracellular Hsp27 and possibilities to control it have not been clarified. Moreover, there are no data on relations between Hsp27, sFas/sFasL system, matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in patients with chronic kidney disease (CKD)-neither children nor adults. The aim of this study was to evaluate serum concentrations of Hsp27 and their potential regulators (sFas, sFasL, MMP-7, TIMP-1) in children with CKD and on chronic dialysis. Twenty-six CKD children stage 5 still on conservative treatment, 19 patients on hemodialysis (HD), 22 children on automated peritoneal dialysis (APD), and 30 controls were examined. Serum concentrations of Hsp27, sFas, sFasL, MMP-7, and TIMP-1 were assessed by ELISA. Median values of Hsp27 were significantly elevated in all dialyzed patients vs. those in pre-dialysis period and vs. controls, the highest values being observed in subjects on HD. Regression analysis revealed that MMP-7, TIMP-1, sFas, and sFasL were the best predictors of Hsp27 concentrations in dialyzed patients. Children with CKD are prone to Hsp27 dysfunction, aggravated by the dialysis commencement, and more pronounced in patients on hemodialysis. Correlations between Hsp27 and examined parameters suggest the potential role for Hsp27 as a marker of cell damage in the pediatric population on chronic dialysis. PMID- 22528052 TI - Heat shock proteins and survival strategies in congeneric land snails (Sphincterochila) from different habitats. AB - Polmunate land snails are subject to stress conditions in their terrestrial habitat, and depend on a range of behavioural, physiological and biochemical adaptations for coping with problems of maintaining water, ionic and thermal balance. The involvement of the heat shock protein (HSP) machinery in land snails was demonstrated following short-term experimental aestivation and heat stress, suggesting that land snails use HSPs as part of their survival strategy. As climatic variation was found to be associated with HSP expression, we tested whether adaptation of land snails to different habitats affects HSP expression in two closely related Sphincterochila snail species, a desert species Sphincterochila zonata and a Mediterranean-type species Sphincterochila cariosa. Our study suggests that Sphincterochila species use HSPs as part of their survival strategy following desiccation and heat stress, and as part of the natural annual cycle of activity and aestivation. Our studies also indicate that adaptation to different habitats results in the development of distinct strategies of HSP expression in response to stress, namely the reduced expression of HSPs in the desert-inhabiting species. We suggest that these different strategies reflect the difference in heat and aridity encountered in the natural habitats, and that the desert species S. zonata relies on mechanisms and adaptations other than HSP induction thus avoiding the fitness consequences of continuous HSP upregulation. PMID- 22528053 TI - Suicidal performances: voicing discontent in a girls' dormitory in Kabul. AB - Female suicide in Afghanistan has generally been given economic and psychological explanations. More rarely has its social dimension been analysed. In this paper, I underline the communicative potential of Afghan women's suicide in the 'post war/reconstruction' context. I highlight its ambiguous symbolic power and its anchorage in the subversive imaginary universe of women's poetic expression. I argue that while reproducing certain cultural ideas about women's inherent emotional fragility, women's suicide also challenges the honour system in powerful ways and opens possibilities for voicing discontent. I qualify female suicide as the 'art of the weak' (De Certeau 1980, 6), a covert form of protest, a performance-in the sense of Bauman (2004)-that builds upon traditional popular 'knowledge' about gender in order to manage the impression of an audience and make women's claims audible. PMID- 22528054 TI - Everyday life, culture, and recovery: carer experiences in care homes for individuals with severe mental illness. AB - Supported homes or Care Homes (CHs) have become in-services that play a fundamental role in social-health systems, particularly in mental health systems in Europe and the United States. They provide settings where residents' day-to day routines are supervised by in-house non-clinician professional carers. Ten semi-structured in-depth interviews were conducted by expert professional carers of persons with schizophrenia to explore interactions and activities between carers and users living in special "Care Homes". Analysis focused primarily on the functions of everyday life and daily routines in the recovery process. Social positioning analysis was used to investigate meanings and subjective experiences of professionals. The analysis revealed the importance of personal interactions in daily routines for recovery. We identified two main concerns guiding professionals' interactions with users: "Bring [users] to the here and now" and "give them the initiative to start actions". We suggest that CHs promote the construction of privileged identity in western urban societies, forming part of the process towards recovery and better social integration. PMID- 22528055 TI - Starting from scratch: the development of the Adolescent Quality of Life-Mental Health Scale (AQOL-MHS). AB - This article documents the initial development of a Spanish mental health quality of life (QOL) instrument based on the adolescents' own assessment of important domains to their QOL. Using a grounded theory approach, we targeted five mental health disorders: attention deficit hyperactivity disorder, conduct disorder, oppositional defiant disorder, generalized anxiety disorder, and major depressive disorder. In-depth interviews (n = 40) and three focus groups (n = 20) were conducted and analyzed using qualitative methods to guide the development of items. A convenient sample of island Puerto Rican adolescents aged 12-18 was recruited from outpatient mental health clinics. Qualitative analysis revealed a total of 87 themes. They were distributed based on core QOL domains such as (1) Self, (2) Peers, (3) Family, (4) School, and (5) Environment. Items were written based on prevailing themes and using as closely as possible, words and phrases used by the adolescents to describe their views and perceptions of QOL. The goal for the AQOL-MHS is to pinpoint specific areas of health-related QOL for each psychiatric diagnostic group that will provide valuable information to assist both patients and providers set, define and evaluate adequate mental health treatment goals. PMID- 22528056 TI - Predictors of chronic trauma-related symptoms in a community sample of New Zealand motor vehicle accident survivors. AB - This study examined 1,500 New Zealand community-residing adults for involvement in serious motor vehicle accident (MVA) and the development of trauma-related symptomatology. The incidence of MVA was 11 %. More than 50 % of the accident victim sub-sample reported hyperarousal, with exaggerated startle, intrusive recollections, situational avoidance, emotional reactivity, and cognitive avoidance. The high incidence of trauma-related symptoms is noteworthy given 59 % of victims reported sustaining no or mild accident injury, and only 27 % were admitted to hospital for severe injury. Trauma-related symptoms were related to measures of injury severity, psychological and social functioning, and persistent medical problems. Pre- and post-accident factors, that is, experience of additional trauma, experience of stressful life events and post-accident social contact were the most important predictors of trauma-related symptoms severity. This study discusses the importance of examining trauma-related symptoms rather than using categorical diagnostic criteria (i.e., post-traumatic stress disorder, PTSD) as a sole means of characterizing the psychological impact of MVA. PMID- 22528057 TI - Automatic knowledge-based recognition of low-level tasks in ophthalmological procedures. AB - PURPOSE: Surgical process models (SPMs) have recently been created for situation aware computer-assisted systems in the operating room. One important challenge in this area is the automatic acquisition of SPMs. The purpose of this study is to present a new method for the automatic detection of low-level surgical tasks, that is, the sequence of activities in a surgical procedure, from microscope video images only. The level of granularity that we addressed in this work is symbolized by activities formalized by triplets . METHODS: Using the results of our latest work on the recognition of surgical phases in cataract surgeries, and based on the hypothesis that most activities occur in one or two phases only, we created a light-weight ontology, formalized as a hierarchical decomposition into phases and activities. Information concerning the surgical tools, the areas where tools are used and three other visual cues were detected through an image-based approach and combined with the information of the current surgical phase within a knowledge based recognition system. Knowing the surgical phases before the activity, recognition allows supervised classification to be adapted to the phase. Multiclass Support Vector Machines were chosen as a classification algorithm. RESULTS: Using a dataset of 20 cataract surgeries, and identifying 25 possible pairs of activities, a frame-by-frame recognition rate of 64.5 % was achieved with the proposed system. CONCLUSIONS: The addition of human knowledge to traditional bottom-up approaches based on image analysis appears to be promising for low-level task detection. The results of this work could be used for the automatic indexation of post-operative videos. PMID- 22528058 TI - Virtual mastoidectomy performance evaluation through multi-volume analysis. AB - PURPOSE: Development of a visualization system that provides surgical instructors with a method to compare the results of many virtual surgeries (n > 100). METHODS: A masked distance field models the overlap between expert and resident results. Multiple volume displays are used side-by-side with a 2D point display. RESULTS: Performance characteristics were examined by comparing the results of specific residents with those of experts and the entire class. CONCLUSIONS: The software provides a promising approach for comparing performance between large groups of residents learning mastoidectomy techniques. PMID- 22528059 TI - Left ventricular myocardium segmentation on delayed phase of multi-detector row computed tomography. AB - RATIONALE AND OBJECTIVES: Advanced ischemic heart disease is usually accompanied by left ventricular (LV) myocardial volume loss and an abnormal enhancing pattern on delayed phase of multi-detector row computed tomography (MDCT). To assist radiologists and physicians in estimating the LV myocardial volume on delayed phase, this paper proposes an adaptive segmentation method for contouring the myocardial region in the delayed-phase MDCT and for computing the volume. MATERIALS AND METHODS: The proposed method uses an anisotropic diffusion filter as a preprocessing procedure to enhance contrast and reduce specks in MDCT imaging. This work picks the middle of mid-ventricular level image slices as the lead slice. The proposed method develops two contouring modes to sketch the myocardium contour on the lead slice. By establishing the obtained contours as the initial contours, the region-growing method is employed to identify the contour of the myocardial region for each slice. The convex-hull finding algorithm is then used to refine the extracted contour. Finally, the width properties of the myocardial region and the morphological operators are used to obtain the entire LV myocardial volume. RESULTS: Twenty-seven healthy patients who had no symptoms of ischemic heart disease are examined to evaluate the performance of the proposed method. Compared with manual contours delineated by two experienced experts, the contouring results using computer simulation reveal that the proposed method reliably identifies contours similar to those obtained using manual sketching. CONCLUSION: The proposed method provides robust contouring for the LV myocardium on delayed-phase MDCT. The potential role of this technique may substantially reduce the time required to sketch manually a precise contour with high stability. PMID- 22528060 TI - Accurate two-dimensional cardiac strain calculation using adaptive windowed Fourier transform and Gabor wavelet transform. AB - PURPOSE: Cardiac strain calculated from tagged magnetic resonance (MR) images provides clinicians information about abnormalities of heart-wall motion in patients. It is important to develop an accurate method to determine the cardiac strain efficiently. An adaptive windowed harmonic phase (AWHARP) method is proposed for cardiac strain calculation. MATERIALS AND METHODS: AWHARP is based on adaptive windowed Fourier transform (AWFT) and 2D Gabor wavelet transform (2D GWT). The AWFT provides a spatially varying representation of the signal spectra, which allows the harmonic phase (HARP) image to be extracted with high accuracy. Instantaneous spatial frequencies are calculated using 2D-GWT, and the widths of the adaptive windows are then determined according to the instantaneous spatial frequencies for multi-resolution analysis of phase extraction. The proposed method was studied using simulated images and patients' MR images. Both single tagged images (SPAMM) and subtracted tagged images (CSPAMM) were generated using our simulation method, and their results calculated using AWHARP and HARP methods were compared. Normal and pathological tagged MR images were also processed to evaluate the performance of our method. RESULTS: Our experimental results show that the accuracies of phase and strain images calculated using the AWHARP method are higher than that calculated using the HARP method especially for large tag line deformation. The improvement in accuracies can be up to 3.2 strain (E1) and 17.3 calculation from MR images reveals that the cardiac strain in the end systolic state is significantly reduced for patients with hypertrophic cardiomyopathy (HCM) compared to that of healthy subjects. CONCLUSION: The proposed AWHARP is an accurate and efficient method for cardiac strain estimation from MR images. This new algorithm can help clinicians to detect left ventricle dysfunctions and myocardial diseases with accurate cardiac strain analysis. PMID- 22528061 TI - [Quality of reporting in studies on bipolar disorders: implications for the development of guidelines]. AB - BACKGROUND: Selective publishing as well as inadequate reporting of clinical trials entail a risk of bias in clinical decision making. Therefore the CONSORT statement was introduced to improve the quality of reporting of randomized controlled trials (RCT). This study aimed to assess the quality of reporting of RCTs on pharmacological treatment of bipolar disorder in relation to publication period and endorsement of publication guidelines. METHODS: In the context of the development of the German evidence and consensus-based S3 guidelines for diagnosis and therapy of bipolar disorders a systematic literature search was carried out to identify all RCTs published between 2000 and 2010 relevant to the pharmacological treatment of bipolar disorders. An adapted checklist based on the CONSORT statement was used to assess the quality of reporting. RESULTS: A total of 134 RCTs were included in this analysis. Of the 72 checklist items, 43% were generally reported adequately (reported in >= 75% of all trials) and 25% inadequately (reported in < 25% of all trials). Reporting was generally poor for randomization, effect size (reported in 22%) and number needed to treat (NNT 16%). No consistent trend could be shown for improvement in quality of reporting over time or for journals that do or do not endorse the URM (uniform requirements for manuscripts submitted to biomedical journals). CONCLUSIONS: Clinical investigators as well as editors and reviewers should be further encouraged to follow publication guidelines otherwise trials have to be downgraded or excluded from systematic evaluations. PMID- 22528063 TI - [Comments on language of psychiatrists and stigmatization of the mentally ill]. AB - Language is determinative for psychiatric action, both for the understanding of the mentally ill and for treatment. More generally spoken, language also may be significant for the stigmatization of the mentally ill and of psychiatric institutions. Not least, language is the expression of the current social and cultural atmosphere, the zeitgeist. This will be demonstrated by examples of 1) the patient-physician dialogue, 2) the stigmatizing effect of words, 3) the sociopsychological mechanisms of politically correct language and 4) the change of connotations over time in unchangingly expressed terms. PMID- 22528064 TI - [A case of Bleuler's disease? 100 years of dementia praecox or group of schizophrenias]. AB - Approximately 100 years ago Eugen Bleuler published the most significant contribution to psychiatry by conceptualizing the term schizophrenia as a diagnostic entity. In modern diagnostic manuals Bleuler's concept is only reflected in subordinated criteria, i.e. the negative symptoms. On the occasion of the anniversary of Bleuler's essential publication, the present work aims to exemplify the differences in diagnostic concepts and it will be illustrated that Bleuler's intention to establish his so-called basic symptom as a guideline for diagnostics has to be considered as failed from a present day viewpoint. PMID- 22528062 TI - [Guillain-Barre syndrome after exposure to influenza]. AB - Guillain-Barre Syndrome (GBS) is an acquired, monophasic inflammatory polyradiculoneuritis of autoimmune origin, which occurs after infection and occasionally also after vaccination. Seasonal and pandemic influenza vaccines have in particular been implicated as triggers for GBS. However, a number of recent studies indicate that infection with influenza virus may also cause GBS. This review summarizes the epidemiological and experimental data of the association of GBS with exposure to influenza antigens by immunization (including vaccines against A/H1N1/2009) and infection. Vaccination against influenza is associated with a very low risk for the occurrence of GBS. In contrast infection with influenza may play a more important role as a triggering factor for GBS than previously assumed. PMID- 22528066 TI - [Prodromal stages of psychoses: qualified as new diagnostic entity in ICD-11 and DSM-5? - Pro]. PMID- 22528065 TI - [Anti-suicidal effect of lithium: current state of research and its clinical implications for the long-term treatment of affective disorders]. AB - Treatment of patients with suicidal behaviour is one of the most challenging tasks for health care professionals. Due to the high mortality, morbidity and costs related to suicide, the development of treatment and preventive strategies for suicidal behaviour have been a focus of psychiatric research. For lithium, one of the oldest pharmacological agents used in psychiatry, anti-suicidal effects have been found since the early 90s in many international studies. Despite this unambiguous evidence and corresponding recommendations in national and international guidelines for the acute and maintenance therapy of affective disorders, the use of lithium is still underrepresented. The following article provides a review of studies investigating the anti-suicidal effects of lithium in affective disorders. Clinical implications for the treatment of affective disorders are discussed. PMID- 22528067 TI - Clarification of intellectual abilities in patients with GLI2 mutations cited by Kevelam et al., 2012 Am J Med Genet Part A. PMID- 22528068 TI - Fiber reinforcement of a biomimetic bone cement. AB - In this study we investigated the influence of electrospun polymer fibers on the properties of a alpha-tricalcium phosphate/gelatin biomimetic cement. To this aim, we added different amounts of poly(L-lactic acid) and poly(lactide-co glycolide) fibers to the cement composition. Fibers enrichment provoked a significant reduction of both initial and final setting times. Moreover electrospun polymer fibers slowed down the conversion of alpha-tricalcium phosphate into calcium deficient hydroxyapatite. As a result, the final cements were more compact than the control cement, because of the smaller crystal dimensions and reduced crystallinity of the apatitic phase. The compressive strength, sigma(b), and Young's modulus, E, of the control cement decreased significantly after 40 days soaking in physiological solution, whereas the more compact microstructure enabled fiber reinforced cements to maintain their mechanical properties in the long term. PMID- 22528069 TI - Comparison study of biomimetic strontium-doped calcium phosphate coatings by electrochemical deposition and air plasma spray: morphology, composition and bioactive performance. AB - In this study, strontium-doped calcium phosphate coatings were deposited by electrochemical deposition and plasma spray under different process parameters to achieve various coating morphologies. The coating composition was investigated by energy dispersive X-ray spectroscopy and X-ray diffraction. The surface morphologies of the coatings were studied through scanning electron microscopy while the cytocompatibility and bioactivity of the strontium-doped calcium phosphate coatings were evaluated using bone cell culture using MC3T3-E1 osteoblast-like cells. The addition of strontium leads to enhanced proliferation suggesting the possible benefits of strontium incorporation in calcium phosphate coatings. The morphology and composition of deposited coatings showed a strong influence on the growth of cells. PMID- 22528070 TI - Production and characterization of miro- and nano-features in biomedical alumina and zirconia ceramics using a tape casting route. AB - A process of micromolding, delivering micro- and nanopatterned ceramic surfaces for biomaterial applications is described in this work. To create the desired structures, tape casting of ceramic slurries on microfabricated silicon mold was used. Several tape casting slurry compositions were tested to evaluate the feasibility of transferring micro- and nano-features from silicon molds. Used ceramics were alumina (alpha-Al(2)O(3)) and yttria stabilized zirconia. Three types of polymeric binders for the green tape (PVB, PES, and PVP) were investigated using three different solvents (ethanol, n-methyl-pyrrolidone, water). Well-defined features in shapes of wells with diameters down to 2.4 MUm and a depth of 10 MUm and pillars with diameters down to 1.7 MUm and a height of 3 MUm were obtained. Morphology, grain size and porosity of the sintered bodies were characterized. Finally fibroblast cells were cultured on the surfaces in order to observe their morphology under influence of the microstructured surfaces. PMID- 22528071 TI - Development of strong and bioactive calcium phosphate cement as a light-cure organic-inorganic hybrid. AB - In this research, light cured calcium phosphate cements (LCCPCs) were developed by mixing a powder phase (P) consisting of tetracalcium phosphate and dicalcium phosphate and a photo-curable resin phase (L), mixture of hydroxyethylmethacrylate (HEMA)/poly acrylic-maleic acid at various P/L ratios of 2.0, 2.4 and 2.8 g/mL. Mechanical strength, phase composition, chemical groups and microstructure of the cured cements were evaluated at pre-set times, i.e. before and after soaking in simulated body fluid (SBF). The proliferation of Rat derived osteoblastic cells onto the LCCPCs as well as cytotoxicity of cement extracts were determined by cell counting and 3-{4,5-dimethylthiazol-2yl}-2,5 diphenyl-2H-tetrazolium bromide assay after different culture times. It was estimated from Fourier transforming infrared spectra of cured cements that the setting process is ruled by polymerization of HEMA monomers as well as formation of calcium poly-carboxylate salts. Microstructure of the cured cements consisted of calcium phosphate particles surrounded by polymerized resin phase. Formation of nano-sized needlelike calcium phosphate phase on surfaces of cements with P/L ratios of 2.4 and 2.8 g/mL was confirmed by scanning electron microscope images and X-ray diffractometry (XRD) of the cured specimen soaked in SBF for 21 days. Also, XRD patterns revealed that the formed calcium phosphate layer was apatite phase in a poor crystalline form. Biodegradation of the cements was confirmed by weight loss, change in molecular weight of polymer and morphology of the samples after different soaking periods. The maximum compressive strength of LCCPCs governed by resin polymerization and calcium polycarboxylate salts formation was about 80 MPa for cement with P/L ratio of 2.8 g/mL, after incubation for 24 h. The strength of all cements decreased by decreasing P/L ratio as well as increasing soaking time. The preliminary cell studies revealed that LCCPCs could support proliferation of osteoblasts cultured on their surfaces and no cytotoxic effect was observed for the extracts of them. PMID- 22528072 TI - The application of layered double hydroxide clay (LDH)-poly(lactide-co-glycolic acid) (PLGA) film composites for the controlled release of antibiotics. AB - Many sites of bacterial infection such as in-dwelling catheters and orthopedic surgical sites require local rather than systemic antibiotic administration. However, currently used controlled release vehicles, such as polymeric films, release water-soluble antibiotics too quickly, whereas nonporous bone cement, used in orthopedics, release very little drug. The purpose of this study was to investigate the use of nanoparticulates composed of layered double hydroxide clays to bind various antibiotics and release them in a controlled manner. Mg-Al (carbonate) layered double hydroxides were synthesized and characterized using established methods. These clay particles were suspended in solutions of the antibiotics tetracycline, doxorubicin (DOX), 5-fluorouracil, vancomycin (VAN), sodium fusidate (SF) and antisense oligonucleotides and binding was determined following centrifugation and quantitation of the unbound fraction by UV/Vis absorbance or HPLC analysis. Drug release from layered double hydroxide clay/drug complexes dispersed in polymeric films was measured by incubation in phosphate buffered saline (pH 7.4) at 37 degrees C using absorbance or HPLC analysis. Antimicrobial activity of drug released from film composites was determined using zonal inhibition studies against S. epidermidis. All drugs bound to the clay particles to various degrees. Generally, drugs released with a large burst phase of release (except DOX) with little further drug release after 4 days. Dispersion of drug/clay complexes in poly(lactic-co-glycolic acid) films resulted in a reduced burst phase of release and a slow continuous release for many weeks with effective antimicrobial amounts of VAN and SF released at later time points. Layered double hydroxide clays may be useful for controlled release applications at sites requiring long-term antibiotic exposure as they maintain the drug in a non-degraded state and release effective amounts of drug over long time periods. LDH clay/drug complexes are amenable to homogenous dispersion in polymeric films where implant coating may be optimal or required. PMID- 22528073 TI - Injection of calcium phosphate pastes: prediction of injection force and comparison with experiments. AB - Calcium phosphate ceramics suspensions (ICPCS) are used in bone and dental surgery as injectable bone substitutes. This ICPCS biomaterial associates biphasic calcium phosphate (BCP) granules with hydroxypropylmethylcellulose (HPMC) polymer. Different ICPCS were prepared and their rheological properties were evaluated in parallel disks geometry as a function of the BCP weight ratio (35, 40, 45 and 50 %). The suspensions show a strongly increased viscosity as compared to the suspending fluid and the high shear rate part of the flow curve can be fitted with a power law model (Ostwald-de Waele model). The fitting parameters depend on the composition of the suspension. A simple device has been used to characterize extrusion of the paste using a disposable syringe fitted with a needle. The injection pressure of four ICPCS formulations was studied under various conditions (needle length and radius and volumetric flow rate), yielding an important set of data. A theoretical approach based on the capillary flow of non-Newtonian fluids was used to predict the necessary pressure for injection, on the basis of flow curves and extrusion conditions. The extrusion pressure calculated from rheological data shows a quantitative agreement with the experimental one for model fluids (Newtonian and HPMC solution) but also for the suspension, when needles with sufficiently large diameters as compared to the size of particles, are used. Depletion and possibly wall slip is encountered in the suspensions when narrower diameters are used, so that the injection pressure is less than that anticipated. However a constant proportionality factor exists between theory and injection experiments. The approach developed in this study can be used to correlate the rheological parameters to the necessary pressure for injection and defines the pertinent experimental conditions to obtain a quantitative agreement between theory and experiments. PMID- 22528074 TI - Electrospinning collagen and hyaluronic acid nanofiber meshes. AB - Collagen and hyaluronic acid (HA) are main components of the extracellular matrix and have been utilized in electrospinning; a technique that creates nanosized fibers for tissue scaffolds. A collagen/HA polymer solution was electrospun into a scaffold material for osteoporosis patients who have reduced bone strength. To synthesize nanofibers, a high voltage was applied to the polymer solution to draw out nanofibers that were collected on a ground plate as a uniform mesh. The meshes were then crosslinked to render them insoluble and conjugated with gold nanoparticles to promote biocompatibility. Characterization of the mesh was performed using scanning electron microscope, electron dispersive spectroscopy and fourier transform infrared spectroscopy. A WST-1 assay determined the potential biocompatibility. The results show that collagen/HA scaffolds were developed that were insoluble in aqueous solutions and promoted cellular attachment that could be used as a tissue engineered scaffold to promote cell growth. PMID- 22528075 TI - Ceramic/metal biocidal nanocomposites for bone-related applications. AB - Hydroxyapatite/silver nanocomposites have been designed and synthesized as an engineering material for biomedical applications. The hydroxyapatite matrix was synthesized by a sol-gel method and, subsequently, the Ag nanoparticles were deposited by heterogeneous precipitation followed by two different reduction routes: thermal or chemical. Both sets were studied and compared and, in all cases, the metal nanoparticles appear perfectly isolated and attached to the surface of the hydroxyapatite. The average metal particle size is below 10 nm, allowing an important contact surface between silver and the microorganisms. The antimicrobial behavior against common bacteria showed a high effectiveness, well above the commercial level, as well as against yeast, in the case of the chemically reduced sample. Due to the nanocomposite microstructure, only a negligible portion of metal was released to the lixiviated liquid after the biocide tests, minimizing the risk of toxicity. These nanocomposites offer a solution to the infections on the surface of implants, one of the main problems in reaching a suitable level of osseointegration. PMID- 22528076 TI - Calcium alginate/dextran methacrylate IPN beads as protecting carriers for protein delivery. AB - In the present study, mechanical and protein delivery properties of a system based on the interpenetration of calcium-alginate (Ca-Alg) and dextran methacrylate (Dex-MA) networks are shown. Interpenetrated hydrogels beads were prepared by means of the alginate chains crosslinking with calcium ions, followed by the exposure to UV light that allows the Dex-MA network formation. Optical microscope analysis showed an average diameter of the IPN beads (Ca-Alg/Dex-MA) of 2 mm. This dimension was smaller than that of Ca-Alg beads because of the Dex MA presence. Moreover, the strength of the IPN beads, and of their corresponding hydrogels, was influenced by the Dex-MA concentration and the crosslinking time. Model proteins (BSA and HRP) were successfully entrapped into the beads and released at a controlled rate, modulated by changing the Dex-MA concentration. The enzymatic activity of HRP released from the beads was maintained. These novel IPN beads have great potential as protein delivery system. PMID- 22528077 TI - Antimicrobial activities of recombinant mouse beta-defensin 3 and its synergy with antibiotics. AB - Mammalian beta-defensins are small cationic peptides of approximately 2-6 kDa that have been implicated in mediating innate immune defenses against microbial infection. This present study investigated the activity of mouse beta-defensin 3 (MBD3) against bacterial and yeast drug-resistant strains in vitro, and whether this molecule acts in synergy with antibiotics. Minimum inhibitory concentrations (MICs) and minimum bactericidal/fungicidal concentrations (MBC/MFC) of recombinant MBD3 (rMBD3) were determined by microdilution assays against different strains of Staphylococcus aureus and Candida albicans. rMBD3 inhibited the growth of S. aureus (MIC, 25 MUg/ml) and C. albicans (MIC, 25 MUg/ml), and showed fungicidal activity against this yeast (MFC, 100 MUg/ml). The influences of rMBD3 on S. aureus and C. albicans cells were examined using electron microscopy. Cells treated with rMBD3 showed morphological and structural changes, including delamination and perforation of the peripheral cell walls, porosity, and inanition of the cytoplasmic contents. Synergistic activities of rMBD3 with different antibiotics were assessed using checkerboard tests. Interestingly, the anti-methicillin-resistant S. aureus activity of rMBD3 in combination with ampicillin was synergistic; however, this was not the case against S. aureus (ATCC 25923). Combinations of rMBD3 with itraconazole, amphotericin or 5 fluorocytosine were synergistic against the two tested C. albicans strains. These results support the interest devoted to defensins as a novel class of antimicrobial agents, and highlight their abilities to potentiate the activities of conventional antibiotics. PMID- 22528078 TI - 1H and 13C NMR spectral assignments of pyridinium salts linked to a N-9 or N-3 adenine moiety. AB - (1)H and (13)C NMR spectral data of 13 new compounds containing a 4 (dimethylamino)- or 4-(pyrrolidin-1-yl)pyridinium moiety linked to the N-9 or N-3 nitrogen atom of an adenine moiety were assigned. 1D and 2D NMR experiments (DEPT, HSQC and HMBC) allowed the unequivocal identification of N-9 and N-3 isomers. PMID- 22528079 TI - Rapid generation of dityrosine cross-linked Abeta oligomers via Cu-redox cycling. AB - There is a great interest in the role of free radicals and oxidative stress in Alzheimer's disease and for the role of transition metals in the generation of oligomers of Abeta peptides. In the literature, there are a multitude of varying methods that can be used to create soluble oligomers of Abeta, however, the processes that create these oligomers are often stochastic by nature and thus reproducibility is an issue. Here we report a simple and reproducible method for the production of radically derived dityrosine cross-linked oligomers of Abeta, through reaction with copper and ascorbic acid. PMID- 22528080 TI - Application of photochemical cross-linking to the study of oligomerization of amyloidogenic proteins. AB - Assembly of amyloidogenic proteins into toxic oligomers and fibrils is an important pathogenic feature of over 30 amyloid-related diseases. Understanding the structures and mechanisms involved in the assembly process is necessary for rational approaches geared at inhibiting formation of these toxic species. Here, we review the application of photo-induced cross-linking of unmodified proteins (PICUP) to two disease-related amyloidogenic proteins (1) islet amyloid polypeptide (IAPP), whose toxic oligomers are thought to cause the demise of pancreatic beta-cells in type-2 diabetes mellitus and (2) alpha-synuclein, which aggregates into toxic oligomers and precipitates in Lewy bodies in Parkinson's disease. PICUP is an effective method allowing chemical "freezing" of dynamically changing oligomers and subsequent study of the oligomer size distribution that existed before cross-linking. The method has provided insights into the factors controlling early oligomerization, which could not be obtained by other means. We discuss sample preparation, experimental details, optimization of parameters, and troubleshooting. PMID- 22528081 TI - Preparation of stable amyloid beta-protein oligomers of defined assembly order. AB - Oligomeric assemblies of the amyloid beta-protein, Abeta, are thought to be the proximate neurotoxic agents in Alzheimer's disease (AD). Oligomer formation is a complex process that produces a polydisperse population of metastable structures. For this reason, formal structure-activity correlations, both in vitro and in vivo, have been difficult to accomplish. An analytical solution to this problem was provided by the application of a photochemical cross-linking method to the Abeta assembly system. This method, photo-induced cross-linking of unmodified proteins (PICUP), enabled the quantitative determination of the oligomer size distribution. We report here the integration of PICUP with SDS-PAGE and alkaline extraction procedures to create a method for the isolation of pure populations of oligomers of defined order. This method has been used successfully to provide material for formal structure-activity studies of Abeta oligomers. PMID- 22528082 TI - Purification and fibrillation of full-length recombinant PrP. AB - Misfolding and aggregation of prion protein (PrP) is related to several neurodegenerative diseases in humans such as Creutzfeldt-Jacob disease, fatal familial insomnia, and Gerstmann-Straussler-Sheinker disease. Certain applications in prion area require recombinant PrP of high purity and quality. Here, we report an experimental procedure for expression and purification of full length mammalian PrP. This protocol has been proved to yield PrP of extremely high purity that lacks PrP adducts, which are normally generated as a result of spontaneous oxidation or degradation. We also describe methods for the preparation of amyloid fibrils from recombinant PrP in vitro. Recombinant PrP fibrils can be used as a noninfectious synthetic surrogate of PrP(Sc) for development of prion diagnostics including the generation of PrP(Sc)-specific antibody. PMID- 22528083 TI - Featuring amyloids with Fourier transform infrared and circular dichroism spectroscopies. AB - Amyloids are fibrillar aggregates of proteins characterized by a basic scaffold consisting of cross beta-sheet structure that can exert physiological or pathological effects. Both far-UV circular dichroism and Fourier transform infrared (FTIR) spectroscopies are techniques used for the fast analysis of protein secondary structure. Both techniques are complementary and preferentially used depending on the physical state of the analyte, the major secondary structure element and the relative abundance of given amino acids. Although there are special setups for working with films, circular dichroism is best suited for ideal diluted solutions of polypeptides exhibiting alpha-helix as major structural element and low content of aromatic residues. During the last decade, a related technique, linear dichroism, has been applied to study the orientation of protein subunits within amyloid oligomers or fibrils in solution. Alternatively, FTIR works best with concentrated solutions, solids and films, and resolves with accuracy the beta-sheet composition, but it is affected by contributions of amide groups. The advent of new infrared techniques based on correlation analysis of time-dependent variations induced by external perturbations that generates two-dimensional IR maps has enabled to greatly increase spectral resolution and to extend its applicability to protein secondary structure characterization in a variety of physical environments. Within the amyloid field, conjunction of both spectroscopies has provided the first filter step for amyloid detection and has contributed to decipher the structural aspects of the amyloid formation mechanism. PMID- 22528084 TI - Quasielastic light scattering study of amyloid beta-protein fibrillogenesis. AB - Quasielastic light scattering (QLS) spectroscopy is a noninvasive optical method for studying the dynamic properties of macromolecular solutions. Its most important application is the determination of diffusion coefficients, from which the sizes of particles in solution may be estimated. The technique thus is particularly useful for monitoring assembly (polymerization and aggregation) reactions without the need for removing aliquots from the assembly system or disrupting the assembly process in any other way. We discuss here two of the most important aspects of QLS: (1) measurement of the correlation function of the scattered light intensity and (2) the use of this correlation function to reconstruct the distribution of sizes of the scattering particles. The ability to monitor the temporal evolution of particle size provides a powerful tool for studying protein assembly. We illustrate here how QLS has been applied to elucidate features of the oligomerization and fibrillogenesis of the amyloid beta protein, Abeta, thought to be the causative agent of Alzheimer's disease. PMID- 22528085 TI - Conformations of microtubule-associated protein Tau mapped by fluorescence resonance energy transfer. AB - The microtubule-associated protein Tau plays a physiological role of stabilizing neuronal microtubules by binding to their lateral surface. Tau belongs to the category of natively unfolded protein as it shows typical features of random coil, as analyzed by various biophysical techniques. In cells, it is subjected to several posttranslational modifications (e.g., phosphorylation, cleavage, ubiquitination, and glycosylation). In neurodegenerative diseases, Tau forms insoluble aggregates called paired helical filaments (PHFs). We have applied fluorescence resonance energy transfer (FRET) to examine the conformations of soluble Tau. We created a series of Tau mutants, each carrying one tryptophan and one cysteine (labeled by IEADANS). This made it possible to measure the distance between these FRET pairs placed in different domains of Tau. This approach enables one to analyze the global folding of soluble Tau and its alteration upon phosphorylation and denaturation. PMID- 22528086 TI - Measuring the kinetics of amyloid fibril elongation using quartz crystal microbalances. AB - Kinetic measurements of amyloid growth provide insight into the free energy landscape of this supramolecular process and are crucial in the search for potent inhibitors of the main disorders with which it is associated, including Alzheimer's and Parkinson's diseases and Type II diabetes. In recent years, a new class of surface-bound biosensor assays, e.g., those based on surface plasmon resonance (SPR) and the quartz crystal microbalance (QCM) have been established as extremely valuable tools for kinetic measurements of amyloid formation. Here we describe detailed protocols of how QCM techniques can be used to monitor the elongation of amyloid fibrils in real time and to study the influence of external factors on the kinetics of amyloid growth with unprecedented accuracy. PMID- 22528087 TI - X-ray fibre diffraction studies of amyloid fibrils. AB - Amyloid fibrils are polymeric assemblies of normally soluble proteins or peptides. To investigate their structure, it is generally not possible to use conventional methods of crystallography and solution nuclear magnetic resonance. To examine the repeating crystalline structure along the fibre axis, X-ray fibre diffraction has been a useful tool. Here we discuss the methods by which amyloid like fibrils may be prepared to form a sample suitable for structural analysis and describe how data may be collected and then analysed to arrive at a potential model structure. PMID- 22528088 TI - Structural characterization of prefibrillar intermediates and amyloid fibrils by small-angle X-ray scattering. AB - Structural investigation of the species present during protein fibrillation is of tremendous importance, yet complicated by the equilibrium between species of very different sizes and life-times. Small-angle X-ray scattering may be applied to solve this problem, providing both information about the process (number of species present and volume fractions of individual species) and low-resolution three-dimensional shape reconstructions of individual species. Here, we describe in detail the challenges associated with the approach, exemplified using data from fibrillating insulin or alpha-synuclein samples. PMID- 22528089 TI - Atomic force fluorescence microscopy in the characterization of amyloid fibril assembly and oligomeric intermediates. AB - Atomic force microscopy (AFM) has become a conventional tool for elucidation of the molecular mechanisms of protein aggregation and, specifically, for analysis of assembly pathways, architecture, aggregation state, and heterogeneity of oligomeric intermediates or mature fibrils. AFM imaging provides useful information about particle dimensions, shape, and substructure with nanometer resolution. Conventional AFM methods have been very helpful in the analysis of polymorphic assemblies formed in vitro from homogeneous proteins or peptides. However, AFM imaging on its own provides limited insight into conformation or composition of assemblies produced in the complex environment of a cell, or prepared from a mixture of proteins as a result of cross-seeding. In these cases, its combination with fluorescence microscopy (AFFM) increases its resolution. PMID- 22528090 TI - Investigating fibrillar aggregates of Tau protein by atomic force microscopy. AB - Atomic force microscopy (AFM) has been used in numerous studies to visualize and analyze the structure and conformation of biological samples, from single molecules to biopolymers to cells. The possibility to analyze native samples without fixation, staining and in physiological buffer conditions, combined with the sub-nanometer resolution, makes AFM a versatile tool for the analysis of protein aggregation and amyloid structures. Here, we describe the application of AFM to study fibrillar Tau protein aggregates. PMID- 22528091 TI - Structural studies of amyloids by quenched hydrogen-deuterium exchange by NMR. AB - The elucidation of the structure of amyloid fibrils and related aggregates is an important step towards understanding the pathogenesis of diseases such as Alzheimer's and Parkinson's, which feature protein misfolding and/or aggregation. However, the large size and poor solubility of amyloid-like fibrils make them resistant to high-resolution structure determination. Here, we describe the use of hydrogen-deuterium exchange coupled with NMR as an indirect strategy to determine the folding regions of amyloid-forming proteins at residue level resolution. PMID- 22528093 TI - Search for amyloid-binding proteins by affinity chromatography. AB - 'Amyloid binging proteins' is a generic term used to designate proteins that interact with different forms of amyloidogenic peptides or proteins and that, as a result, may modulate their physiological and pathological functions by altering solubility, transport, clearance, degradation, and fibril formation. We describe a simple affinity chromatography protocol to isolate and characterize amyloid binding proteins based on the use of sequential elution steps that may provide further information on the type of binding interaction. As an example, we depict the application of this protocol to the study of Alzheimer's amyloid beta (Abeta) peptide-binding proteins derived from human plasma. Biochemical analysis of the proteins eluted under different conditions identified serum amyloid P component (SAP) and apolipoprotein J (clusterin) as the main plasma Abeta-binding proteins while various apolipoproteins (apoA-IV, apoE, and apoA-I), as well as albumin (HSA) and fibulin were identified as minor contributors. PMID- 22528092 TI - Cyclic amplification of prion protein misfolding. AB - Protein misfolding cyclic amplification (PMCA) is a technique that takes advantage of the nucleation-dependent prion replication process to accelerate the conversion of PrP(C) into PrP(Sc) in the test tube. PMCA uses ultrasound waves to fragment the PrP(Sc) polymers, increasing the amount of seeds present in the infected sample without affecting their ability to act as conversion nuclei. Over the past 5 years, PMCA has become an invaluable technique to study diverse aspects of prions. The PMCA technology has been used by several groups to understand the molecular mechanism of prion replication, the cellular factors involved in prion propagation, the intriguing phenomena of prion strains and species barriers, to detect PrP(Sc) in tissues and biological fluids, and to screen for inhibitors against prion replication. In this chapter, we describe a detailed protocol of the PMCA technique, highlighting some of the important technical aspects to obtain a successful and reproducible application of the technology. PMID- 22528094 TI - Establishing the links between Abeta aggregation and cytotoxicity in vitro using biophysical approaches. AB - Aggregation and fibril formation of the amyloid-beta (Abeta) peptides play a pivotal role in the pathogenesis of Alzheimer's disease (AD). The missing links on the pathway to Abeta oligomerization, fibril formation, and neurotoxicity in AD remain the identity of the toxic Abeta species and mechanism(s) of their toxicity. Such information is crucial for the development of mechanism-based therapeutics to treat AD and tools to diagnose and/or monitor the disease progression. Herein, we describe a simple approach that combines standard biophysical methods with cell biology assays to correlate the aggregation state of Abeta peptides with their cytotoxicity in vitro. The individual assays are well-established, commonly used, rely on easily accessible materials and can be performed within 24 h. PMID- 22528095 TI - Preparation of cultured human vascular cells. AB - Cerebral amyloid angiopathy (CAA) results from amyloid accumulation within arteries of the cerebral cortex and leptomeninges. This condition is age-related, especially prevalent in Alzheimer's disease (AD), and the main feature of certain hereditary disorders (i.e., HCHWA-I). The vascular smooth muscle cells (VSMCs) appear to play a vital role in the development of CAA, which makes them well suited as an experimental model to study the disease and screen for possible remedies. We describe two different methods for isolating and culturing human VSMCs. First, using the human umbilical cord as an easy source of robust cells, and secondly, using brain tissue that provides the proper cerebral VSMCs, but is more problematic to work with. The umbilical cord also provides human umbilical vascular endothelial cells (HUVECs), useful primary cells for vascular research. Finally, the maintenance, preservation, and characterization of the isolated vascular cells are described. PMID- 22528096 TI - Murine cerebrovascular cells as a cell culture model for cerebral amyloid angiopathy: isolation of smooth muscle and endothelial cells from mouse brain. AB - The use of murine cerebrovascular endothelial and smooth muscle cells has not been widely employed as a cell culture model for the investigation of cellular mechanisms involved in cerebral amyloid angiopathy (CAA). Difficulties in isolation and propagation of murine cerebrovascular cells and insufficient yields for molecular and cell culture studies have deterred investigators from using mice as a source for cerebrovascular cells in culture. Instead, cerebrovascular cells from larger mammals are preferred and several methods describing the isolation of endothelial and smooth muscle cells from human, canine, rat, and guinea pig have been published. In recent years, several transgenic mouse lines showing CAA pathology have been established; consequently murine cerebrovascular cells derived from these animals can serve as a key cellular model to study CAA. Here, we describe a procedure for isolating murine microvessels that yields healthy smooth muscle and endothelial cell populations and produce sufficient material for experimental purposes. Murine smooth muscle cells isolated using this protocol exhibit the classic "hill and valley" morphology and are immunoreactive for the smooth muscle cell marker alpha-actin. Endothelial cells display a "cobblestone" pattern phenotype and show the characteristic immunostaining for the von Willebrand factor and the factor VIII-related antigen. In addition, we describe methods designed to preserve these cells by storage in liquid nitrogen and reestablishing viable cell cultures. Finally, we compare our methods with protocols designed to isolate and maintain human cerebrovascular cell cultures. PMID- 22528097 TI - In vitro assays measuring protection by proteins such as cystatin C of primary cortical neuronal and smooth muscle cells. AB - Neuronal cell culture models have been used to demonstrate the protective effects of cystatin C against a variety of insults, including the toxicity induced by oligomeric and fibrillar amyloid beta (Abeta). Here, we describe assays quantifying cystatin C protective effects against cytotoxicity induced by nutrient deprivation, oxidative stress, or cytotoxic forms of Abeta. Three methods for the evaluation of either cell death or cell survival are described: measurement of metabolic activity, cell death, and cell division. The cell culture models used are murine primary cortical neurons and murine primary cerebral smooth muscle cells. The effects of exogenously applied cystatin C are studied by comparing the viability of nonstressed control, stressed control, and cystatin C-treated stressed cells. The effect of endogenous level of cystatin C expression is studied by comparing stressed primary cells isolated from brains of cystatin C transgenic, cystatin C knockout, and wild-type mice. PMID- 22528098 TI - Study of neurotoxic intracellular calcium signalling triggered by amyloids. AB - Neurotoxicity in Alzheimer's disease (AD) is associated to dishomeostasis of intracellular Ca(2+) induced by amyloid beta peptide (Abeta) species. Understanding of the effects of Abeta on intracellular Ca(2+) homeostasis requires preparation of the different Abeta assemblies including oligomers and fibrils and the testing of their effects on cytosolic and mitochondrial Ca(2+) in neurons. Procedures for cerebellar granule cell culture, preparation of Abeta species as well as fluorescence and bioluminescence imaging of cytosolic and mitochondrial Ca(2+) in neurons are described. PMID- 22528099 TI - Bacterial amyloids. AB - Many bacteria can assemble functional amyloid fibers on their cell surface. The majority of bacterial amyloids contribute to biofilm or other community behaviors where cells interact with a surface or with another cell. Bacterial amyloids, like all functional amyloids, share structural and biochemical properties with disease-associated eukaryotic amyloids. The general ability of amyloids to bind amyloid-specific dyes, such as Congo red, and their resistance to denaturation have provided useful tools for scoring and quantifying bacterial amyloid formation. Here, we present basic approaches to study bacterial amyloids by focusing on the well-studied curli amyloid fibers expressed by Enterobacteriaceae. These methods exploit the specific tinctorial and biophysical properties of amyloids. The methods described here are straightforward and can be easily applied by any modern molecular biology lab for the study of other bacterial amyloids. PMID- 22528102 TI - Subcutaneous adipose tissue biopsy for amyloid protein studies. AB - Symptoms from a systemic amyloidosis are usually coming from one of the inner organs, e.g., heart or kidney. However, for diagnosis and for material for amyloid protein studies, biopsy from an easier accessible tissue is preferred. This chapter describes biopsy from subcutaneous adipose tissue as a particularly suitable method to obtain amyloid. PMID- 22528101 TI - Cell-to-cell transmission of alpha-synuclein aggregates. AB - It is now recognized that the cell-to-cell transmission of misfolded proteins such as alpha-synuclein contributes to the neurodegenerative phenotype in neurological disorders such as idiopathic Parkinson's disease, Dementia with Lewy bodies, and Parkinson's disease dementia. Thus, establishing cell-based models for the transmission of alpha-synuclein is of importance to understand the mechanisms of neurodegeneration in these disorders and to develop new therapies. Here we describe methods to study the neuron-to-neuron propagation of alpha synuclein in an in vitro setting that also has in vivo applications. PMID- 22528100 TI - Study of amyloids using yeast. AB - We detail some of the genetic, biochemical, and physical methods useful in studying amyloids in yeast, particularly the yeast prions. These methods include cytoduction (cytoplasmic mixing), infection of cells with prion amyloids, use of green fluorescent protein fusions with amyloid-forming proteins for cytology, protein purification and amyloid formation, and electron microscopy of filaments. PMID- 22528103 TI - Analysis of S100 oligomers and amyloids. AB - The S100 proteins are a large family of 10-12 kDa EF-hand signaling proteins that bind calcium, and in some cases zinc and copper, functioning as central regulators in a diversity of cellular processes. These proteins have tissue, cell, and subcellular-specific expression patterns, and many have an extracellular function. Altogether, these properties underlie their functional diversity and involvement in several pathological conditions including cancer, inflammation, and neurodegeneration. S100 proteins exhibit considerable structural plasticity, being able to exist as monomers or assemble into dimers, higher oligomers, and amyloids, frequently in a metal-dependent manner. Many of these oligomers are functionally relevant, and S100 amyloids have been recently found in prostatic inclusions. Here, we report experimental procedures for the isolation and quantitation of S100 oligomers from tissues, purification of recombinant human S100 protein for assays and use as standards, and an amyloidogenesis assay that allows monitoring the formation of S100 beta-oligomers and amyloids in apo- and metal-bound S100 proteins. PMID- 22528105 TI - Isolation of amyloid by solubilization in water. AB - Amyloid fibrils are highly insoluble in neutral aqueous media of regular ionic strengths making solubilization a difficult task that normally calls for extremely harsh treatment. This is among the reasons for the routine employment of synthetic proteins in amyloid research, where the amylogenic components are needed. Here we describe a process for solubilizing amyloid in pure water that we adopted from a method developed by Mordechai Pras and associates. We have used it for solubilizing cystatin C amyloid and extracting it out of leptomeningeal tissue and skin from Hereditary Cerebral Hemorrhage with Amyloidosis-Icelandic type (HCHWA-I) patients. HCHWA-I is a rare and very aggressive heritable form of cerebral amyloid angiopathy (CAA)-specific Icelandic type. Similar approach has been employed for solubilization of different forms of amyloid from other organs suggesting broad range of applicability. PMID- 22528104 TI - S100A8/A9 amyloidosis in the ageing prostate: relating ex vivo and in vitro studies. AB - The family of S100 proteins encompasses more than 20 members characterized by remarkable conformational and functional diversity. S100 proteins act as central regulators of various cellular processes, including cell survival, proliferation, differentiation, and motility. Many S100 proteins are implicated in various types of cancer as well as neurodegenerative, inflammatory, and autoimmune diseases. Recently, we have found that S100A8/A9 proteins are involved in amyloidogenic process in the ageing prostate, contributing to the formation of calcified corpora amylacea (CA) inclusions, which commonly accompany age-dependent prostate tissue remodelling and cancer. Amyloid formation by S100A8/A9 proteins can also be modelled in vitro. Amyloid assembly of S100A8/A9 proteins into oligomeric and fibrillar complexes is modulated by metal ions such as calcium and zinc. Here, we provide insights into the extraction procedures and review the common structural features of ex vivo and in vitro S100A8/A9 amyloids, showing that they share the same generic origin. PMID- 22528107 TI - A pentameric luminescent-conjugated oligothiophene for optical imaging of in vitro-formed amyloid fibrils and protein aggregates in tissue sections. AB - Luminescent-conjugated oligo- and polythiophenes (LCOs and LCPs) are valuable tools for optical imaging of a plethora of protein aggregates associated with amyloidoses. Here, we describe the utilization of an anionic pentameric LCO, p FTAA, for staining of protein aggregates in a variety of platforms, including in vitro-formed amyloid fibrils and tissue sections. PMID- 22528106 TI - Histological staining of amyloid and pre-amyloid peptides and proteins in mouse tissue. AB - The increased availability of transgenic mouse models for studying human diseases has shifted the focus of many laboratories from in vitro to in vivo assays. Herein, methods are described to allow investigators to obtain well-preserved mouse tissue to be stained with the standard histological dyes for amyloid, Congo Red, and Thioflavin S. These sections can as well be used for immunohistological procedures that allow detection of tissue amyloid and pre-amyloid, such as those composed of the amyloid-beta peptide, the tau protein, and the islet amyloid polypeptide. PMID- 22528109 TI - The mouse model for scrapie: inoculation, clinical scoring, and histopathological techniques. AB - Transmission to mice and other laboratory rodents are central to the study of prion diseases. Bioassays are essential for testing the presence of infectivity, as well as for titration and strain typing studies. Given the peculiar nature of prions, their characterization relies mainly on the measurement of the length of the incubation period in inoculated mice and on the study of a number of parameters, such as the clinical manifestations, the type of pathological changes and the biochemical characteristics of PrP(Sc), that call for considerable experience and care in the execution of laboratory procedures and in the reading and interpretation of results. Researchers who are new to the prion field or who would like to expand into studies of rodent models may need information about the practical aspects of prion diseases in mice. This chapter reviews the techniques used in transmission studies, from the preparation of the inocula to pathological investigations, with specific focus on the potential problems that may occur and how to solve them. PMID- 22528108 TI - In vivo magnetic resonance imaging of amyloid-beta plaques in mice. AB - Transgenic mice are used increasingly to model brain amyloidosis, mimicking the pathogenic processes involved in Alzheimer's disease (AD). In this chapter, an in vivo strategy is described that has been successfully used to map amyloid-beta deposits in transgenic mouse models of AD with magnetic resonance imaging (MRI), utilizing both the endogenous contrast induced by the plaques attributed to their iron content and by selectively enhancing the signal from amyloid-beta plaques using molecular-targeting vectors labeled with MRI contrast agents. To obtain sufficient spatial resolution for effective and sensitive mouse brain imaging, magnetic fields of 7-Tesla (T) or more are required. These are higher than the 1.5-T field strength routinely used for human brain imaging. The higher magnetic fields affect contrast agent efficiency and dictate the choice of pulse sequence parameters for in vivo MRI, all addressed in this chapter. Two-dimensional (2D) multi-slice and three-dimensional (3D) MRI acquisitions are described and their advantages and limitations are discussed. The experimental setup required for mouse brain imaging is explained in detail, including anesthesia, immobilization of the mouse's head to reduce motion artifacts, and anatomical landmarks to use for the slice alignment procedure to improve image co-registration during longitudinal studies and for subsequent matching of MRI with histology. PMID- 22528110 TI - Biochemical isolation of insoluble tau in transgenic mouse models of tauopathies. AB - Tau is a highly soluble microtubule-associated protein (MAP) that is abundant in the central nervous system and expressed mainly in neuronal axons. Intracellular aggregates of insoluble tau protein are present in a group of neurodegenerative diseases called tauopathies, which include Alzheimer's disease. Numerous transgenic mouse models of tauopathies have been produced in the last decade, and analysis of insoluble tau in these animals has provided a powerful tool to understand the development of tau pathology. In this short chapter, we aim at reviewing the two main isolation methods, sarkosyl and formic acid extraction (and their variations), used for the biochemical isolation of insoluble tau in transgenic mouse models of tauopathy, and discuss their advantages and drawbacks. PMID- 22528111 TI - Tissue processing prior to analysis of Alzheimer's disease associated proteins and metabolites, including Abeta. AB - Amyloid-containing tissue, whether from human patients or an animal model of a disease, is typically characterized by various biochemical and immunohistochemical techniques, many of which are described in detail in this volume. In this chapter, we describe a straightforward technique for the homogenization of tissue prior to these analyses. The technique is particularly well suited for performing a large number of different biochemical analyses on a single mouse brain hemisphere. Starting with this homogenate multiple characterizations can be done, including western blot analysis and isolation of membrane-associated proteins, both of which are described here. Additional analyses can readily be performed on the tissue homogenate, including the ELISA quantitation of Abeta in the brain of a transgenic mouse model of beta-amyloid deposition. The ELISA technique is described in detail in Chapter 34. PMID- 22528112 TI - Abeta measurement by enzyme-linked immunosorbent assay. AB - The neuritic plaque in the brain of Alzheimer's disease patients consists of an amyloid composed primarily of Abeta, an approximately 4-kDa peptide derived from the amyloid precursor protein. Multiple lines of evidence suggest that Abeta plays a key role in the pathogenesis of the disease, and potential treatments that target Abeta production and/or Abeta accumulation in the brain as beta amyloid are being aggressively pursued. Methods to quantitate the Abeta peptide are, therefore, invaluable to most studies aimed at a better understanding of the molecular etiology of the disease and in assessing potential therapeutics. Although other techniques have been used to measure Abeta in the brains of AD patients and beta-amyloid-depositing transgenic mice, the enzyme-linked immunosorbent assay (ELISA) is one of the most commonly used, reliable, and sensitive methods for quantitating the Abeta peptide. Here we describe methods for the recovery of both soluble and deposited Abeta from brain tissue and the subsequent quantitation of the peptide by sandwich ELISA. PMID- 22528113 TI - Cognitive and sensorimotor tasks for assessing functional impairments in mouse models of Alzheimer's disease and related disorders. AB - In the last couple of decades, substantial progress has been made in the development of transgenic mouse models developing amyloid-beta deposits and/or neurofibrillary tangles. These mouse models of Alzheimer's disease and related disorders provide an excellent tool for investigating etiology, pathogenic mechanisms, and potential treatments. An essential component of their characterization is a detailed behavioral assessment, which clarifies the functional consequences of these pathologies. We have selected and refined a series of cognitive and sensorimotor tasks that are ideal for studying these models and the efficacy of various treatments. PMID- 22528114 TI - Evaluation of current synthetic mesh materials in pelvic organ prolapse repair. AB - With increasing use of synthetic material in pelvic organ prolapse repair, the reporting and incidence of associated complications also have increased. The role of synthetic mesh in pelvic organ prolapse repair remains controversial and it is a therapeutic dilemma whether to continue its use in patients with poor native tissues, despite the recent public safety notification provided by the U.S. Food and Drug Administration. In this article, we review the biomaterials used in pelvic organ prolapse repair and discuss the outcomes and associated complications, paying emphasis to the benefits and the risks. PMID- 22528115 TI - What is the gold standard for posterior vaginal wall prolapse repair: mesh or native tissue? AB - Reports in the literature of high recurrence rates after native tissue repair for pelvic organ prolapse led to the development of alternative techniques, such as those using synthetic mesh. Transvaginal mesh (TVM) delivery systems were implemented in search of better outcomes. Despite reported recurrence as low as 7.1 % after posterior colporrhaphy, mesh kits were developed to correct posterior compartment prolapse. There is a paucity of data to substantiate better results with TVM for rectocele repair. Three randomized controlled trials comparing native tissue repair to synthetic mesh reported posterior compartment outcomes and two of these failed to show a significant difference between groups. Complications of TVM placement are not insignificant and mesh extrusion was reported in up to 16.9 %. Based on currently available data, native tissue repairs have similar outcomes to synthetic mesh without the risks inherent in mesh use and remain the standard of care for the typical patient. PMID- 22528116 TI - Surgery for pelvic organ prolapse: a historical perspective. AB - Surgical treatment of pelvic organ prolapse has evolved from the use of pomegranates as pessary devices to contemporary robot-assisted laparoscopic sacral colpopexy. Symptomatic pelvic organ prolapse requires correction of all the defects to achieve optimal outcomes. Factors to consider in selecting the appropriate repair include patient's age; stage of prolapse; vaginal length; hormonal status; desire for uterine preservation and coitus; symptoms of sexual, urinary, or bowel dysfunction; and any comorbidities that influence her eligibility for anesthesia or chronically increase intra-abdominal pressure. There is currently no consensus as to the best surgical approach for advanced pelvic organ prolapse. Reconstructive surgery for pelvic organ prolapse is currently performed by vaginal or abdominal (open, laparoscopic, and robotic approaches) approaches or a combination. It is important to maintain skills in proven procedures such as abdominal sacrocolpopexy and sacrospinous ligament suspension. This paper discusses the historical evolution of surgery for pelvic organ prolapse from antiquity to date. PMID- 22528117 TI - Current status of robot-assisted laparoscopic ureteral reimplantation and reconstruction. AB - We reviewed the literature on robot-assisted laparoscopic ureteral reimplantation and provide general considerations for indications, perioperative management, and steps of the case. Robot-associated laparoscopic procedures are becoming more common in urologic surgery. The uses of the da Vinci robot (Intuitive Surgical, Sunnyvale, CA) are expanding as well. We examine the use of the robot in distal ureteral reconstruction. A PubMed search was performed using keywords "robot" and "ureter," "distal ureter," "ureteral reimplant," "psoas," and "Boari." Papers that discussed proximal ureteral reconstruction and nephroureterectomy were excluded. A total of nine papers were relevant. Personal experience was also drawn upon. Distal ureteral reconstruction using the robotic technique is feasible, safe, and becoming more and more prevalent as surgeon comfort with the robot increases. PMID- 22528118 TI - Evaluation of current biologic meshes in pelvic organ prolapse repair. AB - Pelvic organ prolapse (POP) is a common disorder estimated to affect 15%-30% of women over the age of 50 years. About 11% of women will require surgery by the age of 80 years and there is an estimated 30% rate of prolapse recurrence. In an attempt to improve surgical outcomes, biologic grafts and synthetic meshes have been implemented in the repair of POP. Biologic grafts have been used with the hope of avoiding complications associated with synthetic mesh. This presents the existing data surrounding the use of biologic grafts in the surgical repair of anterior compartment, vaginal vault, and posterior compartment prolapse. PMID- 22528119 TI - The polyphenolic ellagitannin vescalagin acts as a preferential catalytic inhibitor of the alpha isoform of human DNA topoisomerase II. AB - Polyphenolic ellagitannins are natural compounds that are often associated with the therapeutic activity of plant extracts used in traditional medicine. They display cancer-preventing activity in animal models by a mechanism that remains unclear. Potential targets have been proposed, including DNA topoisomerases II (Top2). Top2alpha and Top2beta, the two isoforms of the human Top2, play a crucial role in the regulation of replication, transcription, and chromosome segregation. They are the target of anticancer agents used in the clinic such as anthracyclines (e.g., doxorubicin) or the epipodophyllotoxin etoposide. It was recently shown that the antitumor activity of etoposide was due primarily to the inhibition of Top2alpha, whereas inhibition of Top2beta was responsible for the development of secondary malignancies, pointing to the need for more selective Top2alpha inhibitors. Here, we show that the polyphenolic ellagitannin vescalagin preferentially inhibits the decatenation activity of Top2alpha in vitro, by a redox-independent mechanism. In CEM cells, we also show that transient small interfering RNA-mediated down-regulation of Top2alpha but not of Top2beta conferred a resistance to vescalagin, indicating that the alpha isoform is a preferential target. We further confirmed that Top2alpha inhibition was due to a catalytic inhibition of the enzyme because it did not induce DNA double-strand breaks in CEM-treated cells but prevented the formation of Top2alpha- rather than Top2beta-DNA covalent complexes induced by etoposide. To our knowledge, vescalagin is the first example of a catalytic inhibitor for which cytotoxicity is due, at least in part, to the preferential inhibition of Top2alpha. PMID- 22528120 TI - Evidence-based medicine: what's the evidence? PMID- 22528122 TI - Systematic and systemic immunology: on the future of research and its applications. AB - This paper is a shortened English transcription of a lecture given on 13 February 2012 at the College de France. The lecture concluded a series of talks delivered the same year on the theme: "Immunity: the game of chance and specificity". The article comprises four parts: I. The game of chance and specificity. II. About the future of research in immunology. III. On the future of the applications of research in immunology. IV. The social conditions of the evolution of research and its applications. PMID- 22528121 TI - Systems immunology: a survey of modeling formalisms, applications and simulation tools. AB - Immunological studies frequently analyze individual components (e.g., signaling pathways) of immune systems in a reductionist manner. In contrast, systems immunology aims to give a synthetic understanding of how these components function together as a whole. While immunological research involves in vivo and in vitro experiments, systems immunology research can also be conducted in silico. With an increasing interest in systems-level studies spawned by high throughput technologies, many immunologists are looking forward to insights provided by computational modeling and simulation. However, modeling and simulation research has mainly been conducted in computational fields, and therefore, little material is available or accessible to immunologists today. This survey is an attempt at bridging the gap between immunologists and systems immunology modeling and simulation. Modeling and simulation refer to building and executing an in silico replica of an immune system. Models are specified within a mathematical or algorithmic framework called formalism and then implemented using software tools. A plethora of modeling formalisms and software tools are reported in the literature for systems immunology. However, it is difficult for a new entrant to the field to know which of these would be suitable for modeling an immunological application at hand. This paper covers three aspects. First, it introduces the field of system immunology emphasizing on the modeling and simulation components. Second, it gives an overview of the principal modeling formalisms, each of which is illustrated with salient applications in immunological research. This overview of formalisms and applications is conducted not only to illustrate their power but also to serve as a reference to assist immunologists in choosing the best formalism for the problem at hand. Third, it lists major software tools, which can be used to practically implement models in these formalisms. Combined, these aspects can help immunologists to start experimenting with in silico models. Finally, future research directions are discussed. Particularly, we identify integrative frameworks to facilitate the coupling of different modeling formalisms and modeling the adaptation properties through evolution of immune systems as the next key research efforts necessary to further develop the multidisciplinary field of systems immunology. PMID- 22528123 TI - Introduction to the special issue on Immunology at Mount Sinai. PMID- 22528124 TI - Regulation of T helper cell differentiation by interferon regulatory factor family members. AB - Interferon regulatory factors (IRFs) consist of a family of transcription factors with diverse functions in the transcriptional regulation of cellular responses in health and diseases. IRFs commonly contain a DNA-binding domain in the N terminus, with most members also containing a C-terminal IRF-associated domain that mediates protein-protein interactions. Ten IRFs and several virus-encoded IRF homologs have been identified in mammals so far. In response to endogenous and microbial stimuli during an immune response, IRFs are activated, and selectively and cooperatively modulate the expression of key cytokine and transcription factors involved in T helper cell differentiation in T cells and/or antigen-presenting cells. This review focuses on recent advances in the understanding of IRF-mediated transcriptional regulation in T helper cell differentiation and discusses the implications on the development of cellular and humoral immune responses and the pathogenesis of immune disorders. PMID- 22528126 TI - Cytokine gene expression profile in monocytic cells after a co-culture with epithelial cells. AB - Epithelial cells represent an important source of cytokines that may modulate the influx and functions of mononuclear phagocytes. The aim of our study was to characterize changes in the gene expression of selected cytokines in human macrophages co-cultured with respiratory epithelial cells. The A549 alveolar type II-like cell line was co-cultured with THP-1 cells (monocyte/macrophage cell line) in filter-separated mode to avoid their cell-cell contact. At different time-points (0, 4, 8, 12 and 24 h), the cells were harvested separately to evaluate their gene and protein expression (IL-1 beta, IL-6, IL-8, IL-10 and GM CSF). Quantitative RT-PCR analysis showed prominent changes in the THP-1 cytokine gene expression induced by a co-culture with A549 cells. Fourfold upregulation of mRNA expression has been found in 12 genes and 4-fold downregulation in 5 genes as compared to the unstimulated control sample with a p value smaller than 0.05. The induction of inhibin beta A and IL-1 beta mRNA after 12 h and the expression of IL-1 alpha and GM-CSF mRNA after 24 h were the most prominent. When looking at the cytokine levels in culture supernatants, IL-1 beta and IL-8 were induced early (at 8 h) as compared to the release of IL-6 and GM-CSF (at 24 h). We conclude that respiratory epithelial cells constitutively regulate the cytokine gene expression of macrophages located in their environment and might further modulate the release of cytokines by posttranslational pathways. PMID- 22528125 TI - Tissue-specific transplantation antigen P35B (TSTA3) immune response-mediated metabolism coupling cell cycle to postreplication repair network in no-tumor hepatitis/cirrhotic tissues (HBV or HCV infection) by biocomputation. AB - We constructed the low-expression tissue-specific transplantation antigen P35B (TSTA3) immune response-mediated metabolism coupling cell cycle to postreplication repair network in no-tumor hepatitis/cirrhotic tissues (HBV or HCV infection) compared with high-expression (fold change >= 2) human hepatocellular carcinoma in GEO data set, by using integration of gene regulatory network inference method with gene ontology analysis of TSTA3-activated up- and downstream networks. Our results showed TSTA3 upstream-activated CCNB2, CKS1B, ELAVL3, GAS7, NQO1, NTN1, OCRL, PLA2G1B, REG3A, SSTR5, etc. and TSTA3 downstream activated BAP1, BRCA1, CCL20, MCM2, MS4A2, NTN1, REG1A, TP53I11, VCAN, SLC16A3, etc. in no-tumor hepatitis/cirrhotic tissues. TSTA3-activated network enhanced the regulation of apoptosis, cyclin-dependent protein kinase activity, cell migration, insulin secretion, transcription, cell division, cell proliferation, DNA replication, postreplication repair, cell differentiation, T-cell homeostasis, neutrophil-mediated immunity, neutrophil chemotaxis, interleukin-8 production, inflammatory response, immune response, B-cell activation, humoral immune response, actin filament organization, xenobiotic metabolism, lipid metabolism, phospholipid metabolism, leukotriene biosynthesis, organismal lipid catabolism, phosphatidylcholine metabolism, arachidonic acid secretion, activation of phospholipase A2, deoxyribonucleotide biosynthesis, heterophilic cell adhesion, activation of MAPK activity, signal transduction by p53 class mediator resulting in transcription of p21 class mediator, G-protein-coupled receptor protein signaling pathway, response to toxin, acute-phase response, DNA damage response, intercellular junction assembly, cell communication, and cell recognition, as a result of inducing immune response-mediated metabolism coupling cell cycle to postreplication repair in no-tumor hepatitis/cirrhotic tissues. PMID- 22528128 TI - Saccharide-modified nanodiamond conjugates for the efficient detection and removal of pathogenic bacteria. AB - The detection and removal of bacteria, such as E. coli in aqueous environments by using safe and readily available means is of high importance. Here we report on the synthesis of nanodiamonds (ND) covalently modified with specific carbohydrates (glyco-ND) for the precipitation of type 1 fimbriated uropathogenic E. coli in solution by mechanically stable agglutination. The surface of the diamond nanoparticles was modified by using a Diels-Alder reaction followed by the covalent grafting of the respective glycosides. The resulting glyco-ND samples are fully dispersible in aqueous media and show a surface loading of typically 0.1 mmol g(-1). To probe the adhesive properties of various ND samples we have developed a new sandwich assay employing layers of two bacterial strains in an array format. Agglutination experiments in solution were used to distinguish unspecific interactions of glyco-ND with bacteria from specific ones. Two types of precipitates in solution were observed and characterized in detail by light and electron microscopy. Only by specific interactions mechanically stable agglutinates were formed. Bacteria could be removed from water by filtration of these stable agglutinates through 10 MUm pore-size filters and the ND conjugate could eventually be recovered by addition of the appropriate carbohydrate. The application of glycosylated ND allows versatile and facile detection of bacteria and their efficient removal by using an environmentally and biomedically benign material. PMID- 22528127 TI - T inflammatory memory CD8 T cells participate to antiviral response and generate secondary memory cells with an advantage in XCL1 production. AB - Besides the classically described subsets of memory CD8 T cells generated under infectious conditions, are T inflammatory memory cells generated under sterile priming conditions, such as sensitization to allergens. Although not fully differentiated as pathogen-induced memory cells, they display memory properties that distinguish them from naive CD8 T cells. Given these memory cells are generated in an antigen-specific context that is devoid of pathogen-derived danger signals and CD4 T cell help, we herein questioned whether they maintained their activation and differentiation potential, could be recruited in an immune response directed against a pathogen expressing their cognate antigen and further differentiate in fully competent secondary memory cells. We show that T inflammatory memory cells can indeed take part to the immune response triggered by a viral infection, differentiate into secondary effectors and further generate typical central memory CD8 T cells and effector memory CD8 T cells. Furthermore, the secondary memory cells they generate display a functional advantage over primary memory cells in their capacity to produce TNF-alpha and the XCL1 chemokine. These results suggest that cross-reactive stimulations and differentiation of cells directed against allergens or self into fully competent pathogen-induced memory cells might have incidences in inflammatory immuno pathologies. PMID- 22528129 TI - Pharmacogenetic aspects in familial hypercholesterolemia with the special focus on FHMarburg (FH p.W556R). AB - OBJECTIVE: Familial hypercholesterolemia (FH) is an autosomal dominant inherited disorder caused by mutations in the low density lipoprotein receptor (LDLR) gene. FH is characterized by elevated plasma LDL cholesterol, premature atherosclerosis, and a high risk of premature myocardial infarction. In general, mutations within LDLR gene can cause five different classes of defects, namely: class I defect: no LDLR synthesis; class II defect: no LDLR transport; class III defect: no low density lipoprotein (LDL) to LDLR binding; class IV defect: no LDLR/LDL internalization; and class V defect: no LDLR recycling. One might expect that both the class of LDLR defect as well as the precise mutation influences the severity of hypercholesterolemia on one hand and the response on drug treatment on the other. To clarify this question we studied the effect of the LDLR mutation p.W556R in two heterozygote subjects. RESULTS: We found that two heterozygote FH patients with the LDLR mutation p.W556R causing a class II LDLR defect (transport defective LDLR) respond exceedingly well to the treatment with simvastatin 40 mg/ezetimibe 10 mg. There was a LDL cholesterol decrease of 55 and 64%, respectively. In contrast, two affected homozygote p.W556R FH patients, in the mean time undergoing LDL apheresis, had no response to statin but a 15% LDL cholesterol decrease on ezetimibe monotherapy. CONCLUSIONS: The LDLR mutation p.W556R is a frequent and severe class II defect for FH. The affected homozygote FH patients have a total loss of the functional LDLR and-as expected-do not respond on statin therapy and require LDL apheresis. In contrast, heterozygote FH patients with the same LDLR defect respond exceedingly well to standard lipid lowering therapy, illustrating that the knowledge of the primary LDLR defect enables us to foresee the expected drug effects. PMID- 22528130 TI - Treatment options for severe hypertriglyceridemia (SHTG): the role of apheresis. AB - Hypertriglyceridemia is associated with a number of severe diseases such as acute pancreatitis and coronary artery disease. In severe hypertriglyceridemia (SHTG, triglycerides > 1,000 mg/dL), rapid lowering of plasma triglycerides (TG) has to be achieved. Treatment regimes include nutritional intervention, the use of antihyperlipidemic drugs, and therapeutic apheresis. Apheretic treatment is indicated in medical emergencies such as hypertriglyceridemic pancreatitis. Reviewing the current literature, plasmapheresis appears to be a safe and useful therapeutic tool in patients suffering from SHTG. Apheretic treatment is able to remove the causative agent for pancreatic inflammation. Data suggests that the use of apheresis should be performed as early as possible in order to achieve best results. The use of plasmapheresis, however, is limited due to the rather high costs and the limited availability of the procedure. PMID- 22528131 TI - Lipid apheresis: oxidative stress, rheology, and vasodilatation. AB - In the treatment of homozygous and therapy-resistant hypercholesterolemia, lipid apheresis enables not only low density lipoprotein (LDL) cholesterol to be lowered by approximately 60%, but also oxidative stress factors to be influenced and adhesion molecules reduced. This was investigated in a group of 12 patients using the heparin-induced extracorporeal LDL precipitation (H.E.L.P.) procedure.A significant lowering of LDL cholesterol and fibrinogen leads to an improvement in rheology and endothelial function, detectable and measurable within approximately 20 h by assessing minimum coronary resistance using positron emission tomography (PET) performed in 35 patients. This effect is detectable even after the first lipid apheresis session (H.E.L.P. procedure), documented in 12 patients.Lipid apheresis appears to be the most effective procedure in the treatment of elevated lipoprotein(a) [Lp(a)]. A chosen group of nine patients with selective elevated Lp(a) illustrated both the influence on endothelial dysfunction, in the shape of sharply increased minimum coronary resistance, and the reduction through lipid apheresis, indicating that Lp(a) seems to exert a similar effect on the vascular wall and vascular function as LDL cholesterol. PMID- 22528132 TI - Fibrinogen/LDL apheresis is a promising rescue therapy for sudden sensorineural hearing loss. AB - BACKGROUND: Fibrinogen/LDL apheresis has been proven to be effective in treatment of sudden sensorineural hearing loss (SSNH). This study is aimed to investigate if reduction of fibrinogen and serum LDL is also effective in patients with SSNH non-responding toward treatment with corticosteroids and plasmaexpanders. METHODS: Remission rates of 217 patients suffering from SSHL were investigated after treatment with apheresis. All patients were non-responders after other therapies such as high doses of steroids or plasmaexpanders. RESULTS: Single apheresis resulted in complete or partial remissions in 61% of patients when given after other unsuccessful conducted therapies such as corticosteroids and plasmaexpanders. CONCLUSION: Fibrinogen/LDL apheresis is a promising rescue therapy for sudden sensorineural hearing loss even after unsuccessful other therapies. PMID- 22528133 TI - Therapeutic apheresis in peripheral and retinal circulatory disorders. AB - In microcirculation disorders, the therapeutic apheresis seems to have two different effects. The first, achieved after only a few sessions, is acute, consisting of drastic reduction of blood viscosity and obtained with the use of low-density lipoprotein (LDL) apheresis, rheopheresis, or fibrinogen apheresis. The second effect is long term, or chronic, and needs to be evaluated after a long course of treatment. The mechanisms underlying the chronic effect are still objects of debate and take into account the pleiotropic effects of apheresis. However, it is likely that the acute effect of apheresis mainly influences the functional components of the vascular damage, and so the derived rheological benefit might last only for a short period. The chronic effect, on the contrary, by acting on the morphological alterations of the vascular walls, requires the apheresis treatment to be prolonged for a longer period or even cycles of treatment to be programmed. PMID- 22528134 TI - Current view: indications for extracorporeal lipid apheresis treatment. AB - BACKGROUND: One of the first investigations concerning extracorporeal treatment of hypercholesterolemia was performed in 1967 by plasma exchange in patients with homozygous or severe heterozygous familial hypercholesterolemia (FH). In the following decades, several specific lipid apheresis systems were developed to efficiently eliminate low-density lipoprotein (LDL) cholesterol and Lp(a) cholesterol in hypercholesterolemic patients. In the early 1980s, the main clinical indication has been homozygous FH including mainly children and pregnant women. In consideration of the current development of lipid-lowering regimens and scientific knowledge of preventing progression of cardiovascular diseases, the spectrum of indications to initiate lipid apheresis was extended due to still insufficient lipid-lowering therapy in some clinical cases. However, a generally accepted indication for lipid apheresis treatment is still under discussion. In Germany, the target-oriented distribution of increasingly limited healthcare resources demand data which support the benefit of established treatment procedures such as lipid apheresis. In recent years, the Federal Joint Committee (G-BA), a paramount decision-making body of the German Healthcare System, issued to reassess the approval of chronic lipid apheresis therapy for regular reimbursement. Therefore, in 2005, an interdisciplinary German Apheresis Working Group has been established by members of both the German societies of nephrology. One of the first goals of this working group was a revision of the indications for lipid apheresis corresponding to current guidelines and recommendations for the treatment of lipid disorders. In addition, recently new pathophysiological perceptions of the impact of lipoproteins on atherogenesis and thrombosis were also considered. METHODS AND RESULTS: Since 2005, the working group met on a regular basis to substantiate the first defined goals. The indications for lipid apheresis were critically revised with respect to actual results from clinical investigations, cardiovascular guidelines, and scientific knowledge and were accepted by the members of the apheresis working group. CONCLUSIONS: There is consensus between the medical societies and health insurance funds regarding the need for general accepted guidelines for lipid apheresis. Recommendations for the indications of lipid apheresis were developed, but additionally these results should be confirmed by medical societies to transform them to guidelines. However, due to limited data showing that lipid apheresis has effects on the progression of cardiovascular diseases all members of the apheresis working group support a project for creating a lipid apheresis registry. This apheresis registry has been developed and recently started. The primary goal is to substantiate prospective long-term data on clinical outcome of chronic lipid apheresis treatment and to support additional clinical research activities in this field. In addition, this registry should comply with the actual requests of the Federal Joint Committee (G-BA). PMID- 22528135 TI - HELP apheresis in hypercholesterolemia and cardiovascular disease: efficacy and adverse events after 8,500 procedures. AB - INTRODUCTION: Low density lipoprotein (LDL-C) apheresis is a last treatment option for hypercholesterolemic patientsresistant to conservative lipid-lowering therapy. In a retrospective analysis of 8,533 heparin-induced extra-corporeal LDL precipitation apheresis treatments (HELP), we evaluated the efficacy of LDL reduction, the rate of adverse events, and the progression of atherosclerosis. METHODS: Between July 1992 and April 2009, we performed 8,533 HELP apheresis therapies in patients with familial hypercholesterolemia (FH). Inclusion criteria were FH with insufficient lipidological status under optimal drug therapy and diet, and at least 50 HELP therapies. Left ventricular function and valvular status was checked prior to the first apheresis therapy and at the end of the individual HELP program. Blood samples were taken directly before and after each therapy. Blood count, electrolytes, total cholesterol, LDL-C, high density lipoprotein (HDL-C), triglycerides, lipoprotein (a) (Lp(a)), and fibrinogen were measured. Adverse events were documented weekly. RESULTS: We evaluated 27 patients (19 men) with FH (age 49.2 +/- 12.5 years (range 10-67 years)). The number of HELP treatments once weekly was between 50 and 790 applications. Mean follow-up time was 7.0 +/- 5.2 years (range 1.3-16.6 years). Prior to the individual apheresis program, 44.4% of the patients had a three vessel disease (VD; 25.9% two VD, 25.9% one VD) and 7.4% had a peripheral arterial occlusive disease. During the time of HELP treatment, none of the patients had a myocardial infarction; 3.7% had one percutaneous coronary intervention (PCI), 11.1% two PCI, 14.8% three PCI, 11.1% >= PCI. The patients received 1.2 +/- 1.6 (range 0-5) PCI during follow-up time. Adverse events directly associated with HELP therapy were very rare (< 3%). Mean elimination of LDL-C was 63.49 +/- 7.1%. DISCUSSION: The HELP apheresis therapy was well accepted by the patients in our programs. Adverse events during HELP apheresis were rare. This data is in line with the experiences published by other authors who reported an adverse event rate of 3.6% in adults. The LDL-HDL ratio, one of the strongest predictors of premature CHD events, improved significantly during the apheresis program. CONCLUSION: HELP is a safe, comfortable, and highly effective treatment in which adverse events are rare. It can reduce the burden of atherosclerosis, with no myocardial infarction and a low coronary intervention rate in our patients. PMID- 22528136 TI - Determining the optimal vaccine vial size in developing countries: a Monte Carlo simulation approach. AB - Outreach immunization services, in which health workers immunize children in their own communities, are indispensable to improve vaccine coverage in rural areas of developing countries. One of the challenges faced by these services is how to reduce high levels of vaccine wastage. In particular, the open vial wastage (OVW) that result from the vaccine doses remaining in a vial after a time for safe use -since opening the vial- has elapsed. This wastage is highly dependent on the choice of vial size and the expected number of participants for which the outreach session is planned (i.e., session size). The use single-dose vials results in zero OVW, but it increases the vaccine purchase, transportation, and holding costs per dose as compared to those resulting from using larger vial sizes. The OVW also decreases when more people are immunized in a session. However, controlling the actual number of people that show to an outreach session in rural areas of developing countries highly depends on factors that are out of control of the immunization planners. This paper integrates a binary integer programming model to a Monte Carlo simulation method to determine the choice of vial size and the optimal reordering point level to implement an (nQ, r, T) lot sizing policy that provides the best tradeoff between procurement costs and wastage. PMID- 22528137 TI - Gold-catalyzed carbene transfer to alkynes: access to 2,4-disubstituted furans. PMID- 22528138 TI - Expression and characterization of recombinant ecarin. AB - The snake venom protease ecarin from Echis carinatus was expressed in stable transfected CHO-S cells grown in animal component free cell culture medium. Recombinant ecarin (r-ecarin) was secreted from the suspension adapted Chinese Hamster Ovary (CHO-S) host cells as a pro-protein and activation to the mature form of r-ecarin occurred spontaneously during continued incubation of the cell culture at 37 degrees C after death of the host cells. Maximal ecarin activity was reached 7 days or more after cell culture viability had dropped to zero. The best producing CHO-S clone obtained produced up to 7,000 EU ecarin/litre in lab scale shaker cultures. The conversion of different concentrations of both prothrombin and prethrombin-2 as substrates for native and r-ecarin were examined with a chromogenic thrombin substrate. At low concentrations both these proteins were converted into thrombin by the two ecarin preparations with comparable rates. However, with prothrombin concentrations above 250 nM r-ecarin apparently had a two times higher turnover than native ecarin, consistent with the observed rapid complete conversion of prothrombin into thrombin by r-ecarin. With r-ecarin a K (m) value of 0.4 MUM prethrombin-2 was determined but only a rough estimate could be made of the K (m) for prothrombin of 0.9 MUM. In conclusion, r-ecarin was identified as a promising candidate for replacement of native ecarin in assays utilizing conversion of prothrombin to thrombin. PMID- 22528139 TI - Cloning, expression, purification and characterization of UMP kinase from Staphylococcus aureus. AB - Uridine monophosphate kinase (UMPK) an enzyme of de novo biosynthesis catalyses the formation of UDP and it is involved in cell wall and RNA biosynthesis. In the present study UMPK of Staphylococcus aureus ATCC12600 was characterized. Analysis of purified UMPK by gel filtration chromatography on Sephadex G-200 indicated a molecular weight of 150 kDa and exhibited monomeric form with molecular weight of 25 kDa in SDS-PAGE confirming homohexamer nature of UMPK in solution. The enzyme kinetics of UMPK showed K(m) of 2.80 +/- 0.1 MUM and Vmax 51.38 +/- 1.39 MUM of NADH/min/mg. The enzyme exhibited cooperative kinetics with ATP as substrate, as GTP decreased this cooperativity and increased affinity for ATP. The UMPK gene was amplified, sequenced (Accession number: FJ415072), cloned in pQE30 vector and overexpressed in Escherichia coli DH5alpha. The purified recombinant UMPK showed similar properties of native UMPK. The UMPK gene sequence showed complete homology with pyrH gene sequence of all S. aureus strains reported in the database, the 3D structure of S. aureus UMPK built from the deduced amino acid sequence was super imposed with human UMPK (PDB ID: 1TEV) to find out the structural identity using the MATRAS programme gave an RMSD value 4.24 A indicating very low homology and extensive structural variations with human UMPK structure. Thus, UMPK may be a potential drug target in the development of antimicrobials. PMID- 22528140 TI - Monte Carlo calculations of the replacement correction factor, P(repl), for cylindrical chamber cavities in clinical photon and electron beams. AB - The purpose of this study was to calculate the replacement correction factor, P(repl) (the product P(gr)P(fl) in the AAPM's notation, or the product p(cav)p(dis) in the IAEA's notation), at a reference depth, d(ref), for cylindrical chamber cavities in clinical photon and electron beams by Monte Carlo simulation. P(repl) was calculated for cavities with a combination of various diameters and lengths. P(repl) values calculated in photon and electron beams were typically higher than those recommended by the TG-51 and TRS-398 dosimetry protocols. P(repl) values for a Farmer chamber cavity were higher by 0.3 to 0.2% and by 0.7 to 0.4%, respectively, than data of TG-51 and TRS-398, at photon energies of (60)Co to 18 MV. Similarly, the P(repl) values for electron beams were higher by 1.5 to 1.1% than data for both protocols, in a range of 6-18 MeV. The P(repl) values depended upon the cavity diameter and length, especially for lower electron energies. We found that P(repl) values of cylindrical chamber cavities for photon and electron beams were significantly different from those recommended by TG-51 and TRS-398. PMID- 22528141 TI - Psychiatrist decision-making towards prescribing benzodiazepines: the dilemma with substance abusers. AB - Psychiatrists' decision making about prescribing benzodiazepines (BZD) was evaluated in a community mental health center. An anonymous survey of outpatient psychiatrists in an academic-affiliated public mental health center was conducted using a 45-item questionnaire developed based on the results of a previous study. Sixty-six percent of responses indicate that, at times, psychiatrists experienced requests for behaviors suspicious for abuse, including 'lost/missing prescriptions' and 'use of BZD by others'. Patient characteristics such as 'history of abuse', 'unknown patient', and 'patient use of illicit substances' were occasional or common reasons for NOT prescribing BZDs (75%). The most common contexts in which the majority of our sample was uncomfortable prescribing BZDs involved a patient history of substance abuse, fear of initiation of dependence, diversion, and feeling manipulated by the patient. Time limitations were a dilemma for 20%. Psychiatrist self-reported dilemma and behavior in prescribing BZDs largely reflected concerns with substance abuse and less frequently workload or time issues. PMID- 22528142 TI - Variation in attraction to host plant odors in an invasive moth has a genetic basis and is genetically negatively correlated with fecundity. AB - Lepidopteran insects are major pests of agricultural crops, and mated female moths exploit plant volatiles to locate suitable hosts for oviposition. We investigated the heritability of odor-guided host location behavior and fecundity in the cosmopolitan oriental fruit moth Grapholita (Cydia) molesta, an oligophagous herbivore that attacks fruit trees. We used a full-sib/half-sib approach to estimate the heritability and the genetic correlation between these two traits. Results document a considerable genetic basis for olfactory attraction of females (h ( 2 ) = 0.37 +/- 0.17) and their fecundity (h ( 2 ) = 0.32 +/- 0.13), as well as a genetic trade-off between female attraction and fecundity (r ( g ) = -0.85 +/- 0.21). These estimations were empirically corroborated by comparing two strains maintained in the laboratory for different numbers of generations. The long-term reared strain lost its olfactory discrimination ability but achieved significantly higher fecundity compared with the short-term reared strain. Our results highlight that genetic studies are relevant for understanding the evolution of odor-guided behavior in herbivore insects and for judging the promise of pest management strategies involving behavioral manipulation with plant volatiles. PMID- 22528143 TI - A light-assisted biomass fuel cell for renewable electricity generation from wastewater. AB - A solar-energy-driven biomass fuel cell for the production of electricity from wastewater using only air and light as additional resources is described. The device consists of a photoelectrochemical cell that contains a nanostructured titanium dioxide or tungsten trioxide film as photoanode and a platinum air electrode as cathode, in separate compartments. The TiO(2) or WO(3) films are fabricated from TiO(2) nanocrystals or from sodium tungstate solutions on top of fluorine-doped tin dioxide. Devices were tested with electrolyte only, synthetic wastewater, or with aqueous glucose solution, under irradiation with sunlight, broad spectral illumination, and monochromatic light. Measured light conversion efficiencies were between 0.007 % and 1.7 %, depending on conditions. The highest efficiency (1.7 %) and power output (0.73 mW cm(-2)) are determined for TiO(2) electrodes under 395 nm illumination. In contrast to TiO(2), the WO(3) electrodes are active under visible light (>440 nm), but the IPCE value is low (2 %). Apart from limited visible-light absorption, the overall performance of the device is limited by the substrate concentration in the water and by transport resistance through the cell. PMID- 22528144 TI - The topography of brain damage at different stages of Parkinson's disease. AB - This study investigated gray matter (GM) and white matter (WM) damage in 89 patients at different clinical stages of Parkinson's disease (PD) (17 early, 46 mild, 14 moderate, and 12 severe) to differentiate the trajectories of tissue injury in this condition. PD patients had a very little GM atrophy even at the more advanced stages of the disease. Microstructural damage to the WM occurs with increasing PD severity and involves the brainstem, thalamocortical pathways, olfactory tracts, as well as the major interhemispheric, limbic, and extramotor association tracts. The most marked WM damage was found in moderate vs. mild cases. WM damage correlated with the degree of global cognitive deficits. WM abnormalities beyond the nigrostriatal system accumulate with increasing PD severity. WM damage is likely to contribute to the more severe motor and nonmotor dysfunctions occurring in patients at the later stages. PMID- 22528145 TI - Noncoding RNA expression in myocardium from infants with tetralogy of Fallot. AB - BACKGROUND: The importance of noncoding RNAs (ncRNA), especially microRNAs (miRNAs), for maintaining stability in the developing vertebrate heart has recently become apparent; however, there is little known about the expression pattern of ncRNA in the human heart with developmental anomalies. METHODS AND RESULTS: We examined the expression of miRNAs and small nucleolar RNAs (snoRNAs) in right ventricular myocardium from 16 infants with nonsyndromic tetralogy of Fallot (TOF) without a 22q11.2 deletion, 3 fetal heart samples, and 8 normally developing infants. We found 61 miRNAs and 135 snoRNAs to be significantly changed in expression in myocardium from children with TOF compared with normally developing comparison subjects. The pattern of ncRNA expression in TOF myocardium had a surprising resemblance to expression patterns in fetal myocardium, especially for the snoRNAs. Potential targets of miRNAs with altered expression were enriched for gene networks of importance to cardiac development. We derived a list of 229 genes known to be critical to heart development and found 44 had significantly changed expression in TOF myocardium relative to normally developing myocardium. These 44 genes had significant negative correlation with 33 miRNAs, each of which also had significantly changed expression. The primary function of snoRNAs is targeting specific nucleotides of ribosomal RNAs and spliceosomal RNAs for biochemical modification. The targeted nucleotides of the differentially expressed snoRNAs were concentrated in the 28S and 18S ribosomal RNAs and 2 spliceosomal RNAs, U2 and U6. In addition, in myocardium from children with TOF, we observed splicing variants in 51% of genes that are critical for cardiac development. Taken together, these observations suggest a link between levels of snoRNA that target spliceosomal RNAs, spliceosomal function, and heart development. CONCLUSIONS: This is the first report characterizing ncRNA expression in a congenital heart defect. The striking shift in expression of ncRNAs reflects a fundamental change in cell biology, likely impacting expression, transcript splicing, and translation of developmentally important genes and possibly contributing to the cardiac defect. PMID- 22528146 TI - Noonan syndrome due to a SHOC2 mutation presenting with fetal distress and fatal hypertrophic cardiomyopathy in a premature infant. AB - We report on a patient with Noonan syndrome due to SHOC2 missense mutation predicting p.Ser2Gly, recently described in association with Noonan syndrome. The male infant presented with fetal distress requiring premature delivery at 32 weeks and was noted to have dysmorphic features, edema, hepatosplenomegaly, leukocytosis, thrombocytopenia, and respiratory distress following birth. An echocardiogram revealed hypertrophic cardiomyopathy with left ventricular outflow tract obstruction. The infant's cardiac lesion rapidly progressed, and he was discharged home for palliative care. Clinical testing of genes causative of Noonan syndrome and related disorders detected the previously reported, pathogenic, de novo SHOC2 missense mutation predicting p.Ser2Gly. The patient's cardiac findings and features were not typical for those individuals previously reported with this SHOC2 mutation and thus expand the clinical phenotype. PMID- 22528147 TI - Declining coronary artery bypass-related mortality: more than meets the eye? PMID- 22528148 TI - Deciding for a child: a comprehensive analysis of the best interest standard. AB - This article critically examines, and ultimately rejects, the best interest standard as the predominant, go-to ethical and legal standard of decision making for children. After an introduction to the presumption of parental authority, it characterizes and distinguishes six versions of the best interest standard according to two key dimensions related to the types of interests emphasized. Then the article brings three main criticisms against the best interest standard: (1) that it is ill-defined and inconsistently appealed to and applied, (2) that it is unreasonably demanding and narrow, and (3) that it fails to respect the family. Finally, it argues that despite the best interest standard's potent rhetorical power, it is irreparably encumbered by too much inconsistency and confusion and should be rejected. PMID- 22528150 TI - Influenza viruses: an introduction. AB - We provide a brief introduction into the genome organization, life cycle, pathogenicity, and host range of influenza A viruses. We also briefly summarize influenza pandemics and currently available measures to control influenza virus outbreaks, including vaccines and antiviral compounds to influenza viruses. PMID- 22528149 TI - The myth of genetic enhancement. AB - The ongoing revolution in molecular genetics has led many to speculate that one day we will be able to change the expression or phenotype of numerous complex traits to improve ourselves in many different ways. The prospect of genetic enhancements has generated heated controversy, with proponents advocating research and implementation, with caution advised for concerns about justice, and critics tending to see the prospect of genetic enhancements as an assault on human freedom and human nature. Both camps base their arguments on the unquestioned assumption that the science will realize either their dreams or nightmares. In this paper, I show that their beliefs are based upon two fundamental mistakes. First, they are based upon an unwarranted reliance in a genetic determinism that takes for granted that the traits that we might most want to enhance, like intelligence, aggression, shyness, and even athletic ability, can be causally directed by specific genes. In so doing, character descriptions are reified to be concrete and discrete entities, in this case, genes. Second, they have accepted on faith that there is, or will be, a science to translate their hopes or worries into reality when, in fact, that is unlikely to occur because of the irreducible complexity of phenotypic expression. PMID- 22528151 TI - Influenza virus isolation. AB - The isolation of influenza viruses is important for the diagnosis of respiratory diseases in lower animals and humans, for the detection of the infecting agent in surveillance programs, and is an essential element in the development and production of vaccine. Since influenza is caused by a zoonotic virus it is necessary to do surveillance in the reservoir species (aquatic waterfowls), intermediate hosts (quails, pigs), and in affected mammals including humans. Two of the hemagglutinin (HA) subtypes of influenza A viruses (H5 and H7) can evolve into highly pathogenic (HP) strains for gallinaceous poultry; some HP H5 and H7 strains cause lethal infection of humans. In waterfowls, low pathogenic avian influenza (LPAI) isolates are obtained primarily from the cloaca (or feces); in domestic poultry, the virus is more often recovered from the respiratory tract than from cloacal samples; in mammals, the virus is most often isolated from the respiratory tract, and in cases of high pathogenic avian influenza (HPAI) from the blood and internal organs of infected birds. Virus isolation procedures are performed by inoculation of clinical specimens into embryonated eggs (primarily chicken eggs) or onto a variety of primary or continuous tissue culture systems. Successful isolation of influenza virus depends on the quality of the sample and matching the appropriate culture method to the sample type. PMID- 22528152 TI - Influenza virus titration, antigenic characterization, and serological methods for antibody detection. AB - This chapter describes some commonly used methods of influenza virus titration, antigenic characterization, and serological methods by antibody detection. These methods are essential not only for virus characterization but also for identifying new antigenic variants, vaccine strain selection, and sero epidemiologic studies of influenza virus transmission and prevalence. Virus titration methods such as the hemagglutination assay, 50% egg or tissue culture infectious dose, and plaque assay are employed to determine the amount of virus particles in a sample. The hemagglutination inhibition assay is a reliable, relatively simple and inexpensive technique to antigenically characterize isolates of influenza viruses. Serological methods such as virus neutralization and hemagglutination inhibition are the fundamental tools used in sero epidemiologic studies of influenza virus transmission and prevalence and in the evaluation of vaccine immunogenicity. While serological methods rarely yield an early diagnosis of acute influenza virus infection, well-timed, paired acute, and convalescent serum samples may establish the diagnosis of a recent influenza infection even when attempts to detect the virus are negative. PMID- 22528153 TI - Diagnosis of influenza virus. AB - The laboratory diagnosis of influenza uses a wide range of techniques including rapid immunoassays, immunofluorescence techniques, virus culture methods, and increasingly sophisticated molecular assays. The potential utility of each of these methods has changed over the years, most dramatically perhaps with the emergence of the pandemic H1N1 2009 influenza virus. While rapid immunoassays had previously been widely used in clinics and emergency departments, their poor detection sensitivity for the 2009 subtype brought their application into question. Concerns were also raised about the detection sensitivities of antibody reagents used in immunofluorescence methods, and the safety of virus culture was initially questioned with regard to the newly emerged subtype. Early molecular detection techniques had been labor intensive, and required separate facilities in order to prevent contamination. Those techniques have largely been supplanted by more modern methods, most notably real-time reverse transcription PCR assays, which are currently the method of choice in many laboratories for the detection and subtyping of influenza viruses. Suspension and low-density array assays are also increasingly used, in an effort to detect larger numbers of viruses in a single assay, and microarrays have proven valuable for outbreak analysis and pathogen discovery. Each laboratory must assess the optimal methods for its situation and the best application of each technique, taking into account numerous factors including its budget, equipment, staff expertise, the patient population that it serves, the needs of its submitting clinicians, and its surveillance and public health responsibilities. PMID- 22528154 TI - Solid-phase assays of receptor-binding specificity. AB - Influenza virus attachment to sialic acid-containing molecules on the cell surface initiates the infection. The spectrum of functional receptors on target cells and decoy receptors on cells and epithelial mucus varies substantially between animal species leading to variations in the receptor-binding specificity of viruses circulating in these species. Analysis of the receptor specificity of different animal and human influenza viruses can give insight into factors and mechanisms that determine viral host range, tissue and cell tropism, replication efficiency, and pathogenesis. Knowledge of viral receptor specificity may also be useful for the development of more efficient influenza vaccines and anti influenza drugs.A majority of known receptor specificity assays measure influenza virus binding to sialic acid-containing natural and synthetic compounds (receptor analogues). Here, we describe protocols of two solid-phase enzyme-linked receptor binding assays which are technically similar to standard ELISA. Each assay determines binding of the virus immobilized in the wells of 96-well plate to receptor analogues in solution. In the direct binding assay, the virus binds to either synthetic biotinylated sialylglycopolymers or to peroxidase-labeled sialylglycoprotein fetuin (Fet-HRP); the apparent association constants of the virus-receptor complexes are calculated from the Scatchard plots of the binding data. In the fetuin-binding inhibition assay, the virus is incubated with a mixture of unlabeled receptor analogue and standard preparation of Fet-HRP; the association constant for analogue is calculated based on the level of its competition with Fet-HRP. PMID- 22528155 TI - The chemiluminescent neuraminidase inhibition assay: a functional method for detection of influenza virus resistance to the neuraminidase inhibitors. AB - Neuraminidase inhibitors (NAIs) represent a newer class of anti-influenza drugs. Widespread natural or acquired resistance to NAIs is a major public health concern as it limits pharmaceutical options available for managing seasonal and pandemic influenza virus infections. Molecular-based methods, such as pyrosequencing, sequencing, and PCR are rapid techniques for detecting known genetic markers of resistance, but they are unable to identify novel mutations that may confer resistance, or subtle differences in the susceptibility of viruses to the NAIs. This chapter describes the chemiluminescent neuraminidase (NA) inhibition (NI) assay, a functional method used for assessing influenza virus susceptibility to NAIs. The assay generates IC(50) values (drug concentration needed to reduce the NA enzymatic activity by 50%) which are determined by curve-fitting analysis. Test viruses showing elevated IC(50) values relative to those of NAI-sensitive reference viruses of the same antigenic type and subtype are further analyzed by pyrosequencing or conventional sequencing to identify known markers of NAI resistance or new changes in the NA. The criteria for NAI resistance are currently not well defined and tend to vary by laboratory and NI assay, therefore harmonization of NI assay conditions and interpretation of results across surveillance laboratories is necessary to improve the NAI susceptibility testing and analysis. PMID- 22528156 TI - The fluorescence neuraminidase inhibition assay: a functional method for detection of influenza virus resistance to the neuraminidase inhibitors. AB - Neuraminidase inhibitors (NAIs) are presently the only effective antiviral drugs for treatment and chemoprophylaxis of influenza A and B infections, due to the high prevalence of resistance to the adamantane class of drugs among influenza A(H3N2) and A(H1N1) viruses, including the 2009 pandemic H1N1 strain. The limited pharmaceutical options currently available for control of influenza infections underscore the critical need for surveillance on NAI susceptibility of influenza viruses circulating globally. This chapter describes the fluorescent neuraminidase (NA) inhibition (NI) assay, a functional method used for assessing influenza virus susceptibility to NAIs. The IC(50) (drug concentration needed to reduce the NA enzymatic activity by 50%) values generated in this assay are used to evaluate the NAI-susceptibility of test viruses relative to those of sensitive reference viruses of the same antigenic type and subtype. Test viruses with significantly elevated IC(50)s are further analyzed by pyrosequencing or conventional sequencing to identify known markers of NAI resistance or novel changes in the NA. The harmonization of NI assay conditions and interpretation of results across surveillance laboratories is necessary to improve NAI susceptibility testing and analysis. PMID- 22528157 TI - Animal models. AB - Five well-established animal models in influenza research are discussed in a schematic fashion. Although there are clear parallels between these models, like viruses used, housing and handling conditions under biosafety conditions, routes of virus inoculation, sampling strategies, and necropsy techniques (mostly elaborated on in Subheading 4), each of these models involves specific differences in their practical applicability that need thorough assessment depending on the scientific question raised. In other words, there is no universal animal model for influenza and depending on the actual question to be answered the model and the experimental conditions should be carefully selected. PMID- 22528158 TI - Influenza virus surveillance, vaccine strain selection, and manufacture. AB - As outlined in other chapters, the influenza virus, existing laboratory diagnostic abilities, and disease epidemiology have several peculiarities that impact on the timing and processes for the annual production of influenza vaccines. The chapter provides an overview on the key biological and other factors that influence vaccine production. They are the reason for an "annual circle race" beginning with global influenza surveillance during the influenza season in a given year to the eventual supply of vaccines 12 months later in time before the next seasonal outbreak and so on. As influenza vaccines are needed for the Northern and Southern Hemisphere outbreaks in fall and spring, respectively, global surveillance and vaccine production has become a year round business. Its highlights are the WHO recommendations on vaccine strains in February and September and the eventual delivery of vaccine doses in time before the coming influenza season. In between continues vaccine strain and epidemiological surveillance, preparation of new high growth reassortments, vaccine seed strain preparation and development of standardizing reagents, vaccine bulk production, fill-finishing and vaccine release, and in some regions, clinical trials for regulatory approval. PMID- 22528159 TI - Genetic engineering of live attenuated influenza viruses. AB - The first live attenuated influenza vaccine (LAIV) was licensed in the USA in 2003; it is a trivalent vaccine composed of two type A (H1N1 and H3N2) and one type B influenza virus each at 10(7) fluorescent focus units (FFU). Each influenza vaccine strain is a reassortant virus that contains the hemagglutinin (HA) and neuraminidase (NA) gene segments from a wild-type influenza virus and the six internal protein gene segments from a master donor virus (MDV) of either cold-adapted A/Ann Arbor/6/60 or B/Ann Arbor/1/66. MDV confers the cold-adapted, temperature-sensitive, and attenuation phenotypes to the vaccine strains. The reassortant vaccine seeds are currently produced by reverse genetics and amplified in specific pathogen-free (SPF) 9-11 days old embryonated chicken eggs for manufacture. In addition, MDCK cell culture manufacture processes have been developed to produce LAIV for research use and with modifications for clinical and/or commercial grade material production. PMID- 22528160 TI - Influenza A virus molecular virology techniques. AB - Molecular biological techniques for genomic analysis and for creation of recombinant viruses are critical tools in our efforts to understand and combat influenza A viruses. These molecular virology approaches are used in diagnostics, basic research, molecular epidemiology, bioinformatics, and vaccine development. The majority of the techniques used to study this segmented negative-sense RNA virus begin by purifying RNA from the virus, or infected cells, and converting it to cDNA, then to dsDNA, and amplifying that dsDNA using reverse transcription in combination with the polymerase chain reaction (RTPCR). The RTPCR amplicons can be probed, sequenced, or cloned into a variety of vectors for further analysis and to create recombinant influenza A viruses by plasmid-based reverse genetics. To accelerate the amplification and cloning process, we developed multi-segment RTPCR (M-RTPCR) techniques that efficiently amplify the eight genomic viral RNA segments (vRNAs) of influenza A virus in a single reaction, irrespective of the virus strain. The M-RTPCR amplicons are ideal for nucleotide sequence analysis and cloning full-length vRNAs into plasmids or other vectors designed for protein expression or reverse genetics. Therefore, we also developed modified reverse genetics plasmids that are designed to rapidly clone M-RTPCR products, or other full-length vRNA amplicons, using recombination-based techniques. The combination of M-RTPCR and recombination-based cloning confers sensitivity, speed, fidelity, and flexibility to the analysis and rescue of any strain/subtype of influenza A virus, without the need for in vitro propagation. The specific topics described in this chapter include purification of high-quality viral RNA, genomic amplification using two different M-RTPCR schemes, sequencing vRNA amplicons, and cloning vRNA amplicons into our modified reverse-genetics plasmids, or commercially available plasmids. PMID- 22528161 TI - Reverse genetics of influenza viruses. AB - The ability to modify influenza viruses at will has revolutionized influenza research. Reverse genetics has been used to generate mutant or reassortant influenza viruses to assess their replication, virulence, pathogenicity, host range, and transmissibility. Moreover, this technology is now being used to generate approved influenza virus vaccines and develop novel vaccines to combat seasonal and (future) pandemic influenza viruses. Several variations of the original system have been established, all of which are considerably robust and efficient. PMID- 22528162 TI - Genetic analysis. AB - Genetic analysis of sequence data is central to determining the evolutionary history and molecular epidemiology of viruses, particularly those such as influenza A virus that have complex ecosystems involving multiple hosts. Here we provide an outline of routine phylogenetic analyses of influenza A viruses including multiple sequence alignment, selecting the best-fit evolutionary model and phylogenetic tree reconstruction using Neighbor joining, Maximum likelihood, and Bayesian inference. PMID- 22528164 TI - Flow velocity patterns in the pulmonary artery and pulmonary hypertension. AB - Pulmonary hypertension impacts negatively on right ventricular function; however, understanding pulmonary vasculature can be difficult. Data from invasive monitoring or traditional echocardiography may not represent the full extent of pulmonary arterial disease. An important element missing from invasive monitoring is the ability to take into account the effects of pulsatile flow; therefore, mean pressures and mean flows are employed in the calculation of pulmonary vascular resistance. Traditional echocardiography yields right ventricular systolic pressures but only in the presence of tricuspid regurgitation. In these Perioperative Cardiovascular Rounds, we show the utility of interpreting pulmonary artery (PA) pulsed-wave Doppler (PWD) and colour-flow Doppler in the assessment of the pulmonary vasculature, and we describe the physiology behind their genesis. We show these concepts in a case vignette involving a patient in a low cardiac output state after a complex re-do sternotomy. Additionally, we describe four distinct patterns of PA PWD tracings and illustrate the ability of PA PWD analysis to assess the pulmonary vasculature in both a qualitative and semi-quantitative way. In the critical care setting, it is vital to understand alterations in the pulmonary circulation, and analysis of PA PWD can provide additional information to complement data from other sources. PMID- 22528163 TI - Anesthesia advanced circulatory life support. AB - PURPOSE: The constellation of advanced cardiac life support (ACLS) events, such as gas embolism, local anesthetic overdose, and spinal bradycardia, in the perioperative setting differs from events in the pre-hospital arena. As a result, modification of traditional ACLS protocols allows for more specific etiology based resuscitation. PRINCIPAL FINDINGS: Perioperative arrests are both uncommon and heterogeneous and have not been described or studied to the same extent as cardiac arrest in the community. These crises are usually witnessed, frequently anticipated, and involve a rescuer physician with knowledge of the patient's comorbidities and coexisting anesthetic or surgically related pathophysiology. When the health care provider identifies the probable cause of arrest, the practitioner has the ability to initiate medical management rapidly. CONCLUSIONS: Recommendations for management must be predicated on expert opinion and physiological understanding rather than on the standards currently being used in the generation of ACLS protocols in the community. Adapting ACLS algorithms and considering the differential diagnoses of these perioperative events may prevent cardiac arrest. PMID- 22528165 TI - STAR VaS--Short Term Atorvastatin Regime for Vasculopathic Subjects: a randomized placebo-controlled trial evaluating perioperative atorvastatin therapy in noncardiac surgery. AB - PURPOSE: Evidence suggests that statins reduce cardiovascular complications in patients undergoing noncardiac surgery, although questions remain regarding the mechanism of benefit and the preferred dosing strategy. In this trial, we evaluated the perioperative effects on C-reactive protein (CRP) that resulted from starting atorvastatin within seven days of noncardiac surgery. The objective was to identify anti-inflammatory effects of atorvastatin prior to conducting a large randomized trial with clinical end points. METHODS: In a single centre, parallel group, placebo-controlled trial, sixty high cardiac risk participants over age 45 yr undergoing noncardiac surgery were assigned randomly to one of three groups to receive atorvastatin 80 mg (A) and/or placebo (P). Group AA (n = 26) received atorvastatin seven days before surgery, the day of surgery, and for seven days post surgery. Group PA (n = 17) received placebo seven days before surgery, atorvastatin on the day of surgery, and atorvastatin for seven days post surgery. Group PP (n = 17) received placebo at all times. All participants, health care professionals, research assistants, and outcome adjudicators were masked to treatment allocation. Analyses were by intention to treat. The primary outcome was the C-reactive protein level at 48 hr. RESULTS: Fifty-six participants completed the 30-day follow-up. The mean (standard deviation) changes in CRP levels from baseline at 48 hr in Groups AA, PA, and PP were 141.0 (72.4), 153.5 (42.2), and 111.2 (84.6), respectively. The mean differences (95% confidence interval) at 48 hr for AA vs PA, AA vs PP, and PA vs PP were: -20.1 ( 81.2 to 41.1), 22.7 (-31.7 to 77.2), and 42.8 (-20.0 to 105.7), respectively, adjusting for baseline CRP, type of procedure, presence of coronary artery disease, use of medications, and for multiple comparisons using Tukey's method. CONCLUSIONS: Administration of atorvastatin, initiated within seven days preoperatively, was not associated with clinically significant reductions in CRP levels. PMID- 22528167 TI - Drug shortages in anesthesia and perioperative medicine: Canada needs a better supply system. PMID- 22528166 TI - Fluid and vasopressor management for Cesarean delivery under spinal anesthesia: continuing professional development. AB - PURPOSE: The purpose of this Continuing Professional Development module is to review the physiology of maternal hypotension induced by spinal anesthesia in pregnant women, and the effects of fluids and vasopressors. PRINCIPAL FINDINGS: Maternal hypotension induced by spinal anesthesia is caused mainly by peripheral vasodilatation and is not usually associated with a decrease in cardiac output. Although the intravenous administration of fluids helps to increase cardiac output, it does not always prevent maternal hypotension. Three strategies of fluid administrations are equivalent for the prevention of maternal hypotension and a reduced need for vasopressors: (1) colloid preload; (2) colloid coload; and (3) crystalloid coload. Crystalloid preload is not as effective as any of those three strategies. Unlike phenylephrine, ephedrine can cause fetal acidosis. Therefore, phenylephrine is recommended as first line treatment of maternal hypotension. A phenylephrine infusion (25-50 MUg x min(-1)) appears to be more effective than phenylephrine boluses to prevent hypotension, and nausea and vomiting. In pre-eclamptic patients, spinal anesthesia produces less hypotension than in normal pregnant women and fluid volumes up to 1,000 mL are usually well tolerated. Therefore mild to moderate intravascular volume loading is recommended, keeping in mind the increased risk for pulmonary edema in this population. In pre-eclamptic patients, hypotension can be treated either with ephedrine or phenylephrine, and phenylephrine infusions are not recommended. CONCLUSION: A volume loading regimen other than crystalloid preload should be adopted. A phenylephrine infusion during elective Cesarean delivery is beneficial for the mother and safe for the newborn. PMID- 22528168 TI - Transient vocal cord deformity caused by a laryngeal mask airway device during flexible fibreoptic bronchoscopy. PMID- 22528169 TI - Is it time to revisit tracheal intubation for Cesarean delivery? PMID- 22528170 TI - [More courage to reform]. PMID- 22528171 TI - [On the history of heart failure]. AB - The heart is by far the organ that is best known and has been identified for a long time. Myogenic weakness of the heart muscle pump with left-ventricular dysfunction remains the cardiac disease with the poorest prognosis while increasing in prevalence and incidence. Aside from all sorts of mystic treatment attempts and dubious herbal medicine, bloodletting was established early on as a superior remedy, which was applied in response to almost all cardiac illnesses. The first and perhaps most important cardiac drug was digitalis, the glycoside of the red and even more so of the white foxglove, described in 1552 by Leonhart Fuchs. In the 1980s, vasodilators and inotropic drugs supplemented the classical medications digitalis and diuretics. ACE inhibitors and beta-receptor blockers were added in the 1990s; at the turn of the millennium, the cardiac resynchronization therapy (CRT) and left-heart assist systems were developed; lately, there have been cellular and genetic approaches as well as xenotransplants. Preliminary results with stem cell technology are encouraging; however, it will be years until a clinical application-if it will happen at all. PMID- 22528172 TI - [Diabetes, sport and exercise]. AB - Physical activity is an essential element in the therapy of type 2 Diabetes mellitus. For physicians and therapists, it is of vital importance to motivate each patient to include exercise into routine daily life. Individual therapy plans are, thus, required. PMID- 22528173 TI - [Multimodal therapy of dyslipidemia]. AB - In the multifactorial process of atherogenesis not only increased LDL-cholesterol but also decreased HDL-cholesterol and raised triglycerides correlate closely to cardiovascular events. Multiple studies have demonstrated a high prevalence of dyslipidemia and the metabolic syndrome in Germany.Statins remain first-line therapy for the treatment of dyslipidemia. However, despite therapy a relevant cardiovascular risk remains. Therefore, it is important to also aim for an adequate treatment of hypertriglyceridemia and also to raise HDL-levels. Many combination therapies have been shown to be effective in treating dyslipidemia. Adding Omega-3-fatty acids, nicotinic acid/laropiprant or a fibrate to statin monotherapy provide additional beneficial lipid-modifying effects for combined dyslipidemia. In the future a recommendation for the treatment of mixed hyperlipoproteinemia with decreased HDL, raised triglycerides and LDL-cholesterol shall have to be added to our guidelines. PMID- 22528174 TI - [Non-invasive diagnostics of chronic stable coronary artery disease: evidence based and non-evidence-based diagnostic algorithms]. AB - In Germany, every second left heart catheterization has no immediate interventional or surgical consequence. One main reason for this limited quality of indication of many left heart catheterizations is presumably the inaccuracy of preinvasive testing that is mainly based on clinical evaluation and exercise ECG in Germany. However, exercise electrocardiography has several limitations. The central issues are the inability to exercise in many, especially elderly patients, and the missing interpretability of the stress ECG in cases with already pathological rest ECG. In 2006, the "Nationale Versorgungsleitlinie Chronische KHK (NVL KHK)" was published in Germany, adopting for the first time the evidence-based algorithms of the American College of Cardiology/American Heart Association (ACC/AHA) guidelines for non-invasive stress testing and complementary stress imaging. Stress imaging methods considered comparable and interchangeable are the following: stress echocardiography combined with physical or pharmacological stress testing, myocardial perfusion imaging with physical or pharmacological stress testing, dobutamine stress magnetic resonance imaging (DSMR), or myocardial perfusion magnetic resonance imaging (MRI). Basically, no stress imaging method is definitely superior to the others, each method has its own advantages and disadvantages that should be considered and adjusted to the individual patient. Of pivotal importance of all stress imaging methods is the high negative predictive value of 99% of a normal study predicting a very low (< 1%) cumulative likelihood of cardiac death or myocardial infarction for at least the next 12 months. Hence, in most clinical circumstances, coronary angiography is not necessary during the 12 months subsequent to a normal stress imaging study. In contrast to these established and evidence-based recommendations of the "Nationale Versorgungsleitlinie Chronische KHK" mainly focusing on ischemia stress imaging, many diagnostic centers have developed their own non-evidence based algorithms. In these non-evidence based algorithms the morphology-oriented non-invasive CT coronary angiography has taken over the diagnostic part of evidence-based ischemia stress imaging. However, beyond the scientifically established prognostic value of calcium scoring, there is so far no scientific evidence showing that morphology-oriented CT coronary angiography protocols are superior to functional stress imaging. A new innovative approach of staged non invasive diagnostics for patients with intermediate likelihood (10-90%) of coronary artery disease are the 2010 recommendations of the National Institute for Health and Clinical Excellence (NICE) guiding the National Health Service (NHS) in the United Kingdom. Following this guidance, in patients with an estimated likelihood of CAD of 10-29% CT calcium scoring should be offered as first-line method, in patients with an estimated likelihood of CAD of 30-60% non invasive functional imaging should be offered primarily, and in patients with an estimated likelihood of CAD of 61-90%, as in patients with an estimated likelihood of CAD of more than 90%, invasive coronary angiography should be preferred. PMID- 22528175 TI - [Exclusion of coronary artery disease using cardiac CT. What impact do CT results have on patient management?]. AB - Rapid advancement of multidetector head computed tomography (MDCT) during the past 10 years has facilitated noninvasive evaluation of CAD (coronary artery disease). Since the introduction of 320-row technology, examination of the whole heart in a single heart beat with diagnostic quality has become feasible. Direct imaging of vessel morphology, a high sensitivity for CAD above 96%, and low requirements of patient compliance represent advantages over other imaging modalities, such as MRI (magnetic resonance imaging), scintigraphy, and echocardiography. In some cases radiation exposure can be reduced to an effective dose below 1 mSV.Current data suggest that cardiac CT represents a more effective diagnostic tool than treadmill testing in order to decide whether cardiac catheterization is indicated. Treadmill testing has been an integral procedure of cardiac examinations for decades, although sensitivity for detecting CAD is as low as 70%.Cardiac CT represents a rather new modality and is almost exclusively performed in diagnostic imaging centers. Innovative concepts in the evaluation of CAD including CT are expected. Some authors propose cardiac CT as a major diagnostic tool for the exclusion of CAD. MRI, scintigraphy, or echocardiography in combination with a stress test remain important procedures in order to evaluate the hemodynamic relevance of coronary artery stenosis. Treadmill testing prior to cardiac CT has become questionable.The future role of cardiac CT in CAD in "change of management" concepts is promising. In order to optimize decisions of patient management on the basis of a cardiac CT examinations, awareness of current data is mandatory for the referring clinician and the performing radiological department. PMID- 22528176 TI - [Cardiac hybrid imaging]. AB - CT coronary angiography and myocardial perfusion scintigraphy are both established noninvasive techniques for the diagnosis of coronary artery disease (CAD). Cardiac hybrid imaging consists of the combination (or fusion) of both modalities and allows obtaining complementary morphological (coronary anatomy, stenoses) and functional (myocardial perfusion) information in a single image. The increased availability of these techniques in clinical practice has also raised a controversy with regard to which patients should undergo such integrated examinations. The feasibility and clinical value of hybrid imaging has been documented in small cohort studies and selected series of patients. The incremental value of the hybrid technique arises from the spatial co-registration of perfusion defects with coronary stenoses. This allows an assessment of the hemodynamic relevance of coronary stenoses and the determination of the need for revascularization procedures in each individual artery. Thus, it can be anticipated that the ongoing efforts to reduce radiation exposure and the increasing clinical interest will further pave the way for an ever-increasing use of cardiac hybrid imaging in clinical practice. PMID- 22528177 TI - [3-year results of the SYNTAX trial--stent or surgery? A surgeon's perspective]. AB - Coronary artery bypass grafting (CABG) is the standard of care for patients with three-vessel or left main coronary artery disease. However, clinical practice has proven to differ substantially with even the most complex coronary lesions being targeted by percutaneous coronary intervention (PCI) today. An abundancy of both large registries and randomized clinical trials has demonstrated superiority of surgery over PCI in advanced coronary artery disease. Recently, these results have been confirmed by the landmark SYNTAX trial where CABG was found to be superior to PCI for three-vessel and/or left main coronary artery disease regarding repeat revascularization, rate of myocardial infarction, and cardiac mortality at the latest follow-up of 3 years. On the other hand, PCI proved to be a viable alternative for less complex forms of left main disease.In conclusion, patients with three-vessel and/or left main coronary artery disease should be discussed in an interdisciplinary heart team consisting of cardiologists and cardiac surgeons within a heart center. Final decision making should be a formal process as recommended in the recently updated guidelines on myocardial revascularization by the European Society of Cardiology. PMID- 22528178 TI - [Transapical aortic valve implantation--indications, risks and limitations]. AB - Calcified aortic stenosis is the predominant valve disease in the western world. Currently, surgical aortic valve replacement is the gold standard procedure for symptomatic severe aortic stenosis that can be performed with low morbidity and mortality. The prevalence of aortic stenosis increases with age, and the incidence of several comorbidities also unavoidably elevates the risk of surgical treatment. Therefore, the most adequate and gentle treatment is needed especially for this population. Since the first transcatheter aortic valve implantation (TAVI) was performed in 2002, the main implanting routes are the transfemoral, retrograde access through the common femoral artery, and the antegrade, transapical approach via anterolateral minithoracotomy. Meanwhile, TAVI has become an alternative treatment for patients who are not suitable candidates for surgical therapy in some centers.The initial clinical results are promising and have confirmed the feasibility of this technique. Due to the restricted long-term data, conventional aortic valve replacement still remains the standard for the treatment of aortic stenosis. Selection of the suitable therapy approach (surgical replacement, transfemoral or transapical aortic valve implantation) must consider each patient's specific risk profile and individual indication. Prospective, randomized trials will be necessary to assess the individual survival benefit of TAVI for various risk populations and to extend the indication. PMID- 22528179 TI - [Anticoagulation in atrial fibrillation. Strategies in special situations]. AB - Morbidity and mortality associated with atrial fibrillation are mainly related to thromboembolic complications, particularly ischemic strokes. The prevention of thromboembolism is an important component of the management of patients with atrial fibrillation. The choice of optimum antithrombotic therapy for a given patient depends on the risk of thromboembolism, on the one hand, and the risk of intracerebral hemorrhage, on the other hand. Concerning the benefit-to-risk stratification, the problem lies in the similar and sometimes even identical risk factors for both thromboembolism and hemorrhage.At present, oral vitamin K antagonists are recommended for patients with atrial fibrillation at moderate or high risk of ischemic stroke. The thromboembolic risk should be assessed using validated stratification schemes, such as the CHADS(2) score for basic orientation and the CHA(2)DS(2)VASc score for extended risk stratification. Aspirin alone is recommended for patients at low risk of thromboembolic complications. Problems in antithrombotic therapy of atrial fibrillation arise treating those patients undergoing percutaneous coronary intervention and stent implantation, those with contraindication for vitamin K antagonists, or those with persisting left atrial thrombus requiring electrical cardioversion. The optimum therapeutic management of these special patients has not yet been defined by proper studies, leaving only empirically based recommendations for their treatment.Hopefully the development of new antithrombotic agents, that are easier to use and have a superior benefit-to-risk ratio, will extend effective prevention of thromboembolic events to a greater part of the atrial fibrillation population at risk. PMID- 22528180 TI - [Catheter ablation of atrial fibrillation. Pulmonary vein isolation by using a new multipolar ablation catheter]. AB - Catheter ablation of atrial fibrillation (AF) is an established therapeutical option, particularly in treatment of paroxysmal atrial fibrillation. This paper presents the results of using the PVAC multi-electrode ablation catheter (PVAC(r), Medtronic Ablation Frontiers, Carlsbad, CA, USA). In 253 patients with paroxysmal or persistant AF, 1051 pulmonary veins were isolated, including ablation of 34 left common ostia and 1 right common ostium. Except one vein, all pulmonary veins in all patients were successfully isolated. In 23 patients with documented typical atrial flutter, the right atrial isthmus was additionally ablated within the same procedure. Follow-up (FU) visits were performed after 1, 3, 6 and 12 months with 12-lead-ECG, 24h-Holter-ECG and 4-days-Holter ECG. Mean FU was 11 +/- 7 months with 1.1 interventions per patient (24 redo cases). During FU, 122 of 181 patients with paroxysmal AF (69%) and 23 of 40 patients with persistant AF (58%) were in stable sinus rhythm (SR) after ablation. 159 (62.8%) patients wer under antiarrhythmic drugs after ablation, 214 (84.5%) patients with additional beta-blockers. Total procedure time was 71 +/- 19 min, and total fluoroscopy time was 16 +/- 6 min. In 3 cases (1.2%) procedure-related complications occured. Pulmonary vein isolation by using the PVAC-ablation catheter is a safe and effective method in treatment of paroxysmal and persistant AF. PMID- 22528181 TI - [Three-dimensional reconstruction and remote navigation for catheter-guided atrial fibrillation ablation. Does it influence procedural outcomes?]. AB - Catheter ablation of atrial fibrillation has evolved as a widely accepted therapy approach and is now also incorporated in the current guidelines.A major limitation consists of the limited three-dimensional visualization of the complex three-dimensional structures in the left atrium since most procedures have routinely been performed using fluoroscopy alone. Another unsolved problem is the limited durability of lesions sets performed with radiofrequency ablation and therefore somewhat disappointing long-term ablation results besides fluoroscopy exposition for patient and operator as required for safe catheter manipulation.In the recent years we have gained substantial insight with respect to arrhythmia mechanism. At the same time new techniques and developments have become available to improve catheter ablation results.The present article summarizes the available opportunities with respect to three-dimensional mapping including CT/MRI image integration and gives an overview of the robotic and magnetic systems available for catheter ablation. PMID- 22528183 TI - AFMBioMed Conference: Paris, France, August 2011. PMID- 22528182 TI - A silver nanocomposite biomaterial for blood-contacting implants. AB - Cardiovascular implants must resist infection and thrombosis. A nanocomposite polymeric material [polyhedral-oligomeric-silsesquioxane-poly(carbonate urea)urethane; POSS-PCU] demonstrates ideal properties for cardiovascular applications. Silver nanoparticles or nanosilver (NS) are recognized for efficient antibacterial properties. This study aims to determine the influence of NS integrated POSS-PCU on thrombogenicity. Silver nitrate was reduced with dimethylformamide and stabilized by the inclusion of fumed silica nanoparticles to prevent aggregation of NS and were incorporated into POSS-PCU to form a range of POSS-PCU-NS concentrations (by weight); 0.20% (NS16), 0.40% (NS32), 0.75% (NS64), and 1.50% (NS128). Surface wettability was determined with sessile-drop water contact angles. Platelets were introduced onto test samples and Alamar Blue (AB), mitochondrial-activity assay, quantified the degree of platelet adhesion whilst platelet-factor-4 (PF4) ELISA quantified the degree of platelet activation. Thromboelastography (TEG) determined the profiles of whole blood kinetics while hemolysis assay demonstrated the degree of blood compatibility. Increasing levels of NS induced greater hydrophilicity. A concentration dependant decrease in platelet adhesion and activation was observed with AB and PF4 readings, respectively. TEG demonstrated that the antithrombogenic properties of POSS-PCU were retained with POSS-PCU-NS16, and enhanced with POSS-PCU-NS32, but was reduced with POSS-PCU-NS64 and POSS-PCU-NS128. POSS-PCU-NS64 and POSS-PCU NS128 demonstrated a hemolytic tendency, but no hemolysis was observed with POSS PCU-NS16 and POSS-PCU-NS32. Overall, POSS-PCU-NS32 rendered potent antithrombogenic properties. PMID- 22528184 TI - Stiffness tomography exploration of living and fixed macrophages. AB - Stiffness tomography is a new atomic force microscopy imaging technique that allows highlighting structures located underneath the surface of the sample. In this imaging mode, such structures are identified by investigating their mechanical properties. We present here, for the first time, a description of the use of this technique to acquire detailed stiffness maps of fixed and living macrophages. Indeed, the mechanical properties of several macrophages were studied through stiffness tomography imaging, allowing some insight of the structures lying below the cell's surface. Through these investigations, we were able to evidence the presence and properties of stiff column-like features located underneath the cell membrane. To our knowledge, this is the first evidence of the presence, underneath the cell membrane, of such stiff features, which are in dimension and form compatible with phagosomes. Moreover, by exposing the cells to cytochalasin, we were able to study the induced modifications, obtaining an indication of the location and mechanical properties of the actin cytoskeleton. PMID- 22528185 TI - Myelinating and demyelinating phenotype of Trembler-J mouse (a model of Charcot Marie-Tooth human disease) analyzed by atomic force microscopy and confocal microscopy. AB - The accumulation of misfolded proteins is associated with various neurodegenerative conditions. Mutations in PMP-22 are associated with the human peripheral neuropathy, Charcot-Marie-Tooth Type 1A (CMT1A). PMP-22 is a short lived 22 kDa glycoprotein, which plays a key role in the maintenance of myelin structure and compaction, highly expressed by Schwann cells. It forms aggregates when the proteasome is inhibited or the protein is mutated. This study reports the application of atomic force microscopy (AFM) as a detector of profound topographical and mechanical changes in Trembler-J mouse (CMT1A animal model). AFM images showed topographical differences in the extracellular matrix and basal lamina organization of Tr-J/+ nerve fibers. The immunocytochemical analysis indicated that PMP-22 protein is associated with type IV collagen (a basal lamina ubiquitous component) in the Tr-J/+ Schwann cell perinuclear region. Changes in mechanical properties of single myelinating Tr-J/+ nerve fibers were investigated, and alterations in cellular stiffness were found. These results might be associated with F-actin cytoskeleton organization in Tr-J/+ nerve fibers. AFM nanoscale imaging focused on topography and mechanical properties of peripheral nerve fibers might provide new insights into the study of peripheral nervous system diseases. PMID- 22528187 TI - Early adhesion of human mesenchymal stem cells on TiO(2) surfaces studied by single-cell force spectroscopy measurements. AB - Understanding the interactions involved in the adhesion of living cells on surfaces is essential in the field of tissue engineering and biomaterials. In this study, we investigate the early adhesion of living human mesenchymal stem cells (hMSCs) on flat titanium dioxide (TiO(2) ) and on nanoporous crystallized TiO(2) surfaces with the use of atomic force microscopy-based single-cell force spectroscopy measurements. The choice of the substrate surfaces was motivated by the fact that implants widely used in orthopaedic and dental surgery are made in Ti and its alloys. Nanoporous TiO(2) surfaces were produced by anodization of Ti surfaces. In a typical force spectroscopy experiment, one living hMSC, immobilized onto a fibronectine-functionalized tipless lever is brought in contact with the surface of interest for 30 s before being detached while recording force-distance curves. Adhesion of hMSCs on nanoporous TiO(2) substrates having inner pore diameter of 45 nm was lower by approximately 25% than on TiO(2) flat surfaces. Force-distance curves exhibited also force steps that can be related to the pulling of membrane tethers from the cell membrane. The mean force step was equal to 35 pN for a given speed independently of the substrate surface probed. The number of tethers observed was substrate dependent. Our results suggest that the strength of the initial adhesion between hMSCs and flat or nanoporous TiO(2) surfaces is driven by the adsorption of proteins deposited from serum in the culture media. PMID- 22528186 TI - Direct immobilization of avidin protein on AFM tip functionalized by acrylic acid vapor at RF plasma. AB - The atomic force microscopy (AFM) has been used as a force sensor to measure unbinding forces of single bound complexes in the nanonewton and piconewton range. Force spectroscopy measurements can be applied to study both intermolecular and intramolecular interactions of complex biological and synthetic macromolecules. Although the AFM has been extensively used as a nano force sensor, the commercially available cantilever is limited to silicon and silicon nitride. Those materials reduce the adhesion sensitivity with specific surface and/or molecule. Here, we functionalized the AFM tip with carboxylic groups by applying acrylic acid (AA) vapor at radio frequency plasma treatment at 100 W for 5 min. This method provides a remarkable sensitivity enhancement on the functional group interaction specificity. The functionalized tip was characterized by scanning electron microscopy. The electron beam high resolution images have not shown significant tip sharpness modification. Silicon wafers (1 0 0)-no treated and functionalized by AA plasma treatment-were characterized by Auger electron spectroscopy to elucidate the silicon surface sputtering and demonstrate functionalization. The Fourier transform-infrared spectroscopy spectrum shows a high absorbance of avidin protein over the silicon surface functionalized by AA plasma treatment.We carried out force spectroscopy assay to measure the unbinding force between the well-established pair biotin-avidin. At pulling speed of 2 um/s, we measured the unbinding force of 106 +/- 23 pN, which is in good agreement with the literature, demonstrating the effectiveness of the tip functionalization by AA plasma treatment in biological studies. PMID- 22528188 TI - Probing cytoskeleton organisation of neuroblastoma cells with single-cell force spectroscopy. AB - Single-cell force spectroscopy is an emerging technique in the field of biomedicine because it has proved to be a unique tool to obtain mechanical and functional information on living cells, with force resolution up to single molecular bonds. This technique was applied to the study of the cytoskeleton organisation of neuroblastoma cells, a life-threatening cancer typically developing during childhood, and the results were interpreted on the basis of reference experiments on human embryonic kidney cell line. An intimate connection emerges among cellular state, cytoskeleton organisation and experimental outcome that can be potentially exploited towards a new method for cancer stadiation of neuroblastoma cells. PMID- 22528189 TI - Force volume and stiffness tomography investigation on the dynamics of stiff material under bacterial membranes. AB - The determination of the characteristics of micro-organisms in clinical specimens is essential for the rapid diagnosis and treatment of infections. A thorough investigation of the nanoscale properties of bacteria can prove to be a fundamental tool. Indeed, in the latest years, the importance of high resolution analysis of the properties of microbial cell surfaces has been increasingly recognized. Among the techniques available to observe at high resolution specific properties of microscopic samples, the Atomic Force Microscope (AFM) is the most widely used instrument capable to perform morphological and mechanical characterizations of living biological systems. Indeed, AFM can routinely study single cells in physiological conditions and can determine their mechanical properties with a nanometric resolution. Such analyses, coupled with high resolution investigation of their morphological properties, are increasingly used to characterize the state of single cells. In this work, we exploit the capabilities and peculiarities of AFM to analyze the mechanical properties of Escherichia coli in order to evidence with a high spatial resolution the mechanical properties of its structure. In particular, we will show that the bacterial membrane is not mechanically uniform, but contains stiffer areas. The force volume investigations presented in this work evidence for the first time the presence and dynamics of such structures. Such information is also coupled with a novel stiffness tomography technique, suggesting the presence of stiffer structures present underneath the membrane layer that could be associated with bacterial nucleoids. PMID- 22528190 TI - Structural, morphological and nanomechanical characterisation of intermediate states in the ageing of erythrocytes. AB - The study of the mechanical properties of biosystems and the relationship with their biochemical and structural functionality is an increasingly interesting subject of investigation. In recent years, in particular, the use of the atomic force microscopy provides the tools for understanding the molecular basis of the mechanical behaviour of the biosystems. The ageing of erythrocytes [red blood cells (RBCs)] constitutes a particularly interesting subject of study because of its fundamental role in triggering the cell turnover by promoting the removal of malfunctioning RBCs when specific ageing markers appear on their surface. Moreover, it is also interesting to study the role that the variation in the cells mechanical properties plays in the progress of the phenomenon. In this study, the ageing of RBCs, accelerated by depleting the cells of their ATP, has been investigated by two methods. The first is a recently developed nondestructive approach that correlates the roughness of the plasma membrane to the mechanical characteristics and the structural integrity of the cell membrane skeleton. The second consists in directly measuring the nanomechanical properties by acquiring and analysing force curves on the cell membrane. The application of the two methods allowed to define, for the first time, the general scheme of alterations the cells experience during the ageing. In particular, a progressive decrease of the membrane roughness, correlated to a weakening of the membrane skeleton support, and a complex pattern of changes in the nanomechanical properties, which drives the morphological variation and the occurrence of the specific ageing markers on the cells, have been revealed. PMID- 22528191 TI - Software for drift compensation, particle tracking and particle analysis of high speed atomic force microscopy image series. AB - Atomic force microscopy (AFM) image acquisition is performed by raster-scanning a faint tip with respect to the sample by the use of a piezoelectric stage that is guided by a feedback system. This process implies that the resulting images feature particularities that distinguish them from images acquired by other techniques, such as the drift of the piezoelectric elements, the unequal image contrast along the fast- and the slow-scan axes, the physical contact between the tip of nondefinable geometry and the sample, and the feedback parameters. Recently, high-speed AFM (HS-AFM) has been introduced, which allows image acquisition about three orders of magnitude faster (500-100 ms frame rate) than conventional AFM (500 s to 100 s frame rate). HS-AFM produces image sequences, large data sets, which report biological sample dynamics. To analyze these movies, we have developed a software package that (i) adjusts individual scan lines and images to a common contrast and z-scale, (ii) filters specifically those scan lines where increased or insufficient force was applied, (iii) corrects for piezo-scanner drift, (iv) defines particle localization and angular orientation, and (v) performs particle tracking to analyze the lateral and rotation displacement of single molecules. PMID- 22528192 TI - Stiffness changes of tumor HEp2 cells correlates with the inhibition and release of TRAIL-induced apoptosis pathways. AB - Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) is a promising apoptotic agent that can selectively act on tumor cells. However, some cancer cells are resistant to TRAIL mediated apoptosis. In specific type of cells, sensitization by chemotherapeutic drugs may overcome the resistance to TRAIL induced apoptosis. In this work, atomic force microscopy (AFM) nanoindentation spectroscopy combined with fluorescence methods were used to investigate the biomechanical aspects of the resistance and unblocking of apoptosis in larynx carcinoma HEp2 cells treated with TRAIL. It is shown that there is a direct correlation between the increase in mechanical cell stiffness and the inhibition of apoptosis induced by TRAIL in HEp2 cells. Conversely, unblocking of apoptosis by sensitization of HEp2 cells with a chemotherapeutic drug Actinomycin D is related to the depolymerization of F-actin and to the decrease in the cell stiffness. Both effects, that is, changes in the mechanical stiffness of the cell and the inhibition of apoptotic pathway, are closely related to the Bcl-2 activity. Most probably, the depolymerization of F-actin results from downregulation of Rho protein, which in turn is accompanied by a lower activity of Bcl-2 and in consequence releases the intrinsic apoptotic channel. The presented results reveal a promising application of nanoindentation spectroscopy with an AFM tip as a novel tool for monitoring the processes of apoptosis inhibition. PMID- 22528193 TI - Atomic force microscopy characterization of silver nanoparticles interactions with marine diatom cells and extracellular polymeric substance. AB - This study highlights the capacity of atomic force microscopy (AFM) for investigating nanoparticle (NP) algal cell interaction with a subnanometer resolution. We designed a set of AFM experiments to characterize NP size, shape, and structure to visualize changes in the cell morphology induced by NPs and to characterize NP interaction with the extracellular polymeric substance (EPS). Samples for AFM imaging were prepared using the same protocol-drop deposition on mica and imaged in air. Here we address the interactions of Ag NPs with ubiquitous, lightly silicified marine diatoms Cylindrotheca fusiformis and Cylindrotheca closterium and their EPS. In natural seawater used throughout this study, the single Ag NPs adopted truncated tetrahedron morphology with particle heights of 10, 20, 30, and 40 nm. This size class Ag NPs penetrates the cell wall through the valve region built of silica NPs embedded in organic matrix. The Ag NPs cause a local damage inside the cell without disintegration of the cell wall. The EPS production has been shown to increase as a feedback response to Ag NP exposure and may contribute to detoxification mechanisms. Imaging EPS at high resolution revealed the incorporation of Ag NPs and their aggregates into the EPS gel matrix, proving their detoxifying capacity. PMID- 22528195 TI - Moral distress: tensions as springboards for action. AB - In the previous four papers in this series, individual versus structural or contextual factors have informed various understandings of moral distress. In this final paper, we summarize some of the key tensions raised in previous papers and use these tensions as springboards to identify directions for action among practitioners, educators, researchers, policymakers and others. In particular, we recognize the need to more explicitly politicize the concept of moral distress in order to understand how such distress arises from competing values within power dynamics across multiple interrelated contexts from interpersonal to international. We propose that the same socio-political values that tend to individualize and blame people for poor health without regard for social conditions in which health inequities proliferate, hold responsible, individualize and even blame health care providers for the problem of moral distress. Grounded in a critical theoretical perspective of context, definitions of moral distress are re-examined and refined. Finally, recommendations for action that emerge from a re-conceptualized understanding of moral distress are provided. PMID- 22528196 TI - Single gene disorders associated with stroke: a review and update on treatment options. AB - OPINION STATEMENT: Single gene stroke disorders are rare but important to consider in the differential diagnosis of cryptogenic stroke. The identification of these disorders has a significant prognostic value and may be instrumental in the development of an appropriate stroke prevention plan. In this review we summarize the clinical features, diagnosis, and treatment of the following single gene disorders: cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL); cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL); Fabry disease; sickle cell disease; and mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). PMID- 22528197 TI - Halogen-arene interactions assist in self-assembly of dyes. PMID- 22528198 TI - How parents of adolescents store and monitor alcohol in the home. AB - In this study, we explored how and where parents store alcohol in the home, and how they monitor this stored alcohol. In-depth, semi-structured interviews were conducted with parents of youths, aged 15-18 years, in northern California. We found that parents typically stored alcohol in unsecured locations easily accessible to adolescents. Parental monitoring of alcohol included counting or marking bottles and hiding alcohol. However, parents reported that they relied primarily on their memory and intuition to monitor alcohol and admitted that they would not notice if small amounts of alcohol disappeared. PMID- 22528199 TI - The Knowledge of Effective Parenting Scale (KEPS): a tool for public health approaches to universal parenting programs. AB - Improving the knowledge, skills, and confidence of parents is often the aim of parenting-focused public health strategies and parenting programs, yet research on parental knowledge is limited compared with research on other parenting variables. In this study, a nonclinical sample of 62 parents of children aged 2-3 years was assessed for knowledge of child development processes and milestones [using the Knowledge of Infant Development Inventory (KIDI)] and knowledge of effective parenting strategies [using the Knowledge of Effective Parenting Scale (KEPS)], along with self-reported measures of parenting dysfunction and nurturance, parental confidence, parental affective state, and problematic child behavior. Additionally, in-home observations of parent-child interactions were conducted with dependent measures of aversive and non-aversive parent behavior, a composite measure of parenting competence, and aversive child behavior. Results showed that KEPS scores were significantly negatively related to self-reported parenting dysfunction, internalized problematic child behavior, and parental anxiety, and positively related to observed parenting competence. Knowledge as assessed by the KIDI was significantly positively associated only with KEPS scores. These results suggest that increasing parental knowledge of effective parenting strategies at a population level is likely to be more beneficial to parents than increasing their knowledge of child development processes and milestones. PMID- 22528200 TI - Axial imidazole binding strengths in porphyrinoid cobalt(III) complexes as studied by tandem mass spectrometry. AB - The Co(II) complexes of twelve meso-tetraaryl-porphyrins, -chlorins, and chlorin analogues containing non-pyrrolic heterocycles were synthesized and converted in situ to the corresponding Co(III) complexes coordinated to one or two imidazoles. Electrospray ionization tandem mass spectrometry (ESI-MS/MS) in conjunction with the energy-variable collision-induced dissociation (CID) technique was used to compare the relative gas-phase binding strength of the axially coordinated imidazoles to the octahedral and square planar Co(III) porphyrinoid complex ions. The observed binding energies of these ligands were rationalized in terms of the effects of porphyrinoid core structure and meso-substitution on the electron density on the central Co(III) centers. Some of these trends were supported by DFT-based computational studies. The study highlights to which extend porphyrins vary from chlorins and chlorin analogues in their coordination abilities and to which extraordinary degree meso-thienyl-substituents influence the electronic structure of porphyrins. The study also defines further the scope and limits CID experiments can be used to interrogate the electronic structures of metalloporphyrin complexes. PMID- 22528201 TI - Specific interaction between negative atmospheric ions and organic compounds in atmospheric pressure corona discharge ionization mass spectrometry. AB - The interaction between negative atmospheric ions and various types of organic compounds were investigated using atmospheric pressure corona discharge ionization (APCDI) mass spectrometry. Atmospheric negative ions such as O(2)(-), HCO(3)(-), COO(-)(COOH), NO(2)(-), NO(3)(-), and NO(3)(-)(HNO(3)) having different proton affinities served as the reactant ions for analyte ionization in APCDI in negative-ion mode. The individual atmospheric ions specifically ionized aliphatic and aromatic compounds with various functional groups as atmospheric ion adducts and deprotonated analytes. The formation of the atmospheric ion adducts under certain discharge conditions is most likely attributable to the affinity between the analyte and atmospheric ion and the concentration of the atmospheric ion produced under these conditions. The deprotonated analytes, in contrast, were generated from the adducts of the atmospheric ions with higher proton affinity attributable to efficient proton abstraction from the analyte by the atmospheric ion. PMID- 22528202 TI - Secondary electrospray ionization of complex vapor mixtures. Theoretical and experimental approach. AB - In secondary electrospray ionization (SESI) systems, gaseous analytes exposed to an electrospray plume become ionized after charge is transferred from the charging electrosprayed particles (the charging agent) to the vapor species. Currently available SESI models are valid for simplified systems having only one type of electrosprayed species, which ionizes only one single vapor species, and for the limit of low vapor concentration. More realistic models require considering other effects. Here we develop a theoretical model that accounts for the effects of high vapor concentration, saturation effects, interferences between different vapor species, and electrosprays producing different types of species from the liquid phase. In spite of the relatively high complexity of the problem, we find simple relations between the different ionic species concentrations that hold independently of the particular ion source configuration. Our model suggests that an ideal SESI system should use highly concentrated charging agents composed preferably of only one dominating species with low mobility. Experimental measurements with a MeOH-H(2)O-NH(3) electrospray and a mixture of fatty acids and lactic acid served to test the theory, which gives good qualitative results. These results also suggest that the SESI ionization mechanism is primarily based on ions rather than on charged droplets. PMID- 22528203 TI - Improved sequence resolution by global analysis of overlapped peptides in hydrogen/deuterium exchange mass spectrometry. AB - Management of the enormous amount of data produced during solution-phase hydrogen/deuterium exchange monitored by mass spectrometry has stimulated software analysis development. The proteolysis step of the experiment generates multiple peptide fragments, most of which overlap. Prior automated data reduction algorithms extract the deuteration level for individual peptides, but do not exploit the additional information arising from fragment overlap. Here, we describe an algorithm that determines discrete rate constant values to each of the amide hydrogens in overlapped fragments. By considering all of the overlapped peptide segments simultaneously, sequence resolution can be improved significantly, sometimes to the individual amino acid level. We have validated the method with simulated deuterium uptake data for seven overlapped fragments of a poly-Ala nonapeptide, and then applied it to extract rate constant values for the first 29 N-terminal amino acids of C22A FK506-binding protein. PMID- 22528204 TI - Radical a-ions in electron capture dissociation: on the origin of species. AB - Radical a* ions appear in electron capture dissociation mass spectra sporadically, but sometimes with high intensity. Mechanistically, radical a ions are hypothesized to arise due to thermodynamically disadvantaged charge solvation on the backbone nitrogen (instead of carbonyl), which upon neutralization produces a hypervalent group instantly fragmenting into a radical b* and conventional y' ion. The former species is unstable and, after releasing a CO molecule, decays to an a* ion. Here we validate this scenario by direct observation of the complementarity of a* and y' ions by interrogation of an ECD MS/MS database of >10,000 doubly and >5,000 triply charged tryptic peptides. Intriguingly, the most abundant a*/y' pairs are found to come from the cleavage of the same backbone link as the most abundant c' and z* complementary ions. This result gives strong support to the "local" N-Calpha bond cleavage mechanism, in which the dissociation occurs at the site of charge solvation. However, a second strong peak is observed in the c'/z* fragment distribution four residues away from the a*/y' cleavage, which supports the indirect N-Calpha bond cleavage mechanism. The size distribution of a ions from doubly (but not triply!) charged precursors shows deficit of a3 ions, and possibly a6 ions. PMID- 22528205 TI - Conformational distribution of bradykinin [bk + 2 H]2+ revealed by cold ion spectroscopy coupled with FAIMS. AB - We employ cold ion spectroscopy (CIS) in conjunction with high-field asymmetric waveform ion mobility spectrometry (FAIMS) to study the peptide bradykinin in its doubly protonated charge state ([bk + 2 H](2+)). Using FAIMS, we partially separate the electrosprayed [bk + 2 H](2+) ions into two conformational families and selectively introduce one of them at a time into a cold ion trap mass spectrometer, where we probe them by UV photofragment spectroscopy. Although the two conformational families have distinct electronic spectra, some cross conformer contamination can be observed under certain conditions. We demonstrate that this contamination comes from isomerization of ions energized during and/or after their separation and not from incomplete separation of the initially electrosprayed conformations in the FAIMS stage. By varying the injection voltage of the ions into our mass spectrometer, we can intentionally induce isomerization to produce what seems to be a gas phase equilibrium distribution of conformers. This distribution is different from the one produced initially by electrospray, indicating that some of the conformers are kinetically trapped and may be related to conformers that are more favored in solution. PMID- 22528206 TI - Membrane-based continuous remover of trifluoroacetic acid in mobile phase for LC ESI-MS analysis of small molecules and proteins. AB - We developed a "continuous" trifluoroacetic acid (TFA) remover based on electrodialysis with bipolar membrane for online coupling of liquid chromatography (LC) and electrospray ionization mass spectrometry (ESI-MS) using TFA containing mobile phase. With the TFA remover as an interface, the TFA anion in the mobile phase was removed based on electrodialysis mechanism, and meanwhile, the anion exchange membrane was self-regenerated by the hydroxide ions produced by the bipolar membrane. So the remover could continuously work without any additional regeneration process. The established LC-TFA remover-MS system has been successfully applied for the qualitative and quantitative analysis of small molecules as well as proteins. PMID- 22528207 TI - Shedding light on large-scale chromatin reorganization in Arabidopsis thaliana. AB - Plants need to respond quickly and appropriately to various types of light signals from the environment to optimize growth and development. The immediate response to shading, reduced photon flux (low light), and changes in spectral quality involves changes in gene regulation. In the case of more persistent shade, the plant shows a dramatic change in the organization of chromatin. Both plant responses are controlled via photoreceptor signaling proteins. Recently, several studies have revealed similar features of chromatin reorganization in response to various abiotic and biotic signals, while others have unveiled intricate molecular networks of light signaling towards gene regulation. This opinion paper briefly describes the chromatin (de)compaction response from a light-signaling perspective to provide a link between chromatin and the molecular network of photoreceptors and E3 ubiquitin ligase complexes. PMID- 22528208 TI - Changes in mental health and quality of life with dental implants as evaluated by General Health Questionnaire (GHQ) and Health Utilities Index (HUI). AB - OBJECTIVES: The purpose of this study was to assess and compare the improvement in oral and systemic conditions and health-related quality of life in patients with missing teeth receiving dental implants and conventional treatment. METHODS: A total of 97 patients with missing teeth, of whom 59 received dental implants and 38 received conventional treatment, were included in this study. The patients were divided into two age groups for a more detailed analysis: a 30- to 59-year age group (young) and a >60-year age group. The changes in oral condition, mental health, and health utility level before and after (pre- and post-, respectively) the procedures were assessed using an original questionnaire, the General Health Questionnaire 12 (GHQ12), and Health Utilities Index Mark 3. RESULTS: Responses to the GHQ12 indicated that treatment with implants significantly improved the oral health of patients in all treatment groups, except for the young group receiving partial dentures (PD). The mental state improved with a lower GHQ score; in terms of pre- versus post-procedure, mental state improved after the procedure in the young group receiving full dentures (FD) (1.75 +/- 2.12 vs. 0.88 +/- 2.10, p < 0.05), in the old group receiving PD (2.61 +/- 3.91 vs. 0.72 +/- 1.71, p < 0.05), and in the old group receiving FD (2.63 +/- 3.12 vs. 0.44 +/- 0.27, p < 0.05). The sleep score also improved by implant in FD of the old group (2.00 vs. 1.00, p < 0.05); it also is better with a lower score. CONCLUSIONS: Recovery of oral function and oral stability in middle-aged people who did not receive implants was possible with PD. However, the results suggest that implant treatment in edentulous denture cases and particularly in elderly people with dentures has a certain efficacy on the physical condition mediated through an improvement in aspects of the mental state. PMID- 22528209 TI - Lead in the Japanese living environment. AB - Lead has long been known to be a neurotoxic heavy metal, particularly in the context of occupational health. However, its adverse effect on the cognitive development of children at lower exposure levels has only recently received attention. Although the exposure level of contemporary Japanese children is among the lowest in the world, it is desirable to reduce exposure as much as reasonably possible due to the absence of a threshold of exposure for adverse effects. In this review, information on lead levels in milieus of our proximate environment, such as the atmosphere, drinking water, soil, house dust, diet and others, of contemporary Japan was compiled with the aim of updating our knowledge on lead distribution. Monitoring data demonstrates that lead concentrations in the atmosphere and lead intake from food consumption have decreased substantially from the 1970s. Lead was hardly detectable in tap water in a recent nation-wide monitoring survey. To the contrary, elevated lead concentrations were detected in surface soil and house dust in one of the studies on daily exposure to lead from all potential sources, and both of these sources were regarded by the authors as significant contributors of lead exposure to general Japanese children. A similar study indicated that diet is the sole major source of lead for Japanese children. A significant difference was present in the estimated dietary lead intake levels in different studies, resulting in significant discrepancies in the current knowledge on lead in our environment. Further studies are warranted to identify the major source(s) of lead exposure in Japanese children in order to establish an effective countermeasure to reduce lead exposure to children. PMID- 22528210 TI - Current status of and factors associated with social isolation in the elderly living in a rapidly aging housing estate community. AB - OBJECTIVES: The aim of this study was to examine social isolation development among elderly persons living in a rapidly aging housing estate community in terms of the frequency of activities of daily living outside the home and social contact with neighbors and to identify associated factors. METHODS: A self administered questionnaire survey was conducted in 2007 (102 subjects) and 2010 (104 subjects) involving elderly residents living on a suburban housing estate. The data collected on the 87 subjects who responded to both surveys were analyzed. The survey investigated physical, psychological, and social factors regarded as being associated with social isolation. The subjects were divided into four social types according to the frequency of activities of daily living outside the home and social contact with neighbors. Multiple logistic regression analysis involved would-be-isolated and non-isolated groups as dependent variables and each factor as an independent variable. RESULTS: Isolated group subjects increased from 2.3 to 7.0 % during the study period, with the would-be isolated group accounting for 33.7 % of the study population in both years. Factors strongly associated with the would-be-isolated group were a low subjective sense of well-being and socioeconomic status were identified in 2007, and an older age, low subjective sense of socioeconomic status, and no provision of emotional support in 2010. CONCLUSIONS: The health condition and social well being of the elderly on a rapidly aging housing estate community tended to decline, revealing that the number of isolated and would-be-isolated subjects is increasing. Taking preventive action against social isolation among the elderly population is essential, suggesting the need to combine community health promotion and social communication interventions and to develop programs aimed at providing opportunities for elderly persons to be emotional support providers. PMID- 22528211 TI - Mortality and its predictors in severe bulimia nervosa patients. AB - BACKGROUND: The risk of mortality remains unclear for bulimia nervosa (BN) patients, especially the most severe. The aims of this study were to improve knowledge on BN and mortality. METHODS: With initial evaluation at admission, 258 BN (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) consecutive inpatients were included (1988-2004). Vital status was established from the French national register. Standardized Mortality Ratio (SMR) calculation and bivariate Cox analysis were performed for the hypothesised predictors of mortality. RESULTS: Mean follow-up duration was 10.5 years. Ten deaths were recorded, and the crude mortality ratio was 3.9%; SMR = 5.52 [CI95 (2.64-10.15)]. The majority of deaths were from suicide [6/10, SMR = 30.9 (5.7-68.7)]. The mean age at time of death was 29.6 years. Predictive factors were previous suicide attempt and low minimum BMI. CONCLUSIONS: Severe BN patients are at higher risk of death (mainly suicide) especially if previous suicide attempt or previous low BMI. More studies are needed to confirm these results. PMID- 22528212 TI - Different mechanisms of action of poly(ethylene glycol) and arginine on thermal inactivation of lysozyme and ribonuclease A. AB - Proteins tend to undergo irreversible inactivation through several chemical modifications, which is a serious problem in various fields. We have recently found that arginine (Arg) suppresses heat-induced deamidation and beta elimination, resulting in the suppression of thermal inactivation of hen egg white lysozyme and bovine pancreas ribonuclease A. Here, we report that poly(ethylene glycol) (PEG) with molecular weight 1,000 acts as a thermoinactivation suppressor for both proteins, especially at higher protein concentrations, while Arg was not effective at higher protein concentrations. This difference suggests that PEG, but not Arg, effectively inhibited intermolecular disulfide exchange among thermally denatured proteins. Investigation of the effects of various polymers including PEG with different molecular weight, poly(vinylpyrolidone) (PVP), and poly(vinyl alcohol) on thermoinactivation of proteins, circular dichroism, solution viscosity, and the solubility of reduced and S-carboxy-methylated lysozyme indicated that amphiphilic PEG and PVP inhibit intermolecular collision of thermally denatured proteins by preferential interaction with thermally denatured proteins, resulting in the inhibition of intermolecular disulfide exchange. These findings regarding the different mechanisms of the effects of amphiphilic polymers--PEG and PVP--and Arg would expand the capabilities of methods to improve the chemical stability of proteins in solution. PMID- 22528213 TI - Availability and quality of emergency obstetric care, an alternative strategy to reduce maternal mortality: experience of Tongji Hospital, Wuhan, China. AB - The burden of maternal mortality (MM) and morbidity is especially high in Asia. However, China has made significant progress in reducing MM over the past two decades, and hence maternal death rate has declined considerably in last decade. To analyze availability and quality of emergency obstetric care (EmOC) received by women at Tongji Hospital, Wuhan, China, this study retrospectively analyzed various pregnancy-related complications at the hospital from 2000 to 2009. Two baseline periods of equal length were used for the comparison of variables. A total of 11 223 obstetric complications leading to MM were identified on a total of 15 730 hospitalizations, either 71.35% of all activities. No maternal death was recorded. Mean age of women was 29.31 years with a wide range of 14-52 years. About 96.26% of women had higher levels of schooling, university degrees and above and received the education of secondary school or college. About 3.74% received primary education at period two (P2) from 2005 to 2009, which was significantly higher than that of period one (P1) from 2000 to 2004 (P<0.05) (OR: 0.586; 95% CI: 0.442 to 0.776). About 65.69% were employed as skilled or professional workers at P2, which was significantly higher than that of P1 (P<0.05). About 34.31% were unskilled workers at P2, which was significantly higher than that of P1 (P<0.05). Caesarean section was performed for 9,930 women (88.48%) and the percentage of the procedure increased significantly from 19.25% at P1 to 69.23% at P2 (P<0.05). We were led to conclude that, despite the progress, significant gaps in the performance of maternal health services between rural and urban areas remain. However, MM reduction can be achieved in China. Priorities must include, but not limited to the following: secondary healthcare development, health policy and management, strengthening primary healthcare services. PMID- 22528214 TI - Service functions of private community health stations in China: A comparison analysis with government-sponsored community health stations. AB - In China, with the restructuring of health care system moving forward, private community health facilities have been playing a complementary but increasingly important role in providing public health and basic medical care services in urban areas. However, only limited evidence is available concerning the service functions of private community health facilities in China. The aim of this study was to explore the functions of private community health stations (PCHSs) to provide evidence-based recommendations for policy-making and practice in the development of urban community health services systems. A total of 818 PCHSs and 4320 government-sponsored community health stations (GCHSs) located in 28 cities of China were investigated in 2008. The percentages of stations that provided health services and the annual workload per community health worker (CHW) were compared between the two types of institutions. The results showed that the percentages of PCHSs providing public health services were significantly higher than those of GCHSs (P<0.05); but no significant differences were found in the percentages of basic medical services providing between PCHSs and GCHSs (P>0.05). The annual workloads of all the public health services and basic medical services per CHW in PCHSs were lighter than those in GCHSs (P<0.05), except for resident health records establishment and health education materials distribution (P>0.05). At present, the GCHSs are still the mainstream in urban China, which will last for a long period in future. However, our findings showed that the annual workloads of CHWs in PCHSs were no heavier than those in GCHSs, and the PCHSs were willing to provide public health services. In view of current inadequacy of health resources in China, it is feasible to further develop PCHSs under the guidance of the government, given that PCHSs can perform the basic functions of community health services, which is useful for the formation of public-private partnerships (PPP) and the improvement of community health services. PMID- 22528215 TI - Enhanced effects of TRAIL-endostatin-based double-gene-radiotherapy on suppressing growth, promoting apoptosis and inducing cell cycle arrest in vascular endothelial cells. AB - This study examined the effects of TRAIL-endostatin-based gene-radiotherapy on cellular growth, apoptosis and cell cycle progression in human vascular endothelial cells ECV304 in vitro. The expression of TRAIL and endostatin protein in ECV304 cells was detected by ELISA after the transfection of recombinant plasmid pshuttle-Egr1-shTRAIL-shES and X-ray irradiation. Then MTT assay was used for determining the cellular proliferation, and flow cytometry (FCM) plus Annexin V and propidium iodide (PI) double-staining or PI single-staining were employed for the detection of apoptosis and cell cycle progression. The results showed that expression of TRAIL and endostatin protein exhibited a time- and dose dependent change in ECV304 cells after pshuttle-Egr1-shTRAIL-shES transfection in conjunction with irradiation. In the TRAIL-endostatin-based single- or double gene-radiotherapy, the cell viability declined in a time- and dose-dependent manner, the percentage of cells at G(2)/M phase and apoptotic rate was increased, and the percentage of cells at G(0)/G(1) phase was lowered as compared with those receiving radiotherapy alone. Moreover, TRAIL-endostatin-based double-gene radiotherapy demonstrated better effects on growth inhibition, promotion of apoptosis and induction of cell cycle arrest in ECV304 cells than single-gene radiotherapy. PMID- 22528216 TI - Co-culture of mesenchymal stem cells with umbilical vein endothelial cells under hypoxic condition. AB - By co-culturing humm mesenchymal stem cells (hMSCs) and human umbilical rein endothelial cells (HUVECs) under hypoxia and creating a microenvironment similar to that of transplanted hMSCs for the treatment of avascular ni ANFH, the effect of hMSCs on survival, apoptosis, migration and angiogenesis of human umbilical vein endothelial cells (HUVECs) under the hypoxic condition were investigated in vitro. hMSCs and HUVECs were cultured and identified in vitro. Three kinds of conditioned media, CdM-CdM(NOR), CdM-CdM(HYP) and HUVEC-CdM(HYP) were prepared. HUVECs were cultured with these conditioned media under hypoxia. The survival rate, apoptosis rate, migration and angiogenesis of HUVECs were respectively detected by CCK-8, flow cytometry, Transwell and tube formation assay. The content of SDF-1alpha, VEGF and IL-6 in CdM was determined by ELISA. Our results showed that hMSCs and HUVECs were cultured and identified successfully. Compared with MSC-CdM(NOR) and HUVEC-CdM(HYP) groups, the survival rate, migration and angiogenesis of HUVECs in MSC-CdM(HYP) group were significantly increased while the apoptosis rate was declined (P<0.05). Moreover, the expression of SDF-1alpha, VEGF and IL-6 in MSC-CdM(HYP) group was up-regulated. Under hypoxia, the apoptosis of HUVECs was inhibited while survival, migration and angiogenesis were improved by co-culture of hMSCs and HUVECs. The underlying mechanism may be that hMSCs could secrete a number of cytokines and improve niche, which might be helpful in the treatment of femoral head necrosis. PMID- 22528217 TI - Astilbin inhibits proliferation of rat aortic smooth muscle cells induced by angiotensin II and down-regulates expression of protooncogene. AB - This study examined the effect of astilbin on the proliferation of rat aortic smooth muscle cells (RASMCs) induced by angiotensin II (AngII) and explored the possible mechanisms. Cell proliferation model of RASMCs was induced by treatmente with AngII. Cells were randomly divided to 8 groups. Normally cultured VSMCs serves as blank control group; in AngII model group, cells were treated with AngII at 10(-7) mol/L; in three astilbin groups, cells were treated with 10, 15, 30 mg/L of astilbin; in three AngII+astilbin groups, cells were treated with AngII (at 10(-7) mol/L) and astilbin at 10, 15, 30 mg/L. Cell proliferation ability was detected by MTT method and the cell cycles and proliferation index were flow cytometrically determined. The expression of c-myc mRNA was assessed by using reverse transcription polymerase chain reaction (RT-PCR), and the expression of NF-kappaB in RASMCs was immunocytochemically observed. Our results showed that MTT metabolism in RASMCs in the basic and AngII stimulated situation was inhibited by astilbin, and the cells numbers of G(0)/G(1) phase were increased and that of G(2)/S phase were decreased markedly. Not only highly expression of c-myc gene stimulated by AngII could be inhibited by Astilbin significantly, but also the expression of NF-kappaB protein can be down regulated by Astilbin. We are led to conclude that astilbin astilbin can inhibit the AngII mediated proliferation of RASMCs by blocking the transition of RASMCs from G(0)/G(1) phase to S phase and by down-regulating the expression of NF-kappaB, c myc gene. PMID- 22528218 TI - Surfactant protein a polymorphism is associated with susceptibility to chronic obstructive pulmonary disease in Chinese Uighur population. AB - This study investigated the correlation between surfactant protein-A (SP-A) polymorphism and the susceptibility of chronic obstructive pulmonary disease (COPD) in Xinjiang Uighurs. Genomic DNA was extracted from peripheral blood of 194 COPD smokers and 201 healthy smokers of Uighur who were hospitalized in or paid a visit to one of the four Xinjiang-based hospitals involved in the study, from March 2009 to December 2010. Single nucleotide polymorphisms (SNPs) were studied at aa62 (CCA/CCG rs1136451) and aa219 (CGG/TGG, rs4253527) in SP-A. Genotypes were determined by using the TaqMan polymerase chain reaction (PCR). Our results showed that genotype frequencies were different between the COPD and normal smokers in aa62 (x (2)=6.852, P=0.033). There were also significant differences in allele genotype frequencies between the COPD and the control and allele G might decrease the risk COPD (x (2)=6.545, P=0.011; OR=0.663; 95% CI: 0.484-0.909). The result suggested that polymorphism of aa62 (CCA/CCG, rs1136451) of SP-A may be associated with the susceptibility to COPD in Xinjiang Uighurs. PMID- 22528219 TI - Reduced expression of the LRP16 gene in mouse insulinoma (MIN6) cells exerts multiple effects on insulin content, proliferation and apoptosis. AB - This study assessed the effects of leukemia-related protein 16 (LRP16) on the regulation of pancreatic functions in mouse insulinoma (MIN6) cells. Cells with down-regulated expression of LRP16 were obtained by a shRNA interference strategy. Insulin content and glucose-stimulated insulin secretion (GSIS) were examined by radioimmunoassay. Western blotting was applied to detect protein expression. Glucose-stimulated sub-cellular localization of PDX-1 was immunocytochemically determined. Cell proliferation and apoptosis were detected by flow cytometry. Our results showed that LRP16 regulated insulin content in MIN6 cells by controlling expression of insulin and insulin transcription factors. LRP16 gene silence in MIN6 cells led to reduced cell proliferation and increased apoptosis. The observation of phosphorylation of serine-473 Akt and the localization of PDX-1 to the nucleus under glucose-stimulation exhibited that LRP16 was a component mediating Akt signaling in MIN6 cells. These results suggest that LRP16 plays a key role in maintaining pancreatic beta-cell functions and may help us to understand the protective effects of estrogen on the functions of pancreatic beta-cells. PMID- 22528220 TI - Effects of long-term administration of low-dose FTY720 on survival of murine cardiac allograft. AB - This study examined the effect of long-term administration of low-dose FTY720 on survival of murine cardiac allograft and the possible mechanism. Murine models of abdominal heterotopic heart transplantation were established. Low-dose FTY720 (0.3 mg/kg) was administrated to the animals 4 days before the transplantation of cardiac allografts until the occurrence of rejection or the observation terminals. The animals without FTY720 treatment and those with syngeneic cardiac grafts transplanted served as controls. The mean survival time (MST) of grafts, and T lymphocyte subsets in grafts, peripheral blood and lymphoid organs were measured by histopathological examination or flow cytometry, and compared among groups. The results showed that the MST of allografts in FTY720-treated mice was more than 40 days, significantly longer than that in the untreated group (MST=8 days, P<0.01). After the long-term administration of FTY720, the proportion of CD4(+) and CD8(+) lymphocytes in peripheral blood was diminished significantly, but the proportion of CD4(+) lymphocytes was increased in mesenteric lymph nodes (MLNs) and spleen. Immunofluorescence staining revealed that the infiltration of CD4(+) and CD8(+) lymphocytes in allografts was significantly inhibited after long-term administration of low-dose FTY720. It was concluded that low-dose long term administration of FTY720 could promote T lymphocytes in lymphatic organs and decrease their infiltration in allografts, resulting in the inhibition of rejection and the long-term survival of allografts. PMID- 22528221 TI - Treatment of complicated hepatic cystic hydatidosis with intrabiliary rupture by pericystectomy in combination with Roux-en-Y hepaticojejunostomy. AB - This study retrospectively reviewed 9 cases of complicated hepatic cystic hydatidosis with intrabiliary rupture who were surgically treated with pericystectomy in combination with Roux-en-Y hepaticojejunostomy in our hospital from 2004 to 2010. The clinical features, results of laboratory tests, B-mode ultrasonography and CT, post-operative recovery, days of hospital stay after the operation and post-operative complications were statistically analyzed and the patients were followed up. The subjects in our series included 7 males and 2 females, whose average age was 50.78+/-7.58 years. Before operation, 9 patients suffered from pain of the right upper quadrant and jaundice, which, in 4 cases (44.45%), were accompanied with fever and chills. Preoperative B-mode ultrosonography and CT showed that all the 9 patients had single hydatid cyst, with their diameter being 9.33+/-1.58 cm on average. The lesions involved segments V, VI in 6 cases, and segment IV in 3 cases. By WHO classification, 7 cases were classified as CE3 and 2 cases as CE4. They all had choledochectasia. The subjects underwent the surgery uneventfully. Intraoperatively, 2-4 biliary fistula orifices were found, with the average of the orifice being (0.79+/-0.20) cm. After the operation, one patient developed incision infection, one had pulmonary infection and one suffered from reflux cholangitis. No anastomotic leaks or peri-operative deaths took place and follow-up revealed no recurrence and implantative metastasis. We are led to conclude that pericystectomy in combination with Roux-en-Y hepaticojejunostomy can achieve satisfactory results for the treatment of complicated hepatic cystic hydatidosis with intrabiliary rupture. PMID- 22528222 TI - Correlation between osteoporosis and degeneration of intervertebral discs in aging rats. AB - This study examined the correlation between osteoporosis and the degeneration of intervertebral discs. Sprague-Dawley rats were maintained up to 22 or 28 months. The femoral bone, tibial bone and lumbar vertebra were histologically studied and the expression of collagen type II and X in intervertebral discs was immunohistochemiscally determined. Several indices for the degeneration of intervertebral discs and osteoporosis and the correlation among them were then analyzed. Close correlations were found among the indices for the degeneration of intervertebral discs, including the relative area of the vascular bud, the ratio of the uncalcified and the calcified layers, the expression of collagen type II and X. The correlation with collagen type X was negative. There existed positive correlations among the indices for osteoporosis, including the thickness ratio of cortical bone, the relative area of bone trabecula, the density of femoral and vertebral body bones, and the maximum stress and strain on bone. Analysis on the relationship of osteoporosis and the disease on disc showed that the indices of osteoporosis were negatively correlated with the indices of the degeneration of intervertebral discs but the expression of collagen type X was positively correlated, with the density of vertebral body bones having the strongest dependence on collagen type X. The maximum stress and strain bore no correlation with the degeneration of intervertebral discs. These results suggest that osteoporosis was negatively correlated with the degeneration of intervertebral discs. PMID- 22528223 TI - Laterodorsal tegmentum and pedunculopontine tegmental nucleus circuits regulate renal functions: Neuroanatomical evidence in mice models. AB - Neurons in the laterodorsal tegmentum (LDTg) and pedunculopontine tegmental nucleus (PPTg) play important roles in central autonomic circuits of the kidney. In this study, we used a combination of retrograde tracers pseudorabies virus (PRV)-614 and fluorescence immunohistochemistry to characterize the neuroanatomic substrate of PPTg and LDTg innervating the kidney in the mouse. PRV-614-infected neurons were retrogradely labeled in the rostral and middle parts of LDTg, and the middle and caudal parts of PPTg after tracer injection in the kidney. PRV 614/TPH double-labeled neurons were mainly localized in the rostral of LDTg, whereas PRV-614/TH neurons were scattered within the three parts of LDTg. PRV 614/TPH and PRV-614/TH neurons were located predominantly in the caudal of PPTg (cPPTg). These data provided direct neuroanatomical foundation for the identification of serotonergic and catecholaminergic projections from the mid brain tegmentum to the kidney. PMID- 22528224 TI - Tamoxifen induces apoptosis of mouse microglia cell line BV-2 cells via both mitochondrial and death receptor pathways. AB - Little is known about whether tamoxifen (TAM) can affect resting state microglia apoptosis and about the cellular mechanism that may account for this. To explore this question, we incubated the microglia cell line BV-2 cells with TAM at different concentrations. Cell viability was assessed by the MTT assay, and flow cytometric analysis was performed to detect the cell apoptosis rate. Furthermore, mitochondrial membrane potential (Deltapsim) was tested by flow cytometry, and Bax, Bcl-2, Fas, and Fas-L expression was detected by Western blot. The results demonstrated that TAM decreased cell viability and induced apoptosis of BV-2 cells in a concentration- and time-dependent manner. In addition, disruption of Deltapsim was followed by up-regulated expression of pro-apoptotic Bax, Fas and Fas-L, and down-regulated expression of anti-apoptotic Bcl-2. These results indicate that TAM may induce apoptosis of BV-2 cells through both mitochondria- and death receptor-mediated pathways. PMID- 22528225 TI - Effects of RNAi-mediated gene silencing of LRIG1 on proliferation and invasion of glioma cells. AB - The effects of RNAi-mediated gene silencing of LRlG1 on proliferation and invasion of the human glioma cell line U251-MG and the possible mechanisms were explored in this study. The plasmids pGenesil2-LRIG1-shRNA1 and pGenesil2-LRIG1 shRNA2 were transfected into U251-MG glioma cells respectively by using Lipofectamine 2000 and the transfected cells in which the LRIG1 expression was stably suppressed were selected by G418. The cells transfected with negative shRNA served as control. The expression levels of LRIG1 mRNA and protein were measured by qRT-PCR and Western blotting, respectively. The cell cycle was analyzed by flow cytometry. The results showed that LRIG1 mRNA expression was reduced by 70% and 58% and LRIG1 protein expression by 58% and 26% in U251-MG cells transfected with pGenesil2-LRIG1-shRNAl and pGenesil2-LRIG1-shRNA2 relative to the negative shRNA-transfected U251-MG cells. The proliferative capacity of the LRIG1 specific siRNA-transfected cells was stronger than that of control cells. Cell cycle analysis showed that silencing LRIG1 significantly increased the percentage of S phase cells and the proliferation index (P<0.01). Moreover, silencing LRIG1 could promote the invasion of U251-MG cells (P<0.05). These findings suggested that LRIG1-targeting siRNA can exert a dramatically inhibitory effect on RNA transcription and protein expression of LRIG1, and LRIG1 down regulation could promote the proliferation of U251-MG cells, arrest U251-MG cells in S phase, and enhance the invasion of U251-MG cells. PMID- 22528226 TI - Effect of Smac on TRAIL-induced apoptosis of prostate cancer cell line PC-3 and the molecular mechanism. AB - The effect of Smac gene on the TRAIL-induced apoptosis of the prostate cancer cell line PC-3 and the molecular mechanism were investigated. The Smac gene was transfected into PC-3 cells under the induction of liposome. The intrinsic Smac gene expression was detected by Western blotting. After treatment with TRAIL as an apoptosis inducer, in vitro cell growth activity was assayed by MTT colorimetry. The apoptosis rate of PC-3 cells was determined by annexin V-FITC and propidium iodide staining flow cytometry. The expression of cellular XIAP and caspase-3 genes was examined by Western blotting. Smac-transfected cells (PC 3/Smac group) had significantly increased Smac protein level as compared with PC 3 controls (P<0.01). After induction with 100-200 ng/mL TRAIL for 12-36 h, cellular proliferation rate in PC-3/Smac group was significantly lower than in PC 3 controls (P<0.05). After induction with 100 ng/mL TRAIL for 24 h, the apoptosis rate in PC-3/Smac group was significantly enhanced as compared with that of PC-3 controls (P<0.05). Accordingly, the XIAP expression level was down-regulated significantly (P<0.05) and caspase-3 subunit P20 was up-regulated significantly (P<0.05). It is suggested that the over-expression of cellular Smac can inhibit inhibitor of apoptosis proteins (IAPs), enhance caspases activity and the apoptosis rate of PC-3 cells induced by TRAIL, which may provide a useful experimental basis for prostate cancer therapy. PMID- 22528227 TI - Impact of 4HPR on the expression of E-Cad in human bladder transitional epithelial cancer cells T24. AB - Previous researches showed that the expression level of E-Cad in most infiltrating cancer cells was reduced or negative. This study explored whether 4HPR restrained the infiltration of bladder cancer cells through regulating the expression of E-Cad. The infiltrating bladder cancer cells T24 were cultured, and then treated by a proper dosage of drug. Their viability was a determined by MTT method. Western blotting and RT-PCR were adopted to detect the changes of E-Cad gene expression at both protein and mRNA levels. Moreover, immunofluorescent staining and confocal fluorescence microscopy were employed for the observation of the expression of E-Cad. The result showed that, at both mRNA and protein levels, the expression level of E-Cad in T24 cells treated by 4HPR was significantly higher than that of control group, while the beta-Cat expression was also relocated from the cell nucleus to cytoplasm. Our findings suggested that the regulatory function of 4HPR on infiltration of bladder cancer cells T24 is at least partly achieved by regulating the expression of E-Cad. PMID- 22528228 TI - Implication of expression of Nanog in prostate cancer cells and their stem cells. AB - Recent studies suggested that the prostate cancer may arise from prostate cancer stem cells that share some same characteristics with normal stem cells. The purpose of this study was to detect the differences of Nanog expression between PC3 prostate cancer cell line and its tumor stem cells, and the relationship was preliminarily examined between Nanog and prostate cancer and its tumor stem cells. By using magnetic active cell sorting (MACS), we isolated a population of CD44(+)/CD133(+) prostate cancer cells that display stem cell characteristics from PC3 cell line. Immunohistochemistry revealed positive expressions of CD44, CD133 and alpha(2)beta(1)-integin in the isolated cells. CCK-8 analysis showed that isolated cells had a strong proliferative ability. The formation of the cell spheres in serum-free medium and holoclones in serum-supplied medium showed that the cells were capable of self-renewing, indicating that the isolated cells were a population of cancer stem-like cells derived from PC3 cell line. Western blotting exhibited that the isolated cells had higher experession of Nanog, an embryonic stem marker, as compared with PC3 cells. Our study showed that Nanog might be helpful in sustaining the self-renewal and the undifferentiation of prostate cancer stem cells, and may serve as a marker for prostate cancer stem cells for isolation and identification. PMID- 22528229 TI - Expression and significance of SHP-2 in human papillomavirus infected cervical cancer. AB - This study investigated the expression and prognostic value of SHP-2 in cervical cancer caused by human papillomavirus (HPV) infection. Forty-five specimens from patients with cervical cancer (stage I-III), 32 specimens from patients with cervical intraepithelial neoplasia (CIN) (I, II) and 20 normal cervical samples from patients with hysteromyoma were collected in Department of Pathology for comparison. The expression levels of SHP-2 and IFN-beta proteins were detected by using immunohistochemistry. The mRNA expression level of SHP-2 was detected by using quantitative real-time polymerase chain reaction (PCR). HPVs were detected by HPV GenoArray Test. The Spearman correlation was used to compare the expression level of SHP-2 in HPV infected cervical cancer vs non-HPV infected normal cervix. The level of SHP-2 protein expression in the cancer tissues (88.8%) was significantly higher than in CIN tissues (62.5%) and normal cervixes (45%) (P<0.05 and P<0.05, respectively). The SHP-2 mRNA levels in the cancer tissues were upregulated as compared with those in the normal cervixes (P<0.05). Twenty-one (46.7%) cervical cancers, 25 (78.1%) CINs and 17 (85%) normal cervixes showed IFN-beta positive staining in cytoplasm. There was statistically significant difference in the expression rate of IFN-beta between cervical cancer and normal cervix (chi (2)=8.378, P<0.05) as well as between cervical cancer and CIN (chi (2)=7.695, P<0.05). HPV16/18 infections could be found in normal cervixs (15%), CINs (68.7%) and cervical cancers (84.4%). There was a correlation between HPV infection and SHP-2 expression in cervical cancer (r (s)=0.653, P<0.05). SHP 2 may be a useful prognostic and diagnostic indicator for HPV infected cervical cancer. In cervical cancers, SHP-2 mRNA and protein overexpression was associated with IFN-beta lower-expression. PMID- 22528232 TI - Inhibition of 5-HT(3) receptors-activated currents by cannabinoids in rat trigeminal ganglion neurons. AB - This study investigated the modulatory effect of synthetic cannabinoids WIN55,212 2 on 5-HT(3) receptor-activated currents (I(5-HT3)) in cultured rat trigeminal ganglion (TG) neurons using whole-cell patch clamp technique. The results showed that: (1) The majority of examined neurons (78.70%) were sensitive to 5-HT (3-300 MUmol/L). 5-HT induced inward currents in a concentration-dependent manner and the currents were blocked by ICS 205-930 (1 MUmol/L), a selective antagonist of the 5-HT(3) receptor; (2) Pre-application of WIN55,212-2 (0.01-1 MUmol/L) significantly inhibited I(5-HT3) reversibly in concentration-dependent and voltage-independent manners. The concentration-response curve of 5-HT(3) receptor was shifted downward by WIN55,212-2 without any change of the threshold value. The EC(50) values of two curves were very close (17.5+/-4.5) MUmol/L vs. (15.2+/ 4.5) MUmol/L and WIN55,212-2 decreased the maximal amplitude of I(5-HT3) by (48.65+/-4.15)%; (3) Neither AM281, a selective CB1 receptor antagonist, nor AM630, a selective CB2 receptor antagonist reversed the inhibition of I(5-HT3) by WIN55,212-2; (4) When WIN55,212-2 was given from 15 to 120 s before 5-HT application, inhibitory effect was gradually increased and the maximal inhibition took place at 90 s, and the inhibition remained at the same level after 90 s. We are led to concluded that-WIN55,212-2 inhibited I(5-HT3) significantly and neither CB1 receptor antagonist nor CB2 receptor antagonist could reverse the inhibition of I(5-HT3) by WIN55,212-2. Moreover, WIN55,212-2 is not an open channel blocker (OCB) of 5-HT(3) receptor. WIN55,212-2 significantly inhibited 5 HT-activated currents in a non-competitive manner. The inhibition of I(5-HT3) by WIN55,212-2 is probably new one of peripheral analgesic mechanisms of WIN55,212 2, but the mechanism by which WIN55,212-2 inhibits I(5-HT3) warrants further investigation. PMID- 22528231 TI - Effect of adenosine A2A receptor antagonist ZM241385 on amygdala-kindled seizures and progression of amygdala kindling. AB - The purpose of this study was to evaluate the effect of adenosine A2A receptor antagonist ZM241385 on amygdala-kindled seizures and its roles in epileptogenesis. Electrodes were implanted into the right amygdala of male adult Wistar rats. Kindling was accomplished by using stimulus strength of 500 MUA applied daily to the amygdala until 10 consecutive stage 5 seizues were induced. Then effect of ZM241385 was studied in fully kindled rats after intracerebroventricular administration of the drug. In addition, the effect on kindling progression was evaluated through ZM241385 injection before daily stimulation. In all experiments, behavioral changes in the rats in response to ZM241385 were monitored closely. The results showed that, in fully amygdala kindled rats, ZM241385 (0.001-0.1 nmol/L) decreased afterdischage duration (ADD), motor seizure duration (MSD), stage 5 duration (S5D) and seizure duration (SD), but only the effect on ADD was dose-dependent. The doses of 0.001-0.1 nmol/L had no influence on stage 4 latency (S4L) and seizure stage (SS). The dosages of 0.0001 and 1 nmol/L of ZM241385 did not exert any effect on all seizure parameters. In contrast to the results in fully amygdala-kindled rats, ZM241385 (0.001-0.1 nmol/L) had minimal or no effects on the progression of amygdala kindled seizures. We are led to the conclusion that although ZM241385 had no influence on the progression of amygdala-kindled seizures, it had potent anti convulsant profile and little adverse effects at the dosage of 0.001-0.1 nmol/L, suggesting that the agent is effective against the amygdala-kindled seizures. PMID- 22528230 TI - Primary screening for breast diseases among 17618 women in Wufeng area, a region with high incidence of cervical cancer in China. AB - In this study, the current status for breast diseases in a region with high incidence of cervical cancer were epidemiologically investigated. From March to August, 2009, 17618 women, from Wufeng area of Hubei province, China, were recruited to screen breast diseases by using breast infrared diagnostic apparatus. Other diagnostic methods, such as B-mode ultrasound, X-ray mammography, needle biopsy and pathological examination were, if necessary, used to further confirm the diagnosis. The screening showed that 5990 of 17618 cases (34.00%) had breast diseases, 5843 (33.16%) had mammary gland hyperplasia, 48 (0.27%) had breast fibroadenoma, 11 (0.06%) had breast carcinoma, and 88 (0.50%) had other breast diseases. The peak morbidity of breast cancer was found in the women aged 50-60 ages. The morbidity of breast cancer was significantly increased in women elder than or equal to 50 years old (n=8, 0.157%) in comparison with that in the subjects younger than 50 years old (n=3, 0.024%) (u=2.327, P<0.05). It was shown that the occurrence of breast diseases was concentrated in women aged 20-40 years, while the total morbidity reached its peak at the age of 30 years and then decreased sharply after age of 40. Compared with the patients elder than or equal to 40 years old (n=3289, 27.46%), the morbidity rate of breast diseases was significantly increased in women less than 40 years old (2648 cases, 47.18%; P<0.001). However, there was no significant difference in the morbidity of breast diseases between the age group of 20-29 years and that of 30 39 years (P=0.453), and both of them were high. There was no significant association between the morbidity of breast diseases and cervical cancer. Since the morbidity of breast diseases was higher among young women, more attention should be paid to the screening of breast diseases among young women for early diagnosis. PMID- 22528233 TI - Psychological factors are closely associated with the Bell's palsy: a case control study. AB - To observe the differences in psychological status between Bell's palsy (BP) patients and healthy subjects, and to examine the relationship between psychological factors and the severity of BP, we conducted a case-control, multi center clinical investigation. A total of 695 subjects were assigned to the case group (n=355) and the control group (n=340). House-Brackmann grading system and Facial Disability Index (FDI) were adopted to assess the BP patients; Kessler Psychological Distress Scale (K10) and 16 Personality Factor (16PF) scale were employed to evaluate the psychological distress and personality profiles of all subjects. Two independent samples t test was used to compare the differences between cases and controls, and to compare the differences among different BP patients. Pearson correlation analysis was used to examine the relationship between psychological factors and severity of facial paralysis. The results showed that psychological distress (K10) in case group (27.09+/-5.80) was significantly higher than that in control group (13.43+/-3.02) (t=-37.219, P=0.000). The scores of personality factor Warmth (A), Openness to Change (Q1), Self-Reliance (Q2) were lower in cases than in the controls (P<0.01, P<0.05, P<0.05, respectively), whereas the scores of Sensitivity (I), Vigilance (L), Apprehension (O), and Tension (Q4) were significantly higher in cases than in the controls (P<0.05, P<0.01, P<0.01, P<0.01, respectively). In addition, the psychological distress was significantly higher in female patients, severe (HB score IV-VI) patients, and subacute (onset time 72-168 h) patients compared with that in male patients, mild (HB score I-III)patients, and acute (onset time[Symbol: see text]72 h) patients (P<0.05). The scores of personality factor in female patients, severe patients, and subacute patients were also significantly different from male patients, mild patients, and acute patients (P<0.05). The result of Pearson correlation analysis showed that psychological factors (K10, personality A, F, L, N, O, Q4) were closely related to HB scores. We are led to conclude that the psychological status between BP patients and healthy people are different; psychological distress and personality factors are closely associated with severity of facial paralysis. PMID- 22528234 TI - Down-regulation of p110beta expression increases chemosensitivity of colon cancer cell lines to oxaliplatin. AB - This study examined the synergetic effect of class IA Phosphoinositide 3-kinases catalytic subunit p110beta knockdown in conjunction with oxaliplatin treatment on colon cancer cells. Down-regulation of p110beta by siRNA interference and oxaliplatin treatment were applied in colon cancer cell lines HT29, SW620 and HCT116. MTT assay was used to measure the inhibitory effect of p110beta knockdown on the proliferation of colon cancer cell lines. SubG1 assay and Annexin-V FITC/PI double-labeling cytometry were applied to detect cell apoptosis. And cell cycle was evaluated by using PI staining and flow cytometry. The expression of caspase 3, cleaved PARP, p-Akt, T-Akt and p110beta was determined by western blotting. The results suggested that down-regulation of p110beta expression by siRNA obviously reduced cell number via accumulation in G(0)-G(1) phase of the cell cycle in the absence of notablely increased apoptosis in colon cancer cell lines HT29 and SW620 (S phase arrest in HCT116). Moreover, inhibition of p110beta expression increased oxaliplatin-induced cell apoptosis and cell cycle arrest in HT29, HCT116 and SW620 cell lines. In addition, increases of cleaved caspase-3 and cleaved PARP induced by oxaliplatin treatment were determined by immunoblotting in p110beta knockdown group compared with normal control group and wild-type group. It is concluded that down-regulated expression of p110beta could inhibit colon cancer cells proliferation and result in increased chemosensitivity of colorectal cancer cells to oxaliplatin through augmentation of oxaliplatin induced cell apoptosis and cell cycle arrest. PMID- 22528235 TI - Expression of IRF-4 and IBP in skin lesions of patients with psoriasis vulgaris. AB - The expression of the interferon regulatory factor 4 (IRF-4) and the IRF-4 binding protein (IBP) in psoriatic skin lesions was investigated. The expression of IRF-4 and IBP in skin lesions of 20 patients with psoriasis vulgaris were immunohistochemically dectected. Normal skin from 10 healthy people was used as normal control. The study showed that expression of IRF-4 was increased significantly in keratinocytes and inflammatory cells in the lesions of psoriasis vulgaris than that in the normal control. The detection revealed that IBP expression in keratinocytes, lymphocytes, hair follicles, and sebaceous glands in normal skin was significantly lower than that in the lesions of psoriasis vulgaris (P<0.05). Both IRF-4 and IBP might be involved in the pathogenesis of psoriasis vulgaris. PMID- 22528236 TI - Inhibition of glial activation in rostral ventromedial medulla attenuates mechanical allodynia in a rat model of cancer-induced bone pain. AB - Descending nociceptive modulation from the supraspinal structures plays an important role in cancer-induced bone pain (CIBP). Rostral ventromedial medulla (RVM) is a critical component of descending nociceptive facilitation circuitry, but so far the mechanisms are poorly known. In this study, we investigated the role of RVM glial activation in the descending nociceptive facilitation circuitry in a CIBP rat model. CIBP rats showed significant activation of microglia and astrocytes, and also up-regulation of phosphorylated p38 mitogen-activated protein kinase (p38 MAPK) and pro-inflammatory mediators released by glial cells (IL-1beta, IL-6, TNF-alpha and brain-derived neurotrophic factor) in the RVM. Stereotaxic microinjection of the glial inhibitors (minocycline and fluorocitrate) into CIBP rats' RVM could reverse the glial activation and significantly attenuate mechanical allodynia in a time-dependent manner. RVM microinjection of p38 MAPK inhibitor (SB203580) abolished the activation of microglia, reversed the associated up-regulation of pro-inflammatory mediators and significantly attenuated mechanical allodynia. Taken together, these results suggest that RVM glial activation is involved in the pathogenesis of CIBP. RVM microglial p38 MAPK signaling pathway is activated and leads to the release of downstream pro-inflammatory mediators, which contribute to the descending facilitation of CIBP. PMID- 22528237 TI - Signal peptide and denaturing temperature are critical factors for efficient mammalian expression and immunoblotting of cannabinoid receptors. AB - Many researchers employed mammalian expression system to artificially express cannabinoid receptors, but immunoblot data that directly prove efficient protein expression can hardly be seen in related research reports. In present study, we demonstrated cannabinoid receptor protein was not able to be properly expressed with routine mammalian expression system. This inefficient expression was rescued by endowing an exogenous signal peptide ahead of cannabinoid receptor peptide. In addition, the artificially synthesized cannabinoid receptor was found to aggregate under routine sample denaturing temperatures (i.e., >=95 degrees C), forming a large molecular weight band when analyzed by immuno-blotting. Only denaturing temperatures <=75 degrees C yielded a clear band at the predicted molecular weight. Collectively, we showed that efficient mammalian expression of cannabinoid receptors need a signal peptide sequence, and described the requirement for a low sample denaturing temperature in immuno-blot analysis. These findings provide very useful information for efficient mammalian expression and immuno-blotting of membrane receptors. PMID- 22528238 TI - Socio-behavioral predictors of self-reported oral health-related quality of life. AB - PURPOSE: To examine the relationship between social and financial support, behavioral and sociodemographic variables, and oral health-related quality of life (OHRQoL) in a national probability sample. METHODS: The National Health and Nutrition Examination Survey (NHANES) 2003-2004 data system was used; there were 12,761 persons selected for the sample, 10,122 of those were interviewed (79.3 %). Oral health-related quality of life, the outcome measure, was evaluated using seven items derived from the 14-item NHANES Oral Health Impact Profile (OHIP) included in the home interview. The aggregated OHRQoL scores ranged from 7 to 28. We included only adults, aged 20 and older, who self-reported their alcohol use during home interview (n = 5,014). Independent variables were social and financial support, and behavioral variables (smoking and alcohol use), with sociodemographic variables as covariates. Multiple linear regression analysis used weighted data representing 124 million persons. RESULTS: Lack of financial support reduced OHRQoL, but not social support. Smoking reduced OHRQoL, but not alcohol use. Compared to ages 20-24, persons aged 24-44 and aged 45-64 had significantly lower OHRQoL scores, but persons aged 65+ did not. Latinos' OHRQoL scores were lower than those of whites; there were no differences between whites and other ethnic groups. CONCLUSION: The model provides insights into the perception of OHRQoL in that oral health related to the ability to pay for care. Those in the middle years (24-64) rate their OHRQoL lower than do their younger cohorts; there is no difference in OHRQoL between the young and the old. PMID- 22528239 TI - Mapping the Oxford hip score onto the EQ-5D utility index. AB - PURPOSE: To assess different mapping methods for the estimation of a group's mean EQ-5D score based on responses to the Oxford hip score (OHS) questionnaire. METHODS: Four models were considered: a) linear regression using total OHS as a continuous regressor; b) linear regression employing responses to the twelve OHS questions as categorical predictors; c) two-part approach combining logistic and linear regression; and d) response mapping. The models were internally validated on the estimation data set, which included OHS and EQ-5D scores for total hip replacements, both before and six months after procedure for 1,759 operations. An external validation was also performed. RESULTS: All models estimated the mean EQ 5D score within 0.005 of an observed health-state utility estimate, ordinary least squares (OLS) continuous being the most accurate and OLS categorical the most consistent. Age, gender and deprivation did not improve the models. More accurate estimations at the individual level were achieved for higher scores of observed OHS and EQ-5D. CONCLUSION: Based on these results, when EQ-5D scores are not available, answers to the OHS questionnaire can be used to estimate a group's mean EQ-5D with a high degree of accuracy. PMID- 22528240 TI - Methods for interpreting change over time in patient-reported outcome measures. AB - PURPOSE: Interpretation guidelines are needed for patient-reported outcome (PRO) measures' change scores to evaluate efficacy of an intervention and to communicate PRO results to regulators, patients, physicians, and providers. The 2009 Food and Drug Administration (FDA) Guidance for Industry Patient-Reported Outcomes (PRO) Measures: Use in Medical Product Development to Support Labeling Claims (hereafter referred to as the final FDA PRO Guidance) provides some recommendations for the interpretation of change in PRO scores as evidence of treatment efficacy. METHODS: This article reviews the evolution of the methods and the terminology used to describe and aid in the communication of meaningful PRO change score thresholds. RESULTS: Anchor- and distribution-based methods have played important roles, and the FDA has recently stressed the importance of cross sectional patient global assessments of concept as anchor-based methods for estimation of the responder definition, which describes an individual-level treatment benefit. The final FDA PRO Guidance proposes the cumulative distribution function (CDF) of responses as a useful method to depict the effect of treatments across the study population. CONCLUSIONS: While CDFs serve an important role, they should not be a replacement for the careful investigation of a PRO's relevant responder definition using anchor-based methods and providing stakeholders with a relevant threshold for the interpretation of change over time. PMID- 22528241 TI - Psychosocial and emotional adjustment for children with pediatric cancer and their primary caregivers and the impact on their health-related quality of life during the first 6 months. AB - PURPOSE: To evaluate caregiver-reported psychosocial adjustment and health related quality of life (HrQoL) of Taiwanese children with newly diagnosed cancer and their caregivers during the first 6 months of treatment. METHODS: Caregivers of 89 newly diagnosed children completed the child behavior checklist, the pediatric quality of life inventory (PedsQL(TM) 4.0), the Parenting Stress Index, and the SF-36 questionnaire at diagnosis, and again 3 and 6 months into treatment. They were compared with a group of age- and sex-matched controls from general community. RESULTS: Significantly worse HrQoL in both children and their caregivers and greater parenting stress were noted in the cancer group than the controls during the first 6 months. Children with cancer were found to have significantly more internalizing behavioral problems and somatic complaints, especially those younger than 12 years old. After starting chemotherapy, significant decrease in parenting stress and improvements of both caregivers and children's HrQoL were noted within the first 6 months, although not to the level comparable with normal controls. CONCLUSIONS: Although children and their caregivers can adjust themselves gradually during the first 6 months after diagnosis of cancer, intervention and efforts aimed at reducing their distress and promoting adjustments are still required during this period. PMID- 22528243 TI - The quality of life of adults with type 2 diabetes in a hospital care clinic in Taiwan. AB - PURPOSE: To assess the impact of diabetes on quality of life (QoL) and identify major determinants affecting that impact using a multiple regression model. METHODS: This was a cross-sectional design. The audit of diabetes-dependent quality of life (ADDQoL) was administered to assess QoL. RESULTS: A sample of 256 outpatients with type 2 diabetes was recruited. A negative impact of diabetes was observed on all life domains. The first three most impacted life domains were 'future', 'freedom to eat', and 'self-confidence'. 'Freedom to eat' was also the domain the most frequently impacted in five previous ADDQoL studies conducted in Singapore, UK, India, the United States, and Slovakia. Factors negatively associated with some domain scores were younger age (future), being male (close personal relationship and sex life), more education (leisure activities, future, dependence, and freedom to drink), low income (leisure activities), having more diabetic complications (do physically and sex life), treatment with insulin (finances and living conditions), and higher HbA1c (freedom to drink). CONCLUSION: QoL is impaired in patients with diabetes, especially for the 'freedom to eat' domain, indicating that an intervention to improve dietary freedom might be a good way of improving QoL. Greater negative impact of diabetes on QoL was associated with being younger, male, more educated with low income, more diabetes complications, higher HbA1c, and using insulin. These need to be considered in responding to patients' individual needs. PMID- 22528242 TI - Parent-reported health outcomes in infants/toddlers: measurement properties and clinical validity of the ITQOL-SF47. AB - PURPOSE: To derive and evaluate a shorter infant/toddler quality of life questionnaire (ITQOL) for use in clinical care. METHODS: Stepwise regression, factor analysis, and item-scaling principles were used to derive and guide item selection using data from a large general sample in the Netherlands (n = 5,211) and a "wheezing illness" sample (n = 138). Item internal consistency, discriminant validity, and floor and ceiling effects were evaluated using a general Dutch sample (Salland Region n = 410) and two clinical samples: Functional abdominal pain (FAP, n = 81) and Burn (n = 194). Reliabilities were estimated using Cronbach's alpha. Relative precision (RP), the ability to distinguish between clinical subgroups, was computed by comparing the proportion of variance explained by the short-form scales versus respective full-length scales. RESULTS: The ITQOL was reduced from 97 to 47 items. Median alpha coefficients were 0.77 Salland sample, 0.76 (FAP), and 0.84 (Burn). Ninety-one to 100 % scaling successes for item discriminant validity were observed for 21 of 24 tests (8 scales, 3 samples). Floor effects were not observed; some ceiling effects were detected. RP estimates in the Salland sample ranged from 2.40 (physical abilities) to 0.58 (temperament and moods). RP estimates in the FAP sample were 0.85 (bodily pain), 1.36 (temperament and moods) and 1.62 (parental impact emotional) and for Burn, 1.51 (temperament and moods) and 0.59 (general health perceptions). CONCLUSION: The ITQOL-SF47 is reliable and valid and exceeds item-level scaling criteria. PMID- 22528244 TI - Engineering the van der Waals interaction in cross-linking-free hydroxide exchange membranes for low swelling and high conductivity. AB - What a swell for hydroxides: The typical trade-off between swelling control and ion conductivity in ion-conducting polymer membranes is overcome by enhancement of van der Waals interactions among polymer chains. Using a quaternary phosphonium-functionalized polymer, the simple combination of high electron density of the polymer and large dipole moment of the functional group leads to low membrane swelling, high hydroxide conductivity, and excellent hydroxide exchange membrane fuel cell performance. PMID- 22528245 TI - A co-occurrence of osteogenesis imperfecta type VI and cystinosis. AB - Osteogenesis imperfecta type VI (OI type VI) is a rare autosomal recessive disorder caused by mutations in the SERPINF1 gene that encodes pigment epithelium derived factor (PEDF). Cystinosis is an autosomal recessive lysosomal transport disorder caused by mutations in the CTNS gene. Both SERPINF1 and CTNS are located on chromosome 17p13.3. We describe an individual presenting with both OI type VI and cystinosis. The patient was diagnosed with cystinosis at the age of 11 months and OI type VI on bone biopsy at the age of 8 years. He has sustained over 30 fractures during his lifetime, and at the age of 19 years entered end-stage renal disease and subsequent renal transplant. An Affymetrix 6.0 array was used to look for areas of loss of heterozygosity on chromosome 17. Sequencing of the SERPINF1 and CTNS genes was performed, followed by quantitative PCR and Western blot of PEDF to characterize the identified mutation. A 6.58 Mb region of homozygosity was identified on the Affymetrix 6.0 array, encompassing both the SERPINF1 and CTNS genes. Sequencing of the genes identified homozygosity for a known pathogenic CTNS mutation and for a novel in-frame duplication in SERPINF1. Skin fibroblasts produced a markedly reduced amount of SERPINF1 transcript and PEDF protein. This patient has the concurrent phenotype of two rare recessive diseases, cystinosis and OI type VI. We identified for the first time an in-frame duplication in SERPINF1 that is responsible for the OI type VI phenotype in this patient. PMID- 22528246 TI - Cypermethrin alters the expression profile of mRNAs in the adult rat striatum: a putative mechanism of postnatal pre-exposure followed by adulthood re-exposure enhanced neurodegeneration. AB - This study was undertaken to investigate the effect of cypermethrin on the expression patterns of mRNAs in the striatum of adulthood alone and postnatal pre exposed followed by adulthood re-exposed rats using discover chips rat microarrays. The expression patterns of V-akt murine thymoma viral oncogene homolog 1, B-cell lymphoma 2 (BCL-2), BCL-2-associated X protein, caspase 1, caspase 9, death-associated protein 3 and interleukin-1beta were validated by the qRT-PCR. The expressions of inducible nitric oxide synthase (iNOS) and major histocompatibility complex (MHC) II were assessed immunohistochemically; however, tumour protein p53 and cytochrome c (mitochondrial and cytosolic) expressions were checked at protein level by western blotting. Cypermethrin differentially regulated 65 transcripts at one or the other stage of exposure and 21 transcripts exhibited more pronounced alterations in the postnatal pre-exposed and adulthood re-challenged rats. The results of qRT-PCR were in accordance with the microarray observations and the expressions of iNOS, p53 and cytosolic cytochrome c and MHC II positivity were increased while the level of mitochondrial cytochrome c was reduced in adulthood treated animals. The effects were more pronounced in the postnatal pre-exposed followed by adulthood re-exposed rats. The results obtained thus suggest that multiple pathways are involved in the neurodegeneration as well as in enhancing the vulnerability of neurons in cypermethrin pre-exposed postnatal animals upon re-exposure during adulthood. PMID- 22528247 TI - In vitro screening for drug-induced depression and/or suicidal adverse effects: a new toxicogenomic assay based on CE-SSCP analysis of HTR2C mRNA editing in SH SY5Y cells. AB - Many drugs in clinical trials, or already on the market, can have psychiatric side effects, independently of their therapeutic indication (e.g., Acomplia, Taranabant, and Roaccutane). There is currently no in vitro or in vivo approved test for the detection/prediction of such adverse effects, and the Food and Drugs Administration (FDA) can only issue general alerts on specific therapeutic classes. The development of a screening assay is therefore of real interest. The anti-viral and anti-tumor action of human interferon-alpha (hIFNalpha) is associated with a variety of neuropsychiatric side effects, including major depression, suicidal ideation and suicide. RNA editing of the serotonin 2C receptor (HTR2C) by adenosine deaminases acting on RNA (ADARs) is a post transcriptional modification, the regulation of which is altered in depressed suicide victims. In this study, we show that in the SH-SY5Y neuroblastoma cell line, hIFNalpha specifically activates the ADAR1a isoform and thereby modifies the HTR2C mRNA editing profile. As this hIFNalpha-induced altered profile partly overlaps with that observed in the brain of depressed suicide victims, we investigated whether it could be used as a signature to identify drugs with depression and/or suicidal side effects. By means of the Biocortech proprietary screening assay, which allows the relative quantification of all the edited HTR2C isoforms in a sample, we blind-tested the effect of 50 marketed molecules on HTR2C mRNA editing in SH-SY5Y cells and identified 17 compounds with an IFN-like editing profile. This new toxicogenomic assay can identify compounds with potential psychiatric adverse events with a positive predictive value of 90 %. PMID- 22528248 TI - Evidence for synergism between cell death mechanisms in a cellular model of neurodegeneration in Parkinson's disease. AB - Delineation of how cell death mechanisms associated with Parkinson's disease (PD) interact and whether they converge would help identify targets for neuroprotective therapies. The purpose of this study was to use a cellular model to address these issues. Catecholaminergic SH-SY5Y neuroblastoma cells were exposed to a range of compounds (dopamine, rotenone, 5,8-dihydroxy-1,4-naphtho 107 quinone [naphthazarin], and Z-Ile-Glu(OBut)-Ala-Leu-al [PSI]) that are neurotoxic when applied to these cells for extended periods of times at specific concentrations. At the concentrations used, these compounds cause cellular stress via mechanisms that mimic those associated with causing neurodegeneration in PD, namely oxidative stress (dopamine), mitochondrial dysfunction (rotenone), lysosomal dysfunction (naphthazarin), and proteasomal dysfunction (PSI). The compounds were applied to the SH-SY5Y cells either alone or in pairs. When applied separately, the compounds produced a significant decrease in cell viability confirming that oxidative stress, mitochondrial, proteosomal, or lysosomal dysfunction can individually result in catecholaminergic cell death. When the compounds were applied in pairs, some of the combinations produced synergistic effects. Analysis of these interactions indicates that proteasomal, lysosomal, and mitochondrial dysfunction is exacerbated by dopamine-induced oxidative stress. Furthermore, inhibition of the proteasome or lysosome or increasing oxidative stress has a synergistic effect on cell viability when combined with mitochondrial dysfunction, suggesting that all cell death mechanisms impair mitochondrial function. Finally, we show that there are reciprocal relationships between oxidative stress, proteasomal dysfunction, and mitochondrial dysfunction, whereas lysosome dysfunction appears to mediate cell death via an independent pathway. Given the highly interactive nature of the various cell death mechanisms linked with PD, we predict that effective neuroprotective strategies should target multiple sites in these pathways, for example oxidative stress and mitochondria. PMID- 22528250 TI - In-situ emergency pediatric surgery in the intensive care unit. AB - BACKGROUND: The role of surgery in the intensive care unit (ICU) remains unclear. Although previous studies have not shown any increase in morbidity when operating on patients in the ICU for surgical procedures; there remains a reluctance to operate on sick patients in the ICU. AIM: We did a retrospective study of critically ill children and neonates who underwent in-situ surgery (ISS) to further evaluate its safety and potential. Surgery was aided with the use of operative loupes and high-intensity headlight. METHODS: The medical records of all patients who had undergone surgical procedures in the pediatric ICU over an 11-year period from January 1998 till December 2008 were retrospectively reviewed. We reviewed our experience looking specifically at wound infection rates along with other morbidities in 543 patients. RESULTS: Our morbidities were comparable with that of operations performed in the operating theater, with low wound infection rates (1%) for all surgeries undertaken in the pediatric ICU. CONCLUSION: ISS avoids the risks of transfer to the operative theater and the potential delays in theater access. Our results suggest that ISS in a tertiary level pediatric surgical hospital is safe and does not impact adversely on clinical outcome. PMID- 22528249 TI - Protective effects of nicotine against aminochrome-induced toxicity in substantia nigra derived cells: implications for Parkinson's disease. AB - Parkinson's disease is a debilitating progressive neurodegenerative disorder that results from the loss of or damage to dopaminergic cells containing neuromelanin in the substantia nigra (SN). The underlying neurodegenerative mechanism(s), however, remain elusive. Aminochrome, the precursor of neuromelanin is an endogenous substance capable of inducing selective neurotoxicity to dopaminergic neurons in SN. Nicotine, on the other hand, may offer protective effects against dopaminergic cell damage induced by various neurotoxins including MPTP and salsolinol. In this study, we sought to determine whether nicotine may also protect against aminochrome-induced toxicity in SN derived RCSN-3 cells. Exposure of RCSN-3 cells to a combination of aminochrome (50 MUM) and dicoumarol (50 MUM) for 48 h induced approximately 70 % cell death. Pretreatment with nicotine, dose dependently blocked this toxicity. The effects of nicotine in turn were dose dependently blocked by mecamylamine, a non-selective nicotinic receptor antagonist. These results suggest involvement of nicotinic receptors in protective effects of nicotine against aminochrome-induced toxicity and provide further evidence for possible therapeutic effects of nicotine or nicotinic agonists in Parkinson's disease. PMID- 22528251 TI - The cost utility of a multi-disciplinary foot protection clinic (MDFPC) in an Irish hospital setting. AB - BACKGROUND: Foot ulceration which may result in lower limb amputation is one of the most feared complications among patients with diabetes and the prevention of both ulceration and amputation is a major challenge facing the health service. Many studies have proposed dedicated diabetic foot teams as the future of diabetic foot care. AIMS: We aimed to quantify the cost benefit and sustainability of a multi-disciplinary foot protection clinic (MDFPC) in an Irish university hospital setting. METHODS: A dedicated bi-weekly consultant-led MDFPC including Vascular Surgery, Endocrinology, Orthopaedic Surgery, Podiatry, Orthotics and Tissue Viability was established in June 2008. RESULTS: Between 2006 and 2010, a total of 221 lower limb procedures (major/minor amputations and debridement) were performed. The number of major amputations decreased from 12 during the control period (2 years before the clinic) to 7 in the study period (2 years after the clinic). After costing all activity associated with the clinic, there was an overall saving of ?114,063 per year associated with the introduction of the MDFPC. CONCLUSION: This is the first study in an Irish context, and one of few international studies, to demonstrate that an aggressive-coordinated approach to diabetic foot care is both cost effective and clinically efficient in reducing the burden of foot-related complications in a diabetic population. PMID- 22528252 TI - Has your work worked you too hard? Physically demanding work and disability in a sample of the older Irish population. AB - BACKGROUND: There is a heightened need for the practitioner to be alert to the determinants of functional limitations and disabilities owing to the ageing workforce. AIM: This study investigated the association between work type and disability in older age in both the paid and the previously unexplored, unpaid worker (household labour). METHODS: Data on demographic factors, physical measurements, work history and functional status were collected on three hundred and fifty seven 57-80-year-olds. Past or present work was identified as either physically demanding or not. Functional limitations and activities of daily living (ADL) disabilities were assessed using validated scales. Logistic regression was used to examine the relationship between the dependent variables and work type (physically demanding work or not physically demanding work). RESULTS: Over half of the sample reported doing physically demanding work. 20% had complete function (n = 67), 65% (n = 223) functional limitations and 15% (n = 53) ADL disability. Physically demanding work was associated with functional limitations [OR 2.52 (1.41, 4.51), p = 0.01] and ADL disability [OR 2.10 (1.06, 4.17), p = 0.03] after adjustment for a measure of obesity and gender. When gender stratified, looking only at females, physically demanding work was associated with ADL disability [OR 2.79 (1.10, 7.07), p = 0.03] adjusted for a measure of obesity and household labour. CONCLUSIONS: Physically demanding work was related to functional limitations and ADL disability in older age. This is valuable information to inform practitioners in the treatment of older people with functional limitations and disabilities and in guiding interventions in the prevention of work related disability. PMID- 22528254 TI - Can we predict the site of entry tear by computed tomography in patients with acute type a aortic dissection? AB - BACKGROUND: In patients with acute type A aortic dissection (AAD), localization of the primary entry tear to be excluded is of major importance for intervention. HYPOTHESIS: There are reliable indirect computed tomography (CT) findings to predict the entry site. METHODS: In 83 patients with type A AAD whose primary entry tears were identified surgically between 2003 and 2009, we retrospectively examined the diagnostic CT scans regarding pericardial effusion, the largest short-axial diameter of the aorta, widths of true and false lumens, and false lumen thrombosis at 6 levels of thoracic aorta from the aortic root to the descending aorta. RESULTS: The primary entry sites identified intraoperatively were proximal ascending in 21 patients, middle ascending in 21, distal ascending in 21, arch in 17, and descending or unknown in 16. The multivariate logistic analysis revealed that pericardial effusion (odds ratio [OR]: 2.2, 95% confidence interval [CI]: 1.2-3.4, P < 0.001) and dilated ascending aorta (OR: 1.6, 95% CI: 1.1-2.4, P = 0.012) were the significant CT findings to predict the entry tear in the ascending aorta. It also revealed that the significant CT finding to predict the entry tear distal to the aortic arch was nonthrombosed false lumen in the descending aorta (OR: 1.2, 95% CI: 1.1-2.1, P = 0.048). CONCLUSIONS: We can predict the primary entry site by the preoperative CT findings in patients with type A AAD, considering pericardial effusion, aortic diameter, widths of true and false lumens, and false lumen thrombosis at different anatomic levels. PMID- 22528253 TI - The vegetative and minimally conscious states: a review of the literature and preliminary survey of prevalence in Ireland. AB - BACKGROUND: In the absence of reliable, objective and direct measures of awareness, the diagnosis and prognosis of the vegetative and minimally conscious states are greatly complicated. This has led to an unacceptably high level of misdiagnosis. Although diagnosis and prognosis have typically relied on bedside behavioural measures, a number of recent studies on neuroimaging and neurophysiological methods offer the possibility of improvement in these areas. OBJECTIVES: We examined current clinical practice and possible future directions in the diagnosis, prognosis and treatment of disorders of consciousness, as well as the ethical and legal dilemmas associated with these disorders. We also summarise epidemiological data from three specialist rehabilitation hospitals in Ireland. CONCLUSIONS: We recommend an international agreement on standard behavioural assessment. This would enable greater consistency in diagnosis and prognostication, as well as improved accuracy of epidemiological data. Based on the current evidence, we advocate the introduction of neuroimaging and neurophysiological techniques into the standardised investigation profile. A more detailed epidemiological study is also required in Ireland. PMID- 22528255 TI - Detecting and characterizing individual molecules with single nanopores. AB - Single-nanometer-scale pores have demonstrated the capability for the detection, identification, and characterization of individual molecules. This measurement method could soon extend the existing commercial instrumentation or provide solutions to niche applications in many fields, including health care and the basic sciences. However, that paradigm shift requires a significantly better understanding of the physics and chemistry that govern the interactions between nanopores and analytes. We describe herein some of our methods and approaches to address this issue. PMID- 22528256 TI - Protein sensing with engineered protein nanopores. AB - The use of nanopores is a powerful new frontier in single-molecule sciences. Nanopores have been used effectively in exploring various biophysical features of small polypeptides and proteins, such as their folding state and structure, ligand interactions, and enzymatic activity. In particular, the alpha-hemolysin (alphaHL) protein pore has been used extensively for the detection, characterization, and analysis of polypeptides because this protein nanopore is highly robust, versatile, and tractable under various experimental conditions. Inspired by the mechanisms of protein translocation across the outer membrane translocases of mitochondria, we have shown the ability to use nanopore-probe techniques in controlling a single protein using engineered alphaHL pores. Here, we provide a detailed protocol for the preparation of alphaHL protein nanopores. Moreover, we demonstrate that placing attractive electrostatic traps is instrumental in tackling single-molecule stochastic sensing of folded proteins. PMID- 22528257 TI - Measurements of DNA immobilized in the alpha-hemolysin nanopore. AB - In the past decade, there have been extensive studies aimed at exploring the potential of protein nanopores to sequence single strands of DNA using resistive pulse sensing. The high speed of DNA electrophoretically driven through these pores (~l MUs/base) necessitates high bandwidth measurements, which prevent resolution of the picoampere differences in blockage current resulting from different nucleotides. Here, we describe a procedure for the immobilization of DNA in the alpha-hemolysin protein nanopore which enables low-noise, high precision measurements capable of resolving subpicoampere differences in blockage current associated with differences in the sequence and structure of the DNA. PMID- 22528258 TI - DNA unzipping and protein unfolding using nanopores. AB - We present here an overview on unfolding of biomolecular structures as DNA double strands or protein folds. After some theoretical considerations giving orders of magnitude about transport timescales through pores, forces involved in unzipping processes ... we present our experiments on DNA unzipping or protein unfolding using a nanopore. We point out the difficulties that can be encountered during these experiments, such as the signal analysis problems, noise issues, or experimental limitations of such system. PMID- 22528259 TI - DNA characterization with ion beam-sculpted silicon nitride nanopores. AB - Solid-state nanopores are emerging as robust single molecule electronic measurement devices and as platforms for confining biomolecules for further analysis. The first silicon nitride nanopore to detect individual DNA molecules was fabricated using ion beam sculpting (IBS), a method that uses broad, low energy ion beams to create nanopores with dimensions ranging from 2 to 20 nm. In this chapter, we discuss the fabrication, characterization, and use of IBS sculpted nanopores as well as efficient uses of pClamp and MATLAB software suites for data acquisition and analysis. The fabrication section covers the repeatability and the pore size limits. The characterization discussion focuses on the geometric properties as measured by low- and high-resolution transmission electron microscopy (TEM), electron energy loss spectroscopy, and energy-filtered TEM. The section on translocation experiments focuses on how to use tools commonly available to the nanopore experimenter to determine whether a pore will be useful for experimentation or if it should be abandoned. A memory-efficient method of taking data using Clampex's event-driven mode and dual-channel recording is presented, followed by an easy-to-implement multithreshold event detection and classification method using MATLAB software. PMID- 22528260 TI - DNA sequencing by nanopore-induced photon emission. AB - Nanopore-based DNA analysis is an extremely attractive area of research due to the simplicity of the method, and the ability to not only probe individual molecules, but also to detect very small amounts of genomic material. Here, we describe the materials and methods of a novel, nanopore-based, single-molecule DNA sequencing system that utilizes optical detection. We convert target DNA according to a binary code, which is recognized by molecular beacons with two types of fluorophores. Solid-state nanopores are then used to sequentially strip off the beacons, leading to a series of photon bursts that can be detected with a custom-made microscope. We do not use any enzymes in the readout stage; thus, our system is not limited by the highly variable processivity, lifetime, and inaccuracy of individual enzymes that can hinder throughput and reliability. Furthermore, because our system uses purely optical readout, we can take advantage of high-end, wide-field imaging devices to record from multiple nanopores simultaneously. This allows an extremely straightforward parallelization of our system to nanopore arrays. PMID- 22528261 TI - Optical tweezers for mechanical control over DNA in a nanopore. AB - The translocation of long-chain molecules, such as DNA or peptides, through membranes is an integral process for the function of living cells. During the translocation process, a number of interactions of electrostatic or hydrophobic nature govern the translocation velocity. Most of these interactions remain largely unexplored on the single-molecule level due to a lack of suitable instrumentation. We have shown that a combination of optical tweezers, single solid-state nanopores, and electrophysiological ionic current detection can provide further insight into the behavior of polymers in confinement. Here, we describe the experimental procedures necessary for manipulation of single biopolymers in a single nanopore not only by electrical fields, but also through mechanical forces using optical tweezers. PMID- 22528262 TI - Analyzing single DNA molecules by nanopore translocation. AB - Small holes in membranes or nanocapillaries can be employed to detect single molecules in solution. In fact, the resistive-pulse technique based on nanopores allows for determination of length, charge, and folding state of deoxyribonucleic acid (DNA). Here, we describe the experimental procedures necessary for measuring single DNA molecules in nanocapillaries. We also discuss the measures for data analysis and how to determine that only single molecule events are observed. PMID- 22528263 TI - DNA characterization by transverse electrical current in a nanochannel. AB - We review an approach for the characterization of single-stranded DNA based on the statistical identification of single bases via transverse electronic transport while DNA translocates in a nanopore or nanochannel. We describe the theoretical methods used to demonstrate this method for experimentally realizable systems and discuss the different physical processes involved. Recent experimental reports have shown the validity of this approach, although further work is necessary to make this a practical fast sequencing tool. PMID- 22528264 TI - Optimization of the molecular dynamics method for simulations of DNA and ion transport through biological nanopores. AB - Molecular dynamics (MD) simulations have become a standard method for the rational design and interpretation of experimental studies of DNA translocation through nanopores. The MD method, however, offers a multitude of algorithms, parameters, and other protocol choices that can affect the accuracy of the resulting data as well as computational efficiency. In this chapter, we examine the most popular choices offered by the MD method, seeking an optimal set of parameters that enable the most computationally efficient and accurate simulations of DNA and ion transport through biological nanopores. In particular, we examine the influence of short-range cutoff, integration timestep and force field parameters on the temperature and concentration dependence of bulk ion conductivity, ion pairing, ion solvation energy, DNA structure, DNA-ion interactions, and the ionic current through a nanopore. PMID- 22528265 TI - Polymer translocation through an electrically tunable nanopore in a multilayered semiconductor membrane. AB - We have developed a two-level computational model that enables us to calculate electrostatic fields created by a semiconductor membrane submerged in electrolytic solution and investigate the effects of these fields on the dynamics of a polymer translocating through a nanopore in the membrane. In order to calculate the electrostatic potentials and the ionic concentrations in a solid state nanopore, we have self-consistently solved Poisson equation within the semiclassical approximation for charge carrier statistics in the membrane and electrolyte. The electrostatic potentials obtained from these simulations are then used in conjunction with Langevin (Brownian) dynamics to model polymer translocation through the nanopore. In this work, we consider single-stranded DNA (ssDNA) translocation through semiconductor membranes consisting of heavily doped p- and n-layers of silicon forming a pn-junction which is capable of creating strong electric fields. We show that the membrane electric field controls dynamics of a biomolecule inside the channel, to either momentarily trap it, slow it down, or allow it to translocate at will. PMID- 22528266 TI - Graphene nanopore devices for DNA sensing. AB - We describe here a method for detecting the translocation of individual DNA molecules through nanopores created in graphene membranes. The devices consist of 1-5-nm thick graphene membranes with electron-beam sculpted nanopores from 5 to 10 nm in diameter. Due to the thin nature of the graphene membranes, and the reduced electrical resistance, we observe larger blocked currents than for traditional solid-state nanopores. We also show how ionic current noise levels can be reduced with the atomic-layer deposition of a few nanometers of titanium dioxide over the graphene surface. Unlike traditional solid-state nanopore materials that are insulating, graphene is an excellent electrical conductor, and its use opens the door to a new future class of nanopore devices in which electronic sensing and control is performed directly at the pore. PMID- 22528267 TI - Measuring single-wall carbon nanotubes with solid-state nanopores. AB - Solid-state nanopores have been used widely to study biological polymers. Here, we expand the technique to analyze single-wall carbon nanotubes. By wrapping them in an amphiphilic layer, individual tubes can be translocated electrically through a nanopore, resulting in temporary interruptions in the trans-pore current reminiscent of measurements on DNA, RNA, and proteins. The technique may find use in discriminating nanotubes by size and thus electrical structure, facilitating their inclusion in electrical devices. PMID- 22528268 TI - Passive and electrically actuated solid-state nanopores for sensing and manipulating DNA. AB - Solid-state nanopores have emerged as powerful new tools for electrically characterizing single DNA molecules. When DNA molecules are made to rapidly translocate a nanopore by electrophoresis, the resulting ionic current blockage provides information about the molecular length and folding conformation. A solid state nanopore can also be integrated with nanofabricated actuators and sensors, such as an embedded gate electrode or transverse tunneling electrodes, to enhance its functionality. Here we describe detailed methods for fabricating passive solid-state nanopores and using them to detect DNA translocations. We also describe procedures for integrating electrodes into the nanopore membrane in order to create an electrically active structure. Finally, we describe how to modulate the ionic conductance through a pore whose inner surface is surrounded by an embedded annular gate electrode. PMID- 22528269 TI - Diastereoselective multicomponent synthesis and anti-HSV-1 evaluation of dihydrofuran-fused derivatives. AB - Enolizable 6-membered cyclic 1,3-dicarbonyls undergo an efficient and diastereoselective domino condensation/addition/heterocyclization reaction with arylaldehydes and phenacyl chloride, producing highly substituted dihydrofuran fused derivatives. Ring size of the cyclic 1,3-dicarbonyls and the presence of at least one keto group are crucial to the reaction's success. The new compounds were evaluated in vitro for antiviral activity against herpes simplex virus type 1 (HSV-1). Interestingly, some of them appeared able to interfere with HSV-1 replication, without detection of cytotoxic effects. PMID- 22528270 TI - Binding site characterization of G protein-coupled receptor by alanine-scanning mutagenesis using molecular dynamics and binding free energy approach: application to C-C chemokine receptor-2 (CCR2). AB - The C-C chemokine receptor 2 (CCR2) was proved as a multidrug target in many diseases like diabetes, inflammation and AIDS, but rational drug design on this target is still lagging behind as the information on the exact binding site and the crystal structure is not yet available. Therefore, for a successful structure based drug design, an accurate receptor model in ligand-bound state is necessary. In this study, binding-site residues of CCR2 was determined using in silico alanine scanning mutagenesis and the interactions between TAK-779 and the developed homology model of CCR2. Molecular dynamic simulation and Molecular Mechanics-Generalized Born Solvent Area method was applied to calculate binding free energy difference between the template and mutated protein. Upon mutating 29 amino acids of template protein and comparison of binding free energy with wild type, six residues were identified as putative hot spots of CCR2. PMID- 22528271 TI - Accessing a small library of pluripotent 1,4,5-trisubstituted 1H-1,2,3-triazoles via diversity-oriented synthesis. AB - Diversity-oriented synthesis of structurally different, novel and small drug like molecules based on 1,4,5-trisubstituted 1,2,3-triazoles is developed in a streamlined sequence of different sets of reactions. The method involves the use of simple, readily available and highly economical substrates and reagents. The molecules developed herein have potential to be exploited either as chemotherapeutic agents or as scaffolds for other biologically active compounds. PMID- 22528272 TI - Synthesis of benzopyrano[4,3-b](N-arylsulfonyl)indoles and benzopyrano[3,4-b](N arylsulfonyl)indoles via intramolecular palladium-catalyzed aryl-aryl coupling reaction. AB - A series of benzopyrano[3,4-b](N-arylsulfonyl) indole derivatives and benzopyrano[4,3-b](N-arylsulfonyl) indole derivatives were synthesized from 2- or 3-methylindole via intermolecular S( N )2 reaction and subsequent intramolecular palladium-catalyzed aryl-aryl coupling reaction for the first time. It was suggested that, besides using the Fischer cyclization, benzopyrano[4,3-b]indoles and benzopyrano[3,4-b]indoles could also be prepared via intermolecular S( N )2 reaction and sequential intramolecular palladium-catalyzed coupling reaction. PMID- 22528273 TI - Catalytic ring expansion of vinyl oxetanes: asymmetric synthesis of dihydropyrans using chiral counterion catalysis. PMID- 22528275 TI - Plantar flexion with noxious dorsal foot stimulation in brain death. AB - BACKGROUND: Plantar flexion with plantar stimulation has been well described in brain death, and is compatible with brain death. However, plantar flexion with stimulation to the dorsal surface of the foot has not been reported previously in brain dead patients. METHODS: Case report with Technetium-99 m hexamethylpropyleneamine oxime brain scan and video. RESULTS: A 46-year-old woman suffered severe anoxic brain injury following massive pulmonary embolism 5 days after arthroscopic knee surgery. Neurologic examination was consistent with brain death, with the exception of plantar flexion when noxious stimulation was applied to the dorsal surface of the great toe on each side. Ancillary testing with a technetium-99 m nuclear scan demonstrated absence of cerebral perfusion, supporting the diagnosis of brain death. CONCLUSIONS: Noxious stimulation to the dorsal surface of the foot may trigger spinally mediated plantar flexion in patients with brain death. PMID- 22528277 TI - Retrospective evaluation of nicardipine versus labetalol for blood pressure control in aneurysmal subarachnoid hemorrhage. AB - BACKGROUND: American Heart Association/American Stroke Association guidelines for management of aneurysmal subarachnoid hemorrhage (aSAH) recommend blood pressure (BP) control, utilizing labetalol or nicardipine, but do not differentiate efficacy between the two agents. The purpose of this retrospective study was to compare BP control between labetalol and nicardipine in patients following aSAH. METHODS: Consecutive adult patients admitted to the ICU with a diagnosis of SAH treated with labetalol or nicardipine were retrospectively identified. Patients were included if they received more than one bolus dose of labetalol or a nicardipine infusion for greater than 3 h. Patients were excluded if they were <18 years of age, experiencing an ICH, acute ischemic stroke or a TIA. Patients were stratified into two groups (labetalol vs. nicardipine) and data was collected for 72 h. The outcomes compared were time within goal mean arterial pressure (MAP), average MAP/patient, MAP variability, initial response to therapy, and treatment failure. Goal MAP was defined as 70-110 mmHg. RESULTS: There were 103 patients evaluated (labetalol n = 43; nicardipine n = 60). Demographics and baseline MAP were similar between the two groups. Nicardipine was associated with a longer time within goal MAP (78 +/- 24 vs. 58 +/- 36 %, p = 0.001) and lower average MAP/patient (93 +/- 11 vs. 106 +/- 12 mmHg, p < 0.001). There was no difference in MAP variability between the nicardipine and labetalol groups (13 +/- 5 mmHg vs. 11 +/- 4 mmHg; p = 0.137). Nicardipine led to a more rapid response to therapy (F = 8.1; p = 0.005) and fewer treatment failures (0 vs. 28 %, p < 0.001). CONCLUSIONS: Our study showed nicardipine to be associated with superior BP control versus labetalol in aSAH. PMID- 22528278 TI - Milrinone and homeostasis to treat cerebral vasospasm associated with subarachnoid hemorrhage: the Montreal Neurological Hospital protocol. AB - INTRODUCTION: For the treatment of cerebral vasospasm, current therapies have focused on increasing blood flow through blood pressure augmentation, hypervolemia, the use of intra-arterial vasodilators, and angioplasty of proximal cerebral vessels. Through a large case series, we present our experience of treating cerebral vasospasm with a protocol based on maintenance of homeostasis (correction of electrolyte and glucose disturbances, prevention and treatment of hyperthermia, replacement of fluid losses), and the use of intravenous milrinone to improve microcirculation (the Montreal Neurological Hospital protocol). Our objective is to describe the use milrinone in our practice and the neurological outcomes associated with this approach. METHODS: Large case series based on the review of all patients diagnosed with delayed ischemic neurologic deficits after aneurysmal subarachnoid hemorrhage between April 1999 and April 2006. RESULTS: 88 patients were followed for a mean time of 44.6 months. An intravenous milrinone infusion was used for a mean of 9.8 days without any significant side effects. No medical complications associated with this protocol were observed. There were five deaths; of the surviving patients, 48.9 % were able to go back to their previous baseline and 75 % had a good functional outcome (modified Rankin scale <= 2). CONCLUSION: A protocol using intravenous milrinone, and the maintenance of homeostasis is simple to use and requires less intensive monitoring and resources than the standard triple H therapy. Despite the obvious limitations of this study's design, we believe that it would be now appropriate to proceed with formal prospective studies of this protocol. PMID- 22528279 TI - Lack of increase in intracranial pressure after epidural blood patch in spinal cerebrospinal fluid leak. AB - BACKGROUND AND IMPORTANCE: Epidural blood patch (EBP) is one therapeutic measure for patients suffering from spontaneous intracranial hypotension (SIH) or post lumbar puncture headaches. It has been proposed that an EBP may directly seal a spinal cerebrospinal fluid (CSF) fistula or result in an increase in intracranial pressure (ICP) by a shift of CSF from the spinal to the intracranial compartment. To the best of our knowledge this is the first case of a patient with SIH and neurological deterioration in whom ICP was measured before, during, and after spinal EBP. CLINICAL PRESENTATION: This 52-year old previously healthy man presented with holocephal headaches. MRI showed a left hemispheric subdural fluid collection causing a significant mass effect. Myelography revealed a CSF leak with epidural contrast at the left side of the L-2 level. To seal the CSF leak, we performed an EBP procedure targeted at left L-2 level and recorded ICP. After applying the epidural blood patch (15 cc) the patient improved rapidly, ICP however remained unchanged before, during, and after the procedure. One day post treatment, he had a GCS score increase from 12 to 15 and no headache or neurological deficits. CONCLUSION: A shift of CSF from the spinal to the cranial compartment with a subsequent rise in ICP might not be a beneficial therapeutic mechanism of spinal epidural blood patching. PMID- 22528274 TI - Guidelines for the evaluation and management of status epilepticus. AB - Status epilepticus (SE) treatment strategies vary substantially from one institution to another due to the lack of data to support one treatment over another. To provide guidance for the acute treatment of SE in critically ill patients, the Neurocritical Care Society organized a writing committee to evaluate the literature and develop an evidence-based and expert consensus practice guideline. Literature searches were conducted using PubMed and studies meeting the criteria established by the writing committee were evaluated. Recommendations were developed based on the literature using standardized assessment methods from the American Heart Association and Grading of Recommendations Assessment, Development, and Evaluation systems, as well as expert opinion when sufficient data were lacking. PMID- 22528280 TI - Decompressive hemicraniectomy in malignant middle cerebral artery infarct: a randomized controlled trial enrolling patients up to 80 years old. AB - BACKGROUND: Decompressive hemicraniectomy (DHC) has proven efficacious for the treatment of malignant middle cerebral artery infarction (mMCAI) only in patients less than 60 years. This study aimed to assess the effectiveness of DHC in patients up to 80. METHODS: This is a prospective, randomized, controlled trail comparing the outcomes with or without DHC in patients aged 18-80 with mMCAI (ChiCTR-TRC-11001757). The primary outcome measure was the modified Rankin Scale (mRS) scores at 6 months. The secondary outcome measures included the 6- and 12 month mortality and the mRS scores after 1 year. The prognosis of patients was evaluated independently by two blinded investigators. In addition, subgroup analyses were done for those above 60 years of age. All analyses were by intention-to-treat. RESULTS: A significant reduction in the poor outcome (mRS > 4) following DHC was reached after 36 patients had completed the follow-up period of 6 months. The trial was then terminated when 47 participants (24 in the surgical group vs. 23 in the medical group) had been recruited. The final analysis, based on the outcome data of the 47 patients, showed that DHC significantly reduced mortality at 6 and 12 months (12.5 vs. 60.9 %, P = 0.001 and 16.7 vs. 69.6 %, P < 0.001, respectively), and significantly fewer patients had a mRS score >4 after surgery (33.3 vs. 82.6 %, P = 0.001 and 25.0 vs. 87.0 %, P < 0.001, respectively). Similar results were present in the subgroup analyses of elderly participants CONCLUSIONS: For patients up to 80 years who suffered mMCAI, DHC within 48 h of stroke onset not only is a life-saving treatment, but also increases the possibility of surviving without severe disability (mRS = 5). PMID- 22528281 TI - Postoperative anticoagulation in patients with mechanical heart valves following surgical treatment of subdural hematomas. AB - BACKGROUND: Thromboembolic events and anticoagulation-associated bleeding events represent frequent complications following cardiac mechanical valve replacement. Management guidelines regarding the timing for resuming anticoagulation therapy following a surgically treated subdural hematoma (SDH) in patients with mechanical valves remains to be determined. OBJECTIVE: To determine optimal anticoagulation management in patients with mechanical heart valves following treatment of SDH. METHODS: Outcomes were retrospectively reviewed for 12 patients on anticoagulation therapy for thromboembolic prophylaxis for mechanical cardiac valves who underwent surgical intervention for a SDH at the Johns Hopkins Hospital between 1995 and 2010. RESULTS: The mean age at admission was 71 years. All patients had St. Jude's mechanical heart valves and were receiving anticoagulation therapy. All patients had their anticoagulation reversed with vitamin K and fresh frozen plasma and underwent surgical evacuation. Anticoagulation was withheld for a mean of 14 days upon admission and a mean of 9 days postoperatively. The average length of stay was 19 days. No deaths or thromboembolic events occurred during the hospitalization. Average follow-up time was 50 months, during which two patients had a recurrent SDH. No other associated morbidities occurred during follow-up. CONCLUSION: Interruptions in anticoagulation therapy for up to 3 weeks pose minimal thromboembolic risk in patients with mechanical heart valves. Close follow-up after discharge is highly recommended, as recurrent hemorrhages can occur several weeks after the resumption of anticoagulation. PMID- 22528282 TI - Predictive biomarkers of recovery in traumatic brain injury. AB - Recent advances in medicine, intensive care and diagnostic imaging modalities have led to a pronounced reduction in deaths and disability resulting from traumatic brain injury. However, there are not sufficient findings to evaluate and quantify the severity of the initial and secondary processes destructive and therefore there are not effective therapeutic measures to effectively predict the outcome. For this reason, in recent decades, researchers and clinicians have focused on specific markers of cellular brain injury to improve the diagnosis and the evaluation of outcome. Many proteins synthesized in the astroglia cells or in the neurons, such as neuron-specific enolase, S100 calcium binding protein B, myelin basic protein, creatine kinase brain isoenzyme, glial fibrillary acidic protein, plasma desoxyribonucleic acid, brain-derived neurotrophic factor, and ubiquitin carboxy-terminal hydrolase-L1, have been proposed as potential markers for cell damage in central nervous system. Usually, the levels of these proteins increase following brain injury and are found in increasing concentrations in the cerebrospinal fluid depending on the injury magnitude, and can also be found in blood stream because of a compromised blood-brain barrier. In this review, we examine the various factors that must be taken into account in the search for a reliable non-invasive biomarkers in traumatic brain injury and their role in the diagnosis and outcome evaluation. PMID- 22528283 TI - Early cerebral metabolic crisis after TBI influences outcome despite adequate hemodynamic resuscitation. AB - BACKGROUND: Optimal resuscitation after traumatic brain injury (TBI) remains uncertain. We hypothesize that cerebral metabolic crisis is frequent despite adequate resuscitation of the TBI patient and that metabolic crisis negatively influences outcome. METHODS: We assessed the effectiveness of a standardized trauma resuscitation protocol in 89 patients with moderate to severe TBI, and determined the frequency of adequate resuscitation. Prospective hourly values of heart rate, blood pressure, pulse oximetry, intracranial pressure (ICP), respiratory rate, jugular venous oximetry, and brain extracellular values of glucose, lactate, pyruvate, glycerol, and glutamate were obtained. The incidence during the initial 72 h after injury of low brain glucose <0.8 mmol/L, elevated lactate/pyruvate ratio (LPR) >25, and metabolic crisis, defined as the simultaneous occurrence of both low glucose and high LPR, were determined for the group. RESULTS: 5 patients were inadequately resuscitated and eight patients had intractable ICP. In patients with successful resuscitation and controlled ICP (n = 76), within 72 h of trauma, 76% had low glucose, 93% had elevated LPR, and 74% were in metabolic crisis. The duration of metabolic crisis was longer in those patients with unfavorable (GOSe <= 6) versus favorable (GOSe >= 7) outcome at 6 months (P = 0.011). In four multivariate models the burden of metabolic crisis was a powerful independent predictor of poor outcome. CONCLUSIONS: Metabolic crisis occurs frequently after TBI despite adequate resuscitation and controlled ICP, and is a strong independent predictor of poor outcome at 6 months. PMID- 22528284 TI - A pilot study of darbepoetin alfa for prophylactic neuroprotection in aortic surgery. AB - BACKGROUND: Descending aortic (DA) surgery poses a high risk for spinal and cerebral infarction and routine use of lumbar drains allows for measurement of CSF markers of neurologic injury. Erythropoiesis medications have extensive preclinical data demonstrating neuroprotection. We hypothesized that prophylactic darbepoetin alfa (DARB) given before surgery reduces neurologic injury in patients undergoing DA repair. METHODS AND RESULTS: We performed a prospective adaptive dose-finding trial of prophylactic DARB ( www.clinicaltrials.gov NCT00647998) that terminated prematurely following publication of an erythropoietin stroke study showing possible harm. Enrollment halted before dose adjustments; nine patients each received 1 mg/kg IV DARB immediately before surgery. A prospective cohort of nine untreated patients was subsequently obtained for comparison. The primary outcome of death or neurologic impairment at discharge occurred in 1/9 (11 %) DARB patients and 3/9 (33 %) controls (p = 0.58). There were no statistical differences in changes of CSF biomarkers from baseline to 48 h comparing DARB patients to controls: S100beta, median 214 versus 260 ng/ml (p = 0.69); glial fibrillary acidic protein (GFAP), median 0.022 versus 0.58 ng/ml (p = 0.45). In patients with early perioperative neurologic ischemia, there were greater changes in CSF biomarkers, compared to those without ischemia: S100beta, median 2301 versus 124 ng/ml (p = 0.04); GFAP, median 31.78 versus 0.31 ng/ml (p = 0.34). CONCLUSIONS: There were no significant effects of prophylactic DARB on clinical outcome or CSF markers of neurologic injury in this pilot study, although all point estimates favored treatment. DA repair is a promising model of prophylactic neuroprotection. PMID- 22528285 TI - Modifications of the 1H NMR metabolite profile of processed mullet (Mugil cephalus) roes under different storage conditions. AB - (1)H NMR spectroscopy was employed to study the modifications over time of the water-soluble low molecular weight metabolites extracted from samples of salted and dried mullet (Mugil cephalus) roes (mullet bottarga) stored at different conditions. Samples of grated mullet bottarga were stored for 7 months at -20 degrees C, at 3 degrees C, and at room temperature in the presence and in the absence of light and then timely extracted and analyzed by NMR. Principal component multivariate data analysis applied to the spectral data indicated that samples stored at -20 degrees C maintained similar features over time whereas, along PC1, samples stored at room temperature in the presence and in the absence of light showed, over time, marked metabolite modifications. The comparative analysis of the integrated areas of the selected regions of the (1)H NMR spectra indicated that the major compositional changes due to storage conditions were (i) the increase of the derivatives of the breakdown of phosphatidylcholine (choline, phosphorylcholine, and glycerol), (ii) the breakdown of nucleosides, (iii) the decrease of methionine, tryptophan, and tyrosine, and (iv) the cyclization of creatine. These changes were observed at different storage conditions, with more pronounced trends in the samples stored at room temperature. The role of metabolites in food aging is discussed. PMID- 22528286 TI - Adolescent religiosity as a mediator of the relationship between parental religiosity and adolescent health outcomes. AB - Studies have demonstrated the positive impacts of both parent and adolescent religiosity on adolescent outcomes; however, the relationships among these variable have not been studied. Our study was conducted to assess whether adolescent religiosity mediates the relationship between parent religiosity and adolescent emotional and behavioral health outcomes. A sample of 491 late adolescents ages 18-22 completed surveys that assessed their parents' religious practices, their own religious practices, deviant behaviors, and internalizing behaviors. Findings suggest that adolescent religiosity mediates the relationship between parents' religiosity and adolescent health outcomes such as drug and alcohol use and depression. PMID- 22528287 TI - Holy fools: a religious phenomenon of extreme behaviour. AB - Monks in Byzantine times (330-1453 AD) often expressed their faith with extreme manifestations of behaviour, such as living on a high column (stylites), on a tree (dendrites) or in crowded urban centres of the empire pretending to be fools for Christ's sake. These Holy Fools exposed themselves to the ridicule and the mistreatment of the citizens, being protected, however, by their state of insanity to mock and violate moral codes and social conventions. The official Church barely tolerated these religious attitudes as promoting deviations from standard orthodoxy, and the Quinisext Ecumenical Council (592 AD) judged them as dangerous and formally denounced the phenomenon. The two most famous of them in Byzantium were Symeon of Emesa and Andrew of Constantinople, whose lives constitute unique testimonies to insanity and the simulation thereof. The survival and transplantation of the Holy Fools in Russia, called "yurodivye", where they met widespread acceptance, confirm their appeal in specific geographic areas and their endurance over time. We attempt to approach the symbolism of holy lunacy and to analyse the personality trends of these "eccentric" saints. PMID- 22528288 TI - Integrating diabetes self-management interventions for mexican-americans into the catholic church setting. AB - Churches provide an innovative and underutilized setting for diabetes self management programs for Latinos. This study sought to formulate a conceptual framework for designing church-based programs that are tailored to the needs of the Latino community and that utilize church strengths and resources. To inform this model, we conducted six focus groups with mostly Mexican-American Catholic adults with diabetes and their family members (N = 37) and found that participants were interested in church-based diabetes programs that emphasized information sharing, skills building, and social networking. Our model demonstrates that many of these requested components can be integrated into the current structure and function of the church. However, additional mechanisms to facilitate access to medical care may be necessary to support community members' diabetes care. PMID- 22528289 TI - Study of the spiritual intelligence role in predicting university students' quality of life. AB - The aim of the study is to investigate the spiritual intelligence role in predicting Quchan University students' quality of life. In order to collect data, a sample of 143 students of Quechan University was selected randomly enrolled for 89-90 academic year. The instruments of the data collecting are World Health Organization Quality of Life (WHOQOL) and Spiritual Intelligence Questionnaire. For analyzing the data, the standard deviation, and Pearson's correlation coefficient in descriptive level, and in inferential level, the regression test was used. The results of the study show that the spiritual intelligence has effective role on predicting quality of life. PMID- 22528290 TI - The recovery of religious and spiritual significance in American Psychiatry. AB - This paper reviews a body of data that identifies underlying influences that have contributed to an evolving change in American Psychiatry toward a more positive and receptive stance toward religion and spirituality over the past three decades. This development, surprising in light of the remedicalization of psychiatry and its predominantly neuro-biological orientation, is attributed to five foundational ideas that have helped to leverage this change. These are significance of culture, creative power of ritual, psychic function of belief, neuro-biology of spirituality, and relevance of recovery narratives. The impact of these factors for psychiatric assessment and treatment is described, as well as the contribution of the Oskar Pfister legacy and award to the ongoing dialogue between religion and psychiatry. Adapted from the American Psychiatric Association's 2011 Oskar Pfister Lecture in Religion and Psychiatry. PMID- 22528291 TI - NMR structure note: human esophageal cancer-related gene 2. PMID- 22528292 TI - Probing water-protein contacts in a MMP-12/CGS27023A complex by nuclear magnetic resonance spectroscopy. AB - Using the case of the catalytic domain of MMP-12 in complex with the known inhibitor CGS27023A, a recently assembled 3D (15)N-edited/(14)N,(12)C-filtered ROESY experiment is used to monitor and distinguish protein amide protons in fast exchange with bulk water from amide protons close to water molecules with longer residence times, the latter possibly reflecting water molecules of structural or functional importance. The (15)N-edited/(14)N,(12)C-filtered ROESY spectra were compared to the original (15)N-edited/(14)N,(12)C-filtered NOESY and the conventional amide-water exchange experiment, CLEANEX. Three protein backbone amide protons experiencing direct dipolar cross relaxation with water in the (15)N-edited/(14)N,(12)C-filtered ROESY spectrum were assigned. In an ensemble of six crystal structures, two conserved water molecules within 3 A of the three amide protons were identified. These two water molecules are buried into cavities in the protein surface and thus sufficiently slowed down by the protein topology to account for the observed dipolar interaction. Structural analysis of an ensemble of six crystal structures ruled out any exchange-relayed contributions for the amide-water interactions of interest. PMID- 22528295 TI - Surgical treatment of Parkinson's disease. PMID- 22528293 TI - A strong 13C chemical shift signature provides the coordination mode of histidines in zinc-binding proteins. AB - Zinc is the second most abundant metal ion incorporated in proteins, and is in many cases a crucial component of protein three-dimensional structures. Zinc ions are frequently coordinated by cysteine and histidine residues. Whereas cysteines bind to zinc via their unique S(gamma) atom, histidines can coordinate zinc with two different coordination modes, either N(delta1) or N(epsilon2) is coordinating the zinc ion. The determination of this coordination mode is crucial for the accurate structure determination of a histidine-containing zinc-binding site by NMR. NMR chemical shifts contain a vast amount of information on local electronic and structural environments and surprisingly their utilization for the determination of the coordination mode of zinc-ligated histidines has been limited so far to (15)N nuclei. In the present report, we observed that the (13)C chemical shifts of aromatic carbons in zinc-ligated histidines represent a reliable signature of their coordination mode. Using a statistical analysis of (13)C chemical shifts, we show that (13)C(delta2) chemical shift is sensitive to the histidine coordination mode and that the chemical shift difference delta{(13)C(epsilon1)} - delta{(13)C(delta2)} provides a reference-independent marker of this coordination mode. The present approach allows the direct determination of the coordination mode of zinc-ligated histidines even with non isotopically enriched protein samples and without any prior structural information. PMID- 22528294 TI - Complications of immunosuppressive/immunomodulatory therapy in neurological diseases. AB - OPINION STATEMENT: The first critical step in the appropriate treatment of neurological infectious disease accompanying immunosuppressive states or immunomodulatory medication is to properly identify the offending organism. Broadly immunosuppressive conditions will predispose to both common and uncommon infectious diseases. There are substantial differences between neurological infectious disorders complicating disturbances of the innate immunity (neutrophils, monocytes and macrophages) and those due to abnormal adaptive immunity (humoral and cellular immunity). Similarly, there are differences in the types of infections with impaired humoral immunity compared to disturbed cellular immunity and between T- and B-cell disorders. HIV/AIDS has been a model of acquired immunosuppression and the nature of opportunistic infections with which it has been associated has been well characterized and generally correlates well with the degree of CD4 lymphopenia. Increasingly, immunotherapies target specific components of the immune system, such as an adhesion molecule or its ligand or surface receptors on a special class of cells. These targeted perturbations of the immune system increase the risk of particular infectious diseases. For instance, natalizumab, an alpha4beta1 integrin inhibitor that is highly effective in multiple sclerosis, increases the risk of progressive multifocal leukoencephalopathy for reasons that still remain unclear. It is likely that other therapies that result in a disruption of a specific component of the immune system will be associated with other unique opportunistic infections. The risk of multiple simultaneous neurological infections in the immunosuppressed host must always be considered, particularly with a failure to respond to a therapeutic regimen. With respect to appropriate and effective therapy, diagnostic accuracy assumes primacy, but occasionally broad spectrum therapy is necessitated. For a number of opportunistic infectious disorders, particularly some viral and fungal diseases, antimicrobial therapy remains inadequate. PMID- 22528296 TI - Developing methacrylate-based copolymers as an artificial Bruch's membrane substitute. AB - Age-related macular degeneration (AMD) is the most common cause of blindness in the developed world. There is currently no treatment for the cellular loss, which is characteristic of AMD. Transplantation of retinal pigment epithelium (RPE) cells represents a potential therapy. Because of AMD-related pathology in the native support, Bruch's membrane, transplanted RPE cells require a scaffold to reside on. We present here the development of an electrospun fibrous scaffold derived from methyl methacrylate and poly(ethylene glycol) (PEG) methacrylate for novel application as an RPE scaffold. Scaffolds were chemically modified to improve cell adhesion by functionalization not previously reported for this type of copolymer system. A human RPE cell line was used to investigate cell-scaffold interactions for up to two weeks in vitro. Scanning electron microscopy was used to characterize the fibrous scaffolds and confirm cell attachment. By day 15, cell area was significantly (p < 0.001) enhanced on scaffolds with chemical modification of the PEG chain terminus. In addition, significantly, less apoptotic cell death was demonstrable on these modified surfaces. PMID- 22528298 TI - Genetic diversity analysis and development of SCAR marker for detection of Indian populations of Fusarium oxysporum f. sp. ciceris causing chickpea wilt. AB - Genetic diversity of the isolates of Fusarium oxysporum f. sp. ciceris causing chickpea wilt collected from 12 states representing different agro-ecological regions of India was determined through randomly amplified polymorphic DNA (RAPD) markers. The UPGMA cluster analysis grouped the isolates into eight categories showing high magnitude of genetic diversity. Each group had the isolates from different states present in various agro-ecological regions of India. Therefore, the groups generated through the RAPD analysis were not corresponding to area of the origin of the isolates. The RAPD primers, namely, OPA 7 and OPA 11 produced Foc specific fragment of ~1.3 kb and ~1.4 kb, respectively in all the isolates. These fragments were eluted, purified, cloned in pGEM-T Easy vector and sequenced. Primers were designed with sequence information of these two fragments using primer.3 software. Two sets of sequence characterized amplified region markers (SC-FOC 1 and SC-FOC 2) developed from the sequences of these fragments were found to be specific to Foc and produced an amplicon of 1.3 and 1.4 kb, respectively. These set of markers were validated against the isolates of the pathogen collected from different locations of India representing various races of the pathogen. They are non-specific to the other Fusarium species, Rhizoctonia solani and R. bataticola. PMID- 22528297 TI - Real-time polymerase chain reaction assay for rapid and sensitive detection of anthrax spores in spiked soil and talcum powder. AB - Real-time polymerase chain reaction (real-time PCR) is a laboratory technique based on PCR. This technique is able to detect sequence-specific PCR products as they accumulate in "real time" during the PCR amplification, and also to quantify the number of substrates present in the initial PCR mixture before amplification begins. In the present study, real-time PCR assay was employed for rapid and real time detection of Bacillus anthracis spores spiked in 0.1 g of soil and talcum powder ranging from 5 to 10(7) spores. DNA was isolated from spiked soil and talcum powder, using PBS containing 1 % Triton-X-100, followed by heat treatment. The isolated DNA was used as template for real-time PCR and PCR. Real-time PCR amplification was obtained in 60 min under the annealing condition at 60 degrees C by employing primers targeting the pag gene of B. anthracis. In the present study, the detection limit of real-time PCR assay in soil was 10(3) spores and 10(2) spores in talcum powder, respectively, whereas PCR could detect 10(4) spores in soil and 10(3) spores in talcum powder, respectively. PMID- 22528299 TI - Bactericidal effect of hydrolysable and condensed tannin extracts on Campylobacter jejuni in vitro. AB - Strategies are sought to reduce intestinal colonisation of food-producing animals by Campylobacter jejuni, a leading bacterial cause of human foodborne illness worldwide. Presently, we tested the antimicrobial activity of hydrolysable-rich blackberry, cranberry and chestnut tannin extracts and condensed tannin-rich mimosa, quebracho and sorghum tannins (each at 100 mg/mL) against C. jejuni via disc diffusion assay in the presence of supplemental casamino acids. We found that when compared to non-tannin-treated controls, all tested tannins inhibited the growth of C. jejuni and that inhibition by the condensed tannin-rich mimosa and quebracho extracts was mitigated in nutrient-limited medium supplemented with casamino acids. When tested in broth culture, both chestnut and mimosa extracts inhibited growth of C. jejuni and this inhibition was much greater in nutrient limited than in full-strength medium. Consistent with observations from the disc diffusion assay, the inhibitory activity of the condensed tannin-rich mimosa extracts but not the hydrolysable tannin-rich chestnut extracts was mitigated by casamino acid supplementation to the nutrient-limited medium, likely because the added amino acids saturated the binding potential of the condensed tannins. These results demonstrate the antimicrobial activity of various hydrolysable and condensed tannin-rich extracts against C. jejuni and reveal that condensed tannins may be less efficient than hydrolysable tannins in controlling C. jejuni in gut environments containing high concentrations of amino acids and soluble proteins. PMID- 22528300 TI - Ability of rumen protozoa Diploplastron affine to utilize beta-glucans. AB - The ability of the rumen ciliates to utilize beta-glucans other than cellulose and xylan is currently being recognized. The objective of the present study was to characterize the ability of the ciliate Diploplastron affine to digest some pachyman, laminarin, pustulan, curdlan and lichean. The protozoa were isolated from the rumen of sheep and either grown in vitro or inoculated into the rumen of ciliate-free sheep and maintained in natural conditions. In vitro culture studies showed that the enrichment of culture medium with the examined saccharides results in an increase in the number of ciliates in comparison to the control cultures. The increase was over 36 and 15 % when the growth medium was supplemented with pachyman (1,3-beta-glucan) and pustulan (1,6-beta-glucan), respectively. A positive correlation was also found between the population density of ciliates and the dose of saccharide supplemented to the growth medium. Enzyme studies were performed using the crude enzyme preparation obtained from ciliates treated with antibiotics. The ability of ciliates to digest the examined beta-glucans was tested by the quantification of reducing sugars released from the mentioned substrates during the incubation with crude enzyme preparation. The results showed that D. affine ciliates were able to digest both of them. The mean degradation rate varied between 6.7 and 28.2 MUmol/L glucose per mg protein per h for pustulan and lichean, respectively, whereas the digestion velocity was the highest at 5.0-5.5 pH and 45-50 degrees C. PMID- 22528301 TI - Inhibitory potential of lactobacilli against Escherichia coli internalization by HT 29 cells. AB - A quantitative fluorescent in situ hybridization method was employed to evaluate the competitive inhibitory effect of three Lactobacillus strains (Lactobacillus reuteri, Lactobacillus gasseri, and Lactobacillus plantarum) against Escherichia coli internalization in a model system of HT 29 cells. Furthermore, aggregation and adhesion abilities of the Lactobacillus strains were examined. All lactobacilli were able to attach to the HT 29 cells and aggregate with pathogens; however, the adhesion and aggregation degree was strain-dependent. L. reuteri possessed a high capacity of adhesion (6.80 +/- 0.63; log CFU +/- SEM per well), whereas lower capacities were expressed by L. gasseri (4.52 +/- 0.55) and L. plantarum (4.90 +/- 0.98). Additionally, L. reuteri showed the rapid or normal ability to aggregate with selected E. coli in comparison with remaining two lactobacilli, which showed only slow or negative aggregative reaction. Internalization of E. coli into the cell lines was markedly suppressed by L. reuteri, while L. gasseri and L. plantarum caused only a minimum anti-invasion effect. The fact that L. reuteri in our experiments showed an outstanding potential for adhering to the colon epithelial cell line, compared with the rest strains, suggested that one of the possible mechanisms of preventing pathogen adhesion and invasion is simple competitions at certain receptors and capability to block receptor binding sites, or that an avid interaction between L. reuteri and the host cell might be modulating intracellular events responsible for the E. coli internalization. Moreover, L. reuteri exhibited a strong ability to aggregate with E. coli, which could be another limiting factor of pathogen invasion. PMID- 22528302 TI - Growth of infant fecal bacteria on commercial prebiotics. AB - Fecal bacteria from 33 infants (aged 1 to 6 months) were tested for growth on commercial prebiotics. The children were born vaginally (20) or by caesarean section (13). Bifidobacteria, lactobacilli, gram-negative bacteria, Escherichia coli, and total anaerobes in fecal samples were enumerated by selective agars and fluorescence in situ hybridization. The total fecal bacteria were inoculated into cultivation media containing 2 % Vivinal(r) (galactooligosaccharides-GOS) or Raftilose(r) P95 (fructooligosaccharides-FOS) as a single carbon source and bacteria were enumerated again after 24 h of anaerobic cultivation. Bifidobacteria dominated, reaching counts of 9-10 log colony-forming units (CFU)/g in 17 children born vaginally and in seven children delivered by caesarean section. In these infants, lactobacilli were more frequently detected and a lower number of E. coli and gram-negative bacteria were determined compared to bifidobacteria-negative infants. Clostridia dominated in children without bifidobacteria, reaching counts from 7 to 9 log CFU/g. Both prebiotics supported all groups of bacteria tested. In children with naturally high counts of bifidobacteria, bifidobacteria dominated also after cultivation on prebiotics, reaching counts from 8.23 to 8.77 log CFU/mL. In bifidobacteria-negative samples, clostridia were supported by prebiotics, reaching counts from 7.17 to 7.69 log CFU/mL. There were no significant differences between bacterial growth on Vivinal(r) and Raftilose(r) P95 and counts determined by cultivation and FISH. Prebiotics should selectively stimulate the growth of desirable bacteria such as bifidobacteria and lactobacilli. However, our results showed that commercially available FOS and GOS may stimulate also other fecal bacteria. PMID- 22528303 TI - Bioinformatic evidence and characterization of novel putative large conjugative transposons residing in genomes of genera Bacteroides and Prevotella. AB - Bioinformatic evidence of the presence of a large conjugative transposon in ruminal bacterium Prevotella bryantii B(1)4(T) is presented. The described transposon appears to be related to another large conjugative transposon CTnBST, described in Bacteroides uniformis WH207 and to the conjugative transposon CTn3 Bf, which was observed in the genome of Bacteroides fragilis strain YCH46. All three transposons share tra gene regions with high amino acid identity and clearly conserved gene order. Additionally, a second conserved region consisting of hypothetical genes was discovered in all three transposons and named the GG region. This region served as a specific sequence signature and made possible the discovery of several other apparently related hypothetical conjugative transposons in bacteria from the genus Bacteroides. A cluster of genes involved in sugar utilization and metabolism was discovered within the hypothetical CTnB(1)4, to a certain extent resembling the polysaccharide utilization loci which were described recently in some Bacteroides strains. This is the first firm report on the presence of a large mobile genetic element in any strain from the genus Prevotella. PMID- 22528304 TI - Intestinal bacterial population of healthy rats during the administration of chitosan and chitooligosaccharides. AB - The effect of the administration of chitosan (CS) and chitooligosaccharides (COS) on rat fecal microbiota was analyzed in this study. The profile of total bacterial population was monitored during 3 weeks of CS or COS application using denaturing gradient gel electrophoresis (DGGE) analysis of 16S rRNA gene amplicons. Quantitative PCR was used for monitoring possible changes in the levels of total bacteria and the levels of individual bacterial groups: Bifidobacteria, Clostridium leptum, Enterobacteriaceae, Lactobacillus Streptococcus-Enterobacter, and Bacteroides-Prevotella. The DGGE profiles revealed a high complexity and individuality of each tested subject, and variations in the composition of band pattern were observed. CS or COS per os administration changed the profile and structure of the microbial ecosystem of the gastrointestinal tract of healthy rats. COS have, in most cases, an opposite effect compared with CS; only the Bacteroides-Prevotella bacterial group and Enterobacteriaceae were influenced in the same way. The Bifidobacteria group was not influenced by the administration CS and COS. PMID- 22528305 TI - Optimization of the DGGE band identification method. AB - Denaturant gradient gel electrophoresis (DGGE) enables insight into the diversity of the studied microbial communities on the basis of separation of PCR amplification products according to their nucleotide sequence composition. However, the success of the method is accompanied by the inherent appearance of various sequence artifacts that bias the impression of community structure by generating additional bands representing no virtual microbes. PCR-DGGE artifacts require optimization of the method when aiming at the phylogenetic identification of the selected DGGE bands. The aim of our study was to develop a procedure which will increase the reliability of the identification. Samples of rumen fluid were used for the optimization since they contain a complex microbial community that supports the generation of artifactual bands. An optimized procedure following band excision and elution of microbial DNA is proposed including nuclease treatment, selection of DNA polymerase with proofreading activity, and cloning prior to sequencing and identification analysis. PMID- 22528306 TI - Rapid flow cytometric method for viability determination of solventogenic clostridia. AB - We endeavored to develop a method for viability determination of solventogenic clostridia and to apply it for monitoring acetone-butanol-ethanol (ABE) fermentation. Six fluorescent probes (propidium iodide [PI], ethidium bromide, fluorescein diacetate, carboxyfluorescein diacetate [cFDA], rhodamine 123, bis (1,3-dibutylbarbituric acid)trimethine oxonol [BOX]) were tested in order to distinguish two subpopulations of live and dead clostridial cells in suspension. Three of them were found to be appropriate (PI, BOX and cFDA) for this purpose. Developed fluorescent staining methods were applied to batch fermentation processes of Clostridium pasteurianum and C. beijerinckii carried out in a laboratory bioreactor under anaerobic conditions. Whereas PI was found to be applicable to both strains, BOX was convenient only for viability determination of C. pasteurianum. Although cFDA can distinguish two cell subpopulations in suspension, it was found to be unsuitable for viability determination under tested conditions, since it reflected more variable esterase activity during sporulation cell cycle than viability. Flow cytometry in combination with convenient fluorescent probe has been proved to be a valuable tool for viability determination. We assume this rapid and simple method can help to obtain more complex and precise information about ABE fermentation. PMID- 22528307 TI - Chitinolytic enzymes of the rumen ciliate Eudiplodinium maggii. AB - The ability of rumen ciliates to digest chitin is clearly recognized. We investigated the chitinolytic system of the rumen ciliate Eudiplodinium maggii. The ciliates were grown in a selectively faunated sheep. They were isolated from the rumen and purified by sedimentation. A crude enzyme preparation was prepared following incubation of ciliates with antibiotics. This was done in order to reduce their contamination with intracellular bacteria. The activity of particular enzymes was examined by quantification of the products released from specific substrates. It was stated that the optimum conditions for the detected activities varied between 4.5 and 5.5 pH, and 45 and 55 degrees C. beta-N Acetylglucosaminidase was found as an enzyme of the highest activity (4.2 MUmol/l released product per mg protein per h). The activities of endochitinase and exochitinase were almost two times lower than that of beta-N acetylglucosaminidase. Zymographic studies revealed the presence of two endochitinases, two exochitinases and two beta-N-acetylglucosaminidases in the examined preparation. PMID- 22528308 TI - PCR detection of uncultured rumen bacteria. AB - 16S rRNA sequences of ruminal uncultured bacterial clones from public databases were phylogenetically examined. The sequences were found to form two unique clusters not affiliated with any known bacterial species: cluster of unidentified sequences of free floating rumen fluid uncultured bacteria (FUB) and cluster of unidentified sequences of bacteria associated with rumen epithelium (AUB). A set of PCR primers targeting 16S rRNA of ruminal free uncultured bacteria and rumen epithelium adhering uncultured bacteria was designed based on these sequences. FUB primers were used for relative quantification of uncultured bacteria in ovine rumen samples. The effort to increase the population size of FUB group has been successful in sulfate reducing broth and culture media supplied with cellulose. PMID- 22528309 TI - Excretome of the chitinolytic bacterium Clostridium paraputrificum J4. AB - A strictly anaerobic mesophilic chitinolytic bacterial strain identified as Clostridium paraputrificum J4 was isolated from human feces. In response to various types of growth substrates, the bacterium produced an array of chitinolytic enzymes representing significant components of the J4 strain secretome. The excreted active proteins were characterized by estimating the enzymatic activities of endochitinase, exochitinase, and N-acetylglucosaminidase induced by cultivation in medium M-10 with colloidal chitin. The enzyme activities produced by J4 strain cultivated in medium M-10 with glucose were significantly lower. The spectrum of extracellularly excreted proteins was separated by SDS-PAGE. The chitinase variability was confirmed on zymograms of renatured SDS-PAGE. The enzymes were visualized under ultraviolet light by using 4-methylumbelliferyl derivatives of N-acetyl-beta-D: -glucosaminide, N,N' diacetyl-beta-D: -chitobiose, or N,N',N"-triacetyl-beta-D: -chitotriose for beta N-acetylglucosaminidase, chitobiosidase, or endochitinase activities, respectively. Protein components of the secretome were separated by 2D-PAGE analysis. The distinct protein bands were excised, isolated, and subsequently characterized by using MALDI-TOF/TOF tandem mass spectrometry. The final identification was performed according to sequence homology by database searching. PMID- 22528310 TI - The antimicrobial action of chitosan, low molar mass chitosan, and chitooligosaccharides on human colonic bacteria. AB - Antibacterial effect of chitooligosaccharides (COS) and low molar mass chitosans (LMWC) is considered as one of the most important characteristics of chitosan (CS) hydrolysates. Here, we show the in vitro effect of different COS, LMWC, and CS on representative anaerobic bacteria isolated from human colon as a possibility of targeting modification of colonic microflora composition by supplementation of dietary CS products by humans. Specific growth rate of seven selected nonpathogenic anaerobic bacterial strains (Clostridium paraputrificum, Clostridium beijerinckii, Roseburia intestinalis, Bacteroides vulgatus, Bacteriodes thetaiotaomicron, Faecalibacterium prausnitzii and Blautia coccoides) was determined in the presence of 0.25 and 0.5% COS (2, 3, and 6 kDa), 0.025 and 0.05% of LMWC (10 and 16 kDa), and 0.025 and 0.1% of CS in vitro. The growth rate decreased in all strains in the presence of COS and LMWC in higher concentrations in comparison to control incubations. A relatively higher resistance to CS hydrolyzates was detected in R. intestinalis and F. prausnitzii, and more susceptible were bacteria belonging to Bacteoides sp. and Clostridium sp. The antimicrobial activity, minimum inhibitory concentrations (MIC), and minimal bactericidal concentrations (MBC) were determined. The antimicrobial activity increased with the degree of polymerization (DP). MIC ranged from 0.25 to 4.5% in dependence on bacterial strain and DP of CS/LMWC. MBC also decreased with DP. The most effective antimicrobial action was detected in LMWC with 16 kDa and CS. Weak antimicrobial activity was found in COS with small molecules (2 and 3 kDa). PMID- 22528311 TI - Variability of Actinobacteria, a minor component of rumen microflora. AB - Actinobacteria (Actinomycetes) are a significant and interesting group of gram positive bacteria. They are regular, though infrequent, members of the microbial life in the rumen and represent up to 3 % of total rumen bacteria; there is considerable lack of information about ecology and biology of rumen actinobacteria. During the characterization of variability of rumen treponemas using non-cultivation approach, we also noted the variability of rumen actinobacteria. By using Treponema-specific primers a specific 16S rRNA gene library was prepared from cow and sheep rumen total DNA. About 10 % of recombinant clones contained actinobacteria-like sequences. Phylogenetic analyses of 11 clones obtained showed the high variability of actinobacteria in the ruminant digestive system. While some sequences are nearly identical to known sequences of actinobacteria, we detected completely new clusters of actinobacteria-like sequences, representing probably new, as yet undiscovered, group of rumen Actinobacteria. Further research will be necessary for understanding their nature and functions in the rumen. PMID- 22528312 TI - Antibiotic resistance and restriction endonucleases in fecal enterococci of chamois (Rupicapra rupicapra Linnaeus, 1758). AB - Two hundred eighty-four isolates of enterococci from feces of wild living chamois from alpine environments were tested for sensitivity to three antibiotics. Low frequency of resistance was observed in studied enterococcal populations (about 5 % for tetracycline and erythromycin and 0 % for ampicillin). In six animals, the population of enterococci lacked any detectable resistance. Our data indicated that enterococcal population in feces of the majority of studied animals did not encounter mobile genetic elements encoding antibiotic resistance probably due to spatial separation and/or due to low exposure to the antibiotics. Based on resistance profiles observed, three populations were analyzed for the presence of restriction endonucleases. The restriction enzymes from two isolates-31K and 1K were further purified and characterized. Restriction endonuclease Efa1KI recognizes CCWGG sequence and is an isoschizomer of BstNI. Endonuclease Efc31KI, a BsmAI isoschizomer, recognizes the sequence GTCTC and it is a first restriction endonuclease identified in Enterococcus faecium. Our data indicate that restriction-modification (R-M) systems do not represent an efficient barrier for antibiotic resistance spreading; enterococcal populations colonized by antibiotics resistance genes were also colonized by the R-M systems. PMID- 22528313 TI - Exposure to Al2O3 nanoparticles changes the fatty acid profile of the anaerobe Ruminococcus flavefaciens. AB - One of the main mechanisms of nanoparticle toxicity is known to be the generation of reactive oxygen species (ROS) which primarily damage cell membranes. However, very limited data on membrane effects in anaerobic environments (where ROS could not be the cause of membrane damage) are available. In the following study, rumen anaerobe Ruminococcus flavefaciens 007C was used as a bacterial model to assess the potential effects of Al(2)O(3) and TiO(2) nanoparticles on membranes in an anaerobic environment. Fatty acid profiles of cultures after exposure to Al(2)O(3) or TiO(2) nanoparticles were analyzed and compared with the profiles of non-exposed cultures or cultures exposed to bulk materials. Analysis revealed dose-effect changes in membrane composition exclusively when cells were exposed to Al(2)O(3) nanoparticles in a concentration range of 3-5 g/L, but were not present in cultures exposed to bulk material. On the other hand, the tested concentrations of nano-TiO(2) did not significantly affect the membrane profile of the exposed bacterium. The results suggest the possibility that Al(2)O(3) induces changes in bacterial membranes by direct physical interaction, which was supported by TEM image analysis. PMID- 22528314 TI - Expression patterns of Ruminococcus flavefaciens 007S cellulases as revealed by zymogram approach. AB - The expression of Ruminococcus flavefaciens 007S cellulases in different incubation time points (growth stages) and their substrate inducibility were analyzed by comparing the zymogram expression profiles of cultures grown on insoluble cellulose (Avicel) with cellobiose-grown cultures. The molecular weights of the enzymes were compared to (putative) cellulases encoded in the R. flavefaciens FD-1 genome. PMID- 22528315 TI - Methanogenic activities in alpine soils. AB - Uncontrolled microbial methane production is playing an important role in global warming. In the present study, we showed that water content and incubation temperature increase the potential for methane formation in the two alpine soils under investigation. Beside these factors, the grazing of cows and thus the amendment of methanogenic microorganisms by cattle dung is the most important factor determining the potential of methane production in those soils. PMID- 22528316 TI - The ability of the rumen ciliate protozoan Diploplastron affine to digest and ferment starch. AB - The ciliate Diploplastron affine is known as a common species of the rumen fauna in cattle and sheep. This protozoon is able to digest cellulose, whereas its amylolytic activity is not well known. The objective of the reported studies was to examine the ability of D. affine to digest starch and to use this polysaccharide to cover the requirement for energy. The enzymatic studies showed that the protozoal cell extract degraded starch to reducing products with the rate being equivalent to 2.4 +/- 0.47 MUmol/L glucose per mg protein per min. Maltose, maltotriose and a small quantity of glucose were the end products of starch degradation. The degradation rate of maltose was only 0.05 MUmol/L glucose per mg protein per min. Two peaks in alpha-amylase and a single peak in maltase activity were found following molecular filtration of ciliate cell extract, whereas three starch-degrading enzymes were identified by a zymographic technique. Incubation of the bacteria-free ciliates with starch in the presence of antibiotics resulted in a release of volatile fatty acids with the net rate of 25 pmol per protozoan per h. Acetic acid followed by butyric acid was the main product of starch fermentation. The results confirmed the ability of D. affine to utilize starch in energy-yielding processes. PMID- 22528317 TI - Short and precise patient self-assessment of heart failure symptoms using a computerized adaptive test. AB - BACKGROUND: Assessment of dyspnea, fatigue, and physical disability is fundamental to the monitoring of patients with heart failure (HF). A plethora of patient-reported measures exist, but most are too burdensome or imprecise to be useful in clinical practice. New techniques used for computer adaptive tests (CATs) may be able to address these problems. The purpose of this study was to build a CAT for patients with HF. METHODS AND RESULTS: Item banks of 74 queries ("items") were developed to assess self-reported physical disability, fatigue, and dyspnea. All queries were administered to 658 adults with HF to build 3 item banks. The resulting HF-CAT was administered to 100 patients with ancillary HF (New York Heart Association I, 11%; II, 53%; III and IV, 36%). In addition, the physical function and vitality domains of the SF-36 Health Survey questionnaire, an established shortness-of-breath scale, and the Minnesota Living with Heart Failure Questionnaire were applied. The HF-CAT assessment took 3:09+/-1:52 minutes to complete and score. All HF-CAT scales demonstrated good construct validity through high correlations with the corresponding SF-36 Health Survey physical function (r=-0.87), vitality (r=-0.85), and shortness-of-breath (r=0.84) scales. Simulation studies showed a more precise measurement of all HF-CAT scales over a larger range than comparable static tools. The HF-CAT scales identified significant differences between patients classified by the New York Heart Association symptom criteria, similar to the Minnesota Living with Heart Failure Questionnaire. CONCLUSIONS: A new CAT for patients with HF was built using modern psychometric methods. Initial results demonstrate its potential to increase the feasibility and precision of patient self-assessments of symptoms of HF with minimized respondent burden. CLINICAL TRIAL REGISTRATION- URL: http://www.projectreporter.nih.gov. Unique identifier: 1R43HL083622-01. PMID- 22528318 TI - Engineering glyceraldehyde-3-phosphate dehydrogenase for switching control of glycolysis in Escherichia coli. AB - Glycolysis has evolved to be a highly robust mechanism for maintaining the cellular metabolism of living organisms. However, relevant modifications of glycolytic activity are required to intentionally modulate cellular phenotypes. Here, we designed a platform that allows switching control of glycolysis in Escherichia coli in response to an environmental signal, in this case, temperature. This system functions by regulating the expression of gapA, which encodes glyceraldehyde-3-phosphate dehydrogenase (GAPDH), one of the key glycolytic enzymes. Because a very low level of gapA expression is capable of maintaining cellular physiology, we also modified GAPDH through directed evolution to provide sensitive regulation of glycolytic activity. The switching control of glycolysis was successfully demonstrated by regulating the expression of engineered gapA through changes in temperature. This system offers potential control over the cell's central carbon-metabolism switch, providing the ability to perform reprogrammed tasks with desired timing depending on environmental signals. PMID- 22528319 TI - Nitrates as an integral part of optimal medical therapy and cardiac rehabilitation for stable angina: review of current concepts and therapeutics. AB - The goals of optimal medical therapy in patients with stable angina pectoris are to reduce the risk of cardiovascular mortality and future cardiovascular events, improve exercise capacity, and enhance quality of life. Whereas myocardial revascularization is frequently employed in the management of patients with stable angina, a variety of pharmacologic interventions are recommended as part of optimal medical management. The use of short- and rapidly-acting nitrates (eg, sublingual nitroglycerin spray and tablets) is at the core of the therapeutic armamentarium and should be integrated into optimal medical therapy for stable angina along with exercise therapy. The potential clinical implications from these observations are that prophylactic sublingual nitrates, when combined with cardiac rehabilitation, may allow the patient with angina to exercise to a greater functional capacity than without sublingual nitrates. PMID- 22528320 TI - A girl with two syndromes: Turner syndrome and Costello syndrome. A case history. PMID- 22528321 TI - Isolated pancreatic tuberculosis mimicking malignancy and causing obstructive jaundice. PMID- 22528322 TI - Advanced Pancreatic Adenocarcinoma: Complete Histological Response After Palliative Therapy with Gemcitabine and Cisplatin. PMID- 22528324 TI - Genetic variations in stem cell-related genes and colorectal cancer prognosis. AB - BACKGROUND: Many properties of cancer cells are reminiscent of those in normal stem cells. Genes important to stem cell development have been significantly implicated in the etiology and clinical outcome of colorectal cancer (CRC). However, the associations of genetic variations in these genes with CRC prognosis have not yet been elucidated. METHODS: We analyzed the effects of eight potentially functional single nucleotide polymorphisms (SNPs) in six stem cell related genes on the prognosis of a well-characterized population of 380 Chinese CRC patients diagnosed from February 2006 to January 2010. RESULTS: The most significant finding was related to rs879882, a variant in the 5' region of POU5F1 gene which encodes a protein essential for embryonic stem cell self-renewal and pluripotency, and induced pluripotent stem cell reprogramming. The variant containing genotypes of rs879882 were associated with an increased risk of recurrence (hazard ratio [HR] = 2.10, 95% confidence interval [CI] 1.17-3.76, P = 0.01). In chemotherapy-stratified analysis, the association remained borderline significant in patients receiving chemotherapy (HR = 1.97, 95% CI 0.89-4.34, P = 0.09). In addition, a nonsynonymous SNP of APC gene was also significantly associated with recurrence risk in chemotherapy-treated patients (HR = 2.63, 95% CI 1.14-6.06 P = 0.02). Further analyses showed a combined effect of the two SNPs in predicting CRC recurrence in patients receiving chemotherapy (P = 0.04) but not in those without chemotherapy (P = 0.43). Moreover, an exploratory multivariate assessment model indicated that these two variants enhanced the power to predict recurrence after chemotherapy. CONCLUSION: We presented one of the first epidemiologic studies showing that stem cell-related genetic variants may impact CRC clinical outcomes, especially in chemotherapy-treated patients. PMID- 22528327 TI - Biomarker science: on a theme of personalized medicine. PMID- 22528326 TI - Impact of CYP2C9*3, VKORC1-1639, CYP4F2rs2108622 genetic polymorphism and clinical factors on warfarin maintenance dose in Han-Chinese patients. AB - To evaluate the impact of gene polymorphisms of Cytochrome P450 2C9 (CYP2C9), Vitamin K epoxide reductase complex subunit 1 (VKORC1) and Cytochrome P450 4F2 (CYP4F2) and clinical factors on warfarin maintenance dose in Han-Chinese patients from main land. DNA was extracted from 115 patients taking warfarin for more than 3 months with a stable international normalized ratio (INR) and genotyped for CYP2C9*3, VKORC1-1639 and CYP4F2 (rs2108622) polymorphisms using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Univariate analysis and multiple regression analysis were undertaken to assess the effect of genetic and clinical factors on the warfarin maintenance dose. Our study demonstrated that patients carrying CYP4F2 CT or TT allele needed a significantly higher warfarin dose compared to those carrying CC ((3.36 +/- 0.14 mg/d vs. 2.77 +/- 0.14 mg/d), P = 0.004). We also confirmed CYP2C9 *3 variant was related to lower warfarin dose (2.01 +/- 0.23 mg/d) requirement compared to wild type (3.21 +/- 0.11 mg/d) (P = 0.001). VKORC1-1639 AG genotype was associated with a higher maintenance dose compared to those with the AA genotype (4.06 +/- 0.21 mg/d vs. 2.95 +/- 0.11 mg/d, P < 0.001). The multiple linear regression model including VKORC1-1639G>A, CYP2C9, CYP4F2 and clinical factors (body surface area (BSA) and age) could explain 42 % of the variance in the warfarin maintenance dose. We developed a dose algorithm based on genetic polymorphism and clinical variables for Han-Chinese patients and evaluated its performance. CYP4F2 rs2108622 has a small but significant association with warfarin stable dose in Han-Chinese population. PMID- 22528325 TI - Biomarkers of deep venous thrombosis. AB - Deep venous thrombosis (DVT), which is associated with pulmonary embolism, is a fatal disease because of its high morbidity and mortality in outpatients and inpatients, especially in hospitalized patients. At the same time, lack of subjective clinical symptoms and objective clinical signs makes the diagnosis complicated. Historically, the primarily imaging modalities, including duplex ultrasound, helical CT scans, and venography, establish the diagnosis of DVT. Currently, both imaging modalities and serology are utilized. These plasma molecules are regarded as the biomarkers of DVT including D-dimer, P-selectin, Factor VIII, thrombin generation, inflammatory cytokines, microparticles, fibrin monomer, leukocyte count and so on. This brief review is used to analyze the contribution of the biomarkers to diagnosis and guidance of therapy for DVT. PMID- 22528329 TI - Diagnosis and endovascular treatment of acute thromboembolic renal artery occlusion presenting with abdominal pain. AB - Acute renal artery thromboembolic occlusion is seldomly encountered with respect to other central and peripheral ones. Patients may present with non-specific abdominal pain and renal colic. Organ functions can be preserved by means of endovascular treatment when early diagnosis is possible. Acute occlusion of renal arteries must be considered in the differential diagnosis of acute flank pain. This paper presents successful endovascular treatment of thromboembolic renal artery occlusion in two cases. PMID- 22528328 TI - Effects on platelet function of a direct acting antagonist of coagulation factor Xa. AB - Because novel direct acting anticoagulants are being tested in the secondary prevention of cardiovascular events, we assessed potential effects of a direct acting antagonist of Factor Xa on platelet function. Blood from patients with known coronary artery disease who were treated with aspirin but no other antithrombotic agent was spiked in vitro with rivaroxaban alone or in combination with a direct acting P2Y12 antagonist (cangrelor). To limit cofounding effects of anticoagulants and to enable interaction between coagulation factors, blood was anticoagulated only with a specific inhibitor of Factor XIIa, corn trypsin inhibitor. Polymerization of fibrin was prevented with the peptide GPRP. Activation of platelets was determined with the use of flow cytometry in response to lipidated tissue factor, thrombin, the collagen mimetic convulxin, and adenosine diphosphate (ADP). Rivaroxaban inhibited the activation of platelets induced by tissue factor and to a lesser extent activation induced by thrombin, effects that were accentuated when combined with cangrelor. Rivaroxaban did not attenuate convulxin-induced activation of platelets; however, a limited but consistent attenuation of ADP-induced platelet activation was seen with blood anticoagulated with rivaroxaban. Effects of rivaroxaban on ADP-induced platelet activation were not mediated by thrombin, tissue factor, or platelet-leukocyte aggregation. In conclusion, rivaroxaban attenuated in vitro the activation of platelets mediated by thrombin. In light of the pivotal role of thrombin in platelet activation after rupture of an atherosclerotic plaque, rivaroxaban should attenuate platelet activation in vivo, an effect that is accentuated by combination with a P2Y12 antagonist. PMID- 22528330 TI - Benefits versus risks of pharmacological prophylaxis to prevent symptomatic venous thromboembolism in unselected medical patients revisited. Meta-analysis of the medical literature. AB - A significant proportion of the outcomes reported in trials assessing venous thromboembolism (VTE) prophylaxis in medical patients are related to asymptomatic events found on routine imaging studies. The implications of these events are controversial. Moreover, such trials did not always reflect the patient mix in today's internal medicine departments. We summarized the evidence assessing the rate of symptomatic VTE events and the benefit of pharmacological prophylaxis in unselected medical patients, and formally evaluated the benefit versus risk of this intervention. We searched MEDLINE, EMBASE and CENTRAL until June 2011 for studies that prospectively followed cohorts of medical patients and assessed the rates of VTE, and randomized controlled trials reporting the effect of prophylaxis on these events, at 3 weeks and 3 months. Eight trials were included. The rates of symptomatic VTE were 0.69 and 3.7 % for short term and long term follow-up periods, respectively. In the interventional meta-analysis, the odds ratio (OR) for overall mortality and for symptomatic VTE at 3 weeks were 0.93 and 0.59, favouring intervention. The OR for major bleeding at 3 weeks was 2.0, favouring no intervention. None of these results were statistically significant. The number needed to treat to prevent one overt VTE event was 292, while the number needed to treat for an additional major bleeding was 336. In unselected medical patients, the rate of symptomatic VTE is lower than the reported overall VTE rate, and the benefit to risk ratio of pharmacological intervention for alleviating this condition in at-risk medical inpatient is questionable. Further specifying the population at risk for an overt VTE, and the clinical significance of asymptomatic events, is warranted. PMID- 22528331 TI - High prevalence of three prothrombotic polymorphisms among Palestinians: factor V G1691A, factor II G20210A and methylenetetrahydrofolate reductase C677T. AB - Factor V leiden G1691A/R506Q (FVL), prothrombin G20210A (FII) and methylenetetrahydrofolate reductase (MTHFR) C677T are related genetic risk factors for venous thromboembolism. Analysis for those mutations is increasingly being performed on patients exhibiting hypercoagulability. The objective of this study was to determine the prevalence of FVL, FII-G20210A and MTHFR-C677T polymorphisms and their coexistence among apparently healthy Palestinians. After institutional approval, 303 apparently healthy students from An-Najah University representative to North and South regions of West Bank with no previous history of cardiovascular diseases participated in this study. A uniform questionnaire was used to collect relevant information through personal interview with the subjects. The collected information included gender, age, smoking habits, weight and height, diseases such as diabetes, cardiovascular and family history of CVD. The frequencies of allelic distribution of the three prothrombotic polymorphisms factor V G1691A/R506Q), prothrombin G2010A, and MTHFR-C677T were 0.114, 0.050 and 0.071, respectively. The prevalence of the three thrombotic polymorphisms (FVL, FII G20210A and MTHFR-C677T) were 20.1, 9.1 and 13.8 %, respectively. Statistical analysis for factor V leiden showed no significant association between place of residence (P value = 0.953) and gender (P value >0.082). The data presented in this study showed the highest prevalence of FVL among healthy Palestinians compared to other populations and this important finding should be followed in terms of clinical significance. PMID- 22528332 TI - To bridge or not to bridge: these are the questions. PMID- 22528334 TI - Relationships among biomarkers of one-carbon metabolism. AB - One-carbon metabolism is a network of metabolic pathways, disruption of which has been associated with cancer and other pathological conditions. Biomarkers of these pathways include homocysteine (HCY), S-adenosylmethionine (SAM), and S adenosylhomocysteine (SAH). A better understanding of the relationships between these biomarkers is needed for their utilization in research. This study investigated the relationships between fasting concentrations of plasma HCY, SAM, SAH and the ratio of SAM:SAH, and serum folate, vitamin B(12) and creatinine in a healthy adult population. A cross-sectional study recruited 678 volunteers; only subjects with complete data (n = 581) were included in this analysis. Correlations were used to examine bivariate relationships among the biomarkers and multivariate linear regression determined independent relationships with HCY, SAM and SAH treated as dependent variables in separate models. Multivariate logistic regression examined determinants of a low SAM:SAH ratio (defined as having a SAM:SAH ratio in the bottom quartile and SAH value in the top quartile). HCY correlated inversely with folate and vitamin B(12) and weakly correlated with SAH and creatinine. Both SAM and SAH correlated with creatinine but were independent of serum folate and vitamin B(12). In multivariate analyses, folate, vitamin B(12), creatinine, sex and age were associated with HCY; age and creatinine were determinants of SAM, and sex and creatinine determinants of SAH. Finally, male sex and increasing creatinine levels were associated with having a low SAM:SAH ratio. Findings suggest that HCY, SAM and SAH are relatively independent parameters and reflect distinct aspects of one-carbon metabolism. PMID- 22528335 TI - Effect of CYP17 and PSA gene polymorphisms on prostate cancer risk and circulating PSA levels in the Slovak population. AB - Cytochrome P-450c17alpha (CYP17) and prostate-specific antigen (PSA) genes, which are involved in the androgen metabolism cascade, have been studied as possible candidates for genetic influences on prostate cancer development. Contradictory results prompted us to evaluate the frequencies of polymorphisms in the CYP17 and PSA genes as well as the association between these genetic variants and serum PSA levels in prostate cancer patients and men routinely screened for prostate cancer with PSA in the Slovak male population. The CYP17 and PSA polymorphisms were determined by the PCR-RFLP analysis in 197 Caucasian prostate cancer patients and 256 Caucasian controls. We did not find any association between the CYP17 and PSA genotypes and prostate cancer risk overall, or by grade. Also the total serum PSA levels in the cases with the AG or AA genotype were not significantly higher than in the men with the GG genotype (P > 0.05). Our study did not provide support for the hypothesized relationship between CYP17 and PSA gene polymorphisms and prostate cancer in the Slovak male population. PMID- 22528336 TI - Association study of interleukin-4 polymorphisms with paranoid schizophrenia in the Polish population: a critical approach. AB - Changes in immunological system are one of dysfunctions reported in schizophrenia. Some changes based on an imbalance between Th1 and Th2 cytokines results from cytokine gene polymorphisms. Interleukin-4 gene (IL4) is considered as a potential candidate gene in schizophrenia association studies. The aim of the current case-control study was to examine whether the -590C/T (rs2243250) and -33C/T (rs2070874) IL4 gene polymorphisms are implicated in paranoid schizophrenia development in the Polish population. Genotyping of polymorphisms was performed by using PCR-RFLP technique. The genotypes and alleles distribution of both SNPs were analysed in patients (n = 182) and healthy individuals constituted the control group (n = 215). The connection between some clinical variables and studied polymorphisms has been examined as well. We did not revealed any association between the -590C/T and -33C/T polymorphisms and paranoid schizophrenia. In case of both SNPs the homozygous TT genotype was extremely rare. Both polymorphic sites of the IL4 gene were found to be in a very strong linkage disequilibrium. However we did not identify a haplotype predispose to paranoid schizophrenia. No associations were also observed between the clinical course and psychopathology of the disease and the genotypes of both analysed polymorphisms. Our results suggest that the polymorphisms -590C/T in IL4 gene promoter region and -33C/T in the 5'-UTR are not involved in the pathophysiology of paranoid schizophrenia in Polish residents. PMID- 22528337 TI - Assessment of radiation dermatitis using objective analysis for patients with breast cancer treated with breast-conserving therapy: influence of body weight. AB - PURPOSE: To evaluate the effect of patient factors on radiation dermatitis for patients with breast cancer who underwent postoperative radiotherapy after breast conserving surgery. MATERIALS AND METHODS: The study population comprised 87 patients who underwent breast-conserving surgery followed by 50 Gy/25 fractions (median) of radiotherapy with or without boost radiation (10 Gy/5 fractions). We examined their treated and contralateral breast skin color by use of an objective analyzer, and expressed findings as L, a, b ratios by dividing by pre-RT values. Next, we examined correlation between patient factors (age, height, body weight, and body mass index, BMI) and change of L and a values by use of correlation coefficients. RESULTS: Radiation therapy caused changes in a and L ratios (p < 0.0001) but not in b ratio. The a ratio (reddish) increased 1.4-fold and peaked after radiotherapy. The L ratio (darkening) decreased by 10 % and reached a minimum value between completion of radiotherapy and 1 month after treatment. Although, age and height did not affect Delta value, body weight and BMI correlated significantly with Deltaa value (p = 0.0012 and 0.0017) not with DeltaL value. CONCLUSION: Body weight and BMI predict degree of radiation dermatitis, and more reddish dermatitis was observed for heavier patients than for their lighter counterparts. PMID- 22528339 TI - Bilateral accessory inferior turbinates and secondary middle turbinates. AB - Bifid inferior nasal turbinates-two inferior turbinates with a single root observed in the nasal cavity-are an extremely rare anatomical variation, especially when they are observed bilaterally and exist with other variations. We report a case of bilateral bifid inferior nasal turbinates with bilateral secondary middle turbinates. We discuss the findings of this rare condition and suggest an appropriate term-accessory inferior turbinate-to replace bilateral inferior turbinate by reason of its embryology. PMID- 22528338 TI - Oblique approach for CT-guided liver radiofrequency ablation using multiplanar reformation images in hepatocellular carcinoma. AB - PURPOSE: To evaluate the feasibility and safety of CT-guided radiofrequency (RF) ablation by caudal-cranial oblique insertion using multiplanar reformation (MPR) images for hepatocellular carcinomas (HCCs). MATERIALS AND METHODS: Twenty-two HCCs in 19 patients that were difficult to demonstrate on ultrasound (mean tumor diameter was 17.5 mm) were treated with CT-guided RF ablation by caudal-cranial oblique insertion to avoid pneumothorax, using MPR images after transcatheter arterial chemoembolization. The insertion point and direction of insertion, avoiding aerated lung parenchyma, bones, large vessels, and intestine, were sought on the MPR images. Technical success was defined as complete eradication of tumor enhancement in the contrast-enhanced CT. Local tumor progression was defined by the appearance of enhanced tumor adjacent to the zone of ablation. The technical success rate, local tumor progression, and complications were investigated. RESULTS: The coronal plane was used for insertion in 18 tumors, the sagittal plane in 3 tumors, and the oblique plane in 1 tumor. RF electrode placement was successful and complete necrosis was obtained in all cases. During the mean follow-up period of 38.0 months, local tumor progression was not detected in any of the patients. There were no major complications, including pneumothorax. CONCLUSION: CT-guided RF ablation by caudal-cranial oblique insertion using MPR images is a feasible and safe therapeutic option. PMID- 22528340 TI - A male case of primary retroperitoneal mucinous cystadenoma: a diagnostic dilemma. AB - We report a male case of primary retroperitoneal mucinous cystadenoma (PRMC) that was at initially misdiagnosed as a complicated renal cyst. On ultrasonography, a 71-year-old man was found to have an abdominal mass suspicious for right renal cyst. The initial computed tomography scan showed an unenhanced, low-density mass that deformed the edge of the right kidney into a beak shape. Four years later, the mass had increased in size. Magnetic resonance imaging revealed a cystic lesion. Its intracystic content showed relatively high intensity on a T1-weighted image, and the coronal gadolinium-enhanced T1-weighted image with fat suppression clearly showed a multilocular cystic mass without enhancing mural nodules. The final diagnosis of PRMC was obtained pathologically after surgery. Because PRMC has malignant potential, this rare entity should be considered when a retroperitoneal cystic tumor is evaluated, even in a male patient. PMID- 22528341 TI - A case of extrapancreatic solid pseudopapillary tumor in the retroperitoneum. AB - Solid pseudopapillary tumor (SPT) is an uncommon epithelial neoplasm of the pancreas. Very rarely it has also been described outside the pancreas. We report such a case located in the right adrenal site in a 37-year-old woman, describing the computed tomography features of the neoplasm. The image features of extrapancreatic SPT in our case are compatible with those of conventional pancreatic SPTs. Although it is still difficult to make an accurate preoperative diagnosis of an extrapancreatic SPT, the presence of an encapsulated solid and cystic mass especially with widely distributed calcifications is at least suggestive of the diagnosis. Being aware of the rare occurrence of primary SPT outside the pancreas may help improve the diagnostic specificity of the disease. PMID- 22528344 TI - Preparation of alkylmagnesium reagents from alkenes through hydroboration and boron-magnesium exchange. PMID- 22528345 TI - Establishment of new lines of human embryonic stem cells: evolution of the methodology. AB - Although since 1998 more than 1,200 different hESC lines have been established worldwide, there is still a recognized interest in the establishment of new lines of hESC, particularly from HLA types and ethnic groups underrepresented among the currently available lines. The methodology of hESC derivation has evolved significantly since the initial derivations using human LIF (hLIF) for maintenance of pluripotency. However, there are still a number of alternative strategies for the different steps involved in establishing a new line of hESC. We have analyzed the different strategies/parameters used between 1998 and 2010 for the derivation of the 375 hESC lines able to form teratomas in immunocompromised mice deposited in two international stem cell registries. Here we describe some trends in the methodology for establishing hESC lines, discussing the developments in the field. Nevertheless, we describe a much greater heterogeneity of strategies for hESCs derivation than what is used for murine ESC lines, indicating that optimum conditions have not been identified yet, and thus, hESC establishment is still an evolving field of research. PMID- 22528342 TI - Hepatitis B virus infection and pregnancy: a practical approach. AB - Hepatitis B virus (HBV) infection is a global problem and the world has 350 million carriers of chronic hepatitis B. Over 50 % of these have acquired their infection vertically from their mothers (mother-to-child transmission [MTCT]). Majority (>90 %) of vertically-acquired infection results into chronic infection, due to induction of an immune-tolerant state. Hence, management of chronic HBV during pregnancy and strategies to prevent MTCT would go a long way in global control of HBV infection and the morbidity and mortality associated with it. However, chronic HBV infection in pregnancy presents a unique challenge, because of existence of a complex relationship between the physiological changes of pregnancy and the pathophysiological response of body to HBV. This relationship may lead to a varied presentation of the patient to the doctor depending on the period of her pregnancy and stage of her liver disease. Each of these modes of presentation raises issues that need to be addressed for successful maternal and fetal outcome, including prevention of MTCT of HBV. This review will try to give a practical approach in addressing these issues. PMID- 22528343 TI - Ursodeoxycholic acid in patients with ulcerative colitis and primary sclerosing cholangitis for prevention of colon cancer: a meta-analysis. AB - PURPOSE/AIM: Colon cancer risk is high in patients with ulcerative colitis (UC) and primary sclerosing cholangitis (PSC). Ursodeoxycholic acid has been shown to have some promise as a chemopreventive agent. A meta-analysis was performed to compare the efficacy of ursodeoxycholic acid in the prevention of colonic neoplasia in patients with UC and PSC. METHODS: Multiple databases were searched (January 2011). Studies examining the use of ursodeoxycholic acid vs. no ursodeoxycholic acid or placebo in adult patients with UC and PSC were included. Data were extracted in standard forms by two independent reviewers. Meta-analysis for the effect of ursodeoxycholic acid was performed by calculating pooled estimates of adenoma or colon cancer formation by odds ratio (OR) with random effects model. Heterogeneity was assessed by calculating the I (2) measure of inconsistency. RevMan 5 was utilized for statistical analysis. RESULTS: Four studies (n = 281) met the inclusion criteria. The studies were of adequate quality. Ursodeoxycholic acid demonstrated no overall improvement in adenoma (OR 0.53; 95 % CI: 0.19-1.48, p = 0.23) or colon cancer occurrence (OR 0.50; 95 % CI: 0.18-1.43, p = 0.20) as compared to no ursodeoxycholic acid or placebo in patients with UC and PSC. CONCLUSION: Ursodeoxycholic acid use in patients with UC and PSC does not appear to decrease the risk of adenomas or colon cancer. PMID- 22528346 TI - Human embryonic stem cells derived in xeno-free conditions. AB - In this chapter, we describe the derivation and characterization of nine hIn this chapter, we describe the derivation and characterization of nine human embryonic stem cells (hESC) (VAL-3 to -11B) from different developmental embryo stages (inner cell mass from a blastocyst, morula, and blastomere from a 3-day embryo) under xeno-free conditions providing the necessary protocols and techniques to carry out their derivation, characterization, and propagation. PMID- 22528347 TI - Procedures for derivation and characterisation of human embryonic stem cells from Odense, Denmark. AB - In 1998, a development occurred in stem cell biology with the first report of the derivation of a human embryonic stem cell (hESC) line. Since then a number of techniques have been used to derive and characterise hESCs. Here, we describe the derivation methods used by our laboratory for isolation of the ICM by immunosurgery and outgrowth of the whole blastocyst. We have added protocols for routine culture, passaging and cryopreservation of our hESC lines as well as the methods we have used for characterisation (flow cytometry, karyotyping, immunocytochemistry, in vitro and in vivo differentiation). Additionally, we have included gene sequences for PCR and an antibody list for immunocytochemistry. PMID- 22528348 TI - Principles for derivation of human embryonic stem cells. AB - This chapter describes the principles for derivation and maintenance of human embryonic stem cells. Detailed protocols are outlined and researchers who are generally skilled in mammalian cell culture should be able to repeat the processes successfully. Further, the protocols are intended for scientists who do not have access to advanced IVF equipment and therefore cannot perform, e.g. assisted hatching. In addition to derivation, we also discuss characterisation and banking of hES cells. PMID- 22528349 TI - Derivation and maintenance of undifferentiated human embryonic stem cells. AB - Human embryonic stem cells (hESCs) are self-renewing, pluripotent cells derived from the inner cell mass of blastocysts, early-stage embryos, or blastomeres. hESCs can be propagated indefinitely in an undifferentiated state in vitro and have the ability to differentiate into all cell types of the body. Therefore, these cells can potentially provide an unlimited source of cells and hold promise for transplantation therapy, regenerative medicine, drug screening and discovery, and basic scientific research. Surplus human embryos donated for hESC derivation are extremely valuable, and inefficient derivation of hESCs would be a terrible waste of human embryos. Here, we describe a method for isolating hESC lines from human blastocysts with high efficiency. We also describe the methods for excising differentiated areas from partially differentiated hESC colonies and re-isolating undifferentiated hESCs from extremely differentiated hESC colonies. PMID- 22528350 TI - Establishment of hESC lines from the inner cell mass of blastocyst-stage embryos and single blastomeres of 4-cell stage embryos. AB - More than 600 human embryonic stem cell (hESC) lines have been reported today at the human European Embryonic Stem Cell Registry ( http://www.hescreg.eu/ ). Despite these high numbers, there are currently no general protocols for derivation, culture, and characterization of hESC. Moreover, data on the culture of the embryo used for the derivation (medium, day of ICM isolation) are usually not available but can have an impact on the derivation rate. We present here the protocols for derivation, culture and characterization as we applied them for the 22 hESC lines (named VUB-hESC) in our laboratory. PMID- 22528351 TI - Analysis of LINE-1 expression in human pluripotent cells. AB - Half of the human genome is composed of repeated DNA, and some types are mobile within our genome (transposons and retrotransposons). Despite their abundance, only a small fraction of them are currently active in our genome (Long Interspersed Element-1 (LINE-1), Alu, and SVA elements). LINE-1 or L1 elements are a family of active non-LTR retrotransposons, the ongoing mobilization of which still impacts our genome. As selfish DNA elements, L1 activity is more prominent in early human development, where new insertions would be transmitted to the progeny. Here, we describe the conventional methods aimed to determine the expression level of LINE-1 elements in pluripotent human cells. PMID- 22528352 TI - Characterization and gene expression profiling of five human embryonic stem cell lines derived in Taiwan. AB - Human embryonic stem cell (hESC) lines have been derived from the inner cell mass of blastocysts. Five hESC lines have been derived from 32 discarded blastocysts in Taiwan, and these lines have since been continuously cultured on mitotically inactivated mouse embryonic fibroblasts as feeder in the hESC medium for more than 44 passages and underwent freezing/thawing processes. All of five hESC lines expressed characteristic undifferentiated hESC markers such as SSEA-4, TRA-1-81, alkaline phosphatase, TERT, transcription factors POU5F1 (OCT4), and NANOG. The hESC lines T1 and T3 possess normal female karyotypes, whereas lines T4 and T5 are normal male, but line T2 is male trisomy 12 (47XY,+12). The hESC lines T1, T2, T3, and T5 were able to produce teratomas in SCID mice, and line T4 could only form embryoid bodies in vitro. Global gene expression profiles of single colonies of these five hESC lines were analyzed using Affymetrix human genome U133 plus 2.0 GeneChip. The results showed that 4,145 transcripts, including 19% of unknown functions, were detected in all five hESC lines. Comparison of the 4,145 genes commonly expressed in the five hESC lines with those genes expressed in teratoma produced by hESC line T1 and placenta revealed 40 genes exclusively expressed in all five hESC lines. These 40 genes include the previously reported stemness genes such as POU5F1 (OCT4), NANOG, TDGF1 (CRIPTO), SALL4, LECT1, and BUB1 responsible for self-renewal and pluripotent differentiation. The global gene expression analysis also indicated that the TGFbeta/activin branch components inhibin BC, ACVR2A, ACVR1 (ALK2), TGFBR1 (ALK5), and SMAD2 were found to be highly expressed in undifferentiated states of these five hESC lines and decreased upon differentiation. The epigenetic states and expression of 32 known imprinted genes in these five hESC lines and/or differentiated derivatives were also investigated. In short, the hESC nature of these five hESC lines is supported by the undifferentiated state, extensive renewal capacity, and pluripotency, including the ability to form teratomas and/or embryoid bodies; and these cell lines will be useful for research on human embryonic stem cell biology and drug development/toxicity testing. The epigenetic states and expression of imprinted genes in hESC lines should be thoroughly studied after extended culture and upon differentiation in order to understand epigenetic stability in hESC lines before their clinical applications. PMID- 22528353 TI - Derivation of human embryonic stem cell lines from poor quality embryos. AB - A serious shortcoming in the derivation of human embryonic stem cell (hESC) lines has been the availability of human embryos. About 60% of human embryos generated by in vitro fertilization (IVF) fail to develop normally and are unusable for fertility treatment. Such embryos often retain sufficient pluripotent cells that can generate genetically normal, pluripotent hESC lines with stable phenotype. We describe here a simple protocol for isolating pluripotent stem cells from abnormally developed grade III human embryos that are an unutilized byproduct of in vitro fertility treatment. Embryos that progress to the blastocyst stage are subjected to immunosurgery or mechanical surgery to isolate the inner cell mass (ICM). Isolated cells are plated on to fibroblast feeders in hESC derivation media. Pluripotent cells that grow from the ICM are isolated mechanically and cultured to obtain a stable hESC line. In this way, we derived two sibling hESC lines BJNhem19 and BJNhem20 that represent the Indian ethnic background and show stable phenotype upon long-term continuous culture of over 225 passages. PMID- 22528354 TI - Derivation, expansion, and characterization of human embryonic stem cell lines from aneuploid embryos. AB - Human embryonic stem cells (hESCs) are an invaluable cell source to study human embryogenesis and development and for exploring the nature of human diseases. Moreover, hESCs can serve as an unlimited source of cells for cell therapy. The first hESC lines were derived from frozen blastocyst-stage embryos. In the past 12 years, the field evolved and the hESC lines are derived from pre-embryos in various developmental stages using several techniques. In parallel, the wide use of hESCs triggered the development of materials and methods for expansion of the cell lines derived. Here, we describe our method for derivation, expansion, and characterization of hESC lines from pre-embryos that were diagnosed to carry aneuploid cells and were destined to be discarded. PMID- 22528355 TI - Mutated human embryonic stem cells for the study of human genetic disorders. AB - Human embryonic stem cells (HESCs) are of great interest in biology and medicine due to their ability to grow indefinitely in culture while maintaining their ability to differentiate into all different cell types in the human body. In addition, HESCs can be used for better understanding the key developmental processes and can, therefore, serve for studying genetic disorders for which no good research model exists. Preimplantation genetic diagnosis of in vitro derived embryos results in affected-spare blastocysts with specific known inherited mutations.These affected blastocysts can be used for the derivation of disease bearing HESCs, which would serve for studying the molecular and pathophysiological mechanisms underlying the genetic disease for which they were diagnosed. This chapter describes the methods to derive HESCs carrying mutations for inherited disorders. PMID- 22528356 TI - Single-cell enzymatic dissociation of hESC lines OxF1-OxF4 and culture in feeder free conditions. AB - Experimental manipulation of hESCs has been hampered by their fragility and susceptibility to apoptosis when dissociated into single cells. The OxF lines are particularly robust and may be successfully passaged as single cells, with the inclusion of ROCK inhibitor in the medium. The protocols here describe the enzymatic dissociation of hESCs into a single-cell suspension and the plating of these cells onto either feeder cells or a protein-coated surface. PMID- 22528357 TI - Protocol for expansion of undifferentiated human embryonic and pluripotent stem cells in suspension. AB - Human embryonic and induced pluripotent stem cells (hESCs and hiPSCs) offer a platform technology with the potential for developmental biology and cell-based therapy. Therefore, robust and cost-effective ways for mass production of them is necessary. Here, we have presented a protocol to grow pluripotent hESCs and hiPSCs in suspension by using a simple, inexpensive, microcarrier-free method. Under this condition, the cells maintained stability during freeze/thaw cycles without the loss of pluripotency markers for extended periods (>1 year). The cells maintained a stable karyotype and showed very similar expression profiles when compared to the adherent culture. The combination of this system with a bioreactor culture system will allow scale up culture of hESCs and hiPSCs needed for clinical and translational applications. PMID- 22528358 TI - Suspension bioreactor expansion of undifferentiated human embryonic stem cells. AB - Embryonic stem cells (ESCs) are unique cells, which have the ability to differentiate into all cell types that comprise the adult organism. Furthermore, ESCs can infinitely self-renew under optimized conditions. These features place human ESCs (hESCs) in a position where these cells can be exploited for tissue engineering and regenerative medicine approaches in treating human degenerative disorders. However, cell therapy approaches will require large amounts of clinically useable cells, not typically achievable using standard static cell culture methods. Here, we describe a method wherein clinically relevant numbers of hESCs can be generated in a cost and time effective manner. PMID- 22528359 TI - Derivation, propagation, and characterization of neuroprogenitors from pluripotent stem cells (hESCs and hiPSCs). AB - The differentiation of human embryonic stem cells (hESCs) and human-induced pluripotent stem cells (hiPSCs) towards functional neurons particularly hold great potential for the cell-based replacement therapy in neurodegenerative diseases. Here, we describe a stepwise differentiation protocol that mimics the early stage of neural development in human to promote the generation of neuroprogenitors at a high yield. Both the hESCs and hiPSCs are initially cultured in an optimized feeder-free condition, which offer an efficient formation of aggregates. To specify the neuroectodermal specification, these aggregates are differentiated in a defined neural induction medium to develop into neural rosettes-like structures. The rosettes are expanded into free floating sphere and can be further propagated or developed into variety of neuronal subtypes. PMID- 22528360 TI - Comparison of neural differentiation potential of human pluripotent stem cell lines using a quantitative neural differentiation protocol. AB - Neural differentiation of human embryonic (ES) and induced pluripotent (iPS) stem cell lines has been used for research in early human development, drug discovery, and cell replacement therapies. It is critical to establish generic differentiation protocols to compare the neural specification potential of each individually derived pluripotent stem cell line and identify the efficacious lines for research and therapeutic use. Here, we describe a reproducible and quantitative protocol to assess the neural progenitor (NP) generation of human pluripotent stem cell lines. This method includes a robust and well-defined neural inducing platform for Pax6(+) neural rosette (neuroectodermal cells) generation, propagation, and subsequent differentiation into nestin(+) NPs. A side-by-side comparison under common culture conditions among three human ES cell lines, TE03, TE06, and BG01V, and one iPS cell line, HD02, showed highly variable efficiency in their differentiation into NPs. PMID- 22528361 TI - Array-comparative genomic hybridization characterization of human pluripotent stem cells. AB - During culture adaptation, human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) tend to acquire chromosomal aberrations. Generally, stem cell lines are screened for large-scale chromosomal changes using low resolution karyotype analysis. Recent studies characterizing human stem cells using array-comparative genomic hybridization (aCGH) suggests most abnormalities acquired during culture are under the resolution of karyotype analysis and therefore are routinely missed. Here, we describe a custom-designed stem cell focused microarray utilizing 44K probes, with increased resolution in relevant stem cell-associated and cancer-related genes. PMID- 22528362 TI - Chromatin immunoprecipitation-based analysis of gene regulatory networks operative in human embryonic stem cells. AB - Chromatin immunoprecipitation (ChIP) followed by microarray-based (ChIP-Chip) or next-generation sequencing-based (ChIP-Seq) analysis has been established as a powerful and widely used method to investigate DNA-protein interactions relative to a genomic location in vivo. Here, we present a ChIP-Chip protocol, which utilizes an alternative, easier amplification protocol and when using high quality ChIP-grade antibodies, will generate enough material for hybridization or sequencing with negligible enrichment bias due to amplification. PMID- 22528363 TI - Analysis of the methylome of human embryonic stem cells employing methylated DNA immunoprecipitation coupled to next-generation sequencing. AB - The analysis of DNA-methylation on a genome-wide scale by next-generation sequencing techniques is an invaluable tool towards the understanding of the epigenetic basis of cellular differentiation. Methylated DNA immunoprecipitation (MeDIP) is an immunocapturing method using an antibody targeting 5-methylcytidine (5 mC) and thereby enriching methylated DNA. MeDIP combined with next-generation sequencing (MeDIP-seq) provides a powerful tool for the analysis of genome-wide DNA-methylation profiles. Here, we describe a protocol for the preparation of MeDIP samples suitable for next-generation sequencing on a Genome Analyser (Illumina). PMID- 22528364 TI - Stable isotope labelling with amino acids in cell culture for human embryonic stem cell proteomic analysis. AB - The identification and quantitative measurements of proteins in human embryonic stem cells (hESC) is a fast growing interdisciplinary area with an enormous impact on understanding the biology of hESC and the mechanism controlling self renewal and differentiation. Using a quantitative mass spectroscopic method of stable isotope labelling with amino acids during cell culture (SILAC), we are able to analyse differential expression of proteins from different cellular compartments and to identify intracellular signalling pathways involved in self renewal and differentiation. In this chapter, we provide a detailed method for creating SILAC media suitable for use in hESC experiments, additionally we describe methods for the isolation of membrane fractions and cytosolic and nuclear/membrane fractions. PMID- 22528365 TI - Changes in biomechanical strain and morphology of rat calvarial sutures and bone after Tgf-beta3 inhibition of posterior interfrontal suture fusion. AB - Craniofacial sutures are bone growth fronts that respond and adapt to biomechanical environments. Little is known of the role sutures play in regulating the skull biomechanical environment during patency and fusion conditions, especially how delayed or premature suture fusion will impact skull biomechanics. Tgf-beta3 has been shown to prevent or delay suture fusion over the short term in rat skulls, yet the long-term patency or its consequences in treated sutures is not known. It was therefore hypothesized that Tgf-beta3 had a long-term impact to prevent suture fusion and thus alter the skull biomechanics. In this study, collagen gels containing 3 ng Tgf-beta3 were surgically placed superficial to the posterior interfrontal suture (IFS) and deep to the periosteum in postnatal day 9 (P9) rats. At P9, P24, and P70, biting forces and strains over left parietal bone, posterior IFS, and sagittal suture were measured with masticatory muscles bilaterally stimulated, after which the rats were sacrificed and suture patency analyzed histologically. Results demonstrated that Tgf-beta3 treated sutures showed less fusion over time than control groups, and strain patterns in the skulls of the Tgf-beta3-treated group were different from that of the control group. Although bite force increased with age, no alterations in bite force were attributable to Tgf-beta3 treatment. These findings suggest that the continued presence of patent sutures can affect strain patterns, perhaps when higher bite forces are present as in adult animals. PMID- 22528366 TI - Leucine-rich repeat kinase 2 and alternative splicing in Parkinson's disease. AB - Mutations of the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of Parkinson's disease (PD) and are associated with pleiomorphic neuropathology. We hypothesize that LRRK2 mediates its pathogenic effect through alternative splicing of neurodegeneration genes. Methods used in this study included western blotting analysis of subcellular protein fractions, exon-array analysis of RNA from cultured neuroblastoma cells transfected with LRRK2 expression vectors, and reverse-transcription polymerase chain reaction (RT-PCR) of RNA from cultured cells and postmortem tissue. Overexpression of the LRRK2 G2019S mutant resulted in a significant (2.6-fold; P = 0.020) decrease in nuclear transactive response DNA-binding protein 43 levels. Exon-array analyses revealed that wild-type LRRK2 had a significant effect on the expression of genes with nuclear (P < 10(-22) ) and cell-cycle functions (P < 10(-15) ). We replicated changes in gene expression in 30% of selected genes by quantitative RT-PCR. Overexpression of LRRK2 resulted in the altered splicing of two genes associated with PD, with an increased inclusion of exon 10 of microtubule-associated protein tau (1.7-fold; P = 0.001) and exon 5 of the alpha-synuclein (SNCA) gene (1.6 fold; P =0.005). Moreover, overexpression of LRRK2 (G2019S) and two mutant genes associated with neurodegeneration, TARDBP (M337V) and FUS (R521H), were associated with decreased inclusion out of the dystonin (DST) 1e precursor exons in SK-N-MC cells. Altered splicing of SNCA (1.9-fold; P < 0.001) and DST genes (log(2) 2.3-fold; P = 0.005) was observed in a cohort of PD, compared with neurologically healthy, brains. This suggests that aberrant RNA metabolism is an important contributor to idiopathic PD. PMID- 22528367 TI - Chemotherapy-resistant metastatic breast cancer. AB - OPINION STATEMENT: Remaining the most common cancer in women through the 21(st) century, breast cancer and the development of treatment strategies continue to highlight advances made in our understanding of the pathogenesis of cancer development and resistance to therapies. Despite significant progress in the treatment of breast cancer, resistance to chemotherapeutic agents remains a consistent obstacle in terms of treatment success. Anthracyclines, first used over 30 years ago, and the more recent addition of taxanes to the treatment armamentarium are integral components for both newly diagnosed and recurrent breast cancer. Unfortunately, along with other constituents of combination chemotherapy for metastatic breast cancer, these agents ultimately become ineffective in controlling disease. With the emergence of a resistant phenotype, tumors are deemed to be drug resistant - frequently multidrug resistant (MDR). A number of processes have been identified that can underlie clinical drug resistance; observations stemming largely from in vitro laboratory-based studies in human cancer cell lines. Recognized mechanisms of resistance include altered expression of the adenosine triphosphate-binding cassette (ABC) superfamily of transporters, alteration in DNA repair pathways, mutations in cellular targets, resistance to initiation of the apoptotic pathway and the development of constitutively activated signaling pathways. As our understanding of mechanisms of resistance expands, the ability to select specific drugs or drug combinations specific to the phenotype of the cancer will become more specific. Illustrative of these advancements are the reported benefits from the use of newer microtubule targeting agents in triple negative breast cancer, such as eribulin and ixabepilone; drugs which may be less susceptible to common pathways of drug resistance. Likewise, the combination usage of agents which intersect in receptor crosstalk, such as between the estrogen receptor and the mammalian target of rapamycin (mTOR), have demonstrated synergy in antitumor effects. The recent report of exemestane used in combination with everolimus, have shown great promise in this regard. For patients with HER2 positive disease, a combination approach with trastuzumab and investigational agents such as pertuzumab appear to result in a more complete blockage of HER2 signaling, and improved progression free survival. Thus, as our understanding of the interconnectedness of signaling pathways in breast cancer improves, the ability to rationally design appropriate chemotherapy regimens and delay emerging resistance will improve. PMID- 22528368 TI - Therapeutic strategies for bone metastases and their clinical sequelae in prostate cancer. AB - OPINION STATEMENT: Skeletal metastases threaten quality of life, functionality, and longevity in patients with metastatic castration-resistant prostate cancer (mCRPC). Therapeutic strategies for bone metastases in prostate cancer can palliate pain, delay/prevent skeletal complications, and prolong survival. Pharmacologic agents representing several drug classes have demonstrated the ability to achieve these treatment goals in men with mCRPC. Skeletal-related events such as fracture and the need for radiation can be delayed using drugs that target the osteoclast/osteoblast pathway. Cancer-related bone pain can be palliated using beta-emitting bone-seeking radiopharmaceuticals such as samarium 153 EDTMP and strontium-89. Also, prospective randomized studies have demonstrated that cytotoxic chemotherapy can palliate bone pain. For the first time, bone-directed therapy has been shown to prolong survival using the novel alpha-emitting radiopharmaceutical radium-223. Given these multifold clinical benefits, treatments targeting bone metabolism, tumor-bone stromal interactions, and bone metastases themselves are now central elements of routine clinical care. Decisions about which agents, alone or in combination, will best serve the patient's and clinician's clinical goals is contingent on the treatment history to date, present disease manifestations, and symptomatology. Clinical trials exploring novel agents such as those targeting c-Met and Src are under way, using endpoints that directly address how patients feel, function, and survive. PMID- 22528370 TI - The influence of ethnicity and adverse life experiences during adolescence on young adult socioeconomic attainment: the moderating role of education. AB - Previous research has documented that adverse life experiences during adolescence, particularly for ethnic minorities, have a long-term influence on income and asset attainment and that this relationship is largely mediated by educational achievement. We extend prior research by investigating three research questions. First, we investigate the extent to which community disadvantage, family factors and race/ethnicity each exert an independent influence on young adult socioeconomic attainment. Second, we examine whether youths' educational attainment mediates these independent influences on socioeconomic attainment. Third, we test whether educational attainment ameliorates the negative influences of disadvantaged community and family conditions and race/ethnicity on socioeconomic attainment. We address these questions using multilevel modeling with longitudinal, prospective data from Waves 1 and 4 of National Longitudinal Study of Adolescent Health, which has a nationally representative sample of adolescents (N = 13, 450; 53 % females). Regarding our first research question, our results indicated that African Americans, youth from disadvantaged communities, lower SES families achieve significantly lower levels of earnings, assets, and job quality during young adulthood. Second, we found that young adults' educational level only partially mediate the influences of family and race/ethnicity influences on young adults' socioeconomic attainment. Third, we found that young adults' educational level buffered the influence of early socioeconomic adversities and accentuated the positive influences of family resources. Findings highlight the importance of social context as well as educational opportunities during childhood and adolescence for economic stability in early adulthood. PMID- 22528369 TI - Oncofertility and the male cancer patient. AB - OPINION STATEMENT: Oncofertility as a discipline plays an important, adjunctive role in the treatment of male patients with cancer. Despite recommendations by the American Society of Clinical Oncology, many clinicians managing malignancies in males fail to consistently incorporate fertility preservation as a routine aspect of health care. Providers involved in the treatment of oncologic patients should have an awareness of the impact of their prescribed treatments on reproductive potential, just as they would be knowledgeable of the potential deleterious effects of cancer therapies on vital organs such as the kidneys, lungs, and liver. Providers should then have a discussion with their patients regarding these potential adverse therapeutic effects or consult a fertility preservation specialist to discuss these matters and fertility preservation options with the patient. Cryopreservation of sperm remains an excellent option for male fertility preservation as it is readily available and results in storage of viable gametes for future use in the event of post treatment infertility. With the use of assisted reproductive techniques (ART), cryopreserved sperm may ultimately result in successful paternity, even in the setting of very low numbers of stored sperm. While sperm cryopreservation is usually an option for adolescent and adult males, fertility preservation in pre-pubertal males presents a more challenging problem. To date, no clinically proven methods are available to preserve fertility in these males. However, some centers do offer experimental protocols under the oversight of an IRB, such as testicular tissue cryopreservation in these males. The hope is that one day science will provide a mechanism for immature germ cells from the testicular tissue of these patients to be used in vivo or in vitro to facilitate reproduction. In closing, studies have shown that the patient's regard for his provider is enhanced when the issue fertility preservation is raised. While oncologic care is often fraught with time constraints and acute medical concerns, fertility preservation care in the male can typically be administered quickly and without disruption of the overall plan of care. PMID- 22528371 TI - Cultural stressors and the hopelessness model of depressive symptoms in Latino adolescents. AB - Depressive symptoms in Latino youth have been related to both culturally universal and culturally-based stressors. However, few studies have examined the unique contributions of culturally-based stressors above and beyond other types of stressors. Moreover, no past studies with Latinos have examined the role of culturally-based stressors within a hopelessness model of depressive symptoms, a cognitive model with the strongest empirical support in adolescence. The current study examined these issues in a sample of 171 Latino adolescents (7th-10th grades; mean age = 14; 46 % male). The Latino adolescents were primarily Mexican American (78 %) and born in the United States (60 %). Students completed measures during a school period on their experiences of parent-child conflict, economic stress, discrimination from peers, and acculturative stress as well as depressive symptoms and attributional style. The results indicated that culturally-based stressors (e.g., acculturative stress and discrimination) predicted greater depressive symptoms even when controlling for culturally-universal stressors (e.g., parent-child conflict, economic stress). Moreover, a negative attributional style moderated the relationship between culturally-universal stressors and depressive symptoms, but this was not the case for culturally-based stressors. Culturally-based stressors play an important role in depressive symptoms among Latino youth. These stressors predicted greater symptomatology even when controlling for other types of stressors and a negative attributional style. These findings suggest that there may be other cognitive risk factors associated with culturally-based stressors. PMID- 22528372 TI - Adolescents with learning disabilities: socioemotional and behavioral functioning and attachment relationships with fathers, mothers, and teachers. AB - Investigation of the role of adolescents' patterns of close relationships with significant adults may be of particular interest in populations with learning disabilities ("LD") during adolescence, because attachment relationship variables may act as risk or protective factors during this developmental period when trajectories are set that can lead to difficulties in adulthood. Specifically, this study examined a model of protective factors comprising patterns of close relationships between adolescents (n=369; 53 % female; aged 15-17) and significant adults (mother, father, homeroom teacher) for explaining adolescents' socioemotional and behavioral adjustment, comparing adolescents with and without LD. The current assessment of adolescents' socioemotional adjustment included both internalizing aspects (loneliness, affect, and internalizing behavior syndrome) and externalizing aspects (externalizing behavior syndrome). On most measures, significant group differences emerged between adolescents with LD (n=181) and adolescents with typical development (n=188). SEM analysis found high fit between the theoretical model and empirical findings. Both groups showed similar paths between adolescent-mother attachment and adolescent adjustment, whereas significant group differences emerged for the contribution of adolescents' close relationships with fathers and teachers to adolescents' adjustment. The discussion focuses on the possible unique value of close relationships with each attachment figure at home and at school for adolescents with LD versus typical development. PMID- 22528373 TI - Injectable in situ forming controlled release implant composed of a poly-ether ester-carbonate and applications in the field of chemotherapy. AB - Polymeric controlled delivery systems hold great promise in the field of modern medicine. Such technology has already been converted into commercially viable products in a myriad of fields. Chemotherapy is an example of such an area where constant efficacious levels of drug can greatly enhance clinical outcomes. The key to designing such therapies is the preparation of the proper delivery system. To this end, a series of bioresorbable polyether-ester-carbonate copolymers have been developed, which when combined with a diluent, are capable injection into the body and consistently forming a drug delivery depot. The study delineated here aimed at producing a more effective treatment of a common drug, paclitaxel, using the polymeric carrier. The polymer carrier system exhibited controlled release of paclitaxel both in vitro and in vivo. Drug concentrations were analyzed by high performance liquid chromatography and apoptotic activity was confirmed through flow cytometry. Relevant success was exhibited by the regression of tumor size following a multiple injection treatment regimen in a murine xenograft model. This multiple injection treatment shows promising results when compared to the traditional paclitaxel paradigm of a single injection for a period of 3 weeks. PMID- 22528374 TI - In vivo three-dimensional motion analysis of chronic radial head dislocations. AB - BACKGROUND: Forearm kinematics and interosseous membrane function in chronic radial head dislocations sustained in childhood are unknown. Several procedures have been performed to reduce the radial head on the basis of static preoperative assessment in only one forearm position, but clinical results are not always favorable. QUESTIONS/PURPOSES: We investigated the in vivo three-dimensional (3D) kinematics and length changes of interosseous membrane ligaments during forearm rotation in chronic radial head dislocations using 3D CT registration techniques. METHODS: We examined 10 patients with chronic radial head dislocations (seven Type 1 and three Type 4 Monteggia lesions). To quantify kinematics, the axis of rotation (AOR) and radial head motion were investigated using computer bone models constructed from CT data placing the forearm in three positions. We also created six interosseous membrane ligaments and calculated their 3D lengths during forearm rotation. RESULTS: In Type 1 lesions, the AOR was located 2.4 mm from the center of the radial head (COR). The COR translated 2.8 mm sagittally and 3.4 mm coronally. Three interosseous membrane ligaments showed little change in length. In Type 4 lesions, the AOR was located 6.2 mm from the COR. The COR translated 10.2 mm sagittally and 4.7 mm coronally. No ligament showed an isometric pattern. CONCLUSIONS: In Type 1 lesions, the radial head showed relatively stable motion in the dislocated position and the isometricity of the interosseous membrane remained, which supports the concept of ulnar osteotomy. Conversely, the radial head was unstable and the normal interosseous membrane ligament tautness pattern was disrupted in Type 4 lesions. LEVEL OF EVIDENCE: Level IV, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 22528375 TI - Femoral bone is preserved using cemented polished stems in young patients. AB - BACKGROUND: Techniques that ensure femoral bone preservation after primary THA are important in younger patients who are likely to undergo revision surgery. QUESTIONS/PURPOSES: We examined femoral stem survival, bone deficiency at revision arthroplasty, and radiographic bone loss in hips implanted with a cemented polished double-taper stem in a cohort of patients younger than 55 years. METHODS: We reviewed 197 hips (median patient age, 47 years; range, 16-54 years) after a minimum followup of 2 years (median, 7 years; range, 2-19 years) since primary THA. Clinically, we determined survival to major and minor stem revision and cases of bone deficiency requiring a long stem or impaction bone grafting or created by the need for femoral osteotomy at revision arthroplasty. Radiographically, we assessed stem loosening, femoral osteolysis, and femoral bone deficiency. RESULTS: Stem survival to major revision for aseptic loosening was 100% at 13 years and for any reason was 97% (95% CI, 93-100%). At revision of seven stems, a long stem was used in one hip, a total femoral replacement in one hip and impaction bone grafting in one hip. No femoral osteotomies were required. Bone was preserved in four hips by cement-within-cement stem exchange. No stems were radiographically loose. Proximal osteolysis was present in 11% of femurs. Femoral bone deficiency was graded as Paprosky Type I (97%) or II (3%) and Endo Klinik Grade 0 (79%) or I (21%). CONCLUSIONS: Cemented polished taper stems have high survival at 13 years in young patients and enable femoral bone preservation for subsequent revision. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 22528376 TI - Preoperative three-dimensional CT predicts intraoperative findings in hip arthroscopy. AB - BACKGROUND: Currently, plain radiographs and MRI are the standard imaging modalities used for diagnosing femoroacetabular impingement (FAI) and preoperative planning for arthroscopic treatment of FAI. The value of three dimensional (3D) CT for these purposes is unclear. QUESTIONS/PURPOSES: We therefore determined the reliability of CT assessment of FAI and whether CT findings of hip disease predict arthroscopic findings. METHODS: We retrospectively assessed the preoperative CT scans of 118 patients who underwent primary hip arthroscopy. Intraoperative findings, including size of the cam lesion, presence of an acetabular labral articular disruption lesion, and one of four types of labral tear were recorded and compared with the retrospectively read CT findings. RESULTS: Agreement analysis between CT and intraoperative detection of FAI yielded kappa values of 0.48 for cam lesions and 0.16 for pincer lesions. Increasing values for the CT-based alpha angle correlated with increasing severity of arthroscopically assessed acetabular labral articular disruption grade. Each pattern of FAI predicted a specific labral tear type. CONCLUSIONS: Our data suggest CT has moderate value in predicting mechanically based labral tear patterns, although better parameters for assessment of pincer lesions are needed. Diagnostic assessment of patients with suspected FAI may be improved with use of 3D CT. PMID- 22528378 TI - Reliability of a complication classification system for orthopaedic surgery. AB - BACKGROUND: Quality of health care and safety have been emphasized by various professional and governmental groups. However, no standardized method exists for grading and reporting complications in orthopaedic surgery. Conclusions regarding outcomes are incomplete without a standardized, objective complication grading scheme applied concurrently. The general surgery literature has the Clavien-Dindo classification that meets the above criteria. QUESTIONS/PURPOSES: We asked whether a previously reported classification would show high intraobserver and interobserver reliabilities when modified for orthopaedic surgery specifically looking at hip preservation surgery. We therefore determined the interreader and intrareader reliabilities of the adapted classification scheme as applied to hip preservation surgery. METHODS: We adapted the validated Clavien-Dindo complication classification system and tested its reliability for orthopaedic surgery, specifically hip preservation surgery. There are five grades based on the treatment required to manage the complication and the potential for long-term morbidity. Forty-four complication scenarios were created from a prospective multicenter database of hip preservation procedures and from the literature. Ten readers who perform hip surgery at eight centers in three countries graded the scenarios at two different times. Fleiss' and Cohen's kappa statistics were performed for interobserver and intraobserver reliabilities, respectively. RESULTS: The overall Fleiss' kappa value for interobserver reliability was 0.887 (95% CI, 0.855-0.891). The weighted kappa was 0.925 (95% CI, 0.894-0.956) for Grade I, 0.838 (95% CI, 0.807-0.869) for Grade II, 0.87 (95% CI, 0.835-0.866) for Grade III, and 0.898 (95% CI, 0.866-0.929) for Grade IV. The Cohen's kappa value for intraobserver reliability was 0.891 (95% CI, 0.857-0.925). CONCLUSIONS: The adapted classification system shows high interobserver and intraobserver reliabilities for grading of complications when applied to orthopaedic surgery looking at complications of hip preservation surgery. This grading scheme may facilitate standardization of complication reporting and make outcome studies more comparable. PMID- 22528379 TI - Joint-preserving surgery improves pain, range of motion, and abductor strength after Legg-Calve-Perthes disease. AB - BACKGROUND: Patients after Legg-Calve-Perthes disease (LCPD) often develop pain, impaired ROM, abductor weakness, and progression of osteoarthritis (OA) in early adulthood. Based on intraoperative observations during surgical hip dislocation, we established an algorithm for more detailed characterization of the underlying pathomorphologies with a proposed joint-preserving surgical treatment. QUESTIONS/PURPOSES: We asked if patients after LCPD treated with our algorithm experienced (1) reduced pain; (2) improved hip function; and/or (3) prevention of OA progression; we then determined (4) the intraoperative damage patterns; (5) the survival of the hip; and (6) factors predicting the need for a conversion to THA; radiographic progression of OA; a Merle d'Aubigne-Postel score below 15 at last followup; and/or the need for revision surgery. METHODS: We retrospectively reviewed 53 patients after LCPD who underwent joint-preserving surgery (40 surgical hip dislocations, eight acetabular osteotomies, four combined procedures, and one intertrochanteric osteotomy). We obtained Merle d'Aubigne Postel scores to assess pain; OA was assessed using Tonnis grades. Survival and predictive factors were calculated with the univariate Cox regression. Fifty of the 53 patients were evaluated at a minimum of 5.1 years (mean, 8.2 years; range, 5.1-12.8 years). RESULTS: Pain and hip function improved at followup from a median of 4 points to 5 points. The mean increase in Tonnis grades at last followup was 0.3 to 0.8. The survival of surgery at 5 years was 86%; 13 factors related to survival. CONCLUSION: Patients with symptoms resulting from pathomorphologic deformities after LCPD benefit from joint-preserving surgery with specific treatment of individual structural abnormalities. PMID- 22528380 TI - Socket position determines hip resurfacing 10-year survivorship. AB - BACKGROUND: Modern metal-on-metal hip resurfacing arthroplasty designs have been used for over a decade. Risk factors for short-term failure include small component size, large femoral head defects, low body mass index, older age, high level of sporting activity, and component design, and it is established there is a surgeon learning curve. Owing to failures with early surgical techniques, we developed a second-generation technique to address those failures. However, it is unclear whether the techniques affected the long-term risk factors. QUESTIONS/PURPOSES: We (1) determined survivorship for hips implanted with the second-generation cementing technique; (2) identified the risk factors for failure in these patients; and (3) determined the effect of the dominant risk factors on the observed modes of failure. METHODS: We retrospectively reviewed the first 200 hips (178 patients) implanted using our second-generation surgical technique, which consisted of improvements in cleaning and drying the femoral head before and during cement application. There were 129 men and 49 women. Component orientation and contact patch to rim distance were measured. We recorded the following modes of failure: femoral neck fracture, femoral component loosening, acetabular component loosening, wear, dislocation, and sepsis. The minimum followup was 25 months (mean, 106.5 months; range, 25-138 months). RESULTS: Twelve hips were revised. Kaplan-Meier survivorship was 98.0% at 5 years and 94.3% at 10 years. The only variable associated with revision was acetabular component position. Contact patch to rim distance was lower in hips that dislocated, were revised for wear, or were revised for acetabular loosening. The dominant modes of failure were related to component wear or acetabular component loosening. CONCLUSIONS: Acetabular component orientation, a factor within the surgeon's control, determines the long-term success of our current hip resurfacing techniques. Current techniques have changed the modes of failure from aseptic femoral failure to wear or loosening of the acetabular component. LEVEL OF EVIDENCE: Level III, prognostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 22528381 TI - Does augmentation with a reinforced fascia patch improve rotator cuff repair outcomes? AB - BACKGROUND: Scaffold devices are used to augment rotator cuff repairs in humans. While the strength of a novel poly-L-lactic acid-reinforced (human) fascia patch has been documented, it is unclear whether such patches will enhance the strength or likelihood of healing of rotator cuff repairs. QUESTIONS/PURPOSES: In a canine shoulder model, we asked: Do tendon repairs augmented with a reinforced fascia patch have (1) increased biomechanical properties at Time 0 and (2) less tendon retraction and increased cross-sectional area and biomechanical properties after 12 weeks of healing compared to repairs without augmentation? (3) Do the biomechanical properties of tendon repairs reach normal values by 12 weeks of healing? And (4) is the host response associated with use of the reinforced fascia patch biocompatible? METHODS: Eleven dogs underwent bilateral shoulder surgery with partial release and acute repair of the infraspinatus tendon, one shoulder with augmentation and one without augmentation. Repair retraction, cross sectional area, biomechanical properties, and biocompatibility were assessed at 12 weeks. RESULTS: At Time 0, the mean +/- SD ultimate load of augmented repairs was 296 +/- 130 N (46% +/- 25%) more than nonaugmented repairs, with no difference in stiffness between groups. At 12 weeks, the ultimate load of augmented repairs averaged 192 +/- 213 N (15% +/- 16%) less than nonaugmented repairs, with no difference in stiffness between groups. At the tendon repair site at 12 weeks, the fascia patch showed a biocompatible host tissue response. CONCLUSIONS: The biomechanical properties of repairs augmented with a reinforced fascia patch demonstrated greater ultimate load at Time 0 than nonaugmented repairs but remained essentially unchanged after 12 weeks of healing, despite improvements in the ultimate load of nonaugmented controls in the same time frame. PMID- 22528382 TI - Quantifying massive allograft healing of the canine femur in vivo and ex vivo: a pilot study. AB - BACKGROUND: Allograft integration in segmental osseous defects is unpredictable. Imaging techniques have not been applied to investigate angiogenesis and bone formation during allograft healing in a large-animal model. QUESTIONS/PURPOSES: We used dynamic contrast-enhanced (DCE)-MRI and cone beam (CB)-CT to quantify vascularity and bone volume in a canine femoral allograft model and determined their relationship with biomechanical testing and histomorphometry. METHODS: Femoral ostectomy was performed in three dogs and reconstructed with a 5-cm allograft and compression plate. At 0.5, 3, and 6 months, we performed DCE-MRI to quantify vascular permeability (Ktrans) and perfused fraction and CB-CT to quantify bone volume. We also performed posteuthanasia torsional testing and dynamic histomorphometry of the grafted and nonoperated femurs. RESULTS: DCE-MRI confirmed the avascular nature of allograft healing (perfused fraction, 2.08% 3.25%). CB-CT demonstrated new bone formation at 3 months (26.2, 3.7, and 2.2 cm(3)) at the graft-host junctions, which remodeled down at 6 months (14.0, 2.2, and 2.0 cm(3)). The increased bone volume in one subject was confirmed with elevated Ktrans (0.22) at 3 months. CB-CT-identified remodeled bone at 6 months was corroborated by histomorphometry. Allografted femurs recovered only 40% of their strength at 6 months. CONCLUSIONS: CB-CT and DCE-MRI can discriminate differences in angiogenesis and bone formation in the canine allograft model, which has potential to detect a small (32%) drug or device effect on biomechanical healing with only five animals per group. PMID- 22528383 TI - Does a prefabricated gentamicin-impregnated, load-bearing spacer control periprosthetic hip infection? AB - INTRODUCTION: Treating deep infection following THA has been a challenge. While the standard treatment has remained a two-stage revision, spacer designs, incorporated antibiotics, and concentrations have varied. Since control of infection may relate to choice and concentration of antibiotics, it is important to report rates of control from various spacers. QUESTIONS/PURPOSES: We therefore determined (1) the rate of infection control and (2) complications associated with a prefabricated, load-bearing, gentamicin-impregnated hip spacer in treating periprosthetic infections of the hip. METHODS: We retrospectively reviewed 33 patients with periprosthetic THA infections treated with a prefabricated, partial load-bearing, gentamicin-impregnated hemiarthroplasty spacer. Thirty of the 33 patients underwent second stage reimplantation after a mean 15 weeks. We collected patient demographic data, laboratory values, infecting organism, size of spacer mold, antibiotic selection, complications, and infection control rates from two academic centers. Recurrent infection at last followup was determined by the presence of physical symptoms or signs or elevated serologic tests. The minimum followup was 24 months (mean, 43 months; range, 24-70 months). RESULTS: Twenty-eight of the 30 patients who underwent reimplantation remained infection free at last followup: one patient became reinfected with a different organism secondary to wound problems; one became reinfected with the same organism, but was restaged with the mold used in this study, reimplanted, and subsequently remained free of infection. Two of the 33 patients had persistently elevated inflammatory markers at the completion of their first stage and were restaged with this mold; both underwent reimplantation and remained free of infection at latest followup. One of the 33 patients was satisfied and ambulatory with their spacer mold. There were no major complications. CONCLUSION: Our data supported the use of a partial load-bearing, gentamicin-impregnated hemiarthroplasty spacer in treating deep periprosthetic THA infections. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 22528384 TI - Is administratively coded comorbidity and complication data in total joint arthroplasty valid? AB - BACKGROUND: Administrative claims data are increasingly being used in public reporting of provider performance and health services research. However, the concordance between administrative claims data and the clinical record in lower extremity total joint arthroplasty (TJA) is unknown. QUESTIONS/PURPOSES: We evaluated the concordance between administrative claims and the clinical record for 13 commonly reported comorbidities and complications in patients undergoing TJA. METHODS: We compared 13 administratively coded comorbidities and complications derived from hospital billing records with clinical documentation from a consecutive series of 1350 primary and revision TJAs performed at three high-volume institutions during 2009. RESULTS: Concordance between administrative claims and the clinical record varied across comorbidities and complications. Concordance between diabetes and postoperative myocardial infarction was reflected by a kappa value > 0.80; chronic lung disease, coronary artery disease, and postoperative venous thromboembolic events by kappa values between 0.60 and 0.79; and for congestive heart failure, obesity, prior myocardial infarction, peripheral arterial disease, bleeding complications, history of venous thromboembolism, prosthetic-related complications, and postoperative renal failure by kappa values between 0.40 and 0.59. All comorbidities and complications had a high degree of specificity (> 92%) but lower sensitivity (29% 100%). CONCLUSIONS: The data suggest administratively coded comorbidities and complications correlate reasonably well with the clinical record. However, the specificity of administrative claims is much higher than the sensitivity, indicating that comorbidities and complications coded in the administrative record were accurate but often incomplete. PMID- 22528385 TI - Re: Increased anteversion of press-fit femoral stems compared with anatomic femur. PMID- 22528386 TI - Adult stem cell mobilization enhances intramembranous bone regeneration: a pilot study. AB - BACKGROUND: Stem cell mobilization, which is defined as the forced egress of stem cells from the bone marrow to the peripheral blood (PB) using chemokine receptor agonists, is an emerging concept for enhancing tissue regeneration. However, the effect of stem cell mobilization by a single injection of the C-X-C chemokine receptor type 4 (CXCR4) antagonist AMD3100 on intramembranous bone regeneration is unclear. QUESTIONS/PURPOSES: We therefore asked: Does AMD3100 mobilize adult stem cells in C57BL/6 mice? Are stem cells mobilized to the PB after marrow ablation? And does AMD3100 enhance bone regeneration? METHODS: Female C57BL/6 mice underwent femoral marrow ablation surgery alone (n = 25), systemic injection of AMD3100 alone (n = 15), or surgery plus AMD3100 (n = 57). We used colony forming unit assays, flow cytometry, and micro-CT to investigate mobilization of mesenchymal stem cells, endothelial progenitor cells, and hematopoietic stem cells to the PB and bone regeneration. RESULTS: AMD3100 induced mobilization of stem cells to the PB, resulting in a 40-fold increase in mesenchymal stem cells. The marrow ablation injury mobilized all three cell types to the PB over time. Administration of AMD3100 led to a 60% increase in bone regeneration at Day 21. CONCLUSIONS: A single injection of a CXCR4 antagonist lead to stem cell mobilization and enhanced bone volume in the mouse marrow ablation model of intramembranous bone regeneration. PMID- 22528387 TI - Letter to the editor: Treatment of early postoperative infections after THA: a decision analysis. PMID- 22528389 TI - Orthopaedic case of the month: Recurrent thigh pain in a 44-year-old man. PMID- 22528390 TI - Alumina heads minimize wear and femoral osteolysis progression after isolated simple acetabular revision. AB - BACKGROUND: Patients with THA requiring cup revision for acetabular osteolysis may have a stable stem component without loosening. However, it is unclear whether isolated cup revision halts femoral osteolysis progression. QUESTION/PURPOSES: We asked (1) whether and to what degree osteolysis progresses after isolated acetabular revision with a change of the femoral head and (2) whether an alumina or metal bearing better reduces osteolysis progression and wear with a polyethylene (PE) cup. METHODS: We retrospectively evaluated 150 patients who underwent 165 acetabular revisions but no treatment for proximal femoral osteolysis in hips with stable femoral components. Mean age at revision was 63 years (range, 48-74 years). All hips received a new PE cup; 83 hips received new alumina heads and 82 new metal heads. Radiographs (mean followup, 15 years; range, 10-25 years) were assessed to measure osteolysis, loosening, and PE wear. Revisions of the femoral stem were recorded. RESULTS: An isolated cup revision with a change of the femoral head halted femoral osteolysis progression for 10 years in 133 hips (81%), with a greater percentage without progression in hips with alumina heads (99% versus 62% with metal head). Alumina heads were better than metal heads at reducing the area of osteolysis progression (47 versus 250 mm(2)) and wear (0.07 versus 0.14 mm/year) and increasing the survival probability before femoral revision (98% versus 85% at 15 years' followup). CONCLUSIONS: An isolated cup revision with a new alumina femoral head (in hips that have a stable stem component without loosening) usually halts femoral osteolysis progression (no change or osseous restoration) over 10 years if the osteolysis is less than 1000 mm(2). LEVEL OF EVIDENCE: Level III, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. PMID- 22528391 TI - Disruptions of the pelvic ring: an update: editorial comment. PMID- 22528392 TI - Light induced transmembrane proton gradient in artificial lipid vesicles reconstituted with photosynthetic reaction centers. AB - Photosynthetic reaction center (RC) is the minimal nanoscopic photoconverter in the photosynthetic membrane that catalyzes the conversion of solar light to energy readily usable for the metabolism of the living organisms. After electronic excitation the energy of light is converted into chemical potential by the generation of a charge separated state accompanied by intraprotein and ultimately transmembrane proton movements. We designed a system which fulfills the minimum structural and functional requirements to investigate the physico/chemical conditions of the processes: RCs were reconstituted in closed lipid vesicles made of selected lipids entrapping a pH sensitive indicator, and electron donors (cytochrome c2 and K4[Fe(CN)6]) and acceptors (decylubiquinone) were added to sustain the photocycle. Thanks to the low proton permeability of our preparations, we could show the formation of a transmembrane proton gradient under illumination and low buffering conditions directly by measuring proton related signals simultaneously inside and outside the vesicles. The effect of selected ionophores such as gramicidin, nigericin and valinomycin was used to gain more information on the transmembrane proton gradient driven by the RC photochemistry. PMID- 22528393 TI - Shrimp oncoprotein nm23 is a functional nucleoside diphosphate kinase. AB - Biosynthesis of nucleoside triphosphates is critical for bioenergetics and nucleic acid replication, and this is achieved by nucleoside diphosphate kinase (NDK). As an emerging biological model and the global importance of shrimp culture, we have addressed the study of the Pacific whiteleg shrimp (Litopenaeus vannamei) NDK. We demonstrated its activity and affinity towards deoxynucleoside diphosphates. Also, the quaternary structure obtained by gel filtration chromatography showed that shrimp NDK is a trimer. Affinity was in the micro molar range for dADP, dGDP, dTDP and except for dCDP, which presented no detectable interaction by isothermal titration calorimetry, as described previously for Plasmodium falciparum NDK. This information is particularly important, as this enzyme could be used to test nucleotide analogs that can block white spot syndrome virus (WSSV) viral replication and to study its bioenergetics role during hypoxia and fasting. PMID- 22528394 TI - Knockdown of NYGGF4 increases glucose transport in C2C12 mice skeletal myocytes by activation IRS-1/PI3K/AKT insulin pathway. AB - NYGGF4, an obesity-related gene, is proposed to be involved in the development of insulin resistance. Skeletal muscle is a primary target organ for insulin and NYGGF4 showed a relatively high expression level in skeletal muscle. Therefore, this study aimed to explore the effect of NYGGF4 on insulin sensitivity of skeletal muscle cells. RNA interference (RNAi) was adopted to silence NYGGF4 expression in mice C2C12 skeletal myocytes. A remarkably increased insulin stimulated glucose uptake and GLUT4 translocation was observed in NYGGF4 silencing C2C12 cells. Importantly, the enhanced glucose uptake induced by NYGGF4 silencing could be abrogated by the PI3K inhibitor LY294002. In addition, the crucial molecules involved in PI3K insulin signaling pathway were detected by western blotting. The results showed that NYGGF4 knockdown dramatically activate the insulin-stimulated phosphorylation of IRS-1 and AKT. Taken together, these data demonstrate that NYGGF4 knockdown increases glucose transport in myocytes by activation of the IRS-1/PI3K/AKT insulin pathway. PMID- 22528395 TI - Silencing of FABP3 promotes apoptosis and induces mitochondrion impairment in embryonic carcinoma cells. AB - Fatty acid binding protein 3 (FABP3) (also known as H-FABP) is a member of the intracellular lipid-binding protein family, and is mainly expressed in cardiac muscle tissue. The in vivo function of FABP3 is proposed to be in fatty acid metabolism, trafficking, and cell signaling. Our previous study found that FABP3 is highly regulated in patients with ventricular septal defect (VSD), and may play a significant role in the development of human VSD. In the present study, we aimed to investigate the impact of FABP3 knockdown by RNA interference (RNAi) on apoptosis and mitochondrial function of embryonic carcinoma (P19) cells. The results revealed that downregulated FABP3 expression promoted apoptosis, and resulted in mitochondrial deformation, increased mitochondrial membrane potential (MMP), and decreased intracellular ATP synthesis. In addition, the knockdown of FABP3 also led to excess intracellular ROS production. However, there was no obvious influence on the amount of mitochondrial DNA. Collectively, our results indicated that FABP3 knockdown promoted apoptosis and caused mitochondrial dysfunction in P19 cells, which might be responsible for the development of human VSD. PMID- 22528396 TI - alpha-Lipoic acid protects 3T3-L1 adipocytes from NYGGF4 (PID1) overexpression induced insulin resistance through increasing phosphorylation of IRS-1 and Akt. AB - NYGGF4 (also called PID1) was demonstrated that it may be related to the development of obesity-related IR. We aimed in the present study to further elucidate the effects of NYGGF4 on IR and the underlying mechanisms through using alpha-Lipoic acid (LA) treatment, which could facilitate glucose transport and utilization in fully differentiated adipocytes. Our data showed that the LA pretreatment strikingly enhanced insulin-stimulated glucose uptake through increasing GLUT4 translocation to the PM in NYGGF4 overexpression adipocytes. The reactive oxygen species (ROS) levels in NYGGF4 overexpression adipocytes were strikingly enhanced, which could be decreased by the LA pretreatment. NYGGF4 overexpression resulted in significant inhibition of tyrosine phosphorylation of IRS-1 and serine phosphorylation of Akt, whereas incubation with LA strongly activated IRS-1 and Akt phosphorylation in NYGGF4 overexpression adipocytes. These results suggest that LA protects 3T3-L1 adipocytes from NYGGF4-induced IR partially through increasing phosphorylation of IRS-1 and Akt and provide evidence that NYGGF4 may be a potential target for the treatment of obesity and obesity-related IR. PMID- 22528398 TI - Finding our way together on the journey to zero. AB - Remember that classic scene from The Wizard of Oz when Dorothy's house is being hurled into the sky and her world and worries are rotating around her in a great tornado? Ever feel that way at work? To be sure, the modern risk manager and safety professional are facing new challenges and expectations: value-based services, mandatory reporting, pay for performance, new compliance standards, and so on. Sometimes it's disorienting, perhaps similar to how Dorothy must have felt when she realized she was not in Kansas anymore. PMID- 22528399 TI - Healthcare innovation barriers: results of a survey of certified professional healthcare risk managers. AB - Medical errors cause significant patient injuries, including deaths. Innovations designed to improve quality and reduce risk are numerous, as are the barriers that prevent innovation implementation. The purpose of this research was to analyze the relationships, if any, between the independent variables of hospital bed size and organizational structure, and the dependent variable barriers to three innovations: implementing a surgical safety checklist, preventing catheter associated urinary tract infections, and adopting patient- and family-centered care. The findings strengthen and expand existing research and serve as the foundation for understanding barriers to implementation of three healthcare innovations. Future research should focus on organizational culture instead of innovation-specific barriers and should incorporate other independent variables, such as organizational profitability. PMID- 22528400 TI - Perspectives on healthcare reform: High Court to decide constitutionality of individual mandate. AB - The U.S. Supreme Court soon will decide a number of issues regarding the constitutionality of the Patient Protection and Affordable Care Act(1) (PPACA), pursuant to an order published on November 14, 2011. This article will identify four issues (Commerce Clause power, severability, Medicaid expansion, and Anti Injunction Act) coming before the Court for argument in the spring of 2012. Also, this article identifies and discusses the pro and con arguments pertaining to each issue. Readers who wish to refresh their memories about all the events leading up to the Supreme Court review may refer to the December 2010 monograph of the American Society for Healthcare Risk Management (ASHRM). PMID- 22528397 TI - Genetic features of cerebrospinal fluid-derived subtype B HIV-1 tat. AB - Since HIV-1 Tat has been associated with neurocognitive dysfunction, we investigated 60 HIV-1 subtype B-infected individuals who were characterized for neurocognitive functioning and had paired CSF and blood plasma samples available. To avoid issues with repeated sampling, we generated population-based HIV-1 tat sequences from each compartment and evaluated these data using a battery of phylogenetic, statistical, and machine learning tools. These analyses identified position HXB2 5905 within the cysteine-rich domain of tat as a signature of CSF derived HIV-1, and a higher number of mixed bases in CSF, as measure of diversity, was associated with HIV-associated neurocognitive disorder. Since identified mutations were synonymous, we evaluated the predicted secondary RNA structures, which showed that this mutation altered secondary structure. As a measure of divergence, the genetic distance between the blood and CSF-derived tat was inversely correlated with current and nadir CD4+ T cell counts. These data suggest that specific HIV-1 features of tat influence neurotropism and neurocognitive impairment. PMID- 22528401 TI - Beyond FMEA: the structured what-if technique (SWIFT). AB - Although it is probably the best-known prospective hazard analysis (PHA) tool, failure mode and effects analysis (FMEA) is far from the only option available. This article introduces one of the alternatives: The structured what-if technique (SWIFT). SWIFT is a flexible, high-level risk identification technique that can be used on a stand-alone basis, or as part of a staged approach to make more efficient use of bottom-up methods like FMEA. In this article we describe the method, assess the evidence related to its use in healthcare with the use of a systematic literature review, and suggest ways in which it could be better adapted for use in the healthcare industry. Based on the limited evidence available, it appears that healthcare workers find it easy to learn, easy to use, and credible. Especially when used as part of a staged approach, SWIFT appears capable of playing a useful role as component of the PHA armamentarium. PMID- 22528402 TI - The risk manager's contribution to patient safety and risk management in the ambulatory or physician practice setting. AB - The landscape of healthcare delivery in the United States is quickly changing. Hospitals and health systems are acquiring physician practices at a rapid rate. Healthcare risk management professionals may be tasked with additional responsibilities associated with physician practices, some of which may not have necessary policies or processes in place to reduce risk. Risk management professionals from the hospital setting may be required to provide additional guidance to office practices. This article describes basic risk management considerations for those who have responsibilities in these settings. PMID- 22528403 TI - Risk management and legal issues with the use of social media in the healthcare setting. AB - Social media have infiltrated all of our lives, both personally and professionally. Most of us could never have envisioned the impact that social media have had on us, particularly in the healthcare arena. Who would have thought even five years ago that a discussion on the ASHRM exchange would involve the use of Twitter in the operating room or that a physician would be reprimanded by a state medical board and have her privileges revoked due to posting information online about a trauma patient? In the coming years, social media use will only increase, causing concern for risk managers across the continuum. Furthermore, although case law and statutory regulations addressing the use of social media are minimal today, it is anticipated that we will see legal challenges to this evolving medium in the future. PMID- 22528404 TI - Patient may not profit from his intentional acts, even if mentally ill. Pompeneo v. Verde Valley Guidance Clinic, 249 P. 3d 1112 (Ct. App. Ariz. 2011). PMID- 22528407 TI - Fundamentals. PMID- 22528405 TI - Disorganized collagen scaffold interferes with fibroblast mediated deposition of organized extracellular matrix in vitro. AB - Many tissue engineering applications require the remodeling of a degradable scaffold either in vitro or in situ. Although inefficient remodeling or failure to fully remodel the temporary matrix can result in a poor clinical outcome, very few investigations have examined in detail, the interaction of regenerative cells with temporary scaffoldings. In a recent series of investigations, randomly oriented collagen gels were directly implanted into human corneal pockets and followed for 24 months. The resulting remodeling response exhibited a high degree of variability which likely reflects differing regenerative/synthetic capacity across patients. Given this variability, we hypothesize that a disorganized, degradable provisional scaffold could be disruptive to a uniform, organized reconstruction of stromal matrix. In this investigation, two established corneal stroma tissue engineering culture systems (collagen scaffold-based and scaffold free) were compared to determine if the presence of the disorganized collagen gel influenced matrix production and organizational control exerted by primary human corneal fibroblast cells (PHCFCs). PHCFCs were cultured on thin disorganized reconstituted collagen substrate (RCS--five donors: average age 34.4) or on a bare polycarbonate membrane (five donors: average age 32.4 controls). The organization and morphology of the two culture systems were compared over the long-term at 4, 8, and 11/12 weeks. Construct thickness and extracellular matrix organization/alignment was tracked optically with bright field and differential interference contrast (DIC) microscopy. The details of cell/matrix morphology and cell/matrix interaction were examined with standard transmission, cuprolinic blue and quick-freeze/deep-etch electron microscopy. Both the scaffold-free and the collagen-based scaffold cultures produced organized arrays of collagen fibrils. However, at all time points, the amount of organized cell-derived matrix in the scaffold-based constructs was significantly lower than that produced by scaffold free constructs (controls). We also observed significant variability in the remodeling of RCS scaffold by PHCFCs. PHCFCs which penetrated the RCS scaffold did exert robust local control over secreted collagen but did not appear to globally reorganize the scaffold effectively in the time period of the study. Consistent with our hypothesis, the results demonstrate that the presence of the scaffold appears to interfere with the global organization of the cell-derived matrix. The production of highly organized local matrix by fibroblasts which penetrated the scaffold suggests that there is a mechanism which operates close to the cell membrane capable of controlling fibril organization. Nonetheless, the local control of the collagen alignment produced by cells within the scaffold was not continuous and did not result in overall global organization of the construct. Using a disorganized scaffold as a guide to produce highly organized tissue has the potential to delay the production of useful matrix or prevent uniform remodeling. The results of this study may shed light on the recent attempts to use disorganized collagenous matrix as a temporary corneal replacement in vivo which led to a variable remodeling response. PMID- 22528406 TI - The incidence of hypoplasia of the corpus callosum in patients with dup (X)(q28) involving MECP2 is associated with the location of distal breakpoints. AB - Duplications of Xq28 harboring the methyl CpG binding protein 2 (MECP2) gene explain approximately 1% of X-linked intellectual disability (XLID). The common clinical features observed in patients with dup(X)(q28) are severe ID, infantile hypotonia, mild dysmorphic features and a history of recurrent infections, and MECP2 duplication syndrome is now recognized as a clinical entity. While some patients with this syndrome have other characteristic phenotypes, the reason for the spectrum of phenotypes has not been clarified. Since dup(X)(q28) rearrangements vary in size and location, genes other than MECP2 might affect the phenotype. We used a high-density oligonucleotide array to carry out precise mapping in eight Japanese families in which dup(X)(q28) was detected using an in house bacterial artificial chromosome-based microarray to screen cohorts of individuals with multiple congenital anomalies and intellectual disability (MCA/ID) or with XLID. We hypothesized that the size, gene content, and location of dup(X)(q28) may contribute to variable expressively observed in MECP2 duplication syndrome. Genotype-phenotype correlation in our cases together with cases reported in the literature suggested that copy-number gains between two low copy repeats (LCRK1 and LCRL1) are associated with the incidence of hypoplasia of the corpus callosum. Further studies are necessary to understand the mechanism of this association. PMID- 22528408 TI - High-voltage power supplies to capillary and microchip electrophoresis. AB - Over the past years, the development of capillary electrophoresis (CE) and microchip electrophoresis (ME) systems has grown due to instrumental simplicity and wide application. In both CE and ME, the application of a high voltage (HV) is a crucial step in the electrokinetic (EK) injection and separation processes. Particularly on ME devices, EK injection is often performed with three different modes: gated, pinched, and unpinched. In all these cases, different potential values may be applied to one or multiple channels to control the injection of small sample volumes as well as the separation process. For this reason, the construction of reliable HV power supplies (HVPS) is required. This review covers the advances of the development of commercial and laboratory-built HVPS for CE and ME. Moreover, it intends to be a guide for new developers of electrophoresis instrumentation. PMID- 22528409 TI - Electro-osmotic flows in a microchannel with patterned hydrodynamic slip walls. AB - We present an analysis of the electro-osmotic flow of electrolytic solutions in a microchannel with patterned hydrodynamic slippage on channel walls. A set of governing equations is formulated to account for the effects of small variations in hydrodynamic slippage over the microchannel walls on the electro-osmotic flow. These equations are then solved analytically by using the perturbation method. Two frequently encountered surface patterns, (i) cosine wave variation and (ii) square wave variation in slip length, are considered in our analyses. The results show that patterned slippage over microchannel walls can induce complex flow patterns (such as vortical flows) in otherwise plug-like electro-osmotic flows, which suggests potential applications of such flows in microfluidic mixers. PMID- 22528410 TI - Determination of the Navier slip coefficient of microchannels exploiting the streaming potential. AB - For most microchannels made of hydrophobic materials such as polymers, velocity slip occurs at the wall, affecting volumetric flow rate of electroosmotic flow Q(eof) and streaming potential (?phi(str)/?z). Since most techniques exploit Q(eof) or (?phi(str)/?z) to determine the zeta potential, zeta, it is very difficult to measure zeta of hydrophobic walls, if the slip coefficient b is not found a priori. Until now, Q(eof) and (?phi(str)/?z) are known to depend on zeta and b in a same functional form, which makes it impossible to estimate zeta or b separately using measurements of Q(eof) and (?phi(str)/?z). However, exploiting the analytic formula for Q(eof) and (?phi(str)/?z) derived in the present work, it is found that the effect of zeta and that of b on Q(eof) and (?phi(str)/?z) can be separated from each other by varying the bulk ionic concentration. Thus, the slip coefficient as well as the zeta potential of hydrophobic microchannels can be found with reasonable accuracy by means of a nonlinear curve fitting method using measured data of Q(eof) and (?phi(str)/?z) at various bulk ionic concentrations. The present method allows an accurate estimation of slip coefficient of hydrophobic microchannels, which is quite simple and cheap compared with methods employing microparticle velocimetry. PMID- 22528411 TI - Electrokinetic particle entry into microchannels. AB - The fundamental understanding of particle electrokinetics in microchannels is relevant to many applications. To date, however, the majority of previous studies have been limited to particle motion within the area of microchannels. This work presents the first experimental and numerical investigation of electrokinetic particle entry into a microchannel. We find that the particle entry motion can be significantly deviated from the fluid streamline by particle dielectrophoresis at the reservoir-microchannel junction. This negative dielectrophoretic motion is induced by the inherent non-uniform electric field at the junction and is insensitive to the microchannel length. It slows down the entering particles and pushes them toward the center of the microchannel. The consequence is the demonstrated particle deflection, focusing, and trapping phenomena at the reservoir-microchannel junction. Such rich phenomena are studied by tuning the AC component of a DC-biased AC electric field. They are also utilized to implement a selective concentration and continuous separation of particles by size inside the entry reservoir. PMID- 22528412 TI - A nonlinear electrophoretic model for PeakMaster: I. mathematical model. AB - We extended the linearized model of electromigration, which is used by PeakMaster, by calculation of nonlinear dispersion and diffusion of zones. The model results in the continuity equation for the shape function phi(x,t) of the zone: phi(t) = -(v(0) + v(EMD) phi)phi(x) + deltaphi(xx) that contains linear (v(0)) and nonlinear migration (v(EMD)), diffusion (delta), and subscripts x and t stand for partial derivatives. It is valid for both analyte and system zones, and we present equations how to calculate characteristic zone parameters. We solved the continuity equation by Hopf-Cole transformation and applied it for two different initial conditions-the Dirac function resulting in the Haarhoff-van der Linde (HVL) function and the rectangular pulse function, which resulted in a function that we denote as the HVLR function. The nonlinear model was implemented in PeakMaster 5.3, which uses the HVLR function to predict the electropherogram for a given background electrolyte and a composition of the sample. HVLR function also enables to draw electropherograms with significantly wide injection zones, which was not possible before. The nonlinear model was tested by a comparison with a simulation by Simul 5, which solves the complete nonlinear model of electromigration numerically. PMID- 22528413 TI - A nonlinear electrophoretic model for PeakMaster: II. experimental verification. AB - We introduce a computer implementation of the mathematical model of capillary zone electrophoresis described in the previous paper in this issue (Hruska et al., Electrophoresis 2012, 33), the program PeakMaster 5.3. The computer model calculates eigenmobilities, which are the eigenvalues of the Jacobian matrix of the electromigration system, and which are responsible for the presence of system eigenzones (system zones, system peaks). The model also calculates parameters of the background electrolyte: pH, conductivity, buffer capacity, ionic strength, etc., and parameters of the separated analytes: effective mobility, transfer ratio, molar conductivity detection response, and relative velocity slope. In addition to what was possible in the previous versions of PeakMaster, Version 5.3 can predict the shapes of the system peaks even for a complex injected sample profile, such as a rectangular plug. PeakMaster 5.3 can replace numerical simulation in many practically important configurations and the results are obtained in a very short time (within seconds). We demonstrate that the results obtained in real experiments agree well with those calculated by PeakMaster 5.3. PMID- 22528414 TI - Simulation of the effects of complex- formation equilibria in electrophoresis: I. mathematical model. AB - Simul 5 Complex is a one-dimensional dynamic simulation software designed for electrophoresis, and it is based on a numerical solution of the governing equations, which include electromigration, diffusion and acid-base equilibria. A new mathematical model has been derived and implemented that extends the simulation capabilities of the program by complexation equilibria. The simulation can be set up with any number of constituents (analytes), which are complexed by one complex-forming agent (ligand). The complexation stoichiometry is 1:1, which is typical for systems containing cyclodextrins as the ligand. Both the analytes and the ligand can have multiple dissociation states. Simul 5 Complex with the complexation mode runs under Windows and can be freely downloaded from our web page http://natur.cuni.cz/gas. The article has two separate parts. Here, the mathematical model is derived and tested by simulating the published results obtained by several methods used for the determination of complexation equilibrium constants: affinity capillary electrophoresis, vacancy affinity capillary electrophoresis, Hummel-Dreyer method, vacancy peak method, frontal analysis, and frontal analysis continuous capillary electrophoresis. In the second part of the paper, the agreement of the simulated and the experimental data is shown and discussed. PMID- 22528415 TI - Simulation of the effects of complex- formation equilibria in electrophoresis: II. experimental verification. AB - The complete mathematical model of electromigration in systems with complexation agents introduced in the Part I of this article (V. Hruska et al., Eletrophoresis, 2012, 33, this issue), which was implemented into our simulation program Simul 5, was verified experimentally. Three different chiral selector (CS) systems differing in the type of the CS, the magnitude of the complexation constants as well as in the experimental conditions were selected for verification. The experiments and simulations were performed at various concentrations of the CSs in order to discuss the influence of the concentration of the CS on the separation. The simulated and experimental electropherograms show very good agreement in the position, shape and amplitude of the analyte peaks. The new Simul 5 Complex offers a deep insight into electrophoretical separations that take place in systems containing complexing agents, for example into enantiomer separations. Using Simul 5 Complex we were able to predict and explain the significant electromigration dispersion of analyte peaks. It was clarified that the electromigration dispersion in these systems results directly from complexation. The new Simul 5 Complex was also shown to be a useful and powerful tool for the prediction of the results of enantioseparations. PMID- 22528416 TI - Dynamic high-resolution computer simulation of electrophoretic enantiomer separations with neutral cyclodextrins as chiral selectors. AB - GENTRANS, a comprehensive one-dimensional dynamic simulator for electrophoretic separations and transport, was extended for handling electrokinetic chiral separations with a neutral ligand. The code can be employed to study the 1:1 interaction of monovalent weak and strong acids and bases with a single monovalent weak or strong acid or base additive, including a neutral cyclodextrin, under real experimental conditions. It is a tool to investigate the dynamics of chiral separations and to provide insight into the buffer systems used in chiral capillary zone electrophoresis (CZE) and chiral isotachophoresis. Analyte stacking across conductivity and buffer additive gradients, changes of additive concentration, buffer component concentration, pH, and conductivity across migrating sample zones and peaks, and the formation and migration of system peaks can thereby be investigated in a hitherto inaccessible way. For model systems with charged weak bases and neutral modified beta-cyclodextrins at acidic pH, for which complexation constants, ionic mobilities, and mobilities of selector-analyte complexes have been determined by CZE, simulated and experimentally determined electropherograms and isotachopherograms are shown to be in good agreement. Simulation data reveal that CZE separations of cationic enantiomers performed in phosphate buffers at low pH occur behind a fast cationic migrating system peak that has a small impact on the buffer composition under which enantiomeric separation takes place. PMID- 22528417 TI - Counterion condensation in short cationic peptides: limiting mobilities beyond the Onsager-Fuoss theory. AB - We investigated the effect of the background electrolyte (BGE) anions on the electrophoretic mobilities of the cationic amino acids arginine and lysine and the polycationic peptides tetraarginine, tetralysine, nonaarginine, and nonalysine. BGEs composed of sodium chloride, sodium propane-1,3-disulfonate, and sodium sulfate were used. For the amino acids, determination of the limiting mobility by extrapolation, using the Onsager-Fuoss (OF) theory expression, yielded consistent estimates. For the peptides, however, the estimates of the limiting mobilities were found to spuriously depend on the BGE salt. This paradox was resolved using molecular modeling. Simulations, on all-atom as well as coarse grained levels, show that significant counterion condensation, an effect not accounted for in OF theory, occurs for the tetra- and nonapeptides, even for low BGE concentrations. Including this effect in the quantitative estimation of the BGE effect on mobility removed the discrepancy between the estimated limiting mobilities in different salts. The counterion condensation was found to be mainly due to electrostatic interactions, with specific ion effects playing a secondary role. Therefore, the conclusions are likely to be generalizable to other analytes with a similar density of charged groups and OF theory is expected to fail in a predictable way for such analytes. PMID- 22528418 TI - Interplay between electrophoretic mobility and intrinsic viscosity of polypeptide chains. AB - The present work is motivated specifically by the need to find a simple interplay between experimental values of electrophoretic mobility and intrinsic viscosity (IV) of polypeptides. The connection between these two properties, as they are evaluated experimentally in a formulated dilute solution, may provide relevant information concerning the physicochemical characterization and separation of electrically charged chains such as polypeptides. Based on this aspect, a study on the relation between the effective electrophoretic mobility and the IV of the following globular proteins is carried out: bovine carbonic anhydrase, staphylococcal nuclease, human carbonic anhydrase, lysozyme, human serum albumin. The basic interpretation of the IV through polypeptide chain conformations involves two unknowns: one is the Flory characteristic ratio involving short range intramolecular interactions and the other is the Mark-Houwink exponent associated with large-range intramolecular interactions. Here, it will be shown via basic and well-established electrokinetic theories and scaling concepts that the IV and global chain flexibility of polypeptides in dilute solutions may be estimated from capillary zone electrophoresis, in addition to classical transport properties. The polypeptide local chain flexibility may change due to electrostatic interactions among closer chain ionizing groups and the hindrance effect of their associated structural water. PMID- 22528420 TI - Capillary zone electrophoresis and polymer dynamics. AB - Capillary electrophoresis with a polymer solution support medium is a well established powerful analytical tool. This paper discusses a possible alternative application of capillary electrophoresis, namely a path for studying the dynamics of polymer solutions. The key to the approach is an inversion of perspective. Instead of treating the migrating species as the object of experimental importance and the support medium as being of importance only because it facilitates separations, one treats the polymer solution as being of experimental importance, and the choice of migrating species as being of interest only because different species may probe different aspects of polymer dynamics. PMID- 22528419 TI - Influence of molecular configuration and conformation on the electromigration of oligosaccharides in narrow bore capillaries. AB - Capillary electrophoresis enables fast, high efficiency separations of oligosaccharides, wherein positional and/or linkage isomers, bearing the same charge-to-mass ratio, can readily be separated based on hydrodynamic radius differences. Fundamental electrophoretic mobility theory was used to investigate the correlation between changes in hydrodynamic volume equivalent radius and corresponding electrophoretic characteristics of oligosaccharides with different molecular properties. Fluorescently derivatized isomeric malto-, cello-, and isomaltooligosaccharide ladders, differing only in their linkage type of alpha1 >4, beta1->4, and alpha1->6, respectively, as well as a sterically larger N acetylchitooligosaccharide ladder were used as model compounds. Mere differences in glycosidic linkage type or anomericity of isomeric oligo-glucoses had a decisive impact on their electromigration behavior, thus reflecting discrepancies in hydrodynamic radii and associated molecular conformations. The impact of hydrogen bridges, and associated availability of hydroxyl groups, on the molecular conformations, was investigated by hydrophilic interaction liquid chromatography. The experimentally observed electrophoretic and chromatographic differences between isomeric oligo-glucoses strongly suggested that special attention must be given when homooligosaccharide ladders are employed for normalization and comparability purposes, for example, in glucose unit calculation based structural elucidation. PMID- 22528421 TI - Statistical properties of the electrophoretic collision of a long DNA molecule with a small obstacle. AB - We present experimental results for the collision of a single lambda-DNA molecule with isolated cylindrical nanoposts whose radii range from 350 nm to 1.37 MUm. The experimental apparatus was fabricated in oxidized silicon using a plasma thinning method. The probability density for the dimensionless holdup time is described by a gamma distribution, which accurately represents the behavior of the probability density for X collisions and U/J collisions for short-lived and long-lived collisions, respectively. The shape parameter of the gamma distribution reflects the nature of the short-lived collisions, whereas the scaling parameter captures the role of the finite size of the post on the U/J collisions. When rendered in an appropriate dimensionless form, the existing models for the role of electric field gradients extend to all post sizes, indicating that 350 nm is still well above the point-sized limit. Our experiments provide insights into a regime that is very challenging for numerical simulations but highly relevant for separation processes. PMID- 22528422 TI - Improving the reproducibility in capillary electrophoresis by incorporating current drift in mobility and peak area calculations. AB - The traditional way of calculating mobility and peak areas in capillary electrophoresis does not take into account the changes in the buffer viscosity at different thermostatic control and that the analytes may accelerate during the individual runs due to Joule heating effects. We present a method for accounting for these changes based on the monitored changes in current during the separation. The calculation method requires measuring the initial resistance of the buffer filled capillary, performed using a 0.2 min voltage ramping at the start of a separation. The mobility calculation corrected for current drift allowed identification of the tested analytes independent from capillary dimensions, electric field strengths and temperature control. Furthermore, the peak areas become less influenced by the experimental conditions, since the velocities of the analytes passing the detector are corrected for the acceleration during the run. The short voltage ramping could be further used to evaluate the heat transfer of the capillary to the surroundings and to estimate the temperature changes during the separation. The temperature was shown to change the ionization of 2-phenylethylamine in accordance to a pKa dependency of primary amines reported in literature. PMID- 22528423 TI - Determination of stability constants of complexes of neutral analytes with charged cyclodextrins by affinity capillary electrophoresis. AB - A novel procedure for the determination of stability constants in systems with neutral analytes and charged complexation agents by affinity capillary electrophoresis was established. This procedure involves all necessary corrections to achieve precise and reliable data. Temperature, ionic strength, and viscosity corrections were applied. Based on the conductivity measurements, the average temperature of the background electrolyte in the capillary was kept at the constant value of 25 degrees C by decreasing the temperature of the cooling medium. The viscosity correction was performed using the viscosity ratio determined by an external viscosimeter. The electrophoretical measurements were performed, at first, at constant ionic strength. In this case, the increase of ionic strength caused by increasing complexation agent concentration was compensated by changing of the running buffer concentration. Subsequently the dependence of the analyte effective mobility on the complexation agent concentration was measured without the ionic strength compensation (at variable ionic strength). The new procedure for determination of the stability constants even from such data was established. These stability constants are in a very good agreement with those obtained at the constant ionic strength. The established procedure was applied for determination of the thermodynamic stability constants of (R, R)-(+)- and (S, S)-(-)-hydrobenzoin and R- and S-(3-bromo-2-methylpropan-1 ol) complexing with 6-monodeoxy-6-mono(3-hydroxy)propylamino-beta-cyclodextrin hydrochloride. PMID- 22528425 TI - Concentration cascade of leading electrolyte using bidirectional isotachophoresis. AB - We present a novel method of creating concentration cascade of leading electrolyte (LE) in isotachophoresis (ITP) by using bidirectional ITP. ITP establishes ion-concentration shock waves between high-mobility LE and low mobility trailing electrolyte (TE) ions. In bidirectional ITP, we set up simultaneous shock waves between anions and cations such that these waves approach each other and interact. The shock interaction causes a sudden decrease in LE concentration ahead of the focused anions and a corresponding decrease in analyte zone concentrations. This readjustment of analyte zone concentrations is accompanied by a corresponding increase in their zone lengths, in accordance to conservation laws. The method generates in situ gradient in the LE concentration, and therefore can be achieved in a single, straight channel simply by establishing the initial electrolyte chemistry. We have developed an analytical model useful in designing the process for maximum sensitivity and estimating increase in sample zone length due to shock interaction. We also illustrate the technique and evaluate its effectiveness in increasing detection sensitivity using transient simulations of species transport equations. We validated the theoretical predictions using experimental visualizations of bidirectional ITP zones for various electrolyte chemistries. Lastly, we use our technique to demonstrate a factor of 20 increase in the sensitivity of ITP-based detection of 2,4,6-trichlorophenol. PMID- 22528424 TI - A novel method for effective field measurements in electrical field-flow fractionation. AB - The electric field that drives separation and retention in electrical field flow fractionation (ElFFF) and cyclical electrical field-flow fractionation (CyElFFF) is a complex function of many parameters such as carrier ionic strength and pH, voltage, channel dimensions, flowrate, and electrode material. Currently there is no accurate or in situ method to measure the field during system operation. This paper introduces a technique to measure the effective electric field during ElFFF and CyElFFF operation using transient electrical spikes. With this technique we can determine the relationship between changes in carrier conductivity and flowrate during a run and their combined effect on effective field and retention in ElFFF. This technique can also be used to measure the voltage drop due to double layer capacitance in CyElFFF and the variation in effective field with frequency of the applied field. The measured effective fields for the CyElFFF and DC ElFFF techniques are also tested with a high ionic-strength buffer solution as carrier. For a high ionic-strength buffer, DC ElFFF generates a near-zero effective field (0.2% in 100 s), whereas CyElFFF can sustain much higher effective fields (~8%) even at relatively high voltages. The ability to measure the effective field allows for experiments to provide better data and for tuning and optimization of the separation run. PMID- 22528426 TI - Integration of on-column catalysis and EKC analysis: investigation of enantioselective sulfoxidations. AB - A novel technique is presented to investigate catalytic reactions by coupling a fused-silica capillary coated with an immobilized catalyst and a bare fused silica capillary to achieve separation of the reaction products and to generate an electroosmotic flow, which drives the transport of the reactants and products through the catalytically active capillary. The principle of this technique is illustrated by the enantioselective sulfoxidation of benzylphenylsulfide with hydrogen peroxide to the corresponding sulfoxide in the presence of a vanadium(IV)-salen catalyst, which is immobilized to nonpolar polysiloxane and permanently bonded to the inner surface of the reaction capillary. The enantiomeric ratio of the reaction product is simultaneously determined by electrokinetic chromatography using 150 mg/mL sulfated beta-cyclodextrin as chiral additive in 10 mM sodium dihydrogenphosphate background electrolyte at pH 8.3. In contrast to conventional enantioselective sulfoxidations of benzylphenylsulfide using the vanadium(IV)-salen catalyst, which give ees of up to 11%, an ee of up to 23% was achieved by this approach. Furthermore, the presented technique offers many more advantages, such as improved substrate selectivity using the nonpolar polysiloxane phase as a solvent, the feasibility to perform high-throughput kinetic measurements of substrate libraries, rapid screening and investigation of stereolabile compounds, that is, chiral sulfoxides, and screening of reactions using only minute amounts of reagents. PMID- 22528427 TI - Diffusiophoresis of a polyelectrolyte in a salt concentration gradient. AB - The diffusiophoresis of a polyelectrolyte subject to an applied salt concentration gradient is modeled theoretically. The entirely porous type of particle is capable of simulating entities such as DNA, protein, and synthetic polymeric particles. The dependence of the diffusiophoretic behavior of the polyelectrolyte on its physical properties, and the types of ionic species and their bulk concentrations are discussed in detail. We show that in addition to the effects coming from the polarization of double layer and the difference in the ionic diffusivities, the polarization of the condensed counterions inside the polyelectrolyte might also be significant. The last effect, which has not been reported previously, reduces both the electric force and the hydrodynamic force acting on the polyelectrolyte. Both the direction and the magnitude of the diffusiophoretic velocity of the polyelectrolyte are found to highly depend upon its physical properties. These results provide valuable references for applications such as DNA sequencing and catalytic nano- or micromotors. PMID- 22528428 TI - Simplified universal method for determining electrolyte temperatures in a capillary electrophoresis instrument with forced-air cooling. AB - Temperature increase due to resistive electrical heating is an inherent limitation of capillary electrophoresis (CE). Active cooling systems are used to decrease the temperature of the capillary, but their capacity is limited; and in addition, they leave "hot spots" at the detection interface and at the capillary ends. Until recently, the matter was complicated by the lack of a fast and generic method for temperature determination in efficiently and inefficiently cooled regions of the capillary. Our group recently introduced such a method, termed "Universal Method for determining Electrolyte Temperatures" (UMET). UMET is a probe-less approach that requires only measuring current versus voltage for different voltages and processing the data using an iterative algorithm. Here, we apply UMET to develop a Simplified Universal Method of Temperature Determination (SUMET) for a CE instrument with a forced-air cooling system using an Agilent 7100 CE instrument (Agilent Technologies, Saint Laurent, Quebec, Canada) as an example. We collected a wide set of empirical voltage-current data for a variety of buffers and capillary diameters. We further constructed empirical equations for temperature calculation in efficiently and inefficiently cooled parts of the capillary that require only the data from a single 1-min voltage-current measurement. The equations are specific for the Agilent 7100 CE instrument (Agilent Technologies) but can be applied to all kinds of capillaries and buffers. Similar SUMET approaches can be developed for other CE instruments with forced-air cooling using our approach. PMID- 22528434 TI - Effective meso fabrications of subporphyrins. PMID- 22528435 TI - Biochemical methods for quantifying sphingolipids: ceramide, sphingosine, sphingosine kinase-1 activity, and sphingosine-1-phosphate. AB - Sphingolipids (ceramide, sphingosine, and sphingosine-1-phosphate) are bioactive lipids with important biological functions in proliferation, apoptosis, angiogenesis, and inflammation. Herein, we describe easy and rapid biochemical methods with the use of radiolabeled molecules ((3)H, (32)P) for their mass determination. Quantitation of sphingosine kinase-1 activity, the most studied isoform, is also included. PMID- 22528436 TI - Isoform-selective assays for sphingosine kinase activity. AB - Sphingosine kinases (SK) 1 and 2 are unique lipid kinases that phosphorylate sphingosine to form -sphingosine-1-phosphate (S1P). S1P is a bioactive molecule eliciting multiple effects both extracellularly via cell surface S1P receptors and intracellularly through a number of recently identified protein targets. The two enzymes arise from different genes, and differ in their cellular localisation, developmental expression, catalytic properties, and in at least some functional roles. Here, we describe methods for selectively detecting SK1 and SK2 activities in vitro, highlighting conditions that can discriminate between the activities of these two enzymes. The assays measure the production of (32)P-labelled S1P following the addition of exogenous sphingosine and [gamma(32)P] adenosine-5'-triphosphate. The S1P product can be purified by Bligh Dyer solvent extraction, separated by thin-layer chromatography (TLC), and the radiolabelled S1P quantified by exposing the TLC plate to a storage phosphor screen. This sensitive, reproducible assay can be used to selectively detect SK1 and SK2 activities in tissue, cell, and recombinant protein samples. PMID- 22528437 TI - Quantification of sphingosine-1-phosphate and related sphingolipids by liquid chromatography coupled to tandem mass spectrometry. AB - Liquid chromatography coupled to tandem mass spectrometry has evolved as the method of choice for the detection of sphingolipid metabolites due to its high sensitivity and superior specificity compared to other methodological approaches. Here, we describe a simple and robust method for the detection and quantification of sphingosine-1-phosphate (S1P) and related sphingolipids in biological samples. Tissue homogenates, cells, supernatant, plasma, and whole blood are spiked with an internal standard to account for loss of material during sample handling. After chloroform extraction of lipids under acidified conditions, the solvent is evaporated, and the remaining lipid extracts are dissolved in 20% CHCl(3) and 80% methanol. Following reversed-phase high-performance liquid chromatography step gradient separation of sphingolipids and positive electrospray ionization, detection is carried out with the AB Sciex QTrap triple-quadrupole mass spectrometer operating in multiple reaction monitoring. Characteristic fragment ions of S1P and related sphingolipids are monitored and subsequently analyzed relative to known standard concentrations of the pure compounds. Known problems of S1P quantification, such as carryover and insufficient HPLC separation, are discussed. PMID- 22528438 TI - A cleanup method for mass spectrometry of sphingosine-1-phosphate in blood and solid tissues using a phosphate capture molecule. AB - Cleanup technology and mass spectrometric determination of sphingosine-1 phosphate using a -phosphate capture molecule are shown. The protocol is rapid, requires neither thin-layer chromatography nor liquid chromatography, and is applicable to both blood and solid tissue samples. PMID- 22528439 TI - Immunohistochemical detection of sphingosine-1-phosphate and sphingosine kinase-1 in human tissue samples. AB - Sphingosine-1-phosphate (S1P) and the enzyme primarily responsible for its production, sphingosine kinase-1 (SphK-1), are thought to be dysregulated in multiple human diseases including cancer, multiple sclerosis (MS), diabetes, neurological diseases, fibrosis, and certain pathologies associated with impaired angiogenesis such as, age-related macular degeneration (AMD). Antibody-based techniques to identify and localize S1P and SphK-1 within cells and tissue specimens represent powerful tools not only to understand the biological role of these molecules but also to validate these unique in-class targets in multiple state diseases. Consequently, the potential applications of these molecules for therapy and diagnostic purposes are currently under investigation. Here, we describe two staining procedures for identification of S1P and SphK-1 in human frozen tissue samples and the challenges encountered in the process of localization in tissue samples of lipid molecules, such as S1P. PMID- 22528440 TI - Assessment of sphingosine-1-phosphate activity in biological samples by receptor internalization and adherens junction formation. AB - Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator involved in many biological actions, including vascular homeostasis and immune cell trafficking. S1P activity is mediated by specific G protein-coupled receptors, leading to multiple physiological responses including adherens junction formation in endothelial cells. Here, we describe bioassays for rapidly assessing S1P activity in biological fluids based on ligand-induced receptor internalization in transfected HEK293 cells and consequent adherens junction formation of vascular endothelial cells. PMID- 22528441 TI - High-throughput assays to measure intracellular Ca2+ mobilization in cells that express recombinant S1P receptor subtypes. AB - Intracellular Ca(2+) mobilization is a useful readout to screen for agonists or antagonists of G-protein -coupled receptors (GPCRs). Here, we describe methods to conduct high-throughput screening of stably or transiently transfected HTC4 cells expressing the individual S1P1-5 receptor subtypes. The cells are grown in 96 well plates and loaded with the cell permeable fluorescent Ca(2+) indicator dye Fura-2-AM. Changes in intracellular Ca(2+) levels in response to S1P or test compounds are detected using a FlexStation II scanning fluorometer with integrated fluidics transfer capabilities. PMID- 22528442 TI - Quantifying sphingosine-1-phosphate-dependent activation of the RhoGTPases. AB - The GPCR-coupled sphingosine-1-phosphate (S1P) receptors regulate a number of important cell -functions, including proliferation, migration, and adhesion. Since these processes require dynamic regulation of the actin cytoskeleton, the ability to monitor S1P-dependent activation of the Rho family GTPases is critical for our understanding of S1P signaling. Herein, we provide methods for the GST pull-down-based assay used to measure Rho, Rac, and Cdc42 activity in cultured cells treated with S1P. PMID- 22528443 TI - Optimized protocols to analyze sphingosine-1-phosphate signal transduction pathways during acrosomal exocytosis in human sperm. AB - Regulated secretion is a central issue for the specific function of many cells; for instance, mammalian sperm acrosomal exocytosis is essential for egg fertilization. Sphingosine 1-phosphate is a bioactive sphingolipid that regulates crucial physiological processes. We have recently reported that sphingosine 1 phosphate and sphingosine kinase are involved in a novel signaling pathway leading to acrosomal exocytosis (Suhaiman L et al., J Biol Chem 285:1630-16314, 2010). Acrosomal exocytosis in mammalian sperm is a regulated secretion with unusual characteristics. We therefore employed biochemical functional assays to assess the sphingolipid signaling in both permeabilized and nonpermeabilized sperm. The exocytosis of the acrosomal content is regulated by Ca(2+). During exocytosis, changes in [Ca(2+)]i occur induced by either Ca(2+)-influx or Ca(2+) mobilization from intracellular stores. By using single cell [Ca(2+)] measurements, we detected intracellular Ca(2+) changes after sphingosine 1 phosphate treatment. Additionally, measuring sphingosine kinase activity, we determined that sphingosine 1-phosphate levels increase after an exocytotic stimulus.This chapter is designed to provide the user with sufficient background to analyze sphingosine 1--phosphate signal transduction pathways during acrosomal exocytosis in human sperm. PMID- 22528444 TI - Use of intravital microscopy and in vitro chemotaxis assays to study the roles of sphingosine-1-phosphate in bone homeostasis. AB - We describe a method to visualize the migration of osteoclast precursors within intact murine bone -marrow in real time using intravital multiphoton microscopy. Conventionally, cell migration has been evaluated using in vitro systems, such as transmigration assays. Although these methods are convenient for quantification and are highly reproducible, these in vitro assay systems may not accurately reflect in vivo cellular behavior. In addition to in vitro analyses, recent technological progress in two-photon excitation-based laser microscopy has enabled the visualization of dynamic cell behavior deep inside intact living organs. Combining this imaging method with in vitro chemoattraction analyses, we have revealed that sphingosine-1-phosphate (S1P), a lipid mediator enriched in blood, bidirectionally controls the trafficking of osteoclast precursors between the circulation and bone marrow cavities via G protein-coupled receptors (GPCRs). PMID- 22528445 TI - Assessment of sphingosine-1-phosphate receptor expression and associated intracellular signaling cascades in primary cells of the human central nervous system. AB - Measuring the effects of sphingosine-1-phosphate (S1P) receptor modulators on human primary neural cells is of particular interest given the recent application of these central nervous system-accessible agents to the treatment of neurodegenerative diseases, such as multiple sclerosis. Issues to consider in experimental studies include the ability of some of these modulators to bind multiple S1P receptor subtypes simultaneously, the nonspecificity of commercially available S1P receptor antibodies, and activation of multiple intracellular signaling cascades by a given S1P receptor. Here, we discuss how to assay S1P receptor expression and activation using multiple agonists/antagonists, by linking the results of real-time reverse transcriptase polymerase chain reaction with the assessment of intracellular signaling derived from Western blot analyses. PMID- 22528446 TI - Sphingosine-1-phosphate signaling in skeletal muscle cells. AB - Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid regulator of numerous important physiological and pathological processes in mammalian and nonmammalian cells. There are emerging evidence that many cell types can produce and release S1P; therefore, the quantification of its intracellular and extracellular content as well as the activity of sphingosine kinase (SphK), the enzyme responsible of S1P synthesis, is crucial to attribute to the SphK/S1P axis a functional significance in response to many different stimuli and in physiopathological conditions.This chapter describes experimental procedures to measure intracellular S1P formation in skeletal muscle cells and skeletal muscle fibers by using sphingolipid precursors. It also underlines the relevance of measuring S1P production in specific cellular compartments in order to attribute to S1P signaling a role in the biology of skeletal muscle cells. PMID- 22528447 TI - Maintenance of human embryonic stem cells by sphingosine-1-phosphate and platelet derived growth factor. AB - Embryonic stem cells are pluripotent and capable of indefinite self-renewal in vitro. Human embryonic stem cells (hESC) have generally been cultivated on feeder layers of primary mouse embryonic fibroblasts (MEF) in media supplemented with fetal calf serum (FCS). However, serum contains a wide variety of biologically active compounds that might adversely affect hESC growth and differentiation. Thus, cultivation of stem cells in FCS complicates experimental approaches to define the intracellular mechanisms required for hESC maintenance. This chapter describes the serum-free maintenance of hESC in culture by addition of sphingosine-1-phosphate (S1P) and platelet-derived growth factor (PDGF). This complete protocol provides a chemically defined serum-free system that is advantageous for studying signaling pathways involved in hESC pluripotency. PMID- 22528448 TI - Ceramide and sphingosine-1-phosphate signaling in embryonic stem cell differentiation. AB - Recent studies show that bioactive lipids are important regulators for stem cell survival and differentiation. The sphingolipid ceramide and its derivative, sphingosine-1-phosphate (S1P), can act synergistically on embryonic stem (ES) cell differentiation. We show here simple methods to analyze sphingolipids in differentiating ES cells and to use ceramide and S1P analogs for the guided differentiation of mouse ES cells toward neuronal and glial lineage. PMID- 22528449 TI - Sphingosine-1-phosphate signaling in neural progenitors. AB - Sphingosine-1-phosphate (S1P) and its receptors are important in nervous system development. Reliable in vitro human model systems are needed to further define specific roles for S1P signaling in neural development. We have recently reported that human embryonic stem cell-derived neuroepithelial progenitor cells (hES-NEP) express functional S1P receptors. These cells can be further differentiated to a neuronal cell type, and therefore represent a good model system to study the role of S1P signaling in human neural development. The following sections describe in detail the culture of hES-NEP cells and two assays to measure S1P signaling in these cells. PMID- 22528450 TI - Utilizing sphingosine-1-phosphate to stimulate sprouting angiogenesis. AB - In vitro models are useful for dissecting cell behavior under controlled conditions. Angiogenesis is a multistep process where endothelial cells (ECs) are activated by pro-angiogenic factors to degrade the basement membrane, migrate into the surrounding matrix, and form sprouting structures connecting neighboring vessels. Sphingosine-1-phosphate (S1P), a biologically active sphingolipid, promotes vessel morphogenesis and angiogenesis during embryonic development and in adults under normal and pathological conditions via its actions on ECs. Here, we describe an in vitro endothelial morphogenic assay that is significantly enhanced by S1P. This method allows for testing whether molecules and their related signaling pathways regulate the initiation of angiogenic sprouts stimulated by S1P, as well as whether individual compounds have pro- or anti angiogenic properties. PMID- 22528451 TI - Systematic review and meta-analysis of insulin therapy and risk of cancer. AB - Recent epidemiological studies suggest that treatment with insulin may promote cancer growth. The present systematic review and meta-analysis of published observational studies was conducted to assess the risk of cancer during treatment with insulin. A search of online database through January 2011 was performed and examined the reference lists of pertinent articles, limited to observational studies in humans. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated with a random-effects model. Fifteen studies (five case-control and ten cohort studies) were included, with 562,043 participants and 14,085 cases of cancer. Insulin treatment was associated with an increased risk of overall cancer [summary RR (95% CI)=1.39 (1.14, 1.70)]. Summary RR (9% CI) for case control studies was 1.83 (0.99, 3.38), whereas RR for cohort studies was 1.28 (1.03, 1.59). These results were consistent between studies conducted in the USA and in Europe. For studies that included combined type 1 and 2 diabetes, the summary estimate was stronger than studies including only type 2 diabetes mellitus. The association between insulin treatment and cancer was stronger for pancreatic cancer [summary RR (95% CI)=4.78 (3.12, 7.32)] than for colorectal cancer [1.50 (1.08, 2.08)]. Insulin treatment was not associated with breast, prostate, and hepatocelluar cancer, and their effect estimates were not statistically significant. Our findings support an association between insulin use and increased risk of overall, pancreatic, and colorectal cancer. PMID- 22528453 TI - Demonstration of an olfactory bulb-brain translocation pathway for ZnO nanoparticles in rodent cells in vitro and in vivo. AB - ZnO nanoparticles (ZnO-NPs) are widely used in the engineering and cosmetic industries, and inhaled airborne particles pose a known hazard to human health; their translocation into humans is a recognized public health concern. The pulmonary-blood pathway for ZnO-NP toxicity is well documented, but whether translocation of these particles can also occur via an olfactory bulb-brain route remains unclear. The potential toxicity of ZnO-NPs for the human central nervous system (CNS) is predicated on the possibility of their translocation. Our study investigated translocation of ZnO-NPs both in vitro using the neuronal cell line PC12 and in vivo in a Sprague-Dawley rat model. Our findings indicate that the zinc-binding dye, Newport-Green DCF, binds ZnO stoichiometrically and that ZnO-NP concentration can therefore be measured by the fluorescence intensity of the bound dye in confocal fluorescence microscopy. Confocal data obtained using Newport-Green DCF-2 K(+)-conjugated ZnO-NPs along with the membrane probe FM1-43 demonstrated endocytosis of ZnO-NPs by PC12 cells. In addition, Fluozin-3 measurement showed elevation of cytosolic Zn(2+) concentration in these cells. Following in vivo nasal exposure of rats to airborne ZnO-NPs, olfactory bulbs and brains that were examined by Newport-Green fluorescence and TEM particle measurement clearly showed the presence of ZnO-NPs in brain. We conclude that an olfactory bulb-brain translocation pathway for airborne ZnO-NPs exists in rats, and that endocytosis is required for interneuron translocation of these particles. PMID- 22528452 TI - Paracrine interactions within islets of Langerhans. AB - Glucose supply fluctuates between meal and fasting periods and its consumption by the body varies greatly depending on bodily metabolism. Pancreatic islets of Langerhans secrete various endocrine hormones including insulin and glucagon to keep blood glucose level relatively constant. Additionally, islet hormones regulate activity of neighboring cells as local autocrine or paracrine modulators. Moreover, islet cells release neurotransmitters such as glutamate and gamma-aminobutyric acid (GABA) to gain more precise regulation of hormones release kinetics. Excitatory glutamate is co-released with glucagon from alpha cells and activates glutamate receptors in the neighboring cells. GABA released from beta-cells was shown to inhibit alpha-cells but to activate beta-cells by acting GABA(A) receptors. This review summarizes the recent progress in understanding the paracrine/autocrine interactions in islets. PMID- 22528454 TI - MicroRNA-21 inhibitor sensitizes human glioblastoma U251 stem cells to chemotherapeutic drug temozolomide. AB - MicroRNAs (miRNAs) are small noncoding RNA molecules that regulate protein expression by cleaving or repressing the translation of target mRNAs. In mammals, their function mainly represses the target mRNA transcripts via imperfect complementary sequences in the 3'UTR of target mRNAs. Several miRNAs have been recently reported to be involved in modulation of glioma development, especially some upregulated miRNAs, such as microRNA-21 (miR-21), which has been found to function as an oncogene in cultured glioblastoma multiforme cells. Temozolomide (TMZ), an alkylating agent, is a promising chemotherapeutic agent for treating glioblastoma. Although chemotherapy with temozolomide may contain tumor growth for some months, invariable tumor recurrence suggests that cancer stem cells maintaining these tumors persist. Previous research showed that TMZ could inhibit the proliferation of human glioblastoma stem cells (GSC), but not induced apoptosis, which could supply the chance for glioblastoma recurrence. Accumulating evidence indicated that downregulation of miR-21 in glioblastoma cells caused repression of growth and increased apoptosis, all of which could theoretically enhance the chemotherapeutic effects of cancer therapy. In this study, we aimed to explore whether miR-21 downregulation could enhance the chemotherapeutic effects of TMZ and induce apoptosis on GSC. Interestingly, the results demonstrated that either miR-21 inhibitor or TMZ could not induce apoptosis on GSC. However, miR-21 inhibitor combined with TMZ significantly enhanced GSC apoptosis. Taken together, a combination of miR-21 inhibitor and TMZ could be an effective therapeutic strategy for GSC apoptosis to prevent potential glioblastoma recurrence. PMID- 22528456 TI - Pretreatment with nonselective cationic channel inhibitors blunts the PACAP induced increase in guinea pig cardiac neuron excitability. AB - Calcium influx is required for the pituitary adenylyl cyclase activating polypeptide (PACAP)-induced increase in guinea pig cardiac neuron excitability, noted as a change from a phasic to multiple action potential firing pattern. Intracellular recordings indicated that pretreatment with the nonselective cationic channel inhibitors, 2-aminoethoxydiphenylborate (2-APB), 1-[beta-[3-(4 methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole HCl (SKF 96365), and flufenamic acid (FFA) reduced the 20-nM PACAP-induced excitability increase. Additional experiments tested whether 2-APB, FFA, and SKF 96365 could suppress the increase in excitability by PACAP once it had developed. The increased action potential firing remained following application of 2-APB but was diminished by FFA. SKF 96365 transiently depressed the PACAP-induced excitability increase. A decrease and recovery of action potential amplitude paralleled the excitability shift. Since semiquantitative PCR indicated that cardiac neurons express TRPC subunit transcripts, we hypothesize that PACAP activates calcium-permeable, nonselective cationic channels, which possibly are members of the TRPC family. Our results are consistent with calcium influx being required for the initiation of the PACAP-induced increase in excitability, but suggest that it may not be required to sustain the peptide effect. The present results also demonstrate that nonselective cationic channel inhibitors could have other actions, which might contribute to the inhibition of the PACAP-induced excitability increase. PMID- 22528457 TI - Genetic variation in glutathione S-transferase genes and risk of nonfatal cerebral stroke in patients suffering from essential hypertension. AB - Oxidative stress resulting from an increased amount of reactive oxygen species and an imbalance between oxidants and antioxidants has been implicated in pathogenesis of cerebral stroke. The purpose of this study was to investigate the relationship between common polymorphisms of glutathione S-transferase M1, T1, and P1 genes and risk of stroke in hypertensive individuals. A total of 667 unrelated Russian individuals with hypertension, including 306 hypertensives who suffered from cerebral stroke and 361 hypertensives who did not have cerebrovascular accidents, were recruited for the study. The deletion polymorphisms of GSTM1 and GSTT1 genes and polymorphism Ile105Val of the GSTP1 gene were genotyped by a multiplex polymerase chain reaction and restriction analyses, respectively. No differences in GSTM1 and GSTP1 genotype distributions between the cases and controls have been observed. The null GSTT1 genotype was found to be associated with increased risk of cerebral stroke after Bonferroni correction and adjusting for confounding variables such as gender, blood pressure, body mass index, and antihypertensive medication use (odds ratio 1.51 95 % CI 1.09-2.07, P = 0.01). The present study was the first to show the association of null genotype of the GSTT1 gene with increased risk of cerebral stroke. PMID- 22528455 TI - PACAP is an endogenous protective factor-insights from PACAP-deficient mice. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP) is a widespread neuropeptide with a diverse array of biological functions. Not surprisingly, the lack of endogenous PACAP therefore results in a variety of abnormalities. One of the important effects of PACAP is its neuroprotective and general cytoprotective role. PACAP protects neurons and other tissues against ischemic, toxic, and traumatic lesions. Data obtained from PACAP-deficient mice provide evidence that endogenous PACAP also has protective functions. Mice lacking PACAP are more vulnerable to different in vitro and in vivo insults. The present review summarizes data on the increased sensitivity of PACAP-deficient mice against harmful stimuli. Mice lacking PACAP respond with a higher degree of injury in cerebral ischemia, autoimmune encephalomyelitis, and axonal lesion. Retinal ischemic and excitotoxic injuries also produce increased cell loss in PACAP deficient mice. In peripheral organs, kidney cell cultures from PACAP-deficient mice are more sensitive to oxidative stress and in vitro hypoxia. In vivo, PACAP deficient mice have a negative histological outcome and altered cytokine response in kidney and small intestine ischemia/reperfusion injury. Large intestinal inflammation, toxic lesion of the pancreas, and doxorubicin-induced cardiomyopathy are also more severe with a lack of endogenous PACAP. Finally, an increased inflammatory response has been described in subacute endotoxin-induced airway inflammation and in an oxazolone-induced allergic contact dermatitis model. In summary, lack of endogenous PACAP leads to higher vulnerability in a number of injuries in the nervous system and peripheral organs, supporting the hypothesis that PACAP is part of the endogenous cytoprotective machinery. PMID- 22528458 TI - Effect of surgical and chemical sensory denervation on non-neural expression of the transient receptor potential vanilloid 1 (TRPV1) receptors in the rat. AB - Pretreatment with the ultrapotent capsaicin analog resiniferatoxin (RTX) has been applied as a selective pharmacological tool in inflammation and pain studies to desensitize transient receptor potential vanilloid 1 (TRPV1) receptor-expressing sensory nerve endings. The discovery of TRPV1 receptor on non-neural cells challenges systemic RTX desensitization as a method acting exclusively on a population of sensory neurons, but not on non-neural cells. Systemic RTX desensitization was used for chemical denervation and transection of the sciatic and saphenous nerves for surgical denervation in rats. Quantitative real-time PCR and immunohistochemistry were applied to investigate the presence and alterations of the TRPV1 receptor mRNA and protein following chemical and surgical denervation. We provided the first evidence for non-neural TRPV1 immunopositivity and mRNA expression in the rat dorsal paw and plantar skin as well as the oral mucosa. Neither chemical nor surgical denervation influenced the level of TRPV1 receptor mRNA and protein expression in non-neural cells of either skin regions or mucosa. Therefore, RTX and consequently capsaicin remain to be considered as selective neurotoxins for a population of primary afferent neurons. PMID- 22528459 TI - Potential contribution of hypoxia-inducible factor-1alpha, aquaporin-4, and matrix metalloproteinase-9 to blood-brain barrier disruption and brain edema after experimental subarachnoid hemorrhage. AB - The current research aimed to investigate the role of hypoxia-inducible factor 1alpha (HIF-1alpha), aquaporin-4 (AQP-4), and matrix metalloproteinase-9 (MMP-9) in blood-brain barrier (BBB) dysfunction and cerebral edema formation in a rat subarachnoid hemorrhage (SAH) model. The SAH model was induced by injection of 0.3 ml fresh arterial, non-heparinized blood into the prechiasmatic cistern in 20 s. Anti-AQP-4 antibody, minocycline (an inhibitor of MMP-9), or 2 methoxyestradiol (an inhibitor of HIF-1alpha), was administered intravenously at 2 and 24 h after SAH. Brain samples were extracted at 48 h after SAH and examined for protein expressions, BBB impairment, and brain edema. Following SAH, remarkable edema and BBB extravasations were observed. Compared with the control group, the SAH animals have significantly upregulated expressions of HIF-1alpha, AQP-4, and MMP-9, in addition to decreased amounts of laminin and tight junction proteins. Brain edema was repressed after inhibition of AQP-4, MMP-9, or HIF 1alpha. Although BBB permeability was also ameliorated after inhibition of either HIF-1alpha or MMP-9, it was not modulated after inhibition of AQP-4. Inhibition of MMP-9 reversed the loss of laminin. Finally, inhibition of HIF-1alpha significantly suppressed the level of AQP-4 and MMP-9, which could induce the expression of laminin and tight junction proteins. Our results suggest that HIF 1alpha plays a role in brain edema formation and BBB disruption via a molecular signaling pathway involving AQP-4 and MMP-9. Pharmacological intervention of this pathway in patients with SAH may provide a novel therapeutic strategy for early brain injury. PMID- 22528460 TI - Low-frequency ultrasound irradiation increases blood-tumor barrier permeability by transcellular pathway in a rat glioma model. AB - Low-frequency ultrasound (LFU) irradiation under certain acoustic intensity can increase blood-brain barrier permeability non-invasively and reversibly. The aim of this study was to find out the effect of LFU irradiation on blood-tumor barrier (BTB) permeability in rat C6 glioma model and the possible mechanism. In this research, Evans blue and H&E staining were used to evaluate the optimal parameter of LFU to open the BTB without damaging the normal brain tissue. Transmission electron microscopy was used to observe the changes of the number of pinocytotic vesicles in cerebral or glioma microvascular endothelial cells. The phosphorylation of tyrosine kinase Src, caveolin-1, and caveolin-2 was detected by western blot. The distribution and expressing levels of caveolae proteins, caveolin-1 and caveolin-2, were detected by immunohistochemical and immunofluorescent staining, RT-PCR, and western blot. Our research data showed that, in rat C6 glioma model, LFU irradiation at a frequency of 1 MHz, a power of 12 mW, and exposure time of 20 s induced the increase of BTB permeability temporally, which reached a peak at 1.5 h, then decreased and restored to normal level at 12 h after LFU irradiation. In the glioma microvascular endothelial cells of rat glioma model, LFU irradiation induced a significant increase of the pinocytotic vesicles' density. The phosphorylation of Src, caveolin-1, and caveolin-2 began to increase at 0.5 h and reached a maximum at 1 h. Immunohistochemical and immunofluorescent staining showed that caveolin-1 and caveolin-2 were co-localized in the glioma microvascular endothelial cells and glioma cells. The mRNA and protein expression levels of caveolin-1 and caveolin-2 were up-regulated, reached the peak value at 1.5 h, and re-normalized at 12 h after LFU irradiation. These results demonstrated that LFU irradiation increased BTB permeability by promoting transcellular transport in glioma microvascular endothelial cells. The phosphorylation of tyrosine kinase Src, caveolin-1, caveolin-2 and up-regulation of caveolin-1 and caveolin-2 were involved in LFU induced caveolae-mediated endocytosis. PMID- 22528461 TI - Searching for new genetic variations in expression databases for the GABAergic and glutamatergic systems. AB - Changes in gene expression and genetic variations in coding regions have likely functional impact, potentially associated with complex diseases, such as neuropsychiatric conditions. A current need for high throughput analysis of genomic data is leading to the development and improvement of sophisticated bioinformatics approaches, which allows the processing of large amounts of sequence and gene expression data. In this study, we identified new potential genetic variations prioritizing genes related to glutamatergic and GABAergic systems, using different bioinformatics resources. The CLCbio Workbench Combined platform was initially used to build expressed sequence tags and mRNA files retrieved, respectively, from the Goldenpath and National Center for Biotechnology Information databases and latter to perform multiple batches of Smith-Waterman alignments. The PMUT software was used to increase an accurate association between potential variations and pathogenic predictions. The annotation revealed various classes of variations and most of them are deletions ranging from 1 to 7 bp. Bioinformatic pipelines seem to be useful approaches to help screening for genetic variations with potential impact in gene expression. Further analysis will foster this aim to provide celerity at the massive analysis of data currently generated in large scale high throughput experiments. PMID- 22528462 TI - Mitogen-activated protein kinase pathways are involved in the upregulation of calcitonin gene-related peptide of rat trigeminal ganglion after organ culture. AB - The trigeminal ganglion (TG) can express and release calcitonin gene-related peptide (CGRP), an important neuropeptide that plays a crucial role in migraine attack and cluster headache. Activation of rat TG increases CGRP expression. However, the regulatory mechanism of CGRP expression in TG neurons remains to be explored. This study aims to evaluate the involvement of mitogen-activated protein kinase (MAPK) pathways in CGRP upregulation after rat TG organ culture. Rat TG was cultured alone for 24 h or cultured in combination with MAPK inhibitors, tumor necrosis factor alpha (TNF-alpha), or interleukin 1beta (IL 1beta) for 24 h. CGRP protein was determined using immunohistochemistry. The mRNA levels of CGRP, TNF-alpha, and IL-1beta were analyzed through real-time quantitative polymerase chain reaction. MAPK phosphorylation was detected via western blot. After rat TG organ culture, the expressions of CGRP, TNF-alpha, and IL-1beta were upregulated at 24 h. The phosphorylation of extracellular signal regulated kinases (ERK1/2), P38, and c-jun N-terminal kinases (JNK) significantly increased at 30 min compared with fresh rat TG. In addition, both CGRP expression and phosphorylation of ERK1/2, P38, and JNK were enhanced obviously after rat TG treatment with TNF-alpha or IL-1beta compared with fresh rat TG. However, they decreased markedly after rat TG pretreatment with PD98059 (ERK1/2 inhibitor), SB203580 (P38 inhibitor), or SP600125 (JNK inhibitor) compared with rat TG co culture with TNF-alpha or IL-1beta. In conclusion, the elevated CGRP expression after rat TG organ culture can be regulated via MAPK pathways. The findings provide insight into the molecular mechanisms and experimental evidence for therapeutic targets of migraine. PMID- 22528463 TI - Inflammatory response and chemokine expression in the white matter corpus callosum and gray matter cortex region during cuprizone-induced demyelination. AB - Brain inflammation plays a central role in multiple sclerosis (MS). Besides lymphocytes, the astroglia and microglia mainly contribute to the cellular composition of the inflammatory infiltrate in MS lesions. Several studies were able to demonstrate that cortical lesions are characterized by lower levels of inflammatory cells among activated microglia/macrophages. The underlying mechanisms for this difference, however, remain to be clarified. In the current study, we compared the kinetics and extent of microglia and astrocyte activation during early and late cuprizone-induced demyelination in the white matter tract corpus callosum and the telencephalic gray matter. Cellular parameters were related to the expression profiles of the chemokines Ccl2 and Ccl3. We are clearly able to demonstrate that both regions are characterized by early oligodendrocyte stress/apoptosis with concomitant microglia activation and delayed astrocytosis. The extent of microgliosis/astrocytosis appeared to be greater in the subcortical white matter tract corpus callosum compared to the gray matter cortex region. The same holds true for the expression of the key chemokines Ccl2 and Ccl3. The current study defines a model to study early microglia activation and to investigate differences in the neuroinflammatory response of white vs. gray matter. PMID- 22528464 TI - An intronic CYP46A1 polymorphism is associated with Alzheimer disease in a Chinese Han population. AB - Excess cholesterol is removed from the brain via hydroxylation mediated by cholesterol 24S-hydroxylase (CYP46), which is a mechanism of maintaining cholesterol homeostasis in the brain. The CYP46A1 gene has been suggested as a genetic risk factor for sporadic late-onset Alzheimer's disease (AD). In this report, we analyzed an intronic CYP46A1 single nucleotide polymorphism (SNP) in 508 sporadic AD patients and 549 controls in a Chinese Han population. Our results indicated that the distribution of CYP46A1 SNP rs754203 genotypes was significantly different in AD patients compared to controls (chi(2) = 6.59, P = 0.037). The frequency of at least one of CYP46A1 T allele (C/T or T/T) was higher in AD patients compared to controls (chi(2) = 6.58, P = 0.01). The age- and sex adjusted odds ratio for the risk of AD in carriers of CYP46A1 T allele (C/T + T/T) was 1.69 (95 % confidence interval, 1.12-2.56). We conclude that this intronic polymorphism in CYP46A1 gene is associated with AD in a Chinese Han population, and the CYP46A1 T allele might be a risk factor for AD. PMID- 22528465 TI - Ectopic overexpression of swine PPARgamma2 upregulated adipocyte genes expression and triacylglycerol in skeletal muscle of mice. AB - Peroxisome proliferator-activated receptor gamma2 (PPARgamma2) is a key regulator of adipocyte differentiation, fatty acid uptake and storage in mammals. The primary goal of the present study was to investigate the consequences of PPARgamma2 overexpression in the muscle. A swine muscle creatine kinase promoter was used to drive swine PPARgamma2 (sPPARgamma2) overexpression in the muscle of a transgenic mice model. The results showed that the mRNA of multiple adipocyte genes was increased in the skeletal muscle, as evidenced by the up-regulation of fatty acid synthase (2.11-fold, P < 0.05), lipoprotein lipase (2.08-fold, P < 0.01), fatty acid-binding protein 4 (14.30-fold, P < 0.01), and CD36 antigen (5.50-fold, P < 0.01). Meanwhile, skeletal muscle triacylglycerol was increased (P < 0.01) and the fatty acid profile of muscle fat was changed in that more polyunsaturated fats acid were augmented. The present study may further serve to develop transgenic pigs with higher intramuscular fat content and improved pork quality. PMID- 22528466 TI - Expression of biologically active human interferon alpha 2 in Aloe vera. AB - Methods necessary for the successful transformation and regeneration of Aloe vera were developed and used to express the human protein, interferon alpha 2 (IFNalpha2). IFNalpha2 is a secreted cytokine that plays a vital role in regulating the cellular response to viral infection. Transgenic plants were regenerated from callus cultures initiated from zygotic embryos. Expression of the IFNA2 transgene in transformed plants was confirmed by RT-PCR and IFNalpha2 protein was detected by immunoblot analysis. Human A549 cells treated with transgenic aloe extracts for 6 h induced expression of the interferon stimulated gene 54, indicating activation of the IFN signaling pathway. The biological activity of the aloe produced IFNalpha2 was assessed using an antiviral assay with A549 cells treated with extracts from both the rind and pulp fractions of the shoot and subsequently infected with the lytic encephalomyocarditis virus. The highest level of activity attributable to recombinant IFNalpha2 was determined to be 625 IU/mg of total soluble protein (TSP) in the rind and 2,108 IU/mg TSP in the pulp. Two daughter plants that vegetatively budded during the course of this study were also confirmed to express IFNalpha2. These results confirm that Aloe vera is capable of expressing a human protein with biological activity, and that a secreted protein targeting the apoplast can be detected in the pulp fraction of the plant. PMID- 22528467 TI - Transgenesis applied to goat: current applications and ongoing research. AB - Compared to experiments involving pigs, cows and/or sheep, transgenesis applied to goats is probably less advertised. However, recent successes and increasing amount of dedicated research make this species of special interest for ongoing biological and physiological questions on genome engineering in large animals. This short review aims at highlighting the current applications and limitations of the goat genome manipulation. PMID- 22528468 TI - Branch-based model for the diameters of the pulmonary airways: accounting for departures from self-consistency and registration errors. AB - We examine a previously published branch-based approach for modeling airway diameters that is predicated on the assumption of self-consistency across all levels of the tree. We mathematically formulate this assumption, propose a method to test it and develop a more general model to be used when the assumption is violated. We discuss the effect of measurement error on the estimated models and propose methods that take account of error. The methods are illustrated on data from MRI and CT images of silicone casts of two rats, two normal monkeys, and one ozone-exposed monkey. Our results showed substantial departures from self consistency in all five subjects. When departures from self-consistency exist, we do not recommend using the self-consistency model, even as an approximation, as we have shown that it may likely lead to an incorrect representation of the diameter geometry. The new variance model can be used instead. Measurement error has an important impact on the estimated morphometry models and needs to be addressed in the analysis. PMID- 22528469 TI - Biochemical analysis and investigation on the prospective applications of alkaline protease from a Bacillus cereus strain. AB - Proteases have prospective financial and environment-friendly applications; hence attention is focused currently on the finding of new protease producing microorganism so as to meet the requirements of industry. A thermophilic bacterial strain producing extracellular protease activity was isolated from soil and identified as Bacillus cereus by analysis of 16S rRNA. Protease production by the microorganism was improved by studying the impact of the type of nitrogen and carbon source, fermentation period, growth temperature and initial pH of the culture medium in cultivation optimization experiments. The enzyme was purified to homogeneity in two step procedure involving Sephadex G-75 and Q-Sepharose chromatography. The molecular weight of purified enzyme was found to be 58 kDa by SDS-PAGE. Protease exhibited a pH and temperature optima of 7.5 and 60 degrees , respectively. The enzyme was active in the pH range of 6.0-9.0 and stable up to 70 degrees C. Histological analysis of protease treated goat and cow skin pelts showed complete removal of non leather forming structures such as hair shaft, hair follicles and glandular structures. The protease showed the stain removing property from blood stained cotton cloth and found to be compatible with six commercially available detergents. The protease could release peptides from natural proteins after digestion of coagulated egg albumin and blood clot. PMID- 22528470 TI - Effectiveness of cognitive training in Chinese older people with subjective cognitive complaints: a randomized placebo-controlled trial. AB - OBJECTIVE: This study examines the short-term and long-term effects of a cognitive training (CT) program in enhancing cognitive function of older people with subjective memory complaints. METHODS: A single-blind randomized placebo controlled trial was carried out in a sample of 223 older adults aged 65 years or above with subjective memory complaints in Hong Kong. They were randomly assigned to either receive CT (intervention group, N = 111) or attend health-related educational lectures only (control group, N = 112). Participants' cognitive abilities were assessed by the Chinese version of Mattis Dementia Rating Scale at baseline, immediately after the training, and nine months after the training. RESULTS: Significant interaction effect of CT and education was detected on participants' CT gains at both T2 (F(2, 200) = 6.329, p = 0.002, eta(2) = 0.060) and T3 (F(2, 189) = 3.294, p = 0.039, eta(2) = 0.034). CONCLUSIONS: Cognitive training was effective in enhancing the overall cognitive functioning of less educated older adults with subjective memory complaints. The positive effect was durable for at least nine months in two cognitive areas, namely conceptualization and memory. PMID- 22528471 TI - The role of smoking in allergy and asthma: lessons from the ECRHS. AB - The European Community Respiratory Health Survey is an international multicenter cohort study of asthma, allergy, and lung function that began in the early-1990s with recruitment of population-based samples of 20- to 44-year-old adults, mainly in Europe. The aims of the study are broad ranging but include assessment of the role of in utero exposure to tobacco smoke, exposure to environmental tobacco smoke, and active smoking on the incidence, prevalence, and prognosis of allergy and asthma. Cross-sectional and longitudinal analyses looking at these associations have been conducted, sometimes only using information collected in one country, and on other occasions using information collected in all the participating centers. This article summarizes the results from these various publications from this large epidemiologic study. PMID- 22528472 TI - The biological response of poly(L-lactide) films modified by different biomolecules: role of the coating strategy. AB - The interactions between the surface of synthetic scaffolds and cells play an important role in tissue engineering applications. To improve these interactions, two strategies are generally followed: surface coating with large proteins and surface grafting with small peptides. The proteins and peptides more often used and derived from the extracellular matrix, are fibronectin, laminin, and their active peptides, RGD and SIKVAV, respectively. The aim of this work was to compare the effects of coating and grafting of poly(L-lactide) (PLLA) films on MRC5 fibroblast cells. Grafting reactions were verified by X-ray photoelectron spectroscopy. Cell adhesion and proliferation on coated and grafted PLLA surfaces were measured by cell counting. Vinculin localization and distribution were performed on cell cultured on PLLA samples using a fluorescence microscopy technique. Finally, western blot was performed to compare signals of cell adhesion proteins, such as vinculin, Rac1, and RhoA, as well as cell proliferation, such as PCNA. These tests showed similar results for fibronectin and laminin coated PLLA, while RGD grafting is more effective compared with SIKVAV grafting. Considering the overall view of these results, although coating and grafting can both be regarded as effective methods for surface modification to enhance cell adhesion and proliferation on a biomaterial, RGD grafted PLLA show better cell adhesion and proliferation than coated PLLA, while SIKVAV grafted PLLA show similar adhesion but worse proliferation. These data verified different biological effects depending on the surface modification method used. PMID- 22528473 TI - A "Link-Psi" strategy using crosslinking indicates that the folding transition state of ubiquitin is not very malleable. AB - Using a combined crosslinking-psi analysis strategy, we examine whether the structural content of the transition state of ubiquitin can be altered. A synthetic dichloroacetone crosslink is first introduced across two beta strands. Whether the structural content in the transition state ensemble has shifted towards the region containing the crosslink is probed by remeasuring the psi value at another region (psi identifies the degree to which an inserted bi Histidine metal ion binding site is formed in the transition state). For sites around the periphery of the obligate transition state nucleus, we find that the resulting changes in psi values are near or at our detection limit, thereby indicating that the structural content of the transition state has not measurably changed upon crosslinking. This work demonstrates the utility of the simultaneous application of crosslinking and psi-analysis for examining potential transition state heterogeneity in globular proteins. PMID- 22528474 TI - Neuroimaging markers of human immunodeficiency virus infection in South Africa. AB - Previous studies have reported cognitive deficits among HIV-positive individuals infected with clade C virus. However, no study has examined whether individuals predominately infected with clade C virus exhibit brain atrophy relative to healthy controls. This study examined volumetric differences between 28 HIV+ individuals and 23 HIV- controls from South Africa. Volumetric measures were obtained from six regions of interest -- caudate, thalamus, corpus callosum, total cortex, total gray matter, and total white matter. HIV+ participants had significantly lower volumes in the total white matter (p<0.01), thalamus (p<0.01) and total gray matter (inclusive of cortical and subcortical regions, p<0.01). This study is the first to provide evidence of brain atrophy among HIV+ individuals in South Africa, where HIV clade C predominates. Additional research that integrates neuroimaging, comprehensive neuropsychological testing, genetic variance in clade-specific proteins, and the impact of treatment with Antiretrovirals (ARV) are necessary to understand the development of HIV-related neurocognitive disorders in South Africa. PMID- 22528475 TI - Cytokine levels in CSF and neuropsychological performance in HIV patients. AB - HIV-associated dementia and its precursors are frequently observed complications of HIV infection, even in the presence of combination antiretroviral treatment (cART). The development, surveillance and treatment of this condition are still not completely understood. Cytokines, as immunological transmitters, may be one key to gaining a deeper understanding of the disease. A total of 33 HIV-positive male patients were evaluated by neuropsychological testing, lumbar and venous puncture, neuroimaging and neurological examination. The cytokine content in the CSF (cerebrospinal fluid) was examined by a solid-phase protein array. The Digit Symbol Test, contraction time analysis, Rey-Osterrieth Figure and Grooved Pegboard Test showed inferior results in the presence of an inflammatory CSF environment, whereas neuroprotective or anti-inflammatory conditions were correlated to better results in contraction time analysis. Higher CSF levels of cytokines were independently correlated with the duration of HIV infection. The study showed a correlation of cytokine levels in the CSF of HIV patients with test results of their neuropsychological functioning. The effect was pronounced with regard to the more complex executive tasks. Determining CSF cytokine levels may be a useful supplement to the assessment of HIV patients and contribute helpful information to predict neurocognitive performance. Therapeutic strategies to ameliorate a negative impact of an altered cytokine milieu may aid in slowing the evolution of neurocognitive dysfunction. PMID- 22528476 TI - Cerebrovascular disease in HIV-infected individuals in the era of highly active antiretroviral therapy. AB - The widespread use of highly active antiretroviral therapy (HAART) in HIV infected individuals mostly in developed countries has dramatically improved their prognosis. In such advantaged regions of the world, therefore, many patients are now transitioning from middle into older age, with altered patterns of disease. While previously a rare complication of HIV infection, cerebrovascular disease (particularly that associated with atherosclerosis) is becoming relatively more important in this treated group of individuals. This review summarises the evidence regarding the shifting epidemiology of cerebrovascular diseases affecting HIV-infected individuals. While outlining the association between HIV infection and AIDS and cerebrovascular disease, as well as opportunistic diseases and HIV-associated vasculopathies, the current evidence supporting an increase in atherosclerotic disease in treated HIV-infected individuals is emphasised and a management approach to ischaemic stroke in HIV infected individuals is presented. Evidence supporting the important role of HAART and HIV infection itself in the pathogenesis of atherosclerotic disease is discussed, together with preventative approaches to this increasingly important disease process as the population ages. Finally, a discussion regarding the significant association between cerebrovascular disease and HIV-associated neurocognitive disorder is presented, together with possible mechanisms behind this relationship. PMID- 22528477 TI - Prevalence of peripheral neuropathy in antiretroviral therapy naive HIV-positive patients and the impact on treatment outcomes--a retrospective study from a large urban cohort in Johannesburg, South Africa. AB - Peripheral neuropathy (PN) is associated with advanced HIV disease and may be a complication of antiretroviral therapy (ART) or anti-tuberculosis (TB) drugs, specifically isoniazid (INH). The effect of non-ART-drug-related PN on treatment outcomes is yet to be determined. We analysed prospectively collected cohort data for HIV-infected ART-naive adults initiating ART at the Themba Lethu Clinic, Johannesburg, South Africa from June 2004 to June 2009. Patients who presented with signs and symptoms of numbness or dysesthesia prior to initiation of ART were defined as having PN. Cox proportional hazard models were used to estimate the effect of PN alone (HIV-related PN) or PN with a history of INH use (TB related PN) on mortality, lost to follow-up (LTFU), persistent and recurrent PN by 12 months of follow-up. Of the 9,399 patients initiating ART, 3.9 % had HIV related PN while a further 1.8 % had TB-related PN. Patients with PN did not have a significantly higher risk of mortality compared to those without PN (hazard ratio (HR) 1.17 95 % CI 0.92-1.49). Patients with TB-related PN were less likely to be LTFU by 12 months (HR 0.65 95 % CI 0.44-0.97) compared to those without PN. Patients with HIV-related PN were at increased risk of persistent PN at 3 months post-ART initiation. Patients with HIV-related PN had a similar risk of recurrent PN compared to those with TB-related PN (HR 1.28 95 % CI 0.72-2.27). We demonstrate that patients with PN at initiation of ART present with advanced HIV disease. Completion of TB treatment may reduce the risk of persistent PN in patients with TB-related PN. Use of HIV drugs, even neurotoxic ones, may overall limit neuropathy. PMID- 22528478 TI - Impact of HIV and aging on neuropsychological function. AB - Cognitive efficiency decreases with age, and advancing age is the leading risk factor for most neurodegenerative disorders that result in dementia. In HIV infection, risk for cognitive impairment is consistently linked to advancing chronological age. As the HIV epidemic enters its fourth decade in the USA, extended life expectancy will likely result in an increased prevalence of cognitive disorders by virtue of these factors. However, it is less clear if HIV potentiates or accelerates the risk for cognitive impairment given that most reports are mixed or demonstrate only a small interaction effect. More critically, it is unclear if HIV will modulate the neuropathology associated with non-HIV cognitive disorders in a manner that will increase risk for diseases such as cerebrovascular and Alzheimer's disease. In the coming years, with increasing numbers of HIV+ patients entering their 60s and 70s, background risk for neurodegenerative disorders will be sufficiently high as to inform this issue on clinical grounds. This review summarizes knowledge of cognition in HIV as it relates to age and presents some emerging controversies. PMID- 22528480 TI - Clinical features and preliminary studies of virological correlates of neurocognitive impairment among HIV-infected individuals in Nigeria. AB - In Nigeria, the incidence and prevalence of human immunodeficiency virus (HIV) related neurocognitive impairment (NCI) are unknown and there currently exists little information related to the viral correlates rates of NCI. Therefore, studies were performed to examine the potential utility of applying an established neuropsychological (NP) screening battery and detailed NP testing to detect NCI and correlations with functional impairment and the presence of specific viral signatures among infected subjects. A total of 60 HIV-1 seropositive antiretroviral-naive individuals and 56 seronegative control subjects were administered the International HIV Dementia Scale (IHDS) and assessed for functional impairment using the Karnofsky performance status scale. Fifteen HIV-infected patients and 11 controls were also administered a detailed NP battery. Blood samples from eight infected subjects, three with evidence of NCI, were obtained for molecular analysis of HIV-1 strain. Unadjusted scores on the IHDS showed that, using a recommended total score cutoff of 10, 28.8% of the HIV-1 seropositive and 16.0% of seropositive individuals scored abnormally. Results from testing using the full NP battery showed that, overall, the HIV seropositive group performed worse than the seronegative group, with effect sizes spanning from small (0.25 on the trail making test A) to large (0.82 on action fluency), and an average effect size across the battery of 0.45, which approaches that which has been recorded in other international settings. Sequencing of partial pol amplicons from viral isolates revealed that two of three patients with NCI were infected with subtype G virus and 1 with the circulating recombinant form (CRF)02_AG; all four individuals without NCI were infected with CRF_02AG. These studies demonstrate the utility of the IHDS in identifying cognitive impairment among HIV infected individuals in Nigeria. Future studies aimed at examining the burden of NCI among the population of individuals with HIV 1 infection in Nigeria and which assess the virologic correlates will contribute to the evolving understanding of the pathogenetic factors that underlie this disorder. PMID- 22528479 TI - Differential expression and HIV-1 regulation of MU-opioid receptor splice variants across human central nervous system cell types. AB - The MU-opioid receptor (MOR) is known to undergo extensive alternative splicing as numerous splice variants of MOR have been identified. However, the functional significance of MOR variants, as well as how splice variants other than MOR-1 might differentially regulate human immunodeficiency virus type-1 (HIV-1) pathogenesis in the central nervous system (CNS), or elsewhere, has largely been ignored. Our findings suggest that there are specific differences in the MOR variant expression profile among CNS cell types, and that the expression levels of these variants are differentially regulated by HIV-1. While MOR-1A mRNA was detected in astroglia, microglia, and neurons, MOR-1 and MOR-1X were only found in astroglia. Expression of the various forms of MOR along with the chimeric G protein qi5 in HEK-293T cells resulted in differences in calcium/NFAT signaling with morphine treatment, suggesting that MOR variant expression might underlie functional differences in MOR-effector coupling and intracellular signaling across different cell types. Furthermore, the data suggest that the expression of MOR-1 and other MOR variants may also be differentially regulated in the brains of HIV-infected subjects with varying levels of neurocognitive impairment. Overall, the results reveal an unexpected finding that MOR-1 may not be the predominant form of MOR expressed by some CNS cell types and that other splice variants of MOR-1, with possible differing functions, may contribute to the diversity of MOR-related processes in the CNS. PMID- 22528481 TI - Increased incidence of symptomatic peripheral neuropathy among adults receiving stavudine- versus zidovudine-based antiretroviral regimens in Kenya. AB - The incidence of peripheral neuropathy (PN) among adults initiating antiretroviral therapy (ART) containing stavudine (d4T) versus zidovudine (ZDV) is not well described. We compared 1-year incidence between d4T- and ZDV-based regimens in adults initiating ART in a programmatic setting in Kenya. Of 1,848 adults on ART, 1,579 (85 %) initiated d4T-based and 269 (15 %) initiated ZDV based regimens. One-year incidence of symptomatic PN per 100 person-years was 21.9 (n=236) among d4T users and 6.9 (n=7) among ZDV users (P=0.0002). D4T was associated with 2.7 greater risk of PN than ZDV (adjusted hazard ratio, 2.7, P=0.009). In settings with continued d4T use, such as Africa, the effects of d4T on PN compared to ZDV should be considered when choosing ART regimens. PMID- 22528482 TI - Heavy chains of inter alpha inhibitor (IalphaI) inhibit the human complement system at early stages of the cascade. AB - Inter alpha inhibitor (IalphaI) is an abundant serum protein consisting of three polypeptides: two heavy chains (HC1 and HC2) and bikunin, a broad-specificity Kunitz-type proteinase inhibitor. The complex is covalently held together by chondroitin sulfate but during inflammation IalphaI may interact with TNF stimulated gene 6 protein (TSG-6), which supports transesterification of heavy chains to hyaluronan. Recently, IalphaI was shown to inhibit mouse complement in vivo and to protect from complement-mediated lung injury but the mechanism of such activity was not elucidated. Using human serum depleted from IalphaI, we found that IalphaI is not an essential human complement inhibitor as was reported for mice and that such serum has unaltered hemolytic activity. However, purified human IalphaI inhibited classical, lectin and alternative complement pathways in vitro when added in excess to human serum. The inhibitory activity was dependent on heavy chains but not bikunin and detected at the level of initiating molecules (MBL, properdin) in the lectin/alternative pathways or C4b in the classical pathway. Furthermore, IalphaI affected formation and assembly of the C1 complex and prevented assembly of the classical pathway C3-convertase. Presence and putative interactions with TSG-6 did not affect the ability of IalphaI to inhibit complement thus implicating IalphaI as a potentially important complement inhibitor once enriched onto hyaluronan moieties in the course of local inflammatory processes. In support of this, we found a correlation between IalphaI/HC-containing proteins and hemolytic activity of synovial fluid from patients suffering from rheumatoid arthritis. PMID- 22528483 TI - Identification of a human trans-3-hydroxy-L-proline dehydratase, the first characterized member of a novel family of proline racemase-like enzymes. AB - A family of eukaryotic proline racemase-like genes has recently been identified. Several members of this family have been well characterized and are known to catalyze the racemization of free proline or trans-4-hydroxyproline. However, the majority of eukaryotic proline racemase-like proteins, including a human protein called C14orf149, lack a specific cysteine residue that is known to be critical for racemase activity. Instead, these proteins invariably contain a threonine residue at this position. The function of these enzymes has remained unresolved until now. In this study, we demonstrate that three enzymes of this type, including human C14orf149, catalyze the dehydration of trans-3-hydroxy-L-proline to Delta(1)-pyrroline-2-carboxylate (Pyr2C). These are the first enzymes of this subclass of proline racemase-like genes for which the enzymatic activity has been resolved. C14orf149 is also the first human enzyme that acts on trans-3-hydroxy-L proline. Interestingly, a mutant enzyme in which the threonine in the active site is mutated back into cysteine regained 3-hydroxyproline epimerase activity. This result suggests that the enzymatic activity of these enzymes is dictated by a single residue. Presumably, human C14orf149 serves to degrade trans-3-hydroxy-L proline from the diet and originating from the degradation of proteins that contain this amino acid, such as collagen IV, which is an important structural component of basement membrane. PMID- 22528484 TI - Sialic acid associated with alphavbeta3 integrin mediates HIV-1 Tat protein interaction and endothelial cell proangiogenic activation. AB - Sialic acid (NeuAc) is a major anion on endothelial cells (ECs) that regulates different biological processes including angiogenesis. NeuAc is present in the oligosaccharidic portion of integrins, receptors that interact with extracellular matrix components and growth factors regulating cell adhesion, migration, and proliferation. Tat is a cationic polypeptide that, once released by HIV-1(+) cells, accumulates in the extracellular matrix, promoting EC adhesion and proangiogenic activation by engaging alpha(v)beta(3). By using two complementary approaches (NeuAc removal by neuraminidase or its masking by NeuAc-binding lectin from Maackia amurensis, MAA), we investigated the presence of NeuAc on endothelial alpha(v)beta(3) and its role in Tat interaction, EC adhesion, and proangiogenic activation. alpha(v)beta(3) immunoprecipitation with biotinylated MAA or Western blot analysis of neuraminidase-treated ECs demonstrated that NeuAc is associated with both the alpha(v) and the beta(3) subunits. Surface plasmon resonance analysis demonstrated that the masking of alpha(v)beta(3)-associated NeuAc by MAA prevents Tat/alpha(v)beta(3) interaction. MAA and neuraminidase prevent alpha(v)beta(3)-dependent EC adhesion to Tat, the consequent FAK and ERK1/2 phosphorylation, and EC proliferation, migration, and regeneration in a wound-healing assay. Finally, MAA inhibits Tat-induced neovascularization in the ex vivo human artery ring sprouting assay. The inhibitions are specific because the NeuAc-unrelated lectin from Ulex europaeus is ineffective on Tat. Also, MAA and neuraminidase affect only weakly integrin-dependent EC adhesion and proangiogenic activation by fibronectin. In conclusion, NeuAc is associated with endothelial alpha(v)beta(3) and mediates Tat-dependent EC adhesion and proangiogenic activation. These data point to the possibility to target integrin glycosylation for the treatment of angiogenesis/AIDS-associated pathologies. PMID- 22528485 TI - Transcellular neuroligin-2 interactions enhance insulin secretion and are integral to pancreatic beta cell function. AB - Normal glucose-stimulated insulin secretion is dependent on interactions between neighboring beta cells. Elucidation of the reasons why this cell-to-cell contact is essential will probably yield critical insights into beta cell maturation and function. In the central nervous system, transcellular protein interactions (i.e. interactions between proteins on the surfaces of different cells) involving neuroligins are key mediators of synaptic functional development. We previously demonstrated that beta cells express neuroligin-2 and that insulin secretion is affected by changes in neuroligin-2 expression. Here we show that the effect of neuroligin-2 on insulin secretion is mediated by transcellular interactions. Neuroligin-2 binds with nanomolar affinity to a partner on the beta cell surface and contributes to the increased insulin secretion brought about by beta cell-to beta cell contact. It does so in a manner seemingly independent of interactions with neurexin, a known binding partner. As in the synapse, transcellular neuroligin-2 interactions enhance the functioning of the submembrane exocytic machinery. Also, as in the synapse, neuroligin-2 clustering is important. Neuroligin-2 in soluble form, rather than presented on a cell surface, decreases insulin secretion by rat islets and MIN-6 cells, most likely by interfering with endogenous neuroligin interactions. Prolonged contact with neuroligin-2 expressing cells increases INS-1 beta cell proliferation and insulin content. These results extend the known parallels between the synaptic and beta cell secretory machineries to extracellular interactions. Neuroligin-2 interactions are one of the few transcellular protein interactions thus far identified that directly enhance insulin secretion. Together, these results indicate a significant role for transcellular neuroligin-2 interactions in the establishment of beta cell function. PMID- 22528486 TI - Nucleophosmin (NPM1/B23) interacts with activating transcription factor 5 (ATF5) protein and promotes proteasome- and caspase-dependent ATF5 degradation in hepatocellular carcinoma cells. AB - Nucleophosmin (NPM1/B23) and the activating transcription factor 5 (ATF5) are both known to subject to cell type-dependent regulation. NPM1 is expressed weakly in hepatocytes and highly expressed in hepatocellular carcinomas (HCC) with a clear correlation between enhanced NPM1 expression and increased tumor grading and poor prognosis, whereas in contrast, ATF5 is expressed abundantly in hepatocytes and down-regulated in HCC. Re-expression of ATF5 in HCC inhibits cell proliferation. We report here that using an unbiased approach, tandem affinity purification (TAP) followed with mass spectrometry (MS), we identified NPM1 as a novel ATF5-interacting protein. Unlike many other NPM1-interacting proteins that interact with the N-terminal oligomerization domain of NPM1, ATF5 binds via its basic leucine zipper to the C-terminal region of NPM1 where its nucleolar localization signal is located. NPM1 association with ATF5, whose staining patterns partially overlap in the nucleoli, promotes ATF5 protein degradation through proteasome-dependent and caspase-dependent pathways. NPM1-c, a mutant NPM1 that is defective in nucleolar localization, failed to stimulate ATF5 polyubiquitination and was unable to down-regulate ATF5. NPM1 interaction with ATF5 displaces HSP70, a known ATF5-interacting protein, from ATF5 protein complexes and antagonizes its role in stabilization of ATF5 protein. NPM1 promoted ATF5 down-regulation diminished ATF5-mediated repression of cAMP responsive element-dependent gene transcription and abrogates ATF5-induced G(2)/M cell cycle blockade and inhibition of cell proliferation in HCC cells. Our study establishes a mechanistic link between elevated NPM1 expression and depressed ATF5 in HCC and suggests that regulation of ATF5 by NPM1 plays an important role in the proliferation and survival of HCC. PMID- 22528487 TI - 1H NMR metabolomics analysis of glioblastoma subtypes: correlation between metabolomics and gene expression characteristics. AB - Glioblastoma multiforme (GBM) is the most common form of malignant glioma, characterized by unpredictable clinical behaviors that suggest distinct molecular subtypes. With the tumor metabolic phenotype being one of the hallmarks of cancer, we have set upon to investigate whether GBMs show differences in their metabolic profiles. (1)H NMR analysis was performed on metabolite extracts from a selection of nine glioblastoma cell lines. Analysis was performed directly on spectral data and on relative concentrations of metabolites obtained from spectra using a multivariate regression method developed in this work. Both qualitative and quantitative sample clustering have shown that cell lines can be divided into four groups for which the most significantly different metabolites have been determined. Analysis shows that some of the major cancer metabolic markers (such as choline, lactate, and glutamine) have significantly dissimilar concentrations in different GBM groups. The obtained lists of metabolic markers for subgroups were correlated with gene expression data for the same cell lines. Metabolic analysis generally agrees with gene expression measurements, and in several cases, we have shown in detail how the metabolic results can be correlated with the analysis of gene expression. Combined gene expression and metabolomics analysis have shown differential expression of transporters of metabolic markers in these cells as well as some of the major metabolic pathways leading to accumulation of metabolites. Obtained lists of marker metabolites can be leveraged for subtype determination in glioblastomas. PMID- 22528488 TI - Induction of Bv8 expression by granulocyte colony-stimulating factor in CD11b+Gr1+ cells: key role of Stat3 signaling. AB - Bv8, also known as prokineticin 2, has been characterized as an important mediator of myeloid cell mobilization and myeloid cell-dependent tumor angiogenesis. Bv8 expression is dramatically enhanced by G-CSF, both in vitro and in vivo. The mechanisms involved in such up-regulation remain unknown. Using pharmacological inhibitors that interfere with multiple signaling pathways known to be activated by G-CSF, we show that signal transducer and activator of transcription 3 (Stat3) activation is required for Bv8 up-regulation in mouse bone marrow cells, whereas other Stat family members and extracellular signal regulated kinase (ERK) activation are not involved. We further identified CD11b(+) Gr1(+) myeloid cells as the primary cell population in which Stat3 signaling is activated by G-CSF. Bv8 expression induced by G-CSF was also significantly reduced by siRNA-mediated Stat3 knockdown. Moreover, chromatin immunoprecipitation studies indicate that G-CSF significantly induces binding of phospho-Stat3 to the Bv8 promoter, which was abolished by pretreatment with the Stat3 inhibitor WP1066. Luciferase assay confirmed that the phospho-Stat3 binding site is a functional enhancer of the Bv8 promoter. The key role of Stat3 signaling in regulating G-CSF-induced Bv8 expression was further confirmed by in vivo studies. We show that the regulation of Bv8 expression in human bone marrow cells is also Stat3 signaling-dependent. Stat3 is recognized as a key regulator of inflammation-dependent tumorigenesis. We propose that such a role of Stat3 reflects at least in part its ability to regulate Bv8 expression. PMID- 22528489 TI - Cathepsin D primes caspase-8 activation by multiple intra-chain proteolysis. AB - During the resolution of inflammatory responses, neutrophils rapidly undergo apoptosis. A direct and fast activation of caspase-8 by cathepsin D was shown to be crucial in the initial steps of neutrophil apoptosis. Nevertheless, the activation mechanism of caspase-8 remains unclear. Here, by using site-specific mutants of caspase-8, we show that both cathepsin D-mediated proteolysis and homodimerization of caspase-8 are necessary to generate an active caspase-8. At acidic pH, cathepsin D specifically cleaved caspase-8 but not the initiator caspase-9 or -10 and significantly increased caspase-8 activity in dimerizing conditions. These events were completely abolished by pepstatin A, a pharmacological inhibitor of cathepsin D. The cathepsin D intra-chain proteolysis greatly stabilized the active site of caspase-8. Moreover, the main caspase-8 fragment generated by cathepsin D cleavage could be affinity-labeled with the active site probe biotin-VAD-fluoromethyl ketone, suggesting that this fragment is enzymatically active. Importantly, in an in vitro cell-free assay, the addition of recombinant human caspase-8 protein, pre-cleaved by cathepsin D, was followed by caspase-3 activation. Our data therefore indicate that cathepsin D is able to initiate the caspase cascade by direct activation of caspase-8. As cathepsin D is ubiquitously expressed, this may represent a general mechanism to induce apoptosis in a variety of immune and nonimmune cells. PMID- 22528490 TI - Regulation of AMP-activated protein kinase signaling by AFF4 protein, member of AF4 (ALL1-fused gene from chromosome 4) family of transcription factors, in hypothalamic neurons. AB - In the hypothalamus, fasting induces a member of the AF4 family of transcription factors, AFF4, which was originally identified as a fusion partner of the mixed lineage leukemia gene in infant acute lymphoblastic leukemia. However, the roles of AFF4 in the hypothalamus remain unclear. We show herein that expression of AFF4 increased upon addition of ghrelin and fasting in the growth hormone secretagogue receptor-expressing neurons of the hypothalamus. In the growth hormone secretagogue receptor-expressing hypothalamic neuronal cell line GT1-7, ghrelin markedly induced expression of AFF4 in a time- and dose-dependent manner. Overexpression of AFF4 in GT1-7 cells specifically induced expression of the AMP activated protein kinase (AMPK) alpha2 subunit but failed to induce other AMPK subunits and AMPK upstream kinases. The promoter activity of the AMPKalpha2 gene increased upon addition of AFF4, suggesting that AFF4 regulates transcription of the AMPKalpha2 gene. Additionally, AFF4 also increased the phosphorylation of acetyl-CoA carboxylase alpha (ACCalpha), a downstream target of AMPK. In GT1-7 cells, ghrelin phosphorylated ACCalpha through AMPKalpha phosphorylation in the early phase (15 min) of the activation. However, ghrelin-induced expression of AMPKalpha2 and phosphorylation of ACCalpha in the late phase (2 h) of the activation were independent of AMPKalpha phosphorylation. Attenuation of expression of AFF4 by its siRNA in GT1-7 cells decreased ghrelin-induced AMPKalpha2 expression and ACCalpha phosphorylation in the late phase of the activation. AFF4 may therefore help to maintain activation of AMPK downstream signaling under conditions of prolonged stimulation with ghrelin, such as during fasting. PMID- 22528491 TI - Native presynaptic metabotropic glutamate receptor 4 (mGluR4) interacts with exocytosis proteins in rat cerebellum. AB - The eight pre- or/and post-synaptic metabotropic glutamatergic receptors (mGluRs) modulate rapid excitatory transmission sustained by ionotropic receptors. They are classified in three families according to their percentage of sequence identity and their pharmacological properties. mGluR4 belongs to group III and is mainly localized presynaptically. Activation of group III mGluRs leads to depression of excitatory transmission, a process that is exclusively provided by mGluR4 at parallel fiber-Purkinje cell synapse in rodent cerebellum. This function relies at least partly on an inhibition of presynaptic calcium influx, which controls glutamate release. To improve the understanding of molecular mechanisms of the mGluR4 depressant effect, we decided to identify the proteins interacting with this receptor. Immunoprecipitations using anti-mGluR4 antibodies were performed with cerebellar extracts. 183 putative partners that co immunoprecipitated with anti-mGluR4 antibodies were identified and classified according to their cellular functions. It appears that native mGluR4 interacts with several exocytosis proteins such as Munc18-1, synapsins, and syntaxin. In addition, native mGluR4 was retained on a Sepharose column covalently grafted with recombinant Munc18-1, and immunohistochemistry experiments showed that Munc18-1 and mGluR4 colocalized at plasma membrane in HEK293 cells, observations in favor of an interaction between the two proteins. Finally, affinity chromatography experiments using peptides corresponding to the cytoplasmic domains of mGluR4 confirmed the interaction observed between mGluR4 and a selection of exocytosis proteins, including Munc18-1. These results could give indications to explain how mGluR4 can modulate glutamate release at parallel fiber-Purkinje cell synapses in the cerebellum in addition to the inhibition of presynaptic calcium influx. PMID- 22528492 TI - Zn2+-Abeta40 complexes form metastable quasi-spherical oligomers that are cytotoxic to cultured hippocampal neurons. AB - The roles of metal ions in promoting amyloid beta-protein (Abeta) oligomerization associated with Alzheimer disease are increasingly recognized. However, the detailed structures dictating toxicity remain elusive for Abeta oligomers stabilized by metal ions. Here, we show that small Zn(2+)-bound Abeta1-40 (Zn(2+) Abeta40) oligomers formed in cell culture medium exhibit quasi-spherical structures similar to native amylospheroids isolated recently from Alzheimer disease patients. These quasi-spherical Zn(2+)-Abeta40 oligomers irreversibly inhibit spontaneous neuronal activity and cause massive cell death in primary hippocampal neurons. Spectroscopic and x-ray diffraction structural analyses indicate that despite their non-fibrillar morphology, the metastable Zn(2+) Abeta40 oligomers are rich in beta-sheet and cross-beta structures. Thus, Zn(2+) promotes Abeta40 neurotoxicity by structural organization mechanisms mediated by coordination chemistry. PMID- 22528493 TI - Uncovering biphasic catalytic mode of C5-epimerase in heparan sulfate biosynthesis. AB - Heparan sulfate (HS), a highly sulfated polysaccharide, is biosynthesized through a pathway involving several enzymes. C(5)-epimerase (C(5)-epi) is a key enzyme in this pathway. C(5)-epi is known for being a two-way catalytic enzyme, displaying a "reversible" catalytic mode by converting a glucuronic acid to an iduronic acid residue, and vice versa. Here, we discovered that C(5)-epi can also serve as a one-way catalyst to convert a glucuronic acid to an iduronic acid residue, displaying an "irreversible" catalytic mode. Our data indicated that the reversible or irreversible catalytic mode strictly depends on the saccharide substrate structures. The biphasic mode of C(5)-epi offers a novel mechanism to regulate the biosynthesis of HS with the desired biological functions. PMID- 22528494 TI - Transmembrane helix 11 is a genuine regulator of the endoplasmic reticulum Ca2+ pump and acts as a functional parallel of beta-subunit on alpha-Na+,K+-ATPase. AB - The housekeeping sarco(endo)plasmic reticulum Ca(2+) ATPase SERCA2b transports Ca(2+) across the endoplasmic reticulum membrane maintaining a vital Ca(2+) gradient. Compared with the muscle-specific isoforms SERCA2a and SERCA1a, SERCA2b houses an 11th transmembrane segment (TM11) and a short luminal extension (LE) at its C terminus (2b-tail). The 2b-tail imposes a 2-fold higher apparent Ca(2+) affinity and lower V(max). Previously, we assumed that LE is the sole functional region of the 2b-tail and that TM11 is a passive element providing an additional membrane passage. However, here we show that peptides corresponding to the TM11 region specifically modulate the activity of the homologous SERCA1a in co reconstituted proteoliposomes and mimic the 2b-tail effect (i.e. lower V(max) and higher Ca(2+) affinity). Using truncated 2b-tail variants we document that TM11 regulates SERCA1a independently from LE, confirming that TM11 is a second, previously unrecognized functional region of the 2b-tail. A phylogenetic analysis further indicates that TM11 is the oldest and most conserved feature of the 2b tail, found in the SERCA pump of all Bilateria, whereas LE is only present in Nematoda and vertebrates. Considering remarkable similarities with the Na(+),K(+) ATPase alpha-beta interaction, we now propose a model for interaction of TM11 with TM7 and TM10 in the anchoring subdomain of the Ca(2+) pump. This model involves a TM11-induced helix bending of TM7. In conclusion, more than just a passive structural feature, TM11 acts as a genuine regulator of Ca(2+) transport through interaction with the pump. PMID- 22528495 TI - Site-specific protein dynamics in communication pathway from sensor to signaling domain of oxygen sensor protein, HemAT-Bs: Time-resolved Ultraviolet Resonance Raman Study. AB - HemAT-Bs is a heme-based signal transducer protein responsible for aerotaxis. Time-resolved ultraviolet resonance Raman (UVRR) studies of wild-type and Y70F mutant of the full-length HemAT-Bs and the truncated sensor domain were performed to determine the site-specific protein dynamics following carbon monoxide (CO) photodissociation. The UVRR spectra indicated two phases of intensity changes for Trp, Tyr, and Phe bands of both full-length and sensor domain proteins. The W16 and W3 Raman bands of Trp, the F8a band of Phe, and the Y8a band of Tyr increased in intensity at hundreds of nanoseconds after CO photodissociation, and this was followed by recovery in ~50 MUs. These changes were assigned to Trp-132 (G helix), Tyr-70 (B-helix), and Phe-69 (B-helix) and/or Phe-137 (G-helix), suggesting that the change in the heme structure drives the displacement of B- and G-helices. The UVRR difference spectra of the sensor domain displayed a positive peak for amide I in hundreds of nanoseconds after photolysis, which was followed by recovery in ~50 MUs. This difference band was absent in the spectra of the full-length protein, suggesting that the isolated sensor domain undergoes conformational changes of the protein backbone upon CO photolysis and that the changes are restrained by the signaling domain. The time-resolved difference spectrum at 200 MUs exhibited a pattern similar to that of the static (reduced - CO) difference spectrum, although the peak intensities were much weaker. Thus, the rearrangements of the protein moiety toward the equilibrium ligand-free structure occur in a time range of hundreds of microseconds. PMID- 22528496 TI - PDZ domain-containing 1 (PDZK1) protein regulates phospholipase C-beta3 (PLC beta3)-specific activation of somatostatin by forming a ternary complex with PLC beta3 and somatostatin receptors. AB - Phospholipase C-beta (PLC-beta) is a key molecule in G protein-coupled receptor (GPCR)-mediated signaling. Many studies have shown that the four PLC-beta subtypes have different physiological functions despite their similar structures. Because the PLC-beta subtypes possess different PDZ-binding motifs, they have the potential to interact with different PDZ proteins. In this study, we identified PDZ domain-containing 1 (PDZK1) as a PDZ protein that specifically interacts with PLC-beta3. To elucidate the functional roles of PDZK1, we next screened for potential interacting proteins of PDZK1 and identified the somatostatin receptors (SSTRs) as another protein that interacts with PDZK1. Through these interactions, PDZK1 assembles as a ternary complex with PLC-beta3 and SSTRs. Interestingly, the expression of PDZK1 and PLC-beta3, but not PLC-beta1, markedly potentiated SST induced PLC activation. However, disruption of the ternary complex inhibited SST induced PLC activation, which suggests that PDZK1-mediated complex formation is required for the specific activation of PLC-beta3 by SST. Consistent with this observation, the knockdown of PDZK1 or PLC-beta3, but not that of PLC-beta1, significantly inhibited SST-induced intracellular Ca(2+) mobilization, which further attenuated subsequent ERK1/2 phosphorylation. Taken together, our results strongly suggest that the formation of a complex between SSTRs, PDZK1, and PLC beta3 is essential for the specific activation of PLC-beta3 and the subsequent physiologic responses by SST. PMID- 22528498 TI - Protein kinase C-delta negatively regulates T cell receptor-induced NF-kappaB activation by inhibiting the assembly of CARMA1 signalosome. AB - T-cell receptor (TCR)-induced T-cell activation is a critical event in adaptive immune responses. The engagement of TCR complex by antigen along with the activation of the costimulatory receptors trigger a cascade of intracellular signaling, in which caspase recruitment domain-containing membrane-associated guanylate kinase 1 (CARMA1) is a crucial scaffold protein. Upon stimulation, CARMA1 recruits downstream molecules including B-cell CLL/lymphoma 10 (Bcl10), mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1), and TRAF6 to assemble a specific TCR-induced signalosome that triggers NF-kappaB and JNK activation. In this report, we identified protein kinase Cdelta (PKCdelta) as a CARMA1-associated protein by a biochemical affinity purification approach. PKCdelta interacted with CARMA1 in TCR stimulation-dependent manner in Jurkat T cells. Overexpression of PKCdelta inhibited CARMA1-mediated NF-kappaB activation, whereas knockdown of PKCdelta potentiated TCR-triggered NF-kappaB activation and IL-2 secretion in Jurkat T cells. Reconstitution experiments with PKCdelta kinase dead mutant indicated that the kinase activity of PKCdelta was dispensable for its ability to inhibit TCR-triggered NF-kappaB activation. Furthermore, we found that PKCdelta inhibited the interaction between MALT1 and TRAF6, but not the association of CARMA1 with PKCtheta, Bcl10, or MALT1. These observations suggest that PKCdelta is a negative regulator in T cell activation through inhibiting the assembly of CARMA1 signalosome. PMID- 22528497 TI - Global analysis of the regulon of the transcriptional repressor LexA, a key component of SOS response in Mycobacterium tuberculosis. AB - The DNA damage response is crucial for bacterial survival. The transcriptional repressor LexA is a key component of the SOS response, the main mechanism for the regulation of DNA repair genes in many bacteria. In contrast, in mycobacteria gene induction by DNA damage is carried out by two mechanisms; a relatively small number of genes are thought to be regulated by LexA, and a larger number by an alternate, independent mechanism. In this study we have used ChIP-seq analysis to identify 25 in vivo LexA-binding sites, including nine regulating genes not previously known to be part of this regulon. Some of these binding sites were found to be internal to the predicted open reading frame of the gene they are thought to regulate; experimental analysis has confirmed that these LexA-binding sites regulate the expression of the expected genes, and transcriptional start site analysis has found that their apparent relative location is due to misannotation of these genes. We have also identified novel binding sites for LexA in the promoters of genes that show no apparent DNA damage induction, show positive regulation by LexA, and those encoding small RNAs. PMID- 22528499 TI - Highly sensitive quenched fluorescent substrate of Legionella major secretory protein (msp) based on its structural analysis. AB - Legionella pneumophila has been shown to secrete a protease termed major secretory protein (Msp). This protease belongs to the M4 family of metalloproteases and shares 62.9% sequence similarity with pseudolysin (EC 3.4.24.26). With the aim of developing a specific enzymatic assay for the detection and quantification of Msp, the Fluofast substrate library was screened using both enzymes in parallel. Moreover, based on the crystal structure of pseudolysin, a model of the Msp structure was built. Screening of the peptide library identified a lead substrate specifically cleaved by Msp that was subsequently optimized by rational design. The proposed model for Msp is consistent with the enzymatic characteristics of the studied peptide substrates and provides new structural information useful for the characterization of the protease. This study leads to the identification of the first selective and high affinity substrate for Msp that is able to detect picomolar concentrations of the purified enzyme. The identified substrate could be useful for the development of a novel method for the rapid detection of Legionella. PMID- 22528500 TI - Caveolin-1 and dynamin-2 are essential for removal of the complement C5b-9 complex via endocytosis. AB - The complement system, an important element of both innate and adaptive immunity, is executing complement-dependent cytotoxicity (CDC) with its C5b-9 protein complex that is assembled on cell surfaces and transmits to the cell death signals. In turn, cells, and in particular cancer cells, protect themselves from CDC in various ways. Thus, cells actively remove the C5b-9 complexes from their plasma membrane by endocytosis. Inhibition of clathrin by transfection with shRNA or of EPS-15 with a dominant negative plasmid had no effect on C5b-9 endocytosis and on cell death. In contrast, inhibition of caveolin-1 (Cav-1) by transfection with an shRNA or a dominant negative plasmid sensitized cells to CDC and inhibited C5b-9 endocytosis. Similarly, both inhibition of dynamin-2 by transfection with a dominant negative plasmid or by treatment with Dynasore reduced C5b-9 endocytosis and enhanced CDC. C5b-9 endocytosis was also disrupted by pretreatment of the cells with methyl-beta-cyclodextrin or Filipin III, hence implicating membrane cholesterol in the process. Analyses by confocal microscopy demonstrated co-localization of Cav-1-EGFP with C5b-9 at the plasma membrane, in early endosomes, at the endocytic recycling compartment and in secreted vesicles. Further investigation of the process of C5b-9 removal by exo-vesiculation demonstrated that inhibition of Cav-1 and cholesterol depletion abrogated C5b-9 exo-vesiculation, whereas, over-expression of Cav-1 increased C5b-9 exo vesiculation. Our results show that Cav-1 and dynamin-2 (but not clathrin) support cell resistance to CDC, probably by facilitating purging of the C5b-9 complexes by endocytosis and exo-vesiculation. PMID- 22528501 TI - Synthesis and biological evaluation of new active For-Met-Leu-Phe-OMe analogues containing para-substituted Phe residues. AB - In the present study, we report synthesis and biological evaluation of the N-Boc protected tripeptides 4a-l and N-For protected tripeptides 5a-l as new For-Met Leu-Phe-OMe (fMLF-OMe) analogues. All the new ligands are characterized by the C terminal Phe residue variously substituted at position 4 of the aromatic ring. The agonism of 5a-l and the antagonism of 4a-l (chemotaxis, superoxide anion production, lysozyme release as well as receptor binding affinity) have been examined on human neutrophils. No synthesized compounds has higher activity than the standard fMLF-OMe tripeptide to stimulate chemotaxis, although compounds 5a and 5c with -CH(3) and -C(CH(3))(3), respectively, in position 4 on the aromatic ring, are better than the standard tripeptide to stimulate the production of superoxide anion, in higher concentration. Compounds 4f and 4i, containing -F and -I in position 4, respectively, on the aromatic ring of phenylalanine, exhibit significant chemotactic antagonism. The influence of the different substitution at the position 4 on the aromatic ring of phenylalanine is discussed. PMID- 22528503 TI - Performance comparison of various maximum likelihood nonlinear mixed-effects estimation methods for dose-response models. AB - Estimation methods for nonlinear mixed-effects modelling have considerably improved over the last decades. Nowadays, several algorithms implemented in different software are used. The present study aimed at comparing their performance for dose-response models. Eight scenarios were considered using a sigmoid E(max) model, with varying sigmoidicity and residual error models. One hundred simulated datasets for each scenario were generated. One hundred individuals with observations at four doses constituted the rich design and at two doses, the sparse design. Nine parametric approaches for maximum likelihood estimation were studied: first-order conditional estimation (FOCE) in NONMEM and R, LAPLACE in NONMEM and SAS, adaptive Gaussian quadrature (AGQ) in SAS, and stochastic approximation expectation maximization (SAEM) in NONMEM and MONOLIX (both SAEM approaches with default and modified settings). All approaches started first from initial estimates set to the true values and second, using altered values. Results were examined through relative root mean squared error (RRMSE) of the estimates. With true initial conditions, full completion rate was obtained with all approaches except FOCE in R. Runtimes were shortest with FOCE and LAPLACE and longest with AGQ. Under the rich design, all approaches performed well except FOCE in R. When starting from altered initial conditions, AGQ, and then FOCE in NONMEM, LAPLACE in SAS, and SAEM in NONMEM and MONOLIX with tuned settings, consistently displayed lower RRMSE than the other approaches. For standard dose-response models analyzed through mixed-effects models, differences were identified in the performance of estimation methods available in current software, giving material to modellers to identify suitable approaches based on an accuracy-versus-runtime trade-off. PMID- 22528502 TI - What about pain in disorders of consciousness? AB - The management and treatment of acute pain is very difficult in non-communicative patients with disorders of consciousness (i.e., vegetative state/unresponsive wakefulness syndrome (VS/UWS) and minimally conscious state), creating an ethical dilemma for caregivers and an emotional burden among both relatives and caregivers. In this review, we summarize recent findings about the neural substrates of nociception and pain in VS/UWS patients as well as recent behavioral assessment methods of nociception specifically designed for patients in altered states of consciousness. We will finally discuss implications for pain treatment in these patients. PMID- 22528504 TI - Toward global standards for comparator pharmaceutical products: case studies of amoxicillin, metronidazole, and zidovudine in the Americas. AB - This study compared in vitro dissolution characteristics and other quality measures of different amoxicillin, metronidazole, and zidovudine products purchased in the Americas to a comparator pharmaceutical product (CPP). These three drugs are classified as Biopharmaceutics Classification System Class I drugs with the possibility that dissolution findings might be used to document bioequivalence. All investigated zidovudine products were found to be in vitro equivalent to the CPP. Only 3 of 12 tested amoxicillin products were found to be in vitro equivalent to the CPP. None of the tested metronidazole products were in vitro equivalent to the CPP. These findings suggest but do not confirm bioinequivalence where in vitro comparisons failed, given that an in vivo blood level study might have confirmed bioequivalence. At times, identifying a CPP in one of the selected markets proved difficult. The study demonstrates that products sold across national markets may not be bioequivalent. When coupled with the challenge of identifying a CPP in different countries, the results of this study suggest the value of an international CPP as well as increased use of BCS approaches as means of either documenting bioequivalence or signaling the need for further in vivo studies. Because of increased movement of medicines across national borders, practitioners and patients would benefit from these approaches. PMID- 22528505 TI - Pain assessment in human fetus and infants. AB - In humans, painful stimuli can arrive to the brain at 20-22 weeks of gestation. Therefore several researchers have devoted their efforts to study fetal analgesia during prenatal surgery, and during painful procedures in premature babies. Aim of this paper is to gather from scientific literature the available data on the signals that the human fetus and newborns produce, and that can be interpreted as signals of pain. Several signs can be interpreted as signals of pain. We will describe them in the text. In infants, these signs can be combined to create specific and sensible pain assessment tools, called pain scales, used to rate the level of pain. PMID- 22528506 TI - A technique to estimate in vivo dissolution profiles without data from a solution. AB - Dissolution tests are expected to ensure adequate in vivo product performance. Given the recent progress in the ability to predict of human permeability, it is possible to synthesize the plasma drug concentration-time profile from human permeability predictions and the results of the first-in-human trial and use these data to synthesize a pharmacokinetic profile for a solution and provide an initial estimate of the in vivo dissolution profile. This manuscript provides details of such a deconvolution methodology in order to provide an initial estimate of in vivo dissolution. Plasma metoprolol concentration-time data from a previously published study examining the pharmacokinetics of three metoprolol formulations (100 mg), slow, moderate, and fast releasing, and an oral solution (50 mg) were used to estimate in vitro dissolution profiles. A one-compartment unit impulse function was used, and the absorption rate was estimated from animal permeability data (synthetic solution method). The results were compared to those obtained using a unit impulse function estimated from the oral solution data. In vivo dissolution profiles estimated from animal permeability data were similar to those estimated from the oral solution data. Ratios of absorption rate constants (synthetic solution method/oral solution) ranged from 1 to 1.3. The synthetic solution method offers a way to estimate in vivo dissolution profile through deconvolution. It is applicable in cases where it is not possible or feasible to obtain data from a solution. It performs best in cases where dissolution is the rate-limiting step in the absorption process. PMID- 22528507 TI - Pharmacokinetic mAb-mAb interaction: anti-VEGF mAb decreases the distribution of anti-CEA mAb into colorectal tumor xenografts. AB - To date, there has been little investigation of the risk for drug-drug interactions involving monoclonal antibodies. The present work examined the effects of an anti-vascular endothelial growth factor (anti-VEGF) antibody on the plasma, tissue, and tumor disposition of T84.66, an anti-carcinoembryonic antigen (CEA) antibody, in mice. SCID mice bearing CEA-expressing human colorectal cancer (LS174T) xenografts were divided into control and anti-VEGF-treated groups. When tumors reached 200-300 mm(3) in size, (125)I-T84.66 was administered intravenously at 10 mg/kg (400 MUCi/kg). Radioactivity in plasma and tissue samples was counted, and T84.66 concentrations were determined. Areas under the concentration vs. time curves (AUC) were calculated. In separate groups of mice, Evans Blue Dye was administered to evaluate the effect of anti-VEGF on tumor vascular permeability. The investigations did not demonstrate significant effects of anti-VEGF therapy on T84.66 pharmacokinetics in plasma or in non-tumor tissues. T84.66 plasma AUC((0-10 days)) values were 2.37 * 10(3) +/- 1.54 * 10(2) and 2.56 * 10(3) +/- 1.01 * 10(2) nM * day, for the control and treated groups (p = 0.148). Conversely, anti-VEGF treatment significantly reduced tumor vascular permeability to Evans Blue Dye by 45.0 % (p = 0.0012), and anti-VEGF therapy decreased T84.66 tumor AUC((0-10 days)) by more than 60 % (7.27 * 10(2) +/- 51.4 vs. 1.98 * 10(3) +/- 90.1 nM * day, p < 0.0001). Our findings suggest that anti VEGF therapies may lead to a substantial reduction in the delivery of monoclonal antibodies to tumor tissues. It is interesting and important to note that this pharmacokinetic interaction occurs at the target site, and that no alterations in T84.66 disposition were visible based on assessment of plasma pharmacokinetics alone. PMID- 22528508 TI - Paradigm shift in toxicity testing and modeling. AB - The limitations of traditional toxicity testing characterized by high-cost animal models with low-throughput readouts, inconsistent responses, ethical issues, and extrapolability to humans call for alternative strategies for chemical risk assessment. A new strategy using in vitro human cell-based assays has been designed to identify key toxicity pathways and molecular mechanisms leading to the prediction of an in vivo response. The emergence of quantitative high throughput screening (qHTS) technology has proved to be an efficient way to decompose complex toxicological end points to specific pathways of targeted organs. In addition, qHTS has made a significant impact on computational toxicology in two aspects. First, the ease of mechanism of action identification brought about by in vitro assays has enhanced the simplicity and effectiveness of machine learning, and second, the high-throughput nature and high reproducibility of qHTS have greatly improved the data quality and increased the quantity of training datasets available for predictive model construction. In this review, the benefits of qHTS routinely used in the US Tox21 program will be highlighted. Quantitative structure-activity relationships models built on traditional in vivo data and new qHTS data will be compared and analyzed. In conjunction with the transition from the pilot phase to the production phase of the Tox21 program, more qHTS data will be made available that will enrich the data pool for predictive toxicology. It is perceivable that new in silico toxicity models based on high-quality qHTS data will achieve unprecedented reliability and robustness, thus becoming a valuable tool for risk assessment and drug discovery. PMID- 22528509 TI - In silico assessment of cell-free systems. AB - Cell-free extract (CFX)-derived biocatalytic systems are usually embedded in a complex metabolic network, which makes chemical insulation of the production system necessary by removing enzymatic connections. While insulation can be performed by different methods, the identification of potentially disturbing reactions can become a rather lengthy undertaking requiring extensive experimental analysis and literature review. Therefore, a tool for network topology analysis in cell-free systems was developed based on genome scale metabolic models. Genome scale metabolic models define a potential network topology for living cells, and can be adapted to the characteristics of cell-free systems by: (i) removal of compartmentalization, (ii) application of different objective functions, (iii) enabling the accumulation of all metabolites, (iv) applying different constraints for substrate supply, and (v) constraining the reaction space through cofactor availability, microarray data, feasible reaction rates, and thermodynamics. The resulting computational tool successfully predicted for Escherichia coli-derived CFXs a previously identified undesired pathway for dihydroxyacetone phosphate (DHAP) production from adenosine phosphates. The tool was then applied to the identification of potentially interfering pathways to further insulate a DHAP-producing multi-enzyme system based on CFX. PMID- 22528510 TI - Nanostructural organization in acetonitrile/ionic liquid mixtures: molecular dynamics simulations and optical Kerr effect spectroscopy. AB - The nanostructural organization and subpicosecond intermolecular dynamics in mixtures of acetonitrile and the ionic liquid (IL) 1-pentyl-3-methylimidazolium bis{(trifluoromethane)sulfonyl}amide ([C(5)mim][NTf(2)]) are studied as a function of concentration using molecular dynamics (MD) simulations and optical heterodyne-detected Raman-induced Kerr effect spectroscopy. The MD simulations show the IL to be nanostructurally organized into an ionic network and nonpolar domains, with CH(3)CN molecules localized in the interfacial region between the ionic network and nonpolar domains, as found previously by other researchers. The MD simulations indicate strong interactions between CH(3)CN and the hydrogen atoms on the imidazolium ring of the cation. The low-frequency (0-200 cm(-1)) intermolecular part of the reduced spectral densities (RSDs) of the mixtures narrows and shifts to lower frequency as the concentration of CH(3)CN increases. These spectral changes can be partly attributed to the increasing contribution of the low-frequency intermolecular modes of CH(3)CN to the RSD. At a given composition, the RSD of a mixture is found to be broader and higher in frequency than the corresponding ideal RSD given by the volume-fraction-weighted sum of the RSDs of the neat liquids. This difference is rationalized in terms of the competition between CH(3)CN-cation interactions and solute-induced disruption of the ionic networks. PMID- 22528511 TI - FG syndrome: the FGS2 locus revisited. PMID- 22528512 TI - Homocysteine exposure affects early hemodynamic parameters of embryonic chicken heart function. AB - Maternal hyperhomocysteinemia has been associated with an increased risk of newborns with a congenital heart defect. This has been substantiated in the chicken embryo, as congenital heart defects have been induced after homocysteine treatment. Comparable heart defects are observed in venous clipping studies, a model of altered embryonic blood flow. Because of this overlap in heart defects, our aim was to test the hypothesis that homocysteine would cause alterations in embryonic heart function that precede the structural malformations previously described. Therefore, Doppler flow velocity waveforms were recorded in both primitive ventricles and the outflow tract of the embryonic heart of homocysteine treated and control chicken embryos at embryonic day 3.5. Homocysteine treatment consisted of 50 MUL 0.05 M L-homocysteine thiolactone at 24, 48, and 72 hr. Homocysteine-treated embryos displayed significantly lower mean heart rates of 134 (SD 22) bpm, compared to 150 (14) bpm in control embryos. Homocysteine treatment caused an inhibiting effect on hemodynamic parameters, and altered heart function was presented by a shift in the proportions of the different wave times in percentage of total cycle time. Homocysteine induces changes in hemodynamic parameters of early embryonic chicken heart function. These changes may precede morphological changes and contribute to the development of CHD defects through alterations in shear stress and shear stress related genes, as seen before in venous clipping studies. PMID- 22528513 TI - High expression of cell division cycle 7 protein correlates with poor prognosis in patients with diffuse large B-cell lymphoma. AB - Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma. According to the clinical risk factors and biological heterogeneity, clinical outcome of DLBCL is extremely various, with 5-year survival rates between 30 and 80 %. Although the International Prognostic Index (IPI) remains the primary clinical tool used to predict outcome for patients with DLBCL, notable variability in outcome is still observed within the same IPI score. The cell division cycle 7 (CDC7) is a serine-threonine kinase, which is required to initiate DNA replication. Study showed that high expression of CDC7 was correlated with poor prognosis in patients with DLBCL. Whether CDC7 is an independent prognostic factor for DLBCL remains debatable. We studied the expression of CDC7 protein in 60 Chinese DLBCL patients with immunohistochemical analysis, 34 patients (56.7 %) categorized as low CDC7 expression and 26 patients (43.3 %) as high CDC7 expression. The median survival time of patients with low CDC7 expression was not achieved and that of high expression was 9 months (P = 0.027). A multivariate analysis showed that IPI score and Ann Arbor stage were independent prognostic factors in relation to patients' OS (P < 0.05). Pearson correlation analysis showed that CDC7 expression level was positively correlated with IPI score and Ann Arbor stage (P < 0.001). The results suggest that CDC7 expression level in combination with IPI score and Ann Arbor stage can be specific prognostic factors for DLBCL patients. CDC7 could also be a potential therapeutic target in DLBCL, especially for ABC-DLBCL. PMID- 22528515 TI - Clinicopathological significance of lymphatic vessel density marked by D2-40 and E-cadherin expression in non-small-cell lung cancer. AB - The aim of our study is to investigate the relationship between lymphatic vessel density (LVD) marked by D2-40 and E-cadherin expression and the clinicopathological characteristics of patients with non-small-cell lung cancer (NSCLC). Immunohistochemical analysis was used to detect the expression of D2-40 and E-cadherin in 46 archival surgical specimens of human NSCLC and 10 cases of benign pulmonary disease. The LVD positively stained with D2-40 was observed and counted. The LVD was mainly distributed in the tumor borderline. The LVD in NSCLC tissues was significantly higher than in benign lesions (p < 0.001), and the LVD marked by D2-40 was significantly associated with lymph node metastasis (p < 0.001). The reduced expression of E-cadherin was present in NSCLC tissues. The positive rate of E-cadherin expression was negatively correlated with TNM stage (p = 0.027), pathological grade (p = 0.032), and lymph node metastasis (p = 0.014), and not significantly correlated with histologic classification (p = 0.714) in NSCLC tissues. A correlation analysis showed that high LVD marked by D2 40 was correlated with reduced E-cadherin expression in NSCLC tissues (t = 36.476, p < 0.001). The new monoclonal antibody D2-40 can specifically recognize lymphatic endothelial cells in NSCLC tissue. The relationship between LVD marked by D2-40 and the reduced expression of E-cadherin and lymph node metastasis in NSCLC was demonstrated. The detection of D2-40 and E-cadherin may be used as an indicator of lymph node metastasis in NSCLC. PMID- 22528514 TI - Clinical correlation of nuclear survivin in esophageal squamous cell carcinoma. AB - To examine the correlation of survivin (both total and nuclear survivin) with clinicopathological parameters of esophageal squamous cell carcinoma (ESCC) patients. Tumors and non-tumor tissues near the proximal resection margins were resected from ESCC patients undergone esophagectomy. Quantitative polymerase chain reaction (qPCR) was performed to detect survivin mRNA expression level in the 10 paired tumor and adjacent non-tumor tissues. To confirm with the clinical situation, survivin mRNA and protein expression were measured by qPCR and immunoblot, respectively, in 5 ESCC cell lines and a non-neoplastic esophageal epithelial cell line. Immunohistochemistry was employed to reveal the cellular localization of survivin in tumor tissues isolated from the 64 ESCC patients undergone surgery alone. Up-regulation of survivin mRNA and protein was found in 5 ESCC lines (HKESC-1, HKESC-2, HKESC-3, HKESC-4, and SLMT-1) when compared to a non-neoplastic esophageal epithelial cell line NE-1. In particular, HKESC-3, HKESC-4, and SLMT-1 cells demonstrated ~50-fold increase in survivin mRNA. High level of survivin mRNA in tumor tissues when compared to non-tumor tissues was found in 70 % (7 of 10) of clinical cases. The increase in expression ranged from ~twofold to ~16-fold. Immunohistochemistry results showed that survivin was found at the cell nuclei in all specimens examined. Nuclear expression of survivin was inversely associated with the likelihood of developing nodal metastasis (p = 0.021) and significantly associated with early-stage ESCC (p = 0.039). Nuclear survivin could serve as a marker for indicating disease status in ESCC patients. PMID- 22528516 TI - Reduced N-Myc downstream-regulated gene 2 expression is associated with CD24 upregulation and poor prognosis in patients with lung adenocarcinoma. AB - N-Myc downstream-regulated gene 2 (NDRG2) has been demonstrated to influence the metastatic potential of hepatocellular carcinoma and breast cancer cells by regulating CD24 expression. The aim of this study was to investigate the roles of NDRG2 and CD24 in the clinical pathology of lung adenocarcinoma and to explore whether the expression of these two markers can be used as independent factors for the prediction of prognosis in patients with this tumor. NDRG2 and CD24 expression in paraffin-embedded specimens gathered from 166 patients with lung adenocarcinoma was detected by immunohistochemical method. The correlation of these two proteins expression with clinicopathological parameters and prognosis was statistically analyzed. NDRG2 and CD24 proteins were highly expressed in 59/166 (35.5 %) and 110/166 (66.3 %) of lung adenocarcinoma patients, respectively. High expression of NDRG2 was frequently found in lung adenocarcinoma tissues in early pTNM stage (p = 0.01) and without pathological metastasis (p = 0.02), whereas the high expression of CD24 was significantly associated with the advanced pTNM stage (p = 0.04) and pathological metastasis (p = 0.01). Univariate analysis indicated that the patients with NDRG2 high expression correlated with favorable prognosis in patients with lung adenocarcinoma (p = 0.001), as opposed to CD24 (p = 0.001). The survival rate of the patients with NDRG2-low/CD24-high expression was the lowest (p < 0.001). Multivariate statistical analysis showed that the conjoined expressions of NDRG2 high/CD24-low and NDRG2-low/CD24-high were independent prognostic indicators of lung adenocarcinoma (p = 0.03 and p = 0.02, respectively). Our results suggest that the decreased expression of NDRG2 or the increased expression of CD24 is an important feature of lung adenocarcinoma. A combined detection of NDRG2/CD24 co expression may benefit us in prediction of the prognosis of lung adenocarcinoma. PMID- 22528517 TI - Survivin expression in patients with newly diagnosed nodal diffuse large B cell lymphoma (DLBCL). AB - Survivin is one of the inhibitors of apoptosis proteins (IAP) that might play an important role in the pathogenesis of diffuse large B cell lymphoma (DLBCL). The present study was designed to investigate the clinical and prognostic significance of survivin expression in nodal DLBCL. We analyzed lymph node biopsy specimens obtained from 56 patients with newly diagnosed nodal DLBCL, treated with immunochemotherapy (R-CHOP). The expression of survivin was analyzed using the standard immunohistochemical method on formalin-fixed and routinely processed paraffin-embedded lymph node specimens and evaluated semiquantitatively as a percentage of tumor cells. Survivin immunoexpression (>45 % positive tumor cells) was found in 22 (39.28 %) and observed as cytoplasmic staining in 15 patients, or mixed (cytoplasmic and nuclear) staining in 7 patients. A significant difference in survivin immunoexpression was noticed between the GCB and the non-GCB subtypes of DLBCL (p = 0.031). However, survivin immunoexpression had no significant association with IPI, "bulky" disease, extranodal localization, hemoglobin, Ki-67 immunoexpression or other clinicopathological parameters. A univariate analysis showed that survivin positivity was an unfavorable factor for therapy response and a predictor of shorter survival in patients with DLBCL (p = 0.048 and p = 0.034, respectively). Patients with survivin overexpression experienced a relapse more often than patients without expression of this apoptotic protein (27.3 vs. 11.8 %), but this difference did not reach statistical significance (p = 0.131). The results of this study showed that disregulation of survivin expression had an important role in the determination of the course of the disease in patients with nodal DLBCL treated with R-CHOP. Therefore, survivin represents a potential target for therapeutic intervention in DLBCL. PMID- 22528518 TI - Evaluation of the effects of mediastinal radiation therapy on autonomic nervous system. AB - In this prospective study, the effects of mediastinal radiation therapy (RT) on autonomic nervous system (ANS) were investigated by heart rate variability (HRV) analysis that is accepted as a non-invasive indicator of ANS. Study was performed with the eligible patients had a histopathologically confirmed diagnosis of malignant disease with no known congestive heart failure, coronary heart disease, hypertension, valvular cardiac disease or arrhythmia history. Electrocardiograms of 14 voluntary patients were recorded for duration of 5 min just before and after irradiation for the first and the 15th fractions. ANS-related HRV analysis parameters were calculated as which were recommended by Task Force of ESC/NASPE (Circulation 93:1043-1065, 1996). HRV parameters that belong to pre- and post-RT treatment of patients were compared statistically. We found that there is not effect of single-dose radiation on HRV parameter. The mean RRI (782.29 +/- 115.65 738.93 +/- 111.01, P < 0.014) and HF power of HRVs PSD (156.94 +/- 229.37-60.71 +/- 77.99, P < 0.045) decreased, and LF/HF ratio (1.38 +/- 0.79-2.03 +/- 1.25, P < 0.039) increased significantly with 28-Gy external radiation dose. As the effect of cumulative dose was investigated on HRV parameters, the above changes were continued to increase with 30-Gy external radiation dose. We found that mediastinal RT involving heart directly in the radiation field decreased vagal and sympathetic ANS activities, and autonomic balance shifted toward sympathetic dominance. PMID- 22528519 TI - Genetic testing and services in Argentina. AB - Argentina is a middle-income country with a population of 40 million people. The structure of morbidity and mortality approaches that of more developed nations, with congenital and genetic disorders contributing significantly to ill health. The health delivery system is mixed, with public, social security, and private sectors which together spend close to 10 % of the GNP. Health subsectors are decentralized at provincial and municipality levels, where health planning and financing occurs, leading to fragmentation, inefficiency, and inequities. There are about 41 clinical genetic units in major medical centers in large cities, staffed by about 120 clinical geneticists, although only a few units are fully comprehensive genetic centers. Duplications, deficiencies, and poor regionalization and coordination affect health care delivery in general and in genetics. Funding for genetic services is limited due to poor understanding and lack of political will on the part of health authorities. Recently, however, there have been some interesting initiatives by national and provincial ministries of health to improve genetic services delivery by increasing coordination and regionalization. At the same time, training in genetics of health professionals is occurring, particularly in primary health care, and registries of congenital defects are being put in place. These developments are occurring in conjunction with a new awareness by health authorities of the importance of genetics in health care and research, a heightened activism of patient organizations demanding services for neglected conditions, as well as of women movements for the right to safe abortion. PMID- 22528520 TI - The complex genetic basis of plasma triglycerides. AB - Demonstration of a direct relationship between plasma triglyceride (TG) concentration and atherosclerosis has proven difficult due to confounding variables that accompany elevated plasma TG, such as other dyslipidemias, obesity, and type 2 diabetes. However, human genetic studies have provided evidence suggesting a causal link between plasma TG and cardiovascular risk. Analyses in human patients with hypertriglyceridemia (HTG) also provides insight into the relationship between genetic variation, predisposition to elevated plasma TG, and risk of subsequent cardiovascular disease. Here, we review recent key studies that have contributed to our understanding of the genetic determinants of plasma TG concentration, including HTG susceptibility and phenotypic heterogeneity, and discuss our maturing model of the allelic and phenotypic spectrum of plasma TG. PMID- 22528522 TI - Intracranial hemorrhage in patients with cancer. AB - Intracranial hemorrhage (ICH) is a common neurological emergency in patients with cancer, typically occurring late in the disease course, although it occasionally heralds the cancer diagnosis. ICH in these patients often occurs from unique mechanisms, especially intratumoral hemorrhage or coagulopathy, whereas hypertensive hemorrhage is rare. Lung, melanoma, breast, and glioblastoma multiforme are the most commonly associated solid tumors, partly because of their ubiquity and frequent brain involvement, whereas leukemia is the most commonly associated hematological cancer. Patients typically present with focal neurological deficits, headache, and encephalopathy, and their initial diagnostic evaluation and management should follow standard guidelines, although steroids and/or surgical resection should be strongly considered in those with intratumoral hemorrhage. Short-term outcomes are comparable to ICH in the community, whereas long-term outcomes are generally poor, corresponding to the prognosis of the underlying cancer. This review focuses on the recent advances and special considerations in cancer-related intracranial hemorrhage. PMID- 22528521 TI - Genetics of cholesterol efflux. AB - Plasma levels of high-density lipoprotein cholesterol (HDL-C) show an inverse association with coronary heart disease (CHD). As a biological trait, HDL-C is strongly genetically determined, with a heritability index ranging from 40 % to 60 %. HDL represents an appealing therapeutic target due to its beneficial pleiotropic effects in preventing CHD. This review focuses on the genetic basis of cellular cholesterol efflux, the rate-limiting step in HDL biogenesis. There are several monogenic disorders (e.g., Tangier disease, caused by mutations within ABCA1) affecting HDL biogenesis. Importantly, many disorders of cellular cholesterol homeostasis cause a reduced HDL-C. We integrate information from family studies and linkage analyses with that derived from genome-wide association studies (GWAS) and review the recent identification of micro-RNAs (miRNA) involved in cellular cholesterol metabolism. The identification of genomic pathways related to HDL may help pave the way for novel therapeutic approaches to promote cellular cholesterol efflux as a therapeutic modality to prevent atherosclerosis. PMID- 22528523 TI - Crystal structure of tandem ACT domain-containing protein ACTP from Galdieria sulphuraria. AB - The ACT domain is a structurally conserved small molecule binding domain which is mostly involved in amino acid and purine metabolism. Here, we report the crystal structure of a tandem ACT domain-containing protein (ACTP) from Galdieria sulphuraria. The two ACTP monomers in the asymmetric unit form a dimer with a non crystallographic twofold axis in a domain-swapped manner, showing a horseshoe like structure with a central crevice. This structure contributes to expand our knowledge on the structural diversity of ACT domain-containing proteins. PMID- 22528524 TI - ACCF/AHA/AMA-PCPI 2011 performance measures for adults with heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Performance Measures and the American Medical Association-Physician Consortium for Performance Improvement. PMID- 22528525 TI - Minding the gaps--and the junctions, too. PMID- 22528526 TI - Gap junctions and connexin hemichannels underpin hemostasis and thrombosis. AB - BACKGROUND: Connexins are a widespread family of membrane proteins that assemble into hexameric hemichannels, also known as connexons. Connexons regulate membrane permeability in individual cells or couple between adjacent cells to form gap junctions and thereby provide a pathway for regulated intercellular communication. We have examined the role of connexins in platelets, blood cells that circulate in isolation but on tissue injury adhere to each other and the vessel wall to prevent blood loss and to facilitate wound repair. METHODS AND RESULTS: We report the presence of connexins in platelets, notably connexin37, and that the formation of gap junctions within platelet thrombi is required for the control of clot retraction. Inhibition of connexin function modulated a range of platelet functional responses before platelet-platelet contact and reduced laser-induced thrombosis in vivo in mice. Deletion of the Cx37 gene (Gja4) in transgenic mice reduced platelet aggregation, fibrinogen binding, granule secretion, and clot retraction, indicating an important role for connexin37 hemichannels and gap junctions in platelet thrombus function. CONCLUSIONS: Together, these data demonstrate that platelet gap junctions and hemichannels underpin the control of hemostasis and thrombosis and represent potential therapeutic targets. PMID- 22528527 TI - Performance evaluation of two serological tests for contagious bovine pleuropneumonia (CBPP) detection in an enzootic area using a Bayesian framework. AB - A Bayesian approach, allowing for conditional dependence between two tests was used to estimate without gold standard the sensitivities of complement fixation test (CFT) and competitive enzyme-linked immunosorbent assay test (cELISA) and the serological prevalence of CBPP in a cattle population of the Central Delta of the Niger River in Mali, where CBPP is enzootic and the true prevalence and animals serological state were unknown. A significant difference (P = 0.99) was observed between the sensitivities of the two tests, estimated at 73.7% (95% probability interval [PI], 63.4-82.7) for cELISA and 42.3% (95% PI, 33.3-53.7) for CFT. Individual-level serological prevalence in the study population was estimated at 14.1% (95% PI, 10.8-16.9). Our results indicate that in enzootic areas, cELISA performs better in terms of sensitivity than CFT. However, negative conditional sensitivity dependence between the two tests was detected, implying that to achieve maximum sensitivity, the two tests should be applied in parallel. PMID- 22528528 TI - Prevalence of bovine tuberculosis in slaughter cattle in Kenya: a postmortem, microbiological and DNA molecular study. AB - A study to determine the presence and prevalence of bovine tuberculosis in slaughter cattle in Kenya was carried out in two abattoirs from July to November 2009. Routine postmortem meat inspection was performed on a subpopulation of 929 cattle selected randomly from among 4,984. Carcases were inspected for gross tuberculous lesions which were then examined for acid-fast bacilli, (AFB), cultured for isolation of mycobacteria and the isolates characterised by DNA molecular analysis. Of the carcases examined, 176 (18.95 %, 95 % CI) had lesions suggestive of tuberculosis. AFB were observed in 63/176 of the lesioned cattle and mycobacteria were isolated from 64 of them. The isolates were identified as Mycobacterium bovis (19/64), Mycobacterium tuberculosis, (2/64) and mycobacteria other than tuberculosis (43/64). The prevalence of M. bovis by molecular analysis was 2.05 % (95 % CI). This study documents for the first time the presence of bovine tuberculosis among slaughter cattle in Kenya. There is therefore a need to formulate and implement control programmes in order to minimise transmission among animals and to humans. Isolation of M. tuberculosis from cattle underscores the risk tuberculous humans pose to animals. PMID- 22528530 TI - Effects of 48-hour calf withdrawal on conception rates of Bos indicus cows and calf weaning weights in extensive production systems. AB - Sixty multiparous Brahman-type cows were randomly selected in the early postpartum period and equally allocated into a calf removal group (RG) and a non removal group (NRG). Calves from cows in the RG were removed for 48 h prior to the breeding season and returned afterwards, whereas in the NRG, calves remained with their dams until weaning. Weaning weights were corrected to 205 days. Conception rates (CRs) were 76 % for RG and 55 % for NRG but did not differ (p > 0.05). CR was correlated with calving to breeding interval and body condition score at the onset of the breeding season. Product-limit survival curves vs breeding to conception interval differed significantly (p < 0.05) between treatment groups. It was estimated with 95 % certainty that 50 % of the cows in the RG will conceive within the first 12 days of the breeding season, while 39 days were required for cows in the NRG. Weaning weights were 135.2 +/- 22 kg for RG and 135.5 +/- 19 kg for NRG. It was concluded that 48-hour calf removal prior to breeding season increased the number of cows that conceive early in the breeding season and enhanced conception rates but did not affect calf weaning weights of Bos indicus cattle in extensive production systems. PMID- 22528529 TI - Assessment of impacts of tsetse and trypanosomosis control measures on cattle herd composition and performance in southern region, Ethiopia. AB - This study was conducted to assess the impact of tsetse and trypanosomosis control measures on cattle herd size and composition, herd dynamics, and milk yield in Wolaita and Gamogofa Zones, southern Ethiopia. The study showed that the average number of cattle herd size in tsetse challenged areas was significantly higher than those in tsetse-controlled areas. The number of non-pregnant dry cows, bulls and oxen were significantly higher in tsetse challenged areas than the other two study areas. The rate of cattle addition to and disposal from the herd were significantly higher in tsetse challenged areas. Cows in Southern Tsetse Eradication Project (STEP) and community tsetse controlled areas were able to give 26-27 %, 25-29 % and 17-21 % more daily milk yield at the beginning, middle and end of lactation, respectively, than those in tsetse-challenged areas. In addition, cows in STEP and community tsetse controlled areas had lactation length longer by 1.20 to 1.35 months; age at first calving was shorter by 5.30 to 5.10 months; and calving interval was shorter by 4.20 to 3.20 months than cows in tsetse-challenged area, respectively. Hence, tsetse and trypanosomosis control both by the community and project would play key role in the improvement of cattle productivity. PMID- 22528531 TI - Detection of virulence-associated genes in Staphylococcus aureus isolated from bovine clinical mastitis milk samples in Guangxi. AB - Staphylococcus aureus is recognized worldwide as a pathogen causing many serious diseases in humans and animals and is one of the most common etiological agents of clinical and subclinical bovine mastitis. The purpose of this study was to determine the presence of genes encoding clfA, fnbA, fnbB, cap5, cap8, hla, hlb, nuc, sea, and tst of S. aureus strains (n = 39) isolated from bovine clinical mastitis in Guangxi by polymerase chain reaction amplification. The results of the present study indicated that all isolates were found to contain one or more virulence-associated genes. The most frequently encountered genes were fnbA (97 %) and nuc (90 %), followed by hla (85 %) and hlb (82 %), respectively. None of the investigated S. aureus strains harbored fnbB and sea genes. The data in the present study showed a relatively wide distribution of the genes fnbA and nuc among the investigated isolates, indicating that they play an important role on bovine mastitis pathogenesis. The study provides a valuable insight into the virulence-associated genes of this important pathogen. PMID- 22528532 TI - Phenotypic characterization of the population of creole wool ewes in the highlands of Puebla State, Mexico. AB - This study characterized the population of wool ewes in the highlands of the State of Puebla, Mexico, considering traits such as fleece color, weight, and body measurements. In this region, dominated by a temperate climate, sheep are a traditional animal species for farming systems. To carry out the work, 2,082 ewes were randomly selected from 14 communities and 124 flocks belonging to the six municipalities that have the largest inventory of sheep in the state. For each ewe, live weight, breed, fleece color pattern, and 18 other body measurements were recorded. Descriptive statistics were estimated for weight and body traits and the morphotype was classified by multivariate analysis. Factor analysis identified the bulk, size, and breed standard as the attributes that best describe the population of ewes. These elements varied in importance among the groups (p < 0.05). Cluster analysis helped to classify the population into small black-faced ewes (28.5 %), small white ewes (11.9 %), black-faced medium-sized ewes (24.1 %), large ewes (12.3 %), and white medium-sized ewes (23.2 %). The groups identified were similar to creole sheep present in rural communities in other environments, but have lower morphostructural values than specialized breeds. PMID- 22528533 TI - Prevalence and risk factors associated with Chlamydophila abortus infection in dairy herds in Jordan. AB - A cross-sectional study was carried out to determine seroprevalence and to identify risk factors associated with Chlamydophila abortus infection in 62 nonvaccinated dairy herds (671 cows) in Jordan between January and June 2007. Information regarding herd management was recorded through a personal interview with farmers. Antibodies against C. abortus were detected using an ELISA test kit. Chi-square analysis and multivariable logistic regression model were used to identify risk factors associated with C. abortus seropositivity. The true prevalence of antibodies against C. abortus in individual cows and cattle herds were 19.9 % and 66.3 %, respectively. Univariable Chi-square analysis revealed three variables with P <= 0.25 that were further offered to multivariable logistic regression analysis. Small-sized herds were identified as a risk factor for seropositivity to C. abortus, while sweeping followed by water hosing and using disinfectants were identified as protective factors. Cows in the age groups of >8 and <= 10 years old and >2 and <= 6 years old had the highest and lowest significant seroprevalence to C. abortus, respectively. Results of this study indicated that C. abortus is highly prevalent in Jordan's dairy herds and Chlamydophila infection could be controlled by applying strict biosecurity measures in the dairy farms. PMID- 22528534 TI - Elephant grass, sugarcane, and rice bran in diets for confined sheep. AB - We aimed to evaluate the effects of diets, based on elephant grass or sugarcane as roughage and corn meal or rice bran as energy concentrate, on performance and body composition in terms of diet intake and digestibility. A total of 30 Santa Ines crossbreds (SIC), castrated male sheep with 19.8 +/- 2.0 kg initial body weight (BW) were used. Six animals were slaughtered at the onset of the experiment to estimate the initial body composition for the other animals. The remaining 24 animals were distributed in a completely randomized 2 * 2 factorial design, with four treatments (two roughages and two concentrates) and six replicates. The sheep were slaughtered when they reached 30.0 kg BW. Elephant grass diets provided higher intake and digestibility than sugarcane diets for the following contents: dry matter (DM), organic matter (OM), crude protein (CP), neutral detergent fibre, minerals, total carbohydrates (TC), and total digestible nutrients (TDN). Among the concentrates, corn meal diets were associated with higher intakes than rice bran diets for the following contents: DM, OM, CP, TC, and TDN. Animals from all of the treatments exhibited low average daily weight gain and low protein and high fat and energy body levels. Sugarcane and rice bran can be used as ingredients in diets for sheep with low weight gain potential. Regardless of roughage or concentrate types used in diets for confined SIC sheep, performance and body composition remained unaltered. PMID- 22528535 TI - Effects of repeated administration of hCG on follicular and luteal characteristics and serum progesterone concentrations in eCG-superovulated Sanjabi ewes. AB - The objective of this study was to evaluate if treatment of equine chorionic gonadotrophin (eCG)-superovulated Sanjabi ewes with repeated administration of human chorionic gonadotropin (hCG) would increase the number of normal corpus luteum (CL) and serum progesterone concentrations and decrease the number of persistent follicles. The superovulated ewes were divided into four groups on day 0 (day of sponge removal); the ewes were treated by an intramuscular administration of 500 IU hCG on day 0 (Group I: n = 10), on days 0 and 1 (Group II: n = 10), or on days 0, 1, and 2 (Group III: n = 10) and no treatment for control group (n = 10). Blood samples were collected on days 0, 1, 2, 5, and 8 (day of slaughter), and serum progesterone concentrations were determined. According to progesterone concentrations, 50 (4/8) and 0 % of the ewes underwent premature luteal regression in the control group and the hCG groups, respectively. There were more CLs in Group III than in Group II and the control group. Ewes treated with hCG had a greater number of normal-looking CL. CL diameter was significantly greater in Group II and Group III than other groups. Total CL weight was significantly (P < 0.05) higher in Group III than in Group I and the control group. Number of persistent follicle and persistent follicle diameter were lower in control group compared to the other groups. Eight days after sponge removal, serum progesterone concentration was significantly higher in Group III than in Group I and the control group. The present results indicate that repeated administration of hCG supported CL formation, increased serum progesterone concentration, and prevented premature luteal regression in eCG superovulated Sanjabi ewes. PMID- 22528536 TI - Productive performance and urinary excretion of mimosine metabolites by hair sheep grazing in a silvopastoral system with high densities of Leucaena leucocephala. AB - The aim of this study was to evaluate daily weight gain (DWG), total dry matter (DM) intake, rumen degradability of forage, and urinary excretion of mimosine metabolites by hair sheep in a silvopastoral system with high densities of Leucaena leucocephala. A completely randomized design was carried out with two treatments: treatment 1 (T1) silvopastoral system with leucaena at a density of 35,000 plants/ha and treatment 2 (T2), leucaena at a density of 55,000 plants/ha. Leucaena was associated with tropical grasses Panicum maximum and Cynodon nlemfluensis. Twenty-four male Pelibuey lambs of 23.2 +/- 3.4 kg live weight (LW) were used (12 lambs per treatment). Results showed differences (P < 0.05) in DWG of T1 (106.41 +/- 11.66 g(-1) sheep(-1)) with respect to that of T2 (81.33 +/- 11.81 g(-1) sheep). Voluntary intake was higher in lambs from T1 (83.81 +/- 04.07 g DM/kg LW(0.75)) with respect to that from T2 (71.67 +/- 8.12 g DM/kg LW(0.75)). There was a difference in color of urine between sheep of T1 and T2, the latter giving positive results for the presence of metabolites derived from mimosine (3 4 dihydroxypyridine and 2-3 dihydroxy pyridone). Rumen degradability of DM of L. leucocephala was higher (P < 0.05) compared to that of P. maximum and C. nlemfluensis (72.94 +/- 0.40 vs. 67.06 +/- 1.50 and 63.25 +/- 1.51 %, respectively). It is concluded that grazing at high densities of L. leucocephala affects daily weight gain of hair sheep, possibly due to ingestion of high amounts of mimosine which may exert an adverse effect on voluntary intake. PMID- 22528537 TI - Environmental and economic impacts of livestock productivity increase in sub Saharan Africa. AB - Livestock production in sub-Saharan Africa (SSA) is not matching the annual 2.5 % growth of its population. Regional per capita meat and milk production corresponds, respectively, to about 13 and 8 % of developed countries indicators. Livestock performances in this region have decreased within the last 30 years. In fact, SSA, with a 12 % bovine extraction rate against a world average of 21 %, includes about 16 % of world cattle, only producing 6 and 2.6 % of global meat and milk, respectively. These low performances have economic and environmental consequences reflecting the necessity for upgrading livestock managing skills in the region. This effort includes various components such as sanitary prophylaxis, reproduction, nutrition, and in particular, substantial increase in livestock yield for human consumption. This will allow for an improved animal and pasture management and soil preservation, enhancing meat production and decreasing methane and nitrogen emissions from enteric fermentation and manure processing. These environmental gains due to increased livestock off-take rates can represent relevant credits in the global Environmental Carbon Market under the United Nations Framework Convention on Climate Change Kyoto protocol. These credits can be used for investments in livestock essential services and marketing facilities leading to improved productivity. PMID- 22528538 TI - Clinical and pathological insights into Johne's disease in buffaloes. AB - Alternative diagnostic tools and interesting epidemiological assumptions were associated with an outbreak of Johne's disease. In a buffalo herd infected with paratuberculosis, seven clinically affected animals and 21 animals with anti Mycobacterium avium ELISA reactions were identified. Total herd included 203 buffaloes. Most lesions were comparable to those described in buffaloes and cattle affected by Johne's disease. Water buffalo behaviors such as communal nursing and allosuckling may be additional risk factors for this disease. Detection of positive Ziehl-Neelsen staining and anti-M. avium immunolabeling in rectal biopsies from one buffalo with paratuberculosis are highlighted as auxiliary diagnostic tools for Johne's disease in live animals. PMID- 22528539 TI - International Journal of Occupational Medicine and Environmental Health. Editorial. PMID- 22528540 TI - Adverse effects of antioxidative vitamins. AB - High doses of synthetic antioxidative vitamins: A, E, C and beta-carotene are often used on long-term basis in numerous preventive and therapeutic medical applications. Instead of expected health effects, the use of those vitamins may however lead to cases of hypervitaminosis and even to intoxication. The article points out main principles of safety which are to be observed during supplementation with antioxidative vitamins. Toxic effects resulting from erroneous administration of high doses of those substances on organs and systems of the organism are also discussed. Attention is drawn to interactions of antioxidative vitamins with concomitantly used drugs, as well as intensification of adverse effects caused by various exogenous chemical factors. Moreover, the article presents the evaluation of supplementation with these vitamins, which was performed in large studies. PMID- 22528541 TI - Woodsmoke marker levoglucosan: kinetics in a self-experiment. AB - OBJECTIVES: Concerns on climate change are leading to the renaissance of wood burning and particulate exposures. Levoglucosan is used as a marker of woodsmoke in air and urine. OBJECTIVES: Contribution of data on urinary excretion of levoglucosan, to improve biomonitoring and source apportionment of woodsmoke. MATERIALS AND METHODS: 1, 3, 5, and 7 hours after 5 mg of levoglucosan had been administered orally, urinary excretion was measured by HPLC and mass spectrometry. RESULTS: After oral intake, urine concentrations increased rapidly, reached highest values after 3 hours, and after 7 hours approximately 70% of the administered dose was excreted. CONCLUSIONS: Urinary levoglucosan may be used for biomonitoring of woodsmoke exposure on the same day. PMID- 22528542 TI - Psychometric properties of the French versions of the Perceived Stress Scale. AB - OBJECTIVES: This study was conducted to examine the psychometric properties of the French versions of the Perceived Stress Scale (PSS) and to compare the appropriateness of the three versions of this scale (14 items, 10 items, or 4 items) in a sample of workers. MATERIALS AND METHODS: Five hundred and one workers were randomly selected in several occupational health care centers of the North of France during 2010. Participants completed a questionnaire including demographic variables and the PSS. The psychometric properties of this scale were analyzed: internal consistency, factorial structure, and discriminative sensibility. RESULTS: For the PSS-14 and PSS-10, the Exploratory Factor Analysis (EFA) provided a two-factor structure, corresponding to the positively and negatively worded items. Those two factors were significantly correlated (r = 0.43 and 0.50, respectively). For the PSS-4, the EFA yielded a one-factor structure. The reliability was high for all three versions of the PSS (Cronbach's alpha values ranged from 0.73 to 0.84). The results concerning the effects of age, gender, marital, parental and occupational statuses showed that the 10-item version had the best discriminative sensibility. CONCLUSIONS: The findings confirmed satisfactory psychometric properties of all the three French versions of the PSS. We recommend the use of the PSS-10 in research settings because of its good psychometric properties. PMID- 22528543 TI - Retraction. Neurological and respiratory symptoms in shipyard welders exposed to manganese. PMID- 22528544 TI - Active site residues critical for flavin binding and 5,6-dimethylbenzimidazole biosynthesis in the flavin destructase enzyme BluB. AB - The "flavin destructase" enzyme BluB catalyzes the unprecedented conversion of flavin mononucleotide (FMN) to 5,6-dimethylbenzimidazole (DMB), a component of vitamin B(12). Because of its unusual chemistry, the mechanism of this transformation has remained elusive. This study reports the identification of 12 mutant forms of BluB that have severely reduced catalytic function, though most retain the ability to bind flavin. The "flavin destructase" BluB is an unusual enzyme that fragments the flavin cofactor FMNH(2) in the presence of oxygen to produce 5,6-dimethylbenzimidazole (DMB), the lower axial ligand of vitamin B(12) (cobalamin). Despite the similarities in sequence and structure between BluB and the nitroreductase and flavin oxidoreductase enzyme families, BluB is the only enzyme known to fragment a flavin isoalloxazine ring. To explore the catalytic residues involved in this unusual reaction, mutants of BluB impaired in DMB biosynthesis were identified in a genetic screen in the bacterium Sinorhizobium meliloti. Of the 16 unique point mutations identified in the screen, the majority were located in conserved residues in the active site or in the unique "lid" domain proposed to shield the active site from solvent. Steady-state enzyme assays of 12 purified mutant proteins showed a significant reduction in DMB synthesis in all of the mutants, with eight completely defective in DMB production. Ten of these mutants have weaker binding affinities for both oxidized and reduced FMN, though only two have a significant effect on complex stability. These results implicate several conserved residues in BluB's unique ability to fragment FMNH(2) and demonstrate the sensitivity of BluB's active site to structural perturbations. This work lays the foundation for mechanistic studies of this enzyme and further advances our understanding of the structure-function relationship of BluB. PMID- 22528545 TI - In vivo osteogenic response to different ratios of BMP-2 and VEGF released from a biodegradable porous system. AB - Bone regeneration and vascularization with porous PLGA scaffolds loaded with VEGF (0.35 and 1.75 MUg) and BMP-2 (3.5 and 17.5 MUg), incorporated in PLGA microspheres, or the combination of either dose of BMP-2 with the low dose of VEGF were investigated in an intramedullary femur defect in rabbits. The system was designed to control growth factor (GF) release and maintain the GFs localized within the defect. An incomplete release was observed in vitro whereas in vivo VEGF and BMP-2 were totally delivered during 3 and 4 weeks, respectively. A weak synergistic effect of the dual delivery of VEGF and BMP-2 (high dose) was found by 4 weeks. However, the absence of an apparent synergistic long-term effect (12 weeks) of the combination over BMP-2 alone suggests that more work has to be done to optimize VEGF dose, sequential presentation, and the ratio of the two GFs to obtain a beneficial bone repair response. PMID- 22528546 TI - Solvent removal and spore inactivation directly in dispensing vials with supercritical carbon dioxide and sterilant. AB - A process is described using supercritical carbon dioxide to extract organic solvents from drug solutions contained in 30-mL serum vials. We report drying times of less than 1 h with quantitative recovery of sterile drug. A six-log reduction of three spore types used as biological indicators is achieved with direct addition of peracetic acid to a final concentration of approximately 5 mM (~0.04 %) to the drug solution in the vial. Analysis of two drugs, acetaminophen and paclitaxel, indicated no drug degradation as a result of the treatment. Furthermore, analysis of the processed drug substance showed that no residual peracetic acid could be detected in the final product. We have demonstrated an effective means to simultaneously dry and sterilize active pharmaceutical ingredients from organic solvents directly in a dispensing container. PMID- 22528548 TI - On the drug-loading capacity of pectin powder for direct compression. PMID- 22528547 TI - Preparation and investigation of sustained drug delivery systems using an injectable, thermosensitive, in situ forming hydrogel composed of PLGA-PEG-PLGA. AB - In situ gelling systems are very attractive for pharmaceutical applications due to their biodegradability and simple manufacturing processes. The synthesis and characterization of thermosensitive poly(D,L-lactic-co-glycolic acid) (PLGA) polyethylene glycol (PEG)-PLGA triblock copolymers as in situ gelling matrices were investigated in this study as a drug delivery system. Ring-opening polymerization using microwave irradiation was utilized as a novel technique, and the results were compared with those using a conventional method of polymerization. The phase transition temperature and the critical micelle concentration (CMC) of the copolymer solutions were determined by differential scanning calorimetry and spectrophotometry, respectively. The size of the micelles was determined with a light scattering method. In vitro drug release studies were carried out using naltrexone hydrochloride and vitamin B12 as model drugs. The rate and yield of the copolymerization process via microwave irradiation were higher than those of the conventional method. The copolymer structure and concentration played critical roles in controlling the sol-gel transition temperature, the CMC, and the size of the nanomicelles in the copolymer solutions. The rate of drug release could be modulated by the molecular weight of the drugs, the concentration of the copolymers, and their structures in the formulations. The amount of release versus time followed zero-order release kinetics for vitamin B12 over 25 days, in contrast to the Higuchi modeling for naltrexone hydrochloride over a period of 17 days. In conclusion, PLGA-PEG1500 PLGA with a lactide-to-glycolide ratio of 5:1 is an ideal system for the long acting, controlled release of naltrexone hydrochloride and vitamin B12. PMID- 22528549 TI - Hypertension in FMR1 premutation males with and without fragile X-associated tremor/ataxia syndrome (FXTAS). AB - Fragile X-associated tremor ataxia syndrome (FXTAS) is a late onset neurodegenerative disease that affects carriers of the fragile X premutation. This study seeks to assess hypertension risk and susceptibility in male premutation carriers with FXTAS. Although many symptoms and diagnostic criteria have been identified, hypertension risk has not been examined in this population. Data from 92 premutation carriers without FXTAS, 100 premutation carriers with FXTAS, and 186 controls was collected via patient medical interview. Age-adjusted logistic regression analysis was used to examine the relative odds of hypertension. We observed a significantly elevated odds ratio (OR) of hypertension relative to controls for premutation carriers with FXTAS (OR = 3.22, 95% CI: 1.72-6.04; P = 0.0003) among participants over 40-year old. The age adjusted estimated odds of hypertension in premutation carriers without FXTAS in the over 40-year-old age group was higher compared to controls (OR = 1.61, 95% CI: 0.82-3.16), but was not statistically significant (P = 0.164). Chronic hypertension contributes to cardiovascular complications, dementia, and increased risk of stroke. Our results indicate that the risk of hypertension is significantly elevated in male premutation carriers with FXTAS compared with carriers without FXTAS and controls. Thus, evaluation of hypertension in patients diagnosed with FXTAS should be a routine part of the treatment monitoring and intervention for this disease. PMID- 22528550 TI - CC-chemokine ligand 4/macrophage inflammatory protein-1beta participates in the induction of neuropathic pain after peripheral nerve injury. AB - BACKGROUND: Neuropathic pain is caused by neural damage or dysfunction and neuropathic pain-related symptoms are resistant to conventional analgesics. Neuroinflammation due to the cytokine-chemokine network may play a pivotal role in neuropathic pain. We demonstrate that macrophage inflammatory protein-1beta (MIP-1beta) participates in neuropathic pain. METHODS: Mice received partial sciatic nerve ligation (PSL), and tactile allodynia and thermal hyperalgesia were assessed by von Frey test and Hargreaves test, respectively. Agents were administered into the region surrounding the sciatic nerve (SCN). RESULTS: Using reverse transcription polymerase chain reaction, the mRNA expressions of MIP 1beta and its receptor (CC-chemokine receptor 5; CCR5) in the injured SCN were up regulated after PSL. MIP-1beta immunoreactivity was localized in macrophages and Schwann cells and increased in the injured SCN on day 1. PSL-induced tactile allodynia on days 4 to 7 was prevented by the administration of MIP-1beta neutralizing antibody (anti-MIP-1beta; on days 0, 3 and 6). PSL-induced up regulations of inflammatory cytokine-chemokine mRNAs in the injured SCN were suppressed with anti-MIP-1beta treatment on day 7. Administration of CCR5 antagonist, D-ala-peptide T-amide (on days 0, 3 and 6) prevented tactile allodynia and thermal hyperalgesia on days 4 to 14. Single administration of recombinant mouse MIP-1beta (rmMIP-1beta) elicited tactile allodynia. Moreover, rmMIP-1beta increased the mRNA expression of inflammatory mediators in the SCN on day 1 after administration. CONCLUSIONS: These results suggest that MIP-1beta is a novel key mediator, and the peripheral MIP-1beta-CCR5 axis contributes to neuropathic pain. Therefore, investigation of this cascade might be a validated approach for the elucidation of neuropathic pain mechanisms. PMID- 22528551 TI - The influence of Hispanic ethnicity on nonsmall cell lung cancer histology and patient survival: an analysis of the Survival, Epidemiology, and End Results database. AB - BACKGROUND: Most studies exploring ethnic/racial disparities in nonsmall cell lung cancer (NSCLC) compare black patients with whites. Currently, the effect of Hispanic ethnicity on the overall survival of NSCLC is poorly understood. Therefore, the authors carried out a large-scale, population-based analysis using the Surveillance, Epidemiology, and End Results (SEER) data base to determine the impact of Hispanic ethnicity the survival of patients with NSCLC. METHODS: The authors identified 172,398 adult patients with pathologically confirmed NSCLC from the SEER data base who were diagnosed between 1988 and 2007. A multivariate Cox proportional hazards regression analysis was used to determine the impact of race/ethnicity on overall survival. Pair-wise comparisons were used to determine whether Hispanic ethnicity influenced NSCLC histology or stage at diagnosis. RESULTS: Compared with non-Hispanic white patients, Hispanic white patients had a statistically significant better overall survival (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.83-0.87), and black patients had worse survival (HR, 1.091; 95% CI, 1.072-1.109). Within the bronchioalveolar carcinoma (BAC) subtype, Hispanic-white patients tend to be over represented (8.1% Hispanic whites vs 5.5% non-Hispanic whites vs 3.7% blacks; P < .001). CONCLUSIONS: The current study demonstrated that Hispanic-white patients with NSCLC had a decreased risk for overall mortality compared with non-Hispanic whites and blacks. Moreover, Hispanic patients were over represented within the BAC histologic subtype. Thus, the overall survival advantage of Hispanic NSCLC patients may be because of their predilection toward developing certain histologic subtypes of NSCLC. Further studies are warranted to determine the etiologies of such predilections and may reveal certain genetic, environmental, and/or epigenetic factors associated with Hispanic ethnicity. PMID- 22528552 TI - Combination of DQ and ZQ coherences for sensitive through-bond NMR correlation experiments in biosolids under ultra-fast MAS. AB - A double-zero quantum (DZQ)-refocused INADEQUATE experiment is introduced for J based NMR correlations under ultra-fast (60 kHz) magic angle spinning (MAS). The experiment records two spectra in the same dataset, a double quantum-single quantum (DQ-SQ) and zero quantum-single quantum (ZQ-SQ) spectrum, whereby the corresponding signals appear at different chemical shifts in omega(1). Furthermore, the spin-state selective excitation (S(3)E) J-decoupling block is incorporated in place of the second refocusing echo of the INADEQUATE scheme, providing an additional gain in sensitivity and resolution. The two sub-spectra acquired in this way can be treated separately by a shearing transformation, producing two diagonal-free single quantum (SQ-SQ)-type spectra, which are subsequently recombined to give an additional sensitivity enhancement, thus offering an improvement greater than a factor of two as compared to the original refocused INADEQUATE experiment. The combined DZQ scheme retains transverse magnetization on the initially polarized (I) spin, which typically exhibits a longer transverse dephasing time (T(2)') than its through-bond neighbour (S). By doing so, less magnetization is lost during the refocusing periods in the sequence to give even further gains in sensitivity for the J correlations. The experiment is demonstrated for the correlation between the carbonyl (CO) and alpha (CA) carbons in a microcrystalline sample of fully protonated, [(15)N,(13)C]-labelled Cu(II),Zn(II) superoxide dismutase, and its efficiency is discussed with respect to other J-based schemes. PMID- 22528553 TI - Quantitative PCR pitfalls: the case of the human placenta. AB - Reverse-transcription quantitative polymerase chain reaction (RT-qPCR) is a rapid and high throughput gene expression quantification technology. In order to obtain accurate results, several key experimental design and standardization steps must be rigorously followed as previously described in the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines. This study investigates the effect of reference gene normalization and the impact of RNA degradation on gene expression of 8-oxoguanine DNA glycosylase in human placenta from pregnancies complicated by preeclampsia and gestational diabetes mellitus and their gestation-matched controls. The data presented here show how RNA quality and appropriate reference gene selection is not only important to obtain accurate and reproducible RT-qPCR data but how different and even opposite results can be reported if the key steps outlined in the MIQE guidelines are not followed. The procedures and associated results presented in this study provide the first practical application of the MIQE guidelines to placental analysis in normal and pathological pregnancies. PMID- 22528554 TI - The role of nitric oxide and L-type calcium channel blocker in the contractility of rabbit ileum in vitro. AB - Nitric oxide (NO) and calcium channel blockers are two agents that can affect gastrointestinal motility. The goal of this work was to study the rabbit intestinal smooth muscle contraction response to (1) sodium nitroprusside (SNP), the NO donor, and its potential mechanism of action, and (2) nifedipine, the L type Ca(2+) channel blocker; to clarify the degree of participation by extra- and intracellular Ca(2+) in smooth muscle contraction. We used standard isometric tension and intracellular micro-electrode recordings. To record the activity of the longitudinal smooth muscle of the ileum, segments of 1.5 cm length of the ileum were suspended vertically in organ baths of Krebs solution. The mechanical activity of the isolated ileal longitudinal muscle was recorded. Different substances were added, and the changes produced on spontaneous contraction were recorded. We found that SNP produced significant decrease, while nitric oxide synthase inhibitor produced significant increase in the amplitude of spontaneous contractions. Both apamin, the Ca(2+)-dependent K(+) channel blocker, and methylene blue, the inhibitor of soluble guanylate cyclase, alone, partially decreased relaxation induced by SNP. Addition of both methylene blue and apamine together abolished the inhibitory effect produced by SNP on spontaneous contractions. Nifedipine produced significant decrease in the amplitude of spontaneous contractions. In conclusion, in longitudinal muscle of rabbit ileum, calcium channels blocker are potent inhibitors of spontaneous activity. However, both extracellular and intracellular Ca(2+) participates in the spontaneous contractions. NO also has inhibitory effect on spontaneous activity, and this effect is mediated by cGMP generation system and Ca(2+)-dependent K(+) channels. PMID- 22528555 TI - Baroreflex activation for the treatment of heart failure. AB - Autonomic dysregulation is a feature of heart failure (HF) characterized by sustained increase of sympathetic drive and by withdrawal of parasympathetic activity. Both maladaptations are independent predictors of poor long-term outcome in patients with HF. Considerable evidence exists that supports the use of pharmacologic agents that partially inhibit sympathetic activity as an effective long-term therapy for patients with HF; the classic example being the use of selective and nonselective beta-adrenergic receptor blockers. In contrast, modulation of parasympathetic activation as potential therapy for HF has received only limited attention. This review discusses the results of recent preclinical animal studies that provide support for the possible use of baroreflex electrical stimulation, also known as baroreflex activation therapy (BAT), as a long-term therapeutic approach for the treatment of patients with chronic HF. In addition to exploring the effects of chronic BAT on left ventricular (LV) function and chamber remodeling, the review will also address the effects of long-term BAT on ventricular arrhythmias and on potential modifiers of the HF state that include maladaptations of both the nitric oxide and beta-adrenergic receptor signal transduction pathways. The results of the preclinical studies conducted to date have shown that in dogs with advanced HF, monotherapy with BAT improves global LV systolic and diastolic function and partially reverses LV remodeling both globally and at cellular and molecular levels. In addition, BAT therapy was shown to markedly increase the threshold for lethal ventricular arrhythmias in dogs with chronic HF. These benefits of BAT support the continued exploration of this therapeutic modality for treating patients with chronic HF and those with increased risk of sudden cardiac death. PMID- 22528556 TI - New anticoagulants in ischemic heart disease. AB - Historically, the use of oral anticoagulants in acute coronary syndromes (ACS) has been controversial. Several prospective trials have shown that vitamin K antagonists (VKAs), such as warfarin or dicoumarol, reduce recurrent ischemic events but with a concomitant increased risk of bleeding. Other trial data have shown a neutral or net negative effect. Regardless, these prior observations are not readily transposable to contemporary practice where many ACS patients receive dual antiplatelet therapy and undergo cardiac catheterization and percutaneous coronary intervention. Because recurrent ischemic events continue to occur following index ACS presentation despite evidence-based practice and knowing the limitations of current oral anticoagulation strategies with VKA, the endeavor continues to find a more effective anticoagulant with predictable, dose proportional pharmacokinetics, and minimal interactions with food and drugs. We review novel, emerging classes of anticoagulants that focus on specific targets in the coagulation cascade with the aim of improving long-term net clinical outcomes. PMID- 22528558 TI - Multivessel versus culprit-only revascularization: one time versus staged procedures for the ACS population. AB - Multivessel coronary artery disease is a frequent finding in patients with acute myocardial infarction. The proper management of nonculprit lesions in the setting of acute coronary syndromes has historically been a topic of major debate. Despite current guidelines that clearly recommend treatment only of the culprit lesion in this setting, unless there is hemodynamic instability, there is still no consensus about the best treatment strategy for these patients. This article summarizes international experience and authors' opinion about this controversial topic. PMID- 22528557 TI - Preservation of myocardium during coronary artery bypass surgery. AB - Myocardial protection aims to prevent reversible post-ischemic cardiac dysfunction (myocardial stunning) and irreversible myocardial cell death (myocardial infarction) that occur as a consequence of myocardial ischemia and/or ischemic-reperfusion injury. Although the mortality rate for isolated coronary artery bypass grafting has been markedly reduced during the past decade, myocardial death, as evidenced by elevation in creatine kinase-myocardial band and/or cardiac troponin, is common. This is ascribed to suboptimal myocardial protection during cardiopulmonary bypass or with off-pump technique, early graft failure, distal embolization, and regional or global myocardial ischemia during surgery. An unmet need in contemporary coronary bypass surgery is to find more effective cardioprotective strategies that have the potential for decreasing the morbidity and mortality associated with suboptimal cardioprotection. In the present review article on myocardial protection in contemporary coronary artery bypass surgery, we attempt to elucidate the clinical problems, summarize the outcomes of selected phase III trials, and introduce new perspectives. PMID- 22528559 TI - Calculation of the relative free energy of oxidation of Azurin at pH 5 and pH 9. AB - Free energy calculations are described for the small copper-containing redox protein Azurin from Pseudomonas aeruginosa. A thermodynamic cycle connecting the reduced and oxidized states at pH 5 and pH 9 is considered, allowing for an assessment of convergence in terms of hysteresis and cycle closure. Previously published thermodynamic integration (TI) data is compared to Hamiltonian replica exchange TI (RE-TI) simulations using different simulation setups. The effects of varying simulation length, initial structure, position restraints on particular atoms, and the strength of temperature coupling are studied. Although the overall simulation times are too short to observe an experimentally described peptide plane rotation, it is found that RE-TI simulations do stimulate the distribution of conformational changes over the relevant values of the TI coupling parameter lambda. This results in significantly improved values for hysteresis and cycle closure when compared to regular TI. PMID- 22528561 TI - Reasons to use stereoselective assay methods. PMID- 22528560 TI - Clinical and pathologic features and clinical impact of false negative thyroid fine-needle aspirations. AB - BACKGROUND: Although thyroid fine-needle aspiration (TFNA) is an excellent test in evaluating thyroid nodules, there are occasionally false negatives (FN). The clinical impact and pathologic features of FN TFNA is understudied in the peer reviewed literature. METHODS: A cohort of patients with thyroid cancer was separated into those with referring FN TFNA and those with referring true positive (TP) TFNA. Preoperative characteristics, pathologic finding, and clinical outcomes were compared within the 2 groups. RESULTS: A total of 192 patients with TP TFNA (n = 162) and FN TFNA (n = 30) were included in the study. There were no significant differences in the demographics or length of follow-up of the 2 groups. The FN TFNA group was more likely to have a larger clinical nodule size and experienced a significant delay from initial TFNA to surgery. The FN TFNA group was more likely to be diagnosed with the follicular variant of papillary thyroid cancer (73.3% vs 25.9%, P < .001), less likely to have positive lymph nodes at surgery (6.7% vs 35.8%, P = .001), and more likely to undergo 2 step surgery (30% vs 9.9%, P = .007). Despite the delay in diagnosis, persistent/recurrent or metastatic disease, incidence of aggressive histologic variants, and pT4 disease was not different in the 2 groups. CONCLUSIONS: The clinical impact of FN TFNA at our high-volume center is minimal. Cancers in this setting are low grade, and outcomes are not adversely affected despite the delay in diagnosis. PMID- 22528562 TI - Mental health workers' views on the criminalization of suicidal behaviour in Uganda. AB - Attempted suicide is still criminalized in Uganda. However, the Ministry of Health has asked the psychiatric community to help in the work to abolish this law. The purpose of this study was to investigate how Ugandan mental health workers view this law. We conducted a qualitative interview study of 30 mental health workers (psychiatrists, psychologists, psychiatric clinical officers and psychiatric nurses). We found that two-thirds of this sample wanted the law abolished, mainly because they view suicidal behaviour as a mental health issue. Some, however, wanted to keep the law because they viewed it as a suicide prevention in that it would deter people from killing themselves. A few were ambivalent. The findings indicate a need for increased awareness of the negative consequences of the law as well as educating mental health workers in understanding of suicidal behaviour and suicidal people. PMID- 22528563 TI - EGFR and KRAS mutations in lung carcinomas in the Dutch population: increased EGFR mutation frequency in malignant pleural effusion of lung adenocarcinoma. AB - BACKGROUND: Frequencies of EGFR and KRAS mutations in non-small cell lung cancer (NSCLC) have predominantly been determined in East Asian and North American populations, showing large differences between these populations. The aim of the present study was to determine the frequency of EGFR and KRAS mutations in NSCLC in the West European Dutch population in primary carcinomas and different metastatic locations. METHODS: EGFR (exons 19, 20 and 21) and KRAS (exons 2 and 3) mutation test results of NSCLC samples of patients in 13 hospitals were collected. The tests were performed on paraffin-embedded tissue or cytological material of primary and metastatic lung carcinomas. RESULTS: EGFR mutations were detected in 71/778 (9.1 %) tested patients; in 66/620 (10.6 %) adenocarcinomas. EGFR mutations were significantly more often detected in female than in male patients (13.4 % vs. 5.5 %, p < 0.001). KRAS mutations were found in 277 out of 832 (33.3 %) tested patients; in 244/662 (36.9 %) adenocarcinomas. A significantly increased frequency of EGFR mutations was observed in patients with malignant pleural/pericardial effusions (26.5 %; odds ratio (OR) 2.80, 95 % confidence interval (CI) 1.22-6.41), whereas the frequency of KRAS mutations was significantly decreased (18.8 %; OR 0.35, 95 % CI 0.14-0.86). CONCLUSIONS: In the investigated Dutch cohort, patients with malignant pleural/pericardial effusion of lung adenocarcinoma have an increased frequency of EGFR mutations. The overall frequency of EGFR mutations in lung adenocarcinomas in this West European population is within the frequency range of North American and South European populations, whereas KRAS mutation frequency is higher than in any population described to date. PMID- 22528564 TI - Clinico-pathological particularities of the shock-related pancreatitis. AB - Acute pancreatitis can develop in patients with shock due to the underlying diseases, surgical interventions or because of severe hypoperfusion. The aim of our work was to study the histological alterations of the pancreas in patients dying after cardiogenic, hypovolemic or septic shock, to demonstrate the presence and severity of pancreatic injury. We performed a retrospective study which included patients who died and who were autopsied after different types of shock, hospitalized between 2007-2009 in general and cardiac intensive care units. We excluded the patients with known pancreatic diseases. From 223 patients included in our study 39 presented necrotising hemorrhagic alteration of the pancreatic tissue. There were no differences in histological and immunohistochemical findings between the different etiopathogenetic types of shock. None of the patients had characteristic clinical signs for acute pancreatitis. The digestive symptoms, they presented, could be related to the underlying disease or to postoperative state. The common findings in these patients were prolonged and severe hypotension, associated renal dysfunction, leucocytosis, hyperglycemia and hypocalcemia. Pancreatitis can occur in patients with shock, due to prolonged hypoperfusion of the pancreas. It is difficult to diagnose it because clinical signs are altered due to severity of underlying disease or analgo-sedation commonly used in intensive care. We therefore recommend in patients with shock to consider the possible development of ischemic pancreatitis for prompt and efficient treatment. PMID- 22528565 TI - Tissue-specific homing of immune cells in malignant skin tumors. AB - Tissue-specific migration of immune cells involved both in physiological and pathological immune responses is a current research subject for medical science. Several homing molecules have been identified orchestrating extravasation of immune cells to certain peripheral non-lymphoid tissues such as gut, lung and skin. Regarding lymphocyte homing to skin, the first-line defense of human body cutaneous lymphocyte associated antigen (CLA) and a group of chemokine-chemokine receptor pairs are considered to be of crucial importance. The aim of the present review is to summarize existing knowledge about skin- and tumor-specific migration of immune cells playing a major pathogenetic role in host immune responses induced by non-lymphoid malignant skin tumors as well as in the development of primary cutaneous T-cell lymphomas (CTCL). Melanoma malignum, squamous and basal cell carcinoma evoke host immune responses and consequently a subset of reactive immune cells is recruited to site of the tumor. Regarding migratory process and exact functional role of these cells a growing number of data is available in literature. On the other hand tissue-specific immune cell homing is regarded as a key process in the pathogenesis of CTCL where malignant T lymphocytes can be found in circulation and symptomatic skin. Hereby homing mechanism of malignant T-cells in mycosis fungoides and Sezary-syndrome as separate clinical entities of CTCL is discussed. A precise insight into the molecular background of skin- and tumor-specific immune cell migration can contribute to developing efficient vaccine therapies in non-lymphoid malignant skin tumors and beneficial treatment modalities in CTCL. PMID- 22528567 TI - How I do it: laparoscopic paraesophageal hernia repair. AB - INTRODUCTION: Paraesophageal hernias are usually complex anatomic abnormalities of the upper gastrointestinal tract capable of causing symptoms and complications including death. Furthermore, they affect patients who are usually older and have other comorbidities. Preferred treatment approach has evolved over time, with laparoscopic repair being the current preferred technique as it causes less hemodynamic changes and is better tolerated than open repairs. TECHNIQUE: In this report, we describe our technique for laparoscopic paraesophageal hernia repair. The most salient technical aspects of this procedure include reduction of the stomach below the diaphragm, circumferential dissection and excision of the hernia sac, closure of the crural defect with our without the addition of mesh, and fundoplication to prevent reflux. CONCLUSION: While this procedure has a low morbidity risk and short hospital stay, anatomic recurrence is frequent even when performed by experienced surgeons. PMID- 22528566 TI - Six cases of rare gene amplifications and multiple copy of fusion gene in childhood acute lymphoblastic leukemia. AB - Cytogenetic aberrations are very important factors in risk assessment of childhood hematological malignancies. We report six childhood acute lymphoid leukemia (ALL) cases with rare cytogenetic aberrations: five with RUNX1, ABL1 or MLL proto-oncogene amplification and one case of multiple copies of ETV6/RUNX1 fusion genes. The simultaneous presence of two adverse genetic aberrations is of special interest: ETV6-RUNX1 fusion gene is associated with good prognosis and intrachromosomal amplification of the homologue RUNX1 gene is associated with poor prognosis. We also report a patient with MLL amplification, a unique finding in childhood T-ALL. Report of these subtle rearrangements contributes to our understanding of diagnostic and prognostic significance of these rare cytogenetic abnormalities. PMID- 22528568 TI - Enteropathy-associated T cell lymphoma presenting with acute abdominal syndrome: a case report and review of literature. AB - INTRODUCTION: Enteropathy-associated T cell lymphoma (EATL) is a rare peripheral non-Hodgkin's T cell lymphoma originating from intraepithelial T lymphocytes of the intestines. In general, this condition has a poor prognosis. A common initial presentation of this cancer which is a small intestinal perforation necessitating emergency surgery is of interest to practicing surgeons. The diagnosis is rarely made prior to pathological examination. METHODS: We report a case of a 39-year old African American man who presented with acute abdomen and was found to have a deep necrotic ulcer of the jejunum during exploratory laparotomy. RESULTS: Pathological examination and laboratory results demonstrated EATL, type 2, which is not associated with celiac disease. A review of the literature on EATL is also presented. PMID- 22528570 TI - Multiple inflammatory myofibroblastic tumor of the duodenum: case report and literature review. AB - INTRODUCTION: Inflammatory myofibroblastic tumor (IMT) is a rare low-grade malignant mesenchymal tumor, which can occur at any location, although the lung is the most commonly affected organ. It is extremely rare in the duodenum and only two cases have been reported previously. We report, to our knowledge, the first case of multiple neoplastic lesions. CASE REPORT: A 20-year-old male presented with the chief complaints of intermittent right epigastric pain, nausea and vomiting. Imaging examination, electronic gastroscopy and preoperative biopsy revealed undefined lesions in the duodenum. Pancreaticoduodenectomy was performed and diagnosis of multiple IMT was confirmed by pathological biopsy of the excised tumor. A satisfactory outcome was proved by the follow-up 1 year after curative operation. CONCLUSION: IMT can be diagnosed by histological examination and immunohistochemical test after surgical resection. Patients can benefit from radical resection with favorable prognosis. PMID- 22528569 TI - C-reactive protein 2 days after laparoscopic gastric bypass surgery reliably indicates leaks and moderately predicts morbidity. AB - BACKGROUND: The aim of the present study was to evaluate whether serum C-reactive protein (CRP) is a useful predictor of early post-operative complications, particularly of intestinal leaks after laparoscopic Roux-en-Y gastric bypass (LRYGB) surgery. METHODS: The present study was a retrospective analysis of a prospectively maintained database with 809 patients who underwent LRYGB from 2002 until 2011. For 410 of these patients, at least one CRP measurement within the first seven post-operative days was available. The diagnostic value was determined by the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. RESULTS: Forty-nine of 410 patients (12.0 %; 95 % confidence intervals [95 % CI], 9.2-15.5 %) developed surgery-related complications. Leaks occurred in 17 patients (4.1 %; 95 % CI, 2.6-6.5 %) at a median of 5 days after surgery. CRP levels 2 days after surgery showed the highest diagnostic value for post-operative complications (AUC, 0.74; 95 % CI, 0.60-0.89). Sensitivity was 0.53 (95 % CI, 0.31-0.74) and specificity was 0.91 (95 % CI, 0.79-0.96) on day 2 (cutoff level, 229 mg/l). The sensitivity for intestinal leaks was 1.00 (95 % CI, 0.51-1.00). CONCLUSION: CRP on post-operative day 2 is a valuable predictor of post-operative complications, in particular intestinal leaks. Radiological imaging studies for intestinal leaks could be restricted to patients with CRP values exceeding 229 mg/l. PMID- 22528571 TI - Randomized trial comparing side-to-side stapled and hand-sewn esophagogastric anastomosis in neck. AB - BACKGROUND: Leak from cervical esophagogastric anastomosis (CEGA) following esophagectomy is associated with morbidity and poor functional outcome. To address this issue, we conducted a randomized trial comparing "hand-sewn" with "stapled side-to-side" CEGA. METHODS: Of 174 patients who underwent esophageal resection and CEGA between 2004 and 2010, 87 each were randomized to "hand-sewn" and "stapled side-to-side" CEGA [ www.Clinical Trials.gov: NCT00497549]. The primary outcome measure was anastomotic leak rate. The secondary outcome measures included CEGA construction time and occurrence of anastomotic stricture during follow up. RESULTS: The overall anastomotic leak rate was 17.2% (major leaks: 8 %). The leak rate was similar among the two groups (hand-sewn: 14/87, stapled: 16/87; p=0.33). The stapled anastomotic technique was faster (25 +/-.5 min vs. 27 +/- 5.5 min; p=0.02). The overall operative mortality and morbidity rates were 6.3 % and 40.8 %, respectively. At a median follow up of 12 (6-42) months, anastomotic stricture occurred in 24 (14.7 %) patients and was significantly more common in the "hand-sewn" group (17/82 vs. 7/81; p=0.045). CONCLUSION: There were no differences in the leak rates and postoperative outcome between the two CEGA techniques. At follow up, anastomotic strictures occurred less frequently following stapled CEGA. The ideal CEGA technique remains elusive. PMID- 22528572 TI - A 10-step intraoperative surgical checklist (ISC) for laparoscopic cholecystectomy-can it really reduce conversion rates to open cholecystectomy? AB - INTRODUCTION: The recent introduction of a Surgical Safety Checklist has significantly reduced the morbidity and mortality of surgery. Such a simple measure that can impact so highly on surgical outcomes causes all surgeons to pause for thought. This paper documents the introduction of a 10-step intraoperative surgical checklist (ISC) to standardize performance, decision making, and training during laparoscopic cholecystectomy (LC). The checklist's impact on conversion rates to open cholecystectomy (OC) is presented. METHODS: In 2004, a 10-step ISC was introduced by a single consultant surgeon for the performance of LCs. Data were collected comparing LCs between 1999-2003 (period 1) and 2004-2008 (period 2). Data on sex, age, American Society of Anesthesiology grade, previous abdominal surgery, severity of gallbladder pathology, and conversion to OC were recorded. The chi-squared test with Yates correction was used to compare groups. RESULTS: In total, 637 LCs were performed, 277 during period 1 and 360 during period 2. Risk factors for conversion (gender, age, previous abdominal surgery, and severity of gallbladder pathology) were not significantly different in the two periods studied. The overall conversion rate to OC fell significantly in period 2 (p=0.001). Subgroup analysis also showed a significant reduction in conversion rates in female patients (p=0.002) and patients with grades III and IV gallbladder disease (p=0.001). CONCLUSIONS: The introduction of a 10-step ISC was temporally related to reduced conversion rates to OC. The standardization of a frequently performed operation such as a LC that could potentially lead to an impact as great the one we observed warrants further attention in prospective, appropriately designed studies. PMID- 22528573 TI - Efficacy and complications of nasojejunal, jejunostomy and parenteral feeding after pancreaticoduodenectomy. AB - BACKGROUND: European nutritional guidelines recommend routine use of enteral feeding after pancreaticoduodenectomy (PD) whereas American guidelines do not. Data on the efficacy and, especially, complications of the various feeding strategies after PD are scarce. METHODS: Retrospective monocenter cohort study in 144 consecutive patients who underwent PD during a period wherein the routine post-PD feeding strategy changed twice. Patients not receiving nutritional support (n=15) were excluded. Complications were graded according to the Clavien Dindo classification and the International Study Group of Pancreatic Surgery (ISGPS) definitions. Analysis was by intention-to-treat. Primary endpoint was the time to resumption of normal oral intake. RESULTS: 129 patients undergoing PD (111 pylorus preserving) were included. 44 patients (34%) received enteral nutrition via nasojejunal tube (NJT), 48 patients (37%) via jejunostomy tube (JT) and 37 patients (29%) received total parenteral nutrition (TPN). Groups were comparable with respect to baseline characteristics, Clavien >=II complications (P=0.99), in-hospital stay (P=0.83) and mortality (P=0.21). There were no differences in time to resumption of normal oral intake (primary endpoint; NJT/JT/TPN: median 13, 16 and 14 days, P=0.15) and incidence of delayed gastric emptying (P=0.30). Duration of enteral nutrition was shorter in the NJT- compared to the JT- group (median 8 vs. 12 days, P=0.02). Tube related complications occurred mainly in the NJT-group (34% dislodgement). In the JT-group, relaparotomy was performed in three patients (6%) because of JT-leakage or strangulation leading to death in one patient (2%). Wound infections were most common in the TPN group (NJT/JT/TPN: 16%, 6% and 30%, P=0.02). CONCLUSION: None of the analysed feeding strategies was found superior with respect to time to resumption of normal oral intake, morbidity and mortality. Each strategy was associated with specific complications. Nasojejunal tubes dislodged in a third of patients, jejunostomy tubes caused few but potentially life-threatening bowel strangulation and TPN doubled the risk of infections. PMID- 22528574 TI - Pre-colectomy appendectomy and risk for Crohn's disease in patients with ileal pouch-anal anastomosis. AB - BACKGROUND: A subset of patients with a pre-operative diagnosis of ulcerative colitis can develop Crohn's disease (CD) of the pouch after restorative proctocolectomy. While appendectomy has been implicated to be associated with an increased risk for CD, its impact on the development of de novo CD of the pouch in patients' ileal pouch-anal anastomosis (IPAA) has not been studied. The aims of the study were to assess the prevalence of CD of the pouch in patients with pre-colectomy appendectomy and to investigate the impact of appendectomy on the development of de novo CD of the pouch. METHODS: All eligible patients with restorative proctocolectomy and IPAA for IBD who had available information on pre colectomy appendectomy were studied. Demographic and clinical characteristics were evaluated. Cox regression analysis was performed. RESULTS: The study included 434 patients (44.9 % male) with a mean age of 45.2 +/- 4.4 years and follow-up of 4.6 +/- 2.3 years. Forty patients (9.2 %) had had appendectomy prior to colectomy. Appendectomy was not shown to be associated with CD of the pouch or its phenotypes in both univariable and multivariable analyses. In the Cox model, independent risk factors associated with CD of the pouch were active smoking (hazard ratio [HR] =1.58; 95 % confidence interval [CI], 1.03-2.43) and family history of CD (HR=1.82; 95 % CI, 0.99-3.32). CONCLUSIONS: While this study has shown no association between previous appendectomy and the development of CD of pouch, active smoking was an independent risk factor for development of CD of the pouch. PMID- 22528575 TI - Retromuscular preperitoneal repair of flank hernias. AB - INTRODUCTION: Flank hernias represent a challenging problem to reconstructive surgeons. Their anatomic proximity to the bony prominence and major neurovascular structures limits fixation options and restricts mesh overlap. We present our technique and outcomes of a preperitoneal repair with wide mesh overlap. METHODS: This study is a retrospective analysis of patients undergoing open flank hernia repair with a retromuscular preperitoneal approach. RESULTS: Between September 2007 and April 2011, 16 patients, mean age 55 years (range 34-80) and BMI 33 kg/m2 (range 26-46), underwent open flank hernia repair. Eight were recurrent hernias; six previously had mesh placed; nine were incarcerated. Mean hernia defect size was 232 cm2 (range 25-800). Mean operative time was 178 min (range 105-245). One intraoperative complication, ureteral injury in a transplant recipient, occurred and was primarily repaired without sequela. Two patients developed wound complications, one requiring superficial debridement and another requiring partial excision (<5 %) of the mesh with secondary healing. With a mean follow-up of 16.8 months (range 2-49), no recurrent hernias were noted. CONCLUSION: Open retromuscular preperitoneal repair of flank hernias with iliac bone fixation is technically feasible, allowing wide mesh overlap for a durable repair. This approach may offer advantages of treating abdominal wall laxity and repair of larger defects when compared to laparoscopic approaches. PMID- 22528576 TI - Irinotecan drug-eluting beads in the treatment of chemo-naive unresectable colorectal liver metastasis with concomitant systemic fluorouracil and oxaliplatin: results of pharmacokinetics and phase I trial. AB - PURPOSE: The primary objective of this study is to evaluate the safety, tolerance, and pharmacokinetic profile of liver-directed therapy with drug eluting beads irinotecan (DEBIRI) in combination with systemic modified FOLFOX in the treatment of unresectable liver metastases in chemotherapy-naive patients with colorectal cancer. DESIGN: DEBIRI, loaded with 100 mg irinotecan (100-300 MUm beads), was administered via hepatic artery during the off week of FOLFOX therapy. Primary endpoints were safety, tolerance, systemic dose-limiting toxicities, and pharmacokinetics of systemic irinotecan and its active metabolite SN-38 at each infusion at 1-, 4-, and 24-h post-DEBIRI. Secondary endpoints were response rate and survival. RESULTS: The ten patients have undergone at least 12 cycles of FOLFOX in combination with at least two DEBIRI bead treatments during the patients' off week. Pharmacokinetic data has demonstrated minimal detectable levels of irinotecan (18.6, 21, and 18.6 ng/ml) and SN-38 (1.06, 1.47, and 1.55 ng/ml) after the first, second, and third DEBIRI treatments, respectively. Currently, there has been only one severe device-related adverse event, a grade 3 hypertensive episode that required 1 day of observation in the hospital. The initial 9- and 12-month response rates have been 100 % (2 CR, 8 PR). Four (40 %) patients were successfully downstaged to resection and/or ablation with a median overall survival of 15.2 months. CONCLUSION: Concomitant DEBIRI and FOLFOX+/ bevacizumab is safe, with a minimal adverse event rate, no dose-limiting toxicities, and enhanced overall response rate. PMID- 22528578 TI - Laser sheath for tunneled dialysis catheters extraction. PMID- 22528577 TI - Pancreatic enucleation: improved outcomes compared to resection. AB - INTRODUCTION: Pancreatic enucleation is associated with a low operative mortality and preserved pancreatic parenchyma. However, enucleation is an uncommon operation, and good comparative data with resection are lacking. Therefore, the aim of this analysis was to compare the outcomes of pancreatic enucleation and resection. MATERIAL AND METHODS: From 1998 through 2010, 45 consecutive patients with small (mean, 2.3 cm) pancreatic lesions underwent enucleation. These patients were matched with 90 patients undergoing pancreatoduodenectomy (n = 38) or distal pancreatectomy (n = 52). Serious morbidity was defined in accordance with the American College of Surgeons-National Surgical Quality Improvement Program. Outcomes were compared with standard statistical analyses. RESULTS: Operative time was shorter (183 vs. 271 min, p < 0.01), and operative blood loss was significantly lower (160 vs. 691 ml, p < 0.01) with enucleation. Fewer patients undergoing enucleation required monitoring in an intensive care unit (20% vs. 41%, p < 0.02). Serious morbidity was less common among patients who underwent enucleation compared to those who had a resection (13% vs. 29%, p = 0.05). Pancreatic endocrine (4% vs. 17%, p = 0.05) and exocrine (2% vs. 17%, p < 0.05) insufficiency were less common with enucleation. Ten-year survival was no different between enucleation and resection. CONCLUSION: Compared to resection, pancreatic enucleation is associated with improved operative as well as short- and long-term postoperative outcomes. For small benign and premalignant pancreatic lesions, enucleation should be considered the procedure of choice when technically appropriate. PMID- 22528579 TI - Elderly dialysis patients: analysis of factors affecting long-term survival in 4 year prospective observation. AB - PURPOSE: To assess factors influencing the long-term survival of elderly dialysis patients. METHODS: The study group consisted of 51 prevalent dialysis patients aged over 70 years (32 F and 19 M, all caucasians), who had been on a chronic hemodialysis (27) or peritoneal dialysis program (24) for at least 2 months; median age was 77 years, median time on dialysis before inclusion was 16 months, and median residual diuresis was 600 ml. The patients were prospectively followed up to 4 years, and an analysis of factors affecting survival was performed. RESULTS: Thirteen patients from the initial cohort of 51 (25.5 %) survived the whole 48-month observation period: 10 HD patients (37 %) and 3 PD patients (12.5 %). Annual mortality rate was 28.2 %: 37.4 % on PD vs. 20.9 % on HD. The dialysis modality had a significant impact on patients' survival (p = 0.049; Cox F-test). The independent mortality risk factors in the Cox proportional hazard regression model were higher plasma pro-atrial natriuretic peptide (pro-ANP) (p = 0.006), lower residual diuresis (p = 0.048), and lower systolic blood pressure (BP) value (p = 0.039). CONCLUSIONS: Paramount for the survival of the elderly on dialysis is adequate extracellular volume control. Residual renal function is a protective factor for the survival of elderly HD patients. This observation is novel, not previously reported in an elderly dialysis population. PMID- 22528580 TI - Effect of sirolimus on the regression of peritoneal sclerosis in an experimental rat model. AB - PURPOSE: Immunosuppressive and anti-inflammatory agents have recently become increasingly popular in the treatment of encapsulating peritoneal sclerosis (EPS). The aim of our study was to investigate the effects of sirolimus on EPS in a rat model. METHODS: We separated 32 non-uremic rats into four groups: 1 control group, 2 ml isotonic saline injected IP daily for 3 weeks; 2 chlorhexidine gluconate (CG) group, 2 ml 0,1 % CG and 15 % ethanol dissolved in saline injected IP daily for 3 weeks; 3 resting group, CG (weeks 0-3) plus peritoneal rest (weeks 3-6); 4 sirolimus group, CG (weeks 0-3), plus 0.2 ml (1 mg/ml) sirolimus (weeks 3 6). Pathological samples were examined by using hematoxylin eosin (HE) and Masson's trichrome stains. Peritoneal thickness, fibrosis, vascular changes, and inflammation were evaluated by light microscopy. Finally, tissue metalloproteinase (MMP)-2 levels were measured by enzyme-linked immunoassay. RESULTS: In the CG group, there was a significant increase in peritoneal thickness, inflammatory activity, and fibrosis score compared to the control group (p < 0.05). We also observed a lower fibrosis score and less peritoneal thickening in the sirolimus group compared to the resting and CG groups (p < 0.05). There was no difference in histopathologic findings, except for the inflammatory activity in the sirolimus group, compared to the control group. Although the CG group had higher tissue MMP-2 levels than the control group, the tissue MMP-2 levels were not significantly different from the other groups. CONCLUSIONS: Sirolimus has a beneficial effect on peritoneal fibrosis induced by CG. This suggests that sirolimus may have therapeutic value in the management of EPS. PMID- 22528581 TI - Does left side renal cell carcinoma (RCC) with renal vein/vena cava thrombus predict worse prognosis than equivalent right side RCC tumor thrombus? AB - PURPOSE: To determine whether renal cell carcinoma (RCC) thrombi that reach the vena cava from the left kidney are associated with a greater risk of RCC death than equivalent thrombi from the right kidney. METHODS: Two hundred and fifty nine patients treated with radical nephrectomy (1970-2006) for unilateral, sporadic RCC with level 1-4 RCC tumor thrombus were identified. Clinicopathologic features between patients with right-sided (N = 183) and left-sided (N = 76) thrombus were compared utilizing Wilcoxon rank sum and Fisher's exact tests. Associations with RCC-specific death using hazard ratios (HR) and 95 % confidence intervals (CIs) from Cox proportional hazards models were evaluated. RESULTS: Left-sided RCC patients with thrombus are less likely to be clear cell subtype (85 % vs. 93 %; p = 0.013) and more likely to have nodal involvement (28 % vs. 16 %; p = 0.018) compared to right side RCC patients with thrombus. Overall, there is little evidence that the risk of RCC death is higher for left versus right sided RCC thrombus (HR = 1.11; 95 % CI 0.81-1.53; p = 0.52). However, among those patients with a thrombus that has reached the vena cava (level III/IV), we observe evidence after multivariate adjustment that the risk of RCC death is higher for left versus right side patients (HR = 2.02; 95 % CI 0.91-4.47; p = 0.08). CONCLUSIONS: Left side RCC with tumor thrombus is not associated with worse prognosis than right-sided tumors (all tumor thrombi levels). Our data suggest that among RCC patients with advanced tumor thrombi (level III/IV), a left side thrombus may be associated with worse prognosis compared to a right side thrombus. PMID- 22528582 TI - Kidney transplantation after desensitization in sensitized patients: a Korean National Audit. AB - INTRODUCTION: The number of end-stage renal disease (ESRD) patients with preformed antibodies waiting for a kidney transplant has been increasing lately. We conducted a nationwide study on the outcomes of kidney transplantation after desensitization in Korea. METHODS: Six transplant centers have run desensitization programs. The patients who underwent living donor kidney transplantation after desensitization from 2002 to 2010 were retrospectively analyzed. RESULTS: A total of 86 cases were enrolled. Thirty-five of these were cases of re-transplantation (40.7 %). Indications of desensitization were positive complement-dependent cytotoxicity (CDC) cross-match responses (CDC(+), 36.0 %), positive flow-cytometric cross-match responses (FCX(+), 54.7 %), and positive donor-specific antibodies (DSA(+), 8.1 %). The desensitization protocols used pre-transplant plasmapheresis (95.3 %), intravenous immunoglobulin (62.8 %), and rituximab (67.4 %). Acute rejection occurred in 18 patients (20.9 %), graft failure occurred in 4 patients, and the 3-year graft survival rate was 93.8 %. The presence of DSA increased the acute rejection rate (P = 0.015) and decreased the 1-year post-transplant estimated glomerular filtration rate (P = 0.006). Although rejection-free survival rates did not differ significantly between the CDC(+) and FCX(+) groups, the 1-year estimated glomerular filtration rate was lower in the CDC(+) group (P = 0.010). Infectious and significant bleeding complications occurred in 15.5 % and 4.7 % of cases, respectively. CONCLUSION: Kidney transplantation after desensitization had good graft outcomes and tolerable complications in Korea, and therefore, this therapy can be recommended for sensitized ESRD patients. PMID- 22528583 TI - Relative contributions of inflammation and inadequate protein intake to hypoalbuminemia in patients on maintenance hemodialysis. AB - PURPOSE: Serum albumin is one of the strongest mortality predictors in maintenance hemodialysis (MHD) patients. Yet, the degree to which serum albumin represents dietary protein intake or an inflammatory state, among others, is not clear. We hypothesize that these inadequate protein intake and inflammation contribute somewhat equally to hypoalbuminemia. METHODS: In a cross-sectional analysis, we examined correlates of low serum albumin, <3.8 g/dL, in 812 MHD patients in whom interleukin-6 (IL-6) and normalized protein nitrogen appearance (nPNA), also known as normalized protein catabolic rate (nPCR), were also measured. Logistic regression estimated odds ratios were employed, and spline models were plotted to examine the likelihood of relatively low serum albumin <3.8 g/dL. RESULTS: Mean age (+/-SD) of patients was 54 +/- 15 years; 53 % of patients were men, 50 % Hispanic, 31 % African-American, and 55 % diabetic. The mean dialysis vintage was 31 +/- 34 months (median: 19, inter-quartile range: 7 44 months). The baseline serum albumin, averaged over a 3-month period (mean +/- SD), was 3.88 +/- 0.38 g/mL. The unadjusted correlation coefficients of l IL-6 and nPNA with serum albumin were -0.36 and +0.20, respectively (p < 0.001 for each comparison). The likelihood for an albumin <3.8 gr/dL increased linearly with decreasing nPNA and rising serum IL-6. This trend was steeper with increasing serum IL-6 up to a concentration of 30 ng/mL. CONCLUSIONS: Both low protein intakes and a high state of inflammation are associated with low serum albumin in MHD patients. PMID- 22528584 TI - Relation between serum estradiol levels and mortality in postmenopausal female hemodialysis patients. AB - BACKGROUND: Recently, low serum estradiol levels have been associated with increased cardiovascular risk and mortality in non-uremic patient populations. We investigated the predictive value of serum estradiol levels for mortality in female hemodialysis patients. METHODS: One hundred and forty-seven prevalent female hemodialysis patients were included in March 2005 and followed up for 32 +/- 16 months. Serum estradiol levels were determined by ELISA at baseline and studied in relation to cardiovascular and overall mortality. RESULTS: Mean serum estradiol level was 28.6 +/- 15.4 pg/ml (5.7-81.3). Patients in the higher estradiol tertile were likely to be more often diabetic and to have more cardiovascular diseases and higher body mass index (BMI). Serum estradiol was inversely correlated with age and urea reduction rate and positively correlated with postdialysis body weight, BMI and hs-CRP levels. During the follow-up period, 52 (35.6 %) patients died. Patients who died were older, had shorter dialysis vintage, were more likely to have a history of diabetes and cardiovascular disease, and lower serum creatinine, albumin, hemoglobin, and higher hs-CRP levels than those who survived. In Cox regression analysis, estradiol levels, in a bimodal (U-shaped) distribution, along with diabetes, low serum albumin and high hs-CRP levels, were predictors for overall mortality. CONCLUSIONS: A U-shaped association between serum estradiol levels and cardiovascular and overall mortality was found in postmenopausal hemodialysis patients. PMID- 22528585 TI - Influence of comorbidities and inactivity on the long-term outcomes of coronary artery bypass graft surgery in a small number of men on chronic hemodialysis. PMID- 22528586 TI - Long-term alpha-blockers and anticholinergic combination treatment for men with lower urinary tract symptoms in real-life practice. AB - PURPOSE: To analyze the treatment outcomes and clinical courses for men with lower urinary tract symptoms, after long-term treatment of alpha-blocker and anticholinergic combination in real-life practice. MATERIALS AND METHODS: A total of 210 men, with lower urinary tract symptoms, had combination therapy for 3 months. Patients were reevaluated and were decided on an alpha-blocker single treatment or a combination therapy, according to the patient-reported outcome for 2 years. The patient responses in 2-year treatment were divided into 3 groups, which depended on clinical courses: 56 patients had an alpha-blocker single therapy after 3-month combination therapy (group I); 106 patients had a continuous alpha-blocker therapy with intermittent 3-month anticholinergic therapy (group II); 48 patients with continuous storage symptoms maintained a combination therapy (group III). Endpoints included 2-year changes in International Prostate Symptom Score (IPSS), Qmax, and residual volume. RESULTS: Group III had significantly increased IPSS total and subscores compared to that of the other groups in the baseline characteristics. IPSS total and subscores significantly decreased at 3 months and were maintained for 2 years in all groups. Increase in Qmax was significant in all the groups at 3 months, and its increase was still significant after 2 years. Residual urine volume increased in all the groups at 3 months, but changes at 2 years were not statistically significant. CONCLUSIONS: After 3 months of alpha-blocker and anticholinergic combination treatment, 73.4 % of the patients still needed a combination therapy. Although only one patient developed acute urinary retention, voiding difficulty was common (13.3 %), after a combination treatment in the real-life practice. PMID- 22528587 TI - Evaluation of acridine orange fluorescence in exfoliative urinary cytology for diagnosing bladder carcinoma. AB - PURPOSE: This study reviewed acridine orange fluorescence (AO-F) in exfoliative urinary cytology results of 1,016 inpatients with urothelial cell carcinoma of the bladder and 804 outpatients to investigate the value of AO-F in the diagnosis of bladder cancer. METHODS: A total of 1,016 bladder cancer inpatients from October 1995 to October 2005 and 804 outpatients from January 2004 to January 2006 were enrolled in this study. Each patient provided the morning urine specimen of 30-50 ml in a sterile container. Urine sediments were stained by acridine orange and observed with a fluorescence microscope; 60 bladder cancer inpatients from January 2006 to July 2007 were also chosen for the control study of three different detection methods, including AO-F, hematoxylin and eosin and Feulgen staining. RESULTS: Of the 1,016 bladder carcinoma samples analyzed, 793 were AO-F positive. Total positive rate of AO-F was 78.05 %. The positive rate was 74.69 % (611/818) for non-muscle invasive bladder carcinoma and 91.91 % (182/198) for muscle invasive bladder carcinoma. A significant correlation of AO F positivity with clinical stage was observed (P < 0.01). The positive rates among various pathological grades were 66.7 % (32/48) for G1, 67.5 % (319/474) for G2 and 90.4 % (413/457) for G3 with significant differences (P < 0.01). For the 804 outpatients, the sensitivity and specificity of bladder carcinoma were 77.11 and 85.29 %, respectively. CONCLUSIONS: With its high sensitivity and specificity, AO-F is superior to other detection methods for bladder carcinoma detection. In addition, it is familiar, non-invasive, quick, cheap and easily repeatable. PMID- 22528588 TI - The influence of vitamin E supplementation on erythropoietin responsiveness in chronic hemodialysis patients with low levels of erythrocyte superoxide dismutase. AB - About 12-15 % of hemodialysis patients have a poor response to recombinant human erythropoietin (rHuEPO). The aim of this prospective study was to examine the influence of oxidative stress and vitamin E supplementation on rHuEPO responsiveness in chronic hemodialysis patients. Sixty-five hemodialysis patients treated with rHuEPO were studied. Those with iron deficiency, blood loss, malignancy, vitamin B12 and folate deficiency, severe hyperparathyroidism, liver cirrhosis, and congestive heart failure were excluded. Twenty-one healthy volunteers served as a control group. Malondialdehyde, carbonyl proteins, erythrocyte superoxide dismutase (SOD), ceruloplasmin, and serum antioxidant capacity were measured. Values of SOD > 150 U/ml were considered as normal. Patients with SOD < 150 U/ml were divided in two groups: group A (n = 11): treated with vitamin E 400 mg/day (600 IU/day) for 8 weeks; group B (n = 13): not treated. A third, group C consisted of patients with normal SOD. rHuEPO doses (U/kg/week) were recorded. rHuEPO responsiveness index was calculated as rHuEPO U/week/hematocrit. A poor response was defined as a rHuEPO responsiveness index >200. SOD positively correlated with hemoglobin (p = 0.0018, R = 0.337) and negatively with rHuEPO responsiveness index (p = 0.0122, R = 0.319). Vitamin E treated patients from group A exhibited significantly increased hemoglobin levels as compared to initial values (10.5 +/- 0.3 vs. 8.6+/-0.4, p = 0.002). In comparison with group B, the vitamin E-treated patients displayed a higher hemoglobin (10.5 +/- 0.3 vs. 9.4 +/- 0.3, p = 0.04), had a lower rHuEPO dose (85.7 +/- 7.4 vs. 136.8 +/- 13.8, p = 0.025), and a significantly improved rHuEPO responsiveness (rHuEPO responsiveness index 177.9 +/- 28.6 vs. 314.1 +/- 34.0, p = 0.006). Patients from group A significantly improved their rHuEPO responsiveness after vitamin E therapy as compared to baseline (rHuEPO responsiveness index 177.9 +/- 28.6 vs. 271.7 +/- 30.3, p = 0.034). We conclude that lower values of SOD correlate with lower hemoglobin, higher rHuEPO dose and poor response to rHuEPO in chronic hemodialysis patients. Vitamin E supplementation significantly improves rHuEPO responsiveness, increases hemoglobin level, and decreases rHuEPO dose. PMID- 22528590 TI - Acute electrocardiographic ST segment elevation may predict hypotension in a swine model of severe cyanide toxicity. AB - Cyanide causes severe cardiac toxicity resulting in tachycardia, hypotension, and cardiac arrest; however, the clinical diagnosis can be difficult to make. A clinical finding that may precede or predict cyanide-induced hypotension may be a trigger to provide treatment earlier and improve outcomes in cyanide toxicity. Our primary objective was to determine if there is a clinically significant change in ST segment deviation measured on ECG during intravenous cyanide infusion that may predict cyanide-induced hypotension. As part of a larger study comparing antidotes for cyanide-induced shock, 30 swine were anesthetized and monitored and then intoxicated with a continuous cyanide infusion until severe hypotension (50 % of baseline mean arterial pressure) occurred. ECGs were obtained at baseline, every 5 min during infusion, and at the development of hypotension. Repeated measures of analysis of variance were used to determine significance. The mean weight for the 30 swine at baseline was 48 kg (range 45 52), pulse rate 86 beats/min (range 55-121), and systolic blood pressure 109 mmHg (range 90-121). The mean time to hypotension was 31 min (range 16-39). The mean amount of cyanide infused was 5 mg/kg (range 2.5-6.3 mg/kg). All animals (30/30) had ECG changes in repolarization or depolarization during cyanide infusion. Significant rhythm, repolarization, and conduction changes from baseline were observed prior to severe hypotension (p < 0.05). Normal sinus rhythm and sinus tachycardia were the most common rhythms preceding hypotension. We observed ST segment elevation in leads V3, V4, III, and aVF and ST segment depression in leads aVL and aVR. The most pronounced ST segment elevation was observed in leads V3 and V4. We also detected significant changes with increased pulse rate, prolonged PR interval, and shortened QTc interval. Other significant changes were increased T axis and reduced QRS axis. We detected ST segment deviations occurring just before the onset of cyanide-induced hypotension in our swine model. Leads V3 and V4 had the most pronounced with ST elevation, but we also detected electrocardiographic ST elevation inferiorly. Shortening of the QTc and lengthening of the PR interval were also detected before hypotension. PMID- 22528591 TI - Toxico-surveillance of infant and toddler poisonings in the United States. AB - Infant and toddler poisonings are important to capture and may be challenging to manage. We aim to describe the Toxicology Investigators Consortium (ToxIC) Case Registry as a tool for toxico-surveillance of this problem in the United States. Using the ToxIC Case Registry database of the American College of Medical Toxicology, we identified infant and toddler poisonings over a 15-month period between April 1, 2010 and June 30, 2011 reported to the 31 Registry sites. Of 6,810 poisoning cases reported to the ToxIC registry, 248 (3.6 %) involved children younger than 2 years (51 % males). Fifty-four percent were hospital inpatients, 42 % were in the Emergency Department and 4 % were outpatients. Sixty three percent were symptomatic. The most common ingested compounds were highly toxic-cardiac drugs (16 %), psychotropics (15 %), recreational drugs, alcohols, and controlled narcotic drugs (13 %), analgesics (9 %), and cleaning compounds (7 %). Fourteen percent of cases involved multiple agents. The ToxIC registry is a potentially useful toxico-surveillance tool to identify and trend clinically significant poisonings in young children, and potentially other populations. These data could be used to target specific preventive interventions. PMID- 22528592 TI - Psychosis from a bath salt product containing flephedrone and MDPV with serum, urine, and product quantification. AB - INTRODUCTION: The use of designer drugs commonly marketed as bath salts or plant food has risen dramatically in recent years. Several different synthetic cathinones have been indentified in these products, including mephedrone, 3,4 methylenedioxypyrovalerone (MDPV), and 4-fluoromethcathinone (flephedrone). We report a case of bath salt intoxication with quantitative MDPV and flephedrone levels in a patient's serum and urine, and from the bath salt product. CASE REPORT: A 23-year-old male with a prior psychiatric history arrived via EMS for bizarre behavior, suicidality, and hallucinations after reportedly insufflating a bath salt. He was found to have MDPV levels of 186 and 136 ng/mL in his serum and urine, respectively, and flephedrone levels of 346 and 257 ng/mL in the serum and urine, respectively. The white powder in question was found to contain 143 MUg MDPV and 142 MUg flephedrone per milligram powder. His psychosis and agitation resolved with lorazepam, droperidol, and observation in the emergency department. DISCUSSION: Agitation, psychosis, movement disorders, tachycardia, and hypertension have all been attributed to the use of MDPV; there are no prior reports detailing clinical experience with flephedrone. Considering that our patient's serum flephedrone levels were twofold higher than his MDPV level, it is likely flephedrone contributed to his clinical toxicity. This case suggests the possibility that fluorinated cathinones, such as flephedrone, may have altered metabolism and/or elimination which may affect their course of clinical toxicity. This case highlights the evolving composition of synthetic cathinones found in bath salt products. PMID- 22528595 TI - Diagnosis of coronary artery disease in persons with diabetes mellitus. AB - Coronary heart disease (CHD) is the leading cause of morbidity and mortality in patients with diabetes. Asymptomatic CHD in these patients is elusive and carries a poor prognosis given the fact that an unheralded acute myocardial infarction or sudden cardiac death frequently constitutes its first presentation. Because effective screening for asymptomatic patients with type 2 diabetes for both the presence and severity of CHD is intuitively appealing, we have summarized the utility and prognostic value of various diagnostic modalities (both functionally and anatomically) in enhancing risk stratification and leading to improved and more aggressive management of the risk factors. There exist some evidence and recommendations for screening of asymptomatic persons with diabetes using certain modalities. More research is needed to define potential subsets of patients with diabetes who may benefit from additional testing for asymptomatic CHD. PMID- 22528594 TI - Diabetes mellitus and acute coronary syndrome: lessons from randomized clinical trials. AB - Diabetes mellitus is a major independent risk factor for acute coronary syndrome (ACS). In addition, diabetic patients with ACS suffer from increased mortality compared to their nondiabetic peers. Driven by multiple pathophysiological disturbances, such patients are predisposed to a proinflammatory, prothrombotic state, which may lead to plaque rupture. To counteract this more complex biology, several therapies and strategies have emerged, with some having unique preferential benefits in this population. Antiplatelet agents such as aspirin and clopidogrel have long been standard of care. Dose adjustment of these therapies remains the subject of continued research. Along with medical therapy, ACS diabetic patients preferentially benefit from primary percutaneous intervention compared to fibrinolysis. However, with advances in reperfusion techniques, the optimal strategy has yet to be determined. With these differences in ACS treatment responses, diabetic individuals may not just be a high-risk group, but may actually constitute a fundamentally different population, requiring dedicated clinical trials and individualized treatment regimens. PMID- 22528596 TI - Update on diabetic cardiomyopathy: inches forward, miles to go. AB - Diabetes causes cardiomyopathy, both directly and by potentiating the effect of its common comorbidities, coronary artery disease and hypertension, on its development. With the common and growing prevalence of diabetes worldwide, diabetic cardiomyopathy is a significant public health problem. Recent research identifies both mitochondrial dysfunction and epigenetic effects as newly recognized factors in the complex pathogenesis of diabetic cardiomyopathy. Diagnostically, specialized echocardiography techniques, cardiac magnetic resonance imaging, and serologic biomarkers all appear to have promise in detecting the early stages of diabetic cardiomyopathy. Research into treatments includes both traditional diabetes and heart failure therapies, but also explores the potential of newer metabolic and anti-inflammatory agents. These recent insights provide important additions to our knowledge about diabetic cardiomyopathy, but much remains unknown. PMID- 22528597 TI - Efficacy and safety of SGLT2 inhibitors in the treatment of type 2 diabetes mellitus. AB - In addition to its central role in the development of microvascular complications, hyperglycemia plays an important role in the pathogenesis of type 2 diabetes mellitus (T2DM) by means of glucotoxicity. Thus, effective glycemic control not only reduces the incidence of microvascular complications but also corrects the metabolic abnormalities that contribute to the progression of the disease. Progressive beta-cell failure and multiple side effects, including hypoglycemia and weight gain, associated with many current therapies present obstacles to the achievement of optimal and durable glycemic control in subjects with T2DM. Most recently, inhibitors of the renal sodium-glucose cotransporter have been developed to reduce the plasma glucose concentration by producing glucosuria. Because the mechanism of action of these oral antidiabetic agents is independent of beta-cell function and tissue sensitivity to insulin, they improve glycemic control while avoiding hypoglycemia and promoting weight loss. In this review, we summarize the available data concerning the mechanism of action, efficacy, and safety of this novel antidiabetic class of therapeutic agents. PMID- 22528593 TI - The interface of protein structure, protein biophysics, and molecular evolution. AB - Abstract The interface of protein structural biology, protein biophysics, molecular evolution, and molecular population genetics forms the foundations for a mechanistic understanding of many aspects of protein biochemistry. Current efforts in interdisciplinary protein modeling are in their infancy and the state of-the art of such models is described. Beyond the relationship between amino acid substitution and static protein structure, protein function, and corresponding organismal fitness, other considerations are also discussed. More complex mutational processes such as insertion and deletion and domain rearrangements and even circular permutations should be evaluated. The role of intrinsically disordered proteins is still controversial, but may be increasingly important to consider. Protein geometry and protein dynamics as a deviation from static considerations of protein structure are also important. Protein expression level is known to be a major determinant of evolutionary rate and several considerations including selection at the mRNA level and the role of interaction specificity are discussed. Lastly, the relationship between modeling and needed high-throughput experimental data as well as experimental examination of protein evolution using ancestral sequence resurrection and in vitro biochemistry are presented, towards an aim of ultimately generating better models for biological inference and prediction. PMID- 22528599 TI - Mechanisms of silicon alkoxide hydrolysis-oligomerization reactions: a DFT investigation. AB - Silica aerogels possess a variety of unique and remarkable properties, but the mechanisms of silicon alkoxide, Si(OR)(4), hydrolyses and oligomerization in the initial stage of sol-gel processes are still not well understood. On the basis of density functional theory calculations at the B3LYP/6-31G(d,p)//B3LYP/6 311++G(d,p) basis set level, the hydrolysis and oligomerization reactions of Si(OR)(4) in neutral, acidic, and alkaline solutions were systematically investigated and we found that in acidic solutions the precursor Si(OCH(3))(4) was inclined to hydrolyze rather than to condense and the hydrolysis processes were energetically more favorable than the neutral ones. In alkaline solutions, the hydrolysis products oligomerize through an S(N)1 dimerization mechanism and the condensation rates are fast to form denser colloidal aerogels. Our calculations also testify that the subsequent cyclization reactions are energetically unfavorable. PMID- 22528598 TI - The role of combination therapy in type 2 diabetes in the post-ACCORD era. PMID- 22528600 TI - Extensive abdominal lipomatosis in a patient with Noonan/LEOPARD syndrome (Noonan syndrome-Multiple Lentigines). AB - Noonan syndrome (NS) is a tumor predisposing disorder. Leukemia is observed in 1 3% of patients with NS, with rare occurrences of solid tumors. It also appears to predispose to non-malignant tumors. We report on a 26-year-old female with features of Noonan syndrome-Multiple Lentigines and a heterozygous mutation: c.1517A > C-p.Gln506Pro in the PTPN11 gene. The patient developed an unusual extensive lipomatosis and we discuss possible relationship between her lipomatosis and NS. PMID- 22528603 TI - Cost-utility analysis of biologic treatments for moderate-to-severe Crohn's disease. AB - STUDY OBJECTIVE: To compare the cost versus utility of four guideline-recommended biologic treatments-infliximab, adalimumab, certolizumab pegol, and natalizumab for the treatment of Crohn's disease from a United States payer perspective. DESIGN: Cost-utility decision analytic model using a Monte Carlo simulation of 10,000 cases. DATA SOURCE: Published primary and tertiary literature. PATIENTS: Patients with moderate-to-severe Crohn's disease, as categorized by the Crohn's Disease Activity Index, that failed to respond to standard therapy and who were treatment naive to biologics. MEASUREMENTS AND MAIN RESULTS: The decision analytic model base case was a 35-year-old patient weighing 70 kg with moderate to-severe Crohn's disease. Therapeutic efficacy data were obtained from published clinical trials. Online prescription drug, hospitalization data, and Current Procedural Terminology codes were used to estimate cost. Utility measures were estimated using published data obtained from patients with Crohn's disease. The time end point used for the model was 54 weeks. The analysis demonstrated considerable overlap in quality-adjusted life years gained with the four agents (i.e., mean values across four treatments 0.79-0.80). Although infliximab had the lowest median cost, there was overlap in the 95% confidence intervals (CIs) compared with the other three biologic products: mean (95% CI) cost for infliximab $22,663 ($19,105-26,433), adalimumab $27,515 ($23,796-31,584), certolizumab pegol $29,062 ($24,952-33,882), and natalizumab $31,166 ($25,915 37,195). However, the cost-effectiveness acceptability curve demonstrated that infliximab had the most scenarios (95.2%) when it was the most cost-effective biologic therapy using a willingness-to-pay threshold of $100,000/quality adjusted life years gained. CONCLUSION: Patients with moderate-to-severe Crohn's disease that failed to respond to standard treatment should preferentially receive infliximab as their initial biologic treatment, since this agent had the highest probability of being the most cost-effective therapy compared with the other biologic treatment options. PMID- 22528601 TI - Cell cycle activation and aneuploid neurons in Alzheimer's disease. AB - Alzheimer's disease (AD) is a chronic neurodegenerative disorder, characterized by synaptic degeneration associated with fibrillar aggregates of the amyloid-beta peptide and the microtubule-associated protein tau. The progression of neurofibrillary degeneration throughout the brain during AD follows a predictive pattern which provides the basis for the neuropathological staging of the disease. This pattern of selective neuronal vulnerability against neurofibrillary degeneration matches the regional degree of neuronal plasticity and inversely recapitulates ontogenetic and phylogenetic brain development which links neurodegenerative cell death to neuroplasticity and brain development. Here, we summarize recent evidence for a loss of neuronal differentiation control as a critical pathogenetic event in AD, associated with a reactivation of the cell cycle and a partial or full replication of DNA giving rise to neurons with a content of DNA above the diploid level. Neurons with an aneuploid set of chromosomes are also present at a low frequency in the normal brain where they appear to be well tolerated. In AD, however, where the number of aneuploid neurons is highly increased, a rather selective cell death of neurons with this chromosomal aberrancy occurs. This finding add aneuploidy to the list of critical molecular events that are shared between neurodegeneration and oncogenesis. It defines a molecular signature for neuronal vulnerability and directs our attention to a failure of neuronal differentiation control as a critical pathogenetic event and potential therapeutic target in AD. PMID- 22528604 TI - The effect of Cu(II)-loaded brushite scaffolds on growth and activity of osteoblastic cells. AB - Bone substitute materials such as calcium phosphate cements (CPC) are frequently used as growth factor carriers for the stimulation of osteoblast-formation around an implant. However, biological modification based on delicate protein factors like extracellular matrix proteins or growth factors is subject to a number of shortcomings like the need for storage below room temperature and cost of production. The aim of this study was to investigate ionic modification as an alternative bioinorganic route for implant modification. Although it is known that Cu(II) plays a role in angiogenesis and bone formation, not all involved processes are well understood yet. In this study the in vitro effect of Cu(II) on growth and activity of osteoblastic cells seeded on brushite (CaHPO(4) . 2 H(2) O) scaffolds as well as on glass discs was investigated. The results show that Cu(II) enhances cell activity and proliferation of osteoblastic cells on CPC and furthermore affects the expression of several bone specific proteins such as bone sialo protein or osteocalcin. Therefore, the modification of CPC with Cu(II) may offer a promising alternative to protein based modification to stimulate cellular activity for an improved bone healing. PMID- 22528602 TI - Aberrant dendritic excitability: a common pathophysiology in CNS disorders affecting memory? AB - Discovering the etiology of pathophysiologies and aberrant behavior in many central nervous system (CNS) disorders has proven elusive because susceptibility to these diseases can be a product of multiple factors such as genetics, epigenetics, and environment. Advances in molecular biology and wide-scale genomics have shown that a large heterogeneity of genetic mutations are potentially responsible for the neuronal pathologies and dysfunctional behaviors seen in CNS disorders. Despite this seemingly complex array of genetic and physiological factors, many disorders of the CNS converge on common dysfunctions in memory. In this review, we propose that mechanisms underlying the development of many CNS disorders may share an underlying cause involving abnormal dendritic integration of synaptic signals. Through understanding the relationship between molecular genetics and dendritic computation, future research may uncover important links between neuronal physiology at the cellular level and higher order circuit and network abnormalities observed in CNS disorders, and their subsequent affect on memory. PMID- 22528605 TI - Functional up-regulation of P2X3 receptors in dorsal root ganglion in a rat model of bone cancer pain. AB - BACKGROUND: Cancer-induced bone pain remains a clinical challenge due to the poor understanding of the mechanisms. Recent study revealed extracellular adenosine triphosphate (ATP) and P2X receptors may be implicated in nociceptive signalling under cancer pain state. Therefore, here we investigated the potential role of P2X(3) receptor in a rat model of bone cancer pain. METHODS: Walker 256 tumour cells were inoculated into the left tibia of Wistar rats. The model was verified by X-ray imaging, pathology and behaviour examinations. The expression of P2X(3) receptors in dorsal root ganglia (DRG) was examined. Functional significance of altered P2X(3) receptors was investigated by measuring influx upon alpha,beta meATP stimulation in acutely dissociated DRG neurons. Moreover, A-317491, an antagonist of P2X(3) receptors, was administrated intrathecally or locally to evaluate its analgesia effect in the cancer pain animals. RESULTS: The P2X(3) receptor was up-regulated for about 50% in DRG neurons in rats with bone cancer at both protein and mRNA levels and correlated with the pain behaviour in bone cancer rats. A 51.9% increase of alpha,beta-me ATP (10 MUM, for 4 s) evoked transient response currents and a higher percentage of neurons responsive to the application of alpha,beta-me ATP was detected in bone cancer rats. Intrathecal or local injection of A-317491 significantly attenuated pain behaviour induced by bone cancer. CONCLUSIONS: These results suggest that the P2X(3) receptor is functionally up-regulated in DRG in cancer rats. P2X(3) receptor is a promising target for therapeutic intervention in cancer patients for pain management. PMID- 22528606 TI - Innovative models for investigation of pathomechanisms leading to late diabetic complications. PMID- 22528608 TI - The role of orientation processing in the scintillating grid illusion. AB - In the scintillating grid illusion, illusory dark spots are perceived on white patches at the intersections of gray bars. Previous studies have suggested that processing related to the orientation of the bars plays a role in this illusion, but the specific underlying mechanisms are unclear. In the present study, we investigated the role of orientation processing across the intersection in generating the scintillating grid illusion. The results revealed that the illusion was attenuated when the patch was located at the intersection of short bars (Experiment 1), irrespective of the spatial distance between patches (Experiment 2). The local cruciform patterns determined the strength of the illusion, even when lateral offset of the patches was employed (Experiment 3). The illusion was observed even when a small spatial gap was introduced around the patches. A larger gap produced a weaker illusion (Experiment 4). Spatial offsets of the bars across the gapped intersection greatly reduced the illusion (Experiment 5). We discuss these findings with regard to the activity of S1-type simple cells that respond to the luminance along an oriented edge across the intersection. PMID- 22528609 TI - Anticipation of visual form independent of knowing where the form will occur. AB - We investigated how selective preparation for specific forms is affected by concurrent preknowledge of location when upcoming visual stimuli are anticipated. In three experiments, participants performed a two-choice response time (RT) task in which they discriminated between standard upright and rotated alphanumeric characters while fixating a central fixation cross. In different conditions, we gave the participants preknowledge of only form, only location, both location and form, or neither location nor form. We found main effects of both preknowledge of form and preknowledge of location, with significantly lower RTs when preknowledge was present than when it was absent. Our main finding was that the two factors had additive effects on RTs. A strong interaction between the two factors, such that preknowledge of form had little or no effect without preknowledge of location, would have supported the hypothesis that form anticipation relies on depictive, perception-like activations in topographically organized parts of the visual cortex. The results provided no support for this hypothesis. On the other hand, by an additive-factors logic Sternberg (Sternberg, Acta Psychologica 30:276 315, 1969), the additivity of our effects suggested that preknowledge of form and location, respectively, affected two functionally independent, serial stages of processing. We suggest that the two stages were, first, direction of attention to the stimulus location and, subsequently, discrimination between upright and rotated stimuli. Presumably, preknowledge of location advanced the point in time at which attention was directed at the stimulus location, whereas preknowledge of form reduced the time subsequently taken for stimulus discrimination. PMID- 22528607 TI - The Tolz Temporal Topography Study: mapping the visual field across the life span. Part II: cognitive factors shaping visual field maps. AB - Part I described the topography of visual performance over the life span. Performance decline was explained only partly by deterioration of the optical apparatus. Part II therefore examines the influence of higher visual and cognitive functions. Visual field maps for 95 healthy observers of static perimetry, double-pulse resolution (DPR), reaction times, and contrast thresholds, were correlated with measures of visual attention (alertness, divided attention, spatial cueing), visual search, and the size of the attention focus. Correlations with the attentional variables were substantial, particularly for variables of temporal processing. DPR thresholds depended on the size of the attention focus. The extraction of cognitive variables from the correlations between topographical variables and participant age substantially reduced those correlations. There is a systematic top-down influence on the aging of visual functions, particularly of temporal variables, that largely explains performance decline and the change of the topography over the life span. PMID- 22528612 TI - Increased spatial salience in the social Simon task: a response-coding account of spatial compatibility effects. AB - A spatial compatibility effect (SCE) is typically observed in forced two-choice tasks in which a spatially defined response (e.g., pressing a left vs. a right key) has to be executed to a nonspatial feature of a stimulus (e.g., discriminating red from green) that is additionally connoted by a spatial feature (e.g., the stimulus points to the left or the right). Responses are faster and more accurate when the response side and the spatial stimulus feature are compatible than when they are incompatible. Previous research has demonstrated that SCEs are diminished when stimuli from only one response category are responded to in individual go/no-go tasks, whereas SCEs reemerge when two participants work jointly on two complementary, individual go/no-go tasks in a joint go/no-go task setting. This social Simon effect has been considered evidence for shared task representations. We show that SCEs emerge in individual go/no-go tasks when the spatial dimension is made more salient, whereas SCEs are eliminated in joint go/no-go tasks when the spatial dimension is made less salient. These findings are consistent with an account of social Simon effects in terms of spatial response coding, whereas they are inconsistent with an account of shared task representations. The relevance of social factors for spatial response coding is discussed. PMID- 22528611 TI - Primes and flankers: source confusions and discounting. AB - Visual identification of briefly presented target words is affected by the presence of nondiagnostic prime words that immediately precede the target, flanker words simultaneously presented adjacent to the target, and visual masks that immediately follow the target in the same location. Priming is duration dependent: In a forced choice target identification task, brief primes produce a strong preference to choose the primed alternative, whereas long primes have the opposite effect. The ROUSE model (Huber, Shiffrin, Lyle, & Ruys, Psychological Review 108:149-182, 2001) predicts this interaction by positing that prime features are confused with target features and that evidence regarding the prime features is discounted less for short primes and more for long primes, when both are compared with the optimal level. In the present study, we augmented the typical short-term priming experiment by adding flankers that appeared simultaneously with the target and remained for a short or long duration. In the experiment, we replicated previous priming effects and produced novel effects of flanker duration. ROUSE accounted for both the priming and flanker findings with the previously posited processes, but with different quantitative parameters for flankers: Relative to optimal levels of discounting, all flanker features were underdiscounted, but longer flankers were discounted more than short flankers. PMID- 22528613 TI - Local form-motion interactions influence global form perception. AB - Object motion perception depends on the integration of form and motion information into a unified neural representation. Historically, form and motion perception are thought to be independent processes; however, research has demonstrated that these processes interact in numerous and complex ways. For example, an object's orientation relative to its direction of motion will influence its perceived speed (Georges, Series, Fregnac, & Lorenceau, Vision Research 42:2757-2772, 2002). Here, we investigated whether this local form motion interaction influences global form processing. In Experiment 1, we replicated the effect of orientation-dependent modulation of speed. In Experiment 2, we investigated whether the perceived speed of local elements could influence the perceived shape of a global object constructed from grouping of those elements. The results indicated that the orientation of local elements indeed influenced the perceived shape of a global object. We propose that inputs from local form-motion processes are one of perhaps many neural mechanisms underlying global form integration. PMID- 22528614 TI - ERKALE-A flexible program package for X-ray properties of atoms and molecules. AB - ERKALE is a novel software program for computing X-ray properties, such as ground state electron momentum densities, Compton profiles, and core and valence electron excitation spectra of atoms and molecules. The program operates at Hartree-Fock or density-functional level of theory and supports Gaussian basis sets of arbitrary angular momentum and a wide variety of exchange-correlation functionals. ERKALE includes modern convergence accelerators such as Broyden and ADIIS and it is suitable for general use, as calculations with thousands of basis functions can routinely be performed on desktop computers. Furthermore, ERKALE is written in an object oriented manner, making the code easy to understand and to extend to new properties while being ideal also for teaching purposes. PMID- 22528616 TI - Abstracts from the 35th Annual Meeting of the Society of General Internal Medicine. May 9-12, 2012. Orlando, Florida, USA. PMID- 22528615 TI - A new taxonomy for stakeholder engagement in patient-centered outcomes research. AB - Despite widespread agreement that stakeholder engagement is needed in patient centered outcomes research (PCOR), no taxonomy exists to guide researchers and policy makers on how to address this need. We followed an iterative process, including several stages of stakeholder review, to address three questions: (1) Who are the stakeholders in PCOR? (2) What roles and responsibilities can stakeholders have in PCOR? (3) How can researchers start engaging stakeholders? We introduce a flexible taxonomy called the 7Ps of Stakeholder Engagement and Six Stages of Research for identifying stakeholders and developing engagement strategies across the full spectrum of research activities. The path toward engagement will not be uniform across every research program, but this taxonomy offers a common starting point and a flexible approach. PMID- 22528618 TI - Professional language interpretation and inpatient length of stay and readmission rates. AB - BACKGROUND: The population of persons seeking medical care is linguistically diverse in the United States. Language barriers can adversely affect a patient's ability to explain their symptoms. Among hospitalized patients, these barriers may lead to higher readmission rates and longer hospitalizations. Trained interpreters help overcome communication barriers; however, interpreter usage among patients is suboptimal. OBJECTIVE: To investigate differences among patients with limited English proficiency (LEP) in their length of stay (LOS) and 30-day readmission rate associated with their receiving professional interpretation at admission or discharge. DESIGN: We analyzed the rates of interpretation at admission and discharge of all LEP patients admitted to a tertiary care hospital over a three-year period. We calculated length of stay in days and as log of LOS. We also examined 30-day readmission. Using multivariable regression models, we explored differences among patients who received interpretation at admission, discharge, or both, controlling for patient characteristics, including age, illness severity, language, and gender. PARTICIPANTS: All LEP patients admitted between May 1, 2004 and April 30, 2007. MAIN MEASURES: Length of hospital stay as related to use of professional interpreters; readmission to the hospital within 30 days. KEY RESULTS: Of the 3071 patients included in the study, 39 % received language interpretation on both admission and discharge date. Patients who did not receive professional interpretation at admission or both admission/discharge had an increase in their LOS of between 0.75 and 1.47 days, compared to patients who had an interpreter on both day of admission and discharge (P<0.02). Patients receiving interpretation at admission and/or discharge were less likely than patients receiving no interpretation to be readmitted with 30 days. CONCLUSIONS: The length of a hospital stay for LEP patients was significantly longer when professional interpreters were not used at admission or both admission/discharge. PMID- 22528617 TI - Transferred and delayed care of patients with colorectal cancer in a safety-net hospital system--manifestations of a distressed healthcare system. AB - BACKGROUND: Safety-net hospital systems provide care to a large proportion of United States' under- and uninsured population. We have witnessed delayed colorectal cancer (CRC) care in this population and sought to identify demographic and systemic differences in these patients compared to those in an insured health-care system. DESIGN, PATIENTS, AND APPROACH/MEASUREMENTS: We collected demographic, socioeconomic, and clinical data from 2005-2007 on all patients with CRC seen at Parkland Health and Hospital System (PHHS), a safety net health system and at Presbyterian Hospital Dallas System (Presbyterian), a community health system, and compared characteristics among the two health-care systems. Variables associated with advanced stage were identified with multivariate logistic regression analysis and odds ratios were calculated. RESULTS: Three hundred and eighteen patients at PHHS and 397 patients at Presbyterian with CRC were identified. An overwhelming majority (75 %) of patients seen at the safety-net were diagnosed after being seen in the emergency department or at an outside facility. These patients had a higher percentage of stage 4 disease compared to the community. Patients within the safety-net with Medicare/private insurance had lower rates of advanced disease than uninsured patients (25 % vs. 68 %, p < 0.001). Insurance status and physician encounter resulting in diagnosis were independent predictors of disease stage at diagnosis. CONCLUSIONS: A large proportion of patients seen in the safety-net health system were transferred from outside systems after diagnosis, thus leading to delayed care. This delay in care drove advanced stage at diagnosis. The data point to a pervasive and systematic issue in patients with CRC and have fundamental health policy implications for population-based CRC screening. PMID- 22528619 TI - Association between race, depression, and antiretroviral therapy adherence in a low-income population with HIV infection. AB - BACKGROUND: Racial disparities exist in many aspects of HIV/AIDS. Comorbid depression adds to the complexity of disease management. However, prior research does not clearly show an association between race and antiretroviral therapy (ART) adherence, or depression and adherence. It is also not known whether the co existence of depression modifies any racial differences that may exist. OBJECTIVE: To examine racial differences in ART adherence and whether the presence of comorbid depression moderates these differences among Medicaid enrolled HIV-infected patients. DESIGN: Retrospective cohort study. SETTING: Multi-state Medicaid database (Thomson Reuters MarketScan(r)). PARTICIPANTS: Data for 7,034 HIV-infected patients with at least two months of antiretroviral drug claims between 2003 and 2007 were assessed. MAIN MEASURES: Antiretroviral therapy adherence (90 % days covered) were measured for a 12-month period. The main independent variables of interest were race and depression. Other covariates included patient variables, clinical variables (comorbidity and disease severity), and therapy-related variables. KEY RESULTS: In this study sample, over 66 % of patients were of black race, and almost 50 % experienced depression during the study period. A significantly higher portion of non-black patients were able to achieve optimal adherence (>=90 %) compared to black patients (38.6 % vs. 28.7 %, p < 0.001). In fact, black patients had nearly 30 % decreased odds of being optimally adherent to antiretroviral drugs compared to non-black patients (OR = 0.70, 95 % CI: 0.63-0.78), and was unchanged regard less of whether the patient had depression. Antidepressant treatment nearly doubled the odds of optimal ART adherence among patients with depression (OR = 1.92, 95 % CI: 1.12-3.29). CONCLUSIONS: Black race was significantly associated with worse ART adherence, which was not modified by the presence of depression. Under-diagnosis and under-treatment of depression may hinder ART adherence among HIV-infected patients of all races. PMID- 22528620 TI - Readability of patient education materials available at the point of care. AB - BACKGROUND: Many patient education materials (PEMs) available on the internet are written at high school or college reading levels, rendering them inaccessible to the average US resident, who reads at or below an 8(th) grade level. Currently, electronic health record (EHR) providers partner with companies that produce PEMs, allowing clinicians to access PEMs at the point of care. OBJECTIVE: To assess the readability of PEMs provided by a popular EHR vendor as well as the National Library of Medicine (NLM). DESIGN: We included PEMs from Micromedex, EBSCO, and MedlinePlus. Micromedex and EBSCO supply PEMs to Meditech, a popular EHR supplier in the US. MedlinePlus supplies the NLM. These PEM databases have high market penetration and accessibility. MEASUREMENTS: Grade reading level of the PEMs was calculated using three validated indices: Simple Measure of Gobbledygook (SMOG), Gunning Fog (GFI), and Flesch-Kincaid (FKI). The percentage of documents above target readability and average readability scores from each database were calculated. RESULTS: We randomly sampled 100 disease-matched PEMs from three databases (n = 300 PEMs). Depending on the readability index used, 30 100% of PEMs were written above the 8(th) grade level. The average reading level for MedlinePlus, EBSCO, and Micromedex PEMs was 10.2 (1.9), 9.7 (1.3), and 8.6 (0.9), respectively (p <= 0.000) as estimated by the GFI. Estimates of readability using SMOG and FKI were similar. CONCLUSIONS: The majority of PEMS available through the NLM and a popular EHR were written at reading levels considerably higher than that of the average US adult. PMID- 22528621 TI - Factors associated with non-compliance during 16-hour long call shifts. AB - BACKGROUND: Duty hour restrictions limit shift length to 16 hours during the 1(st) post-graduate year. Although many programs utilize a 16-hour "long call" admitting shift on inpatient services, compliance with the 16-hour shift length and factors responsible for extended shifts have not been well examined. OBJECTIVE: To identify the incidence of and operational factors associated with extended long call shifts and residents' perceptions of the safety and educational value of the 16-hour long call shift in a large internal medicine residency program. DESIGN, PARTICIPANTS, AND MAIN MEASURES: Between August and December of 2010, residents were sent an electronic survey immediately following 16-hour long call shifts, assessing departure time and shift characteristics. We used logistic regression to identify independent predictors of extended shifts. In mid-December, all residents received a second survey to assess perceptions of the long call admitting model. KEY RESULTS: Two-hundred and thirty surveys were completed (95 %). Overall, 92 of 230 (40 %) shifts included >= 1 team member exceeding the 16-hour limit. Factors independently associated with extended shifts per 3-member team were 3-4 patients (adjusted OR 5.2, 95 % CI 1.9-14.3) and>4 patients (OR 10.6, 95 % CI 3.3-34.6) admitted within 6 hours of scheduled departure and>6 total admissions (adjusted OR 2.9, 95 % CI 1.05-8.3). Seventy nine of 96 (82 %) residents completed the perceptions survey. Residents believed, on average, teams could admit 4.5 patients after 5 pm and 7 patients during long call shifts to ensure compliance. Regarding the long call shift, 73 % agreed it allows for safe patient care, 60 % disagreed/were neutral about working too many hours, and 53 % rated the educational value in the top 33 % of a 9-point scale. CONCLUSIONS: Compliance with the 16-hour long call shift is sensitive to total workload and workload timing factors. Knowledge of such factors should guide systems redesign aimed at achieving compliance while ensuring patient care and educational opportunities. PMID- 22528622 TI - Palliative care and rehabilitation for stroke survivors: managing symptoms and burden, maximizing function. PMID- 22528623 TI - Dermatologic manifestations as indicators of immune status in HIV/AIDS. PMID- 22528624 TI - Low-frequency pulsed ultrasound in the nasal cavity and paranasal sinuses: a feasibility and distribution study. AB - BACKGROUND: Bacterial biofilms have been implicated in refractory rhinosinusitis. Biofilms have been shown to respond to treatment with low-frequency ultrasound (LFU) therapy in vitro, and exposure to LFU has shown efficacy in wound repair and topical drug delivery in other fields. This preliminary study was designed to evaluate the safety and feasibility of LFU for use in the nasal cavity and paranasal sinuses. METHODS: This was an experimental observational study. Six cadaver heads were used to deliver a mixture of Renografin and methylene blue solvent to the paranasal sinuses via LFU both before and after resident endoscopic sinus dissection. Sinus computed tomography (CT) scans of the cadaver heads were performed before and after mixture delivery, and blinded assessments were made for distribution to individual sinuses. Mucosa was harvested from 2 subsites to evaluate LFU-treated cadaver tissue. RESULTS: Predissection, LFU delivered solution to 12 of 12 inferior and middle turbinates, 6 of 12 of the superior turbinates and ethmoid sinuses, and 1 of 12 maxillary sinuses as shown by contrast radiography. Postdissection, all heads showed delivery to the maxillary and sphenoid sinuses, with 8 of 12 sinus cavities showing delivery to the ethmoid region, and 4 of 11 to the frontal recess. Using hematoxylin and eosin (H&E) staining of tissue frozen sections, harvested tissue demonstrated no architectural damage to the mucosal layer from LFU exposure. CONCLUSION: LFU appears to be capable of reliably delivering topical solution to the turbinates and ethmoid region preoperatively and to all sinuses, except the frontal, postoperatively. The nasal epithelium does not appear to be disrupted histologically from LFU at this time and distance. This data provides a foundation for a prospective human protocol studying the efficacy of this modality in the treatment of patients with chronic rhinosinusitis and biofilm formation. PMID- 22528625 TI - Dietary soy protein induces hepatic lipogenic enzyme gene expression while suppressing hepatosteatosis in obese female Zucker rats bearing DMBA-initiated mammary tumors. AB - Fatty liver is associated with obesity and breast cancer. We used an obese rat model of mammary cancer to examine whether hepatosteatosis is modifiable by diet and associated with altered expression of hepatic lipogenic enzyme genes, thyroid hormone system genes and cholesterol metabolism-related genes. Beginning at the age of 5 weeks, lean and obese female Zucker rats were fed high-isoflavone soy protein- or casein (control protein)-containing diets. Rats were euthanized at 200 days of age [corresponding to 147 days after administration of carcinogen to induce mammary tumors; (Hakkak et al. in, Oncol Lett 2:29-36, 2011)]. Obese rats had a greater degree of liver steatosis than lean rats. Obese casein-fed rats had marked steatosis with small foci of mononuclear infiltration, whereas obese soy protein-fed rats had a significantly lower steatosis index. Comparisons between lean and obese casein-fed rats showed that obesity was associated with significant reductions in hepatic mRNA abundance for Glucose 6-Phosphate Dehydrogenase (G6PD), 6-Phosphogluconate Dehydrogenase (6PGD), Thyroid Receptor Alpha 1 (TRalpha1), Thyroid Receptor Beta 1 (TRbeta1) and Iodothyronine Deiodinase 1 (DIO1). The soy protein diet was associated with increased expression of Fatty Acid Synthase (FASN), Malic Enzyme 1 (ME1), 6PGD, Sterol Regulatory Element Binding Protein-1c (SREBP-1c) and SREBP-2 genes in the livers of obese but not lean rats. Western blot analysis showed a significant induction of ME1 protein expression in the livers of obese, soy protein-fed rats, which paralleled the increased serum insulin level in this group. Long-term soy protein consumption can counter hepatic steatosis while coincidently promoting hepatic lipogenic gene expression, the latter likely a consequence of elevated serum insulin. We suggest that elevations in serum insulin, hepatic lipogenesis and cholesterol synthesis all contributed to the increased tumorigenesis previously observed for the obese, soy protein-fed rats. PMID- 22528626 TI - Lifestyle factors modify obesity risk linked to PPARG2 and FTO variants in an elderly population: a cross-sectional analysis in the SUN Project. AB - Genetic factors may interact with lifestyle factors to modify obesity risk. FTO and PPARG2 are relevant obesogenes. Our aim was to explore the effect of Pro12Ala (rs1801282) of PPARG2 and rs9939609 of FTO on obesity risk and to examine their interaction with lifestyle factors in an elderly population. Subjects (n = 978; aged 69 +/- 6) were recruited from the SUN (Seguimiento Universidad de Navarra) Project. DNA was obtained from saliva, and lifestyle and dietary data were collected by validated self-reported questionnaires. Genotyping was assessed by RT-PCR plus allele discrimination. Subjects carrying the Ala allele of PPARG2 gene had a significantly increased obesity risk compared to non-carrier (Pro12Pro) subjects (OR, 1.66; 95 % CI, 1.01-2.74; p = 0.045). Greater obesity risk was also found in inactive or high carbohydrate intake subjects with the Ala12 allele of PPARG2 gene. Interestingly, subjects carrying the Ala allele of the PPARG2 gene and with a high CHO (>246 g/day) intake had an increased obesity risk compared to Pro12Pro subjects (OR, 2.67; 95 % CI, 1.3-5.46; p = 0.007; p for [CHO * PPARG2] interaction = 0.046). Moreover, in subjects with a high CHO intake, the co-presence of the Ala allele of PPARG2 gene and one minor A allele (rs9939609) of FTO gene did increase obesity risk (OR, 3.26; 95 % CI, 1.19-8.89; p = 0.021) when compared to non-carrier (Pro12Pro/TT) subjects. In conclusion, it appears that lifestyle factors may act as effect modifiers for obesity risk linked to Ala12 allele of the PPARG2 gene and the minor A allele of FTO gene in an elderly population. PMID- 22528627 TI - Feeling inter- or intramolecular interactions with the polymer chain as probe: recent progress in SMFS studies on macromolecular interactions. AB - Single-molecule force spectroscopy (SMFS) opens new avenues for elucidating the structures and functions of large coiled molecules such as synthetic and biopolymers at the single-molecule level. In addition, some of the features in the force-extension curves (i.e. force spectra) are closely related to primary/secondary structures of the molecules being stretched. For example, the long force plateau in the DNA stretching curve is related to the double-helix structure. These features can be regarded as the force fingerprints of individual macromolecules. These force fingerprints can therefore be used as indicators/criteria of single-molecule manipulation during the measurement of some unknown intra- or intermolecular interactions. By comparing the force spectra of a single polymer chain before and after interaction with other molecules, the mode/strength of such molecular interactions can be derived. This Review focuses on recent advances in AFM-based SMFS studies on molecular interactions in both synthetic and biopolymer systems using a single macromolecular chain as probe, including interactions between nucleic acids and proteins, mechanochemistry of covalent bonds, conformation-regulated enzymatic reactions, adsorption and desorption of biopolymers on a flat surface or from the nanopore of a carbon nanotube, and polymer interactions in the condensed state. PMID- 22528628 TI - Effectiveness of videos improving cancer prevention knowledge in people with profound hearing loss. AB - Deaf persons have a poorer understanding of cancer prevention, which is felt to be partly due to communication barriers. One hundred ninety-seven d/Deaf persons completed a survey and video on cancer prevention. Half viewed a spoken English program designed for hearing persons (control group); the other half viewed an amended program that had American Sign Language, captions, and printed English options added (experimental group). Knowledge was measured before and after the video, including 1 and 6 months later. Respondents were primarily Caucasian, had low incomes, lost hearing at young ages, and had d/Deaf spouses. Although overall knowledge improved after viewing the video, the presence of culture-specific communications (American Sign Language, captions) did not improve scores compared to the control group, either immediately after the intervention or over time. Moreover, percentage correct on all pretest, and almost all post-test, questions was <50% for both experimental and control groups. For all subjects, regardless of which group they were in, a hearing spouse (p < 0.001) and more healthcare information sources (p = 0.001) improved knowledge, while African-Americans showed a trend to lesser improvement (p = 0.06). Using culture-specific language did not improve cancer prevention knowledge in this d/Deaf population, and overall knowledge remained low. More study is needed to determine the best way to increase cancer prevention knowledge in this population. PMID- 22528629 TI - The influence of distress on knowledge transfer for men newly diagnosed with prostate cancer. AB - The purpose of this inquiry was to evaluate the efficacy of prostate cancer education sessions. Implementation of 3-h patient educational sessions was intended to provide men newly diagnosed with localized prostate cancer, who face difficult and complex decisions, information about potential treatment options. Fifty-seven men completed the distress thermometer assessment before the education session to assess baseline levels of distress. Seven of the men were interviewed post-educational session to determine the degree of knowledge transfer from the session. This study explored the efficacy of the patients' learning experience using an interpretive phenomenological research approach. Resulting data revealed that these patients, as adult learners, were distressed and that, despite the availability of pertinent medical content, the subject material was not learned as intended or readily understood. The conclusion drawn from this preliminary applied educational research study was that the education model used was less than efficacious at ensuring that sufficient knowledge transfer was achieved for medical treatment decision-making processes. These findings suggest a need for future research to explore the application of adult learning theories and approaches that may offer enhanced knowledge translation and transfer for prostate cancer education programs. PMID- 22528630 TI - Knowledge of reproductive system cancers, their treatments and side effects. AB - We explored, via an online questionnaire, knowledge of breast and reproductive system cancers in patients and non-patients who access the internet for information on these diseases. We compared that knowledge to the attention the diseases have received in medical research and on the Internet. Data were collected from 690 respondents (37 % male, 63 % female) about their knowledge of prevalence, lethality, treatments and side effects of testicular, prostate, breast, uterine, cervical and ovarian cancers. Most males, but only half of the female participants, were patients themselves. Although participants showed better knowledge of cancers specific to their own sex, both sexes felt familiar with breast cancer and less aware of other cancers. Women were as aware as men of side effects of treatments for male reproductive cancers. Sex differences in awareness appear to reflect different attitudes towards illness, bias toward females as caregivers, and the disproportionate media attention given to breast cancer. PMID- 22528631 TI - An achievement of professional, public, and patient education: the design and evaluation of a comprehensive cancer control plan for Alabama. AB - This Alabama statewide cancer control plan for 2011-2015 seeks to build on the successes of two previous 5-year plans while developing new objectives that address cancer disparities and cancer prevention over the entire lifespan. The approach to defining objectives for this Plan was systematic and sought input from all members of the Alabama Comprehensive Cancer Control Coalition (ACCCC). The Plan that was fashioned is based on input from academic medical centers, private physicians, government agencies, regulatory agencies, health societies, private citizens, and cancer survivors, all of whom are active Coalition members who exchange information, opinions, and knowledge from their respective points of view. The Plan could not have taken shape without the full input of health professionals, statisticians, graduate students, former patients, and concerned citizens; it is truly an example of the synergy of professional, public, and patient education. PMID- 22528632 TI - Assessing awareness and use of evidence-based programs for cancer control in Puerto Rico. AB - The Community Cancer Control Outreach Program (CCCOP) is a community-academic partnership aimed at developing and implementing a cancer control outreach, research, and training program in Puerto Rico. The CCCOP surveyed 56 partners to assess their awareness, training needs, and use of resources related to evidence based programs (EBPs). Despite relatively high levels (70 %) of confidence in adopting EBPs, there were low levels of awareness (37 %) and use (25 %) of existing EBPs resources. Respondents' who had used EBPs resources were more likely to have positive beliefs about EBPs than nonusers (p<0.05). Training needs were high among respondents and no significant differences were found between those who had and had not used existing EBPs resources. These findings can guide the development of training tools and technical assistance to increase the use of EBPs for Latino audiences. PMID- 22528633 TI - Developing partnerships and recruiting dyads for a prostate cancer informed decision making program: lessons learned from a community-academic-clinical team. AB - Prostate cancer (PrCA) is the most commonly diagnosed non-skin cancer among men. PrCA mortality in African-American (AA) men in South Carolina is ~50% higher than for AAs in the U.S as a whole. AA men also have low rates of participation in cancer research. This paper describes partnership development and recruitment efforts of a Community-Academic-Clinical research team for a PrCA education intervention with AA men and women that was designed to address the discordance between high rates of PrCA mortality and limited participation in cancer research. Guided by Vesey's framework on recruitment and retention of minority groups in research, recruitment strategies were selected and implemented following multiple brainstorming sessions with partners having established community relationships. Based on findings from these sessions culturally appropriate strategies are recommended for recruiting AA men and women for PrCA education research. Community-based research recruitment challenges and lessons learned are presented. PMID- 22528634 TI - A competency-based approach to expanding the cancer care workforce part III- improving cancer pain and palliative care competency. AB - As part of an effort to address shortages in the cancer workforce, C-Change developed competency standards and logic model-driven implementation tools for strengthening the cancer knowledge and skills of non-oncology health professionals. These standards and tools were applied by four diverse grant programs to yield gains in the management of pain and palliative care, thereby improving the quality of care for individuals experiencing or recovering from cancer treatment. The results from the four grant sites and tools used to achieve them are described in this article. PMID- 22528635 TI - "The best care possible" by Ira Byock--a lesson for all of us in cancer education. PMID- 22528636 TI - Creating a cadre of junior investigators to address the challenges of cancer related health disparities: lessons learned from the community networks program. AB - Community-based participatory research (CBPR) initiatives such as the National Cancer Institute's Community Networks Program (CNP) (2005-2010) often emphasize training of junior investigators from underrepresented backgrounds to address health disparities. From July to October 2010, a convenience sample of 80 participants from the 25 CNP national sites completed our 45-item, web-based survey on the training and mentoring of junior investigators. This study assessed the academic productivity and CBPR-related experiences of the CNP junior investigators (n=37). Those from underrepresented backgrounds reported giving more presentations in non-academic settings (nine vs. four in the last 5 years, p=0.01), having more co-authored publications (eight vs. three in the last 5 years, p=0.01), and spending more time on CBPR-related activities than their non underrepresented counterparts. Regardless of background, junior investigators shared similar levels of satisfaction with their mentors and CBPR experiences. This study provides support for the success of the CNP's training program, especially effort directed at underrepresented investigators. PMID- 22528637 TI - An ET-CURE pilot project supporting undergraduate training in cancer research, emerging technology, and health disparities. AB - The National Cancer Institute's Center to Reduce Cancer Health Disparities has created pilot training opportunities under the "Continuing Umbrella of Research Experiences" program that focus on emerging technologies. In this pilot project, an 18-month cancer biology research internship was reinforced with: instruction in an emerging technology (proteomics), a transition from the undergraduate laboratory to a research setting, education in cancer health disparities, and community outreach activities. A major goal was to provide underrepresented undergraduates with hands-on research experiences that are rarely encountered at the undergraduate level, including mentoring, research presentations, and participation in local and national meetings. These opportunities provided education and career development for the undergraduates, and they have given each student the opportunity to transition from learning to sharing their knowledge and from being mentored to mentoring others. Here, we present the concepts, curriculum, infrastructure, and challenges for this training program along with evaluations by both the students and their mentors. PMID- 22528638 TI - Gastroenterologists' perceived barriers to optimal pre-colonoscopy bowel preparation: results of a national survey. AB - Poor quality bowel preparation has been reported in almost one third of all colonoscopies. To better understand factors associated with poor bowel preparation, we explored perceived patient barriers to optimal pre-colonoscopy bowel preparation from the perspective of the gastroenterologist. A random sample of physician members of the American College of Gastroenterology was surveyed via the internet and postal mailing. Demographic and practice characteristics and practice-related and perceived patient barriers to optimal bowel preparation were assessed among 288 respondents. Lack of time, no patient education reimbursement, and volume of information were not associated with physician level of suboptimal bowel preparation. Those reporting >= 10 % suboptimal bowel preparations were more likely to believe patients lack understanding of the importance of following instructions, have problems with diet, and experience trouble tolerating the purgative. Bowel preparation instruction communication and unmet patient educational needs contribute to suboptimal bowel preparation. Educational interventions should address both practice and patient-related factors. PMID- 22528639 TI - Molecular characterization and phylogenetic analysis of porcine epidemic diarrhea virus (PEDV) field strains in south China. AB - A total of 127 porcine samples were collected from 48 farms in six provinces in south China. The positive rate of porcine epidemic diarrhea virus (PEDV) was 43.0 % (55/127), and the co-infection rate of PEDV and transmissible gastroenteritis virus (TGEV) was 12.0 % (15/127). The partial S gene and complete M gene were amplified from PEDV-positive strains by RT-PCR, cloned, sequenced and compared with each other, as well as with the reference strains in GenBank. Sequence homology results of the partial S gene and complete M gene showed that all south China field PEDV strains had nucleotide (deduced amino acid) sequence identities of 86.7-98.7 % (83.2-99.3 %) and 96.1-100 % (95.0-100%), respectively, with the foreign reference strains reported in GenBank. Phylogenetic analysis of the partial S gene showed that all the south China PEDV strains and two Thailand strains (08UB01 and 08RB07) belong to the same group and differ genetically from European strains and early domestic strains. Phylogenetic analysis of the complete M gene showed that all south China PEDV strains have a close relationship with most of the strains in Korea and Thailand, but differ genetically from the vaccine strain (CV777). PMID- 22528640 TI - Phylogenetic analysis of partial RNA-polymerase blocks II and III of Rabies virus isolated from the main rabies reservoirs in Brazil. AB - This study describes the results of the sequencing and analysis of segments of Blocks II and III of the RNA polymerase L gene of Rabies virus isolates from different reservoir species of Brazil. The phylogenetic relations of the virus were determined and a variety of species-specific nucleotides were found in the analyzed areas, but the majority of these mutations were found to be synonymous. However, an analysis of the putative amino acid sequences were shown to have some characteristic mutations between some reservoir species of Brazil, indicating that there was positive selection in the RNA polymerase L gene of Rabies virus. On comparing the putative viral sequences obtained from the Brazilian isolates and other Lyssavirus, it was determined that amino acid mutations occurred in low restriction areas. This study of the L gene of Rabies virus is the first to be conducted with samples of virus isolates from Brazil, and the results obtained will help in the determination of the phylogenetic relations of the virus. PMID- 22528641 TI - Prion protein gene polymorphism and genetic risk evaluation for scrapie in all Turkish native sheep breeds. AB - The aim of this study was to identify the prion protein (PrP) gene polymorphism in a total of 1,110 healthy sheep from 18 Turkish native sheep breeds. There were nine alleles and 22 genotypes observed based on codons 136, 154, and 171 of the PrP gene. The ARQ allele was predominant for all breeds. The most resistant allele to scrapie, ARR, was present in all breeds. The VRQ allele, associated with the highest susceptibility to scrapie, was detected at low frequencies in Ivesi (0.06), Kivircik (0.021), Sakiz (0.010), Karayaka (0.011), Cine Capari (0.012), and Guneykaraman (0.017). In general, the ARQ/ARQ genotype was predominant in all breeds. The most resistant genotype to scrapie, ARR/ARR, was found with the frequency lower than 0.180. The most susceptible genotype, VRQ/VRQ, was found in only Kivircik. The TRR and TRH alleles and the genotypes of ARR/TRR, ARR/ARK, and ARH/TRH have been found for the first time in Turkish native sheep breeds. According to these results, all breeds belong to risk group R3 followed by R2. It is propounded that the susceptibility to scrapie increased from eastern to western part of Turkey. Our findings of Turkish native sheep breeds with PrP gene polymorphisms will assist the sheep breeding program for selection of scrapie resistance genotypes to reduce the risk of scrapie. PMID- 22528642 TI - Kobuvirus in South Korean black goats. AB - Kobuviruses have been detected in humans and several animal species, including cattle, swine, sheep, canines, mice, and probably bats. While investigating the possibility of Kobuviruses infecting additional animal host species, we detected kobuvirus in three fecal samples from domestic Korean black goats. In a maximum parsimony tree and a Bayesian tree, the 08KG680 strain fell within the bovine kobuvirus lineage, but the 09KG172 and 10KG056 strains did not fall within any of the known animal kobuvirus lineages. Comparative analysis of the partial nucleotide sequences of the RNA-dependent RNA polymerase (RdRp) gene of the 08KG680 strain also revealed high amino acid sequence identity and a close genetic relationship with bovine kobuvirus, but the amino acid sequences of the other two strains had low similarity to those of known kobuvirus isolates from any animal species. The similarity of the sequence of the 08KG680 strains with the bovine kobuvirus indicate that the infectious may have originated from cattle, but the possible source for remaining strains could not be classified. PMID- 22528643 TI - No evidence for translation of pog, a predicted overlapping gene of Solenopsis invicta virus 1. AB - An overlapping open reading frame (ORF) with a potential to encode a functional protein has been identified within the 3'-proximal ORF of Solenopsis invicta virus 1 (SINV-1) and three bee viruses. This ORF has been referred to as predicted overlapping gene (pog). Protein motif searches of POG revealed weak relationships precluding assignment of a potential function. Neither a transcript nor a protein encoded by the pog ORF has been detected. However, recently, a protein encoded by the corresponding +1 overlapping ORF (termed ORFx) in the Israeli acute paralysis virus (IAPV) was demonstrated by recombinant means as well as in IAPV-infected honey bees. The objective of our study was to attempt to provide empirical evidence for the presence of a pog-derived protein from SINV-1 infected fire ants. A number of different laboratory and field SINV-1-infected Solenopsis invicta preparations were examined by western blotting for the presence of a POG protein sequence. In every case, these preparations failed to yield any detectable bands when probed with a polyclonal antibody preparation raised to a portion of the pog predicted protein sequence. Although impossible to prove a negative result, proper controls used in these studies suggested that the pog ORF is not translated into a functional protein in SINV-1. PMID- 22528644 TI - A distinct tymovirus infecting Cassia hoffmannseggii in Brazil. AB - Leaves of Cassia hoffmannseggii, a wild fabaceous species found in the Atlantic Forest, with a severe mosaic symptom were collected in Pernambuco State, Brazil. By transmission electron microscopy, two types of virus particles were found: the first was recognized as particles of a potyvirus, which was later identified as Cowpea aphid-borne mosaic virus; and the second was isometric and present in high concentration. The observation of vesicles at the periphery of chloroplasts suggested a tymovirus infection, which was confirmed by subsequent assays. A serological assay against several tymovirus antisera resulted in positive reaction of this tymo-like virus with an antiserum of Passion fruit yellow mosaic virus. By means of RT-PCR and using degenerated primers for the conserved region of RNA-dependent RNA polymerase (RdRp) gene of tymoviruses, a specific DNA fragment was amplified and sequenced. Based on this sequence, a specific forward primer was synthesized and successfully used to amplify the 3' terminal genome region, containing the partial RdRp gene and the complete coat protein (CP) sequences. The CP was 188 amino acids (aa) long, and the highest CP aa identity was observed with Kennedya yellow mosaic virus (61 %). Based on the current ICTV demarcation criterion, this isolate was considered as a distinct tymovirus and tentatively named as Cassia yellow mosaic-associated virus. PMID- 22528645 TI - Evaluation of bacterial diversity in Palk Bay sediments using terminal restriction fragment length polymorphisms (T-RFLP). AB - Although it is known that Palk Bay sediments harbor diverse and novel bacteria with important ecological and environmental functions, a comprehensive view of their molecular diversity is still lacking. In the present study, bacterial diversity in Palk Bay sediments was characterized using the molecular method terminal-restriction fragment length polymorphisms (T-RFLP). The bacterial assemblages detected by T-RFLP analysis revealed that the nearshore sediment harbored high number of bacterial count, whereas the 2.5-m sediment harbored diverse and distinct bacterial composition with fine heterogeneity. The major bacterial groups detected in all the three sediment samples were Actinobacteria, Bacteroidetes, Firmicutes, Proteobacteria (including alpha (alpha), gamma (gamma), delta (delta), and epsilon (epsilon)-Proteobacteria), and uncultured bacteria. This is the first study that reveals the presence of Bacteroidetes, delta (delta)- and epsilon (epsilon)-Proteobacteria, and uncultured bacteria in Palk Bay sediments. The hitherto unexplored wide microbial diversity of Palk Bay coastal area was unraveled in the current study through culture-independent approach. These data suggest that the continued use of cultivation-independent techniques will undoubtedly lead to the discovery of additional bacterial diversity and provide a direct means to learn more about the ecophysiology and biotechnological potential of Palk Bay coastal area. PMID- 22528646 TI - Sago pith residue as an alternative cheap substrate for fermentable sugars production. AB - Sago pith residue is one of the most abundant lignocellulosic biomass which can serve as an alternative cheap substrate for fermentable sugars production. This residue is the fibrous waste left behind after the starch extraction process and contains significant amounts of starch (58%), cellulose (23%), hemicellulose (9.2%) and lignin (3.9%). The conversion of sago pith residue into fermentable sugars is commonly performed using cellulolytic enzymes or known as cellulases. In this study, crude cellulases were produced by two local isolates, Trichoderma asperellum UPM1 and Aspergillus fumigatus, UPM2 using sago pith residue as substrate. A. fumigatus UPM2 gave the highest FPase, CMCase and beta-glucosidase activities of 0.39, 23.99 and 0.78 U/ml, respectively, on day 5. The highest activity of FPase, CMCase and beta-glucosidase by T. asperellum UPM1 was 0.27, 12.03 and 0.42 U/ml, respectively, on day 7. The crude enzyme obtained from A. fumigatus UPM2 using beta-glucosidase as the rate-limiting enzyme (3.9, 11.7 and 23.4 IU) was used for the saccharification process to convert 5% (w/v) sago pith residue into reducing sugars. Hydrolysis of sago pith residue using crude enzyme containing beta-glucosidase with 23.4 IU, produced by A. fumigatus UPM2 gave higher reducing sugars production of 20.77 g/l with overall hydrolysis percentage of 73%. PMID- 22528647 TI - Kinetic modeling of fructooligosaccharide production using Aspergillus oryzae N74. AB - In this study, the kinetic for the bioconversion of sucrose to fructooligosaccharides (FOS) by free cells of Aspergillus oryzae N74 was modeled. In addition, the effect of immobilized glucose isomerase (IGI) on FOS production yield was evaluated and considered in the kinetic model. The selected kinetic models were based on a proposed reaction mechanism described by elementary rate equations and modified Michaelis-Menten kinetic equations. The use of IGI allowed to increase the FOS production yield (FOS(Yield)) and to decrease the glucose/fructose (G/F) ratio. At shake flask scale, the FOS(Yield) was increased in 4.7 % (final yield 58.3 %), while the G/F ratio was reduced 6.2-fold. At bench scale, the FOS(Yield) was increased in 2.2 % (final yield 57.3 %), while the G/F ratio was reduced 4.5-fold. The elementary rate equation model was the one that best adjusted experimental data for FOS production using either the fungus biomass or the mixture fungus biomass-IGI, with an overall average percentage error of 7.2. Despite that FOS production yield was not highly improved by the presence of IGI in the reaction mixture, it favored the reduction of residual glucose in the mixture, avoiding the loss of material owe to glucose transformation to fructose that can be used in situ for FOS production by the fructosyltransferase. PMID- 22528648 TI - Brugia malayi thioredoxin peroxidase as a potential vaccine candidate antigen for lymphatic filariasis. AB - Attempts were made to evaluate the protective efficacy of Brugia malayi thioredoxin peroxidase (BmTPX) in a mouse model. Mice immunized with a protein vaccine containing rBmTPX developed higher titres (1:5,000/1:10,000) of anti BmTPX antibodies, compared with the mice immunized with the alum control. There was a higher level of cellular proliferative response in mice immunized with BmTPX compared with the alum control (p < 0.05), which was associated with a Th2 type of response. In order to compare the prophylactic efficacy of BmTPX in natural infection, we evaluated the human immune responses to these antigens in endemic normals (EN) and infected individuals (microfilaraemic and chronic pathology). Results showed that EN subjects carry BmTPX-specific IgG1 and IgG3 circulating antibodies against natural exposure to filariasis. Peripheral blood mononuclear cells from EN subjects responded strongly to rBmTPX by proliferating, as well as by secreting interferon (IFN)-gamma (Th1) and IL-5 (Th2), a mixed type of response to rBmTPX. In the case of infected individuals, there was no IFN gamma or IL-5 response. Thus, there was a clear dichotomy in the cytokine production by infected versus EN individuals. Our findings suggest that BmTPX may be a suitable antigen candidate for lymphatic filariasis, but a further study is still required. PMID- 22528649 TI - A novel bioassay for high-throughput screening microorganisms with N-acyl homoserine lactone degrading activity. AB - A novel biosensor strain (Escherichia coli ALM403) that responded to N-acyl homoserine lactone (AHL) was constructed using a luxR-Plux cassette as a regulatory sequence and beta-mannanase as a reporter gene. Dinitrosalicylic acid method was used to detect the response of the sensor strain to N-acyl homoserine lactone. By investigating the response to a range of concentrations of N-beta oxooctanoyl-L-homoserine lactone (OOHL), it was demonstrated that the expression of mannanase in E. coli ALM403 could be greatly enhanced by OOHL and resulted in an assayable phenotype. A high-throughput screening approach was developed to isolate AHL-degrading microorganisms, and a marine Halomonas sp. S66-4 showing a marked AHL-degrading ability was successfully isolated. In conclusion, the bioassay system provided a simple and efficient approach to isolate AHL-degrading bacteria. PMID- 22528650 TI - Improvement of adenosylcobalamin production by metabolic control strategy in Propionibacterium freudenreichii. AB - An efficient metabolic control approach was developed to improve the industrial anaerobic fermentation of adenosylcobalamin (ado-cbl) by Propionibacterium freudenreichii. The effects of 5,6-dimethylbenzimidazole (DMB) on cell growth and ado-cbl biosynthesis were investigated. Subsequently, the results obtained from the batch culture showed that an important intermediate of ado-cbl separated from the cell extract was identified as adenosylcobinamide (ado-cbi) by high performance liquid chromatography coupled to an ultraviolet diode array detector and ESI mass spectrometry analysis. Ado-cbi can be converted to ado-cbl when linked to DMB, which is an essential compound for ado-cbi bioconversion. This key ado-cbi is useful not only in determining ado-cbl concentration in the fermentation process but also in serving as an effective compound to guide DMB incorporation for the harvest of the maximum ado-cbl concentration. Accordingly, with scaling up to 100 L fermentation, the experimental results showed that the discrepancy was less than 1 % using the developed prediction technique. Overall, the findings show that the method is efficient in evaluating the fermentation of ado-cbl by propionibacteria. PMID- 22528651 TI - The assessment of phytoremediation potential of invasive weed Amaranthus spinosus L. AB - Presently the environment is heavily polluted by various toxic metals, which creates danger for all living beings. Heavy metals are toxic above certain threshold levels. Phytoremediation is an emerging technology which is quite a novel technique of cleaning polluted sites through the use of plants. Phytoremediation methods are comparatively cheap and ecologically advantageous, compared to conventional and physicochemical methods like precipitation, evaporation and chemical reduction. In this respect, plants can be compared to solar-driven pumps capable of extracting and concentrating certain elements from their environment. Amaranthus spinosus, an invasive weed seen on road sides and bare land belonging to the family Amaranthaceae, was selected for the present study. A greenhouse experiment was conducted and consisted of a range-finding test and definitive test for various concentrations of heavy metals Cu, Zn, Cr, Pb and Cd. Plants were grown in soil treated with different concentration of metals depending upon the threshold level. The bio-organics of the plant such as soluble sugar, protein, lipid, phenol, amino acid and photosynthetic pigments were estimated after 30 days of treatment. The bio-organics showed profound variation in response to accumulation of heavy metals. Accumulation of Cu, Pb and Cd was high in the roots followed by stem and leaves and that of Zn and Cr remained high in aerial parts. A steady increase was noticed in the bioaccumulation of copper, zinc and cadmium on enhancing the concentration of the corresponding metal in the soil. The bioconcentration factor and translocation factor were above unity in most of the treatments and increased as the concentration of treatment increased which indicated that A. spinosus is a potential agent for heavy metal accumulation and translocation. PMID- 22528652 TI - One-component styrene monooxygenases: an evolutionary view on a rare class of flavoproteins. AB - Styrene monooxygenases (SMOs) are catalysts for the enantioselective epoxidation of terminal alkenes. Most representatives comprise a reductase and a monooxygenase which are encoded by separate genes (styA, styB). Only six presumed self-sufficient one-component SMOs (styA2B) have previously been submitted to databases, and one has so far been characterized. StyA2B can be supported by another epoxidase (StyA1) encoded by styA1, a gene in direct neighborhood of styA2B. The present report describes the identification of a further styA1/styA2B like SMO, which was detected in Rhodococcus opacus MR11. Based on the initially available sequences of styA2B-type SMOs, primers directed at conserved sequences were designed and a 7,012-bp genomic fragment from strain MR11 was obtained after PCRs and subsequent genome walking. Six open reading frames (ORFs) were detected and compared to genomic fragments of strains comprising either two- or one component SMOs. Among the proteins encoded by the ORFs, the monooxygenase StyA1/StyA2B showed the highest divergence on amino acid level when comparing proteins from different sources. That finding, a rare distribution of styA2B genes among bacteria, and the general observation of evolution from simple to complex systems indicate that one-component SMOs evolved from two-component ancestors. Analysis of gene products from styA/styB- and styA1/styA2B-like SMOs revealed that a fusion of styA/styB to styA2B might have happened at least twice among microorganisms. This points to a convergent evolution of one-component SMOs. PMID- 22528653 TI - Identification of cellulase gene from the metagenome of Equus burchelli fecal samples and functional characterization of a novel bifunctional cellulolytic enzyme. AB - The metagenomic approach has been used successfully to isolate novel biocatalyst gene from uncultured microorganisms. The gene encoding exo-1,4-beta-glucanase avicelase was amplified from the metagenome of the Equus burchelli fecal sample and cloned. The gene was found to be of 1,007 bp of nucleotide which encodes a protein of 318 amino acids with a calculated MW of 36 kDa. The deduced amino acid sequence was homologous with cellulases belonging to the glycosyl hydrolases 6 superfamily. The expressed protein was active towards the substrates avicel and carboxymethyl cellulose, indicating that it has bifunctional cellulolytic enzyme activity. The recombinant protein showed an activity of 5.23 U with specific activity of 6.8 U mg(-1) protein with the substrate avicel, while when CMC was used, an activity of 3.0 U with a specific activity of 4.2 U mg(-1) protein was achieved. Its optimum pH was determined to be 7.0 and optimum temperature of 35 degrees C. PMID- 22528654 TI - Extrusion pretreatment of pine wood chips. AB - Pretreatment is the first step to open up lignocellulose structure in the conversion of biomass to biofuels. Extrusion can be a viable pretreatment method due to its ability to simultaneously expose biomass to a range of disruptive conditions in a continuous flow process. Extruder screw speed, barrel temperature, and feedstock moisture content are important factors that can influence sugar recovery from biomass. Hence, the current study was undertaken to investigate the effects of these parameters on extrusion pretreatment of pine wood chips. Pine wood chip at 25, 35, and 45 % wb moisture content were pretreated at various barrel temperatures (100, 140, and 180 degrees C) and screw speeds (100, 150, and 200 rpm) using a screw with compression ratios of 3:1. The pretreated pine wood chips were subjected to standard enzymatic hydrolysis followed by sugar and byproducts quantification. Statistical analyses revealed the existence of significant differences in sugar recovery due to independent variables based on comparing the mean of main effects and interaction effects. Pine wood chips pretreated at a screw speed of 150 rpm and a barrel temperature of 180 degrees C with a moisture content of 25 % resulted in a maximum cellulose, hemicellulose, and total sugar recoveries of 65.8, 65.6, and 66.1 %, respectively, which was about 6.7, 7.9, and 6.8 fold higher than the control (unpretreated pine chips). Furthermore, potential fermentation inhibitors such as furfural, hydroxyl methyl furfural, and acetic acid were not found in any of the treatment combinations. PMID- 22528655 TI - Effect of microwave irradiation on xylanase production from wheat bran and biobleaching of eucalyptus kraft pulp. AB - Microwave irradiation (MWI) was used as pretreatment of wheat bran and eucalyptus kraft pulp to examine its effect on xylanase production by Bacillus halodurans FNP 135 using solid state fermentation and biobleaching with xylanase, respectively. Irradiation of wheat bran under optimized conditions (600 W, 6 min, and 20 % consistency) resulted in 56.8, and 31.7 % increase in xylanase yield and water absorbance of wheat bran and 17.3 % reduction in reducing sugars content. Optimized MWI of kraft pulp at 850 W, 2 min, and 20 % consistency led to 0.9 % increase in brightness, 10 % decrease in kappa number, 7.7 % increase in water absorbance, 4.6 % decrease in tear factor, 0.9 % increase in burst factor, and 7.5 % increase in viscosity. Also, MWI enhanced xylanase-mediated biobleaching by increasing brightness (1.1 %) and decreasing kappa number (14.3 %) and leading to a total of about 20 % reduction in chlorine consumption. MWI is an economical, efficient, and environment-friendly pretreatment of wheat bran and pulp for enhanced enzyme yield and rapid heating, respectively. PMID- 22528656 TI - Evaluation of enzyme activity and fiber content of soybean cotyledon fiber and distiller's dried grains with solubles by solid state fermentation. AB - To increase the value of coproducts from corn ethanol fermentation and soybean aqueous processing, distiller's dried grains with solubles (DDGS) and soybean cotyledon fiber were used as the substrates for solid state fermentation (SSF) to improve feed digestibility. Aspergillus oryzae, Trichoderma reesei, and Phanerochaete chrysosporium were chosen as they produce desirable enzymes and are widely used in SSF for feed. The results showed that the cellulase and xylanase activities were significantly increased after 7 days of fermentation, and cellulose and hemicellulose degradation was also greatly increased. When soybean fiber was used as SSF substrate, the maximum activities of the cellulase and xylanase were 10.3 and 84.2 IU/g substrate (dry weight basis) after SSF treatment, respectively. However, the enzyme activities were relatively low in DDGS, and the growth of the three fungi was poor. The fungi grew better when soybean cotyledon fiber was added to DDGS, and cellulase and xylanase activity increased with the increase of soybean fiber content. Porosity was identified as an important factor for SSF because the addition of inert soybean hull alone improved the fungi growth significantly. These data suggest that the nutritional value of DDGS and soybean cotyledon fiber as monogastric animal feed could be greatly enhanced by SSF treatment. PMID- 22528657 TI - Development and characterization of a solid-phase biocatalyst based on cyclodextrin glucantransferase reversibly immobilized onto thiolsulfinate agarose. AB - Reduction of disulfide bonds and introduction of "de novo" thiol groups in cyclodextrin glucantransferase from Thermoanaerobacter sp. were assessed in order to perform reversible covalent immobilization onto thiol-reactive supports (thiolsulfinate-agarose). Only the thiolation process dramatically improved the immobilization yield, from 0 % for the native and reduced enzyme, up to nearly 90 % for the thiolated enzyme. The mild conditions of the immobilization process (pH 6.8-7.0 and 22 degrees C) allowed the achievement of 100 % coupling efficiencies when low loads were applied. Ionic strength was a critical parameter for the immobilization process; for high activity recoveries, 50 mM phosphate buffer supplemented with 0.15 M NaCl was required. The kinetic parameters, pH and thermal stabilities for the immobilized biocatalyst were similar to those for the native enzyme. For beta-cyclization activity, optimal pH range and temperature were 4.0-5.4 and 85 degrees C. The possibility of reusing the support was demonstrated by the reversibility of enzyme-support binding. PMID- 22528659 TI - Can I help you? Physicians' expectations as predictor for treatment outcome. AB - BACKGROUND: Patients' expectations of acupuncture treatment have widely been investigated; however, little focus has been on the physicians' expectations. We aimed to investigate (1) which patient characteristics lead to different expectations of physicians, and (2) whether physicians' expectations predict pain reduction and physical functioning in acupuncture and usual care treatment for chronic pain. METHODS: In four large multi-centre, randomized trials patients with chronic pain were randomized to receive usual care alone or 10 additional acupuncture treatments. Data were pooled. Baseline characteristics of the three expectation groups were compared, and the physicians' expectation and its interaction with the treatment group were included in two linear regression models predicting pain reduction and change in physical functioning. Other patient characteristics were included for adjustment. RESULTS: 9900 patients treated by 2781 physicians were analysed. Age, education and disease-related variables differed in the expectation groups. There was no interaction between treatment group and expectation. Patients, for whom the physicians had expected substantial improvement, showed more pain reduction (p < 0.001) and better physical functioning (p < 0.001) than patients for whom moderate improvement was expected. No significant differences were found between expected moderate and expected lack of success. However, the proportion of explained variance that was due to physicians' expectations was small considering total explained variance. CONCLUSIONS: Physicians' high expectations at baseline predict better outcome, independent of the treatment. Since we adjusted for several patient variables including duration and severity of disease, this cannot be explained by prognostic factors only. Other explanations are discussed and recommended for future research. PMID- 22528658 TI - Structural basis of interleukin-5 dimer recognition by its alpha receptor. AB - Interleukin-5 (IL-5), a major hematopoietin, stimulates eosinophil proliferation, migration, and activation, which have been implicated in the pathogenesis of allergic inflammatory diseases, such as asthma. The specific IL-5 receptor (IL 5R) consists of the IL-5 receptor alpha subunit (IL-5RA) and the common receptor beta subunit (betac). IL-5 binding to IL-5R on target cells induces rapid tyrosine phosphorylation and activation of various cellular proteins, including JAK1/JAK2 and STAT1/STAT5. Here, we report the crystal structure of dimeric IL-5 in complex with the IL-5RA extracellular domains. The structure revealed that IL 5RA sandwiches the IL-5 homodimer by three tandem domains, arranged in a "wrench like" architecture. This association mode was confirmed for human cells expressing IL-5 and the full-length IL-5RA by applying expanded genetic code technology: protein photo-cross-linking experiments revealed that the two proteins interact with each other in vivo in the same manner as that in the crystal structure. Furthermore, a comparison with the previously reported, partial GM-CSF*GM-CSFRA*betac structure enabled us to propose complete structural models for the IL-5 and GM-CSF receptor complexes, and to identify the residues conferring the cytokine-specificities of IL-5RA and GM-CSFRA. PMID- 22528660 TI - Management and prognosis of acute liver failure in children. AB - Although the etiologies of pediatric acute liver failure (ALF) are diverse, ultimate pathophysiologic pathways and management challenges for these disorders, usually lethal in the pre-transplant era, are similar. This review considers particularly the mechanisms of, and monitoring for, intracranial hypertension and coagulopathy; summarizes detailed advice for management of the ALF-associated failures of multiple body systems; and reviews the variety of prognostic scores available to guide management and assist in choosing the patients most apt to benefit from liver transplantation and the optimal timing for such transplantation. PMID- 22528661 TI - Gastroesophageal reflux in cystic fibrosis: current understandings of mechanisms and management. AB - Cystic fibrosis (CF) is an inherited disease that affects both the lungs and the digestive system in children and adults. Thick mucus fills the gut and blocks lumens of the pancreas and hepatobiliary systems, creating insufficient pancreas function and liver disease. Chronic gastrointestinal (GI) complications, including intestinal obstruction, occur in neonates, and poor digestion and gastroesophageal reflux disease (GERD) in children. Although GI symptoms tend to improve with age, CF and associated GERD eventually create respiratory insufficiency; the only available treatment option at this stage is a bilateral lung transplant, which carries considerable morbidity and mortality. While GERD may reoccur as a complication of lung transplantation, GERD symptoms are often reduced following a fundoplication. PMID- 22528663 TI - How shape influences uptake: interactions of anisotropic polymer nanoparticles and human mesenchymal stem cells. AB - Among several nanoparticle properties, shape is important for their interaction with cells and, therefore, relevant for uptake studies and applications. In order to further investigate such characteristics, fluorescently labeled spherical polymer nanoparticles are synthesized by free-radical polymerization via the miniemulsion process. The spherical nanoparticles are subsequently submitted to controlled mechanical deformation to yield quasi-ellipsoidal polymeric nanoparticles with different aspect ratios. The uptake behaviors of spherical and non-spherical particles with equal volume are investigated qualitatively and quantitatively by electron microscopy, confocal laser scanning microscopy, and flow cytometry measurements. Non-spherical particles show fewer uptake by cells than their spherical counterparts with a negative correlation between aspect ratio and uptake rate. This is attributed to the larger average curvature radius of adsorbed non-spherical particles experienced by the cells. PMID- 22528662 TI - Medical update and potential advances in the treatment of pediatric intestinal failure. AB - Short bowel syndrome (SBS) and intestinal failure are chronic malabsorption disorders with considerable nutritional and growth consequences in children. Intestinal failure occurs when the functional gastrointestinal mass is reduced even if there is normal anatomical gastrointestinal length. A number of management strategies are often utilized to achieve successful intestinal rehabilitation and maintain adequate nutrition to avoid intestinal transplant. These strategies include minimizing the effect of parenteral associated liver disease, limiting catheter complications, and treating bacterial overgrowth in the remaining small intestine. In addition, there continues to be significant research interest in enhancing intestinal adaptation with targeted therapies. The purpose of this review is to discuss current perspectives and to highlight recent medical advances in novel investigational therapies. PMID- 22528665 TI - Transcriptional and post-transcriptional regulation in TGF-beta-mediated epithelial-mesenchymal transition. AB - Epithelial-mesenchymal transition (EMT) is a crucial event in appropriate embryonic development as well as in wound healing, tissue repair and cancer progression in adult tissues. EMT endows cells with migratory and invasive properties, inhibits apoptosis and senescence, contributes to immunosuppression and induces stress resistance and stem cell properties. Many secreted polypeptide factors act in a sequential or cooperative manner to elicit EMT. Transforming growth factor (TGF)-beta can initiate and maintain EMT by activating intracellular signalling pathways. Recent studies have provided new insights into molecular mechanisms by which TGF-beta mediates changes in transcription of EMT regulators and EMT marker proteins, as well as changes in alternative splicing controlled by epithelial splicing regulatory proteins 1 and 2. Here, we present some of the emerging molecular mechanisms that mediate EMT upon exposure to TGF beta. PMID- 22528664 TI - In vitro assessment of poly(methylmethacrylate)-based bone cement containing magnetite nanoparticles for hyperthermia treatment of bone tumor. AB - Poly(methylmethacrylate) (PMMA)-based cements containing magnetite (C PMMA/Fe(3)O(4)) is useful in hyperthermia treatment for bone tumor. We have prepared C-PMMA/Fe(3)O(4) by incorporating Fe(3) O(4) powders of different diameters (means of 300, 35, and 11 nm) into the polymerization reaction of methyl methacrylate monomer to develop a new bone cement with high heating efficiencies in alternating current (AC) magnetic fields. Further, we have investigated the in vitro heating capability of the cements in different AC magnetic fields. The mechanical strength and biocompatibility of the resultant cements were also assessed. Their heat generation strongly depends on the magnetite nanoparticle sizes and applied magnetic fields. The cement containing Fe(3)O(4) with mean diameter around 35 nm exhibited the highest heating capability in AC magnetic fields of 120 and 300 Oe at 100 kHz while that with mean diameter around 11 nm exhibited optimum heating capability in AC magnetic fields of 40 Oe at 600 kHz. The incorporation of Fe(3)O(4) into cement-30 wt % of the total amount of cement-did not significantly change the compressive strength of cement, and the proliferation of rat fibroblast Rat-1 cells on cement discs was not inhibited. Our investigations are useful for designing new PMMA/Fe(3)O(4) bone cement with high heating efficiencies and biocompatibilities for bone tumor treatments. PMID- 22528666 TI - Deuterium kinetic isotope effects in heterotetrameric sarcosine oxidase from Corynebacterium sp. U-96: the anionic form of the substrate in the enzyme substrate complex is a reactive species. AB - Heterotetrameric sarcosine oxidase is a flavoprotein that catalyses the oxidative demethylation of sarcosine. It is thought that the dehydrogenated substrate is the anionic form of sarcosine. To verify this assumption, the rate of flavin adenine dinucleotide (FAD) reduction (k(red)) was analysed using protiated and deuterated sarcosine (N-methyl-d(3)-Gly) at various pH values using stopped-flow method. By increasing the pH from 6.2 to 9.8, k(red) increased for both substrates and reached a plateau, but the pK(a) value (reflecting the ionization of the enzyme-substrate complex) was 6.8 and 7.1 for protiated and deuterated sarcosine, respectively, and the kinetic isotope effect of k(red) decreased from approximately 19 to 8, indicating deprotonation of the bound sarcosine. The k(red)/K(d) (K(d), sarcosine dissociation constant) increased with increasing pH and reached a plateau. The pK (reflecting the ionization of free enzyme or free sarcosine) was 7.0 for both substrates, suggesting deprotonation of the betaLys358 residue, which has a pK(a) of 6.7, as the pK(a) of the free sarcosine amine proton was determined to be approximately 10.1. These results indicate that the amine proton of sarcosine is transferred to the unprotonated Lys residue in the enzyme-substrate complex. PMID- 22528667 TI - Implication of TGF-beta as a survival factor during tumour development. AB - Transforming growth factor (TGF)-beta is a pleiotropic secretory protein which inhibits and potentiates tumour progression during early and late stage of tumourigenicity, respectively. However, it still remains veiled how TGF-beta signalling reveals its two faces. Hoshino et al. (Autocrine TGF-beta protects breast cancer cells from apoptosis through reduction of BH3-only protein, Bim, J. Biochem. 2011;149:55-65) demonstrated a new aspect of TGF-beta as a survival factor in highly metastatic breast cancer cells from which TGF-beta1 and TGF beta3 are abundantly expressed. They found that TGF-beta suppressed the expression of BH3-only protein Bim which promotes programmed death signalling via release of cytochrome c from mitochondria. Further interestingly, forkhead box C1 (Foxc1) whose expression is suppressed upon TGF-beta stimulation is involved in the expression of Bim. Based on their results, autocrine TGF-beta signalling in certain breast cancers promotes cell survival via inhibition of apoptotic signalling. Thus, the inhibitors for activin receptor-like kinase (ALK)5 kinase might exert a curative influence on certain types of metastatic breast cancers. PMID- 22528668 TI - An anticancer agent, pyrvinium pamoate inhibits the NADH-fumarate reductase system--a unique mitochondrial energy metabolism in tumour microenvironments. AB - Increased glycolysis is the principal explanation for how cancer cells generate energy in the absence of oxygen. However, in actual human tumour microenvironments, hypoxia is often associated with hypoglycemia because of the poor blood supply. Therefore, glycolysis cannot be the sole mechanism for the maintenance of the energy status in cancers. To understand energy metabolism in cancer cells under hypoxia-hypoglycemic conditions mimicking the tumour microenvironments, we examined the NADH-fumarate reductase (NADH-FR) system, which functions in parasites under hypoxic condition, as a candidate mechanism. In human cancer cells (DLD-1, Panc-1 and HepG2) cultured under hypoxic hypoglycemic conditions, NADH-FR activity, which is composed of the activities of complex I (NADH-ubiquinone reductase) and the reverse reaction of complex II (quinol-FR), increased, whereas NADH-oxidase activity decreased. Pyrvinium pamoate (PP), which is an anthelmintic and has an anti-cancer effect within tumour-mimicking microenvironments, inhibited NADH-FR activities in both parasites and mammalian mitochondria. Moreover, PP increased the activity of complex II (succinate-ubiquinone reductase) in mitochondria from human cancer cells cultured under normoxia-normoglycemic conditions but not under hypoxia hypoglycemic conditions. These results indicate that the NADH-FR system may be important for maintaining mitochondrial energy production in tumour microenvironments and suggest its potential use as a novel therapeutic target. PMID- 22528669 TI - Reactive oxygen species production and activation mechanism of the rice NADPH oxidase OsRbohB. AB - Reactive oxygen species (ROS) produced by plant NADPH oxidases (NOXes) are important in plant innate immunity. The Oryza sativa respiratory burst oxidase homologue B (OsRbohB) gene encodes a NOX the regulatory mechanisms of which are largely unknown. Here, we used a heterologous expression system to demonstrate that OsRbohB shows ROS-producing activity. Treatment with ionomycin, a Ca(2+) ionophore, and calyculin A, a protein phosphatase inhibitor, activated ROS producing activity; it was thus OsRbohB activated by both Ca(2+) and protein phosphorylation. Mutation analyses revealed that not only the first EF-hand motif but also the upstream amino-terminal region were necessary for Ca(2+)-dependent activation, while these regions are not required for phosphorylation-induced ROS production. PMID- 22528670 TI - Empirical van der Waals corrections to solid-state density functional theory: Iodine and phosphorous containing molecular crystals. AB - Parameters are derived for a molecular mechanics type dispersive correction to solid-state density functional theory calculations on molecular crystals containing iodine and phosphorous. The molecular C(6) coefficients are derived from photoabsorption differential oscillator strength spectra determined from accurate (e,e) dipole spectra. The cross-over parameters, which ensure correct behavior at short internuclear distances, are obtained by fitting predicted crystal lattice parameters to experimental data. The accuracy of the parameterization is assessed by optimizing the experimental structures of several additional phosphorous and iodine containing molecular crystals and by examining the relative stabilities of the known polymorphs of phosphorous pentoxide and the stabilities of different packings of an iodine containing molecular crystal, 2,9 bis(iodo)anthanthrone, which has been the subject of a crystal structure prediction study. Optimizations of the experimental crystal structures did not lead to significant geometric deviations. The optimized experimental structure of 2,9-bis(iodo)anthanthrone is the lowest energy packing found, indicating a satisfactory description of both energy and structure for these molecular crystals. PMID- 22528671 TI - Comparison of magnetic resonance enteroclysis and capsule endoscopy with balloon assisted enteroscopy in patients with obscure gastrointestinal bleeding. AB - BACKGROUND AND STUDY AIMS: New modalities are available for visualization of the small bowel in patients with possible obscure gastrointestinal bleeding (OGIB), but their performance requires further comparison. This study compared the diagnostic yield of magnetic resonance enteroclysis (MRE) and capsule endoscopy in patients with OGIB, using balloon-assisted enteroscopy (BAE) as the reference standard. PATIENTS AND METHODS: Consecutive consenting patients who were referred for evaluation of OGIB were prospectively included. Patients underwent MRE followed by capsule endoscopy and BAE. Patients with high grade stenosis at MRE did not undergo capsule endoscopy. The reference standard was BAE findings in visualized small-bowel segments and expert panel consensus for segments not visualized during BAE. RESULTS: Over a period of 26 months, 38 patients were included (20 female [53 %]; mean age 58 years, range 28 - 75 years). Four patients (11 %) did not undergo capsule endoscopy due to high grade small-bowel stenosis at MRE (n = 3; 8 %) or timing issues (n = 1; 3 %). Capsule endoscopy was non-diagnostic in one patient. The reference standard identified abnormal findings in 20 patients (53 %). MRE had sensitivity, specificity, and positive and negative likelihood ratios of 21 %, 100 %, infinity, and 0.79, respectively. The corresponding values for capsule endoscopy were 61 %, 85 %, 4.1, and 0.46. The reference standard and capsule endoscopy did not differ in percent positive findings (P = 0.34), but MRE differed significantly from the reference BAE (P < 0.001). Capsule endoscopy was superior to MRE for detecting abnormalities (P = 0.0015). CONCLUSION: Capsule endoscopy performed better than MRE in the detection of small-bowel abnormality in patients with OGIB. MRE may be considered as an alternative for the initial examination in patients with clinical suspicion of small-bowel stenosis. PMID- 22528672 TI - Endoscopic ultrasound staging in gastric cancer: Does it help management decisions in the era of neoadjuvant treatment? AB - BACKGROUND AND STUDY AIMS: Endoscopic ultrasonography (EUS) has been shown to be the most accurate test for locoregional staging of upper gastrointestinal tumors; however, recent studies have questioned its accuracy level in daily clinical application. The present retrospective study analyzes the accuracy of EUS in guiding interdisciplinary treatment decisions. PATIENTS AND METHODS: 123 primarily operated patients (63 % men, mean age 61.4 years) were included; only cases with tumor-free resection margins and without evidence of distant metastases were selected. EUS and histopathological findings were compared. Main outcome parameter was the distinction between tumors to be primarily operated (T1 /2N0) and those to be treated by neoadjuvant or perioperative chemotherapy (T3/4, or any N + ), based on an assumed algorithm for treatment stratification. RESULTS: Overall staging accuracy of EUS was 44.7 % for T and 71.5 % for N status irrespective of tumor location. Overstaging was the main problem (44.9 % for T, 42.9 % for N staging). The overall EUS classification was correct in 79.7 % (accuracy), with a sensitivity 91.9 % and specificity 51.4 %; only 19 out of 37 cases with histopathological T1/2N0 were correctly classified by EUS. Positive and negative predictive values of EUS in diagnosing advanced tumor stage for assignment to neoadjuvant therapy were 81.4 % and 73.1 %, respectively. CONCLUSIONS: Whereas EUS has a high sensitivity in the diagnosis of locally advanced gastric cancer, endosonographic overstaging of T2 cancers appears to be a frequent problem. EUS stratification between local (T1 /2N0) and advanced (T3/4 or any N + ) tumors would thus result in incorrect assignment to neoadjuvant treatment in half of cases. PMID- 22528673 TI - Endoscopic submucosal dissection in large sessile lesions of the rectosigmoid: learning curve in a European center. AB - BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) in the colorectum is not currently a standard procedure. Few data are available from the Western world. The aim of the present study was to report on the first experiences and the learning curve of colorectal ESD in a European center. PATIENTS AND METHODS: A total of 82 rectosigmoid lesions were referred for ESD. Lesion characteristics, resection rates, procedure times, complications, and recurrences were recorded prospectively. Results were compared between three consecutive study periods in order to determine the learning curve. RESULTS: Lesions were located in the rectum (86.6 %) and the sigmoid colon (13.4 %). Median diameter was 45.5 mm. Lesions were of Paris type 0-Is with pit pattern type V (n = 8), 0-IIa (n = 33), 0-IIa + Is (n = 36), and 0-IIa + IIc (n = 5). The malignancy rate in these groups was 100 %, 0 %, 14 %, and 20 %, respectively. ESD was possible in 76 lesions (92.7 %). En bloc resection rate and R0 resection rate were 81.6 % and 69.7 %, respectively. Median procedure time was 176 minutes. Between the three consecutive study periods, en bloc resection rate increased (60.0 %, 88.0 %, 96.2 %), R0 resection rate increased (48.0 %, 76.0 %, 84.5 %; P < 0.001), and procedure time decreased (200, 193, 136 minutes; P = 0.027). The perforation and bleeding rates were 1.3 % and 7.9 %, respectively. Recurrence risk was 0 % after R0 en bloc resection and 41.7 % after piecemeal resection (P < 0.05). Median follow-up was 23.6 months. CONCLUSIONS: In the European setting, ESD in the distal colon is feasible with acceptable complication risks. Resection rates were not as high as those from Japanese studies; however, a clear learning curve could be shown. Colorectal ESD needs to be further evaluated, particularly in Europe where ESD experience is low. PMID- 22528674 TI - Contrast-enhanced harmonic endoscopic ultrasound. AB - Second-generation intravenous blood-pool ultrasound contrast agents are increasingly used in endoscopic ultrasound (EUS) for characterization of microvascularization, differential diagnosis of benign and malignant focal lesions, and improving staging and guidance of therapeutic procedures. Although initially used as Doppler signal enhancers, second-generation microbubble contrast agents are now used with specific contrast harmonic imaging techniques, which benefit from the highly nonlinear behavior of the microbubbles. Contrast specific modes based on multi-pulse technology are used to perform contrast enhanced harmonic EUS based on a very low mechanical index (0.08 - 0.12). Quantification techniques based on dynamic contrast-enhanced ultrasound have been recommended for perfusion imaging and monitoring of anti-angiogenic treatment, mainly based on time-intensity curve analysis. Most of the clinical applications include the differential diagnosis of focal pancreatic masses, with adenocarcinoma having a distinct hypovascular (hypo-enhanced) appearance compared with neuroendocrine tumors, which are hypervascular (with strong arterial hyper enhancement). However, pseudotumoral chronic pancreatitis and autoimmune pancreatitis also have an iso- or hypervascular appearance, making the differential diagnosis difficult. Even more promising is the use of dynamic contrast-enhanced harmonic EUS for the longitudinal monitoring of the effects of chemotherapy and/or anti-angiogenic therapy in advanced digestive cancers, which are difficult to examine by conventional cross-sectional imaging techniques. PMID- 22528675 TI - Transvaginal access for NOTES: a cohort study of microbiological colonization and contamination. AB - BACKGROUND AND STUDY AIMS: Animal data and limited clinical evidence suggest a low incidence of infection following transvaginal natural orifice transluminal endoscopic surgery (NOTES). However, a systematic microbiological evaluation has not yet been carried out. The aim of this prospective cohort study was to evaluate the extent of microbiological contamination of the peritoneal cavity caused by the transvaginal access for NOTES and the impact of preoperative vaginal disinfection on vaginal colonization. PATIENTS AND METHODS: Consecutive female patients with symptomatic cholecystolithiasis were offered either transvaginal rigid-hybrid cholecystectomy (tvCCE) or conventional laparoscopic cholecystectomy. Patients who opted for tvCCE were prospectively evaluated between February and June 2010. Disinfection in patients undergoing tvCCE included hexetidine tablets and octenidine applied vaginally. All patients received a single dose of perioperative cefuroxime. Swabs were obtained from the posterior fornix and the peritoneal cavity at different intervals. RESULTS: Of 32 patients, 27 (84 %) opted to undergo tvCCE. One patient (4 %; 95 % confidence interval [CI] 0.7 % - 18.3 %) had a positive bacterial culture in the Douglas pouch prior to transvaginal access compared with two patients (7 %; 95 %CI 2.1 % 23.4 %) following colpotomy closure (P = 1.000). Vaginal disinfection significantly decreased vaginal bacterial load (P = 0.001) and bacterial growth in routine cultures (P < 0.001); in 16 patients (59 %; 95 %CI 40.7 % - 75.5 %) vaginal swabs were sterile after disinfection. No postoperative surgical site infections occurred (95 %CI 0 % - 12.5 %). CONCLUSIONS: In selected patients and following vaginal antisepsis, transvaginal access for NOTES is associated with microbiological contamination of the peritoneal cavity in a minority of patients, indicating a low risk of peritoneal contamination caused by the transvaginal access. PMID- 22528676 TI - Cardiovascular disease risk in young people with type 1 diabetes. AB - Cardiovascular disease (CVD) is the most frequent cause of death in people with type 1 diabetes (T1D), despite modern advances in glycemic control and CVD risk factor modification. CVD risk identification is essential in this high-risk population, yet remains poorly understood. This review discusses the risk factors for CVD in young people with T1D, including hyperglycemia, traditional CVD risk factors (dyslipidemia, smoking, physical activity, hypertension), as well as novel risk factors such as insulin resistance, inflammation, and hypoglycemia. We present evidence that adverse changes in cardiovascular function, arterial compliance, and atherosclerosis are present even during adolescence in people with T1D, highlighting the need for earlier intervention. The methods for investigating cardiovascular risk are discussed and reviewed. Finally, we discuss the observational studies and clinical trials which have thus far attempted to elucidate the best targets for early intervention in order to reduce the burden of CVD in people with T1D. PMID- 22528677 TI - Phenotypic and functional alterations on inflammatory peripheral blood cells after acute myocardial infarction. AB - The frequency and function of T cells, monocytes, and dendritic cell subsets were investigated in 12 patients after acute myocardial infarction (AMI)-(T0), 1 month after the episode (T1), and in 12 healthy individuals (HG). The cell characterization and the functional studies were performed by flow cytometry and by RT-PCR, after cell sorting. The most important findings at T0 moment, when compared with T1 and HG, were: a decrease in the frequency of IL-2-producing T cells; a lower frequency of TNF-alpha- and IL-6-producing monocytes, myeloid dendritic cells, and CD14(-/low)CD16(+)DCs; and a lower TNF-alpha mRNA expression, after sorting these cells. Moreover, the regulatory function of Treg cells, at T0 moment, was upregulated, based on the FoxP3, CTLA-4, and TGF-beta mRNA expression increase. The majority of these phenotypic and functional alterations disappeared at T1. Our data demonstrate that AMI induces a significant change in the immune system homeostasis. PMID- 22528678 TI - P2Y(12) receptors in platelets and other hematopoietic and non-hematopoietic cells. AB - The P2Y(12) receptor is a Gi-coupled ADP receptor first described in blood platelets where it plays a central role in the complex processes of activation and aggregation. Platelet granules store important amounts of ADP which are released upon stimulation by interaction of platelets with the damaged vessel wall. Therefore, the P2Y(12) receptor is a key player in primary hemostasis and in arterial thrombosis and is an established target of antithrombotic drugs like the thienopyridine compounds ticlopidine, clopidogrel, and prasugrel or the direct, reversible antagonists ticagrelor and cangrelor. Beyond the platelet physiology and pharmacology, recent studies have revealed the expression of the P2Y(12) receptor in other hematopoietic cells including leukocyte subtypes and microglia in the central nervous system as well as in vascular smooth muscle cells. These studies indicate putative roles of the P2Y(12) receptor in inflammatory states and diseases of the brain, lung, and blood vessels. The selective role of P2Y(12) among other P2 receptors as well as the possible impact of P2Y(12) targeting drugs in these processes remain to be evaluated. PMID- 22528680 TI - ATP synthesis and storage. AB - Since 1929, when it was discovered that ATP is a substrate for muscle contraction, the knowledge about this purine nucleotide has been greatly expanded. Many aspects of cell metabolism revolve around ATP production and consumption. It is important to understand the concepts of glucose and oxygen consumption in aerobic and anaerobic life and to link bioenergetics with the vast amount of reactions occurring within cells. ATP is universally seen as the energy exchange factor that connects anabolism and catabolism but also fuels processes such as motile contraction, phosphorylations, and active transport. It is also a signalling molecule in the purinergic signalling mechanisms. In this review, we will discuss all the main mechanisms of ATP production linked to ADP phosphorylation as well the regulation of these mechanisms during stress conditions and in connection with calcium signalling events. Recent advances regarding ATP storage and its special significance for purinergic signalling will also be reviewed. PMID- 22528681 TI - P2X4 purinoceptor signaling in chronic pain. AB - ATP, acting via P2 purinergic receptors, is a known mediator of inflammatory and neuropathic pain. There is increasing evidence that the ATP-gated P2X4 receptor (P2X4R) subtype is a locus through which activity of spinal microglia and peripheral macrophages instigate pain hypersensitivity caused by inflammation or by injury to a peripheral nerve. The present article highlights the recent advances in our understanding of microglia-neuron interactions in neuropathic pain by focusing on the signaling and regulation of the P2X4R. We will also develop a framework for understanding converging lines of evidence for involvement of P2X4Rs expressed on macrophages in peripheral inflammatory pain. PMID- 22528679 TI - Vesicular and conductive mechanisms of nucleotide release. AB - Extracellular nucleotides and nucleosides promote a vast range of physiological responses, via activation of cell surface purinergic receptors. Virtually all tissues and cell types exhibit regulated release of ATP, which, in many cases, is accompanied by the release of uridine nucleotides. Given the relevance of extracellular nucleotide/nucleoside-evoked responses, understanding how ATP and other nucleotides are released from cells is an important physiological question. By facilitating the entry of cytosolic nucleotides into the secretory pathway, recently identified vesicular nucleotide and nucleotide-sugar transporters contribute to the exocytotic release of ATP and UDP-sugars not only from endocrine/exocrine tissues, but also from cell types in which secretory granules have not been biochemically characterized. In addition, plasma membrane connexin hemichannels, pannexin channels, and less-well molecularly defined ATP conducting anion channels have been shown to contribute to the release of ATP (and UTP) under a variety of conditions. PMID- 22528683 TI - Purinergic trophic signalling in glial cells: functional effects and modulation of cell proliferation, differentiation, and death. AB - In the last decades, the discovery that glial cells do not only fill in the empty space among neurons or furnish them with trophic support but are rather essential participants to the various activities of the central and peripheral nervous system has fostered the search for the signalling pathways controlling their functions. Since the early 1990s, purines were foreseen as some of the most promising candidate molecules. Originally just a hypothesis, this has become a certainty as experimental evidence accumulated over years, as demonstrated by the exponentially growing number of articles related to the role of extracellular nucleotides and nucleosides in controlling glial cell functions. Indeed, as new functions for already known glial cells (for example, the ability of parenchymal astrocytes to behave as stem cells) or new subtypes of glial cells (for example, NG2(+) cells, also called polydendrocytes) are discovered also, new actions and new targets for the purinergic system are identified. Thus, glial purinergic receptors have emerged as new possible pharmacological targets for various acute and chronic pathologies, such as stroke, traumatic brain and spinal cord injury, demyelinating diseases, trigeminal pain and migraine, and retinopathies. In this article, we will summarize the most important and promising actions mediated by extracellular purines and pyrimidines in controlling the functions, survival, and differentiation of the various "classical" types of glial cells (i.e., astrocytes, oligodendrocytes, microglial cells, Muller cells, satellite glial cells, and enteric glial cells) but also of some rather new members of the family (e.g., polydendrocytes) and of other cells somehow related to glial cells (e.g., pericytes and spinal cord ependymal cells). PMID- 22528686 TI - Efficacy of the pedicled nasoseptal flap without cerebrospinal fluid (CSF) diversion for repair of skull base defects: incidence of postoperative CSF leaks. AB - BACKGROUND: The advances in endoscopic skull base surgery have led to the resection of increasingly larger cranial base lesions and the creation of larger skull base defects with the potential for increased postoperative high-flow cerebrospinal fluid (CSF) leaks. These concerns led to the development of the vascularized pedicled nasoseptal flap (PNSF), which is now used as the mainstay for repair of large skull base defects in many academic centers. In this report, we review the incidence of postoperative CSF leaks in our institution in patients undergoing endoscopic skull base repair of high-flow CSF leaks with a vascularized PNSF without concurrent CSF diversion. METHODS: We performed a retrospective analysis at our tertiary care medical center on patients who underwent endoscopic repair of high-flow CSF leaks using a PNSF without CSF diversion between July 2008 and August 2011. Repair materials, incidence of postoperative CSF leaks, and demographic data were collected. RESULTS: Fifty-nine high-flow CSF leaks were repaired with a PNSF and other repair materials, without the use of lumbar catheter drainage. No postoperative CSF leak occurred in this cohort of patients. The overall postoperative CSF leak rate was 0%. CONCLUSION: Meticulous multilayer-closure of skull base defects is critical to prevent postoperative CSF leaks. Although lumbar drainage may be useful in select scenarios, it carries inherent risks of intracranial hypotension and pneumocephalus, and may not be necessary for routine management of high-flow CSF leaks in conjunction with a robust PNSF. Further prospective randomized controlled studies may be warranted to evaluate the efficacy of postoperative lumbar drainage. PMID- 22528685 TI - The touching story of purinergic signaling in epithelial and endothelial cells. PMID- 22528682 TI - Neuroprotective roles of the P2Y(2) receptor. AB - Purinergic signaling plays a unique role in the brain by integrating neuronal and glial cellular circuits. The metabotropic P1 adenosine receptors and P2Y nucleotide receptors and ionotropic P2X receptors control numerous physiological functions of neuronal and glial cells and have been implicated in a wide variety of neuropathologies. Emerging research suggests that purinergic receptor interactions between cells of the central nervous system (CNS) have relevance in the prevention and attenuation of neurodegenerative diseases resulting from chronic inflammation. CNS responses to chronic inflammation are largely dependent on interactions between different cell types (i.e., neurons and glia) and activation of signaling molecules including P2X and P2Y receptors. Whereas numerous P2 receptors contribute to functions of the CNS, the P2Y(2) receptor is believed to play an important role in neuroprotection under inflammatory conditions. While acute inflammation is necessary for tissue repair due to injury, chronic inflammation contributes to neurodegeneration in Alzheimer's disease and occurs when glial cells undergo prolonged activation resulting in extended release of proinflammatory cytokines and nucleotides. This review describes cell-specific and tissue-integrated functions of P2 receptors in the CNS with an emphasis on P2Y(2) receptor signaling pathways in neurons, glia, and endothelium and their role in neuroprotection. PMID- 22528684 TI - New insights regarding the regulation of chemotaxis by nucleotides, adenosine, and their receptors. AB - The directional movement of cells can be regulated by ATP, certain other nucleotides (e.g., ADP, UTP), and adenosine. Such regulation occurs for cells that are "professional phagocytes" (e.g., neutrophils, macrophages, certain lymphocytes, and microglia) and that undergo directional migration and subsequent phagocytosis. Numerous other cell types (e.g., fibroblasts, endothelial cells, neurons, and keratinocytes) also change motility and migration in response to ATP, other nucleotides, and adenosine. In this article, we review how nucleotides and adenosine modulate chemotaxis and motility and highlight the importance of nucleotide- and adenosine-regulated cell migration in several cell types: neutrophils, microglia, endothelial cells, and cancer cells. We also discuss difficulties in conducting experiments and drawing conclusions regarding the ability of nucleotides and adenosine to modulate the migration of professional and non-professional phagocytes. PMID- 22528687 TI - Tibiofemoral cartilage contact biomechanics in patients after reconstruction of a ruptured anterior cruciate ligament. AB - We investigated the in vivo cartilage contact biomechanics of the tibiofemoral joint in patients after reconstruction of a ruptured anterior cruciate ligament (ACL). A dual fluoroscopic and MR imaging technique was used to investigate the cartilage contact biomechanics of the tibiofemoral joint during in vivo weight bearing flexion of the knee in eight patients 6 months following clinically successful reconstruction of an acute isolated ACL rupture. The location of tibiofemoral cartilage contact, size of the contact area, cartilage thickness at the contact area, and magnitude of the cartilage contact deformation of the ACL reconstructed knees were compared with those previously measured in intact (contralateral) knees and ACL-deficient knees of the same subjects. Contact biomechanics of the tibiofemoral cartilage after ACL reconstruction were similar to those measured in intact knees. However, at lower flexion, the abnormal posterior and lateral shift of cartilage contact location to smaller regions of thinner tibial cartilage that has been described in ACL-deficient knees persisted in ACL-reconstructed knees, resulting in an increase of the magnitude of cartilage contact deformation at those flexion angles. Reconstruction of the ACL restored some of the in vivo cartilage contact biomechanics of the tibiofemoral joint to normal. Clinically, recovering anterior knee stability might be insufficient to prevent post-operative cartilage degeneration due to lack of restoration of in vivo cartilage contact biomechanics. PMID- 22528689 TI - Pain sensitivity in fibromyalgia is associated with catechol-O-methyltransferase (COMT) gene. AB - BACKGROUND: Recent evidence suggests that genetic factors might contribute to individual differences in pain sensitivity, risk for developing clinical pain conditions and efficacy of pain treatments. The purpose of the present study was to investigate the relationship of three common haplotypes of COMT gene affecting the metabolism of catecholamines on pain sensitivity in patients with fibromyalgia (FM). METHODS: One hundred and thirteen FM patients and 65 age matched healthy volunteers participated in the study. We genotyped four single nucleotide polymorphisms (SNPs) (rs6269, rs4633, rs4818 and rs4680 or Val158Met) and identified haplotypes previously designated as low (LPS), average (APS) and high pain sensitivity (HPS). Thermal, pressure and touch thresholds were also examined using a quantitative sensory testing protocol. RESULTS: The frequency of genetic variations associated with low COMT enzyme activity was significantly higher in FM patients than in healthy volunteers. FM patients were more sensitive to experimental pain than healthy volunteers and, in particular, FM individuals with the met/met genotype (Val158Met SNP) or the HPS-APS haplotypes showing higher sensitivity to thermal and pressure pain stimuli than patients carrying the LPS haplotype or val alleles (Val158Met SNP). No differences due to genotype or haplotypes were found on non-painful touch thresholds. CONCLUSIONS: According with previous research, our findings revealed that haplotypes of the COMT gene and genotypes of the Val158Met polymorphism play a key role on pain sensitivity in FM patients. PMID- 22528688 TI - The neurohormonal network in the RAAS can bend before breaking. AB - The renin-angiotensin-aldosterone system (RAAS) has evolved in humans as one of the main physiological networks by which blood pressure and blood flow to vital organs is maintained. The RAAS has evolved to circumvent life-threatening events such as hemorrhage and starvation. Although short-term activation of this system had been well suited to counteract such catastrophes of early man, excessive chronic activation of the RAAS plays a fundamental role in the development and progression of cardiovascular disease in modern man. The RAAS is an intricate network comprising a number of major organ systems (heart, kidney, and vasculature) and signaling pathways. The main protagonists are renin, angiotensinogen (Ang), angiotensin I (Ang I), angiotensin II (Ang II), and aldosterone (Aldo). The study and delineation of each of these substances has allowed modern medicine to create targets by which cardiovascular disease can be treated. The main modulators that have been synthesized in this respect are angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), mineralocorticoid receptor blockers (MRBs), and direct renin inhibitors (DRIs). Over the past few decades, each of these substances has proven efficacious to varying degrees amongst a number of clinical settings. Additionally, there exists data for and against the use of these agents in combination. The use of these agents in combination poses a larger question conceptually: can excessive pharmacological inhibition of the RAAS lead to patient harm? This perspective will examine the concept of a neurohormonal inhibition ceiling in pertinent experimental and clinical trials. PMID- 22528690 TI - The interplay between physical and chemical properties of protein films affects their bioactivity. AB - Although mechanical properties, roughness, and receptor molecule expression have all been shown to influence the cellular reactivity of collagen-based biomaterials, their relative contribution, in a given system remains unclear. Here, we study films containing combinations of collagen, gelatin, and soluble and insoluble elastin, crosslinking of which results in altered film stiffness and roughness. Collagen and gelatin have similar amino acid sequences but altered cell-binding sites. We studied cell response with both C2C12 myoblast cells (which possess RGD-recognizing integrins alpha(V)beta(3) and alpha(5)beta(1)) and C2C12-alpha2+ cells (which, in addition, express the collagen-binding integrin alpha(2)beta(1)) to establish the effect of altering the available binding sites on cell adhesion and spreading on films. Systematically altering the composition, crosslinking and cell type, allows us to deconvolute the effects of physical parameters and available binding sites on the cell reactivity of films in this system. Collagen-based films were rougher and stiffer and supported lower cell surface coverage than gelatin-based films. Additionally, C2C12-alpha2+ cells showed preferential attachment to collagen-based films compared with C2C12 cells, but no significant difference was seen using gelatin-based films. The cell count and surface coverage were found to decrease significantly on all films after crosslinking (Coll XL coverage = 2-6%, Gel XL coverage = 20-32%), but cell area and aspect ratio on collagen films were affected to a greater extent than on gelatin films. The results show that, in this system, the composition, and more significantly, crosslinking, of films affects the cell reactivity to a greater extent than their stiffness or roughness. PMID- 22528691 TI - [Are digital rectal examinations obsolete?]. PMID- 22528692 TI - Diagnostic accuracy of current sonographic criteria for the detection of outflow abnormalities in the internal jugular veins. AB - OBJECTIVES: This study was aimed at evaluation of the diagnostic value of Doppler sonography for the assessment of abnormalities in the internal jugular veins (IJVs). METHOD: One hundred and sixteen IJVs were assessed in 58 patients with associated multiple sclerosis. Findings of Doppler sonography were compared with results of the reference test: catheter venography. RESULTS: At least one positive extracranial sonographic criterion suggesting venous abnormality was found in 92.2% of the assessed veins. Yet, sensitivity, specificity, positive and negative predictive values of sonography were low: 93.4%, 12.0%, 79.4% and 33.3% for at least one positive criterion, and for at least two positive criteria: 29.3%, 75.0%, 81.8% and 21.7%, respectively. CONCLUSIONS: Our research has shown that currently used extracranial sonographic criteria for the detection of obstructive venous abnormalities in the IJVs are of limited diagnostic value. For the time being, diagnosis of this vascular pathology should be given using catheter venography. PMID- 22528693 TI - Recurrent pulmonary embolism secondary to popliteal vein aneurysm with intraluminal wall ulcer. AB - The popliteal vein is the most frequent site of venous aneurysm. Surgical treatment is indicated above a 2.5 cm diameter to prevent complications, notably deep venous thrombosis and pulmonary embolism (PE). Here we report a case of recurrent episodes of severe PE, leading to cardio-circulatory shock caused by a popliteal vein aneurysm (PVA) despite oral anticoagulant therapy. When surgical correction of the aneurysm was performed, we found an ulcerative lesion in the inner aspect of the vein that was acting as a 'thrombogenic focus' inside the aneurysm. An accurate inspection of the intimal wall is always important during surgery of PVA, particularly when tangential resection is performed. PMID- 22528694 TI - Prevalence and presentation of chronic venous disease in Pakistan: a multicentre study. AB - Our objective was to study the prevalence and clinical pattern of chronic venous disease (CVD) in the Pakistani population. This was a multicentre cross-sectional study in which 100 primary care physicians examined 3000 subjects. The study population was aged 18-95 years (mean +/- SD = 39 +/- 13.2) comprised 47.4% women and 52.6% men. The prevalence of CVD was 34.8%, being significantly higher (P < 0.04) among men (36.4%) than women (33.0%). The maximum prevalence was of C3 (36.7%), followed by C2 (15.8%). The most frequent symptom was pain in the legs (59.2%) followed by heavy legs (42.7%) and night cramps (34.4%). The prevalence of symptoms increased with age but was similarly distributed between men and women. Family history of CVD, blood clots in veins and lack of exercise were significant risk factors. The roles of age or gender as risk factors could not be established. In conclusion, the prevalence and presentation of CVD in Pakistan is similar to most other countries. PMID- 22528695 TI - Outcome of meningitis among children less than 2-y-old in Haryana. AB - Incidence of neurological complications and disability following meningitis among children less than 2 y in a community setting in Haryana was assessed. Cases were enrolled from hospitals of in Yamunanagar district. They were first assessed for disability or neurological complications at their home by health workers 1 y after hospital discharge using standard WHO ten questionnaire screening tool, and then by medical officers; finally they were examined by a pediatrician. Eighty one children could be contacted from a total of 91 meningitis cases. Among these 16 children had died (case fatality ratio 19.7 %). Among 65 survivors, disability was observed in 11 (17 %), and neurological complications were found in 24 (37 %) children. Microcephaly (8.6 %), seizures (6.7 %), cerebral palsy, hemiparesis and development deficit (some with hearing impairment, and language delay) were the major disabilities/neurological complications. PMID- 22528696 TI - PFAPA with facial swelling- a new association? AB - PFAPA (periodic fever, apthous stomatitis, pharyngitis, cervical adenitis) is a rare condition of unknown cause affecting children. Although the exact etiology is unknown, inflammatory, immunological or genetic causes have been suggested. The diagnosis is made by exclusion of other causes of periodic fever. Although management is essentially symptomatic, single corticosteroid dose, tonsillectomy and Cimetidine has been shown to be associated with resolution of symptoms. Although abdominal pain and genital ulcers have been reported in association with PFAPA, unilateral transient facial swelling has not been previously reported. The authors present a hitherto unreported association of PFAPA with recurrent episodes of unilateral facial swelling. PMID- 22528697 TI - Neuroblastoma: a review of management and outcome. AB - Solid tumors in children are a major cause of death in the developed countries and now even in the developing countries. Of these tumors, neuroblastoma, the most common tumor in children, despite extensive and on-going research and clinical trials still remains an enigma. About 50 % of children with neuroblastoma overall succumb to the disease. This tumor generates lot of curiosity in developing newer therapies for management, but creates equal amount of frustration albeit a risk-stratification system, patients with the same clinical-pathologic parameters and being treated with the same protocols may have markedly different clinical courses and outcomes. Most of the neuroblastomas are sporadic but some are familial. This article aims at understanding the different protocols existing for the risk stratification and management of neuroblastomas. Further, it also aims to study the outcomes of the several different stages of the tumor all across the country as well as in India. PMID- 22528703 TI - Occurrence and predictors of left ventricular systolic dysfunction at hospital discharge and in long-term follow-up after acute myocardial infarction treated with primary percutaneous coronary intervention. AB - BACKGROUND: Post-ST-segment elevation myocardial infarction (STEMI) left ventricular systolic dysfunction (LVSD) has been identified as an important marker of poor prognosis. AIM: To assess the prevalence and course of LVSD at hospital discharge and in long-term follow-up in STEMI patients treated with primary percutaneous coronary intervention (pPCI). METHODS: We enrolled 205 patients (157 male, 48 female) with a first STEMI. Echocardiography was performed before hospital discharge and 12 months after STEMI. Left ventricular systolic function (LVSF) parameters were assessed: left ventricular ejection fraction (LVEF), wall motion score index (WMSI), and average peak systolic mitral annular velocity (S') by tissue Doppler echocardiography (TDE). B-type natriuretic peptide plasma concentration was measured at admission (BNP(admission)) and at discharge (BNP(discharge)). RESULTS: We found moderate LVSD, both at hospital discharge and after 12 months. Significant global LVSD (LVEF <= 40%) was observed in 34% of patients at discharge, and 21% after 12 months (p < 0.001). Significant regional LVSD (WMSI >= 1.7) after 12 months was less frequent than at discharge (21% vs 33%; p < 0.001). More patients had significant longitudinal LVSD (S' <= 6.0 cm/s) after 12 months compared to discharge (28% vs 23%; p < 0.001). Severe global LVSD (LVEF <= 30%) was rare. Univariate logistic regression analysis revealed the predictors of significant global LVSD at 12 months after STEMI to be: anterior location of STEMI; pre-discharge echocardiographic parameters of LVSF and left ventricle size and mass; prepPCI angiographic indices; ratio of the difference of BNP(discharge) and BNPa(dmission) to BNP(admission) expressed as % (BNP(delta) %); time from onset of pain to balloon, and the use of abciximab. Multivariate logistic regression analysis found independent predictors of significant global LVSD at 12 months to be: BNP(delta) % and LVEF at discharge with optimal cut-off values of 728.2% for BNP(delta) % and 37% for LVEF. CONCLUSIONS: Patients with a first STEMI treated with pPCI present moderate LVSD, both at hospital discharge and after 12 months. In long-term follow-up, we found an improvement in global LVSF, and, albeit a smaller, improvement in regional LVSF. No improvement in longitudinal LVSF was observed. The increase of BNP during hospitalisation, and LVEF at discharge, are independent predictors of significant global LVSD at 12 months after a first STEMI treated with pPCI. Pre discharge peak systolic mitral annular velocity obtained by TDE may be useful in predicting LVEF in long-term follow-up in this group of patients. PMID- 22528704 TI - [Is it possible to predict the improvement or deterioration of left ventricular function after a heart attack?]. PMID- 22528705 TI - Impact of atherosclerotic changes of carotid vessels on long-term outcome in relatively young patients with acute coronary syndrome. AB - BACKGROUND: Complex stenoses of coronary vessels as well as unstable plaques are part of the widespread atherosclerotic process. AIM: The possible association between the incidence of unstable coronary artery disease (CAD) and the morphology of carotid artery wall and cardiovascular events (MACE) was assessed prospectively in a two-year follow-up study. METHODS AND RESULTS: Ninety-seven consecutive patients, aged under 60, admitted to hospital with suspected acute coronary syndrome (ACS) were included. Angiography was performed in all patients. Coronary artery disease was confirmed in 78 patients. This was the CAD(+) group. In 19 patients, coronary arteries were normal. This was the CAD(-) group. In all cases, carotid ultrasound was performed before discharge and at two-year follow up, with evaluation of carotid arteries wall morphology: carotid intima-media thickness (CIMT) in far distal wall of common carotid artery and the presence of plaques. Carotid atherosclerosis was defined as CIMT > 0.9 mm or incidence of plaques; MACE was defined as death, ACS, stroke or need for urgent coronary revascularisation. Sixty patients from the CAD(+) group met the carotid atherosclerosis criteria. This was named the CAR(+) subgroup; 18 patients with normal carotid morphology comprised the CAR(-) subgroup. During the two years, MACE occurred only in the CAD(+) group (22 events). There was no statistical difference in the MACE-free survival curve of the CAR(+) and CAR(-) subgroups (p = 0.91). CONCLUSIONS: The presence of atherosclerotic process in carotid region coexists well with the incidence of CAD; however, it does not determine prognosis after ACS. PMID- 22528706 TI - [Subclinical atherosclerosis and prognosis of acute coronary syndrome]. PMID- 22528707 TI - Benign symptomatic premature ventricular complexes: short- and long-term efficacy of antiarrhythmic drugs and radiofrequency ablation. AB - BACKGROUND: There is little data on the long-term efficacy of antiarrhythmic drugs (AADs) and radiofrequency catheter ablation (RFCA) in patients with symptomatic premature ventricular complexes (PVCs) and no organic heart disease. AIM: To evaluate the short- and long-term efficacy and tolerance of AAD therapy and RFCA in patients with idiopathic PVCs. METHODS: This was a prospective, crossover, open-label study performed in 84 consecutive patients (mean age 47 +/- 15 years; 60% women) with symptomatic idiopathic PVCs (mean PVCs/24 h, 13,768 +/- 9,424; range 1,693-42,687). Patients were treated for 2-3 weeks with metoprolol, propafenone or verapamil. Then patients were referred for RFCA, if they had drug intolerance, inefficacy or did not wish to have prolonged AAD treatment. RESULTS: The most efficacious agent was propafenone, followed by verapamil, and then metoprolol [35 (42%), 13 (15%) and eight (10%) responders, respectively, p < 0.01 vs propafenone]. Only responders to drug treatment had a significant reduction in symptom severity (Visual Analogue Scale score: 6.2 +/- 1.4 vs 2.7 +/- 2.0, p < 0.001). After AAD, 50 (60%) patients underwent RFCA. During long-term follow-up (48 +/- 10 months), RFCA (mean 1.2 procedures/patient) was effective in 44/50 (88%) patients. Of the 34 remaining patients, 21 remained on effective AAD, 6 patients remained on ineffective AAD, and 7 patients were taken off AADs therapy due to spontaneous remission of PVCs or a decrease in symptom severity. conclusions: Short-term treatment with propafenone was more effective than verapamil or metoprolol in suppressing idiopathic PVCs. However, optimal benefit was achieved with RFCA, which was effective and safe during long-term follow-up. PMID- 22528708 TI - [Not so simple procedure in "simple" arrhythmias of ventricular]. PMID- 22528709 TI - QRS complex widening as a predictor of appropriate implantable cardioverter defibrillator (ICD) therapy and higher mortality risk in primary prevention ICD patients. AB - BACKGROUND AND AIM: Effectiveness of implantable cardioverter-defibrillators (ICD) in patients with reduced left ventricular ejection fraction after myocardial infarction has been documented in large randomised trials. We analysed the predictive value of clinical factors at the time of implantation for adequate ICD interventions and mortality risk. METHODS: We analysed 121 consecutive patients (15 women, 106 [88%] men; mean age 62 +/- 10 years) with coronary artery disease in whom ICD was implanted for primary prevention between 2001 and 2007. Mean duration of follow-up was 876 +/- 538 days. RESULTS: Forty-four (36.4%) patients had adequate ICD interventions. In the Cox analysis, wider QRS complexes (hazard ration [HR] per each 10 ms increment: 1.13, confidence interval [CI] 1.039-1.229, p = 0.0045) and younger age at the time of ICD implantation (HR per each 10 year increment: 0.7, CI 0.5-0.9, p = 0.0081) were associated with a higher probability of adequate intervention. Wider QRS complexes were associated with a higher probability of electrical storm (HR 1.059, CI 1.014-1.045, p = 0.0002). During follow-up, 21 (17.4%) patients died. In the Cox analysis, wider QRS complexes (HR per each 10 ms increment: 1.123, CI 1.011-1.248, p = 0.0306 [in univariate analysis only]), older age at the time of implantation (HR per each 10 year increment: 1.7, CI 1.1-2.8, p = 0.0396) and higher NYHA class (HR 4.4, CI 1.7-11.5, p = 0.0022) were associated with increased mortality. Mortality was reduced by previous revascularisation (HR 0.3, CI 0.1-0.7, p = 0.006). CONCLUSIONS: Patients with wider QRS complexes at the time of ICD implantation had a higher probability of adequate device intervention and mortality risk. QRS complex widening was also associated with a higher incidence of electrical storm. PMID- 22528710 TI - [QRS duration and ICD interventions]. PMID- 22528711 TI - Early screening for critical congenital heart defects in asymptomatic newborns in Mazovia province: experience of the POLKARD pulse oximetry programme 2006-2008 in Poland. AB - BACKGROUND: Early diagnosis of critical congenital heart defects (CCHD) may be missed both during prenatal echocardiography and the short stay in the neonatal nursery, leading to circulatory collapse or death of the newborn before readmission to hospital. AIM: To assess the usefulness of pulse oximetry as a screening test in early diagnosis of CCHD in newborns. METHODS: A prospective screening pulse oximetry test was conducted in 51 neonatal units in the Mazovia province of Poland as part of the POLKARD 2006-2008 programme between 16 January, 2007 and 31 January, 2008. Newborns with no circulatory symptoms or coexisting diseases, and no prenatal diagnosis, were enrolled. The test was performed between the 2(nd) and 24(th) hours of life in stable newborns. A double arterial oxygen saturation (SpO(2)) reading < 95% on a lower extremity led to cardiovascular evaluation and echocardiography. RESULTS: From a population of 52,993 newborns (14.2% of births in Poland), a group of 51,698 asymptomatic infants was isolated. CCHD was diagnosed solely by pulse oximetry in 15 newborns, which constituted 18.3% of all CCHD; 14 (0.026%) false positives were obtained and there were four false negative results. The sensitivity of the test was 78.9% and specificity 99.9%. The positive predictive value was 51.7% and negative 99.9%. CONCLUSIONS: Pulse oximetry fulfilling the screening test criteria, performed on a large population of newborns in Poland, proved useful in supporting prenatal diagnostics and postnatal physical examination in the early detection of initially asymptomatic CCHD. Good sensitivity and specificity results of the pulse oximetry test have allowed it to be recommended for use in neonatal units nationwide. PMID- 22528712 TI - [Pulse oximetry in critical congenital heart defects in newborns]. PMID- 22528713 TI - Carotid artery stenting according to the tailored-CAS algorithm is associated with a low complication rate at 30 days: data from the TARGET-CAS study. AB - BACKGROUND: The rate of early complications of carotid artery stenting (CAS) should not exceed 3% in asymptomatic and 6% in symptomatic patients. However, some recent studies/registries failed to reach this threshold, fueling a debate on the role of CAS in the treatment of patients with carotid artery stenosis. AIM: To evaluate 30-day safety of CAS using different embolic protection devices and different stent types according to the tailored-CAS algorithm and to identify risk factors for complications. METHODS: Between 2002 and 2010, we performed 1176 CAS procedures in 1081 patients (age 38-86 years, mean 66.3 +/- 8.4 years, 51.5% symptomatic) according to the tailored-CAS algorithm that included extracranial ultrasound and computed tomography angiography to select the most appropriate embolic protection device (EPD) and stent type. Proximal EPD and closed-cell (CC) stents were preferentially used for high-risk lesions (HR - soft/thrombus containing/tight/ulcerated, 36.14% of all lesions) and in symptomatic patients. RESULTS: Procedural success rate was 99.8%. In symptomatic patients, proportion of HR lesions was higher (41.1%) than in the asymptomatic group (30.8%, p = 0.001) and the usage of CC stents (76.2% vs 71.7%, p = 0.103) and proximal EPD (P EPD, 34.8% vs 27.7% among asymptomatic patients, p = 0.010) was more frequent. CC stents were used in 82.4% of CAS procedures involving HR lesions (vs 69.1% for non-HR lesions, p < 0.01), and P-EPD were used in 83.1% of procedures involving HR lesions (vs 2.5% for non-HR lesions, p < 0.001). In-hospital complications included 6 (0.55%) deaths, 1 (0.08%) major stroke and 19 (1.61%) minor strokes. No myocardial infarctions (MI) were noted. Among 7 (0.59%) cases of hyperperfusion syndrome, 2 were fatal. Thirty-day complication rate (death/any stroke/MI) was 2.38%. Age > 75 years was a predictor of death (p = 0.015), and prior neurological symptoms were a predictor of death/stroke (p = 0.030). There were 4 cases of periprocedural embolic cerebral artery occlusion, all treated with combined intracranial mechanical and local thrombolytic therapy. CONCLUSIONS: CAS with EPD and stent type selection on the basis of thorough non invasive diagnostic work-up (tailored- -CAS) is safe. Advanced age was associated with an increased risk of death and the presence of prior neurological symptoms was a predictor of death/stroke at 30 days. With the tailored-CAS approach, high risk lesion features (soft/thrombus- -containing/tight/ulcerated) are eliminated as a risk factor. Hyperperfusion syndrome is a severe CAS complication which may lead to intracranial bleeding and death. Acute, iatrogenic embolic cerebral artery occlusion is rare and may be managed by combined intracranial mechanical and local thrombolytic therapy. PMID- 22528714 TI - [Treatment of carotid stenting should be performed by an experienced team of operators]. PMID- 22528715 TI - [Additional mass on the intracardiac lead - diagnostic doubts and the optimal choice of treatment]. AB - We describe a case of a 30 year-old female with implantable cardioverter defibrillator. One and a half year later the patient suffered from endocarditis und undevent surgery. The factor V Leiden mutation was diagnosed. Diagnosis and treatment of device-related interactive complications is discussed. PMID- 22528716 TI - [Constrictive pericarditis as complication of viral respiratory infection]. AB - A 24 year-old man with 3-months medical history of recurrent respiratory infections and pericardial effusion, despite treatment with nonsteroid anti inflammatory drugs, was admitted to the hospital with dyspnea on exertion. On admission he presented the symptoms of right heart insufficiency. Computed tomography of the chest demonstrated a thickened pericardium. Echocardiographic examination and right heart catheterisation established the diagnosis of constrictive pericarditis. Serologic tests suggested viral aetiology. The patient was referred to cardiothoracic surgery, partial pericardiectomy was performed with marked haemodynamic improvement. PMID- 22528718 TI - [Is stress-induced cardiomyopathy always benign? The patient with long QT and torsade de pointes]. AB - Stress-induced cardiomyopathy is usually described as syndrome with good prognosis. Although the QT prolongation is usually associated with this cardiomyopathy, the life threatening arrhythmias are less frequent than expected. We present middle age woman with torsade de pointes caused by significant QTc interval prolongation on the basis of tako-tsubo cardiomyopathy, which could suggest not always mild course of this syndrome. PMID- 22528719 TI - [Late renal artery stent thrombosis treated with aspiration trombectomy in a patient with renal insufficiency and renal hypertension]. PMID- 22528720 TI - [Clinical significance of anatomical and haemodynamical changes after acute pulmonary embolism]. PMID- 22528721 TI - [An overview of methods dedicated to protection of the digestive tract in patients treated with aspirin. Focus on clinical effectiveness and antiplatelet properties]. PMID- 22528722 TI - [Early repolarisation syndrome and sudden cardiac death A.D. 2012. Early repolarisation or delayed depolarisation syndrome?]. AB - Early repolarisation syndrome (ERS) appears in 2-7% of general population, mainly seen in young men, athletes and blacks. Recent publications change the benign character of ERS. It was suggested that ERS can be associated with sudden cardiac death, idiopathic ventricular fibrillation. This article described history and evolution of ERS. PMID- 22528723 TI - [Early repolarization syndrome - still a lot of questions]. PMID- 22528724 TI - [Severe mitral regurgitation as the first symptom of systemic lupus erythematosus in a young women required mitral valve replacement]. AB - Systemic lupus erythematosus (SLE) is an autoimmune disorder resulting in multiorgan inflammatory damage. The heart is frequently involved in SLE. The best known cardiac manifestations are pericarditis and Libman-Saks endocarditis. Severe valvular impairment is rather rare and occurs in few years and in advanced stage of the disease. In this study we report a case of a young women with SLE and heart failure due to mitral regurgitation as the first manifestation of the disease. PMID- 22528725 TI - [Angina pectoris due to coronary-subclavian steal syndrome caused by the LIMA graft in the patient after CABG with the use of the right and left mammary artery]. AB - We present a case of a patient with unstable angina pectoris two years after coronary artery by-pass graft surgery with the use of the right and left mammary artery. The symptoms were caused by the critical RIMA stenosis and coronary subclavian steal syndrome through the LIMA graft. Unsuccessful attempt of percutaneous angioplasty of the closed left subclavian artery was made. The angioplasty of the proximal part of the RIMA with the implantation of a drug eluting stent followed by the angioplasty of both left circumflex artery and obtuse marginal artery with the implantation of bare metal stents was performed. These procedures resulted in disappearance of anginal symptoms. Neurological examination did not reveal any signs of vertebrobasilar steal. PMID- 22528729 TI - [Not Available]. PMID- 22528727 TI - [Aspiration thrombectomy during percutaneous coronary intervention in a patient with cardiogenic shock caused by left main occlusion]. AB - CASE STUDY: 56-year-old male patient in cardiogenic shock with a large thrombus in LM, succesfully treated by PTCA with aspiration thrombectomy. FOLLOW-UP: 9 months control angiography. PMID- 22528730 TI - [Not Available]. PMID- 22528732 TI - On the biocompatibility between TiO2 nanotubes layer and human osteoblasts. AB - Titanium and its alloys are the most popular biomaterials replacing hard tissues in implant surgeries. Clinicians are generally pleased by titanium mechanical properties and non-toxicity performances; on the other hand, there have been reported several cases of titanium implantation failure, phenomenon explained sometimes as "non adherence of human tissue to the metallic surface." Yet, researchers reported that titanium surfaces are favorable for osteoblasts adhesion. Therefore, titanium integration into the human body remains an unsolved problem. In the present study, biocompatibility tests were performed on titanium and TiO(2) nanotubes substrates, involving human bone marrow cells. The combination of a newly developed analytical model based on the hybrid interphase concept, applicable to systems consisting of inert materials when in contact with living tissues, together with experimental results, confirmed previous research studies and lead to the conclusion that osteoblasts adhere efficiently to titanium surfaces. However, the present results suggest that osteoblasts strong anchorage at the very first moment of their contact with the metallic material leads to their apoptosis. It is most probable that in several cases this is the reason of failed implantation surgeries involving titanium. PMID- 22528731 TI - Cytogenetic and molecular predictors of outcome in acute lymphocytic leukemia: recent developments. AB - During the last decade a tremendous technologic progress based on genome-wide profiling of genetic aberrations, structural DNA alterations, and sequence variations has allowed a better understanding of the molecular basis of pediatric and adult B/T-acute lymphoblastic leukemia (ALL), contributing to a better recognition of the biological heterogeneity of ALL and to a more precise definition of risk factors. Importantly, these advances identified novel potential targets for therapeutic intervention. This review will be focused on the cytogenetic/molecular advances in pediatric and adult ALL based on recently published articles. PMID- 22528733 TI - Efficient and robust star polymer catalysts for living radical polymerization: cooperative activation in microgel-core reactors. AB - Multifunctional microgel-core star polymers with ruthenium catalysts are designed as catalyst-bearing nanoreactors to improve activity, controllability, and functionality tolerance in living radical polymerization. Multifunctional ligands are efficiently incorporated into the core of star polymers by sequential tandem procedures: 1) ruthenium-catalyzed living radical polymerization, 2) in situ core hydrogenation, and 3) core-ruthenium removal. Typically, the star polymer ligands comprising multiple phosphines and amines within the core cooperatively enclose a ruthenium complex (>100 per core). As a result, the in-core pseudo hetero P,N chelation of the ruthenium complexes not only showed high activity for methyl methacrylate but also high tolerance to unprotected methacrylic acid. PMID- 22528734 TI - rTMS stimulation on left DLPFC increases the correct recognition of memories for emotional target and distractor words. AB - According to a recent hypothesis, the prefrontal cortex has been proposed as the site of emotional memory integration, because it is sensitive to the recognition of emotional contents. In the present research, we explored the role of the dorsolateral prefrontal cortex (DLPFC) in memory recognition processes for positive versus negative emotional stimuli when old (target) and new (distractor, either semantically related or unrelated to the target) stimuli were presented. The role of the DLPFC was analysed using an rTMS (repeated transcranial magnetic stimulation) paradigm that induced increased cortical activation of the left DLPFC. The subjects were required to perform a task that consisted of two experimental phases (i.e., an encoding and a recognition phase) in which the targets and the distractors were presented and recognition performance was measured. rTMS stimulation was provided over the left DLPFC during the recognition phase. We found that the rTMS stimulation affected the memory recognition of positive emotional material. Moreover, related and unrelated distractors were discarded better when they were positively valenced, and a more significant effect (i.e., increased performance) was produced in response to related distractors. This result suggests that the activation of the left DLPFC favours the memory recognition of positive emotional information, and that such activation is able to induce a more appropriate selective process to distinguish target from distractor stimuli in the presence of more complex processes (related distractors). The valence model of emotional cue processing may explain this increased performance by demonstrating the distinct role of the left hemisphere in the retrieval of positive emotional information. PMID- 22528736 TI - Inhibitory effects of Carpinus tschonoskii leaves extract on CpG-stimulated pro inflammatory cytokine production in murine bone marrow-derived macrophages and dendritic cells. AB - This report describes the anti-inflammatory effects of MeOH extract from leaves of Carpinus tschonoskii (CE) on primary bone marrow-derived macrophage (BMDMs) and dendritic cells (BMDCs). Primary BMDMs and BMDCs were used for pro inflammatory cytokine production and Western blot analysis. Human embryonic kidney cell line 293 T (HEK293 T) was used to access NF-kappaB activity. In all cases, CpG DNA was used to stimulate the cells. The CE (0-150 MUg/ml) was treated to BMDMs, BMDCs, and HEK293T cells. CE pre-treatment in CpG-stimulated BMDMs and BMDCs showed a dose-dependent inhibitory effect on pro-inflammatory cytokine (e.g., IL-12 p40, IL-6, and TNF-alpha) production as compared to non-treated controls. The CE pre-treatment had no significant inhibition on mitogen-activated protein kinases (MAPKs) phosphorylation but strongly inhibited IkappaBalpha degradation. In NF-kappaB reporter gene assay, the CE pre-treatment inhibited NF kappaB-dependent luciferase activity in a dose-dependent manner. Taken together, these data suggest that CE has significant inhibitory effect on pro-inflammatory cytokine production and warrant further studies concerning potentials of CE for medicinal uses. PMID- 22528735 TI - Effect of neuronal induction on NSE, Tau, and Oct4 promoter methylation in bone marrow mesenchymal stem cells. AB - Cell differentiation involves widespread epigenetic reprogramming, including modulation of DNA methylation patterns. The differentiation potential differences in DNA methylation patterns might function in pluripotency restriction, while tissue-specific differences might work in lineage restriction. To investigate the effects of neuronal induction on promoter methylation pattern in rat bone marrow mesenchymal stem cells (MSCs), we used bisulfite sequencing to analyze the methylation status of the promoter regions in neuron-specific enolase (NSE), microtubule-associated protein Tau, and Oct4 genes in MSCs pre- and post-chemical induction. Neurocytes from the newborn rat brains were used as control. Data showed that NSE and Tau were abundantly expressed in the brain cells and MSC derived neurocyte-like cells as well but not in the MSCs. However, both NSE promoter (-214~+57 bp) and Tau promoter (-239~+131 bp) were hypomethylated (<4 % CpG methylation). Oct4 was expressed in MSCs, and the Oct4 promoter (-293~-85 bp) was hypermethylated (>79 % CpG methylation). Interestingly, it was found that the methylation of the locus -113 bp upstream of Oct4 transcription start site was specifically enhanced in the process of MSCs' neuronal differentiation. Further experiments in hepatocytes derived from MSCs and hepar tissue proved that the 113 bp locus methylation increased also in non-neurogenic lineages. Tfsitescan prediction showed that AP-2-alpha/gamma and Sp1 might regulate Oct4 transcription upon MSC differentiation by binding the -113 bp locus. So, we conclude that promoter methylation modifies pluripotency-specific gene, rather than regulates the expression of neural-specific genes when MSCs differentiate into neurocyte like cells. PMID- 22528740 TI - Effects of antifungal agents alone and in combination against Candida glabrata strains susceptible or resistant to fluconazole. AB - The rise of Candida spp. resistant to classic triazole antifungal agents has led to a search for new therapeutic options. Here, we evaluated combinations of antifungals in a checkerboard assay against two groups of Candida glabrata strains: one containing fluconazole-susceptible clinical isolates (FS) and another containing fluconazole-resistant laboratory derivative (FR). The most synergistic combination observed was amphotericin B + flucytosine (synergistic for 61.77 % of FS strains and 76.47 % of FR strains). The most antagonistic combination observed was ketoconazole + flucytosine (FS 61.77 % and FR 55.88 %). Surprisingly, most combinations evidenced indifferent interactions, and the best synergism appeared when amphotericin B and flucytosine were combined against both groups of isolates. PMID- 22528741 TI - Antifungal activities of different extracts of marine macroalgae against dermatophytes and Candida species. AB - Algae are bioactive natural resources, and due to the medical importance of superficial mycoses, we focused the action of macroalgae extracts against dermatophytes and Candida species. Seaweed obtained from the Riacho Doce beach, Alagoas (Brazil), were screened for the antifungal activity, through crude extracts using dichloromethane, chloroform, methanol, ethanol, water and chloroform and hexane fractions of green, brown and red algae in assays with standard strains of the dermatophytes Trichophyton rubrum, T. tonsurans, T. mentagrophytes, Microsporum canis, M. gypseum and yeasts Candida albicans, C. krusei, C. guilliermondi and C. parapsilosis. The M44-A and M27-A2/M38A manuals by CLSI were followed, and the minimum inhibitory concentration (MIC) ranged from 0.03 to 16.00 MUg ml(-1), and an inhibition halo of 10.00-25.00 mm was observed for dermatophytes, while for yeast, it was from 8.00 to 16.00 MUg ml(-1) and 10.00-15.00 mm. M. canis showed MIC of 0.03 MUg ml(-1) and the largest inhibition halo in T. rubrum (25.00 mm) through the use of the methanol extract. For C. albicans, dichloromethane, methanol and ethanol extracts formed the largest inhibition halo. The ethanol extract was shown to be the best inhibiting fungi growth, and chloroform and hexane fractions of H. musciformis inhibited the growth of all dermatophytes and C. albicans, yielding the conclusion that apolar extracts obtained from algae presented the best activity against important pathogenic fungi. PMID- 22528742 TI - Successful medical management of recalcitrant Fusarium solani keratitis: molecular identification and susceptibility patterns. AB - Fungal keratitis is a rare but sight-threatening infection of the cornea that may be caused by several fungal pathogens. A delay in diagnosis and inadequate treatment may even lead to loss of the affected eye. Fungal keratitis is often misdiagnosed as bacterial keratitis because isolation and identification of the fungal pathogen is difficult and requires experience, and fungal growth in culture requires time. In this report, a 14-year-old boy with recalcitrant Fusarium solani keratitis, unresponsive to initial therapy, is presented. CLSI M38-A2 in vitro antifungal susceptibility tests demonstrated that only amphotericin B (0.5 MUg/ml) had potent activity against F. solani; however, fluconazole (>64 MUg/ml), itraconazole (>16 MUg/ml), voriconazole (8 MUg/ml), and posaconazole (>16 MUg/ml) had high minimum inhibitory concentrations. In addition, caspofungin (>16 MUg/ml) and anidulafungin (>16 MUg/ml) exhibited high minimum effective concentrations. Repeated intrastromal voriconazole injections, topical voriconazole, and caspofungin combined with systemic antifungal agents improved of the corneal lesion with a significant increase in visual acuity. Intrastromal voriconazole injection may be used as an adjunctive treatment method for recalcitrant fungal keratitis with no prominent complications. The intrastromal route could be an effective route of administration of antifungal agents, especially for F. solani keratitis, as in this case. A combination of various antifungal agents administered by different routes prevented loss of the eye. PMID- 22528743 TI - Beyond blood pressure: evidence for cardiovascular, cerebrovascular, and renal protective effects of renin-angiotensin system blockers. AB - For patients with hypertension, effective control of blood pressure (BP) reduces cardiovascular (CV), and renal risk. Antihypertensive agents that offer benefits that extend beyond those associated with BP reduction alone, to include tissue protective effects and effects on the vasculature, may be of benefit for many patients with increased CV risk due to comorbidities or prior history of CV events. Renin-angiotensin system (RAS) blockers [angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs)] are guideline recognized, highly effective antihypertensive agents that exert their BP-lowering action through different mechanisms at different levels of the RAS. Large-scale clinical studies suggest that small, between-treatment differences in BP lowering do not account for observed outcome differences between RAS blockers and other antihypertensive agents. Analysis of data from seminal clinical studies and meta analyses identify that, controlling for effects on BP control, RAS blockers may be more effective than calcium channel blockers (CCBs) in reducing risk of myocardial infarction and congestive heart failure; ARBs may be more effective than either ACEIs or beta blockers in stroke prevention; CCBs may be more effective than RAS blockers in stroke prevention; and ARBs may be more effective than beta blockers in reducing left ventricular hypertrophy. This review considers the rationale and evidence for benefits of RAS blockade beyond BP lowering, and highlights the differences between ARBs and ACEIs, and between agents within these drug classes. PMID- 22528744 TI - Significance of circulating endothelial progenitor cells in patients with fracture healing process. AB - Fracture healing is a complex bone formation process, and neovascularization may contribute to new bone regeneration. The circulating endothelial progenitor cell (EPC) mobilization and homing could involve in neovascularization and vasculogenesis. In this study, we investigate the changes of circulating EPC during bone fracture healing, and the possible contribution of EPCs to increased neovascularization and fracture healing. The number of circulating EPCs was monitored in twenty-four patients with long bone traumatic fracture within the first 48 h and at 3, 5, 10, and 14 days post-fracture. The mononuclear cells which isolated from peripheral blood were analyzed by flow cytometry. Peripheral blood counts of leukocytes and platelets were measured by hematology analyzer. The amount of peripheral EPCs significantly increased in patients with fracture compared to age-matched healthy control subjects within the first 48 h after injury, and peaked at 3 days post-fracture. There was no significant difference in the change trend of early EPCs between male and female, but the number of early EPCs was significantly greater in younger patients compared to older patients. A comparison of the EPCs levels between patients with severe injury (ISS > 16) and patients with mild injury (ISS <= 16) revealed no statistically significant difference. The level of early EPCs was inverse correlation with the level of plate after fracture, but no correlation with the level of peripheral leucocytes. These findings suggest traumatic fracture may induce the mobilization of EPCs into the peripheral circulation. The increased EPCs may contribute to neovascularization and involve in fracture healing. PMID- 22528745 TI - Non-lithographic SERS substrates: tailoring surface chemistry for Au nanoparticle cluster assembly. AB - Near-field plasmonic coupling and local field enhancement in metal nanoarchitectures, such as arrangements of nanoparticle clusters, have application in many technologies from medical diagnostics, solar cells, to sensors. Although nanoparticle-based cluster assemblies have exhibited signal enhancements in surface-enhanced Raman scattering (SERS) sensors, it is challenging to achieve high reproducibility in SERS response using low-cost fabrication methods. Here an innovative method is developed for fabricating self organized clusters of metal nanoparticles on diblock copolymer thin films as SERS active structures. Monodisperse, colloidal gold nanoparticles are attached via a crosslinking reaction on self-organized chemically functionalized poly(methyl methacrylate) domains on polystyrene-block-poly(methyl methacrylate) templates. Thereby nanoparticle clusters with sub-10-nanometer interparticle spacing are achieved. Varying the molar concentration of functional chemical groups and crosslinking agent during the assembly process is found to affect the agglomeration of Au nanoparticles into clusters. Samples with a high surface coverage of nanoparticle cluster assemblies yield relative enhancement factors on the order of 109 while simultaneously producing uniform signal enhancements in point-to-point measurements across each sample. High enhancement factors are associated with the narrow gap between nanoparticles assembled in clusters in full-wave electromagnetic simulations. Reusability for small-molecule detection is also demonstrated. Thus it is shown that the combination of high signal enhancement and reproducibility is achievable using a completely non-lithographic fabrication process, thereby producing SERS substrates having high performance at low cost. PMID- 22528746 TI - Development of a high-throughput real-time PCR assay for the detection of the R81T mutation in the nicotinic acetylcholine receptor of neonicotinoid-resistant Myzus persicae. AB - BACKGROUND: Myzus persicae is a globally important aphid pest that is mainly controlled through the application of chemical insecticides. Recently, a clone of M. persicae exhibiting control-compromising levels of resistance to neonicotinoid insecticides was described. The resistance of this clone was associated with reduced affinity of imidacloprid for the target site (the nicotinic acetylcholine receptor) as a result of mutation of a key amino acid residue (R81T) in the loop D region of a nAChR beta1 subunit. The potent levels of resistance conferred by this mechanism are cause for considerable concern, and the frequency and distribution of the mutation in worldwide populations of M. persicae require careful monitoring. In this study, a high-throughput assay has been developed that allows detection of the mutation in individual aphids. RESULTS: A real-time TaqMan assay to detect the R81T substitution was developed that proved to be sensitive and specific in tests of analytical sensitivity and in a blind genotyping trial of DNA extracted from individual aphids comprising the three possible genotypes. The assay was then used to examine the frequency of the R81T mutation in aphids collected and stored in ethanol from peach orchards in southern France. The R81T frequency varied from 33 to 100% in seven populations from the department of Gard, France. CONCLUSIONS: This study describes a rapid and sensitive assay that very effectively detects the R81T mutation in individual aphids. The results also have practical significance for the control of M. persicae in southern France and provide contemporary data to inform current resistance management strategies. PMID- 22528747 TI - What influences midwives in estimating labour pain? AB - BACKGROUND: Clinicians' estimates of patients' pain are frequently used as a basis for delivering care, and the characteristics of the clinician and of the patient influence this estimate. METHODS: We studied pain estimation by midwives attending women in uncomplicated labour. Sixty-six practising midwives of varied age, ethnicity and professional experience were asked to complete a trait empathy measure and then to estimate the maximum pain and anxiety experienced by six women whose filmed labour contractions they viewed. Additionally, they rated similarity to the labouring women in ethnicity, and described their beliefs about pain expression according to ethnicity. RESULTS: Midwife estimates of pain and anxiety were highly correlated. Longer professional experience was associated with lower pain estimates, while more births to the midwife herself was associated with higher pain estimates. A multiple regression model identified number of births to the midwife herself, and two components of empathy (perspective taking and identification), to be important in predicting midwife pain estimates for women in labour. Midwives expressed clear beliefs about women's expression of pain during labour according to ethnicity, but these beliefs were not consistent across midwives, even between midwives of similar ethnicity. CONCLUSION: Midwives' personal characteristics can bias the estimation of pain in woman in labour and therefore influence treatment. PMID- 22528748 TI - Comparison of caspase-3 activation in tumor cells upon treatment of chemotherapeutic drugs using capillary electrophoresis. AB - Caspases play important roles in cell apoptosis. Measurement of the dynamics of caspase activation in tumor cells not only facilitates understanding of the molecular mechanisms of apoptosis but also contributes to the development, screening, and evaluation of anticancer drugs that target apoptotic pathways. The fluorescence resonance energy transfer (FRET) technique provides a valuable approach for defining the dynamics of apoptosis with high spatio-temporal resolution. However, FRET generally functions in the single-cell level and becomes ineffective when applied in the high throughput detection of caspase activation. In the current study, a FRET sensor was combined with capillary electrophoresis (CE) to achieve a high throughput method for cellular caspase detection. The FRET-based CE system is composed of a homemade CE system and a laser source for detecting the dynamics of caspase-3 in various cells expressing sensors of caspase-3 that have been treated with anticancer drugs, such as cell cycle-independent drug cisplatin and specific cell cycle drugs camptothecin and etoposide, as well as their combination with tumor necrosis factor (TNF). A positive correlation between the caspase-3 activation velocity and drug concentration was observed when the cells were treated with cisplatin, but cells induced by camptothecin and etoposide did not show any apparent correlation with their concentrations. Moreover, different types of cells presented distinct sensitivities under the same drug treatment, and the combination treatment of TNF and anticancer drugs significantly accelerated the caspase-3 activation process. Its high throughput capability and detection sensitivity make the FRET-based CE system a useful tool for investigating the mechanisms of anticancer drugs and anticancer drug screening. PMID- 22528749 TI - How carnivorous fungi use three-celled constricting rings to trap nematodes. AB - Predacious fungi form specialized hyphae structures to trap nematodes and other microscopic animals. Among the six kinds of trapping devices, the constricting ring is the only one that actively captures nematodes. When a nematode enters the aperture of the ring, which is formed by three cells, the cells rapidly triple their volume, close the aperture and hold the nematode in place. Hyphae then penetrate and consume the nematode. This paper reviews the data and hypotheses on conserving the evolution of constricting rings and their cytological and molecular mechanisms. PMID- 22528750 TI - Non-viral iPSCs: a safe way for therapy? PMID- 22528752 TI - Fine-tune of intrinsic ERK activity by extrinsic BMP signaling in mouse embryonic stem cells. AB - Embryonic stem (ES) cells hold great promise in regenerative medicine and it is an urgent task to understand the underlying molecular mechanisms that control ES cell fate choice between self-renewal and differentiation. In mouse ES cells, extrinsic leukemia inhibitory factor (LIF) and bone morphogenetic protein (BMP) signaling pathways play pivotal roles in maintaining the self-renewal status under serum and feeder free culture conditions. Intrinsic extracellular-signal regulated kinase (ERK) activity is also important in determining mouse ES cell fate-low ERK activity keeps mouse ES cell self-renewal while high ERK activity drives differentiation. We recently found that while LIF signaling augments ERK activity, BMP signaling inhibits ERK activity in mouse ES cells via direct upregulation of an ERK phosphatase-dual-specificity phosphatase 9. The cooperative effects of LIF and BMP signaling keep appropriate ERK activity and maintain mouse ES cell self-renewal (Li et al., 2012). These findings shed light on how extrinsic signals converge to intrinsic signaling molecules to regulate cell fate determination. This perspective summarizes our recent new findings and discusses the current unsolved questions and future directions. PMID- 22528751 TI - The genomic stability of induced pluripotent stem cells. AB - With their capability to undergo unlimited self-renewal and to differentiate into all cell types in the body, induced pluripotent stem cells (iPSCs), reprogrammed from somatic cells of human patients with defined factors, hold promise for regenerative medicine because they can provide a renewable source of autologous cells for cell therapy without the concern for immune rejection. In addition, iPSCs provide a unique opportunity to model human diseases with complex genetic traits, and a panel of human diseases have been successfully modeled in vitro by patient-specific iPSCs. Despite these progresses, recent studies have raised the concern for genetic and epigenetic abnormalities of iPSCs that could contribute to the immunogenicity of some cells differentiated from iPSCs. The oncogenic potential of iPSCs is further underscored by the findings that the critical tumor suppressor p53, known as the guardian of the genome, suppresses induced pluripotency. Therefore, the clinic application of iPSCs will require the optimization of the reprogramming technology to minimize the genetic and epigenetic abnormalities associated with induced pluripotency. PMID- 22528754 TI - Metabolic regulatory and anti-oxidative effects of modified Bushen Huoxue decoction on experimental rabbit model of osteoarthritis. AB - OBJECTIVE: To observe the metabolic, regulatory and anti-oxidative effects of modified Bushen Huoxue Decoction (BSHXD), a Chinese herbal medicine for kidney (Shen)-reinforcement and blood-activation, on an osteoarthritis (OA) rabbit model. METHODS: A rabbit model for knee joint OA was established by the classic Hulth's method. The OA model rabbits were randomized into 5 groups: the model control group, the positive control group treated with glucosamine sulfate, and the three BSHXD treated groups treated respectively with low, moderate, and high doses of BSHXD. In addition, a normal control group and a sham-operated group were set up. Experimental animals were sacrificed after a 7-week treatment, and pathological changes in cartilaginous tissue were estimated using the Mankin criteria. Hydroxyproline (Hyp) and malonaldehyde (MDA) contents in blood serum and urine, as well as superoxide dismutase (SOD) activity and nitric oxide (NO) content in blood serum and knee joint synovial homogenates were detected. RESULTS: Mankin scoring showed insignificant statistical differences between the various treatment groups (P >0.05), but all were better than the model control group (P <0.05). Serum and urinary contents of Hyp and MDA as well as serum and synovial levels of NO were significantly lower, but the SOD activity in blood serum and synovial tissue was higher in the BSHXD treated groups than in the model group P <0.01); the effect of BSHXD was dose-dependent to some extent. CONCLUSION: The modified BSHXD shows an effect of improving cartilage metabolism in experimental rabbits with OA, and possesses osteo-chondric protective effects in antagonizing peroxidation injury. PMID- 22528753 TI - Neuronal stem cells in the central nervous system and in human diseases. AB - The process of cortical expansion in the central nervous system is a key step of mammalian brain development to ensure its physiological function. Radial glial (RG) cells are a glial cell type contributing to this progress as intermediate neural progenitor cells responsible for an increase in the number of cortical neurons. In this review, we discuss the current understanding of RG cells during neurogenesis and provide further information on the mechanisms of neurodevelopmental diseases and stem cell-related brain tumorigenesis. Knowledge of neuronal stem cell and relative diseases will bridge benchmark research through translational studies to clinical therapeutic treatments of these diseases. PMID- 22528756 TI - Drug discovery enters a new era with multi-target intervention strategy. AB - In the past century, as medical research has become increasingly precise, it has become clear that the incidence and progression of many diseases involve multiple factors and pathologies; this is particularly true for the degenerative and metabolic diseases facing industrialized societies. At the same time, it becomes increasingly clear that single-target action drugs cannot effectively treat these diseases. Researchers are looking toward the chemical industry as well as traditional herbal medicines to find multi-target interventions. Thus, a new era in drug discovery has begun. Specifically, three approaches have proven effective in seeking multi-target drugs. These are: (1) designing drugs with multiple components; (2) discovering drugs through the study of synergistic compound compound interactions in medicinal herbs or among chemical drugs and herbal components; and (3) developing drugs to tackle complex multi-component diseases. The authors conclude that there is an increasing need for multi-component remedies to treat the complex chronic diseases afflicting modern populations. Given this situation and the growing body of evidence that these new approaches are effective, multi-target intervention appears to have great potential for discovering, designing, and developing effective new drugs for today's diseases. PMID- 22528755 TI - Total alkaloids from Sophora alopecuroides L. increase susceptibility of extended spectrum beta-lactamases producing Escherichia coli isolates to cefotaxime and ceftazidime. AB - OBJECTIVE: To evaluate the antimicrobial activity of total alkaloids extracted from Sophorea alopecuroides L. (TASA) against clinical isolated extended-spectrum beta-lactamases (ESBLs) producing Escherichia coli (E. coli) strains. METHODS: The antibacterial activity of TASA either itself or in combination with cefotaxime (CTX) or ceftazidime (CAZ) was investigated by using the microbroth dilution method and phenotypic confirmatory disk diffusion test against three clinical isolated ESBLs-producing E. coli strains; the interactions of TASA and CTX or CAZ were ascertained by evaluating the fractional inhibitory concentration index (FICI). RESULTS: The antibacterial activity of either TASA itself or in combination with CTX or CAZ was found. The minimum inhibitory concentration (MICs) of TASA against the ESBLs producing isolates was 12.5 mg/mL. In the combinations with a sub-inhibitory concentration of TASA, a synergistic effect on CTX and CAZ against the ESBLs producing isolates was observed. Similarly, the isolates exposed to lower dose of TASA yielded an increased susceptibility to CTX and CAZ by 8-16 folds determined by microdilution assay. Moreover, enzymatic detection of ESBLs demonstrated that TASA induced reversal resistance to CTX and CAZ partially by a mechanism of inhibition of ESBLs activity in these isolates. Additionally, in the tested isolates following the exposure of TASA, molecular analysis verified the SHV-type beta-lactamase encoding ESBL gene in these isolates, and no mutation was introduced into the ESBL gene. CONCLUSIONS: These results suggest that TASA could be used as a source of natural compound with pharmacological activity of reversal resistance to antimicrobial agent. These findings also indicated that the application of the TASA in combination with antibiotics might prove useful in the control and treatment of infectious diseases caused by the ESBLs producing enterobacteriaceae. PMID- 22528757 TI - A randomized, double blinded, placebo-controlled clinical trial of silymarin in ulcerative colitis. AB - OBJECTIVE: To evaluate the clinical efficacy of silymarin in ulcerative colitis (UC) patients. METHODS: A randomized double blinded placebo-controlled clinical trial was conducted in 80 UC patients whose disease had been documented and were in remission state between September 2009 and October 2010. Patients were assigned to silymarin group (42 cases) and placebo group (38 cases) using a random number table. Either silymarin (140 mg) or placebo (lactose mono-hydrate, corn starch magnesium stearate) tablets were given once daily for 6 months along with their standard therapy. The efficacies were assessed by disease activity index (DAI), frequency difference of the disease flare-up, and paraclinical data. RESULTS: Ten patients (4 in the silymarin group due to nausea and 6 in the placebo group due to disease flare-up and abdominal pain) discontinued the study. An improvement in hemoglobin level (11.8+/-1.6 g/dL vs. 13.4+/-1.2 g/dL,P<0.05) and erythrocyte sedimentation rate (23.7+/-11.5 mm/h vs.10.8+/-3.2 mm/h,P<0.05) was observed in the silymarin group but not in the placebo group. DAI significantly decreased in the silymarin group and reached from 11.3+/-3.5 to 10.7+/-2.8 (P<0.05). Thirty-five out of 38 patients in the silymarin group were in complete remission with no flare-up after 6 months as compared to 21 out of 32 patients in the placebo group (P=0.5000). CONCLUSION: Silymarin as a natural supplement may be used in UC patients to maintain remission. PMID- 22528758 TI - Effects and mechanisms of the functional parts of Dahuang Zhechong pill containing serum on platelet-derived growth factor-stimulated proliferation of vascular smooth muscle cells. AB - OBJECTIVE: To investigate and compare the effects and mechanisms of three functional parts of Dahuang Zhechong Pill (DHZCP), including drugs with the function of removing blood stasis and promoting blood circulation (FP-I), drugs with the function of expelling heat and moistening dryness (FP-II), and drugs with the function of nourishing yin and replenishing blood (FP-III) of DHZCP, on platelet-derived growth factor (PDGF)-stimulated vascular smooth muscle cells (VSMCs) proliferation with the method of serum pharmacology. METHODS: VSMCs proliferation of rat was assayed by measuring the cell viability with the 3-(4, 5 dimethylthiazol-2yl)-2, 5-diphenyltetrazolium bromide (MTT) method. DNA synthesis in VSMCs was examined by detecting 5'-bromo-2'-deoxyuridine incorporation with the immunocytochemical method. Cycle of VSMCs was evaluated with flow cytometry. Expression of cyclin D1, p27, PKCalpha, and phosphorylated extracellular signal regulated kinase 1/2 (ERK1/2) was quantified by the Western blotting method. RESULTS: The FP-I and FP-III containing serum was capable of inhibiting PDGF stimulated proliferation and DNA synthesis of VSMCs, arrested VSMCs in G phase, downregulated cyclin D1, and upregulated p27 expression (P <0.01 or P <0.05). The FP-I and FP-III containing serum also inhibited the PDGF-induced phosphorylation of tyrosine of ERK1/2 and PKCalpha expression (P <0.01 or P <0.05). CONCLUSIONS: FP-I and FP-III of DHZCP are able to inhibit VSMCs proliferation via interrupting PKCalpha-ERK1/2 signaling, modulating the expression of cell cycle proteins to result in arresting the cells in G phase. The inhibitory effect is mainly related to the function of removing blood stasis and promoting blood circulation, slightly to the function of nourishing yin and replenishing blood, but not to the function of expelling heat and moistening dryness. PMID- 22528759 TI - Combined common femoral artery endarterectomy with superficial femoral artery stenting plus Shuxuening Injection infusion for chronic lower extremity ischemia: 3-year results. AB - OBJECTIVE: To investigate the efficacy and safety of combined common femoral artery (CFA) endarterectomy with superficial femoral artery (SFA) stenting plus Shuxuening Injection infusion in patients with complex multifocal arterial steno obstructive lesions of the lower extremities. METHODS: From March 2006 to March 2011, 104 lower limbs in 96 patients with multilevel peripheral arterial steno occlusive disease, involving SFA as well as CFA and deep femoral artery (DFA) orifice, were treated by combined surgical with endovascular therapy, such as SFA stenting as an adjunct to CFA endarterectomy and patch angioplasty with the great saphenous vein. Before the end of the operation, 20 mL of Shuxuening Injection was infused through the catheter located in the treated artery. Technical and hemodynamic success, as well as primary and primary-assisted patency, was determined according to the Society for Vascular Surgery Guidelines. During follow-up, clinical status assessment, ankle-brachial index (ABI) test, and duplex Doppler ultrasound were administered every 6 months, and computed tomography angiography or magnetic resonance angiography was performed at 12, 24, and 36 months after discharge. RESULTS: All patients underwent successful combined CFA endarterectomy with SFA stenting treatment. The average ABI after the combination treatment increased from pretreatment of 0.32+/-0.21 to 0.82+/ 0.24 (P<0.01). No perioperative death and major limb amputations occurred. The mean duration of follow-up for 104 limbs from 96 patients was 1,180 days (range, 196-2,064 days). During follow-up, 5 patients died due to myocardial infarction, cerebral infarction, or pneumonia, and 5 patients were lost to follow-up. There were 21 cases (21.4%) of restenosis, with 15 that occurred in-stent and 6 near the distal end of the stent. A total of 18 (18.3%) reinterventions were performed, including 6 balloon angioplasty, 8 restenting procedures, 2 bypass surgeries, and 2 major limb amputations. The primary patency rates were 92.2%, 76.8%, and 61.3% at 12, 24, and 36 months, respectively, while the primary assisted patency rates were 94.4%, 83.2%, and 75.6% at 12, 24, and 36 months, respectively. CONCLUSION: The combined CFA endarterectomy with SFA stenting plus Shuxuening Injection infusion appears to offer a safe, less invasive, and effective treatment option to patients with chronic lower extremity ischemia due to complex multifocal peripheral artery disease. PMID- 22528760 TI - Oxidative damage of lung and its protective mechanism in mice caused by long-term exposure to titanium dioxide nanoparticles. AB - Exposure to titanium dioxide nanoparticles (TiO(2) NPs) elicits an adverse response such as oxidative damage. The molecular targets of TiO(2) NPs remain largely unidentified. In the present study, the function and signal pathway of nuclear factor erythroid 2 related factor 2 (Nrf2) in protection against TiO(2) NPs-induced oxidative stress in the mouse lung were investigated. Mice were exposed to 10 mg/kg body weight by an intratracheal administration for 15-90 days. With increasing exposed terms, TiO(2) NPs were significantly accumulated and increased the reactive oxygen species (ROS) production in lung, which resulted in severe pulmonary edema, inflammatory response and pneumonocyte apoptosis for 90 days. Furthermore, TiO(2) NPs exposure could greatly induce expression of Nrf2, heme oxygenase 1 (HO-1), and glutamate-cysteine ligase catalytic subunit (GCLC) from 15-day to 75-day exposure, whereas 90-day exposure caused significant decreases of three factors expression levels in lung. Our findings imply that the induction of Nrf2 expression is an adaptive intracellular response to TiO(2) NPs-induced oxidative stress in the mouse lung, and that Nrf2 is protective against TiO(2) NPs-induced pulmonary damages during certain exposure terms. PMID- 22528761 TI - High-resolution computed tomography analysis of the medial infratemporal fossa: a pilot study. AB - BACKGROUND: The medial aspect of the infratemporal fossa (ITF) can be accessed endoscopically. Two important landmarks to help guide dissection in this area have previously been identified: the anterior border of the foramen ovale (AFO) and the "bony bridge" (BB), a consistent bridge of bone between the foramen ovale and spinosum. We conducted a pilot study using high-resolution computed tomography (HRCT) to measure the distances to these structures. METHODS: Thirty measurements were acquired from 15 adult patients undergoing HRCT scans of the sinuses. The position of the anterior nasal spine (ANS), AFO, and BB on the 3 orthogonal planes were identified by 3 observers. Euclidian distances between each of these structures were calculated. A cadaveric dissection was performed and images were acquired to provide an endoscopic view. RESULTS: Fifteen HRCT scans of the sinuses (8 females) were analyzed. The mean distances from the ANS to the AFO and BB were 78.5 +/- 5.9 mm and 83.2 +/- 6.0 mm, respectively. For males alone, these distances were 80.3 +/- 4.3 mm and 85.3 +/- 4.8 mm, respectively, and in females 77.0 +/- 6.5 mm and 81.4 +/- 6.7 mm, respectively. CONCLUSION: Average distance from the ANS to the AFO and BB was 78.5 mm and 83.2 mm, respectively. These measurements can be used by endoscopic skull base surgeons to guide dissection in the ITF. PMID- 22528762 TI - Size-controlled fabrication of polydiacetylene-embedded microfibers on a microfluidic chip. AB - A microfluidic technique was employed to fabricate polydiacetylene (PDA)-embedded hydrogel microfibers. By taking advantage of calcium ion-induced insoluble hydrogel formation, supramolecularly assembled diacetylene (DA)-surfactant complexes were successfully immobilized in the calcium alginate fibers. Thus, instantaneous microfiber formation was observed when the core flow of DA supramolecules-containing alginate solution met the sheath flow of calcium ions. UV irradiation of the resulting fibers afforded blue colored PDAs, and the formation of a conjugated polymer was confirmed by heat-induced phase transition and by Raman spectroscopy. By adjusting the core and sheath flow rates, PDA embedded hydrogel fibers of various sizes were obtained. PMID- 22528763 TI - Analysis of stromal gene expression for the identification of prognostic and predictive molecular markers in cancer therapy. PMID- 22528764 TI - Treating women with HIV: is it different than treating men? AB - While antiretroviral therapy (ART) has had a tremendous impact on the morbidity and mortality of patients with HIV, there is evidence that many HIV-infected women experience treatment challenges that are different from men and these challenges are often associated with poorer outcomes. In the United States, blacks and Latino women are disproportionately affected by the HIV epidemic related to lack of access to high-quality HIV care, and socioeconomic factors. In Africa and Asia, HIV infection in women is affected by gender norms that often leave women dependent upon men (either emotionally or financially) and vulnerable in relationships. These gender norms and, in some cases, fears of violence make it difficult for women to refuse unprotected sex, and can contribute to higher infection rates in women and delayed entry to care. Many African migrants in Europe and Australia may feel stigmatized and fear discrimination when accessing care. As a consequence, despite the availability of highly active antiretroviral therapy, women with HIV often have delayed entry into care and experience poor outcomes. With the notable exception of treatment during pregnancy, there is little in the published literature to suggest that the treatment of choice for treatment-naive patients should be determined by the patient's sex. While virologic efficacy of ART may be similar in large clinical trials, differences in the frequency of treatment-related side effects and the impact of pregnancy and/or child-bearing status on treatment choice is well documented. In this paper we aim to discuss antiretroviral therapy in HIV-infected women, the sex-specific barriers to starting care, the differences in outcomes, and complications. PMID- 22528765 TI - Therapeutic options for low bone mineral density in HIV-infected subjects. AB - With the advent of effective antiretroviral therapy (ART), the recognition and management of long-term complications of HIV infection and ART are increasingly important for HIV physicians. Low bone mineral density (BMD) is more common in those with HIV infection and this review will outline therapeutic options for the management of low bone mineral density relevant to HIV-infected populations. PMID- 22528768 TI - (1)H-, (13)C- and (15)N-NMR assignment of the N-terminal domain of human cerebral dopamine neurotrophic factor (CDNF). AB - Parkinson's disease (PD) is a neurodegenerative disorder that is caused by the death of midbrain dopaminergic neurons. Current therapies for PD do not halt the neurodegeneration nor repair the affected neurons. Therefore, search for novel neurotrophic factors (NTF) for midbrain dopaminergic neurons, which could be used in novel therapeutic approaches, is highly wanted. In 2007, a potent NTF for dopaminergic neurons was described as the conserved dopamine neurotrophic factor (CDNF). Single doses of this protein protect and restore dopaminergic neurons in experimental models of PD. CDNF has two domains; an N-terminal saposin-like domain, which may bind to membranes; and a presumably intrinsically unstructured C-terminal which contains an internal cysteine bridge in a CXXC motif similar to that of thiol/disulphide oxidoreductases and isomerases, and may thus reduce the endoplasmic reticulum stress caused by incorrectly folded proteins. We show for the first time the nuclear magnetic resonance assignment of N-terminal domain of recombinant CDNF (residues 1-105) by solution 2D and 3D NMR spectroscopy. We were able to obtain a nearly complete resonance assignment, which is the first step toward the solution structure determination of this neurotrophic factor. PMID- 22528767 TI - (1)H, (13)C, and (15)N resonance assignment of photoactive yellow protein. AB - Photoactive yellow protein (PYP) is involved in the negative phototactic response towards blue light of the bacterium Halorhodospira halophila. Here, we report nearly complete backbone and side chain (1)H, (13)C and (15)N resonance assignments at pH 5.8 and 20 degrees C of PYP in its electronic ground state. PMID- 22528766 TI - HIV and inflammation: mechanisms and consequences. AB - Persistent immune activation and inflammation despite sustained antiretroviral therapy (ART)-mediated viral suppression has emerged as a major challenge of the modern HIV treatment era. While immune activation, inflammatory, and coagulation markers typically decline during suppressive ART, they remain abnormally elevated in many HIV-infected individuals and predict subsequent mortality and non-AIDS morbidities including cardiovascular disease. The goal of this review is to summarize the current state of our knowledge regarding the underlying causes of persistent immune activation during ART-mediated viral suppression as well as the link between persistent immune activation and morbidity and mortality in this setting. Several recent studies have linked surrogate markers of this persistent inflammatory state to clinical outcomes, validating persistent immune activation as a viable therapeutic target. Other recent studies have helped clarify the roles of persistent HIV expression and/or replication, microbial translocation, and co-infections in driving this persistent inflammatory state, identifying targets for novel interventions. PMID- 22528769 TI - The effect of c-Fos demethylation on sodium fluoride-induced apoptosis in L-02 cells. AB - To investigate the effects of sodium fluoride (NaF) on apoptosis, c-Fos mRNA and protein expression levels, and methylation status as well as Dnmt1, Dnmt3a, and Dnmt3b mRNA expression levels in human embryo hepatocyte (L-02) which were exposed to different concentrations of NaF (0, 20, 40, and 80 mg/l) for 24 h in vitro. Results showed that the percentage of apoptosis and c-Fos mRNA and protein expression levels in 40 and 80 mg/l NaF-treated groups were higher than those in the control group (P<0.05). Further, Dnmt1 mRNA expression level was significantly decreased in the 80 mg/l NaF-treated groups compared to the control group (P<0.05); Dnmt3a and Dnmt3b mRNA expression levels were significantly decreased in 40 and 80 mg/l NaF-treated groups compared to the control group (P<0.05). c-Fos methylation levels, according to the bisulfite sequencing results, were decreased in 20, 40, and 80 mg/l NaF-treated groups against the control group. These results suggest that NaF could induce apoptosis and upregulate mRNA and protein expression level of c-Fos as well as decrease mRNA expression levels of Dnmt1, Dnmt3a, and Dnmt3b in L-02 cells. The decrease in c Fos methylation levels might be involved in the early phase of apoptosis induced by NaF in L-02 cells. PMID- 22528771 TI - Biodegradation of an organoselenium compound to elemental selenium by Lentinula edodes (shiitake) mushroom. AB - The present paper reports for the first time the transformation of an organic selenium compound into red selenium (Se), which causes the intense red pigmentation of Lentinula edodes (shiitake mushroom) mycelia. The biotransformation of 1,5-diphenyl-3-selenopentanedione-1,5 (diacetophenonyl selenide, preparation DAPS-25) was studied in liquid- and solid-phase cultures of L. edodes. In liquid culture medium, a red color develops in the mycelium at initial DAPS-25 concentrations equal to or higher than 0.1 mmol/l. The intensity and initiation time of coloration is Se concentration-dependent. Semiquantitative data obtained by physicochemical methods on the extent of Se and acetophenone production suggest that L. edodes is able to absorb and/or destruct this organic Se xenobiotic. PMID- 22528770 TI - Vitamin A modulates the expression of genes involved in iron bioavailability. AB - Iron bioavailability seems to be regulated by vitamin A (VA) but the molecular events involved in this mechanism are not well understood. It is also known that retinoids mediate most of their function via interaction with retinoid receptors, which act as ligand-activated transcription factors controlling the expression of a number of target genes. Here, we evaluated the VA effects on the modulation of the levels of mRNA encoding proteins involved in the iron bioavailability, whether in the intestinal absorption process or in the liver iron metabolism. The expression of genes involved in iron intestinal absorption (divalent metal transporter 1, duodenal cytochrome B, ferroportin 1 FPN1, and ferritin) were evaluated in vitro by treating Caco-2 cells with retinoic acid or in vivo by observing the effects of vitamin A deficiency (VAD) in BALB/C mice. Liver hepcidin and ferritin mRNA levels were upregulated by VAD; however, this condition did not promote any change on the expression of those genes that participate in the iron absorption. Moreover, data from the in vitro analysis showed that VA induced FPN1 gene expression by a hepcidin-independent manner. Therefore, the in vivo results support the idea that VAD may not affect iron absorption but would rather affect iron mobilization mechanisms. On the other hand, our results using Caco-2 cells raises the possibility that VA addition to intestinal epithelium may improve iron absorption through the induction of FPN1 gene expression. PMID- 22528772 TI - Toxic metals in breast milk samples from Ankara, Turkey: assessment of lead, cadmium, nickel, and arsenic levels. AB - Toxic metals are one of the significant groups of chemical contaminants that humans are exposed to by oral, inhalation, and dermal routes. Exposure to these chemicals begins with intrauterine life and continues during lactation period at the first years of life. Breastfeeding has a much more special place than other nutrition options for infants. However, when possibility of contaminant transfer by breast milk is considered, its safety and quality is essential. Regarding infant and mother health and limited number of information on this field in Turkey, measuring contamination levels in breast milk is important. Therefore, in the present study, lead (Pb), cadmium (Cd), nickel (Ni), and arsenic (As) levels were measured by atomic absorption spectrometry in 64 breast milk samples obtained from mothers from Ankara, Turkey. Pb and Ni levels in breast milk samples were found to be 391.45+/-269.01 MUg/l and 43.94+/-33.82 MUg/l (mean +/- SD), respectively. Cd was found only in one of 64 samples, and the level was 4.62 MUg/l. As level was below the limit of quantification (LOQ, 7.6 MUg/l) in all samples. These findings will accurately direct strategies and solutions of protection against contaminants in order to reduce their levels in biological fluids. PMID- 22528773 TI - Titanium dioxide nanoparticles-mediated in vitro cytotoxicity does not induce Hsp70 and Grp78 expression in human bronchial epithelial A549 cells. AB - Titanium dioxide nanoparticles (TiO(2)NPs) are increasingly being used in various industrial applications including the production of paper, plastics, cosmetics and paints. With the increasing number of nano-related products, the concern of governments and the general public about the health and environmental risks, especially with regard to occupational and other environmental exposure, are gradually increasing. However, there is insufficient knowledge about the actual affects upon human health and the environment, as well as a lack of suitable biomarkers for assessing TiO(2)NP-induced cytotoxicity. Since the respiratory tract is likely to be the main exposure route of industrial workers to TiO(2)NPs, we investigated the cytotoxicity of the anatase and rutile crystalline forms of TiO(2)NPs in A549 cells, a human alveolar type II-like epithelial cell line. In addition, we evaluated the transcript and protein expression levels of two heat shock protein (HSP) members, Grp78 and Hsp70, to ascertain their suitability as biomarkers of TiO(2)NP-induced toxicity in the respiratory system. Ultrastructural observations confirmed the presence of TiO(2)NPs inside cells. In vitro exposure of A549 cells to the anatase or rutile forms of TiO(2)NPs led to cell death and induced intracellular ROS generation in a dose-dependent manner, as determined by the MTS and dichlorofluorescein (DCF) assays, respectively. In contrast, the transcript and protein expression levels of Hsp70 and Grp78 did not change within the same TiO(2)NPs dose range (25-500 MUg/ml). Thus, whilst TiO(2)NPs can cause cytotoxicity in A549 cells, and thus potentially in respiratory cells, Hsp70 and Grp78 are not suitable biomarkers for evaluating the acute toxicological effects of TiO(2)NPs in the respiratory system. PMID- 22528774 TI - Matrix metalloproteinase-9 and the Cu/Zn ratio as ancillary diagnostic tools in distinguishing between the classical and follicular variants of papillary thyroid carcinoma. AB - The most common histological variants of papillary thyroid carcinoma (PTC), classical (CPTC) and follicular (FPTC), have different diagnostic features, molecular biology, and prognosis. Matrix metalloproteinase-9 (MMP-9) endopeptidase which degrades the components of the extracellular matrix is essential in the invasive growth and metastasizing of malignant tumors. The serum copper (Cu)/zinc (Zn) ratios are sensitive diagnostic and prognostic indicators in oncology since Cu- and Zn-dependent enzymes play important roles in the genesis and the progression of tumors. The aim of this study was to examine the expressions of MMP-9 in tissues of CPTC and FPTC, as well as to determine the Cu/Zn ratios in the same samples. MMP-9 was determined immunohistochemically, and the concentrations of copper and zinc in thyroid tissue were determined by means of flame atomic absorption spectrometry. The results obtained revealed significantly higher expressions of MMP-9 in CPTC in comparison with FPTC, as well as higher Cu/Zn ratios in CPTC than in FPTC. Thus, determining MMP-9 activities and the Cu/Zn ratios could improve the accuracy of the standard histopathological diagnosis of these two types of PTC. PMID- 22528775 TI - Postmenopausal vegetarians' low serum ferritin level may reduce the risk for metabolic syndrome. AB - The present study was conducted to compare the serum ferritin status between the postmenopausal vegetarians and non-vegetarians and to identify the relation of serum ferritin with metabolic syndrome (MetS) risk factors in postmenopausal women. The two study groups consisted of postmenopausal vegetarians (n=59) who maintained a vegetarian diet for over 20 years and age-matched non-vegetarian controls (n=48). Anthropometric measurements, dietary intakes, serum metabolic syndrome-related parameters, and serum ferritin level between the two groups were compared. The vegetarians exhibited significantly lower weight (p<0.01), body mass index (BMI) (p<0.001), percentage of body fat (p<0.001), waist circumference (p<0.01), SBP (p<0.001), DBP (p<0.001), and fasting glucose (p<0.05). According to the National Cholesterol Education Program (NCEP)-Adult Treatment Panel III criteria for MetS applying Korean guidelines for waist circumference, the prevalence of MetS was lower in vegetarians (33.9 %) than in non-vegetarians (47.9 %). Vegetarians had significantly lower serum level of ferritin (p<0.01) than non-vegetarians. In the correlation analysis, serum ferritin was positively related to fasting glucose (r=0.264, p<0.01), triglycerides (r=0.232, p<0.05), and the NCEP score (r=0.214, p<0.05) and negatively related to high-density lipoprotein-cholesterol (r=-0.225, p<0.05) after adjusting for BMI, lifestyle, and dietary factors (animal protein, animal fat, and dietary fiber intake). In conclusion, postmenopausal vegetarians had lower MetS presence and a lower serum ferritin level compared to non-vegetarians. Furthermore, vegetarians' low serum ferritin level may reduce the risk of MetS in postmenopausal women. PMID- 22528776 TI - Nickel and ultraviolet-B stresses induce differential growth and photosynthetic responses in Pisum sativum L. seedlings. AB - Enhanced level of UV-B radiation and heavy metals in irrigated soils due to anthropogenic activities are deteriorating the environmental conditions necessary for growth and development of plants. The present study was undertaken to study the individual and interactive effects of heavy metal nickel (NiCl(2).6H(2)O; 0.01, 0.1, 1.0 mM) and UV-B exposure (0.4 W m(-2); 45 min corresponds to 1.08 KJ m(-2)) on growth performance and photosynthetic activity of pea (Pisum sativum L.) seedlings. Ni treatment at high doses (0.1 and 1.0 mM Ni) and UV-B alone reduced chlorophyll content and photosynthetic activity (oxygen yield, carbon fixation, photorespiration, and PSI, PSII, and whole chain electron transport activities), and declining trends continued with combined doses. In contrast to this, Ni at 0.01 mM appeared to be stimulatory for photosynthetic pigments and photosynthetic activity, thereby enhanced biomass was observed at this concentration. However, combined dose (UV-B + 0.01 mM Ni) caused inhibitory effects. Carotenoids showed different responses to each stress. Nickel at high doses strongly inhibited PSII activity and the inhibition was further intensified when chloroplasts were simultaneously exposed to UV-B radiation. PSI activity appeared to be more resistant to each stress. High doses of Ni (0.1 and 1.0 mM) and UV-B alone interrupted electron flow at the oxygen evolving complex. Similar damaging effects were caused by 0.01 and 0.1 mM Ni together with UV-B, but the damage extended to PSII reaction center in case of 1.0 mM Ni in combination with UV-B. In conclusion, the results demonstrate that low dose of Ni stimulated the growth performance of pea seedlings in contrast to its inhibitory role at high doses. However, UV-B alone and together with low as well as high doses of Ni proved to be toxic for P. sativum L. PMID- 22528777 TI - Bioelement status with oral administration of fish oil methyl ester and diesel fuel in male rats. AB - This paper is a study on the effects on the amounts of trace elements in case of possible repeat accidental or environmental exposure with fish oil biodiesel. For this purpose, 35 male Wistar albino rats were used in the study. Rats were divided into five groups. The first group was determined as the control group. The rats in this group were gavaged orally with 250 mg/kg sunflower oil. The rats in the second and third groups were administered by oral gavage of 250 mg/kg (D1) and 500 mg/kg (D2) diesel fuel mixed with equal amounts of sunflower oil, respectively. The rats in the fourth group were administered by oral gavage of 250 mg/kg fish oil biodiesel (F1) and the rats in the fifth group were administered by oral gavage of 500 mg/kg fish oil biodiesel (F2), both mixed with equal amounts of sunflower oil. At the end of the study, bioelement concentrations in the serum and the kidney, lung, and liver tissues were measured using inductively coupled plasma-optical emission spectroscopy. It was observed that serum Ca, Mg, and Sr concentrations were significantly (p<0.001) higher and Cu concentration was significantly (p<0.01) higher in the control group than in the biodiesel groups. Kidney Mg concentration was significantly (p<0.01) lower in the control group than in the diesel groups. Kidney Mg concentration was significantly (p<0.001) lower in the D2 group than in the F2 group. Kidney Mg concentration was significantly (p<0.01) lower in the control group than in the diesel groups. Lung Cd, Co, Cu, Cr, Na, and Zn concentrations were different significantly higher in the control group than in the other groups. Liver Al concentration was different significantly higher in the control group than in the other groups. Liver Ca concentration was significantly (p<0.05) higher in the control group than in the biodiesel groups. Serum and lung tissue bioelements concentrations were lower in diesel and biodiesel groups than in control group. Due to consumption for biochemical reaction of these elements, bioelements concentration could be low in diesel and biodiesel groups. Some trace elements concentrations in the kidney and liver were very high in the diesel groups. High concentration of these elements in the diesel groups might cause toxic effects. Fish oil biodiesel could be chosen as an alternative fuel instead of diesel fuel. PMID- 22528778 TI - Dietary fiber intake increases the risk of zinc deficiency in healthy and diabetic women. AB - Phytic acid is a major determinant of zinc bioavailability. Little is known about phytic acid intakes or indices of zinc bioavailability in type 2 diabetes mellitus (DM), a condition that predisposes to zinc deficiency. The aim of this cross-sectional study was to measure and explore the relationships among phytic acid intake, zinc bioavailability, and molecular markers of zinc homeostasis in 20 women with DM compared to 20 healthy women. The phytate/zinc, (calcium)(phytate)/zinc, and (calcium + magnesium)(phytate)/zinc molar ratios were used to indicate zinc bioavailability. Plasma zinc concentrations and zinc transporter (ZnT1, ZnT8, and Zip1) gene expression in mononuclear cells were measured. Participants with DM consumed 1,194 +/- 824 mg/day (mean +/- SD) phytic acid, an amount similar to the intake of healthy women (1,316 +/- 708 mg/day). Bread products and breakfast cereals contributed more than 40 % of the phytic acid intake in each group. A positive relationship was observed in all participants between phytic acid and dietary fiber (r = 0.6, P < 0.001) and between dietary fiber and the (calcium)(phytate)/zinc ratio (r = 0.5, P < 0.001). Compared to the healthy group, the messenger RNA ratio of ZnT1 (zinc export) to Zip1 (zinc import) was lower in participants with DM, which may indicate perturbed zinc homeostasis in the disorder. The plasma zinc concentration was not predicted by age, body mass index, health status, zinc bioavailability, or zinc transporter expression. Healthy and diabetic women consume phytic acid in amounts that are likely to decrease the bioavailability of dietary zinc. Recommendations to consume greater amounts of dietary fiber, much of which is associated with phytate, increase the risk of zinc deficiency. PMID- 22528779 TI - Effect of dietary vanadium on intestinal microbiota in broiler. AB - The purpose of this 42-day study was to examine the effect of dietary vanadium on intestinal microorganism diversity in the duodenum, ileum, cecum, and rectum segments of broilers by the plate count and polymerase chain reaction-denaturing gradient gel electrophoresis (DGGE). A total of 420 1-day-old avian broilers were divided into six groups and fed on a control diet or the same diet supplemented with vanadium at the doses of 5, 15, 30, 45, and 60 mg/kg in the form of ammonium metavanadate. In comparison with control group, the dietary vanadium at the doses of 45 and 60 mg/kg could decrease the counts of Bifidobacterium spp. in the intestinal tract at 21 and 42 days of age. With increasing level in dietary vanadium, the counts of Escherichia coli were significantly increased in the ileum, cecum, and rectum and were decreased in the duodenum at 21 and 42 days of age. However, the counts of Lactobacilli were decreased in the cecum and rectum and increased in the ileum of 45 and 60 mg/kg groups. The colonization of these three bacteria could be affected by dietary vanadium. DGGE analysis showed that the number of bands in duodenum, ileum, cecum, and rectum were obviously decreased in the 30, 45, and 60 mg/kg groups at 21 and 42 days of age. In conclusion, the dietary vanadium in excess of 30 mg/kg could alter the amount and diversity of intestinal bacteria in broilers, implying that the structure and initial balance in the intestinal microbiota were disrupted. PMID- 22528780 TI - Luteolin reduces zinc-induced tau phosphorylation at Ser262/356 in an ROS dependent manner in SH-SY5Y cells. AB - In brain, excess zinc alters the metabolism of amyloid precursor protein, leading to beta-amyloid protein deposition, one of the hallmarks of Alzheimer's disease (AD) pathology. Recently, it has been reported that zinc accelerates in vitro tau fibrillization, another hallmark of AD. In the current study, we examined the effect of high-concentration zinc on tau phosphorylation in human neuroblastoma SH-SY5Y cells. We found that incubation of cells with zinc resulted in abnormal tau phosphorylation at Ser262/356. Moreover, the current study has investigated whether luteolin (Lu), a bioflavonoid, could decrease zinc-induced tau hyperphosphorylation and its underlying mechanisms. Using Western blot and protein phosphatase activity assay, activities of tau kinases and phosphatase were investigated. Our data suggest (1) that zinc induces tau hyperphosphorylation at Ser262/356 epitope and (2) that Lu efficiently attenuates zinc-induced tau hyperphosphorylation through not only its antioxidant action but also its regulation of the phosphorylation/dephosphorylation system. PMID- 22528781 TI - Association of blood lead with calcium, iron, zinc and hemoglobin in children aged 0-7 years: a large population-based study. AB - Lead exposure in children has received increasing attention from scientists and public health institutions worldwide. Deficiencies of nutritional essential metals can increase the hazard from lead exposure by enhancing absorption and toxicity of dietary lead. Lead, as a ubiquitous toxicity metal, may interact metabolically with nutritional essential metals. A large population-based study was conducted to investigate blood lead, calcium, iron, zinc and hemoglobin levels in healthy children aged 0-7 years. Based on the records, 158 (3.57 %) of 4,429 children had a blood lead levels (BLLs) >= 10 MUg/dl, and 1,324 (30.30 %) children had a BLL >= 7 MUg/dl. BLLs in children aged less than 3 years was lower than those in older children. BLLs had a negative correlation with blood calcium and iron level (r = -0.357 and r = -0.070, P < 0.01). Multiple logistic regression analysis also showed that BLLs had a negative correlation with blood calcium and iron. BLLs can be influenced by the status of some essential trace metals in children. Supplement of nutritional elements may help reduce lead absorption. Children with elevated BLLs (>= 10 MUg/dl) were controlled well in recent years in Chengdu. But the burden of reducing BLLs remains extremely arduous, which requires the joint efforts of both government agencies and the public. PMID- 22528782 TI - Hepatoprotective activity of CrPic against alloxan-induced hepatotoxicity in mice. AB - This study focused on oxidation hepatic injury induced by alloxan treatment in mice and the hepatoprotective effect of chromium picolinate (CrPic) against such injury. The mice were randomly divided into three groups (control, alloxan, and CrPic). The CrPic mice were given Cr(3+) (40 MUg/kg bm/day), and other mice were given equivalent intragastric doses of water every day. After 4 weeks, the groups alloxan and CrPic were treated with alloxan (40 mg/kg/day) through intraperitoneal injection daily for 6 days. Biochemical and enzymatic characteristics were assayed in these animals. The MDA levels of the control and CrPic groups were 33.93 % and 28.45 % lower, respectively, than that of the alloxan group. The levels of superoxide dismutase (SOD) and GSH-Px in the alloxan group were 15.30 % and 15.69 % higher, respectively,than those of the control group. Both the SOD and GSH-Px levels of the control and CrPic groups were about the same. Levels of CuZnSOD mRNA of the control and CrPic groups were 0.27 fold and 1.03 fold lower than in the alloxan group. The transcription levels of GSH-Px in the control and CrPic groups were 1.57 fold and 0.99 fold below those of the alloxan group. These results show that significant hepatic injury can be induced by alloxan treatment in mice; in addition, CrPic may be useful in health products meant to treat human liver disease. PMID- 22528783 TI - Effects of high-intensity training and resumed training on macroelement and microelement of elite basketball athletes. AB - The purpose of this study was to assess the effects of high-intensity training and resumed training in hot and humid environment on plasma macro- and microelements levels of elite Han Chinese basketball players. Ten well-trained elite basketball athletes' plasma macroelements (chlorin, sodium, potassium, and calcium), creatine kinase (CK), and creatine kinase-MB (CK-MB) were measured before and after a 2-h high-intensity training, and microelements (zinc, copper, iron, and selenium) were determined before and after a 1-week high-intensity training and after a 1-week resumed training. The blood CK and CK-MB levels of the elite basketball athletes were significantly increased (P < 0.05) after high intensity basketball training. The macroelements (chlorin, sodium, and calcium) levels of blood increased significantly except potassium after high-intensity basketball training. No significant differences (P > 0.05) were found in zinc and copper levels; nevertheless, the levels of plasma selenium and plasma iron were significantly lower (P < 0.05) after a 1-week high-intensity training. After a 1 week resumed training, except zinc, all of microelements measured had a trend toward original levels. These results implicated that high-intensity training would provoke the change of macroelements which would lead to electrolyte disturbance. In addition, the present study suggested that a 1-week high intensity training would have an impact on microelement levels, especially for selenium and iron. PMID- 22528784 TI - The effects of Ce on the proliferation, osteogenic differentiation and mineralization function of MC3T3-E1 cells in vitro. AB - The effects of Ce on the proliferation, osteogenic differentiation and mineralization function of a murine preosteoblast cell line MC3T3-E1 in vitro were investigated at cell and molecular levels. The results showed that Ce promoted the proliferation, osteogenic differentiation and mineralization function of MC3T3-E1 cells at concentrations of 0.0001, 0.001, 0.01, 0.1 and 1 MUM, but turned to inhibit the proliferation, osteogenic differentiation and mineralization function at concentrations of 10, 100 and 1000 MUM. Ce displayed the up-regulation of Runx2, BMP2, ALP, BSP, Col I and OCN genes at concentrations of 0.0001 and 0.1 MUM; these genes were down-regulated in the MC3T3-E1 cells treated with 1000 MUM Ce. The expression of BMP2, Runx2 and OCN proteins was promoted by Ce at concentrations of 0.0001 and 0.1 MUM, but these proteins were down-regulated after 1000 MUM Ce treatment. The results suggest that Ce likely up regulates or down-regulates the expression of Runx2, which subsequently up- or down-regulates OB marker genes Col I and BMP2 at early stages and ALP and OCN at later stages of differentiation, thus causing to promote or inhibit the proliferation, osteogenic differentiation and mineralization function of MC3T3-E1 cells. PMID- 22528785 TI - Contextual modulation of attention in human category learning. AB - In a category-learning experiment, we assessed whether participants were able to selectively attend to different components of a compound stimulus in two distinct contexts. The participants were presented with stimulus compounds for which they had to learn categorical labels. Each compound comprised one feature from each of two dimensions, and on different trials the compound was presented in two contexts, X and Y. In Context X, Dimension A was relevant to the solution of the categorization task and Dimension B was irrelevant, whereas in Context Y, Dimension A was irrelevant and Dimension B was relevant. The results of transfer tests to novel stimuli suggested that people learned to attend selectively to Dimension A in Context X and Dimension B in Context Y. These findings contribute to the growing body of evidence that people can learn to selectively attend to particular dimensions of stimuli dependent on the context in which the stimuli are presented. Furthermore, the findings demonstrate that context-dependent changes in attention transfer to other categorization tasks involving novel stimuli. PMID- 22528786 TI - Hierarchical formation of supramolecular transient networks in water: a modular injectable delivery system. AB - A modular one-component supramolecular transient network in water, based on poly(ethylene glycol) and end-capped with four-fold hydrogen bonding units, is reported. Due to its nonlinear structural formation, this system allows active proteins to be added to the hydrogel during formation. Once implanted in vivo it releases the protein by erosion of both the protein and polymer via dissolution. PMID- 22528787 TI - Phenytoin reduces 5-aminolevulinic acid-induced protoporphyrin IX accumulation in malignant glioma cells. AB - Epileptic seizures are among the presenting clinical signs of malignant glioma patients, frequently necessitating treatment with antiepileptic drugs (AEDs). The efficacy of 5-aminolevulinic acid (5-ALA)-based intraoperative fluorescence guided surgery and photodynamic therapy (PDT) in glioblastoma multiforme (GBM) patients depends on the specific accumulation and total amount of intracellularly synthesized protoporphyrin IX (PpIX) in tumour cells. In this study, we investigated the effect of the AEDs phenytoin (PHY) and levetiracetam (LEVE) on 5 ALA-induced PpIX accumulation in two glioma cell lines (U373 MG and U-87 MG) and primary GBM cells isolated from a human biopsy. After treatment with PHY and LEVE for three days cells were incubated with 1 mM: 5-ALA for 4 h and PpIX accumulation was determined by fluorescence measurement. We observed a decrease in PpIX synthesis of up to 55 +/- 12 % in primary GBM cells after incubation with phenytoin. This reduction was dose-dependent for all tested cell lines and primary GBM cells. LEVE on the other hand did not alter PpIX concentration in GBM cells. PDT was performed in vitro by irradiating the GBM cells with light doses from 0.5 to 10 J cm(-2) at 627 nm after AED and 5-ALA treatment. Although less PpIX accumulated in PHY-treated cells, efficacy of PDT was not affected. We assume that damage to the mitochondrial membrane by PHY inhibits PpIX synthesis in vitro, because we showed mitochondrial dysfunction as a result of reduced mitochondrial membrane potential in PHY-treated cells. No change in glutathione status was observed. To evaluate further the effect of PHY on PpIX fluorescence, and to establish its significance in clinical practice, animal and clinical studies are required, because the results presented here imply PHY may reduce intracellular accumulation of PpIX in patients with high-grade gliomas. PMID- 22528788 TI - Sleep dysfunction in long term survivors of craniopharyngioma. AB - Craniopharyngiomas are slow growing tumors of the sellar and parasellar region and may also involve the hypothalamus. Treatment involves maximal surgical excision or subtotal resection followed by focal radiation therapy. Late effects of treatment include endocrinopathies, cognitive deficits, behavioral changes, obesity and sleep dysfunction. We conducted a retrospective review of all patients with craniopharyngioma more than 2 years off treatment and who were evaluated in the neuro-oncology survivorship clinic between 2003 and 2007. Clinical data, extent of resection, treatment modalities, endocrine status, patient symptom report and sleep study results were collected to evaluate the presence of patient reported daytime sleepiness and sleep disturbance and to determine possible risk factors. 28 patients were identified (25 %) female. 19/28 self-reported daytime fatigue or sleep disturbance; this included 4/6 patients with gross total resection and 15/22 with subtotal resection. 16/22 patients treated with cranial irradiation reported sleep-related abnormalities, compared to 3/6 patients who did not receive radiation. All but one patient had pituitary dysfunction requiring hormonal replacement. Patients with more than >=2 sleep related complaints had a higher BMI (44.6 vs. 32.6, p = 0.0192). 8 patients underwent formal sleep evaluation. 3 patients had documented central or obstructive sleep apnea. The mean arousal index was 11.0/h (normal <5). Two patients were treated with melatonin for sleep disturbance and 2 were treated with stimulants for excessive daytime sleepiness. A majority of patients with craniopharyngioma have self-reported daytime fatigue and/or sleep dysfunction after treatment. Extent of resection did not increase the likelihood of patient reported daytime sleepiness and/sleep dysfunction; however, patients who received radiation more frequently reported daytime sleepiness and/or sleep dysfunction. Patients with a higher BMI were more likely to experience sleep disturbance. Formal sleep evaluations should be considered in all patients with craniopharyngioma. PMID- 22528789 TI - Trans-membrane peptide therapy for malignant glioma by use of a peptide derived from the MDM2 binding site of p53. AB - A new strategy is required against glioblastoma, a highly aggressive and fatal disease. In recent studies the protein transduction domains (PTDs) of some proteins, which are able to cross biological membranes, have been identified as critical domains for protein transduction. Here, we show that this protein delivery system is a powerful tool for transduction of p53, a biologically active tumor-suppressor protein, into cancer cells, to suppress their proliferation. A 15-amino-acid sequence corresponding to the mouse double minutes clone2 (MDM2) binding site of p53 was shown by cell proliferation assay and MTT assay to have a proliferation-inhibiting effect on glioma cells. The polyarginine11R as a PTD, nuclear localization sequence (NLS), and laminin (Ln) fused to the p53 peptide corresponding to the MDM2 binding site (p53-NLS-Ln-11R) effectively penetrated the plasma membrane of the glioma cells and was translocated into the nucleus. At a 10 MUM: concentration, this peptide inhibited the proliferation of human glioma cells, whether the p53 gene had mutated or not. These results suggest that this protein-transduction method using the p53-NSL-Ln-11R peptide may become a promising glioma therapy as an alternative gene therapy. PMID- 22528790 TI - No prognostic value of IDH1 mutations in a series of 100 WHO grade II astrocytomas. AB - Mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) have been identified in approximately 70-80 % of astrocytomas and oligodendrogliomas of WHO grades II and III, and in secondary glioblastomas. In addition, a low incidence of IDH2 mutations has been detected in these tumors, and the occurence of IDH1 and IDH2 mutations is mutually exclusive. For patients with anaplastic gliomas and glioblastomas with IDH1 mutations, overall survival was significantly longer than for patients with wild-type tumours. However, the prognostic value of IDH1 in low-grade gliomas remains ambiguous. IDH1 codon 132 and IDH2 codon 172 mutation status were determined by direct sequencing for a retrospective series of 100 patients with histologically diagnosed Astrocytomas WHO Grad II (A II), and investigated for association with patient outcome. For the patient cohort analysed, median progression-free survival (PFS) was 44.6 months (95 %-CI 1.0 267.0), time to progression (median time to malignant progression (TtMP) was 74.9 months (95 %-CI 1.6-236.2), and median overall survival (OS) was 81.4 months (95 %-CI 5.5-274.8). IDH1 mutations were identified in 79 % of the patients. IDH2 mutations were not observed. Univariate and multivariate analysis revealed no association between IDH1 mutation status and PFS, TtMP, and OS. Furthermore, there were no significant differences regarding PFS, TtMP, and OS between patients with and without IDH1 mutations who did not receive adjuvant treatment. The prognostic value of IDH1 mutations in low-grade astrocytomas is rather low compared with that in high-grade gliomas. PMID- 22528791 TI - Optimizing the extent of resection in eloquently located gliomas by combining intraoperative MRI guidance with intraoperative neurophysiological monitoring. AB - Several methods have been introduced to improve the extent of resection in glioma surgery. Yet, radical tumor resections must not be attempted at the cost of neurological deterioration. We sought to assess whether the use of an intraoperative MRI (iMRI) in combination with multimodal neurophysiological monitoring is suitable to increase the extent of resection without endangering neurological function in patients with eloquently located gliomas. Fifty-four patients were included in this study. In 21 patients (38.9 %), iMRI led to additional tumor resection. A radiologically complete resection was achieved in 31 patients (57.4 %), while in 12 of these, iMRI had depicted residual tumor tissue before resection was continued. The mean extent of resection was 92.1 % according to volumetric analyses. Postoperatively, 13 patients (24.1 %) showed new or worsening of pre-existing sensory motor deficits. They were severe in 4 patients (7.4 %). There was no correlation between the occurrence of either any new (P = 0.77) or severe (P = 1.0) sensory motor deficit and continued resection after intraoperative image acquisition. Likewise, tumor location, histology, and tumor recurrence did not influence complication rate on uni- and multivariate analysis. We conclude that the combination of iMRI guidance with multimodal neurophysiological monitoring allows for extended resections in glioma surgery without inducing higher rates of neurological deficits, even in patients with eloquently located tumors. PMID- 22528792 TI - A retroperitoneal NF1-independent malignant peripheral nerve sheath tumor with elevated serum CA125: case report and discussion. AB - Malignant peripheral nerve sheath tumors (MPNSTs) are usually located in the trunk, extremities, head, or neck, and most occur with neurofibromatosis type 1 (NF1; von Recklinghausen's disease). No biomarkers have previously been found to be associated with their progression. Retroperitoneal NF1-independent MPNSTs are rare; they are considered to be less aggressive and to have better prognoses compared to NF1-related tumors. Currently, en bloc excision is the only consensus treatment approach. In a 27-year-old male with a giant retroperitoneal MPNST and no stigmata or family history of neurofibromatosis type-1 (NF1), a remarkable elevation of serum CA125 was detected. The high-grade tumor displayed a striking progression: the primary lesion, 25 cm in diameter, recurred in its previous site as a 17-cm MPNST less than 50 days after total excision. Subsequent treatment with microwave ablation and huachansu, a traditional Chinese medication, proved ineffective, and the patient died within 3 months. Our case suggests that retroperitoneal MPNSTs can deteriorate rapidly even if NF1 independent, that aggressive treatment may not benefit large high-grade MPNSTs, and that novel and effective treatment is urgently needed. Our case also suggests the possibility of using serum tumor markers in the early detection and monitoring of MPNSTs. PMID- 22528793 TI - Rho GTPases in primary brain tumor malignancy and invasion. AB - Gliomas are the most common type of malignant primary brain tumor in humans, accounting for 80 % of malignant cases. Expression and activity of Rho GTPases, which coordinate several cellular processes including cell-cycle progression and cell migration, are commonly altered in many types of primary brain tumor. Here we review the suggested effects of deregulated Rho GTPase signaling on brain tumor malignancy, highlighting the controversy in the field. For instance, whereas expression of RhoA and RhoB has been found to be significantly reduced in astrocytic tumors, other studies have reported Rho-dependent LPA-induced migration in glioma cells. Moreover, whereas the Rac1 expression level has been found to be reduced in astrocytic tumor, it was overexpressed and induced invasion in medulloblastoma tumors. In addition to the Rho GTPases themselves, several of their downstream effectors (including ROCK, mDia, and N-WASP) and upstream regulators (including GEFs, GAPs, PI3K, and PTEN) have also been implicated in primary brain tumors. PMID- 22528794 TI - Patients with brain tumor-related epilepsy. AB - Patients with brain tumor-related epilepsy (BTRE) present a complex therapeutic profile and require a unique and multidisciplinary approach. They, in fact, must face two different pathologies at the same time, brain tumor and epilepsy. Therefore, it is necessary to develop a customized treatment plan for each individual with BTRE. This requires a vision of patient management concerned not only with medical therapies related to the oncological disease and to the correct choice of antiepileptic therapies but also with emotional and psychological support for the individual and his/her family. The choice of antiepileptic drugs is challenging for these patients because BTRE is often drug-resistant, has a strong impact on the quality of life, and weighs heavily on public health expenditures. In brain tumor patients, the presence of epilepsy is considered the most important risk factor for long-term disability. The problem of the proper administration of medications and their potential side effects is of great importance, because good seizure control also has a significant impact on the patient's psychological and relational sphere. PMID- 22528795 TI - Stereotactic radiosurgery and fractionated stereotactic radiotherapy: comparison of efficacy and toxicity in 260 patients with brain metastases. AB - We retrospectively evaluated and compared the efficacy and the toxicity profile of stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) for the treatment of patients with brain metastases (BM). Between 2000 and 2009, 260 patients with 1-3 BM were treated using either SRS (median dose 20 Gy; n = 138) or two different FSRT dose concepts: 7 * 5 Gy (n = 61) or 10 * 4 Gy (n = 61). The median survival for SRS, 7 * 5 Gy and 10 * 4 Gy was 8, 7 and 10 months (p = 0.575), respectively, and the overall survival (OS) was 9 months. Follow-up imaging data were available in 214 of the 260 patients. The 1-year local progression-free survival (LPFS) was 73, 75 and 71 %, respectively (p = 0.191). After a mean follow-up of 28 months (range: 2.1-77 months), the rate of complete remission, partial remission, stable disease and progressive disease were 29, 40, 21 and 10 %, respectively. On multivariate analysis, RPA class I was associated with better OS and regional progression-free survival (both p < 0.001). SRS was associated with a higher toxicity rate (grade I-III) compared to the 7 * 5 Gy and 10 * 4 Gy groups (14 vs. 6 vs. 2 %, respectively; p = 0.01). Although FSRT was used for large lesions and/or lesions near critical structures, the LPFS was comparable to SRS. Importantly, FSRT presented low toxicity and appears to be an effective and safe treatment for BM not amenable to SRS. The 10 * 4 Gy fractionation scheme warrants further investigation due to its efficacy and safe toxicity profile. PMID- 22528796 TI - Papillary tumors of the pineal region: a novel therapeutic option-stereotactic 125iodine brachytherapy. AB - We evaluated the efficacy of interstitial brachytherapy (IBT) using (125)Iodine ((125)I) seeds for treatment of papillary tumors of the pineal region. Between September 2003 and September 2010, four patients (M/F = 2/2; median age, 57.3 years; range 29.2-69.1 years) with papillary tumors of the pineal region underwent IBT using (125)I seeds. Before brachytherapy two patients underwent endoscopic ventriculo-cisternotomy, because of occlusive hydrocephalus, and subsequent microsurgical resection was performed on one; three patients were primarily treated with IBT. Median tumor volume was 3.3 ml (range 1.6-4 ml), the tumor surface dose ranged between 50 and 65 Gy. For three patients the seeds were implanted permanently whereas one patient received temporary implants (28 days). The median follow-up time was 53.6 months (range 13-103.4 months). After brachytherapy, follow-up MR images revealed complete remission in one patient, partial remission in two, and stable disease in the remaining patient. Neurological status improved in all patients (reduced headache and nausea/vomiting for four patients; improvement of oculomotor dysfunction for two of three patients partially and for one of three patients completely). Neither treatment-related morbidity nor mortality was observed. Our results are indicative of good local control of papillary tumors of the pineal region after IBT, without treatment-related morbidity. PMID- 22528797 TI - Valproic acid affected the survival and invasiveness of human glioma cells through diverse mechanisms. AB - The effects of valproic acid (VPA) on the viability, apoptosis, and invasiveness of two glioma cells (A172 and T98G) and the underlying mechanisms were studied. VPA induced cytotoxicity and apoptosis, and suppressed the invasiveness of both cells. VPA increased the activity of matrix metalloproteinase-2 (MMP-2) and MMP-9 in A172 cells, but decreased it in T98G cells. siRNA blockade of reversion inducing cysteine-rich protein with Kazal motifs (RECK) expression partially reversed VPA-mediated effects in T98G cells, but had no effect on A172 cells. VPA increased the expression of phospho-JNK1 and phospho-ERK1/2 in A172 cells, but decreased it in T98G cells. Inhibition of JNK1 and/or ERK1/2 partially reversed the VPA effects in A172 cells. In conclusion, the effects of VPA (loss of viability, increased apoptosis, and decreased invasiveness) are, at least partly, mediated through the RECK-MMPs pathway in T98G cells and the mitogen-activated protein kinase pathways in A172 cells. The action of VPA seems to be cell type specific in glioma cells. PMID- 22528798 TI - Dual contrast perfusion MRI in a single imaging session for assessment of pediatric brain tumors. AB - Ferumoxytol, an iron nanoparticle used as an intravascular contrast agent for perfusion magnetic resonance imaging (MRI), has never been explored in the pediatric population. The purpose of this prospective study is to characterize the vascular and permeability properties of pediatric brain tumors using two contrast agents during a single imaging session: ferumoxytol for dynamic susceptibility weighted contrast (DSC) MRI and gadoteridol for dynamic contrast enhanced (DCE) MRI. In a single imaging session, patients received intravenous ferumoxytol for DSC MRI followed by gadoteridol for DCE MRI. Relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF), transfer coefficient (K(trans)), and extravascular extracellular space volume fraction (v(e)) of the brain lesions were calculated. Patients underwent serial imaging sessions over the course of 2 years. Of the 7 patients enrolled thus far, none has experienced an adverse event. Two patients with medulloblastoma were enrolled preoperatively. In the first, rCBV(max), rCBF, K(trans) max, and v(e) max values were 3.74, 3.12, 0.47 min (-1), and 0.08, respectively, while in the second patient, rCBV(max), rCBF, K(trans) max, and v(e) max values were 4.72, 3.47, 0.60 min(-1), and 0.05, respectively. Four patients were enrolled after new gadolinium enhancement was noted in the tumor resection cavity. In 80 % of these lesions, rCBV was <1 suggestive of pseudoprogression secondary to radiochemotherapy. These preliminary results demonstrate that use of ferumoxytol and gadoteridol contrast agents during a single imaging session is feasible, safe, and appears useful for assessing tumor perfusion and permeability characteristics in children. PMID- 22528799 TI - Evaluation of brain tumors using dynamic 11C-methionine-PET. AB - The aim of this study is to assess whether dynamic imaging of (11)C-methionine (MET) uptake on positron emission tomography (PET) is useful for the differential diagnosis of brain tumor histology. Regional MET uptake in static brain PET scans from three consecutive phases (5-15, 15-25, and 25-35 min) after intravenous injection were measured in 144 patients with brain tumors. Regions of interest (ROI) were placed in the pituitary gland, confluence, choroid plexus, coronal radiation, brainstem, frontal cortex, parietal cortex, cerebellum, and brain tumors. The standard uptake value (SUV) of the ROIs in the normal brain structures and brain tumors were measured, and the mean MET SUV region/normal frontal lobe cortex uptake ratio (R/N ratio) of the normal brain structures and the maximum MET SUV tumor/normal frontal cortex uptake ratio (T/N ratio) were evaluated semi-quantitatively. There were significant dynamic declines of the mean MET R/N ratio in the normal pituitary gland and confluence; however, there were significant dynamic increases in white matter. Significant dynamic decrease of the maximum MET T/N ratio was seen in meningiomas and oligodendrocytic tumors, whereas significant dynamic increase was seen in glioblastomas and malignant lymphomas. Dynamic changes of MET uptake vary significantly with the normal brain structures and brain tumor histology. These results suggest that MET-PET may be useful in the differential diagnosis of brain tumors. PMID- 22528802 TI - Angiogenesis and myogenesis in mouse tibialis anterior muscles during distraction osteogenesis: VEGF, its receptors, and myogenin genes expression. AB - Angiogenesis and myogenesis occur in the surrounding skeletal muscles following distraction osteogenesis, but their molecular mechanisms remain unclear. The present study investigated morphological features of lengthened muscles and the time course change of vascular endothelial growth factor (VEGF), its receptors (VEGFR-1 and VEGFR-2) and myogenin gene expression profiles related to angiogenesis and myogenesis in tibialis anterior (TA) muscles with a mouse model of distraction osteogenesis, which involves 1 week of waiting period (latency phase), 2 weeks of intermittent distraction (distraction phase), and 5 weeks of remodeling period (consolidation phase). Macroscopic findings showed that lengthened TA muscles increased to approximately 42% longer and 10% heavier at the end of the process when compared to pre-surgery. During the distraction phase, VEGF and its receptors were induced in the vascular endothelial cells, myogenin-positive satellite cells and myocytes, and subsequently, capillary progression and myogenesis were increased. Real-time RT-PCR showed that Vegf, Vegfr-1, Vegfr-2, and myogenin genes expression was enhanced during the muscle lengthening. Vegf and Vegfr-1 were upregulated following the recession of angiogenesis at the consolidation phase. We conclude that upregulation of VEGF and its receptors by mechanical tension-stress could be involved in the process of angiogenesis and myogenesis in lengthened muscles. PMID- 22528800 TI - p38 MAPK inhibitors attenuate pro-inflammatory cytokine production and the invasiveness of human U251 glioblastoma cells. AB - Increasing evidence suggests that an inflammatory microenvironment promotes invasion by glioblastoma (GBM) cells. Together with p38 mitogen-activated protein kinase (MAPK) activation being regarded as promoting inflammation, we hypothesized that elevated inflammatory cytokine secretion and p38 MAPK activity contribute to expansion of GBMs. Here we report that IL-1beta, IL-6, and IL-8 levels and p38 MAPK activity are elevated in human glioblastoma specimens and that p38 MAPK inhibitors attenuate the secretion of pro-inflammatory cytokines by microglia and glioblastoma cells. RNAi knockdown and immunoprecipitation experiments suggest that the p38alpha MAPK isoform drives inflammation in GBM cells. Importantly, p38 MAPK inhibition strongly reduced invasion of U251 glioblastoma cells in an inflammatory microenvironment, providing evidence for a p38 MAPK-regulated link between inflammation and invasiveness in GBM pathophysiology. PMID- 22528803 TI - Is axillary dissection unnecessary in patients with a positive sentinel lymph node? PMID- 22528804 TI - Prognostic significance of NANOG and KLF4 for breast cancer. AB - BACKGROUND: Some of the induced pluripotent stem cell (iPS cell)-inducing factors have been reported to be expressed in breast cancer. The aim of the present study was to examine the relationship between the expression of iPS cell-inducing factors and the prognosis of breast cancer patients. METHODS: In 100 breast cancer patients, the expression of c-MYC, KLF4, NANOG, OCT4, and SOX2 was determined by immunohistochemistry using a tissue microarray analysis. RESULTS: Patients with strong expression of NANOG had significantly lower disease-free survival (DFS) and overall survival rates than those with weak expression of NANOG (P = 0.004 and 0.033, respectively). In contrast, patients with strong expression of KLF4 had better DFS (P = 0.014). CONCLUSIONS: Strong expression of NANOG is an indicator of a poor prognosis for breast cancer patients, whereas KLF4 is a favorable prognostic indicator. Our results suggest that NANOG stimulates the growth and metastasis of breast cancer cells, whereas KLF4 inhibits these processes. PMID- 22528806 TI - New perspectives on the vitamin D binding protein. AB - The serum vitamin D binding protein (DBP), also known as GC-globulin, is a multifunctional protein known for its role in the transport of vitamin D metabolites. DBP also binds fatty acids and actin monomers, preventing their polymerization that could be detrimental in the circulatory system. DBP may have immune functions independent of its role as a transporter of vitamin D. Because of the abundance of DBP, many aspects of its basic biochemistry were quickly established. Other features of vitamin D action, particularly transcriptional mechanisms of regulation, received greater focus and early interest in DBP centred on its value as a tool for population genetics because of its intriguing genetic variations. Nonetheless, knowledge of DBP mechanisms in physiology was obtained, and functions beyond vitamin D ligand binding were identified. With the recent increased attention regarding the benefits of vitamin D (bone health and immunological regulation), there has been a resurgence of interest in DBP. Because DBP is the primary transporter of vitamin D, it has a role in maintaining the total levels of vitamin D for the organism and in regulating the amounts of free (unbound) vitamin D available for specific tissues and cell types to utilize. This review will describe the findings on the basic biochemistry and molecular biology of DBP, the studies that elucidated its biological functions and highlight these results in light of the current renewed interest in vitamin D and human health, as well as the debate over what constitutes sufficient levels of vitamin D. PMID- 22528805 TI - Opportunistic breast cancer screening by mammography in Japan for women in their 40s at our preventive medical center: harm or benefit? AB - BACKGROUND: After recent revised grading by the US Preventive Services Task Force of mammography (MMG) recommendations for women in their 40s, it is urgent to collect data on the benefits and harm of MMG screenings in Japan. In this paper, we study the actual status and effectiveness of opportunistic breast cancer screening by MMG for women in their 40s. METHODS: From January to December 2008, the total number of opportunistic breast cancer screenings by MMG at our institute was 12823. Of them, 398 (3.1 %) who were diagnosed as category 3 or more on MMG required further exams. The data were compared between two groups (women in their 40s, women aged 50 and older). Recall rate, detection rate of breast cancers, and implementation rate of further exams were evaluated. RESULTS: Recall rate was 4.0 % (166/4138) for women in their 40s and 2.4 % (166/6949) for women aged 50 and older. Detection rate of breast cancers was higher in women in their 40s (0.56 %) than women aged 50 and older (0.26 %). Non-cancer rate among women receiving invasive examination was higher in women in their 40s (0.76 %) than women aged 50 and older (0.42 %) (p = 0.02). The number of false positives required to detect one true cancer patient was smaller in women in their 40s (4.5) than women aged 50 and older (5.3). CONCLUSION: The results from our single institute revealed that opportunistic breast cancer screening by MMG for women in their 40s shows higher net benefits than for women aged 50 and older. PMID- 22528807 TI - Vkorc1 variation in house mice during warfarin and difenacoum field trials. AB - BACKGROUND: Field studies guided by genetic monitoring of Vkorc1 need to be done to implicate mutations conclusively with rodent control problems due to the presence of animals resistant to anticoagulant rodenticides. Rodent control success in relation to Vkorc1 genotypes in house mice (Mus musculus domesticus) was studied on two farms (I and II) in Germany. Tests were carried out to determine whether certain resistance profiles and Vkorc1 genotypes displayed dynamics over the course of sequential treatments with warfarin and difenacoum that were consistent with single nucleotide polymorphisms (SNPs) in Vkorc1 as indicators of resistance. RESULTS: On farms I and II, respectively, three (A to C) and two (A and B) types of control problem with anticoagulants (i.e. proxies for resistance) were encountered in spatially segregated subunits: A = none; B = control problems with warfarin but not with difenacoum; C = control problems with both anticoagulants. Unexpectedly, resistance was encountered in a population where only Vkorc1 wild-type mice were detected. In addition, the Arg58Gly Vkorc1 variant was found not to correlate with observed control failures. CONCLUSION: Control problems were encountered that cannot be explained by Vkorc1 coding or intronic SNPs, and therefore are likely due to non-coding Vkorc1 SNPs or due to other genetic or non-genetic factors. PMID- 22528808 TI - Tubular perfusion system culture of human mesenchymal stem cells on poly-L-lactic acid scaffolds produced using a supercritical carbon dioxide-assisted process. AB - In vitro human mesenchymal stem cell (hMSC) proliferation and differentiation is dependent on scaffold design parameters and specific culture conditions. In this study, we investigate how scaffold microstructure influences hMSC behavior in a perfusion bioreactor system. Poly-L-lactic acid (PLLA) scaffolds are fabricated using supercritical carbon dioxide (SC-CO(2)) gel drying. This production method results in scaffolds fabricated with nanostructure. To introduce a microporous structure, porogen leaching was used in addition to this technique to produce scaffolds of average pore size of 100, 250, and 500 MUm. These scaffolds were then cultured in static culture in well plates or dynamic culture in the tubular perfusion system (TPS) bioreactor. Results indicated that hMSCs were able to attach and maintain viability on all scaffolds with higher proliferation in the 250 MUm and 500 MUm pore sizes of bioreactor cultured scaffolds and 100 MUm pore size of statically cultured scaffolds. Osteoblastic differentiation was enhanced in TPS culture as compared to static culture with the highest alkaline phosphatase expression observed in the 250 MUm pore size group. Bone morphogenetic protein-2 was also analyzed and expression levels were highest in the 250 MUm and 500 MUm pore size bioreactor cultured samples. These results demonstrate cellular response to pore size as well as the ability of dynamic culture to enhance these effects. PMID- 22528810 TI - Cryptomycota: the missing link. PMID- 22528809 TI - Molecular signatures from omics data: from chaos to consensus. AB - In the past 15 years, new "omics" technologies have made it possible to obtain high-resolution molecular snapshots of organisms, tissues, and even individual cells at various disease states and experimental conditions. It is hoped that these developments will usher in a new era of personalized medicine in which an individual's molecular measurements are used to diagnose disease, guide therapy, and perform other tasks more accurately and effectively than is possible using standard approaches. There now exists a vast literature of reported "molecular signatures". However, despite some notable exceptions, many of these signatures have suffered from limited reproducibility in independent datasets, insufficient sensitivity or specificity to meet clinical needs, or other challenges. In this paper, we discuss the process of molecular signature discovery on the basis of omics data. In particular, we highlight potential pitfalls in the discovery process, as well as strategies that can be used to increase the odds of successful discovery. Despite the difficulties that have plagued the field of molecular signature discovery, we remain optimistic about the potential to harness the vast amounts of available omics data in order to substantially impact clinical practice. PMID- 22528813 TI - Effects of untreated preoperative essential hypertension on post-operative pain after major abdominal surgery. AB - BACKGROUND: Hypertension has been associated with hypoalgesia. This prospective study was designed to test the effects of untreated preoperative essential hypertension on post-operative pain intensity and morphine requirement after major abdominal surgery. METHODS: Sixty subjects (30 untreated essential hypertensives and 30 normotensives) scheduled for abdominal surgery were included in this study. All subjects received standardized anaesthetic with intra operative fentanyl and patient-controlled analgesia with morphine for 48 h post operatively as the only analgesics. Pain intensity scores, cumulative morphine requirement and side effects were recorded until 48 h post-operatively. RESULTS: All subjects with essential hypertension had systolic hypertension, 93.3% had grade 1 severity and 6.7% had grade 2 severity. 23.3% of essential hypertensive subjects had elevated diastolic blood pressure. Essential hypertensive subjects had significantly lower total post-operative morphine requirement (29.6 mg vs. 49.9 mg; p = 0.002), significantly lower verbal rating scale post-operative pain intensity scores at rest and with coughing (p = 0.000), and significantly less incidence of post-operative pruritus (p = 0.048) over 48 h than normotensive subjects. There were no post-operative differences in the incidence of post operative nausea (p = 0.982) or vomiting (p = 0.644) between the two groups. CONCLUSION: Untreated essential hypertension is associated with significantly reduced post-operative morphine requirement and pain intensity, suggesting hypertension-associated hypoalgesia. PMID- 22528814 TI - Grayanotoxin poisoning: 'mad honey disease' and beyond. AB - Many plants of the Ericaceae family, Rhododendron, Pieris, Agarista and Kalmia, contain diterpene grayanotoxins. Consumption of grayanotoxin containing leaves, flowers or secondary products as honey may result in intoxication specifically characterized by dizziness, hypotension and atrial-ventricular block. Symptoms are caused by an inability to inactivate neural sodium ion channels resulting in continuous increased vagal tone. Grayanotoxin containing products are currently sold online, which may pose an increasing risk. In humans, intoxication is rarely lethal, in contrast to cattle and pet poisoning cases. Scientific evidence for the medicinal properties of grayanotoxin containing preparations, such as honey or herbal preparation in use in folk medicine, is scarce, and such use may even be harmful. PMID- 22528815 TI - Cardiovascular responses to Bothrops alternatus (Urutu) snake venom in anesthetized dogs. AB - The cardiovascular responses to Bothrops alternatus snake venom in anesthetized dogs were investigated. Venom (0.3 mg/kg, i.v.) markedly decreased arterial blood pressure, coronary perfusion pressure, and cardiac output (CO) after 5 min, with progressive recovery of the first two parameters to pre-venom levels after 3 h; CO showed little recovery. There was an abrupt, sustained decrease in left and right ventricular systolic work and stroke volume but no significant changes in heart rate, electrocardiogram, and pulmonary hemodynamics; systemic vascular resistance increased from 1 h onwards. A venom dose of 1 mg/kg produced more pronounced cardiovascular alterations, with a progressive decrease to death. There were no significant changes in blood gas (pO(2), pCO(2), HCO(3), SBC, and SBE) and metabolic (pH, lactate, glucose, creatine kinase activity, Na(+), and K(+)) parameters, although there was a transitory increase in plasma lactate dehydrogenase 2 min after the lower venom dose. There were no cardiac histological alterations, but microaneurysms and epithelial desquamation were seen in renal tubules. Circulating venom concentrations (determined by ELISA) decreased rapidly after administration, but venom was still detectable after 4 h. These results show that in dogs, B. alternatus venom produces marked hypotension and a direct cardiac action, with few metabolic alterations. PMID- 22528816 TI - Cardiac toxicity of targeted therapies used in the treatment for solid tumours: a review. AB - Cardiotoxicity associated with conventional cytostatics is a known phenomenon and is related to their general cytotoxic effects. This damage to the myocardium is usually irreversible. Despite the attempts to optimize safety profile of targeted anticancer drugs during their development, evidence shows that these new treatment modalities also have cardiotoxic potential or may adversely affect vascular system. Over the last years, a significant number of these agents have been introduced in medical practice. Arterial hypertension, arrhythmias, left ventricular dysfunction and a heart failure are the most frequent cardiovascular adverse effects of targeted anticancer agents, but this toxicity seems to be reversible. To enable early interventions and to minimize these cardiovascular adverse effects, health care professionals have to be well-informed and familiar with the safety profiles of the drugs they administered, the patient's cardiovascular condition and co-morbidities, and they must regularly monitor their patients for potential adverse effects. The aim of this paper is to provide an overview of cardiotoxic effects caused by targeted anticancer drugs used in the treatment of solid tumours. We discuss pathophysiological mechanisms, diagnostics and treatment, risk factors and options for prevention. PMID- 22528817 TI - Case report: an unusual heart rhythm associated with organophosphate poisoning. AB - Organophosphate pesticides have emerged as a common cause of poisoning, particularly in developing countries. The most common electrocardiographic abnormalities observed in organophosphate poisoning are sinus tachycardia, QT interval prolongation, and, very rarely, ventricular arrhythmias. We report a case of organophosphate poisoning associated with atrial fibrillation, right bundle branch block, QT interval prolongation, and intermittent narrow QRS complexes that were most likely due to automaticity from the region of the left posterior fascicle. PMID- 22528818 TI - A patient with Leiden V mutation, multiple sclerosis, psoriasis, and sicca syndrome: could celecoxib and fingolimod adversely affect the heart? AB - The paper describes the case of a patient affected by a combination of genetic and autoimmune diseases (multiple sclerosis, psoriatic arthritis, Leiden V mutation, and sicca syndrome) and hypertension. The psoriatic arthritis was treated with celecoxib and multiple sclerosis with fingolimod. The patient developed high fever and endocarditis, resulting in severe mitral regurgitation, atrial fibrillation, and congestive heart failure. Evidence is suggestive of adverse effects of potent immunosuppressive and anti-inflammatory therapies with biologic agents and the cardiovascular system. Fingolimod increases susceptibility to infections and induced endocarditis resulting in severe mitral regurgitation, atrial fibrillation, and congestive heart failure. Managed care systems limit the contact among basic care physicians and specialists. However, the process by which the optimal decision may be reached for a patient with a complex pathology is shared decision making, where the risk of severe complications and medical expenses may be reduced. PMID- 22528819 TI - Naked and self-clickable propargylic-decorated single-chain nanoparticle precursors via redox-initiated RAFT polymerization. AB - Protection of acetylenic monomers is a common practice to avoid parasitic side reactions during polymerization. Herein, we report that redox-initiated RAFT polymerization allows the direct, room temperature synthesis of a variety of single-chain nanoparticle precursors (displaying narrow molecular weight dispersity, M[overline](W)/M[overline](n) = 1.12 -1.37 up to M[overline](W) = 100 kDa) containing well-defined amounts of naked, unprotected acetylenic functional groups available for rapid and quantitative intrachain cross-linking via metal catalyzed carbon-carbon coupling (i.e., C-C "click" chemistry). To illustrate the useful "self-clickable" character of the new unprotected acetylenic precursors, single-chain nanoparticles have been prepared for the first time in a facile and highly efficient manner by copper-catalyzed alkyne homocoupling (i.e., Glaser-Hay coupling) at room temperature under normal air atmosphere. PMID- 22528820 TI - Evidence on self-fitting hearing aids. AB - The research on self-fitting hearing aids is reviewed using evidence-based principles. The evaluation begins with a definition of the research questions followed by a detailed search of the literature and then a review of the relevant studies. Four features of self-fitting hearing aids are reviewed: in-situ threshold measurement, whether an initial fitting prescribed using standard prescription formulae will approximate user preferences, outcomes with training of hearing aids for preferred responses, and assembly and use of the aids. There is at least good quality evidence suggesting that in-situ thresholds can be reliably obtained, that prescribed initial fittings approximate preferred responses, and that users are able to train the hearing aids and would prefer the trained responses. However, evidence on other outcomes and the ability of users to assemble and use such instruments is limited. Gaps in research with self fitting hearing aids are identified. PMID- 22528821 TI - The latent factor structure of Young's early maladaptive schemas: are schemas organized into domains? AB - OBJECTIVE: In previous research it has not been clarified whether the first-order schema factors of the Young Schema Questionnaire (YSQ) can be structured into higher order domains. We examined whether investigators' subjective choices between complex models of the YSQ or chance as opposed to clinical diversity of the samples may be responsible for the heterogeneity of results reported in the literature. METHOD: We used confirmatory factor analysis to compare several a priori defined domain models in a sample of 542 undergraduate students (82.8% female; mean age 24.1 years) and 590 nonstudent adults (73.9% female; mean age 34.5 years) form an Internet survey. An additional Monte Carlo simulation study was performed to gain further insights on model selection. RESULTS: The analyses did not provide unequivocal support for the presence of a second-order domain structure. However, study findings suggested that the structure of the YSQ could be represented by a bifactor model including a first-order generic factor on which all items load and correlated first-order specific schema factors on which only the items load that were meant to measure the respective schemas. CONCLUSION: In the YSQ either several second-order domain structures are present that cannot be ranked by statistical measures alone or a first-order generic factor is present making second-order domains dispensable. Future research should include theoretical arguments and incorporate the clinical experience of practitioners. PMID- 22528823 TI - Multistate memory devices based on free-standing VO2/TiO2 microstructures driven by Joule self-heating. AB - Two-terminal multistate memory elements based on VO(2)/TiO(2) thin film microcantilevers are reported. Volatile and non-volatile multiple resistance states are programmed by current pulses at temperatures within the hysteretic region of the metal-insulator transition of VO(2). The memory mechanism is based on current-induced creation of metallic clusters by self-heating of micrometric suspended regions and resistive reading via percolation. PMID- 22528825 TI - Widening the boundaries of the production effect. AB - Words that are read aloud are more memorable than words that are read silently. The boundaries of this production effect (MacLeod, Gopie, Hourihan, Neary, & Ozubko, Journal of experimental psychology: learning, memory, and cognition, 36, 671-685, 2010) have been found to extend beyond speech. MacLeod and colleagues demonstrated that mouthing also facilitates memory, leading them to speculate that any distinct, item-specific response should result in a production effect. In experiment 1, we found support for this conjecture: Relative to silent reading, three unique productions-spelling, writing, and typing-all boosted explicit memory. In experiment 2, we tested the sensitivity of the production effect. Although mouthing, writing, and whispering all improved explicit memory when compared to silent reading, these other production modalities were not as beneficial as speech. We argue that the enhanced distinctiveness of speech relative to other productions-and of other productions relative to silent reading underlies this pattern of results. PMID- 22528824 TI - The process-dissociation approach two decades later: convergence, boundary conditions, and new directions. AB - The process-dissociation procedure was developed to separate the controlled and automatic contributions of memory. It has spawned the development of a host of new measurement approaches and has been applied across a broad range of fields in the behavioral sciences, ranging from studies of memory and perception to neuroscience and social psychology. Although it has not been without its shortcomings or critics, its growing influence attests to its utility. In the present article, we briefly review the factors motivating its development, describe some of the early applications of the general method, and review the literature examining its underlying assumptions and boundary conditions. We then highlight some of the specific issues that the methods have been applied to and discuss some of the more recent applications of the procedure, along with future directions. PMID- 22528826 TI - Cervical dedifferentiated liposarcoma with meningothelial-like whorling. AB - Liposarcomas are the most common soft-tissue sarcoma of adults, but rare in the head and neck. Recently, a subtype of dedifferentiated liposarcoma with meningiothelial-like whorls was reported and we present the first description of such a tumor in the head and neck. A 65 year old male underwent a resection of a calcified retroesophageal mass that was in close relation to the left hemithyroid and recurrent laryngeal nerve. It was resected en bloc with the left thyroid lobe. Initial pathologic evaluation suggested the mass was a schwanomma of the recurrent laryngeal nerve, but positive staining for MDM2 and CDK4 indicated the tumor was a dedifferentiated liposarcoma. Further evaluation elucidated the unique meningothelial-like whorls within the tumor. This case demonstrates dedifferentiated liposarcomas do appear in the head and neck. Furthermore, this is the first report in the head and neck of the mengiothelial-like whorling pattern type of dedifferentiated liposarcoma. PMID- 22528827 TI - HPV positive squamous cell carcinoma of the oropharynx. Are we observing an unusual pattern of metastases? AB - To describe the clinical, histopathologic, immunohistochemical and molecular features of human papilloma virus (HPV)+ squamous cell carcinomas of the oropharynx that had an atypical clinical course. METHODS AND RESULTS: Four patients with HPV+ oropharyngeal squamous cell carcinoma (OPSCC) were identified retrospectively based on unanticipated clinical behavior. The histopathology, immunohistochemistry and molecular studies of both the primary tumor and the metastases were analyzed to look for any predictors to explain the clinical course. The four patients were all male (average age 55) who presented initially with a neck mass and had stage IVA disease. Three of the primary tumors were nonkeratinizing squamous cell carcinoma and one case was a hybrid tumor of both high-grade squamous cell carcinoma and nonkeratinizing type, and all were p16 and HPV 16/18 positive. All patients received concurrent chemoradiation as primary therapy and had a complete response. Disease-free survival ranged from 7 to 15 months and metastases in 3 patients occurred only in bone, including the sternum, humerus, clavicle, and vertebrae. In one patient, distant metastases were identified in the pancreas, liver, lung and skull base. All metastatic lesions were nonkeratinizing morphology and were p16 and/or HPV positive. Two patients died of their disease, one patient is alive with disease and one patient is disease-free. Although infrequent, unanticipated clinical outcomes can occur in HPV-related OPSCC including distant metastases and bone-only metastases. The tumor morphology of the metastases was comparable to the primary and retained p16 and HPV expression. PMID- 22528828 TI - Epithelioid osteoblastoma. PMID- 22528829 TI - Cognitive rehabilitation correlates with the functional connectivity of the anterior cingulate cortex in patients with multiple sclerosis. AB - We investigated how resting state (RS) functional connectivity (FC) of the anterior cingulate cortex (ACC) correlates with cognitive rehabilitation in relapsing remitting multiple sclerosis (RRMS) patients. A neuropsychological assessment and RS fMRI at baseline and after 12 weeks were obtained from 20 RRMS patients, who were assigned randomly to undergo treatment (n = 10) (treatment group-TG), which entailed computer-assisted cognitive rehabilitation of attention/information processing and executive functions for 3 days/week, or not to receive any cognitive rehabilitation (n = 10) (control group-CG). Voxel-wise changes of ACC RS FC were assessed using SPM8. In both groups, at the two study time points, ACC activity was correlated with the bilateral middle and inferior frontal gyrus, basal ganglia, posterior cingulate cortex, cerebellum, precuneus, middle temporal gyrus, and inferior parietal lobule (IPL). At follow up, compared to baseline, the TG showed an increased FC of the ACC with the right middle frontal gyrus (MFG) and right IPL, while the CG showed a decreased FC of the ACC with the right cerebellum and right inferior temporal gyrus (ITG). A significant "treatment * time" interaction was found for the increased FC of the right IPL and for the decreased FC of the right ITG. In the TG only, significant correlations (p < 0.001) were found between improvement of PASAT performance and RS FC of the ACC with the right MFG (r = 0.88) and right IPL (r = 0.76). In MS, cognitive rehabilitation correlates with changes in RS FC of brain regions subserving the trained functions. fMRI might be useful to monitor rehabilitative strategies in MS. PMID- 22528830 TI - Folic acid prevents behavioral impairment and Na(+), K(+) -ATPase inhibition caused by neonatal hypoxia-ischemia. AB - Folic acid plays an important role in neuroplasticity and acts as a neuroprotective agent, as observed in experimental brain ischemia studies. The aim of this study was to investigate the effects of folic acid on locomotor activity, aversive memory and Na(+),K(+)-ATPase activity in the frontal cortex and striatum in animals subjected to neonatal hypoxia-ischemia (HI). Wistar rats of both sexes at postnatal day 7 underwent HI procedure and were treated with intraperitoneal injections of folic acid (0.011 MUmol/g body weight) once a day, until the 30th postnatal day. Starting on the day after, behavioral assessment was run in the open field and in the inhibitory avoidance task. Animals were sacrificed by decapitation 24 h after testing and striatum and frontal cortex were dissected out for Na(+),K(+)-ATPase activity analysis. Results show anxiogenic effect in the open field and an impairment of aversive memory in the inhibitory avoidance test in HI rats; folic acid treatment prevented both behavioral effects. A decreased Na(+),K(+)-ATPase activity in striatum, both ipsilateral and contralateral to ischemia, was identified after HI; a total recovery was observed in animals treated with folic acid. A partial recovery of Na(+),K(+)-ATPase activity was yet seen in frontal cortex of HI animals receiving folic acid supplementation. Presented results support that folic acid treatment prevents memory deficit and anxiety-like behavior, as well as prevents Na(+),K(+) ATPase inhibition in the striatum and frontal cortex caused by neonatal hypoxia ischemia. PMID- 22528831 TI - Antipsychotic induced alteration of growth and proteome of rat neural stem cells. AB - Neural stem cells (NSCs) play a crucial role in the development and maturation of the central nervous system and therefore have the potential to target by therapeutic agents for a wide variety of diseases including neurodegenerative and neuropsychiatric illnesses. It has been suggested that antipsychotic drugs have significant effects on NSC activities. However, the molecular mechanisms underlying antipsychotic-induced changes of NSC activities, particularly growth and protein expression, are largely unknown. NSCs were treated with either haloperidol (HD; 3 MUM), risperidone (RS; 3 MUM) or vehicle (DMSO) for 96 h. Protein expression profiles were studied through a proteomics approach. RS promoted and HD inhibited the growth of NSCs. Proteomics analysis revealed that 15 protein spots identified as 12 unique proteins in HD-, and 20 protein spots identified as 14 proteins in RS-treated groups, were differentially expressed relative to control. When these identified proteins were compared between the two drug-treated groups, 2 proteins overlapped leaving 10 HD-specific and 12 RS specific proteins. Further comparison of the overlapped altered proteins of 96 h treatment with the neuroleptics-induced overlapped proteins at 24 h time interval (Kashem et al. [40] in Neurochem Int 55:558-565, 2009) suggested that overlapping altered proteins expression at 24 h was decreased (17 proteins i.e. 53 % of total expressed proteins) with the increase of time (96 h) (2 proteins; 8 % of total expressed proteins). This result indicated that at early stage both drugs showed common mode of action but the action was opposite to each other while administration was prolonged. The opposite morphological pattern of cellular growth at 96 h has been associated with dominant expression of oxidative stress and apoptosis cascades in HD, and activation of growth regulating metabolic pathways in RS treated cells. These results may explain RS induced repairing of neural damage caused by a wide variety of neural diseases including schizophrenia. PMID- 22528832 TI - The anticonvulsant and neuroprotective effects of baicalin on pilocarpine-induced epileptic model in rats. AB - Baicalin, a flavonoid compound purified from plant Scutellaria baicalensis Georgi, has been reported to possess a wide variety of pharmacological properties including anti-oxidative, anti-apoptotic and neuroprotective properties. Oxidative stress can dramatically alter neuronal function and has been linked to status epilepticus (SE). However, the neuroprotective effect of baicalin on epilepsy is unclear. In this study we investigated whether Baicalin could exert anticonvulsant and neuroprotective effects in the pilocarpine-induced epileptic model in rats. To this end, we recorded the latency to first limbic seizure and SE and observed the incidence of SE and mortality. The changes of oxidative stress were measured 24 h after pilocarpine-induced SE. Nissl staining, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and Fluoro-Jade B staining were performed to detect the neuronal loss, apoptosis and degeneration in hippocampus 72 h after pilocarpine-induced seizure. Pretreatment with baicalin significantly delayed the onset of the first limbic seizures and SE, reduced the mortality rate, and attenuated the changes in the levels of lipid peroxidation, nitrite content and reduced glutathione in the hippocampus of pilocarpine-treated rats. Furthermore, we also found that baicalin attenuated the neuronal cell loss, apoptosis, and degeneration caused by pilocarpine-induced seizures in rat hippocampus. Collectively, these results indicated remarkable anticonvulsant and neuroprotective effects of baicalin and should encourage further studies to investigate baicalin as an adjuvant in epilepsy both to prevent seizures and to protect against seizure induced brain injury. PMID- 22528833 TI - Exocytosis in astrocytes: transmitter release and membrane signal regulation. AB - Astrocytes, a type of glial cells in the brain, are eukaryotic cells, and a hallmark of these are subcellular organelles, such as secretory vesicles. In neurons vesicles play a key role in signaling. Upon a stimulus-an increase in cytosolic concentration of free Ca(2+) ([Ca(2+)](i))-the membrane of vesicle fuses with the presynaptic plasma membrane, allowing the exit of neurotransmitters into the extracellular space and their diffusion to the postsynaptic receptors. For decades it was thought that such vesicle-based mechanisms of gliotransmitter release were not present in astrocytes. However, in the last 30 years experimental evidence showed that astrocytes are endowed with mechanisms for vesicle- and non-vesicle-based gliotransmitter release mechanisms. The aim of this review is to focus on exocytosis, which may play a role in gliotransmission and also in other forms of cell-to-cell communication, such as the delivery of transporters, ion channels and antigen presenting molecules to the cell surface. PMID- 22528834 TI - Phosphorylation of GFAP is associated with injury in the neonatal pig hypoxic ischemic brain. AB - Glial fibrillary acidic protein (GFAP) is an intermediate filament protein expressed in the astrocyte cytoskeleton that plays an important role in the structure and function of the cell. GFAP can be phosphorylated at six serine (Ser) or threonine (Thr) residues but little is known about the role of GFAP phosphorylation in physiological and pathophysiological states. We have generated antibodies against two phosphorylated GFAP (pGFAP) proteins: p8GFAP, where GFAP is phosphorylated at Ser-8 and p13GFAP, where GFAP is phosphorylated at Ser-13. We examined p8GFAP and p13GFAP expression in the control neonatal pig brain and at 24 and 72 h after an hypoxic-ischemic (HI) insult. Immunohistochemistry demonstrated pGFAP expression in astrocytes with an atypical cytoskeletal morphology, even in control brains. Semi-quantitative western blotting revealed that p8GFAP expression was significantly increased at 24 h post-insult in HI animals with seizures in frontal, parietal, temporal and occipital cortices. At 72 h post-insult, p8GFAP and p13GFAP expression were significantly increased in HI animals with seizures in brain regions that are vulnerable to cellular damage (cortex and basal ganglia), but no changes were observed in brain regions that are relatively spared following an HI insult (brain stem and cerebellum). Increased pGFAP expression was associated with poor neurological outcomes such as abnormal encephalography and neurobehaviour, and increased histological brain damage. Phosphorylation of GFAP may play an important role in astrocyte remodelling during development and disease and could potentially contribute to the plasticity of the central nervous system. PMID- 22528835 TI - Brain region-specific glutathione redox imbalance in autism. AB - Autism is a heterogeneous, behaviorally defined neurodevelopmental disorder. Recently, we reported a brain region-specific increase in lipid peroxidation, and deficits in mitochondrial electron transport chain complexes in autism, suggesting the role of oxidative stress and mitochondrial dysfunction in the pathophysiology of autism. However, the antioxidant status of the brain is not known in autism. Glutathione is a major endogenous antioxidant that plays a crucial role in protecting cells from exogenous and endogenous toxins, particularly in the central nervous system. The present study examines the concentrations of glutathione (GSH, reduced form; and GSSG, oxidized form) and the redox ratio of GSH to GSSG (marker of oxidative stress) in different regions of brains from autistic subjects and age-matched control subjects. In the cerebellum and temporal cortex from subjects with autism, GSH levels were significantly decreased by 34.2 and 44.6 %, with a concomitant increase in the levels of GSSG by 38.2 and 45.5 %, respectively, as compared to the control group. There was also a significant decrease in the levels of total GSH (tGSH) by 32.9 % in the cerebellum, and by 43.1 % in the temporal cortex of subjects with autism. In contrast, there was no significant change in GSH, GSSG and tGSH levels in the frontal, parietal and occipital cortices in autism versus control group. The redox ratio of GSH to GSSG was also significantly decreased by 52.8 % in the cerebellum and by 60.8 % in the temporal cortex of subjects with autism, suggesting glutathione redox imbalance in the brain of individuals with autism. These findings indicate that autism is associated with deficits in glutathione antioxidant defense in selective regions of the brain. We suggest that disturbances in brain glutathione homeostasis may contribute to oxidative stress, immune dysfunction and apoptosis, particularly in the cerebellum and temporal lobe, and may lead to neurodevelopmental abnormalities in autism. PMID- 22528836 TI - Modulation of RAGE isoforms expression in the brain and plasma of rats exposed to transient focal cerebral ischemia. AB - Activation of RAGE (receptor for advanced glycation endproducts) and of its subtypes may play a role in neuronal damage and neuroinflammation associated with brain ischemia, though the underlying mechanisms remain unclear. In this study, we have examined by Western blotting the expression of RAGE isoforms in the cerebral cortex and striatum of Wistar rats subjected to transient (1 or 2 h) middle cerebral artery occlusion (tMCAo). The findings show that the full-length RAGE (~50 kDa) and its isoforms in the 26-43 kDa range are significantly decreased in the ischemic cortex, but not in the striatum, after 1 and 2 h tMCAo when compared to the sham group. By contrast, in the striatum, ischemia reperfusion injury caused a significant increase of full-length RAGE and its isoforms in the 72-100 kDa range. We also investigated the soluble form of RAGE, which was significantly decreased in the plasma of rats subjected to transient or permanent MCAo. In conclusion, the present data demonstrate that regional brain expression of RAGE is differentially affected by tMCAo in rat. These modifications are accompanied by a decrease in the plasma levels of soluble RAGE, thereby suggesting a potential role for soluble RAGE as a peripheral biomarker of focal ischemia. PMID- 22528837 TI - Inhibition of nuclear factor erythroid 2-related factor 2 exacerbates HIV-1 gp120 induced oxidative and inflammatory response: role in HIV associated neurocognitive disorder. AB - The HIV epidemic continues to be the most severe public health problem and concern within USA and across the globe. In spite of the highly active antiretroviral therapy, HIV infected subjects experience major neurological complications that range from HIV associated dementia to moderate neurocognitive and motor impairments collectively termed as HIV associated neurocognitive disorders (HAND). Astrocytes play an important role in the neuropathogenesis of HAND. Further, in the recent years it has been shown that oxidative stress plays a major role in the neuropathogenesis of HAND. Nuclear factor erythroid 2-related factor 2 (Nrf2), a leucine zipper redox-sensitive transcription factor, is an important regulator of cell survival and adaptive mechanisms and has been shown to possess a protective role in a variety of neurological and inflammatory disorders. Earlier we have shown that Nrf2 is upregulated in response to HIV-1 gp120 and such upregulation of Nrf2 may be a protective mechanism against the HIV induced oxidative stress. We hypothesize that Nrf2-mediated antioxidant pathways are important in regulating the HIV-induced oxidative stress and that the disruption of Nrf2 makes the cells more susceptible to HIV gp120-induced deleterious effects. Our results indicate that when astrocytes are exposed to gp120 there is an increase in the expression of NOX2, a subunit of NADPH oxidase, and also an upregulated expression of nuclear factor kappa B, tumor necrosis factor-alpha (TNF-alpha) and matrix metalloproteinase-9 (MMP-9). However, the degree of expression was significantly higher in those cells where Nrf2 was silenced by siRNA. Taken together, these results suggest a possible protective role of Nrf2 in regulating the levels of pro-oxidative and pro-inflammatory molecules in HAND. PMID- 22528838 TI - Differential activation of the ER stress factor XBP1 by oligomeric assemblies. AB - Several neurodegenerative disorders are characterized by protein misfolding, a phenomenon that results in perturbation of cellular homeostasis. We recently identified the protective activity of the ER stress response factor XBP1 (X-box binding protein 1) against Amyloid-beta1-42 (Abeta42) neurotoxicity in cellular and Drosophila models of Alzheimer's disease. Additionally, subtoxic concentrations of Abeta42 soluble aggregates (oligomers) induced accumulation of spliced (active) XBP1 transcripts, supporting the involvement of the ER stress response in Abeta42 neurotoxicity. Here, we tested the ability of three additional disease-related amyloidogenic proteins to induce ER stress by analyzing XBP1 activation at the RNA level. Treatment of human SY5Y neuroblastoma cells with homogeneous preparations of alpha-Synuclein (alpha-Syn), Prion protein (PrP106-126), and British dementia amyloid peptide (ABri1-34) confirmed the high toxicity of oligomers compared to monomers and fibers. Additionally, alpha-Syn oligomers, but not monomers or fibers, demonstrated potent induction of XBP1 splicing. On the other hand, PrP106-126 and ABri1-34 did not activate XBP1. These results illustrate the biological complexity of these structurally related assemblies and argue that oligomer toxicity depends on the activation of amyloid specific cellular responses. PMID- 22528839 TI - Gemfibrozil, a lipid lowering drug, inhibits the activation of primary human microglia via peroxisome proliferator-activated receptor beta. AB - Microglial activation participates in the pathogenesis of various neuroinflammatory and neurodegenerative diseases. However, mechanisms by which microglial activation could be controlled are poorly understood. Peroxisome proliferator-activated receptors (PPAR) are transcription factors belonging to the nuclear receptor super family with diverse effect. This study underlines the importance of PPARbeta/delta in mediating the anti-inflammatory effect of gemfibrozil, an FDA-approved lipid-lowering drug, in primary human microglia. Bacterial lipopolysachharides (LPS) induced the expression of various proinflammatory molecules and upregulated the expression of microglial surface marker CD11b in human microglia. However, gemfibrozil markedly suppressed proinflammatory molecules and CD11b in LPS-stimulated microglia. Human microglia expressed PPAR-beta and -gamma, but not PPAR-alpha. Interestingly, either antisense knockdown of PPAR-beta or antagonism of PPAR-beta by a specific chemical antagonist abrogated gemfibrozil-mediated inhibition of microglial activation. On the other hand, blocking of PPAR-alpha and -gamma had no effect on gemfibrozil-mediated anti-inflammatory effect in microglia. These results highlight the fact that gemfibrozil regulates microglial activation by inhibiting inflammatory gene expression in a PPAR-beta dependent pathway and further reinforce its therapeutic application in several neuroinflammatory and neurodegenerative diseases. PMID- 22528840 TI - Metabolic modeling of dynamic brain 13C NMR multiplet data: concepts and simulations with a two-compartment neuronal-glial model. AB - Metabolic modeling of dynamic (13)C labeling curves during infusion of (13)C labeled substrates allows quantitative measurements of metabolic rates in vivo. However metabolic modeling studies performed in the brain to date have only modeled time courses of total isotopic enrichment at individual carbon positions (positional enrichments), not taking advantage of the additional dynamic (13)C isotopomer information available from fine-structure multiplets in (13)C spectra. Here we introduce a new (13)C metabolic modeling approach using the concept of bonded cumulative isotopomers, or bonded cumomers. The direct relationship between bonded cumomers and (13)C multiplets enables fitting of the dynamic multiplet data. The potential of this new approach is demonstrated using Monte Carlo simulations with a brain two-compartment neuronal-glial model. The precision of positional and cumomer approaches are compared for two different metabolic models (with and without glutamine dilution) and for different infusion protocols ([1,6-(13)C(2)]glucose, [1,2-(13)C(2)]acetate, and double infusion [1,6 (13)C(2)]glucose + [1,2-(13)C(2)]acetate). In all cases, the bonded cumomer approach gives better precision than the positional approach. In addition, of the three different infusion protocols considered here, the double infusion protocol combined with dynamic bonded cumomer modeling appears the most robust for precise determination of all fluxes in the model. The concepts and simulations introduced in the present study set the foundation for taking full advantage of the available dynamic (13)C multiplet data in metabolic modeling. PMID- 22528841 TI - Nocturnal blood pressure, morning blood pressure surge, and cerebrovascular events. AB - Cerebrovascular disease is a common cause of death and major cause of disability worldwide. Even in silent cases (e.g., silent cerebral infarction, white matter lesion), cerebrovascular disease can lead to physical and cognitive impairment, thereby substantially reducing the activities of daily living. Accordingly, the earliest possible action to prevent not only symptomatic but also silent cerebrovascular disease has become a major public health challenge. Hypertension is a potent risk factor for both symptomatic and silent cerebrovascular disease. Twenty-four-hour blood pressure (BP) rather than office BP is closely associated with cerebrovascular disease and/or poor physical and cognitive function. In particular, nocturnal BP and morning BP surge have attracted much attention as risk factors for cerebrovascular diseases independently of 24-h BP level. This review is an attempt to summarize some of the evidence on nocturnal BP level or nocturnal BP dipping status, and morning BP surge as potent risk factors for cerebrovascular disease. PMID- 22528842 TI - Management of bilateral complex fracture-dislocation of proximal ulna and radius: a case report. AB - Complex fracture-dislocation of proximal ulna and radius (FDUR) are rare, representing only 2-5 % of elbow injuries. Monteggia-like lesions and transolecranon fractures include various patterns of complex FDUR, which are not well defined. The management of these injuries is considered extremely difficult, and clinical results are often poor. In this report, we present a case of a 66 year-old woman with bilateral complex FDUR. This pattern of injury is very rare and little information is available about its management. Diagnosis, surgical technique, rehabilitation programme and clinical results are reported. The bilaterality of the condition does not appear to influence the treatment and results. PMID- 22528843 TI - Arthroscopically assisted latissimus dorsi transfer with a minimally invasive harvesting technique: surgical technique and anatomic study. AB - Latissimus dorsi musculotendinous transfer has been described for the treatment of massive rotator cuff defects. The aim of this paper is to present the relevant surgical anatomy of an arthroscopically assisted technique associated with a modified harvesting of the tendon. For tendon harvesting, a skin incision of about 5-6 cm in length is made in the axillary crease orthogonal to the longitudinal axis of the upper arm. For the musculotendinous transfer, we propose to increase vector action of the latissimus dorsi by passing the transferred tendon ahead the triceps muscle under or over the Teres Major and fixing the transferred tendon behind the humeral head center of rotation in a more posterolateral position. In order to check the feasibility and safety of this new surgical technique, two fresh-frozen adult cadaveric hemithorax specimens with an intact upper extremity were dissected, and the relationships between the tendons and local neurologic structures were described during various steps of the latissimus dorsi transfer procedure. PMID- 22528845 TI - Subdeltoid lipomas: a consecutive series of 13 cases. AB - We describe 13 consecutive cases of patients presenting with shoulder mass and limited function, and to whom we formulated a diagnosis of subdeltoid lipoma. Between 2002 and 2010, 14 patients had a diagnosis of subdeltoid lipoma. Of these, one was excluded from this review because of a concomitant cuff tear. Shoulder was evaluated with X-ray, MRI, EMG and pre-/post-operatively with constant score (CS) and subjective shoulder value (SSV). All patients had complete excision of the mass. Minimum follow-up was 12 months. In 14 cases, the lipoma was causing slight pain or discomfort, and in four cases (28.57 %), it was causing limitation of joint movement. EMG showed axillary nerve neuro apraxia in two cases (14.28 %). Preoperative CS and SSV were on average 80 and 80, respectively. At one-year follow-up, CS and SSV were meanly 92 and 95, respectively (p = 0.034). No recurrence of the lesion was noted. Subdeltoid lipomas quickly grow up and may cause compression of axillary nerve. Surgery is the treatment of these lesions if symptomatic. After complete excision, subdeltoid lipomas do not recur, and clinical signs disappear. Level of evidence Case series, Level IV. PMID- 22528844 TI - The long head of biceps as a source of pain in active population: tenotomy or tenodesis? A comparison of 2 case series with isolated lesions. AB - The tendon of the long head of the biceps (LHB) is a common source of pain in the shoulder, and the surgical treatments proposed are tenotomy or tenodesis performed in different ways. The purpose of this study is to compare the clinical results (objective and subjective) of tenotomy versus soft tissue tenodesis. One hundred and four patients with an isolated LHB pathology, arthroscopically treated between 2004 and 2007, were observed retrospectively. Forty-eight of these patients were treated with tenotomy and 56 with a soft tissue tenodesis technique. All the patients were evaluated by an independent observer with a minimum follow-up of 2 years which included VAS, DASH questionnaire, Constant score and ROM evaluation with a goniometer. All these evaluations were performed pre- and post-operatively. An independent expert radiologist then performed an ultrasound examination only in the post-operative evaluation of the tenodesis group looking to confirm the effectiveness of the procedure. In both groups, the scores were significantly improved. In the tenotomy group, 16.6 % of the patients had bicipital cramps for a mean post-operative time of 1 month. Constant score improved in both groups: 46.6 to 86.1 in tenotomy group and 48.9-84.9 in tenodesis group; VAS improved from 8.4 to 1.5 in tenotomy group and from 8.8 to 1.4 in tenodesis group; DASH scores changed from 42.5 to 13.6 in tenotomy group and from 55.8 to 11.4 in tenodesis group. Popeye sign was present in 37.5 % in the tenotomy group and in 5.3 % in tenodesis group. In 3 patients of the tenodesis group, ultrasound revealed complete failure of the tenodesis. In conclusion, both procedures are effective in terms of treatment of LHB pathologies. Tenotomy does not require specific post-operative treatment and is easy to perform, but cramp and Popeye sign may occur after surgery. The soft tissue tenodesis technique is an easy and cost-effective way to perform tenodesis with good results, especially in preventing the Popeye sign, but requires a longer rehabilitation time. Level of evidence IV. PMID- 22528846 TI - Effectiveness of ultrasound-guided injections combined with shoulder exercises in the treatment of subacromial adhesive bursitis. AB - The aim of this study was to evaluate whether the association of exercises for the shoulder with ultrasound-guided injection into the bursa significantly improves the treatment outcome in adhesive bursitis. Two groups of 35 patients, one treated with ultrasound-guided injection (UGI) and the other one with ultrasound-guided injection and home exercise program (UGI-exercise) for 1 month, were assessed for pain and shoulder function before treatment, 1 and 3 months post-treatment. Fourteen patients in UGI group and 23 patients in the UGI exercises group were completely free of pain after 1 month (p = 0.031). At 3 months' follow-up, patients in the UGI-exercise group showed a significant improvement with respect to the other group (p = 0.005). No differences were found in function assessment. The UGI combined with shoulder exercises in the treatment of subacromial adhesive bursitis is effective to ensure a more frequent complete pain relief in the medium term. PMID- 22528847 TI - Non-orthopaedic causes of shoulder pain: what the shoulder expert must remember. AB - Aim of this review is to underline some specific patterns of shoulder pain that are not related to musculoskeletal diseases but are manifestations of gastrointestinal, neurological, cardiological or rheumatological diseases. The most important pathologies (like gallstones, myocardial ischaemia and Parsonage Turner syndrome...) that can manifest with shoulder pain will be presented by specialty doctors and elements for differential diagnosis will be discussed. Orthopaedic shoulder surgeons should always suspect other causes of pain, different from those related to bone, tendons and joint. If there is something unfair, patients should be referred to family doctor for further investigations in order to exclude major systemic diseases. PMID- 22528848 TI - Reverse total shoulder arthroplasty: radiological and clinical result using an eccentric glenosphere. AB - In reverse shoulder arthroplasty, an eccentric glenosphere has been developed with the aim of lowering the centre of rotation, in order to prevent inferior scapular notching as occurs with concentric designs. The objective of this retrospective study was to evaluate clinical and radiographic outcomes using the eccentric glenosphere and to determine whether this design might prevent inferior scapular notching. Between 2006 and 2010, 40 patients affected by cuff tear arthropathy underwent reverse shoulder arthroplasty with an eccentric 36-mm glenoid component. Patients with less than 2 years' follow-up were excluded. The results for 25 patients with a minimum of 24 months' follow-up are reported. Clinical and radiographic evaluation was performed preoperatively and at 1, 3, 6 months, 1 year and annually thereafter. All patients were evaluated with MRI or CT scan preoperatively and with X-ray examinations postoperatively to evaluate the presence of inferior scapular notching and to measure the prosthesis-scapular neck angle (PSNA), the peg-glenoid rim distance (PGRD) and the distance between the scapula neck and the glenosphere. At last follow-up (average 27.5 months, range 24-46), the Constant Score, the VAS score and range of motion had improved significantly. The average PSNA was 92 degrees + 29 degrees , the average PGRD was 21.2 mm + 9 mm and the average distance between the inferior bony glenoid rim and the inferior edge of the glenosphere was 4.3 mm + 0.8 mm. No inferior scapular notching and no implant-related complications were seen. The data suggest that use of an eccentric glenosphere lowers the centre of rotation, reducing the risk of inferior scapular notching. Level of evidence IV. PMID- 22528849 TI - The relationship between acromion thickness and body habitus: practical implications in subacromial decompression procedures. AB - To define the bone's amount that should be removed during an acromioplasty has always been a challenge. We aimed to verify the correlations between scapular dimensions and acromial thickness, assess the differences between the two genders, investigate the relationship between acromial type and thickness. We examined 500 dried scapulae, measuring the major axis of the scapular body and the acromial thickness; these were also catalogued according to gender. Acromial shape was classified according to Bigliani's method. Frequencies: Type I 38.9 %, Type II 39.4 %, Type III 21.7 %. The mean acromial thickness was 0.85 cm, and it resulted wider in men. There was a direct linear relationship between scapular dimensions and acromial thickness. The range of thickness of Type III acromion was significantly different from the others. We should be aware that gender, scapular dimensions and acromial shape should be evaluated preoperatively since they influence the acromial thickness. PMID- 22528850 TI - The classification of complex 4-part humeral fractures revisited: the missing fifth fragment and indications for surgery. AB - We describe a new classification of complex 4-part proximal humeral fractures (PHF). Its novelty lies in the involvement of fractures of the calcar area (i.e., the missing fifth fragment) in relation to fragments of the head, tuberosities and shaft. The classification consists of 6 groups (divided into 15 subgroups) of calcar fracture patterns. We hypothesized that this classification could aid surgical decision making in terms of osteosynthesis versus prothesis. To test this hypothesis, two shoulder surgeons, trained in the classification, re examined the X-rays and CT scans of 100 cases of 4-part PHF to codify each calcar fracture pattern. CT scans proved to be essential for this process. We then theoretically assigned the most appropriate treatment to each subgroup. Subsequent verification of clinical records confirmed our hypothesis that this classification could help the surgeon to decide the best approach to complex 4 part PHF. PMID- 22528851 TI - Displaced mid-shaft clavicular fractures: surgical treatment with a pre-contoured angular stability plate. AB - The treatment for displaced mid-shaft clavicle fracture is highly controversial. In the last years, several biomechanical studies showed better functional results after surgical treatment. The purpose of this study is to evaluate the use of pre contoured angular stability plate in this type of fracture. From June 2005 to July 2009, we have surgically treated 89 patients with displaced clavicle fracture. We have reevaluated 68 patients for a total of 70 interventions. Outcomes were assessed with Constant score, Dash questionnaire and X-rays. The mean follow-up period was 2 years. Excellent and good results were achieved for all the patients revaluated. The mean Constant score was 94.1 pt, and DASH score was 4.1. We had two cases of nonunion (2.9 %), while there was no case of infection and vascular or nervous lesions. A review of the international literature indicates that there is not a largely accepted gold standard for the treatment for displaced mid-shaft clavicle fractures. In the last 10 years, biomechanical and clinical studies have shown that nonoperative treatment for this type of fractures, with marked shortening or diastasis of the clavicle superior to 2 cm, may result in lower functional outcomes or higher percentage of nonunion. Nowadays, a lot of surgical options are available for the treatment for displaced mid-shaft clavicle fractures. Our experience with pre-contoured angular stability plates has shown excellent clinical outcome. On the basis of our study, we support the use of pre-contoured angular stability plate. PMID- 22528852 TI - The fifth monographic issue of Musculoskeletal Surgery edited by the Italian Society of Shoulder and Elbow Surgery exhibits a further progress in contents and in quality. PMID- 22528853 TI - Radial head replacement with unipolar and bipolar SBi system: a clinical and radiographic analysis after a 2-year mean follow-up. AB - Radial head prosthetic replacement is indicated in case of comminuted fracture not amenable to internal fixation, especially when the radial head fracture is part of a pattern of lesions configuring a complex instability of the elbow. Thirty-one SBi radial head prostheses were implanted in 30 patients (one bilateral simultaneous fracture) over a 2 years period. In 10 patients, the mean time from trauma to surgical treatment was 2.4 days, while the remaining 20 patients were treated as "second opinion" cases presenting with elbow stiffness or instability after an average of 19 days from trauma. The implants were monopolar in 12 cases and bipolar in 19. The clinical results were evaluated through the Mayo Elbow performance scoring system. At an average follow-up of 2 years (range 13-36 months), the mean MEPS was 90 points (range 65-100). At late radiographic analysis, radiolucent lines around the stem were found in 11 of the 31 cases. Heterotopic ossifications were found in 14 cases. Bone resorption was observed in 9 cases. Two of the 31 prostheses were removed after 16 and 20 months, in one case to correct stiffness in pronation/supination, in the other one for asymptomatic aseptic mobilization. These short-term results are satisfactory, especially when considering that they were obtained in complex elbow lesions treated in many cases at a delayed stage. Our preference over time went more and more to bipolar implants, but from a comparison of the results we could find no evidence of a superiority of bipolar or monopolar implants. The evolution of these prostheses needs to be evaluated with further studies to assess mid-term and long-term follow-up results. PMID- 22528854 TI - Axial correction of the lower limb deformities in a girl with anauxetic dysplasia. AB - Valgus subtrochanteric osteotomies and hemiepiphyseodesis around the knees have been performed to correct severe coxa vara and genua valga in a girl patient who manifested extreme dwarfism associated with spondylometaepiphyseal dysplasia consistent with anauxetic dysplasia. To the best of our knowledge, this is the first description of the combined orthopaedic intervention in a girl with anauxetic dysplasia. PMID- 22528855 TI - Role and regulation of VEGF and its receptors 1 and 2 in the aseptic loosening of total hip implants. AB - It was hypothesized that vascular endothelial growth factor (VEGF) in fibroblasts participates in aseptic loosening of total hip replacement (THR) implants. Therefore, osteoarthritic (OA) samples (n = 11) were compared with synovial membrane-like interface tissues from revision THR (n = 10). VEGF-A and its receptors were stained using streptavidin-immunoperoxidase method. Their regulation by hypoxia and cytokines were studied in cultured fibroblasts using quantitative real-time polymerase chain reaction (qRT-PCR). VEGFR1(+) lining cells (p < 0.01), stromal fibroblast-like cells (p = 0.001) and stromal macrophage-like cells (p < 0.05) were more numerous in rTHR than in OA. As to VEGFR2(+), only stromal fibroblast-like cells in rTHR outnumbered those found in OA (p < 0.05). VEGFRs in synovial fibroblasts were not affected by hypoxia, but VEGF increased 2.4-fold (p < 0.05). Interleukin-4 up-regulated VEGFR1 expression 23-fold. This is the first study to describe a difference between rTHR and OA in VEGF receptors, particularly VEGFR1. Hypoxia increased VEGF, but the VEGFR1 increase in the lining and stroma is probably IL-4 driven, in accordance with the M2-type macrophage dominance in interface tissues. VEGF/VEGFR system is also affected by hypoxia and may play a role in angiogenesis and bone pathology in aseptic loosening of total hip implants. PMID- 22528857 TI - Doped quantum dots for white-light-emitting diodes without reabsorption of multiphase phosphors. AB - A white-light-emitting diode (white LED) with good color rendering index is fabricated based on a blue LED combined with high-fluorescence CdS:Cu/ZnS quantum dots (QDs) and YAG:Ce phosphors. The reabsorption problem is overcome by the excellent optical properties and enlarged Stokes shift of the QDs with low absorption of light of wavelengths longer than 470 nm. PMID- 22528856 TI - Short-term information processing, long-term responses: Insights by mathematical modeling of signal transduction. Early activation dynamics of key signaling mediators can be predictive for cell fate decisions. AB - How do cells interpret information from their environment and translate it into specific cell fate decisions? We propose that cell fate is already encoded in early signaling events and thus can be predicted from defined signal properties. Specifically, we hypothesize that the time integral of activated key signaling molecules can be correlated to cellular behavior such as proliferation or differentiation. The identification of these decisive key signal mediators and their connection to cell fate is facilitated by mathematical modeling. A possible mechanistic linkage between signaling dynamics and cellular function is the directed control of gene regulatory networks by defined signals. Targeted experiments in combination with mathematical modeling can increase our understanding of how cells process information and realize distinct cell fates. PMID- 22528858 TI - Investigation of the haemodynamic environment of bifurcation plaques within the left coronary artery in realistic patient models based on CT images. AB - The aim of this study was to investigate the plaques at the left coronary artery (LCA) and their effect on the haemodynamic and wall shear stress (WSS) in realistic patient models. Three sample patients with left coronary disease were selected based on CT data. The plaques were present at the left anterior descending and left circumflex branches with more than 50 % lumen narrowing. Computational fluid dynamics analysis was used to perform simulation of patient specific models with realistic physiological conditions that demonstrate in vivo cardiac flow. WSS and blood flow in the LCA were measured during cardiac cycles. Our results showed that WSS was found to increase at the stenotic locations and decrease at pre- and post-plaque locations, whilst the recirculation location was found at post-plaque regions. There is a strong correlation between coronary bifurcation plaques and hemodynamic and WSS changes, based on the realistic coronary disease models. PMID- 22528859 TI - Specific paucity of unmyelinated C-fibers in cutaneous peripheral nerves of the African naked-mole rat: comparative analysis using six species of Bathyergidae. AB - In mammalian peripheral nerves, unmyelinated C-fibers usually outnumber myelinated A-fibers. By using transmission electron microscopy, we recently showed that the saphenous nerve of the naked mole-rat (Heterocephalus glaber) has a C-fiber deficit manifested as a substantially lower C:A-fiber ratio compared with other mammals. Here we determined the uniqueness of this C-fiber deficit by performing a quantitative anatomical analysis of several peripheral nerves in five further members of the Bathyergidae mole-rat family: silvery (Heliophobius argenteocinereus), giant (Fukomys mechowii), Damaraland (Fukomys damarensis), Mashona (Fukomys darlingi), and Natal (Cryptomys hottentotus natalensis) mole rats. In the largely cutaneous saphenous and sural nerves, the naked mole-rat had the lowest C:A-fiber ratio (~1.5:1 compared with ~3:1), whereas, in nerves innervating both skin and muscle (common peroneal and tibial) or just muscle (lateral/medial gastrocnemius), this pattern was mostly absent. We asked whether lack of hair follicles alone accounts for the C-fiber paucity by using as a model a mouse that loses virtually all its hair as a consequence of conditional deletion of the beta-catenin gene in the skin. These beta-catenin loss-of function mice (beta-cat LOF mice) displayed only a mild decrease in C:A-fiber ratio compared with wild-type mice (4.42 compared with 3.81). We suggest that the selective cutaneous C-fiber deficit in the cutaneous nerves of naked mole-rats is unlikely to be due primarily to lack of skin hair follicles. Possible mechanisms contributing to this unique peripheral nerve anatomy are discussed. PMID- 22528860 TI - Liquid-phase laser process for simple and area-specific calcium phosphate coating. AB - Simple, mild, and area-specific calcium phosphate (CaP) coating techniques are useful for the production and surface modification of biomaterials. In this study, an area-specific CaP coating technique for polymer substrates was successfully developed using a liquid-phase laser process. In the proposed method, Nd-YAG laser light (355 nm, 30 Hz, and 1-3 W) irradiated an ethylene vinyl alcohol copolymer (EVOH) substrate immersed in a supersaturated CaP solution for various periods of time (up to 30 min). The CaP-forming ability increased with an increase in the laser power and irradiation period. At the optimal laser power (3 W), a continuous CaP layer formed within 30 min on the laser-irradiated surface of the EVOH substrate. The formation of CaP was attributed to laser absorption by the EVOH substrate, which promoted the surface modification of EVOH and an increase in the temperature of the solution near the surface of the substrate. The resulting CaP coating showed better cell adhesion property than the naked EVOH substrate. The proposed CaP coating technique is simple (quick and single step) and area specific. Furthermore, the present process is carried out under mild conditions, that is, at normal pressures and temperatures in a safe aqueous medium. These are significant advantages of the proposed CaP coating technique. PMID- 22528861 TI - Translational rodent models of Korsakoff syndrome reveal the critical neuroanatomical substrates of memory dysfunction and recovery. AB - Investigation of the amnesic disorder Korsakoff Syndrome (KS) has been vital in elucidating the critical brain regions involved in learning and memory. Although the thalamus and mammillary bodies are the primary sites of neuropathology in KS, functional deactivation of the hippocampus and certain cortical regions also contributes to the chronic cognitive dysfunction reported in KS. The rodent pyrithiamine-induced thiamine deficiency (PTD) model has been used to study the extent of hippocampal and cortical neuroadaptations in KS. In the PTD model, the hippocampus, frontal and retrosplenial cortical regions display loss of cholinergic innervation, decreases in behaviorally stimulated acetylcholine release and reductions in neurotrophins. While PTD treatment results in significant impairment in measures of spatial learning and memory, other cognitive processes are left intact and may be recruited to improve cognitive outcome. In addition, behavioral recovery can be stimulated in the PTD model by increasing acetylcholine levels in the medial septum, hippocampus and frontal cortex, but not in the retrosplenial cortex. These data indicate that although the hippocampus and frontal cortex are involved in the pathogenesis of KS, these regions retain neuroplasticity and may be critical targets for improving cognitive outcome in KS. PMID- 22528862 TI - Neuroanatomy and neuropathology associated with Korsakoff's syndrome. AB - Although the neuropathology of Korsakoff's syndrome (KS) was first described well over a century ago and the characteristic brain pathology does not pose a diagnostic challenge to pathologists, there is still controversy over the neuroanatomical substrate of the distinctive memory impairment in these patients. Cohort studies of KS suggest a central role for the mammillary bodies and mediodorsal thalamus, and quantitative studies suggest additional damage to the anterior thalamus is required. Rare cases of KS caused by pathologies other than those of nutritional origin provide support for the role of the anterior thalamus and mammillary bodies. Taken together the evidence to date shows that damage to the thalamus and hypothalamus is required, in particular the anterior thalamic nucleus and the medial mammillary nucleus of the hypothalamus. As these nuclei form part of wider memory circuits, damage to the inter-connecting white matter tracts can also result in a similar deficit as direct damage to the nuclei. Although these nuclei and their connections appear to be the primary site of damage, input from other brain regions within the circuits, such as the frontal cortex and hippocampus, or more distant regions, including the cerebellum and amygdala, may have a modulatory role on memory function. Further studies to confirm the precise site(s) and extend of brain damage necessary for the memory impairment of KS are required. PMID- 22528863 TI - Remote memory function and dysfunction in Korsakoff's syndrome. AB - Korsakoff's syndrome (KS) is a pervasive disorder of memory characterized by both anterograde and retrograde amnesia. Although retrograde memory impairment in KS has been less frequently studied, the status of remote memory in KS has been tested across a number of different tasks that measure knowledge of public information (e.g., famous faces/news events), general semantic information (e.g., vocabulary words), personal semantic information (e.g., facts about oneself), and autobiographical events (e.g., events from one's personal past). In each of these domains, Korsakoff patients demonstrate remote memory impairments that can extend back many years or decades. In addition, a majority of studies report that the extensive remote memory impairment in KS is temporally graded, with relative preservation of memories from childhood and early adulthood. The current paper reviews published experimental studies of remote memory in KS, with particular attention paid to (a) the selectivity of the deficit with respect to the age of the memory and (b) the relationship of memory impairment to underlying neuropathology. We discuss the significance of the reported pattern and extent of remote memory impairment with respect to theories about the nature of the underlying cognitive deficits in KS. PMID- 22528864 TI - Bioluminescence imaging correlates with tumor serum marker, organ weights, histology, and human DNA levels during treatment of orthotopic tumor xenografts with antibodies. AB - PURPOSE: In this study, we correlate results of bioluminescence measurements with established readouts for assessing therapeutic efficacy of antibodies in orthotopic cancer xenografts. PROCEDURES: An orthotopic tumor model of pancreatic cancer (AsPC-1-luc) and experimental lung metastasis (A549-luc) were established. Whole-body bioluminescence imaging (BLI) was performed to observe tumor progression under therapy with antibodies targeting different receptor kinases (primary readout). For purpose of verification, anti-tumoral efficacy was cross validated with results obtained by measurement of organ weights, histology, tumor serum marker analysis (CYFRA 21-1), and quantification of human DNA concentration in the organ of interest (secondary readouts). RESULTS: Anti-tumoral efficacy is demonstrated for the antibodies tested. In the pancreas xenograft, a tumor growth inhibition of 95% (p < 0.01) was achieved as compared to control. Therapeutic efficacy could be identified as soon as 1 week after initiation of treatment. In the model of experimental lung metastasis, antibody treatment significantly suppressed tumor growth up to 75% (p < 0.05). All imaging results were confirmed by correlation analysis showing excellent agreement with the secondary readouts. CONCLUSIONS: BLI was demonstrated to be a reliable tool for monitoring early drug responses in orthotopic small animal cancer models. BLI allows rapid and non invasive assessment of tumor load in the animal over time and, thus, provides a suitable method for routine use in preclinical cancer research. PMID- 22528865 TI - Biological characteristics and effect of human umbilical cord mesenchymal stem cells (hUC-MSCs) grafting with blood plasma on bone regeneration in rats. AB - We evaluated the biological characteristics/effect of human umbilical cord derived mesenchymal stem cells (hUC-MSCs) grafting with blood plasma on bone regeneration in rat tibia nonunion. SD rats (142) were randomly divided into four groups: fracture group (positive control); nonunion group (negative control); hUC MSCs grafting with blood plasma group; and hUC-MSCs grafting with saline group. Rats were administered tetracycline (30 mg/kg) and calcein blue (5 mg/kg) 8 days before killing. The animals were killed under deep anesthesia at 4 and 8 weeks post fracture for radiological evaluation and histological/immunohistological studies. The hUC-MSCs grafting with blood plasma group was similar to fracture group: the fracture line blurred in 4 weeks and disappeared in 8 weeks postoperatively. Histological/immunohistological studies showed that hUC-MSCs were of low immunogenicity which merged in rat bone tissue, differentiated into osteogenic lineages, and completed the healing of nonunion. After stem cell transplantation, regardless of whether plasma or saline was used, new multi center bone formation was observed; fracture site density was better in stem cell grafting with blood plasma group. We, therefore, concluded that the biological characteristics of hUC-MSCs-treated nonunion were different from the standard fracture healing process, and the proliferative and localization capacity of hUC MSCs might benefit from the use of blood plasma. PMID- 22528866 TI - Despite concern about reliability of basic data source, asthma in children remains a major public health problem with unmet needs. PMID- 22528867 TI - Social insurance for occupational diseases. PMID- 22528869 TI - Does media multitasking always hurt? A positive correlation between multitasking and multisensory integration. AB - Heavy media multitaskers have been found to perform poorly in certain cognitive tasks involving task switching, selective attention, and working memory. An account for this is that with a breadth-biased style of cognitive control, multitaskers tend to pay attention to various information available in the environment, without sufficient focus on the information most relevant to the task at hand. This cognitive style, however, may not cause a general deficit in all kinds of tasks. We tested the hypothesis that heavy media multitaskers would perform better in a multisensory integration task than would others, due to their extensive experience in integrating information from different modalities. Sixty three participants filled out a questionnaire about their media usage and completed a visual search task with and without synchronous tones (pip-and-pop paradigm). It was found that a higher degree of media multitasking was correlated with better multisensory integration. The fact that heavy media multitaskers are not deficient in all kinds of cognitive tasks suggests that media multitasking does not always hurt. PMID- 22528870 TI - Electrophysiological evidence of different loci for case-mixing and word frequency effects in visual word recognition. AB - Do word frequency and case mixing affect different processing stages in visual word recognition? Some studies of online reading have suggested that word frequency affects an earlier, perceptual-encoding stage and that case mixing affects a later, central decision stage (e.g., Reingold, Yang, & Rayner, Journal of Experimental Psychology: Human Perception and Performance 36:1677-1683 2010); others have suggested otherwise (e.g., Allen, Smith, Lien, Grabbe, & Murphy, Journal of Experimental Psychology: Human Perception and Performance 31:713-721 2005; Besner & McCann, 1987). To determine the locus of the word frequency and case-mixing effects, we manipulated word frequency (high vs. low) and case type (consistent lower case vs. mixing case) in a lexical-decision paradigm. We measured two event-related-potential components: the N170 (an early peak occurring 140-240 ms after stimulus onset, related to structural encoding) and the P3 (a late peak occurring 400-600 ms after stimulus onset, related to stimulus categorization). The critical finding was that the N170 amplitude was sensitive to case mixing, but the P3 amplitude was sensitive to word frequency and lexicality. These results suggest that case mixing affects an earlier processing stage than does word frequency, at least with respect to lexical decision processes. PMID- 22528871 TI - Reflexive orienting by central arrows: evidence from the inattentional blindness task. AB - It was demonstrated that central arrows produce orienting of attention even when they are nonpredictive as to the target location. This finding was suggested to indicate reflexive orienting of attention by central arrows. However, it is not clear whether central arrows can produce an attentional effect without awareness. In two experiments, using a variation of the inattentional blindness task, we examine whether orienting of attention by a central arrow can be demonstrated without conscious perception of the arrow. We found that attention could be directed to the cued location even when the arrow was not consciously perceived. PMID- 22528872 TI - Cognitive control over working memory biases of selection. AB - Across many studies, researchers have found that representations in working memory (WM) can guide visual attention toward items that match the features of the WM contents. While some researchers have contended that this occurs involuntarily, others have suggested that the impact of WM contents on attention can be strategically controlled. Here, we varied the probability that WM items would coincide with either targets or distractors in a visual search task to examine (1) whether participants could intentionally enhance or inhibit the influence of WM items on attention and (2) whether cognitive control over WM biases would also affect access to the memory contents in a surprise recognition test. We found visual search to be faster when the WM item coincided with the search target, and this effect was enhanced when the memory item reliably predicted the location of the target. Conversely, visual search was slowed when the memory item coincided with a search distractor, and this effect was diminished, but not abolished, when the memory item was reliably associated with distractors. This strategic dampening of the influence of WM items on attention came at a price to memory, however, as participants were slowest to perform WM recognition tests on blocks in which the WM contents were consistently invalid. These results document that attentional capture by WM contents is partly, but not fully, malleable by top-down control, which appears to adjust the state of the WM contents to optimize search behavior. These data illustrate the role of cognitive control in modulating the strength of WM biases of selection, and they support a tight coupling between WM and attention. PMID- 22528873 TI - Adding the goal to learn strengthens learning in an unintentional learning task. AB - Previous research has demonstrated that contingency learning can take place in the absence of the intention to learn. For instance, in the color-word contingency learning task, each distracting word is presented most often in a given target color (e.g., "month" in red and "plate" in green), and less often in the other colors. Participants respond more quickly and accurately when the word is presented in the expected rather than an unexpected color, even though there is no reason why they would have the intention to learn the contingencies between the words and the colors. It remains to be determined, however, whether learning in such situations would benefit or suffer from adding the goal to learn contingencies. In the reported experiment, half of the participants were informed that each word was presented most often in a certain color, and they were instructed to try to learn these contingencies. The other half of the participants were not informed that contingencies would be present. The participants given the learning goal produced a larger response time contingency effect than did the control participants. In contrast to some results from other learning paradigms, these results suggest that intentional learning adds to, rather than interferes with, unintentional learning, and we propose an explanation for some of the conflicting results. PMID- 22528868 TI - MicroRNAs and lung cancers: from pathogenesis to clinical implications. AB - Lung cancer is the leading cause of cancer-related deaths in the US and worldwide. Better understanding of the disease is warranted for improvement in clinical management. Here we summarize the functions of small-RNA-based, posttranscriptional gene regulators, i.e. microRNAs, in the pathogenesis of lung cancers. We discuss the microRNAs that play oncogenic as well as tumor suppressive roles. We also touch on the value of microRNAs as markers for diagnosis, prognosis and the promising field of microRNA-based novel therapies for lung cancers. PMID- 22528874 TI - Signification of Hypermethylated in Cancer 1 (HIC1) as Tumor Suppressor Gene in Tumor Progression. AB - Hypermethylated in cancer 1(HIC1) was identified as a strong suppressor gene in chromosome region 17p13.3 telomeric to TP53. This gene encodes a transcriptional repressor and is ubiquitously expressed in normal tissues but downexpressed in different tumor tissues where it is hypermethylated. The hypermethylation of this chromosomal region leads to epigenetic inactivation of HIC1, which would prompt cancer cells to alter survival and signaling pathways or specific transcription factors during the period of tumorigenesis. In vitro, HIC1 function is mainly a sequence-specific transcriptional repressor interacting with a still growing range of histone deacetylase(HDAC)-dependent and HDAC-independent corepressor complexes. Furthermore, a role for HIC1 in tumor development is firmly supported by Hic1 deficient mouse model and two double heterozygote models cooperate with p53 and Ptch1. Notably, our findings suggest that potential factors derived from tumor microenviroment may play a role in modulating HIC1 expression in tumor cells by epigenetic modification, which is responsible for tumor progression. In this review, we will describe genomic and proteinic structure of HIC1, and summary the potential role of HIC1 in human various solid tumors and leukemia, and explore the influence of tumor microenviroment on inducing HIC1 expression in tumor cells. PMID- 22528875 TI - Soiling the seed: microenvironment and epithelial mesenchymal plasticity. PMID- 22528878 TI - Highly undersampled phase-contrast flow measurements using compartment-based k-t principal component analysis. AB - The applicability of cine blood flow measurements in a clinical setting is often compromised by the long scan times associated with phase-contrast imaging. In this work, we propose an extension to the k-t principal component analysis method and demonstrate that by definition of spatial compartment-dependent temporal basis functions, significant improvements in reconstruction accuracy can be achieved relative to the original k-t principal component analysis and k-t SENSE formulations. Using this method, it is shown that prospective nominal undersampling of up to 16 corresponding to a net acceleration factor of 8 including training data acquisition can be realized while keeping the error in stroke volume below 5%. As a practical application, the acquisition of cine flow data in the aorta is demonstrated permitting assessment of two-dimensional velocity images and pulse wave velocities at 100 frames per second in a single breathhold per slice. PMID- 22528879 TI - Domain shuffling and the increasing complexity of biological networks. AB - Domains can spread among proteins in a process called domain shuffling and this has been identified as one of the major mechanisms leading to the formation of new proteins throughout evolution. This process has an impact on the topology of protein-protein interaction networks as it may create new hubs and also increase interconnectivity. PMID- 22528876 TI - Lysyl oxidase, extracellular matrix remodeling and cancer metastasis. AB - Lysyl oxidase (LOX) family oxidases, LOX and LOXL1-4, oxidize lysine residues in collagens and elastin, resulting in the covalent crosslinking and stabilization of these extracellular matrix (ECM) structural components, thus provide collagen and elastic fibers much of their tensile strength and structural integrity. Abnormality in LOX expression and/or activity results in connective tissue disorders and fibrotic diseases. Despite LOX family oxidases have been reported to function as tumor suppressors, recent studies have highlighted the roles of LOX family oxidases in promoting cancer metastasis. LOX family oxidases are highly expressed in invasive tumors, and are closely associated with metastasis and poor patient outcome. Consistent to their roles in connective tissue homeostasis, LOX family oxidases expedite tumorigenesis and metastasis through active remodeling of tumor microenvironment. LOX family oxidases are also actively involved in the process of epithelial-mesenchymal transition (EMT), an event critical in cancer cell invasion and metastasis. In this review, we will summarize the recent progress on LOX family oxidases, with much of the focus on the roles and mechanism of LOX in tumor progression and metastasis. PMID- 22528880 TI - Multigeneration reproductive study of hydroxyprogesterone caproate (HPC) in the rat: laboratory results and clinical significance. AB - To demonstrate reproductive safety of a new commercial product for reducing the risk of preterm birth, HPC (17alpha-hydroxyprogesterone caproate, Makena; manufactured by Baxter Pharmaceutical Solutions, Bloomington IN for Ther-Rx Corporation, St. Louis, MO) was administered intramuscularly in Charles River LaboratoryCD strain rats. HPC was given at intervals equal to the half-life measured in rats during three phases of embryo-fetal development: during the period of ovarian development (RP1, days 8, 14, and 20), following implantation of the embryo (TP, days 6, 12, and 18), and, corresponding to the start of the drug in week 16 or later in humans, after gonadal formation including differentiation of the testes (RP2, day 17). Dose levels up to 30* the human therapeutic doses were utilized including 0 (vehicle), 5, 25, and 150 mg/kg (volume 0.6 ml/kg). Four groups of 25 time-mated rats each were used for each phase. In addition, equal numbers of naive (untreated) rats of opposite gender were used for F(1) breeding studies. HPC did not produce any consistent test article-related findings in the treated F(0) dams, their developing F(1) fetuses and did not affect the ability of the latter to produce a viable F(2) generation. The F(1) offspring did not evidence any adverse effects during their behavioral, sensory, and developmental assessments, including teratogenicity. Based on the cumulative data obtained from rats treated over two generations and during development in this study, the No-observable-effect-level (NOEL) was established as 150 mg/kg. This study supports the absence of reproductive toxicity with HPC in published studies in animal models and in human clinical trials. PMID- 22528881 TI - Antidepressants cause bradycardia and heart block in GD 13 rat embryos in vitro. AB - This study investigated the effects of a range of antidepressant drugs on the heart of gestation day 13 rat embryos in vitro. The general hypothesis was that the drugs would adversely affect the function of the embryonic heart since they all have some cardiac ion channel blocking activity in addition to their main pharmacological effect on neurotransmitters. The results showed that all the tested drugs caused bradycardia in a generally concentration-dependent manner. At higher concentrations most of the drugs caused some degree of heart block consistent with sodium channel blockade and some drugs also showed negative inotropy associated with blockade of the L-type calcium channel. One drug, trazodone, caused arrhythmia consistent with blockade of the hERG (human ether-a go-go related gene) potassium channel. In general the effects on the embryonic rat heart were only seen at "free drug" concentrations much greater than those likely to occur in pregnant women taking antidepressant medication. The least margin of safety was seen with the tricyclic antidepressants and the serotonin antagonist and reuptake inhibitor trazodone. PMID- 22528877 TI - Role of bone marrow-derived cells in angiogenesis: focus on macrophages and pericytes. AB - Tumor growth relies on the formation of new blood vessels to receive an adequate supply of oxygen and nutrient. This process is facilitated by both the remodeling of the pre-existing vasculatures and the recruitment of the progenitor/stem cells originated from bone marrow-derived cells (BMDCs). Evidences from both animal studies and human trials have reported that these tumor-associated BMDCs differentiate into a series of stromal cells including macrophages and pericytes, and regulate tumor angiogenesis in various aspects. Macrophages constitute a large portion of the BMDCs infiltrated in the tumor microenvironment, and have been shown to disrupt the balance of pro- and anti-angiogenic signalings by the secretion of various cytokines. Pericytes, mainly derived from the subpopulation of PDGFRbeta(+) BMDCs, can provide both pro-survival signaling and mechanical support to maintain the newly formed endothelium via the direct interactions with endothelial cells. In the current review, we summarize the recruitment mechanisms of BMDC-derived macrophages and pericytes within tumor microenvironment, and also review the contribution of these cells to the different aspects of angiogenesis, with particular emphasis on their therapeutic implications as potential targets for anti-tumor strategies. PMID- 22528882 TI - Fabrication of arrays of polymer gradients using inkjet printing. AB - Arrays of 84 polymer gradients, fabricated on a single glass microscope slide, were generated by inkjet printing, allowing a combination of high-throughput and true combinatorial methods. The gradual change of composition within the polymer gradients, consisting of two different monomers and a cross-linker, was validated by XPS and fluorescence analysis. Cellular screening of the gradients allowed the rapid identification of optimal polymer compositions for binding of the suspension cell line K562 and the adherent cell line HeLa. The polymers identified were identical to those identified by previous microarray data, providing proof of concept for the successful application of the polymer gradient arrays as a screening tool. In addition, the polymer gradients could be readily modified by conjugation enabling the generation of bio-molecule gradients. PMID- 22528883 TI - The central complex of the flesh fly, Neobellieria bullata: recordings and morphologies of protocerebral inputs and small-field neurons. AB - The central complex in the brains of insects is a series of midline neuropils involved in motor control, sensory integration, and associative learning. To understand better the role of this center and its supply of sensory information, intracellular recordings and dye fills were made of central complex neurons in the fly, Neobellieria bullata. Recordings were obtained from 24 neurons associated with the ellipsoid body, fan-shaped body, and protocerebral bridge, all of which receive both visual and mechanosensory information from protocerebral centers. One neuron with dendrites in an area of the lateral protocerebrum associated with motion-sensitive outputs from the optic lobes invades the entire protocerebral bridge and was driven by visual motion. Inputs to the fan-shaped body and ellipsoid body responded both to visual stimuli and to air puffs directed at the head and abdomen. Intrinsic neurons in both of these structures respond to changes in illumination. A putative output neuron connecting the protocerebral bridge, the fan-shaped body, and one of the lateral accessory lobes showed opponent responses to moving visual stimuli. These recordings identify neurons with response properties previously known only from extracellular recordings in other species. Dye injections into neurons connecting the central complex with areas of the protocerebrum suggest that some classes of inputs into the central complex are electrically coupled. PMID- 22528884 TI - Electrospun TiO2 nanofiber-based cell capture assay for detecting circulating tumor cells from colorectal and gastric cancer patients. AB - A nanostructured platform that combines electrospun TiO(2) nanofibers (TiNFs) deposited substrate and cell-capture agent realizes significant capture of circulating tumor cells (CTCs). The enhanced local topographic interactions between the horizontally packed TiNFs deposited substrates and extracellular matrix scaffolds, in addition to anti-EpCAM/EpCAM biological recognition, contributes to the significantly enhanced capture efficiency compared to flat surfaces. PMID- 22528886 TI - Falls, older adults, and the trend in utilization of CT in a level I trauma center. AB - OBJECTIVE: The purpose of this article is to evaluate the trend in the utilization of CT for fall victims older than 55 years admitted to a level I trauma center. MATERIALS AND METHODS: We used trauma registry data (1996-2006) of a level I trauma center. By using the International Classification of Disease, Ninth Revision (Clinical Modification) codes, we identified the type and frequency of CT examinations for each patient. We used negative binomial regression to evaluate the association between CT utilization rates and age, year of admission, sex, insurance status, ethnicity, ICU admission status, injury severity score, and final disposition (i.e., deceased vs alive). We used logistic regression to evaluate predictors of repeat (i.e., >= 2) CT scans. RESULTS: During the study period, the utilization rate of head, abdomen, thorax, and other body region (including spine and extremities) CT examinations increased, on average, by 7%, 16%, 14%, and 15% per year, respectively. Older age was associated with a higher utilization of head CT. Male sex and ICU admission were associated with higher utilization for all types of CT examinations. Repeat head and abdominal CT scans increased, on average, by 28% (95% CI, 20-36%) and 24% (95% CI, 2-51%) per year, respectively. CONCLUSION: We quantified the increase in utilization rates of all types of CT scans for fall victims admitted to a level I trauma center. We found a marked increase in CT use over time, both for initial as well as repeat studies, and an association between CT use and variables such as sex. Future studies should focus on the evaluation of CT appropriateness and their influence on patient outcomes. PMID- 22528885 TI - Is boron a prebiotic element? A mini-review of the essentiality of boron for the appearance of life on earth. AB - Boron is probably a prebiotic element with special importance in the so-called "sugars world". Boron is not present on Earth in its elemental form. It is found only in compounds, e.g., borax, boric acid, kernite, ulexite, colemanite and other borates. Volcanic spring waters sometimes contain boron-based acids (e.g., boric, metaboric, tetraboric and pyroboric acid). Borates influence the formation of ribofuranose from formaldehyde that feeds the "prebiotic metabolic cycle". The importance of boron in the living world is strongly related to its implications in the prebiotic origins of genetic material; consequently, we believe that throughout the evolution of life, the primary role of boron has been to provide thermal and chemical stability in hostile environments. The complexation of boric acid and borates with organic cis-diols remains the most probable chemical mechanism for the role of this element in the evolution of the living world. Because borates can stabilize ribose and form borate ester nucleotides, boron may have provided an essential contribution to the "pre-RNA world". PMID- 22528887 TI - Large-scale quality improvement for radiation protection of children worldwide: lessons from the past applied to the present. AB - OBJECTIVE: The objective of this article is to highlight strategies that can be used to implement changes locally for improved safety of pediatric patients. Specific examples of international organizations engaged with quality improvement are discussed. CONCLUSION: Large-scale quality improvement to promote radiation protection for children is being aggressively pursued by numerous international organizations. These international agencies use quality improvement methods on a global scale to optimize medical imaging for all diagnostic imaging modalities that use ionizing radiation with the intent of lowering radiation dose to children. This work, although vast in scope, requires highly focused project goals with access to scientific expertise. In addition, these coordinated efforts must provide education, collegial support, and resources (both financial and technical) that enable radiology professionals to implement change locally for improved safety of pediatric patients. PMID- 22528888 TI - Sonography of the pediatric scrotum: emphasis on the Ts--torsion, trauma, and tumors. AB - OBJECTIVE: The purpose of this article is to review the different scrotal disease entities in the pediatric population, focusing on acute scrotum, traumatic injuries, and testicular tumors. CONCLUSION: Many pediatric scrotal disorders can be well characterized on sonography. An understanding of the various disease entities, their clinical presentations, and the typical sonographic features should all be combined to make an accurate diagnosis. PMID- 22528889 TI - Imaging and classification of congenital cystic renal diseases. AB - OBJECTIVE: The purpose of this clinical perspective is to describe a decision tree approach to the finding of hyperechoic kidneys as signs of congenital renal cystic disease in fetuses and children. This approach takes into account the latest classification of inherited renal cystic diseases. The basis of the approach is a detailed sonographic analysis in addition to assessment of clinical data and the familial history. CONCLUSION: With the decision-tree approach, typical sonographic patterns can be described and used for accurate diagnosis of isolated renal cystic diseases and polymalformative syndromes. In some cases, however, the diagnosis is not achieved, and complementary examinations are needed. PMID- 22528890 TI - A timetable for the radiologic features of fracture healing in young children. AB - OBJECTIVE: Fracture dating significantly shapes decisions in child protection. With a dearth of primary evidence underpinning fracture dating in children, we examined the key radiologic features of fracture healing and their timelines. MATERIALS AND METHODS: Digital radiographs of children younger than 72 months old with accidental long bone fractures of known timing were reviewed independently by three pediatric radiologists blinded to the age of the fractures. Six radiologic features of fracture healing were evaluated: soft-tissue swelling, periosteal reaction, soft callus, hard callus, bridging, and remodeling. Interobserver agreement was assessed using kappa analysis. RESULTS: Two hundred twenty-eight films of 82 fractures in 63 children (mean age, 4.8 years) were assessed. Soft-tissue swelling was identified by two or more radiologists in 59% of the radiographs at days 1-2 after fractures, and prevalence sharply declined thereafter. Periosteal reaction was first seen at day 5 and was present in 62% of the films obtained between 15 and 35 days after the fracture. Soft callus was first seen at day 12 and was prevalent in 41% between 22 and 35 days. Hard callus and bridging began at day 19, increasing to 60% prevalence from 36 days onward. Remodeling was observed only in fractures 45 days old or more. Kappa scores were between 0.55 and 0.80 overall, with greater agreement when there was no plaster cast. CONCLUSION: The results of this study show that fractures in young children may be dated as acute (< 1 week), recent (8-35 days), or old (>= 36 days) on the basis of the presence of six key radiologic features in combination. Furthermore, good interobserver agreement suggests these results are reproducible. PMID- 22528891 TI - IAEA survey of pediatric CT practice in 40 countries in Asia, Europe, Latin America, and Africa: Part 1, frequency and appropriateness. AB - OBJECTIVE: The purpose of this study was to assess the frequency of pediatric CT in 40 less-resourced countries and to determine the level of appropriateness in CT use. MATERIALS AND METHODS: Data on the increase in the number of CT examinations during 2007 and 2009 and appropriate use of CT examinations were collected, using standard forms, from 146 CT facilities at 126 hospitals. RESULTS: The lowest frequency of pediatric CT examinations in 2009 was in European facilities (4.3%), and frequencies in Asia (12.2%) and Africa (7.8%) were twice as high. Head CT is the most common CT examination in children, amounting to nearly 75% of all pediatric CT examinations. Although regulations in many countries assign radiologists with the main responsibility of deciding whether a radiologic examination should be performed, in fact, radiologists alone were responsible for only 6.3% of situations. Written referral guidelines for imaging were not available in almost one half of the CT facilities. Appropriateness criteria for CT examinations in children did not always follow guidelines set by agencies, in particular, for patients with accidental head trauma, infants with congenital torticollis, children with possible ventriculoperitoneal shunt malfunction, and young children (< 5 years old) with acute sinusitis. In about one third of situations, nonavailability of previous images and records on previously received patient doses have the potential to lead to unnecessary examinations and radiation doses. CONCLUSION: With increasing use of CT in children and a lack of use of appropriateness criteria, there is a strong need to implement guidelines to avoid unnecessary radiation doses to children. PMID- 22528892 TI - Pre- and postoperative imaging of the Rex shunt in children: what radiologists should know. AB - OBJECTIVE: The objective of this article is to illustrate the imaging features of patients with extrahepatic portal venous obstruction who are evaluated before or after a Rex shunt surgery. CONCLUSION: The Rex shunt is a potentially curative surgical procedure that reestablishes physiologic hepatopetal portal flow. It is typically accomplished by interposing a vascular conduit between the superior mesenteric vein to the still patent intrahepatic portal venous system. This procedure results in resolution of portal hypertension. PMID- 22528893 TI - Pediatric bone imaging: diagnostic imaging of osteoid osteoma. AB - OBJECTIVE: Osteoid osteomas are benign painful skeletal neoplasms that preferentially afflict young male patients and are readily treatable. This article focuses on the various imaging manifestations of the tumor, while also discussing its clinical presentation, pathogenesis, and treatment. CONCLUSION: Knowledge of the common imaging features of osteoid osteomas will improve our diagnosis of this condition, subsequently facilitating treatment and reducing morbidity. PMID- 22528894 TI - Pediatric bone imaging: imaging elbow trauma in children--a review of acute and chronic injuries. AB - OBJECTIVE: Pediatric elbow trauma is challenging because of the complex nature of the growing skeleton. The objectives of this article are to review the anatomy and radiographic landmarks and to discuss common acute and chronic injuries sustained. CONCLUSION: Radiographic evaluation of elbow trauma in the acute setting requires a firm understanding of developmental anatomy, radiographic landmarks, and the common injury patterns. Both radiography and MRI are vital tools for diagnosing chronic elbow overuse injuries in adolescent athletes. PMID- 22528895 TI - Classification of human coronary atherosclerotic plaques using ex vivo high resolution multicontrast-weighted MRI compared with histopathology. AB - OBJECTIVE: The objective of our study was to evaluate the feasibility of ex vivo high-resolution multicontrast-weighted MRI to accurately classify human coronary atherosclerotic plaques according to the American Heart Association classification. MATERIALS AND METHODS: Thirteen human cadaver heart specimens were imaged using high-resolution multicontrast-weighted MR technique (T1 weighted, proton density-weighted, and T2-weighted). All MR images were matched with histopathologic sections according to the landmark of the bifurcation of the left main coronary artery. The sensitivity and specificity of MRI for the classification of plaques were determined, and Cohen's kappa analysis was applied to evaluate the agreement between MRI and histopathology in the classification of atherosclerotic plaques. RESULTS: One hundred eleven MR cross-sectional images obtained perpendicular to the long axis of the proximal left anterior descending artery were successfully matched with the histopathologic sections. For the classification of plaques, the sensitivity and specificity of MRI were as follows: type I-II (near normal), 60% and 100%; type III (focal lipid pool), 80% and 100%; type IV-V (lipid, necrosis, fibrosis), 96.2% and 88.2%; type VI (hemorrhage), 100% and 99.0%; type VII (calcification), 93% and 100%; and type VIII (fibrosis without lipid core), 100% and 99.1%, respectively. Isointensity, which indicates lipid composition on histopathology, was detected on MRI in 48.8% of calcified plaques. Agreement between MRI and histopathology for plaque classification was 0.86 (p < 0.001). CONCLUSION: Ex vivo high-resolution multicontrast-weighted MRI can accurately classify advanced atherosclerotic plaques in human coronary arteries. PMID- 22528896 TI - Chest CT features of North American paragonimiasis. AB - OBJECTIVE: The purpose of this study was to characterize the chest CT findings of North American paragonimiasis due to Paragonimus kellicotti in the largest (to our knowledge) case series reported to date and to compare the findings with those reported for paragonimiasis infections in other regions. MATERIALS AND METHODS: A retrospective review was performed of chest CT examinations of eight patients with North American paragonimiasis treated at our institution between 2006 and 2010. Findings were characterized by site of involvement, including lungs and pleura, heart and pericardium, lymph nodes, and upper abdomen. RESULTS: The most common chest CT findings in this case series were pleural effusions and internal mammary and cardiophrenic lymphadenopathy. Pulmonary parenchymal findings included peripheral lung nodules of 1-3.5 cm in size with surrounding ground-glass opacity; many nodules had a linear track to the pleural surface that may correspond to the worm's burrow tunnel. Pericardial involvement (5/8 patients) and omental inflammation (5/7 patients), which are uncommon in Asian paragonimiasis, were common in this series. CONCLUSION: Pleural and pulmonary features of North American paragonimiasis are generally similar to those reported from Asia. The presence of a track between a pulmonary nodule and the pleura may help distinguish paragonimiasis from mimickers, including chronic eosinophilic pneumonia, tuberculosis, fungal infection, or malignancy. Pericarditis, lymphadenopathy, and omental inflammation were more common in our series than in reports on paragonimiasis from other regions. These differences may be related to the infecting parasite species or to the fact that radiologic examinations in the present series were performed relatively early in the course of infection. PMID- 22528897 TI - CT enterography at 80 kVp with adaptive statistical iterative reconstruction versus at 120 kVp with standard reconstruction: image quality, diagnostic adequacy, and dose reduction. AB - OBJECTIVE: The objective of our study was to evaluate the image quality and diagnostic adequacy of the following two CT enterography protocols in patients weighing less than 160 lb (72 kg): 80-kVp imaging with the adaptive statistical iterative reconstruction (ASIR) in comparison with 120-kVp imaging with the filtered back projection reconstruction. MATERIALS AND METHODS: We retrospectively reviewed 133 CT enterography examinations of 127 patients weighing less than 160 lb, 64 80-kVp examinations, and 69 120-kVp examinations. Image quality for evaluation of the bowel wall, mesenteric vessels, and hepatic parenchyma and the overall image quality were graded on a scale of 1-5 (1 = poor, 2 = acceptable, 3 = good, 4 = very good, 5 = excellent). Diagnostic accuracy for the detection of inflammatory bowel disease was evaluated. The volume CT dose index (CTDI(vol)) was recorded and effective dose was calculated from scanner generated dose-length product. RESULTS: There was a statistically significant decrease in the mean image quality scores for 80-kVp examinations compared with 120-kVp examinations for evaluation of the bowel wall (3.19 vs 3.70, respectively) and liver (3.12 vs 3.81) and for overall image quality (3.23 vs 3.68), but there was no significant decrease in score for evaluation of the mesenteric vessels (3.63 vs 3.67). None of the 80-kVp examinations was graded as poor, and all were considered to be of acceptable quality. Both techniques had comparable diagnostic accuracy for the detection of inflammatory bowel disease. Interobserver agreement was fair to moderate for qualitative image grading and was substantial for the detection of features of inflammatory bowel disease. The mean CTDI(vol) and effective dose for the 80-kVp examinations were 6.15 mGy and 4.60 mSv, respectively, and for the 120-kVp examinations, 20.79 mGy and 15.81 mSv. CONCLUSION: In patients weighing less than 160 lb, CT enterography examinations at 80 kVp with 30% ASIR produce diagnostically acceptable image quality with an average CTDI(vol) of 6.15 mGy and an average effective dose of 4.60 mSv. PMID- 22528898 TI - Colorectal liver metastasis after 90Y radioembolization therapy: pilot study of change in MDCT attenuation as a surrogate marker for future FDG PET response. AB - OBJECTIVE: The purpose of this study was to investigate whether changes in attenuation and size of liver metastatic lesions of colorectal cancer at MDCT 1 month after (90)Y radioembolization treatment are predictive of response at FDG PET 3 months after treatment. MATERIALS AND METHODS: Twenty patients with colorectal liver metastasis consecutively treated with (90)Y radioembolization underwent triphasic MDCT of the liver at baseline and 1 and 3 months after treatment and FDG PET at baseline and 3 months after treatment. Percentage change in tumor attenuation at MDCT (volumetric attenuation), tumor size at MDCT (according to Response Evaluation Criteria in Solid Tumors [RECIST] and World health Organization [WHO] criteria), and volume-weighted maximum standardized uptake value at FDG PET were evaluated. The correlation between FDG PET response 3 months after treatment and response according to RECIST, WHO criteria, and attenuation 1 month after treatment was evaluated. RESULTS: Only 13.3% of patients with FDG PET findings of response 3 months after treatment were identified according to RECIST and WHO criteria 1 month after treatment. According to attenuation criteria at 1 month, however, 53.3% of patients with an FDG PET response at 3 months were identified. A strong association was found between FDG PET response at 3 months and response based on attenuation criteria (odds ratio, 12.4; 95% CI, 0.58-265.3; p = 0.05). CONCLUSION: Early changes in the attenuation of liver metastatic lesions of colon cancer after (90)Y radioembolization treatment may be predictive of future response at FDG PET. PMID- 22528899 TI - Visceral adiposity and hepatic steatosis at abdominal CT: association with the metabolic syndrome. AB - OBJECTIVE: Visceral adiposity and hepatic steatosis may correlate with the metabolic syndrome but are not currently among the diagnostic criteria. We evaluated these features at unenhanced MDCT. MATERIALS AND METHODS: Semiautomated measurements of subcutaneous fat area, visceral fat area, and visceral fat percentage were obtained at the umbilical level at unenhanced MDCT of 474 adults (217 men, 257 women; mean age, 58.3 years) using a dedicated application (Fat Assessment Tool, EBW version 4.5). Unenhanced liver attenuation was also recorded. Metabolic syndrome was defined using the criteria proposed by the International Diabetes Federation in 2005. RESULTS: The prevalence of metabolic syndrome was 35.0% (76/217) among men and 35.8% (92/257) among women. The area under the receiver operating characteristic curve (AUC) for visceral fat area was 0.830 (95% CI, 0.784-0.867) in men and 0.887 (0.848-0.918) in women (p = 0.162). The AUC for subcutaneous fat area was 0.865 (0.823-0.899) in men and 0.762 (0.711 0.806) in women (p = 0.024). The AUC for visceral fat percentage was 0.527 (0.472 0.581) in men and 0.820 (0.774-0.859) in women (p < 0.001). The AUC for liver attenuation was 0.706 (0.653-0.754). Thresholds of subcutaneous fat area greater than 204 cm(2) in men, visceral fat area greater than 70 cm(2) in women, and liver attenuation less than 50 HU yielded a sensitivity and specificity of 80.3% and 83.7%; 83.7% and 80.0%; and 22.0% and 96.7%, respectively. Visceral fat area was elevated in 55% of patients without metabolic syndrome (11/20) but with a documented cardiovascular event or complication and in 32.1% of patients with a body mass index of 30 kg/m(2) or less. CONCLUSION: Accumulation of visceral fat was the best predictor for metabolic syndrome in women. Unexpectedly, the percentage of visceral fat was a poor predictor for metabolic syndrome in men and subcutaneous fat area was best. Decreased liver attenuation was insensitive but was highly specific for metabolic syndrome. The implications of these sex specific differences and the relationship of fat-based CT measures to cardiovascular risk warrant further investigation. PMID- 22528900 TI - Evaluation of transplanted kidneys using blood oxygenation level-dependent MRI at 3 T: a preliminary study. AB - OBJECTIVE: The objective of our study was to investigate the feasibility and reproducibility of blood oxygenation level-dependent (BOLD) MRI using different gradient echoes at 3 T in patients with renal allografts and healthy volunteers and to evaluate whether BOLD MRI can be used to distinguish between cases of acute allograft rejection and normally functioning allografts. SUBJECTS AND METHODS: BOLD MRI at 3 T was performed of eight patients with normal allografts, four patients with acute allograft rejection, and 10 healthy volunteers. Multiple fast-field echo sequences were performed at gradient echoes of 8, 16, and 20 to obtain T2(*)-weighted images. The reproducibility of BOLD MRI was evaluated in patients with normal allografts. RESULTS: Cortical and medullary R2(*) values were not significantly different between healthy volunteers and patients with normal allografts, but medullary R2(*) values were significantly greater than cortical R2(*) values in both groups for all three protocols (p < 0.01). Medullary R2(*) values were significantly lower in cases of acute allograft rejection than in normal allografts for all three protocols (p < 0.001). The mean difference in cortical or medullary R2(*) values was 3.8% or less in all protocols. CONCLUSION: BOLD MRI performed using different gradient echoes at 3 T is feasible and reproducible in patients with renal allografts and can show significant changes in medullary oxygenation in patients with acute rejection. PMID- 22528901 TI - Renal cell carcinoma: attenuation values on unenhanced CT. AB - OBJECTIVE: The purpose of this study is to analyze the attenuation values of pathologically proven renal cell carcinomas (RCCs) on unenhanced CT and to determine the range of values wherein malignancy should be considered. MATERIALS AND METHODS: A retrospective review was performed of 189 consecutive patients with 193 pathologically proven RCCs 1 cm or larger on unenhanced CT. For each RCC, attenuation values were assessed throughout the tumor by continuous sampling with a 25-100-mm(2) region of interest (ROI), avoiding foci of calcification and peritumoral volume averaging. The lowest and highest ROI attenuation values per lesion were recorded. Each tumor was categorized as either homogeneous or heterogeneous on the basis of visual inspection with soft-tissue window settings. RESULTS: The 193 malignant tumors ranged in size from 1.1 to 20.1 cm (mean [+/- SD], 5.1 +/- 3.4 cm). Eighteen RCCs (9.3%) were homogeneous in appearance on unenhanced CT. The minimum and maximum ROI attenuation values obtained by sampling throughout each tumor were 27.5 +/- 10.4 HU (range, 4-67 HU) and 39.7 +/ 10.6 HU (range, 21-80 HU), respectively. Regional areas of minimum attenuation less than 20 HU and maximum attenuation greater than 70 HU were seen in 24.9% (48/193) and 2.1% (4/193) of RCCs, respectively. However, all 193 RCCs (100%) were predominantly composed of noncalcific regions within 20-70 HU; 72.5% (140/193) fell entirely within this 20-70 HU "danger zone," including all 18 homogeneous lesions. CONCLUSION: All proven RCCs in this series contained substantial noncalcified regions that measured 20-70 HU in ROI attenuation on unenhanced CT. Indeterminate renal lesions on unenhanced CT measuring within this 20-70-HU danger zone warrant further workup, whereas lesions that fall entirely outside this range may be considered benign. PMID- 22528902 TI - Optimizing peer review: A year of experience after instituting a real-time comment-enhanced program at a children's hospital. AB - OBJECTIVE: Peer review has become an essential component of a comprehensive radiology department quality assurance program. Multiple commercial programs, such as RADPEER, are available to fill this need but may be limited by low radiologist compliance and delayed or limited feedback. Consequently, these peer review programs may not achieve the greater goal of improving diagnostic quality. This article presents data from a peer review system implemented in an academic radiology group at a large urban multidisciplinary children's hospital. The peer review system offered instantaneous feedback with an enhanced comment feature for peer radiologists. MATERIALS AND METHODS: Peer review data were collected on 5278 radiologic studies over a 12-month period including 15 radiologists. The data were analyzed for compliance rate, discrepancy rate, and comment usage. RESULTS: The compliance rate for peer review averaged 52% for the 12-month period. The compliance rate trended upward over the course of the year, with a final month's compliance rate of 76%. The discrepancy rate between original interpretation and peer review was 3.6%. Comments were voluntarily included in 7.3% of nondiscrepant peer review scores. CONCLUSION: Our peer review process was enhanced by real-time comment-enriched feedback on both discrepant and nondiscrepant peer reviews. We show improved radiologist compliance over the course of a year in a peer review program with no incentives or penalties for performing reviews. To our knowledge, no compliance rates exist in current literature for comparison. PMID- 22528903 TI - A hybrid iterative reconstruction algorithm that improves the image quality of low-tube-voltage coronary CT angiography. AB - OBJECTIVE: We investigated whether a hybrid iterative reconstruction (HIR) algorithm improves image quality at low-tube-voltage coronary CT angiography (CTA) compared with filtered back projection (FBP). SUBJECTS AND METHODS: Eighteen patients (seven men, 11 women; mean age, 67.8 years) underwent retrospectively gated coronary CTA at 80 kV with a volume CT dose index (CTDI(vol)) of 18.8 mGy on a 64-MDCT scanner. CT images were reconstructed using only FBP and only HIR. For each patient, CT images subjected to the two different reconstructions were reviewed by two observers. Quantitative image quality parameters-that is, CT attenuation (HU) of the coronary arteries, image noise, and contrast-to-noise ratio (CNR)-were calculated and compared for the two reconstruction methods and the overall image quality for each reconstruction was visually scored on a 5-point scale. RESULTS: The mean estimated effective radiation dose for 80-kV coronary CTA was 4.7 +/- 0.4 (SD) mSv. The two reconstruction methods did not significantly differ with respect to the CT attenuation of the coronary arteries. The image noise was significantly lower with HIR than with FBP (20.3 +/- 5.3 vs 49.4 +/- 12.0 HU, respectively; p < 0.01), and the CNR was significantly higher with HIR than with FBP (29.8 +/- 7.4 vs 12.7 +/- 2.9, p < 0.01). The visual scores for image quality were higher with HIR than with FBP (p < 0.01). CONCLUSION: The HIR algorithm can reduce image noise and improve image quality at low-tube-voltage coronary CTA. PMID- 22528904 TI - Organ-based dose current modulation and thyroid shields: techniques of radiation dose reduction for neck CT. AB - OBJECTIVE: The purpose of this study was to assess the difference in absorbed organ dose and image quality for MDCT neck protocols using automatic tube current modulation alone compared with organ-based dose modulation and in-plane thyroid bismuth shielding. MATERIALS AND METHODS: An anthropomorphic female phantom with metal oxide semiconductor field effect transistor (MOSFET) detectors was scanned on a 64-MDCT scanner. The protocols included a reference neck CT protocol using automatic tube current modulation and three modified protocols: organ-based dose modulation, automatic tube current modulation with thyroid shield, and organ based dose modulation with thyroid shield. Image noise was evaluated quantitatively with the SD of the attenuation value, and subjectively by two neuroradiologists. RESULTS: Organ-based dose modulation, automatic tube current modulation with thyroid shield, and organ-based dose modulation with thyroid shield protocols reduced the thyroid dose by 28%, 33%, and 45%, respectively, compared with the use of automatic tube current modulation alone (p <= 0.005). Organ-based dose modulation also reduced the radiation dose to the ocular lens (33-47%) compared with the use of automatic tube current modulation (p <= 0.04). There was no significant difference in measured noise and subjective image quality between the protocols. CONCLUSION: Both organ-based dose modulation and thyroid shields significantly reduce the thyroid organ dose without degradation of subjective image quality compared with automatic tube current modulation. Organ-based dose modulation has the additional benefit of dose reduction to the ocular lens. PMID- 22528905 TI - Effect of beam-flow angle on velocity measurements in modern Doppler ultrasound systems. AB - OBJECTIVE: The purpose of this article is to examine the effect of different beam flow angles on the accuracy of Doppler ultrasound velocity measurements in modern ultrasound systems. MATERIALS AND METHODS: A flow phantom was used to create a steady flow of water in a 4.3-mm-diameter tube. Using three different modern university-grade ultrasound systems, flow was measured at 30 degrees , 40 degrees , 50 degrees , 60 degrees , 70 degrees , 80 degrees , and 88 degrees beam-flow angles twice by two radiologists in consensus using a convex and linear probe. Measured flow ratio, defined as measured velocity divided by estimated actual velocity, was calculated. Intraprobe, interprobe, and intermachine mean variation of measured flow ratio were calculated. RESULTS: Measured flow ratio increased as beam-flow angles increased. Measured flow ratios for the angles 30 degrees , 40 degrees , 50 degrees , 60 degrees , 70 degrees , 80 degrees , and 88 degrees were 0.90, 0.97, 1.10, 1.22, 1.62, 2.34, and 10.29, respectively. Intraprobe, interprobe, and intermachine variation did not show marked differences. For angles grouped as 30-40 degrees , 50-60 degrees , 70 degrees , and 80-88 degrees , intraprobe variation was 12%, 15%, 15%, and 26%; interprobe variation was 20%, 16%, 13%, and 26%; and intermachine variation was 16%, 16%, 17%, and 54%, respectively. As beam-flow angle increased, an increase in spectral broadening was also noted. CONCLUSION: There is no simple cutoff beam-flow value, such as the well-quoted less than 60 degrees , at which velocity measurements can be considered accurate. For follow-up imaging, beam-flow angle differences should be considered, and the same beam-flow angles should be used when possible. Follow-up imaging by different sonography machines is feasible. PMID- 22528906 TI - Frequency of incomplete atypical femoral fractures in asymptomatic patients on long-term bisphosphonate therapy. AB - OBJECTIVE: The purpose of our study was to determine the frequency and imaging features of atypical femoral fractures in a consecutive asymptomatic patient population on long-term bisphosphonate treatment and search for distinguishing clinical and laboratory parameters in the subset of patients with fractures. SUBJECTS AND METHODS: Two hundred femoral radiographs in 100 asymptomatic patients (93 women and seven men; age range, 47-94 years; mean age, 69.3 years) were prospectively reviewed by two radiologists. All patients had received bisphosphonate treatment for at least 3 years and had no history of pain or recent trauma. MRI studies were performed when a fracture was suspected on radiographs. Bone mineral density, serum calcium, albumin, 25-hydroxy vitamin D, intact parathyroid hormone (iPTH), serum C-telopeptide, and urine N-telopeptide values were obtained. RESULTS: Two of 100 patients (2%) had three insufficiency fractures. Both patients, 50 and 57 years old, were white, active, and had been receiving bisphosphonate therapy for 8 years. The patient with bilateral atypical femoral fractures showed typical features of bisphosphonate-related incomplete atypical femoral fractures. MRI confirmed the radiographic findings in both patients. The two patients with incomplete atypical femoral fractures were significantly younger than those without atypical femoral fractures. There were no significant differences among the fracture and nonfracture groups in terms of clinical or laboratory results, except for mean iPTH, which was significantly decreased in the fracture group. CONCLUSION: The 2% frequency of incomplete atypical femoral fractures in asymptomatic patients on long-term bisphosphonate therapy is higher than suggested in the literature. Aside from age and mean iPTH, there were no significant differences in clinical or laboratory data between the two groups. PMID- 22528907 TI - Radiologic guide to surgical treatment of first carpometacarpal joint osteoarthritis. AB - OBJECTIVE: The purpose of this article is to provide a radiologic guide to surgical treatment of first carpometacarpal osteoarthritis, a common problem especially in older women. CONCLUSION: Knowledge of the indications, surgical technique, component design, normal postoperative imaging assessment, and imaging findings of complications is important to providing a meaningful radiologic evaluation of patients after first carpometacarpal joint surgeries, including arthroplasty and arthrodesis. PMID- 22528908 TI - New criteria for the sonographic diagnosis of a plaque ulcer in the extracranial carotid artery. AB - OBJECTIVE: The diagnostic power of carotid sonography in detecting plaque ulcers may be inadequate when using the conventional criteria. We aimed to evaluate the usefulness of new criteria that we devised through a preliminary analysis of 50 endarterectomy cases before the present series. SUBJECTS AND METHODS: Thirty carotid arteries of 30 consecutive patients who underwent endarterectomy (28 men; age range, 46-83 years) were studied. In the long- and short-axis B-mode images of carotid arteries, the concavity of the plaque surface and the surface echo intensity were carefully investigated. The conventional criteria stipulate a concavity larger than 2 * 2 mm with a well-defined back wall and flow reversal within the recess. Our new criteria specify a concavity in the plaque with the basal border echo weaker than that of the adjacent plaque surface, regardless of size. The final diagnosis was based on surgical and histologic findings. RESULTS: Among the 30 carotid arteries, 14 arteries had 14 ulcers at surgery. Seventeen concavities were detected by sonography, and 12 of them, including six smaller than 2 * 2 mm, were truly ulcers. Two concavities with an echo intensity of the basal border equal to or greater than that of the adjacent surface were not true ulcers. Only two of 14 ulcers were not detected by sonography. The sensitivity and specificity of the conventional criteria were 35.7% and 75.0%, respectively, and those of our new criteria were 85.7% and 81.3%, respectively. CONCLUSION: Our new criteria for the sonographic diagnosis of plaque ulcer are more useful than the conventional ones. PMID- 22528909 TI - Quantitative brain diffusion-tensor MRI findings in patients with sickle cell disease. AB - OBJECTIVE: The aim of this study was to evaluate the microstructure of various regions of the brain using diffusion-tensor imaging (DTI) in patients with sickle cell disease (SCD) and in age- and sex-matched healthy control subjects. We also investigated the fiber tractography findings of the corpus callosum (CC) and corticospinal tracts (CSTs). SUBJECTS AND METHODS: Sixteen right-handed patients with SCD and 14 age- and sex-matched right-handed healthy control subjects were scanned using conventional MR sequences and DTI. Fractional anisotropy (FA) and apparent diffusion coefficients (ADCs) were calculated and regions of interest were selected in various brain areas (superior and inferior frontal, parietal, occipital, and temporal white matter areas), anterior and posterior periventricular areas, centrum semiovale, basal ganglia (lentiform nucleus, head of caudate nucleus), thalamus, cerebral peduncles, pons, cerebellar white matter areas, and CC. Diffusion-tensor tractography of the CC and CSTs was also performed. RESULTS: For the patients with SCD, significantly reduced FA values, increased ADC values, or both were seen clustered in several brain areas, including the CC, frontal white matter, centrum semiovale, periventricular areas, head of the caudate nucleus, thalamus, brainstem, and pons (p < 0.05). Statistically significant reductions in fiber counts in the first and fifth segments of the CC and in CSTs bilaterally were also observed in patients with SCD (p < 0.05). CONCLUSION: DTI shows microstructural abnormalities of various brain areas in patients with SCD. PMID- 22528910 TI - Utility of FDG PET/CT in the assessment of myeloid sarcoma. AB - OBJECTIVE: Myeloid sarcoma (MS) is a rare extramedullary manifestation of acute myeloid leukemia that often presents during remission or disease relapse. With awareness of this clinical entity and the appropriate clinical history, MS can be detected despite its nonspecific radiologic features. CONCLUSION: This article highlights the utility of (18)F-FDG PET/CT, which has high sensitivity in detecting early MS and provides a systemic overview of tumor burden, and its potential role in monitoring of treatment response. PMID- 22528911 TI - Vascular thoracic outlet syndrome: protocol design and diagnostic value of contrast-enhanced 3D MR angiography and equilibrium phase imaging on 1.5- and 3-T MRI scanners. AB - OBJECTIVE: The purpose of this article is to evaluate the efficiency and reproducibility of a contrast-enhanced 3D MR angiography (MRA) protocol, using the provocative arm position on 1.5- and 3-T MRI scanners, and to determine the frequency and distribution of vascular compression and vascular complications in the thoracic outlet. MATERIALS AND METHODS: Seventy-eight consecutive patients with clinically suspected thoracic outlet syndrome (TOS) were included in the study. Two radiologists independently analyzed all eligible vessel segments, and interobserver agreement was determined using kappa statistics. The distribution of vascular compression with regard to the clinical presentation at referral was also analyzed. RESULTS: A venous component, which presented with mainly venous symptoms and findings, was confirmed in 85% of the subjects. An arterial component, which presented with clinical symptoms and findings of vascular TOS syndrome, was seen in 82% of the subjects. The vascular component of TOS, which presented with mainly neurogenic or indeterminate symptoms or findings, was excluded in 61% of the subjects. CONCLUSION: Contrast-enhanced 3D MRA using provocative arm positioning allows excellent imaging of the arteries and veins on both sides and thus provides a noninvasive imaging alternative to digital subtraction angiography in patients with suspected vascular TOS. Contrast enhanced 3D MRA is also an ideal imaging modality for postsurgical follow-up for identifying restenosis or residual vascular compression. However, all imaging studies, including the contrast-enhanced 3D MRA protocol described here, should be treated as complementary tests for the diagnosis of TOS. PMID- 22528912 TI - Simultaneous MR arteriography and venography with blood pool contrast agent detects deep venous thrombosis in suspected arterial disease. AB - OBJECTIVE: The purpose of this study was to investigate the prevalence of incidental deep venous thrombosis (DVT) in patients with clinically suspected peripheral arterial occlusive disease (PAOD) using contrast-enhanced MR angiography (MRA) with a blood pool contrast agent. SUBJECTS AND METHODS: Two hundred fifty-nine MRA examinations with blood pool contrast agent in 245 consecutive patients (161 men; age range, 36-92 years), yielding a total of 4102 assessable arterial and venous vessel segments, were assessed with regard to the rate of incidentally observed acute and organized DVT and arterial stenosis grades. Incidental DVT was confirmed using duplex ultrasound. Contralateral nondiseased veins served as internal controls. The relationship between PAOD stages and acute and organized DVT was investigated using chi-square tests and a Mann-Whitney U test. RESULTS: Arterial stenosis grading using MRA with blood pool contrast agent revealed less than 50% luminal stenosis in 78% of segments (3199/4102), 50% or greater stenosis in 8% of segments (317/4102), and occlusion in 14% of segments (586/4102). Incidental DVT was observed in 26 of 245 patients (11%) (acute DVT was seen in 10 patients and 26 segments; organized DVT was seen in 17 patients and 35 segments; and one patient had both acute and organized DVT). All incidentally diagnosed cases of DVT were confirmed by duplex ultrasound. Internal controls revealed no false-positive or -negative findings (26 patients and 172 segments). Incidental acute DVT was significantly more common among patients without arterial stenosis greater than 50% (p < 0.05). Otherwise, there was no significant relationship between Fontaine PAOD stages and the occurrence of acute (p = 0.688) or organized (p = 0.995) DVT. CONCLUSION: Incidental DVT was prevalent in 11% of patients with clinically suspected PAOD. MRA with blood pool contrast agent has a potential role in the simultaneous assessment of arteries and veins and can detect concomitant venous disease affecting therapeutic management. PMID- 22528913 TI - Locoregional chemoembolic delivery: prediction with transcatheter intraarterial perfusion MRI. AB - OBJECTIVE: To our knowledge there is currently no quantitative preprocedural method for predicting the distribution and selectivity of delivery of chemoembolic material during trans-arterial chemoembolization. Transcatheter intraarterial perfusion MRI has been developed as a method of quantifying hepatic arterial perfusion. The purpose of this study was to investigate whether findings at transcatheter intraarterial perfusion MRI before chemoembolization can be used to predict uptake of the chemoembolic material delivered during chemoembolization. SUBJECTS AND METHODS: We compared quantitative prechemoembolization transcatheter intraarterial perfusion MRI parameters with analogous postchemoembolization CT chemoembolic distribution parameters and analyzed correlation using the Pearson correlation coefficient. These MRI and CT parameters included volume of distribution (a metric for volumetric liver perfusion or therapeutic agent delivery) and chemoembolic delivery selectivity factor (a ratio of volume-normalized tumor to background signal intensity that indicates the selectivity of chemoembolic delivery). RESULTS: Twenty-four hepatocellular carcinomas were targeted in 18 patients (14 men, four women; mean age, 66 years), and segmental or lobar chemoembolization with intraprocedural transcatheter intraarterial perfusion MRI was successful in all 18. Transcatheter intraarterial perfusion MRI and CT volume of distribution did not differ significantly (MRI, 233 cm(3); CT, 235 cm(3); p = 0.857). Transcatheter intraarterial perfusion MRI selectivity factor was an underestimate of CT selectivity factor (MRI, 0.20; CT, 0.25; p = 0.005). Prechemoembolization transcatheter intraarterial perfusion MRI and postchemoembolization CT volume of distribution (r = 0.93; p < 0.001) and selectivity factor (r = 0.95; p < 0.001) showed significant correlation. CONCLUSION: Tumor perfusion measured with transcatheter intraarterial perfusion MRI is predictive of uptake of chemoembolic material before delivery. This MRI technique may have utility as a method of quantifying delivery of the therapeutic agent during chemoembolization and, potentially, other liver-directed locoregional therapies. PMID- 22528914 TI - Placement of a covered expandable metallic stent to treat nonanastomotic malignant jejunal obstructions after total gastrectomy with esophagojejunostomy. AB - OBJECTIVE: The objective of our study was to assess the technical feasibility and clinical effectiveness of expandable metallic stent placement in patients with nonanastomotic malignant jejunal obstruction after total gastrectomy with esophagojejunostomy. MATERIALS AND METHODS: We retrospectively analyzed data from 21 patients with malignant jejunal obstruction after total gastrectomy with esophagojejunostomy who received one of two types of expandable metallic stent. Clinical effectiveness was assessed using the following variables: technical and clinical outcomes, complications, dysphagia scores before and after stent placement, patient survival, and stent patency. Complications with related interventions were evaluated and compared between the two stent types. RESULTS: Stent placement was technically successful in 20 of the 21 patients (95%) with 19 of 20 patients (95%) showing symptomatic improvement. Type A stents were used in 10 patients and type B stents in the remaining 10 patients. Complications occurred with seven of 20 stents (35%) and involved stent migration (n = 3), tumor overgrowth (n = 3), or pain (n = 1). The dysphagia score before stent placement (mean +/- SD, 3.2 +/- 0.5) had improved by 3 days after stent placement (1.3 +/- 0.9, p < 0.001) and was maintained compared with the initial score up to 1 month (1.7 +/- 1.1, p < 0.001) and 3 months (2.1 +/- 1.5, p = 0.021) after stent placement. The median patient survival and stent patency were 114 and 46 days, respectively. The type of stent was not significantly related to complications (p = 0.350). CONCLUSION: Placement of expandable metallic stents to treat nonanastomotic malignant jejunal obstruction in patients who have undergone total gastrectomy with esophagojejunostomy is feasible and clinically effective. PMID- 22528915 TI - Benign anastomotic strictures after esophagectomy: long-term effectiveness of balloon dilation and factors affecting recurrence in 155 patients. AB - OBJECTIVE: The purpose of this article is to retrospectively evaluate the long term clinical results of balloon dilation in the treatment of benign anastomotic strictures after esophagectomy and to identify factors associated with stricture recurrence. MATERIALS AND METHODS: From January 1996 to June 2011, a total of 309 sessions of balloon dilation were performed in 155 patients with benign anastomotic strictures after esophagectomy. Long-term clinical effectiveness was assessed using the following variables: technical and clinical success, complications, and patency rates. Factors independently related to recurrence were evaluated with the Cox model. Tested variables were age, sex, operation type, postoperative anastomotic leakage, balloon size, length of stricture, time to postoperative stricture development, complications, and neoadjuvant chemoradiotherapy. RESULTS: The mean follow-up period was 37 months (range, 1-159 months). Overall clinical success was achieved in 153 patients (99%) after a single (n = 78) or multiple (n = 75) balloon dilations. During follow-up, recurrence of the stricture requiring repeated dilation was seen in 77 of 155 patients (50%). Esophageal rupture (mostly intramural rupture) occurred in 22 of 155 patients (14%) and 34 of 309 balloon dilations (11%). In multivariate analysis, early development of stricture within 10 weeks after surgery (p = 0.002) and McKeown esophagectomy (p = 0.002) were independently related to recurrence after initial balloon dilation. CONCLUSION: Balloon dilation under fluoroscopic guidance has encouraging long-term results in the treatment of benign anastomotic strictures after esophagectomy. However, recurrence after balloon dilation was common, with McKeown esophagectomy and development of stricture within 10 weeks after surgery associated with recurrent strictures. PMID- 22528916 TI - Number needed to screen: appropriate use of this new basis for screening mammography guidelines. PMID- 22528917 TI - Neglecting to screen women between the ages of 40 and 49 years with mammography: what is the impact on breast cancer diagnosis? AB - OBJECTIVE: The purpose of this study was to compare breast cancer stage at diagnosis in two groups of women between 40 and 49 years old: women undergoing screening mammography and women with a symptom needing diagnostic workup. This comparison is indicative of the impact of forgoing screening in this age group, as recommended by the United States Preventive Services Task Force. MATERIALS AND METHODS: A retrospective chart review was used to collect the results of imaging guided core needle biopsies performed in women between the ages of 40 and 49 years from January 1, 2008, to December 31, 2009. In patients diagnosed with breast cancer or a high-risk lesion, the reason for presentation, pathology, tumor size, stage, and receptor characteristics were recorded. The chi-square test was used for statistical analysis. RESULTS: Of 108 primary breast cancers, 71 were detected in the screened group and 37 in the unscreened group. The screened group was significantly more likely to be diagnosed with ductal carcinoma in situ than the unscreened group (22 vs 1, chi-square = 11.6, p = 0.001). Furthermore, screened patients with invasive carcinoma were significantly more likely to be diagnosed at earlier stages (chi-square = 5.02, p = 0.025). The size of invasive breast cancer in the screened group was significantly smaller as well (chi-square = 9.3, p = 0.002). Of the high-risk lesions, atypical ductal hyperplasia (n = 29) and lobular carcinoma in situ (n = 8) were most frequently seen. CONCLUSION: Breast cancer patients undergoing screening mammography were diagnosed at earlier stages with smaller tumors. Screening also allows detection of high-risk lesions, which may prompt chemoprevention and lower subsequent breast cancer risk. We continue to support screening mammography in women between the ages of 40 and 49 years. PMID- 22528918 TI - High-spatial-resolution 3-T breast MRI of nonmasslike enhancement lesions: an analysis of their features as significant predictors of malignancy. AB - OBJECTIVE: The purpose of this study was to analyze the features of nonmasslike enhancement detected on 3-T MRI and to determine which of these features are significant predictors of malignancy. MATERIALS AND METHODS: Retrospective review was performed of 124 consecutive patients with nonmasslike enhancement detected on 3-T MRI after biopsy or surgery. We described nonmasslike enhancement using the descriptors in the BI-RADS MRI lexicon. In addition to the BI-RADS descriptors, whether clustered ring enhancement was present and whether surrounding high signal intensity (SI) was present on T2-weighted imaging were assessed. RESULTS: Cancer was identified in 85 lesions (69%). Of these lesions, ductal carcinoma in situ (DCIS) was found in 41 (48%) and invasive cancer in 44 (52%). The features found to be significant predictors of malignancy were segmental (p = 0.001), focal (p = 0.006), dendritic (p = 0.017), and clustered ring enhancement (p = 0.026) and surrounding high SI on T2-weighted imaging (p < 0.0001). The features found to be significant predictors of invasive cancer were dendritic enhancement (p < 0.0001) and surrounding high SI on T2-weighted imaging (p < 0.0001). There were no significant predictive features for DCIS. Homogeneous enhancement was found to be a significant predictor of benignancy (p = 0.001). Kinetic patterns were not significant predictors of malignancy. Nonmasslike enhancement of 1 cm or larger was more often malignant than lesions smaller than 1 cm (p < 0.0001). In multivariate analysis, a lesion size of 1 cm or larger was found to be the only significant predictor of malignancy for nonmasslike enhancement. CONCLUSION: Segmental, focal, dendritic, and clustered ring enhancement; surrounding high SI on T2-weighted imaging; and a lesion size of 1 cm or larger can act as predictors of malignancy for nonmasslike enhancement detected on 3-T MRI, but kinetic characteristics cannot. PMID- 22528920 TI - Unilateral hyperlucent lung in children. PMID- 22528921 TI - Informed consent in professionalism. PMID- 22528922 TI - Cervical spine evaluation in pediatric trauma. AB - OBJECTIVE: This article will review the current literature as it relates to imaging of the child suspected to have cervical spine injury (CSI) and the imaging findings of pediatric CSI, focusing on strategies to minimize radiation dose while maximizing diagnostic yield. CONCLUSION: Although CSI is uncommon in children, the clinical implications of failure to correctly diagnose CSI are significant. Clinical decision rules proven effective in predicting CSI in adults cannot be uniformly applied to children. PMID- 22528923 TI - Adnexal masses in female pediatric patients. AB - OBJECTIVE: This article reviews the range of adnexal masses that present in pediatric females. The preferred imaging modalities, the appearance of the normal ovaries, and the epidemiology of ovarian diseases and abnormalities are discussed. The illustrated abnormalities include simple and complex ovarian and paraovarian cysts, neoplasms, ovarian torsion, ectopic pregnancy, and tuboovarian abscess, with attention to the imaging features and vascular flow patterns that help distinguish surgical from nonsurgical cases, malignant from benign lesions, and ovarian abnormalities from mimickers. CONCLUSION: The critical clinical questions to the radiologist in the setting of adnexal lesions are the site of origin, benign versus malignant features, and presence of infection or abscess. Pairing clinical presentation and imaging findings will direct appropriate management, whether it is reassurance, follow-up imaging, or surgery. PMID- 22528924 TI - Unique MRI findings as an early predictor of osteonecrosis in pediatric acute lymphoblastic leukemia. AB - OBJECTIVE: Osteonecrosis is a potential complication of glucocorticoid chemotherapy in children surviving leukemia. Early diagnosis may allow effective interventions to minimize or ameliorate joint deterioration and obviate surgical intervention. We investigated the significance of MRI signal changes that precede the currently recognized "double-line" changes, which are considered pathognomic of osteonecrosis. MATERIALS AND METHODS: We retrospectively reviewed MRI scans acquired during prospective screening and follow-up of pediatric patients with leukemia for osteonecrosis. RESULTS: Of 481 patients, we identified 21 cases (4.3%; 12 boys; median age at leukemia diagnosis, 12.8 years) with subtle poorly defined geographically delineated MRI signal abnormalities in knees or hips, or both, that progressed over a median of 4 months (range, 1.6-18.5 months) to florid MRI signs of osteonecrosis. Articular surface collapse developed in three hips (two patients) and three knees (three patients). Three patients subsequently underwent surgical intervention (one bilateral total hip arthroplasty and one bilateral and one unilateral hip core decompression). The median duration of follow-up was 27 months (range, 1.9-90.7 months). CONCLUSION: The MRI signal abnormalities described here appear to herald extensive osteonecrosis and precede the typical MRI findings of osteonecrosis previously reported in the literature. PMID- 22528925 TI - Susceptibility-weighted imaging of the pediatric brain. AB - OBJECTIVE: The purpose of this article is to present and discuss the susceptibility-weighted imaging signal characteristics of the normal pediatric brain and those of a variety of pediatric brain pathologic abnormalities. CONCLUSION: Its high susceptibility for blood products, iron depositions, and calcifications makes susceptibility-weighted imaging an important additional sequence for the diagnostic workup of pediatric brain pathologic abnormalities. Compared with conventional MRI sequences, susceptibility-weighted imaging may show lesions in better detail or with higher sensitivity. Familiarity with the pediatric susceptibility-weighted imaging signal variance is essential to prevent misdiagnosis. PMID- 22528926 TI - MRI of pediatric patients: Part 1, normal and abnormal cartilage. AB - OBJECTIVE: Cartilage development has a profound impact on musculoskeletal growth. The objective of this article is to offer insights about the maturation of hyaline cartilage through MRI. We begin by briefly describing the molecular make up of hyaline cartilage. We will then follow with a discussion of the basic principles to apply to optimize hyaline cartilage imaging. The remainder of the article will focus on the MR appearances of the distinct histologic types of hyaline cartilage, normal variations in cartilage development, and the sequelae of cartilage injury on normal skeletal development. CONCLUSION: Knowledge of the normal and abnormal appearances of hyaline cartilage on MRI of pediatric patients will allow readers to avoid mistaking the changes associated with skeletal maturation for pathologic findings. PMID- 22528927 TI - MRI of pediatric patients: Part 2, normal variants and abnormalities of the knee. AB - OBJECTIVE: The purpose of this article is to discuss MRI of the pediatric knee and familiarize the reader with conditions encountered in the pediatric population. Clinical scenarios are included to convey important concepts and to orient the learner to normal variants and abnormalities of the pediatric knee. The conditions discussed include, but are not limited to, distal femoral metaphysial irregularity, isolated popliteus tendon avulsion, juvenile idiopathic arthritis, and discoid meniscus. CONCLUSION: The knee is the joint that is most commonly imaged by MRI in children. Injury patterns and signs of other pathologic processes seen in skeletally immature patients are different from those seen in adults. Interpreting pediatric knee MRI studies may be a challenge for those unfamiliar with the evolving patterns of normal development and of the signs of conditions that are more prevalent in children. Through case scenarios, this article describes and provides images that depict conditions commonly encountered in the pediatric knee. Most of the described normal findings and abnormalities are more prevalent in the pediatric population than in adults, and a few of the conditions are, in fact, unique to pediatric patients. PMID- 22528928 TI - Developmental aortic arch anomalies in infants and children assessed with CT angiography. AB - OBJECTIVE: The purpose of this article is to review the normal anatomy of the aortic arch and the most common variations of congenital aortic arch anomalies using low-radiation-dose, defined as a dose-length product of 7-15 mGy * cm, MDCT angiography. CONCLUSION: Radiologists should be prepared to fully describe congenital aortic arch anomalies; recognize them on CT angiography, especially the presence or absence of vascular rings or aberrant arteries; and explain their association with the trachea and esophagus. PMID- 22528929 TI - Fat-corrected T2 measurement as a marker of active muscle disease in inflammatory myopathy. AB - OBJECTIVE: We sought to improve the utility of T2 measurement as a marker of active muscle disease in patients with idiopathic inflammatory myopathy by correcting for T2 prolongations caused by fatty replacement of muscle that accompnaies chronic muscle damage. SUBJECTS AND METHODS: Twenty-one patients with idiopathic inflammatory myopathy underwent a standardized MRI evaluation of the thighs. Fat fraction maps were calculated from dual-echo gradient-echo images. Fat-corrected T2 maps were generated from multiecho spin-echo images on the basis of a biexponential model that incorporated voxelwise fat fraction estimates. Semiautomated summaries of conventional and fat-corrected muscle T2 values were compared with one another and with standardized visual scores of muscle disease based on T1-weighted spin-echo and STIR images. RESULTS: Fat-corrected muscle T2 maps showed lower mean values and greater histogram entropy than conventional T2 maps, as analyzed over a standardized portion of the thigh muscles. Conventional and fat-corrected T2 values correlated with visual scores of active muscle disease on STIR images and with the varying intensity of disease depicted with STIR in focal muscle regions. CONCLUSION: MRI T2 maps of muscle can be corrected for varying fat content by combining the information from chemical shift sensitive gradient-echo and multiecho spin-echo images. Use of this strategy may prove useful in the study of idiopathic inflammatory myopathy and other diseases characterized by both muscle inflammation and atrophy. PMID- 22528930 TI - Medullary carcinoma of the breast: MRI findings. AB - OBJECTIVE: The objective of our study was to describe the MRI findings of medullary carcinoma of the breast and to correlate those findings with the histopathologic findings. MATERIALS AND METHODS: From January 2005 to June 2010, MR images of 15 patients (age range, 32-73 years; mean age, 50 years) with pathologically confirmed medullary carcinoma of the breast were retrospectively evaluated according to BI-RADS. MR images were reviewed for the following: enhancement type (mass vs nonmass), size, shape, margins, contrast enhancement, signal intensity, and time-intensity curve pattern on a dynamic study. These MR features were correlated with the histopathologic features. RESULTS: All 15 tumors were seen as a mass on MRI. The median size of the masses was 2.7 cm (range, 1.5-6.3 cm) and the most common features were an oval or lobular shape (13/15, 86.7%) and a circumscribed margin (13/15, 86.7%). Rim enhancement with enhancing internal septations was seen in seven masses (46.7%), and rim enhancement was seen in six masses (40%). A hypointense rim on T2-weighted images was seen in nine tumors (9/15, 60%). Last, the kinetics curve showed a rapid initial increase in enhancement and a washout or plateau pattern on delayed phase imaging in all 15 tumors. CONCLUSION: On MRI, medullary carcinomas of the breast appeared as masses with an oval or lobular shape and circumscribed margins. Rim enhancement with or without enhancing internal septations was frequently seen on contrast enhancement. PMID- 22528931 TI - Evaluation of breast cancer using proton MR spectroscopy: total choline peak integral and signal-to-noise ratio as prognostic indicators. AB - OBJECTIVE: The purpose of this article is to determine whether the peak integral and signal-to-noise ratio (SNR) of total choline-containing compounds obtained by MR spectroscopy (MRS) correlate with histologic biomarkers currently used for predicting prognosis in patients with breast cancer. MATERIALS AND METHODS: Single-voxel proton MRS using a 1.5-T scanner was performed in 184 patients (mean age, 48 years; range, 28-72 years) with breast cancer. We obtained absolute total choline-containing compound peak integral, total choline-containing compound peak integral normalized for the volume of interest, and SNR after MRI. On surgical pathology, pathologic subtype and prognostic factors such as nuclear grade, histologic grade, estrogen receptor (ER), HER-2?neu, extensive intraductal component (EIC), lymphovascular invasion, and lymph node metastasis were also evaluated. Statistical analysis was performed using Mann-Whitney U test and Spearman rank correlation. RESULTS: The total choline-containing compound SNR, absolute total choline-containing compound peak integral, and normalized total choline-containing compound integral were significantly higher for invasive ductal carcinoma, cancer of high nuclear or histologic grade, and EIC-negative cancer (p < 0.001) than for in situ or other invasive carcinomas (p = 0.005), cancer of low nuclear or histologic grade (p = 0.009), and EIC-positive cancer (p = 0.017). There was a significant difference in the total choline-containing compound SNR between ER-positive and -negative groups (p = 0.007) and between triple-negative and non-triple-negative groups (p = 0.002). A positive correlation was found between the volume of interest (p < 0.001), tumor size (p = 0.011), and three MRS parameters (p = 0.003). CONCLUSION: Our study suggests that proton MRS can play a role in predicting prognostic indicators of tumor aggressiveness in patients with newly diagnosed breast cancer. PMID- 22528932 TI - A young radiologist's malpractice worries. PMID- 22528933 TI - MR-conditional pacemakers. PMID- 22528934 TI - Ablation of hepatocellular carcinoma: an incomplete review. PMID- 22528935 TI - Optimal pulsing windows for prospective ECG gating in patients with a heart rate above 65 beats per minute. PMID- 22528936 TI - Infrascapular abnormalities: location-specific fat-containing chest wall lesions. PMID- 22528937 TI - Vacuum-assisted infiltration of chitosan or polycaprolactone as a structural reinforcement for sintered cancellous bovine bone graft. AB - Sintered cancellous bovine bone (SCBB) offers numerous advantages as a bone graft substitute material; however, its mechanical properties require improvement. In this study, SCBB was infiltrated with epsilon-polycaprolactone (PCL) or chitosan/monetite to improve mechanical properties while retaining valuable SCBB structure. Organic infiltrating solutions consisted of (i) chitosan and monetite (CaHPO(4)) dissolved in hydrochloric acid; (ii) chitosan, monetite (CaHPO(4)), and genipin dissolved in hydrochloric acid; or (iii) PCL polymer dissolved in tetrahydrofuran (THF). Porous SCBB materials were infiltrated with one of the three solutions using vacuum-assisted infiltration. Chitosan and CaHPO(4) were immobilized in the SCBB structure by reprecipitation following a pH increase in an ammonia atmosphere. Genipin was used in one sample group to immobilize chitosan via crosslinking. PCL was immobilized by evaporating the THF carrier solvent. Mechanical compression testing showed an improvement in ultimate stress for the SCBB with chitosan/CaHPO(4) infiltrates, whereas PCL samples showed an increase in modulus. All SCBB samples were found to demonstrate favorable in vitro biocompatibility when subjected to L929 mouse fibroblast cells but required a vigorous washing regime to eradicate toxic ammonia residue. In conclusion, infiltration of SCBB with a polymeric or organic/mineral composite matrix positively modifies SCBB mechanical properties in favor of bone grafting applications. PMID- 22528938 TI - Role of HE4, CA72.4, and CA125 in monitoring ovarian cancer. AB - The aim of this study was to investigate the role of biomarkers CA125, HE4, and CA72.4 at diagnosis and throughout the follow-up in patients with epithelial ovarian cancer (EOC). Thirty-nine patients with EOC were deemed eligible, and 20 were followed up. CA125, HE4, and CA72.4 serum levels were determined for all patients at initial diagnosis of EOC. Among these patients, the number of cases with an elevated level of each individual marker was CA125 77 %, HE4 85 %, and CA72.4 72 %. A statistically significant difference was observed between the level of HE4 when compared to CA72.4 (p < 0.02). In the follow-up phase, we observed tumor marker levels fluctuating according to response to chemotherapy. When combining two out of the three biomarkers together, we observed increased values of CA125 and CA72.4 in 55 % of the patients, increased values of CA125 and HE4 in 65 % of the patients, and finally increased HE4 and CA72.4 in 75 % of the patients. A statistically significant difference was observed when combining HE4 and CA72.4, but not CA125 and CA 72.4 (p < 0.002). In conclusion, our study demonstrates that the association of three biomarkers CA125, HE4, and CA72.4 provides a valuable contribution in the follow-up of EOC patients. PMID- 22528939 TI - Effects of ARHI on cell cycle progression and apoptosis levels of breast cancer cells. AB - The purposes of this study were to investigate the role of Aplysia Ras Homolog I (ARHI) on cell growth, proliferation, apoptosis, and other biological characteristics of HER2-positive breast cancer cells. Our goal was to provide experimental evidence for the development of future effective treatments of HER2 positive breast cancer. A pcDNA3.1-ARHI eukaryotic expression vector was constructed and transfected into the human HER2-positive breast cancer cell lines SK-BR-3 and JIMT-1. Then, various experimental methods were utilized to analyze the biological characteristics of ARHI-expressing breast cancer cells and to examine the impact of expression of the ARHI gene on cyclin D1, p27(Kip1), and calpain1 expression. We further analyzed the cells in each group after treatment with trastuzumab to examine the effects of this drug on various cellular characteristics. When we compared pcDNA3.1-ARHI-expressing SK-BR-3 and JIMT-1 cells to their respective empty vector and control groups, we found that cell viability was significantly lower (p < 0.05) in the ARHI-expressing cells, and the proportions of G1 phase cells and apoptotic cells were significantly higher in the ARHI-expressing cells (p < 0.05). In all groups of SK-BR-3 cells, trastuzumab treatment significantly decreased cell growth (p < 0.05). The proportion of cells in G1 phase and the number of apoptotic cells in the pcDNA3.1 ARHI-expressing group were significantly higher than that in the empty vector group and the control group (p < 0.05). The growth of pcDNA3.1-ARHI-transfected JIMT-1 cells was significantly decreased (p < 0.05), while the proportion of apoptotic cells was significantly increased (p < 0.05). Cell growth, viability, and the percentage of apoptotic cells were similar between the JIMT-1 empty vector and control groups. ARHI expression inhibited cyclin D1 expression in SK BR-3 cells and JIMT-1 cells, while it promoted p27(Kip1) and calpain1 expression in these cells. ARHI expression inhibits the growth and proliferation of HER2 positive breast cancer cells, while it also promotes apoptosis in these cells. ARHI expression also improves the sensitivity of JIMT-1 cells to trastuzumab by inducing apoptosis. PMID- 22528940 TI - No evidence for the role of somatic mutations and promoter hypermethylation of FH gene in the tumorigenesis of nonsyndromic uterine leiomyomas. AB - Fumarate hydratase (FH) gene is reported to have specific involvement in syndromic uterine tumors, but its role in nonsyndromic forms is still unclear. Hence, the present study has aimed to screen the role of promoter methylation status and mutations in exon 2 and 7 regions of FH gene in the genesis of nonsyndromic uterine leiomyomas. Leiomyoma and myometrium tissues were collected from 85 hysterectomized uterine specimens. DNA from each of the biopsy was subjected to PCR, methylation-specific restriction assay, and DNA sequencing. In silico analysis was carried out to identify the impact of sequence variants on the protein structure. Chi-square (chi (2)) test was used to compare the promoter methylation proportions of leiomyoma and myometrium tissues. No sequence variants were observed in exon 2 region, but three novel heterozygous germ line sequence variants, i.e., c.1010A > C, c.1021 G > A, and c.1066 T > C in exon 7 region of the FH gene were detected in 14/85 (16.5 %) of the cases examined. In silico analysis results showed that c.1010A > C and c.1021 G > A mutations damage the structure and function of FH, whereas c.1066 T > C mutation is mostly tolerant or neutral. No significant difference of FH promoter methylation status between the leiomyoma (11.76 %) and myometrium (5.88 %) tissues was observed (P = 0.176). Therefore, it is concluded that somatic mutations in FH do not show pronounced effect in nonsyndromic uterine leiomyomas compared to that of their syndromic counterparts. However, higher frequency of FH mutations in leiomyoma cases raises the need to conduct larger number of prospective case-control and family-based studies to assess them as risk markers to nonsyndromic leiomyomas. PMID- 22528941 TI - EphB4 is overexpressed in papillary thyroid carcinoma and promotes the migration of papillary thyroid cancer cells. AB - EphB4 tyrosine kinase receptor has been involved in various physiologic and pathologic processes, and the role of the EphB4 in tumorigenesis has recently attracted much interest. However, its function in papillary thyroid carcinoma remains poorly understood. In this study, we explored the function of EphB4 in papillary thyroid carcinoma. We found that the expression of EphB4 was significantly upregulated in clinical samples. Overexpression of EphB4 in papillary thyroid carcinoma cell lines accelerated cell migration. In contrast, downregulation of EphB4 inhibited cell migration and suppressed in vivo tumor metastasis. Furthermore, we showed that EphB4 promoted cell migration by inhibiting the phosphorylation of FAK and paxillin. Moreover, EphB4 promoted cell migration in a kinase-independent manner. Taken together, our findings suggest that EphB4 plays an important role in the progression of papillary thyroid carcinoma by stimulating cell migration and EphB4 might be a potential therapeutic target in papillary thyroid carcinoma. PMID- 22528942 TI - Expression of Frat1 correlates with expression of beta-catenin and is associated with a poor clinical outcome in human SCC and AC. AB - Overexpression of frequently rearranged in advanced T-cell lymphomas 1 (Frat1) has been reported in several human malignant tumors, but the relationship between Frat1 and beta-catenin in lung cancer is still unclear. Our goal was to investigate the correlation between Frat1 and beta-catenin in patients with lung cancers. Immunohistochemistry was performed in 110 cases of non-small cell lung cancer (NSCLC) with clinical follow-up. Results showed that both Frat1 and beta catenin were overexpressed in NSCLC. The expression of Frat1 and beta-catenin was significantly correlated with tumor differentiation, TNM stage, and lymph node metastasis. Interestingly, the overexpression of beta-catenin was positively correlated with the overexpression of Frat1 (correlation coefficient = 0.285; P = 0.003). In addition, overexpression of Frat1 and abnormal expression of beta catenin were found to represent a poor prognosis for the patients. Furthermore, based on the transfection of Frat1 and beta-catenin, we found that Frat1 can upregulate the expression of beta-catenin in BE1 cells. PMID- 22528943 TI - Impact of methylenetetrahydrofolate reductase (MTHFR) polymorphisms on methotrexate-induced toxicities in acute lymphoblastic leukemia: a meta-analysis. AB - The associations between methylenetetrahydrofolate reductase (MTHFR) polymorphism and methotrexate (MTX)-induced toxicities in patients with acute lymphoblastic leukemia (ALL) have been evaluated in various populations, with the results remained conflicting. Therefore, we conducted a meta-analysis by combining available data to derive a more precise estimation of the association. PubMed, Embase, and China National Knowledge Infrastructure were searched until 21 September 2011 to identify eligible studies. A total of 14 studies were included, with all studies investigating MTHFR C677T polymorphism while nine of them investigating MTHFR A1298C polymorphism only. Results suggested that MTHFR C677T polymorphism was associated with significantly increased risk of MTX-induced toxicity, specifically liver toxicity (TT/CT vs. CC: odds ratio (OR) = 1.70, 95 % confidence interval (CI) = 1.05-2.75), myelosuppression (TT vs. CT/CC: OR = 2.82, 95 %CI = 1.25-6.34), oral mucositis (TT/CT vs. CC: OR = 3.68, 95 %CI = 1.73 7.85), gastrointestinal toxicity (TT/CT vs. CC: OR = 2.36, 95 %CI = 1.36-4.11), and skin toxicity (T vs. C: OR = 2.26, 95 %CI = 1.07-4.74). MTHFR A1298C polymorphism was found to be associated with decreased risk of skin toxicity (CC/AC vs. AA: OR = 0.11, 95 %CI = 0.01-0.85). Genotyping of MTHFR polymorphism, C677T particularly, prior to treatment for ALL is likely to be useful with the aim of tailoring MTX therapy and thus reducing the MTX-related toxicities. However, further studies with larger data set and well-designed models are required to validate our findings. PMID- 22528945 TI - Cyclin D1 G870A polymorphism and lung cancer risk: a meta-analysis. AB - Many studies have investigated the association between Cyclin D1 (CCND1) G870A polymorphism and lung cancer risk, but the impact of CCND G870A polymorphism on lung cancer is unclear owing to the obvious inconsistence among those studies. This study aimed to quantify the strength of association between CCND1 G870A polymorphism and lung cancer risk. We searched the PubMed, Embase, and Wangfang databases for articles on studies relating the CCND1 G870A polymorphism to the risk of lung cancer in humans. We estimated summary odds ratios (ORs) with their confidence intervals (CIs) to assess the association. Meta-analyses of total studies showed that CCND1 G870A polymorphism was associated with lung cancer risk under three genetic models (OR(A versus G) = 1.13, 95 % CI 1.03-1.24; OR(AA versus GG) = 1.20, 95 % CI 1.07-1.35; OR(AA versus AG + GG) = 1.23, 95 % CI 1.02 1.50). Meta-analyses of studies with high quality showed that CCND1 G870A polymorphism was associated with lung cancer risk under two genetic models (OR(A versus G) = 1.08, 95 % CI 1.02-1.15; OR(AA versus GG) = 1.17, 95 % CI 1.04-1.32). Subgroup analyses by ethnicity and sensitivity analyses further identified the significant association above. No evidence of publication bias was observed. Meta analyses of available data show a significant association between the CCND1 G870A polymorphism and lung cancer risk, and CCND1 G870A polymorphic variant A contributes to increased risk of lung cancer. PMID- 22528944 TI - MicroRNA-10b promotes migration and invasion through CADM1 in human hepatocellular carcinoma cells. AB - MicroRNA-10b (miR-10b) was recently reported to be dysregulated in some types of cancer and to play a role in invasion and metastasis. However, effects and potential mechanisms of action of miR-10b in the metastasis of hepatocellular carcinoma (HCC) have not been explored. In this study, we confirmed that miR-10b is highly expressed in metastatic HCC tissues and in metastatic HCC cell lines by qRT-PCR. Moreover, patients with higher miR-10b expression had significantly poorer overall survival, and high miR-10b expression was an independent predictor of poor prognosis. Inhibition of miR-10b reduced cell migration and invasion in MHCC97H cells, whereas over-expression of miR-10b in HepG2 cells increased cell migration and invasion. Bioinformatics and luciferase reporter assays revealed that miR-10b binds the 3'-UTR of CADM1 mRNA and represses its translation. Western blot and qRT-PCR showed that CADM1 is inhibited by miR-10b over expression. Silencing of CADM1 resulted in substantially increased cell motility and invasion similar to that observed with over-expression of miR-10b in HepG2 cells. These results suggest that miR-10b may positively regulate the invasion and metastasis of HCC through targeting CADM1. PMID- 22528946 TI - Rsf-1 overexpression correlates with poor prognosis and cell proliferation in colon cancer. AB - Rsf-1 (HBXAP) was recently reported to be overexpressed in various cancers and associated with the malignant behavior of cancer cells. However, the expression of Rsf-1 and its biological roles in colon cancer have not been reported. The molecular mechanism of Rsf-1 in cancer aggressiveness remains ambiguous. In the present study, we analyzed the expression pattern of Rsf-1 in colon cancer tissues and found that Rsf-1 was overexpressed in 50.4 % of colon cancer specimens. There was a significant association between Rsf-1 overexpression and TNM stage (p = 0.0205), lymph node metastasis (p = 0.0025), and poor differentiation (p = 0.0235). Furthermore, Rsf-1 overexpression correlated with a poor prognosis in colon cancer patients (p = 0.0011). In addition, knockdown of Rsf-1 expression in HT29 and HCT116 cells with high endogenous Rsf-1 expression decrease cell proliferation and colony formation ability. Further analysis showed that Rsf-1 knockdown decreased cyclin E expression and phospho-Rb level. In conclusion, Rsf-1 is overexpressed in colon cancers and contributes to malignant cell growth by cyclin E and phospho-Rb modulation, which makes Rsf-1 a candidate therapeutic target in colon cancer. PMID- 22528947 TI - Expression of ezrin correlates with malignant phenotype of lung cancer, and in vitro knockdown of ezrin reverses the aggressive biological behavior of lung cancer cells. AB - Ezrin, one of the ezrin-radixin-moesin proteins, is involved in the formation of cell membrane processes such as lamellipodia and filopodia and acts as a membrane cytoskeleton linker. Its aberrant expression correlates with development and progression of several human cancers. However, the expression of ezrin and its role in lung cancer are currently unknown. In this study, we performed ezrin small interfering RNA transfection in two lung cancer cell lines and examined the effects on malignant phenotypes in cancer cells by using 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide, wound healing, and chamber transwell assays. Ezrin knockdown significantly reduced the proliferation, migration, and invasion of lung cancer cells in vitro. To address the possible mechanisms, we evaluated the expression of adhesion molecules E-cadherin and beta-catenin by Western blot and reverse transcriptase-polymerase chain reaction analyses. The results demonstrated that downregulation of ezrin reduced beta-catenin and increased E cadherin at the protein level but had no effects on their mRNA levels, suggesting posttranscriptional regulation of these two adhesion molecules. Immunofluorescence assays revealed that ezrin knockdown restored membranous expression of E-cadherin and decreased cytoplasmic beta-catenin in lung cancer cells. In addition, ezrin expression was immunohistochemically evaluated on 135 normal and 183 lung cancer tissues. The expression of ezrin was significantly higher in cancer samples than paired autologous normal lung tissues. In normal bronchial epithelium, ezrin was mainly localized on the apical membrane, while in lung cancers and metastatic foci, ezrin was primarily distributed in cytoplasm. Among lung cancer tissues, expression of ezrin was higher in the invasive front of primary lesions and the highest in lymphatic metastasis. Statistical analysis demonstrated that ezrin expression correlated significantly with lymphatic metastasis and advanced TNM stage. Our data suggest that ezrin may play a crucial role in governing the biological behavior of lung cancer. PMID- 22528949 TI - The challenge of understanding peripherally mediated antinociception: commentary on a paper by Chung et al. (2012, this issue). PMID- 22528948 TI - A translocator protein ligand PK11195 shows antigrowth activity in human choriocarcinoma cells. AB - The potential anticancer agent 1-(2-chlorophenyl-N-methylpropyl)-3 isoquinolinecarboxamide (PK11195), a translocator protein ligand (initially described as a ligand for the peripheral benzodiazepine receptor), induces apoptosis in some lines of human tumor cells. We investigated the effect of PK11195 in the choriocarcinoma cell line, BeWo. BeWo cells were treated with various concentrations of PK11195, and changes in cell growth, the cell cycle, apoptosis, and related parameters were examined. A WST-1 assay showed that BeWo cells were sensitive to the growth inhibitory effect of PK11195. In contrast, the nonsite selective ligand diazepam has a little effect on these cells. Cell cycle analysis indicated that exposure to PK11195 decreased the proportion of cells in the S phase and increased the proportion in the G0/G1 phases of the cell cycle. Induction of apoptosis was confirmed by Annexin V staining of externalized phosphatidylserine, by the loss of mitochondrial transmembrane potential, and by antibodies directed against histones from fragmented DNA. This induction occurred in conjunction with the altered expression of genes related to cell growth, malignant phenotype, and apoptosis. These results suggest that PK11195 may serve as a therapeutic agent for the treatment of choriocarcinoma. PMID- 22528950 TI - Subjective sleepiness and daytime functioning in bariatric patients with obstructive sleep apnea. AB - PURPOSE: The purpose of this study was to evaluate associations between obstructive sleep apnea (OSA) severity and self-reported sleepiness and daytime functioning in patients considering bariatric surgery for treatment of obesity. METHODS: Using a retrospective cohort design, we identified 342 patients who had sleep evaluations prior to bariatric surgery. Our final sample included 269 patients (78.6 % of the original cohort, 239 females; mean age = 42.0 +/- 9.5 years; body mass index = 50.2 +/- 7.7 kg/m(2)) who had overnight polysomnography and completed the Epworth Sleepiness Scale (ESS) and the Functional Outcomes of Sleep Questionnaire (FOSQ). Patients' OSA was classified as none/mild (apnea hypopnea index (AHI) < 15, n = 112), moderate (15 <= AHI < 30, n = 77), or severe (AHI >= 30, n = 80). We calculated the proportion of unique variance (PUV) for the five FOSQ subscales. ANOVA was used to determine if ESS and FOSQ were associated with OSA severity. Unpaired t tests compared ESS and FOSQ scores in our sample with published data. RESULTS: The average AHI was 29.5 +/- 31.5 events per hour (range = 0-175.8). The mean ESS score was 6.3 +/- 4.8, and the mean global FOSQ score was 100.3 +/- 18.2. PUVs for FOSQ subscales showed moderate-to high unique contributions to FOSQ variance. ESS and global FOSQ score did not differ by AHI group. Only the FOSQ vigilance subscale differed by OSA severity with the severe group reporting more impairment than the moderate and none/mild groups. Our sample reported less sleepiness and daytime impairment than previously reported means in patients and controls. CONCLUSIONS: Subjective sleepiness and functional impairment were not associated significantly with OSA severity in our sample of patients considering surgery for obesity. Further research is needed to understand individual differences in sleepiness in patients with OSA. If bariatric patients underreport symptoms, self-report measures are not an adequate substitute for objective assessment and clinical judgment when evaluating bariatric patients for OSA. Patients with severe obesity need evaluation for OSA even in the absence of subjective complaints. PMID- 22528951 TI - Bone mineral density in patients with obstructive sleep apnea syndrome. PMID- 22528952 TI - Mirsaid M. Mirrakhimov (1927-2008): memoriam tribute for the clinician, scientist, and teacher. An obituary dedicated on the occasion of his day of birth. PMID- 22528953 TI - Determinants of continuous positive airway pressure adherence in a sleep clinic cohort of South Florida Hispanic veterans. AB - PURPOSE: There are little existing data on continuous positive airway pressure (CPAP) adherence in US Hispanic veterans with obstructive sleep apnea (OSA). Our aim was to describe determinants of 1-month adherence in a sleep clinic cohort of South Florida Hispanic veterans. METHODS: Hispanic veterans referred to the Miami VA sleep clinic were recruited and completed questionnaires about sleep apnea risk, sleep quality, insomnia symptoms, sleepiness, depression/anxiety, acculturation, personality traits, and cognitions about OSA and CPAP. Individuals at risk for OSA were scheduled for baseline polysomnography (PSG), followed by in lab CPAP titration or a trial of auto-CPAP. Participants with OSA accepting CPAP therapy were asked to return after 7 and 30 days of treatment for adherence verification and to repeat questionnaires. RESULTS: One hundred twenty-four participants (94 % men) were enrolled with 114 completing overnight PSG. Eighty six out of 95 participants (91 %) with sleep apnea syndrome or moderate to severe OSA accepted CPAP treatment. Fifty-nine participants completed both follow-up visits with a mean CPAP use at 30 days of 3.6 +/- 2.0 h. The only independent predictor of 7-day mean daily CPAP use was the baseline Insomnia Severity Index while the best predictor of 30-day mean daily CPAP use was the 7-day mean daily use. CONCLUSIONS: Our study suggests that South Florida Hispanic veterans with OSA evaluated in a sleep clinic show poor CPAP adherence. Insomnia and poor early use predicted poor adherence overall. Larger prospective studies with other race ethnic groups are needed to determine the role of ethnicity and race in CPAP adherence among US veterans with OSA. PMID- 22528954 TI - Lipid peroxidation and paraoxonase activity in nocturnal cyclic and sustained intermittent hypoxia. AB - PURPOSE: Obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD) have been known to be associated with atherosclerosis and hypoxia which was suggested to have an important role in this process by the way of increased oxidative stress. In the present study, we aimed to evaluate the effects of nocturnal hypoxia pattern (intermittent versus sustained) on serum lipid peroxidation and paraoxonase (PON) activity. METHODS: Blood collections were performed in 44 OSA, 11 non-apneic, nocturnal desaturated COPD, and 14 simple snorer patients after full-night polysomnographic recordings. Nocturnal sleep and respiratory parameters, oxygen desaturation indexes, serum malondialdehyde (MDA) levels by measuring with the help of the formation of thiobarbituric acid reactive substances (TBARS), and PON activity were assessed in all subjects. RESULTS: OSA and COPD patients showed nocturnal hypoxemia, with a minimum oxygen saturation (SaO(2)) in ranges of 53-92 % and 50-87 %, respectively. The mean levels of TBARS was 15.7 +/- 3.6 nmol and 15.3 +/- 3.4 nmol malondialdehyde (MDA)/ml in OSA and COPD patients, respectively, while the mean level of the control group was 4.1 +/- 1.2 nmol MDA/ml. The mean PON activity was found to be 124.2 +/- 35.5 U/l in OSA patients and 124.6 +/- 28.4 U/l in COPD patients. The mean PON activity of the control group was 269.0 +/- 135.8 U/l. The increase in TBARS levels and the decrease in PON1 levels were statistically significant in both OSA and COPD patients according to controls (p < 0.001 for TBARS as well as PON1). CONCLUSION: The results of this study revealed that both OSA and non apneic, nocturnal desaturated COPD patients showed increased levels of lipid peroxidation and decreased PON activity despite the differences in nocturnal hypoxia pattern. PMID- 22528957 TI - Numerical predictions for serial, parallel, and coactive logical rule-based models of categorization response time. AB - Recent theoretical advances in theories of categorization response times have made it possible to differentiate mental architectures that specify how processes occurring over several information-processing channels are combined (e.g., in serial or in parallel). This article introduces the numerical computations necessary to generate predictions for a class of logical rule-based models that have recently been used to account for speeded perceptual categorization judgments (Fific, M., Little, D.R. & Nosofsky, R. M. . Psychological Review, 117:309-348, 2010). PMID- 22528955 TI - Negative association between self-reported jaw symptoms and apnea-hypopnea index in patients with symptoms of obstructive sleep apnea syndrome: a pilot study. AB - OBJECTIVES: Prior to oral appliance therapy for snoring and obstructive sleep apnea syndrome (OSAS), patients are screened for jaw symptoms (e.g., pain). However, the presence of jaw symptoms in a large spectrum of OSAS patients remains unknown. This study aimed to assess the distribution of subjective jaw symptoms in patients with symptoms of OSAS. METHODS: Five hundred and eleven consecutive patients (66 female, 445 male; mean age 49.6 +/- 12.6 years) with clinical symptoms of OSAS were enrolled for cardiorespiratory evaluation. Self administered questionnaires were used to assess jaw symptoms, tooth grinding and clenching during sleep, morning oral dryness, morning heartburn sensation, and pain in the neck and back. RESULTS: The mean apnea-hypopnea (AHI) index was 32.5 +/- 30.6 per hour of sleep. Nineteen percent of patients (n = 96) reported at least one jaw symptom. The presence of jaw symptoms was more frequently reported by patients with AHI less than 15 (25 %) than those with AHI of 15 and more (15 %, p = 0.012). In the crude analyses, jaw symptoms were associated with tooth grinding, tooth clenching, morning oral dryness, morning heartburn sensation, and neck/back pain. Multiple logistic regression analysis confirmed that jaw symptoms were associated with AHI less than 15 (odds ratio (OR) 1.99, p = 0.009), tooth clenching (OR 1.79, p = 0.006), morning oral dryness (OR 2.17, p = 0.02), and neck/back pain (OR 1.99, p = 0.005). CONCLUSIONS: Jaw symptoms can be found in 19 % of patients with symptoms of OSAS and are more frequently reported in patients with lower AHI, a patient population for whom oral appliances are often prescribed. PMID- 22528958 TI - Structural equation modeling with small sample sizes using two-stage ridge least squares estimation. AB - In covariance structure analysis, two-stage least-squares (2SLS) estimation has been recommended for use over maximum likelihood estimation when model misspecification is suspected. However, 2SLS often fails to provide stable and accurate solutions, particularly for structural equation models with small samples. To address this issue, a regularized extension of 2SLS is proposed that integrates a ridge type of regularization into 2SLS, thereby enabling the method to effectively handle the small-sample-size problem. Results are then reported of a Monte Carlo study conducted to evaluate the performance of the proposed method, as compared to its nonregularized counterpart. Finally, an application is presented that demonstrates the empirical usefulness of the proposed method. PMID- 22528956 TI - Insulin resistance and adipose-derived hormones in young men with untreated obstructive sleep apnea. AB - PURPOSE: Obstructive sleep apnea (OSA) increases the risk for insulin resistance (IR). The mechanisms that link the two are not clear and are frequently confounded by obesity. OSA is associated with alterations in adipose-derived hormones (adipokines) that increase IR; however, previous studies have focused on middle-aged and older adults. The objective of this study was to determine if IR and alterations in adipokines exist in young men with OSA, independent of obesity. METHODS: Subjects were assigned into the following groups based on body mass index and presence of OSA: obese with OSA (OSA, n = 12), obese without OSA (NOSA, n = 18), and normal weight without OSA (CON, n = 15). Fasting blood was obtained for batch analysis of biomarkers of IR. The homeostasis model assessment (HOMA) method was used to assess IR. RESULTS: HOMA and leptin were higher in the OSA group than the CON group. There were no differences in insulin, tumor necrosis factor alpha (TNF-alpha), and interleukin-6 (IL-6) between the OSA and NOSA groups. Adiponectin was lower in the OSA group vs. NOSA and CON; however, when controlled for central abdominal fat (CAF), the difference was nullified. When controlled for total body adiposity, however, CAF was 24 % higher in the subjects with OSA vs. subjects without OSA. CONCLUSIONS: These findings suggest that excess CAF in young men with OSA may contribute to risk for type 2 diabetes indirectly by a degree that would otherwise not be reached through obesity, although further research is needed. PMID- 22528959 TI - Improved partial volume correction for single inversion time arterial spin labeling data. AB - Arterial spin labeling has relatively low spatial resolution, which affects cerebral blood flow measurements by partial volume effect occurring at tissue interfaces, e.g., between gray matter, white matter, and cerebrospinal fluid. This can be an important source of cerebral blood flow quantification error. To correct for partial volume effect in arterial spin labeling, a linear regression method was recently proposed. Because this method assumes that tissue magnetization and cerebral blood flow are constant over an n(2) * 1 regression kernel, an inherent spatial blurring is introduced. In this study, a modified least trimmed squares algorithm is proposed for partial volume effect correction. It is demonstrated using simulations that the modified least trimmed square method can correct for partial volume effect and produce less blurring than the linear regression method. This is achieved without either acquiring additional datasets or increasing the computation burden. These capabilities were further demonstrated in vivo. The modified least trimmed square method should, therefore, play an important role in arterial spin labeling studies. PMID- 22528960 TI - Assessing ventilatory control in infants at high risk of sleep disordered breathing: a study of infants with cleft lip and/or palate. AB - Neonatal exposure to intermittent hypoxia results in altered ventilatory response to subsequent hypoxia in animal models. The effect of similar exposure in human infants is unknown. Our objective was to determine the impact of sleep disordered breathing (SDB) in early infancy on ventilatory response in infants. We recruited consecutive infants with cleft lip and/or palate (CL/P) to undergo ventilatory response testing using exposure to a hypoxic (15% O(2) ) gas mixture during sleep. This population is at high risk of SDB because of smaller airway caliber and abnormal palatal muscle attachments predisposing them to airway obstruction of ranging severity from birth. Ventilatory responses were compared between infants with a low apnea-hypopnea index (AHI; AHI < 15 events/hr) and a high AHI (AHI >= 15 events/hr). Testing was successfully completed in 22 of 23 infants who underwent testing at 4.4 +/- 4.8 months. Infants with high AHI had lower weight z scores, higher number of oxygen desaturation events during sleep, but similar oxygen saturation (S(p) O(2) ) nadir compared to infants with low AHI. The pattern of ventilatory response to hypoxia differed between the two groups; infants with high AHI had an earlier ventilatory decline and a blunted maximal ventilatory response to hypoxia. Infants with a high AHI use a different strategy to augment ventilation in response to hypoxia; while infants with a low AHI initially increased respiratory rate, tidal volume was the first parameter to increase in infants with high AHI. These results demonstrate that SDB in infancy is associated with altered ventilatory response to hypoxia. PMID- 22528961 TI - Surface characterization of Ca-P/Ag/TiO2 nanotube composite layers on Ti intended for biomedical applications. AB - The new generation of medical implants made by titanium is functionalized with different coatings to improve their bioactivity and reduce a risk of infection. This article describes how these goals can be achieved via deposition of silver nanoparticles and calcium phosphate coating. TiO(2) nanotubes were grown on a Ti substrate via electrochemical oxidation at constant voltage in a mixture of glycerol, deionized water, and NH(4) F. Silver particles with a size of 2-50 nm were deposited on the surface using the sputter deposition technique. Calcium phosphate coatings were grown on the nanotubular titania by simple immersion in Hanks' solution. It has been found that the silver nanoparticles are distributed homogeneously in the coating, which is promising for maintaining a steady antibacterial effect. The results show also that the Ag-incorporated TiO(2) nanotubes significantly stimulate apatite deposition from Hanks' solution. The highly ordered Ag-incorporated TiO(2) nanotube arrays with apatite coating may offer unique surface features for biomedical implants, ensuring both biocompatibility and antibacterial properties. PMID- 22528962 TI - Sex-dependent behavioral functions of the Purkinje cell-specific Galphai/o binding protein, Pcp2(L7). AB - We previously reported motor and non-motor enhancements in a mouse mutant with an inactivated Purkinje cell-specific gene, Pcp2(L7), that encodes a GoLoco domain containing modulator of Gi/o protein-coupled receptors. Effects included elevated learning asymptote with repeated rotarod training, increased acquisition rate in tone-cued fear conditioning (FC), and subtle male-specific changes in both acoustic startle habituation and pre-pulse inhibition. We have further analyzed this mutant strain this time with a focus on male-female differences, and here we report a sex-dependent anxiety-like phenotype: male mutants are less anxious, and female mutants are more anxious, than same-sex wild types. Similarly, the fear responses measured during the tone in FC acquisition are decreased in male mutants and increased in female mutants relative to same-sex wild types. Overall, the dynamics of both acquisition and extinction of FC is affected in mutants but memory was not affected. In the social realm, compositional analysis of sociability and preference for social novelty data supports that both L7 genotype and sex contribute to these behaviors. These results provide direct evidence of emotional functions of the cerebellum due to the unambiguous cerebellar specificity of Pcp2(L7) expression and the lack of any confounding motor defects in the mutant. We attempt to synthesize these new data with what is previously known both about Pcp2(L7) and about the effects of sex and sex hormones on anxiety and fear behaviors: specifically, L7 is a bidirectional and sex-dependent damper that regulates the amplitude and/or rate of sensorimotor responses, potentially acting as a mood stabilizer. PMID- 22528963 TI - Characterizing POLG ataxia: clinics, electrophysiology and imaging. AB - Mutations in the mitochondrial DNA polymerase gamma (POLG) cause a highly pleomorphic disease spectrum, and reports about their frequencies in ataxia populations yield equivocal results. This leads to uncertainties about the role of POLG genetics in the workup of patients with unexplained ataxia. A comprehensive characterization of POLG-associated ataxia (POLG-A) will help guide genetic diagnostics and advance our understanding of the disease processes underlying POLG-A. Thirteen patients with POLG-A were assessed by standardized clinical investigation, nerve conduction studies, motor-evoked potentials, magnetic resonance imaging (MRI) and transcranial sonography (TCS). The findings were compared with 13 matched patients with Friedreich's ataxia (FA). In addition to the well-known POLG-associated features of chronic external ophthalmoplegia (100 %), areflexia to the lower extremity (100 %), impaired vibration sense (100 %), bilateral ptosis (69 %) and epilepsy (38 %), also hyperkinetic movement disorders were frequent in POLG-A patients, including chorea (31 %), dystonia (31 %) and myoclonus (23 %). Similar to FA, polyneuropathy was of sensory axonal type (100 %). In contrast to FA, none of the POLG-A patients showed impaired central motor conduction. TCS demonstrated less enlargement of the fourth ventricle and more diffuse cerebellar hyperechogenicity in POLG-A. Corresponding to TCS, MRI revealed no or only mild cerebellar atrophy in most POLG-A patients (85 %). POLG ataxia presents with the clinical characteristics of both afferent and cerebellar ataxia. Cerebellar alterations diffusely involve various parts of the cerebellum, yet cerebellar atrophy is generally mild. POLG-A presents with a high load of distinct non-ataxia features, namely, sensory neuropathy, external ophthalmoplegia, ptosis, epilepsy and/or hyperkinetic movement disorders. Involvement of the corticospinal tract, however, is rare. PMID- 22528964 TI - Macrocerebellum: significance and pathogenic considerations. AB - Macrocerebellum is a rare finding characterized by an abnormally large cerebellum. Only few patients with a syndromal or isolated macrocerebellum have been reported so far. This article aims to categorize the magnetic resonance imaging (MRI) findings, quantitate the macrocerebellum by volumetric analysis, characterize the neurological and dysmorphic features and cognitive outcome, and report the results of genetic analyses in children with macrocerebellum. All MR images were qualitatively evaluated for infratentorial and supratentorial abnormalities. Volumetric analysis was performed. Data about neurological and dysmorphic features, outcome, and genetic analysis were collected from clinical histories and follow-up examinations. Five patients were included. Volumetric analysis in three patients confirmed large cerebellar size compared to age matched controls. MR evaluation showed that thickening of the cortical gray matter of the cerebellar hemispheres is responsible for the macrocerebellum. Additional infratentorial and supratentorial abnormalities were present in all patients. Muscular hypotonia, as well as impaired motor and cognitive development, was found in all patients, with ocular movement disorders in three of five patients. The five patients differed significantly in terms of dysmorphic features and involvement of extracerebral organs. Submicroscopic chromosomal aberrations were found in two patients. Macrocerebellum is caused by thickening of the cortical gray matter of the cerebellar hemispheres, suggesting that cerebellar granule cells may be involved in its development. Patients with macrocerebellum show highly heterogeneous neuroimaging, clinical, and genetic findings, suggesting that macrocerebellum is not a nosological entity, but instead represents the structural manifestation of a deeper, more basic biological disturbance common to heterogeneous disorders. PMID- 22528966 TI - Cutaneous sympathetic dysfunction in patients with Machado-Joseph disease. AB - Although the clinical symptoms of Machado-Joseph disease (MJD) vary widely, those involving the autonomic nervous system, such as cutaneous sympathetic dysfunction, have rarely been investigated. In addition, there are no reports on cutaneous vasomotor function in patients with MJD. To determine the effects of MJD on cutaneous sympathetic function, we evaluated cutaneous vasomotor and sudomotor responses in the palms of 15 patients (mean age, 49 +/- 15 years; seven men and eight women) who were genetically diagnosed with MJD as well as in the palms of 15 age-matched, healthy controls (mean age, 48 +/- 16 years; nine men and six women). Sweat response was absent in 10 (67 %) patients with MJD, and the mean amplitude of sweat response was significantly lower (p<0.0001) in patients with MJD than in healthy controls following mental stress (mental arithmetic) and physiological stimuli. Although vasoconstrictive response was absent in three patients with MJD (20 %), there were no significant differences in the mean amplitude of vasoconstrictive response between patients with MJD and healthy controls. These results indicate that patients with MJD have reduced cutaneous sympathetic response, including severely impaired sudomotor functions and mildly affected vasomotor functions. PMID- 22528965 TI - Electrophysiological, morphological, and topological properties of two histochemically distinct subpopulations of cerebellar unipolar brush cells. AB - Unipolar brush cells (UBCs) are excitatory cerebellar granular layer interneurons whose brush-like dendrites receive one-to-one mossy fiber inputs. Subclasses of UBCs differ primarily by expressing metabotropic glutamate receptor (mGluR) 1alpha or calretinin. We used GENSAT Tg(Grp-EGFP) BAC transgenic mice, which selectively express enhanced green fluorescent protein (EGFP) in mGluR1alpha positive UBCs to compare the functional properties of the two subclasses. Compared to EGFP-negative UBCs, which include the calretinin-positive cells, EGFP positive UBCs had smaller somata (area 48 vs 63 MUm(2)), lower specific membrane resistance (6.4 vs. 13.7 KOmega cm(2)), were less prone to intrinsic firing, and showed more irregular firing (in cell-attached ~49 % were firing vs. ~88 %, and the CV was 0.53 vs. 0.32 for EGFP-negative cells). Some of these differences are attributable to higher density of background K(+) currents in EGFP-positive cells (at -120 mV, the barium-sensitive current was 94 vs. 37 pA in EGFP-negative cells); Ih, on the contrary, was more abundantly expressed in EGFP-negative cells (at -140 mV, it was -122 vs. -54 pA in EGFP-positive neurons); furthermore, while group II mGluR modulation of the background potassium current in EGFP-negative UBCs was maintained after intracellular dialysis, mGluR modulation in EGFP positive UBCs was lost in whole-cell recordings. Finally, cell-attached firing was reversibly abolished by the GABA(B) activation in EGFP-positive, but not in EGFP-negative UBCs. Immunohistochemistry showed that EGFP-negative UBCs express GIRK2 at high density, while mGluR1alpha UBCs are GIRK2 negative, suggesting that GIRK2 mediates the mGluR-sensitive current in EGFP-negative UBCs. These data suggest that the two subclasses perform different functions in the cerebellar microcircuits. PMID- 22528967 TI - Direct causality between single-Purkinje cell activities and motor learning revealed by a cerebellum-machine interface utilizing VOR adaptation paradigm. AB - A cerebellum-machine interface (CMI) was developed to test direct causality between single-unit cerebellar Purkinje cell activities and motor learning. The CMI converts Purkinje cell simple spike firing rates into a pulse width modulation signal that drives a single-joint robot arm. The CMI has no adaptive capability, thus any changes observed in the robot arm motion can be attributed directly to changes in the Purkinje cell's firing activities. We employed a vestibuloocular reflex (VOR) adaptation paradigm in goldfish as an example of motor learning where desired motion and control error signal of the robot arm were given to the fish as its head rotation and retinal slip, respectively. It is demonstrated that the control error of the robot arm decreased gradually, but not monotonically and in many cases only in one direction. This is the first direct evidence that a single Purkinje cell is capable of adaptive motor control. The results also suggest that a single Purkinje cell can be responsible for directional selective VOR motor learning previously reported in goldfish by Yoshikawa et al. (Conf Proc IEEE Eng Med Biol Soc 1:478-481, 2004) and monkeys by Hirata et al. (J Neurophysiol 85(5):2267-2288, 2002). PMID- 22528968 TI - Updating of visual space across horizontal saccades in cerebellar and thalamic lesion patients. AB - Efference copies of motor commands are used to update visual space across saccades, ultimately ensuring transsaccadic constancy of space. Thalamic lesions have been shown to impair efference copy-based saccadic updating in an oculomotor context, i.e., when two successive saccades are required. Moreover, the cerebellum has also been discussed as one possible source of saccade-related efference copy signals. The present study aimed to investigate the effects of thalamic and cerebellar lesions on saccadic updating in a perceptual context. To this end, seven patients with focal cerebellar lesions, seven patients with focal thalamic lesions and 11 healthy controls completed a perceptual localisation task in which the position of a target had to be updated across a single horizontal saccade, while saccade-related event-related potentials (ERPs) were recorded. Contrary to the expectations, localisation precision in both patient groups did not differ from the respective controls. A positive ERP component with centroparietal distribution occurring from about 300 to 500 ms after saccade onset in the updating condition was observed equally pronounced in controls and thalamic lesion patients. In cerebellar lesion patients, there was evidence of a reduction of this relative positivity in the updating condition, particularly for leftward saccades. This finding suggests that cerebellar damage altered the neural processes underlying saccadic updating in a perceptual context without causing overt behavioural deficits. PMID- 22528970 TI - Bremsstrahlung parameters of praseodymium-142 in different human tissues: a dosimetric perspective for (142)Pr radionuclide therapy. AB - OBJECTIVE: Praseodymium-142 [T 1/2 = 19.12 h, [Formula: see text] = 2.162 MeV (96.3%), Egamma = 1575 keV (3.7%)] is one of the (141)Pr radioisotopes. Many studies have been attempted to assess the significance of usage (142)Pr in radionuclide therapy. In many studies, the dosimetric parameters of (142)Pr sources were calculated by modeling (142)Pr sources in the water phantom and scoring the energy deposited around it. However, the medical dosimetry calculations in water phantom consider Bremsstrahlung production, raising the question: "How important is to simulate human tissues instead of using water phantom?" This study answers these questions by estimation of (142)Pr Bremsstrahlung parameters. METHODS: The Bremsstrahlung parameters of (142)Pr as therapeutic beta nuclides in different human tissues (adipose, blood, brain, breast, cell nucleus, eye lens, gastrointestinal tract, heart, kidney, liver, lung deflated, lymph, muscle, ovary, pancreas, cartilage, red marrow, spongiosa, yellow marrow, skin, spleen, testis, thyroid and different skeleton bones) were calculated by extending the national council for radiation protection model. The specific Bremsstrahlung constant (Gamma Br), probability of energy loss by beta during Bremsstrahlung emission (P Br) and Bremsstrahlung activity (A release)Br were estimated. It should be mentioned that Monte Carlo simulation was used for estimation of (142)Pr Bremsstrahlung activity based on the element compositions of different human tissues and the calculated exposures from the anthropomorphic phantoms. RESULTS: Gamma Br for yellow marrow was smallest amount (1.1962 * 10( 3) C/kg-cm(2)/MBq-h) compared to the other tissues and highest for cortical bone (2.4764 * 10(-3) C/kg-cm(2)/MBq-h), and, overall, Gamma Br for skeletal tissues were greater than other tissues. In addition, Gamma Br breast was 1.8261 * 10(-3) C/kg-cm(2)/MBq-h which was greater than sacrum and spongiosa bones. Moreover, according to (A release)Br of (142)Pr, the patients receiving (142)Pr do not have to be hospitalized for radiation precautions and the Bremsstrahlung production does not prevent the therapy for outpatients. CONCLUSION: However, modeling (142)Pr source in water phantom for simulation of (142)Pr source in soft tissues could be acceptable due to similarity of Gamma Br in water and soft tissues; this approximation is a gross computation in the mediums encompassing high atomic numbers. These data may be practical in the investigation of Bremsstrahlung absorbed dose where (142)Pr is involved in radionuclide therapy. PMID- 22528969 TI - Polarised localisation of the voltage-gated sodium channel Na(v)1.2 in cerebellar granule cells. AB - Voltage-gated sodium channels are responsible for action potential initiation and propagation in electrically excitable cells. In this study, we used biochemical, immunohistochemical and quantitative immunoelectron microscopy techniques to reveal the temporal and spatial expression of the Na(v)1.2 channel subunit in granule cells of cerebellum. Using histoblot, we detected Na(v)1.2 widely distributed in the adult brain, but prominently expressed in the cerebellum. During postnatal development, Na(v)1.2 mRNA and protein were detected low during the first and second postnatal week, increased to P15 and then continue to decrease until adult levels. At the light microscopic level, Na(v)1.2 immunoreactivity concentrated in the molecular layer of the cerebellar cortex. Using immunofluorescence, Na(v)1.2 colocalised with VGluT1, but not with VGluT2, demonstrating that the subunit was preferentially present in parallel fibre axons and axon terminals. At the electron microscopic level, Na(v)1.2 immunoparticles were exclusively detected at presynaptic sites in granule cell axons and axon terminals of granule cells, with occasional clustering in their axon initial segment. This was demonstrated using quantitative immunogold analysis. In the axon terminals, the distribution of Na(v)1.2 was relatively uniform along the extrasynaptic plasma membrane and never detected in the active zone. We could not find detectable levels of Na(v)1.2 at postsynaptic elements of granule cells or other cerebellar cell types. The present findings show a polarised distribution of Na(v)1.2 along the neuronal surface of granule cells and suggest its primary involvement in the transmission of information from granule cells to Purkinje cells. PMID- 22528971 TI - New semi-quantitative 123I-MIBG estimation method compared with scoring system in follow-up of advanced neuroblastoma: utility of total MIBG retention ratio versus scoring method. AB - OBJECTIVE: The purpose of this study is to evaluate a new semi-quantitative estimation method using (123)I-MIBG retention ratio to assess response to chemotherapy for advanced neuroblastoma. METHOD: Thirteen children with advanced neuroblastoma (International Neuroblastoma Risk Group Staging System: stage M) were examined for a total of 51 studies with (123)I-MIBG scintigraphy (before and during chemotherapy). We proposed a new semi-quantitative method using MIBG retention ratio (count obtained with delayed image/count obtained with early image with decay correction) to estimate MIBG accumulation. We analyzed total (123)I-MIBG retention ratio (TMRR: total body count obtained with delayed image/total body count obtained with early image with decay correction) and compared with a scoring method in terms of correlation with tumor markers. RESULT: TMRR showed significantly higher correlations with urinary catecholamine metabolites before chemotherapy (VMA: r(2) = 0.45, P < 0.05, HVA: r(2) = 0.627, P < 0.01) than MIBG score (VMA: r(2) = 0.19, P = 0.082, HVA: r(2) = 0.25, P = 0.137). There were relatively good correlations between serial change of TMRR and those of urinary catecholamine metabolites (VMA: r(2) = 0.274, P < 0.001, HVA: r(2) = 0.448, P < 0.0001) compared with serial change of MIBG score and those of tumor markers (VMA: r(2) = 0.01, P = 0.537, HVA: 0.084, P = 0.697) during chemotherapy for advanced neuroblastoma. CONCLUSION: TMRR could be a useful semi quantitative method for estimating early response to chemotherapy of advanced neuroblastoma because of its high correlation with urine catecholamine metabolites. PMID- 22528973 TI - Hyperprolactinaemia on depot risperidone treated with aripiprazole. PMID- 22528974 TI - Mind and heart: heart rate variability in major depressive disorder and coronary heart disease - a review and recommendations. AB - OBJECTIVE: There is a reciprocal association between major depressive disorder (MDD) and coronary heart disease (CHD). These conditions are linked by a causal network of mechanisms. This causal network should be quantitatively studied and it is hypothesised that the investigation of vagal function represents a promising starting point. Heart rate variability (HRV) has been used to investigate cardiac vagal control in the context of MDD and CHD. This review aims to examine the relationship of HRV to both MDD and CHD in the context of vagal function and to make recommendations for clinical practice and research. METHODS: The search terms 'heart rate variability', 'depression' and 'heart disease' were entered into an electronic multiple database search engine. Abstracts were screened for their relevance and articles were individually selected and collated. RESULTS: Decreased HRV is found in both MDD and CHD. Both diseases are theorized to disrupt autonomic control feedback loops on the heart and are linked to vagal function. Existing theories link vagal function to both mood and emotion as well as cardiac function. However, several factors can potentially confound HRV measures and would thus impact on a complete understanding of vagal mechanisms in the link between MDD and CHD. CONCLUSIONS: The quantitative investigation of vagal function using HRV represents a reasonable starting point in the study of the relationship between MDD and CHD. Many psychotropic and cardiac medications have effects on HRV, which may have clinical importance. Future studies of HRV in MDD and CHD should consider antidepressant medication, as well as anxiety, as potential confounders. PMID- 22528975 TI - Psychiatric diagnoses are not mental processes: Wittgenstein on conceptual confusion. AB - BACKGROUND: Empirical explanation and treatment repeatedly fail for psychiatric diagnoses. Diagnosis is mired in conceptual confusion that is illuminated by Ludwig Wittgenstein's later critique of philosophy (Philosophical Investigations). This paper examines conceptual confusions in the foundation of psychiatric diagnosis from some of Wittgenstein's important critical viewpoints. ARGUMENT: Diagnostic terms are words whose meanings are given by usages not definitions. Diagnoses, by Wittgenstein's analogy with 'games', have various and evolving usages that are connected by family relationships, and no essence or core phenomenon connects them. Their usages will change according to the demands and contexts in which they are employed. Diagnoses, like many psychological terms, such as 'reading' or 'understanding', are concepts that refer not to fixed behavioural or mental states but to complex apprehensions of the relationship of a variety of behavioural phenomena with the world. A diagnosis is a sort of concept that cannot be located in or explained by a mental process. CONCLUSION: A diagnosis is an exercise in language and its usage changes according to the context and the needs it addresses. Diagnoses have important uses but they are irreducibly heterogeneous and cannot be identified with or connected to particular mental processes or even with a unity of phenomena that can be addressed empirically. This makes understandable not only the repeated failure of empirical science to replicate or illuminate genetic, neurophysiologic, psychic or social processes underlying diagnoses but also the emptiness of a succession of explanatory theories and treatment effects that cannot be repeated or stubbornly regress to the mean. Attempts to fix the meanings of diagnoses to allow empirical explanation will and should fail as there is no foundation on which a fixed meaning can be built and it can only be done at the cost of the relevance and usefulness of diagnosis. PMID- 22528972 TI - A frontier in the understanding of synaptic plasticity: solving the structure of the postsynaptic density. AB - The postsynaptic density (PSD) is a massive multi-protein complex whose functions include positioning signalling molecules for induction of long-term potentiation (LTP) and depression (LTD) of synaptic strength. These processes are thought to underlie memory formation. To understand how the PSD coordinates bidirectional synaptic plasticity with different synaptic activation patterns, it is necessary to determine its three-dimensional structure. A structural model of the PSD is emerging from investigation of its molecular composition and connectivity, in addition to structural studies at different levels of resolution. Technical innovations including mass spectrometry of cross-linked proteins and super resolution light microscopy can drive progress. Integrating different information relating to PSD structure is challenging since the structure is so large and complex. The reconstruction of a PSD subcomplex anchored by AKAP79 exemplifies on a small scale how integration can be achieved. With its entire molecular structure coming into focus, this is a unique opportunity to study the PSD. PMID- 22528976 TI - Predicting clinically significant change in an inpatient program for people with severe mental illness. AB - OBJECTIVE: The first aim of this study was to assess the proportion of patients who achieved reliable and clinically significant change over the course of treatment in an inpatient psychosocial rehabilitation program. The second aim was to determine whether age, gender, length of stay, and diagnosis and co-morbid diagnosis predicted those who were classified as improved or not improved, using clinical significance criteria. METHOD: Three hundred and thirty-seven patients from inpatient units at Bloomfield Hospital, Orange, New South Wales, Australia were assessed at admission, 3-month reviews and discharge using the expanded Brief Psychiatric Rating Scale, the Health of the Nation Outcome Scales and the Kessler 10. RESULTS: Reliable and clinically significant improvement was found for 32.4% of inpatients on psychiatric symptomatology, 19.5% on psychosocial functioning and 20.2% on psychological distress. Logistic regression analyses found that the predictor variables collectively predicted those who made reliable and clinically significant improvement on psychiatric symptomatology, but not on psychosocial functioning or psychological distress. Those with a primary diagnosis of schizo-affective disorder had higher rates of improvement in psychiatric symptomatology compared to those with a diagnosis of schizophrenia. Those with co-morbid substance abuse disorders showed a trend towards greater improvement. CONCLUSIONS: Inpatient treatment is associated with clinically significant improvements for some patients with a severe mental illness. Patients with schizo-affective disorders are proportionally more likely to make improvement. PMID- 22528977 TI - Management of lithium-associated hyperparathyroidism. PMID- 22528978 TI - Total synthesis of (-)-atrop-abyssomicin C. PMID- 22528979 TI - The development of thermal nanoprobe methods as a means of characterizing and mapping plasticizer incorporation into ethylcellulose films. AB - PURPOSE: The phase composition and distribution of ethylcellulose (EC) films containing varying amounts of the plasticizer fractionated coconut oil (FCO) were studied using a novel combination of thermal and mapping approaches. METHODS: The thermal and thermomechanical properties of films containing up to 30% FCO were characterized using modulated temperature differential scanning calorimetry (MTDSC) and dynamic mechanical analysis (DMA). Film surfaces were mapped using atomic force microscopy (AFM; topographic and pulsed force modes) and the composition of specific regions identified using nanothermal probes. RESULTS: Clear evidence of distinct conjugate phases was obtained for the 20-30% FCO/EC film systems. We suggest a model whereby the composition of the distinct phases may be estimated via consideration of the glass transition temperatures observed using DSC and DMA. By combining pulsed force AFM and nano-thermal analysis we demonstrate that it is possible to map the two separated phases. In particular, the use of thermal probes allowed identification of the distinct regions via localized thermomechanical analysis, whereby nanoscale probe penetration is measured as a function of temperature. CONCLUSION: The study has indicated that by using thermal and imaging techniques in conjunction it is possible to both identify and map distinct regions in binary films. PMID- 22528980 TI - Dissolution techniques for in vitro testing of dry powders for inhalation. AB - PURPOSE: To evaluate different dissolution testing methods and subsequently develop a simple to perform but reproducible and discriminating dissolution technique for inhalative powders. METHODS: From a dry powder a fraction of aerosolized particles with an aerodynamic particle size below 5 MUm was collected on regenerated cellulose membranes using an abbreviated Andersen cascade impactor. The membrane was then transferred to the respective dissolution set up either paddle apparatus with membrane holder, flow through cell or Franz diffusion cell. RESULTS: All tested dissolution techniques could discriminate between good and poorly soluble substances, but only the paddle apparatus differentiated between small variations of solubility. We showed that membrane coverage and particle diameter play an important role for the dissolution rate. The profiles were fitted with mathematical models (e.g., Weibull, first order) choosing the best fit for determination of the mean dissolution time. Furthermore, a correlation between the dissolution profiles obtained with Franz cell compared to paddle apparatus could be shown. CONCLUSION: The paddle apparatus with membrane holder has the best discrimination power with optimal reproducibility. PMID- 22528981 TI - Mekong at the crossroads: next steps for impact assessment of large dams. PMID- 22528982 TI - Cleaning of the Singapore River and Kallang Basin in Singapore: human and environmental dimensions. PMID- 22528983 TI - Open environmental data in developing countries: who benefits? PMID- 22528984 TI - In vitro performance of 13-93 bioactive glass fiber and trabecular scaffolds with MLO-A5 osteogenic cells. AB - This in vitro study was performed to evaluate the ability of two types of porous bioactive glass scaffolds to support the growth and differentiation of an established osteogenic cell line. The two scaffold types tested included 13-93 glass fiber and trabecular-like scaffolds seeded with murine MLO-A5 cells and cultured for intervals of 2 to 12 days. Culture in MTT-containing medium showed metabolically active cells both on the surface and within the interior of the scaffolds. Scanning electron microscopy revealed well-attached cells on both types of scaffolds with a continual increase in cell density over a 6-day period. Protein measurements also showed a linear increase in cell density during the incubation. Activity of alkaline phosphatase, a key indicator of osteoblast differentiation, increased about 10-fold during the 6-day incubation with both scaffold types. The addition of mineralization media to MLO-A5 seeded scaffolds triggered extensive formation of alizarin red-positive mineralized extracellular material, additional evidence of cell differentiation and completion of the final step of bone formation on the constructs. Collectively, the results indicate that the 13-93 glass fiber and trabecular scaffolds promote the attachment, growth, and differentiation of MLO-A5 osteogenic cells and could potentially be used for bone tissue engineering applications. PMID- 22528987 TI - Biodegradation of benzene, toluene, and xylene (BTX) in liquid culture and in soil by Bacillus subtilis and Pseudomonas aeruginosa strains and a formulated bacterial consortium. AB - PURPOSE: The major aromatic constituents of petroleum products viz. benzene, toluene, and mixture of xylenes (BTX) are responsible for environmental pollution and inflict serious public concern. Therefore, BTX biodegradation potential of individual as well as formulated bacterial consortium was evaluated. This study highlighted the role of hydrogen peroxide (H(2)O(2)), nitrate, and phosphate in stimulating the biodegradation of BTX compounds under hypoxic condition. MATERIALS AND METHODS: The individual bacterium viz. Bacillus subtilis DM-04 and Pseudomonas aeruginosa M and NM strains and a consortium comprising of the above bacteria were inoculated to BTX-containing liquid medium and in soil. The bioremediation experiment was carried out for 120 h in BTX-containing liquid culture and for 90 days in BTX-contaminated soil. The kinetics of BTX degradation either in presence or absence of H(2)O(2), nitrate, and phosphate was analyzed using biochemical and gas chromatographic (GC) technique. RESULTS: Bacterial consortium was found to be superior in degrading BTX either in soil or in liquid medium as compared to degradation of same compounds by individual strains of the consortium. The rate of BTX biodegradation was further enhanced when the liquid medium/soil was exogenously supplemented with 0.01 % (v/v) H(2)O(2), phosphate, and nitrate(.) The GC analysis of BTX biodegradation (90 days post-inoculation) in soil by bacterial consortium confirmed the preferential degradation of benzene compared to m-xylene and toluene. CONCLUSIONS: It may be concluded that the bacterial consortium in the present study can degrade BTX compounds at a significantly higher rate as compared to the degradation of the same compounds by individual members of the consortium. Further, addition of H(2)O(2) in the culture medium as an additional source of oxygen, and nitrate and phosphate as an alternative electron acceptor and macronutrient, respectively, significantly enhanced the rate of BTX biodegradation under oxygen-limited condition. PMID- 22528986 TI - Hypogonadism in male cancer patients. AB - Prevalence of hypogonadism in men with cancer has been reported between 40% and 90%, which is significantly higher than in the general population. Hypogonadism is likely to affect the quality of life in these patients by contributing to non specific symptoms, including decreased energy, anorexia, sarcopenia, weight loss, depression, insomnia, fatigue, weakness, and sexual dysfunction. Pathogenesis of hypogonadism in cancer patients is thought to be multi-factorial. Inflammation may play an important role, but leptin, opioids, ghrelin, and high-dose chemotherapy through different mechanisms have all been implicated as the cause. Hypogonadism is also associated with poor survival in cancer patients. Data looking into the treatment of hypogonadal male cancer patients with testosterone are limited. However, improvements in body weight, muscle strength, lean body mass, and quality of life have been shown in hypogonadal men with other chronic diseases on testosterone replacement therapy. Prospective and interventional trials are needed to test the efficacy and safety of testosterone treatment in improving quality of life of these patients. PMID- 22528985 TI - Biomimetic delivery with micro- and nanoparticles. AB - The nascent field of biomimetic delivery with micro- and nanoparticles (MNP) has advanced considerably in recent years. Drawing inspiration from the ways that cells communicate in the body, several different modes of "delivery" (i.e., temporospatial presentation of biological signals) have been investigated in a number of therapeutic contexts. In particular, this review focuses on (1) controlled release formulations that deliver natural soluble factors with physiologically relevant temporal context, (2) presentation of surface-bound ligands to cells, with spatial organization of ligands ranging from isotropic to dynamically anisotropic, and (3) physical properties of particles, including size, shape and mechanical stiffness, which mimic those of natural cells. Importantly, the context provided by multimodal, or multifactor delivery represents a key element of most biomimetic MNP systems, a concept illustrated by an analogy to human interpersonal communication. Regulatory implications of increasingly sophisticated and "cell-like" biomimetic MNP systems are also discussed. PMID- 22528988 TI - A recreational water quality index using chemical, physical and microbiological parameters. AB - PURPOSE: The aim of this paper was to develop a new recreational water quality index (RWQI) as a tool to ensure the health of swimmers and to take practical decisions. METHODS: RWQI was elaborated with epidemiological data, and we carried out an exhaustive study of the different guidelines for recreational waters proposed by different organisations around the world. Different parameters were chosen, considering, as a priority, the swimmer's contact and the possibility of ingestion of water during the recreational activity. Furthermore, rating curves were established for pH, chemical oxygen demand, nitrate, phosphate, detergents, enterococci, total coliforms, faecal coliforms and Escherichia coli. RESULTS AND CONCLUSIONS: The index was applied to the data set on water quality of the Potrero de los Funes River (San Luis, Argentina), generated during 2 years (2009 2010). Following the RWQI values classification, most of the Potrero de los Funes water samples fell in the good quality range during the study period. PMID- 22528989 TI - Acute effect of benzo[a]anthracene on the biodegradation of peptone under aerobic conditions. AB - BACKGROUND: This study investigated the acute effect of benzo[a]anthracene, a significant compound among polycyclic aromatic hydrocarbons, on the biodegradation of a synthetic organic substrate-a peptone/meat extract mixture under aerobic conditions. METHODS: A laboratory-scale sequencing batch reactor was sustained at steady state at a sludge age of 10 days with substrate feeding. Inhibition tests involved running a series of batch reactors initially seeded with the biomass obtained from the parent reactor. After the biomass seeding, the reactors were started with the peptone mixture and a range of initial benzo[a]anthracene concentrations between 0.5 and 88 mg/L. Experimental profiles of oxygen uptake rates and polyhydroxyalkanoates were evaluated by calibration of a selected model. RESULTS: Lower doses of benzo[a]anthracene had no effect on process kinetics. The noticeable acute impact was only observed with the addition of 88 mg/L of benzo[a]anthracene, but it was limited with the storage mechanism: the amount of organic substrate diverted to polyhydroxyalkanoates was significantly reduced with a corresponding decrease in the maximum storage rate, k (STO), from 2.7 down to 0.6 day(-1). Similarly, the maximum growth rate from internally stored polyhydroxyalkanoates was lowered from 2.3 to 1.0 day(-1). CONCLUSION: Among the mechanisms for direct substrate utilization, only the hydrolysis rate was slightly reduced, but otherwise, the overall COD removal efficiency was not affected. PMID- 22528990 TI - Isolation and characterization of a Rhodococcus strain with phenol-degrading ability and its potential use for tannery effluent biotreatment. AB - INTRODUCTION: Wastewater derived from leather production may contain phenols, which are highly toxic, and their degradation could be possible through bioremediation technologies. MATERIALS, METHODS AND RESULTS: In the present work, microbial degradation of phenol was studied using a tolerant bacterial strain, named CS1, isolated from tannery sediments. This strain was able to survive in the presence of phenol at concentrations of up to 1,000 mg/L. On the basis of morphological and biochemical properties, 16S rRNA gene sequencing, and phylogenetic analysis, the isolated strain was identified as Rhodococcus sp. Phenol removal was evaluated at a lab-scale in Erlenmeyer flasks and at a bioreactor scale in a stirred tank reactor. Rhodococcus sp. CS1 was able to completely remove phenol in a range of 200 to 1,000 mg/L in mineral medium at 30 +/- 2 degrees C and pH 7 as optimal conditions. In the stirred tank bioreactor, we studied the effect of some parameters, such as agitation (200-600 rpm) and aeration (1-3 vvm), on growth and phenol removal efficiency. Faster phenol biodegradation was obtained in the bioreactor than in Erlenmeyer flasks, and maximum phenol removal was achieved at 400 rpm and 1 vvm in only 12 h. Furthermore, Rhodococcus sp. CS1 strain was able to grow and completely degrade phenols from tannery effluents after 9 h of incubation. CONCLUSION: Based on these results, Rhodococcus sp. CS1 could be an appropriate microorganism for bioremediation of tannery effluents or other phenol-containing wastewaters. PMID- 22528991 TI - Effect of C/N ratios on the performance of earthworm eco-filter for treatment of synthetics domestic sewage. AB - PURPOSE: The performances of filter systems that use earthworms and plants, combined with earthworm eco-filter (EE) systems in treating synthetic domestic sewage (SDS) with different C/N ratios, were investigated for a 9-month period. METHODS: The effects of the combination of filters, earthworms, plants, as well as the combination of earthworms and plants on SDS nutrient removal efficiency were separately investigated to select the optimum system for treating SDS. The results of the current study could be used to determine how treatment performance responds to different C/N ratios and to explain and predict the performance of an operating EE system. RESULTS: EE systems with earthworms and plants (EP groups) consistently performed better than the other types of systems (CK, E, and P; that is, without earthworms and without plants, with earthworms and without plants, and without earthworms and with plants, respectively) under all C/N ratios. The highest removal efficiencies of chemical oxygen demand, total nitrogen, total phosphorus, and total organic carbon were achieved under C/N ratios of 6:1, 6:1, 6:1, and 9:1, respectively. The optimum nutrient removal efficiency was achieved at C/N = 6, and the contribution order for nutrient removal was EP > P > E > CK. CONCLUSIONS: Influent C/N ratios, the time of year, and the synergetic effects of earthworm behavior and microorganisms significantly affected nutrient removal efficiencies. Considering the removal of all nutrients, EE systems with plants and earthworms achieved optimum removal effects in July when the influent C/N ratio was controlled at 6. Appropriate control of carbon and nitrogen source concentrations permitted the achievement of optimal nutrient removal effects. PMID- 22528992 TI - Changing pollutants to green biogases for the crop food cycle chain. AB - PURPOSE: When fossil fuels on the Earth are used up, which kind of green energy can be used to replace them? Do every bioenergy generation or crop food chain results in environmental pollution? These questions are major concerns in a world facing restricted supplies of energy and food as well as environmental pollutions. To alleviate these issues, option biogases are explored in this paper. MATERIALS AND METHODS: Two types of biogas generators were used for modifying the traditional crop food chain [viz. from atmospheric CO(2) photosynthesis to crops, crop stem/husk biowastes (burnt in cropland or as home fuels), to livestock droppings (dumping away), pork and people foods, then to CO(2)], via turning the biowaste pollutants into green bioenergies. By analyzing the traditional food chain via observation method, the drawbacks of by-product biowastes were revealed. Also, the whole cycle chain was further analyzed to assess its "greenness," using experimental data and other information, such as the material balance (e.g., the absorbed CO(2), investment versus generated food, energy, and wastes). RESULTS AND DISCUSSION: The data show that by using the two types of biogas generators, clean renewable bioenergy, crop food, and livestock meat could be continuously produced without creating any waste to the world. The modification chain largely reduced CO(2) greenhouse gas and had a low-cost investment. The raw materials for the gas generators were only the wastes of crop stems and livestock droppings. Thus, the recommended CO(2) bioenergy cycle chain via the modification also greatly solved the environmental biowaste pollutions in the world. CONCLUSIONS: The described two type biogases effectively addressed the issues on energy, food, and environmental pollution. The green renewable bioenergy from the food cycle chain may be one of suitable alternatives to fossil and tree fuels for agricultural countries. PMID- 22528993 TI - Cellular alterations and modulation of protein expression in bitumen-challenged human osteoblast cells. AB - PURPOSE: There are many arguments on the carcinogenic potential of bitumen extract. The mechanism of bitumen-induced damage is not well understood at the molecular level. Therefore, in the present study, cell-transforming and tumor inducing potential of bitumen extract was studied using in vitro [human osteosarcoma (HOS) cells] and in vivo [nude and severe combined immunodeficiency (SCID) mice] models. METHODS: Gas chromatography/mass spectrometry (GC/MS) analysis was carried out to find out the existence of carcinogenic compounds in the bitumen extract. Cell transformation test, anchorage independence assay, karyotyping assay, tumorigenicity assay, and 2-DE analysis were used to find out the effect of bitumen using the in vitro and in vivo models. RESULTS: GC/MS analysis showed the existence of carcinogenic compounds in the bitumen extract. HOS cells were treated with different concentrations (25, 50, and 100 MUl/ml) of bitumen extract. Compared to the parental HOS cells, bitumen transformants (HOS T1 and HOS T2) showed the characteristics of anchorage independency, chromosomal anomaly, and cellular transformation. Interestingly, bitumen transformants were not able to form tumor in nude/SCID mice. Proteomic analysis revealed the existence of 19 differentially expressed proteins involved in progression of cancer, angiogenesis, cell adhesion, etc. CONCLUSIONS: Exposure of bitumen extract to HOS cells results in the cellular transformation similar to cancer cells and can modulate proteins involved in the progression of cancer. We state that the non-tumorogenic potential of bitumen transformant in nude/SCID mice can be attributed to the downregulation of galectin-1, chromodomain helicase DNA binding protein 1-like gene, and membrane-associated guanylate kinase 2 protein. PMID- 22528995 TI - Fine and ultrafine particles emitted from laser printers as indoor air contaminants in German offices, Tao Tang, Julia Hurrabeta, Richard Gminski, Volker Mersch-Sundermann (2011) Environ Sci Pollut Res; DOI: 10.1007/s11356-011 0647-5. PMID- 22528994 TI - Microbial structure and chemical components of aerosols caused by rotating brushes in a wastewater treatment plant. AB - PURPOSE: Bacterial community structure and the chemical components in aerosols caused by rotating brushes in an Orbal oxidation ditch were assessed in a Beijing municipal wastewater treatment plant. METHODS: Air samples were collected at different distances from the aerosol-generating rotating brushes. Molecular culture-independent methods were used to characterize the community structure of the airborne bacteria in each sample regardless of cell culturability. A clone library of 16S rDNA directly amplified from air DNA of each sample was constructed and sequenced to analyze the community composition and diversity. Insoluble particles and water-soluble ions emitted with microorganisms in aerosols were analysis by a scanning electron microscope together with energy dispersive X-ray spectroscopy and ion chromatogram analyzer. RESULTS: In total, most of the identified bacteria were Proteobacteria. The majority of sequences near the rotating brushes (the main source of the bioaerosols) were Proteobacteria (62.97 %) with beta-(18.52 %) and gamma-(44.45 %) subgroups and Bacteroidetes (29.63 %). Complex patterns were observed for each sampling location, suggesting a highly diverse community structure, comparable to that found in water in the Orbal oxidation ditch. Accompany with microorganisms, 46.36 MUg/m(3) of SO (4) (2-) , 29.35 MUg/m(3) of Cl(-), 21.51 MUg/m(3) of NO (3) (-) , 19.76 MUg/m(3) of NH (4) (+) , 11.42 MUg/m(3) of PO (4) (3-) , 6.18 MUg/m(3) of NO (2) (-) , and elements of Mg, Cl, K, Na, Fe, S, and P were detected from the air near the aerosols source. CONCLUSIONS: Differences in the structure of the bacterial communities and chemical components in the aerosols observed between sampling sites indicated important site-related variability. The composition of microorganisms in water was one of the most important sources of bacterial communities in bioaerosols. Chemical components in bioaerosols may provide a media for airborne microorganism attachment, as well as a suitable microenvironment for their growth and survival in the air. This study will be benefit for the formulation of pollution standards, especially for aerosols, that take into account plant workers' health. PMID- 22528996 TI - Influences of natural emission sources (wildfires and Saharan dust) on the urban organic aerosol in Barcelona (Western Mediterranean Basis) during a PM event. AB - The urban air quality in Barcelona in the Western Mediterranean Basin is characterized by overall high particulate matter (PM) concentrations, due to intensive local anthropogenic emissions and specific meteorological conditions. Moreover, on several days, especially in summer, natural PM sources, such as long range transported Saharan dust from Northern Africa or wildfires on the Iberian Peninsula and around the Mediterranean Basin, may influence the levels and composition of the organic aerosol. In the second half of July 2009, daily collected PM(10) filter samples in an urban background site in Barcelona were analyzed on organic tracer compounds representing several emission sources. During this period, an important PM peak event was observed. Individual organic compound concentrations increased two to five times during this event. Although highest increase was observed for the organic tracer of biomass burning, the contribution to the organic aerosol was estimated to be around 6 %. Organic tracers that could be related to Saharan dust showed no correlation with the PM and OC levels, while this was the case for those related to fossil fuel combustion from traffic emissions. Moreover, a change in the meteorological conditions gave way to an overall increase of the urban background contamination. Long-range atmospheric transport of organic compounds from primary emissions sources (i.e., wildfires and Saharan dust) has a relatively moderate impact on the organic aerosol in an urban area where the local emissions are dominating. PMID- 22528997 TI - Integrated Bacillus sp. immobilized cell reactor and Synechocystis sp. algal reactor for the treatment of tannery wastewater. AB - The wastewater discharged from leather industries lack biodegradability due to the presence of xenobiotic compounds. The primary clarification and aerobic treatment in Bacillus sp. immobilized Chemo Autotrophic Activated Carbon Oxidation (CAACO) reactor removed considerable amount of pollution parameters. The residual untreated organics in the wastewater was further treated in algal batch reactor inoculated with Synechocystis sp. Sodium nitrate, K(2)HPO(4), MgSO(4).7H(2)O, NH(4)Cl, CaCl(2).2H(2)O, FeCl(3) (anhydrous), and thiamine hydrochloride, rice husk based activated carbon (RHAC), immobilization of Bacillus sp. in mesoporous activated carbon, sand filter of dimensions diameter, 6 cm and height, 30 cm; and the CAACO reactor of dimensions diameter, 5.5 cm and height, 30 cm with total volume 720 ml, and working volume of 356 ml. In the present investigation, the CAACO treated tannery wastewater was applied to Synechocystis sp. inoculated algal batch reactor of hydraulic residence time 24 h. The BOD(5), COD, and TOC of treated wastewater from algal batch reactor were 20 +/- 7, 167 +/- 29, and 78 +/- 16 mg/l respectively. The integrated CAACO system and Algal batch reactor was operated for 30 days and they accomplished a cumulative removal of BOD(5),COD, TOC, VFA and sulphide as 98 %, 95 %, 93 %, 86 %, and 100 %, respectively. The biokinetic constants for the growth of algae in the batch reactor were specific growth rate, 0.095(day(-1)) and yield coefficient, 3.15 mg of algal biomass/mg of COD destructed. The degradation of xenobiotic compounds in the algal batch reactor was confirmed through HPLC and FT IR techniques. The integrated CAACO-Algal reactor system established a credible reduction in pollution parameters in the tannery wastewater. The removal mechanism is mainly due to co-metabolism between algae and bacterial species and the organics were completely metabolized rather than by adsorption. PMID- 22528998 TI - Influence of angular exposure and proximity to vehicular traffic on the diversity of epiphytic lichens and the bioaccumulation of traffic-related elements. AB - This study investigated the influence of angular exposure and distance from vehicular traffic on the diversity of epiphytic lichens and the bioaccumulation of traffic-related elements in a town of central Italy. An Index of Lichen Diversity (ILD) was calculated on the street-facing and the opposite side of road lining trees and in a urban park 250 m away, and the content of selected trace elements (Al, Ba, Ce, Cd, Cr, Cu, Fe, Mn, Ni, Pb, Sb, V, and Zn) was determined in samples of the lichen Punctelia borreri (Sm.) Krog growing on tree bark, both on the exposed and opposite sides. ILD increases with distance from traffic emissions. However, at the site with vehicle traffic, non-nitrophilous lichens decreased while nitrophilous ones increased. The concentration of the traffic related elements Ba, Cr, Cu, Mn, Sb, and Zn accumulated in thalli of P. borreri was higher on roadside trees than in trees from the urban park. ILD was not affected by the angular exposure to the road and the bioaccumulation of traffic related elements was similar in lichens from the side of the bole exposed to traffic emissions and particulate resuspension and from the opposite side. The angular exposure in respect to the traffic source does not influence trace element accumulation. These results are important when using lichens for biomonitoring purposes, both for planning future studies and for the reliability of the interpretation of past surveys that do not report information about the angular exposure of the collected lichen material. PMID- 22528999 TI - Effect of groundwater geochemistry on pentachlorophenol remediation by smectite templated nanosized Pd0/Fe0. AB - Zero-valent iron holds great promise in treating groundwater, and its reactivity and efficacy depend on many surrounding factors. In the present work, the effects of solution chemistry such as pH, humic acid (HA), and inorganic ions on pentachlorophenol (PCP) dechlorination by smectite-templated Pd(0)/Fe(0) were systematically studied. Smectite-templated Pd(0)/Fe(0) was prepared by saturating the negatively charged sites of smectite clay with Fe(III) and a small amount of Pd(II), followed by borohydride reduction to convert Fe(III) and Pd(II) into zero valent metal clusters. Batch experiments were conducted to investigate the effects of water chemistry on PCP remediation. The PCP dechlorination rate critically depends on the reaction pH over the range 6.0~10.0; the rate constant (k (obs)) increases with decreasing the reaction pH value. Also, the PCP remediation is inhibited by HA, which can be attributed to the electron competition of HA with H(+). In addition, the reduction of PCP can be accelerated by various anions, following the order: Cl(-) > HCO (3) (-) > SO (4) (2-) ~no anion. In the case of cations, Ca(2+) and Mg(2+) (10 mM) decrease the dechlorination rate to 0.7959 and 0.7798 from 1.315 h(-1), respectively. After introducing HA into the reaction systems with cations or/and anions, the dechlorination rates are similar to that containing HA alone. This study reveals that low pH and the presence of some anions such as Cl(-) facilitate the PCP dechlorination and induce the rapid consumption of nanosized zero-valent iron simultaneously. However, the dechlorination rate is no longer correlated to the inhibitory or accelerating effects by cations and anions in the presence of 10 mg/L HA. PMID- 22529000 TI - Air-dust-borne associations of phototrophic and hydrocarbon-utilizing microorganisms: promising consortia in volatile hydrocarbon bioremediation. AB - Aquatic and terrestrial associations of phototrophic and heterotrophic microorganisms active in hydrocarbon bioremediation have been described earlier. The question arises: do similar consortia also occur in the atmosphere? Dust samples at the height of 15 m were collected from Kuwait City air, and analyzed microbiologically for phototrophic and heterotrophic hydrocarbon-utilizing microorganisms, which were subsequently characterized according to their 16S rRNA gene sequences. The hydrocarbon utilization potential of the heterotrophs alone, and in association with the phototrophic partners, was measured quantitatively. The chlorophyte Gloeotila sp. and the two cyanobacteria Nostoc commune and Leptolyngbya thermalis were found associated with dust, and (for comparison) the cynobacteria Leptolyngbya sp. and Acaryochloris sp. were isolated from coastal water. All phototrophic cultures harbored oil vapor-utilizing bacteria in the magnitude of 10(5) g(-1). Each phototrophic culture had its unique oil-utilizing bacteria; however, the bacterial composition in Leptolyngbya cultures from air and water was similar. The hydrocarbon-utilizing bacteria were affiliated with Acinetobacter sp., Aeromonas caviae, Alcanivorax jadensis, Bacillus asahii, Bacillus pumilus, Marinobacter aquaeolei, Paenibacillus sp., and Stenotrophomonas maltophilia. The nonaxenic cultures, when used as inocula in batch cultures, attenuated crude oil in light and dark, and in the presence of antibiotics and absence of nitrogenous compounds. Aqueous and diethyl ether extracts from the phototrophic cultures enhanced the growth of the pertinent oil-utilizing bacteria in batch cultures, with oil vapor as a sole carbon source. It was concluded that the airborne microbial associations may be effective in bioremediating atmospheric hydrocarbon pollutants in situ. Like the aquatic and terrestrial habitats, the atmosphere contains dust-borne associations of phototrophic and heterotrophic hydrocarbon-utilizing bacteria that are active in hydrocarbon attenuation. PMID- 22529001 TI - Novel insights in Al-MCM-41 precursor as adsorbent for regulated haloacetic acids and nitrate from water. AB - High concentration of NO (3) (-) in groundwater has raised concern over possible contamination of drinking water supplies. In addition, the formation of haloacetic acids (HAAs) as by-products during disinfection with chlorine-based agents is still a relevant issue, since HAAs pose serious health hazard. In this work, we investigated the affinity of a precursor of Al-MCM-41 (a mesostructured hexagonal aluminosilicate containing the template surfactant) towards nitrate and HAAs, for its possible application in the removal of these pollutants from natural and drinking waters. Additionally, adsorption kinetics and isotherms were studied. The adsorbent was synthesized using cetyltrimethylammonium bromide as surfactant and characterized by physico-chemical techniques. Simulated drinking water was spiked with the EPA-regulated HAAs (monochloroacetic (MCAA), monobromoacetic (MBAA), dichloroacetic (DCAA), dibromoacetic (DBAA), and trichloroacetic (TCAA) acids) and placed in contact with the adsorbent. The effect of matrix composition was studied. Adsorption kinetic studies were performed testing three kinetics models. For the adsorption studies, three adsorption isotherm approaches have been tested to experimental data. The pollutant recoveries were evaluated by suppressed ion chromatography. The affinity of the adsorbent was TCAA = DBAA = DCAA > MBAA > MCAA with DCAA, DBAA, and TCAA completely removed. A removal as high as 77 % was achieved for 13 mg/L nitrate. The adsorption isotherms of NO (3) (-) and monochloroacetic acid can be modeled by the Freundlich equation, while their adsorption kinetics follow a pseudo-second-order rate mechanism. The adsorbent exhibited high affinity towards HAAs in simulated drinking water even at relevant matrix concentrations, suggesting its potential application for water remediation technologies. PMID- 22529002 TI - Bioremediation of Cd and carbendazim co-contaminated soil by Cd-hyperaccumulator Sedum alfredii associated with carbendazim-degrading bacterial strains. AB - The objective of this study was to develop a bioremediation strategy for cadmium (Cd) and carbendazim co-contaminated soil using a hyperaccumulator plant (Sedum alfredii) combined with carbendazim-degrading bacterial strains (Bacillus subtilis, Paracoccus sp., Flavobacterium and Pseudomonas sp.). A pot experiment was conducted under greenhouse conditions for 180 days with S. alfredii and/or carbendazim-degrading strains grown in soil artificially polluted with two levels of contaminants (low level, 1 mg kg(-1) Cd and 21 mg kg(-1) carbendazim; high level, 6 mg kg(-1) Cd and 117 mg kg(-1) carbendazim). Cd removal efficiencies were 32.3-35.1 % and 7.8-8.2 % for the low and high contaminant level, respectively. Inoculation with carbendazim-degrading bacterial strains significantly (P < 0.05) increased Cd removal efficiencies at the low level. The carbendazim removal efficiencies increased by 32.1-42.5 % by the association of S. alfredii with carbendazim-degrading bacterial strains, as compared to control, regardless of contaminant level. Cultivation with S. alfredii and inoculation of carbendazim-degrading bacterial strains increased soil microbial biomass, dehydrogenase activities and microbial diversities by 46.2-121.3 %, 64.2-143.4 %, and 2.4-24.7 %, respectively. Polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) analysis revealed that S. alfredii stimulated the activities of Flavobacteria and Bradyrhizobiaceae. The association of S. alfredii with carbendazim-degrading bacterial strains enhanced the degradation of carbendazim by changing microbial activity and community structure in the soil. The results demonstrated that association of S. alfredii with carbendazim degrading bacterial strains is promising for remediation of Cd and carbendazim co contaminated soil. PMID- 22529003 TI - A simple method to prepare magnetic modified beer yeast and its application for cationic dye adsorption. AB - The purpose of this research is to use a simple method to prepare magnetic modified biomass with good adsorption performances for cationic ions. The magnetic modified biomass was prepared by two steps: (1) preparation of pyromellitic dianhydride (PMDA) modified biomass in N, N-dimethylacetamide solution and (2) preparation of magnetic PMDA modified biomass by a situ co precipitation method under the assistance of ultrasound irradiation in ammonia water. The adsorption potential of the as-prepared magnetic modified biomass was analyzed by using cationic dyes: methylene blue and basic magenta as model dyes. Optical micrograph and x-ray diffraction analyses showed that Fe(3)O(4) particles were precipitated on the modified biomass surface. The as-prepared biosorbent could be recycled easily by using an applied magnetic field. Titration analysis showed that the total concentration of the functional groups on the magnetic PMDA modified biomass was calculated to be 0.75 mmol g(-1) by using the first derivative method. The adsorption capacities (q(m)) of the magnetic PMDA modified biomass for methylene blue and basic magenta were 609.0 and 520.9 mg g(-1), respectively, according to the Langmuir equation. Kinetics experiment showed that adsorption could be completed within 150 min for both dyes. The desorption experiment showed that the magnetic sorbent could be used repeatedly after regeneration. The as-prepared magnetic modified sorbent had a potential in the dyeing industry wastewater treatment. PMID- 22529004 TI - Phytoremediation potential of Petunia grandiflora Juss., an ornamental plant to degrade a disperse, disulfonated triphenylmethane textile dye Brilliant Blue G. AB - Phytoremediation provides an ecofriendly alternative for the treatment of pollutants like textile dyes. The purpose of this study was to explore phytoremediation potential of Petunia grandiflora Juss. by using its wild as well as tissue-cultured plantlets to decolorize Brilliant Blue G (BBG) dye, a sample of dye mixture and a real textile effluent. In vitro cultures of P. grandiflora were obtained by seed culture method. The decolorization experiments were carried out using wild as well as tissue-cultured plants independently. The enzymatic analysis of the plant roots was performed before and after decolorization of BBG. Metabolites formed after dye degradation were analyzed using UV-vis spectroscopy, high-performance liquid chromatography, Fourier transform infrared spectroscopy, and gas chromatography-mass spectrometry. Phytotoxicity studies were performed. Characterization of dye mixture and textile effluent was also studied. The wild and tissue-cultured plants of P. grandiflora showed the decolorized BBG up to 86 %. Significant increase in the activities of lignin peroxidase, laccase, NADH-2,6 dichlorophenol-indophenol reductase, and tyrosinase was found in the roots of the plants. Three metabolites of BBG were identified as 3 {[ethyl(phenyl)amino]methyl}benzenesulfonic acid, 3-{[methyl (phenyl)amino]methyl}benzenesulfonic amino acid, and sodium-3-[(cyclohexa-2,5 dien-1-ylideneamino)methyl]benzenesulfonate. Textile effluent sample and a synthetic mixture of dyes were also decolorized by P. grandiflora. Phytotoxicity test revealed the nontoxic nature of metabolites. P. grandiflora showed the potential to decolorize and degrade BBG to nontoxic metabolites. The plant has efficiently treated a sample of dye mixture and textile effluent. PMID- 22529005 TI - Speciation distribution and mass balance of copper and zinc in urban rain, sediments, and road runoff. AB - Heavy metal pollution in road runoff had caused widespread concern since the last century. However, there are little references on metal speciation in multiple environmental media (e.g., rain, road sediments, and road runoff). Our research targeted the investigation of metal speciation in rain, road sediments, and runoff; the analysis of speciation variation and mass balance of metals among rain, road sediments, and runoff; the selection of main factors by principal component analysis (PCA); and the establishment of equation to evaluate the impact of rain and road sediments to metals in road runoff. Sequential extraction procedure contains five steps for the chemical fractionation of metals. Flame atomic absorption spectrometry (Shimadzu, AA-6800) was used to determine metal speciation concentration, as well as the total and dissolved fractions. The dissolved fractions for both Cu and Zn were dominant in rain. The speciation distribution of Zn was different from that of Cu in road sediments, while speciation distribution of Zn is similar to that of Cu in runoff. The bound to carbonates for both Cu and Zn in road sediments were prone to be dissolved by rain. The levels of Cu and Zn in runoff were not obviously influenced by rain, but significantly influenced by road sediments. The masses for both Cu and Zn among rain, road sediments, and road runoff approximately meet the mass balance equation for all rainfall patterns. Five principal factors were selected for metal regression equation based on PCA, including rainfall, average rainfall intensity, antecedent dry periods, total suspended particles, and temperature. The established regression equations could be used to predict the effect of road runoff on receiving environments. PMID- 22529006 TI - Toxic heavy metal contamination and risk assessment of street dust in small towns of Shanghai suburban area, China. AB - The aims of this paper were to quantify the heavy metal concentrations in street dust of small towns in Shanghai suburban area compared with those in urban area, and examine their seasonal and spatial variations, and to assess their risks to water environment and local populations. Street dust samples were collected from three small towns and urban area in Shanghai in different seasons. Levels of heavy metals were determined by atomic adsorption spectrophotometer analyzer. The method of potential ecological risk index and the health risk assessment model were used to evaluate the potential risks to water bodies and local residents, respectively. The mean metal concentrations in street dust of small towns were far above soil background values but still lower than those in the urban area. No significant seasonal change was observed except for Cr, Ni, and Zn concentrations. Higher metal concentrations tended to be located in central area of towns and township roads. The integrated metal contamination was high and posed a strong potential ecological risk. Children had greater health risk than adults. The carcinogenic risk probabilities were under the acceptable level. The hazard index values to children were close to the safe level. Street dust from the studied area has been contaminated by heavy metals. The contamination of these elements is related more to the pollution source than seasonal change. The combination of the six metals may threaten the water environment and has non cancer health risk to children, but not to adults. PMID- 22529007 TI - Phytoremediation of an arsenic-contaminated site using Pteris vittata L. and Pityrogramma calomelanos var. austroamericana: a long-term study. AB - This field study investigated the phytoremediation potential of two arsenic (As) hyperaccumulating fern species, Pityrogramma calomelanos var. austroamericana and Pteris vittata over 27-month duration at a disused As-contaminated cattle-dip site located at Wollongbar, NSW, Australia. Ferns planted in January 2009 were harvested following 10, 22 and 27 months of growth. A detailed soil sampling was undertaken in June 2009 (initial, n = 42 per plot) and limited sampling in April 2011 (after 27 months, n = 15 per plot) to measure total and phosphate extractable As concentrations in soil at 0 - 20-, 20 - 40- and 40 - 60-cm depths. The choice of the limited number of samples was considered sufficient to estimate the changes in soil As concentration following phytoremediation based on a geostatistical model. The average frond dry biomass, As concentration and As uptake were significantly (P < 0.001 - 0.05) greater in P. calomelanos var. austroamericana than P. vittata, at all three harvests (1.6 - 4.3, 1.3 - 1.5 and 2.2 - 5.7 times, respectively). After 27-months of growth, P. calomelanos var. austroamericana removed 8,053 mg As (i.e. cumulative over three harvests) in plot B (25.4 kg As ha(-1)) that was 2.65 times higher than that depleted by P. vittata (3,042 mg As in plot A (9.7 kg As ha(-1))). The cumulative frond As uptake data of the two fern species revealed that P. calomelanos var. austroamericana extracted 1.7 - 3.9 % and P. vittata removed 0.53 - 1.5 % of total As from soil at three depths. However, for the surface (0 - 20 cm) and subsurface (40 - 60 cm) layers, the (post-experiment) soil As data indicated that total As concentration in soil was reduced by 49 and 63 % (P < 0.05), respectively, using P. calomelanos var. austroamericana; and 17 and 15 % (P > 0.05), respectively, by P. vittata. Our results show that phytoremediation time based on observed changes in soil As based on limited sampling is not reliable; hence, it is recommended that the frond As uptake should be considered in order to evaluate the phytoremediation efficiency of the two fern species at the experimental site. Using As uptake of the two fern species, we estimate that with P. calomelanos var. austroamericana it would take 55 - 125 years to decrease mean total As content below the ecological investigation level (20 mg kg(-1)) in the surface and subsurface soils, whereas with P. vittata 143 - 412 years would be required to achieve this target. PMID- 22529010 TI - Strength of bone tunnel versus suture anchor and push-lock construct in Brostrom repair. AB - BACKGROUND: Operative treatment of mechanical ankle instability is indicated for patients who have had multiple sprains and have continued episodes of instability despite bracing and rehabilitation. Anatomic reconstruction has been shown to have improved outcomes and return to sport as compared with nonanatomic reconstruction. HYPOTHESIS: The use of 2 suture anchors and a push-lock anchor is equal to 2 bone tunnels in strength to failure for anatomic Brostrom repair. STUDY DESIGN: Controlled laboratory study. METHODS: In 7 matched pairs of human cadaver ankles, the calcaneofibular ligament (CFL) and anterior talofibular ligament (ATFL) were incised from their origin on the fibula. A No. 2 Fiberwire suture was placed into the CFL and a separate suture into the ATFL in a running Krackow fashion with a total of 4 locking loops. In 1 ankle of the matched pair, the ligaments were repaired to their anatomic insertion with bone tunnels. In the other, 2 suture anchors were used to reattach the ligaments to their anatomic origins, and a push-lock was used proximally to reinforce these suture anchors. The ligaments were cyclically loaded 20 times and then tested to failure. Torque to failure, degrees to failure, and stiffness were measured. The authors performed a matched pair analysis. An a priori power analysis of 0.8 demonstrated 6 pairs were needed to show a difference of 30% with a 15% standard error at a significance level of .05. RESULTS: There was no difference in the degrees to failure, torque to failure, and stiffness. A post hoc power analysis of torque to failure showed a power of .89 with 7 samples. Power for initial stiffness was .97 with 7 samples. Eleven of 14 specimens failed at either the suture anchor or the bone tunnel. CONCLUSION: There is no statistical difference in strength or stiffness for a suture anchor and push-lock construct as compared with a bone tunnel construct for an anatomic repair of the lateral ligaments of the ankle. CLINICAL RELEVANCE: The use of suture anchors in lateral ligament stabilization allows for a smaller incision, less surgical dissection, and improved surgical efficiency. It is up to the discretion of the performing surgeon based on preference, ease of use, operative time, and cost profile to choose either of these constructs for anatomic repair of the lateral ligaments of the ankle. The suture repair at the ligament was significantly strong enough such that the majority of ankles failed at the bone interface. PMID- 22529009 TI - Prospective respiratory motion correction for coronary MR angiography using a 2D image navigator. AB - Respiratory motion remains the major impediment in a substantial amount of patients undergoing coronary magnetic resonance angiography. Motion correction in coronary magnetic resonance angiography is typically performed with a diaphragmatic 1D navigator (1Dnav) assuming a constant linear relationship between diaphragmatic and cardiac respiratory motion. In this work, a novel 2D navigator (2Dnav) is proposed, which prospectively corrects for translational motion in foot-head and left-right direction. First, 1Dnav- and 2Dnav-based motion correction are compared in 2D real time imaging experiments, by evaluating the residual respiratory motion in 10 healthy subjects as well as in a moving vessel phantom. Subsequently, 1Dnav and 2Dnav corrected high-resolution 3D coronary MR angiograms were acquired, and both objective and subjective image quality were assessed. For a gating window of 10 mm, 1Dnav and 2Dnav performed equally well; however, without any respiratory gating, the 1Dnav had a lower visual score for all coronary arteries compared with 10 mm gating, whereas the 2Dnav without gating performed similar to 1Dnav with 10 mm gating. PMID- 22529011 TI - Calcium carbonate microparticles used as a gene vector for delivering p53 gene into cancer cells. AB - Calcium carbonate (CaCO(3) ) microparticles were for the first time used for efficient delivery of p53 gene to transfect human cancer cells HeLa. CaCO(3) microparticles (2-4 MUm) absorbed pEGFP-C1-p53 (expressing GFP-P53 fusion protein) to transfect HeLa cells. Flow cytometer (FCM) was used to evaluate the gene transfection efficiency in HeLa cells, which were stably transduced with a green fluorescent protein gene. In this study, CaCO(3) delivering pEGFP-C1-p53 could transfect about 5% of the tumor cells in culture. However, the efficiency of tumor cell apoptosis was surprisingly up to 80%. Meanwhile, the results of MTT assay and crystal violet staining showed that the CaCO(3) microparticles had low cytotoxicity. These findings showed that CaCO(3) microparticles were perspective to be used as new vectors for gene therapy. PMID- 22529012 TI - Genetic control of intestinal stem cell specification and development: a comparative view. AB - Stem cells of the adult vertebrate intestine (ISCs) are responsible for the continuous replacement of intestinal cells, but also serve as site of origin of intestinal neoplasms. The interaction between multiple signaling pathways, including Wnt/Wg, Shh/Hh, BMP, and Notch, orchestrate mitosis, motility, and differentiation of ISCs. Many fundamental questions of how these pathways carry out their function remain unanswered. One approach to gain more insight is to look at the development of stem cells, to analyze the "programming" process which these cells undergo as they emerge from the large populations of embryonic progenitors. This review intends to summarize pertinent data on vertebrate intestinal stem cell biology, to then take a closer look at recent studies of intestinal stem cell development in Drosophila. Here, stem cell pools and their niche environment consist of relatively small numbers of cells, and questions concerning the pattern of cell division, niche-stem cell contacts, or differentiation can be addressed at the single cell level. Likewise, it is possible to analyze the emergence of stem cells during development more easily than in vertebrate systems: where in the embryo do stem cells arise, what structures in their environment do they interact with, and what signaling pathways are active sequentially as a result of these interactions. Given the high degree of conservation among genetic mechanisms controlling stem cell behavior in all animals, findings in Drosophila will provide answers that inform research in the vertebrate stem cell field. PMID- 22529013 TI - A critical re-evaluation of CD24-positivity of human embryonic stem cells differentiated into pancreatic progenitors. AB - Differentiation of embryonic stem cells (ESCs) into insulin-producing cells for cell replacement therapy of diabetes mellitus comprises the stepwise recapitulation of in vivo developmental stages of pancreatic organogenesis in an in vitro differentiation protocol. The chemical compounds IDE-1 and (-) indolactam-V can be used to direct mouse and human ESCs through these stages to form definitive endoderm via an intermediate mesendodermal stage and finally into pancreatic endoderm. Cells of the pancreatic endoderm express the PDX1 transcription factor and contribute to all pancreatic cell types upon further in vitro or in vivo differentiation. Even though this differentiation approach is highly effective and reproducible, it generates heterogeneous populations containing PDX1-expressing pancreatic progenitors amongst other cell types. Thus, a technique to separate PDX1-expressing cells from this mixture is very desirable. Recently it has been reported that PDX1-positive pancreatic progenitors, derived from human embryonic stem cells, express the surface marker CD24. Therefore were subjected mouse and human ESCs to a small molecule differentiation approach and the expression of the surface marker CD24 was monitored in undifferentiated cells, cells committed to the definitive endoderm and cells reminiscent of the pancreatic endoderm. We observed that both mouse and human ESCs expressed CD24 in the pluripotent state, during the whole process of endoderm formation and upon further differentiation towards pancreatic endoderm. Thus CD24 is not a suitable cell surface marker for identification of PDX1 positive progenitor cells. PMID- 22529014 TI - Human stromal (mesenchymal) stem cells from bone marrow, adipose tissue and skin exhibit differences in molecular phenotype and differentiation potential. AB - Human stromal (mesenchymal) stem cells (hMSCs) are multipotent stem cells with ability to differentiate into mesoderm-type cells e.g. osteoblasts and adipocytes and thus they are being introduced into clinical trials for tissue regeneration. Traditionally, hMSCs have been isolated from bone marrow, but the number of cells obtained is limited. Here, we compared the MSC-like cell populations, obtained from alternative sources for MSC: adipose tissue and skin, with the standard phenotype of human bone marrow MSC (BM-MSCs). MSC from human adipose tissue (human adipose stromal cells (hATSCs)) and human skin (human adult skin stromal cells, (hASSCs) and human new-born skin stromal cells (hNSSCs)) grew readily in culture and the growth rate was highest in hNSSCs and lowest in hATSCs. Compared with phenotype of hBM-MSC, all cell populations were CD34(-), CD45(-), CD14(-), CD31(-), HLA-DR(-), CD13(+), CD29(+), CD44(+), CD73(+), CD90(+),and CD105(+). When exposed to in vitro differentiation, hATSCs, hASSCs and hNSSCs exhibited quantitative differences in their ability to differentiate into adipocytes and to osteoblastic cells. Using a microarray-based approach we have unveiled a common MSC molecular signature composed of 33 CD markers including known MSC markers and several novel markers e.g. CD165, CD276, and CD82. However, significant differences in the molecular phenotype between these different stromal cell populations were observed suggesting ontological and functional differences. In conclusion, MSC populations obtained from different tissues exhibit significant differences in their proliferation, differentiation and molecular phenotype, which should be taken into consideration when planning their use in clinical protocols. PMID- 22529016 TI - Adipose derived stem cells protect skin flaps against ischemia-reperfusion injury. AB - BACKGROUND: Advances in the treatment of ischemia- reperfusion injury have created an opportunity for plastic surgeons to apply these treatments to flaps and implanted tissues. We examined the capability of adipose derived stem cells (ADSCs) to protect tissue against IRI using an extended inferior epigastric artery skin flap as a flap ischemia- reperfusion injury (IRI) model. METHODS: ADSCs were isolated from Lewis rats and cultured in vitro. Twenty- four rats were randomly divided into three groups. Group I was the sham group and did not undergo ischemic insult; rather, the flap was raised and immediately sutured back (non-ischemic control group). Group II (ischemia control) and group III (ADSCs treatment) underwent 3 h of ischemic insult. During reperfusion group III was treated by intravenous application of ADSCs and group II was left untreated. Five days postoperatively, flap survival and perfusion were assessed. Microvessel density was visualized by immunohistochemistry and semi- quantitative real-time polymerase chain reaction addressed differential gene expression. RESULTS: Treatment with ADSCs significantly increased flap survival (p<0.001) and flap perfusion (p<0.001) when compared to the control group II. Microvessel- density in ADSCs treated group was not significantly increased in any group. No significant differences showed the comparison of the experimental group III and the sham operated control group I. ADSCs treatment (Group III) was accompanied by a significantly enhanced expression of pro-angiogenic and pro-inflammatory genes. CONCLUSION: Overall, our study demonstrates that ADSCs treatment significantly enhances skin flap survival in the aftermath of ischemia to an extent that almost equals surgical results without ischemia. This effect is accompanied with a pronounced and significant angiogenic response and an improved blood perfusion. PMID- 22529017 TI - Induced pluripotent stem cell technology and direct conversion: new possibilities to study and treat Parkinson's disease. AB - Recent developments in in vitro disease modeling and regenerative medicine have placed induced pluripotent stem cells (iPSCs) in the center of attention as a unique source to study Parkinson's disease. After only 5 years of intensive research, human iPSCs can be generated without viral integration and under xeno free conditions. This, combined with increasingly sophisticated methods to differentiate iPSCs into functional dopaminergic (DA) neurons, led us to recapitulate the most important findings concerning the use of iPSC technology as a prospective tool to treat symptoms of Parkinson's disease as well as to obtain insight in disease related cell pathogenesis. Moreover, we touch upon some of the latest discoveries in which patient-derived autologous DA neurons come into even more direct reach thanks to a method that allows transdifferentiation of fibroblasts into DA neurons. PMID- 22529015 TI - Optimization of the cardiovascular therapeutic properties of mesenchymal stromal/stem cells-taking the next step. AB - Despite current treatment options, cardiac failure is associated with significant morbidity and mortality highlighting a compelling clinical need for novel therapeutic approaches. Based on promising pre-clinical data, stem cell therapy has been suggested as a possible therapeutic strategy. Of the candidate cell types evaluated, mesenchymal stromal/stem cells (MSCs) have been widely evaluated due to their ease of isolation and ex vivo expansion, potential allogeneic utility and capacity to promote neo-angiogenesis and endogenous cardiac repair. However, the clinical application of MSCs for mainstream cardiovascular use is currently hindered by several important limitations, including suboptimal retention and engraftment and restricted capacity for bona fide cardiomyocyte regeneration. Consequently, this has prompted intense efforts to advance the therapeutic properties of MSCs for cardiovascular disease. In this review, we consider the scope of benefit from traditional plastic adherence-isolated MSCs and the lessons learned from their conventional use in preclinical and clinical studies. Focus is then given to the evolving strategies aimed at optimizing MSC therapy, including discussion of cell-targeted techniques that encompass the preparation, pre-conditioning and manipulation of these cells ex vivo, methods to improve their delivery to the heart and innovative substrate-directed strategies to support their interaction with the host myocardium. PMID- 22529018 TI - The ontogeny of somatic stem cells. PMID- 22529019 TI - PCr/ATP ratio mapping of the human head by simultaneously imaging of multiple spectral peaks with interleaved excitations and flexible twisted projection imaging readout trajectories at 9.4 T. AB - Quantitative (31)P magnetic resonance imaging of the whole human brain is often time-consuming even at low spatial resolution due to the low concentrations, long T(1) relaxation times, and low detection sensitivity of phosphorus metabolites. We report herein the results of combining the increased detection sensitivity of an ultra-high field 9.4 T scanner designed for human imaging with a new pulse sequence termed simultaneously imaging of multiple spectral peaks with interleaved excitations and flexible twisted projection imaging readout trajectories to rapidly sample multiple resonances in the (31)P spectrum. The phosphocreatine and gamma-adenosine triphosphate images, obtained simultaneously from the entire human head, are demonstrated at 1.5 cm isotropic nominal resolution in a total acquisition time of 33 min. The phosphocreatine/gamma adenosine triphosphate ratio calculated for brain parenchyma (1-2) and the superficial temporalis muscle (3-5) are in agreement with literature values. PMID- 22529020 TI - Identification of prostatic acid phosphatase (PAP) specific HLA-DR1-restricted T cell epitopes. AB - BACKGROUND: Prostatic acid phosphatase (PAP) is a prostate cancer tumor antigen and is an immunological target in several active immunotherapy clinical trials for the treatment of prostate cancer. We and others have demonstrated that PAP specific T-cell responses can be elicited and augmented following antigen specific immunization in both humans and animal models. We have previously reported that prostate cancer patients immunized with a DNA vaccine encoding PAP (pTVG-HP) developed both CD4+ and CD8+ T-cell responses. PAP-specific, CD4+ T cell proliferative responses were generated in three out of four HLA-DRB1*0101 patients suggesting the possibility that DR1-restricted epitopes exist. METHODS: To identify PAP-specific HLA-DRB1*0101 restricted epitopes, we immunized HLA A2.01/HLA-DRB1*0101 (A2/DR1) transgenic mice with the pTVG-HP DNA vaccine. To map DRB1*0101-restricted epitopes, splenocytes from immunized mice were screened against a library of overlapping 15-residue, PAP-derived peptides using an IFNgamma ELISPOT assay. RESULTS: We identified four HLA-DRB1*0101 epitopes for PAP in A2/DR1 mice (PAP(161-175) , PAP(181-195) , PAP(191-205) , and PAP (351 365) ). T cells specific for one epitope (PAP(181-195) ) were found to be augmented after immunization in a HLA-DRB1*0101+ prostate cancer patient. CONCLUSIONS: The identification of MHC class II epitopes may provide tools to directly monitor immune responses after vaccination and may be important for the design of future prostate cancer vaccines. PMID- 22529021 TI - Downregulation of phosphodiesterase 4B (PDE4B) activates protein kinase A and contributes to the progression of prostate cancer. AB - BACKGROUND: Prostate cancer is the most commonly diagnosed non-cutaneous cancer in American men. Unfortunately, few successful therapies for castration-resistant prostate cancer (CRPC) exist. The protein kinase A (PKA) pathway is a critical mediator of cellular proliferation and differentiation in various normal and cancerous cells. However, the PKA activity and the mechanism of regulation in CRPC remain unclear. Then, in this study, we intended to reveal the PKA activity and the mechanism of regulation in CRPC. METHODS: Western blotting, quantitative real-time polymerase chain reaction, cytotoxicity analysis, and cell proliferation assay were used to resolve the regulatory role of PKA in prostate cancer cell line, LNCaP and their derivatives. RESULTS: cAMP-specific phosphodiesterase 4B (PDE4B) was downregulated and the PKA pathway was activated in castration-resistant LNCaP derivatives (CxR cells). Rolipram activated the PKA pathway via inhibition of PDE4B, resulting in AR transactivation while the PKA inhibitor, H89 reduced AR transactivation. In response to hydrogen peroxide and in hydrogen peroxide-resistant LNCaP derivatives (HPR50 cells) PDE4B was decreased and as a result PKA activity was increased. Moreover, PDE4B expression was reduced in advanced prostate cancer and PDE4B knockdown promoted castration resistant growth of LNCaP cells. CONCLUSIONS: Oxidative stress may suppress PDE4B expression and activate the PKA pathway. The PDE4B/PKA pathway contributed to progression of androgen-dependent prostate cancer to CRPC. This pathway may represent an attractive therapeutic molecular target. PMID- 22529022 TI - Homogeneous biogenic paramagnetic nanoparticle synthesis based on a microfluidic droplet generator. PMID- 22529023 TI - Statin medication in patients treated with antiepileptic drugs in Norway. AB - PURPOSE: The lipid-lowering response of statins metabolized by cytochrome P450 3A4 (CYP3A4) has previously been shown to be diminished by concurrent use of enzyme-inducing antiepileptic drugs (EIAEDs). The aim of this study was to compare statin prescription in patients receiving EIAEDs versus non-enzyme inducing antiepileptic drugs (NEIAEDs), before and after introduction of prescribing restrictions for statins in Norway. METHODS: The Norwegian Prescription Database was used to extract data on patients using antiepileptic drugs and statins during 2004 and 2008. Statin type and dose used were compared between patients treated with at least one EIAED (i.e., carbamazepine, phenobarbital, phenytoin, primidone) and those receiving NEIAEDs only (i.e., all other antiepileptic drugs). RESULTS: The number of included patients co-medicated with statins and AEDs was 4855 in 2004 and 9880 in 2008. Among these patients, 2827 and 3160, respectively, were treated with EIAEDs. The CYP3A4 statins (i.e., simvastatin, atorvastatin and lovastatin) accounted for 85% of all statins in 2004, increasing to 93% in 2008. There was no significant difference in the likelihood of being prescribed a CYP3A4 statin versus a non-CYP3A4 statin among patients receiving EIAEDs and NEIAEDs. The average daily dose of individual CYP3A4 statins was not different between the AED groups. CONCLUSIONS: The present study shows that the interaction risk between CYP3A4-metabolized statins and EIAEDs is largely overlooked in Norwegian clinical practice. To avoid therapeutic failure of statin treatment in patients using AEDs, implementation of strategies for systematic management of drug interactions is warranted. PMID- 22529025 TI - Definition and outpatient management of the very low-birth-weight infant with bronchopulmonary dysplasia. AB - Bronchopulmonary dysplasia (BPD), also known as chronic lung disease of prematurity, is the major cause of pulmonary disease in infants. The pathophysiology and management of BPD have evolved over the past four decades as improved neonatal intensive care unit (NICU) modalities have increased survival rates. The likelihood for developing BPD increases with the degree of prematurity and reaches 25-35% in very low-birth-weight and extremely low-birth-weight infants. BPD affects many organ systems, and infants with BPD are at increased risk for rehospitalization and numerous complications following NICU discharge. The management of BPD and medically related problems, particularly during the first 2 years of life, remains a continuing challenge for parents and healthcare providers. It is important that a multidisciplinary team consisting of the neonatologist/attending physician, primary care physician, and other specialized support staff work in concert and meet regularly to provide continuity of care and accurate patient assessments. PMID- 22529024 TI - Acceptance and safety of the intradermal influenza vaccine among the elderly in Italy: an on-field national study. AB - INTRODUCTION: An observational multicenter study was carried out in Italy, to evaluate the acceptability and safety of the new intradermal (ID) influenza vaccine (Intanza Sanofi Pasteur SA, Lyon, France) among subjects aged>=60 years, compared with that of other intramuscular (IM) influenza vaccines. Compliance with the use of the ID vaccine by healthcare professionals was also assessed. METHODS: A previously validated and self-administered questionnaire, Vaccinees' Perception of Injection (VAPI(r)), consisting of 21 questions, mainly focused on four dimensions (bother, arm movements, sleep, and acceptability), was administered to >1,600 individuals with spontaneous access to outpatient clinics, located in Northern, Central, and Southern Italy, to evaluate the acceptance of the vaccines. Occurrence of solicited and unsolicited side effects and of serious adverse events was assessed in a subset of subjects (n=500), using a clinical diary filled in by vaccinees following immunization. Compliance with the new ID vaccine by healthcare professionals was investigated using an ad-hoc questionnaire. RESULTS: A very favorable opinion concerning the acceptability of both the vaccines under survey, with the most positive answers ranging between 75.5% and 94.9%, was registered within the study population. Also the compliance by healthcare professionals (n=130) with the novel ID vaccine was favorable. No serious adverse event occurred during the 6-month follow-up period. The frequency of solicited systemic reactions was comparable between the two study groups, while solicited local reactions were significantly higher in the ID-vaccine group than in the IM-vaccine group, even if at values lower than those reported in phase 3 clinical trials (ranges=18.5-32.6% vs. 29.5-70.9%). These local events were mild and transient, thus without any clinical relevance. CONCLUSION: The novel ID influenza vaccine can be widely recommended in clinical practice, representing a useful tool to improve immunization coverage rates, and thus the control of influenza. PMID- 22529026 TI - Comparison of corneal and aqueous humor penetration of moxifloxacin, gatifloxacin and levofloxacin during keratoplasty. AB - INTRODUCTION: Achieving high antibiotic concentrations is important for preventing and treating postoperative infections. However, no study has simultaneously compared the achieved concentrations of moxifloxacin, gatifloxacin, and levofloxacin in the human cornea and aqueous humor. The authors therefore performed a randomized study to determine the concentrations of 0.5% moxifloxacin, 0.3% gatifloxacin, and 0.5% levofloxacin in the corneal tissue and aqueous humor after topical instillation in patients undergoing penetrating keratoplasty. METHODS: Patients who required penetrating keratoplasty were eligible for this study. The topical preparations of 0.5% moxifloxacin, 0.3% gatifloxacin, and 0.5% levofloxacin used in the study were preservative free (Japanese formulations). Patients were randomly assigned to one of three sequential drug groups, in which each drug was administered three times before surgery. In each administration cycle, the patients received two drops of each drug at 2-minute intervals. Samples of corneal tissue and aqueous humor were collected during surgery. The concentrations of each drug in the samples were determined by high-performance liquid chromatography. RESULTS: A total of 63 patients across eight centers in Japan were enrolled in the study. Overall, 61 corneal and 58 aqueous humor samples were evaluated. The concentration (mean+/ standard deviation) of moxifloxacin in corneal tissues was 12.66+/-8.93 MUg/g, which was significantly higher than that of gatifloxacin (4.71+/-3.39 MUg/g; P<0.0001) and levofloxacin (5.95+/-4.02 MUg/g; P<0.0001). The mean concentration of moxifloxacin in aqueous humor samples was 1.40+/-1.17 MUg/mL, which was significantly higher than that of gatifloxacin (0.65+/-0.80 MUg/mL; P=0.0001) and levofloxacin (0.89+/-0.86 MUg/mL; P<0.05). The sequence of drug administration did not significantly affect the results. CONCLUSION: These results show that 0.5% moxifloxacin achieved superior ocular concentration than both 0.3% gatifloxacin and 0.5% levofloxacin. PMID- 22529028 TI - Assessment of a five-layer laminate technique to measure the saturation solubility of drug in pressure-sensitive adhesive film. AB - A five-layer laminate technique is used to determine the saturation solubility of a drug in a thin polymer film, c(p)(s), of pressure-sensitive adhesive (PSA) used to prepare transdermal patches. A drug-loaded donor polymer film is attached via a separating membrane to an initially drug-free acceptor polymer film. Diffusion of drug occurs into the acceptor up to saturation solubility equilibrium. This systematic study of the technique using the drug tamsulosin and the PSA Duro Tak 87-4098 was a kinetic analysis of the diffusion process. It was found that the technique gives an equilibrium value for c(p)(s) in a PSA polymer film in the presence of crystalline phase of the drug in the donor. A highly permeable Perthese-separating membrane caused overshoot in the acceptor, most likely induced by initial supersaturation of the donor. Change to a less-permeable ethylene-vinyl-acetate-separating membrane avoided overshoot, but gave a prolonged time, >300 days, to equilibrium. Preloading the acceptor accelerated the equilibration process to approximately 50 days with the Perthese. Suitable experimental conditions are identified that, if performed correctly, allow the technique to give an equilibrium value for c(p)(s). PMID- 22529027 TI - Management of diabetic foot ulcers. AB - Diabetic foot is a serious complication of diabetes which aggravates the patient's condition whilst also having significant socioeconomic impact. The aim of the present review is to summarize the causes and pathogenetic mechanisms leading to diabetic foot, and to focus on the management of this important health issue. Increasing physicians' awareness and hence their ability to identify the "foot at risk," along with proper foot care, may prevent diabetic foot ulceration and thus reduce the risk of amputation. PMID- 22529029 TI - A comparative study on structure-property elucidation of P3/4HB and PEG-based block polyurethanes. AB - A series of alternating block polyurethanes (abbreviated as PU3/4HB-alt-PEG) and random block polyurethanes (abbreviated as PU3/4HB-ran-PEG) based on biodegradable polyester poly(3-hydroxybutyrate-co-4-hydroxybutrate) (P3/4HB-diol) and poly(ethylene glycol) (PEG) with similar chemical compositions were synthesized using 1, 6-hexamethylene diisocyanate (HDI) as coupling agent. The chemical structure, molecular weight and distribution were characterized by FTIR, (1)H NMR, and GPC. The thermal differences were investigated by DSC. The hydrophilicity was studied by static contact angle and the results revealed that PU3/4HB-alt-PEG is more hydrophilic with a higher surface energy than PU3/4HB-ran PEG. With SEM observation, PU3/4HB-alt-PEG exhibited a regular characterized microstructure with flower-type patterns on the surface, while PU3/4HB-ran-PEG displayed no regular pattern. A platelet adhesion study illustrated that PU3/4HB alt-PEG possesses better hemocompatibility due to its more hydrophilic surface and evident surface microstructure. The cell culture assay demonstrated that fibroblasts and rat glial cells were more favorable for attachment on PU3/4HB-alt PEG films. By comparison, alternating block polyurethanes provides a way to control the exact structure of the biomaterials and tailor better properties to biomedical requirements. PMID- 22529030 TI - Structure-activity relationships and mechanism of action of Eph-ephrin antagonists: interaction of cholanic acid with the EphA2 receptor. AB - The Eph-ephrin system, including the EphA2 receptor and the ephrinA1 ligand, plays a critical role in tumor and vascular functions during carcinogenesis. We previously identified (3alpha,5beta)-3-hydroxycholan-24-oic acid (lithocholic acid) as an Eph-ephrin antagonist that is able to inhibit EphA2 receptor activation; it is therefore potentially useful as a novel EphA2 receptor targeting agent. Herein we explore the structure-activity relationships of a focused set of lithocholic acid derivatives based on molecular modeling investigations and displacement binding assays. Our exploration shows that while the 3-alpha-hydroxy group of lithocholic acid has a negligible role in recognition of the EphA2 receptor, its carboxylate group is critical for disrupting the binding of ephrinA1 to EphA2. As a result of our investigation, we identified (5beta)-cholan-24-oic acid (cholanic acid) as a novel compound that competitively inhibits the EphA2-ephrinA1 interaction with higher potency than lithocholic acid. Surface plasmon resonance analysis indicates that cholanic acid binds specifically and reversibly to the ligand binding domain of EphA2, with a steady-state dissociation constant (K(D) ) in the low micromolar range. Furthermore, cholanic acid blocks the phosphorylation of EphA2 as well as cell retraction and rounding in PC3 prostate cancer cells, two effects that depend on EphA2 activation by the ephrinA1 ligand. These findings suggest that cholanic acid can be used as a template structure for the design of effective EphA2 antagonists, and may have potential impact in the elucidation of the role played by this receptor in pathological conditions. PMID- 22529031 TI - Characterization of a new human melanoma cell line with CD133 expression. AB - A novel human malignant melanoma cell line, designated MEL-RC08, was established from a pericranial metastasis of a malignant melanoma of the skin. The cell line has been subcultured for more than 150 passages and is tumorigenic in nude mice. Growth kinetics, cytogenetics, flow cytometry, and molecular techniques for analysis of the genes implicated in cell cycle control; mutations in BRAF, NRAS, C-KiT, RB, and TP53 genes; and amplification of MDM2, CDK4, and cyclin D1 have been studied. Cytogenetically, the tumor and the cell line showed a hypertriploid karyotype with many clonal numeric and structural abnormalities. DNA flow cytometry showed an aneuploid peak with a DNA index value of 1.5. Mutations in TP53 and BRAF genes were demonstrated in both tumor and cell line. Furthermore, stem cell marker CD133 expression was detected in most cells, together with other stem cell markers, suggesting the presence of cells with tumor-initiating potential in this cell line. PMID- 22529033 TI - Templating assembly of multifunctional hybrid colloidal spheres. AB - 3D hybrid colloidal spheres with integrated functions and collective properties are fabricated using a variety of common inorganic nano-objects as building blocks in association with polyelectrolyte encapsulation through a facile template strategy. The fabrication strategy is generally suited for design of functional colloidal spheres in a simple and controllable manner, and thus opens a new avenue for developing hybrid materials with multiple functions and collective properties. PMID- 22529032 TI - Ensheathing cell-conditioned medium directs the differentiation of human umbilical cord blood cells into aldynoglial phenotype cells. AB - Despite their similarities to bone marrow precursor cells (PC), human umbilical cord blood (HUCB) PCs are more immature and, thus, they exhibit greater plasticity. This plasticity is evident by their ability to proliferate and spontaneously differentiate into almost any cell type, depending on their environment. Moreover, HUCB-PCs yield an accessible cell population that can be grown in culture and differentiated into glial, neuronal and other cell phenotypes. HUCB-PCs offer many potential therapeutic benefits, particularly in the area of neural replacement. We sought to induce the differentiation of HUCB PCs into glial cells, known as aldynoglia. These cells can promote neuronal regeneration after lesion and they can be transplanted into areas affected by several pathologies, which represents an important therapeutic strategy to treat central nervous system damage. To induce differentiation to the aldynoglia phenotype, HUCB-PCs were exposed to different culture media. Mononuclear cells from HUCB were isolated and purified by identification of CD34 and CD133 antigens, and after 12 days in culture, differentiation of CD34+ HUCB-PCs to an aldynoglia phenotypic, but not that of CD133+ cells, was induced in ensheathing cell (EC)-conditioned medium. Thus, we demonstrate that the differentiation of HUCB-PCs into aldynoglia cells in EC-conditioned medium can provide a new source of aldynoglial cells for use in transplants to treat injuries or neurodegenerative diseases. PMID- 22529034 TI - Simplified gyral pattern with cerebellar hypoplasia in Sedaghatian type spondylometaphyseal dysplasia: a clinical report and review of the literature. AB - We report on a patient with Sedaghatian type spondylometaphyseal dysplasia (SSMD) who presented with metaphyseal dysplasia, congenital atrioventricular block, simplified gyral pattern, hypogenesis of corpus callosum, and severe cerebellar hypoplasia. We want to emphasize that in this rare congenital lethal skeletal dysplasia with unknown etiology, central nervous system malformations might be a major component of the disorder and should be evaluated in detail to possibly uncover the underlying pathophysiology. PMID- 22529035 TI - Youth in group home care: youth characteristics and predictors of later functioning. AB - This paper presents the findings of an exploratory research study of foster care youth residing in group homes in a mid-Atlantic state in the USA. The aims of the present study were to (1) describe youth characteristics, (2) explore whether baseline functioning differed by gender or ethnicity, (3) explore predictors of cross-time differences in psychosocial functioning, and (4) explore predictors of later functioning, specifically age, gender, and length of stay. Psychosocial functioning at two time points (i.e., T1 = admission into group home; T2 = current or discharge) in 180 charts from 29 randomly selected group homes were reviewed. Youth were on average 14.86 years of age, predominantly male (71%; n = 128), and predominantly African American (79%). Findings suggest that group home placement may benefit some youth but not others, particularly girls and younger children with lower initial level of need. Findings underscore the potential complexity of intervention impact in the context of unique youth, family, and environment factors. PMID- 22529036 TI - A neurobehavioral intervention incorporated into a state early intervention program is associated with higher perceived quality of care among parents of high risk newborns. AB - The purpose of this study is to compare two models of early intervention (EI) service delivery-a neurobehavioral intervention and usual care-on parents' perceived quality of EI service delivery. Families of newborns referred to EI were randomly assigned to a neurobehavioral intervention or usual care group and followed until the infant was 12 weeks corrected gestational age. The intervention group (n = 25) received a weekly neurobehavioral intervention. The usual care group (n = 13) received standard weekly home visits. Mothers completed the Home Visiting Index (HVI) measuring the quality of EI service delivery. Mixed linear regression was used to examine group differences in quality scores. The intervention group reported higher quality of care related to facilitating optimal parent-infant social interaction (mean difference = 2.17, 95% CI: 0.41, 3.92).A neurobehavioral model of service delivery can be successfully integrated into EI programming and appears to be associated with higher parent-reported perceived quality. PMID- 22529037 TI - A systematic review and meta-analysis of willingness-to-pay values: the case of malaria control interventions. AB - The increasing use of willingness to pay (WTP) to value the benefits of malaria control interventions offers a unique opportunity to explore the possibility of estimating a transferable indicator of mean WTP as well as studying differences across studies. As regression estimates from individual WTP studies are often assumed to transfer across populations it also provides an opportunity to question this practice. Using a qualitative review and meta analytic methods, this article determines what has been studied and how, provides a summary mean WTP by type of intervention, considers how and why WTP estimates vary and advises on future reporting of WTP studies. WTP has been elicited mostly for insecticide treated nets, followed by drugs for treatment. Mean WTP, including zeros, is US$2.79 for insecticide-treated nets, US$6.65 for treatment and US$2.60 for other preventive services. Controlling for a limited number of sample and design effects, results can be transferred to different countries using the value function. The main concerns are the need to account for a broader range of explanators that are study specific and the ability to transfer results into malaria contexts beyond those represented by the data. Future studies need to improve the reporting of WTP. PMID- 22529038 TI - Measurement of vibration-induced volumetric strain in the human lung. AB - Noninvasive image-based measurement of intrinsic tissue pressure is of great interest in the diagnosis and characterization of diseases. Therefore, we propose to exploit the capability of phase-contrast MRI to measure three-dimensional vector fields of tissue motion for deriving volumetric strain induced by external vibration. Volumetric strain as given by the divergence of mechanical displacement fields is related to tissue compressibility and is thus sensitive to the state of tissue pressure. This principle is demonstrated by the measurement of three-dimensional vector fields of 50-Hz oscillations in a compressible agarose phantom and in the lungs of nine healthy volunteers. In the phantom, the magnitude of the oscillating divergence increased by about 400% with 4.8 bar excess air pressure, corresponding to an effective-medium compression modulus of 230 MPa. In lungs, the averaged divergence magnitude increased in all volunteers (N = 9) between 7 and 78% from expiration to inspiration. Measuring volumetric strain by MRI provides a compression-sensitive parameter of tissue mechanics, which varies with the respiratory state in the lungs. In future clinical applications for diagnosis and characterization of lung emphysema, fibrosis, or cancer, divergence-sensitive MRI may serve as a noninvasive marker sensitive to disease-related alterations of regional elastic recoil pressure in the lungs. PMID- 22529039 TI - Bound cations significantly stabilize the structure of multiprotein complexes in the gas phase. PMID- 22529041 TI - Conceptualizing psychosocial risk factors for cardiovascular disease: a comment on Ewart et al. PMID- 22529042 TI - Type D personality and heart disease: walking the line between enthusiasm and disbelief. PMID- 22529040 TI - Belief in divine control, coping, and race/ethnicity among older women with breast cancer. AB - BACKGROUND: Belief in divine control is often assumed to be fatalistic. However, the assumption has rarely been investigated in racial/ethnic minorities. OBJECTIVES: This study aims to examine the association between belief in divine control and coping and how the association was moderated by ethnicity/acculturation in a multi-ethnic sample of breast cancer patients. METHODS: Latina, African American, and non-Hispanic White older women with newly diagnosed breast cancer (N=257) from a population-based survey completed the scale of Belief in Divine Control and the Brief COPE. RESULTS: Belief in divine control was positively related to approach coping (i.e., positive reframing, active coping, and planning) in all ethnic groups. Belief in divine control was positively related to acceptance and negatively related to avoidance coping (i.e., denial and behavioral disengagement) among low-acculturated Latinas. CONCLUSIONS: Negative presumptions about fatalistic implications of belief in divine control should be critically reappraised, especially when such skepticism is applied to racial/ethnic minority patients. PMID- 22529044 TI - Hemodynamic profile in rabbits of fospropofol disodium injection relative to propofol emulsion following rapid bolus injection. AB - The effects of aqueous fospropofol disodium (FP) and propofol emulsion (PE) on hemodynamics and sympathetic nerve activity in rabbits following bolus injection were evaluated. Barodenervated and neuraxis-intact rabbits received PE at 4 mg/kg (PE(4)) or FP equal to 4 or 8 mg/kg propofol equivalents (FP(4) and FP(8), respectively) intravenously as a rapid bolus injection, and mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were recorded for 20 min. The plasma propofol pharmacokinetic behavior from FP and PE was evaluated to support the pharmacodynamic observations. In barodenervated animals, MAP and RSNA decreased significantly in all groups (PE(4) > FP(8) > FP(4)). HR decreased only in the PE(4) group. The time for the maximum reduction of MAP was significantly longer with FP(8) compared with PE(4). MAP decreased, and RSNA and HR increased significantly in the neuraxis-intact animals (PE(4) > FP(8) > FP(4)). The time for maximum reduction of MAP was essentially the same in all neuraxis-intact groups. Plasma propofol levels from FP were lower than those from PE in the first 4 min following administration. The results suggest that the tachycardia observed in humans following injection of FP is not a direct physiological effect of the agent. PMID- 22529045 TI - Stirred flow bioreactor modulates chondrocyte growth and extracellular matrix biosynthesis in chitosan scaffolds. AB - The aim of this study is to show the favorable effect of simple dynamic culture conditions on chondrogenesis of previously expanded human chondrocytes seeded in a macroporous scaffold with week cell-pore walls adhesion. We obtained enhanced chondrogenesis by the combination of chitosan porous supports with a double micro and macro-pore structure and cell culture in a stirring bioreactor. Cell scaffold constructs were cultured under static or mechanically stimulated conditions using an intermittent stirred flow bioreactor during 28 days. In static culture, the chondrocytes were homogeneously distributed throughout the scaffold pores; cells adhered to the scaffold pore walls, showed extended morphology and were able to proliferate. Immunofluorescense and biochemical assays showed abundant type I collagen deposition at day 28. However, the behavior of chondrocytes submitted to mechanical stimuli in the bioreactor was completely different. Mechanical loading influenced cell morphology and extracellular matrix composition. Under dynamic conditions, chondrocytes kept their characteristic phenotype and tended to form cell aggregates surrounded by a layer of the main components of the hyaline cartilage extracellular matrix, type II collagen, and aggrecan. An enhanced aggrecan and collagen type II production was observed in engineered cartilage constructs cultured under stirred flow compared with those cultured under static conditions. PMID- 22529046 TI - 2,3,4,5-Tetraphenylsilole-based conjugated polymers: synthesis, optical properties, and as sensors for explosive compounds. AB - A series of linear 2,5-tetraphenylsilole-vinylene-type polymers were successfully synthesized for the first time. The tetraphenylsilole moieties were linked at their 2,5-positions through a vinylene bridge with p-dialkoxybenzenes to obtain polymer PSVB and with 3,6-carbazole to obtain polymer PSVC. For comparison, 2,5 tetraphenylsilole-ethyne-type polymer PSEB was also synthesized, in which the vinylene bridge of PSVB was replaced with an ethyne bridge. Very interestingly, the bridging group (vinylene or ethyne) had a significant effect on the photophysical properties of the corresponding polymers. The fluorescence peak of PSEB at 504 nm in solution originated from the emission of its silole moieties, whereas PSVB and PSVC emitted yellow light and no blueish-green emission from the silole moieties was observed, thus demonstrating that the emissions of PSVB and PSVC were due to their polymer backbones. More importantly, the 2,5 tetraphenylsilole-ethyne polymer exhibited a pronounced aggregation-enhanced emission (AEE) effect but the 2,5-tetraphenylsilole-vinylene polymer was AEE inactive. Moreover, both AEE-active 2,5-tetraphenylsilole-ethyne polymer and AEE inactive 2,5-tetraphenylsilole-vinylene polymers were successfully applied as fluorescent chemosensors for the detection of explosive compounds. PMID- 22529047 TI - Complex genomic rearrangement in the SOX9 5' region in a patient with Pierre Robin sequence and hypoplastic left scapula. AB - Pierre Robin sequence (PRS) can occur as a component of campomelic dysplasia (CD) and acampomelic CD (ACD) caused by dysfunction or dysregulation of SOX9, although it can also take place as an isolated form. Recently, genomic alterations in the far upstream and the far downstream region of SOX9 have been identified in patients with isolated PRS. Here, we report on a male patient with PRS and a heterozygous genomic rearrangement in the 5' region of SOX9. Clinical analysis revealed PRS-compatible craniofacial anomalies, mild hypoplasia of the left scapula, and normal male external genitalia. Molecular analysis identified a paracentric inversion on the long arm of chromosome 17 with breakpoints at 17q21.31 and 17q24.3, and a microdeletion spanning from -4.15 to -1.16 Mb relative to SOX9. These findings indicate that the chromosomal region more than 1.16 Mb apart from SOX9 contains at least one developmental enhancer(s) for SOX9 that plays a critical role in the development of the mandible and a relatively small role in the development of the scapula. Moreover, the concept of exclusion mapping argues that putative CD/ACD loci are located within the 1.16 Mb region closest to SOX9 coding exons, which remain intact in this Non-CD/ACD patient. This study provides a novel example for long-range cis-regulatory mutations of SOX9. PMID- 22529048 TI - Three new triterpenoids from Panax ginseng exhibit cytotoxicity against human A549 and Hep-3B cell lines. AB - Three new triterpenoid derivatives, 3-O-beta-D-glucopyranosyl-20(S) protopanaxtriol (1), 3-formyloxy-20-O-beta-D-glucopyranosyl-20(S)-protopanaxtriol (2) and 26-hydroxyl-24(E)-20(S)-protopanaxtriol (3), along with six known ginsenosides, were isolated from leaves of Panax ginseng. Their structures were established on the basis of spectral analysis (IR, 1D and 2D NMR, HRESI-MS). Compounds 1-3 exhibited various degree of cytotoxicity towards human A549 pulmonary carcinoma cells and Hep3B hepatoma cells. PMID- 22529049 TI - Collagenase inhibitors from Viola yedoensis. AB - Fractionation of acetone and methanol extracts of Viola yedoensis, under the guidance of inhibition against Clostridium histolyticum collagenase (ChC), resulted in the isolation of esculetin (1) (IC(50) 12 MUM) and scopoletin (2) (IC(50) 1.8 MUM) as the active constituents, together with trans-p-coumaric acid (3), cis-p-coumaric acid (4), 3-O-beta-D-glucosyl-7-O-alpha-L-rhamnosylkaempferol (5), rutin (6), isovitexin (7), isoorientin (8), vicenin-2 (9), isoscoparin (10), vanillic acid (11) and adenosine (12). Modification of phenolic hydroxy groups of 1 showed that small O-alkyl groups largely increased the activity, whereas larger O-alkyl groups decreased the activity, and 6,7-dimethoxycoumarin (scoparone 13) potently inhibited ChC (IC(50) 24 nM). PMID- 22529050 TI - Anti-inflammatory activity of diterpenes from Croton stellatopilosus on LPS induced RAW264.7 cells. AB - An acyclic diterpene (plaunotol; 1) and two furanoditerpenes (plaunolide, 2 and plaunol E, 3), were isolated from Croton stellatopilosus leaves, and assessed for their inhibitory activity on nitric oxide (NO) production by lipopolysaccharide (LPS)-induced RAW264.7 cells. Plaunotol, plaunolide and plaunol E exhibited inhibitory activity with IC(50) values of 3.41, 17.09 and 2.79 MUM, respectively. Cytotoxic effects were observed at concentrations of >=100 MUM for plaunotol and >=10 MUM for plaunol E. In order to understand the mechanism of this anti inflammatory activity, transcription profiles of the COX-1, COX-2 and iNOS genes were measured using a quantitative RT-PCR technique. The level of gene expression was expressed as a relative quantitation according to the comparative C (T) method. The results indicated that plaunotol stimulated the COX-1 and COX-2 genes, and suppressed expression of the iNOS gene. Treatment of cells with plaunolide caused a downregulation of the expressions of the COX-1, COX-2 and iNOS genes. In contrast, plaunol E inhibited the expression of the COX-2, stimulated COX-1 and iNOS expressions. In summary, the present study shows that different diterpenes from C. stellatopilosus leaves exhibit anti-inflammatory activity towards LPS-activated RAW264.7 cells by different mechanisms. Our results provide data to support further investigations into the possibility that these diterpenes could be alternatives to act as anti-inflammatory agents. PMID- 22529051 TI - Chemical analysis reveals the botanical origin of shatavari products and confirms the absence of alkaloid asparagamine A in Asparagus racemosus. AB - Shatavari-a famous Ayurveda materia medica used mainly as a tonic for women-is distributed in health food products all over the world. The Ayurvedic Pharmacopoeia of India identifies the botanical origin of shatavari as the tuberous root of Asparagus racemosus. We recently investigated by DNA analysis the botanical origin of shatavari products on the Japanese market. The results suggested that their botanical origin was Asparagus; however, species identification was difficult. In this study, we analyzed steroidal saponins, including those specific to this plant, in these products and confirmed their origin as A. racemosus. Next, alkaloid analyses of an authentic A. racemosus plant and these products were performed, because several papers have reported the isolation of a pyrrolo[1,2-a]azepine alkaloid, asparagamine A, from this plant. Our results suggest that neither plant material nor products contained asparagamine A. It has been pointed out that Stemona plants are sometimes mistaken for shatavari, because their tuberous roots have a similar shape to that of A. racemosus, and pyrrolo[1,2-a]azepine alkaloids are thought to be Stemona specific. These data strongly suggest that A. racemosus does not contain asparagamine A, and that previous isolation of asparagamine A from materials claimed as originating from A. racemosus was likely caused by misidentification of Stemona plants as A. racemosus. PMID- 22529052 TI - Stereoselective palladium-catalyzed functionalization of homoallylic alcohols: a convenient synthesis of di- and trisubstituted isoxazolidines and beta-amino delta-hydroxy esters. AB - Enantiopure, Boc-protected alkoxyamines 12 and 13, derived from the readily available homoallylic alcohols 4 via a reaction that involves either inversion or retention of configuration, undergo a diastereoselective Pd-catalyzed ring closing carbonylative amidation to produce isoxazolidines 16/17 (<=50:1 diastereoisomer ratio (d.r.)) that can be readily converted into the N-Boc protected esters of beta-amino-delta-hydroxy acids and their gamma-substituted homologues 37. The key carbonylative cyclization proceeds through an unusual syn addition of the palladium and the nitrogen nucleophile across the C=C bond (19 >21), as revealed by the reaction of 15, which afforded isoxazolidine 18 with high diastereoselectivity. PMID- 22529053 TI - Efficiency and equity: a stated preference approach. AB - Outcome measurement in the economic evaluation of health care considers outcomes independent of to whom they accrue. This article reports on a discrete choice experiment designed to elicit population preferences regarding the allocation of health gain between hypothetical groups of potential patients. A random-effects probit model is estimated, and a technique for converting these results into equity weights for use in economic evaluation is adopted. On average, the modelling predicts a relatively high social value on health gains accruing to nonsmokers, carers, those with a low income and those with an expected age of death less than 45 years. Respondents tend to favour individuals with similar characteristics to themselves. These results challenge the conventional practice of assuming constant equity weighting. For decision makers, whether a formal equity weighting system represents an improvement on more informal approaches to weighing up equity and efficiency concerns remains uncertain. PMID- 22529054 TI - Switch of selectivity in the synthesis of alpha-methylene-gamma-lactones: palladium-catalyzed intermolecular carboesterification of alkenes with alkynes. PMID- 22529055 TI - Quality of life in patients with hereditary hemorrhagic telangiectasia in Norway: a population based study. AB - Hereditary hemorrhagic telangiectasia (HHT) is a rare, autosomal dominant disease characterized by the presence of recurrent epistaxis and small characteristic malformations of the peripheral blood vessels near the surface of the skin or mucosal linings. Arteriovenous malformations (AVM) of the lung, liver, and CNS are also known clinical findings. The purpose of this study was to examine quality of life (QoL) in patients with HHT in Norway. Sixty-six affected patients (39 women and 27 men) were included. QoL on overall-, health-related (HR-QoL), and disease-specific levels were measured with Cantril's Ladder (CL), Short Form 36 (SF-36), and a Symptom-specific QoL question in HHT patients (SFB-HHT-Q), respectively. Comparisons were made between patients and an age and gender adjusted normative sample from the Norwegian population (N = 990). Overall, the results reflected that several HHT disease-related variables were associated with reduced QoL on all three levels; overall QoL (CL), HR-QoL (SF36) as well as disease-specific QoL (SFB-HHT-Q), while demographic variables impacted HR-QoL in HHT patients. Compared to the normative sample, all subscales of SF36, but bodily pain, were significantly poorer in the HHT patients. HHT disease variables had the strongest association with QoL compared to demographic variables. The results substantiate that disease severity is associated with poorer QoL in this patients. Pain contributed independently to all levels of QoL. PMID- 22529056 TI - Zinc-diluted magnetic metal formate perovskites: synthesis, structures, and magnetism of [CH3NH3][Mn(x)Zn(1-x)(HCOO)3] (x = 0-1). AB - The preparation, structures, and magnetic properties of a series of metal formate perovskites [CH(3)NH(3)][Mn(x)Zn(1-x)(HCOO)(3)] were investigated. The isostructural solid solution can be prepared in the complete range of x=0-1. The metal-organic perovskite structures consist of an anionic NaCl type [Mn(x)Zn(1 x)(HCOO)(3)(-)] framework with CH(3)NH(3)(+) templates located in the nearly cubic cavities and forming hydrogen bonds to the framework. When the proportion of Mn increased (i.e., x changed from 0 to 1), the lattice dimensions and metal oxygen and metal-metal distances show a slight, nonlinear increase because of the increased averaged metal ionic radius and the local structure distortion. Through the series, the magnetism changes from the long-range ordering of spin-canted antiferromagnetism for x>=0.40 to paramagnetism when x<=0.30, and the percolation limit was estimated to be x(P)=0.31(2) for this simple cubic lattice. In the low temperature region, enhancement of magnetization and the gradual decrease and final disappearance of coercive field, remnant magnetization, and spin-flop field upon dilution were observed through this isotropic Heisenberg magnetic series. IR spectroscopic and thermal properties were also investigated. PMID- 22529058 TI - Structures and dynamic solution behavior of cationic, two-coordinate gold(I)-pi allene complexes. AB - A family of seven cationic gold complexes that contain both an alkyl substituted pi-allene ligand and an electron-rich, sterically hindered supporting ligand was isolated in >90% yield and characterized by spectroscopy and, in three cases, by X-ray crystallography. Solution-phase and solid-state analysis of these complexes established preferential binding of gold to the less substituted C=C bond of the allene and to the allene pi face trans to the substituent on the uncomplexed allenyl C=C bond. Kinetic analysis of intermolecular allene exchange established two-term rate laws of the form rate=k(1)[complex]+k(2)[complex][allene] consistent with allene-independent and allene-dependent exchange pathways with energy barriers of DeltaG(?)(1)=17.4-18.8 and DeltaG(?)(2)=15.2-17.6 kcal mol( 1), respectively. Variable temperature (VT) NMR analysis revealed fluxional behavior consistent with facile (DeltaG(?)=8.9-11.4 kcal mol(-1)) intramolecular exchange of the allene pi faces through eta(1)-allene transition states and/or intermediates that retain a staggered arrangement of the allene substituents. VT NMR/spin saturation transfer analysis of [{P(tBu)(2)o-binaphthyl}Au(eta(2)-4,5 nonadiene)](+)SbF(6)(-) (5), which contains elements of chirality in both the phosphine and allene ligands, revealed no epimerization of the allene ligand below the threshold for intermolecular allene exchange (DeltaG(?)(298K)=17.4 kcal mol(-1)), which ruled out the participation of a eta(1)-allylic cation species in the low-energy pi-face exchange process for this complex. PMID- 22529057 TI - Synthesis of cationic magnetic nanoparticles and evaluation of their gene delivery efficacy in Hep G2 cells. AB - Well-defined cationic polymers were synthesized via the reversible addition fragmentation chain transfer polymerization and were subsequently used as stabilizer for the synthesis of cationic iron-oxide magnetic nanoparticles via the coprecipitation method. The surface-coated iron-oxide nanoparticles made stable suspension in water and were characterized by a range of techniques such as dynamic light scattering, transmission electron microscopy, and thermogravimetric analysis. The presence of protonated amine and carbohydrate residues onto the surface of the nanoparticles allowed their facile complexation with DNA and the resulting nanocomplexes were then studied for their efficacy as DNA carriers in Hep G2 cells. PMID- 22529059 TI - Synergistic effect on the photoactivation of the methane C-H bond over Ga(3+) modified ETS-10. PMID- 22529060 TI - Rare copy number variants in isolated sporadic and syndromic atrioventricular septal defects. AB - Atrioventricular septal defects (AVSDs) are a frequent but not universal component of Down syndrome (DS), while AVSDs in otherwise normal individuals have no well-defined genetic basis. The contribution of copy number variation (CNV) to specific congenital heart disease (CHD) phenotypes including AVSD is unknown. We hypothesized that de novo CNVs on chromosome 21 might cause isolated sporadic AVSDs, and separately that CNVs throughout the genome might constitute an additional genetic risk factor for AVSD in patients with DS. We utilized a custom oligonucleotide arrays targeted to CNV hotspots that are flanked by large duplicated segments of high sequence identity. We assayed 29 euploid and 50 DS individuals with AVSD, and compared to general population controls. In patients with isolated-sporadic AVSD we identified two large unique deletions outside of chromosome 21 not seen in the expanded set of 8,635 controls, each overlapping with larger deletions associated with similar CHD reported in the DECIPHER database. There was a small duplication in one patient with DS and AVSD. We conclude that isolated sporadic AVSDs may be occasionally associated with large de novo genomic structural variation outside of chromosome 21. The absence of CNVs on chromosome 21 in patients with isolated sporadic AVSD suggests that sub chromosomal duplications or deletions of greater than 150 kbp on chromosome 21 do not cause sporadic AVSDs. Large CNVs do not appear to be an additive risk factor for AVSD in the DS population. PMID- 22529061 TI - Ruthenium-catalyzed intramolecular [2+2+2] cyclization of allene-yne-enes: construction of fused-tricyclic skeletons. AB - Three's not a crowd: An intramolecular [2+2+2] cyclization between three different components, allene, alkyne, and alkene, has been realized using a catalytic amount of [Cp*RuCl(cod)] complex (cod = 1,5-cyclooctadiene), and afforded fused-tricyclic compounds in a highly stereoselective manner. PMID- 22529062 TI - On the origin of the 1602 cm-1 Raman band of yeasts; contribution of ergosterol. AB - The 1602 cm(-1) Raman signature, which we call the "Raman spectroscopic signature of life" in yeasts, is a marker Raman band for cell metabolic activity. Despite the established fact that its intensity sensitively reflects the metabolic status of the cell, its molecular origin remained unclear. In this work, we propose ergosterol as the major contributor of the 1602 cm(-1) Raman signature. The theoretical isotope shift calculation for ergosterol agreed with previous observations. Furthermore, experiments showed that the Raman spectrum of ergosterol corresponds very well with the depleting spectral component in yeast that behaves together with the 1602 cm(-1) signature when the cells are under stress. This work implies that the 1602 cm(-1) Raman signature could serve as an intrinsic ergosterol marker in yeasts for the study of sterol metabolism in vivo and in a label-free manner, which could not be done by any other techniques at the current stage. PMID- 22529063 TI - High-temperature proton-exchange-membrane fuel cells using an ether-containing polybenzimidazole membrane as electrolyte. AB - Herein, poly[2,2'-(p-oxydiphenylene)-5,5'-benzimidazole] (PBI) is synthesized from 3,3'-diaminobenzidine and 4,4'-oxybisbenzoic acid, and the membrane is prepared by solvent casting. The main characteristics of PBI are studied. In the preparation of the PBI/H(3) PO(4) composite membrane, the absorbing temperature of H(3) PO(4) is 120 degrees C, which leads to a membrane with a high content of H(3) PO(4) . Membrane electrode assemblies (MEAs) are fabricated from PBI/H(3) PO(4) membranes with the catalyst layer made of Pt/C, PBI, and polyvinylidene fluoride (230:12:7 w/w). The fabricated MEA is tested at 150 degrees C with dry hydrogen and oxygen gas at 0.2 MPa for both anode and cathode feeds. No degradation of voltage is seen during stability testing of the PBI/H(3) PO(4) membrane at a constant current for 100 h. The maximum power density is 1.17 W cm( 2) , and the maximum current density is 6.0 A cm(-2) with a Pt loading of 0.5 mg cm(-2) . The high performance of these membrane materials demonstrates that PBI can be regarded as an alternative membrane material for high-temperature proton exchange-membrane fuel cells. PMID- 22529064 TI - Sudden cardiac death and genetic ion channelopathies: long QT, Brugada, short QT, catecholaminergic polymorphic ventricular tachycardia, and idiopathic ventricular fibrillation. PMID- 22529065 TI - Has the time come for a national cardiovascular emergency care system? PMID- 22529066 TI - Mediastinal fibrosis mimicking proximal chronic thromboembolic disease. PMID- 22529067 TI - Cardiology patient page: stroke prevention in atrial fibrillation. PMID- 22529068 TI - Aorto-right ventricular tunnel causing functional tricuspid atresia. PMID- 22529069 TI - Recent progress in the understanding and management of postoperative right ventricular outflow tract dysfunction in patients with congenital heart disease. PMID- 22529071 TI - Letter by Lumley et al regarding article, "arterial pulse wave dynamics after percutaneous aortic valve replacement: fall in coronary diastolic suction with increasing heart rate as a basis for angina symptoms in aortic stenosis". PMID- 22529072 TI - Letter by Bernstein et al regarding article, "reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. PMID- 22529073 TI - Letter by Marlu et al regarding article, "reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects". PMID- 22529074 TI - Indications for reverse shoulder replacement: a systematic review. AB - The outcome of an anatomical shoulder replacement depends on an intact rotator cuff. In 1981 Grammont designed a novel large-head reverse shoulder replacement for patients with cuff deficiency. Such has been the success of this replacement that it has led to a rapid expansion of the indications. We performed a systematic review of the literature to evaluate the functional outcome of each indication for the reverse shoulder replacement. Secondary outcome measures of range of movement, pain scores and complication rates are also presented. PMID- 22529075 TI - Haematogenous acute and subacute paediatric osteomyelitis: a systematic review of the literature. AB - A delay in the diagnosis of paediatric acute and subacute haematogenous osteomyelitis can lead to potentially devastating morbidity. There are no definitive guidelines for diagnosis, and recommendations in the literature are generally based on expert opinions, case series and cohort studies. All articles in the English literature on paediatric osteomyelitis were searched using MEDLINE, CINAHL, EMBASE, Google Scholar, the Cochrane Library and reference lists. A total of 1854 papers were identified, 132 of which were examined in detail. All aspects of osteomyelitis were investigated in order to formulate recommendations. On admission 40% of children are afebrile. The tibia and femur are the most commonly affected long bones. Clinical examination, blood and radiological tests are only reliable for diagnosis in combination. Staphylococcus aureus is the most common organism detected, but isolation of Kingella kingae is increasing. Antibiotic treatment is usually sufficient to eradicate the infection, with a short course intravenously and early conversion to oral treatment. Surgery is indicated only in specific situations. Most studies were retrospective and there is a need for large, multicentre, randomised, controlled trials to define protocols for diagnosis and treatment. Meanwhile, evidence-based algorithms are suggested for accurate and early diagnosis and effective treatment. PMID- 22529076 TI - Management of the contralateral hip in patients with unilateral slipped upper femoral epiphysis: to fix or not to fix--consequences of two strategies. AB - In the majority of patients with slipped upper femoral epiphysis only one hip is involved at primary diagnosis. However, the contralateral hip often becomes involved over time. There are no reliable factors predicting a contralateral slip. Whether or not the contralateral hip should undergo prophylactic fixation is a matter of controversy. We present a number of essential points that have to be considered both when choosing to fix the contralateral hip prophylactically as well as when refraining from surgery and instead following the patients with repeat radiographs. PMID- 22529077 TI - The double-mobility acetabular component in revision total hip replacement: the United Kingdom experience. AB - We present our experience with a double-mobility acetabular component in 155 consecutive revision total hip replacements in 149 patients undertaken between 2005 and 2009, with particular emphasis on the incidence of further dislocation. The mean age of the patients was 77 years (42 to 89) with 59 males and 90 females. In all, five patients died and seven were lost to follow-up. Indications for revision were aseptic loosening in 113 hips, recurrent instability in 29, peri-prosthetic fracture in 11 and sepsis in two. The mean follow-up was 42 months (18 to 68). Three hips (2%) in three patients dislocated within six weeks of surgery; one of these dislocated again after one year. All three were managed successfully with closed reduction. Two of the three dislocations occurred in patients who had undergone revision for recurrent dislocation. All three were found at revision to have abductor deficiency. There were no dislocations in those revised for either aseptic loosening or sepsis. These results demonstrate a good mid-term outcome for this component. In the 29 patients revised for instability, only two had a further dislocation, both of which were managed by closed reduction. PMID- 22529078 TI - A customised collared polished stem may reduce the complication rate of impaction grafting in revision hip surgery: a 12-year follow-up study. AB - We describe the results of 81 consecutive revision total hip replacements with impaction grafting in 79 patients using a collared polished chrome-cobalt stem, customised in length according to the extent of distal bone loss. Our hypothesis was that the features of this stem would reduce the rate of femoral fracture and subsidence of the stem. The mean follow-up was 12 years (8 to 15). No intra operative fracture or significant subsidence occurred. Only one patient suffered a post-operative diaphyseal fracture, which was associated with a fall. All but one femur showed incorporation of the graft. No revision for aseptic loosening was recorded. The rate of survival of the femoral component at 12 years, using further femoral revision as the endpoint, was 100% (95% confidence interval (CI) 95.9 to 100), and at nine years using re-operation for any reason as the endpoint, was 94.6% (95% CI 92.0 to 97.2). These results suggest that a customised cemented polished stem individually adapted to the extent of bone loss and with a collar may reduce subsidence and the rate of fracture while maintaining the durability of the fixation. PMID- 22529079 TI - Femoral revision surgery with impaction bone grafting: 31 hips followed prospectively for ten to 15 years. AB - The purpose of this prospective study was to evaluate the long-term clinical and radiological outcomes of revision of the femoral component of a total hip replacement using impaction bone grafting. Femoral revision with an impacted allograft was performed on 29 patients (31 hips). In all, 21 hips (68%) had grade III or IV femoral defects according to the Endo-Klinik classification. A total of 11 patients (12 hips) died before the ten-year follow-up period. Of the remaining patients, 18 patients (19 hips) were followed for 10 to 15 years; three further patients died during this time. None of the 31 stems underwent further revision of their stem. However, four stems showed extensive subsidence (> 15 mm). One of these patients had a femoral fracture that required fixation. Three other patients had a femoral fracture, two of which required fixation and the other was treated conservatively. Patients with a femoral fracture and/or severe subsidence had significantly more grade IV defects (six of seven hips; p = 0.004). One patient needed a closed reduction for dislocation. Impaction allografting in revision hip surgery gives good long-term results for femora with grades I, II and III Endo-Klinik-classified defects. Extensive subsidence and femoral fractures were seen mainly in patients with grade IV damaged femora. PMID- 22529080 TI - A financial analysis of revision hip arthroplasty: the economic burden in relation to the national tariff. AB - Revision arthroplasty of the hip is expensive owing to the increased cost of pre operative investigations, surgical implants and instrumentation, protracted hospital stay and drugs. We compared the costs of performing this surgery for aseptic loosening, dislocation, deep infection and peri-prosthetic fracture. Clinical, demographic and economic data were obtained for 305 consecutive revision total hip replacements in 286 patients performed at a tertiary referral centre between 1999 and 2008. The mean total costs for revision surgery in aseptic cases (n = 194) were L11 897 (sd 4629), for septic revision (n = 76) L21 937 (sd 10 965), for peri-prosthetic fracture (n = 24) L18 185 (sd 9124), and for dislocation (n = 11) L10 893 (sd 5476). Surgery for deep infection and peri prosthetic fracture was associated with longer operating times, increased blood loss and an increase in complications compared to revisions for aseptic loosening. Total inpatient stay was also significantly longer on average (p < 0.001). Financial costs vary significantly by indication, which is not reflected in current National Health Service tariffs. PMID- 22529081 TI - Imageless versus image-based registration in navigated arthroscopy of the hip: a cadaver-based assessment. AB - The aim of this study was to determine the accuracy of registration and the precision of the resection volume in navigated hip arthroscopy for cam-type femoroacetabular impingement, using imageless and image-based registration. A virtual cam lesion was defined in 12 paired cadaver hips and randomly assigned to either imageless or image-based (three-dimensional (3D) fluoroscopy) navigated arthroscopic head-neck osteochondroplasty. The accuracy of patient-image registration for both protocols was evaluated and post-operative imaging was performed to evaluate the accuracy of the surgical resection. We found that the estimated accuracy of imageless registration in the arthroscopic setting was poor, with a mean error of 5.6 mm (standard deviation (sd) 4.08; 95% confidence interval (CI) 4.14 to 7.19). Because of the significant mismatch between the actual position of the probe during surgery and the position of that probe as displayed on the navigation platform screen, navigated femoral osteochondroplasty was physically impossible. The estimated accuracy of image-based registration by means of 3D fluoroscopy had a mean error of 0.8 mm (sd 0.51; 95% CI 0.56 to 0.94). In terms of the volume of bony resection, a mean of 17% (sd 11; -6% to 28%) more bone was resected than with the virtual plan (p = 0.02). The resection was a mean of 1 mm deeper (sd 0.7; -0.3 to 1.6) larger than on the original virtual plan (p = 0.02). In conclusion, given the limited femoral surface that can be reached and digitised during arthroscopy of the hip, imageless registration is inaccurate and does not allow for reliable surgical navigation. However, image-based registration does acceptably allow for guided femoral osteochondroplasty in the arthroscopic management of femoroacetabular impingement. PMID- 22529082 TI - The outcome at 15 years of endoscopic anterior cruciate ligament reconstruction using hamstring tendon autograft for 'isolated' anterior cruciate ligament rupture. AB - The purpose of this study was to report the outcome of 'isolated' anterior cruciate ligament (ACL) ruptures treated with anatomical endoscopic reconstruction using hamstring tendon autograft at a mean of 15 years (14.25 to 16.9). A total of 100 consecutive men and 100 consecutive women with 'isolated' ACL rupture underwent four-strand hamstring tendon reconstruction with anteromedial portal femoral tunnel drilling and interference screw fixation by a single surgeon. Details were recorded pre-operatively and at one, two, seven and 15 years post-operatively. Outcomes included clinical examination, subjective and objective scoring systems, and radiological assessment. At 15 years only eight of 118 patients (7%) had moderate or severe osteo-arthritic changes (International Knee Documentation Committee Grades C and D), and 79 of 152 patients (52%) still performed very strenuous activities. Overall graft survival at 15 years was 83% (1.1% failure per year). Patients aged < 18 years at the time of surgery and patients with > 2 mm of laxity at one year had a threefold increase in the risk of suffering a rupture of the graft (p = 0.002 and p = 0.001, respectively). There was no increase in laxity of the graft over time. ACL reconstructive surgery in patients with an 'isolated' rupture using this technique shows good results 15 years post-operatively with respect to ligamentous stability, objective and subjective outcomes, and does not appear to cause osteoarthritis. PMID- 22529083 TI - The correctness of fit of current total knee prostheses compared with intra operative anthropometric measurements in Korean knees. AB - We aimed to obtain anthropometric data on Korean knees and to compare these with data on commonly available total knee arthroplasties (TKAs). The dimensions of the femora and tibiae of 1168 knees were measured intra-operatively. The femoral components were found to show a tendency toward mediolateral (ML) under-coverage in small femurs and ML overhang in the large femurs. The ML under-coverage was most prominent for the small prostheses. The ML/anteroposterior (ML/AP) ratio of Korean tibiae was greater than that of tibial components. This study shows that, for different reasons, current TKAs do not provide a reasonable fit for small or large Korean knees, and that the 'gender-specific' and 'stature-specific' components help for large Korean femurs but offer less satisfactory fits for small femurs. Specific modifications of prostheses are needed for Asian knees. PMID- 22529084 TI - Computer-assisted total knee replacement in patients with arthritis and a recurvatum deformity. AB - We retrospectively reviewed the records of 1150 computer-assisted total knee replacements and analysed the clinical and radiological outcomes of 45 knees that had arthritis with a pre-operative recurvatum deformity. The mean pre-operative hyperextension deformity of 11 degrees (6 degrees to 15 degrees ), as measured by navigation at the start of the operation, improved to a mean flexion deformity of 3.1 degrees (0 degrees to 7 degrees ) post-operatively. A total of 41 knees (91%) were managed using inserts <= 12.5 mm thick, and none had mediolateral laxity > 2 mm from a mechanical axis of 0 degrees at the end of the surgery. At a mean follow-up of 26.4 months (13 to 48) there was significant improvement in the mean Knee Society, Oxford knee and Western Ontario and McMaster Universities Osteoarthritis Index scores compared with the pre-operative values. The mean knee flexion improved from 105 degrees (80 degrees to 125 degrees ) pre-operatively to 131 degrees (120 degrees to 145 degrees ), and none of the limbs had recurrent recurvatum. These early results show that total knee replacement using computer navigation and an algorithmic approach for arthritic knees with a recurvatum deformity can give excellent radiological and functional outcomes without recurrent deformity. PMID- 22529085 TI - A randomised controlled clinical trial and gait analysis of fixed- and mobile bearing total knee replacements with a five-year follow-up. AB - This study compared the outcome of total knee replacement (TKR) in adult patients with fixed- and mobile-bearing prostheses during the first post-operative year and at five years' follow-up, using gait parameters as a new objective measure. This double-blind randomised controlled clinical trial included 55 patients with mobile-bearing (n = 26) and fixed-bearing (n = 29) prostheses of the same design, evaluated pre-operatively and post-operatively at six weeks, three months, six months, one year and five years. Each participant undertook two walking trials of 30 m and completed the EuroQol questionnaire, Western Ontario and McMaster Universities osteoarthritis index, Knee Society score, and visual analogue scales for pain and stiffness. Gait analysis was performed using five miniature angular rate sensors mounted on the trunk (sacrum), each thigh and calf. The study population was divided into two groups according to age (<= 70 years versus > 70 years). Improvements in most gait parameters at five years' follow-up were greater for fixed-bearing TKRs in older patients (> 70 years), and greater for mobile-bearing TKRs in younger patients (<= 70 years). These findings should be confirmed by an extended age controlled study, as the ideal choice of prosthesis might depend on the age of the patient at the time of surgery. PMID- 22529086 TI - Fungal peri-prosthetic joint infection after primary total knee replacement. AB - We retrospectively reviewed 30 two-stage revision procedures in 28 patients performed for fungal peri-prosthetic joint infection (PJI) after a primary total knee replacement. Patients were followed for at least two years or until the infection recurred. The mean follow-up for patients who remained free of infection was 4.3 years (2.3 to 6.1). Overall, 17 patients were assessed as American Society of Anesthesiologists grade 3 or 4. The surgical protocol included removal of the infected implant, vigorous debridement and insertion of an articulating cement spacer. This was followed by at least six weeks of antimicrobial treatment and delayed reimplantation in all patients. The mean interval between removal of the prosthesis and reimplantation was 9.5 weeks (6 to 24). After reimplantation, patients took antifungal agents orally for a maximum of six months. Two knees became reinfected at one and two months post operatively, respectively: one of these subsequently required arthrodesis because of uncontrolled infection. Fungal PJIs can be treated successfully by removal of all infected material, appropriate antimicrobial treatment and delayed reimplantation. PMID- 22529087 TI - Incomplete avulsion of the proximal insertion of the hamstring: outcome two years following surgical repair. AB - Incomplete avulsion of the proximal hamstrings can be a severely debilitating injury that causes weakness, pain while sitting and inability to run. The results of the surgical treatment of 23 consecutive patients with such injuries at least two years after surgery are described. The surgery consisted of the repair of the hamstrings directly onto the ischial tuberosity. At review, using a visual analogue scale (VAS, 0 to 100), pain while sitting improved from a mean of 40 (0 to 100) to 64 (0 to 100) (p = 0.024), weakness from a mean of 39 (0 to 90) to 76 (7 to 100) (p = 0.0001) and the ability to run from a mean of 24 (0 to 88) to 64 (0 to 95) (p = 0.0001). According to a VAS, satisfaction was rated at a mean of 81 (0 to 100) and 20 patients (87%) would have the same procedure again. Hamstring strength measured pre- and post-operatively had improved significantly from a mean of 64% (0% to 95%) to 88% (50% to 114%) compared with the normal side. Most of these patients with symptomatic incomplete hamstring avulsions unresponsive to conservative treatment had an improved outcome after surgical repair. PMID- 22529088 TI - Biomechanical comparison of four methods of repair of the Achilles tendon: a laboratory study with bovine tendons. AB - We tested four types of surgical repair for load to failure and distraction in a bovine model of Achilles tendon repair. A total of 20 fresh bovine Achilles tendons were divided transversely 4 cm proximal to the calcaneal insertion and randomly repaired using the Dresden technique, a Krackow suture, a triple-strand Dresden technique or a modified oblique Dresden technique, all using a Fiberwire suture. Each tendon was loaded to failure. The force applied when a 5 mm gap was formed, peak load to failure, and mechanism of failure were recorded. The resistance to distraction was significantly greater for the triple technique (mean 246.1 N (205 to 309) to initial gapping) than for the Dresden (mean 180 N (152 to 208); p = 0.012) and the Krackow repairs (mean 101 N (78 to 112; p < 0.001). Peak load to failure was significantly greater for the triple-strand repair (mean 675 N (453 to 749)) than for the Dresden (mean 327.8 N (238 to 406); p < 0.001), Krackow (mean 223.6 N (210 to 252); p < 0.001) and oblique repairs (mean 437.2 N (372 to 526); p < 0.001). Failure of the tendon was the mechanism of failure for all specimens except for the tendons sutured using the Krackow technique, where the failure occurred at the knot. The triple-strand technique significantly increased the tensile strength (p = 0.0001) and gap resistance (p = 0.01) of bovine tendon repairs, and might have advantages in human application for accelerated post-operative rehabilitation. PMID- 22529089 TI - A new technique for repair of acute or chronic extensor tendon injuries in zone 1. AB - We describe a new surgical technique for the treatment of lacerations of the extensor tendon in zone I, which involves a tenodesis using a length of palmaris longus tendon one-quarter of its width. After exposing the dorsal aspect of the distal interphalangeal joint and harvesting the tendon, a 1.5 mm drill bit is passed through the insertion of the extensor tendon into the distal phalanx where it penetrates through the skin of the pulp of the digit. The palmaris longus tendon is threaded through the drill hole from dorsal to ventral and the ventral end is tied in a simple knot and trimmed. The palmaris longus tendon is then sutured to the extensor tendon close to its insertion, and also at the middle of the middle phalanx. The operation was undertaken on 67 patients: 27 with an acute injury and 40 patients with a chronic mallet deformity. One finger (or the thumb) was involved in each patient. At a mean follow-up of 12 months (6 to 18), 66 patients (98.5%) received excellent or good results according to both the American Society for Surgery of the Hand (ASSH) classification and Miller's classification. Tenodesis using palmaris longus tendon after complete division of an extensor tendon in zone 1 is a reliable form of treatment for isolated acute or chronic ruptures. PMID- 22529090 TI - Pressurisation leads to better cement penetration into the glenoid bone: a cadaveric study. AB - The aim of this study was to compare a third-generation cementing procedure for glenoid components with a new technique for cement pressurisation. In 20 pairs of scapulae, 20 keeled and 20 pegged glenoid components were implanted using either a third-generation cementing technique (group 1) or a new pressuriser (group 2). Cement penetration was measured by three-dimensional (3D) analysis of micro-CT scans. The mean 3D depth of penetration of the cement was significantly greater in group 2 (p < 0.001). The mean thickness of the cement mantle for keeled glenoids was 2.50 mm (2.0 to 3.3) in group 1 and 5.18 mm (4.4 to 6.1) in group 2, and for pegged glenoids it was 1.72 mm (0.9 to 2.3) in group 1 and 5.63 mm (3.6 to 6.4) in group 2. A cement mantle < 2 mm was detected less frequently in group 2 (p < 0.001). Using the cement pressuriser the proportion of cement mantles < 2 mm was significantly reduced compared with the third-generation cementing technique. PMID- 22529091 TI - Modic changes in the cervical spine: prospective 10-year follow-up study in asymptomatic subjects. AB - We conducted a prospective follow-up MRI study of originally asymptomatic healthy subjects to clarify the development of Modic changes in the cervical spine over a ten-year period and to identify related factors. Previously, 497 asymptomatic healthy volunteers with no history of cervical trauma or surgery underwent MRI. Of these, 223 underwent a second MRI at a mean follow-up of 11.6 years (10 to 12.7). These 223 subjects comprised 133 men and 100 women with a mean age at second MRI of 50.5 years (23 to 83). Modic changes were classified as not present and types 1 to 3. Changes in Modic types over time and relationships between Modic changes and progression of degeneration of the disc or clinical symptoms were evaluated. A total of 31 subjects (13.9%) showed Modic changes at follow-up: type 1 in nine, type 2 in 18, type 3 in two, and types 1 and 2 in two. Modic changes at follow-up were significantly associated with numbness or pain in the arm, but not with neck pain or shoulder stiffness. Age (>= 40 years), gender (male), and pre-existing disc degeneration were significantly associated with newly developed Modic changes. In the cervical spine over a ten-year period, type 2 Modic changes developed most frequently. Newly developed Modic changes were significantly associated with age, gender, and pre-existing disc degeneration. PMID- 22529092 TI - Scoliosis in patients with Friedreich's ataxia. AB - We reviewed 31 consecutive patients with Friedreich's ataxia and scoliosis. There were 24 males and seven females with a mean age at presentation of 15.5 years (8.6 to 30.8) and a mean curve of 51 degrees (13 degrees to 140 degrees ). A total of 12 patients had thoracic curvatures, 11 had thoracolumbar and eight had double thoracic/lumbar. Two patients had long thoracolumbar collapsing scoliosis with pelvic obliquity and four had hyperkyphosis. Left-sided thoracic curves in nine patients (45%) and increased thoracic kyphosis differentiated these deformities from adolescent idiopathic scoliosis. There were 17 patients who underwent a posterior instrumented spinal fusion at mean age of 13.35 years, which achieved and maintained good correction of the deformity. Post-operative complications included one death due to cardiorespiratory failure, one revision to address nonunion and four patients with proximal junctional kyphosis who did not need extension of the fusion. There were no neurological complications and no wound infections. The rate of progression of the scoliosis in children kept under simple observation and those treated with bracing was less for lumbar curves during bracing and similar for thoracic curves. The scoliosis progressed in seven of nine children initially treated with a brace who later required surgery. Two patients presented after skeletal maturity with balanced curves not requiring correction. Three patients with severe deformities who would benefit from corrective surgery had significant cardiac co-morbidities. PMID- 22529093 TI - Causes and predictors of early re-admission after surgery for a fracture of the hip. AB - The aim of this study was to examine the rates and potential risk factors for 28 day re-admission following a fracture of the hip at a high-volume tertiary care hospital. We retrospectively reviewed 467 consecutive patients with a fracture of the hip treated in the course of one year. Causes and risk factors for unplanned 28-day re-admissions were examined using univariate and multivariate analysis, including the difference in one-year mortality. A total of 55 patients (11.8%) were re-admitted within 28 days of discharge. The most common causes were pneumonia in 15 patients (27.3%), dehydration and renal dysfunction in ten (18.2%) and deteriorating mobility in ten (18.2%). A moderate correlation was found between chest infection during the initial admission and subsequent re admission with pneumonia (r = 0.44, p < 0.001). A significantly higher mortality rate at one year was seen in the re-admission group (41.8% (23 of 55) vs. 18.7% (77 of 412), p < 0.001). Logistic regression analysis identified advancing age, admission source, and the comorbidities of diabetes and neurological disorders as the strongest predictors for re-admission. Early re-admission following hip fracture surgery is predominantly due to medical causes and is associated with higher one-year mortality. The risk factors for re-admission can have implications for performance-based pay initiatives in the NHS. Multidisciplinary management in reducing post-operative active clinical problems may reduce early re-admission. PMID- 22529094 TI - Gustilo IIIC fractures in the lower limb: our 15-year experience. AB - Controversy continues to surround the management of patients with an open fracture of the lower limb and an associated vascular injury (Gustilo type IIIC). This study reports our 15-year experience with these fractures and their outcome in 18 patients (15 male and three female). Their mean age was 30.7 years (8 to 54) and mean Mangled Extremity Severity Score (MESS) at presentation was 6.9 (3 to 10). A total of 15 lower limbs were salvaged and three underwent amputation (two immediate and one delayed). Four patients underwent stabilisation of the fracture by external fixation and 12 with an internal device. A total of 11 patients had damage to multiple arteries and eight had a vein graft. Wound cover was achieved with a pedicled flap in three and a free flap in six. Seven patients developed a wound infection and four developed nonunion requiring further surgery. At a mean follow-up of five years (4.1 to 6.6) the mean visual analogue scale for pain was 64 (10 to 90). Depression and anxiety were common. Activities were limited mainly because of pain, and the MESS was a valid predictor of the functional outcome. Distal tibial fractures had an increased rate of nonunion when associated with posterior tibial artery damage, and seven patients (39%) were not able to return to their previous occupation. PMID- 22529095 TI - A randomised pilot trial of "locking plate" fixation versus intramedullary nailing for extra-articular fractures of the distal tibia. AB - The ideal form of fixation for displaced, extra-articular fractures of the distal tibia remains controversial. In the UK, open reduction and internal fixation with locking-plates and intramedullary nailing are the two most common forms of treatment. Both techniques provide reliable fixation but both are associated with specific complications. There is little information regarding the functional recovery following either procedure. We performed a randomised pilot trial to determine the functional outcome of 24 adult patients treated with either a locking-plate (n = 12) or an intramedullary nailing (n = 12). At six months, there was an adjusted difference of 13 points in the Disability Rating Index in favour of the intramedullary nail. However, this was not statistically significant in this pilot trial (p = 0.498). A total of seven patients required further surgery in the locking-plate group and one in the intramedullary nail group. This study suggests that there may be clinically relevant, functional differences in patients treated with nail versus locking-plate fixation for fractures of the distal tibia and differences in related complications. Further trials are required to confirm the findings of this pilot investigation. PMID- 22529096 TI - Surgical treatment of Sprengel's shoulder: experience at the Rizzoli Orthopaedic Institute 1975-2010. AB - The outcome of 56 children (61 shoulders) treated surgically at the Rizzoli Institute between April 1975 and June 2010 for congenital elevation of the scapula is reported. There were 31 girls and 25 boys with a mean age at surgery of 6.4 years (2 to 15). The deformity involved the right shoulder in 20 cases, the left in 31 and was bilateral in five. The degree of the deformity was graded clinically and radiologically according to the classifications of Cavendish and Rigault, respectively. All patients underwent a modified Green procedure combined, in selected cases, with resection of the superomedial portion of the scapula and excision of any omovertebral connection. After a mean follow-up of 10.9 years (1 to 29.3), there was cosmetic improvement by at least one Cavendish grade in 54 shoulders (88.5%). The mean abduction of the shoulder improved from 92 degrees (50 degrees to 155 degrees ) to 112 degrees (90 degrees to 170 degrees ) and the mean flexion improved from 121 degrees (80 degrees to 160 degrees ) to 155 degrees (120 degrees to 175 degrees ). The unsatisfactory cosmetic result in seven shoulders was due to coexistent scoliosis in two cases and insufficient reduction of the scapular elevation in the other five. An incomplete upper brachial plexus palsy occurred post-operatively in three patients but resolved within seven months. We suggest that a modified Green procedure combined with resection of the superomedial portion of the scapula provides good cosmetic and functional results in patients with Sprengel's shoulder. PMID- 22529097 TI - Increasing stability by pre-bending the nails in elastic stable intramedullary nailing: a biomechanical analysis of a synthetic femoral spiral fracture model. AB - Elastic stable intramedullary nailing (ESIN) is generally acknowledged to be the treatment of choice for displaced diaphyseal femoral fractures in children over the age of three years, although complication rates of up to 50% are described. Pre-bending the nails is recommended, but there are no published data to support this. Using synthetic bones and a standardised simulated fracture, we performed biomechanical testing to determine the influence on the stability of the fracture of pre-bending the nails before implantation. Standard ESIN was performed on 24 synthetic femoral models with a spiral fracture. In eight cases the nails were inserted without any pre-bending, in a further eight cases they were pre-bent to 30 degrees and in the last group of eight cases they were pre-bent to 60 degrees . Mechanical testing revealed that pre-bending to 60 degrees produced a significant increase in the stiffness or stability of the fracture. Pre-bending to 60 degrees showed a significant positive influence on the stiffness compared with unbent nails. Pre-bending to 30 degrees improved stiffness only slightly. These findings validate the recommendations for pre-bending, but the degree of pre-bend should exceed 30 degrees . Adopting higher degrees of pre-bending should improve stability in spiral fractures and reduce the complications of varus deformity and shortening. PMID- 22529099 TI - Novel aspects of mevalonate pathway inhibitors as antitumor agents. AB - The mevalonate pathway for cholesterol biosynthesis and protein prenylation has been implicated in various aspects of tumor development and progression. Certain classes of drugs, such as statins and bisphosphonates, inhibit mevalonate metabolism and therefore have also been tested as antitumor agents. This concept is strongly supported by the recent finding that mutant p53, which is present in more than half of all human cancers, can significantly upregulate mevalonate metabolism and protein prenylation in carcinoma cells. The first evidence that mevalonate pathway inhibitors may have the potential to reverse the malignant phenotype has already been obtained. Moreover, recently discovered immunomodulatory properties of statins and bisphosphonates may also contribute to their known anticancer effects. Drug-induced inhibition of protein prenylation may induce sequential cellular stress responses, including the unfolded protein response and autophagy, that eventually translate into inflammasome-dependent and caspase-1-mediated activation of innate immunity. This review focuses on these novel capabilities of mevalonate pathway inhibitors to beneficially affect tumor biology and contribute to tumor immune surveillance. PMID- 22529100 TI - The Trim39 ubiquitin ligase inhibits APC/CCdh1-mediated degradation of the Bax activator MOAP-1. AB - Proapoptotic Bcl-2 family members, such as Bax, promote release of cytochrome c from mitochondria, leading to caspase activation and cell death. It was previously reported that modulator of apoptosis protein 1 (MOAP-1), an enhancer of Bax activation induced by DNA damage, is stabilized by Trim39, a protein of unknown function. In this paper, we show that MOAP-1 is a novel substrate of the anaphase-promoting complex (APC/C(Cdh1)) ubiquitin ligase. The influence of Trim39 on MOAP-1 levels stems from the ability of Trim39 (a RING domain E3 ligase) to directly inhibit APC/C(Cdh1)-mediated protein ubiquitylation. Accordingly, small interfering ribonucleic acid-mediated knockdown of Cdh1 stabilized MOAP-1, thereby enhancing etoposide-induced Bax activation and apoptosis. These data identify Trim39 as a novel APC/C regulator and provide an unexpected link between the APC/C and apoptotic regulation via MOAP-1. PMID- 22529101 TI - A wound-induced keratin inhibits Src activity during keratinocyte migration and tissue repair. AB - Injury to the epidermis triggers an elaborate homeostatic response resulting in tissue repair and recovery of the vital barrier function. The type II keratins 6a and 6b (K6a and K6b) are among the genes induced early on in wound-proximal keratinocytes and maintained during reepithelialization. Paradoxically, genetic ablation of K6a and K6b results in enhanced keratinocyte migration. In this paper, we show that this trait results from activation of Src kinase and key Src substrates that promote cell migration. Endogenous Src physically associated with keratin proteins in keratinocytes in a K6-dependent fashion. Purified Src bound K6-containing filaments via its SH2 domain in a novel phosphorylation-independent manner, resulting in kinase inhibition. K6 protein was enriched in the detergent resistant membrane (DRM), a key site of Src inhibition, and DRMs from K6-null keratinocytes were depleted of both keratin and Src. We conclude that K6 negatively regulates Src kinase activity and the migratory potential of skin keratinocytes during wound repair. Our findings may also be important in related contexts such as cancer. PMID- 22529102 TI - Trichoplein and Aurora A block aberrant primary cilia assembly in proliferating cells. AB - The primary cilium is an antenna-like organelle that modulates differentiation, sensory functions, and signal transduction. After cilia are disassembled at the G0/G1 transition, formation of cilia is strictly inhibited in proliferating cells. However, the mechanisms of this inhibition are unknown. In this paper, we show that trichoplein disappeared from the basal body in quiescent cells, whereas it localized to mother and daughter centrioles in proliferating cells. Exogenous expression of trichoplein inhibited primary cilia assembly in serum-starved cells, whereas ribonucleic acid interference-mediated depletion induced primary cilia assembly upon cultivation with serum. Trichoplein controlled Aurora A (AurA) activation at the centrioles predominantly in G1 phase. In vitro analyses confirmed that trichoplein bound and activated AurA directly. Using trichoplein mutants, we demonstrate that the suppression of primary cilia assembly by trichoplein required its ability not only to localize to centrioles but also to bind and activate AurA. Trichoplein or AurA knockdown also induced G0/G1 arrest, but this phenotype was reversed when cilia formation was prevented by simultaneous knockdown of IFT-20. These data suggest that the trichoplein-AurA pathway is required for G1 progression through a key role in the continuous suppression of primary cilia assembly. PMID- 22529103 TI - An intrinsically disordered yeast prion arrests the cell cycle by sequestering a spindle pole body component. AB - Intrinsically disordered proteins play causative roles in many human diseases. Their overexpression is toxic in many organisms, but the causes of toxicity are opaque. In this paper, we exploit yeast technologies to determine the root of toxicity for one such protein, the yeast prion Rnq1. This protein is profoundly toxic when overexpressed but only in cells carrying the endogenous Rnq1 protein in its [RNQ(+)] prion (amyloid) conformation. Surprisingly, toxicity was not caused by general proteotoxic stress. Rather, it involved a highly specific mitotic arrest mediated by the Mad2 cell cycle checkpoint. Monopolar spindles accumulated as a result of defective duplication of the yeast centrosome (spindle pole body [SPB]). This arose from selective Rnq1-mediated sequestration of the core SPB component Spc42 in the insoluble protein deposit (IPOD). Rnq1 does not normally participate in spindle pole dynamics, but it does assemble at the IPOD when aggregated. Our work illustrates how the promiscuous interactions of an intrinsically disordered protein can produce highly specific cellular toxicities through illicit, yet highly specific, interactions with the proteome. PMID- 22529105 TI - Combined use of 68Ga-DOTATATE and 18F-FDG PET/CT to localize a bronchial carcinoid associated with ectopic ACTH syndrome. PMID- 22529104 TI - Hic-5 promotes invadopodia formation and invasion during TGF-beta-induced epithelial-mesenchymal transition. AB - Transforming growth factor beta (TGF-beta)-stimulated epithelial-mesenchymal transition (EMT) is an important developmental process that has also been implicated in increased cell invasion and metastatic potential of cancer cells. Expression of the focal adhesion protein Hic-5 has been shown to be up-regulated in epithelial cells in response to TGF-beta. Herein, we demonstrate that TGF-beta induced Hic-5 up-regulation or ectopic expression of Hic-5 in normal MCF10A cells promoted increased extracellular matrix degradation and invasion through the formation of invadopodia. Hic-5 was tyrosine phosphorylated in an Src-dependent manner after TGF-beta stimulation, and inhibition of Src activity or overexpression of a Y38/60F nonphosphorylatable mutant of Hic-5 inhibited matrix degradation and invasion. RhoC, but not RhoA, was also required for TGF-beta- and Hic-5-induced matrix degradation. Hic-5 also induced matrix degradation, cell migration, and invasion in the absence of TGF-beta via Rac1 regulation of p38 MAPK. These data identify Hic-5 as a critical mediator of TGF-beta-stimulated invadopodia formation, cell migration, and invasion. PMID- 22529106 TI - How good are BMI charts for monitoring children's attempts at obesity reduction? AB - INTRODUCTION: Body mass index (BMI) is the pragmatic measure to assess children's obesity clinically and BMI charts are widely used for counselling families about children's weight management over time. AIMS: To explore the variability in clinicians' interpretation of BMI patterns and to ascertain the diagnostic accuracy of their judgement by relating it to change in body composition by dual emission x-ray absorptiometry (DXA). METHODS: Data from 70 children who participated in a trial of a weight management programme for obese children were analysed. BMI was plotted on UK 1990 charts at baseline, 6 months and 12 months, and four clinicians experienced in obesity management independently scored the charts on a five-point scale for how successful children were in tackling their obesity over a 6-month period. Scores were compared with change in BMI, fat mass and lean mass z-scores as measured by DXA. RESULTS: 54 children (aged 8-15 years; BMI z-score 2.93 (SD 0.48)) had simultaneous BMI and DXA scans performed, giving 104 pairs of measurements 6 months apart. There was good consistency between clinicians' scores for weight management and these related well to change in BMI and fat mass z-scores, but not lean mass z-score. They reported that measurement proximity to centile lines and crossing of lines influenced their confidence in making a decision and change in severe obesity was harder to judge as higher centile lines are so far apart. CONCLUSIONS: BMI charts are useful for assessing children's attempts at weight management, and provide a reasonably accurate indication of change in body fat. Recommendations are made regarding BMI chart design and guidance in interpreting measurements. PMID- 22529107 TI - Point: the American Diabetes Association and the International Association of Diabetes and Pregnancy study groups recommendations for diagnosing gestational diabetes should be used worldwide. PMID- 22529108 TI - MicroRNAs regulate expression of oncogenes. PMID- 22529109 TI - Serum S100B determination in the management of pediatric mild traumatic brain injury. AB - BACKGROUND: The place of serum S100B measurement in mild traumatic brain injury (mTBI) management is still controversial. Our prospective study aimed to evaluate its utility in the largest child cohort described to date. METHODS: Children younger than 16 years presenting at a pediatric emergency department within 3 h after TBI were enrolled prospectively for blood sampling to determine serum S100B concentrations. The following information was collected: TBI severity determined by using the Masters classification [1: minimal or Glasgow Coma Scale (GCS) 15, 2: mild or GCS 13-15, and 3: severe or GCS <13]; whether hospitalized or not; good or bad clinical evolution (CE); whether cranial computed tomography (CCT) was prescribed; and related presence (CCT+) or absence (CCT-) of lesions. RESULTS: For the 446 children enrolled, the median concentrations of S100B were 0.21, 0.31, and 0.44 MUg/L in Masters groups 1, 2, and 3, respectively, with a statistically significant difference between these groups (P < 0.05). In Masters group 2, 65 CCT scans were carried out. Measurement of S100B identified patients as CCT+ with 100% (95% CI 85-100) sensitivity and 33% (95% CI 20-50) specificity. Of the 424 children scored Masters 1 or 2, 21 presented "bad CE." S100B identified bad CE patients with 100% (95% CI 84-100) sensitivity and 36% (95% CI 31-41) specificity. Of the 242 children hospitalized, 81 presented an S100B concentration within the reference interval. CONCLUSIONS: Serum S100B determination during the first 3 h of management of children with mTBI has the potential to reduce the number of CCT scans, thereby avoiding unnecessary irradiation, and to save hospitalization costs. PMID- 22529110 TI - Hyperglycosylated human chorionic gonadotropin in serum of testicular cancer patients. AB - BACKGROUND: Hyperglycosylated human chorionic gonadotropin (hCG-h) contains larger and more complex carbohydrate chains than regular human chorionic gonadotropin (hCG). hCG-h is thought to be the major form of hCG produced by testicular cancers and it has been suggested to play a key role in tumor invasion, but studies on hCG-h in testicular cancer are limited. We studied whether serum hCG is hyperglycosylated, and whether measurement of hCG-h in serum offers clinical value in the management of testicular cancer. METHODS: We determined the serum concentrations of hCG-h, hCG, and the free beta subunit of hCG (hCGbeta) by time-resolved immunofluorometric assays in 176 serum samples (preoperative n = 67, relapse n = 20, follow-up n = 89) obtained from 84 testicular cancer patients. We analyzed the association between preoperative serum concentrations of hCG, hCG-h, and hCGbeta with known prognostic factors and progression-free survival time. RESULTS: A major proportion of hCG was hyperglycosylated preoperatively, at relapse, and shortly after treatment. The serum concentrations of hCG-h and hCG correlated strongly with each other and had similar diagnostic value. The preoperative serum concentration of hCG-h correlated with prognostic factors and outcome in the same way as hCG. Increased preoperative hCGbeta concentration predicted shorter progression-free survival. CONCLUSIONS: Most of the hCG expressed by testicular cancers is hyperglycosylated and therefore it is important that hCG assays used for management of testicular cancer recognize hCG-h. PMID- 22529112 TI - An error management system in a veterinary clinical laboratory. AB - Error recording and management is an integral part of a clinical laboratory quality management system. Analysis and review of recorded errors lead to corrective and preventive actions through modification of existing processes and, ultimately, to quality improvement. Laboratory errors can be divided into preanalytical, analytical, and postanalytical errors depending on where in the laboratory cycle the errors occur. The purpose of the current report is to introduce an error management system in use in a veterinary diagnostic laboratory as well as to examine the amount and types of error recorded during the 8-year period from 2003 to 2010. Annual error reports generated during this period by the error recording system were reviewed, and annual error rates were calculated. In addition, errors were divided into preanalytical, analytical, postanalytical, and "other" categories, and their frequency was examined. Data were further compared to that available from human diagnostic laboratories. Finally, sigma metrics were calculated for the various error categories. Annual error rates per total number of samples ranged from 1.3% in 2003 to 0.7% in 2010. Preanalytical errors ranged from 52% to 77%, analytical from 4% to 14%, postanalytical from 9% to 21%, and other error from 6% to 19% of total errors. Sigma metrics ranged from 4.1 to 4.7. All data were comparable to that reported in human clinical laboratories. The incremental annual reduction of error shows that use of an error management system led to quality improvement. PMID- 22529113 TI - Sustained high-throughput polymerase chain reaction diagnostics during the European epidemic of Bluetongue virus serotype 8. AB - A real-time reverse transcription polymerase chain reaction assay (PCR test) based on genome segment 10 of Bluetongue virus (BTV) was developed. The PCR test consists of robotized viral RNA isolation from blood samples and an all-in-one method including initial denaturation of genomic double-stranded RNA, reverse transcription polymerase chain reaction (RT-PCR), and real-time detection and analysis. Reference strains of the 24 recognized BTV serotypes, isolates from different years, and geographic origins were detected. Other orbiviruses such as African horse sickness virus, Epizootic hemorrhagic disease virus, and Equine encephalosis virus were not detected. Experimentally infected animals were PCR positive from 2 days postinoculation, which was earlier than fever, other clinical signs, or seroconversion. The diagnostic sensitivity and specificity were very close to or even 100%. The PCR test played a key role in the detection of BTV serotype 8 in August 2006 in The Netherlands. The outbreak in a completely naive ruminant population allowed for further evaluation of the PCR test with field samples. In 2006, the correlation between enzyme-linked immunosorbent assay and PCR results was estimated to be 95%. In the following years, the PCR test was used for diagnosis of diseased animals, for testing of healthy animals for trade purposes, and for detection of BTV RNA in different species of the insect vector, Culicoides. In the autumn of 2008, BTV serotype 6 unexpectedly emerged in northwest Europe and was also detected with the PCR test developed in the current study. The performance in routine use over 5 years has been recorded and evaluated. PMID- 22529114 TI - Detection of disease resistance and susceptibility alleles in pigs using oligonucleotide microarray hybridization. AB - A multiplex DNA microarray chip aimed at the identification of allelic polymorphisms was developed for simultaneous detection of swine disease resistance genes underlying malignant hyperthermia (RYR), postweaning diarrhea, edema disease (FUT1), neonatal diarrhea (MUC4), and influenza (MX1). The on-chip detection was performed with fragmented polymerase chain reaction (PCR)-amplified products. Particular emphasis was placed on the reduction of the number of PCR reactions required. The targets were biotin labeled during the PCR reaction, and the arrays were detected using a colorimetric methodology. Target recognition was provided by specific capture probes designed for each susceptible or resistant allelic variant. Sequencing was chosen as the gold standard to assess chip accuracy. All genotypes retrieved from the microarray (476) fit with sequencing data despite the fact that each pig was heterozygote for at least 1 target gene. PMID- 22529115 TI - Genetic and phenotypic characterization of methicillin-resistant staphylococci isolated from veterinary hospitals in South Korea. AB - Staphylococci were isolated from veterinary staff, hospitalized animals, and medical equipment from 2 major tertiary veterinary hospitals in South Korea to investigate antimicrobial resistance and genetic relatedness. The detection rate for staphylococci was 55.2% (111/201 samples), and 11 species were identified among the collected staphylococcal strains. The most prevalent species were Staphylococcus pseudintermedius (52/111, 46.8%), Staphylococcus epidermidis (21/111, 18.9%), and Staphylococcus aureus (19/111, 17.1%). The methicillin resistance rates of staphylococci isolated from veterinary staff and medical equipment were higher than those from hospitalized animals. The genotype of methicillin-resistant S. aureus (MRSA) strains in the current study was sequence type (ST)72-SCCmec IVc-t324, which is similar to the genotype of prevalent MRSA strains in human beings and food animals in South Korea. Among the mecA-positive S. pseudintermedius isolates, SCCmec V was most prevalent in strains originating from both veterinary staff and hospitalized animals. SCCmec IVa was detected in methicillin-resistant S. epidermidis, whereas SCCmec IVc was found in other methicillin-resistant, coagulase-negative staphylococci. The SCCmec typing, antimicrobial susceptibility tests, and pulsed field gel electrophoresis results showed that methicillin-resistant staphylococci dissemination between hospitalized animals and veterinary staff is possible in South Korean veterinary hospitals. PMID- 22529116 TI - Diagnostic performance of the canine influenza A virus subtype H3N8 hemagglutination inhibition assay. AB - Canine Influenza A virus subtype H3N8 (H3N8 CIV) was recognized in 2004 as a novel respiratory pathogen for dogs. To date, infections have been diagnosed in thousands of dogs in 38 U.S. states. Diagnostic techniques such as reverse transcription polymerase chain reaction (RT-PCR) and virus isolation may yield false-negative results if samples are collected after virus shedding has ceased. Therefore, serology is often necessary to confirm diagnosis. The hemagglutination inhibition (HI) assay is the test of choice for serological diagnosis of influenza infections in animals. However, discrepancies exist between diagnostic laboratories and research groups in some of the test parameters for the H3N8 CIV HI assay and the cutoff antibody titer for seropositivity. The objectives of the current study were 1) to assess the diagnostic performance of a H3N8 CIV HI assay using field sera from canine infectious respiratory disease outbreaks and 2) to evaluate the effect of test parameter variations on test performance, including the use of different red blood cell (RBC) species, serum treatment methods, and virus isolates. Based on a receiver operating characteristic analysis using serum microneutralization assay titers as the gold standard, the H3N8 CIV HI assay described in the present study is highly sensitive (99.6%) and specific (94.6%) when the cutoff antibody titer for seropositivity is 32. Evaluation of parameter variations determined that the sensitivity and specificity of the H3N8 CIV HI assay depend on serum pretreatment with a receptor-destroying enzyme or periodate, use of 0.5% turkey or chicken RBCs, and use of antigenically well matched H3N8 virus strains. PMID- 22529117 TI - Development of an antigen-capture monoclonal antibody-based enzyme-linked immunosorbent assay and comparison with culture for detection of Salmonella enterica serovar Enteritidis in poultry hatchery environmental samples. AB - An antigen-capture enzyme-linked immunosorbent assay (ELISA) was developed for use as a presumptive screening test for detection of Salmonella enterica serovar Enteritidis and other group D Salmonella in poultry hatchery environments. A mixture of 2 monoclonal antibodies that recognize different forms of the lipopolysaccharide O-antigen was used for specific detection of group D Salmonella. The performance of the ELISA was evaluated in comparison to standard Salmonella culture procedures. Culture for each sample included nonselective enrichment with buffered peptone water and primary selective enrichment and delayed secondary enrichment with both tetrathionate and Rappaport-Vassiliadis broths. One thousand fifty-seven samples were collected from poultry hatcheries over a 5-year period (received in 85 submissions), and S. Enteritidis was recovered from 106 (10%) of them. The diagnostic sensitivity and specificity of the ELISA relative to culture were 97.2% and 99.6%, respectively, on a sample basis and were both 100% on a submission basis. Delayed secondary enrichment increased the number of S. Enteritidis culture and ELISA-positive samples as compared to nonselective enrichment and primary selective enrichment by 25%. A significantly higher (P < 0.05) number of S. Enteritidis culture- and ELISA positive results were obtained from Rappaport-Vassiliadis broth than from tetrathionate broth or buffered peptone water cultures. The results indicate that this ELISA procedure may be useful for screening poultry hatchery environmental samples for the presence of S. Enteritidis. PMID- 22529119 TI - Utility of nuclear morphometry in the cytologic evaluation of canine cutaneous soft tissue sarcomas. AB - Cytopathologists lack reliable criteria to distinguish neoplastic from reactive spindle cells; however, with computer-based nuclear morphometry, it is now possible to more objectively and precisely quantify differences between selected populations of cells. Forty-four cutaneous soft tissue sarcomas and 5 cases of reactive spindle cell proliferations in the dog were morphometrically analyzed with regard to median and standard deviation (SD) of nuclear area, diameter (max, min, mean), radius (max, min), perimeter, and roundness. Overall, nuclei from reactive spindle cells were larger, with greater variation in nuclear size and shape. Significant differences (P < 0.05) were found for several nuclear parameters, including the median and SD of maximum diameter and radius, as well as the SD of roundness. No significant differences were found in nuclear parameters between soft tissue sarcomas divided by histologic grade, mitotic index, or tumor necrosis score. Analysis of the sources of variation indicated near-perfect intraobserver and substantial interobserver agreement. The largest source of variation was due to selection of different measurement fields, reflecting the inherent biological variation in nuclear size within the tumor cell population. The results indicate that nuclear morphometry on cytologic preparations is a reproducible method that may be able to differentiate cutaneous soft tissue sarcomas from reactive mesenchymal lesions in the dog. Further studies, including a larger number of cases, are warranted to assess repeatability of results. PMID- 22529118 TI - Myxobolus albi infection in cartilage of captive lumpfish (Cyclopterus lumpus). AB - Myxobolus albi was diagnosed in the cartilage of captive lumpfish (Cyclopterus lumpus) from 2 public aquaria. Eleven fish were affected, with the most common clinical signs being exophthalmos and grossly visible 1- to 2-mm white to tan scleral nodules. Myxozoan cysts were identified in the cartilage of the skull, branchial arch, sclera, vertebrae, tongue, all fin insertions, and the pectoral girdle. Cysts resulted in expansile, deforming, space-occupying lesions, resulting in exophthalmos but often lacking significant tissue damage or inflammation. Once cysts ruptured, free spores elicited a mild to marked inflammatory response. Spores measured 7.5 to 9.0 um * 3.0 to 6.0 um and contained 2 pyriform polar capsules oriented at one pole as well as occasional 1 um-diameter basophilic nuclei. Identification was based on spore morphology together with polymerase chain reaction and sequence comparison of 18S ribosomal DNA. Isolates had 99% similarity to M. albi. PMID- 22529120 TI - Reference intervals for mineral concentrations in whole blood and serum of bighorn sheep (Ovis canadensis) in California. AB - Whole blood and serum mineral concentrations were measured in diverse bighorn sheep (Ovis canadensis) metapopulations in California, and 90% reference intervals were determined. While there were some statistical differences between median concentrations among the different metapopulations, detected values were generally in good agreement with concentrations reported for other bighorn sheep populations and with reference ranges widely accepted for domestic sheep (Ovis aries). Although median whole blood selenium and serum copper concentrations were within adequate ranges reported for domestic sheep, some metapopulations had substantial numbers of individuals whose concentrations would be considered suboptimal for domestic sheep. There are a number of factors that can influence mineral concentrations in wildlife species such as bighorn sheep and that make the establishment of reference ranges challenging. However, the establishment of mineral reference ranges is important for such species, as their health and productivity are increasingly scrutinized and actively managed. PMID- 22529121 TI - Clinical evaluation of the QuickVet/RapidVet canine dog erythrocyte antigen 1.1 blood-typing test. AB - In transfusion medicine, blood typing is an integral part of pretransfusion testing. The objective of the current study was the clinical evaluation of an automated canine cartridge dog erythrocyte antigen (DEA) 1.1 blood-typing method (QuickVet/RapidVet) and comparison of the results with a gel column-based method (ID-Gel Test Canine DEA 1.1). Ethylenediamine tetra-acetic acid-anticoagulated blood samples from 11 healthy and 85 sick dogs were available for typing. Before blood typing, all samples were tested for agglutination and hemolysis. All samples were tested once or multiple times with both methods according to the manufacturer's guidelines. With the gel method, 53 dogs tested DEA 1.1 positive and 42 dogs DEA 1.1 negative; blood typing was not possible due to erythrocyte autoagglutination in 1 dog. With the cartridge test, 53 samples tested DEA 1.1 positive, 34 samples tested DEA 1.1 negative, and 6 results were inconclusive (3 samples were not included due to autoagglutination or severe hemolysis). Without taking the inconclusive samples into account, the agreement between both methods was 96.5%. The sensitivity and specificity for samples that were definitively typed by both methods were 100% and 91.9%, respectively. The cartridge test was suitable for in-clinic canine DEA 1.1 blood typing, although some discrepancies compared to the gel method existed. The cartridge test is software-directed, is easy to use, and does not require user interpretation, but preanalytical guidelines (sample evaluation for agglutination and hemolysis) have to be followed. For inconclusive results, an alternate blood-typing method should be performed. PMID- 22529122 TI - Bovine viral diarrhea virus antigen detection across whole cattle hides using two antigen-capture enzyme-linked immunosorbent assays. AB - Bovine viral diarrhea virus is a costly disease of cattle that can be controlled by vaccination, biosecurity, and removal of persistently infected cattle. Development and proficiency testing of assays to identify persistently infected cattle requires substantial quantities of known positive- and negative-sample material. The objective of this study was to determine what sections of bovine skin contained Bovine viral diarrhea virus antigen. Two commercially available antigen-capture enzyme-linked immunoassays were used to test subsamples representing the entire skin of 3 persistently infected calves. Both assays detected Bovine viral diarrhea virus antigen in the samples indicated for use by assay protocol. However, one assay identified all subsamples as positive, while the second assay identified 64.4% of subsamples as positive. These results show that use of samples other than those specified by the assay protocol must be validated for each individual assay. In this study, alternative sample sites and use of the entire hide for proficiency testing would be acceptable for only one of the assays tested. PMID- 22529123 TI - Bovine viral diarrhea virus: correlation between herd seroprevalence and bulk tank milk antibody levels using 4 commercial immunoassays. AB - The aim of the present study was to establish a relationship between the results obtained using the enzyme-linked immunosorbent assay (ELISA) technique for antibodies in blood serum and milk at herd level. For this purpose, 325 samples of bulk tank milk were analyzed with 4 antibody ELISAs from dairy herds with a prevalence of seropositive animals; seroprevalence was also evaluated. Data were arranged to analyze the sensitivity of the bulk tank milk test to detect herds with high risk of active infection (>65% seroprevalence) and the specificity to detect those with very few (<5%) or no (0%) seropositive animals, respectively. The sensitivity values ranged from 0.92 to 0.70 and the specificity from 0.83 to 0.54 to detect free herds (0% seroprevalence) and from 0.88 to 0.77 to detect herds with <5% of seropositive animals. In a quantitative approach, Pearson correlation coefficients, reported as a measure of linear association between herd seroprevalence and transformed optical density values recorded in bulk tank milk, ranged from 0.71 to 0.86. According to these results, the 4 antibody ELISAs would be valid tests for carrying out a herd classification program using milk samples. PMID- 22529124 TI - Prolonged incubation time in sheep with prion protein containing lysine at position 171. AB - Sheep scrapie susceptibility or resistance is a function of genotype, with polymorphisms at codon 171 in the sheep prion gene playing a major role. Glutamine (Q) at codon 171 contributes to scrapie susceptibility, while arginine (R) is associated with resistance. In some breeds, lysine (K) occurs at codon 171, but its effect on scrapie resistance has not been determined. Charge and structural similarities between K and R suggest that they may contribute to prion disease susceptibility in a similar way, but studies have not been performed to confirm this. The purpose of the current study was to compare susceptibility and incubation times of AA(136)RR(154)QQ(171) (where the letter denotes the amino acid and the number the position) with AA(136)RR(154)QK(171) sheep after inoculation with scrapie. Barbado AA(136)RR(154)QQ(171) and AA(136)RR(154)QK(171) sheep were inoculated with scrapie intracerebrally to assess their susceptibility to scrapie. After inoculation, sheep were observed daily for clinical signs and were euthanized and necropsied after clinical signs were unequivocal. Tissues were collected at necropsy for immunohistochemistry and Western blot analyses. The QQ(171) sheep had clinical signs approximately 12 months after inoculation, whereas QK(171) animals had an average incubation time of 30 months to onset of clinical signs. The distribution of abnormal prion protein was similar in QQ(171) and QK(171) sheep. Results of the study indicate that sheep with a single K allele at codon 171 are susceptible to scrapie but with a prolonged incubation time. Work is currently underway to examine relative scrapie susceptibility or resistance of KK(171) sheep. PMID- 22529125 TI - Evaluation of a commercial rapid test kit for detecting bovine enteric pathogens in feces. AB - Recently a commercial antigen-capture enzyme-linked immunosorbent assay kit in the form of a dipstick (Bovine Enterichek, Biovet Inc.) was made available to bovine practitioners and producers for the rapid detection of Betacoronavirus 1 (BCV-1), Rotavirus A (RV-A), Escherichia coli K99(+), and Cryptosporidium parvum in feces from diarrheic calves. The diagnostic performance of Bovine Enterichek was evaluated in comparison with a multiplex real-time polymerase chain reaction assay (mrtPCR). One hundred fecal samples were procured from diagnostic submissions to Iowa State University Veterinary Diagnostic Laboratory and were used for the assessment. The agreement quotient (kappa) in results for each pathogen between Bovine Enterichek and mrtPCR were 0.095 (BCV-1), 0.521 (RV-A), 0.823 (E. coli K99( + )), and 0.840 (C. parvum). In comparison to mrtPCR, the diagnostic sensitivity of Bovine Enterichek was 60.0%, 42.3%, 71.4%, and 81.5%, and the diagnostic specificity was 51.4%, 100%, 100%, and 98.6% for BCV-1, RV-A, E. coli K99( + ), and C. parvum, respectively. The current study suggested that Bovine Enterichek can be a rapid test tool in the field for detection of RV-A, C. parvum, or E. coli K99(+) in feces from calves at acute stage of clinical disease. However, test results for BCV-1 by the kit should be interpreted with caution due to low specificity and sensitivity of the kit. PMID- 22529126 TI - Evaluation of different embryonating bird eggs and cell cultures for isolation efficiency of avian influenza A virus and avian paramyxovirus serotype 1 from real-time reverse transcription polymerase chain reaction-positive wild bird surveillance samples. AB - Virus isolation rates for influenza A virus (FLUAV) and Avian paramyxovirus serotype 1 (APMV-1) from wild bird surveillance samples are lower than molecular detection rates for the specific viral genomes. The current study was conducted to examine the possibility of increased virus isolation rates from real-time reverse transcription polymerase chain reaction (real-time RT-PCR) using alternative virus isolation substrates such as embryonating duck eggs (EDEs), embryonating turkey eggs (ETEs), Madin-Darby canine kidney (MDCK) cell cultures, and African green monkey kidney (Vero) cell cultures. Rectal swabs of birds in the orders Anseriformes and Charadriiformes were tested by real-time RT-PCR for the presence of FLUAV and APMV-1 genomes, and virus isolation (VI) was attempted on all real-time RT-PCR-positive samples. Samples with threshold cycle (Ct) <= 37 had VI rates for FLUAV of 62.5%, 50%, 43.8%, 31.5%, and 31.5% in embryonating chicken eggs (ECEs), ETEs, EDEs, MDCK cells, and Vero cells, respectively. A higher isolation rate was seen with ECEs compared to either cell culture method, but similar isolation rates were identified between the different embryonating avian eggs. Virus isolation rates for APMV-1 on samples with real-time RT-PCR Ct <= 37 were 75%, 100%, 100%, 0%, and 37.5% in ECEs, ETEs, EDEs, MDCK cells, and Vero cells, respectively. Significantly higher VI rates were seen with ECEs as compared to either cell culture method for all real-time RT-PCR-positive samples. Because of the limited availability and high cost of ETEs and EDEs, the data support the continuing usage of ECEs for primary isolation of both FLUAV and APMV 1 from real-time RT-PCR-positive wild bird surveillance samples. PMID- 22529127 TI - A rapid mismatch polymerase chain reaction assay to detect carriers of complex vertebral malformation in Holstein cattle. AB - Three Holstein sires were identified as complex vertebral malformation (CVM) carriers using the polymerase chain reaction-primer introduced restriction analysis (PCR-PIRA) method. Using the carriers as positive controls, the PCR mismatch amplification mutation assay (MAMA PCR) method was developed and validated by sequence analysis. With MAMA PCR, 154 Chinese Holstein sires were tested for CVM, among which 24 were confirmed to be CVM carriers. With DNA isolated from hair follicles, 10 daughters of one CVM-positive bull were detected, among which 7 were confirmed to be CVM carriers. PMID- 22529128 TI - Chimeric protein A/G conjugate for detection of anti-Toxoplasma gondii immunoglobulin G in multiple animal species. AB - Serological testing for toxoplasmosis diagnosis remains the method of choice in human medicine due to the accessibility of the requisite sample, the difficulty in predicting the parasite's location in the host for direct detection, and the availability of established commercial methods. In veterinary medicine, although the first 2 conditions are unchanged, there is a need for commercially produced test methods that are validated for Toxoplasma gondii detection across the range of animal species that can serve as intermediate hosts. The development of such a serological method for animals would allow the diagnosis of toxoplasmosis in individual animals and a higher throughput method for population-level toxoplasmosis surveys. The incorporation of a non-species-specific chimeric protein A/G conjugate into an anti-Toxoplasma immunoglobulin G enzyme-linked immunosorbent assay is described. Serum from potential intermediate hosts was reevaluated using this method and compared with earlier testing using an established agglutination procedure. Very good agreement between the 2 tests was noted (kappa = 0.81), establishing the method as a useful option for veterinary diagnostic testing. PMID- 22529129 TI - Detection of six novel papillomavirus sequences within canine pigmented plaques. AB - In dogs, papillomaviruses are thought to cause oral and cutaneous papillomas and pigmented plaques. Eight canine papillomaviruses have been fully sequenced to date. Four of these canine papillomaviruses, including Canis familiaris papillomavirus (CPV)-3, CPV-4, CPV-5, and CPV-8, were amplified from pigmented plaques. Given the identification of several different canine papillomaviruses within pigmented plaques, it is likely that there are additional papillomavirus sequences that have not been previously identified. The aim of the present study was to amplify papillomavirus DNA from pigmented plaques and identify potentially novel papillomavirus sequences through nucleotide sequence analysis. Polymerase chain reaction was used to amplify DNA sequences of the papillomavirus L1 gene from 27 pigmented plaques. Identification of novel papillomavirus sequences was based on less than 90% shared DNA homology to any known papillomavirus. DNA from 10 different papillomaviruses was identified within the pigmented plaques, including 6 putative novel papillomavirus sequences. CPV-4 was detected within 41% (11/27) of the pigmented plaques, while CPV-5 was identified within 2 pigmented plaques and CPV-3 within a single pigmented plaque. A previously identified novel papillomavirus sequence was identified within 2 pigmented plaques. The remaining 11 pigmented plaques contained 6 papillomavirus DNA sequences that have not been previously reported. These putative novel PV sequences were most similar to the canine papillomaviruses that have been detected within canine pigmented plaques. PMID- 22529130 TI - Clinical, pathological, and genetic characterization of Listeria monocytogenes causing sepsis and necrotizing typhlocolitis and hepatitis in a foal. AB - Listeria monocytogenes was isolated from the blood, lungs, and liver of a 5-week old American Quarter Horse filly that presented with a 2-day history of fever, lethargy, ataxia, and seizure activity. The foal was born on a well-managed breeding facility to a multiparous mare with no periparturient complications. At 8 hr of age, the foal had an adequate passive transfer of immunity (immunoglobulin G > 2,000 mg/dl). Since the time of birth, the foal reportedly had mild, intermittent diarrhea that responded to gastrointestinal protectants and probiotics. Despite prompt and aggressive treatment after hospital referral, the foal's condition deteriorated, and the foal was humanely euthanized. Postmortem gross and histopathologic examination revealed severe hepatitis with necrosis and fibrinonecrotic typhlitis and colitis. In addition to a positive blood culture for L. monocytogenes, immunohistochemistry confirmed the presence of this bacterium in the liver, cecum, and colon. Furthermore, a multiplex polymerase chain reaction identified the etiologic organism as a virulent L. monocytogenes strain. PMID- 22529131 TI - A suprasellar germ cell tumor in a 16-month-old Wagyu heifer calf. AB - A 16-month-old Wagyu heifer calf presented for depression, inappetence, and polyuria/polydipsia. Physical examination revealed that the heifer calf was mentally dull, subjectively small for her age, bradycardic, and hypothermic and had bilateral nasal discharge. Laboratory tests revealed marked serum and cerebrospinal fluid hypernatremia and hyperchloremia with increased cerebrospinal fluid protein. The heifer calf was treated with Ringer solution intravenously for dehydration and electrolyte abnormalities, and with 1 dose each of thiamine and penicillin. Clinical deterioration prompted the owner to elect humane euthanasia. Necropsy revealed a mass lesion in the suprasellar region. Histopathology was consistent with a suprasellar germ cell tumor; the mass stained positive on immunohistochemistry for cytokeratin, vimentin, and c-kit. Suprasellar germ cell tumors have previously been reported in human beings and dogs. PMID- 22529132 TI - Cryptosporidiosis outbreak in captive chelonians (Testudo hermanni) with identification of two Cryptosporidium genotypes. AB - An outbreak of diarrhea in an outdoor group of captive Hermann's tortoises (Testudo hermanni) was associated with fecal shedding of cryptosporidial oocysts, as determined by coproscopic and immunoassay examinations. With partial sequencing of the 18S ribosomal RNA gene, 2 different Cryptosporidium genotypes could be identified in the fecal samples. Cryptosporidium tortoise genotype has previously been found in tortoise and ophidian species, and Cryptosporidium ducismarci has been reported from a snake and a chameleon, and it has been linked to intestinal disease in tortoises. The Hermann's tortoises described were also infected with oxyurid nematodes. Treatment specific for reptilian cryptosporidiosis was administered. The clinical signs and fecal shedding ceased, but 9 months later, diarrhea and fecal shedding were seen in 3 animals again. Either the oocyst shedding was temporarily suppressed below detection limits, or the animals were reinfected by oocysts still present in the environment. At least 1 of the detected Cryptosporidium genotypes was presumed to contribute to the clinical symptoms. PMID- 22529133 TI - Mycobacterium DNA detection in liver and skin of a horse with generalized sarcoidosis. AB - Sarcoidosis is a rare equine skin disease characterized primarily by an exfoliative and granulomatous dermatitis but also presenting granulomatous inflammation of multiple systems. The current report presents the clinical and histopathological findings of sarcoidosis in a 16-year-old American Quarter Horse gelding with nested polymerase chain reaction Mycobacterium spp. DNA detection within hepatic and skin samples. Mycobacterium spp. may play a role in the pathogenesis of equine sarcoidosis as has been proposed for human sarcoidosis. PMID- 22529134 TI - An outbreak of equine botulism type A associated with feeding grass clippings. AB - In September 2010, an outbreak of type A botulism involved 4 horses in northern California that were fed grass clippings obtained from a nearby park. All 4 animals developed a progressive flaccid paralysis syndrome clinically consistent with exposure to preformed Clostridium botulinum neurotoxin (BoNT). Within 48 hr of consuming the grass clippings, all 4 horses showed marked cervical weakness (inability to raise their heads to a normal position) and died or were euthanized within 96 hr. One horse was submitted for diagnostic examination and subsequent necropsy. At necropsy, extensive edema was observed in areas of the nuchal ligament and inguinal fascia. A sample of the grass clippings tested positive for preformed BoNT type A by the mouse bioassay test. Emphasis should be placed on early case recognition, rapid initiation of treatment with the trivalent antitoxin product, and preventing exposure to BoNT in spoiled forages. PMID- 22529135 TI - Fatal Canid herpesvirus 1 infection in an adult dog. AB - Canid herpesvirus 1 (CaHV-1) is a well-known cause of fatal hepatic and renal necrosis in neonatal puppies. In adult dogs infected with CaHV-1, papulovesicular genital lesions may be observed. CaHV-1 infection during pregnancy can lead to embryonic resorption, abortion, and stillbirth. In high-density dog populations, CaHV-1 can also contribute to kennel cough. Furthermore, recent literature has clearly documented that CaHV-1 can induce ocular disease in immature and adult dogs. The current study describes a case of fatal CaHV-1 infection in a 9-year old spayed female Bichon Frise dog. Following a history of vomiting and diarrhea, the dog deteriorated and subsequently died. The main lesions were multifocal areas of necrosis with intranuclear inclusion bodies in the liver, adrenal gland, and small intestine, similar to the lesions observed in CaHV-1-infected puppies. Infection with CaHV-1 was confirmed on samples of liver by polymerase chain reaction, immunohistochemistry, and in situ hybridization. There was no indication of immunosuppression in this dog. Based on the results presented herein, CaHV-1 should be included in the list of differential diagnoses of hepatic necrosis in adult dogs. PMID- 22529136 TI - Metastasizing testicular seminoma in a pet rabbit. AB - In the present study, a case of a spontaneously metastasizing seminoma in 9-year old pet lionhead rabbit is described. The rabbit was presented with unilateral testicular enlargement and a palpable abdominal mass. Spiral computed tomography revealed the presence of an abdominal-pelvic mass in the region of the sublumbar lymph nodes. Testes and lymph nodes were collected, fixed in formalin, and submitted for histopathological examination. Microscopically, the normal architecture of the enlarged testis and lymph node was completely replaced by a diffuse malignant seminoma. PMID- 22529137 TI - Vascular mineralization in the brain of horses. AB - Vascular mineralization (siderocalcinosis) in the brain of horses has been usually assumed to be an incidental age-related finding with no clinic significance. In the present study, eight 15-32-year-old horses of different breeds with cerebral siderocalcinosis were studied. Four of these horses had acute and severe central nervous system clinical signs of unknown etiology, 2 horses had neurological signs of known cause, and 2 horses did not have neurological signs. Gross examination of the brains in 4 animals revealed symmetrical foci of malacia in the cerebellar white matter. Histologically, moderate to severe mineralization of blood vessels and parenchyma were observed in all 8 horses, occasionally associated with necrosis of the adjacent tissue. Some horses were tested by virus isolation, polymerase chain reaction, immunohistochemistry, and serology to investigate Rabies virus; West Nile virus; Equid herpesvirus 1 and 4; Eastern, Western, Venezuelan, and Saint Louis encephalitis virus; and Sarcocystis neurona infection. These tests were negative in all samples analyzed. Brain cholinesterase activity and heavy metal screening were also unremarkable. The significance of the vascular and parenchymal mineralization in the brains of some of these horses remains undetermined. However, the severity of the lesions observed in the brains of some of the animals in the present study, coupled with the negative results for other common causes of neurological disease in horses, suggests a possible relationship between siderocalcinosis and the clinical signs observed. PMID- 22529138 TI - Endogenous lipid (cholesterol) pneumonia in three captive Siberian tigers (Panthera tigris altaica). AB - During the years 2009-2011, 7 Siberian tigers (Panthera tigris altaica), aged between 2 and 14 years, from the Safaripark of Pombia were referred for necropsy to the Department of Animal Pathology of the University of Turin (Italy). Three tigers, aged 10 (2 animals) and 14 years, had multifocal, irregularly distributed, white, soft, subpleural, 3-mm nodules scattered throughout the lungs. Histologically, there was a marked infiltration of macrophages, with foamy cytoplasm, and multinucleate giant cells interspersed with numerous clusters of cholesterol clefts. A mild lymphocytic infiltration was localized around the lesion. The findings were consistent with endogenous lipid pneumonia, which was considered an incidental finding of no clinical significance. PMID- 22529139 TI - Intramedullary lumbosacral teratoma in a domestic ferret (Mustela putorius furo). AB - An 18-month-old, female, spayed domestic ferret (Mustela putorius furo) was presented for progressive hind limb paresis of 1 week duration. The ferret was mentally appropriate but cachexic and ataxic with neurological deficits, which localized the lesion to the lumbosacral region. A depression in the lumbosacral spine was associated with discomfort on palpation. Results of whole body radiographs were consistent with an abnormal angle between vertebrae L6 and S1, which resulted in hyperflexion of the spine. The ferret was euthanized, and histopathological examination revealed an intramedullary lumbosacral teratoma effacing much of the spine in the region of the mass. PMID- 22529140 TI - Lipid emboli in a Vietnamese potbellied pig (Sus scrofa). AB - A 2-year-old, spayed female Vietnamese potbellied pig (Sus scrofa) was evaluated due to polyuria, polydipsia, lethargy, and hyporexia. The pig was obese, and a large abdominal mass was palpated. Additional findings included hypercalcemia, hyperglycemia, glucosuria, and an inflammatory leukogram. At surgery, the abdominal mass was biopsied and found to be bilaterally symmetric adipose tissue with mineralization and granulomatous steatitis. An additional surgery was performed to collect additional diagnostic samples, but the pig died while recovering from anesthesia. A cosmetic necropsy was performed, and lipid emboli were identified microscopically in various tissues. The presence of lipid emboli in the lung and kidney was supported by antifibrinogen immunohistochemistry. Obesity is a common finding in potbellied pigs; however, mineralization and saponification of fat are uncommon, particularly the bilateral symmetrical distribution found in the abdomen of the present case. This may present as a single intra-abdominal mass complicating diagnostic interpretation. Whether mineralization and saponification of fat facilitate the development of fat embolism is undetermined. Lipid emboli should be considered in obese pigs undergoing medical or surgical procedures. Factors that may predispose to the development of fat embolism, such as excessive handling or bruising of fat stores, should be avoided. PMID- 22529142 TI - Cutaneous toxoplasmosis in two dogs. AB - Cutaneous toxoplasmosis has been previously reported in human beings, rarely reported in cats, and reported in 1 dog with systemic toxoplasmosis. The present report describes 2 cases of cutaneous toxoplasmosis in 2 dogs treated with immunosuppressive therapy. One of the dogs developed generalized cutaneous pustules and pruritus, and the other dog only had a single subcutaneous nodule. Microscopically, skin biopsies showed moderate to severe pyogranulomatous and necrotizing dermatitis and panniculitis, with multifocal vasculitis and vascular thrombosis. Single or aggregates of protozoal tachyzoites were mostly intracytoplasmic and occasionally extracellular. The etiology was confirmed in both cases by immunohistochemistry and by polymerase chain reaction assays, which were followed by nucleic acid sequencing. Both patients were treated with clindamycin. The dog with generalized lesions developed pulmonary and neurological signs and was euthanized. The dog with a single nodule recovered completely with no remission of cutaneous lesions. PMID- 22529145 TI - Admission of adolescents to psychiatric units. PMID- 22529141 TI - Locally infiltrative ameloblastic fibroma in a rhesus macaque (Macaca mulatta) with characterizations of its proliferating activity and biological behavior. AB - An 8-year-old male rhesus macaque (Macaca mulatta) presented with unilateral enlargement of the left mandible. Radiographs revealed a marked expansion of the left mandible with a multilocular radiolucent mass with abundant osteolysis. The mass was grossly firm, fleshy, and gelatinous on the cut surface. Histologically, the mass was locally infiltrative and composed of neoplastic epithelial and mesenchymal components that stained positive for cytokeratin and vimentin, respectively. Occasional densely spherical condensations of fibroblasts resembling the cap stage of odontogenesis were present in the mesenchyma. Immunohistochemical staining with Ki-67, S-100, and CD34 indicated that both epithelial and mesenchymal components of the neoplasm had low proliferation. Alcian blue, periodic acid-Schiff, and trichrome stains showed an immature stromal component with no collagen formation. Based on the clinical, histologic, and immunophenotypic features, the tumor was identified as a locally infiltrative ameloblastic fibroma. PMID- 22529146 TI - The difficulties of diagnosing clozapine myocarditis: damned if you do, damned if you don't. PMID- 22529147 TI - Is there a link between street racing and mental health? PMID- 22529151 TI - Obituary: emeritus professor John Cawte (1925-2011). PMID- 22529160 TI - Near-infrared spectroscopy assessment following exercise training in patients with intermittent claudication and in untrained healthy participants. AB - Selected near-infrared spectroscopy (NIRS) parameters were assessed in healthy untrained participants and in peripheral arterial disease (PAD) trained patients to evaluate their usefulness in rehabilitative outcome. Forty-five PAD and 15 healthy participants were studied at entry and at 34 +/- 2 weeks. Healthy participants performed their usual activities. Patients with PAD performed 2 home based programs: structured at prescribed pace (S-pre, n = 31) and unstructured at free pace (U-free, n = 14). We measured ankle-brachial index (ABI), NIRS calf oxygen consumption at rest, NIRS dynamic muscle perfusion during an incremental test, and walking capacity. In all patients with PAD the NIRS parameters significantly increased approaching the stable values of untrained healthy participants. Among PAD, only S-pre group showed significant improvements in hemodynamic, functional, and NIRS parameters with selective adaptations in the worse legs. The assessment of NIRS parameters, that were found stable without training in healthy and modified in PAD only following structured training, might outline the local exercise-induced adaptations. PMID- 22529161 TI - Urinalysis is more specific and urinary neutrophil gelatinase-associated lipocalin is more sensitive for early detection of acute kidney injury. AB - BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) protein is a promising biomarker to detect acute kidney injury (AKI). Earlier detection of AKI could facilitate evaluation of novel therapeutic strategies. METHODS: Random and 24-h urine samples were prospectively obtained from 125 normal volunteers for analytic validation of a urinary enzyme-linked immunosorbent assay for NGAL. For clinical validation of the test, urine from 363 emergency department patients admitted to the hospital was obtained for NGAL enzyme-linked immunosorbent assay and urinalysis and AKI was determined by the use of Acute Kidney Injury Network (AKIN) criteria. RESULTS: NGAL was stable in urine for 7 days when ambient, 4 degrees C or frozen (-20 or -70 degrees C). The assay was linear between 0.24 and 10,000 ng/mL with a limit of quantitation of 0.24 ng/mL. Intra- and inter assay precision were excellent (coefficient of variation <5%); however, urinary white blood cells were associated with increased NGAL levels. The 95th percentile reference value for NGAL in females is <= 65.0 and <= 23.4 ng/mL in males. Urinary NGAL levels increased with AKI stage but had only fair sensitivity (65%) and specificity (65%) to differentiate no AKI versus Stages 1, 2 or 3 (area under the curve 0.70). Urinalysis with microscopy was very specific (91%) but not very sensitive (22%) with an area under the curve of 0.57. CONCLUSIONS: NGAL can be reliably measured in clinical urine samples, although pyuria is an important potential confounder. In our cohort, increased urinary NGAL was associated with AKI by the AKIN criteria; however, the sensitivity and specificity were only fair, in part because patients with pre-renal causes are not excluded by AKIN criteria. Conversely, findings on microscopic urinalysis are very specific for AKI. PMID- 22529162 TI - Investigating FGF-23 concentrations and its relationship with declining renal function in paediatric patients with pre-dialysis CKD Stages 3-5. AB - BACKGROUND: The aims of our study were to investigate (i) the prevalence of elevated fibroblast growth factor-23 (FGF-23), (ii) the relationship between FGF 23 concentrations and level of renal dysfunction and (iii) the main determinants of elevation of FGF-23 concentration in children with pre-dialysis chronic kidney disease (CKD) Stages 3-5. METHODS: In this single-centre prospective observational study, 71 children with pre-dialysis CKD Stages 3-5, aged 11.9 +/- 3.1 years, had FGF-23 levels measured. Anthropometry and routine laboratory investigations were measured. RESULTS: Fourteen (19.7%) patients had normal FGF 23 concentrations defined as < 50 ng/L. FGF-23 [median (interquartile range)] concentrations were 78.7 (55.6-137.6) ng/L and following log transformation normalized data with log FGF-23 [mean (SD)] values of 1.96 +/- 0.4 ng/L. Log FGF 23 concentrations had a negative reciprocal relationship with estimated glomerular filtration rate (eGFR) (P < 0.0001) and 1,25 vitamin D3 levels (P = 0.01) and a positive relationship with phosphate (P = 0.03) and percent fractional excretion of phosphate (P = 0.01) but not with log-intact parathyroid hormone (PTH) (P = 0.22). Multiple linear regression demonstrated a strong relationship between log FGF-23 and eGFR only. CONCLUSIONS: Elevated FGF-23 concentrations were observed in the majority of a carefully managed cohort of children with non-dialysis CKD with a dominant effect on FGF-23 concentrations with glomerular filtration rate (GFR). These data allow the potential confounding effects of PTH and phosphate elevation with declining GFR to be removed, leaving a clearer picture of the FGF-23-GFR relationship. PMID- 22529163 TI - Baseline characteristics of subjects enrolled in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial. AB - BACKGROUND: Secondary hyperparathyroidism (sHPT) and other abnormalities associated with chronic kidney disease-mineral bone disorder can contribute to dystrophic (including vascular) calcification. Dietary modification and variety of medications can be used to attenuate the severity of sHPT. However, it is unknown whether any of these approaches can reduce the high risks of death and cardiovascular disease in patients with end-stage renal disease. METHODS: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial was designed to test the hypothesis that treatment with the calcimimetic agent cinacalcet compared with placebo (on a background of conventional therapy including phosphate binders +/- vitamin D sterols) reduces time to death or non fatal cardiovascular events (specifically myocardial infarction, unstable angina, heart failure and peripheral arterial disease events) among patients on hemodialysis with sHPT. This report describes baseline characteristics of enrolled subjects with a focus on regional variation. RESULTS: There were 3883 subjects randomized from 22 countries, including the USA, Canada, Australia, three Latin American nations, Russia and 15 European nations. The burden of overt cardiovascular disease at baseline was high (e.g. myocardial infarction 12.4%, heart failure 23.3%). The median plasma parathyroid hormone concentration at baseline was 692 pg/mL (10%, 90% range, 363-1694 pg/mL). At baseline, 87.2% of subjects were prescribed phosphate binders and 57.5% were prescribed activated vitamin D derivatives. Demographic data, comorbid conditions and baseline laboratory data varied significantly across regions. CONCLUSIONS: EVOLVE enrolled 3883 subjects on hemodialysis with moderate to severe sHPT. Inclusion of subjects from multiple global regions with varying degrees of disease severity will enhance the external validity of the trial results. PMID- 22529164 TI - Synthesis and fragmentation of hyaluronan in renal ischaemia. AB - BACKGROUND: The turnover of hyaluronan (HA), especially the production of low molecular-weight fragments of HA, was examined in a model of unilateral renal ischaemia-reperfusion (IR) in rats. METHODS: HA was extracted from the outer and inner stripe of the outer medulla (OSOM and ISOM) at different times following IR. Its fragmentation was measured using membrane filtration and size-exclusion chromatography. Quantitative reverse transcription-polymerase chain reaction, zymography and immunohistochemistry were used to assess the expression and localization of various forms of HA synthase (HAS) and hyaluronidase (HYAL). Macrophage infiltration was evaluated using immunohistochemistry. RESULTS: HA accumulated at Day 1 mostly as high-molecular-weight (HMW) species with an elution profile similar to a reference 2500 kDa HA and at Day 14 mostly as medium to low-size fragments. Within 1 day, HAS1 messenger RNA was up-regulated > 50- and 35-fold in OSOM and ISOM, respectively. Thereafter, HAS1 tended to normalize, while HAS2 increased steadily. Both synthetic enzymes were localized around tubules and in the interstitium. Conversely, HYAL1, HYAL2 and global hyaluronidase activity were repressed during the first 24 h. The patterns were identical in the OSOM and ISOM despite markedly different amounts of HA at baseline. There was no obvious correlation between HA deposits and macrophage infiltration. CONCLUSIONS: In the post-ischaemic kidney, HA starts to accumulate at Day 1 mostly as HMW species. Later on, a large proportion becomes degraded into smaller fragments. This pattern is explained by coordinated changes in the expression of HA synthases and hyaluronidases, especially an early induction of HAS1. The current data open the door to timed pharmacological interventions blocking the production of HA fragments. PMID- 22529165 TI - Initial studies of the recovery of Cu from MSWI fly ash leachates using solvent extraction. AB - Large volumes of ash from combustion of municipal solid waste are produced and most of it is landfilled. As this type of ash contains significant amounts of metal compounds the landfilling strategy is not optimal when considered from a resource conservation perspective. A better situation would be created if metals were recovered from the ash. In the present study leaching and solvent extraction was applied for release and separation of copper from municipal solid waste combustion fly ashes. The results showed promising results with Cu yields of 50 95%. The yield was heavily dependent on the efficiency of the initial leaching of Cu from the ash. PMID- 22529166 TI - Amiodarone-induced pulmonary toxicity. PMID- 22529168 TI - Canadian drug shortage: recent history of a mystery. PMID- 22529167 TI - Perspectives of patients, family caregivers and physicians about the use of opioids for refractory dyspnea in advanced chronic obstructive pulmonary disease. AB - BACKGROUND: A recent national practice guideline recommends the use of opioids for the treatment of refractory dyspnea in patients with advanced chronic obstructive pulmonary disease (COPD). We conducted two qualitative studies to explore the experiences of patients and family caregivers with opioids for refractory COPD-related dyspnea and the perspectives and attitudes of physicians toward opioids in this context. METHODS: Patients (n = 8; 5 men, 3 women), their caregivers (n = 12; 5 men, 7 women) and physicians (n = 28, 17 men, 11 women) in Nova Scotia participated in the studies. Semistructured interviews were recorded, transcribed verbatim, coded conceptually and analyzed for emergent themes using interpretive description methodology. RESULTS: Patients reported that opioids provided a sense of calm and relief from severe dyspnea. Family caregivers felt that opioids helped patients to breathe more "normally," observed improvements in patients' symptoms of anxiety and depression, and experienced reductions in their own stress. Patients reported substantial improvements in their quality of life. All patients and family caregivers wanted opioid therapy to continue. Most physicians were reluctant to prescribe opioids for refractory dyspnea, describing a lack of related knowledge and experience, and fears related to the potential adverse effects and legal censure. INTERPRETATION: Discrepancies between the positive experiences of patients and family caregivers with opioids and the reluctance of physicians to prescribe opioids for refractory dyspnea constitute an important gap in care. Bridging this gap will require initiatives to improve the uptake of practice guidelines and to increase confidence in prescribing opioids for dyspnea refractory to conventional treatment. PMID- 22529169 TI - Nocturnal enuresis. PMID- 22529170 TI - Physicians should be paid to report adverse drug reactions, experts say. PMID- 22529173 TI - Seeking hard data on adverse effects of drugs. PMID- 22529171 TI - Surge in Down syndrome prenatal testing anticipated. PMID- 22529174 TI - Residents call for duty hour reform. PMID- 22529175 TI - India to offer microloans for people living with HIV. PMID- 22529177 TI - A patient charter of rights: how to avoid a toothless tiger and achieve system improvement. PMID- 22529178 TI - Using ODIN for a PharmGKB revalidation experiment. AB - The need for efficient text-mining tools that support curation of the biomedical literature is ever increasing. In this article, we describe an experiment aimed at verifying whether a text-mining tool capable of extracting meaningful relationships among domain entities can be successfully integrated into the curation workflow of a major biological database. We evaluate in particular (i) the usability of the system's interface, as perceived by users, and (ii) the correlation of the ranking of interactions, as provided by the text-mining system, with the choices of the curators. PMID- 22529180 TI - Levothyroxine treatment of subclinical hypothyroidism, fatal and nonfatal cardiovascular events, and mortality. AB - BACKGROUND Subclinical hypothyroidism (SCH) has been associated with ischemic heart disease (IHD); however, it is unknown whether treatment of SCH with levothyroxine sodium will reduce the risk of IHD. The aim of this study was to investigate the association between levothyroxine treatment of SCH with IHD morbidity and mortality. METHODS We used the United Kingdom General Practitioner Research Database to identify individuals with new SCH (serum thyrotropin levels of 5.01-10.0 mIU/L and normal free thyroxine levels) recorded during 2001 with outcomes analyzed until March 2009. All analyses were performed separately for younger (40-70 years) and older (>70 years) individuals. Hazard ratios (HRs) for IHD events (fatal and nonfatal) were calculated after adjustment for conventional IHD risk factors, baseline serum thyrotropin levels, and initiation of levothyroxine treatment as a time-dependent covariate. RESULTS Subclinical hypothyroidism was identified in 3093 younger and 1642 older individuals. For a median follow-up period of 7.6 years, 52.8% and 49.9% of younger and older patients with SCH were treated with levothyroxine, respectively. There were 68 incident IHD events in 1634 younger patients treated with levothyroxine (4.2%) vs 97 IHD events in 1459 untreated individuals (6.6%) (multivariate-adjusted HR, 0.61; 95% CI, 0.39-0.95). In contrast, in the older group there were 104 events in 819 treated patients (12.7%) vs 88 events in 823 untreated individuals (10.7%) (HR, 0.99; 95% CI, 0.59-1.33). CONCLUSIONS Treatment of SCH with levothyroxine was associated with fewer IHD events in younger individuals, but this was not evident in older people. An appropriately powered randomized controlled trial of levothyroxine in SCH examining vascular outcomes is now warranted. PMID- 22529179 TI - Towards semi-automated curation: using text mining to recreate the HIV-1, human protein interaction database. AB - Manual curation has long been used for extracting key information found within the primary literature for input into biological databases. The human immunodeficiency virus type 1 (HIV-1), human protein interaction database (HHPID), for example, contains 2589 manually extracted interactions, linked to 14,312 mentions in 3090 articles. The advancement of text-mining (TM) techniques has offered a possibility to rapidly retrieve such data from large volumes of text to a high degree of accuracy. Here, we present a recreation of the HHPID using the current state of the art in TM. To retrieve interactions, we performed gene/protein named entity recognition (NER) and applied two molecular event extraction tools on all abstracts and titles cited in the HHPID. Our best NER scores for precision, recall and F-score were 87.5%, 90.0% and 88.6%, respectively, while event extraction achieved 76.4%, 84.2% and 80.1%, respectively. We demonstrate that over 50% of the HHPID interactions can be recreated from abstracts and titles. Furthermore, from 49 available open-access full-text articles, we extracted a total of 237 unique HIV-1-human interactions, as opposed to 187 interactions recorded in the HHPID from the same articles. On average, we extracted 23 times more mentions of interactions and events from a full-text article than from an abstract and title, with a 6-fold increase in the number of unique interactions. We further demonstrated that more frequently occurring interactions extracted by TM are more likely to be true positives. Overall, the results demonstrate that TM was able to recover a large proportion of interactions, many of which were found within the HHPID, making TM a useful assistant in the manual curation process. Finally, we also retrieved other types of interactions in the context of HIV-1 that are not currently present in the HHPID, thus, expanding the scope of this data set. All data is available at http://gnode1.mib.man.ac.uk/HIV1-text-mining. PMID- 22529181 TI - What is the clinical importance of subclinical hyperthyroidism? PMID- 22529183 TI - Health care as a "market good"? Appendicitis as a case study. PMID- 22529184 TI - IOM's clarion call for health care transformation: the role of nursing science. PMID- 22529182 TI - Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. AB - BACKGROUND: Data from prospective cohort studies regarding the association between subclinical hyperthyroidism and cardiovascular outcomes are conflicting.We aimed to assess the risks of total and coronary heart disease (CHD) mortality, CHD events, and atrial fibrillation (AF) associated with endogenous subclinical hyperthyroidism among all available large prospective cohorts. METHODS: Individual data on 52 674 participants were pooled from 10 cohorts. Coronary heart disease events were analyzed in 22 437 participants from 6 cohorts with available data, and incident AF was analyzed in 8711 participants from 5 cohorts. Euthyroidism was defined as thyrotropin level between 0.45 and 4.49 mIU/L and endogenous subclinical hyperthyroidism as thyrotropin level lower than 0.45 mIU/L with normal free thyroxine levels, after excluding those receiving thyroid-altering medications. RESULTS: Of 52 674 participants, 2188 (4.2%) had subclinical hyperthyroidism. During follow-up, 8527 participants died (including 1896 from CHD), 3653 of 22 437 had CHD events, and 785 of 8711 developed AF. In age- and sex-adjusted analyses, subclinical hyperthyroidism was associated with increased total mortality (hazard ratio[HR], 1.24, 95% CI, 1.06 1.46), CHD mortality (HR,1.29; 95% CI, 1.02-1.62), CHD events (HR, 1.21; 95%CI, 0.99-1.46), and AF (HR, 1.68; 95% CI, 1.16-2.43).Risks did not differ significantly by age, sex, or preexisting cardiovascular disease and were similar after further adjustment for cardiovascular risk factors, with attributable risk of 14.5% for total mortality to 41.5% forAF in those with subclinical hyperthyroidism. Risks for CHD mortality and AF (but not other outcomes) were higher for thyrotropin level lower than 0.10 mIU/L compared with thyrotropin level between 0.10 and 0.44 mIU/L(for both, P value for trend, .03). CONCLUSION: Endogenous subclinical hyperthyroidism is associated with increased risks of total, CHD mortality, and incident AF, with highest risks of CHD mortality and AF when thyrotropin level is lower than 0.10 mIU/L. PMID- 22529185 TI - Stage migration: results of lymph node dissection in the era of modern imaging and invasive staging for lung cancer. AB - OBJECTIVES: Lung cancer staging has improved in recent years. Assuming that contemporary detailed preoperative staging may yield a lower rate of stage change after surgery, we were interested to determine the impact of our lymph node dissections performed at the time of surgical resection. METHODS: We retrospectively analysed a database in our surgical unit that prospectively captured information on all patients assessed and treated for lung cancer. We reviewed the data on patients who underwent lung cancer surgery with curative intent between January 2006 and August 2010 so as to reflect contemporary practice. Prior to potentially curative treatment, patients systematically underwent staging computerized tomography (CT), integrated positron emission tomography (PET) with CT and brain imaging. Enlarged and/or PET-positive nodes were subject to invasive evaluation to establish the nodal status in line with the current guidelines. This was performed by needle aspiration or biopsy usually with ultrasound guidance, endobronchial or endo-oesophageal ultrasound with needle biopsy; mediastinoscopy; mediastinotomy; video-assisted or open surgery. RESULTS: Three hundred and twelve lung cancer resections were performed (a mean age of 68 years [range 42-86] and a male-to-female ratio of 1.14:1). Despite thorough preoperative evaluations, 25.3% of patients had a change in nodal status after lung resection and lymph node dissection; of which 20.8% of patients had a nodal status upstaging. Occult N2 disease was identified in 31 (9.9%) of 312 patients. Patients with cT1 tumours showed a nodal upstaging of 12.3% compared with 25.3% in cT2 tumours. There was no difference in the rate of N2 disease for different tumour histological types. CONCLUSIONS: Despite systematic preoperative staging, there continues to be a high rate of nodal status change following surgical resection and lymph node dissection. If considering non-surgical treatments for the early stage lung cancer, the impact of this discrepancy should be considered. If not, errors in prognosis and in determining correct adjuvant treatment may arise. PMID- 22529186 TI - High expression of octamer-binding transcription factor 4A, prominin-1 and aldehyde dehydrogenase strongly indicates involvement in the initiation of lung adenocarcinoma resulting in shorter disease-free intervals. AB - OBJECTIVES: The increasing relevance of the cancer stem cell (CSC) hypothesis and the impact of CSC-associated markers in the carcinogenesis of solid tumours may provide potential prognostic implications in lung cancer. We propose that a collective genetic analysis of established CSC-related markers will generate data to better define the role of putative CSCs in lung adenocarcinoma (LAC). METHODS: Sixty-four paired tumour and non-tumour biopsies from LAC patients were included in this study. Using the quantitative reverse transcriptase-polymerase chain reaction, we assessed the expression profiles of established CSC-related biomarkers: octamer-binding transcription factor 4 (OCT4A), CD133, aldehyde dehydrogenase (ALDH), BMI-1, ATP-binding cassette subfamily G, member 2 (ABCG2), SRY (sex-determining region Y)-box 2 (SOX2) and uPAR, and evaluated their relation to clinicopathological parameters and disease prognosis. RESULTS: All of the above-mentioned CSC-related markers were detectable in both tumour and corresponding normal tissues. Importantly, expression levels of OCT4A, CD133, BMI 1, SOX2 and uPAR were significantly higher (OCT4A, P = 0.0003; CD133, P = 0.002; BMI-1, P = 0.04; SOX2, P = 0.0003; uPAR, P = 0.03) in the tumour compared with those in the non-tumour tissues. By contrast, the quantities of ACBG2 and ALDH were markedly reduced (ACBG2, P = 0.0006; ALDH, P = 0.007) in the tumour relative to those in the normal biopsies. Using multivariate analysis, elevated ALDH and CD133 revealed significant associations in tumour stage (ALDH, P = 0.03; CD133, P = 0.007) and differentiation (ALDH, P = 0.03; CD133, P = 0.018). We observed that ALDH and OCT4A were associated with nodal status (ALDH, P = 0.05; OCT4A, P = 0.03) having lower mRNA levels in tumours with lymph node metastasis, N+, compared with that in N0. High OCT4A levels were significantly correlated with tumour size of <3 cm, decrease in tumours >3 cm (P = 0.03). Kaplan-Meier correlation analyses, showed that OCT4A and CD133 were correlated to short disease-free intervals (OCT4A, P = 0.047; CD133, P = 0.033) over a period of 29 months. CONCLUSIONS: Our study reveals that CSC-associated markers: OCT4A, CD133 and ALDH are involved in the initial phase of carcinogenesis of LAC, and can be used as predictors of early stage LAC and poor disease-free intervals. In addition, this work validates the relevance of the CSC hypothesis in LAC. PMID- 22529187 TI - Surgical management of pulmonary large cell neuroendocrine carcinomas: a 10-year experience. AB - OBJECTIVES: Large cell neuroendocrine carcinoma (LCNEC) represents a relatively rare and poorly studied entity whose management is not clearly established. The aim of this study was to assess clinico-pathological characteristics, treatment modalities and outcomes of LCNEC. METHODS: A retrospective study of patients operated on for LCNEC between 2000 and 2010 was carried out. RESULTS: Sixty-three patients (49 men, median age 64 years) with pathologically confirmed LCNEC of the lung were operated on between 2000 and 2010. Neoadjuvant chemotherapy was administered in 16 cases. Standard lobectomy, sleeve lobectomy, bilobectomy and pneumonectomy were performed in 63.5%, 9.5%, 1.6% and 15.8% of cases. There were two cases of extended resection. Sublobar resections were performed in four patients. Postoperative mortality was 1.6%. Postoperative staging was IA, IB, IIA, IIB, IIIA, IIIB and IV in 15.9%, 19%, 20.6%, 4.8%, 34.9%, 4.8% and 0% of cases, respectively. Adjuvant treatments were administered in 70% of cases. Overall 5-, and 8- year survival rates were 49.2% (37-61.6%) and 42% (28.8 56.4%), respectively. Multivariate analysis, including age >64 years, cumulative tobacco consumption, size of tumour, pT and pN parameters showed that only age (P = 0.05, RR 2.1 [0.99-4.43]) and pT parameter (P = 0.0078, RR 2.93[1.33-6.46]) were independent predictors of survival. CONCLUSIONS: Surgery may achieve satisfactory results in terms of survival, in spite of the similarities of LCNEC with small cell lung cancer. Multimodality management seems necessary. PMID- 22529188 TI - Surgical correction of hypertrophic obstructive cardiomyopathy in patients with simultaneous obstruction of left ventricular midcavity and right ventricular outflow tract. AB - OBJECTIVE: The classic Morrow technique for hypertrophic obstructive cardiomyopathy (HOCM) in patients with simultaneous obstruction of left ventricular (LV) midcavity and right ventricular outflow tract (RVOT) combined with extreme left ventricular hypertrophy, is not effective. A new technique for HOCM surgical correction in patients with severe hypertrophy is proposed. METHODS: The excision of the asymmetrical hypertrophied area of the interventricular septum (IVS) causing simultaneous midventricular and RVOT obstruction was performed from the conal part of the right ventricle (RV) in the middle part of the right side of the IVS. Conceptually, this approach offers a number of advantages: it affords the excision of the asymmetrically hypertrophied area of the ventricular septum without penetration into the left ventricular cavity, it avoids mechanical damage to the heart conduction system and aortic valve and, for the surgeon, it improves the visual inspection of the area to be resected. Seven patients with the midventricular obstruction of the LV associated with RVOT obstruction [mean New York Heart Association (NYHA) class 3.0] underwent this procedure. The follow-up period was 24.8 +/- 11.3 months. RESULTS: Six patients were free of symptoms (NYHA class I) and one was in NYHA class 2. There were no early or late deaths. The mean value of the echocardiographic intraventricular gradients in the LV decreased from 86.3 +/- 9.9 to 10.3 +/- 5.3 mmHg, the mean value of the gradients in the RVOT decreased to 44.9 +/- 9.6 versus 4.1 +/- 1.2 mmHg. Sinus rhythm without the block of the bundle of the right branch was noted in all patients after surgery. No patients needed the implantation of a cardioverter-defibrillator. CONCLUSION: This technique for the surgical correction of HOCM provides the effective simultaneous elimination of LV midventricular and RVOT obstruction. A major advantage is that injuries, in particular to the conduction system, are easily avoided. PMID- 22529189 TI - Two-stage biventricular rehabilitation for critical aortic stenosis with severe left ventricular dysfunction. AB - OBJECTIVES: Critical aortic valve stenosis (CAS) in the newborn is treated by balloon or surgical aortic valve intervention with nearly equal success, but the subset of patients with severe left ventricular (LV) dilation and dysfunction present a significant mortality risk. We describe a two-stage surgical management approach for those infants who represent an unusually high failure risk for either aortic valvotomy or conventional stage 1 single ventricle (Norwood) palliation because of severe LV dysfunction at the time of presentation. METHODS: A two-stage surgical palliation was undertaken consisting of surgical aortic valvotomy, bilateral pulmonary artery banding and atrial septectomy (stage 1), followed by patch closure of the atrial septal defect, ligation of the ductus arteriosus and removal of the pulmonary artery bands (stage 2) with prostaglandin infusion continued between stages to maintain right ventricular contribution to systemic perfusion via the ductus arteriosus. RESULTS: Four neonates with CAS and severely depressed LV systolic function were treated using this strategy. LV dilation resolved and systolic function improved in three patients after 2, 2 and 4 weeks, enabling stage 2. LV dysfunction did not improve in one patient who expired before conversion to biventricular circulation. Of the three who proceeded to stage 2, one infant continued to have poor biventricular diastolic function that precluded conversion, and this patient also died. The remaining two infants are now alive and well at 34 and 44 months of age. These two had the most severe LV dilation (internal dimension Z-scores of 6.9 and 7.7) and the worst systolic function (fractional shortening 4 and 10%) at presentation, and both were born prematurely (32 and 35 weeks). CONCLUSIONS: A two-stage surgical approach may improve the likelihood of survival in selected patients with CAS presenting with severely depressed LV systolic function. Relief of LV distention may have contributed to the improvement of LV function in these infants. PMID- 22529190 TI - A cardiac gunshot wound--pneumocardium diagnostic of cardiac chamber penetration: demonstration by computed tomographic scanning. PMID- 22529191 TI - Visual cortex excitability and plasticity associated with remission from chronic to episodic migraine. AB - OBJECTIVE: Previous magnetoencephalographic (MEG) studies showed different P100m (where 'm' denotes the magnetic counterpart of P100 in conventional visual evoked potentials) responses between episodic migraine (EM) and chronic migraine (CM) interictally. This study investigated the changes of visual P100m in CM patients who remitted to EM from CM after treatment. METHODS: At baseline, 25 patients with CM were studied interictally. For each patient, 30 sequential blocks of 50 P100m responses were obtained by MEG. Sub-averaged amplitudes at blocks 2, 9, 16, 23 and 30 were further compared with that at block 1 to assess response habituation or potentiation (i.e. significant decrease or increase at either block vs block 1). The same study was repeated in those patients who remitted from CM to EM after topiramate treatment. RESULTS: In total, 10 CM patients remitted to EM after treatment. In the follow-up study of these patients during the interictal stage, the P100m at block 1 decreased in amplitude from 53.6 +/- 6.6 nAm before remission to 43.0 +/- 5.1 nAm (p = 0.028), and the responses at subsequent blocks switched from habituation (amplitude block 30 < block 1 before remission, p = 0.011) to potentiation (block 2 > block 1, p = 0.028). CONCLUSION: The pattern of P100m responses to consecutive stimulation changes with the transition from CM to EM. Visual cortex plasticity might be a potential biomarker reflecting clinical remission of CM. PMID- 22529192 TI - Differences in clinical characteristics and frequency of accompanying migraine features in episodic and chronic cluster headache. AB - INTRODUCTION: Data on clinical differences between episodic (eCH) and chronic cluster headache (cCH) and accompanying migraine features are limited. METHODS: History and clinical features of 209 consecutive cluster headache patients (144 eCH, 65 cCH; male:female ratio 3.4 : 1) were obtained in a tertiary headache centre by face-to-face interviews. Relationship between occurrence of accompanying symptoms, pain intensity, comorbid migraine, and circannual and circadian rhythmicity was analysed. RESULTS: 99.5% of patients reported a minimum of one ipsilateral cranial autonomic symptom (CAS); 80% showed at least three CAS. A seasonal rhythmicity was observed in both eCH and cCH. A comorbid headache disorder occurred in 25%. No significant difference was detected between patients with comorbid migraine and without regarding occurrence of phonophobia, photophobia or nausea during cluster attacks. Patients with comorbid migraine reported allodynia significantly (p = 0.022) more often during cluster attacks than patients without comorbid migraine. CONCLUSION: Occurrence of CAS and attack frequency, as well as periodic patterns of attacks, are relatively uniform in eCH and cCH. Multiple CAS are not related to pain intensity. Allodynia during cluster attacks is a frequent symptom. The unexpectedly high rate of accompanying migrainous features during cluster attacks cannot be explained by comorbid migraine. PMID- 22529193 TI - Paroxysmal sneezing after hypothalamic deep brain stimulation for cluster headache. AB - BACKGROUND: Cluster headache (CH) is the most common of the trigeminal autonomic cephalalgias (TAC), presenting with excruciatingly severe, short-lasting, unilateral headache accompanied by cranial autonomic symptoms. Chronic CH occurs in 10-15% of patients. Deep brain stimulation in the posterior hypothalamic region (hDBS) is successful in treating about 60% of patients otherwise refractory to medical treatment. CASE: A 28-year-old man had hDBS for medically refractory left-sided chronic CH, with a resultant reduction in frequency and severity of his attacks. He developed recurrent paroxysms of sneezing soon after the stimulation was started that have reduced after increasing the pulse width from 60 to 90 us. DISCUSSION: Stimulation of the brain in the region of the posterior hypothalamus could produce sneezing from activation of facial nerve parasympathetic or trigeminal afferent pathway activation through the trigeminohypothalamic tract, or through other central mechanisms. DBS in general offers the opportunity to illuminate our understanding of brain function and for CH offers particular opportunities to understand a devastating primary headache syndrome. PMID- 22529194 TI - P2X7 receptor blockade reverses purinergic facilitation of neck muscle nociception in mice. AB - INTRODUCTION: Facilitation of neck muscle nociception mediated via purinergic signalling may play a role in the pathophysiology of tension-type headache (TTH). The present study addressed reversal of purinergic facilitation of brainstem nociception via P2X7 antagonist action in anaesthetized mice. METHODS: Following administration of alpha,beta-meATP (i.m. 20 uL/min, 20 uL each) into semispinal neck muscles, the impact of neck muscle nociceptive input on brainstem processing was monitored by the jaw-opening reflex in anaesthetized mice (n = 20). The hypothesized involvement of the P2X7 receptor in the alpha,beta-meATP effect was addressed with i.p. (systemic) and i.m. (semispinalis, 20 uL/min, 20 uL each) administration of P2X7 inhibitor A438079 during established facilitation; i.p. saline served as control. RESULTS: alpha,beta-meATP reliably induced jaw-opening reflex facilitation (256 +/- 48% (mean +/- SEM), n = 20). I.p. A438079 (150, 300 umol/kg) completely reversed this alpha,beta-meATP effect dose-dependently. Neither saline nor intramuscular A438079 (100 uM) altered facilitated brainstem nociceptive processing. DISCUSSION: These data suggest that muscular structures are not directly involved in the P2X7 antagonist-mediated reversal of purinergic facilitation. Instead, involvement of neuronal structures, particularly of the central nervous system, seems more probable. The results from this animal experimental model may point to involvement of purinergic P2X7 receptors in TTH pathophysiology and may suggest potential future targets for its pharmacological treatment. PMID- 22529195 TI - Predilection to deafferentation pain syndrome after radiosurgery in cluster headache. AB - Cluster-tic syndrome is a rare, disabling disorder. We report the first case of cluster-tic syndrome with a successful response to stereotactic radiosurgery. After failing optimal medical treatment, a 58-year-old woman suffering from cluster-tic syndrome was treated with gamma knife radiosurgery. The trigeminal nerve and sphenopalatine ganglion were targeted with a maximum dose of 85 and 90 Gy respectively. The patient experienced a complete resolution of the initial pain, but developed, as previously described after radiosurgical treatment for cluster headache, a trigeminal nerve dysfunction. This suggests that trigeminal nerve sensitivity to radiosurgery can be extremely different depending on the underlying pathological condition, and that there is an abnormal sensitivity of the trigeminal nerve in cluster headache patients. We do not recommend trigeminal nerve radiosurgery for treatment of cluster headache. PMID- 22529196 TI - Motion processing deficits in migraine are related to contrast sensitivity. AB - BACKGROUND: There are conflicting reports concerning the ability of people with migraine to detect and discriminate visual motion. Previous studies used different displays and none adequately assessed other parameters that could affect performance, such as those that could indicate precortical dysfunction. METHODS: Motion-direction detection, discrimination and relative motion thresholds were compared from participants with and without migraine. Potentially relevant visual covariates were included (contrast sensitivity; acuity; stereopsis; visual discomfort, stress, triggers; dyslexia). RESULTS: For each task, migraine participants were less accurate than a control group and had impaired contrast sensitivity, greater visual discomfort, visual stress and visual triggers. Only contrast sensitivity correlated with performance on each motion task; it also mediated performance. CONCLUSIONS: Impaired performance on certain motion tasks can be attributed to impaired contrast sensitivity early in the visual system rather than a deficit in cortical motion processing per se. There were, however, additional differences for global and relative motion thresholds embedded in noise, suggesting changes in extrastriate cortex in migraine. Tasks to study the effects of noise on performance at different levels of the visual system and across modalities are recommended. A battery of standard visual tests should be included in any future work on the visual system and migraine. PMID- 22529197 TI - Impact of short-term high-fat feeding and insulin-stimulated FGF21 levels in subjects with low birth weight and controls. AB - OBJECTIVE: Fibroblast growth factor 21 (FGF21) is a metabolic factor involved in glucose and lipid metabolism. However, little is known about the physiological role of FGF21 during a dietary challenge in humans. RESEARCH DESIGN AND METHODS: Twenty healthy low birth weight (LBW) with known risk of type 2 diabetes and 26 control (normal birth weight (NBW)) young men were subjected to 5 days of high fat (HF) overfeeding (+50%). Basal and clamp insulin-stimulated serum FGF21 levels were examined before and after the diet, and FGF21 mRNA expression was measured in muscle and fat biopsies respectively. RESULTS: Five days of HF overfeeding diet significantly (P<0.001) increased fasting serum FGF21 levels in both the groups (P<0.001). Furthermore, insulin infusion additionally increased serum FGF21 levels to a similar extent in both the groups. Basal mRNA expression of FGF21 in muscle was near the detection limit and not present in fat in both the groups before and after the dietary challenge. However, insulin significantly (P<0.001) increased FGF21 mRNA in both muscle and fat in both the groups during both diets. CONCLUSION: Short-term HF overfeeding markedly increased serum FGF21 levels in healthy young men with and without LBW but failed to increase muscle or fat FGF21 mRNA levels. This suggests that the liver may be responsible for the rise of serum FGF21 levels during overfeeding. In contrast, the increase in serum FGF21 levels during insulin infusion may arise from increased transcription in muscle and fat. We speculate that increased serum FGF21 levels during HF overfeeding may be a compensatory response to increase fatty acid oxidation and energy expenditure. PMID- 22529198 TI - Depth and duration of hypoglycaemia achieved during the insulin tolerance test. AB - CONTEXT: The insulin tolerance test (ITT) is the gold standard for assessment of the pituitary adrenal axis but its use is limited because of concerns relating to the risk of hypoglycaemia. OBJECTIVE: This study examined the depth and duration of hypoglycaemia achieved during the test in a large cohort of patients. DESIGN: Two hundred and twenty ITTs were performed from 2005 to 2010. SETTING: A 1200-bed University Teaching Hospital. PATIENTS: Two hundred and twenty ITTs were carried out in patients with suspected or known pituitary disorders. INTERVENTIONS: Intravenous insulin was administered to achieve nadir plasma glucose (NPG) of 2.2 mmol/l (39.6 mg/dl). Blood chemistry to show the cortisol and GH response to hypoglycaemic stress was measured. MAIN OUTCOME MEASURES: Predictors of depth and duration of hypoglycaemia, adverse events and within-subject variability of nadir glucose, peak cortisol and peak GH were studied. RESULTS: Thirty percent of the cohort achieved a nadir glucose of <2.0 mmol/l (36 mg/dl) that lasted for 60 min or more. The NPG correlated positively with fasting plasma glucose (FPG; r=0:56; P<0.0005), insulin dose (r=0.27; P<0.0005) and weight (r=0.21; P<0.004). The within subject variability of nadir glucose was 15.2%, peak cortisol was 11.7% and peak GH was 6.4%. The factors determining nadir blood glucose were FPG (b=0.56, P<0.0005, 20% contribution) and weight (b=0.14, P<0.05, 2% contribution). The five patients with adverse events had NPG and insulin dose comparable with the rest of the population. CONCLUSIONS: The hypoglycaemia achieved during the ITT is much lower than the target required. However, adverse events are few and do not relate to the depth of hypoglycaemia. PMID- 22529200 TI - The Neurology((r)) resident & fellow section: 2004-2012. PMID- 22529199 TI - Ichthyotic skin disorders in the neonate. PMID- 22529201 TI - Worldwide status of clinical experimentation with stem cells in neurologic diseases. PMID- 22529202 TI - Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. AB - OBJECTIVE: To provide updated evidence-based recommendations for the preventive treatment of migraine headache. The clinical question addressed was: What pharmacologic therapies are proven effective for migraine prevention? METHODS: The authors analyzed published studies from June 1999 to May 2009 using a structured review process to classify the evidence relative to the efficacy of various medications available in the United States for migraine prevention. RESULTS AND RECOMMENDATIONS: The author panel reviewed 284 abstracts, which ultimately yielded 29 Class I or Class II articles that are reviewed herein. Divalproex sodium, sodium valproate, topiramate, metoprolol, propranolol, and timolol are effective for migraine prevention and should be offered to patients with migraine to reduce migraine attack frequency and severity (Level A). Frovatriptan is effective for prevention of menstrual migraine (Level A). Lamotrigine is ineffective for migraine prevention (Level A). PMID- 22529203 TI - Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. AB - OBJECTIVE: To provide updated evidence-based recommendations for the preventive treatment of migraine headache. The clinical question addressed was: Are nonsteroidal anti-inflammatory drugs (NSAIDs) or other complementary treatments effective for migraine prevention? METHODS: The authors analyzed published studies from June 1999 to May 2009 using a structured review process to classify the evidence relative to the efficacy of various medications for migraine prevention. RESULTS: The author panel reviewed 284 abstracts, which ultimately yielded 49 Class I or Class II articles on migraine prevention; of these 49, 15 were classified as involving nontraditional therapies, NSAIDs, and other complementary therapies that are reviewed herein. RECOMMENDATIONS: Petasites (butterbur) is effective for migraine prevention and should be offered to patients with migraine to reduce the frequency and severity of migraine attacks (Level A). Fenoprofen, ibuprofen, ketoprofen, naproxen, naproxen sodium, MIG-99 (feverfew), magnesium, riboflavin, and subcutaneous histamine are probably effective for migraine prevention (Level B). Treatments considered possibly effective are cyproheptadine, Co-Q10, estrogen, mefenamic acid, and flurbiprofen (Level C). Data are conflicting or inadequate to support or refute use of aspirin, indomethacin, omega-3, or hyperbaric oxygen for migraine prevention. Montelukast is established as probably ineffective for migraine prevention (Level B). PMID- 22529205 TI - Corpus callosum lipoma. PMID- 22529204 TI - Contextual social cognition and the behavioral variant of frontotemporal dementia. AB - The significance of social situations is commonly context-embedded. Although the role of context has been extensively studied in basic sensory processing or simple stimulus-response settings, its relevance for social cognition is unknown. We propose the social context network model (SCNM), a fronto-insular-temporal network responsible for processing social contextual effects. The SCNM may 1) update the context and use it to make predictions, 2) coordinate internal and external milieus, and 3) consolidate context-target associative learning. We suggest the behavioral variant of frontotemporal dementia (bvFTD) as a specific disorder in which the reported deficits in social cognition (e.g., facial recognition, empathy, decision-making, figurative language, theory of mind) can be described as context impairments due to deficits in the SCNM. Disruption of orbitofrontal-amygdala circuit, as well as the frontal, temporal, and insular atrophy in bVFTD, suggests a relationship between context-sensitive social cognition and SCNM. In considering context as an intrinsic part of social cognition, we highlight the need for a situated cognition approach in social cognition research as opposed to an abstract, universal, and decontextualized approach. The assessment of context-dependent social cognition paradigms, the SCNM, and their possible application to neuropsychiatric disorders may provide new insight into bvFTD and other related frontal disorders. PMID- 22529206 TI - Combined MRI lesions and relapses as a surrogate for disability in MS. PMID- 22529207 TI - Predicting outcome of IV thrombolysis-treated ischemic stroke patients: the DRAGON score. PMID- 22529208 TI - Residency training: the King-Devick test and sleep deprivation: study in pre- and post-call neurology residents. AB - OBJECTIVE: The current study investigates the effect of sleep deprivation on the speed and accuracy of eye movements as measured by the King-Devick (K-D) test, a <1-minute test that involves rapid number naming. METHODS: In this cohort study, neurology residents and staff from the University of Pennsylvania Health System underwent baseline followed by postcall K-D testing (n = 25); those not taking call (n = 10) also completed baseline and follow-up K-D testing. Differences in the times and errors between baseline and follow-up K-D scores were compared between the 2 groups. RESULTS: Residents taking call had less improvement from baseline K-D times when compared to participants not taking call (p < 0.0001, Wilcoxon rank sum test). For both groups, the change in K-D time from baseline was correlated to amount of sleep obtained (r(s) = -0.50, p = 0.002) and subjective evaluation of level of alertness (r(s) = 0.33, p = 0.05) but had no correlation to time since last caffeine consumption (r(s) = -0.13, p = 0.52). For those residents on their actual call night, the duration of sleep obtained did not correlate with change in K-D scores from baseline (r(s) = 0.13, p = 0.54). CONCLUSIONS: The K-D test is sensitive to the effects of sleep deprivation on cognitive functioning, including rapid eye movements, concentration, and language function. As with other measures of sleep deprivation, K-D performance demonstrated significant interindividual variability in vulnerability to sleep deprivation. Severe fatigue appears to reduce the degree of improvement typically observed in K-D testing. PMID- 22529210 TI - Teaching neuroimages: differential diagnosis of scapular winging. PMID- 22529211 TI - Preventing Alzheimer disease with exercise? PMID- 22529212 TI - A genome-wide expression profile of adrenocortical cells in knockout mice lacking steroidogenic acute regulatory protein. AB - Steroidogenic acute regulatory protein (StAR) facilitates cholesterol transfer into the inner mitochondrial membrane in the acute phase of steroidogenesis. Mice lacking StAR (Star(-/-)) share phenotypes with human individuals having congenital lipoid adrenal hyperplasia including compromised production of steroid hormones and florid accumulation of cholesterol esters in adrenal glands and gonads. To define a specific pattern of molecular changes with StAR deficiency, we performed transcriptome analysis of adrenal cells selectively isolated by fluorescent-activated cell sorting at embryonic d 17.5 or 18.5 in seven wild-type (Star(+/+)) or four Star(-/-) mice having the transgene targeting the enhanced green fluorescent protein to cell lineages that express StAR. A gene expression profile was obtained by whole-mouse genome microarray and confirmed by quantitative real-time PCR, identifying 1206 and 767 significantly up-regulated and down-regulated genes, respectively, in Star(-/-) mice compared with Star(+/+) mice (fold difference >= 2 and P value < 0.05 with false discovery rate < 0.2). In Star(-/-) mice, expression levels of genes involved in cholesterol efflux and the inflammatory response were significantly up-regulated, whereas those related to steroid hormone biosynthesis or cholesterol biosynthesis and influx were not significantly changed. Immunoreactive Iba1 or F4/80 (macrophage marker) in adrenal glands of Star(-/-) mice was detected not only in an increased number of resident macrophages but also in most adrenocortical cells. These findings expand our understanding of the pathophysiology of adrenal glands with the disruption of StAR and propose a reciprocal interaction between adrenocortical cells and resident macrophages inside adrenal glands of Star(-/-) mice. PMID- 22529213 TI - Mild endoplasmic reticulum stress augments the proinflammatory effect of IL-1beta in pancreatic rat beta-cells via the IRE1alpha/XBP1s pathway. AB - The prevalence of obesity and type 1 diabetes in children is increasing worldwide. Insulin resistance and augmented circulating free fatty acids associated with obesity may cause pancreatic beta-cell endoplasmic reticulum (ER) stress. We tested the hypothesis that mild ER stress predisposes beta-cells to an exacerbated inflammatory response when exposed to IL-1beta or TNF-alpha, cytokines that contribute to the pathogenesis of type 1 diabetes. INS-1E cells or primary rat beta-cells were exposed to a low dose of the ER stressor cyclopiazonic acid (CPA) or free fatty acids, followed by low-dose IL-1beta or TNF-alpha. ER stress signaling was inhibited by small interfering RNA. Cells were evaluated for proinflammatory gene expression by RT-PCR and ELISA, gene reporter activity, p65 activation by immunofluorescence, and apoptosis. CPA pretreatment enhanced IL-1beta- induced, but not TNF-alpha-induced, expression of chemokine (C C motif) ligand 2, chemokine (C-X-C motif) ligand 1, inducible nitric oxide synthase, and Fas via augmented nuclear factor kappaB (NF-kappaB) activation. X box binding protein 1 (XBP1) and inositol-requiring enzyme 1, but not CCAAT/enhancer binding protein homologous protein, knockdown prevented the CPA induced exacerbation of NF-kappaB-dependent genes and decreased IL-1beta-induced NF-kappaB promoter activity. XBP1 modulated NF-kappaB activity via forkhead box O1 inhibition. In conclusion, rat beta-cells facing mild ER stress are sensitized to IL-1beta, generating a more intense and protracted inflammatory response through inositol-requiring enzyme 1/XBP1 activation. These observations link beta cell ER stress to the triggering of exacerbated local inflammation. PMID- 22529215 TI - Effect of atorvastatin monotherapy and low-dose atorvastatin/ezetimibe combination on fasting and postprandial triglycerides in combined hyperlipidemia. PMID- 22529214 TI - Dynamic changes in cervical glycosaminoglycan composition during normal pregnancy and preterm birth. AB - Glycosaminoglycans (GAG) have diverse functions that regulate macromolecular assembly in the extracellular matrix. During pregnancy, the rigid cervix transforms to a pliable structure to allow birth. Quantitative assessment of cervical GAG is a prerequisite to identify GAG functions in term and preterm birth. In the current study, total GAG levels increased at term, yet the abundance, chain length, and sulfation levels of sulfated GAG remained constant. The increase in total GAG resulted exclusively from an increase in hyaluronan (HA). HA can form large structures that promote increased viscosity, hydration, and matrix disorganization as well as small structures that have roles in inflammation. HA levels increased from 19% of total GAG in early pregnancy to 71% at term. Activity of the HA-metabolizing enzyme, hyaluronidase, increased in labor, resulting in metabolism of large to small HA. Similar to mice, HA transitions from high to low molecular weight in term human cervix. Mouse preterm models were also characterized by an increase in HA resulting from differential expression of the HA synthase (Has) genes, with increased Has1 in preterm in contrast to Has2 induction at term. The Has2 gene but not Has1 is regulated in part by estrogen. These studies identify a shift in sulfated GAG dominance in the early pregnant cervix to HA dominance in term and preterm ripening. Increased HA synthesis along with hyaluronidase-induced changes in HA size in mice and women suggest diverse contributions of HA to macromolecular changes in the extracellular matrix, resulting in loss of tensile strength during parturition. PMID- 22529217 TI - Adaptive immunity is related to coronary artery disease severity after acute coronary syndrome in subjects with metabolic syndrome. AB - Metabolic syndrome (MetS) is an inflammatory state associated with high coronary disease risk. Inflammation and adaptive immunity modulate atherosclerosis and plaque instability. We examined early changes in anti-oxidized low-density lipoprotein (LDL) (anti-oxLDL) autoantibodies (Abs) in patients with MetS after an acute coronary syndrome (ACS). Patients of both genders (n=116) with MetS were prospectively included after an acute myocardial infarction (MI) or hospitalization due to unstable angina. Anti-oxLDL Abs (IgG class) were assayed at baseline, three and six weeks after ACS. The severity of coronary disease was evaluated by the Gensini score. We observed a decrease in anti-oxLDL Abs titers (p<0.002 vs. baseline), mainly in males (p=0.01), in those under 65 y (p=0.03), and in subjects with Gensini score above median (p=0.04). In conclusion, early decrease in circulating anti-oxLDL Abs is associated with coronary disease severity among subjects with MetS. PMID- 22529218 TI - Neural correlates of forethought in ADHD. AB - OBJECTIVE: The purpose of the present investigation was to delineate the neural correlates of forethought in the ADHD children relative to typically developing (TD) children. METHOD: In all, 21 TD and 23 ADHD adolescents underwent functional magnetic resonance imaging (fMRI) while performing a forethought task. The participants had to identify congruent and incongruent stimuli from cartoon stories representing sequences of action. RESULTS: The findings revealed significantly greater activation in the bilateral prefrontal cortex (PFC) in TD versus ADHD children, and more activation in the cerebellar vermis in the adolescents with ADHD versus TD, during performance of the incongruent relative to congruent condition. CONCLUSION: The inverse pattern of activation of the PFC and the cerebellar vermis in both groups could reflect a compensatory role played by the cerebellum or suggest the malfunction of the neural network between those regions in ADHD. Further research of the neural correlates of forethought in ADHD is warranted. PMID- 22529219 TI - Maternal smoking during pregnancy and ADHD: a comprehensive clinical and neurocognitive characterization. AB - INTRODUCTION: Evidence from epidemiological studies has consistently shown an association between maternal smoking during pregnancy (MSDP) and attention deficit/hyperactivity disorder (ADHD). The objective of this study is to test the hypothesis that children with ADHD exposed to MSDP show a distinctive clinical and neurocognitive profile when compared with unexposed children. METHODS: Four hundred and thirty-six children diagnosed with ADHD were stratified by exposure to MSDP and compared with regard to severity of illness, comorbidity, IQ, and executive function as assessed by a battery of neuropsychological tests. All comparisons were adjusted for socioeconomic status, ethnicity, mother's age at child's birth, and maternal alcohol consumption during pregnancy. RESULTS: Exposed children had more severe behavioral problems with greater externalizing symptoms and more conduct and oppositional defiant disorder items, lower verbal IQ, and a sluggish cognitive profile on the Continuous Performance Test (CPT). Linear regression analyses revealed a dose-response relationship between the average number of cigarettes smoked per day during pregnancy and verbal IQ, CPT omission errors T score and several other clinical variables. CONCLUSIONS: These results suggest that MSDP is associated with a more severe form of ADHD, characterized by more severe clinical manifestations and poorer neuropsychological performance. This phenotypic signature associated with MSDP may help to identify a more homogenous subgroup of children with ADHD. PMID- 22529220 TI - An internet survey of use, opinions and preferences for smoking cessation medications: nicotine, varenicline, and bupropion. AB - INTRODUCTION: We assessed use, compliance and preferences among smoking cessation medications in a "real world" sample of current and former smokers. METHODS: Internet survey on a smoking cessation website (French/English, 2008-2010) to assess use of nicotine replacement therapies (NRT), varenicline, and bupropion. RESULTS: There were 885 participants (39% current smokers, 61% former smokers), the majority of the sample (70%) was female. The most frequently used medications were, in order: patches (40%), varenicline (23%), nicotine gum (16%), nicotine lozenge/tablet (10%), bupropion (8%), and inhaler (3%). Satisfaction, perceived relief of craving/withdrawal and effectiveness were best for varenicline and lowest for gum. In current users, duration of use was longest for gum (121 days), lozenge/tablet (152 days) and shortest for patch (25 days). Daily use was good for lozenge (9 pieces/day) but less than recommended for gum (6 pieces/day) and inhaler (2 plugs/day). People who tried more than 1 medication found varenicline more effective and satisfactory than NRT or bupropion; and users preferred patch to gum. By smoking status, former smokers had more education, reported greater use of medications (daily, over time) and reported more satisfaction with medications than current smokers. CONCLUSIONS: An Internet survey showed smoking cessation medications differed significantly in perceived effectiveness, satisfaction, and smoking status (former vs. current smoking). Except for lozenge/tablet, insufficient daily use remained a problem with acute NRTs. For all medications, improving outcome may require better instruction for proper use, approval of new indications (precessation) or development of new medications that bypass compliance issues that undermine success. PMID- 22529221 TI - Prevalence and psychosocial determinants of nicotine dependence in nine countries of the former Soviet Union. AB - INTRODUCTION: Despite the high prevalence of smoking in the former Soviet Union (fSU), particularly among men, there is very little information on nicotine dependence in the region. The study aim was to describe the prevalence of nicotine dependence in 9 countries of the fSU and to examine the psychosocial factors associated with nicotine dependence. METHODS: Cross-sectional, nationally representative surveys using multistage random sampling were conducted in 2010 with men and women aged 18 years and over in Armenia, Azerbaijan, Belarus, Georgia, Kazakhstan, Kyrgyzstan, Moldova, Russia, and Ukraine. The main outcome of interest was nicotine dependence using the Fagerstrom Test for Nicotine Dependence. Multivariate regression analysis was then used to explore the influence of a range of psychosocial factors on higher nicotine dependence. RESULTS: Mean nicotine dependence among men in the region as a whole was 3.96, with high dependence ranging from 17% in Belarus to 40% in Georgia. Among women, mean dependence was 2.96, with a prevalence of high dependence of 11% for the region. Gender (men), younger age of first smoking, lower education level, not being a member of an organization, bad household economic situation, high alcohol dependence, and high psychological distress showed significant associations with higher nicotine dependence. CONCLUSIONS: High nicotine dependence among men was recorded in a number of study countries. Findings highlight the need for tobacco programmes to target early age smokers and less educated and poorer groups and suggest common ground for programmes seeking to reduce nicotine dependence, harmful alcohol use, and psychological distress. PMID- 22529222 TI - Flavored and nonflavored smokeless tobacco products: rate, pattern of use, and effects. AB - INTRODUCTION: The initiation and maintenance of tobacco use are influenced by several factors, but of equal and often overlooked importance, until recently, is the palatability of the product. Because of the role that flavor may play in the initiation and maintenance of tobacco use, the Food and Drug Administration has decided to ban the use of flavorings, other than menthol, from cigarettes. To date, little attention has been paid to the impact of flavoring in smokeless tobacco (ST) products. METHODS: This study combined the data from 5 previously completed treatment or switching studies to examine the choice of brand flavor in the course of ST use, from initiation to regular use. RESULTS: The analyses revealed that a majority of subjects' first and current choice of product was flavored, specifically mint or wintergreen, and that a significant number of ST users switched to a flavored brand after already initiating ST use with a regular nonflavored product. In this population, however, flavored products did not appear to lead to greater dependence or increased exposure to nicotine or carcinogens. CONCLUSIONS: More treatment seeking ST users began by using mint flavored product and switched to and were current users of mint-flavored products. It is possible that mint products play a role in the initiation and maintenance of ST use. PMID- 22529223 TI - Nicotine levels in electronic cigarettes. AB - INTRODUCTION: The electronic cigarette (EC) is a plastic device that imitates conventional cigarettes and was developed to deliver nicotine in a toxin-free vapor. Nicotine in a solution is heated and vaporized when a person puffs through the device and is inhaled as a vapor into the mouth. The EC is a new product on the market and little is known about its safety and nicotine delivery efficacy. The aim of the study was to analyze nicotine levels in vapor generated from various EC brands and models. The study was designed to assess efficacy and consistency of various ECs in converting nicotine to vapor and to analyze dynamics of nicotine vaporization. METHODS: Sixteen ECs were selected based on their popularity in the Polish, U.K. and U.S. markets. Vapors were generated using an automatic smoking machine modified to simulate puffing conditions of real EC users. Nicotine was absorbed in a set of washing bottles with methanol and analyzed with gas chromatography. RESULTS: The total level of nicotine in vapor generated by 20 series of 15 puffs varied from 0.5 to 15.4 mg. Most of the analyzed ECs effectively delivered nicotine during the first 150-180 puffs. On an average, 50%-60% of nicotine from a cartridge was vaporized. CONCLUSIONS: ECs generate vapor that contains nicotine, but EC brands and models differ in their efficacy and consistency of nicotine vaporization. In ECs, which vaporize nicotine effectively, the amount inhaled from 15 puffs is lower compared with smoking a conventional cigarette. PMID- 22529225 TI - The psychopharmacological management of RLS in psychiatric conditions: a review of the literature. AB - BACKGROUND: Restless legs syndrome (RLS) is a movement disorder treated with dopamine agonists. RLS is often diagnosed as a comorbid condition with psychiatric disorders, which are treated with dopamine antagonists or antidepressants resulting in onset or exacerbation of RLS symptoms. OBJECTIVES: The objectives of this article are to provide a review of the literature to (a) describe the comorbidity of psychiatric disorders associated with RLS, (b) identify the treatment of psychiatric disorders that cause or exacerbate symptoms of RLS, and (c) provide clinical recommendations for psychiatric health care providers. DESIGN: A review of the literature of English articles included the databases of Medline, Pubmed, PsychINFO, and CINAHL for "Restless Legs Syndrome" with major psychiatric disorders including mood disorders (depression and bipolar), schizophrenia, and anxiety disorders (anxiety, panic disorder, obsessive compulsive disorder). The PRISMA guidelines were used to improve the reporting of the review of the literature. RESULTS: There were 61 articles that met the inclusion and exclusion criteria identified for the review of the literature, including RLS with mood disorders (n = 36), schizophrenia (n = 9), and anxiety disorders (n = 16). CONCLUSIONS: Clinical trials are lacking on the best treatment for persons with RLS and psychiatric disorders; the most rigorous research found in the literature related to depression and anxiety. Studies lack evidence to document the best practice for persons with RLS and comorbid psychiatric disorders. Psychiatric health care providers should be aware of RLS, which is influenced by psychiatric medications. PMID- 22529224 TI - Tobacco dependence among intermittent smokers. AB - INTRODUCTION: Intermittent smokers (ITS) are an increasingly prevalent segment of smokers, yet it is unknown whether or how dependence severity may vary across ITS. METHODS: Participants were 217 ITS (70 never daily ITS [NITS], 138 converted ITS [CITS], and 9 unknown), who smoked 4-27 days per month, and 197 daily smokers (DS), recruited for a study on smoking patterns. Participants completed questionnaires on dependence (time to first cigarette after waking, Fagerstrom Test of Nicotine Dependence [FTND], Nicotine Dependence Syndrome Scale [NDSS], Wisconsin Inventory of Smoking Dependence Motives [WISDM], and Hooked on Nicotine Checklist [HONC]) and recorded each cigarette in real time over 3 weeks using Ecological Momentary Assessment. Logistic regression assessed differences in dependence between groups (DS vs. ITS; CITS vs. NITS), and least squares regression examined associations between dependence and smoking behavior (mean, maximum cigarettes per day; proportion of days smoked; longest period of abstinence) within ITS. RESULTS: As expected, DS were significantly more dependent than ITS: FTND, NDSS, and WISDM discriminated between ITS and DS with greater than 90% accuracy. Similarly, among ITS, NITS demonstrated lower dependence than CITS. Within ITS, dependence measures also correlated with observed smoking rate and duration of abstinence. CONCLUSIONS: The study confirmed that DS are more dependent than ITS and that CITS are more dependent than NITS. Importantly, ITS exhibit features of dependence, and there is meaningful variation in dependence within ITS, suggesting that some aspects of dependence may appear with very infrequent smoking. Future work should examine implications for ITS' potential progression to daily smoking and cessation outcome. PMID- 22529226 TI - Adolescent dating violence and Peplau's dimensions of the self. AB - BACKGROUND: Adolescent dating violence (ADV) is a significant public health problem. Despite an association between ADV and lowered self-esteem, little research has examined identity issues in persons who have experienced ADV. OBJECTIVES: To use Peplau's model of the dimensions of the self to describe identity concerns in those who experienced ADV. DESIGN: Verbatim comments that met Peplau's definitions of self-statements were extracted from the narratives of 50 young adults who had taken part in an ongoing qualitative study on ADV. The statements were coded into Peplau's dimensions using content analysis. RESULTS: 175 verbatim sentences were extracted from the narratives. The statements addressed 16 different personal characteristics, including strength, sociability, and aggressiveness. CONCLUSIONS: Individuals who have experienced ADV have a number of concerns related to self-concept. Recommendations are made regarding how these concerns may be addressed with investigative counseling, as described by Peplau. PMID- 22529229 TI - Variation in use of dual-chamber implantable cardioverter-defibrillators: results from the national cardiovascular data registry. AB - BACKGROUND: Among patients without an indication for a pacemaker, current evidence is inconclusive whether a dual-chamber implantable cardioverter defibrillator (ICD) is superior to a single-chamber ICD. The current use of dual chamber ICDs is not well characterized. METHODS: We conducted a cross-sectional study exploring hospital-level variation in the use of dual-chamber ICDs across the United States. Patients receiving a primary prevention ICD from 2006 through 2009 without a documented indication for a pacemaker were included. Multivariate hierarchical logistic regression was used to explore patient, health care provider, and physician factors related to the use of a dual-chamber device. RESULTS: Dual-chamber devices were implanted in 58% of the 87,115 patients without a pacing indication among 1293 hospitals, with hospital rates ranging from 0% in 33 centers to 100% in 109 centers. In multivariate analysis, geographic region was a strong independent predictor of dual-chamber device use, ranging from 36.4% in New England (reference region) to 66.4% in the Pacific region (odds ratio [OR], 5.25; 95% CI, 3.35-8.21). Hospital clustering was assessed using a median OR which was 3.96, meaning that 2 identical patients at different hospitals would have nearly a 4-fold difference in their chance of receiving a dual-chamber ICD. CONCLUSIONS: Use of dual-chamber ICDs for the primary prevention of sudden cardiac death among patients without an indication for permanent pacing varies markedly at the hospital level in the United States. This is a clear example of how practice can vary independent of patient factors. PMID- 22529231 TI - Cardiovascular primary prevention: how high should we set the bar? AB - Recent trials in cardiovascular medicine have contradicted current practice, and, accordingly, are medical reversals. Extended-release niacin and fenofibrate have failed to provide mortality benefit when added to statin therapy, though both drugs have been used for this purpose for years. Cardiovascular primary prevention is no small matter. Annual spending on statins exceeded $19 billion in 2005, ezetimibe cost over $5 billion in 2007, and fenofibrate costs passed $1 billion in 2009. Given the tremendous price of these medications, and recent trials that have undermined years of practice, we propose that the bar for cardiovascular primary prevention has been raised. Large studies must show improvements in overall mortality before novel agents are recommended and used. The implications of this proposal are considered. PMID- 22529227 TI - Drug-eluting vs bare-metal stents in primary angioplasty: a pooled patient-level meta-analysis of randomized trials. AB - BACKGROUND: Concerns have emerged regarding a higher risk of stent thrombosis after drug-eluting stent (DES) implantation, especially in the setting of ST segment elevation myocardial infarction (STEMI). Our objective was to perform a meta-analysis using individual patient data to evaluate the long-term safety and effectiveness of DES compared with bare-metal stents (BMS) in patients undergoing primary percutaneous coronary intervention for STEMI. DATA SOURCES: Formal searches of electronic databases (MEDLINE and CENTRAL) and scientific session presentations from January 2000 to June 2011. STUDY SELECTION: We examined all completed randomized trials of DES for STEMI. DATA EXTRACTION: Individual patient data. DATA SYNTHESIS: Individual patient data were obtained from 11 of 13 trials identified, including a total of 6298 patients (3980 [63.2%] randomized to DES [99% sirolimus-eluting or paclitaxel-eluting stents] and 2318 [36.8%] randomized to BMS). At long-term follow-up (mean [SD], 1201 [440] days), DES implantation significantly reduced the occurrence of target-vessel revascularization (12.7% vs 20.1%; hazard ratio [95% CI], 0.57 [0.50-0.66]; P < .001, P value for heterogeneity, .20), without any significant difference in terms of mortality, reinfarction, and stent thrombosis. However, DES implantation was associated with an increased risk of very late stent thrombosis and reinfarction. CONCLUSIONS: The present pooled patient-level meta-analysis demonstrates that among patients with STEMI undergoing primary percutaneous coronary intervention, sirolimus eluting and paclitaxel-eluting stents compared with BMS are associated with a significant reduction in target-vessel revascularization at long-term follow-up. Although there were no differences in cumulative mortality, reinfarction, or stent thrombosis, the incidence of very late reinfarction and stent thrombosis was increased with these DES. PMID- 22529233 TI - Treatment intensity at the end of life in older adults receiving long-term dialysis. PMID- 22529235 TI - Comparing physician-reported cancer management plans with Medicare services received. PMID- 22529236 TI - Resistance training promotes cognitive and functional brain plasticity in seniors with probable mild cognitive impairment. PMID- 22529237 TI - Primary care providers' response to the US Preventive Services Task Force draft recommendations on screening for prostate cancer. PMID- 22529238 TI - Coronary artery calcium scanning and conflicts of interest. PMID- 22529239 TI - Cardiac implantable electronic devices: prevention starts from ethics. PMID- 22529240 TI - Alternative estimates for the likelihood that a woman with screen-detected breast cancer has had her "life saved" by that screening. PMID- 22529241 TI - Realistic appraisal of the benefits of mammography. PMID- 22529243 TI - Defining developmental enamel defect-associated childhood caries: where are we now? PMID- 22529242 TI - Hypoplasia-associated severe early childhood caries--a proposed definition. AB - We propose a new classification of severe early childhood caries (S-ECC): hypoplasia-associated severe early childhood caries (HAS-ECC). This form of caries affects mostly young children living at or below poverty, characterized by structurally damaged primary teeth that are particularly vulnerable to dental caries. These predisposing developmental dental defects are mainly permutations of enamel hypoplasia (EHP). Anthropologists and dental researchers consider EHP an indicator for infant and maternal stresses including malnutrition, a variety of illnesses, and adverse birthing conditions. Differentiation of HAS-ECC from other forms of early childhood caries is warranted because of its distinct etiology, clinical presentation, and eventual management. Defining HAS-ECC has important clinical implications: Therapies that control or prevent other types of caries are likely to be less effective with HAS-ECC because the structural integrity of the teeth is compromised prior to their emergence into the oral cavity. By the time these children present to the dentist, the treatment options often become limited to surgical management under general anesthesia. To prevent HAS-ECC, dentists must partner with other health providers to develop interventions that begin with pregnant mothers, with the aim of eliminating or ameliorating the covariates accompanying poverty, including better pre- and post natal care and nutrition. PMID- 22529244 TI - Where is family in the family nurse practitioner program? Results of a U.S. family nurse practitioner program survey. AB - Though recent progress in family nursing science can serve the family nurse practitioner (FNP) to intervene in the regulation of family health, whether those advances are taught to FNP students has been unclear. All 266 FNP programs in the United States were invited to participate in a survey to assess the content and clinical application of family nursing theories in the curriculum. The majority of FNP programs frame family as the context of care for the individual. Though FNP students receive a foundation in family nursing theory in core courses, they are not usually expected to use family assessment methods in clinical practicum courses or to plan interventions for the family as the unit of care. The authors challenge educators to consider family nursing science as an essential component of the FNP program as the Doctor of Nursing Practice (DNP) evolves and becomes requisite for entry into advanced practice. PMID- 22529245 TI - Human colostrum and breast milk contain high levels of TNF-related apoptosis inducing ligand (TRAIL). AB - BACKGROUND: TNF-related apoptosis inducing ligand (TRAIL) is a pleiotropic cytokine, which plays a key role in the immune system as well as in controlling the balance of apoptosis and proliferation in various organs and tissues. OBJECTIVE: To investigate the presence and levels of soluble TRAIL in human colostrum and milk. METHODS: The levels of soluble human TRAIL were measured in human colostrum (day 2 after delivery) and breast milk (day 5 after delivery). The presence of TRAIL was also measured in infant formula. RESULTS: Levels of soluble TRAIL in the colostrum and mature human milk were, respectively, at least 400 and 100 fold higher than those detected in human serum. No TRAIL was detected in formula. CONCLUSION: Human soluble TRAIL is present at extremely high levels in human colostrum and human milk and might have a significant role in mediating the anti-cancer activity of human milk. PMID- 22529246 TI - CSF biomarkers for secondary prevention trials: why markers of amyloid deposition and neurodegeneration are both important. PMID- 22529248 TI - Frontotemporal dementia in elderly individuals. AB - OBJECTIVE: To determine whether cases of frontotemporal lobar degeneration (FTLD) do exist in elderly individuals and have clinical and neuropathological features distinct from those with presenile onset. DESIGN: Retrospective matched cohort study. SETTING: Regional Neuroscience Centre, North East England. PATIENTS: We compared clinicopathological features of 11 cases of FTLD in elderly individuals with 19 cases of presenile-onset FTLD. RESULTS: Retrospective case note analysis showed that most elderly patients with FTLD had behavioral features consistent with orbitofrontal and basofrontal involvement, similar to presenile-onset FTLD, though symptomatic memory loss was present in 91% (10 of 11) of elderly patients with FTLD compared with only 36% (7 of 19) of patients with presenile-onset FTLD. Neuropathologically, the group of elderly patients with FTLD comprised 7 with FTLD-TDP-43, 1 with ubiquitin-positive FTLD, 2 with FTLD-tau/Pick disease, and 1 with FTLD-tau/neurofibrillary tangle-predominant dementia with TDP-43, a composition similar to presenile-onset FTLD. However, hippocampal sclerosis was more common in elderly patients with FTLD than patients with presenile-onset FTLD (82% vs 37%) and more severe in elderly patients with FTLD (P < .05). By contrast, severe atrophy of the frontal and temporal lobes was less common in elderly patients with FTLD (frontal: 45%; temporal: 27%) than patients with presenile-onset FTLD (frontal: 63%; temporal: 78%). Elderly patients with FTLD represented 3.2% of all elderly patients with dementia autopsied at Newcastle General Hospital. CONCLUSIONS: Frontotemporal lobar degeneration in elderly patients does exist as a separate entity from presenile-onset FTLD. Its main features include (1) clinically frequent memory loss and behavioral change predominating over language and semantic dysfunction and (2) neuropathologically prominent hippocampal sclerosis but less pronounced cortical lobar atrophy. Clinically, FTLD in elderly patients is underrecognized and should be considered in the elderly subjects presenting with an "atypical Alzheimer disease" phenotype. PMID- 22529249 TI - Thoracal radiculopathy owing to disc herniation. PMID- 22529250 TI - Spinal cord glioma metastasizing to the brain. PMID- 22529252 TI - Waiting for a miracle. PMID- 22529251 TI - A new measure of time-varying association for shared frailty models with bivariate current status data. AB - In this paper, a new measure for assessing the temporal variation in the strength of association in bivariate current status data is proposed. This novel measure is relevant for shared frailty models. We show that this measure is particularly convenient, owing to its connection with the relative frailty variance and its interpretability in suggesting appropriate frailty models. We introduce a method of estimation and standard errors for this measure. We discuss its properties and compare it to an existing measure of association applicable to current status data. Small sample performance of the measure in realistic scenarios is investigated using simulations. The methods are illustrated with bivariate serological survey data on a pair of infections, where the time-varying association is likely to represent heterogeneities in activity levels and/or susceptibility to infection. PMID- 22529247 TI - Amyloid-beta--associated clinical decline occurs only in the presence of elevated P-tau. AB - OBJECTIVE: To elucidate the relationship between the 2 hallmark proteins of Alzheimer disease (AD), amyloid-(Abeta) and tau, and clinical decline over time among cognitively normal older individuals. DESIGN: A longitudinal cohort of clinically and cognitively normal older individuals assessed with baseline lumbar puncture and longitudinal clinical assessments. SETTING: Research centers across the United States and Canada. PATIENTS: We examined 107 participants with a Clinical Dementia Rating (CDR) of 0 at baseline examination. MAIN OUTCOME MEASURES: Using linear mixed effects models, we investigated the relationship between cerebrospinal fluid (CSF) phospho-tau 181 (p-tau(181p)),CSF Abeta(1-42), and clinical decline as assessed using longitudinal change in global CDR, CDR-Sum of Boxes, and the Alzheimer Disease Assessment Scale-cognitive subscale. RESULTS: We found a significant relationship between decreased CSF Abeta(1-42) and longitudinal change in global CDR,CDR-Sum of Boxes, and Alzheimer Disease Assessment Scale-cognitive subscale in individuals with elevated CSFp-tau(181p). In the absence of CSF p-tau(181p), the effect of CSF Abeta(1-42) on longitudinal clinical decline was not significantly different from 0. CONCLUSIONS: In cognitively normal older individuals,A-associated clinical decline during a mean of 3 years may occur only in the presence of ongoing downstream neurodegeneration. PMID- 22529253 TI - Functional T cells targeting NY-ESO-1 or Melan-A are predictive for survival of patients with distant melanoma metastasis. AB - PURPOSE: To analyze the prognostic relevance of circulating T cells responding to NY-ESO-1, Melan-A, MAGE-3, and survivin in patients with melanoma with distant metastasis. PATIENTS AND METHODS: We examined 84 patients with follow-up after analysis (cohort A), 18 long-term survivors with an extraordinarily favorable course of disease before analysis (> 24 months survival after first occurrence of distant metastases; cohort B), and 14 healthy controls. Circulating antigen reactive T cells were characterized by intracellular cytokine staining after in vitro stimulation. RESULTS: In cohort A patients, the presence of T cells responding to peptides from NY-ESO-1, Melan-A, or MAGE-3 and the M category according to the American Joint Committee on Cancer classification were significantly associated with survival. T cells responding to NY-ESO-1 and Melan A (hazard ratios, 0.29 and 0.18, respectively) remained independent prognostic factors in Cox regression analysis and were superior to the M category in predicting outcome. Median survival of patients possessing T cells responding to NY-ESO-1, Melan-A, or both was 21 months, compared with 6 months for all others. NY-ESO-1-responsive T cells were detected in 70% of cohort A patients surviving > 18 months and in 50% of cohort B patients. Melan-A responses were found in 42% and 47% of patients in cohorts A and B, respectively. In contrast, the proportion was only 22% for NY-ESO-1 and 23% for Melan-A in those who died within 6 months. CONCLUSION: The presence of circulating T cells responding to Melan-A or NY-ESO-1 had strong independent prognostic impact on survival in advanced melanoma. Our findings support the therapeutic relevance of Melan-A and NY-ESO-1 as targets for immunotherapy. PMID- 22529254 TI - Impact of intraoperative stimulation brain mapping on glioma surgery outcome: a meta-analysis. AB - PURPOSE: Surgery for infiltrative gliomas aims to balance tumor removal with preservation of functional integrity. The usefulness of intraoperative stimulation mapping (ISM) has not been addressed in randomized trials. This study addresses glioma surgery outcome on the basis of a meta-analysis of observational studies. METHODS: A systematic search retrieved 90 reports published between 1990 and 2010 with 8,091 adult patients who had resective surgery for supratentorial infiltrative glioma, with or without ISM. Quality criteria consisted of postoperative neurologic examination details and follow-up timing. New postoperative neurologic deficits were categorized on the basis of timing and severity. Meta-analysis with a Bayesian random effects model determined summary event rates of deficits as well as gross total resection rate and eloquent locations. Meta-regression analysis explored heterogeneity among studies. RESULTS: Late severe neurologic deficits were observed in 3.4% (95% CI, 2.3% to 4.8%) of patients after resections with ISM, and in 8.2% (95% CI, 5.7% to 11.4%) of patients after resections without ISM (adjusted odds ratio, 0.39; 95% CI, 0.23 to 0.64). The percentages of radiologically confirmed gross total resections were 75% (95% CI, 66% to 82%) with ISM and 58% (95% CI, 48% to 69%) without ISM. Eloquent locations were involved in 99.9% (95% CI, 99.9% to 100%) of resections with ISM and in 95.8% (95% CI, 73.1% to 99.8%) of resections without ISM. Relevant sources of heterogeneity among studies were ISM, continent, and academic setting. CONCLUSION: Glioma resections using ISM are associated with fewer late severe neurologic deficits and more extensive resection, and they involve eloquent locations more frequently. This indicates that ISM should be universally implemented as standard of care for glioma surgery. PMID- 22529255 TI - Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. AB - PURPOSE: Preoperative chemoradiotherapy (CRT) has been established as standard treatment for locally advanced rectal cancer after first results of the CAO/ARO/AIO-94 [Working Group of Surgical Oncology/Working Group of Radiation Oncology/Working Group of Medical Oncology of the Germany Cancer Society] trial, published in 2004, showed an improved local control rate. However, after a median follow-up of 46 months, no survival benefit could be shown. Here, we report long term results with a median follow-up of 134 months. PATIENTS AND METHODS: A total of 823 patients with stage II to III rectal cancer were randomly assigned to preoperative CRT with fluorouracil (FU), total mesorectal excision surgery, and adjuvant FU chemotherapy, or the same schedule of CRT used postoperatively. The study was designed to have 80% power to detect a difference of 10% in 5-year overall survival as the primary end point. Secondary end points included the cumulative incidence of local and distant relapses and disease-free survival. RESULTS: Of 799 eligible patients, 404 were randomly assigned to preoperative and 395 to postoperative CRT. According to intention-to-treat analysis, overall survival at 10 years was 59.6% in the preoperative arm and 59.9% in the postoperative arm (P = .85). The 10-year cumulative incidence of local relapse was 7.1% and 10.1% in the pre- and postoperative arms, respectively (P = .048). No significant differences were detected for 10-year cumulative incidence of distant metastases (29.8% and 29.6%; P = .9) and disease-free survival. CONCLUSION: There is a persisting significant improvement of pre- versus postoperative CRT on local control; however, there was no effect on overall survival. Integrating more effective systemic treatment into the multimodal therapy has been adopted in the CAO/ARO/AIO-04 trial to possibly reduce distant metastases and improve survival. PMID- 22529256 TI - Long-term follow-up of a paradigm-changing study: the paradigm still holds. PMID- 22529257 TI - Induction chemotherapy and dose intensification of the radiation boost in locally advanced anal canal carcinoma: final analysis of the randomized UNICANCER ACCORD 03 trial. AB - PURPOSE: Concomitant radiochemotherapy (RCT) is the standard for locally advanced anal canal carcinoma (LAACC). Questions regarding the role of induction chemotherapy (ICT) and a higher radiation dose in LAACC are pending. Our trial was designed to determine whether dose escalation of the radiation boost or two cycles of ICT before concomitant RCT lead to an improvement in colostomy-free survival (CFS). PATIENTS AND METHODS: Patients with tumors >= 40 mm, or < 40 mm and N1-3M0 were randomly assigned to one of four treatment arms: (A) two ICT cycles (fluorouracil 800 mg/m(2)/d intravenous [IV] infusion, days 1 through 4 and 29 to 32; and cisplatin 80 mg/m(2) IV, on days 1 and 29), RCT (45 Gy in 25 fractions over 5 weeks, fluorouracil and cisplatin during weeks 1 and 5), and standard-dose boost (SD; 15 Gy); (B) two ICT cycles, RCT, and high-dose boost (HD; 20-25 Gy); (C): RCT and SD boost (reference arm); and (D) RCT and HD boost. RESULTS: Two hundred eighty-three of 307 patients achieved full treatment. With a median follow-up period of 50 months, the 5-year CFS rates were 69.6%, 82.4%, 77.1%, and 72.7% in arms A, B, C, and D, respectively. Considering the 2 * 2 factorial analysis, the 5-year CFS was 76.5% versus 75.0% (P = .37) in groups A and B versus C and D, respectively (ICT effect), and 73.7% versus 77.8% in groups A and C versus B and D, respectively (RT-dose effect; P = .067). CONCLUSION: Using CFS as our main end point, we did not find an advantage for either ICT or HD radiation boost in LAACC. Nevertheless, the results of the most treatment intense arm B should prompt the design of further intensification studies. PMID- 22529258 TI - Adjuvant chemotherapy for non-small-cell lung cancer in the elderly: a population based study in Ontario, Canada. AB - PURPOSE: Non-small-cell lung cancer (NSCLC) is predominantly a disease of the elderly. Retrospective analyses of the National Cancer Institute of Canada Clinical Trials Group JBR.10 trial and the Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis suggest that the elderly benefit from adjuvant chemotherapy. However, the elderly were under-represented in these studies, raising concerns regarding the reproducibility of the study results in clinical practice. PATIENTS AND METHODS: By using the Ontario Cancer Registry, we identified 6,304 patients with NSCLC who were treated with surgical resection from 2001 to 2006. Registry data were linked to electronic treatment records. Uptake of chemotherapy was compared across age groups: younger than 70, 70 to 74, 75 to 79, and >= 80 years. As a proxy of survival benefit from chemotherapy, we compared survival of patients diagnosed from 2004 to 2006 with survival of those diagnosed from 2001 to 2003. Hospitalization rates within 6 to 24 weeks of surgery served as a proxy of severe chemotherapy-related toxicity. RESULTS: In all, 2,763 (43.8%) of 6,304 surgical patients were elderly (age >= 70 years). Uptake of adjuvant chemotherapy in the elderly increased from 3.3% (2001 to 2003) to 16.2% (2004 to 2006). Among evaluable elderly patients, 70% received cisplatin and 28% received carboplatin based regimens. Requirements for dose adjustments or drug substitutions were similar across age groups. Hospitalization rates within 6 to 24 weeks of surgery were similar across age groups (28.0% for patients age < 70 years; 27.8% for patients age >= 70 years; P = .54). Four-year survival of elderly patients increased significantly (47.1% for patients diagnosed from 2001 to 2003; 49.9% for patients diagnosed from 2004 to 2006; P = .01). Survival improved in all subgroups except patients age >= 80 years. CONCLUSION: Uptake of adjuvant chemotherapy for NSCLC increased in patients age 70 years or older following reporting of pivotal adjuvant chemotherapy trials, but it remained below that for patients younger than age 70 years. Adoption of adjuvant chemotherapy appears to be associated with significant survival benefit in the elderly (age >= 70 years), with tolerability apparently similar to that of patients who are younger than age 70 years. PMID- 22529259 TI - Outcome after surgery alone or with restricted use of chemotherapy for patients with low-risk neuroblastoma: results of Children's Oncology Group study P9641. AB - PURPOSE: The primary objective of Children's Oncology Group study P9641 was to demonstrate that surgery alone would achieve 3-year overall survival (OS) >= 95% for patients with asymptomatic International Neuroblastoma Staging System stages 2a and 2b neuroblastoma (NBL). Secondary objectives focused on other low-risk patients with NBL and on those who required chemotherapy according to protocol defined criteria. PATIENTS AND METHODS: Patients underwent maximally safe resection of tumor. Chemotherapy was reserved for patients with, or at risk for, symptomatic disease, with less than 50% tumor resection at diagnosis, or with unresectable progressive disease after surgery alone. RESULTS: For all 915 eligible patients, 5-year event-free survival (EFS) and OS were 89% +/- 1% and 97% +/- 1%, respectively. For patients with asymptomatic stage 2a or 2b disease, 5-year EFS and OS were 87% +/- 2% and 96% +/- 1%, respectively. Among patients with stage 2b disease, EFS and OS were significantly lower for those with unfavorable histology or diploid tumors, and OS was significantly lower for those >= 18 months old. For patients with stage 1 and 4s NBL, 5-year OS rates were 99% +/- 1% and 91% +/- 1%, respectively. Patients who required chemotherapy at diagnosis achieved 5-year OS of 98% +/- 1%. Of all patients observed after surgery, 11.1% experienced recurrence or progression of disease. CONCLUSION: Excellent survival rates can be achieved in asymptomatic low-risk patients with stages 2a and 2b NBL after surgery alone. Immediate use of chemotherapy may be restricted to a minority of patients with low-risk NBL. Patients with stage 2b disease who are older or have diploid or unfavorable histology tumors fare less well. Future studies will seek to refine risk classification. PMID- 22529260 TI - Bevacizumab advanced melanoma (BEAM) was a positive trial. PMID- 22529261 TI - Adjuvant therapy in the treatment of biliary tract cancer: a systematic review and meta-analysis. AB - PURPOSE: The benefit of adjuvant therapy (AT) for biliary tract cancer (BTC) is unclear, with conflicting results from nonrandomized studies. We report a systematic review and meta-analysis to determine the impact of AT on survival. METHODS: Studies published between 1960 and November 2010, which evaluated adjuvant chemotherapy (CT), radiotherapy (RT), or both (CRT) compared with curative-intent surgery alone for resected BTC were included. Only tumors of the gallbladder and bile ducts were assessed. Published data were extracted and computed into odds ratios (ORs) for death at 5 years. Subgroup analyses of benefit based on lymph node (LN) or resection margin positivity (R1) were prespecified. Data were weighted by generic inverse variance and pooled using random-effect modeling. RESULTS: Twenty studies involving 6,712 patients were analyzed. There was a nonsignificant improvement in overall survival with any AT compared with surgery alone (pooled OR, 0.74; P = .06). There was no difference between gallbladder and bile duct tumors (P = .68). The association was significant when the two registry analyses were excluded. Those receiving CT or CRT derived statistically greater benefit than RT alone (OR, 0.39, 0.61, and 0.98, respectively; P = .02). The greatest benefit for AT was in those with LN positive disease (OR, 0.49; P = .004) and R1 disease (OR, 0.36; P = .002). CONCLUSION: This analysis supports AT for BTC. Prospective randomized trials are needed to provide better rationale for this commonly used strategy. On the basis of our data, such trials could involve two active comparators rather than a no treatment arm among patients with LN-positive or R1 disease. PMID- 22529262 TI - Intravascular B-cell lymphoma: an elusive diagnosis. PMID- 22529263 TI - Going beyond 7 + 3 regimens in the treatment of adult acute myeloid leukemia. PMID- 22529264 TI - Impact of a bladder cancer diagnosis on smoking behavior. AB - PURPOSE: Bladder cancer is the second most common tobacco-related malignancy. A new bladder cancer diagnosis may be an opportunity to imprint smoking cessation. Little is known about the impact of a diagnosis of bladder cancer on patterns of tobacco use and smoking cessation among patients with incident bladder cancer. PATIENTS AND METHODS: A simple random sample of noninvasive bladder cancer survivors diagnosed in 2006 was obtained from the California Cancer Registry. Respondents completed a survey on history of tobacco use, beliefs regarding bladder cancer risk factors, and physician influence on tobacco cessation. Respondents were compared by smoking status. Those respondents smoking at diagnosis were compared with general population controls obtained from the California Tobacco Survey to determine the impact of a diagnosis of bladder cancer on patterns of tobacco use. RESULTS: The response rate was 70% (344 of 492 eligible participants). Most respondents (74%) had a history of cigarette use. Seventeen percent of all respondents were smoking at diagnosis. Smokers with a new diagnosis of bladder cancer were almost five times as likely to quit smoking as smokers in the general population (48% v 10%, respectively; P < .001). The bladder cancer diagnosis and the advice of the urologist were the reasons cited most often for cessation. Respondents were more likely to endorse smoking as a risk factor for bladder cancer when the urologist was the source of their understanding. CONCLUSION: The diagnosis of bladder cancer is an opportunity for smoking cessation. Urologists can play an integral role in affecting the patterns of tobacco use of those newly diagnosed. PMID- 22529265 TI - OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. AB - PURPOSE: This randomized, multicenter, blinded, placebo-controlled phase III trial tested the efficacy and safety of bevacizumab (BV) with gemcitabine and carboplatin (GC) compared with GC in platinum-sensitive recurrent ovarian, primary peritoneal, or fallopian tube cancer (ROC). PATIENTS AND METHODS: Patients with platinum-sensitive ROC (recurrence >= 6 months after front-line platinum-based therapy) and measurable disease were randomly assigned to GC plus either BV or placebo (PL) for six to 10 cycles. BV or PL, respectively, was then continued until disease progression. The primary end point was progression-free survival (PFS) by RECIST; secondary end points were objective response rate, duration of response (DOR), overall survival, and safety. RESULTS: Overall, 484 patients were randomly assigned. PFS for the BV arm was superior to that for the PL arm (hazard ratio [HR], 0.484; 95% CI, 0.388 to 0.605; log-rank P < .0001); median PFS was 12.4 v 8.4 months, respectively. The objective response rate (78.5% v 57.4%; P < .0001) and DOR (10.4 v 7.4 months; HR, 0.534; 95% CI, 0.408 to 0.698) were significantly improved with the addition of BV. No new safety concerns were noted. Grade 3 or higher hypertension (17.4% v < 1%) and proteinuria (8.5% v < 1%) occurred more frequently in the BV arm. The rates of neutropenia and febrile neutropenia were similar in both arms. Two patients in the BV arm experienced GI perforation after study treatment discontinuation. CONCLUSION: GC plus BV followed by BV until progression resulted in a statistically significant improvement in PFS compared with GC plus PL in platinum sensitive ROC. PMID- 22529266 TI - Phase I study of RO4929097, a gamma secretase inhibitor of Notch signaling, in patients with refractory metastatic or locally advanced solid tumors. AB - PURPOSE: To determine the maximum-tolerated dose (MTD) and assess safety, pharmacokinetics, pharmacodynamics, and evidence of antitumor activity of RO4929097, a gamma secretase inhibitor of Notch signaling in patients with advanced solid malignancies. PATIENTS AND METHODS: Patients received escalating doses of RO4929097 orally on two schedules: (A) 3 consecutive days per week for 2 weeks every 3 weeks; (B) 7 consecutive days every 3 weeks. To assess reversible CYP3A4 autoinduction, the expanded part of the study tested three dosing schedules: (B) as above; modified A, 3 consecutive d/wk for 3 weeks; and (C) continuous daily dosing. Positron emission tomography scans with [(18)F]fluorodeoxyglucose (FDG-PET) were used to assess tumor metabolic effects. RESULTS: Patients on schedule A (n = 58), B (n = 47), and C (n = 5; expanded cohort) received 302 cycles of RO4929097. Common grade 1 to 2 toxicities were fatigue, thrombocytopenia, fever, rash, chills, and anorexia. Transient grade 3 hypophosphatemia (dose-limiting toxicity, one patient) and grade 3 pruritus (two patients) were observed at 27 mg and 60 mg, respectively; transient grade 3 asthenia was observed on schedule A at 80 mg (one patient). Tumor responses included one partial response in a patient with colorectal adenocarcinoma with neuroendocrine features, one mixed response (stable disease) in a patient with sarcoma, and one nearly complete FDG-PET response in a patient with melanoma. Effect on CYP3A4 induction was observed. CONCLUSION: RO4929097 was well tolerated at 270 mg on schedule A and at 135 mg on schedule B; the safety of schedule C has not been fully evaluated. Further studies are warranted on the basis of a favorable safety profile and preliminary evidence of clinical antitumor activity. PMID- 22529267 TI - Pushing the limits of glioma resection using electrophysiologic brain mapping. PMID- 22529268 TI - Ectopic restriction of DNA repair reveals that UNG2 excises AID-induced uracils predominantly or exclusively during G1 phase. AB - Immunoglobulin (Ig) affinity maturation requires the enzyme AID, which converts cytosines (C) in Ig genes into uracils (U). This alone produces C:G to T:A transition mutations. Processing of U:G base pairs via U N-glycosylase 2 (UNG2) or MutSalpha generates further point mutations, predominantly at G:C or A:T base pairs, respectively, but it is unclear why processing is mutagenic. We aimed to test whether the cell cycle phase of U processing determines fidelity. Accordingly, we ectopically restricted UNG2 activity in vivo to predefined cell cycle phases by fusing a UNG2 inhibitor peptide to cell cycle-regulated degradation motifs. We found that excision of AID-induced U by UNG2 occurs predominantly during G1 phase, inducing faithful repair, mutagenic processing, and class switching. Surprisingly, UNG2 does not appear to process U:G base pairs at all in Ig genes outside G1 phase. PMID- 22529270 TI - Evaluation of a clinical dehydration scale in children requiring intravenous rehydration. AB - OBJECTIVES: To evaluate the reliability and validity of a previously derived clinical dehydration scale (CDS) in a cohort of children with gastroenteritis and evidence of dehydration. METHODS: Participants were 226 children older than 3 months who presented to a tertiary care emergency department and required intravenous rehydration. Reliability was assessed at treatment initiation, by comparing the scores assigned independently by a trained research nurse and a physician. Validity was assessed by using parameters reflective of disease severity: weight gain, baseline laboratory results, willingness of the physician to discharge the patient, hospitalization, and length of stay. RESULTS: Interobserver reliability was moderate, with a weighted kappa of 0.52 (95% confidence interval [CI] 0.41, 0.63). There was no correlation between CDS score and percent weight gain, a proxy measure of fluid deficit (Spearman correlation coefficient = -0.03; 95% CI -0.18, 0.12). There were, however, modest and statistically significant correlations between CDS score and several other parameters, including serum bicarbonate (Pearson correlation coefficient = -0.35; 95% CI -0.46, -0.22) and length of stay (Pearson correlation coefficient = 0.24; 95% CI 0.11, 0.36). The scale's discriminative ability was assessed for the outcome of hospitalization, yielding an area under the receiver operating characteristic curve of 0.65 (95% CI 0.57, 0.73). CONCLUSIONS: In children administered intravenous rehydration, the CDS was characterized by moderate interobserver reliability and weak associations with objective measures of disease severity. These data do not support its use as a tool to dictate the need for intravenous rehydration or to predict clinical course. PMID- 22529269 TI - Artemis C-terminal region facilitates V(D)J recombination through its interactions with DNA Ligase IV and DNA-PKcs. AB - Artemis is an endonuclease that opens coding hairpin ends during V(D)J recombination and has critical roles in postirradiation cell survival. A direct role for the C-terminal region of Artemis in V(D)J recombination has not been defined, despite the presence of immunodeficiency and lymphoma development in patients with deletions in this region. Here, we report that the Artemis C terminal region directly interacts with the DNA-binding domain of Ligase IV, a DNA Ligase which plays essential roles in DNA repair and V(D)J recombination. The Artemis-Ligase IV interaction is specific and occurs independently of the presence of DNA and DNA-protein kinase catalytic subunit (DNA-PKcs), another protein known to interact with the Artemis C-terminal region. Point mutations in Artemis that disrupt its interaction with Ligase IV or DNA-PKcs reduce V(D)J recombination, and Artemis mutations that affect interactions with Ligase IV and DNA-PKcs show additive detrimental effects on coding joint formation. Signal joint formation remains unaffected. Our data reveal that the C-terminal region of Artemis influences V(D)J recombination through its interaction with both Ligase IV and DNA-PKcs. PMID- 22529271 TI - Clinical research involving children: registration, completeness, and publication. AB - BACKGROUND AND OBJECTIVE: Effective health care for children must be based on thorough analyses of the best research evidence. The objective of this study was to examine registration, completeness, and publication of studies involving children. METHODS: We searched the ClinicalTrials.gov registry to identify all closed studies involving children and examined them for completeness and availability of results. We examined publication in peer-reviewed journals for 160 randomly selected National Institutes of Health (NIH)-funded studies from 2000 through 2010 and for 758 randomly selected completed studies. RESULTS: Of 3428 closed studies involving children identified in ClinicalTrials.gov, 2385 (70%) were completed, 28 (0.8%) suspended, 152 (4.4%) terminated, and 38 (1.1%) withdrawn. The proportion of non-completed studies (terminated and suspended) increased linearly by 186% between 2001 and 2009, from 1.9% to 8.4%. Of the 152 terminated studies, 48 did not report reasons for termination, 21 cited safety concerns, and 83 cited poor recruitment or other administrative reasons. Only 29% of completed studies were published. Publication that did occur was an average of 2 years after study completion. Completed interventional studies were published more often than observational studies. Completed industry-funded studies were published less often than studies funded by the NIH. Registered NIH-funded trials were published more often than unregistered. CONCLUSIONS: Results are unavailable for more than half of the studies involving children, revealing a substantial publication bias. Registration and posting of results on ClinicalTrials.gov should be mandatory for all studies involving children. PMID- 22529272 TI - Pediatric clinical trial registration and trial results: an urgent need for improvement. PMID- 22529273 TI - Race and unequal burden of perioperative pain and opioid related adverse effects in children. AB - BACKGROUND: Interindividual variability in pain perception and analgesic response is a major problem in perioperative practice. Adult studies suggest pain management is influenced by patient's race. The objective of this study is to evaluate the influence of race on perioperative pain treatment in children. METHODS: Prospective observational study evaluating effect of race on analgesia and opioid related adverse effects after tonsillectomy in African American and Caucasian children. A sample of 194 healthy children between 6 and 15 years of age were included. Race was self-identified by parents. All participants received standard perioperative care with a standard anesthetic and an intraoperative dose of morphine. Analgesia outcomes included maximum postoperative pain scores, postoperative opioid requirement, and analgesic interventions. Safety outcomes included incidences of opioid related adverse effects. RESULTS: African American children experienced significantly more postoperative pain than Caucasian children as measured by postoperative opioid requirement (P = .0011), maximum postoperative pain scores (P < .0001), and analgesic interventions (P < .0001) in the recovery room. Although Caucasian children received relatively less opioids perioperatively, they had significantly higher opioid related adverse effects (P = .039). African American children with obstructive sleep apnea were more likely to have prolonged post anesthesia recovery unit stay due to inadequate pain control. CONCLUSIONS: After similar uses of intraoperative morphine for tonsillectomy, there was an unequal burden of increased pain in African American children and increased opioid adverse effects in Caucasian children in the recovery room. Though Caucasian children received relatively less opioids perioperatively, they had higher incidences of opioid related adverse effects than African American children. PMID- 22529274 TI - Developmental care for premature infants: a state of mind. PMID- 22529275 TI - Excessive blinking and ataxia in a child with occult neuroblastoma and voltage gated potassium channel antibodies. AB - A previously healthy 9-year-old girl presented with a 10-day history of slowly progressive unsteadiness, slurred speech, and behavior change. On examination there was cerebellar ataxia and dysarthria, excessive blinking, subtle perioral myoclonus, and labile mood. The finding of oligoclonal bands in the cerebrospinal fluid prompted paraneoplastic serological evaluation and search for an occult neural crest tumor. Antineuronal nuclear autoantibody type 1 (anti-Hu) and voltage-gated potassium channel complex antibodies were detected in serum. Metaiodobenzylguanidine scan and computed tomography scan of the abdomen showed a localized abdominal mass in the region of the porta hepatis. A diagnosis of occult neuroblastoma was made. Resection of the stage 1 neuroblastoma and treatment with pulsed corticosteroids resulted in resolution of all symptoms and signs. Excessive blinking has rarely been described with neuroblastoma, and, when it is not an isolated finding, it may be a useful clue to this paraneoplastic syndrome. Although voltage-gated potassium channel complex autoimmunity has not been described previously in the setting of neuroblastoma, it is associated with a spectrum of paraneoplastic neurologic manifestations in adults, including peripheral nerve hyperexcitability disorders. PMID- 22529276 TI - Decreasing prevalence of obesity among young children in Massachusetts from 2004 to 2008. AB - OBJECTIVE: To examine whether the obesity prevalence is increasing, level, or decreasing among young US children (aged <6 years) in the past decade; and to compare regional data to those of 2 national databases. METHODS: We analyzed data from 108 762 well-child visits (36 827 children) at a multisite pediatric practice in eastern Massachusetts during 1999-2008. By using the Centers for Disease Control and Prevention 2000 gender-specific growth charts, we defined obesity as weight-for-length >=95th percentile for children aged <24 months and BMI >=95th percentile for children aged 24 to <72 months. By using multivariable logistic regression, we estimated gender-specific obesity trends in 2 separate periods, 1999-2003 and 2004-2008, adjusting for age group, race/ethnicity, health insurance, and practice site. RESULTS: From 1999 to 2003, the obesity prevalence was fairly stable among both boys and girls. From 2004 to 2008, the obesity prevalence substantially decreased among both boys and girls. The decline in obesity prevalence during 2004-2008 was more pronounced among children insured by non-Medicaid health plans than among those insured by Medicaid. CONCLUSIONS: Among children aged <6 years at this multisite pediatric practice, obesity prevalence decreased during 2004-2008, which is in line with national data showing no increase in prevalence during this time period. The smaller decrease among Medicaid-insured children may portend widening of socioeconomic disparities in childhood obesity. PMID- 22529277 TI - 2011 Joseph W. St Geme Jr lecture: five things I'd like to see changed in American pediatrics, five lessons I've learned. AB - OBJECTIVE: In response to limitations in access to subspecialty care, I present personal observations and suggestions related to education of future pediatricians regarding development of critical thinking skills, care of complex and chronically ill patients, development of empathy, and restoration of responsibility that may help ameliorate this serious problem. Toward this end, I also offer 1 approach, a 24/7 telephone consultation network, for enriching interaction of primary care providers (PCPs) and subspecialists who can potentially provide rapid access to needed advice, reduce demand for subspecialty appointments, bolster decision-making and expertise, and realign resources with need. METHODS: Data were obtained from 579 requests by PCPs for telephone consultation by subspecialists in 8 areas (including child psychiatry). RESULTS: Of calls, 27% took <5 minutes and 79% took 5 to 15 minutes. Of calls, 28% resulted in a clinic visit; 8% prompted hospital transfer, hospital admission, or referral to an emergency department; and the remaining 64% resulted in continued management by PCP with reinforcement of the plan. Assuming most inquiries would have resulted in referral to a subspecialist were there no telephone consultation, we estimated that 70% (8+64%) of consultations realigned resources with need, resulting in large saving of unnecessary clinic visits, travel, expense to families, lost days at work, or missed school. CONCLUSIONS: Development of rapid telephone consultation networks could provide increased access to care for those children in greatest need, use limited resources more efficiently, foster collegial and productive relationships between medical providers, and increase expertise of PCPs and subspecialists. PMID- 22529278 TI - Comparison of adolescent, young adult, and adult women's maternity experiences and practices. AB - BACKGROUND AND OBJECTIVE: Pregnant adolescents face unique challenges. Understanding the experiences, knowledge, and behaviors of adolescents during the pregnancy and postpartum periods may contribute to improvement of their maternity care. The purpose of this study was to compare the maternity experiences, knowledge, and behaviors of adolescent, young adult, and adult women by using a nationally representative sample. METHODS: This study used data from the Canadian Maternity Experiences Survey (N = 6421). The weighted proportions of each variable were calculated by using survey sample weights. Logistic regression was used to estimate odds ratios. Bootstrapping techniques were used to calculate variance estimates for prevalence and 95% confidence intervals. RESULTS: Adolescents and young adults were more likely to experience physical abuse in the previous 2 years, initiate prenatal care late, not take folic acid before or during pregnancy, have poor prenatal health behaviors, have a lower cesarean delivery rate, have lower breastfeeding initiation and duration rates, experience more stressful life events, experience postpartum depression symptoms, and rate their infant's health as suboptimal than adult women. Adolescents were more likely to rate their own health as suboptimal. CONCLUSIONS: Adolescents have unique needs during pregnancy and postpartum. Health care professionals should seek to provide care in a manner that acknowledges these needs. PMID- 22529279 TI - Pharmacologic treatment of repetitive behaviors in autism spectrum disorders: evidence of publication bias. AB - OBJECTIVE: The goal of this study was to examine the efficacy of serotonin receptor inhibitors (SRIs) for the treatment of repetitive behaviors in autism spectrum disorders (ASD). METHODS: Two reviewers searched PubMed and Clinicaltrials.gov for randomized, double-blind, placebo-controlled trials evaluating the efficacy of SRIs for repetitive behaviors in ASD. Our primary outcome was mean improvement in ratings scales of repetitive behavior. Publication bias was assessed by using a funnel plot, the Egger's test, and a meta-regression of sample size and effect size. RESULTS: Our search identified 5 published and 5 unpublished but completed trials eligible for meta-analysis. Meta analysis of 5 published and 1 unpublished trial (which provided data) demonstrated a small but significant effect of SRI for the treatment of repetitive behaviors in ASD (standardized mean difference: 0.22 [95% confidence interval: 0.07-0.37], z score = 2.87, P < .005). There was significant evidence of publication bias in all analyses. When Duval and Tweedie's trim and fill method was used to adjust for the effect of publication bias, there was no longer a significant benefit of SRI for the treatment of repetitive behaviors in ASD (standardized mean difference: 0.12 [95% confidence interval: -0.02 to 0.27]). Secondary analyses demonstrated no significant effect of type of medication, patient age, method of analysis, trial design, or trial duration on reported SRI efficacy. CONCLUSIONS: Meta-analysis of the published literature suggests a small but significant effect of SRI in the treatment of repetitive behaviors in ASD. This effect may be attributable to selective publication of trial results. Without timely, transparent, and complete disclosure of trial results, it remains difficult to determine the efficacy of available medications. PMID- 22529280 TI - Qualitative brain MRI at term and cognitive outcomes at 9 years after very preterm birth. AB - OBJECTIVE: A prospective study was performed to assess the relationship between the appearance of cerebral MRI at term and the cognitive functioning at 9 years old in very preterm born infants. METHODS: Seventy-six very preterm born infants (birth weight <1500 g or gestational age <=32 weeks) obtained cerebral MRI at term-equivalent period, which was assessed by using established composite scores for the white and gray matter; cognitive outcomes at 9 years old were assessed in 60 subjects by using Wechsler Intelligence Scale for Children, Third Edition. RESULTS: Mildly low scores on the different IQ indices (<85) were observed in 23.3% (verbal IQ), 41.7% (performance IQ), and 30.0% (full-scale IQ) of the cohort, whereas moderately low scores (<70) were noted in 3.3% (verbal IQ), 11.7% (performance IQ), and 11.7% (full-scale IQ); cerebral palsy was diagnosed in 10.0%, whereas special assistance at school was required in 56.7%. Abnormal white matter appearances predicted mildly low verbal, performance, and full-scale IQs; moderately low performance and full-scale IQs; cerebral palsy; and the requirement for special assistance at school. Abnormal white matter appearances predicted mild cognitive impairment even after the adjustment for known clinical risk factors. In contrast, abnormal gray matter appearances did not predict any of the outcome measures. CONCLUSIONS: In a cohort of very preterm born infants, abnormal white matter appearance on term MRI showed consistent associations with cognitive impairments at 9 years old, further supporting the benefit of obtaining term MRI for very preterm born infants. PMID- 22529282 TI - Why do pertussis vaccines fail? PMID- 22529281 TI - Child and adult outcomes of chronic child maltreatment. AB - OBJECTIVE: To describe how child maltreatment chronicity is related to negative outcomes in later childhood and early adulthood. METHODS: The study included 5994 low-income children from St Louis, including 3521 with child maltreatment reports, who were followed from 1993-1994 through 2009. Children were 1.5 to 11 years of age at sampling. Data include administrative and treatment records indicating substance abuse, mental health treatment, brain injury, sexually transmitted disease, suicide attempts, and violent delinquency before age 18 and child maltreatment perpetration, mental health treatment, or substance abuse in adulthood. Multivariate analysis controlled for potential confounders. RESULTS: Child maltreatment chronicity predicted negative childhood outcomes in a linear fashion (eg, percentage with at least 1 negative outcome: no maltreatment = 29.7%, 1 report = 39.5%, 4 reports = 67.1%). Suicide attempts before age 18 showed the largest proportionate increase with repeated maltreatment (no report versus 4+ reports = +625%, P < .0001). The dose-response relationship was reduced once controls for other adverse child outcomes were added in multivariate models of child maltreatment perpetration and mental health issues. The relationship between adult substance abuse and maltreatment report history disappeared after controlling for adverse child outcomes. CONCLUSIONS: Child maltreatment chronicity as measured by official reports is a robust indicator of future negative outcomes across a range of systems, but this relationship may desist for certain adult outcomes once childhood adverse events are controlled. Although primary and secondary prevention remain important approaches, this study suggests that enhanced tertiary prevention may pay high dividends across a range of medical and behavioral domains. PMID- 22529283 TI - Profound neonatal hypoglycemia and lactic acidosis caused by pyridoxine-dependent epilepsy. AB - Pyridoxine-dependent epilepsy (PDE) was first described in 1954. The ALDH7A1 gene mutations resulting in alpha-aminoadipic semialdehyde dehydrogenase deficiency as a cause of PDE was identified only in 2005. Neonatal epileptic encephalopathy is the presenting feature in >50% of patients with classic PDE. We report the case of a 13-month-old girl with profound neonatal hypoglycemia (0.6 mmol/L; reference range >2.4), lactic acidosis (11 mmol/L; reference range <2), and bilateral symmetrical temporal lobe hemorrhages and thalamic changes on cranial MRI. She developed multifocal and myoclonic seizures refractory to multiple antiepileptic drugs that responded to pyridoxine. The diagnosis of alpha-aminoadipic semialdehyde dehydrogenase deficiency was confirmed based on the elevated urinary alpha-aminoadipic semialdehyde excretion, compound heterozygosity for a known splice mutation c.834G>A (p.Val278Val), and a novel putative pathogenic missense mutation c.1192G>C (p.Gly398Arg) in the ALDH7A1 gene. She has been seizure-free since 1.5 months of age on treatment with pyridoxine alone. She has motor delay and central hypotonia but normal language and social development at the age of 13 months. This case is the first description of a patient with PDE due to mutations in the ALDH7A1 gene who presented with profound neonatal hypoglycemia and lactic acidosis masquerading as a neonatal-onset gluconeogenesis defect. PDE should be included in the differential diagnosis of hypoglycemia and lactic acidosis in addition to medically refractory neonatal seizures. PMID- 22529284 TI - Purification and characterization of ZmRIP1, a novel reductant-inhibited protein tyrosine phosphatase from maize. AB - Protein tyrosine phosphatases (PTPases) have long been thought to be activated by reductants and deactivated by oxidants, owing to the presence of a crucial sulfhydryl group in their catalytic centers. In this article, we report the purification and characterization of Reductant-Inhibited PTPase1 (ZmRIP1) from maize (Zea mays) coleoptiles, and show that this PTPase has a unique mode of redox regulation and signaling. Surprisingly, ZmRIP1 was found to be deactivated by a reductant. A cysteine (Cys) residue (Cys-181) near the active center was found to regulate this unique mode of redox regulation, as mutation of Cys-181 to arginine-181 allowed ZmRIP1 to be activated by a reductant. In response to oxidant treatment, ZmRIP1 was translocated from the chloroplast to the nucleus. Expression of ZmRIP1 in Arabidopsis (Arabidopsis thaliana) plants and maize protoplasts altered the expression of genes encoding enzymes involved in antioxidant catabolism, such as At1g02950, which encodes a glutathione transferase. Thus, the novel PTPase identified in this study is predicted to function in redox signaling in maize. PMID- 22529285 TI - Transcription factors of Lotus: regulation of isoflavonoid biosynthesis requires coordinated changes in transcription factor activity. AB - Isoflavonoids are a class of phenylpropanoids made by legumes, and consumption of dietary isoflavonoids confers benefits to human health. Our aim is to understand the regulation of isoflavonoid biosynthesis. Many studies have shown the importance of transcription factors in regulating the transcription of one or more genes encoding enzymes in phenylpropanoid metabolism. In this study, we coupled bioinformatics and coexpression analysis to identify candidate genes encoding transcription factors involved in regulating isoflavonoid biosynthesis in Lotus (Lotus japonicus). Genes encoding proteins belonging to 39 of the main transcription factor families were examined by microarray analysis of RNA from leaf tissue that had been elicited with glutathione. Phylogenetic analyses of each transcription factor family were used to identify subgroups of proteins that were specific to L. japonicus or closely related to known regulators of the phenylpropanoid pathway in other species. R2R3MYB subgroup 2 genes showed increased expression after treatment with glutathione. One member of this subgroup, LjMYB14, was constitutively overexpressed in L. japonicus and induced the expression of at least 12 genes that encoded enzymes in the general phenylpropanoid and isoflavonoid pathways. A distinct set of six R2R3MYB subgroup 2-like genes was identified. We suggest that these subgroup 2 sister group proteins and those belonging to the main subgroup 2 have roles in inducing isoflavonoid biosynthesis. The induction of isoflavonoid production in L. japonicus also involves the coordinated down-regulation of competing biosynthetic pathways by changing the expression of other transcription factors. PMID- 22529286 TI - Cyclin-A1 represents a new immunogenic targetable antigen expressed in acute myeloid leukemia stem cells with characteristics of a cancer-testis antigen. AB - Targeted T-cell therapy is a potentially less toxic strategy than allogeneic stem cell transplantation for providing a cytotoxic antileukemic response to eliminate leukemic stem cells (LSCs) in acute myeloid leukemia (AML). However, this strategy requires identification of leukemia-associated antigens that are immunogenic and exhibit selective high expression in AML LSCs. Using microarray expression analysis of LSCs, hematopoietic cell subpopulations, and peripheral tissues to screen for candidate antigens, cyclin-A1 was identified as a candidate gene. Cyclin-A1 promotes cell proliferation and survival, has been shown to be leukemogenic in mice, is detected in LSCs of more than 50% of AML patients, and is minimally expressed in normal tissues with exception of testis. Using dendritic cells pulsed with a cyclin-A1 peptide library, we generated T cells against several cyclin-A1 oligopeptides. Two HLA A*0201-restricted epitopes were further characterized, and specific CD8 T-cell clones recognized both peptide pulsed target cells and the HLA A*0201-positive AML line THP-1, which expresses cyclin-A1. Furthermore, cyclin-A1-specific CD8 T cells lysed primary AML cells. Thus, cyclin-A1 is the first prototypic leukemia-testis-antigen to be expressed in AML LSCs. The pro-oncogenic activity, high expression levels, and multitude of immunogenic epitopes make it a viable target for pursuing T cell-based therapy approaches. PMID- 22529288 TI - Residual plasmatic activity of ADAMTS13 is correlated with phenotype severity in congenital thrombotic thrombocytopenic purpura. AB - The quantification of residual plasmatic ADAMTS13 activity in congenital thrombotic thrombocytopenic purpura (TTP) patients is constrained by limitations in sensitivity and reproducibility of commonly used assays at low levels of ADAMTS13 activity, blunting efforts to establish genotype-phenotype correlations. In the present study, the residual plasmatic activity of ADAMTS13 was measured centrally by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (limit of detection = 0.5%) in 29 congenital TTP patients. The results were used to study correlations among ADAMTS13 genotype, residual plasmatic activity, and clinical phenotype severity. An ADAMTS13 activity above 0.5% was measured in 26 (90%) patients and lower levels of activity were associated with earlier age at first TTP episode requiring plasma infusion, more frequent recurrences, and prescription of fresh-frozen plasma prophylaxis. Receiver operating characteristic curve analysis showed that activity levels of less than 2.74% and 1.61% were discriminative of age at first TTP episode requiring plasma infusion < 18 years, annual rate of TTP episodes > 1, and use of prophylaxis. Mutations affecting the highly conserved N-terminal domains of the protein were associated with lower residual ADAMTS13 activity and a more severe phenotype in an allelic-dose dependent manner. The results of the present study show that residual ADAMTS13 activity is associated with the severity of clinical phenotype in congenital TTP and provide insights into genotype-phenotype correlations. PMID- 22529287 TI - miR-3151 interplays with its host gene BAALC and independently affects outcome of patients with cytogenetically normal acute myeloid leukemia. AB - High BAALC expression levels are associated with poor outcome in cytogenetically normal acute myeloid leukemia (CN-AML) patients. Recently, miR-3151 was discovered in intron 1 of BAALC. To evaluate the prognostic significance of miR 3151 expression levels and to gain insight into the biologic and prognostic interplay between miR-3151 and its host, miR-3151 and BAALC expression were measured in pretreatment blood of 179 CN-AML patients. Gene-expression profiling and miRNA-expression profiling were performed using microarrays. High miR-3151 expression was associated with shorter disease-free and overall survival, whereas high BAALC expression predicted failure of complete remission and shorter overall survival. Patients exhibiting high expression of both miR-3151 and BAALC had worse outcome than patients expressing low levels of either gene or both genes. In gene-expression profiling, high miR-3151 expressers showed down-regulation of genes involved in transcriptional regulation, posttranslational modification, and cancer pathways. Two genes, FBXL20 and USP40, were validated as direct miR-3151 targets. The results of the present study show that high expression of miR-3151 is an independent prognosticator for poor outcome in CN-AML and affects different outcome end points than its host gene, BAALC. The combination of both markers identified a patient subset with the poorest outcome. This interplay between an intronic miR and its host may have important biologic implications. PMID- 22529289 TI - A new mouse model mimicking thrombotic thrombocytopenic purpura: correction of symptoms by recombinant human ADAMTS13. AB - Deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), a VWF-cleaving protease, is the key factor in the pathogenesis of thrombotic thrombocytopenic purpura (TTP), a life-threatening thrombotic microangiopathy. It is well established that ADAMTS13 deficiency results in elevated plasma levels of ultra-large VWF multimers (ULVWF), which are prone to induce platelet aggregation; however, the actual trigger of TTP development remains uncertain. Here we describe a new animal model in which some TTP-like symptoms can be triggered in ADAMTS13 knockout mice by challenge with 2000 units/kg body weight of recombinant human VWF containing ULVWF multimers. Animals rapidly showed clinical symptoms and developed severe thrombocytopenia. Schistocytosis, a decrease in hematocrit, and elevated serum lactate dehydrogenase levels were observed. The heart was identified as the most sensitive target organ with rapid onset of extensive platelet aggregation in the ventricles and myocardial necrosis. Prophylactic administration of 200 units/kg recombinant human ADAMTS13 protected ADAMTS13 knockout mice from developing TTP. Therapeutic administration of 320 units/kg rhADAMTS13 reduced the incidence and severity of TTP findings in a treatment interval-dependent manner. We therefore consider this newly established mouse model of thrombotic microangiopathy highly predictive for investigating the efficacy of new treatments for TTP. PMID- 22529290 TI - Mitochondrial dysfunction in antiphospholipid syndrome: implications in the pathogenesis of the disease and effects of coenzyme Q(10) treatment. AB - The exact mechanisms underlying the role of oxidative stress in the pathogenesis and the prothrombotic or proinflammatory status of antiphospholipid syndrome (APS) remain unknown. Here, we investigate the role of oxidative stress and mitochondrial dysfunction in the proatherothrombotic status of APS patients induced by IgG-antiphospholipid antibodies and the beneficial effects of supplementing cells with coenzyme Q(10) (CoQ(10)). A significant increase in relevant prothrombotic and inflammatory parameters in 43 APS patients was found compared with 38 healthy donors. Increased peroxide production, nuclear abundance of Nrf2, antioxidant enzymatic activity, decreased intracellular glutathione, and altered mitochondrial membrane potential were found in monocytes and neutrophils from APS patients. Accelerated atherosclerosis in APS patients was found associated with their inflammatory or oxidative status. CoQ(10) preincubation of healthy monocytes before IgG-antiphospholipid antibody treatment decreased oxidative stress, the percentage of cells with altered mitochondrial membrane potential, and the induced expression of tissue factor, VEGF, and Flt1. In addition, CoQ(10) significantly improved the ultrastructural preservation of mitochondria and prevented IgG-APS-induced fission mediated by Drp-1 and Fis-1 proteins. In conclusion, the oxidative perturbation in APS patient leukocytes, which is directly related to an inflammatory and pro-atherothrombotic status, relies on alterations in mitochondrial dynamics and metabolism that may be prevented, reverted, or both by treatment with CoQ(10). PMID- 22529291 TI - Whole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides. AB - The longitudinal evolution of a myeloma genome from diagnosis to plasma cell leukemia has not previously been reported. We used whole-genome sequencing (WGS) on 4 purified tumor samples and patient germline DNA drawn over a 5-year period in a t(4;14) multiple myeloma patient. Tumor samples were acquired at diagnosis, first relapse, second relapse, and end-stage secondary plasma cell leukemia (sPCL). In addition to the t(4;14), all tumor time points also shared 10 common single-nucleotide variants (SNVs) on WGS comprising shared initiating events. Interestingly, we observed genomic sequence variants that waxed and waned with time in progressive tumors, suggesting the presence of multiple independent, yet related, clones at diagnosis that rose and fell in dominance. Five newly acquired SNVs, including truncating mutations of RB1 and ZKSCAN3, were observed only in the final sPCL sample suggesting leukemic transformation events. This longitudinal WGS characterization of the natural history of a high-risk myeloma patient demonstrated tumor heterogeneity at diagnosis with shifting dominance of tumor clones over time and has also identified potential mutations contributing to myelomagenesis as well as transformation from myeloma to overt extramedullary disease such as sPCL. PMID- 22529292 TI - Mutations in the mechanotransduction protein PIEZO1 are associated with hereditary xerocytosis. AB - Hereditary xerocytosis (HX, MIM 194380) is an autosomal dominant hemolytic anemia characterized by primary erythrocyte dehydration. Copy number analyses, linkage studies, and exome sequencing were used to identify novel mutations affecting PIEZO1, encoded by the FAM38A gene, in 2 multigenerational HX kindreds. Segregation analyses confirmed transmission of the PIEZO1 mutations and cosegregation with the disease phenotype in all affected persons in both kindreds. All patients were heterozygous for FAM38A mutations, except for 3 patients predicted to be homozygous by clinical and physiologic studies who were also homozygous at the DNA level. The FAM38A mutations were both in residues highly conserved across species and within members of the Piezo family of proteins. PIEZO proteins are the recently identified pore-forming subunits of channels that mediate mechanotransduction in mammalian cells. FAM38A transcripts were identified in human erythroid cell mRNA, and discovery proteomics identified PIEZO1 peptides in human erythrocyte membranes. These findings, the first report of mutation in a mammalian mechanosensory transduction channel-associated with genetic disease, suggest that PIEZO proteins play an important role in maintaining erythrocyte volume homeostasis. PMID- 22529294 TI - A novel Th cell epitope of Candida albicans mediates protection from fungal infection. AB - Fungal pathogens are a frequent cause of opportunistic infections. They live as commensals in healthy individuals but can cause disease when the immune status of the host is altered. T lymphocytes play a critical role in pathogen control. However, specific Ags determining the activation and function of antifungal T cells remain largely unknown. By using an immunoproteomic approach, we have identified for the first time, to our knowledge, a natural T cell epitope from Candida albicans. Isolation and sequencing of MHC class II-bound ligands from infected dendritic cells revealed a peptide that was recognized by a major population of all Candida-specific Th cells isolated from infected mice. Importantly, human Th cells also responded to stimulation with the peptide in an HLA-dependent manner but without restriction to any particular HLA class II allele. Immunization of mice with the peptide resulted in a population of epitope specific Th cells that reacted not only with C. albicans but also with other clinically highly relevant species of Candida including the distantly related Candida glabrata. The extent of the reaction to different Candida species correlated with their degree of phylogenetic relationship to C. albicans. Finally, we show that the newly identified peptide acts as an efficient vaccine when used in combination with an adjuvant inducing IL-17A secretion from peptide specific T cells. Immunized mice were protected from fatal candidiasis. Together, these results uncover a new immune determinant of the host response against Candida ssp. that could be exploited for the development of antifungal vaccines and immunotherapies. PMID- 22529293 TI - A2A adenosine receptor signaling in lymphocytes and the central nervous system regulates inflammation during experimental autoimmune encephalomyelitis. AB - Extracellular adenosine has an important role in regulating the severity of inflammation during an immune response. Although there are four adenosine receptor (AR) subtypes, the A2AAR is both highly expressed on lymphocytes and known as a prime mediator of adenosine's anti-inflammatory effects. To define the importance of A2AAR signaling during neuroinflammatory disease progression, we used the experimental autoimmune encephalomyelitis (EAE) animal model for multiple sclerosis. In EAE induction experiments, A2AAR antagonist treatment protected mice from disease development and its associated CNS lymphocyte infiltration. However, A2AAR(-/-) mice developed a more severe acute EAE phenotype characterized by more proinflammatory lymphocytes and activated microglia/macrophages. Interestingly, very high levels of A2AAR were expressed on the choroid plexus, a well-established CNS lymphocyte entry point. To determine the contribution of A2AAR signaling in lymphocytes and the CNS during EAE, we used bone marrow chimeric mice. Remarkably, A2AAR(-/-) donor hematopoietic cells potentiated severe EAE, whereas lack of A2AAR expression on nonhematopoietic cells protected against disease development. Although no defect in the suppressive ability of A2AAR(-/-) regulatory T cells was observed, A2AAR(-/-) lymphocytes were shown to proliferate more and produced more IFN-gamma following stimulation. Despite this more proinflammatory phenotype, A2AAR antagonist treatment still protected against EAE when A2AAR(-/-) lymphocytes were adoptively transferred to T cell-deficient A2AAR(+/+) mice. These results indicate that A2AAR expression on nonimmune cells (likely in the CNS) is required for efficient EAE development, while A2AAR lymphocyte expression is essential for limiting the severity of the inflammatory response. PMID- 22529295 TI - Long-lived bone marrow plasma cells are induced early in response to T cell independent or T cell-dependent antigens. AB - The signals required to generate long-lived plasma cells remain unresolved. One widely cited model posits that long-lived plasma cells derive from germinal centers (GCs) in response to T cell-dependent (TD) Ags. Thus, T cell-independent (TI) Ags, which fail to sustain GCs, are considered ineffective at generating long-lived plasma cells. However, we show that long-lived hapten-specific plasma cells are readily induced without formation of GCs. Long-lived plasma cells developed in T cell-deficient mice after a single immunization with haptenated LPS, a widely used TI Ag. Long-lived plasma cells also formed in response to TD Ag when the GC response was experimentally prevented. These observations establish that long-lived plasma cells are induced in both TI and TD responses, and can arise independently of B cell maturation in GCs. PMID- 22529296 TI - Tumor-expressed inducible nitric oxide synthase controls induction of functional myeloid-derived suppressor cells through modulation of vascular endothelial growth factor release. AB - Inducible NO synthase (iNOS) is a hallmark of chronic inflammation that is also overexpressed in melanoma and other cancers. Whereas iNOS is a known effector of myeloid-derived suppressor cell (MDSC)-mediated immunosuppression, its pivotal position at the interface of inflammation and cancer also makes it an attractive candidate regulator of MDSC recruitment. We hypothesized that tumor-expressed iNOS controls MDSC accumulation and acquisition of suppressive activity in melanoma. CD11b(+)GR1(+) MDSC derived from mouse bone marrow cells cultured in the presence of MT-RET-1 mouse melanoma cells or conditioned supernatants expressed STAT3 and reactive oxygen species (ROS) and efficiently suppressed T cell proliferation. Inhibition of tumor-expressed iNOS with the small molecule inhibitor L-NIL blocked accumulation of STAT3/ROS-expressing MDSC, and abolished their suppressive function. Experiments with vascular endothelial growth factor (VEGF)-depleting Ab and recombinant VEGF identified a key role for VEGF in the iNOS-dependent induction of MDSC. These findings were further validated in mice bearing transplantable MT-RET-1 melanoma, in which L-NIL normalized elevated serum VEGF levels; downregulated activated STAT3 and ROS production in MDSC; and reversed tumor-mediated immunosuppression. These beneficial effects were not observed in iNOS knockout mice, suggesting L-NIL acts primarily on tumor- rather than host-expressed iNOS to regulate MDSC function. A significant decrease in tumor growth and a trend toward increased tumor-infiltrating CD8(+) T cells were also observed in MT-RET transgenic mice bearing spontaneous tumors. These data suggest a critical role for tumor-expressed iNOS in the recruitment and induction of functional MDSC by modulation of tumor VEGF secretion and upregulation of STAT3 and ROS in MDSC. PMID- 22529297 TI - 1,25-Dihyroxyvitamin D3 promotes FOXP3 expression via binding to vitamin D response elements in its conserved noncoding sequence region. AB - FOXP3-positive regulatory T (Treg) cells are a unique subset of T cells with immune regulatory properties. Treg cells can be induced from non-Treg CD4(+) T cells (induced Treg [iTreg] cells) by TCR triggering, IL-2, and TGF-beta or retinoic acid. 1,25-Dihyroxyvitamin D(3) [1,25(OH)(2)VD(3)] affects the functions of immune cells including T cells. 1,25(OH)(2)VD(3) binds the nuclear VD receptor (VDR) that binds target DNA sequences known as the VD response element (VDRE). Although 1,25(OH)(2)VD(3) can promote FOXP3 expression in CD4(+) T cells with TCR triggering and IL-2, it is unknown whether this effect of 1,25(OH)(2)VD(3) is mediated through direct binding of VDR to the FOXP3 gene without involving other molecules. Also, it is unclear whether FOXP3 expression in 1,25(OH)(2)VD(3) induced Treg (VD-iTreg) cells is critical for the inhibitory function of these cells. In this study, we demonstrated the presence of VDREs in the intronic conserved noncoding sequence region +1714 to +2554 of the human FOXP3 gene and the enhancement of the FOXP3 promoter activity by such VDREs in response to 1,25(OH)(2)VD(3). Additionally, VD-iTreg cells suppressed the proliferation of target CD4(+) T cells and this activity was dependent on FOXP3 expression. These findings suggest that 1,25(OH)(2)VD(3) can affect human immune responses by regulating FOXP3 expression in CD4(+) T cells through direct VDR binding to the FOXP3 gene, which is essential for inhibitory function of VD-iTreg cells. PMID- 22529298 TI - Mast cell TLR2 signaling is crucial for effective killing of Francisella tularensis. AB - TLR signaling is critical for early host defense against pathogens, but the contributions of mast cell TLR-mediated mechanisms and subsequent effector functions during pulmonary infection are largely unknown. We have previously demonstrated that mast cells, through the production of IL-4, effectively control Francisella tularensis replication. In this study, the highly human virulent strain of F. tularensis SCHU S4 and the live vaccine strain were used to investigate the contribution of mast cell/TLR regulation of Francisella. Mast cells required TLR2 for effective bacterial killing, regulation of the hydrolytic enzyme cathepsin L, and for coordination and trafficking of MHC class II and lysosomal-associated membrane protein 2. Infected TLR2(-/-) mast cells, in contrast to wild-type and TLR4(-/-) cells, lacked detectable IL-4 and displayed increased cell death with a 2-3 log increase of F. tularensis replication, but could be rescued with rIL-4 treatment. Importantly, MHC class II and lysosomal associated membrane protein 2 localization with labeled F. tularensis in the lungs was greater in wild-type than in TLR2(-/-) mice. These results provide evidence for the important effector contribution of mast cells and TLR2-mediated signaling on early innate processes in the lung following pulmonary F. tularensis infection and provide additional insight into possible mechanisms by which intracellular pathogens modulate respiratory immune defenses. PMID- 22529299 TI - Stem cell factor programs the mast cell activation phenotype. AB - Mast cells, activated by Ag via FcepsilonRI, release an array of proinflammatory mediators that contribute to allergic disorders, such as asthma and anaphylaxis. The KIT ligand, stem cell factor (SCF), is critical for mast cell expansion, differentiation, and survival, and under acute conditions, it enhances mast cell activation. However, extended SCF exposure in vivo conversely protects against fatal Ag-mediated anaphylaxis. In investigating this dichotomy, we identified a novel mode of regulation of the mast cell activation phenotype through SCF mediated programming. We found that mouse bone marrow-derived mast cells chronically exposed to SCF displayed a marked attenuation of FcepsilonRI-mediated degranulation and cytokine production. The hyporesponsive phenotype was not a consequence of altered signals regulating calcium flux or protein kinase C, but of ineffective cytoskeletal reorganization with evidence implicating a downregulation of expression of the Src kinase Hck. Collectively, these findings demonstrate a major role for SCF in the homeostatic control of mast cell activation with potential relevance to mast cell-driven disease and the development of novel approaches for the treatment of allergic disorders. PMID- 22529300 TI - Stathmin regulates microtubule dynamics and microtubule organizing center polarization in activated T cells. AB - Polarization of T cells involves reorientation of the microtubule organizing center (MTOC). Because activated ERK is localized at the immunological synapse, we investigated its role by showing that ERK activation is important for MTOC polarization. Suspecting that ERK phosphorylates a regulator of microtubules, we next focused on stathmin, a known ERK substrate. Our work indicates that during T cell activation, ERK is recruited to the synapse, allowing it to phosphorylate stathmin molecules near the immunological synapse. Supporting an important role of stathmin phosphorylation in T cell activation, we showed that T cell activation results in increased microtubule growth rate dependent on the presence of stathmin. The significance of this finding was demonstrated by results showing that CTLs from stathmin(-/-) mice displayed defective MTOC polarization and defective target cell cytolysis. These data implicate stathmin as a regulator of the microtubule network during T cell activation. PMID- 22529303 TI - All applicants to medical school should be interviewed. PMID- 22529304 TI - Spain plans to recoup 1bn euro by properly charging EU countries for their citizens' use of its health services. PMID- 22529302 TI - Second generation endometrial ablation techniques for heavy menstrual bleeding: network meta-analysis. AB - OBJECTIVE: To determine the relative effectiveness of second generation ablation techniques in the treatment of heavy menstrual bleeding. DESIGN: Network meta analysis on the primary outcome measures of amenorrhoea, heavy bleeding, and patients' dissatisfaction with treatment. DATA SOURCES: Nineteen randomised controlled trials (involving 3287 women) were identified through electronic searches of the Cochrane Library, Medline, Embase and PsycINFO databases from inception to April 2011. The reference lists of known relevant articles were searched for further articles. Two reviewers independently selected articles without language restrictions. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials involving second generation endometrial destruction techniques for women with heavy menstrual bleeding unresponsive to medical treatment. RESULTS: Of the three most commonly used techniques, network meta analysis showed that bipolar radiofrequency and microwave ablation resulted in higher rates of amenorrhoea than thermal balloon ablation at around 12 months (odds ratio 2.51, 95% confidence interval 1.53 to 4.12, P<0.001; and 1.66, 1.01 to 2.71, P=0.05, respectively), but there was no evidence of a convincing difference between the three techniques in the number of women dissatisfied with treatment or still experiencing heavy bleeding. Compared with bipolar radio frequency and microwave devices, an increased number of women still experienced heavy bleeding after free fluid ablation (2.19, 1.07 to 4.50, P=0.03; and 2.91, 1.23 to 6.88, P=0.02, respectively). Compared with radio frequency ablation, free fluid ablation was associated with reduced rates of amenorrhoea (0.36, 0.19 to 0.67, P=0.004) and increased rates of dissatisfaction (4.79, 1.07 to 21.5, P=0.04). Of the less commonly used devices, endometrial laser intrauterine thermotherapy was associated with increased rates of amenorrhoea compared with all the other devices, while cryoablation led to a reduced rate compared with bipolar radio frequency and microwave. CONCLUSIONS: Bipolar radio frequency and microwave ablative devices are more effective than thermal balloon and free fluid ablation in the treatment of heavy menstrual bleeding with second generation endometrial ablation devices. PMID- 22529305 TI - Community support needs higher priority in disaster relief. PMID- 22529301 TI - The Thai phase III trial (RV144) vaccine regimen induces T cell responses that preferentially target epitopes within the V2 region of HIV-1 envelope. AB - The Thai HIV phase III prime/boost vaccine trial (RV144) using ALVAC-HIV (vCP1521) and AIDSVAX B/E was, to our knowledge, the first to demonstrate acquisition efficacy. Vaccine-induced, cell-mediated immune responses were assessed. T cell epitope mapping studies using IFN-gamma ELISPOT was performed on PBMCs from HIV-1-uninfected vaccine (n = 61) and placebo (n = 10) recipients using HIV-1 Env peptides. Positive responses were measured in 25 (41%) vaccinees and were predominantly CD4(+) T cell-mediated. Responses were targeted within the HIV Env region, with 15 of 25 (60%) of vaccinees recognizing peptides derived from the V2 region of HIV-1 Env, which includes the alpha(4)beta(7) integrin binding site. Intracellular cytokine staining confirmed that Env responses predominated (19 of 30; 63% of vaccine recipients) and were mediated by polyfunctional effector memory CD4(+) T cells, with the majority of responders producing both IL-2 and IFN-gamma (12 of 19; 63%). HIV Env Ab titers were higher in subjects with IL-2 compared with those without IL-2-secreting HIV Env-specific effector memory T cells. Proliferation assays revealed that HIV Ag-specific T cells were CD4(+), with the majority (80%) expressing CD107a. HIV-specific T cell lines obtained from vaccine recipients confirmed V2 specificity, polyfunctionality, and functional cytolytic capacity. Although the RV144 T cell responses were modest in frequency compared with humoral immune responses, the CD4(+) T cell response was directed to HIV-1 Env and more particularly the V2 region. PMID- 22529306 TI - Responsible officers could test language skills of EU doctors. PMID- 22529307 TI - Prosecution of parents over baby's death raises controversy over diagnosing child abuse. PMID- 22529310 TI - Bridging therapy in acute ischemic stroke: a systematic review and meta-analysis. AB - BACKGROUND AND PURPOSE: Pending the results of randomized controlled trials, the benefit and safety of bridging therapy (combined intravenous and intra-arterial thrombolysis) remain to be determined. The aim of this analysis was to give reliable estimates of efficacy and safety outcomes of bridging therapy. METHODS: We conducted a systematic review of all studies using bridging therapy published between January 1966 and March 2011. RESULTS: The literature search identified 15 studies. The pooled estimate for recanalization rate was 69.6% (95% CI, 63.9% 75.0%). Meta-analysis on clinical outcomes showed a pooled estimate of 48.9% (95% CI, 42.9%-54.9%) for favorable outcome, 17.9% (95% CI, 12.7%-23.7%) for mortality, and 8.6% (95% CI, 6.8%-10.6%) for symptomatic intracranial hemorrhage. In meta-regression analysis, the shorter mean time to intravenous treatment, the greater the recanalization rate (per 10-minute decrease: OR, 1.24; 95% CI, 1.02 1.51) and the lower mortality rate (per 10-minute decrease: OR, 0.75; 95% CI, 0.60-0.94). By using the control groups of intravenous alteplase-treated patients in 8 studies, bridging therapy was associated with a favorable outcome (OR, 2.26; 95% CI, 1.16-4.40), but no differences in mortality or symptomatic intracranial hemorrhage outcomes were found. CONCLUSIONS: Bridging therapy is associated with acceptable safety and efficacy in stroke patients. Time to intravenous treatment is critical to improve recanalization rates and favorable outcomes. PMID- 22529311 TI - All patients should be admitted to the hospital after a transient ischemic attack. PMID- 22529312 TI - Not all patients should be admitted to the hospital for observation after a transient ischemic attack. PMID- 22529313 TI - Hospital admission after transient ischemic attack: unmasking wolves in sheep's clothing. PMID- 22529315 TI - Characterization of the cellular immune responses to Rhizopus oryzae with potential impact on immunotherapeutic strategies in hematopoietic stem cell transplantation. AB - Infections due to mucormycetes have a poor outcome, in particular in allogeneic hematopoietic stem cell transplantation (HSCT). In order to evaluate the cellular host response against mucormycetes, we enriched and cultivated anti-Rhizopus oryzae T cells from healthy individuals. These cells were characterized as memory/effector T(H)1 cells, they proliferated upon restimulation, they exhibited cross-reactivity to some but not all Mucorales species tested, and they increased the activity of phagocytes. Compared with the original cell fraction, the generated cells exhibited significant lower alloreactivity. Our data may form the basis for further investigations, which may ultimately lead to adoptive immunotherapeutic strategies for allogeneic HSCT recipients suffering from mucormycosis. PMID- 22529314 TI - Rates of hospitalizations for respiratory syncytial virus, human metapneumovirus, and influenza virus in older adults. AB - BACKGROUND: We performed a prospective study to determine the disease burden of respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) in older adults in comparison with influenza virus. METHODS: During 3 consecutive winters, we enrolled Davidson County (Nashville, TN) residents aged >= 50 years admitted to 1 of 4 hospitals with acute respiratory illness (ARI). Nasal/throat swabs were tested for influenza, RSV, and HMPV with reverse-transcriptase polymerase chain reaction. Hospitalization rates were calculated. RESULTS: Of 1042 eligible patients, 508 consented to testing. Respiratory syncytial virus was detected in 31 participants (6.1%); HMPV was detected in 23 (4.5%) patients; and influenza was detected in 33 (6.5%) patients. Of those subjects aged >= 65 years, 78% received influenza vaccination. Compared with patients with confirmed influenza, patients with RSV were older and more immunocompromised; patients with HMPV were older, had more cardiovascular disease, were more likely to have received the influenza vaccination, and were less likely to report fever than those with influenza. Over 3 years, average annual rates of hospitalization were 15.01, 9.82, and 11.81 per 10,000 county residents due to RSV, HMPV, and influenza, respectively. CONCLUSIONS: In adults aged >= 50 years, hospitalization rates for RSV and HMPV were similar to those associated with influenza. PMID- 22529316 TI - US Congress considers new tracking system for medical devices after excessive recalls. PMID- 22529317 TI - Supervised injectable heroin treatment is expensive but cost effective, report says. PMID- 22529318 TI - Paediatric HIV infection in Western Africa: the long way to the standard of care. AB - In sub-Saharan Africa, newborns and children continue to suffer from insufficient access to early diagnosis and antiretroviral (ARV) treatments. A survey had been conducted in Burkina Faso, Ghana and Ivory Coast, from January 2010 to February 2011 to identify the major challenges regarding HIV prophylaxis and treatment of children in western Africa. The results of this survey highlight that only a small proportion of HIV-exposed newborns receive ARV prophylaxis. However, this problem is often not perceived at the national level. The problem could be faced by improving the communication process between the peripheral health services and the national procurement system. Moreover, supporting the development of local pharmaceutical industries could facilitate the availability of child-sized drugs, contextualized to the socio-cultural needs of such area, adequate not only in terms of efficacy, safety and tolerability, but also in terms of palatability, storage, distribution and cost. PMID- 22529319 TI - Is serum cystatin C a better marker than serum creatinine for monitoring renal function in pediatric intensive care unit? AB - In critically ill patients, mild to moderate reductions in glomerular filtration rate are not instantly followed by parallel changes in serum creatinine (SCr). The aim of this study was to identify a value of serum cystatin C (cys-C) level as a marker for monitoring renal function in critically ill pediatric patients. Creatinine clearance was used to estimate glomeruler filtration rate (eGFR). The correlation between the inverse of serum cys-C and eGFR (r = -0.70, p < 0.0001) was better than the correlation between the inverse of SCr and eGFR (r = -0.27, p = 0.008). Serum cys-C was found to be superior to SCr to predict renal impairment (area under the curve for cys-C, 0.932 and for SCr, 0.658). It can be concluded that cys-C is superior to SCr for the detection of renal impairment in critically ill children. PMID- 22529320 TI - Vitamin D status of low birth weight infants in Delhi: a comparative study. AB - OBJECTIVE: To evaluate vitamin D status of preterm and term low birthweight (LBW) and term normal birth weight (NBW; weight >= 2500 g) infants at birth and in early infancy. METHODS: We enrolled 220 LBW and 119 NBW infants along with their mothers. Blood samples of both infants and mothers were taken within 48 h of birth, and that of infants were repeated at 3 months. Serum levels of calcium, phosphate, alkaline phosphatase, 25 hydroxyvitamin D (25OHD) and parathormone (PTH) were estimated using standard tests. Our primary outcome was vitamin D deficiency (VDD; serum 25OHD <20 ng/ml in mothers and <15 ng/ml in infants). Other outcomes were raised PTH (>46 pg/ml), raised AlkP (>120 U/l in mothers and 420 U/l in infants), and clinical rickets. FINDINGS: VDD was present in 186 (87.3%) of LBW and 103 (88.6%) of NBW infants at birth, and in 77 (60.6%) of LBW and 55 (71.6%) of NBW infants at a median corrected age of 12 and 15 weeks, respectively. VDD was almost universal (93-97%) among mothers of both groups. Raised PTH was present in 138 (63.6%) of LBW and 48 (41.4%) of NBW infants at birth, and in 58 (45.7%) of LBW and 38 (49.3%) of NBW infants at follow-up. Clinical rickets was present in 17 (13.4%) of LBW and 4 (4.9%) of NBW infants at 12-14 weeks of corrected age. CONCLUSIONS: High prevalence of VDD in LBW as well as NBW infants with clinical rickets at an early age underlines the need to study the effect of various vitamin D supplementation regimens in these infants to identify the optimal dose. PMID- 22529321 TI - Simultaneous video stabilization and moving object detection in turbulence. AB - Turbulence mitigation refers to the stabilization of videos with nonuniform deformations due to the influence of optical turbulence. Typical approaches for turbulence mitigation follow averaging or dewarping techniques. Although these methods can reduce the turbulence, they distort the independently moving objects, which can often be of great interest. In this paper, we address the novel problem of simultaneous turbulence mitigation and moving object detection. We propose a novel three-term low-rank matrix decomposition approach in which we decompose the turbulence sequence into three components: the background, the turbulence, and the object. We simplify this extremely difficult problem into a minimization of nuclear norm, Frobenius norm, and l1 norm. Our method is based on two observations: First, the turbulence causes dense and Gaussian noise and therefore can be captured by Frobenius norm, while the moving objects are sparse and thus can be captured by l1 norm. Second, since the object's motion is linear and intrinsically different from the Gaussian-like turbulence, a Gaussian-based turbulence model can be employed to enforce an additional constraint on the search space of the minimization. We demonstrate the robustness of our approach on challenging sequences which are significantly distorted with atmospheric turbulence and include extremely tiny moving objects. PMID- 22529322 TI - Object matching using a locally affine invariant and linear programming techniques. AB - In this paper, we introduce a new matching method based on a novel locally affine invariant geometric constraint and linear programming techniques. To model and solve the matching problem in a linear programming formulation, all geometric constraints should be able to be exactly or approximately reformulated into a linear form. This is a major difficulty for this kind of matching algorithm. We propose a novel locally affine-invariant constraint which can be exactly linearized and requires a lot fewer auxiliary variables than other linear programming-based methods do. The key idea behind it is that each point in the template point set can be exactly represented by an affine combination of its neighboring points, whose weights can be solved easily by least squares. Errors of reconstructing each matched point using such weights are used to penalize the disagreement of geometric relationships between the template points and the matched points. The resulting overall objective function can be solved efficiently by linear programming techniques. Our experimental results on both rigid and nonrigid object matching show the effectiveness of the proposed algorithm. PMID- 22529323 TI - Learning multivariate distributions by competitive assembly of marginals. AB - We present a new framework for learning high-dimensional multivariate probability distributions from estimated marginals. The approach is motivated by compositional models and Bayesian networks, and designed to adapt to small sample sizes. We start with a large, overlapping set of elementary statistical building blocks, or "primitives," which are low-dimensional marginal distributions learned from data. Each variable may appear in many primitives. Subsets of primitives are combined in a Lego-like fashion to construct a probabilistic graphical model; only a small fraction of the primitives will participate in any valid construction. Since primitives can be precomputed, parameter estimation and structure search are separated. Model complexity is controlled by strong biases; we adapt the primitives to the amount of training data and impose rules which restrict the merging of them into allowable compositions. The likelihood of the data decomposes into a sum of local gains, one for each primitive in the final structure. We focus on a specific subclass of networks which are binary forests. Structure optimization corresponds to an integer linear program and the maximizing composition can be computed for reasonably large numbers of variables. Performance is evaluated using both synthetic data and real datasets from natural language processing and computational biology. PMID- 22529324 TI - Image transformation based on learning dictionaries across image spaces. AB - In this paper, we propose a framework of transforming images from a source image space to a target image space, based on learning coupled dictionaries from a training set of paired images. The framework can be used for applications such as image super-resolution and estimation of image intrinsic components (shading and albedo). It is based on a local parametric regression approach, using sparse feature representations over learned coupled dictionaries across the source and target image spaces. After coupled dictionary learning, sparse coefficient vectors of training image patch pairs are partitioned into easily retrievable local clusters. For any test image patch, we can fast index into its closest local cluster and perform a local parametric regression between the learned sparse feature spaces. The obtained sparse representation (together with the learned target space dictionary) provides multiple constraints for each pixel of the target image to be estimated. The final target image is reconstructed based on these constraints. The contributions of our proposed framework are three-fold. 1) We propose a concept of coupled dictionary learning based on coupled sparse coding which requires the sparse coefficient vectors of a pair of corresponding source and target image patches to have the same support, i.e., the same indices of nonzero elements. 2) We devise a space partitioning scheme to divide the high dimensional but sparse feature space into local clusters. The partitioning facilitates extremely fast retrieval of closest local clusters for query patches. 3) Benefiting from sparse feature-based image transformation, our method is more robust to corrupted input data, and can be considered as a simultaneous image restoration and transformation process. Experiments on intrinsic image estimation and super-resolution demonstrate the effectiveness and efficiency of our proposed method. PMID- 22529325 TI - Biologically Inspired Object Tracking Using Center-Surround Saliency Mechanisms. AB - A biologically inspired discriminant object tracker is proposed. It is argued that discriminant tracking is a consequence of top-down tuning of the saliency mechanisms that guide the deployment of visual attention. The principle of discriminant saliency is then used to derive a tracker that implements a combination of center-surround saliency, a spatial spotlight of attention, and feature-based attention. In this framework, the tracking problem is formulated as one of continuous target-background classification, implemented in two stages. The first, or learning stage, combines a focus of attention (FoA) mechanism, and bottom-up saliency to identify a maximally discriminant set of features for target detection. The second, or detection stage, uses a feature-based attention mechanism and a target-tuned top-down discriminant saliency detector to detect the target. Overall, the tracker iterates between learning discriminant features from the target location in a video frame and detecting the location of the target in the next. The statistics of natural images are exploited to derive an implementation which is conceptually simple and computationally efficient. The saliency formulation is also shown to establish a unified framework for classifier design, target detection, automatic tracker initialization, and scale adaptation. Experimental results show that the proposed discriminant saliency tracker outperforms a number of state-of-the-art trackers in the literature. PMID- 22529326 TI - ViSizer: A Visualization Resizing Framework. AB - Visualization resizing is useful for many applications where users may use different display devices. General resizing techniques (e.g., uniform scaling) and image-resizing techniques suffer from several drawbacks, as they do not consider the content of the visualizations. This work introduces ViSizer, a perception-based framework for automatically resizing a visualization to fit any display. We formulate an energy function based on a perception model (feature congestion), which aims to determine the optimal deformation for every local region. We subsequently transform the problem into an optimization problem by the energy function. An efficient algorithm is introduced to iteratively solve the problem, allowing for automatic visualization resizing. PMID- 22529327 TI - Computing Reeb Graphs as a Union of Contour Trees. AB - The Reeb graph of a scalar function tracks the evolution of the topology of its level sets. This paper describes a fast algorithm to compute the Reeb graph of a piecewise-linear (PL) function defined over manifolds and non-manifolds. The key idea in the proposed approach is to maximally leverage the efficient contour tree algorithm to compute the Reeb graph. The algorithm proceeds by dividing the input into a set of subvolumes that have loop-free Reeb graphs using the join tree of the scalar function and computes the Reeb graph by combining the contour trees of all the subvolumes. Since the key ingredient of this method is a series of union find operations, the algorithm is fast in practice. Experimental results demonstrate that it outperforms current generic algorithms by a factor of up to two orders of magnitude, and has a performance on par with algorithms that are catered to restricted classes of input. The algorithm also extends to handle large data that do not fit in memory. PMID- 22529328 TI - Double-Sided 2.5D Graphics. AB - This paper introduces double-sided 2.5D graphics, aiming at enriching the visual appearance when manipulating conventional 2D graphical objects in 2.5D worlds. By attaching a back texture image on a single-sided 2D graphical object, we can enrich the surface and texture detail on 2D graphical objects and improve our visual experience when manipulating and animating them. A family of novel operations on 2.5D graphics, including rolling, twisting, and folding, are proposed in this work, allowing users to efficiently create compelling 2.5D visual effects. Very little effort is needed from the user's side. In our experiment, various creative designs on double-sided graphics were worked out by the recruited participants including a professional artist, which show and demonstrate the feasibility and applicability of our proposed method. PMID- 22529329 TI - Scaffold filling under the breakpoint and related distances. AB - Motivated by the trend of genome sequencing without completing the sequence of the whole genomes, a problem on filling an incomplete multichromosomal genome (or scaffold) I with respect to a complete target genome G was studied. The objective is to minimize the resulting genomic distance between I' and G, where I' is the corresponding filled scaffold. We call this problem the onesided scaffold filling problem. In this paper, we conduct a systematic study for the scaffold filling problem under the breakpoint distance and its variants, for both unichromosomal and multichromosomal genomes (with and without gene repetitions). When the input genome contains no gene repetition (i.e., is a fragment of a permutation), we show that the two-sided scaffold filling problem (i.e., G is also incomplete) is polynomially solvable for unichromosomal genomes under the breakpoint distance and for multichromosomal genomes under the genomic (or DCJ--Double-Cut-and-Join) distance. However, when the input genome contains some repeated genes, even the one-sided scaffold filling problem becomes NP-complete when the similarity measure is the maximum number of adjacencies between two sequences. For this problem, we also present efficient constant-factor approximation algorithms: factor-2 for the general case and factor 1.33 for the one-sided case. PMID- 22529330 TI - A hybrid Factored Frontier algorithm for Dynamic Bayesian Networks with a biopathways application. AB - Dynamic Bayesian Networks (DBNs) can serve as succinct probabilistic dynamic models of biochemical networks. To analyze these models, one must compute the probability distribution over system states at a given time point. Doing this exactly is infeasible for large models; hence one must use approximate algorithms. The Factored Frontier algorithm (FF) is one such algorithm. However FF as well as the earlier Boyen-Koller (BK) algorithm can incur large errors. To address this, we present a new approximate algorithm called the Hybrid Factored Frontier (HFF) algorithm. At each time slice, in addition to maintaining probability distributions over local states-as FF does-HFF explicitly maintains the probabilities of a number of global states called spikes. When the number of spikes is 0, we get FF and with all global states as spikes, we get the exact inference algorithm. We show that by increasing the number of spikes one can reduce errors while the additional computational effort required is only quadratic in the number of spikes. We validated the performance of HFF on large DBN models of biopathways. Each pathway has more than 30 species and the corresponding DBN has more than 3,000 nodes. Comparisons with FF and BK show that HFF is a useful and powerful approximate inferencing algorithm for DBNs. PMID- 22529331 TI - Detection of outlier residues for improving interface prediction in protein heterocomplexes. AB - Sequence-based understanding and identification of protein binding interfaces is a challenging research topic due to the complexity in protein systems and the imbalanced distribution between interface and noninterface residues. This paper presents an outlier detection idea to address the redundancy problem in protein interaction data. The cleaned training data are then used for improving the prediction performance. We use three novel measures to describe the extent a residue is considered as an outlier in comparison to the other residues: the distance of a residue instance from the center instance of all residue instances of the same class label (Dist), the probability of the class label of the residue instance (PCL), and the importance of within-class and between-class (IWB) residue instances. Outlier scores are computed by integrating the three factors; instances with a sufficiently large score are treated as outliers and removed. The data sets without outliers are taken as input for a support vector machine (SVM) ensemble. The proposed SVM ensemble trained on input data without outliers performs better than that with outliers. Our method is also more accurate than many literature methods on benchmark data sets. From our empirical studies, we found that some outlier interface residues are truly near to noninterface regions, and some outlier noninterface residues are close to interface regions. PMID- 22529332 TI - Evaluation of design strategies for time course experiments in genetic networks: case study of the XlnR regulon in Aspergillus niger. AB - One of the challenges in genetic network reconstruction is finding experimental designs that maximize the information content in a data set. In this paper, the information value of mRNA transcription time course experiments was used to compare experimental designs. The study concerns the dynamic response of genes in the XlnR regulon of Aspergillus niger, with the goal to find the best moment in time to administer an extra pulse of inducing D-xylose. Low and high D-xylose pulses were used to perturb the XlnR regulon. Evaluation of the experimental methods was based on simulation of the regulon. Models that govern the regulation of the target genes in this regulon were used for the simulations. Parameter sensitivity analysis, the Fisher Information Matrix (FIM) and the modified E criterion were used to assess the design performances. The results show that the best time to give a second D-xylose pulse is when the D-xylose concentration from the first pulse has not yet completely faded away. Due to the presence of a repression effect the strength of the second pulse must be optimized, rather than maximized. The results suggest that the modified E-criterion is a better metric than the sum of integrals of absolute sensitivity for comparing alternative designs. PMID- 22529333 TI - Time series dependent analysis of unparametrized Thomas networks. AB - This paper is concerned with the analysis of labeled Thomas networks using discrete time series. It focuses on refining the given edge labels and on assessing the data quality. The results are aimed at being exploitable for experimental design and include the prediction of new activatory or inhibitory effects of given interactions and yet unobserved oscillations of specific components in between specific sampling intervals. On the formal side, we generalize the concept of edge labels and introduce a discrete time series interpretation. This interpretation features two original concepts: 1) Incomplete measurements are admissible, and 2) it allows qualitative assumptions about the changes in gene expression by means of monotonicity. On the computational side, we provide a Python script, erda.py, that automates the suggested workflow by model checking and constraint satisfaction. We illustrate the workflow by investigating the yeast network IRMA. PMID- 22529334 TI - Rapamycin increases oxidative stress response gene expression in adult stem cells. AB - Balancing quiescence with proliferation is of paramount importance for adult stem cells in order to avoid hyperproliferation and cell depletion. In some models, stem cell exhaustion may be reversed with the drug rapamycin, which was shown can suppress cellular senescencein vitro and extend lifespan in animals. We hypothesized that rapamycin increases the expression of oxidative stress response genes in adult stem cells, and that these gene activities diminish with age. To test our hypothesis, we exposed mice to rapamycin and then examined the transcriptome of their spermatogonial stem cells (SSCs). Gene expression microarray analysis revealed that numerous oxidative stress response genes were upregulated upon rapamycin treatment, including superoxide dismutase 1, glutathione reductase, and delta-aminolevulinate dehydratase. When we examined the expression of these genes in 55-week-old wild type SSCs, their levels were significantly reduced compared to 3-week-old SSCs, suggesting that their downregulation is coincident with the aging process in adult stem cells. We conclude that rapamycin-induced stimulation of oxidative stress response genes may promote cellular longevity in SSCs, while a decline in gene expression in aged stem cells could reflect the SSCs' diminished potential to alleviate oxidative stress, a hallmark of aging. PMID- 22529335 TI - ATM-dependent phosphorylation of SNEVhPrp19/hPso4 is involved in extending cellular life span and suppression of apoptosis. AB - Defective DNA repair is widely acknowledged to negatively impact on healthy aging, since mutations in DNA repair factors lead to accelerated and premature aging. However, the opposite, namely if improved DNA repair will also increase the life or health span is less clear, and only few studies have tested if overexpression of DNA repair factors modulates life and health span in cells or organisms. Recently, we identified and characterized SNEVhPrp19/hPso4, a protein that plays a role in DNA repair and pre-mRNA splicing, and observed a doubling of the replicative life span upon ectopic overexpression, accompanied by lower basal DNA damage and apoptosis levels as well as an increased resistance to oxidative stress. Here we find that SNEVhPrp19/hPso4 is phosphorylated at S149 in an ataxia telangiectasia mutated protein (ATM)-dependent manner in response to oxidative stress and DNA double strand break inducing agents. By overexpressing wild-type SNEVhPrp19/hPso4 and a phosphorylation-deficient point-mutant, we found that S149 phosphorylation is necessary for mediating the resistance to apoptosis upon oxidative stress and is partially necessary for elongating the cellular life span. Therefore, ATM dependent phosphorylation of SNEVhPrp19/hPso4 upon DNA damage or oxidative stress might represent a novel axis capable of modulating cellular life span. PMID- 22529342 TI - Laurdan generalized polarization fluctuations measures membrane packing micro heterogeneity in vivo. AB - Cellular membranes are heterogeneous in composition, and the prevailing theory holds that the structures responsible for this heterogeneity in vivo are small structures (10-200 nm), sterol- and sphingolipid-enriched, of different sizes, highly dynamic denominated rafts. Rafts are postulated to be platforms, which by sequestering different membrane components can compartmentalize cellular processes and regulate signaling pathways. Despite an enormous effort in this area, the existence of these domains is still under debate due to the characteristics of the structures itself: small in size and highly mobile, which from the technical point of view implies using techniques with high spatial and temporal resolution. In this report we measured rapid fluctuations of the normalized ratio of the emission intensity at two wavelengths of Laurdan, a membrane fluorescent dye sensitive to local membrane packing. We observed generalized polarization fluctuations in the plasma membrane of intact rabbit erythrocytes and Chinese hamster ovary cells that can be explained by the existence of tightly packed micro-domains moving in a more fluid background phase. These structures, which display different lipid packing, have different sizes; they are found in the same cell and in the entire cell population. The small size and characteristic high lipid packing indicate that these micro domains have properties that have been proposed for lipid rafts. PMID- 22529343 TI - Overspill avalanching in a dense reservoir network. AB - Sustainability of communities, agriculture, and industry is strongly dependent on an effective storage and supply of water resources. In some regions the economic growth has led to a level of water demand that can only be accomplished through efficient reservoir networks. Such infrastructures are not always planned at larger scale but rather made by farmers according to their local needs of irrigation during droughts. Based on extensive data from the upper Jaguaribe basin, one of the world's largest system of reservoirs, located in the Brazilian semiarid northeast, we reveal that surprisingly it self-organizes into a scale free network exhibiting also a power-law in the distribution of the lakes and avalanches of discharges. With a new self-organized-criticality-type model we manage to explain the novel critical exponents. Implementing a flow model we are able to reproduce the measured overspill evolution providing a tool for catastrophe mitigation and future planning. PMID- 22529344 TI - Phage-based molecular probes that discriminate force-induced structural states of fibronectin in vivo. AB - Applied forces and the biophysical nature of the cellular microenvironment play a central role in determining cellular behavior. Specifically, forces due to cell contraction are transmitted into structural ECM proteins and these forces are presumed to activate integrin "switches." The mechanism of such switches is thought to be the partial unfolding of integrin-binding domains within fibronectin (Fn). However, integrin switches remain largely hypothetical due to a dearth of evidence for their existence, and relevance, in vivo. By using phage display in combination with the controlled deposition and extension of Fn fibers, we report the discovery of peptide-based molecular probes capable of selectively discriminating Fn fibers under different strain states. Importantly, we show that the probes are functional in both in vitro and ex vivo tissue contexts. The development of such tools represents a critical step in establishing the relevance of theoretical mechanotransduction events within the cellular microenvironment. PMID- 22529345 TI - Gas-liquid transfer data used to analyze hydrophobic hydration and find the nature of the Kauzmann-Tanford hydrophobic factor. AB - Hydrophobic free energy for protein folding is currently measured by liquid liquid transfer, based on an analogy between the folding process and the transfer of a nonpolar solute from water into a reference solvent. The second part of the analogy (transfer into a nonaqueous solvent) is dubious and has been justified by arguing that transfer out of water probably contributes the major part of the free energy change. This assumption is wrong: transfer out of water contributes no more than half the total, often less. Liquid-liquid transfer of the solute from water to liquid alkane is written here as the sum of 2 gas-liquid transfers: (i) out of water into vapor, and (ii) from vapor into liquid alkane. Both gas liquid transfers have known free energy values for several alkane solutes. The comparable values of the two different transfer reactions are explained by the values, determined in 1991 for three alkane solutes, of the cavity work and the solute-solvent interaction energy. The transfer free energy is the difference between the positive cavity work and the negative solute-solvent interaction energy. The interaction energy has similar values in water and liquid alkane that are intermediate in magnitude between the cavity work in water and in liquid alkane. These properties explain why the transfer free energy has comparable values (with opposite signs) in the two transfers. The current hydrophobic free energy is puzzling and poorly defined and needs a new definition and method of measurement. PMID- 22529347 TI - Accumulation of impact markers in desert wetlands and implications for the Younger Dryas impact hypothesis. AB - The Younger Dryas impact hypothesis contends that an extraterrestrial object exploded over North America at 12.9 ka, initiating the Younger Dryas cold event, the extinction of many North American megafauna, and the demise of the Clovis archeological culture. Although the exact nature and location of the proposed impact or explosion remain unclear, alleged evidence for the fallout comes from multiple sites across North America and a site in Belgium. At 6 of the 10 original sites (excluding the Carolina Bays), elevated concentrations of various "impact markers" were found in association with black mats that date to the onset of the Younger Dryas. Black mats are common features in paleowetland deposits and typically represent shallow marsh environments. In this study, we investigated black mats ranging in age from approximately 6 to more than 40 ka in the southwestern United States and the Atacama Desert of northern Chile. At 10 of 13 sites, we found elevated concentrations of iridium in bulk and magnetic sediments, magnetic spherules, and/or titanomagnetite grains within or at the base of black mats, regardless of their age or location, suggesting that elevated concentrations of these markers arise from processes common to wetland systems, and not a catastrophic extraterrestrial impact event. PMID- 22529346 TI - Self-regulated viscous channel in the nuclear pore complex. AB - The nuclear pore complex (NPC), the sole gateway for nucleocytoplasmic exchange in eukaryotic cells, allows for the passive diffusion of small molecules and transport-receptor-facilitated translocation of signal-dependent cargo molecules. Whether small molecules passively diffuse through a single central channel or through multiple holes of a hydrogel network is a subject of debate. Additionally, whether the passive and facilitated transport systems occupy distinct or overlapping physical regions of the NPC remains unclear. Here, we directly test these models using three-dimensional super-resolution fluorescence microscopy of human cells. This approach reveals that a single viscous central channel in the NPC acts as the sole pathway for passive diffusion of various small molecules; transport receptors and their cargo complexes take distinct transport routes in the periphery, which is occluded by phenylalanine-glycine filaments. Furthermore, the passive and facilitated passageways in the NPC are closely correlated, and their conformations can be simultaneously regulated by Importin beta1 (a major transport receptor) and RanGTP (a critical regulator of transport directionality). These results strongly favor a self-regulated viscous channel configuration in native NPCs over the porous hydrogel meshwork model. PMID- 22529348 TI - Order parameter fluctuations at a buried quantum critical point. AB - Quantum criticality is a central concept in condensed matter physics, but the direct observation of quantum critical fluctuations has remained elusive. Here we present an X-ray diffraction study of the charge density wave (CDW) in 2H-NbSe(2) at high pressure and low temperature, where we observe a broad regime of order parameter fluctuations that are controlled by proximity to a quantum critical point. X-rays can track the CDW despite the fact that the quantum critical regime is shrouded inside a superconducting phase; and in contrast to transport probes, allow direct measurement of the critical fluctuations of the charge order. Concurrent measurements of the crystal lattice point to a critical transition that is continuous in nature. Our results confirm the long-standing expectations of enhanced quantum fluctuations in low-dimensional systems, and may help to constrain theories of the quantum critical Fermi surface. PMID- 22529349 TI - Foraging success of biological Levy flights recorded in situ. AB - It is an open question how animals find food in dynamic natural environments where they possess little or no knowledge of where resources are located. Foraging theory predicts that in environments with sparsely distributed target resources, where forager knowledge about resources' locations is incomplete, Levy flight movements optimize the success of random searches. However, the putative success of Levy foraging has been demonstrated only in model simulations. Here, we use high-temporal-resolution Global Positioning System (GPS) tracking of wandering (Diomedea exulans) and black-browed albatrosses (Thalassarche melanophrys) with simultaneous recording of prey captures, to show that both species exhibit Levy and Brownian movement patterns. We find that total prey masses captured by wandering albatrosses during Levy movements exceed daily energy requirements by nearly fourfold, and approached yields by Brownian movements in other habitats. These results, together with our reanalysis of previously published albatross data, overturn the notion that albatrosses do not exhibit Levy patterns during foraging, and demonstrate that Levy flights of predators in dynamic natural environments present a beneficial alternative strategy to simple, spatially intensive behaviors. Our findings add support to the possibility that biological Levy flight may have naturally evolved as a search strategy in response to sparse resources and scant information. PMID- 22529350 TI - Accurately estimating neuronal correlation requires a new spike-sorting paradigm. AB - Neurophysiology is increasingly focused on identifying coincident activity among neurons. Strong inferences about neural computation are made from the results of such studies, so it is important that these results be accurate. However, the preliminary step in the analysis of such data, the assignment of spike waveforms to individual neurons ("spike-sorting"), makes a critical assumption which undermines the analysis: that spikes, and hence neurons, are independent. We show that this assumption guarantees that coincident spiking estimates such as correlation coefficients are biased. We also show how to eliminate this bias. Our solution involves sorting spikes jointly, which contrasts with the current practice of sorting spikes independently of other spikes. This new "ensemble sorting" yields unbiased estimates of coincident spiking, and permits more data to be analyzed with confidence, improving the quality and quantity of neurophysiological inferences. These results should be of interest outside the context of neuronal correlations studies. Indeed, simultaneous recording of many neurons has become the rule rather than the exception in experiments, so it is essential to spike sort correctly if we are to make valid inferences about any properties of, and relationships between, neurons. PMID- 22529351 TI - Identifying sources of variation and the flow of information in biochemical networks. AB - To understand how cells control and exploit biochemical fluctuations, we must identify the sources of stochasticity, quantify their effects, and distinguish informative variation from confounding "noise." We present an analysis that allows fluctuations of biochemical networks to be decomposed into multiple components, gives conditions for the design of experimental reporters to measure all components, and provides a technique to predict the magnitude of these components from models. Further, we identify a particular component of variation that can be used to quantify the efficacy of information flow through a biochemical network. By applying our approach to osmosensing in yeast, we can predict the probability of the different osmotic conditions experienced by wild type yeast and show that the majority of variation can be informational if we include variation generated in response to the cellular environment. Our results are fundamental to quantifying sources of variation and thus are a means to understand biological "design." PMID- 22529352 TI - Insights into proton-coupled electron transfer mechanisms of electrocatalytic H2 oxidation and production. AB - The design of molecular electrocatalysts for H(2) oxidation and production is important for the development of alternative renewable energy sources that are abundant, inexpensive, and environmentally benign. Recently, nickel-based molecular electrocatalysts with pendant amines that act as proton relays for the nickel center were shown to effectively catalyze H(2) oxidation and production. We developed a quantum mechanical approach for studying proton-coupled electron transfer processes in these types of molecular electrocatalysts. This theoretical approach is applied to a nickel-based catalyst in which phosphorous atoms are directly bonded to the nickel center, and nitrogen atoms of the ligand rings act as proton relays. The catalytic step of interest involves electron transfer between the nickel complex and the electrode as well as intramolecular proton transfer between the nickel and nitrogen atoms. This process can occur sequentially, with either the electron or proton transferring first, or concertedly, with the electron and proton transferring simultaneously without a stable intermediate. The electrochemical rate constants are calculated as functions of overpotential for the concerted electron-proton transfer reaction and the two electron transfer reactions in the sequential mechanisms. Our calculations illustrate that the concerted electron-proton transfer standard rate constant will increase as the equilibrium distance between the nickel and nitrogen atoms decreases and as the pendant amines become more flexible to facilitate the contraction of this distance with a lower energy penalty. This approach identifies the favored mechanisms under various experimental conditions and provides insight into the impact of substituents on the nitrogen and phosphorous atoms. PMID- 22529353 TI - Histidine pairing at the metal transport site of mammalian ZnT transporters controls Zn2+ over Cd2+ selectivity. AB - Zinc and cadmium are similar metal ions, but though Zn(2+) is an essential nutrient, Cd(2+) is a toxic and common pollutant linked to multiple disorders. Faster body turnover and ubiquitous distribution of Zn(2+) vs. Cd(2+) suggest that a mammalian metal transporter distinguishes between these metal ions. We show that the mammalian metal transporters, ZnTs, mediate cytosolic and vesicular Zn(2+) transport, but reject Cd(2+), thus constituting the first mammalian metal transporter with a refined selectivity against Cd(2+). Remarkably, the bacterial ZnT ortholog, YiiP, does not discriminate between Zn(2+) and Cd(2+). A phylogenetic comparison between the tetrahedral metal transport motif of YiiP and ZnTs identifies a histidine at the mammalian site that is critical for metal selectivity. Residue swapping at this position abolished metal selectivity of ZnTs, and fully reconstituted selective Zn(2+) transport of YiiP. Finally, we show that metal selectivity evolves through a reduction in binding but not the translocation of Cd(2+) by the transporter. Thus, our results identify a unique class of mammalian transporters and the structural motif required to discriminate between Zn(2+) and Cd(2+), and show that metal selectivity is tuned by a coordination-based mechanism that raises the thermodynamic barrier to Cd(2+) binding. PMID- 22529355 TI - Global models of ant diversity suggest regions where new discoveries are most likely are under disproportionate deforestation threat. AB - Most of the described and probably undescribed species on Earth are insects. Global models of species diversity rarely focus on insects and none attempt to address unknown, undescribed diversity. We assembled a database representing about 13,000 records for ant generic distribution from over 350 regions that cover much of the globe. Based on two models of diversity and endemicity, we identified regions where our knowledge of ant diversity is most limited, regions we have called "hotspots of discovery." A priori, such regions might be expected to be remote and untouched. Instead, we found that the hotspots of discovery are also the regions in which biodiversity is the most threatened by habitat destruction. Our results not only highlight the immediate need for conservation of the remaining natural habitats in these regions, but also the extent to which, by focusing on well-known groups such as vertebrates, we may fail to conserve the far greater diversity of the smaller species yet to be found. PMID- 22529354 TI - Anxiety in liver X receptor beta knockout female mice with loss of glutamic acid decarboxylase in ventromedial prefrontal cortex. AB - Anxiety disorders are the most prevalent mental disorders in adolescents in the United States. Female adolescents are more likely than males to be affected with anxiety disorders, but less likely to have behavioral and substance abuse disorders. The prefrontal cortex (PFC), amygdala, and dorsal raphe are known to be involved in anxiety disorders. Inhibitory input from the PFC to the amygdala controls fear and anxiety typically originating in the amygdala, and disruption of the inhibitory input from the PFC leads to anxiety, fear, and personality changes. Recent studies have implicated liver X receptor beta (LXRbeta) in key neurodevelopmental processes and neurodegenerative diseases. In the present study, we used elevated plus-maze, startle and prepulse inhibition, open field, and novel object recognition tests to evaluate behavior in female LXRbeta KO (LXRbeta(-/-)) mice. We found that the female LXRbeta(-/-) mice were anxious with impaired behavioral responses but normal locomotion and memory. Immunohistochemistry analysis revealed decreased expression of the enzyme responsible for GABA synthesis, glutamic acid decarboxylase (65+67), in the ventromedial PFC. Expression of tryptophan hydroxylase 2 in the dorsal raphe was normal. We conclude that the anxiogenic phenotype in female LXRbeta(-/-) mice is caused by reduced GABAergic input from the ventromedial PFC to the amygdala. PMID- 22529356 TI - Whole-genome resequencing of two elite sires for the detection of haplotypes under selection in dairy cattle. AB - Using a combination of whole-genome resequencing and high-density genotyping arrays, genome-wide haplotypes were reconstructed for two of the most important bulls in the history of the dairy cattle industry, Pawnee Farm Arlinda Chief ("Chief") and his son Walkway Chief Mark ("Mark"), each accounting for ~7% of all current genomes. We aligned 20.5 Gbp (~7.3* coverage) and 37.9 Gbp (~13.5* coverage) of the Chief and Mark genomic sequences, respectively. More than 1.3 million high-quality SNPs were detected in Chief and Mark sequences. The genome wide haplotypes inherited by Mark from Chief were reconstructed using ~1 million informative SNPs. Comparison of a set of 15,826 SNPs that overlapped in the sequence-based and BovineSNP50 SNPs showed the accuracy of the sequence-based haplotype reconstruction to be as high as 97%. By using the BovineSNP50 genotypes, the frequencies of Chief alleles on his two haplotypes then were determined in 1,149 of his descendants, and the distribution was compared with the frequencies that would be expected assuming no selection. We identified 49 chromosomal segments in which Chief alleles showed strong evidence of selection. Candidate polymorphisms for traits that have been under selection in the dairy cattle population then were identified by referencing Chief's DNA sequence within these selected chromosome blocks. Eleven candidate genes were identified with functions related to milk-production, fertility, and disease-resistance traits. These data demonstrate that haplotype reconstruction of an ancestral proband by whole-genome resequencing in combination with high-density SNP genotyping of descendants can be used for rapid, genome-wide identification of the ancestor's alleles that have been subjected to artificial selection. PMID- 22529358 TI - Live imaging of nascent RNA dynamics reveals distinct types of transcriptional pulse regulation. AB - Transcription of genes can be discontinuous, occurring in pulses or bursts. It is not clear how properties of transcriptional pulses vary between different genes. We compared the pulsing of five housekeeping and five developmentally induced genes by direct imaging of single gene transcriptional events in individual living Dictyostelium cells. Each gene displayed its own transcriptional signature, differing in probability of firing and pulse duration, frequency, and intensity. In contrast to the prevailing view from both prokaryotes and eukaryotes that transcription displays binary behavior, strongly expressed housekeeping genes altered the magnitude of their transcriptional pulses during development. These nonbinary "tunable" responses may be better suited than stochastic switch behavior for housekeeping functions. Analysis of RNA synthesis kinetics using fluorescence recovery after photobleaching implied modulation of housekeeping-gene pulse strength occurs at the level of transcription initiation rather than elongation. In addition, disparities between single cell and population measures of transcript production suggested differences in RNA stability between gene classes. Analysis of stability using RNAseq revealed no major global differences in stability between developmental and housekeeping transcripts, although strongly induced RNAs showed unusually rapid decay, indicating tight regulation of expression. PMID- 22529357 TI - Maternal cortisol over the course of pregnancy and subsequent child amygdala and hippocampus volumes and affective problems. AB - Stress-related variation in the intrauterine milieu may impact brain development and emergent function, with long-term implications in terms of susceptibility for affective disorders. Studies in animals suggest limbic regions in the developing brain are particularly sensitive to exposure to the stress hormone cortisol. However, the nature, magnitude, and time course of these effects have not yet been adequately characterized in humans. A prospective, longitudinal study was conducted in 65 normal, healthy mother-child dyads to examine the association of maternal cortisol in early, mid-, and late gestation with subsequent measures at approximately 7 y age of child amygdala and hippocampus volume and affective problems. After accounting for the effects of potential confounding pre- and postnatal factors, higher maternal cortisol levels in earlier but not later gestation was associated with a larger right amygdala volume in girls (a 1 SD increase in cortisol was associated with a 6.4% increase in right amygdala volume), but not in boys. Moreover, higher maternal cortisol levels in early gestation was associated with more affective problems in girls, and this association was mediated, in part, by amygdala volume. No association between maternal cortisol in pregnancy and child hippocampus volume was observed in either sex. The current findings represent, to the best of our knowledge, the first report linking maternal stress hormone levels in human pregnancy with subsequent child amygdala volume and affect. The results underscore the importance of the intrauterine environment and suggest the origins of neuropsychiatric disorders may have their foundations early in life. PMID- 22529360 TI - From EPOthilone to EPO: Aa challenge for natural product synthesis. PMID- 22529361 TI - Mechanistic stoichiometry of proton translocation by cytochrome cbb3. AB - Cytochrome cbb(3) belongs to the superfamily of respiratory heme-copper oxidases that couple the reduction of molecular oxygen to proton translocation across the bacterial or mitochondrial membrane. The cbb(3)-type enzymes are found only in bacteria, and are both structurally and functionally the most distant from their mitochondrial counterparts. The mechanistic H(+)/e(-) stoichiometry of proton translocation in these cbb(3)-type cytochrome c oxidases has remained controversial. A stoichiometric efficiency of only one-half that of the mitochondrial aa(3)-type enzyme was recently proposed to be related to adaptation of the organism to microaerobic environments. Here, proton translocation by the Rhodobacter sphaeroides enzyme was studied using purified cytochrome cbb(3) reconstituted into liposomes. An H(+)/e(-) stoichiometry of proton translocation close to unity was observed using the oxygen pulse method, but solely in conditions in which the vast majority of the enzyme was fully reduced in the anaerobic state before the O(2) pulse. These data were compared with results using whole cells or spheroplasts, and the discrepancies in the literature data were discussed. Our results suggest that a proton-pumping efficiency of 1 H(+)/e( ) may be achieved using the single-proton uptake pathway identified in the structure of cytochrome cbb(3). The mechanism of proton pumping thus differs from that of the aa(3)-type oxidases of mitochondria and bacteria. PMID- 22529359 TI - SINGLET OXYGEN RESISTANT 1 links reactive electrophile signaling to singlet oxygen acclimation in Chlamydomonas reinhardtii. AB - Acclimation of Chlamydomonas reinhardtii cells to low levels of singlet oxygen, produced either by photoreactive chemicals or high light treatment, induces a specific genetic response that strongly increases the tolerance of the algae to subsequent exposure to normally lethal singlet oxygen-producing conditions. The genetic response includes the increased expression of various oxidative stress response and detoxification genes, like the glutathione peroxidase homologous gene GPXH/GPX5 and the sigma-class glutathione-S-transferase gene GSTS1. To identify components involved in the signal transduction and activation of the singlet oxygen-mediated response, a mutant selection was performed. This selection led to the isolation of the singlet oxygen resistant 1 (sor1) mutant, which is more tolerant to singlet oxygen-producing chemicals and shows a constitutively higher expression of GPXH and GSTS1. Map-based cloning revealed that the SOR1 gene encodes a basic leucine zipper transcription factor, which controls its own expression and the expression of a large number of oxidative stress response and detoxification genes. In the promoter region of many of these genes, a highly conserved 8-bp palindromic sequence element was found to be enriched. This element was essential for GSTS1 induction by increased levels of lipophilic reactive electrophile species (RES), suggesting that it functions as an electrophile response element (ERE). Furthermore, GSTS1 overexpression in sor1 requires the ERE, although it is unknown whether it occurs through direct binding of SOR1 to the ERE. RES can be formed after singlet oxygen-induced lipid peroxidation, indicating that RES-stimulated and SOR1-mediated responses of detoxification genes are part of the singlet oxygen-induced acclimation process in C. reinhardtii. PMID- 22529362 TI - Dysregulation of dopamine receptor D2 as a sensitive measure for Huntington disease pathology in model mice. AB - The ability to quantitatively evaluate the impact of a potential therapeutic intervention for Huntington disease (HD) in animal models for the disease is a critical step in the pathway to development of an effective therapy for this devastating neurodegenerative disorder. We report here an approach that combines a cell-based assay's quantitative accuracy and direct relationship to molecular processes with the ability to directly monitor effects in HD model mouse neurons. To accomplish this goal, we have developed an accurate quantitative reporter assay for a transcript known to be down-regulated as an early consequence of mutant huntingtin expression. This system uses mouse strains carrying a GFP reporter for the expression of the dopamine receptor D2, expressed in the medium spiny neurons of the basal ganglion. This receptor consistently demonstrates reduced expression in patients and murine models, and the FACS-based assay gives a highly accurate and quantitative readout of this pathology in mouse neurons expressing mutant huntingtin. For four genetic models and one viral model, a highly reproducible time course of loss of reporter expression is observed. This quantitative measure of HD pathology can be used to measure the effects of HD therapeutics in small cohorts with high confidence. We further demonstrate that the introduction of an shRNA against the huntingtin transgene by virus can improve this pathological status in medium spiny neurons transduced with the construct. We believe this system can be of great utility in the validation of effective therapeutic interventions for HD. PMID- 22529363 TI - Action controls dopaminergic enhancement of reward representations. AB - Dopamine is widely observed to signal anticipation of future rewards and thus thought to be a key contributor to affectively charged decision making. However, the experiments supporting this view have not dissociated rewards from the actions that lead to, or are occasioned by, them. Here, we manipulated dopamine pharmacologically and examined the effect on a task that explicitly dissociates action and reward value. We show that dopamine enhanced the neural representation of rewarding actions, without significantly affecting the representation of reward value as such. Thus, increasing dopamine levels with levodopa selectively boosted striatal and substantia nigra/ventral tegmental representations associated with actions leading to reward, but not with actions leading to the avoidance of punishment. These findings highlight a key role for dopamine in the generation of appetitively motivated actions. PMID- 22529364 TI - Proteins under pressure. PMID- 22529365 TI - Differences in intradomain and interdomain motion confer distinct activation properties to structurally similar Galpha proteins. AB - Proteins with similar crystal structures can have dissimilar rates of substrate binding and catalysis. Here we used molecular dynamics simulations and biochemical analysis to determine the role of intradomain and interdomain motions in conferring distinct activation rates to two Galpha proteins, Galpha(i1) and GPA1. Despite high structural similarity, GPA1 can activate itself without a receptor, whereas Galpha(i1) cannot. We found that motions in these proteins vary greatly in type and frequency. Whereas motion is greatest in the Ras domain of Galpha(i1), it is greatest in helices alphaA and alphaB from the helical domain of GPA1. Using protein chimeras, we show that helix alphaA from GPA1 is sufficient to confer rapid activation to Galpha(i1). Galpha(i1) has less intradomain motion than GPA1 and instead displays interdomain displacement resembling that observed in a receptor-heterotrimer crystal complex. Thus, structurally similar proteins can have distinct atomic motions that confer distinct activation mechanisms. PMID- 22529367 TI - In planta gene targeting. AB - The development of designed site-specific endonucleases boosted the establishment of gene targeting (GT) techniques in a row of different species. However, the methods described in plants require a highly efficient transformation and regeneration procedure and, therefore, can be applied to very few species. Here, we describe a highly efficient GT system that is suitable for all transformable plants regardless of transformation efficiency. Efficient in planta GT was achieved in Arabidopsis thaliana by expression of a site-specific endonuclease that not only cuts within the target but also the chromosomal transgenic donor, leading to an excised targeting vector. Progeny clonal for the targeted allele could be obtained directly by harvesting seeds. Targeted events could be identified up to approximately once per 100 seeds depending on the target donor combination. Molecular analysis demonstrated that, in almost all events, homologous recombination occurred at both ends of the break. No ectopic integration of the GT vector was found. PMID- 22529366 TI - MicroRNA-200a serves a key role in the decline of progesterone receptor function leading to term and preterm labor. AB - During pregnancy, uterine quiescence is maintained by increased progesterone receptor (PR) activity, but labor is facilitated by a series of events that impair PR function. Previously, we discovered that miR-200 family members serve as progesterone (P(4))-modulated activators of contraction-associated genes in the pregnant uterus. In this study, we identified a unique role for miR-200a to enhance the local metabolism of P(4) in myometrium and, thus, decrease PR function during the progression toward labor. miR-200a exerts this action by direct repression of STAT5b, a transcriptional repressor of the P(4)-metabolizing enzyme 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD). We observed that miR 200a expression increased and STAT5b expression coordinately decreased in myometrium of mice as they progressed to labor and in laboring myometrium from pregnant women. These changes were associated with a dramatic increase in expression and activity of 20alpha-HSD in laboring myometrium from mouse and human. Notably, overexpression of miR-200a in cultured human myometrial cells (hTERT-HM) suppressed STAT5b and increased 20alpha-HSD mRNA levels. In uterine tissues of ovariectomized mice injected with P(4), miR-200 expression was significantly decreased, STAT5b expression was up-regulated, and 20alpha-HSD mRNA was decreased, but in 15 d postcoitum pregnant mice injected with the PR antagonist RU486, preterm labor was associated with increased miR-200a, decreased STAT5b, and enhanced 20alpha-HSD expression. Taken together, these findings implicate miR-200a as an important regulator of increased local P(4) metabolism in the pregnant uterus near term and provide insight into the importance of miR 200s in the decline in PR function leading to labor. PMID- 22529369 TI - Visual attention and the acquisition of information in human crowds. AB - Pedestrian crowds can form the substrate of important socially contagious behaviors, including propagation of visual attention, violence, opinions, and emotional state. However, relating individual to collective behavior is often difficult, and quantitative studies have largely used laboratory experimentation. We present two studies in which we tracked the motion and head direction of 3,325 pedestrians in natural crowds to quantify the extent, influence, and context dependence of socially transmitted visual attention. In our first study, we instructed stimulus groups of confederates within a crowd to gaze up to a single point atop of a building. Analysis of passersby shows that visual attention spreads unevenly in space and that the probability of pedestrians adopting this behavior increases as a function of stimulus group size before saturating for larger groups. We develop a model that predicts that this gaze response will lead to the transfer of visual attention between crowd members, but it is not sufficiently strong to produce a tipping point or critical mass of gaze-following that has previously been predicted for crowd dynamics. A second experiment, in which passersby were presented with two stimulus confederates performing suspicious/irregular activity, supports the predictions of our model. This experiment reveals that visual interactions between pedestrians occur primarily within a 2-m range and that gaze-copying, although relatively weak, can facilitate response to relevant stimuli. Although the above aspects of gaze following response are reproduced robustly between experimental setups, the overall tendency to respond to a stimulus is dependent on spatial features, social context, and sex of the passerby. PMID- 22529368 TI - Photothermic regulation of gene expression triggered by laser-induced carbon nanohorns. AB - The development of optical methods to control cellular functions is important for various biological applications. In particular, heat shock promoter-mediated gene expression systems by laser light are attractive targets for controlling cellular functions. However, previous approaches have considerable technical limitations related to their use of UV, short-wavelength visible (vis), and infrared (IR) laser light, which have poor penetration into biological tissue. Biological tissue is relatively transparent to light inside the diagnostic window at wavelengths of 650-1,100 nm. Here we present a unique optical biotechnological method using carbon nanohorn (CNH) that transforms energy from diagnostic window laser light to heat to control the expression of various genes. We report that with this method, laser irradiation within the diagnostic window resulted in effective heat generation and thus caused heat shock promoter-mediated gene expression. This study provides an important step forward in the development of light-manipulated gene expression technologies. PMID- 22529370 TI - Pay-what-you-want, identity, and self-signaling in markets. AB - We investigate the role of identity and self-image consideration under "pay-what you-want" pricing. Results from three field experiments show that often, when granted the opportunity to name the price of a product, fewer consumers choose to buy it than when the price is fixed and low. We show that this opt-out behavior is driven largely by individuals' identity and self-image concerns; individuals feel bad when they pay less than the "appropriate" price, causing them to pass on the opportunity to purchase the product altogether. PMID- 22529371 TI - Locomotive implication of a Pliocene three-toed horse skeleton from Tibet and its paleo-altimetry significance. AB - The Tibetan Plateau is the youngest and highest plateau on Earth, and its elevation reaches one-third of the height of the troposphere, with profound dynamic and thermal effects on atmospheric circulation and climate. The uplift of the Tibetan Plateau was an important factor of global climate change during the late Cenozoic and strongly influenced the development of the Asian monsoon system. However, there have been heated debates about the history and process of Tibetan Plateau uplift, especially the paleo-altimetry in different geological ages. Here we report a well-preserved skeleton of a 4.6 million-y-old three-toed horse (Hipparion zandaense) from the Zanda Basin, southwestern Tibet. Morphological features indicate that H. zandaense was a cursorial horse that lived in alpine steppe habitats. Because this open landscape would be situated above the timberline on the steep southern margin of the Tibetan Plateau, the elevation of the Zanda Basin at 4.6 Ma was estimated to be ~4,000 m above sea level using an adjustment to the paleo-temperature in the middle Pliocene, as well as comparison with modern vegetation vertical zones. Thus, we conclude that the southwestern Tibetan Plateau achieved the present-day elevation in the mid Pliocene. PMID- 22529372 TI - A prominent pattern of year-to-year variability in Indian Summer Monsoon Rainfall. AB - The dominant patterns of Indian Summer Monsoon Rainfall (ISMR) and their relationships with the sea surface temperature and 850-hPa wind fields are examined using gridded datasets from 1900 on. The two leading empirical orthogonal functions (EOFs) of ISMR over India are used as basis functions for elucidating these relationships. EOF1 is highly correlated with all India rainfall and El Nino-Southern Oscillation indices. EOF2 involves rainfall anomalies of opposing polarity over the Gangetic Plain and peninsular India. The spatial pattern of the trends in ISMR from 1950 on shows drying over the Gangetic Plain projects onto EOF2, with an expansion coefficient that exhibits a pronounced trend during this period. EOF2 is coupled with the dominant pattern of sea surface temperature variability over the Indian Ocean sector, which involves in-phase fluctuations over the Arabian Sea, the Bay of Bengal, and the South China Sea, and it is correlated with the previous winter's El Nino-Southern Oscillation indices. The circulation anomalies observed in association with fluctuations in the time-varying indices of EOF1 and EOF2 both involve distortions of the low-level monsoon flow. EOF1 in its positive polarity represents a southward deflection of moist, westerly monsoon flow from the Arabian Sea across India, resulting in a smaller flux of moisture to the Himalayas. EOF2 in its positive polarity represents a weakening of the monsoon trough over northeastern India and the westerly monsoon flow across southern India, reminiscent of the circulation anomalies observed during break periods within the monsoon season. PMID- 22529373 TI - Dependence of Wilms tumor cells on signaling through insulin-like growth factor 1 in an orthotopic xenograft model targetable by specific receptor inhibition. AB - We have previously demonstrated an increased DNA copy number and expression of IGF1R to be associated with poor outcome in Wilms tumors. We have now tested whether inhibiting this receptor may be a useful therapeutic strategy by using a panel of Wilms tumor cell lines. Both genetic and pharmacological targeting resulted in inhibition of downstream signaling through PI3 and MAP kinases, G(1) cell cycle arrest, and cell death, with drug efficacy dependent on the levels of phosphorylated IGF1R. These effects were further associated with specific gene expression signatures reflecting pathway inhibition, and conferred synergistic chemosensitisation to doxorubicin and topotecan. In the in vivo setting, s.c. xenografts of WiT49 cells resembled malignant rhabdoid tumors rather than Wilms tumors. Treatment with an IGF1R inhibitor (NVP-AEW541) showed no discernable antitumor activity and no downstream pathway inactivation. By contrast, Wilms tumor cells established orthotopically within the kidney were histologically accurate and exhibited significantly elevated insulin-like growth factor-mediated signaling, and growth was significantly reduced on treatment with NVP-AEW541 in parallel with signaling pathway ablation. As a result of the paracrine effects of enhanced IGF2 expression in Wilms tumor, this disease may be acutely dependent on signaling through the IGF1 receptor, and thus treatment strategies aimed at its inhibition may be useful in the clinic. Such efficacy may be missed if only standard ectopic models are considered as a result of an imperfect recapitulation of the specific tumor microenvironment. PMID- 22529374 TI - Mind bomb 1 is required for pancreatic beta-cell formation. AB - During early pancreatic development, Notch signaling represses differentiation of endocrine cells and promotes proliferation of Nkx6-1(+)Ptf1a(+) multipotent progenitor cells (MPCs). Later, antagonistic interactions between Nkx6 transcription factors and Ptf1a function to segregate MPCs into distal Nkx6-1( )Ptf1a(+) acinar progenitors and proximal Nkx6-1(+)Ptf1a(-) duct and beta-cell progenitors. Distal cells are initially multipotent, but evolve into unipotent, acinar cell progenitors. Conversely, proximal cells are bipotent and give rise to duct cells and late-born endocrine cells, including the insulin producing beta cells. However, signals that regulate proximodistal (P-D) patterning and thus formation of beta-cell progenitors are unknown. Here we show that Mind bomb 1 (Mib1) is required for correct P-D patterning of the developing pancreas and beta cell formation. We found that endoderm-specific inactivation of Mib1 caused a loss of Nkx6-1(+)Ptf1a(-) and Hnf1beta(+) cells and a corresponding loss of Neurog3(+) endocrine progenitors and beta-cells. An accompanying increase in Nkx6 1(-)Ptf1a(+) and amylase(+) cells, occupying the proximal domain, suggests that proximal cells adopt a distal fate in the absence of Mib1 activity. Impeding Notch-mediated transcriptional activation by conditional expression of dominant negative Mastermind-like 1 (Maml1) resulted in a similarly distorted P-D patterning and suppressed beta-cell formation, as did conditional inactivation of the Notch target gene Hes1. Our results reveal iterative use of Notch in pancreatic development to ensure correct P-D patterning and adequate beta-cell formation. PMID- 22529375 TI - Membrane protein expression triggers chromosomal locus repositioning in bacteria. AB - It has long been hypothesized that subcellular positioning of chromosomal loci in bacteria may be influenced by gene function and expression state. Here we provide direct evidence that membrane protein expression affects the position of chromosomal loci in Escherichia coli. For two different membrane proteins, we observed a dramatic shift of their genetic loci toward the membrane upon induction. In related systems in which a cytoplasmic protein was produced, or translation was eliminated by mutating the start codon, a shift was not observed. Antibiotics that block transcription and translation similarly prevented locus repositioning toward the membrane. We also found that repositioning is relatively rapid and can be detected at positions that are a considerable distance on the chromosome from the gene encoding the membrane protein (>90 kb). Given that membrane protein-encoding genes are distributed throughout the chromosome, their expression may be an important mechanism for maintaining the bacterial chromosome in an expanded and dynamic state. PMID- 22529376 TI - Env-less endogenous retroviruses are genomic superspreaders. AB - Endogenous retroviruses (ERVs) differ from typical retroviruses in being inherited through the host germline and therefore are a unique combination of pathogen and selfish genetic element. Some ERV lineages proliferate by infecting germline cells, as do typical retroviruses, whereas others lack the env gene required for virions to enter cells and thus behave like retrotransposons. We wished to know what factors determined the relative abundance of different ERV lineages, so we analyzed ERV loci recovered from 38 mammal genomes by in silico screening. By modeling the relationship between proliferation and replication mechanism in detail within one group, the intracisternal A-type particles (IAPs), and performing simple correlations across all ERV lineages, we show that when ERVs lose the env gene their proliferation within that genome is boosted by a factor of ~30. We also show that ERV abundance follows the Pareto principle or 20/80 rule, with ~20% of lineages containing 80% of the loci. This rule is observed in many biological systems, including infectious disease epidemics, where commonly ~20% of the infected individuals are responsible for 80% of onward infection. We thus borrow simple epidemiological and ecological models and show that retrotransposition and loss of env is the trait that leads endogenous retroviruses to becoming genomic superspreaders that take over a significant proportion of their host's genome. PMID- 22529377 TI - Kruppel-like Factor 7 engineered for transcriptional activation promotes axon regeneration in the adult corticospinal tract. AB - Axon regeneration in the central nervous system normally fails, in part because of a developmental decline in the intrinsic ability of CNS projection neurons to extend axons. Members of the KLF family of transcription factors regulate regenerative potential in developing CNS neurons. Expression of one family member, KLF7, is down-regulated developmentally, and overexpression of KLF7 in cortical neurons in vitro promotes axonal growth. To circumvent difficulties in achieving high neuronal expression of exogenous KLF7, we created a chimera with the VP16 transactivation domain, which displayed enhanced neuronal expression compared with the native protein while maintaining transcriptional activation and growth promotion in vitro. Overexpression of VP16-KLF7 overcame the developmental loss of regenerative ability in cortical slice cultures. Adult corticospinal tract (CST) neurons failed to up-regulate KLF7 in response to axon injury, and overexpression of VP16-KLF7 in vivo promoted both sprouting and regenerative axon growth in the CST of adult mice. These findings identify a unique means of promoting CST axon regeneration in vivo by reengineering a developmentally down regulated, growth-promoting transcription factor. PMID- 22529378 TI - Astrocytic high-mobility group box 1 promotes endothelial progenitor cell mediated neurovascular remodeling during stroke recovery. AB - Crosstalk between the brain and systemic responses in blood is increasingly suspected of playing critical roles in stroke. However, how this communication takes place remains to be fully understood. Here, we show that reactive astrocytes can release a damage-associated molecular-pattern molecule called high mobility-group-box-1 (HMGB1) that promotes endothelial progenitor cell (EPC) mediated neurovascular remodeling during stroke recovery. Conditioned media from reactive astrocytes increase EPC proliferation in vitro. siRNA suppression of HMGB1 in astrocytes or blockade of the HMGB1 receptor for advanced glycation endproducts in EPCs prevents this effect. In a mouse model of focal cerebral ischemia, reactive astrocytes in the peri-infarct cortex up-regulate HMGB1 at 14 d poststroke, along with an accumulation of endogenous EPCs. In vivo siRNA suppression of HMGB1 blocks this EPC response, reduces peri-infact angiogenesis, and worsens neurological deficits. Taken together, these molecular and in vivo findings support a previously undescribed mechanism of crosstalk between reactive astrocytes and EPCs wherein HMGB1 promotes neurovascular remodeling and functional recovery after stroke and brain injury. PMID- 22529379 TI - Profile of Marc R. Montminy. PMID- 22529380 TI - Subcellular distribution of Lck during CD4 T-cell maturation in the thymic medulla regulates the T-cell activation threshold. AB - Mature peripheral T cells respond to foreign but not to self-antigens. During development in the thymus, deletion of high-affinity self-reactive immature thymocytes contributes to tolerance of mature T cells. However, double-positive thymocytes are positively selected to survive if they respond to self-peptide-MHC complexes; thus, there must be mechanisms to prevent overt reactivity to those same complexes in the periphery. "Developmental tuning" is the active process through which T-cell receptor (TCR)-associated signaling pathways of single positive (SP) thymocytes are attenuated to respond appropriately to self-peptide MHC complexes in the periphery. We previously showed that MHC class II expression in the thymic medulla was necessary to tune CD4(+) SP (CD4 SP) thymocytes. CD4 SP thymocytes from mice lacking medullary MHC class II expression had inappropriately enhanced proximal TCR signaling to low-affinity self-ligands that was associated with altered cellular distribution of the tyrosine kinase Lck. Now, we report that activation of both tuned and untuned CD4 SP thymocytes is Lck dependent. Untuned CD4 SP cells contain a pool of Lck with increased basal phosphorylation that is not associated with the CD4 coreceptor. Phosphorylation of this pool of Lck decreases with tuning. Immunogold transmission electron microscopy of membrane sheets permitted direct visualization of Lck. In the absence of tuning, a significant proportion of Lck and the TCR subunit CD3zeta are expressed on the same protein island; this close association of Lck and the TCR probably explains the enhanced activation of untuned CD4 SP cells. Thus, changes in membrane topography during thymic maturation determine the set point for TCR responsiveness. PMID- 22529381 TI - Cage assembly of DegP protease is not required for substrate-dependent regulation of proteolytic activity or high-temperature cell survival. AB - DegP, a member of the highly conserved HtrA family, performs quality-control degradation of misfolded proteins in the periplasm of gram-negative bacteria and is required for high-temperature survival of Escherichia coli. Substrate binding transforms DegP from an inactive oligomer containing two trimers into active polyhedral cages, typically containing four or eight trimers. Although these observations suggest a causal connection, we show that cage assembly and proteolytic activation can be uncoupled. Indeed, DegP variants that remain trimeric, hexameric, or dodecameric in the presence or absence of substrate still display robust and positively cooperative substrate degradation in vitro and, most importantly, sustain high-temperature bacterial growth as well as the wild type enzyme. Our results support a model in which substrate binding converts inactive trimers into proteolytically active trimers, and simultaneously leads to cage assembly by enhancing binding of PDZ1 domains in one trimer to PDZ2' domains in neighboring trimers. Thus, both processes depend on substrate binding, but they can be uncoupled without loss of biological function. We discuss potential coupling mechanisms and why cage formation may have evolved if it is not required for DegP proteolysis. PMID- 22529382 TI - Altered subcellular localization of transcription factor TEAD4 regulates first mammalian cell lineage commitment. AB - In the preimplantation mouse embryo, TEAD4 is critical to establishing the trophectoderm (TE)-specific transcriptional program and segregating TE from the inner cell mass (ICM). However, TEAD4 is expressed in the TE and the ICM. Thus, differential function of TEAD4 rather than expression itself regulates specification of the first two cell lineages. We used ChIP sequencing to define genomewide TEAD4 target genes and asked how transcription of TEAD4 target genes is specifically maintained in the TE. Our analyses revealed an evolutionarily conserved mechanism, in which lack of nuclear localization of TEAD4 impairs the TE-specific transcriptional program in inner blastomeres, thereby allowing their maturation toward the ICM lineage. Restoration of TEAD4 nuclear localization maintains the TE-specific transcriptional program in the inner blastomeres and prevents segregation of the TE and ICM lineages and blastocyst formation. We propose that altered subcellular localization of TEAD4 in blastomeres dictates first mammalian cell fate specification. PMID- 22529383 TI - Structural basis of human DNA polymerase eta-mediated chemoresistance to cisplatin. AB - Cisplatin (cis-diamminedichloroplatinum) and related compounds cause DNA damage and are widely used as anticancer agents. Chemoresistance to cisplatin treatment is due in part to translesion synthesis by human DNA polymerase eta (hPol eta). Here, we report crystal structures of hPol eta complexed with intrastrand cisplatin-1,2-cross-linked DNA, representing four consecutive steps in translesion synthesis. In contrast to the generally enlarged and nondiscriminating active site of Y-family polymerases like Dpo4, Pol eta is specialized for efficient bypass of UV-cross-linked pyrimidine dimers. Human Pol eta differs from the yeast homolog in its binding of DNA template. To incorporate deoxycytidine opposite cisplatin-cross-linked guanines, hPol eta undergoes a specific backbone rearrangement to accommodate the larger base dimer and minimizes the DNA distortion around the lesion. Our structural analyses show why Pol eta is inefficient at extending primers after cisplatin lesions, which necessitates a second translesion DNA polymerase to complete bypass in vivo. A hydrophobic pocket near the primer-binding site in human Pol eta is identified as a potential drug target for inhibiting translesion synthesis and, thereby, reducing chemoresistance. PMID- 22529384 TI - Symbiont-mediated insecticide resistance. AB - Development of insecticide resistance has been a serious concern worldwide, whose mechanisms have been attributed to evolutionary changes in pest insect genomes such as alteration of drug target sites, up-regulation of degrading enzymes, and enhancement of drug excretion. Here, we report a previously unknown mechanism of insecticide resistance: Infection with an insecticide-degrading bacterial symbiont immediately establishes insecticide resistance in pest insects. The bean bug Riptortus pedestris and allied stinkbugs harbor mutualistic gut symbiotic bacteria of the genus Burkholderia, which are acquired by nymphal insects from environmental soil every generation. In agricultural fields, fenitrothion degrading Burkolderia strains are present at very low densities. We demonstrated that the fenitrothion-degrading Burkholderia strains establish a specific and beneficial symbiosis with the stinkbugs and confer a resistance of the host insects against fenitrothion. Experimental applications of fenitrothion to field soils drastically enriched fenitrothion-degrading bacteria from undetectable levels to >80% of total culturable bacterial counts in the field soils, and >90% of stinkbugs reared with the enriched soil established symbiosis with fenitrothion-degrading Burkholderia. In a Japanese island where fenitrothion has been constantly applied to sugarcane fields, we identified a stinkbug population wherein the insects live on sugarcane and ~8% of them host fenitrothion-degrading Burkholderia. Our finding suggests the possibility that the symbiont-mediated insecticide resistance may develop even in the absence of pest insects, quickly establish within a single insect generation, and potentially move around horizontally between different pest insects and other organisms. PMID- 22529385 TI - Influenza A virus entry into cells lacking sialylated N-glycans. AB - Influenza A virus (IAV) enters host cells after attachment of its hemagglutinin (HA) to surface-exposed sialic acid. Sialylated N-linked glycans have been reported to be essential for IAV entry [Chu VC, Whittaker GR (2004) Proc Natl Acad Sci USA 102:18153-18158], thereby implicating the requirement for proteinaceous receptors in IAV entry. Here we show, using different N acetylglucosaminyl transferase 1 (GnT1)-deficient cells, that N-linked sialosides can mediate, but are not required for, entry of IAV. Entry into GnT1-deficient cells was fully dependent on sialic acid. Although macropinocytic entry appeared to be affected by the absence of sialylated N-glycans, dynamin-dependent entry was not affected at all. However, binding of HA to GnT1-deficient cells and subsequent entry of IAV were reduced by the presence of serum, which could be reversed by back-transfection of a GnT1-encoding plasmid. The inhibitory effect of serum was significantly increased by inhibition of the viral receptor destroying enzyme neuraminidase (NA). Our results indicate that decoy receptors on soluble serum factors compete with cell surface receptors for binding to HA in the absence of sialylated N-glycans at the cell surface. This competition is particularly disturbed by the additional presence of NA inhibitors, resulting in strongly reduced IAV entry. Our results indicate that the balance between HA and NA is important not only for virion release, but also for entry into cells. PMID- 22529387 TI - Cenozoic imprints on the phylogenetic structure of palm species assemblages worldwide. AB - Despite long-standing interest in the origin and maintenance of species diversity, little is known about historical drivers of species assemblage structure at large spatiotemporal scales. Here, we use global species distribution data, a dated genus-level phylogeny, and paleo-reconstructions of biomes and climate to examine Cenozoic imprints on the phylogenetic structure of regional species assemblages of palms (Arecaceae), a species-rich plant family characteristic of tropical ecosystems. We find a strong imprint on phylogenetic clustering due to geographic isolation and in situ diversification, especially in the Neotropics and on islands with spectacular palm radiations (e.g., Madagascar, Hawaii, and Cuba). Phylogenetic overdispersion on mainlands and islands corresponds to biotic interchange areas. Differences in the degree of phylogenetic clustering among biogeographic realms are related to differential losses of tropical rainforests during the Cenozoic, but not to the cumulative area of tropical rainforest over geological time. A largely random phylogenetic assemblage structure in Africa coincides with severe losses of rainforest area, especially after the Miocene. More recent events also appear to be influential: phylogenetic clustering increases with increasing intensity of Quaternary glacial interglacial climatic oscillations in South America and, to a lesser extent, Africa, indicating that specific clades perform better in climatically unstable regions. Our results suggest that continental isolation (in combination with limited long-distance dispersal) and changing climate and habitat loss throughout the Cenozoic have had strong impacts on the phylogenetic structure of regional species assemblages in the tropics. PMID- 22529386 TI - Plant hormone jasmonate prioritizes defense over growth by interfering with gibberellin signaling cascade. AB - Plants must effectively defend against biotic and abiotic stresses to survive in nature. However, this defense is costly and is often accompanied by significant growth inhibition. How plants coordinate the fluctuating growth-defense dynamics is not well understood and remains a fundamental question. Jasmonate (JA) and gibberellic acid (GA) are important plant hormones that mediate defense and growth, respectively. Binding of bioactive JA or GA ligands to cognate receptors leads to proteasome-dependent degradation of specific transcriptional repressors (the JAZ or DELLA family of proteins), which, at the resting state, represses cognate transcription factors involved in defense (e.g., MYCs) or growth [e.g. phytochrome interacting factors (PIFs)]. In this study, we found that the coi1 JA receptor mutants of rice (a domesticated monocot crop) and Arabidopsis (a model dicot plant) both exhibit hallmark phenotypes of GA-hypersensitive mutants. JA delays GA-mediated DELLA protein degradation, and the della mutant is less sensitive to JA for growth inhibition. Overexpression of a selected group of JAZ repressors in Arabidopsis plants partially phenocopies GA-associated phenotypes of the coi1 mutant, and JAZ9 inhibits RGA (a DELLA protein) interaction with transcription factor PIF3. Importantly, the pif quadruple (pifq) mutant no longer responds to JA-induced growth inhibition, and overexpression of PIF3 could partially overcome JA-induced growth inhibition. Thus, a molecular cascade involving the COI1-JAZ-DELLA-PIF signaling module, by which angiosperm plants prioritize JA-mediated defense over growth, has been elucidated. PMID- 22529388 TI - Integrating ecosystem-service tradeoffs into land-use decisions. AB - Recent high-profile efforts have called for integrating ecosystem-service values into important societal decisions, but there are few demonstrations of this approach in practice. We quantified ecosystem-service values to help the largest private landowner in Hawaii, Kamehameha Schools, design a land-use development plan that balances multiple private and public values on its North Shore land holdings (Island of O'ahu) of ~10,600 ha. We used the InVEST software tool to evaluate the environmental and financial implications of seven planning scenarios encompassing contrasting land-use combinations including biofuel feedstocks, food crops, forestry, livestock, and residential development. All scenarios had positive financial return relative to the status quo of negative return. However, tradeoffs existed between carbon storage and water quality as well as between environmental improvement and financial return. Based on this analysis and community input, Kamehameha Schools is implementing a plan to support diversified agriculture and forestry. This plan generates a positive financial return ($10.9 million) and improved carbon storage (0.5% increase relative to status quo) with negative relative effects on water quality (15.4% increase in potential nitrogen export relative to status quo). The effects on water quality could be mitigated partially (reduced to a 4.9% increase in potential nitrogen export) by establishing vegetation buffers on agricultural fields. This plan contributes to policy goals for climate change mitigation, food security, and diversifying rural economic opportunities. More broadly, our approach illustrates how information can help guide local land-use decisions that involve tradeoffs between private and public interests. PMID- 22529389 TI - Crystal structure of a Trypanosoma brucei metacaspase. AB - Metacaspases are distantly related caspase-family cysteine peptidases implicated in programmed cell death in plants and lower eukaryotes. They differ significantly from caspases because they are calcium-activated, arginine-specific peptidases that do not require processing or dimerization for activity. To elucidate the basis of these differences and to determine the impact they might have on the control of cell death pathways in lower eukaryotes, the previously undescribed crystal structure of a metacaspase, an inactive mutant of metacaspase 2 (MCA2) from Trypanosoma brucei, has been determined to a resolution of 1.4 A. The structure comprises a core caspase fold, but with an unusual eight-stranded beta-sheet that stabilizes the protein as a monomer. Essential aspartic acid residues, in the predicted S1 binding pocket, delineate the arginine-specific substrate specificity. In addition, MCA2 possesses an unusual N terminus, which encircles the protein and traverses the catalytic dyad, with Y31 acting as a gatekeeper residue. The calcium-binding site is defined by samarium coordinated by four aspartic acid residues, whereas calcium binding itself induces an allosteric conformational change that could stabilize the active site in a fashion analogous to subunit processing in caspases. Collectively, these data give insights into the mechanistic basis of substrate specificity and mode of activation of MCA2 and provide a detailed framework for understanding the role of metacaspases in cell death pathways of lower eukaryotes. PMID- 22529390 TI - Dynamic integration of information about salience and value for saccadic eye movements. AB - Humans shift their gaze to a new location several times per second. It is still unclear what determines where they look next. Fixation behavior is influenced by the low-level salience of the visual stimulus, such as luminance, contrast, and color, but also by high-level task demands and prior knowledge. Under natural conditions, different sources of information might conflict with each other and have to be combined. In our paradigm, we trade off visual salience against expected value. We show that both salience and value information influence the saccadic end point within an object, but with different time courses. The relative weights of salience and value are not constant but vary from eye movement to eye movement, depending critically on the availability of the value information at the time when the saccade is programmed. Short-latency saccades are determined mainly by salience, but value information is taken into account for long-latency saccades. We present a model that describes these data by dynamically weighting and integrating detailed topographic maps of visual salience and value. These results support the notion of independent neural pathways for the processing of visual information and value. PMID- 22529391 TI - Kinase-independent function of checkpoint kinase 1 (Chk1) in the replication of damaged DNA. AB - The checkpoint kinases Chk1 and ATR are broadly known for their role in the response to the accumulation of damaged DNA. Because Chk1 activation requires its phosphorylation by ATR, it is expected that ATR or Chk1 down-regulation should cause similar alterations in the signals triggered by DNA lesions. Intriguingly, we found that Chk1, but not ATR, promotes the progression of replication forks after UV irradiation. Strikingly, this role of Chk1 is independent of its kinase domain and of its partnership with Claspin. Instead, we demonstrate that the ability of Chk1 to promote replication fork progression on damaged DNA templates relies on its recently identified proliferating cell nuclear antigen-interacting motif, which is required for its release from chromatin after DNA damage. Also supporting the importance of Chk1 release, a histone H2B-Chk1 chimera, which is permanently immobilized in chromatin, is unable to promote the replication of damaged DNA. Moreover, inefficient chromatin dissociation of Chk1 impairs the efficient recruitment of the specialized DNA polymerase eta (pol eta) to replication-associated foci after UV. Given the critical role of pol eta during translesion DNA synthesis (TLS), these findings unveil an unforeseen facet of the regulation by Chk1 of DNA replication. This kinase-independent role of Chk1 is exclusively associated to the maintenance of active replication forks after UV irradiation in a manner in which Chk1 release prompts TLS to avoid replication stalling. PMID- 22529392 TI - Secrets of tubule engineering by epithelial cells. PMID- 22529393 TI - Dynamics of unconscious contextual effects in orientation processing. AB - Contextual effects abound in the real world; how we perceive an object depends on what surrounds it. A classic example of this is the tilt illusion (TI) whereby the presence of a surround shifts the perceived orientation of a target. Surprisingly, the magnitude and direction of this shift depend on the orientation difference between the target and surround: when their orientations are similar, the perceived difference is amplified and the target appears repelled in orientation from the surround (i.e., the TI). However, when their orientations are close to perpendicular, the difference is decreased and the target appears attracted in orientation toward the surround (i.e., the indirect TI). These misperceptions of orientation have revealed much about the underlying detectors involved in visual processing and how they interact with each other. What remains at stake are the levels of processing involved. To examine this, we designed a reverse-correlation technique whereby observers are blind to the orientation of the surround. We find that the TI and indirect TI occur reliably and over a similar time course, supporting the role of a single mechanism underlying orientation biases that operates in the early stages of visual processing before the conscious extraction of the surround orientation. PMID- 22529394 TI - Eukaryotic-type plastid nucleoid protein pTAC3 is essential for transcription by the bacterial-type plastid RNA polymerase. AB - Plastid transcription is mediated by two distinct types of RNA polymerases (RNAPs), bacterial-type RNAP (PEP) and phage-type RNAP (NEP). Recent genomic and proteomic studies revealed that higher plants have lost most prokaryotic transcription regulators and have acquired eukaryotic-type proteins during plant evolution. However, in vivo dynamics of chloroplast RNA polymerases and eukaryotic-type plastid nucleoid proteins have not been directly characterized experimentally. Here, we examine the association of the alpha-subunit of PEP and eukaryotic-type protein, plastid transcriptionally active chromosome 3 (pTAC3) with transcribed regions in vivo by using chloroplast chromatin immunoprecipitation (cpChIP) assays. PEP alpha-subunit preferentially associates with PEP promoters of photosynthesis and rRNA genes, but not with NEP promoter regions, suggesting selective and accurate recognition of PEP promoters by PEP. The cpChIP assays further demonstrate that the peak of PEP association occurs at the promoter-proximal region and declines gradually along the transcribed region. pTAC3 is a putative DNA-binding protein that is localized to chloroplast nucleoids and is essential for PEP-dependent transcription. Density gradient and immunoprecipitation analyses of PEP revealed that pTAC3 is associated with the PEP complex. Interestingly, pTAC3 associates with the PEP complex not only during transcription initiation, but also during elongation and termination. These results suggest that pTAC3 is an essential component of the chloroplast PEP complex. In addition, we demonstrate that light-dependent chloroplast transcription is mediated by light-induced association of the PEP-pTAC3 complex with promoters. This study illustrates unique dynamics of PEP and its associated protein pTAC3 during light-dependent transcription in chloroplasts. PMID- 22529397 TI - A middle-aged man with a painful muscular mass. PMID- 22529396 TI - Mechanisms of activation of the paternally expressed genes by the Prader-Willi imprinting center in the Prader-Willi/Angelman syndromes domains. AB - The Prader-Willi syndrome/Angelman syndrome (PWS/AS) imprinted domain is regulated by a bipartite imprinting control center (IC) composed of a sequence around the SNRPN promoter (PWS-IC) and a 880-bp sequence located 35 kb upstream (AS-IC). The AS-IC imprint is established during gametogenesis and confers repression upon PWS-IC on the maternal allele. Mutation at PWS-IC on the paternal allele leads to gene silencing across the entire PWS/AS domain. This silencing implies that PWS-IC functions on the paternal allele as a bidirectional activator. Here we examine the mechanism by which PWS-IC activates the paternally expressed genes (PEGs) using transgenes that include the PWS-IC sequence in the presence or absence of AS-IC and NDN, an upstream PEG, as an experimental model. We demonstrate that PWS-IC is in fact an activator of NDN. This activation requires an unmethylated PWS-IC in the gametes and during early embryogenesis. PWS-IC is dispensable later in development. Interestingly, a similar activation of a nonimprinted gene (APOA1) was observed, implying that PWS-IC is a universal activator. To decipher the mechanism by which PWS-IC confers activation of remote genes, we performed methylated DNA immunoprecipitation (MeDIP) array analysis on lymphoblast cell lines that revealed dispersed, rather than continued differential methylation. However, chromatin conformation capture (3c) experiments revealed a physical interaction between PWS-IC and the PEGs, suggesting that activation of PEGs may require their proximity to PWS-IC. PMID- 22529395 TI - HIV-1 incorporation of host-cell-derived glycosphingolipid GM3 allows for capture by mature dendritic cells. AB - The interaction between HIV and dendritic cells (DCs) is an important early event in HIV-1 pathogenesis that leads to efficient viral dissemination. Here we demonstrate a HIV gp120-independent DC capture mechanism that uses virion incorporated host-derived gangliosides with terminal alpha2-3-linked sialic acid linkages. Using exogenously enriched virus and artificial liposome particles, we demonstrate that both alpha2-3 gangliosides GM1 and GM3 are capable of mediating this interaction when present in the particle at high levels. In the absence of overexpression, GM3 is the primary ligand responsible for this capture mechanism, because siRNA depletion of GM3 but not GM1 from the producer cell and hence virions, resulted in a dramatic decrease in DC capture. Furthermore, HIV-1 capture by DCs was competitively inhibited by targeting virion-associated GM3, but was unchanged by targeting GM1. Finally, virions were derived from monocytoid THP-1 cells that constitutively display low levels of GM1 and GM3, or from THP-1 cells induced to express high surface levels of GM1 and GM3 upon stimulation with the TLR2/1 ligand Pam3CSK4. Compared with untreated THP-1 cells, virus produced from Pam3CSK4-stimulated THP-1 cells incorporated higher levels of GM3, but not GM1, and showed enhanced DC capture and trans-infection. Our results identify a unique HIV-1 DC attachment mechanism that is dependent on a host-cell-derived ligand, GM3, and is a unique example of pathogen mimicry of host-cell recognition pathways that drive virus capture and dissemination in vivo. PMID- 22529398 TI - Grey Turner's sign. PMID- 22529399 TI - Does evidence really matter? PMID- 22529400 TI - [Not Available]. PMID- 22529401 TI - Effect of Misalignment between Hospital and Provincial Formularies on Medication Discrepancies at Discharge: PPITS (Proton Pump Inhibitor Therapeutic Substitution) Study. AB - BACKGROUND: Medication discrepancies may occur on admission, transfer, or discharge from hospital. Therapeutic interchange within a drug class is a common practice in hospitals, and orders for specific proton pump inhibitors (PPIs) are often substituted with the hospital's formulary PPI through therapeutic interchange protocols. Rabeprazole is the PPI on the formulary of the British Columbia PharmaCare program. However, different PPIs may appear on the formularies of the province's hospitals. This misalignment and use of therapeutic interchange may lead to increased rates of medication discrepancies at the time of discharge. OBJECTIVE: To evaluate the effect of formulary misalignment for PPIs between St Paul's Hospital in Vancouver and the British Columbia PharmaCare program and use of therapeutic interchange on the occurrence of medication discrepancies at discharge. METHODS: A cohort chart review was performed to compare discharge discrepancy rates for PPI orders between 2 periods: June 2006 to June 2008, when the same PPI appeared on the hospital and provincial formularies, and July 2008 to July 2010, when the designated PPIs differed between the hospital and provincial formularies. Data for the first study period were used to establish the baseline discharge discrepancy rate, and data for the later period represented the discharge discrepancy rate in the presence of misalignment between the hospital and PharmaCare formularies. RESULTS: The discharge discrepancy rate for PPIs was 27.3% (24/88) when the 2 formularies were aligned and 49.1% (81/165) when the formularies were misaligned. This represents an absolute increase of 21.8 percentage points in the risk of discharge discrepancies (95% confidence interval 9.8-33.9 percentage points; p < 0.001) when the hospital and provincial formularies were misaligned and the hospital's therapeutic interchange protocol was used. CONCLUSIONS: Misalignment between the PPIs specified in the hospital and provincial formularies, combined with use of therapeutic interchange, was associated with a significant increase in medication discrepancies at discharge. PMID- 22529402 TI - Economic evaluation of dexmedetomidine relative to midazolam for sedation in the intensive care unit. AB - BACKGROUND: Dexmedetomidine is an alpha(2)-receptor agonist administered by continuous infusion in the intensive care unit (ICU) for sedation of critically ill patients who are undergoing mechanical ventilation following intubation. Relative to ICU patients receiving midazolam (a gamma-aminobutyric acid agonist) for sedation, those receiving dexmedetomidine spent less time on ventilation, had fewer episodes of delirium, and had a lower incidence of tachycardia and hypertension. OBJECTIVE: To assess the economic impact, in a Canadian context, of dexmedetomidine, relative to midazolam, for sedation in the ICU. METHODS: This economic evaluation was based on a cost-consequences analysis, from the perspective of the Canadian health care system. The selected time horizon was an ICU stay (maximum 30 days). Clinical data were obtained from a previously published prospective, randomized, double-blind trial comparing dexmedetomidine and midazolam. This evaluation considered the costs of the medications, mechanical ventilation, and delirium episodes, as well as costs associated with adverse events requiring an intervention. All costs were adjusted to 2010 and are reported in Canadian dollars. RESULTS: The average cost of the medication was higher for dexmedetomidine than midazolam ($1929.57 versus $180.10 per patient), but the average costs associated with mechanical ventilation and management of delirium were lower with dexmedetomidine than with midazolam ($2939 versus $4448 for ventilation; $2127 versus $3012 for delirium). The overall cost per patient was lower with dexmedetomidine than with midazolam ($7022 versus $7680). Deterministic sensitivity analysis confirmed the robustness of the difference. CONCLUSIONS: The use of dexmedetomidine was, in most contexts, a more favourable strategy than the use of midazolam, in terms of clinical consequences and economic impact. Dexmedetomidine was less expensive than midazolam and was associated with lower occurrence of delirium and shorter duration of mechanical ventilation. PMID- 22529403 TI - Evaluation of the use of inhaled medications by hospital inpatients with chronic obstructive pulmonary disease. AB - BACKGROUND: The prevalence of chronic obstructive pulmonary disease (COPD) is increasing. Patients with COPD are treated with a variety of inhaled medications. Previous studies evaluating inhaler technique have had varied results but have generally found high rates of misuse of these devices. There is a paucity of studies of inhaler technique focusing on North American patients with COPD who have been admitted to hospital. OBJECTIVE: To evaluate the inhaler technique of patients with COPD who have been admitted to hospital and to identify baseline patient characteristics and/or inhaler devices associated with poor inhaler technique. METHODS: Patients with a diagnosis of COPD who were admitted to the hospitalist or internal medicine service at a tertiary care hospital in British Columbia between October 2010 and April 2011 were identified. After giving informed consent, recruited patients demonstrated their inhaler technique, which was evaluated with standardized checklists. Errors in technique were categorized as either noncritical or critical. Critical errors were defined as those resulting in little or no medication reaching the lungs. RESULTS: Thirty-seven patients (mean age 78 years) participated in the study. Twenty-two (59%) of the patients made critical errors while demonstrating their inhaler technique. Patients using metered-dose inhalers were more likely to make a critical error than patients using other inhalers (13/14 [93%] versus 9/23 [39%]; relative risk 2.38, p = 0.002). On average, 26% of the steps for using an inhaler were performed incorrectly. Twenty-three (62%) of the patients reported having received previous counselling on inhaler technique, but only 13 (57%) of these 23 patients had received such counselling in the previous 6 months. CONCLUSIONS: More than half of the patients in this study misused their inhaler devices, and many made critical errors that would result in inadequate amounts of drug reaching the lung. Many of the patients were not receiving regular counselling on appropriate inhaler technique. Health care professionals should be aware of poor inhaler technique, should routinely evaluate their patients' inhaler technique, and should provide counselling. PMID- 22529404 TI - Prioritizing pharmaceutical activities: a simulation exercise. PMID- 22529406 TI - Practice spotlight: emergency department pharmacist who makes house calls. PMID- 22529407 TI - Should All High-Risk Patients Receive Acetylsalicylic Acid 81 mg Daily for Primary Prevention of Cardiovascular Disease? PMID- 22529408 TI - Drug shortages in health care institutions: perspectives in early 2012. PMID- 22529409 TI - Research Grants from the CSHP Research and Education Foundation. PMID- 22529410 TI - [Not Available]. PMID- 22529405 TI - Role of the Pharmacist in Caring for Patients with HIV/AIDS: Clinical Practice Guidelines. PMID- 22529411 TI - PharmACTION! PMID- 22529412 TI - Fraud in anaesthetic research and publication. PMID- 22529414 TI - Simulation and anaesthesia. AB - Training in anaesthesia relies on the duration and quality of clinical experience. It involves exposure to a range of interventions. This works well in routine cases, but when an uncommon and life-threatening event occurs, the anaesthetist needs to carry out multiple tasks simultaneously. Aviation has remarkable similarities with the practice of anaesthesia. Over the years, the aviation industry has used simulation to train and assess individuals very effectively. Anaesthetists face rapidly evolving clinical situations. This needs appropriate decision-making and communication with others in the theatre team. Simulation, using current technology, offers innovative and reproducible training experience. It enables standardised scenario building and reflective learning. Various non-technical aspects of an anaesthetist's day-to-day work could also be addressed to during such training. The technology could be used very effectively for the assessment of competence too. Simulation has been used for technology development and appraisal over the years. PMID- 22529413 TI - Psychiatric patient and anaesthesia. AB - Many patients with psychiatric illnesses are prescribed long-term drug treatment, and the anaesthesiologist must be aware of potential interactions with anaesthetic agents. Psychotropic drugs often given in combination with each other or with other non-psychiatric drugs generally exert profound effects on the central and peripheral neurotransmitter and ionic mechanisms. Hence, prior intake of these drugs is an important consideration in the management of the patient about to undergo anaesthesia and surgery. This article highlights the effects of anaesthetics on patients taking antipsychotics, tricyclic antidepressants, monoamine oxidase inhibitors and lithium carbonate. The risk that should be considered in the perioperative period are the extent of surgery, the patient's physical state, anaesthesia, the direct and indirect effects of psychotropics, risk of withdrawal symptoms and risk of psychiatric recurrence and relapse. PMID- 22529415 TI - Comparative evaluation of ropivacaine and lignocaine with ropivacaine, lignocaine and clonidine combination during peribulbar anaesthesia for phacoemulsification cataract surgery. AB - BACKGROUND: Peribulbar block is the most common type of local anaesthesia administered for cataract surgery, and continuous efforts are on to find a long acting local anaesthetic (LA) drug with the safest pharmacological profile. OBJECTIVES: A double-blind, prospective and randomized study was carried out in our institute to compare the anaesthetic effects of ropivacaine with the combination of ropivacaine and clonidine in administration of peribulbar block for phacoemulsification cataract surgery. METHODS: A total of 200 patients of both sexes aged 50-80 years of American Society of Anaesthesiologists grade I and II, scheduled for phacoemulsification cataract surgery under monitored anaesthesia care, were enrolled for the study. Patients were assigned into two groups of 100 each; ropivacaine group (R) and ropivacaine clonidine group (RC). Group R received 10 mL of LA solution containing 5 mL of 2% lignocaine, 5 mL of 0.75% ropivacaine and 100 units of hyaluronidase while group RC received 8 mL of a similar mixture with the addition of clonidine 1 MUg/kg and saline to make a total volume of 10 mL. Heart rate (HR), mean arterial pressure (MAP), pulse oximetry (SpO(2)), respiratory rate (RR), intraocular pressure (IOP), eye muscle movement scores and quality of peribulbar block were observed and recorded throughout the study period at regular intervals. At the end of the research project, the data was compiled systematically and was subjected to statistical analysis using the ANOVA test with post hoc significance for continuous variables and Chi-square test for qualitative data. Value of P<0.05 was considered significant and P<0.0001 as highly significant. RESULTS: Demographic characteristics, SpO(2) and RR were comparable in both the groups. Mean HR and MAP were also comparable after a significant variation in the first 2-3 min (P<0.05). Onset and establishment of sensory and motor blocks were significantly earlier in the RC group (P<0.05). IOP decreased significantly during the first 6 7 min in the RC group after the administration of the peribulbar block. Duration of analgesia was prolonged in the RC group (6.5+/-2.1 h) as compared with the R group (4.2+/-1.8 h). The side-effect profile revealed a higher incidence of nausea, vomiting, headache and dizziness in Group R, while a considerably higher incidence of dry mouth was observed in Group RC. CONCLUSIONS: Addition of clonidine to ropivacaine not only decreases the total volume of LA to be used but also augments early onset and prolonged offset of sensory analgesia as well as provides smooth operating conditions with a good sedation level as well by providing a wider safety margin of LA. PMID- 22529416 TI - Multiple-injection thoracic paravertebral block as an alternative to general anaesthesia for elective breast surgeries: A randomised controlled trial. AB - BACKGROUND: General anaesthesia is currently the conventional technique used for surgical treatment of breast lump. Paravertebral block (PVB) has been used for unilateral procedures such as thoracotomy, breast surgery, chest wall trauma, hernia repair or renal surgery. METHODS: We compared unilateral thoracic PVB with general anaesthesia (GA) in 60 consenting ASA physical status I and II female patients of 18-65 years age, scheduled for unilateral breast surgery. Patients were randomly assigned into two groups, P (n=30) or G (n=30), to receive either PVB or GA, respectively. RESULTS: The average time to first post-operative analgesic requirement at visual analogue scale score>=4 (primary endpoint) was significantly longer in group P (303.97+/-76.08 min) than in group G (131.33+/ 21.36 min), P<0.001. Total rescue analgesic (Inj. Tramadol) requirements in the first 24 h were 105.17+/-20.46 mg in group P as compared with 176.67+/-52.08 mg in group G (P<0.001). Significant post-operative nausea and vomiting requiring treatment occurred in three (10.34%) patients of the PVB group and eight (26.67%) patients in the GA group. CONCLUSION: The present study concludes that unilateral PVB is more efficacious in terms of prolonging post-operative analgesia and reducing morbidities in patients undergoing elective unilateral breast surgery. PMID- 22529417 TI - Post-operative pain and analgesic requirements after paravertebral block for mastectomy: A randomized controlled trial of different concentrations of bupivacaine and fentanyl. AB - BACKGROUND: Paravertebral block (PVB) is useful for post-operative analgesia after breast surgery. Bupivacaine is used for PVB at higher concentrations (0.5%), which may lead to systemic toxicity after absorption. Therefore, we proposed to evaluate the efficacy of lower concentrations of bupivacaine with and without fentanyl for thoracic PVB in patients undergoing surgery for carcinoma breast. METHODS: Forty-eight patients scheduled for surgery for breast cancer were enrolled in this prospective, randomized, double-blinded, placebo-controlled trial and were allocated to one of four groups: 0.25% bupivacaine with epinephrine 5 mcg/ ml, 0.25% bupivacaine + epinephrine 5 mcg/ ml with 2 mcg/ml fentanyl, 0.5% bupivacaine + epinephrine 5 mcg/ml or isotonic saline. PVB was performed and 0.3 ml/kg of the test drug was administered before induction of general anaesthesia. The primary outcome assessed was post-operative analgesic requirement for a period of 24 h. Secondary outcome measures were post-operative pain scores at rest and on movement of the arm, latency to first opioid, post operative nausea and vomiting, quality of sleep, ability to move arm and patient satisfaction. RESULTS: The patient characteristics and anaesthetic technique were comparable among the groups. The rescue analgesic consumption as well as cumulative pain scores at rest and on movement were significantly less in 0.25% bupivacaine+epinephrine with fentanyl and 0.5% bupivacaine+epinephrine groups (P<0.05). The average duration of analgesia was found to be 18 h after either 0.25% bupivacaine with epinephrine+fentanyl or 0.5% bupivacaine with epinephrine. CONCLUSIONS: Lower concentrations of bupivacaine can be combined with fentanyl to achieve analgesic efficacy similar to bupivacaine at higher concentrations, decreasing the risk of toxicity in PVB. PMID- 22529418 TI - Intra-operative change of gastric pH during laparotomic cholecystectomy under general anaesthesia: A prospective case-control study. AB - BACKGROUND: Gastric decompression by suctioning often shows greenish/greenish yellow-coloured gastric aspirates following cholecystectomy under general anaesthesia (GA). Possible intraoperative regurgitation of duodenal contents into stomach because of surgical manipulation may be the reason for such alteration in colour of the gastric secretions. AIM: We conducted this study to determine whether there were any pH changes of gastric secretions during laparotomic cholecystectomy operation to confirm our hypothesis of regurgitation of duodenal contents into the stomach. SETTINGS AND DESIGNS: Prospective observational controlled study in the Department of Anaesthesiology and Critical Care in a tertiary care university teaching hospital. METHODS: Fifty adult ASA I and II patients scheduled for open cholecystectomy operation under GA were included in the study group and another 50 non-abdominal surgical patients without any gall bladder disease were taken as controls. Three to five milliliters of gastric secretions were aspirated just after intubation and also before reversal of residual neuromuscular blockade for analysis of pH. STATISTICAL ANALYSIS: Analysis of variance test and Chi-square test with Fisher's exact correction were used for statistical analysis. Differences were significant when the P value was <0.05. RESULTS: Post-operative values of pH in the study group were significantly higher than their pre-operative values (2.40+/-1.10 vs. 4.04+/-1.6, P<=0.001). Forty-nine patients (98%) in the study group had altered coloured post-operative gastric aspirations, while no patient in the control group had such changes (P<0.001). CONCLUSIONS: A significant change in gastric pH takes place during laparotomic cholecystectomy due to reflux of duodenal content into the stomach. PMID- 22529419 TI - Size 2.5 ProSeal(TM) LMA: Is it associated with increased attempts at insertion? AB - BACKGROUND: This randomized controlled study evaluated the success rate of insertion and the associated oropharyngeal morbidity for sizes 1.5,2 and 2.5 of ProSeal(TM) laryngeal mask airway (PLMA) using an alternative digital technique (D) with conventional technique using the introducer tool (IT) technique. METHODS: After approval from the hospital ethics committee, 250 healthy children, 6-months to 10 years of age, undergoing elective sub-umbilical surgeries, were included and randomly allocated to D and IT groups for PLMA insertion. The standard anaesthesia protocol was followed. The primary outcomes were success rate of insertion at first attempt and blood on device on removal and the secondary outcomes were oropharyngeal leak pressure and gastric tube placement. RESULTS: The success rate of PLMA insertion at first attempt for sizes 1.5 and 2 did not differ between the two groups. However, for size 2.5, it was significantly lower than that for the other two sizes in both groups. The incidence of blood on device was higher with the 2.5 airway in both groups, reaching statistical significance only in group D. Other parameters did not differ between the two groups. CONCLUSION: We conclude that size 2.5 PLMA is associated with a lower success rate of insertion and a higher incidence of blood on device using both techniques. Insertion of PLMA sizes 1.5 and 2 by an alternative digital technique is comparable to the IT technique. PMID- 22529420 TI - Oral pregabalin premedication for attenuation of haemodynamic pressor response of airway instrumentation during general anaesthesia: A dose response study. AB - BACKGROUND: The airway instrumentation of direct laryngoscopy and tracheal intubation are powerful noxious stimuli that should be attenuated by appropriate premedication, smooth induction and rapid intubation. The present study evaluated the safe and clinically effective dose of oral pregabalin premedication for attenuation of haemodynamic pressor response of airway instrumentation. METHODS: A total of 90 normotensive adult consented patients aged 24-56 years, ASA grade I and II, of both gender were randomized into three treatment groups of 30 patients each. Group I received oral placebo, Group II oral pregabalin 75 mg and Group III oral pregabalin 150 mg 1 h prior to induction. Anaesthetic technique was standardized and all groups were assessed for pre-operative sedation, haemodynamic changes after the premedication, before and after induction, after laryngoscopy and intubation, along with intraoperative haemodynamic stability and post-operative side-effects. RESULTS: Pre-operative sedation levels were higher with pregabalin premedication. Significant increase in heart rate and mean arterial pressure was observed in Groups I and II after airway instrumentation, while statistically significant attenuation of mean arterial pressure was seen in Group III. No significant decrease in heart rate was observed in any group. None of the patient has suffered from any post-operative side-effects, and no significant differences in the parameters of recovery and awakening time were observed. CONCLUSION: Oral pregabalin premedication has adequately sedated the patients. The haemodynamic pressor response of airway instrumentation was attenuated in a dose-related fashion. The premedicated patients were haemodynamically stable perioperatively without prolongation of recovery time and side-effects. PMID- 22529421 TI - Seizures after intravenous tramadol given as premedication. AB - A 35-year-old, 50-kg female with a history of epilepsy was scheduled for elective breast surgery (fibroadenoma) under general anaesthesia. She was given glycopyrrolate 0.2 mg, ondansetron 4 mg and tramadol 100 mg i.v. as premedication. Within 5 min, she had an acute episode of generalised tonic-clonic seizure that was successfully treated with 75 mg thiopentone i.v. and after 30 min, she was given general anaesthesia with endotracheal intubation. Surgery, intra-operative period, extubation and post-operative period were uneventful. We conclude that tramadol may provoke seizures in patients with epilepsy even within the recommended dose range. PMID- 22529422 TI - Unilateral neurogenic pulmonary oedema: An unusual cause for post-operative respiratory dysfunction following clipping of ruptured intracranial aneurysm. AB - A variety of central nervous system lesions like stroke, subarachnoid haemorrhage, trauma and seizure activity can result in neurogenic pulmonary oedema (NPE). Unilateral neurogenic pulmonary oedema is very rare. There are no reports of unilateral NPE with aneurysmal vasospasm. We present the case of a 55 year-old female who developed respiratory distress with unilateral pulmonary oedema and mild left ventricular dysfunction in the context of postoperative cerebral vasospasm following clipping of ruptured intracranial aneurysm. Neurogenic pulmonary oedema should always be in the differential diagnosis when patients with presumed neurogenic pathology develop respiratory compromise. The diagnosis of unilateral neurogenic pulmonary oedema requires a high index of suspicion. Early initiation of supportive treatment results in good outcome. PMID- 22529423 TI - Negative-pressure pulmonary oedema in a patient undergoing shoulder arthroscopy. AB - An 18-year-old ASA-I patient who underwent elective left shoulder arthroscopy developed severe airway obstruction post-extubation due to fluid extravasation from the shoulder joint into the neck and airway tissue. Re-intubation for relief of obstruction resulted in negative-pressure pulmonary oedema. The patient was electively ventilated in the intensive care unit and recovered uneventfully. A high index of suspicion along with monitoring of neck circumference can prevent this kind of complication. PMID- 22529424 TI - Anaesthetic management of a patient with isolated pulmonary stenosis posted for caesarean section. AB - Cardio circulatory changes associated with pregnancy result in a significant haemodynamic burden and lead to morbidity and even mortality in women with cardiac disease. We report a rare case of severe pulmonary stenosis who underwent elective caesarean section under general anaesthesia with satisfactory maternal and neonatal outcome. PMID- 22529425 TI - Timely 'off-label' use of recombinant activated factor VII (NovoSeven((r))) can help in avoiding hysterectomy in intractable obstetric bleeding complicated with disseminated intravascular coagulation: A case report and review of the literature. AB - Massive intra-operative bleeding is not an infrequent occurrence in obstetrics. Worldwide obstetric bleeding remains a major cause of morbidity and mortality. Conventional management of this bleeding consists of resuscitation with fluids, blood, surgical maneuvers, and embolisation of feeding blood vessels. But in most of cases, these measures appear to be ineffective in controlling bleeding. Recently, the 'off-label' use of the recombinant activated factor VII (rFVIIa) concentrate has emerged as promising treatment for such bleeding when conventional measures fail. We came across a similar scenario in which a young lady was admitted with per-vaginal bleeding due to abruptio placentae. In spite of usual surgical and medical interventions, she continued to bleed. rFVIIa was administered as a desperate measure to avoid hysterectomy and the bleeding could be stopped. She recovered successfully without any complication. Thus, the timely use of rFVIIa, hence, can be used to save life and fertility in cases of intractable obstetric bleeding. PMID- 22529426 TI - Congenital complete heart block and spinal anaesthesia for caesarean section. AB - Congenital complete heart block could be absolutely asymptomatic. Increased awareness of suspecting an atrioventricular heart block in patients with slow heart rate and electrocardiograph examination will ensure recognition of this problem. The possibility of sudden cardiac death in these patients should not be forgotten. The goal in the peri-operative anaesthetic management is to preserve the heart rate and maintain haemodynamic stability. Herein, we present a case of congenital complete heart block posted for elective caesarean section for an obstetric indication. We would like to highlight the advantage of bupivacaine fentanyl combination in maintaining haemodynamic stability and peri-operative heart rate control with temporary pacemaker. PMID- 22529427 TI - Novel anaesthetic approach for surgical access and haemodynamic management during off-pump coronary artery bypass through a left thoracotomy. AB - For myocardial revascularization on a beating heart through a thoracotomy, a properly deployed endobronchial blocker (EBB) provides ideal conditions for surgical access. In addition, adequate volume replacement to achieve optimal cardiac performance is a primary goal of haemodynamic management in patients undergoing off-pump coronary artery bypass grafting. To achieve both these ends, this case report describes the combined use of a left-sided EBB along with a volumetric pulmonary artery catheter in a patient who underwent a successful off pump coronary artery bypass surgery through an anterolateral thoracotomy. PMID- 22529428 TI - Transdermal nitroglycerine enhances the post-operative analgesic effect of intrathecal clonidine in abdominal hysterectomies. PMID- 22529429 TI - A rare, potentially hazardous, malposition of the nasotracheal tube. PMID- 22529430 TI - Comparison of arm and calf blood pressure. PMID- 22529431 TI - Successful conservative management in post-intubation tracheal rupture. PMID- 22529432 TI - Anaesthesia for non-cardiac surgery in a cardiac transplant recipient. PMID- 22529433 TI - Fentanyl, rather than Tramadol: A cause of respiratory depression. PMID- 22529434 TI - Potassium chloride: A high risk drug for medication error. PMID- 22529435 TI - Can we use Tramadol as an anti-shivering agent? PMID- 22529436 TI - Removal of sewing needle in upper oesophagus: An innovative role of Magill forceps. PMID- 22529437 TI - A new flexible laryngeal mask airway introducer. PMID- 22529438 TI - Lidocaine not so innocent: Cardiotoxicity after topical anaesthesia for bronchoscopy. PMID- 22529439 TI - Ayurvedic medicine and anaesthesia. PMID- 22529440 TI - Pre-emptive use of bivalirudin for emergent off-pump coronary artery bypass surgery in a suspected case of heparin-induced thrombocytopenia. PMID- 22529441 TI - An unusual site of an occult air leak in an armoured endotracheal tube in the midst of surgery. PMID- 22529442 TI - Pneumothorax and surgical emphysema during therapeutic endobronchial suctioning. PMID- 22529443 TI - Weaning from prolonged mechanical ventilation: The complete picture. PMID- 22529444 TI - Authors' reply. PMID- 22529445 TI - Ultrasound-guided transversus abdominis plane block in obese patients. PMID- 22529446 TI - Vesicobullous disorders of female genitalia. AB - Blistering over the vulval region can be due to multiple causes, each having nearly a similar presentation. Thus, a thorough understanding of the various etiologies is necessary to make a correct diagnosis. Clinically, there always remains some ambiguity as to the precise diagnosis, thus investigations, such as biopsy, play a very essential role in clinching the correct diagnosis. Most of these disorders are amenable to treatment and thus an early intervention is a must to prevent morbidity associated with these diseases. PMID- 22529447 TI - Exploring dynamics of anal sex among female sex workers in Andhra Pradesh. AB - OBJECTIVE: The anal sex among heterosexual couples is on the rise as reported in many scientific studies. Considering that unprotected anal sex has higher risk of human immunodeficiency virus (HIV) transmission than the vaginal sex, we undertook a study to understand the anal sex practices among Female Sex Workers (FSW). MATERIALS AND METHODS: The study was conducted among FSW attending 11 randomly selected sexually transmitted infection (STI) clinics in Bill and Melinda Gates supported targeted interventions in Andhra Pradesh. A structured questionnaire was administered to the 555 FSW attending these clinics by project clinic counselors. Informed consent was obtained from all the study participants. RESULTS: Engaging in anal sex was self reported by 22% of sex workers, though demand from clients was reported to be much higher (40%). The reasons for anal sex practices included more money (61%), clout/influence of the client (45%), risk of losing client (27%), and forced sex (1.2%). Factors associated with anal sex were higher number of clients, higher duration of sex work, higher income, and older age group. Associated risks perceived by FSW were bleeding and injury to anal canal (98%) while only 28% associated it with higher HIV transmission risk. Reported Condom and lubricant use was about 88% and 39% respectively. CONCLUSION: The study shows that there is frequent anal sex, inconsistent condom and infrequent lubricant usage, economic and physical coercion, and low awareness of STI/HIV transmission risk among FSW, which have serious implications for HIV prevention programmes. There is a need to focus on anal sex education and use of lubricants along with condoms during anal sex in FSW-targeted interventions in AP. PMID- 22529449 TI - Initial assessment of scaled-up sexually transmitted infection intervention in Himachal Pradesh under National AIDS Control Program - III. AB - OBJECTIVES: To assess the impact of scaled-up sexually transmitted infection (STI) intervention under National AIDS Control Program (NACP) III and to examine the profile of STI/RTI clinic (now named Suraksha Clinic) attendees. MATERIALS AND METHODS: A retrospective study by data analysis was done from April 2008 to March 2010. The scaled-up intervention comprised of (i) adopting enhanced syndromic approach, (ii) capacity building by appointing counselors and trainings of staff, (iii) strengthening STI/RTI clinics by provision of logistics and privacy by civil works, and (iv) supervisory support. The outcome which directly influenced service delivery was evaluated within this framework. RESULTS: Sixteen "Suraksha Clinics" have been remodeled, equipped with supplies and laboratory set up. A total of 64,554 clinic visits were reported of which 27,317 [42%] attended the clinics for index STI/RTI complaint(s). Majority of the clients (44%) were young, 25-44 years old. Male to female ratio was 1:1.8. In females, the commonest complaint was lower abdominal pain (25%) and vaginal discharge (33%), the commonest syndrome. Amongst laboratory-confirmed STIs, 305 (1.4%) attendees were positive for trichomoniasis, while bacterial vaginosis was corroborated in 230 (1.07%) patients with clue cells. Amongst antenatal women, 251 were reactive for syphilis (>=1:8 dilutions). 10,579 partners of index STI/RTI patients were notified and partner management was attained to the level of 99%. CONCLUSION: Preliminary results show increased utilization of STI clinical services, though laboratory services need further strengthening. Continued supportive supervision and capacity building will enable skill development and quality monitoring. PMID- 22529448 TI - Sexually transmitted diseases among men who have sex with men: A retrospective analysis from Suraksha clinic in a tertiary care hospital. AB - BACKGROUND: Men who have sex with men (MSMs) are a vulnerable population for spread of sexually transmitted diseases (STDs) and human immunodeficiency virus (HIV). Apart from being important for HIV transmission, they tend to have a different distribution patterns of STDs. Few Indian studies have looked into this aspect. OBJECTIVE: We retrospectively analyzed the available data on MSM from Suraksha clinic of a tertiary care hospital in a metropolitan city from 2004 to 2010. MATERIALS AND METHODS: A total of 75 MSM constituting 11.4% of the total 660 patients visited our Suraksha clinic in these 6 years. The clinical and behavioral profile of each patient along with the pattern of STDs was evaluated. OBSERVATIONS AND RESULTS: 75% of the MSMs were promiscuous; one-third of them indulging in only homosexual activities. Syphilis was the most common STD, followed by condyloma acuminata, herpes genitalis, and gonorrhea. On comparing the data on the STD profiles of the heterosexual males, predisposition toward bacterial STDs among MSMs was observed. CONCLUSION: Identification of MSMs is important as most of them are bisexual and promiscuous, thereby playing a role in spread of STDs in vast number of partners. The profile of STDs also differs in MSM, which makes it all the more important to identify them. PMID- 22529450 TI - Clinical features and sociodemographic factors affecting Trichomonas vaginalis infection in women attending a central sexually transmitted diseases clinic in Sri Lanka. AB - INTRODUCTION: Trichomoniasis is a relatively neglected area of research in Sri Lanka. Given the number of infections observed, an analysis of sociodemographic characteristics of patients would be valuable in prevention. MATERIALS AND METHODS: Data were collected from 359 newly registered women at a tertiary level sexually transmitted diseases clinic over a period of 18 months. Trichomoniasis was diagnosed by culture of vaginal swabs collected from the posterior fornix. RESULTS: The prevalence of trichomoniasis in the sample was 7.2%. Of those who tested positive for trichomoniasis, 76% were in the age group of 21-45 years, 68% were married and living with a spouse and 60% were unemployed. A diagnosis of Trichomoniasis was associated with being married (OR, 1.6; CI, 0.56-4.41), age over 33 years (OR=1.3, CI, 0.55-2.9), being employed (OR, 1.3; CI, 0.56 - 2.94), having an education of less than ten years at school (OR, 3.0; CI 1.28-7.26) and not using condoms during the last sexual act (OR 2.0, CI 0.84-4.86). The risk was less among commercial sex workers (OR, 0.3, CI: 0.14-0.85), those with multiple sexual partners (OR, 0.2; CI; 0.073-0.408) and women reporting extramarital sexual relationships (OR, 0.3; CI, 0.128-0.733). CONCLUSIONS: Education on safe sex and recognition of symptoms is currently targeted at high risk groups such as commercial sex workers. Extending these programmes to the rest of the community will further reduce the risk of transmission of trichomonas. PMID- 22529451 TI - Current status of acquired syphilis: A hospital-based 5-year study. AB - INTRODUCTION: Prevalence of sexually transmitted infection shows regional variations. Though a rising trend of prevalence of viral STI s has been observed, syphilis still continues to remain a commonly diagnosed STI. AIM: To study the current status of acquired syphilis in a tertiary care hospital. MATERIALS AND METHODS: Retrospective analysis of all the cases of acquired syphilis registered in our hospital from 2005 to 2009 was done. Complete epidemiological, clinical, and investigational data were recorded and assessed. OBSERVATION: Total of 570 cases attended the STI clinic from year 2005 to 2009. 42 (7.36%) cases were diagnosed as syphilis. There were 32 (74%) males and 11 (26%) were females. 25 (60%) were married. Only two patients were less than 15 years of age. Primary syphilis was diagnosed in 21 (50%), secondary in 10 (24%), and latent in 11 (26%) cases. Two (9.5%) of primary syphilis showed multiple chancre. Concomitant primary chancre and lesions of secondary syphilis were seen in 2 (20%) patients. Secondary syphilis presented as condyloma lata (50%), maculo-papular rash (40%), and lues maligna in one patient who was HIV positive. Mixed infection was diagnosed in eight patients of which herpes genitalis was the commonest. Two patients were serologically positive for HIV. CONCLUSION: Incidence of syphilis had shown a constant trend over last 5 years. In lieu of change in trends of sexual practices, condyloma was the commonest presentation of secondary syphilis. Pustular syphilis was observed in association with HIV and could be a marker of the immune-deficient state. PMID- 22529452 TI - Cutaneous lymphangiectasia of the vulva secondary to tuberculosis. AB - Cutaneous lymphangiectasia, also called as acquired lymphangioma, is a benign cutaneous disorder involving the dermal and subcutaneous lymphatic channels. It can rarely occur on the vulva. We describe a 35-year-old woman who came with multiple raised lesions over the vulva and left upper thigh of 1 year duration. She gave history of getting treated for multiple swellings that developed over right side of the neck and inguinal regions on both sides three decades ago. On local genital examination, the patient had a large polypoidal growth involving both sides of the vulva, left upper thigh, and over pubic area. Multiple linear scars were present over the upper thighs and groin bilaterally. The patient underwent simple vulvectomy and left thigh growth excision. Histopathological examination of the vulvectomy specimen confirmed our diagnosis. PMID- 22529453 TI - Penicillinosis in a HIV-positive individual. AB - Penicillium marneffei is a dimorphic fungus, which can cause fatal infection in HIV-infected patients. The aim of this article is to report a rare case of penicillinosis in an HIV-positive patient from a nonendemic area such as Paonta Sahib, Himachal Pradesh. The patient presented with nonhealing painful ulcer on tongue, chest pain, cough, and chronic diarrhea. Diagnosis was made possible through blood investigations and culture reports of saliva and blood samples. PMID- 22529454 TI - Recurrent deep venous thrombosis in an HIV-positive and injecting drug user woman. AB - We report a case of recurrent deep venous thrombosis in a 44-year-old woman, intravenous drug user and HIV-infected, who injected cocaine in the groins and veins of the dorsum of the feet. She suffered several episodes of deep venous thrombosis and soft-tissue infections in the lower limbs. Images of Doppler ultrasound scan revealed thrombosis in the right popliteal vein with partial recanalization and calcified thrombi in the territory of the right femoral vein. After use of heparin and oral anticoagulation, her clinical evolution was uneventful, and she was asymptomatic at the occasion of the hospital discharge. This report calls for better awareness about injections in the groins and superficial femoral veins, which are part of the deep venous system. Thrombosis related to HIV infection is highlighted. PMID- 22529455 TI - Immune reconstitution disease or mycobacteria other than tuberculosis or both: A dilemma in a patient of AIDS. AB - A 35-year-old male diagnosed as HIV with tuberculous lymphadenopathy, presented with acute increase in size of neck swelling and fever. The patient was on antiretroviral therapy and antitubercular treatment. Investigations revealed raised CD4 counts and the pus from swelling showed mycobacteria other than tuberculosis (MOTT) on bacteriological examination.The patient was started on steroids, azithromycin, and ciprofloxacin to which he responded well. We report this case to highlight the occurrence of immune reconstitution disease in HIV patients and also to bring out the fact that atypical infection like MOTT may confound the diagnosis even in regions like ours where MOTT is rarely reported. PMID- 22529456 TI - Gonorrhoea presenting as red eye: Rare case. AB - Gonorrhoea is a sexually transmitted disease marked by urethritis in males; it may also be transmitted to other organs through contact with infected genital secretions or urine, although rare in this era of modern antibiotics and rapid diagnostic tools. It could pose a difficult situation when we encounter emerging resistant strains. This paper reports a male who presented initially with unilateral gonococcal conjunctivitis contracted via autoinoculation and was found out to be suffering from gonococcal urethritis. PMID- 22529457 TI - Matching research design to clinical research questions. AB - The importance of randomized controlled trials (RCTs) versus observational studies has been debated for several years. However, the question is not whether RCTs are better than observational study designs. RCTs certainly provide the most unbiased answers in scenarios where it is logistically and ethically feasible to conduct both RCTs and observational studies. That is, study design is not a choice but a function of matching the research question to provide the most unbiased answers. The basic concept that underpins every clinical research project is the requirement of a clearly defined research question domain. Broadly, the clinical research question domain relates to prognosis, diagnostic accuracy, treatment or adverse events. While RCTs provide the most unbiased answers on questions related to the efficacy of treatments, other designs are better suited to answer questions related to prognosis or diagnostic accuracy of tests. In this paper, we illustrate the significance of matching study design to the research question domain while using clinical scenarios as an example. Although there are several other question domains that also concern the practice of medicine, we are only focusing on study designs concerning the issue of prognosis and diagnostic accuracy in this paper. PMID- 22529458 TI - Cleft lip as a presentation of congenital syphilis. AB - Congenital syphilis may present with unusual symptoms in early stages which needs to be identified for prompt treatment. Here, we present a case of 13-day-old female child with congenital syphilis presenting with cleft lip. PMID- 22529459 TI - Cryptococcal mesenteric lymphadenitis in an immunocompromised host. PMID- 22529460 TI - Coinfection of hepatitis B and hepatitis C in human immunodeficiency virus infected patients in a tertiary care hospital in North West India. PMID- 22529461 TI - Diffuse cutaneous leishmaniasis - A rare cutaneous presentation in an HIV positive patient. PMID- 22529462 TI - A study of the changing trends in the pattern of sexually transmitted infections in the state of Kerala. PMID- 22529463 TI - Skin diseases in HIV-infected patients: Impact of immune status and histological correlation. PMID- 22529464 TI - Comments: "Pattern of sexually transmitted infections and performance of syndromic management against etiological diagnosis in patients attending STI clinic of a tertiary care hospital". PMID- 22529465 TI - Authors' reply. PMID- 22529466 TI - Challenges in the treatment of cardiometabolic syndrome. PMID- 22529467 TI - Renin angiotensin system: A novel target for migraine prophylaxis. AB - Migraine constitutes 16% of primary headaches affecting 10-20% of general population according to International Headache Society. Till now nonsteroidalanti inflammatory drugs (NSAIDS), opioids and triptans are the drugs being used for acute attack of migraine. Substances with proven efficacy for prevention include beta-blockers, calcium channel blockers, antiepileptic drugs and antidepressants. All the already available drugs have certain limitations. Either they are unable to produce complete relief or 30-40% patients are no responders or drugs produce adverse effects. This necessitates the search for more efficacious and well tolerated drugs. A new class of drugs like angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor antagonists have recently been studied for their off label use in prophylaxis of migraine. Studies, done so far, have shown results in favour of their clinical use because of the ability to reduce number of days with headache, number of days with migraine, hours with migraine, headache severity index, level of disability, improved Quality of life and decrease in consumption of specific or nonspecific analgesics. This article reviews the available evidence on the efficacy and safety of these drugs in prophylaxis of migraine and can give physician a direction to use these drugs for chronic migraineurs. Searches of pubmed, Cochrane database, Medscape, Google and clinicaltrial.org were made using terms like ACE inhibitors, angiotensin II receptor antagonists and migraine. Relevant journal articles were chosen to provide necessary information. PMID- 22529469 TI - Data management in clinical research: An overview. AB - Clinical Data Management (CDM) is a critical phase in clinical research, which leads to generation of high-quality, reliable, and statistically sound data from clinical trials. This helps to produce a drastic reduction in time from drug development to marketing. Team members of CDM are actively involved in all stages of clinical trial right from inception to completion. They should have adequate process knowledge that helps maintain the quality standards of CDM processes. Various procedures in CDM including Case Report Form (CRF) designing, CRF annotation, database designing, data-entry, data validation, discrepancy management, medical coding, data extraction, and database locking are assessed for quality at regular intervals during a trial. In the present scenario, there is an increased demand to improve the CDM standards to meet the regulatory requirements and stay ahead of the competition by means of faster commercialization of product. With the implementation of regulatory compliant data management tools, CDM team can meet these demands. Additionally, it is becoming mandatory for companies to submit the data electronically. CDM professionals should meet appropriate expectations and set standards for data quality and also have a drive to adapt to the rapidly changing technology. This article highlights the processes involved and provides the reader an overview of the tools and standards adopted as well as the roles and responsibilities in CDM. PMID- 22529468 TI - Chemically modified tetracyclines: Novel therapeutic agents in the management of chronic periodontitis. AB - Chronic periodontitis is a complex infection initiated by gram-negative bacteria which destroy the supporting structures of the tooth. Recently, it has been recognized that it is the host response to bacterial infection which causes greater destruction of the connective tissue elements, periodontal ligament and alveolar bone in periodontitis. This has led to the development of various host modulating approaches to target cells and their destructive mediators involved in tissue degradation. Chemically modified tetracyclines (CMTs) are derivatives of tetracycline group of drugs which lack antimicrobial action but have potent host modulating affects. They inhibit pathologically elevated matrix metal loproteinases, pro-inflammtory cytokines and other destructive mediators. Bone resorption is also suppressed due to their combined anti-proteinase and apoptotic affects on osteoblasts and osteoclasts, respectively. Development of resistant bacteria and gastrointestinal toxicity seen with parent tetracyclines is not produced by CMTs. Hence, CMTs are viewed as potential therapeutic agents in the management of chronic diseases like periodontitis that involve destruction of connective tissue and bone. PMID- 22529470 TI - Efficacy and safety of add on low-dose mirtazapine in depression. AB - OBJECTIVES: Although antidepressant medications are effective, they have a delayed onset of effect. Mirtazapine, an atypical antidepressant is an important option for add-on therapy in major depression. There is insufficient data on mirtazapine in Indian population; hence this study was designed to study the add on effect of low-dose mirtazapine with selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder (MDD) in Indian population. MATERIALS AND METHODS: In an open, randomized study, 60 patients were divided into two groups. In Group A (n=30) patients received conventional SSRIs for 6 weeks. In Group B (n=30) patients received conventional SSRIs with low-dose mirtazapine for 6 weeks. Patients were evaluated at baseline and then at 1, 2, 3, 4, 5, and 6 weeks. RESULTS: There was significant improvement in Hamilton Depression Rating Scale (HDRS), Montgomery and Asberg depression rating scale (MADRS) scores (P<0.05) in both groups. Mirtazapine in low dose as add on therapy showed improvement in scores, had earlier onset of action, and more number of responders and remitters as compared to conventional treatment (P<0.05). No serious adverse event was reported in either of the groups. CONCLUSION: Low-dose mirtazapine as add-on therapy has shown better efficacy, earlier onset of action and more number of responders and remitters as compared to conventional treatment in MDD in Indian patients. PMID- 22529471 TI - Cardioprotective effect of methanolic extract of Ixora coccinea Linn. leaves on doxorubicin-induced cardiac toxicity in rats. AB - OBJECTIVES: To investigate the effect of methanolic extract of Ixora coccinea Linn. (MEIC) leaves against doxorubicin-induced cardiac toxicity in rats. MATERIAL AND METHODS: Albino Wistar rats were pretreated with the methanolic extract of Ixora coccinea Linn. leaves (200 and 400 mg/kg, orally) for 1 week followed with the simultaneous treatment with doxorubicin (cumulative dose of 15 mg/kg in six divided doses for 2 weeks) along with the extracts for the next 14 days. On the 22(nd) day hemodynamic parameters such as blood pressure and ECG were recorded. Biochemical study including biomarkers like creatine kinase - MB (CK - MB), lactate dehydrogenase (LDH), SGOT and SGPT, tissue antioxidant markers viz. catalase (CAT), superoxide dismutase (SOD) and extent of lipid peroxidation viz. malondialdehyde (MDA) was estimated. Histopathology of heart was also done to assess the cardioprotective effect. RESULTS: Pretreatment with MEIC significantly reduced (P<0.01) the ST segment elevation and also maintained the BP (P<0.01) close to normal. The MEIC significantly reduced the elevated level of biomarkers like CK - MB, LDH, SGOT, SGPT (P<0.01) near to normal, the MEIC also increased the tissue antioxidant markers viz. CAT, SOD and decreased the level of MDA (P<0.01) in cardiac tissue by dose-dependant manner. The histopathology of heart also further confirmed the cardioprotection provided by the methanolic extract of Ixora coccinea Linn. leaves. CONCLUSION: The results suggest a cardioprotective effect of Ixora coccinea Linn. leaves due to its antioxidant properties. PMID- 22529472 TI - Effect of phenolic acids on functions of rat aorta, vas deferens and on metabolic changes in streptozotocin-induced diabetes. AB - OBJECTIVES: This study aimed to investigate the effects of antioxidant treatment on streptozotocin (STZ)-induced diabetic metabolic and smooth muscle (SM) complications in rats. MATERIALS AND METHODS: Threeweeks after STZ injection (i.v.), vehicle, p-OH benzoic (p-OHBA), protocatechic (PA) and gallic acids (GA) were separately administered (10 mg/kg each, i.p.) to the rats everyday for 3 weeks. Metabolic functions were observedregularly. The rats in all groups were sacrificed andaorta and Vas deferens were dissected. Theresponses of isolated organs to agonists (acetylcholine and phenylephrine) were recorded. RESULTS: Protocatechic acid prevented increase in food consumption and feces output significantly. The responses of isolated organs to agonists increased in the STZ diabetic rats. The test drugs either prevented, exacerbated or didnot affect the SMchanges in the STZ-diabetic rats. CONCLUSIONS: It was concluded that p-OHBA, PA and GA may cause effects independently of their antioxidant effect and/or of diabeticcomplications. They may exhibit pro-oxidant activities in the experimental conditions applied. PMID- 22529473 TI - Anxiolytic and antidepressant-like effects of Melissa officinalis (lemon balm) extract in rats: Influence of administration and gender. AB - OBJECTIVE: To analyse the behavioral effects of Melissa officinalis extract in rats following acute or subacute treatment. MATERIALS AND METHODS: The behavioral effects of an acute or subacute (10-day course) orally administered M. officinalis (MO; 0, 30, 100 or 300 mg/kg) ethanol extract were evaluated in male and female Wistar rats in elevated plus-maze (EPM), forced swimming (FS) and open field (OF) tests. The effects of diazepam (DZP; 1 mg/kg) and fluoxetine (FXT; 10 mg/kg) were also assessed. RESULTS: In the EPM test, the percentage of open arm entries and open arm times of both males and females given the subacute M. officinalis ethanol extract were significantly higher than those of the vehicle treated animals but were at levels similar to those observed in the DZP group, regardless of the treatment length. In the FS test, immobility duration was significantly lower in both males and females treated with the plant extract when compared to vehicle-treated counterparts. A 10-day treatment with FXT induced the same antidepressant response, regardless of gender, and was more effective than the M. officinalis extract. Male and female rats demonstrated distinct gender profiles, and treatment * gender interactions were observed. Locomotion in the EPM and OF tests was not significantly altered by treatments. CONCLUSION: The potential psychoactive properties of M. officinalis may provide a unique pharmacological alternative for certain psychiatric disorders; however, the efficacy appears to be dependent on both gender and administration length. PMID- 22529474 TI - A comparison of hypotension and bradycardia following spinal anesthesia in patients on calcium channel blockers and beta-blockers. AB - OBJECTIVES: Hypotension is a common complication of spinal anesthesia and is frequent in patients with hypertension. Antihypertensive agents decrease this effect by controlling blood pressure. There are conflicting reports on the continuation of antihypertensive drugs on the day of surgery in patients undergoing spinal anesthesia. Sudden hypotension could have detrimental effect on the organ systems. This study was undertaken to compare the variation in blood pressure in hypertensive patients on beta-blockers and calcium channel blockers undergoing spinal anesthesia. MATERIALS AND METHODS: Ninety patients were enrolled for the study, 30 each in the control, beta-blocker and the calcium channel blocker groups. RESULTS: The incidence of hypotension was not different among the three groups. However, the number of times mephentermine used to treat hypotension was significant in the patients receiving calcium channel blockers while incidence of bradycardia in patients treated with beta-blockers was significant (P<0.001). CONCLUSION: The incidence of hypotension following spinal anesthesia is not different in patients receiving beta-blockers and calcium channel blockers among the three groups. PMID- 22529475 TI - Molecular docking and ex vivo pharmacological evaluation of constituents of the leaves of Cleistanthus collinus (Roxb.) (Euphorbiaceae). AB - OBJECTIVE: To investigate the involvement of alpha adrenergic receptors in hypotension induced by cleistanthin A and cleistanthin B. MATERIALS AND METHODS: Cleistanthins A and B were isolated from the leaves of Cleistanthus collinus using a column chromatographic method and purified. Structures were confirmed by spectroscopic analysis. The compounds were prepared for molecular docking studies using Ligprep 2.3 module and Induced Fit Docking was carried out against alpha-1 adrenergic receptors using Glide. The ex vivo experiments were carried out on male Wistar rats. Under anaesthesia, the femoral vein and carotid artery were cannulated for drug administration and for monitoring the blood pressure, respectively. The effect of epinephrine, norepinephrine, acetylcholine, histamine and dopamine were recorded before and after the administration of cleistanthin A or cleistanthin B. The molecular docking studies showed favorable molecular interactions, glide score, energy and emodel. RESULT: Cleistanthins A and B per se reduced the mean blood pressure and the effect was dose dependent. Both the compounds reduced the effect of epinephrine, norepinephrine and alpha-1 receptor activity of dopamine. Cleistanthin B significantly increased the duration of action of acetylcholine on mean blood pressure. CONCLUSION: The molecular docking and ex vivo studies conclude that cleistanthin A and cleistanthin B have significant alpha-1 adrenergic receptor antagonist effect on the peripheral vascular system. PMID- 22529477 TI - Study of drug utilization pattern of antihyperglycemic agents in a South Indian tertiary care teaching hospital. AB - OBJECTIVE: To determine the drug utilization pattern of antihyperglycemic agents (AHA) in a tertiary care teaching hospital. MATERIALS AND METHODS: This was a prospective observational study. All the relevant data were collected and drug utilization pattern of AHA was determined. Direct cost associated with the use of antihyperglycemic medicines was calculated and consumption of the antihyperglycemic medicines was measured as defined daily dose (DDD)/100 bed days. The adverse drug reactions (ADRs) related to anti-diabetic medicines were monitored. STATISTICAL ANALYSIS USED: Chi square test (chi(2)), mean+/-standard deviation. RESULTS: During the study period, 350 patients diagnosed as diabetes mellitus (DM) were admitted. Insulin was prescribed as monotherapy to 81% and to 52% patients during hospital stay and discharge, respectively. Increase in utilization of insulin was recorded in majority of the patients due to presence of co-morbid conditions or resistance to oral hypoglycemic drugs. Use of insulin at the time of discharge decreased significantly (P<0.05) by 29%. Among the oral AHA, combination of glimepiride with metformin was more prevalent during hospital stay and at the time of discharge monotherapy of metformin followed by glimepiride was more prevalent. During hospital stay, cost of AHA was found to be Rs. 95.27 +/- 119.03. The total antihyperglycemic drug consumption in the medicine ward during study period was 13.42 DDD/100 bed-days. Fifty ADRs were reported and descriptions of ADRs were found to be only hypoglycemia. CONCLUSION: The study exhibited a significant increase in the utilization of two drug combination therapies and monotherapy of oral AHA and decrease in the utilization of insulin at the time of discharge. PMID- 22529476 TI - Cytochrome P-450-catalyzed reactive oxygen species production mediates the ( )schisandrin B-induced glutathione and heat shock responses in H9c2 cardiomyocytes. AB - OBJECTIVE: Schisandrin B (Sch B) is the most abundant, active dibenzocyclooctadiene derivative isolated from the fruit of Schisandra chinensis (Turcz) Baillon (Schisandraceae). (-)Sch B was found to be the most potent stereoisomer of Sch B in producing cytoprotective action in H9c2 cardiomyocytes. The elucidation of biochemical mechanism underlying the cytoprotection of (-)Sch B has attracted much interest in the area of preventive medicine. Here, we examined whether the (-)Sch B-induced enhancement of glutathione antioxidant and heat shock responses and the associated cytoprotection against hypoxia/reoxygenation-induced apoptosis are mediated by reactive oxygen species (ROS) arising from cytochrome P-450 (CYP)-catalyzed metabolism of (-)Sch B in H9c2 cardiomyocytes. MATERIALS AND METHODS: The effects of CYP inhibitor (1 aminobenzotriazole, ABT) and antioxidant (dimethylthiouracil, DMTU) on (-)Sch B induced ROS production and associated increases in cellular-reduced glutathione (GSH) level as well as heat shock protein (Hsp) 25/70 production were investigated in H9c2 cardiomyocytes. The (-)Sch B-induced ROS generation was monitored with or without ABT/DMTU for 6 h in situ, while (-)Sch B-induced cellular GSH level and Hsp 25/70 production, as well as cytoprotection were measured at 16 h post-(-)Sch B exposure. RESULTS: The results indicated that ( )Sch B caused a dose-dependent increase in ROS production in H9c2 cardiomyocytes, which was completely suppressed by pre- and co-treatment with ABT or DTMU. The incubation with (-)Sch B for 6 h caused dose-dependent increases in cellular GSH level and Hsp 25/70 production, as well as protection against hypoxia/reoxygenation-induced apoptosis at 16-h post-drug exposure in H9c2 cardiomyocytes. All these cellular responses were abrogated by treatment with ABT or DMTU. CONCLUSION: The results suggest that ROS arising from the CYP-catalyzed metabolism of (-)Sch B elicit glutathione antioxidant and heat shock responses, thereby protecting against oxidant-induced apoptosis in H9c2 cardiomyocytes. PMID- 22529478 TI - Zimelidine attenuates the development of tolerance to morphine-induced antinociception. AB - OBJECTIVES: The aim of this study was to investigate effect of zimelidine (a serotonin reuptake inhibitor) on morphine-induced tolerance in rats. MATERIALS AND METHODS: Male Wistar albino rats weighing 160-180 g were used in these experiments (n=72). A 3-day cumulative dosing regimen was used for the induction of morphine tolerance. To constitute of morphine tolerance, animals received morphine twice daily for 3 days. After the last dose morphine was injected on the fourth day, morphine tolerance was evaluated. The analgesic effects of zimelidine (15 mg/kg; i.p.) and morphine (5 mg/kg) were considered at 30-min time intervals (0, 30, 60, 90 and 120 min) by tail-flick and hot-plate analgesiometer (n=6 in each experimental group). RESULTS: The results showed that zimelidine significantly attenuated the development and expression of morphine tolerance. The maximal antinociceptive effect of zimelidine was obtained at the 60 minutes measurements in the zimelidine group and at the 30 minutes measurements in the morphine tolerant group by the tail-flick and hot-plate tests. Administration of zimelidine with morphine showed additive analgesic effect. CONCLUSION: In conclusion, our results show that zimelidine reduces the development of tolerance to morphine-induced antinociception in rats. PMID- 22529479 TI - Antidiabetic and antihyperlipidemic effects of ethanolic extract of leaves of Punica granatum in alloxan-induced non-insulin-dependent diabetes mellitus albino rats. AB - OBJECTIVES: Punica granatum L., (Family: Punicaceae) is used in Indian Unani medicine for treatment of diabetes mellitus. Therefore, the present study was done to evaluate the antidiabetic and antihyperlipidemic effects of ethanolic extract of leaves of P. granatum in alloxan-induced diabetic rats. MATERIALS AND METHODS: Healthy Wistar albino rats (100-150 g) were divided into four groups of six animals each. Groups A and B received normal saline [(10 ml/kg/day/per oral (p.o.)]; group C received ethanolic extract of leaves of P. granatum (500 mg/kg/p.o.); and group D received glibenclamide (0.5 mg/kg/day/p.o.). The extracts were given for 1 week in all groups. To induce diabetes, alloxan 150 mg/kg, intraperitoneal (i.p.) single dose was administered to groups B, C, and D. Blood glucose and serum lipids [Total Cholesterol (TC), Triglycerides (TG), Low Density Lipoproteins (LDL), and High Density Lipoproteins (HDL)] and the atherogenic index were estimated after one week. For mechanism of antidiabetic action glycogen estimation on the liver, cardiac and skeletal muscle, and intestinal glucose absorption was done. RESULTS: Group B showed a significant (P<0.01) increase in blood glucose as compared to group A. Groups C and D showed significant decrease (P<0.01) in blood glucose level in comparison to group B. The test drug showed a significant (P<0.01) increase in glycogen content in the liver, cardiac, and skeletal muscle; it significantly (P<0.01) reduced intestinal glucose absorption. Groups C and D showed significant (P<0.01) decrease in serum TC, TG, LDL, and AI as compared to Group B, which showed a significant (P<0.01) increase. Groups C and D showed significant (P<0.01) increase in serum HDL as compared to Group B, which showed a significant (P<0.01) decrease in all values. CONCLUSION: P. granatum leaves possess significant antidiabetic and antihyperlipidemic activity. PMID- 22529480 TI - Antiproliferative and antioxidant activity of Aegle marmelos (Linn.) leaves in Dalton's Lymphoma Ascites transplanted mice. AB - OBJECTIVE: The present investigation was performed to evaluate the antiproliferative and antioxidant activity of Aegle marmelos leaves in Dalton's Lymphoma Ascites (DLA)-bearing mice. MATERIALS AND METHODS: The DLA cells maintained in vivo in Swiss albino mice were used for developing ascitic tumor in mice by intraperitoneal transplantation. The standardized 50% ethanolic extract of A. marmelos leaves (AMEE) was administered intraperitoneally in dose levels 200 and 400 mg/kg, after 24 hours of tumor inoculation in mice for two weeks. RESULTS: The AMEE treatment significantly prevented (P<0.001) the increase in body weight due to tumor cell growth and increased the mean survival time of the tumor-bearing mice as compared to the untreated DLA control mice. The treatment of DLA-bearing mice brought down the Alanine Aminotransferase (ALAT), Aspartate Aminotransferase (ASAT), and alkaline phosphatase to normal levels. The extract decreased the levels of hepatic lipid peroxidation and increased the levels of hepatic antioxidants Glutathione, Superoxide Dismutase (SOD), and catalase. All the changes observed with AMEE treatment were dose dependent. CONCLUSION: The hydroalcoholic extract of A. marmelos exhibits strong antitumor and antioxidant activities in DLA-bearing mice. PMID- 22529481 TI - Non-invasive measurement of aortic pressure in patients: Comparing pulse wave analysis and applanation tonometry. AB - OBJECTIVE: The aim of the present study was to validate and compare novel methods to determine aortic blood pressure non-invasively based on Oscillometric Pulse Wave Velocity (PWV) measurement using four limb-cuff pressure waveforms and two lead Electrocardiogram (ECG) with a validated tonometric pulse wave analysis system in patients. MATERIALS AND METHODS: After receiving the consent, in 49 patients with hypertension, coronary artery disease, diabetes mellitus, PWV, and central blood pressures were recorded in a randomised manner using both the oscillometric and tonometric devices. All recordings were performed 10 minutes after the patient lying comfortably in a noise-free temperature-controlled room. The test was performed between 09 am and 10 am after overnight fast. A minimum of three measurements were performed by the same skilled and trained operator. From the raw data obtained with two devices, software calculated the final vascular parameters. RESULTS: A total of 49 patients (8 women and 41 men), of mean age 40.5 years (range: 19-81 years) participated in the present study. After transforming the brachial pressures into aortic pressures, the correlation coefficient between the Aortic Systolic Pressure (ASP) values obtained with two methods was 0.9796 (P<0.0001). The mean difference between ASP with two methods was 0.3 mm Hg. Similarly, Aortic Diastolic Pressure (ADP) values obtained with two methods also correlated significantly with correlation coefficient of 0.9769 (P<0.0001). The mean difference of ADP was 0.2 mm Hg. In case of Aortic Pulse Pressure (APP), the mean difference was 0.1 mm Hg. All parameters of central aortic pressures obtained with two methods correlated significantly. CONCLUSION: The new method of transforming the Carotid Femoral PWV (cfPWV) and brachial blood pressure values into aortic blood pressure values seems to be reasonably good. The significant correlation between the values obtained by tonometric device and oscillometric PWV method shows that the latter can be used non-invasively in patients to find the aortic pressure. PMID- 22529482 TI - Comparison of three a-priori models in the prediction of serum lithium concentration. AB - CONTEXT: Mathematical models are valuable for optimizing drug dose and dosing regimens. AIMS: To compare the precision and bias of three a-priori methods in the prediction of serum level of lithium in patients with bipolar disorder, and to determine their sensitivity and specificity in detecting serum lithium levels outside the therapeutic range. SETTINGS AND DESIGN: Hospital-based, retrospective study. MATERIALS AND METHODS: In a retrospective study of 31 in-patients, the serum level of lithium was calculated using three different a-priori methods. Mean Prediction Error was used as a measure of bias while Mean Absolute Error and Root Mean Squared Error were used as a measure of precision. The sensitivity and specificity of the methods was calculated. RESULTS: All three models underestimated serum lithium level. Precision was best with the model described by Pepin et al., while bias of prediction was the least with the method of Abou Auda et al. The formula by Pepin et al. was able to predict serum lithium level with a mean error of 36.57%. The sensitivity and specificity of the models in identifying serum lithium levels outside the therapeutic range was 80% and 76.19% for Pepin et al., 90% and 74.19% for Zetin et al., and 90% and 66.67% for Abou Auda et al., respectively. CONCLUSION: The study demonstrates the difference in precision and bias of three a-priori methods, with no one method being superior to the other in the prediction of serum concentration. PMID- 22529484 TI - A comparative study of oral single dose of metronidazole, tinidazole, secnidazole and ornidazole in bacterial vaginosis. AB - OBJECTIVE: To compare the cure rates of oral single dose of metronidazole (2 g), tinidazole (2 g), secnidazole (2 g), and ornidazole (1.5 g) in cases of bacterial vaginosis. MATERIALS AND METHODS: This was a prospective, comparative, randomized clinical trial on 344 Indian women (86 women in each group) who attended a gynecology outpatient department with complaint of abnormal vaginal discharge or who had abnormal vaginal discharge on Gynecological examination but they did not complaint of it. For diagnosis and cure rate of bacterial vaginosis, Amsel's criteria were used. Statistical analysis was done by Chi-square test of proportions. The cure rate was compared considering metronidazole cure rate as gold standard. RESULTS: At 1 week, the cure rate of tinidazole and ornidazole was 100% and at 4 weeks, it was 97.7% for both drugs (P<0.001). Secnidazole had cure rate of 80.2% at 4 weeks (P=NS). Metronidazole showed a cure rate of 77.9% at 4 weeks, which is the lowest of all four drugs. CONCLUSION: Tinidazole and ornidazole have better cure rate as compared to metronidazole in cases of bacterial vaginosis. PMID- 22529483 TI - A comparative clinical study of hypolipidemic efficacy of Amla (Emblica officinalis) with 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitor simvastatin. AB - OBJECTIVES: To evaluate the efficacy of Amla in patients with type II hyperlipidemia and compare its hypolipidemic effects with those of simvastatin. MATERIALS AND METHODS: Sixty type II hyperlipidemic patients of both sexes with plasma total cholesterol and low density lipoprotein level more than 240 mg% and 130 mg%, respectively, were selected for the trial. Out of total 60 selected patients, 40 were treated with Amla capsule (500 mg) daily for 42 days and 20 patients were given simvastatin capsule (20 mg) daily for 42 days. After the day of enrolment, all patients were followed up twice during the 42-day period. Blood samples were analyzed for various biochemical parameters and the values of Total Cholesterol (TC), Low Density Lipoprotein (LDL), High Density Lipoprotein (HDL), and Very Low Density Lipoprotein (VLDL) were measured before and after completion of the treatment with Amla and simvastatin. Cardiovascular parameters were recorded before and after completion of treatment. RESULTS: Treatment with Amla produced significant reduction of TC (P<0.0001), LDL (P<0.0001), triglyceride (TG) and VLDL (P<0.0002), and a significant increase in HDL levels (P<0.0002). Similarly, treatment with simvastatin produced significant reduction of TC (P<0.0001), LDL (P<0.0009), TG and VLDL (P<0.017), and a significant increase in HDL levels (P<0.0001). Both treatments produced significant reduction in blood pressure; however, this beneficial effect was more marked in patients receiving Amla. CONCLUSION: In view of the above findings, it is suggested that Amla produced significant hypolipidemic effect along with a reduction in blood pressure. Addition of Amla to the currently available hypolipidemic therapy would offer significant protection against atherosclerosis and coronary artery disease, with reduction in the dose and adverse effects of the hypolipidemic agents. PMID- 22529485 TI - Pharmacokinetic interaction of garlic and atorvastatin in dyslipidemic rats. AB - OBJECTIVE: To assess pharmacokinetic interaction of garlic with atorvastatin in dyslipidemic rats. MATERIALS AND METHODS: Sprague Dawley rats with induced dyslipidemia were divided into five groups of eight rats each. Group 1 was given atorvastatin (10 mg/kg body weight (b.wt) orally), group 2 was given atorvastatin (10 mg/kg b.wt orally)+garlic (1% w/w in feed), group 3 was maintained on atorvastatin (5 mg/kg b.wt orally)+garlic (0.5% w/w in feed), group 4 was maintained on atorvastatin (7.5 mg/kg b.wt orally)+garlic (0.25% w/w in feed), and group 5 was maintained on atorvastatin (2.5 mg/kg b.wt orally)+garlic (0.75% w/w in feed) for 12 weeks. Blood samples were collected at predetermined time intervals for kinetic analysis after the first and last oral dosing of atorvastatin for single and multiple dose studies, respectively. Plasma samples were assayed for atorvastatin concentration by High-Performance Liquid Chromatography (HPLC) and then the concentration-time data were analyzed. RESULTS: Maximum observed plasma concentration (C(max)), half-life, Area Under Plasma Concentration Time Curve (AUC), and Mean Resident Time (MRT) were significantly (P<0.05) increased during multiple dose kinetic study and elimination rate constant was significantly (P<0.05) decreased in comparison with their respective single-dose values, while there was no significant difference in time to achieve maximum concentration (t(max)) in all groups during both phases of the study. The highest values for kinetic parameters were observed in group 2 with correspondingly low activity of Cytochrome P(450) (CYP(450)). CONCLUSION: The study revealed higher values [C(max), AUC, Area Under The Moment Curve (AUMC), MRT, and half-life] of atorvastatin in garlic-treated groups. PMID- 22529486 TI - Cooperative learning with role play in Chinese pharmacology education. AB - BACKGROUND: Cooperative learning (CL) and role play are both efficient educational tools for enhancing Chinese student active learning and communication skills. OBJECTIVE: This study was designed to obtain student feedback on the format of CL together with role play in the study of pharmacology in Chinese pharmaceutical undergraduates. MATERIALS AND METHODS: CL was used in the self study of new drugs used clinically but neglected in textbook and class teaching, so that groups of students were assigned to become "specialists" in one area of new drugs. Then, these "specialists" taught their new-found knowledge to other groups in role play approach involving an interaction between the pharmacist and a patient. Student perceptions of CL together with role play were examined using an eight-item survey instrument. RESULTS: Students were satisfied with CL together with role play. Majority of the students believed this teaching method enhanced their learning experience, made them gain more pharmacological expertise, increased the awareness of their career in future and self-educational abilities, and fostered their cooperation spirit and confidence. The materials on CL and role play were also believed pertinent. Only 63.4-76.5% and 63.1-37.3% of the students thought "CL and role-play were very funny" and "I felt very relaxed during CL together with role-play", respectively. CONCLUSION: CL together with role play is an efficient educational tool for enhancing student active-learning and communication skills. But Chinese students will take some time to adapt to this new teaching method. PMID- 22529487 TI - A prospective study of adverse drug reactions to artemisinin-based combination therapy in a tertiary care hospital in India. AB - OBJECTIVES: Antimalarial drugs are commonly prescribed for the treatment of malaria and suspected cases of malaria in India. The recent trend is to prescribe ACT and the incidence of adverse reactions to this therapy is notwell-documented in Indian population. Therefore, this study was designed to assess ADR pattern of antimalarial drugs particularly ACT in India. MATERIALS AND METHODS: Over a period of 1 year, 500 patients who were administered antimalarial drugs were enrolled in the study. The World Health Organization causality assessment scale was used for classifying the ADR. RESULTS: In this study out of 500 patients, 251 complained of ADRs. The sex-wise difference in reporting of ADRs was statistically not significant (P=0.0943). The most common ADRs reported were nausea, anorexia and vomiting. ADRs were most commonly reported when chloroquine was coprescribed. CONCLUSIONS: This study indicates that ACT was commonlyused in the treatment of malaria. Results of the analysis suggest that all the ADRs were of moderate intensity and no serious ADR was observed. This baseline information will be useful to implement the ACT in India. PMID- 22529488 TI - A comparative effect of atorvastatin with other statins in patients of hyperlipidemia. AB - OBJECTIVE: The objective of the study was to evaluate the safety and efficacy of atorvastatin compared with simvastatin and pravastatin in patients of hyperlipidemia. MATERIALS AND METHODS: This was a randomized, parallel group, open-label study conducted at KG hospital, Coimbatore, Tamilnadu, India. Twenty hyperlipidemia patients each taking atorvastatin 20 mg, pravastatin 20 mg and simvastatin 20 mg tablets were selected for the study after clinical and baseline investigations. The patients were reviewed after 3(rd) and 5(th) month of statin therapy for lipid profile. The liver enzyme levels (SGOT, SGPT, ALP), albumin, bilirubin, protein and biochemical infraction parameters (Creatine Kinase, Creatine Kinase - Myocardial Band) after 5(th) month of treatment with statins were also reviewed. RESULTS: The results showed that atorvastatin significantly reduced the lipid levels (LDL-C, TC, TG, VLDL) when compared to simvastatin and pravastatin after 3(rd) and 5(th) month of treatment. Atorvastatin increased the HDL-C levels significantly when compared to simvastatin and pravastatin after 5 months of treatment. Atorvastatin also significantly reduced the CK levels when compared to pravastatin but no increase in liver enzyme levels was observed. CONCLUSION: The study showed that atorvastatin is more effective when compared to simvastatin and pravastatin in patients with hyperlipidemia. PMID- 22529489 TI - Phenytoin in treatment of amiodarone-induced Torsades de pointes. AB - Phenytoin, a class IB anti-arrhythmic agent, is considered the drug of choice for ventricular arrhythmias due to digoxin toxicity. We report successful reversion of polymorphic ventricular tachycardia secondary to amiodarone toxicity by phenytoin administration that was resistant to the conventional drugs (magnesium sulphate, lidocaine and atropine). PMID- 22529490 TI - Metoclopramide-induced oculogyric crisis presenting as encephalitis in a young girl. AB - Drug-related dystonic reactions are not uncommon and often misdiagnosed as encephalitis, seizures, tetanus, tetany, etc. Eliciting thorough history is important to avoid unnecessary investigations and treatments as these are potentially reversible reactions. Metoclopramide-induced oculogyric crisis is described in this case report. PMID- 22529491 TI - Carbamazepine-induced hepato-splenomegaly with erythematous rashes in a child. AB - Carbamazepine is an antiepileptic drug. In clinical trials the total incidence of reported adverse reaction to this drug is 4.5 per million at defined daily doses, corresponding to 2.7 per million at prescribed daily doses. Among the adverse reactions of carbamazepine, most often reported are skin reactions (48%), hematological (14%), hepatic disorder (10%). Herein, we present a case with erythematous skin rashes and hepato-splenomegaly. PMID- 22529493 TI - Toxic Epidermal Necrolysis induced by rarely implicated drugs. AB - Toxic Epidermal Necrolysis (TEN) and Steven-Johnson Syndrome (SJS) are serious disorders commonly caused as idiosyncratic reactions to drugs, the most common ones being oxicams, anticonvulsants, allopurinol, and sulfonamides. We present a case of TEN in a patient who developed the lesions after ingesting multiple drugs including paracetamol, metoclopramide, antihistamines, and multivitamins. These drugs have rarely been implicated in this disorder. The suspected drugs in this case were paracetamol and metoclopramide. However, the role of other drugs could not be ruled out definitely. The patient was managed with antibiotics, corticosteroids, and parenteral fluids and recovered well. PMID- 22529494 TI - Students' performance in written and viva-voce components of final summative pharmacology examination in MBBS curriculum: A critical insight. PMID- 22529492 TI - Severe hypercalcemia due to teriparatide. AB - Osteoporosis that is by far the most common metabolic bone disease, has been defined as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. Anabolic therapy with teriparatide, recombinant human parathyroid hormone (PTH 1-34), stimulates bone formation and resorption and improves trabecular and cortical microarchitecture. Teriparatide is indicated for the treatment of men and postmenopausal women with osteoporosis who are at high risk for fracture, including those who have failed or are intolerant of previous osteoporosis therapy. In conclusion, although teriparatide seems quite effective in the treatment of osteoporosis, it may cause life-threatening hypercalcemia. Therefore, patients should be closely monitored if symptoms of hypercalcemia are present during teriparatide treatment. Sustained hypercalcemia due to teriparatide treatment can not be seen in literature so we wanted to emphasize that severe hypercalcemia may develop due to teriperatide. PMID- 22529495 TI - Meropenem-induced hypokalemia and metabolic alkalosis. PMID- 22529496 TI - In vitro antioxidant and anti-inflammatory potential of Polyalthia longifolia in rats. PMID- 22529497 TI - Single dose cefazolin plus metronidazole versus existing multi-dose regimen for prophylaxis in caesarean section. PMID- 22529498 TI - Ethical dilemmas in dentistry. PMID- 22529499 TI - A comparison of axillary with rectal thermometry in under 5 children. AB - BACKGROUND: Body temperature measurement is a crucial clinical assessment in the care of an acutely ill child, especially the under fives. Most temperature measurements in our hospital are done from the axilla. OBJECTIVE: To study the relationship between temperatures taken in the axilla with those taken in the rectum in febrile and afebrile children less than 5 years. MATERIALS AND METHODS: Rectal and axillary temperatures were taken concurrently in 400 febrile and 400 afebrile children aged less than 5 years using mercury-in-glass thermometers. RESULT: The rectal temperature measurements ranged from 38.0 to 41.4 degrees C and 36.4 to 37.9 degrees C in the febrile and afebrile groups of children respectively while the axillary temperatures ranged from 36.7 to 41.0 degrees C and 35.9 to 37.5 degrees C in the febrile and afebrile groups of children, respectively. There were significant differences between the temperatures measured at the two sites in all the age groups studied. There was good positive correlation between the rectal and axillary temperatures. A linear relationship between axillary and rectal temperatures was derived using the simple regression analysis. The equation is: rectal temperature = 0.94*axillary temperature+2.92. CONCLUSION: Although there's good correlation between axillary and rectal temperatures, significant difference exits between them that cannot be explained by the addition of any single value or any particular equation. PMID- 22529500 TI - Benign breast lesions in an African population: A 25-year histopathological review of 1864 cases. AB - OBJECTIVE: The objective of this study was to delineate the prevalence and characterize the histologic pattern of benign breast diseases (BBDs) in the University of Benin Teaching Hospital, Benin City, Nigeria. MATERIALS AND METHODS: A 25-year-old (1985-2009) retrospective study of all patients presenting with BBD. RESULTS: During the 25-year-old study period, 1864 cases of BBD constituting 72.4% of all breast lesions were seen. The female to male ratio was 28.6:1. An increasing incidence of BBDs was observed. The overall mean age for BBD was 27.5 years, SD+/-11.3 with an age range of 9-84 years and a peak age occurrence in the third decade. The single most common lesion was fibroadenoma accounting for 43.1% of cases, followed by fibrocystic change (23.8%) with mean ages of 22.3 years and 30.2 years, respectively. Both lesions had a peak occurrence in the third decade. Other major lesions encountered were sclerosing adenosis (7.3%), atypical ductal hyperplasia (3.6%), and blunt duct adenosis (2.3%). Gynecomastia (2.1%) was the predominant lesion in males. Inflammatory lesions constituted 8.1% of cases while stromal and skin lesions accounted for 1.1% and 0.9% of cases respectively. CONCLUSION: BBDs constituted 70% of breast lumps and were mostly fibroadenoma and fibrocystic change. BBDs occurred predominantly in young females with a peak in the third decade. Though premalignant lesions of atypical hyperplasia were less common, biopsy of all BBDs should be done to exclude these lesions and routine mammographic screening of at risk individuals instituted to increase their detection. PMID- 22529501 TI - Histological study of smoke extract of Tobacco nicotiana on the heart, liver, lungs, kidney, and testes of male Sprague-Dawley rats. AB - BACKGROUND: Some of the effects of tobacco on man's health are well documented in many scientific reports. Whenever tobacco is used either in smoked or chewed form, nicotine is absorbed by the lungs and oral cavity and is spontaneously moved into the bloodstream where it is circulated throughout the body system. MATERIALS AND METHODS: Ten male Sprague-Dawley rats were used for this investigation. The animals were randomly assigned into two groups, A and B, of five animals each. The animals in group B (treatment group) were exposed to smoke from a completely burnt 0.74 g leaf extract of Tobacco nicotiana, wrapped in 0.5 g of sterilized cotton wool for 5 minutes three times daily (7 am, 10 am, and 1 pm). The animals in group A (control group) were exposed to smoke from completely burnt 1.24 g of sterilized cotton wool with the same parameters as observed with the treatment groups. The duration of exposure was 5 days. Three hours after the last exposure, all the animals were killed by cervical dislocation. The heart, liver, lungs, kidney, and testes were carefully excised, blotted dry, and fixed in formol saline for histological analysis using Hematoxylin and Eosin stain. RESULTS: Using the light microscope, it was observed that the histoarchitectural profiles of the studied organs in the sections obtained from the control animals were well preserved. Histopathological observations of the heart, liver, lungs, kidney, and testes in the treated animals showed a varying pattern of histological alterations, and distortions such as mild edema and occasional destruction of myocardial fibers, degeneration of the hepatocytes, reduction in the population of the germ cells, enlargement of the alveoli, alveolar hemorrhage, shrinkage of the glomerulus and glomerular hemorrhage were observed in the sections of the organs of the study of the animals in the treatment group when compared with the control group, hence showing that the smoke extract of Tobacco nicotiana has adverse and compromising effects on the heart, liver, lungs, kidney, and testes of male Sprague-Dawley rats. CONCLUSION: From these observations, it can be inferred that the exposure of male Sprague-Dawley rats to the smoke extract of Tobacco nicotiana may be associated with structural damage of some vital organs. PMID- 22529502 TI - Hydatidiform mole in Jos, Nigeria. AB - BACKGROUND: Hydatidiform mole is a relatively common gynecological problem which could present like spontaneous abortion, one of the commonest gynecological emergencies. It has the propensity to become malignant but can easily be identified and treated. The aim of this study was to determine the demographics, clinical features, treatment options and outcome of patients with hydatidiform mole in our environment. MATERIALS AND METHODS: This was a retrospective review of all the cases of hydatidiform mole seen at the Jos University Teaching Hospital (JUTH), Jos, Nigeria over a 5-year period. RESULTS: There were 34 cases of hydatidiform mole giving an incidence of 1 in 357 deliveries. However only 25 case notes were available for analysis and the mean age of patients was 28+/-3 years. Vaginal bleeding (92%), honeycomb appearance on ultrasound scan (84%), and passage of vesicles (60%) were the most common clinical findings while suction curettage was the mode of treatment for all the patients in this study. Twenty eight percent of cases were confirmed by histology. No patient came for follow-up after the third month of diagnosis. Twenty percent of the patients booked for antenatal care within 9 months of diagnosis while 12% of patients presented as gynecological emergencies with features of malignant disease within six months of diagnosis. CONCLUSION: Hydatidiform mole is common in Jos, North Central Nigeria, and presents most commonly with vaginal bleeding with over 10% becoming malignant. Hence all patients who present with vaginal bleeding should be screened for HM. None of the patients completed the recommended duration of follow-up and only about 1/4 had histology reports. Concerted efforts need to be made to address the challenges of patients adhering to recommended follow-up protocols and having to pay first before investigations are done. PMID- 22529503 TI - Donor blood procurement and the risk of transfusion transmissible viral infections in a tertiary health facility in South-South Nigeria. AB - BACKGROUND: Blood and blood products are scarce commodities. The demand often outweighs the supply. This study is directed at investigating the blood procurement sources and the risk of viral transfusion transmissible infection. MATERIALS AND METHODS: The records of the blood transfusion unit of a tertiary health facility in south-south Nigeria were studied. The procurement and screening records from 1 January to 31 December 2009 were analyzed. RESULTS: 7,552 donor records were analyzed, 6,931 were commercial donor and 621 replacement donors. 891 commercial donors were infected, 500 (7.2%) were HIV positive, 323 (4.7%) HBV positive, 42 (0.6%) had HIV and HBV co-infection, while 28 (0.4%) were HCV positive. Twenty-three replacement donors were infected, 16 (2.6%) were HIV positive, 6 (1%) were HBV positive, while 1 (0.2%) were HCV positive. None of the replacement donors had co-infection. The risk of infection was significantly higher with commercial donor procurement (X2=45.07, P<0.001, OD=3.845). CONCLUSION: Commercial blood donors are still the major source of blood to the hospital and they also have the highest prevalence of transfusion transmissible viral infections in this region thus constitute a major risk transmitting infections to potential recipients. PMID- 22529504 TI - Rupture of the gravid uterus in a tertiary health facility in the Niger delta region of Nigeria: A 5-year review. AB - BACKGROUND: Ruptured uterus is a major life-threatening condition encountered mostly in developing countries and is an index of failure of obstetric care at a point in time in a woman's reproductive career. With worsening economic condition, increasing caesarean section rates, and patients' aversion for operative delivery this condition would still remain a major obstetric matter for discussion. OBJECTIVE: To identify the incidence, sociodemographic variables, clinical characteristics, causes, and outcome of ruptured uterus at the University of Port Harcourt Teaching Hospital. MATERIALS AND METHODS: A 5-year retrospective study of cases of ruptured uterus at the University of Port Harcourt Teaching Hospital was carried out. The case notes of 40 patients with uterine rupture during the period 2003-2007 were analyzed. Data collected included sociodemographic characteristics, etiologic factors, clinical presentation, and outcome. Data were analyzed using Microsoft Excel version 2007 and SPSS 14.0 computer software. RESULTS: The incidence of rupture of the gravid uterus was 1:258 deliveries. In patients with rupture of the gravid uterus, 65% (26) of patients were unbooked; 37.5% (15) were aged between 25 and 29 years. A total of 42.5% (17) of patients had secondary education and 21 (52.5%) were housewives. Rupture of a previous scar was the commonest etiologic factor accounting for 32.5% (11). The commonest presentation was abdominal pain in 92.5% of cases. Perinatal mortality and maternal mortality were 80% and 17.5% respectively. CONCLUSION: Rupture of the gravid uterus still remains a major cause of maternal mortality. Injudicious use of oxytocics should be discouraged in peripheral health facilities and reinforcement of the need for hospital based deliveries in patients with previous caesarean sections should also be intensified to improve outcome. PMID- 22529505 TI - The role of prophylactic antimalarial in the reduction of placental parasitemia among pregnant women in Calabar, Nigeria. AB - INTRODUCTION: Intermittent preventive treatment of malaria with sulfadoxine pyrimethamine is a recommendation of the World Health Organization as part of the malaria control strategy in pregnancy in areas with malaria burden. AIM: This study set out to appraise the effectiveness of this regimen in the prevention of placental parasitemia among parturients in Calabar, Nigeria. MATERIALS AND METHODS: Pretested, precoded questionnaires were administered to eligible women at the antenatal clinic and later updated at the labor ward. Intermittent preventive treatment was administered under direct observation at the clinic, while packed cell volume, placental parasitemia, and other laboratory tests were measured at the labor ward. RESULTS: The gross presence of placental malaria in the intermittent preventive treatment (IPT)-treated and the control groups was 10.6% and 11.3% respectively (P=0.76). Anemia occurred in 3.1% of the IPT-treated group compared to 11.7% among the control group (P=0.000). Only 7.9% of the IPT treated women had moderate to severe placental parsitemia whereas as many as 53.2% of women in the control group had moderate to severe parasitemia (P=0.000). CONCLUSION: Intermittent preventive treatment of malaria with sulfadoxine pyrimethamine was associated with significant reduction in the degree of placental parasitemia among women in the IPT-treated group, although it did not completely eradicate placental malaria in the treatment group. PMID- 22529506 TI - Hospital-acquired infections in a Nigerian tertiary health facility: An audit of surveillance reports. AB - BACKGROUND: Hitherto efforts to implement data driven prevention guidelines for hospital-acquired infections (HAI) in Nigeria have been limited by the inadequate knowledge of the risks of these infections. This study evaluated the occurrence of HAI in a foremost tertiary health facility over a 5-year period for the purpose of reinforcing control efforts. MATERIALS AND METHODS: A retrospective survey of records from the infection control unit of the University College Hospital, Ibadan, Nigeria, was done for the years 2005-09. For the 5 years studied 22,941 in-patients were reviewed and the data of those who developed infections during admission were retrieved and analyzed. The prevalence, types, and causative organisms of HAI were determined. The chi-square test was used to evaluate associations. RESULTS: The prevalence of HAI over the 5-year period was 2.6% (95% CI: 2.4-2.8). Surgical and medical wards had the most infections (48.3%) and (20.5%) respectively. Urinary tract infection (UTI) and surgical site infection (30.7%) were the most prevalent (43.9%) HAI. UTIs were significantly higher in surgical and medical wards, surgical site infections in obstetrics and gynecology wards, and soft tissue infections and bacteremia in pediatric wards (P<0.05). Gram-negative infections occurred about four times as often as gram positive infections with Klebsiella sp. and staphylococcus aureus being the predominant isolates (34.3%) and (20.1%) respectively. CONCLUSION: Efforts to limit HAI should be guided by local surveillance data if progress is to be made in improving the quality of patient care in Nigeria. PMID- 22529508 TI - Socioeconomic consequences of HIV/AIDS in the family system. AB - INTRODUCTION: HIV/AIDS can lead to poverty affecting particularly women and young people and can halt or reverse socioeconomic development of a country. OBJECTIVE: The objective of this study was to assess the socioeconomic consequences of HIV/AIDS within the family. MATERIALS AND METHODS: A cross-sectional descriptive study was carried out among patients admitted in in-patient department and those attending integrated counseling and testing centre (ICTC) of School of Tropical Medicine, Kolkata. Data were gathered by interviewing the patients by using a predesigned questionnaire. RESULTS: For prolonged duration and severity of disease, higher proportion of indoor patients reported loss of job, decreased family income, increased expenditure for care seeking, and faced greater economic consequences, reflected by selling assets. Loss of job was mainly due to illness (86.8%), disclosure of sero-status (13.2%), and predominantly among skilled workers. Assets were sold mainly to meet the cost of own illness for indoor patients, but more to meet the expenditure for husband's illness, in the case of ICTC patients. High school dropout seen in both groups was mainly due to economic reasons. HIV/AIDS status was known to other members of family for 84.8% of indoor patients out of which 15.4% experienced rejection by family members. Out of 72 ever married women indoor patients whose in-laws were aware of their HIV/AIDS status, 41.7%, 40.9%, and 33.33% reportedly were blamed for spouse's illness, and had strained relation with in-laws and spouse, respectively. CONCLUSION: Intensive behavior change communication and provision of care and support are required to curb AIDS-related stigma, discrimination, and to maintain physical, mental, and social wellbeing of people living with HIV/AIDS. PMID- 22529507 TI - Social determinants of alcohol use among drivers in Calabar. AB - OBJECTIVE: Hazardous use of alcohol is a public health problem which accounts for 4.0% of global disease burden. Although the prevalence of alcohol use among drivers of commercial vehicles in Nigeria has been documented, not much is known about its social determinants. This study was, therefore, aimed at assessing the social determinants of alcohol use among drivers of commercial vehicles in Calabar. MATERIALS AND METHODS: A cross-sectional descriptive study was conducted among 360 male commercial drivers. A semistructured questionnaire, which included the World Health Organization Alcohol Use Disorders Identification Test, was administered at interview. Binary and multinomial logistic regression analyses were used to identify social determinants of any and hazardous alcohol use. RESULTS: Determinants of any alcohol use (binary logistic) were history of use by parents (adjusted odds ratios (AOR)=2.7; 95% CI=1.1-6.3), friends (AOR=3.2; 95% CI=1.3-7.8) and ready availability (AOR=4.1; 95% CI=1.9-8.8) while determinants of hazardous use (multinomial logistic) were history of use by parents (AOR=5.8; 95% CI=2.0-16.9), siblings (AOR=7.0; 95% CI=2.6-16.9), friends (AOR=6.6; 95% CI=1.8-24.4), hostile upbringing environment (AOR=3.8; 95% CI=1.3-11.1), use of other drugs (AOR=55.6, 95% CI=14.5-200), and respondents who had fathers with a maximum of primary or no formal education (AOR=4.6; 95% CI=1.8-11.8). CONCLUSION: Alcohol use was associated with family use, friends' use, and use of other drugs. Multiple health education interventions are needed to tackle these challenges. PMID- 22529509 TI - Does concern about halitosis influence individual's oral hygiene practices? AB - OBJECTIVE: The objective of this study was to assess whether the concern about halitosis influence oral health attitude and practices among young literate adults in Nigeria. MATERIALS AND METHODS: This cross-sectional survey of 400 randomly selected temporary camp resident adults in Anambra state, South Eastern Nigeria was conducted using a modified version of the Hiroshima University-Dental Behavioral Inventory questionnaire. RESULTS: Out of the 400 questionnaires distributed, only 294 were filled and returned giving an overall response rate of 73.5%. Half (50.0%) of the participants in this study expressed concern about halitosis. The participants that expressed concern about halitosis were mostly in the 25- to 27-year-old age group, females, known smoker, regular dental floss, and mouth wash users, had incorrect tooth brushing knowledge, brushed teeth more frequently and more forcefully, had no previous dental treatment, prefer symptomatic dental visit, experienced gingival bleeding, expressed worry about the color of their gingiva and teeth but were satisfied with the dental appearance. CONCLUSION: Data from this study showed that concerns about halitosis triggered behavioral reaction in oral self-care practices namely tooth brushing frequency, tooth brushing force, mouth wash, and dental floss use. Also revealed were poorer oral health and lower preventive dental visit practices among participants concerned about halitosis. There is need for improved public knowledge and awareness about halitosis by the dentist in Nigeria. PMID- 22529510 TI - An audit of 3859 preadmission chest radiographs of apparently healthy students in a Nigerian Tertiary Institution. AB - BACKGROUND: Chest radiographs are routinely requested as part of the medical screening process prior to admission to institutions. Literature on the yield of such an exercise is sparse especially in the Nigerian setting. This study was therefore carried out to assess the usefulness of routine chest radiography for students at the time of admission. MATERIALS AND METHODS: This was a prospective study of 3859 chest X-rays taken at the department of radiology, University of Benin Teaching Hospital for one admission screening for the 2008/2009 academic year. The age and sex of the subjects were also recorded. The heart, lung fields and bony thorax were examined for any abnormality. RESULTS: Out of the 3859 pre admission chest radiographs studied, there were 1951 males or 50.56% and 1908 females or 49.44% subjects. The mean age for males was 21.15+/-3. CONCLUSION: This study has shown that pre-admission routine chest radiography in asymptomatic patients remains a relevant screening tool for medical fitness during admissions into institutions. However because of dangers of exposure to ionizing radiation, we advise that a detailed medical history and physical examination be done to restrict its use to only those subjects with signs and symptoms suggestive of disease. PMID- 22529511 TI - Elective caesarean section in a tertiary hospital in Sokoto, north western Nigeria. AB - BACKGROUND: Elective caesarean sections have been considered safer for both mother and the fetus compared to their emergency counterpart. However, emergency caesarean sections have continued to form bulk of caesarean deliveries in our facility. OBJECTIVE: The objective of this study was to determine the caesarean section rate together with the trend, indications, and maternal mortality associated with elective caesarean operation. MATERIALS AND METHODS: A retrospective analysis of clinical records of all the patients that had caesarean section between January 2002 and December 2010 (9 years) at Usmanu Danfodiyo University Teaching Hospital (UDUTH) Sokoto, Nigeria was conducted. RESULTS: During the 9 year study period, 2284 caesarean sections were performed out of 22,985 total deliveries at UDUTH Sokoto, thus giving a caesarean section rate of 9.9%. Emergency and elective operations accounted for 1784 (78.2%) and 498 (21.8%) of the cases respectively. The rate of elective caesarean section increased from 1.7% in 2002 to 3.2% in 2007. Thereafter it declined gradually to 1.8% in 2010. Repeat caesarean section (30.7%) and malpresentation (17.1%) were the most common indications for elective caesarean operation. There were 18 maternal deaths from caesarean section and only one from the elective caesarean procedure. CONCLUSION: The rising trend in the elective caesarean section rate in this study underscores the need for better and improved patient selection together with counseling on its benefits and risks. This is because despite the fact that it is safer than emergency caesarean operation, it is not entirely devoid of complications. Routine use of spinal anesthesia in performing the procedure should be encouraged. PMID- 22529512 TI - Prevalence of intestinal parasites and bacteria among food handlers in a tertiary care hospital. AB - OBJECTIVES: The aim of this work is to determine the prevalence of intestinal parasites and bacteria among the food handlers. MATERIALS AND METHODS: Two hundred food-handlers were subjected to a cross-sectional study working in the kitchen of a tertiary care hospital, i.e., Alnoor Specialist Hospital, Makkah, Saudi Arabia from February 2 to 27, 2009. The stool samples were examined for intestinal parasites following direct microscopic examination, formol ether concentration (Ritchie), and staining with modified acid fast staining techniques. For enteropathogenic bacteria samples were inoculated onto MacConkey's agar, deoxycholate citrate agar, xylose lysine deoxycholate agar as per the World Health Organization protocol. Fingernail materials were examined microscopically for enteropathogenic bacteria and parasites. RESULTS: The majority (80%) of the food-handlers were young adults aged from 22 to 42 years. No intestinal parasites were detected from fingernail contents. Forty six (23%) stool specimens were positive for intestinal para!sites. Giardia lamblia 18 (9%) was most frequent among the 10 different types of detected intestinal parasites followed by Entamoeba histolytica 9 (4.5%). No pathogenic bacteria were detected in all stool samples, whereas finger nails showed isolation of microorganisms as coagulase-negative staphylococci 79 (39.5%), followed by Staphylococcus aureus 35 (17.5%). CONCLUSION: The findings emphasized the importance of food handlers as potential sources of infections and suggested health institutions for appropriate hygienic and sanitary control measures. PMID- 22529514 TI - Finding maurice pappworth. PMID- 22529513 TI - Effect of interval training program on white blood cell count in the management of hypertension: A randomized controlled study. AB - OBJECTIVE: Elevated white blood cell (WBC) count is considered to be prospectively and positively associated with cardiovascular diseases, particularly hypertension. Also, the positive role of exercise in the management of hypertension has been well and long established. However the relationship between WBC count and hypertensive management particularly in the nonpharmacological technique is ambiguous and unclear. Therefore the purpose of the present study was to determine the effect of interval training program on WBC count and cardiovascular parameters in male hypertensive patients. MATERIALS AND METHODS: A total of 245 male patients with mild to moderate (systolic blood pressure (SBP) between 140 mmHg and 179 mmHg and diastolic blood pressure (DBP) between 90 mmHg and 109 mmHg) essential hypertension were age matched and grouped into experimental and control groups. The experimental (n=140; 58.90+/-7.35 years) group involved in an 8-week interval training (60-79% HR max reserve) program of between 45 minutes to 60 minutes, while the age-matched controls hypertensive (n=105; 58.27+/-6.24 years) group remain sedentary during this period. Cardiovascular parameters (SBP, DBP, and VO(2) max) and WBC count were assessed. Student's t and Pearson correlation tests were used in data analysis. RESULTS: Findings of the study revealed a significant effect of the interval training program on VO2max, SBP, and DBP and WBC count at P<0.05 and VO2max is negatively related to the WBC count (r=-0.339) at P<0.01. CONCLUSIONS: It was concluded that the interval training program is an effective adjunct nonpharmacological management of hypertension and the therapeutic effect of exercise programs may be mediated through suppression of inflammatory (WBC count) reaction. PMID- 22529516 TI - Systemic inflammatory effects of traumatic brain injury, femur fracture, and shock: an experimental murine polytrauma model. AB - OBJECTIVE: Despite broad research in neurotrauma and shock, little is known on systemic inflammatory effects of the clinically most relevant combined polytrauma. Experimental investigation in an animal model may provide relevant insight for therapeutic strategies. We describe the effects of a combined injury with respect to lymphocyte population and cytokine activation. METHODS: 45 male C57BL/6J mice (mean weight 27 g) were anesthetized with ketamine/xylazine. Animals were subjected to a weight drop closed traumatic brain injury (WD-TBI), a femoral fracture and hemorrhagic shock (FX-SH). Animals were subdivided into WD TBI, FX-SH and combined trauma (CO-TX) groups. Subjects were sacrificed at 96 h. Blood was analysed for cytokines and by flow cytometry for lymphocyte populations. RESULTS: Mortality was 8%, 13% and 47% for FX-SH, WD-TBI and CO-TX groups (P < 0.05). TNFalpha (11/13/139 for FX-SH/WD-TBI/CO-TX; P < 0.05), CCL2 (78/96/227; P < 0.05) and IL-6 (16/48/281; P = 0.05) showed significant increases in the CO-TX group. Lymphocyte populations results for FX-SH, WD-TBI and CO-TX were: CD-4 (31/21/22; P = n.s.), CD-8 (7/28/34, P < 0.05), CD-4-CD-8 (11/12/18; P = n.s.), CD-56 (36/7/8; P < 0.05). CONCLUSION: This study shows that a combination of closed TBI and femur-fracture/ shock results in an increase of the humoral inflammation. More attention to combined injury models in inflammation research is indicated. PMID- 22529517 TI - The effect of conventional and mini-invasive cardiopulmonary bypass on neutrophil activation in patients undergoing coronary artery bypass grafting. AB - Interleukin-10 (IL-10) is considered to be a cytokine with potent anti inflammatory properties, which have been previously linked to increased incidence of sepsis. The level of IL-10 is elevated by cardiac surgery when cardiopulmonary bypass (CPB) and methylprednisolone are used. In our study, we compare the level of IL-10, IL-10 Receptor (IL-10R), and percentage of neutrophils between two groups of cardiac surgical patients undergoing Coronary Artery Bypass Grafting, both of which were not given methylprednisolone. The first group was operated with conventional CPB, while the second group was operated with minimally invasive CPB (mini-CPB). We detected enhanced level of IL-10 during surgery and at the end of surgery in both groups of patients. While no correlation between IL 10 and IL10R was found, IL-10 was positively correlated with increased percentage of neutrophils at the time points when the level of IL-10 peaked. PMID- 22529515 TI - Pathogenesis of abdominal aortic aneurysms: role of nicotine and nicotinic acetylcholine receptors. AB - Inflammation, proteolysis, smooth muscle cell apoptosis, and angiogenesis have been implicated in the pathogenesis of abdominal aortic aneurysms (AAAs), although the well-defined initiating mechanism is not fully understood. Matrix metalloproteinases (MMPs) such as MMP-2 and -9 and other proteinases degrading elastin and extracellular matrix are the critical pathogenesis of AAAs. Among the risk factors of AAAs, cigarette smoking is an irrefutable one. Cigarette smoke is practically involved in various aspects of the AAA pathogenesis. Nicotine, a major alkaloid in tobacco leaves and a primary component in cigarette smoke, can stimulate the MMPs expression by vascular SMCs, endothelial cells, and inflammatory cells in vascular wall and induce angiogenesis in the aneurysmal tissues. However, for the inflammatory and apoptotic processes in the pathogenesis of AAAs, nicotine seems to be moving in just the opposite direction. Additionally, the effects of nicotine are probably dose dependent or associated with the exposure duration and may be partly exerted by its receptors--nicotinic acetylcholine receptors (nAChRs). In this paper, we will mainly discuss the pathogenesis of AAAs involving inflammation, proteolysis, smooth muscle cell apoptosis and angiogenesis, and the roles of nicotine and nAChRs. PMID- 22529518 TI - Zerumbone attenuates the severity of acute necrotizing pancreatitis and pancreatitis-induced hepatic injury. AB - This paper investigated the potential effects of zerumbone pretreatment on an acute necrotizing pancreatitis rat model induced by sodium taurocholate. The pancreatitis injury was evaluated by serum AMY, sPLA2, and pancreatic pathological score. Pancreatitis-induced hepatic injury was measured by ALT, AST, and hepatic histopathology. The expression of I-kappaBalpha and NF-kappaB protein was evaluated by western blot and immunohistochemistry assay while ICAM-1 and IL 1beta mRNA were examined by RT-PCR. The results showed that AMY, sPLA2, ALT, and AST levels and histopathological assay of pancreatic and hepatic tissues were significantly reduced following administration of zerumbone. Applying zerumbone also has been shown to inhibit NF-kappaB protein and downregulation of ICAM-1 and IL-1beta mRNA. The present paper suggests that treatment of zerumbone on rat attenuates the severity of acute necrotizing pancreatitis and pancreatitis induced hepatic injury, via inhibiting NF-kappaB activation and downregulating the expression of ICAM-1 and IL-1beta. PMID- 22529519 TI - LPS counter regulates RNA expression of extracellular proteases and their inhibitors in murine macrophages. AB - Besides their evident importance in host defense, macrophages have been shown to play a detrimental role in different pathological conditions, including chronic inflammation, atherosclerosis, and cancer. Regardless of the exact situation, macrophage activation and migration are intimately connected to extracellular matrix degradation. This process is accomplished by multiple proteolytic enzymes, including serine proteases and members of the matrix metalloproteinase family. In this study, we have utilized qPCR arrays to simultaneously analyze the temporal expression pattern of a range of genes involved in extracellular matrix metabolism in the mouse derived-macrophage cell line RAW 264.7 following stimulation with LPS. Our results revealed that LPS induces the expression of matrix metalloproteinases while at the same time decreased the expression of matrix metalloproteinase inhibitors. The opposite scenario was found for the genes encoding serine proteases, which were downregulated while their inhibitors were upregulated. In addition, intergenic comparison of the expression levels of related proteases revealed large differences in their basal expression level. These data highlight the complexity of the gene expression regulation implicated in macrophage-dependent matrix degradation and furthermore emphasize the value of qPCR array techniques for the investigation of the complex regulation of the matrix degradome. PMID- 22529520 TI - Lactoferrin levels in the gastric tissue of Helicobacter pylori-positive and negative patients and its effect on anemia. AB - AIM: To determine gastric tissue lactoferrin (Lf) levels of Helicobacter pylori- (Hp-) positive and -negative patients and its effect on anemia. METHODS: Cases in which initial presentation was of abdominal pain and that were Hp-positive at endoscopy were included. Hp-positive cases and -negative controls were divided into two groups. RESULTS: The study included 64 cases (average: 10.2 +/- 0.4 years, 39 male and 25 female). Lf levels were subsequently studied on 61 cases. 45 (73.8%) of these were Hp-positive, while 16 (22.2%) were Hp-negative. In Hp positive cases, mean staining percentages and density of glands in the antral mucosa were 45.5 +/- 4.7% and 1.9 +/- 0.1, respectively. Hp-negative cases showed significantly different values of 17.8 +/- 4.5% and 1.3 +/- 0.2, respectively. Hemoglobin and serum ferritin values of Hp-positive cases were 12.7 +/- 0.2 g/dL and 32.5 +/- 2 ng/mL, but these were comparable with Hp-negative cases (12.6 +/- 0.1 g/dL and 30.7 +/- 4.4 ng/mL). CONCLUSIONS: Tissue Lf was significantly higher in Hp-positive cases compared to Hp-negative cases, but no difference was observed between the two groups with regards to hemoglobin and ferritin level. As a result, it is difficult to say that this rise in Lf plays a role in the development of iron deficiency anemia in Hp-positive patients. PMID- 22529521 TI - The absence of Nrf2 enhances NF-kappaB-dependent inflammation following scratch injury in mouse primary cultured astrocytes. AB - It has been proved that Nrf2 depletion enhances inflammatory process through activation of NF-kappaB in the brain after TBI, but little is known about the relationship between Nrf2 and NF-kappaB in astrocytes after TBI. Hence, we used primary cultured astrocytes from either Nrf2 wildtype or knockout mice to study the influence of Nrf2 on the activation of NF-kappaB and expression of proinflammatory cytokines in a model of TBI in vitro. Primary cultured astrocytes were scratched to mimic the traumatic injury in vitro. Then the DNA-binding activity of NF-kappaB was evaluated by EMSA. The mRNA and protein levels of TNF alpha, IL-1beta, IL-6, and MMP9 were also evaluated. Gelatin zymography was performed to detect the activity of MMP9. The activity of NF-kappaB and expression of proinflammatory cytokines mentioned above were upregulated at 24 h after scratch. The expression and activity of MMP9 were also elevated. And such tendency was much more prominent in Nrf2 KO astrocytes than that in WT astrocytes. These results suggest that the absence of Nrf2 may induce more aggressive inflammation through activation of NF-kappaB and downstream proinflammatory cytokines in astrocytes. PMID- 22529522 TI - Essential role of mast cells in the visceral hyperalgesia induced by T. spiralis infection and stress in rats. AB - Mast cells (MCs) deficient rats (Ws/Ws) were used to investigate the roles of MCs in visceral hyperalgesia. Ws/Ws and wild control (+/+) rats were exposed to T. spiralis or submitted to acute cold restraint stress (ACRS). Levels of proteinase activated receptor 2 (PAR2) and nerve growth factor (NGF) were determined by immunoblots and RT-PCR analysis, and the putative signal pathways including phosphorylated extracellular-regulated kinase (pERK1/2) and transient receptor potential vanilloid receptor 1 (TRPV1) were further identified. Visceral hyperalgesia triggered by ACRS was observed only in +/+ rats. The increased expression of PAR2 and NGF was observed only in +/+ rats induced by T. spiralis and ACRS. The activation of pERK1/2 induced by ACRS occurred only in +/+ rats. However, a significant increase of TRPV1 induced by T. spiralis and ACRS was observed only in +/+ rats. The activation of PAR2 and NGF via both TRPV1 and pERK1/2 signal pathway is dependent on MCs in ACRS-induced visceral hyperalgesia rats. PMID- 22529523 TI - Biomarkers of subclinical atherosclerosis in patients with autoimmune disorders. AB - Atherosclerosis is accelerated in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). We investigated a possible association of oxidized low-density lipoproteins (ox-LDLs), nitric oxide (NO), 3-nitrotyrosine, vitamin A, vitamin E, and beta-carotene serum levels with subclinical atherosclerosis in RA and PsA. By the use of ELISA, we observed higher ox-LDL levels in patients with intima-media thickness (IMT) > 1 than in patients with IMT <= 1 and a negative correlation between NO levels and IMT values. By the use of high-performance liquid chromatography, we determined higher levels of vitamin A in patients with PsA and IMT <= 1 than in controls and lower levels of beta-carotene in patients with RA and PsA than in controls. beta-carotene concentrations were negatively correlated to the duration of disease in RA. Our study confirms that ox-LDLs and NO may be markers of accelerated atherosclerosis in RA and PsA whereas vitamins seem to be associated only to the presence of the autoimmune disorders. PMID- 22529524 TI - The anti-inflammatory cytokine, interleukin-10, inhibits inflammatory mediators in human epithelial cells and mouse macrophages exposed to live and UV inactivated Chlamydia trachomatis. AB - Chlamydia trachomatis infects macrophages and epithelial cells evoking acute and chronic inflammatory conditions, which, if not controlled, may put patients at risk for major health issues such as pelvic inflammatory disease, chronic abdominal pain, and infertility. Here we hypothesized that IL-10, with anti inflammatory properties, will inhibit inflammatory mediators that are produced by innate immune cells exposed to C. trachomatis. We used human epithelial (HeLa) cells and mouse J774 macrophages as target cells along with live and UV inactivated C. trachomatis mouse pneumonitis (MoPn) as stimulants. Confocal microscopy employing an anti-Chlamydia antibody confirmed cells infectivity by day 1, which persisted up to day 3. Kinetics studies revealed that live C. trachomatis induced TNF, IL-6, and IL-8, as a function of time, with day-2 infection inducing the highest cytokine levels. Exogenous IL-10 inhibited TNF, IL 6, and IL-8 as secreted by day-2 infected cells. Similarly, IL-10 diminished cytokine levels as produced by macrophages exposed to UV-inactivated Chlamydia, suggesting the IL-10-mediated inhibition of cytokines is not restricted to live organisms. Our data imply that IL-10 is an important regulator of the initial inflammatory response to C. trachomatis infection and that further investigations be made into IL-10 use to combat inflammation induced by this bacterium. PMID- 22529525 TI - Circulating leukotriene B4 identifies respiratory complications after trauma. AB - BACKGROUND: Leukotriene B4 (LTB4), a proinflammatory lipid mediator correlates well with the acute phase of Acute Respiratory Distress Syndrome (ARDS). Therefore, LTB4-levels were investigated to determine whether they might be a useful clinical marker in predicting pulmonary complications (PC) in multiply traumatized patients. METHODS: Plasma levels of LTB4 were determined in 100 patients on admission (ED) and for five consecutive days (daily). Twenty healthy volunteers served as control. LTB4-levels were measured by ELISA. Thirty patients developed PC (pneumonia, respiratory failure, acute lung injury (ALI), ARDS, pulmonary embolism) and 70 had no PC (OPC). RESULTS: LTB4-levels in the PC-group [127.8 pg/mL, IQR: 104-200pg/ml] were significantly higher compared to the OPC group on admission [95.6 pg/mL, IQR: 55-143 pg/mL] or control-group [58.4 pg/mL, IQR: 36-108 pg/mL]. LTB4 continuously declined to basal levels from day 1 to 5 without differences between the groups. The cutoff to predict PC was calculated at 109.6 pg/mL (72% specificity, 67% sensitivity). LTB4 was not influenced by overall or chest injury severity, age, gender or massive transfusion. Patients with PC received mechanical ventilation for a significantly longer period of time, and had prolonged intensive care unit and overall hospital stay. CONCLUSION: High LTB4-levels indicate risk for PC development in multiply traumatized patients. PMID- 22529526 TI - Reduced plasma nonesterified fatty acid levels and the advent of an acute lung injury in mice after intravenous or enteral oleic acid administration. AB - Although exerting valuable functions in living organisms, nonesterified fatty acids (NEFAs) can be toxic to cells. Increased blood concentration of oleic acid (OLA) and other fatty acids is detected in many pathological conditions. In sepsis and leptospirosis, high plasma levels of NEFA and low albumin concentrations are correlated to the disease severity. Surprisingly, 24 h after intravenous or intragastric administration of OLA, main NEFA levels (OLA inclusive) were dose dependently decreased. However, lung injury was detected in intravenously treated mice, and highest dose killed all mice. When administered by the enteral route, OLA was not toxic in any tested conditions. Results indicate that OLA has important regulatory properties on fatty acid metabolism, possibly lowering circulating fatty acid through activation of peroxisome proliferator-activated receptors. The significant reduction in blood NEFA levels detected after OLA enteral administration can contribute to the already known health benefits brought about by unsaturated-fatty-acid-enriched diets. PMID- 22529527 TI - Association of mitral annulus calcification with high-sensitivity C-reactive protein, which is a marker of inflammation. AB - OBJECTIVES: There are limited clinical data revealing the relationship between mitral annular calcification (MAC) and systemic inflammation. The goal of the present study was to compare high-sensitivity C-reactive protein (hs-CRP) levels in patients with and without MAC and investigate the relationship between MAC and hs-CRP. METHODS: One hundred patients with MAC who underwent transthoracic echocardiography (TTE) and 100 age-matched controls without MAC who underwent TTE were included in our study. Hs-CRP levels were compared between groups. RESULTS: Prevalence of female gender, hypertension, and coronary artery disease were significantly higher in the MAC group than in the control group (64% versus 45%, P = 0.007, 42% versus 28%, P = 0.03 and 37% versus 18%, P = 0.003, resp.). On multivariate analysis, age, gender, and coronary artery disease were the only independent predictors of MAC. The levels of hs-CRP were higher in the MAC group than in the control group (2.02 +/- 0.35 versus 1.43 +/- 0.47 mg/dl, P < 0.001). This increase in hs-CRP levels in the MAC group persisted in patients without hypertension, coronary artery disease, and in male patients when compared to the control group. CONCLUSIONS: Our study demonstrated that hs-CRP, which is a sensitive marker of systemic inflammation, increased in patients with MAC. PMID- 22529528 TI - Role of PGE2 in asthma and nonasthmatic eosinophilic bronchitis. AB - Eosinophilic bronchitis is a common cause of chronic cough, which like asthma is characterized by sputum eosinophilia, but unlike asthma there is no variable airflow obstruction or airway hyperresponsiveness. Several studies suggest that prostaglandins may play an important role in orchestrating interactions between different cells in several inflammatory diseases such as asthma. PGE(2) is important because of the multiplicity of its effects on immune response in respiratory diseases; however, respiratory system appears to be unique in that PGE(2) has beneficial effects. We described that the difference in airway function observed in patients with eosinophilic bronchitis and asthma could be due to differences in PGE(2) production. PGE(2) present in induced sputum supernatant from NAEB patients decreases BSMC proliferation, probably due to simultaneous stimulation of EP2 and EP4 receptors with inhibitory activity. This protective effect of PGE(2) may not only be the result of a direct action exerted on airway smooth-muscle proliferation but may also be attributable to the other anti-inflammatory actions. PMID- 22529529 TI - Peripheral leukocytapheresis attenuates acute lung injury induced by lipopolysaccharide in vivo. AB - The mortality of acute lung injury and acute respiratory distress syndrome (ALI/ARDS) remains high and efforts for prevention and treatments have shown little improvement over the past decades. The present study investigated the efficacy and mechanism of leukocytapheresis (LCAP) to partially eliminate peripheral neutrophils and attenuate lipopolysaccharide (LPS)-induced lung injury in dogs. A total of 24 healthy male mongrel dogs were enrolled and randomly divided into LPS, LCAP and LCAP-sham groups. All animals were injected with LPS to induce endotoxemia. The serum levels of leucocytes, neutrophil elastase, arterial blood gas, nuclear factor-kappa B (NF-kappaB) subunit p65 in lung tissues were measured. The histopathology and parenchyma apoptosis of lung tissues were examined. We found that 7, 3, and 7 animals in the LPS, LCAP, and sham-LCAP groups, respectively, developed ALI 36 h after LPS infusion. The levels of NF-kappaB p65 in lung tissue, neutrophils and elastase in blood, decreased significantly following LCAP. LCAP also alleviated apoptosis, and NF-kappaB p65 in lung tissues. Collectively, our results show that partial removal of leucocytes from peripheral blood decreases elastase level in serum. This, in turn, attenuates lung injuries and may potentially decrease the incidence of ALI. PMID- 22529531 TI - India without Poliomyelitis: Time to Make it a Reality. PMID- 22529530 TI - Superoxide dismutase 3 limits collagen-induced arthritis in the absence of phagocyte oxidative burst. AB - Extracellular superoxide dismutase (SOD3), an enzyme mediating dismutation of superoxide into hydrogen peroxide, has been shown to reduce inflammation by inhibiting macrophage migration into injured tissues. In inflamed tissues, superoxide is produced by the phagocytic NOX2 complex, which consists of the catalytic subunit NOX2 and several regulatory subunits (e.g., NCF1). To analyze whether SOD3 can regulate inflammation in the absence of functional NOX2 complex, we injected an adenoviral vector overexpressing SOD3 directly into the arthritic paws of Ncf1(*/*) mice with collagen-induced arthritis. SOD3 reduced arthritis severity in both oxidative burst-deficient Ncf1(*/*) mice and also in wild-type mice. The NOX2 complex independent anti-inflammatory effect of SOD3 was further characterized in peritonitis, and SOD3 was found to reduce macrophage infiltration independently of NOX2 complex functionality. We conclude that the SOD3-mediated anti-inflammatory effect on arthritis and peritonitis operates independently of NOX2 complex derived oxidative burst. PMID- 22529532 TI - Health promotion: an effective tool for global health. AB - Health promotion is very relevant today. There is a global acceptance that health and social wellbeing are determined by many factors outside the health system which include socioeconomic conditions, patterns of consumption associated with food and communication, demographic patterns, learning environments, family patterns, the cultural and social fabric of societies; sociopolitical and economic changes, including commercialization and trade and global environmental change. In such a situation, health issues can be effectively addressed by adopting a holistic approach by empowering individuals and communities to take action for their health, fostering leadership for public health, promoting intersectoral action to build healthy public policies in all sectors and creating sustainable health systems. Although, not a new concept, health promotion received an impetus following Alma Ata declaration. Recently it has evolved through a series of international conferences, with the first conference in Canada producing the famous Ottawa charter. Efforts at promoting health encompassing actions at individual and community levels, health system strengthening and multi sectoral partnership can be directed at specific health conditions. It should also include settings-based approach to promote health in specific settings such as schools, hospitals, workplaces, residential areas etc. Health promotion needs to be built into all the policies and if utilized efficiently will lead to positive health outcomes. PMID- 22529533 TI - Connecting the DOTS: Spectre of a Public Health Iatrogenesis? PMID- 22529534 TI - Self-medication patterns and drug use behavior in housewives belonging to the middle income group in a city in northern India. AB - OBJECTIVES: The objective was to assess the self-medication patterns and drug use behavior in housewives belonging to the middle income group in a city of Haryana State in Northern India. MATERIALS AND METHODS: A detailed questionnaire designed to assess the self-medication patterns and drug use behavior and interview technique was used to elicit the requisite information. One hundred housewives of the middle income group were interviewed in Rohtak. RESULTS: Most of the housewives were in the habit of keeping the medicines though only 73% of them were in the habit of using it without any prescription. Also it was seen that those housewives who were taking self-medication were better educated than those not indulged in self-medication. All of them were using allopathic drugs on a regular basis while other modes of medications were less used. The self medication was most commonly based on the previous prescriptions issued by the doctors followed by the suggestions from friends, advertisement on the television, and newspapers. For most of them the reasons for self-medication were financial restraints and lack of time to go to the medical practitioner. CONCLUSIONS: The study delineates the difference in the self-medication patterns and drug use behavior in housewives in a city of Northern India. The results emphasize the need for comprehensive measures for intervention strategies to promote rational drug therapy by improving prescribing patterns and influencing self-medication. PMID- 22529535 TI - Beliefs regarding diet during childhood illness. AB - BACKGROUND: Fifty percent to 70% of the burden of childhood diarrhea and respiratory infections is attributable to undernutrition. It is compounded by food restriction during illness due to false beliefs, leading to a vicious cycle of malnutrition and infection. In the long run, it decreases the child's productivity, which is an obstacle to sustainable socioeconomic development. OBJECTIVES: To assess the dietary practices during different illnesses, to study the role of education, culture and religion in feeding an ill child and to create awareness against detrimental practices. MATERIALS AND METHODS: A cross-sectional study was undertaken among 126 caregivers of ill children using an open-ended pretested questionnaire. Statistical package for social sciences software was used for data analysis. Simple proportions, percentages and Chi-square were used. RESULTS: Caregivers believed that a child must be fed less during illness. Educational status did not play a role in maintaining beliefs, but elders and religion did. Doctors too were responsible for unwanted dietary restrictions. Media did not have an impact in spreading nutrition messages. Decreased breast feeds, initiating bottle feeds, feeding diluted milk and reducing complementary feeds during illness was widely practiced. Calorie intake during illness was very less and statistically significant. Firmly rooted beliefs about "hot" and "cold" foods lead to restriction of food available at home. CONCLUSIONS: Healthy feeding practices were few, and inappropriate ones predominant. Dietary education was overlooked. While planning community-based nutrition programs, firmly rooted beliefs should be kept in mind. Involving the elderly caregivers and mothers actively along with the health workers is the need of the hour. PMID- 22529536 TI - Healthcare-seeking behavior of patients with epileptic seizure disorders attending a tertiary care hospital, kolkata. AB - INTRODUCTION: Neurological diseases are very important causes of prolonged morbidity and disability, leading to profound financial loss. Epilepsy is one of the most important neurological disorders Healthcare seeking by epilepsy patients is quite diverse and unique. AIMS AND OBJECTIVES: The study was conducted among the epilepsy patients, to assess their healthcare-seeking behavior and its determinants. MATERIALS AND METHODS: Three hundred and fifteen epilepsy patients, selected by systematic random sampling, in the neuromedicine outpatient department of a tertiary care hospital were interviewed with a predesigned, pretested, semi-structured proforma. RESULTS AND CONCLUSION: More than 90% sought healthcare just after the onset of a seizure. The majority opted for allopathic medicine and the causes for not seeking initial care from allopaths were ignorance, faith in another system, constraint of money, and so on. A significant association existed between rural residence and low social status of the patients with initial care seeking from someone other than allopaths. No association was found among sex, type of seizure, educational status of the patients, and care seeking. The mean treatment gap was 2.98 +/- 10.49 months and the chief motivators were mostly the family members. Patients for anti epileptic drugs preferred neurologists in urban areas and general practitioners in rural areas. District care model of epilepsy was proposed in the recommendation. PMID- 22529537 TI - A time motion study in the immunization clinic of a tertiary care hospital of kolkata, west bengal. AB - BACKGROUND: A time and motion study is used to determine the amount of time required for a specific activity, work function, or mechanical process. Few such studies have been reported in the outpatient department of institutions, and such studies based exclusively on immunization clinic of an institute is a rarity. MATERIALS AND METHODS: This was an observational cross sectional study done in the immunization clinic of R.G. Kar Medical College, Kolkata, over a period of 1 month (September 2010). The study population included mother/caregivers attending the immunization clinics with their children. The total sample was 482. Pre synchronized stopwatches were used to record service delivery time at the different activity points. RESULTS: Median time was the same for both initial registration table and nutrition and health education table (120 seconds), but the vaccination and post vaccination advice table took the highest percentage of overall time (46.3%). Maximum time spent on the vaccination and post vaccination advice table was on Monday (538.1 s) and nutritional assessment and health assessment table took maximum time on Friday (217.1 s). Time taken in the first half of immunization session was more in most of the tables. CONCLUSION: The goal for achieving universal immunization against vaccine-preventable diseases requires multifaceted collated response from many stakeholders. Efficient functioning of immunization clinics is therefore required to achieve the prescribed goals. This study aims to initiate an effort to study the utilization of time at a certain health care unit with the invitation of much more in depth analysis in future. PMID- 22529538 TI - Community-based study of reproductive tract infections among women of the reproductive age group in the urban health training centre area in hubli, karnataka. AB - BACKGROUND: Reproductive tract infections (RTIs) is a global health problem including both sexually transmitted infections (STIs) and non-sexually transmitted infections (non-STIs) of the reproductive tract. RTI/STI is an important concern, as it possess risk for human immunodeficiency virus transmission. Hence a community study was done in Hubli, in terms of active search of the cases based on the symptoms, clinical examination, and feasible laboratory tests along with providing treatment, counseling, and follow-up. OBJECTIVES: The objective was to know the prevalence of RTIs among the reproductive age group women and the socio-demographic factors influencing the occurrence of the disease. MATERIALS AND METHODS: A cross-sectional study was done using a simple random sampling technique to select households. A pretested structured pro forma was used to collect data on RTIs from 656 women of 15-45 years, residing in the field practice area. This was followed by clinical examination and collection of samples for laboratory tests in Urban Health Training Centre, attached to Karnataka Institute of Medical Sciences, Hubli. RESULTS: The prevalence of RTIs among the reproductive age group women was 40.4% based on their symptoms, with majority having abnormal vaginal discharge. The prevalence of RTIs based on clinical finding was 37.4% with majority having vaginitis. The laboratory test revealed a prevalence of 34.3% with majority having Candidiasis. The influence of socio-demographic factors like increased parity, poor socio-economic conditions, poor menstrual hygiene, illiteracy has its direct effect on occurrence of RTI in the community. CONCLUSION: This depicts that whereever possible, clinical and laboratory findings should support self reported morbidity to know the exact prevalence of any disease in the community. PMID- 22529539 TI - Antibiotic resistance pattern of community acquired uropathogens at a tertiary care hospital in jaipur, rajasthan. AB - BACKGROUND: Urinary tract infections (UTIs) are amongst the most common infections described in outpatients setting. OBJECTIVES: A study was conducted to evaluate the uropathogenic bacterial flora and its antimicrobial susceptibility profile among patients presenting to the out-patient clinics of a tertiary care hospital at Jaipur, Rajasthan. MATERIALS AND METHODS: 2012 consecutive urine specimens from symptomatic UTI cases attending to the outpatient clinics were processed in the Microbiology lab. Bacterial isolates obtained were identified using biochemical reactions. Antimicrobial susceptibility testing was performed by the Kirby-Bauer disc diffusion method. Extended spectrum beta lactamase (ESBL) production was determined by the double disk approximation test and the Clinical and Laboratory Standards Institute (formerly NCCLS) confirmatory method. RESULTS: Pathogens were isolated from 346 (17.16%) of the 2012 patients who submitted a urine sample. Escherichia coli was the most frequently isolated community acquired uropathogen accounting for 61.84% of the total isolates. ESBL production was observed in 23.83% of E. coli strains and 8.69% of Klebsiella strains. With the exception of Nitrofurantoin, resistance to agents commonly used as empiric oral treatments for UTI was quite high. CONCLUSION: The study revealed E. coli as the predominant bacterial pathogen for the community acquired UTIs in Jaipur, Rajasthan. An increasing trend in the production ESBLs among UTI pathogens in the community was noted. Nitrofurantoin should be used as empirical therapy for primary, uncomplicated UTIs. PMID- 22529540 TI - Occupational exposure to human immunodeficiency virus in health care providers: a retrospective analysis. AB - OBJECTIVES: To determine the population at risk, risk factors, and outcome of occupational exposure to blood and body fluids in health care providers. MATERIALS AND METHODS: Retrospective review of two and half year data of ongoing surveillance of occupational exposure to blood and body fluids in a tertiary care hospital. RESULTS: 103 Health Care Providers (HCP) reported an occupational exposure to blood and body fluids during the period under review. These comprised 72 (69.9%) doctors, 20 (19.4%) nursing personnel, and 11 (10.6%) cleaning staff. Of the doctors, 65% were interns. 53.4% HCP had work experience of less than one year. Circumstances of exposure included clinical procedures (48%), sweeping/handling used sharps (29%), recapping (16%), and surgery (6.9%). 74.3% of the exposures were due to non-compliance with universal precautions and were thus preventable. The device most frequently implicated in causing injury was hollow bore needle (n=85, 82.5%). Human Immunodeficiency Virus (HIV) status of the source was positive in 6.8% cases, negative in 53.4% cases, and unknown in remaining 39.8% cases. Postexposure prophylaxis (PEP) was indicated in 100 (97.08%) cases and was initiated within 2 h of exposure in 26.8% HCP. In 23.2% HCP, PEP initiation was delayed beyond 72 h of exposure due to late reporting. Thirteen HCP received expanded and the remaining received basic regime. Of the 82 HCP followed up, 15 completed the full course, while 55 stopped PEP after the first dose due to negative source status. Twelve HCP with exposure to blood of unknown HIV status discontinued PEP despite counseling. Complete follow-up for seroconversion was very poor among the HCP. HIV status at 6 month of exposure is not known for any HCP. CONCLUSIONS: Failure to follow universal precautions including improper disposal of waste was responsible for majority of occupational exposures. HCP need to be sensitized regarding hospital waste management, management of occupational exposure, need for PEP, and continued follow-up. PMID- 22529541 TI - All Slums are Not Equal: Maternal Health Conditions Among Two Urban Slum Dwellers. AB - BACKGROUND: Pregnant women inhabiting urban slums are a "high risk" group with limited access to health facilities. Hazardous maternal health practices are rampant in slum areas. Barriers to utilization of health services are well documented. Slums in the same city may differ from one another in their health indicators and service utilization rates. The study examines whether hazardous maternal care practices exist in and whether there are differences in the utilization rates of health services in two different slums. MATERIALS AND METHODS: A cross-sectional study was carried out in two urban slums of Aligarh city (Uttar Pradesh, India). House-to-house survey was conducted and 200 mothers having live births in the study period were interviewed. The outcome measures were utilization of antenatal care, natal care, postnatal care, and early infant feeding practices. Rates of hazardous health practices and reasons for these practices were elicited. RESULTS: Hazardous maternal health practices were common. At least one antenatal visit was accepted by a little more than half the mothers, but delivery was predominantly home based carried out under unsafe conditions. Important barriers to utilization included family tradition, financial constraints, and rude behavior of health personnel in hospitals. Significant differences existed between the two slums. CONCLUSION: The fact that barriers to utilization at a local level may differ significantly between slums must be recognized, identified, and addressed in the district level planning for health. Empowerment of slum communities as one of the stakeholders can lend them a stronger voice and help improve access to services. PMID- 22529542 TI - Age-Sex Distribution and Seasonality Pattern among Influenza Virus Infected Patients in Delhi, 2009-2010. PMID- 22529543 TI - Is silence really golden? PMID- 22529544 TI - Euthanasia: does the onus rest with the physicians? PMID- 22529546 TI - Padmashree award in the field of medicine and health care. PMID- 22529545 TI - Oral cancer screening. PMID- 22529547 TI - Unilateral ureteric obstruction: Role of renin angiotensin system blockade on renal recovery: An experimental study. AB - AIMS: To study and compare the effects of angiotensin II antagonist (Losartan) and angiotensin converting enzyme (ACE) inhibitor (Enalapril) on renal recovery following reversal of iatrogenic unilateral upper ureteric obstruction. MATERIALS AND METHODS: Unilateral upper ureteric obstruction was created in 96 adult Wistar rats that were reversed after predetermined intervals. Losartan and Enalapril were given to different subgroups of rats following relief of obstruction. Rats were sacrificed and kidneys were subjected to planimetric and histopathological analysis. RESULTS: Dorsal lumbotomy approach provided a rapid and safe approach to kidneys in rats. The planimetric and histopathological changes were most severe in the group of rats in whom obstruction was not relieved before sacrifice. Addition of Enalapril and Losartan significantly hastened the reversal of renal changes following relief of obstruction as compared with the group in which no treatment was given following reversal of blockade. CONCLUSIONS: Renin angiotensin system (RAS) is the major pathway responsible for renal damage following outflow obstruction. However, this damage can be reversed with the use of drugs acting on the RAS. PMID- 22529548 TI - Pediatric hydrocephalus: Does the shunt device pressure selection affect the outcome? AB - AIM: To compare the efficacy of low- versus medium-pressure shunts in pediatric hydrocephalus in a randomized controlled trial. MATERIALS AND METHODS: Forty patients of pediatric hydrocephalus were randomized into two groups. The Chhabra differential pressure VP shunt (low or medium) was inserted in every patient. Postoperative follow-up was performed for symptomatic improvement and radiological evaluation (by sonography or computed tomography scan) for ventricle hemispheric ratio (VHR). Comparative analysis of pre- and postoperative VHR and need of redo surgery for shunt malformation were carried out to establish outcomes. RESULTS: Nineteen patients had a low-pressure and 21 patients had a medium-pressure shunt inserted. The age of the patients ranged from 1 day to 10 years. The average preoperative VHR in group A was 55.37%, which reduced to 40% postoperatively (P = 0.00005); likewise, the pre- and postoperative VHR in group B were 61.57% and 42%, respectively, which was statistically significant (P = 0.0006). The complications of shunts and incidence of redo shunt surgery in both groups were not found to be statistically significant (P = 0.5614). CONCLUSIONS: The study found no significant difference in the outcome of patients with low- or medium-pressure shunt placement in pediatric hydrocephalus. PMID- 22529549 TI - Chronic cervical lymphadenopathy in children: Role of ultrasonography. AB - AIM: To assess the usefulness of ultrasonography in the differentiation of causes of chronic cervical lymphadenopathy in children. MATERIALS AND METHODS: Children with palpable cervical lymph nodes were included. An ultrasonographic examination was performed to delineate multiple lymph nodes, irregular margins, tendency towards fusion, internal echos, the presence of strong echoes and echogenic thin layer. RESULTS: The total number of patients was 120. Echogenic thin layer and strong internal echoes were specific for tuberculosis. Long axis to short axis (L/S) ratio was more than 2 in most of the tubercular nodes (85.71%). Hilus was present in 50 (73.53%) tubercular lymphadenitis, 12 (40%) lymphoma and 10 (62.5%) cases with metastatic lymph nodes. Hypoechoic center was present in 60 (88.24%) tubercular lymphadenitis cases followed by 62.5% metastatic and 60% malignant lymphoma cases. CONCLUSIONS: Ultrasonography is a non-invasive tool for lymph nodal evaluation in children. It may be used to differentiate cervical lymphadenopathy with different etiologies in children. When correlated clinically, it may avoid biopsy in a patient. PMID- 22529550 TI - Regenerative urethroplasty in reoperative hypospadias: Buried strip principle revisited. AB - AIM: Reporting the feasibility of the Denis Browne (buried strip) principle along with tunica vaginalis (TV) pedicled wrapping of the strip in reoperative urethroplasty in hypospadias. MATERIALS AND METHODS: Over a period of 5 years, 32 patients presented with failure of previous urethroplasty and the range of failure was between 2 and 6 times; mean 2.5 times. Mean age was 12.9 (range 2 to 26 years) years. "Buried strip" urethroplasty (i.e., without tubularization of urethral plate) and wrapping with TV were done along with supra pubic cystostomy (SPC) for diversion of urine. Mean follow-up was 29.8 (range 12 to 56 months) months. RESULTS: One patient had fistula and vertical slit meatus was possible in 26 patients. The flow of urine was satisfactory in 31 patients and one patient developed pouch in penile urethra. CONCLUSIONS: The buried strip along with the additional coverage with TV was found to be simple and effective in salvaging the failed urethroplasty. PMID- 22529551 TI - Completely isolated enteric duplication cyst associated with a classic enterogenous duplication cyst. AB - This report describes an 18-month-old boy with a completely isolated duplication cyst (CIDC) of the ileum associated with another classic enteric duplication cyst in the adjacent bowel and presenting as an acute abdomen due to torsion of the pedicle of the CIDC. Cysts excision was curative. PMID- 22529552 TI - Duodenal atresia in association with situs inversus abdominus. AB - We report a rare association of duodenal atresia with situs inversus abdominus in a newborn. The infantogram revealed "reverse double-bubble sign" without dextrocardia. The sonography and echocardiography confirmed the diagnosis of situs inversus abdominus with multiple cardiac anomalies. Laparotomy and a duodenoduodenostomy were carried out. PMID- 22529553 TI - Hydatid cyst of liver: Spontaneous rupture and cystocutaneous fistula formation in a child. AB - A case of spontaneous formation of cutaneous fistula from rupture of an infected hydatid cyst of liver in a female child is reported. PMID- 22529554 TI - Tessier 30 facial cleft. AB - A case of midline cleft of the lower lip with cleft of the mandible and complete duplication of the tongue is reported here. Median cleft of the lower lip, mandible and bifid tongue with ankyloglossia is reported in the literature, but complete duplication of the tongue as part of the Tessier 30 cleft is not yet reported. PMID- 22529555 TI - Thoracoschisis with limb agenesis. AB - A rare case of thoracoschisis, diaphragmatic and supraumbilical abdominal wall defect with right upper limb agenesis in a neonate is reported. PMID- 22529556 TI - Pyloroduodenal duplication cyst. AB - A 4-year-old girl presented with non-bilious vomiting and loss of appetite and weight. At laparotomy, a non-communicating pyloroduodenal duplication cyst was present. Subtotal excision of the cyst and cauterization of the mucosal lining of the common wall was performed. The post-operative recovery was uneventful. PMID- 22529557 TI - Simultaneous acute appendicitis with right testicular torsion. AB - We present a child with both acute appendicitis and torsion of the right testis presenting at the same time. Testicular torsion possibly occurring due to vomiting in acute appendicitis so far has not been reported in the literature. PMID- 22529558 TI - Proceedings of tumor board meeting. AB - The Tumour Board Meeting was held on August 16, 2011, in the Seminar Hall at B.J. Wadia Hospital for children. The panelists of the meeting were Dr. S. Ranganathan, Pediatric Pathologist from Children's Hospital of Pittsburgh; Dr. Archana Swami, Consultant Pediatric Oncologist at Wadia Children's Hospital; Dr. Sajid Qureshi Onco-surgeon (Pediatric) at Tata Memorial Hospital and Dr. Sushmita Bhatnagar. PMID- 22529559 TI - Urethral transection following neonatal circumcision using a Plastibell device. PMID- 22529560 TI - Amyand's hernia. PMID- 22529561 TI - Bananas and neonatal gastric perforation. PMID- 22529562 TI - Newer variant of congenital pouch colon with double colovesical fistulae. PMID- 22529563 TI - Reply: Congenital pouch colon with ileovesical and colovesical fistulae: A new variant. PMID- 22529564 TI - Response to "Interventional sialendoscopy for treatment of juvenile recurrent parotitis". PMID- 22529565 TI - Authors' reply. PMID- 22529566 TI - Response to: Hydronephrosis due to pelviureteric junction narrowing: Utility of urinary enzymes to predict the need for surgical management and follow up. PMID- 22529567 TI - Authors' reply. PMID- 22529568 TI - Oral lichen planus: An update on pathogenesis and treatment. AB - Oral lichen planus (OLP) is a chronic inflammatory disease that affects the mucus membrane of the oral cavity. It is a T-cell mediated autoimmune disease in which the cytotoxic CD8+ T cells trigger apoptosis of the basal cells of the oral epithelium. Several antigen-specific and nonspecific inflammatory mechanisms have been put forward to explain the accumulation and homing of CD8+ T cells subepithelially and the subsequent keratinocyte apoptosis. A wide spectrum of treatment modalities is available, from topical corticosteroids to laser ablation of the lesion. In this review, we discuss the various concepts in the pathogenesis and current treatment modalities of OLP. PMID- 22529569 TI - Plastination: A novel, innovative teaching adjunct in oral pathology. AB - The study of gross specimens is an integral part in learning oral pathology. Unfortunately their storage and handling using traditional formalin is discouragingly difficult. This review describes an alternative approach called "plastination" to study and teach gross specimens using silicone polymers. The process is simple, inexpensive, and can be carried out in any histology laboratory to produce dry, odorless, durable, life-like, maintenance-free, and nonhazardous specimens. Unfortunately the process of plastination for oral specimens has received little attention since its invention. Therefore, an innovative attempt on oral specimens using locally available resin was tried by us. The specimens remained well preserved in dry state without any color change. We recommend this process for any oral pathology department for maintaining museum and for both undergraduate and postgraduate training. PMID- 22529570 TI - Gnathic osteosarcomas: Review of literature and report of two cases in maxilla. AB - Primary neoplasms of the skeleton are rare, accounting for 0.2% of overall human tumor burden. Osteosarcoma (OS) accounts for 15-35% of all primary bone tumors, while gnathic osteosarcomas (GOS) represent 4-8% of all osteosarcomas. GOS shows a predilection for men, a peak incidence of 33 years, and affects the mandible more than the maxilla. We review the scientific literature for a better understanding of the clinical, radiographic, and histopathological features of GOS, along with its etiology, staging, treatment protocol, prognosis, and survival. Evidence from molecular research suggests that it is a differentiation disease that disrupts osteoblasts differentiation from mesenchymal stem cells. The classical radiographic finding of a "sunburst" appearance is appreciated only in 50% of GOS. The universally accepted staging system is not commonly used due to the rarity with which they metastasize to the regional lymph nodes. A number of distinct histopathological subtypes have been described, of which osteoblastic GOS are most common. The treatment protocol is multimodal consisting of preoperative chemotherapy followed by surgery and postoperative chemotherapy, and has a 60-70% five-year survival rate. We present two case reports of osteosarcoma involving the maxillary that were initially misdiagnosed as peripheral giant cell granuloma and osteoma of the maxilla, respectively. These case reports demonstrate the diverse clinical, radiographic, and histopathological features that can be encountered in GOS. PMID- 22529571 TI - Systemic manifestations of oral diseases. AB - The oral cavity is the site of much infectious and inflammatory disease which has been associated with systemic diseases such as diabetes, cardiovascular disease and pre-term low births. This article emphasizes on the oral-systemic disease connection which is now a rapidly advancing area of research. The possible systemic diseases which arise from oral microorganisms are hereby focused. PMID- 22529573 TI - Clinical and histopathological evaluation of collagen fiber orientation in patients with oral submucous fibrosis. AB - BACKGROUND: Oral submucous fibrosis is a chronic debilitating disease of oral mucosa and is characterized by generalized fibrosis of the oral soft tissues which tends to present itself clinically as palpable vertical fibrous bands. Hence, this study was conducted to evaluate histopathologically the collagen fiber bundle orientation in relation to epithelium and to find the reason for unidirectional orientation of clinically palpable fibrous bands. MATERIALS AND METHODS: The study included 33 cases of oral submucous fibrosis and 8 cases of normal tissue. RESULTS: Histologically most of the collagen fibers were parallel to the epithelium, and there was a statistically significant difference in orientation between oral submucous fibrosis and control groups in both buccal mucosa and labial mucosa. CONCLUSION: The reason for unidirectional alignment of clinical fibrous bands could be due to chronic stimulation of oral mucosa by the irritants leading to change in the orientation of collagen fiber bundles, which might result in scar formation similar to that of wound healing, where the collagen fibers are oriented parallel to the epidermis. PMID- 22529572 TI - Proliferation and apoptosis markers in oral submucous fibrosis. AB - BACKGROUND: Premalignant/potentially malignant-oral lesions and conditions such as oral submucous fibrosis are known to transform into oral cancer. The malignant transformation is often associated with changes at the genetic level that in turn is reflected by the altered expression of proteins related to cell cycle, proliferation, and apoptosis. AIM: To evaluate the expression of p53, Ki67 (MIB), bcl2, and bax in oral submucous fibrosis and oral squamous cell carcinoma. MATERIALS AND METHODS: To assess the immunohistochemical expression of p53, Ki67 (MIB), bcl2, and bax in 50 cases of oral submucous fibrosis (OSF) and ten each of normal and oral squamous cell carcinoma (OSCC). RESULTS: The labeling indices (LI) of OSF and OSCC were comparable for p53 and Ki67.The p53 LI ranged from 7.9 to 71.9 in OSF and 65.2 to 85.9 in OSCC, and for Ki67 it ranged from 4.39 to 43.23, 18.35 to 42.33, respectively. CONCLUSION: The p53, Ki67, and bax profiles of OSF and OSCC were altered compared to the normal and these markers could be used as surrogate markers of malignant transformation in OSF. PMID- 22529574 TI - A study to evaluate the efficacy of xylene-free hematoxylin and eosin staining procedure as compared to the conventional hematoxylin and eosin staining: An experimental study. AB - CONTEXT: Use of diluted dish washing solution (DWS) has been experimented successfully as a substitute for xylene to deparaffinize tissue sections during hematoxylin and eosin (H and E) staining. AIMS: (1) Test the hypothesis that xylene- and methanol-free sections (XMF) deparaffinized with diluted DWS are better than or at par with conventional H and E sections. (2) To compare the efficacy of xylene-free sections with the conventional H and E sections. SETTINGS AND DESIGN: Single blinded experimental study. MATERIALS AND METHODS: Sixty paraffin blocks were considered. One section was stained with conventional H and E method (Group A) and the other with XMF H and E (Group B). Slides were scored for parameters; nuclear staining, cytoplasmic staining (adequate = score1, inadequate = score0), uniformity, clarity, crispness (present = score1, absent = score0). Score >/= 2 was inadequate for diagnosis and 3-5 was adequate for diagnosis. STATISTICAL ANALYSIS USED: Z test. RESULTS: Adequate nuclear staining, 96.66% sections in group A and 98.33% in Group B (Z = 0.59, P>0.05); adequate cytoplasmic staining, 93.33% in group A and 83.33% in Group B (Z = 1.97, P<0.05); uniform staining, 70% in group A, 50% in group B (Z = 1.94, P<0.05), clarity present in 85% of group A, 88.33% of group B sections (Z = 0.27, P>0.05), crisp staining in 76.66% in group A and 83.33% in Group B (Z = 1.98, P<0.05), 88.33% Group A sections stained adequately for diagnosis as compared with 90% in Group B (Z = 0.17, P>0.05). CONCLUSION: Xylene- and methanol-free H and E staining is a better alternative to the conventional H and E staining procedure. PMID- 22529575 TI - A study on histological grading of oral squamous cell carcinoma and its co relationship with regional metastasis. AB - BACKGROUND: Histological grading is an important diagnostic tool to predict the clinical and biological behaviour of cancer. Cervical lymph node metastasis indicate poor prognosis of oral cancer. Considering economical status of a third world country, Anneroth's grading system is less expensive, more informative than TNM staging and Broder's grading system. Anneroth's grading system also shows co relationship with lymph node metastasis. So we are trying to evaluate the Anneroth's grading as a standard one among these three system. OBJECTIVE: To study the grading of histological malignancy according to Anneroth's classification of biopsy specimens in relation to metastasis in the cervical lymph nodes and comparing the Anneroth's with the other two recognized classifications. MATERIALS AND METHODS: Fifty(50) patients with oral squamous cell carcinoma was included in the study. Specimen of 35 non-metastatic tumors were compared with 15 metastatic cases. All of the patients were graded to TNM, Broder's and Anneroth's system. TNM is clinical assessment and Broder's is based on only differentiation of cells. On the other hand, six parameters of Anneroth's gives a detail about the morphology of the tumor, invasion criteria in the host tissue and show its correlation with lymph node metastasis. Scoring system of Annearoth's grading indicates demarcation points of worseness of tumor and signifies the possibility of lymph node metastasis. RESULTS: Both Anneroth's(P=0.002) and Broder's grading(P=0.012) have been significant but Anneroth's one is more significant then Broder's. CONCLUSION: Anneroth's classification can be taken as a standerd diagnostic factor and predictive factor of lymph node metastasis. PMID- 22529576 TI - Nuclear features in oral squamous cell carcinoma: A computer-assisted microscopic study. AB - BACKGROUND AND OBJECTIVES: Oral squamous cell carcinoma (OSCC) is one of the most common tobacco-related cancers affecting the Indian population. Various malignancy-grading systems based on different histopathological features have been proposed for OSCC. Due to inherent subjectivity, inter-observer variation and reproducibility of a grading system remains a problem. Grading systems based on nuclear morphometry have been proposed for laryngeal, renal and pharyngeal carcinomas. In this study, an attempt was made to grade oral OSCC based on computer-assisted microscopic evaluation of nuclear features. Our intention was also to evaluate the use of Feulgen stain for studying nuclear features. MATERIALS AND METHODS: Sections made from buccal mucosa biopsies of normal mucosa as well as different grades OSCC were stained by Feulgen reaction. The nuclear features were evaluated by computer-assisted microscopic image analysis for nuclear area (NA), nuclear perimeter (NP) and nuclear form factor (NF) and correlated with histologic grading of OSCC. Nuclear shape, membrane outline, chromatin clumps, nucleoli, and abnormal mitoses were also evaluated. RESULTS: NA and NP were observed to be significantly increased in OSCC (P < 0.001) when compared with the control group. These values increased in correlation with increasing grades of OSCC. However, NF was found to more in the control group (P < 0.001). CONCLUSION: It may be concluded from the results that computer-assisted nuclear morphometry is a reliable tool for grading OSCC. A new grading system based on nuclear features for OSCC has been proposed. PMID- 22529577 TI - A study of antifungal drug sensitivity of Candida isolated from human immunodeficiency virus infected patients in Chennai, South India. AB - BACKGROUND: The purpose of this study was to study the drug sensitivity pattern of Candida seen in HIV seropositive patients in Chennai, South India. MATERIALS AND METHODS: 36 oral rinse samples were collected from HIV seropositive individuals with (21 patients) and without (15 patients) clinical candidiasis. The type of Candidiasis, quantitative estimation, differentiation of candida species and antifungal susceptibility testing was done using different tests. RESULTS: In the 21 patients with candidiasis, pseudomembranous type predominated with low CD4 counts and high colony forming units. Antifungal Drug sensitivity test revealed resistance to fluconazole which is attributed to long term exposure to the drug. CONCLUSION: The results of the study confirm the hypothesis that candidal species can be isolated in HIV positive patients with clinical candidiasis. In HIV infection there are fluconazole resistant candida species emerging mainly due to long term exposure to the drug. PMID- 22529578 TI - Verrucous hyperplasia: A clinico-pathological study. AB - CONTEXT: Oral verrucous hyperplasia (OVH) is a premalignant lesion that may transform into an oral cancer. AIMS: The present retrospective study was carried out to analyze the clinico-pathological features of verrucous hyperplasia (VH). MATERIALS AND METHODS: Total 19 diagnosed cases of verrucous hyperplasia were retrospectively analyzed for demographic, clinical and histopathological features including dysplasia. RESULTS: Average age of occurrence of lesion was 4 (th) decade of life, with male predominance (2:1) and common site of occurrence being buccal mucosa. Clinically it present as verrucous exophytic growth with sharp or blunt projections on surface, which corresponds histologically. Tobacco lime quid placement in buccal vestibule was key etiologic factor. Histopathologicaly 68% cases showed dysplasia out of which moderate dysplasia predominates (42%). Moderately dysplastic cases were found to be associated with mixed habit pattern. Maximum cases were treated with excision. CONCLUSION: Biopsy specimen comprising of adjacent normal epithelium is key in distinguishing verrucous hyperplasia from verrucous carcinoma. Clinical behavior and recurrence potential needs to be assessed with long term follow up studies. PMID- 22529579 TI - Basaloid squamous cell carcinoma of retromolar trigone: A case report with review of literature. AB - Basaloid squamous cell carcinoma (BSCC) is a rare distinct histologic variant of squamous - cell carcinoma of the head and neck region. BSCC is more aggressive and has a poorer prognosis, although histologically, it is associated with squamous cell carcinoma and squamous atypia. The usual site of occurrence for BSCC is the upper aerodigestive tract, floor of the mouth and base of the tongue. This is a case report of an unusual case of BSCC of retromolar trigone, which is quite rare. PMID- 22529580 TI - Florid osseous dysplasia. AB - The concept of 'fibro-osseous lesions' of bone has evolved over the last several decades and now includes two major entities, viz., fibrous dysplasia and ossifying fibroma, as well as other less common entities such as periapical dysplasia, focal osseous dysplasia, florid osseous dysplasia and familial gigantiform cementoma. Florid osseous dysplasia is a central lesion of the bone and periodontium, which has caused considerable controversy because of confusion regarding terminology and criteria for diagnosis. This paper reports a rare case of florid osseous dysplasia affecting maxilla and mandible bilaterally in a 14 year-old Indian male patient. PMID- 22529582 TI - Primary intraosseous carcinoma of the mandible: A case report with literature review. AB - Primary intraosseous carcinoma (PIOC) is a rare tumor that has been infrequently reported. Some diagnostic criteria have been proposed to consider a lesion as PIOC: (1) absence of ulcer in the oral mucosa overlying the tumor, (2) absence of another primary tumor at the time of diagnosis and for at least 6 months during the follow-up, and (3) histological evidence of squamous cell carcinoma. The etiology is not clear, although odontogenic embryonic origin has been reported. Probably, PIOC derives from the remnants of odontogenic tissue, either the epithelial rests of Malassez or the remnants of the dental lamina. PMID- 22529581 TI - Ameloblastic carcinoma: Secondary dedifferentiated carcinoma of the mandible: Report of a rare entity with a brief review. AB - Epithelial odontogenic tumors arise from odontogenic epithelial structures. Malignant epithelial odontogenic tumors are extremely rare. Ameloblastic carcinomas may present denovo, ex ameloblastoma or ex odontogenic cyst. Most ameloblastic carcinomas are presumed to present denovo. To date less than 45 cases of ameloblastoma with metastasis have been reported. It occurs primarily in the mandible in a wide range of age groups; no sex or race predilection has been noted. It may present as a cystic lesion with benign clinical features or as a large tissue mass with ulceration, significant bone resorption, and tooth mobility. The lesion is usually found unexpectedly after an incisional biopsy or the removal of a cyst. Histologic features of ameloblastic carcinoma shows tumor cells that resemble the cells seen in ameloblastoma, but they show cytologic atypia. Moreover, they lack the characteristic arrangement seen in ameloblastoma. The clinical course of ameloblastic carcinoma is typically aggressive, with extensive local destruction. Here we describe a rare case of ameloblastic carcinoma (secondary dedifferentiated carcinoma) of mandible in a 40-year-old female patient. Ameloblastic carcinoma: Secondary dedifferentiated carcinoma of the mandible. PMID- 22529583 TI - Cervical lymph node metastasis in renal cell carcinoma. AB - Renal cell carcinoma represents 3% of all adult malignant tumors. It occurs more frequently in the fifth and sixth decade of life and in a male-female ratio of 1.5 : 1. Among all the primary tumors that arise below the level of the clavicle, renal cell carcinoma is the third most common neoplasm that metastasizes to the head and neck region, but rarely has it been described as the presenting symptom of this tumor. In 7.5% of the patients with renal cell carcinoma, head and neck metastasis is the presenting complaint. However, only 1% of the patients with renal cell carcinoma have metastases confined only to the head and neck; and a solitary cervical metastatic mass, as in the case of our patient, is rare.It seems that head and neck metastasis of renal cell carcinoma should preferentially be treated with surgical excision because of the associated morbidity and quality of-life issues. Renal cell carcinoma should be considered in the differential diagnosis of any growing lesion in the head and neck. PMID- 22529584 TI - Multiple metastatic tumors in the oral cavity. AB - Metastatic lesions to the oral region are uncommon and account for approximately 1% of all malignant oral tumors. In 25% of the cases, oral metastases are found to be the first sign of the metastatic spread; and in 23% of the cases, it is the first indication of an undiscovered malignancy at a distant site. Metastases to oral soft tissues are even less frequent than jaw bones. Because of its rarity, the clinical presentation of a metastatic lesion in the oral cavity can be deceiving, leading to a misdiagnosis of a benign process; therefore, in any case where the clinical presentation is unusual, especially in patients with a known malignant disease, a biopsy is mandatory. Here, we are presenting a rare case of multiple secondary tumors in the attached gingiva in an otherwise apparently healthy patient with no other symptoms of the primary tumor. It subsequently led to the diagnosis of Pancoast tumor (bronchoalveolar carcinoma) metastasizing simultaneously to multiple sites in the oral cavity and bilateral adrenal glands. PMID- 22529585 TI - Cysticercosis of the upper lip. AB - Cysticercosis is a parasitic infestation caused by the larval stage of Taenia solium. It is common in regions where humans and animals live in close contact, with poor sanitation, and due to consumption of infected meat. The tissues affected are the subcutaneous layers, brain, muscle, heart, liver, lungs, and peritoneum. Oral manifestations are very rare. The most common intra-oral site is the tongue. Here, we present a case in a who sought treatment for an asymptomatic nodule in the upper lip. A gross specimen revealed a cystic cavity containing clear watery fluid and white membranous flecks. The histopathology showed features of cysticercosis. PMID- 22529586 TI - Rapidly enlarging mass following dental extraction. AB - Oral melanoma (OM) is a rare, malignant neoplasm of melanocytic origin. It accounts for 0.2 - 8% of all melanomas. In contrast to its cutaneous counterpart, OM has poor prognosis, possibly due to late clinical diagnosis, nonexistence of standardized clinical or histopathological grading and anatomical limitation in complete excision of the lesion. For better understanding of the lesion, case reports are still considered to be the source of information. Here we present a case of oral primary melanoma occurring in an uncommon site, the mandibular gingiva, with review of related literature. PMID- 22529587 TI - Unicystic ameloblastoma of the mandible. AB - Unicystic ameloblastoma refers to those cystic lesions that show clinical, radiographic or gross features of a jaw cyst but on histologic examination show a typical ameloblastomatous epithelium lining the cyst cavity, with or without luminal and/or mural tumor proliferation unicystic ameloblastoma is a less encountered variant of the ameloblastoma and believed to be less aggressive. As this tumor shows considerable similarities with dentigerous cysts, both clinically and radiographically the biologic behaviour of this tumor group was reviewed. Moreover, recurrence of unicystic ameloblastoma may be long delayed and a long-term post-operative follow up is essential for proper management of these patients. Here we are presenting a case of unicystic ameloblastoma in a 18 year old female patient. PMID- 22529588 TI - Myxoglobulosis of lower lip: Report of two cases. AB - In this paper, we present two case reports of myxoglobulosis, in a 24-year-old female and a 40-year-old male patient who came to our hospital with a chief complaint of painless swelling of the lower lip of approximately 6 months duration. A study of two case reports has been given here. In these patients, histological examination of the surgically excised tissue was carried out. Histopathological examination showed an extravasation mucocele with the lumen exhibiting unique globular organizations of mucin surrounded by granulation tissue capsule and lacking an epithelial lining. Our two cases are possibly an analogue of myxoglobulosis, a rare variant of the appendical mucocele. Thus, though rare, the possibility of occurrence of myxoglobulosis in cystic lesions of the lip should be considered. The prognosis is regarded better as compared to the other types of mucoceles with low recurrence rate due to good host response and globular organizations of mucin. However, follow- up of these cases and more such cases is required to confirm the prognosis. The need for study of many such cases to confirm the etiology, pathogenesis and biologic nature of this variant is being felt. PMID- 22529589 TI - Recurrent unicystic ameloblastoma in a child. AB - Unicystic ameloblastoma (UCA) is a clinical subtype of ameloblastoma that is considered prognostically different. The purpose of this report is to present a case of UCA showing dual radiographic pattern in a child. A detailed study of the lesion was carried out in an 8 year old female child who presented to our department of oral and maxillofacial pathology. Clinical, radiological and histopathological findings were recorded. In March 2005, a painless swelling in the left side of the mandible was noted, which on radiographic examination showed a unilocular radioluceny enclosing the crown of mandibular left permanent second molar, extending between the left first permanent molar and anterior margin of the ramus. Histopathologic diagnosis was UCA. The lesion was treated by enucleation. The patient returned with recurrence in 2009, at this time the lesion radiographically presented as a multilocular radiolucency with a soap bubble appearance, extending between the anterior border of the ramus and second premolar. Histopathologic diagnosis was UCA. The lesion was treated by segmental resection with immediate reconstruction. Although a number of treatment modalities are available to treat UCA, many factors need to be taken into consideration in the treatment of UCA in children. PMID- 22529590 TI - Biphasic synovial sarcoma in mandibular region. AB - The term synovioma was coined by Smith in 1927, and later in 1936 Knox suggested the name synovial sarcoma. It occurs primarily in the paraarticular regions, usually in close association with tendon sheaths, bursae, and joint capsules. On rare occasions it may be seen in areas without any apparent relationship to synovial structures as in parapharyngeal region or the abdominal cavity. The first description of synovial sarcoma in the head and neck region was by Pack and Ariel in 1950. The majority of these tumors seem to take origin from paravertebral connective tissue spaces and manifest as solitary retropharyngeal or parapharyngeal masses near the carotid bifurcation. Synovial sarcoma has been reported in soft palate, tongue, maxillofacial region, angle of mandible, sternoclavicular region, scapular region, and the esophagus. We report a case of 28-year-old male patient with synovial sarcoma in mandibular region with biphasic pattern. PMID- 22529591 TI - Ectodermal dysplasia with true anodontia. AB - The hereditary condition known as ectodermal dysplasia is characterized by the absence or defect of two or more ectodermally derived structures. The most commonly observed forms of ectodermal dysplasia are the hidrotic and hypohidrotic types; discrimination is based on the absence or presence of sweat glands. A case of 8-year-old male child with hypohidrotic ectodermal dysplasia with complete anodontia of primary as well as secondary dentitions is presented. The child had a short stature, low intelligent quotient (I.Q.,), and was underweight. The patient experienced episodes of high fever, was intolerant to heat, and did not sweat. He exhibited smooth and dry skin, sparse light-colored eyebrows. Dental clinicians can be the first to diagnose ectodermal dysplasia due to the absence of teeth. PMID- 22529592 TI - Heterogenecity of fibroblasts. AB - Fibroblasts are a major stromal cell type present in human connective tissue maintaining the structural integrity in health. Depending on the situation, location and various conditions, fibroblasts exhibit considerable variation in morphology, size and shape that suggest the existence of discrete cellular subsets. The purpose of this short communication is to provide information regarding the heterogenecity of fibroblasts and its variability in physiological and pathological conditions. PMID- 22529593 TI - Clinical errors. PMID- 22529594 TI - Congenital mitral valve lesions : Correlation between morphology and imaging. AB - Congenital malformations of the mitral valve are often complex and affect multiple segments of the valve apparatus. They may occur in isolation or in association with other congenital heart defects. The majority of mitral valve malformations are not simply classified, and descriptive terms with historical significance (parachute, mitral, or arcade) often lack the specificity that cardiac surgeons demand as part of preoperative echocardiographic morphological assessment. This paper examines the strengths and limitations of commonly used descriptions and classification systems of congenitally malformed mitral valves. It correlates pathological, surgical, and echocardiographic findings. Finally, it makes recommendations for the systematic evaluation of the congenitally malformed mitral valve using segmental echocardiographic analysis to assist precise communication and optimal surgical management. PMID- 22529595 TI - Mitral valve operations at a high-volume pediatric heart center: Evolving techniques and improved survival with mitral valve repair versus replacement. AB - Mitral valve disease is quite variable and can occur as an isolated defect or in association with other complex left sided lesions. These lesions are often best described with detailed pre-operative imaging studies to define the valve anatomy and to access associated left heart disease. Depending on the type of mitral valve disease, various surgical repair techniques have led to improved survival in the recent era. We describe lesion specific approach to mitral valve repair and results. PMID- 22529596 TI - Impact of congenital heart disease on brain development in newborn infants. AB - OBJECTIVE: To assess brain development and brain injury in neonates with cyanotic and acyanotic congenital heart disease (CHD). METHODS: The study included 52 term infants with CHD who were divided into two groups: Cyanotic (n=21) and acyanotic (n=31). Fifteen healthy neonates of matched age and sex were enrolled in the study as controls. Three-dimensional proton magnetic resonance spectroscopic imaging and diffusion tensor imaging were used to assess brain development and injury. We calculated the ratio of N-acetylaspartate (NAA) to choline (which increases with maturation), average diffusivity (which decreases with maturation), fractional anisotropy of white matter (which increases with maturation), and the ratio of lactate to choline (which increases with brain injury). RESULTS: As compared with control neonates, those with CHD had significant decrease in NAA/choline ratio (P<0.001), significant increase in lactate/choline ratio (P<0.0001), significant increase in average diffusivity (P<0.0001), and significant decrease of white matter fractional anisotropy (P<0.001). Neonates with cyanotic CHD had significant less brain development and more brain injury than those with acyanotic CHD (P<0.05). CONCLUSIONS: Newborn infants with cyanotic and acyanotic CHD are at high risk of brain injury and impaired brain maturity. PMID- 22529598 TI - The Contegra bovine jugular valved conduit: Living up to expectations? PMID- 22529597 TI - The Contegra conduit: Late outcomes in right ventricular outflow tract reconstruction. AB - OBJECTIVES: To report the clinical outcomes (early death, late death, and rate of reintervention) and performance of the Contegra conduit as a right ventricle outflow tract implant and to determine the risk factors for early reintervention. METHODS: Forty-nine Contegra conduits were implanted between January 2002 and June 2009. Data collection was retrospective. The mean age and follow-up duration of Contegra recipients was 3.5 +/- 4.6 years and 4.2 +/- 2.0 years, respectively. RESULTS: There were three deaths (two early, one late), giving a survival rate of 93.9%. The rate of conduit-related reintervention was 19.6% and was most often due to distal conduit stenosis. Age at implantation of <3 months, receipt of a conduit of 12-16 mm diameter, and a diagnosis of truncus arteriosus were each significant contributors to the rate of reintervention. CONCLUSION: The Contegra is a cost-effective and readily available solution. However, there is a limited range of larger calibers, which means that the homograft conduit (>22 mm) remains the first choice of implant in older children. The rates of reintervention are significantly higher with a diagnosis of truncus arteriosus, age at implantation of <3 months, and implantation of conduits sized 12-16 mm. PMID- 22529599 TI - Pulmonary artery banding in the current era: Is it still useful? AB - BACKGROUND: The objective of this study was to assess the results of the pulmonary artery (PA) banding in patients with congenital heart defects (CHD) and pulmonary hypertension (PH) in the current era. METHODS: We analyzed data from 305 patients who underwent PA banding between April 2005 and April 2010 at our centre. All patients were approached through a left thoracotomy. Twenty percent of patients underwent PA banding based on Trusler's rule (Group 1), 55% of them underwent PA banding based on PA pressure measurement (Group 2), and the rest of them (25%) based on surgeon experience (Group 3). The follow-up period was 39 +/- 20 month and 75% of patients (230 cases) had definitive repair at mean interval 23 +/- 10 months. RESULTS: The rate of anatomically and functionally effectiveness of PA banding in all groups was high (97% and 92%, respectively). There were no significant differences in anatomically and functionally efficacy rate between all groups (P=0.77, P=0.728, respectively). There was PA bifurcation stenosis in six cases (2%), and pulmonary valve injury in one case (0.3%). The mortality rate in PA banding was 2% and in definitive repair was 3%. CONCLUSIONS: We believe that PA banding still plays a role in management of patients with CHD, particularly for infants with medical problems such as sepsis, low body weight, intracranial hemorrhage and associated non cardiac anomalies. PA banding can be done safely with low morbidity and mortality. PMID- 22529600 TI - Pulmonary artery banding: Rationale and possible indications in the current era. PMID- 22529601 TI - Neonatal pulmonary artery thrombosis. AB - Pulmonary artery thrombosis in neonates is a rare entity. We describe two neonates with this diagnosis; their presentation, evaluation, and management. These cases highlight the importance of this differential diagnosis when evaluating the cyanotic neonate. PMID- 22529602 TI - "Vanishing" pulmonary valve stenosis. AB - OBJECTIVE: Both spontaneous resolution and progression of mild pulmonary valve stenosis (PS) have been reported. We reviewed characteristics of the pulmonary valve (PV) to determine factors that could influence resolution of mild PS. METHODS: Fifteen asymptomatic pediatric patients with spontaneous resolution of isolated mild PS were retrospectively reviewed. RESULTS: There was no correlation between the PV gradient, clinical presentation, age at diagnosis, or PV morphology. The PV annulus was small at initial presentation, which normalized at follow up. When corrected for the body surface area (z-score), the PV annulus was normal in all patients, including at initial evaluation. CONCLUSIONS: Based on our observation, neither age at diagnosis, nor PV-morphology-influenced resolution of mild PS. The variable clinical presentation makes it difficult to categorize and observe mild PS by auscultation alone. The PV annulus z-score could be a useful adjunct to determine the course and serial observation of mild PS. PMID- 22529603 TI - Protein losing enteropathy secondary to a pulmonary artery stent. AB - A 2-year-old patient with hypoplastic left heart syndrome presented 6 months following Fontan completion with protein-losing enteropathy (PLE). He had undergone stent implantation in the left pulmonary artery after the Norwood procedure, followed by redilation of the stent prior to Fontan completion. Combined bronchoscopic and catheterization studies during spontaneous breathing confirmed left bronchial stenosis behind the stent, and diastolic systemic ventricular pressure during expiration of 25 mm Hg. We postulate that the stent acts as a valve, against which the patient generates high expiratory pressures, which are reflected in the ventricular diastolic pressure. This may be the cause of PLE. PMID- 22529604 TI - Percutaneous pulmonary valve implantation. PMID- 22529605 TI - Approach to postoperative fever in pediatric cardiac patients. AB - Fever in the postoperative period in children undergoing surgery for congenital heart disease is fairly common and tends to cause anxiety to both the surgeon and the patient. Such fever is associated with the metabolic response to trauma, systemic response to the cardiopulmonary bypass, hypothermia, presence of drainage tubes, drugs, blood transfusion as well as infections. Establishing the diagnosis requires proper assessment of the patient with focused history, targeted physical examination and judicious use of investigations with the knowledge of the common causes. PMID- 22529606 TI - An unusual case of left main coronary artery aneurysm with right ventricle fistula. AB - A 4-year-old boy presented with repeated respiratory tract infections. Echocardiography showed dilation of the left main coronary artery with flow into the Right Ventricular Outflow Tract (RVOT). Diagnosis of Left Coronary Artery Aneurysm (LMCA) with RVOT fistula was made. A surgical repair of LMCA aneurysm by two-patch technique was performed. The patient had an excellent outcome postoperatively and is asymptomatic on follow-up. PMID- 22529607 TI - Iatrogenic diversion of IVC to left atrium after surgical closure of ASD. AB - Iatrogenic diversion of the inferior vena cava (IVC) to the left atrium during surgical closure of an atrial septal defect (ASD) is a very rare complication in the era of cardiopulmonary bypass. The eustachian valve could be mistaken for the margin of the ASD. We report a case with this complication after closure of a sinus venosus ASD of the IVC type. PMID- 22529608 TI - Endovascular stenting of the obstructed vertical vein in a neonate with supracardiac total anomalous pulmonary venous return. AB - A newborn baby presented with respiratory distress, cyanosis and shock within 2 hours of birth. The cardiac evaluation showed supracardiac total anomalous pulmonary venous return with critically obstructed vertical vein. The baby underwent successful stenting of the vertical vein at 12 hours of life. PMID- 22529609 TI - Congenital giant cardiac tumor with severe left-ventricular inflow and outflow obstruction and arrhythmia treated with pulmonary artery banding and long-term amiodarone infusion. AB - We report a congenital giant cardiac tumor that occupied the majority of left ventricular cavity with severe left ventricular inflow and outflow obstruction. The hemodynamics were similar to univentricular physiology. He was treated with prostaglandins and bilateral pulmonary artery banding. He had frequent supraventricular tachycardia associated with ventricular pre-excitation that was controlled by long-term administration of intravenous amiodarone. The patient died due to sepsis after 3 months. PMID- 22529610 TI - Right atrial hemangioma in the newborn: Utility of fetal imaging. AB - We present a rare primary right atrial tumor diagnosed in-utero with fetal echocardiography, and further characterized as a congenital hemangioma with magnetic resonance imaging. Surgical resection was done six days after birth. This case illustrates the complementary roles of evolving advanced imaging techniques for fetuses and infants with congenital heart disease that allows for surgery early in the neonatal period. PMID- 22529611 TI - Occult systemic lupus erythematosus with active lupus nephritis presenting as Libman-Sacks endocarditis. AB - The diagnosis of systemic lupus erythematosus (SLE) depends on clinical evidence of renal, rheumatologic, cutaneous, and neurologic involvement, supported by serological markers. A previously healthy 14-year-old girl presented with Libman Sacks endocarditis involving the aortic valve as the first manifestation of SLE. Even though she did not satisfy the American College of Rheumatology criteria for diagnosing SLE, she had anemia, proteinuria, elevated erythrocyte sedimentation rate, low complement 4 (C4) levels, and strongly positive antinuclear antibody titer. A renal biopsy showed stage IV lupus nephritis. Treatment was initiated with immunosuppressants and steroids. This type of presentation may be misdiagnosed as infective endocarditis missing the underlying collagen vascular disease. PMID- 22529612 TI - Silent embolization of an Amplatzer septal occluder into the left ventricular outflow tract requiring emergent surgical retrieval. AB - Percutaneous closure of secundum atrial septal defect is an established safe alternative to surgery with rare complications and high primary success rate. This procedure can be complicated by early or late device embolizations. We report an asymptomatic delayed nonobstructive embolization of an amplatzer septal occluder (ASO) into the left ventricle outflow tract detected by routine transthoracic echocardiography 1 week after implantation, which required emergent surgical retrieval in a stable patient. PMID- 22529613 TI - Cor triatriatum dexter: A rare cause of childhood cyanosis. AB - Cor triatriatum dexter is a rare congenital heart anomaly where the right atrium is divided into two chambers by a membrane. We report a boy who had persistent mild cyanosis and diagnosed to have cor triatriatum dexter with secundum atrial septal defect by transoesophageal echocardiography. Interestingly, he had persistent mild cyanosis despite insignificant obstruction to the right ventricular inflow and normal pulmonary artery pressure. The pathophysiology, approach to the diagnosis, and mode of treatment are also discussed. PMID- 22529614 TI - Anomalous origin of right coronary artery from pulmonary artery. AB - Anomalous origin of coronary artery from the pulmonary artery is a rare anomaly that most frequently involves the left coronary artery and very rarely the right coronary artery. These lesions can be missed on echocardiography unless carefully looked for. We describe a case of isolated anomalous origin of right coronary artery from pulmonary artery diagnosed on echocardiography and confirmed by computed tomography (CT) angiography. PMID- 22529615 TI - Resynchronization therapy in an adolescent with pacemaker-related ventricular dysfunction. PMID- 22529616 TI - Atrial septal aneurysm and stroke. PMID- 22529617 TI - Selected summaries. PMID- 22529618 TI - State of the globe: the relationship between male circumcision and genitourinary infections. PMID- 22529619 TI - Male Circumcision and HIV: Do All Roads Lead to Rome? PMID- 22529620 TI - Increased Likelihood of Bacterial Pathogens in the Coronal Sulcus and Urethra of Uncircumcised Men in a Diverse Group of HIV Infected and Uninfected Patients in India. AB - BACKGROUND: The biological mechanism of circumcision as potentiating HIV prevention is poorly understood. Foreskin microbiota has been postulated as having a potential role; however, little is known about the relationship between bacterial pathogens and circumcision in adults. MATERIALS AND METHODS: We sampled the coronal sulcus of a diverse group of circumcised and uncircumcised men (n=315) from a government chest hospital and fertility clinic in Hyderabad, Andhra Pradesh, India. Genital examination was conducted on three groups of men: Group 1 - HIV infected; Group 2 - TB infected; Group 3 - control. Aerobic and anaerobic specimens were cultured according to standard clinical protocols, and results were analyzed following multivariate logistic regression models. RESULTS: Three hundred fifteen study participants - 47.6% of Group 1, 36.5% of Group 2, and 15.9% of Group 3 - were enrolled in the study and included in all analyses. Overall 37.1% of the participants were circumcised without variation across groups (P=0.29). Smegma was observed in 18.7% of the participants with no cases observed in Group 3 (P<0.001). Gram-negative pathogens were more prevalent among study participants in Group 1 (22.7%) and Group 2 (30.4%) as compared with those in Group 3 (6.0%) (P=0.003). In multivariate regression analysis, controlling for group, age, and presence of smegma, uncircumcised men were more likely to be colonized with gram positives [Adjusted Odds Ratio (AOR) 1.9; P<0.05)], gram negatives (AOR 2.4; P<0.05), or any pathogen (AOR 2.8; P<0.005). CONCLUSIONS: Uncircumcised men in this population in South India are more likely to harbor bacterial pathogens in the coronal sulcus than do their circumcised counterparts. Future studies should examine the relationship between foreskin microbiota and HIV transmission. PMID- 22529621 TI - Prevalence and risk factors of intestinal helminth infection among rural malay children. AB - BACKGROUND: Soil-transmitted intestinal helminth infection is prevalent in rural communities of Malaysia. Risk factors contributing to helminth infections are largely unknown in the country. AIM: To determine the prevalence and risk factors of intestinal helminth infections among children in Beris Lalang, a rural Muslim community of Malaysia. SETTINGS AND DESIGN: In this cross-sectional study, children aged 7-9 years were recruited during the mass Friday prayer at Beris Lalang mosque by trained imams (religious leaders). A standardized questionnaire was used to obtain information on socio-demographic profile, daily hygienic practices, and history of helminth infection. RESULTS: Out of 79 samples, 29 (37%) were positive for helminthic ova, of which 24 were ova of Trichuris trichiura. Poor education of the mother (primary education or less) (P=0.015), eating raw salad (P=0.03), and no physical activities (P=0.03) were found independent risk factors for the child's helminth infections in univariate analysis. A higher proportion of children with helminth infections complained of tiredness and fatigue compared to those without such infections (36% vs. 12%, P=0.019). In a multivariate analysis of predictors of helminth infection, poor education of the mother (P=0.02) and eating raw salad (P=0.04) remained statistically significant, after controlling for several other potential risk factors. CONCLUSIONS: T. trichiura was the most prevalent intestinal helminth infection in children in rural Malaysia. Risk factors of helminth infection included mother's poor education and eating raw salad and vegetables. PMID- 22529622 TI - International nosocomial infection control consortium findings of device associated infections rate in an intensive care unit of a lebanese university hospital. AB - OBJECTIVES: To determine the rates of device-associated healthcare-associated infections (DA-HAI), microbiological profile, bacterial resistance, length of stay (LOS), excess mortality and hand hygiene compliance in one intensive care unit (ICU) of a hospital member of the International Infection Control Consortium (INICC) in Beirut, Lebanon. MATERIALS AND METHODS: An open label, prospective cohort, active DA-HAI surveillance study was conducted on adults admitted to a tertiary-care ICU in Lebanon from November 2007 to March 2010. The protocol and methodology implemented were developed by INICC. Data collection was performed in the participating ICUs. Data uploading and analyses were conducted at INICC headquarters on proprietary software. DA-HAI rates were recorded by applying the definitions of the National Healthcare Safety Network (NHSN) at the US Centers for Disease Control and Prevention (CDC). We analyzed the DA-HAI, mechanical ventilator-associated pneumonia (VAP), central line-associated bloodstream infection (CLA-BSI), and catheter-associated urinary tract infection (CAUTI) rates, microorganism profile, excess LOS, excess mortality, and hand hygiene compliance. RESULTS: A total of 666 patients hospitalized for 5,506 days acquired 65 DA-HAIs, an overall rate of 9.8% [(95% confidence interval (CI) 7.6-12.3], and 11.8 (95% CI 9.1-15.0) DA-HAIs per 1000 ICU-days. The CLA-BSI rate was 5.2 (95% CI 2.8-8.7) per 1000 catheter-days; the VAP rate was 8.1 (95% CI 5.5-11.7) per 1000 ventilator-days; and the CAUTI rate was 4.1 (95% CI 2.6-6.2) per 1000 catheter-days. LOS of patients was 7.3 days for those without DA-HAI, 13.8 days for those with CLA-BSI, 18.8 days for those with VAP. Excess mortality was 40.9% [relative risk (RR) 3.14; P 0.004] for CLA-BSI. Mortality of VAP and CAUTI was not significantly different from patients without DA-HAI. Escherichia coli was the most common isolated microorganism. Overall hand hygiene compliance was 84.9% (95% CI 82.3-87.3). CONCLUSIONS: DA-HAI rates, bacterial resistance, LOS and mortality were moderately high, below INICC overall data and above CDC-NHSN data. Infection control programs including surveillance and antibiotic policies are essential and continue to be a priority in Lebanon. PMID- 22529623 TI - Diagnosis of Trichomonas Vaginalis from Vaginal Specimens by Wet Mount Microscopy, In Pouch TV Culture System, and PCR. AB - BACKGROUND: In recent years, trichomoniasis has emerged as the most common sexually transmitted disease and limited data are available on the effective screening technique for the diagnosis of Trichomonas vaginalis. AIM: The aim was to compare and evaluate different diagnostic methods like wet mount microscopy, In Pouch TV culture, and Polymerase chain reaction (PCR) to establish which method or combination of methods was most effective for detection of Trichomonas vaginalis in vaginal swab specimens. SETTINGS AND DESIGN: This is a cross sectional study. MATERIALS AND METHODS: A total of 200 patients complaining of vaginal discharge were included in the study. Three vaginal swabs were screened for trichomoniasis by wet mount microscopy, In Pouch TV culture system and PCR, using TVK3 and TVK7 specific primers. RESULTS: Of the 200 cases studied, 36 (18%) were positive by wet mount microscopy, 44 (22%) by In Pouch TV culture system and 60(30%) by PCR. Sensitivity and specificity of wet mount were 60% and 100%, respectively, whereas sensitivity and specificity of the In Pouch TV culture system were 73.33% and 100%, respectively when compared to PCR. CONCLUSION: Comparison of different methods showed that at least two techniques, such as wet mount microscopy and culture have a better chance of detection of T. vaginalis infection. Diagnosis of trichomoniasis by PCR was found to be highly specific and sensitive, but its availability and cost effectiveness limit its use in routine diagnostic laboratories. PMID- 22529624 TI - Enterococcal Bacteremia is Associated with Prolonged Stay in the Medical Intensive Care Unit. AB - BACKGROUND: Although enterococci are relatively common nosocomial pathogens in surgical intensive care units (ICUs), their significance in blood cultures from patients in the medical ICU is unclear. MATERIALS AND METHODS: In this retrospective study spanning 2 years, the clinical and microbiological characteristics of enterococcal bacteremia among medical ICU patients were evaluated. RESULTS: Of 1325 admissions, 35 with enterococcal bacteremia accounted for 14.8% of positive blood cultures. They were significantly older (P=0.03) and had various co-morbidities. Most had vascular (96.9%) and urinary (85.3%) catheters, and 67.7% were mechanically ventilated. In addition to blood, enterococci were isolated from vascular catheters (8.6%) and other sites (20%), while no focus was identified in 77% of patients. Prior use of broad-spectrum antimicrobials was nearly universal. All isolates tested were sensitive to vancomycin and linezolid. Resistance to ampicillin and gentamicin were 44.7% and 52.6%, respectively. Compared with other medical ICU patients, patients with enterococcal bacteremia had a longer ICU stay (P<0.0001) and a trend toward higher ICU mortality (P=0.08). CONCLUSIONS: Enterococcal bacteremia is an important nosocomial infection in the medical ICU, with a predilection for older patients with multiple comorbidities. Its occurrence is associated with a significantly longer ICU stay and a trend to a higher mortality. The choice of antibiotics should be dictated by local susceptibility data. PMID- 22529625 TI - Application of polymerase chain reaction to detect burkholderia pseudomallei and Brucella species in buffy coat from patients with febrile illness among rural and peri-urban population. AB - CONTEXT: Melioidosis and Brucellosis are important endemic infections among people in India, especially in rural settings. Conventional detection techniques have several limitations. Only a few studies exist on the prevalence of Melioidosis and Brucellosis in rural area especially in India. AIM: We sought to evaluate detection of Burkholderia pseudomallei and Brucella spp. among patients presenting febrile illness. MATERIAL AND METHODS: Previously described polymerase chain reaction (PCR) assays for both pathogens were evaluated with Deoxyribonucleic acid extracts of buffy coat samples collected from 301 patients recruited prospectively. Data was not amenable to statistical analysis. RESULTS: The PCR showed specific amplification and no non-specific amplification with heterologous Gram-negative bacilli. The lower limit of detection of the assay for B. pseudomallei was determined to be 1 colony-forming unit /mL and for Brucella it was 1.95 * 10(3) plasmids per microliter. Blood culture in automated blood culture system was negative for all the samples. This prospective study carried out in southern India for the first time. PCR for Brucella was positive in 1% of the patient samples whereas 0.3% was positive for B. pseudomallei. CONCLUSION: The finding of Brucella and Burkholderia infections in our populations leads us to suggest that tests for Brucella and B. pseudomallei should also form part of a diagnostic platform for patients with Pyrexia of unknown origin in tropical developing countries. PMID- 22529626 TI - Assessment of helicobacter pylori prevalence by scorpion real-time PCR in chronic tonsillitis patients. AB - BACKGROUND: Occasionally, bacteria or viruses enter the tonsils and these organs become overwhelmed by bacterial or viral infection leading to inflammation. Some studies confirmed the presence of Helicobacter pylori in tonsillar specimens of patients suffering from chronic tonsillitis and some others did not. The difference in results in various studies might be due to different laboratory methods. The aim of this study was to investigate the presence of H. pylori Deoxynucleic acid (DNA) in archival tonsillar tissues of patients with chronic tonsillitis by a rapid, sensitive, and specific technique of Scorpion real-time polymerase chain reaction (PCR). MATERIALS AND METHODS: Scorpion real-time PCR and modified McMullen's staining was performed on 103 archival paraffin-embedded tonsillar samples collected from patients with chronic tonsillitis following tonsillectomy operation. RESULTS: Our findings showed that H Cell and Molecular Research Center. pylori DNA was present in 21.35% of total specimens by using Scorpion real-time PCR. Modified McMullen's staining of paraffin-embedded sections was positive in 19 patients. Out of our 103 samples, 50 samples showed positive a rapid urease test whereas 53 samples demonstrated negative results, 20 produced positive PCR results, and 83 were negative for H. pylori. There was no significant relationship between the presence of H. pylori, sex, age, and place of residence. CONCLUSION: Although the existence of H. pylori in tonsillar tissue samples of patients with chronic tonsillitis is controversial, however, our results showed that in our studied specimens, a significant number of patients with chronic tonsillitis had H. pylori colonization. PMID- 22529627 TI - Analyzing a Potential Drug Target N-Myristoyltransferase of Plasmodium falciparum Through In Silico Approaches. AB - BACKGROUND: Despite concerted global efforts to combat malaria, malaria elimination is still a remote dream. Fast evolution rate of malarial parasite along with its ability to respond quickly to any drug resulting in partial or complete resistance has been a cause of concern among researcher communities. MATERIALS AND METHODS: Molecular modeling approach was adopted to gain insight about the structure and various analyses were performed. Modeller 9v3, Protparam, Protscale, MEME, NAMD and other tools were employed for this study. PROCHECK and other tools were used for stereo-chemical quality evaluation. RESULTS AND CONCLUSION: It was observed during the course of study that this protein contains 32.2% of aliphatic amino acids among which Leucine (9.5%) is predominant. Theoretical pI of 8.39 identified the protein as basic in nature and most of the amino acids present in N-Myristoyltransferase are hydrophobic (46.1%). Secondary structure analysis shows predominance of alpha helices and random coils. Motif analyses revealed that this target protein contains 2 signature motifs, i.e., EVNFLCVHK and KFGEGDG. Apart from motif search, three-dimensional model was generated and validated and the stereo-chemical quality check confirmed that 97.7% amino acid residues fall in the core region of Ramachandran plot. Molecular dynamics simulation resulted in maximum 1.3 A Root Mean Square Deviation (RMSD) between the initial structure and the trajectories obtained later on. The template and the target molecule has shown 1.5 A RMSD for the C alpha trace. A docking study was also conducted with various ligand molecules among which specific benzofuran compounds turned out to be effective. This derived information will help in designing new inhibitor molecules for this target protein as well in better understanding the parasite protein. PMID- 22529628 TI - An investigation of an outbreak of viral hepatitis B in modasa town, gujarat, India. AB - BACKGROUND: Most outbreaks of viral hepatitis in India are caused by hepatitis E. Recently in the year 2009, Modasa town of Sabarkantha district in Gujarat witnessed the outbreak of hepatitis B. PURPOSE: An attempt was made to study the outbreak clinically and serologically, to estimate the seropositivity of hepatitis B Virus among the cases and their contacts and to know the seroprevalence of hepatitis B envelope antigen (HBeAg) and IgM antibody against hepatitis B core antigen (IgM HBcAb) out of all the Hepatitis B surface Antigen (HBsAg) positive ones. MATERIALS AND METHODS: Eight hundred and fifty-six (856) cases and 1145 contacts were evaluated for hepatitis B markers namely HBsAg, HBeAg and IgM HBcAb by enzyme-linked immuno Sorbent Assay (ELISA) test. RESULTS: This outbreak of viral hepatitis B in Modasa, Gujarat was most likely due to unsafe injection practices. Evidence in support of this was collected by Government authorities. Most of the patients and approximately 40% of the surveyed population gave history of injections in last 1.5-6 months. Total 664/856 (77.57%) cases and 20/1145 (1.75%) contacts were found to be positive for HBsAg. 53.41% of the positive cases and 52.93% of the positive contacts were HBeAg-positive and thus in a highly infectious stage. CONCLUSIONS: Inadequately sterilized needles and syringes are an important cause of transmission of hepatitis B in India. Our data reflects the high positivity rate of a hepatitis B outbreak due to such unethical practices. There is a need to strengthen the routine surveillance system, and to organise a health education campaign targeting all health care workers including private practitioners, especially those working in rural areas, as well as the public at large, to take all possible measures to prevent this often fatal infection. PMID- 22529629 TI - Oral Myiasis is a Potential Risk in Patients with Special Health Care Needs. AB - Myiasis is a rare disease caused by invasion of tissue by larvae of certain dipteran flies. It is more common in countries with tropical climate. Oral myiasis is not a very common condition and many clinicians are unaware of its diagnosis. Common predisposing factors are poor oral hygiene, halitosis, trauma, senility, learning disabilities, physically and mentally challenged conditions. Oral myiasis can lead to rapid tissue destruction and disfigurement and requires immediate treatment. Treatment consists of manual removal of maggots from oral cavity after application of chemical agents. Use of antibiotics reduces the duration of infection and hastens the recovery period. Good sanitation, personal and environmental hygiene and cleanliness and special care for debilitated persons are the best methods to prevent oral myiasis. PMID- 22529630 TI - Nanotechnology Applications to HIV Vaccines and Microbicides. AB - Human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) remains one of the most serious threats to global health. Today there are no HIV vaccines which can prevent HIV infection. All of the candidates being studied are in the experimental stage. Preventive vaccine candidates are being tested in HIV negative people to see if they can prevent infection. With of the development of a safe and effective vaccine still likely to be years away, topical microbicide formulations that are applied vaginally and rectally are receiving greater interest as an effective alternative to slow down the global spread of HIV. Current microbicide trials that aim to prevent the sexual transmission of HIV are using gels, creams, rings, films and there is also work underway to explore other types of 'delivery' systems. There have been numerous reports on safety and lack of toxicity of the application of nanotechnology for targeted delivery and slow, sustained release of drugs, proteins, peptides or nucleic acids by any route to maximize effectiveness and minimize adverse effects. The application of nanotechnology for targeting drugs and macromolecules to specific tissues or cells is one of the most important areas in nanomedicine research. Thus far nanoparticles provide a strong platform to combine protein and DNA based vaccines/microbicides and will facilitate the production, preclinical evaluation and clinical testing in the future. PMID- 22529631 TI - Infection control during filoviral hemorrhagic Fever outbreaks. AB - Breaking the human-to-human transmission cycle remains the cornerstone of infection control during filoviral (Ebola and Marburg) hemorrhagic fever outbreaks. This requires effective identification and isolation of cases, timely contact tracing and monitoring, proper usage of barrier personal protection gear by health workers, and safely conducted burials. Solely implementing these measures is insufficient for infection control; control efforts must be culturally sensitive and conducted in a transparent manner to promote the necessary trust between the community and infection control team in order to succeed. This article provides a review of the literature on infection control during filoviral hemorrhagic fever outbreaks focusing on outbreaks in a developing setting and lessons learned from previous outbreaks. The primary search database used to review the literature was PUBMED, the National Library of Medicine website. PMID- 22529632 TI - Suprasellar tuberculoma presenting as sudden onset blindness in a patient of lupus. AB - Tuberculosis can be an opportunistic infection complicating the course of patients receiving prolonged immunosuppression. In these patients, the tuberculosis can involve the central nervous system and can cause diagnostic difficulty due to atypical features. Often, the diagnosis of central nervous system tuberculosis in resource limited settings is indirect, like imaging. But anti-tubercular drugs, given even on empirical basis can be life saving. A case of a young female systemic lupus erythematosus patient (on prolonged steroids) with intracranial tuberculoma is presented here. She presented with blindness and headache and her computed tomography scan showed a calcified mass in the suprasellar location. However, she responded well to anti-tubercular drugs. The differential diagnoses of such lesions are also discussed. PMID- 22529633 TI - Mycobacterium chelonae infection of the parotid gland. AB - Mycobacterium chelonae can cause numerous infections, including lung disease, local cutaneous disease, osteomyelitis, joint infections and ocular disease. With the exception of lung disease, these syndromes commonly develop after direct inoculation. The most common clinical presentation in immunocompetent individuals is skin and soft tissue infection. We present a case of M. chelonae infection of the parotid gland that was successfully treated with clarithromycin monotherapy. To our knowledge, this is the first case report of M. chelonae parotitis in an adult. PMID- 22529634 TI - Recurrent sepsis due to bacillus licheniformis. AB - Bacillus licheniformis is recognized as a human pathogen causing infections, mainly in immunocompromised patients. We present a case of sepsis in an immunocompetent patient, caused by B. licheniformis. This case is of particular interest because the patient had no history of any immune deficiency and the disease did not respond to antibiotic treatment. PMID- 22529635 TI - A 12-year-old Child with Trichinellosis, Pyomyositis and Secondary Osteomyelitis. AB - Trichinellosis is a parasitic infestation affecting the skeletal muscles. Cases of trichinellosis in humans have been reported from most regions of the world. However, a review of literature revealed only two reported cases of human trichinellosis in India. Further, a diagnosis of superimposed pyomyositis in trichinellosis with secondary osteomyelitis has not been reported to our knowledge. This article reports this rare case presentation in a 12-year-old child. Timely intervention helped prevent long-term morbidity in our patient. In our case report, we also discuss in detail the pathogenesis of such a condition and discuss the role of imaging modalities and an early magnetic resonance imaging (MRI) to diagnose the condition and start an early treatment. PMID- 22529636 TI - Salmonella paratyphi neck abscess. PMID- 22529637 TI - Similarity in the Isolation Rate of Mycobacterium tuberculosis for New and Treated Cases of Tuberculosis in Sputum Specimens Preserved Under Cetylpyridinium Chloride. PMID- 22529638 TI - Ayurveda: think globally... act locally.... PMID- 22529639 TI - Report on the status of Indian medicine and folk healing-with a focus on the benefits that the systems have given the public. PMID- 22529640 TI - Ayurpathy: A modern perspective of Ayurveda. PMID- 22529641 TI - "Ayurpathy": Misconceived and unwarranted. PMID- 22529642 TI - Development and standardization of Mysore Tridosha scale. AB - The authors have developed a personality scale to assess Tridoshas i.e. Vata, Pitta, and Kapha from psychological perspective in human beings. The Tridoshas are composed of the Pancha Mahabhutas, but one or the other Dosha is dominant singularly or in combination. There can never be a state when one or the other Pancha Mahabhutas and consequently the Tridoshas are absent totally. All five are essential to sustain life. Vata Dosha is composed of Akasa and Vayu Mahabhuta. Pitta Dosha is composed of Tejas or Agni and Ap Mahabhuta. Kapha Dosha is composed of Ap and Prithvi Mahabhuta. Although Tridosha is studied, understood, and applied in Ayurveda, the present authors have tried to validate the same from the domain of psychology. Since the authors are not from the domain of Ayurveda but of Psychology, there are some constructs that are not amenable for psychological testing which have been ignored. Only those constructs that can be used by psychologists to assess the psychological aspects of the Dosha Prakriti have been used to build items for the assessment of personality. In this process, the psychometric properties of the scale are established. The scale assesses the psychological manifestation of the Tridoshas, which was the basic objective. The standardization procedure involved in the development of the Mysore Psychological Tridosha Scale is herewith delineated. PMID- 22529643 TI - Effect of dietary, social, and lifestyle determinants of accelerated aging and its common clinical presentation: A survey study. AB - Aging is unavoidable and natural phenomenon of life. Modern gerontologists are realizing the fact that aging is a disease, which Ayurveda had accepted as natural disease since long. Rate of aging is determined by one's biological, social, lifestyle, and psychological conditions and adversity of which leads to accelerated form of aging (Akalaja jara or premature aging). The aim of this study is to identify potential factors that may accelerate aging in the context of dietry factors, lifestyle and mental makeup. The 120 diagnosed subjects of premature-ageing of 30-60 years were randomly selected in the survey study. Premature ageing was common among females (75.83%), in 30-40 age group (70%), 86.67% were married, had secondary level of education (36.66%), house-views (61.67%), belongs top middle class (58.33%) and engaged in occupations that dominating physical labour (88.33%). The maximum patients are constipated (60%), had mandagni (80%), vata-kapha prakriti (48.33%), rajasika prakriti (58.33%), madhyama vyayama shakti (73.33%), and madhyama jarana shakti (85.83%). Collectively, 43.33% patients were above normal BMI. The more patients had anushna (38.33%) and vishamasana dietary pattern (25.83%), consumed Lavana (88.33%) and Amla rasa (78.33%) in excess on regular basis. Some patients had addicted to tobacco (11.67%) and beetle chewing (5.83%). The maximum patients had no any exercise (79.17%) and specific hobby (79.17%) in their leisure times. Analyzing Hamilton Anxiety and Depression Rating Scales revealed that 39.80%, 37.86%, 33.98%, 24.27% and 18.44% patients had insomnia, depression, tension, GIT symptoms and anxious mood respectively. These data suggest that certain social, dietary and lifestyle factors contribute towards accelerated ageing among young individuals. PMID- 22529644 TI - Efficacy of Ashwagandha (Withania somnifera Dunal. Linn.) in the management of psychogenic erectile dysfunction. AB - Erectile dysfunction (ED) has been defined as the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual performance. By 2025, men with ED will be approximately 322 million, an increase of nearly 170 million men from 1995. The present study was aimed to evaluate the efficacy of Ashwagandha (Withania somnifera) in the management of psychogenic erectile dysfunction. In this study, a total of 95 patients with psychogenic erectile dysfunction satisfying the DSM IV TR diagnostic criteria were selected, out of them 86 patients completed the course of treatment. In Trial Group, Ashwagandha root powder and in Control group, Placebo (Wheat powder) were given for 60 days. Treatment selection and its allocation were done by following computerized randomization plan. Criterion of assessment was based on the scoring of International Index of Erectile Function (IIEF) Scale. Paired and Unpaired t test were used for statistical analysis. In Trial group (n=41), 12.6% and in Control group (n=45), 19.11% of improvement was observed with the significance of (P<0.001). There was no significant difference (P>0.05) found in between the two groups. Both Ashwagandha and Placebo provided no relief (<25% improvement on IIEF) in psychogenic erectile dysfunction. PMID- 22529646 TI - A clinical study of some Ayurvedic compound drugs in the assessment quality of life of patients with Eka Kushtha (psoriasis). AB - Psoriasis is a chronic disease that can have substantial psychological and social impact on patient's life. Psoriasis has been shown to affect health-related Quality of Life to an extent similar to the effects of other chronic diseases such as depression, myocardial infarction, hypertension, etc. The modern treatment options not only provide temporary relief but also have serious side effects. Thus, the chronic and recurring nature of the disease hampers the Quality of Life to a great extent. In the present study, patients were randomly divided into two groups. Koshtha Shuddhi was done by Eranda bhrushta haritaki (6 g at night with ushnodaka) in patients of both the groups for 3 days before starting the treatment. A total of 111 patients were selected for the present study and were grouped into two. Patients of group A (45) were given "Navayasa rasayana leha" and "Dhatryadhyo lepa" for external application. Stress is a well known precipitating factor of Psoriasis. Hence, to study the efficacy of Medhya rasayana drugs, patients of group B (49) were given Medhya rasayana tablet along with the application of Dhatryadhyo lepa. The duration of the study was 3 months and follow-up was done for one month. Both the groups showed equally good results on improving the quality of life in the patients in terms of Dermatology life quality index and Psoriasis disability index. PMID- 22529645 TI - A pilot study to clinically evaluate the role of herbomineral compound "Rakatchap Har" in the management of essential hypertension. AB - The aim of the present study was to investigate the clinical efficacy of a herbomineral medicine Rakatchaphar (Each 500 mg cap contains Sarpgandha 150 mg, Shankhpushpi 75 mg, Jatamansi 75 mg, Jahar Mohra Khatai Pishti 75 mg, Moti Pishti 75 mg, Ras Sindoor 50 mg) in essential hypertension, an observational prospective study was done at Shri Ashutosh Maharaj (SAM) Ayurvedic Treatment and Research Centre, Noormahal. Ninety-eight patients in the age group 28-76 years with essential hypertension without any co-morbid illness were included in the study. Patients were treated with cap Rakatchaphar 500 mg twice a day. Blood pressure (BP) was monitored on subsequent follow-up visits at 2, 4, 6, and 8 weeks. Change in Diastolic BP (DBP), Systolic BP (SBP), and Mean BP (MBP) were analyzed statistically by Student's t test, ANOVA, and Post hoc Bonferroni test. On first visit the mean SBP, DBP, and MBP was 164.16+/-17.27, 101.88+/-9.20, and 122.27+/ 10.57 mm Hg, respectively. After 8 weeks of therapy there was a statistically significant fall in SBP (122.98+/-11.36), DBP (80.90+/-8.57), and MBP (94.86+/ 9.24) in mmHg (P value <0.0001). Rakatchap Har offers an efficacious and safe combination of natural products available for the treatment of hypertension. PMID- 22529647 TI - Prevalence of Adhyashana in patients attending IPGT and RA Hospital and its effect on health. AB - Adhyashana is a technical term of Ayurveda, which means eating before digestion of previous food. All the ancient classics describe the ill effects of Adhyashana. Charaka mentioned it as a prime causative factor for Grahani dosha. It is also said that Adhyashana can cause severe and incurable diseases or even death. All these references indicate the importance of Adhyashana as one of the health destroying factors, and yet this subject remained untouched by the Ayurvedic scientists for research. The present study was carried out to search the prevalence of Adhyashana in the patients of various diseases. For this purpose a survey study was planned and a total of 235 subjects attending outpatient and inpatient department of the Institute for Post Graduate Teaching and Research Hospital were surveyed. Among these patients 62.98% were found to be habituated to Adhyashana. Purishvaha Srotodushti was found in a maximum number of patients, which was 42%. Status of the disease was Krichchhra saadhya in maximum of these patients. PMID- 22529648 TI - Ayurveda in critical care: Illustrating Ayurvedic intervention in a case of hepatic encephalopathy. AB - Ayurvedic interventions have largely been considered helpful in chronic debilitating conditions where active management of a clinical condition is not required. It is for this notion; Ayurvedic therapies have never been approached in any critical care condition requiring an active management. A perception that herbo-metallic components of various Ayurvedic drugs may actually harm the patients who are in compromised vital status has further added to this apprehension against use of such medicines in critical care. Contrary to the conventional belief, we observed a case of grade three hepatic encephalopathy with severely compromised liver function that was successfully treated with Ayurvedic therapy containing many heavy metal containing compounds. The liver function got improved in this case following the Ayurvedic intervention. The symptomatic improvements in this case were also identifiable through biochemical tests showing the functional status of liver. This case therefore is worthy of taking a note for possible inclusion of Ayurvedic interventions in critical care where Ayurvedic therapies are discarded without being given a chance of getting evaluated. PMID- 22529649 TI - A clinical study on the effect of Arka Taila in the management of Karnasrava (Otomycosis). AB - Karnasrava is the condition characterized by discharge from Karna and occurs mainly due to Avarana of Vata Dosha. Otomycosis denotes diffuse otitis externa due to fungal infection in ear. Otomycosis being one of the causes of Karnasrava was selected for the study. The present study is done on 28 patients of Karnasrava, who were grouped in to two with 14 patients in each group. Group-A was treated with Arka TailaKarnapurana and Group-B with Clotrimazole ear drops (standard control). The signs and symptoms were studied before and after treatment. Result of the study indicates that Arka Taila and Clotrimazole are equally effective in all the signs and symptoms of Karnasrava (Otomycosis). PMID- 22529650 TI - Effect of Atibalamula and Bhumyamalaki on thirty-three patients of diabetic neuropathy. AB - Diabetic neuropathy is a relatively early and common complication affecting approximately 30% of diabetic patients. According to Ayurvedic principles there is involvement of Vata and Pitta Dosa in diabetic neuropathy. Bhumyamalaki (Phyllanthus niruri) is a plant which shows possibility to pacify these two Dosas. Another plant Atibala (Abutilon indicum) has also Vata pacifying qualities. Present study has been carried out to study the effects of Bhumyamalaki and Atibala on 33 patients of diabetic neuropathy. All the patients have been given Bhumyamalaki Churna 3 g twice a day and decoction of 10 g of Atibala-mula twice a day for 30 days. Neuropathy analyzer machine has been used for exact recording of sensory perception of vibration, cold and hot sensations before and after treatment. Changes in numbness, tingling, burning sensation and pain in lower limbs have also been assessed before and after treatment. Results have been analyzed statistically by applying the 't' test. It can be stated from the results that use of Bhumyamalaki and Atibalamula in the patients of diabetic neuropathy can revert the diminished sensory perception and can reduce the symptoms significantly. PMID- 22529651 TI - A comparative clinical study of Shatapatrayadi churna tablet and Patoladi yoga in the management of Amlapitta. AB - Amlapitta is a very common disease caused by Vidagdha Pitta with features such as Amlodgara, Hrid Kantha Daha, and Avipaka. This is a burning problem of the society. Irregular and improper food habits, and busy stressful lifestyle is one of the main culprit. Amlapitta is the GI disorder described in Ayurvedic texts that closely resembles with Gastritis in modern science. In chronic stage, it may lead to ulcerative conditions. In this study, total 41 patients were registered and were randomly divided into two groups. In group A, Shatapatrayadichurna tablet and in group B Patoladi Yoga tablet were given for 1 month. The Nidana, signs, and symptoms were observed carefully to get idea about the Samprapti of the disease. The effect of Patoladi Yoga on Roga Bala is 65.79%, 62.11% on Agni Bala, and 63.35% on Deha and Chetasa bala. The overall relief was 63.75%. The effect of Shatapatrayadi tablet on Roga Bala was 71.94%, 73.15% on Agni Bala, and 77.68% on Deha and Chetas Bala. The overall relief was 74.25%. PMID- 22529652 TI - Effect of rasanjana madhu ashchyotana in netra abhishyanda (mucopurulent conjunctivitis). AB - To evaluate the comparative efficacy of Ayurvedic formulation a Rasanjana Madhu (RM) eye drops and Honey Rose (HR) water eye drops in Netra Abhishyanda in mucopurulent conjunctivitis, the current study is planned. Total of 35 patients attending the outpatient department of Shalakya Tantra at R. G. G. Postgraduate Ayurvedic College, Paprola, Distt. Kangra, Himachal Pradesh with characteristic features of Netra Abhishyanda were selected for the present study. Twenty patients were given trial drug, i.e., RM eye drops, while 15 patients were given HR eye drops. Random sampling technique was adopted for the present study. The duration of the treatment was 7 days with 1 week follow-up. Patients receiving the trial group demonstrated reduction of redness, burning sensation, lacrimation, photophobia, foreign body sensation, discharge, and congestion, which were statistically significant with 93% patients cured or markedly improved category. Signs and symptoms stated above were also statistically reduced with HR eye drops, probably because of well-documented hygroscopic and bacteriocidal properties of honey. Based on the study, it can be concluded that, RM eye drops are very effective in the management of Netra Abhishyanda viz. Infective conjunctivitis. PMID- 22529653 TI - Clinical effect of Kukkutanda Twak Bhasma in the management of Swetapradara. AB - Swetapradara is an important gynecological disorder nowadays. Most women in the reproductive age group complain about white discharge. Due to white discharge, they are prone to so many other symptoms, such as backache, itching in vulva, and burning micturition. According to Ayurveda, swetapradara is caused by the vitiation of Kapha and Vata dosha. Kukkutanda twak is also said to be Kapha Vata shamaka and swetapradara shamaka. In Ayurveda so many drugs are mentioned in the treatment of swetapradara. Among them Kukkutanda twak bhasma is a good medicine. In this clinical study Kukkutanda twak bhasma has shown statistically significant improvement in white discharge, backache, itching, anemia, weakness, and urinary tract infection. PMID- 22529654 TI - Evaluation of anti-depressant and anxiolytic activity of Rasayana Ghana Tablet (A compound Ayurvedic formulation) in albino mice. AB - In recent years, many Ayurvedic formulations are being researched to provide an effective antidepressant and anxiolytic drug in the field of psycho-pharmacology. The present study was planned to evaluate the anti-depressant and anxiolytic activity of Rasayana Ghana Tablet comprising three herbs Guduchi (Tinospora cordifolia Miers), Aamalaki (Emblica officinalis Garten) (RGT) and Gokshura (Tribulus terrestris Linn). Swiss albino mice were divided into four groups of six animals each, comprising of both male and female in each group. Group I received water served as normal control (WC), group II received vehicle and served as vehicle control (VC), group III received Rasayana Ghana tablet and group IV received standard drug diazepam (2 mg/kg) for anxiolytic study in elevated plus maze and standard antidepressant imipramine (5 mg/kg) for anti depressant activity in behavior despair test. Rasayana Ghana tablet along with ghee and honey as vehicle is found to be having antidepressant and anxiolytic activity in experimental animals. Thus, this formulation can be used in prevention and treatment of depression and anxiety. PMID- 22529655 TI - Psychotropic activity of Argyreia speciosa roots in experimental animals. AB - Argyreia speciosa (L.f.) Sweet (convolvulaceae) commonly known as Briddhadaraka is regarded as a "Rasayana" drug in the ayurvedic system of medicine to cure diseases of nervous system. In this study, hydroalcoholic root extract of A. speciosa was subjected to evaluate psychotropic effects in classical experimental models. Effect of the extract on spontaneous motor activity, pentobarbital induced sleeping time, motor coordination, exploratory behavior, and apomorphine induced stereotypy were investigated in mice. Effect of the extract on catalepsy and haloperidol-induced catalepsy were studied in rats. Preliminary phytochemical and acute toxicity screenings were also performed. The extract (100, 200, and 500 mg/kg, p.o.) significantly decreased spontaneous motor activity, exploratory behavior, and prolonged pentobarbital sleeping time in mice. The extract also remarkably attenuated the intensity of apomorphine-induced stereotypy but had no effect on motor coordination. The extract produced catalepsy and potentiated haloperidol-induced catalepsy in rats. These results provide evidence that the hydroalcoholic extract of A. speciosa roots may contain psychoactive substances that are sedative in nature with possible neuroleptic properties. PMID- 22529656 TI - Study on the diuretic activity of Euphorbia fusiformis Buch.-Ham. in albino rats. AB - The present study was undertaken to evaluate diuretic activity of Euphorbia fusiformis root powder in Wistar strain albino rats. Randomly selected animals were divided into three groups of six animals each. The root powder was suspended in distilled water and administered orally at a dose of 90 mg/kg therapeutically equivalent dose (TED) and 180 mg/kg (TED * 02) to overnight fasted rats. The diuretic activity was evaluated by determination of urine volume and urinary electrolyte concentrations. Test drug showed significant increase in urine volume and urinary electrolyte excretion in a dose-dependant manner. Thus, from this study, it can be concluded that roots of E. fusiformis possess diuretic activity. PMID- 22529657 TI - Antioxidant and anticancer evaluation of Scindapsus officinalis (Roxb.) Schott fruits. AB - Several methods exist for the treatment of cancer in modern medicine. These include chemotherapy, radiotherapy, and surgery; most cancer chemotherapeutants severely affect the host normal cells. Hence the use of natural products now has been contemplated of exceptional value in the control of cancer. Plant-derived natural products such as flavonoids, terpenes, alkaloids, etc., have received considerable attention in recent years due to their diverse pharmacological properties including cytotoxic and cancer chemopreventive effects. Looking into this, the antioxidant and anticancer evaluation of Scindapsus officinalis (Roxb.) Schott fruits has been attempted to investigate its antitumor activity. The collection and authentication of the plant material mainly fruits and their various extractions was done. Identification of plant's active constituents by preliminary phytochemical screening was carried out. An in-vitro cytotoxic assay using the brine shrimp lethality assay with brine shrimp eggs (Artemia salina) at a dose of 1-10 MUg/ml with the fruit extract was performed by the method described by Mayer et al. Cell viability using the Trypan blue dye exclusion test at a dose of 20, 40, 80, 120, and 160 MUg/ml dissolved in DMSO (final concentration 0.1%), and cytotoxicity using the MTT assay where viable cells convert MTT into a formazan salt were performed. All pharmacological screening for acute toxicity and anti tumour studies using EAC 1 * 10(6) cells/mouse treated Swiss albino mice at a dose of 100 and 200 mg/kg/day orally was carried out. Biochemical and antioxidants predictions from various parameters like hematological, RBC, WBC count, PVC, total protein, Tissue Lipid Peroxidation, SOD, CATALASE, GPx, GST levels and anti tumour activity of Scindapsus officinalis were observed. The data was statistically analyzed by one-way ANOVA followed by Dunnett's and Tukey's multiple comparison test. The antitumor effect of the extract is evident from the increase in mean survival time (MST) lifespan, reduction in the solid tumor volume, and also the reversal of altered hematological parameters almost equal to normal. The methanolic extract (100-200 mg/kg/day orally) was found to be cytotoxic on human cancer cell lines. In addition, the methanolic extract had an antioxidant effect as reflected by a decrease in LPO, GST, and GPx (oxidant enzymes), and an increase in SOD and catalase. PMID- 22529658 TI - Study on the diuretic activity of Veerataru Kwatha in albino rats. AB - The purpose of the present study was to evaluate the diuretic activity of Veerataru [Dichrostachys cinerea (Linn.)] Kwatha in experimental animals by following the standard procedure. Randomly selected animals were divided into three groups of six animals each. The root of Veerataru was administered orally in the form of Kwatha at a dose of 5.4 and 10.8 ml/kg. Parameters like volume of urine, pH of urine and urinary electrolyte concentrations like sodium, potassium and chloride were studied. Veerataru Kwatha increased the urine output in a dose dependent manner. However, it did not affect the urinary electrolyte concentrations. From the present study, it can be concluded that the root of Veerataru has diuretic property. PMID- 22529659 TI - Pharmacognostical study of Tamalaki (Phyllanthus fraternus Webster), a herb used in Tamaka-svasa. AB - Tamalaki is a herbacious medicinal plant, described in Ayurvedic texts in many occurrences with different properties, actions, uses and synonyms, supposed to indicate more than one species commonly used in practice. Modern scholars mostly suggest Phyllanthus fraternus Webster (syn. P. niruri Linn.), P. amarus Schum. and Thonn. and P. urinaria Linn. as the source plants of Tamalaki. In this study, an attempt has been made to designate P. fraternus as the source plant of Tamalaki used in the treatment of Tamaka-svasa (Bronchial asthma) and other respiratory disorders by analyzing therapeutic uses, actions, properties, taste, synonyms as well as pharmacognostical characters. Smooth capsule, six tepals, less and short fibrous root, pentagonal outline with wing-shaped young stem are some of the specific characters observed in this species. PMID- 22529660 TI - Effect of Shodhana (processing) on Kupeelu (Strychnos nux-vomica Linn.) with special reference to strychnine and brucine content. AB - Kupeelu (Strychnos nux-vomica Linn.) commonly known as nux vomica is a poisonous plant used extensively in various ayurvedic formulations, with great therapeutic significance. Ayurveda recommended the administration of Kupeelu only after purification in different media like cow's urine (Go mutra), cow's milk (Go dugdha), cow's ghee (Go ghrita), Kanji (sour gruel), and so on. Apart from the classical methods some other methods are also adopted by the traditional practitioners using castor oil (Eranda taila), ginger juice (Ardraka swarasa), in the purification of Kupeelu seeds. In the present study an attempt has been made to purify the seeds by performing two different methods (one classical and another traditional) using Kanji and Ardrakaswarasa as Shodhana media. This study reveals that both the methods studied reduce the strychnine and brucine contents in comparison to the raw seeds as determined by high performance thin layer chromatography (HPTLC). After purification in Kanji and Ardraka swarasa, the strychnine content was reduced by 39.25% and 67.82%, respectively, and the brucine content in the purified seeds was also found to have decreased by 17.60% and 40.06%, in comparison to the raw seeds. PMID- 22529661 TI - A progressive review of Sandhana kalpana (Biomedical fermentation): An advanced innovative dosage form of Ayurveda. AB - Sandhana kalpana (biomedical fermented formulations) are one of the best dosage forms of Ayurveda in practice since thousands of years. In order to prepare these medicaments, certain sets of conditions are prearranged, which lead to fermentation. Thus, products bequeath with self-generated ethyl alcohol, which potentiate these preparations (Asava-Arishta), pharmaceutically and therapeutically. Commonly, medicinal and commercial components of these formulations are prompting many researchers to contribute in manufacturing, quality control, safety, and efficacy of these formulations. To cope up with this, literature related to Asava-Arishta has been surveyed from the Vedic period to recent publications of Government of India, ie, Ayurvedic Formulary of India, and presented briefly here. In this review paper, we have discussed pioneering facts such as nature and amount of carbohydrate, type of containers, optimum temperature, variety and relevance of initiator of fermentation, manufacturing, regulatory rules, and business aspects of Asava-Arishta. After going through this basic information, any academician or researcher may show a way to further strengthen this dosage form. PMID- 22529662 TI - Modified ksharasutra chikitsa for 'shambukawarta bhagandara'. AB - Horse-shoe Fistula is a big challenge for both Modern and Ayurvedic Surgeons. We can correlate this with 'Shambukawarta Bhagandara' described by Sushruta. Here, fistula forms secondary to an ischiorectal abscess and both the ischiorectal fossae are involved. Also, they open posteriorly into the anal canal, at the 6 o'clock position, and are associated with a big cavity lying superior (above the levatorani). Therefore, in such a clinical feature neither Fistulotomy ('Wanley operation') nor 'Ksharasutra' treatment alone, prove useful. After going through this, we can say that there is a definite need for newer surgical innovative techniques, to tackle this challenging disease. An integral approach of 'Fistulectomy along the arms of the Horse-shoe fistula with Ksharasutra ligation' in the remaining track connected to the anal canal, and drainage of the postanal space abscess, proved to be very successful. We have tried the same technique with very good results. No recurrence was found in the patients during the follow up period of three years. The given diagrammatic presentation of the plan of surgery will help to understand the procedure. PMID- 22529663 TI - A critical review of the philosophical concepts of Carakopaskara commentary. AB - Philosophy is the prime specialty as it fulfills the ultimate goal of life with the depiction of the liberation of the soul. The human body composed of mind, other sensory organs along with five proto-elements, is to be treated from the clinical applicability of the philosophical series of events. The current review is the categorical analysis of the philosophical thought depicted in "Carakopaskara commentary" of Pandit Jogindranath Sen in the purview of underlined theme of Caraka Samhita and classical orthodox philosophy. PMID- 22529664 TI - Effect of different Avaleha in the management of Tamaka Shwasa (Bronchial Asthma). AB - Avaleha, which are generally elegant preparations, can be used for both preventive and curative purposes. Many research works have been carried out on different Avalehas. A number of studies with different Avalehas and their respective clinical efficacy in Tamaka Shwasa (Bronchial Asthma) have been carried-out at Department of Rasashastra and Bhaishajya Kalpana, IPGT & RA, Jamnagar. A review has been carried out of such works to know the better one. In the work, it has been found that highly significant (P<0.001) results on Shwasakastata were found in all the groups, except in the Kamsa Haritaki Avaleha (B) group which was insignificant (P<0.02). PMID- 22529665 TI - Mehamudgaravati and type 2 diabetes mellitus. PMID- 22529666 TI - Authors' reply. PMID- 22529667 TI - Tailabindupariksha of the urine. PMID- 22529668 TI - Authors' reply. PMID- 22529669 TI - Vamana procedure. PMID- 22529670 TI - Authors' reply. PMID- 22529671 TI - Two years of J-AIM. PMID- 22529672 TI - Effect of shilajit on the heart of Daphnia: A preliminary study. AB - Shilajit is a mineral-rich complex organic compound used in the traditional system of Ayurvedic medicine for treating hypertension and improving the cardiac function with many herbomineral preparations. However, very little experimental evidence is available about its effect on the cardiac function. We used Daphnia as a model organism for observing the effect of shilajit on its heart due to its myogenic properties and its response to number of cardioactive drugs that are known to affect human heart function. Genome of Daphnia shows the strongest homology with the human genome. These characteristics of Daphnia make it an ideal organism for biomedical research. Our results suggest that this complex organic compound lowers the heart beats as its concentration increases from 1.0 to 100 ppm. The beats come to near normal condition at 1000 ppm. Above 1000 ppm, the beats are very fast and impossible to count. These results indicate a negative chronotropic effect on the Daphnia heart at low concentrations and a positive chronotropic effect to arrhythmia and finally failure at increasing higher concentrations of shilajit. PMID- 22529673 TI - Pharmacognostical and physicochemical analysis of Tamarindus indica Linn. stem. AB - Tamarindus indica Linn. fruits (Chincha) are extensively used in culinary preparations in Indian civilization. Its vast medicinal uses are documented in Ayurvedic classics and it can be used singly or as a component of various formulations. Besides fruit, the Kasta (wood) of T. indica L. is also important and used to prepare Kshara (alkaline extract) an Ayurvedic dosage form. Pharmacognostical and physicochemical details of Chincha Kasta are not available in authentic literature including API (Ayurvedic Pharmacopoeia of India). The study is an attempt in this direction. T. indica L. stem with heartwood was selected and morphological, microscopic and physicochemical standardization characters along with TLC finger print, and fluorescence analysis were documented. Transverse section of stem showed important characters such as phelloderm, stone cells layer, fiber groups, calcium oxalate, crystal fibers, and tylosis in heartwood region. Four characteristic spots were observed under UV long wave, in thin layer chromatography with the solvent combination of toluene: ethyl acetate (8:2). The study can help correct identification and standardization of this plant material. PMID- 22529674 TI - Antimalarial plants of northeast India: An overview. AB - The need for an alternative drug for malaria initiated intensive efforts for developing new antimalarials from indigenous plants. The information from different tribal communities of northeast India along with research papers, including books, journals and documents of different universities and institutes of northeast India was collected for information on botanical therapies and plant species used for malaria. Sixty-eight plant species belonging to 33 families are used by the people of northeast India for the treatment of malaria. Six plant species, namely, Alstonia scholaris, Coptis teeta, Crotolaria occulta, Ocimum sanctum, Polygala persicariaefolia, Vitex peduncularis, have been reported by more than one worker from different parts of northeast India. The species reported to be used for the treatment of malaria were either found around the vicinity of their habitation or in the forest area of northeast India. The most frequently used plant parts were leaves (33%), roots (31%), and bark and whole plant (12%). The present study has compiled and enlisted the antimalarial plants of northeast India, which would help future workers to find out the suitable antimalarial plants by thorough study. PMID- 22529675 TI - Ayurveda research: Ontological challenges. AB - Collaborative research involving Ayurveda and the current sciences is undoubtedly an imperative and is emerging as an exciting horizon, particularly in basic sciences. Some work in this direction is already going on and outcomes are awaited with bated breath. For instance the 'ASIIA (A Science Initiative In Ayurveda)' projects of Dept of Science and Technology, Govt of India, which include studies such as Ayurvedic Prakriti and Genetics. Further intense and sustained collaborative research needs to overcome a subtle and fundamental challenge-the ontologic divide between Ayurveda and all the current sciences. Ontology, fundamentally, means existence; elaborated, ontology is a particular perspective of an object of existence and the vocabulary developed to share that perspective. The same object of existence is susceptible to several ontologies. Ayurveda and modern biomedical as well as other sciences belong to different ontologies, and as such, collaborative research cannot be carried out at required levels until a mutually acceptable vocabulary is developed. PMID- 22529676 TI - Critical review on the pharmaceutical vistas of Lauha Kalpas (Iron formulations). AB - Iron is one among the major metals present in the earth's crust and is essential for sound sustenance of human body. Its deficiency leads to various health ailments. Contemporary medicine advises iron supplements in iron deficiency anemia. Ayurvedic classics also quote significant information about administration of iron. Lauha Kalpas are the unique compound herbo-mineral formulations where iron (Lauha) is used as a major ingredient. Relevant literature (Bhaishajya Ratnavali, Charaka Samhita, Rasendra Sara Samgraha etc.) reviewed to gather information about Lauha Kalpas. Critical analysis of these Lauha Kalpas reveals that ancient seers administered iron in a better acceptable form. Unlike popular understanding these are not only Khalviya preparations; but Churna (powders), Avaleha (confectionaries), Rasakriya (solidified decoctions), and Putapaka (incinerated) form of preparations are also found. Apart from solid dosage forms, semisolid dosage forms mentioned in classics are very much useful. Unfortunately most of the formulations are not found in the market. Hence Pharmaceutical firms may bring these unique dosage forms in to the market to supply the healthcare needs of the community. It is interesting that iron preparations are used in Ayurveda in different medical conditions apart from anemia (Pandu). This leaves a scope for further researches on different dosage forms of iron and their indications. PMID- 22529677 TI - A comparison of the antioxidant property of five Ayurvedic formulations commonly used in the management of vata vyadhis. AB - BACKGROUND: The five kashayams (kwaths - decoctions) Manjishtadi kashayam (MK), Rasna erandadi kashayam (REK), Sahacharadhi kashayam (SK), Maharasnadi (or Rasna dwiguna bhagam) kashayam (MRK) and Dhanwantharam kashayam (DK) are widely used in the management of diseases manifested due to vitiation of vata and vatarakta (mostly diseases of connective tissues, bones, joints and nervous system). Free radicals are generated subsequent to the inflammatory changes in such conditions, and these cytotoxic reactive oxygen species cause oxidative damage to the cells. Phenolic compounds are the most common water soluble antioxidant compounds in plants. OBJECTIVE: The present study aims at evaluating the phenolic content and antioxidant properties of these five kashayams and their probable protective role in the management of vata vyadhis. MATERIALS AND METHOD: The total phenolic contents of these five Ayurvedic decoctions were determined using Folin-Ciocalteu method and the antioxidant properties were estimated by DPPH (2'2-diphenyl-1 picryl hydrazine) radical scavenging activity. RESULT: MK exhibited higher property (total phenolic content-15.61 +/- 0.006 mg/g wt, EC50-7.2MUg/ml) when compared to other kashayams. DK with phenolic content 12.056 +/- 0.004 mg/g wt and 22 MUg/ml effective concentration for 50% inhibition comes next in the present study. REK, SK and MRK show almost similar phenolic content and antioxidant property. CONCLUSION: From the observations, it is seen that the total phenolic content and the antioxidant property of the products justify the protective and corrective effects produced by the products in vata and vatarakta disorders. PMID- 22529678 TI - Anti-inflammatory activity of Ajmodadi Churna extract against acute inflammation in rats. AB - BACKGROUND: Ayurvedic polyherbal formulations are widely prescribed for a wide range of inflammatory conditions, yet, despite widespread use, there has been no systematic documentation of their safety and efficacy. OBJECTIVE: The present study was undertaken to evaluate the anti-inflammatory activity of aqueous extracts of Ajmodadi churna (AJM) in rats. MATERIALS AND METHODS: Carrageenan induced hind paw edema and air pouch inflammation models were used for the study. RESULTS: The extracts showed significant antiinflammatory activity, reducing paw edema volume by 0.417 +/- 0.097 and 0.379 +/- 0.049, respectively. In the carrageenan-induced air pouch model, AJM reduced total leukocyte count by 73.09 +/- 7.13 and 62.17 +/- 10.53, granulocyte count by 69.48 +/- 5.44 and 63.33 +/- 4.13, and myeloperoxidase activity by 14.84 +/- 0.91 and 18.44 +/- 3.18, respectively, compared to controls. DISCUSSION AND CONCLUSION: AJM significantly reduced paw edema, during the second phase of edema development. In the carrageenan-induced air pouch model, AJM inhibited cellular infiltration into the air pouch fluid. We conclude that AJM is an effective candidate for prevention or treatment of acute inflammation. PMID- 22529679 TI - Evaluating higher doses of Shunthi - Guduchi formulations for safety in treatment of osteoarthritis knees: A Government of India NMITLI arthritis project. AB - BACKGROUND: Results of an exploratory trial suggested activity trends of Zingiber officinale-Tinopsora cordifolia (platform combination)-based formulations in the treatment of Osteoarthritis (OA) Knees. These formulations were "platform combination+Withania somnifera+Tribulus terrestris" (formulation B) and "platform combination+Emblica officinale" (formulation C). This paper reports safety of these formulations when used in higher doses (1.5-2 times) along with Sallaki Guggul and Bhallataka Parpati (a Semecarpus anacardium preparation). MATERIALS AND METHODS: Ninety-two patients with symptomatic OA knees were enrolled in a 6 weeks investigator blind, randomized parallel efficacy 4-arm multicenter drug trial. The 4 arms were (I) formulation B, 2 t.i.d.; (II) formulation B, 2 q.i.d.; (III) platform combination+Sallaki Guggul; (IV) Bhallataka Parpati+formulation C. A detailed enquiry was carried out for adverse events (AE) and drug toxicity as per a priori check list and volunteered information. Laboratory evaluation included detailed hematology and metabolic parameters. Patients were examined at baseline, first and fourth weeks, and on completion. Standard statistical program (SPSS version 12.5) was used for analysis. RESULTS: None of the patients reported serious AE or withdrew due to any drug-related toxicity. Mild gut-related (mostly epigastric burning) AE was reported. A mild increase in liver enzymes [serum glutamic pyruvate transaminase (SGPT), serum glutamic oxaloacetic transaminase (SGOT)] without any other hepatic abnormality was reported in 2 patients (group IV). Other laboratory parameters remained normal. The mean improvement in active pain visual analog scale (1.4, CI 0.5-2.22), WOMAC (functional activity questionnaire) pain score (1.37, CI 0.22-2.5), and urinary C-TAX (cartilage collagen breakdown product) assay was maximum (NS) in group IV. Lower dose group I showed numerically superior improvement compared with higher dose group II. CONCLUSION: The results suggested that despite higher doses, standardized Ayurvedic formulations demonstrated a good safety profile. An improved efficacy and likely chondroprotective effect was shown by group IV intervention. A confirmatory drug trial with adequate power and sample size was planned based on the learning from this trial. PMID- 22529680 TI - Shri Madhavacharya Gurukulam, Pune: An attempt to strengthen roots of classical Ayurveda. PMID- 22529681 TI - Vidyarthimitra vaidya madhav vasudev kolhatkar. PMID- 22529682 TI - The jerusalem international conference on integrative medicine, Israel. PMID- 22529683 TI - Consensus statement AIGO/SICCR: diagnosis and treatment of chronic constipation and obstructed defecation (part I: diagnosis). AB - Chronic constipation is a common and extremely troublesome disorder that significantly reduces the quality of life, and this fact is consistent with the high rate at which health care is sought for this condition. The aim of this project was to develop a consensus for the diagnosis and treatment of chronic constipation and obstructed defecation. The commission presents its results in a "Question-Answer" format, including a set of graded recommendations based on a systematic review of the literature and evidence-based medicine. This section represents the consensus for the diagnosis. The history includes information relating to the onset and duration of symptoms and may reveal secondary causes of constipation. The presence of alarm symptoms and risk factors requires investigation. The physical examination should assess the presence of lesions in the anal and perianal region. The evidence does not support the routine use of blood testing and colonoscopy or barium enema for constipation. Various scoring systems are available to quantify the severity of constipation; the Constipation Severity Instrument for constipation and the obstructed defecation syndrome score for obstructed defecation are the most reliable. The Constipation-Related Quality of Life is an excellent tool for evaluating the patient's quality of life. No single test provides a pathophysiological basis for constipation. Colonic transit and anorectal manometry define the pathophysiologic subtypes. Balloon expulsion is a simple screening test for defecatory disorders, but it does not define the mechanisms. Defecography detects structural abnormalities and assesses functional parameters. Magnetic resonance imaging and/or pelvic floor sonography can further complement defecography by providing information on the movement of the pelvic floor and the organs that it supports. All these investigations are indicated to differentiate between slow transit constipation and obstructed defecation because the treatments differ between these conditions. PMID- 22529684 TI - Adjuvant and neoadjuvant treatment in pancreatic cancer. AB - Pancreatic adenocarcinoma is one of the most aggressive human malignancies, ranking 4th among causes for cancer-related death in the Western world including the United States. Surgical resection offers the only chance of cure, but only 15 to 20 percent of cases are potentially resectable at presentation. Different studies demonstrate and confirm that advanced pancreatic cancer is among the most complex cancers to treat and that these tumors are relatively resistant to chemotherapy and radiotherapy. Currently there is no consensus around the world on what constitutes "standard" adjuvant therapy for pancreatic cancer. This controversy derives from several studies, each fraught with its own limitations. Standards of care also vary somewhat with regard to geography and economy, for instance chemo-radiotherapy followed by chemotherapy or vice versa is considered the optimal therapy in North America while chemotherapy alone is the current standard in Europe. Regardless of the efforts in adjuvant and neoadjuvant improved therapy, the major goal to combat pancreatic cancer is to find diagnostic markers, identifying the disease in a pre-metastatic stage and making a curative treatment accessible to more patients. In this review, authors examined the different therapy options for advanced pancreatic patients in recent years and the future directions in adjuvant and neoadjuvant treatments for these patients. PMID- 22529685 TI - 2011 update on esophageal achalasia. AB - There have been some breakthroughs in the diagnosis and treatment of esophageal achalasia in the past few years. First, the introduction of high-resolution manometry with pressure topography plotting as a new diagnostic tool has made it possible to classify achalasia into three subtypes. The most favorable outcome is predicted for patients receiving treatment for type II achalasia (achalasia with compression). Patients with type I(classic achalasia) and type III achalasia (spastic achalasia) experience a less favorable outcome. Second, the first multicenter randomized controlled trial published by the European Achalasia Trial group reported 2-year follow-up results indicating that laparoscopic Heller myotomy was not superior to endoscopic pneumatic dilation (PD). Although the follow-up period was not long enough to reach a convincing conclusion, it merits the continued use of PD as a generally available technique in gastroenterology. Third, the novel endoscopic technique peroral endoscopic myotomy is a promising option for treating achalasia, but it requires increased experience and cautious evaluation. Despite all this good news, the bottom line is a real breakthrough from the basic studies to identify the actual cause of achalasia that may impede treatment success is still anticipated. PMID- 22529686 TI - Dual regulatory role for phosphatase and tensin homolog in specification of intestinal endocrine cell subtypes. AB - AIM: To investigate the impact of phosphatase and tensin homolog (Pten) in the specification of intestinal enteroendocrine subpopulations. METHODS: Using the Cre/loxP system, a mouse with conditional intestinal epithelial Pten deficiency was generated. Pten mutant mice and controls were sacrificed and small intestines collected for immunofluorescence and quantitative real-time polymerase chain reaction. Blood was collected on 16 h fasted mice by cardiac puncture. Enzyme linked immunosorbent assay was used to measure blood circulating ghrelin, somatostatin (SST) and glucose-dependent insulinotropic peptide (GIP) levels. RESULTS: Results show an unexpected dual regulatory role for epithelial Pten signalling in the specification/differentiation of enteroendocrine cell subpopulations in the small intestine. Our data indicate that Pten positively regulates chromogranin A (CgA) expressing subpopulations, including cells expressing secretin, ghrelin, gastrin and cholecystokinin (CCK). In contrast, Pten negatively regulates the enteroendocrine subtype specification of non expressing CgA cells such as GIP and SST expressing cells. CONCLUSION: The present results demonstrate that Pten signalling favours the enteroendocrine progenitor to specify into cells expressing CgA including those producing CCK, gastrin and ghrelin. PMID- 22529687 TI - Overexpression of Dickkopf-3 induces apoptosis through mitochondrial pathway in human colon cancer. AB - AIM: To investigate the mechanisms of the biological roles of Dickkopf-3 (Dkk-3) in cell invasion, survival and apoptosis in colon cancer cells. METHODS: Three human colon cancer cell lines, i.e., HT-29, LoVo and SW480, were used. Overexpression of Dkk-3 induced by pEGFP-N1-Dkk-3-GFP plasmid in LoVo cells was performed using Lipofectamine 2000 reagent. Reverse transcription polymerase chain reaction and Western blotting were performed to determine the mRNA and protein expression levels of Dkk-3, respectively. Cell proliferation assay, cell cycle analysis, hoechst 33258 assay and Matrigel invasion assay were performed on Dkk-3 overexpressing transfectants. RESULTS: The mRNA and protein expressions of Dkk-3 in HT-29 (mRNA: 0.06 +/- 0.02, protein: 0.06 +/- 0.01) and LoVo (mRNA: 0.07 +/- 0.02, protein: 0.07 +/- 0.02) cells were significantly lower than that in SW480 cells (mRNA: 0.92 +/- 0.04, protein: 0.69 +/- 0.13; all P < 0.05), and the greatest levels of invasiveness was in LoVo cells. Dkk-3 overexpression inhibited the proliferation and invasion of LoVo cells and induced cell cycle arrest at G(0)/G(1) phase and subsequent apoptosis, as indicated by increased chromatin condensation and fragments, upregulated Bax and cytochrome c protein, downregulated survivin and Bcl-2 protein, and the activation of caspase-3 and caspase-9. Furthermore, Dkk-3 overexpression reduced the accumulation of cytosolic fraction of beta-catenin. CONCLUSION: Dkk-3 overexpression induced apoptosis in human colon cancer possibly through the mitochondrial pathway. Dkk-3 may be involved in the Wnt/beta-catenin signaling pathways in colon cancer. PMID- 22529688 TI - Toxicarioside A inhibits SGC-7901 proliferation, migration and invasion via NF kappaB/bFGF signaling. AB - AIM: To investigate the inhibitory role of toxicarioside A on the gastric cancer cell line human gastric cancer cell line (SGC-7901) and determine the underlying molecular mechanism. METHODS: After SGC-7901 cells were treated with toxicarioside A at various concentrations (0.5, 1.5, 4.5, 9.0 MUg/mL) for 24 h or 48 h, cell viability was determined by 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl 2H-tetrazolium bromide assay, and the motility and invasion of tumor cells were assessed by the Transwell chamber assay. Immunofluorescence staining, reverse transcription polymerase chain reaction and Western blotting were performed to detect the expression of basic fibroblast growth factor (bFGF) and fibroblast growth factor receptor-1 (FGFR1), and nuclear factor-kappa B (NF-kappaB) activation was examined by electrophoretic mobility shift assay. RESULTS: The results showed that toxicarioside A was capable of reducing cell viability, inhibiting cell growth, and suppressing cell migration and invasion activities in a time- and dose-dependent manner in SGC-7901 cells. Further analysis revealed that not only the expression of bFGF and its high-affinity receptor FGFR1 but also the NF-kappaB-DNA binding activity were effectively blocked by toxicarioside A in a dose-dependent manner compared with the control group (P < 0.05 or P < 0.01). Interestingly, application of the NF-kappaB specific inhibitor, pyrrolidinedithiocarbamate (PDTC), to SGC-7901 cells significantly potentized the toxicarioside A-induced down-regulation of bFGF compared with the control group (P < 0.05). CONCLUSION: These findings suggest that toxicarioside A has an anti gastric cancer activity and this effect may be achieved partly through down regulation of NF-kappaB and bFGF/FGFR1 signaling. PMID- 22529689 TI - Medical treatment for sphincter of oddi dysfunction: can it replace endoscopic sphincterotomy? AB - AIM: To report the results of a medical management of sphincter of oddi dysfunction (SOD) after an intermediate follow-up period. METHODS: A total of 59 patients with SOD (2 men and 57 women, mean age 51 years old) were included in this prospective study. After medical treatment for one year, the patients were clinically re-evaluated after an average period of 30 mo. RESULTS: The distribution of the patients according to the Milwaukee's classification was the following: 11 patients were type 1, 34 were type 2 and 14 were type 3. Fourteen patients underwent an endoscopic sphincterotomy (ES) after one year of medical treatment. The median intermediate follow-up period was 29.8 +/- 3 mo (3-72 mo). The initial effectiveness of the medical treatment was complete, partial and poor among 50.8%, 13.5% and 35%, respectively, of the patients. At the end of the follow-up period, 37 patients (62.7%) showed more than 50% improvement. The rate of improvement in patients who required ES was not significantly different compared with the patients treated conservatively (64.2% vs 62.2%, respectively). CONCLUSION: Our study confirms that conservative medical treatment could be an alternative to endoscopic sphincterotomy because, after an intermediate follow-up period, the two treatments show the same success rates. PMID- 22529690 TI - Impact of comorbidities on the severity of chronic hepatitis B at presentation. AB - AIM: To evaluate the clinical relevance of each cofactor on clinical presentation of chronic hepatitis B. METHODS: Out of 1366 hepatitis B surface antigen (HBsAg) positive subjects consecutively observed in 79 Italian hospitals, 53 (4.3%) showed as the only cofactor hepatitis D virus (HDV) infection [hepatitis B virus (HBV)/HDV group], 130 (9.5%) hepatitis C virus (HCV) (group HBV/HCV), 6 (0.4%) human immunodeficiency virus (HIV) (group HBV/HIV), 138 (10.2%) alcohol abuse (group HBV/alcohol); 109 (8.0%) subjects had at least two cofactors and 924 were in the cofactor-free (CF) group. RESULTS: Compared with patients in group CF those in group HBV/alcohol were older and more frequently had cirrhosis (P < 0.001), those in group HBV/HDV were younger (P < 0.001), more frequently resided in the south of the country and had cirrhosis (P <0.001), those in group HBV/HCV were older (P < 0.001) and more frequently had cirrhosis (P < 0.001). These cofactors were all independent predictors of liver cirrhosis in HBsAg positive patients. Multivariate analysis showed that an older age [odds ratio (OR) 1.06, 95% CI: 1.05-1.08], alcohol abuse with more than 8 drinks daily (OR 2.89, 95% CI: 1.81-4.62) and anti-HDV positivity (OR 3.48, 95% CI: 2.16-5.58) are all independently associated with liver cirrhosis. This association was found also for anti-HCV positivity in univariate analysis, but it was no longer associated (OR 1.23, 95% CI: 0.84-1.80) at multivariate analysis. CONCLUSION: Older age, HDV infection and alcohol abuse are the major determinants of severe liver disease in chronic HBV infection, while HCV replication plays a lesser role in the severity of hepatic damage. PMID- 22529691 TI - No evidence of circulating autoantibodies against osteoprotegerin in patients with celiac disease. AB - AIM: To investigate risk factors for low bone mineral density (BMD) in celiac disease (CD) patients, focusing on circulating autoantibodies against osteoprotegerin (OPG). METHODS: Seventy asymptomatic CD adult patients on gluten free diet (GFD) and harbouring persistent negative CD-related serology were recruited. Conventional risk factors for osteoporosis (e.g., age, sex, menopausal status, history of fractures, smoke, and body mass index) were checked and BMD was assessed by dual energy X ray absorptiometry. Serum calcium and parathyroid hormone (PTH) levels were evaluated. Thirty-eight patients underwent repeat duodenal biopsy. Serum samples from a selected sub-group of 30 patients, who were also typed for human leukocyte antigen (HLA) DQ2 and DQ8 haplotype, were incubated with homodimeric recombinant human OPG and tested by western blotting with an anti-OPG antibody after immunoprecipitation. RESULTS: Despite persistent negative CD-related serology and strict adherence to GFD, 49 out of the 70 (74%) patients displayed low BMD. Among these patients, 13 (24%) showed osteoporosis and 36 (76%) osteopenia. With the exception of age, conventional risk factors for osteoporosis did not differ between patients with normal and low BMD. Circulating serum calcium and PTH levels were normal in all patients. Duodenal mucosa healing was found in 31 (82%) out of 38 patients who underwent repeat duodenal biopsy with 20 (64%) still displaying low BMD. The remaining 7 patients had an incomplete normalization of duodenal mucosa with 6 (84%) showing low BMD. No evidence of circulating antibodies against OPG was found in the serum of 30 celiac patients who were tested for, independent of BMD, duodenal histology, and HLA status. CONCLUSION: If any, the role of circulating autoantibodies against OPG in the pathogenesis of bone derangement in patients with CD is not a major one. PMID- 22529692 TI - Mucosa-associated bacteria in two middle-aged women diagnosed with collagenous colitis. AB - AIM: To characterize the colon microbiota in two women histologically diagnosed with collagenous colitis using a culture-independent method. METHODS: Biopsies were taken from the ascending colon and the total DNA was extracted. Universal bacterial primers were used to amplify the bacterial 16S rRNA genes. The amplicons were then cloned into competent Escherichia coli cells. The clones were sequenced and identified by comparison to known sequences. RESULTS: The clones could be divided into 44 different phylotypes. The microbiota was dominated by Firmicutes and Bacteroidetes. Seven phylotypes were found in both patients and constituted 47.5% of the total number of clones. Of these, the most dominating were clones similar to Bacteroides cellulosilyticus, Bacteroides caccae, Bacteroides thetaiotaomicron, Bacteroides uniformis and Bacteroides dorei within Bacteroidetes. Sequences similar to Faecalibacterium prausnitzii and Clostridium citroniae were also found in both patients. CONCLUSION: A predominance of potentially pathogenic Bacteroides spp., and the presence of clones showing similarity to Clostridium clostridioforme were found but the overall colon microbiota showed similarities to a healthy one. Etiologies for collagenous colitis other than an adverse bacterial flora must also be considered. PMID- 22529693 TI - Randomized controlled trial of pancreatic stenting to prevent pancreatitis after endoscopic retrograde cholangiopancreatography. AB - AIM: To determine the effectiveness of pancreatic duct (PD) stent placement for the prevention of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) in high risk patients. METHODS: Authors conducted a single-blind, randomized controlled trial to evaluate the effectiveness of a pancreatic spontaneous dislodgement stent against post-ERCP pancreatitis, including rates of spontaneous dislodgement and complications. Authors defined high risk patients as having any of the following: sphincter of Oddi dysfunction, difficult cannulation, prior history of post-ERCP pancreatitis, pre-cut sphincterotomy, pancreatic ductal biopsy, pancreatic sphincterotomy, intraductal ultrasonography, or a procedure time of more than 30 min. Patients were randomized to a stent group (n = 60) or to a non-stent group (n = 60). An abdominal radiograph was obtained daily to assess spontaneous stent dislodgement. Post-ERCP pancreatitis was diagnosed according to consensus criteria. RESULTS: The mean age (+/- standard deviation) was 67.4 +/- 13.8 years and the male: female ratio was 68:52. In the stent group, the mean age was 66 +/- 13 years and the male: female ratio was 33:27, and in the non-stent group, the mean age was 68 +/- 14 years and the male: female ratio was 35:25. There were no significant differences between groups with respect to age, gender, final diagnosis, or type of endoscopic intervention. The frequency of post-ERCP pancreatitis in PD stent and non-stent groups was 1.7% (1/60) and 13.3% (8/60), respectively. The severity of pancreatitis was mild in all cases. The frequency of post-ERCP pancreatitis in the stent group was significantly lower than in the non-stent group (P = 0.032, Fisher's exact test). The rate of hyperamylasemia were 30% (18/60) and 38.3% (23 of 60) in the stent and non-stent groups, respectively (P = 0.05, chi(2) test). The placement of a PD stent was successful in all 60 patients. The rate of spontaneous dislodgement by the third day was 96.7% (58/60), and the median (range) time to dislodgement was 2.1 (2-3) d. The rates of stent migration, hemorrhage, perforation, infection (cholangitis or cholecystitis) or other complications were 0% (0/60), 0% (0/60), 0% (0/60), 0% (0/60), 0% (0/60), respectively, in the stent group. Univariate analysis revealed no significant differences in high risk factors between the two groups. The pancreatic spontaneous dislodgement stent safely prevented post-ERCP pancreatitis in high risk patients. CONCLUSION: Pancreatic stent placement is a safe and effective technique to prevent post-ERCP pancreatitis. Therefore authors recommend pancreatic stent placement after ERCP in high risk patients. PMID- 22529694 TI - Relationship between hepatitis C virus infection and type 2 diabetes mellitus: meta-analysis. AB - AIM: To investigate the association between hepatitis C infection and type 2 diabetes mellitus. METHODS: Observational studies assessing the relationship between hepatitis C infection and type 2 diabetes mellitus were identified via electronic and hand searches. Studies published between 1988 to March 2011 were screened, according to the inclusion criteria set for the present analysis. Authors performed separate analyses for the comparisons between hepatitis C virus (HCV) infected and not infected, and HCV infected and hepatitis B virus infected. The included studies were further subgrouped according to the study design. Heterogenity was assessed using I(2) statistics. The summary odds ratios with their corresponding 95% CIs were calculated based on a random-effects model. The included studies were subgrouped according to the study design. To assess any factor that could potentially affect the outcome, results were further stratified by age group (proportion of >= 40 years), gender (proportion of male gender), body mass index (BMI) (proportion of BMI >= 27), and family history of diabetes (i.e., self reported). For stability of results, a sensitivity analysis was conducted including only prospective studies. RESULTS: Combining the electronic database and hand searches, a total of 35 observational studies (in 31 articles) were identified for the final analysis. Based on random-effects model, 17 studies (n = 286,084) compared hepatitis C-infected patients with those who were uninfected [summary odds ratio (OR): 1.68, 95% CI: 1.15-2.45]. Of these 17 studies, 7 were both a cross-sectional design (41.2%) and cohort design (41.2%), while 3 were case-control studies (17.6%). Nineteen studies (n = 51,156) compared hepatitis C-infected participants with hepatitis B-infected (summary OR: 1.92, 95% CI: 1.41-2.62). Of these 19 studies, 4 (21.1%), 6 (31.6%) and 9 (47.4%) were cross-sectional, cohort and case-control studies, respectively. A sensitivity analysis with 3 prospective studies indicated that hepatitis C-infected patients had a higher risk of developing type 2 diabetes compared with uninfected controls (summary odds ratio: 1.41, 95% CI: 1.17-1.7; I(2) = 0%). Among hepatitis C infected patients, male patients (OR: 1.26, 95% CI: 1.03-1.54) with age over 40 years (summary OR: 7.39, 95% CI: 3.82-9.38) had an increased frequency of type 2 diabetes. Some caution must be taken in the interpretation of these results because there may be unmeasured confounding factors which may introduce bias. CONCLUSION: The findings support the association between hepatitis C infection and type 2 diabetes mellitus. The direction of association remains to be determined, however. Prospective studies with adequate sample sizes are recommended. PMID- 22529695 TI - A population-based cohort study of symptomatic gallstone disease in diabetic patients. AB - AIM: To investigate the prevalence of gallstone disease (GSD) and to evaluate the risk of symptomatic GSD among diabetic patients. METHODS: The study was conducted by analyzing the National Health Research Institutes (NHRI) dataset of ambulatory care patients, inpatient claims, and the updated registry of beneficiaries from 2000 to 2008. A total of 615,532 diabetic patients without a prior history of hospital treatment or ambulatory care visits for symptomatic GSD were identified in the year 2000. Age- and gender-matched control individuals free from both GSD and diabetes from 1997 to 1999 were randomly selected from the NHIR database (n = 614,871). The incidence densities of symptomatic GSD were estimated according to the subjects' diabetic status. The distributions of age, gender, occupation, income, and residential area urbanization were compared between diabetic patients and control subjects using Cox proportion hazards models. Differences between the rates of selected comorbidities were also assessed in the two groups. RESULTS: Overall, 60,734 diabetic patients and 48,116 control patients developed symptomatic GSD and underwent operations, resulting in cumulative operation rates of 9.87% and 7.83%, respectively. The age and gender distributions of both groups were similar, with a mean age of 60 years and a predominance of females. The diabetic group had a significantly higher prevalence of all comorbidities of interest. A higher incidence of symptomatic GSD was observed in females than in males in both groups. In the control group, females under the age of 64 had a significantly higher incidence of GSD than the corresponding males, but this difference was reduced with increasing age. The cumulative incidences of operations for symptomatic GSD in the diabetic and control groups were 13.06 and 9.52 cases per 1000 person-years, respectively. Diabetic men exhibited a higher incidence of operations for symptomatic GSD than did their counterparts in the control group (12.35 vs 8.75 cases per 1000 person-years). CONCLUSION: The association of diabetes with increased symptomatic GSD may provide insight to the treatment or management of diabetes in clinical settings. PMID- 22529696 TI - Swab culture monitoring of automated endoscope reprocessors after high-level disinfection. AB - AIM: To conduct a bacterial culture study for monitoring decontamination of automated endoscope reprocessors (AERs) after high-level disinfection (HLD). METHODS: From February 2006 to January 2011, authors conducted randomized consecutive sampling each month for 7 AERs. Authors collected a total of 420 swab cultures, including 300 cultures from 5 gastroscope AERs, and 120 cultures from 2 colonoscope AERs. Swab cultures were obtained from the residual water from the AERs after a full reprocessing cycle. Samples were cultured to test for aerobic bacteria, anaerobic bacteria, and mycobacterium tuberculosis. RESULTS: The positive culture rate of the AERs was 2.0% (6/300) for gastroscope AERs and 0.8% (1/120) for colonoscope AERs. All the positive cultures, including 6 from gastroscope and 1 from colonoscope AERs, showed monofloral colonization. Of the gastroscope AER samples, 50% (3/6) were colonized by aerobic bacterial and 50% (3/6) by fungal contaminations. CONCLUSION: A full reprocessing cycle of an AER with HLD is adequate for disinfection of the machine. Swab culture is a useful method for monitoring AER decontamination after each reprocessing cycle. Fungal contamination of AERs after reprocessing should also be kept in mind. PMID- 22529697 TI - Prognostic significance of PTEN, Ki-67 and CD44s expression patterns in gastrointestinal stromal tumors. AB - AIM: To develop a prognostic approach for gastrointestinal stromal tumors (GISTs) using a cluster of indicators and follow-up information. METHODS: One hundred and four GISTs that had not been subjected to targeted therapies were collected and classified by NIH risk assessment and anatomic location. By immunohistochemistry, the expressions of PTEN, Ki-67, CD44s matrix metalloproteinase (MMP)-9 and TIMP-1 were detected on tissue microarray. Univariate and multimarker survival analyses were performed and then a COX hazard proportion model was constructed to evaluate a cluster of predictors of GIST. RESULTS: Our data showed small intestinal GIST are more aggressive than gastric GIST. The NIH risk assessment correlated with disease-free survival for either gastric GIST or small intestinal GIST. Immunohistochemical analysis revealed that Ki-67 labeling indexes (LIs) < 5% predicted higher disease-specific survival (DSS) in gastric and small intestinal GIST. CD44s positivity and PTEN LIs >= 50% correlated with higher DSS in gastric GIST. MMP-9 and TIMP-1 had no correlation with survival. Multimarker analysis revealed that the expression pattern of PTEN LIs >= 50% combined with Ki-67 LIs < 5% and CD44s positivity reliably predicted favorable outcomes for gastric GIST (P = 0.009), as did the combination of PTEN LIs >= 50% and Ki-67 LIs < 5% for small intestinal GIST (P = 0.011). Authors also found that high NIH risk grade was correlated with DSS in patients with gastric GIST and disease-free survival in patients with small intestinal GIST. CONCLUSION: PTEN LIs >= 50%, Ki-67 LIs < 5% and CD44s positivity provides an accurate, favorable prognosis for gastric GIST. PTEN LIs >= 50% and Ki-67 LIs < 5% does the same for small intestinal GIST. Ki-67 LIs enhances the NIH assessment. PMID- 22529699 TI - Heme oxygenase-1 prevents liver fibrosis in rats by regulating the expression of PPARgamma and NF-kappaB. AB - AIM: To investigate the effects of heme oxygenase (HO)-1 on liver fibrosis and the expression of peroxisome proliferator-activated receptor gamma (PPARgamma) and nuclear factor-kappa B (NF-kappaB) in rats. METHODS: Sixty Wistar rats were used to construct liver fibrosis models and were randomly divided into 5 groups: group A (normal, untreated), group B (model for 4 wk, untreated), group C (model for 6 wk, untreated), group D [model for 6 wk, treated with zinc protoporphyrin IX (ZnPP-IX) from week 4 to week 6], group E (model for 6 wk, treated with hemin from week 4 to week 6). Next, liver injury was assessed by measuring serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and albumin levels. The degree of hepatic fibrosis was evaluated by measuring serum hyaluronate acid (HA), type IV collagen (IV-C) and by histological examination. Hydroxyproline (Hyp) content in the liver homogenate was determined. The expression levels of alpha-smooth muscle actin (alpha-SMA) in liver tissue were measured by real-time quantitative polymerase chain reaction (RT-PCR). The expression levels of PPARgamma and NF-kappaB were determined by RT-PCR and Western blotting. RESULTS: The expression of HO-1 increased with the development of fibrosis. Induction of HO-1 by hemin significantly attenuated the severity of liver injury and the levels of liver fibrosis as compared with inhibition of HO-1 by ZnPP-IX. The concentrations of serum ALT, AST, HA and IV-C in group E decreased compared with group C and group D (P < 0.01). Amount of Hyp and alpha SMA in the liver tissues in group E decreased compared with group C (0.62 +/- 0.14 vs 0.84 +/- 0.07, 1.42 +/- 0.17 vs 1.84 +/- 0.17, respectively, P < 0.01) and group D (0.62 +/- 0.14 vs 1.11 +/- 0.16, 1.42 +/- 0.17 vs 2.56 +/- 0.37, respectively, P < 0.01). The expression of PPARgamma at levels of transcription and translation decreased with the development of fibrosis especially in group D; and it increased in group E compared with groups C and D (0.88 +/- 0.15 vs 0.56 +/- 0.19, 0.88 +/- 0.15 vs 0.41 +/- 0.11, respectively, P < 0.01). The expression of NF-kappaB increased with the development of fibrosis especially in group D; and it decreased in group E compared with groups C and D (1.43 +/- 0.31 vs 1.89 +/- 0.29, 1.43 +/- 0.31 vs 2.53 +/- 0.54, respectively, P < 0.01). CONCLUSION: Our data demonstrate a potential mechanism that HO-1 can prevent liver fibrosis by enhancing the expression of PPARgamma and decreasing the expression of NF kappaB in liver tissues. PMID- 22529700 TI - Treatment of cholecystitis with Chinese herbal medicines: a systematic review of the literature. AB - AIM: To analyze the literature on the use of Chinese herbal medicines for the treatment of cholecystitis. METHODS: The literature on treatment of cholecystitis with traditional Chinese medicines (TCM) was analyzed based on the principles and methods described by evidence-based medicine (EBM). Eight databases including MEDLINE, EMbase, Cochrane Central (CCTR), four Chinese databases (China Biological Medicine Database, Chinese National Knowledge Infrastructure Database, Database of Chinese Science and Technology Periodicals, Database of Chinese Ministry of Science and Technology) and Chinese Clinical Registry Center, were searched. Full text articles or abstracts concerning TCM treatment of cholecystitis were selected, categorized according to study design, the strength of evidence, the first author's hospital type, and analyzed statistically. RESULTS: A search of the literature published from 1977 through 2009 yielded 1468 articles in Chinese and 9 in other languages; and 93.92% of the articles focused on clinical studies. No article was of level I evidence, and 9.26% were of level II evidence. The literature cited by Science Citation Index (SCI), MEDLINE and core Chinese medical journals accounted for 0.41%, 0.68% and 7.29%, respectively. Typically, the articles featured in case reports of illness, examined from the perspective of EBM, were weak in both quality and evidence level, which inconsistently conflicted with the fact that most of the papers were by authors from Level-3 hospitals, the highest possible level evaluated based on their comprehensive quality and academic authenticity in China. CONCLUSION: The published literature on TCM treatment of cholecystitis is of low quality and based on low evidence, and cognitive medicine may functions as a useful supplementary framework for the evaluation. PMID- 22529698 TI - Vitamin D receptor gene polymorphisms and colorectal cancer risk: a systematic meta-analysis. AB - AIM: To investigate the relationship between polymorphisms present in the vitamin D receptor (VDR) gene and colorectal cancer risk, a systematic meta-analysis of population-based studies was performed. METHODS: A total of 38 relevant reports published between January 1990 and August 2010 were identified, of which only 23 qualified for this meta-analysis based on our selection criteria. Five polymorphic variants of the VDR gene, including Cdx-2 (intron 1e) and FokI (exon 2) present in the 5' region of the gene, and BsmI (intron 8), ApaI (intron 8), and TaqI (exon 9) sites present in the 3' untranslated region (UTR), were evaluated for possible associations with colorectal cancer risk. Review manager 4.2 was used to perform statistical analyses. RESULTS: In the meta-analysis performed, only the BsmI polymorphism was found to be associated with colorectal cancer risk. In particular, the BsmI B genotype was found to be related to an overall decrease in the risk for colorectal cancer [BB vs bb: odds ratio (OR) = 0.87, 95% CI: 0.80-0.94, P = 3 * 10(-4); BB vs Bb + bb: OR = 0.90, 95% CI: 0.84 0.97, P = 5 * 10(-4)]. Moreover, in subgroup analyses, the BsmI B genotype was significantly associated with colon cancer, and not rectal cancer. An absence of between-study heterogeneity was also observed. CONCLUSION: A meta-analysis of 23 published studies identified the BsmI polymorphism of the VDR gene to be associated with an increased risk of colon cancer. PMID- 22529701 TI - High resolution impedance manometric findings in dysphagia of Huntington's disease. AB - Conventional manometry presents significant challenges, especially in assessment of pharyngeal swallowing, because of the asymmetry and deglutitive movements of oropharyngeal structures. It only provides information about intraluminal pressure and thus it is difficult to study functional details of esophageal motility disorders. New technology of solid high resolution impedance manometry (HRIM), with 32 pressure sensors and 6 impedance sensors, is likely to provide better assessment of pharyngeal swallowing as well as more information about esophageal motility disorders. However, the clinical usefulness of application of HRIM in patients with oropharyngeal dysphagia or esophageal dysphagia is not known. We experienced a case of Huntington's disease presenting with both oropharyngeal and esophageal dysphagia, in which HRIM revealed the mechanism of oropharyngeal dysphagia and provided comprehensive information about esophageal dysphagia. PMID- 22529702 TI - Rifaximin for the prevention of spontaneous bacterial peritonitis. AB - According to a review article by Biecker et al published in a previous issue of World Journal of Gastroenterology in March 2011, intestinal decontamination with norfloxacin remains the mainstay of primary prophylaxis of spontaneous bacterial peritonitis (SBP) at the expense of development of quinolone-resistant bacteria after long-term use. In our research, the administration of a 4-wk regimen with rifaximin 1200 mg/d reduced significantly the ascitic neutrophil count in cirrhotic patients with sterile ascites in line with a significant decrease in plasma endotoxin levels. Our observations concur with recent findings, showing a significantly reduced 5-year probability of SBP in cirrhotic patients taking rifaximin. PMID- 22529703 TI - Hyperosmolarity potentiates toxic effects of benzalkonium chloride on conjunctival epithelial cells in vitro. AB - PURPOSE: Benzalkonium chloride (BAK), the most commonly used preservative in eye drops, is known to induce ocular irritation symptoms and dry eye in long-term treated patients and animal models. As tear film hyperosmolarity is diagnostic of some types of dry eye disease, we determined in vitro on conjunctival epithelial cells the cytoxicity of BAK in hyperosmolar conditions through cell viability, apoptosis, and oxidative stress assays. METHODS: The Wong Kilbourne derivative of Chang conjunctival epithelial cells were cultured for 24 h or 48 h either in NaCl induced hyperosmolar conditions (400-425-500 mOsM), in low concentrations of BAK (10(-4)%, 3.10(-4)%, and 5.10(-4)%), or in combination of both. We investigated cell viability through lysosomal integrity evaluation, cell death (cell membrane permeability and chromatin condensation), and oxidative stress (reactive oxygen species, superoxide anion) using spectrofluorimetry. Immunohistochemistry was performed for cytoskeleton shrinkage (phalloidin staining), mitochondrial permeability transition pore (cytochrome c release), the apoptosis effector active caspase-3, and the caspase-independent apoptosis factor AIF. We also observed early effects induced by the experimental conditions on the conjunctival cell layers using phase contrast imaging of live cells. RESULTS: As compared to standard culture solutions, hyperosmolar stress potentiated BAK cytotoxicity on conjunctival cells through the induction of oxidative stress; reduction of cell viability; cell membrane permeability increase; cell shrinkage with cell blebbing, as shown in phase contrast imaging of live cells; and chromatin condensation. Like BAK, but to a much lesser extent, hyperosmolarity increased cell death in a concentration-dependent manner through a caspase-dependent apoptosis characterized by a release of cytochrome c in the cytoplasm from mitochondria and the activation of caspase-3. Moreover, the caspase-independent apoptosis factor AIF was found translocated from mitochondria to the nucleus in both conditions. CONCLUSIONS: This study showed increased cytotoxic effects of BAK in hyperosmotic conditions, with characteristic cell death processes, namely caspase-dependent and independent apoptosis and oxidative stress. As BAK is known to disrupt tear film, which could promote evaporative dry eye and tear hyperosmolarity, BAK could promote the conditions enhancing its own cytotoxicity. This in vitro hyperosmolarity model thus highlights the risk of inducing a vicious cycle and the importance of avoiding BAK in patients with dry eye conditions. PMID- 22529704 TI - SPECT molecular imaging in Parkinson's disease. AB - Parkinson's disease (PD) is a common disorder, and the diagnosis of Parkinson's disease is clinical and relies on the presence of characteristic motor symptoms. The accuracy of the clinical diagnosis of PD is still limited. Functional neuroimaging using SPECT technique is helpful in patients with first signs of parkinsonism. The changes detected may reflect the disease process itself and/or compensatory responses to the disease, or they may arise in association with disease- and/or treatment-related complications. This paper addresses the value of SPECT in early differential diagnosis of PD and its potential as a sensitive tool to assess the pathophysiology and progression, as well as the therapeutic efficacy of PD. PMID- 22529705 TI - Comparative characterisation of genotypically different clones of MRSA in the production of biofilms. AB - The ability to adhere and produce biofilms is characteristic of enhanced virulence among isolates of methicillin-resistant Staphylococcus aureus (MRSA). The aim of the study is to find out whether these characteristics are consistently similar among isolates variations of MRSA. The study used 30 various isolates of MRSA belong to 13 spa types and 5 MLST types and determined the aggregation, the adherence, and the production of biofilms and slime for each isolate. The methods used to evaluate these characteristics were a modified Congo red agar assay (MCRA), a microtiter plate assay (MPA), high-magnification light microscopy, scanning electron microscopy (SEM), and PCR. The study found that isolates belonging to similar Spa, SCCmec, and ST types have similar abilities to produce biofilms; however, their ability to produce slime on CRA was found to be different. Moreover, isolates that have different Spa types showed high variation in their ability to produce biofilms. The results of light microscope revealed the isolates that produced strong and weak biofilms and formed similar aggregation on the glass surfaces. SEM results showed that all 30 MRSA isolates that were tested were 100% positive for biofilm formation, although to varying degrees. Further testing using PCR confirmed that 100% of the 30 isolates tested were positive for the presence of the icaADBC, fnbA, eno, ebps, clfA, and clfB genes. The prevalence of fib, cna, fnbB, and bbp in MRSA clones was 90, 93.33, 53.33, and 10%, respectively. This study indicate that differences in biofilm production capacities are caused by the differences in surface protein A (Spa) type and are not due to differences in MLST and SCCmec types. PMID- 22529707 TI - Antimicrobial resistance: The never ending story. PMID- 22529708 TI - Consensus conference on Lyme disease. PMID- 22529706 TI - Molecular imaging in therapeutic efficacy assessment of targeted therapy for nonsmall cell lung cancer. AB - Membrane distillation is a thermally driven membrane process for seawater desalination and purification at moderate temperatures and pressures. A hydrophobic micro-porous membrane is used in this process, which separates hot and cold water, allowing water vapor to pass through; while restricting the movement of liquid water, due to its hydrophobic nature. This paper provides an experimental investigation of heat and mass transfer in tubular membrane module for water desalination. Different operating parameters have been examined to determine the mass transport mechanism of water vapor. Based on the experimental results, the effects of operating parameters on permeate flux and the heat transfer analysis have been presented and discussed in details. PMID- 22529709 TI - Field studies on Lyme disease in North America. AB - The primary tick vector of Borrelia burgdorferi in eastern and central North America is Ixodes dammini; in western North America, Ixodes pacificus. Searching for the appropriate vector is the first step in determining whether a region is endemic and enzootic for the spirochete B burgdorferi, the etiological agent of Lyme disease, followed by examination of the ticks (questing or already attached to hosts) and wildlife for the spirochete. Questing ticks can be collected through a variety of methods. The two major animal hosts for I dammini are the white-footed mouse Peromyscus leucopus and the white-tailed deer Odocoileus virginianus. Sampling strategies should consider habitat and season. All three life stages of the vector tick should be located, indicating a self-sustaining population. Although B burgdorferi can be detected in many ways, there is no substitute for isolating the spirochete in Barbour-Stoenner-Kelly II medium for definitive proof of the presence of the Lyme disease spirochete. PMID- 22529710 TI - Epidemiology of Lyme disease. AB - Investigation of the epidemiology of Lyme disease depends upon information generated from several sources. Human disease surveillance can be conducted by both passive and active means involving physicians, public health agencies and laboratories. Passive and active tick surveillance programs can document the extent of tick-borne activity, identify the geographic range of potential vector species, and determine the relative risk of exposure to Lyme disease in specific areas. Standardized laboratory services can play an important role in providing data. Epidemiologists can gain a better understanding of Lyme disease through the collection of data from such programs. The interpretation of data and provision of information to the medical and general communities are important functions of public health agencies. PMID- 22529711 TI - Overview of the clinical manifestations of Borrelia burgdorferi infection. AB - Lyme disease, caused by the spirochete Borrelia burgdorferi, has classically been divided into three stages: erythema migrans; neurological or cardiac involvement; and arthritis. Rather than defining a set disease pattern, however, one should, more logically, conceptualize a progressive infection that may be localized or disseminated, acute or chronic. Erythema migrans, the earliest and most easily recognized manifestation of B burgdorferi infection, is an expanding annular erythematous skin lesion with a central clearing that develops soon after the bite of an infected ixodes tick. Musculoskeletal manifestations are common, with approximately one-half of untreated individuals developing arthritis. Of these, only 10% have chronic arthritis. Invasion of the central nervous system occurs as the infection disseminates hematogenously, with encephalitis, myelitis and meningopolyneuritis being the most severe results. Acute cardiac involvement is recognized in up to 8% of adult patients, and less often in children. Early antibiotic treatment of the infection is highly effective. PMID- 22529712 TI - Laboratory confirmation of Lyme disease. AB - Lyme disease can be confirmed in the laboratory by isolation or detection of its causative agent, a tick-borne spirochete Borrelia burgdorferi, or by a diagnostic change in the titre of antibodies specific to the agent. B burgdorferi can be isolated and cultivated in Barbour-Stoenner-Kelly II medium. It can be detected by light microscopy in tissue sections or, rarely, in blood smears using various staining methods. There is interest in the development of alternative detection methods, including identification of specific antigens of B burgdorferi in the urine of suspected cases and demonstration of the presence of species-specific DNA using polymerase chain reaction assays. Currently, serological tests (indirect immunofluorescence assay, enzyme-linked immunosorbent assay and Western immunoblot) are the most practical and available methods for confirming Lyme disease. The quest to improve the specificity and sensitivity of serological tests - for example, through the use of specific recombinant antigens - continues. PMID- 22529713 TI - Prevalence of antibody to hepatitis C virus in an isolated Canadian Inuit settlement. AB - Sera from 720 inhabitants of Baker Lake, Northwest Territories, a community with high rates of hepatitis A and B infection, were tested for antibody to hepatitis C virus by commercial enzyme-linked immunosorbent assay. Only two individuals (0.3%) were positive, a 63-year-old female and an unrelated 10-year-old male. Neither individual was at increased risk of hepatitis C virus exposure. The results of this study indicate that hepatitis C virus infection is no more common in this northern Canadian Inuit settlement than it is in the blood donor population of southern Canada. PMID- 22529715 TI - The polymerase chain reaction: An overview and development of diagnostic PCR protocols at the LCDC. PMID- 22529716 TI - What do we do about Listeria monocytogenes? PMID- 22529714 TI - The potential role of recombinant hematopoietic colony-stimulating factors in preventing infections in the immunocompromised host. AB - Hematopoietic colony-stimulating factors coordinate the proliferation and maturation of bone marrow and peripheral blood cells during normal hematopoiesis. Most of these factors are now available as recombinant human colony-stimulating factors, and preclinical and clinical testing is proceeding rapidly. Granulocyte and granulocyte/macrophage colony-stimulating factors have been the most extensively studied to date. In human clinical trials, granulocyte colony stimulating factor improves neutrophil counts and function, reduces episodes of febrile neutropenia, improves neutrophil recovery after disease- or treatment induced myelosuppression, and reduces the number of serious infections in several neutropenic disease states. Granulocyte/macrophage colony-stimulating factor has similar biological properties but may also improve eosinophil proliferation and function, and platelet cell recovery after myelotoxic bone marrow injury, Interleukin-1 boosts the effects of granulocyte colony-stimulating factor and granulocyte/macrophage colony-stimulating factor, but also may promote the resolution of established infections in conjunction with antibiotics. The therapeutic realities and future therapeutic implications of these agents for the therapy of infections, cancer and hemopoietic disorders are discussed. PMID- 22529717 TI - Imported arbovirus infections in Canada 1974-89. AB - From 1974 to 1989, sera from symptomatic patients with histories of recent travel outside Canada were tested for antibodies to several arboviruses, principally of the alphavirus and flavivirus families. Diagnostic seroconversions were documented in 84 individuals from six provinces, including one alphavirus (Chikungunya) and 83 flavivirus seroconvertors. Dengue 1 virus was isolated from the blood of one patient. Most flavivirus seroconvertors were likely infected with dengue virus, but infections with tick-borne encephalitis, St Louis encephalitis and Powassan viruses were also recognized. Patients had histories of recent travel to the Caribbean, South America, Asia, Africa, North America (outside Canada), Tahiti, Fiji and Europe. Possible imported infections due to Japanese encephalitis, Ross River, western equine encephalitis and Colorado tick fever viruses were also encountered. PMID- 22529718 TI - Effectiveness and cost-benefit of an influenza vaccination program for health care workers. AB - This study retrospectively reviewed the effectiveness of a vaccination program for hospital workers in a large tertiary care hospital, quantified influenza induced absenteeism, and examined the factors determining the costs and benefits of this program. Absenteeism among high risk hospital workers was increased by 35% (P=0.001) during the virulent influenza epidemic of 1987-88. Benefits, measured as the value of sick time avoided, compared with costs, including materials, occupational nursing staff time, employee time during vaccination, and time lost due to adverse reactions, revealed a net benefit of $39.23 per vaccinated employee. Sensitivity analyses highlighted vaccine efficacy and absenteeism due to influenza and adverse reactions to vaccination as the most important factors; with time lost due to adverse reactions as much as 0.013 days per vaccinated employee and a vaccine efficacy of 70%, net positive benefits could be achieved if influenza-induced absenteeism is 0.5% or greater of paid employee time during the epidemic season. The results suggested that the net cost benefit of a hospital employee vaccination program to decrease both employee morbidity and nosocomial influenza among patients, would be increased by active promotion of the vaccination program, especially for employees in high risk areas. PMID- 22529720 TI - Prevention of foodborne listeriosis. AB - Listeria monocytogenes is a Gram-positive, rod-shaped bacterium which, although recognized in the medical literature as an opportunistic pathogen for the past 60 years, has only recently gained prominence as an important foodborne pathogen. Factors which make this organism unique among foodborne pathogens include its ability both to survive in foods under a variety of adverse conditions and to grow at low refrigeration temperatures. The organism is very widespread in the environment and can be found in a wide variety of foods. At least four major outbreaks definitively linked to the consumption of food containing L monocytogenes have occurred. In addition there have been a number of recent sporadic cases of listeriosis linked to the consumption of meat, fish and dairy products. The primary concern of the Health Protection Branch is contaminated foods in which L monocytogenes can grow well, and which would not normally be heated prior to consumption. Worldwide, the disease appears to be increasing in incidence, but definite links to foods are difficult to make. In most cases, individuals who come down with listeriosis include the immunocompromised, the elderly (older than 65 years) and pregnant women and their fetuses. Primary manifestations of the disease include meningitis, spontaneous abortion and septicemia. Mortality rates in foodborne listeriosis outbreaks are approximately 30%. Diagnosis of listeriosis usually requires isolation of the organism from sterile sites such as blood, cerebrospinal fluid, placenta and meconium and gastric aspirates from neonates. The recommended drug of choice is high dose intravenous ampicillin. Advice to physicians concerning measures to prevent foodborne listeriosis in high risk groups is reviewed. Included among these recommendations is avoidance of consumption of potentially hazardous foods such as soft cheese and raw products of animal origin. PMID- 22529719 TI - The diagnosis of Epstein-Barr virus-associated polymorphic B cell lymphoma in immunocompromised patients: Review of methods. AB - Polymorphic B cell lymphoma and diffuse B cell lymphoproliferation associated with Epstein-Barr virus infection is increasingly reported in immunodeficient patients. Accurate diagnosis of these pathologies is essential because the appropriate treatment regimens for the patients in question differ from those for patients with other lymphoproliferative diseases. Two complementary techniques are currently used in the diagnosis and characterization of Epstein-Barr virus associated B cell lymphomas and diffuse B cell lymphoproliferation. Immunofluorescence allows specific detection of Epstein-Barr nuclear antigens in lymphomatous tissue. Molecular hybridization with the Bam H1-W and/or Bam H1-NJ probes confirms the presence of the Epstein-Barr virus genome in tumour cells. The Bam H1-NJ probe is also useful in determining the clonality of the tumour and the replication mode, episomal or linear, of the viral genome. The polymerase chain reaction method allows detection of the Epstein-Barr virus genome within 24 h in these tumours and is more sensitive. PMID- 22529721 TI - Anti-retroviral strategies for AIDS and related diseases. AB - The replication cycle of human immunodeficiency virus type 1 (HIV-1) and other retroviruses consists of four stages: attachment of the virus to specific receptors on the cell surface; uncoating of the viral nucleic acid and conversion to DNA; production of viral RNA and proteins; and assembly and liberation of progeny virus from the cell. Each of these steps represents a potential target for antiviral chemotherapy. Combinations of drugs which act against different steps in the viral replication cycle might be expected to have synergistic potential. Zidovudine (AZT) is the most widely used drug to date for impeding the replication of HIV-1. Although AZT therapy has been reasonably successful, it has not been free from toxicity. In addition, there have been several reports of isolation of AZT-resistant variants of HIV-1. PMID- 22529722 TI - The Field Epidemiology Training Program at the LCDC. PMID- 22529723 TI - Tuberculosis - Still a major health problem. PMID- 22529724 TI - An epidemic of primary tuberculosis in a Canadian aboriginal community. AB - In 1987, an outbreak of primary tuberculosis occurred in a Canadian aboriginal community of 350 people. The source case was a young woman who had been symptomatic for four months with smear positive cavitary pulmonary tuberculosis. Her 17 siblings and their families were frequent close contacts. Among the 626 persons surveyed in the community and environs, 35 additional active cases of tuberculosis were identified. The mean age of cases was 13 years and the median age 10 years. The method of diagnosis was bacteriological in 20 and radiological in 16. There were 257 positive tuberculin reactors of whom 120 had no previous record of a positive skin test. Isoniazid prophylaxis was recommended to all new reactors, close household contacts, reactors under the age of 35 years and reactors with lung scars. One late case was identified at one year of follow-up in a contact who had refused prophylaxis. The rates of infection and disease were higher in the family (65% and 46%, respectively) than in the community and environs (19% and 5.6%, respectively). This report illustrates the nature of a point source epidemic of primary tuberculosis in a susceptible community with a predictable reservoir of infection. The delay in diagnosis of the source case allowed numerous new infections to occur. However, prompt aggressive contact follow-up was successful in containing the epidemic. To prevent future outbreaks, the reservoir of infected persons must be identified and administered chemoprophylaxis. PMID- 22529725 TI - Pyuria in institutionalized elderly subjects. AB - Two hundred and forty-three urine specimens from 76 elderly institutionalized residents were obtained for urine culture, quantitative leukocyte count and urinalysis. Significant bacteriuria was present in 153 specimens (63%), including 33 (22%) with more than one organism. Pyuria (greater than or equal to 10 leukocytes/mm(3)) was present in 214 specimens (88%), including 116 (97%) with single organism bacteriuria, 27 (82%) with multiple organism bacteriuria, and 71 (80%) without significant bacteriuria. The leukocyte esterase test had a positive predictive value of 99% for pyuria but a negative predictive value of only 30%. The quantitative level of pyuria was associated with the level of proteinuria and inversely with pH. A relatively constant level of pyuria tended to persist over months to years in a given individual if bacteriuria persisted. Pyuria is significantly associated with bacteriuria in the institutionalized elderly, but is also common in the nonbacteriuric. The clinical significance of pyuria requires further assessment. PMID- 22529726 TI - Spontaneous bacterial peritonitis: Analysis of treatment and outcome. AB - Spontaneous bacterial peritonitis occurred on 44 separate occasions in 43 patients during a five year period, including 27 culture positive and 17 probable cases of spontaneous bacterial peritonitis. Alcoholic liver disease was the underlying cause of 72% of cases. Of the 27 culture positive cases, Escherichia coli was the most common isolate (14 cases), followed by Klebsiella pneumoniae (three cases), group G streptococci (three cases), group B streptococci (two cases) and one case each of five other organisms. Bacteremia occurred in 50% of cases and was the same as the peritoneal isolate 88% of the time. The overall mortality rate was 65% (66% culture positive and 60% probable spontaneous bacterial peritonitis). The mean interval between onset of symptoms and death was 10.2+/-8.6 days in fatal cases. Spontaneous bacterial peritonitis was felt to be a contributing cause of mortality in 70% of fatal cases. Survivors were younger (44+/-20 years versus 59+/-13, P<0.05) and less likely to develop renal insufficiency than nonsurvivors (38% versus 73%, P<0.05). Patients who were treated with an aminoglycoside were more likely to develop renal failure compared to those treated with nonaminoglycoside regimens (P<0.05). There was no difference in mortality rate between culture positive and culture negative spontaneous bacterial peritonitis, total peritoneal leukocyte counts, Gram positive versus Gram-negative organisms, presence of bacteremia, or serum albumin or bilirubin levels. The mortality rate for this disease remains unacceptably high, indicating a need for the development of new strategies in the prevention, diagnosis and management of this disease. PMID- 22529727 TI - A review of tuberculous meningitis in a Canadian pediatric hospital. AB - Tuberculous meningitis is a disease associated with high morbidity and mortality. Experience with this disease at the Hospital for Sick Children in Toronto was reviewed to determine whether changes in prognosis have occurred in the past decade. All patients from whom the organism was recovered from the cerebrospinal fluid, or who had a positive Mantoux test in association with a compatible history, were included. Thirteen patients were identified from 1978 to 1989. The median age was six years (range 11 months to 17.5 years). Nine patients were born in Canada, but all except one were members of recently immigrant families. History of close contact with an adult with tuberculosis, or travel to an endemic area in the preceding six months, was present in seven cases. All patients had clinical manifestations and mild pleocytosis with elevated protein content in the cerebrospinal fluid. Patients were all diagnosed within 20 days after admission (median one day). Computed tomography scan of the head was abnormal in all patients within three weeks of admission. No patient died, although long term sequelae developed in five. The prognosis of tuberculous meningitis has improved in the past decade. Although a specific reason for this improvement cannot be definitively stated, earlier diagnosis and better chemotherapy may contribute. PMID- 22529728 TI - Pneumococcal endometritis with peritonitis: Case report and review of the literature. AB - The first case of pneumococcal endometritis with peritonitis in a woman using tampons is described. The patient responded to removal of the tampon and administration of broad spectrum antibiotics. The pathogenesis of pneumococcal endometritis and peritonitis and the potential significance of a tampon in situ are discussed. PMID- 22529729 TI - DNA amplification fingerprinting: Another diagnostic tool? PMID- 22529730 TI - Multicentre clinical trials in infectious diseases in Canada. PMID- 22529731 TI - Acellular versus whole-cell pertussis vaccines. PMID- 22529732 TI - An ounce of prevention - The new wave in HIV therapy. PMID- 22529733 TI - Carriage of Neisseria species in communities with different rates of meningococcal disease. AB - A single clone, Neisseria meningitidis serogroup C (C:2a:P1.2), was isolated from seven patients during a cluster of cases of meningococcal disease in Ontario in 1989. To determine whether the clone was present in asymptomatic individuals in the same population, pharyngeal swabs were taken from 7% (644 of 9125) of residents who were vaccinated during the outbreak. Rates of isolation of Neisseria species were also compared to those in two other geographical areas which did not have an elevated incidence of meningococcal disease. The rate of carriage of N meningitidis in the asymptomatic individuals sampled was between 1.9% and 5.4%. The clone isolated from patients was not present among the carrier strains as determined by sero- and subtyping and electrophoretic analysis of metabolic enzymes. Age greater than six years was the only factor associated with colonization with N meningitidis. PMID- 22529734 TI - Effect of ribavirin on hepatitis A virus replication in vitro. AB - The effect of ribavirin on fetal Rhesus monkey kidney cells (FRhK-4) acutely or chronically infected with hepatitis A virus was studied. The effect of ribavirin on hepatitis A virus yield as detected by radioimmunoassay in acutely infected FRhK-4 cells was dependent on hepatitis A virus inoculum dose. Treatment with 100 MUg/mL ribavirin completely inhibited hepatitis A virus growth in cultures infected with 100 to 800 tissue culture infectious dose 50 (TCID(50)) hepatitis A virus, but inocula of 800 to 1600 TCID(50) resulted in limited production of virus. The effect was time dependent and required more than 96 h of treatment to inhibit the virus completely. Ribavirin was less effective in treating cells persistently infected with hepatitis A virus, although there was significant inhibition of hepatitis A virus (82%) in persistently infected cells as well. Ribavirin had some inhibitory effect on cell growth; treatment with 25, 50 or 100 MUg/mL ribavirin reduced cell growth by approximately 0, 20 and 40%, respectively. PMID- 22529735 TI - Bacterial meningitis in HIV-infected patients: Case reports and review of the literature. AB - Meningitis is not an uncommon complication of the acquired immune deficiency syndrome. Purulent meningitis is not a well recognized infection in human immunodeficiency virus (HIV) positive patients. Three cases of bacterial meningitis caused by Streptococcus pneumoniae, Neisseria meningitidis and Listeria monocytogenes are presented. These cases illustrate that common community organisms may present in HIV positive patients. An acquired B cell defect may predispose to bacterial infections responsible for meningitis in HIV infected patients. PMID- 22529736 TI - Pediatric infections. PMID- 22529737 TI - Multicentre Canadian clinical trials on neutropenic patients. PMID- 22529738 TI - Opportunistic infections in HIV-infected patients. PMID- 22529739 TI - Unanswered questions in central nervous system infection. PMID- 22529740 TI - Bone and joint infections. PMID- 22529742 TI - Prostate cancer stem cells: The case for model systems. AB - Advanced prostate cancers are treated with androgen deprivation therapy, which usually leads to a rapid and significant reduction in tumor burden but subsequent development of castration-resistant and metastatic disease almost always occurs. The source of tumor heterogeneity and the accompanying mechanisms leading to treatment resistance are major areas of prostate cancer research. Although our understanding of tumor heterogeneity is evolving, the functional isolation of tumor propagating populations, also known as cancer stem cells (CSCs), is fundamental to the identification and molecular characterization of castration resistant prostate cancer cells. Of clinical importance, knowledge of prostate CSCs has implications for design of next generation-targeted therapies aimed at both eradicating primary tumor mass and preventing castration-resistant disease. The inability to routinely transplant fractionated primary human prostate tumors has prevented progress in analyzing the source of heterogeneous and treatment resistant populations in prostate cancer. Here, we briefly overview the mechanisms of castration resistance, including the hypothesis for the existence of androgen-independent prostate CSCs. Finally, we discuss the interpretation of preclinical models and their utility for characterizing prostate CSCs in androgen replete and androgen-deprived conditions. PMID- 22529741 TI - Plastics and carcinogenesis: The example of vinyl chloride. AB - The manufacture, use and disposal of various plastics can pose numerous health risks, including the risk of cancer. A model example of carcinogenic risk from plastics is provided by polyvinyl chloride, since it is composed of the known human carcinogen vinyl chloride (VC). In recent years, much has been learned about the molecular biological pathways of VC carcinogenesis. This has led to molecular epidemiologic studies of VC carcinogenesis in exposed human populations which have identified useful biomarkers of exposure, effect and susceptibility for VC. These studies have in turn provided the basis for new molecular approaches for the prevention and treatment of VC cancers. This model could have much wider applicability for many other carcinogenic exposures and many other human cancers. PMID- 22529743 TI - The burden of prostate cancer in Asian nations. AB - INTRODUCTION: In this review, the International Agency for Research on Cancer's cancer epidemiology databases were used to examine prostate cancer (PCa) age standardized incidence rates (ASIR) in selected Asian nations, including Cancer Incidence in Five Continents (CI5) and GLOBOCAN databases, in an effort to determine whether ASIRs are rising in regions of the world with historically low risk of PCa development. MATERIALS AND METHODS: Asian nations with adequate data quality were considered for this review. PCa ASIR estimates from CI5 and GLOBOCAN 2008 public use databases were examined in the four eligible countries: China, Japan, Korea and Singapore. Time trends in PCa ASIRs were examined using CI5 Volumes I-IX. RESULTS: While PCa ASIRs remain much lower in the Asian nations examined than in North America, there is a clear trend of increasing PCa ASIRs in the four countries examined. CONCLUSION: Efforts to systematically collect cancer incidence data in Asian nations must be expanded. Current CI5 data indicate a rise in PCa ASIR in several populous Asian countries. If these rates continue to rise, it is uncertain whether there will be sufficient resources in place, in terms of trained personnel and infrastructure for medical treatment and continuum of care, to handle the increase in PCa patient volume. The recommendation by some experts to initiate PSA screening in Asian nations could compound a resource shortfall. Obtaining accurate estimates of PCa incidence in these countries is critically important for preparing for a potential shift in the public health burden posed by this disease. PMID- 22529744 TI - Rapid de novo evolution of X chromosome dosage compensation in Silene latifolia, a plant with young sex chromosomes. AB - Silene latifolia is a dioecious plant with heteromorphic sex chromosomes that have originated only ~10 million years ago and is a promising model organism to study sex chromosome evolution in plants. Previous work suggests that S. latifolia XY chromosomes have gradually stopped recombining and the Y chromosome is undergoing degeneration as in animal sex chromosomes. However, this work has been limited by the paucity of sex-linked genes available. Here, we used 35 Gb of RNA-seq data from multiple males (XY) and females (XX) of an S. latifolia inbred line to detect sex-linked SNPs and identified more than 1,700 sex-linked contigs (with X-linked and Y-linked alleles). Analyses using known sex-linked and autosomal genes, together with simulations indicate that these newly identified sex-linked contigs are reliable. Using read numbers, we then estimated expression levels of X-linked and Y-linked alleles in males and found an overall trend of reduced expression of Y-linked alleles, consistent with a widespread ongoing degeneration of the S. latifolia Y chromosome. By comparing expression intensities of X-linked alleles in males and females, we found that X-linked allele expression increases as Y-linked allele expression decreases in males, which makes expression of sex-linked contigs similar in both sexes. This phenomenon is known as dosage compensation and has so far only been observed in evolutionary old animal sex chromosome systems. Our results suggest that dosage compensation has evolved in plants and that it can quickly evolve de novo after the origin of sex chromosomes. PMID- 22529745 TI - Molecular requirements for peroxisomal targeting of alanine-glyoxylate aminotransferase as an essential determinant in primary hyperoxaluria type 1. AB - Alanine-glyoxylate aminotransferase is a peroxisomal enzyme, of which various missense mutations lead to irreversible kidney damage via primary hyperoxaluria type 1, in part caused by improper peroxisomal targeting. To unravel the molecular mechanism of its recognition by the peroxisomal receptor Pex5p, we have determined the crystal structure of the respective cargo-receptor complex. It shows an extensive protein/protein interface, with contributions from residues of the peroxisomal targeting signal 1 and additional loops of the C-terminal domain of the cargo. Sequence segments that are crucial for receptor recognition and hydrophobic core interactions within alanine-glyoxylate aminotransferase are overlapping, explaining why receptor recognition highly depends on a properly folded protein. We subsequently characterized several enzyme variants in vitro and in vivo and show that even minor protein fold perturbations are sufficient to impair Pex5p receptor recognition. We discuss how the knowledge of the molecular parameters for alanine-glyoxylate aminotransferase required for peroxisomal translocation could become useful for improved hyperoxaluria type 1 treatment. PMID- 22529746 TI - Project brainstorm: using neuroscience to connect college students with local schools. PMID- 22529747 TI - A blossoming field of research: how florigen is transported to create flowers. PMID- 22529748 TI - Sex chromosome equality in plants. PMID- 22529749 TI - FTIP1 is an essential regulator required for florigen transport. AB - The capacity to respond to day length, photoperiodism, is crucial for flowering plants to adapt to seasonal change. The photoperiodic control of flowering in plants is mediated by a long-distance mobile floral stimulus called florigen that moves from leaves to the shoot apex. Although the proteins encoded by FLOWERING LOCUS T (FT) in Arabidopsis and its orthologs in other plants are identified as the long-sought florigen, whether their transport is a simple diffusion process or under regulation remains elusive. Here we show that an endoplasmic reticulum (ER) membrane protein, FT-INTERACTING PROTEIN 1 (FTIP1), is an essential regulator required for FT protein transport in Arabidopsis. Loss of function of FTIP1 exhibits late flowering under long days, which is partly due to the compromised FT movement to the shoot apex. FTIP1 and FT share similar mRNA expression patterns and subcellular localization, and they interact specifically in phloem companion cells. FTIP1 is required for FT export from companion cells to sieve elements, thus affecting FT transport through the phloem to the SAM. Our results provide a mechanistic understanding of florigen transport, demonstrating that FT moves in a regulated manner and that FTIP1 mediates FT transport to induce flowering. PMID- 22529750 TI - New methodology for estimating the burden of infectious diseases in Europe. AB - Mirjam Kretzschmar and colleagues describe the BCoDE project, which uses a pathogen-based incidence approach to better estimate the infectious disease burden in Europe. PMID- 22529751 TI - Long-term exposure to silica dust and risk of total and cause-specific mortality in Chinese workers: a cohort study. AB - BACKGROUND: Human exposure to silica dust is very common in both working and living environments. However, the potential long-term health effects have not been well established across different exposure situations. METHODS AND FINDINGS: We studied 74,040 workers who worked at 29 metal mines and pottery factories in China for 1 y or more between January 1, 1960, and December 31, 1974, with follow up until December 31, 2003 (median follow-up of 33 y). We estimated the cumulative silica dust exposure (CDE) for each worker by linking work history to a job-exposure matrix. We calculated standardized mortality ratios for underlying causes of death based on Chinese national mortality rates. Hazard ratios (HRs) for selected causes of death associated with CDE were estimated using the Cox proportional hazards model. The population attributable risks were estimated based on the prevalence of workers with silica dust exposure and HRs. The number of deaths attributable to silica dust exposure among Chinese workers was then calculated using the population attributable risk and the national mortality rate. We observed 19,516 deaths during 2,306,428 person-years of follow-up. Mortality from all causes was higher among workers exposed to silica dust than among non-exposed workers (993 versus 551 per 100,000 person-years). We observed significant positive exposure-response relationships between CDE (measured in milligrams/cubic meter-years, i.e., the sum of silica dust concentrations multiplied by the years of silica exposure) and mortality from all causes (HR 1.026, 95% confidence interval 1.023-1.029), respiratory diseases (1.069, 1.064 1.074), respiratory tuberculosis (1.065, 1.059-1.071), and cardiovascular disease (1.031, 1.025-1.036). Significantly elevated standardized mortality ratios were observed for all causes (1.06, 95% confidence interval 1.01-1.11), ischemic heart disease (1.65, 1.35-1.99), and pneumoconiosis (11.01, 7.67-14.95) among workers exposed to respirable silica concentrations equal to or lower than 0.1 mg/m(3). After adjustment for potential confounders, including smoking, silica dust exposure accounted for 15.2% of all deaths in this study. We estimated that 4.2% of deaths (231,104 cases) among Chinese workers were attributable to silica dust exposure. The limitations of this study included a lack of data on dietary patterns and leisure time physical activity, possible underestimation of silica dust exposure for individuals who worked at the mines/factories before 1950, and a small number of deaths (4.3%) where the cause of death was based on oral reports from relatives. CONCLUSIONS: Long-term silica dust exposure was associated with substantially increased mortality among Chinese workers. The increased risk was observed not only for deaths due to respiratory diseases and lung cancer, but also for deaths due to cardiovascular disease. Please see later in the article for the Editors' Summary. PMID- 22529752 TI - Prioritizing CD4 count monitoring in response to ART in resource-constrained settings: a retrospective application of prediction-based classification. AB - BACKGROUND: Global programs of anti-HIV treatment depend on sustained laboratory capacity to assess treatment initiation thresholds and treatment response over time. Currently, there is no valid alternative to CD4 count testing for monitoring immunologic responses to treatment, but laboratory cost and capacity limit access to CD4 testing in resource-constrained settings. Thus, methods to prioritize patients for CD4 count testing could improve treatment monitoring by optimizing resource allocation. METHODS AND FINDINGS: Using a prospective cohort of HIV-infected patients (n=1,956) monitored upon antiretroviral therapy initiation in seven clinical sites with distinct geographical and socio-economic settings, we retrospectively apply a novel prediction-based classification (PBC) modeling method. The model uses repeatedly measured biomarkers (white blood cell count and lymphocyte percent) to predict CD4(+) T cell outcome through first stage modeling and subsequent classification based on clinically relevant thresholds (CD4(+) T cell count of 200 or 350 cells/ul). The algorithm correctly classified 90% (cross-validation estimate=91.5%, standard deviation [SD]=4.5%) of CD4 count measurements <200 cells/ul in the first year of follow-up; if laboratory testing is applied only to patients predicted to be below the 200 cells/ul threshold, we estimate a potential savings of 54.3% (SD=4.2%) in CD4 testing capacity. A capacity savings of 34% (SD=3.9%) is predicted using a CD4 threshold of 350 cells/ul. Similar results were obtained over the 3 y of follow up available (n=619). Limitations include a need for future economic healthcare outcome analysis, a need for assessment of extensibility beyond the 3-y observation time, and the need to assign a false positive threshold. CONCLUSIONS: Our results support the use of PBC modeling as a triage point at the laboratory, lessening the need for laboratory-based CD4(+) T cell count testing; implementation of this tool could help optimize the use of laboratory resources, directing CD4 testing towards higher-risk patients. However, further prospective studies and economic analyses are needed to demonstrate that the PBC model can be effectively applied in clinical settings. Please see later in the article for the Editors' Summary. PMID- 22529753 TI - Are there differences in access to care, treatment, and outcomes for children with appendicitis treated at county versus private hospitals? AB - INTRODUCTION: We conducted a study to determine whether hospital type (county [ie, safety-net] vs private) affects health care access (appendiceal perforation [AP] rates), treatment (laparoscopic appendectomy [LA] rates), and outcomes in children with appendicitis. METHODS: A review of cases involving children who had appendicitis between 1998 and 2007 was performed. Data from county and private hospitals were compared. Outcomes were AP rates, LA rates, need for postoperative abscess drainage, length of hospitalization (LOH), and cost. RESULTS: Multivariate analysis confirmed that among 7902 patients, (county = 682; private = 7220), county-hospital patients had lower incomes, higher AP rates, higher LA rates, lower postoperative abscess drainage rates, and longer LOH than did private-hospital patients. The longer LOH at the county institution led to higher costs. Within the county hospital, outcomes were similar across all ethnic groups and income levels. CONCLUSIONS: Children with appendicitis treated at a county hospital were of lower socioeconomic background and had higher AP rates, longer LOH, and higher costs than their counterparts at private hospitals, but were more likely to undergo LA and require less abscess drainage. Within the county hospital, ethnic and socioeconomic disparities were not apparent; thus, these differences between institutions might have been caused by underlying disparities in ethnicity, income, and health care access. PMID- 22529755 TI - "Our culture is medicine": perspectives of Native healers on posttrauma recovery among American Indian and Alaska Native patients. AB - American Indian and Alaska Native (Native) people experience more traumatic events and are at higher risk for developing posttraumatic stress disorder compared with the general population. We conducted in-depth interviews with six Native healers about their perspectives on traumatic injury and healing. We analyzed the interviews using an inductive approach to identify common themes. We categorized these themes into four categories: causes and consequences of traumatic injury, risk factors, protective factors, and barriers to care. The implications of our study include a need for improving cultural competence among health care and social services personnel working with Native trauma patients. Additional cumulative analyses of Native healers and trauma patients would contribute to a much-needed body of knowledge on improving recovery and promoting healing among Native trauma patients. PMID- 22529754 TI - Supported exercise improves controlled eating and weight through its effects on psychosocial factors: extending a systematic research program toward treatment development. AB - BACKGROUND: Behavioral weight-loss treatments have been overwhelmingly unsuccessful. Many inadequately address both behavioral theory and extant research--especially in regard to the lack of viability of simply educating individuals on improved eating and exercise behaviors. OBJECTIVE: The aim was to synthesize research on associations of changes in exercise behaviors, psychosocial factors, eating behaviors, and weight; and then conduct further direct testing to inform the development of an improved treatment approach. METHODS: A systematic program of health behavior-change research based on social cognitive theory, and extensions of that theory applied to exercise and weight loss, was first reviewed. Then, to extend this research toward treatment development and application, a field-based study of obese adults was conducted. Treatments incorporated a consistent component of cognitive-behaviorally supported exercise during 26 weeks that was paired with either standard nutrition education (n = 183) or cognitive-behavioral methods for controlled eating that emphasized self-regulatory methods such as goal setting and caloric tracking, cognitive restructuring, and eating cue awareness (n = 247). RESULTS: Both treatment conditions were associated with improved self-efficacy, self regulation, mood, exercise, fruit and vegetable consumption, weight, and waist circumference; with improvements in self-regulation for eating, fruit and vegetable consumption, weight, and waist circumference significantly greater in the cognitive-behavioral nutrition condition. Changes in exercise- and eating related self-efficacy and self-regulation were associated with changes in exercise and eating (R(2) = 0.40 and 0.17, respectively), with mood change increasing the explanatory power to R(2) = 0.43 and 0.20. Improved self-efficacy and self-regulation for exercise carried over to self-efficacy and self regulation for controlled eating (beta= 0.53 and 0.68, respectively). CONCLUSIONS: Development and longitudinal testing of a new and different approach to behavioral treatment for sustained weight loss that emphasizes exercise program-induced psychosocial changes preceding the facilitation of improved eating and weight loss should be guided by our present research. PMID- 22529756 TI - Pharmacist glycemic control team improves quality of glycemic control in surgical patients with perioperative dysglycemia. AB - CONTEXT: Perioperative hyperglycemia is a risk factor for increased morbidity and mortality. Improved glycemic control has been demonstrated to reduce surgical site infections, reduce perioperative morbidity, and reduce length of stay. However, safe and effective perioperative glycemic control can be limited by expert clinician availability. OBJECTIVE: To improve quality by reliably providing safe and effective glycemic control to surgical patients with diabetes or stress hyperglycemia. DESIGN: A designated group of pharmacists, the Glycemic Control Team (GCT), worked under protocol, on a consultation basis, to manage perioperative dysglycemia during hospitalization. We used a pre-post, observational study design to assess the effectiveness of the intervention and implementation of the GCT. MAIN OUTCOME MEASURES: The proportion of patients pre- and postintervention with good glycemic control and with hypoglycemia were measured and compared. We defined good glycemic control as having all, or all but one, point-of-care blood glucose values between 70-180 mg/dL in each 24-hour period. We defined hypoglycemia as having any point-of-care test glucose value <70 mg/dL in any of the 3 days evaluated. RESULTS: During the preimplementation period, 77.4% of postoperative patient days demonstrated good glycemic control. In the postimplementation period, this percentage increased to 90.3%. Over the same period, the rate of hypoglycemia decreased from 8.6% to 4.6%. CONCLUSION: Implementation of a pharmacist team to manage glycemic control in hospitalized, postoperative patients led to safer and better quality of glycemic care as measured by improved glycemic control and lower rates of hypoglycemia. PMID- 22529757 TI - How do adolescents access health information? And do they ask their physicians? AB - OBJECTIVE: To improve understanding about how high school students use electronic tools to obtain health information and how this information affects their behavior. DESIGN/METHODS: Using a cross-sectional design, we administered an anonymous survey to high school students in grades 9 through 12 at a single private Catholic high school, inquiring about their use of electronic tools to obtain health information, topics of interest, sources used to obtain information, and modifications in their behavior based on that information. Descriptive statistics and multivariate analysis of variance were used to compare trends across grade levels. RESULTS: Of 705 students enrolled, 24.7% were either absent or chose not to participate in the survey. Of the remaining 531 students, 497 completed the surveys, for a response rate of 70.5% (497 of 705) and a participation rate of 93.6% (497 of 531). All students were comfortable using the Internet, and >90% used it at home and in school. Access to broadband applications averaged 95% at home and 80% at school. A significant proportion (0.66; p < 0.0001) of students reported that they trusted the information found online, and 22% (not significant) modified their behavior on the basis of the information they found. Forty-two percent searched for general health information, and 43% investigated specific medical conditions or disease states. Topics related to skin were researched significantly more than nutrition, birth control, and sexually transmitted diseases. Although a significant number of students (p < 0.05) reported conducting e-mail conversations related to health topics with their teachers, <5% had e-mail communications with physicians. CONCLUSIONS: These data indicate that most high school students used the Internet and broadband applications at school and at home as resources for health care information. A significant number of students trusted the online information, and at nearly one-quarter subsequently modified their behavior. Students conducted e mail conversations with teachers about health-related topics, but few students used this tool to communicate with their physicians. This information raises questions about design and implementation of strategies to provide adolescents access to appropriate health care information, including that provided by physicians. PMID- 22529758 TI - The power of the National Surgical Quality Improvement Program--achieving a zero pneumonia rate in general surgery patients. AB - The National Surgical Quality Improvement Program (NSQIP) of the American College of Surgeons provides risk-adjusted surgical outcome measures for participating hospitals that can be used for performance improvement of surgical mortality and morbidity. A surgical clinical nurse reviewer collects 135 clinical variables including preoperative risk factors, intraoperative variables, and 30-day postoperative mortality and morbidity outcomes for patients undergoing major surgical procedures. A report on mortality and complications is prepared twice a year. This article summarizes briefly the history of NSQIP and how its report on surgical outcomes can be used for performance improvement within a hospital system. In particular, it describes how to drive performance improvement with NSQIP data using the example of postoperative respiratory complications--a major factor of postoperative mortality. In addition, this article explains the benefit of a collaborative of several participating NSQIP hospitals and describes how to develop a "playbook" on the basis of an outcome improvement project. PMID- 22529759 TI - Single-incision laparoscopic surgery--hype or reality: a historical control study. AB - INTRODUCTION: Single-incision laparoscopic surgery (SILS) is a "new" method to perform "old" operations. Though SILS has been referred to by many names, for the sake of this paper, any procedure done laparoscopically through one incision (regardless of the number of ports or working channels) will be considered a SILS procedure. This brief review will discuss the history of SILS, current applications, and potential pitfalls. METHODS: To explore the outcomes of SILS cholestectomy in a community setting, we conducted a historical control study comparing, through retrospective review, 50 laparoscopic cholecystectomies to 50 SILS cholecystectomies, all performed by one of the authors (DT). RESULTS: Of the 50 patients selected, 12 patients had cholangiograms performed at the same time. The mean operative time for all cases was 50.4 minutes (range 31 minutes to 108 minutes). For the noncholangiogram group, the mean operative time was 48 minutes whereas it was 57.7 minutes for patients requiring a cholangiogram. Mean estimated blood loss was 28 mL. There was a 20% "conversion" rate (n = 10): 4 with an additional trocar, 5 with a 4-port technique, 1 with an open procedure. DISCUSSION: We conclude that, although SILS is a relatively new procedure for general surgery, we feel it is here to stay. Although the only documented benefit is cosmetic, SILS is equivalent to conventional laparoscopy in all other respects. PMID- 22529760 TI - A case of baffling fatigue with a spectral twist. PMID- 22529761 TI - Transparency matters: Kaiser Permanente's National Guideline Program methodological processes. AB - INTRODUCTION: The practice-guideline process of collecting, critically appraising, and synthesizing available evidence, then developing expert panel recommendations based on appraised evidence, makes it possible to provide high quality care for patients. Unwanted variability in the quality and rigor of evidence summaries and Clinical Practice Guidelines has been a long-standing challenge for clinicians seeking evidence-based guidance to support patient care decisions. METHODS: A multidisciplinary group of stakeholders, with representation from all eight Kaiser Permanente Regions, is responsible for creating National Guidelines. Conducting high-quality systematic reviews and creating clinical guidelines are time-, labor-, and resource-intensive processes, which raises challenges for an organization striving to balance rigor with efficiency. For these reasons, the National Guideline Program elected to allow for the identification, assessment, and possible adoption of existing evidence based guidelines and systematic reviews using the ADAPTE; Appraisal of Guidelines Research and Evaluation; Assessment of Multiple Systematic Reviews (AMSTAR); and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) frameworks. If no acceptable external guidelines are identified, the Guideline Development Team then systematically searches for relevant high-quality systematic reviews, meta-analyses, and original studies. Existing systematic reviews are assessed for quality using a measurement tool to assess systematic reviews (the AMSTAR systematic review checklist). STUDY APPRAISAL: Following the screening and selection process, the included studies (the "body of evidence") are critically appraised for quality, using the GRADE methodology, which focuses on four key factors that must be considered when assigning strength to a recommendation: balance between desirable and undesirable effects, quality of evidence, values and preferences, and cost. The evidence is then used to create preliminary clinical recommendations. The strength of these recommendations is graded to reflect the extent to which a guideline panel is confident that the desirable effects of an intervention outweigh undesirable effects (or vice versa) across the range of patients for whom the recommendation is intended. DISSEMINATION: The Care Management Institute disseminates all KP national guidelines to its eight Regions via postings on its Clinical Library Intranet site, a Web-based internal information resource. PMID- 22529762 TI - Altered mental status in an elderly woman with concurrent takotsubo syndrome and polymyalgia rheumatica: a case of treatable geriatric delirium. AB - We present a unique case of a patient, aged 80 years, who presented with delirium and takotsubo syndrome. Also known as "broken heart syndrome" because it often originates following an emotional stress, takotsubo syndrome may be difficult to distinguish from myocardial infarction because of similar symptoms and demographics. However, the distinction of these opposing diagnoses is significant because takotsubo syndrome is associated with more favorable prognosis for complete recovery, especially with early diagnosis and expedient supportive therapy. To our knowledge, we present the first case of takotsubo syndrome in which the diagnosis was made in an elderly patient presenting with delirium and in the absence of the hallmark symptoms of chest pain and dyspnea. Finally, we describe this patient's coexistent diagnosis of polymyalgia rheumatica and speculate on its possible theoretic relationship to takotsubo syndrome. PMID- 22529763 TI - Patient safety in surgical residency: root cause analysis and the surgical morbidity and mortality conference--case series from clinical practice. AB - Although the surgical morbidity and mortality conference (SMMC) has been a core educational venue for surgical education and quality assurance (QA), its current format focuses mainly on human errors rather than system failures, which are responsible for the vast majority of medical errors. To avoid having surgeons seemingly put on trial, root cause analysis (RCA) can be used as an effective way of analyzing system failures and of finding possible solutions for them. Preliminary data confirm the value of RCA in that respect and promise a great potential for improving patient safety away from the culture of blame. Bringing the findings of RCA to the SMMC has the advantage of having both perspectives- human errors and systems failures--thus enhancing surgical education, improving QA, and hopefully improving patient safety. However, although this seems to be a novel approach, several factors should be considered before its implementation, such as the quality of analysis, cost-effectiveness, and actual impact on patient safety. We believe that to maximize learning, sentinel events that currently require RCA should not be discussed in SMMCs until the findings of RCA are available for review. The use of some of the tools of RCA should be considered when discussing nonsentinel events during SMMCs. PMID- 22529764 TI - Image diagnosis: Perilunate and lunate dislocations. PMID- 22529765 TI - Peer review: innovating change. AB - Medicine has traditionally focused on specialty and subspecialty expertise, which subsequently leads to fragmentation, inefficiencies, and lack of accountability. From this focus came a new idea: The Institute. The Institute has transformed our culture, fundamentally affecting the way we approach patient care and how we foster accountability rather than blame. It focuses on system failures rather than on individual ones, which ultimately drives us to act. The result is a peer review process built on strong interdisciplinary relationships. PMID- 22529768 TI - Biomarkers in osteoarthritis. PMID- 22529767 TI - Genome-scale modeling of light-driven reductant partitioning and carbon fluxes in diazotrophic unicellular cyanobacterium Cyanothece sp. ATCC 51142. AB - Genome-scale metabolic models have proven useful for answering fundamental questions about metabolic capabilities of a variety of microorganisms, as well as informing their metabolic engineering. However, only a few models are available for oxygenic photosynthetic microorganisms, particularly in cyanobacteria in which photosynthetic and respiratory electron transport chains (ETC) share components. We addressed the complexity of cyanobacterial ETC by developing a genome-scale model for the diazotrophic cyanobacterium, Cyanothece sp. ATCC 51142. The resulting metabolic reconstruction, iCce806, consists of 806 genes associated with 667 metabolic reactions and includes a detailed representation of the ETC and a biomass equation based on experimental measurements. Both computational and experimental approaches were used to investigate light-driven metabolism in Cyanothece sp. ATCC 51142, with a particular focus on reductant production and partitioning within the ETC. The simulation results suggest that growth and metabolic flux distributions are substantially impacted by the relative amounts of light going into the individual photosystems. When growth is limited by the flux through photosystem I, terminal respiratory oxidases are predicted to be an important mechanism for removing excess reductant. Similarly, under photosystem II flux limitation, excess electron carriers must be removed via cyclic electron transport. Furthermore, in silico calculations were in good quantitative agreement with the measured growth rates whereas predictions of reaction usage were qualitatively consistent with protein and mRNA expression data, which we used to further improve the resolution of intracellular flux values. PMID- 22529769 TI - Evaluation of dietary intake in Danish adults by means of an index based on food based dietary guidelines. AB - BACKGROUND: Data on dietary intake and physical activity has been collected from a representative sample of the Danish population from 2003-2008. OBJECTIVES: The aim of the present study was to describe the habitual diet in Denmark and to evaluate the overall diet quality using a diet quality index based on the National Food-Based Dietary Guidelines (FBDG), which consists of seven guidelines regarding diet and one regarding physical activity. DESIGN: Data from the Danish National Survey of Diet and Physical Activity 2003-2008 (n=3354) were included. The diet quality index was constructed based on five of the seven dietary guidelines. Individuals were categorised according to quartiles of the diet quality index, and food and nutrient intakes were estimated in each of the groups. RESULTS: Macronutrient distribution did not meet recommendations in any of the groups, as energy from total fat and especially saturated fat was too high. A high intake of high-fat milk products, fat on bread and processed meat contributed to a high intake of total fat and saturated fat, and sugar-sweetened soft drinks contributed to a high intake of added sugars in the group below the lowest quartile of the diet quality index. Individuals above in the highest quartile had higher intakes of 'healthy foods' such as fish, fruit and vegetables, rye bread, and also a higher consumption of water and wine. Overall, intakes of micronutrients were sufficient in all groups. CONCLUSIONS: The diet quality index is a useful tool in assessing food and nutrient intake in individuals with high vs. low degree of compliance towards the dietary guidelines, and provides a valuable tool in future studies investigating variations in dietary intakes with respect to lifestyle, demographic and regional differences in Denmark. PMID- 22529770 TI - What are the Odds? The Neural Correlates of Active Choice during Gambling. AB - Gambling is a widespread recreational activity and requires pitting the values of potential wins and losses against their probability of occurrence. Neuropsychological research showed that betting behavior on laboratory gambling tasks is highly sensitive to focal lesions to the ventromedial prefrontal cortex (vmPFC) and insula. In the current study, we assessed the neural basis of betting choices in healthy participants, using functional magnetic resonance imaging of the Roulette Betting Task. In half of the trials, participants actively chose their bets; in the other half, the computer dictated the bet size. Our results highlight the impact of volitional choice upon gambling-related brain activity: Neural activity in a distributed network - including key structures of the reward circuitry (midbrain, striatum) - was higher during active compared to computer dictated bet selection. In line with neuropsychological data, the anterior insula and vmPFC were more activated during self-directed bet selection, and responses in these areas were differentially modulated by the odds of winning in the two choice conditions. In addition, responses in the vmPFC and ventral striatum were modulated by the bet size. Convergent with electrophysiological research in macaques, our results further implicate the inferior parietal cortex (IPC) in the processing of the likelihood of potential outcomes: Neural responses in the IPC bilaterally reflected the probability of winning during bet selection. Moreover, the IPC was particularly sensitive to the odds of winning in the active-choice condition, when the processing of this information was required to guide bet selection. Our results indicate an important role of the IPC in human decision making under risk and help to integrate neuropsychological data of risk-taking following vmPFC and insula damage with models of choice derived from human neuroimaging and monkey electrophysiology. PMID- 22529772 TI - What if I Get Busted? Deception, Choice, and Decision-Making in Social Interaction. AB - Deception is an essentially social act, yet little is known about how social consequences affect the decision to deceive. In this study, participants played a computerized game of deception without constraints on whether or when to attempt to deceive their opponent. Participants were questioned by an opponent outside the scanner about their knowledge of the content of a display. Importantly, questions were posed so that, in some conditions, it was possible to be deceptive, while in other conditions it was not. To simulate a realistic interaction, participants could be confronted about their claims by the opponent. This design, therefore, creates a context in which a deceptive participant runs the risk of being punished if their deception is detected. Our results show that participants were slower to give honest than to give deceptive responses when they knew more about the display and could use this knowledge for their own benefit. The condition in which confrontation was not possible was associated with increased activity in subgenual anterior cingulate cortex. The processing of a question which allows a deceptive response was associated with activation in right caudate and inferior frontal gyrus. Our findings suggest the decision to deceive is affected by the potential risk of social confrontation rather than the claim itself. PMID- 22529771 TI - Regulation of thalamic development by sonic hedgehog. AB - The thalamus is strategically positioned within the caudal diencephalic area of the forebrain, between the mesencephalon and telencephalon. This location is important for unique aspects of thalamic function, to process and relay sensory and motor information to and from the cerebral cortex. How the thalamus comes to reside within this region of the central nervous system has been the subject of much investigation. Extracellular signals secreted from key locations both extrinsic and intrinsic to the thalamic primordium have recently been identified and shown to play important roles in the growth, regionalization, and specification of thalamic progenitors. One factor in particular, the secreted morphogen Sonic hedgehog (Shh), has been implicated in spatiotemporal and threshold models of thalamic development that differ from other areas of the CNS due, in large part, to its expression within two signaling centers, the basal plate and the zona limitans intrathalamica, a dorsally projecting spike that separates the thalamus from the subthalamic region. Shh signaling from these dual sources exhibit unique and overlapping functions in the control of thalamic progenitor identity and nuclei specification. This review will highlight recent advances in our understanding of Shh function during thalamic development, revealing similarities, and differences that exist between species. PMID- 22529773 TI - Circadian Oscillations within the Hippocampus Support Memory Formation and Persistence. AB - The ability to sustain memories over long periods of time, sometimes even a lifetime, is one of the most remarkable properties of the brain. Much knowledge has been gained over the past few decades regarding the molecular correlates of memory formation. Once a memory is forged, however, the molecular events that provide permanence are as of yet unclear. Studies in multiple organisms have revealed that circadian rhythmicity is important for the formation, stability, and recall of memories (Gerstner et al., 2009).The neuronal events that provide this link need to be explored further. This article will discuss the findings related to the circadian regulation of memory-dependent processes in the hippocampus. Specifically, the circadian-controlled mitogen-activated protein kinase (MAPK) and cAMP signal transduction pathway plays critical roles in the consolidation of hippocampus-dependent memory. A series of studies have revealed the circadian oscillation of this pathway within the hippocampus, an activity that is absent in memory-deficient, transgenic mice lacking Ca(2+)-stimulated adenylyl cyclases. Interference with these oscillations proceeding the cellular memory consolidation period impairs the persistence of hippocampus-dependent memory. These data suggest that the persistence of long-term memories may depend upon reactivation of this signal transduction pathway in the hippocampus during the circadian cycle. New data reveals the dependence of hippocampal oscillation in MAPK activity on the suprachiasmatic nucleus, again underscoring the importance of this region in maintaining the circadian physiology of memory. Finally, the downstream ramification of these oscillations in terms of gene expression and epigenetics should be considered, as emerging evidence is pointing strongly to a circadian link between epigenetics and long-term synaptic plasticity. PMID- 22529775 TI - Glucose-6-phosphate reduces calcium accumulation in rat brain endoplasmic reticulum. AB - Brain cells expend large amounts of energy sequestering calcium (Ca(2+)), while loss of Ca(2+) compartmentalization leads to cell damage or death. Upon cell entry, glucose is converted to glucose-6-phosphate (G6P), a parent substrate to several metabolic major pathways, including glycolysis. In several tissues, G6P alters the ability of the endoplasmic reticulum (ER) to sequester Ca(2+). This led to the hypothesis that G6P regulates Ca(2+) accumulation by acting as an endogenous ligand for sarco-endoplasmic reticulum calcium ATPase (SERCA). Whole brain ER microsomes were pooled from adult male Sprague-Dawley rats. Using radio isotopic assays, (45)Ca(2+) accumulation was quantified following incubation with increasing amounts of G6P, in the presence or absence of thapsigargin, a potent SERCA inhibitor. To qualitatively assess SERCA activity, the simultaneous release of inorganic phosphate (Pi) coupled with Ca(2+) accumulation was quantified. Addition of G6P significantly and decreased Ca(2+) accumulation in a dose dependent fashion (1-10 mM). The reduction in Ca(2+) accumulation was not significantly different that seen with addition of thapsigargin. Addition of glucose-1-phosphate or fructose-6-phosphate, or other glucose metabolic pathway intermediates, had no effect on Ca(2+) accumulation. Further, the release of Pi was markedly decreased, indicating G6P-mediated SERCA inhibition as the responsible mechanism for reduced Ca(2+) uptake. Simultaneous addition of thapsigargin and G6P did decrease inorganic phosphate in comparison to either treatment alone, which suggests that the two treatments have different mechanisms of action. Therefore, G6P may be a novel, endogenous regulator of SERCA activity. Additionally, pathological conditions observed during disease states that disrupt glucose homeostasis, may be attributable to Ca(2+) dystasis caused by altered G6P regulation of SERCA activity. PMID- 22529774 TI - Circadian and wakefulness-sleep modulation of cognition in humans. AB - Cognitive and affective processes vary over the course of the 24 h day. Time of day dependent changes in human cognition are modulated by an internal circadian timekeeping system with a near-24 h period. The human circadian timekeeping system interacts with sleep-wakefulness regulatory processes to modulate brain arousal, neurocognitive and affective function. Brain arousal is regulated by ascending brain stem, basal forebrain (BF) and hypothalamic arousal systems and inhibition or disruption of these systems reduces brain arousal, impairs cognition, and promotes sleep. The internal circadian timekeeping system modulates cognition and affective function by projections from the master circadian clock, located in the hypothalamic suprachiasmatic nuclei (SCN), to arousal and sleep systems and via clock gene oscillations in brain tissues. Understanding the basic principles of circadian and wakefulness-sleep physiology can help to recognize how the circadian system modulates human cognition and influences learning, memory and emotion. Developmental changes in sleep and circadian processes and circadian misalignment in circadian rhythm sleep disorders have important implications for learning, memory and emotion. Overall, when wakefulness occurs at appropriate internal biological times, circadian clockwork benefits human cognitive and emotion function throughout the lifespan. Yet, when wakefulness occurs at inappropriate biological times because of environmental pressures (e.g., early school start times, long work hours that include work at night, shift work, jet lag) or because of circadian rhythm sleep disorders, the resulting misalignment between circadian and wakefulness-sleep physiology leads to impaired cognitive performance, learning, emotion, and safety. PMID- 22529776 TI - NCS-1 associates with adenosine A(2A) receptors and modulates receptor function. AB - Modulation of G protein-coupled receptor (GPCR) signaling by local changes in intracellular calcium concentration is an established function of Calmodulin (CaM) which is known to interact with many GPCRs. Less is known about the functional role of the closely related neuronal EF-hand Ca(2+)-sensor proteins that frequently associate with CaM targets with different functional outcome. In the present study we aimed to investigate if a target of CaM-the A(2A) adenosine receptor is able to associate with two other neuronal calcium binding proteins (nCaBPs), namely NCS-1 and caldendrin. Using bioluminescence resonance energy transfer (BRET) and co-immunoprecipitation experiments we show the existence of A(2A)-NCS-1 complexes in living cells whereas caldendrin did not associate with A(2A) receptors under the conditions tested. Interestingly, NCS-1 binding modulated downstream A(2A) receptor intracellular signaling in a Ca(2+)-dependent manner. Taken together this study provides further evidence that neuronal Ca(2+) sensor proteins play an important role in modulation of GPCR signaling. PMID- 22529777 TI - Early appearance and possible functions of non-neuromuscular cholinesterase activities. AB - The biological function of the cholinesterase (ChE) enzymes has been studied since the beginning of the twentieth century. Acetylcholinesterase plays a key role in the modulation of neuromuscular impulse transmission in vertebrates, while in invertebrates pseudo cholinesterases are preeminently represented. During the last 40 years, awareness of the role of ChEs role in regulating non neuromuscular cell-to-cell interactions has been increasing such as the ones occurring during gamete interaction and embryonic development. Moreover, ChE activities are responsible for other relevant biological events, including regulation of the balance between cell proliferation and cell death, as well as the modulation of cell adhesion and cell migration. Understanding the mechanisms of the regulation of these events can help us foresee the possible impact of neurotoxic substances on the environmental and human health. PMID- 22529778 TI - Restoration of the striatal circuitry: from developmental aspects toward clinical applications. AB - In the basal ganglia circuitry, the striatum is a highly complex structure coordinating motor and cognitive functions and it is severely affected in Huntington's disease (HD) patients. Transplantation of fetal ganglionic eminence (GE) derived precursor cells aims to restore neural circuitry in the degenerated striatum of HD patients. Pre-clinical transplantation in genetic and lesion HD animal models has increased our knowledge of graft vs. host interactions, and clinical studies have been shown to successfully reduce motor and cognitive effects caused by the disease. Investigating the molecular mechanisms of striatal neurogenesis is a key research target, since novel strategies aim on generating striatal neurons by differentiating embryonic stem cells or by reprogramming somatic cells as alternative cell source for neural transplantation. PMID- 22529779 TI - Epigenetic effects of stress and corticosteroids in the brain. AB - Stress is a common life event with potentially long lasting effects on health and behavior. Stress, and the corticosteroid hormones that mediate many of its effects, are well known for their ability to alter brain function and plasticity. While genetic susceptibility may influence the impact of stress on the brain, it does not provide us with a complete understanding of the capacity of stress to produce long lasting perturbations on the brain and behavior. The growing science of epigenetics, however, shows great promise of deepening our understanding of the persistent impacts of stress and corticosteroids on health and disease. Epigenetics, broadly defined, refers to influences on phenotype operating above the level of the genetic code itself. At the molecular level, epigenetic events belong to three major classes: DNA methylation, covalent histone modification and non-coding RNA. This review will examine the bi-directional interactions between stress and corticosteroids and epigenetic mechanisms in the brain and how the novel insights, gleaned from recent research in neuro-epigenetics, change our understanding of mammalian brain function and human disease states. PMID- 22529780 TI - Models of grid cell spatial firing published 2005-2011. AB - Since the discovery of grid cells in rat entorhinal cortex, many models of their hexagonally arrayed spatial firing fields have been suggested. We review the models and organize them according to the mechanisms they use to encode position, update the positional code, read it out in the spatial grid pattern, and learn any patterned synaptic connections needed. We mention biological implementations of the models, but focus on the models on Marr's algorithmic level, where they are not things to individually prove or disprove, but rather are a valuable collection of metaphors of the grid cell system for guiding research that are all likely true to some degree, with each simply emphasizing different aspects of the system. For the convenience of interested researchers, MATLAB implementations of the discussed grid cell models are provided at ModelDB accession 144006 or http://people.bu.edu/zilli/gridmodels.html. PMID- 22529782 TI - Introduction to the research topic on standard brain atlases. PMID- 22529781 TI - Optophysiological analysis of associational circuits in the olfactory cortex. AB - Primary olfactory cortical areas receive direct input from the olfactory bulb, but also have extensive associational connections that have been mainly studied with classical anatomical methods. Here, we shed light on the functional properties of associational connections in the anterior and posterior piriform cortices (aPC and pPC) using optophysiological methods. We found that the aPC receives dense functional connections from the anterior olfactory nucleus (AON), a major hub in olfactory cortical circuits. The local recurrent connectivity within the aPC, long invoked in cortical autoassociative models, is sparse and weak. By contrast, the pPC receives negligible input from the AON, but has dense connections from the aPC as well as more local recurrent connections than the aPC. Finally, there are negligible functional connections from the pPC to aPC. Our study provides a circuit basis for a more sensory role for the aPC in odor processing and an associative role for the pPC. PMID- 22529783 TI - Activation of nucleus accumbens NMDA receptors differentially affects appetitive or aversive taste learning and memory. AB - Taste memory depends on motivational and post-ingestional consequences; thus, it can be aversive (e.g., conditioned taste aversion, CTA) if a novel, palatable taste is paired with visceral malaise, or it can be appetitive if no intoxication appears after novel taste consumption, and a taste preference is developed.The nucleus accumbens (NAc) plays a role in hedonic reactivity to taste stimuli, and recent findings suggest that reward and aversion are differentially encoded by the activity of NAc neurons. The present study examined whether the requirement for N-methyl-D-aspartate (NMDA) receptors in the NAc core during rewarding appetitive taste learning differs from that during aversive taste conditioning, as well as during retrieval of appetitive vs. aversive taste memory, using the taste preference or CTA model, respectively. Bilateral infusions of NMDA (1 MUg/MUl, 0.5 MUl) into the NAc core were performed before acquisition or before retrieval of taste preference or CTA. Activation of NMDA receptors before taste preference training or CTA acquisition did not alter memory formation. Furthermore, NMDA injections before aversive taste retrieval had no effect on taste memory; however, 24 h later, CTA extinction was significantly delayed. Also, NMDA injections, made before familiar appetitive memory retrieval, interrupted the development of taste preference and produced a preference delay 24 h later. These results suggest that memory formation for a novel taste produces neurochemical changes in the NAc core that have differential requirements for NMDA receptors during retrieval of appetitive or aversive memory. PMID- 22529784 TI - Memory-enhancing intra-basolateral amygdala infusions of clenbuterol increase Arc and CaMKIIalpha protein expression in the rostral anterior cingulate cortex. AB - Activation of beta-adrenoceptors in the basolateral complex of the amygdala (BLA) modulates memory through interactions with multiple memory systems. The cellular mechanisms for this interaction remain unresolved. Memory-modulating BLA manipulations influence expression of the protein product of the immediate early gene activity-regulated cytoskeletal-associated protein (Arc) in the dorsal hippocampus, and hippocampal expression of Arc protein is critically involved in memory consolidation and long-term potentiation. The present studies examined whether this influence of the BLA is specific to the hippocampus and to Arc protein. Like the hippocampus, the rostral portion of the anterior cingulate cortex (rACC) is involved in the consolidation of inhibitory avoidance (IA) memory, and IA training increases Arc protein in the rACC. Because the BLA interacts with the rACC in the consolidation of IA memory, the rACC is a potential candidate for further studies of BLA modulation of synaptic plasticity. The alpha isoform of the Calcium/Calmodulin-dependent protein kinase II (CaMKIIalpha) and the immediate early gene c-Fos are involved in long-term potentiation and memory. Both Arc and CaMKIIalpha proteins can be translated in isolated synapses, where the mRNA is localized, but c-Fos protein remains in the soma. To examine the influence of memory-modulating manipulations of the BLA on expression of these memory and plasticity-associated proteins in the rACC, male Sprague-Dawley rats were trained on an IA task and given intra-BLA infusions of either clenbuterol or lidocaine immediately after training. Findings suggest that noradrenergic stimulation of the BLA may modulate memory consolidation through effects on both synaptic proteins Arc and CaMKIIalpha, but not the somatic protein c-Fos. Furthermore, protein changes observed in the rACC following BLA manipulations suggest that the influence of the BLA on synaptic proteins is not limited to those in the dorsal hippocampus. PMID- 22529785 TI - The brain on art: intense aesthetic experience activates the default mode network. AB - Aesthetic responses to visual art comprise multiple types of experiences, from sensation and perception to emotion and self-reflection. Moreover, aesthetic experience is highly individual, with observers varying significantly in their responses to the same artwork. Combining fMRI and behavioral analysis of individual differences in aesthetic response, we identify two distinct patterns of neural activity exhibited by different sub-networks. Activity increased linearly with observers' ratings (4-level scale) in sensory (occipito-temporal) regions. Activity in the striatum (STR) also varied linearly with ratings, with below-baseline activations for low-rated artworks. In contrast, a network of frontal regions showed a step-like increase only for the most moving artworks ("4" ratings) and non-differential activity for all others. This included several regions belonging to the "default mode network" (DMN) previously associated with self-referential mentation. Our results suggest that aesthetic experience involves the integration of sensory and emotional reactions in a manner linked with their personal relevance. PMID- 22529786 TI - Malleability of the approximate number system: effects of feedback and training. AB - Prior research demonstrates that animals and humans share an approximate number system (ANS), characterized by ratio dependence and that the precision of this system increases substantially over human development. The goal of the present research was to investigate the malleability of the ANS (as measured by Weber fraction) in adult subjects in response to feedback and to explore the relationship between ANS acuity and acuity on another magnitude comparison task. We tested each of 20 subjects over six 1-h sessions. The main findings were that (a) Weber fractions rapidly decreased when trial-by-trial feedback was introduced in the second session and remained stable over continued training, (b) Weber fractions remained steady when trial-by-trial feedback was removed in session 6, (c)Weber fractions from the number comparison task were positively correlated with Weber fractions from a line length comparison task, (d) improvement in Weber fractions in response to feedback for the number task did not transfer to the line length task, (e) finally, the precision of the ANS was positively correlated with math, but not verbal, standardized aptitude scores. Potential neural correlates of the perceptual information and decision processes are considered, and predictions regarding the neural correlates of ANS malleability are discussed. PMID- 22529787 TI - An abundance of riches: cross-task comparisons of semantic richness effects in visual word recognition. AB - There is considerable evidence (e.g., Pexman et al., 2008) that semantically rich words, which are associated with relatively more semantic information, are recognized faster across different lexical processing tasks. The present study extends this earlier work by providing the most comprehensive evaluation to date of semantic richness effects on visual word recognition performance. Specifically, using mixed effects analyses to control for the influence of correlated lexical variables, we considered the impact of number of features, number of senses, semantic neighborhood density, imageability, and body-object interaction across five visual word recognition tasks: standard lexical decision, go/no-go lexical decision, speeded pronunciation, progressive demasking, and semantic classification. Semantic richness effects could be reliably detected in all tasks of lexical processing, indicating that semantic representations, particularly their imaginal and featural aspects, play a fundamental role in visual word recognition. However, there was also evidence that the strength of certain richness effects could be flexibly and adaptively modulated by task demands, consistent with an intriguing interplay between task-specific mechanisms and differentiated semantic processing. PMID- 22529788 TI - A neuroanatomical examination of embodied cognition: semantic generation to action-related stimuli. AB - The theory of embodied cognition postulates that the brain represents semantic knowledge as a function of the interaction between the body and the environment. The goal of our research was to provide a neuroanatomical examination of embodied cognition using action-related pictures and words. We used functional magnetic resonance imaging (fMRI) to examine whether there were shared and/or unique regions of activation between an ecologically valid semantic generation task and a motor task in the parietal-frontocentral network (PFN), as a function of stimulus format (pictures versus words) for two stimulus types (hand and foot). Unlike other methods for neuroimaging analyses involving subtractive logic or conjoint analyses, this method first isolates shared and unique regions of activation within-participants before generating an averaged map. The results demonstrated shared activation between the semantic generation and motor tasks, which was organized somatotopically in the PFN, as well as unique activation for the semantic generation tasks in proximity to the hand or foot motor cortex. We also found unique and shared regions of activation in the PFN as a function of stimulus format (pictures versus words). These results further elucidate embodied cognition in that they show that brain regions activated during actual motor movements were also activated when an individual verbally generates action related semantic information. Disembodied cognition theories and limitations are also discussed. PMID- 22529789 TI - Apples are not the only fruit: the effects of concept typicality on semantic representation in the anterior temporal lobe. AB - Intuitively, an apple seems a fairly good example of a fruit, whereas an avocado seems less so. The extent to which an exemplar is representative of its category, referred to here as concept typicality, has long been thought to be a key dimension determining semantic representation. Concept typicality is, however, correlated with a number of other variables, in particular age of acquisition (AoA) and name frequency. Consideration of picture naming accuracy from a large case-series of semantic dementia (SD) patients demonstrated strong effects of concept typicality that were maximal in the moderately impaired patients, over and above the impact of AoA and name frequency. Induction of a temporary virtual lesion to the left anterior temporal lobe, the region most commonly affected in SD, via repetitive Transcranial Magnetic Stimulation produced an enhanced effect of concept typicality in the picture naming of normal participants, but did not affect the magnitude of the AoA or name frequency effects. These results indicate that concept typicality exerts its influence on semantic representations themselves, as opposed to the strength of connections outside the semantic system. To date, there has been little direct exploration of the dimension of concept typicality within connectionist models of intact and impaired conceptual representation, and these findings provide a target for future computational simulation. PMID- 22529790 TI - "You can't kid a kidder": association between production and detection of deception in an interactive deception task. AB - Both the ability to deceive others, and the ability to detect deception, has long been proposed to confer an evolutionary advantage. Deception detection has been studied extensively, and the finding that typical individuals fare little better than chance in detecting deception is one of the more robust in the behavioral sciences. Surprisingly, little research has examined individual differences in lie production ability. As a consequence, as far as we are aware, no previous study has investigated whether there exists an association between the ability to lie successfully and the ability to detect lies. Furthermore, only a minority of studies have examined deception as it naturally occurs; in a social, interactive setting. The present study, therefore, explored the relationship between these two facets of deceptive behavior by employing a novel competitive interactive deception task (DeceIT). For the first time, signal detection theory (SDT) was used to measure performance in both the detection and production of deception. A significant relationship was found between the deception-related abilities; those who could accurately detect a lie were able to produce statements that others found difficult to classify as deceptive or truthful. Furthermore, neither ability was related to measures of intelligence or emotional ability. We, therefore, suggest the existence of an underlying deception-general ability that varies across individuals. PMID- 22529791 TI - Error awareness and the error-related negativity: evaluating the first decade of evidence. AB - From its discovery in the early 1990s until this day, the error-related negativity (ERN) remains the most widely investigated electrophysiological index of cortical error processing. When researchers began addressing the electrophysiology of subjective error awareness more than a decade ago, the role of the ERN, alongside the subsequently occurring error positivity (Pe), was an obvious locus of attention. However, the first two studies explicitly addressing the role of error-related event-related brain potentials (ERPs) would already set the tone for what still remains a controversy today: in contrast to the clear-cut findings that link the amplitude of the Pe to error awareness, the association between ERN amplitude and error awareness is vastly unclear. An initial study reported significant differences in ERN amplitude with respect to subjective error awareness, whereas the second failed to report this result, leading to a myriad of follow-up studies that seemed to back up or contradict either view. Here, I review those studies that explicitly dealt with the role of the error related ERPs in subjective error awareness, and try to explain the differences in reported effects of error awareness on ERN amplitude. From the point of view presented here, different findings between studies can be explained by disparities in experimental design and data analysis, specifically with respect to the quantification of subjective error awareness. Based on the review of these results, I will then try to embed the error-related negativity into a widely known model of the implementation of access consciousness in the brain, the global neuronal workspace (GNW) model, and speculate as the ERN's potential role in such a framework. At last, I will outline future challenges in the investigation of the cortical electrophysiology of error awareness, and offer some suggestions on how they could potentially be addressed. PMID- 22529792 TI - Relationship between neural response and adaptation selectivity to form and color: an ERP study. AB - Adaptation is widely used as a tool for studying selectivity to visual features. In these studies it is usually assumed that the loci of feature selective neural responses and adaptation coincide. We used an adaptation paradigm to investigate the relationship between response and adaptation selectivity in event-related potentials (ERPs). ERPs were evoked by the presentation of colored Glass patterns in a form discrimination task. Response selectivities to form and, to some extent, color of the patterns were reflected in the C1 and N1 ERP components. Adaptation selectivity to color was reflected in N1 and was followed by a late (300-500 ms after stimulus onset) effect of form adaptation. Thus for form, response and adaptation selectivity were manifested in non-overlapping intervals. These results indicate that adaptation and response selectivity can be associated with different processes. Therefore, inferring selectivity from an adaptation paradigm requires analysis of both adaptation and neural response data. PMID- 22529793 TI - Can executive control be influenced by performance feedback? Two experimental studies with younger and older adults. AB - Executive control describes a wide range of cognitive processes which are critical for the goal-directed regulation of stimulus processing and action regulation. Previous studies have shown that executive control performance declines with age but yet, it is still not clear whether different internal and external factors-as performance feedback and age-influence these cognitive processes and how they might interact with each other. Therefore, we investigated feedback effects in the flanker task in young as well as in older adults in two experiments. Performance feedback significantly improved executive performance in younger adults at the expense of errors. In older adults, feedback also led to higher error rates, but had no significant effect on executive performance which might be due to stronger interference. Results indicate that executive functions can be positively influenced by performance feedback in younger adults, but not necessarily in older adults. PMID- 22529795 TI - Visual search in spatial neglect studied with a preview paradigm. AB - Impaired visual search is a hallmark of spatial neglect. When searching for an unique feature (e.g., color) neglect patients often show only slight visual field asymmetries. In contrast, when the target is defined by a combination of features (e.g., color and form) they exhibit a severe deficit of contralesional search. This finding suggests a selective impairment of the serial deployment of spatial attention. Here, we examined this deficit with a preview paradigm. Neglect patients searched for a target defined by the conjunction of shape and color, presented together with varying numbers of distracters. The presentation time was varied such that on some trials participants previewed the target together with same-shape/different-color distracters, for 300 or 600 ms prior to the appearance of additional different-shape/same-color distracters. On the remaining trials the target and all distracters were shown simultaneously. Healthy participants exhibited a serial search strategy only when all items were presented simultaneously, whereas in both preview conditions a pop-out effect was observed. Neglect patients showed a similar pattern when the target was presented in the right hemifield. In contrast, when searching for a target in the left hemifield they showed serial search in the no-preview condition, as well as with a preview of 300 ms, and partly even at 600 ms. A control experiment suggested that the failure to fully benefit from item preview was probably independent of accurate perception of time. Our results, when viewed in the context of existing literature, lead us to conclude that the visual search deficit in neglect reflects two additive factors: a biased representation of attentional priority in favor of ipsilesional information and exaggerated capture of attention by ipsilesional abrupt onsets. PMID- 22529796 TI - Investigating social gaze as an action-perception online performance. AB - Gaze represents a major non-verbal communication channel in social interactions. In this respect, when facing another person, one's gaze should not be examined as a purely perceptive process but also as an action-perception online performance. However, little is known about processes involved in the real-time self regulation of social gaze. The present study investigates the impact of a gaze contingent viewing window on fixation patterns and the awareness of being the agent moving the window. In face-to-face scenarios played by a virtual human character, the task for the 18 adult participants was to interpret an equivocal sentence which could be disambiguated by examining the emotional expressions of the character speaking. The virtual character was embedded in naturalistic backgrounds to enhance realism. Eye-tracking data showed that the viewing window induced changes in gaze behavior, notably longer visual fixations. Notwithstanding, only half of the participants ascribed the window displacements to their eye movements. These participants also spent more time looking at the eyes and mouth regions of the virtual human character. The outcomes of the study highlight the dissociation between non-volitional gaze adaptation and the self ascription of agency. Such dissociation provides support for a two-step account of the sense of agency composed of pre-noetic monitoring mechanisms and reflexive processes, linked by bottom-up and top-down processes. We comment upon these results, which illustrate the relevance of our method for studying online social cognition, in particular concerning autism spectrum disorders (ASD) where the poor pragmatic understanding of oral speech is considered linked to visual peculiarities that impede facial exploration. PMID- 22529794 TI - The hippocampus and visual perception. AB - In this review, we will discuss the idea that the hippocampus may be involved in both memory and perception, contrary to theories that posit functional and neuroanatomical segregation of these processes. This suggestion is based on a number of recent neuropsychological and functional neuroimaging studies that have demonstrated that the hippocampus is involved in the visual discrimination of complex spatial scene stimuli. We argue that these findings cannot be explained by long-term memory or working memory processing or, in the case of patient findings, dysfunction beyond the medial temporal lobe (MTL). Instead, these studies point toward a role for the hippocampus in higher-order spatial perception. We suggest that the hippocampus processes complex conjunctions of spatial features, and that it may be more appropriate to consider the representations for which this structure is critical, rather than the cognitive processes that it mediates. PMID- 22529797 TI - Examining the McGurk illusion using high-field 7 Tesla functional MRI. AB - In natural communication speech perception is profoundly influenced by observable mouth movements. The additional visual information can greatly facilitate intelligibility but incongruent visual information may also lead to novel percepts that neither match the auditory nor the visual information as evidenced by the McGurk effect. Recent models of audiovisual (AV) speech perception accentuate the role of speech motor areas and the integrative brain sites in the vicinity of the superior temporal sulcus (STS) for speech perception. In this event-related 7 Tesla fMRI study we used three naturally spoken syllable pairs with matching AV information and one syllable pair designed to elicit the McGurk illusion. The data analysis focused on brain sites involved in processing and fusing of AV speech and engaged in the analysis of auditory and visual differences within AV presented speech. Successful fusion of AV speech is related to activity within the STS of both hemispheres. Our data supports and extends the audio-visual-motor model of speech perception by dissociating areas involved in perceptual fusion from areas more generally related to the processing of AV incongruence. PMID- 22529798 TI - Learning from open source software projects to improve scientific review. AB - Peer-reviewed publications are the primary mechanism for sharing scientific results. The current peer-review process is, however, fraught with many problems that undermine the pace, validity, and credibility of science. We highlight five salient problems: (1) reviewers are expected to have comprehensive expertise; (2) reviewers do not have sufficient access to methods and materials to evaluate a study; (3) reviewers are neither identified nor acknowledged; (4) there is no measure of the quality of a review; and (5) reviews take a lot of time, and once submitted cannot evolve. We propose that these problems can be resolved by making the following changes to the review process. Distributing reviews to many reviewers would allow each reviewer to focus on portions of the article that reflect the reviewer's specialty or area of interest and place less of a burden on any one reviewer. Providing reviewers materials and methods to perform comprehensive evaluation would facilitate transparency, greater scrutiny, and replication of results. Acknowledging reviewers makes it possible to quantitatively assess reviewer contributions, which could be used to establish the impact of the reviewer in the scientific community. Quantifying review quality could help establish the importance of individual reviews and reviewers as well as the submitted article. Finally, we recommend expediting post publication reviews and allowing for the dialog to continue and flourish in a dynamic and interactive manner. We argue that these solutions can be implemented by adapting existing features from open-source software management and social networking technologies. We propose a model of an open, interactive review system that quantifies the significance of articles, the quality of reviews, and the reputation of reviewers. PMID- 22529799 TI - Non-linear blend coding in the moth antennal lobe emerges from random glomerular networks. AB - Neural responses to odor blends often exhibit non-linear interactions to blend components. The first olfactory processing center in insects, the antennal lobe (AL), exhibits a complex network connectivity. We attempt to determine if non linear blend interactions can arise purely as a function of the AL network connectivity itself, without necessitating additional factors such as competitive ligand binding at the periphery or intrinsic cellular properties. To assess this, we compared blend interactions among responses from single neurons recorded intracellularly in the AL of the moth Manduca sexta with those generated using a population-based computational model constructed from the morphologically based connectivity pattern of projection neurons (PNs) and local interneurons (LNs) with randomized connection probabilities from which we excluded detailed intrinsic neuronal properties. The model accurately predicted most of the proportions of blend interaction types observed in the physiological data. Our simulations also indicate that input from LNs is important in establishing both the type of blend interaction and the nature of the neuronal response (excitation or inhibition) exhibited by AL neurons. For LNs, the only input that significantly impacted the blend interaction type was received from other LNs, while for PNs the input from olfactory sensory neurons and other PNs contributed agonistically with the LN input to shape the AL output. Our results demonstrate that non-linear blend interactions can be a natural consequence of AL connectivity, and highlight the importance of lateral inhibition as a key feature of blend coding to be addressed in future experimental and computational studies. PMID- 22529801 TI - Reactivation of Tuberculosis in Three Cases of Psoriasis after Initiation of Anti TNF Therapy. AB - New biological therapies for disabling diseases such as psoriasis may carry both short- and long-term risks. Tuberculosis (TB) reactivation is a frequent complication of anti-tumor necrosis factor (TNF) therapy. We present 3 cases of psoriasis that were treated with different types of anti-TNF and developed TB infection (TBI) during therapy. One of the cases was diagnosed as active pulmonary TB and the other 2 cases as latent TBI. All cases received appropriate anti-TB treatment, and the anti-TNF therapy was interrupted and then resumed according to various clinical considerations. PMID- 22529800 TI - Synaptic inhibition controls transient oscillatory synchronization in a model of the insect olfactory system. AB - In a variety of neuronal systems it has been hypothesized that inhibitory interneurons corral principal neurons into synchronously firing groups that encode sensory information and sub-serve behavior (Buzsaki and Chrobak, 1995; Buzsaki, 2008). This mechanism is particularly relevant to the olfactory system where spatiotemporal patterns of projection neuron (PN) activity act as robust markers of odor attributes (Laurent et al., 1996; Wehr and Laurent, 1996). In the insect antennal lobe (AL), a network of local inhibitory interneurons arborizes extensively throughout the AL (Leitch and Laurent, 1996) providing inhibitory input to the cholinergic PNs. Our theoretical work has attempted to elaborate the exact role of inhibition in the generation of odor specific PN responses (Bazhenov et al., 2001a,b; Assisi et al., 2011). In large-scale AL network models we characterized the inhibitory sub-network by its coloring (Assisi et al., 2011) and showed that it can entrain excitatory PNs to the odor specific patterns of transient synchronization. In this focused review, we further examine the dynamics of entrainment in more detail by simulating simple model networks in various parameter regimes. Our simulations in conjunction with earlier studies point to the key role played by lateral (between inhibitory interneurons) and feedback (from inhibitory interneurons to principal cells) inhibition in the generation of experimentally observed patterns of transient synchrony. PMID- 22529802 TI - Cellulitis with leukocytopenia as an initial sign of acute promyelocytic leukemia. AB - Patients with hematologic malignancies are immunosuppressive and may develop cutaneous or invasive infections as a primary sign of immune suppression. Acute promyelocytic leukemia (acute myeloid leukemia M3) is caused by translocation of reciprocal chromosomal rearrangement t(15;17), which produces an oncogenic protein. We herein describe a 71-year-old man having cellulitis with leukocytopenia as a first sign of acute promyelocytic leukemia. Dermatologists and hematologists should keep in mind that patients with a hematologic malignancy, such as acute promyelocytic leukemia, can develop cellulitis with leukocytopenia. PMID- 22529803 TI - Cutaneous lymphadenoma: a case report and immunohistochemical study. AB - Cutaneous lymphadenoma is a rare neoplasm, and characterized by a florid mononuclear cell infiltration that appears to be an integral component of the tumor. Several reports suggested that these infiltrated lymphocytes mainly consist of T cells and Langerhans cells, but no detailed phenotypical analysis of these cells has been demonstrated yet. In this report, we describe a 70-year-old Japanese patient with cutaneous lymphadenoma. In the present case, we investigated the immunohistochemical profiles of tumor-infiltrating cells in cutaneous lymphadenoma, especially focusing on the profiles of T cell subsets. In addition, there are abundant mucin deposits within the tumor stroma, and tumor lobules are composed of BerEP4-positive cells. To the best of our knowledge, this is the first report that employed immunohistochemical staining of cutaneous lymphadenoma to verify the types of cells composing such tumors with special focus on the profiles of the T cell subsets. PMID- 22529804 TI - Nonarteritic anterior ischemic optic neuropathy and double thrombophilic defect: a new observation. AB - WE REPORT THE FIRST CASE OF NONARTERITIC ANTERIOR ISCHEMIC NEUROPATHY (NAION) ASSOCIATED WITH DOUBLE THROMBOPHILIA: protein S deficiency and prothrombin G20210A mutation. A 58-year-old man is presented including the clinical and laboratory findings, cardiovascular profile and thrombophilia screening. The patient presented with 3/10 vision and an inferior altitudinal defect in the right eye. Funduscopic examination of the right eye revealed a hyperemic optic disk with blurred superior optic disk border and sectoral nerve fiber layer edema. Complete blood count, erythrocyte sedimentation rate and C-reactive protein were normal, suggesting a NAION. A workup of cardiovascular risk factors revealed hyperlipidemia, arterial hypertension and high-risk asymptomatic coronary artery disease. Due to the family history of deep vein thrombosis in the patient's daughter, a thrombophilia screening was additionally performed. The results revealed a double thrombophilic defect, namely congenital protein S deficiency and heterozygosity for prothrombin G20210A mutation, which were also identified in the patient's daughter. Anticoagulant warfarin therapy was initiated and the patient underwent a triple bypass surgery. At three-month follow-up, the right optic disk edema had resolved, leaving a pale superior optic nerve head. Visual acuity in the right eye had slightly improved to 4/10; however, the dense inferior altitudinal field defect had remained unchanged. The patient is currently treated with warfarin, atorvastatin, irbesartan and metoprolol. This case suggests that the first line of investigation in all patients with NAION involves assessment of cardiovascular risk factors. However, careful history taking will identify NAION patients who are eligible for additional thrombophilia screening: young patients without vasculopathic risk factors, bilateral or recurrent NAION, idiopathic or recurrent venous thromboembolism (VTE), positive family history of VTE, and VTE in young age or in unusual sites (e.g. cerebral, hepatic, mesenteric, or renal vein). PMID- 22529805 TI - Radiation Macular Edema after Ru-106 Plaque Brachytherapy for Choroidal Melanoma Resolved by an Intravitreal Dexamethasone 0.7-mg Implant. AB - PURPOSE: To report the effective treatment of radiation macular edema following ruthenium-106 plaque brachytherapy for a choroidal melanoma with a dexamethasone 0.7-mg (Ozurdex((r))) intravitreal implant. METHODS: An interventional case report with optical coherence tomography (OCT) scans. RESULTS: A 65-year-old Caucasian woman was suffering from radiation macular edema following ruthenium 106 plaque brachytherapy for a choroidal melanoma on her left eye. She had undergone one intravitreal injection of 0.5 mg bevacizumab (Avastin((r)), Genentech/Roche) in the following months without functional or anatomical improvement. Seven months after the development of radiation macular edema, she received a single intravitreal injection of dexamethasone 0.7 mg (Ozurdex). Four weeks following the injection, her best-corrected visual acuity improved from 0.3 to 0.5. Radiation macular edema resolved with a reduction of central retinal thickness from 498 MUm before Ozurdex injection to 224 MUm after Ozurdex injection, as measured by OCT scan. CONCLUSION: Dexamethasone 0.7 mg (Ozurdex) has proven to be an effective treatment option in retinal vein occlusion and noninfectious uveitis. It can also be considered as off-label treatment in radiation macular edema following ruthenium-106 plaque brachytherapy for a choroidal melanoma. PMID- 22529806 TI - Intravitreal ranibizumab in the treatment of butterfly-shaped pattern dystrophy associated with choroidal neovascularization: a case report. AB - PURPOSE: To present and document the effectiveness of intravitreal ranibizumab in the treatment of patients with choroidal neovascularization due to butterfly shaped pattern dystrophy (PD) of the macula. METHODS: Three intravitreal ranibizumab injections of 0.5 mg/0.05 ml in monthly intervals were given to a patient with a previously diagnosed butterfly-shaped PD who subsequently developed subfoveal choroidal neovascularization on the right eye. The patient had previously received a combination of verteporfin/photodynamic therapy for a juxtafoveal choroidal neovascular membrane on the left eye. RESULTS: At the end of the treatment course, there was significant improvement of the patient's vision and the appearance of the macula on optic coherence tomography and fluorescein angiography. Best-corrected visual acuity improved from 6/12 to 6/6 and retinal thickness at the macula decreased from 323 to 247 MUm. No subretinal fluid remained. The patient is clinically stable over a 12-month follow-up period. CONCLUSIONS: Intravitreal ranibizumab seems to be an effective and safe option for the treatment of subfoveal choroidal neovascularization in patients with butterfly-shaped PD. PMID- 22529807 TI - Fuchs' adenoma of the choroid simulating a choroidal hemangioma. AB - We report the case of a 54-year-old female who was referred to us with an amelanotic mass on the posterior pole of the left eye involving the macula. Fundus fluorescein angiography revealed a hyperfluorescent choroidal mass. Indocyanine green chorioangiography revealed a hypofluorescent choroidal lesion with hyperfluorescent margins. B-scan ultrasonography showed a choroidal mass with moderate reflectivity. Choroidal biopsy was performed, which revealed the diagnosis of Fuchs' adenoma. PMID- 22529808 TI - Keratoconjunctivitis and Periorbital Edema due to Ecballium elaterium. AB - PURPOSE: To report on a case of keratoconjunctivitis with periorbital edema after accidental exposure to undiluted juice of Ecballium elaterium fruit during the ripening season of this plant. METHODS: Case report. RESULTS: Keratoconjunctivitis with Descemet's membrane folds and superficial upper corneal well-defined edematous areas were noted after an Ecballium elaterium fruit burst and its juice splashed into the patient's left eye. Prompt administration of antibiotic and steroid eye drops along with per os antihistamine therapy, resulted in quick regression of symptoms. CONCLUSIONS: This report demonstrates the toxic effects of this herb to the eye and also that prompt therapy is effective. PMID- 22529809 TI - Systematic review of membrane components of gram-positive bacteria responsible as pyrogens for inducing human monocyte/macrophage cytokine release. AB - Fifty years after the elucidation of lipopolysaccharides (LPS, endotoxin) as the principal structure of Gram-negative bacteria activating the human immune system, its Gram-positive counterpart is still under debate. Pyrogen tests based on the human monocyte activation have been validated for LPS detection as an alternative to the rabbit test and, increasingly, the limulus amebocyte lysate test. For full replacement, international validations with non-endotoxin pyrogens are in preparation. Following evidence-based medicine approaches, a systematic review of existing evidence as to the structural nature of the Gram-positive pyrogen was undertaken. For the three major constituents suggested, i.e., peptidoglycan, lipoteichoic acids (LTA), and bacterial lipoproteins (LP), the questions to be answered and a search strategy for relevant literature was developed, starting in MedLine. The evaluation was based on the Koch-Dale criteria for a mediator of an effect. A total of 380 articles for peptidoglycan, 391 for LP, and 285 for LTA were retrieved of which 12, 8, and 24, respectively, fulfilled inclusion criteria. The compiled data suggest that for peptidoglycan two Koch-Dale criteria are fulfilled, four for LTA, and two for bacterial LP. In conclusion, based on the best currently available evidence, LTA is the only substance that fulfills all criteria. LTA has been isolated from a large number of bacteria, results in cytokine release patterns inducible also with synthetic LTA. Reduction in bacterial cytokine induction with an inhibitor for LTA was shown. However, this systematic review cannot exclude the possibility that other stimulatory compounds complement or substitute for LTA in being the counterpart to LPS in some Gram positive bacteria. PMID- 22529811 TI - Mexiletine differentially restores the trafficking defects caused by two brugada syndrome mutations. AB - The human cardiac sodium channel Na(v)1.5 encoded by the SCN5A gene plays a critical role in cardiac excitability and the propagation of action potentials. Na(v)1.5 dysfunctions due to mutations cause cardiac diseases such as the LQT3 form of long QT syndrome, conduction disorders, and Brugada syndrome (BrS). They have also recently been associated with dilated cardiomyopathy. BrS is characterized by coved ST-segment elevation on surface ECGs and lethal ventricular arrhythmias in an apparently structurally normal heart. Na(v)1.5 mutations that cause BrS result in a loss of channel function. Our aim was to functionally characterize two novel Na(v)1.5 mutations (A124D and V1378M) in BrS patients. Wild-type (WT) and mutant Na(v)1.5 channels were expressed in tsA201 cells in the presence of the beta(1)-auxiliary subunit. The patch-clamp technique and immunocytochemistry approaches were used to study the mutant channels and their cellular localization. The two mutant channels displayed a dramatic reduction in current density but had normal gating properties. The reduction in current density was caused by the retention of channel proteins in the endoplasmic reticulum (ER). Mutant channel retention could be partially reversed by incubating transfected cells at 25 degrees C and by treating them with mexiletine (for V1378M but not A124D), or with curcumin or thapsigargin, two drugs that target ER resident proteins. It is likely that the clinical phenotypes observed in these two BrS patients were related to a surface expression defect caused by ER retention. PMID- 22529810 TI - Biological role of aldo-keto reductases in retinoic Acid biosynthesis and signaling. AB - Several aldo-keto reductase (AKR) enzymes from subfamilies 1B and 1C show retinaldehyde reductase activity, having low K(m) and k(cat) values. Only AKR1B10 and 1B12, with all-trans-retinaldehyde, and AKR1C3, with 9-cis-retinaldehyde, display high catalytic efficiency. Major structural determinants for retinaldehyde isomer specificity are located in the external loops (A and C for AKR1B10, and B for AKR1C3), as assessed by site-directed mutagenesis and molecular dynamics. Cellular models have shown that AKR1B and 1C enzymes are well suited to work in vivo as retinaldehyde reductases and to regulate retinoic acid (RA) biosynthesis at hormone pre-receptor level. An additional physiological role for the retinaldehyde reductase activity of these enzymes, consistent with their tissue localization, is their participation in beta-carotene absorption. Retinaldehyde metabolism may be subjected to subcellular compartmentalization, based on enzyme localization. While retinaldehyde oxidation to RA takes place in the cytosol, reduction to retinol could take place in the cytosol by AKRs or in the membranes of endoplasmic reticulum by microsomal retinaldehyde reductases. Upregulation of some AKR1 enzymes in different cancer types may be linked to their induction by oxidative stress and to their participation in different signaling pathways related to cell proliferation. AKR1B10 and AKR1C3, through their retinaldehyde reductase activity, trigger a decrease in the RA biosynthesis flow, resulting in RA deprivation and consequently lower differentiation, with an increased cancer risk in target tissues. Rational design of selective AKR inhibitors could lead to development of novel drugs for cancer treatment as well as reduction of chemotherapeutic drug resistance. PMID- 22529812 TI - Regulation of Voltage-Activated K(+) Channel Gating by Transmembrane beta Subunits. AB - Voltage-activated K(+) (K(V)) channels are important for shaping action potentials and maintaining resting membrane potential in excitable cells. K(V) channels contain a central pore-gate domain (PGD) surrounded by four voltage sensing domains (VSDs). The VSDs will change conformation in response to alterations of the membrane potential thereby inducing the opening of the PGD. Many K(V) channels are heteromeric protein complexes containing auxiliary beta subunits. These beta subunits modulate channel expression and activity to increase functional diversity and render tissue specific phenotypes. This review focuses on the K(V) beta subunits that contain transmembrane (TM) segments including the KCNE family and the beta subunits of large conductance, Ca(2+)- and voltage-activated K(+) (BK) channels. These TM beta subunits affect the voltage dependent activation of K(V) alpha subunits. Experimental and computational studies have described the structural location of these beta subunits in the channel complexes and the biophysical effects on VSD activation, PGD opening, and VSD-PGD coupling. These results reveal some common characteristics and mechanistic insights into K(V) channel modulation by TM beta subunits. PMID- 22529813 TI - Excitatory GABA: How a Correct Observation May Turn Out to be an Experimental Artifact. AB - The concept of the excitatory action of GABA during early development is based on data obtained mainly in brain slice recordings. However, in vivo measurements as well as observations made in intact hippocampal preparations indicate that GABA is in fact inhibitory in rodents at early neonatal stages. The apparent excitatory action of GABA seems to stem from cellular injury due to the slicing procedure, which leads to accumulation of intracellular Cl(-) in injured neurons. This procedural artifact was shown to be attenuated through various manipulations such as addition of energy substrates more relevant to the in vivo situation. These observations question the very concept of excitatory GABA in immature neuronal networks. PMID- 22529815 TI - Omega-3 Fatty acids: anti-arrhythmic, pro-arrhythmic, or both? AB - This review focuses on developments after 2008, when the topic was last reviewed by the author. Pertinent publications were found by medline searches and in the author's personal data base. Prevention of atrial fibrillation (AF) was investigated in a number of trials, sparked by one positive report on the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), considerations of upstream therapy, data from electrophysiologic laboratories and animal experiments. If EPA + DHA prevent postoperative AF, the effect is probably smaller than initially expected. The same is probably true for maintenance of sinus rhythm after cardioversion and for new-onset AF. Larger trials are currently ongoing. Prevention of ventricular arrhythmias was studied in carriers of an implanted cardioverter-defibrillator, with no clear results. This might have been due to a broad definition of the primary endpoint, including any ventricular arrhythmia and any action of the device. Epidemiologic studies support the contention that high levels of EPA + DHA prevent sudden cardiac death (SCD). However, since SCD is a rare occurrence, it is difficult to conduct an adequately powered trial. In patients with congestive heart failure, EPA + DHA reduced total mortality and rehospitalizations, but not SCD or presumed arrhythmic death. Of three trials in patients after a myocardial infarction, two were inadequately powered, and in one, the dose might have been too low. Taken together, while epidemiologic studies support an inverse relation between EPA + DHA and occurrence of SCD or arrhythmic death, demonstrating this effect in intervention trials remained elusive so far. A pro-arrhythmic effect of EPA + DHA has not been seen in intervention studies, and results of epidemiologic and animal studies also rather argue against such an effect. A different, and probably more productive, perspective is provided by a standardized analytical assessment of a person's status in EPA + DHA by use of the omega-3 index, EPA + DHA in red cell fatty acids. In populations with a high omega-3 index, SCD is rare. Intervention trials can become more effective by including a low omega-3 index into the inclusion criteria, thus creating a study population more likely to demonstrate an effect of EPA + DHA. This is especially relevant in case of rare endpoints, like new-onset AF or SCD. PMID- 22529814 TI - Endocannabinoid-dopamine interactions in striatal synaptic plasticity. AB - The nigrostriatal dopaminergic system is implicated in action control and learning. A large body of work has focused on the contribution of this system to modulation of the corticostriatal synapse, the predominant synapse type in the striatum. Signaling through the D2 dopamine receptor is necessary for endocannabinoid-mediated depression of corticostriatal glutamate release. Here we review the known details of this mechanism and discuss newly discovered signaling pathways interacting with this system that ultimately exert dynamic control of cortical input to the striatum and striatal output. This topic is timely with respect to Parkinson's disease given recent data indicating changes in the striatal endocannabinoid system in patients with this disorder. PMID- 22529817 TI - A neuroanatomical correlate of sensorimotor recovery in response to repeated vaginocervical stimulation in rats. AB - Gentle probing against the cervix via the vagina (vaginocervical stimulation, VCS) increases tail flick latency (TFL) to radiant heat; greater force abolishes the tail flick response and other withdrawal responses. This effect occurs in spinal cord-transected rats and in intact rats. On the basis of our earlier finding that VCS releases vasoactive intestinal peptide (VIP) into the spinal cord, and others' reports of neurotrophic effects of VIP in vitro, we hypothesized that repeated VCS would stimulate sprouting and sensorimotor function of terminals of genital nerve primary afferents in the sacral spinal cord. To test this hypothesis, in the present study, we denervated the genital tract only unilaterally, which significantly reduced the TFL-elevating effect of VCS. Then we applied repeated daily VCS for 1 week and compared the subsequent effectiveness of acute VCS in elevating TFL. The rats that received the repeated daily VCS showed a significantly greater elevation in TFL in response to acute VCS than control rats that did not receive the repeated stimulation. Then, to test whether daily repeated VCS stimulates sprouting of genital primary afferents in such unilaterally genital tract-denervated rats, we transected the contralateral remaining intact pelvic nerve, applied horseradish peroxidase (HRP) to its proximal cut end for 1-2 h, and 2-3 days later counted HRP particles in its terminal zone (L6-S1) in the spinal cord. There were significantly more HRP particles in the rats that received the daily repeated VCS than in the control rats. In the context of these findings, we conclude that VCS in rats can produce a functional sensorimotor recovery via a neurotrophic effect on compromised primary afferents in the spinal cord. PMID- 22529818 TI - Metabolic turnover of hydrogen sulfide. PMID- 22529816 TI - Nerve-cancer interactions in the stromal biology of pancreatic cancer. AB - Interaction of cancer cells with diverse cell types in the tumor stroma is today recognized to have a fate-determining role for the progression and outcome of human cancers. Despite the well-described interactions of cancer cells with several stromal components, i.e., inflammatory cells, cancer-associated fibroblasts, endothelial cells, and pericytes, the investigation of their peculiar relationship with neural cells is still at its first footsteps. Pancreatic cancer (PCa) with its abundant stroma represents one of the best studied examples of a malignant tumor with a mutually trophic interaction between cancer cells and the intratumoral nerves embedded in the desmoplastic stroma. Nerves in PCa are a rich source of neurotrophic factors like nerve growth factor (NGF), glial-cell-derived neurotrophic factor (GDNF), artemin; of neuronal chemokines like fractalkine; and of autonomic neurotransmitters like norepinephrine which can all enhance the invasiveness of PCa cells via matrix metalloproteinase (MMP) upregulation, trigger neural invasion (NI), and activate pro-survival signaling pathways. Similarly, PCa cells themselves provide intrapancreatic nerves with abundant trophic agents which entail a remarkable neuroplasticity, leading to emergence of more routes for NI and cancer spread, to augmented local neuro-surveillance, neural sensitization, and neuropathic pain. The strong correlation of NI with PCa-associated desmoplasia suggests the potential presence of a triangular relationship between nerves, PCa cells, and other stromal partners like myofibroblasts and pancreatic stellate cells which generate tumor desmoplasia. Hence, although not a classical hallmark of human cancers, nerve-cancer interactions can be considered as an indispensable sub class of cancer-stroma interactions in PCa. The present article provides an overview of the so far known nerve-cancer interactions in PCa and illustrates their ominous role in the stromal biology of human PCa. PMID- 22529819 TI - Scaling in cognitive performance reflects multiplicative multifractal cascade dynamics. AB - Self-organized criticality purports to build multi-scaled structures out of local interactions. Evidence of scaling in various domains of biology may be more generally understood to reflect multiplicative interactions weaving together many disparate scales. The self-similarity of power-law scaling entails homogeneity: fluctuations distribute themselves similarly across many spatial and temporal scales. However, this apparent homogeneity can be misleading, especially as it spans more scales. Reducing biological processes to one power-law relationship neglects rich cascade dynamics. We review recent research into multifractality in executive-function cognitive tasks and propose that scaling reflects not criticality but instead interactions across multiple scales and among fluctuations of multiple sizes. PMID- 22529820 TI - Antidiuretic effects of the endothelin receptor antagonist avosentan. AB - Several clinical studies have investigated the potential benefits of endothelin receptor antagonism in chronic pathologies such as diabetic kidney disease. However, fluid retention and edema have been identified as major side effects of endothelin receptor antagonists. In the present study we hypothesized that avosentan which was described as a predominant ET(A) receptor antagonist would produce fluid retention at high concentrations where non-specific blockade of ET(B) receptors may occur. Incremental doses of the predominant ET(A) receptor antagonist SPP301 (0.003; 0.03; 3 mg/kg) were administered intravenously to anesthetized Sprague-Dawley rats undergoing saline diuresis. Diuresis, glomerular filtration rate, and blood pressure (BP) were monitored. SPP301 decreased urine output (5.6; 34.8; 58.8% decrease from vehicle) and fractional excretion of water (5.7; 31.7; 56.4% decrease from vehicle) in a concentration-dependent manner. Glomerular filtration rate was unchanged while BP was reduced by 10 mmHg only by the highest dose of SPP301. Administration of the ET(B) selective receptor antagonist BQ-788 (3 mg/kg) following SPP301 3 mg/kg did not further decrease urine output or water excretion and was without effect on glomerular filtration rate. These data indicate that increasing concentrations of SPP301 may also block ET(B) receptors and cause antidiuresis. This effect could explain why fluid retention and edema occur during treatment with predominant ET(A) receptor blockers. PMID- 22529822 TI - Unanticipated Rapid Remission of Refractory Bulimia Nervosa, during High-Dose Repetitive Transcranial Magnetic Stimulation of the Dorsomedial Prefrontal Cortex: A Case Report. AB - A woman with severe, refractory bulimia nervosa (BN) underwent treatment for comorbid depression using repetitive transcranial magnetic stimulation (rTMS) of the dorsomedial prefrontal cortex (DMPFC) using a novel technique. Unexpectedly, she showed a rapid, dramatic remission from BN. For 5 months pre-treatment, she had reported two 5-h binge-purge episodes per day. After rTMS session 2 the episodes stopped entirely for 1 week; after session 10 there were no further recurrences. Depression scores improved more gradually to remission at session 10. Full remission from depression and binge-eating/purging episodes was sustained more than 2 months after treatment completion. In neuroimaging studies, the DMPFC is important in impulse control, and is underactive in BN. DMPFC-rTMS may have enhanced the patient's ability to deploy previously acquired strategies to avoid binge-eating and purging via a reduction in her impulsivity. A larger sham-controlled trial of DMPFC-rTMS for binge-eating and purging behavior may be warranted. PMID- 22529821 TI - Healthy aging - insights from Drosophila. AB - Human life expectancy has nearly doubled in the past century due, in part, to social and economic development, and a wide range of new medical technologies and treatments. As the number of elderly increase it becomes of vital importance to understand what factors contribute to healthy aging. Human longevity is a complex process that is affected by both environmental and genetic factors and interactions between them. Unfortunately, it is currently difficult to identify the role of genetic components in human longevity. In contrast, model organisms such as C. elegans, Drosophila, and rodents have facilitated the search for specific genes that affect lifespan. Experimental evidence obtained from studies in model organisms suggests that mutations in a single gene may increase longevity and delay the onset of age-related symptoms including motor impairments, sexual and reproductive and immune dysfunction, cardiovascular disease, and cognitive decline. Furthermore, the high degree of conservation between diverse species in the genes and pathways that regulate longevity suggests that work in model organisms can both expand our theoretical knowledge of aging and perhaps provide new therapeutic targets for the treatment of age related disorders. PMID- 22529824 TI - Expression of monoamine transporters, nitric oxide synthase 3, and neurotrophin genes in antidepressant-stimulated astrocytes. AB - BACKGROUND: There is increasing evidence that glial cells play a role in the pathomechanisms of mood disorders and the mode of action of antidepressant drugs. METHODS: To examine whether there is a direct effect on the expression of different genes encoding proteins that have been implicated in the pathophysiology of affective disorders, primary astrocyte cell cultures from rats were treated with two different antidepressant drugs, imipramine and escitalopram, and the RNA expression of brain-derived neurotrophic factor (Bdnf), serotonin transporter (5Htt), dopamine transporter (Dat), and endothelial nitric oxide synthase (Nos3) was examined. RESULTS: Stimulation of astroglial cell culture with imipramine, a tricyclic antidepressant, led to a significant increase of the Bdnf RNA level whereas treatment with escitalopram did not. In contrast, 5Htt was not differentially expressed after antidepressant treatment. Finally, neither Dat nor Nos3 RNA expression was detected in cultured astrocytes. CONCLUSION: These data provide further evidence for a role of astroglial cells in the molecular mechanisms of action of antidepressants. PMID- 22529825 TI - A Call to Action: Alcohol Interventions in HIV-Infected Patients. PMID- 22529826 TI - Attention and visuospatial working memory share the same processing resources. AB - Attention and visuospatial working memory (VWM) share very similar characteristics; both have the same upper bound of about four items in capacity and they recruit overlapping brain regions. We examined whether both attention and VWM share the same processing resources using a novel dual-task costs approach based on a load-varying dual-task technique. With sufficiently large loads on attention and VWM, considerable interference between the two processes was observed. A further load increase on either process produced reciprocal increases in interference on both processes, indicating that attention and VWM share common resources. More critically, comparison among four experiments on the reciprocal interference effects, as measured by the dual-task costs, demonstrates no significant contribution from additional processing other than the shared processes. These results support the notion that attention and VWM share the same processing resources. PMID- 22529823 TI - Connectomic intermediate phenotypes for psychiatric disorders. AB - Psychiatric disorders are phenotypically heterogeneous entities with a complex genetic basis. To mitigate this complexity, many investigators study so-called intermediate phenotypes (IPs) that putatively provide a more direct index of the physiological effects of candidate genetic risk variants than overt psychiatric syndromes. Magnetic resonance imaging (MRI) is a particularly popular technique for measuring such phenotypes because it allows interrogation of diverse aspects of brain structure and function in vivo. Much of this work however, has focused on relatively simple measures that quantify variations in the physiology or tissue integrity of specific brain regions in isolation, contradicting an emerging consensus that most major psychiatric disorders do not arise from isolated dysfunction in one or a few brain regions, but rather from disturbed interactions within and between distributed neural circuits; i.e., they are disorders of brain connectivity. The recent proliferation of new MRI techniques for comprehensively mapping the entire connectivity architecture of the brain, termed the human connectome, has provided a rich repertoire of tools for understanding how genetic variants implicated in mental disorder impact distinct neural circuits. In this article, we review research using these connectomic techniques to understand how genetic variation influences the connectivity and topology of human brain networks. We highlight recent evidence from twin and imaging genetics studies suggesting that the penetrance of candidate risk variants for mental illness, such as those in SLC6A4, MAOA, ZNF804A, and APOE, may be higher for IPs characterized at the level of distributed neural systems than at the level of spatially localized brain regions. The findings indicate that imaging connectomics provides a powerful framework for understanding how genetic risk for psychiatric disease is expressed through altered structure and function of the human connectome. PMID- 22529827 TI - A robotics-based approach to modeling of choice reaching experiments on visual attention. AB - The paper presents a robotics-based model for choice reaching experiments on visual attention. In these experiments participants were asked to make rapid reach movements toward a target in an odd-color search task, i.e., reaching for a green square among red squares and vice versa (e.g., Song and Nakayama, 2008). Interestingly these studies found that in a high number of trials movements were initially directed toward a distractor and only later were adjusted toward the target. These "curved" trajectories occurred particularly frequently when the target in the directly preceding trial had a different color (priming effect). Our model is embedded in a closed-loop control of a LEGO robot arm aiming to mimic these reach movements. The model is based on our earlier work which suggests that target selection in visual search is implemented through parallel interactions between competitive and cooperative processes in the brain (Heinke and Humphreys, 2003; Heinke and Backhaus, 2011). To link this model with the control of the robot arm we implemented a topological representation of movement parameters following the dynamic field theory (Erlhagen and Schoener, 2002). The robot arm is able to mimic the results of the odd-color search task including the priming effect and also generates human-like trajectories with a bell-shaped velocity profile. Theoretical implications and predictions are discussed in the paper. PMID- 22529828 TI - Micro-valences: perceiving affective valence in everyday objects. AB - Perceiving the affective valence of objects influences how we think about and react to the world around us. Conversely, the speed and quality with which we visually recognize objects in a visual scene can vary dramatically depending on that scene's affective content. Although typical visual scenes contain mostly "everyday" objects, the affect perception in visual objects has been studied using somewhat atypical stimuli with strong affective valences (e.g., guns or roses). Here we explore whether affective valence must be strong or overt to exert an effect on our visual perception. We conclude that everyday objects carry subtle affective valences - "micro-valences" - which are intrinsic to their perceptual representation. PMID- 22529829 TI - A Practical Guide to Calculating Cohen's f(2), a Measure of Local Effect Size, from PROC MIXED. AB - Reporting effect sizes in scientific articles is increasingly widespread and encouraged by journals; however, choosing an effect size for analyses such as mixed-effects regression modeling and hierarchical linear modeling can be difficult. One relatively uncommon, but very informative, standardized measure of effect size is Cohen's f(2), which allows an evaluation of local effect size, i.e., one variable's effect size within the context of a multivariate regression model. Unfortunately, this measure is often not readily accessible from commonly used software for repeated-measures or hierarchical data analysis. In this guide, we illustrate how to extract Cohen's f(2) for two variables within a mixed effects regression model using PROC MIXED in SAS((r)) software. Two examples of calculating Cohen's f(2) for different research questions are shown, using data from a longitudinal cohort study of smoking development in adolescents. This tutorial is designed to facilitate the calculation and reporting of effect sizes for single variables within mixed-effects multiple regression models, and is relevant for analyses of repeated-measures or hierarchical/multilevel data that are common in experimental psychology, observational research, and clinical or intervention studies. PMID- 22529830 TI - Effect of the survival judgment task on memory performance in subclinically depressed people. AB - Many reports have described that a survival judgment task that requires participants to judge words according to their relevance to a survival situation can engender better recall than that obtained in other judgment tasks such as semantic or self-judgment tasks. We investigated whether memory enhancement related to the survival judgment task is elicited or not in subclinically depressed participants. Based on the BDI score, participants were classified as either depressed or non-depressed participants. Then 20 depressed participants and 24 non-depressed participants performed a survival judgment task and an autobiographical recall task. Results showed memory enhancement related to the survival judgment task in both depressed and non-depressed participants, but showed lower memory enhancement related to the survival judgment task in depressed participants than in non-depressed participants. These results suggest that the survival judgment task benefit is a robust phenomenon. Moreover, that benefit was reduced by depressed emotion. The combination hypothesis better explains the mechanism of memory enhancement related to the survival judgment task than the functional, emotional, and arousal or congruency hypothesis does. PMID- 22529831 TI - Cognitive control in Russian-german bilinguals. AB - Bilingual speakers are faced with the problem to keep their languages apart, but do so with interindividually varying success. Cognitive control abilities might be an important factor to explain such interindividual differences. Here we compare two late, balanced and highly proficient bilingual groups (mean age 24 years, L1 Russian, L2 German) which were established according to their language control abilities on a bilingual picture-naming task. One group had difficulties to remain in the instructed target language and switched unintentionally to the non-target language ("switchers"), whereas the other group rarely switched unintentionally ("non-switchers"). This group-specific behavior could not be explained by language background, socio-cultural, or demographic variables. Rather, the non-switchers also demonstrated a faster and better performance on four cognitive control tests (Tower of Hanoi, Ruff Figural Fluency Test, Divided Attention, Go/Nogo). Here, we focus on two additional executive function tasks, the Wisconsin Card Sorting Test (WCST) and the Flanker task requiring conflict monitoring and conflict resolution. Non-switchers outperformed switchers with regard to speed and accuracy, and were better at finding and applying the correct rules in the WCST. Similarly, in the Flanker task non-switchers performed faster and better on conflict trials and had a higher correction rate following an error. Event-related potential recordings furthermore revealed a smaller error related negativity in the non-switchers, taken as evidence for a more efficient self-monitoring system. We conclude that bilingual language performance, in particular switching behavior, is related to performance on cognitive control tasks. Better cognitive control, including conflict monitoring, results in decreased unintentional switching. PMID- 22529832 TI - Meditate to create: the impact of focused-attention and open-monitoring training on convergent and divergent thinking. AB - The practice of meditation has seen a tremendous increase in the western world since the 60s. Scientific interest in meditation has also significantly grown in the past years; however, so far, it has neglected the idea that different type of meditations may drive specific cognitive-control states. In this study we investigate the possible impact of meditation based on focused-attention (FA) and meditation based on open-monitoring (OM) on creativity tasks tapping into convergent and divergent thinking. We show that FA meditation and OM meditation exert specific effect on creativity. First, OM meditation induces a control state that promotes divergent thinking, a style of thinking that allows many new ideas of being generated. Second, FA meditation does not sustain convergent thinking, the process of generating one possible solution to a particular problem. We suggest that the enhancement of positive mood induced by meditating has boosted the effect in the first case and counteracted in the second case. PMID- 22529833 TI - Carrion crows cannot overcome impulsive choice in a quantitative exchange task. AB - The ability to control an immediate impulse in return for a more desirable - though delayed - outcome has long been thought to be a uniquely human feature. However, studies on non-human primates revealed that some species are capable of enduring delays in order to get food of higher quality or quantity. Recently two corvid species, common raven (Corvus corax) and carrion crow (Corvus corone corone), exchanged food for a higher quality reward though seemed less capable of enduring delays when exchanging for the same food type in a higher quantity. In the present study, we specifically investigated the ability of carrion crows to overcome an impulsive choice in a quantitative exchange task. After a short delay, individuals were asked to give back an initial reward (cheese) to the human experimenter in order to receive a higher amount of the same reward (two, four, or eight pieces). We tested six captive crows - three individuals never exchanged the initial reward for a higher quantity; the other three birds did exchange though at very low rates. We performed a preference test between one or more pieces of cheese in order to address whether crow poor performance could be due to an inability to discriminate between different quantities or not attributing a higher value to the higher quantities. All birds chose the higher quantities significantly more often, indicating that they can discriminate between quantities and that higher quantities are more desirable. Taken together, these results suggest that, although crows may possess the cognitive abilities to judge quantities and to overcome an impulsive choice, they do so only in order to optimize the qualitative but not quantitative output in the exchange paradigm. PMID- 22529834 TI - Meditation and its regulatory role on sleep. AB - Intense meditation practices help to achieve a harmony between body and mind. Meditation practices influence brain functions, induce various intrinsic neural plasticity events, modulate autonomic, metabolic, endocrine, and immune functions and thus mediate global regulatory changes in various behavioral states including sleep. This brief review focuses on the effect of meditation as a self regulatory phenomenon on sleep. PMID- 22529835 TI - Hippocampal sleep features: relations to human memory function. AB - The recent spread of intracranial electroencephalographic (EEG) recording techniques for presurgical evaluation of drug-resistant epileptic patients is providing new information on the activity of different brain structures during both wakefulness and sleep. The interest has been mainly focused on the medial temporal lobe, and in particular the hippocampal formation, whose peculiar local sleep features have been recently described, providing support to the idea that sleep is not a spatially global phenomenon. The study of the hippocampal sleep electrophysiology is particularly interesting because of its central role in the declarative memory formation. Recent data indicate that sleep contributes to memory formation. Therefore, it is relevant to understand whether specific patterns of activity taking place during sleep are related to memory consolidation processes. Fascinating similarities between different states of consciousness (wakefulness, REM sleep, non-REM sleep) in some electrophysiological mechanisms underlying cognitive processes have been reported. For instance, large-scale synchrony in gamma activity is important for waking memory and perception processes, and its changes during sleep may be the neurophysiological substrate of sleep-related deficits of declarative memory. Hippocampal activity seems to specifically support memory consolidation during sleep, through specific coordinated neurophysiological events (slow waves, spindles, ripples) that would facilitate the integration of new information into the pre-existing cortical networks. A few studies indeed provided direct evidence that rhinal ripples as well as slow hippocampal oscillations are correlated with memory consolidation in humans. More detailed electrophysiological investigations assessing the specific relations between different types of memory consolidation and hippocampal EEG features are in order. These studies will add an important piece of knowledge to the elucidation of the ultimate sleep function. PMID- 22529836 TI - Efficacy of zolpidem for dystonia: a study among different subtypes. AB - Although there are some newly developed options to treat dystonia, its medical treatment is not always satisfactory. Zolpidem, an imidazopyridine agonist with a high affinity on benzodiazepine subtype receptor BZ1 (omega1), was found to improve clinical symptoms of dystonia in a limited number of case reports. To investigate what subtype of dystonia is responsive to the therapy, we conducted an open label study to assess the efficacy of zolpidem (5-20 mg) in 34 patients suffering from miscellaneous types of dystonia using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). Patients were entered into the study if they had been refractory to other medications as evaluated by BFMDRS (no change in the previous two successive visits). After zolpidem therapy, the scores in the patients as a whole were decreased from 7.2 +/- 7.9 to 5.5 +/- 5.0 (P = 0.042). Patients with generalized dystonia, Meige syndrome/blepharospasm, and hand dystonia improved in the scale by 27.8, 17.8, and 31.0%, respectively, whereas no improvement was found in cervical dystonia patients. Overall response rate among patients were comparable to that of trihexyphenidyl. Zolpidem may be a therapeutic option for generalized dystonia, Meige syndrome, and hand dystonia including musician's. Drowsiness was the dose-limiting factor. PMID- 22529837 TI - The effects of glycine on subjective daytime performance in partially sleep restricted healthy volunteers. AB - Approximately 30% of the general population suffers from insomnia. Given that insomnia causes many problems, amelioration of the symptoms is crucial. Recently, we found that a non-essential amino acid, glycine subjectively and objectively improves sleep quality in humans who have difficulty sleeping. We evaluated the effects of glycine on daytime sleepiness, fatigue, and performances in sleep restricted healthy subjects. Sleep was restricted to 25% less than the usual sleep time for three consecutive nights. Before bedtime, 3 g of glycine or placebo were ingested, sleepiness, and fatigue were evaluated using the visual analog scale (VAS) and a questionnaire, and performance were estimated by personal computer (PC) performance test program on the following day. In subjects given glycine, the VAS data showed a significant reduction in fatigue and a tendency toward reduced sleepiness. These observations were also found via the questionnaire, indicating that glycine improves daytime sleepiness and fatigue induced by acute sleep restriction. PC performance test revealed significant improvement in psychomotor vigilance test. We also measured plasma melatonin and the expression of circadian-modulated genes expression in the rat suprachiasmatic nucleus (SCN) to evaluate the effects of glycine on circadian rhythms. Glycine did not show significant effects on plasma melatonin concentrations during either the dark or light period. Moreover, the expression levels of clock genes such as Bmal1 and Per2 remained unchanged. However, we observed a glycine-induced increase in the neuropeptides arginine vasopressin and vasoactive intestinal polypeptide in the light period. Although no alterations in the circadian clock itself were observed, our results indicate that glycine modulated SCN function. Thus, glycine modulates certain neuropeptides in the SCN and this phenomenon may indirectly contribute to improving the occasional sleepiness and fatigue induced by sleep restriction. PMID- 22529839 TI - Disassembling iron availability to phytoplankton. AB - The bioavailability of iron to microorganisms and its underlying mechanisms have far reaching repercussions to many natural systems and diverse fields of research, including ocean biogeochemistry, carbon cycling and climate, harmful algal blooms, soil and plant research, bioremediation, pathogenesis, and medicine. Within the framework of ocean sciences, short supply and restricted bioavailability of Fe to phytoplankton is thought to limit primary production and curtail atmospheric CO(2) drawdown in vast ocean regions. Yet a clear-cut definition of bioavailability remains elusive, with elements of iron speciation and kinetics, phytoplankton physiology, light, temperature, and microbial interactions, to name a few, all intricately intertwined into this concept. Here, in a synthesis of published and new data, we attempt to disassemble the complex concept of iron bioavailability to phytoplankton by individually exploring some of its facets. We distinguish between the fundamentals of bioavailability - the acquisition of Fe-substrate by phytoplankton - and added levels of complexity involving interactions among organisms, iron, and ecosystem processes. We first examine how phytoplankton acquire free and organically bound iron, drawing attention to the pervasiveness of the reductive uptake pathway in both prokaryotic and eukaryotic autotrophs. Turning to acquisition rates, we propose to view the availability of various Fe-substrates to phytoplankton as a spectrum rather than an absolute "all or nothing." We then demonstrate the use of uptake rate constants to make comparisons across different studies, organisms, Fe compounds, and environments, and for gaging the contribution of various Fe substrates to phytoplankton growth in situ. Last, we describe the influence of aquatic microorganisms on iron chemistry and fate by way of organic complexation and bio-mediated redox transformations and examine the bioavailability of these bio-modified Fe species. PMID- 22529840 TI - Evidence for horizontal gene transfer of anaerobic carbon monoxide dehydrogenases. AB - Carbon monoxide (CO) is commonly known as a toxic gas, yet both cultivation studies and emerging genome sequences of bacteria and archaea establish that CO is a widely utilized microbial growth substrate. In this study, we determined the prevalence of anaerobic carbon monoxide dehydrogenases ([Ni,Fe]-CODHs) in currently available genomic sequence databases. Currently, 185 out of 2887, or 6% of sequenced bacterial and archaeal genomes possess at least one gene encoding [Ni,Fe]-CODH, the key enzyme for anaerobic CO utilization. Many genomes encode multiple copies of [Ni,Fe]-CODH genes whose functions and regulation are correlated with their associated gene clusters. The phylogenetic analysis of this extended protein family revealed six distinct clades; many clades consisted of [Ni,Fe]-CODHs that were encoded by microbes from disparate phylogenetic lineages, based on 16S rRNA sequences, and widely ranging physiology. To more clearly define if the branching patterns observed in the [Ni,Fe]-CODH trees are due to functional conservation vs. evolutionary lineage, the genomic context of the [Ni,Fe]-CODH gene clusters was examined, and superimposed on the phylogenetic trees. On the whole, there was a correlation between genomic contexts and the tree topology, but several functionally similar [Ni,Fe]-CODHs were found in different clades. In addition, some distantly related organisms have similar [Ni,Fe]-CODH genes. Thermosinus carboxydivorans was used to observe horizontal gene transfer (HGT) of [Ni,Fe]-CODH gene clusters by applying Kullback-Leibler divergence analysis methods. Divergent tetranucleotide frequency and codon usage showed that the gene cluster of T. carboxydivorans that encodes a [Ni,Fe]-CODH and an energy-converting hydrogenase is dissimilar to its whole genome but is similar to the genome of the phylogenetically distant Firmicute, Carboxydothermus hydrogenoformans. These results imply that T carboxydivorans acquired this gene cluster via HGT from a relative of C. hydrogenoformans. PMID- 22529838 TI - Alzheimer's disease: a clinical practice-oriented review. AB - Investigation in the field of Alzheimer's disease (AD), the commonest cause of dementia, has been very active in recent years and it may be difficult for the clinician to keep up with all the innovations and to be aware of the implications they have in clinical practice. The authors, thus, reviewed recent literature on the theme in order to provide the clinician with an updated overview, intended to support decision-making on aspects of diagnosis and management. This article begins to focus on the concept of AD and on its pathogenesis. Afterward, epidemiology and non-genetic risk factors are approached. Genetics, including genetic risk factors and guidelines for genetic testing, are mentioned next. Recommendations for diagnosis of AD, including recently proposed criteria, are then reviewed. Data on the variants of AD is presented. First approach to the patient is dealt with next, followed by neuropsychological evaluation. Biomarkers, namely magnetic resonance imaging, single photon emission tomography, FDG PET, PiB PET, CSF tau, and Abeta analysis, as well as available data on their diagnostic accuracy, are also discussed. Factors predicting rate of disease progression are briefly mentioned. Finally, non-pharmacological and pharmacological treatments, including established and emerging drugs, are addressed. PMID- 22529841 TI - Multistarter from organic viticulture for red wine Montepulciano d'Abruzzo production. AB - In the last years the use of a multistarter fermentation process has been proposed to improve the organoleptic characteristics of wines. In the present study the fermentation performances and the interactions of mixed and sequential cultures of Hanseniasporauvarum, Candida zemplinina, and a strain of Saccharomycescerevisiae isolated from organic musts were investigated. To evaluate the oenological performances of the tested strains microvinifications in pasteurized red grape juice from Montepulciano d'Abruzzo cultivar were compared. The course of fermentation has been controlled through classical determinations (CO(2) evolution, ethanol, glycerol, pH, total titratable acidity, sugar content, free sulfur dioxide (SO(2)), dry extract, sugars, organic acids, and volatile compounds). Moreover, the yeast population was determined by both culture dependent and independent approaches. In particular, the pure culture of H. uvarum and C. zemplinina did not end the fermentation. On the contrary, when S. cerevisiae was added, fermentations were faster confirming that yeast interactions influence the fermentation kinetics. Moreover, C. zemplinina showed a good interaction with S. cerevisiae by increasing the fermentation kinetic in high gravity Montepulciano must, with low ethyl acetate and acetic acid production. This study confirmed that non-Saccharomyces yeasts play a crucial role also in organic wines and their activity could be modulated through the selection of appropriate strains that correctly interact with S. cerevisiae. PMID- 22529842 TI - The languages spoken in the water body (or the biological role of cyanobacterial toxins). AB - Although intensification of toxic cyanobacterial blooms over the last decade is a matter of growing concern due to bloom impact on water quality, the biological role of most of the toxins produced is not known. In this critical review we focus primarily on the biological role of two toxins, microcystins and cylindrospermopsin, in inter- and intra-species communication and in nutrient acquisition. We examine the experimental evidence supporting some of the dogmas in the field and raise several open questions to be dealt with in future research. We do not discuss the health and environmental implications of toxin presence in the water body. PMID- 22529844 TI - Telmatocola sphagniphila gen. nov., sp. nov., a novel dendriform planctomycete from northern wetlands. AB - Members of the phylum Planctomycetes are common inhabitants of northern wetlands. We used barcoded pyrosequencing to survey bacterial diversity in an acidic (pH 4.0) Sphagnum peat sampled from the peat bog Obukhovskoye, European North Russia. A total of 21189 bacterial 16S rRNA gene sequences were obtained, of which 1081 reads (5.1%) belonged to the Planctomycetes. Two-thirds of these sequences affiliated with planctomycete groups for which characterized representatives have not yet been available. Here, we describe two organisms from one of these previously uncultivated planctomycete groups. One isolate, strain OB3, was obtained from the peat sample used in our molecular study, while another strain, SP2(T) (=DSM 23888(T) = VKM B-2710(T)), was isolated from the peat bog Staroselsky moss. Both isolates are represented by aerobic, budding, pink pigmented, non-motile, spherical cells that are arranged in unusual, dendriform like structures during growth on solid media. These bacteria are moderately acidophilic and mesophilic, capable of growth at pH 4.0-7.0 (optimum pH 5.0-5.5) and at 6-30 degrees C (optimum 20-26 degrees C). The preferred growth substrates are various heteropolysaccharides and sugars, the latter being utilized only if provided in low concentrations (<=0.025%). In contrast to other described planctomycetes, strains SP2(T) and OB3 possess weak cellulolytic potential. The major fatty acids are C16:1omega5c, C18:1omega5c, C16:0, and C18:0. Characteristic lipids are the n-C31 polyunsaturated alkene (9-10 double bonds) and C30:1/C32:1 (omega-1) hydroxy fatty acids. The G + C content of the DNA is 58.5-59.0 mol%. Strains SP2(T) and OB3 share identical 16S rRNA gene sequences, which exhibit only 86 and 87% similarity to those of Gemmata obscuriglobus and Zavarzinella formosa. Based on the characteristics reported here, we propose to classify these novel planctomycetes as representatives of a novel genus and species, Telmatocola sphagniphila gen. nov., sp. nov. PMID- 22529843 TI - Treatment of Kaposi sarcoma-associated herpesvirus-associated cancers. AB - Kaposi sarcoma (KS) is the most frequent AIDS-defining cancer worldwide. KS associated herpesvirus (KSHV) is the etiological agent of KS, and the virus is also associated with two lymphoproliferative diseases. Both KS and KSHV associated lymphomas, are cancers of unique molecular composition. They represent a challenge for cancer treatment and an opportunity to identify new mechanisms of transformation. Here, we review the current clinical insights into KSHV associated cancers and discuss scientific insights into the pathobiology of KS, primary effusion lymphoma, and multicentric Castleman's disease. PMID- 22529845 TI - Poliovirus trafficking toward central nervous system via human poliovirus receptor-dependent and -independent pathway. AB - In humans, paralytic poliomyelitis results from the invasion of the central nervous system (CNS) by circulating poliovirus (PV) via the blood-brain barrier (BBB). After the virus enters the CNS, it replicates in neurons, especially in motor neurons, inducing the cell death that causes paralytic poliomyelitis. Along with this route of dissemination, neural pathway has been reported in humans, monkeys, and PV-sensitive human PV receptor (hPVR/CD155)-transgenic (Tg) mice. We demonstrated that a fast retrograde axonal transport process is required for PV dissemination through the sciatic nerve of hPVR-Tg mice and that intramuscularly inoculated PV causes paralysis in a hPVR-dependent manner. We also showed that hPVR-independent axonal transport of PV exists in hPVR-Tg and non-Tg mice, indicating that several different pathways for PV axonal transport exist in these mice. Circulating PV after intravenous inoculation in mice cross the BBB at a high rate in a hPVR-independent manner. We will implicate an involvement of a new possible receptor for PV to permeate the BBB based on our recent findings. PMID- 22529846 TI - Recent progress in melioidosis and glanders. PMID- 22529847 TI - Strains of Staphylococcus and Bacillus isolated from traditional sausages as producers of biogenic amines. AB - Histidine, lysine, ornithine, and tyrosine decarboxylase activities were tested in 38 strains of Staphylococcus (15 of S. equorum, 11 of S. epidermidis, 7 of S. saprophyticus, and 5 of S. pasteuri) and 19 strains of Bacillus (13 of B. subtilis and 6 of B. amyloliquefaciens) isolated from two Spanish traditional sausage varieties. The four decarboxylase activities were present in most of the strains studied, but some variability was observed between strains within each microbial species. Accumulation of putrescine and cadaverine was assessed in the culture media of the strains that displayed ornithine and lysine decarboxylase activities. The aminogenic potential of the strains was low, with amounts accumulated lower than 25 mg/L for the putrescine and than 5 mg/L for the cadaverine, with the exception of a strain of S. equorum that produced 1415 mg/L of putrescine, and of a strain of S. epidermidis that accumulated 977 mg/L of putrescine and 36 mg/L of cadaverine. PMID- 22529848 TI - The Nematode Caenorhabditis elegans, Stress and Aging: Identifying the Complex Interplay of Genetic Pathways Following the Treatment with Humic Substances. AB - Low concentrations of the dissolved leonardite humic acid HuminFeed((r)) (HF) prolonged the lifespan and enhanced the thermal stress resistance of the model organism Caenorhabditis elegans. However, growth was impaired and reproduction delayed, effects which have also been identified in response to other polyphenolic monomers, including Tannic acid, Rosmarinic acid, and Caffeic acid. Moreover, a chemical modification of HF, which increases its phenolic/quinonoid moieties, magnified the biological impact on C. elegans. To gain a deep insight into the molecular basis of these effects, we performed global transcriptomics on young adult (3 days) and old adult (11 days) nematodes exposed to two different concentrations of HF. We also studied several C. elegans mutant strains in respect to HF derived longevity and compared all results with data obtained for the chemically modified HF. The gene expression pattern of young HF-treated nematodes displayed a significant overlap to other conditions known to provoke longevity, including various plant polyphenol monomers. Besides the regulation of parts of the metabolism, transforming growth factor-beta signaling, and Insulin like signaling, lysosomal activities seem to contribute most to HF's and modified HF's lifespan prolonging action. These results support the notion that the phenolic/quinonoid moieties of humic substances are major building blocks that drive the physiological effects observed in C. elegans. PMID- 22529849 TI - Exosomal miRNAs: Biological Properties and Therapeutic Potential. AB - MicroRNAs (miRNAs), small non-coding regulatory RNAs that regulate gene expression at the post-transcriptional level, are master regulators of a wide array of cellular processes. Altered miRNA expression could be a determinant of disease development and/or progression and manipulation of miRNA expression represents a potential avenue of therapy. Exosomes are cell-derived extracellular vesicles that promote cell-cell communication and immunoregulatory functions. These "bioactive vesicles" shuttle various molecules, including miRNAs, to recipient cells. Inappropriate release of miRNAs from exosomes may cause significant alterations in biological pathways that affect disease development, supporting the concept that miRNA-containing exosomes could serve as targeted therapies for particular diseases. This review briefly summarizes recent advances in the biology, function, and therapeutic potential of exosomal miRNAs. PMID- 22529850 TI - Little evidence of systemic and adipose tissue inflammation in overweight individuals(?). AB - CONTEXT: The effect of weight loss by diet alone or diet in conjunction with exercise on low-grade inflammation in non-obese (overweight) individuals is not known. OBJECTIVE: Test the hypothesis that 24 weeks of moderate calorie restriction (CR; 25%) by diet only or with aerobic exercise would reduce markers of systemic inflammation and attenuate inflammation gene expression in subcutaneous adipose tissue. DESIGN: Randomized controlled trial. SETTING: Institutional Research Center. PARTICIPANTS: Thirty-five overweight (body mass index: 27.8 +/- 0.7 kg/m(2)) but otherwise healthy participants (16M/19F) completed the study. INTERVENTION: PARTICIPANTS were randomized to either CR (25% reduction in energy intake, n = 12), caloric restriction + exercise (CR + EX: 12.5% reduction in energy intake + 12.5% increase in exercise energy expenditure, n = 12), or control (healthy weight-maintenance diet, n = 11) for 6 months. MAIN OUTCOME MEASURES: Fasting serum markers of inflammation [leptin, highly sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), adiponectin] and inflammation-related genes [CD68, IL-6, TNF-alpha, macrophage migration inhibitory factor (MIF), monocyte chemoattractant protein-1 (MCP-1), adiponectin, plasminogen activator inhibitor-1 (PAI-1)] in subcutaneous adipose tissue. RESULTS: CR and CR + EX lost similar amounts of body weight (-10 +/- 1%), fat mass (-24 +/- 3%), visceral fat (-27 +/- 3%), and had increased insulin sensitivity (CR: 40 +/- 20%, CR + EX: 66 +/- 22%). Leptin was significantly decreased from baseline (p < 0.001) in both groups however TNF alpha and IL-6 were not changed. hsCRP was decreased in CR + EX. There was no change in the expression of genes involved in macrophage infiltration (CD68, MIF MCP-1, PAI-1) or inflammation (IL-6, TNF-alpha, adiponectin) in either CR or CR + EX. CONCLUSION: A 10% weight loss with a 25% CR diet alone or with exercise did not impact markers of systemic inflammation or the expression of inflammation related adipose genes in overweight individuals. PMID- 22529851 TI - HD-RNAS: An Automated Hierarchical Database of RNA Structures. AB - One of the important goals of most biological investigations is to classify and organize the experimental findings so that they are readily useful for deriving generalized rules. Although there is a huge amount of information on RNA structures in PDB, there are redundant files, ambiguous synthetic sequences etc. Moreover, a systematic hierarchical organization, reflecting RNA classification, is missing in PDB. In this investigation, we have classified all the available RNA structures from PDB through a programmatic approach. Hence, it would be now a simple assignment to regularly update the classification as and when new structures are released. The classification can further determine (i) a non redundant set of RNA structures and (ii) if available, a set of structures of identical sequence and function, which can highlight structural polymorphism, ligand-induced conformational alterations etc. Presently, we have classified the available structures (2095 PDB entries having RNA chain longer than nine nucleotides solved by X-ray crystallography or NMR spectroscopy) into nine functional classes. The structures of same function and same source are mostly seen to be similar with subtle differences depending on their functional complexation. The web-server is available online at http://www.saha.ac.in/biop/www/HD-RNAS.html and is updated regularly. PMID- 22529853 TI - Drugs during Pregnancy and Lactation: New Solutions to Serious Challenges. PMID- 22529854 TI - Fertility-sparing surgery in early epithelial ovarian cancer: a viable option? AB - Epithelial ovarian cancer (EOC) continues to represent one of the most lethal conditions in women in the western countries. With the shifting of childbearing towards higher age, EOC increasingly affects women with active childbearing wish, resulting in major impacts on treatment management. Next to the optimal therapeutic treatment strategies, gynecologic oncologists are being asked to incorporate into their decision-making processes the patients' wish for fertility preserving alternatives ideally without compromising oncologic safety. Nowadays, fertility-sparing surgery represents an effective alternative to conventional radical cytoreduction in younger women with early stages of the disease. As such, this paper considers indications for fertility sparing surgery in EOC, reflects on outcomes from the oncologic and reproductive data of the largest and most relevant series outcomes data, reporting on fertility sparing techniques in EOC, reviews medicamentous efforts to prevent chemotherapy induced gonadotoxicity, and discusses future aspects in the gynecologic cancer management. PMID- 22529852 TI - Yeast toxicogenomics: genome-wide responses to chemical stresses with impact in environmental health, pharmacology, and biotechnology. AB - The emerging transdisciplinary field of Toxicogenomics aims to study the cell response to a given toxicant at the genome, transcriptome, proteome, and metabolome levels. This approach is expected to provide earlier and more sensitive biomarkers of toxicological responses and help in the delineation of regulatory risk assessment. The use of model organisms to gather such genomic information, through the exploitation of Omics and Bioinformatics approaches and tools, together with more focused molecular and cellular biology studies are rapidly increasing our understanding and providing an integrative view on how cells interact with their environment. The use of the model eukaryote Saccharomyces cerevisiae in the field of Toxicogenomics is discussed in this review. Despite the limitations intrinsic to the use of such a simple single cell experimental model, S. cerevisiae appears to be very useful as a first screening tool, limiting the use of animal models. Moreover, it is also one of the most interesting systems to obtain a truly global understanding of the toxicological response and resistance mechanisms, being in the frontline of systems biology research and developments. The impact of the knowledge gathered in the yeast model, through the use of Toxicogenomics approaches, is highlighted here by its use in prediction of toxicological outcomes of exposure to pesticides and pharmaceutical drugs, but also by its impact in biotechnology, namely in the development of more robust crops and in the improvement of yeast strains as cell factories. PMID- 22529855 TI - Optimal timing for oocyte denudation and intracytoplasmic sperm injection. AB - Objectives. To analyze the impact of oocyte denudation and microinjection timings on intracytoplasmic sperm injection (ICSI) outcomes. Study Design. We included ICSI cycles with the following parameters: rank 1 or 2, female age <36 years, male factor infertility, long protocol using GnRH agonist and rFSH for ovarian stimulation, and use of freshly ejaculated sperm (n = 110). Several ICSI parameters were analyzed according to the time between oocyte retrieval and denudation (T(1)) and the time between denudation and ICSI (T(2)) using a statistical logistic regression analysis. Results. Neither T(1) nor T(2) had a significant influence on the Metaphase II (MII) rate but the fertilisation rate (FR) showed a significant improvement when T(1) was longer (optimal results at T(1) = 3 hours) while FR significantly decreased with the increase of T(2). Optimal implantation (IR) and pregnancy (PR) rates were obtained when T(1) was around 2 hours. Conclusion. Incubation of oocytes around 2 hours between retrieval and denudation may not increase MII rate but appears to lead to the optimal combination of FR and IR. PMID- 22529857 TI - Infertility. PMID- 22529856 TI - Circulating unmetabolized folic Acid: relationship to folate status and effect of supplementation. AB - There are increasing concerns that exposure to unmetabolized folic acid, which results from folic acid intakes that overwhelm the liver's metabolic capacity, may be associated with adverse effects. In this paper, we examined the folic acid status of women of reproductive age in relation to dietary intake and the effect of folic acid supplementation (1.1 mg or 5 mg). Plasma unmetabolized folic acid was not significantly correlated with folate intake estimated by food frequency questionnaire or biomarkers. The proportion of women with detectable levels of unmetabolized folic acid increased from 65% to 100% after twelve weeks of supplementation (P < 0.05); however, the increase in concentrations did not reach statistical significance and the effect was not sustained. Moreover, there were no significant differences between the two doses. This suggests that there are mechanisms by which the body adapts to high folic acid intakes to limit exposure to unmetabolized folic acid. PMID- 22529858 TI - Comparison of Fetal Nuchal Fold Thickness Measurements by Two- and Three Dimensional Ultrasonography (3DXI Multislice View). AB - Purpose. To compare the measurements of fetal nuchal fold (NF) thickness by two dimensional (2D) and three-dimensional (3D) ultrasonography using the three dimensional extended imaging (3DXI). Methods. A cross-sectional study was performed with 60 healthy pregnant women with a gestational age between 16 and 20 weeks and 6 days. The 2D-NF measurements were made as the distance from the outer skull bone to the outer skin surface in the transverse axial image in the suboccipital-bregmatic plane of the head. For the 3D we employed the 3DXI multislice view software, in which 3 * 2 tomographic planes was displayed on the screen and the distance between the tomographic slices was 0.5 mm. Maximum, minimum, mean, and standard deviation were calculated for 2D and 3D ultrasonography, as well the maximum and minimum, mean, and standard deviation for the difference between both methods. The Wilcoxon signed-rank test was used to compare the two different techniques. Results. 2D-NF showed a mean of thickness of 3.52 +/- 0.95 mm (1.69-7.14). The mean of 3D-NF was 3.90 +/- 1.02 mm (2.13-7.72). The mean difference between the methods was 0.38 mm, with a maximum difference of 3.12 mm. Conclusion. The NF thickness measurements obtained by 3D ultrasonography were significantly larger than those detected with 2D ultrasonography. PMID- 22529859 TI - Complications of uterine fibroids and their management. PMID- 22529861 TI - Natural breeding places for phlebotomine sand flies (Diptera: psychodidae) in a semiarid region of bahia state, Brazil. AB - Few microhabitats have been previously identified as natural breeding places for phlebotomine sand flies so far, and little is known about the influence of climate variables in their density. The present study was conducted in a dry region with a semiarid climate, where visceral leishmaniasis occurs in humans and dogs. The occurrence of breeding places in specific microhabitats was investigated in soil samples collected from five houses, which were also the location used for sampling of adults. All the microhabitats sampled by our study were identified as natural breeding places due to the occurrence of immature forms of sand flies. On a weekly basis, the number of adult sand flies captured was positively correlated with the mean temperature from preceding weeks. These results, in addition to promoting an advance in the knowledge of sand flies biology, may furnish a tool for optimizing the control of the sand flies, by indicating the most suitable periods and microhabitats for the application of insecticides. PMID- 22529860 TI - Cancer, fertility preservation, and future pregnancy: a comprehensive review. AB - Given the increases in 5-year cancer survival and recent advances in fertility preserving technologies, an increasing number of women with cancer are presenting for discussion of fertility preserving options. This review will summarize the risk of infertility secondary to cancer treatment, available treatment options for fertility preservation, and techniques to reduce future risks for patients. Concerns that will be addressed include the risk of the medications and procedures, the potential delay in cancer treatment, likelihood of pregnancy complications, as well as the impact of future pregnancy on the recurrence risk of cancer. Recent advances in oocyte cryopreservation and ovarian stimulation protocols will be discussed. Healthcare providers need to be informed of available treatment options including the risks, advantages, and disadvantages of fertility preserving options to properly counsel patients. PMID- 22529862 TI - Structure-function of falcipains: malarial cysteine proteases. AB - Evidence indicates that cysteine proteases play essential role in malaria parasites; therefore an obvious area of investigation is the inhibition of these enzymes to treat malaria. Studies with cysteine protease inhibitors and manipulating cysteine proteases genes have suggested a role for cysteine proteases in hemoglobin hydrolysis. The best characterized Plasmodium cysteine proteases are falcipains, which are papain family enzymes. Falcipain-2 and falcipain-3 are major hemoglobinases of P. falciparum. Structural and functional analysis of falcipains showed that they have unique domains including a refolding domain and a hemoglobin binding domain. Overall, the complexes of falcipain-2 and falcipain-3 with small and macromolecular inhibitors provide structural insight to facilitate the design or modification of effective drug treatment against malaria. Drug development targeting falcipains should be aided by a strong foundation of biochemical and structural studies. PMID- 22529864 TI - Effect of seasonality and ecological factors on the prevalence of the four malaria parasite species in northern mali. AB - Background. We performed 2 cross-sectional studies in Menaka in the Northeastern Mali across 9 sites in different ecological settings: 4 sites have permanent ponds, 4 without ponds, and one (City of Menaka) has a semipermanent pond. We enrolled 1328 subjects in May 2004 (hot dry season) and 1422 in February 2005 (cold dry season) after the rainy season. Objective. To examine the seasonality of malaria parasite prevalence in this dry northern part of Mali at the edge of the Sahara desert. Results. Slide prevalence was lower in hot dry than cold dry season (4.94 versus 6.85%, P = 0.025). Gametocyte rate increased to 0.91% in February. Four species were identified. Plasmodium falciparum was most prevalent (74.13 and 63.72%). P. malariae increased from 9.38% to 22.54% in February. In contrast, prevalence of P. vivax was higher (10.31%) without seasonal variation. Smear positivity was associated with splenomegaly (P = 0.007). Malaria remained stable in the villages with ponds (P = 0.221); in contrast, prevalence varied between the 2 seasons in the villages without ponds (P = 0.004). Conclusion. Malaria was mesoendemic; 4 species circulates with a seasonal fluctuation for Plasmodium falciparum. PMID- 22529863 TI - Biologic and genetics aspects of chagas disease at endemic areas. AB - The etiologic agent of Chagas Disease is the Trypanosoma cruzi, transmitted through blood-sucking insect vectors of the Triatominae subfamily, representing one of the most serious public health concerns in Latin America. There are geographic variations in the prevalence of clinical forms and morbidity of Chagas disease, likely due to genetic variation of the T. cruzi and the host genetic and environmental features. Increasing evidence has supported that inflammatory cytokines and chemokines are responsible for the generation of the inflammatory infiltrate and tissue damage. Moreover, genetic polymorphisms, protein expression levels, and genomic imbalances are associated with disease progression. This paper discusses these key aspects. Large surveys were carried out in Brazil and served as baseline for definition of the control measures adopted. However, Chagas disease is still active, and aspects such as host-parasite interactions, genetic mechanisms of cellular interaction, genetic variability, and tropism need further investigations in the attempt to eradicate the disease. PMID- 22529865 TI - Efficacy and Tolerability of Malartin and Sulphadoxine-Pyrimethamine Combination against Uncomplicated Falciparum Malaria in Dibanda, Southwest Cameroon. AB - Artemisinin derivatives are now the most potent and rapidly acting antimalarials. The aim of this study was to assess the in vivo efficacy and tolerability of a combination of Malartin (an artesunate) and sulphadoxine-pyrimethamine (SP) in the treatment of uncomplicated falciparum malaria in Dibanda, Cameroon. A total of 197 subjects were recruited into the study and administered Malartin for 3 days and SP as a single dose on day 0. Only 174 of the subjects were successfully followed up on days 3, 7, and 14. The overall success rate of the drug combination was 92.53%. Parasite density decreased during the follow-up period in different age groups, sexes, and social classes. The prevalence of anaemia decreased from 22.99% at enrolment to 9.77% on day 14, and the difference was significant (P < 0.05) on all days of followup. The drug combination did not give rise to any serious side effects. PMID- 22529866 TI - Genetic Diversity of Toll-Like Receptors and Immunity to M. leprae Infection. AB - Genetic association studies of leprosy cohorts across the world have identified numerous polymorphisms which alter susceptibility and outcome to infection with Mycobacterium leprae. As expected, many of the polymorphisms reside within genes that encode components of the innate and adaptive immune system. Despite the preponderance of these studies, our understanding of the mechanisms that underlie these genetic associations remains sparse. Toll-like receptors (TLRs) have emerged as an essential family of innate immune pattern recognition receptors which play a pivotal role in host defense against microbes, including pathogenic strains of mycobacteria. This paper will highlight studies which have uncovered the association of specific TLR gene polymorphisms with leprosy or tuberculosis: two important diseases resulting from mycobacterial infection. This analysis will focus on the potential influence these polymorphic variants have on TLR expression and function and how altered TLR recognition or signaling may contribute to successful antimycobacterial immunity. PMID- 22529867 TI - Effects of Artificial Flooding for Hydroelectric Development on the Population of Mansonia humeralis (Diptera: Culicidae) in the Parana River, Sao Paulo, Brazil. AB - The closure of two phases of the dam at the Porto Primavera Hydroelectric Plant on the Parana River flooded a flawed system located in the Municipality of Presidente Epitacio, Sao Paulo state, favoring the proliferation of aquatic weeds. This study aimed to observe the population of Mansonia humeralis in the area, monitoring the richness, diversity, and dominance of this species both before and during different phases of reservoir flooding as well as evaluate its possible consequences concerning human and animal contact. Adult mosquitoes were collected monthly in the following periods: at the original level, after the first flood, and after the maximum level had been reached between 1997 and 2002. Collection methods used were an aspirator, a Shannon trap, and the Human Attractive Technique. A total of 30,723 mosquitoes were collected, Ma. humeralis accounting for 3.1% in the preflood phase, 59.6% in the intermediate, and 53.8% at maximum level. This species is relevant to public health, since the prospect of continued contact between Ma. humeralis and the human population enhances the dam's importance in the production of nuisance mosquitoes, possibly facilitating the transmission of arboviruses. Local authorities should continue to monitor culicid activity through sustainable entomological surveillance. PMID- 22529869 TI - Classic and new diagnostic approaches to childhood tuberculosis. AB - Tuberculosis in childhood differs from the adult clinical form and even has been suggested that it is a different disease due to its differential signs. However, prevention, diagnostics, and therapeutic efforts have been biased toward adult clinical care. Sensibility and specificity of new diagnostic approaches as GeneXpert, electronic nose (E-nose), infrared spectroscopy, accelerated mycobacterial growth induced by magnetism, and flow lateral devices in children populations are needed. Adequate and timely assessment of tuberculosis infection in childhood could diminish epidemiological burden because underdiagnosed pediatric patients can evolve to an active state and have the potential to disseminate the etiological agent Mycobacterium tuberculosis, notably increasing this worldwide public health problem. PMID- 22529868 TI - Dengue virus entry as target for antiviral therapy. AB - Dengue virus (DENV) infections are expanding worldwide and, because of the lack of a vaccine, the search for antiviral products is imperative. Four serotypes of DENV are described and they all cause a similar disease outcome. It would be interesting to develop an antiviral product that can interact with all four serotypes, prevent host cell infection and subsequent immune activation. DENV entry is thus an interesting target for antiviral therapy. DENV enters the host cell through receptor-mediated endocytosis. Several cellular receptors have been proposed, and DC-SIGN, present on dendritic cells, is considered as the most important DENV receptor until now. Because DENV entry is a target for antiviral therapy, various classes of compounds have been investigated to inhibit this process. In this paper, an overview is given of all the putative DENV receptors, and the most promising DENV entry inhibitors are discussed. PMID- 22529870 TI - Peritoneal dialysis in dengue shock syndrome may be detrimental. AB - Dengue shock syndrome is the most severe form of Dengue that can be fatal. Nonresponders to standard therapy need intensive care. This paper outlines the clinical features, complications, and outcomes of Dengue Shock Syndrome not responding to standard therapies and needing supportive care in a tertiary referral intensive care unit of a developing country. Nearly one-third die within 3 days of admission to ICU. Peritoneal dialysis predicts the worst outcomes. PMID- 22529871 TI - Comparative evaluation of permissiveness to dengue virus serotype 2 infection in primary rodent macrophages. AB - Infection with dengue virus presents a broad clinical spectrum, which can range from asymptomatic cases to severe cases that are characterised by haemorrhagic syndrome and/or shock. The reason for such variability remains unknown. This work evaluated the in vitro permissiveness of mouse, rat, hamster and guinea pig macrophages to infection by dengue virus 2 (DENV2). The results established that macrophages derived from the BALB/c mouse strain showed higher permissiveness to DENV2 infection than macrophages from other rodent species, although all rodent species studied had the C820T mutation in the oligoadenylate synthetase 1b gene, indicating no relationship to the different in vitro susceptibilities of mouse cells at this locus. Other molecular mechanisms related to flavivirus susceptibility remain to be explored. PMID- 22529873 TI - SIGIRR, a negative regulator of colon tumorigenesis. AB - Inappropriate activation of the Toll-IL-1R (TL-IL-1) signaling by commensal bacteria contributes to the pathogenesis of inflammatory bowel diseases and colitis-associated cancer. Recent studies have identified SIGIRR as a negative regulator of TL-IL-1 signaling. It dampens intestinal inflammation and tumorigenesis in the colon. In this review, we will discuss the role of SIGIRR in different cell types and the mechanisms underlying its tumor suppressor function. PMID- 22529874 TI - Study of a vocal feature selection method and vocal properties for discriminating four constitution types. AB - The voice has been used to classify the four constitution types, and to recognize a subject's health condition by extracting meaningful physical quantities, in traditional Korean medicine. In this paper, we propose a method of selecting the reliable variables from various voice features, such as frequency derivative features, frequency band ratios, and intensity, from vowels and a sentence. Further, we suggest a process to extract independent variables by eliminating explanatory variables and reducing their correlation and remove outlying data to enable reliable discriminant analysis. Moreover, the suitable division of data for analysis, according to the gender and age of subjects, is discussed. Finally, the vocal features are applied to a discriminant analysis to classify each constitution type. This method of voice classification can be widely used in the u-Healthcare system of personalized medicine and for improving diagnostic accuracy. PMID- 22529872 TI - Evaluation of the quick environmental exposure and sensitivity inventory in a Danish population. AB - OBJECTIVES: To evaluate a Danish translation of the Quick Environmental Exposure and Sensitivity Inventory (QEESI). METHODS: The study included two groups: one comprised a random sample of 2000 individuals drawn from the Danish Civil Registration System; the other comprised 315 patients with chemical intolerance. RESULTS: The evaluation suggested good reliability for the four QEESI scales in terms of internal consistency and coefficients between test and retest scores. The discriminatory validity was the largest for the Chemical (inhalant) Intolerance and Life Impact Scales. Using combined cut-off scores for these two scales provided a sensitivity of 92.1 and a specificity of 91.8 and yielded a prevalence of 8.2% in the population group. CONCLUSIONS: The Danish translation of the QEESI showed overall good reliability and validity. We recommend the use of the combined Chemical (inhalant) Intolerance and Life Impact Scales in future studies. PMID- 22529875 TI - The Bethesda System thyroid diagnostic categories in the African-American population in conjunction with surgical pathology follow-up. AB - BACKGROUND: It has been reported that African-Americans (AA) have a higher prevalence of overall malignancy compared to Caucasians, in the United States, yet the incidence of thyroid malignancy is half. The aim of this study is to assess the rate of malignant versus benign thyroid disease in AA from an urban based hospital with an academic setting. Our study analyzed the AA population with respect to fine needle aspiration (FNA) of thyroid lesions, in correlation with final surgical pathology. This is the first study of its kind to our knowledge. DESIGN: We retrospectively reviewed thyroid FNA cytology between January 2005 and February 2011. Consecutive FNA specimens with corresponding follow-up surgical pathology were included. The patients were categorized as African- American (AA) and Non-African-American (NAA), which included Caucasians (C), Hispanics (H), and Others (O). The FNA results were classified using the latest edition of The Bethesda System for Reporting Thyroid Cytopathology (TBS Thy) and the follow-up surgical pathology was used for the final categorization. RESULTS: We studied 258 cases: 144 AA (56%) and 114 NAA [43 C (17%), 3 H (1%), and 68 O (28%)]. The average age for AA was 51 years (range 20 - 88) and for NAA was 53 years (range 25 - 86). There were more females than males in the AA versus the NAA group (85 vs. 75%). The incidence of thyroid lesions in the FNA specimens was similar between these two populations. The distribution of benign versus malignant diagnosis on follow-up surgical pathology was examined across TBS-Thy class. CONCLUSION: Our data suggest that distribution of benign versus malignant lesions in the thyroid FNA of AA versus NAA, with follow-up surgical pathology, is comparable for TBS-Thy classes, non-diagnostic (I), benign (II), suspicious for malignancy (V), and malignant (VI) in AA versus NAA. PMID- 22529876 TI - Effects of power frequency electromagnetic fields on melatonin and sleep in the rat. AB - BACKGROUND: Studies investigating the effect of power frequency (50-60 Hz) electromagnetic fields (EMF) on melatonin synthesis in rats have been inconsistent with several showing suppression of melatonin synthesis, others showing no effect and a few actually demonstrating small increases. Scant research has focused on the ensuing sleep patterns of EMF exposed rats. The present study was designed to examine the effects of extremely low power frequency electromagnetic fields (EMF) on the production of melatonin and the subsequent sleep structure in rats. METHODS: Eighteen male Sprague-Dawley rats were exposed to a 1000 milligauss (mG) magnetic field for 1 month. Urine was collected for the final 3 days of the exposure period for analysis of 6 sulphatoxymelatonin, the major catabolic product of melatonin found in urine. Subsequent sleep was analyzed over a 24-hour period. RESULTS: Melatonin production was mildly increased in exposed animals. Although there were no statistically significant changes in sleep structure, exposed animals showed slight decreases in REM (rapid eye movement) sleep as compared to sham (non exposed) animals. CONCLUSIONS: Power frequency magnetic fields induced a marginally statistically significant increase in melatonin levels in exposed rats compared to control. Subsequent sleep analysis indicated little effect on the sleep architecture of rats, at least not within the first day after 1 month's continuous exposure. Varying results in the literature are discussed and future research suggested. PMID- 22529877 TI - Lymphoma cells with increased anti-oxidant defenses acquire chemoresistance. AB - Chronic inflammation increases lymphoma risk. Chronic inflammation exposes cells to increased reactive oxygen species (ROS). Constant exposure to ROS selects for oxidative stress-resistant cells with upregulated anti-oxidant defense enzymes. The impact of oxidative stress resistance on the redox biology and chemotherapy response in lymphoma has not been rigorously tested. To measure the effect of antioxidant defense enzyme upregulation in lymphoid cells, we created oxidative stress-resistant WEHI7.2 thymic lymphoma cell variants. We selected a population of WEHI7.2 cells for resistance to hydrogen peroxide and constructed catalase overexpressing WEHI7.2 transfectants. The WEHI7.2 variants had: i) increased catalase and total superoxide dismutase activities; ii) an altered GSSG/2GSH redox potential; iii) a more oxidized NADP(+)/NADPH pool; and iv) increased phase 2 enzymes, NAD(P)H:quinone oxidoreductase and glutathione S-transferases MU and pi. Regression analysis showed a correlation between the GSSG/2GSH redox potential and the increased phase 2 enzyme activities. As predicted from the anti oxidant defense enzyme profile, the variants were more resistant to the oxidants hydrogen peroxide and paraquat. The variants exhibited resistance to the common lymphoma chemotherapeutics, cyclophosphamide, doxorubicin, vincristine and glucocorticoids. These data indicate that chronic ROS exposure results in lymphoid cells with multiple changes in their redox biology and a chemoresistance phenotype. These data further suggest that lymphomas that arise at the site of chronic inflammation develop chemoresistance due to a combination of drug detoxification and removal of ROS. PMID- 22529878 TI - The analgesic effect of different antidepressants combined with aspirin on thermally induced pain in Albino mice. AB - BACKGROUND: Combination analgesics provide more effective pain relief for a broader spectrum of pain. This research examines the possible potentiation of the analgesic effect of different classes of antidepressants when combined with aspirin in thermal model of pain using Albino mice. METHODS: Different groups of six animals each were injected intraperitoneally by different doses of aspirin (50, 100, or 200 mg/kg), imipramine (2.5, 7.5, 15 or 30 mg/kg), fluoxetine (1.25, 2.5, 5 or 7.5 mg/kg), mirtazapine (1.25, 2.5, or 5 mg/kg) and a combination of a fixed dose of aspirin (100 mg/kg) with the different doses of the three antidepressants. One hour later the analgesic effect of these treatments were evaluated against thermally induced pain. All data were subjected to statistical analysis using unpaired Student's t-test. RESULTS: Aspirin had no analgesic effect in thermally induced pain. The three selected antidepressants produced dose dependent analgesia. The addition of a fixed dose of aspirin to imipramine significantly increased the reaction time (RT) of the lowest dose (by 23%) and the highest dose (by 20%). The addition of the fixed dose of aspirin to fluoxetine significantly increased RT by 13% of the dose 2.5 mg/kg. Finally, the addition of the fixed dose of aspirin significantly potentiated the antinociceptive effect of the different doses of mirtazapine (RT was increased by 24, 54 and 38% respectively). CONCLUSION: Combination of aspirin with an antidepressant might produce better analgesia, increasing the efficacy of pain management and reduces side effects by using smaller doses of each drug. PMID- 22529879 TI - Early ambulation and discharge after four French femoral artery catheterisation for diagnostic coronary angiography. PMID- 22529880 TI - Protein Kinase A Subunit alpha Catalytic and A Kinase Anchoring Protein 79 in Human Placental Mitochondria. AB - Components of protein phosphorylation signalling systems have been discovered in mitochondria and it has been proposed that these molecules modulate processes including oxidative phosphorylation, apoptosis and steroidogenesis. We used electrophoresis and Western blots probed with specific antibodies to protein kinase A alpha catalytic subunit (PKAalpha Cat) and A kinase anchoring protein of approximately 79 kDa molecular weight (AKAP79) to demonstrate the presence of these two proteins in human placental mitochondria. Heavy mitochondria characteristic of cytotrophoblast were separated from light mitochondria characteristic of syncytiotrophoblast by centrifugation. PKAalpha Cat and AKAP79 were present in both heavy and light mitochondria with no significant difference in concentration. Sucrose density gradient separation of submitochondrial fractions indicated PKAalpha Cat is located predominantly in the outer membrane whereas AKAP79 is present mainly in the contact site fractions. These data indicate that PKAalpha Cat is present in the cytoplasm, nucleus and mitochondria of placental cells. AKAP79 is also present in human placental mitochondria but there may be anchoring proteins other than AKAP79 responsible for fixing PKA to the outer membrane. PKA may play roles in mitochondrial protein phosphorylation systems in both cytotrophoblast and syncytiotrophoblast. PMID- 22529881 TI - Self-Perception of Malocclusion Among Nigerian Adolescents Using The Aesthetic Component of The IOTN. AB - INTRODUCTION: The practice of orthodontics is very young in South-South Nigeria and there is need for base line data for informed planning. This study was carried out to investigate the self-perception of malocclusion among Nigerian school children aged 12 to 18 years in order to compare their perception with that of an orthodontist and also to determine the influence of gender and age on self-perception. MATERIALS AND METHODOLOGY: A total of 612 randomly selected schoolchildren comprising 299 (48.9%) males and 313 (51.1%) females with a mean age of 15 + 2.0 years were included in the study, the Aesthetic Component (AC) of the Index of Orthodontic Treatment Need (IOTN) was the instrument used to measure the perception of malocclusion by both the school children and the orthodontist. RESULTS: Majority of the students (82.5%) rated their teeth towards the more attractive end of the scale (Grades 1-4). Although self - perception was not found to be related to gender, older children (16-18 years) had an increased level of perception of need. Males and older children were found to be more in need of treatment by the orthodontist. CONCLUSIONS: A significant difference was found between the orthodontist's rating and the students' ratings of the attractiveness of their occlusions. Age and gender were not found to influence self- perceived orthodontic treatment need. Therefore, for effective orthodontic care, self- perception and not only professional assessment must be taken into consideration when formulating treatment plans to ensure patient satisfaction. PMID- 22529882 TI - Characterization of the Relative Abundance of the Citrus Pathogen Ca. Liberibacter Asiaticus in the Microbiome of Its Insect Vector, Diaphorina citri, using High Throughput 16S rRNA Sequencing. AB - The relationship between the causal agent of Huanglongbing (HLB), Ca. Liberibacter asiaticus(Las), and the naturally occurring endosymbiotic community of its insect vector, the Asian citrus psyllid (ACP), Diaphorina citri, was studied. Variation was observed in the titer of Las within an ACP population feeding on the same material. The cause of this disparity is unknown, and has implications for Las transmission and the spread of HLB. This study utilizes culture independent methods to establish the relationship between the ACP's microbial community and Las acquisition. DNA from 21 psyllids was amplified using universal 16S rRNA primers with Illumina adaptor regions and a sample-specific 7- base identifier. These amplicons were then batch-sequenced on the Illumina platform. The resulting sequences were separated by the identifier, and compared to known sequences in a 16S rRNA database. The microbial communities of each psyllid were compared to determine whether a correlation exists between the ACP's endosymbionts and level of Las acquisition.ACPs were dominated by the same four bacterialgenera regardless of the abundance of Ca.Liberibacter. A combination of qPCR and Illumina sequencing was used to establish an infection gradient among the sampled ACPs. The Ca. Liberibacter titer within the insect was found to have a strong negative relationship with an endosymbiont residing in the syncytium of the mycetocyte and a positive relationship with Wolbachia. These correlations have implications in the acquisition of Las by the ACP as well as the activities of Las within this vector. PMID- 22529883 TI - Pancreatitis in systemic lupus erythematosus - case series from a tertiary care center in South India. AB - Pancreatitis in Systemic Lupus Erythematosus (SLE) is a rare, but life threatening complication. We aimed to study the characteristics and treatment outcome of SLE patients with acute pancreatitis in comparison with those with abdominal pain due to causes other than pancreatitis. Records of SLE patients admitted in our ward with pain abdomen between January 2008 and July 2010 were studied retrospectively. Of 551 SLE in-patients during the study period, 28 (5%) had abdominal pain and 11 (2%) of them were diagnosed to have acute pancreatitis. Five of the 11 patients had severe pancreatitis and 6 had mild pancreatitis. Seizures, arthritis and lack of prior use of steroids were significantly more common in patients with pancreatitis as compared to those with abdominal pain of non pancreatic origin. Seizure occurred more often in severe pancreatitis group as compared to mild pancreatitis. There was no difference in prevalence of lupus anticoagulant and anticardiolipin antibody (40%) between SLE patients with pancreatitis and those with other causes of abdominal pain. CONCLUSION: Association of pancreatitis in our cohort of SLE patients include withdrawal of maintenance dose of steroids, seizures and arthritis in univariate analysis. However there was no independent predictor of this complication in our study. PMID- 22529884 TI - Choroidal neovascularization following implantation of verisyseTM iris-supported phakic intraocular lens in a pregnant myopic patient. AB - Both choroidal neovascularization during pregnancy, and choroidal neovascularization following implantation of phakic intraocular lenses have been reported in the literature. To our knowledge, this is the first case reported of a gravid woman developing choroidal neovascularization in an eye with a phakic intraocular lens. A 31-year-old woman became aware of her pregnancy three weeks after placement of the VerisyseTM iris-supported phakic intraocular lens. She was at 15 weeks gestation when she developed a Fuch's spot consistent with choroidal neovascularization. By eight months gestation, her symptoms nearly resolved. While the development of choroidal neovascularization in this patient may appear incidental, women of childbearing age considering phakic intraocular lenses warrant additional discussion on the possible increased likelihood of choroidal neovascularization. PMID- 22529890 TI - Serum starvation induced cell cycle synchronization facilitates human somatic cells reprogramming. AB - Human induced pluripotent stem cells (iPSCs) provide a valuable model for regenerative medicine and human disease research. To date, however, the reprogramming efficiency of human adult cells is still low. Recent studies have revealed that cell cycle is a key parameter driving epigenetic reprogramming to pluripotency. As is well known, retroviruses such as the Moloney murine leukemia virus (MoMLV) require cell division to integrate into the host genome and replicate, whereas the target primary cells for reprogramming are a mixture of several cell types with different cell cycle rhythms. Whether cell cycle synchronization has potential effect on retrovirus induced reprogramming has not been detailed. In this study, utilizing transient serum starvation induced synchronization, we demonstrated that starvation generated a reversible cell cycle arrest and synchronously progressed through G2/M phase after release, substantially improving retroviral infection efficiency. Interestingly, synchronized human dermal fibroblasts (HDF) and adipose stem cells (ASC) exhibited more homogenous epithelial morphology than normal FBS control after infection, and the expression of epithelial markers such as E-cadherin and Epcam were strongly activated. Futhermore, synchronization treatment ultimately improved Nanog positive clones, achieved a 15-20 fold increase. These results suggested that cell cycle synchronization promotes the mesenchymal to epithelial transition (MET) and facilitates retrovirus mediated reprogramming. Our study, utilization of serum starvation rather than additional chemicals, provide a new insight into cell cycle regulation and induced reprogramming of human cells. PMID- 22529891 TI - Pairing mechanism for the high-TC superconductivity: symmetries and thermodynamic properties. AB - The pairing mechanism for the high-Tc superconductors based on the electron phonon (EPH) and electron-electron-phonon (EEPH) interactions has been presented. On the fold mean-field level, it has been proven, that the obtained s-wave model supplements the predictions based on the BCS van Hove scenario. In particular: (i) For strong EEPH coupling and T < T(C) the energy gap (Deltatot) is very weak temperature dependent; up to the critical temperature Deltatot extends into the anomalous normal state to the Nernst temperature. (ii) The model explains well the experimental dependence of the ratio R(1) = 2Delta(tot)(0)/k(B)T(C) on doping for the reported superconductors in the terms of the few fundamental parameters. In the presented paper, the properties of the d-wave superconducting state in the two-dimensional system have been also studied. The obtained results, like for s wave, have shown the energy gap amplitude crossover from the BCS to non-BCS behavior, as the value of the EEPH potential increases. However, for T > T(C) the energy gap amplitude extends into the anomalous normal state to the pseudogap temperature. Finally, it has been presented that the anisotropic model explains the dependence of the ratio R(1) on doping for the considered superconductors. PMID- 22529892 TI - Geographic and racial variation in premature mortality in the U.S.: analyzing the disparities. AB - Life expectancy at birth, estimated from United States period life tables, has been shown to vary systematically and widely by region and race. We use the same tables to estimate the probability of survival from birth to age 70 (S(70)), a measure of mortality more sensitive to disparities and more reliably calculated for small populations, to describe the variation and identify its sources in greater detail to assess the patterns of this variation. Examination of the unadjusted probability of S(70) for each US county with a sufficient population of whites and blacks reveals large geographic differences for each race-sex group. For example, white males born in the ten percent healthiest counties have a 77 percent probability of survival to age 70, but only a 61 percent chance if born in the ten percent least healthy counties. Similar geographical disparities face white women and blacks of each sex. Moreover, within each county, large differences in S(70) prevail between blacks and whites, on average 17 percentage points for men and 12 percentage points for women. In linear regressions for each race-sex group, nearly all of the geographic variation is accounted for by a common set of 22 socio-economic and environmental variables, selected for previously suspected impact on mortality; R(2) ranges from 0.86 for white males to 0.72 for black females. Analysis of black-white survival chances within each county reveals that the same variables account for most of the race gap in S(70) as well. When actual white male values for each explanatory variable are substituted for black in the black male prediction equation to assess the role explanatory variables play in the black-white survival difference, residual black white differences at the county level shrink markedly to a mean of -2.4% (+/ 2.4); for women the mean difference is -3.7% (+/-2.3). PMID- 22529893 TI - The biased nucleotide composition of HIV-1 triggers type I interferon response and correlates with subtype D increased pathogenicity. AB - The genome of human immunodeficiency virus (HIV) has an average nucleotide composition strongly biased as compared to the human genome. The consequence of such nucleotide composition on HIV pathogenicity has not been investigated yet. To address this question, we analyzed the role of nucleotide bias of HIV-derived nucleic acids in stimulating type-I interferon response in vitro. We found that the biased nucleotide composition of HIV is detected in human cells as compared to humanized sequences, and triggers a strong innate immune response, suggesting the existence of cellular immune mechanisms able to discriminate RNA sequences according to their nucleotide composition or to detect specific secondary structures or linear motifs within biased RNA sequences. We then extended our analysis to the entire genome scale by testing more than 1300 HIV-1 complete genomes to look for an association between nucleotide composition of HIV-1 group M subtypes and their pathogenicity. We found that subtype D, which has an increased pathogenicity compared to the other subtypes, has the most divergent nucleotide composition relative to the human genome. These data support the hypothesis that the biased nucleotide composition of HIV-1 may be related to its pathogenicity. PMID- 22529894 TI - Amerind ancestry, socioeconomic status and the genetics of type 2 diabetes in a Colombian population. AB - The "thrifty genotype" hypothesis proposes that the high prevalence of type 2 diabetes (T2D) in Native Americans and admixed Latin Americans has a genetic basis and reflects an evolutionary adaptation to a past low calorie/high exercise lifestyle. However, identification of the gene variants underpinning this hypothesis remains elusive. Here we assessed the role of Native American ancestry, socioeconomic status (SES) and 21 candidate gene loci in susceptibility to T2D in a sample of 876 T2D cases and 399 controls from Antioquia (Colombia). Although mean Native American ancestry is significantly higher in T2D cases than in controls (32% v 29%), this difference is confounded by the correlation of ancestry with SES, which is a stronger predictor of disease status. Nominally significant association (P<0.05) was observed for markers in: TCF7L2, RBMS1, CDKAL1, ZNF239, KCNQ1 and TCF1 and a significant bias (P<0.05) towards OR>1 was observed for markers selected from previous T2D genome-wide association studies, consistent with a role for Old World variants in susceptibility to T2D in Latin Americans. No association was found to the only known Native American-specific gene variant previously associated with T2D in a Mexican sample (rs9282541 in ABCA1). An admixture mapping scan with 1,536 ancestry informative markers (AIMs) did not identify genome regions with significant deviation of ancestry in Antioquia. Exclusion analysis indicates that this scan rules out ~95% of the genome as harboring loci with ancestry risk ratios >1.22 (at P < 0.05). PMID- 22529895 TI - Chromogranin A (CgA) as poor prognostic factor in patients with small cell carcinoma of the cervix: results of a retrospective study of 293 patients. AB - BACKGROUND: Small cell carcinoma of the cervix (SCCC) is a very rare tumor. Due to its rarity and the long time period, there is a paucity of information pertaining to prognostic factors associated with survival. The objective of this study was to determine whether clinicopathologic finings or immunohistochemical presence of molecular markers predictive of clinical outcome in patients with SCCC. METHODOLOGY AND FINDINGS: We retrospectively reviewed a total of 293 patients with SCCC (47 patients from Cancer Center of Sun Yat-sen University in china, 71 patients from case report of china journal, 175 patients from case report in PubMed database). Of those 293 patients with SCCC, the median survival time is 23 months. The 3-year overall survival rates (OS) and 3-year disease-free survival rates (DFS) for all patients were 34.5% and 31.1%, respectively. Univariate and multivariate analysis showed that FIGO stage (IIb-IV VS I-IIa, Hazard Ratio (HR) = 3.08, 95% confidence interval (CI) of ratio = [2.05, 4.63], P<0.001), tumor mass size (>= 4 cm VS <4 cm, HR = 2.37, 95% CI = [1.28, 4.36], P = 0.006) and chromogranin A (CgA) (Positive VS Negative, HR = 1.81, 95% CI = [1.12, 2.91], P = 0.015) were predictive of poor prognosis. CgA stained positive was found to be highly predictive of death in early-stage (FIGO I-IIa) patient specifically. CONCLUSIONS: Patients with SCCC have poor prognosis. FIGO stage, tumor mass size and CgA stained positive may act as a surrogate for factors prognostic of survival. CgA may serve as a useful marker in prognostic evaluation for early-stage patients with SCCC. PMID- 22529896 TI - GalNAc/Gal-binding Rhizoctonia solani agglutinin has antiproliferative activity in Drosophila melanogaster S2 cells via MAPK and JAK/STAT signaling. AB - Rhizoctonia solani agglutinin, further referred to as RSA, is a lectin isolated from the plant pathogenic fungus Rhizoctonia solani. Previously, we reported a high entomotoxic activity of RSA towards the cotton leafworm Spodoptera littoralis. To better understand the mechanism of action of RSA, Drosophila melanogaster Schneider S2 cells were treated with different concentrations of the lectin and FITC-labeled RSA binding was examined using confocal fluorescence microscopy. RSA has antiproliferative activity with a median effect concentration (EC(50)) of 0.35 uM. In addition, the lectin was typically bound to the cell surface but not internalized. In contrast, the N-acetylglucosamine-binding lectin WGA and the galactose-binding lectin PNA, which were both also inhibitory for S2 cell proliferation, were internalized whereas the mannose-binding lectin GNA did not show any activity on these cells, although it was internalized. Extracted DNA and nuclei from S2 cells treated with RSA were not different from untreated cells, confirming inhibition of proliferation without apoptosis. Pre-incubation of RSA with N-acetylgalactosamine clearly inhibited the antiproliferative activity by RSA in S2 cells, demonstrating the importance of carbohydrate binding. Similarly, the use of MEK and JAK inhibitors reduced the activity of RSA. Finally, RSA affinity chromatography of membrane proteins from S2 cells allowed the identification of several cell surface receptors involved in both signaling transduction pathways. PMID- 22529897 TI - Dimethyl sulfoxide promotes the multiple functions of the tumor suppressor HLJ1 through activator protein-1 activation in NSCLC cells. AB - BACKGROUND: Dimethyl sulfoxide (DMSO) is an amphipathic molecule that displays a diversity of antitumor activities. Previous studies have demonstrated that DMSO can modulate AP-1 activity and lead to cell cycle arrest at the G1 phase. HLJ1 is a newly identified tumor and invasion suppressor that inhibits tumorigenesis and cancer metastasis. Its transcriptional activity is regulated by the transcription factor AP-1. However, the effects of DMSO on HLJ1 are still unknown. In the present study, we investigate the antitumor effects of DMSO through HLJ1 induction and demonstrate the mechanisms involved. METHODS AND FINDINGS: Low-HLJ1 expressing highly invasive CL1-5 lung adenocarcinoma cells were treated with various concentrations of DMSO. We found that DMSO can significantly inhibit cancer cell invasion, migration, proliferation, and colony formation capabilities through upregulation of HLJ1 in a concentration-dependent manner, whereas ethanol has no effect. In addition, the HLJ1 promoter and enhancer reporter assay revealed that DMSO transcriptionally upregulates HLJ1 expression through an AP-1 site within the HLJ1 enhancer. The AP-1 subfamily members JunD and JunB were significantly upregulated by DMSO in a concentration-dependent manner. Furthermore, pretreatment with DMSO led to a significant increase in the percentage of UV-induced apoptotic cells. CONCLUSIONS: Our results suggest that DMSO may be an important stimulator of the tumor suppressor protein HLJ1 through AP-1 activation in highly invasive lung adenocarcinoma cells. Targeted induction of HLJ1 represents a promising approach for cancer therapy, which also implied that DMSO may serve as a potential lead compound or coordinated ligand for the development of novel anticancer drugs. PMID- 22529898 TI - A 3-year study reveals that plant growth stage, season and field site affect soil fungal communities while cultivar and GM-trait have minor effects. AB - In this three year field study the impact of different potato (Solanum tuberosum L.) cultivars including a genetically modified (GM) amylopectin-accumulating potato line on rhizosphere fungal communities are investigated using molecular microbiological methods. The effects of growth stage of a plant, soil type and year on the rhizosphere fungi were included in this study. To compare the effects, one GM cultivar, the parental isoline, and four non-related cultivars were planted in the fields and analysed using T-RFLP on the basis of fungal phylum specific primers combined with multivariate statistical methods. Additionally, fungal biomass and some extracellular fungal enzymes (laccases, Mn peroxidases and cellulases) were quantified in order to gain insight into the function of the fungal communities. Plant growth stage and year (and agricultural management) had the strongest effect on both diversity and function of the fungal communities while the GM-trait studied was the least explanatory factor. The impact of cultivar and soil type was intermediate. Occasional differences between cultivars, the amylopectin-accumulating potato line, and its parental variety were detected, but these differences were mostly transient in nature and detected either only in one soil, one growth stage or one year. PMID- 22529899 TI - Biodegradable thermosensitive hydrogel for SAHA and DDP delivery: therapeutic effects on oral squamous cell carcinoma xenografts. AB - BACKGROUND: OSCC is one of the most common malignancies and numerous clinical agents currently applied in combinative chemotherapy. Here we reported a novel therapeutic strategy, SAHA and DDP-loaded PECE (SAHA-DDP/PECE), can improve the therapeutic effects of intratumorally chemotherapy on OSCC cell xenografts. OBJECTIVE/PURPOSE: The objective of this study was to evaluate the therapeutic efficacy of the SAHA-DDP/PECE in situ controlled drug delivery system on OSCC cell xenografts. METHODS: A biodegradable and thermosensitive hydrogel was successfully developed to load SAHA and DDP. Tumor-beared mice were intratumorally administered with SAHA-DDP/PECE at 50 mg/kg (SAHA) +2 mg/kg (DDP) in 100 ul PECE hydrogel every two weeks, SAHA-DDP at 50 mg/kg(SAHA) +2 mg/kg(DDP) in NS, 2 mg/kg DDP solution, 50 mg/kg SAHA solution, equal volume of PECE hydrogel, or equal volume of NS on the same schedule, respectively. The antineoplastic actions of SAHA and DDP alone and in combination were evaluated using the determination of tumor volume, immunohistochemistry, western blot, and TUNEL analysis. RESULTS: The hydrogel system was a free-flowing sol at 10 degrees C, become gel at body temperature, and could sustain more than 14 days in situ. SAHA-DDP/PECE was subsequently injected into tumor OSCC tumor-beared mice. The results demonstrated that such a strategy as this allows the carrier system to show a sustained release of SAHA and DDP in vivo, and could improved therapeutic effects compared with a simple additive therapeutic effect of SAHA and DDP on mouse model. CONCLUSIONS: Our research indicated that the novel SAHA DDP/PECE system based on biodegradable PECE copolymer enhanced the therapeutic effects and could diminished the side effects of SAHA/DDP. The present work might be of great importance to the further exploration of the potential application of SAHA/DDP-hydrogel controlled drug release system in the treatment of OSCC. PMID- 22529900 TI - Role of the cellular prion protein in oligodendrocyte precursor cell proliferation and differentiation in the developing and adult mouse CNS. AB - There are numerous studies describing the signaling mechanisms that mediate oligodendrocyte precursor cell (OPC) proliferation and differentiation, although the contribution of the cellular prion protein (PrP(c)) to this process remains unclear. PrP(c) is a glycosyl-phosphatidylinositol (GPI)-anchored glycoprotein involved in diverse cellular processes during the development and maturation of the mammalian central nervous system (CNS). Here we describe how PrP(c) influences oligodendrocyte proliferation in the developing and adult CNS. OPCs that lack PrP(c) proliferate more vigorously at the expense of a delay in differentiation, which correlates with changes in the expression of oligodendrocyte lineage markers. In addition, numerous NG2-positive cells were observed in cortical regions of adult PrP(c) knockout mice, although no significant changes in myelination can be seen, probably due to the death of surplus cells. PMID- 22529901 TI - Differential patterns of food appreciation during consumption of a simple food in congenitally anosmic individuals: an explorative study. AB - Food is evaluated for various attributes. One of the key food evaluation domains is hedonicity. As food is consumed, its hedonic valence decreases (due to prolonged sensory stimulation) and hedonic habituation results. The aim of the present study was to investigate changes in food pleasantness ratings during consumption of a simple food by individuals without olfactory experience with food as compared to normosmics. 15 congenital anosmics and 15 normosmic controls were each presented with ten 10 g banana slices. Each was visually inspected, then smelled and chewed for ten seconds and subsequently rated for hedonicity on a 21-point scale. There was a significant difference in pleasantness ratings between congenital anosmics and controls (F(1, 26) = 6.71, p = .02) with the anosmics exhibiting higher ratings than the controls, a significant main repeated measures effect on the ratings (F(1.85, 48) = 12.15, p<.001), which showed a decreasing trend over the course of consumption, as well as a significant portion*group interaction (F(1.85, 48) = 3.54, p = .04), with the anosmic participants experiencing a less pronounced decline. The results of the present explorative study suggest that over the course of consumption of a simple food, congenitally anosmic individuals experience differential patterns of appreciation of food as compared to normosmics. In this particular case, the decrease of hedonic valence was less pronounced in congenital anosmics. PMID- 22529902 TI - Adapting to the destitute situations: poverty cues lead to short-term choice. AB - BACKGROUND: Why do some people live for the present, whereas others save for the future? The evolutionary framework of life history theory predicts that preference for delay of gratification should be influenced by social economic status (SES). However, here we propose that the decision to choose alternatives in immediate and delayed gratification in poverty environments may have a psychological dimension. Specifically, the perception of environmental poverty cues may induce people alike to favor choices with short-term, likely smaller benefit than choices with long-term, greater benefit. METHODOLOGY/PRINCIPAL FINDINGS: The present study was conducted to explore how poverty and affluence cues affected individuals' intertemporal choices. In our first two experiments, individuals exposed explicitly (Experiment 1) and implicitly (Experiment 2) to poverty pictures (the poverty cue) were induced to prefer immediate gratification compared with those exposed to affluence pictures (the affluence cue). Furthermore, by the manipulation of temporary perceptions of poverty and affluence status using a lucky draw game; individuals in the poverty state were more impulsive in a manner, which made them pursue immediate gratification in intertemporal choices (Experiment 3). Thus, poverty cues can lead to short-term choices. CONCLUSIONS/SIGNIFICANCE: Decision makers chose more frequently the sooner-smaller reward over the later-larger reward as they were exposed to the poverty cue. This indicates that it is that just the feeling of poverty influences intertemporal choice - the actual reality of poverty (restricted resources, etc.) is not necessary to get the effect. Furthermore, our findings emphasize that it is a change of the poverty-affluence status, not a trait change, can influence individual preference in intertemporal choice. PMID- 22529903 TI - Exogenous amino acids are essential for interleukin-7 induced CD8 T cell growth. [corrected]. AB - IL-7 signalling is important in regulating both survival and cellular size (growth) of T cells. While glucose metabolism has previously been implicated in the mechanism of IL-7 induced survival and growth, the role of amino acids has not before been reported. Here, we show IL-7 dependent T cell survival does not require either exogenous glucose or amino acids. In contrast, maintenance of cell size and IL-7 induced growth were specifically dependent on amino acids. Furthermore, cellular amino acid uptake was implicated in the mechanism of IL-7 induced growth. Analysis of IL-7 regulated gene expression revealed that neutral and cationic amino acid transporters were specific transcriptional targets of IL 7 signalling. In contrast, none of the four glucose transporters expressed in T cells were modulated. Taken together, these data reveal for the first time the central importance of amino acid homeostasis for IL-7 regulated T cell growth. PMID- 22529904 TI - Accumulation of an antidepressant in vesiculogenic membranes of yeast cells triggers autophagy. AB - Many antidepressants are cationic amphipaths, which spontaneously accumulate in natural or reconstituted membranes in the absence of their specific protein targets. However, the clinical relevance of cellular membrane accumulation by antidepressants in the human brain is unknown and hotly debated. Here we take a novel, evolutionarily informed approach to studying the effects of the selective serotonin reuptake inhibitor sertraline/Zoloft(r) on cell physiology in the model eukaryote Saccharomyces cerevisiae (budding yeast), which lacks a serotonin transporter entirely. We biochemically and pharmacologically characterized cellular uptake and subcellular distribution of radiolabeled sertraline, and in parallel performed a quantitative ultrastructural analysis of organellar membrane homeostasis in untreated vs. sertraline-treated cells. These experiments have revealed that sertraline enters yeast cells and then reshapes vesiculogenic membranes by a complex process. Internalization of the neutral species proceeds by simple diffusion, is accelerated by proton motive forces generated by the vacuolar H(+)-ATPase, but is counteracted by energy-dependent xenobiotic efflux pumps. At equilibrium, a small fraction (10-15%) of reprotonated sertraline is soluble while the bulk (90-85%) partitions into organellar membranes by adsorption to interfacial anionic sites or by intercalation into the hydrophobic phase of the bilayer. Asymmetric accumulation of sertraline in vesiculogenic membranes leads to local membrane curvature stresses that trigger an adaptive autophagic response. In mutants with altered clathrin function, this adaptive response is associated with increased lipid droplet formation. Our data not only support the notion of a serotonin transporter-independent component of antidepressant function, but also enable a conceptual framework for characterizing the physiological states associated with chronic but not acute antidepressant administration in a model eukaryote. PMID- 22529905 TI - Swim-training changes the spatio-temporal dynamics of skeletogenesis in zebrafish larvae (Danio rerio). AB - Fish larvae experience many environmental challenges during development such as variation in water velocity, food availability and predation. The rapid development of structures involved in feeding, respiration and swimming increases the chance of survival. It has been hypothesized that mechanical loading induced by muscle forces plays a role in prioritizing the development of these structures. Mechanical loading by muscle forces has been shown to affect larval and embryonic bone development in vertebrates, but these investigations were limited to the appendicular skeleton. To explore the role of mechanical load during chondrogenesis and osteogenesis of the cranial, axial and appendicular skeleton, we subjected zebrafish larvae to swim-training, which increases physical exercise levels and presumably also mechanical loads, from 5 until 14 days post fertilization. Here we show that an increased swimming activity accelerated growth, chondrogenesis and osteogenesis during larval development in zebrafish. Interestingly, swim-training accelerated both perichondral and intramembranous ossification. Furthermore, swim-training prioritized the formation of cartilage and bone structures in the head and tail region as well as the formation of elements in the anal and dorsal fins. This suggests that an increased swimming activity prioritized the development of structures which play an important role in swimming and thereby increasing the chance of survival in an environment where water velocity increases. Our study is the first to show that already during early zebrafish larval development, skeletal tissue in the cranial, axial and appendicular skeleton is competent to respond to swim-training due to increased water velocities. It demonstrates that changes in water flow conditions can result into significant spatio-temporal changes in skeletogenesis. PMID- 22529906 TI - Differential expression of miRNAs in colorectal cancer: comparison of paired tumor tissue and adjacent normal mucosa using high-throughput sequencing. AB - We present the results of a global study of dysregulated miRNAs in paired samples of normal mucosa and tumor from eight patients with colorectal cancer. Although there is existing data of miRNA contribution to colorectal tumorigenesis, these studies are typically small to medium scale studies of cell lines or non-paired tumor samples. The present study is to our knowledge unique in two respects. Firstly, the normal and adjacent tumor tissue samples are paired, thus taking into account the baseline differences between individuals when testing for differential expression. Secondly, we use high-throughput sequencing, thus enabling a comprehensive survey of all miRNAs expressed in the tissues. We use Illumina sequencing technology to perform sequencing and two different tools to statistically test for differences in read counts per gene between samples: edgeR when using the pair information and DESeq when ignoring this information, i.e., treating tumor and normal samples as independent groups. We identify 37 miRNAs that are significantly dysregulated in both statistical approaches, 19 down regulated and 18 up-regulated. Some of these miRNAs are previously published as potential regulators in colorectal adenocarcinomas such as miR-1, miR-96 and miR 145. Our comprehensive survey of differentially expressed miRNAs thus confirms some existing findings. We have also discovered 16 dysregulated miRNAs, which to our knowledge have not previously been associated with colorectal carcinogenesis: the following significantly down-regulated miR-490-3p, -628-3p/-5p, -1297, -3151, -3163, -3622a-5p, -3656 and the up-regulated miR-105, -549, -1269, -1827, -3144 3p, -3177, -3180-3p, -4326. Although the study is preliminary with only eight patients included, we believe the results add to the present knowledge on miRNA dysregulation in colorectal carcinogenesis. As such the results would serve as a robust training set for validation of potential biomarkers in a larger cohort study. Finally, we also present data supporting the hypothesis that there are differences in miRNA expression between adenocarcinomas and neuroendocrine tumors of the colon. PMID- 22529907 TI - A conceptual muddle: an empirical analysis of the use of 'sex' and 'gender' in 'gender-specific medicine' journals. AB - BACKGROUND: At the same time as there is increasing awareness in medicine of the risks of exaggerating differences between men and women, there is a growing professional movement of 'gender-specific medicine' which is directed towards analysing 'sex' and 'gender' differences. The aim of this article is to empirically explore how the concepts of 'sex' and 'gender' are used in the new field of 'gender-specific medicine', as reflected in two medical journals which are foundational to this relatively new field. METHOD AND PRINCIPAL FINDINGS: The data consist of all articles from the first issue of each journal in 2004 and an issue published three years later (n = 43). In addition, all editorials over this period were included (n = 61). Quantitative and qualitative content analyses were undertaken by the authors. Less than half of the 104 papers used the concepts of 'sex' and 'gender'. Less than 1 in 10 papers attempted any definition of the concepts. Overall, the given definitions were simple, unspecific and created dualisms between men and women. Almost all papers which used the two concepts did so interchangeably, with any possible interplay between 'sex' and gender' referred to only in six of the papers. CONCLUSION: The use of the concepts of 'sex' and gender' in 'gender-specific medicine' is conceptually muddled. The simple, dualistic and individualised use of these concepts increases the risk of essentialism and reductivist thinking. It therefore highlights the need to clarify the use of the terms 'sex' and 'gender' in medical research and to develop more effective ways of conceptualising the interplay between 'sex' and 'gender' in relation to different diseases. PMID- 22529908 TI - The derived allele of ASPM is associated with lexical tone perception. AB - The ASPM and MCPH1 genes have been implicated in the adaptive evolution of the human brain [Mekel-Bobrov N. et al., 2005. Ongoing adaptive evolution of ASPM, a brain size determinant in homo sapiens. Science 309; Evans P.D. et al., 2005. Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans. Science 309]. Curiously, experimental attempts have failed to connect the implicated SNPs in these genes with higher-level brain functions. These results stand in contrast with a population-level study linking the population frequency of their alleles with the tendency to use lexical tones in a language [Dediu D., Ladd D.R., 2007. Linguistic tone is related to the population frequency of the adaptive haplogroups of two brain size genes, ASPM and microcephalin. Proc. Natl. Acad. Sci. U.S.A. 104]. In the present study, we found a significant correlation between the load of the derived alleles of ASPM and tone perception in a group of European Americans who did not speak a tone language. Moreover, preliminary results showed a significant correlation between ASPM load and hemodynamic responses to lexical tones in the auditory cortex, and such correlation remained after phonemic awareness, auditory working memory, and non-verbal IQ were controlled. As in previous studies, no significant correlation between ASPM and cognitive measures were found. MCPH1 did not correlate with any measures. These results suggest that the association between the recently derived allele of ASPM is likely to be specific and is tied to higher level brain functions in the temporal cortex related to human communication. PMID- 22529909 TI - Discovery of pod shatter-resistant associated SNPs by deep sequencing of a representative library followed by bulk segregant analysis in rapeseed. AB - BACKGROUND: Single nucleotide polymorphisms (SNPs) are an important class of genetic marker for target gene mapping. As of yet, there is no rapid and effective method to identify SNPs linked with agronomic traits in rapeseed and other crop species. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrate a novel method for identifying SNP markers in rapeseed by deep sequencing a representative library and performing bulk segregant analysis. With this method, SNPs associated with rapeseed pod shatter-resistance were discovered. Firstly, a reduced representation of the rapeseed genome was used. Genomic fragments ranging from 450-550 bp were prepared from the susceptible bulk (ten F2 plants with the silique shattering resistance index, SSRI <0.10) and the resistance bulk (ten F2 plants with SSRI >0.90), and also Solexa sequencing-produced 90 bp reads. Approximately 50 million of these sequence reads were assembled into contigs to a depth of 20-fold coverage. Secondly, 60,396 'simple SNPs' were identified, and the statistical significance was evaluated using Fisher's exact test. There were 70 associated SNPs whose -log(10)p value over 16 were selected to be further analyzed. The distribution of these SNPs appeared a tight cluster, which consisted of 14 associated SNPs within a 396 kb region on chromosome A09. Our evidence indicates that this region contains a major quantitative trait locus (QTL). Finally, two associated SNPs from this region were mapped on a major QTL region. CONCLUSIONS/SIGNIFICANCE: 70 associated SNPs were discovered and a major QTL for rapeseed pod shatter-resistance was found on chromosome A09 using our novel method. The associated SNP markers were used for mapping of the QTL, and may be useful for improving pod shatter-resistance in rapeseed through marker assisted selection and map-based cloning. This approach will accelerate the discovery of major QTLs and the cloning of functional genes for important agronomic traits in rapeseed and other crop species. PMID- 22529910 TI - A study of trait anhedonia in non-clinical Chinese samples: evidence from the Chapman Scales for Physical and Social Anhedonia. AB - BACKGROUND: Recent studies suggest that anhedonia, an inability to experience pleasure, can be measured as an enduring trait in non-clinical samples. In order to examine trait anhedonia in a non-clinical sample, we examined the properties of a range of widely used questionnaires capturing anhedonia. METHODS: 887 young adults were recruited from colleges. All of them were administered a set of checklists, including Chapman Scale for Social Anhedonia (CRSAS) and the Chapman Scale for Physical Anhedonia Scale (CPAS), The Temporal Experience of Pleasure Scale(TEPS), and The Schizotypal Personality Questionnaire (SPQ). RESULTS: Males showed significantly higher level of physical (F = 5.09, p<0.001) and social (F = 4.38, p<0.005) anhedonia than females. As expected, individuals with schizotypal personality features also demonstrated significantly higher scores of physical (t = 3.81, p<0.001) and social (t = 7.33, p<0.001) trait anhedonia than individuals without SPD features, but no difference on self-report anticipatory and consummatory pleasure experience. CONCLUSIONS: Concerning the comparison on each item of physical and social anhedonia, the results indicated that individuals with SPD feature exhibited higher than individuals without SPD features on more items of social anhedonia than physical anhedonia scale. These preliminary findings suggested that trait anhedonia can be identified a non-clinical sample. Exploring the demographic and clinical correlates of trait anhedonia in the general population may provide clues to the pathogenesis of psychotic disorder. PMID- 22529911 TI - Altered thymic function during interferon therapy in HCV-infected patients. AB - Interferon alpha (IFNalpha) therapy, despite good efficacy in curing HCV infection, leads to major side effects, in particular inducement of a strong peripheral T-cell lymphocytopenia. We here analyze the early consequences of IFNalpha therapy on both thymic function and peripheral T-cell homeostasis in patients in the acute or chronic phase of HCV-infection as well as in HIV/HCV co infected patients. The evolution of T-cell subsets and T-cell homeostasis were estimated by flow cytometry while thymic function was measured through quantification of T-cell receptor excision circles (TREC) and estimation of intrathymic precursor T-cell proliferation during the first four months following the initiation of IFNalpha therapy. Beginning with the first month of therapy, a profound lymphocytopenia was observed for all T-cell subsets, including naive T cells and recent thymic emigrants (RTE), associated with inhibition of intrathymic precursor T-cell proliferation. Interleukin (IL)-7 plasma concentration rapidly dropped while lymphocytopenia progressed. This was neither a consequence of higher consumption of the cytokine nor due to its neutralization by soluble CD127. Decrease in IL-7 plasma concentration under IFNalpha therapy correlated with the decline in HCV viral load, thymic activity and RTE concentration in blood. These data demonstrate that IFNalpha-based therapy rapidly impacts on thymopoiesis and, consequently, perturbs T-cell homeostasis. Such a side effect might be detrimental for the continuation of IFNalpha therapy and may lead to an increased level of infectious risk, in particular in HIV/HCV co-infected patients. Altogether, this study suggests the therapeutic potential of IL-7 in the maintenance of peripheral T-cell homeostasis in IFNalpha-treated patients. PMID- 22529913 TI - Interaction of aspirin (acetylsalicylic acid) with lipid membranes. AB - We studied the interaction of Aspirin (acetylsalicylic acid) with lipid membranes using x-ray diffraction for bilayers containing up to 50 mol% of aspirin. From 2D x-ray intensity maps that cover large areas of reciprocal space we determined the position of the ASA molecules in the phospholipid bilayers and the molecular arrangement of the molecules in the plane of the membranes. We present direct experimental evidence that ASA molecules participate in saturated lipid bilayers of DMPC (1,2-dimyristoyl-sn-glycero-3-phosphocholine) and preferably reside in the head group region of the membrane. Up to 50 mol% ASA molecules can be dissolved in this type of bilayer before the lateral membrane organization is disturbed and the membranes are found to form an ordered, 2D crystal-like structure. Furthermore, ASA and cholesterol were found to co-exist in saturated lipid bilayers, with the ASA molecules residing in the head group region and the cholesterol molecules participating in the hydrophobic membrane core. PMID- 22529912 TI - Dysregulation of cell polarity proteins synergize with oncogenes or the microenvironment to induce invasive behavior in epithelial cells. AB - Changes in expression and localization of proteins that regulate cell and tissue polarity are frequently observed in carcinoma. However, the mechanisms by which changes in cell polarity proteins regulate carcinoma progression are not well understood. Here, we report that loss of polarity protein expression in epithelial cells primes them for cooperation with oncogenes or changes in tissue microenvironment to promote invasive behavior. Activation of ErbB2 in cells lacking the polarity regulators Scribble, Dlg1 or AF-6, induced invasive properties. This cooperation required the ability of ErbB2 to regulate the Par6/aPKC polarity complex. Inhibition of the ErbB2-Par6 pathway was sufficient to block ErbB2-induced invasion suggesting that two polarity hits may be needed for ErbB2 to promote invasion. Interestingly, in the absence of ErbB2 activation, either a combined loss of two polarity proteins, or exposure of cells lacking one polarity protein to cytokines IL-6 or TNFalpha induced invasive behavior in epithelial cells. We observed the invasive behavior only when cells were plated on a stiff matrix (Matrigel/Collagen-1) and not when plated on a soft matrix (Matrigel alone). Cells lacking two polarity proteins upregulated expression of EGFR and activated Akt. Inhibition of Akt activity blocked the invasive behavior identifying a mechanism by which loss of polarity promotes invasion of epithelial cells. Thus, we demonstrate that loss of polarity proteins confers phenotypic plasticity to epithelial cells such that they display normal behavior under normal culture conditions but display aggressive behavior in response to activation of oncogenes or exposure to cytokines. PMID- 22529914 TI - CXCL12 and [N33A]CXCL12 in 5637 and HeLa cells: regulating HER1 phosphorylation via calmodulin/calcineurin. AB - In the human neoplastic cell lines 5637 and HeLa, recombinant CXCL12 elicited, as expected, downstream signals via both G-protein-dependent and beta-arrestin dependent pathways responsible for inducing a rapid and a late wave, respectively, of ERK1/2 phosphorylation. In contrast, the structural variant [N33A]CXCL12 triggered no beta-arrestin-dependent phosphorylation of ERK1/2, and signaled via G protein-dependent pathways alone. Both CXCL12 and [N33A]CXCL12, however, generated signals that transinhibited HER1 phosphorylation via intracellular pathways. 1) Prestimulation of CXCR4/HER1-positive 5637 or HeLa cells with CXCL12 modified the HB-EGF-dependent activation of HER1 by delaying the peak phosphorylation of tyrosine 1068 or 1173. 2) Prestimulation with the synthetic variant [N33A]CXCL12, while preserving CXCR4-related chemotaxis and CXCR4 internalization, abolished HER1 phosphorylation. 3) In cells knockdown of beta-arrestin 2, CXCL12 induced a full inhibition of HER1 like [N33A]CXCL12 in non-silenced cells. 4) HER1 phosphorylation was restored as usual by inhibiting PCK, calmodulin or calcineurin, whereas the inhibition of CaMKII had no discernable effect. We conclude that both recombinant CXCL12 and its structural variant [N33A]CXCL12 may transinhibit HER1 via G-proteins/calmodulin/calcineurin, but [N33A]CXCL12 does not activate beta-arrestin-dependent ERK1/2 phosphorylation and retains a stronger inhibitory effect. Therefore, we demonstrated that CXCL12 may influence the magnitude and the persistence of signaling downstream of HER1 in turn involved in the proliferative potential of numerous epithelial cancer. In addition, we recognized that [N33A]CXCL12 activates preferentially G-protein dependent pathways and is an inhibitor of HER1. PMID- 22529915 TI - Vaccine efficacy against malaria by the combination of porcine parvovirus-like particles and vaccinia virus vectors expressing CS of Plasmodium. AB - With the aim to develop an efficient and cost-effective approach to control malaria, we have generated porcine parvovirus-like particles (PPV-VLPs) carrying the CD8(+) T cell epitope (SYVPSAEQI) of the circumsporozoite (CS) protein from Plasmodium yoelii fused to the PPV VP2 capsid protein (PPV-PYCS), and tested in prime/boost protocols with poxvirus vectors for efficacy in a rodent malaria model. As a proof-of concept, we have characterized the anti-CS CD8(+) T cell response elicited by these hybrid PPV-VLPs in BALB/c mice after immunizations with the protein PPV-PYCS administered alone or in combination with recombinant vaccinia virus (VACV) vectors from the Western Reserve (WR) and modified virus Ankara (MVA) strains expressing the entire P. yoelii CS protein. The results of different immunization protocols showed that the combination of PPV-PYCS prime/poxvirus boost was highly immunogenic, inducing specific CD8+ T cell responses to CS resulting in 95% reduction in liver stage parasites two days following sporozoite challenge. In contrast, neither the administration of PPV PYCS alone nor the immunization with the vectors given in the order poxvirus/VLPs was as effective. The immune profile induced by VLPs/MVA boost was associated with polyfunctional and effector memory CD8+ T cell responses. These findings highlight the use of recombinant parvovirus PPV-PYCS particles as priming agents and poxvirus vectors, like MVA, as booster to enhance specific CD8+ T cell responses to Plasmodium antigens and to control infection. These observations are relevant in the design of T cell-inducing vaccines against malaria. PMID- 22529916 TI - Going solo: discovery of the first parthenogenetic gordiid (Nematomorpha: Gordiida). AB - Despite the severe fitness costs associated with sexual reproduction, its persistence and pervasiveness among multicellular organisms testifies to its intrinsic, short-term advantages. However, the reproductive assurance hypothesis predicts selection favoring asexual reproduction in sparse populations and when mate finding is difficult. Difficulties in finding mates is especially common in parasites, whose life cycles involve multiple hosts, or being released from the host into the external environment where the parasite can find itself trapped without a sexual partner. To solve this problem and guarantee reproduction, parasites in numerous phyla have evolved reproductive strategies, as predicted by the reproductive assurance hypothesis, such as hermaphroditism or parthenogenesis. However, this type of strategy has not been reported from species in the phylum Nematomorpha, whose populations have often been described as sparse. A new Nematomorpha species, Paragordius obamai n. sp., was discovered from Kenya, Africa, and appears to have solved the problem of being trapped without a mate by eliminating the need for males. Paragordius obamai n. sp. represents the first and only known species within this phylum to reproduce asexually. To determine the mechanism of this mating strategy, we ruled out the involvement of reproduction manipulating endosymbionts by use of next generation sequencing data, thus suggesting that parthenogenesis is determined genetically and may have evolved as a means to assure reproduction. Since this new parthenogenetic species and a closely related gonochoristic North American congener, P. varius, are easy to propagate in the laboratory, these gordiids can be used as model systems to test hypotheses on the genetic advantages and disadvantages of asexual reproduction and the genetic determinants of reproductive strategies in parasites. PMID- 22529917 TI - Collective human mobility pattern from taxi trips in urban area. AB - We analyze the passengers' traffic pattern for 1.58 million taxi trips of Shanghai, China. By employing the non-negative matrix factorization and optimization methods, we find that, people travel on workdays mainly for three purposes: commuting between home and workplace, traveling from workplace to workplace, and others such as leisure activities. Therefore, traffic flow in one area or between any pair of locations can be approximated by a linear combination of three basis flows, corresponding to the three purposes respectively. We name the coefficients in the linear combination as traffic powers, each of which indicates the strength of each basis flow. The traffic powers on different days are typically different even for the same location, due to the uncertainty of the human motion. Therefore, we provide a probability distribution function for the relative deviation of the traffic power. This distribution function is in terms of a series of functions for normalized binomial distributions. It can be well explained by statistical theories and is verified by empirical data. These findings are applicable in predicting the road traffic, tracing the traffic pattern and diagnosing the traffic related abnormal events. These results can also be used to infer land uses of urban area quite parsimoniously. PMID- 22529918 TI - Cross-talk and information transfer in mammalian and bacterial signaling. AB - In mammalian and bacterial cells simple phosphorylation circuits play an important role in signaling. Bacteria have hundreds of two-component signaling systems that involve phosphotransfer between a receptor and a response regulator. In mammalian cells a similar pathway is the TGF-beta pathway, where extracellular TGF-beta ligands activate cell surface receptors that phosphorylate Smad proteins, which in turn activate many genes. In TGF-beta signaling the multiplicity of ligands begs the question as to whether cells can distinguish signals coming from different ligands, but transduced through a small set of Smads. Here we use information theory with stochastic simulations of networks to address this question. We find that when signals are transduced through only one Smad, the cell cannot distinguish between different levels of the external ligands. Increasing the number of Smads from one to two significantly improves information transmission as well as the ability to discriminate between ligands. Surprisingly, both total information transmitted and the capacity to discriminate between ligands are quite insensitive to high levels of cross-talk between the two Smads. Robustness against cross-talk requires that the average amplitude of the signals are large. We find that smaller systems, as exemplified by some two component systems in bacteria, are significantly much less robust against cross talk. For such system sizes phosphotransfer is also less robust against cross talk than phosphorylation. This suggests that mammalian signal transduction can tolerate a high amount of cross-talk without degrading information content. This may have played a role in the evolution of new functionalities from small mutations in signaling pathways, allowed for the development of cross-regulation and led to increased overall robustness due to redundancy in signaling pathways. On the other hand the lack of cross-regulation observed in many bacterial two component systems may partly be due to the loss of information content due to cross-talk. PMID- 22529919 TI - Plasmodium vivax adherence to placental glycosaminoglycans. AB - BACKGROUND: Plasmodium vivax infections seldom kill directly but do cause indirect mortality by reducing birth weight and causing abortion. Cytoadherence and sequestration in the microvasculature are central to the pathogenesis of severe Plasmodium falciparum malaria, but the contribution of cytoadherence to pathology in other human malarias is less clear. METHODOLOGY: The adherence properties of P. vivax infected red blood cells (PvIRBC) were evaluated under static and flow conditions. PRINCIPAL FINDINGS: P. vivax isolates from 33 patients were studied. None adhered to immobilized CD36, ICAM-1, or thrombospondin, putative ligands for P. falciparum vascular cytoadherence, or umbilical vein endothelial cells, but all adhered to immobilized chondroitin sulphate A (CSA) and hyaluronic acid (HA), the receptors for adhesion of P. falciparum in the placenta. PvIRBC also adhered to fresh placental cells (N = 5). Pre-incubation with chondroitinase prevented PvIRBC adherence to CSA, and reduced binding to HA, whereas preincubation with hyaluronidase prevented adherence to HA, but did not reduce binding to CSA significantly. Pre-incubation of PvIRBC with soluble CSA and HA reduced binding to the immobilized receptors and prevented placental binding. PvIRBC adhesion was prevented by pre-incubation with trypsin, inhibited by heparin, and reduced by EGTA. Under laminar flow conditions the mean (SD) shear stress reducing maximum attachment by 50% was 0.06 (0.02) Pa but, having adhered, the PvIRBC could then resist detachment by stresses up to 5 Pa. At 37 degrees C adherence began approximately 16 hours after red cell invasion with maximal adherence at 30 hours. At 39 degrees C adherence began earlier and peaked at 24 hours. SIGNIFICANCE: Adherence of P. vivax-infected erythrocytes to glycosaminoglycans may contribute to the pathogenesis of vivax malaria and lead to intrauterine growth retardation. PMID- 22529921 TI - Tinnitus: distinguishing between subjectively perceived loudness and tinnitus related distress. AB - OBJECTIVES: Overall success of current tinnitus therapies is low, which may be due to the heterogeneity of tinnitus patients. Therefore, subclassification of tinnitus patients is expected to improve therapeutic allocation, which, in turn, is hoped to improve therapeutic success for the individual patient. The present study aims to define factors that differentially influence subjectively perceived tinnitus loudness and tinnitus-related distress. METHODS: In a questionnaire based cross-sectional survey, the data of 4705 individuals with tinnitus were analyzed. The self-report questionnaire contained items about subjective tinnitus loudness, type of onset, awareness and localization of the tinnitus, hearing impairment, chronic comorbidities, sleep quality, and psychometrically validated questionnaires addressing tinnitus-related distress, depressivity, anxiety, and somatic symptom severity. In a binary step-wise logistic regression model, we tested the predictive power of these variables on subjective tinnitus loudness and tinnitus-related distress. RESULTS: The present data contribute to the distinction between subjective tinnitus loudness and tinnitus-related distress. Whereas subjective loudness was associated with permanent awareness and binaural localization of the tinnitus, tinnitus-related distress was associated with depressivity, anxiety, and somatic symptom severity. CONCLUSIONS: Subjective tinnitus loudness and the potential presence of severe depressivity, anxiety, and somatic symptom severity should be assessed separately from tinnitus-related distress. If loud tinnitus is the major complaint together with mild or moderate tinnitus-related distress, therapies should focus on auditory perception. If levels of depressivity, anxiety or somatic symptom severity are severe, therapies and further diagnosis should focus on these symptoms at first. PMID- 22529920 TI - Computational refinement of functional single nucleotide polymorphisms associated with ATM gene. AB - BACKGROUND: Understanding and predicting molecular basis of disease is one of the major challenges in modern biology and medicine. SNPs associated with complex disorders can create, destroy, or modify protein coding sites. Single amino acid substitutions in the ATM gene are the most common forms of genetic variations that account for various forms of cancer. However, the extent to which SNPs interferes with the gene regulation and affects cancer susceptibility remains largely unknown. PRINCIPAL FINDINGS: We analyzed the deleterious nsSNPs associated with ATM gene based on different computational methods. An integrative scoring system and sequence conservation of amino acid residues was adapted for a priori nsSNP analysis of variants associated with cancer. We further extended our approach on SNPs that could potentially influence protein Post Translational Modifications in ATM gene. SIGNIFICANCE: In the lack of adequate prior reports on the possible deleterious effects of nsSNPs, we have systematically analyzed and characterized the functional variants in both coding and non coding region that can alter the expression and function of ATM gene. In silico characterization of nsSNPs affecting ATM gene function can aid in better understanding of genetic differences in disease susceptibility. PMID- 22529922 TI - Chromatic signals control proboscis movements during hovering flight in the hummingbird hawkmoth Macroglossum stellatarum. AB - Most visual systems are more sensitive to luminance than to colour signals. Animals resolve finer spatial detail and temporal changes through achromatic signals than through chromatic ones. Probably, this explains that detection of small, distant, or moving objects is typically mediated through achromatic signals. Macroglossum stellatarum are fast flying nectarivorous hawkmoths that inspect flowers with their long proboscis while hovering. They can visually control this behaviour using floral markings known as nectar guides. Here, we investigate whether this is mediated by chromatic or achromatic cues. We evaluated proboscis placement, foraging efficiency, and inspection learning of naive moths foraging on flower models with coloured markings that offered either chromatic, achromatic or both contrasts. Hummingbird hawkmoths could use either achromatic or chromatic signals to inspect models while hovering. We identified three, apparently independent, components controlling proboscis placement: After initial contact, 1) moths directed their probing towards the yellow colour irrespectively of luminance signals, suggesting a dominant role of chromatic signals; and 2) moths tended to probe mainly on the brighter areas of models that offered only achromatic signals. 3) During the establishment of the first contact, naive moths showed a tendency to direct their proboscis towards the small floral marks independent of their colour or luminance. Moths learned to find nectar faster, but their foraging efficiency depended on the flower model they foraged on. Our results imply that M. stellatarum can perceive small patterns through colour vision. We discuss how the different informational contents of chromatic and luminance signals can be significant for the control of flower inspection, and visually guided behaviours in general. PMID- 22529923 TI - Acute and chronic effects of particles on hospital admissions in New-England. AB - BACKGROUND: Many studies have reported significant associations between exposure to PM(2.5) and hospital admissions, but all have focused on the effects of short term exposure. In addition all these studies have relied on a limited number of PM(2.5) monitors in their study regions, which introduces exposure error, and excludes rural and suburban populations from locations in which monitors are not available, reducing generalizability and potentially creating selection bias. METHODS: Using our novel prediction models for exposure combining land use regression with physical measurements (satellite aerosol optical depth) we investigated both the long and short term effects of PM(2.5) exposures on hospital admissions across New-England for all residents aged 65 and older. We performed separate Poisson regression analysis for each admission type: all respiratory, cardiovascular disease (CVD), stroke and diabetes. Daily admission counts in each zip code were regressed against long and short-term PM(2.5) exposure, temperature, socio-economic data and a spline of time to control for seasonal trends in baseline risk. RESULTS: We observed associations between both short-term and long-term exposure to PM(2.5) and hospitalization for all of the outcomes examined. In example, for respiratory diseases, for every 10-ug/m(3) increase in short-term PM(2.5) exposure there is a 0.70 percent increase in admissions (CI = 0.35 to 0.52) while concurrently for every 10-ug/m(3) increase in long-term PM(2.5) exposure there is a 4.22 percent increase in admissions (CI = 1.06 to 4.75). CONCLUSIONS: As with mortality studies, chronic exposure to particles is associated with substantially larger increases in hospital admissions than acute exposure and both can be detected simultaneously using our exposure models. PMID- 22529924 TI - Assigning backbone NMR resonances for full length tau isoforms: efficient compromise between manual assignments and reduced dimensionality. AB - Tau protein is the longest disordered protein for which nearly complete backbone NMR resonance assignments have been reported. Full-length tau protein was initially assigned using a laborious combination of bootstrapping assignments from shorter tau fragments and conventional triple resonance NMR experiments. Subsequently it was reported that assignments of comparable quality could be obtained in a fully automated fashion from data obtained using reduced dimensionality NMR (RDNMR) experiments employing a large number of indirect dimensions. Although the latter strategy offers many advantages, it presents some difficulties if manual intervention, confirmation, or correction of the assignments is desirable, as may often be the case for long disordered and degenerate polypeptide sequences. Here we demonstrate that nearly complete backbone resonance assignments for full-length tau isoforms can be obtained without resorting either to bootstrapping from smaller fragments or to very high dimensionality experiments and automation. Instead, a set of RDNMR triple resonance experiments of modest dimensionality lend themselves readily to efficient and unambiguous manual assignments. An analysis of the backbone chemical shifts obtained in this fashion indicates several regions in full length tau with a notable propensity for helical or strand-like structure that are in good agreement with previous observations. PMID- 22529925 TI - The expression of microRNA and microRNA clusters in the aging heart. AB - BACKGROUND: The microRNAs have been implicated in the process of cardiac development, cardiac hypertrophy, and heart failure. However, the impact of adult aging on cardiac expression of miRNA clusters, as well as both miRNA guide (miR) and passenger (miR*) strands has not been well established. METHODS/RESULTS: We explored the expression profile of both miR and miR* in the hearts of young adult versus old mice. We found that 65 miRNAs were differentially expressed in the old versus young adult hearts; approximately half of them were clustered miRNAs that were distributed in 11 miRNA clusters. Each miRNA cluster contained from 2 to as many as 71 miRNA genes. The majority of the clusters displayed similar expression, with most cluster members within a cluster being either increased or decreased together, suggesting that most clusters are likely to be regulated by a common signaling mechanism and that the combined expression of multiple miRNA genes in a cluster could pose an impact on a broad range of targets during aging. We also found age-related changes in the expression of miR*s. The expression of both miR and miR* correlated with that of pri-miRNA transcript over the time course from development and maturation through adult aging. Age-related changes in the expression of Ago1 and Ago2 proteins in the heart were also observed. Transfection assay revealed that both Ago1 and Ago2 synergistically induced miR 21 and miR-21* when the mir-21 plasmid was co-transfected with either. CONCLUSION: The data revealed age-related changes in the expression of pri-miRNA transcript, Argonaut proteins and both miR and miR* strands. The major changes occurred later in life, from middle to old age. It is likely that the expression of miR and miR* is regulated by both pri-miRNA transcription as well as Ago1 and Ago2 proteins during adult aging. PMID- 22529927 TI - Establishment of a replicating plasmid in Rickettsia prowazekii. AB - Rickettsia prowazekii, the causative agent of epidemic typhus, grows only within the cytosol of eukaryotic host cells. This obligate intracellular lifestyle has restricted the genetic analysis of this pathogen and critical tools, such as replicating plasmid vectors, have not been developed for this species. Although replicating plasmids have not been reported in R. prowazekii, the existence of well-characterized plasmids in several less pathogenic rickettsial species provides an opportunity to expand the genetic systems available for the study of this human pathogen. Competent R. prowazekii were transformed with pRAM18dRGA, a 10.3 kb vector derived from pRAM18 of R. amblyommii. A plasmid-containing population of R. prowazekii was obtained following growth under antibiotic selection, and the rickettsial plasmid was maintained extrachromosomally throughout multiple passages. The transformant population exhibited a generation time comparable to that of the wild type strain with a copy number of approximately 1 plasmid per rickettsia. These results demonstrate for the first time that a plasmid can be maintained in R. prowazekii, providing an important genetic tool for the study of this obligate intracellular pathogen. PMID- 22529926 TI - Natural reward experience alters AMPA and NMDA receptor distribution and function in the nucleus accumbens. AB - Natural reward and drugs of abuse converge upon the mesolimbic system which mediates motivation and reward behaviors. Drugs induce neural adaptations in this system, including transcriptional, morphological, and synaptic changes, which contribute to the development and expression of drug-related memories and addiction. Previously, it has been reported that sexual experience in male rats, a natural reward behavior, induces similar neuroplasticity in the mesolimbic system and affects natural reward and drug-related behavior. The current study determined whether sexual experience causes long-lasting changes in mating, or ionotropic glutamate receptor trafficking or function in the nucleus accumbens (NAc), following 3 different reward abstinence periods: 1 day, 1 week, or 1 month after final mating session. Male Sprague Dawley rats mated during 5 consecutive days (sexual experience) or remained sexually naive to serve as controls. Sexually experienced males displayed facilitation of initiation and performance of mating at each time point. Next, intracellular and membrane surface expression of N-methyl-D-aspartate (NMDA: NR1 subunit) and alpha-amino-3-hydroxy-5 methylisoxazole-4-propionate (AMPA: GluA1, GluA2 subunits) receptors in the NAc was determined using a bis(sulfosuccinimidyl)suberate (BS(3)) protein cross linking assay followed by Western Blot analysis. NR1 expression was increased at 1 day abstinence both at surface and intracellular, but decreased at surface at 1 week of abstinence. GluA2 was increased intracellularly at 1 week and increased at the surface after 1 month of abstinence. Finally, whole-cell patch clamp electrophysiological recordings determined reduced AMPA/NMDA ratio of synaptic currents in NAc shell neurons following stimulation of cortical afferents in sexually experienced males after all reward abstinence periods. Together, these data show that sexual experience causes long-term alterations in glutamate receptor expression and function in the NAc. Although not identical, this sex experience-induced neuroplasticity has similarities to that caused by psychostimulants, suggesting common mechanisms for reinforcement of natural and drug reward. PMID- 22529928 TI - Developmental exposure to a toxic spill compromises long-term reproductive performance in a wild, long-lived bird: the white stork (Ciconia ciconia). AB - BACKGROUND/OBJECTIVE: Exposure to environmental contaminants may result in reduced reproductive success and long-lasting population declines in vertebrates. Emerging data from laboratory studies on model species suggest that certain life stages, such as development, should be of special concern. However, detailed investigations of long-term consequences of developmental exposure to environmental chemicals on breeding performance are currently lacking in wild populations of long-lived vertebrates. Here, we studied how the developmental exposure to a mine spill (Aznalcollar, SW Spain, April 1998) may affect fitness under natural conditions in a long-lived bird, the White Stork (Ciconia ciconia). METHODOLOGY: The reproductive performance of individually-banded storks that were or not developmentally exposed to the spill (i.e. hatched before or after the spill) was compared when these individuals were simultaneously breeding during the seven years after the spill occurred (1999-2005). PRINCIPAL FINDINGS: Female storks developmentally exposed to the spill experienced a premature breeding senescence compared with their non-developmentally exposed counterparts, doing so after departing from an unusually higher productivity in their early reproductive life (non-developmentally exposed females: 0.5 +/- 0.33SE fledglings/year at 3-yr old vs. 1.38 +/- 0.31SE at 6-7 yr old; developmentally exposed females: 1.5 +/- 0.30SE fledglings/year at 3-yr old vs. 0.86 +/- 0.25SE at 6-7 yr old). CONCLUSIONS/SIGNIFICANCE: Following life-history theory, we propose that costly sub-lethal effects reported in stork nestlings after low-level exposure to the spill-derived contaminants might play an important role in shaping this pattern of reproduction, with a clear potential impact on population dynamics. Overall, our study provides evidence that environmental disasters can have long-term, multigenerational consequences on wildlife, particularly when affecting developing individuals, and warns about the risk of widespread low-level contamination in realistic scenarios. PMID- 22529929 TI - High hemocyte load is associated with increased resistance against parasitoids in Drosophila suzukii, a relative of D. melanogaster. AB - Among the most common parasites of Drosophila in nature are parasitoid wasps, which lay their eggs in fly larvae and pupae. D. melanogaster larvae can mount a cellular immune response against wasp eggs, but female wasps inject venom along with their eggs to block this immune response. Genetic variation in flies for immune resistance against wasps and genetic variation in wasps for virulence against flies largely determines the outcome of any fly-wasp interaction. Interestingly, up to 90% of the variation in fly resistance against wasp parasitism has been linked to a very simple mechanism: flies with increased constitutive blood cell (hemocyte) production are more resistant. However, this relationship has not been tested for Drosophila hosts outside of the melanogaster subgroup, nor has it been tested across a diversity of parasitoid wasp species and strains. We compared hemocyte levels in two fly species from different subgroups, D. melanogaster and D. suzukii, and found that D. suzukii constitutively produces up to five times more hemocytes than D. melanogaster. Using a panel of 24 parasitoid wasp strains representing fifteen species, four families, and multiple virulence strategies, we found that D. suzukii was significantly more resistant to wasp parasitism than D. melanogaster. Thus, our data suggest that the relationship between hemocyte production and wasp resistance is general. However, at least one sympatric wasp species was a highly successful infector of D. suzukii, suggesting specialists can overcome the general resistance afforded to hosts by excessive hemocyte production. Given that D. suzukii is an emerging agricultural pest, identification of the few parasitoid wasps that successfully infect D. suzukii may have value for biocontrol. PMID- 22529931 TI - Insight on an arginine synthesis metabolon from the tetrameric structure of yeast acetylglutamate kinase. AB - N-acetyl-L-glutamate kinase (NAGK) catalyzes the second, generally controlling, step of arginine biosynthesis. In yeasts, NAGK exists either alone or forming a metabolon with N-acetyl-L-glutamate synthase (NAGS), which catalyzes the first step and exists only within the metabolon. Yeast NAGK (yNAGK) has, in addition to the amino acid kinase (AAK) domain found in other NAGKs, a ~150-residue C terminal domain of unclear significance belonging to the DUF619 domain family. We deleted this domain, proving that it stabilizes yNAGK, slows catalysis and modulates feed-back inhibition by arginine. We determined the crystal structures of both the DUF619 domain-lacking yNAGK, ligand-free as well as complexed with acetylglutamate or acetylglutamate and arginine, and of complete mature yNAGK. While all other known arginine-inhibitable NAGKs are doughnut-like hexameric trimers of dimers of AAK domains, yNAGK has as central structure a flat tetramer formed by two dimers of AAK domains. These dimers differ from canonical AAK dimers in the -110 degrees rotation of one subunit with respect to the other. In the hexameric enzymes, an N-terminal extension, found in all arginine-inhibitable NAGKs, forms a protruding helix that interlaces the dimers. In yNAGK, however, it conforms a two-helix platform that mediates interdimeric interactions. Arginine appears to freeze an open inactive AAK domain conformation. In the complete yNAGK structure, two pairs of DUF619 domains flank the AAK domain tetramer, providing a mechanism for the DUF619 domain modulatory functions. The DUF619 domain exhibits the histone acetyltransferase fold, resembling the catalytic domain of bacterial NAGS. However, the putative acetyl CoA site is blocked, explaining the lack of NAGS activity of yNAGK. We conclude that the tetrameric architecture is an adaptation to metabolon formation and propose an organization for this metabolon, suggesting that yNAGK may be a good model also for yeast and human NAGSs. PMID- 22529930 TI - Phenotypic diversification is associated with host-induced transposon derepression in the sudden oak death pathogen Phytophthora ramorum. AB - The oomycete pathogen Phytophthora ramorum is responsible for sudden oak death (SOD) in California coastal forests. P. ramorum is a generalist pathogen with over 100 known host species. Three or four closely related genotypes of P. ramorum (from a single lineage) were originally introduced in California forests and the pathogen reproduces clonally. Because of this the genetic diversity of P. ramorum is extremely low in Californian forests. However, P. ramorum shows diverse phenotypic variation in colony morphology, colony senescence, and virulence. In this study, we show that phenotypic variation among isolates is associated with the host species from which the microbe was originally cultured. Microarray global mRNA profiling detected derepression of transposable elements (TEs) and down-regulation of crinkler effector homologs (CRNs) in the majority of isolates originating from coast live oak (Quercus agrifolia), but this expression pattern was not observed in isolates from California bay laurel (Umbellularia californica). In some instances, oak and bay laurel isolates originating from the same geographic location had identical genotypes based on multilocus simples sequence repeat (SSR) marker analysis but had different phenotypes. Expression levels of the two marker genes analyzed by quantitative reverse transcription PCR were correlated with originating host species, but not with multilocus genotypes. Because oak is a nontransmissive dead-end host for P. ramorum, our observations are congruent with an epi-transposon hypothesis; that is, physiological stress is triggered on P. ramorum while colonizing oak stems and disrupts epigenetic silencing of TEs. This then results in TE reactivation and possibly genome diversification without significant epidemiological consequences. We propose the P. ramorum-oak host system in California forests as an ad hoc model for epi transposon mediated diversification. PMID- 22529932 TI - Complete genome and transcriptomes of Streptococcus parasanguinis FW213: phylogenic relations and potential virulence mechanisms. AB - Streptococcus parasanguinis, a primary colonizer of the tooth surface, is also an opportunistic pathogen for subacute endocarditis. The complete genome of strain FW213 was determined using the traditional shotgun sequencing approach and further refined by the transcriptomes of cells in early exponential and early stationary growth phases in this study. The transcriptomes also discovered 10 transcripts encoding known hypothetical proteins, one pseudogene, five transcripts matched to the Rfam and additional 87 putative small RNAs within the intergenic regions defined by the GLIMMER analysis. The genome contains five acquired genomic islands (GIs) encoding proteins which potentially contribute to the overall pathogenic capacity and fitness of this microbe. The differential expression of the GIs and various open reading frames outside the GIs at the two growth phases suggested that FW213 possess a range of mechanisms to avoid host immune clearance, to colonize host tissues, to survive within oral biofilms and to overcome various environmental insults. Furthermore, the comparative genome analysis of five S. parasanguinis strains indicates that albeit S. parasanguinis strains are highly conserved, variations in the genome content exist. These variations may reflect differences in pathogenic potential between the strains. PMID- 22529934 TI - Designing and analyzing clinical trials with composite outcomes: consideration of possible treatment differences between the individual outcomes. AB - When the individual outcomes within a composite outcome appear to have different treatment effects, either in magnitude or direction, researchers may question the validity or appropriateness of using this composite outcome as a basis for measuring overall treatment effect in a randomized controlled trial. The question remains as to how to distinguish random variation in estimated treatment effects from important heterogeneity within a composite outcome. This paper suggests there may be some utility in directly testing the assumption of homogeneity of treatment effect across the individual outcomes within a composite outcome. We describe a treatment heterogeneity test for composite outcomes based on a class of models used for the analysis of correlated data arising from the measurement of multiple outcomes for the same individuals. Such a test may be useful in planning a trial with a primary composite outcome and at trial end with final analysis and presentation. We demonstrate how to determine the statistical power to detect composite outcome treatment heterogeneity using the POISE Trial data. Then we describe how this test may be incorporated into a presentation of trial results with composite outcomes. We conclude that it may be informative for trialists to assess the consistency of treatment effects across the individual outcomes within a composite outcome using a formalized methodology and the suggested test represents one option. PMID- 22529933 TI - Protein high-force pulling simulations yield low-force results. AB - All-atom explicit-solvent molecular dynamics simulations are used to pull with extremely large constant force (750-3000 pN) on three small proteins. The introduction of a nondimensional timescale permits direct comparison of unfolding across all forces. A crossover force of approximately 1100 pN divides unfolding dynamics into two regimes. At higher forces, residues sequentially unfold from the pulling end while maintaining the remainder of the protein force-free. Measurements of hydrodynamic viscous stresses are made easy by the high speeds of unfolding. Using an exact low-Reynolds-number scaling, these measurements can be extrapolated to provide, for the first time, an estimate of the hydrodynamic force on low-force unfolding. Below 1100 pN, but surprisingly still at extremely large applied force, intermediate states and cooperative unfoldings as seen at much lower forces are observed. The force-insensitive persistence of these structures indicates that decomposition into unfolded fragments requires a large fluctuation. This finding suggests how proteins are constructed to resist transient high force. The progression of [Formula: see text] helix and [Formula: see text] sheet unfolding is also found to be insensitive to force. The force insensitivity of key aspects of unfolding opens the possibility that numerical simulations can be accelerated by high applied force while still maintaining critical features of unfolding. PMID- 22529936 TI - An indirect cue of predation risk counteracts female preference for conspecifics in a naturally hybridizing fish Xiphophorus birchmanni. AB - Mate choice is context dependent, but the importance of current context to interspecific mating and hybridization is largely unexplored. An important influence on mate choice is predation risk. We investigated how variation in an indirect cue of predation risk, distance to shelter, influences mate choice in the swordtail Xiphophorus birchmanni, a species which sometimes hybridizes with X. malinche in the wild. We conducted mate choice experiments to determine whether females attend to the distance to shelter and whether this cue of predation risk can counteract female preference for conspecifics. Females were sensitive to shelter distance independent of male presence. When conspecific and heterospecific X. malinche males were in equally risky habitats (i.e., equally distant from shelter), females associated primarily with conspecifics, suggesting an innate preference for conspecifics. However, when heterospecific males were in less risky habitat (i.e., closer to shelter) than conspecific males, females no longer exhibited a preference, suggesting that females calibrate their mate choices in response to predation risk. Our findings illustrate the potential for hybridization to arise, not necessarily through reproductive "mistakes", but as one of many potential outcomes of a context-dependent mate choice strategy. PMID- 22529935 TI - Up-regulated expression of extracellular matrix remodeling genes in phagocytically challenged trabecular meshwork cells. AB - BACKGROUND: Cells in the trabecular meshwork (TM), the tissue responsible for draining aqueous humor out of the eye, are known to be highly phagocytic. Phagocytic function in TM cells is thought to play an important role in the normal functioning of the outflow pathway. Dysfunction of phagocytosis could lead to abnormalities of outflow resistance and increased intraocular pressure (IOP). However, the molecular mechanisms triggered by phagocytosis in TM cells are completely unknown. METHODOLOGY/PRINCIPAL FINDINGS: Gene expression profile analysis of human TM cells phagocytically challenged to E. coli or pigment under physiological and oxidative stress environment were performed using Affymetrix U133 plus 2.0 array and analyzed with Genespring GX. Despite the differential biological response elicited by E. coli and pigment particles, a number of genes, including MMP1, MMP3, TNFSF11, DIO2, KYNU, and KCCN2 showed differential expression with both phagocytic ligands in all conditions. Data was confirmed by qPCR in both human and porcine TM cells. Metacore pathway analysis and the usage of recombinant adenovirus encoding the dominant negative mutant of IkB identified NF-kappaB as a transcription factor mediating the up-regulation of at least MMP1 and MMP3 in TM cells with phagocytosis. In-gel zymography demonstrated increased collagenolytic and caseinolytic activities in the culture media of TM cells challenge to E. coli. In addition, collagenolytic I activity was further confirmed using the self-quenched fluorescent substrate DQ-Collagen I. CONCLUSIONS/SIGNIFICANCE: Here we report for the first time the differential gene expression profile of TM cells phagocytically challenged with either E. coli or pigment. Our data indicate a potential role of phagocytosis in outflow pathway tissue homeostasis through the up-regulation and/or proteolytic activation of extracellular matrix remodeling genes. PMID- 22529937 TI - RNA-seq analysis reveals that an ECF sigma factor, AcsS, regulates achromobactin biosynthesis in Pseudomonas syringae pv. syringae B728a. AB - Iron is an essential micronutrient for Pseudomonas syringae pv. syringae strain B728a and many other microorganisms; therefore, B728a has evolved methods of iron acquirement including the use of iron-chelating siderophores. In this study an extracytoplasmic function (ECF) sigma factor, AcsS, encoded within the achromobactin gene cluster is shown to be a major regulator of genes involved in the biosynthesis and secretion of this siderophore. However, production of achromobactin was not completely abrogated in the deletion mutant, implying that other regulators may be involved such as PvdS, the sigma factor that regulates pyoverdine biosynthesis. RNA-seq analysis identified 287 genes that are differentially expressed between the AcsS deletion mutant and the wild type strain. These genes are involved in iron response, secretion, extracellular polysaccharide production, and cell motility. Thus, the transcriptome analysis supports a role for AcsS in the regulation of achromobactin production and the potential activity of both AcsS and achromobactin in the plant-associated lifestyle of strain B728a. PMID- 22529938 TI - Diabetic neuropathy and axon reflex-mediated neurogenic vasodilatation in type 1 diabetes. AB - OBJECTIVE: Axon reflex-mediated neurogenic vasodilatation in response to cutaneous heating may reflect early, pre-clinical small fibre dysfunction. We aimed to evaluate the distribution of the vascular flare area measured by laser doppler imaging ("LDI(FLARE) area") in type 1 diabetes and in healthy volunteers. RESEARCH AND METHODS: Concurrent with clinical and electrophysiological examination to classify diabetic sensorimotor polyneuropathy (DSP), LDI(FLARE) area (cm(2)) was determined in 89 type 1 diabetes subjects matched to 64 healthy volunteers. We examined the association and diagnostic performance of LDI with clinical and subclinical measures of DSP and its severity. RESULTS: Compared to the 64 healthy volunteers, the 56 diabetes controls without DSP had significantly lower LDI(FLARE) area (p = 0.006). The 33 diabetes cases with DSP had substantially lower LDI(FLARE) area as compared to controls without DSP (p = 0.002). There was considerable overlap in LDI(FLARE) area between all groups such that the ROC curve had an AUC of 0.72 and optimal sensitivity of 70% for the detection of clinical DSP. Use of a subclinical definition for DSP, according to subclinical sural nerve impairment, was associated with improved AUC of 0.75 and sensitivity of 79%. In multivariate analysis higher HbA1c and body mass index had independent associations with smaller LDI(FLARE) area. CONCLUSIONS: Axon reflex mediated neurogenic vasodilatation in response to cutaneous heating is a biomarker of early nerve dysfunction in DSP. Its independent association with glycemic exposure in diabetes subjects and both glycemic exposure and BMI in healthy volunteers highlights the existence of small-fibre dysfunction in the natural history of DSP. PMID- 22529939 TI - Effect of the G375C and G346E achondroplasia mutations on FGFR3 activation. AB - Two mutations in FGFR3, G380R and G375C are known to cause achondroplasia, the most common form of human dwarfism. The G380R mutation accounts for 98% of the achondroplasia cases, and thus has been studied extensively. Here we study the effect of the G375C mutation on the phosphorylation and the cross-linking propensity of full-length FGFR3 in HEK 293 cells, and we compare the results to previously published results for the G380R mutant. We observe identical behavior of the two achondroplasia mutants in these experiments, a finding which supports a direct link between the severity of dwarfism phenotypes and the level and mechanism of FGFR3 over-activation. The mutations do not increase the cross linking propensity of FGFR3, contrary to previous expectations that the achondroplasia mutations stabilize the FGFR3 dimers. Instead, the phosphorylation efficiency within un-liganded FGFR3 dimers is increased, and this increase is likely the underlying cause for pathogenesis in achondroplasia. We further investigate the G346E mutation, which has been reported to cause achondroplasia in one case. We find that this mutation does not increase FGFR3 phosphorylation and decreases FGFR3 cross-linking propensity, a finding which raises questions whether this mutation is indeed a genetic cause for human dwarfism. PMID- 22529940 TI - Testosterone and cortisol release among Spanish soccer fans watching the 2010 World Cup final. AB - This field study investigated the release of testosterone and cortisol of a vicarious winning experience in Spanish fans watching the finals between Spain and the Netherlands in the 2010 FIFA World Cup Soccer. Spanish fans (n = 50) watched the match with friends or family in a public place or at home and also participated in a control condition. Consistent with hypotheses, results revealed that testosterone and cortisol levels were higher when watching the match than on a control day. However, neither testosterone nor cortisol levels increased after the victory of the Spanish team. Moreover, the increase in testosterone secretion was not related to participants' sex, age or soccer fandom, but the increase in total cortisol secretion during the match was higher among men than among women and among fans that were younger. Also, increases in cortisol secretion were greater to the degree that people were a stronger fan of soccer. Level of fandom further appeared to account for the sex effect, but not for the age effect. Generally, the testosterone data from this study are in line with the challenge hypothesis, as testosterone levels of watchers increased to prepare their organism to defend or enhance their social status. The cortisol data from this study are in line with social self-preservation theory, as higher cortisol secretion among young and greater soccer fans suggests that especially they perceived that a negative outcome of the match would threaten their own social esteem. PMID- 22529941 TI - Did clinical trials in which erythropoietin failed to reduce acute myocardial infarct size miss a narrow therapeutic window? AB - BACKGROUND: To test a hypothesis that in negative clinical trials of erythropoietin in patients with acute myocardial infarction (MI) the erythropoietin (rhEPO) could be administered outside narrow therapeutic window. Despite overwhelming evidence of cardioprotective properties of rhEPO in animal studies, the outcomes of recently concluded phase II clinical trials have failed to demonstrate the efficacy of rhEPO in patients with acute MI. However, the time between symptoms onset and rhEPO administration in negative clinical trials was much longer that in successful animal experiments. METHODOLOGY/PRINCIPAL FINDINGS: MI was induced in rats either by a permanent ligation of a descending coronary artery or by a 2-hr occlusion followed by a reperfusion. rhEPO, 3000 IU/kg, was administered intraperitoneally at the time of reperfusion, 4 hrs after beginning of reperfusion, or 6 hrs after permanent occlusion. MI size was measured histologically 24 hrs after coronary occlusion. The area of myocardium at risk was similar among groups. The MI size in untreated rats averaged ~42% of area at risk, or ~24% of left ventricle, and was reduced by more than 50% (p<0.001) in rats treated with rhEPO at the time of reperfusion. The MI size was not affected by treatment administered 4 hrs after reperfusion or 6 hrs after permanent coronary occlusion. Therefore, our study in a rat experimental model of MI demonstrates that rhEPO administered within 2 hrs of a coronary occlusion effectively reduces MI size, but when rhEPO was administered following a delay similar to that encountered in clinical trials, it had no effect on MI size. CONCLUSIONS/SIGNIFICANCE: The clinical trials that failed to demonstrate rhEPO efficacy in patients with MI may have missed a narrow therapeutic window defined in animal experiments. PMID- 22529942 TI - Pilot scale production of highly efficacious and stable enterovirus 71 vaccine candidates. AB - BACKGROUND: Enterovirus 71 (EV71) has caused several epidemics of hand, foot and mouth diseases (HFMD) in Asia and now is being recognized as an important neurotropic virus. Effective medications and prophylactic vaccine against EV71 infection are urgently needed. Based on the success of inactivated poliovirus vaccine, a prototype chemically inactivated EV71 vaccine candidate has been developed and currently in human phase 1 clinical trial. PRINCIPAL FINDING: In this report, we present the development of a serum-free cell-based EV71 vaccine. The optimization at each step of the manufacturing process was investigated, characterized and quantified. In the up-stream process development, different commercially available cell culture media either containing serum or serum-free was screened for cell growth and virus yield using the roller-bottle technology. VP-SFM serum-free medium was selected based on the Vero cell growth profile and EV71 virus production. After the up-stream processes (virus harvest, diafiltration and concentration), a combination of gel-filtration liquid chromatography and/or sucrose-gradient ultracentrifugation down-stream purification processes were investigated at a pilot scale of 40 liters each. Although the combination of chromatography and sucrose-gradient ultracentrifugation produced extremely pure EV71 infectious virus particles, the overall yield of vaccine was 7-10% as determined by a VP2-based quantitative ELISA. Using chromatography as the downstream purification, the virus yield was 30-43%. To retain the integrity of virus neutralization epitopes and the stability of the vaccine product, the best virus inactivation was found to be 0.025% formalin-treatment at 37 degrees C for 3 to 6 days. Furthermore, the formalin-inactivated virion vaccine candidate was found to be stable for >18 months at 4 degrees C and a microgram of viral proteins formulated with alum adjuvant could induce strong virus-neutralizing antibody responses in mice, rats, rabbits, and non-human primates. CONCLUSION: These results provide valuable information supporting the current cell-based serum-free EV71 vaccine candidate going into human Phase I clinical trials. PMID- 22529943 TI - Discovery of an auto-regulation mechanism for the maltose ABC transporter MalFGK2. AB - The maltose transporter MalFGK(2), together with the substrate-binding protein MalE, is one of the best-characterized ABC transporters. In the conventional model, MalE captures maltose in the periplasm and delivers the sugar to the transporter. Here, using nanodiscs and proteoliposomes, we instead find that MalE is bound with high-affinity to MalFGK2 to facilitate the acquisition of the sugar. When the maltose concentration exceeds the transport capacity, MalE captures maltose and dissociates from the transporter. This mechanism explains why the transport rate is high when MalE has low affinity for maltose, and low when MalE has high affinity for maltose. Transporter-bound MalE facilitates the acquisition of the sugar at low concentrations, but also captures and dissociates from the transporter past a threshold maltose concentration. In vivo, this maltose-forced dissociation limits the rate of transport. Given the conservation of the substrate-binding proteins, this mode of allosteric regulation may be universal to ABC importers. PMID- 22529944 TI - Anthrax toxin receptor 2 functions in ECM homeostasis of the murine reproductive tract and promotes MMP activity. AB - Anthrax Toxin Receptor proteins function as receptors for anthrax toxin, however physiological activity remains unclear. To evaluate the biological role of Antxr2, we generated Antxr2-/- mice. Antxr2-/- mice were viable, however Antxr2 is required for parturition in young females and for preserving fertility in older female mice. Histological analysis of the uterus and cervix revealed aberrant deposition of extracellular matrix proteins such as type I collagen, type VI collagen and fibronectin. A marked disruption of both the circular and longitudinal myometrial cell layers was evident in Antxr2-/- mice. These changes progressed as the mice aged, resulting in a thickened, collagen dense, acellular stroma and the disappearance of normal uterine architecture. To investigate the molecular mechanism underlying the uterine fibrosis we performed immunoblotting for MMP2 using uterine lysates and zymography using conditioned medium from Antxr2-/- mouse embryonic fibroblasts and found reduced levels of activated MMP2 in both. This prompted us to investigate MT1-MMP status, as MMP2 processing is regulated by MT1-MMP. We found MT1-MMP activity, as measured by MMP2 processing and activation, was enhanced by expression of either ANTXR1 or ANTXR2. We identified an ANTXR2/MT1-MMP complex and demonstrated that MT1-MMP activity is dependent on ANTXR2 expression levels in cells. Thus, we have discovered that ANTXR1 and ANTXR2 function as positive regulators of MT1-MMP activity. PMID- 22529945 TI - Use of praziquantel as an adjuvant enhances protection and Tc-17 responses to killed H5N1 virus vaccine in mice. AB - BACKGROUND: H5N1 is a highly pathogenic influenza A virus, which can cause severe illness or even death in humans. Although the widely used killed vaccines are able to provide some protection against infection via neutralizing antibodies, cytotoxic T-lymphocyte responses that are thought to eradicate viral infections are lacking. METHODOLOGY/PRINCIPAL FINDINGS: Aiming to promote cytotoxic responses against H5N1 infection, we extended our previous finding that praziquantel (PZQ) can act as an adjuvant to induce IL-17-producing CD8(+) T cells (Tc17). We found that a single immunization of 57BL/6 mice with killed viral vaccine plus PZQ induced antigen-specific Tc17 cells, some of which also secreted IFN-gamma. The induced Tc17 had cytolytic activities. Induction of these cells was impaired in CD8 knockout (KO) or IFN-gamma KO mice, and was even lower in IL-17 KO mice. Importantly, the inoculation of killed vaccine with PZQ significantly reduced virus loads in the lung tissues and prolonged survival. Protection against H5N1 virus infection was obtained by adoptively transferring PZQ-primed wild type CD8(+) T cells and this was more effective than transfer of activated IFN-gamma KO or IL-17 KO CD8(+) T cells. CONCLUSIONS/SIGNIFICANCE: Our results demonstrated that adding PZQ to killed H5N1 vaccine could promote broad Tc17-mediated cytotoxic T lymphocyte activity, resulting in improved control of highly pathogenic avian influenza virus infection. PMID- 22529947 TI - Confocal laser scanning microscopy, a new in vivo diagnostic tool for schistosomiasis. AB - BACKGROUND: The gold standard for the diagnosis of schistosomiasis is the detection of the parasite's characteristic eggs in urine, stool, or rectal and bladder biopsy specimens. Direct detection of eggs is difficult and not always possible in patients with low egg-shedding rates. Confocal laser scanning microscopy (CLSM) permits non-invasive cell imaging in vivo and is an established way of obtaining high-resolution images and 3-dimensional reconstructions. Recently, CLSM was shown to be a suitable method to visualize Schistosoma mansoni eggs within the mucosa of dissected mouse gut. In this case, we evaluated the suitability of CLSM to detect eggs of Schistosoma haematobium in a patient with urinary schistosomiasis and low egg-shedding rates. METHODOLOGY/PRINCIPAL FINDINGS: The confocal laser scanning microscope used in this study was based on a scanning laser system for imaging the retina of a living eye, the Heidelberg Retina Tomograph II, in combination with a lens system (image modality). Standard light cystoscopy was performed using a rigid cystoscope under general anaesthesia. The CLSM endoscope was then passed through the working channel of the rigid cystoscope. The mucosal tissue of the bladder was scanned using CLSM. Schistoma haematobium eggs appeared as bright structures, with the characteristic egg shape and typical terminal spine. CONCLUSION/SIGNIFICANCE: We were able to detect schistosomal eggs in the urothelium of a patient with urinary schistosomiasis. Thus, CLSM may be a suitable tool for the diagnosis of schistosomiasis in humans, especially in cases where standard diagnostic tools are not suitable. PMID- 22529946 TI - Human occupancy as a source of indoor airborne bacteria. AB - Exposure to specific airborne bacteria indoors is linked to infectious and noninfectious adverse health outcomes. However, the sources and origins of bacteria suspended in indoor air are not well understood. This study presents evidence for elevated concentrations of indoor airborne bacteria due to human occupancy, and investigates the sources of these bacteria. Samples were collected in a university classroom while occupied and when vacant. The total particle mass concentration, bacterial genome concentration, and bacterial phylogenetic populations were characterized in indoor, outdoor, and ventilation duct supply air, as well as in the dust of ventilation system filters and in floor dust. Occupancy increased the total aerosol mass and bacterial genome concentration in indoor air PM(10) and PM(2.5) size fractions, with an increase of nearly two orders of magnitude in airborne bacterial genome concentration in PM(10). On a per mass basis, floor dust was enriched in bacterial genomes compared to airborne particles. Quantitative comparisons between bacterial populations in indoor air and potential sources suggest that resuspended floor dust is an important contributor to bacterial aerosol populations during occupancy. Experiments that controlled for resuspension from the floor implies that direct human shedding may also significantly impact the concentration of indoor airborne particles. The high content of bacteria specific to the skin, nostrils, and hair of humans found in indoor air and in floor dust indicates that floors are an important reservoir of human-associated bacteria, and that the direct particle shedding of desquamated skin cells and their subsequent resuspension strongly influenced the airborne bacteria population structure in this human-occupied environment. Inhalation exposure to microbes shed by other current or previous human occupants may occur in communal indoor environments. PMID- 22529948 TI - Post-weaning protein malnutrition increases blood pressure and induces endothelial dysfunctions in rats. AB - Malnutrition during critical periods in early life may increase the subsequent risk of hypertension and metabolic diseases in adulthood, but the underlying mechanisms are still unclear. We aimed to evaluate the effects of post-weaning protein malnutrition on blood pressure and vascular reactivity in aortic rings (conductance artery) and isolated-perfused tail arteries (resistance artery) from control (fed with Labina(r)) and post-weaning protein malnutrition rats (offspring that received a diet with low protein content for three months). Systolic and diastolic blood pressure and heart rate increased in the post weaning protein malnutrition rats. In the aortic rings, reactivity to phenylephrine (10(-10)-3.10(-4) M) was similar in both groups. Endothelium removal or L-NAME (10(-4) M) incubation increased the response to phenylephrine, but the L-NAME effect was greater in the aortic rings from the post-weaning protein malnutrition rats. The protein expression of the endothelial nitric oxide isoform increased in the aortic rings from the post-weaning protein malnutrition rats. Incubation with apocynin (0.3 mM) reduced the response to phenylephrine in both groups, but this effect was higher in the post-weaning protein malnutrition rats, suggesting an increase of superoxide anion release. In the tail artery of the post-weaning protein malnutrition rats, the vascular reactivity to phenylephrine (0.001-300 ug) and the relaxation to acetylcholine (10(-10)-10(-3) M) were increased. Post-weaning protein malnutrition increases blood pressure and induces vascular dysfunction. Although the vascular reactivity in the aortic rings did not change, an increase in superoxide anion and nitric oxide was observed in the post-weaning protein malnutrition rats. However, in the resistance arteries, the increased vascular reactivity may be a potential mechanism underlying the increased blood pressure observed in this model. PMID- 22529949 TI - Relationship between Audiometric slope and tinnitus pitch in tinnitus patients: insights into the mechanisms of tinnitus generation. AB - BACKGROUND: Different mechanisms have been proposed to be involved in tinnitus generation, among them reduced lateral inhibition and homeostatic plasticity. On a perceptual level these different mechanisms should be reflected by the relationship between the individual audiometric slope and the perceived tinnitus pitch. Whereas some studies found the tinnitus pitch corresponding to the maximum hearing loss, others stressed the relevance of the edge frequency. This study investigates the relationship between tinnitus pitch and audiometric slope in a large sample. METHODOLOGY: This retrospective observational study analyzed 286 patients. The matched tinnitus pitch was compared to the frequency of maximum hearing loss and the edge of the audiogram (steepest hearing loss) by t-tests and correlation coefficients. These analyses were performed for the whole group and for sub-groups (uni- vs. bilateral (117 vs. 338 ears), pure-tone vs. narrow-band (340 vs. 115 ears), and low and high audiometric slope (114 vs. 113 ears)). FINDINGS: For the right ear, tinnitus pitch was in the same range and correlated significantly with the frequency of maximum hearing loss, but differed from and did not correlate with the edge frequency. For the left ear, similar results were found but the correlation between tinnitus pitch and maximum hearing loss did not reach significance. Sub-group analyses (bi- and unilateral, tinnitus character, slope steepness) revealed identical results except for the sub-group with high audiometric slope which revealed a higher frequency of maximum hearing loss as compared to the tinnitus pitch. CONCLUSION: The study-results confirm a relationship between tinnitus pitch and maximum hearing loss but not to the edge frequency, suggesting that tinnitus is rather a fill-in-phenomenon resulting from homeostatic mechanisms, than the result of deficient lateral inhibition. Sub group analyses suggest that audiometric steepness and the side of affected ear affect this relationship. Future studies should control for these potential confounding factors. PMID- 22529950 TI - Physical fitness and mitochondrial respiratory capacity in horse skeletal muscle. AB - BACKGROUND: Within the animal kingdom, horses are among the most powerful aerobic athletic mammals. Determination of muscle respiratory capacity and control improves our knowledge of mitochondrial physiology in horses and high aerobic performance in general. METHODOLOGY/PRINCIPAL FINDINGS: We applied high resolution respirometry and multiple substrate-uncoupler-inhibitor titration protocols to study mitochondrial physiology in small (1.0-2.5 mg) permeabilized muscle fibres sampled from triceps brachii of healthy horses. Oxidative phosphorylation (OXPHOS) capacity (pmol O(2) * s(-1) * mg(-1) wet weight) with combined Complex I and II (CI+II) substrate supply (malate+glutamate+succinate) increased from 77 +/- 18 in overweight horses to 103 +/- 18, 122 +/- 15, and 129 +/- 12 in untrained, trained and competitive horses (N = 3, 8, 16, and 5, respectively). Similar to human muscle mitochondria, equine OXPHOS capacity was limited by the phosphorylation system to 0.85 +/- 0.10 (N = 32) of electron transfer capacity, independent of fitness level. In 15 trained horses, OXPHOS capacity increased from 119 +/- 12 to 134 +/- 37 when pyruvate was included in the CI+II substrate cocktail. Relative to this maximum OXPHOS capacity, Complex I (CI)-linked OXPHOS capacities were only 50% with glutamate+malate, 64% with pyruvate+malate, and 68% with pyruvate+malate+glutamate, and ~78% with CII-linked succinate+rotenone. OXPHOS capacity with glutamate+malate increased with fitness relative to CI+II-supported ETS capacity from a flux control ratio of 0.38 to 0.40, 0.41 and 0.46 in overweight to competitive horses, whereas the CII/CI+II substrate control ratio remained constant at 0.70. Therefore, the apparent deficit of the CI- over CII-linked pathway capacity was reduced with physical fitness. CONCLUSIONS/SIGNIFICANCE: The scope of mitochondrial density-dependent OXPHOS capacity and the density-independent (qualitative) increase of CI-linked respiratory capacity with increased fitness open up new perspectives of integrative and comparative mitochondrial respiratory physiology. PMID- 22529951 TI - X-ray repair cross-complementing group 1 (XRCC1) genetic polymorphisms and risk of childhood acute lymphoblastic leukemia: a meta-analysis. AB - BACKGROUND: Recently, there have been a number of studies on the association between XRCC1 polymorphisms and childhood acute lymphoblastic leukemia (ALL) risk. However, the results of previous reports are inconsistent. Thus, we performed a meta-analysis to clarify the effects of XRCC1 variants on childhood ALL risk. METHODS: A meta-analysis was performed to examine the association between XRCC1 polymorphisms (Arg399Gln, Arg194Trp, and Arg280His) and childhood ALL risk. We critically reviewed 7 studies with a total of 880 cases and 1311 controls for Arg399Gln polymorphism, 3 studies with a total of 345 cases and 554 controls for Arg280His polymorphism, and 6 studies with a total of 783 cases and 1180 controls for Arg194Trp polymorphism, respectively. Odds ratio (OR) and its 95% confidence interval (CI) were used. RESULTS: Significant association between XRCC1 Arg399Gln polymorphism and childhood ALL risk was observed in total population analyses (OR(additive model) = 1.501, 95% CI 1.112-2.026, P(OR) = 0.008; OR(dominant model) = 1.316, 95% CI = 1.104-1.569, P(OR) = 0.002) and Asian subgroup analyses (OR(additive model) = 2.338, 95%CI = 1.254-4.359, P(OR) = 0.008; OR(dominant model) = 2.108, 95%CI = 1.498-2.967, P(OR) = 0.000). No association was detected in Caucasians, Metizo and mixed populations. Ethnicity was considered as a significant source of heterogeneity in the meta-regression model. For the other two XRCC1 polymorphisms, no association with childhood ALL risk was found. CONCLUSIONS: The meta-analysis results suggested that XRCC1 Arg399Gln polymorphism might be associated with elevated childhood ALL risk among Asian population. PMID- 22529952 TI - Maternal risk of breeding failure remained low throughout the demographic transitions in fertility and age at first reproduction in Finland. AB - Radical declines in fertility and postponement of first reproduction during the recent human demographic transitions have posed a challenge to interpreting human behaviour in evolutionary terms. This challenge has stemmed from insufficient evolutionary insight into individual reproductive decision-making and the rarity of datasets recording individual long-term reproductive success throughout the transitions. We use such data from about 2,000 Finnish mothers (first births: 1880s to 1970s) to show that changes in the maternal risk of breeding failure (no offspring raised to adulthood) underlay shifts in both fertility and first reproduction. With steady improvements in offspring survival, the expected fertility required to satisfy a low risk of breeding failure became lower and observed maternal fertility subsequently declined through an earlier age at last reproduction. Postponement of the age at first reproduction began when this risk approximated zero-even for mothers starting reproduction late. Interestingly, despite vastly differing fertility rates at different stages of the transitions, the number of offspring successfully raised to breeding per mother remained relatively constant over the period. Our results stress the importance of assessing the long-term success of reproductive strategies by including measures of offspring quality and suggest that avoidance of breeding failure may explain several key features of recent life-history shifts in industrialized societies. PMID- 22529953 TI - Genome-wide gene expression analysis implicates the immune response and lymphangiogenesis in the pathogenesis of fetal chylothorax. AB - Fetal chylothorax (FC) is a rare condition characterized by lymphocyte-rich pleural effusion. Although its pathogenesis remains elusive, it may involve inflammation, since there are increased concentrations of proinflammatory mediators in pleural fluids. Only a few hereditary lymphedema-associated gene loci, e.g. VEGFR3, ITGA9 and PTPN11, were detected in human fetuses with this condition; these cases had a poorer prognosis, due to defective lymphangiogenesis. In the present study, genome-wide gene expression analysis was conducted, comparing pleural and ascitic fluids in three hydropic fetuses, one with and two without the ITGA9 mutation. One fetus (the index case), from a dizygotic pregnancy (the cotwin was unaffected), received antenatal OK-432 pleurodesis and survived beyond the neonatal stage, despite having the ITGA9 mutation. Genes and pathways involved in the immune response were universally up regulated in fetal pleural fluids compared to those in ascitic fluids. Furthermore, genes involved in the lymphangiogenesis pathway were down-regulated in fetal pleural fluids (compared to ascitic fluid), but following OK-432 pleurodesis, they were up-regulated. Expression of ITGA9 was concordant with overall trends of lymphangiogenesis. In conclusion, we inferred that both the immune response and lymphangiogenesis were implicated in the pathogenesis of fetal chylothorax. Furthermore, genome-wide gene expression microarray analysis may facilitate personalized medicine by selecting the most appropriate treatment, according to the specific circumstances of the patient, for this rare, but heterogeneous disease. PMID- 22529954 TI - Micronutrient deficits are still public health issues among women and young children in Vietnam. AB - BACKGROUND: The 2000 Vietnamese National Nutrition Survey showed that the population's dietary intake had improved since 1987. However, inequalities were found in food consumption between socioeconomic groups. As no national data exist on the prevalence of micronutrient deficiencies, a survey was conducted in 2010 to assess the micronutrient status of randomly selected 1526 women of reproductive age and 586 children aged 6-75 mo. PRINCIPAL FINDINGS: In women, according to international thresholds, prevalence of zinc deficiency (ZnD, 67.2 +/- 2.6%) and vitamin B12 deficiency (11.7 +/- 1.7%) represented public health problems, whereas prevalence of anemia (11.6 +/- 1.0%) and iron deficiency (ID, 13.7 +/- 1.1%) were considered low, and folate (<3%) and vitamin A (VAD, <2%) deficiencies were considered negligible. However, many women had marginal folate (25.1%) and vitamin A status (13.6%). Moreover, overweight (BMI >= 23 kg/m(2) for Asian population) or underweight occurred in 20% of women respectively highlighting the double burden of malnutrition. In children, a similar pattern was observed for ZnD (51.9 +/- 3.5%), anemia (9.1 +/- 1.4%) and ID (12.9 +/- 1.5%) whereas prevalence of marginal vitamin A status was also high (47.3 +/- 2.2%). There was a significant effect of age on anemia and ID prevalence, with the youngest age group (6-17 mo) having the highest risk for anemia, ID, ZnD and marginal vitamin A status as compared to other groups. Moreover, the poorest groups of population had a higher risk for zinc, anemia and ID. CONCLUSION: The prevalence of anemia and ID in Vietnam has been markedly reduced over the last decade, but a large part of the population is still at risk for other deficiencies such as zinc, vitamin A, folate and vitamin B(12) especially the youngest children aged 6-17 mo. Consequently specific interventions to improve food diversity and quality should be implemented, among them food fortification of staple foods and condiments and improvement of complementary feeding. PMID- 22529955 TI - Primary cultures of glomerular parietal epithelial cells or podocytes with proven origin. AB - Parietal epithelial cells (PECs) are crucially involved in the pathogenesis of rapidly progressive glomerulonephritis (RPGN) as well as in focal and segmental glomerulosclerosis (FSGS). In this study, transgenic mouse lines were used to isolate pure, genetically tagged primary cultures of PECs or podocytes using FACsorting. By this approach, the morphology of primary glomerular epithelial cells in culture could be resolved: Primary podocytes formed either large cells with intracytoplasmatic extensions or smaller spindle shaped cells, depending on specific culture conditions. Primary PECs were small and exhibited a spindle shaped or polygonal morphology. In the very early phases of primary culture, rapid changes in gene expression (e.g. of WT-1 and Pax-2) were observed. However, after prolonged culture primary PECs and podocytes still segregated clearly in a transcriptome analysis--demonstrating that the origin of primary cell cultures is important. Of the classical markers, synaptopodin and podoplanin expression were differentially regulated the most in primary PEC and podocyte cultures. However, no expression of any endogenous gene allowed to differentiate between the two cell types in culture. Finally, we show that the transcription factor WT1 is also expressed by PECs. In summary, genetic tagging of PECs and podocytes is a novel and necessary tool to derive pure primary cultures with proven origin. These cultures will be a powerful tool for the emerging field of parietal epithelial cell biology. PMID- 22529956 TI - Insights into the mechanism of bovine CD38/NAD+glycohydrolase from the X-ray structures of its Michaelis complex and covalently-trapped intermediates. AB - Bovine CD38/NAD(+)glycohydrolase (bCD38) catalyses the hydrolysis of NAD(+) into nicotinamide and ADP-ribose and the formation of cyclic ADP-ribose (cADPR). We solved the crystal structures of the mono N-glycosylated forms of the ecto-domain of bCD38 or the catalytic residue mutant Glu218Gln in their apo state or bound to aFNAD or rFNAD, two 2'-fluorinated analogs of NAD(+). Both compounds behave as mechanism-based inhibitors, allowing the trapping of a reaction intermediate covalently linked to Glu218. Compared to the non-covalent (Michaelis) complex, the ligands adopt a more folded conformation in the covalent complexes. Altogether these crystallographic snapshots along the reaction pathway reveal the drastic conformational rearrangements undergone by the ligand during catalysis with the repositioning of its adenine ring from a solvent-exposed position stacked against Trp168 to a more buried position stacked against Trp181. This adenine flipping between conserved tryptophans is a prerequisite for the proper positioning of the N1 of the adenine ring to perform the nucleophilic attack on the C1' of the ribofuranoside ring ultimately yielding cADPR. In all structures, however, the adenine ring adopts the most thermodynamically favorable anti conformation, explaining why cyclization, which requires a syn conformation, remains a rare alternate event in the reactions catalyzed by bCD38 (cADPR represents only 1% of the reaction products). In the Michaelis complex, the substrate is bound in a constrained conformation; the enzyme uses this ground state destabilization, in addition to a hydrophobic environment and desolvation of the nicotinamide-ribosyl bond, to destabilize the scissile bond leading to the formation of a ribooxocarbenium ion intermediate. The Glu218 side chain stabilizes this reaction intermediate and plays another important role during catalysis by polarizing the 2'-OH of the substrate NAD(+). Based on our structural analysis and data on active site mutants, we propose a detailed analysis of the catalytic mechanism. PMID- 22529957 TI - Tuftsin promotes an anti-inflammatory switch and attenuates symptoms in experimental autoimmune encephalomyelitis. AB - Multiple sclerosis (MS) is a demyelinating autoimmune disease mediated by infiltration of T cells into the central nervous system after compromise of the blood-brain barrier. We have previously shown that administration of tuftsin, a macrophage/microglial activator, dramatically improves the clinical course of experimental autoimmune encephalomyelitis (EAE), a well-established animal model for MS. Tuftsin administration correlates with upregulation of the immunosuppressive Helper-2 T cell (Th2) cytokine transcription factor GATA-3. We now show that tuftsin-mediated microglial activation results in shifting microglia to an anti-inflammatory phenotype. Moreover, the T cell phenotype is shifted towards immunoprotection after exposure to tuftsin-treated activated microglia; specifically, downregulation of pro-inflammatory Th1 responses is triggered in conjunction with upregulation of Th2-specific responses and expansion of immunosuppressive regulatory T cells (Tregs). Finally, tuftsin shifted T cells, delivered into animals via adoptive transfer, reverse the pathology observed in mice with established EAE. Taken together, our findings demonstrate that tuftsin decreases the proinflammatory environment of EAE and may represent a therapeutic opportunity for treatment of MS. PMID- 22529958 TI - A selection index for gene expression evolution and its application to the divergence between humans and chimpanzees. AB - The importance of gene regulation in animal evolution is a matter of long standing interest, but measuring the impact of selection on gene expression has proven a challenge. Here, we propose a selection index of gene expression as a straightforward method for assessing the mode and strength of selection operating on gene expression levels. The index is based on the widely used McDonald Kreitman test and requires the estimation of four quantities: the within-species and between-species expression variances as well as the sequence heterozygosity and divergence of neutrally evolving sequences. We apply the method to data from human and chimpanzee lymphoblastoid cell lines and show that gene expression is in general under strong stabilizing selection. We also demonstrate how the same framework can be used to estimate the proportion of adaptive gene expression evolution. PMID- 22529959 TI - A meta-analysis of probiotic efficacy for gastrointestinal diseases. AB - BACKGROUND: Meta-analyses on the effects of probiotics on specific gastrointestinal diseases have generally shown positive effects on disease prevention and treatment; however, the relative efficacy of probiotic use for treatment and prevention across different gastrointestinal diseases, with differing etiology and mechanisms of action, has not been addressed. METHODS/PRINCIPAL FINDINGS: We included randomized controlled trials in humans that used a specified probiotic in the treatment or prevention of Pouchitis, Infectious diarrhea, Irritable Bowel Syndrome, Helicobacter pylori, Clostridium difficile Disease, Antibiotic Associated Diarrhea, Traveler's Diarrhea, or Necrotizing Enterocolitis. Random effects models were used to evaluate efficacy as pooled relative risks across the eight diseases as well as across probiotic species, single vs. multiple species, patient ages, dosages, and length of treatment. Probiotics had a positive significant effect across all eight gastrointestinal diseases with a relative risk of 0.58 (95% (CI) 0.51-0.65). Six of the eight diseases: Pouchitis, Infectious diarrhea, Irritable Bowel Syndrome, Helicobacter pylori, Clostridium difficile Disease, and Antibiotic Associated Diarrhea, showed positive significant effects. Traveler's Diarrhea and Necrotizing Enterocolitis did not show significant effects of probiotcs. Of the 11 species and species mixtures, all showed positive significant effects except for Lactobacillus acidophilus, Lactobacillus plantarum, and Bifidobacterium infantis. Across all diseases and probiotic species, positive significant effects of probiotics were observed for all age groups, single vs. multiple species, and treatment lengths. CONCLUSIONS/SIGNIFICANCE: Probiotics are generally beneficial in treatment and prevention of gastrointestinal diseases. Efficacy was not observed for Traveler's Diarrhea or Necrotizing Enterocolitis or for the probiotic species L. acidophilus, L. plantarum, and B. infantis. When choosing to use probiotics in the treatment or prevention of gastrointestinal disease, the type of disease and probiotic species (strain) are the most important factors to take into consideration. PMID- 22529960 TI - Molecular-phylogenetic characterization of the microbiota in ulcerated and non ulcerated regions in the patients with Crohn's disease. AB - BACKGROUND: The dysbiosis of intestinal microbiota has been established in Crohn's disease (CD), but the molecular characterization of this dysbiosis in Chinese subjects with CD remains unclear. This study aims to investigate the predominant bacterial composition of the faecal and mucosal-associated microbiota in Chinese CD patients using culture-independent techniques. METHODS/PRINCIPAL FINDINGS: Eighteen patients with CD and 9 healthy controls were included in this study. The faeces and the intestinal mucosal tissues from the ulcerated and nonulcerated sites were subjected to bacterial community fingerprinting using denaturing gradient gel electrophoresis (DGGE). The predominant bacterial composition in the faeces and mucosa was determined with DNA sequencing and BLAST. We showed that the bacterial diversity in the faeces of CD patients was reduced compared with that in healthy controls (p<0.01). The faecal bacterial dysbiosis of the patients was characterized by an elevated abundance of gamma Proteobacteria (especially Escherichia coli and Shigella flexneri) and a reduced proportion of Bacteroidetes and Firmicutes. Five bacterial species defined the microbiota imbalance of the ulcerated mucosa in CD, including an increase in Escherichia coli, a decrease in Faecalibacterium prausnitzii, Lactobacillus coleohominis, Bacteroides sp and Streptococcus gallolyticus in the bacterial community as compared with the nonulcerated (p<0.01). CONCLUSIONS/SIGNIFICANCE: This is the first description of intestinal microbiota dysbiosis in Chinese CD patients. These results allow a better understanding of the faecal and mucosal microbiota in CD, showing a predominance of some opportunistic pathogenic bacteria and a decrease in beneficial bacterial species. The findings may provide novel insights into the pathogenesis of CD in Chinese population. PMID- 22529961 TI - Myosin light chain kinase mediates intestinal barrier disruption following burn injury. AB - BACKGROUND: Severe burn injury results in the loss of intestinal barrier function, however, the underlying mechanism remains unclear. Myosin light chain (MLC) phosphorylation mediated by MLC kinase (MLCK) is critical to the pathophysiological regulation of intestinal barrier function. We hypothesized that the MLCK-dependent MLC phosphorylation mediates the regulation of intestinal barrier function following burn injury, and that MLCK inhibition attenuates the burn-induced intestinal barrier disfunction. METHODOLOGY/PRINCIPAL FINDINGS: Male balb/c mice were assigned randomly to either sham burn (control) or 30% total body surface area (TBSA) full thickness burn without or with intraperitoneal injection of ML-9 (2 mg/kg), an MLCK inhibitor. In vivo intestinal permeability to fluorescein isothiocyanate (FITC)-dextran was measured. Intestinal mucosa injury was assessed histologically. Tight junction proteins ZO-1, occludin and claudin-1 was analyzed by immunofluorescent assay. Expression of MLCK and phosphorylated MLC in ileal mucosa was assessed by Western blot. Intestinal permeability was increased significantly after burn injury, which was accompanied by mucosa injury, tight junction protein alterations, and increase of both MLCK and MLC phosphorylation. Treatment with ML-9 attenuated the burn-caused increase of intestinal permeability, mucosa injury, tight junction protein alterations, and decreased MLC phosphorylation, but not MLCK expression. CONCLUSIONS/SIGNIFICANCE: The MLCK-dependent MLC phosphorylation mediates intestinal epithelial barrier dysfunction after severe burn injury. It is suggested that MLCK-dependent MLC phosphorylation may be a critical target for the therapeutic treatment of intestinal epithelial barrier disruption after severe burn injury. PMID- 22529962 TI - Pentraxin 3 (PTX3) expression in allergic asthmatic airways: role in airway smooth muscle migration and chemokine production. AB - BACKGROUND: Pentraxin 3 (PTX3) is a soluble pattern recognition receptor with non redundant functions in inflammation and innate immunity. PTX3 is produced by immune and structural cells. However, very little is known about the expression of PTX3 and its role in allergic asthma. OBJECTIVES AND METHODS: We sought to determine the PTX3 expression in asthmatic airways and its function in human airway smooth muscle cells (HASMC). In vivo PTX3 expression in bronchial biopsies of mild, moderate and severe asthmatics was analyzed by immunohistochemistry. PTX3 mRNA and protein were measured by real-time RT-PCR and ELISA, respectively. Proliferation and migration were examined using (3)H-thymidine incorporation, cell count and Boyden chamber assays. RESULTS: PTX3 immunoreactivity was increased in bronchial tissues of allergic asthmatics compared to healthy controls, and mainly localized in the smooth muscle bundle. PTX3 protein was expressed constitutively by HASMC and was significantly up-regulated by TNF, and IL-1beta but not by Th2 (IL-4, IL-9, IL-13), Th1 (IFN-gamma), or Th-17 (IL-17) cytokines. In vitro, HASMC released significantly higher levels of PTX3 at the baseline and upon TNF stimulation compared to airway epithelial cells (EC). Moreover, PTX3 induced CCL11/eotaxin-1 release whilst inhibited the fibroblast growth factor-2 (FGF-2)-driven HASMC chemotactic activity. CONCLUSIONS: Our data provide the first evidence that PTX3 expression is increased in asthmatic airways. HASMC can both produce and respond to PTX3. PTX3 is a potent inhibitor of HASMC migration induced by FGF-2 and can upregulate CCL11/eotaxin-1 release. These results raise the possibility that PTX3 may play a dual role in allergic asthma. PMID- 22529963 TI - Staphylococcal Panton-Valentine leukocidin induces pro-inflammatory cytokine production and nuclear factor-kappa B activation in neutrophils. AB - Panton-Valentine leukocidin (PVL) is a cytotoxin secreted by Staphylococcus aureus and associated with severe necrotizing infections. PVL targets polymorphonuclear leukocytes, especially neutrophils, which are the first line of defense against infections. Although PVL can induce neutrophil death by necrosis or apoptosis, the specific inflammatory responses of neutrophils to this toxin are unclear. In this study, both in vivo and in vitro studies demonstrated that recombinant PVL has an important cytotoxic role in human neutrophils, leading to apoptosis at low concentrations and necrosis at high concentrations. Recombinant PVL also increased the levels of pro-inflammatory cytokine secretion from neutrophils. The up-regulation of pro-inflammatory cytokines was due to nuclear factor-kappa B (NF-kappaB) activation induced by PVL. Moreover, blocking NF kappaB inhibited the production of inflammatory cytokines. To test the role of neutrophil immune responses during the pathogenesis of PVL-induced acute lung injury, we used immunocompetent or neutropenic rabbits to develop a model of necrotizing pneumonia. Immunocompetent rabbits challenged with PVL demonstrated increased inflammation containing neutrophilic infiltrates. In addition, there were elevated levels of inflammatory cytokines (IL-6, IL-8, TNF-alpha and IL-10) and NF-kappaB in the lung homogenate. In contrast, the lung tissues from neutropenic rabbits contained mild or moderate inflammation, and the levels of inflammatory cytokines and NF-kappaB increased only slightly. Data from the current study support growing evidence that neutrophils play an important role in the pathogenesis of PVL-induced tissue injury and inflammation. PVL can stimulate neutrophils to release pro-inflammatory mediators, thereby causing an acute inflammatory response. The ability of PVL to induce inflammatory cytokine release may be associated with the activation of NF-kappaB or its pore-forming properties. PMID- 22529964 TI - High and persistent HIV seroincidence in men who have sex with men across 47 U.S. cities. AB - OBJECTIVE: To provide HIV seroincidence data among men who have sex with men (MSM) in the United States and to identify predictive factors for seroconversion. METHODS: From 1998-2002, 4684 high-risk MSM, age 18-60 years, participated in a randomized, placebo-controlled HIV vaccine efficacy trial at 56 U.S. clinical trial sites. Demographics, behavioral data, and HIV status were assessed at baseline and 6 month intervals. Since no overall vaccine efficacy was detected, data were combined from both trial arms to calculate HIV incidence based on person-years (py) of follow-up. Predictors of seroconversion, adjusted hazards ratio (aHR), were evaluated using a Cox proportional hazard model with time varying covariates. RESULTS: Overall, HIV incidence was 2.7/100 py and was relatively uniform across study sites and study years. HIV incidence was highest among young men and men reporting unprotected sex, recreational drug use, and a history of a sexually transmitted infection. Independent predictors of HIV seroconversion included: age 18-30 years (aHR = 2.4; 95% CI 1.4,4.0), having >10 partners (aHR = 2.4; 95% CI 1.7,3.3), having a known HIV-positive male sex partner (aHR = 1.6; 95% CI 1.2, 2.0), unprotected anal intercourse with HIV positive/unknown male partners (aHR = 1.7; 95% CI 1.3, 2.3), and amphetamine (aHR = 1.6; 95% CI 1.1, 2.1) and popper (aHR = 1.7; 95% CI 1.3, 2.2) use. CONCLUSIONS: HIV seroincidence was high among MSM despite repeated HIV counseling and reported declines in sexual risk behaviors. Continuing development of new HIV prevention strategies and intensification of existing efforts will be necessary to reduce the rate of new HIV infections, especially among young men. PMID- 22529965 TI - Regulation of chemokine and chemokine receptor expression by PPARgamma in adipocytes and macrophages. AB - BACKGROUND: PPARgamma plays a key role in adipocyte biology, and Rosiglitazone (Rosi), a thiazolidinedione (TZD)/PPARgamma agonist, is a potent insulin sensitizing agent. Recent evidences demonstrate that adipose tissue inflammation links obesity with insulin resistance and that the insulin-sensitizing effects of TZDs result, in part, from their anti-inflammatory properties. However the underlying mechanisms are unclear. METHODOLOGY AND PRINCIPAL FINDINGS: In this study, we establish a link between free fatty acids (FFAs) and PPARgamma in the context of obesity-associated inflammation. We show that treatment of adipocytes with FFAs, in particular Arachidonic Acid (ARA), downregulates PPARgamma protein and mRNA levels. Furthermore, we demonstrate that the downregulation of PPARgamma by ARA requires the activation the of Endoplamsic Reticulum (ER) stress by the TLR4 pathway. Knockdown of adipocyte PPARgamma resulted in upregulation of MCP1 gene expression and secretion, leading to enhanced macrophage chemotaxis. Rosi inhibited these effects. In a high fat feeding mouse model, we show that Rosi treatment decreases recruitment of proinflammatory macrophages to epididymal fat. This correlates with decreased chemokine and decreased chemokine receptor expression in adipocytes and macrophages, respectively. CONCLUSIONS AND SIGNIFICANCE: In summary, we describe a novel link between FAs, the TLR4/ER stress pathway and PPARgamma, and adipocyte-driven recruitment of macrophages. We thus both describe an additional potential mechanism for the anti-inflammatory and insulin-sensitizing actions of TZDs and an additional detrimental property associated with the activation of the TLR4 pathway by FA. PMID- 22529966 TI - The Q705K polymorphism in NLRP3 is a gain-of-function alteration leading to excessive interleukin-1beta and IL-18 production. AB - BACKGROUND: The Q705K polymorphism in NLRP3 has been implicated in several chronic inflammatory diseases. In this study we determine the functional role of this commonly occurring polymorphism using an in-vitro system. PRINCIPAL FINDINGS: NLRP3-WT and NLRP3-Q705K were retrovirally transduced into the human monocytic cell line THP-1, followed by the assessment of IL-1beta and IL-18 levels in the cell culture supernatant. THP-1 cells expressing the above NLRP3 variants were sorted based upon Green Fluorescent Protein (GFP) expression. Cytokine response to alum (one of the most widely used adjuvants in vaccines) in the cells stably expressing NLRP3-WT and NLRP3-Q705K were determined. IL-1beta and IL-18 levels were found to be elevated in THP-1 cells transduced with NLRP3 Q705K compared to the NLRP3-WT. Upon exposure to alum, THP-1 cells stably expressing NLRP3-Q705K displayed an increased release of IL-1beta, IL-18 and TNF alpha, in a caspase-1 and IL-1 receptor-dependent manner. CONCLUSIONS: Collectively, these findings show that the Q705K polymorphism in NLRP3 is a gain of-function alteration leading to an overactive NLRP3 inflammasome. The option of IL-1beta blockade may be considered in patients with chronic inflammatory disorders that are unresponsive to conventional treatments. PMID- 22529967 TI - Toward a global phylogeny of the "living fossil" crustacean order of the Notostraca. AB - Tadpole shrimp (Crustacea, Notostraca) are iconic inhabitants of temporary aquatic habitats worldwide. Often cited as prime examples of evolutionary stasis, surviving representatives closely resemble fossils older than 200 mya, suggestive of an ancient origin. Despite significant interest in the group as 'living fossils' the taxonomy of surviving taxa is still under debate and both the phylogenetic relationships among different lineages and the timing of diversification remain unclear. We constructed a molecular phylogeny of the Notostraca using model based phylogenetic methods. Our analyses supported the monophyly of the two genera Triops and Lepidurus, although for Triops support was weak. Results also revealed high levels of cryptic diversity as well as a peculiar biogeographic link between Australia and North America presumably mediated by historic long distance dispersal. We concluded that, although some present day tadpole shrimp species closely resemble fossil specimens as old as 250 mya, no molecular support was found for an ancient (pre) Mesozoic radiation. Instead, living tadpole shrimp are most likely the result of a relatively recent radiation in the Cenozoic era and close resemblances between recent and fossil taxa are probably the result of the highly conserved general morphology in this group and of homoplasy. PMID- 22529968 TI - Functional dissection of SseF, a membrane-integral effector protein of intracellular Salmonella enterica. AB - During intracellular life, the bacterial pathogen Salmonella enterica translocates a complex cocktail of effector proteins by means of the SPI2-encoded type III secretions system. The effectors jointly modify the endosomal system and vesicular transport in host cells. SseF and SseG are two effectors encoded by genes within Salmonella Pathogenicity Island 2 and both effector associate with endosomal membranes and microtubules and are involved in the formation of Salmonella-induced filaments. Our previous deletional analyses identified protein domains of SseF required for the effector function. Here we present a detailed mutational analysis that identifies a short hydrophobic motif as functionally essential. We demonstrate that SseF and SseG are still functional if translocated as a single fusion protein, but also mediate effector function if translocated in cells co-infected with sseF and sseG strains. SseF has characteristics of an integral membrane protein after translocation into host cells. PMID- 22529969 TI - TGF-beta1 exerts opposing effects on grass carp leukocytes: implication in teleost immunity, receptor signaling and potential self-regulatory mechanisms. AB - In fish immunity, the regulatory role of transforming growth factor-beta1 (TGF beta1) has not been fully characterized. Here we examined the immunoregulatory effects of TGF-beta1 in grass carp peripheral blood leukocytes (PBL) and head kidney leukocytes (HKL). It is interesting that TGF-beta1 consistently stimulated the cell viability and the mRNA levels of pro-inflammatory cytokines (Tnfalpha and Ifngamma) and T/B cell markers [Cd4-like (Cd4l), Cd8alpha, Cd8beta and IgMU] in PBL, which contrasted with its inhibitory tone in HKL. Further studies showed that grass carp TGF-beta1 type I receptor, activin receptor-like kinase 5 (ALK5), was indispensable for the immunoregulatory effects of TGF-beta1 in PBL and HKL. Notably, TGF-beta1 persistently attenuated ALK5 expression, whereas immunoneutralization of endogenous grass carp TGF-beta1 could increase ALK5 mRNA and protein levels. It is consistent with the observation that TGF-beta1 decreased the number of ALK5(+) leukocytes in PBL and HKL, revealing a negative regulation of TGF-beta1 signaling at the receptor level. Moreover, transient treatment with TGF-beta1 for 24 h was sufficient to induce similar cellular responses compared with the continuous treatment. This indicated a possible mechanism by which TGF-beta1 triggered the down-regulation of ALK5 mRNA and protein, leading to the desensitization of grass carp leukocytes toward TGF beta1. Accordingly, our data revealed a dual role of TGF-beta1 in teleost immunity in which it can serve as a positive or negative control device and provided additional mechanistic insights as to how TGF-beta1 controls its signaling in vertebrate leukocytes. PMID- 22529970 TI - Integrated ratio of metastatic to examined lymph nodes and number of metastatic lymph nodes into the AJCC staging system for colon cancer. AB - OBJECTIVE: At present, only the number of metastatic lymph nodes (LNs+) is used for the pN category of AJCC TNM system for colon cancer. Recently, the ratio of metastatic to examined lymph nodes (LNR) has been reported to represent powerful independent predictive capacity in colon cancer. We sought to propose a novel category (nLN) which intergrades LNR and LNs+ into the AJCC staging system for colon cancer. DESIGN: 34476 patients from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) dataset with stage III colon cancer were reviewed. Harrell's C statistic was used to evaluate the predictive capacity. The Cox proportional hazards model was used to construct a novel category. RESULTS: The LNR category had more predictive capacity than the pN category in whole groups of patients (Harrell's C index: 0.6194 vs 0.6113, p = 0.003). Subgroup analysis showed that the LNR category was not better than pN category in predictive capacity if the number of lymph nodes examined was more than 13. We also found that there was significant survival heterogeneity among different pN categories at the same LNR category (P<0.001). The Harrell's C index for our nLN category which intergrades LNR and LNs+ was 0.6228, which was significant higher than that of the pN category (Harrell's C index: 0.6113, P<0.001) or LNR category (Harrell's C index: 0.6194, P = 0.005), respectively. CONCLUSION: To evaluate the prognosis of colon cancer, our nLN category which intergrades LNR with LNs+ is more accurate than the pN category or LNR category, respectively. PMID- 22529971 TI - MAPK signaling determines anxiety in the juvenile mouse brain but depression-like behavior in adults. AB - MAP kinase signaling has been implicated in brain development, long-term memory, and the response to antidepressants. Inducible Braf knockout mice, which exhibit protein depletion in principle forebrain neurons, enabled us to unravel a new role of neuronal MAPK signaling for emotional behavior. Braf mice that were induced during adulthood showed normal anxiety but increased depression-like behavior, in accordance with pharmacological findings. In contrast, the inducible or constitutive inactivation of Braf in the juvenile brain leads to normal depression-like behavior but decreased anxiety in adults. In juvenile, constitutive mutants we found no alteration of GABAergic neurotransmission but reduced neuronal arborization in the dentate gyrus. Analysis of gene expression in the hippocampus revealed nine downregulated MAPK target genes that represent candidates to cause the mutant phenotype.Our results reveal the differential function of MAPK signaling in juvenile and adult life phases and emphasize the early postnatal period as critical for the determination of anxiety in adults. Moreover, these results validate inducible gene inactivation as a new valuable approach, allowing it to discriminate between gene function in the adult and the developing postnatal brain. PMID- 22529972 TI - Functional analysis of alleged NOGGIN mutation G92E disproves its pathogenic relevance. AB - We identified an amino acid change (p.G92E) in the Bone Morphogenetic Protein antagonist NOGGIN in a 22-month-old boy who presented with a unilateral brachydactyly type B phenotype. Brachydactyly type B is a skeletal malformation that has been associated with increased Bone Morphogenetic Protein pathway activation in other patients. Previously, the amino acid change p.G92E in NOGGIN was described as causing fibrodysplasia ossificans progressiva, a rare genetic disorder characterized by limb malformations and progressive heterotopic bone formation in soft tissues that, like Brachydactyly type B, is caused by increased activation of Bone Morphogenetic Protein signaling. To determine whether G92E NOGGIN shows impaired antagonism that could lead to increased Bone Morphogenetic Protein signaling, we performed functional assays to evaluate inhibition of BMP signaling. Interestingly, wt-NOGGIN shows different inhibition efficacies towards various Bone Morphogenetic Proteins that are known to be essential in limb development. However, comparing the biological activity of G92E-NOGGIN with wt NOGGIN, we observed that G92E-NOGGIN inhibits activation of bone morphogenetic protein signaling with equal efficiency as wt-NOGGIN, supporting that G92E-NOGGIN does not cause pathological effects. Genetic testing of the child's parents revealed the same amino acid change in the healthy father, further supporting that p.G92E is a neutral amino acid substitution in NOGGIN. We conclude that p.G92E represents a rare polymorphism of the NOGGIN gene-- causing neither brachydactyly nor fibrodysplasia ossificans progressiva. This study highlights that a given genetic variation should not be considered pathogenic unless supported by functional analyses. PMID- 22529973 TI - Flexibility of a eukaryotic lipidome--insights from yeast lipidomics. AB - Mass spectrometry-based shotgun lipidomics has enabled the quantitative and comprehensive assessment of cellular lipid compositions. The yeast Saccharomyces cerevisiae has proven to be a particularly valuable experimental system for studying lipid-related cellular processes. Here, by applying our shotgun lipidomics platform, we investigated the influence of a variety of commonly used growth conditions on the yeast lipidome, including glycerophospholipids, triglycerides, ergosterol as well as complex sphingolipids. This extensive dataset allowed for a quantitative description of the intrinsic flexibility of a eukaryotic lipidome, thereby providing new insights into the adjustments of lipid biosynthetic pathways. In addition, we established a baseline for future lipidomic experiments in yeast. Finally, flexibility of lipidomic features is proposed as a new parameter for the description of the physiological state of an organism. PMID- 22529974 TI - Docosahexaenoic acid inhibits Helicobacter pylori growth in vitro and mice gastric mucosa colonization. AB - H. pylori drug-resistant strains and non-compliance to therapy are the major causes of H. pylori eradication failure. For some bacterial species it has been demonstrated that fatty acids have a growth inhibitory effect. Our main aim was to assess the ability of docosahexaenoic acid (DHA) to inhibit H. pylori growth both in vitro and in a mouse model. The effectiveness of standard therapy (ST) in combination with DHA on H. pylori eradication and recurrence prevention success was also investigated. The effects of DHA on H. pylori growth were analyzed in an in vitro dose-response study and n in vivo model. We analized the ability of H. pylori to colonize mice gastric mucosa following DHA, ST or a combination of both treatments. Our data demonstrate that DHA decreases H. pylori growth in vitro in a dose-dependent manner. Furthermore, DHA inhibits H. pylori gastric colonization in vivo as well as decreases mouse gastric mucosa inflammation. Addition of DHA to ST was also associated with lower H. pylori infection recurrence in the mouse model. In conclusion, DHA is an inhibitor of H. pylori growth and its ability to colonize mouse stomach. DHA treatment is also associated with a lower recurrence of H. pylori infection in combination with ST. These observations pave the way to consider DHA as an adjunct agent in H. pylori eradication treatment. PMID- 22529975 TI - Modulation of human muscle spindle discharge by arterial pulsations--functional effects and consequences. AB - Arterial pulsations are known to modulate muscle spindle firing; however, the physiological significance of such synchronised modulation has not been investigated. Unitary recordings were made from 75 human muscle spindle afferents innervating the pretibial muscles. The modulation of muscle spindle discharge by arterial pulsations was evaluated by R-wave triggered averaging and power spectral analysis. We describe various effects arterial pulsations may have on muscle spindle afferent discharge. Afferents could be "driven" by arterial pulsations, e.g., showing no other spontaneous activity than spikes generated with cardiac rhythmicity. Among afferents showing ongoing discharge that was not primarily related to cardiac rhythmicity we illustrate several mechanisms by which individual spikes may become phase-locked. However, in the majority of afferents the discharge rate was modulated by the pulse wave without spikes being phase locked. Then we assessed whether these influences changed in two physiological conditions in which a sustained increase in muscle sympathetic nerve activity was observed without activation of fusimotor neurones: a maximal inspiratory breath-hold, which causes a fall in systolic pressure, and acute muscle pain, which causes an increase in systolic pressure. The majority of primary muscle spindle afferents displayed pulse-wave modulation, but neither apnoea nor pain had any significant effect on the strength of this modulation, suggesting that the physiological noise injected by the arterial pulsations is robust and relatively insensitive to fluctuations in blood pressure. Within the afferent population there was a similar number of muscle spindles that were inhibited and that were excited by the arterial pulse wave, indicating that after signal integration at the population level, arterial pulsations of opposite polarity would cancel each other out. We speculate that with close-to-threshold stimuli the arterial pulsations may serve as an endogenous noise source that may synchronise the sporadic discharge within the afferent population and thus facilitate the detection of weak stimuli. PMID- 22529976 TI - Reference gene selection for quantitative real-time PCR normalization in Quercus suber. AB - The use of reverse transcription quantitative PCR technology to assess gene expression levels requires an accurate normalization of data in order to avoid misinterpretation of experimental results and erroneous analyses. Despite being the focus of several transcriptomics projects, oaks, and particularly cork oak (Quercus suber), have not been investigated regarding the identification of reference genes suitable for the normalization of real-time quantitative PCR data. In this study, ten candidate reference genes (Act, CACs, EF-1alpha, GAPDH, His3, PsaH, Sand, PP2A, beta-Tub and Ubq) were evaluated to determine the most stable internal reference for quantitative PCR normalization in cork oak. The transcript abundance of these genes was analysed in several tissues of cork oak, including leaves, reproduction cork, and periderm from branches at different developmental stages (1-, 2-, and 3-year old) or collected in different dates (active growth period versus dormancy). The three statistical methods (geNorm, NormFinder, and CV method) used in the evaluation of the most suitable combination of reference genes identified Act and CACs as the most stable candidates when all the samples were analysed together, while beta-Tub and PsaH showed the lowest expression stability. However, when different tissues, developmental stages, and collection dates were analysed separately, the reference genes exhibited some variation in their expression levels. In this study, and for the first time, we have identified and validated reference genes in cork oak that can be used for quantification of target gene expression in different tissues and experimental conditions and will be useful as a starting point for gene expression studies in other oaks. PMID- 22529978 TI - GRP78 knockdown enhances apoptosis via the down-regulation of oxidative stress and Akt pathway after epirubicin treatment in colon cancer DLD-1 cells. AB - INTRODUCTION: The 78-kDa glucose-regulated protein (GRP78) is induced in the cancer microenvironment and can be considered as a novel predictor of responsiveness to chemotherapy in many cancers. In this study, we found that intracellular reactive oxygen species (ROS) and nuclear factor erythroid 2 related factor 2 (Nrf2) nuclear translocation were higher in GRP78 knockdown DLD 1 colon cancer cells compared with scrambled control cells. METHODOLOGY/PRINCIPAL FINDINGS: Treatment with epirubicin in GRP78 knockdown DLD-1 cells enhanced apoptosis and was associated with decreased production of intracellular ROS. In addition, apoptosis was increased by the antioxidants propyl gallate (PG) and dithiothreitol (DTT) in epirubicin-treated scrambled control cells. Epirubicin treated GRP78 knockdown cells resulted in more inactivated Akt pathway members, such as phosphorylated Akt and GSK-3beta, as well as downstream targets of beta catenin expression. Knockdown of Nrf2 with small interfering RNA (siRNA) increased apoptosis in epirubicin-treated GRP78 knockdown cells, which suggested that Nrf2 may be a primary defense mechanism in GRP78 knockdown cells. We also demonstrated that epirubicin-treated GRP78 knockdown cells could decrease survival pathway signaling through the redox activation of protein phosphatase 2A (PP2A), which is a serine/threonine phosphatase that negatively regulates the Akt pathway. CONCLUSIONS: Our results indicate that epirubicin decreased the intracellular ROS in GRP78 knockdown cells, which decreased survival signaling through both the Akt pathway and the activation of PP2A. Together, these mechanisms contributed to the enhanced level of epirubicin-induced apoptosis that was observed in the GRP78 knockdown cells. PMID- 22529979 TI - Proliferation of hydroelectric dams in the Andean Amazon and implications for Andes-Amazon connectivity. AB - Due to rising energy demands and abundant untapped potential, hydropower projects are rapidly increasing in the Neotropics. This is especially true in the wet and rugged Andean Amazon, where regional governments are prioritizing new hydroelectric dams as the centerpiece of long-term energy plans. However, the current planning for hydropower lacks adequate regional and basin-scale assessment of potential ecological impacts. This lack of strategic planning is particularly problematic given the intimate link between the Andes and Amazonian flood plain, together one of the most species rich zones on Earth. We examined the potential ecological impacts, in terms of river connectivity and forest loss, of the planned proliferation of hydroelectric dams across all Andean tributaries of the Amazon River. Considering data on the full portfolios of existing and planned dams, along with data on roads and transmission line systems, we developed a new conceptual framework to estimate the relative impacts of all planned dams. There are plans for 151 new dams greater than 2 MW over the next 20 years, more than a 300% increase. These dams would include five of the six major Andean tributaries of the Amazon. Our ecological impact analysis classified 47% of the potential new dams as high impact and just 19% as low impact. Sixty percent of the dams would cause the first major break in connectivity between protected Andean headwaters and the lowland Amazon. More than 80% would drive deforestation due to new roads, transmission lines, or inundation. We conclude with a discussion of three major policy implications of these findings. 1) There is a critical need for further strategic regional and basin scale evaluation of dams. 2) There is an urgent need for a strategic plan to maintain Andes-Amazon connectivity. 3) Reconsideration of hydropower as a low-impact energy source in the Neotropics. PMID- 22529980 TI - Agreement among health care professionals in diagnosing case Vignette-based surgical site infections. AB - OBJECTIVE: To assess agreement in diagnosing surgical site infection (SSI) among healthcare professionals involved in SSI surveillance. METHODS: Case-vignette study done in 2009 in 140 healthcare professionals from seven specialties (20 in each specialty, Anesthesiologists, Surgeons, Public health specialists, Infection control physicians, Infection control nurses, Infectious diseases specialists, Microbiologists) in 29 University and 36 non-University hospitals in France. We developed 40 case-vignettes based on cardiac and gastrointestinal surgery patients with suspected SSI. Each participant scored six randomly assigned case vignettes before and after reading the SSI definition on an online secure relational database. The intraclass correlation coefficient (ICC) was used to assess agreement regarding SSI diagnosis on a seven-point Likert scale and the kappa coefficient to assess agreement for superficial or deep SSI on a three point scale. RESULTS: Based on a consensus, SSI was present in 21 of 40 vignettes (52.5%). Intraspecialty agreement for SSI diagnosis ranged across specialties from 0.15 (95% confidence interval, 0.00-0.59) (anesthesiologists and infection control nurses) to 0.73 (0.32-0.90) (infectious diseases specialists). Reading the SSI definition improved agreement in the specialties with poor initial agreement. Intraspecialty agreement for superficial or deep SSI ranged from 0.10 (-0.19-0.38) to 0.54 (0.25-0.83) (surgeons) and increased after reading the SSI definition only among the infection control nurses from 0.10 (-0.19-0.38) to 0.41 (-0.09-0.72). Interspecialty agreement for SSI diagnosis was 0.36 (0.22-0.54) and increased to 0.47 (0.31-0.64) after reading the SSI definition. CONCLUSION: Among healthcare professionals evaluating case-vignettes for possible surgical site infection, there was large disagreement in diagnosis that varied both between and within specialties. PMID- 22529982 TI - Generosity pays in the presence of direct reciprocity: a comprehensive study of 2 * 2 repeated games. AB - By applying a technique previously developed to study ecosystem assembly [Capitan et al., Phys. Rev. Lett. 103, 168101 (2009)] we study the evolutionary stable strategies of iterated 2 * 2 games. We focus on memory-one strategies, whose probability to play a given action depends on the actions of both players in the previous time step. We find the asymptotically stable populations resulting from all possible invasions of any known stable population. The results of this invasion process are interpreted as transitions between different populations that occur with a certain probability. Thus the whole process can be described as a Markov chain whose states are the different stable populations. With this approach we are able to study the whole space of symmetric 2 * 2 games, characterizing the most probable results of evolution for the different classes of games. Our analysis includes quasi-stationary mixed equilibria that are relevant as very long-lived metastable states and is compared to the predictions of a fixation probability analysis. We confirm earlier results on the success of the Pavlov strategy in a wide range of parameters for the iterated Prisoner's Dilemma, but find that as the temptation to defect grows there are many other possible successful strategies. Other regions of the diagram reflect the equilibria structure of the underlying one-shot game, albeit often some non expected strategies arise as well. We thus provide a thorough analysis of iterated 2 * 2 games from which we are able to extract some general conclusions. Our most relevant finding is that a great deal of the payoff parameter range can still be understood by focusing on win-stay, lose-shift strategies, and that very ambitious ones, aspiring to obtaining always a high payoff, are never evolutionary stable. PMID- 22529981 TI - Alzheimer's disease-linked mutations in presenilin-1 result in a drastic loss of activity in purified gamma-secretase complexes. AB - BACKGROUND: Mutations linked to early onset, familial forms of Alzheimer's disease (FAD) are found most frequently in PSEN1, the gene encoding presenilin-1 (PS1). Together with nicastrin (NCT), anterior pharynx-defective protein 1 (APH1), and presenilin enhancer 2 (PEN2), the catalytic subunit PS1 constitutes the core of the gamma-secretase complex and contributes to the proteolysis of the amyloid precursor protein (APP) into amyloid-beta (Abeta) peptides. Although there is a growing consensus that FAD-linked PS1 mutations affect Abeta production by enhancing the Abeta1-42/Abeta1-40 ratio, it remains unclear whether and how they affect the generation of APP intracellular domain (AICD). Moreover, controversy exists as to how PS1 mutations exert their effects in different experimental systems, by either increasing Abeta1-42 production, decreasing Abeta1-40 production, or both. Because it could be explained by the heterogeneity in the composition of gamma-secretase, we purified to homogeneity complexes made of human NCT, APH1aL, PEN2, and the pathogenic PS1 mutants L166P, DeltaE9, or P436Q. METHODOLOGY/PRINCIPAL FINDINGS: We took advantage of a mouse embryonic fibroblast cell line lacking PS1 and PS2 to generate different stable cell lines overexpressing human gamma-secretase complexes with different FAD-linked PS1 mutations. A multi-step affinity purification procedure was used to isolate semi purified or highly purified gamma-secretase complexes. The functional characterization of these complexes revealed that all PS1 FAD-linked mutations caused a loss of gamma-secretase activity phenotype, in terms of Abeta1-40, Abeta1-42 and APP intracellular domain productions in vitro. CONCLUSION/SIGNIFICANCE: Our data support the view that PS1 mutations lead to a strong gamma-secretase loss-of-function phenotype and an increased Abeta1 42/Abeta1-40 ratio, two mechanisms that are potentially involved in the pathogenesis of Alzheimer's disease. PMID- 22529977 TI - Seasonal changes in patterns of gene expression in avian song control brain regions. AB - Photoperiod and hormonal cues drive dramatic seasonal changes in structure and function of the avian song control system. Little is known, however, about the patterns of gene expression associated with seasonal changes. Here we address this issue by altering the hormonal and photoperiodic conditions in seasonally breeding Gambel's white-crowned sparrows and extracting RNA from the telencephalic song control nuclei HVC and RA across multiple time points that capture different stages of growth and regression. We chose HVC and RA because while both nuclei change in volume across seasons, the cellular mechanisms underlying these changes differ. We thus hypothesized that different genes would be expressed between HVC and RA. We tested this by using the extracted RNA to perform a cDNA microarray hybridization developed by the SoNG initiative. We then validated these results using qRT-PCR. We found that 363 genes varied by more than 1.5 fold (>log(2) 0.585) in expression in HVC and/or RA. Supporting our hypothesis, only 59 of these 363 genes were found to vary in both nuclei, while 132 gene expression changes were HVC specific and 172 were RA specific. We then assigned many of these genes to functional categories relevant to the different mechanisms underlying seasonal change in HVC and RA, including neurogenesis, apoptosis, cell growth, dendrite arborization and axonal growth, angiogenesis, endocrinology, growth factors, and electrophysiology. This revealed categorical differences in the kinds of genes regulated in HVC and RA. These results show that different molecular programs underlie seasonal changes in HVC and RA, and that gene expression is time specific across different reproductive conditions. Our results provide insights into the complex molecular pathways that underlie adult neural plasticity. PMID- 22529983 TI - Glioblastoma therapy with cytotoxic mesenchymal stromal cells optimized by bioluminescence imaging of tumor and therapeutic cell response. AB - Genetically modified adipose tissue derived mesenchymal stromal cells (hAMSCs) with tumor homing capacity have been proposed for localized therapy of chemo- and radiotherapy resistant glioblastomas. We demonstrate an effective procedure to optimize glioblastoma therapy based on the use of genetically modified hAMSCs and in vivo non invasive monitoring of tumor and therapeutic cells. Glioblastoma U87 cells expressing Photinus pyralis luciferase (Pluc) were implanted in combination with hAMSCs expressing a trifunctional Renilla reniformis luciferase-red fluorescent protein-thymidine kinase reporter in the brains of SCID mice that were subsequently treated with ganciclovir (GCV). The resulting optimized therapy was effective and monitoring of tumor cells by bioluminescence imaging (BLI) showed that after 49 days GCV treatment reduced significantly the hAMSC treated tumors; by a factor of 10(4) relative to controls. Using a Pluc reporter regulated by an endothelial specific promoter and in vivo BLI to image hAMSC differentiation we gained insight on the therapeutic mechanism. Implanted hAMSCs homed to tumor vessels, where they differentiated to endothelial cells. We propose that the tumor killing efficiency of genetically modified hAMSCs results from their association with the tumor vascular system and should be useful vehicles to deliver localized therapy to glioblastoma surgical borders following tumor resection. PMID- 22529985 TI - Transmission dynamics of the recently-identified BYD virus causing duck egg-drop syndrome. AB - Baiyangdian (BYD) virus is a recently-identified mosquito-borne flavivirus that causes severe disease in ducks, with extremely rapid transmission, up to 15% mortality within 10 days and 90% reduction in egg production on duck farms within 5 days of infection. Because of the zoonotic nature of flaviviruses, the characterization of BYD virus and its epidemiology are important public health concerns. Here, we develop a mathematical model for the transmission dynamics of this novel virus. We validate the model against BYD outbreak data collected from duck farms in Southeast China, as well as experimental data obtained from an animal facility. Based on our model, the basic reproductive number of BYD virus is high (R(0) = 21) indicating that this virus is highly transmissible, consistent with the dramatic epidemiology observed in BYDV-affected duck farms. Our results indicate that younger ducks are more vulnerable to BYD disease and that ducks infected with BYD virus reduce egg production (to about 33% on average) for about 3 days post-infection; after 3 days infected ducks are no longer able to produce eggs. Using our model, we predict that control measures which reduce contact between mosquitoes and ducks such as mosquito nets are more effective than insecticides. PMID- 22529984 TI - Unique profile of ordered arrangements of repetitive elements in the C57BL/6J mouse genome implicating their functional roles. AB - The entirety of all protein coding sequences is reported to represent a small fraction (~2%) of the mouse and human genomes; the vast majority of the rest of the genome is presumed to be repetitive elements (REs). In this study, the C57BL/6J mouse reference genome was subjected to an unbiased RE mining to establish a whole-genome profile of RE occurrence and arrangement. The C57BL/6J mouse genome was fragmented into an initial set of 5,321 units of 0.5 Mb, and surveyed for REs using unbiased self-alignment and dot-matrix protocols. The survey revealed that individual chromosomes had unique profiles of RE arrangement structures, named RE arrays. The RE populations in certain genomic regions were arranged into various forms of complexly organized structures using combinations of direct and/or inverse repeats. Some of these RE arrays spanned stretches of over 2 Mb, which may contribute to the structural configuration of the respective genomic regions. There were substantial differences in RE density among the 21 chromosomes, with chromosome Y being the most densely populated. In addition, the RE array population in the mouse chromosomes X and Y was substantially different from those of the reference human chromosomes. Conversion of the dot-matrix data pertaining to a tandem 13-repeat structure within the Ch7.032 genome unit into a line map of known REs revealed a repeat unit of ~11.3 Kb as a mosaic of six different RE types. The data obtained from this study allowed for a comprehensive RE profiling, including the establishment of a library of RE arrays, of the reference mouse genome. Some of these RE arrays may participate in a spectrum of normal and disease biology that are specific for mice. PMID- 22529986 TI - Methylcap-seq reveals novel DNA methylation markers for the diagnosis and recurrence prediction of bladder cancer in a Chinese population. AB - PURPOSE: There is a need to supplement or supplant the conventional diagnostic tools, namely, cystoscopy and B-type ultrasound, for bladder cancer (BC). We aimed to identify novel DNA methylation markers for BC through genome-wide profiling of BC cell lines and subsequent methylation-specific PCR (MSP) screening of clinical urine samples. EXPERIMENTAL DESIGN: The methyl-DNA binding domain (MBD) capture technique, methylCap/seq, was performed to screen for specific hypermethylated CpG islands in two BC cell lines (5637 and T24). The top one hundred hypermethylated targets were sequentially screened by MSP in urine samples to gradually narrow the target number and optimize the composition of the diagnostic panel. The diagnostic performance of the obtained panel was evaluated in different clinical scenarios. RESULTS: A total of 1,627 hypermethylated promoter targets in the BC cell lines was identified by Illumina sequencing. The top 104 hypermethylated targets were reduced to eight genes (VAX1, KCNV1, ECEL1, TMEM26, TAL1, PROX1, SLC6A20, and LMX1A) after the urine DNA screening in a small sample size of 8 normal control and 18 BC subjects. Validation in an independent sample of 212 BC patients enabled the optimization of five methylation targets, including VAX1, KCNV1, TAL1, PPOX1, and CFTR, which was obtained in our previous study, for BC diagnosis with a sensitivity and specificity of 88.68% and 87.25%, respectively. In addition, the methylation of VAX1 and LMX1A was found to be associated with BC recurrence. CONCLUSIONS: We identified a promising diagnostic marker panel for early non-invasive detection and subsequent BC surveillance. PMID- 22529988 TI - Detoxification center-based sampling missed a subgroup of higher risk drug users, a case from Guangdong, China. AB - BACKGROUND: Injection drug use remains among the most important HIV transmission risk in China. Representativeness of drug users sampled from detoxification centers is questionable. A respondent driven sampling survey was conducted to compare the results with those from the detoxification center in the same city. METHODS: In 2008, two independent surveys were conducted in Dongguan, China, one for community-based drug users using respondent driven sampling and the other for drug users in a compulsory detoxification center as routine sentinel surveillance. Demographic and behavioral information were collected using the same structured questionnaire. Intravenous blood samples were collected to measure antibodies to HIV-1, and syphilis. RESULTS: Compared to those 400 drug users recruited from the detoxification center, the 303 community-based drug users had higher HIV prevalence (14.7% versus 4.0%, P = 0.04), lower syphilis prevalence (4.7% versus 10.8%, P = 0.07), higher proportion of injection drug use (83.9% versus 60.2%, P = 0.01) and syringe sharing (47.8% versus 36.3%, P = 0.10), more likely to be separated (12.4% versus 3.8%, P = 0.01) and being migrants from Guangxi province (31.4% versus 18.0%, P = 0.09), more engaging in commercial sex (64.4% versus 52.5%, P = 0.04). HIV prevalence and rate of syringe sharing were consistently higher among drug users from Guangxi. CONCLUSIONS: Detoxification center-based sampling missed a subgroup with higher HIV prevalence and higher rate of injection drug use. While detoxification center-based sampled can be used to monitor the trend of HIV prevalence and risk behaviors over time, periodic community-based sampling is still necessary to avoid possible systematic error in detoxification center-based samples. PMID- 22529987 TI - Respective prognostic value of genomic grade and histological proliferation markers in early stage (pN0) breast carcinoma. AB - BACKGROUND: Genomic grade (GG) is a 97-gene signature which improves the accuracy and prognostic value of histological grade (HG) in invasive breast carcinoma. Since most of the genes included in the GG are involved in cell proliferation, we performed a retrospective study to compare the prognostic value of GG, Mitotic Index and Ki67 score. METHODS: A series of 163 consecutive breast cancers was retained (pT1-2, pN0, pM0, 10-yr follow-up). GG was computed using MapQuant Dx(R). RESULTS: GG was low (GG-1) in 48%, high (GG-3) in 31% and equivocal in 21% of cases. For HG-2 tumors, 50% were classified as GG-1, 18% as GG-3 whereas 31% remained equivocal. In a subgroup of 132 ER+/HER2- tumors GG was the most significant prognostic factor in multivariate Cox regression analysis adjusted for age and tumor size (HR = 5.23, p = 0.02). CONCLUSIONS: In a reference comprehensive cancer center setting, compared to histological grade, GG added significant information on cell proliferation in breast cancers. In patients with HG-2 carcinoma, applying the GG to guide the treatment scheme could lead to a reduction in adjuvant therapy prescription. However, based on the results observed and considering (i) the relatively close prognostic values of GG and Ki67, (ii) the reclassification of about 30% of HG-2 tumors as Equivocal GG and (iii) the economical and technical requirements of the MapQuant micro-array GG test, the availability in the near future of a PCR-based Genomic Grade test with improved performances may lead to an introduction in clinical routine of this test for histological grade 2, ER positive, HER2 negative breast carcinoma. PMID- 22529989 TI - A dynamic real time in vivo and static ex vivo analysis of granulomonocytic cell migration in the collagen-induced arthritis model. AB - Neutrophilic granulocytes and monocytes (granulomonocytic cells; GMC) drive the inflammatory process at the earliest stages of rheumatoid arthritis (RA). The migratory behavior and functional properties of GMC within the synovial tissue are, however, only incompletely characterized. Here we have analyzed GMC in the murine collagen-induced arthritis (CIA) model of RA using multi-photon real time in vivo microscopy together with ex vivo analysis of GMC in tissue sections.GMC were abundant as soon as clinical arthritis was apparent. GMC were motile and migrated randomly through the synovial tissue. In addition, we observed the frequent formation of cell clusters consisting of both neutrophilic granulocytes and monocytes that actively contributed to the inflammatory process of arthritis. Treatment of animals with a single dose of prednisolone reduced the mean velocity of cell migration and diminished the overall immigration of GMC.In summary, our study shows that the combined application of real time in vivo microscopy together with elaborate static post-mortem analysis of GMC enables the description of dynamic migratory characteristics of GMC together with their precise location in a complex anatomical environment. Moreover, this approach is sensitive enough to detect subtle therapeutic effects within a very short period of time. PMID- 22529990 TI - Sharing more than friendship--nasal colonization with coagulase-positive staphylococci (CPS) and co-habitation aspects of dogs and their owners. AB - BACKGROUND: Since the relationship between dogs and their owners has changed, and dogs moved from being working dogs to family members in post-industrial countries, we hypothesized that zoonotic transmission of opportunistic pathogens like coagulase positive staphylococci (CPS) is likely between dogs and their owners. METHODOLOGY/PRINCIPAL FINDINGS: CPS- nasal carriage, different aspects of human-to-dog relationship as well as potential interspecies transmission risk factors were investigated by offering nasal swabs and a questionnaire to dog owners (108) and their dogs (108) at a dog show in 2009. S. aureus was found in swabs of 20 (18.5%) humans and two dogs (1.8%), and spa types which correspond to well known human S. aureus lineages dominated (e.g. CC45, CC30 and CC22). Multilocus sequence typing (MLST) of the two canine strains revealed ST72 and ST2065 (single locus variant of ST34). Fifteen dogs (13.9%) and six owners (5.6%) harboured S. pseudintermedius, including one mecA-positive human isolate (MRSP). Pulsed field gel electrophoresis (PFGE) revealed that one dog/owner pair harboured indistinguishable S. pseudintermedius- isolates of ST33. Ten (48%) of the 21 S. pseudintermedius-isolates showed resistance towards more than one antimicrobial class. 88.9% of the dog owners reported to allow at least one dog into the house, 68.5% allow the dog(s) to rest on the sofa, 39.8% allow their dogs to come onto the bed, 93.5% let them lick their hands and 52.8% let them lick their face. Bivariate analysis of putative risk factors revealed that dog owners who keep more than two dogs have a significantly higher chance of being colonized with S. pseudintermedius than those who keep 1-2 dogs (p<0.05). CONCLUSIONS/RECOMMENDATIONS: In conclusion, CPS transmission between dog owners and their dogs is possible. Further investigation regarding interspecies transmission and the diverse adaptive pathways influencing the epidemiology of CPS (including MRSA and MRSP) in different hosts is needed. PMID- 22529991 TI - Enhancement of cell-based therapeutic angiogenesis using a novel type of injectable scaffolds of hydroxyapatite-polymer nanocomposite microspheres. AB - BACKGROUND: Clinical trials demonstrate the effectiveness of cell-based therapeutic angiogenesis in patients with severe ischemic diseases; however, their success remains limited. Maintaining transplanted cells in place are expected to augment the cell-based therapeutic angiogenesis. We have reported that nano-hydroxyapatite (HAp) coating on medical devices shows marked cell adhesiveness. Using this nanotechnology, HAp-coated poly(l-lactic acid) (PLLA) microspheres, named nano-scaffold (NS), were generated as a non-biological, biodegradable and injectable cell scaffold. We investigate the effectiveness of NS on cell-based therapeutic angiogenesis. METHODS AND RESULTS: Bone marrow mononuclear cells (BMNC) and NS or control PLLA microspheres (LA) were intramuscularly co-implanted into mice ischemic hindlimbs. When BMNC derived from enhanced green fluorescent protein (EGFP)-transgenic mice were injected into ischemic muscle, the muscle GFP level in NS+BMNC group was approximate fivefold higher than that in BMNC or LA+BMNC groups seven days after operation. Kaplan Meier analysis demonstrated that NS+BMNC markedly prevented hindlimb necrosis (P<0.05 vs. BMNC or LA+BMNC). NS+BMNC revealed much higher induction of angiogenesis in ischemic tissues and collateral blood flow confirmed by three dimensional computed tomography angiography than those of BMNC or LA+BMNC groups. NS-enhanced therapeutic angiogenesis and arteriogenesis showed good correlations with increased intramuscular levels of vascular endothelial growth factor and fibroblast growth factor-2. NS co-implantation also prevented apoptotic cell death of transplanted cells, resulting in prolonged cell retention. CONCLUSION: A novel and feasible injectable cell scaffold potentiates cell-based therapeutic angiogenesis, which could be extremely useful for the treatment of severe ischemic disorders. PMID- 22529992 TI - Mycobacterium tuberculosis Rv3586 (DacA) is a diadenylate cyclase that converts ATP or ADP into c-di-AMP. AB - Cyclic diguanosine monophosphate (c-di-GMP) and cyclic diadenosine monophosphate (c-di-AMP) are recently identified signaling molecules. c-di-GMP has been shown to play important roles in bacterial pathogenesis, whereas information about c-di AMP remains very limited. Mycobacterium tuberculosis Rv3586 (DacA), which is an ortholog of Bacillus subtilis DisA, is a putative diadenylate cyclase. In this study, we determined the enzymatic activity of DacA in vitro using high performance liquid chromatography (HPLC), mass spectrometry (MS) and thin layer chromatography (TLC). Our results showed that DacA was mainly a diadenylate cyclase, which resembles DisA. In addition, DacA also exhibited residual ATPase and ADPase in vitro. Among the potential substrates tested, DacA was able to utilize both ATP and ADP, but not AMP, pApA, c-di-AMP or GTP. By using gel filtration and analytical ultracentrifugation, we further demonstrated that DacA existed as an octamer, with the N-terminal domain contributing to tetramerization and the C-terminal domain providing additional dimerization. Both the N-terminal and the C-terminal domains were essential for the DacA's enzymatically active conformation. The diadenylate cyclase activity of DacA was dependent on divalent metal ions such as Mg(2+), Mn(2+) or Co(2+). DacA was more active at a basic pH rather than at an acidic pH. The conserved RHR motif in DacA was essential for interacting with ATP, and mutation of this motif to AAA completely abolished DacA's diadenylate cyclase activity. These results provide the molecular basis for designating DacA as a diadenylate cyclase. Our future studies will explore the biological function of this enzyme in M. tuberculosis. PMID- 22529994 TI - Local and landscape factors determining occurrence of phyllostomid bats in tropical secondary forests. AB - Neotropical forests are being increasingly replaced by a mosaic of patches of different successional stages, agricultural fields and pasture lands. Consequently, the identification of factors shaping the performance of taxa in anthropogenic landscapes is gaining importance, especially for taxa playing critical roles in ecosystem functioning. As phyllostomid bats provide important ecological services through seed dispersal, pollination and control of animal populations, in this study we assessed the relationships between phyllostomid occurrence and the variation in local and landscape level habitat attributes caused by disturbance. We mist-netted phyllostomids in 12 sites representing 4 successional stages of a tropical dry forest (initial, early, intermediate and late). We also quantitatively characterized the habitat attributes at the local (vegetation structure complexity) and the landscape level (forest cover, area and diversity of patches). Two focal scales were considered for landscape characterization: 500 and 1000 m. During 142 sampling nights, we captured 606 individuals representing 15 species and 4 broad guilds. Variation in phyllostomid assemblages, ensembles and populations was associated with variation in local and landscape habitat attributes, and this association was scale-dependent. Specifically, we found a marked guild-specific response, where the abundance of nectarivores tended to be negatively associated with the mean area of dry forest patches, while the abundance of frugivores was positively associated with the percentage of riparian forest. These results are explained by the prevalence of chiropterophilic species in the dry forest and of chiropterochorous species in the riparian forest. Our results indicate that different vegetation classes, as well as a multi-spatial scale approach must be considered for evaluating bat response to variation in landscape attributes. Moreover, for the long-term conservation of phyllostomids in anthropogenic landscapes, we must realize that the management of the habitat at the landscape level is as important as the conservation of particular forest fragments. PMID- 22529993 TI - Propylthiouracil is teratogenic in murine embryos. AB - BACKGROUND: Hyperthyroidism during pregnancy is treated with the antithyroid drugs (ATD) propylthiouracil (PTU) and methimazole (MMI). PTU currently is recommended as the drug of choice during early pregnancy. Yet, despite widespread ATD use in pregnancy, formal studies of ATD teratogenic effects have not been performed. METHODS: We examined the teratogenic effects of PTU and MMI during embryogenesis in mice. To span different periods of embryogenesis, dams were treated with compounds or vehicle daily from embryonic day (E) 7.5 to 9.5 or from E3.5 to E7.5. Embryos were examined for gross malformations at E10.5 or E18.5 followed by histological and micro-CT analysis. Influences of PTU on gene expression levels were examined by RNA microarray analysis. RESULTS: When dams were treated from E7.5 to E9.5 with PTU, neural tube and cardiac abnormalities were observed at E10.5. Cranial neural tube defects were significantly more common among the PTU-exposed embryos than those exposed to MMI or vehicle. Blood in the pericardial sac, which is a feature indicative of abnormal cardiac function and/or abnormal vasculature, was observed more frequently in PTU-treated than MMI-treated or vehicle-treated embryos. Following PTU treatment, a total of 134 differentially expressed genes were identified. Disrupted genetic pathways were those associated with cytoskeleton remodeling and keratin filaments. At E 18.5, no gross malformations were evident in either ATD group, but the number of viable PTU embryos per dam at E18.5 was significantly lower from those at E10.5, indicating loss of malformed embryos. These data show that PTU exposure during embryogenesis is associated with delayed neural tube closure and cardiac abnormalities. In contrast, we did not observe structural or cardiac defects associated with MMI exposure except at the higher dose. We find that PTU exposure during embryogenesis is associated with fetal loss. These observations suggest that PTU has teratogenic potential. PMID- 22529996 TI - Cardiac myosin binding protein C and MAP-kinase activating death domain containing gene polymorphisms and diastolic heart failure. AB - OBJECTIVE: Myosin binding protein C (MYBPC3) plays a role in ventricular relaxation. The aim of the study was to investigate the association between cardiac myosin binding protein C (MYBPC3) gene polymorphisms and diastolic heart failure (DHF) in a human case-control study. METHODS: A total of 352 participants of 1752 consecutive patients from the National Taiwan University Hospital and its affiliated hospital were enrolled. 176 patients diagnosed with DHF confirmed by echocardiography were recruited. Controls were matched 1-to-1 by age, sex, hypertension, diabetes, renal function and medication use. We genotyped 12 single nucleotide polymorphisms (SNPs) according to HapMap Han Chinese Beijing databank across a 40 kb genetic region containing the MYBPC3 gene and the neighboring DNA sequences to capture 100% of haplotype variance in all SNPs with minor allele frequencies >= 5%. We also analyzed associations of these tagging SNPs and haplotypes with DHF and linkage disequilibrium (LD) structure of the MYBPC3 gene. RESULTS: In a single locus analysis, SNP rs2290149 was associated with DHF (allele-specific p = 0.004; permuted p = 0.031). The SNP with a minor allele frequency of 9.4%, had an odds ratio 2.14 (95% CI 1.25-3.66; p = 0.004) for the additive model and 2.06 for the autosomal dominant model (GG+GA : AA, 95% CI 1.17 3.63; p = 0.013), corresponding to a population attributable risk fraction of 12.02%. The haplotypes in a LD block of rs2290149 (C-C-G-C) was also significantly associated with DHF (odds ratio 2.10 (1.53-2.89); permuted p = 0.029). CONCLUSIONS: We identified a SNP (rs2290149) among the tagging SNP set that was significantly associated with early DHF in a Chinese population. PMID- 22529995 TI - Iron accumulation in deep cortical layers accounts for MRI signal abnormalities in ALS: correlating 7 tesla MRI and pathology. AB - Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by cortical and spinal motor neuron dysfunction. Routine magnetic resonance imaging (MRI) studies have previously shown hypointense signal in the motor cortex on T(2)-weighted images in some ALS patients, however, the cause of this finding is unknown. To investigate the utility of this MR signal change as a marker of cortical motor neuron degeneration, signal abnormalities on 3T and 7T MR images of the brain were compared, and pathology was obtained in two ALS patients to determine the origin of the motor cortex hypointensity. Nineteen patients with clinically probable or definite ALS by El Escorial criteria and 19 healthy controls underwent 3T MRI. A 7T MRI scan was carried out on five ALS patients who had motor cortex hypointensity on the 3T FLAIR sequence and on three healthy controls. Postmortem 7T MRI of the brain was performed in one ALS patient and histological studies of the brains and spinal cords were obtained post-mortem in two patients. The motor cortex hypointensity on 3T FLAIR images was present in greater frequency in ALS patients. Increased hypointensity correlated with greater severity of upper motor neuron impairment. Analysis of 7T T(2)(*) weighted gradient echo imaging localized the signal alteration to the deeper layers of the motor cortex in both ALS patients. Pathological studies showed increased iron accumulation in microglial cells in areas corresponding to the location of the signal changes on the 3T and 7T MRI of the motor cortex. These findings indicate that the motor cortex hypointensity on 3T MRI FLAIR images in ALS is due to increased iron accumulation by microglia. PMID- 22529997 TI - DNA aptamers against the Lup an 1 food allergen. AB - Using in vitro selection, high affinity DNA aptamers to the food allergen Lup an 1, beta-conglutin, were selected from a pool of DNA, 93 bases in length, containing a randomised sequence of 49 bases. beta-conglutin was purified from lupin flour and chemically crosslinked to carboxylated magnetic beads. Peptide mass fingerprinting was used to confirm the presence of the beta-conglutin. Single stranded DNA was generated from the randomised pool using T7 Gene 6 Exonuclease and was subsequently incubated with the magnetic beads and the captured DNA was released and amplified prior to a further round of Systematic Evolution of Ligands by Exponential Enrichment (SELEX). Evolution was monitored using enzyme linked oligonucleotide assay and surface plasmon resonance. Once a plateau in evolution was reached, the isolated DNA sequences were cloned and sequenced. The consensus motif was identified via alignment of the sequences and the affinities of these sequences for immobilised beta-conglutin were determined using surface plasmon resonance. The selected aptamer was demonstrated to be highly specific, showing no cross-reactivity with other flour ingredients or with other conglutin fractions of lupin. The secondary structures of the selected aptamers were predicted using m-fold. Finally, the functionality of the selected aptamers was demonstrated using a competitive assay for the quantitative detection of beta-conglutin. . Future work will focus on structure elucidation and truncation of the selected sequences to generate a smaller aptamer for application to the analysis of the Lup an 1 allergen in foodstuffs. PMID- 22529998 TI - Symbiodinium transcriptomes: genome insights into the dinoflagellate symbionts of reef-building corals. AB - Dinoflagellates are unicellular algae that are ubiquitously abundant in aquatic environments. Species of the genus Symbiodinium form symbiotic relationships with reef-building corals and other marine invertebrates. Despite their ecologic importance, little is known about the genetics of dinoflagellates in general and Symbiodinium in particular. Here, we used 454 sequencing to generate transcriptome data from two Symbiodinium species from different clades (clade A and clade B). With more than 56,000 assembled sequences per species, these data represent the largest transcriptomic resource for dinoflagellates to date. Our results corroborate previous observations that dinoflagellates possess the complete nucleosome machinery. We found a complete set of core histones as well as several H3 variants and H2A.Z in one species. Furthermore, transcriptome analysis points toward a low number of transcription factors in Symbiodinium spp. that also differ in the distribution of DNA-binding domains relative to other eukaryotes. In particular the cold shock domain was predominant among transcription factors. Additionally, we found a high number of antioxidative genes in comparison to non-symbiotic but evolutionary related organisms. These findings might be of relevance in the context of the role that Symbiodinium spp. play as coral symbionts.Our data represent the most comprehensive dinoflagellate EST data set to date. This study provides a comprehensive resource to further analyze the genetic makeup, metabolic capacities, and gene repertoire of Symbiodinium and dinoflagellates. Overall, our findings indicate that Symbiodinium possesses some unique characteristics, in particular the transcriptional regulation in Symbiodinium may differ from the currently known mechanisms of eukaryotic gene regulation. PMID- 22529999 TI - Role of direct repeat and stem-loop motifs in mtDNA deletions: cause or coincidence? AB - Deletion mutations within mitochondrial DNA (mtDNA) have been implicated in degenerative and aging related conditions, such as sarcopenia and neuro degeneration. While the precise molecular mechanism of deletion formation in mtDNA is still not completely understood, genome motifs such as direct repeat (DR) and stem-loop (SL) have been observed in the neighborhood of deletion breakpoints and thus have been postulated to take part in mutagenesis. In this study, we have analyzed the mitochondrial genomes from four different mammals: human, rhesus monkey, mouse and rat, and compared them to randomly generated sequences to further elucidate the role of direct repeat and stem-loop motifs in aging associated mtDNA deletions. Our analysis revealed that in the four species, DR and SL structures are abundant and that their distributions in mtDNA are not statistically different from randomized sequences. However, the average distance between the reported age associated mtDNA breakpoints and their respective nearest DR motifs is significantly shorter than what is expected of random chance in human (p<10(-4)) and rhesus monkey (p = 0.0034), but not in mouse (p = 0.0719) and rat (p = 0.0437), indicating the existence of species specific difference in the relationship between DR motifs and deletion breakpoints. In addition, the frequencies of large DRs (>10 bp) tend to decrease with increasing lifespan among the four mammals studied here, further suggesting an evolutionary selection against stable mtDNA misalignments associated with long DRs in long-living animals. In contrast to the results on DR, the probability of finding SL motifs near a deletion breakpoint does not differ from random in any of the four mtDNA sequences considered. Taken together, the findings in this study give support for the importance of stable mtDNA misalignments, aided by long DRs, as a major mechanism of deletion formation in long-living, but not in short-living mammals. PMID- 22530000 TI - Rapid determination of myosin heavy chain expression in rat, mouse, and human skeletal muscle using multicolor immunofluorescence analysis. AB - Skeletal muscle is a heterogeneous tissue comprised of fibers with different morphological, functional, and metabolic properties. Different muscles contain varying proportions of fiber types; therefore, accurate identification is important. A number of histochemical methods are used to determine muscle fiber type; however, these techniques have several disadvantages. Immunofluorescence analysis is a sensitive method that allows for simultaneous evaluation of multiple MHC isoforms on a large number of fibers on a single cross-section, and offers a more precise means of identifying fiber types. In this investigation we characterized pure and hybrid fiber type distribution in 10 rat and 10 mouse skeletal muscles, as well as human vastus lateralis (VL) using multicolor immunofluorescence analysis. In addition, we determined fiber type-specific cross sectional area (CSA), succinate dehydrogenase (SDH) activity, and alpha glycerophosphate dehydrogenase (GPD) activity. Using this procedure we were able to easily identify pure and hybrid fiber populations in rat, mouse, and human muscle. Hybrid fibers were identified in all species and made up a significant portion of the total population in some rat and mouse muscles. For example, rat mixed gastrocnemius (MG) contained 12.2% hybrid fibers whereas mouse white tibialis anterior (WTA) contained 12.1% hybrid fibers. Collectively, we outline a simple and time-efficient method for determining MHC expression in skeletal muscle of multiple species. In addition, we provide a useful resource of the pure and hybrid fiber type distribution, fiber CSA, and relative fiber type-specific SDH and GPD activity in a number of rat and mouse muscles. PMID- 22530001 TI - Transcriptional profiling of formalin fixed paraffin embedded tissue: pitfalls and recommendations for identifying biologically relevant changes. AB - Expression profiling techniques have been used to study the biology of many types of cancer but have been limited to some extent by the requirement for collection of fresh tissue. In contrast, formalin fixed paraffin embedded (FFPE) samples are widely available and represent a vast resource of potential material. The techniques used to handle the degraded and modified RNA from these samples are relatively new and all the pitfalls and limitations of this material for whole genome expression profiling are not yet clarified. Here, we analyzed 70 FFPE tongue carcinoma samples and 17 controls using the whole genome DASL array covering nearly 21000 genes. We identified that sample age is related to quality of extracted RNA and that sample quality influences apparent expression levels in a non-random manner related to gene probe sequence, leading to spurious results. However, by removing sub-standard samples and analysing only those 28 cancers and 15 controls that had similar quality we were able to generate a list of 934 genes significantly altered in tongue cancer compared to control samples of tongue. This list contained previously identified changes and was enriched for genes involved in many cancer-related processes such as tissue remodelling, inflammation, differentiation and apoptosis. Four novel genes of potential importance in tongue cancer development and maintenance, SH3BGL2, SLC2A6, SLC16A3 and CXCL10, were independently confirmed, validating our data. Hence, gene expression profiling can be performed usefully on archival material if appropriate quality assurance steps are taken to ensure sample consistency and we present some recommendations for the use of FFPE material based on our findings. PMID- 22530002 TI - Methanocella conradii sp. nov., a thermophilic, obligate hydrogenotrophic methanogen, isolated from Chinese rice field soil. AB - BACKGROUND: Methanocellales contributes significantly to anthropogenic methane emissions that cause global warming, but few pure cultures for Methanocellales are available to permit subsequent laboratory studies (physiology, biochemistry, etc.). METHODOLOGY/PRINCIPAL FINDINGS: By combining anaerobic culture and molecular techniques, a novel thermophilic methanogen, strain HZ254(T) was isolated from a Chinese rice field soil located in Hangzhou, China. The phylogenetic analyses of both the 16S rRNA gene and mcrA gene (encoding the alpha subunit of methyl-coenzyme M reductase) confirmed its affiliation with Methanocellales, and Methanocella paludicola SANAE(T) was the most closely related species. Cells were non-motile rods, albeit with a flagellum, 1.4-2.8 um long and by 0.2-0.3 um in width. They grew at 37-60 degrees C (optimally at 55 degrees C) and salinity of 0-5 g NaCl l(-1) (optimally at 0-1 g NaCl l(-1)). The pH range for growth was 6.4-7.2 (optimum 6.8). Under the optimum growth condition, the doubling time was 6.5-7.8 h, which is the shortest ever observed in Methanocellales. Strain HZ254(T) utilized H(2)/CO(2) but not formate for growth and methane production. The DNA G+C content of this organism was 52.7 mol%. The sequence identities of 16S rRNA gene and mcrA gene between strain HZ254(T) and SANAE(T) were 95.0 and 87.5% respectively, and the genome based Average Nucleotide Identity value between them was 74.8%. These two strains differed in phenotypic features with regard to substrate utilization, possession of a flagellum, doubling time (under optimal conditions), NaCl and temperature ranges. Taking account of the phenotypic and phylogenetic characteristics, we propose strain HZ254(T) as a representative of a novel species, Methanocella conradii sp. nov. The type strain is HZ254(T) ( = CGMCC 1.5162(T) = JCM 17849(T) = DSM 24694(T)). CONCLUSIONS/SIGNIFICANCE: Strain HZ254(T) could potentially serve as an excellent laboratory model for studying Methanocellales due to its fast growth and consistent cultivability. PMID- 22530003 TI - Agouti revisited: transcript quantification of the ASIP gene in bovine tissues related to protein expression and localization. AB - Beside its role in melanogenesis, the agouti signaling protein (ASIP) has been related to obesity. The potentially crucial role in adipocyte development makes it a tempting candidate for economic relevant, fat related traits in farm animals. The objective of our study was to characterize the mRNA expression of different ASIP transcripts and of putative targets in different bovine tissues, as well as to study consequences on protein abundance and localization. ASIP mRNA abundance was determined by RT-qPCR in adipose and further tissues of cattle representing different breeds and crosses. ASIP mRNA was up-regulated more than 9 fold in intramuscular fat of Japanese Black cattle compared to Holstein (p<0.001). Further analyses revealed that a transposon-derived transcript was solely responsible for the increased ASIP mRNA abundance. This transcript was observed in single individuals of different breeds indicating a wide spread occurrence of this insertion at the ASIP locus in cattle. The protein was detected in different adipose tissues, skin, lung and liver, but not in skeletal muscle by Western blot with a bovine-specific ASIP antibody. However, the protein abundance was not related to the observed ASIP mRNA over-expression. Immuno histochemical analyses revealed a putative nuclear localization of ASIP additionally to the expected cytosolic signal in different cell types. The expression of melanocortin receptors (MCR) 1 to 5 as potential targets for ASIP was analyzed by RT-PCR in subcutaneous fat. Only MC1R and MC4R were detected indicating a similar receptor expression like in human adipose tissue. Our results provide evidence for a widespread expression of ASIP in bovine tissues at mRNA and, for the first time, at protein level. ASIP protein is detectable in adipocytes as well as in further cells of adipose tissue. We generated a basis for a more detailed investigation of ASIP function in peripheral tissues of various mammalian species. PMID- 22530004 TI - Role of the CCAAT-binding protein NFY in SCA17 pathogenesis. AB - Spinocerebellar ataxia 17 (SCA17) is caused by expansion of the polyglutamine (polyQ) tract in human TATA-box binding protein (TBP) that is ubiquitously expressed in both central nervous system and peripheral tissues. The spectrum of SCA17 clinical presentation is broad. The precise pathogenic mechanism in SCA17 remains unclear. Previously proteomics study using a cellular model of SCA17 has revealed reduced expression of heat shock 70 kDa protein 5 (HSPA5) and heat shock 70 kDa protein 8 (HSPA8), suggesting that impaired protein folding may contribute to the cell dysfunction of SCA17 (Lee et al., 2009). In lymphoblastoid cells, HSPA5 and HSPA8 expression levels in cells with mutant TBP were also significantly lower than that of the control cells (Chen et al., 2010). As nuclear transcription factor Y (NFY) has been reported to regulate HSPA5 transcription, we focused on if NFY activity and HSPA5 expression in SCA17 cells are altered. Here, we show that TBP interacts with NFY subunit A (NFYA) in HEK 293 cells and NFYA incorporated into mutant TBP aggregates. In both HEK-293 and SH-SY5Y cells expressing TBP/Q(61~79), the level of soluble NFYA was significantly reduced. In vitro binding assay revealed that the interaction between TBP and NFYA is direct. HSPA5 luciferase reporter assay and endogenous HSPA5 expression analysis in NFYA cDNA and siRNA transfection cells further clarified the important role of NFYA in regulating HSPA5 transcription. In SCA17 cells, HSPA5 promoter activity was activated as a compensatory response before aggregate formation. NFYA dysfunction was indicated in SCA17 cells as HSPA5 promoter activity reduced along with TBP aggregate formation. Because essential roles of HSPA5 in protection from neuronal apoptosis have been shown in a mouse model, NFYA could be a target of mutant TBP in SCA17. PMID- 22530005 TI - Pulmonary hypertension in patients with chronic kidney disease on dialysis and without dialysis: results of the PEPPER-study. AB - Pulmonary hypertension (PH) is common in patients with dialysis-dependent chronic kidney disease and is an independent predictor of mortality. However, specific hemodynamics of the pulmonary circulation, changes induced by hemodialysis and characterization into pre- or postcapillary PH have not been evaluated in patients with chronic kidney disease. We assessed consecutive patients with end stage chronic kidney disease in WHO FC >= II with dyspnea unexplained by other causes on hemodialysis (group 1, n = 31) or without dialysis (group 2, n = 31) using right heart catheterization (RHC). In group 1, RHC was performed before and after dialysis. In end-stage chronic kidney disease, prevalence of precapillary PH was 13% (4/31), and postcapillary PH was discovered in 65% (20/31). All four cases of precapillary PH were unmasked after dialysis. In group 2, two cases of precapillary PH were detected (6%), and postcapillary PH was diagnosed in 22 cases (71%). This is the first study examining a large cohort of patients with chronic kidney disease invasively by RHC for the prevalence of PH. The prevalence of precapillary PH was 13% in patients with end-stage kidney disease. That suggests careful screening for precapillary PH in this selected patient population. RHC should be performed after hemodialysis. PMID- 22530006 TI - Nuclear reprogramming: kinetics of cell cycle and metabolic progression as determinants of success. AB - Establishment of totipotency after somatic cell nuclear transfer (NT) requires not only reprogramming of gene expression, but also conversion of the cell cycle from quiescence to the precisely timed sequence of embryonic cleavage. Inadequate adaptation of the somatic nucleus to the embryonic cell cycle regime may lay the foundation for NT embryo failure and their reported lower cell counts. We combined bright field and fluorescence imaging of histone H(2b)-GFP expressing mouse embryos, to record cell divisions up to the blastocyst stage. This allowed us to quantitatively analyze cleavage kinetics of cloned embryos and revealed an extended and inconstant duration of the second and third cell cycles compared to fertilized controls generated by intracytoplasmic sperm injection (ICSI). Compared to fertilized embryos, slow and fast cleaving NT embryos presented similar rates of errors in M phase, but were considerably less tolerant to mitotic errors and underwent cleavage arrest. Although NT embryos vary substantially in their speed of cell cycle progression, transcriptome analysis did not detect systematic differences between fast and slow NT embryos. Profiling of amino acid turnover during pre-implantation development revealed that NT embryos consume lower amounts of amino acids, in particular arginine, than fertilized embryos until morula stage. An increased arginine supplementation enhanced development to blastocyst and increased embryo cell numbers. We conclude that a cell cycle delay, which is independent of pluripotency marker reactivation, and metabolic restraints reduce cell counts of NT embryos and impede their development. PMID- 22530007 TI - The Temporal Experience of Pleasure Scale (TEPS): exploration and confirmation of factor structure in a healthy Chinese sample. AB - BACKGROUND: The Temporal Experience of Pleasure Scale (TEPS) is a measure specifically designed to capture the anticipatory and consummatory facets of pleasure. However, few studies have examined the structure of the measure in non Western samples. The current study aimed to evaluate the factor structure and psychometric properties of the TEPS in a Chinese sample. METHODS: We administered the Chinese version of the TEPS to 2275 healthy Chinese college students. They were randomly split into two sub-samples. The first sub-sample was used for exploratory factor analysis (EFA) to examine the structure of the TEPS in a Chinese sample. The second sub-sample was used as a validation sample for the identified structure from the EFA and confirmatory factor analysis (CFA) was adopted. RESULTS: Results of the EFA suggested a four-factor model (consummatory contextual, consummatory abstract, anticipatory contextual, and anticipatory abstract factors) instead of the original two-factor model (consummatory and anticipatory factors) ascertained from Western samples in the United States. The CFA results confirmed these results in the second sub-sample. Internal consistency and test-retest stability of the TEPS factors were good. CONCLUSIONS: The TEPS has four factors among Chinese participants. Possible reasons for cultural difference and potential applications of the TEPS for cross-cultural comparison are discussed. PMID- 22530008 TI - 9G4 autoreactivity is increased in HIV-infected patients and correlates with HIV broadly neutralizing serum activity. AB - The induction of a broadly neutralizing antibody (BNAb) response against HIV-1 would be a desirable feature of a protective vaccine. Vaccine strategies thus far have failed to elicit broadly neutralizing antibody responses; however a minority of HIV-infected patients do develop circulating BNAbs, from which several potent broadly neutralizing monoclonal antibodies (mAbs) have been isolated. The findings that several BNmAbs exhibit autoreactivity and that autoreactive serum antibodies are observed in some HIV patients have advanced the possibility that enforcement of self-tolerance may contribute to the rarity of BNAbs. To examine the possible breakdown of tolerance in HIV patients, we utilized the 9G4 anti idiotype antibody system, enabling resolution of both autoreactive VH4-34 gene expressing B cells and serum antibodies. Compared with healthy controls, HIV patients had significantly elevated 9G4+ serum IgG antibody concentrations and frequencies of 9G4+ B cells, a finding characteristic of systemic lupus erythematosus (SLE) patients, both of which positively correlated with HIV viral load. Compared to the global 9G4-IgD--memory B cell population, the 9G4+IgD- memory fraction in HIV patients was dominated by isotype switched IgG+ B cells, but had a more prominent bias toward "IgM only" memory. HIV envelope reactivity was observed both in the 9G4+ serum antibody and 9G4+ B cell population. 9G4+ IgG serum antibody levels positively correlated (r = 0.403, p = 0.0019) with the serum HIV BNAbs. Interestingly, other serum autoantibodies commonly found in SLE (anti-dsDNA, ANA, anti-CL) did not correlate with serum HIV BNAbs. 9G4-associated autoreactivity is preferentially expanded in chronic HIV infection as compared to other SLE autoreactivities. Therefore, the 9G4 system provides an effective tool to examine autoreactivity in HIV patients. Our results suggest that the development of HIV BNAbs is not merely a consequence of a general breakdown in tolerance, but rather a more intricate expansion of selective autoreactive B cells and antibodies. PMID- 22530009 TI - 18S rDNA phylogeny of lamproderma and allied genera (Stemonitales, Myxomycetes, Amoebozoa). AB - The phylogenetic position of the slime-mould genus Lamproderma (Myxomycetes, Amoebozoa) challenges traditional taxonomy: although it displays the typical characters of the order Stemonitales, it appears to be sister to Physarales. This study provides a small subunit (18S or SSU) ribosomal RNA gene-based phylogeny of Lamproderma and its allies, with new sequences from 49 specimens in 12 genera. We found that the order Stemonitales and Lamproderma were both ancestral to Physarales and that Lamproderma constitutes several clades intermingled with species of Diacheopsis, Colloderma and Elaeomyxa. We suggest that these genera may have evolved from Lamproderma by multiple losses of fruiting body stalks and that many taxonomic revisions are needed. We found such high genetic diversity within three Lamproderma species that they probably consist of clusters of sibling species. We discuss the contrasts between genetic and morphological divergence and implications for the morphospecies concept, highlighting the phylogenetically most reliable morphological characters and pointing to others that have been overestimated. In addition, we showed that the first part (~600 bases) of the SSU rDNA gene is a valuable tool for phylogeny in Myxomycetes, since it displayed sufficient variability to distinguish closely related taxa and never failed to cluster together specimens considered of the same species. PMID- 22530010 TI - Performance of survivin mRNA as a biomarker for bladder cancer in the prospective study UroScreen. AB - BACKGROUND: Urinary biomarkers have the potential to improve the early detection of bladder cancer. Most of the various known markers, however, have only been evaluated in studies with cross-sectional design. For proper validation a longitudinal design would be preferable. We used the prospective study UroScreen to evaluate survivin, a potential biomarker that has multiple functions in carcinogenesis. METHODS/RESULTS: Survivin was analyzed in 5,716 urine samples from 1,540 chemical workers previously exposed to aromatic amines. The workers participated in a surveillance program with yearly examinations between 2003 and 2010. RNA was extracted from urinary cells and survivin was determined by Real Time PCR. During the study, 19 bladder tumors were detected. Multivariate generalized estimation equation (GEE) models showed that beta-actin, representing RNA yield and quality, had the strongest influence on survivin positivity. Inflammation, hematuria and smoking did not confound the results. Survivin had a sensitivity of 21.1% for all and 36.4% for high-grade tumors. Specificity was 97.5%, the positive predictive value (PPV) 9.5%, and the negative predictive value (NPV) 99.0%. CONCLUSIONS: In this prospective and so far largest study on survivin, the marker showed a good NPV and specificity but a low PPV and sensitivity. This was partly due to the low number of cases, which limits the validity of the results. Compliance, urine quality, problems with the assay, and mRNA stability influenced the performance of survivin. However, most issues could be addressed with a more reliable assay in the future. One important finding is that survivin was not influenced by confounders like inflammation and exhibited a relatively low number of false-positives. Therefore, despite the low sensitivity, survivin may still be considered as a component of a multimarker panel. PMID- 22530011 TI - Selenium promotes T-cell response to TCR-stimulation and ConA, but not PHA in primary porcine splenocytes. AB - There is controversy in the literature over whether the selenium (Se) influences cellular immune responses, and the mechanisms possibly underlying these effects are unclear. In this study, the effects of Se on T-cell proliferation and IL-2 production were studied in primary porcine splenocytes. Splenocytes were treated with different mitogens in the presence of 0.5-4 umol/L sodium selenite. Se significantly promoted T-cell receptor (TCR) or concanavalin A (ConA)-induced T cell proliferation and IL-2 production but failed to regulate T-cell response to phytohemagglutinin (PHA). In addition, Se significantly increased the levels of cytosolic glutathione peroxidase (GPx1) and thioredoxin reductase 1 (TR1) mRNA, the activity of GPx1 and the concentration of reduced glutathione (GSH) in the unstimulated, or activated splenocytes. These results indicated that Se improved the redox status in all splenocytes, including unstimulated, TCR, ConA and PHA stimulated, but only TCR and ConA-induced T-cell activation was affected by the redox status. N-acetylcysteine (NAC), a pharmacological antioxidant, increased T cell proliferation and IL-2 production by TCR and ConA stimulated splenocytes but had no effect on the response to PHA in primary porcine splenocytes confirming that PHA-induced T-cell activation is insensitive to the redox status. We conclude that Se promotes GPx1 and TR1 expression and increases antioxidative capacity in porcine splenocytes, which enhances TCR or ConA -induced T-cell activation but not PHA-induced T-cell activation. The different susceptibilities to Se between the TCR, ConA and PHA -induced T-cell activation may help to explain the controversy in the literature over whether or not Se boosts immune responses. PMID- 22530012 TI - Conformational states of a bacterial alpha2-macroglobulin resemble those of human complement C3. AB - alpha(2) macroglobulins (alpha(2)Ms) are broad-spectrum protease inhibitors that play essential roles in the innate immune system of eukaryotic species. These large, multi-domain proteins are characterized by a broad-spectrum bait region and an internal thioester, which, upon cleavage, becomes covalently associated to the target protease, allowing its entrapment by a large conformational modification. Notably, alpha(2)Ms are part of a larger protein superfamily that includes proteins of the complement system, such as C3, a multi-domain macromolecule which is also characterized by an internal thioester-carrying domain and whose activation represents the pivotal step in the complement cascade. Recently, alpha(2)M/C3-like genes were identified in a large number of bacterial genomes, and the Escherichia coli alpha(2)M homolog (ECAM) was shown to be activated by proteases. In this work, we have structurally characterized ECAM by electron microscopy and small angle scattering (SAXS) techniques. ECAM is an elongated, flexible molecule with overall similarities to C3 in its inactive form; activation by methylamine, chymotrypsin, or elastase induces a conformational modification reminiscent of the one undergone by the transformation of C3 into its active form, C3b. In addition, the proposed C terminus of ECAM displays high flexibility and different conformations, and could be the recognition site for partner macromolecules. This work sheds light on a potential bacterial defense mechanism that mimics structural rearrangements essential for activation of the complement cascade in eukaryotes, and represents a possible novel target for the development of antibacterials. PMID- 22530013 TI - Polysaccharide specific monoclonal antibodies provide passive protection against intranasal challenge with Burkholderia pseudomallei. AB - Burkholderia pseudomallei is a Gram-negative bacillus that is the causative agent of melioidosis. The bacterium is inherently resistant to many antibiotics and mortality rates remain high in endemic areas. The lipopolysaccharide (LPS) and capsular polysaccharide (CPS) are two surface-associated antigens that contribute to pathogenesis. We previously developed two monoclonal antibodies (mAbs) specific to the CPS and LPS; the CPS mAb was shown to identify antigen in serum and urine from melioidosis patients. The goal of this study was to determine if passive immunization with CPS and LPS mAbs alone and in combination would protect mice from a lethal challenge with B. pseudomallei. Intranasal (i.n.) challenge experiments were performed with B. pseudomallei strains 1026b and K96423. Both mAbs provided significant protection when administered alone. A combination of mAbs was protective when low doses were administered. In addition, combination therapy provided a significant reduction in spleen colony forming units (cfu) compared to results when either the CPS or LPS mAbs were administered alone. PMID- 22530014 TI - Epidemiologic behavior of obesity in the Maracaibo City metabolic syndrome prevalence study. AB - INTRODUCTION: Obesity is a worldwide public health issue. Since the epidemiological behaviour of this disease is not well established in our country, the purpose of this study was to determinate its prevalence in the Maracaibo City, Zulia State- Venezuela. MATERIALS AND METHODS: A cross-sectional study was undertaken using the data set from the Maracaibo City Metabolic Syndrome Prevalence Study. The sample consists of 2108 individuals from both genders and randomly selected: 1119 (53.09%) women and 989 (46.91%) men. The participants were interrogated for a complete clinical history and anthropometric measurements. To classify obesity, the WHO criteria for Body Mass Index (BMI), and Waist Circumference (WC) from the IDF/NHLBI/AHA/WHF/IAS/IASO-2009 (IDF-2009) and ATPIII statements were applied. RESULTS: For BMI, obesity had an overall prevalence of 33.3% (n = 701), and according to gender women had 32.4% (n = 363) and men had 34.2% (n = 338). Overweight had a prevalence of 34.8% (n = 733), Normal weight had 29.8% (n = 629), and Underweight had 2.1% (n = 45). Adding Obesity and Overweight results, the prevalence of elevated BMI (>25 Kg/m(2)) was 68.1%. Using the IDF-2009 WC's cut-off, Obesity had 74.2% prevalence, compared to 51.7% using the ATPIII parameters. CONCLUSIONS: These results show a high prevalence of abdominal obesity in our locality defined by the WHO, IDF-2009 and ATPIII criteria, which were not designed for Latin-American populations. We suggest further investigation to estimate the proper values according to ethnicity, genetic background and sociocultural aspects. PMID- 22530016 TI - Expression of VjbR under nutrient limitation conditions is regulated at the post transcriptional level by specific acidic pH values and urocanic acid. AB - VjbR is a LuxR homolog that regulates transcription of many genes including important virulence determinants of the facultative intracellular pathogen Brucella abortus. This transcription factor belongs to a family of regulators that participate in a cell-cell communication process called quorum sensing, which enables bacteria to respond to changes in cell population density by monitoring concentration of self produced autoinducer molecules. Unlike almost all other LuxR-type proteins, VjbR binds to DNA and activates transcription in the absence of any autoinducer signal. To investigate the mechanisms by which Brucella induces VjbR-mediated transcriptional activation, and to determine how inappropriate spatio-temporal expression of the VjbR target genes is prevented, we focused on the study of expression of vjbR itself. By assaying different parameters related to the intracellular lifestyle of Brucella, we identified a restricted set of conditions that triggers VjbR protein expression. Such conditions required the convergence of two signals of different nature: a specific pH value of 5.5 and the presence of urocanic acid, a metabolite involved in the connection between virulence and metabolism of Brucella. In addition, we also observed an urocanic acid, pH-dependent expression of RibH2 and VirB7, two additional intracellular survival-related proteins of Brucella. Analysis of promoter activities and determination of mRNA levels demonstrated that the urocanic acid-dependent mechanisms that induced expression of VjbR, RibH2, and VirB7 act at the post-transcriptional level. Taken together, our findings support a model whereby Brucella induces VjbR-mediated transcription by modulating expression of VjbR in response to specific signals related to the changing environment encountered within the host. PMID- 22530015 TI - Inhibition of diacylglycerol-sensitive TRPC channels by synthetic and natural steroids. AB - TRPC channels are a family of nonselective cation channels that regulate ion homeostasis and intracellular Ca(2+) signaling in numerous cell types. Important physiological functions such as vasoregulation, neuronal growth, and pheromone recognition have been assigned to this class of ion channels. Despite their physiological relevance, few selective pharmacological tools are available to study TRPC channel function. We, therefore, screened a selection of pharmacologically active compounds for TRPC modulating activity. We found that the synthetic gestagen norgestimate inhibited diacylglycerol-sensitive TRPC3 and TRPC6 with IC(50)s of 3-5 uM, while half-maximal inhibition of TRPC5 required significantly higher compound concentrations (>10 uM). Norgestimate blocked TRPC mediated vasopressin-induced cation currents in A7r5 smooth muscle cells and caused vasorelaxation of isolated rat aorta, indicating that norgestimate could be an interesting tool for the investigation of TRP channel function in native cells and tissues. The steroid hormone progesterone, which is structurally related to norgestimate, also inhibited TRPC channel activity with IC(50)s ranging from 6 to 18 uM but showed little subtype selectivity. Thus, TRPC channel inhibition by high gestational levels of progesterone may contribute to the physiological decrease of uterine contractility and immunosuppression during pregnancy. PMID- 22530018 TI - A hypothetico-deductive approach to assessing the social function of chemical signalling in a non-territorial solitary carnivore. AB - The function of chemical signalling in non-territorial solitary carnivores is still relatively unclear. Studies on territorial solitary and social carnivores have highlighted odour capability and utility, however the social function of chemical signalling in wild carnivore populations operating dominance hierarchy social systems has received little attention. We monitored scent marking and investigatory behaviour of wild brown bears Ursus arctos, to test multiple hypotheses relating to the social function of chemical signalling. Camera traps were stationed facing bear 'marking trees' to document behaviour by different age sex classes in different seasons. We found evidence to support the hypothesis that adult males utilise chemical signalling to communicate dominance to other males throughout the non-denning period. Adult females did not appear to utilise marking trees to advertise oestrous state during the breeding season. The function of marking by subadult bears is somewhat unclear, but may be related to the behaviour of adult males. Subadults investigated trees more often than they scent marked during the breeding season, which could be a result of an increased risk from adult males. Females with young showed an increase in marking and investigation of trees outside of the breeding season. We propose the hypothesis that females engage their dependent young with marking trees from a young age, at a relatively 'safe' time of year. Memory, experience, and learning at a young age, may all contribute towards odour capabilities in adult bears. PMID- 22530017 TI - Serum cholesterol and nigrostriatal R2* values in Parkinson's disease. AB - BACKGROUND: The occurrence of Parkinson's disease (PD) is known to be associated both with increased nigrostriatal iron content and with low serum cholesterol and PD, but there has been no study to determine a potential relationship between these two factors. METHODS: High-resolution MRI (T1-, T2, and multiple echo T2* weighted imaging) and fasting lipid levels were obtained from 40 patients with PD and 29 healthy controls. Iron content was estimated from mean R2* values (R2* = 1/T2*) calculated for each nigrostriatal structure including substantia nigra, caudate, putamen, and globus pallidus. This was correlated with serum cholesterol levels after controlling for age, gender, and statin use. RESULTS: In patients with PD, higher serum cholesterol levels were associated with lower iron content in the substantia nigra (R = -0.43, p = 0.011 for total-cholesterol, R = -0.31, p = 0.080 for low-density lipoprotein) and globus pallidus (R = -0.38, p = 0.028 for total-cholesterol, R = -0.27, p = 0.127 for low-density lipoprotein), but only a trend toward significant association of higher total-cholesterol with lower iron content in the striatum (R = -0.34, p = 0.052 for caudate; R = -0.32, p = 0.061 for putamen). After adjusting for clinical measures, the cholesterol iron relationships held or became even stronger in the substantia nigra and globus pallidus, but weaker in the caudate and putamen. There was no significant association between serum cholesterol levels and nigrostriatal iron content for controls. CONCLUSIONS: The data show that higher serum total-cholesterol concentration is associated with lower iron content in substantia nigra and globus pallidus in Parkinson's disease patients. Further studies should investigate whether this is mechanistic or epiphenomenological relationship. PMID- 22530019 TI - Inverse fusion PCR cloning. AB - Inverse fusion PCR cloning (IFPC) is an easy, PCR based three-step cloning method that allows the seamless and directional insertion of PCR products into virtually all plasmids, this with a free choice of the insertion site. The PCR-derived inserts contain a vector-complementary 5'-end that allows a fusion with the vector by an overlap extension PCR, and the resulting amplified insert-vector fusions are then circularized by ligation prior transformation. A minimal amount of starting material is needed and experimental steps are reduced. Untreated circular plasmid, or alternatively bacteria containing the plasmid, can be used as templates for the insertion, and clean-up of the insert fragment is not urgently required. The whole cloning procedure can be performed within a minimal hands-on time and results in the generation of hundreds to ten-thousands of positive colonies, with a minimal background. PMID- 22530020 TI - Counteraction of tetherin antiviral activity by two closely related SIVs differing by the presence of a Vpu gene. AB - In different primate lentiviruses, three proteins (Vpu, Env and Nef) have been shown to have anti-tetherin activities. SIVden is a primate lentivirus harbored by a Cercopithecus denti (C. denti) whose genome code for a Vpu gene. We have compared the activity of HIV-1 Vpu and of SIVden Vpu on tetherin proteins from humans, from C. denti and from Cercopithecus neglectus (C. neglectus), a monkey species that is naturally infected by SIVdeb, a virus closely related to SIVden but which does not encode a Vpu protein. Here, we demonstrate that SIVden Vpu, is active against C. denti tetherin, but not against human tetherin. Interestingly, C. neglectus tetherin was more sensitive to SIVden Vpu than to HIV-1 Vpu. We also identify residues in the tetherin transmembrane domains that are responsible for the species-specific Vpu effect. Simultaneous mutation (P40L and T45I) of human tetherin conferred sensitivity to SIVden Vpu, while abolishing its sensitivity to HIV-1 Vpu. We next analyzed the anti-tetherin activity of the Nef proteins from HIV-1, SIVden and SIVdeb. All three Nef proteins were unable to rescue virus release in the presence of human or C. denti tetherin. Conversely, SIVdeb Nef enhanced virus release in the presence of C. neglectus tetherin, suggesting that SIVdeb relies on Nef in its natural host. Finally, while HIV-1 Vpu not only removed human tetherin from the cell surface but also directed it for degradation, SIVden Vpu only induced the redistribution of both C. denti and C. neglectus tetherins, resulting in a predominantly perinuclear localization. PMID- 22530021 TI - Modeling E. coli tumbles by rotational diffusion. Implications for chemotaxis. AB - The bacterium Escherichia coli in suspension in a liquid medium swims by a succession of runs and tumbles, effectively describing a random walk. The tumbles randomize incompletely, i.e. with a directional persistence, the orientation taken by the bacterium. Here, we model these tumbles by an active rotational diffusion process characterized by a diffusion coefficient and a diffusion time. In homogeneous media, this description accounts well for the experimental reorientations. In shallow gradients of nutrients, tumbles are still described by a unique rotational diffusion coefficient. Together with an increase in the run length, these tumbles significantly contribute to the net chemotactic drift via a modulation of their duration as a function of the direction of the preceding run. Finally, we discuss the limits of this model in propagating concentration waves characterized by steep gradients. In that case, the effective rotational diffusion coefficient itself varies with the direction of the preceding run. We propose that this effect is related to the number of flagella involved in the reorientation process. PMID- 22530022 TI - Limited genetic diversity preceded extinction of the Tasmanian tiger. AB - The Tasmanian tiger or thylacine was the largest carnivorous marsupial when Europeans first reached Australia. Sadly, the last known thylacine died in captivity in 1936. A recent analysis of the genome of the closely related and extant Tasmanian devil demonstrated limited genetic diversity between individuals. While a similar lack of diversity has been reported for the thylacine, this analysis was based on just two individuals. Here we report the sequencing of an additional 12 museum-archived specimens collected between 102 and 159 years ago. We examined a portion of the mitochondrial DNA hyper-variable control region and determined that all sequences were on average 99.5% identical at the nucleotide level. As a measure of accuracy we also sequenced mitochondrial DNA from a mother and two offspring. As expected, these samples were found to be 100% identical, validating our methods. We also used 454 sequencing to reconstruct 2.1 kilobases of the mitochondrial genome, which shared 99.91% identity with the two complete thylacine mitochondrial genomes published previously. Our thylacine genomic data also contained three highly divergent putative nuclear mitochondrial sequences, which grouped phylogenetically with the published thylacine mitochondrial homologs but contained 100-fold more polymorphisms than the conserved fragments. Together, our data suggest that the thylacine population in Tasmania had limited genetic diversity prior to its extinction, possibly as a result of their geographic isolation from mainland Australia approximately 10,000 years ago. PMID- 22530023 TI - Biology of Francisella tularensis subspecies holarctica live vaccine strain in the tick vector Dermacentor variabilis. AB - BACKGROUND: The gamma-proteobacterium Francisella tularensis is the etiologic agent of seasonal tick-transmitted tularemia epizootics in rodents and rabbits and of incidental infections in humans. The biology of F. tularensis in its tick vectors has not been fully described, particularly with respect to its quanta and duration of colonization, tissue dissemination, and transovarial transmission. A systematic study of the colonization of Dermacentor variabilis by the F. tularensis subsp. holarctica live vaccine strain (LVS) was undertaken to better understand whether D. variabilis may serve as an inter-epizootic reservoir for F. tularensis. METHODOLOGY/PRINCIPAL FINDINGS: Colony-reared larva, nymph, and adult D. variabilis were artificially fed LVS via glass capillary tubes fitted over the tick mouthparts, and the level of colonization determined by microbial culture. Larvae and nymphs were initially colonized with 8.8 +/- 0.8 * 10(1) and 1.1 +/- 0.03 * 10(3) CFU/tick, respectively. Post-molting, a significant increase in colonization of both molted nymphs and adults occurred, and LVS persisted in 42% of molted adult ticks at 126 days post-capillary tube feeding. In adult ticks, LVS initially colonized the gut, disseminated to hemolymph and salivary glands by 21 days, and persisted up to 165 days. LVS was detected in the salivary secretions of adult ticks after four days post intra-hemocoelic inoculation, and LVS recovered from salivary gland was infectious to mice with an infectious dose 50% of 3 CFU. LVS in gravid female ticks colonized via the intra-hemocoelic route disseminated to the ovaries and then to the oocytes, but the pathogen was not recovered from the subsequently-hatched larvae. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that D. variabilis can be efficiently colonized with F. tularensis using artificial methods. The persistence of F. tularensis in D. variabilis suggests that this tick species may be involved in the maintenance of enzootic foci of tularemia in the central United States. PMID- 22530024 TI - A beta-Lactamase based reporter system for ESX dependent protein translocation in mycobacteria. AB - Protein secretion is essential for all bacteria in order to interact with their environment. Mycobacterium tuberculosis depends on protein secretion to subvert host immune response mechanisms. Both the general secretion system (Sec) and the twin-arginine translocation system (Tat) are functional in mycobacteria. Furthermore, a novel type of protein translocation system named ESX has been identified. In the genome of M. tuberculosis five paralogous ESX regions (ESX-1 to ESX-5) have been found. Several components of the ESX translocation apparatus have been identified over the last ten years. The ESX regions are composed of a basic set of genes for the translocation machinery and the main substrate - a heterodimer. The best studied of these heterodimers is EsxA (ESAT-6)/EsxB (CFP 10), which has been shown to be exported by ESX-1. EsxA/B is heavily involved in virulence of M. tuberculosis. EsxG/H is exported by ESX-3 and seems to be involved in an essential iron-uptake mechanism in M. tuberculosis. These findings make ESX-3 components high profile drug targets. Until now, reporter systems for determination of ESX protein translocation have not been developed. In order to create such a reporter system, a truncated beta-lactamase ('bla TEM-1) was fused to the N-terminus of EsxB, EsxG and EsxU, respectively. These constructs have then been tested in a beta-lactamase (BlaS) deletion strain of Mycobacterium smegmatis. M. smegmatis DeltablaS is highly susceptible to ampicillin. An ampicillin resistant phenotype was conferred by translocation of Bla TEM-1-Esx fusion proteins into the periplasm. BlaTEM-1-Esx fusion proteins were not found in the culture filtrate suggesting that plasma membrane translocation and outer membrane translocation are two distinct steps in ESX secretion. Thus we have developed a powerful tool to dissect the molecular mechanisms of ESX dependent protein translocation and to screen for novel components of the ESX systems on a large scale. PMID- 22530025 TI - Capsule independent uptake of the fungal pathogen Cryptococcus neoformans into brain microvascular endothelial cells. AB - Cryptococcosis is a life-threatening fungal disease with a high rate of mortality among HIV/AIDS patients across the world. The ability to penetrate the blood brain barrier (BBB) is central to the pathogenesis of cryptococcosis, but the way in which this occurs remains unclear. Here we use both mouse and human brain derived endothelial cells (bEnd3 and hCMEC/D3) to accurately quantify fungal uptake and survival within brain endothelial cells. Our data indicate that the adherence and internalisation of cryptococci by brain microvascular endothelial cells is an infrequent event involving small numbers of cryptococcal yeast cells. Interestingly, this process requires neither active signalling from the fungus nor the presence of the fungal capsule. Thus entry into brain microvascular endothelial cells is most likely a passive event that occurs following 'trapping' within capillary beds of the BBB. PMID- 22530026 TI - Acanthaster planci outbreak: decline in coral health, coral size structure modification and consequences for obligate decapod assemblages. AB - Although benthic motile invertebrate communities encompass the vast majority of coral reef diversity, their response to habitat modification has been poorly studied. A variety of benthic species, particularly decapods, provide benefits to their coral host enabling them to cope with environmental stressors, and as a result benefit the overall diversity of coral-associated species. However, little is known about how invertebrate assemblages associated with corals will be affected by global perturbations, (either directly or indirectly via their coral host) or their consequences for ecosystem resilience. Analysis of a ten year dataset reveals that the greatest perturbation at Moorea over this time was an outbreak of the corallivorous sea star Acanthaster planci from 2006 to 2009 impacting habitat health, availability and size structure of Pocillopora spp. populations and highlights a positive relationship between coral head size and survival. We then present the results of a mensurative study in 2009 conducted at the end of the perturbation (A. planci outbreak) describing how coral-decapod communities change with percent coral mortality for a selected coral species, Pocillopora eydouxi. The loss of coral tissue as a consequence of A. planci consumption led to an increase in rarefied total species diversity, but caused drastic modifications in community composition driven by a shift from coral obligate to non-obligate decapod species. Our study highlights that larger corals left with live tissue in 2009, formed a restricted habitat where coral obligate decapods, including mutualists, could subsist. We conclude that the size structure of Pocillopora populations at the time of an A. planci outbreak may greatly condition the magnitude of coral mortality as well as the persistence of local populations of obligate decapods. PMID- 22530027 TI - Alternative polyadenylation and nonsense-mediated decay coordinately regulate the human HFE mRNA levels. AB - Nonsense-mediated decay (NMD) is an mRNA surveillance pathway that selectively recognizes and degrades defective mRNAs carrying premature translation termination codons. However, several studies have shown that NMD also targets physiological transcripts that encode full-length proteins, modulating their expression. Indeed, some features of physiological mRNAs can render them NMD sensitive. Human HFE is a MHC class I protein mainly expressed in the liver that, when mutated, can cause hereditary hemochromatosis, a common genetic disorder of iron metabolism. The HFE gene structure comprises seven exons; although the sixth exon is 1056 base pairs (bp) long, only the first 41 bp encode for amino acids. Thus, the remaining downstream 1015 bp sequence corresponds to the HFE 3' untranslated region (UTR), along with exon seven. Therefore, this 3' UTR encompasses an exon/exon junction, a feature that can make the corresponding physiological transcript NMD-sensitive. Here, we demonstrate that in UPF1 depleted or in cycloheximide-treated HeLa and HepG2 cells the HFE transcripts are clearly upregulated, meaning that the physiological HFE mRNA is in fact an NMD target. This role of NMD in controlling the HFE expression levels was further confirmed in HeLa cells transiently expressing the HFE human gene. Besides, we show, by 3'-RACE analysis in several human tissues that HFE mRNA expression results from alternative cleavage and polyadenylation at four different sites- two were previously described and two are novel polyadenylation sites: one located at exon six, which confers NMD-resistance to the corresponding transcripts, and another located at exon seven. In addition, we show that the amount of HFE mRNA isoforms resulting from cleavage and polyadenylation at exon seven, although present in both cell lines, is higher in HepG2 cells. These results reveal that NMD and alternative polyadenylation may act coordinately to control HFE mRNA levels, possibly varying its protein expression according to the physiological cellular requirements. PMID- 22530028 TI - Performance of papanicolaou testing and detection of cervical carcinoma in situ in participants of organized cervical cancer screening in South Korea. AB - BACKGROUND: The present study measured the performance of the Papanicolaou (Pap) test and detection of cervical carcinoma in situ (CIS) and cancer in participants of organized cervical cancer screening in South Korea, and examined differences in the proportion of CIS according to socio-demographic factors. METHODS: Data were obtained from the National Cancer Screening Program and National Health Insurance Cancer Screening Program databases. We analyzed data from 4,072,997 screenings of women aged 30 years or older who underwent cervical cancer screening by Pap test between January 1, 2005 and December 31, 2006. We calculated the performances of the Pap test and compared that according to socio demographic factors. RESULTS: The positivity rate for all screenings was 6.6%. The cancer detection rate (CDR) and interval cancer rate (ICR) were 0.32 per 1,000 screenings, and 0.13 per 1,000 negative screenings, respectively. About 63.4% of screen-detected CIS+ cases (CIS or invasive cervical cancer) were CIS. The CDR and ICR, and percentage of CIS among all CIS+ were significantly different by age group and health insurance status. The odds ratios of CDR and ICR were higher for Medical Aid Program (MAP) recipients compared with National Health Insurance (NHI) beneficiaries. The likelihood of a detected CIS+ case to be CIS was significantly lower among MAP recipients than among NHI beneficiaries. CONCLUSIONS: The difference in performance of cervical cancer screening among different socio-demographic groups may indicate an important influence of socio demographic factors on preventive behavior. The findings of the study support the critical need for increasing efforts to raise awareness and provide more screening in at-risk populations, specifically low-income groups. PMID- 22530029 TI - Confocal microscopy and image analysis indicates a region-specific relation between active caspases and cytoplasm in ejaculated and epididymal sperm. AB - Previously, it was suggested a relation between the presence of apoptosis markers with cytoplasm in mammalian sperm. In this work, flow cytometry, confocal microscopy and image analysis were used to analyze the relationship between active caspase-3 and -7 and intracellular esterases expression in ejaculated or epididymal ram sperm. Sperm obtained from ejaculates from the caput, corpus, or cauda of the epididymis were treated with an inhibitor of active caspase-3 and -7 and a marker of cytoplasmic esterases. Additionally, ejaculated sperm were incubated for one, two, or three hours before evaluation for active caspases. Sperm subpopulations positive for active caspases and/or intracellular esterases were detected by flow cytometry and confocal microscopy; however, image analysis of confocal images showed that the correlation between active caspases and cytoplasmic esterases in sperm is region-specific. Lower values of Spearman correlation coefficients were found when whole sperm or head sperm was analyzed; however, a high correlation was observed for midpiece sperm. Incubation of sperm for two or three hours promoted the autoactivation of caspases. It has been suggested that the presence of apoptotic markers in sperm are related with a process of abortive apoptosis and with errors during spermiogenesis. Our results permit us suggest that the origin of the relationship between active caspases and cytoplasmic esterases is due to differentiation errors occurring during spermiogenesis because the percentages of sperm with active caspases are not different in the caput, corpus, or cauda of the epididymis. In this study we demonstrate that existing sperm subpopulations can express active caspases and intracellular esterases and that the correlation between these molecules is high in midpiece sperm. PMID- 22530030 TI - Network analysis of oyster transcriptome revealed a cascade of cellular responses during recovery after heat shock. AB - Oysters, as a major group of marine bivalves, can tolerate a wide range of natural and anthropogenic stressors including heat stress. Recent studies have shown that oysters pretreated with heat shock can result in induced heat tolerance. A systematic study of cellular recovery from heat shock may provide insights into the mechanism of acquired thermal tolerance. In this study, we performed the first network analysis of oyster transcriptome by reanalyzing microarray data from a previous study. Network analysis revealed a cascade of cellular responses during oyster recovery after heat shock and identified responsive gene modules and key genes. Our study demonstrates the power of network analysis in a non-model organism with poor gene annotations, which can lead to new discoveries that go beyond the focus on individual genes. PMID- 22530031 TI - The spatial distribution of LGR5+ cells correlates with gastric cancer progression. AB - In this study we tested the prevalence, histoanatomical distribution and tumour biological significance of the Wnt target protein and cancer stem cell marker LGR5 in tumours of the human gastrointestinal tract. Differential expression of LGR5 was studied on transcriptional (real-time polymerase chain reaction) and translational level (immunohistochemistry) in malignant and corresponding non malignant tissues of 127 patients comprising six different primary tumour sites, i.e. oesophagus, stomach, liver, pancreas, colon and rectum. The clinico pathological significance of LGR5 expression was studied in 100 patients with gastric carcinoma (GC). Non-neoplastic tissue usually harboured only very few scattered LGR5(+) cells. The corresponding carcinomas of the oesophagus, stomach, liver, pancreas, colon and rectum showed significantly more LGR5(+) cells as well as significantly higher levels of LGR5-mRNA compared with the corresponding non neoplastic tissue. Double staining experiments revealed a coexpression of LGR5 with the putative stem cell markers CD44, Musashi-1 and ADAM17. Next we tested the hypothesis that the sequential changes of gastric carcinogenesis, i.e. chronic atrophic gastritis, intestinal metaplasia and invasive carcinoma, are associated with a reallocation of the LGR5(+) cells. Interestingly, the spatial distribution of LGR5 changed: in non-neoplastic stomach mucosa, LGR5(+) cells were found predominantly in the mucous neck region; in intestinal metaplasia LGR5(+) cells were localized at the crypt base, and in GC LGR5(+) cells were present at the luminal surface, the tumour centre and the invasion front. The expression of LGR5 in the tumour centre and invasion front of GC correlated significantly with the local tumour growth (T-category) and the nodal spread (N category). Furthermore, patients with LGR5(+) GCs had a shorter median survival (28.0+/-8.6 months) than patients with LGR5(-) GCs (54.5+/-6.3 months). Our results show that LGR5 is differentially expressed in gastrointestinal cancers and that the spatial histoanatomical distribution of LGR5(+) cells has to be considered when their tumour biological significance is sought. PMID- 22530032 TI - Overcoming multidrug resistance via photodestruction of ABCG2-rich extracellular vesicles sequestering photosensitive chemotherapeutics. AB - Multidrug resistance (MDR) remains a dominant impediment to curative cancer chemotherapy. Efflux transporters of the ATP-binding cassette (ABC) superfamily including ABCG2, ABCB1 and ABCC1 mediate MDR to multiple structurally and functionally distinct antitumor agents. Recently we identified a novel mechanism of MDR in which ABCG2-rich extracellular vesicles (EVs) form in between attached neighbor breast cancer cells and highly concentrate various chemotherapeutics in an ABCG2-dependent manner, thereby sequestering them away from their intracellular targets. Hence, development of novel strategies to overcome MDR modalities is a major goal of cancer research. Towards this end, we here developed a novel approach to selectively target and kill MDR cancer cells. We show that illumination of EVs that accumulated photosensitive cytotoxic drugs including imidazoacridinones (IAs) and topotecan resulted in intravesicular formation of reactive oxygen species (ROS) and severe damage to the EVs membrane that is shared by EVs-forming cells, thereby leading to tumor cell lysis and the overcoming of MDR. Furthermore, consistent with the weak base nature of IAs, MDR cells that are devoid of EVs but contained an increased number of lysosomes, highly accumulated IAs in lysosomes and upon photosensitization were efficiently killed via ROS-dependent lysosomal rupture. Combining targeted lysis of IAs loaded EVs and lysosomes elicited a synergistic cytotoxic effect resulting in MDR reversal. In contrast, topotecan, a bona fide transport substrate of ABCG2, accumulated exclusively in EVs of MDR cells but was neither detected in lysosomes of normal breast epithelial cells nor in non-MDR breast cancer cells. This exclusive accumulation in EVs enhanced the selectivity of the cytotoxic effect exerted by photodynamic therapy to MDR cells without harming normal cells. Moreover, lysosomal alkalinization with bafilomycin A1 abrogated lysosomal accumulation of IAs, consequently preventing lysosomal photodestruction of normal breast epithelial cells. Thus, MDR modalities including ABCG2-dependent drug sequestration within EVs can be rationally converted to a pharmacologically lethal Trojan horse to selectively eradicate MDR cancer cells. PMID- 22530034 TI - Mobility, expansion and management of a multi-species scuba diving fishery in East Africa. AB - BACKGROUND: Scuba diving fishing, predominantly targeting sea cucumbers, has been documented to occur in an uncontrolled manner in the Western Indian Ocean and in other tropical regions. Although this type of fishing generally indicates a destructive activity, little attention has been directed towards this category of fishery, a major knowledge gap and barrier to management. METHODOLOGY AND PRINCIPAL FINDINGS: With the aim to capture geographic scales, fishing processes and social aspects the scuba diving fishery that operate out of Zanzibar was studied using interviews, discussions, participant observations and catch monitoring. The diving fishery was resilient to resource declines and had expanded to new species, new depths and new fishing grounds, sometimes operating approximately 250 km away from Zanzibar at depths down to 50 meters, as a result of depleted easy-access stock. The diving operations were embedded in a regional and global trade network, and its actors operated in a roving manner on multiple spatial levels, taking advantage of unfair patron-client relationships and of the insufficient management in Zanzibar. CONCLUSIONS AND SIGNIFICANCE: This study illustrates that roving dynamics in fisheries, which have been predominantly addressed on a global scale, also take place at a considerably smaller spatial scale. Importantly, while proposed management of the sea cucumber fishery is often generic to a simplified fishery situation, this study illustrates a multifaceted fishery with diverse management requirements. The documented spatial scales and processes in the scuba diving fishery emphasize the need for increased regional governance partnerships to implement management that fit the spatial scales and processes of the operation. PMID- 22530033 TI - Role of serine racemase in behavioral sensitization in mice after repeated administration of methamphetamine. AB - BACKGROUND: The N-methyl-D-aspartate (NMDA) receptors play a role in behavioral abnormalities observed after administration of the psychostimulant, methamphetamine (METH). Serine racemase (SRR) is an enzyme which synthesizes D serine, an endogenous co-agonist of NMDA receptors. Using Srr knock-out (KO) mice, we investigated the role of SRR on METH-induced behavioral abnormalities in mice. METHODOLOGY/PRINCIPAL FINDINGS: Evaluations of behavior in acute hyperlocomotion, behavioral sensitization, and conditioned place preference (CPP) were performed. The role of SRR on the release of dopamine (DA) in the nucleus accumbens after administration of METH was examined using in vivo microdialysis technique. Additionally, phosphorylation levels of ERK1/2 proteins in the striatum, frontal cortex and hippocampus were examined using Western blot analysis. Acute hyperlocomotion after a single administration of METH (3 mg/kg) was comparable between wild-type (WT) and Srr-KO mice. However, repeated administration of METH (3 mg/kg/day, once daily for 5 days) resulted in behavioral sensitization in WT, but not Srr-KO mice. Pretreatment with D-serine (900 mg/kg, 30 min prior to each METH treatment) did not affect the development of behavioral sensitization after repeated METH administration. In the CPP paradigm, METH-induced rewarding effects were demonstrable in both WT and Srr-KO mice. In vivo microdialysis study showed that METH (1 mg/kg)-induced DA release in the nucleus accumbens of Srr-KO mice previously treated with METH was significantly lower than that of the WT mice previously treated with METH. Interestingly, a single administration of METH (3 mg/kg) significantly increased the phosphorylation status of ERK1/2 in the striatum of WT, but not Srr-KO mice. CONCLUSIONS/SIGNIFICANCE: These findings suggest first, that SRR plays a role in the development of behavioral sensitization in mice after repeated administration of METH, and second that phosphorylation of ERK1/2 by METH may contribute to the development of this sensitization as seen in WT but not Srr-KO mice. PMID- 22530035 TI - Ethanol-mediated regulation of cytochrome P450 2A6 expression in monocytes: role of oxidative stress-mediated PKC/MEK/Nrf2 pathway. AB - Cytochrome P450 2A6 (CYP2A6) is known to metabolize nicotine, the major constituent of tobacco, leading to the production of toxic metabolites and induction of oxidative stress that result in liver damage and lung cancer. Recently, we have shown that CYP2A6 is induced by ethanol and metabolizes nicotine into cotinine and other metabolites leading to generation of reactive oxygen species (ROS) in U937 monocytes. However, the mechanism by which CYP2A6 is induced by ethanol is unknown. In this study, we have examined the role of the PKC/Nrf2 pathway (protein kinase C-mediated phosphorylation and translocation of nuclear erythroid 2-related factor 2 to the nucleus) in ethanol-mediated CYP2A6 induction. Our results showed that 100 mM ethanol significantly induced CYP2A6 mRNA and protein (~150%) and increased ROS formation, and induction of gene expression and ROS were both completely blocked by treatment with either a CYP2E1 inhibitor (diallyl sulfide) or an antioxidant (vitamin C). The results suggest the role of oxidative stress in the regulation of CYP2A6 expression. Subsequently, we investigated the role of Nrf2 pathway in oxidative stress mediated regulation of CYP2A6 expression in U937 monocytes. Our results showed that butylated hydroxyanisole, a stabilizer of nuclear Nrf2, increased CYP2A6 levels >200%. Staurosporine, an inhibitor of PKC, completely abolished ethanol induced CYP2A6 expression. Furthermore, our results showed that a specific inhibitor of mitogen-activated protein kinase kinase (MEK) (U0126) completely abolished ethanol-mediated CYP2A6 induction and Nrf2 translocation. Overall, these results suggest that CYP2E1-mediated oxidative stress produced as a result of ethanol metabolism translocates Nrf2 into the nucleus through PKC/MEK pathway, resulting in the induction of CYP2A6 in monocytes. An increased level of CYP2A6 in monocytes is expected to further increase oxidative stress in smokers through CYP2A6-mediated nicotine metabolism. Thus, this study has clinical relevance because of the high incidence of alcohol use among smokers, especially in HIV infected individuals. PMID- 22530036 TI - Brewhouse-resident microbiota are responsible for multi-stage fermentation of American coolship ale. AB - American coolship ale (ACA) is a type of spontaneously fermented beer that employs production methods similar to traditional Belgian lambic. In spite of its growing popularity in the American craft-brewing sector, the fermentation microbiology of ACA has not been previously described, and thus the interface between production methodology and microbial community structure is unexplored. Using terminal restriction fragment length polymorphism (TRFLP), barcoded amplicon sequencing (BAS), quantitative PCR (qPCR) and culture-dependent analysis, ACA fermentations were shown to follow a consistent fermentation progression, initially dominated by Enterobacteriaceae and a range of oxidative yeasts in the first month, then ceding to Saccharomyces spp. and Lactobacillales for the following year. After one year of fermentation, Brettanomyces bruxellensis was the dominant yeast population (occasionally accompanied by minor populations of Candida spp., Pichia spp., and other yeasts) and Lactobacillales remained dominant, though various aerobic bacteria became more prevalent. This work demonstrates that ACA exhibits a conserved core microbial succession in absence of inoculation, supporting the role of a resident brewhouse microbiota. These findings establish this core microbial profile of spontaneous beer fermentations as a target for production control points and quality standards for these beers. PMID- 22530037 TI - Anti-angiogenic activity of a small molecule STAT3 inhibitor LLL12. AB - BACKGROUND: Recent data indicate the Signal Transducer and Activator of Transcription 3 (STAT3) pathway is required for VEGF production and angiogenesis in various types of cancers. STAT3 inhibitors have been shown to reduce tumor microvessel density in tumors but a direct anti-angiogenic activity has not been described. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the direct action of a small molecule inhibitor of STAT3 (LLL12) in human umbilical cord vascular endothelial cells (HUVECs) in vitro, in a Matrigel model for angiogenesis in vivo, and its antitumor activity in a xenograft model of osteosarcoma. LLL12 (100 nM) significantly inhibited VEGF-stimulated STAT3 phosphorylation in HUVECs, reduced their proliferation/migration and inhibited VEGF-induced tube formation. Morphologic analysis of LLL12 treated HUVECs demonstrated marked changes in actin/tubulin distribution and bundling. In scid mice, LLL12 reduced microvessel invasion into VEGF-infused Matrigel plugs by ~90% at a dose of 5 mg/kg daily. Following a period of tumor progression (2 weeks), LLL12 completely suppressed further growth of established OS-1 osteosarcoma xenografts. Pharmacodynamic studies showed robust phosphorylated STAT3 in control tumors, whereas phospho STAT3 was not detected in LLL12-treated OS-1 tumors. Treated tumors demonstrated decreased proliferation (Ki67 staining), and decreased microvessel density (CD34 staining), but no significant increase in apoptosis (TUNEL staining), relative to controls. Assay of angiogenic factors, using an antibody array, showed VEGF, MMP 9, Angiopoietin1/2, Tissue Factor and FGF-1 expression were dramatically reduced in LLL12-treated tumors compared to control tumors. CONCLUSIONS: These findings provide the first evidence that LLL12 effectively inhibits tumor angiogenesis both in vitro and in vivo. PMID- 22530038 TI - Environmental effects on vertebrate species richness: testing the energy, environmental stability and habitat heterogeneity hypotheses. AB - BACKGROUND: Explaining species richness patterns is a central issue in biogeography and macroecology. Several hypotheses have been proposed to explain the mechanisms driving biodiversity patterns, but the causes of species richness gradients remain unclear. In this study, we aimed to explain the impacts of energy, environmental stability, and habitat heterogeneity factors on variation of vertebrate species richness (VSR), based on the VSR pattern in China, so as to test the energy hypothesis, the environmental stability hypothesis, and the habitat heterogeneity hypothesis. METHODOLOGY/PRINCIPAL FINDINGS: A dataset was compiled containing the distributions of 2,665 vertebrate species and eleven ecogeographic predictive variables in China. We grouped these variables into categories of energy, environmental stability, and habitat heterogeneity and transformed the data into 100 * 100 km quadrat systems. To test the three hypotheses, AIC-based model selection was carried out between VSR and the variables in each group and correlation analyses were conducted. There was a decreasing VSR gradient from the southeast to the northwest of China. Our results showed that energy explained 67.6% of the VSR variation, with the annual mean temperature as the main factor, which was followed by annual precipitation and NDVI. Environmental stability factors explained 69.1% of the VSR variation and both temperature annual range and precipitation seasonality had important contributions. By contrast, habitat heterogeneity variables explained only 26.3% of the VSR variation. Significantly positive correlations were detected among VSR, annual mean temperature, annual precipitation, and NDVI, whereas the relationship of VSR and temperature annual range was strongly negative. In addition, other variables showed moderate or ambiguous relations to VSR. CONCLUSIONS/SIGNIFICANCE: The energy hypothesis and the environmental stability hypothesis were supported, whereas little support was found for the habitat heterogeneity hypothesis. PMID- 22530039 TI - Self care behavior among patients with diabetes in Harari, Eastern Ethiopia: the health belief model perspective. AB - BACKGROUND: Diabetes mellitus is a chronic disease that requires lifelong medical treatments and a life style adjustment. To prevent serious morbidity and mortality, it requires dedication to demanding self-care behaviors in multiple domains. The objective of this study was to identify predictors of self care behaviors among patients with diabetes. METHODS: From a total of 425 follow up diabetic patients, a quantitative cross sectional study was conducted among 222 of them from three different hospitals in Harar town, from March to April, 2011. The sample was taken using simple random sampling method. Data was collected using pretested questionnaire. Descriptive statistics multiple logistic regression analysis were also used to assess the predicators of self care behaviors among patients with diabetes. RESULT: Majority of the study respondents 134 (60.4%) were female and the mean age was 49.7 (SD +/- 14.7) years. More than half 147(66.2%) of them were medically diagnosed with type-2 diabetes. 208(93.7%) had general knowledge about diabetes and specific knowledge about diabetes self care 207(93.2%). Large proportion of them had moderate perceived susceptibility 174(78.4%) and severity 112(50.5%). More than half of the respondents 149(67.1%) had less perceived barrier while only 30 (13.5%) of them had high self efficacy to self care practices related to diabetes mellitus. Only 87(39.2%) followed the recommended self care practices on diabetes. CONCLUSIONS: Patients with less frequent information were less likely to take diabetes self care. Patients who were more educated, middle income, had high perceived severity of diabetes and less perceived barrier to self care were more likely to take diabetes self care. To increase the self care behavior, diabetes messages should focus on severity of diabetes and how to overcome barriers for self care by segmenting the audiences based on income and educational status with increasing the frequency and reach of message on diabetes. PMID- 22530040 TI - Toxoplasma gondii actively inhibits neuronal function in chronically infected mice. AB - Upon infection with the obligate intracellular parasite Toxoplasma gondii, fast replicating tachyzoites infect a broad spectrum of host cells including neurons. Under the pressure of the immune response, tachyzoites convert into slow replicating bradyzoites, which persist as cysts in neurons. Currently, it is unclear whether T. gondii alters the functional activity of neurons, which may contribute to altered behaviour of T. gondii-infected mice and men. In the present study we demonstrate that upon oral infection with T. gondii cysts, chronically infected BALB/c mice lost over time their natural fear against cat urine which was paralleled by the persistence of the parasite in brain regions affecting behaviour and odor perception. Detailed immunohistochemistry showed that in infected neurons not only parasitic cysts but also the host cell cytoplasm and some axons stained positive for Toxoplasma antigen suggesting that parasitic proteins might directly interfere with neuronal function. In fact, in vitro live cell calcium (Ca(2+)) imaging studies revealed that tachyzoites actively manipulated Ca(2+) signalling upon glutamate stimulation leading either to hyper- or hypo-responsive neurons. Experiments with the endoplasmatic reticulum Ca(2+) uptake inhibitor thapsigargin indicate that tachyzoites deplete Ca(2+) stores in the endoplasmatic reticulum. Furthermore in vivo studies revealed that the activity-dependent uptake of the potassium analogue thallium was reduced in cyst harbouring neurons indicating their functional impairment. The percentage of non-functional neurons increased over time In conclusion, both bradyzoites and tachyzoites functionally silence infected neurons, which may significantly contribute to the altered behaviour of the host. PMID- 22530041 TI - A novel dual-color reporter for identifying insulin-producing beta-cells and classifying heterogeneity of insulinoma cell lines. AB - Many research studies use immortalized cell lines as surrogates for primary beta- cells. We describe the production and use of a novel "indirect" dual-fluorescent reporter system that leads to mutually exclusive expression of EGFP in insulin producing (INS(+)) beta-cells or mCherry in non-beta-cells. Our system uses the human insulin promoter to initiate a Cre-mediated shift in reporter color within a single transgene construct and is useful for FACS selection of cells from single cultures for further analysis. Application of our reporter to presumably clonal HIT-T15 insulinoma cells, as well as other presumably clonal lines, indicates that these cultures are in fact heterogeneous with respect to INS(+) phenotype. Our strategy could be easily applied to other cell- or tissue-specific promoters. We anticipate its utility for FACS purification of INS(+) and glucose responsive beta-like-cells from primary human islet cell isolates or in vitro differentiated pluripotent stem cells. PMID- 22530042 TI - Limitations of gene duplication models: evolution of modules in protein interaction networks. AB - It has been generally acknowledged that the module structure of protein interaction networks plays a crucial role with respect to the functional understanding of these networks. In this paper, we study evolutionary aspects of the module structure of protein interaction networks, which forms a mesoscopic level of description with respect to the architectural principles of networks. The purpose of this paper is to investigate limitations of well known gene duplication models by showing that these models are lacking crucial structural features present in protein interaction networks on a mesoscopic scale. This observation reveals our incomplete understanding of the structural evolution of protein networks on the module level. PMID- 22530043 TI - Electrocardiographic left ventricular hypertrophy and outcome in hemodialysis patients. AB - BACKGROUND AND AIMS: Electrocardiography (ECG) is the most widely used initial screening test for the assessment of left ventricular hypertrophy (LVH), an independent predictor of cardiovascular mortality in patients with end-stage renal disease (ESRD). However, traditional ECG criteria based only on voltage to detect LVH have limited clinical utility for the detection of LVH because of their poor sensitivity. METHODS: This prospective observational study was undertaken to compare the prognostic significance of commonly used ECG criteria for LVH, namely Sokolow-Lyon voltage (SV) or voltage-duration product (SP) and Cornell voltage (CV) or voltage-duration product (CP) criteria, and to investigate the association between echocardiographic LV mass index (LVMI) and ECG-LVH criteria in ESRD patients, who consecutively started maintenance hemodialysis (HD) between January 2006 and December 2008. RESULTS: A total of 317 patients, who underwent both ECG and echocardiography, were included. Compared to SV and CV criteria, SP and CP criteria, respectively, correlated more closely with LVMI. In addition, CP criteria provided the highest positive predictive value for echocardiographic LVH. The 5-year cardiovascular survival rates were significantly lower in patients with ECG-LVH by each criterion. In multivariate analyses, echocardiographic LVH [adjusted hazard ratio (HR): 11.71; 95% confidence interval (CI): 1.57-87.18; P = 0.016] and ECG-LVH by SP (HR: 3.43; 95% CI: 1.32-8.92; P = 0.011) and CP (HR: 3.07; 95% CI: 1.16-8.11; P = 0.024) criteria, but not SV and CV criteria, were significantly associated with cardiovascular mortality. CONCLUSIONS: The product of QRS voltage and duration is helpful in identifying the presence of LVH and predicting cardiovascular mortality in incident HD patients. PMID- 22530044 TI - Identifying acute coronary syndrome patients approaching end-of-life. AB - BACKGROUND: Acute coronary syndrome (ACS) is common in patients approaching the end-of-life (EoL), but these patients rarely receive palliative care. We compared the utility of a palliative care prognostic tool (Gold Standards Framework (GSF)) and the Global Registry of Acute Coronary Events (GRACE) score, to help identify patients approaching EoL. METHODS AND FINDINGS: 172 unselected consecutive patients with confirmed ACS admitted over an eight-week period were assessed using prognostic tools and followed up for 12 months. GSF criteria identified 40 (23%) patients suitable for EoL care while GRACE identified 32 (19%) patients with >= 10% risk of death within 6 months. Patients meeting GSF criteria were older (p = 0.006), had more comorbidities (1.6 +/- 0.7 vs. 1.2 +/- 0.9, p = 0.007), more frequent hospitalisations before (p = 0.001) and after (0.0001) their index admission, and were more likely to die during follow-up (GSF+ 20% vs GSF- 7%, p = 0.03). GRACE score was predictive of 12-month mortality (C-statistic 0.75) and this was improved by the addition of previous hospital admissions and previous history of stroke (C-statistic 0.88). CONCLUSIONS: This study has highlighted a potentially large number of ACS patients eligible for EoL care. GSF or GRACE could be used in the hospital setting to help identify these patients. GSF identifies ACS patients with more comorbidity and at increased risk of hospital readmission. PMID- 22530046 TI - Stable expression of antibiotic-resistant gene ble from Streptoalloteichus hindustanus in the mitochondria of Chlamydomonas reinhardtii. AB - The mitochondrial expression of exogenous antibiotic resistance genes has not been demonstrated successfully to date, which has limited the development of antibiotic resistance genes as selectable markers for mitochondrial site-directed transformation in Chlamydomonas reinhardtii. In this work, the plasmid pBSLPNCB was constructed by inserting the gene ble of Streptoalloteichus hindustanus (Sh ble), encoding a small (14-kilodalton) protective protein into the site between TERMINVREP-Left repeats and the cob gene in a fragment of mitochondrial DNA (mtDNA) of C. reinhardtii. The fusion DNA-construct, which contained TERMINVREP Left, Sh ble, cob, and partial nd4 sequence, were introduced into the mitochondria of the respiratory deficient dum-1 mutant CC-2654 of C. reinhardtii by biolistic particle delivery system. A large number of transformants were obtained after eight weeks in the dark. Subsequent subculture of the transformants on the selection TAP media containing 3 ig/mL Zeomycin for 12 months resulted in genetically modified transgenic algae MT-Bs. Sequencing and Southern analyses on the mitochondrial genome of the different MT-B lines revealed that Sh ble gene had been integrated into the mitochondrial genome of C. reinhardtii. Both Western blot, using the anti-BLE monoclonal antibody, and Zeomycin tolerance analysis confirmed the presence of BLE protein in the transgenic algal cells. It indicates that the Sh ble gene can be stably expressed in the mitochondria of C. reinhardtii. PMID- 22530045 TI - Differential regulation of cutaneous oncoprotein HPVE6 by wtp53, mutant p53R248W and DeltaNp63alpha is HPV type dependent. AB - UV exposure and p53 mutations are major factors in non-melanoma skin cancer, whereas a role for HPV infections has not been defined. Previous data demonstrated the wtp53-mediated degradation of cutaneous HPV20E6 by caspase-3. DeltaNp63alpha and hot-spot mutant p53R248W conveyed a protective effect on HPV20E6 under these conditions. We demonstrate a differential regulation by wtp53 of the E6 genes of cutaneous types HPV4, HPV5, HPV7, HPV27, HPV38, HPV48, HPV60 and HPV77. Caspase- or proteasome-mediated down-regulation was HPV type dependent. Mutant p53R248W up-regulated expression of all these E6 proteins as did DeltaNp63alpha except for HPV38E6 which was down-regulated by the latter. None of these cellular proteins affected HPV41E6 expression. Ectopic expression of both mutp53R248W and DeltaNp63alpha in the normal NIKS keratinocyte cell line harbouring endogenous p53 and p63however led to a down-regulation of HPV20E6. We demonstrate that HPV20E6 expression in these cells is modulated by additional, yet unidentified, cellular protein(s), which are not necessarily involved in apoptosis or autophagy. We further demonstrate proliferation of HPV20E6 expressing keratinocytes. Levels of proteins involved in cell cycle control, cyclin-D1, cdk6 and p16(INK4a), phosphorylated pRB, as well as c-Jun and p-c-Jun, were all increased in these cells. HPV20E6 did not compete for the interaction between p16(INK4a) with cyclin-D1 or cdk6. Phosphorylation of pRB in the HPV20E6 expressing cells seems to be sufficient to override the cytokenetic block induced by the p16(INK4a)/pRB pathway. The present study demonstrates the diverse influence of p53 family members on individual cutaneous HPVE6 proteins. HPV20E6 expression also resulted in varying protein levels of factors involved in proliferation and differentiation. PMID- 22530047 TI - Identification of protein networks involved in the disease course of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. AB - A more detailed insight into disease mechanisms of multiple sclerosis (MS) is crucial for the development of new and more effective therapies. MS is a chronic inflammatory autoimmune disease of the central nervous system. The aim of this study is to identify novel disease associated proteins involved in the development of inflammatory brain lesions, to help unravel underlying disease processes. Brainstem proteins were obtained from rats with MBP induced acute experimental autoimmune encephalomyelitis (EAE), a well characterized disease model of MS. Samples were collected at different time points: just before onset of symptoms, at the top of the disease and following recovery. To analyze changes in the brainstem proteome during the disease course, a quantitative proteomics study was performed using two-dimensional difference in-gel electrophoresis (2D DIGE) followed by mass spectrometry. We identified 75 unique proteins in 92 spots with a significant abundance difference between the experimental groups. To find disease-related networks, these regulated proteins were mapped to existing biological networks by Ingenuity Pathway Analysis (IPA). The analysis revealed that 70% of these proteins have been described to take part in neurological disease. Furthermore, some focus networks were created by IPA. These networks suggest an integrated regulation of the identified proteins with the addition of some putative regulators. Post-synaptic density protein 95 (DLG4), a key player in neuronal signalling and calcium-activated potassium channel alpha 1 (KCNMA1), involved in neurotransmitter release, are 2 putative regulators connecting 64% of the identified proteins. Functional blocking of the KCNMA1 in macrophages was able to alter myelin phagocytosis, a disease mechanism highly involved in EAE and MS pathology. Quantitative analysis of differentially expressed brainstem proteins in an animal model of MS is a first step to identify disease-associated proteins and networks that warrant further research to study their actual contribution to disease pathology. PMID- 22530049 TI - Male-dominant activation of rat renal organic anion transporter 1 (Oat1) and 3 (Oat3) expression by transcription factor BCL6. AB - BACKGROUND: Organic anion transporters 1 (Oat1) and 3 (Oat3) mediate the transport of organic anions, including frequently prescribed drugs, across cell membranes in kidney proximal tubule cells. In rats, these transporters are known to be male-dominant and testosterone-dependently expressed. The molecular mechanisms that are involved in the sex-dependent expression are unknown. Our aim was to identify genes that show a sex-dependent expression and could be involved in male-dominant regulation of Oat1 and Oat3. METHODOLOGY/PRINCIPAL FINDINGS: Promoter activities of Oat1 and Oat3 were analyzed using luciferase assays. Expression profiling was done using a SurePrint G3 rat GE 8 * 60K microarray. RNA was isolated from renal cortical slices of four adult rats per sex. To filter the achieved microarray data for genes expressed in proximal tubule cells, transcription database alignment was carried out. We demonstrate that predicted androgen response elements in the promoters of Oat1 and Oat3 are not functional when the promoters were expressed in OK cells. Using microarray analyses we analyzed 17,406 different genes. Out of these genes, 56 exhibit a sex-dependent expression in rat proximal tubule cells. As genes potentially involved in the regulation of Oat1 and Oat3 expression, we identified, amongst others, the male dominant hydroxysteroid (17-beta) dehydrogenase 1 (Hsd17b1), B-cell CLL/lymphoma 6 (BCL6), and polymerase (RNA) III (DNA directed) polypeptide G (Polr3g). Moreover, our results revealed that the transcription factor BCL6 activates promoter constructs of Oat1 and Oat3. CONCLUSION: The results indicate that the male-dominant expression of both transporters, Oat1 and Oat3, is possibly not directly regulated by the classical androgen receptor mediated transcriptional pathway but appears to be regulated by the transcription factor BCL6. PMID- 22530048 TI - Transcriptional portrait of Actinobacillus pleuropneumoniae during acute disease- potential strategies for survival and persistence in the host. AB - BACKGROUND: Gene expression profiles of bacteria in their natural hosts can provide novel insight into the host-pathogen interactions and molecular determinants of bacterial infections. In the present study, the transcriptional profile of the porcine lung pathogen Actinobacillus pleuropneumoniae was monitored during the acute phase of infection in its natural host. METHODOLOGY/PRINCIPAL FINDINGS: Bacterial expression profiles of A. pleuropneumoniae isolated from lung lesions of 25 infected pigs were compared in samples taken 6, 12, 24 and 48 hours post experimental challenge. Within 6 hours, focal, fibrino hemorrhagic lesions could be observed in the pig lungs, indicating that A. pleuropneumoniae had managed to establish itself successfully in the host. We identified 237 differentially regulated genes likely to encode functions required by the bacteria for colonization and survival in the host. This group was dominated by genes involved in various aspects of energy metabolism, especially anaerobic respiration and carbohydrate metabolism. Remodeling of the bacterial envelope and modifications of posttranslational processing of proteins also appeared to be of importance during early infection. The results suggested that A. pleuropneumoniae is using various strategies to increase its fitness, such as applying Na+ pumps as an alternative way of gaining energy. Furthermore, the transcriptional data provided potential clues as to how A. pleuropneumoniae is able to circumvent host immune factors and survive within the hostile environment of host macrophages. This persistence within macrophages may be related to urease activity, mobilization of various stress responses and active evasion of the host defenses by cell surface sialylation. CONCLUSIONS/SIGNIFICANCE: The data presented here highlight the importance of metabolic adjustments to host conditions as virulence factors of infecting microorganisms and help to provide insight into the mechanisms behind the efficient colonization and persistence of A. pleuropneumoniae during acute disease. PMID- 22530051 TI - Dormancy signatures and metastasis in estrogen receptor positive and negative breast cancer. AB - Breast cancers can recur after removal of the primary tumor and treatment to eliminate remaining tumor cells. Recurrence may occur after long periods of time during which there are no clinical symptoms. Tumor cell dormancy may explain these prolonged periods of asymptomatic residual disease and treatment resistance. We generated a dormancy gene signature from published experimental models and applied it to both breast cancer cell line expression data as well as four published clinical studies of primary breast cancers. We found that estrogen receptor (ER) positive breast cell lines and primary tumors have significantly higher dormancy signature scores (P<0.0000001) than ER- cell lines and tumors. In addition, a stratified analysis combining all ER+ tumors in four studies indicated 2.1 times higher hazard of recurrence among patients whose tumors had low dormancy scores (LDS) compared to those whose tumors had high dormancy scores (HDS) (p<0.000005). The trend was shown in all four individual studies. Suppression of two dormancy genes, BHLHE41 and NR2F1, resulted in increased in vivo growth of ER positive MCF7 cells. The patient data analysis suggests that disseminated ER positive tumor cells carrying a dormancy signature are more likely to undergo prolonged dormancy before resuming metastatic growth. Furthermore, genes identified with this approach might provide insight into the mechanisms of dormancy onset and maintenance as well as dormancy models using human breast cancer cell lines. PMID- 22530050 TI - The role of methylation in the intrinsic dynamics of B- and Z-DNA. AB - Methylation of cytosine at the 5-carbon position (5 mC) is observed in both prokaryotes and eukaryotes. In humans, DNA methylation at CpG sites plays an important role in gene regulation and has been implicated in development, gene silencing, and cancer. In addition, the CpG dinucleotide is a known hot spot for pathologic mutations genome-wide. CpG tracts may adopt left-handed Z-DNA conformations, which have also been implicated in gene regulation and genomic instability. Methylation facilitates this B-Z transition but the underlying mechanism remains unclear. Herein, four structural models of the dinucleotide d(GC)(5) repeat sequence in B-, methylated B-, Z-, and methylated Z-DNA forms were constructed and an aggregate 100 nanoseconds of molecular dynamics simulations in explicit solvent under physiological conditions was performed for each model. Both unmethylated and methylated B-DNA were found to be more flexible than Z-DNA. However, methylation significantly destabilized the BII, relative to the BI, state through the Gp5mC steps. In addition, methylation decreased the free energy difference between B- and Z-DNA. Comparisons of alpha/gamma backbone torsional angles showed that torsional states changed marginally upon methylation for B-DNA, and Z-DNA. Methylation-induced conformational changes and lower energy differences may contribute to the transition to Z-DNA by methylated, over unmethylated, B-DNA and may be a contributing factor to biological function. PMID- 22530052 TI - Incidence and risk factors for hepatocellular carcinoma in Texas Latinos: implications for prevention research. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is increasing in the U.S. despite a decline in cancer overall. Latinos have higher rates of HCC than the general population according to the Surveillance, Epidemiology, and End Results (SEER) Program. Not included in SEER, Texas Latinos make up one-fifth of the U.S. Latino population. To determine whether HCC incidence differs among U.S. and Texas Latinos, this descriptive study compares HCC incidence from 1995 through 2006 among three Latino populations: U.S. SEER, Texas overall and a South Texas subset. To identify lines of prevention research, we compare prevalence of known HCC risk factors among these Latino groups. METHODS: Data were collected from the U.S. SEER Program, Texas Cancer Registry and Texas Department of State Health Services (TDSHS). Annual age-specific and age-adjusted HCC incidence rates, annual percent changes (APCs) and 95% confidence intervals were calculated as well as prevalence of obesity, diabetes, heavy alcohol use and cigarette smoking. RESULTS: Of the three Latino groups compared, South Texas Latinos had the highest age-adjusted HCC incidence rates and SEER Latinos had the lowest (10.6/100,000 (10.1-11.1) and 7.5/100,000 (7.2-7.7), respectively). HCC incidence significantly increased over time (APCs>0) among Latinos in all three geographic groups. Between 1995 and 2006, there was an increase in obesity among all three populations, and obesity was highest among South Texas Latinos. Diabetes increased among U.S. Latinos, and Latino women in South Texas had significantly higher diabetes prevalence than U.S. Latino women. Cigarette smoking and heavy alcohol use were similar among groups. CONCLUSIONS: The incidence of HCC among Latinos in South Texas is higher than elsewhere in the United States. Higher rates of HCC among Texas and South Texas Latinos may be associated with greater prevalence of obesity and diabetes, risk factors for HCC that are amenable to intervention. PMID- 22530053 TI - An iterative jackknife approach for assessing reliability and power of FMRI group analyses. AB - For functional magnetic resonance imaging (fMRI) group activation maps, so-called second-level random effect approaches are commonly used, which are intended to be generalizable to the population as a whole. However, reliability of a certain activation focus as a function of group composition or group size cannot directly be deduced from such maps. This question is of particular relevance when examining smaller groups (<20-27 subjects). The approach presented here tries to address this issue by iteratively excluding each subject from a group study and presenting the overlap of the resulting (reduced) second-level maps in a group percent overlap map. This allows to judge where activation is reliable even upon excluding one, two, or three (or more) subjects, thereby also demonstrating the inherent variability that is still present in second-level analyses. Moreover, when progressively decreasing group size, foci of activation will become smaller and/or disappear; hence, the group size at which a given activation disappears can be considered to reflect the power necessary to detect this particular activation. Systematically exploiting this effect allows to rank clusters according to their observable effect size. The approach is tested using different scenarios from a recent fMRI study (children performing a "dual-use" fMRI task, n = 39), and the implications of this approach are discussed. PMID- 22530054 TI - Selenocysteine insertion sequence binding protein 2L is implicated as a novel post-transcriptional regulator of selenoprotein expression. AB - The amino acid selenocysteine (Sec) is encoded by UGA codons. Recoding of UGA from stop to Sec requires a Sec insertion sequence (SECIS) element in the 3' UTR of selenoprotein mRNAs. SECIS binding protein 2 (SBP2) binds the SECIS element and is essential for Sec incorporation into the nascent peptide. SBP2-like (SBP2L) is a paralogue of SBP2 in vertebrates and is the only SECIS binding protein in some invertebrates where it likely directs Sec incorporation. However, vertebrate SBP2L does not promote Sec incorporation in in vitro assays. Here we present a comparative analysis of SBP2 and SBP2L SECIS binding properties and demonstrate that its inability to promote Sec incorporation is not due to lower SECIS affinity but likely due to lack of a SECIS dependent domain association that is found in SBP2. Interestingly, however, we find that an invertebrate version of SBP2L is fully competent for Sec incorporation in vitro. Additionally, we present the first evidence that SBP2L interacts with selenoprotein mRNAs in mammalian cells, thereby implying a role in selenoprotein expression. PMID- 22530055 TI - Hope modified the association between distress and incidence of self-perceived medical errors among practicing physicians: prospective cohort study. AB - The presence of hope has been found to influence an individual's ability to cope with stressful situations. The objective of this study is to evaluate the relationship between medical errors, hope and burnout among practicing physicians using validated metrics. Prospective cohort study was conducted among hospital based physicians practicing in Japan (N = 836). Measures included the validated Burnout Scale, self-assessment of medical errors and Herth Hope Index (HHI). The main outcome measure was the frequency of self-perceived medical errors, and Poisson regression analysis was used to evaluate the association between hope and medical error. A total of 361 errors were reported in 836 physician-years. We observed a significant association between hope and self-report of medical errors. Compared with the lowest tertile category of HHI, incidence rate ratios (IRRs) of self-perceived medical errors of physicians in the highest category were 0.44 (95%CI, 0.34 to 0.58) and 0.54 (95%CI, 0.42 to 0.70) respectively, for the 2(nd) and 3(rd) tertile. In stratified analysis by hope score, among physicians with a low hope score, those who experienced higher burnout reported higher incidence of errors; physicians with high hope scores did not report high incidences of errors, even if they experienced high burnout. Self-perceived medical errors showed a strong association with physicians' hope, and hope modified the association between physicians' burnout and self-perceived medical errors. PMID- 22530057 TI - Flea diversity as an element for persistence of plague bacteria in an East African plague focus. AB - Plague is a flea-borne rodent-associated zoonotic disease that is caused by Yersinia pestis and characterized by long quiescent periods punctuated by rapidly spreading epidemics and epizootics. How plague bacteria persist during inter epizootic periods is poorly understood, yet is important for predicting when and where epizootics are likely to occur and for designing interventions aimed at local elimination of the pathogen. Existing hypotheses of how Y. pestis is maintained within plague foci typically center on host abundance or diversity, but little attention has been paid to the importance of flea diversity in enzootic maintenance. Our study compares host and flea abundance and diversity along an elevation gradient that spans from low elevation sites outside of a plague focus in the West Nile region of Uganda (~725-1160 m) to higher elevation sites within the focus (~1380-1630 m). Based on a year of sampling, we showed that host abundance and diversity, as well as total flea abundance on hosts was similar between sites inside compared with outside the plague focus. By contrast, flea diversity was significantly higher inside the focus than outside. Our study highlights the importance of considering flea diversity in models of Y. pestis persistence. PMID- 22530056 TI - miRNAs expression analysis in paired fresh/frozen and dissected formalin fixed and paraffin embedded glioblastoma using real-time pCR. AB - miRNAs are small molecules involved in gene regulation. Each tissue shows a characteristic miRNAs epression profile that could be altered during neoplastic transformation. Glioblastoma is the most aggressive brain tumour of the adult with a high rate of mortality. Recognizing a specific pattern of miRNAs for GBM could provide further boost for target therapy. The availability of fresh tissue for brain specimens is often limited and for this reason the possibility of starting from formalin fixed and paraffin embedded tissue (FFPE) could very helpful even in miRNAs expression analysis. We analysed a panel of 19 miRNAs in 30 paired samples starting both from FFPE and Fresh/Frozen material. Our data revealed that there is a good correlation in results obtained from FFPE in comparison with those obtained analysing miRNAs extracted from Fresh/Frozen specimen. In the few cases with a not good correlation value we noticed that the discrepancy could be due to dissection performed in FFPE samples. To the best of our knowledge this is the first paper demonstrating that the results obtained in miRNAs analysis using Real-Time PCR starting from FFPE specimens of glioblastoma are comparable with those obtained in Fresh/Frozen samples. PMID- 22530058 TI - Evidence of differential allelic effects between adolescents and adults for plasma high-density lipoprotein. AB - A recent meta-analysis of genome-wide association (GWA) studies identified 95 loci that influence lipid traits in the adult population and found that collectively these explained about 25-30% of heritability for each trait. Little is known about how these loci affect lipid levels in early life, but there is evidence that genetic effects on HDL- and LDL-cholesterol (HDL-C, LDL-C) and triglycerides vary with age. We studied Australian adults (N = 10,151) and adolescents (N = 2,363) who participated in twin and family studies and for whom we have lipid phenotypes and genotype information for 91 of the 95 genetic variants. Heterogeneity tests between effect sizes in adult and adolescent cohorts showed an excess of heterogeneity for HDL-C (p(Het)<0.05 at 5 out of 37 loci), but no more than expected by chance for LDL-C (1 out of 14 loci), or trigycerides (0 out 24). There were 2 (out of 5) with opposite direction of effect in adolescents compared to adults for HDL-C, but none for LDL-C. The biggest difference in effect size was for LDL-C at rs6511720 near LDLR, adolescents (0.021 +/- 0.033 mmol/L) and adults (0.157 +/- 0.023 mmol/L), p(Het) = 0.013; followed by ZNF664 (p(Het) = 0.018) and PABPC4 (p(Het) = 0.034) for HDL C. Our findings suggest that some of the previously identified variants associate differently with lipid traits in adolescents compared to adults, either because of developmental changes or because of greater interactions with environmental differences in adults. PMID- 22530059 TI - The osteopontin level in liver, adipose tissue and serum is correlated with fibrosis in patients with alcoholic liver disease. AB - BACKGROUND: Osteopontin (OPN) plays an important role in the progression of chronic liver diseases. We aimed to quantify the liver, adipose tissue and serum levels of OPN in heavy alcohol drinkers and to compare them with the histological severity of hepatic inflammation and fibrosis. METHODOLOGY/PRINCIPAL FINDINGS: OPN was evaluated in the serum of a retrospective and prospective group of 109 and 95 heavy alcohol drinkers, respectively, in the liver of 34 patients from the retrospective group, and in the liver and adipose tissue from an additional group of 38 heavy alcohol drinkers. Serum levels of OPN increased slightly with hepatic inflammation and progressively with the severity of hepatic fibrosis. Hepatic OPN expression correlated with hepatic inflammation, fibrosis, TGFbeta expression, neutrophils accumulation and with the serum OPN level. Interestingly, adipose tissue OPN expression also correlated with hepatic fibrosis even after 7 days of alcohol abstinence. The elevated serum OPN level was an independent risk factor in estimating significant (F >= 2) fibrosis in a model combining alkaline phosphatase, albumin, hemoglobin, OPN and FibroMeter(r) levels. OPN had an area under the receiving operator curve that estimated significant fibrosis of 0.89 and 0.88 in the retrospective and prospective groups, respectively. OPN, Hyaluronate (AUROC: 0.88), total Cytokeratin 18 (AUROC: 0.83) and FibroMeter(r) (AUROC: 0.90) estimated significance to the same extent in the retrospective group. Finally, the serum OPN levels also correlated with hepatic fibrosis and estimated significant (F >= 2) fibrosis in 86 patients with chronic hepatitis C, which suggested that its elevated level could be a general response to chronic liver injury. CONCLUSION/SIGNIFICANCE: OPN increased in the liver, adipose tissue and serum with liver fibrosis in alcoholic patients. Further, OPN is a new relevant biomarker for significant liver fibrosis. OPN could thus be an important actor in the pathogenesis of this chronic liver disease. PMID- 22530060 TI - A redox-sensitive luciferase assay for determining the localization and topology of endoplasmic reticulum proteins. AB - Correct localization and transmembrane topology are crucial for the proteins residing and functioning in the endoplasmic reticulum (ER). We have developed a rapid and convenient assay, based on the redox-sensitive luciferase from Gaussia princeps (Gluc) and green fluorescence protein (GFP), to determine the localization or topology of ER proteins. Using the tandem Gluc-GFP reporter fused to different positions of a target protein, we successfully characterized the topologies of two ER transmembrane proteins Herp and HRD1 that are involved in the ER quality control system. This assay method may also be applicable to the proteins in secretory pathway, plasma membrane, and other compartments of cells. PMID- 22530061 TI - A screen for genes expressed in the olfactory organs of Drosophila melanogaster identifies genes involved in olfactory behaviour. AB - BACKGROUND: For insects the sense of smell and associated olfactory-driven behaviours are essential for survival. Insects detect odorants with families of olfactory receptor proteins that are very different to those of mammals, and there are likely to be other unique genes and genetic pathways involved in the function and development of the insect olfactory system. METHODOLOGY/PRINCIPAL FINDINGS: We have performed a genetic screen of a set of 505 Drosophila melanogaster gene trap insertion lines to identify novel genes expressed in the adult olfactory organs. We identified 16 lines with expression in the olfactory organs, many of which exhibited expression of the trapped genes in olfactory receptor neurons. Phenotypic analysis showed that six of the lines have decreased olfactory responses in a behavioural assay, and for one of these we showed that precise excision of the P element reverts the phenotype to wild type, confirming a role for the trapped gene in olfaction. To confirm the identity of the genes trapped in the lines we performed molecular analysis of some of the insertion sites. While for many lines the reported insertion sites were correct, we also demonstrated that for a number of lines the reported location of the element was incorrect, and in three lines there were in fact two pGT element insertions. CONCLUSIONS/SIGNIFICANCE: We identified 16 new genes expressed in the Drosophila olfactory organs, the majority in neurons, and for several of the gene trap lines demonstrated a defect in olfactory-driven behaviour. Further characterisation of these genes and their roles in olfactory system function and development will increase our understanding of how the insect olfactory system has evolved to perform the same essential function to that of mammals, but using very different molecular genetic mechanisms. PMID- 22530062 TI - Phylogeographic analysis of HIV-1 subtype C dissemination in Southern Brazil. AB - The HIV-1 subtype C has spread efficiently in the southern states of Brazil (Rio Grande do Sul, Santa Catarina and Parana). Phylogeographic studies indicate that the subtype C epidemic in southern Brazil was initiated by the introduction of a single founder virus population at some time point between 1960 and 1980, but little is known about the spatial dynamics of viral spread. A total of 135 Brazilian HIV-1 subtype C pol sequences collected from 1992 to 2009 at the three southern state capitals (Porto Alegre, Florianopolis and Curitiba) were analyzed. Maximum-likelihood and Bayesian methods were used to explore the degree of phylogenetic mixing of subtype C sequences from different cities and to reconstruct the geographical pattern of viral spread in this country region. Phylogeographic analyses supported the monophyletic origin of the HIV-1 subtype C clade circulating in southern Brazil and placed the root of that clade in Curitiba (Parana state). This analysis further suggested that Florianopolis (Santa Catarina state) is an important staging post in the subtype C dissemination displaying high viral migration rates from and to the other cities, while viral flux between Curitiba and Porto Alegre (Rio Grande do Sul state) is very low. We found a positive correlation (r(2) = 0.64) between routine travel and viral migration rates among localities. Despite the intense viral movement, phylogenetic intermixing of subtype C sequences from different Brazilian cities is lower than expected by chance. Notably, a high proportion (67%) of subtype C sequences from Porto Alegre branched within a single local monophyletic sub cluster. These results suggest that the HIV-1 subtype C epidemic in southern Brazil has been shaped by both frequent viral migration among states and in situ dissemination of local clades. PMID- 22530063 TI - Interactive network analytical tool for instantaneous bespoke interrogation of food safety notifications. AB - BACKGROUND: The globalization of food supply necessitates continued advances in regulatory control measures to ensure that citizens enjoy safe and adequate nutrition. The aim of this study was to extend previous reports on network analysis relating to food notifications by including an optional filter by type of notification and in cases of contamination, by type of contaminant in the notified foodstuff. METHODOLOGY/PRINCIPAL FINDINGS: A filter function has been applied to enable processing of selected notifications by contaminant or type of notification to i) capture complexity, ii) analyze trends, and iii) identify patterns of reporting activities between countries. The program rapidly assesses nations' roles as transgressor and/or detector for each category of contaminant and for the key class of border rejection. In the open access demonstration version, the majority of notifications in the Rapid Alert System for Food and Feed were categorized by contaminant type as mycotoxin (50.4%), heavy metals (10.9%) or bacteria (20.3%). Examples are given demonstrating how network analytical approaches complement, and in some cases supersede, descriptive statistics such as frequency counts, which may give limited or potentially misleading information. One key feature is that network analysis takes the relationship between transgressor and detector countries, along with number of reports and impact simultaneously into consideration. Furhermore, the indices that compliment the network maps and reflect each country's transgressor and detector activities allow comparisons to be made between (transgressing vs. detecting) as well as within (e.g. transgressing) activities. CONCLUSIONS/SIGNIFICANCE: This further development of the network analysis approach to food safety contributes to a better understanding of the complexity of the effort ensuring food is safe for consumption in the European Union. The unique patterns of the interplay between detectors and transgressors, instantly revealed by our approach, could supplement the intelligence gathered by regulatory authorities and inform risk based sampling protocols. PMID- 22530064 TI - The effects of two types of sleep deprivation on visual working memory capacity and filtering efficiency. AB - Sleep deprivation has adverse consequences for a variety of cognitive functions. The exact effects of sleep deprivation, though, are dependent upon the cognitive process examined. Within working memory, for example, some component processes are more vulnerable to sleep deprivation than others. Additionally, the differential impacts on cognition of different types of sleep deprivation have not been well studied. The aim of this study was to examine the effects of one night of total sleep deprivation and 4 nights of partial sleep deprivation (4 hours in bed/night) on two components of visual working memory: capacity and filtering efficiency. Forty-four healthy young adults were randomly assigned to one of the two sleep deprivation conditions. All participants were studied: 1) in a well-rested condition (following 6 nights of 9 hours in bed/night); and 2) following sleep deprivation, in a counter-balanced order. Visual working memory testing consisted of two related tasks. The first measured visual working memory capacity and the second measured the ability to ignore distractor stimuli in a visual scene (filtering efficiency). Results showed neither type of sleep deprivation reduced visual working memory capacity. Partial sleep deprivation also generally did not change filtering efficiency. Total sleep deprivation, on the other hand, did impair performance in the filtering task. These results suggest components of visual working memory are differentially vulnerable to the effects of sleep deprivation, and different types of sleep deprivation impact visual working memory to different degrees. Such findings have implications for operational settings where individuals may need to perform with inadequate sleep and whose jobs involve receiving an array of visual information and discriminating the relevant from the irrelevant prior to making decisions or taking actions (e.g., baggage screeners, air traffic controllers, military personnel, health care providers). PMID- 22530065 TI - Similar genetic basis of resistance to Bt toxin Cry1Ac in Boll-selected and diet selected strains of pink bollworm. AB - Genetically engineered cotton and corn plants producing insecticidal Bacillus thuringiensis (Bt) toxins kill some key insect pests. Yet, evolution of resistance by pests threatens long-term insect control by these transgenic Bt crops. We compared the genetic basis of resistance to Bt toxin Cry1Ac in two independently derived, laboratory-selected strains of a major cotton pest, the pink bollworm (Pectinophora gossypiella [Saunders]). The Arizona pooled resistant strain (AZP-R) was started with pink bollworm from 10 field populations and selected with Cry1Ac in diet. The Bt4R resistant strain was started with a long term susceptible laboratory strain and selected first with Bt cotton bolls and later with Cry1Ac in diet. Previous work showed that AZP-R had three recessive mutations (r1, r2, and r3) in the pink bollworm cadherin gene (PgCad1) linked with resistance to Cry1Ac and Bt cotton producing Cry1Ac. Here we report that inheritance of resistance to a diagnostic concentration of Cry1Ac was recessive in Bt4R. In interstrain complementation tests for allelism, F(1) progeny from crosses between AZP-R and Bt4R were resistant to Cry1Ac, indicating a shared resistance locus in the two strains. Molecular analysis of the Bt4R cadherin gene identified a novel 15-bp deletion (r4) predicted to cause the loss of five amino acids upstream of the Cry1Ac-binding region of the cadherin protein. Four recessive mutations in PgCad1 are now implicated in resistance in five different strains, showing that mutations in cadherin are the primary mechanism of resistance to Cry1Ac in laboratory-selected strains of pink bollworm from Arizona. PMID- 22530066 TI - Population-attributable risks for ischemic stroke in a community in South Brazil: a case-control study. AB - BACKGROUND: Risk factors for ischemic stroke are mostly known, but it is still unclear in most countries, what are their combined population-attributable risk percent (PAR%). In a case-control study the individual odds ratios (ORs) and the individual and combined PAR%, including risk factors not addressed in previous studies were estimated. METHODS: Cases and controls were selected from patients attending to an emergency department. Cases were patients aged with 45 years or more with the first episode of ischemic stroke, characterized by a focal neurological deficit or change in the mental status occurring during the previous 24 hours. Controls, matched to cases by age and gender, were selected from patients without neurological complaints. RESULTS: 133 cases and 272 controls were studied. Odds ratios for ischemic stroke were: atrial fibrillation (27.3; CI 95% 7.5-99.9), left ventricular hypertrophy (20.3; CI 95% 8.8-46.4), history of hypertension (11.2; CI 95% 5.4-23.3), physical inactivity (6.6; CI 95% 3.3-13.1), low levels of HDL-cholesterol (5.0; CI 95%2.8-8.9), heavy smoking (2.8; CI 95% 1.5-5.0), carotid bruit (2.5; CI 95% 1.3-4.6), diabetes (2.4; CI 95% 1.4-4.0) and alcohol abuse (2.1; CI 95% 1.1-4.0), The combination of these risk factors accounted for 98.9% (95% CI; 96.4%-99.7%) of the PAR% for all stroke. CONCLUSIONS: Nine risk factors, easily identified, explain almost 100% of the population attributable risk for ischemic stroke. PMID- 22530067 TI - The p250GAP gene is associated with risk for schizophrenia and schizotypal personality traits. AB - BACKGROUND: Hypofunction of the glutamate N-Methyl-d-aspartate (NMDA) receptor has been implicated in the pathophysiology of schizophrenia. p250GAP is a brain enriched NMDA receptor-interacting RhoGAP. p250GAP is involved in spine morphology, and spine morphology has been shown to be altered in the post-mortem brains of patients with schizophrenia. Schizotypal personality disorder has a strong familial relationship with schizophrenia. Several susceptibility genes for schizophrenia have been related to schizotypal traits. METHODS: We first investigated the association of eight linkage disequilibrium-tagging single nucleotide polymorphisms (SNPs) that cover the p250GAP gene with schizophrenia in a Japanese sample of 431 schizophrenia patients and 572 controls. We then investigated the impact of the risk genetic variant in the p250GAP gene on schizotypal personality traits in 180 healthy subjects using the Schizotypal Personality Questionnaire. RESULTS: We found a significant difference in genotype frequency between the patients and the controls in rs2298599 (chi(2) = 17.6, p = 0.00015). The minor A/A genotype frequency of rs2298599 was higher in the patients (18%) than in the controls (9%) (chi(2) = 15.5, p = 0.000083). Moreover, we found that subjects with the rs2298599 risk A/A genotype, compared with G allele carriers, had higher scores of schizotypal traits (F(1,178) = 4.08, p = 0.045), particularly the interpersonal factor (F(1,178) = 5.85, p = 0.017). DISCUSSION: These results suggest that a genetic variation in the p250GAP gene might increase susceptibility not only for schizophrenia but also for schizotypal personality traits. We concluded that the p250GAP gene might be a new candidate gene for susceptibility to schizophrenia. PMID- 22530068 TI - Allergen micro-bead array for IgE detection: a feasibility study using allergenic molecules tested on a flexible multiplex flow cytometric immunoassay. AB - BACKGROUND: Allergies represent the most prevalent non infective diseases worldwide. Approaching IgE-mediated sensitizations improved much by adopting allergenic molecules instead of extracts, and by using the micro-technology for multiplex testing. OBJECTIVE AND METHODS: To provide a proof-of-concept that a flow cytometric bead array is a feasible mean for the detection of specific IgE reactivity to allergenic molecules in a multiplex-like way. A flow cytometry Allergenic Molecule-based micro-bead Array system (ABA) was set by coupling allergenic molecules with commercially available micro-beads. Allergen specific polyclonal and monoclonal antibodies, as well as samples from 167 allergic patients, characterized by means of the ISAC microarray system, were used as means to show the feasibility of the ABA. Three hundred and thirty-six sera were tested for 1 or more of the 16 selected allergens, for a total number of 1,519 tests on each of the two systems. RESULTS: Successful coupling was initially verified by detecting the binding of rabbit polyclonal IgG, mouse monoclonal, and pooled human IgE toward three allergens, namely nDer s 1, nPen m 1, and nPru p 3. The ABA assay showed to detect IgE to nAct d 1, nAct d 11, rAln g 1, nAmb a 1, nArt v 3, rBet v 1, rCor a 1, nCup a 1, nDer p 1, nDer s 1, rHev b 5, nOle e 1, rPar j 2, nPen m 1, rPhl p 1, and nPru p 3. Results obtained by ABA IgE testing were highly correlated to ISAC testing (r = 0.87, p<0.0001). No unspecific binding was recorded because of high total IgE values. CONCLUSION: The ABA assay represents a useful and flexible method for multiplex IgE detection using allergenic molecules. As also shown by our initial experiments with monoclonals and polyclonals, ABA is suitable for detecting other human and non-human immunoglobulins. PMID- 22530069 TI - Stereoselective regulations of P-glycoprotein by ginsenoside Rh2 epimers and the potential mechanisms from the view of pharmacokinetics. AB - Chirality is an interesting topic and it is meaningful to explore the interactions between chiral small molecules and stereoselective biomacromolecules, with pre-clinical and clinical significances. We have previously demonstrated that 20(S)-ginsenoside Rh2 is an effective P-glycoprotein (P-gp) inhibitor in vitro and in vivo. Considering the stereochemistry of ginsenoside Rh2, in our present study, the regulatory effects of 20(R)-Rh2 on P gp were assayed in vivo, and the differential regulations of P-gp by ginsenoside Rh2 epimers in vivo were compared and studied. Results showed that 20(S)-Rh2 enhanced the oral absorption of digoxin in rats in a dose-dependent manner; 20(R) Rh2 at low dosage increased the oral absorption of digoxin, but this effect diminished with elevated dosage of 20(R)-Rh2. Further studies indicated stereoselective pharmacokinetic profiles and intestinal biotransformations of Rh2 epimers. In vitro studies showed that Rh2 epimers and their corresponding deglycosylation metabolites protopanaxadiol (Ppd) epimers all exhibited stereoselective regulations of P-gp. In conclusion, in view of the in vitro and in vivo dispositions of Rh2 and the regulations of P-gp by Rh2 and Ppd, it is suggested that the P-gp regulatory effect of Rh2 in vivo actually is a double actions of both Rh2 and Ppd, and the net effect is determined by the relative balance between Rh2 and Ppd with the same configuration. Our study provides new evidence of the chiral characteristics of P-gp, and is helpful to elucidate the stereoselective P-gp regulation mechanisms of ginsenoside Rh2 epimers in vivo from a pharmacokinetic view. PMID- 22530071 TI - Additive protection by antioxidant and apoptosis-inhibiting effects on mosquito cells with dengue 2 virus infection. AB - Cytopathic effects (CPEs) in mosquito cells are generally trivial compared to those that occur in mammalian cells, which usually end up undergoing apoptosis during dengue virus (DENV) infection. However, oxidative stress was detected in both types of infected cells. Despite this, the survival of mosquito cells benefits from the upregulation of genes related to antioxidant defense, such as glutathione S transferase (GST). A second defense system, i.e., consisting of antiapoptotic effects, was also shown to play a role in protecting mosquito cells against DENV infection. This system is regulated by an inhibitor of apoptosis (IAP) that is an upstream regulator of caspases-9 and -3. DENV-infected C6/36 cells with double knockdown of GST and the IAP showed a synergistic effect on activation of these two caspases, causing a higher rate of apoptosis (> 20%) than those with knockdown of each single gene (-10%). It seems that the IAP acts as a second line of defense with an additional effect on the survival of mosquito cells with DENV infection. Compared to mammalian cells, residual hydrogen peroxide in DENV-infected C6/36 cells may signal for upregulation of the IAP. This novel finding sheds light on virus/cell interactions and their coevolution that may elucidate how mosquitoes can be a vector of DENV and probably most other arboviruses in nature. PMID- 22530070 TI - Gut microbiome of the critically endangered New Zealand parrot, the kakapo (Strigops habroptilus). AB - The kakapo, a parrot endemic to New Zealand, is currently the focus of intense research and conservation efforts with the aim of boosting its population above the current 'critically endangered' status. While virtually nothing is known about the microbiology of the kakapo, given the acknowledged importance of gut associated microbes in vertebrate nutrition and pathogen defense, it should be of great conservation value to analyze the microbes associated with kakapo. Here we describe the first study of the bacterial communities that reside within the gastrointestinal tract (GIT) of both juvenile and adult kakapo. Samples from along the GIT, taken from the choana (~ throat), crop and faeces, were subjected to 16 S rRNA gene library analysis. Phylogenetic analysis of >1000 16 S rRNA gene clones, derived from six birds, revealed low phylum-level diversity, consisting almost exclusively of Firmicutes (including lactic acid bacteria) and Gammaproteobacteria. The relative proportions of Firmicutes and Gammaproteobacteria were highly consistent among individual juveniles, irrespective of sampling location, but differed markedly among adult birds. Diversity at a finer phylogenetic resolution (i.e. operational taxonomic units (OTUs) of 99% sequence identity) was also low in all samples, with only one or two OTUs dominating each sample. These data represent the first analysis of the bacterial communities associated with the kakapo GIT, providing a baseline for further microbiological study, and facilitating conservation efforts for this unique bird. PMID- 22530072 TI - Dengue deaths in Puerto Rico: lessons learned from the 2007 epidemic. AB - BACKGROUND: The incidence and severity of dengue in Latin America has increased substantially in recent decades and data from Puerto Rico suggests an increase in severe cases. Successful clinical management of severe dengue requires early recognition and supportive care. METHODS: Fatal cases were identified among suspected dengue cases reported to two disease surveillance systems and from death certificates. To be included, fatal cases had to have specimen submitted for dengue diagnostic testing including nucleic acid amplification for dengue virus (DENV) in serum or tissue, immunohistochemical testing of tissue, and immunoassay detection of anti-DENV IgM from serum. Medical records from laboratory-positive dengue fatal case-patients were reviewed to identify possible determinants for death. RESULTS: Among 10,576 reported dengue cases, 40 suspect fatal cases were identified, of which 11 were laboratory-positive, 14 were laboratory-negative, and 15 laboratory-indeterminate. The median age of laboratory-positive case-patients was 26 years (range 5 months to 78 years), including five children aged < 15 years; 7 sought medical care at least once prior to hospital admission, 9 were admitted to hospital and 2 died upon arrival. The nine hospitalized case-patients stayed a mean of 15 hours (range: 3-48 hours) in the emergency department (ED) before inpatient admission. Five of the nine case-patients received intravenous methylprednisolone and four received non isotonic saline while in shock. Eight case-patients died in the hospital; five had their terminal event on the inpatient ward and six died during a weekend. Dengue was listed on the death certificate in only 5 instances. CONCLUSIONS: During a dengue epidemic in an endemic area, none of the 11 laboratory-positive case-patients who died were managed according to current WHO Guidelines. Management issues identified in this case-series included failure to recognize warning signs for severe dengue and shock, prolonged ED stays, and infrequent patient monitoring. PMID- 22530073 TI - Long-term impact of the World Bank Loan Project for schistosomiasis control: a comparison of the spatial distribution of schistosomiasis risk in China. AB - BACKGROUND: The World Bank Loan Project (WBLP) for controlling schistosomiasis in China was implemented during 1992-2001. Its short-term impact has been assessed from non-spatial perspective, but its long-term impact remains unclear and a spatial evaluation has not previously been conducted. Here we compared the spatial distribution of schistosomiasis risk using national datasets in the lake and marshland regions from 1999-2001 and 2007-2008 to evaluate the long-term impact of WBLP strategy on China's schistosomiasis burden. METHODOLOGY/PRINCIPAL FINDINGS: A hierarchical Poisson regression model was developed in a Bayesian framework with spatially correlated and uncorrelated heterogeneities at the county-level, modeled using a conditional autoregressive prior structure and a spatially unstructured Gaussian distribution, respectively. There were two important findings from this study. The WBLP strategy was found to have a good short-term impact on schistosomiasis control, but its long-term impact was not ideal. It has successfully reduced the morbidity of schistosomiasis to a low level, but can not contribute further to China's schistosomiasis control because of the current low endemic level. A second finding is that the WBLP strategy could not effectively compress the spatial distribution of schistosomiasis risk. To achieve further reductions in schistosomiasis-affected areas, and for sustainable control, focusing on the intermediate host snail should become the next step to interrupt schistosomiasis transmission within the two most affected regions surrounding the Dongting and Poyang Lakes. Furthermore, in the lower reaches of the Yangtze River, the WBLP's morbidity control strategy may need to continue for some time until snails in the upriver provinces have been well controlled. CONCLUSION: It is difficult to further reduce morbidity due to schistosomiasis using a chemotherapy-based control strategy in the lake and marshland regions of China because of the current low endemic levels of infection. The future control strategy for schistosomiasis should instead focus on a snail-based integrated control strategy to maintain the program achievements and sustainably reduce the burden of schistosomiasis in China. PMID- 22530074 TI - Synergistic interactions between the NS3(hel) and E proteins contribute to the virulence of dengue virus type 1. AB - BACKGROUND: Dengue includes a broad range of symptoms, ranging from fever to hemorrhagic fever and may occasionally have alternative clinical presentations. Many possible viral genetic determinants of the intrinsic virulence of dengue virus (DENV) in the host have been identified, but no conclusive evidence of a correlation between viral genotype and virus transmissibility and pathogenicity has been obtained. METHODOLOGY/PRINCIPAL FINDINGS: We used reverse genetics techniques to engineer DENV-1 viruses with subsets of mutations found in two different neuroadapted derivatives. The mutations were inserted into an infectious clone of DENV-1 not adapted to mice. The replication and viral production capacity of the recombinant viruses were assessed in vitro and in vivo. The results demonstrated that paired mutations in the envelope protein (E) and in the helicase domain of the NS3 (NS3(hel)) protein had a synergistic effect enhancing viral fitness in human and mosquito derived cell lines. E mutations alone generated no detectable virulence in the mouse model; however, the combination of these mutations with NS3(hel) mutations, which were mildly virulent on their own, resulted in a highly neurovirulent phenotype. CONCLUSIONS/SIGNIFICANCE: The generation of recombinant viruses carrying specific E and NS3(hel) proteins mutations increased viral fitness both in vitro and in vivo by increasing RNA synthesis and viral load (these changes being positively correlated with central nervous system damage), the strength of the immune response and animal mortality. The introduction of only pairs of amino acid substitutions into the genome of a non-mouse adapted DENV-1 strain was sufficient to alter viral fitness substantially. Given current limitations to our understanding of the molecular basis of dengue neuropathogenesis, these results could contribute to the development of attenuated strains for use in vaccinations and provide insights into virus/host interactions and new information about the mechanisms of basic dengue biology. PMID- 22530075 TI - Mate tea prevents oxidative stress in the blood and hippocampus of rats with acute or chronic ethanol administration. AB - OBJECTIVE: The aim of this study was to evaluate the influence of acute and chronic intake of mate tea on the effects elicited by acute and chronic administration of ethanol. METHODS: Oxidative stress was evaluated by measuring thiobarbituric acid-reactive substances (TBARS), as well as the activities of the antioxidant enzymes, catalase (CAT), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) in the hippocampus and blood of rats. Male Wistar rats were randomly assigned to four groups, for both acute and chronic treatment: (1) control group, (2) treated group, (3) intoxicated group, (4) and intoxicated group treated with mate tea. RESULTS: Both ethanol administrations significantly increased TBARS in plasma and hippocampus of rats and altered antioxidant enzyme activities, changes which were reverted by mate tea administration. CONCLUSIONS: Data indicate that acute and chronic ethanol administration induced oxidative stress in hippocampus and blood and that mate tea treatment was able to prevent this situation. PMID- 22530076 TI - The redox imbalance and the reduction of contractile protein content in rat hearts administered with L-thyroxine and Doxorubicin. AB - Oxidative stress and disorders in calcium balance play a crucial role in the doxorubicin-induced cardiotoxicity. Moreover, many cardiotoxic targets of doxorubicin are regulated by iodothyronine hormones. The aim of the study was to evaluate effects of tetraiodothyronine (0.2, 2 mg/L) on oxidative stress in the cardiac muscle as well as contractility and cardiomyocyte damage markers in rats receiving doxorubicin (1.5 mg/kg) once a week for ten weeks. Doxorubicin was administered alone (DOX) or together with a lower (0.2T(4) + DOX) and higher dose of tetraiodothyronine (2T(4) + DOX). Two groups received only tetraiodothyronine (0.2T(4), 2T(4)). Coadministration of tetraiodothyronine and doxorubicin increased the level of lipid peroxidation products and reduced RyR2 level when compared to untreated control and group exposed exclusively to doxorubicin. Insignificant differences in SERCA2 and occasional histological changes were observed. In conclusion, an increase of tetraiodothyronine level may be an additional risk factor of redox imbalance and RyR2 reduction in anthracycline cardiotoxicity. PMID- 22530077 TI - A nonpolar blueberry fraction blunts NADPH oxidase activation in neuronal cells exposed to tumor necrosis factor-alpha. AB - Inflammation and oxidative stress are key to the progressive neuronal degeneration common to chronic pathologies, traumatic injuries, and aging processes in the CNS. The proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) orchestrates cellular stress by stimulating the production and release of neurotoxic mediators including reactive oxygen species (ROS). NADPH oxidases (NOX), ubiquitously expressed in all cells, have recently emerged as pivotal ROS sources in aging and disease. We demonstrated the presence of potent NOX inhibitors in wild Alaska bog blueberries partitioning discretely into a nonpolar fraction with minimal antioxidant capacity and largely devoid of polyphenols. Incubation of SH-SY5Y human neuroblastoma cells with nonpolar blueberry fractions obstructed the coalescing of lipid rafts into large domains disrupting NOX assembly therein and abolishing ROS production characteristic for TNF-alpha exposure. These findings illuminate nutrition-derived lipid raft modulation as a novel therapeutic approach to blunt inflammatory and oxidative stress in the aging or diseased CNS. PMID- 22530079 TI - Conservative management of cholestasis with and without fever in acute biliary pancreatitis. AB - The presence of cholestasis in both mild and severe forms of acute biliary pancreatitis (ABP) does not justify, of itself, early endoscopic retrograde cholangiography (ERC) or endoscopic sphincterotomy (ES). Clinical support treatment of acute pancreatitis for one to two weeks is usually accompanied by regression of pancreatic edema, of cholestasis and by stone migration to the duodenum in 60%-88% of cases. On the other hand, in cases with both cholestasis and fever, a condition usually characterized as ABP associated with cholangitis, early ES is normally indicated. However, in daily clinical practice, it is practically impossible to guarantee the coexistence of cholangitis and mild or severe acute pancreatitis. Pain, fever and cholestasis, as well as mental confusion and hypotension, may be attributed to inflammatory and necrotic events related to ABP. Under these circumstances, evaluation of the bile duct by endo ultrasonography (EUS) or magnetic resonance cholangiography (MRC) before performing ERC and ES seems reasonable. Thus, it is necessary to assess the effects of the association between early and opportune access to the treatment of local and systemic inflammatory/infectious effects of ABP with cholestasis and fever, and to characterize the possible scenarios and the subsequent approaches to the common bile duct, directed by less invasive examinations such as MRC or EUS. PMID- 22530078 TI - A decade in gastric cancer curative surgery: Evidence of progress (1999-2009). AB - To investigate the progress in evidence-based surgical treatment of non metastatic gastric cancer, we reviewed the last ten years' literature. The data used in this review were identified by searches made on MEDLINE, Current Contents, PubMed, and other references taken from relevant original articles (on prospective and retrospective studies) concerning gastric cancer surgery. Only papers published in English between January 1999 and December 2009 were selected. Data from ongoing studies were obtained in December 2009, from the trials registry of the United States National Institutes of Health (http://www.clinicaltrial.gov). The citations list was presented according to evidence based relevance (i.e., randomized controlled trials, prospective studies, retrospective series). In the last ten years, many challenges have been faced relating to the extension of gastric resection and nodal dissection as well as surgical timing, but we found only limited evidence, regardless of latitude of study. The ongoing phase-III trials may provide answers that will be valid for the coming decades, and which may bring definitive answers for the currently unresolved questions. PMID- 22530081 TI - Primary hepatic benign schwannoma. AB - Schwannoma is predominantly a benign neoplasm of the Schwann cells in the neural sheath of the peripheral nerves. Occurrence of schwannoma in parenchymatous organs, such as liver, is extremely rare. A 64-year-old man without neurofibromatosis was observed to have a space-occupying lesion of 23mm diameter in the liver during follow-up examination for a previously resected gastrointestinal stromal tumor (GIST) in the small intestine. He underwent lateral segmentectomy of the liver under a provisional diagnosis of hepatic metastatic recurrence of the GIST. Histological examination confirmed the diagnosis of a benign schwannoma, confirmed by characteristic pathological findings and positive immunoreactions with the neurogenic marker S-100 protein, but negative for c-kit, or CD34. The tumor was the smallest among the reported cases. When the primary hepatic schwannoma is small in size, preoperative clinical diagnosis is difficult. Therefore, this disease should be listed as differential diagnosis for liver tumor with clinically benign characteristics. PMID- 22530082 TI - Giant mesenteric fibromatosis: Report of a case and review of the literature. AB - Mesenteric fibromatosis poses a diagnostic and therapeutic challenge. This paper presents a 35-year-old female complaining of vague abdominal pain of 2 mo duration. Her computed tomography scan and magnetic resonance imaging revealed a pelvi-abdominal heterogenous mass with significant displacement of the small bowel and urinary bladder. She underwent surgical excision of the mass with resection and anastomosis of the involved loop of the small intestine. Histological examination confirmed mesenteric fibromatosis without infiltration of the bowel. The patient remained well during the 6 mo follow-up. PMID- 22530083 TI - Rapid, cost-effective, sensitive and quantitative detection of Acinetobacter baumannii from pneumonia patients. AB - BACKGROUND AND OBJECTIVES: Pneumonia with Acinetobacter baumannii has a major therapeutic problem in health care settings. Decision to initiate correct antibiotic therapy requires rapid identification and quantification of organism. The aim of this study was to develop a rapid and sensitive method for direct detection of A. baumannii from respiratory specimens. MATERIALS AND METHODS: A Taqman real time PCR based on the sequence of bla(oxa-51) was designed and used for direct detection of A. baumannii from 361 respiratory specimens of patients with pneumonia. All specimens were checked by conventional bacteriology in parallel. RESULTS: The new real time PCR could detect less than 200 cfu per ml of bacteria in specimens. There was agreement between the results of real time PCR and culture (Kappa value 1.0, p value<0.001). The sensitivity, specificity and predictive values of real time PCR were 100%. The prevalence of A. baumannii in pneumonia patients was 10.53 % (n=38). Poly-microbial infections were detected in 65.71% of specimens. CONCLUSION: Acinetobacter baumannii is the third causative agent in nosocomial pneumonia after Pseudomonas aeroginosa (16%) and Staphylococcus aureus (13%) at Tehran hospitals. We recommend that 104 CFU be the threshold for definition of infection with A. baumannii using real time PCR. PMID- 22530080 TI - Inflammation and cancer. AB - There is evidence supporting the hypothesis that inflammation participates in providing conditions that lead to cancer. An unresolved inflammation due to any failure in the precise control of the immune response can continue to perturb the cellular microenvironment, thereby leading to alterations in cancer-related genes and posttranslational modification in crucial cellular proteins involved in the cell cycle, DNA repair and apoptosis. In addition, there are data indicating that inflammatory cells and immunomodulatory mediators present in the tumor microenvironment influence tumor progression and metastasis. Historically, tumor infiltrating leukocytes have been considered to be manifestations of an intrinsic defence mechanism against developing tumors. However, increasing evidence indicates that leukocyte infiltration can promote tumor phenotypes, such as angiogenesis, growth and invasion. This may be due to inflammatory cells that probably can influence cancer promotion by secreting cytokines, growth factors, chemokines and proteases, which stimulate proliferation and invasiveness of cancer cells. Consequently, events and molecules implicated in this cross talk between the tumor microenvironment and inflammatory process may emerge as attractive targets in anticancer therapeutic interventions with significant clinical impact. PMID- 22530084 TI - Dye labelled monoclonal antibody assay for detection of Toxic Shock Syndrome Toxin -1 from Staphylococcus aureus. AB - OBJECTIVE: The aim of study was to develop a rapid assay, dye labelled monoclonal antibody assay (DLMAA), using non-radioactive organic synthetic dyes for identification of Toxic Shock Syndrome Toxin-1 (TSST-1) producing strains of Staphylococcus aureus. MATERIALS AND METHODS: The assay protocol required only two simple steps; addition of TSST-1 antigen to a nitrocellulose membrane and then adding a colloidal dye labelled antibody (D/A) suspension detection reagent. RESULTS: The sensitivity and specificity of the assay was determined relative to positive and negative strains compared to an ELISA assay. Overall 100% agreement was found between both assays. The sensitivity for detection of TSST-1 was 30 ng. CONCLUSION: The DLMAA did not require handling and disposal of radioactive materials. It is a rapid qualitative technique for detection of TSST-1 toxin at room temperature within a short time. PMID- 22530085 TI - Detection of human Papillomavirus 18 in cervical cancer samples using PCR-ELISA (DIAPOPS). AB - BACKGROUND AND OBJECTIVES: Human Papillomavirus (HPV) infection is a major risk factor for adenocarcinoma of the cervix. The high-risk types of the virus such as HPV16 and HPV18, which possess the E6 and E7 oncogenes, are responsible for approximately 50% of all cervical cancers. A rapid, sensitive and specific test has been proposed for detection of HPV to improve cervical cancer screening programs. OBJECTIVES: The aim of this study was to develop a fast PCR-ELISA assay designated as DIAPOPS (Detection of Immobilized Amplified Products in a One Phase System)for detection of HPV16 and HPV18 types in SCC samples and Pap smears. The type specific primers and probes were designed for PCR and PCR-ELISA. The amplified products were hybridized with a specific biotin-labeled probe for HPV18 inner amplicons. The hybrids were detected with peroxidase conjugated avidin. The test was performed on the paraffin block and Pap smear samples from the cervical cancer patients, and the results of DIAPOPS were compared with conventional PCR assay. RESULTS: The 70 samples (SCC and Pap smear samples) were collected from Imam Khomeini and Mirzakoochak Khan Hospitals in Tehran. The PCR-based method detected six HPV16 positive, three HPV18 positive and Two HPV33 positive samples. DIAPOPS results were compared with the conventional PCR results and they showed an increase in sensitivity of the DIAPOPS test. Not only all of them were confirmed by PCR-ELISA but also three samples that conventional PCR showed negative for HPV18, were demonstrated positive by the PCR-ELISA method. CONCLUSION: The results of the study show that modified PCR-ELISA assay is more sensitive to detect HPV types and can be used for diagnostic purposes. PMID- 22530086 TI - Susceptibility of clinical Candida species isolates to antifungal agents by E test, Southern Iran: A five year study. AB - BACKGROUND AND OBJECTIVES: The incidence of fungal infections in immunocompromised patients, especially by Candida species, has increased in recent years. This study was designed to identify Candida species and determine antifungal susceptibility patterns of 595 yeast strains isolated from various clinical specimens. MATERIAL AND METHODS: Identification of the isolates were determined by the API 20 C AUX kit and antifungal susceptibilities of the species to fluconazole, amphotericin B, ketoconazole, itraconazole, voriconazole, and caspofungin were determined by the agar-based E-test method. RESULTS: Candida albicans (48%) was the most frequently isolated species, followed by Candida kruzei (16.1%), Candida glabrata (13.5%), Candida kefyr (7.4%), Candida parapsilosis (4.8%), Candida tropicalis (1.7%) and other species (8.5%). Resistance varies depending on the species and the respective antifungal agents. Comparing the MIC90 for all the strains, the lower MIC90 was observed for caspofungin (0.5 ug/ml). The MIC90 for all Candida species were 64 ug/ml for fluconazole, 0.75 ug/ml for amphotericin B, 4 ug/ml for ketoconazole, 4 ug/ml for itraconazole, and 2 ug/ml for voriconazole. CONCLUSIONS: Species definition and determination of antifungal susceptibility patterns are advised for the proper management and treatment of patients at risk for systemic candidiasis. Resistance to antifungal agents is an alarming sign for the emerging common nosocomial fungal infections. PMID- 22530087 TI - Modified Hodge test: A simple and effective test for detection of carbapenemase production. AB - BACKGROUND AND OBJECTIVES: Resistance among bacterial isolates is the leading cause of increased mortality and morbidity worldwide. Carbapenems once thought to be effective are becoming ineffective mostly due to the emergence of carbapenemase. This study was designed to determine in vitro efficacy of Modified Hodge test for detection of carbapenemase production in Gram negative rods. MATERIAL AND METHODS: The study was done in the Department of Microbiology, Armed Forces Institute of Pathology Rawalpindi Pakistan from January 2010 to December 2010. A total of 200 Gram negative rods from different clinical samples were taken. Those isolates which showed intermediate or susceptible zones i.e 16mm 21mm on disc diffusion were included in the study. These isolates were then subjected to Modified Hodge test. RESULT: Out of 200 isolates, 138 (69%) were positive for carbapenemase production by Modified Hodge test. Out of 138 MHT positive organisms, the frequency of E. coli was 38%, followed by Pseudomonas aeruginosa (30%), Klebsiella pneumoniae (17%), Acinetobacter baumannii (12%), Citrobacter diversus (2%) and Enterobacter agglomerans (1.4%). CONCLUSION: Modified Hodge test is a simple test which can be performed in the routine lab for detection of carbapenemases in isolates showing intermediate or sensitive zone diameter on disc diffusion. PMID- 22530088 TI - Chemical composition and antimicrobial activity of Satureja hortensis and Trachyspermum copticum essential oil. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the chemical composition and antimicrobial activity of Satureja hortensis and Trachyspermum copticum essential oils against different kinds of microorganisms in vitro. MATERIAL AND METHODS: The antimicrobial activity was evaluated by micro broth dilution assay and the chemical composition of essential oils was analyzed by GC and GC/MS. RESULTS: Thymol, p-cymene, gamma-terpinene and carvacrol were the main components of S. hortensis oil while thymol, gamma-terpinene, and o-cymene were the major components of T. copticum oil. Two essential oils exhibited strong antimicrobial activity but the antimicrobial activity of T. copticum oil was higher than that of S. hortensis oil. CONCLUSION: Thymol as a main component of oils plays an important role in antimicrobial activity. PMID- 22530089 TI - Screening and characterization of proline dehydrogenase flavoenzyme producing Pseudomonas entomophila. AB - BACKGROUND AND OBJECTIVES: Proline dehydrogenase (ProDH; 1.5.99.8) plays an important role in specific determination of plasma proline level in biosensor and diagnostic kits. The goal of this research was to isolate and characterize ProDH enzyme from Iranian soil microorganisms. MATERIALS AND METHODS: Screening of L proline degradative enzymes from soil samples was carried out employing enrichment culture techniques. The isolate was characterized by biochemical reactions and specific PCR amplification. The target ProDH was purified and the effects of pH and temperature on the activity and stability were also tested. RESULTS: Among the 250 isolates recovered from 40 soil samples, only one strain characterized as Pseudomonas entomophila displayed the highest enzyme activity toward L-proline (350 U/l) than others. The enzyme of interest was identified as a ProDH and had K(m) value of 32 mM for L-proline. ProDH exhibited its best activity at temperature range of 25 to 35 degrees C and its highest activity was achieved at 30 degrees C. It was almost stable at temperatures between 25-30 degrees C for 2 hours. The optimum pH activity of ProDH reaction was 8.5 and its activity was stable in pH range of 8.0-9.0 upto 24 hours. The enzyme was purified with a yield of 8.5% and a purification factor of 37.7. The molecular mass of the purified ProDH was about 40 kDa, and determined to be a monomeric protein. CONCLUSION: This is the first report concerning the ProDH production by a P. entomophila bacterium isolated from soil sample. PMID- 22530090 TI - Immobilization of Pichia pastoris cells containing alcohol oxidase activity. AB - BACKGROUND AND OBJECTIVES: The attempts were made to describe the development of a whole cell immobilization of P. pastoris by entrapping the cells in polyacrylamide gel beads. The alcohol oxidase activity of the whole cell Pichia pastoris was evaluated in comparison with yeast biomass production. MATERIALS AND METHODS: Methylotrophic yeast P. pastoris was obtained from Collection of Standard Microorganisms, Department of Bacterial Vaccines, Pasteur Institute of Iran (CSMPI). Stock culture was maintained on YPD agar plates. Alcohol oxidase was strongly induced by addition of 0.5% methanol as the carbon source. The cells were harvested by centrifugation then permeabilized. Finally the cells were immobilized in polyacrylamide gel beads. The activity of alcohol oxidase was determined by method of Tane et al. RESULTS: At the end of the logarithmic phase of cell culture, the alcohol oxidase activity of the whole cell P. Pastoris reached the highest level. In comparison, the alcohol oxidase activity was measured in an immobilized P. pastoris when entrapped in polyacrylamide gel beads. The alcohol oxidase activity of cells was induced by addition of 0.5% methanol as the carbon source. The cells were permeabilized by cetyltrimethylammonium bromide (CTAB) and immobilized. CTAB was also found to increase the gel permeability. Alcohol oxidase activity of immobilized cells was then quantitated by ABTS/POD spectrophotometric method at OD (420.) There was a 14% increase in alcohol oxidase activity in immobilized cells as compared with free cells. By addition of 2-butanol as a substrate, the relative activity of alcohol oxidase was significantly higher as compared with other substrates added to the reaction media. CONCLUSION: Immobilization of cells could eliminate lengthy and expensive procedures of enzyme separation and purification, protect and stabilize enzyme activity, and perform easy separation of the enzyme from the reaction media. PMID- 22530091 TI - Impact of gamma rays on the Phaffia rhodozyma genome revealed by RAPD-PCR. AB - BACKGROUND AND OBJECTIVES: Phaffia rhodozyma is a red yeast which produces astaxanthin as the major carotenoid pigment. Astaxanthin is thought to reduce the incidence of cancer and degenerative diseases in man. It also enhances the immune response and acts as a free-radical quencher, a precursor of vitamin A, or a pigment involved in the visual attraction of animals as mating partners. The impact of gamma irradiation was studied on the Phaffia rhodozyma genome. MATERIALS AND METHODS: Ten mutant strains, designated Gam1-Gam10, were obtained using gamma irradiation. Ten decamer random amplified polymorphic DNA (RAPD) primers were employed to assess genetic changes. RESULTS: Nine primers revealed scorable polymorphisms and a total of 95 band positions were scored; amongst which 38 bands (37.5%) were polymorphic. Primer F with 3 bands and primer J20 with 13 bands produced the lowest and the highest number of bands, respectively. Primer A16 produced the highest number of polymorphic bands (70% polymorphism) and primer F showed the lowest number of polymorphic bands (0% polymorphism). Genetic distances were calculated using Jaccard's coefficient and the UPGMA method. A dendrogram was created using SPSS (version 11.5) and the strains were clustered into four groups. CONCLUSION: RAPD markers could distinguish between the parental and the mutant strains of P. rhodozyma. RAPD technique showed that some changes had occurred in the genome of the mutated strains. This technique demonstrated the capability to differentiate between the parental and the mutant strains. PMID- 22530092 TI - Synthesis and activity of a novel diether phosphonoglycerol in phospholipase resistant synthetic lipid:peptide lung surfactants(). AB - This paper reports the chemical synthesis and purification of a novel phospholipase-resistant C16:0, C16:1 diether phosphonoglycerol with structural analogy to ester-linked anionic phosphatidylglycerol (PG) in endogenous pulmonary surfactant. This diether phosphonoglycerol (PG 1) is studied for phospholipase A(2) (PLA(2)) resistance and for surface activity in synthetic exogenous surfactants combined with Super Mini-B (S-MB) peptide and DEPN-8, a previously reported diether phosphonolipid analog of dipalmitoyl phosphatidylcholine (DPPC, the major zwitterionic phospholipid in native lung surfactant). Activity experiments measured both adsorption and dynamic surface tension lowering due to the known importance of these surface behaviors in lung surfactant function in vivo. Synthetic surfactants containing 9 : 1 DEPN-8:PG 1 + 3% S-MB were resistant to degradation by PLA(2) in chromatographic studies, while calf lung surfactant extract (CLSE, the substance of the bovine clinical surfactant Infasurf(r)) was significantly degraded by PLA(2). The 9 : 1 DEPN-8:PG 1 + 3% S-MB mixture also had small but consistent increases in both adsorption and dynamic surface tension lowering ability compared to DEPN-8 + 3% S-MB. Consistent with these surface activity increases, molecular dynamics simulations using Protein Modeller, GROMACS force-field, and PyMOL showed that bilayers containing DPPC and palmitoyl oleoyl-PC (POPC) as surrogates of DEPN-8 and PG 1 were penetrated to a greater extent by S-MB peptide than bilayers of DPPC alone. These results suggest that PG 1 or related anionic phosphono-PG analogs may have functional utility in phospholipase-resistant synthetic surfactants targeting forms of acute pulmonary injury where endogenous surfactant becomes dysfunctional due to phospholipase activity in the innate inflammatory response. PMID- 22530093 TI - Strong quantum memory at resonant Fermi edges revealed by shot noise. AB - Studies of non-equilibrium current fluctuations enable assessing correlations involved in quantum transport through nanoscale conductors. They provide additional information to the mean current on charge statistics and the presence of coherence, dissipation, disorder, or entanglement. Shot noise, being a temporal integral of the current autocorrelation function, reveals dynamical information. In particular, it detects presence of non-Markovian dynamics, i.e., memory, within open systems, which has been subject of many current theoretical studies. We report on low-temperature shot noise measurements of electronic transport through InAs quantum dots in the Fermi-edge singularity regime and show that it exhibits strong memory effects caused by quantum correlations between the dot and fermionic reservoirs. Our work, apart from addressing noise in archetypical strongly correlated system of prime interest, discloses generic quantum dynamical mechanism occurring at interacting resonant Fermi edges. PMID- 22530094 TI - Pressure-induced amorphous-to-amorphous configuration change in Ca-Al metallic glasses. AB - Pressure-induced amorphous-to-amorphous configuration changes in Ca-Al metallic glasses (MGs) were studied by performing in-situ room-temperature high-pressure x ray diffraction up to about 40 GPa. Changes in compressibility at about 18 GPa, 15.5 GPa and 7.5 GPa during compression are detected in Ca(80)Al(20), Ca(72.7)Al(27.3), and Ca(66.4)Al(33.6) MGs, respectively, whereas no clear change has been detected in the Ca(50)Al(50) MG. The transfer of s electrons into d orbitals under pressure, reported for the pressure-induced phase transformations in pure polycrystalline Ca, is suggested to explain the observation of an amorphous-to-amorphous configuration change in this Ca-Al MG system. Results presented here show that the pressure induced amorphous-to-amorphous configuration is not limited to f electron-containing MGs. PMID- 22530096 TI - No doctor is an island. PMID- 22530095 TI - Genomic analysis of Pseudomonas putida: genes in a genome island are crucial for nicotine degradation. AB - Nicotine is an important chemical compound in nature that has been regarded as an environmental toxicant causing various preventable diseases. Several bacterial species are adapted to decompose this heterocyclic compound, including Pseudomonas and Arthrobacter. Pseudomonas putida S16 is a bacterium that degrades nicotine through the pyrrolidine pathway, similar to that present in animals. The corresponding late steps of the nicotine degradation pathway in P. putida S16 was first proposed and demonstrated to be from 2,5-dihydroxy-pyridine through the intermediates N-formylmaleamic acid, maleamic acid, maleic acid, and fumaric acid. Genomics of strain S16 revealed that genes located in the largest genome island play a major role in nicotine degradation and may originate from other strains, as suggested by the constructed phylogenetic tree and the results of comparative genomic analysis. The deletion of gene hpo showed that this gene is essential for nicotine degradation. This study defines the mechanism of nicotine degradation. PMID- 22530097 TI - Reflections on the rise and fall of PVD, medical nanotechnology and Australia covered with houseflies. PMID- 22530098 TI - Obesity and pulmonary arterial hypertension: Is adiponectin the molecular link between these conditions? AB - Pulmonary arterial hypertension (PAH) is a condition of unknown etiology whose pathological features include increased vascular resistance, perivascular inflammatory cell infiltration and pulmonary arteriolar remodeling. Although risk factors for PAH are poorly defined, recent studies indicate that obesity may be an important risk factor for this condition. The mechanisms leading to this association are largely unknown, but bioactive mediators secreted from adipose tissue have been implicated in this process. One of the most important mediators released from adipose tissue is the adipokine adiponectin. Adiponectin is highly abundant in the circulation of lean healthy individuals, and possesses well described metabolic and antiinflammatory actions. Levels of adiponectin decrease with increasing body mass, and low levels are directly linked to the development of PAH in mice. Moreover, overexpression of adiponectin has been shown to protect mice from developing PAH in response to inflammation and hypoxia. Based on the findings from these studies, it is suggested that the effects of adiponectin are mediated, in part, through its antiinflammatory and antiproliferative properties. In this review, we discuss the emerging evidence demonstrating a role for adiponectin in lung vascular homeostasis and discuss how deficiency in this adipocyte-derived hormone might explain the recent association between obesity and PAH. PMID- 22530099 TI - (18)FDG PET imaging can quantify increased cellular metabolism in pulmonary arterial hypertension: A proof-of-principle study. AB - The past decade has seen increased application of 18-flurodeoxyglucose positron emission tomography ((18)FDG-PET) imaging to help diagnose and monitor disease, particularly in oncology, vasculitis and atherosclerosis. Disordered glycolytic metabolism and infiltration of plexiform lesions by inflammatory cells has been described in idiopathic pulmonary arterial hypertension (IPAH). We hypothesized that increased (18)FDG uptake may be present in the lungs, large pulmonary arteries and right ventricle of patients with pulmonary hypertension, and that this uptake would be related to markers of immune activation. We imaged the thorax of 14 patients with pulmonary hypertension (idiopathic and chronic thromboembolic) and six controls by (18)FDG-PET/computed tomography (CT) and measured uptake in the lung parenchyma, large pulmonary arteries and right ventricle. (18)FDG uptake in the lungs and pulmonary arteries was normalized for venous blood activity to give a target-to-background ratio (TBR). Blood was contemporaneously drawn for high-sensitivity CRP - C-reactive protein (CRP) (hsCRP), N-Terminal Probrain natriuteric peptide (NT-ProBNP) and other inflammatory cytokines. IPAH patients had significantly higher lung parenchymal TBR (P=0.034) and right ventricle FDG uptake (P=0.007) than controls. Uptake in the main pulmonary arteries was similar in chronic thromboembolic pulmonary hypertension, IPAH and controls. There were no correlations between (18)FDG uptake and hsCRP or inflammatory cytokine levels. NT-ProBNP correlated with RV uptake in those with pulmonary hypertension (r=0.55, P=0.04). In this pilot study, we found increased (18)FDG uptake in the lung parenchyma and right ventricle of subjects with IPAH. The lung uptake might be useful as a surrogate marker of increased cellular metabolism and immune activation as underlying mechanisms in this disease. Further evaluation of the impact of targeted therapies in treatment-naive patients and the significance of right ventricular uptake is suggested. PMID- 22530100 TI - Significant intrapulmonary Schistosoma egg antigens are not present in schistosomiasis-associated pulmonary hypertension. AB - Schistosomiasis-associated pulmonary arterial hypertension (PAH) is one of the most common causes of pulmonary hypertension worldwide. A potential contributing mechanism to the pathogenesis of this disease is a localized immune reaction to retained and persistent parasite-derived antigens. We sought to identify Schistosoma-derived egg antigens present in the lungs of individuals who died of the disease. We obtained 18 lung samples collected at autopsy from individuals who died of schistosomiasis-associated PAH in Brazil. A rabbit polyclonal antibody was created to known Schistosoma mansoni-soluble egg antigen (SEA). Histologic assessment and immunostaining of the human tissue was performed, along with immunostaining and immunoblotting of lung tissue from mice experimentally infected with S. mansoni. All 18 lung samples had evidence of pulmonary vascular remodeling with plexiform lesions and arterial medial thickening, but no visible eggs were seen. The anti-SEA antibody detected S. mansoni egg antigens in visible eggs in mouse lung and human intestine specimens, but did not identify a significant amount of egg antigen in the human lung specimens. In mouse granulomas containing degraded eggs, we observed colocalization of egg antigens and macrophage lysosomes. In conclusion, there is unlikely to be a significant amount of persistent parasite-derived antigens within the lungs of individuals who die of schistosomiasis-associated PAH. This suggests that retained and persistent parasite proteins are not contributing to a localized immune response in the pathogenesis of this disease. PMID- 22530101 TI - High-altitude pulmonary hypertension in cattle (brisket disease): Candidate genes and gene expression profiling of peripheral blood mononuclear cells. AB - High-altitude pulmonary hypertension (HAPH) is a consequence of chronic alveolar hypoxia, leading to hypoxic vasoconstriction and remodeling of the pulmonary circulation. Brisket disease in cattle is a naturally occurring animal model of hypoxic pulmonary hypertension. Genetically susceptible cattle develop severe pulmonary hypertension and right heart failure at altitudes >7,000 ft. No information currently exists regarding the identity of the pathways and gene(s) responsible for HAPH or influencing severity. We hypothesized that initial insights into the pathogenesis of the disease could be discovered by a strategy of (1) sequencing of functional candidates revealed by single nucleotide polymorphism (SNP) analysis and (2) gene expression profiling of affected cattle compared with altitude-matched normal controls, with gene set enrichment analysis (GSEA) and Ingenuity pathway analysis (IPA). We isolated blood from a single herd of Black Angus cattle of both genders, aged 12-18 months, by jugular vein puncture. Mean pulmonary arterial pressures were 85.6+/-13 mmHg STD in the 10 affected and 35.3+/-1.2 mmHg STD in the 10 resistant cattle, P<0.001. From peripheral blood mononuclear cells, DNA was hybridized to an Affymetrix 10K Gene Chip SNP, and RNA was used to probe an Affymetrix Bovine genome array. SNP loci were remapped using the Btau 4.0 bovine genome assembly. mRNA data was analyzed by the Partek software package to identify sets of genes with an expression that was statistically different between the two groups. GSEA and IPA were conducted on the refined expression data to identify key cellular pathways and to generate networks and conduct functional analyses of the pathways and networks. Ten SNPs were identified by allelelic association and four candidate genes were sequenced in the cohort. Neither endothelial nitric oxide synthetase, NADH dehydrogenase, TG-interacting factor-2 nor BMPR2 were different among affected and resistant cattle. A 60-gene mRNA signature was identified that differentiated affected from unaffected cattle. Forty-six genes were overexpressed in the affected and 14 genes were downregulated in the affected cattle by at least 20%. GSEA and Ingenuity analysis identified respiratory diseases, inflammatory diseases and pathways as the top diseases and disorders (P<5.14*10(-14)), cell development and cell signaling as the top cellular functions (P<1.20*10(-08)), and IL6, TREM, PPAR, NFkB cell signaling (P<8.69*10(-09)) as the top canonical pathways associated with this gene signature. This study provides insights into differences in RNA expression in HAPH at a molecular level, and eliminates four functional gene candidates. Further studies are needed to validate and refine these preliminary findings and to determine the role of transcribed genes in the development of HAPH. PMID- 22530102 TI - Quantitative estimation of right ventricular hypertrophy using ECG criteria in patients with pulmonary hypertension: A comparison with cardiac MRI. AB - In patients with pulmonary arterial hypertension (PAH), right ventricular mass (RVM) correlates linearly with pulmonary artery pressure, and decreases with successful treatment. Accurate measurement of RVM currently requires cardiovascular magnetic resonance (CMR) imaging. We therefore tested the relationship between RVM and a simple, 12 lead ECG-derived value, the Butler Leggett (BL) score. This has previously been validated in patients with RV hypertrophy (RVH) due to mitral stenosis. We also tested the diagnostic accuracy of the BL score in detecting RVH. The Scottish Pulmonary Vascular Unit database was reviewed retrospectively. Twenty-eight patients with PAH were identified, in whom CMR and ECG data had been recorded no more than 28 days apart. All had completed a comprehensive clinical assessment, including right heart catheterization. CMR-derived absolute RVM and RV mass index (RVMI=RV mass/LV mass) were correlated against BL score. The ability of this score to detect RVH was tested using 2 x 2 contingency tables. RVM and RVMI correlated with BL score (r=0.77, P<0.001 and r=0.78, P<0.001, respectively). A BL score >0.7 mV proved a highly specific but insensitive indicator of RVH, based on either absolute RVM (sensitivity 74%, specificity 100%) or a high RVMI (sensitivity 61%, specificity 100%). The BL score, which can be defined using a standard 12-lead ECG, correlates with RVM and RVMI in patients with PAH. A score >0.7 mV was a highly specific but insensitive indicator of RVH in these patients. PMID- 22530103 TI - Pulmonary artery endothelium resident endothelial colony-forming cells in pulmonary arterial hypertension. AB - Proliferative pulmonary vascular remodeling is the pathologic hallmark of pulmonary arterial hypertension (PAH) that ultimately leads to right heart failure and death. Highly proliferative endothelial cells known as endothelial colony-forming cells (ECFC) participate in vascular homeostasis in health as well as in pathological angiogenic remodeling in disease. ECFC are distinguished by the capacity to clonally proliferate from a single cell. The presence of ECFC in the human pulmonary arteries and their role in PAH pathogenesis is largely unknown. In this study, we established a simple technique for isolating and growing ECFC from cultured pulmonary artery endothelial cells (PAEC) to test the hypothesis that ECFC reside in human pulmonary arteries and that the proliferative vasculopathy of PAH is related to greater numbers and/or more proliferative ECFC in the pulmonary vascular wall. Flow cytometric forward and side scatter properties and aggregate correction were utilized to sort unmanipulated, single PAEC to enumerate ECFC in primary PAEC cultures derived from PAH and healthy lungs. After 2 weeks, wells were assessed for ECFC formation. ECFC derived from PAH PAEC were more proliferative than control. A greater proportion of PAH ECFC formed colonies following subculturing, demonstrating the presence of more ECFC with high proliferative potential among PAH PAEC. Human androgen receptor assay showed clonality of progeny, confirming that proliferative colonies were single cell-derived. ECFC expressed CD31, von Willebrand factor, endothelial nitric oxide synthase, caveolin-1 and CD34, consistent with an endothelial cell phenotype. We established a simple flow cytometry method that allows ECFC quantification using unmanipulated cells. We conclude that ECFC reside among PAEC and that PAH PAEC contain ECFC that are more proliferative than ECFC in control cultures, which likely contributes to the proliferative angiopathic process in PAH. PMID- 22530104 TI - Hypoxia modulates the expression of leucine zipper-positive MYPT1 and its interaction with protein kinase G and Rho kinases in pulmonary arterial smooth muscle cells. AB - We have shown previously that acute hypoxia downregulates protein kinase G (PKG) expression and activity in ovine fetal pulmonary vessels and pulmonary arterial smooth muscle cells (SMC). Here, we report that acute hypoxia also reduces the expression of leucinezipper-positive MYPT1 (LZ(+)MYPT1), a subunit of myosin light chain (MLC) phosphatase, in ovine fetal pulmonary arterial SMC. We found that in hypoxia, there is greater interaction between LZ(+) MYPT1 and RhoA and Rho kinase 1 (ROCK1)/Rho kinase 2 (ROCK2) and decreased interaction between LZ(+) MYPT1 and PKG, resulting in increased MLC(20) phosphorylation, a higher pMLC(20)/MLC(20) ratio and SMC contraction. In normoxic SMC PKG overexpression, LZ(+) MYPT1 expression is upregulated while PKG knockdown had an opposite effect. LZ(+) MYPT1 overexpression enhanced the interaction between PKG and LZ(+) MYPT1. Overexpression of a mutant LZ(-) MYPT1 isoform in SMC mimicked the effects of acute hypoxia and decreased pMLC(20)/MLC(20) ratio. Collectively, our data suggest that hypoxia downregulates LZ(+) MYPT1 expression by suppressing PKG levels, reduces the interaction of LZ(+) MYPT1 with PKG and promotes LZ(+) MYPT1 interaction with RhoA or ROCK1/ROCK2, thereby promoting pulmonary arterial SMC contraction. PMID- 22530105 TI - Cardiopulmonary hemodynamic clues for pulmonary vein stenosis diagnosis. AB - Pulmonary vein stenosis (PVS) post radiofrequency ablation for chronic atrial fibrillation poses a diagnostic challenge for the clinician. PVS presents with nonspecific symptoms, signs and radiographic features, and may be associated with significant pulmonary vascular involvement. Interestingly, others have described variation of the pulmonary artery wedge pressure between sites of the lung as a clue to pulmonary veno-occlusive disorders. We report, to the best of our knowledge, the first case that describes the regional loss of V waves while recording the mean pulmonary artery wedge pressure (mPawp) as well as the difference in pulmonary artery wedge pressure gradients as the main diagnostic clues for PVS. PMID- 22530106 TI - Morbidity of 200 consecutive cases of hand-assisted laparoscopic living donor nephrectomies: a single-center experience. AB - Background. Recipients of laparoscopically procured kidneys have been reported to have delayed graft function, a slower creatinine nadir, and potential significant complications. As the technique has evolved laparoscopic donor nephrectomy technique is becoming the gold standard for living donation. Study Design. We retrospectively reviewed the data of the first 200 hand-assisted laparoscopic living donor nephrectomies performed between January 2003 and February 2009. The initial 41 donors and their recipients (Group 1) were compared to the next 159 donors and their recipients (Group 2). The estimated blood loss, serum creatinine at discharge and 6 months, and the incidence of delayed graft function and perioperative complications were analyzed. Results. The median donor serum creatinine at discharge and 6 months was 1.2 mg/dL in each group. None of the laparoscopic procedures required conversion to an open procedure, and none of the donors required perioperative blood transfusion. The median recipient serum creatinine at 6 months after transplant was 1.2 mg/dL for each group. No ischemic ureteral complications related to the laparoscopic technique were seen. Conclusions. HALDN with meticulous surgical technique allows kidney procurement with very low morbidity and no mortality. This improved safety and decreased invasiveness from laparoscopic approach may further decrease morbidity of the procedure and increase organ donation. PMID- 22530108 TI - The hepatoprotective effect of sodium nitrite on cold ischemia-reperfusion injury. AB - Liver ischemia-reperfusion injury is a major cause of primary graft non-function or initial function failure post-transplantation. In this study, we examined the effects of sodium nitrite supplementation on liver IRI in either Lactated Ringer's (LR) solution or University of Wisconsin (UW) solution. The syngeneic recipients of liver grafts were also treated with or without nitrite by intra peritoneal injection. Liver AST and LDH release were significantly reduced in both nitrite-supplemented LR and UW preservation solutions compared to their controls. The protective effect of nitrite was more efficacious with longer cold preservation times. Liver histological examination demonstrated better preserved morphology and architecture with nitrite treatment. Hepatocellular apoptosis was significantly reduced in the nitrite-treated livers compared their controls. Moreover, liver grafts with extended cold preservation time of 12 to 24 hours demonstrated improved liver tissue histology and function post-reperfusion with either the nitrite-supplemented preservation solution or in nitrite-treated recipients. Interestingly, combined treatment of both the liver graft and recipient did not confer protection. Thus, nitrite treatment affords significant protection from cold ischemic and reperfusion injury to donor livers and improves liver graft acute function post-transplantation. The results from this study further support the potential for nitrite therapy to mitigate ischemia reperfusion injury in solid organ transplantation. PMID- 22530107 TI - Ischemia-Reperfusion Injury and Ischemic-Type Biliary Lesions following Liver Transplantation. AB - Ischemia-reperfusion (I-R) injury after liver transplantation (LT) induces intra- and/or extrahepatic nonanastomotic ischemic-type biliary lesions (ITBLs). Subsequent bile duct stricture is a significant cause of morbidity and even mortality in patients who underwent LT. Although the pathogenesis of ITBLs is multifactorial, there are three main interconnected mechanisms responsible for their formation: cold and warm I-R injury, injury induced by cytotoxic bile salts, and immunological-mediated injury. Cold and warm ischemic insult can induce direct injury to the cholangiocytes and/or damage to the arterioles of the peribiliary vascular plexus, which in turn leads to apoptosis and necrosis of the cholangiocytes. Liver grafts from suboptimal or extended-criteria donors are more susceptible to cold and warm I-R injury and develop more easily ITBLs than normal livers. This paper, focusing on liver I-R injury, reviews the risk factors and mechanisms leading to ITBLs following LT. PMID- 22530109 TI - Inflammation and microvasculopathy in renal ischemia reperfusion injury. AB - Acute renal failure (ARF) severely worsens prognosis of hospitalized patients. The most frequent cause of intrarenal ARF is transient or prolonged renal hypoperfusion (ischemia). Ischemia primarily affects the function and structure of tubular epithelial cells, which, in severe cases, is characterized by epithelial cell necrosis. Nevertheless, ischemia does not exclusively lead to alterations of epithelial cells but also causes interstitial inflammation and interstitial microvasculopathy. Both inflammation and microvasculopathy are particularly important in terms of postischemic kidney repair. Postischemic microvasculopathy is characterized by endothelial cell swelling with subsequent microvascular occlusion. Thus, reperfusion is inhibited (no-reflow phenomenon). Such endothelial cell dysfunction offers new therapeutic perspectives in ischemic ARF. Newer observations point towards the role of the so-called endothelial progenitor cells (EPCs) in the treatment of ARF. Systemic administration of EPCs to mice with bilateral renal ischemia mitigates postischemic endothelial cell dysfunction and protects animals from acute renal failure. PMID- 22530111 TI - Association of Sleep Duration with Obesity among US High School Students. AB - Increasing attention is being focused on sleep duration as a potential modifiable risk factor associated with obesity in children and adolescents. We analyzed data from the national Youth Risk Behavior Survey to describe the association of obesity (self-report BMI >=95th percentile) with self-reported sleep duration on an average school night, among a representative sample of US high school students. Using logistic regression to control for demographic and behavioral confounders, among female students, compared to 7 hours of sleep, both shortened (<=4 hours of sleep; adjusted odds ratio (95% confidence interval), AOR = 1.50 (1.05-2.15)) and prolonged (>=9 hours of sleep; AOR = 1.54 (1.13-2.10)) sleep durations were associated with increased likelihood of obesity. Among male students, there was no significant association between obesity and sleep duration. Better understanding of factors underlying the association between sleep duration and obesity is needed before recommending alteration of sleep time as a means of addressing the obesity epidemic among adolescents. PMID- 22530112 TI - Multidisciplinary treatments, patient characteristics, context of care, and adverse incidents in older, hospitalized adults. AB - The purpose of this study was to examine factors that contribute to adverse incidents by creating a model that included patient characteristics, clinical conditions, nursing unit context of care variables, medical treatments, pharmaceutical treatments, and nursing treatments. Data were abstracted from electronic, administrative, and clinical data repositories. The sample included older adults hospitalized during a four-year period at one, academic medical facility in the Midwestern United States who were at risk for falling. Relational databases were built and a multistep, statistical model building analytic process was used. Total registered nurse (RN) hours per patient day (HPPD) and HPPDs dropping below the nursing unit average were significant explanatory variables for experiencing an adverse incident. The number of medical and pharmaceutical treatments that a patient received during hospitalization as well as many specific nursing treatments (e.g., restraint use, neurological monitoring) were also contributors to experiencing an adverse incident. PMID- 22530113 TI - The impact of nursing characteristics and the work environment on perceptions of communication. AB - Failure to communicate openly and accurately to members of the healthcare team can result in medical error. The purpose of this study was to explore the impact of nursing characteristics and environmental values on communication in the acute care setting. Nurses (n = 135) on four medical-surgical units in two hospitals completed a survey asking nurses' perceptions of communication, work environment, and nursing demographics. LPNs perceived significantly higher levels of open communication with nurses than did RNs (P = .042). RNs noted higher levels of accuracy of communication among nurses than did LPNs (P < .001). Higher experience levels resulted in greater perceptions of open communication. Only environmental values (e.g., trust, respect) were a significant predictor of both openness and accuracy of communication. These findings suggest understanding the environment (e.g., presence or absence of trust, respect, status equity, and time availability) is a foundational step that must occur before implementing any strategies aimed at improving communication. PMID- 22530114 TI - Evaluation of a Brief Intervention to Improve the Nursing Care of Young Children in a High HIV and AIDS Setting. AB - The HIV epidemic in South Africa is putting great strain on health services, including the inpatient care of young children. Caregivers and young children (107 pairs) and 17 nurses participated in an intervention to improve the care of young children in hospital in a high HIV and AIDS setting. The intervention addressed caregiver expectations about admission and treatment, responsive feeding, coping with infant pain and distress, assistance with medical procedures, and preparation for discharge and home care. Following a preparatory and piloting phase, measures of nurse burnout, caregiver physical and emotional well-being, and caregiver-child interaction were made before and after intervention. No changes were found between before and after intervention on assessments of caregiver wellbeing. However, mothers in the postintervention phase rated nurses as more supportive; mother-child interaction during feeding was more relaxed and engaged, and babies were less socially withdrawn. While the intervention proved useful in improving certain outcomes for children and their caregivers, it did not address challenging hospital and ward administration or support needed by caregivers at home following discharge. To address the latter need, the intervention has been extended into the community through home-based palliative care and support. PMID- 22530115 TI - Dignity and deferral narratives as strategies in facilitated technology-based support groups for people with advanced cancer. AB - This paper examines the value of facilitated telephone and online support groups for palliative care. Telephone interviews were conducted with twenty people living with advanced cancer who had participated in either a telephone or online support group facilitated by the Cancer Council Victoria, Melbourne, Australia. Two dominant participant narratives emerged: a focus on dying with dignity or an interest in deferring discussion of death and dying to focus on the present. Despite the different approaches, participants found the technology-based support groups to be accessible and safe environments in which to discuss difficult topics in privacy. Technology-based strategies provide opportunities for health professionals to provide social and emotional care to more people by moving beyond individualised care and facilitate peer-to-peer support at the end of life, especially to those with specific needs. Such options are feasible for palliative care services to set up and acceptable to a group of clients, especially for younger clients or those socially or geographically isolated. PMID- 22530116 TI - Single-access laparoscopic surgery for ileal disease. AB - Aim. Single-access laparoscopic surgery (SALS) can be effective for benign and malignant diseases of the ileum in both the elective and urgent setting. Methods. Ten consecutive, nonselected patients with ileal disease requiring surgery over a twelve month period were included. All had a preoperative abdominopelvic computerized tomogram. Peritoneal access was achieved via a single transumbilical incision and a "surgical glove port" utilized as our preferred access device. With the pneumoperitoneum established, the relevant ileal loop was located using standard rigid instruments. For ileal resection, anastomosis, or enterotomy, the site of pathology was delivered and addressed extracorporeally. Result. The median (range) age of the patients was 42.5 (22-78) years, and the median body mass index was 22 (20.2-28) kg/m(2). Procedures included tru-cut biopsy of an ileal mesenteric mass, loop ileostomy and ileotomy for impacted gallstone extraction as well as ileal (n = 3) and ileocaecal resection (n = 4). Mean (range) incision length was 2.5 (2-5) cm. All convalescences were uncomplicated. Conclusions. These preliminary results show that SALS is an efficient and safe modality for the surgical management of ileal disease with all the advantages of minimal access surgery and without requiring a significant increase in theatre resource or cost or incurring extra patient morbidity. PMID- 22530110 TI - Role of Mitogen-Activated Protein Kinases in Myocardial Ischemia-Reperfusion Injury during Heart Transplantation. AB - In solid organ transplantation, ischemia/reperfusion (IR) injury during organ procurement, storage and reperfusion is an unavoidable detrimental event for the graft, as it amplifies graft inflammation and rejection. Intracellular mitogen activated protein kinase (MAPK) signaling pathways regulate inflammation and cell survival during IR injury. The four best-characterized MAPK subfamilies are the c Jun NH2-terminal kinase (JNK), extracellular signal- regulated kinase-1/2 (ERK1/2), p38 MAPK, and big MAPK-1 (BMK1/ERK5). Here, we review the role of MAPK activation during myocardial IR injury as it occurs during heart transplantation. Most of our current knowledge regarding MAPK activation and cardioprotection comes from studies of preconditioning and postconditioning in nontransplanted hearts. JNK and p38 MAPK activation contributes to myocardial IR injury after prolonged hypothermic storage. p38 MAPK inhibition improves cardiac function after cold storage, rewarming and reperfusion. Small-molecule p38 MAPK inhibitors have been tested clinically in patients with chronic inflammatory diseases, but not in transplanted patients, so far. Organ transplantation offers the opportunity of starting a preconditioning treatment before organ procurement or during cold storage, thus modulating early events in IR injury. Future studies will need to evaluate combined strategies including p38 MAPK and/or JNK inhibition, ERK1/2 activation, pre- or postconditioning protocols, new storage solutions, and gentle reperfusion. PMID- 22530117 TI - Crackle Pitch Rises Progressively during Inspiration in Pneumonia, CHF, and IPF Patients. AB - Objective. It is generally accepted that crackles are due to sudden opening of airways and that larger airways produce crackles of lower pitch than smaller airways do. As larger airways are likely to open earlier in inspiration than smaller airways and the reverse is likely to be true in expiration, we studied crackle pitch as a function of crackle timing in inspiration and expiration. Our goal was to see if the measurement of crackle pitch was consistent with this theory. Methods. Patients with a significant number of crackles were examined using a multichannel lung sound analyzer. These patients included 34 with pneumonia, 38 with heart failure, and 28 with interstitial fibrosis. Results. Crackle pitch progressively increased during inspirations in 79% of all patients. In these patients crackle pitch increased by approximately 40 Hz from the early to midinspiration and by another 40 Hz from mid to late-inspiration. In 10% of patients, crackle pitch did not change and in 11% of patients crackle pitch decreased. During expiration crackle pitch progressively decreased in 72% of patients and did not change in 28% of patients. Conclusion. In the majority of patients, we observed progressive crackle pitch increase during inspiration and decrease during expiration. Increased crackle pitch at larger lung volumes is likely a result of recruitment of smaller diameter airways. An alternate explanation is that crackle pitch may be influenced by airway tension that increases at greater lung volume. In any case improved understanding of the mechanism of production of these common lung sounds may help improve our understanding of pathophysiology of these disorders. PMID- 22530118 TI - The Diagnostic Value of the Interstitial Biomarkers KL-6 and SP-D for the Degree of Fibrosis in Combined Pulmonary Fibrosis and Emphysema. AB - The combined pulmonary fibrosis and emphysema (CPFE) was reported first in 1990, but it has been comparatively underestimated until recently. Although the diagnostic findings of both emphysematous and fibrotic regions are detectable by high-resolution computed tomography (HRCT) of the chest, the degree of progressive fibrosis, which increases with emphysematous lesions, is difficult to evaluate. In this study, we hypothesized that the biomarkers for pulmonary fibrosis, surfactant protein D (SP-D), and KL-6 would serve as good indicators of fibrotic lesions in CPFE. We recruited 46 patients who had been diagnosed in our hospital with both emphysema and fibrosis by their CT scan image from April 2003 to March 2008. The correlation among their pulmonary function tests, composite physiologic index (CPI), and the serum levels of SP-D and KL-6 was evaluated. We found a correlation between KL-6 and %VC, %TLC, or CPI and between SP-D and %VC or CPI. Interestingly, the combined product of KL-6 and SP-D (KL-6xSP-D) was found to highly correlate with %VC and %TLC or CPI. These results show that both KL-6 and SP-D, and especially the product of SP-D and KL-6, are good indicators of the presence of fibrotic lesions in the lungs of CPFE patients. PMID- 22530119 TI - Effect of nebulized morphine on dyspnea of mustard gas-exposed patients: a double blind randomized clinical trial study. AB - Background. Dyspnea is one of the main complaints in a group of COPD patients due to exposure to sulfur mustard (SM) and is refractory to conventional therapies. We designed this study to evaluate effectiveness of nebulized morphine in such patients. Materials and Methods. In a double-blind clinical trial study, 40 patients with documented history of exposure to SM were allocated to two groups: group 1 who received 1 mg morphine sulfate diluted by 4 cc normal saline 0.5% using nebulizer once daily for 5 days and group 2 serving as control who received normal saline as placebo. They were visited by pulmonologist 7 times per day to check symptoms and signs and adverse events. Different parameters including patient-scored peak expiratory flow using pick flow meter, visual analogue scale (VAS) for dyspnea, global quality of life and cough, and number of respiratory rate, night time awaking for dyspnea and cough have been assessed. Results. The scores of VAS for dyspnea, cough and quality of life and also respiratory rate, heart rate, and night time awaking due to dyspnea and night time awaking due to cough improved significantly after morphine nebulization without any major adverse events. Also pick expiratory flow has been improved significantly after nebulization in each day. Conclusion. Our results showed the clinical benefit of nebulized morphine on respiratory complaints of patients due to exposure to SM without significant side effects. PMID- 22530120 TI - The Effect of Path and Beginning Time of Ascending on Incidence of Acute Mountain Sickness around Mount Damavand in Iran (5671 m). AB - Background. This study was designed to evaluate the incidence of acute mountain sickness (AMS) occurring on different climbing routes on Mount Damavand and the effect of beginning time of ascent in Iranian trekkers. Methods. This study was a descriptive cohort investigation, performed in summer 2007. All trekkers who ascended Mount Damavand from northern, western, eastern, and southern paths and passed 4200 m altitude were included in the study. Two questionnaires were completed for each trekker (personal information and Lake Louise score questionnaire). Multiple logistic regression analysis was used to explore the independent predicting variables for AMS. Results. Overall incidence rate of AMS was 53.6%. This rate was the highest in south route (61.5%) (P < 0.001). There was no difference in the incidence of AMS on other paths. AMS history, AMS history on Damavand, the beginning time of climbing, sleeping at 4200 m altitude, and home altitude had significant effect on AMS incidence, but by multiple logistic regression analysis south route and AMS history on Mount Damavand had positive effect on incidence of AMS (P = 0.019 and P < 0.001). Conclusion. The path and the beginning time of ascent can affect incidence of AMS. The risk of occurrence of AMS was 1.9 times as large for trekkers who ascended from southern route. PMID- 22530121 TI - Novel therapies in glioblastoma. AB - Conventional treatment of glioblastoma has advanced only incrementally in the last 30 years and still yields poor outcomes. The current strategy of surgery, radiation, and chemotherapy has increased median survival to approximately 15 months. With the advent of molecular biology and consequent improved understanding of basic tumor biology, targeted therapies have become cornerstones for cancer treatment. Many pathways (RTKs, PI3K/AKT/mTOR, angiogenesis, etc.) have been identified in GBM as playing major roles in tumorigenesis, treatment resistance, or natural history of disease. Despite the growing understanding of the complex networks regulating GBM tumors, many targeted therapies have fallen short of expectations. In this paper, we will discuss novel therapies and the successes and failures that have occurred. One clear message is that monotherapies yield minor results, likely due to functionally redundant pathways. A better understanding of underlying tumor biology may yield insights into optimal targeting strategies which could improve the overall therapeutic ratio of conventional treatments. PMID- 22530122 TI - The Clinical and Prognostic Significance of Activated AKT-mTOR Pathway in Human Astrocytomas. AB - Astrocytomas, the most common type of gliomas, and especially grade IV glioblastomas are "endowed" with strong proliferation and invasion potentials, high recurrence rate, and poor patients' prognosis. Aberrant signaling of AKT mTOR (mammalian target of rapamycin) has been implicated in carcinogenesis. This paper is focused on the impact of deregulated AKT-mTOR signaling components in the clinical outcome and prognosis of human astrocytomas. Current therapeutic targeting of astrocytomas with AKT-mTOR inhibitors in preclinical and clinical stage is also discussed, including future perspectives regarding the management of these devastating tumors. PMID- 22530123 TI - Screening and Evaluation of Deleterious SNPs in APOE Gene of Alzheimer's Disease. AB - Introduction. Apolipoprotein E (APOE) is an important risk factor for Alzheimer's disease (AD) and is present in 30-50% of patients who develop late-onset AD. Several single-nucleotide polymorphisms (SNPs) are present in APOE gene which act as the biomarkers for exploring the genetic basis of this disease. The objective of this study is to identify deleterious nsSNPs associated with APOE gene. Methods. The SNPs were retrieved from dbSNP. Using I-Mutant, protein stability change was calculated. The potentially functional nonsynonymous (ns) SNPs and their effect on protein was predicted by PolyPhen and SIFT, respectively. FASTSNP was used for functional analysis and estimation of risk score. The functional impact on the APOE protein was evaluated by using Swiss PDB viewer and NOMAD-Ref server. Results. Six nsSNPs were found to be least stable by I-Mutant 2.0 with DDG value of >-1.0. Four nsSNPs showed a highly deleterious tolerance index score of 0.00. Nine nsSNPs were found to be probably damaging with position-specific independent counts (PSICs) score of >=2.0. Seven nsSNPs were found to be highly polymorphic with a risk score of 3-4. The total energies and root-mean-square deviation (RMSD) values were higher for three mutant-type structures compared to the native modeled structure. Conclusion. We concluded that three nsSNPs, namely, rs11542041, rs11542040, and rs11542034, to be potentially functional polymorphic. PMID- 22530124 TI - The role of cytokines and inflammatory cells in perinatal brain injury. AB - Perinatal brain injury frequently complicates preterm birth and leads to significant long-term morbidity. Cytokines and inflammatory cells are mediators in the common pathways associated with perinatal brain injury induced by a variety of insults, such as hypoxic-ischemic injury, reperfusion injury, toxin mediated injury, and infection. This paper examines our current knowledge regarding cytokine-related perinatal brain injury and specifically discusses strategies for attenuating cytokine-mediated brain damage. PMID- 22530125 TI - Regional differences in susceptibility to hypoxic-ischemic injury in the preterm brain: exploring the spectrum from white matter loss to selective grey matter injury in a rat model. AB - Models of premature brain injury have largely focused on the white matter injury thought to underlie periventricular leukomalacia (PVL). However, with increased survival of very low birth weight infants, injury patterns involving grey matter are now recognized. We aimed to determine how grey matter lesions relate to hypoxic-ischemic- (HI) mediated white matter injury by modifying our rat model of PVL. Following HI, microglial infiltration, astrocytosis, and neuronal and axonal degeneration increased in a region-specific manner dependent on the severity of myelin loss in pericallosal white matter. The spectrum of injury ranged from mild, where diffuse white matter abnormalities were dominant and were associated with mild axonal injury and local microglial activation, to severe HI injury characterized by focal MBP loss, widespread neuronal degeneration, axonal damage, and gliosis throughout the neocortex, caudate putamen, and thalamus. In sum, selective regional white matter loss occurs in the preterm rat concomitantly with a clinically relevant spectrum of grey matter injury. These data demonstrate an interspecies similarity of brain injury patterns and further substantiates the reliable use of this model for the study of preterm brain injury. PMID- 22530126 TI - Perinatal cerebellar injury in human and animal models. AB - Cerebellar injury is increasingly recognized through advanced neonatal brain imaging as a complication of premature birth. Survivors of preterm birth demonstrate a constellation of long-term neurodevelopmental deficits, many of which are potentially referable to cerebellar injury, including impaired motor functions such as fine motor incoordination, impaired motor sequencing and also cognitive, behavioral dysfunction among older patients. This paper reviews the morphogenesis and histogenesis of the human and rodent developing cerebellum, and its more frequent injuries in preterm. Most cerebellar lesions are cerebellar hemorrhage and infarction usually leading to cerebellar abnormalities and/or atrophy, but the exact pathogenesis of lesions of the cerebellum is unknown. The different mechanisms involved have been investigated with animal models and are primarily hypoxia, ischemia, infection, and inflammation Exposure to drugs and undernutrition can also induce cerebellar abnormalities. Different models are detailed to analyze these various disturbances of cerebellar development around birth. PMID- 22530128 TI - Combined RASSF1A and RASSF2A Promoter Methylation Analysis as Diagnostic Biomarker for Bladder Cancer. AB - Promoter hypermethylation, a widely studied epigenetic event known to influence gene expression levels, has been proposed as a potential biomarker in multiple types of cancer. Clinical diagnostic biomarkers are needed for reliable prediction of bladder cancer recurrence. In this paper, DNA promoter methylation of five C-terminal Ras-association family members (RASSF1A, RASSF2A, RASSF4, RASSF5, and RASSF6) was studied in 64 formalin-fixed paraffin-embedded (FFPE) bladder cancer and normal adjacent tissues using methylation-specific high resolution melting (MS-HRM) analysis. Results showed that 73% (30/41) of transitional cell carcinoma, 100% (3/3) of squamous cell carcinoma, and 100% (4/4) of small cell carcinoma demonstrated promoter methylation of the RASSF1A or RASSF2A gene, but only 6% (1/16) of normal tissues had promoter methylation of RASSF genes. Testing positive for hypermethylation of RASSF1A or RASSF2A promoter provided 77% sensitivity and 94% specificity for identification of cancer tissues with an area under the curve of 0.854, suggesting that promoter methylation analysis of RASSF1A and RASSF2A genes has potential for use as a recurrence biomarker for bladder cancer patients. PMID- 22530127 TI - Current trends in targeted therapies for glioblastoma multiforme. AB - Glioblastoma multiforme (GBM) is one of the most frequently occurring tumors in the central nervous system and the most malignant tumor among gliomas. Despite aggressive treatment including surgery, adjuvant TMZ-based chemotherapy, and radiotherapy, GBM still has a dismal prognosis: the median survival is 14.6 months from diagnosis. To date, many studies report several determinants of resistance to this aggressive therapy: (1) O(6)-methylguanine-DNA methyltransferase (MGMT), (2) the complexity of several altered signaling pathways in GBM, (3) the existence of glioma stem-like cells (GSCs), and (4) the blood-brain barrier. Many studies aim to overcome these determinants of resistance to conventional therapy by using various approaches to improve the dismal prognosis of GBM such as modifying TMZ administration and combining TMZ with other agents, developing novel molecular-targeting agents, and novel strategies targeting GSCs. In this paper, we review up-to-date clinical trials of GBM treatments in order to overcome these 4 hurdles and to aim at more therapeutical effect than conventional therapies that are ongoing or are about to launch in clinical settings and discuss future perspectives. PMID- 22530129 TI - Where Do AQP4 Antibodies Fit in the Pathogenesis of NMO? AB - Recent advances in the field of neuromyelitis optica (NMO) research provided convincing evidence that anti-AQP4 antibody (AQP4-Ab) not only serves as a highly specific disease marker, but also plays an essential role in the pathogenesis of the disease. Although it is now widely recognized that AQP4-Ab induces astrocytic necrosis in a complement-dependent manner, additional triggers are also suspected as a prerequisite for the development of the disease. Unraveling these unresolved aspects of the disease will provide substantial insight into still controversial issues in the pathogenesis of NMO. PMID- 22530130 TI - Castration-resistant prostate cancer: mechanisms, targets, and treatment. AB - Patients with castration-resistant prostate cancer (CRPC), who progress after docetaxel therapy, had until very recently, only a few therapeutic options. Recent advances in this field brought about new perspectives in the treatment of this disease. Molecular, basic, and translational research has given us a better understanding on the mechanisms of CRPC. This great investment has turned into a more rational approach to the development of new drugs. Some of the new treatments are already available to our patients outside clinical trials and may include inhibitors of androgen biosynthesis; new chemotherapy agents; bone targeted therapy; and immunotherapy. This paper aims to review the mechanisms of prostate cancer resistance, possible therapeutic targets, as well as new options to treat CRPC. PMID- 22530131 TI - Postoperative radiotherapy after radical prostatectomy: indications and open questions. AB - Biochemical relapse after radical prostatectomy occurs in approximately 15-40% of patients within 5 years. Postoperative radiotherapy is the only curative treatment for these patients. After radical prostatectomy, two different strategies can be offered, adjuvant or salvage radiotherapy. Adjuvant radiotherapy is defined as treatment given directly after surgery in the presence of risk factors (R1 resection, pT3) before biochemical relapse occurs. It consists of 60-64 Gy and was shown to increase biochemical relapse-free survival in three randomized controlled trials and to increase overall survival after a median followup of 12.7 years in one of these trials. Salvage radiotherapy, on the other hand, is given upon biochemical relapse and is the preferred option, by many centers as it does not include patients who might be cured by surgery alone. As described in only retrospective studies the dose for salvage radiotherapy ranges from 64 to 72 Gy and is usually dependent on the absence or presence of macroscopic recurrence. Randomized trials are currently investigating the role of adjuvant and salvage radiotherapy. Patients with biochemical relapse after prostatectomy should at the earliest sign of relapse be referred to salvage radiotherapy and should preferably be treated within a clinical trial. PMID- 22530132 TI - Markers of inflammation and fibrosis in alcoholic hepatitis and viral hepatitis C. AB - High levels of profibrinogenic cytokine transforming factor beta (TGF-beta), metalloprotease (MMP2), and tissue inhibitor of matrix metalloprotease 1 (TIMP1) contribute to fibrogenesis in hepatitis C virus (HCV) infection and in alcohol induced liver disease (ALD). The aim of our study was to correlate noninvasive serum markers in ALD and HCV patients with various degrees of inflammation and fibrosis in their biopsies. Methods. Serum cytokines levels in HCV-infected individuals in the presence or absence of ALD were measured. Student's-t-test with Bonferroni correction determined the significance between the groups. Results. Both tumor-necrosis-factor- (TNF)-alpha and TGF-beta levels increased significantly with the severity of inflammation and fibrosis. TGF-beta levels increased significantly in ALD patients versus the HCV patients. Proinflammatory cytokines' responses to viral and/or toxic injury differed with the severity of liver inflammation. A combination of these markers was useful in predicting and diagnosing the stages of inflammation and fibrosis in HCV and ALD. Conclusion. Therapeutic monitoring of TGF-beta and metalloproteases provides important insights into fibrosis. PMID- 22530134 TI - Chemotherapeutic Efficacy of Indigofera aspalathoides on 20-Methylcholanthrene Induced Fibrosarcoma in Rats. AB - The present study was undertaken to test the chemopreventive effects of one herbal medicinal plant, Indigofera aspalathoides, on chemically induced carcinogenesis in rats. A well-known polyaromatic hydrocarbon, namely, 20 methylcholanthrene, which is a known carcinogenic substance, was used to induce fibrosarcoma in Wistar strain of male albino rats. Fibrosarcoma rats were treated with aqueous extracts of Indigofera aspalathoides. The rats were divided into four groups, each consisting of six animals. Group I served as normal control, Group II served as fibrosarcoma-induced animals, Group III were fibrosarcoma bearing animals treated with aqueous extracts of Indigofera aspalathoides, and Group IV animals, which were normal healthy animals treated with Indigofera aspalathoides aqueous extract, served as drug control set. Group III and Group IV animals were treated with aqueous extract of Indigofera aspalathoides intraperitoneally at a dose of 250 mg/kg. b.w. for 30 days. The fibrosarcoma was proved by pathological examinations. The activity levels of nucleic acids such as total DNA and RNA and hexose, hexosamine, and sialic acid in liver and kidney of treated rats were used to monitor the chemopreventive role of the plant extract. The observed increase in the levels of DNA, RNA, hexose, hexosamine, and sialic acid in liver and kidney tissues of fibrosarcoma-bearing animals reached near normal state after the treatment with aqueous extracts of Indigofera aspalathoides, suggesting that Indigofera aspalathoides does have a chemotherapeutic role. PMID- 22530133 TI - Activity of Cuban Plants Extracts against Leishmania amazonensis. AB - Natural products have long been providing important drug leads for infectious diseases. Leishmaniasis is a major health problem worldwide that affects millions of people especially in the developing nations. There is no immunoprophylaxis (vaccination) available for Leishmania infections, and conventional treatments are unsatisfactory; therefore, antileishmanial drugs are urgently needed. In this work, 48 alcoholic extracts from 46 Cuban plants were evaluated by an in vitro bioassay against Leishmania amazonensis. Furthermore, their toxicity was assayed against murine macrophage. The three most potent extracts against the amastigote stage of Leishmania amazonensis were from Hura crepitans, Bambusa vulgaris, and Simarouba glauca. PMID- 22530135 TI - How to predict the impact of methylphenidate on cardiovascular risk in children with attention deficit disorder: methylphenidate improves autonomic dysfunction in children with ADHD. AB - Background. Although stimulants have long been touted as treatments for attention deficit disorder with or without hyperactivity (ADHD), in recent years, increasing concerns have been raised about the cardiovascular safety of these medications. We aimed to prove if measurements of autonomic function with time domain analysis of heart rate variability (HRV) in 24-hour Holter ECG are useful to predict the risk of sudden cardiac death in ADHD children and adolescents. Methods. We analysed HRV obtained from children with the diagnosis of ADHD prior to (N = 12) or during medical therapy (N = 19) with methylphenidate (MPH), aged 10.8 +/- 2.0 years (mean +/- SD), who were referred to our outpatient Paediatric Cardiology Clinic to rule out heart defect. As a control group, we compared the HRV data of 19 age-matched healthy children without heart defect. Results. Average HRV parameters from 24-hour ECG in the ADHD children prior to MPH showed significant lower values compared to healthy children with respect to rMSSD (26 +/- 4 ms versus 44 +/- 10 ms, P <= 0.0001) and pNN50 (6.5 +/- 2.7% versus 21.5 +/ 9.0%, P <= 0.0001). These values improved in MPH-treated children with ADHD (RMSSD: 36 +/- 8 ms; pNN50: 14.2 +/- 6.9%). Conclusion. Children who suffer from ADHD show significant changes in HRV that predominantly reflects diminished vagal tone, a well-known risk factor of sudden cardiac death in adults. In our pilot study, MPH treatment improved HRV. PMID- 22530136 TI - Unusual effects of nicotine as a psychostimulant on ambulatory activity in mice. AB - The present study examined the effect of nicotine, alone and in combination with various drugs that act on the CNS, on ambulatory activity, a behavioral index for locomotion, in ICR (CD-1) strain mice. Nicotine at 0.25-2 mg/kg acutely reduced ambulatory activity of ICR mice. The effect of nicotine was similar to that of haloperidol and fluphenazine but distinct from that of bupropion and methylphenidate. ICR mice developed tolerance against the inhibitory effect of nicotine on ambulatory activity when nicotine was repeatedly administered. This effect was also distinct from bupropion and methylphenidate as they produced augmentation of their ambulation-stimulating effects in ICR mice. Nicotine reduced the ambulation-stimulating effects of bupropion and methylphenidate as well as haloperidol and fluphenazine. Taken together, nicotine exhibited unusual effects as a psychostimulant on ambulatory activity in ICR mice. PMID- 22530138 TI - Anticonvulsant drugs, brain glutamate dehydrogenase activity and oxygen consumption. AB - Glutamate dehydrogenase (GDH, E.C. 1.4.1.3.) is a key enzyme for the biosynthesis and modulation of glutamate (GLU) metabolism and an indirect gamma-aminobutyric acid (GABA) source, here we studied the effect of anticonvulsants such as pyridoxal phosphate (PPAL), aminooxyacetic acid (AAOA), and hydroxylamine (OHAMINE) on GDH activity in mouse brain. Moreover, since GLU is a glucogenic molecule and anoxia is a primary cause of convulsions, we explore the effect of these drugs on oxygen consumption. Experiments were performed in vitro as well as in vivo for both oxidative deamination of GLU and reductive amination of alpha ketoglutarate (alphaK). Results in vitro showed that PPAL decreased oxidative deamination of GLU and oxygen consumption, whereas AAOA and OHAMINE inhibited GDH activity competitively and also inhibited oxygen consumption when alphaK reductive amination was carried out. In contrast, results showed that in vivo, all anticonvulsants enhanced GLU utilization by GDH and also decreased oxygen consumption. Together, results suggest that GDH activity has repercussions on oxygen consumption, which may indicate that the enzyme activity is highly regulated by energy requirements for metabolic activity. Besides, GDH may participate in regulation of GLU and, indirectly GABA levels, hence in neuronal excitability, becoming a key enzyme in seizures mechanism. PMID- 22530137 TI - Plasma drug level validates self-reported adherence but predicts limited specificity for nonadherence to antiretroviral therapy. AB - Introduction. Adherence to antiretroviral therapy (ART) in low-income countries is mainly assessed by self-reported adherence (S-RA) without drug level determination. Nonadherence is an important factor in the emergence of resistance to ART, presenting a need for drug level determination. Objective. We set out to establish the relationship between plasma stavudine levels and S-RA and validate S-RA against the actual plasma drug concentrations. Methods. A cross-sectional investigation involving 234 patients in Uganda. Stavudine plasma levels were determined using high-performance liquid chromatography. We compared categories of plasma levels of stavudine with S-RA using multivariable logistic regression models. Results. Overall, 194/234 patients had S-RA >= 95% (good adherence) and 166/234 had stavudine plasma concentrations >= 36 nmol/L (therapeuticconcentration). Patients with good S-RA were eight times more likely to have stavudine levels within therapeutic concentration (Adjusted Odds Ratio: 7.7, 95% Confidence Interval: 3.5-7.0). However, of the 194 patients with good S RA, 21.7% had below therapeutic concentrations. S-RA had high sensitivity for adherence (91.6%), but limited specificity for intrinsic poor adherence (38.2%). Conclusions. S-RA is a good tool for assessing adherence, but has low specificity in detecting nonadherence, which has implications for emergence of resistance. PMID- 22530139 TI - Effects of stimulation and blockade of d(2) receptor on depression-like behavior in ovariectomized female rats. AB - The aim of the present study was to explore the hedonic effects of D(2) receptor agonist, quinpirole and D(2) receptor antagonist, and sulpiride alone or in combination with a low dose of 17beta-E(2)-estradiol (17beta-E(2)) in the adult ovariectomized female rats (OVX). OVX rats of Wistar strain were used in all experiments. Two weeks after surgery rats were chronically treated with vehicle, a low dose of 17beta-E(2) (5.0 MUg/rat), quinpirole (0.1 mg/kg), sulpiride (10.0 mg/kg), quinpirole plus 17beta-E(2), or sulpiride plus 17beta-E(2) for 14 days before the forced swimming test. We found that sulpiride significantly decreased immobility time in the OVX females. A combination of sulpiride with a low dose of 17beta-E(2) induced more profound decrease of immobility time in the OVX rats compared to the rats treated with sulpiride alone. On the contrary, quinpirole failed to modify depression-like behavior in the OVX rats. In addition, quinpirole significantly blocked the antidepressant-like effect of 17beta-E(2) in OVX rats. Thus, the D(2) receptor antagonist sulpiride alone or in combination with a low dose of 17beta-E(2) exerted antidepressant-like effect in OVX female rats, while the D(2) receptor agonist quinpirole produced depressant-like profile on OVX rats. PMID- 22530141 TI - Staphylococcus aureus Infection Induced Oxidative Imbalance in Neutrophils: Possible Protective Role of Nanoconjugated Vancomycin. AB - Staphylococcus aureus infection causes oxidative stress in neutrophils. The immune cells use reactive oxygen species (ROS) for carrying out their normal functions while an excess amount of ROS can attack cellular components that lead to cell damage. The present study was aimed to test the protective role of nanoconjugated vancomycin against vancomycin-sensitive Staphylococcus aureus (VSSA) and vancomycin-resistant Staphylococcus aureus (VRSA) infection induced oxidative stress in neutrophils. VSSA- and VRSA-infection were developed in Swiss mice by intraperitoneal injection of 5 * 10(6) CFU/mL bacterial solutions. Nanoconjugated vancomycin was treated to VSSA- and VRSA-infected mice at its effective dose for 10 days. Vancomycin was treated to VSSA and VRSA infected mice at similar dose, respectively, for 10 days. The result reveals that in vivo VSSA and VRSA infection significantly increases the level of lipid peroxidation, protein oxidation, oxidized glutathione level, and nitrite generation and decreases the level of reduced glutathione, antioxidant enzyme status, and glutathione-dependent enzymes as compared to control group; which were increased or decreased significantly near to normal in nanoconjugated vancomycin-treated group. These finding suggests the potential use and beneficial protective role of nanoconjugated vancomycin against VSSA and VRSA infection induced oxidative imbalance in neutrophils. PMID- 22530140 TI - Isoflavones-Enriched Soy Protein Prevents CCL(4)-Induced Hepatotoxicity in Rats. AB - The burden of liver disease in Egypt is exceptionally high due to the highest prevalence of hepatitis C virus (HCV) resulting in rising rates of hepatocellular carcinoma (HCC). The aim of the current study was to determine the isoflavones in soy and to evaluate the protective role of soy against CCl(4)-induced liver damage in rats. Four experimental groups were treated for 8 weeks and included the control group, soy-supplemented diet (20% w/w) group, the group treated orally with CCl(4) (100 mg/kg bw) twice a week, and the group fed soy supplemented diet and treated with CCl(4). Blood and liver tissue samples were collected for biochemical analyses and histological examination. The results indicated that protein content was 45.8% and the total isoflavones recorded 167.3 mg/100 g soy. Treatment with CCl(4) resulted in a significant biochemical changes in serum liver tissue accompanied with severe oxidative stress and histological changes. Supplementation with soy succeeded to restore the elevation of liver enzymes activities and improved serum biochemical parameters. Moreover, soy supplementation improved the antioxidant enzymes, decreased lipid peroxidation, and improved the histological picture of the liver tissue. It could be concluded that soy-protein-enriched isoflavones may be a promising agent against liver diseases. PMID- 22530142 TI - Remedial Prospective of Hippophae rhamnoides Linn. (Sea Buckthorn). AB - Sea buckthorn (Hippophae rhamnoides L.) constitutes thorny nitrogen fixing deciduous shrub. Sea buckthorn(SBT) is primarily valued for its very rich vitamins A, B(1), B(12), C, E, K, and P; flavonoids, lycopene, carotenoids, and phytosterols. and therapeutically important since it is rich with potent antioxidants. Scientifically evaluated pharmacological actions of SBT are like inflammation inhibited by reduced permeability, loss of follicular aggregation of lymphocytes from the inflamed synovium and suppress lymphocyte proliferation. SBT reduced recurrence of angina, ischemic electrocardiogram which might be due to decreased myocardial oxygen consumption and inhibition of platelet aggregation induced by collagen. SBT can kill both cancer cells of S180, P388, SGC7901 and lymphatic leukemia (L1200). The antiulcer activity may be related to reduce gastric empty time, inhibiting proteolytic activity and promoting wound reparation processes of mucosa. SBT exerts antihypertensive effect in part by blocking angiotensin-2 receptor on cell surface. SBT decreased the level of stress hormones and enhanced hypoxic tolerance in animals indicating its anti stress, adaptogenic activity. A lot of research work is still needed to find cellular and molecular mechanisms of these activities and also yet to be explored for its activity in osteoporosis, hemorrhage, cataract, urinary stone, acne, psoriasis, polyneuritis, cheilosis, glossities, baldness, anti-obesity, gout, and chronic prostitis. PMID- 22530143 TI - Anti-Inflammatory, Analgesic, and Antipyretic Activities of the Ethanol Extract of Piper interruptum Opiz. and Piper chaba Linn. AB - Piper interruptum Opiz. and Piper chaba Linn. are herbaceous plants in the Piperaceae family. The ethanol extract of P. interruptum and P. chaba inhibited ethyl phenylpropiolate-induced ear edema and carrageenan-induced hind paw edema in rats. Both extracts reduced transudative and granuloma weights as well as body weight gain and thymus weight of the chronic inflammatory model using cotton pellet-induced granuloma formation in rats. Moreover, both extracts exhibited analgesic activity on both early phase and late phase of formalin test in mice and also showed antipyretic activity on yeast-induced hyperthermia in rats. PMID- 22530144 TI - Bedtime single-dose prednisolone in clinically stable rheumatoid arthritis patients. AB - Introduction. Sign and symptoms of rheumatoid arthritis have circadian rhythms and are more prominent in the morning. Timing of glucocorticoid administration may be important with respect to the natural secretion of endogenous glucocorticoids. Herein, we intended to test the hypothesis that bedtime administration of prednisolone could be more efficient in controlling signs and symptoms in patients with RA. Material and Methods. Sixty patients with stable disease were treated with single dose prednisolone at 8 a.m. for the first three months and thereafter with similar dose at 10 PM for the next three months (before-after method). We compared fatigue scores, morning stiffness and pain scores, Clinical Disease Activity Indices, erythrocyte sedimentation rates, C Reactive Protein, and profile of adverse effects. Results. The mean of morning stiffness, fatigue scores, CRP and CDAI decreased statistically when prednisolone was administrated at 10 p.m. The means of pain scores and ESR were also decreased when the patients took prednisolone at night, without significant statistical difference. Conclusion. Administration of low-dose oral prednisolone could reduce disease activity scores in morning in clinically stable patients with RA. So it could be supposed that administrating bedtime prednisolone may permit the smallest possible dose. PMID- 22530145 TI - The new method developed for evaluation of anthelmintic activity by housefly worms and compared with conventional earthworm method. AB - Evaluation of anthelmintic activity of any drug when carried out in laboratory conditions by using the isolated worms from nature cannot be adaptable with artificial laboratory conditions. Therefore, the present study aims at developing a new adaptable method for evaluation of anthelmintic activity. The present anthelmintic activity study reveals a new methodology with housefly worms cultured in laboratory conditions that resemble parasitic pinworms found in human being. We studied the anthelmintic activities of various drugs on housefly worms and earthworms. The results showed that the housefly worms had taken more time for paralysis and death. Even after paralysis the time taken for death is more in housefly worms in spite of smaller size and lesser weight of the worms compared to earthworms. The study concluded that the earthworms have not adapted to the artificial laboratory conditions leading to erratic results. Therefore, culturing of housefly worms was carried out to evaluate the anthelmintic activity and found an easy, prominent, eco-friendly, and reproducible method in all aspects such as equal age, size, and weight of worms used for the experiment. PMID- 22530147 TI - Epithelial cell dissemination and readhesion: analysis of factors contributing to metastasis formation in breast cancer. AB - Although considerable progress has been achieved in breast cancer diagnosis and treatment, the live-saving effect of mammography has hardly been measurable and the benefit of taxanes regarded as highly active is still a matter of debate, possibly because treatment effects have hitherto been mainly determined from the solid part of the tumor, due to lack of measurability of the systemic part of the disease. Here, we have quantified the influence on the systemic disease, cells mobilized from the solid tumor. Increased numbers of circulating epithelial cells were observed in screened individuals and still higher numbers in breast cancer patients with repeated mammograms as compared to mammogram naive individuals. Taxanes as part of the subsequent systemic treatment led to mobilization of tumor suspect cells in up to 78% cases and the majority of relapses have occurred in these patients. Surgery-induced activation of disseminated cells may additionally contribute to metastasis formation. PMID- 22530148 TI - Toll-like receptors as novel therapeutic targets for ovarian cancer. AB - Ovarian cancer (OC) is an aggressive disease that affects approximately 1 in 70 women and has a poor prognosis (<50%, 5-year survival rate), in part because it is often diagnosed at a late stage. There are three main types of OC: neoplasms of surface epithelial, germ cell, or stromal origin, with surface epithelial tumors comprising about 80% of all OCs. In addition to improving diagnostics, it is necessary to develop more effective treatments for epithelial-origin OC. Here, we describe the paradoxical roles of toll-like receptor (TLR) signaling in the progression of cancer and discuss how its modulation may result in decreased tumor growth and metastasis via the attenuation of proangiogenic cytokines and potentiation of proapoptotic factors. In particular, it has been found that TLR activity can behave like a "double-edged sword", as its signaling pathways have been implicated as having both tumor-suppressive and tumor-promoting effects. With particular emphasis on OC, we discuss the need to consider the signaling details of TLRs and associated proteins in the multiple cell types present in the tumor milieu to achieve safe and effective design of TLR-based cancer therapies. PMID- 22530146 TI - Behcet's Disease: New Concepts in Cardiovascular Involvements and Future Direction for Treatment. AB - Behcet's disease (BD) is the only systemic vasculitis involving both arteries and vein in any sizes. It frequently encounters in rheumatology clinics. It has some major morbidities and even fatal outcomes in some cases. The aim of this paper is to analyze the main concepts on pathophysiology and treatment options in BD, focusing on cardiovascular aspects, thrombosis, and potential future treatment. PMID- 22530149 TI - Comparing lung cancer risks in sweden, USA, and Japan. AB - Objective. To develop a conceptual model for lung cancer rates to describe and quantify observed differences between Sweden and USA contra Japan. Method. A two parameter lognormal distribution was used to describe the lung cancer rates over time after a 1-year period of smoking. Based on that risk function in combination with smoking prevalence, the calculated age-standardized rates were adjusted to fit reported data from Japan, Sweden, and the USA by parameter variation. Results. The risk of lung cancer is less in Japan than in Sweden and in the USA at the same smoking prevalence and intensity. Calculated age-specific rates did also fit well to reported rates without further parameter adjustments. Conclusions. This new type of cancer model appears to have high degree of predictive value. It is recommended that data from more countries are studied to identify important life-style factors related to lung cancer. PMID- 22530151 TI - Pediatric thyroid carcinoma incidence and temporal trends in the USA (1973-2007): race or shifting diagnostic paradigm? AB - Pediatric thyroid carcinoma is relatively uncommon. But variability in incidence rate by race, sex, age at onset/diagnosis, and geographic local had been observed in adult thyroid carcinoma in the USA. We aimed to examine the patterns, rates, and temporal trends of thyroid carcinoma among pediatric patients (0-19 years) between 1973 and 2007. The Surveillance, Epidemiology, and End Results (SEER) data of the National Cancer Institute were utilized. Data were available on sex, age at diagnosis, race/ethnicity, and geographic locale (9 SEER registries) and were used for rates and trends computation. The frequency and percentage, percent changes (PCs) were calculated by using 1 year of each endpoint. Similarly, the annual percent changes (APCs) were calculated as well, with APCs estimated using weighted least square methods. Between 1973 and 2007, 1,360 thyroid cancer cases were ascertained in the 9 SEER areas (n = 247,638,734) in the USA. The percent change was 47.9, while the APC was significantly different from 0, 1.0 (95% CI: 0.5-1.6, P < 0.0001). The rate ratio (RR) was significantly lower in 1975 (RR: 0.62, 95% CI: 0.38-0.98, P = 0.03) relative to the rate between 1973 and 2007 (RR: 1.60, per 100,000, 95% CI: 1.50-1.70), but higher in 2007 (RR: 2.3 per 100,000, 95% CI: 1.70-3.10; RR: 1.44, 95% CI: 1.05-1.93, P = 0.02). The rate was significantly higher in whites relative to blacks, highest among age group of 15 19 years and girls, and in some SEER registries, with some significant PC in Connecticut. This temporal trend study of pediatric thyroid carcinoma indicates increase in the rate of this malignancy given the percent change and the annual percent change between 1973 and 2007. In addition, the incidence was higher among girls, lower among blacks, highest in age group of 15-19 years, and relatively higher in SEER registries with predominantly white or Hispanic populations. PMID- 22530150 TI - Comparison of whole genome amplification methods for analysis of DNA extracted from microdissected early breast lesions in formalin-fixed paraffin-embedded tissue. AB - To understand cancer progression, it is desirable to study the earliest stages of its development, which are often microscopic lesions. Array comparative genomic hybridization (aCGH) is a valuable high-throughput molecular approach for discovering DNA copy number changes; however, it requires a relatively large amount of DNA, which is difficult to obtain from microdissected lesions. Whole genome amplification (WGA) methods were developed to increase DNA quantity; however their reproducibility, fidelity, and suitability for formalin-fixed paraffin-embedded (FFPE) samples are questioned. Using aCGH analysis, we compared two widely used approaches for WGA: single cell comparative genomic hybridization protocol (SCOMP) and degenerate oligonucleotide primed PCR (DOP-PCR). Cancer cell line and microdissected FFPE breast cancer DNA samples were amplified by the two WGA methods and subjected to aCGH. The genomic profiles of amplified DNA were compared with those of non-amplified controls by four analytic methods and validated by quantitative PCR (Q-PCR). We found that SCOMP-amplified samples had close similarity to non-amplified controls with concordance rates close to those of reference tests, while DOP-amplified samples had a statistically significant amount of changes. SCOMP is able to amplify small amounts of DNA extracted from FFPE samples and provides quality of aCGH data similar to non-amplified samples. PMID- 22530152 TI - A Twelve-Year Experience in Ambulatory Surgery within Urology. AB - Purpose. The aim of this study is to show you the results we obtained through the integration of the Urology Department into the Ambulatory Surgery Unit for the very first twelve years. Scope. We will explain both the criteria we followed for patients to join in and the surgical and anesthetic procedures we used with those 1544 patients who were ambulatory subjected to urological diseases. After those patients were treated, they reached up to 95% of reasonable results. Conclusions. Most of urological patients liable to have surgical treatment are bound to be included in an ambulatory surgery program, which implies neither a worse healthcare service standard nor a worse satisfaction in patients. PMID- 22530153 TI - Why I cannot find the prostate? Behind the subjectivity of rectal exam. AB - Background. Most physicians use digital rectal examination (DRE) to help detect prostate cancer and to estimate the prostates' size. The accuracy of DRE is known to be limited. We evaluate the ability of doctors to palpate the whole prostate with DRE. Methods. At time of transrectal ultrasound (TRUS) the distances from the anus to the apex and base of prostates were measured. The TRUS's distances were compared to the mean index finger length of our clinic doctors. Results. The ability of the urologist to reach and examine the apex, half, three quarters and the whole prostate was in 93.7%, 66.3%, 23.2% and 3.2% of cases respectively. Conclusions. In most cases it was impossible to palpate the whole prostate. Anatomical location and volume of the examined prostate, as well as the length of his own index finger limit DRE and allow the examination of only a small portion of the prostate. PMID- 22530154 TI - Identification and characterization of two novel RNA editing sites in grin1b transcripts of embryonic Danio rerio. AB - Discovering RNA editing sites in model organisms provides an insight into their adaptations in addition to finding potential sites for the regulation of neural activity and the basis of integrated models of metazoan editing with a variety of applications, including potential clinical treatments of neural dysregulation. The zebrafish, Danio rerio, is an important vertebrate model system. We focused on the grin1b gene of zebrafish due to its important function in the nervous tissue as a glutamate receptor. Using a comparative sequence-based approach, we located possible RNA editing events within the grin1b transcript. Surprisingly, sequence analysis also revealed a new editing site which was not predicted by the comparative approach. We here report the discovery of two novel RNA editing events in grin1b transcripts of embryonic zebrafish. The frequency of these editing events and their locations within the grin1b transcript are also described. PMID- 22530155 TI - Tumor necrosis factor alpha mediates GABA(A) receptor trafficking to the plasma membrane of spinal cord neurons in vivo. AB - The proinflammatory cytokine TNFalpha contributes to cell death in central nervous system (CNS) disorders by altering synaptic neurotransmission. TNFalpha contributes to excitotoxicity by increasing GluA2-lacking AMPA receptor (AMPAR) trafficking to the neuronal plasma membrane. In vitro, increased AMPAR on the neuronal surface after TNFalpha exposure is associated with a rapid internalization of GABA(A) receptors (GABA(A)Rs), suggesting complex timing and dose dependency of the CNS's response to TNFalpha. However, the effect of TNFalpha on GABA(A)R trafficking in vivo remains unclear. We assessed the effect of TNFalpha nanoinjection on rapid GABA(A)R changes in rats (N = 30) using subcellular fractionation, quantitative western blotting, and confocal microscopy. GABA(A)R protein levels in membrane fractions of TNFalpha and vehicle treated subjects were not significantly different by Western Blot, yet high resolution quantitative confocal imaging revealed that TNFalpha induces GABA(A)R trafficking to synapses in a dose-dependent manner by 60 min. TNFalpha-mediated GABA(A)R trafficking represents a novel target for CNS excitotoxicity. PMID- 22530157 TI - Synaptic structure and function in the mouse somatosensory cortex during chronic pain: in vivo two-photon imaging. AB - Recent advances in two-photon microscopy and fluorescence labeling techniques have enabled us to directly see the structural and functional changes in neurons and glia, and even at synapses, in the brain of living animals. Long-term in vivo two-photon imaging studies have shown that some postsynaptic dendritic spines in the adult cortex are rapidly eliminated or newly generated, in response to altered sensory input or synaptic activity, resulting in experience/activity dependent rewiring of neuronal circuits. In vivo Ca2+ imaging studies have revealed the distinct, input-specific response patterns of excitatory neurons in the brain. These updated in vivo approaches are just beginning to be used for the study of pathophysiological mechanisms of chronic diseases. In this paper, we introduce recent in vivo two-photon imaging studies demonstrating how plastic changes in synaptic structure and function of the mouse somatosensory cortex, following peripheral injury, contribute to chronic pain conditions, like neuropathic and inflammatory pain. PMID- 22530156 TI - Erasing synapses in sleep: is it time to be SHY? AB - Converging lines of evidence strongly support a role for sleep in brain plasticity. An elegant idea that may explain how sleep accomplishes this role is the "synaptic homeostasis hypothesis (SHY)." According to SHY, sleep promotes net synaptic weakening which offsets net synaptic strengthening that occurs during wakefulness. SHY is intuitively appealing because it relates the homeostatic regulation of sleep to an important function (synaptic plasticity). SHY has also received important experimental support from recent studies in Drosophila melanogaster. There remain, however, a number of unanswered questions about SHY. What is the cellular mechanism governing SHY? How does it fit with what we know about plasticity mechanisms in the brain? In this review, I discuss the evidence and theory of SHY in the context of what is known about Hebbian and non-Hebbian synaptic plasticity. I conclude that while SHY remains an elegant idea, the underlying mechanisms are mysterious and its functional significance unknown. PMID- 22530159 TI - Differentiated thyroid cancer: management of patients with radioiodine nonresponsive disease. AB - Differentiated thyroid carcinoma (papillary and follicular) has a favorable prognosis with an 85% 10-year survival. The patients that recur often require surgery and further radioactive iodine to render them disease-free. Five percent of thyroid cancer patients, however, will eventually succumb to their disease. Metastatic thyroid cancer is treated with radioactive iodine if the metastases are radioiodine avid. Cytotoxic chemotherapies for advanced or metastatic noniodine avid thyroid cancers show no prolonged responses and in general have fallen out of favor. Novel targeted therapies have recently been discovered that have given rise to clinical trials for thyroid cancer. Newer aberrations in molecular pathways and oncogenic mutations in thyroid cancer together with the role of angiogenesis in tumor growth have been central to these discoveries. This paper will focus on the management and treatment of metastatic differentiated thyroid cancers that do not take up radioactive iodine. PMID- 22530158 TI - GABA metabolism and transport: effects on synaptic efficacy. AB - GABAergic inhibition is an important regulator of excitability in neuronal networks. In addition, inhibitory synaptic signals contribute crucially to the organization of spatiotemporal patterns of network activity, especially during coherent oscillations. In order to maintain stable network states, the release of GABA by interneurons must be plastic in timing and amount. This homeostatic regulation is achieved by several pre- and postsynaptic mechanisms and is triggered by various activity-dependent local signals such as excitatory input or ambient levels of neurotransmitters. Here, we review findings on the availability of GABA for release at presynaptic terminals of interneurons. Presynaptic GABA content seems to be an important determinant of inhibitory efficacy and can be differentially regulated by changing synthesis, transport, and degradation of GABA or related molecules. We will discuss the functional impact of such regulations on neuronal network patterns and, finally, point towards pharmacological approaches targeting these processes. PMID- 22530160 TI - New genetic insights from autoimmune thyroid disease. AB - The autoimmune thyroid diseases (AITDs) (Graves' disease and Hashimoto's thyroiditis) are complex genetic diseases which most likely have more than 20 genes contributing to the clinical phenotypes. To date, the genes known to be contributing fall into two categories: immune regulatory genes (including HLA, CTLA4, PTPN22, CD40, CD25, and FCRL3) and thyroid-specific genes (TG and TSHR). However, none of these genes contribute more than a 4-fold increase in risk of developing one of these diseases, and none of the polymorphisms discovered is essential for disease development. Hence, it appears that a variety of different gene interactions can combine to cause the same clinical disease pattern, but the contributing genes may differ from patient to patient and from population to population. Furthermore, this possible mechanism leaves open the powerful influence of the environment and epigenetic modifications of gene expression. For the clinician, this means that genetic profiling of such patients is unlikely to be fruitful in the near future. PMID- 22530161 TI - LSVT LOUD and LSVT BIG: Behavioral Treatment Programs for Speech and Body Movement in Parkinson Disease. AB - Recent advances in neuroscience have suggested that exercise-based behavioral treatments may improve function and possibly slow progression of motor symptoms in individuals with Parkinson disease (PD). The LSVT (Lee Silverman Voice Treatment) Programs for individuals with PD have been developed and researched over the past 20 years beginning with a focus on the speech motor system (LSVT LOUD) and more recently have been extended to address limb motor systems (LSVT BIG). The unique aspects of the LSVT Programs include the combination of (a) an exclusive target on increasing amplitude (loudness in the speech motor system; bigger movements in the limb motor system), (b) a focus on sensory recalibration to help patients recognize that movements with increased amplitude are within normal limits, even if they feel "too loud" or "too big," and (c) training self cueing and attention to action to facilitate long-term maintenance of treatment outcomes. In addition, the intensive mode of delivery is consistent with principles that drive activity-dependent neuroplasticity and motor learning. The purpose of this paper is to provide an integrative discussion of the LSVT Programs including the rationale for their fundamentals, a summary of efficacy data, and a discussion of limitations and future directions for research. PMID- 22530162 TI - Web-based assessment of visual and visuospatial symptoms in Parkinson's disease. AB - Visual and visuospatial dysfunction is prevalent in Parkinson's disease (PD). To promote assessment of these often overlooked symptoms, we adapted the PD Vision Questionnaire for Internet administration. The questionnaire evaluates visual and visuospatial symptoms, impairments in activities of daily living (ADLs), and motor symptoms. PD participants of mild to moderate motor severity (n = 24) and healthy control participants (HC, n = 23) completed the questionnaire in paper and web-based formats. Reliability was assessed by comparing responses across formats. Construct validity was evaluated by reference to performance on measures of vision, visuospatial cognition, ADLs, and motor symptoms. The web-based format showed excellent reliability with respect to the paper format for both groups (all P's < 0.001; HC completing the visual and visuospatial section only). Demonstrating the construct validity of the web-based questionnaire, self-rated ADL and visual and visuospatial functioning were significantly associated with performance on objective measures of these abilities (all P's < 0.01). The findings indicate that web-based administration may be a reliable and valid method of assessing visual and visuospatial and ADL functioning in PD. PMID- 22530163 TI - Postmortem Interval Influences alpha-Synuclein Expression in Parkinson Disease Brain. AB - Duplications and triplications of the alpha-synuclein (SNCA) gene increase risk for PD, suggesting increased expression levels of the gene to be associated with increased PD risk. However, past SNCA expression studies in brain tissue report inconsistent results. We examined expression of the full-length SNCA transcript (140 amino acid protein isoform), as well as total SNCA mRNA levels in 165 frontal cortex samples (101 PD, 64 control) using quantitative real-time polymerase chain reaction. Additionally, we evaluated the relationship of eight SNPs in both 5' and 3' regions of SNCA with the gene expression levels. The association between postmortem interval (PMI) and SNCA expression was different for PD and control samples: SNCA expression decreased with increasing PMI in cases, while staying relatively constant in controls. For short PMI, SNCA expression was increased in PD relative to control samples, whereas for long PMI, SNCA expression in PD was decreased relative to control samples. PMID- 22530165 TI - SLIC 2: Improved decision support for subaxial cervical spine injury. PMID- 22530164 TI - Parkinson's disease and mesenchymal stem cells: potential for cell-based therapy. AB - Cell transplantation is a strategy with great potential for the treatment of Parkinson's disease, and many types of stem cells, including neural stem cells and embryonic stem cells, are considered candidates for transplantation therapy. Mesenchymal stem cells are a great therapeutic cell source because they are easy accessible and can be expanded from patients or donor mesenchymal tissues without posing serious ethical and technical problems. They have trophic effects for protecting damaged tissues as well as differentiation ability to generate a broad spectrum of cells, including dopamine neurons, which contribute to the replenishment of lost cells in Parkinson's disease. This paper focuses mainly on the potential of mesenchymal stem cells as a therapeutic cell source and discusses their potential clinical application in Parkinson's disease. PMID- 22530166 TI - The prognostic significance of the timing of total enteral feeding in traumatic brain injury. AB - BACKGROUND: To study the effect of timing of total enteral feeding on various nutritional parameters and neurological outcome in patients with severe traumatic brain injury (TBI). METHODS: One hundred and fourteen patients, in the age group of 20-60 years, admitted within 24 h of TBI with Glasgow Coma Scale (GCS) 4-8 were enrolled for the study. Nineteen patients who had expired before the attainment of total enteral feeding were excluded from the analysis. Total enteral feeding was attained before 3 days, 4-7 days, and after 7 days in 12, 52, and 31 patients, respectively, depending on gastric tolerance. They were prospectively assessed for various markers of nutrition and outcome was assessed at 3 and 6 months. RESULTS: Prospective assessment of 67 hospitalized patients at 3 weeks revealed significant differences in anthropometric measurements, total protein, albumin levels, clinical features of malnutrition, and mortality among the three groups. 80% of those fed before 3 days had favorable outcome at 3 months compared to 43% among those fed later. The odds ratio (OR) was 5.29 (95% CI 1.03-27.03) and P value was 0.04. The difference between those fed before 3 days and 4-7 days was not significant at 6 months even though patients fed before 7 days had still significantly higher favorable outcome compared to those fed after 7 days (OR 7.69, P = 0.002). Multivariate analysis for unfavorable outcome showed significance of P = 0.03 for feeding after 3 days and P = 0.01 for feeding after 7 days. CONCLUSIONS: In severe TBI, unfavorable outcome was significantly associated with attainment of total enteral feeding after 3 days and more so after 7 days following injury. PMID- 22530167 TI - Spontaneous intraparenchymal otogenic pneumocephalus: A case report and review of literature. AB - BACKGROUND: Pneumocephalus is commonly associated with head and facial trauma, ear infection, or surgical interventions. Spontaneous pneumocephalus caused by a primary defect at the temporal bone level without association with pathological conditions is very rare. Few cases have been published with purely intraparenchymal involvement. We describe a rare case of spontaneous pneumocephalus arising from the mastoid cells with intraparenchymal location and present an extensive review of the existing literature. CASE DESCRIPTION: A 57 year-old woman presented a brief episode of sudden otalgia in her left ear that was followed by a motor aphasia. Imaging revealed a left temporal intraparenchymal pneumocephalus in a close relationship with a highly pneumatized temporal bone. Left temporal craniotomy and decompression were performed. Further subtemporal exploration confirmed a dural defect and other osseous defects in the tegmen tympani, which were both consequently closed watertight. CONCLUSION: Although extremely rare, a spontaneous intraparenchymal pneumocephalus with mastoidal origin should be considered as a possible diagnosis in patients with suggestive otological symptoms and other non-specific neurological manifestations. Surgery is indicated to repair bone and dural defects. PMID- 22530168 TI - Acute neurological deterioration as a result of two synchronous hemorrhagic spinal ependymomas. AB - BACKGROUND: Ependymomas are the most common intramedullary tumors in adults and are the most common in mid-adult years. The presence of synchronous ependymomas in different sites of the spine is not common and it is even more infrequent to find hemorrhage from a spinal ependymoma as a cause of neurological deterioration. CASE DESCRIPTION: A 32-year-old man presented with back pain and progressive paraparesia. Magnetic resonance (MR) showed two intradural extramedullary lesions on spinal canal with signs of acute hemorrhage. The patient underwent emergent surgical decompression and resection. Pathology revealed myxopapillary ependymomas. CONCLUSION: To our knowledge, we report the first case of a patient with acute neurological deterioration as a consequence of synchronous bleeding of two spinal ependymomas located at different levels in the spinal cord. This study illustrates the importance of recognizing the rare, but known occurrence of acute neurological deterioration after spontaneous hemorrhage in spinal ependymomas. PMID- 22530169 TI - Meningioangiomatosis without neurofibromatosis simulating encephalitis in neuroimaging. AB - BACKGROUND: Meningioangiomatosis (MA) is a rare entity characterized by a focal lesion that affects the leptomeninges and the cerebral cortex. CASE DESCRIPTION: We describe a case of a 32-year-old man diagnosed with MA not associated with hamartomatous lesions or with type 2 neurofibromatosis. Magnetic resonance images (MRI) showed an extensive parieto-occipital lesion and another right frontal lesion, initially suggestive of encephalitis. A biopsy of the meninges and brain was performed via a right parieto-occipital craniotomy. The histopathologic diagnosis, complemented by immunohistochemical studies, was MA. CONCLUSION: Diagnosis of MA is very difficult based only on images, therefore lesions compromising the brain cortex, associated or not with calcifications, should be further examined through biopsy so as to have a precise diagnosis. PMID- 22530170 TI - Dual-port technique in navigation-guided endoscopic resection for intraparenchymal brain tumor. AB - BACKGROUND: In navigation-guided endoscopic surgery performed via a single port, the interference of surgical instruments often disturbs the resection and hemostasis. CASE DESCRIPTION: With regard to this, we designed a dual-port technique for navigation-guided endoscopic surgery in a 62-year-old man, with intraparenchymal anaplastic astrocytoma. Two transparent sheaths with Nelaton tubes were inserted in the front of the target lesion via an infinity-shaped burr hole, under the control of the navigation system. The lesion was removed partially using a rigid endoscope and several surgical tools through the bilateral ports. Using the new method, it was convenient to perform hemostasis with bipolar coagulation and aspiration, without any interference from the surgical instruments during the surgery. CONCLUSION: The offered dual-port technique may be included in surgery planning for elderly patients or patients in particular conditions, with intraparenchymal brain tumors. PMID- 22530171 TI - Spinal cord decompression: Is country of surgery a predictor of outcome? PMID- 22530172 TI - Brain death after Concorde positioning for supracerebellar-infratentorial approach: Unanswered questions and lessons learned. PMID- 22530173 TI - Subdural hematoma of the posterior fossa due to posterior communicating artery aneurysm rupture. AB - BACKGROUND: We describe an unusual presentation of a ruptured aneurysm of the posterior communicating artery with an acute subdural hematoma (SDH) located in the posterior fossa. We also reviewed the literature, focusing on the location of this intracranial hematoma. CASE DESCRIPTION: An 83-year-old woman was admitted to our institution with recent sudden headache and dizziness. Magnetic resonance imaging showed a thin collection of blood in the subdural space adjacent to the clivus, along the wall of the posterior fossa, and at the cervical spine level. A right posterior communicating artery aneurysm was diagnosed using computed tomography angiography and digital subtraction angiography. The aneurysm had two lobes, one of which was attached to the right dorsum sellae. The aneurysm was occluded by stent-assisted coil embolization. The patient was discharged 3 weeks after admission with absence of neurological deficit. CONCLUSION: A ruptured aneurysm of the posterior communicating artery may cause an acute SDH. PMID- 22530175 TI - Minimally invasive surgical treatment of lumbar spinal stenosis: Two-year follow up in 54 patients. AB - OBJECTIVE: Minimally invasive surgery has seen increasing application in the treatment of spinal disorders. Treatment of degenerative spinal stenosis, with or without spondylolisthesis, with minimally invasive technique preserves stabilizing ligaments, bone, and muscle. Satisfactory results can be achieved without the need for fusion in most cases. METHODS: Fifty-four consecutive patients underwent bilateral decompressions from a unilateral approach for spinal stenosis using METRx instrumentation. Visual Analog Scale (VAS) pain scores were recorded preoperatively and patients were interviewed, in person or by phone, by our office nurse practitioner (LD) to assess postoperative VAS scores, and patient satisfaction with the clinical results 21-39 months postoperatively (median 27 months). RESULTS: Fifty-four patients underwent decompression at 77 levels (L4/5 = 43, L3/4 = 22, L5/S1 = 8, L1/2 = 4, L2/3 = 4), (single = 35, double = 16, triple = 2, quadruple = 1). There were 39 females and 15 males. The average age was 67 years. The average operative time was 78 minutes and the average blood loss was 37 ml per level. Twenty-seven patients had preoperative degenerative spondylolisthesis (Grade 1 = 26, Grade 2 = 1). Eight patients had discectomies and four had synovial cysts. Patient satisfaction was high. Use of pain medication for leg and back pain was low, and VAS scores improved by more than half. There were three dural tears. There were no deaths or infections. One patient with an unrecognized dural tear required re-exploration for repair of a pseudomeningocele and one patient required a lumbar fusion for pain associated with progression of her spondylolisthesis. CONCLUSIONS: Minimally invasive bilateral decompression of acquired spinal stenosis from a unilateral approach can be successfully accomplished with reasonable operative times, minimal blood loss, and acceptable morbidity. Two-year outcomes in this series revealed high patient satisfaction and only one patient progressed to lumbar fusion. PMID- 22530174 TI - The hydrokinetic parameters of shunts for hydrocephalus might be inadequate. AB - Long-term treatment of hydrocephalus continues to be dismal. Shunting is the neurosurgical procedure more frequently associated with complications, which are mostly related with dysfunctions of the shunting device, rather than to mishaps of the rather simple surgical procedure. Overdrainage and underdrainage are the most common dysfunctions; of them, overdrainage is a conspicuous companion of most devices. Even when literally hundreds of different models have been proposed, developed, and tested, overdrainage has plagued all shunts for the last 60 years. Several investigations have demonstrated that changes in the posture of the subject induce unavoidable and drastic differences of intraventricular hydrokinetic pressure and cerebrospinal fluid (CSF) drainage through the shunt. Of all the parameters that participate in the pathophysiology of hydrocephalus, the only invariable one is cerebrospinal fluid production at a constant rate of approximately 0.35 ml/min. However, this feature has not been considered in the design of currently available shunts. Our experimental and clinical studies have shown that a simple shunt, whose drainage capacity complies with this unique parameter, would prevent most complications of shunting for hydrocephalus. PMID- 22530176 TI - Tryggo: Old norse for truth: The real truth about ground truth: New insights into the challenges of generating ground truth maps for WSI CAD algorithm evaluation. PMID- 22530177 TI - Referenceless image quality evaluation for whole slide imaging. AB - OBJECTIVE: The image quality in whole slide imaging (WSI) is one of the most important issues for the practical use of WSI scanners. In this paper, we proposed an image quality evaluation method for scanned slide images in which no reference image is required. METHODS: While most of the conventional methods for no-reference evaluation only deal with one image degradation at a time, the proposed method is capable of assessing both blur and noise by using an evaluation index which is calculated using the sharpness and noise information of the images in a given training data set by linear regression analysis. The linear regression coefficients can be determined in two ways depending on the purpose of the evaluation. For objective quality evaluation, the coefficients are determined using a reference image with mean square error as the objective value in the analysis. On the other hand, for subjective quality evaluation, the subjective scores given by human observers are used as the objective values in the analysis. The predictive linear regression models for the objective and subjective image quality evaluations, which were constructed using training images, were then used on test data wherein the calculated objective values are construed as the evaluation indices. RESULTS: The results of our experiments confirmed the effectiveness of the proposed image quality evaluation method in both objective and subjective image quality measurements. Finally, we demonstrated the application of the proposed evaluation method to the WSI image quality assessment and automatic rescanning in the WSI scanner. PMID- 22530178 TI - Integration of digital gross pathology images for enterprise-wide access. AB - BACKGROUND: Sharing digital pathology images for enterprise- wide use into a picture archiving and communication system (PACS) is not yet widely adopted. We share our solution and 3-year experience of transmitting such images to an enterprise image server (EIS). METHODS: Gross pathology images acquired by prosectors were integrated with clinical cases into the laboratory information system's image management module, and stored in JPEG2000 format on a networked image server. Automated daily searches for cases with gross images were used to compile an ASCII text file that was forwarded to a separate institutional Enterprise Digital Imaging and Communications in Medicine (DICOM) Wrapper (EDW) server. Concurrently, an HL7-based image order for these cases was generated, containing the locations of images and patient data, and forwarded to the EDW, which combined data in these locations to generate images with patient data, as required by DICOM standards. The image and data were then "wrapped" according to DICOM standards, transferred to the PACS servers, and made accessible on an institution-wide basis. RESULTS: In total, 26,966 gross images from 9,733 cases were transmitted over the 3-year period from the laboratory information system to the EIS. The average process time for cases with successful automatic uploads (n=9,688) to the EIS was 98 seconds. Only 45 cases (0.5%) failed requiring manual intervention. Uploaded images were immediately available to institution- wide PACS users. Since inception, user feedback has been positive. CONCLUSIONS: Enterprise- wide PACS- based sharing of pathology images is feasible, provides useful services to clinical staff, and utilizes existing information system and telecommunications infrastructure. PACS-shared pathology images, however, require a "DICOM wrapper" for multisystem compatibility. PMID- 22530179 TI - Clinical fellowship training in pathology informatics: A program description. AB - BACKGROUND: In 2007, our healthcare system established a clinical fellowship program in pathology informatics. In 2011, the program benchmarked its structure and operations against a 2009 white paper "Program requirements for fellowship education in the subspecialty of clinical informatics", endorsed by the Board of the American Medical Informatics Association (AMIA) that described a proposal for a general clinical informatics fellowship program. METHODS: A group of program faculty members and fellows compared each of the proposed requirements in the white paper with the fellowship program's written charter and operations. The majority of white paper proposals aligned closely with the rules and activities in our program and comparison was straightforward. In some proposals, however, differences in terminology, approach, and philosophy made comparison less direct, and in those cases, the thinking of the group was recorded. After the initial evaluation, the remainder of the faculty reviewed the results and any disagreements were resolved. RESULTS: The most important finding of the study was how closely the white paper proposals for a general clinical informatics fellowship program aligned with the reality of our existing pathology informatics fellowship. The program charter and operations of the program were judged to be concordant with the great majority of specific white paper proposals. However, there were some areas of discrepancy and the reasons for the discrepancies are discussed in the manuscript. CONCLUSIONS: After the comparison, we conclude that the existing pathology informatics fellowship could easily meet all substantive proposals put forth in the 2009 clinical informatics program requirements white paper. There was also agreement on a number of philosophical issues, such as the advantages of multiple fellows, the need for core knowledge and skill sets, and the need to maintain clinical skills during informatics training. However, there were other issues, such as a requirement for a 2-year fellowship and for informatics fellowships to be done after primary board certification, that pathology should consider carefully as it moves toward a subspecialty status and board certification. PMID- 22530180 TI - Board certification for pathologists in clinical informatics: Are you a lumper or a splitter? PMID- 22530181 TI - Isolation and two-step classification of normal white blood cells in peripheral blood smears. AB - INTRODUCTION: An automated system for differential white blood cell (WBC) counting based on morphology can make manual differential leukocyte counts faster and less tedious for pathologists and laboratory professionals. We present an automated system for isolation and classification of WBCs in manually prepared, Wright stained, peripheral blood smears from whole slide images (WSI). METHODS: A simple, classification scheme using color information and morphology is proposed. The performance of the algorithm was evaluated by comparing our proposed method with a hematopathologist's visual classification. The isolation algorithm was applied to 1938 subimages of WBCs, 1804 of them were accurately isolated. Then, as the first step of a two-step classification process, WBCs were broadly classified into cells with segmented nuclei and cells with nonsegmented nuclei. The nucleus shape is one of the key factors in deciding how to classify WBCs. Ambiguities associated with connected nuclear lobes are resolved by detecting maximum curvature points and partitioning them using geometric rules. The second step is to define a set of features using the information from the cytoplasm and nuclear regions to classify WBCs using linear discriminant analysis. This two step classification approach stratifies normal WBC types accurately from a whole slide image. RESULTS: System evaluation is performed using a 10-fold cross validation technique. Confusion matrix of the classifier is presented to evaluate the accuracy for each type of WBC detection. Experiments show that the two-step classification implemented achieves a 93.9% overall accuracy in the five subtype classification. CONCLUSION: Our methodology achieves a semiautomated system for the detection and classification of normal WBCs from scanned WSI. Further studies will be focused on detecting and segmenting abnormal WBCs, comparison of 20* and 40* data, and expanding the applications for bone marrow aspirates. PMID- 22530182 TI - Asymptomatic Incidental Ductal Carcinoma in situ in a Male Breast Presenting with Contralateral Gynecomastia. AB - Ductal carcinoma in situ (DCIS) in males is rare and usually presents with symptoms on the affected side, such as, palpable mass or bloody nipple discharge. Even as DCIS has been reported in conjunction with gynecomastia in the same breast, we report an unusual case of a 62-year-old Caucasian male, with no family history of breast cancer, who presented with symptomatic side gynecomastia, and was incidentally found to have DCIS in a completely asymptomatic left breast. To the best of our knowledge, this case is the first report in literature of asymptomatic, incidentally discovered DCIS in a male patient. PMID- 22530183 TI - Assessing the performance of imaging health systems in five selected hospitals in Uganda. AB - OBJECTIVES: The first objective of the study was to develop an index termed as the 'Imaging Coverage' (IC), for measuring the performance of the imaging health systems. This index together with the Hospital-Based Utilization (HBU) would then be calculated for five Ugandan hospitals. Second, was to relate the financial resources and existing health policy to the performance of the imaging systems. MATERIALS AND METHODS: This was a cross-sectional survey employing the triangulation methodology, conducted in Mulago National Referral Hospital. The qualitative study used cluster sampling, in-depth interviews, focus group discussions, and self-administered questionnaires to explore the non-measurable aspects of the imaging systems' performances. RESULTS: The IC developed and tested as an index for the imaging system's performance was 36%. General X-rays had the best IC followed by ultrasound. The Hospital-Based Utilization for the five selected hospitals was 186 per thousand and was the highest for general radiography followed by ultrasound. CONCLUSION: The IC for the five selected hospitals was 36% and the HBU was 186 per thousand, reflecting low performance levels, largely attributable to inadequate funding. There were shortfalls in imaging requisitions and inefficiencies in the imaging systems, financing, and health policy. Although the proportion of inappropriate imaging was small, reducing this inappropriateness even further would lead to a significant total saving, which could be channeled into investigating more patients. Financial resources stood out as the major limitation in attaining the desired performance and there is a need to increase budget funding so as to improve the performance of the imaging health systems. PMID- 22530185 TI - Focal lipoatrophy of face: a rare esthetic complaint. AB - A well-proportioned face combines features that are balanced and symmetrical. Any structural alteration that leads to facial asymmetry causes esthetical and psychological disturbances. Lipoatrophy is one such condition, which results in loss of subcutaneous fat layer and manifests as a depression. Although many subtypes with varying clinical and etiological backgrounds exist, the idiopathic form is rare and facial involvement is the rarest. Computed tomography is one of the accepted diagnostic tools to determine the atrophic layer of facial anatomy. This report presents the clinical types, diagnosis, and management of a case of facial lipoatrophy. PMID- 22530186 TI - Post-traumatic Cavernosal Artery Pseudoaneurysm Presenting as Right Hip Pain: An Imaging Evaluation. AB - Pseudoaneurysm of the cavernosal artery is quite rare. Herein, we describe color Doppler findings of post-traumatic pseudoaneurysm of the right cavernosal artery in a 19-year-old adolescent boy who presented with right hip pain. Doppler showed turbulence of flow with arterial inflow and outflow from the aneurysm. Selective transarterial catheterization of the internal iliac and internal pudental artery with microcatheter and embolization of pseudoaneurysm using histocryl resulted in alleviation of symptoms. PMID- 22530187 TI - Measuring fitness in female gymnasts: the gymnastics functional measurement tool. AB - PURPOSE/BACKGROUND: A reliable and valid method of measuring and monitoring a gymnast's total physical fitness level is needed to assist female gymnasts in achieving healthy, injury-free participation in the sport. The Gymnastics Functional Measurement Tool (GFMT) was previously designed as a field-test to assess physical fitness in female competitive gymnasts. The purpose of this study was to further develop the GFMT by establishing a scoring system for individual test items and to initiate the process of establishing the test-retest reliability and construct validity of the GFMT. METHODS: A total of 105 competitive female gymnasts ages 6-18 underwent testing using the GFMT. Fifty of these subjects underwent re-testing one week later in order to assess test-retest reliability. Construct validity was assessed using a simple regression analysis between total GFMT scores and the gymnasts' competition level to calculate the coefficient of determination (r(2)). Test-retest reliability was analyzed using Model 1 Intraclass correlation coefficients (ICC). Statistical significance was set at the p<0.05 level. RESULTS: The relationship between total GFMT scores and subjects' current USAG competitive level was found to be good (r(2) = 0.60). Reliability testing of the GFMT total score showed good test-retest reliability over a one week period (ICC=0.97). Test-retest reliability of the individual component items was good (ICC = 0.80-0.92). CONCLUSIONS: The results of this study provide initial support for the construct validity and test-retest reliability of the GFMT. PMID- 22530184 TI - Imaging techniques in endodontics: an overview. AB - This review provides an overview of the relevance of imaging techniques such as, computed tomography, cone beam computed tomography, and ultrasound, to endodontic practice. Many limitations of the conventional radiographic techniques have been overcome by the newer methods. Advantages and disadvantages of various imaging techniques in endodontic practice are also discussed. PMID- 22530188 TI - Exploration of the y-balance test for assessment of upper quarter closed kinetic chain performance. AB - BACKGROUND: Although upper extremity (UE) closed kinetic chain (CKC) exercises have become commonplace in most rehabilitation programs, a clinically meaningful UE CKC functional test of unilateral ability has continued to be elusive. OBJECTIVES: To examine reliability of the Upper Quarter Y-Balance Test (UQYBT), evaluate the effects of arm dominance on UQYBT performance, and to determine how the UQYBT is related to specific components of the test (trunk rotation, core stability and UE function and performance) in a college-aged population. METHODS: A sample of healthy college students performed the UQYBT and a series of 6 additional dynamic tests designed to assess trunk rotation, core stability, and UE performance. The relationship of these tests compared to the UQYBT was assessed. The effect of upper limb dominance for the UQYBT was also explored. Finally, test re-test reliability was established for the UQYBT. RESULTS: Thirty subjects (24 males, 6 females, mean ages 19.5 6 1.2 and 18.8 6 0.8 years) were assessed during the study. The test re-test reliability was excellent for UQYBT measurements (intraclass correlation coefficient > 0.9). A significant (p <0.05) fair to moderate association was observed between the UQYBT and several core stability and UE functional tests. There was no significant difference in UQYBT performance between dominant and non-dominant limbs. DISCUSSION: The UQYBT is a reliable UE CKC test that can be used to assess unilateral UE function in a closed chain manner. The UQYBT appears to be most related to dynamic tests involving core stability and UE performance. Similarity on the UQYBT between dominant and non-dominant limbs indicates that performance on this test using a non-injured UE may serve as a reasonable measure for "normal" when testing an injured UE. Future research is needed to determine the clinical applicability of the UQYBT. LEVEL OF EVIDENCE: 2b. PMID- 22530189 TI - Differences in dynamic balance scores in one sport versus multiple sport high school athletes. AB - PURPOSE/BACKGROUND: Researchers have previously reported on the importance of dynamic balance in assessing an individual's risk for injury during sport. However, to date there is no research on whether multiple sport participation affects dynamic balance ability. Therefore, the purpose of this study was to determine if there was a difference in dynamic balance scores in high school athletes that competed in one sport only as compared athletes who competed in multiple sports, as tested by the Lower Quarter Y Balance Test (YBT-LQ). METHODS: Ninety-two high school athletes who participated in one sport were matched, by age, gender and sport played, to athletes who participated in the same sport as well as additional sports. All individuals were assessed using the YBT-LQ to examine differences in composite reach score and reach direction asymmetry between single sport and multiple sport athletes. The greatest reach distance of three trials in each reach direction for right and left lower-extremities was normalized by limb length and used for analysis. A two-way ANOVA (gender x number of sports played) was used to statistically analyze the variables in the study. RESULTS: No significant interactions or main effects related to number of sports played were observed for any YBT-LQ score (p>0.05). Male athletes exhibited significantly greater normalized reach values for the posteromedial, posterolateral, and composite reach while also exhibiting a larger anterior reach difference when compared to the females. Athletes who participated in multiple sports had similar performances on the YBT-LQ when compared to athletes who participated in a single sport. CONCLUSIONS: The findings of this study suggest that the number of sports played by a high school athlete does not need to be controlled for when evaluating dynamic balance with the YBT-LQ. PMID- 22530190 TI - Effect of athletic taping and kinesiotaping(r) on measurements of functional performance in basketball players with chronic inversion ankle sprains. AB - BACKGROUND: Chronic inversion ankle sprains are common in basketball players. The effect of taping on functional performance is disputed in the literature. Kinesiotaping(r) (KT(r)) is a new method that is being used as both a therapeutic and performance enhancement tool. To date, it appears that no study has investigated the effect of ankle KT(r) on functional performance. PURPOSE: To investigate the effects of different types of taping (KT(r) using Kinesio Tex(r), athletic taping) on functional performance in athletes with chronic inversion sprains of the ankle. STUDY DESIGN: Crossover Study Design METHODS: Fifteen male basketball players with chronic inversion ankle sprains between the ages of 18 and 22 participated in this study. Functional performance tests (Hopping test by Amanda et al, Single Limb Hurdle Test, Standing Heel Rise test, Vertical Jump Test, The Star Excursion Balance Test [SEBT] and Kinesthetic Ability Trainer [KAT] Test) were used to quantify agility, endurance, balance, and coordination. These tests were conducted four times at one week intervals using varied conditions: placebo tape, without tape, standard athletic tape, and KT(r). One way ANOVA tests were used to examine difference in measurements between conditions. Bonferroni correction was applied to correct for repeated testing. RESULTS: There were no significant differences among the results obtained using the four conditions for SEBT (anterior p=0.0699; anteromedial p=0.126; medial p=0.550; posteromedial p=0.587; posterior p=0.754; posterolateral p=0.907; lateral p=0.124; anterolateral p=0.963) and the KAT dynamic measurement (p=0.388). Faster performance times were measured with KT(r) and athletic tape in single limb hurdle test when compared to placebo and non-taped conditions (Athletic taping- placebo taping: p=0.03; athletic taping- non tape p=0.016;KT(r) Placebo taping p=0.042; KT(r)-Non tape p=0.016). In standing heel rise test and vertical jump test, athletic taping led to decreased performance. (Standing heel rise test: Athletic taping- placebo taping p=0.035; athletic taping- non tape p=0.043; athletic tape- KT(r) p<0.001) (Vertical jump test: Athletic taping- placebo taping p=0.002: athletic taping- non tape p=0.002; KT(r)- athletic tape p<0.001) CONCLUSION: Kinesiotaping(r) had no negative effects on a battery of functional performance tests and improvements were seen in some functional performance tests. CLINICAL RELEVANCE: Ankle taping using Kinesio Tex(r) Tape did not inhibit functional performance. PMID- 22530191 TI - Diagnosis of an isolated posterior malleolar fracture in a young female military cadet: a resident case report. AB - BACKGROUND AND PURPOSE: The ankle is the most commonly injured joint during athletic activity. While ankle sprains are certainly the most common injury, ankle fractures can occur frequently. One type of ankle fracture with a reportedly low incidence is the isolated posterior malleolar fracture. Because of the low incidence, isolated posterior malleolar fractures can present a diagnostic challenge. The purpose of this case report is to describe the diagnostic process used for this rare injury that occurred in a physically active college-aged female who injured her ankle when landing from a fall during performance on a military obstacle course. CASE DESCRIPTION: A 19 year old female United States Military Academy cadet presented to a direct access physical therapy clinic. She was limping, not using any assistive device, and was wearing an ace bandage around her right ankle/foot. Two days earlier she fell from a "10 foot high" structure while performing the military obstacle course. She did not recall details of impact, but she was told by several bystanders that it appeared that she landed on her right foot followed immediately by a transition to her buttocks and then to her back. OUTCOMES: Ottawa Ankle Rules and ligamentous testing were negative; however, she was tender to palpation just anterior to the achilles tendon and lateral to the posterior edge of the medial malleolus. Based on mechanism of injury and tenderness of the posterior ankle, a potential posterior ankle fracture was suspected and subsequently confirmed by radiographic studies of the ankle including standard radiographs and computerized tomography. DISCUSSION: While the Ottawa Ankle Rules are generally effective in detecting many types of ankle fractures, clinicians should not rely solely on such prediction rules. This case highlights the importance of completing a thorough history and performing a thorough physical examination. This case report focuses on differential diagnosis. It is important to consider all aspects of the patient evaluation process collectively instead of examination pieces individually. PMID- 22530192 TI - Rehabilitation after hip arthroscopy and labral repair in a high school football athlete. AB - STUDY DESIGN: Case Report BACKGROUND: Femoral acetabular impingement (FAI) has been implicated in the etiology of acetabular labral tears. The rehabilitation of younger athletes following arthroscopic surgery for FAI and labral tears is often complex and multifactorial. A paucity of evidence exists to describe the rehabilitation of younger athletes who have undergone arthroscopic hip surgery. CASE PRESENTATION: This case report describes a four-phase rehabilitation program for a high school football player who underwent hip arthroscopy with a labral repair and chondroplasty. OUTCOMES: The player returned to training for football 16 weeks later and at the 4 month follow-up was pain free with no signs of FAI. DISCUSSION: There is little evidence regarding the rehabilitation of younger athletes who undergo arthroscopic hip surgery. This case study described a four phase rehabilitation program for a high school football player who underwent hip arthroscopy and labral repair. The patient achieved positive outcomes with a full return to athletic activity and football. The overall success of these patients depends on the appropriate surgical procedure and rehabilitation program. KEYWORDS: Femoral acetabular impingement (FAI), hip, hip impingement LEVEL OF EVIDENCE: 4-Case report. PMID- 22530193 TI - Rehabilitation considerations for all epiphyseal acl reconstruction. AB - BACKGROUND: The management of the pediatric patient with an Anterior Cruciate Ligament (ACL) rupture is evolving towards earlier reconstruction. The rehabilitation progression and outcomes for skeletally immature individuals undergoing ACL reconstruction (ACL-R) are not well described in the literature. Differences in surgical procedure, age related physiology, and emotional maturity may have a significant impact on recovery and return to sports. The purpose of this case report is to present the rehabilitation and outcome of a skeletally immature patient that underwent an all-epiphyseal ACL-R, highlight important considerations in the rehabilitation process and present topics for future research. CASE DESCRIPTION: Single subject case report of an 8 year-old boy who underwent all epiphyseal ACL-R after complete ACL rupture. OUTCOMES: The patient was able to achieve at least 90% strength symmetry and pass all necessary functional criteria to return to sports by 9 months post surgery. Two year follow up data indicated that the patient was able to make a full return to previous level of athletic activity, as well as maintain lower extremity strength and power over time. DISCUSSION: Objective outcome measures, rehabilitation protocols and time frame for return to sports for skeletally immature patients following physeal sparing or all epiphyseal ACL-R are not well described in the literature. This case report outlines objective measures of strength and functional recovery in a patient from this unique population. As ACL-R in the skeletally immature patient is studied more, new information on rehabilitation progression and outcomes may alter the rehabilitation program and timeline for return to unrestricted activity. LEVEL OF EVIDENCE: 4, Case Report. PMID- 22530194 TI - Rehabilitation after arthroscopic rotator cuff repair: current concepts review and evidence-based guidelines. AB - PURPOSE: To provide an overview of the characteristics and timing of rotator cuff healing and provide an update on treatments used in rehabilitation of rotator cuff repairs. The authors' protocol of choice, used within a large sports medicine rehabilitation center, is presented and the rationale behind its implementation is discussed. BACKGROUND: If initial nonsurgical treatment of a rotator cuff tear fails, surgical repair is often the next line of treatment. It is evident that a successful outcome after surgical rotator cuff repair is as much dependent on surgical technique as it is on rehabilitation. To this end, rehabilitation protocols have proven challenging to both the orthopaedic surgeon and the involved physical therapist. Instead of being based on scientific rationale, traditionally most rehabilitation protocols are solely based on clinical experience and expert opinion. METHODS: A review of currently available literature on rehabilitation after arthroscopic rotator cuff tear repair on PUBMED / MEDLINE and EMBASE databases was performed to illustrate the available evidence behind various postoperative treatment modalities. RESULTS: There is little high-level scientific evidence available to support or contest current postoperative rotator cuff rehabilitation protocols. Most existing protocols are based on clinical experience with modest incorporation of scientific data. CONCLUSION: Little scientific evidence is available to guide the timing of postsurgical rotator cuff rehabilitation. To this end, expert opinion and clinical experience remains a large facet of rehabilitation protocols. This review describes a rotator cuff rehabilitation protocol that incorporates currently available scientific literature guiding rehabilitation. PMID- 22530195 TI - Lisfranc fracture-dislocation in a female soccer athlete. AB - Individuals with midfoot injuries may present to physical therapists in a variety of clinical settings. The ability of the physical therapy practitioner to optimally manage the care of such an individual may be dependent on understanding the diagnostic imaging that is indicated or has been been completed. Among the potentially most debilitating midfoot injuries are Lisfranc fracture dislocations. This case outlines the use of conventional radiology, standard computerized tomography (CT), and three-dimensional CT for differential diagnosis of Lisfranc and associated midfoot injury in a 26 year-old female recreational athlete. Her subsequent surgical and post-surgical management is briefly discussed.Physical therapists evaluating patients with suspected midfoot injuries should be cognizant of the tendency for Lisfranc injuries to escape initial detection, possibly precipitating misdiagnosis or delay to diagnosis. Nonweight bearing radiography may be insensitive to demonstrating the anatomical disruption of significant midfoot injuries. Weight-bearing radiographic views along with selective use of MRI and CT aid in proper identification of injury to the tarsometatarsal joints and optimal management of patients with these injuries. PMID- 22530197 TI - Medical sports injuries in the youth athlete: emergency management. AB - As the number of youth sports participants continues to rise over the past decade, so too have sports related injuries and emergency department visits. With low levels of oversight and regulation observed in youth sports, the responsibility for safety education of coaches, parents, law makers, organizations and institutions falls largely on the sports medicine practitioner. The highly publicized catastrophic events of concussion, sudden cardiac death, and heat related illness have moved these topics to the forefront of sports medicine discussions. Updated guidelines for concussion in youth athletes call for a more conservative approach to management in both the acute and return to sport phases. Athletes younger than eighteen suspected of having a concussion are no longer allowed to return to play on the same day. Reducing the risk of sudden cardiac death in the young athlete is a multi-factorial process encompassing pre participation screenings, proper use of safety equipment, proper rules and regulations, and immediate access to Automated External Defibrillators (AED) as corner stones. Susceptibility to heat related illness for youth athletes is no longer viewed as rooted in physiologic variations from adults, but instead, as the result of various situations and conditions in which participation takes place. Hydration before, during and after strenuous exercise in a high heat stress environment is of significant importance. Knowledge of identification, management and risk reduction in emergency medical conditions of the young athlete positions the sports physical therapist as an effective provider, advocate and resource for safety in youth sports participation. This manuscript provides the basis for management of 3 major youth emergency sports medicine conditions. PMID- 22530198 TI - Thoracic region self-mobilization: a clinical suggestion. AB - Limitations in thoracic spine motion may be due to restrictions in contractile or non-contractile tissues. Joint mobilizations are indicated when hypomobility of a joint (non-contractile tissue) is identified. The ability for a patient to perform self-mobilizations of the thoracic spine and ribs may help maximize intervention outcomes. The purpose of this article is to describe a low cost, portable device which can be used for thoracic spine self-mobilization techniques. PMID- 22530196 TI - The effectiveness of resistance training using unstable surfaces and devices for rehabilitation. AB - BACKGROUND AND PURPOSE: WHILE THE POPULARITY OF INSTABILITY RESISTANCE TRAINING (RESISTANCE TRAINING THAT INVOLVES THE USE OF UNSTABLE SURFACES AND DEVICES: IRT) is evident in fitness training facilities, its effectiveness for optimal sport performance training has been questioned. The purpose of this clinical commentary is to explore the resistance training literature, which implements the use of unstable surfaces and devices to determine the suitability of IRT for rehabilitation. DESCRIPTION OF TOPIC AND RELATED EVIDENCE: The criticism of IRT for athletic conditioning is based on the findings of impaired kinetic measures such as force, power and movement velocity during a bout of IRT compared to traditional resistance training with more stable surfaces or devices. However, these deficits occur concurrently with minimal changes or in some cases increases in trunk and limb muscle activation. Compared to the kinetic deficits that are reported during unstable resistance exercises, the relatively greater trunk muscle activation indicates a greater stabilizing function for the muscles. IRT exercises can also provide training adaptations for coordination and other motor control issues, which may be more important for low back pain rehabilitation than strength or power enhancements. RELATION TO CLINICAL PRACTICE: Improvements in postural stability from balance training without resistance can improve force output which can then lead to a training progression involving an amalgamation of balance and IRT leading to higher load traditional resistance training. PMID- 22530199 TI - A sensitive switch for visualizing natural gene silencing in single cells. AB - RNA interference is a natural gene expression silencing system that appears throughout the tree of life. As the list of cellular processes linked to RNAi grows, so does the demand for tools to accurately measure RNAi dynamics in living cells. We engineered a synthetic RNAi sensor that converts this negative regulatory signal into a positive output in living mammalian cells, thereby allowing increased sensitivity and activation. Furthermore, the circuit's modular design allows potentially any microRNA of interest to be detected. We demonstrated that the circuit responds to an artificial microRNA and becomes activated when the RNAi target is replaced by a natural microRNA target (miR-34) in U2OS osteosarcoma cells. Our studies extend the application of rationally designed synthetic switches to RNAi, providing a sensitive way to visualize the dynamics of RNAi activity rather than just the presence of miRNA molecules. PMID- 22530201 TI - An unusual presentation of subacute osteomyelitis: a talus brodie abscess with tendon involvement. AB - Brodie abscess is a subacute localized osteomyelitis with a presenting report of intermittent pain of long duration. In this article, we report a case of talus Brodie abscess with tenosynovitis of posterior tibialis and long flexor tendons of the foot. We describe the radiologic and diagnostic features of this osteomyelitis and outline its management and prognosis. To our knowledge, this is the first report of such a case with this unusual presentation. PMID- 22530200 TI - The Effects of EPA+DHA and Aspirin on Inflammatory Cytokines and Angiogenesis Factors. AB - OBJECTIVE: In a recent study, we showed that the combination of aspirin plus the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) synergistically inhibited platelet function. As aspirin, EPA, and DHA have demonstrated anti-inflammatory properties, we hypothesized that the ingestion of EPA and DHA, with and without aspirin, would reduce plasma levels of inflammatory cytokines and angiogenesis factors more than aspirin alone and before aspirin was ingested. METHODS: Using multiplex technology, we investigated the effects of aspirin (single-dose 650 mg on day 1), EPA+DHA (3.4 g/d for days 2-29), and aspirin with EPA+DHA (day 30) on plasma levels of inflammatory cytokines and angiogenesis factors in healthy adults. RESULTS: Aspirin alone had no effect on any factor versus baseline, but EPA+DHA, with and without aspirin, significantly reduced concentrations of 8 of 9 factors. Although EPA+DHA plus aspirin reduced concentrations of a subset of the factors compared to baseline, neither aspirin alone nor the combination significantly reduced the level of any analyte more robustly than EPA+DHA alone. CONCLUSIONS: These data suggest that EPA+DHA has more pronounced down-regulatory effects on inflammation and angiogenesis than aspirin. The implications of these findings for the use of combined therapy for cardiovascular disease remain to be clarified. PMID- 22530202 TI - Neuropathic arthropathy of the elbow: two case reports. AB - Neuropathic arthropathy (NA), or Charcot joint, is a chronic and progressive degenerative arthropathy associated with an underlying neurologic disorder. NA of the elbow is a rare entity, with few cases reported in the literature. We report the cases of 2 patients with NA of the elbow. In case 1, the probable etiology was an intramedullary lesion, most likely syringomyelia and likely diabetes mellitus. In case 2, the probable etiology was syringomyelia and likely diabetes mellitus. The aim in NA treatment is to manage the underlying disease and reduce the rate of deformity to its lowest level. Management of NA is usually conservative. The diagnosis of NA should be considered in destructive cases without an evident pain report, and the underlying neurologic problem should be addressed. PMID- 22530203 TI - Missed obturator hip dislocation in a 19-year-old man. AB - Traumatic obturator hip dislocations are rare injuries that are typically diagnosed and managed acutely. We encountered a patient who presented with a painful hip 2 months after sustaining an undiagnosed traumatic obturator hip dislocation. After failed closed treatment, the hip was reduced with open reduction, utilizing a Kocher approach and a trochanteric osteotomy. At 15 months postoperatively, the patient maintained a functional range of motion without clinical or radiographic signs of posttraumatic arthritis or avascular necrosis. PMID- 22530204 TI - Challenges of spine surgery in obese patients. AB - Obesity, one of the most common health problems in the United States, is becoming more prevalent. At the same time, because of technological advances, the rate of spine surgeries is on the rise. Given these trends in obesity and spine surgeries, it can be inferred that the number of obese patients who undergo spine surgeries will increase as well. When spine surgeries are planned for obese patients, several factors must be considered. Obesity is closely correlated with additional medical comorbidities including hypertension, coronary artery disease, and diabetes mellitus. Preoperative evaluation may be more difficult, as more extensive medical testing may be needed. Adequate radiographic images can be difficult to obtain because of patient size and equipment limitations. Administering anesthesia becomes more difficult, as does proper patient positioning. After surgery, obese patients are at higher risk for wound infection and deep vein thrombosis. Nevertheless, appropriate clinical outcomes can be achieved in obese patients who undergo spine surgery. Obesity is not a contraindication for spine surgery. Patient selection is key in achieving favorable clinical outcomes. PMID- 22530205 TI - Military orthopedic residency: the good, the challenging, and the different. PMID- 22530206 TI - Beware: orthopedic surgery is hazardous to our health. PMID- 22530207 TI - An analysis of suboptimal outcomes of medial malleolus fractures in skeletally immature children. AB - We retrospectively analyzed cases of intra-articular medial malleolar fractures in skeletally-immature patients (Salter-Harris III and IV) with suboptimal outcomes at St. Louis Children's Hospital and Shriner's Hospital for Children. Common causes of poor outcome were frac-ture malunion or malreduction and physeal damage. Malreductions of only 2 mm does not appear to be toler-ated and the concept of "remodeling" does not apply to these fracture patterns. Based on this study, we "recom-mend" fracture reduction and fixation if there is greater than 1 mm of fracture step-off.. PMID- 22530208 TI - Clinical outcomes of osteomyelitis patients infected with methicillin-resistant Staphylococcus aureus USA-300 strains. AB - Methicillin-resistant Staphylococcus aureus (MRSA) USA-300 strains have emerged as an important cause of community-acquired infections. These strains have been recognized as an etiology of osteomyelitis but data on their incidence and outcomes are limited. We retrospectively studied the incidence and clinical outcomes of MRSA USA-300 osteomyelitis in patients at the University of Louisville Hospital and the Henry Ford Health System between January 2007 and March 2008. Pulsed-field gel electrophoresis was used to determine USA type. Clinical outcomes were defined as management success versus failure at 12 months. Chi-square tests, Fisher exact tests, and Mann-Whitney tests were used to compare patient characteristics on the basis of clinical outcomes and USA type. Of the 50 patients with MRSA osteomyelitis, 27 (54%) had the USA-300 strain. Clinical failure was identified in 22% (6/27) of the patients with MRSA USA-300 and in 30% (7/23) of the patients with MRSA non-USA-300 osteomyelitis (P = .509). Our results showed that MRSA USA-300 is a significant etiology of MRSA osteomyelitis. With current surgical and medical management, outcomes of patients with MRSA USA 300 osteomyelitis are similar to those of patients with MRSA non-USA-300 osteomyelitis. PMID- 22530209 TI - A survey on management of chronic achilles tendon ruptures. AB - No controlled trials regarding management of chronic Achilles tendon ruptures have been published. We conducted an online survey of orthopedic surgeons affiliated with US medical schools. One hundred twenty-seven surgeons responded, but not all responded to each survey question. Thirty-six percent had foot and ankle fellowship training. Nearly all respondents diagnosed tendon rupture by using palpation of the tendon gap (97%) and the Thompson calf-squeeze test (96%). The Matles test was used by 37% of respondents, with foot and ankle specialists nearly 5 times more likely to use it than nonspecialists (P<.001). For surgical repair of a ruptured tendon, most surgeons used the end-to-end Bunnell technique for gaps of a few centimeters, transitioning to the flexor hallucis longus procedure or V-Y tendinoplasty for larger gaps. Ninety-three percent of respondents used nonabsorbable sutures; absorbable suture use tended to increase with years of practice. Most surgeons (72%) preferred postoperative immobilization for up to 6 weeks and non-weight-bearing for up to 6 weeks (96%). In most instances, the responses of foot and ankle specialists did not differ significantly from those of other orthopedic surgeons, allowing generalization of the survey results to practice trends among all orthopedic surgeons. Practice trends tended to follow published expert opinions. PMID- 22530210 TI - Occupational hazards facing orthopedic surgeons. AB - Physicians are exposed to occupational hazards of which they are often unaware. Orthopedic surgery has a particularly hazardous work environment in which surgeons are at increased risk for exposure to infection, radiation, smoke, chemicals, excessive noise, musculoskeletal injuries, as well as emotional and psychological disturbances. Understanding these risks and the precautions that can be taken to avoid them will help protect orthopedic surgeons from potential harm. PMID- 22530211 TI - Calcaneal plate fixation of distal femoral fractures. AB - Open reduction and internal fixation constitute the standard of care for management of displaced distal femoral condylar fractures. The techniques most commonly used include conventional and locked plating with the primary goal of articular surface congruency. However, a specific implant for the isolated medial femoral condyle fracture is lacking. We report the use of a calcaneal plate as a novel technique for managing medial and lateral femoral condylar fractures. PMID- 22530212 TI - Congruency of scapula locking plates: implications for implant design. AB - We conducted a study to evaluate the congruency of fit of current scapular plate designs. Three-dimensional image-processing and -analysis software, and computed tomography scans of 12 cadaveric scapulae were used to generate 3 measurements: mean distance from plate to bone, maximum distance, and percentage of plate surface within 2 mm of bone. These measurements were used to quantify congruency. The scapular spine plate had the most congruent fit in all 3 measured variables. The lateral border and glenoid plates performed statistically as well as the scapular spine plate in at least 1 of the measured variables. The medial border plate had the least optimal measurements in all 3 variables. With locking-plate technology used in a wide variety of anatomical locations, the locking scapula plate system can allow for a fixed-angle construct in this region. Our study results showed that the scapular spine, glenoid, and lateral border plates are adequate in terms of congruency. However, design improvements may be necessary for the medial border plate. In addition, we describe a novel method for quantifying hardware congruency, a method that can be applied to any anatomical location. PMID- 22530214 TI - Updates on intra-articular hyaluronic Acid therapy for knee osteoarthritis. PMID- 22530213 TI - Fracture-site osteoid osteoma in a 26-year-old man. PMID- 22530215 TI - Crisis in medicine: education, a vehicle that brings us together. PMID- 22530216 TI - Pressurized radio-opaque dye integrity test. PMID- 22530217 TI - Efficacy of erythrocyte sedimentation rate and C-reactive protein level in determining periprosthetic hip infections. AB - The diagnosis of periprosthetic hip infections is often challenging. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level blood laboratory tests are commonly used to aid in the diagnosis. We studied the sensitivity, specificity, and false-negative rates of ESR and CRP level in a prospective group of patients who underwent revision total hip arthroplasty between 2000 and 2008. Seventy-seven patients with periprosthetic hip infections and ESR and CRP data were identified. Chi-square analysis was performed to determine the significance of false-negatives, compared with sex, body mass index, primary diagnosis, infection type, and immunity status. ESR had 89% sensitivity and 69% specificity. CRP level had 93% sensitivity and 40% specificity. The false-negative rate was 10.8% for ESR and 7% for CRP level. The false-negative rate for ESR and CRP level combined (with either result positive) was 3%. All false-negatives in the combined group were immunocompromised. Chi-square analysis did not find a significant correlation between false-negatives and any other variables. ESR and CRP level are useful in the diagnosis of periprosthetic hip infections. Ordering these tests concurrently reduces the chance of false-negative results. PMID- 22530218 TI - Traumatic posterior hip instability and femoroacetabular impingement in athletes. AB - We describe 3 cases of posterior hip instability associated with femoroacetabular impingement. In each case, we obtained a detailed medical history, performed a physical examination, evaluated imaging, recorded intraoperative findings, and clinically followed the patient for 1 year. Two of the 3 patients sustained a traumatic posterior hip subluxation caused by noncontact injuries. All patients had decreased internal rotation on physical examination, radiographic evidence of acetabular retroversion, a cam lesion, an elevated alpha angle, and a posterior acetabular rim fracture with associated labral injury. All patients underwent hip arthroscopy and direct repair of the bony acetabular fragment using 3 to 5 suture anchors. One-year follow-up in all cases demonstrated good to excellent results and full return to activities without restriction. Patients with femoroacetabular impingement may be predisposed to traumatic posterior dislocation or subluxation and a concomitant posterior acetabular rim fracture with labral injury. We propose that FAI predisposed these athletes to posterior hip instability. PMID- 22530219 TI - Chlorhexidine burns after shoulder arthroscopy. AB - Chlorhexidine is an antiseptic and disinfectant commonly used for surgical site preparation and cleansing. It is active against a broad spectrum of bacteria, viruses, mycobacteria, and fungi. We report 3 cases of patients with superficial partial thickness burns immediately following shoulder arthroscopic surgery with the use of a Chloraprep 26 mL applicator (2% chlorhexidine gluconate and 70% isopropyl alcohol; CareFusion, Leawood, Kansas). All 3 patients reported pain as the anesthetic waned at a localized area on the anterior arm near the axilla. Erythema and blistering were noticeable. These areas were immediately treated with irrigation and local application of ice, and subsequently with topical triple-antibiotic ointment. All 3 cases were resolved within 3 months of surgery, but noticeable scars remained. We believe a combination of chlorhexidine skin preparation, local swelling inherent to shoulder arthroscopy, and traction contributed to these postoperative complications. PMID- 22530220 TI - Simultaneous proximal femoral rotational and distal femoral varus osteotomies for femoral retroversion and genu valgum. AB - Whereas excess femoral anteversion and its related symptoms have been described many times, excess femoral retroversion is less well documented. We report the case of a 30-year-old woman who had a history of chronic bilateral hip and knee pain and evidence of excess femoral retroversion, genu valgum, early-onset lateral and patellofemoral compartment osteoarthritis of both knees, and hip arthritis. She experienced symptomatic relief after undergoing staged bilateral simultaneous proximal femoral rotational and distal femoral lateral opening wedge osteotomies. Although this combination of alignment problems is not an infrequent clinical occurrence, we have found no literature on this condition or treatment. The patient provided written informed consent for print and electronic publication of this case report. PMID- 22530221 TI - Hemostatic matrix application after open synovectomy in a hemophilic patient. AB - Recurrent, spontaneous bleeding is common in patients with hemophilia. The joints are commonly and repeatedly affected, and this can result in chronic synovitis and joint damage. Synoviorthesis or synovectomy are indicated after failure of appropriate medical management. Hemostasis in the perioperative period is paramount in these patients. We report a case study of a patient with hemophilia A inhibitors undergoing open synovectomy complicated by postoperative bleeding. In addition to an infusion of bypassing agents due to the presence of inhibitors, a topical hemostatic agent, FLOSEAL, and absorbable Gelfoam were applied. Hemostasis was achieved rapidly. The patient recovered without complications. PMID- 22530223 TI - Total joint arthroplasty in patients with a history of cancer. AB - In this review, we describe the pertinent issues that reconstructive surgeons face when treating patients with cancer. These issues include the various cancer management options and their influence on total joint arthroplasty outcomes, as well as prosthesis types and fixation types. We also present a strategy for reducing morbidity and complications during the perioperative period. PMID- 22530222 TI - Combined orthopedic and vascular lower extremity injuries: sequence of care and outcomes. AB - Combined vascular and orthopedic injuries requiring repair are rare. However, these injuries have a high amputation rate and significant morbidity. In a retrospective review of lower extremity injuries managed at a level I trauma center over 9 years, we identified 26 patients with combined vascular and orthopedic injuries. We evaluated their rates of amputation and revascularization procedures based on sequence of care and initial intervention. Patients were stratified into 3 groups based on the initial intervention given: definitive vascular repair (n = 17), orthopedic stabilization (n = 4), and temporary shunt (n = 5). Amputation rates were 29% (5/17) in the vascular group and 20% (1/5) in the shunt group; there were no amputations in the orthopedic group (0/4). Revascularization rates were 41% (7/17), 25% (1/4), and 20% (1/5) in the vascular, orthopedic, and shunt group, respectively. Mangled Extremity Severity Scores higher than 6 had an overall relative risk of 5.5 for amputation (P<.05). We conclude that temporary vascular shunting followed by orthopedic stabilization and then definitive vascular repair is the most reasonable sequence of care for minimizing rates of amputation and revascularization procedures in this cohort of patients. PMID- 22530224 TI - Erythroid leukemia evolving from multiple myeloma. PMID- 22530226 TI - Climacteric commentaries. Type and timing of menopause and all-cause and cardiovascular mortality. PMID- 22530225 TI - Evidence-based treatment and prevention of external genital warts in female pediatric and adolescent patients. AB - External anogenital warts, or condylomata acuminata, are caused by the proliferation of squamous epithelial cells secondary to human papillomavirus infection. In sexually active adults and adolescents, anogenital warts are a common sexually transmitted disease, but in children they may be a sign of sexual abuse. There are several treatment options available for anogenital warts, but no treatment has been proven to be the most efficacious, and recurrence after clinical clearance is common. Evidence-based treatment of genital warts is challenging because of the lack of controlled trials comparing treatments, especially in pediatric and adolescent populations. This paper discusses various treatment modalities such as physical destruction, cytotoxic agents, and immunomodulating therapies. Many variables influence the selection of a treatment, such as the size, quantity, and location of the warts; and the patient and provider preference, and its availability and cost. All treatments can cause local side effects, and patient tolerability must also be factored into treatment selection. Many treatments have similar clearance and recurrence rates, and none of the treatments completely eliminates the virus. With the numerous challenges surrounding the treatment of anogenital warts, the primary prevention of HPV infection through vaccination is a key component in decreasing the incidence of the disease. PMID- 22530227 TI - Transition from pediatric to adult care for adolescents and young adults with a disorder of sex development. AB - Over the past twenty years, there has been an increasing awareness of the transition to adult-oriented health care in adolescents and young adults with a chronic illness. While general guidelines for health care transition have been established, some have called for illness-specific guidelines which are tailored to the needs of specific illness populations. The current paper sought to outline illness-specific guidelines for health care transition in adolescents and young adults with disorders of sex development based upon the recent American Academy of Pediatrics guidelines. We also suggest indicators of successful transition for adolescents and young adults with disorders of sex development as well as areas for future research. PMID- 22530228 TI - Climacteric commentaries. Where do women get their information about hormone therapy--and whom do/should they trust? PMID- 22530229 TI - Intimate partner violence and adolescent mothers. PMID- 22530230 TI - Climacteric commentaries. Surgical menopause and early mortality in the California Teachers Study. PMID- 22530231 TI - The hidden strength of prevention politics. PMID- 22530232 TI - [Kidney and cancer: cross-over management]. PMID- 22530235 TI - [Jean-Pierre Castel (1938-2011)]. PMID- 22530236 TI - Re: Klotho: a novel regulator of calcium and phosphorus homeostasis. PMID- 22530237 TI - Re: Urodynamic parameters after retrourethral transobturator male sling and their influence on outcome. PMID- 22530238 TI - Re: Tadalafil Versus Solifenacin for Persistent Storage Symptoms After Prostate Surgery in Patients With Erectile Dysfunction: A Prospective Randomized Study. PMID- 22530239 TI - On the coexistence of cooperators,defectors and conditional cooperators in the multiplayer iterated Prisoner's Dilemma. AB - Recent experimental evidence [Grujic Fosco, Araujo, Cuesta, Sanchez, 2010. Social experiments in the mesoscale: humans playing a spatial Prisoner's dilemma. PLoS ONE 5, e13749] on the spatial Prisoner's Dilemma suggests that players choosing to cooperate or not on the basis of their previous action and the actions of their neighbors coexist with steady defectors and cooperators. We here study the coexistence of these three strategies in the multiplayer iterated Prisoner's Dilemma by means of the replicator dynamics. We consider groups with n=2, 3, 4 and 5 players and compute the payoffs to every type of player as the limit of a Markov chain where the transition probabilities between actions are found from the corresponding strategies. We show that for group sizes up to n=4 there exists an interior point in which the three strategies coexist, the corresponding basin of attraction decreasing with increasing number of players, whereas we have not been able to locate such a point for n=5. We analytically show that in the limit n --> infinity no interior points can arise. We conclude by discussing the implications of this theoretical approach on the behavior observed in experiments. PMID- 22530240 TI - Molecular cloning and characterization of nucleotide binding and oligomerization domain-1 (NOD1) receptor in the Indian Major Carp, rohu (Labeo rohita), and analysis of its inductive expression and down-stream signalling molecules following ligands exposure and Gram-negative bacterial infections. AB - Nucleotide binding and oligomerization domain-1 (NOD1) is a cytoplasmic pattern recognition receptor (PRR), and is a member of the NOD-like receptor (NLR) family. It senses a wide range of bacteria and viruses or their products, and plays a key role in inducing innate immunity. In this report, NOD1 gene was cloned and characterized in rohu (Labeo rohita), a fish species of highest commercial importance in the Indian subcontinent. The full-length rohu NOD1 (rNOD1) cDNA comprised of 3168 bp with a single open reading frame (ORF) of 2814 bp, encoding a polypeptide of 937 amino acids (aa) with an estimated molecular mass of 106.13 kDa. Structurally, it comprised of one caspase recruitment domain (CARD) at N-terminal, seven leucine rich repeat (LRR) regions at C-terminal and one NACHT domain in between N and C-terminals. Phylogenetically, rNOD1 was closely related to grass carp NOD1 (gcNOD1), and exhibited significant similarity (95.8%) and identity (91.0%) in their amino acids. Ontogenic expression analysis of rNOD1 and its associated down-stream signaling molecule RICK (receptor interacting serine-threonine kinase) by quantitative real-time PCR (qRT-PCR) revealed their constitutive expression in all embryonic developmental stages. Basal expression analysis of rNOD1 showed its wide range of expression in all examined tissues, highest was in spleen and the lowest was in blood. Inductive expression of rNOD1 was observed following LPS and poly I:C exposure, and Aeromonas hydrophila, Edwardsiella tarda and Shigella flexneri infections. Expression of RICK in various organs was significantly enhanced by ligands exposure and bacterial infections, and was correlated with the inductive expression of rNOD1. Together, these findings highlighted the important role of NOD1 in fish in response to pathogenic invasion. PMID- 22530241 TI - Molecular characterization of Cynoglossus semilaevis CD28. AB - T lymphocyte activation requires a combination of signals, one of which is provided by interaction between CD28 and its ligands on antigen presenting cells. Although CD28-like sequences have been identified in a few teleosts, the function of fish CD28 is virtually unknown. In this study, we cloned and analyzed a CD28 gene, CsCD28, from half-smooth tongue sole (Cynoglossus semilaevis). The deduced amino acid sequence of CsCD28 contains 229 residues and shares 20.2%-40.3% overall sequence identities with known fish CD28 sequences. CsCD28 possesses structural features conserved in mammalian and teleost CD28, which include the MYPPPY motif in the extracellular immunoglobulin-like domain and the YXN motif in the cytoplasmic domain. The CsCD28 gene is 2746 bp and composed of four exons and three introns, which in organization resemble those of mammalian and trout CD28. Quantitative real time RT-PCR analysis showed that CsCD28 expression occurred predominately in kidney, spleen, gut, and gill. CsCD28 is localized on the surface of head kidney lymphocytes, and antibody ligation of CsCD28 induced significant levels of cellular proliferation. Taken together, these results indicate that CsCD28 is similar to mammalian CD28 in genetic and protein structures and possibly plays a role in T cell activation. PMID- 22530242 TI - Prophylaxis versus no prophylaxis for reflux. PMID- 22530243 TI - France's next president faces tough decisions on health. PMID- 22530244 TI - Promising new era dawns for cystic fibrosis treatment. PMID- 22530245 TI - Outsider Art. PMID- 22530246 TI - The regulation of nicotine in the United Kingdom: how nicotine gum came to be a medicine, but not a drug. AB - This article explores the utility of actor-network theory (ANT) as a tool for socio-legal research. ANT is deployed in a study of the evolution of divided regulatory responsibility for tobacco and medicinal nicotine (MN) products in the United Kingdom, with a particular focus on how the latter came to be regulated as a medicine. We examine the regulatory decisions taken in the United Kingdom in respect of the first MN product: a nicotine-containing gum developed in Sweden, which became available in the United Kingdom in 1980 as a prescription-only medicine under the Medicines Act 1968. We propose that utilizing ANT to explore the development of nicotine gum and the regulatory decisions taken about it places these decisions into the wider context of ideas about tobacco control and addiction, and helps us to understand better how different material actors acted in different networks, leading to very different systems of regulation. PMID- 22530247 TI - The donor-conceived child's "Right to Personal Identity": the public debate on donor anonymity in the United Kingdom. AB - On 1 April 2005, with the implementation of the Human Fertilisation and Embryology Authority (Disclosure of Donor Information) Regulations 2004, United Kingdom law was changed to allow children born through gamete donation to access details identifying the donor. Drawing on trends in adoption law, the decision to abolish donor anonymity was strongly influenced by a discourse that asserted the 'child's right to personal identity'. Through examination of the donor anonymity debate in the public realm, while adopting a social constructionist approach, this article discusses how donor anonymity has been defined as a social problem that requires a regulative response. It focuses on the child's 'right to personal identity' claims, and discusses the genetic essentialism behind these claims. By basing its assumptions on an adoption analogy, United Kingdom law ascribes a social meaning to the genetic relatedness between gamete donors and the offspring. PMID- 22530248 TI - The emergence of biobanks in the legal landscape: towards a new model of governance. AB - Biobanks are increasingly seen as new tools for medical research. Their main purpose is to collect, store, and distribute human body materials. These activities are regulated by legal instruments which are heterogeneous in source (national and international), and in form (binding and non-binding). We analyse these to underline the need for a new model of governance for modern biobanks. The protection initially ensured by respect for fundamental rights will need to focus on more interactions with society in order to ensure biobanks' sustainability. International regulation is more oriented on ethical principles and traces the limits of the uses of genetics, while European regulation is more concerned with the protection of fundamental rights and the elaboration of standards for biobanks' quality assurance. But is this protection adequate and sufficient? Do we need to move from the biomedical research analogy to new forms of legal protection, and governance systems which involve citizens? PMID- 22530249 TI - The legal landscape for advanced therapies: material and institutional implementation of European Union rules in France and the United Kingdom. AB - In 2007, the European Union adopted a lex specialis, Regulation (EC) No. 1394/2007 on advanced therapy medicinal products (ATMPs), a new legal category of medical product in regenerative medicine. The regulation applies to ATMPs prepared industrially or manufactured by a method involving an industrial process. It also provides a hospital exemption, which means that medicinal products not regulated by EU law do not benefit from a harmonized regime across the European Union but have to respect national laws. This article describes the recent EU laws, and contrasts two national regimes, asking how France and the United Kingdom regulate ATMPs which do and do not fall under the scope of Regulation (EC) No. 1394/2007. What are the different legal categories and their enforceable regimes, and how does the evolution of these highly complex regimes interact with the material world of regenerative medicine and the regulatory bodies and socioeconomic actors participating in it? PMID- 22530250 TI - Bodies of science and law: forensic DNA profiling, biological bodies, and biopower. AB - How is jurisdiction transferred from an individual's biological body to agents of power such as the police, public prosecutors, and the judiciary, and what happens to these biological bodies when transformed from private into public objects? These questions are examined by analysing bodies situated at the intersection of science and law. More specifically, the transformation of 'private bodies' into 'public bodies' is analysed by going into the details of forensic DNA profiling in the Dutch jurisdiction. It will be argued that various 'forensic genetic practices' enact different forensic genetic bodies'. These enacted forensic genetic bodies are connected with various infringements of civil rights, which become articulated in exploring these forensic genetic bodies''normative registers'. PMID- 22530251 TI - Sensing design and workmanship: the haptic skills of shoppers in eighteenth century London. AB - This article explores how eighteenth-century shoppers understood the material world around them. It argues that retail experiences exposed shoppers to different objects, which subsequently shaped their understanding of this world. This article builds on recent research that highlights the importance of shop environments and browsing in consumer choice. More particularly, it differentiates itself by examining the practice of handling goods in shops and arguing that sensory interaction with multiple goods was one of the key means by which shoppers comprehended concepts of design and workmanship. In doing so, it affirms the importance of sensory research to design history. The article focuses on consumer purchases of ceramic objects and examines a variety of sources to demonstrate the role of haptic skills in this act. It shows how different literary sources described browsing for goods in gendered and satirical terms and then contrasts these readings against visual evidence to illustrate how handling goods was also represented as a positive act. It reads browsing as a valued practice requiring competence, patience and haptic skills. Through an examination of diary sources, letters and objects this article asks what information shoppers gained from touching various objects. It concludes by demonstrating how repetitive handling in search of quality meant that shoppers acquired their own conception of what constituted workmanship and design. PMID- 22530252 TI - Offspring sex preference in frontier America. AB - Analysis of the fertility histories of women born between 1850 and 1900, as given in the Utah Population Database (UPDB), reveals the effect of the number, as well as the sex composition, of previous children on birth-stopping and birth-spacing decisions. Specifically, agricultural and Church of Jesus Christ of Latter-day Saints (LDS) households-two sub-populations that might have placed different values on male and female children for economic, social, and/or cultural reasons showed a distinct preference for male children, as expressed by birth stopping after the birth of a male child and shorter birth intervals in higher-parity births when most previous children were female. Remarkably, women in both the early "natural fertility" and the later contraceptive eras used spacing behavior to achieve a desired sex mix. Although the LDS population had relatively high fertility rates, it had the same preferences for male children as the non-LDS population did. Farmers, who presumably had a need for family labor, were more interested in the quantity than in the sex mix of their children. PMID- 22530253 TI - Intergenerational transmission of reproductive behavior during the demographic transition. AB - New evidence from the Utah Population Database (UPDP) reveals that at the onset of the fertility transition, reproductive behavior was transmitted across generations - between women and their mothers, as well as between women and their husbands' family of origin. Age at marriage, age at last birth, and the number of children ever born are positively correlated in the data, most strongly among first-born daughters and among cohorts born later in the fertility transition. Intergenerational ties, including the presence of mothers and mothers-in-law, influenced the hazard of progressing to a next birth. The findings suggest that the practice of parity-dependent marital fertility control and inter-birth spacing behavior derived, in part, from the previous generation and that the potential for mothers and mothers-in-law to help in the rearing of children encouraged higher marital fertility. PMID- 22530254 TI - Is sibling rivalry fatal?: siblings and mortality clustering. AB - Evidence drawn from nineteenth-century Belgian population registers shows that the presence of similarly aged siblings competing for resources within a household increases the probability of death for children younger than five, even when controlling for the preceding birth interval and multiple births. Furthermore, in this period of Belgian history, such mortality tended to cluster in certain families. The findings suggest the importance of segmenting the mortality of siblings younger than five by age group, of considering the presence of siblings as a time-varying covariate, and of factoring mortality clustering into analyses. PMID- 22530255 TI - Migrants and the diffusion of low marital fertility in Belgium. AB - Although the diffusion of fertility behavior between different social strata in historical communities has received considerable attention in recent studies, the relationship between the diffusion of fertility behavior and the diffusion of people (migration) during the nineteenth century remains largely underexplored. Evidence from population registers compiled in the Historical Database of the Liege Region, covering the period of 1812 to 1900, reveals that migrant couples in Sart, Belgium, from 1850 to 1874 and from 1875 to 1899 had a reduced risk of conception. The incorporation of geographical mobility, as well as the migrant status of both husbands and wives, into this fertility research sheds light not only on the spread of ideas and behaviors but also on the possible reasons why the ideas and behaviors of immigrants might have been similar to, or different from, those of a native-born population. PMID- 22530256 TI - Reproductive behavior during the pre-transitional period: evidence from rural Bologna. AB - A longitudinal, micro-level study of the effect of socioeconomic transformations on fertility mechanisms in the rural hinterland of Bologna between 1818 and 1900 (the beginning of the demographic transition) demonstrates that the premature death of a last-born child reduces the interval between two consecutive childbirths. Thus does it confirm the importance of breast-feeding in determining birth spacing. Women living in complex sharecropping households experienced a significantly higher risk of childbirth than did women in families headed by daily wage earners. In addition, the reproductive behavior of sharecroppers seemed to be substantially invariant to short-term ouctuations in prices, whereas the laborers' group experienced a negative price effect. Both descriptive and multivariate analyses indicate a slight and gradual decrease in fertility levels during the period in question. PMID- 22530257 TI - Releasing mother's burdens: child abandonment and retrieval in Madrid, 1890-1935. AB - In nineteenth-century Europe, the foundling hospital grew beyond its traditional purpose of mitigating the shame of unwed mothers by also permitting widows, widowers, and poor married couples to abandon their children there temporarily. In the Foundling Hospital of Madrid (FHM), this new short-term abandonment could be completely anonymous due to the implementation of a wheel-a device on the outside wall of the institution that could be turned to place a child inside which remained open until 1929. The use of survival-analysis techniques to disentangle the determinants of retrieval in a discrete framework reveals important differences in the situations of the women who abandoned their children at the FHM, partly depending on whether they accessed it through the Maternity Hospital after giving birth or they accessed it directly. The evidence suggests that those who abandoned their children through the Maternity Hospital retrieved them only when they had attained a certain degree of economic stability, whereas those who abandoned otherwise did so just as soon as the immediate condition prompting the abandonment had improved. PMID- 22530258 TI - Body, society, and subjectivity in religious studies. AB - Attention to bodies has transformed the study of religion in the past thirty years, aiding the effort to overcome the discipline's Protestant biases by shifting interest from beliefs to practices. And yet much of this work has unwittingly perpetuated an individualist notion of the religious subject. Although religionists are now well aware that bodies cannot be studied apart from the social forces that shape them, all too often the religious subject stands alone in a crowd, participating in communal rituals, subject to religious authorities and disciplinary practices, but oddly detached from intimate relationships. In this article, I first argue that the turn to the body was motivated by what it appeared to reject: theoretical questions about subjectivity. I then seek to challenge prevailing trends by arguing that these same theoretical insights should now prod us to attend to the import of intimacy and personal relationships. PMID- 22530259 TI - The future of urban water services in Latin America. AB - In recent decades, problems with the provision of drinking water and sanitation services around the world have increasingly been addressed by attempts at privatisation, recasting clean water as an essentially economic, rather than public, good. This approach gained particular acceptance in Latin America, but with limited success. In order to address the full range of social, economic and environmental values necessary to sustain water resources over time, public and governmental involvement in establishing integrated water management, pursuing 'soft path' approaches, assuring stakeholder input and setting policy will be essential to the process. PMID- 22530260 TI - Public-private partnerships in solid waste management: sustainable development strategies for Brazil. AB - An often overlooked issue in the discussion of sustainable development is that of municipal solid waste management. Yet solid waste management is pervasive in all sustainable development objectives: its management, or lack thereof, can have major implications for the health of the environment, economy and society. This article argues the need for a governance dimension in the sustainability model, taking into account implementation strategies, monitoring and institutional controls. This focus heavily relies on integrated public-private partnerships and deliberative democracy approaches in order to achieve sustainability within the solid waste management sector. In this article, national and local policies in Brazil are analysed, primarily focusing on the inclusion of informal waste collection into municipal solid waste management schemes. The city of Curitiba, in the state of Parana, which is world-renowned for its innovative sustainable development policies, is used to frame and illustrate the case. PMID- 22530261 TI - "It just kind of like falls in your hands": factors that influence black aunts' decisions to parent their nieces and nephews. AB - Using a modified grounded theory method and Black feminist theory, the author explored the factors that influence the decision-making processes of Black aunts parenting nieces and nephews. Analysis revealed six themes that facilitated beliefs in a lack of agency in the decision-making process: perceptions of a crisis, fulfillment of family obligations, personal identities, faith in God, gendered expectations, and the role of the Black aunt. Findings emphasized the impact of cultural traditions and gendered expectations on the meanings that Black aunts attach to familial roles and the influence of past and current racism on their definitions of the situation. PMID- 22530262 TI - Regulating public space on the beachfronts of Rio de Janeiro. AB - Despite the fortification of buildings, streets, and public squares, Rio de Janeiro's beaches remain widely regarded as democratic spaces of social diversity and accessibility. Our study revisits the question of Rio's "democratic" beachfronts, based on local interviews, field observations, official reports, and newspaper accounts. We focus on historical and contemporary perceptions of planning, privatization, and public-order programs on the city's southern seaside. Institutional discourses have justified increasing regulation to combat threats of disorder and insecurity. While residents value the relative openness of beachfronts, they also acknowledge issues of safety, social segmentation, and subtle forms of bias. The public generally applauds recent "Shock of Order" policing and commercial revitalization, although critics lament the loss of traditional freedoms for informal beach vendors and casual sports. These paradoxes highlight enduring tensions between social order and hierarchy on one hand, and democratic rights and equality on the other. PMID- 22530263 TI - GOOD or BAD responder? Behavioural and neuroanatomical markers of clinical response to donepezil in dementia. AB - We explored the neuropsychological and neuromorphometrical differences between probable Alzheimer's disease patients showing a good or a bad response to nine months treatment with donepezil. Before treatment, the neuropsychological profile of the two patient groups was perfectly matched. By the ninth month after treatment, the BAD-responders showed a decline of the MMSE score together with a progressive impairment of executive functions. A voxel-based morphometry investigation (VBM), at the time of the second neuropsychological assessment, showed that the BAD-responders had larger grey and white matter atrophies involving the substantia innominata of Meynert bilaterally, the ventral part of caudate nuclei and the left uncinate fasciculus, brain areas belonging to the cholinergic pathways. A more widespread degeneration of the central cholinergic pathways may explain the lack of donepezil efficacy in those patients not responding to a treatment that operates on the grounds that some degree of endogeneous release of acetylcholine is still available. PMID- 22530264 TI - Neural control of voluntary eye closure: a case study and an fMRI investigation of blinking and winking. AB - The current paper describes a rare case of a patient who suffered from unilateral apraxia of eye closure as a result of a bilateral stroke. Interestingly, the patient's ability to voluntarily close both eyelids (i.e. blinking) was not affected, indicating that different neural mechanisms control each type of eye closure. The stroke caused damage to a large part of the right frontal cortex, including the motor cortex, pre-motor cortex and the frontal eye field (FEF). The lesion in the left hemisphere was restricted to the FEF. In order to further study the neural mechanisms of eye closure, we conducted an fMRI study in a group of neurological healthy subjects. We found that all areas of the oculomotor cortex were activated by both left and right winking, including the FEF, supplementary eye field (SEF), and posterior parietal cortex (PPC). Blinking activated FEF and SEF, but not PPC. Both FEF and PPC were significantly more active during winking than blinking. Together, these results provide evidence for a critical role of the FEF in voluntary unilateral eye closure. PMID- 22530265 TI - Semantic and phonemic verbal fluency in Parkinson's disease: Influence of clinical and demographic variables. AB - Changes of cognitive function in PD have been extensively documented and defined as a 'frontal' type executive dysfunction. One of the main components of this executive dysfunction is the impairment of verbal fluency. The aim of the present study was to assess semantic and phonemic fluency in a large sample of PD patients and to investigate the effect of clinical and sociodemographic variables on verbal fluency in this patient group. Three hundred patients with idiopathic Parkinson's disease who were consecutive referrals to our clinic and 50 age and education matched healthy controls completed the phonemic and semantic verbal fluency tasks. Both phonemic and semantic verbal fluency were significantly impaired in PD patients relative to matched controls. Stage of illness, presence of depression, education and age influenced verbal fluency measures. Regression analyses established that global measures of cognitive ability (MMSE) and executive function (FAB) and side of onset of motor symptoms predicted 36-37% of variance of phonemic or semantic verbal fluency measures. Thus, future studies aimed at assessing cognitive functioning in PD patients treated by deep brain stimulation (DBS) should adequately take into account several factors (stage of illness, depression, executive functioning) which may potentially influence performance on verbal fluency tasks. PMID- 22530266 TI - The influence of playing a non-reward game on motor ability and executive function in Parkinson's disease. AB - The aim of this study is to evaluate the acute effect of playing games on executive function and motor ability in Parkinson's disease (PD). Consecutive cases with PD were studied with the Unified Parkinson Disease Rating Scale (UPDRS), Mini-Mental State examination (MMSE), Beck Depression Inventory (BDI), Stroop test, finger tapping and 14-meter walk test. After randomization, patients performed a game of dominoes and were tested before and after experiment being further categorized as control, winners or non-winners. Forty patients, 27 male (67.5%), aged 48 to 84 years (63.2 +/- 8.5), Hoehn & Yahr I to III were included. Twenty-eight (70%) presented depressive symptoms (BDI > 10). Groups (Control N = 13; Winners = 14 and Non-winners = 13) were not different regarding age, disease duration, age at onset, BMI, MMSE scores, depressive symptoms, levodopa dose, and previous practice of games. Winners presented significantly better results on executive function (Stroop test, p = 0.002) and on motor activity (Finger tapping, p = 0.01). Non-winners showed a trend of better performance in the 14 meter-walk test. This study shows that the practice of a non-reward game acutely improved memory and motor skills in PD. Our results suggest a role for the reward system in the modulation of the dopaminergic function of the basal ganglia in these patients. PMID- 22530267 TI - Altered glycosylation of circulatory IgA1 involved in Henoch-Schonlein purpura and IgA nephropathy. PMID- 22530268 TI - Clinical wisdom and evidence-based medicine are (indeed) complementary: a reply to Bursztajn and colleagues. PMID- 22530269 TI - [Prescription of drugs with ASMR V in patients over 65 years in a primary care ambulatory setting. Drug prescription analysis in the Midi-Pyrenees region (France)]. AB - In French patients over 65 years, drug intake is characterized by polytherapy, causing iatrogenic events. The general practitioner is the main actor in the follow-up and reassessment of drug prescriptions. OBJECTIVE: To assess the proportion of ASMR V (Amelioration du service medical rendu - additional therapeutic benefit versus current standards) drugs [drugs producing no medical improvement] prescribed to patients over 65 years in the management of a chronic disease. MATERIAL AND METHOD: In May 2009, 849 drug prescriptions were collected from 34 general practitioners in the Midi-Pyrenees region. Specialties with ASMR V were classified according to the anatomical therapeutic chemical (ATC) classification system. RESULTS: 58.8% of the prescriptions concerned female patients; 67.4% of the prescriptions contained at least one ASMR-V drug. Approximately 20% of the prescriptions in subjects over 65 years contained ASMR-V drugs. DISCUSSION: This study shows that older subjects are being prescribed a significant number of ASMR-V drugs. However, this classification combines several situations, including a product line extension, a fixed combination of preexisting drugs, an insufficient therapeutic benefit, the absence of additional therapeutic benefit versus a comparative drug, the absence of comparative study in some indications, or a less favorable benefit-risk ratio comparing to that of the reference drug.This classification includes as well the generic drugs prescribed using the international non proprietary names. This study did not analyze the influence of certain factors, such as treatment history, history of drug allergy or dose titration, which could influence the physician's decision. CONCLUSION: Following this study, it appears useful to extend this type of survey to other general practitioners in other French regions, and to analyze the reasons for prescribing ASMR-V drugs. These data would help increasing general practitioners' awareness of "proper drug use" to reduce the proportion of "inadequate" drugs prescribed to older subjects. One could also consider conducting a survey amongst older patients under polytherapy, to question them on the treatments taken. PMID- 22530270 TI - [Acute fever: has the media coverage of the swine flu generated a medical overconsumption in primary care in France?]. AB - OBJECTIVE: Based on patient's declarations, evaluate if the media coverage of the pandemic flu (H1N1) has lead to an overconsumption of primary care. Identify the opinions of the general practionners (GP) concerning this media coverage and the health crisis. METHODS: A prospective study, based on an electronic questionnaire, was conducted during the main period of the pandemic flu. Each GP was invited to include one patient who presented fever since less than 2 days, associated to two of four following clinical signs: cough, headache, coat throat and ache. RESULTS: 730 questionnaires were fully completed and analyzed. 96 patients (12,9%) have declared to the GP an overconsumption, and two thirds of them because of their concern about the swine flu and a quarter because the social control. This concern was noted by 80% of the GP from the beginning of the flu 77% of the GP have considered the media coverage of the flu alarming, while 69% of them have declared to feel serene concerning the pandemic. No statistic link has been noticed between the GP opinions and the overconsumption of their patients. DISCUSSION: Media coverage of the swine flu and the state organization of the crisis have lead to an overconsumption estimated to 13%. Many efforts must be done in the future to reassure patients about flu and its vaccination. PMID- 22530271 TI - [Concordance between three definitions for metabolic syndrome (Hypertriglyceridemic waist, National Cholesterol Education Program, International Diabetes Federation), and prevalence of the syndrome in a French population]. AB - BACKGROUND: The metabolic syndrome is associated with an increased risk of diabetes and cardiovascular disease. However, only the Hypertriglyceridemic waist (HTGW) criterions have been chosen for their ability to identify a group of patients with a higher cardiovascular risk independently of the traditional risk factors. AIM: The aim of this study was to examinate the real concordance of the metabolic syndrome according to the HTGW definition, National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) definition and the International Diabetes Federation (IDF) definition. We also evaluated the prevalence of the metabolic syndrome in a French population. METHOD: The study was conducted on a sample of 232 patients, of both sexes, aged from 30 to 65 years old, recruited in general practice. Patients had a medical examination, and biological analyses were performed to assess their metabolic status. RESULTS: Kappa concordance coefficient was 0.46 between HTGW and NCEP ATP III; it was 0.43 between HTGW and IDF, and 0.59 between NCEP ATP III and IDF. The prevalence of the metabolic syndrome according to the HTGW in the sample was 16.8%, 18.3% in men and 15.4% in women. According to NCEP ATP IlI prevalence were respectively 20.3%, 20.9%, and 19.7%. According to IDF they were respectively 28.4%, 33%, and 23.9%. CONCLUSION: We recommend paying the same attention to the metabolic syndrome than to the traditional cardiovascular risk factors, and we recommend the use of the HTGW definition as diagnostic tool. PMID- 22530272 TI - [Tests and scales: restrains to use them by general practitioners. Descriptive transversal study]. AB - INTRODUCTION: Tests, even though recommended, are only few used by general practitioners (GP's). The aim of this study was to understand the reasons of this underuse. METHOD: Descriptive transversal study, to explore knowledge, use and restrains to using ten tests related in the first 50 results of consultation in general practice. We questioned 121 GP's from Charente, selected ad random. RESULTS: The oldest tests (MMS, MNA, Fagerstrom, mini-GDS, IPSS, depression) are known by more than half of the GP's. Only one third is familiar with more recent tests devoted to ambulatory care (TSTS, FACE, venous thromboembolic risk), which are also used less (20% at most). Systematic use of all tests mixed up, never exceeds 30% of all GP's. The principal restrain to use these tests is lack of training (53%), which seems indeed to be inefficient in this domain; 20 to 60% of GP's who know the tests, do not use them, mainly because of doubts regarding their usefulness (38%). DISCUSSION: What really is the utility of these tests in ambulatory care? Their validity in general practice shows some gaps: their validation results seldom on studies conducted in primary care, impact studies to evaluate the benefits for patients are lacking, and tests designed for specific use by GP's are rare and lacking in validity. CONCLUSION: Development of research in primary care in this field would be desirable in order to develop relevant, feasible and acceptable tools to help decision making in general practice. PMID- 22530273 TI - [Buprenorphin and benzodiazepines, an association with high risk. Reality of co prescriptions by the general practitioners]. AB - BACKGROUND: The buprenorphine (BHD) is an effective maintenance treatment for opioid dependence, used in France until 1996. From 1996 to 2001, it is involved in 137 deaths by respiratory depression including 91 attributable to the benzodiazepines (BDZ) association. The number of deaths caused by the BHD and BDZ, when they are taken jointly, is probably underestimated. The reasons for this association are the misuse, the self-medication and the co-prescription. OBJECTIVE: The objective of this study was to assess the co-prescription of these two drugs by the general practitioners (GPs) of Nancy (France). METHOD: A survey was conducted during the first semester 2007. Using the datas of the Caisse Primaire d'Assurance Maladie (the French national health service), all the requests for a reimbursement of BHD in Nancy were analysed. RESULTS: 1655 BHD consumers were included in this survey. Thirty-one percent of them asked for the reimbursement of at least one BZD at the same time. The BZD consumers were old, consulted more than one prescriber or chemist and more often consumed high dosages of BHD. CONCLUSION: The BZD consumption is often associated to BHD intake (31%). GPs need a better training on the subject: "How to take care of patients who depend on opiod". This would reduce the risks. A better information for the BHD users would be necessary as well as a lowest prescription of BZD by the GPs. Before any BHD prescription, the GPs should assess a possible co-dependence to BZD in order to improve the BHD prescription. PMID- 22530274 TI - [How do physicians sleep and dream?]. AB - INTRODUCTION: Satisfying sleep is especially important for physicians. Our study analyses physicians' sleep and dream from the point of view of continuous night and-day duty. SAMPLE AND METHOD: Questionnaires were completed by 125 physicians among whom the proportion of night shift taking and only day-time working persons was equal. The questionnaire contained the Athens Insomnia Scale and the Dream Quality Questionnaire as well as questions about demographical characteristics and work circumstances. RESULTS: Almost each doctor mentioned sleep problems, principally daytime sleepiness (78%) and sleep deprivation (70%). Long sleep latency is reported more often by women doctors; the frequency of night awakenings increases, while daytime sleepiness decreases by age. The feeling of performance-loss is more prevalent among night shift takers. Dream characteristics differ significantly neither along demographical characteristics nor by work shifts. CONCLUSION: Although sleep problems are more frequent among physicians when comparing to the Hungarian general population, the frequency of clinical level insomnia is not higher. On the other hand, physicians can recall their dreams more often (25% vs 7%) and the emotional load of their dreams influence their daytime mood more commonly. PMID- 22530276 TI - [Surrealistic art as reflected in psychoanalysis]. PMID- 22530275 TI - [I didn't have any motivation, desire, impulse and condom -- Geza Csath's activity as a balneologist]. PMID- 22530277 TI - [Playing with passion]. PMID- 22530278 TI - [Radium in pharmacies! First Part : Pharmaceutical used of radium before the first World War]. AB - The authors present in this part the creation of first radioactiv drugs, since the discovery of radium to the first World War. They present the industrial and chemist Emile Armet de Lisle and the pharmacist Alexandre Antonin Jaboin, first manufacturers of those new way of treatment. PMID- 22530279 TI - [The influence of the French pharmacy along the centuries throughout the emigration]. AB - The influence of the French Pharmacy abroad has been effective through discoveries, reference books, congresses, universal exhibits, but also thanks to French pharmacists and apothecaries leaving France. For several reasons (religion, poverty, interest for adventure...), these pharmacists took with them the French pharmaceutical culture and products that were in their pharmacopeias or coming from their pharmaceutical industry. Consequently, they have influenced some countries by changing the local legislation, reference books, new products and pharmaceutical products quality. The present publication try to examine those pharmacists that have decided, temporarily or definitively to leave France and to live in other countries. PMID- 22530280 TI - [Inspection of pharmacies in Morocco during the French protectorate 1912-1956]. AB - In Morocco, the inspection of the pharmacy as currently practiced has enjoyed a great evolution: from a small body born during the protectorate, which originally had two inspectors, it has become a well-organized and prioritized sector. This article revisits the birth and history of this inspection during the French protectorate. Based on the available literature, we examined and analyzed the arrangements related to the establishment of the inspection, its various reorganizations as well as the powers allocated to inspectors. PMID- 22530281 TI - [A pharmacist designer and manufacturer of veterinarian patent medicines, Paul Mere, de Chantilly]. AB - In the last quarter of the 19th century, Paul Mere, pharmacist in Chantilly (Oise), worked out and marketed a range of veterinarian medicines mainly intended for horses. He pursued his activity in Orleans (Loiret), giving her a big extension with export of his patents medicines in numerous foreign countries, this company having remained up to the Second World War. PMID- 22530282 TI - [A inspection in the pharmacy belonging to Jacques Francois Cordier in Commercy on 1752 December 9th]. AB - The respect of regulation in pharmaceutical activity was ever a preoccupation for the legal powers. When the Royal College of Medicine was created in Nancy in 1752, this institution received some prerogatives in this field. The report studied here shows how such a survey is conducted in the pharmacy of a practitioner recently settled in Commercy. We are also informed of current human, hierarchal and social relations. Jacques Francois Cordier, whose biography is presented, was the introducer and the "godfather" of two famous pharmacists: Jean Nicolas Trusson in Paris, and Henri Braconnot in Nancy. PMID- 22530283 TI - [From ancient pot collections to the modern medicines. Menier's pot collection 19th century]. AB - At the beginning of the 19th century in 1816, Jean Antoine Brutus Menier founded the "Maison Centrale de Droguerie Menier". It supplied most of the pharmacies in France with drugs of animal, plant and mineral origin for the pharmaceutical preparations recommended at that time. The company provided training for many chemists and pharmacists, and as such, had a collection of pots containing over seven hundred drugs that is currently held at the head office of the Council of the College of Pharmacists in Paris. After having described the pot collection, set it against the 19th century background which experienced a real revolution within this profession, and after retracing its history, a study was then carried out in order to compare the former uses with the modern uses for each of the drugs. Thanks to this detailed, comparative analysis it is now possible to evaluate the relevance of the therapeutic range of drugs in the first half of the 19th century, before the significant rise in chemistry. The Germinal Law changed the pharmacist's profession, and with the birth of chemistry, the art of the pharmacy was revolutionised. However, the drugs, and particularly those of plant origin, have managed to keep a dominant position in today's pharmaceutical domain and in the French or European Pharmacopoeia. PMID- 22530284 TI - Reducing health disparities: medical advice received for minorities with diabetes. AB - OBJECTIVE: to examine the relationships among reported medical advice, diabetes education, health insurance and health behavior of individuals with diabetes by race/ethnicity and gender. METHOD: Secondary analysis of data (N = 654) for adults ages > or = 21 years with diabetes acquired through the National Health and Nutrition Examination Survey (NHANES) for the years 2007-2008 comparing Black, non-Hispanics (BNH) and Mexican-Americans (MA) with White, non-Hispanics (WNH). The NHANES survey design is a stratified, multistage probability sample of the civilian noninstitutionalized U.S. population. Sample weights were applied in accordance with NHANES specifications using the complex sample module of IBM SPSS version 18. RESULTS: The findings revealed statistical significant differences in reported medical advice given. BNH [OR = 1.83 (1.16, 2.88), p = 0.013] were more likely than WNH to report being told to reduce fat or calories. Similarly, BNH [OR = 2.84 (1.45, 5.59), p = 0.005] were more likely than WNH to report that they were told to increase their physical activity. Mexican-Americans were less likely to self-monitor their blood glucose than WNH [OR = 2.70 (1.66, 4.38), p < 0.001]. There were differences by race/ethnicity for reporting receiving recent diabetes education. Black, non-Hispanics were twice as likely to report receiving diabetes education than WNH [OR = 2.29 (1.36, 3.85), p = 0.004]. Having recent diabetes education increased the likelihood of performing several diabetes self-management behaviors independent of race. CONCLUSIONS: There were significant differences in reported medical advice received for diabetes care by race/ethnicity. The results suggest ethnic variations in patient-provider communication and may be a consequence of their health beliefs, patient-provider communication as well as length of visit and access to healthcare. These findings clearly demonstrate the need for government sponsored programs, with a patient-centered approach, augmenting usual medical care for diabetes. Moreover, the results suggest that public policy is needed to require the provision of diabetes education at least every two years by public health insurance programs and recommend this provision for all private insurance companies. PMID- 22530286 TI - Benefits and costs of a free community-based primary care clinic. AB - This study estimates the benefits and costs of a free clinic providing primary care services. Using matched data from a free clinic and its corresponding regional hospital on a sample of newly enrolled clinic patients, patients' non urgent emergency department (ED) and inpatient hospital costs in the year prior to clinic enrollment were compared to those in the year following enrollment to obtain financial benefits. We compare these to annual estimates of the costs associated with the delivery of primary care to these patients. For our sample (n = 207), the annual non-urgent ED and inpatient costs at the hospital fell by $170 per patient after clinic enrollment. However, the cost associated with delivering primary care in the first year after clinic enrollment cost $505 per patient. The presence of a free primary care clinic reduces hospital costs associated with non urgent ED use and inpatient care. These reductions in costs need to be sustained for at least 3 years to offset the costs associated with the initially high diagnostic and treatment costs involved in the delivery of primary care to an uninsured population. PMID- 22530285 TI - Is there an association between local health department organizational and administrative factors and childhood immunization coverage rates? AB - BACKGROUND: Vaccines are valuable, cost-effective tools for preventing disease and improving community health. Despite the importance and ubiquity of vaccinations, childhood immunization coverage rates vary widely by geography, race, and ethnicity. These differences have been documented for nearly two decades, but their sources are poorly understood. Between 2005 and 2008, immunization staff of the National Association of County & City Health Officials (NACCHO) visited 17 local health department (LHD) immunization programs in 10 states to assess their immunization service delivery (ISD) practices and their impact on community childhood immunization coverage rates. PURPOSE: To qualitatively characterize LHD immunization programs and specific organizational factors underlying ISD performance challenges and successes related to community childhood immunization coverage rates. METHODS: Case studies were conducted in a convenience sample of 17 geographically and demographically diverse LHDs, predicated on each LHD's childhood immunization coverage rates per data from the National Immunization Survey and/or Kindergarten Retrospective Survey. NACCHO staff selected LHDs with high (> or = 80% up to date [UTD]), moderate (> or = 75% UTD but < 80% UTD), and low (< 75% UTD) coverage rates. All immunization staff members interviewed (n = 112) were included in focus group interviews at each LHD per a standard semi-structured interview script developed by NACCHO staff. Supporting documents from each LHD immunization program were also collected for inclusion in the analysis. Content and thematic analyses of interview transcripts and supporting documents were conducted. RESULTS: Two thematic dimensions and six key factors emerged from the data. The dimensions of the themes were success and challenge elements. The organizational factors that were associated with success and/or challenges with regard to improving childhood immunization coverage rates included 1) leadership: organizational leadership and management related to aligning ISD with other child-focused services within the LHD; 2) resources: organizational efforts focused on aligning federal and state ISD financing with local ISD needs; 3) politics: political advocacy and partnering with local community stakeholders, including local political entities and boards of health to better organize ISD; 4) community engagement/coalitions and partnerships: partnerships, coalitions, and community engagement to support local immunization related decision-making and prioritization; 5) credibility: agency credibility and its ability to influence community attitudes and perspectives on the health department's value in terms of child health; and 6) cultural competency of LHD staff: LHD staff members' perceptions and understandings of its community's cultural, economic, and demographic attributes shaped their responses to and understandings of the community and how they interacted with it in terms of service delivery. DISCUSSION: Public health researchers are in a nascent stage of understanding how health department organizational factors may contribute to specific community health outcomes, such as childhood immunization coverage rates. An implicit challenge to LHD immunization programs is to implement strategies that lead to equitable and high vaccination coverage among children, despite shrinking resources and community demographic differences. Community specific attributes (e.g., poverty, lack of health insurance, or geographic isolation) affect childhood immunization coverage rates, but internal LHD aspects such as leadership and organizational culture also likely have a significant impact. PMID- 22530287 TI - Organizational change for services integration in public human service organizations: experiences in seven counties. AB - This is a study of organizational change strategies employed in seven county human service agencies to improve the coordination of services through the structural integration of previously free standing organizations or the development of voluntary interagency collaborative service delivery systems. The central question involves the identification of organizational change tactics which contributed to the success of the organizational change initiatives. The literature on organizational change is reviewed, with particular attention to a framework developed by Fernandez and Rainey based on their extensive review and synthesis of the research on successful change strategies in the public and business sectors. Qualitative and quantitative data were gathered from over 250 individuals and from agency documents. Findings are compared with the success factors identified by Fernandez and Rainey, and refinements to their propositions are suggested. More precise methods for measuring successful and unsuccessful change initiatives are suggested. Implications for practice and research are presented. PMID- 22530288 TI - Interview with James W. Begun, PhD, James A. Hamilton Professor of Healthcare Management, School of Public Health, University of Minnesota. Interview by Stephen J. O'Connor. PMID- 22530289 TI - The evolution of patient-centered care. PMID- 22530290 TI - Improving patient flow through a better discharge process. PMID- 22530291 TI - Success under duress: policies and practices managers view as keys to profitability in five California hospitals with challenging payer mix. AB - Hospitals with a challenging payer mix (CPM)-high proportions of uninsured and Medicaid patients and a low proportion of commercially insured patients-are an important source of care for low-income, uninsured people. Achieving profitability is difficult for CPM hospitals. From 2005 through 2008, only one third of 67 CPM hospitals in California reported positive total margins. In-depth group interviews were completed with the management leadership teams of a diverse group of five profitable CPM hospitals to identify the management strategies and practices that the hospitals' leadership teams credited for their financial success. Twelve management policy and practice topics were identified. Four of the policies and practices that managers identified involve organizational actions to increase hospital revenue or operational efficiency. These factors are consistent with those identified in previous research. However, managers also identified eight factors not previously revealed in research on hospital profitability, including management policies and practices that establish the organizational culture, workforce, relationships, monitoring systems, and governance necessary to ensure that hospital employees and affiliated physicians support and successfully implement organizational actions necessary to achieve profitability. PMID- 22530292 TI - Organizational and market factors associated with leadership development programs in hospitals: a national study. AB - Effective leadership in hospitals is widely recognized as the key to organizational performance. Clinical, financial, and operational performance is increasingly being linked to the leadership practices of hospital managers. Moreover, effective leadership has been described as a means to achieve competitive advantage. Recent environmental forces, including reimbursement changes and increased competition, have prompted many hospitals to focus on building leadership competencies to successfully address these challenges. Using the resource dependence theory as our conceptual framework, we present results from a national study of hospitals examining the association of organizational and market factors with the provision of leadership development program activities, including the presence of a leadership development program, a diversity plan, a program for succession planning, and career development resources. The data are taken from the American Hospital Association's (AHA) 2008 Survey of Hospitals, the Area Resource File, and the Centers for Medicare & Medicaid Services. The results of multilevel logistic regressions of each leadership development program activity on organizational and market factors indicate that hospital size, system and network affiliation, and accreditation are significantly and positively associated with all leadership development program activities. The market factors significantly associated with all leadership development activities include a positive odds ratio for metropolitan statistical area location and a negative odds ratio for the percentage of the hospital's service area population that is female and minority. For-profit hospitals are less likely to provide leadership development program activities. Additional findings are presented, and the implications for hospital management are discussed. PMID- 22530293 TI - Promoting employee voice and upward communication in healthcare: the CEO's influence. AB - As noted by the Institute of Medicine (2004), a lack of critical upward feedback in the hospital setting has adverse effects on direct patient care and health outcomes. Employees are oftentimes reluctant to share information, as those above them might interpret the information to be negative or threatening. Leaders then may make important decisions based on assumptions or inaccurate feedback. The situation is especially significant in the healthcare setting, where hierarchical structures (Nembhard and Edmondson 2006), divisions between administrators and clinicians, and lack of collaboration across teams reinforce employee silence and undermine organizational learning (Ramanujam and Rousseau 2006). Chief executive officers play a key role in developing a culture that fosters employee voice and upward communication (Ashford, Sutcliffe, and Christianson 2009). Hospitals winning performance excellence awards, such as those utilizing the Malcolm Baldrige National Quality Award Criteria for Performance Excellence, present a model of high performance with demonstrated results. The purpose of this study was to understand specific CEO behaviors and actions promoting employee voice and upward communication in performance excellence award-winning healthcare organizations. Results suggested the award-winning CEOs facilitated employee voice by being approachable, mainly achieved through their regular presence throughout the organization. By being consistently visible and available to employees these CEOs fostered relationships, built trust, and promoted open communication. Leaders in the study created a cultural focus on continuous improvement largely built around transparency of information, particularly looking for the bad news from their employees. Voice invitation and positive voice response from leaders reinforced that critical upward feedback is not only welcome, but expected. PMID- 22530294 TI - Does the internet change how we die and mourn? Overview and analysis. AB - The article outlines the issues that the internet presents to death studies. Part 1 describes a range of online practices that may affect dying, the funeral, grief and memorialization, inheritance and archaeology; it also summarizes the kinds of research that have been done in these fields. Part 2 argues that these new online practices have implications for, and may be illuminated by, key concepts in death studies: the sequestration (or separation from everyday life) of death and dying, disenfranchisement of grief, private grief, social death, illness and grief narratives, continuing bonds with the dead, and the presence of the dead in society. In particular, social network sites can bring dying and grieving out of both the private and public realms and into the everyday life of social networks beyond the immediate family, and provide an audience for once private communications with the dead. PMID- 22530295 TI - Deathbed visions from the Republic of Moldova: a content analysis of family observations. AB - This is an interview-based study of 102 families and their observations of the last weeks and days of a dying family member. Forty-one families reported hearing about "visions," "hallucinations," or "dreams" from their dying loved one before their death. Of these 41 mixed cases, 37 cases demonstrated classic features of deathbed visions-reports of seeing dead relatives or friends communicating to the dying person. This article reports a content analysis of these 37 cases in order to identify the major psychosocial themes that seem to be conveyed by these kinds of experiences. Six major themes are identified. These themes are: support, comfort, companionship, reunion, prognosis, and choice and control. Implications of these themes are discussed in relation to their role in providing significant support for the psychological morale and social well being of dying people. PMID- 22530296 TI - Beyond words: some uses of music in the funeral setting. AB - Music is a common feature of funerals, both in terms of sacred music and also secular music when a funeral is personalized to the individual who has died. Drawing on data from research exploring Scottish funeral practices, this article examines some of the ways in which music can be used during a funeral. It suggests five specific uses of music in the funeral context: the use of music as a means of control; the use of music as a means of inclusion and exclusion; music as a source of collective activity; music as a means of creating or shifting emotion; and music as a means of evoking the memory of the deceased person. These uses of music are described and discussed, and suggestions made for further research exploring the use of music in funerals. PMID- 22530297 TI - Therapeutic implications of continuing bonds expressions following the death of a pet. AB - Through the exploration of 12 continuing bonds expressions (CBE), this current study investigated the grief reaction and continuing impact of the death of a pet. Thirty-three individuals were interviewed to determine the degree of connection maintained with the deceased pet and how that affects their coping. Findings emphasize that the majority of respondents frequently maintain ongoing meaningful ties with their deceased pet through the use of CBE such as fond memories, rituals, dreams. The findings suggest that it is not the number of CBE but the degree of adaptability that is significant. The importance of recognizing the unique, total experience of those grieving the death of a pet is addressed. Implications for those working with and supporting those in grief are included. Future directions for research are described. PMID- 22530298 TI - Exploring death anxiety among elderly people: a literature review and empirical investigation. AB - Given the growing number of elderly persons in society and concerns about their health and well-being, the aim was to review the available literature on their death anxiety, and to explore features of this experience among a small sample of older men and women in care facilities. In both the review and empirical parts of this study, components and correlates of death anxiety were investigated. The review revealed limited research focus on death anxiety among the elderly, particularly among those in institutions, but suggested both components and correlates for inclusion in our empirical study. Results showed that, among our elderly participants in an assisted living facility (N = 49; age range: 60-96 years), there were higher levels of fear for others and of the dying process than for fear of the unknown. Notably, among the correlates identified, fear for significant others was associated with poor physical health; fear of the dying process was related to low self-esteem, little purpose in life, and poor mental well-being. Gender differences in death anxiety were found: women showed greater fear for the death of loved ones and for the consequences of their own death on these loved ones, than did men. These patterns are discussed in the light of concerns about the welfare of elderly persons; scientific implications are also considered. PMID- 22530299 TI - Quantitative structure-interaction relationship analysis of 1,4-dihydropyridine drugs in concomitant administration with grapefruit juice. AB - Quantitative structure-interaction relationship (QSIR) analyses of 1,4 dihydropyridine drugs were performed on grapefruit juice interaction potentials to characterize the interaction and evaluate drugs not yet tested in clinical research. AUC ratios of drugs with and without grapefruit juice ingestion were estimated as grapefruit juice interaction potentials from clinical studies on dihydropyridine drugs such as amlodipine, azelnidipine, benidipine, cilnidipine, felodipine, manidipine, nicardipine, nifedipine, nimodipine, nisoldipine, and pranidipine. The minimal energy conformation in each dihydropyridine drug was searched for using Merck Molecular Force Field (MMFFaq), and then geometry optimization was performed by density-functional-theory (DFT) calculation (B3LYP/6-31G**). The geometric, electronic, and physicochemical features including molecular size, dipole moment, total energy, HOMO/LUMO energies, and logP values were then obtained. Dragon descriptors were also calculated by optimized 3D-structures. The relation between the potentials and over 1000 of the molecular properties was investigated using statistical techniques including partial least squares analysis with genetic algorithm (GA-PLS) to a variable subset selection. Some PLS regression equations including logP values and dragon descriptors as explanatory variables were constructed in which the maximal contribution coefficient was 94%. These models could be applied to estimate the interaction potentials of other dihydropyridine drugs that have gone unreported in interactions with drugs such as aranidipine, barnidipine, clevidipine, lemildipine, lercanidipine, niguldipine, niludipine, and nilvadipine. In the assessment of major dihydropyridines, amlodipine was found to be the safest drug to avoid interactions among the drugs investigated in the present study. PMID- 22530300 TI - Solid lipid nanoparticles: a possible vehicle for zinc oxide and octocrylene. AB - An efficient sunscreen formulation shows good absorption in the relevant UV range. Efficacy also means that the UV absorber must be easily incorporated in any kind of formulation. In this study, a chemical absorber, octocrylene, and one of the most important physical blockers, zinc oxide, could be successfully incorporated into Solid Lipid Nanoparticle (SLN) systems which themselves have UV blocking potential similar to physical sunscreens, and remained stable for a period of 360 days while providing UVA and UVB protection. Crystalline structure related to the chemical nature of the solid lipid is a key factor to decide whether a sunscreening agent will be expelled or incorporated in the long-term and for a controlled optimization of active ingredient incorporation and loading, intensive characterization of the physical state of the lipid particles was highly essential. Thus, FT-IR, NMR, XRD and DSC analyses were performed and the results did not indicate stability problems. pH values of the SLN systems were found to be between 5.4-5.9 in all formulations which may be buffered by the skin. Transpore test results proved the UV blocking potential of the SLNs with not any active ingredient and the synergistic effects by the incorporation of molecular sunscreens. Therefore, concentration of molecular sunscreens in the formulations was decreased to 0.6%. UVA and UVB screening potentials of octocrylene and zinc oxide formulations were compared in the 290-400 nm wavelength region. Zinc oxide loaded SLN suspensions were found to be more effective in the UVA region while octocrylene loaded ones performed better in the UVB region. PMID- 22530301 TI - Enhancement of the in-vitro dissolution and in-vivo oral bioavailability of silymarin from liquid-filled hard gelatin capsules of semisolid dispersion using Gelucire 44/14 as a carrier. AB - OBJECTIVE: The purpose of this study was to improve peroral bioavailability of the very poorly water-soluble hepatoprotectant silymarin through formation of semisolid dispersion (SD) system with Gelucire 44/14. METHOD: Binary SD systems were prepared by the solvent-fusion method and confirmed by differential scanning calorimetry (DSC). The solubility and in vitro release at pH values of 1.2 and 7.4 were then determined. The pharmacokinetic parameters and relative bioavailability of orally administrated silymarin pure (SP), silymarin-Gelucire 44/14 SD (GL) capsules were assessed and compared to that of Hepaticum (silybin cyclodextrin) capsules (CP) as a reference standard (RF) using New Zealand albino rabbits. RESULTS: A linear increase in solubility of silymarin with respect to the weight fraction of the carrier has been observed. RESULTS: The solubility of silymarin SD increased - 1.5-to-7-fold (relative to pure silymarin) at 1-to-15% of Gelucire 44/14 which in turn dramatically increased the dissolution rate of silymarin-Gelucire SD (91% within 10 min). The DSC study showed complete disappearance of the silymarin endothermic peak confirming formation of silymarin SD. In the bioavailability study, SD of silymarin with Gelucire 44/14 profoundly increased the AUC(0-12) and C(max) values (-13-fold relative to RS). CONCLUSION: The solubility and dissolution pattern of silymarin were found to be carrier ratio dependent. Moreover, the in vitro solubility and dissolution data established very good correlation with the calculated in vivo pharmacokinetic parameters. The ratios between the mean AUC(0-12) for GL capsules and that of CP capsules was significantly higher (156.2%). However, the Tmax values of the three formulations remained eventually unchanged. PMID- 22530302 TI - Improved compressibility, flowability, dissolution and bioavailability of pioglitazone hydrochloride by emulsion solvent diffusion with additives. AB - Spherical agglomerates of pioglitazone hydrochloride were prepared by the emulsion solvent diffusion method with additives (polyethylene glycol 6000, polyvinyl pyrrolidone, beta cyclodextrin, eudragit RS100, low acyl gellan gum and xanthan gum) using methanol, chloroform and water as a good solvent, bridging liquid and poor solvent respectively. Prepared agglomerates were evaluated for compressibility, solubility, dissolution rate and bioavailability, and characterized by SEM, XRPD, DSC and FTIR spectroscopy. Particle size, flowability, compactibility, packability, solubility, dissolution rate and bioavailability of plain agglomerates and agglomerates with additives (except with polyvinyl pyrrolidone) were advantageously improved compared with raw crystalline pioglitazone hydrochloride. These improved properties for direct compression were due to their large-spherical shape and enhanced fragmentation during compaction, together with increased tensile strength and reduced elastic recovery of the compacts. XRPD and DSC studies indicated polymorphic transition of pioglitazone hydrochloride from form II to I during recrystallization but this was not associated with any chemical transition, as indicated by FTIR spectra, well supported by stability studies. Thus spherical crystallization by the emulsion solvent diffusion method with selected additives is a satisfactory method for direct tableting of pioglitazone hydrochloride giving improved bioavailability. PMID- 22530303 TI - Hyaluronic acid L-cysteine conjugate exhibits controlled-release potential for mucoadhesive drug delivery. AB - Hyaluronic acid-L-cysteine conjugate, a novel thiolated polymer, was synthesized and characterized for mucoadhensive drug delivery. L-Cysteine was covalently attached to hyaluronic acid via the formation of an amide bond. Adhesion studies on the mucosa indicated a 4.82-fold increase in the adhesion force of the obtained conjugate (containing 210.58 micromol thiol groups per gram polymer) versus unmodified hyaluronic acid. The results of a peptidase inhibition study revealed that the inhibitory effect of hyaluronic acid toward trypsin and chymotrypsin was significantly improved compared to hyaluronic acid. Permeation studies utilizing a MDCK cell monolayer system demonstrated a sustained drug release. Based on these features the novel thiolated polymer might represent a promising multifunctional excipient for various drug delivery systems. PMID- 22530304 TI - Impregnation of plasmid DNA into three-dimensional PLGA scaffold enhances DNA expression of mesenchymal stem cells in vitro. AB - Current efforts had been made to undertake a three-dimensional (3-D) reverse transfection of bone marrow-derived mesenchymal stem cells (BM-MSCs) in PLGA scaffolds. As a kind of multipotent stem cells, BM-MSCs show great potential and tremendous capacity in the gene transfection field and PLGA 3-D scaffold has been shown to be a biomaterial that provides structural support to cells proliferation and tissue engineering. The objective of this study was to assess the transfection efficiency of BM-MSCs with a 3-D reverse transfection method by using PLGA scaffold and observe the SEM photographs of BM-MSCs cultured on PLGA scaffold. BM-MSCs were cultured in 3-D PLGA scaffold which was incorporated with pullulan-spermine/pGL3. It was shown that the gene expression duration of BM-MSCs transfected using 3D reverse method with pullulan-spermine/DNA in the presence of serum maintained 12 days at high levels as compared with the plasmid DNA in medium, and scanning electronic microscopy (SEM) photographs of BM-MSCs cultured on PLGA scaffold exhibited robust cell attachment and viability when cultured in PLGA scaffold in vitro. This study demonstrates that the 3-D reverse transfection method of BM-MSCs using PLGA scaffold could achieve long gene expression in a relatively high level, therefore this transfection system is promising in gene transfection and tissue engineering. PMID- 22530305 TI - Phase I clinical study to select a novel oral formulation for ibandronate containing the excipient sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC). AB - The aim of this study was to select a novel oral formulation for ibandronate (IBN, CAS number: 13892619). In four cohorts of 28, 21, 19 and 29 healthy volunteers, the impact of the carrier molecule sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC, CAS number: 203787-91-1) on the bioavailability of IBN was investigated. Within each cohort different oral formulations with one dose of ibandronate (30 mg) and three different ratios of IBN:SNAC (1:5, 1:10 and 1:20) were compared to the approved oral IBN tablet formulations (150 and 50 mg IBN) in a 4-way cross-over design and a one week washout between the administrations. The highest mean IBN exposure was achieved with a capsule formulation containing drug coated beadlets and an IBN:SNAC ratio of 1:5. AUC(last) and C(max) of IBN were approximately 1.3- and 2.2-fold higher compared to the reference treatment (150 mg IBN without SNAC). Increasing the post-dose fasting duration from 15 to 30 min resulted in a more than 2-fold increase in AUC(last), while superimposable IBN serum concentration-time profiles were achieved after a 30 and 60 min fast. The tolerability of the IBN/SNAC treatments in all cohorts was similar to that in the IBN reference groups and most adverse events (AEs) were of mild to moderate intensity. PMID- 22530306 TI - Effects of Ougan juice on P450 activities using a cocktail method. AB - Ougan (Citrus suavissima Hort. ex Tanaka) is an important domesticated fruit which is used medicinally in China. To date, a number of methods for its identification and chemical analysis have been studied. However, the effects of Ougan juice on CYP isozymes have not been reported. Therefore, the objective of our study was to evaluate the potential effects of Ougan juice on the CYP isozymes CYP1A2, CYP2C9, CYP2C19 and CYP2D6 in rats using a cocktail approach involving the probe drugs phenacetin, tolbutamide, omeprazole and dextromethorphan. These four probe drugs were simultaneously administered to rats after single and multiple dosing of Ougan juice by gastric irrigation. The pharmacokinetics of the probes in the plasma were simultaneously determined by HPLC-MS. The main pharmacokinetic parameters of the four probe drugs were not significantly different in rats after single dose of Ougan juice. The t1/2 and AUC(0-infinity) of phenacetin and omeprazole increased significantly and their CL(z) decreased markedly after multiple dosing of Ougan juice. However, the t1/2 of tolbutamide decreased notably, while the t1/2 of dextromethorphan was not changed. The findings of this study suggest that a single administration of Ougan juice had little effect on P450 activities while multiple administration of Ougan juice tended to inhibit CYP1A2 and CYP2C19 and induce CYP2C9, but did not influence CYP2D6. PMID- 22530307 TI - OIC-A006-loaded true bone ceramic heals rabbit critical-sized segmental radial defect. AB - It has been reported that OIC-A006, an osteogenically inducible compound, is able to promote osteogenesis in vitro and in vivo. In this study, we used a rabbit critical-sized segmental radial defect model (CSD) (15 mm) to analyse the osteogenic activity of OIC-A006 in non-cell-seeded tissue engineering bone substitutes. The scaffold carrier was bovine sintered bone "true bone ceramic (TBC)". OIC-A006 was delivered by PLGA (D,L-lactide-co-glycolide acid) microspheres. Drug-free PLGA microspheres and rhBMP-2-loaded PLGA microspheres were used as negative and positive control groups, respectively. Three kinds of composite were fabricated by coupling TBC, type-I collagen and the corresponding microspheres. The animals were randomly divided into 4 groups: (1) Group A: defect only, (2) group B:TBC/Collagen/drug-free-microspheres, (3) group C:TBC/Collagen/ OIC-A006-microspheres, (4) group D: TBC/Collagen/rhBMP-2 microspheres. The samples were analysed by histology, X-ray,microcomputed tomography (micro-CT), and biomechanical analyses. The results showed that OIC A006 promoted bone regeneration to a remarkable extent. It is suggested that the application of OIC-A006 might be a valuable method in bone tissue engineering for healing large segmental defects of long bones. However, the biomechanical strength was a little inferior to that of BMPs. PMID- 22530308 TI - Rho GDP-dissociation inhibitor alpha is associated with cancer metastasis in colon and prostate cancer. AB - Since metastasis is one of the most important prognostic factors in colorectal cancer, development of new methods to diagnose and prevent metastasis is highly desirable. However, the molecular mechanisms leading to the metastatic phenotype have not been well elucidated. In this study, a proteomics-based search was carried out for metastasis-related proteins in colorectal cancer by analyzing the differential expression of proteins in primary versus metastasis focus-derived colorectal tumor cells. Protein expression profiles were determined using a tissue microarray (TMA), and the results identified Rho GDP-dissociation inhibitor alpha (Rho GDI) as a metastasis-related protein in colon and prostate cancer patients. Consequently, Rho GDI may be useful as a diagnostic biomarker and/or a therapeutic to prevent colon and prostate cancer metastasis. PMID- 22530309 TI - Lycopene ameliorates erectile dysfunction in streptozotocin-induced diabetic rats. AB - Diabetes mellitus (DM) is characterized by oxidative stress, which is one of the major pathophysiological mechanisms underlying diabetic erectile dysfunction (ED). Lycopene is one of the most potent antioxidants among the natural carotenoids. The present study was aimed to investigate whether lycopene could lower oxidative stress and attenuate ED in diabetic rats. Lycopene (10, 30, 60 mg/kg/d) was administered via intragastric intubation for 8 weeks to streptozotocin (STZ) (50 mg/kg, i.v.) induced diabetic rats. The results showed that chronic lycopene treatment significantly and dose dependently restored ED in diabetic rats by lowering blood glucose, reducing oxidative stress and up regulating eNOS expression. These results indicated that lycopene treatment is potentially a new strategy for treating diabetic ED. PMID- 22530310 TI - Effects of an aqueous extract of Orbignya phalerata Mart on locomotor activity and motor coordination in mice and as antioxidant in vitro. AB - The antioxidant activities of aqueous extract (AE) of Orbignya phalerata were assessed in vitro as well as its effect on locomotor activity and motor coordination in mice. AE does not possesses a strong antioxidant potential according to the scavenging assays; it also did not present scavenger activity in vitro. Following oral administration, AE (1, 2 and 3 g/kg) did not significantly change the motor activity of animals when compared with the control group, up to 24 h after administration and did not alter the remaining time of the animals on the Rota-rod apparatus. Further studies currently in progress will enable us to understand the mechanisms of action of the aqueous extract of Orbignya phalerata widely used in Brazilian flok medicine. PMID- 22530311 TI - An early medicine chest. PMID- 22530312 TI - A Julep of Gems. PMID- 22530313 TI - Two green cosmetics of ancient Egypt? PMID- 22530314 TI - Oxymel in medieval Persia. PMID- 22530315 TI - Getting medical information to the people: the role of Nicholas Culpeper 1616 1654. PMID- 22530316 TI - Cosmetics for eternity in ancient Egypt. PMID- 22530317 TI - The illusion of ethics outside of time. PMID- 22530318 TI - Bioethics and law: from the abundance of sources to the confusion of genders. AB - The law of bioethics reveals frequent confusion in the definition and role devolved to the law and ethics. The purpose of this paper is to illustrate some of these confusions. PMID- 22530319 TI - [Searching for a social consensus in the establishment of bioethical norms]. AB - Although France has just acquired a third generation bioethics law, the convention on bioethics that was held in the spring of 2009, as well as all the reports drawn up in France with a view to revising the 2004 bioethics law, raise questions about the process by which bioethics norms are formed. This is a consideration of the formation of the norm and its content. As for the formation of the norm, since the early 1980s, it can be seen that in France there has been a study of the place of the bioethic norm in the hierarchy of positive law. While the legislator's intervention was delayed in 1988 (in particular by the Braibant report), 2008 saw questions about the place of the Constitution in the process. Although the rl61e of the legislator emerged consolidated, at the same time the participation of the citizens by means of the convention is seen to be reinforced. The place of agencies, in particular the bioethics agency created in 2004, also has a great impact on the production of norms. Next, as far as the content is concerned, the debates on biomedical ethics for the last 30 years seem curiously to keep raising the same questions (post-mortem insemination, surrogate motherhood, presumed consent to organ donation...). This recurrence is interesting. Why can't France, or rather the French, manage to answer these questions once and for all? While our neighbours, in particular the United Kingdom and Spain, behave more serenely in this area (eg the giving up of anonymity for donated gametes in the UK), France is perpetually questioning, caught between the need to follow the evolution of our neighbours' norms and maintaining our more conservative position. On this point too the Convention and the life of the biomedicine agency make it possible to take stock of French social values which are growing stronger as the years go by. It is then tempting to draw a parallel with the founding texts of the French republic, and particularly the declaration of human rights in 1789 in order to find the place of man. PMID- 22530320 TI - Precautionary principle and normativity: brief remarks on the complex relationship between law and the risks. AB - The precautionary principle is objet of an intense discussion in different legal orders. It is easy to understand the reason why: the regulation of risks challenges the legal thought. The positivist approach has shown its limits. It is now important to ask ourselves about the way in which we can deal with uncertainty effectively. The task is difficult, but we can point out two different aspects. Firstly, it is important to understand the complexity of the technological risks in a transdisciplinary way. This is an unavoidable step in evaluating the ability of the law to prevent them. Secondly, the precautionary principle presupposes a pluralistic conception of nature in which the economic sphere can be seen as a tool to express the relationship between man and nature. PMID- 22530321 TI - [Why the patent of the life is a discussed economic activity? The European legal development and related penal aspects]. PMID- 22530322 TI - The venality of human body parts and products in French law and common law. AB - The successive bioethics laws in France have constantly argued that the human body is not for sale and consecrated an absolute principle of free and anonymous donations, whether of semen, ova, blood, tissues or organs. Nonetheless, this position is not shared by all countries. These legal divergences upset today our moral principles and the development of these practices leads us to question the legal status of human biological material and its gradual commodification. This paper outlines the current law principles that protect people's interests in their bodies, excised body parts and tissues without conferring the rights of full legal ownership in French law and in Common law. Contrary to what many people believe, people do not legally 'own' their bodies, body parts or tissues. However, they do have some legal rights in relation to their bodies and excised body material. For lawyers, the exact relationship people have with their bodies has raised a host of complex questions and long debates about the status we should grant to human body parts. The significance of this issue is due to two reasons:first, because of the imperative protection we have to assure to human dignity and then, because of the economic value which is attached to human products. PMID- 22530323 TI - What can law do for the development of bio-economy? AB - Bio-technology has become a new impeller to the development of the world economy since the 1970's. The development of bio-economy has two sides for mankind which calls for intervention by law. During the legislation of bioeconomy, some special principles should be esteemed and observed by legislators. It is necessary for the healthy development of bio-economy. PMID- 22530324 TI - New melanoma treatments: a panacea or a Pandora's box? PMID- 22530325 TI - A 79-year-old man presented with a 1.2-cm nodule on the left arm. The best diagnosis is: phaeohyphomycosis. PMID- 22530326 TI - What is your diagnosis? Anal mucosal melanoma. PMID- 22530327 TI - Burkitt lymphoma in a child with atopic dermatitis and a 7-year history of regular topical tacrolimus use. AB - We describe the case of a boy who presented with abdominal Burkitt lymphoma; he had been regularly using tacrolimus ointment 0.1% for severe recurrent atopic dermatitis for 7 years immediately prior to developing cancer. We present his medical history and review the current knowledge regarding a link between topical tacrolimus and malignancy risk. PMID- 22530328 TI - Sweet syndrome associated with hydralazine-induced lupus erythematosus. AB - Sweet syndrome (SS) is a distinctive but poorly understood clinical syndrome, which likely represents an immunologic reaction pattern to a wide range of underlying or preceding conditions, including viral illnesses, inflammatory bowel disease, and malignancies. We report the case of a patient who presented with an acute eruption that was clinically and histologically consistent with SS. The patient also met diagnostic criteria for systemic lupus erythematosus with serositis, stomatitis, positive antinuclear antibody (ANA), and positive anti double-stranded DNA antibodies. Additionally, positive antihistone antibodies and exposure to hydralazine supported the specific diagnosis of drug-induced lupus erythematosus, and we concluded that his SS was a manifestation of hydralazine induced lupus. We also briefly review the precedence for this unusual dual diagnosis in the literature. PMID- 22530329 TI - Metastatic melanoma and melanogenuria. AB - We report a case of a 70-year-old Hawaiian man with an exophytic black nodule on the left suprascapular region of several years' duration. Histopathologic examination of the excised lesion showed a nodular melanoma with 17-mm Breslow thickness. The patient had firm fixed lymph nodes circumferentially around his neck. He underwent palliative cervical lymph node dissection to remove the compressive nodes but declined further therapy. One year later, the patient's skin was noted to have a generalized uniformly gray-brown color. Physical examination showed ulcerated masses on his trunk, right arm, and both axillae. A urine specimen initially was dark yellow but turned black after exposure to air at room temperature and ambient light for several minutes. Black urine, termed melanuria, is a rare finding in patients with disseminated melanoma. In melanogenuria, the urine is yellow and darkens as the colorless melanin precursors oxidize in the presence of air. Detection of these urinary melanin precursors may someday help determine the prognosis of melanoma and monitor response to treatment. PMID- 22530330 TI - Cutaneous angiosarcoma with skin metastases and persistent bloody pleural effusions. AB - Cutaneous angiosarcoma is a rare aggressive malignancy of vascular origin that usually arises in the scalp or face of elderly men. We describe a case of primary cutaneous angiosarcoma with skin metastases and presumed metastases to the lung in a 58-year-old man who presented with persistent bloody pleural effusions, an asymptomatic nontraumatic red patch on the forehead of 2 to 3 months' duration, and a pair of purpuric papules on his left mid back of unknown duration. Cutaneous metastases of angiosarcoma are uncommon. Spontaneous persistent bloody effusions without hemoptysis are distinctly uncommon, and pleural fluid cytology is repeatedly negative in lung or pleural angiosarcoma, making it difficult to diagnose without tissue biopsy. PMID- 22530331 TI - Malignant melanoma in transplant patients: a case report and review of the literature. AB - The clinical course and outcome of malignant melanoma (MM) are well-established for immunocompetent groups; however, they are not well-documented for immunosuppressed populations. Specifically, the influence of immunosuppression may result in poorer outcomes, especially in more advanced cases of melanoma. We report a 67-year-old woman who had previously undergone a kidney and pancreas transplant and presented with American Joint Committee on Cancer (AJCC) stage IIIA melanoma with subsequent rapid demise. As medicine advances with greater numbers of organ transplant recipients, a multi-institutional prospective study for this at-risk population would be greatly beneficial to help characterize the incidence, progression, and prognosis of melanoma in posttransplant immunosuppressed populations. PMID- 22530332 TI - Basal cell carcinoma arising in a bacille Calmette-Guerin vaccination scar. AB - Cases of cutaneous neoplasms occurring on prior sites of trauma and scars are common. Vaccination scars are common sites of this phenomenon. We report a case of superficial basal cell carcinoma (BCC) occurring on a prior bacille Calmette Guerin (BCG) site in a 59-year-old man. Any modification on a prior vaccination scar should prompt a skin biopsy to be performed to rule out a cutaneous malignancy. PMID- 22530333 TI - Eruptive xanthoma: a case report. AB - Eruptive xanthomatosis is a papular skin disorder resulting from hyperlipidemia, specifically hypertriglyceridemia. It is characterized by yellowish red papules concentrated on extensor surfaces of the arms and legs. The hyperlipidemia responsible for this disorder can be caused by a primary genetic defect, a secondary disorder, or both. Eruptive xanthomas often rapidly resolve after treatment of the hyperlipidemia has begun. PMID- 22530334 TI - The appearance of pili annulati following alopecia areata. AB - Pili annulati is a rare autosomal-dominant hair shaft abnormality. It is characterized by alternating light and dark bands along the shaft due to air filled cavities within the cortex of the hair shaft. Alopecia areata has been previously described as a common association with pili annulati, with improvement in alopecia areata coinciding with resolution of pili annulati. We report the case of a patient with a history of alopecia areata and alopecia universalis who developed the characteristic banded hair of pili annulati upon resolution of her alopecia areata. We provide direct microscopic examination of postregrowth hairs compared to normal and cross-polarized light microscopy. PMID- 22530335 TI - Meehan says he understands challenges for LTC sector. PMID- 22530336 TI - Age irrelevant when it comes to heart. PMID- 22530337 TI - Inviting spaces. PMID- 22530338 TI - A look at MDS 3.0 psychosocial changes. PMID- 22530339 TI - A slippery slope? PMID- 22530340 TI - Animals in space: reaching for the stars. PMID- 22530341 TI - Pioneers of Canadian veterinary medicine. PMID- 22530342 TI - The emergence of shelter medicine in veterinary education: from nonexistent to necessary. PMID- 22530343 TI - Genetic variants influencing fluoropyrimidine based-therapy and available methods to detect them. AB - BACKGROUND: Many clinicians acknowledge the importance of genetics in drug response and are favourable about using genetic tests to guide therapy. The 5 Fluorouracil (5-FU) is the backbone of different regimens for the treatment of several solid tumours. Unlikely, some patients develop gastrointestinal and hematologic toxicities when treated by the 5-FU, leading to the suspension of therapy. Current evidences of pharmacogenomics, have reported different polymorphisms associated to genes involved with fluoropyrimidine biotransformation. A multitude of methods has been applied to assess the mutational status of these genes, without defining a golden standard for the daily diagnostic routine, so far. AIMS: Some adverse drug response due to the administration of 5-FU can be predicted through pharmacogenomics testing tools. This report reviews the recent findings on the polymorphism for genes that are involved in the biotransformation of the drug and its association with the toxic effect in patients receiving 5-FU in mono o polychemoterapy. Most common fluoropyrimidines-based regimens are finely described. Also, we will take in considerations the recent methods used to identify these genetic alterations. CONCLUSION: Recent and evolving technological advances for genotyping will result in personalized treatment. In the next future the oncologists will have new means based on the genetic composition of the individual, to make treatment decisions for their patients maximizing benefit and minimizing toxicity. Based on these purpose, clinician and lab manager may join together to evaluate advantages and limitation, in terms of costs and applicability, of the most appropriate methods to set molecular diagnostics of 5-FU pharmacogenomics tests. PMID- 22530344 TI - Grape seed proanthocyanidins extracts promote apolipoprotein A-I mRNA expression in HepG2 cells under experimental sugar and high-sugar conditions. AB - OBJECTIVES: In this study, we investigated the effect of grape seed proanthocyanidins extracts (GSPE), which have been proved to have anti-oxidative and anti-aging functions, on the expression of apoA-L at mRNA level of HepG2 cells in vitro under the experimental conditions of high-sugar and sugar. MATERIALS AND METHODS: Cell viability was measured by sulforhodamine B (SRB). The apoA-I mRNA expression was assayed by real-time fluorescence quantitative polymerase chain reaction. Firstly, HepG2 cells were incubated in 10% inactivated newborn calf serum in Dulbecco's Modified Eagle Medium (DMEM). Next, cells were incubated with high-sugar and sugar serum-free medium, and added different concentration of GSPE (2.5, 5 and 10 microg/ml) for more than 24 hours, and thereafter, investigated whether GSPE can promote more apoA-I expression in HepG2 cells under the experimental conditions of high-sugar and sugar. RESULTS: In this experiment, HepG2 cells were incubated with high-sugar and sugar serum-free medium, and HepG2 cells incubated with high-sugar medium produced less apoA-I at mRNA level. The difference was significant (p < 0.05). When HepG2 cells were incubated with GSPE at concentration of 20 microg/ml or above for about 4 hours, cell viability measured by SRB was lower than 50%. However, cell viability of HepG2 cells incubated with GSPE at concentration of 10 microg/ml or below was higher than 70%. Therefore, we chose the HepG2 cells incubated with GSPE concentration of 2.5, 5, 10 microg/ml to observe the effect of GSPE on the mRNA expression of apoA-I. After incubated with GSPE, the apoA-I expression of HepG2 cells were significantly elevated at mRNA level compared to that of high sugar control (p < 0.05). Moreover, this action of GSPE showed dose dependent, and the dose of 2.5 microg/ml was optimal. CONCLUSIONS: GSPE (concentration of higher than 20 microg/ml) could inhibit HepG2 cell survival, and in HepG2 cells, endogenous apoA-I was significantly suppressed following 24h of exposure to high concentrations of glucose. Meanwhile GSPE could promote expression of apoA-L dose dependently at mRNA level when its concentration was lower than 10 microg/ml. PMID- 22530345 TI - The innovative crisis as a current pharmaceutical research problem: causes, consequences, responses and solutions. AB - The innovative crisis is a consequence of scientific stagnation in pharmaceutical research. As a result of innovative crisis the number of innovative drugs put on the market has decreased. Biopharmaceutical research methods combined with findings in molecular mechanism of diseases will allow the discovery of new innovative diagnostics and drugs. PMID- 22530346 TI - Functional changes cardiovascular: normobaric activity and microgravity in young healthy human subjects. AB - BACKGROUND: The cardiovascular system works to maintain homeostasis through a series of adaptive responses to physiological requirements. Different self regulatory mechanism prevent the effects induced by hydrostatic pressure changes on oncotic pressure caused by postural changes. Gravity exerts a strong influence on the postural changes with implications on the cardiovascular system. In orbit, gravity (+Gz) is responsible of mass redistribution of circulating blood flow. The aim of this study was the evaluation of the adaptive responses of cardiovascular system to postural changes with and without the use of the Lower Body Negative Pressure (LBNP). We considered that pressure changes that occur in human body in orbit can be simulated experimentally with use of Tilt-Test (Clino/ortho; Clino/head-down; head-down/ortho). This investigation could be useful for studying the influence on astronauts of long flights. SUBJECTS AND METHODS: We studied in 12 months, 30 young healthy volunteers (20 males, 10 female) during postural change tests. In the first evaluation they were submitted to tilt-test for 40 minutes, remaining in head-up +60 degrees (this state corresponds to a kind of gravitational stress +Gz) and in head-down to -30 degrees (-Gz) for 20 minutes. During the second assessment (after 5 +/- 1 days) all volunteers wear a device that simulate a state of LBNP at -20 mmHg. Afterwards, they were processed to 20 minutes in Head Down -8 degrees and after 2 hours of rest to 20 minutes at -15 degrees. Volunteers were monitored measuring blood pressure, heart rate and by Transthoracic Echocardiogram (TTE). RESULTS: Collected data were elaborated by a statistical analysis. We observed during orthostatic position for 40 min (+60 degrees) without LBNP, lower diameters and volumes of left and right ventricular (p < 0.05) and an increase in heart rate in comparison with the baseline conditions in clinostatism. Despite the reduction of preload volume, the mean value of cardiac output does not vary significantly. In Trendelemburg (-15 degrees) data show a non-significant variation (p > 0.05) of left and right ventricular diameters and volumes, while cardiac output and systolic blood pressure varies significantly (p < 0.05) compared to clinostatic and orthostatic position. With LBNP in head down to -8 degrees and -15 degrees, systolic and diastolic arterial pressure, ventricular volumes and cardiac output were unchanged if compared to values obtained in clinostatism with and without LBNP. If compared to -30 degrees in Trendelemburg without LBNP, data reached statistical significance (p < 0.05). CONCLUSIONS: The cardiovascular system and the autonomic nervous system, respond to postural changes and to volemia alterations, maintaining the physiological cardiac output, in order to preserve the metabolic requirements of body. PMID- 22530348 TI - An unreported complication of intravenously administered ibuprofen: gastrointestinal bleeding. AB - Ibuprofen is used for the closure of ductus arteriosus either intravenously or enterally. Although intraventricular hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia, transient renal failure, oliguria, hyponatremia and thrombocytopenia are reported complications during or after ibuprofen treatment, gastrointestinal bleeding, to our knowledge, has not been reported previously. We herein report a premature newborn, in whom ibuprofen was used intravenously for the closure of ductus arteriosus and gastrointestinal bleeding developed as a complication, and aim to discuss this rare adverse effect. In conclusion, we emphasize the importance of close follow-up of premature newborns during intravenous ibuprofen treatment considering also the other rare systemic side effects reported in the literature. PMID- 22530347 TI - Evaluation of echocardiographic indices for the prediction of major adverse events during long-term follow-up in chronic hemodialysis patients with normal left ventricular ejection fraction. AB - BACKGROUND: Cardiovascular disease is the leading cause of mortality in endstage renal failure. Prognostic role of echocardiography has not been fully elucidated in chronic hemodialysis patients. AIM: To assess the ability of Doppler echocardiographic parameters of left ventricular (LV) diastolic function along with conventional echocardiographic indices to predict long-term adverse major events in chronic hemodialysis patients with normal LV ejection fraction (EF). PATIENTS AND METHODS: A total of 45 chronic hemodialysis patients (aged 49 +/- 15 years) were included to the study. All patients underwent complete standard and tissue Doppler imaging echocardiography before and immediately after hemodialysis session and were followed-up prospectively. Major outcome measure was the combination of all-cause death and hospitalization for any cardiovascular event. RESULTS: During the follow up period (52 +/- 26 months) 23 major events occured (17 all-cause deaths and 6 cardiovascular events requring hospitalization). Post dialytic values of mean left atrial diameter, mitral E (peak early mitral inflow velocity), E/Vp [ratio of mitral E to flow propagation velocity (Vp)] and E/Ea [ratio of mitral E to peak early diastolic mitral annular velocity (Ea)] (average of 4 segments of mitral annulus) were significantly higher in patients who had major events. In Cox proportional hazard analysis only E/Ea ratio predicted combined endpoint of all-cause mortality and nonfatal cardiovascular events (hazard ratio: 1.20; confidence interval: 1.03-1.39; p = 0.018). The optimum cut off value for E/Ea determined by ROC curve analysis revealed that E/Ea ratio higher than 9.8 predicted future events with sensitivity of 74% and specificity of 86%. CONCLUSIONS: E/Ea might be an accurate echocardiographic indice during long-term follow up for the prediction of major adverse events in chronic hemodialysis patients with normal LV EF. PMID- 22530349 TI - Statins improve myocardial perfusion in metabolic syndrome patients who have perfusion defects on myocardial perfusion imaging and angiographically normal coronary arteries. AB - OBJECTIVE: Previous studies in hypercholesterolemic patients with coronary artery disease (CAD) have demonstrated that lipid lowering therapy restores coronary endothelium dependent vasodilatation and increases myocardial perfusion. However, there is not enough data showing the effects of statins on myocardial perfusion in metabolic syndrome (MetS) patients who have perfusion abnormalities but not evident CAD, which are attributed to microvascular dysfunction. We aimed to evaluate whether or not statin therapy improves myocardial perfusion, as assessed by Technetium (Tc)-99m single-photon emission computed tomography (SPECT), in patients with MetS and angiographically normal epicardial coronary anatomy. MATERIALS AND METHODS: The study population consisted of 55 selected patients (mean age: 52, 72% female) with MetS who have perfusion defect on exercise stress Tc-99m SPECT and normal coronary arteries. Patients were treated with 20 mg atorvastatin for six months regardless of baseline lipid levels and SPECT study was repeated after the therapy. The summed stress score (SSS), summed rest score (SRS) and summed difference score (SDS), and left ventricular (LV) volumes and ejection fractions (EF) at rest and stress were obtained. RESULTS: We found significant improvements in SSS, SRS and SDS after six months of statin therapy (p = 0.001, 0.001 and 0.002, respectively). In addition, end-diastolic volumes at rest and stress, and stroke volume at rest were significantly decreased (p = 0.001, 0.001 and 0.026, respectively). Also, LV EF at stress was significantly increased (p = 0.035). CONCLUSIONS: Statin therapy in patients with MetS who have perfusion defects on Tc-99m SPECT and normal coronary arteries produces significant improvements in myocardial perfusion abnormalities. PMID- 22530350 TI - Lys656Asn polymorphism of leptin receptor, leptin levels and insulin resistance in patients with non alcoholic fatty liver disease. AB - BACKGROUND: Some studies have pointed to a role of leptin and insulin resistance in pathogenesis of non alcoholic fatty liver disease (NAFLD). The aim of our study was to investigate the influence of Lys656Asn polymorphism LEPR gene on the histological changes, insulin resistance and leptin levels in overweight patients. MATERIAL AND METHODS: A population of 76 patients with NAFLD was recruited in a cross sectional study. A biochemical analysis of serum was measured. Genotype of LEPR gene Lys656Asn was studied. RESULTS: Nineteen patients (25%) had the genotype Lys656Asn and 4 patients genotype Asn656Asn (mutant type group) and 53 patients (69.7%) Lys656Lys (wild type group). Body mass index, weight, fat mass, waist circumference, waist to hip ratio, glucose levels and HOMA-IR were higher in mutant than wild type group. LEPR polymorphism is in any way related with liver lesions. The multivariate analysis adjusted by age, sex, BMI and genotype showed an independently association of lobular inflammation 4.19 (CI95%: 1.37-12.77), portal inflammation 1.97 (CI95%: 1.05-3.74) and steatosis 9.23 (CI95%: 1.47-57.83) with HOMA. Liver steatosis was associated with leptin levels (1.09 (CI95%: 1.06-1.18)), too. CONCLUSION: Lys656Asn polymorphism of LEPR gene is associated with obesity parameters, insulin resistance and glucose levels in patients with NAFLD. In logistic regression analysis, only insulin resistance was associated with portal inflammation), lobular inflammation and steatosis; liver steatosis was related with leptin levels, too. PMID- 22530352 TI - Correlation between oxidative stress and antioxidant defence in South Indian urban vegetarians and non-vegetarians. AB - BACKGROUND AND OBJECTIVES: The diet is a key environmental factor implicated in health and disease. Oxidative stress, antioxidant status and their relation to diet is a subject of interest in recent years. The objective of the study was to compare lipid peroxidation and antioxidant status in healthy vegetarians and non vegetarians. METHODS: The present study comprises 100 healthy individuals (50 vegetarians and 50 non-vegetarians) residing in Belgaum urban area. All the participants were in the age group of 40-60 years of both sexes. This cross sectional study was done in one year period from April 2007 to March 2008. Malondialdehyde (MDA) (lipid peroxidation product) was estimated by thiobarbituric acid method, glutathione peroxidase by Beutler's method, Vitamin A and Vitamin E by Bessay et al and Quife et al methods respectively. RESULTS: Our study revealed that the blood MDA level was significantly increased (p value < 0.001) in non-vegetarians compared to lactovegetarians and lacto-ovo-vegetarians. There was significant decrease in the level of enzymatic antioxidant glutathione peroxidase and non-enzymatic antioxidants Vitamin A and Vitamin E in non vegetarians compared to lactovegetarians and lacto-ovo-vegetarians (p value < 0.001). CONCLUSIONS: Results of this investigation present study indicate that there was an increased lipid peroxidation and a low antioxidant status in non vegetarians compared to vegetarians. Vegetarian nutrition provides adequate antioxidants which effectively prevent free radicals generation. PMID- 22530351 TI - The effect of oral L-arginine supplementation on fasting glucose, HbA1c, nitric oxide and total antioxidant status in diabetic patients with atherosclerotic peripheral arterial disease of lower extremities. AB - INTRODUCTION: Numerous studies indicate hyperglycemia and oxidative stress as factors responsible for endothelium dysfunction and the following development of angiopathy. Increased production of free radicals by vascular endothelium causes disturbance in production and/or decreases bioaccessibility of nitric oxide (NO). It has been suggested that L-arginine supplementation is a reasonable method to increase endothelium NO production and lower free radicals formation. There is a growing number of evidence showing that dietary supplementation of arginine reverses endothelial dysfunction associated with major cardiovascular risk factors and ameliorates many common cardiovascular disorders. OBJECTIVE: The aim of the study was to evaluate the potential influence of two-months oral L arginine supplementation on fasting glucose, HbA1c, nitric oxide and total antioxidant status (TAS). MATERIALS AND METHODS: 38 patients with atherosclerotic peripheral arterial disease of lower extremities at Fontaine's stage II and coexisting type 2 diabetes and 12 healthy volunteers as control group were studied. All patients were treated with oral L-arginine (3 x 2 g/day) for two months. Fasting glucose, HbAlc, nitric oxide and total antioxidant status (TAS) were measured before and after the study. RESULTS: Fasting glucose and HbAlc did not change significantly after L-arginine treatment. Statistically significant increase in NO concentration and TAS level was found. CONCLUSIONS: Oral two-month supplementation with L-arginine (3 x 2 g/day) had no effect on fasting glucose and HbA1 level in diabetic patients with atherosclerotic peripheral arterial disease of lower extremities at Fontaine's stage II. The supplementation of L arginine led to substantial increase in NO concentration and TAS level in these patients, suggesting its indirect antioxidative effect. PMID- 22530353 TI - Acute carotid stent thrombosis after carotid artery stenting. AB - BACKGROUND: Carotid artery stenting (CAS) is a reasonable alternative to carotid endarterectomy (CEA), especially in patients at high risk for surgery. Carotid artery thrombosis of the treated segment is a rare, early but potentially devastating complication of this endovascular procedure. The aim of this article is to identify and critically review cases of acute stent thrombosis reported in the literature. MATERIALS AND METHODS: Previous trials that compared CEA with CAS were rather heterogeneous and not large enough to allow reliable conclusions. Furthermore, because there is limited follow-up information to date, the long term effect of CAS remains unclear. Acute carotid thrombosis after angioplasty and stenting is a very rare but potentially fatal complication, and there are very few reports in the literature. This article reviews twelve cases of acute carotid thrombosis published in the English literature from eight different Vascular and Radiology Departments around the world. RESULTS: The different ways of immediate treatment of this rare complication of acute carotid thrombosis after CAS are, open surgical procedure with thrombus removal and thromboendarterectomy with or without removing of the stent, selective local or facilitated thrombolysis with the rescue use of GPIs (glycoprotein IIb/IIIa receptor inhibitors), recanalization by instent percutaneous transluminal angioplasty with distal protection and additional stent placement on the stented portion of the internal carotid artery (ICA) in conjunction with the intravenous administration of recombinant tissue plasminogen activator (rtPA: 1300,000 IU). CONCLUSION: Carotid artery stenting has to be performed under specific pro- and post procedure protocol from experienced endovascular specialists. The treatment of acute carotid thrombosis after CAS must be urgent and immediate in order to regain restoration of blood flow and avoid major neurological adverse events. PMID- 22530354 TI - May etanercept and PTH (1-34) association heal erosions in early rheumatoid arthritis? A pilot study. AB - INTRODUCTION: Rheumatoid arthritis (RA) is characterized by the formation in the joints of an inflammatory tissue, which causes the appearance of localized erosions on the margins of the joints. The molecular mechanism that causes the bone erosion is multifactorial. Inflammatory cytokines imbalance and OPG-RANK-L system are involved. OBJECTIVE OF THE STUDY: The aim of the study is to evaluate the possibility of inducing healing or reduction in the number of erosions in Rheumatoid Arthritis patients treated with anti-TNF-alpha adding Teriparatide (PTH1-34) to standard treatment with anti-TNF. PATIENTS AND METHODS: Twenty adult patients with active RA diagnosed according to American Rheumatism Association (ARA) criteria at least 6 months before study begin were enrolled. Only patients affected by established RA (6 to 18 months from symptoms beginning) were recruited. Eligible patients were randomized to receive a standard dosage of etanercept (50 mg/week) or etanercept at same dosage with an addition of teriparatide (20 mg). Evaluation of eventual healing of arthritic erosions by magnetic resonance imaging was performed at time zero and then at twelve months. The following evaluation was assessed at baseline and after 12 months according to the Outcome Measures in Rheumatology Clinical Trials (OMERACT) definitions: number of erosion and presence or absence of synovitis, effusion and bone oedema. A comparative examination of quantitative and qualitative assessment of each parameter was applied. Plain radiographs of the hands were obtained at baseline and 52 weeks. Radiographs were scored blindly using the van der Heijde modification of the Sharp method. Safety of each treatment was evaluated by means of the adverse events (AES) evaluation and report. RESULTS: There were no significant differences in baseline characteristics between the groups. The study did not achieve its primary endpoint of healing erosions. In the active arm no healing of erosions was found. At 52 weeks, there were no new MRI erosions in two arms. Bone oedema scores were significantly improved at 52 weeks in favour of both treatments versus baseline scores, without inter-groups differences. X-ray patterns were unchanged in all patients of both groups. No new erosions or previous erosions' healing were observed. No AEs were reported. Patients from both groups demonstrated a significant reduction in the DAS 28 scores at 52 weeks (p < 0.005) if compared with baseline values. CONCLUSIONS: These data confirm rapid control of inflammation and MRI damage benefits after Etanercept administration without a significant improvement in MRI findings after concomitant addition of teriparatide. Even though these results could seem to suggest to avoid the simultaneous use of these two drugs to treat RA erosions, further studies might be suggested to asses if sequential adminstration of an anabolic agent such as Teriparatide, after achieving clinical remission, may be able to improve bone damage. PMID- 22530355 TI - Pancreatic injury during AAA repair: a comparison between EVAR and open repair. AB - OBJECTIVES: Enzymatic pancreatic injury (EPI) in abdominal aortic aneurysm (AAA) treatment has been scarcely studied in the literature. Aim of this work was to compare perioperative EPI in AAA patients treated by endovascular repair (EVAR) or open repair (OR). METHODS: Forty AAA patients consecutively treated with either EVAR (GI, 20 pts) or OR (GII, 20 pts) were prospectively evaluated in terms of epidemiology, comorbidities and technical details. Serum levels of amylase, lipase and pancreatic isoamylase were assessed before treatment (T0), before aortic clamping/endograft deployment (T1), 1, 2, and 6 hours after aortic declamping/endograft deployment (T2, T3, T4) and 24, 48, and 72 hours after the procedure (T5, T6, T7). GI and GII were compared by Mann Whitney test with significance set at p < 0.05. RESULTS: GI patients were significantly older and with higher frequency of preoperative renal insufficiency than GII ones (p = 0.001 and 0.047 respectively). Other characteristics were not significantly different. Pancreatic enzymes values at T0 were within normal parameters in all patients. Total serum amylase was significantly greater at T4 (p = 0.003), T5 (p = 0.010), T6 (p = 0.003), T7 (p = 0.011) and isoamylase at T3 (p = 0.052), T4 (p = 0.037), T5 (p = 0.016) and T6 (p = 0.014) in GII compared with GI. Amylase and isoamylase peak occurred 24 hours after the procedure. Lipase was significantly different in the two groups only in T4 (p = 0.028). No acute pancreatitis occurred in the whole study group. CONCLUSIONS: EVAR significantly reduces EPI compared with OR in the AAA treatment. PMID- 22530356 TI - Folate in gastrointestinal health and disease. AB - OBJECTIVE: Folate has heterogeneous functions and is involved in several activities in both animal and human body. It is an important constituent of our organism, and its bioavailability is mainly dependent from the correct function of our gastrointestinal tract. Our aim is to describe what happens to folate homeostasis in gastrointestinal health and disease, analyzing the alterations of folate metabolism in some specific conditions of intestinal and liver impairment. DISCUSSION: Folate absorption and metabolization involve the small intestine and the liver; in conditions of gastrointestinal tract disease (i.e. celiac disease, liver disease) folate function may be compromised with important consequences on the whole organism. Moreover, folate deficiency may produce gastrointestinal alterations too. For this reason, the gastrointestinal tract could be the responsible but also the victim of folate deficiency. CONCLUSIONS: The presence of folate deficiency should always be assessed in patients with a gastrointestinal disease. Further studies are needed to assess the role of folates in gastrointestinal tract diseases and in other gynecologic, neurologic, psychiatric, cardiovascular, ophthalmic and neoplastic diseases. Folates supplementation could be considered, in the future, as an effective complimentary therapy in several pathologic conditions. PMID- 22530357 TI - Larvicidal efficacy of botanical extracts against two important vector mosquitoes. AB - OBJECTIVE: To determine the larvicidal efficacy of different solvent leaf extract of Ervatamia coronaria and Caesalpinia pulcherrima against Anopheles subpictus and Culex tritaeniorhynchus. MATERIALS AND METHODS: Twenty five early third instar larvae of Anopheles subpictus and Culex tritaeniorhynchus were exposed to various concentrations and were assayed in the laboratory. The larval mortality was observed after 24 h of treatment. RESULTS: Among three solvent extracts tested the maximum efficacy was observed in the methanol extract. The LC50 (LC90) values of Ervatamia coronaria and Caesalpinia pulcherrima against early third instar of Anopheles subpictus were 86.47 (159.59) and 113.26 (207.73) ppm and Culex tritaeniorhynchus were 131.53 (245.37) and 165.28 (299.45) ppm, respectively. No mortality was observed in controls. CONCLUSIONS: From the results it can be concluded the crude extract of Ervatamia coronaria and Caesalpinia pulcherrima were excellent potential for controlling Anopheles subpictus and Culex tritaeniorhynchus mosquito larvae. PMID- 22530358 TI - Thirtyfour years of liposuction: past, present and future. AB - Initial, variably successful attempts of fat sculpting date back to the beginning of the 20th Century, but Gerard Illouz was the first to introduce the modern, safe, widespread method of liposuction. Preoperative injection of local anaesthesia, saline, distilled water, adrenaline and hyaluronidase, defined wet technique, established as a safe and effective adjunct to lipoaspiration. This procedure was initially based on an automatic pump system, but then the accuracy of syringe aspiration was popularized by Toledo in the eighties. Liposuction in the subcutaneous tissue, just 3-4 mm deep to dermis, also called superficial liposuction, is a modern effective evolution of the technique, but requires a good mastery in order to avoid disfiguring outcomes. Ultrasound and laser lipoplasty methods have provided further advancement in the range of technical choices offered to the plastic surgeon. Liposuction is a purely surgical procedure, and as such, carries risks of minor and major complications. In the nineties, an interplay between abdominoplasty and abdominal liposuction as simultaneous procedures, also called lipoabdominoplasty, has become more and more popular. Reinjection of the harvested fat with the purpose of liposculpture for both reconstructive and cosmetic indications is a relatively recent development which has established as a successful, world-wide accepted procedure. Adipose stem cells, extracted from the unlimited source represented by human adipose tissue, are a great promise for future tissue-engineering. Liposuction has nowadays become a safe, effective, popular procedure for contouring adipose tissue and human body in general, in many reconstructive and cosmetic indications. PMID- 22530359 TI - Treatment of facial vascular malformations with embolisation and surgical resection. AB - INTRODUCTION: Facial arteriovenous malformations (AVMs) are quite rare morbid conditions that clinically present themselves mainly as a massive bleeding or a significant aesthetic defect. Vascular malformations do not regress spontaneously; this is the reason why their resection is necessary. The successful treatment of these vascular anomalies is often compromised, since a high incidence of recurrence could be expected if the lesion is not managed properly. A multidisciplinary approach is needed for the assessment and treatment of these lesions. The therapeutic management involves a preoperative superselective embolisation, a surgical resection of the lesion within the following 24 hours and finally an aesthetic reconstruction. PATIENTS AND METHODS: The study was carried out on a total of 62 patients with facial AVMs; all the patients underwent surgical procedures from 2000 to 2010. RESULTS: The case series consisted of 8 patients with haemangiomas and 54 patients with AVMs; in 31 cases of the latter group the vascular malformations showed a low blood flow, whereas the remaining 23 cases had a high blood flow. The lips were the most common localization. All 54 patients with AVMs underwent a surgical resection. Among the 23 patients with facial high-blood flow AVM, 21.7% were classified as stage I Schobinger, 47.9% as stage II, and 30.4% as stage III. The treatment consisting of associated embolisation and resection was performed in 14 arteriovenous malformations (stage II, III) with high blood flow; 5 of them required a flap reconstruction. CONCLUSION: Recent advances in microsurgery and interventional angioradiology have improved the prognosis of treatment for these malformations. Combining embolisation and resection with aesthetic flap reconstruction represents the therapy of choice for facial arteriovenous malformations, as it prevents their recurrence. PMID- 22530360 TI - Upper eyelid necrosis and reconstruction after spider byte: case report and review of the literature. AB - Spider bites are not very common, especially in the Mediterranean area, and those affecting the ocular-palpebral region involving reconstructive surgery are particularly rare. In May 2010, the case of a Caucasian 24-year-old female patient was brought to the attention of the Dermatology Department, University of Cagliari, Italy. The patient reported she woke up feeling an intense pain with itching and that also she had noticed a spider of an unknown species on her bed. The dermatosis had affected the right orbital region, where there was a considerable red and violet erythema and a hard edema, not foldable. When the necrosis appeared the patient was treated at the Plastic Surgery Unit where she underwent a reconstruction of the eyelid with a full thickness skin graft from the retroauricular area. The post-operative course was regular with a perfect in take of the skin graft. When the patient was discharged she was sent to an Entomological University Centre to identify the spider species and the possible venom which caused the skin lesion. The spider which caused the injury has been a Loxosceles rufescens (Dufour, 1820). Loxoscelism is a necrotic arachnoidism caused by the poisonous bite of spiders belonging to the Loxosceles species. It is very important to identify what sort of lesion it is and to treat it in a combined way in order to choose the proper timing for surgery to avoid damages to the eyelid functioning. PMID- 22530361 TI - An alternative micrographic method for decreasing bleeding and recurrence in the treatment of rhinophyma. AB - Rhinophyma is a subtype of rosacea which develops at the advanced stage of rosacea and is characterized by an excessive enlargement of the sebaceous glands. Its etiology is not well-defined beyond the following usual suspects: vitamin deficiencies, stress, hormonal factors and the Demodex folliculorum mite. Carcinoma may develop in rhinophyma patients. The first surgical process for rhinophyma was applied by Daniel Sennert in 1629. The ideal surgical method for treatment of rhinophyma is still unclear and controversial. Massive bleeding makes a controlled excision of the mass impossible, which contributes to the recurrence of rhinophyma. In this case, we combined trichloroacetic acid (TCA 45%) with dermabrasion, a treatment which hasn't been reported previously. Our method was suggested by the Mohs micrographic surgery technique, which employs serial excisions. PMID- 22530362 TI - Endoscopic palliative treatement of a post-radiation tracheoesophageal fistula. AB - Malignant Tracheoesophageal Fistula (TEF) is a life-threatening condition and conventional palliative surgical approach sometimes could be very dangerous or not suitable. We describe a case of a post-radiation TEF involving distal trachea and main carina treated by the placement of endotracheal silicon stent. PMID- 22530363 TI - [Health insurance reimbursement of dental care in Hungary]. AB - The aim of this study was to assess the annual health insurance reimbursement of dental health service in Hungary. The assessment base of the study was the annual reports of National Health Insurance Fund Administration (OEP). Only the data collected from the services in contractual relationship with the OEP and delivered in 2008 were evaluated. Dental care services are organised in different levels: general dental service, specialist dental care, special dental care on university level and inpatient departments. Our study covers primary, outpatient and hospital dental care. Dental care was supplied by 3.378 general and specialist dental care services at the end of 2008. For the hospital treatment of more serious cases 17 inpatient departments are available with 154 patient beds. Within the period of examination (2008) 23.6 million interventions were carried out in 7.6 million cases. The total health insurance reimbursement of dental care (including primary, outpatient and hospital care) was 24.92 billion HUF (88.82 million Euro) in 2008. The health insurance reimbursement of dental care in Hungary is approximately 2% of the total health insurance expenditures of the National Health Insurance Fund Administration (OEP). Within the period under investigation, the health insurance reimbursement of dental care did not change significantly. PMID- 22530364 TI - [Histological investigations in ambulatory oral surgery practice]. AB - In the practice of oral surgery correspondence with the pathologist is required in order to identify the lesions in question by histologic examination. By current legal regulations the histological evaluation of removed tissues is mandatory. In the presentation the authors process the data obtained in their Department since 2008. Coincidence of the clinical and histological diagnosis is analysed statistically such is the occurrence of various types of oral mucosa lesions and cysts. In cases of presumed malignancy the biopsies were carried out in a department with adequate oncological background. In indications of autoimmun deseases mainly in cases of Sjogren's syndrome the Department has been requested to carry out minor salivary gland biopsies. Statistical analysis of the findings of the minor salivary gland biopsies will also be discussed. The histological diagnoses have been provided by Prof. Zsuzsanna Suba MD, DMD, PhD of the Semmelweis University, Department of Oral and Maxillofacial Surgery, Oral Pathology Unit. In order of prevalence the most common histologically verified lesions were: radicular cyst, fibromas and granulation tissue. In 84.5% of the cases the histological findings confirmed the clinical diagnoses. In 44,5% of the cases Sjogren's syndrome was verified by the minor salivary gland biopsy. Although in most cases the histological examination supported the clinical diagnoses, close cooperation of the oral surgeon and pathologist is essential. PMID- 22530365 TI - [The role of occlusion and extraction in orthodontics. Historical overview]. AB - Occlusion is important in each unit of dentistry. The authors describe not only the meaning of normal occlusion and dysgnathy but also the historical background focusing on the most important orthodontists, their achievements and literary works. This article gives an overview of the development of orthodontics from the very beginning (ancient times) to nowadays. The most important figures of these periods are: P. Fauchard, F. C. Kneisel, E. H. Angle, C. Case (dark ages); C. F. Ballard, P. R. Begg, C. H. Tweed (golden ages); L. F. Andrews and R. H. Roth (contemporary period). Along these three eras development and changing of the extraction-principles are shown. Nowadays the orthodontists still use Angle's classification and orthodontic treatment with extraction is also accepted. However it is not a separate treatment method, but only used as complement treatment. The authors stress on the importance of normal occlusion, which should be result of every orthodontic, but also prothetic and gnathological treatment. PMID- 22530366 TI - [Dental fear and anxiety scores of a Hungarian population living in the Hungarian Slovakian border region. A pilot study]. AB - The aim of the authors was to investigate whether living as a minority has an influence on the dental fear and anxiety values. In this study 201 volunteers (n = 201, inside border Hungarians 144, outside border Hungarians 57, male 90, female 111; age 8 to 83 years, mean 44 +/- 16 yrs.) were investigated. Our methods included collection of demographic data (gender, age, marital status, profession), and administration of the Hungarian versions of dental fear and anxiety related scales namely: DAS, DAQ, DASQ, DFS, DBS, STAI-S, STAI-T and Expectation Scale. Mean values of the scales were: DAS: 10,34 +/- 3,54; DAQ: 2,3 +/- 1,15; DASQ: 12,58 +/- 4,55; DFS: 40,37 +/- 15,67; DBS: 32,89 +/- 12,94; Expectation Scale: 2,87 +/- 3,56, STAI-S: 39,51 +/- 10,68; STAI-T 41,65 +/- 9,08. The mean scores of all the scales were higher in the case of Hungarians living inside the borders of Hungary. The differences were significant in the case of DAS, DAQ, DASQ and DFS scales (p < 0,05). Data of our study indicate that living as a minority not necessarily leads to the increase of dental fear and anxiety. PMID- 22530367 TI - [Examination of periodontal status after removal of impacted lower wisdom teeth, a comparative analysis of two flap design]. AB - AIM OF THE STUDY: Before removing impacted lower wisdom teeth, a mucoperiosteal flap is prepared. In the practice we use 2 types of flaps: with or without a releasing incision. There are few publications about how the removal of impacted wisdom teeth damage the periodontium of the second molars. In our study, we examined whether there is any difference in the healing between the two flap designs. MATERIALS AND METHODS: A total of 76 lower wisdom teeth have been removed. Two types of flaps were used. Prior surgery, at suture removal, 3 and 6 months after surgery 6 periodontal depth points were investigated around the second molars. We compared the technical events during surgery, complaints, probing depths after surgery and their correlance in function of flap design. RESULTS: After removal of lower impacted wisdom teeth, we measured greater probing depths using envelope flap than L-shaped flap. However, this difference was not significant, and after 6 months, no differences were noted. PMID- 22530368 TI - [The characteristics of oral lichen planus]. AB - Lichen is a chronic, mucocutan disease with unknown origin. Oral lesions are usually bilateral, the most frequent location of the reticular form is the posterior part of the buccal mucosa. It undergo only rarely spontaneous remission, and it has a potential to turn into malignant tumor. It is hypothesized that due to an antigen-specific mechanism, auto-cytotoxic T-cells infiltrates the affected region. T-lymphocytes induces apoptosis in the keratinocytes of the basal epithelium. Since etiology is unknown, there is no cure for lichen. The symptomatic treatment has been focused on reducing the subjective discomfort and to maintain or improve the quality of life. The main course of therapy are topical retinoids, locally given steroids, but immunosuppressive therapies have been also tried. Data about exact etiology, diagnostical criteria and effective treatment are still limited. Therefore, besides the early detection of the disease, symptomatic treatment, and the close observation of dysplastic lesions is recommended. PMID- 22530370 TI - The peculiarities of the Scots? Scottish influences on the development of English psychiatry, 1700-1980. AB - This paper examines the multiple influences Scottish psychiatrists have exercised over the shape of English responses to mental illness during nearly three centuries, beginning with George Cheyne and ending with R.D. Laing. Scotland's distinctive response to mental illness was largely ignored until recently, as though it had simply followed the English path. The neglect has begun to be rectified, but the powerful influence of the Scots on developments south of the border requires more sustained attention than it has received hitherto. PMID- 22530369 TI - Alexandre Brierre de Boismont and the origins of the Spanish psychiatric profession. AB - This article examines the influence of the French alienist Alexandre Brierre de Boismont in the first development of the Spanish psychiatric profession during the third quarter of the 19th century. As an outstanding figure of French psychological medicine, Brierre enjoyed great scientific prestige among Spanish doctors, but he also took an active part in promoting and legitimizing the cause of alienism in Spain. For instance, he was involved in projects for the reform or creation of new mental hospitals, supported the admission of some Spanish colleagues into the Societe Medico-Psychologique and made a decisive contribution to the social recognition of the professional and medico-legal expertise of alienists in Spain. His case is thus an excellent example of the important role played by international relations and the scientific and professional networks of European alienism in spreading the discourses and practices of the emerging psychological medicine. PMID- 22530371 TI - Institutionalization of mentally-impaired children in Scotland, c. 1855-1914. AB - This article examines two institutions which were established in Scotland specifically for the accommodation of mentally-impaired children: Baldovan Asylum near Dundee and the 'Scottish National Institution for the Education of Imbecile Children' in Larbert, Stirlingshire. It surveys the aims and agendas of the institutions in the spheres of residential childcare, mental health, and education and training. It compares the admission regimes of these institutions and considers whether they complemented one another in serving an unsatisfied demand for places, or whether they were in competition for admissions, staff and charitable support. The survey covers the period from the opening of both institutions to the implementation of the Mental Deficiency Act of 1913 which required the (re)certification of all children. PMID- 22530372 TI - 'Him bid sona sel': psychiatry in the Anglo-Saxon Leechbooks. AB - Classical Greek and Roman writers documented the diagnosis and treatment of psychiatric illness in ancient times. Following the fall of the Western Roman Empire however, we find little writing on the topic in early Medieval Europe. Yet in Britain, medical texts survived and were complemented by local traditions and treatments. This article explores the best-known Anglo-Saxon medical texts, the Leechbooks and Lacnunga, for evidence of psychiatric illness and the treatments employed by physicians in the tenth century. The difficulties encountered when working with sources translated from Old English and speculations about the supernatural aetiology ascribed to these illnesses are detailed. The efficacy of the leechdoms (treatments) described are also investigated for both their placebo and potential pharmacological effects. PMID- 22530373 TI - Women and melancholy in nineteenth-century German psychiatry. AB - This study examines depictions of the relationship between women and melancholia in German psychiatric textbooks published between 1803 and 1913. Focusing in particular on how these texts present the female life cycle, nineteenth-century views about female 'nature' and gender traits, and women's familial and professional roles, it reveals how nineteenth-century psychiatrists were caught between the scientific demand for objective clinical observation and the gender norms of the culture to which they belonged. On the one hand, psychiatrists carefully and sensitively describe female melancholia with evidence obtained through the scientific methods of clinical observation, anatomical investigation and self-questioning. On the other hand, language choice contributes to the naturalization of gender difference by assigning cultural meaning to clinical observations. PMID- 22530374 TI - The fight for 'traumatic neurosis', 1889-1916: Hermann Oppenheim and his opponents in Berlin. AB - The concept of traumatic neurosis conceived by Hermann Oppenheim (1858-1919) located post-traumatic nervous symptoms between hysteria and neurasthenia, considering them a consequence of physical reactions to fright and a cause of molecular tissue changes. As early as 1890, his concept was criticized at an international congress in Berlin. In February 1916, there was a significant debate of the issue in Berlin, and eventually Oppenheim's concept was completely defeated at the war meeting of German neuropsychiatrists in September 1916 in Munich. In the Berlin debate, a range of views on war neurosis was presented. Partly as a result of this, but also due to the powerful position of Oppenheim himself, it was not until after the end of WWI that traumatic neurosis was excluded from medico-legal assessments. The differing views of physiological brain-mind relations from that time do not differ greatly from present concepts. However, Oppenheim's traumatic neurosis with its more quasi-neurological picture should not be equated with PTSD. PMID- 22530375 TI - Aaron T. Beck's drawings and the psychoanalytic origin story of cognitive therapy. AB - In this essay the author challenges the standard origin story of cognitive therapy, namely, that its founder Aaron T. Beck broke with psychoanalysis to pursue a more pragmatic, parsimonious, and experimentalist cognitive model. It is true that Beck broke with psychoanalysis in large measure as a result of his experimental disconfirmation of key psychoanalytic ideas. His new school of cognitive therapy brought the experimental ethos into every corner of psychological life, extending outward into the largest multisite randomized controlled studies of psychotherapy ever attempted and inward into the deepest recesses of our private worlds. But newly discovered hand-sketched drawings from 1964 of the schema, a conceptual centerpiece of cognitive therapy, as well as unpublished personal correspondence show that Beck continued to think psychoanalytically even after he broke with psychoanalysis. The drawings urge us to consider an origin story much more complex than the one of inherited tradition. This new, multifaceted origin story of cognitive therapy reaches beyond sectarian disagreements and speaks to a broader understanding of the theoretical underpinnings of cognitive therapy. PMID- 22530376 TI - The Roosevelt years: crucial milieu for Carl Rogers' innovation. AB - This study explores broad features of political culture and event of the 1930s and World War 2 years, viewed in relation to the emergence and rapid early growth of the new therapy of Carl Rogers. The paper traces Rogers' early professional life and examines distinctive emphases in sociopolitical thought and development during Franklin D. Roosevelt's leadership as President over the prolonged emergency of the Great Depression and the crisis of the War. The study includes a focus on the President's own outlook and style, pertinent New Deal innovations, and wartime needs. Twelve features of this larger context are discriminated as together having vital importance for the new therapy and its founder. The congruent courses of the macrocontext and of Rogers' innovation are followed to the ending of Roosevelt's life. Direct causation is not attributed, but the evidence adduced newly points to particular contours of a larger environment favorable for the expression of Rogers' values and rare ability. In sum, the author concludes that a synergy of highly conducive historical circumstance and individual exceptionality contributed to the philosophical underpinnings, attitudinal values and early momentum of Rogers' client-centered therapy. PMID- 22530377 TI - Why did Wundt abandon his early theory of the unconscious? Towards a new interpretation of Wundt's psychological project. AB - Despite the numerous and important contributions brought by Wundt scholarship in recent decades, some aspects of his work remain unclear and poorly understood. The aim of this paper is to explore one of these aspects, namely, the relationship between philosophy and psychology in Wundt's thought. To this end, we shall discuss an important yet neglected moment in Wundtian psychology, which remains unexplained to date: Why did Wundt abandon his early theory of the unconscious? According to the interpretation offered here, this can only be adequately explained by his intense philosophical studies in the period preceding the publication of the Grundzuge in 1874. Finally, we will point out some implications of this analysis to the general interpretation of Wundt's psychological project. PMID- 22530378 TI - The long past and short history of the vocabulary of Anglophone psychology. AB - How do particular words come to be part of the vocabulary of Anglophone psychology? The present study sampled 600 words with psychological senses from the Oxford English Dictionary, which not only gives the number of senses for each word but also the date and author for the earliest known occurrence of each sense. Analogous information for the same words was taken from PsycINFO. One can distinguish between words for which their psychological sense is the first to occur in the history of the written language (primary psychological words) and words for which their psychological sense only emerges after one or more other senses have become established in the written language (secondary psychological words). To use a distinction made famous by Ebbinghaus, secondary psychological words have both a past and a history in psychology, while primary psychological words only have a history. Secondary psychological words have more connections to other words and occur more frequently in PsycINFO than do primary psychological words. For secondary psychological words, it is possible to trace a process of metaphoric polysemy that provides a basis for the eventual occurrence of the psychological sense of a word. Some primary psychological words are now developing secondary, nonpsychological senses, showing that they are subject to the same metaphoric process as are any other words. PMID- 22530379 TI - Genius [corrected] without the "Great Man": new possibilities for the historian of psychology. AB - The Carlylian style of history, more commonly known as the "Great Man" approach, presented the "genius" as an individual worthy of celebration: history as hero worship. This style, which characterized the first wave of the history of psychology, has gone out of historiographic fashion. In its place is the "new history," which is marked by its external focus and privileging of social factors and cultural context in its explanations. This shift in historiographic sensibilities has also led to a revision in the appropriate subject matter for psychologist-historians. This article argues, in contrast, that it is possible to study eminent individuals without resorting to hagiography, and it presents various methods that could be used for this purpose. The aim of such an endeavor is to create a space for critically and historically informed perspectives on greatness and to suggest a reconsideration of the value of an "historical psychology". PMID- 22530380 TI - History from within? Contextualizing the new neurohistory and seeking its methods. AB - "Histories from below" sought to give voice to those ordinary folk whose social position had failed to afford them great power, wealth, or responsibility: the neglected undocumented. Now, Lynn Hunt (2009) calls for a revolution that would task historians with giving voice to feelings--what I will call a "history from within." This is what led her to endorse Daniel Lord Smail's (2008) suggestion that historians appeal to neuroscience and thereby construct a "new neurohistory." The purpose would be to introduce a common factor to all human stories: a tool to think with when describing what it was like (cf. Nagel, 1974). If successful, this would be quite powerful: in Hunt's view, such a project could lead to a universalization of human rights. But the program is not without challenges, one of which is to provide an acceptable explanation for the type of looping causation that applies to bio-cultural kinds. Smail's solution involves an appeal to evolutionary theory, but how this solves the problem of causation is not clear. Here, therefore, an attempt is made to clarify his solution. Smail and Hunt's views on the role of evidence in history are also made plain. The paper then concludes by importing related ideas from the recent history of philosophy. If one is going to have a brain-based view of felt-history, then the neurohistorian's task is to situate historical individuals in contexts of shared experience--to not just read evidence through lenses of intellectual "thought collectives" (generalized from paradeigma), but also through "experiential" or "moral categories" (aisthanomai). PMID- 22530381 TI - Animal experiments, vital forces and courtrooms: Mateu Orfila, Francois Magendie and the study of poisons in nineteenth-century France. AB - The paper follows the lives of Mateu Orfila and Francois Magendie in early nineteenth-century Paris, focusing on their common interest in poisons. The first part deals with the striking similarities of their early careers: their medical training, their popular private lectures, and their first publications. The next section explores their experimental work on poisons by analyzing their views on physical and vital forces in living organisms and their ideas about the significance of animal experiments in medicine. The last part describes their contrasting research on the absorption of poisons and the divergences in their approaches, methods, aims, standards of proof, and intended audiences. The analysis highlights the connections between nineteenth-century courtrooms and experimental laboratories, and shows how forensic practice not only prompted animal experimentation but also provided a substantial body of information and new research methods for dealing with major theoretical issues like the absorption of poisons. PMID- 22530382 TI - Is chess the drosophila of artificial intelligence? A social history of an algorithm. AB - Since the mid 1960s, researchers in computer science have famously referred to chess as the 'drosophila' of artificial intelligence (AI). What they seem to mean by this is that chess, like the common fruit fly, is an accessible, familiar, and relatively simple experimental technology that nonetheless can be used productively to produce valid knowledge about other, more complex systems. But for historians of science and technology, the analogy between chess and drosophila assumes a larger significance. As Robert Kohler has ably described, the decision to adopt drosophila as the organism of choice for genetics research had far-reaching implications for the development of 20th century biology. In a similar manner, the decision to focus on chess as the measure of both human and computer intelligence had important and unintended consequences for AL research. This paper explores the emergence of chess as an experimental technology, its significance in the developing research practices of the AI community, and the unique ways in which the decision to focus on chess shaped the program of AI research in the decade of the 1970s. More broadly, it attempts to open up the virtual black box of computer software--and of computer games in particular--to the scrutiny of historical and sociological analysis. PMID- 22530383 TI - Timing is everything: the demarcation of 'later' abortions in Scotland. AB - Feminist STS analyses of contemporary reproductive medicine have illustrated the proliferation of practices that position fetuses as individual subjects, and have highlighted the major implications of such practices for pregnant women. In an attempt to challenge medicine's claims to 'know' the fetus, this body of literature has also demonstrated the renegotiable basis of pregnant/fetal subjectivity, using detailed empirical analyses of the practices through which particular pregnant and fetal subjects emerge in particular contexts. In this paper I contribute to this endeavour utilizing an empirical case study of an important, but neglected aspect of reproductive healthcare: the demarcation of temporal thresholds on abortion provision in the absence of diagnosed fetal abnormality. Drawing on semi-structured interviews with Scottish health professionals, I explore the discursive practices through which they demarcate 'later' abortion as a problematic decision. I argue that such practices are intimately dependent on particular co-constructions of temporality and pregnant/fetal subjectivity, and support this argument with reference to the counter-representations of the gestational timing of abortion that emerge from a minority of health professionals' accounts. I suggest that, collectively, this body of data illustrates the opportunities that (re)presenting temporality would afford those engaged in attempts to foster the construction of less oppressive pregnant/fetal subjectivities. My broader aim is to illustrate the insights that feminist theorizations of pregnant/fetal subjectivity gain from explicit engagement with another important theme of contemporary STS scholarship, namely, the constitutive role played by representations of temporality in technoscientific innovation and practice. PMID- 22530384 TI - How does the World Trade Organization know? The mobilization and staging of scientific expertise in the GMO trade dispute. AB - The World Trade Organization (WTO) dispute settlement procedure is a key arena for establishing global legal norms for what counts as relevant knowledge. As a high-profile case, the WTO trade dispute on GMOs mobilized scientific expertise in somewhat novel ways. Early on, the Panel put the dispute under the Sanitary and Phytosanitary (SPS) Agreement through a new legal ontology; it classified transgenes as potential pests and limited all environmental issues to the 'plant and animal health' category. The selection of scientific experts sought a multi party consensus through a fast adversarial process, reflecting a specific legal epistemology. For the SPS framing, focusing on the defendant's regulatory procedures, the Panel staged scientific expertise in specific ways that set up how experts were questioned, the answers they would give, their specific role in the legal arena, and the way their statements would complement the Panel's findings. In these ways, the dispute settlement procedure co-produced legal and scientific expertise within the Panel's SPS framework. Moreover, the Panel operated a procedural turn in WTO jurisprudence by representing its findings as a purely legal-administrative judgement on whether the EC's regulatory procedures violated the SPS Agreement, while keeping implicit its own judgements on substantive risk issues. As this case illustrates, the WTO settlement procedure mobilizes scientific expertise for sophisticated, multiple aims: it recruits a source of credibility from the scientific arena, thus reinforcing the standard narrative of 'science-based trade discipline', while also constructing new scientific expertise for the main task--namely, challenging trade restrictions for being unduly cautious. PMID- 22530385 TI - How places matter: telecare technologies and the changing spatial dimensions of healthcare. AB - Dominant discourses on telecare technologies often celebrate the erasure of distance and place. This paper provides a critical intervention into these discourses by investigating how spaces still matter, despite the move from physical to virtual encounters between healthcare professionals and patients. I argue that science and technology studies (STS) research on telecare, as well as other technologies, can be enriched by including a focus on place to understand the dynamic interactions between people and things. Adopting insights of human geographers, I show how places in which technologies are used affect how technologies enable or constrain human actions and identities. Whereas some spaces may facilitate the incorporation of technologies, others may resist technologies. A focus on how places matter is important for understanding how telecare technologies reorder and redefine healthcare. Although other healthcare technologies are also important actors in transforming healthcare, telecare technologies do this in a very specific way: they redefine the spatial dimensions of healthcare. To capture and further explore this changing spatial configuration of healthcare, I introduce the notion of technogeography of care. This concept provides a useful heuristic to study how places matter in healthcare. Although telecare technologies introduce virtual encounters between healthcare providers and patients, the use of telecare devices still largely depends on locally grounded, situated care acts. Based on interviews with users of several cardiac telecare applications, including healthcare professionals and patients in Germany and The Netherlands, the paper shows how patients' homes and public spaces are important for shaping the implementation and use of telecare technologies, and vice versa. Last, but not least, telecare devices are implicated as well. The paper emphasizes the place-dependency of the use and meaning of technical devices by showing how the same technological device can do and mean different things in different places. PMID- 22530386 TI - Teaching materials and the fate of dynamic biology in American classrooms after Sputnik. PMID- 22530387 TI - Negotiating nonalignment. Dilemmas attendant on initiating pharmaceutical production in India. PMID- 22530388 TI - "Standardization through mechanization". Germ-free life and the engineering of the ideal laboratory animal. PMID- 22530389 TI - The perfect solution. How trans fats became the healthy replacement for saturated fats. PMID- 22530390 TI - The art of science: a 'rediscovery' of the Lister copperplates. AB - In 1712 Martin Lister bequeathed the collection of more than 1000 copperplates to the University of Oxford that he used for his Historiae Conchyliorum, the first comprehensive study of conchology. In the mid-eighteenth century, William Huddesford, keeper of the Bodleian Library, used the copperplates to create another edition of Historiae, but after that they are not mentioned again in the published literature. I recently 'rediscovered' the plates in the Bodleian Library, since their transfer from the Ashmolean Museum in 1860. I use historical analysis, as well as a selective study of the copperplates with X-ray fluorescence techniques, to examine a portion of the plates and the process of their production. I show that Martin Lister's daughter engraved a paper for Philosophical Transactions, and demonstrate that she was among the first female scientific illustrators to use a microscope. Furthermore, one of the Lister copperplates may be the last survivor of those engraved for Philosophical Transactions, the rest having been surrendered to the nation in World War I. The significant intellectual and artisanal challenges presented to a skilful naturalist in the transformation of a field specimen into an aesthetically pleasing illustration as well as a scientific object conveying taxonomic information are delineated. PMID- 22530391 TI - The Portuguese Cholera morbus epidemic of 1853-56 as seen by the press. AB - This is a study of how scientific knowledge reached common citizens in nineteenth century Portugal, using newspapers as the main source. Despite the population's limited access to written material, each leading newspaper might be read by 30 000 people a day in Lisbon. This made newspapers the most widely available vehicle for the diffusion of the latest scientific information to the general public. With a cholera morbus epidemic affecting the second largest Portuguese town and all the northern regions, as well as the Algarve, reports on the course of the epidemic were considered essential. The author bases her study on a database of news about the disease in 1855 and 1856, especially with regard to prevention and treatment. PMID- 22530392 TI - Back on the chain gang: the new/old prison labor paradigm. PMID- 22530394 TI - On the pot calling the kettle black: the perils of psychohistorical partisanship. PMID- 22530395 TI - Prenatal period of life as a matrix for our lives and our societies. PMID- 22530393 TI - Dreams away from his mother: Ann Dunham and Barack Obama. PMID- 22530396 TI - The family legends of populist and rightists' majority in the Hungarian parliament. PMID- 22530397 TI - A controlled study of depression among attendees of an oncology clinic in West Africa. AB - OBJECTIVE: Depression is commonly encountered among cancer patients and has been linked with grave consequences if not promptly treated. This study was set to determine the prevalence of depression in cancer patients. METHOD: The samples were recruited using systematic random sampling and made up of 200 cancer patients and 200 age and sex matched controls that consented and met the inclusion criteria. The instruments used included: Socio-demographic and clinical profile questionnaire, Centre for Epidemiological Studies Depression Scale Revised (CES-DR), and the Schedule for Clinical Assessment in Neuropsychiatry (SCAN). The instruments were administered by the researchers on the subjects and controls, and data obtained were analyzed using SPSS-15. RESULTS: A larger proportion of cancer patients compared to controls had depressive symptomatology (CES-DR score of 16 and above) made up of 98 (49.0%) cancer patients compared to 40 (20.0%) controls, and the difference was statistically significant, p = < 0.001. Seventy-four (18.5%) subjects from the two groups had depressive disorder using SCAN. The prevalence of depression in cancer subjects was 27.5% with 9.5% in controls and the difference was statistically significant with p = < 0.001. A substantial proportion of cancer patients with depression, 36 (65.5%, n = 55), had moderate depression, 15 (27.3%, n = 55) were mildly depressed, and 7.2% (n = 55) had severe depression. CONCLUSION: A significant proportion of cancer patients had depression compared with the controls with acute medical conditions. Prompt identification and treatment of cancer, mental disorders like depression should be integrated into cancer care in this part of the world. PMID- 22530398 TI - Physician prescribing patterns of innovative antidepressants in the United States: the case of MDD patients 1993-2007. AB - OBJECTIVE: Innovative antidepressants such as SSRIs and SNRIs have been widely adopted. However, the differences in their adoption across patients' and physicians' characteristics, geographic regions, and insurance status need to be further explored. This study was trying to disentangle the patterns of physician antidepressant prescribing and medication choice for major depressive disorder treatment. METHOD: A retrospective cross-sectional study was conducted using the 1993-2007 National Ambulatory Medical Care Survey database. A multinomial logistic regression with the Heckman two-step selection procedure was applied to capture the two-step nature of physician prescription decision making. RESULTS: The weighted logistic regression indicated that patients' race/ethnicity and primary source of payment for services, physician ownership status, and physicians' practice regions were associated with differential likelihood of physician' antidepressant prescribing. Non-Hispanic white patients were more likely to be prescribed antidepressants compared to Hispanic patients (OR = 1.52, 95% CI 1.24-1.87). Physicians' choice on antidepressant varied across with patient age and health insurance status. Compared to private insurance, patients who were primarily covered by Medicare were less likely to be prescribed only SSRIs/SNRIs or other newer antidepressants (RRRs = 0.42 and 0.39; 95% CIs 0.21 0.83 and 0.18-0.84, respectively). CONCLUSIONS: We observed strong associations between sociological factors and physicians' antidepressant prescribing patterns. Possible health disparities and gaps between optimal and suboptimal healthcare for patient mental health caused by systematic differences in sociological factors need to be mitigated. We need policy makers to design effective policy interventions to improve physician practice guidelines adherence to eliminate possible variations among physician practices. PMID- 22530399 TI - Mental disorders in obese patients with and without metabolic syndrome. AB - OBJECTIVE: The authors sought to evaluate lifetime prevalence of mental disorders in patients affected by metabolic syndrome compared with patients affected by central obesity alone. METHODS: One hundred eighty-six (63.5%) patients affected by central obesity and 107 (36.5%) affected by metabolic syndrome according to ICF criteria were interviewed by means of SCID I and SCID II. RESULTS: Axis I and axis II lifetime prevalence were respectively 53.8% and 30.1% among patients with central obesity, 50.5% and 28% among patients with metabolic syndrome, differences which were not significant. No statistically significant differences were found between groups as far as each single axis I and II diagnostic category was considered. CONCLUSION: Metabolic syndrome is not associated with a higher risk of mental disorders compared to central obesity alone. PMID- 22530400 TI - Why John wasn't healed by prayer: perspectives across disciplines. AB - Patients and family members often turn to prayer in response to serious, life threatening illness. Prayer for a miraculous cure is often the request. While prayer can keep hope alive, it may also promote unrealistic expectations that fuel demands for life-preserving technology in medically futile situations. Furthermore, if prayer does not achieve the desired results, then disappointment and disillusionment may follow and make the coping process even more difficult. We present here a case of a seriously ill man whose family and faith community prayed for his healing. John, however, was not healed. A medical internist, two psychiatrists, a sociologist, and a theologian discuss their perspectives on the apparent failure of prayer to heal John. This cross-disciplinary discussion reveals insights that we believe physicians can use when confronting such issues with patients. PMID- 22530401 TI - Posttraumatic stress disorder following myocardial infarction: personality, coping, and trauma exposure characteristics. AB - OBJECTIVE: This study aimed to investigate the interrelationship between trauma exposure characteristics of myocardial infarction (MI), MI patients' personality traits, coping strategies, post-MI PTSD, and general psychological distress. METHOD: One hundred and twenty MI patients were recruited from two general practices. The MI patients were interviewed using a MI experience questionnaire and completed the Posttraumatic Stress Diagnostic Scale (PDS), the General Health Questionnaire-28 (GHQ-28), the NEO-Five Factor Inventory (NEO-FFI), and the COPE Scale. RESULTS: Neuroticism was directly associated with post-MI PTSD and general psychological distress, while agreeableness did not link to the outcomes directly. Neuroticism influenced MI exposure characteristics which in turn influenced PTSD. Agreeableness affected PTSD and general psychological distress through MI exposure characteristics. Neuroticism influenced problem-focused coping which in turn affected general psychological distress. Agreeableness influenced problem-focused coping which in turn affected PTSD and general psychological distress. CONCLUSIONS: Patients developed PTSD and general psychological distress following MI. Neurotic and antagonistic personality traits combined with patients' subjective experiences of MI and usage of problem-focused coping influenced the severity of outcomes. PMID- 22530402 TI - Does having a chronic physical condition affect the likelihood of treatment seeking for a mental health problem and does this vary by ethnicity? AB - OBJECTIVE: The comorbidity of mental disorders with chronic physical conditions is known to have important clinical consequences, but it is not known whether mental-physical comorbidity influences mental health treatment seeking. This study investigates whether the presence of a chronic physical condition influences the likelihood of seeking treatment for a mental health problem, and whether that varies among ethnic subgroups in New Zealand. METHODS: Analyses were based on a subsample (n = 7,435) of The New Zealand Mental Health Survey, a nationally representative household survey of adults (response rate 73.3%). Ethnic subgroups (Maori and Pacific peoples) were oversampled. DSM-IV mental disorders were measured face-to-face with the Composite International Diagnostic Interview (CIDI 3.0). Ascertainment of chronic physical conditions was via self report. RESULTS: In the general population, having a chronic medical condition increased the likelihood of seeking mental health treatment from a general practitioner (OR: 1.58), as did having a chronic pain condition (OR: 2.03). Comorbid chronic medical conditions increased the likelihood of seeking mental health treatment most strongly among Pacific peoples (ORs: 2.86-4.23), despite their being less likely (relative to other ethnic groups) to seek mental health treatment in the absence of physical condition comorbidity. CONCLUSION: In this first investigation of this topic, this study finds that chronic physical condition comorbidity increases the likelihood of seeking treatment for mental health problems. This provides reassurance to clinicians and health service planners that the difficult clinical problem of mental-physical comorbidity is not further compounded by the comorbidity itself constituting a barrier to mental health treatment seeking. PMID- 22530404 TI - APN prescriptive authority barriers. PMID- 22530405 TI - The relationship between nurse involvement and outcomes in Colorado hospitals. PMID- 22530406 TI - Nurse managed clinics-Sheridan Health Services a prime Colorado model. PMID- 22530403 TI - An initial study of modifiable and non-modifiable factors for late-life psychosis. AB - OBJECTIVE: To determine rates of psychotic symptoms and associated modifiable and non-modifiable factors among elderly long term nursing home residents without prior history of psychiatric illness. METHOD: A cross-sectional design using the Scale for the Assessment of Positive Symptoms (SAPS) to measure psychotic symptoms, the Folstein's Mini-Mental State Exam (MMSE), and Mattis Dementia Rating Scale (DRS) to evaluate cognitive impairment. Frequency and rates of global psychotic symptoms and hallucinations, delusions, formal thought disorder, and bizarre behavior were calculated. Logistic regression was used to examine modifiable (e.g., medication use) and non-modifiable clinical characteristics (e.g., older age) associated with late-life psychosis. RESULTS: There were 15.9% of subjects reporting delusions and 7.3% reporting hallucinations. History of stroke, poorer cognition, and receiving multiple medications showed significant association with late-life psychosis. Only stroke (OR = 9.12; 95% CI: 1.58-52.74) and receiving different classes of medications (benzodiazepines, neuroleptics, and antidepressants) (OR = 13.17; 95% CI: 2.10-85.82) remained significantly associated with psychosis after adjusting for Mattis DRS total score. Further analyses excluding subjects with MMSE scores of 24 or lower (n = 24) showed essentially the same results but subjects with better cognitive function suffered a less severe form of psychosis, essentially constituted by one symptom type (i.e., visual hallucinations). CONCLUSIONS: Rates of late-life psychosis in this sample of nursing home residents without previous psychiatric history were high. Simultaneous use of medications including antidepressants, sedatives, and stimulants may be a clinically relevant modifiable factor to be targeted in prevention studies. Severity and type of psychosis is dependent on the severity of cognitive impairment. PMID- 22530407 TI - CEARP/CNE review & update. PMID- 22530408 TI - [Unequal access to health care in the country: assisted peritoneal dialysis not offered to all who need it]. PMID- 22530409 TI - [The modern age requires a changed medical education. Knowledge of organization, processes, IT, advanced leadership are good tools]. PMID- 22530410 TI - [A national questionnaire shows the quality of Swedish medical education. Physicians' perspectives two years after examination]. PMID- 22530411 TI - [Systemic mastocytosis. Underestimated condition in patients with idiopathic anaphylaxis]. PMID- 22530413 TI - [Pulse oximetry screening of newborns detects congenital heart defects. Experiences from Kalmar]. PMID- 22530412 TI - [Three unusual cases of tularemia in the county of Varmland. Suspected transmission via water, contaminated well and insects]. PMID- 22530415 TI - [Population studies are needed--also LifeGene!]. PMID- 22530414 TI - [Possible interaction between pomegranate juice and warfarin]. PMID- 22530416 TI - [Breast implant scandal shows weaknesses in the European information practice]. PMID- 22530417 TI - [The risks with a high-fat diet are exaggerated]. PMID- 22530418 TI - [Vitamin B1 store is decisive for survival of human beings without food]. PMID- 22530419 TI - [To administer parenteral nutrition initially at ICU is not given]. PMID- 22530420 TI - [Tobacco smoking must be banned]. PMID- 22530421 TI - [Physicians have an important role in the fight against tobacco-related deaths]. PMID- 22530422 TI - [Tobacco dependence is strong...and difficult to break]. PMID- 22530424 TI - [Physician is the first link in the smoking cessation chain]. PMID- 22530423 TI - [Quitting smoking brings quick health benefits]. PMID- 22530425 TI - [Smoking cessation intervention prior to surgery]. PMID- 22530426 TI - [Use of snuff is a controversial public health issue]. PMID- 22530427 TI - [Resistant bacteria threaten health care. Notification and transmission tracing of resistant intestinal bacteria now introduced]. PMID- 22530428 TI - [Mass vaccination--reasonable but not correct]. PMID- 22530429 TI - [Four kilograms of prejudice celebrated as science. Herman Lundborg and the population in the garden of Sweden]. PMID- 22530430 TI - Virtual diabetes management. Programs and devices to meet your needs. PMID- 22530431 TI - Diabetes in the military. PMID- 22530432 TI - Enjoying healthy eating. Low-fat cooking. PMID- 22530433 TI - Carbohydrate counting, glycemic index, and glycemic load. Putting them all together. PMID- 22530434 TI - Supermarket smarts. Protein foods. PMID- 22530435 TI - Diabetes quiz. How much do you know about eggs? PMID- 22530436 TI - Proximate composition, extraction, characterization and comparative assessment of coconut (Cocos nucifera) and melon (Colocynthis citrullus) seeds and seed oils. AB - Proximate composition, extraction, characterization and comparative assessment of Cocos nucifera and Colocynthis citrullus seeds and seed oils were evaluated in this work using standard analytical techniques. The results showed the percentage (%) moisture, crude fibre, ash, crude protein, lipids and total carbohydrate contents of the seeds as 7.51 and 4.27, 7.70 and 5.51, 1.02 and 2.94, 10.57 and 11.67, 47.80 and 50.42 and 32.84 and 29.47 while the calorific values were 553.99 and 567.32 Kcal/100 g for C. nucifera and C. citrullus, respectively. The two seed oils were odourless and at room temperature (30 degrees C) liquids, with a pale yellow to yellowish colouration. Lipid indices of the seed oils indicated the Acid Values (AV) as 2.06-6.36 mg NaOH g(-1) and 2.99-6.17 mg NaOH g(-1), Free Fatty Acids (FFA) as 1.03-3.18 and 1.49-3.09%, Saponification Values (SV) as 252.44-257.59 and 196.82-201.03 mg KOH g(-1), Iodine Values (IV) as 9.73-10.99 and 110.93-111.46 mg of I2 g(-1) of oil and Peroxide Values (PV) as 0.21-0.21 and 1.53-2.72 mg O2 kg(-1) for soxhlet-mechanical extracted C. nucifera and C. citrullus seed oils, respectively. The studied characteristics of the oil extracts in most cases compared favourably with most conventional vegetable oils sold in the Nigeria markets; however, there were some observed levels of significant differences in the values at p < or = 0.05. These results suggest that the seeds examined may be nutritionally potent and also viable sources of seed oils judging by their oil yield. The data also showed that the seed oils were edible inferring from their low AV and their corresponding low FFA contents. Industrially, the results revealed the seed oils to have great potentials in soap manufacturing industries because of their high SV. They were also shown to be non drying due to their low IV which also suggested that the oils contain few unsaturated bonds and therefore have low susceptibility to oxidative rancidity and deterioration as confirmed by their low PV which also serves as indicators of the presence or high levels of anti-oxidants in the oils. PMID- 22530438 TI - Culture of Pangasianodon hypophthalmus into India: impacts and present scenario. AB - Pangasianodon aquaculture is the fastest growing food producing sector of the world. Recent national production of Pangasianodon hypophthalmus in India accounts for 0.7 million tonnes at present. Being influenced by trade and markets, P. hypophthalmus has been introduced to many countries including India. There has been a steady increase in the production of P. hypophthalmus by small and marginal farmers of the country. However, concern has arisen about the long term sustainability due to diseases and its negative impacts on socio-economic aspects and biodiversity. Unregulated culture of P. hypophthalmus has been causing concern to environmental safety and warranting a very cautious and regulated approach to its culture. The standards, protocols and guidelines have been developed to address the issues of sustainability of Pangasianodon catfish production. PMID- 22530437 TI - Evaluation of food protective property of five natural products using fresh-cut apple slice model. AB - The present study evaluated the antioxidant (AA), antimicrobial and preservation effects of five plant derived natural products viz., Rosmarinic Acid (RA), p Coumaric Acid (pCA), Trans-Cinnamic Acid (TCA), Hydroxyphenyllactic Acid (HPA) and Caffeic acid (CA) along with synthetic compounds (Ascorbic acid, gallic acid, citric acid and BHA) on fresh cut apple slices. Antimicrobial efficacy of these compounds against Bacillus licheniformis, Pseudomonas vulgaris, Shigella boydii, Salmonella typhi, Staphylococcus aureus, Listeria monocytogenes and Escherichia coli was found to be concentration dependent with the maximum inhibition observed at 500 microg mL(-1). A considerable AA potential of these compounds was observed in in vitro based assay system, with RA exhibiting significantly higher effect than the other compounds at 500 microg mL(-1). Furthermore the compounds at 500 microg mL(-1) significantly reduced the browning, maintained the acidic pH and restricted growth of L. monocytogenes even after 10 days of treatment. Ethanol accumulation in fresh cut apple slices increased significantly throughout the experimental period. Over all RA exhibited maximum effect in all the food preservation parameters studied suggesting that it has synchronized food protection effect and can be recommended as food additive. PMID- 22530439 TI - Effect of Quercus infectoria and Rosa damascena on lipid profile and atherosclerotic plaque formation in rabbit model of hyperlipidemia. AB - Hyperlipidemia is the cause of many complications in the human societies. In this study, the effect of methanol extracts of Quercus infectoria (QI) galls and Rosa damascena (RD) Mill flower were studied on lipid profile and atherosclerotic plaques formation in hyperlipidemic rabbits. Thirty-six New Zeland white rabbits randomly divided into 6 groups as control (I), hyperlipidemic (II), hyperlipidemic+QI (III), hyperlipidemic+RD (IV), +Atorvastolin (V) and hyperlipidemic+Orlistat (VI) and were fed with high fat diet (0.5% cholesterol and 16% hydrogenated vegetable oil) for 45 days. At the end of the study period, lipid profile and plaque formation were assessed. Total Cholesterol (TC), Low Density Lipoprotein (LDL) and Triglyceride (TG) levels were significantly increased in hyperlipidemic group compared with control group (p < 0.001). Methanol extract consumption of Quercus infectoria significantly decreased plasma levels of TC, TG and LDL (p < 0.001). It also decreased plaques formation in semi lunar valve and thoracic aorta. Rosa damascena mill flower methanol extract moderately decreased the levels of TC, TG, LDL and plaques formation but it was not significant. HDL levels and weight of animals did not show significant difference among groups. Based on the doses used in this study, our finding indicated that QI but no RD methanol extract has anti atherogenic and hypolipidemic activities. PMID- 22530440 TI - Effect of sewage irrigation on nitrate accumulation and nitrate reductase activity in leafy vegetables. AB - The effect of sewage water irrigation along with the N-fertilizers on NO3 accumulation and on the in vivo NR assay in three leafy vegetable crops were studied. It was found that the NO3 content in the leaves from the experimental sites were around two fold than the control and the NR enzyme activity was comparatively more in the control samples. The in vivo NRA with NaCl treatment increased at low level of NaCl where as with high level of NaCl, the enzyme activity decreased considerably. This is suggestive of the fact that NO3 accumulation may be due to antagonistic effect of chloride ions. PMID- 22530441 TI - Production and optimization of indole acetic acid by indigenous micro flora using agro waste as substrate. AB - Indole Acetic Acid (IAA) producing bacterium was isolated from the Rhizosphere soil and identified as Rhizobium sp. and Bacillus sp., Optimization of Indole acetic acid production was carried out at different cultural conditions, such as pH, temperature and substrate with Rhizobium sp., Bacillus sp. and Rhizobium sp., produced higher amount of Indole acetic acid (6.1 mg mL(-1)) than the Bacillus sp., (4.4 mg mL(-1)) at pH 7 and 37 degrees C in the Bengal gram substrate. Partial purification of Indole acetic acid was done by Thin Layer Chromatography (TLC). In conclusion Rhizobium sp., appear to be a suitable soil microorganism for high level of IAA production. PMID- 22530442 TI - Persistence of metalaxyl and mancozeb on potato leaves and their residues in tubers. AB - The persistence of fungicides on two commercial cultivars of potato was determined under field conditions at Punjab Agricultural University, Ludhiana, Punjab. Initial deposits of mancozeb on potato leaves were found to be 26.9 and 38.7 mg kg(-1), following application of ready mixture of fungicide metalaxyl 8% + mancozeb 64% (Ridomil MZ) at the rate of 1260 and 2520 g a.i. ha(-1), whereas metalaxyl residues were found to be 35.1 and 49.5 mg kg(-1), respectively. The residue level of mancozeb in potato leaves 15 days after application at single and double doze were 19.0 and 27.0 mg kg(-1) showing a loss of 29.6 and 30.3%, whereas the values for metalaxyl at single and double doze were 0.40 and 0.80 mg kg(-1) showing a loss of 98.9 and 98.4%, respectively. Residues of mancozeb and metalaxyl were not detected at 0.04 and 0.02 mg kg(-1) level in potato tubers at harvest (PHI = 53 days) at both the dosages, respectively. The persistence and dissipation of mancozeb with the application of Ridomil MZ followed similar trend as in Indofil M-45. The rate of fungicide dissipation increased with time after application in both the potato cultivars 'Kufri Chandramukhi' and 'Chipsona'. No significant difference was observed on initial deposit, persistence and dissipation of the two molecules between the two potato cultivars. PMID- 22530443 TI - Essential oil and methanolic extract of Zataria multiflora Boiss with anticholinesterase effect. AB - One of the most common strategies in the treatment of cognitive disorders is enhancing the acetylcholine level in the brain through the inhibition of acetylcholinesterase. Despite the effectiveness of current modern drugs, more attention has been paid for finding new anticholinesterase agents from medicinal plants. Zatraia multiflora Boiss. is an endemic plant to Iran which has different uses in traditional medicine as anti-inflammatory, antimicrobial, anti spasmodic. We intended to evaluate the in vitro anticholinesterase and free radical scavenging activity of the essential oil and methanolic extract of Z. multiflora. The essential oil and methanolic extract of the plant were evaluated for anticholinesterase activity using modified Ellman method. The free radical scavenging effect of the samples were studied by using of the diphenylpicrylhydrazyl (DPPH). IC50 and the percent of inhibition of acetylcholinesterase was calculated from regression equation. The results showed that both the essential oil and methanolic extract of the plant exhibited high anticholinesterase activity (95.3 +/- 3.4 and 87.9 +/- 2.2% inhibition, respectively) which was similar to eserine (96.2 +/- 1.7% inhibition). The IC50 value of essential oil was determined as 0.97 +/- 0.12 microg mL(-1) in comparison to eserine (0.13 +/- 0.02 microg mL(-1)). The results of antioxidant assay showed that both the essential oil and methanolic extract potentially inhibit DPPH free radical (94.8 +/- 2.4 and 93.2 +/- 1.7% inhibition, respectively). The essential oil and methanolic extract of Z. multiflora have beneficial effect in health promotion and this plant would be good candidate for further studies. PMID- 22530444 TI - Wolbachia infection and mitochondrial DNA comparisons among Culex mosquitoes in South West Iran. AB - The control of mosquito borne diseases needs new methods given widespread insecticide resistance in many mosquito species. The inherited endosymbiont Wolbachia, found in many arthropods, provides a biological system to reduce the transmission of these diseases and replace the population of vectors with non vectors using cytoplasmic incompatibility. The aim of this study was to understand the rate of Wolbachia infection among Culex species in the region and to see the effect of Wolbachia infection on mitochondrial genome. In this study three species of Culex mosquitoes were collected from Shoushtar in south west of Iran and examined for Wolbachia infection by Polymerase Chain Reaction (PCR). All of the C. quinquefasciatus specimens were infected with Wolbachia, while C. tritaeniorynchus and C. theileri showed no infection with Wolbachia. The 340 bp of AT rich of mtDNA was sequenced from 30 individuals, 10 individuals of each species. Three sequence haplotypes were found in C. tritaeniorynchus and C. theileri while there was only one haplotype in C. quinquefasciatus. The reduction of haplotypes diversity may be result of a sweep of Wolbachia in this species. PMID- 22530445 TI - Some people say a man is made out of mud ... miners, miracles and the old red devil. PMID- 22530446 TI - Variability in hyperbaric oxygen treatment for acute carbon monoxide poisoning. AB - CONTEXT: In patients with acute carbon monoxide (CO) poisoning, we have noted wide clinical variability in both criteria for hyperbaric oxygen (HBO2) treatment as well as HBO2 treatment regimens. Our aim was to survey Midwest hyperbaric centers for insight into specific criteria and protocols for treating acute CO toxicity with HBO2. METHODS: Hyperbaric centers were identified from the published list of the Undersea and Hyperbaric Medical Society. Ninety-three centers from nine Midwestern states were contacted via telephone. A standard script was used to minimize surveyor bias. RESULTS: Thirty centers that treat CO poisonings were identified. One did not participate in the study. Nineteen reported a specific level of carboxyhemoglobin (COHb) that served as an independent indication for initiation of HBO2 treatment. Four centers used the COHb level as the exclusive indication for HBO2 treatment. Ten centers relied solely on reported symptoms, while the remaining centers used a combination of symptoms plus COHb levels. There were 19 separate treatment protocols. CONCLUSION: No uniform practice for either the initiation or implementation of HBO2 therapy for CO poisoning exists among U.S. Midwest hyperbaric centers responding to a survey. We see opportunity for specific targeted educational programs as well as further study. PMID- 22530447 TI - Questionnaire results of hyperbaric oxygen therapy for acute carbon monoxide poisoning in Japan. AB - Carbon monoxide (CO) poisoning results in not only severe psychoneurological disorders, but can also cause secondary delayed psychoneurological disorders. Therefore, timely and appropriate treatment in the acute stage is crucial to prevent such direct neurological damage and secondary disorders. However, various conflicting results have been reported in studies of CO poisoning treatment, and the efficacy of hyperbaric oxygen therapy (HBO2T) for CO poisoning has not been established. This retrospective multi-institutional study was performed by the questionnaire in 1667 cases of acute CO poisoning in Japan. The effectiveness of HBO2T for CO poisoning was evaluated based on prognoses in cases and various classes of hospital based on the grade of their positive stance regarding HBO2T. The results showed that the prognosis in the group treated with HBOT was significantly better than that in the group treated with normobaric oxygen therapy (NBO2T) (P < 0.01), thus confirming the effectiveness of HBO2T for CO poisoning. Furthermore, while hospitals were separated into three groups according to their indication criteria for HBO2T, the ineffective ratio of NBO2T was dependent on the indication criteria, even though the effective ratio of HBO2T was the same in all three groups. In conclusion, a retrospective multi institutional study showed that HBO2T is an effective form of therapy for CO poisoning. PMID- 22530448 TI - Partnering with a medical specialty society to perform online public health surveillance. AB - While accidental carbon monoxide (CO) poisoning is common, it is felt to be largely preventable through targeted public education. Development of effective education programs requires accurate epidemiologic information about the condition. Many acute, severe cases of CO poisoning are treated with hyperbaric oxygen (HBO2) at hospital-based facilities staffed by members of the Undersea and Hyperbaric Medical Society (UHMS). In 2008, the Centers for Disease Control and Prevention (CDC) began sponsoring a UHMS proposal to use online reporting by UHMS members of cases treated with HBO2. This report describes development and implementation of the internet-based surveillance system, as well as its first year of operation. From August 2008 to July 2009, a total of 740 cases were reported by the 82 hyperbaric facilities participating nationwide. Extensive epidemiologic information about CO poisoning in the United States has been collected, and the utility of partnering with a medical specialty society for disease-specific surveillance demonstrated. PMID- 22530449 TI - Symptoms of carbon monoxide poisoning do not correlate with the initial carboxyhemoglobin level. AB - BACKGROUND: Symptoms in carbon monoxide (CO) poisoned patients have traditionally been described as being related to corresponding carboxyhemoglobin (COHb) levels without substantive support for the relationship. This study sought to determine whether prospectively collected symptoms correlate with specific COHB level ranges in a large population of CO-poisoned patients. METHODS: Data from patients reported in the initial two years of operation of the joint UHMS/CDC CO Poisoning Surveillance System were used to compare presenting COHb levels with symptoms collected with a standardized questionnaire. RESULTS: Data from 1,323 CO-poisoned patients referred for hyperbaric oxygen therapy from August 2008 to July 2010 were analyzed with regard to initial COHb level and symptoms. Of approximately 50 categories of symptoms reported, none was associated with a specific range of COHb levels. CONCLUSIONS: While symptoms are common in acute CO poisoning, none can be directly correlated to COHb levels, even in a population of more than 1,000 patients. The concept of a table relating specific symptoms to specific COHb levels is invalid. One such table that has often been published comes from a 1923 U.S. government publication and appears to be based at least in part upon the symptoms experienced by three men in a total of 10 low-level laboratory CO exposures. PMID- 22530450 TI - The UHMS/CDC carbon monoxide poisoning surveillance program: three-year data. PMID- 22530451 TI - Carbon monoxide poisoning mimicking arterial gas embolism in a commercial diver. AB - A 32-year-old male commercial diver was working at 7,000 feet of altitude in a municipal water tank, at a depth of 27 feet for two hours. While surfacing from a compressed-air surface-supplied dive, he exhibited loss of consciousness and neurological symptoms. He was presumptively diagnosed with arterial gas embolism, flown by pressurized aircraft to a regional medical center and treated with hyperbaric oxygen. During the U.S. Navy Treatment Table 6, new information suggested the patient's air supply had been contaminated by a continuously running engine and compressor. His admission blood was then assayed for carboxyhemoglobin (COHb), which measured 8.8% six hours after surfacing, including four hours of normobaric oxygen inhalation. His estimated COHb based on rough reported half-life calculations at the conclusion of the dive was approximately 45%. The patient's diagnosis was changed to carbon monoxide poisoning from contaminated breathing gas. Upon hospital discharge, he exhibited problems with balance and gait, nystagmus, word-finding limitations and slurred speech. Also, he had cardiac injury treated with carvedilol. When evaluating diving-related casualties, including in commercial divers, clinicians should consider carbon monoxide poisoning as a differential diagnosis. PMID- 22530452 TI - Predictive value of computed tomography coronary angiography for the evaluation of acute chest pain: single center preliminary experience. AB - AIM: To assess the predictive value of CT coronary angiography (CT-CA) in the stratification of patients with acute chest pain. MATERIALS AND METHODS: We enrolled 48 patients (31 males and 17 females, mean age 61.0 +/- 14yrs) with acute chest pain of suspected coronary origin, without diagnostic alterations of the ECG and/or increase of the myocardial biomarkers. Sixty-four slice CT-CA was performed within 48-72 hours. Depending on the clinical judgment, the patients were dismissed or underwent conventional coronary angiography (CAG). Patients underwent clinical follow-up at 6 months, recording the prevalence of major cardiovascular events. RESULTS: One patient was excluded from the analysis because of poor image quality. CT-CA showed no coronary artery disease in 38.3% (18/47) of the patients, no significant coronary artery disease (<50% lumen reduction) in 31.9% (15/47) of the patients, significant coronary artery disease (> or = 50% lumen reduction) in 29.8% (14/47) of the patients. In 87.2% (41/47) of the patients no indication for CAG was present. In 6 (12,8%) patients with significant stenosis at CT-CA indication for CAG was present. In 50% (3/6) of these patients, CAG showed no significant coronary artery disease and in the remaining 50%(3/6) CAG was followed by percutaneous coronary angioplasty. At follow-up no major cardiovascular events were observed. CONCLUSIONS: CT-CA showed high sensitivity for the detection of significant coronary artery disease and a negative predictive value at 6-month follow-up. PMID- 22530453 TI - Celiac disease in children with type 1 diabetes: impact of gluten free diet on diabetes management. AB - Background and aim of the work the coexistence of Type 1 Diabetes (T1D) and celiac disease (CD) has been long established. METHODS: Between January 2000 and December 2009, biopsy-proven CD was diagnosed in 12 children with T1D, giving a prevalence of 4.8 % in our out-patient clinic population. For each patient with coexisting T1D and CD, two control subjects with T1D and without CD who matched for age, sex and duration of diabetes were chosen. Prospective study follow up lasted 24 months. At the enrolment time, and at 2-month intervals, time from diagnosis of T1D to diagnosis of CD, presence of gastrointestinal symptoms, HbA1c value, body mass index (BMI), Height and Weight SDS were collected by a single observer. Daily insulin requirements were also retained. RESULTS: In 3 children, CD predated the onset of T1D and these children were excluded from the analysis. The 9 children who subsequently developed CD became earlier diabetic than control group (p=0.002). Eight of these children had CD diagnosis within 1 year after T1D onset. Seven out of 9 children were positive for TTG antibodies and all were positive for EMA. A significant increase in insulin requirement was found in CD children after 1 year of GFD (p= 0.02). The mean HbAlc value in CD children was higher than in the control subjects (p<0.01).A significant increase in the insulin requirement after 1 year in the GFD compliant children was found. There was a significant improvement in height-SDS after institution of GFD in the GFD compliant children. Families of children with both T1D and CD reported higher burden than those affected by T1D only (p=0.001). The health care providers perceived family burden to increase with CD appearance (p<0.05). CONCLUSION: Our study supports the importance of screening for CD in children with T1D 1. The early treatment with GFD of biopsy-confirmed CD children promotes a significant catch-up growth and prevents a growth failure during the follow-up. PMID- 22530454 TI - Eating behaviour and body image in a sample of young athletes. AB - BACKGROUND ANDAIM: Adolescence is a period of great risk for the development of eating disorders since many teenagers engage in long periods of dieting or exhausting sports activities in order to achieve their ideal body image. Research has shown that a potential majority of athletes display attitudes very similar to those observed in cases involving disturbed eating behaviour, particularly with regard to their exaggerated attention to their body image and the type of diet that they consider necessary for their activities. The aim of this study is to analyze young athletes dedicated to attaining the mesomorphic physical ideal and to identify possible dysfunctional eating habits like risk factors in the development of more serious disturbances. We further plan to evaluate possible differences in how members of the sample group perceive their bodies and behave in connection with their diet. METHODS: The sample is made up of 109 males and females, aged 16-24 years. Participants completed the Pisa Survey for Eating Disorders and underwent measurements for the calculation of body mass index (BMI). RESULTS: The young athletes in our sample show a markedly distorted perception of their own bodies. They show a widespread presence of eating behaviour that is not functional to high athletic achievement as well as a series of noteworthy risk factors connected with the onset of eating behaviour disturbances. CONCLUSIONS: The obtained results underscore the need for primary projects in prevention against and awareness of eating problems and awareness of dysmorphic and phobic disturbances in young athletes. PMID- 22530455 TI - Retroperitoneal tumor invasion of the inferior vena cava. A single-centre experience in tumor thrombectomy. AB - BACKGROUND AND AIM: Radical surgical treatment improves survival in patients suffering from retroperitoneal tumors with co- existing inferior vena cava thrombus. The extraction excision can be performed through many techniques such as liver mobilization which is performed in liver transplantation procedures. METHODS: During 2000-2007, 11 patients with retroperitoneal tumors and inferior vena cava thrombus were surgically treated in our department. Classification of the thrombus was defined as suggested by Neves and Zinke. All patients were categorized as level I or level II. In all cases a transabdominal approach, liver mobilization and extraction of the thrombus by milking down or Fogarty catheter were used. RESULTS: No peri-operative mortality was observed. One case of pulmonary embolisation was conservatively treated. One patient presented recurrence 6 months after the procedure. CONCLUSIONS: The use of liver transplantation techniques in the surgical management of retroperitoneal tumors with inferior vena cava thrombus, is a safe procedure that improves the survival of these patients. PMID- 22530456 TI - Efficacy of nutrition counseling in young people with diabetes. AB - AIM: The aim of this study is to investigate if a non-prescriptive diet plan in young children with type 1 diabetes mellitus is unfavourable in comparison with classic prescriptive diet plan, paying particular attention to glycemic control, lipid profile and body mass index. METHODS: We carried out a longitudinal and 8 year retrospective study based on a well-defined cohort of children aged < 18 years with type 1 diabetes followed-up every three months from our Unit beginning from 1999 to 2007. The study included a total of 49 patients with type 1 diabetes aged 16-19 years, the mean duration of diabetes was 13 +/- 4 years. During the study all the patients continued to receive flexible multiple daily injection insulin therapy according to basal-bolus plan. In order to investigate the lipid profile we collected total cholesterol, LDL, HDL and triglyceride levels once a year and to asses the metabolic control in diabetic patients, blood samples were collected for assay of HbA1c every three months all years during the study. RESULTS: No abnormalities about lipid profile were observed during the analysed years. LDL, HDL, total cholesterol and triglyceride values were normal and their trend was uniform and lower than the normal range of general people. CONCLUSIONS: These outcomes showed no differences between diabetics and normal people at risk to develop metabolic alterations. Non-prescriptive diet plan in children with insulin dependent diabetes mellitus is not unfavourable in comparison with classic prescriptive diet-plan, in particular with regard to the metabolic control which reflect the international data of reference. PMID- 22530457 TI - Interaction between ticlopidine or warfarin or cardioaspirin with a highly standardized deterpened Ginkgo biloba extract (VR456) in rat and human. AB - Ginkgo biloba is available in Europe as an over-the-counter drug and it is reported to cause hemorrhage when co-administered with other anti-platelet agents. We set out to study the interactions of ticlopidine with Ginkgo biloba extract or VR456, a new highly standardized deterpened extract from Ginkgo biloba leaves. Male Wistar rats were used to study the effects of ticlopidine (50-100 mg/kg/day), given alone and in combination for 5 days with Ginkgo biloba extract (50 mg/kg/day) or VR456 (50 mg/kg/day), on bleeding time and ex vivo ADP-induced platelet aggregation measurements. In addition, human studies were performed with the compounds under investigation. Combined treatment of ticlopidine and undeterpened Ginkgo biloba extract increased anti-platelet effect and prolonged the bleeding time in the rat. On the contrary, the combination treatment of ticlopidine and VR456 increased anti-platelet effect but did not prolong bleeding time. Moreover, daily administration of 360 mg of VR456 for 14 days to ticlopidine-treated humans did not highlight any unwanted effect and did not alter PT/INR and PTT parameters. Same results have been also obtained in warfarin or in cardioaspirin-treated patients. These data point out the clear role played by the terpenoid, PAF-antagonist fraction of Ginkgo biloba extract in affecting bleeding risk in anticoagulant-treated subjects and suggest VR456 as a possible option treatment in geriatric people subjected to anticoagulant treatment where the use of standard Ginkgo biloba extracts are discouraged. PMID- 22530458 TI - Vaccine co-administration in paediatric age: the experience of the Local Health Unit of Cuneo-1 (Ambito di Cuneo), Italy. AB - BACKGROUND AND AIM OF THE WORK: The immunization schedule might be continuously updated on the basis of the new scientific and epidemiological knowledge, possible changes in operational requirements and the availability of new products. A high vaccination compliance is strictly related to factors such as tolerability, effectiveness and number of injections. This last has always been a critical point and combined vaccines guarantee high levels of safety and immunogenicity requiring fewer injections and accesses to services. Co administration should be considered in order to expand the supply of important vaccinations, (eg. meningococcal and pneumococcal), avoiding the increase of the number of accesses to services. METHODS: Since January 2007, an experience with the co-administration of hexavalent vaccine together with conjugate pneumococcal and meningococcal C vaccines started at the LHU CN1-Ambito di Cuneo. The target of this co-administration, based on scientific criteria, is to provide immunization against St. pneumoniae and N. meningitidis in newborns. RESULTS: Considering that the coverage rate (VC%) with hexavalent vaccine has been always high and that, at the end of 2006, the VC% for the pneumococcal and meningococcal C conjugate vaccines were equal to 50.4% and 44.4%, in this first year of experience the compliance to co-administration has significantly increased from 47% of doses administered in the first quarter of 2007 to 65% in the first quarter of 2008. CONCLUSIONS: Co-administration could be an useful mean to introduce new immunizations into the vaccination schedule and to achieve high vaccination coverage rates. PMID- 22530459 TI - A survey on microorganisms and their sensitivity by E-test in ventilator associated pneumonia at Toxicological-Intensive Care Unit of Loghman-Hakim Hospital. AB - INTRODUCTION: Ventilator associated pneumonia (VAP) is the most common nosocomial infection at ICUs, with high mortality and morbidity. The diagnostic method for VAP is based on the combination of clinical, radiological, and microbiological criteria. Lower respiratory tract culture results are useful to confirm the etiology of VAP and adjusted antibiotics. Endotracheal aspiration (EA) is the simplest noninvasive technique for performing lower respiratory tract culture, with high sensitivity and moderately high specificity. The aim of this survey was to evaluate the quantitative cultures of endotracheal aspirates in VAP patients and the sensitivity patterns of microorganisms through E-test. METHOD: Among 582 ICU admitted patients who were under mechanical ventilation for more than 48 hours, 72 suspected patients of VAP were prospectively evaluated during a 10 month period. Evaluation of our ICU standards by APACHE III scoring, and GCS were carried out on the first day of admission in all patients. Quantitative cultures of EA were performed on all 72 patients. Antibiotic resistance pattern of isolated pathogens was defined by E-test. RESULTS: VAP was confirmed in 46 out of 72 cases (50, 69.4% males and 22, 30.6% females - mean age was 33 +/- 12 years) through quantitative cultures of EA samples. The probable incidence of VAP was 7.9% (per ventilated patients > or = 48 hours). The mean APACHE III score was 31.28 +/- 16. GCS in most of the patients was between 8 and 12. Staphylococcus aureus was the most frequently isolated organism (58.7%), with high sensitivity to Amikacin, Ciprofloxacin, and Teicoplanin (>92%); Pseudomonas aeruginosa was the second most frequent organism (17.4 percent); Acinetobacter isolates were potentially drug resistant, and only Amikacin was effective. CONCLUSION: Tracheal aspirates in combination with clinical findings show important roles in the management of VAP and decrease inappropriate antimicrobial therapy. S. aureus is the main agent leading to VAP in the TICU of the Loghman Hakim Hospital. PMID- 22530460 TI - Coxibs: a significant therapeutic opportunity. AB - Pain is the main reason why people decide to see a doctor; hence, the widespread use of anti-inflammatory drugs which were specifically developed to control pain and inflammation. One of the main causes of pain is represented by osteoarticular conditions, the most common one being arthrosis. Paracetamol is universally indicated as the therapy of first choice in degenerative pathologies of the joints, although it is often insufficient to control adequately the clinical picture and less efficacious than anti-inflammatory drugs. These latter, however, especially when taken chronically, exhibit an unfavourable safety profile. The most common side effect of anti-inflammatory drugs is gastric discomfort; coxibs COX-2 selective inhibitors - were developed to solve this problem. The use of these drugs, relative to conventional NSAIDs, is associated to a significantly lesser gastroduodenal ulcer rate and to fewer clinically relevant complications, as well as to a smaller rate of treatment discontinuation due to gastrointestinal (GI) symptoms. From a clinical and practical standpoint, the use of coxibs is associated to a remarkably reduced risk of gastroduodenal lesions, similar as the one resulting from the combination of a conventional NSAID and a proton-pump inhibitor. By adding a proton-pump inhibitor to a coxib, such risk seems to become virtually non-existent, even in a high risk population and regardless of ASA administration. It is important to stress that the better tolerability of coxibs does not imply an inferior anti-inflammatory and pain-relieving efficacy, especially with regard to etoricoxib, whose efficacy is at least equivalent as other competing NSAIDs, even in quite severe and complex musculoskeletal pain models. This clear-cut advantage of coxibs at gastric level clashed against a documented increased cardiovascular (CV) risk, which led to the much-talked-about withdrawal of rofecoxib from the market. The most credited pathogenetic hypothesis to explain the association between chronic use of coxibs and CV risk seems to be related to a trombophilic effect due to an imbalance of prothrombotic and antithrombotic factors. Several observational and case-control studies, however, led to suspect that conventional NSAIDs share with coxibs an increased cardiovascular risk; such suspicion was experimentally confirmed by the MEDAL trial. In this trial, the cardiovascular risk of thrombosis among patients who were treated on a long-term basis with a coxib (etoricoxib) was shown to be similar as the risk observed in patients receiving a conventional NSAID (diclofenac). In conclusion, coxibs represent a valid therapeutic option in the treatment of patients with osteoarticular conditions. In terms of cardiovascular risk their efficacy is associated to a similar safety profile as conventional NSAIDs, whereas the gastrointestinal risk related to coxibs seems to be significantly lesser. PMID- 22530461 TI - Brain abscess of odontogenic origin in a man with interatrial defect. AB - A 65-year-old man with previous surgery for cyanotic congenital heart disease was admitted to our hospital with fever, headache and visual disturbances due to a right occipital brain abscess as shown through CT-scan. A comprehensive workup looking for a source of infection was negative except for an orthopantomogram showing multiple dental caries. A transesophageal echocardiogram (TEE) bubble study revealed the permanence of an atrial septal defect with a moderate right-to left shunt. The culture of the abscess content showed flora commonly found in the oropharynx that responded to antimicrobial therapy. We hypothesize that the underlying mechanism is a significant bacterial load from dental infections that enters the arterial circulation through the interatrial defect. If a brain abscess is identified without any adjacent source of infection, then a transesophageal echocardiogram is indicated to exclude right to left shunt. If a shunt is found, then hematogenous spread of flora normally found in the oropharynx should be suspected. Surgical evacuation followed by antimicrobial therapy is warranted. Once the infection is eliminated, long term anticoagulation or anatomic closure of the interatrial defect with good oral hygiene could be valid strategies for preventing recurrence. PMID- 22530462 TI - Advanced adenocarcinoma of terminal ileum: an unusual neoplasm revealed by an unusual diagnostic tool. AB - BACKGROUND AND AIM: Terminal ileum adenocarcinoma is a rare tumour. Its incidence or prevalence among the other sites of gastro-intestinal tract is unknown, since it has been only sporadically described. Since contrast enhanced ultrasonography has been recently used to study bowel alterations in the course of neoplastic or inflammatory disorders, we report here a case of a rare tumour (terminal ileum poorly differentiated adenocarcinoma) in which the investigation played a pivotal role to obtain a defined diagnosis. MATERIALS AND METHODS (CASE REPORT): Here we report the case of a 62 year old male patient. Due to intestinal occlusive symptoms and body weight decrease of about 8 Kg, he performed an abdominal computed tomography, intestinal magnetic resonance with double contrast medium, colonoscopy and contrast enhanced ultrasonography using a second generation medium. RESULTS: In our case the peculiar aspect is that no arterial enhancement was observed and the finding remained unchanged for about 2.48 minutes as well as after a further administration of 1.5 ml of contrast medium. This aspect was not suggestive of an active inflammation such as Crohn's disease, where a marked contrast medium enhancement should be expected. CONCLUSIONS: At present it is too speculative to emphasize contrast enhanced ultrasonography as usefulness tool in the diagnosis of terminal ileum tumors. Nevertheless, our preliminary experience strongly encourages the diffusion of the method. PMID- 22530463 TI - Synovial sarcoma of the foot enlightening etiology: a case report. AB - Synovial sarcoma which mainly affects the periarticular tissues of the extremities in young adults is an uncommon seen soft tissue sarcoma with uncertain causative factors. We report a long-course primary synovial sarcoma of the left foot in a 46-year-old man. The initial symptom occurred when he was 26 year-old. During these 20 years, he underwent two operations, with the diagnosis of synovial cyst and nodular synovitis. This time, a lobulated 7 x 5.5 x 6 cm mass was found on computed tomography, and a final diagnosis of synovial sarcoma was made by histological study. The patient underwent a below knee amputation. We report this case aiming to discuss about the potential etiology of synovial sarcoma. Physicians should be aware of the possibility of this malignant mass. PMID- 22530464 TI - [Riks-HIA will develop a new index for areas with room for improvement]. PMID- 22530465 TI - [Mammography screening is here to stay. Individual screening programs may be more effective]. PMID- 22530466 TI - [Mortality in breast cancer is decreasing--but not because of screening. Time to abolish the mammography screening]. PMID- 22530467 TI - [Eye screening in the maternity ward is efficient. Time for more distinct Swedish guidelines, according to prospective registry study]. PMID- 22530468 TI - [Adaptation of the continuity of care for mental retardation and dementia. Experiences from Kristianstad demonstrate the need of interventions near the patient ]. PMID- 22530469 TI - [Acute salicylate poisoning may cause non-cardiogenic pulmonary edema]. PMID- 22530470 TI - [Equalis criteria for carotid artery diagnostics--under continuous revision]. PMID- 22530471 TI - ["If subordinates were to be negligent in their position..."Processing in 200 years of medical error in Sweden]. PMID- 22530472 TI - Variability of postoperative esophagrams after endoscopic cricopharyngeal myotomy: technique dependence. AB - OBJECTIVES: We illustrate the dependence of postoperative day (POD) 1 esophagram findings on the closure technique used after endoscopic cricopharyngeal myotomy (ECPM). METHODS: We performed a retrospective chart review of POD 1 fluoroscopic examinations of the cervical esophagus utilizing contrast dye after ECPM to assess radiologic findings associated with three different techniques of addressing the exposed buccopharyngeal fascia (BPF). RESULTS: Each technique resulted in specific and different findings on the POD 1 esophagram. When the BPF was untreated, the esophagram demonstrated a pseudodiverticulum with free flow of contrast dye. When a fibrin glue seal was used, the esophagram demonstrated a curvilinear focus of contrast dye projected over the retropharyngeal soft tissue persisting after the swallow, similar to a leak. When fibrin glue application was combined with single-suture reapproximation of the mucosal incision, the pattern was similar to esophagrams performed 6 weeks after myotomy. CONCLUSIONS: Different techniques used to address the exposed BPF following ECPM result in specific findings on the POD 1 esophagram. Recognition of these imaging differences and open communication with the fluoroscopist will avoid a misdiagnosis of a pharyngeal leak, which might cause an unnecessary delay of oral feeding and hospital discharge. PMID- 22530474 TI - Rate of recurrent vestibular schwannoma after total removal via different surgical approaches. AB - OBJECTIVES: The objective of this study was to assess the differences in the recurrence rates of vestibular schwannoma (VS) after total tumor removal through enlarged translabyrinthine (ETL), retrosigmoid (RS), and middle cranial fossa (MCF) approaches. Our results were compared with previously published data, and literature reviews were done to identify the possible causes for the recurrence of VS. METHODS: We performed a retrospective analysis of 2,400 cases of VS that underwent removal at the Gruppo Otologico, Piacenza, Italy, from 1983 until 2010. The minimum postoperative follow-up was 12 months. We also reviewed the previously published data on recurrence rates of VS after ETL, RS, and MCF approaches. RESULTS: Total tumor removal was achieved in 2,252 cases (93.8%). The recurrence rate was 0.05% for the ETL approach, 0.7% for the RS approach, and 1.8% for the MCF approach. Literature reviews of 3 previously published case series utilizing the translabyrinthine approach showed that none of the primary tumors were less than 2.0 cm in size. Recurrences were seen between 1 and 13 years after the initial surgery. CONCLUSIONS: The rate of VS recurrence after total removal is exceptionally low in experienced hands. Undetected microscopic deposits left on crucial points such as the facial nerve, the preserved cochlea nerve, or the fundus of the internal auditory canal could be possible causes for the recurrence. A definite advantage of an ETL approach is the excellent internal auditory canal exposure, resulting in an extremely low rate of VS recurrence. The patients should be followed up to 15 years with gadolinium-enhanced magnetic resonance imaging (with fat suppression sequence in ETL approach cases). Recurrent VS may exhibit a faster growth rate than primary VS. PMID- 22530473 TI - Reducing fistula rates following laryngotracheal separation. AB - OBJECTIVES: Laryngotracheal separation (LTS) is an uncommonly performed but highly effective procedure for intractable aspiration in patients with amyotrophic lateral sclerosis and other neurodegenerative conditions. Previously published series have noted rates of postoperative tracheocutaneous fistula formation as high as 1 in 3 patients. This report details the use of a muscle flap-reinforced imbrication technique to reduce the incidence of fistula formation after LTS surgery. METHODS: All patients who underwent LTS surgery at the reporting institutions between 2004 and 2010 were identified. The principal diagnosis, patient characteristics, the presence of a preexisting tracheotomy, and postoperative complications were recorded. We describe the technique for imbrication closure of the proximal stump with strap muscle reinforcement. RESULTS: Thirteen patients (10 male, 3 female; median age, 53 years; interquartile range, 45 to 66 years) underwent the LTS procedure; amyotrophic lateral sclerosis was the principal diagnosis in 8 of the 13 patients. Six patients had a preexisting tracheotomy. None developed tracheocutaneous fistula, hematoma, or wound infection. Two patients required stomaplasty at a later date. CONCLUSIONS: Strap muscle flap-reinforced imbrication closure of the proximal tracheal stump after LTS surgery allows for a low incidence of postoperative fistula formation. PMID- 22530475 TI - Risk factors for deterioration of bone conduction hearing in cases of labyrinthine fistula caused by middle ear cholesteatoma. AB - OBJECTIVES: We evaluated the risk factors and outcomes of bone conduction (BC) hearing in cases of labyrinthine fistulas treated under the basic principle of complete removal of the cholesteatoma matrix. METHODS: A total of 47 patients with labyrinthine fistulas were analyzed. The fistulas were classified into smaller (no more than 3 mm) and larger fistulas (more than 3 mm). The fistulas were classified by depth into 3 stages. Preoperative symptoms and postoperative results with special reference to BC hearing were analyzed. RESULTS: Total preoperative loss of BC hearing was found in 3 of 36 ears (9%) in the smaller fistula group and 4 of 11 ears (36%) in the larger-fistula group; this was a statistically significant difference. The BC hearing was preserved after operation in 30 of 31 ears (97%) in the smaller-fistula group and 5 of 7 ears (71%) in the larger-fistula group; this difference was also significant. The stage (depth) of the fistula did not correlate with the postoperative BC hearing. CONCLUSIONS: In smaller labyrinthine fistulas, complete removal of the cholesteatoma matrix can be relatively safely performed. However, in patients with larger fistulas, there is a potential for a complete loss of BC hearing. PMID- 22530476 TI - Postoperative results of tympanoplasty with mastoidectomy in elderly patients with chronic otitis media. AB - OBJECTIVES: We evaluated the long-term results of tympanoplasty with mastoidectomy in elderly patients with chronic otitis media (COM). METHODS: We included 192 patients with intractable COM who underwent both tympanoplasty and mastoidectomy from the same surgeon between January 2003 and December 2006 and were followed up for more than 3 years. The patients were divided into two groups: an "old COM group" of 83 patients (more than 65 years of age) and a "young COM group" of 109 patients (between 21 and 40 years of age). We compared the preoperative and postoperative levels of hearing, the types of tympanoplasty and mastoidectomy, and the postoperative complications of the two groups. RESULTS: Among the old COM group, 11 patients (13.3%) showed temporary postoperative complaints without serious sequelae. Between the old and young COM groups, there were no significant differences in the rates of associated cholesteatoma, middle ear swab culture results, or type of tympanoplasty, ossiculoplasty, and mastoidectomy. In the comparison of postoperative hearing improvement, both the old and young COM groups showed a significant decrease in airbone gap, although the old COM group showed a significantly worse preoperative air-bone gap. There were no significant differences in the rates of re perforation of the tympanic membrane or of reoperation between the two groups. CONCLUSIONS: From this study, we conclude that there is no reason to withhold surgery for COM on the assumption that older patients do not have good results or that the procedure is too risky. PMID- 22530477 TI - Evaluation of volitional and reflexive swallowing in elderly patients with a history of pneumonia. AB - OBJECTIVES: Precise assessment of the risk of aspiration is critical in older patients with a history of pneumonia. However, the currently popular videofluoroscopic and videoendoscopic examinations of swallowing only evaluate volitional swallowing. A method for quantitative analysis of reflexive swallowing is not yet available. METHODS: We evaluated volitional swallowing in the sitting position by videoendoscopic examination and then measured the volume of injected water that triggered reflexive swallowing in the supine position in 54 patients with a history of pneumonia and 24 control patients of a similar age who had no history of pneumonia. RESULTS: The volume of injected water that triggered reflexive swallowing was larger in the pneumonia group than in the control group (mean, 1.64 +/- 0.61 mL versus 0.71 +/- 0.28 mL; p < 0.001). Both impaired volitional swallowing and impaired reflexive swallowing independently correlated with a history of pneumonia. CONCLUSIONS: The endoscopic supine swallow-evoking test ("ESSET") may detect previously omitted risk factors for aspiration in patients who can volitionally swallow. PMID- 22530478 TI - Assessment of a neurophysiological model of the mandibular branch of the facial nerve in rats by electromyography. AB - OBJECTIVES: Our objective was to develop an experimental model for the noninvasive and objective evaluation of facial nerve regeneration in rats using a motor nerve conduction test (electromyography). METHODS: Twenty-two rats were submitted to neurophysiological evaluation using motor nerve conduction of the mandibular branch of the facial nerve to obtain the compound muscle action potentials (CMAPs). To record the CMAPs, we used two needle electrodes that were inserted into the lower lip muscle of the rat. A supramaximal electrical stimulus was applied, and the values of CMAP latency, amplitude, length, area, and stimulus intensity obtained from each side were compared by use of the Wilcoxon test. RESULTS: There was no significant difference (all p > 0.05) in latency, amplitude, duration, area, or intensity of stimuli between the two sides. The amplitudes ranged between 1.61 and 8.30 mV, the latencies between 1.03 and 1.97 ms, and the stimulus intensities between 1.50 and 2.90 mA. CONCLUSIONS: This is a noninvasive, easy, and highly reproducible method that contributes to an improvement of the techniques previously described and may contribute to future studies of the degeneration and regeneration of the facial nerve. PMID- 22530479 TI - Long-term postoperative vocal function after thyroplasty type I and fat injection laryngoplasty. AB - OBJECTIVES: We evaluated the differences in the long-term functional results of medialization thyroplasty type I (MT) and autologous fat injection laryngoplasty (FIL) in patients with unilateral vocal fold paralysis. METHODS: Forty-one patients underwent MT, and 73 patients underwent FIL. The voice functions before and after both surgeries were examined by aerodynamic, pitch and intensity, and acoustic analyses. The postoperative voice examinations were performed 12 months (median) after the MT, and 4 years (median) after the FIL. The differences between the preoperative and postoperative parameters were examined with a paired t-test for each group separately. For each variable, a comparison of the effects of surgery was conducted with an analysis of covariance model, with the change between the preoperative and postoperative values as the dependent variable and the preoperative value as the covariate. RESULTS: In both groups, all parameters significantly improved after surgery. In particular, there was a significant difference for the postoperative acoustic analyses. However, the aerodynamic analysis after FIL improved more significantly in comparison to that after MT because of the respiratory handicap. CONCLUSIONS: We found that MT and FIL provided almost the same effectiveness, and that both surgeries were reliable in improving the vocal function in patients with vocal fold paralysis. PMID- 22530480 TI - Modified osteoplastic flap approach for frontal sinus disease. AB - OBJECTIVES: We review the use and outcomes of osteoplastic flap surgery in the current era of almost entirely endoscopic management of frontal sinus disease. METHODS: A retrospective review was performed of 312 consecutive sinus surgeries performed for frontal sinus disease at the University of Iowa Hospitals and Clinics from July 2002 to July 2008. RESULTS: Seventeen subjects (10 men and 7 women; mean age, 56 years) were identified. The indications for osteoplastic flap surgery were laterally located mucoceles in 8 patients, tumors in 7 patients, and osteomyelitis in 2 patients. Ten patients had skull base erosion, and 5 underwent cranialization for large posterior frontal bone defects. The average blood loss was 175 mL, and the average hospital stay was 3 days. There were no major intraoperative or perioperative complications. Two patients with mucoceles required revision surgery for disease recurrence. The mean follow-up was 25 months (range, 6 to 66 months). CONCLUSIONS: Osteoplastic flap surgery is an uncommon procedure in the modern endoscopic era of sinus surgery. In our series it was most commonly indicated for laterally located disease. Osteoplastic flap surgery is relatively safe and effective for a wide range of recalcitrant and complicated frontal sinus disorders. PMID- 22530481 TI - DFNA5, a gene involved in hearing loss and cancer: a review. AB - OBJECTIVES: The DFNA5 gene was identified in 1998 as a gene that causes an autosomal dominant form of hearing impairment. Five different DFNA5 mutations have been found; each results in skipping of exon 8 at the messenger RNA level. This finding indicates that DFNA5-associated hearing loss is attributable to a highly specific gain-of-function mutation. Interestingly, later reports revealed that DFNA5 also plays a role in tumor biology. METHODS: Recent data have shed more light on the biological function of DFNA5. Through a literature search, the current knowledge of this gene is reviewed. RESULTS: DFNA5 is the first gene for monogenic deafness that is known to involve apoptosis as a disease mechanism--a mechanism that was shown to be involved in frequent types of hearing loss caused by age, noise, or drugs. In line with its apoptosis-inducing properties, DFNA5 is a tumor suppressor gene with an important role in major types of tumors. CONCLUSIONS: DFNA5 is a tumor suppressor gene that is involved in apoptosis pathways and as such performs a basic role in cell survival. In view of the known role of apoptosis in several forms of hearing loss, DFNA5 may be a player in the underlying disease mechanisms. PMID- 22530482 TI - Distribution of gentamicin in inner ear after local administration via a chitosan glycerophosphate hydrogel delivery system. AB - OBJECTIVES: We examined the distribution of gentamicin sulfate in the inner ear after delivery via a chitosan glycerophosphate (CGP) hydrogel system and examined the change in morphology of the hair cells so as to determine how gentamicin affected the function of the inner ear. METHODS: A matrix of CGP hydrogel loaded with gentamicin conjugated with Texas Red (GTTR) was injected into the round window niche of the left ear of C57/BL6 mice. The mice were painlessly killed on day 1 or day 7 after injection. Confocal fluorescence microscopy was used to locate the gentamicin in the cochlear and vestibular systems. RESULTS: In the vestibule, the intensity of GTTR staining in the hair cells of the macula of the saccule on day 1 was significantly stronger than that on day 7, and the number of hair cell bundles on top of the cuticular plate on day 7 was obviously decreased in comparison to that on day 1. In the cochlea, the intensity of GTTR staining in the basal turn was significantly stronger than that in the medial turn on both day 1 and day 7. Negligible fluorescence was observed in the apical turn on both day 1 and day 7. Less-intense GTTR staining was detected on day 7 than on day 1 in both the basal turn and the medial turn. There was some outer hair cell loss in the basal turn on day 7, and no hair cell loss in the medial and apical turns at any time point. CONCLUSIONS: Gentamicin is distributed in the inner ear via the CGP hydrogel delivery system in a time-dependent and basal-to-apical manner. This finding implies that the vestibule and the basal turn may retain more gentamicin for a longer period than do other sites in the inner ear. These two characteristics may account for the high-frequency hearing loss and vestibular dysfunction seen with use of this system to deliver gentamicin into the inner ear. PMID- 22530483 TI - Geographical expansion and the reconfiguration of medical authority: Garcia de Orta's Colloquies on the simples and drugs of India (1563). AB - The Colloquies on the simples and drugs of India (1563) were conceived and published at a sensitive moment, both in terms of the history of print culture and of European geographical expansion. They represented the culmination of a life-time project for their author Garcia de Orta who had lived for almost thirty years in Portuguese Goa. Although the importance of the work in sixteenth-century natural history and medicine has been generally acknowledged in Portuguese and international historiography, there are very few recent, detailed studies of the book informed by new approaches. This paper presents an integrated analysis of Orta's Colloquies as a literary, medical and cultural text. It aims to reveal not only the rich and subtle dynamics of the work but also to contribute to a better understanding of Orta's legitimation strategies as an author in a sixteenth century world reconfigured by the new opportunities of the printing press, geographical expansion and increased material and cultural mobility. PMID- 22530484 TI - From Bacon to Banks: the vision and the realities of pursuing science for the common good. AB - Francis Bacon's call for philosophers to investigate nature and "join in consultation for the common good" is one example of a powerful vision that helped to shape modern science. His ideal clearly linked the experimental method with the production of beneficial effects that could be used both as "pledges of truth" and for "the comforts of life." When Bacon's program was implemented in the following generation, however, the tensions inherent in his vision became all too real. The history of the Royal Society of London, from its founding in 1660 to the 42-year presidency of Joseph Banks (1778-1820), shows how these tensions led to changes in the way in which both the experimental method and the ideal of the common good were understood. A more nuanced understanding of the problems involved in recent philosophical analyses of science in the public interest can be achieved by appreciating the complexity revealed from this historical perspective. PMID- 22530485 TI - Kuhn and the genesis of the "new historiography of science". AB - In this paper I identify a tension between the two sets of works by Kuhn regarding the genesis of the "new historiography of science". In the first, it could be said that the change from the traditional to the new historiography is strictly endogenous (referring to internal causes or reasons). In the second, the change is predominantly exogenous. To address this question, I draw on a text that is considered to be less important among Kuhn's works, but which, as shall be argued, allows some contact between Kuhn's two approaches via Koyre. I seek to point out and differentiate the roles of Koyre and Kuhn--from Kuhn's point of view--in the development of the historiography of science and, as a complement, present some reflections regarding the justification of the new historiography. PMID- 22530486 TI - The spiral of scientific culture and cultural well-being: Brazil and Ibero America. AB - The set of factors, events and actions of mankind in the social processes dedicated to the production the dissemination, the teaching and the publication of scientific knowledge constitutes the conditions for the development of a particular type of culture, quite commonplace in the contemporary world, which may be called scientific culture. In this article, we intend to present the representation of the dynamics of this area of knowledge in the form of a spiral: The Spiral of Scientific Culture. Also, we introduce the term cultural well-being -the kind of comfort, other than the social well-being, which has to do with society's relationships with the technosciences, involving values and attitudes, habits and information, and presupposing an actively critical participation on the part of that society in the totality of these relationships. PMID- 22530487 TI - Investigating CSI: portrayals of DNA testing on a forensic crime show and their potential effects. AB - The popularity of forensic crime shows such as CSI has fueled debate about their potential social impact. This study considers CSI's potential effects on public understandings regarding DNA testing in the context of judicial processes, the policy debates surrounding crime laboratory procedures, and the forensic science profession, as well as an effect not discussed in previous accounts: namely, the show's potential impact on public understandings of DNA and genetics more generally. To develop a theoretical foundation for research on the "CSI effect," it draws on cultivation theory, social cognitive theory, and audience reception studies. It then uses content analysis and textual analysis to illuminate how the show depicts DNA testing. The results demonstrate that CSI tends to depict DNA testing as routine, swift, useful, and reliable and that it echoes broader discourses about genetics. At times, however, the show suggests more complex ways of thinking about DNA testing and genetics. PMID- 22530488 TI - Mediating subpolitics in US and UK science news. AB - The development of therapeutic cloning research sparked a scientific controversy pitting patients' hopes for cures against religious and anti-abortion opposition. The present study investigates this controversy by examining the production and content of Anglo-American print media coverage of the branch of embryonic stem cell research known as "therapeutic cloning." Data collection included press articles about therapeutic cloning (n = 5,185) and qualitative interviews with journalists (n = 18). Patient activists and anti-abortion groups emerged as key news sources in this coverage. Significant qualitative differences in the mediation of these subpolitical groups and their arguments for and against therapeutic cloning are identified. Results suggest that the perceived human interest news value of narratives of patient suffering may give patient advocacy groups a privileged position in journalistic coverage. Finally, Ulrich Beck's theoretical arguments about subpolitics are critically applied to the results to elicit further insights. PMID- 22530489 TI - Managing uncertainties: the making of the IPCC's special report on carbon dioxide capture and storage. AB - Carbon dioxide capture and storage (CCS) is a technology that receives growing recognition because of its extremely great in mitigating climate change. However, uncertainties concerning the viability of this approach exist. With this background, the Intergovernmental Panel on Climate Change (IPCC) published a report in 2005 assessing of CCS. This article discusses the compilation process of the report, based on information collected through interviews with key participants and document research, highlighting how CCS's key uncertainties were estimated in the face of two disparate needs: scientific rigor and policy relevance. PMID- 22530490 TI - Values, objectivity and credibility of scientists in a contentious natural resource debate. AB - In contentious natural resource debates, the credibility of scientists is at risk. In this case study, citizens in contending communities and scientists in a forest management controversy constructed the scientists' credibility differently. Shared values and views of the nature of science and objectivity were primary factors for constructing scientists' credibility. Citizens who expected value-free, objective scientists to authenticate their knowledge were concerned about how the values of scientists on the opposite side affected research framing. Citizens who emphasized limited objectivity were less skeptical of scientists. Scientists acknowledged their values but defended their credibility in terms of professional standards, balance and resource constraints. In short, scientists' credibility is relative because each individual has unique values and views of the nature of science and objectivity. Through a collaborative policymaking process, citizens and scientists should develop shared values and visions to reconstruct a temporary, intersubjective sense of credibility. PMID- 22530491 TI - [Evidence based medicine - -historical perspectives on contingency of scientific objectivity]. PMID- 22530492 TI - [What is EBM and what is not?]. PMID- 22530493 TI - ["I bet 10 to 1 that you will feel something unusual even without faith". The table salt trials of Nurnberg - a ground breaking experiment as a result of public dispute]. PMID- 22530494 TI - [Summation toxins. On the evidence problem of the pharmacology of cancer-inducing substances in the 1950's]. PMID- 22530495 TI - [Evidence - "counter public" as program. The development of pharmaceutical care]. PMID- 22530496 TI - [Long-lived smoking mice and self mutilation. On the genealogy of the smoking ban at the work site in West Germany (1930-1990)]. PMID- 22530497 TI - [Is passive smoking carcinogenic? German toxicologists and their link with the tobacco industry]. PMID- 22530498 TI - [Evidence in conflict of interest: the passive smoking example]. PMID- 22530499 TI - Advances in high-throughput methodologies for crystallizing proteins. PMID- 22530500 TI - LC-MS-based protein and peptide quantification using stable isotope labels: from ICAT in general to differential N-terminal coding (dNIC) in particular. PMID- 22530501 TI - Crosslinking strategies for the study of membrane protein complexes and protein interaction interfaces. PMID- 22530502 TI - History and current status of nuclear transfer cloning. PMID- 22530503 TI - Promoting gene therapy: expression systems for transgenes and posttranscriptional gene silencing. AB - In this review, we have discussed expression systems employed for both transgene expression and post-transcriptional gene silencing. Although constitutive expression systems can function well for gene therapy protocols for simple Mendelian disorders, other protocols may require carefully designed systems that either ensure targeting to cells of interest or alternatively, transcription that is tightly regulated and conditionally activated. Indeed, it is of utmost importance to regulate expression of potentially immunogenic proteins, such as those encoded by suicide genes, to limit their immunogenic potential. Meanwhile, RNAi may be employed for therapeutic silencing of aberrant cellular or viral genes, but the potential for off-target effects due to activation of double stranded RNA response pathways or undesired targeting of partial complementary sequences may necessitate carefully controlled and regulated expression of short hairpin RNAs. As we exhaust the current repertoire of simple promoter systems for transgene expression or for RNAi, we need to develop newer systems that combine the high activity of viral promoters with cell type specificity or conditionally active cis-elements. Novel combinations of promoter elements should be one approach for creating such regulated promoters. PMID- 22530504 TI - Genome-wide mapping of histone modifications by GMAT. PMID- 22530505 TI - Signalling through chromatin modifications and protein-protein interactions. PMID- 22530506 TI - Insect transgenesis: mechanisms, applications, and ecological safety. AB - The ability to routinely genetically modify insect species holds great promise for fundamental research that explores the functional activity of genomic sequences, and the use of this information to control the viability, fitness, and behaviour of both beneficial and pest insects. Currently, almost all insect genetic modifications rely on the use of transposon vector systems, and a detailed understanding of the mechanisms that result in mobility is critical to applications that require optimal or maximum frequencies of transposition, and to applications where immobilization is necessary for vector stabilization. Great progress has been made in understanding the biophysical mechanisms and interactions between the transposase enzyme for the Hermes and Mos1 transposons and their respective ITR sequence substrates, but the relevance of this knowledge to other transposon vectors can only be speculated upon. It is clear, however, that mutations in the transposon sequence can result in their hyperactivity, and an effective means of screening for these mutations should improve our understanding and applied use of all the available vectors. Progress also has been made in testing recombinant-based constructs for their ability to diminish the vectorial capacity of mosquito disease vectors, but the ability to drive these transgenes into an endemic population is largely unknown. Genetic drive systems, such as autonomous vectors or meiotic drive, have been speculated upon, but serious testing in targeted species remains to be done. Development of transgenic strains for biocontrol has also been initiated, especially for tephritid fruit flies, and conditional lethality systems may supersede current programmes such as SIT. To do so, nearly complete, if not complete lethality will be needed at a consistent level, and model systems have yet to achieve this. To develop such strains, repetitive introductions of transgene vectors into a host genome may be required, but a difficulty in comparing efficacy is the varying influence of different insertion sites on transgene expression and host fitness. A prospective problem for transposon-mediated vector insertions is the potential re-mobilization of the vector by an unintended source of transposase. The development of a new class of vectors that allow genomic targeting by RMCE, and transposon immobilization by ITR deletion, should have a significant impact on the efficient creation and testing of new transgenic strains, as well as minimizing the ecological risk of their release into the environment. PMID- 22530507 TI - Analysing the metabolic capabilities of Desulfovibrio species through genetic manipulation. PMID- 22530508 TI - Endophytic bacteria and their potential application to improve the phytoremediation of contaminated environments. PMID- 22530509 TI - Transformation-induced mutations in transgenic plants: analysis and biosafety implications. PMID- 22530510 TI - Self-processing polyproteins: a strategy for co-expression of multiple proteins in plants. PMID- 22530511 TI - Plantibodies: a novel strategy to create pathogen-resistant plants. PMID- 22530512 TI - Mechanisms controlling self-renewal and pluripotency in human embryonic stem cells. PMID- 22530513 TI - Adipose-derived mesenchymal cells (AMCs): a promising future for skeletal tissue engineering. PMID- 22530514 TI - Dendrimer-based drugs as macromolecular medicines. PMID- 22530515 TI - Patenting applied to genetic sequence information. PMID- 22530516 TI - [On the proper use of bibliometrics to evaluate physicians and scientists]. AB - Quantitative analysis of publications and their citations, a procedure known as bibliometrics, has become increasingly important in the evaluation of scientists and clinicians. In the clinical setting, bibliometrics is used for the calculation of hospital budgets. While bibliometrics is attractive because it rapidly provides numbers that bear a certain relation to scientific productivity, it is often misused. The parameters chosen are questionable and sometimes worthless because of material errors or inappropriate use. More importantly, reducing the activity of a scientist or physician simply to the number of his or her publications or citations, without analyzing the importance and impact of the work itself can lead to serious errors. PMID- 22530517 TI - [The burden of diabetes in Africa: a major public health problem]. AB - W.H.O. predicts that there will be some 438 million diabetic patients in 2030, most of them living in developing countries. The IFD estimates that the prevalence of diabetes will rise by 98% in Africa during the next 20 years, with dramatic implications for public health and national budgets of the poorest countries. Type 2 diabetes is the most common form in Africa; type 1 is rarer than in western countries and tends to occur later. Two other forms seem specific to black Africans: ketosis-prone atypical diabetes, and tropical malnutrition related diabetes. An increasing prevalence of obesity, diabetes and impaired glucose tolerance is observed in all parts of Africa. Several factors contribute to this situation, including aging, dietary transitions and lack of physical activity, all of which are related to rapid urbanization. In Africa, diabetes is associated with a high mortality rate, especially among insulin-dependent patients. Poor metabolic control can lead to severe ketosis and hypoglycemic accidents that carry a poor prognosis. Microvascular complications include retinopathy and nephropathy, and most patients cannot afford hemodialysis. Foot ulcers are frequent, due to trauma and neuropathies. Macrovascular complications are also increasing, with a high prevalence of hypertension. The poor prognosis of diabetes in Africa is related to late diagnosis, poor education, inadequate access to insulin, antidiabetic drugs and glycemia self-monitoring devices, absence of controlled diets, and difficult access to medical care in rural areas. Patient empowerment, knowledge and self-care must be improved. African governments must develop national prevention programs. Special attention must be paid to the prevention of obesity and diabetes. The urban environment, infrastructure, education, exercise and safe nutrition must be part of an overall policy designed to reduce the burden of chronic non transmissible diseases. PMID- 22530518 TI - [Smoking in developing countries: a health risk and a factor in poverty]. AB - Smoking is the leading preventable cause of death worldwide. In 2000, smoking related deaths (approximately 5 million) were evenly divided between industrialized and developing countries, whereas by 2030 it is expected that some 70-80% of the predicted 8-10 million smoking-related deaths will occur in developing countries. This heavy health burden is compounded by the economic burden of smoking at both the individual and national levels. Smoking aggravates poverty for both smokers and their families, diverting meager financial resources away from essentials such as food, education and healthcare. Women and children are the first victims. And, as tobacco consumption shifts increasingly from rich countries to poor countries, smoking represents a further obstacle to development, notably by increasing national healthcare costs and absorbing valuable arable land for tobacco cultivation. The tobacco industry is exploiting markets in developing countries through price cuts, smuggling, widespread advertising, and promotion of positive images of smokers. As in other countries, prevention campaigns must encourage young people not to start the habit, help current users to quit, and protect non-smokers from second-hand smoke. Developing countries have a special incentive to build on the Framework Convention on Tobacco Control (FCTC), the first international public health treaty signed under the auspices of WHO, adopted in 2003 and ratified by over 170 countries. This treaty not only plays a major role in health policy, but also constitutes a powerful instrument for economic development and resistance to manipulation by the tobacco industry PMID- 22530519 TI - [Particularities and management of arterial hypertension in sub-saharan Africa]. AB - More than 25% of adults worldwide have high blood pressure, and this proportion is expected to rise in coming years. In sub-Saharan Africa, it is estimated that 150 million persons will be hypertensive by 2025. This increase appears to be related to the growth and aging of the population, as well as to the growing number of overweight and obese persons. The association with type-2 diabetes is frequent and deleterious. These trends are associated with urbanization and lifestyle westernization. Hypertension presents several etiopathogenic particularities in sub-Saharan Africa, especially with respect to sodium sensitivity and low renin activity. Target organ damage is more common, due to delayed and inadequate therapeutic management and to a likely genetic predisposition. Heart failure, stroke and renal failure often occur in young people. The mainstay of treatment is the use of thiazide diuretics and calcium channel blockers, combined with lifestyle and dietary measures (especially sodium restriction). Because of logistic and economic difficulties, recommendations issued by international societies may not be applicable at the community level. PMID- 22530520 TI - [Microbiota and colorectal cancer: genotoxic bacteria in the intestinal tract]. AB - Numerous studies support a role for the intestinal microbiota in colorectal tumorigenesis. Although colon cancer has not yet been epidemiologically linked to specific bacterial species, recent results suggest that certain toxigenic commensal bacteria may be oncogenic Strains of Escherichia coli, a ubiquitous member of the colonic flora, synthesize a genotoxin called colibactin. These bacteria induce DNA double-strand breaks in intestinal cells and trigger chromosomal instability, gene mutations and cell transformation. Thus, long-term colonization of the colon by rogue commensal bacteria capable of causing chronic DNA damage could contribute to the development of sporadic colorectal cancer. PMID- 22530522 TI - [Principles of cognitive remediation in schizophrenia]. AB - Cognitive remediation is an innovative psychosocial therapy which can provide a substantial benefit, especially for schizophrenic patients. As its name implies, the aim of cognitive remediation is to restore cognitive functions. Most cognitive domains (attention, memory and executive functions) are impaired in schizophrenia. Remediation therapy must be administered by an expert, and is based on cognitive training on the one hand, and on learning of cognitive strategies on the other hand. With these techniques the patient is better able to solve complex cognitive problems and to apply these new skills to everyday situations. Several techniques are available in France, using either computer based or paper/pencil approaches. The programs are administered over several months, with one or more sessions per week. Cognitive remediation itself provides only a modest cognitive benefit, which must be enhanced by the adjunction of other therapies such as behavioral therapy, learning of social skills, or a vocational program during the first months of employment. PMID- 22530521 TI - [Pharmacovigilance study of influenza A H1N1 vaccination during the 2009-2010 season in France]. AB - We analyzed safety data on A (H1N1) v vaccines collected by the French Network of Pharmacovigilance centers from 21 October 2009 to 15 June 2010, and reported online by both practitioners and patients. During the campaign, 4.1 millions doses of Pandemrix and 1.6 million doses of Panenza were administered. With Pandemrix, 4183 AEs were reported, including 193 "serious" events. With Panenza, 566 AEs were reported, including 70 "serious" events. The most frequently reported serious AEs were neurological disorders, both with Pandemrix (38.9%, mainly isolated ascending paresthesia, with no other neurological symptoms or complications) and with Panenza (39.9%). Febrile seizures were the most frequent neurological AEs in children vaccinated with Panenza. All reported deaths (n = 22) were attributed to causes other than recent A (H1N1) v vaccination. No causal relationship was established between the AEs and vaccination. Among AEs of particular interest, 13 cases of confirmed Guillain Barre syndrome and 15 cases of demyelinating disorders were notified. No reports of narcolepsy were received during the study period. This study shows that neurological AEs (isolated ascending paresthesia with Pandemrix and febrile seizures with Panenza) are among the most frequently reported serious AEs with both vaccines. Despite the limits of this survey, based on spontaneous reports, no alert signals were noted during 8 months of follow-up. The safety profile of A (H1N1) v vaccines appears similar to that of seasonal influenza vaccines. PMID- 22530523 TI - [Contribution of epidemiology to the prevention of drug allergies]. AB - Drug allergies are heterogeneous and multifactorial. They can be life-threatening and lead to market withdrawal of particularly risky drugs. Immunological research has improved our understanding of drug allergies but has not yet been able to prevent them. In contrast, epidemiological research not only provides information on the incidence and risk factors of such reactions, but can now, in conjunction the most recent immunological data, also help to prevent some of them. For example, prior pholcodine consumption has been shown to increase the risk of anaphylaxis due to neuromuscular blocking agents during general anesthesia. This review examines the place of interventional epidemiology in the field of drug allergy, taking as examples both myorelaxant-induced anaphylaxis and abacavir induced DRESS. PMID- 22530524 TI - [Virtual endoscopic navigation and body transparency based on computed tomography. A step towards in vivo imaging]. AB - Progress in HR-CTdata processing has led to lower X-ray exposure and to better diagnostic performance. We describe 19 adult patients (among 5000) examined by HR CT with 64 detectors, acquisition and exposure protocols in mSv, spiral, 0.6-mm slices, 5To PACS. After the two usual processing steps (60 gray values, 5122 and 10242 matrices, dedicated workstations for coronaroscopy and virtual coloscopy, 2D multiplanar reformation, surfacic, 3D volumes with dissection and navigation), a third original data processing step on additional workstations was added. Variable matrix extrapolated images, flexible colored curves (different from anatomical conventions), lighting (sources) and transparencies (unavailable with traditional endoscopy) were used. The digital film is a 16-minute "journey "consisting of 19 endo-body navigations in 5 regions, from the head to the bronchi, from the heart to the coronary arteries, and from the digestive tract to the abdomen and pelvis. One possible application is post-operative verification of an aortic graft. The movie is illustrated here with ten plates. This new approach is cost-effective and beneficial for the patient, in terms of early diagnosis and therapeutic follow-up. Ethical issues are also examined. PMID- 22530525 TI - [Jean Fernel and the humanist spirit]. AB - Jean Fernel (1497-1558) embodied the humanist spirit of the Renaissance. He studied philosophy (especially Aristotle), astrology, arithmetic, mathematics and Latin literature before devoting his life to medicine. He conducted a comprehensive synthesis of the medical system of Galen, and invented the terms "physiology" and "pathology". His taste for teaching, his extensive clinical practice, his benevolent attitude to the sick, and his consideration for individuals and for human nature all contribute to Jean Fernel's image as a humanist. He was the most famous physician of his time, although his work relying on philosophy and galenic dogmatism eventually became obsolete. Forgotten for half a millennium, this distant precursor of holistic medicine is worthy of renewed interest. PMID- 22530526 TI - Occupy Wall Street, Bay Street and the street nearest you. PMID- 22530527 TI - The role of public health inspectors in maintaining housing in northern and rural communities: recommendations to support public health practice. AB - OBJECTIVE: Although there is much evidence about the effects of particular housing conditions on health, less is known about the practices of public health inspectors (PHIs) in relation to minimizing or eliminating potential housing health risks. The purpose of this qualitative study was to illuminate the practices of PHIs in relation to types of biological and physical housing risks. METHOD: This study used photo vignettes to focus on PHIs' perceptions, options, and resultant interventions with regards to typical housing risks encountered by PHIs in northeastern Ontario. The vignettes represented two general categories of potential housing risks: biological exposures, and physical characteristics of housing. During a semi-structured interview, 34 PHI participants viewed the vignettes, assessed the housing hazard depicted in each, and described the most appropriate intervention. Traditional content analysis methods were used. RESULTS: The assessment of the physical housing hazards was fairly consistent among the PHIs. There seemed to be more variation in their assessment of risk associated with biological factors. Variation in responses was often explained by their different interpretations of the scope of the provincial legislation as well as local public health unit policies and practices. CONCLUSION: This study demonstrated that PHIs' assessment and responses to potential physical housing hazards were influenced by an interplay between variables related to residents, local service partners, organizational culture, and policy. The recommendations for action also range from specific public health unit protocol to broader research and policy advocacy initiatives. Collectively, the recommendations focus on strategies for optimizing the role of PHIs in reducing housing health risks in mid-size urban or rural areas. PMID- 22530528 TI - Investigation of a pandemic H1N1 influenza outbreak in a remote First Nations community in northern Manitoba, 2009. AB - OBJECTIVES: First Nations communities in Manitoba were significantly affected by the pandemic H1N1 influenza virus (pH1N1) in 2009. Our objective was to conduct an epidemiologic investigation of a pH1N1 outbreak in one remote First Nations community (population 3,300) in northern Manitoba to inform a timely public health response and provide recommendations for preventing future outbreaks. METHODS: Chart reviews were conducted at the nursing station for patients meeting the influenza-like illness (ILI) case definition during the study period (April 20 to June 11, 2009). Descriptive analyses examined age, gender, clinical presentation, management, outcomes and risk factors. Comparisons were made for hospitalized versus non-hospitalized cases and laboratory-confirmed versus possible cases using Pearson's chi-square test for gender and symptoms and using a t-test for age. RESULTS: There were 180 ILI cases, including 23 laboratory confirmed cases of pH1N1. Forty percent of children < 1 year old in the community and 9.4% of pregnant women presented to the nursing station with ILI. Most ILI cases were managed through the community nursing station, although 18.3% of cases (n = 33) were medically evacuated and 16.1% (n = 29) were hospitalized. There were no differences between hospitalized versus non-hospitalized or laboratory confirmed versus possible cases. Risk factors identified in a subset of cases included exposure to an individual with ILI prior to illness onset, overcrowding and inadequate access to household water. CONCLUSIONS: Early arrival and rapid transmission of pH1N1 rendered usual non-pharmacological control measures largely ineffective. Recommendations for prevention of future outbreaks include an effective communications strategy and daily surveillance for disease detection and monitoring. Key determinants of health should be addressed in remote First Nations communities to prevent disease and protect the health of these populations. PMID- 22530529 TI - Household income, food insecurity and nutrition in Canadian youth. AB - OBJECTIVE: The contribution of nutrition to health inequalities is poorly understood, particularly with regard to children. The objective of this study was to examine the influence of income and the conjoint influence of low income and food insecurity on several dietary indicators in a representative sample of Canadian youth. METHODS: We used data from the Canadian Community Health Survey (CCHS) Cycle 2.2, a nationally representative population-based sample, to examine the diets of 8,938 youth aged 9-18 years. A single 24-hour recall was used to collect dietary information. Interviews were conducted in person, and anthropometric measurements were available for 71% of the sample. Estimates of variance were calculated using bootvar with weights specific to the CCHS. Generalized linear models were used to examine the associations between both low income and low-income food insecurity and anthropometric measures, food and nutrient intakes. RESULTS: Youth from low-income households had lower height percentiles than youth from higher-income households. Low-income girls (but not low-income boys) had a higher prevalence of BMI > or = 85th percentile than their higher-income counterparts. Among low-income food-insecure households, there was a higher prevalence of BMI > or = 85th percentile in boys than among the food secure low-income boys. Calcium and vitamin D intakes were lower among boys and girls living in low-income households. Similarly, milk consumption was lower in low-income boys. Low-income food-insecure girls had lower milk intakes and higher intake of sweetened beverages. CONCLUSIONS: We found some evidence of nutritional deprivation among Canadian youth from disadvantaged households. Longer-term indicators of nutritional status such as lower height and greater weight among disadvantaged households were consistent with these findings. PMID- 22530530 TI - A ban on marketing of foods/beverages to children: the who, why, what and how of a population health intervention. AB - There is increasing recognition in Canada and elsewhere of the need for population-level interventions related to diet. One example of such an intervention is a ban on the marketing of foods/beverages to children, for which several health organizations have or are in the process of developing position statements. Considering the federal government's inaction to impose restrictions that would yield meaningful impact, there is opportunity for the health community to unite in support of a stronger set of policies. However, several issues and challenges exist, some of which we outline in this commentary. We emphasize that, despite challenges, the present and predicted future of diet-related illness in Canadian children is such that population-level intervention is necessary and becoming increasingly urgent, and there is an important role for the health community in facilitating action. PMID- 22530531 TI - A review of findings from the Canadian Incidence Study of Reported Child Abuse and Neglect (CIS). AB - OBJECTIVE: This article critically assesses and reviews analyses derived from three cycles of the Canadian Incidence Study of Reported Child Abuse and Neglect (CIS) published between 2001 and October 2011. METHODS: Articles were retrieved from the Public Health Agency of Canada's data request records, which tracked database access and ensuing publications. The included articles were reviewed and appraised independently by the authors. SYNTHESIS: Overall, 37 peer-reviewed articles using CIS data were included in the review. These articles revealed an increased likelihood of substantiation or placement if investigations 1) uncovered the presence of emotional or physical harm in a child, 2) involved older children, 3) identified the presence of risk indicators in caregivers, or 4) documented unstable or unsafe housing. A similar proportion of articles used a descriptive or multivariate approach to analyze CIS data, and strengths and limitations were identified. CONCLUSION: Researchers have analyzed and interpreted the CIS extensively, although several issues are understudied - such as neglect and emotional maltreatment - especially using multivariate approaches. We hope this review will contribute to helping address gaps in the CIS literature. PMID- 22530532 TI - Risk of childhood asthma prevalence attributable to residential proximity to major roads in Montreal, Canada. AB - OBJECTIVES: Exposure to traffic-related air pollutants plays a role in several health outcomes. A large body of evidence tends to link asthma in children with traffic exposure. Increasing asthma prevalence and incidence in children in Canadian cities has been of concern for public health authorities. The following study focuses on estimating the risk of asthma prevalence attributable to residing in proximity to major roads on the Island of Montreal, Canada. METHODS: Risk functions pertaining to asthma in children and residential proximity to major roads were selected from the literature and applied to Montreal. Asthma prevalence was taken from population-based studies. Population data were retrieved from Canadian census. Exposure was estimated using the proximity to major road and highway category of the Desktop Mapping Technologies Inc. database (DMTI Spatial Inc.). RESULTS: Based on different studies, the percentage of prevalent asthma cases attributable to residing within 50 metres of a major road or highway for children aged 2, 4 and 6 years varied between 2.4% (0-4.3), 5.6% (0.1-8.6) and 5.9% (0.1-9.0). For the 5-7 year age group residing within 75 m of a major road or highway, the percent of cases was 6.4% (2.6-9.3). For children aged 8 to 10 residing within 75 m of a highway only, the percent of cases was 0.7% (0.2-0.9). CONCLUSION: These numbers represent the best crude estimates and are an indication of a possible range of cases linked to residential proximity to major roads. As there are uncertainties linked to the application of exposure response functions, these estimates will be reassessed as new evidence is gathered through further research. PMID- 22530533 TI - [The distribution of health resources: a hybrid model of equality and maximization]. AB - In the allocation of resources for health care, it is generally acknowledged that models based exclusively either on efficiency and maximizing the cost/benefit ratio of interventions, or on equity and justice through the notion of "maximin," are unsatisfactory when taken separately. To fill this gap, this commentary suggests a hybrid model of resource allocation that integrates the idea of a random distribution of resources using a lottery. The general aim of this model is to safeguard the notions of justice and equal access to resources to the maximum extent possible in a climate where budget restrictions and the economic downturn may lead to future reductions in services. PMID- 22530534 TI - The case for a vaccine injury compensation program for Canada. AB - Despite its being deliberated since at least the 1980s, a national vaccine injury compensation program still does not exist in Canada. The omission of such a program stands as a gap in Canadian immunization policy in comparison to many other equivalently developed countries. This article outlines the arguments for a compensation program and the design elements that would be best suited to a program in the Canadian context. PMID- 22530535 TI - Canada moving backwards on illegal drugs. AB - Internationally, illegal drug use remains a major public health problem. In response, many countries have begun to shift their illegal drug policies away from enforcement and towards public health objectives. Recently, both the Global Commission on Drug Policy and the Supreme Court of Canada have endorsed this change in direction, supporting empirically sound illegal drug policies that reduce criminalization and stigmatization of drug users and bolster treatment and harm reduction efforts. Until recently, Canada was a participant in this growing movement towards rational drug policy. Unfortunately, in recent years, policy changes have made Canada one of the few remaining advocates of a "war-on-drugs" approach. Indeed, the current government has implemented a number of new illegal drug policies that contradict well-established scientific evidence from public health, criminology and other fields. As such, their approach is expected to do little to reduce the harms associated with substance use in Canada. The authors call on the current government to heed the recommendations of the Global Commission's report and learn from the many countries that are innovating in illegal drug policy by prioritizing evidence, human rights and public health. PMID- 22530536 TI - Supporting southern-led research: implications for North-South research partnerships. AB - BACKGROUND: Global health research partnerships are commonly led by Northern investigators who come from resource-rich research environments, while Southern partners participate with a paucity of research skills and resources. This power asymmetry within North-South research partnerships may further exacerbate the unequal distribution of benefits from the research process. METHODS: This study is designed to present the benefits and challenges of engaging in the research process from the perspective of The AIDS Support Organization (TASO), an HIV/AIDS care and treatment organization that has been involved in global health research partnerships. It uses a validated research tool entitled "Is Research Working for You?" to facilitate qualitative interviews surrounding the experienced benefits and challenges in engaging in the research partnerships as described by TASO staff. RESULTS: Three key themes emerged from the content and thematic analysis: 1) the reported benefits of research (e.g., evidence-based management, advocacy, etc.), 2) the challenges the research committee members face in becoming more involved in the research process (e.g., lack of data analysis skill, lack of inclusion in the research process, etc.), and 3) the institutional ambition at TASO to develop a Southern-led research agenda. CONCLUSIONS: This is one of the few studies to document the development of a Southern-led research agenda in addition to the challenges of engaging in the research process. Mechanisms for moderating power dynamics within North-South partnerships can provide opportunities for improved research capacity and quality. PMID- 22530537 TI - Prevalence of smoking among the lesbian, gay, bisexual, transsexual, transgender and queer (LGBTTQ) subpopulations in Toronto--the Toronto Rainbow Tobacco Survey (TRTS). AB - OBJECTIVES: Research in the United States has found a higher likelihood of smoking among lesbian, gay and bisexual people compared to the general population. However, the smoking prevalence of these subpopulations in Canada is not well documented. The objective of this study was to determine the prevalence of smoking among the LGBTTQ subpopulations in Toronto, Ontario. METHODS: A self report questionnaire was administered from April to July 2006 to a convenience sample of lesbian, gay, bisexual, transsexual, transgender and queer (LGBTTQ) community members in Toronto, Ontario. Items measured included: past and current smoking behaviour, sexual orientation, gender identity, age and residential area. RESULTS: In total, 3,140 LGBTTQ community members completed the Toronto Rainbow Tobacco Survey (TRTS). Overall, 36% of LGBTTQ participants reported current smoking, 25% were former smokers and 39% had never smoked. The smoking prevalence rates ranged from 24% to 45% across the different sexual orientation and gender identity groups of the sample, with bisexual women and bisexual men reporting the highest smoking rate at 45%. The study also reports the first known smoking prevalence rate for gender queer people at 44%. Younger LGBTTQ participants reported even higher smoking rates. CONCLUSION: This study corroborates prior research done in other jurisdictions by finding similar and higher smoking rates among Toronto's LGBTTQ subpopulations compared to the "mainstream" population. The relatively higher rates among LGBTTQ youth, bisexual and gender queer people have implications for targeted awareness and cessation initiatives. Need for future research is discussed. PMID- 22530538 TI - Estimates of smoking-attributable mortality and hospitalization in BC, 2002-2007. AB - OBJECTIVE: The objective of this paper was to estimate the number and rate of deaths and hospitalizations attributable to smoking in British Columbia (BC) from 2002 to 2007. METHODS: Using attributable fractions adjusted to BC smoking prevalence and mortality and hospital administrative data, estimates of smoking attributable mortality (SAM) and smoking-attributable hospitalization (SAH) were calculated by year, disease category, sex, and geographic region. RESULTS: Among active smoking adults 15 years of age and older, there were an estimated 4,851 deaths and 25,314 hospitalizations attributed to smoking in BC in 2007. SAM and SAH rates in 2007 were estimated as 119 and 633 per 100,000, respectively. Rates increased from 2002 to 2005 but have declined in subsequent years. Lung cancer and chronic obstructive pulmonary disease were responsible for the largest proportion of SAM and SAH, respectively. There were regional differences, with the Northern Health authority having the highest rate of SAM and SAH and Vancouver Coastal Health authority having the lowest. CONCLUSION: Smoking still presents a substantial human and economic burden in BC. Estimates of annual SAM and SAH provide researchers with the ability to detect emerging trends, target intervention and cessation programs, and evaluate current smoking reduction programs. The methodology can be adapted to other provinces to allow for cross province comparisons. PMID- 22530539 TI - Implications for HIV prevention programs from a serobehavioural survey of men who have sex with men in Vancouver, British Columbia: the ManCount study. AB - BACKGROUND: We examined HIV prevalence, awareness of HIV serostatus and HIV risk behaviour among a sample of men who have sex with men (MSM) in Vancouver. METHODS: MSM > or = 18 years were recruited from August 2008 to February 2009 through community venues. Participants completed a questionnaire and provided a dried blood spot (DBS) for HIV and other STI testing. We performed descriptive statistics and bivariate analyses of key explanatory variables. RESULTS: A total of 1,169 participants completed questionnaires; of these, 1,138 (97.3%) provided DBS specimens suitable for testing. The median age was 33 years (IQR 26-44). A total of 206 (18%) were HIV-positive by DBS, of whom 86% were aware they were positive. HIV seropositivity increased from 7.1% in those < 30 years of age to 19% in those 30-44 years and 34% among those > or = 45 years (p < 0.001 for test of trend). Of the 933 who self-reported as HIV-negative or unknown, 28 (3.0%) tested HIV-positive. Among those not tested for HIV in the previous 2 years, the reasons for not testing differed between participants with undiagnosed HIV infection and those who were HIV-negative. A total of 62% of study participants who self-reported as HIV-negative reported using a condom the last time they had anal sex. The use of risk-reduction measures was reported by 91.1% of all study participants (72% if excluding consistent condom use). CONCLUSION: The majority of MSM in Vancouver have adopted behaviours that reduce their HIV-related risk. However, prevention programs must continue to promote condom use, increase HIV testing, and better inform MSM of the value and limitations of other risk reduction strategies. PMID- 22530540 TI - Body mass index and risk of cardiovascular disease, cancer and all-cause mortality. AB - OBJECTIVES: To determine the dose-response relationship between body mass index (BMI) and cause-specific mortality among Canadian adults. METHODS: The sample includes 10,522 adults 18-74 years of age who participated in the Canadian Heart Health Surveys (1986-1995). Participants were divided into 5 BMI categories (< 18.5, 18.5-24.9, 25-29.9, 30-34.9, and > or = 35 kg/m2). Multivariate-adjusted (age, sex, exam year, smoking status, alcohol consumption and education) hazard ratios for all-cause, cardiovascular disease (CVD) and cancer mortality were estimated using Cox proportional hazards regression. RESULTS: There were 1,149 deaths (402 CVD; 412 cancer) over an average of 13.9 years (range 0.5 to 19.1 years), and the analyses are based on 145,865 person-years. The hazard ratios (95% CI) across successive BMI categories for all-cause mortality were 1.25 (0.83 1.90), 1.00 (reference), 1.06 (0.92-1.22), 1.27 (1.07-1.51) and 1.65 (1.29-2.10). The corresponding hazard ratios for CVD mortality were 1.30 (0.60-2.83), 1.00 (reference), 1.57 (1.22-2.01), 1.72 (1.27-2.33) and 2.09 (1.35-3.22); and for cancer, the hazard ratios were 1.02 (0.48-2.21), 1.00 (reference), 1.14 (0.90 1.44), 1.34 (1.01-1.78) and 1.82 (1.22-2.71). There were significant linear trends across BMI categories for all-cause (p = 0.0001), CVD (p < 0.0001) and cancer mortality (p = 0.003). CONCLUSIONS: The results demonstrate significant relationships between BMI and mortality from all causes, CVD and cancer. The increased risk of all-cause, CVD and cancer mortality associated with an elevated BMI was significant at levels above 30 kg/m2; however, overweight individuals (BMI 25-29.9 kg/m2) also had an approximately 60% higher risk of CVD mortality. PMID- 22530541 TI - A study of the association between characteristics of CLSCs and the risk of small for gestational age births among term and preterm births in Quebec, Canada. AB - OBJECTIVES: The objective of this study was to describe whether the social environment of the territory of residence is associated with indicators of foetal growth retardation. METHODS: All newborns (n = 667,254) from 143 Centres locaux de services communautaires (CLSC) territories of Quebec, Canada, 2000-2008 were included in this study. Small for gestational age (SGA), very small for gestational age (VSGA) and SGA-preterm births were identified. Social characteristics and access to medical services of the population in the CLSCs were obtained from the Canadian Community Health Survey. Data on material deprivation, racial diversity and social isolation were obtained from the 2001 and 2006 Canadian censuses. A compromise between two methods, stepwise and best subset, was used to select variables for multivariate logistic modelling. The model was fitted on each studied outcome: SGA, VSGA and SGA among preterm births. RESULTS: When investigating material deprivation, racial diversity, social isolation, proportion of sedentary residents and proportion with fair or poor availability of health care services in the CLSC territories, material deprivation, racial diversity, social isolation and sedentary residents showed increased adjusted risk of SGA. Results of the model fit on VSGA birth and on SGA among preterm births were similar. CONCLUSION: CLSC characteristics of material deprivation, racial diversity, social isolation as well as the contextual variable of sedentary lifestyle were associated with indicators of foetal growth retardation. Further work on features of the CLSCs could help understand how the outcome of SGA is associated with contextual factors and identify groups for intervention. PMID- 22530542 TI - The need for continuous systems thinking in public health in Canada. PMID- 22530543 TI - Smokers and non-smokers differ in their beliefs about their addiction: public health implications. PMID- 22530544 TI - Child maltreatment data in Canada. PMID- 22530545 TI - Employer revolt? Convenient care rescue. PMID- 22530546 TI - Why evidence-based practice matters. PMID- 22530547 TI - Targeting the priming response: intranasal steroid therapy for allergic rhinitis. PMID- 22530548 TI - Acute lower extremity compartment syndrome: avoiding limb loss and long-term complications. PMID- 22530549 TI - Finding your first job: timing, resume writing and other advice. PMID- 22530550 TI - A different top 10: key lessons in my first year of practice. PMID- 22530551 TI - Solving skin rash in primary care: use of a diagnostic decision tree. PMID- 22530553 TI - Bicontinuous ceramics with high surface area from block copolymer templates. AB - Mesoporous polymers with gyroid nanochannels can be fabricated from the self assembly of degradable block copolymer, polystyrene-b-poly(L-lactide) (PS-PLLA), followed by hydrolysis of PLLA block. Well-defined polymer/ceramic nanohybrid materials with inorganic gyroid nanostructures in a PS matrix can be obtained by using the mesoporous PS as a template for sol-gel reaction. Titanium tetraisopropoxide (TTIP) is used as a precursor to give a model system for the fabrication of metal oxide nanostructures from reactive transition metal alkoxides. By controlling the rates of capillary-driven pore filling and sol-gel reaction, the templated synthesis can be well-developed. Also, by taking advantage of calcination, bicontinuous TiO(2) with controlled crystalline phase (i.e., anatase phase) can be fabricated after removal of the PS template and crystallization of TiO(2) by calcination leading to high photocatalytic efficiency. This new approach provides an easy way to fabricate high-surface-area and high-porosity ceramics with self-supporting structure and controlled crystalline phase for practical applications. As a result, a platform technology to fabricate precisely controlled polymer/ceramic nanohybrids and mesoporous ceramic materials can be established. PMID- 22530552 TI - Takovite-aluminosilicate-Cr materials prepared by adsorption of Cr3+ from industrial effluents as catalysts for hydrocarbon oxidation reactions. AB - The catalytic efficiency of takovite-aluminosilicate-chromium catalysts obtained by adsorption of Cr(3+) ions from aqueous solutions by a takovite-aluminosilicate nanocomposite adsorbent is reported. The adsorbent was synthesized by the coprecipitation method. The catalytic activity of the final Cr-catalysts depended on the amount of adsorbed chromium. (Z)-cyclooctene conversion up to 90% with total selectivity for the epoxide was achieved when the oxidation was carried out with hydrogen peroxide, at room temperature. After five consecutive runs, the catalysts maintained high activity, although after the sixth reuse, the epoxide yields strongly decreased to 35%. The catalysts were also efficient for cyclohexane oxidation, reaching up to 18% conversion, with cyclohexanone/cyclohexanol selectivity close to 1.2. On the whole, their use as catalysts gives a very interesting application for the solids obtained by adsorption of a contaminant cation such as Cr(3+). PMID- 22530554 TI - Correlations between conjugation length, macromolecular dynamics, and photophysics of phenylene-vinylene/aliphatic multiblock copolymers. AB - This work reports a detailed spectroscopy study of a series of multiblock conjugated nonconjugated copolymers built by p-phenylene vinylene type units (PV) and octamethylene spacers, namely, poly(1,8-octanedioxy-2,6-dimethoxy-1,4 phenylene-1,2-ethenylene) (LaPPS18). The relative proportions of the PV and aliphatic segments were estimated on the basis of solid-state NMR and Raman spectroscopy. The overall structure was characterized by wide angle X-ray diffraction; (1)H wide-line dipolar chemical shift correlation (DIPSHIFT), and centerband-only detection of exchange (CODEX) NMR data, that together with glass transition temperatures allowed us to identify the groups involved in the molecular dynamics. These different structural properties were used to explain the photoluminescence properties in terms of peak position and spectral profile. PMID- 22530555 TI - Accelerated solvent extraction of alkylresorcinols in food products containing uncooked and cooked wheat. AB - This research focuses on the overall extraction process of alkylresorcinols (ARs) from uncooked grains and baked products that have been processed with wheat, corn, rice, and white flour. Previously established extraction methods developed by Ross and colleagues, as well as a semiautomated method involving accelerated solvent extraction (ASE), were applied to extract ARs within freshly ground samples. For extraction of alkylresorcinols, nonpolar solvents such as ethyl acetate have been recommended for the extraction of uncooked foods, and polar solvents such as 1-propanol:water (3:1 v/v) have been recommended for the extraction of baked foods that contain rye, wheat, or other starch-rich grains. A comparison of AR extraction methods has been investigated with the application of gas chromatography and a flame ionization detector (GC-FID) to quantify the AR content. The goal of this research was to compare the rapid accelerated solvent extraction of the alkylresorcinols (ASE-AR) method to the previous manual AR extraction methods. Results for this study as well as the investigation of the overall efficiency of ASE-AR extraction with the use of a spiking study indicated that it can be comparable to current extraction methods but with less time required. Furthermore, the extraction time for ASE (approximately 40 min) is much more convenient and less tedious and time-consuming than previously established methods, which range from 5 h for processed foods to 24 h for raw grains. PMID- 22530556 TI - Partial characterization of the Sox2+ cell population in an adult murine model of digit amputation. AB - Tissue regeneration in response to injury in adult mammals is generally limited to select tissues. Nonmammalian species such as newts and axolotls undergo regeneration of complex tissues such as limbs and digits via recruitment and accumulation of local and circulating multipotent progenitors preprogrammed to recapitulate the missing tissue. Directed recruitment and activation of progenitor cells at a site of injury in adult mammals may alter the default wound healing response from scar tissue toward regeneration. Bioactive molecules derived from proteolytic degradation of extracellular matrix (ECM) proteins have been shown to recruit a variety of progenitor cells in vitro and in vivo to the site of injury. The present study further characterized the population of cells accumulating at the site of injury after treatment with ECM degradation products in a well-established model of murine digit amputation. After a mid-second phalanx digit amputation in 6-8-week-old adult mice, treatment with ECM degradation products resulted in the accumulation of a heterogeneous population of cells, a subset of which expressed the transcription factor Sox2, a marker of pluripotent and adult progenitor cells. Sox2+ cells were localized lateral to the amputated P2 bone and coexpressed progenitor cell markers CD90 and Sca1. Transgenic Sox2 eGFP/+ and bone marrow chimeric mice showed that the bone marrow and blood circulation did not contribute to the Sox2+ cell population. The present study showed that, in addition to circulating progenitor cells, resident tissue-derived cells also populate at the site of injury after treatment with ECM degradation products. Although future work is necessary to determine the contribution of Sox2+ cells to functional tissue at the site of injury, recruitment and/or activation of local tissue-derived cells may be a viable approach to tissue engineering of more complex tissues in adult mammals. PMID- 22530557 TI - Identification and expression analysis of methyl jasmonate responsive ESTs in paclitaxel producing Taxus cuspidata suspension culture cells. AB - BACKGROUND: Taxol((r)) (paclitaxel) promotes microtubule assembly and stabilization and therefore is a potent chemotherapeutic agent against wide range of cancers. Methyl jasmonate (MJ) elicited Taxus cell cultures provide a sustainable option to meet the growing market demand for paclitaxel. Despite its increasing pharmaceutical importance, the molecular genetics of paclitaxel biosynthesis is not fully elucidated. This study focuses on identification of MJ responsive transcripts in cultured Taxus cells using PCR-based suppression subtractive hybridization (SSH) to identify genes involved in global pathway control. RESULTS: Six separate SSH cDNA libraries of paclitaxel-accumulating Taxus cuspidata P991 cell lines were constructed at three different post elicitation time points (6h, 18h and 5 day) to identify genes that are either induced or suppressed in response to MJ. Sequencing of 576 differentially screened clones from the SSH libraries resulted in 331 unigenes. Functional annotation and Gene Ontology (GO) analysis of up-regulated EST libraries showed enrichment of several known paclitaxel biosynthetic genes and novel transcripts that may be involved in MJ-signaling, taxane transport, or taxane degradation. Macroarray analysis of these identified genes unravelled global regulatory expression of these transcripts. Semi-quantitative RT-PCR analysis of a set of 12 candidate genes further confirmed the MJ-induced gene expression in a high paclitaxel accumulating Taxus cuspidata P93AF cell line. CONCLUSIONS: This study elucidates the global temporal expression kinetics of MJ responsive genes in Taxus suspension cell culture. Functional characterization of the novel genes identified in this study will further enhance the understanding of paclitaxel biosynthesis, taxane transport and degradation. PMID- 22530559 TI - Palladium-catalyzed asymmetric 6-endo cyclization of dienamides with substituent driven activation. AB - Chiral 2-piperidinone compounds with various C-6 substituents were successfully synthesized via a Pd-catalyzed asymmetric 6-endo cyclization of dienamides, which were evidently activated by both N-p-toluenesulfonyl and C-3 ester substituents. PMID- 22530558 TI - Metabolism of deoxypyrimidines and deoxypyrimidine antiviral analogs in isolated brain mitochondria. AB - The goal of this project was to characterize deoxypyrimidine salvage pathways used to maintain deoxynucleoside triphosphate pools in isolated brain mitochondria and to determine the extent that antiviral pyrimidine analogs utilize or affect these pathways. Mitochondria from rat brains were incubated in media with labeled and unlabeled deoxynucleosides and deoxynucleoside analogs. Products were analyzed by HPLC coupled to an inline UV monitor and liquid scintillation counter. Isolated mitochondria transported thymidine and deoxycytidine into the matrix, and readily phosphorylated both of these to mono-, di-, and tri-phosphate nucleotides. Rates of phosphorylation were much higher than rates observed in mitochondria from heart and liver. Deoxyuridine was phosphorylated much more slowly than thymidine and only to dUMP. 3'-azido-3' deoxythymidine, zidovudine (AZT), an antiviral thymidine analog, was phosphorylated to AZT-MP as readily as thymidine was phosphorylated to TMP, but little if any AZT-DP or AZT-TP was observed. AZT at 5.5 +/- 1.7 MUM was shown to inhibit thymidine phosphorylation by 50%, but was not observed to inhibit deoxycytidine phosphorylation except at levels > 100 MUM. Stavudine and lamivudine were inert when incubated with isolated brain mitochondria. The kinetics of phosphorylation of thymidine, dC, and AZT were significantly different in brain mitochondria compared to mitochondria from liver and heart. PMID- 22530560 TI - Immune activation and increased IL-21R expression are associated with the loss of memory B cells during HIV-1 infection. AB - OBJECTIVES: Microbial translocation and chronic immune activation were previously shown to be associated with impairment of T cell functions and disease progression during infection with human immunodeficiency virus type-1 (HIV-1); however, their impact on B cell function and number remains unknown. By measuring markers of immune activation and molecules involved in apoptosis regulation, we have evaluated the association between microbial translocation and loss of memory B cells in HIV-1-infected patients. METHODS: Markers of activation [the interleukin-21 receptor (IL-21R) and CD38] and apoptosis (Bim, Bcl-2 and annexin V) were measured in B cell subpopulations by multicolour flow cytometry. Levels of soluble CD14 (sCD14) and lipopolysaccharide (LPS), measures of microbial translocation, were determined in plasma. Purified B cells were also exposed in vitro to Toll-like receptor (TLR) ligands. RESULTS: IL-21R expression was higher in cells from HIV-1-infected patients, compared with control subjects, with the highest levels in nontreated patients. An inverse correlation was observed between IL-21R expression and percentages of circulating resting memory (RM) B cells. IL-21R-positive memory B cells were also more susceptible to spontaneous apoptosis and displayed lower levels of Bcl-2. It is interesting that the levels of sCD14, which are increased during HIV-1 infection, were correlated with decreased percentages of RM B cells and high IL-21R expression. In the plasma of HIV-1-infected individuals, a correlation was found between sCD14 and LPS levels. TLR activation of B cells in vitro resulted in IL-21R up-regulation. CONCLUSIONS: Microbial translocation and the associated immune activation during HIV-1 infection may lead to high expression levels of the IL-21R activation marker in RM B cells, a feature associated with increased apoptosis and a reduced number of these cells in the circulation. PMID- 22530561 TI - Formulation factors affecting the release of ezetimibe from different liquisolid compacts. AB - CONTEXT: Liquisolid technique is one of the methods used to improve the dissolution rate of the poorly water soluble drugs utilizing non volatile liquids. OBJECTIVES: Enhancement of the release of ezetimibe from different liquisolid formulations. MATERIALS AND METHODS: Four liquid vehicles were used to prepare the liquid medications with different drug concentrations. The interaction between the drug and the excipients in liquisolid powders were characterized by DSC, X-ray, FTIR and SEM. Furthermore, the powder characteristics were evaluated by Carr's Index and powder wetting time determinations, respectively. All prepared formulations were compressed at different pressures to end with the same constant porosity and the tablets were evaluated by different tests and compared with conventional formula. RESULTS AND DISCUSSION: No interaction had been detected in all liquisolid formulations as shown in the results of XRD, FTIR, DSC and SEM. In addition to that, all liquisolid compacts had expressed faster dissolution profiles compared with that of conventional formula. CONCLUSION: The dissolution rate was affected by the drug concentration, solubility of the drug in the liquid vehicle and type of carrier. In addition, the presence of the liquid vehicle has been found to affect the mechanical properties of the liquisolid formulations. PMID- 22530564 TI - Workplace learning in continuing interprofessional education. PMID- 22530565 TI - Different patterns of decompensation in patients with alcoholic vs. non-alcoholic liver cirrhosis. AB - BACKGROUND: The histological pattern of fibrosis in liver cirrhosis varies in different chronic liver diseases, and hepatic decompensation may be differentiated in consequences of fibrosis (i.e. ascites, variceal bleeding) or in lack of function (i.e. jaundice) resulting in aetiology-specific variable morbidity and mortality. AIM: To evaluate patterns of hepatic decompensation in relation to the aetiology of liver cirrhosis. METHODS: Two different cohorts were retrospectively evaluated between 2002 and 2007. Cohort A was for hypothesis generation and consisted of 220 cirrhotic patients. To confirm the initial observations a second cohort B (n = 217) was analysed. The different patterns of hepatic decompensation evaluated were ascites, jaundice, encephalopathy, variceal bleeding, spontaneous bacterial peritonitis, hepatorenal syndrome or hepatocellular carcinoma. Furthermore, we analysed survival in relation to pattern of decompensation in alcoholic vs. non-alcoholic liver disease. RESULTS: Alcoholics were more frequently hospitalised for ascites (cohort A: 81.4% vs. 65.4%, P = 0.016; cohort B 71.3% vs. 58.5%, P = 0.085). In contrast, non alcoholics presented with higher rates of hepatocellular carcinoma (cohort A: 23.1% vs. 11.9%, P = 0.046; cohort B 38.6% vs. 22.5%, P = 0.018). There were no significant differences in jaundice, variceal bleeding, hepatorenal syndrome or encephalopathy. Survival was significantly impaired in non-alcoholic cirrhosis once ascites occurred (P = 0.003), whereas ascites did not predict higher mortality in patients with alcoholic cirrhosis. CONCLUSIONS: Ascites is the leading initial pattern of decompensation in alcoholic cirrhosis whereas hepatocellular carcinoma dominates in non-alcoholics. Non-alcoholics developing ascites show a poor survival. PMID- 22530567 TI - Development and assessment of indicators for quality of care in severe preeclampsia/eclampsia and postpartum hemorrhage. AB - Severe preeclampsia/eclampsia and postpartum hemorrhage (PPH) are serious obstetric problems worldwide. Quality improvement of care measured by evidence based indicators is recommended as a recent important strategy; however, the indicators for quality of care of these two conditions have not been established. This study aimed to develop such indicators and assess their validity, reliability, and feasibility at different contextual levels. Of 32 initially valid indicators for care of severe preeclampsia/eclampsia, after two rounds of Delphi technique, 21 and 30 indicators were agreed to be suitable to monitor care at district and referral hospitals. Of 13 initial indicators for PPH, 8 and 13 indicators were selected, respectively. The interrater reliability of indicators varied from 0.28 to 0.63. At least three-fourths of all indicators rated by local doctors and nurses were assessed as feasible in terms of relevance, measurability, and improvability. The process identified reliable and feasible performance indicators to monitor quality of care in severe preeclampsia/eclampsia and PPH for either basic or comprehensive emergency obstetric care (EmOC). The informative applicability of these indicators in clinical practice needs further evaluation. PMID- 22530566 TI - Differentiated swine airway epithelial cell cultures for the investigation of influenza A virus infection and replication. AB - BACKGROUND: Differentiated human airway epithelial cell cultures have been utilized to investigate cystic fibrosis, wound healing, and characteristics of viral infections. These cultures, grown at an air-liquid interface (ALI) in media with defined hormones and growth factors, recapitulate many aspects of the in vivo respiratory tract and allow for experimental studies at the cellular level. OBJECTIVES: To optimize growth conditions for differentiated swine airway epithelial cultures and to use these cultures to examine influenza virus infection and replication. METHODS: Primary swine respiratory epithelial cells were grown at an air-liquid interface with varying amounts of retinoic acid and epidermal growth factor. Cells grown with optimized concentrations of these factors for 4 weeks differentiated into multilayer epithelial cell cultures resembling the lining of the swine respiratory tract. Influenza virus infection and replication were examined in these cultures. RESULTS/CONCLUSIONS: Retinoic acid promoted ciliogenesis, whereas epidermal growth factor controlled the thickness of the pseudoepithelium. The optimal concentrations for differentiated swine cell cultures were 1.5 ng/ml epidermal growth factor and 100nm retinoic acid. Influenza A viruses infected and productively replicated in these cultures in the absence of exogenous trypsin, suggesting that the cultures express a protease capable of activating influenza virus hemagglutinin. Differences in virus infection and replication characteristics found previously in pigs in vivo were recapitulated in the swine cultures. This system could be a useful tool for a range of applications, including investigating influenza virus species specificity, defining cell tropism of influenza viruses in the swine respiratory epithelium, and studying other swine respiratory diseases. PMID- 22530569 TI - Targeting NKG2D in tumor surveillance. AB - INTRODUCTION: NKG2D (natural killer group 2, member D) is expressed on the surface of all mouse and human NK cells, and subpopulation of T cells. Stimulation of NK cells through NKG2D triggers cell-mediated cytotoxicity and induces the production of cytokines. NKG2D binds to family of unique ligands with structurally similar to MHC class I, however, NKG2D ligands can be up-regulated in their expression on stressed cells including tumor cells unlike conventional MHC class I molecules. Mounting evidences clearly implicate that NKG2D recognition plays an important role in tumor immune surveillance. AREAS COVERED: While NKG2D detect for potentially dangerous cells, various inhibitory and/or escape mechanisms counteract immune surveillance system and thereby limit effective elimination of transformed tumor cells. In addition, tumors often generate an immunosuppressive microenvironment where inhibitory molecules or cytokines negatively effect the function of anti-tumor immune responses. NKG2D ligand expression can be up-regulated by transcriptional or posttranscriptional mechanisms, therefore, certain therapy targeting those regulatory mechanisms could regain the expression of NKG2D ligands on tumor cells to be detected by the host immune responses. EXPERT OPINION: Our knowledge in the precise mechanism of anti-tumor immunity is rapidly increasing. While NKG2D is known as primary cytotoxicity receptor in NK cell activation by recognizing 'induced-self' ligands on stressed cells including tumor cells, there are increasing evidences that NKG2D recognition can result in both immune activation and immune silencing. Future combined application of conventional cancer therapy and new therapy utilizing such stress-induced recognition systems will provide a novel opportunity to control malignant tumor progression of cancer disease. PMID- 22530568 TI - Apoptosis signal-regulating kinase 1-thioredoxin complex dissociation by capsaicin causes pancreatic tumor growth suppression by inducing apoptosis. AB - AIM: In this study, we evaluated the effect of capsaicin on the interaction of redox-sensitive thioredoxin (Trx)/apoptosis signal-regulating kinase 1 (ASK1) in pancreatic cancer cells. RESULTS: Capsaicin treatment downregulated Trx and increased the phosphorylation (activation) of ASK1 at Thr845 and kinase activity in AsPC-1 and BxPC-3 cells. Capsaicin treatment also activated downstream effector molecules MKK4/7, caspase-9, and caspase-3. Antioxidants tiron or PEG catalase blocked the activation of ASK1 cascade by capsaicin and protected the cells from apoptosis, indicating the involvement of reactive oxygen species in the activation of ASK1. Our results further revealed that Trx overexpression suppressed the effects of capsaicin, whereas ASK1 overexpression enhanced the apoptosis-inducing effects of capsaicin. beta-mercaptoethanol, a reducing agent, blocked capsaicin-mediated activation of ASK1, indicating that Trx-ASK1 complex exists and requires reducing conditions in the cell. On the other hand, the Trx inhibitor (1-chloro-2-4-dinitrobenzene) increased capsaicin-induced ASK1 kinase activity, suggesting that Trx inhibition by capsaicin is essential for ASK1 activation. Oral administration of 5 mg capsaicin/kg body weight substantially suppressed the growth of tumors in xenograft and orthotopic mouse model. Tumors from capsaicin-treated mice showed reduced levels of Trx, increased phosphorylation of ASK1 at Thr845, and cleavage of caspase-3 and poly (ADP ribose) polymerase. INNOVATION: Our results for the first time demonstrated a new perspective that Trx-ASK1 complex can be targeted by capsaicin in pancreatic cancer. CONCLUSION: Capsaicin reduces Trx expression and dissociates Trx-ASK1 complex resulting in the activation of ASK1 and downstream effectors leading to apoptosis in pancreatic tumor cells in vitro and in vivo. PMID- 22530570 TI - Chest ultrasound in practice: a review of utility in the clinical setting. AB - Clinician-performed chest ultrasound is rapidly entering clinical practice in the fields of intensive care, respiratory medicine and acute medicine. Ultrasound is clearly useful in the diagnosis and characterisation of pleural diseases. It is also critical in improving the safety of pleural interventions. More recently, attention has also focused on the use of lung ultrasound. While the normal aerated lung is not well imaged by ultrasound, lung pathology reaching the pleura often provides an 'acoustic window' for a number of lung conditions. Lung ultrasound is useful to diagnose pneumothorax, interstitial and alveolar lung abnormalities, and pleurally based lung masses. There is some evidence that integrating routine chest ultrasound into clinical practice has benefit in the emergency and intensive care settings. In the future, chest ultrasound is likely to become an essential physician skill, and training requirements are evolving in light of current developments. PMID- 22530571 TI - Bonding, ion mobility, and rate-limiting steps in deintercalation reactions with ThCr2Si2-type KNi2Se2. AB - Here, we study the nature of metal-metal bonding in the ThCr(2)Si(2) structure type by probing the rate-limiting steps in the oxidative deintercalation of KNi(2)Se(2). For low extents of oxidation, alkali ions are removed exclusively to form K(1-x)Ni(2)Se(2). For greater extents of oxidation, the rate of the reaction decreases dramatically, concomitant with the extraction of both potassium and nickel to form K(1-x)Ni(2-y)Se(2). The appreciable mobility of transition metal ions is unexpected, but illustrates the relative energy scales of different defects in the ThCr(2)Si(2) structure type. Furthermore, the fully oxidized compounds, K(0.25)Ni(1.5)Se(2), spontaneously convert from the tetrahedral [NiSe(4)]-containing ThCr(2)Si(2) structure to a vacancy-ordered NiAs structure with [NiSe(6)] octahedra. From analysis of the atom positions and kinetic data, we have determined that this transformation occurs by a continuous, low-energy pathway via subtle displacements of Ni atoms and buckling of the Se sublattice. These results have profound implications for our understanding of the stability, mobility, and reactivity of ions in materials. PMID- 22530572 TI - Willebrand disease. PMID- 22530573 TI - The role of natural VWF/FVIII complex concentrates in contemporary haemophilia care: a guideline for the next decade. AB - Current treatment for haemophilia provides excellent efficacy and safety albeit with a number of unresolved issues. The development of inhibitors following treatment with factor VIII (FVIII) is the most challenging complication of haemophilia and bears the highest economic burden for a chronic disease. Moreover, prophylactic therapy for haemophilia requires repeated infusions of FVIII, frequently as often as two or three times weekly, which can impact greatly on patients' daily lives. As considerable scope remains for further advancements in the management of this condition, the primary focus of this paper relates to issues regarding current treatment and strategies in place to resolve the various issues. For countries approaching access to replacement therapy, it is important to know whether or not plasma-derived and recombinant products are associated with different risks of inhibitor development in previously untreated patients with severe haemophilia. The ongoing international SIPPET study is expected to provide an answer to this clinical dilemma. Methods under investigation to prolong the half-life of factor concentrates offer new hope to reduce the burden of prophylaxis for patients with haemophilia, with early results suggesting greater benefits with FIX. PMID- 22530574 TI - Management of bleeding disorders: basic science. AB - Development of factor VIII (FVIII) inhibitors is the most severe and challenging complication of haemophilia A treatment and represents the highest economic burden for a chronic disease. Therefore, major research efforts are ongoing to optimize the therapeutic approaches able to minimize this complication. FVIII inhibitors have variable immuno-reactivity against different FVIII concentrates and generally have a lower reactivity against von Willebrand factor (VWF) containing FVIII concentrates than plasma-derived FVIII (pdFVIII) or recombinant FVIII (rFVIII) that are devoid of VWF, in particular when the inhibitors are directed against the light chain of FVIII. This paper provides an overview of several in vitro and in vivo studies that compared three clinically available clinical FVIII products (Kogenate(r), Bayer AG, Leverkusen, Germany; Advate(r), Baxter Healthcare, Zurich, Switzerland; and Fanhdi(r), Grifols S.A., Barcelona, Spain) in order to evaluate the functional actvity of the FVIII fractions in rFVIII that cannot bind VWF; explore the use of the thrombin generation assay (TGA) as a potential tool for optimizing the choice of FVIII concentrate for use in haemophilia A patients with inhibitors; compare the kinetics of the interactions between anti-FVIII antibodies and FVIII both in the presence/absence of VWF, using surface plasmon resonance. PMID- 22530575 TI - Management of bleeding disorders in children. AB - Haemophilia, if not properly managed, can lead to chronic disease and lifelong disabilities. The challenges and issues in infants/young children are different from those in older children and adults although episodes of bleeding still predominate as the diagnostic trigger. Awareness of clinical manifestations and treatment complications are crucial in instituting appropriate management and implementing preventive strategies. Currently, inhibitor development is a challenging complication of paediatric haemophilia and prophylaxis is emerging as the optimal preventive care strategy. In this section we will review some important aspects of haemophilia in children including early prophylaxis, current evidence relating to inhibitor development, including the aims of the SIPPET study which is already ongoing and involves boys <6 years, and the potential of immune tolerance therapy for eradicating the inhibitor and permitting a resumption of standard dosing schedules. PMID- 22530576 TI - Management of bleeding disorders in adults. AB - Development of FVIII inhibitors is currently the most severe and challenging complication of haemophilia A treatment and represents a very large economic burden for a chronic disease. As a result, clinical research is making major efforts to optimize the therapeutic approaches for this condition. In this section we will review some important aspects of the management of haemophilia in adults, including an overview of bleeding in women with von Willebrand disease, an analysis of FVIII consumption in patients with severe haemophilia A, an update of the ongoing RES.I.ST study, long-term prophylaxis and experience from the Pro.Will study, current evidence relating to economic aspects of the treatment of haemophilic patients with inhibitors (based on the PROFIT study), and an overview of musculoskeletal complications in adults with severe bleeding disorders. PMID- 22530577 TI - Management of bleeding disorders in the elderly. AB - We are entering a new phase in the management of patients with bleeding disorders such as haemophilia. This is the result of the positive effects that disease management strategies have had on patient longevity over the last 10-15 years. A greater number of individuals are entering middle- to old-age and, as a result, we face a new era of having to manage haemophiliac patients at risk of, or suffering from, age-related diseases. We can clearly learn from the experiences of geriatricians who have made many advances in the management of chronic disorders such as cardiovascular diseases and osteoporosis. However, the hypocoagulable state brings challenges of its own and it is important that we communicate our experiences so that the shared information can help drive improved levels of care and better clinical outcomes. In this article we look at factors that have impacted the life expectancy of patients with haemophilia over the last few decades, and we also review some of the early literature relating to cardiovascular risk management and the treatment of osteoporosis. PMID- 22530578 TI - Recent advances in the treatment of HIV/HBV and HIV/HCV co-infection. AB - Concurrent infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) in patients positive for human immunodeficiency virus (HIV) is relatively common. The treatment of co-infected individuals is rather complex because the anti-viral therapy may be associated with drug-resistance, hepatotoxicity and lack of response. Herein, we present a summary of the available compounds and the recent recommendations concerning the therapeutic management of HIV/HBV and HIV/HCV co infections. PMID- 22530579 TI - Metabotropic glutamate receptors: a review on prospectives and therapeutic aspects. AB - The metabotropic glutamate (mGluRs) receptors are a distinct class of G-protein coupled receptors that act through activation of phospholipase C and/or inhibition of adenylate cyclase. They encompass seven-transmembrane domain proteins, comprehensively expressed in neuronal and glial cells within the brain, spinal cord and periphery and are involved in controlling pathophysiology of a number of diseases. These receptors may be sorted into three groups based on similarity of amino acid sequence, pharmacology and the transducer pathways they couple. The agonists and antagonists act at the N-terminal glutamate binding site and present a pharmacological strategy to modulate pathogenesis. A number of these compounds are positive or negative allosteric modulators that bind within the receptor transmembrane heptahelical domains. This imparts improved subtype selectivity, improved bioavailability and better drug like properties (e.g. CNS penetration). The mGluRs are presently the focal point of sizeable attention because of their potential as drug targets for the treatment of neurological and psychiatric disorders of the brain including Schizophrenia, Alzheimer's disease, Parkinson's disease, addiction, anxiety, depression, epilepsy and pain. The present review focuses on signal transduction mechanisms implicated to control and functionally upregulate the glutamatergic transmission system. The article also hallmarks agonists and antagonists for mGluRs as pivotal agents to ameliorate an array of neurological and psychiatric disorders. PMID- 22530580 TI - Guide for calculating and interpreting effect sizes and confidence intervals in intellectual and developmental disability research studies. AB - This paper includes a nontechnical description of methods for calculating effect sizes in intellectual and developmental disability studies. Different hypothetical studies are used to illustrate how null hypothesis significance testing (NHST) and effect size findings can result in quite different outcomes and therefore conflicting results. Whereas NHST uses probability levels (e.g., p < .05) to evaluate the results of studies, effect size analyses focus on the magnitude of differences between groups or contrasting conditions and the strength of the relationship among variables of interest to report and interpret study results. Two families of effect sizes are described (mean difference, correlation coefficients) that are likely to be applicable to most intellectual and developmental disability studies. Sources of information on effect size calculators are included to provide researchers ready-available data analysis procedures for computing effect sizes and confidence intervals for different types of research designs and studies. PMID- 22530582 TI - Characterization of the human smooth muscle cell secretome for regenerative medicine. AB - Smooth muscle cells (SMC) play a central role in maintaining the structural and functional integrity of muscle tissue. Little is known about the early in vitro events that guide the assembly of 'bioartificial tissue' (constructs) and recapitulate the key aspects of smooth muscle differentiation and development before surgical implantation. Biomimetic approaches have been proposed that enable the identification of in vitro processes which allow standardized manufacturing, thus improving both product quality and the consistency of patient outcomes. One essential element of this approach is the description of the SMC secretome, that is, the soluble and deposited factors produced within the three dimensional (3D) extracellular matrix (ECM) microenvironment. In this study, we utilized autologous SMC from multiple tissue types that were expanded ex vivo and generated with a rigorous focus on operational phenotype and genetic stability. The objective of this study was to characterize the spatiotemporal dynamics of the first week of organoid maturation using a well-defined in vitro-like, 3D engineered scale model of our validated manufacturing process. Functional proteomics was used to identify the topological properties of the networks of interacting proteins that were derived from the SMC secretome, revealing overlapping central nodes related to SMC differentiation and proliferation, actin cytoskeleton regulation, and balanced ECM accumulation. The critical functions defined by the Ingenuity Pathway Analysis included cell signaling, cellular movement and proliferation, and cellular and organismal development. The results confirm the phenotypic and functional similarity of the SMC generated by our platform technology at the molecular level. Furthermore, these data validate the biomimetic approaches that have been established to maintain manufacturing consistency. PMID- 22530583 TI - Functional reconstruction of epignathus with cleft palate using part of a mature teratoma. AB - Epignathus is an extremely rare, benign, congenital teratoma that arises from the oral cavity. When treating epignathus with cleft palate, it is particularly important to consider velopharyngeal function and maxillary growth after surgical repair. The case of an infant with a complete cleft palate and a large mass, histologically diagnosed as a mature teratoma, that protruded from the right soft palate is described. At 8 months of age, a double-opposing Z-plasty was performed using a part of the tumor over the right soft palate that had been left at the time of primary excision at 3 months of age for an epignathus protruding from the mouth. Though all that could be done was suture tumor tissue on the right side and the left hypoplastic levator veli palatine muscle using the double-opposing Z plasty, velopharyngeal function and maxillary growth were good at 10 years of age. PMID- 22530586 TI - In search of meaning: semantic effects on past-tense inflection. AB - Within single-mechanism connectionist models of inflectional morphology, generating the past-tense form of a verb depends upon the interaction of semantic and phonological representations, with semantic information being particularly important for irregular or exception verbs. We assessed this hypothesis in two experiments requiring normal speakers to produce the past tense from a verb stem that takes a regular or exceptional past tense. Experiment 1 revealed significant latency advantages for high- over low-imageability words for both regular verbs (e.g., "lunged" faster than "loved") and exception items (e.g., "drank" faster than "dealt"); but critically, this effect was significantly larger for exceptions than for regulars. Experiment 2 employed a semantic priming paradigm where participants inflected verb stems (e.g., sit) preceded by related (e.g., chair) or unrelated primes (e.g., jug) and revealed a priming effect in accuracy that was confined to the exception items. Our results are consistent with predictions from single-mechanism connectionist models of inflectional morphology and converge with findings from neurological patients and studies of reading aloud. PMID- 22530584 TI - The potential use of toxin antibodies as a strategy for controlling acute Staphylococcus aureus infections. AB - INTRODUCTION: The pandemic human pathogen, Staphylococcus aureus, displays high levels of antibiotic resistance and is a major cause of hospital- and community associated infections. S. aureus disease manifestation is to a great extent due to the production of a large arsenal of virulence factors, which include a series of secreted toxins. Antibodies to S. aureus toxins are found in people who are infected or asymptomatically colonized with S. aureus. Immunotherapies consisting of neutralizing anti-toxin antibodies could provide immediate aid to patients with impaired immune systems or in advanced stages of disease. AREAS COVERED: Important S. aureus toxins, their roles in pathogenesis, rationales for selecting S. aureus toxins for immunization efforts, and caveats associated with monoclonal antibody-based passive immunization are discussed. This review will focus on hyper-virulent community-associated methicillin-resistant S. aureus because of their recent surge and clinical importance. EXPERT OPINION: Antibodies against genome-encoded toxins may be more broadly applicable than those directed against toxins found only in a sub-population of S. aureus isolates. Furthermore, there is substantial functional redundancy among S. aureus toxins. Thus, an optimal anti-S. aureus formulation may consist of multiple antibodies directed against a series of key S. aureus genome-encoded toxins. PMID- 22530587 TI - Hidden relationship between conserved residues and locally conserved phosphate binding structures in NAD(P)-binding proteins. AB - A one-dimensional (1D) motif usually comprises conserved essential residues involved in catalysis, ligand binding, or maintaining a specific structure. However, it cannot be easily detected in proteins with low sequence identity because it is difficult to (1) identify protein sequences suspected to contain the motif, and (2) align sequences with little sequence identity to spot the conserved residues. Here, we present a strategy for discovering phosphate-binding 1D motifs in NAD(P)-binding proteins sharing low sequence identity that overcomes these two hurdles by determining all distinct locally conserved pyrophosphate binding structures and aligning the same-length sequences comprising each of these structures to identify the conserved residues. We show that the sequence motifs derived from the distinct pyrophosphate-binding structures yield different numbers/spacing of conserved Gly residues. We also show that they depend on the side chain orientations and cofactor type (NAD or NADP). Thus, sequence motifs derived from local similarity of backbone structures without consideration of the cofactor type and/or side chain orientations would reduce their reliability in annotating protein function from sequence alone. The three-dimensional (3D) and 1D motifs comprising conserved residues in nonredundant proteins reveal hidden relationships between the protein structure/function and sequence as well as protein-cofactor interactions. PMID- 22530588 TI - New monolithic capillary columns with well-defined macropores based on poly(styrene-co-divinylbenzene). AB - Macroporous polymer monoliths based on poly(styrene-co-divinylbenzene) with varied styrene/divinylbenzene ratios have been prepared by organotellurium mediated living radical polymerization. The well-defined cocontinuous macroporous structure can be obtained by polymerization-induced spinodal decomposition, and the pore structures are controlled by adjusting the starting composition. The separation efficiency of small molecules (alkylbenzenes) in the obtained monoliths has been evaluated in the capillary format by high-performance liquid chromatography (HPLC) under the isocratic reversed-phase mode. Baseline separations of these molecules with a low pressure drop (~2 MPa) have been achieved because of the well-defined macropores and to the less-heterogeneous cross-linked networks. PMID- 22530585 TI - Mitochondrial thiols in the regulation of cell death pathways. AB - SIGNIFICANCE: Regulation of mitochondrial H(2)O(2) homeostasis and its involvement in the regulation of redox-sensitive signaling and transcriptional pathways is the consequence of the concerted activities of the mitochondrial energy- and redox systems. RECENT ADVANCES: The energy component of this mitochondrial energy-redox axis entails the formation of reducing equivalents and their flow through the respiratory chain with the consequent electron leak to generate [Formula: see text] and H(2)O(2). The mitochondrial redox component entails the thiol-based antioxidant system, largely accounted for by glutathione- and thioredoxin-based systems that support the activities of glutathione peroxidases, peroxiredoxins, and methionine sulfoxide reductase. The ultimate reductant for these systems is NADPH: mitochondrial sources of NADPH are the nicotinamide nucleotide transhydrogenase, isocitrate dehydrogenase-2, and malic enzyme. NADPH also supports the glutaredoxin activity that regulates the extent of S-glutathionylation of mitochondrial proteins in response to altered redox status. CRITICAL ISSUES: The integrated network of these mitochondrial thiols constitute a regulatory device involved in the maintenance of steady-state levels of H(2)O(2), mitochondrial and cellular redox and metabolic homeostasis, as well as the modulation of cytosolic redox-sensitive signaling; disturbances of this regulatory device affects transcription, growth, and ultimately influences cell survival/death. FUTURE DIRECTIONS: The modulation of key mitochondrial thiol proteins, which participate in redox signaling, maintenance of the bioenergetic machinery, oxidative stress responses, and cell death programming, provides a pivotal direction in developing new therapies towards the prevention and treatment of several diseases. PMID- 22530589 TI - Lipid domain pixelation patterns imposed by e-beam fabricated substrates. AB - This work describes a technique for forming nanometer-scale pixilated lipid domains that are self-organized into geometric patterns residing on a square lattice. In this process, a lipid multibilayer stack is deposited onto a silica substrate patterned with a square lattice array of bumps, hemispherical on their sides, formed by electron beam lithography. Domain patterns are shown to be confined to the flat grid between the bumps and composed of connected and individual domain pixels. Analysis of lattices of varying sizes shows that domain pattern formation is driven by mechanical energy minimization and packing constraints. We demonstrate single lattice sizes and a gradient in lattice size varying from the micrometer to the 100 nm scale applicable to precise arraying, patterning, and transport of biomolecules that partition to lipid domains. PMID- 22530591 TI - Quantum beats in crystalline tetracene delayed fluorescence due to triplet pair coherences produced by direct singlet fission. AB - A detailed analysis of the oscillations seen in the delayed fluorescence of crystalline tetracene is presented in order to study the mechanism of singlet fission. Three quantum beat frequencies of 1.06 +/- 0.05, 1.82 +/- 0.05, and 2.92 +/- 0.06 GHz are resolved, which are damped on a time scale of 20 ns. The effects of sample morphology, excitation wavelength, and temperature are examined. A density matrix model for singlet fission is developed that quantitatively describes the frequencies, amplitudes, and damping of the oscillations. The model assumes a direct coupling of the initially excited singlet exciton to the triplet pair manifold. There is no electronic coherence between the singlet and triplet pair states, but the rapid singlet decay time of ~200 ps in solution-grown single crystals provides the impulsive population transfer necessary to create a coherent superposition of three zero-field triplet pair states |xx>, |yy>, and |zz> with overall singlet character. This superposition of the three states gives rise to the three quantum beat frequencies seen in the experiment. Damping of the quantum beats results from both population exchange between triplet and singlet manifolds and pure dephasing between the triplet pair states. By lowering the temperature and slowing the SF rate, the visibility of the oscillations decreases. There is no evidence of magnetic dipole-dipole coupling between the product triplets. Our model provides good overall agreement with the data, supporting the conclusion that singlet fission in tetracene proceeds through the "direct" mechanism without strong electronic coupling between the singlet and triplet pair states. PMID- 22530592 TI - Patient and environmental service employee satisfaction of using germicidal bleach wipes for patient room cleaning. AB - More healthcare institutions are using bleach products which are sporicidal to reduce Clostridium difficile infection (CDI). There may be patient and employee concerns about the appearance of bleach residue left on surfaces, odors, and respiratory tract irritation. The intervention used bleach wipes for daily and terminal patient room cleaning to reduce transmission of CDI and was implemented on patient care units with a relatively high incidence of CDI. Both patients and Environmental Services (ES) staff were surveyed to assess their satisfaction of the bleach wipe product used during room cleaning. Patients (n = 94) (91%) continued to be very satisfied with how well their rooms were cleaned every day. Bleach wipes were well tolerated by patients (n = 44) (100%) surveyed on the medical units and less tolerated by patients (n = 50) (22%) on the hematology oncology units. ES staff (6) reported less satisfaction and more respiratory irritation from using the bleach wipes; however, later their satisfaction improved. PMID- 22530593 TI - The wheat chloroplastic small heat shock protein (sHSP26) is involved in seed maturation and germination and imparts tolerance to heat stress. AB - The nuclear-encoded chloroplast small heat shock proteins (sHSPs) are present in all plant species from algae to angiosperms. Expression analysis shows that the wheat chloroplastic sHSP (HSP26) is highly inducible by heat stress in almost all the vegetative and generative tissues and is also expressed constitutively in certain developmental growth stages. We characterize wheat chloroplastic sHSP 26 through transgenic approach using Arabidopsis and report cloning of the promoter and its characterization. Transgenic Arabidopsis plants were substantially tolerant under continuous high temperature regimen than wild-type plants, as measured by photosystem II (PSII) activity, accumulation of more photosynthetic pigments, higher biomass and seed yield. Transgenic plants produced bold seeds under high temperature, having higher germination potential than the wild-type plants. Further, antisense Arabidopsis plants showed negligible tolerance even for non-lethal heat shock, impaired in basal thermo-tolerance, and accumulated less biomass and seed yield under normal growth conditions. Promoter analysis revealed the presence of several heat and other abiotic stress responsive cis acting elements along with developmental stage and tissue-specific elements. Analysis of promoter through GUS reporter system in both transgenic rice and Arabidopsis further confirms the role of chloroplastic sHsp26 in heat and other abiotic stresses as well as during seed maturation and germination. Genome-wide expression analysis of overexpression Arabidopsis plants revealed that the transcriptome remained unchanged in the transgenic plants and the tolerance was due to the overexpression of chloroplastic heat shock protein (HSP) only. PMID- 22530594 TI - On the perturbation of the H-bonding interaction in ethylene glycol clusters upon hydration. AB - Ab initio and density functional methods have been employed to study the structure, stability, and spectral properties of various ethylene glycol (EG(m)) and ethylene glycol-water (EG(m)W(n)) (m = 1-3, n = 1-4) clusters. The effective fragment potential (EFP) approach was used to explore various possible EG(m)W(n) clusters. Calculated interaction energies of EG(m)W(n) clusters confirm that the hydrogen-bonding interaction between EG molecules is perturbed by the presence of water molecules and vice versa. Further, energy decomposition analysis shows that both electrostatic and polarization interactions predominantly contribute to the stability of these clusters. It was found from the same analysis that ethylene glycol-water interaction is predominant over the ethylene glycol-ethylene glycol and water-water interactions. Overall, the results clearly illustrate that the presence of water disrupts the ethylene glycol-ethylene glycol hydrogen bonds. PMID- 22530595 TI - Hemicelluloses prior to aspen chemithermomechanical pulping: pre-extraction, separation, and characterization. AB - A portion of hemicelluloses and acetic acid can be pre-extracted with dilute sulfuric acid prior to the aspen chemithermomechanical pulp process. The streams collected from the second press-impregnation stage after acid pre-extraction contain a significant amount of acid pre-extracted hemicelluloses. Most of the total sugars obtained from the pressate were xylan, in which xylan was further hydrolyzed to sugar monomers under the acid pre-extraction condition. To fully understand the characteristics of hemicelluloses yielded prior to pulping, the pre-extracted hemicelluloses were separated and characterized by FT-IR, (1)H NMR, and thermogravimetric analysis in this study. Most of the FT-IR bonds from the hemicelluloses agreed well with the other two spectra of birch xylan and CA0050 xylan, except a new absorption at 1734 cm(-1) contributed to acetyl groups. The hemicelluloses obtained from acid pre-extraction began to decompose significantly at about 225 degrees C, slightly lower in comparison with organosolv and alkaline hemicelluloses reported in the literature. PMID- 22530596 TI - Revaluation manipulations produce emergence of underselected stimuli following simultaneous discrimination in humans. AB - Stimulus overselectivity occurs when only one of potentially many aspects of the environment controls behaviour. In four experiments, human participants were trained and tested on a trial-and-error simultaneous discrimination task involving two two-element compound stimuli. Overselectivity emerged in all experiments (i.e., one element from the reinforced compound controlled behaviour at the expense of the other). Following revaluation (extinction) of the previously overselected stimulus, behavioural control by the underselected stimulus element emerged without any direct training of that stimulus element. However, while a series of extinction manipulations targeting the revaluation of the overselected stimulus produced differential extinction of that stimulus, they did not result in differential emergence of the previously underselected stimuli. The results are discussed with respect to the theoretical implications for attention-based accounts of overselectivity. PMID- 22530597 TI - Comparison of recommendations for radiotherapy from two contemporaneous thoracic multidisciplinary meeting formats: co-located and video conference. AB - BACKGROUND: Thoracic multidisciplinary meetings (TMDM) are a key component of lung cancer patient management. The optimal design, organisation and function of TMDM are uncertain, and different models may serve different purposes. In the Auckland/Northland region, there are two contemporaneous weekly TMDM using different formats; one is a co-located TMDM (C-TMDM), and the other is a video conference TMDM (V-TMDM) connecting different locations. AIMS: To determine whether the rates of referral for radiotherapy (RT) and concordance between recommendations for RT and actual treatment received differed between the two TMDM formats. METHOD: A retrospective review of demographical and clinical data for cases referred for RT from both TMDM between January-June 2009 and the actual RT delivered. RESULTS: Seventy-nine and 31 lung cancers were referred for RT from the co-located TMDM and the video conference TMDM respectively. While there were significant differences in demographics related to areas of domicile, there were no significant differences between the TMDM in (i) the proportion of cases referred for RT that received RT, (ii) the intent of treatment recommended by the TMDM and the intent of RT delivered, or (iii) transit times to commencement of RT between cases referred from the different TMDM. CONCLUSION: The similar results from the different formats of TMDM indicate that cases discussed with the use of e-health technologies are not disadvantaged with respect to recommended therapy nor in the appropriateness of decisions of the TMDM. Use of such technology may reduce the existing disparities in health outcomes between urban and rural patients. PMID- 22530598 TI - NO APICAL MERISTEM (MtNAM) regulates floral organ identity and lateral organ separation in Medicago truncatula. AB - * The CUP-SHAPED COTYLEDON (CUC)/NO APICAL MERISTEM (NAM) family of genes control boundary formation and lateral organ separation, which is critical for proper leaf and flower patterning. However, most downstream targets of CUC/NAM genes remain unclear. * In a forward screen of the tobacco retrotransposon1 (Tnt1) insertion population in Medicago truncatula, we isolated a weak allele of the no apical-meristem mutant mtnam-2. Meanwhile, we regenerated a mature plant from the null allele mtnam-1. These materials allowed us to extensively characterize the function of MtNAM and its downstream genes. * MtNAM is highly expressed in vegetative shoot buds and inflorescence apices, specifically at boundaries between the shoot apical meristem and leaf/flower primordia. Mature plants of the regenerated null allele and the weak allele display remarkable floral phenotypes: floral whorls and organ numbers are reduced and the floral organ identity is compromised. Microarray and quantitative RT-PCR analyses revealed that all classes of floral homeotic genes are down-regulated in mtnam mutants. Mutations in MtNAM also lead to fused cotyledons and leaflets of the compound leaf as well as a defective shoot apical meristem. * Our results revealed that MtNAM shares the role of CUC/NAM family genes in lateral organ separation and compound leaf development, and is also required for floral organ identity and development. PMID- 22530590 TI - Characterization of the transcriptome of an ecologically important avian species, the Vinous-throated Parrotbill Paradoxornis webbianus bulomachus (Paradoxornithidae; Aves). AB - BACKGROUND: Adaptive divergence driven by environmental heterogeneity has long been a fascinating topic in ecology and evolutionary biology. The study of the genetic basis of adaptive divergence has, however, been greatly hampered by a lack of genomic information. The recent development of transcriptome sequencing provides an unprecedented opportunity to generate large amounts of genomic data for detailed investigations of the genetics of adaptive divergence in non-model organisms. Herein, we used the Illumina sequencing platform to sequence the transcriptome of brain and liver tissues from a single individual of the Vinous throated Parrotbill, Paradoxornis webbianus bulomachus, an ecologically important avian species in Taiwan with a wide elevational range of sea level to 3100 m. RESULTS: Our 10.1 Gbp of sequences were first assembled based on Zebra Finch (Taeniopygia guttata) and chicken (Gallus gallus) RNA references. The remaining reads were then de novo assembled. After filtering out contigs with low coverage (<10X), we retained 67,791 of 487,336 contigs, which covered approximately 5.3% of the P. w. bulomachus genome. Of 7,779 contigs retained for a top-hit species distribution analysis, the majority (about 86%) were matched to known Zebra Finch and chicken transcripts. We also annotated 6,365 contigs to gene ontology (GO) terms: in total, 122 GO-slim terms were assigned, including biological process (41%), molecular function (32%), and cellular component (27%). Many potential genetic markers for future adaptive genomic studies were also identified: 8,589 single nucleotide polymorphisms, 1,344 simple sequence repeats and 109 candidate genes that might be involved in elevational or climate adaptation. CONCLUSIONS: Our study shows that transcriptome data can serve as a rich genetic resource, even for a single run of short-read sequencing from a single individual of a non model species. This is the first study providing transcriptomic information for species in the avian superfamily Sylvioidea, which comprises more than 1,000 species. Our data can be used to study adaptive divergence in heterogeneous environments and investigate other important ecological and evolutionary questions in parrotbills from different populations and even in other species in the Sylvioidea. PMID- 22530600 TI - Cerebrospinal fluid biomarkers in Alzheimer's disease and geriatric depression: preliminary findings from Brazil. AB - AIMS: Depression is a highly prevalent disorder in the elderly and one of the risk factors for developing dementia. The present study involves patients with Alzheimer's disease (AD), geriatric major depressive disorder (MDD) and cognitively healthy controls aiming to compare baseline cerebrospinal fluid (CSF) biomarkers. METHODS: The study included 52 patients with more than 60 years of age with a diagnosis of MDD, AD, and healthy controls. All individuals underwent a medical history, physical, and neurologic examination, laboratory tests and neuropsychological assessment to rule out any clinical diseases or disorders. Measurement of CSF P-tau(181) , T-tau, and Abeta42 was performed using commercial assays (ELISA). RESULTS: CSF Abeta42 levels of depressed patients and normal controls were significantly higher than in AD. There was not any significant difference in measures of P-tau among the groups. T-tau, however, showed to be significantly different among the groups, with higher measures in AD group. Higher levels of P-tau were observed in four MDD patients compared with controls. CONCLUSION: CSF Abeta42, T-tau, and P-tau levels may differentiate between AD and depression in a Brazilian sample. PMID- 22530601 TI - Australian general practitioner uptake of a remunerated Medicare health assessment for people with intellectual disability. PMID- 22530599 TI - Angiotensin II, NADPH oxidase, and redox signaling in the vasculature. AB - SIGNIFICANCE: Angiotensin II (Ang II) influences the function of many cell types and regulates many organ systems, in large part through redox-sensitive processes. In the vascular system, Ang II is a potent vasoconstrictor and also promotes inflammation, hypertrophy, and fibrosis, which are important in vascular damage and remodeling in cardiovascular diseases. The diverse actions of Ang II are mediated via Ang II type 1 and Ang II type 2 receptors, which couple to various signaling molecules, including NADPH oxidase (Nox), which generates reactive oxygen species (ROS). ROS are now recognized as signaling molecules, critically placed in pathways activated by Ang II. Mechanisms linking Nox and Ang II are complex and not fully understood. RECENT ADVANCES: Ang II regulates vascular cell production of ROS through various recently characterized Noxs, including Nox1, Nox2, Nox4, and Nox5. Activation of these Noxs leads to ROS generation, which in turn influences many downstream signaling targets of Ang II, including MAP kinases, RhoA/Rho kinase, transcription factors, protein tyrosine phosphatases, and tyrosine kinases. Activation of these redox-sensitive pathways regulates vascular cell growth, inflammation, contraction, and senescence. CRITICAL ISSUES: Although there is much evidence indicating a role for Nox/ROS in Ang II function, there is still a paucity of information on how Ang II exerts cell-specific effects through ROS and how Nox isoforms are differentially regulated by Ang II. Moreover, exact mechanisms whereby ROS induce oxidative modifications of signaling molecules mediating Ang II actions remain elusive. FUTURE DIRECTIONS: Future research should elucidate these issues to better understand the significance of Ang II and ROS in vascular (patho) biology. PMID- 22530603 TI - An efficient fermentation method for the degradation of cyanogenic glycosides in flaxseed. AB - Recently, flaxseed has become increasingly popular in the health food market because it contains a considerable amount of specific beneficial nutrients such as lignans and omega-3 fatty acids. However, the presence of cyanogenic glycosides (CGs) in flaxseed severely limits the exploitation of its health benefits and nutritive value. We, therefore, developed an effective fermentation method, optimised by response surface methodology (RSM), for degrading CGs with an enzymatic preparation that includes 12.5% beta-glucosidase and 8.9% cyanide hydratase. These optimised conditions resulted in a maximum CG degradation level of 99.3%, reducing the concentration of cyanide in the flaxseed power from 1.156 to 0.015 mg g(-1) after 48 h of fermentation. The avoidance of steam heat to evaporate hydrocyanic acid (HCN) results in lower energy consumption and no environmental pollution. In addition, the detoxified flaxseed retained the beneficial nutrients, lignans and fatty acids at the same level as untreated flaxseed, and this method could provide a new means of removing CGs from other edible plants, such as cassava, almond and sorghum by simultaneously expressing cyanide hydratase and beta-glucosidase. PMID- 22530602 TI - Nanoparticle-assisted stimulated-emission-depletion nanoscopy. AB - We show that metal nanoparticles can be used to improve the performance of super resolution fluorescence nanoscopes based on stimulated-emission-depletion (STED). Compared with a standard STED nanoscope, we show theoretically a resolution improvement by more than an order of magnitude, or equivalently, depletion intensity reductions by more than 2 orders of magnitude and an even stronger photostabilization. Our scheme may allow improvement of existing STED nanoscopes and assist in the development of low-power, low-cost nanoscopes. This has the potential to increase the availability of STED nanoscopes and lead to a significant expansion of our understanding of biological and biochemical phenomena occurring on the nanoscale. PMID- 22530604 TI - Palladium-catalyzed synthesis of 4-oxaspiro[2.4]heptanes via central attack of oxygen nucleophiles to pi-allylpalladium intermediates. AB - A palladium-catalyzed decarboxylative cyclopropanation of gamma-methylidene-delta valerolactones with aromatic aldehydes has been developed to give 4 oxaspiro[2.4]heptanes with high selectivity. The site of nucleophilic attack to a pi-allylpalladium intermediate has been controlled with a sterically demanding phosphine ligand. The course of the reaction is highly dependent on ligands and solvents, and selective formation of methylenetetrahydropyrans has also been realized. PMID- 22530606 TI - Therapeutic potential of the chemokine-receptor duo fractalkine/CX3CR1: an update. AB - INTRODUCTION: The chemokine fractalkine/CX3CL1 and its highly selective receptor CX3CR1 mediate critical physiological events during inflammatory responses. The fractalkine/CX3CR1 axis has been shown to play a key role in the pathogenesis and the progression of a large number of diseases in which imbalance of the immune response is frequently seen. Since our last review published in early 2010, the fractalkine/CX3CR1 axis has gained vast attention as a potential therapeutic target in the scientific community, which can be clearly seen in the large number of studies that have been published on this issue since then. AREAS COVERED: A Medline/PubMed search was performed to detect all recently published studies on the role of the fractalkine/CX3CR1 axis as a therapeutic target in a wide range of clinical diseases. EXPERT OPINION: Recently published studies further underline the high potential of the fractalkine/CX3CR1 axis as a major target for future treatment of pain, inflammation and cancer. However, no clinical trials on novel therapeutics targeting fractalkine or CX3CR1 have been initiated so far, so that the fractalkine/CX3CR1 axis does still not find application in daily clinical practice. PMID- 22530605 TI - Joint distraction results in clinical and structural improvement of haemophilic ankle arthropathy: a series of three cases. AB - The incidence of haemophilic arthropathy in multiple joints decreased due to treatment with clotting factor. Nowadays patients are enabled to live a rather normal life, resulting in more (sports) trauma-induced arthropathy in isolated joints like the ankle. As surgical treatment options, fusion of the tibiotalar joint and total ankle replacement are available. Both standard treatments have complications and therefore an alternative treatment is desired. In this study, treatment of haemophilic ankle arthropathy with joint distraction was explored. Three patients with haemophilic ankle arthropathy were treated with joint distraction using an Ilizarov external fixator. Clinical outcomes like function, participation and pain were evaluated in retrospect with three different questionnaires: haemophilia activities list, impact on participation and autonomy and the Van Valburg questionnaire. Structural changes were assessed blinded on X ray by the Pettersson score and ankle images digital analysis (AIDA) and by an MRI score. All three patients were very satisfied with the clinical outcome of the procedure. They reported a clear improvement for self-perceived functional health, participation in society and autonomy and pain. Partial ankle joint mobility was preserved in the three patients. The Pettersson score remained the same in one patient and slightly improved in the two other patients, while joint space width measured by AIDA and the MRI score demonstrated improvement for all three patients after ankle distraction. This study suggests that joint distraction is a promising treatment for individual cases of haemophilic ankle arthropathy, without additional risk of bleedings during treatment. PMID- 22530607 TI - Implications of PNPLA3 polymorphism in chronic hepatitis C patients receiving peginterferon plus ribavirin. AB - BACKGROUND: Homozygosity for the PNPLA3 p.I148M polymorphism influences steatosis and fibrogenesis in chronic hepatitis C (CHC). AIM: To evaluate the effect of p.148M/M on sustained virological response (SVR) and viral kinetics in patients who underwent antiviral therapy with peg-interferon and ribavirin, stratified according to viral genotype and fibrosis severity, and secondarily, the interaction with interleukin-28B ( IL28B ) genotype on liver damage. METHODS: In this observational study, we considered 602 treatment-naive consecutive patients from tertiary referral centres in Milan and Vienna [61% genotype 1 (G1), 30% advanced fibrosis, 33% IL28B rs12979860 CC]. RESULTS: The p.148M/M genotype, detected in 8% of patients, did not influence SVR in the overall series (P = 0.29), but it was associated with SVR (3/17, 17% vs. 56/121, 46%; P = 0.034) and complete early viral response (4/17, 23% vs. 68/121, 56%; P = 0.018) in G1/4 patients with advanced fibrosis. After adjustment for age, viral load, IL28B CC genotype, treatment dose, and steatosis, p.148M/M remained a predictor of SVR in G1/4 patients with advanced fibrosis (OR 0.23, 95% CI 0.04-0.87). The p.148M/M genotype was associated with more advanced fibrosis in the overall series (P = 0.049), whereas the rs12979860 IL28B CC genotype only in patients negative for p.148M/M (P = 0.017), independently of age, BMI and alanine transaminase levels (OR 1.51, 95% CI 1.01-2.27). CONCLUSIONS: PNPLA3 p.148M/M genotype was negatively associated with SVR and early viral kinetics independently of steatosis, albeit only in difficult-to-cure G1/4 patients with advanced fibrosis, whereas stratification for the p.148M/M PNPLA3 genotype unmasked an association between IL28B CC genotype and more severe liver fibrosis. PMID- 22530608 TI - Bacteruria with group-B streptococcus: is it a risk factor for adverse pregnancy outcomes? AB - OBJECTIVE: To investigate pregnancy outcomes of patients with and without group-B streptococcus (GBS) bacteriuria. METHODS: A retrospective study comparing pregnancy outcomes of women with GBS bacteriuria during pregnancy, those with positive GBS vaginal cultures and those without GBS colonization during pregnancy was conducted. RESULTS: A significant linear association was found with regard to intrapartum fever (U-GBS 0.5%, V-GBS 0.3%, no GBS 0.1%, p = 0.001) and chorioamnionitis (U-GBS 3.3%, V-GBS 1%, no GBS 0.7%, p = 0.001). In addition preterm delivery (15.3% vs. 7.9%, p = 0.001) and premature rupture of membranes (10.7% vs. 7.9, p = 0.001) were significantly higher in the U-GBS group compared to no GBS. Woman with U-GBS had higher rates of diabetes mellitus, hypertensive disorders, and habitual abortions as well as a higher risk for intrauterine growth restriction (IUGR). In addition patients with U-GBS underwent induction of labor and cesarean delivery more frequently. CONCLUSIONS: Our study showed a significant association between U-GBS and adverse obstetrical outcomes. In addition a linear association was found between GBS culture location and obstetric complications. However, GBS was not associated with adverse perinatal outcome in our population. PMID- 22530609 TI - HKT2;2/1, a K+-permeable transporter identified in a salt-tolerant rice cultivar through surveys of natural genetic polymorphism. AB - We have investigated OsHKT2;1 natural variation in a collection of 49 cultivars with different levels of salt tolerance and geographical origins. The effect of identified polymorphism on OsHKT2;1 activity was analysed through heterologous expression of variants in Xenopus oocytes. OsHKT2;1 appeared to be a highly conserved protein with only five possible amino acid substitutions that have no substantial effect on functional properties. Our study, however, also identified a new HKT isoform, No-OsHKT2;2/1 in Nona Bokra, a highly salt-tolerant cultivar. No-OsHKT2;2/1 probably originated from a deletion in chromosome 6, producing a chimeric gene. Its 5' region corresponds to that of OsHKT2;2, whose full-length sequence is not present in Nipponbare but has been identified in Pokkali, a salt tolerant rice cultivar. Its 3' region corresponds to that of OsHKT2;1. No OsHKT2;2/1 is essentially expressed in roots and displays a significant level of expression at high Na+ concentrations, in contrast to OsHKT2;1. Expressed in Xenopus oocytes or in Saccharomyces cerevisiae, No-OsHKT2;2/1 exhibited a strong permeability to Na+ and K+, even at high external Na+ concentrations, like OsHKT2;2, and in contrast to OsHKT2;1. Our results suggest that No-OsHKT2;2/1 can contribute to Nona Bokra salt tolerance by enabling root K+ uptake under saline conditions. PMID- 22530611 TI - Comment on "Puzzle of the protein dynamical transition". PMID- 22530610 TI - Effect of exercise training and isoflavones on hepatic steatosis in overweight postmenopausal women. AB - OBJECTIVES: Postmenopausal women are particularly inclined to an increased risk of developing non-alcoholic hepatic steatosis. The purpose of this study was to investigate whether adding isoflavone supplementation to exercise training could reduce the risk. METHODS: In a 6-month, double-blind, randomized, controlled trial, 54 healthy overweight-to-obese (body mass index 28-40 kg/m2) postmenopausal women were randomly assigned to one of the following groups: (1) exercise and isoflavones (Ex-Iso; n = 26), (2) exercise and placebo (Ex-Pla; n = 28). Exercise training consisted of three weekly sessions of mixed training. We examined the plasma level of specific hepatic enzymes (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, and alkaline phosphatase) as a reflection of fatty liver along with the calculation of the fatty liver index. All measures were obtained at baseline and after the 6-month intervention. RESULTS: Following the intervention, a lower fatty liver index (p <0.01; 29% in Ex-Iso, 18% in Ex-Pla) and plasma gamma-glutamyltransferase (p <0.01; 22% in Ex Iso, 16% in Ex-Pla) were observed in both groups, with a higher reduction in the Ex-Iso group. On the other hand, for all other hepatic enzymes, there was no change. CONCLUSIONS: Our results show that exercise training appears to bring favorable changes in the plasma level of hepatic enzymes, possibly due to the lowering of liver fat content. While postmenopausal women can benefit from this intervention to decrease the risk of developing non-alcoholic hepatic steatosis, it seems that the addition of isoflavones to exercise training provides some additional effects to those provided by exercise alone. PMID- 22530612 TI - Styrene-spaced copolymers including anthraquinone and beta-O-4 lignin model units: synthesis, characterization and reactivity under alkaline pulping conditions. AB - A series of random copoly(styrene)s has been synthesized via radical polymerization of functionalized anthraquinone (AQ) and beta-O-4 lignin model monomers. The copolymers were designed to have a different number of styrene spacer groups between the AQ and beta-O-4 lignin side chains aiming at investigating the distance effects on AQ/beta-O-4 electron transfer mechanisms. A detailed molecular characterization, including techniques such as size exclusion chromatography, MALDI-TOF mass spectrometry, and (1)H, (13)C, (31)P NMR and UV vis spectroscopies, afforded quantitative information about the composition of the copolymers as well as the average distribution of the AQ and beta-O-4 groups in the macromolecular structures. TGA and DSC thermal analysis have indicated that the copolymers were thermally stable under regular pulping conditions, revealing the inertness of the styrene polymer backbone in the investigation of electron transfer mechanisms. Alkaline pulping experiments showed that close contact between the redox active side chains in the copolymers was fundamental for an efficient degradation of the beta-O-4 lignin model units, highlighting the importance of electron transfer reactions in the lignin degradation mechanisms catalyzed by AQ. In the absence of glucose, AQ units oxidized phenolic beta-O-4 lignin model parts, mainly by electron transfer leading to vanillin as major product. By contrast, in presence of glucose, anthrahydroquinone units (formed by reduction of AQ) reduced the quinone-methide units (issued by dehydration of phenolic beta-O-4 lignin model part) mainly by electron transfer leading to guaiacol as major product. Both processes were distance dependent. PMID- 22530613 TI - Bulk and surface excitons in alloyed and phase-separated ZnO-MgO particulate systems. AB - The rational design of composite nanoparticles with desired optical and electronic properties requires the detailed analysis of surface and bulk contributions to the respective overall function. We use flame spray pyrolysis (FSP) to generate nanoparticles of the ternary Zn-Mg-O system the compositions of which range from solid solutions of Zn(2+) ions in periclase MgO to phase separated particle mixtures which consist of periclase (cubic) MgO and wurtzite (hexagonal) ZnO phases. The structure and composition of the composite Zn(x)Mg(1 x)O (0 <= x <= 0.3) particles are investigated using X-ray diffraction and high resolution transmission electron microscopy, whereas UV diffuse reflectance and photoluminescence (PL) spectroscopy are used for the investigation of their optical properties. Vacuum annealing has been carried out to track the effects of stepwise elimination of surface adsorbates on the photoexcitation and PL emission properties. We demonstrate that for Zn(0.1)Mg(0.9)O particles, the admixed ZnO suppresses the MgO specific surface excitons and produces a PL emission band at 470 nm. Although gaseous oxygen partially reduces the emission intensity of hydroxylated particles, it leads to entire quenching in completely dehydroxylated samples after vacuum annealing at 1173 K. Consequently, surface hydroxyls at the solid-gas interface play a significant role as protecting groups against the PL quenching effects of O(2). The obtained results are relevant for the characterization of ZnO-based devices as well as for other metal oxide materials where the impact of the surface composition on the photoelectronic properties is usually neglected. PMID- 22530614 TI - Transparent coatings made from spray deposited colloidal suspensions. AB - The goal of this study is to elaborate few-micrometer thick optically active coatings based on nanoparticles spray-deposited onto a substrate and to control their scattering properties through a progressive suppression of the coffee-ring effect. The modification of the aggregation state of the nanoparticles to be sprayed induces a change of the surface roughness of the films and consequently of their optical transmission. We draw the counterintuitive conclusion that a nonstable colloidal solution gives a smoother coating than a highly stabilized colloidal solution, leading to a more transparent coating. This phenomenon is demonstrated in the case of commercial TiO(2) nanoparticles, as well as of homemade luminescent YVO(4):Eu nanoparticles, and seems to be generalized to a large range of systems. PMID- 22530616 TI - The British welfare state and mental health problems: the continuing relevance of the work of Claus Offe. AB - It is now over thirty years since Claus Offe theorised the crisis tendencies of the welfare state in late capitalism. As part of that work he explored ongoing and irresolvable forms of crisis management in parliamentary democracies: capitalism cannot live with the welfare state but also cannot live without it. This article examines the continued relevance of this analysis by Offe, by applying its basic assumptions to the response of the British welfare state to mental health problems, at the turn of the twenty first century. His general theoretical abstractions are tested against the empirical picture of mental health service priorities, evident since the 1980s, in sections dealing with: re commodification tendencies; the ambiguity of wage labour in the mental health workforce; the emergence of new social movements; and the limits of legalism. PMID- 22530615 TI - Functional organization and its implication in evolution of the human protein protein interaction network. AB - BACKGROUND: Based on the distinguishing properties of protein-protein interaction networks such as power-law degree distribution and modularity structure, several stochastic models for the evolution of these networks have been purposed, motivated by the idea that a validated model should reproduce similar topological properties of the empirical network. However, being able to capture topological properties does not necessarily mean it correctly reproduces how networks emerge and evolve. More importantly, there is already evidence suggesting functional organization and significance of these networks. The current stochastic models of evolution, however, grow the network without consideration for biological function and natural selection. RESULTS: To test whether protein interaction networks are functionally organized and their impacts on the evolution of these networks, we analyzed their evolution at both the topological and functional level. We find that the human network is shown to be functionally organized, and its function evolves with the topological properties of the network. Our analysis suggests that function most likely affects local modularity of the network. Consistently, we further found that the topological unit is also the functional unit of the network. CONCLUSION: We have demonstrated functional organization of a protein interaction network. Given our observations, we suggest that its significance should not be overlooked when studying network evolution. PMID- 22530617 TI - Stoichiometric self-assembly of isomeric, shape-persistent, supramacromolecular bowtie and butterfly structures. AB - Two novel macromolecular constitutional isomers have been self-assembled from previously unreported terpyridine ligands in a three-component system. The terpyridine ligands were synthesized in high yields via a key Suzuki coupling. Restrictions of the possible outcomes for self-assembly ultimately provided optimum conditions for isolation of either a molecular bowtie or its isomeric butterfly motif. These isomers have been characterized by ESI-MS, TWIM-MS, (1)H NMR, and (13)C NMR. Notably, these structural isomers have remarkably different drift times in ion mobility separation, corresponding to different sizes and shapes at high charge states. PMID- 22530618 TI - Improving quality of care and patient safety through morbidity and mortality conferences. AB - The objective was to evaluate the analysis of adverse events and the decisions for quality improvement decided during morbidity and mortality conferences (MMCs). We conducted a prospective observational study of MMCs conducted in a teaching hospital between November 2007 and May 2008. Two observers attended the conferences and collected data on the structure of MMCs, the discussion between attendees, and the decisions or actions for quality improvement. Twenty-four MMCs were studied including 146 cases. A majority of the senior physicians present (87.7%) took part in debating the cases; the participation of residents was lower (32.6%) and varied between departments (p < .001). Few paramedical professionals and other attendees participated in the debate. Shortcomings were sought in 91% of cases, but a structured method was used in less than 10% of cases. An analysis of underlying factors contributing to these shortcomings was observed in 75% of cases, with 4% considered structured and thorough. Eighty-five decisions or actions to improve quality of care or patient safety were listed, with 28 of them (33%) planned for implementation. Discussion of adverse events appears to lack a structured method and although a large number of decisions for quality improvement were declared, fewer actions were planned with a timeline. PMID- 22530619 TI - Arabidopsis RAP2.2 plays an important role in plant resistance to Botrytis cinerea and ethylene responses. AB - * Ethylene plays a crucial role in plant resistance to necrotrophic pathogens, in which ETHYLENE RESPONSE FACTORs (ERFs) are often involved. * Here, we evaluated the role of an ERF transcription factor, RELATED TO AP2 2 (RAP2.2), in Botrytis resistance and ethylene responses in Arabidopsis. We analyzed the resistance of transgenic plants overexpressing RAP2.2 and the T-DNA insertion mutant to Botrytis cinerea. We assessed its role in the ethylene signaling pathway by molecular and genetic approaches. * RAP2.2-overexpressing transgenic plants showed increased resistance to B. cinerea, whereas its T-DNA insertion mutant rap2.2-3 showed decreased resistance. Overexpression of RAP2.2 in ethylene insensitive 2 (ein2) and ein3 ein3-like 1 (eil1) mutants restored their resistance to B. cinerea. Both ethylene and Botrytis infection induced the expression of RAP2.2 and the induction was disrupted in ein2 and ein3 eil1 mutants. We identified rap2.12-1 as a T-DNA insertion mutant of RAP2.12, the closest homolog of RAP2.2. The hypocotyls of rap2.2-3 rap2.12-1 double mutants showed ethylene insensitivity. The constitutive triple response in constitutive triple response1 (ctr1) was partially released in the rap2.2-3 rap2.12-1 ctr1 triple mutants. * Our findings demonstrate that RAP2.2 functions as an important regulator in Botrytis resistance and ethylene responses. PMID- 22530620 TI - The effects of ageing and visual noise on conceptual integration during sentence reading. AB - The effortfulness hypothesis implies that difficulty in decoding the surface form, as in the case of age-related sensory limitations or background noise, consumes the attentional resources that are then unavailable for semantic integration in language comprehension. Because ageing is associated with sensory declines, degrading of the surface form by a noisy background can pose an extra challenge for older adults. In two experiments, this hypothesis was tested in a self-paced moving window paradigm in which younger and older readers' online allocation of attentional resources to surface decoding and semantic integration was measured as they read sentences embedded in varying levels of visual noise. When visual noise was moderate (Experiment 1), resource allocation among young adults was unaffected but older adults allocated more resources to decode the surface form at the cost of resources that would otherwise be available for semantic processing; when visual noise was relatively intense (Experiment 2), both younger and older participants allocated more attention to the surface form and less attention to semantic processing. The decrease in attentional allocation to semantic integration resulted in reduced recall of core ideas in both experiments, suggesting that a less organized semantic representation was constructed in noise. The greater vulnerability of older adults at relatively low levels of noise is consistent with the effortfulness hypothesis. PMID- 22530621 TI - How do Australian optometrists manage work-related physical discomfort? AB - BACKGROUND: Work-related physical discomfort exists within the optometric profession. It is not well understood how optometrists manage this issue in their workplaces. METHOD: An online questionnaire was sent by e-mail to approximately 1,700 Australian optometrists. Participants were asked if they experienced work related discomfort in any of eight nominated body regions. If so, they were asked to describe specific work tasks, which contribute to their work-related discomfort, and strategies they have adopted to minimise their discomfort. These data were subject to qualitative and quantitative analyses. RESULTS: There was a 25 per cent response rate and 416 optometrists participated in the questionnaire. Work-related physical discomfort was reported by 339 respondents (81 per cent), most commonly with the use of the phoropter (n = 144, 35 per cent) and slitlamp (n = 94, 23 per cent). Males were more likely to report lower back discomfort with phoropter use (Chi-squared, p < 0.01) and ophthalmoscopy (Chi-squared, p < 0.01). To minimise discomfort, optometrists 41 years and older were more likely to report that they adjust their posture (Chi-squared, p < 0.03) and females were more likely to report that they alter their work schedule (Chi-squared, p < 0.05). A recurrent theme expressed by participants was an inability to make changes to improve their comfort due to room and equipment design, poorly maintained equipment, non-supply of suitable equipment or furniture and inherent difficulties within optometric tasks. CONCLUSION: There is a need for all optometrists to have skills to evaluate their own personal risk of discomfort in the consultation room. Owners and managers of optometric practices also need greater awareness of the importance of room and equipment design and maintenance on work-related discomfort. This has implications for the well-being of optometrists, for their productivity and for compliance with health and safety legislation. PMID- 22530622 TI - Thiol-based redox modulation of a cyanobacterial eukaryotic-type serine/threonine kinase required for oxidative stress tolerance. AB - AIMS: Protein phosphorylation is a principal signaling mechanism that mediates regulation of enzymatic activities, modulation of gene expression, and adaptation to environmental changes. Recent studies have shown a ubiquitous distribution of eukaryotic-type Serine/Threonine protein kinases in prokaryotic genomes, though the functions, substrates, and possible regulation of these enzymes remain largely unknown. In this study, we investigated whether cyanobacterial protein phosphorylation may be subject to redox regulation through modulation of the cysteine redox state, as has previously been reported for animals and plants. We also explored the role of a cyanobacterial Serine/Threonine kinase in oxidative stress tolerance. RESULTS: The Synechocystis sp. PCC 6803 Serine/Threonine kinase SpkB was found to be inhibited by oxidation and reactivated by thioredoxin catalyzed reduction. A Synechocystis mutant devoid of the SpkB kinase was unable to phosphorylate the glycyl-tRNA synthetase beta-subunit (GlyS), one of the most prominent phosphoproteins in the wild type, and recombinant purified SpkB could phosphorylate purified GlyS. In vivo characterization of the SpkB mutant showed a pronounced hypersensitivity to oxidative stress and displayed severe growth retardation or death in response to menadione, methyl viologen, and elevated light intensities. INNOVATION: This study points out a previously unrecognised complexity of prokaryotic regulatory pathways in adaptation to the environment and extends the roles of bacterial eukaryotic-like Serine/Threonine kinases to oxidative stress response. CONCLUSION: The SpkB kinase is required for survival of the cyanobacterium Synechocystis sp. PCC 6803 under conditions implying increased concentrations of reactive oxygen species, and the activity of SpkB depends on the redox state of its cysteines. PMID- 22530625 TI - Synthesis of alcohols from m-fluorophenylsulfones and dialkylboranes: application to the C14-C35 building block of E7389. AB - The reaction of m-fluorophenylsulfone anions with dialkylboranes, followed by alkaline hydroperoxide oxidation, yields alcohols in high yields. Optimization of the process, scope and limitation, and application to the synthesis of one of the C14-C35 building blocks of E7389, a right half analogue of halichondrin B, are reported. PMID- 22530626 TI - Low-loss impedance-matched optical metamaterials with zero-phase delay. AB - Metamaterials have dramatically expanded the range of available optical properties, enabling an array of new devices such as superlenses, perfect absorbers, and ultrafast switches. Most research has focused on demonstrating negative- and high-index metamaterials at terahertz and optical wavelengths. However, far less emphasis has been placed on low-loss near-zero-index metamaterials that exhibit unique properties including quasi-infinite phase velocity and infinite wavelength. Here, we experimentally demonstrate a free standing metallodielectric fishnet nanostructure that has polarization insensitive, zero-index properties with nearly ideal transmission at 1.55 MUm. This goal was achieved by optimizing the metamaterial geometry to allow both its effective permittivity and permeability to approach zero together, which simultaneously produces a zero index and matched impedance to free space. The ability to design and fabricate low-loss, near-zero-index optical metamaterials is essential for new devices such as beam collimators, zero-phase delay lines, and transformation optics lenses. PMID- 22530623 TI - Seizure management at Auckland City Hospital Emergency Department between July and December 2009: time for a change? AB - AIMS: To assess the management of epileptic seizures and status epilepticus in adult patients at Auckland City Hospital emergency department. This information will form the basis of future seizure management protocols and further research on the management of status epilepticus. METHODS: The prehospital and acute hospital management of all adult seizure patients seen between 1 July 2009 and 31 December 2009 was reviewed with respect to seizure type, presence of first seizure, pre-existing epilepsy diagnosis and disposition from the emergency department. RESULTS: Two hundred and fifty-five seizure events were identified in 227 patients. Nineteen patients presented twice during the study period and three patients presented three or more times. Generalised seizures were much more common than focal seizures. There were 75 presentations with first seizure (29.4%). Thirty-seven patients (49.3%) with a first seizure received treatment with an anti-epileptic drug. Status epilepticus occurred on 12 occasions (4.7%) with only three patients receiving lorazepam as treatment. The majority of seizure patients were managed by emergency department staff (58.4%) while general medicine (17.6%) and neurology (11.8%) teams managed fewer patients. Phenytoin was used in 56 patients (22%) with the majority (n= 43) receiving intravenous phenytoin. Many of the patients who received intravenous phenytoin were not subsequently discharged on that medication (46%). CONCLUSIONS: More patients than would be expected received treatment after their first seizure. Phenytoin was a widely used anti-epileptic drug. There was a wide variability in the management of status epilepticus, and intravenous lorazepam was underutilised. PMID- 22530628 TI - Cotinine: a potential new therapeutic agent against Alzheimer's disease. AB - Tobacco smoking has been correlated with a lower incidence of Alzheimer's disease (AD). This negative correlation has been attributed to nicotine's properties. However, the undesired side-effects of nicotine and the absence of clear evidence of positive effects of this drug on the cognitive abilities of AD patients have decreased the enthusiasm for its therapeutic use. In this review, we discuss evidence showing that cotinine, the main metabolite of nicotine, has many of the beneficial effects but none of the negative side-effects of its precursor. Cotinine has been shown to be neuroprotective, to improve memory in primates as well as to prevent memory loss, and to lower amyloid-beta (Abeta)) burden in AD mice. In AD, cotinine's positive effect on memory is associated with the inhibition of Abeta aggregation, the stimulation of pro-survival factors such as Akt, and the inhibition of pro-apoptotic factors such as glycogen synthase kinase 3 beta (GSK3beta). Because stimulation of the alpha7 nicotinic acetylcholine receptors (alpha7nAChRs) positively modulates these factors and memory, the involvement of these receptors in cotinine's effects are discussed. Because of its beneficial effects on brain function, good safety profile, and nonaddictive properties, cotinine may represent a new therapeutic agent against AD. PMID- 22530627 TI - Pain management in patients with haemophilia: a European survey. AB - There are no evidence-based guidelines on pain management in people with haemophilia (PWH), who may suffer acute, disabling pain from haemarthroses and chronic arthropathic pain. To review evidence and to investigate current clinical practice in pain assessment and management in PWH the European Haemophilia Therapy Standardisation Board undertook a literature review and a survey in 22 Haemophilia Treatment Centres (HTC), using a questionnaire and seven clinical scenarios. Consensus was sought on pain assessment and management in PWH. Few clinical studies on pain management in PWH were identified. The HTCs care for 1678 children (47% severe haemophilia, 84% on prophylaxis, 17% with arthropathy and 8% with chronic pain) and 5103 adults (44% severe haemophilia, 40% on prophylaxis, 67% with arthropathy and 35% with chronic pain). Analgesics are prescribed by HTCs in 80% of cases (median; range 0-100%) and in 10% (median; range 0-80%) are bought over the counter. Pain and analgesic use are assessed when reported by patients and at check-ups. Only eight centres use a specific pain scale and/or have specific pain guidelines. Two HTCs arrange regular consultations with pain specialists. For acute pain, the preferred first-line drug is paracetamol for children, and paracetamol or non-steroidal anti inflammatory drugs (NSAIDs) for adults. Children with chronic pain are treated with paracetamol or NSAIDs, whereas adults usually receive Cox-2 inhibitors. Second-line therapy is heterogeneous. There is little published evidence to guide pain assessment and management in PWH, and clinical practice varies considerably across Europe. General and specific recommendations are needed. PMID- 22530629 TI - The effect of maternal Class III obesity on neonatal outcomes: a retrospective matched cohort study. AB - OBJECTIVES: To compare outcomes of neonates born from women with Class III obesity with those whose mothers were of normal body weight. METHODS: A retrospective cohort study of live-born singleton infants was undertaken. Maternal prepregnancy body mass index (BMI) defined matched normal and Class III obese cohorts. Multivariable regression models were used to determine adjusted relative odds ratios (aOR) and 95% confidence intervals (CI) for selected adverse neonatal outcomes. RESULTS: Newborns exposed to maternal Class III obesity had greater risks of fetal overgrowth and low cord artery pH. Class III obesity was protective against small for gestational age and low birthweight. There was no difference in the risk of preterm delivery, meconium in the amniotic fluid or breastfeeding initiation. CONCLUSIONS: The new knowledge generated by this study provides further information on unique challenges faced by newborns of women with Class III obesity, suggesting more specialized care in the intrapartum and neonatal periods may be beneficial. PMID- 22530630 TI - Coloration signals the ability to cope with elevated stress hormones: effects of corticosterone on growth of barn owls are associated with melanism. AB - Stressful situations during development can shape the phenotype for life by provoking a trade-off between development and survival. Stress hormones, mainly glucocorticoids, play an important orchestrating role in this trade-off. Hence, how stress sensitive an animal is critically determines the phenotype and ultimately fitness. In several species, darker eumelanic individuals are less sensitive to stressful conditions than less eumelanic conspecifics, which may be due to the pleiotropic effects of genes affecting both coloration and physiological traits. We experimentally tested whether the degree of melanin based coloration is associated with the sensitivity to an endocrine response to stressful situations in the barn owl. We artificially administered the mediator of a hormonal stress response, corticosterone, to nestlings to examine the prediction that corticosterone-induced reduction in growth rate is more pronounced in light eumelanic nestlings than in darker nest mates. To examine whether such an effect may be genetically determined, we swapped hatchlings between randomly chosen pairs of nests. We first showed that corticosterone affects growth and, thus, shapes the phenotype. Second, we found that under corticosterone administration, nestlings with large black spots grew better than nestlings with small black spots. As in the barn owl the expression of eumelanin based coloration is heritable and not sensitive to environmental conditions, it is therefore a reliable, genetically based sign of the ability to cope with an increase in blood corticosterone level. PMID- 22530631 TI - Comparison of the effectiveness of two protocols for vaccination (standard and double dosage) against hepatitis B virus in patients with inflammatory bowel disease. AB - BACKGROUND: The response rate to hepatitis B virus (HBV) vaccination in patients with inflammatory bowel disease (IBD) is low. AIM: To compare two vaccination protocols-the standard dose and the double dose-in IBD patients. METHODS: Patients diagnosed with IBD from three tertiary hospitals were vaccinated against HBV with two different protocols: the standard protocol (Engerix-B single dose at 0, 1 and 6 months) and the new faster protocol based on a double dose (Engerix B double dose at 0, 1 and 2 months). Anti-HBs titres were measured 1-3 months after the last dose. A multivariate analysis was performed to identify factors that were predictive of response to the vaccine. RESULTS: The study sample comprised 148 patients (mean age 40 years, 69% Crohn's disease), 70% of whom were receiving immunosuppressive therapy (22% thiopurines, 23% anti-TNF and 25% both). The standard protocol was followed in 46% of patients and the double dose protocol in 54%. Considering anti-HBs >10 IU/L as a successful response to vaccination, the seroconversion rate was higher among patients vaccinated with the double dose than with the standard dose: 75% (95% CI, 65-85%) vs. 41% (95% CI, 29-54%) (P < 0.001). In the multivariate analysis, vaccination with the double dose was the only factor associated with a better response to the vaccine (OR, 4; 95% CI, 2-8; P < 0.001). CONCLUSIONS: The response rate to the HBV vaccination in IBD patients is low. Administration of a double dose was associated with a higher response rate. Therefore, the double dose protocol could be a suitable option in patients with IBD. PMID- 22530632 TI - Rheumatology mini focus. PMID- 22530633 TI - Targeted drug development for arthritis. PMID- 22530634 TI - Local injections of serotonin type-3 receptor antagonists as a therapeutic option in rheumatology. PMID- 22530635 TI - News & analysis. PMID- 22530636 TI - Cannabinoids: novel therapies for arthritis? AB - A key feature of osteoarthritis and rheumatoid arthritis is the loss of articular cartilage. Cartilage breakdown is mediated by complex interactions of proinflammatory cytokines, such as IL-1, inflammatory mediators, including nitric oxide and prostaglandin E(2), and proteases, including matrix metalloproteinases and aggrecanases, such as ADAMTS-4 and -5. Cannabinoids have been shown to reduce joint damage in animal models of arthritis. They have also been shown to prevent IL-1-induced matrix breakdown of collagen and proteoglycan, indicating that cannabinoids may mediate chondroprotective effects. Cannabinoids produce their effects via several cannabinoid receptors and it is important to identify the key cannabinoids and their receptors that are involved in chondroprotection. This review aims to outline the current and future prospects of cannabinoids as anti arthritic therapeutics, in terms of their ability to prevent cartilage breakdown. PMID- 22530637 TI - Sphingosine kinase and sphingosine-1-phosphate receptors: novel therapeutic targets of rheumatoid arthritis? AB - Rheumatoid arthritis (RA) is a chronic, destructive, autoimmune joint disease characterized by elevated levels of proinflammatory cytokine production. Sphingosine kinase (SphK) phosphorylates sphingosine into sphingosine-1 phosphate. Synovial fluid of RA patients exhibits significantly higher levels of S1P than their non-inflammatory osteoarthritis counterparts. SphK blockade suppresses cytokines and MMP-9 release in RA peripheral blood mononuclear cells. In addition, downregulation of SphK1 either through a specific siRNA approach or transgenic human TNF-alpha SphK1-deficient mice (hTNF-alpha/SphK1(-/-)) exhibit significantly less synovial inflammation and joint pathology. By contrast, SphK2 modulation leads to disease exacerbation. These results clearly demonstrate that such anti- and proinflammatory potential of SphK1/2 modulation may alter the outcome in RA synovitis and raises the possibility that drugs that specifically target SphK1 activity may play a beneficial role in the treatment of RA and other autoimmune rheumatic diseases. PMID- 22530638 TI - Pleiotropic targets: the problem of shared signaling circuitry in rheumatoid arthritis disease progression and protection. AB - The immune response is replete with feedback control at many levels. These protective circuits are even functional within the arthritic joint, tempering disease to varying extents. An optimal therapy would inhibit autoimmune processes while maintaining protective circuitry. However, many of the cells and proteins that serve as important mediators of disease progression also play an active role in these protective circuits. The hypothesis considered in this review is that the inadvertent inhibition of protective circuitry adversely affects efficacy. Conversely, if therapeutics can be designed, which avoid inhibiting known regulatory circuits, efficacy will be improved. Understanding where these processes share signaling molecules will be crucial to the development of the next generation of therapeutics. This review discusses three well-defined signal transduction cascades; IL-2, IFNgamma and TNF-alpha, and demonstrate within two cell types, T cells and macrophages, how these cytokines may contribute both to protection and to disease progression. PMID- 22530639 TI - PBEF/NAMPT/visfatin: a promising drug target for treating rheumatoid arthritis? AB - NAMPT, also known as pre-B-cell colony-enhancing factor and visfatin, has been proposed to be involved in preventing apoptosis in cancer cells and, as such, has received a great deal of attention in recent years and stimulated the development to specific inhibitors for treating cancer. The role of NAMPT inhibitors as potential therapeutic agents for other diseases has not been studied extensively. Here, we describe their applicability for treating rheumatoid arthritis. We summarize current knowledge of NAMPT expression in healthy and diseased tissues, thereafter, we focus on pathological mechanisms relevant to rheumatoid arthritis that involve the NAMPT pathway and review the current status of NAMPT inhibitors being evaluated in clinical trials. PMID- 22530640 TI - Discovery of fingolimod, the sphingosine 1-phosphate receptor modulator and its application for the therapy of multiple sclerosis. AB - Fingolimod (FTY720) is a first-in-class, orally active, sphingosine 1-phosphate (S1P)-receptor modulator with a structure closely related to sphingosine. The compound was discovered by chemical modification of a natural product, myriocin. Phosphorylated form of FTY720 acts as a functional antagonist at S1P receptor type 1 (S1P(1)), inhibits lymphocyte egress from secondary lymphoid organs and shows immunomodulating effects. Phase III studies in multiple sclerosis demonstrated that oral FTY720 had superior efficacy compared with intramuscular IFN-beta1a (AVONEX((r))) with regard to reducing the rate of relapse and the number of inflammatory lesions in the CNS. FTY720 has been approved as a new therapeutic drug for multiple sclerosis in more than 50 countries, including the USA, Japan and some of those in the EU. PMID- 22530641 TI - Ferrocene-based antimalarials. AB - Resistance to commercially available antimalarial drugs is a public health problem. Since the end of the last century, no new antimalarial drugs have been introduced into clinical practice, and new drug development has been quite disappointing. There is therefore a real need to develop new class of antimalarial drugs that could be used alone or in combination. This review describes the development and recent advances on the preparation of ferrocenic compounds as a new class of antimalarial agents with potential for clinical development. PMID- 22530642 TI - An update on dual Src/Abl inhibitors. AB - c-Src and Bcr-Abl are two cytoplasmatic tyrosine kinases (TKs) involved in the development of malignancies. In particular, Bcr-Abl is the etiologic agent of chronic myeloid leukemia, where Src is also involved; the latter is hyperactivated in several solid tumors. Because of the structural homology between Src and Abl, several compounds originally synthesized as Src inhibitors have also been shown to be Abl inhibitors, useful in overcoming the onset of some types of chronic myeloid leukemia resistances, which frequently appear in the advanced phases of pathology. In recent years, the development of such compounds has been promoted by both excellent preclinical and clinical results, and by the theory that dual or multi-targeted inhibitors might be more effective than selective inhibitors. This review is an update on the most important dual inhibitors already in clinical trials and includes information regarding compounds that have appeared in the literature in recent years. PMID- 22530645 TI - Theoretical study of H-abstraction reactions from CH3Cl and CH3Br molecules by ClO and BrO radicals. AB - The rate constants of the H-abstraction reactions from CH(3)Cl and CH(3)Br molecules by ClO and BrO radicals have been estimated over the temperature range of 300-2500 K using four different levels of theory. Calculations of optimized geometrical parameters and vibrational frequencies are performed using B3LYP and MP2 methods combined with the cc-pVTZ basis set. Single-point energy calculations have been carried out with the highly correlated ab initio coupled cluster method in the space of single, double, and triple (perturbatively) electron excitations CCSD(T) using the cc-pVTZ and cc-pVQZ basis sets. Canonical transition-state theory combined with an Eckart tunneling correction has been used to predict the rate constants as a function of temperature. In order to choose the appropriate levels of theory with chlorine- and bromine-containing species, the reference reaction Cl ((2)P(3/2)) + CH(3)Cl -> HCl + CH(2)Cl (R(ref)) was first theoretically studied because its kinetic parameters are well-established from numerous experiments, evaluation data, and theoretical studies. The kinetic parameters of the reaction R(ref) have been determined accurately using the CCSD(T)/cc-pVQZ//MP2/cc-pVTZ level of theory. This level of theory has been used for the rate constant estimation of the reactions ClO + CH(3)Cl (R(1)), ClO + CH(3)Br (R(2)), BrO + CH(3)Cl (R(3)), and BrO + CH(3)Br (R(4)). Six-parameter Arrhenius expressions have been obtained by fitting to the computed rate constants of these four reactions (including cis and trans pathways) over the temperature range of 300-2500 K. PMID- 22530644 TI - HRT decreases DNA and lipid oxidation in postmenopausal women. AB - BACKGROUND: Postmenopausal women have increased oxidative stress and decreased antioxidant status. Estrogen has great antioxidant capacity both in vitro and in vivo. Few authors have studied the effect that hormone replacement therapy (HRT) has on the oxidant and antioxidant status and none have studied the effect on DNA oxidation as a possible explanation for the aging process itself. AIM: The aim of this study was to evaluate both oxidation and antioxidation markers in postmenopausal woman and to determine the effects that HRT has on them. METHOD: Sixty-two postmenopausal women with similar biophysical characteristics were divided into three groups: (1) 18 not taking any HRT, (2) 20 receiving estrogen only replacement therapy (ERT, conjugated equine estrogen), and (3) 22 receiving combined estrogen/progestin HRT (conjugated equine estrogen + medroxyprogesterone acetate). Specific molecular oxidative damage was detected by measuring 8- hydroxy-2-deoxy guanosine (8-OH-2dG) (DNA damage), standardized thiobarbituric acid reactive substances (TBARS) (lipid damage) and protein carbonyl (proteins). Antioxidant enzyme activity was detected by measuring catalase activity, and total antioxidant status was measured using 1,1,difenil-2-picril hydrazil. Both ELISA and photometric methods were used. RESULTS: 8-OH-2dG levels were significantly lower in women who received combined HRT compared to women who did not receive HRT (ANOVA, p < 0.05). Lipid oxidation was significantly lower in women on ERT compared to women taking no HRT (ANOVA, p < 0.05). Pearson correlation showed that lipid oxidation decreased as the estradiol concentration increased within the study range (r = -0.362, p < 0.05). No statistical difference was noted for protein oxidation and catalase activity among the groups. No statistical difference was found for total antioxidant status between the groups (ANOVA). CONCLUSIONS: HRT decreases oxidative damage to both DNA and lipids in postmenopausal women. Lipid oxidation status may be inversely related to estrogen levels in postmenopausal women. PMID- 22530646 TI - Protein adsorption at the electrified air-water interface: implications on foam stability. AB - The surface chemistry of ions, water molecules, and proteins as well as their ability to form stable networks in foams can influence and control macroscopic properties such as taste and texture of dairy products considerably. Despite the significant relevance of protein adsorption at liquid interfaces, a molecular level understanding on the arrangement of proteins at interfaces and their interactions has been elusive. Therefore, we have addressed the adsorption of the model protein bovine serum albumin (BSA) at the air-water interface with vibrational sum-frequency generation (SFG) and ellipsometry. SFG provides specific information on the composition and average orientation of molecules at interfaces, while complementary information on the thickness of the adsorbed layer can be obtained with ellipsometry. Adsorption of charged BSA proteins at the water surface leads to an electrified interface, pH dependent charging, and electric field-induced polar ordering of interfacial H(2)O and BSA. Varying the bulk pH of protein solutions changes the intensities of the protein related vibrational bands substantially, while dramatic changes in vibrational bands of interfacial H(2)O are simultaneously observed. These observations have allowed us to determine the isoelectric point of BSA directly at the electrolyte-air interface for the first time. BSA covered air-water interfaces with a pH near the isoelectric point form an amorphous network of possibly agglomerated BSA proteins. Finally, we provide a direct correlation of the molecular structure of BSA interfaces with foam stability and new information on the link between microscopic properties of BSA at water surfaces and macroscopic properties such as the stability of protein foams. PMID- 22530647 TI - Molecular perspective on diazonium adsorption for controllable functionalization of single-walled carbon nanotubes in aqueous surfactant solutions. AB - Functionalization of single-walled carbon nanotubes (SWCNTs) using diazonium salts allows modification of their optical and electronic properties for a variety of applications, ranging from drug-delivery vehicles to molecular sensors. However, control of the functionalization process remains a challenge, requiring molecular-level understanding of the adsorption of diazonium ions onto heterogeneous, charge-mobile SWCNT surfaces, which are typically decorated with surfactants. In this paper, we combine molecular dynamics (MD) simulations, experiments, and equilibrium reaction modeling to understand and model the extent of diazonium functionalization of SWCNTs coated with various surfactants (sodium cholate, sodium dodecyl sulfate, and cetyl trimethylammonium bromide). We show that the free energy of diazonium adsorption, determined using simulations, can be used to rank surfactants in terms of the extent of functionalization attained following their adsorption on the nanotube surface. The difference in binding affinities between linear and rigid surfactants is attributed to the synergistic binding of the diazonium ion to the local "hot/cold spots" formed by the charged surfactant heads. A combined simulation-modeling framework is developed to provide guidance for controlling the various sensitive experimental conditions needed to achieve the desired extent of SWCNT functionalization. PMID- 22530648 TI - Predicting foreign-accent adaptation in older adults. AB - We investigated comprehension of and adaptation to speech in an unfamiliar accent in older adults. Participants performed a speeded sentence verification task for accented sentences: one group upon auditory-only presentation, and the other group upon audiovisual presentation. Our questions were whether audiovisual presentation would facilitate adaptation to the novel accent, and which cognitive and linguistic measures would predict adaptation. Participants were therefore tested on a range of background tests: hearing acuity, auditory verbal short-term memory, working memory, attention-switching control, selective attention, and vocabulary knowledge. Both auditory-only and audiovisual groups showed improved accuracy and decreasing response times over the course of the experiment, effectively showing accent adaptation. Even though the total amount of improvement was similar for the auditory-only and audiovisual groups, initial rate of adaptation was faster in the audiovisual group. Hearing sensitivity and short-term and working memory measures were associated with efficient processing of the novel accent. Analysis of the relationship between accent comprehension and the background tests revealed furthermore that selective attention and vocabulary size predicted the amount of adaptation over the course of the experiment. These results suggest that vocabulary knowledge and attentional abilities facilitate the attention-shifting strategies proposed to be required for perceptual learning. PMID- 22530650 TI - Under one leaf: an historical perspective on the UK Plant Science Federation. PMID- 22530651 TI - Making a case for human health risk-based ranking nanoparticles in water for monitoring purposes. PMID- 22530652 TI - Arabidopsis senescence-associated protein DMP1 is involved in membrane remodeling of the ER and tonoplast. AB - BACKGROUND: Arabidopsis DMP1 was discovered in a genome-wide screen for senescence-associated membrane proteins. DMP1 is a member of a novel plant specific membrane protein family of unknown function. In rosette leaves DMP1 expression increases from very low background level several 100fold during senescence progression. RESULTS: Expression of AtDMP1 fused to eGFP in Nicotiana benthamiana triggers a complex process of succeeding membrane remodeling events affecting the structure of the endoplasmic reticulum (ER) and the vacuole. Induction of spherical structures ("bulbs"), changes in the architecture of the ER from tubular to cisternal elements, expansion of smooth ER, formation of crystalloid ER, and emergence of vacuolar membrane sheets and foamy membrane structures inside the vacuole are proceeding in this order. In some cells it can be observed that the process culminates in cell death after breakdown of the entire ER network and the vacuole. The integrity of the plasma membrane, nucleus and Golgi vesicles are retained until this stage. In Arabidopsis thaliana plants expressing AtDMP1-eGFP by the 35S promoter massive ER and vacuole vesiculation is observed during the latest steps of leaf senescence, whereas earlier in development ER and vacuole morphology are not perturbed. Expression by the native DMP1 promoter visualizes formation of aggregates termed "boluses" in the ER membranes and vesiculation of the entire ER network, which precedes disintegration of the central vacuole during the latest stage of senescence in siliques, rosette and cauline leaves and in darkened rosette leaves. In roots tips, DMP1 is strongly expressed in the cortex undergoing vacuole biogenesis. CONCLUSIONS: Our data suggest that DMP1 is directly or indirectly involved in membrane fission during breakdown of the ER and the tonoplast during leaf senescence and in membrane fusion during vacuole biogenesis in roots. We propose that these properties of DMP1, exacerbated by transient overexpression, may cause or contribute to the dramatic membrane remodeling events which lead to cell death in infiltrated tobacco leaves. PMID- 22530653 TI - Three-dimensionally macroporous Fe/C nanocomposites as highly selective oil absorption materials. AB - In this study, three-dimensionally macroporous Fe/C nanocomposites were investigated as highly selective absorption materials for removing oils from water surface. The macroporous nanocomposites were synthesized by sintering a mixture of closely packed polystyrene microspheres and ferric nitrate precursor. These nanocomposites exhibited superhydrophobic and superoleophilic properties without the modification of low-surface-energy chemicals. And the pore size of the nanocomposites, which is crucial for the oil-absorption capacity, was tuned by varying the diameter of polystyrene microspheres. The macroporous nanocomposites fast and selectively absorbed a wide range of oils and hydrophobic organic solvents on water surface, and the removal of the absorbed oils from the water surface was readily achieved under a magnetic field. Moreover, the nanocomposites still kept highly hydrophobic and oleophilic characteristics after repeatedly removing oils from water surface for many cycles. Because of frequently occurring environmental pollution arising from oil spills and chemicals leakage, the results of this study might offer a kind of efficient and selective absorbent materials for removing oils and nonpolar organic solvents from the surface of water. PMID- 22530654 TI - Total synthesis of 7'-desmethylkealiiquinone. AB - The total synthesis of an analogue of the marine alkaloid kealiiquinone has been completed through application of an intramolecular Diels-Alder reaction of an imidazole-containing enyne. Oxidative aromatization of the lactone adduct and N methylation facilitates C2-oxidation via the imidazolium salt. Conversion of the lactone to the phthalaldehyde derivative and then to the dihydroxybenzoquinone was achieved via a reaction with glyoxal in the presence of KCN. Esterification of the vinylogous diacid and deprotection provided 7'-desmethylkealiiquinone. PMID- 22530656 TI - Comparison of salivary and plasma antioxidant levels in lichen planus patients and healthy subjects. AB - INTRODUCTION: Oral lichen planus (OLP) is a chronic, mucocutaneous, inflammatory disease. It has become more evident that the immune system plays a primary role in the development of this disease. The aim of the present study was to evaluate the total antioxidant status (TAS) of saliva and serum in patients with erosive OLP. METHOD AND MATERIALS: This study was designed as case-control. In total, 48 patients with erosive OLP (34 women and 14 men) were enrolled as case group, and 44 self-admitted healthy people (34 women and 10 men) were selected as control group. Measurement of total antioxidant status was carried out in saliva and plasma. t-test was used for statistical analysis with significant level set at P < 0.05. RESULTS: The mean +/- SD of salivary TAS in case group was 0.98 +/- 0.12, and in control group was 1.32 +/- 0.18 mM, respectively, and there were significant differences between groups (P < 0.02). The mean +/- SD of the plasma TAS in the case group and the control group was 1.24 +/- 0.17 and 1.84 +/- 0.34 mM, respectively. There were significant differences between two groups (P < 0.01). CONCLUSION: Our results showed that salivary and plasma levels of total antioxidant status in erosive OLP patients were lower than those in healthy subjects. PMID- 22530655 TI - Risk factors for hypertrophic surgical scar development after thyroidectomy. AB - Postoperative neck scarring is a major concern for patients who undergo thyroid surgery; however, the treatments for hypertrophic scars are generally considered by patients to provide unsatisfactory outcomes. Therefore, risk factors should be identified and prevention of these factors is considered to be critical in management. We reviewed the medical records of 96 thyroidectomy patients who were divided into two groups based on scar type: patients with hypertrophic (n = 61) and linear flat scars (n = 35). Multivariable logistic regression model was developed to identify risk factors for developing hypertrophic scar. There was no significant difference between the two groups in terms of age, gender ratio, tumor type, and type of operation. Multivariable analysis showed that hypertrophic scar development was associated with scars located within 1 cm above the sternal notch (odds ratio [OR] = 5.94, p = 0.01), prominent sternocleidomastoid muscles (OR = 12.03, p < 0.01), and a high body mass index (OR = 1.33, p = 0.01). The area under the receiver operating characteristic curve for risk factors was 0.85. Development of hypertrophic scar after thyroidectomy was found to be associated with specific preoperative factors such as incision site near the sternal notch, prominent sternocleidomastoid muscles, and high body mass index. PMID- 22530657 TI - Ultra-high vacuum scanning thermal microscopy for nanometer resolution quantitative thermometry. AB - Understanding energy dissipation at the nanoscale requires the ability to probe temperature fields with nanometer resolution. Here, we describe an ultra-high vacuum (UHV)-based scanning thermal microscope (SThM) technique that is capable of quantitatively mapping temperature fields with ~15 mK temperature resolution and ~10 nm spatial resolution. In this technique, a custom fabricated atomic force microscope (AFM) cantilever, with a nanoscale Au-Cr thermocouple integrated into the tip of the probe, is used to measure temperature fields of surfaces. Operation in an UHV environment eliminates parasitic heat transport between the tip and the sample enabling quantitative measurement of temperature fields on metal and dielectric surfaces with nanoscale resolution. We demonstrate the capabilities of this technique by directly imaging thermal fields in the vicinity of a 200 nm wide, self-heated, Pt line. Our measurements are in excellent agreement with computational results-unambiguously demonstrating the quantitative capabilities of the technique. UHV-SThM techniques will play an important role in the study of energy dissipation in nanometer-sized electronic and photonic devices and the study of phonon and electron transport at the nanoscale. PMID- 22530659 TI - Survival of myeloma patients following the introduction of thalidomide as a second-line therapy: a retrospective study at a single New Zealand centre. AB - AIM: This retrospective study compares the overall survival (OS) of multiple myeloma (MM) patients following treatment at a New Zealand hospital over a period in which novel therapies were available but restricted, almost exclusively, to thalidomide as a second-line therapy. METHODS: Clinical, laboratory and OS data were collected on 361 MM patients who were treated at Christchurch Hospital during 2000-2010. Patients were subdivided according to the clinical criteria used to determine front-line treatment decisions. Older patients (age >=66, n = 180) generally received standard-dose chemotherapy without autologous stem cell transplant (SCT) and formed one group. Younger patients were further subdivided according to whether they received autologous SCT (n = 89), allogeneic SCT (n = 24) or no SCT (n = 68). RESULTS: Older patients had a significantly shorter OS (P < 0.0001) than younger patients (median OS = 25 vs 78 months) however treated. Analysis of relative survival demonstrated that the increased mortality of older patients was greater than that attributable to normal ageing. Younger patients who received no transplant had a significantly shorter OS (P < 0.0001) than those who received autologous SCT or allogeneic SCT with 5-year survivals of 38%, 70% and 72% respectively. Use of novel therapies was significantly higher in younger than older patients (60% vs 47%, P = 0.011). CONCLUSIONS: The front-line treatment groupings of hospital MM patients had significantly different survivals. The OS of SCT ineligible patients remains poor despite the introduction of thalidomide. PMID- 22530661 TI - Would the real myeloma cell please stand up? PMID- 22530660 TI - Targeting calcium channels to block tumor vascularization. AB - Blood vessels and endothelial cells (ECs) are highly versatile in order to accomplish local tissutal needs in the physiological and pathological conditions. Tumor vasculature, in particular, exhibits special morphological and functional features, partly due to the peculiarity of tumor-derived ECs (TECs). This is of great importance for the discovery of selective molecular targets potentially suitable to interfere with tumor growth and spread. In normal ECs, proangiogenic calcium signaling is mediated by different calcium channels, mainly TRPs and Orai, that could play a pivotal role in physiological angiogenesis. They are regulated through multiple mechanisms, involving their interaction with bioactive lipids (arachidonic acid and its metabolites), nitrosylation, sulfhydration, phosphorylation, cytoskeleton-mediated membrane trafficking, and calcium stores depletion. On the other hand, proangiogenic calcium events in TECs have been investigated only recently and their characterization is still preliminary. ECs obtained from human breast and renal carcinomas (B-TECs and R-TECs respectively) display altered calcium signals, which are associated with modified expression and function of TRP channels. Here, we review the state of the art in the field of calcium signaling and tumor vascularization, the related recent literature and patents. Finally, we provide some suggestions for future developments. PMID- 22530662 TI - A hemodialysis patient with higher-risk myelodysplastic syndrome treated with standard-dose azacitidine. PMID- 22530663 TI - Are lymphoma survivors really at higher risk for unemployment/underemployment? PMID- 22530664 TI - Rational administration schedule for high-dose methotrexate in patients with primary central nervous system lymphoma. AB - Methotrexate (MTX) at a dose of >=1 g/m(2) remains the most efficient treatment against primary central nervous system lymphoma (PCNSL), and is the most widely used drug in prospective clinical trials. MTX is a folate analog that inhibits dihydrofolate reductase, thereby blocking de novo purine synthesis. MTX as well as 7-hydroxy-MTX, its main metabolite in serum, are both eliminated by the kidneys. The elimination of MTX is prolonged in patients with renal impairment and third-space fluid collections, and in patients receiving concurrent non steroidal antirheumatic drugs, benzimidazoles and sulfonamides, among others. Main adverse events with high-dose MTX include severe myelosuppression, renal dysfunction and stomatitis. Supportive measures such as rigorous hydration, urine alkalinization and careful drug monitoring with supplemental leucovorin rescue are crucial to avoid significant toxicity. Strategies to optimize clinical efficacy of high-dose MTX in patients with PCNSL include administration of 3 h instead of longer infusions, potentially supplemented with an additional intravenous MTX bolus, and maintaining MTX dose intensity over the course of four treatment cycles. Some pharmacological studies suggest that achieving an MTX area under the plasma concentration-time curve (AUC(MTX)) of between 1000 and 1100 MUmol.h/L may improve clinical outcome, but clinical data are not conclusive at present. In this review, we analyze the impact of patient, lymphoma and pharmacokinetic variables on the antitumor activity of high-dose MTX in patients with PCNSL, summarize recommendations for daily clinical practice and give some suggestions for future trials. PMID- 22530665 TI - Cytosine arabinoside potentiates the apoptotic effect of bendamustine on several B- and T-cell leukemia/lymphoma cells and cell lines. AB - Bendamustine and cytosine arabinoside (ara-c) are commonly used cytotoxic agents with unique mechanisms of action. We have previously reported a striking additive cytotoxic effect of the consecutive combination of bendamustine and ara-c in mantle cell lymphoma (MCL) cell lines. In the present study, cell lines of follicular lymphoma (DOHH-2), chronic lymphocytic leukemia/lymphoma (EHEB), diffuse large B-cell lymphoma (SU-DHL-4), T-cell leukemia/lymphoma (JURKAT and KARPAS-299) and MCL (JEKO-1 and GRANTA-519) were exposed to the two single drugs or the drugs combined, given simultaneously and consecutively. Peripheral blood chronic lymphocytic leukemia (CLL) B-cells from five patients were also analyzed. Apoptosis, cell proliferation/metabolic activity and mitochondrial damage were evaluated. The combination index (CI) was used to assess synergy between the drugs. Bendamustine exhibited a relevant cytotoxic effect that was dose- and time dependent, except for SU-DHL-4 and T-cell lymphoma cells. The addition of ara-c after bendamustine significantly potentiated the single-drug cytotoxic effect of bendamustine on all cell lines, including 17p - CLL B-cells, JURKAT and SU-DHL-4, the latter presenting the highest synergism (CI < 0.01). Bendamustine and ara-c are highly synergistic on T- and B-cell lymphoma cells and cell lines, similar to MCL, overcoming resistance to the single agents. PMID- 22530667 TI - The usefulness of HbA1c in postpartum reclassification of gestational diabetes. AB - To investigate the role of HbA1c in postpartum reclassification of gestational diabetes (GDM) we studied 364 women with GDM attending the postpartum reclassification assessment of their glucose tolerance status. A 75-g oral glucose tolerance test (OGTT) was performed and HbA1c was determined. Diabetes was diagnosed in 12 (3.3%), 7 (1.9%) and 2 (0.6%) women according to the fasting plasma glucose (FPG) and/or the 2-hour OGTT, the FPG alone and HbA1c levels, respectively. The sensitivity and specificity for HbA1c to diagnose diabetes was 16.7% and 100%, respectively, for FPG and OGTT criteria. The combination of a cutoff value of 5.5% for HbA1c and FPG allowed us to identify 95.1% of women with any kind of glucose intolerance. We conclude that in the early postpartum period, the cutoff of 6.5% for HbA1c alone has low sensitivity for the diagnosis of diabetes compared with OGTT, but the combination of FPG and HbA1c at a lower cutoff value is very useful to identify women with any kind of glucose intolerance. PMID- 22530668 TI - Sexual selection uncouples the evolution of brain and body size in pinnipeds. AB - The size of the vertebrate brain is shaped by a variety of selective forces. Although larger brains (correcting for body size) are thought to confer fitness advantages, energetic limitations of this costly organ may lead to trade-offs, for example as recently suggested between sexual traits and neural tissue. Here, we examine the patterns of selection on male and female brain size in pinnipeds, a group where the strength of sexual selection differs markedly among species and between the sexes. Relative brain size was negatively associated with the intensity of sexual selection in males but not females. However, analyses of the rates of body and brain size evolution showed that this apparent trade-off between sexual selection and brain mass is driven by selection for increasing body mass rather than by an actual reduction in male brain size. Our results suggest that sexual selection has important effects on the allometric relationships of neural development. PMID- 22530666 TI - Protein-thiol oxidation and cell death: regulatory role of glutaredoxins. AB - SIGNIFICANCE: Glutaredoxin (Grx) is the primary enzyme responsible for catalysis of deglutathionylation of protein-mixed disulfides with glutathione (GSH) (protein-SSG). This reversible post-translational modification alters the activity and function of many proteins important in regulation of critical cellular processes. Aberrant regulation of protein glutathionylation/deglutathionylation reactions due to changes in Grx activity can disrupt both apoptotic and survival signaling pathways. RECENT ADVANCES: Grx is known to regulate the activity of many proteins through reversible glutathionylation, such as Ras, Fas, ASK1, NFkappaB, and procaspase-3, all of which play important roles in control of apoptosis. Reactive oxygen species and/or reactive nitrogen species mediate oxidative modifications of critical Cys residues on these apoptotic mediators, facilitating protein-SSG formation and thereby altering protein function and apoptotic signaling. CRITICAL ISSUES: Much of what is known about the regulation of apoptotic mediators by Grx and reversible glutathionylation has been gleaned from in vitro studies of discrete apoptotic pathways. To relate these results to events in vivo it is important to examine changes in protein-SSG status in situ under natural cellular conditions, maintaining relevant GSH:GSSG ratios and using appropriate inducers of apoptosis. FUTURE DIRECTIONS: Apoptosis is a highly complex, tightly regulated process involving many different checks and balances. The influence of Grx activity on the interconnectivity among these various pathways remains unknown. Knowledge of the effects of Grx is essential for developing novel therapeutic approaches for treating diseases involving dysregulated apoptosis, such as cancer, heart disease, diabetes, and neurodegenerative diseases, where alterations in redox homeostasis are hallmarks for pathogenesis. PMID- 22530669 TI - Kinetics of n-butoxy and 2-pentoxy isomerization and detection of primary products by infrared cavity ringdown spectroscopy. AB - The primary products of n-butoxy and 2-pentoxy isomerization in the presence and absence of O(2) have been detected using pulsed laser photolysis-cavity ringdown spectroscopy (PLP-CRDS). Alkoxy radicals n-butoxy and 2-pentoxy were generated by photolysis of alkyl nitrite precursors (n-butyl nitrite or 2-pentyl nitrite, respectively), and the isomerization products with and without O(2) were detected by infrared cavity ringdown spectroscopy 20 MUs after the photolysis. We report the mid-IR OH stretch (nu(1)) absorption spectra for delta-HO-1-C(4)H(8)*, delta HO-1-C(4)H(8)OO*, delta-HO-1-C(5)H(10)*, and delta-HO-1-C(5)H(10)OO*. The observed nu(1) bands are similar in position and shape to the related alcohols (n butanol and 2-pentanol), although the HOROO* absorption is slightly stronger than the HOR* absorption. We determined the rate of isomerization relative to reaction with O(2) for the n-butoxy and 2-pentoxy radicals by measuring the relative nu(1) absorbance of HOROO* as a function of [O(2)]. At 295 K and 670 Torr of N(2) or N(2)/O(2), we found rate constant ratios of k(isom)/k(O(2)) = 1.7 (+/-0.1) * 10(19) cm(-3) for n-butoxy and k(isom)/k(O(2)) = 3.4(+/-0.4) * 10(19) cm(-3) for 2-pentoxy (2sigma uncertainty). Using currently known rate constants k(O(2)), we estimate isomerization rates of k(isom) = 2.4 (+/-1.2) * 10(5) s(-1) and k(isom) ~ 3 * 10(5) s(-1) for n-butoxy and 2-pentoxy radicals, respectively, where the uncertainties are primarily due to uncertainties in k(O(2)). Because isomerization is predicted to be in the high pressure limit at 670 Torr, these relative rates are expected to be the same at atmospheric pressure. Our results include corrections for prompt isomerization of hot nascent alkoxy radicals as well as reaction with background NO and unimolecular alkoxy decomposition. We estimate prompt isomerization yields under our conditions of 4 +/- 2% and 5 +/- 2% for n-butoxy and 2-pentoxy formed from photolysis of the alkyl nitrites at 351 nm. Our measured relative rate values are in good agreement with and more precise than previous end-product analysis studies conducted on the n-butoxy and 2 pentoxy systems. We show that reactions typically neglected in the analysis of alkoxy relative kinetics (decomposition, recombination with NO, and prompt isomerization) may need to be included to obtain accurate values of k(isom)/k(O(2)). PMID- 22530670 TI - Morphological processing during visual word recognition in developing readers: evidence from masked priming. AB - Masked priming studies with adult readers have provided evidence for a form-based morpho-orthographic segmentation mechanism that "blindly" decomposes any word with the appearance of morphological complexity. The present studies investigated whether evidence for structural morphological decomposition can be obtained with developing readers. We used a masked primed lexical decision design first adopted by Rastle, Davis, and New (2004), comparing truly suffixed (golden-GOLD) and pseudosuffixed (mother-MOTH) prime-target pairs with nonsuffixed controls (spinach-SPIN). Experiment 1 tested adult readers, showing that priming from both pseudo- and truly suffixed primes could be obtained using our own set of high frequency word materials. Experiment 2 assessed a group of Year 3 and Year 5 children, but priming only occurred when prime and target shared a true morphological relationship, and not when the relationship was pseudomorphological. This pattern of results indicates that morpho-orthographic decomposition mechanisms do not become automatized until a relatively late stage in reading development. PMID- 22530672 TI - Resveratrol enhances the antitumor effects of temozolomide in glioblastoma via ROS-dependent AMPK-TSC-mTOR signaling pathway. AB - BACKGROUND AND PURPOSE: Resveratrol has been regarded as a promising candidate for cancer prevention and treatment. The present study was to investigate the impact of resveratrol on the antitumor effects of temozolomide (TMZ), a standard treatment regiment of glioblastoma (GBM), in vitro and in vivo. METHODS AND RESULTS: We found that the combination of resveratrol and TMZ significantly resulted in G(2)/M cell cycle arrest by flow cytometry, triggered a robust increase in expression of astrocyte differentiation marker glial fibrillary acid protein (GFAP), downregulated the expression of matrix metalloproteinase-9 (MMP 9) by immunohistochemistry and western blot analysis as well as inhibited cell migration by scratch wound assay. Further study revealed that TMZ in combination with resveratrol remarkably increased reactive oxygen species (ROS) production, which serves as an upstream signal for AMP-activated protein kinase (AMPK) activation. Subsequently, activated AMPK inhibited mTOR signaling and downregulated antiapoptosis protein Bcl-2, which was contributed to the additive antiproliferation effects of combination treatment. In an orthotopic xenograft model of GBM, TMZ plus resveratrol treatment significantly reduced the volume of tumor, which was confirmed by decreased expression of Ki-67, a marker of proliferation index. CONCLUSIONS: Our findings demonstrate for the first time that resveratrol can enhance TMZ-mediated antitumor effects in GBM in vitro and in vivo, via ROS-dependent AMPK-TSC-mTOR signaling pathway. PMID- 22530673 TI - Biomimetic conversion of aconitine-type C19-diterpenoid alkaloids to lactone-type alkaloids. AB - The first biomimetic conversion from the aconitine-type C(19)-diterpenoid alkaloids to the corresponding alkaloids of lactone-type C(19)-diterpenoid alkaloid has been achieved. Chasmanine was used as starting material with Baeyer Villiger oxidation as a key reaction. It was also observed that the oxygenated group at C-16 did not change the relative migration tendencies of C-13 and C-9 during the oxidation. Meantime, a novel D-ring fragmented compound was obtained during the course of the present investigation. The plausible mechanism of the formation of this compound was also proposed. PMID- 22530671 TI - Gene expression changes in C57BL/6J and DBA/2J mice following prenatal alcohol exposure. AB - BACKGROUND: Prenatal alcohol exposure can result in fetal alcohol spectrum disorders (FASD). Not all women who consume alcohol during pregnancy have children with FASD and studies have shown that genetic factors can play a role in ethanol teratogenesis. We examined gene expression in embryos and placentae from C57BL/6J (B6) and DBA/2J (D2) mice following prenatal alcohol exposure. B6 fetuses are susceptible to morphological malformations following prenatal alcohol exposure while D2 are relatively resistant. METHODS: Male and female B6 and D2 mice were mated for 2 hours in the morning, producing 4 embryonic genotypes: true bred B6B6 and D2D2, and reciprocal B6D2 and D2B6. On gestational day 9, dams were intubated with 5.8 g/kg ethanol, an isocaloric amount of maltose dextrin, or nothing. Four hours later, dams were sacrificed and embryos and placentae were harvested. RNA was extracted, labeled and hybridized to Affymetrix Mouse Genome 430 v2 microarray chips. Data were normalized, subjected to analysis of variance and tested for enrichment of gene ontology molecular function and biological process using the Database for Annotation, Visualization and Integrated Discovery (DAVID). RESULTS: Several gene classes were differentially expressed in B6 and D2 regardless of treatment, including genes involved in polysaccharide binding and mitosis. Prenatal alcohol exposure altered expression of a subset of genes, including genes involved in methylation, chromatin remodeling, protein synthesis, and mRNA splicing. Very few genes were differentially expressed between maltose exposed tissues and tissues that received nothing, so we combined these groups for comparisons with ethanol. While we observed many expression changes specific to B6 following prenatal alcohol exposure, none were specific for D2. Gene classes up- or down-regulated in B6 following prenatal alcohol exposure included genes involved in mRNA splicing, transcription, and translation. CONCLUSIONS: Our study identified several classes of genes with altered expression following prenatal alcohol exposure, including many specific for B6, a strain susceptible to ethanol teratogenesis. Lack of strain specific effects in D2 suggests there are few gene expression changes that confer resistance. Future studies will begin to analyze functional significance of the expression changes. PMID- 22530674 TI - Isolation, identification, semi-synthesis of aziditaxel derivatives and their biological evaluation. AB - Two new taxoids (5 and 6) were obtained by isolating impurities in aziditaxel, and their structures were characterized based on data analysis of (1)H NMR, (13)C NMR, HPLC-MS, and through comparison with literature. In order to test their cytotoxicities against human nonsmall lung cancer cell lines (A549), sufficient amounts of compounds 5 and 6 were obtained by semi-synthesis and both of them showed equipotent cytotoxiesty compared with taxol, docetaxel, and aziditaxel. PMID- 22530675 TI - Two new quaternary protoberberine alkaloids from Corydalis yanhusuo. AB - Two new quaternary protoberberine alkaloids, namely corydayanine (1) and yanhusuine (2), were isolated from the tubers of Corydalis yanhusuo. On the basis of extensive chemical and spectroscopic evidences, especially 1D and 2D NMR and HRMS experiments, their structures were elucidated as 5,6-dihydro-3,9-dihydroxy 2,10-dimethoxy-13-methyl-dibenzo[a,g] quinolizinium alkaloid and 5,6-dihydro-12 hydroxy-2,3,9-trimethoxy-13-methyl-dibenzo[a,g] quinolizinium alkaloid, respectively. PMID- 22530676 TI - Two new C13-norisoprenoids from Solanum lyratum. AB - Two new C(13)-norisoprenoids, named lyratols E and F (1-2), were isolated from the whole plant of Solanum lyratum Thunb, and their structures were elucidated by extensive spectroscopic analyses. In vitro, two new compounds were found to show significant cytotoxicity against selected cancer cells including P-388 and HT-29. PMID- 22530677 TI - Grasshopper ketone 3-O-primveroside from Sinocrassula indica. AB - A new megastigmane glycoside, grasshopper ketone 3-O-primveroside (1), was isolated from the methanolic extract of the whole herbs of Sinocrassula indica (Crassulaceae). Its structure was elucidated on the basis of spectral and chemical evidence. PMID- 22530678 TI - Three new phloroglucinol derivatives from Hypericum scabrum. AB - A chemical investigation on the aerial parts of Hypericum scabrum L. resulted in the isolation of three new phloroglucinol derivatives, hyperscabrins A (1), B (2), and C (3), together with one known compound, (2R,3R,4S,6R)-3-methyl-4,6-di(3 methyl-2-butenyl)-2-(2-methyl-1-oxopropyl)-3-(4-methyl-3-pentenyl)-cyclohexanone (4). The structures were elucidated by means of spectroscopic methods, including MS, IR, 1D NMR, and 2D NMR, and the absolute configurations of chiral centers in these phloroglucinol derivatives were determined for the first time by studying their circular dichroism spectra. PMID- 22530679 TI - The effect of gonadotrophin-releasing hormone agonist treatment over 3 years on bone mineral density and body composition in girls with central precocious puberty. AB - OBJECTIVE: Puberty is a period characterized by growth spurt and rapid change in body composition. The effect of GnRH agonist therapy for central precocious puberty on bone mineral density is unclear. We demonstrated changes in bone mineral density in subjects with central precocious puberty, who were treated with GnRH agonist for more than 3 years. DESIGN: The changes in bone mineral density and body compositions were tested with analysis of variance with repeated measures to identify statistical significance over the treatment period. PATIENTS: One hundred ninety-five Korean girls with central precocious puberty were treated with GnRH agonist, and among these subjects, 39 patients were treated for more than 3 years. MEASUREMENTS: Dual-energy X-ray absorptiometry was performed on the subjects at the initial evaluation and once yearly thereafter while on the treatment. RESULTS: The bone mineral density parameters for chronological age tended to decrease near the mean for the treatment period; however, they increased significantly for bone age excluding bone mineral apparent density. An increment of the BMI was not significant for the chronological age. CONCLUSIONS: Three-year treatment with GnRH agonist in central precocious puberty patients did not impair bone maturation. GnRH agonist could be effectively commenced in girls with precocious puberty from an early age. PMID- 22530680 TI - Release mechanisms of poly(ethylene glycol) macroions from aqueous charged nanodroplets. AB - Ion-release processes in nanodroplets that contain excess charge are of central importance in atmospheric aerosols as well as in determining the charge state distributions of macroions that are detected in electrospray mass spectrometry (ESMS) experiments. We performed molecular simulations of systems of a poly(ethylene glycol) (PEG) associated with various ions (Na(+), Li(+),Ca(2+)) in aqueous charged nanodroplets in order to investigate the manner that the macroion emerges from an aqueous nanodroplet as well as its final charge state. In the study we focused on a specific region of the parameter space with respect to charge and size of droplets that is close to the Rayleigh limit. We found that for sizes of droplets with linear dimensions of several nanometers and length of PEG up to 100 monomers, the PEG macroion emerges from the droplet following a three-step process: (i) phase separation, (ii) gradual extension of the macroion out of the droplet, and (iii) drying-out of the solvent or spontaneous detachment of the macroion from the droplet. The third step is determined by the ratio of charge on the macroion to the ions in the water portion of the droplet. The chemical transformation that is caused in PEG by the transfer of ions from the solvent into PEG determines its release mechanism. When the charge is carried by macroions, the charge-induced instability manifests by following one of the expected scenarios of Rayleigh instability; however, the assumptions of the Rayleigh model break down. We also examined the release of the macroion below the Rayleigh limit, and we found that the macroion emerges from the droplet by drying out of the solvent. On balance of phenomenological evidence, we concluded that the ion-evaporation mechanism (IEM) in its most common meaning is not the followed mechanism for the parameter space of the systems that we studied. The final charge state of the macroion is in excellent agreement with the experimental data of Fenn and co-workers. PMID- 22530681 TI - Ipilimumab: in previously treated patients with advanced melanoma. AB - Ipilimumab is a recombinant, fully human, monoclonal antibody targeted at cytotoxic T-lymphocyte-associated antigen 4 that is available for the treatment of advanced melanoma. This review focuses on the efficacy and tolerability of ipilimumab in advanced melanoma and provides an overview of its pharmacology. In a randomized, double-blind, multinational, phase III trial in previously treated patients with advanced melanoma, median overall survival (OS) was significantly longer with ipilimumab 3 mg/kg plus glycoprotein (gp) 100 peptide vaccine or ipilimumab plus placebo than with gp100 peptide vaccine plus placebo (10.0 and 10.1 vs 6.4 months). Hazard ratios for death were 0.68 (p < 0.001) with ipilimumab plus gp100 peptide vaccine versus gp100 peptide vaccine plus placebo and 0.66 (p = 0.003) for ipilimumab plus placebo versus gp100 peptide vaccine plus placebo, with corresponding 32% and 34% relative reductions in the risk of death. There was no significant difference in OS between patients receiving ipilimumab plus gp100 peptide vaccine and those receiving ipilimumab plus placebo. Novel immune-related events that are not typical of other anticancer agents, most commonly dermatologic and gastrointestinal disorders, can occur with ipilimumab, necessitating specific monitoring and management protocols. In the phase III trial, grade 3/4 immune-related adverse events occurred in 10-15% of ipilimumab 3 mg/kg recipients versus 3% of gp100 peptide vaccine plus placebo recipients. In all, 2.1% of patients died as a result of treatment-related adverse events, with half of the deaths attributed to immune-related adverse events. PMID- 22530682 TI - Burn injury has a systemic effect on reinnervation of skin and restoration of nociceptive function. AB - Burn injury can lead to abnormal sensory function at both the injury and at distant uninjured sites. Here, we used a mouse model to investigate return of nociceptive function and reinnervation of the skin at the wound and uninjured distant sites following a 3% total burn surface area full-thickness burn injury. We have previously shown that topical application of zinc-metallothionein-IIA (Zn(7) -MT-IIA) accelerates healing following burn injury, and here, we investigated the potential of Zn(7) -MT-IIA to enhance reinnervation and sensory recovery. In all burn-injured animals, there was a significant reduction in nociceptive responses (Semmes-Weinstein filaments) at locations near and distant to the wound up to 8 weeks following injury. Cutaneous nerve reinnervation (assessed using protein gene product 9.5 immunohistochemistry) of the wound center was slow in the epidermis but rapid in the dermis. In the dermis, nerves subsequently degenerated both at the wound center and in distant uninjured areas. In contrast, epidermal nerve densities in the distant uninjured areas returned to normal, uninjured levels. Zn(7) -MT-IIA did not influence return of nociceptive function nor reinnervation. We conclude that burn injury compromises nociceptive function and nerve regeneration both at the injury site and systemically; thus, therapies in addition to Zn(7) -MT-IIA should be explored to return normal sensory function. PMID- 22530683 TI - Response to "Letter to the editor regarding 'crossing turbulent boundaries: interfacial flux in environmental flows'". PMID- 22530684 TI - Factors associated with metabolic syndrome in climacteric women of southern Brazil. AB - AIM: To investigate the association between socioeconomic, demographic, behavioral, and reproductive factors and the metabolic syndrome (MS) in climacteric women. METHOD: This cross-sectional study was carried out in a sample of 527 women aged 40-65 years seen at an outpatient menopause and gynecologic surgery clinic in Southern Brazil. MS was defined according to NCEP-ATP III diagnostic criteria. Poisson regression was used to calculate crude and adjusted prevalence ratios and their respective 95% confidence intervals (CI). RESULTS: The prevalence of MS was 54.8% (95% CI 50.6-59.1%), varying with menopausal status (45.7% before menopause, 56.3% in perimenopause, and 57.5% in postmenopausal women). Among the components of MS, hypertension and abdominal obesity were the most prevalent (84.8% and 66.8%, respectively). The prevalence of MS rose with advancing age and increasing parity. Women with low education (years of schooling) showed a higher prevalence of MS compared to those with a high education level (64% vs. 36.8%). Women with early menarche (<=11 years of age) showed an increase of 32% in MS prevalence (95% CI 1.08-1.62) compared to those with a late menarche (>=14 years of age). CONCLUSION: These findings are relevant to public health, particularly as they show the significance of exposure to long-term, hard-to-reverse effects, such as early menarche and low educational achievement, in the development of metabolic syndrome. PMID- 22530685 TI - Spray drying of monodispersed microencapsulates: implications of formulation and process parameters on microstructural properties and controlled release functionality. AB - Particulates for pharmaceutical applications require stringent control over their characteristics to realize the optimal therapeutic performance. By generating uniform spray-dried silica particles encapsulating different model drugs via a microfluidic jet spray drying technique, we demonstrated how the effects of formulation and process parameters on the investigated properties could be directly quantified without the complications of wide particle distributions typical of conventional spray drying. The implemented strategies included incorporating lactose to modify the internal microstructures to regulate release, and increasing drying temperature during synthesis to modify the surface features of particles. The physicochemical properties of encapsulated drugs were shown to influence particle morphologies and release profiles, while the pH of initial precursors influenced the particle morphologies with slight effects on the initial release rates. The outcomes would be useful to indentify appropriate formulations and manufacturing parameters in designing spray-dried silica-based microencapsulates with tailor-made controlled release functionalities. PMID- 22530686 TI - In the arc of history: AIHA and the movement to reform the Toxic Substances Control Act. AB - Dr. Michael P. Wilson of UC Berkeley delivered his keynote address before the general assembly of the American Industrial Hygiene Conference and Exhibition (AIHce) in Portland, Oregon, in May 2011. Here, Dr. Wilson again discusses the political and economic drivers of occupational disease in the United States and proposes a role for AIHA in helping to highlight and resolve them. He proposes that until these underlying drivers are acknowledged and ameliorated, the toll of occupational disease will persist, despite the hard work of industrial hygienists in the workplace. Among these drivers, Dr. Wilson points to the decline of labor rights and unionization; economic inequality; economic insecurity; political resistance to public health protections for workers, notably the OSHA and NIOSH programs; and weaknesses in the Federal Toxic Substances Control Act of 1976 (TSCA). Of these, Dr. Wilson calls on the AIHA to participate in the historic effort to rewrite TSCA. He points to weaknesses in TSCA that have produced a chemicals market dominated by the function, price, and performance of chemicals, with little attention given to their health and environmental effects. Under these conditions, he argues, hazardous chemicals have remained economically competitive, and innovation in inherently safer chemicals-in green chemistry-has been held back by a lack of market transparency and public accountability in the industry. TSCA reform has the potential to shift the market toward green chemistry, with long-term implications for occupational disease prevention, industrial investment, and renewed energy in the industrial hygiene profession. Dr. Wilson proposes that, like previous legislative changes in the United States, TSCA reform is likely to occur in response to myriad social pressures, which include the emergence of the European Union's REACH regulation; recent chemicals policy actions in 18 U.S. states; growing support from downstream businesses; increasing public awareness; and a social movement that reaches across traditional boundaries. Dr. Wilson urges the AIHA to involve itself in this effort by building alliances with professional associations and other groups that share similar goals. PMID- 22530687 TI - Continuous infusion in haemophilia: current practice in Europe. AB - Summary. Continuous infusion (CI) of factor VIII (FVIII) is an effective method for replacement therapy in haemophilia. Recently, concerns have been raised regarding association of CI with the development of inhibitors. The aim of this study was to gain information on the current practices in Europe regarding CI and the true inhibitor incidence after this mode of therapy. In a cross sectional study performed in 22 Comprehensive Care Centres (CCCs), we evaluated CI techniques, treatment protocols, efficacy, safety and complications of CI including inhibitors. Thirteen (59%) CCCs reported a total of 1079 CI treatments, given peri-operatively or for major bleeds, in 742 patients. Most centres used 'adjusted dose' CI aimed at median target FVIII level of 0.8 IU mL(-1). CI was haemostatically very effective with a low incidence of complications: median incidence of postoperative bleeding was 1.8%, six centres observed phlebitis in 2 11% of CI treatments. Only nine (1.2%) patients developed inhibitors (0.45% of 659 severe and 7.2% of 83 mild haemophilia patients). Additional analysis of inhibitor patients revealed several confounding factors (low number of prior FVIII exposure days, high steady-state factor levels during CI, high-risk genotype). In this unprecedentedly large cohort, CI treatment appears to be an effective and safe treatment that does not increase the risk of inhibitor development in patients with severe haemophilia. Thus, previous small case series reports suggesting that CI may increase inhibitors cannot be confirmed. Inhibitor risk in mild haemophilia could not be evaluated as the influence of other, potentially confounding, risk factors could not be excluded. PMID- 22530688 TI - Prevalence of food allergy in Taiwan: a questionnaire-based survey. AB - AIM: Food allergy is common in children and adults, and could be potentially fatal in minor groups. It is important for physicians to identify the prevalence of food allergies and to recognise common food allergens to make precise diagnosis and choose correct therapeutic approaches. METHODS: We used a nationwide, cross-sectional, random questionnaire-based survey to estimate the self-reported and expert-screened prevalence of food allergies and to identify the common food allergens in Taiwan. In this study, the perceptional diagnosis of food allergies was screened by physicians according to descriptions of convincing symptoms and medical recordings; in the meantime, non-allergic adverse reactions to foods, including food intolerance or food avoidance, were clarified. RESULTS: A total of 30 018 individuals who met the inclusion criteria was evaluated, and 6.95% of them were diagnosed as victims of food allergies. The prevalence was 3.44% in children under 3 years of age, 7.65% in children aged 4-18 years and 6.40% in adults respectively. About 77.33% of the food allergy population had experienced recurrent allergic attacks. Systemic reactions happened about 4.89% in food allergies group. The most commonly reported food allergen in Taiwan is seafood, including shrimp, crab, fish and mollusc. In addition, mango, milk, peanuts and eggs were also important food allergens in the general population; while milk, shellfish, peanuts and eggs were common in children. CONCLUSIONS: Less than 10% of the Taiwan population suffers from food allergy with different allergic symptoms to variable food allergens in different age groups. PMID- 22530689 TI - Thioredoxin system in cell death progression. AB - SIGNIFICANCE: The thioredoxin (Trx) system, comprising nicotinamide adenine dinucleotide phosphate, Trx reductase (TrxR), and Trx, is critical for maintaining cellular redox balance and antioxidant function, including control of oxidative stress and cell death. RECENT ADVANCES: Here, we focus on the research progress that is involved in the regulation of apoptosis by Trx systems. In mammalian cells, cytosolic Trx1 and mitochondrial Trx2 systems are the major disulfide reductases supplying electrons to enzymes for cell proliferation and viability. The reduced/dithiol form of Trxs binds to apoptosis signal-regulating kinase 1 (ASK1) and inhibits its activity to prevent stress- and cytokine-induced apoptosis. When Trx is oxidized, it dissociates from ASK1 and apoptosis is stimulated. The binding of Trx by its inhibitor Trx interacting protein (TXNIP) also contributes to the apoptosis process by removing Trx from ASK1. TrxRs are large homodimeric selenoproteins with an overall structure which is similar to that of glutathione reductase, and contain an active site GCUG in the C-terminus. CRITICAL ISSUES AND FUTURE DIRECTIONS: In the regulation of cell death processes, Trx redox state and TrxR activities are key factors that determine the cell fate. The high reactivity of Sec in TrxRs and its accessible location make TrxR enzymes emerge as targets for pharmaceutic drugs. TrxR inactivation by covalent modification does not only change the redox state and activity of Trx, but may also convert TrxR into a reactive oxygen species generator. Numerous electrophilic compounds including some environmental toxins and pharmaceutical drugs inhibit TrxR. We have classified these compounds into four types and propose some useful principles to understand the reaction mechanism of the TrxR inhibition by these compounds. PMID- 22530690 TI - Ocular application of chitosan. AB - INTRODUCTION: A major problem in ocular therapeutics with classical formulations is the maintenance of an effective drug concentration at the site of action for a long period of time. Enhancement of ocular bioavailability with increased dose penetration and longer retention time at desired sites can be achieved by recent formulations. Chitosan stands out with its unique structural advantageous characteristics for different types of formulations like in situ gelling systems, micro- and nanoparticles, inserts, etc. AREAS COVERED: In this review, the authors focus on ocular therapeutics and the characteristics that make chitosan more acceptable in ocular applications. EXPERT OPINION: Chitosan seems to be one of the most promising polymeric carriers for both hydrophilic and lipophilic drugs for ocular application. PMID- 22530691 TI - The Candida albicans plasma membrane protein Rch1p, a member of the vertebrate SLC10 carrier family, is a novel regulator of cytosolic Ca2+ homoeostasis. AB - Candida albicans RCH1 (regulator of Ca(2+) homoeostasis 1) encodes a protein of ten TM (transmembrane) domains, homologous with human SLC10A7 (solute carrier family 10 member 7), and Rch1p localizes in the plasma membrane. Deletion of RCH1 confers hypersensitivity to high concentrations of extracellular Ca(2+) and tolerance to azoles and Li(+), which phenocopies the deletion of CaPMC1 (C. albicans PMC1) encoding the vacuolar Ca(2+) pump. Additive to CaPMC1 mutation, lack of RCH1 alone shows an increase in Ca(2+) sensitivity, Ca(2+) uptake and cytosolic Ca(2+) level. The Ca(2+) hypersensitivity is abolished by cyclosporin A and magnesium. In addition, deletion of RCH1 elevates the expression of CaUTR2 (C. albicans UTR2), a downstream target of the Ca(2+)/calcineurin signalling. Mutational and functional analysis indicates that the Rch1p TM8 domain, but not the TM9 and TM10 domains, are required for its protein stability, cellular functions and subcellular localization. Therefore Rch1p is a novel regulator of cytosolic Ca(2+) homoeostasis, which expands the functional spectrum of the vertebrate SLC10 family. PMID- 22530692 TI - Experimental evidence for the ancestry of allotetraploid Trifolium repens and creation of synthetic forms with value for plant breeding. AB - BACKGROUND: White clover (Trifolium repens) is a ubiquitous weed of the temperate world that through use of improved cultivars has also become the most important legume of grazed pastures world-wide. It has long been suspected to be allotetraploid, but the diploid ancestral species have remained elusive. Putative diploid ancestors were indicated by DNA sequence phylogeny to be T. pallescens and T. occidentale. Here, we use further DNA evidence as well as a combination of molecular cytogenetics (FISH and GISH) and experimental hybridization to test the hypothesis that white clover originated as a hybrid between T. pallescens and T. occidentale. RESULTS: T. pallescens plants were identified with chloroplast trnL intron DNA sequences identical to those of white clover. Similarly, T. occidentale plants with nuclear ITS sequences identical to white clover were also identified. Reciprocal GISH experiments, alternately using labeled genomic DNA probes from each of the putative ancestral species on the same white clover cells, showed that half of the chromosomes hybridized with each probe. F1 hybrids were generated by embryo rescue and these showed strong interspecific chromosome pairing and produced a significant frequency of unreduced gametes, indicating the likely mode of polyploidization. The F1 hybrids are inter-fertile with white clover and function as synthetic white clovers, a valuable new resource for the re-incorporation of ancestral genomes into modern white clover for future plant breeding. CONCLUSIONS: Evidence from DNA sequence analyses, molecular cytogenetics, interspecific hybridization and breeding experiments supports the hypothesis that a diploid alpine species (T. pallescens) hybridized with a diploid coastal species (T. occidentale) to generate tetraploid T. repens. The coming together of these two narrowly adapted species (one alpine and the other maritime), along with allotetraploidy, has led to a transgressive hybrid with a broad adaptive range. PMID- 22530693 TI - Bifunctional fluoroionphore-ionic liquid hybrid for toxic heavy metal ions: improving its performance via the synergistic extraction strategy. AB - Several heavy metal ions (HMIs), such as Cd(2+), Pb(2+), and Hg(2+), are highly toxic even at very low concentrations. Although a large number of fluoroionphores have been synthesized for HMIs, only a few of them show detection limits that are below the maximum contamination levels in drinking water (usually in the nM range), and few of them can simultaneously detect and remove HMIs. In this work, we report a new fluoroionphore-ionic liquid hybrid-based strategy to improve the performance of classic fluoroionphores via a synergistic extraction effect and realize simultaneous instrument-free detection and removal of HMIs. As a proof-of concept, Hg(2+) was chosen as a model HMI, and a rhodamine thiospirolactam was chosen as a model fluoroionphore to construct bifunctional fluoroionphore-ionic liquid hybrid 1. The new sensing system could provide obviously improved sensitivity by simply increasing the aqueous-to-ionic liquid phase volume ratio to 10:1, resulting in a detection limit of 800 pM for Hg(2+), and afford extraction efficiencies larger than 99% for Hg(2+). The novel strategy provides a general platform for highly sensitive detection and removal of various HMIs in aqueous samples and holds promise for environmental and biomedical applications. PMID- 22530694 TI - Incidence of highly pathogenic avian influenza H5N1 in Nigeria, 2005-2008. AB - Outbreaks of highly pathogenic avian influenza (HPAI) H5N1 occurred in Nigeria between December 2005 and July 2008. We describe temporal and spatial characteristics of these outbreaks at State and Local Government Area (LGA) levels. A total of 25 of 37 States (67.6%; Exact 95% CI: 50.2-82.0%) and 81 of 774 LGAs (10.5%; Exact 95% CI: 8.4-12.8%) were affected by HPAI outbreaks over the period from 2005 to 2008. The incidence risk of HPAI outbreak occurrence at the State level was 5.6% (0.7-18.7%) for 2005, 50.0% (30.7-69.4%) for 2006, 54.5% (29.9-80.3%) for 2007 and 0% for 2008. Only very few LGAs experienced HPAI outbreaks within the affected States. The incidence risk of HPAI outbreak occurrence on a LGA level was 0.3% (0.0-0.9%) for 2005, 6.6% (4.9-8.6%) for 2006, 4.2% (2.9-6.0%) for 2007 and 0% for 2008. The mean period between farmers noticing HPAI outbreaks and reporting them to veterinary authorities, and between reporting HPAI outbreaks and the depopulation of infected premises, was for both 4.5 days; both periods also had medians of 1 day. We have estimated the spatially smoothed incidence risk for the whole outbreak period and identified the existence of a large corridor in the western part of Nigeria and a smaller corridor in south-eastern part, where the risk of HPAI occurrence was lower than in the rest of the country. The effect of HPAI control policies on the outbreaks patterns are discussed, as well as possible reasons why HPAI did not become endemic in Nigeria. PMID- 22530695 TI - Interfacial behavior of recombinant forms of human pulmonary surfactant protein SP-C. AB - The behavior at air-liquid interfaces of two recombinant versions of human surfactant protein SP-C has been characterized in comparison with that of native palmitoylated SP-C purified from porcine lungs. Both native and recombinant proteins promoted interfacial adsorption of dipalmitoylphosphatidylcholine bilayers to a limited extent, but catalyzed very rapid formation of films from different lipid mixtures containing both zwitterionic and anionic phospholipids. Once at the interface, the recombinant variants exhibited compression-driven structural transitions, consistent with changes in the orientation of the deacylated N-terminal segment, which were not observed in the native protein. Compression isotherms of lipid/protein films suggest that the recombinant SP-C forms promote expulsion at high pressures of a higher number of lipid molecules per mole of protein than does native SP-C. A more dynamic conformation of the N terminal segment in recombinant SP-C forms is likely also responsible for facilitating compression-driven condensation of domains in anionic phospholipid films as observed by epifluorescence microscopy. Finally, both native palmitoylated SP-C and the phenylalanine-containing recombinant versions facilitate similarly the repetitive compression-expansion dynamics of lipid/protein films, which were able to reach maximal surface pressures with practically no hysteresis along multiple quasi-static or dynamic cycles. PMID- 22530697 TI - Dielectric behavior of some small ketones as ideal polar molecules. AB - The dielectric behaviors of some small symmetric ketone molecules, including acetone, 3-pentanone, cyclopentanone, 4-heptanone, and cyclohexanone, were investigated as a function of temperature (T) over a wide frequency range from 50 MHz (3.14 * 10(8) s(-1), in angular frequency) to 3 THz (1.88 * 10(13) s(-1)). The temperature dependencies of the rotational diffusion times (tau(r)) determined using (17)O NMR spin-lattice relaxation time (T(1)) measurements and viscosities of the ketones were also examined. The obtained temperature dependencies of the parameters for the ketones were compared with those of ideal polar molecules, which obey the Stokes-Einstein-Debye (SED) relationship without the formation of intermolecular dimeric associations and without orientational correlations between dipoles (molecular axes), that is, free rotation. Kirkwood correlation factors (g(K)) of only acetone and 3-pentanone were close to unity over a wide temperature range, whereas those of other ketones were obviously less than unity. These results revealed that no correlations exist between the rotational motions of dipoles in acetone and 3-pentanone, as expected in ideal polar molecules. However, other ketones exhibited orientational correlations in their dipoles because of dipole-dipole interactions via antiparallel configurations. Furthermore, because acetone and 3-pentanone satisfied the SED relationship and because their microscopic dielectric relaxation times (tau(MU)), which were calculated from the determined dielectric relaxation times (tau(D)) via the relationship tau(MU) = tau(D)g(K)(-1), were identical to 3tau(r) and were proportional to Veta(k(B)T)(-1) over the wide temperature range examined, where V, k(B), and eta represent the effective molecular volume, Boltzmann's constant, and the viscosity of the liquid molecules, respectively, these two ketone molecules behave as ideal polar molecules. In addition, other ketones not significantly larger than acetone and 3-pentanone in molecular size likely form dimeric intermolecular associations with antiparallel cyclic configurations, which demonstrates the g(K) values less than unity. PMID- 22530696 TI - Dynamic Wolbachia prevalence in Acromyrmex leaf-cutting ants: potential for a nutritional symbiosis. AB - Wolbachia are renowned as reproductive parasites, but their phenotypic effects in eusocial insects are not well understood. We used a combination of qrt-PCR, fluorescence in situ hybridization and laser scanning confocal microscopy to evaluate the dynamics of Wolbachia infections in the leaf-cutting ant Acromyrmex octospinosus across developmental stages of sterile workers. We confirm that workers are infected with one or two widespread wsp genotypes of Wolbachia, show that colony prevalence is always 100% and characterize two rare recombinant genotypes. One dominant genotype is always present and most abundant, whereas another only proliferates in adult workers of some colonies and is barely detectable in larvae and pupae. An explanation may be that Wolbachia genotypes compete for host resources in immature stages while adult tissues provide substantially more niche space. Tissue-specific prevalence of the two genotypes differs, with the rarer genotype being over-represented in the adult foregut and thorax muscles. Both genotypes occur extracellularly in the foregut, suggesting an unknown mutualistic function in worker ant nutrition. Both genotypes are also abundant in the faecal fluid of the ants, suggesting that they may have extended functional phenotypes in the fungus garden that the ants manure with their own faeces. PMID- 22530698 TI - Biomolecule-based antibacterial coating on a stainless steel surface: multilayer film build-up optimization and stability study. AB - The goal of this paper was to establish the durability profile of antibacterial multilayer thin films under storage and usage conditions. Thin films were built on stainless steel (SS) by means of a layer-by-layer process alternating a negatively charged polyelectrolyte, polyacrylic acid, with a cationic antibacterial peptide, nisin. SS coupons coated with the antibacterial film were challenged under environmental and usage conditions likely to be encountered in real-world applications. The change in antibacterial activity elicited by the challenge was used as an indicator of multilayer film resistance. Antibacterial SS samples could be stored for several weeks at 4 degrees C in ambient air and antibacterial films were resistant to dipping and mild wiping in water and neutral detergent. The multilayer coating showed some weaknesses, however, that need to be addressed. PMID- 22530699 TI - Prognostic significance of Ki-67 in salivary gland carcinomas. AB - BACKGROUND: Salivary gland carcinomas are a heterogeneous group of tumors with varying malignant potential. In this study, we evaluated the proliferative marker Ki-67 in salivary gland carcinomas and related the Ki-67 index to clinical data. METHODS: A total of 176 salivary gland carcinomas of 13 different subtypes were stained immunohistochemically for Ki-67. The number of Ki-67 positive cells was counted and the Ki-67 index was calculated as the percentage of positive tumor cells. RESULTS: The Ki-67 median value was 26 (range 1-99). The median follow-up time was 6.9 years (range 0-19 years). The 5- and 10-year crude survival was 70% and 59%, respectively. In univariate analysis, Ki-67 index, stage, vascular invasion and tumor grade were significantly related to crude survival, but in multivariate analysis only Ki-67 index, age, and stage were independent prognostic factors. CONCLUSION: We showed that irrespective of subtyping, grading or morphological appearance of tumor, the Ki-67 index is an important and independent prognosticator. Clinical and histo-pathological data must be considered, when planning the treatment of the individual patient. We have shown that besides stage and age of the patient, Ki-67 is a strong, independent prognostic factor. PMID- 22530701 TI - Enhanced performance of short-channel carbon nanotube field-effect transistors due to gate-modulated electrical contacts. AB - We use numerical simulations to analyze recent experimental measurements of short channel carbon nanotube field-effect transistors with palladium contacts. We show that the gate strongly modulates the contact properties, an effect that is distinct from that observed in Schottky barrier carbon nanotube transistors. This modulation of the contacts by the gate allows for the realization of superior subthreshold swings for short channels, and improved scaling behavior. These results further elucidate the behavior of carbon nanotube-metal contacts, and should be useful in the optimization of high-performance carbon nanotube electronics. PMID- 22530700 TI - The association between vitamin D status and type 2 diabetes in a Thai population, a cross-sectional study. AB - OBJECTIVE: To explore vitamin D status in relation to diabetes, based on data from a national health examination survey in Thailand. DESIGN AND METHODS: A total of 2641 adults, aged 15-98 years, were randomly selected according to geographical region from the Thai 4th National Health Examination Survey sample. Logistic regressions were used to examine the cross-sectional association between diabetes status and level of 25(OH)D separately by age groups and areas of residence. RESULTS: Fifty per cent of the subjects were men and 5.8% had diabetes. The mean level of 25(OH)D was 79.3 +/- 0.8 nm. Based on cut-off values of 50 and 75 nm, six per cent and 45% had vitamin D insufficiency, respectively. In a regression model, it was found that 25(OH)D3 and total 25(OH)D were positively associated with diabetes. In addition, logistic regression analysis showed that low circulating 25(OH)D3, but not 25(OH)D2, levels was significantly associated with an increased odds of diabetes in older persons (aged >=70 years) in urban areas. However, for subjects residing in rural areas, no association between serum 25(OH)D3 or total 25(OH)D and diabetes was found. Furthermore, vitamin D insufficiency was associated with a higher risk of diabetes (OR, 1.56; 95% CI, 1.10-1.12) only in the urban elderly. CONCLUSION: Low vitamin D status is modestly associated with a small increase in the risk of diabetes in the urban Thai elderly. The observation that higher vitamin D status is associated with increased diabetic risk in young adults needs to be further explored and confirmed. PMID- 22530702 TI - Electron attachment to the guanine-cytosine nucleic acid base pair and the effects of monohydration and proton transfer. AB - The guanine-cytosine (GC) radical anion and its interaction with a single water molecule is studied using ab initio and density functional methods. Z-averaged second-order perturbation theory (ZAPT2) was applied to GC radical anion for the first time. Predicted spin densities show that the radical character is localized on cytosine. The Watson-Crick monohydrated GC anion is compared to neutral GC.H2O, as well as to the proton-transferred analogue on the basis of structural and energetic properties. In all three systems, local minima are identified that correspond to water positioned in the major and minor grooves of macromolecular DNA. On the anionic surface, two novel structures have water positioned above or below the GC plane. On the neutral and anionic surfaces, the global minimum can be described as water interacting with the minor groove. These structures are predicted to have hydration energies of 9.7 and 11.8 kcal mol(-1), respectively. Upon interbase proton-transfer (PT), the anionic global minimum has water positioned in the major groove, and the hydration energy increases to 13.4 kcal mol(-1). PT GC.H2O(*-) has distonic character; the radical character resides on cytosine, while the negative charge is localized on guanine. The effects of proton transfer are further investigated through the computed adiabatic electron affinities (AEA) of GC and monohydrated GC, and the vertical detachment energies (VDE) of the corresponding anions. Monohydration increases the AEAs and VDEs by only 0.1 eV, while proton-transfer increases the VDEs substantially (0.8 eV). The molecular charge distribution of monohydrated guanine-cytosine radical anion depends heavily on interbase proton transfer. PMID- 22530703 TI - Spatial interference between gaze direction and gaze location: a study on the eye contact effect. AB - Perceived gaze in faces is an important social cue that influences spatial orienting of attention. In three experiments, we examined whether the social relevance of gaze direction modulated spatial interference in response selection, using three different stimuli: faces, isolated eyes, and symbolic eyes (Experiments 1, 2, and 3, respectively). Each experiment employed a variant of the spatial Stroop paradigm in which face location and gaze direction were put into conflict. Results showed a reverse congruency effect between face location to the right or left of fixation and gaze direction only for stimuli with a social meaning to participants (Experiments 1 and 2). The opposite was observed for the nonsocial stimuli used in Experiment 3. Results are explained as facilitation in response to eye contact. PMID- 22530705 TI - Drug Burden Index and hospitalization among community-dwelling older people. AB - BACKGROUND: Medications with anticholinergic and sedative effects carry significant risks in older people. Adverse events arising from the use of these medications may also lead to hospitalization and contribute to length of stay. The Drug Burden Index (DBI) is a tool that measures a person's total exposure to medications with anticholinergic and sedative properties, using the principles of dose response and maximal effect. Cumulative anticholinergic and sedative drug burden measured using the DBI has been associated with clinically important outcomes in older people. The association between the DBI and hospitalization still remains relatively unknown. OBJECTIVE: The main aim of this study was to evaluate the relationship between DBI and hospitalization in a population-based sample of community-dwelling older Finns over a 1-year period. METHODS: The health status and medication use of 339 community-dwelling >=75-year-old Finns were assessed in 2004. Data on hospitalizations over the following year were obtained from the national discharge register. Two different measures were used to assess hospitalizations in the study sample: (i) the proportion of hospitalized participants; and (ii) the number of hospital days per person-year. Estimates for the number of hospital days per person-year and rate ratios (RRs) with 95% confidence intervals (CIs) were calculated using Poisson or negative binomial regression analysis. RESULTS: A total of 127 participants (38%) were exposed to DBI medications; 27% had a low DBI (>0 to <1), and 11% had a high DBI (>=1). The number of hospital days per person-year was 7.9 (95% CI 7.6, 8.3) for the unexposed participants (DBI = 0) and 13.4 (95% CI 12.8, 14.1) for the exposed participants (DBI >1); the age, gender and co-morbidity adjusted RR of hospital days per person-year between the exposed and unexposed participants was 1.26 (95% CI 1.18, 1.35). Between the low and high DBI groups, the difference in the number of hospital days per person-year was insignificant (p = 0.42). In multivariate analyses, the number of regularly used medications (RR = 1.12 [95% CI 1.00, 1.26] per additional medication) and the measure of basic activities of daily living Barthel Index (RR = 0.94 [95% CI 0.88, 0.99] per increase) were independently associated with the use of hospital days. CONCLUSION: Exposure to DBI medications was associated with a greater use of hospital days, but a cumulative dose response relationship between DBI and hospitalization was not observed. The number of regularly used medications and functioning in the basic activities of daily living predicted hospital care utilization. PMID- 22530704 TI - Glucose and low-density lipoprotein cholesterol lowering in elderly patients with type 2 diabetes: focus on combination therapy with colesevelam HCl. AB - The prevalence of type 2 diabetes mellitus is high among the elderly population. Treatment of elderly patients with type 2 diabetes presents challenges because of co-morbidities and the potential increase in the risk of adverse effects. Hyperlipidaemia is also common in the elderly population. Glucose- and lipid lowering treatment in elderly patients should be individualized on the basis of the patient's life expectancy, health status and cardiovascular risk factors, and evidence-based guideline recommendations. Because elderly patients often have impaired renal and hepatic function, careful considerations must be made when selecting appropriate glucose- and lipid-lowering therapy. There are a number of potential safety issues associated with various glucose- and lipid-lowering therapies that are relevant to elderly patients, including increased risk of heart failure exacerbations, weight loss, increased risk of hypoglycaemia, increased risk of myopathy, and contraindications of some agents in patients with hepatic or renal impairment. The bile acid sequestrant colesevelam HCl is unique compared with other glucose- and lipid-lowering therapies because it is the only product approved by the US Food and Drug Administration, as an adjunct to diet and exercise, to lower both glucose and low-density lipoprotein cholesterol (LDL C) in adults with type 2 diabetes and primary hyperlipidaemia, respectively. Furthermore, colesevelam has been shown to have similar glucose- and lipid lowering efficacy in patients aged <65 years and those aged >=65 years. Colesevelam was not associated with weight gain, was associated with a low incidence of hypoglycaemia, and can be safely combined with a broad range of glucose-lowering agents (metformin, sulfonylureas and insulin) and lipid-lowering statins. Currently, colesevelam is available in tablet form and as a powder for oral suspension formulation; the latter may be of benefit to elderly patients with swallowing difficulties. As colesevelam has both glucose- and lipid-lowering effects, its use may reduce the drug burden in elderly patients receiving multiple agents for glucose and lipid lowering. Colesevelam may be a valuable treatment option as an add-on to existing glucose- and/or lipid-lowering therapy to help improve haemoglobin A(1c) and to lower LDL-C levels in elderly patients with type 2 diabetes and primary hyperlipidaemia. PMID- 22530707 TI - Chitosan: a potential polymer for colon-specific drug delivery system. AB - INTRODUCTION: There is an enormous growth and awareness of the potential applications of natural polymers for colon delivery of therapeutic bioactives. Chitosan (CH), a cationic polysaccharide, has a number of vital applications in the field of colon delivery and has attracted a great deal of attention from formulation scientists, academicians and environmentalists due to its unique properties. AREAS COVERED: CH has been widely explored for the delivery of drugs, peptides, proteins and genes to the colon for different therapeutic applications. Sustained and controlled delivery can be achieved with CH-based formulations like CH-coated tablets, capsules, beads, gels, microparticles and nanoparticles. This review mainly focuses on various aspects of CH-based formulations, particularly development of colon-specific delivery of drug. EXPERT OPINION: The vital properties of CH make it a versatile excipient, not only for sustained/controlled release applications but also as biodegradable, biocompatible, bioadhesive polymer. The colon is recognized as the preferred absorption site for orally administered protein and peptide drugs. The main problem associated with CH is limited solubility at higher pH due to reduced cationic nature, which also reduces mucoadhesiveness. The application of newer targeting moiety with CH-based formulations for highly site-specific delivery of bioactive has to be evaluated for further improvement of therapeutic index (bioavailability). PMID- 22530706 TI - Menopausal symptoms appear before the menopause and persist 5 years beyond: a detailed analysis of a multinational study. AB - OBJECTIVE: Few Latin American studies have described menopausal symptoms in detail by means of a standardized assessment tool. The objective of this study was to assess the prevalence and severity of menopausal symptoms and their impact over quality of life among mid-aged Latin American women. METHOD: In this cross sectional study, 8373 otherwise healthy women aged 40-59 years from 12 Latin American countries were asked to fill out the Menopause Rating Scale (MRS) and a questionnaire containing personal sociodemographic data. Menopause status (pre-, peri- and postmenopausal) was defined according to the criteria of the Stages of Reproductive Aging Workshop. RESULTS: Of all the studied women, 90.9% had at least one menopausal symptom (complaint) that they rated. Muscle and joint discomfort, physical and mental exhaustion and depressive mood were highly prevalent and rated as severe-very severe (scores of 3 and 4), at a higher rate than vasomotor symptoms (15.6%, 13.8% and 13.7% vs. 9.6%, respectively). Of premenopausal women (40-44 years), 77.0% reported at least one rated complaint, with 12.9% displaying MRS scores defined as severe (> 16). The latter rate increased to 26.4% in perimenopausal, 31.6% in early postmenopausal and 29.9% among late postmenopausal women. As measured with the MRS, the presence of hot flushes increased the risk of impairment of overall quality of life in both premenopausal (odds ratio 12.67; 95% confidence interval 9.53-16.83) and peri/postmenopausal women (odds ratio 9.37; 95% confidence interval 7.85-11.19). CONCLUSION: In this large, mid-aged, female Latin American series, muscle/joint discomfort and psychological symptoms were the most prevalent and severely rated menopausal symptoms. The symptoms appear early in the premenopause, significantly impair quality of life and persist 5 years beyond the menopause. PMID- 22530708 TI - Cisplatin plus etoposide versus other platin-based regimens for patients with extensive small-cell lung cancer: a systematic review and meta-analysis of randomised, controlled trials. AB - AIM: To determine whether the cisplatin plus etoposide (EP) combination was more efficacious and less toxic than other platinum-based regimens for patients with extensive-stage small-cell lung cancer. METHODS: We performed an extensive literature search (from their inception to July 2010). Two reviewers independently assessed search results and methodological quality of included studies. Pooled hazard ratios (HRs) and relative risks (RRs) were calculated according to a random-effects model. RESULTS: Twelve randomised, controlled trials involving seven different platinum-based chemotherapy regimens were included into this meta-analysis. The meta-analysis showed that compared with EP regimen, irinotecan plus cisplatin (IP) might decrease the risk of death (HR = 0.87, 95% confidence interval (CI) 0.78-0.97, P = 0.01) (five trials), unlike the sensitivity analysis (HR = 0.91, 95% CI 0.81-1.02, P = 0.12), progression-free survival (HR = 0.95, 95% CI 0.86-1.05, P = 0.28) and overall response rate (RR 1.08, 95% CI 0.93-1.24) that were not superior for IP. IP regimen produced more non-haematological toxicities and less haematological toxicities. One trial found that etoposide + cisplatin + epirubicin + cyclophosphamide and cisplatin + etoposide + ifosfamide regimen might prolong the overall survival respectively. Etoposide + cisplatin + epirubicin + cyclophosphamide regimen also might improve progression-free survival but with high rate of haematological toxicities. None of the other trials included in the study demonstrated a significant improvement in survival. CONCLUSIONS: There is no strong evidence that any clinical advantage for extensive small-cell lung carcinoma patients requiring chemotherapy when comparing EP with other platin-based regimens, with exception of IP that might prolong overall survival. The decision to prescribe which chemotherapy should take into consideration both cost and treatment preference. PMID- 22530709 TI - Office workers' sick building syndrome and indoor carbon dioxide concentrations. AB - This study attempted to determine whether any association exists between sick building syndrome (SBS) and indoor carbon dioxide (CO(2)) concentrations. We evaluated SBS among 111 office workers in August and November 2003. The environmental conditions in the office, including CO(2) concentrations, temperature, relative humidity, and fine particulate matter (PM(2.5)), were continuously monitored. The most prevalent symptoms of the five SBS groups were eye irritation and nonspecific and upper respiratory symptoms. The generalized estimating equation (GEE) models show that workers exposed to indoor CO(2) levels greater than 800 ppm were likely to report more eye irritation or upper respiratory symptoms. PMID- 22530710 TI - Procyanidins improve some disrupted glucose homoeostatic situations: an analysis of doses and treatments according to different animal models. AB - This review analyses the potential beneficial effects of procyanidins, the main class of flavonoids, in situations in which glucose homeostasis is disrupted. Because the disruption of glucose homeostasis can occur as a result of various causes, we critically review the effects of procyanidins based on the specific origin of each type of disruption. Where little or no insulin is present (Type I diabetic animals), summarized studies of procyanidin treatment suggest that procyanidins have a short-lived insulin-mimetic effect on the internal targets of the organism, an effect not reproduced in normoglycemic, normoinsulinemic healthy animals. Insulin resistance (usually linked to hyperinsulinemia) poses a very different situation. Preventive studies using fructose-fed models indicate that procyanidins may be useful in preventing the induction of damage and thus in limiting hyperglycemia. But the results of other studies using models such as high-fat diet treated rats or genetically obese animals are controversial. Although the effects on glucose parameters are hazy, it is known that procyanidins target key tissues involved in its homeostasis. Interestingly, all available data suggest that procyanidins are more effective when administered in one acute load than when mixed with food. PMID- 22530711 TI - Evaluation of the safety and efficacy of hydroxycitric acid or Garcinia cambogia extracts in humans. AB - Several studies have shown that Garcinia cambogia plays an important role in the regulation of endogenous lipid biosynthesis. This effect is specially attributed to (-)-hydroxycitric acid (HCA) inhibiting the enzyme ATP-dependent citrate lyase, which catalyzes the cleavage of citrate to oxaloacetate and acetyl-CoA. Although several studies have found that the administration of G. cambogia extracts is associated with body weight and fat loss in both experimental animals and humans, we should be cautious when interpreting the results as other randomized, placebo-controlled clinical trials have not reported the same outcomes. Furthermore, most studies in humans have been conducted on small samples and mainly in the short term. None of them have shown whether these effects persist beyond 12 weeks of intervention. Therefore, there is still little evidence to support the potential effectiveness and long-term benefits of G. cambogia extracts. With regard to toxicity and safety, it is important to note that except in rare cases, studies conducted in experimental animals have not reported increased mortality or significant toxicity. Furthermore, at the doses usually administered, no differences have been reported in terms of side effects or adverse events (those studied) in humans between individuals treated with G. cambogia and controls. PMID- 22530712 TI - Factors affecting quality and safety of fresh-cut produce. AB - The quality of fresh-cut fruit and vegetable products includes a combination of attributes, such as appearance, texture, and flavor, as well as nutritional and safety aspects that determine their value to the consumer. Nutritionally, fruit and vegetables represent a good source of vitamins, minerals, and dietary fiber, and fresh-cut produce satisfies consumer demand for freshly prepared, convenient, healthy food. However, fresh-cut produce deteriorates faster than corresponding intact produce, as a result of damage caused by minimal processing, which accelerates many physiological changes that lead to a reduction in produce quality and shelf-life. The symptoms of produce deterioration include discoloration, increased oxidative browning at cut surfaces, flaccidity as a result of loss of water, and decreased nutritional value. Damaged plant tissues also represent a better substrate for growth of microorganisms, including spoilage microorganisms and foodborne pathogens. The risk of pathogen contamination and growth is one of the main safety concerns associated with fresh cut produce, as highlighted by the increasing number of produce-linked foodborne outbreaks in recent years. The pathogens of major concern in fresh-cut produce are Listeria monocytogenes, pathogenic Escherichia coli mainly O157:H7, and Salmonella spp. This article describes the quality of fresh-cut produce, factors affecting quality, and various techniques for evaluating quality. In addition, the microbiological safety of fresh-cut produce and factors affecting pathogen survival and growth on fresh-cut produce are discussed in detail. PMID- 22530714 TI - Proteins in oats; their synthesis and changes during germination: a review. AB - Oats (Avena sativa L.) are distinct among cereals due to their considerably higher protein concentration. At the same time oats possess a protein quality of high nutritional value and a special protein composition. Most cereals like wheat, barley, and rye have a high percentage of prolamins, the alcohol-soluble fraction, which usually contains most of the storage proteins, but oats are an exception. Their major storage proteins belong to the salt-water soluble globulin fraction, whereas oats prolamins are a minor component. During oats groat development, most obvious is the fairly linear increase in the globulin fraction. Oats globulins share structural features with the 11 S globulins of legumes and other dicots. Amino acid composition of oats is superior to that of other cereals due to the higher amount of limiting amino acids like lysine and threonine. During germination, total amino acid analysis revealed an increase in essential amino acids like lysine and tryptophan, which leads to an increased nutritional value of germinated oats. Oats protein products including globulin have been chemically modified by various methods to improve their functional properties. PMID- 22530715 TI - Ethylene vinyl alcohol: a review of barrier properties for packaging shelf stable foods. AB - Ethylene vinyl alcohol (EVOH) is one of the best known flexible thermoplastic oxygen barrier materials in use today. It is especially important for refrigerated and shelf-stable foods where oxygen deteriorates the quality of packaged products and reduces their shelf life. EVOH accounts for a majority of thermoplastic barrier materials used for rigid or semi-rigid retortable food containers. However. it is of limited use in flexible packages or lid films for rigid trays used for packaging thermally processed shelf-stable low acid foods due to its moisture sensitivity. Nevertheless, current use of other oxygen barrier materials such as polyvinylidene chloride and aluminum foil creates environmental concerns. Innovations in food processing technologies provide opportunities for increased use of EVOH in food packaging. The aim of this review is to give an overview of research on the oxygen barrier properties of EVOH from the perspective of structure-barrier property relationships and the consequences of food processing conditions. PMID- 22530713 TI - Successful development of satiety enhancing food products: towards a multidisciplinary agenda of research challenges. AB - In the context of increasing prevalence of overweight and obesity in societies worldwide, enhancing the satiating capacity of foods may help people control their energy intake and weight. This requires an integrated approach between various food-related disciplines. By structuring this approach around the new product development process, this paper aims to present the contours of such an integrative approach by going through the current state of the art around satiety enhancing foods. It portrays actual food choice as the end result of a complex interaction between internal satiety signals, other food benefits, and environmental cues. Three interrelated routes to satiating enhancement are to change the food composition to develop stronger physiological satiation and satiety signals, anticipate and build on smart external stimuli at the moment of purchase and consumption, and improve palatability and acceptance of satiety enhanced foods. Key research challenges in achieving these routes in the field of nutrition, food technology, consumer, marketing, and communication are outlined. PMID- 22530716 TI - Prediction of spontaneous preterm delivery in women with threatened preterm labour: a prospective cohort study of multiple proteins in maternal serum. AB - OBJECTIVE: To analyse whether specific proteins in maternal serum and cervical length, alone or in combination, can predict the likelihood that women with intact membranes with threatened preterm labour will deliver spontaneously within 7 days of sampling. DESIGN: Cohort study. SETTING: Sahlgrenska University Hospital, Gothenburg, Sweden. POPULATION: Women at between 22 and 33 weeks of gestation with threatened preterm labour (n = 142) admitted to the Sahlgrenska University Hospital, Gothenburg, Sweden, in 1995-2005. METHODS: Maternal serum was tested for 27 proteins using multiplex xMAP technology. Individual levels of each protein were compared, and calculations were performed to investigate potential associations between different proteins, cervical length and spontaneous preterm delivery. Receiver operating characteristic curves were used to find the best cut-off values for continuous variables in relation to spontaneous preterm delivery within 7 days of sampling. Prediction models were created based on a stepwise logistic regression using binary variables. MAIN OUTCOME MEASURE: Spontaneous preterm delivery within 7 days. RESULTS: In order to determine the best prediction model, we analysed models of serum proteins alone, cervical length alone, and the combination of serum proteins and cervical length. We found one multivariable combined model through the data analysis that more accurately predicted spontaneous preterm delivery within 7 days. This model was based on serum interleukin-10 (IL-10) levels, serum RANTES levels and cervical length (sensitivity 74%, specificity 87%, positive predictive value 76%, negative predictive value 86%, likelihood ratio 5.8 and area under the curve 0.88). CONCLUSIONS: A combination of maternal serum proteins and cervical length constituted the best prediction model, and would help determine whether women with threatened preterm labour are likely to deliver within 7 days of measurement. PMID- 22530718 TI - Toward the identification of a reliable 3D QSAR pharmacophore model for the CCK2 receptor antagonism. AB - The present study describes application of computational approaches to identify a validated and reliable 3D QSAR pharmacophore model for the CCK-2R antagonism through integrated ligand and structure based studies using anthranilic sulfonamide and 1,3,4-benzotriazepine based CCK-2R antagonists. The best hypothesis consisted five features viz. two aliphatic hydrophobic, one aromatic hydrophobic, one H-bond acceptor, and one ring aromatic feature with an excellent correlation for 34 training set (r2(training) = 0.83) and 58 test set compounds (r2(test) = 0.74). This model was validated through F-test and docking studies at the active site of the plausible CCK-2R where the 99% significance and well corroboration with the pharmacophore model respectively describes the model's reliability. The model also predicts well to other known clinically effective CCK 2R antagonists. Therefore, the developed model may useful in finding new scaffolds that may aid in design and develop new chemical entities (NCEs) as potent CCK-2R antagonists before their synthesis. PMID- 22530717 TI - Individual participant data meta-analysis of prognostic factor studies: state of the art? AB - BACKGROUND: Prognostic factors are associated with the risk of a subsequent outcome in people with a given disease or health condition. Meta-analysis using individual participant data (IPD), where the raw data are synthesised from multiple studies, has been championed as the gold-standard for synthesising prognostic factor studies. We assessed the feasibility and conduct of this approach. METHODS: A systematic review to identify published IPD meta-analyses of prognostic factors studies, followed by detailed assessment of a random sample of 20 articles published from 2006. Six of these 20 articles were from the IMPACT (International Mission for Prognosis and Analysis of Clinical Trials in traumatic brain injury) collaboration, for which additional information was also used from simultaneously published companion papers. RESULTS: Forty-eight published IPD meta-analyses of prognostic factors were identified up to March 2009. Only three were published before 2000 but thereafter a median of four articles exist per year, with traumatic brain injury the most active research field. Availability of IPD offered many advantages, such as checking modelling assumptions; analysing variables on their continuous scale with the possibility of assessing for non linear relationships; and obtaining results adjusted for other variables. However, researchers also faced many challenges, such as large cost and time required to obtain and clean IPD; unavailable IPD for some studies; different sets of prognostic factors in each study; and variability in study methods of measurement. The IMPACT initiative is a leading example, and had generally strong design, methodological and statistical standards. Elsewhere, standards are not always as high and improvements in the conduct of IPD meta-analyses of prognostic factor studies are often needed; in particular, continuous variables are often categorised without reason; publication bias and availability bias are rarely examined; and important methodological details and summary results are often inadequately reported. CONCLUSIONS: IPD meta-analyses of prognostic factors are achievable and offer many advantages, as displayed most expertly by the IMPACT initiative. However such projects face numerous logistical and methodological obstacles, and their conduct and reporting can often be substantially improved. PMID- 22530719 TI - What is a clinical skill? Searching for order in chaos through a modified Delphi process. AB - BACKGROUND: Everybody seems to know what a clinical skill (CS) is but closer consideration shows that the concept of a CS is not as clear as might be assumed. Some seem to use "CSs" when just referring to physical examination skills, whereas others use the term to also include diagnostic, communication and practical skills. CSs are more than a simple performance, but clinicians are often not consciously aware of the complex interplay of different components of a CS that they are practicing and accordingly do not teach all these aspects to students. METHODS: A modified Delphi research was designed to explore concepts around the definition of a CS and its components for learning and teaching. The panel consisted of a group of British doctors, all involved in teaching CSs. RESULTS: One hundred and twenty-two items were identified and ranked through two rounds of a Delphi process, coded into thirty-seven codes and clustered into six principle themes: professional roles; components of CSs; performance; psychomotor aspects; educational environment; and teacher versus student centeredness. CONCLUSIONS: A CS may contain one or several different domains such as: physical examination skills, practical procedure, communication skills, and management. Acquiring CSs includes three components: learning how to perform certain movements (procedural knowledge), why one should do so (underlying basic science knowledge), and what the findings might mean (clinical reasoning). If we are to teach CSs for clinical practice, we must take these three different components into account in our instructional design. PMID- 22530720 TI - Structural investigation of HCN polymer isotopomers by solution-state multidimensional NMR. AB - Hydrogen cyanide is considered as an important precursor to amino acids and nucleic acids, and its polymers could have profound implications on prebiotic chemistry. Several structures of HCN polymers are speculated, but these structures are disparate both chemically as well as structurally. Here, we employ solution-state NMR spectroscopy to investigate the structure of HCN polymers with (13)C and (15)N isotopic enrichment. From the multinuclear and multidimensional NMR investigations, we identify some discrete structural units for the most concentrated small molecular components and suggest that the dominating polymers are polyimine chain-like structures, which are formed by base-catalyzed nucleophilic addition reactions. PMID- 22530721 TI - Distinct functional roles of the two terminal halves of eukaryotic phosphofructokinase. AB - Eukaryotic PFK (phosphofructokinase), a key regulatory enzyme in glycolysis, has homologous N- and C-terminal domains thought to result from duplication, fusion and divergence of an ancestral prokaryotic gene. It has been suggested that both the active site and the Fru-2,6-P2 (fructose 2,6-bisphosphate) allosteric site are formed by opposing N- and C-termini of subunits orientated antiparallel in a dimer. In contrast, we show in the present study that in fact the N-terminal halves form the active site, since expression of the N-terminal half of the enzymes from Dictyostelium discoideum and human muscle in PFK-deficient yeast restored growth on glucose. However, the N-terminus alone was not stable in vitro. The C-terminus is not catalytic, but is needed for stability of the enzyme, as is the connecting peptide that normally joins the two domains (here included in the N-terminus). Co-expression of homologous, but not heterologous, N and C-termini yielded stable fully active enzymes in vitro with sizes and kinetic properties similar to those of the wild-type tetrameric enzymes. This indicates that the separately translated domains can fold sufficiently well to bind to each other, that such binding of complementary domains is stable and that the alignment is sufficiently accurate and tight as to preserve metabolite binding sites and allosteric interactions. PMID- 22530722 TI - The fungal T-2 toxin alters the activation of primary macrophages induced by TLR agonists resulting in a decrease of the inflammatory response in the pig. AB - T-2 toxin is known to be one of the most toxic trichothecene mycotoxins. Exposure to T-2 toxin induces many hematologic and immunotoxic disorders and is involved in immuno-modulation of the innate immune response. The objective of this work was to evaluate the effects of T-2 toxin on the activation of macrophages by different agonists of Toll-like receptors (TLR) using an in vitro model of primary porcine alveolar macrophages (PAM). Cytotoxic effects of T-2 toxin on PAM were first evaluated. An IC50 of 19.47 +/- 0.9753 nM was determined for the cytotoxicity of T-2 toxin. A working concentration of 3 nM of T-2 toxin was chosen to test the effect of T-2 toxin on TLR activation; this dose was not cytotoxic and did not induce apoptosis as demonstrated by Annexin/PI staining. A pre-exposure of macrophages to 3 nM of T-2 toxin decreased the production of inflammatory mediators (IL-1 beta, TNF-alpha, nitric oxide) in response to LPS and FSL1, TLR4 and TLR2/6 agonists respectively. The decrease of the pro inflammatory response is associated with a decrease of TLR mRNA expression. By contrast, the activation of TLR7 by ssRNA was not modulated by T-2 toxin pre treatment. In conclusion, our results suggest that ingestion of low concentrations of T-2 toxin affects the TLR activation by decreasing pattern recognition of pathogens and thus interferes with initiation of inflammatory immune response against bacteria and viruses. Consequently, mycotoxins could increase the susceptibility of humans and animals to infectious diseases. PMID- 22530723 TI - Effect of abamectin exposure on semen parameters indicative of reduced sperm maturity: a study on farmworkers in Antalya (Turkey). AB - Environmental exposure to pesticides may cause serious health risks including fertility and reproductive function. The aim of this study was to highlight whether there is a relationship between exposure to abamectin and male fertility parameters of farmworkers. Twenty male farmworkers who were using abamectin and 20 men not exposed to pesticides were recruited as experimental and control groups, respectively. Semen analysis, molecular markers of sperm maturity and serum reproductive hormone levels were evaluated. In experimental group, high plasma abamectin levels were detected. These men have decreased sperm motility. Moreover, diminished molecular markers of sperm maturity, such as decreased hyaluronic acid (HA) binding of sperm, increased numbers of aniline blue positive sperm and increased percentage of creatine kinase (CK) positive sperm, were observed in abamectin-exposed men. Their serum testosterone, LH and FSH levels did not change significantly. We conclude that exposure to abamectin may impair male fertility by effecting semen quality. PMID- 22530724 TI - Coexistent idiopathic left ventricular tachycardia and atrial fibrillation induced by maintained VA conduction during ventricular tachycardia. PMID- 22530725 TI - Correlated evolution of phenotypic plasticity in metamorphic timing. AB - Phenotypic plasticity has long been a focus of research, but the mechanisms of its evolution remain controversial. Many amphibian species exhibit a similar plastic response in metamorphic timing in response to multiple environmental factors; therefore, more than one environmental factor has likely influenced the evolution of plasticity. However, it is unclear whether the plastic responses to different factors have evolved independently. In this study, we examined the relationship between the plastic responses to two experimental factors (water level and food type) in larvae of the salamander Hynobius retardatus, using a cause-specific Cox proportional hazards model on the time to completion of metamorphosis. Larvae from ephemeral ponds metamorphosed earlier than those from permanent ponds when kept at a low water level or fed conspecific larvae instead of larval Chironomidae. This acceleration of metamorphosis depended only on the permanency of the larvae's pond of origin, but not on the conspecific larval density (an indicator of the frequency of cannibalism) in the ponds. The two plastic responses were significantly correlated, indicating that they may evolve correlatively. Once plasticity evolved as an adaptation to habitat desiccation, it might have relatively easily become a response to other ecological factors, such as food type via the pre-existing developmental pathway. PMID- 22530726 TI - Short and long-term management of haemophilia A patient requiring heart valve surgery. PMID- 22530727 TI - Clear cell variant of ductal carcinoma in situ of the breast. PMID- 22530728 TI - A point mutant of apolipoprotein A-I (V156K) showed enhancement of cellular insulin secretion and potent activity of facultative regeneration in zebrafish. AB - Sensitivity of glycation and functional changes were compared between wild-type (WT) and the V156K mutant of apolipoprotein A-I in the reconstituted high-density lipoproteins (rHDL) state. WT-rHDL showed increased production of advanced glycated end (AGE) products with proteolytic fragmentation by fructose treatment (final 5 mM) for 48 hr; however, V156K-rHDL was more resistant to the same fructosylation and protein cleavage. Glycated WT-rHDL severely lost antioxidant activity; in contrast, V156K-rHDL showed much less AGE production and retained stronger antioxidant properties in the glycated state. In both native and glycated states, V156K-rHDL showed significantly enhanced stimulation activity for insulin secretion from the rat pancreatic beta-cell, whereas WT-rHDL induced less insulin secretion by glycation. In the zebrafish model, under diabetic and hyperlipidemic diet conditions, injection of native V156K-rHDL caused an approximate five-fold increase in fin regeneration activity compared to native WT rHDL over 120 hr. Under the same conditions, injection of glycated WT-rHDL caused severe tissue damage in tail fins after 48 hr, whereas glycated V156K-rHDL showed normal regeneration. In conclusion, insulin secretion and tissue rejuvenation activities of WT-rHDL were nearly depleted by fructosylation, but V156K-rHDL did not lose its beneficial activity. These results suggest that V156K-rHDL can be applied to facilitate facultative regeneration in aging-related complications. PMID- 22530729 TI - Association between age-related decline of kidney function and plasma malondialdehyde. AB - Oxidative stress is a key factor linked renal function decline with age. However, there is still no large cohort study exploring the potential role of oxidative stress in mild insufficiency of kidney function (MIKF) and chronic kidney disease (CKD) after adjusting for confounding factors. This study tested the hypothesis that oxidative stress, indicated by plasma malondialdehyde (MDA), is associated with the prevalence of MIKF and CKD after controlling the effects of confounding factors. Plasma levels of MDA and serum levels of fasting glucose, cholesterol, triglycerides, creatinine, alanine aminotransferase, and aspartate aminotransferase were analyzed from 2,169 Chinese Han adults. A questionnaire and physical examination were performed to identify and suspect risk factors of renal function decline with age. Kidney function, as indicated by estimated glomerular filtration rate, showed a significant decline with age in both male and female. Although the association between age and plasma MDA levels was nonlinear, MDA was negatively related to kidney function. The multivariate-adjusted odds ratios showed that plasma MDA had a significantly graded relation to the prevalence of MIKF and CKD with or without adjustment for covariates. By comparison with the lowest quartile, individuals with the highest quartile of MDA level had a 99% and 223% increased risk of developing MIKF and CKD, respectively. Further results from multiinteraction analysis demonstrated that plasma MDA may be the mediator linking different covariates with renal function decline. The most striking finding of this study was that oxidative stress, as indicated by plasma MDA levels, is associated with the prevalence of MIKF and/or CKD. Although imposing an increasing burden on the kidney and/or promoting a cyclical process of oxidative stress in the body, high levels of MDA in plasma may link the decline of kidney function with age. PMID- 22530730 TI - Leukocyte telomere length: a focus on cerebrovascular events. AB - Telomeres are specialized DNA structures located at the ends of chromosomes. Their length is reduced at each cell cycle, especially when the cumulative burden of oxidative stress is high. The purpose of this study was to determine the associations between telomere length and clinical and biological risk factors in ischemic stroke patients. A total of 215 stroke patients hospitalized in the Dijon, France, stroke unit were prospectively and continuously included from January to September, 2004. The telomere length measured from peripheral blood leukocytes--leukocyte telomere length (LTL)--was determined by real-time quantitative polymerase chain reaction. The results were compared with clinical and biological variables of interest collected at admission to find significant associations. Possible relationships between LTL and stroke subtypes were evaluated. A multiple regression that included all the variables significantly associated (p<0.20) with LTL in univariate analysis and age and subtypes of stroke confirmed a significant association with age (p<0.001), homocysteinemia (p=0,049), and levels of both antiphospholipid antibodies (p=0.019) and triglycerides (p=0.007). Linearity was verified and confirmed for each variable. The subtype of stroke did not significantly affect telomere length. We were able to highlight significant associations between LTL and certain cerebrovascular risk factors in a general population of stroke patients. These associations did not depend on the ischemic stroke subtype. PMID- 22530731 TI - Relationship of low-circulating "anti-aging" klotho hormone with disability in activities of daily living among older community-dwelling adults. AB - The aging suppressor gene klotho encodes a single-pass transmembrane protein klotho that in mice is known to extend life span when overexpressed and to resemble accelerated aging, with skeletal muscle atrophy and decreased bone mineral density, when expression is disrupted. We sought to examine the relationship between plasma klotho and disability in activities of daily living (ADL) in older community-dwelling adults. In a cross-sectional study, plasma klotho was measured in a population-based sample of 802 adults, >= 65 years, who participated in the "Invecchiare in Chianti" (Aging in the Chianti Area) (InCHIANTI) study in Tuscany, Italy. The overall proportion of adults with ADL disability was 11.9%. Mean (standard deviation) klotho concentrations were 689 (238) pg/mL. From the lowest to the highest tertile of plasma klotho, 16.1%, 9.7%, and 5.6% of participants, respectively, had ADL disability (p=0.0004). Plasma klotho, per 1 standard deviation increase, was associated with ADL disability (odds ratio=0.57, 95% confidence interval 0.35-0.93, p=0.02) in a multivariate logistic regression model adjusting for age, education, cognition, physical activity, physical performance, total cholesterol, alcohol and tobacco use, and chronic diseases. Low plasma klotho concentrations were independently associated with ADL disability among older community-dwelling men and women. PMID- 22530733 TI - Optical funneling and trapping of gold colloids in convergent laser beams. AB - The simultaneous trapping of a large number of sedimenting Au colloids by optical radiation forces has been studied in detail. The particles are collected by a convergent laser beam and compressed against gravity and osmotic pressure at the upper window of the cell, thereby forming a dense colloidal gas. A minimum critical laser power is required to transport colloids into the trap. In contrast to conventional optical tweezers, the trap cannot be described by a 3D potential. Once the trap is sufficiently filled, the laser power can be reduced below the critical value, thereby stabilizing the trap population. Some characteristic properties of the trap, like the critical laser power and the transit time, are readily understood from a simple deterministic model. A detailed description that is capable of quantitatively accounting for the time dependence of the trap population, the finite leak rate at low power levels, or hysteresis effects requires the incorporation of fluctuations by means of a proper Langevin equation. Multiple independent traps are realized by time multiplexing of the laser beam, which allows for splitting up, independent manipulation, and subsequent recombination of a trapped colloidal cloud. PMID- 22530732 TI - High-precision isothermal titration calorimetry with automated peak-shape analysis. AB - Isothermal titration calorimetry (ITC) is a powerful classical method that enables researchers in many fields to study the thermodynamics of molecular interactions. Primary ITC data comprise the temporal evolution of differential power reporting the heat of reaction during a series of injections of aliquots of a reactant into a sample cell. By integration of each injection peak, an isotherm can be constructed of total changes in enthalpy as a function of changes in solution composition, which is rich in thermodynamic information on the reaction. However, the signals from the injection peaks are superimposed by the stochastically varying time-course of the instrumental baseline power, limiting the precision of ITC isotherms. Here, we describe a method for automated peak assignment based on peak-shape analysis via singular value decomposition in combination with detailed least-squares modeling of local pre- and postinjection baselines. This approach can effectively filter out contributions of short-term noise and adventitious events in the power trace. This method also provides, for the first time, statistical error estimates for the individual isotherm data points. In turn, this results in improved detection limits for high-affinity or low-enthalpy binding reactions and significantly higher precision of the derived thermodynamic parameters. PMID- 22530734 TI - Dual targeting antibacterial peptide inhibitor of early lipid A biosynthesis. AB - UDP-3-O-(R-3-hydroxyacyl)GlcN N-acyltransferase (LpxD) has been shown to be essential to survival of lipid A producing Gram-negative bacteria. In this study, LpxD-binding peptides 12 amino acids in length were identified from a phage-bound random peptide library screen. Three peptides displayed antibacterial activity when expressed intracellularly, one of which (RJPXD33) represented 15% of the total hits. RJPXD33 binds to E. coli LpxD with a K(d) of 6 MUM and is competitive with R-3-hydroxymyristoyl-ACP binding. RJPXD33 can be C-terminally fused in vivo with thioredoxin or N-terminally modified in vitro with beta-alanyl-fluorescein and maintain LpxD binding. The latter was used to develop an LpxD fluorescent binding assay used to evaluate unlabeled ligands and is amenable to small molecule library screening. Furthermore, RJPXD33 also binds to and inhibits E. coli UDP-N-acetylglucosamine acyltransferase (LpxA) with a K(d) of 20 MUM, unearthing the possibility for the development of small molecule, dual-binding LpxA/LpxD inhibitors as novel antimicrobials. PMID- 22530736 TI - Confusion: acetaminophen dosing changes based on NO evidence in adults. AB - Acetaminophen (paracetamol) plays a vital role in American health care, with in excess of 25 billion doses being used annually as a nonprescription medication. Over 200 million acetaminophen-containing prescriptions, usually in combination with an opioid, are dispensed annually. While acetaminophen is recognized as a safe and effective analgesic and antipyretic, it is also associated with significant morbidity and mortality (hepatotoxicity) if doses in excess of the therapeutic amount are ingested inappropriately. The maximum daily therapeutic dose of 3900-4000 mg was established in separate actions in 1977 and 1988, respectively, via the Food and Drug Administration (FDA) monograph process for nonprescription medications. The FDA has conducted multiple advisory committee meetings to evaluate acetaminophen and its safety profile, and has suggested (but not mandated) a reduction in the maximum daily dosage from 3900-4000 mg to 3000 3250 mg. In 2011, McNeil, the producer of the Tylenol(r) brand of acetaminophen, voluntarily reduced the maximum daily dose of its 500 mg tablet product to 3000 mg/day, and it has pledged to change the labeling of its 325 mg/tablet product to reflect a maximum of 3250 mg/day. Generic manufacturers have not changed their dosing regimens and they have remained consistent with the established monograph dose. Therefore, confusion will be inevitable as both consumers and health care professionals try to determine the proper therapeutic dose of acetaminophen. Which is the correct dose of acetaminophen: 3000 mg if 500 mg tablets are used, 3250 mg with 325 mg tablets, or 3900 mg when 650 mg arthritis-strength products are used? PMID- 22530735 TI - Microscopic rearrangement of bound minor groove binders detected by NMR. AB - Thermodynamic and structural studies are commonly utilized to optimize small molecules for specific DNA interactions, and, thus, a significant amount of binding data is available. However, the dynamic processes that are involved in minor groove complex formation and maintenance are not fully understood. To help define the processes involved, we have conducted 1D and 2D NMR in conjunction with biosensor-SPR experiments with a variety of compounds and symmetric, as well as asymmetric, AT tract DNA sequences. Surprisingly, the NMR data clearly show exchange between equivalent binding sites for strongly binding compounds like netropsin and DB921 (Ka > 10(8) M(-1)) that does not involve dissociation off the DNA. A quantitative analysis of the data revealed that these bound exchange rates are indeed much faster than the macroscopic dissociation rates which were independently determined by biosensor-SPR. Additionally, we could show the existence of at least two 1:1 compound DNA complexes at the same site for the interaction of these compounds with an asymmetric DNA sequence. To explain this behavior we introduced a model in which the ligand is rapidly flipping between two orientations while in close association with the DNA. The ligand reorientation will contribute favorably to the binding entropy. As the potential of minor groove binders to form more than a single complex with asymmetric, as well as symmetric, duplexes is widely unknown, the consequences for binding thermodynamics and compound design are discussed. PMID- 22530737 TI - Antibiotic prophylaxis in the era of multidrug-resistant bacteria. AB - The prophylactic use of antibiotics can only be justified when clinical benefits on relevant patient outcomes, such as morbidity or mortality, cost-effectiveness, and absence of immediate emergence of antibiotic resistance have been unequivocally demonstrated. In some intensive care unit (ICU) patients, antibiotic prophylaxis is used as part of selective digestive tract decontamination (SDD) and selective oropharyngeal decontamination (SOD). Recent trials in ICUs with low levels of antibiotic resistance strongly suggest that both regimens reduce the incidence of ICU-acquired infections and improve patient survival. Naturally, the unique microbial ecology of such settings reduce generalizability of results. Therefore, the routine use of SOD and SDD remains highly controversial, especially in ICUs with higher levels of antibiotic resistance. Moreover, convincing evidence is still missing on several important aspects related to efficacy and safety. Despite numerous trials, effects of SDD and SOD on antibiotic resistance during and after decolonization treatment have still been insufficiently investigated, and existing results are contradicting. Furthermore, the effects of both regimens on the non-culturable part of the intestinal flora remain unknown. Finally, cost-effectiveness has not been thoroughly investigated, and prices of the antimicrobial agents that have been used have increased dramatically in recent years. In this review, important knowledge gaps that so far prevent the widespread use of SDD and SOD will be addressed. PMID- 22530738 TI - A romantic delusion: de Clerambault's syndrome in dementia. AB - Erotromania (also known as de Clerambault's syndrome) is a rare disorder in which an individual has a delusional belief that a person of a socially higher standing falls in love with her/him. It has rarely been described in older people, but many cases have been reported in conjunction with psychiatric and neurological disorders. The purpose of this paper was to examine the phenomenon of erotomania in people with dementia. We carried out a search of electronic databases for literature on this subject. The search terms used were: erotomania, de Clerambault's syndrome, erotomanic delusion and dementia. The literature on erotomania in the course of dementia consists mostly of case reports and small samples of patients. Misinterpretation of events is common in brain disease, especially with diffuse or multifocal disorders, but erotomania has rarely been reported in dementia. The relationship between dementia and de Clerambault's syndrome remains uncertain. Erotic delusion arising late in life should be thoroughly investigated to rule out organicity. PMID- 22530739 TI - Stability, dynamics, and lubrication of MoS2 platelets and nanotubes. AB - A model is introduced to investigate structure, stability, dynamics, and properties of MoS(2). The tribological behavior of the material is obtained from the autocorrelation function, ACF, of the forces, using the Green-Kubo equation, and by the classical Amontons' laws. In the idealized system, i.e. without defects, junctions, vacancies, asperities, and impurities, both models find a superlubrication regime, in agreement with some experiments. In nanotubes, NTs, friction is an order of magnitude lower than in the layered systems. The calculations also show that there is a substantial stabilization, per atom, for the formation of multiwall NTs with at least four walls. PMID- 22530740 TI - Molecular mechanisms linking endometriosis under oxidative stress with ovarian tumorigenesis and therapeutic modalities. AB - Inflammation plays a role in the pathogenesis of endometriosis. Endometriosis associated ovarian carcinogenesis might be promoted through oxidative stress induced increased genomic instability, aberrant methylation, and aberrant chromatin remodeling, as well as mutations of tumor suppressor genes. Aberrant expression of ARID1A, PIK3CA, and NF-kB genes has been recognized as the major target genes involved in oxidative stress-induced carcinogenesis. HNF-1beta appears to play a key role in anti-oxidative defense mechanisms. We discuss the pathophysiologic roles of oxidative stress as somatic mutations as well as highly specific agents that effectively modulate these targets. PMID- 22530741 TI - The oxidative DNA lesions 8,5'-cyclopurines accumulate with aging in a tissue specific manner. AB - Accumulation of DNA damage is implicated in aging. This is supported by the fact that inherited defects in DNA repair can cause accelerated aging of tissues. However, clear-cut evidence for DNA damage accumulation in old age is lacking. Numerous studies report measurement of DNA damage in nuclear and mitochondrial DNA from tissues of young and old organisms, with variable outcomes. Variability results from genetic differences between specimens or the instability of some DNA lesions. To control these variables and test the hypothesis that elderly organisms have more oxidative DNA damage than young organisms, we measured 8,5' cyclopurine-2'-deoxynucleosides (cPu), which are relatively stable, in tissues of young and old wild-type and congenic progeroid mice. We found that cPu accumulate spontaneously in the nuclear DNA of wild-type mice with age and to a greater extent in DNA repair-deficient progeroid mice, with a similar tissue-specific pattern (liver > kidney > brain). These data, generated under conditions where genetic and environmental variables are controlled, provide strong evidence that DNA repair mechanisms are inadequate to clear endogenous lesions over the lifespan of mammals. The similar, although exaggerated, results obtained from progeroid, DNA repair-deficient mice and old normal mice support the conclusion that DNA damage accumulates with, and likely contributes to, aging. PMID- 22530742 TI - Statin use is associated with a reduced incidence of colorectal cancer: a colonoscopy-controlled case-control study. AB - BACKGROUND: The aetiology of colorectal cancer (CRC) remains elusive in the majority of cases. There is experimental evidence to show that HMG-CoA reductase inhibitors (statins) may inhibit proliferation and induce cause apoptosis in CRC cells and although some clinical studies have suggested that statins may protect against the development of CRC, this has not been a consistent finding. Therefore we have examined any potential protective effects of statins by comparing statin use in patients with colorectal cancer against a control group. METHODS: This was a case-control study examining statin use in symptomatic patients attending for diagnostic colonoscopy. Statin use was compared between patients with CRC and a control group, who had all had normal colonoscopy. Structured interviews and clinical records notes were used to determine drug exposure. Logistic regression was used to compare statin exposure and correct for confounding factors. RESULTS: There was a significant inverse association between previous statin use and a diagnosis of CRC (OR = 0.43 (95% confidence interval 0.25 - 0.80), p<0.01). This inverse association was stronger with higher statin doses (OR = 0.19 (0.07 - 0.47), p<0.01) and greater duration of statin use (statin use >years: OR = 0.18 (0.06 - 0.55), p<0.01). CONCLUSIONS: Statins use was associated with a protective effect against the development of CRC. This effect is associated with a significant dose and duration response. These findings need to be repeated in other observational studies before an interventional study can be considered. PMID- 22530744 TI - Toxin-producing Ostreopsis cf. ovata are likely to bloom undetected along coastal areas. AB - Mass appearances of the toxic dinoflagellate genus Ostreopsis are known to cause dangerous respiratory symptoms in humans exposed to aerosols. The outbreaks can appear in shallow marine waters of temperate regions around the globe. We followed a massive bloom event on a public beach on the northern Adriatic coast near Rovinj, Croatia. We identified the responsible species and the produced toxins as well as the dynamics of the event with respect to environmental conditions. Ostreopsis cf. ovata appeared in masses from September through October 2010 on a public beach near Rovinj, Croatia but stayed undetected by public health organizations. Respiratory symptoms were observed whenever humans were exposed to substrate samples containing large numbers of Ostreopsis cells. During the mass abundance of O. cf. ovata also exposure to the aerosols on the beach evoked respiratory symptoms in humans. Our measurements showed high cell abundances and high toxin contents with a stable relative contribution of putative Palytoxin and Ovatoxins a-e. Artificial beach structures proved to dramatically reduce settling of the observed Ostreopsis biofilm. Blooms like those reported herein have a high potential to happen undetected with a high potential of affecting the health of coastal human populations. Increased monitoring efforts are therefore required to understand the ecology and toxicology of those bloom events and reduce their negative impact on coastal populations. PMID- 22530745 TI - ToF-SIMS depth profiling of cells: z-correction, 3D imaging, and sputter rate of individual NIH/3T3 fibroblasts. AB - Proper display of three-dimensional time-of-flight secondary ion mass spectrometry (ToF-SIMS) imaging data of complex, nonflat samples requires a correction of the data in the z-direction. Inaccuracies in displaying three dimensional ToF-SIMS data arise from projecting data from a nonflat surface onto a 2D image plane, as well as possible variations in the sputter rate of the sample being probed. The current study builds on previous studies by creating software written in Matlab, the ZCorrectorGUI (available at http://mvsa.nb.uw.edu/), to apply the z-correction to entire 3D data sets. Three dimensional image data sets were acquired from NIH/3T3 fibroblasts by collecting ToF-SIMS images, using a dual beam approach (25 keV Bi(3)(+) for analysis cycles and 20 keV C(60)(2+) for sputter cycles). The entire data cube was then corrected by using the new ZCorrectorGUI software, producing accurate chemical information from single cells in 3D. For the first time, a three-dimensional corrected view of a lipid-rich subcellular region, possibly the nuclear membrane, is presented. Additionally, the key assumption of a constant sputter rate throughout the data acquisition was tested by using ToF-SIMS and atomic force microscopy (AFM) analysis of the same cells. For the dried NIH/3T3 fibroblasts examined in this study, the sputter rate was found to not change appreciably in x, y, or z, and the cellular material was sputtered at a rate of approximately 10 nm per 1.25 * 10(13) ions C(60)(2+)/cm(2). PMID- 22530747 TI - Isotopic effects on the dynamics of the CH3(+) + H2 -> CH5(+) -> CH3(+) + H2 reaction. AB - Diffusion Monte Carlo is used to investigate the anharmonic zero-point energy corrected energies for the CH(3)(+) + H(2)-> CH(5)(+) -> CH(3)(+) + H(2) process as a function of the center of mass separation of the two fragments. In addition to the title reaction, all possible deuterated and several tritiated (CH(4)T(+) and CH(3)T(2)(+)) analogues of this reaction are investigated. As anticipated, the replacement of one or more of the hydrogen atoms with deuterium or tritium atoms lowers the zero-point energy of the system. Further, in the partially deuterated or tritiated isotopologues, the lowest energy configuration generally has the heavy atoms in the CH(3)(+) fragment. Analysis of the wave functions allows us to study how zero-point energy influences the approach geometries sampled during low-energy collisions between CH(3)(+) and H(2), and to gain insights into how the dynamics is affected by the substitution of heavier isotopes for one or more of the hydrogen atoms. Differences between quantum and classical descriptions of the title reaction are also discussed. PMID- 22530746 TI - Bone-to-implant contact after maxillary sinus floor augmentation with Bio-Oss and autogenous bone in different ratios in mini pigs. AB - OBJECTIVES: The objective was to test the hypotheses: (i) no differences in bone to-implant contact formation, and (ii) no differences between the use of autogenous mandibular or iliac bone grafts, when autogenous bone, Bio-Oss mixed with autogenous bone, or Bio-Oss is used as graft for the maxillary sinus floor augmentation. MATERIAL AND METHODS: Bilateral sinus floor augmentation was performed in 40 mini pigs with: (A) 100% autogenous bone, (B) 75% autogenous bone and 25% Bio-Oss, (C) 50% autogenous bone and 50% Bio-Oss, (D) 25% autogenous bone and 75% Bio-Oss, or (E) 100% Bio-Oss. Autogenous bone was harvested from the iliac crest or the mandible and the graft composition was selected at random and placed concomitant with the implant placement. The animals were euthanized 12 weeks after surgery. Bone-to-implant contact was estimated by stereological methods and summarized as median percentage with 95% confidence interval (CI). Bone-to-implant contact formation was evaluated by fluorochrome labelling and assessed by median odds ratios (OR) with 95% (CI). RESULTS: Median bone-to implant contact was: (A) 42.9% (95% CI: 32.1-54.5%), (B) 37.8% (95% CI: 27.1 49.9%), (C) 43.9% (95% CI: 32.6-55.9%), (D) 30.2% (95% CI: 21.6-40.3%), and (E) 13.9% (95% CI: 11.4-16.9%). Bone-to-implant contact was significantly higher for A, B, C, D as compared to E (P < 0.0001). Bone-to-implant contact was not significantly influenced by the ratio of Bio-Oss and autogenous bone (P = 0.19) or the origin of the autogenous bone (P = 0.72). Fluorochrome labelling revealed extensive variation in bone-to-implant contact formation over time. The labelling at weeks 2-3 was significantly increased with A compared to E (OR = 8.1 CI: 5.0 13.1, P < 0.0001), whereas E showed a significantly increased labelling at weeks 8-9 compared to A (OR = 0.5 CI: 0.3-0.7, P = 0.0028). CONCLUSIONS: The hypothesis of no differences in bone-to-implant contact between the various treatment modalities was rejected since the bone-to-implant contact was significantly increased with autogenous bone or Bio-Oss mixed with autogenous bone as compared to Bio-Oss. Early bone-to-implant contact formation was more advanced with autogenous bone. No differences between the use of mandibular or iliac bone grafts were observed since the bone-to-implant contact was not significantly influenced by the origin of the bone graft. PMID- 22530743 TI - Targeted gene therapies: tools, applications, optimization. AB - Many devastating human diseases are caused by mutations in a single gene that prevent a somatic cell from carrying out its essential functions, or by genetic changes acquired as a result of infectious disease or in the course of cell transformation. Targeted gene therapies have emerged as potential strategies for treatment of such diseases. These therapies depend upon rare-cutting endonucleases to cleave at specific sites in or near disease genes. Targeted gene correction provides a template for homology-directed repair, enabling the cell's own repair pathways to erase the mutation and replace it with the correct sequence. Targeted gene disruption ablates the disease gene, disabling its function. Gene targeting can also promote other kinds of genome engineering, including mutation, insertion, or gene deletion. Targeted gene therapies present significant advantages compared to approaches to gene therapy that depend upon delivery of stably expressing transgenes. Recent progress has been fueled by advances in nuclease discovery and design, and by new strategies that maximize efficiency of targeting and minimize off-target damage. Future progress will build on deeper mechanistic understanding of critical factors and pathways. PMID- 22530748 TI - A comparison of time-motion performance between age groups in judo matches. AB - The aim of this study was to compare time-motion indicators during judo matches performed by athletes from different age groups. The following age groups were analysed: Pre-Juvenile (13-14 years, n = 522), Juvenile (15-16 years, n = 353); Junior (19 years, n = 349) and Senior (>20 years, n = 587). The time-motion indicators included: Total Combat Time, Standing Combat Time, Displacement Without Contact, Gripping Time, Groundwork Combat Time and Pause Time. Analysis of variance (ANOVA) one-way and the Tukey test, as well as the Kruskal-Wallis test and Mann-Whitney (for non-parametric data), were conducted, using P < 0.05 as significance level. The results showed that all analysed groups obtained a median of 7 (first quantile - 3, third quantile - 12) sequences of combat/pause cycles. In total time of combat, the result was: for Total Combat Time, Standing Combat Time and Gripping Time: Pre-Juvenile and Senior were significantly longer than Juvenile and Junior. Considering Displacement Without Contact, Junior was significantly longer than all other age groups. For Groundwork Combat Time, Senior was significantly longer than all other age groups and Pre-Juvenile was longer than Junior. These results can be used to improve the physiological performance in intermittent practices, as well as technical-tactical training during judo sessions. PMID- 22530750 TI - Knowledge of local anesthetic use among dermatologists. AB - BACKGROUND: Local anesthesia is widely used in general dermatology practices. The onus is on the practitioner to have a sound knowledge of the pharmacology and dosing of any drug used, including local anesthesia. The dermatologist should also be aware of the signs, symptoms, and management of toxicity of local anesthetic use. The level of knowledge of dermatologists on this topic has not been previously assessed. OBJECTIVE: To assess levels of knowledge of local anesthetic pharmacology, local anesthetic systemic toxicity (LAST), and the management of the latter of dermatologists. METHODS: A survey designed to test knowledge of absolute dosing limits; calculation of patient-specific dosing using clinical vignettes; and awareness of the signs, symptoms, and management of LAST was distributed electronically to the membership of three professional dermatological organizations in the United Kingdom and Ireland, including one specialist dermatologic surgery group. RESULTS: Knowledge of local anesthetic use of dermatologists was comprehensive enough to practice safely, without necessarily being entirely accurate. Awareness of the signs and symptoms of local anesthetic toxicity was good, but awareness of the specific agent now recommended for the management of LAST in official guidelines was poor. CONCLUSIONS: Knowledge of local anesthetic dosing and toxicity is reasonable among dermatologists. Awareness of the guidelines for management of LAST, released by the American and Great Britain and Ireland associations of anesthetists, and in particular the use of lipid emulsion in this setting, could be improved. PMID- 22530749 TI - Management of patients with drug-induced atrioventricular block. AB - OBJECTIVE: To identify the frequency of atrioventricular (AV) conduction improvement after discontinuation of the culprit drug in patients with AV block. BACKGROUND: AV blockers are considered as reversible causes of AV block that do not require pacemaker (PM) implantation. However, controversial reports declared that a major part of these drug-induced AV blocks are persistent or recurrent. METHODS: Of 668 consecutive patients with symptomatic type II second- or third degree AV block, 2:1 AV block, atrial fibrillation, and bradyarrhythmia, 108 patients (62 patients enrolled prospectively) using AV blockers without myocardial infarction, electrolyte abnormalities, digitalis toxicity, and vasovagal syncope were enrolled into the present study. The level of AV block (AV nodal or infranodal) was defined according to electrocardiographic characteristics. RESULTS: The most frequent culprit medications were beta blockers followed by digoxin. Drug discontinuation was followed by resolution of AV block in 72% of cases, whereas spontaneous resolution of AV block occurred in only 6.6% of patients who had AV block in the absence of medications. However, 27% of patients with improved AV conduction experienced a recurrence of AV block despite discontinuation of the culprit drug. Twenty-one of 24 carvedilol-induced AV blocks resolved after discontinuation of the drug and never recurred, whereas 24 of 36 metoprolol-induced AV blocks persisted or recurred. A digoxin-induced AV block usually improved (28 of 39) after withdrawal of the drug. Roughly half of the patients with drug-induced AV block underwent permanent PM implantation. CONCLUSION: Drug-induced AV block is a serious disease that requires a permanent PM for almost half of the patients. PMID- 22530751 TI - Anomalous origin of coronary arteries: when one sinus fits all. AB - A right coronary artery origin from the left coronary sinus and a left coronary origin from the right sinus although rarely encountered during routine cardiac catheterization, they represent two relatively common autopsy findings in young patients suffering sudden cardiac death. The interarterial course of the aberrant artery, between the aortic root and the pulmonary artery has been considered as a malignant variant, because of the higher risk of myocardial ischemia and sudden death. We present two rare cases of ectopic coronary origin from the opposite sinus of Valsalva. PMID- 22530752 TI - Shape-programmed folding of stimuli-responsive polymer bilayers. AB - We investigated the folding of rectangular stimuli-responsive hydrogel-based polymer bilayers with different aspect ratios and relative thicknesses placed on a substrate. It was found that long-side rolling dominates at high aspect ratios (ratio of length to width) when the width is comparable to the circumference of the formed tubes, which corresponds to a small actuation strain. Rolling from all sides occurs for higher actuation, namely when the width and length considerably exceed the deformed circumference. In the case of moderate actuation, when both the width and length are comparable to the deformed circumference, diagonal rolling is observed. Short-side rolling was observed very rarely and in combination with diagonal rolling. On the basis of experimental observations, finite-element modeling and energetic considerations, we argued that bilayers placed on a substrate start to roll from corners due to quicker diffusion of water. Rolling from the long-side starts later but dominates at high aspect ratios, in agreement with energetic considerations. We have shown experimentally and by modeling that the main reasons causing a variety of rolling scenarios are (i) non-homogenous swelling due to the presence of the substrate and (ii) adhesion of the polymer to the substrate. PMID- 22530753 TI - Chronic cerebrospinal venous insufficiency and venous stenoses in multiple sclerosis. AB - OBJECTIVES: The traditional view that multiple sclerosis (MS) is an autoimmune disease has recently been challenged by the claim that MS is caused by chronic cerebrospinal venous insufficiency (CCSVI). Although several studies have questioned this vascular theory, the CCSVI controversy is still ongoing. Our aim was to assess the prevalence of CCSVI in Danish MS patients using sonography and compare these findings with MRI measures of venous flow and morphology. METHODS: We investigated cervical and cerebral veins in 24 patients with relapsing remitting MS (RRMS) and 15 healthy controls, using extracranial high-resolution ultrasound colour Doppler (US-CD) and transcranial colour Doppler sonography (TCDS), as well as magnetic resonance imaging (MRI) and phase-contrast MR blood flow measurements (PC-MR) of the cervical veins. RESULTS: US-CD could not identify the left internal jugular vein (IJV) in one MS patient, other ultrasound examinations were normal in patients with MS. There was no difference in mean cross-sectional area of the IJV in MS patients compared with controls. Only one patient with MS and two healthy controls fulfilled one CCSVI criterion, and none fulfilled more than one CCSVI criterion. MR venography showed insignificant IJV stenosis (1-49%) in two patients with MS, whereas 50-69% IJV stenosis was detected in two healthy controls. There was no difference in PC-MR measurements of mean IJV blood flow between patients with MS and controls. CONCLUSION: Our results do not corroborate the presence of vascular pathology in RRMS and we found no evidence supporting the CCSVI hypothesis. PMID- 22530754 TI - Effect of bisecting GlcNAc and core fucosylation on conformational properties of biantennary complex-type N-glycans in solution. AB - The introduction of bisecting GlcNAc and core fucosylation in N-glycans is essential for fine functional regulation of glycoproteins. In this paper, the effect of these modifications on the conformational properties of N-glycans is examined at the atomic level by performing replica-exchange molecular dynamics (REMD) simulations. We simulate four biantennary complex-type N-glycans, namely, unmodified, two single-substituted with either bisecting GlcNAc or core fucose, and disubstituted forms. By using REMD as an enhanced sampling technique, five distinct conformers in solution, each of which is characterized by its local orientation of the Manalpha1-6Man glycosidic linkage, are observed for all four N glycans. The chemical modifications significantly change their conformational equilibria. The number of major conformers is reduced from five to two and from five to four upon the introduction of bisecting GlcNAc and core fucosylation, respectively. The population change is attributed to specific inter-residue hydrogen bonds, including water-mediated ones. The experimental NMR data, including nuclear Overhauser enhancement and scalar J-coupling constants, are well reproduced taking the multiple conformers into account. Our structural model supports the concept of "conformer selection", which emphasizes the conformational flexibility of N-glycans in protein-glycan interactions. PMID- 22530755 TI - The interplay among preschool child and family factors and the development of ODD symptoms. AB - The present study examined (a) the interactions between early behavior, early parenting, and early family adversity in predicting later oppositional defiant disorder (ODD) symptoms, and (b) the reciprocal relations between parent functioning and ODD symptoms across the preschool years. Participants were 258 three-year-old children (138 boys, 120 girls) and their parents from diverse backgrounds who participated in a 4-year longitudinal study. Early child behavior, parenting, and family adversity did not significantly interact in the predicted direction. Reciprocal relations between ODD symptoms and parent functioning were observed for maternal and paternal depression, and maternal warmth. Paternal laxness at age 4 predicted ODD symptoms at age 5 and paternal laxness at age 5 predicted ODD symptoms at age 6, but child ODD did not significantly predict paternal laxness. Results suggest that ODD symptoms may develop through a transactional process between parent and child functioning across the preschool years. PMID- 22530756 TI - Obesity is associated with an improved cancer-specific survival, but an increased rate of postoperative complications after surgery for renal cell carcinoma. AB - OBJECTIVE: This study aimed to assess the impact of preoperative body mass index (BMI) on postoperative complications, cancer-specific survival (CSS) and overall survival (OS) in patients operated for renal cell carcinoma (RCC). MATERIAL AND METHODS: The study included 397 patients with BMI values, who underwent surgery for RCC between 1 January 1997 and 31 December 2010. Obese patients (BMI > 30 kg/m(2)) were compared to non-obese patients (BMI < 30 kg/m(2)) in regard to CSS and OS. A Cox proportional hazard model was used for the multivariate survival analyses. The mean age of the patients was 62.1 years. There were 259 males (65%) and 325 patients (82%) were non-obese. Mean BMI was 26 kg/m(2). RESULTS: In the total material, CSS was 94.7% for obese patients and 74.8% for non-obese patients (p = 0.06). The obese group had significantly better CSS in univariate analysis for presumed radically treated disease (pT1-3N0M0). Obesity was a significant protective prognostic factor in multivariate analysis. An accelerating protective effect for CSS was found with increasing levels of BMI. In regard to OS, no difference was found between the two groups. Obese patients had a significantly lower age, and a higher rate of diabetes mellitus, hypertension and incidental detection. Obese patients had a significantly higher total incidence of postoperative complications, but not surgery-related complications. CONCLUSIONS: In this material, increasing BMI was associated with improved CSS for presumed radically treated patients. However, obese patients had a higher total rate of postoperative complications. PMID- 22530757 TI - The periodontium of periodontitis patients contains citrullinated proteins which may play a role in ACPA (anti-citrullinated protein antibody) formation. AB - AIM: To determine the presence and location (stroma versus epithelium) of citrullinated proteins in periodontitis tissue as compared to non-periodontitis tissue and synovial tissue of RA patients. MATERIALS & METHODS: Periodontitis, healthy periodontal and RA-affected synovial tissue samples were collected in addition to buccal swabs. These samples were stained for the presence of citrullinated proteins using polyclonal (Ab5612) and monoclonal (F95) antibodies. Furthermore, Western blotting with F95 was performed on lysates prepared from periodontal and synovial tissues. RESULTS: In periodontitis stroma, increased citrullinated protein presence (80%) was observed compared with control stroma (33%), the latter was associated with inflammation of non-periodontitis origin. Periodontal epithelium always stained positive for Ab5612. Noteworthy, only periodontitis-affected epithelium stained positive for F95. All buccal mucosal swabs and 3 of 4 synovial tissue samples stained positive for both Ab5612 and F95. Western blotting with F95 showed presence of similar citrullinated proteins in both periodontitis and RA-affected synovial tissue. CONCLUSION: Within the periodontal stroma, citrullination is an inflammation-depended process. In periodontal epithelium, citrullination is a physiological process. Additional citrullinated proteins are formed in periodontitis, apparently similar to those formed in RA-affected synovial tissue. Periodontitis induced citrullination may play a role in the aetiology of rheumatoid arthritis. PMID- 22530758 TI - New therapeutic approaches to subarachnoid hemorrhage. AB - INTRODUCTION: Subarachnoid hemorrhage (SAH) is associated with significant morbidity and mortality, even for patients who receive early neurointerventionist management. AREAS COVERED: Early mechanisms of secondary brain injury precede the delayed vasospasm phase and contribute to the poor outcome. These mechanisms and their intervention are discussed, including high intracranial pressure (ICP), low cerebral perfusion pressure (CPP), acute vasospasm, disturbed cerebral autoregulation, cerebral edema, oxidative stress, seizures, microvascular damage and hyperglycemia. Erythropoietin, statins and magnesium have been particularly promising in experimental studies. EXPERT OPINION: Multiple mechanisms, including delayed vasospasm, may contribute to cerebral ischemia and poor outcome following SAH. Treatments that simultaneously target multiple secondary injury pathways show significant potential as therapeutic agents, particularly those that attenuate vasospasm in addition to having other neuroprotective properties. PMID- 22530760 TI - HORMAD1-dependent checkpoint/surveillance mechanism eliminates asynaptic oocytes. AB - Meiotic pachytene checkpoints monitor the failure of homologous recombination and synapsis to ensure faithful chromosome segregation during gamete formation. To date, the molecular basis of the mammalian pachytene checkpoints has remained largely unknown. We here report that mouse HORMAD1 is required for a meiotic prophase checkpoint that eliminates asynaptic oocytes. Hormad1-deficient mice are infertile and show an extensive failure of homologous pairing and synapsis, consistent with the evolutionarily conserved function of meiotic HORMA domain proteins. Unexpectedly, Hormad1-deficient ovaries contain a normal number of oocytes despite asynapsis and consequently produce aneuploid oocytes, indicating a checkpoint failure. By the analysis of Hormad1/Spo11 double mutants, the Hormad1 deficiency was found to abrogate the massive oocyte loss in the Spo11 deficient ovary. The Hormad1 deficiency also causes the eventual loss of pseudo sex body in the Spo11-deficient ovary and testis. These results suggest the involvement of HORMAD1 in the repressive chromatin domain formation that is proposed to be important in the meiotic prophase checkpoints. We also show the extensive phosphorylation of HORMAD1 in the Spo11-deficient testis and ovary, suggesting an involvement of novel DNA damage-independent phosphorylation signaling in the surveillance mechanism. Our present results provide clues to HORMAD1-dependent checkpoint in response to asynapsis in mammalian meiosis. PMID- 22530761 TI - Sarcopenia in the elderly: basic and clinical issues. AB - The original definition of sarcopenia refers to the age-related loss of muscle mass. The literature suggests that the prevalence of sarcopenia in 60- to 70-year olds is in the range of 5-13%. Prevalence estimates increase to 11-50% for the population aged 80 years or older. Estimates by the World Health Organization suggest that there were 600 million people aged 60 years or older in the year 2000, and that this number will increase to 1.2 billion by the year 2025. There are, however, limited published data on serial measures of muscle mass in older subjects to establish the age-related changes in muscle mass and to relate this change with adverse health consequences. This review is focused on the definition, prevalence, symptoms, pharmacy and physical therapy of sarcopenia in older subjects with the aim of promoting the recognition and treatment of age related sarcopenia in the clinical setting. PMID- 22530762 TI - Are we still evolving? PMID- 22530759 TI - Identification of drug modulators targeting gene-dosage disease CMT1A. AB - The structural integrity of myelin formed by Schwann cells in the peripheral nervous system (PNS) is required for proper nerve conduction and is dependent on adequate expression of myelin genes including peripheral myelin protein 22 (PMP22). Consequently, excess PMP22 resulting from its genetic duplication and overexpression has been directly associated with the peripheral neuropathy called Charcot-Marie-Tooth disease type 1A (CMT1A), the most prevalent type of CMT. Here, in an attempt to identify transcriptional inhibitors with therapeutic value toward CMT1A, we developed a cross-validating pair of orthogonal reporter assays, firefly luciferase (FLuc) and beta-lactamase (betaLac), capable of recapitulating PMP22 expression, utilizing the intronic regulatory element of the human PMP22 gene. Each compound from a collection of approximately 3,000 approved drugs was tested at multiple titration points to achieve a pharmacological end point in a 1536-well plate quantitative high-throughput screen (qHTS) format. In conjunction with an independent counter-screen for cytotoxicity, the design of our orthogonal screen platform effectively contributed to selection and prioritization of active compounds, among which three drugs (fenretinide, olvanil, and bortezomib) exhibited marked reduction of endogenous Pmp22 mRNA and protein. Overall, the findings of this study provide a strategic approach to assay development for gene dosage diseases such as CMT1A. PMID- 22530763 TI - Supraventricular tachycardia as a presenting feature of volvulus in a 15-month old boy. AB - A 15-month-old boy presented in shock with a supraventricular tachycardia following a 12-h history of worsening abdominal pain and vomiting. The supraventricular tachycardia reverted to sinus tachycardia with fluid resuscitation and adenosine. He was noted to have a distended and firm abdomen. A presumptive diagnosis of intestinal ischaemia was subsequently confirmed at laparotomy when an internal hernia with a distal small bowel volvulus and necrosis was found. Intestinal ischaemia presenting with a life-threatening cardiac dysrhythmia in a child appears not to have been reported previously. PMID- 22530764 TI - Arachnoid cyst and costovertebral defects in Aicardi syndrome. PMID- 22530765 TI - 'Childhood drowning in low- and middle-income countries: urgent need for intervention trials'. PMID- 22530766 TI - Caecal volvulus in cornelia de Lange syndrome: is its' prevention possible? PMID- 22530767 TI - Atypical onset of multiple sclerosis in an adolescent with monosymptomatic chronic tension-type headache. PMID- 22530769 TI - Assessment of multiple sustainability demands for wastewater treatment alternatives: a refined evaluation scheme and case study. AB - Current estimation schemes as decision support tools for the selection of wastewater treatment alternatives focus primarily on the treatment efficiency, effluent quality, and environmental consequences for receiving water bodies. However, these schemes generally do not quantify the potential to convert pollutants in wastewater to recoverable resources. This study proposes a refined evaluation scheme for choices of wastewater treatment processes that quantifies not only adverse environmental effects but also bioenergy and nutrient recovery indices. An original means of data processing was established and clear estimate indicators were consequently obtained to allow a smooth overall estimation. An array of wastewater treatment alternatives that meet three effluent limits were used as case studies to demonstrate how the present scheme works, simultaneously, to identify optimum choices. It is concluded in the overall estimation that the lower sustainability of wastewater treatment contributed by increasingly stringent discharge demands was offset and mitigated by the resource-recovery scenarios involved, and the scenario of recovering nutrients via excess-sludge composting was of more benefit. Thus, before tightening wastewater discharge requirements, one should bear in mind the situation of multiple sustainability by setting a goal to achieve not only the greatest reduction in environmental burden but also the maximum resource-recovery benefits. PMID- 22530768 TI - Inability of NS1 protein from an H5N1 influenza virus to activate PI3K/Akt signaling pathway correlates to the enhanced virus replication upon PI3K inhibition. AB - BACKGROUND: Phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, activated during influenza A virus infection, can promote viral replication via multiple mechanisms. Direct binding of NS1 protein to p85beta subunit of PI3K is required for activation of PI3K/Akt signaling. Binding and subsequent activation of PI3K is believed to be a conserved character of influenza A virus NS1 protein. Sequence variation of NS1 proteins in different influenza A viruses led us to investigate possible deviation from the conservativeness. RESULTS: In the present study, NS1 proteins from four different influenza A virus subtypes/strains were tested for their ability to bind p85beta subunit of PI3K and to activate PI3K/Akt. All NS1 proteins efficiently bound to p85beta and activated PI3K/Akt, with the exception of NS1 protein from an H5N1 virus (A/Chicken/Guangdong/1/05, abbreviated as GD05), which bound to p85beta but failed to activate PI3K/Akt, implying that as-yet-unidentified domain(s) in NS1 may alternatively mediate the activation of PI3K. Moreover, PI3K inhibitor, LY294002, did not suppress but significantly increased the replication of GD05 virus. CONCLUSIONS: Our study indicates that activation of PI3K/Akt by NS1 protein is not highly conserved among influenza A viruses and inhibition of the PI3K/Akt pathway as an anti influenza strategy may not work for all influenza A viruses. PMID- 22530770 TI - Resistive-pulse detection of multilamellar liposomes. AB - The resistive-pulse method was used to monitor the pressure-driven translocation of multilamellar liposomes with radii between 190 and 450 nm through a single conical nanopore embedded in a glass membrane. Liposomes (0% and 5% 1,2-dioleoyl sn-glycero-3-phospho-l-serine (sodium salt) in 1,2-dilauroyl-sn-glycero-3 phosphocholine or 0%, 5%, and 9% 1,2-dipalmitoyl-sn-glycero-3-phospho(1'-rac glycerol) (sodium salt) in 1,2-dipalmitoyl-sn-glycero-3-phosphocholine) were prepared by extrusion through a polycarbonate membrane. Liposome translocation through a glass nanopore was studied as a function of nanopore size and the temperature relative to the lipid bilayer transition temperature, T(c). All translocation events through pores larger than the liposome, regardless of temperature, show translocation times between 30 and 300 MUs and current pulse heights between 0.2% and 15% from the open pore baseline. However, liposomes at temperatures below the T(c) were captured at the pore orifice when translocation was attempted through pores of smaller dimensions, but squeezed through the same pores when the temperature was raised above T(c). The results provide insights into the deformation and translocation of individual liposomes through a porous material. PMID- 22530771 TI - Peri-implantitis susceptibility as it relates to periodontal therapy and supportive care. AB - OBJECTIVE: To assess the long-term survival of implants inserted in periodontally susceptible patients and to investigate the influence of residual pockets on the incidence of peri-implantitis and implant loss. MATERIALS AND METHODS: For 70 patients, comprehensive periodontal treatment was followed by installation of 165 Straumann Dental implants. Subsequently, 58 patients entered a University supportive periodontal therapy (SPT) program and 12 had SPT in a private practice. The follow-up time ranged from 3 to 23 years (mean 7.9 years). Bleeding on probing (BOP), clinical attachment level (CAL), and peri-implant probing depths (PPD) were evaluated at baseline (T0), completion of active treatment (T1), and at follow-up (T2). Peri-implant bone levels were assessed on radiographs at T2. Patients were categorized as having implants not affected by peri-implantitis (non-PIP), or affected by peri-implantitis (PIP). RESULTS: From 165 implants inserted, six implants were lost, translating into a cumulative survival rate of 95.8%. Solid screw implants yielded significantly higher survival rates than the hollow cylinder and hollow screw implants (99.1% vs. 89.7%). Implants lost due to peri-implant infection were included in the PIP groups. When peri-implantitis (PPD >= 5 mm, BOP+) was analyzed, 22.2% of the implants and 38.6% of patients had one or more implants affected by peri implantitis. Using the peri-implantitis definition (PPD >= 6 mm, BOP+), the prevalence was reduced to 8.8% and 17.1%, respectively. Moreover, all these implants demonstrated significant (>= 2 mm) bone loss at T2. At T1, the non-PIP group had significantly (P = 0.011) fewer residual pockets (>= 5 mm) per patient than the PIP group (1.9 vs. 4.1). At T2, the PIP group displayed an increased number of residual pockets compared to T1, whereas in the non-PIP group, the number remained similar to T1. At T2, mean PPD, mean CAL and BOP were significantly higher in the PIP group compared with the non-PIP group. The prevalence of peri-implantitis was lower in the group that was in a well organized SPT at the University. CONCLUSIONS: In periodontitis susceptible patients, residual pockets (PPD >= 5 mm) at the end of active periodontal therapy represent a significant risk for the development of peri-implantitis and implant loss. Moreover, patients in SPT developing re-infections are at greater risk for peri-implantitis and implant loss than periodontally stable patients. PMID- 22530772 TI - IL-33 and HMGB1 alarmins: sensors of cellular death and their involvement in liver pathology. AB - 'Alarmins' are a group of proteins or molecules that are released from cells during cellular demise to alert the host immune system. Two of them, Interleukin 33 (IL-33) and high-mobility group box-1 (HMGB1), share many similarities of cellular localization, functions and involvement in various inflammatory pathologies including hepatitis. The expressions of IL-33 and HMGB1, and their receptors ST2 and receptor for advanced glycation end products (RAGE), are substantially up-regulated during acute and chronic hepatitis. Recent data evidence a possible protective role of IL-33/ST2 axis during liver injury. A contrast in expression of IL-33 and HMGB1 alarmins were associated with type of hepatocellular death mediated by immune cells or hepato-toxic agents. The massive release of active form of IL-33 from hepatocytes may affect the recruitment and activation of its ST2-positive target immune cells in the liver to confer its alarmin functions. This review highlights the emerging roles of alarmin proteins in various liver pathologies, by focusing on classical HMGB1 and a newly discovered alarmin, the IL-33. PMID- 22530773 TI - Effectiveness of CO2-insufflated endoscopic submucosal dissection with the duodenal balloon occlusion method for early esophageal or gastric cancer: a randomized case control prospective study. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) has typically been performed using air insufflation. Recently, however, insufflation of CO2 has been increasingly used to avoid complications. This prospective study was designed to compare the CO2 concentration, intestinal volume, and acid-base balance using the duodenal balloon procedure. METHODS: From June 2010 to February 2011, we enrolled 44 patients with esophageal or gastric cancer and randomly allocated them into two groups. We compared 22 patients undergoing CO2-insufflated ESD with a balloon placed into the duodenal bulb (duodenal balloon group) and 22 patients undergoing regular CO2-insufflated ESD (regular group). Three-dimensional computed tomography was performed before and after the procedure to measure intestinal volume. CO2 concentrations were measured every 10 minutes. The visual analogue system (VAS) scores for postoperative symptoms were recorded, and pH was measured immediately after the procedure. This was a prospective case control study randomized by the sealed envelope method. RESULTS: Intestinal CO2 gas volume before and after ESD was lower in the duodenal balloon group than in the regular group (P = 0.00027). The end-tidal CO2 level was significantly lower in the duodenal balloon group than in the regular group (P = 0.0001). No significant differences in blood DeltapH were found between the two groups. The VAS score for the occurrence of nausea due to abdominal distension after ESD indicated a significant difference (P = 0.031). CONCLUSIONS: ESD using the duodenal balloon occlusion method is effective for reduction of post-ESD intestinal CO2 gas volume, resulting in a lower total amount of CO2 insufflation during ESD and reducing harmful influences on the human body to some extent. PMID- 22530774 TI - Recombinant lectins: an array of tailor-made glycan-interaction biosynthetic tools. AB - Lectins are a heterogeneous group of proteins found in plants, animals and microorganisms, which possess at least one non-catalytic domain that binds reversibly to specific mono- or oligosaccharides. The range of lectins and respective biological activities is unsurprising given the immense diversity and complexity of glycan structures and the multiple modes of interaction with proteins. Recombinant DNA technology has been traditionally used for cloning and characterizing newly discovered lectins. It has also been employed as a means of producing pure and sequence-defined lectins for different biotechnological applications. This review focuses on the production of recombinant lectins in heterologous organisms, and highlighting the Escherichia coli and Pichia pastoris expression systems, which are the most employed. The choice of expression host depends on the lectin. Non-glycosylated recombinant lectins are produced in E. coli and post-translational modified recombinant lectins are produced in eukaryotic organisms, namely P. pastoris and non-microbial hosts such as mammalian cells. Emphasis is given to the applications of the recombinant lectins especially (a) in cancer diagnosis and/or therapeutics, (b) as anti-microbial, anti-viral, and anti-insect molecules or (c) in microarrays for glycome profiling. Most reported applications are from recombinant plant lectins. These applications benefit from the tailor-made design associated with recombinant production and will aid in unraveling the complex biological mechanisms of glycan interactions, bringing recombinant lectins to the forefront of glycobiology. In conclusion, recombinant lectins are developing into valuable biosynthetic tools for biomedical research. PMID- 22530775 TI - A family of carbon-based nanocomposite tubular structures created by in situ electron beam irradiation. AB - We report a unique approach for the fabrication of a family of curling tubular nanostructures rapidly created by a rolling up of carbon membranes under in situ TEM electron beam irradiation. Multiwall tubes can also be created if irradiation by electron beam is performed long enough. This general approach can be extended to curve the conductive carbon film loaded with various functional nanomaterials, such as nanocrystals, nanorods, nanowires, and nanosheets, providing a unique strategy to make composite tubular structures and composite materials by a combination of desired optical, electronic, and magnetic properties, which could find potential applications, including fluid transportation, encapsulation, and capillarity on the nanometer scale. PMID- 22530776 TI - Polymorphisms of the SAMHD1 gene are not associated with the infection and natural control of HIV type 1 in Europeans and African-Americans. AB - The HIV-1 restriction factor SAM domain and HD domain-containing protein 1 (SAMHD1) blocks HIV-1 infection in human myeloid cells. Mutations in the SAMHD1 gene are associated with rare genetic diseases including Aicardi-Goutieres syndrome. However, it is unknown whether polymorphisms of SAMHD1 are associated with infection and natural control of HIV-1 in humans. Our objective was to determine whether the expression of SAMHD1 mRNA is affected by common single nucleotide polymorphisms (SNPs) in SAMHD1 and whether the SNPs are associated with HIV-1 infection status. Using a tagging SNP approach, we determined the association between eight tagging SNPs in SAMHD1 and the mRNA expression in B lymphocyte cell lines from 70 healthy white donors. We identified one SNP (rs1291142) that was significantly associated with SAMHD1 mRNA expression, with minor allele carriers having 30% less mRNA levels (p=0.015). However, after analyzing the published genome-wide association study data of 857 HIV-1 controllers and 2088 HIV-1 progressors from the European and African-American cohorts, we did not find a significant association between SNPs in SAMHD1 and HIV 1 infection status, including SNP rs1291142 (p>0.05). We also observed 2- to 6 fold variations of SAMHD1 mRNA levels in primary B-lymphocytes, CD4(+) T lymphocytes, and CD14(+) monocytes from five healthy donors. Our results suggest that common regulatory polymorphism(s) exist in the SAMHD1 gene that affects its mRNA expression in B-lymphocyte cell lines from healthy whites. However, polymorphisms of SAMHD1 are unlikely to contribute to the infection and natural control of HIV-1 in European and African-American individuals. PMID- 22530777 TI - Effects of replica running shoes upon external forces and muscle activity during running. AB - Twelve participants ran (9 km . h(-1)) to test two types of running shoes: replica and original shoes. Ground reaction force, plantar pressure and electromyographic activity were recorded. The shoes were tested randomly and on different days. Comparisons between the two experimental conditions were made by analysis of variance (ANOVA) test (P <= 0.05). The time to first peak, loading rate of the first peak and impulse of the first 75 ms of stance were significantly different between the shoes (P <= 0.05), revealing an increase of impact forces for the replica shoes. The peak plantar pressure values were significantly higher (P <= 0.05) when wearing replica shoes. During running, the contact area was significantly smaller (P <= 0.05) for the replica shoe. The electromyographic activity of the analysed muscles did not show changes between the two shoes in running. These findings suggest that the use of replica running shoes can increase the external load applied to the human body, but may not change the muscle activity pattern during locomotion. This new mechanical situation may increase the risk of injuries in these movements. PMID- 22530778 TI - Color coordinating embedding medium and slide labels to reduce errors in Mohs surgery. PMID- 22530779 TI - Naphthoquinones from Onosma paniculata induce cell-cycle arrest and apoptosis in melanoma Cells. AB - Activity-guided fractionation of a petroleum ether-soluble extract of the roots of Onosma paniculata, which has been shown to affect the cell cycle and to induce apoptosis in melanoma cells, led to the isolation of several shikonin derivatives, namely, beta-hydroxyisovalerylshikonin (1), acetylshikonin (2), dimethylacrylshikonin (3), and a mixture of alpha-methylbutyrylshikonin and isovalerylshikonin (4+5). All compounds exhibited strong cytotoxicity against eight cancer cell lines and MRC-5 lung fibroblasts, with 3 found to possess the most potent cytotoxicity toward four melanoma cell lines (SBcl2, WM35, WM9, and WM164). Furthermore, 3 and the mixture of 4+5 were found to interfere with cell cycle progression in these cell lines and led to an increasing number of cells in the subG1 region as well as to caspase-3/7 activation, indicating apoptotic cell death. PMID- 22530780 TI - Impact of five SNPs in dopamine-related genes on executive function. AB - OBJECTIVES: Dopamine neurotransmission is a critical factor for executive function, which is controlled by the prefrontal cortex in humans. Although the contribution of genetic factors to the regulation of brain dopaminergic activity is widely acknowledged, identification of a genotype-phenotype association has not yet been clearly established. In this study, we therefore evaluated the effects of five functional single-nucleotide polymorphisms (SNPs) in specific genes related to dopamine neurotransmission on executive function in a general population. MATERIALS AND METHODS: Participants of the health examination at the Shimane Institute of Health Science were recruited for this study (n = 964). To evaluate executive function, the Frontal Assessment Battery (FAB) was administered. SNPs were genotyped using the TaqMan method. RESULTS: A significant association was found between an SNP in the catechol-O-methyltransferase (COMT) gene (rs4680) encoding the low-activity Met allele and FAB score (P = 0.003). Of note, the flexibility subset of the FAB was associated with the SNP in COMT (P = 0.003) after adjustment for confounding factors. The generalized multifactor dimensionality reduction method identified that the combination of two SNPs in the COMT gene (rs4680) and the dopamine D4 receptor gene (rs1800955) had a significant effect on FAB score. CONCLUSIONS: Our study indicates a contribution of rs4680 in the COMT gene to the variability in executive function, as assessed by the FAB. In addition, we have indicated that a complex gene-gene interaction between SNPs in the genes related to dopamine neurotransmission may influence executive function in a general population. PMID- 22530781 TI - Tunable fluorescent/phosphorescent platinum(II) porphyrin-fluorene copolymers for ratiometric dual emissive oxygen sensing. AB - A series of new platinum(II) 5,15-bis(pentafluorophenyl)-10,20 bis(phenyl)porphyrin-9,9-dioctylfluorene copolymers, in which the relative intensities of the blue fluorescence and red phosphorescence can be easily tuned by the initial feed ratio of the two monomers or energy transfer between the fluorescent and phosphorescent units, have been designed and prepared for the application in ratiometric dual emissive oxygen sensing. To the best of our knowledge, this is the first example of a ratiometric oxygen sensor based on dual fluorescent/phosphorescent polymers or copolymers containing transition-metal complexes. It also provides an alternative and easy way to achieve dual emissive oxygen sensing. PMID- 22530784 TI - Burden of rotavirus hospitalisations in young children in three paediatric hospitals in the United States determined by active surveillance compared to standard indirect methods. AB - AIM: The number of rotavirus hospitalisations is usually estimated from assigned diagnosis codes for gastroenteritis despite lack of validation for these indirect methods. Reliable estimates before and after introduction of vaccines are needed to quantify the absolute impact of new immunisation programs. METHODS: This 2-year study conducted at three hospitals prior to the licensure of the rotavirus vaccines in the USA compared two indirect methods for estimating hospitalisations for rotavirus gastroenteritis with estimates derived from prospective recruitment of children presenting with diarrhoea, vomiting or fever. For active surveillance, rotavirus gastroenteritis was confirmed by demonstration of stool antigen. The indirect residual and proportional methods assumed rotavirus to have caused a proportion of hospitalisations coded as acute gastroenteritis identified from computerised records. RESULTS: There were 447 rotavirus hospitalisations among inpatients 31 days through 4 years of age admitted with vomiting and/or diarrhoea, compared with 306 and 228 hospitalisations identified by the two indirect methods. Only 52% of children hospitalised with gastroenteritis received a qualifying diagnosis code at discharge. Relative to active surveillance, the sensitivity and specificity (95% confidence interval (CI)) in identifying rotavirus-attributable hospitalisations was 45% (95% CI: 43-48%) and 89% (88-90%) for the residual method and 34% (30 39%) and 92% (90-94%) for the proportional method. CONCLUSIONS: Many children admitted to the hospital with diarrhoea, vomiting or fever were not assigned discharge codes for acute gastroenteritis. Consequently, standard indirect methods missed a substantial number of rotavirus-associated hospitalisations, thereby underestimating the absolute number of children who could potentially benefit from vaccination. PMID- 22530785 TI - Editorial comment to low incidence of benign lesions in resected suspicious renal masses greater than 2 cm: Single-center experience from Japan. PMID- 22530787 TI - Mini Nutritional Assessment and functional capacity in community-dwelling elderly in rural Luozi, Democratic Republic of Congo. AB - AIM: Good nutrition is beneficial both for the health and the functional capacity of the elderly. However, malnutrition is a serious health problem among the elderly, particularly the elderly living in rural areas in many developing countries. The aim of the present study was to carry out a cross-sectional study of the elderly in the city of Luozi, Democratic Republic of Congo, through the use of the long and the short forms of the Mini Nutritional Assessment (MNA) scale. METHODS: We carried out a cross-sectional study in the city of Luozi, a city facing serious socioeconomic problems as a result of wartime conditions in the country. The study included 370 volunteer community-dwelling elderly people aged 65-88 years, both male and female. Investigations took into account the MNA, the activities of daily living, and the instrumental activities of daily living, falls, current diseases and lifestyle. RESULTS: Approximately 57.8% of the participants were at risk of malnutrition, whereas 28.4% were malnourished according to the MNA scale. MNA scores were significantly lower (Student's t test, P=0.03) in those with a fall history (MNA score 18.3+/-4.0) compared with those who did not (MNA score, 21.0+/-2.7). All the participants with malnutrition suffered from at least one chronic disease. The percentage of participants with dependency was significantly higher in the malnourished participants (87.6%) than in well-nourished participants (50.9%). CONCLUSION: These findings provide information that malnutrition is a serious health concern among elderly people in the city of Luozi, and shows the need for adequate nutrition and social programs for the elderly. PMID- 22530790 TI - Emerging drugs for major depressive disorder: an update. PMID- 22530786 TI - Efficiency of spatio-temporal vaccination regimes in wildlife populations under different viral constraints. AB - Classical Swine Fever (CSF) is considered an endemic disease in European wild boar populations. In view of the high economic impact of the introduction of the virus into domestic pig units, huge efforts are invested in the preventive control of CSF in wild boar populations. Recent European Community guidelines favour oral mass vaccination against CSF in wild boar populations. The guidelines are explicit on the temporal structure of the vaccination protocol, but little is known about the efficacy of different spatial application schemes, or how they relate to outbreak dynamics.We use a spatially explicit, individual-based wild boar model that represents the ecology of the hosts and the epidemiology of CSF, both on a regional scale and on the level of individual course of infection. We simulate adaptive spatial vaccination schemes accounting for the acute spread of an outbreak while using the temporal vaccination protocol proposed in the Community guidelines.Vaccination was found to be beneficial in a wide range of scenarios. We show that the short-term proactive component of a vaccination strategy is not only as decisive as short-term continuity, but also that it can outcompete alternative practices while being practically feasible. Furthermore, we show that under certain virus-host conditions vaccination might actually contribute to disease persistence in local populations. PMID- 22530791 TI - Adhesion properties of uric acid crystal surfaces. AB - Two key steps in kidney stone formation--crystal aggregation and attachment to renal tissues--depend on the surface adhesion properties of the crystalline components. Anhydrous uric acid (UA) is the most common organic crystalline phase found in human kidney stones. Using chemical force microscopy, the adhesion force between various functional groups and the largest (100) surface of UA single crystals was measured in both aqueous solution and model urine. Adhesion trends in the two solutions were identical, but were consistently lower in the latter. Changes in the solution ionic strength and pH were also found to affect the magnitude of the adhesion. UA surfaces showed the strongest adhesion to cationic functionalities, which is consistent with ionization of some surface uric acid molecules to urate. Although hydrogen-bonding and van der Waals interactions are usually considered to be dominant forces in the association between neutral organic compounds, this work demonstrates that electrostatic interactions can be important, particularly when dealing with weak acids under certain solution conditions. PMID- 22530792 TI - Elevated circulating soluble interleukin-2 receptor in patients with chronic liver diseases is associated with non-classical monocytes. AB - BACKGROUND: The soluble interleukin-2 receptor (sIL-2R, sIL2R, sTAC, sCD25) is a reliable biomarker for disease activity in inflammatory disorders such as sarcoidosis. Based on the essential pathogenic role of inflammation for progression of liver diseases, we hypothesized that sIL-2R might be an indicator of inflammatory cell activation and disease severity in patients with chronic liver diseases (CLD). METHODS: We measured sIL-2R serum levels in 71 patients with different stages and etiologies of CLD in comparison to 41 healthy controls. Serum sIL-2R concentrations were correlated with laboratory markers of liver diseases, cytokine / chemokine levels and circulating immune cell subpopulations as simultaneously assessed by FACS analysis from peripheral leukocytes. RESULTS: CLD patients showed significantly elevated serum sIL-2R levels compared with controls. sIL-2R was significantly higher in patients with compared to patients without established liver cirrhosis and increased with the Child-Pugh stage of cirrhosis, independent of the underlying etiology. sIL-2R levels correlated inversely with parameters indicating the hepatic biosynthetic capacity, such as albumin or international normalized ratio, and positively with non-invasive markers of liver fibrosis such as hyaluronic acid or procollagen-III-peptide. Circulating immune cells might represent a major source of sIL-2R. In fact, sIL2 R levels correlated closely with circulating monocytes, especially non-classical CD14+ CD16+ monocytes, which were found to express high levels of CD25 by FACS. Pro-inflammatory cytokines, including IL-2, IFNgamma or IL-6, and chemokines were also associated with sIL2-R. In addition, renal failure was an important confounder of sIL-2R levels independent of liver dysfunction and inflammation. CONCLUSIONS: sIL-2R is elevated in patients with liver diseases and cirrhosis, is associated with circulating inflammatory cells and is increased in concomitant renal failure. These data indicate that sIL-2R might be a potential marker for immune cell activation in CLD, especially for proinflammatory and profibrogenic non-classical CD14 + CD16+ monocytes. PMID- 22530793 TI - Fresh-frozen bone blocks for horizontal ridge augmentation in the upper maxilla: 6-month outcomes of a randomized controlled trial. AB - PURPOSE: This randomized controlled trial compared fresh-frozen versus autologous bone blocks for maxillary horizontal ridge augmentation in patients with Cawood and Howell class IV atrophies. MATERIALS AND METHODS: Twenty-four patients were allocated to the autologous and fresh-frozen groups in a 1:1 ratio. Patients underwent computed tomography scans 1 week and 6 months after surgery for graft volume and density analysis. Doxycycline was administered at day 120 and day 150 to label new bone formation. Biopsy for histologic and histomorphometric analyses was performed at reentry for implant insertion, 6 months after grafting. RESULTS: Fresh-frozen grafts had lower density than autologous bone. Autologous and fresh frozen grafts lost, respectively, 25% and 52% of their initial volume (p = .0041). Histology revealed the presence of newly formed bone within both graft types, but clear signs of inflammation were present in fresh-frozen blocks. CONCLUSIONS: According to these 6-month results, autologous bone blocks are preferable to fresh-frozen bone grafts. PMID- 22530796 TI - Effects of competition level on the centre forward role of men's water polo. AB - This study aimed to compare specific technical and tactical indicators of the team and centre forward role of Euro League, and Italian Serie A1, Serie A2, and Serie B men's water polo club competitions. A notational analysis was performed on 21 water polo matches to evaluate the occurrence of technical and tactical team and centre forward indicators, highlighting differences among championships according to chi-square analyses. Differences emerged for Counterattack (P < 0.001) and Power-Play (P < 0.001) possessions, Even (P < 0.001; Euro League: 3 +/ 1, Serie A1: 3 +/- 2, Serie A2: 3 +/- 2, Serie B: 6 +/- 4) and Power-Play (P = 0.001) goals, and exclusions and penalties (P = 0.008) of the team during Even possessions. Relatively to the role analyses, effects emerged for perimeter players playing events (P = 0.049), as well as for centre forwards' goals (P = 0.007) and exclusions and penalties (P < 0.001; Euro League: 8 +/- 1, Serie A1: 6 +/- 2, Serie A2: 6 +/- 2, Serie B: 3 +/- 2) occurring at the end of Even possessions. Therefore, in Euro League, and Italian Serie A1 and Serie A2, teams perform a high occurrence of Power-Play possessions following up an exclusion, especially achieved by the centre forward during Even possessions, while, in Italian Serie B, goals were mostly scored during Even possessions, with a relevant contribution from the centre forward role. PMID- 22530797 TI - Synthesis and physical properties of K4[Fe(C5O5)2(H2O)2](HC5O5)2.4H2O (C5O5(2-) = croconate): a rare example of ferromagnetic coupling via H-bonds. AB - The reaction of the croconate dianion (C(5)O(5))(2-) with a Fe(III) salt has led, unexpectedly, to the formation of the first example of a discrete Fe(II) croconate complex without additional coligands, K(4)[Fe(C(5)O(5))(2)(H(2)O)(2)](HC(5)O(5))(2).4H(2)O (1). 1 crystallizes in the monoclinic P2(1)/c space group and presents discrete octahedral Fe(II) complexes coordinated by two chelating C(5)O(5)(2-) anions in the equatorial plane and two trans axial water molecules. The structure can be viewed as formed by alternating layers of trans-diaquabis(croconato)ferrate(II) complexes and layers containing the monoprotonated croconate anions, HC(5)O(5)(-), and noncoordinated water molecules. Both kinds of layers are directly connected through a hydrogen bond between an oxygen atom of the coordinated dianion and the protonated oxygen atom of the noncoordinated croconate monoanion. A H-bond network is also formed between the coordinated water molecule and one oxygen atom of the coordinated croconate. This H-bond can be classified as strong-moderate being the O...O bond distance (2.771(2) A) typical of moderate H-bonds and the O-H...O bond angle (174(3) degrees ) typical of strong ones. This H-bond interaction leads to a quadratic regular layer where each [Fe(C(5)O(5))(2)(H(2)O)(2)](2-) anion is connected to its four neighbors in the plane through four equivalent H-bonds. From the magnetic point of view, these connections lead to an S = 2 quadratic layer. The magnetic properties of 1 have been reproduced with a 2D square lattice model for S = 2 ions with g = 2.027(2) and J = 4.59(3) cm(-1). This model reproduces quite satisfactorily its magnetic properties but only above the maximum. A better fit is obtained by considering an additional antiferromagnetic weak interlayer coupling constant (j) through a molecular field approximation with g = 2.071(7), J = 2.94(7) cm(-1), and j = -0.045(2) cm(-1) (the Hamiltonian is written as H = -JS(i)S(j)). Although this second model might still be improved since there is also an extra contribution due to the presence of ZFS in the Fe(II) ions, it confirms the presence of weak ferromagnetic Fe-Fe interactions through H-bonds in compound 1 which represents one of the rare examples of ferromagnetic coupling via H-bonds. PMID- 22530795 TI - Precision of multiple reaction monitoring mass spectrometry analysis of formalin fixed, paraffin-embedded tissue. AB - We compared the reproducibility of multiple reaction monitoring (MRM) mass spectrometry-based peptide quantitation in tryptic digests from formalin-fixed, paraffin-embedded (FFPE) and frozen clear cell renal cell carcinoma tissues. The analyses targeted a candidate set of 114 peptides previously identified in shotgun proteomic analyses, of which 104 were detectable in FFPE and frozen tissue. Although signal intensities for MRM of peptides from FFPE tissue were on average 66% of those in frozen tissue, median coefficients of variation (CV) for measurements in FFPE and frozen tissues were nearly identical (18-20%). Measurements of lysine C-terminal peptides and arginine C-terminal peptides from FFPE tissue were similarly reproducible (19.5% and 18.3% median CV, respectively). We further evaluated the precision of MRM-based quantitation by analysis of peptides from the Her2 receptor in FFPE and frozen tissues from a Her2 overexpressing mouse xenograft model of breast cancer and in human FFPE breast cancer specimens. We obtained equivalent MRM measurements of HER2 receptor levels in FFPE and frozen mouse xenografts derived from HER2-overexpressing BT474 cells and HER2-negative Sum159 cells. MRM analyses of 5 HER2-positive and 5 HER negative human FFPE breast tumors confirmed the results of immunohistochemical analyses, thus demonstrating the feasibility of HER2 protein quantification in FFPE tissue specimens. The data demonstrate that MRM analyses can be performed with equal precision on FFPE and frozen tissues and that lysine-containing peptides can be selected for quantitative comparisons, despite the greater impact of formalin fixation on lysine residues. The data further illustrate the feasibility of applying MRM to quantify clinically important tissue biomarkers in FFPE specimens. PMID- 22530799 TI - Alcohol, drugs, and diving: implications for health and fitness to dive. PMID- 22530794 TI - Methamphetamine use and neuropsychiatric factors are associated with antiretroviral non-adherence. AB - The present study assesses the impact of methamphetamine (METH) on antiretroviral therapy (ART) adherence among HIV+ persons, as well as examines the contribution of neurocognitive impairment and other neuropsychiatric factors [i.e., major depressive disorder (MDD), antisocial personality disorder (ASPD), and attention deficit disorder (ADHD)] for ART non-adherence. We examined HIV+ persons with DSM IV-diagnosed lifetime history of METH abuse/dependence (HIV+ /METH+ ; n=67) as compared to HIV+ participants with no history of METH abuse/dependence (HIV+ /METH - ; n=50). Ancillary analyses compared these groups with a small group of HIV+ /METH+ persons with current METH abuse/dependence (HIV+ /CU METH+ ; n=8). Non-adherence was defined as self-report of any skipped ART dose in the last four days. Neurocognitive functioning was assessed with a comprehensive battery, covering seven neuropsychological domains. Lifetime METH diagnosis was associated with higher rates of detectable levels of plasma and CSF HIV RNA. When combing groups (i.e., METH+ and METH- participants), univariate analyses indicated co occurring ADHD, ASPD, and MDD predicted ART non-adherence (p's < 0.10; not lifetime METH status or neurocognitive impairment). A significant multivariable model including these variables indicated that only MDD uniquely predicted ART non-adherence after controlling for the other variables (p<0.05). Ancillary analyses indicated that current METH users (use within 30 days) were significantly less adherent (50% prevalence of non-adherence) than lifetime METH+ users and HIV+ /METH- participants and that neurocognitive impairment was associated with non-adherence (p's < 0.05). METH use disorders are associated with worse HIV disease outcomes and ART medication non-adherence. Interventions often target substance use behaviors alone to enhance antiretroviral treatment outcomes; however, in addition to targeting substance use behaviors, interventions to improve ART adherence may also need to address coexisting neuropsychiatric factors and cognitive impairment to improve ART medication taking. PMID- 22530798 TI - Synthetic cannabinoids as drugs of abuse. AB - In the last decade a number of products have appeared in various countries that contain synthetic cannabinoids. This article reviews the history of the sale of these drugs, and the evidence that they contain synthetic cannabinoids. The biochemistry of the synthetic cannabinoids identified thus far is discussed, including a discussion of chemical structures and biochemical targets. The cannabinoid receptor targets for these drugs are discussed, as well as other possible targets such as serotonin receptors. Evidence for the abuse potential of these drugs is reviewed. The toxicity of synthetic cannabinoids and cannabinoid products is reviewed and compared to that of the phytocannabinoid Delta9- tetrahydrocannabinol (THC). As cannabinoids are a structurally diverse class of drugs, it is concluded that synthetic cannabinoids should be classified by biological activity rather than by structure, and that if this isn't done, novel synthetic cannabinoids will continue to emerge that fall outside of current regulatory classification models. PMID- 22530800 TI - Is EC class predictable from reaction mechanism? AB - BACKGROUND: We investigate the relationships between the EC (Enzyme Commission) class, the associated chemical reaction, and the reaction mechanism by building predictive models using Support Vector Machine (SVM), Random Forest (RF) and k Nearest Neighbours (kNN). We consider two ways of encoding the reaction mechanism in descriptors, and also three approaches that encode only the overall chemical reaction. Both cross-validation and also an external test set are used. RESULTS: The three descriptor sets encoding overall chemical transformation perform better than the two descriptions of mechanism. SVM and RF models perform comparably well; kNN is less successful. Oxidoreductases and hydrolases are relatively well predicted by all types of descriptor; isomerases are well predicted by overall reaction descriptors but not by mechanistic ones. CONCLUSIONS: Our results suggest that pairs of similar enzyme reactions tend to proceed by different mechanisms. Oxidoreductases, hydrolases, and to some extent isomerases and ligases, have clear chemical signatures, making them easier to predict than transferases and lyases. We find evidence that isomerases as a class are notably mechanistically diverse and that their one shared property, of substrate and product being isomers, can arise in various unrelated ways.The performance of the different machine learning algorithms is in line with many cheminformatics applications, with SVM and RF being roughly equally effective. kNN is less successful, given the role that non-local information plays in successful classification. We note also that, despite a lack of clarity in the literature, EC number prediction is not a single problem; the challenge of predicting protein function from available sequence data is quite different from assigning an EC classification from a cheminformatics representation of a reaction. PMID- 22530801 TI - The joint association of REST and NFKB1 polymorphisms on the risk of colorectal cancer. AB - Due to the high morbidity and mortality of colorectal cancer (CRC), this study aims to determine the joint association of RE-1-silencing transcription factor (REST) and nuclear factor-kappaB 1 (NFKB1) genes with CRC in a population-based study. A well-matched case-control study including 390 controls and 388 patients with CRC was enrolled in China. The selected single nucleotide polymorphisms (SNPs) in the REST and NFKB1 genes were genotyped by Illumina SnapShot Chip. After adjustment for important covariates, the associations of SNPs and joint association of REST and NFKB1 with CRC were evaluated by multiple logistic regression models. The subjects with the rs2228991 AA genotype of the REST gene had a decreased risk for CRC (OR = 0.38; 95%CI: 0.19-0.74), compared with the GG genotype. There were no significant associations between three SNPs in the NFKB1 gene, their haplotype and CRC risk. However, a significant combined effect of rs3774959 and rs3774964 in the NFKB1 gene with rs2228991 in the REST gene on CRC risk was observed. In conclusion, the present study found that mutation in the REST gene rather than the NFKB1 gene was associated with the risk of CRC. Furthermore, significant REST-NFKB1 joint association was observed for CRC, colon cancer and rectal cancer risk. PMID- 22530802 TI - Effect of oral health dental state and risk of malnutrition in elderly people. AB - AIM: To determine the risk of malnutrition in both institutionalized and non institutionalized elderly people of the region of Murcia in Spain. METHODS: A cross-sectional study was carried out on 465 participants (213 men and 252 women) aged 65 years or older, and representative of the population of the region of Murcia in Spain. The nutritional condition was determined with the Mini Nutritional Assessment screening tool. The following clinical oral health variables were recorded: number of teeth in the mouth, use of removable dentures and hygiene. RESULTS: The prevalence of malnutrition was 7% in the study population, whereas the risk of malnutrition was 49%. A greater prevalence was recorded in the older and in the institutionalized participants. There were no significant differences in terms of malnutrition or the risk of malnutrition between the participants with or without dentures or between the dentate or edentulous participants. CONCLUSIONS: Age and institutionalization are parameters to be taken into account for detecting the risk of malnutrition in elderly people. PMID- 22530811 TI - Linear measurements using virtual study models. AB - OBJECTIVE: To perform a systematic review of the literature to assess the reliability and validity of linear measurements using virtual vs plaster study models. MATERIALS AND METHODS: A search strategy was developed for four online databases, and references were further hand searched for studies additional papers. Three researchers determined the eligibility of papers by applying specific selection criteria and ultimately selected 17 papers. Grouped by virtual model acquisition type and the number of landmarks used in a given measurement, the data were weighted by sample size and analyzed in terms of the reliability and validity of linear measurements. RESULTS: The intrarater reliability was high for two-landmark and >two-landmark linear measurements performed on laser acquired models or cone-beam computed tomography (CBCT)-acquired models and were similar to measurements on plaster models. Validity was high for two-landmark and >two-landmark linear measurements comparing laser-acquired models or CBCT acquired models to plaster study models, and the weighted mean differences were clinically insignificant. Agreement of measurements was excellent, with less variability than correlation. Acquisition type had no perceived influences on reliability and validity. More than two-landmark measures tended to have higher mean differences than two-landmark measures. CONCLUSIONS: Virtual study models are clinically acceptable compared with plaster study models with regard to intrarater reliability and validity of selected linear measurements. PMID- 22530812 TI - Profile of infants born to drug-using mothers: a state-wide audit. AB - AIMS: To ascertain the characteristics and short-term outcomes of infants born to illicit drug-using mothers in public hospitals in the state of New South Wales and the Australian Capital Territory during 2004. METHODS: Patients were identified retrospectively by hospital records searches using ICD-10 morbidity codes and records of local Drug and Alcohol Services. Records were reviewed on site. All public hospitals (n= 101) with obstetric services were included. RESULTS: A total of 879 (1.4%, 95% confidence interval: 1.3-1.5%) drug-using mothers were identified from 62,682 confinements. Opiates (46.8%), amphetamines (23.0%) and polydrug (16.4%) exposure were most common. There were eight stillbirths. Among these 871 infants, prematurity (23.6%) and low birthweight (27.1%) were common and 51.1% were admitted to nurseries for further care. Two infants died. Major congenital anomalies were detected in 15 infants. Pharmacological treatment for withdrawal was required for 202 (23.2%), and 143 (70.8%) infants were discharged home on medication. Infants who completed inpatient pharmacological treatment were hospitalised longer (median 26.0 vs. 12.0 days) and were more likely to be premature (37.3 vs. 14.0%). Child-at-risk notifications affected 40.6% of the infants, and 7.6% were fostered prior to discharge. A total of 333 (38.2%) infants were breastfed at discharge. CONCLUSIONS: Our regional study highlights a substantial prevalence of drug use in pregnancy with considerable adverse perinatal and hospital outcomes in infants born to these mothers. Coordinated health care and resources are needed to support these mother-infant pairs because of their social, medical and mental health issues. PMID- 22530814 TI - Seasonal and age effects on energy requirements in domestic short-hair cats (Felis catus) in a temperate environment. AB - There is little information known about the energy requirements of cats in temperature climates. Energy requirement of domestic short-haired cats was determined using three groups of mixed gender - old kept outside (approximately 9.9 years of age; 4.8 kg; n = 9), young kept outside (approximately 3.1 years of age; 3.9 kg; n = 8) or young kept inside (approximately 3.1 years of age; 3.9 kg; n = 8). Cats were housed individually for 5 weeks during summer (18.5 +/- 0.5 degrees C) and winter (8.5 +/- 0.4 degrees C) and were fed a commercially available maintenance diet ad libitum. In both periods, energy expenditure was determined from the rates of (2) H and (18) O elimination for blood H2 O over a 12 day period, from a doubly labelled water bolus (2) H2 O (0.7 g/kg BW) and H2 (18) O (0.13 g/kg BW) administered intravenously. During the summer period, macronutrient digestibility was determined. Older cats had a reduction (p < 0.05) in apparent digestibility of dry matter (approximately 9%), energy (approximately 8%) and protein (6%). There was a significant effect of age and season on energy intake and energy expenditure. While lean mass was affected by age and season, there was no effect of age or season on energy expenditure when expressed as a proportion of lean mass. Possible seasonal differences in nutrient digestibility may explain these results. PMID- 22530813 TI - Antiprotozoal and antimicrobial compounds from the plant pathogen Septoria pistaciarum. AB - Four new 1,4-dihydroxy-5-phenyl-2-pyridinone alkaloids, 17-hydroxy-N-(O methyl)septoriamycin A (1), 17-acetoxy-N-(O-methyl)septoriamycin A (2), 13-(S) hydroxy-N-(O-methyl)septoriamycin A (3), and 13-(R)-hydroxy-N-(O methyl)septoriamycin A (4), together with the known compounds (+)-cercosporin (5), (+)-14-O-acetylcercosporin (6), (+)-di-O-acetylcercosporin (7), lumichrome, and brassicasterol, were isolated from an ethyl acetate extract of a culture medium of Septoria pistaciarum. Methylation of septoriamycin A (8) with diazomethane yielded three di-O-methyl analogues, two of which existed as mixtures of rotamers. We previously reported antimalarial activity of septoriamycin A. This compound also exhibited significant activity against Leishmania donovani promastigotes. Compounds 5-7 showed moderate in vitro activity against L. donovani promastigotes and chloroquine-sensitive (D6) and resistant (W2) strains of Plasmodium falciparum, whereas compound 5 was fairly active against methicillin-sensitive and methicillin-resistant strains of Staphylococcus aureus. Compounds 5-7 also displayed moderate phytotoxic activity against both a dicot (lettuce, Lactuca sativa) and a monocot (bentgrass, Agrostis stolonifera) and cytotoxicity against a panel of cell lines. PMID- 22530816 TI - HIV-1 low-level viraemia assessed with 3 commercial real-time PCR assays show high variability. AB - BACKGROUND: Current real-time PCR-based HIV-1 viral load (VL) assays allow the detection of residual viraemia in antiretroviral-treated patients. The clinical outcome of HIV1 patients experiencing low-level replication (<50 cop/mL) in comparison with fully suppressed patients is currently debated. We analysed variability of 3 VL assays <50 cop/mL, and evaluated the reproducibility of viral blips <100 cop/mL. METHODS: Three commercial VL assays were tested: Versant HIV-1 RNA 1.0 kPCR (Siemens), Abbott Realtime HIV-1, and Cobas Ampliprep/Cobas Taqman HIV-1 v2.0 (Roche). Ten replicates of a reference sample at 4 low target dilutions were tested to evaluate assay variability. Prospective collection of 181 clinical samples with detectable VL <50 cop/mL was used to evaluate intra-and inter-assay variability by triplicate testing. Samples from 26 patients experiencing a viral blip were retested. RESULTS: All assays showed substantial variability at low VL level: the coefficient of variation at 100, 50, 25 and 12 cop/mL ranged respectively from 32 to 44%, 35 to 68%, 41 to 83% and 33 to 77%. In the intra-assay evaluation of repeatability, 52.5 to 57.5% of detectable VL <50 cop/mL tested in triplicate showed at least one fully undetected result. Variability was similar in the inter-assay arm. The VL blips could only be reproduced in 19% of cases. CONCLUSIONS: The most recent versions of widespread commercial VL assays showed substantial variability at low levels and residual viraemia could not be consistently reproduced. Patient outcome studies comparing residual VL to full suppression are therefore biased when using commercial assays. PMID- 22530817 TI - The contribution of adult attachment and perceived social support to depressive symptoms in patients with HIV. AB - The present study investigated the relationship between adult attachment style and depressive symptomatology in patients with HIV. Moreover, perceived social support was investigated as a potential mediator between adult attachment and depressive symptoms. A sample of 233 HIV-infected patients (90% male) completed questionnaires assessing adult attachment style (Relationship Questionnaire), depressive symptoms (Beck Depression Inventory), and perceived social support (Medical Outcomes Study Social Support Survey). After controlling for demographic and medical variables, an insecure adult attachment style was found to be strongly related with depressive symptoms. Half of the insecurely attached patients reported clinically elevated levels of distress, while one in nine securely attached patients reported elevated levels of distress (chi(2)=32.25, p=0.001). Moreover, the association between attachment style and depressive symptomatology was found to be partly mediated through perceived social support. This study strongly supports the notion that an insecure attachment style is a vulnerability factor for developing depressive symptoms that would warrant clinical attention when confronted with a chronic illness such as HIV. The clinical implications of these findings are discussed. PMID- 22530815 TI - Fear extinction and BDNF: translating animal models of PTSD to the clinic. AB - Brain-derived neurotrophic factor (BDNF) is the most studied neurotrophin involved in synaptic plasticity processes that are required for long-term learning and memory. Specifically, BDNF gene expression and activation of its high-affinity tropomyosin-related kinase B (TrkB) receptor are necessary in the amygdala, hippocampus and prefrontal cortex for the formation of emotional memories, including fear memories. Among the psychiatric disorders with altered fear processing, there is post-traumatic stress disorder (PTSD) which is characterized by an inability to extinguish fear memories. Since BDNF appears to enhance extinction of fear, targeting impaired extinction in anxiety disorders such as PTSD via BDNF signalling may be an important and novel way to enhance treatment efficacy. The aim of this review is to provide a translational point of view that stems from findings in the BDNF regulation of synaptic plasticity and fear extinction. In addition, there are different systems that seem to alter fear extinction through BDNF modulation like the endocannabinoid system and the hypothalamic-pituitary adrenal axis. Recent work also finds that the pituitary adenylate cyclase-activating polypeptide and PAC1 receptor, which are upstream of BDNF activation, may be implicated in PTSD. Especially interesting are data that exogenous fear extinction enhancers such as antidepressants, histone deacetylases inhibitors and D-cycloserine, a partial N-methyl d-aspartate agonist, may act through or in concert with the BDNF-TrkB system. Finally, we review studies where recombinant BDNF and a putative TrkB agonist, 7,8-dihydroxyflavone, may enhance extinction of fear. These approaches may lead to novel agents that improve extinction in animal models and eventually humans. PMID- 22530818 TI - Pediatric travel medicine: where we are and where we hope to go. PMID- 22530819 TI - Loiasis: new epidemiologic insights and proposed treatment strategy. PMID- 22530820 TI - Travel-related morbidity in children: a prospective observational study. AB - OBJECTIVE: Scarce data are available on the occurrence of ailments and diseases in children during travel. We studied the characteristics and frequencies of ailments in children aged 0 to 18 years and their parents during traveling. METHODS: A prospective observational study on ailments reported by children and parents traveling to (sub)tropical countries was conducted. The ailments were semi-quantitatively graded as mild, moderate, or severe; ailments were expressed as ailment rates per personmonth of travel. RESULTS: A total of 152 children and 47 parents kept track of their ailments for a total of 497 and 154 weeks, respectively. The children reported a mean ailment rate of 7.0 (5.6-8.4) ailments per personmonth of travel; 17.4% of the ailments were graded as moderate and 1.4% as severe. The parents reported a mean ailment rate of 4.4 (3.1-5.7); 10.8% of the ailments were graded as moderate and 5.5% as severe. Skin problems like insect bites, sunburn and itch, and abdominal complaints like diarrhea were frequently reported ailments in both children and parents. Children in the age category 12 to 18 years showed a significantly higher ailment rate of 11.2 (6.8 14.1) than their parents. CONCLUSIONS: Skin problems and abdominal problems like diarrhea are frequently reported ailments in children and their parents and show a high tendency to recur during travel. The majority of these ailments are mild but occasionally interfere with planned activities. Children in the age group 12 to 18 years are at a greater risk of developing ailments during a stay in a (sub)tropical country and they should be actively informed about the health risks of traveling to the tropics. PMID- 22530821 TI - Spectrum of imported infectious diseases among children and adolescents returning from the tropics and subtropics. AB - BACKGROUND: About 50 million people travel each year from industrialized countries to destinations in the tropics and subtropics. Among them, there are more than 2 million minors traveling. Although their number is increasing constantly, data on health risks during travel are limited. METHODS: This study analyzed demographic, travel, and clinical data of 890 travelers of age <20 years presenting at the outpatient travel clinic of the University of Munich between 1999 and 2009 after returning from the tropics and subtropics. RESULTS: Most (87%) of these young travelers were born in Germany. Among them, the main travel destination was Africa (46%), followed by Asia (35%) and Latin America (19%). The most frequent syndrome groups were acute diarrhea (25%, especially in age 0-4 y), dermatologic disorders (21%, especially in age 0-9 y), febrile/systemic diseases (20%), respiratory disorders (8%), chronic diarrhea (5%), and genitourinary disorders (3%). The 10 most frequent diagnosed infectious diseases were giardiasis (8%), schistosomiasis (4%), superinfected insect bites (4%), Campylobacter enteritis (4%), Salmonella enteritis (4%), cutaneous larva migrans (3%), amebiasis (3%), dengue fever (2%), mononucleosis (2%), and malaria (2%). The relative risk (RR) for acquiring any infectious disease during travel was highest in Central, West, and East Africa, followed by South America, South Asia, and Southeast Asia. CONCLUSIONS: Age of young travelers and destination of travel were the most important variables being strongly correlated with the risk for acquiring infectious diseases in the tropics and subtropics. The highest risk was carried by very young travelers and those staying in sub-Saharan Africa (except Southern Africa). PMID- 22530822 TI - Profile of travel-associated illness in children, Zurich, Switzerland. AB - BACKGROUND: The number of families traveling with their children to their country of origin and/or to tropical destinations has increased in Switzerland and includes a changing profile and multinational range of patients. Defining the profile of reported travel-associated illnesses will help to improve the prevention and treatment of such illnesses in children. METHODS: This study includes children aged up to 16 years who sought medical advice for a presumed travel-related illness at the emergency room of the University of Zurich Children's Hospital during the period July 2007 to December 2008. RESULTS: We analyzed data on 328 children (58.8% male, mean age: 4.62 y) who presented with travel-associated illness. Our analysis included 155 traditional (mainly tourist) travelers, 162 children who were visiting friends and relatives (VFR), and 11 immigrants. Some 11% were hospitalized. No deaths occurred. The main conditions recorded were diarrheal illness (39%), respiratory (28.7%) and febrile/systemic illness (13.4%). With increasing age, the proportion of children with diarrheal disease increased, while the proportion with respiratory illness declined. There were significant associations between geographic area of exposure and the profile of travel-related disease (p < 0.001). Among 36 children with more serious diseases requiring hospitalization, 12 (3.7% overall) presented with potentially serious diseases: malaria (n = 2), Salmonella typhi (n = 3), Salmonella paratyphi (n = 2), meningococcal meningitis (n = 1), tuberculosis (n = 2), visceral leishmania (n = 1), and hepatitis A (n = 1). Eleven of the 12 children presenting with these potentially serious illnesses were VFR or immigrant children. CONCLUSION: The main diagnoses for ill-returned Zurich children who presented for emergency care were diarrhea, respiratory, and febrile/systemic illness. A broad spectrum of morbidity was seen including meningococcal meningitis, malaria, tuberculosis, typhoid fever, leishmania, and hepatitis A. Diagnoses varied between geographic regions visited, and VFR child travelers constituted a large proportion of sick-returned children presenting for emergency care. PMID- 22530823 TI - Protective practices and respiratory illness among US travelers to the 2009 Hajj. AB - BACKGROUND: All mass gatherings can place travelers at risk for infectious diseases, but the size and density of the annual Hajj pilgrimage to the Kingdom of Saudi Arabia (KSA) present important public health and infection control challenges. This survey of protective practices and respiratory illness among US travelers to the 2009 Hajj was designed to evaluate whether recommended behavioral interventions (hand hygiene, wearing a face mask, cough etiquette, social distancing, and contact avoidance) were effective at mitigating illness among travelers during the 2009 Hajj. METHODS: US residents from Minnesota and Michigan completed anonymous surveys prior to and following travel to the 2009 Hajj. Surveys assessed demographics, knowledge, attitudes, and practices (KAP) related to influenza A(H1N1), vaccination, health-seeking behaviors, sources of health information, protective behaviors during the Hajj, and respiratory illness during and immediately after the Hajj. RESULTS: Pre- and post-travel surveys were completed by 186 participants. Respiratory illness was reported by 76 (41.3%) respondents; 144 (77.4%) reported engaging in recommended protective behaviors during the Hajj. Reduced risk of respiratory illness was associated with practicing social distancing, hand hygiene, and contact avoidance. Pilgrims who reported practicing more recommended protective measures during the Hajj reported either less occurrence or shorter duration of respiratory illness. Noticing influenza A(H1N1) health messages during the Hajj was associated with more protective measures and with shorter duration of respiratory illness. CONCLUSIONS: Recommended protective behaviors were associated with less respiratory illness among US travelers to the 2009 Hajj. Influenza A(H1N1) communication and education in KSA during the Hajj may also have been an effective component of efforts to mitigate illness. Evaluations of communication efforts and preventive measures are important in developing evidence-based public health plans to prevent and mitigate disease outbreaks at the Hajj and other mass gatherings. PMID- 22530824 TI - Travel-associated illness in older adults (>60 y). AB - BACKGROUND: Older individuals represent a substantial proportion of international travelers. Because of physiological changes and the increased probability of underlying medical conditions, older travelers might be at higher risk for at least some travel-associated diseases. METHODS: With the aim of describing the epidemiology of travel-associated diseases in older adults, medical data were prospectively collected on ill international travelers presenting to GeoSentinel sites from 1997 to 2009. Seven thousand thirty-four patients aged 60 years and over were identified as older travelers and were compared to 56,042 patients aged 18-45 years, who were used as the young adult reference population. RESULTS: The proportionate morbidity of several etiological diagnoses was higher in older ill travelers compared to younger ill, including notably lower respiratory tract infections, high-altitude pulmonary edema, phlebitis and pulmonary embolism, arthropod bites, severe malaria, rickettsiosis, gastritis, peptic ulcers, esophagitis and gastroesophageal reflux disease, trauma and injuries, urinary tract infections, heart disease, and death. In contrast, acute diarrhea, upper respiratory tract infections, flu and flu-like illnesses, malaria, dengue, genital infections, sexually transmitted diseases, and schistosomiasis proportionate morbidities were lower among the older group. CONCLUSION: Older ill travelers are more likely to suffer from certain life-threatening diseases and would benefit from reinforcement of specific preventive measures including use of anti-thrombosis compression stockings and sufficient hydration and exercises during long-distance flights, hand hygiene, use of disposable handkerchiefs, consideration of face-masks in crowded conditions, influenza and pneumococcal vaccines, progressive acclimatization to altitude, consideration of acetazolamide, and use of repellents and mosquito nets. Antibiotics for the presumptive treatment of respiratory and urinary tract infections may be considered, as well as antacid medications. At-risk patients should be referred to a specialist for medical evaluation before departing, and optimal control of co-morbidities such as cardiovascular and chronic obstructive pulmonary diseases should be achieved, particularly for high-altitude travel. PMID- 22530825 TI - Strongyloides, dengue fever, and tuberculosis conversions in New Zealand police deploying overseas. AB - BACKGROUND: Members of New Zealand Police (NZP) deploy overseas in a variety of roles. There is limited published data on travel-related morbidity in police as a subgroup of travelers. METHODS: An audit of pre- and postdeployment medical files for all NZP personnel deploying overseas during 2004 to 2010 was undertaken. Of all deployments, 58.9% were within Oceania. RESULTS: Positive Strongyloides stercoralis serology was returned in 6.07% (95% CI: 3.80%-9.13%) at a rate of 9.00/1,000 person deployment months (pdm) (95% CI: 5.57-13.8). Dengue fever seroconversion was recorded in 4.91% (95% CI: 3.40%-6.83%) at a rate of 8.57/1,000 pdm (95% CI: 5.90-12.0). The relative risk of dengue infection was 7.47 for Timor Leste compared to all other deployment destinations. An association between seroconverting for both dengue fever and Strongyloides was found. Tuberculosis conversion was recorded in 1.76% (95% CI: 0.85%-3.21%) at a rate of 2.92/1,000 pmd (95% CI: 1.48-5.375). A single case of human immunodeficiency virus (HIV) seroconversion was recorded. There were no recorded hepatitis C seroconversions. CONCLUSIONS: Police deploying overseas appear to have similar rates of dengue and tuberculosis conversion as other groups of travelers, and they appear to be at low risk of hepatitis C and HIV. Strongyloidiasis appears to be a significant risk; postdeployment prevalence was markedly higher than that reported in a small number of studies. PMID- 22530826 TI - Transient facial swellings in a patient with a remote African travel history. AB - We present a case of Loa loa infection in a patient, 21 years after visiting an endemic area for only 4 days. To our knowledge, this case represents the longest time for the diagnosis of loiasis to be made post-exposure in a traveler and emphasizes that even short exposures can place travelers at risk. PMID- 22530827 TI - Loiasis with pleural and peritoneal involvement. AB - We describe a case of atypical loiasis presenting with a chronic pleuroperitoneal effusion in a 50-year-old woman from the Democratic Republic of Congo. Effusions disappeared with conventional treatment and no recurrence was detected after 4 months of follow-up. Such cases of loiasis involving visceral sites have been unusually reported in the literature. PMID- 22530828 TI - A cluster of acute diarrhea suspected to be cholera in French travelers in Haiti, December 2010. AB - A cluster of 21 cases of watery diarrhea suspected to be cholera that involved French military policemen and young volunteers occurring in the context of the Haiti cholera outbreak is described. The attack rate (AR) was higher among young volunteers (71.4%) than among policemen (15.3%) (p < 0.0001). There was a significant association between raw vegetables consumption and watery diarrhea in the young volunteer group. If we consider the raw vegetables consumers only, AR was lower among doxycycline-exposed subjects (relative risk: 0.2; 95% confidence interval: 0.1-0.4). The main aspect that is of scientific interest is the potential prophylactic effect of doxycycline used for malaria prophylaxis on the watery diarrhea AR. PMID- 22530830 TI - Trichinellosis in immigrants in Switzerland. AB - We describe a case of trichinellosis diagnosed at the Division of Infectious Diseases, Hospital of Lugano, in January 2009. This case was associated with a cluster of cases and was traced to the consumption of contaminated meat after a wild boar hunt in Bosnia. PMID- 22530829 TI - Coccidioidomycosis: first imported case in Italy. AB - We report a case of pulmonary coccidioidomycosis imported from the United States to Italy. This disease should enter in the differential diagnosis of any febrile patient (especially if presenting with pulmonary symptoms, with or without hypereosinophilia) coming from Coccidioides immitis endemic areas. PMID- 22530831 TI - Inoperable cerebral alveolar echinococcosis controlled with high dosages of albendazole adjusted with monitoring of blood levels. AB - Cerebral alveolar echinococcosis (AE) is a rare and difficult-to-treat zoonosis caused by Echinococcus multilocularis. A 29-year-old immigrant from Siberia with a past history of hepatic AE, presented with acute onset of grand mal seizures, weakness of the left leg, and cephalgia. Magnetic resonance imaging of the brain revealed inoperable right-sided infiltrative lesions, suggesting cerebral AE. Despite anthelmintic treatment only slow improvement occurred. PMID- 22530832 TI - Low risk of hepatitis E among Dutch short-term travelers. AB - Hepatitis E is endemic in (sub)tropical countries while only sporadic cases have been described in industrialized countries. In a prospective study among 1270 short-term Dutch travelers to (sub)tropical countries we found no seroconversion to anti-hepatitis E virus (HEV) antibodies, indicating a very low risk for travelers to acquire a hepatitis E infection. PMID- 22530833 TI - Expanding the steric coverage offered by bis(amidosilyl) chelates: isolation of low-coordinate N-heterocyclic germylene complexes. AB - The synthesis and coordination chemistry of a series of dianionic bis(amido)silyl and bis(amido)disilyl, [NSiN] and [NSiSiN], chelates with N-bound aryl or sterically modified triarylsilyl (SiAr(3)) groups is reported. In order to provide a consistent comparison of the steric coverage afforded by each ligand construct, various two-coordinate N-heterocyclic germylene complexes featuring each ligand set were prepared and oxidative S-atom transfer chemistry was explored. In the cases where clean oxidation transpired, sulfido-bridged centrosymmetric germanium(IV) dimers of the general form [LGe(MU-S)](2) (L = bis(amidosilyl) ligands) were obtained in lieu of the target monomeric germanethiones with discrete Ge?S double bonds. These results indicate that the reported chelates possess sufficient conformational flexibility to allow for the dimerization of LGe?S units to occur. Notably, the new triarylsilyl groups (4 RC(6)H(4))(3)Si- (R = (t)Bu and (i)Pr) still offer considerably expanded degrees of steric coverage relative to the parent congener, -SiPh(3,) and thus the use of substituted triarylsilyl groups within ligand design strategies should be a generally useful concept in advancing low-coordination main group and transition metal chemistry. PMID- 22530834 TI - Complete eradication of xenograft hepatoma by oncolytic adenovirus ZD55 harboring TRAIL-IETD-Smac gene with broad antitumor effect. AB - Cancer-targeting dual-gene virotherapy (CTGVT-DG) is an important modification of CTGVT, in which two suitable genes are used to obtain an excellent antitumor effect. A key problem is to join the two genes to form one fused gene, and then to clone it into the oncolytic viral vector so that only one investigational new drug application, instead of two, is required for clinical use. Many linkers (e.g., internal ribosome entry site) are used to join two genes together, but they are not all equally efficacious. Here, we describe finding the best linker, that is, sequence encoding the four amino acids IETD, to join the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene and the second mitochondria derived activator of caspase (Smac) gene to form TRAIL-IETD-Smac and inserting it into oncolytic viral vector ZD55 to construct ZD55-TRAIL-IETD-Smac, which matched ZD55-TRAIL plus ZD55-Smac in completely eliminating xenograft hepatoma. ZD55 TRAIL-IETD-Smac works by quantitative cleavage at IETD?by inducing caspase-8; activation or inhibition of caspase-8 could up- or downregulate cleavage, respectively. The cleaved product, TRAIL-IETD, does not affect the function of TRAIL. Numerous experiments have shown that the combined use of ZD55-TRAIL plus ZD55-X could completely eradicate many xenograft tumors, and therefore the IETD is potentially a useful linker to construct many antitumor drugs, for example, ZD55-TRAIL-IETD-X, where X has a compensative or synergetic effect on TRAIL. We found that the antitumor effect of ZD55-IL-24-IETD-TRAIL also has an equivalent antitumor effect compared with the combined use of ZD55-IL-24 plus ZD55-TRAIL, because ZD55-IL-24 could also induce caspase-8. This means that IETD, as a two gene linker, may have broad use. PMID- 22530835 TI - Porphyromonas gingivalis: an invasive and evasive opportunistic oral pathogen. AB - Porphyromonas gingivalis is a Gram-negative oral anaerobe that is involved in the pathogenesis of periodontitis, an inflammatory disease that destroys the tissues supporting the tooth, eventually leading to tooth loss. Porphyromonas gingivalis has can locally invade periodontal tissues and evade the host defence mechanisms. In doing so, it utilizes a panel of virulence factors that cause deregulation of the innate immune and inflammatory responses. The present review discusses the invasive and evasive strategies of P. gingivalis and the role of its major virulence factors in these, namely lipopolysaccharide, capsule, gingipains and fimbriae. Moreover, the role of P. gingivalis as a 'keystone' biofilm species in orchestrating a host response, is highlighted. PMID- 22530836 TI - Changes in union status during the transition to parenthood in eleven European countries, 1970s to early 2000s. AB - Couples who have children are increasingly likely to have lived together without being married at some point in their relationship. Some couples begin their unions with cohabitation and marry before first conception, some marry during pregnancy or directly after the first birth, while others remain unmarried 3 years after the first birth. Using union and fertility histories since the 1970s for eleven countries, we examine whether women who have children in unions marry, and if so, at what stage in family formation. We also examine whether women who conceive when cohabiting are more likely to marry or separate. We find that patterns of union formation and childbearing develop along different trajectories across countries. In all countries, however, less than 40 per cent of women remained in cohabitation up to 3 years after the first birth, suggesting that marriage remains the predominant institution for raising children. PMID- 22530837 TI - Mitochondrial targeting for development of novel drug strategies in brain injury. AB - For years, therapeutic approach to brain injury has been mostly physiological in essence, either based on revascularization of ischemic tissue in stroke or decompression of the swollen brain in neurotrauma. Despite tremendous efforts for the development of new strategies, translational research targeting specific cellular pathophysiological processes triggered by the injury has provided deceiving results. During the past decade, disruption of mitochondrial function and structural integrity has emerged as a pivotal event in the generation of cell damage. Following the injury, a vast array of deleterious signals are generated and integrated at the mitochondrial level resulting in impairment of three major mitochondrial functions: calcium homeostasis, free radicals generation and detoxification and energy production. Increasing understanding of the biochemical complexity of these events has led to the development of new therapeutic strategies targeting mitochondrial damage that has shown encouraging data in various models of injury. Importantly, translational efforts have been already initiated with promising preliminary data in several phase II clinical studies. In this review, we will briefly describe the process of mitochondrial damage and dysfunction following brain injury and discuss the various therapeutic strategies aiming at mitochondrial protection. PMID- 22530838 TI - Emerging drugs for cervical cancer. AB - INTRODUCTION: There is a shortage of therapeutical agents for invasive cervical cancer in late stages of development; however, a number of promising molecules are currently in early phases of development. AREAS COVERED: This review briefly discusses the current achievements in treating cervical cancer with an emphasis in emerging agents based on a literature search on pubmed and related sites for cervical cancer information. This is not a systematic review. EXPERT OPINION: In advanced disease, modest survival gains have been achieved with cisplatin doublets. Contrariwise, chemoradiation has increased survival rates in locally advanced disease, but there is still room for improvement. Anti-vascular endothelial growth factor and anti-epidermal growth factor receptor monoclonal antibodies are promising molecules that are at present in late-phase development, but a high number of miscellaneous agents are in early development. Strong experimental bases support that the 'Achilles' heel' of cervical cancer are the HPV-E6/E7 oncogenes. Unfortunately, agents aimed at targeting these cervical cancer-driven players are found in very early development; hence, major research efforts must be focused on developing technological strategies for their effective targeting using nucleic acid-based vehicles for safe and effective delivery to cancer cells as well as accelerating the search for small-molecule inhibitors of E6/E7 themselves or their interacting cellular proteins. PMID- 22530839 TI - NICU-only versus universal screening for newborn hearing loss: Population audit. AB - AIM: Targeted newborn hearing screening for infants in neonatal intensive care units (NICUs) may be considered when resources preclude universal newborn hearing screening (UNHS). However, process outcomes have not been compared between stand alone NICU hearing screening programs and NICU screening within a full UNHS program. METHODS: Comparison of two consecutive hearing screening programs delivered under similar conditions in the four NICUs in Victoria, Australia. All NICU infants were eligible for pre-discharge automated auditory brainstem response (AABR) hearing screening. Capture, referral and diagnostic data were collected for all NICU infants during the NICU-only (April 2003-February 2005) and subsequent UNHS (April 2005-June 2006) programs. RESULTS: 4704 eligible infants were admitted during the 23-month NICU-only period, and 3160 during the 15-month UNHS period. Double AABR using ALGO 3i equipment was planned for both programs but, due to clinician concern about this high-risk clinical population, the NICU-only protocol was amended to single AABR using AccuScreen equipment. Capture rates were 71.1% (NICU-only) vs. 95.4% (UNHS) (P < 0.001), successful follow-up rates were 85.8% vs. 96% (P= 0.004), and mean corrected age at the first audiology appointment was 51.5 vs. 40.2 days (P= 0.05). CONCLUSIONS: NICU screening offered within a larger UNHS program outperformed the stand-alone NICU hearing screening program on all measured parameters. Greater resourcing might address shortcomings of the stand-alone program but would also reduce its potential savings. The high loss to follow-up also argues against the often advocated approach of referring all NICU infants for diagnostic audiologic testing, bypassing hearing screening altogether. PMID- 22530840 TI - Reconstruction of surfaces from mixed hydrocarbon and PEG components in water: responsive surfaces aid fouling release. AB - Coatings derived from surface active block copolymers (SABCs) having a combination of hydrophobic aliphatic (linear hydrocarbon or propylene oxide derived groups) and hydrophilic poly(ethlyene glycol) (PEG) side chains have been developed. The coatings demonstrate superior performance against protein adsorption as well as resistance to biofouling, providing an alternative to coatings containing fluorinated side chains as the hydrophobe, thus reducing the potential environmental impact. The surfaces were examined using dynamic water contact angle, captive air-bubble contact angle, atomic force microscopy, X-ray photoelectron spectroscopy, and near-edge X-ray absorption fine structure analysis. The PS(8K)-b-P(E/B)(25K)-b-PI(10K) triblock copolymer precursor (K3) initially dominated the dry surface. In contrast to previous studies with mixed fluorinated/PEG surfaces, these new materials displayed significant surface changes after exposure to water that allowed fouling resistant behavior. PEG groups buried several nanometers below the surface in the dry state were able to occupy the coating surface after placement in water. The resulting surface exhibits a very low contact angle and good antifouling properties that are very different from those of K3. The surfaces are strongly resistant to protein adsorption using bovine serum albumin as a standard protein challenge. Biofouling assays with sporelings of the green alga Ulva and cells of the diatom Navicula showed the level of adhesion was significantly reduced relative to that of a PDMS standard and that of the triblock copolymer precursor of the SABCs. PMID- 22530845 TI - Current treatments and strategies for type 2 diabetes: can we do better with GLP 1 receptor agonists? AB - Abstract Diet, lifestyle modification, and pharmacotherapy with metformin are appropriate initial treatments for many patients with type 2 diabetes (T2DM). However, most individuals do not maintain glycemic control with metformin alone. Addition of other oral antidiabetes drugs (OADs), including sulfonylurea, meglitinide, or thiazolidinedione, is often the next step. Newer options, including incretin-based glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, offer important benefits as monotherapies or in combination with OADs, with low risk for hypoglycemia. Reductions in glycated hemoglobin (A1C) have been reported among patients treated with GLP-1 RAs (exenatide, -0.8 to -1.1%; liraglutide, -0.8 to -1.6%), as has weight loss (exenatide, -1.6 to -3.1 kg; liraglutide, -1.6 to -3.2 kg). GLP-1 RAs also stimulate beta-cell responses and have positive effects on cardiovascular risk factors often present in patients with T2DM. The most common adverse events associated with GLP-1 RAs are nausea, which diminishes over time, and hypoglycemia (when used in combination with a sulfonylurea). A large number of trials demonstrated benefits of GLP-1 RAs, suggesting they could provide suitable treatment options for patients with T2DM. PMID- 22530846 TI - Structural insight for imidazopyridazines as malarial kinase PfPK7 inhibitors using QSAR techniques. AB - With a view to the rational design of a selected series of 35 imidazopyridazine derivatives, 2D and 3D QSAR models have been developed for the prediction of antimalarial activity. The statistically best 2D QSAR model having r(2) = 0.9242 and q(2) = 0.8691 with pred_r(2) = 0.9206 was developed by SW-MLR and best 3D QSAR model having q(2) = 0.8607 with pred_r(2) = 0.8332 was developed by k nearest neighbor molecular field analysis (kNN-MFA). Molecular docking study was also carried out to better understand of the interactions between PfPK7 enzyme target (pdb: 2pnm) and inhibitors in this series. The docking study suggests that these PfPK7 inhibitors interact with Met120, Lys55, Tyr117, Asp123, Leu179, Leu34, Asn35, Ala53, Glu88, Leu101, Tyr119, Ser124, Ser189 and Asp190 amino acid residues of protein PfPK7. Both QSAR and docking studies of such derivatives provide guidance for further lead optimization and designing of more potent PfPK7 inhibitors. PMID- 22530841 TI - Cost-effectiveness of 2 + 1 dosing of 13-valent and 10-valent pneumococcal conjugate vaccines in Canada. AB - BACKGROUND: Thirteen-valent pneumococcal conjugate vaccine (PCV13) and 10-valent pneumococcal conjugate vaccine (PCV10) are two recently approved vaccines for the active immunization against Streptococcus pneumoniae causing invasive pneumococcal disease in infants and children. PCV13 offers broader protection against Streptococcus pneumoniae; however, PCV10 offers potential protection against non-typeable Haemophilus influenza (NTHi). We examined public health and economic impacts of a PCV10 and PCV13 pediatric national immunization programs (NIPs) in Canada. METHODS: A decision-analytic model was developed to examine the costs and outcomes associated with PCV10 and PCV13 pediatric NIPs. The model followed individuals over the remainder of their lifetime. Recent disease incidence, serotype coverage, population data, percent vaccinated, costs, and utilities were obtained from the published literature. Direct and indirect effects were derived from 7-valent pneumococcal vaccine. Additional direct effect of 4% was attributed to PCV10 for moderate to severe acute otitis media to account for potential NTHi benefit. Annual number of disease cases and costs (2010 Canadian dollars) were presented. RESULTS: In Canada, PCV13 was estimated to prevent more cases of disease (49,340 when considering both direct and indirect effects and 7,466 when considering direct effects only) than PCV10. This translated to population gains of 258 to 13,828 more quality-adjusted life-years when vaccinating with PCV13 versus PCV10. Annual direct medical costs (including the cost of vaccination) were estimated to be reduced by $5.7 million to $132.8 million when vaccinating with PCV13. Thus, PCV13 dominated PCV10, and sensitivity analyses showed PCV13 to always be dominant or cost-effective versus PCV10. CONCLUSIONS: Considering the epidemiology of pneumococcal disease in Canada, PCV13 is shown to be a cost-saving immunization program because it provides substantial public health and economic benefits relative to PCV10. PMID- 22530848 TI - Who are corresponding authors? PMID- 22530847 TI - Emerging analgesic drugs for Parkinson's disease. AB - INTRODUCTION: Pain affects between 40 and 85% of Parkinson's disease (PD) patients. It is a frequently disabling and overlooked feature, which can significantly reduce health-related quality of life. Unfortunately, there are no universally recommended treatments for this condition. AREAS COVERED: Evidence about the efficacy and safety of available analgesic treatments is summarized in this review. Potential targets for upcoming therapies are then discussed in light of what is currently known about the physiopathology of pain in PD. Protocols for efficacy and safety assessment of novel analgesic therapies are discussed. Finally, critical aspects of study protocol design such as patient selection or outcomes to be evaluated are discussed. EXPERT OPINION: Preliminary results indicate that duloxetine, cranial electrotherapy stimulation, rotigotine, subthalamic or pallidum nuclei stimulation or lesion or levodopa could be effective for treating pain in PD. Similarly, some case reports indicate that repetitive transcranial magnetic stimulation (rTMS) or apomorphine could be effective for relieving painful off-period dystonia. Clinical trials with rTMS or oxycodone/naloxone prolonged-release tablets for neuropathic pain or botulinum toxin for off-period dystonia are underway. Success of clinical trials about analgesic strategies in PD will depend on the selection of the right PD population to be treated, according to the type of pain, and the proper selection of study outcomes and follow-up of international recommendations. PMID- 22530853 TI - Human amniotic mesenchymal stem cell-derived induced pluripotent stem cells may generate a universal source of cardiac cells. AB - Human amniotic mesenchymal stem cells (hAMSCs) demonstrated partially pluripotent characteristics with a strong expression of Oct4 and Nanog genes and immunomodulatory properties characterized by the absence of HLA-DR and the presence of HLA-G and CD59. The hAMSCs were reprogrammed into induced pluripotent stem cells (iPSCs) that generate a promising source of universal cardiac cells. The hAMSC-derived iPSCs (MiPSCs) successfully underwent robust cardiac differentiation to generate cardiomyocytes. This study investigated 3 key properties of the hAMSCs and MiPSCs: (1) the reprogramming efficiency of the partially pluripotent hAMSCs to generate MiPSCs; (2) immunomodulatory properties of the hAMSCs and MiPSCs; and (3) the cardiac differentiation potential of the MiPSCs. The characteristic iPSC colony formation was observed within 10 days after the transduction of the hAMSCs with a single integration polycistronic vector containing 4 Yamanaka factors. Immunohistology and reverse transcription polymerase chain reaction assays revealed that the MiPSCs expressed stem cell surface markers and pluripotency-specific genes. Furthermore, the hAMSCs and MiPSCs demonstrated immunomodulatory properties enabling successful engraftment in the SVJ mice. Finally, the cardiac differentiation of MiPSCs exhibited robust spontaneous contractility, characteristic calcium transience across the membrane, a high expression of cardiac genes and mature cardiac phenotypes, and a contractile force comparable to cardiomyocytes. Our results demonstrated that the hAMSCs are reprogrammed with a high efficiency into MiPSCs, which possess pluripotent, immunomodulatory, and precardiac properties. The MiPSC-derived cardiac cells express a c-kit cell surface marker, which may be employed to purify the cardiac cell population and enable allogeneic cardiac stem cell therapy. PMID- 22530854 TI - Metabolic risk factors and skin cancer in the Metabolic Syndrome and Cancer Project (Me-Can). AB - BACKGROUND: Little is known about the associations of metabolic aberrations with malignant melanoma (MM) and nonmelanoma skin cancer (NMSC). OBJECTIVES: To assess the associations between metabolic factors (both individually and combined) and the risk of skin cancer in the large prospective Metabolic Syndrome and Cancer Project (Me-Can). METHODS: During a mean follow-up of 12 years of the Me-Can cohort, 1728 (41% women) incident MM, 230 (23% women) fatal MM and 1145 (33% women) NMSC were identified. Most NMSC cases (76%) were squamous cell carcinoma (SCC) (873, 33% women). Hazard ratios (HRs) were estimated by Cox proportional hazards regression for quintiles and standardized z-scores (with a mean of 0 and SD of 1) of body mass index (BMI), blood pressure, glucose, cholesterol, triglycerides and for a combined metabolic syndrome score. Risk estimates were corrected for random error in the measurements. RESULTS: Blood pressure per unit increase of z-score was associated with an increased risk of incident MM cases in men and women [HR 1.17, 95% confidence interval (CI) 1.04-1.31 and HR 1.18, 95% CI 1.03-1.36, respectively] and fatal MM cases among women (HR 2.39, 95% CI 1.58 3.64). In men, all quintiles for BMI above the reference were associated with a higher risk of incident MM. In women, SCC NMSC risk increased across quintiles for glucose levels (P-trend 0.02) and there was a trend with triglyceride concentration (P-trend 0.09). CONCLUSION: These findings suggest that mechanisms linked to blood pressure may be involved in the pathogenesis of MM. SCC NMSC in women could be related to glucose and lipid metabolism. PMID- 22530856 TI - What constitutes original scholarship? PMID- 22530855 TI - Social constraints to TB/HIV healthcare: accounts from coinfected patients in South Africa. AB - There is a growing imperative to improve the coordination and collaboration of tuberculosis (TB) and HIV healthcare services in response to escalating rates of TB/HIV coinfection. Patient-specific challenges associated with the delivery of TB/HIV care have been minimally explored in this regard. As part of a larger study conducted in South Africa, this article highlights coinfected patients' experiences with TB and HIV healthcare in light of their broader social environments. Qualitative, in-depth interviews were conducted with 40 adult, coinfected patients (24 women and 16 men) and eight key-informant healthcare workers at three urban/peri-urban, ambulatory, public health clinics in the high burden province of KwaZulu-Natal. Transcribed interviews were analyzed under a modified grounded theory approach to capture subjective meanings of healthcare experience subsequent to patients' codiagnosis with TB and HIV. Emerging analytic themes highlighted critical sociomedical constraints to TB/HIV care in relation to patients' income and employment, eligibility for social assistance and antiretroviral treatment, fears around illness disclosure, social and material support, and treatment adherence. Patients' healthcare experiences were bound by their poor access to essential resources, multiple life responsibilities, disparate gender roles, limits within the healthcare system, and the stigmatizing social symbolism of their illness. Overlapping social inequalities perpetuated coinfected patients' experiences with stigma and collectively mediated their health decisions around disclosure, adherence, and retention in medical care. The study urges a contextualized understanding of the social challenges associated with TB/HIV healthcare and helps inform more patient-sensitive and socially responsive interventions against the co-epidemic. PMID- 22530857 TI - Cardinal John Henry Newman and 'the ideal state and purpose of a university': nurse education, research and practice development for the twenty-first century. AB - Cardinal John Henry Newman's book, The Idea of a University, first published in the mid nineteenth century, is often invoked as the epitome of the liberal Enlightenment University in discussions and debates about the role and purpose of nurse education. In this article I will examine Newman's book in greater detail and with a more critical eye than is generally the case in the writing of nurse academics. In particular, I will focus on the claims that Newman was a champion of the Enlightenment University of the nineteenth century, that he promoted the idea of 'disinterested' universal knowledge for its own sake, that he was an early advocate of the pursuit of knowledge through scientific research, and the supposition that he would have welcomed the discipline of nursing into the University. In each case, I will suggest that these claims are based on an extremely selective reading of Newman's work. I will conclude by employing the example of practice development to propose an alternative way for nursing to find its place in the modern University that does not involve a retreat into what I will argue is an outdated and nostalgic view of the aims and purpose of higher education. PMID- 22530858 TI - Academic freedom and the obligation to ensure morally responsible scholarship in nursing. AB - Academic freedom is generally regarded as being of critical importance to the development, improved understanding, and dissemination of new knowledge in a field. Although of obvious importance to the discipline of nursing, the nature, extent and value of academic freedom and the controversies surrounding it have rarely been considered in the nursing literature. It is a key aim of this paper to redress this oversight by providing a brief examination of: (i) the principle of academic freedom; (ii) the distinction between academic freedom, freedom of speech, and the academic freedom to publish; (iii) the problem of ideological judgments being dressed up as scientific or discipline judgments to supports 'bad' conclusions; and (iv) the standards that might otherwise be appealed to for determining whether maverick manuscripts supporting morally abhorrent conclusions should be accepted for publication. It is suggested that the tenets of academic freedom require robust international debate, with due attention being given to such issues as the development of an international declaration on academic freedom to publish in nursing, how to ensure a robust rebuttal system in nursing journals to counter specious scholarship, and how to better promote the letters pages of nursing journals as a venue for facilitating debate on controversial issues. PMID- 22530859 TI - Finding middle ground: negotiating university and tribal community interests in community-based participatory research. AB - Community-based participatory research (CBPR) has been hailed as an alternative approach to one-sided research endeavors that have traditionally been conducted on communities as opposed to with them. Although CBPR engenders numerous relationship strengths, through its emphasis on co-sharing, mutual benefit, and community capacity building, it is often challenging as well. In this article, we describe some of the challenges of implementing CBPR in a research project designed to prevent cardiovascular disease among an indigenous community in the Pacific Northwest of the United States and how we addressed them. Specifically, we highlight the process of collaboratively constructing a Research Protocol/Data Sharing Agreement and qualitative interview guide that addressed the concerns of both university and tribal community constituents. Establishing these two items was a process of negotiation that required: (i) balancing of individual, occupational, research, and community interests; (ii) definition of terminology (e.g., ownership of data); and (iii) extensive consideration of how to best protect research participants. Finding middle ground in CBPR requires research partners to examine and articulate their own assumptions and expectations, and nurture a relationship based on compromise to effectively meet the needs of each group. PMID- 22530860 TI - What makes patients perceive their health care worker as an epistemic authority? AB - Health care workers' (HCW) perceived epistemic authority (EA) may have an effect on patient decision-making and compliance. The present study investigated the hypotheses that higher EA is attributed to staff perceived to be experts; to physicians rather than nurses; to HCWs who recommend taking a test more than to the ones who make no recommendation. The study was based on a factorial 2 * 2 * 2 within-between subjects design. The questionnaire presented four scenarios, each illustrating a HCW presenting information on a devastating genetic disease. The three variables manipulated were: HCW expertise, HCW role, and making a recommendation or not. After each scenario participants were asked questions about the EA they attributed to the HCW in the scenario. The results show main effects for perceived expertise and recommendation/no recommendation on the level of EA attributed. Expert nurses were judged to have the same high EA as expert physicians. But expert physicians who recommended taking a test were judged as having significantly higher EA than expert physicians who made no recommendation. Among nurses who made no recommendation, expert nurses were evaluated as having significantly higher EA than novices. Since expert nurses were perceived to have equal expertise as expert physicians, it follows that information given by both nurses and physicians can reduce patient uncertainty. PMID- 22530861 TI - Reframing caring as discursive practice: a critical review of conceptual analyses of caring in nursing. AB - This study critically examines the way in which the concept of caring is presented in the nursing literature through conceptual analytic approaches. A critical reflection on the potential consequences of representing a concept of caring as vague and ambiguous, yet central to ontology and epistemology in professional nursing is presented drawing on comparisons between the conceptual analyses of caring, and of structuralist perspectives of language, and how this potentially limits scholarship in this area. A search of the literature revealed nine conceptual papers. These papers highlight the self-referential characteristics of the concept of caring, and of analytical methods in general. It is proposed that this is the result of a systematic adherence to a rigid, structuralist view of language, whereby stable relationships between words and their meanings are assumed. An alternative perspective is offered by viewing caring as a discursive practice rather than a fixed conceptual entity, calling into question the role that the concept plays in nursing practice. A poststructuralist perspective requires caring to be perceived as a discourse of nursing that is fluid and contingent, rather than a central and guiding concept, opening up a new orientation for nursing scholarship in caring research. PMID- 22530862 TI - Owning solutions: a collaborative model to improve quality in hospital care for Aboriginal Australians. AB - Well-documented health disparities between Aboriginal and Torres Strait Islander (hereafter referred to as Aboriginal) and non-Aboriginal Australians are underpinned by complex historical and social factors. The effects of colonisation including racism continue to impact negatively on Aboriginal health outcomes, despite being under-recognised and under-reported. Many Aboriginal people find hospitals unwelcoming and are reluctant to attend for diagnosis and treatment, particularly with few Aboriginal health professionals employed on these facilities. In this paper, scientific literature and reports on Aboriginal health care, methodology and cross-cultural education are reviewed to inform a collaborative model of hospital-based organisational change. The paper proposes a collaborative model of care to improve health service delivery by building capacity in Aboriginal and non-Aboriginal personnel by recruiting more Aboriginal health professionals, increasing knowledge and skills to establish good relationships between non-Aboriginal care providers and Aboriginal patients and their families, delivering quality care that is respectful of culture and improving Aboriginal health outcomes. A key element of model design, implementation and evaluation is critical reflection on barriers and facilitators to providing respectful and culturally safe quality care at systemic, interpersonal and patient/family-centred levels. Nurses are central to addressing the current state of inequity and are pivotal change agents within the proposed model. PMID- 22530863 TI - Black nurse in white space? Rethinking the in/visibility of race within the Australian nursing workplace. AB - This article presents an analysis of data from a critical qualitative study with 14 skilled black African migrant nurses, which document their experiences of nurse-to-nurse racism and racial prejudice in Australian nursing workplaces. Racism generally and nurse-to-nurse racism specifically, continues to be under researched in explorations of these workplaces; when racism is researched, the focus is nurse-to-patient racism and racial prejudice. Similarly, research on the experiences of migrant nurses from a variety of ethnicities in Australia has tended to neglect their experiences of the social dynamics of the workplace, thus reinforcing their racialisation. When racialised, the migrant nurse becomes 'the problem' through a focus on English language competency and ensuing communication barriers. This paper applies Essed's framework of 'everyday racism' to theorise narratives of racism by black African migrant nurses in Australia. In so doing, it not only brings to the fore silenced discussions of nurse-to-nurse racism in Australia, but also exposes the subtle, mundane nature of contemporary racism. For this reason, while the data we present must be read within their context, that is, the Australian nursing workplace, it has significance for advancing a critical analysis of racialised minority groups' experiences of racism within seemingly 'race-less' nursing workplaces internationally. PMID- 22530864 TI - How nurses understand and care for older people with delirium in the acute hospital: a Critical Discourse Analysis. AB - Delirium is a common presentation of deteriorating health in older people. It is potentially deleterious in terms of patient experience and clinical outcomes. Much of what is known about delirium is through positivist research, which forms the evidence base for disease-based classification systems and clinical guidelines. There is little systematic study of nurses' day-to-day practice of nursing patients with delirium. The aim was to uncover the kinds of knowledge that informs nurses' care and to explicate the basis of that knowledge. Critical Discourse Analysis is underpinned by the premise that powerful interests within society mediate how social practices are constructed. Links were made between the grammatical and lexical features of nurses' language about care in interviews and naturalistic settings, and the healthcare context. Care focused on the continuous surveillance of patients with delirium by nurses themselves or vicariously through other patients, and containment. Nurses influenced by major discourses of risk reduction and safety, constructed patients with delirium as risk objects. The philosophy of person-centred and dignified care advocated in nursing literature and government policy is an emerging discourse, though little evident in the data. The current dominant discourses on safety must give space to discourses of dignity and compassion. PMID- 22530865 TI - Rethinking shiftwork: mid-life nurses making it work! AB - Many current analyses of shiftwork neglect nurses' own voices when describing the dis/advantages of a shiftworking lifestyle. This paper reports the findings of a critical re-analysis of two studies conducted with female mid-life Australian nurses to explore the contention that the 'problem-centred' focus of current shiftwork research does not effectively address the 'real' issue for mid-life nurses, that is, how to develop and maintain shiftwork tolerance. Participants used shiftwork to: (i) manage, navigate and negotiate various aspects of their nursing work and the workplace itself; (ii) facilitate more manageable work/life negotiations; and (iii) self-identify opportunities to engage in their own self care (body work and mind work). The findings thus went beyond simply exposing what nursing bodies do in time and space by bringing to the fore discussions of 'time-body' relationships, the embodiment of time and nurses re/configuration of that time demonstrating that the frequently unacknowledged positive aspects of shiftwork, when centred in discussions, give voice to other ways to think about shiftwork and a shiftworking lifestyle. Thus, our contention is that the 'problem centred' focus of current shiftwork debates does little to address the 'real' issue for shiftworking mid-life female nurses - the development and maintenance of shiftwork tolerance. PMID- 22530867 TI - Grid expansion: a rhombiclike [L4Fe2(Ag2)2] complex containing Ag2 dumbbells at two vertices. AB - The pyrazolate-based ditopic ligand HL forms a strongly hydrogen-bonded corner complex dimer [Fe(II)(HL)(2)](2)(BF(4))(4) (1) with a [2 * 2] gridlike arrangement of four ligand strands. The two empty vertices can then be filled with {Ag(2)}(2+) dumbbells, yielding the unprecedented diferric complex [L(4)Fe(III)(2)(Ag(I)(2))(2)](BF(4))(6) (2) that features a rhombiclike structure with an almost planar hexagon of metal ions. PMID- 22530868 TI - A rat model of smoke inhalation injury. AB - CONTEXT: Smoke inhalation injury is the leading cause of acute respiratory failure in critical burn victims. Advances in the treatment of smoke inhalation injury have been limited in the past years. To further explore the pathogenesis, stable and practical animal models are necessary. OBJECTIVE: To develop a rat model of smoke inhalation injury. MATERIALS AND METHODS: The smoke composition including the particulate matters, irritant gases, chemical carcinogens was measured. The blood gas values, pro-inflammatory and protein concentration in bronchoalveolar lavage fluid and lung wet to dry weight ratio were assayed. Pathological evaluations of pulmonary were performed at 24 h, 96 h, 7 days and 28 days post-injury. Masson-Goldner trichrome staining was performed on day 7 and 28 post-injury, along with the measurement of hydroxyproline and collagen I and III. RESULTS: In our present animal model, smoke inhalation caused a significant hypoxemia and CO poisoning. A surge of pro-inflammatory response and microvascular hyperpermeability with neutrophils accumulations were also found in our animal model. At 24 h post-smoke inhalation, the hematoxylin and eosin results exhibited that there were inflammatory exudates and diffuse hemorrhage in the lung tissue with significant edema. With the time going, the lung injuries appeared at alveolar collapse and alveolar septum thickening, which indicated that smoke inhalation further induced damage to lung parenchyma. Specially, the markedly collagen deposition appeared at 28 days post-injury indicated that pulmonary fibrosis happened. DISCUSSION AND CONCLUSION: In conclusion, this rat smoke inhalation injury model induced by our novel self-made smoke generator could be used for acute and chronic lung injury experiments. PMID- 22530869 TI - Negative emotion can enhance human motor cortical plasticity. AB - Although emotion often primes us for action, its effects on the human motor system are not well understood. The relationship between emotion and motor plasticity also remains unclear, despite the close link between emotion and memory formation. Here, we tested the hypothesis that emotion modulates the plasticity of the human primary motor cortex, using the International Affective Picture System and transcranial magnetic stimulation. Intermittent theta-burst stimulation was applied to the primary motor cortex to produce long-term potentiation-like changes in normal volunteers experimentally. Primary motor cortex plasticity was enhanced and sustained in both excitatory and inhibitory systems only when intermittent theta-burst stimulation was combined with the presentation of pictures that induced negative, but not positive or neutral, emotion. Moreover, negative emotion was found to enhance the inhibitory networks within the primary motor cortex, and to improve motor behavior during the choice reaction-time task. Our findings indicate that negative emotion can increase primary motor cortex plasticity by modulating the intracortical GABAergic system, as well as N-methyl-d-aspartic acid receptor-dependent changes. These findings could help to explain the physiological basis of abnormal motor symptoms in psychogenic movement disorders following emotional events. PMID- 22530871 TI - Synergistic action of both Aspergillus niger and Burkholderia cepacea in co culture increases phosphate solubilization in growth medium. AB - Co-inoculation of the fungus Aspergillus niger and the bacterium Burkholderia cepacia was undertaken to understand the interaction between different species of phosphate-solubilizing microorganisms (PSM). PSM were inoculated in a single or mixed (A. niger-B. cepacia) culture. During 9 days of incubation, microbial biomass was enhanced, accompanied with increases in the levels of soluble phosphate and titratable acidity, as well as increased acid phosphatase activity. Production of acids and levels of phosphate solubilization were greater in the co culture of A. niger-B. cepacia than in the single culture. The quantity of phosphate solubilized by the co-culture ranged from 40.51 +/- 0.60 to 1103.64 +/- 1.21 MUg PO(4) 3- mL(-1) and was 9-22% higher than single cultures. pH of the medium dropped from 7.0 to 3.0 in the A. niger culture, 3.1 in the co-culture, and 4.2 in the B. cepacia culture. On the third day of postinoculation, acid production by the co-culture (mean 5.40 +/- 0.31 mg NaOH mL(-1)) was 19-90% greater than single cultures. Glucose concentration decreased almost completely (97-99% of the starting concentration) by the ninth day of the incubation. These results show remarkable synergism by the co-culture in comparison with single cultures in the solubility of CaHPO(4) under in vitro conditions. This synergy between microorganisms can be used in poor available phosphate soils to enhance phosphate solubilization. PMID- 22530870 TI - Polyploid evolution and Pleistocene glacial cycles: A case study from the alpine primrose Primula marginata (Primulaceae). AB - BACKGROUND: Recent studies highlighted the role of Pleistocene climatic cycles in polyploid speciation and of southern Alpine refugia as reservoirs of diversity during glacial maxima. The polyploid Primula marginata, endemic to the southwestern Alps, includes both hexaploid and dodecaploid cytotypes that show no ecological or morphological differences. We used flow cytometry to determine variation and geographic distribution of cytotypes within and between populations and analyses of chloroplast (cp) and nuclear ribosomal (nr) DNA sequences from the Internal Transcribed Spacer (ITS) region to infer the evolutionary history of the two cytotypes and the auto- vs. allopolyploid origin of dodecaploid populations. RESULTS: We did not detect any intermediate cytotypes or variation of ploidy levels within populations. Hexaploids occur in the western and dodecaploids in the eastern part of the distributional range, respectively. The cpDNA and nrDNA topologies are in conflict, for the former supports shared ancestry between P. marginata and P. latifolia, while the latter implies common origins between at least some ITS clones of P. marginata and P. allionii. CONCLUSIONS: Our results suggest an initial episode of chloroplast capture involving ancestral lineages of P. latifolia and P. marginata, followed by polyploidization between P. marginata-like and P. allionii-like lineages in a southern refugium of the Maritime Alps. The higher proportion of ITS polymorphisms in dodecaploid than in hexaploid accessions of P. marginata and higher total nucleotide diversity of ITS clones in dodecaploid vs. hexaploid individuals sequences are congruent with the allopolyploid hypothesis of dodecaploid origin. PMID- 22530872 TI - Investigation of enzymatic hydrolysis conditions on the properties of protein hydrolysate from fish muscle (Collichthys niveatus) and evaluation of its functional properties. AB - This study was carried out to investigate the enzymatic hydrolysis conditions on the properties of protein hydrolysate from fish muscle of the marine fish species Collichthys niveatus. About 160 fish samples were tested, and the analyzed fish species was found to be a lean fish with low fat (1.77 +/- 0.01%) and high protein (16.76 +/- 1.21%). Fish muscle of C. niveatus was carefully collected and hydrolyzed with four commercial enzymes: Alcalase, Neutrase, Protamex, and Flavourzyme under the conditions recommended by the manufacturers. Among the tested proteases, Neutrase catalyzed the hydrolysis process most effectively since the hydrolysate generated by Neutrase has the highest content of sweet and umami taste amino acids (SUA). The effect of hydrolysis conditions was further optimized using response surface methodology (RSM), and the optimum values for temperature, pH, and enzyme/substrate ratio (E/S ratio) were found to be 40.7 degrees C, 7.68, and 0.84%, respectively. Finally, the amino acid composition of the hydrolysate was analyzed by AccQ.Tag derivatization and HPLC-PDA determination. Major amino acids of the muscle of C. niveatus were threonine, glutamic acid, phenyalanine, tryptophan, and lysine, accounting for respectively 10.92%, 10.85%, 10.79%, 9.86%, and 9.76% of total amino acid content. The total content of essential amino acids was 970.7 ng.mL(-1), while that of nonessential amino acids was 709.1 ng.mL(-1). The results suggest that the fish muscle and its protein hydrolysate from C. niveatus provide a versatile supply of the benefits and can be incorporated as supplements in health-care foods. PMID- 22530873 TI - Hydroclimatological variability and dengue transmission in Dhaka, Bangladesh: a time-series study. AB - BACKGROUND: While floods can potentially increase the transmission of dengue, only few studies have reported the association of dengue epidemics with flooding. We estimated the effects of river levels and rainfall on the hospital admissions for dengue fever at 11 major hospitals in Dhaka, Bangladesh. METHODS: We examined time-series of the number of hospital admissions of dengue fever in relation to river levels from 2005 to 2009 using generalized linear Poisson regression models adjusting for seasonal, between-year variation, public holidays and temperature. RESULTS: There was strong evidence for an increase in dengue fever at high river levels. Hospitalisations increased by 6.9% (95% CI: 3.2, 10.7) for each 0.1 metre increase above a threshold (3.9 metres) for the average river level over lags of 0-5 weeks. Conversely, the number of hospitalisations increased by 29.6% (95% CI: 19.8, 40.2) for a 0.1 metre decrease below the same threshold of the average river level over lags of 0-19 weeks. CONCLUSIONS: Our findings provide evidence that factors associated with both high and low river levels increase the hospitalisations of dengue fever cases in Dhaka. PMID- 22530874 TI - The impact of macular edema on visual function in intermediate, posterior, and panuveitis. AB - PURPOSE: To evaluate the impact of macular edema on visual acuity and visual field sensitivity in uveitis. DESIGN: This study utilized baseline data from the Multicenter Uveitis Steroid Treatment (MUST) Trial, a randomized, parallel treatment clinical trial comparing alternative treatments for intermediate, posterior and panuveitis. PATIENTS & METHODS: 255 patients (481 eyes with uveitis) recruited at 23 subspecialty centers. Visual acuity, optical coherence tomography and Humphrey 24-2 visual field testing. RESULTS: Macular edema was associated with impaired visual acuity (p < 0.01). Different phenotypes of macular edema were associated with different degrees of visual impairment: cystoid changes without retinal thickening were associated with moderately impaired visual acuity (-5 ETDRS letters), but visual acuity was worse in eyes with retinal thickening (-13 letters) and with both cysts and thickening (-19 letters). Uveitis sufficient to satisfy the study's inclusion criteria was associated with impaired visual field sensitivity, but eyes with macular edema had even worse visual field sensitivity (p < 0.01). CONCLUSIONS: The observation that macular edema substantially reduces visual function suggests macular edema itself is an important endpoint to study in the treatment of uveitis. As uveitis and macular edema both impair visual field sensitivity as measured by Humphrey 24 2 perimetry, both should be considered when evaluating patients with uveitis and raised intraocular pressure for glaucoma. PMID- 22530875 TI - Current and emerging indications for implantable cardiac monitors. AB - Implantable cardiac monitors (ICMs) continuously monitor the patient's electrocardiogram and perform real-time analysis of the heart rhythm, for up to 36 months. The current clinical use of ICMs involves the evaluation of transitory symptoms of possible arrhythmic origin, such as unexplained syncope and palpitations. Moreover, ICMs can also be used for the evaluation of difficult cases of epilepsy and unexplained falls, though current indications for their application in these sectors are less clearly defined. Finally, the ability of new-generation ICMs to automatically record arrhythmic episodes suggests that these devices could also be used to study asymptomatic arrhythmias, and thus could be proposed for the long-term evaluation of the total (symptomatic and asymptomatic) arrhythmic burden in patients at risk of arrhythmic events. In particular, ICMs may have an emerging role in the management of patients with atrial fibrillation and in those at risk of ventricular arrhythmias. PMID- 22530876 TI - Can the 50-g glucose challenge test be important for subsequent pregnancies? AB - AIM: Our aim in this study was to examine the risk factors associated with gestational diabetes mellitus (GDM) in women who did not have GDM during a previous pregnancy. MATERIALS AND METHODS: In this retrospective cohort study, we reviewed the charts of all pregnant women who delivered two pregnancies between January 2000 and June 2010. Group 1 consisted of patients with gestational diabetes and Group 2 served as the control. RESULTS: There were 743 women who underwent GDM screening by means of the 50-g glucose challenge test (GCT). Thirty eight women (5.1%) were excluded because of a previous history of GDM. The recurrence of GDM was 42.1% in this group (16 of the 38). The remaining 705 patients were divided into the GDM group (n = 38) and the control group (n = 667). Undergoing a 50-g GCT during the previous pregnancy (p = 0.000, 95% CI +0.01 to +0.002), age (p = 0.009, 95% CI +0.001 to +0.009), and weight differences between the pregnancies at the first trimester (p = 0.005, 95% CI +0.001 to +0.007) were independent parameters related to GDM. CONCLUSION: The 50 g GCT during the previous pregnancy was, interestingly, increased in the GDM group. It was also an independent risk factor for women without a history of GDM. PMID- 22530878 TI - Analytical methods for characterizing high-mass complex polydisperse hydrocarbon mixtures: an overview. PMID- 22530877 TI - Socio-economic and ethnic differences in the prevalence of overweight and obesity among school children. AB - AIMS: To trial the collection of measurements to provide population-based prevalence of overweight and obesity in school children in western Sydney and examine the association between healthy weight and ethnicity and socio-economic status (SES) in a socio-economically and culturally diverse population. METHODS: A cross-sectional population-based survey of 2341 children in Years 4 and 7 (mean ages 9 and 12 years, respectively) in 2007. RESULTS: Nineteen percent of children were overweight and a further 6% were obese. The prevalence of combined overweight and obesity was similar for boys and girls (26% vs. 24%, P= 0.35). SES was significantly associated with the prevalence of unhealthy weight: the odds of being overweight or obese were 1.79 times (95% confidence interval (CI) 1.35 to 2.36) higher for children from the lowest quartile than for children from the highest quartile. Compared to children from an English speaking background, children from a non-English speaking background were significantly more likely to be overweight or obese (21% vs. 31%, P < 0.001). The prevalence of combined overweight and obesity was significantly higher for children from a Pacific Island (odds ratio (OR) 2.66, 95% CI 1.63 to 4.33), Middle Eastern (OR 1.63, 95% CI 1.22 to 2.17) or European (OR 1.67, 95% CI 1.12 to 2.49) background than for English speaking background children. CONCLUSION: Large jumps in the prevalence of overweight and obesity in children observed from the 1980s appear to be diminishing, with comparable prevalence reports in 2004 and 2007. Ethnicity and SES are each independently associated with the prevalence of unhealthy weight in children. PMID- 22530879 TI - Overweight and obese boys reduce food intake in response to a glucose drink but fail to increase intake in response to exercise of short duration. AB - The effect of short duration exercise (EXR) on food intake (FI) and energy balance (EB) is not well understood in either normal weight (NW) or overweight (OW) and obese (OB) 9-14 years old children. Our purpose was to describe the effects of activity and a glucose drink on short term FI, appetite, and EB in NW, OW, and OB boys. Each boy received in random order either a noncaloric Sucralose sweetened control or glucose (1.0 g.kg(-1) body weight) drink 5 min after either exercise (EXR) or sedentary (SED) activity. Boys exercised for 15 min at their ventilation threshold (V(T)) in experiment 1 or at 25% above their V(T) in experiment 2. FI was measured at an ad libitum pizza meal 30 min after drink consumption. FI was lower after the glucose drink (p < 0.001) but not affected by activity, even though EXR increased appetite (p < 0.001). OW/OB boys ate more total food than NW boys (p = 0.020). EB over the duration of the experiments was reduced by EXR in OW/OB boys (p = 0.013) but not in NW boys in either experiment (p > 0.05). We conclude that intake regulation in OW/OB boys in response to a glucose drink is similar to NW boys, but it may be less responsive to activity. PMID- 22530880 TI - Evaluation of the pharmacokinetics and clinical utility of isavuconazole for treatment of invasive fungal infections. AB - INTRODUCTION: Invasive fungal infections remain a leading cause of infectious morbidity and mortality in immunocompromised patients. There are relatively few effective antifungal agents, and currently available agents all have significant limitations. Isavuconazole is a novel second-generation triazole with broad spectrum antifungal activity, and a favorable pharmacokinetic-pharmacodynamic profile. Isavuconazole is available as an oral and intravenous formulation. Phase III studies that are examining the efficacy of isavuconazole for invasive candidiasis and invasive aspergillosis are currently in progress. AREAS COVERED: This review provides a summary of the pharmacological characteristics of isavuconazole and the potential future use of this agent. The preclinical and clinical pharmacokinetics and pharmacodynamics are discussed. This review was constructed by searching isavuconazole, triazole, pharmacokinetics and pharmacodynamics in PubMed. References and abstracts that were not identified by this method were retrieved from the respective publications. EXPERT OPINION: Isavuconazole has the potential to become an important agent for the treatment of invasive fungal infections, principally because of its relatively broad and potent in vitro antifungal activity, and its favorable pharmacokinetic profile. Further preclinical and clinical studies are required to define the clinical utility of this agent, especially for invasive candidiasis and invasive aspergillosis. Further information is required on the likely drug interactions, and in vitro susceptibility breakpoints for medically important invasive fungal pathogens. Further pharmacokinetic studies are also required in a range of patient populations to quantify the extent and sources of pharmacokinetic variability. PMID- 22530883 TI - Elevated factor VIII levels and risk of venous thrombosis. AB - Modern thrombophilia testing fails to identify any underlying prothrombotic tendency in a significant number of patients presenting with objectively confirmed venous thromboemboembolism (VTE). This observation has led to a search for other novel inherited or acquired human thrombophilias. Although a number of putative mechanisms have been described, the evidence behind many of these candidates remains weak. In contrast, an increasing body of work supports the hypothesis that increased plasma factor VIII (FVIII) levels may be important in this context. An association between elevated plasma FVIII levels and VTE was first described in the Leiden Thrombophilia Study (LETS). Subsequently, these conclusions have been supported by an increasing number of independent case control studies. Cumulatively, these studies have clearly demonstrated that high FVIII levels constitute a prevalent, dose-dependent risk factor for VTE. Furthermore, more recent studies have shown that the risk of recurrent venous thrombosis is also significantly increased in patients with high FVIII levels. In this review, we present the evidence supporting the hypothesis that elevated FVIII levels constitute a clinically important thrombophilia. In addition, we examine the biological mechanisms that may underlie persistently elevated FVIII levels, and the pathways through which high FVIII may serve to increase thrombotic risk. PMID- 22530884 TI - Structural features of the C-terminus from the human neurokinin-1 receptor. AB - The neurokinin-1 receptor (NK1R) is a G-protein coupled receptor found in the central and peripheral nervous systems of vertebrates, and is responsible for many physiological processes. The C-terminus domain seems to be essential for coupling to the corresponding G-protein and beta-arrestin, and is important for receptor desensitization, internalization and recycling. We have focused our study on expression of the human NK1R (hNK1R) C-terminus in Escherichia coli, and its purification and characterization, in order to elucidate its structural properties. CD and Fourier transform infrared spectroscopy showed that the hNK1R C-terminus, rather than having a random structure, has well-defined secondary structure patterns. The presence of three tyrosine residues in the primary sequence of the hNK1R C-terminus facilitated the use of UV and fluorescence spectroscopy techniques which revealed tyrosine fluorescence and UV absorption at anomalous wavelengths. In their entirety, the results show that the hNK1R C terminus has clearly defined secondary (25% alpha-helix, 27% unordered structure and 48% beta-sheets and beta-turns) and tertiary structures which, it is believed, are tightly related to its multiple functions. PMID- 22530882 TI - Mesenchymal stem cell-based tumor-targeted gene therapy in gastrointestinal cancer. AB - Mesenchymal stem (or stromal) cells (MSCs) are nonhematopoietic progenitor cells that can be obtained from bone marrow aspirates or adipose tissue, expanded and genetically modified in vitro, and then used for cancer therapeutic strategies in vivo. Here, we review available data regarding the application of MSC-based tumor targeted therapy in gastrointestinal cancer, provide an overview of the general history of MSC-based gene therapy in cancer research, and discuss potential problems associated with the utility of MSC-based therapy such as biosafety, immunoprivilege, transfection methods, and distribution in the host. PMID- 22530885 TI - Effect of ageing on post-lesion oestradiol treatment on mouse cholinergic neurones in vivo. AB - A single 17beta-oestradiol (E(2)) treatment reduces the loss in cholinergic fibre density in the cortex after NMDA lesion into the nucleus basalis magnocellularis (NBM) of the basal forebrain (BF) in young female mice. In the present study, we examined whether age influences this protective effect of E(2) on cholinergic neurones in male and female mice. Gonad-intact young and aged animals of both sexes were treated with E(2) after unilateral NMDA lesion into the NBM. NMDA lesion elicited ipsilateral cholinergic cell loss in the NBM and ipsilateral fibre loss in the somatosensory cortex to the same extent, irrespective of age or sex. A single E(2) injection performed 1 h post-lesion did not affect the cholinergic cell loss but reduced the loss of fibres in the ipsilateral cortex in young male and female mice. By contrast, E(2) did not have an effect on the NMDA induced cholinergic cell and fibre loss in aged male or female mice. The oestrous stage of young female mice did not alter the number of cholinergic cells/fibres or the protective effect of E(2) on cholinergic fibres after NMDA injection. Our results show that E(2) has a protective action on BF cholinergic fibres in young males and females, although the treatment potential of E(2) declines with age. PMID- 22530886 TI - Synthesis, structure, and reactivity of dinuclear nickel amino-thiophenolate complexes bearing bridging VO2(OH)2- and VO2(OR)2- coligands. AB - A series of novel mixed ligand dinickel complexes of the type [Ni(II)(2)L(MU L')](+), where L' is a tetrahedral oxo-alkoxo vanadate (L' = [O(2)V(V)(OR)(2)]( ), R = H or alkyl) and L a macrocyclic N(6)S(2) supporting ligand, have been prepared, and their esterification reactivity has been studied. The orthovanadate complex [Ni(2)L(MU-O(2)V(OH)(2))](+) (2), prepared by reaction between [Ni(2)L(MU Cl)]ClO(4) with Na(3)VO(4) and a phase transfer reagent in CH(3)CN, reacts smoothly with MeOH and EtOH forming the vanadate diesters [Ni(2)L(MU O(2)V(OMe)(2))](+) (3) and [Ni(2)L(MU-O(2)V(OEt)(2))](+) (4). The dialkyl orthovanadate esters in 3 and 4 are readily transesterified with mono- and difunctional alcohols. Complex 3 can also be generated from 4 by transesterification with MeOH. Complexes 3 and 4 react with diols (ethylene glycol, propylene glycol and diethylene glycol) as well to afford the complexes [Ni(2)L(MU-O(2)V(OH)(OCH(2)CH(2)OH))](+) (5), [Ni(2)L(MU O(2)V(OCH(2))(2)CH(2))](+) (6), and [Ni(2)L(MU-O(2)V(OCH(2)CH(2))(2)O)] (7). The crystal structures of the tetraphenylborate salts of complexes 3-7 reveal in each case four-coordinate O(2)V(V)(OR)(2)(-) groups bonded in a MU(1,3)-bridging mode to generate trinuclear complexes with a central N(3)Ni(MU-S)(2)(MU(1,3) O(2)V(OR)(2))NiN(3) core. The stabilization of the four-coordinate V(V)O(2)(OR)(2)(-) moieties is a consequence of both the two-point coordinative fixation to and the steric protection of the bowl-shape binding pocket of the [Ni(2)L](2+) fragment. Cyclic voltammetry experiments reveal that the encapsulated vanadate esters are not reduced in a potential window of -2.0 to +2.5 V vs SCE. The spins of the nickel(II) (S(i) = 1 ions) in 3 are weakly ferromagnetically coupled (J = +23 cm(-1), (H = -2JS(1)S(2))) to produce an S = 2 ground state. PMID- 22530887 TI - Four-component synthesis of 1,2-dihydropyridine derivatives and their evaluation as anticancer agents. AB - Two series of compounds with the general formula of 4,6-diaryl-2-oxo-1,2 dihydropyridine-3-carbonitriles and their isosteric imino derivatives were synthesized through a one pot reaction of acetophenone, aldehyde and ammonium acetate with ethyl cyanoacetate or malononitrile, respectively. The synthesized compounds were evaluated for tumor cell growth inhibitory using the human HT-29 colon and MDA-MB-231 breast tumor cell lines. Compound 4-(2- Ethoxyphenyl)-2 imino-6-(4-fluorophenyl)-1,2-dihydropyridine-3 carbonitrile (6) showed IC50 value of 0.70 MUM versus HT-29. Meanwhile, compound 4-(2-Hydroxyphenyl)-2-imino-6-(4 fluorophenyl)-1,2-dihydropyridine-3-carbonitrile (4) showed IC50 value of 4.6 MUM versus MDA-MB-231. Docking compound 10 to possible molecular targets, survivin and PIM1 kinase showed appreciable interactions with both, which suggest possible targets for the antitumor activity of this novel class of anticancer compounds. PMID- 22530888 TI - CoMFA and CoMSIA studies of 1,2-dihydropyridine derivatives as anticancer agents. AB - Taking advantage of our in-house experimental data on 3-cyano-2-imino-1, 2 dihydropyridine and 3-cyano-2- oxo-1,2-dihydropyridine derivatives as inhibitors of the growth of the human HT-29 colon adenocarcinoma tumor cell line, we have established a highly significant CoMFA and CoMSIA models (q2cv=0.70/0.639). The models were investigated to assure their stability and predictivity (r2pred=0.65/0.61) and successfully applied to design two new potential cell growth inhibitory agents with IC50s in the submicromolar range. PMID- 22530889 TI - First study on antimicriobial activity and synergy between isothiocyanates and antibiotics against selected Gram-negative and Gram-positive pathogenic bacteria from clinical and animal source. AB - The emergence of new diseases and the resurgence of several infections that were controlled in the past, associated with recent increase of bacterial resistance have created the necessity for more studies towards to the development of new antimicrobials and new treatment strategies. The aim of the present study was to evaluate the in vitro synergy between different classes of important glucosinolates hydrolysis products-isothiocyanates with antibiotics (gentamycin and vancomycin), against important pathogenic bacteria: Escherichia coli, Enterococcus faecalis, Listeria monocytogenes, Pseudomonas aeruginosa and Staphylococcus aureus. A disc diffusion method was used to evaluate the antibacterial activity. The antimicrobial activity of phytochemicals and combinations between gentamycin, vancomycin and phytochemicals were quantitatively assessed by measuring the inhibitory halos. The results showed a selective antimicrobial effect of isothiocyanates, and this effect was strictly related with their chemical structure. In general the benzylisothiocyanate was the most effective compound against both Gram-positive and Gram-negative bacteria. The Listeria monocytogenes and Staphylococcus aureus were the bacteria most affected either by the phytochemicals alone or by the combination phytochemical-antibiotic. The bacteria Pseudomonas aeruginosa was the less affected pathogen. The most important synergism detected occurred between the commercial antibiotics with benzylisothiocyanate and 2-phenylethylisothiocyanate. In conclusion, some isothiocyanates are effective inhibitors of in vitro bacterial growth, and they can act synergistically with antibiotics. PMID- 22530890 TI - In vitro anti-glycation and anti-oxidant properties of synthesized Schiff bases. AB - A series of mono, bis and mixed Schiff bases (1-7) were synthesised and evaluated for potential anti-glycation and anti-oxidant activities using the bovine serum albumin-glucose assay and 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical assay respectively. All compounds showed significant (p<0.05) antiglycating activities with IC50 values (4.02x10(-24)+/-0.1-2.88x10(-1)+/-1.35 mM) which were lower than the standard positive control aminoguanidine (IC50: 1.51x10(-3)+/-2.11 mM). Moreover, compounds 1-7 were found to possess significant (p<0.05) DPPH radical scavenging properties with SC50 values (1.31x10(-19)+/-0.05 to 2.25x10(-1)+/-1.24 mM) lower than the standard ascorbic acid (SC50: 5.50x10(-3)+/-2.11 mM). Compound 6 was found to be the most potent anti-glycating molecule (IC50 value: 4.02x10( 24)+/-0.1 mM) while compound 5 was the most potent anti-oxidant molecule (SC50: 1.31x10(-19)+/-0.05 mM); both being significantly lower (p<0.05) than the respective positive controls used. The present data showed that the number of phenolic OH together with structural changes influence both the anti-glycation and anti-oxidant observed herein. This study provides for the first time a series of potential template molecules for possible pharmaceutical applications that warrant further investigation as potential anti-glycation and anti-oxidant agents which could be of importance in metabolic diseases including diabetes mellitus. PMID- 22530891 TI - Synthesis and biological evaluation of the salicylamide and salicylic acid derivatives as anti-estrogen agents. AB - Alkylphenols have xenoestrogenic activity, which mimic the action of physiological estrogens and these mimicking activities are mainly mediated by nongenomic pathway. Nongenomic pathway plays a pivotal role in breast, endometrial and ovarian cancers' growth and development. In this study, various alkylphenol derivatives were prepared and screened for their anti-uterotrophic and uterotrophic activity. Among these compounds, 2-hydroxy-5-nonanoylbenzamide (compound 1b) showed 93.99% inhibitory activity in the anti-uterotrophic test performed, and was found inactive in the uterotrophic activity test. Moreover, all test compounds were examined for the effect on uterine histopathological changes, and plasma 17beta-estradiol (E2) level. Compound 1b was also tested for in vitro anti-cancer activity against ER+, human breast cancer cell line MCF-7, and it reduced cell viability to 74.01% at 50 nM concentration. PMID- 22530892 TI - Synthesis and activity of [{Cis-PtCl(NH3)2}2u{trans-Pt(3 Hydroxypyridine)2(H2N(CH2)6NH2)2}]Cl4 in the human ovarian tumour models. AB - A novel trinuclear platinum compound with a cis-geometry for terminal metal centres coded as QH1 has been synthesized, characterized and investigated for activity against the human ovarian A2780, A2780cisR and A2780ZD0473R cancer cell lines. The cellular accumulation of platinum, level of platinum-DNA binding and the nature of interaction of the compound with pBR322 plasmid DNA have also been determined. QH1 is found to be more active against the resistant cell lines than the parent cell line, thus indicating that the compound has been able to overcome mechanisms of resistance operating in the A2780cisR and A2780ZD0473R cell lines. The high activity of QH1 is associated with high platinum accumulation and high level of platinum-DNA binding in all the three ovarian cancer cell lines. Provided QH1 has the right toxicity profile and its in vitro activity is matched with sufficient activity in vivo, the compound has the potential for development as a novel platinum-based anticancer drug targeted to the ovarian cancer. PMID- 22530893 TI - Biological and anti-inflammatory evaluation of two thiazole compounds in RAW cell line: potential cyclooxygenase-2 specific inhibitors. AB - The anti-inflammatory effect of two new thiazoles derivatives CX-32 (N-[4-(4 hydroxy-3-methoxyphenyl)-1,3-thiazol-2-yl]acetamide) and CX-35 (4-(2-amino-1,3 thiazol-4-yl)-2-methoxyphenol), was investigated in LPS-stimulated RAW 264.7 cell line. Synthesis, structure analysis and purity of these compounds were evaluated by high performance liquid chromatography, H1 NMR, and C13 NMR. Assessment of CX 32 and CX-35 inhibitory effect on cyclooxygenase-2 (COX-2) activity was achieved by incubating LPS-activated RAW cells with 25 MUM, 50 MUM or 100 MUM of CX-32 or CX-35 respectively. Levels of secreted PGE2 were evaluated by enzyme immunoassay (EIA) and levels of COX-2 protein were measured by western blot. Finally, cell viability experiments were undertaken to assess the toxicity of each compound. Treatment of LPS-activated RAW cells with 25 MUM, 50 MUM, or 100 MUM of CX-35 or CX-32 respectively, prevented the production of prostaglandins, but was without effect on COX-2 protein levels. Moreover, CX-35 and CX-32 reduced PGE2 production to levels comparable to those obtained in LPS-activated RAW cells incubated with the selective COX-2 inhibitor NS 398. Furthermore, both CX-32 and CX-35 showed no toxic effects, since viability of non-treated Hela cells was similar to Hela cells incubated with either CX-35 or CX-32. Our data demonstrated that CX-32 and CX-35 significantly blocked prostaglandin production induced during inflammatory cellular stress, possibly acting through specific COX-2 inhibition; confirmation of this hypothesis requires further investigation. PMID- 22530894 TI - New adamantane derivatives with sigma affinity and antiproliferative activity. AB - The synthesis of 4-(1-adamantyl)-4,4-diarylbutylamines 1, 5-(1-adamantyl)-5,5 diarylpentylamines 2 and 6-(1-adamantyl)-6,6-diarylhexylamines 3 is described and the sigma1, sigma2-receptors and sodium channels binding affinity of compounds 1 were investigated. The in vitro activity of compounds 1, 2 and 3 against main cancer cell lines is significant. One of the most active analogs, 1a, had an interesting in vivo anticancer profile against the ovarian cancer cell line IGROV 1, which was associated with an anagelsic activity against the neuropathic pain induced by the main anticancer drugs. PMID- 22530895 TI - Synthesis of novel 4-aryl-1,2,3,4-tetrahydroisoquinolines as probes for dopamine receptor ligands. AB - Dopamine (DA) agonists, bearing catechol or phenol rings, are endowed with low oral bioavailability and short effect duration. In this report, the synthesis of novel differently substituted 4-(3-pyridyl)-1,2,3,4-tetrahydroisoquinolines and (1,2,3,4-tetrahydroisoquinolin-4-yl)phenylmethanols as potential non phenolic and non catecholic DA receptor ligands is reported. The new compounds, evaluated by binding tests on cerebral striatal membranes, bound to DA receptors with moderate affinity. Anyhow, they may represent a starting point to develop new DA ligands endowed with better pharmacokinetic and metabolic properties. PMID- 22530896 TI - A quantitative structure-activity relationship study on a few series of anti hepatitis C virus agents. AB - A 2-Dimensional Quantitative Structure-Activity Relationship study has been performed on 2 series of hepatitis C virus (HCV) inhibitors, i.e., Isothiazoles and Thiazolones. In each case significant correlations are found between the anti HCV potencies and some physicochemical, electronic and steric properties of the compounds, indicating that for the first series the activity is controlled by density and two indicator parameters (one for halogen and other for methyl), while for the second series density, Hammett constant and Kier's first order valence molecular connectivity index are important for anti-HCV activity. The validity of the correlation has been judged by leave-one-out jackknife procedure and predicting the activity of some test compounds. Using the correlations obtained, some new compounds of high potency have been predicted in each series. PMID- 22530897 TI - Synthesis and antiglycation activity of kaempferol-3-O-rutinoside (nicotiflorin). AB - Kaempferol-3-O-alpha-L-rhamanopyranosyl-(1'''-6'')-beta-D-glucopyranoside (1) (Nicotiflorin or kaempferol-3-O-rutinoside), isolated from the aerial parts of Osyris wightiana Wall. ex Wight, exhibited a potent antiglycation activity in vitro. A short and efficient route to kaempferol-3-O-rutinoside (1) is also described in this paper. To study the structure-activity relationship, few other derivatives of kaempferol were also evaluated for their antiglycation activity. Moreover the cytotoxicity analysis was also performed for these compounds. The Structure-Activity Relationship (SAR) studies showed that sugar derivatives of kaempferol possess a promising antiglycation activity. PMID- 22530899 TI - Synthesis and biological evaluation of some new N4-aryl substituted 5 chloroisatin-3-thiosemicarbazones. AB - A new series of sixteen N4-aryl substituted 5-chloroisatin-3-thiosemicarbazones 2a-2p has been synthesized, characterized and tested for selected biological activities i.e. cytotoxicity, phytotoxicity and urease inhibition. In the brine shrimp bioassay, all the synthesized compounds gave LD50 values>2.30x10(-4) M 2.79x10(-4) M and were, therefore, found to be almost inactive, whereas in phytotoxicity assay, regardless of the nature of aryl substituents, they displayed weak to moderate (5-40%) phytotoxic activity at the highest tested concentrations (500 or 1000 MUg/mL). In urease inhibition bioassay, compounds 2a, 2c, 2e, 2f, 2k and 2m exhibited relatively a higher degree of urease inhibition with IC50 values ranging from 38.91 MUM to 76.65 MUM and thus proved to be potent inhibitors of the enzyme. Of these, 2f and 2m displayed pronounced inhibition with IC50 values 38.91 MUM and 39.50 MUM, respectively, and may act as lead compounds for further studies. Structure-activity relationship (SAR) studies revealed that electronic effects of the substituents about the phenyl ring at N4 of the thiosemicarbazone moiety played an important role in enhancing the urease inhibitory potential of some of the synthesized compounds. PMID- 22530898 TI - Synthesis and beta-glucuronidase inhibitory potential of benzimidazole derivatives. AB - Benzimidazole derivatives 1-24 have been synthesized and their in vitro beta glucuronidase inhibitory activitiy was evaluated. Compounds 15 (IC50=6.33+/-0.40 MUM), 7 (IC50=22.0+/-0.33 MUM), 2 (IC50=23.1+/-1.78 MUM), 17 (IC50=23.9+/-1.46 MUM), and 3 (IC50=33.8+/-1.61 MUM) showed more potent beta-glucuronidase inhibitory activity than the standard (D-saccharic acid 1,4 lactone, IC50=48.4+/ 1.25 MUM). This study has identified a new series of potential beta-glucuronidase inhibitors. A structure-activity relationship has also been studied. PMID- 22530900 TI - 2,4,6-Trichlorophenylhydrazine Schiff bases as DPPH radical and super oxide anion scavengers. AB - Syntheses of thirty 2,4,6-trichlorophenylhydrazine Schiff bases 1-30 were carried out and evaluated for their in vitro DPPH radical and super oxide anion scavenging activities. Compounds 1-30 have shown a varying degree of DPPH radical scavenging activity and their IC50 values range between 4.05-369.30 uM. The compounds 17, 28, 18, 14, 8, 15, 12, 2, 29, and 7 exhibited IC50 values ranging between 4.05+/-0.06-24.42+/-0.86 uM which are superior to standard n propylgallate (IC50=30.12+/-0.27 uM). Selected compounds have shown a varying degree of superoxide anion radical scavenger activity and their IC50 values range between 91.23-406.90 uM. The compounds 28, 8, 17, 15, and 14, showed IC50 values between 91.23+/-1.2-105.31+/-2.29 uM which are superior to standard n propylgallate (IC50=106.34+/-1.6 uM). PMID- 22530901 TI - Application of artificial neural networks for the prediction of antitumor activity of a series of acridinone derivatives. AB - Artificial neural networks (ANNs) have been applied for the quantitative structure-activity relationships (QSAR) studies of antitumor activity of acridinone derivatives. Molecular modeling studies were performed with the use of HyperChem and Dragon computer programs and molecular geometry optimization using MM+ molecular mechanics and semi-empirical AM1 method, and several molecular descriptors of agents were obtained. A high correlation resulted between the ANN predicted antitumor activity and that one from biological experiments for the data used in the testing set of acridinones was obtained with correlation coefficient on the level of 0.9484. Moreover, the sensitivity analysis indicated that molecular parameters describing geometrical properties as well as lipophilicity of acridinone derivative molecule are important for acridinones antitumor activity. PMID- 22530902 TI - Synthesis and biological evaluation of 3'-C-ethynyl and 3'-C-(1,4-disubstituted 1,2,3-triazolo) double-headed pyranonucleosides. AB - A novel series of 3'-C-ethynyl and 3'-C-(1,4-disubstituted-1,2,3-triazolo) double headed pyranonucleosides has been designed and synthesized. Reaction of 3-keto glucoside 1 with ethynyl magnesium bromide gave the desired precursor 3-C-ethynyl 1,2:5,6-di-O-isopropylidene-alpha-D-allofuranose (2). Hydrolysis followed by acetylation led to the 1,2,4,6-tetra-O-acetyl-3-C-ethynyl-beta-D-allopyranose (3). Compound 3 was condensed with silylated 5-fluorouracil, uracil, thymine, N4 benzoylcytosine and N6-benzoyladenine, respectively and deacetylated to afford the target 1-(3'-C-ethynyl-beta-D-allopyranosyl)nucleosides 5a-c,f,g. Copper Catalyzed Azide-Alkyne Cycloaddition (CuAAC) reaction was utilized to couple the 3'-C-ethynyl pyranonucleoside derivatives with azidoethyl adenine, 5-fluorouracil and thymine, respectively to afford novel triazole double-headed nucleoside analogs 8a-h. 3'-C-Ethynyl pyranonucleosides and the new double-headed analogues were evaluated for their antiviral and cytostatic activities. Although none of the compounds showed pronounced cytostatic activity and were devoid of a significant antiviral potential, the double-headed nucleoside derivatives 8a, 8c and 8e showed a moderate cytostatic activity against human cervix carcinoma HeLa cells which may be the basis for the synthesis of analogous derivatives with improved cytostatic potential. PMID- 22530903 TI - Structure-activity relationships of pyrrole hydrazones as new anti-tuberculosis agents. AB - Preliminary investigations of our research team have shown that some pyrrole hydrazones posses strong inhibitory activity against the tuberculosis bacilli, and thus represent a new perspective for development of anti-tuberculosis agents. In this work the anti-tuberculosis activity of an in-house series of pyrrole hydrazones was investigated by quantitative structure-activity relationships (QSAR) analysis and by pharmacophore modelling. Different constitutional, topological, physicochemical, and quantum-mechanical descriptors of the chemical structure were calculated. The QSAR models included the number of chlorine, fluorine and nitrogen atoms, molecular flexibility and shape indexes, and magnitudes of charged molecular surfaces areas and hydrophobic volumes, suggesting importance of these structural characteristics for the activity. Next, a pharmacophore analysis was applied. A possible pharmacophore responsible for the compound interactions with their biological target in the 3D space consisted of five features, including hydrophobic centres, a potential H-bond acceptor and a potential metal ligator. PMID- 22530904 TI - S-nitrosylation and attenuation of excessive calcium flux by pentacycloundecane derivatives. AB - A novel series of polycyclic amines, containing nitrogen monoxide donating moieties, were synthesised and tested for calcium channel and N-methyl-D aspartate receptor modulating activity. The synthesised compounds were classified into two groups, based on their nitrogen monoxide donating moieties: unsaturated nitro compounds (1, 2 and 3) and nitro esters, or nitrates (4, 5 and 6). The nitrates were obtained via the reaction of hydroxyl functionalities with thionylchloride nitrate. All of the compounds synthesised exhibited significant (p<0.01) S-nitrosylation capacity. The calcium channel activity of the polycyclic amines was evaluated using a KCl mediated fluorescent calcium flux assay. All the compounds exhibited better calcium channel antagonism than the lead structure, NGP1-01, with compound 1 exhibiting calcium channel blockade comparable to the commercially available nimodipine at concentrations of 10 MUM and 1 MUM. Compounds 3 and 4 inhibited calcium flux to these levels at 10 MUM concentrations. NMDA/glycine mediated N-methyl-D-aspartate receptor (NMDAR) calcium influx inhibition was evaluated at a 100 MUM concentration using a fluorescent calcium flux assay. All the compounds exhibited NMDAR antagonism with compounds 1 (25.4%), 2 (20.24%), 3 (33.14%) and 6 (24.55%) showing the most significant NMDAR inhibitory activity (p<0.01). No clear correlation was observed between the S-nitrosylation capabilities of the compounds and their calcium channel activity or NMDAR channel antagonism, indicating that other factors probably play a more decisive role in the mechanism of pentacycloundecylamine channel modulation. This could include the geometric and steric bulk considerations that have been described to contribute to the channel activities of the pentacycloundecylamines. All the compounds synthesised exhibited promising calcium channel and NMDAR channel inhibitory activity and show promise as potential lead compounds for drug development against neurodegeneration. PMID- 22530905 TI - Serum specific vasopressin-degrading activity is related to blood total cholesterol levels in men but not in women. AB - The role of vasopressin (AVP) in the pathophysiology of cardiovascular disease is controversial, but this peptide hormone is elevated in heart failure and some forms of hypertension. Also, AVP has vasoconstrictor, mitogenic, hyperplasic and renal fluid retaining properties which, by analogy with angiotensin II, may have deleterious effects when present in chronic excess. Furthermore, cholesterol blood levels are also associated with hypertension, although the underlying mechanism is not known. Here we analyze the relationship between blood total cholesterol levels and serum vasopressin- degrading cystyl-aminopeptidase activity (AVP-DA) in healthy humans, and the differences between men and women. Linear correlation coefficients were calculated to test relationships between AVP DA and blood total cholesterol levels. Sex differences were observed for AVP-DA, being this activity higher in men than in women. According to the linear model of the regression analysis, AVP-DA showed a significant negative correlation with blood total cholesterol levels in men, whereas no correlation was observed in women. Several studies in humans demonstrate the existence of greater plasma AVP concentrations in normal men compared to normal women, which could explain the gender-differences observed in the present work in relation with AVP-DA. However, AVP-DA is related to blood cholesterol levels only in men, although in our hands, women showed higher blood cholesterol levels than men. This could indicate that the risk of high cholesterol-related hypertension is more probable in men than in women. Although AVP-DA misregulation could be involved in the pathogenesis of hypertension, its relation with cholesterol levels appears only in men, but not in women. PMID- 22530906 TI - SAR analysis of new dual targeting fluoroquinolones. Implications of the benzenesulfonyl group. AB - When a benzenesulfonyl moiety (BS) was bound to the N-piperazinyl ring of antibacterial fluoroquinolones (AMFQs) norfloxacin (NOR) or ciprofloxacin (CIP), the resulting benzenesulfonyl-fluoroquinolone (BSFQs) analogs showed an improved in vitro activity against Gram-positive strains. A bioisosterical replacement of the sulfonyl group for a carbonyl group led to the benzenecarboxamide fluoroquinolones (BCFQs) that showed a similar trend in the antibacterial activity and spectrum. The BSFQs and BCFQs are considered members of the "dual targeting" fluoroquinolones, targeting both DNA gyrase and topoisomerase IV. To disclose the real contribution of the BS/BC moiety in anti-staphylococcal activity, a 3D-QSAR analysis that included calculation of theoretical molecular descriptors and pharmacophore generation was performed. Previous and present QSAR results have confirmed the positive influence on activity of small electron donating p-substituent on the BS or BC moiety. The generated phamacophore model showed that both phenyl and SO2/CO groups are involved in the interaction with receptor. We postulate that the enhanced potency of BSFQs against Staphylococcus aureus compared to CIP and NOR could be caused by the presence of the BS moiety that resulted in enhanced binding to DNA gyrase of Sa. Additionally, their greater ability to enter bacterial cells by diffusion and a reduced susceptibility to FQ-specific efflux pumps could also make a contribution. PMID- 22530908 TI - Synthesis and biological evaluation of naloxone and naltrexone-derived hybrid opioids. AB - The synthesis and biological evaluation of hybrid opioids consisting of Naloxone or Naltrexone and a partial opioid peptide are described. These compounds were synthesized in a homogeneous solution as well as in solid phase. A hydrazone linkage was employed to connect the alkaloids to the tetrapeptides. In synthesizing the peptides some non-traditional methods, which provided excellent results, were explored. The solid phase synthesis was achieved by anchoring the Fmoc-Phe to the 2-chlorotrityl resin, followed by stepwise addition of two Fmoc Gly units. Each addition step preceded by standard piperidine removal of the Fmoc from the prior amino acid (AA) residue. The final AA, Tyr, was added as its Boc derivative. The Boc-tetrapeptide was then separated from the resin with a TFE/AcOH/CH(2)Cl(2) mixture. In the solution synthesis, each peptide elongation step was accomplished by one-pot removal of the Fmoc from the prior AA residue and addition of the next Fmoc-AA. TBAF-thiol was used to cleanly remove the Fmoc, before adding the next Fmoc-AA in the presence of DIPEA and TBTU. All prepared hybrid ligands exhibited high affinities toward all three opioid receptors; moderate preferences for kappa and MU receptors over delta receptor were observed. [(35)S]GTPgammaS binding assays indicated that these hybrid opioids are delta and MU antagonists but partial kappa agonist. PMID- 22530909 TI - A QSAR analysis of 2-phenoxy-N-substituted acetamide analogues as hypoxia inducible factor-1(HIF-1) inhibitors: a rational approach to anticancer drug design. AB - A set of thirty one substituted 2-phenoxy-N-phenylacetamide derivatives with HIF 1 inhibitory activities was subjected to 2D and 3D Quantitative Structure Activity Relationship (QSAR) studies using various combinations of descriptors. 2D-QSAR was performed using Multiple Linear Regression (MLR), Principal Component Regression (PCR) and Partial Least Squares Regression (PLS) methods. Among these three methods Multiple Linear Regression (MLR) led to the statistically significant best 2D-QSAR Model-I having correlation coefficient r(2) = 0.9469 and cross validated squared correlation coefficient q(2) = 0.8933 with external predictive ability of pred_r(2) = 0.7128 with the descriptors like SssNHE-index, slogp, T_O_N_1 and T_2_Cl_1. 3D-QSAR study was performed using the simulated annealing variable selection procedures k-nearest neighbor molecular field analysis approach. 3D-QSAR shows interesting results in terms of internal and external predictability. Molecular field analysis was applied for the generation of steric, hydrophobic and electrostatic descriptors based on aligned structures which shows good correlative and predictive capabilities in terms of q(2) = 0.9672 and pred_r(2) = 0.8480. Hence the model proposed in this work provides important structural insight in designing novel derivatives with specific HIF-1 inhibitory activity. PMID- 22530910 TI - Synthesis, in vitro and in silico NS5B polymerase inhibitory activity of benzimidazole derivatives. AB - Hepatitis C virus (HCV) NS5B polymerase is the key replicating protein of the virus and thus an attractive target for drug development. Here we report on the synthesis and biological evaluation of a new series of benzimidazole derivatives as HCV NS5B inhibitors. This yielded compound 6b and 6d bearing 2-(2 benzyloxy)phenyl and 2-(4-methylbenzyloxy)phenyl moieties, respectively, as promising leads. Binding mode of compound 6d in allosteric pocket (AP)-1 of NS5B will form the basis for future structure-activity relationship optimization. PMID- 22530911 TI - A new class of anticonvulsants possessing 6 Hz psychomotor seizure test activity: 2-(1H-benzotriazol-1-yl)-N'-[substituted] acetohydrazides. AB - A series of 2-(1H-Benzotriazol-1-yl)-N'-[substituted]acetohydrazides were designed & synthesized keeping in view the structural requirement of pharmacophore and evaluated for anticonvulsant activity and neurotoxicity. The new compounds were characterized using FT-IR, 1H NMR, mass spectral data and elemental analysis. The anticonvulsant activity of the titled compounds was assessed using the 6 Hz psychomotor seizure test. The neurotoxicity was assessed using the rotorod method. The most active compound of the series was N'-[4-(1,3 Benzodioxol-5-yloxy)benzylidene]-2-(1H-benzotriazol-1-yl)acetohydrazide (BTA 9), which showed good activity with 75 % protection (3/4, 0.5 h) at a dose of 100 mg/kg in mice. All the compounds exhibited no neurotoxicity. A computational study was carried out for calculation of pharmacophore pattern and prediction of pharmacokinetic properties. Titled compounds have also exhibited good binding properties with epilepsy molecular targets such as glutamate, GABA (A) delta, GABA (A) alpha-1 receptors and Na/H exchanger, in Lamarckian genetic algorithm based flexible docking studies. PMID- 22530907 TI - Prodrug strategies in ocular drug delivery. AB - Poor bioavailability of topically instilled drug is the major concern in the field of ocular drug delivery. Efflux transporters, static and dynamic ocular barriers often possess rate limiting factors for ocular drug therapy. Different formulation strategies like suspension, ointment, gels, nanoparticles, implants, dendrimers and liposomes have been employed in order to improve drug permeation and retention by evading rate limiting factors at the site of absorption. Chemical modification such as prodrug targeting various nutrient transporters (amino acids, peptide and vitamin) has evolved a great deal of interest to improve ocular drug delivery. In this review, we have discussed various prodrug strategies which have been widely applied for enhancing therapeutic efficacy of ophthalmic drugs. The purpose of this review is to provide an update on the utilization of prodrug concept in ocular drug delivery. In addition, this review will highlight ongoing academic and industrial research and development in terms of ocular prodrug design and delivery. PMID- 22530912 TI - Synthesis and biological evaluation of a series of 6,7-dimethoxy-1-(3,4 dimethoxybenzyl)-2-substituted tetrahydroisoquinoline derivatives. AB - Multidrug resistance in cancer is a major cause of failure in cancer chemotherapy. In search of new compounds with strong reversal activity and simple molecular structure, we have synthesized a series of compounds in which different substituents were linked to the 2-position of the 6,7-dimethoxy-1-(3,4 dimethoxybenzyl)- tetrahydroisoquinoline system. Compounds were analyzed for their cytotoxicity by MTT in K562 cell line in vitro, all of the derivatives exhibited little cytotoxic activity. In the meantime, these compounds were evaluated by MTT in K562/A02 cell line in vitro, 6e, 6h and 7c exhibited similar or more potent activities than verapamil with the IC50 values at 0.66, 0.65 and 0.96MUM, and with the ratio factor of 24.13, 24.50 and 16.59, respectively. PMID- 22530913 TI - Generation of pharmacophore and atom based 3D-QSAR model of novel isoquinolin-1 one and quinazolin-4-one-type inhibitors of TNFalpha. AB - In the present report, 3D-QSAR analysis was executed on the previously synthesized and evaluated derivatives of isoquinolin-1-ones and quinazolin-4 ones; potent inhibitors of tumor necrosis factor alpha (TNFalpha). Statistically significant 3D-QSAR models were generated using 42 molecules in the training set. The predictive ability of models was determined using a randomly chosen test set of 16 molecules, which gave excellent predictive correlation coefficients for 3-D models, suggesting good predictive index. Pharmacophore prediction generated a five point pharmacophore (AAHRR): two hydrogen bond acceptor (A), one hydrophobic (H) and two ring (RR) features. This pharmacophore hypothesis furnished a statistically meaningful 3D-QSAR model with partial least-square (PLS) factors seven having R2=0.9965, Q2=0.6185, Root Mean Squared Error=0.4284 and Pearson R=0.853. Docking study revealed the important amino acid residues (His 15, Tyr 59, Tyr 151, Gly 121 and Gly 122) in the active site of TNFalpha that are involved in binding of the active ligand. Orientation of the pharmacophore hypothesis AAHRR.25 corresponded very closely with the binding mode recorded in the active site of ligand bound complex. The results of ligand based pharmacophore hypothesis and atom based 3D-QSAR furnished crucial structural insights and also highlighted the important binding features of isoquinolin-1 ones and quinazolin-4-ones derivatives, which may provide guidance for the rational design of novel and more potent TNFalpha inhibitors. PMID- 22530914 TI - A QSAR study of biphenyl analogues of 2-nitroimidazo-[2, 1-b] [1, 3]-oxazines as antitubercular agents using genetic function approximation. AB - A QSAR study was performed on ninety eight substituted biphenyl analogues of 2 nitroimidazo-[2, 1-b] [1, 3]-oxazines as antitubercular agents to explore the importance of topological, thermodynamic, spatial and physicochemical properties of the molecules towards the antitubercular activity. Genetic function approximation (GFA) was used as the chemometric tool for the study. The study shows that ortho and meta linked attachments of the biphenyl analogs to 2- nitroimidazo-[2, 1-b] [1, 3]-oxazines are detrimental for the antitubercular activity. Hydrophobicity, branching and presence of electronegative atoms enhance the activity. Based on the r(m)(2)((overall)) criterion, which considers both internal validation and external validation, a GFA model with spatial, thermodynamic and topological descriptors appears to be the best model (r(m)(2)((overall)) = 0.556). PMID- 22530915 TI - Differences in vanadocene dichloride and cisplatin effect on MOLT-4 leukemia and human peripheral blood mononuclear cells. AB - Modern chemotherapy is interested in developing new agents with high efficiency of treatment in low-dose medication strategies, lower side toxicity and stronger specificity to the tumor cells. Vanadocene dichloride (VDC) belongs to the group of the most promising metallocene antitumor agents; however, its mechanism of action and cytotoxicity profile are not fully understood. In this paper we assess cytotoxic effects of VDC in comparison to cisplatin using opposite prototype of cells; human peripheral blood mononuclear (PBMCs) cells and human acute lymphoblastic leukemia cell line (MOLT-4). Our findings showed cytotoxic effect of VDC on leukemia cells, but unfortunately on human peripheral blood mononuclear cells as well. VDC induces apoptosis in leukemia cells; the induction is, however, lower than that of cisplatin, and in contrary to cisplatin, VDC does not induce p53 up-regulation. Cytotoxic effect of VDC on leukemia cells is less pronounced than that of cisplatin and more pronounced in PBMCs than in MOLT-4 cells. PMID- 22530916 TI - In vitro synergy testing of anidulafungin with fluconazole, tioconazole, 5 flucytosine and amphotericin B against some Candida spp. AB - In this paper the authors investigated a synergistic antimycotic effect between four antifungal drugs Amphotericin B, Fluconazole, Tioconazole, and Flucytosine individually combined with Anidulafungin compound. This latter is considered a drug of choice in the treatment of fungal infections; it has good activity both in vitro and in vivo against yeasts and moulds, as Candida and Aspergillus. The goal of this study was to evaluate the in vitro interaction of Anidulafungin in the synergic combinations with previous reported drugs against 12 Candida strains according to CLSI M27-A3 protocol. A synergistic interaction was observed against the most antifungal strains; in particular an increasing of the antimycotic efficacy was obtained from the association between Anidulafungin and Amphotericin B or Fluconazole (Mixture 4:6). In contrast the association Tioconazole/Anidulafungin was less effective on fungal species growth. The antimycotics MIC reduction values were more evident against some strains as C. glabrata, C. krusei, C. tropicalis and C. parapsilosis. PMID- 22530917 TI - The distribution of a germline methylation marker suggests a regional mechanism of LINE-1 silencing by the piRNA-PIWI system. AB - BACKGROUND: A defense system against transposon activity in the human germline based on PIWI proteins and piRNA has recently been discovered. It represses the activity of LINE-1 elements via DNA methylation by a largely unknown mechanism. Based on the dispersed distribution of clusters of piRNA genes in a strand specific manner on all human chromosomes, we hypothesized that this system might work preferentially on local and proximal sequences. We tested this hypothesis with a methylation-associated SNP (mSNP) marker which is based on the density of C-T transitions in CpG dinucleotides as a surrogate marker for germline methylation. RESULTS: We found significantly higher density of mSNPs flanking piRNA clusters in the human genome for flank sizes of 1-16 Mb. A dose-response relationship between number of piRNA genes and mSNP density was found for up to 16 Mb of flanking sequences. The chromosomal density of hypermethylated LINE-1 elements had a significant positive correlation with the chromosomal density of piRNA genes (r = 0.41, P = 0.05). Genome windows of 1-16 Mb containing piRNA clusters had significantly more hypermethylated LINE-1 elements than windows not containing piRNA clusters. Finally, the minimum distance to the next piRNA cluster was significantly shorter for hypermethylated LINE-1 compared to normally methylated elements (14.4 Mb vs 16.1 Mb). CONCLUSIONS: Our observations support our hypothesis that the piRNA-PIWI system preferentially methylates sequences in close proximity to the piRNA clusters and perhaps physically adjacent sequences on other chromosomes. Furthermore they suggest that this proximity effect extends up to 16 Mb. This could be due to an unknown localization signal, transcription of piRNA genes near the nuclear membrane or the presence of an unknown RNA molecule that spreads across the chromosome and targets the methylation directed by the piRNA-PIWI complex. Our data suggest a region specific molecular mechanism which can be sought experimentally. PMID- 22530918 TI - Calreticulin as a hydrophilic chimeric molecular adjuvant enhances IgG responses to the spike protein of severe acute respiratory syndrome coronavirus. AB - Fragment 450-650 of the spike (S) protein (S450-650) of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) contains epitopes capable of being recognized by convalescent sera of SARS patients. Vaccination of mice with recombinant S450-650 (rS450-650) can induce Abs against SARS-CoV, although the titer is relatively low. In the present study, a fusion protein linking a fragment (residues 39-272) of murine calreticulin (CRT) to S450-650 in a prokaryotic expression system was created. Compared with target antigen alone, the recombinant fusion product (rS450-650-CRT) has much improved hydrophilicity and immunogenicity. The S450-650-specific IgG Abs of BALB/c mice subcutaneously immunized with rS450-650-CRT were in substantially higher titer (approximately fivefold more). Furthermore, the fusion protein, but not rS450-650 alone, was able to elicit S450-650-specific IgG responses in T cell deficient nude mice. Given that rCRT/39-272 can drive the maturation of bone-marrow-derived dendritic cells, directly activate macrophages and B cells, and also elicit helper T cell responses in vivo, we propose that fragment 39-272 of CRT is an effective molecular adjuvant capable of enhancing target Ag-specific humoral responses in both a T cell-dependent and independent manner. Fusion protein rS450-650-CRT is a potential candidate vaccine against SARS-CoV infection. PMID- 22530920 TI - Mass production of rubusoside using a novel stevioside-specific beta-glucosidase from Aspergillus aculeatus. AB - Rubusoside (R) is a natural sweetener and a solubilizing agent with antiangiogenic and antiallergic properties. However, currently, its production is quite expensive, and therefore, we have investigated nine commercially available glycosidases to optimize an economically viable R-production method. A stevioside (ST)-specific beta-glucosidase (SSGase) was selected and purified 7-fold from Aspergillus aculeatus Viscozyme L by a two-step column chromatography procedure. The 79 kDa protein was stable from pH 3.0 to pH 7.0 at 50-60 degrees C. Hydrolysis of ST by SSGase produced R and steviol monoglucosyl ester as determined by (1)H and (13)C nuclear magnetic resonance (NMR). Importantly, SSGase showed higher activity toward ST than other beta-linked glucobioses. The optimal conditions for R production were 280 mM ST and 16.6 MUL of SSGase at pH 5.1 and 63 degrees C. This is the first discussion detailing the production of R by enzymatic hydrolysis of ST and is useful for the food additive and pharmaceutical industries. PMID- 22530919 TI - Immunological status of the progeny of breeder hens kept on ochratoxin A (OTA)- and aflatoxin B(1) (AFB(1))-contaminated feeds. AB - This study aimed to evaluate the immunological status of progeny of hens kept on ochratoxin A (OTA)- and aflatoxin B(1) (AFB(1))-contaminated feed. For this purpose, White Leghorn (WL) layer breeder hens (40-weeks-of-age) were divided into six groups (A-F). Hens in Group A were fed a commercial layer ration while those in Groups B and C were kept on a diet amended with 3 and 5 mg OTA/Kg, respectively. Group D was fed a ration containing 5 mg AFB(1)/Kg, while hens in Groups E and F were kept on feed amended with OTA and AFB(1) each. All feedings were for 1, 2, or 3 weeks. Fertile eggs were set for hatching on a weekly basis to obtain progeny of each week separately. At 14 days-of-age, subsets of progeny were euthanized and the frequency of immunoglobulin(s)-bearing cells in their spleen and bursa of Fabricius assessed; at 16 days-of-age, other chicks in each set were utilized to determine their lymphoblastogenic responses against phytohemagglutinin (PHA-P). At 30 days-of-age, the final sub-set of chicks/group was euthanized and their peritoneal macrophages harvested for measurements of phagocytic potential and nitrite production. Relative weights of the bursa of Fabricius and of the spleen were significantly lower in the progeny of hens fed mycotoxin-contaminated diets for 14 and 21 days. The frequencies of IgA-, IgG-, and IgM-bearing cells were also significantly lower in the bursa of Fabricius and spleen of progeny chicks obtained from hens fed the OTA + AFB(1) mixed diet. Feeding contaminated diets to breeder hens also resulted in significantly lower responses to PHA-P. In addition, the percentages of peritoneal macrophages displaying phagocytosis of sheep red blood cells (SRBC), the number of SRBC/macrophage, and nitrite production were each significantly lower in cells from progeny chicks from OTA- and AFB(1)-fed hens. The findings of the present study indicated there were severe immunosuppressive effects in progeny chicks as a result of exposure of their parent hens to OTA and AFB(1) either alone or in combination. These studies provide emphasis for the need for mycotoxin regulation policy with respect to the ingredients used in poultry feed, since it is clear that feeding multi-mycotoxin-contaminated diets to breeder hens will almost certainly result in the hatching of manifestly unhealthy chicks. PMID- 22530921 TI - Socio-economic influence on weight status through time in schoolchildren. AB - AIM: This paper describes the developmental trajectory of adiposity in relation to socio-demographic status in primary schoolchildren studying in local schools in Hong Kong. METHODS: Body mass index (BMI) and prevalence of overweight and obesity were determined in a cohort of primary schoolchildren annually from 2001/2002 to 2005/2006. To study the associations between socio-demographic status and adiposity, repeated measures analysis of variance was used for the longitudinal change in BMI, while logistic regression was used with overweight and obesity development as outcomes. RESULTS: Prevalence of overweight and obesity was 12.1% and 4.0%, respectively, at baseline, and 16.7% and 3.3%, respectively, at the end of the study period. Boys were more likely to be overweight and obese. Parents in the 'Professional' occupational group were less likely to have overweight and obese children. Among 32,781 children with normal weight at baseline, 2885 (8.8%) became overweight or obese after 4 years. Among 6286 children who were initially overweight or obese, 2079 (33.1%) returned to normal weight. Boys were more likely to move up from normal weight to overweight or obesity and less likely to move down the opposite direction during the study period. Parental education at degree level and the occupational group of 'Professionals' were, in general, associated with more favourable changes in weight status during follow-up. CONCLUSION: Overweight and obesity were not firmly established during early primary school years. Interventions at the school level on students and their parents might help prevent and control the future development of the obesity epidemic in the population. PMID- 22530922 TI - Introducing multiple treatment plan-based comparison to investigate the performance of gantry angle optimisation (GAO) in IMRT for head and neck cancer. AB - BACKGROUND AND PURPOSE: The purpose of this study was to evaluate the performance of gantry angle optimisation (GAO) compared to equidistant beam geometry for two inverse treatment planning systems (TPSs) by utilising the information obtained from a range of treatment plans. MATERIAL AND METHODS: The comparison was based on treatment plans generated for four different head and neck (H&N) cancer cases using two inverse treatment planning systems (TPSs); Varian EclipseTM representing dynamic MLC intensity modulated radiotherapy (IMRT) and Oncentra(r) Masterplan representing segmented MLC-based IMRT. The patient cases were selected on the criterion of representing different degrees of overlap between the planning target volume (PTV) and the investigated organ at risk, the ipsilateral parotid gland. For each case, a number of 'Pareto optimal' plans were generated in order to investigate the trade-off between the under-dosage to the PTV (V(PTV,D < 95%)) or the decrease in dose homogeneity (D(5)-D(95)) to the PTV as a function of the mean absorbed dose to the ipsilateral parotid gland ((parotid gland)). RESULTS: For the Eclipse system, GAO had a clear advantage for the cases with smallest overlap (Cases 1 and 2). The set of data points, representing the underlying trade-offs, generated with and without using GAO were, however, not as clearly separated for the cases with larger overlap (Cases 3 and 4). With the OMP system, the difference was less pronounced for all cases. The Eclipse GAO displays the most favourable trade-off for all H&N cases. CONCLUSIONS: We have found differences in the effectiveness of GAO as compared to equidistant beam geometry, in terms of handling conflicting trade-offs for two commercial inverse TPSs. A comparison, based on a range of treatment plans, as developed in this study, is likely to improve the understanding of conflicting trade-offs and might apply to other thorough comparison techniques. PMID- 22530924 TI - Attachment of the sulfonic acid group in the interlayer space of a layered alkali silicate, octosilicate. AB - The surface modification of a layered alkali silicate, octosilicate (Na(2)Si(8)O(17).nH2O), with a sulfonic acid group was conducted. The sulfonic acid group was attached to the silicate layer by the reaction of octosilicate with phenethyl(dichloro)methylsilane and the subsequent sulfonation of the attached phenethyl groups with chlorosulfonic acid. The modified octosilicate is a solid acid as indicated by the intercalation of dodecylamine. A systematic expansion of the interlayer space was observed by the ion exchange with a series of alkyltrimethylammonium ions to show the variation of the layer charge density. PMID- 22530923 TI - Surface modification using phosphonic acids and esters. PMID- 22530925 TI - Late entry into HIV care: lessons from Brazil, 2003 to 2006. AB - BACKGROUND: To ascertain the population rates and proportion of late entry into HIV care, as well as to determine whether such late entry correlates with individual and contextual factors. METHODS: Data for the 2003-2006 period in Brazil were obtained from public health records. A case of late entry into HIV care was defined as one in which HIV infection was diagnosed at death, one in which HIV infection was diagnosed after the condition of the patient had already been aggravated by AIDS-related diseases, or one in which the CD4(+) T-cell count was <= 200 cells/mm(3) at the time of diagnosis. We also considered extended and stricter sets of criteria (in which the final criterion was <= 350 cells/mm(3) and <= 100 cells/mm(3), respectively). The estimated risk ratio was used in assessing the effects of correlates, and the population rates (per 100,000 population) were calculated on an annual basis. RESULTS: Records of 115,369 HIV infected adults were retrieved, and 43.6% (50,358) met the standard criteria for late entry into care. Diagnosis at death accounted for 29% (14,457) of these cases. Late entry into HIV care (standard criterion) was associated with certain individual factors (sex, age, and transmission category) and contextual factors (region with less economic development/increasing incidence of AIDS, lower local HIV testing rate, and smaller municipal population). Use of the extended criteria increased the proportion of late entry by 34% but did not substantially alter the correlations analyzed. The overall population rate of late entry was 9.9/100,000 population, specific rates being highest for individuals in the 30-59 year age bracket, for men, and for individuals living in regions with greater economic development/higher HIV testing rates, collectively accounting for more than half of the cases observed. CONCLUSIONS: Although the high proportion of late entry might contribute to spreading the AIDS epidemic in less developed regions, most cases occurred in large cities, with broader availability of HIV testing, and in economically developed regions. PMID- 22530926 TI - Microemulsion synthesis, characterization of highly visible light responsive rare earth-doped Bi2O3. AB - In this paper, Bi(2)O(3) and rare earth (La, Ce)-doped Bi(2)O(3) visible-light driven photocatalysts were prepared in a Triton X-100/n-hexanol/cyclohexane/water reverse microemulsion. The resulting materials were characterized by X-ray powder diffraction (XRD), transmission electron microscopy (TEM), Brunauer-Emmett-Teller (BET) surface area, photoluminescence spectra (PLS) and UV-Vis diffuse reflectance spectroscopy. The XRD patterns of the as-prepared catalysts calcined at 500 degrees C exhibited only the characteristic peaks of monoclinic alpha Bi(2)O(3). PLS analysis implied that the separation efficiency for electron-hole has been enhanced when Bi(2)O(3) was doped with rare earth. UV-Vis diffuse reflectance spectroscopy measurements presented an extension of light absorption into the visible region. The photocatalytic activity of the samples was evaluated by degradation of methyl orange (MO) and 2,4-dichlorophenol (2,4-DCP). The results displayed that the photocatalytic activity of rare earth-doped Bi(2)O(3) was higher than that of dopant-free Bi(2)O(3). The optimal dopant amount of La or Ce was 1.0 mol%. And the mechanisms of influence on the photocatalytic activity of the catalysts were discussed. PMID- 22530927 TI - Inverse dynamics analysis evaluation of tibial tuberosity advancement for cranial cruciate ligament failure in dogs. AB - OBJECTIVE: To evaluate, using inverse dynamic analysis, the biomechanical outcome from tibial tuberosity advancement (TTA) surgery in dogs affected by unilateral cranial cruciate ligament failure (CCLF). STUDY DESIGN: Retrospective case series. ANIMALS: Dogs (n = 13) 11-20 months after surgery. METHODS: Kinematic and force data were collected from 13 dogs 11-20 months after TTA and inverse dynamics analysis of the dogs' pelvic limb mechanical function performed. Angle, moment, and power were calculated for each joint. Total support moment (TSM) was calculated. RESULTS: Six dogs were affected on the right side (Raff) and 7 on the left (Laff). Peak stifle flexor moment was significantly larger for the right stifle compared with the left in Laff dogs, but similar in Raff dogs. Peak stifle extensor moment was significantly larger for the left stifle compared with the right in Raff dogs, and was also larger for the left stifle compared with the right in Laff dogs. Stifle power in early stance was larger on the left in Raff dogs and significantly larger on the right in Laff dogs. TSM was larger on the right in Raff dogs and significantly larger on the right in Laff dogs. CONCLUSIONS: Affected limbs had a reduction in power of the stifle flexors. Irrespective of the side of CCLF, TSM was larger on the right side and the stifle extensor moment in late stance was larger on the left, perhaps indicating a mechanical limb dominance effect. PMID- 22530928 TI - Transurethral vapor enucleation and resection of the prostate with plasma vaporization button electrode for the treatment of benign prostatic hyperplasia: a feasibility study. AB - Various improvements and modifications to the surgical treatment of benign prostatic hyperplasia have emerged over the last decade. Most techniques often initially claimed superiority only to turn out to be mediocre with time. Holmium laser enucleation of the prostate has been associated with superior outcomes compared with transurethral resection of the prostate and demonstrated improvement in long-term outcomes, while its clinical use has limitations. We describe the first use of plasma vaporization button electrode combined with loop electrode for transurethral vapor enucleation and resection of the prostate. PMID- 22530929 TI - Unravelling the reaction mechanism of the reductive ring contraction of 1,2 pyridazines. AB - Substituted pyrroles may be synthesized from selected 1,2-pyridazines through a reductive ring contraction involving the addition of four electrons and four protons. Our density functional theory computations of this reaction mechanism show that the first reduction event must be preceded by the uptake of one proton by 1,2-pyridazine and that the reaction proceeds through a 2e(-)/3H(+)-bearing intermediate. In the absence of electron-withdrawing groups able to resonate charge away from the ring, this intermediate lies too high in energy, making the reaction sequence thermodynamically inaccessible. After another two-electron reduction and the addition of two more protons, the original 1,2-pyridazine ring opens. Ring contraction and ammonia elimination then proceed with very small barriers, irrespective of the substituents present in the original 1,2 pyridazine. By establishing the need for electron-withdrawing resonant groups in the 3- and 6-positions to stabilize the critical intermediate in the initial stages of the reaction, this work suggests that the scope of the reductive ring contraction of 1,2-pyridazines may be expanded to pyridazines bearing COCH(3) groups, amides or aryls in these positions. We also explain the lack of reactivity of unsubstituted 1,2-pyridazine and analyze the feasibility of bypassing the high energy 2e(-)/3H(+)-intermediate through disproportionation of earlier 2e(-)/2H(+)-bearing intermediates. PMID- 22530931 TI - High fasting serum glucose in non-diabetic subjects >=45 years is an indicator of future cardiovascular events as it is positively associated with atherogenic index of plasma. AB - BACKGROUND: Atherogenic index of plasma, a newly emerging lipid parameter, has been employed only in a few studies in diabetics and not at all in non-diabetics. METHODS: Association between fasting serum glucose and lipid parameters in 321 non-diabetic males aged 30 to 60 years was studied retrospectively. Glucose and lipid parameters were measured on fully automated analyser using standard reagent kits. Body mass index was also ascertained. RESULTS: On comparing the various lipid parameters between normo-glycaemic and pre-diabetic men, a significant increase in TG (p = 0.0328), VLDL-C (p = 0.0328) and AIP (p = 0.0373) was observed only in pre-diabetic men >= 45 years. In non-diabetic men >= 45 years a slight but statistically positive correlation between glucose and AIP was also seen. CONCLUSIONS: Increased blood glucose in men >= 45 years, even in the non diabetic range is associated with increased risk of CVD, as indicated by an increased atherogenic index of plasma. PMID- 22530933 TI - Molecular thinking for nanoplasmonic design. AB - The development of nanoplasmonics has been tremendous during the past two decades, driven in part by the improvements in colloidal synthesis of nanocrystals and manipulation of nanoparticle surface functionalities. This has granted access not only to exquisite control over the morphology of nanoparticles but also to novel multiparticle nanostructures with a variety of organizational motifs. Driven by such new possibilities, completely unforeseen plasmonic effects have been found, which let us think about applications in a variety of fields. In this Perspective, we discuss the evolution of plasmonic nanomaterials and their corresponding properties and correlations with molecular concepts that have been around for a long time. Additional thinking along these lines may lead to further expansion of nanoplasmonics and to multiple surprising discoveries in this field. PMID- 22530932 TI - Adipose-derived stem cell collection and characterization in bottlenose dolphins (Tursiops truncatus). AB - To assess the regenerative properties and potential therapeutic value of adipose derived stem cells (ASCs) in the bottlenose dolphin, there is a need to determine whether an adequate adipose depot exists, in addition to the development of a standardized technique for minimally invasive adipose collection. In this study, an ultrasound-guided liposuction technique for adipose collection was assessed for its safety and efficacy. The ultrasound was utilized to identify and measure the postnuchal adipose depot and aid in the guidance of the liposuction cannula during aspiration. Liposuction procedures from 6 dolphins yielded 0.9-12.7 g of adipose. All samples yielded sufficient nucleated cells to initiate primary cell cultures, and at passage 2, were successfully differentiated into adipogenic, chondrogenic, neurogenic, and osteogenic cell lineages. The cultured dolphin cells expressed known stem-cell-associated CD markers, CD44 and CD90. Ultrasound guided liposuction proved to be a safe and minimally invasive procedure that resulted in the successful isolation of ASCs in bottlenose dolphins. This is the first article that conclusively establishes the presence of stem cells in the dolphin. PMID- 22530934 TI - Distinct localization of T cell Agrin during antigen presentation--evidence for the expression of Agrin receptor(s) in antigen-presenting cells. AB - Agrin is over-expressed by activated and autoimmune T cells, and synergizes with the T cell receptor (TCR) to augment cell activation. In the present study, we show that Agrin accumulates to distinct areas of the plasma membrane and that cell activation causes its redistribution. During antigen presentation, Agrin primarily accumulates to the periphery of the mature immunological synapse, mostly in lamellipodia-like protrusions that wrap around the antigen-presenting cell and, conversely, anti-Agrin sera induced a significant redistribution of TCR at the plasma membrane. We also provide evidence for the expression of Agrin receptors in peripheral blood monocytes, dendritic cells and a fraction of B cells. Interestingly, interferon-alpha treatment, which induces the expression of Agrin in T cells, also augmented Agrin binding to monocytes. Stimulation of monocytes with recombinant Agrin induced the clustering of surface receptors, including major histocompatibility complex class II, activation of intracellular signalling cascades, as well as enhanced dsRNA-induced expression of pro inflammatory cytokines interleukin-6 and tumour necrosis factor-alpha. Collectively, these results confirm the location of Agrin at the immunological synapse between T cells and antigen-presenting cells and justify further characterization of its receptors in the immune system. PMID- 22530935 TI - Embryonic development of kisspeptin neurones in rat. AB - Kisspeptins, encoded by the Kiss1 gene, play a key role in the regulation of reproductive function, although very little is known about the ontogenesis of this system. The present study aimed to determine the period of arcuate nucleus (ARC) kisspeptin cell birth and the embryonic stage and neuroanatomical sites of onset of kisspeptin immunoreactivity. Bromodeoxyuridine (BrdU) was administered to female rats at various gestational stages and double immunohistochemistry against kisspeptin and BrdU was performed on brain sections from their offspring. The period of neurogenesis of ARC kisspeptin neurones begun between embryonic day (E) 12.5 and E13.5, reached its peak at E15.5 and was not completely over at E17.5. Kiss1 mRNA was detected in mediobasal hypothalamic punches of embryos aged E14.5, E16.5, E18.5 and E22.5 by real-time reverse transcriptase-polymerase chain reaction. Accordingly, kisspeptin-immunoreactive (-IR) cells were consistently detected in the embryonic ARC from E14.5 and their number increased until E18.5 to reach approximately half the level observed in adults. Between E18.5 and E22.5, the number of kisspeptin-IR cells and hypothalamic Kiss1 expression significantly decreased, regardless of sex, and this decrease persisted until birth. Taken together, these results demonstrate that rat ARC kisspeptin neurones are born locally during an extended embryonic period and are able to synthesise kisspeptins rapidly after their birth, consistent with the hypothesis of a role during embryonic activation of the hypothalamic-hypophyseal-gonadal axis. A sex independent decrease of kisspeptin-IR cell numbers was observed during the perinatal period, suggestive of important regulations of kisspeptin neurones around birth. PMID- 22530936 TI - Consequences of TCDD treatment on intra-hepatic lymphocytes during liver regeneration. AB - Increasing evidence demonstrates a physiological role for the aryl hydrocarbon receptor (AhR) in regulating hepatocyte cell cycle progression. Previous studies have used a murine model of liver regeneration to show that exposure to the potent exogenous AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), suppresses hepatocyte proliferation in vivo. Based on recent reports that natural killer (NK) cells negatively regulate liver regeneration, coupled with the well established immunomodulatory effects of TCDD, it was hypothesized that alterations in lymphocyte activation contribute to the suppression of liver regeneration in TCDD-treated mice. To test this, mice were treated with TCDD (20 MUg/kg) 1 day prior to 70% partial hepatectomy (PH), in which two-thirds of the liver was surgically resected. Lymphocytes were collected from the remnant liver and analyzed by flow cytometry. Whereas exposure to TCDD did not alter the number of NK cells or CD3(+) T-cells recovered from the regenerating liver, it reduced the percentage and number of intra-hepatic NKT cells 42 h after PH. With regard to lymphocyte activation, TCDD treatment transiently increased CD69 expression on NK and NKT cells 12 h after PH, but had no effect on intracellular levels of IFNgamma in NK, NKT, or CD3(+) T-cells. To determine the relevance of NK cells to the suppression of liver regeneration by TCDD, mice were treated with anti-Asialo GM-1 (ASGM-1) antibody to deplete NK cells prior to TCDD treatment and PH, and hepatocyte proliferation was measured using bromodeoxyuridine incorporation. Exposure to TCDD was found to inhibit hepatocyte proliferation in the regenerating liver of NK cell-depleted mice and control mice to the same extent. Hence, it is unlikely that enhanced numbers or increased activation of NK cells contribute to the suppression of liver regeneration in TCDD-treated mice. PMID- 22530938 TI - Mindfulness-based cognitive therapy to treat multiple chemical sensitivities: a randomized pilot trial. AB - Multiple chemical sensitivities (MCS) is a medically unexplained and socially disabling disorder characterized by negative health effects attributed to exposure to common airborne chemicals. Currently, there is no evidence-based treatment. The objectives of the study were to assess the feasibility of an 8 week mindfulness-based cognitive therapy program (MBCT) for adults with MCS and to evaluate possible effects on psychological distress and illness perception. The study design was a randomized clinical trial. The MBCT programme comprised 8 weekly sessions of 21/2 hours. Forty-two adults were screened for eligibility and 37 were included. Mean age of the participants was 51.6 years, 35 (94.6%) were female and 21 (56.8%) were unemployed. Measures of psychological distress and illness perceptions were assessed at baseline, 4 weeks, 8 weeks and at 3 months follow-up. No significant differences in effect measures were found between the groups. However, those who completed the MBCT program generally reported benefiting in terms of improved coping strategies and sleep quality. The positive verbal feedback from the participants in the MBCT group suggests that a larger randomized clinical trial on the effect of MBCT for MCS could be considered. PMID- 22530939 TI - Heavy atom free singlet oxygen generation: doubly substituted configurations dominate S1 states of bis-BODIPYs. AB - S(0), S(1), and T(1) states of various orthogonal 8,8' and 8,2'-bis-boradiaza-s indacene (BODIPY) dyes, recently (Angew. Chem., Int. Ed.2011, 50, 11937) proposed as heavy atom free photosensitizers for O(2)((1)Delta(g)) generation, were studied by multireference quantum chemical approaches. S(0)->S(1) excitation characteristics of certain bis-BODIPYs are shown to be drastically different than the parent BODIPY chromophore. Whereas a simple HOMO->LUMO-type single substitution perfectly accounts for the BODIPY core, S(1) states of certain orthogonal bis-BODIPYs are described as linear combinations of doubly substituted (DS) configurations which overall yield four electrons in four singly occupied orbitals. Computed DS character of S(1), strongly correlated with facile (1)O(2) production, was presumed to occur via S(1)->T(1) intersystem crossing (ISC) of the sensitizer. Further confirmation of this relation was provided by newly synthesized BODIPY derivatives and comparison of spectroscopic properties of their dimers and monomers. Near-IR absorption, desired for potential photodynamic therapy applications, was not pursuable for bis-chromophores by the standard strategy of pi-extension, as DS singlet states are destabilized. Decreased exchange coupling in pi-extended cases appears to be responsible for this destabilization. Comparisons with iodine incorporated bis-BODIPYs suggest that the dynamics of (1)O(2) generation via DS S(1) states are qualitatively different from that via ISC originating from heavy atom spin-orbit coupling. Although red shifting the absorption wavelength to enter the therapeutic window does not seem attainable for orthogonal bis-BODIPYs with DS S(1) states, modifications in the chromophore cores are shown to be promising in fine-tuning the excitation characteristics. PMID- 22530937 TI - Evaluation of selection criteria for validating paired umbilical cord blood gas samples: an observational study. AB - OBJECTIVE: To compare six validation criteria for umbilical cord blood gas (UCBG) values in vigorous and nonvigorous neonates. DESIGN: Retrospective cohort study. SETTING: Single tertiary obstetric centre, King Edward Memorial Hospital (KEMH), Perth, Western Australia. SAMPLE: A total of 37,763 consecutive deliveries at >23 weeks of gestation. METHODS: Six validation criteria were compared to evaluate the proportion of deliveries with 'valid' UCBG data; and the proportion of vigorous and nonvigorous neonates with metabolic acidaemia. MAIN OUTCOMES: Proportion of deliveries with 'valid' UCBG values; proportions of vigorous and nonvigorous neonates with normal, borderline and abnormal UCBG values. RESULTS: The criteria based on KEMH 5th centile arteriovenous pH and Pco(2) differences resulted in a higher proportion of neonates with 'valid' UCBG values than the previously described Westgate and Kro criteria. The increase in 'valid' UCBG values occurred across the entire study population including vigorous and nonvigorous neonates. Among neonates with short-term neonatal complications there was an increase in nonvigorous neonates with umbilical artery metabolic acidaemia. There was no corresponding increase in vigorous neonates diagnosed with abnormal UCBG values. CONCLUSIONS: Use of the KEMH criteria results in an increase in the proportion of nonvigorous term neonates with UCBG data considered 'valid' to aid clinicians in the management of the neonate shortly after delivery. This change occurs without increasing the rate of false-positive diagnoses of acidaemia in vigorous neonates. The KEMH 'validation' criteria were developed from an entire presenting population and provide a simple algorithm that can be universally applied to identify neonates with nonphysiological UCBG values. PMID- 22530941 TI - Highly selective intramolecular carbene insertion into primary C-H bond of alpha diazoacetamides mediated by a (p-cymene)ruthenium(II) carboxylate complex. AB - Complex [(p-cymene)Ru(eta(1)-O(2)CCF(3))(2)(OH(2))] mediated transformation of alpha-diazoacetamides ArCH(2)N(C(CH(3))(3))C(O)CHN(2) to result in carbene insertion into the primary C-H bond exclusively, with the gamma-lactam products being isolated in up to 98% yield. This unexpected reaction is striking in view of the presence of usually more reactive sites such as secondary C-H bonds in the substrates. DFT calculations based on proposed Ru-carbene species provide insight into this unique selectivity. PMID- 22530942 TI - Sickle-cell disease and the heart: review of the current literature. AB - Sickle cell disease (SCD) is an inherited chronic haemolytic anaemia whose clinical manifestations arise from the tendency of the haemoglobin to polymerize and deform red blood cells into the characteristic sickle shape due to a single nucleotide change in the beta-globin. Vascular occlusion of small and large vessels can lead to chronic damage of multiple organs including brain, lung, bone, kidney, liver, spleen, and retina. However, the extent to which SCD impacts myocardial function is not very clear. Cardiovascular manifestations include both right and left ventricular systolic and diastolic dysfunction, elevated cardiac output, cardiomegaly and myocardial ischaemia. Progressive heart damage from iron overload occurs in patients requiring routine transfusion therapy. Pulmonary hypertension resulting from intravascular haemolysis has also been recognized as a major complication that independently correlates with survival. This review summarizes all available data for the heart complications in SCD to update the physicians for their appearance, diagnostic procedures and possible management. PMID- 22530940 TI - Genome-wide host responses against infectious laryngotracheitis virus vaccine infection in chicken embryo lung cells. AB - BACKGROUND: Infectious laryngotracheitis virus (ILTV; gallid herpesvirus 1) infection causes high mortality and huge economic losses in the poultry industry. To protect chickens against ILTV infection, chicken-embryo origin (CEO) and tissue-culture origin (TCO) vaccines have been used. However, the transmission of vaccine ILTV from vaccinated- to unvaccinated chickens can cause severe respiratory disease. Previously, host cell responses against virulent ILTV infections were determined by microarray analysis. In this study, a microarray analysis was performed to understand host-vaccine ILTV interactions at the host gene transcription level. RESULTS: The 44 K chicken oligo microarrays were used, and the results were compared to those found in virulent ILTV infection. Total RNAs extracted from vaccine ILTV infected chicken embryo lung cells at 1, 2, 3 and 4 days post infection (dpi), compared to 0 dpi, were subjected to microarray assay using the two color hybridization method. Data analysis using JMP Genomics 5.0 and the Ingenuity Pathway Analysis (IPA) program showed that 213 differentially expressed genes could be grouped into a number of functional categories including tissue development, cellular growth and proliferation, cellular movement, and inflammatory responses. Moreover, 10 possible gene networks were created by the IPA program to show intermolecular connections. Interestingly, of 213 differentially expressed genes, BMP2, C8orf79, F10, and NPY were expressed distinctly in vaccine ILTV infection when compared to virulent ILTV infection. CONCLUSIONS: Comprehensive knowledge of gene expression and biological functionalities of host factors during vaccine ILTV infection can provide insight into host cellular defense mechanisms compared to those of virulent ILTV. PMID- 22530944 TI - The association of moderate renal dysfunction with impaired preference-based health-related quality of life: third Korean national health and nutritional examination survey. AB - BACKGROUND: Only a few large-scale studies have investigated the association between health-related quality of life (HRQOL) and renal function. Moreover, the HRQOL of patients with moderate renal dysfunction is frequently underestimated by healthcare providers. This study assessed the impact of renal function on preference-based HRQOL in Korean adult population. METHODS: We analyzed data for 5,555 adults from the 3(rd) Korean National Health and Nutritional Examination Survey 2005. The EuroQol-5D (EQ-5D) utility score was used to evaluate HRQOL. The study subjects were stratified into three groups based on their estimated glomerular filtration rates (eGFRs): >= 90.0, 60.0-89.9 and 30.0-59.9 mL/min/1.73 m(2). Individuals with advanced renal dysfunction were excluded from the analysis. RESULTS: The proportions of participants who reported problems in each of the five EQ-5D dimensions increased significantly with decreasing eGFR. However, a significant decrease in the EQ-5D utility score was observed among participants with an eGFR of 30.0-59.9 mL/min/1.73 m(2). Participants with an eGFR of 30.0-59.9 mL/min/1.73 m(2) had an almost 1.5-fold higher risk of impaired health utility (the lowest quartile of EQ-5D utility score) compared with those participants with eGFRs >= 90.0 mL/min/1.73 m(2), after adjustment for age, gender, health-related behaviors, socioeconomic and psychological variables, and other comorbidities. Among the five dimensions of the EQ-5D, an eGFR of 30.0-59.9 mL/min/1.73 m(2) was an independent determinant of self-reported problems in the mobility and pain/discomfort dimensions. CONCLUSIONS: Although age affects the association between renal dysfunction and the EQ-5D, moderate renal dysfunction seems to be an important determinant of impaired health utility in a general population and may affect the mobility and pain/discomfort dimensions of health utility. PMID- 22530945 TI - A novel cryo-reduction method to investigate the molecular mechanism of nitric oxide synthases. AB - Nitric oxide synthases (NOSs) are hemoproteins responsible for the biosynthesis of NO in mammals. They catalyze two successive oxidation reactions. The mechanism of oxygen activation is based on the transfer of two electrons and two protons. Despite structural analogies with cytochromes P450, the molecular mechanism of NOS remains yet to be elucidated. Because of extremely high reaction rates, conventional kinetics methods failed to trap and characterize the major reaction intermediates. Cryo-reduction methods offer a possibility to circumvent this technological lock, by triggering oxygen activation at cryogenic temperatures by using water radiolysis. However, this method is not adapted to the NOS mechanism because of the high instability of the initial Fe(II)O2 complex (extremely fast autoxidation and/or reaction with the cofactor H4B). This imposed a protocol with a stable Fe(II)O2 complex (observed only for one NOS-like protein) and that excludes any redox role for H4B. A relevant approach to the NOS mechanism would use H4B to provide the (second) electron involved in oxygen activation; water radiolysis would thus provide the first electron (heme reduction). In this context, we report here an investigation of the first electron transfer by this alternative approach, i.e., the reduction of native NOS by water radiolysis. We combined EPR and resonance Raman spectroscopies to analyze NOS reduction for a combination of different substrates, cofactor, and oxygen concentrations, and for different NOS isoforms. Our results show that cryo-reduction of native NOS is achieved for all conditions that are relevant to the investigation of the NOS mechanism. PMID- 22530946 TI - Intramolecular free-radical cyclization reactions on pentose sugars for the synthesis of carba-LNA and carba-ENA and the application of their modified oligonucleotides as potential RNA targeted therapeutics. PMID- 22530947 TI - NMR-based metabolic profiling of rice wines by F(2)-selective total correlation spectra. AB - In this study, we performed NMR-based metabolic profiling of major rice wines (Japanese sake, Chinese Shaoxing wine, and Korean makgeolli). In the (1)H NMR spectra, the rice wines showed broad resonances in the region of about 7.9-9.0 ppm. These resonances showed many and complex correlations with approximately 0.5 4.5 ppm in the F(2)-selective TOCSY (total correlation spectroscopy) spectra, and these correlations were attributed mainly to peptides. These spectral patterns were characteristic of individual rice wines, and the combination of F(2) selective TOCSY spectra and principal component analysis enabled us to classify the rice wine species. Furthermore, it also provided information about raw materials, namely, what type of koji (rice koji or wheat koji) was used. These spectra may be useful as a new "fingerprint" for quality control or food authentication. PMID- 22530948 TI - Influence of fatty acids on mitochondrial metabolism of adipocyte progenitors and endothelial cells. AB - CONTEXT: In obesity, the cells are exposed to excessive amounts of nutrients, especially free fatty acids (FFAs) that induce a variety of metabolic changes. OBJECTIVE: We investigated the effect of FFAs on the mitochondrial function in different cell populations under stress conditions. METHODS: Human adipose tissue progenitor cells (SVF) or endothelial cells (HUVECs) were incubated with 30MUM of selected saturated or unsaturated FFA for 24 h, at times supplemented with 5ng/mL tumour necrosis factor alpha (TNFalpha) for the last 4 h. Changes in oxygen respiration rate, mitochondrial membrane potential (mitoMP) and total ATP content were monitored. RESULTS: Saturated palmitic acid demonstrated no effect, while a selection of unsaturated FFAs ameliorated metabolism of the progenitor SVF cells. TNFalpha either did not affect or nullified some of the favourable FFA-induced effects. CONCLUSIONS: The mitoMP was the most sensitive parameter reflecting positive impact of the unsaturated FFA on the adipose SVF cells' metabolism. PMID- 22530949 TI - Compression of silver sulfide: X-ray diffraction measurements and total-energy calculations. AB - Angle-dispersive X-ray diffraction measurements have been performed in acanthite, Ag(2)S, up to 18 GPa in order to investigate its high-pressure structural behavior. They have been complemented by ab initio electronic structure calculations. From our experimental data, we have determined that two different high-pressure phase transitions take place at 5 and 10.5 GPa. The first pressure induced transition is from the initial anti-PbCl(2)-like monoclinic structure (space group P2(1)/n) to an orthorhombic Ag(2)Se-type structure (space group P2(1)2(1)2(1)). The compressibility of the lattice parameters and the equation of state of both phases have been determined. A second phase transition to a P2(1)/n phase has been found, which is a slight modification of the low-pressure structure (Co(2)Si-related structure). The initial monoclinic phase was fully recovered after decompression. Density functional and, in particular, GGA+U calculations present an overall good agreement with the experimental results in terms of the high-pressure sequence, cell parameters, and their evolution with pressure. PMID- 22530950 TI - Resettable fluorescence logic gate based on calcein/layered double hydroxide ultrathin films. AB - A fluorescent logic gate was fabricated based on calcein/layered double hydroxide ultrathin films (UTFs) via alternate assembly technique, which exhibits high stability, reversibility, and resettability. The logic gate was manipulated by utilizing pH value, Hg(2+) and Cl(-) ion as inputs, and the fluorescence emission of the (calcein/LDH)(16) UTF as output, serving as a three-input logic gate that combines the YES and INHIBIT operation. PMID- 22530951 TI - Purification of human and avian influenza viruses using cellulose sulfate ester (Cellufine Sulfate) in the process of vaccine production. AB - Affinity chromatography using sulfated, spherical cellulose beads (Cellufine Sulfate) was assessed for purification of influenza A and influenza B viruses. Recovery rates of viruses eluted from the beads were high for all tested virus strains. This method was also useful for removing chicken egg-derived impurities from allantoic fluids containing influenza viruses; the hemagglutination activity per amount of protein in the eluted sample was significantly higher than that in the applied sample. These results suggest that use of Cellufine Sulfate is a practical method for primary purification of influenza viruses in the process of influenza vaccine production. PMID- 22530952 TI - Adeno-associated virus-mediated doxycycline-regulatable TRAIL expression suppresses growth of human breast carcinoma in nude mice. AB - BACKGROUND: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) functions as a cytokine to selectively kill various cancer cells without toxicity to most normal cells. Numerous studies have demonstrated the potential use of recombinant soluble TRAIL as a cancer therapeutic agent. We have showed previous administration of a recombinant adeno-associated virus (rAAV) vector expressing soluble TRAIL results in an efficient suppression of human tumor growth in nude mice. In the present study, we introduced Tet-On gene expression system into the rAAV vector to control the soluble TRAIL expression and evaluate the efficiency of the system in cancer gene therapy. METHODS: Controllability of the Tet-On system was determined by luciferase activity assay, and Western blotting and enzyme-linked immunoabsorbent assay. Cell viability was determined by MTT assay. The breast cancer xenograft animal model was established and recombinant virus was administrated through tail vein injection to evaluate the tumoricidal activity. RESULTS: The expression of soluble TRAIL could be strictly controlled by the Tet-On system in both normal and cancer cells. Transduction of human cancer cell lines with rAAV-TRE-TRAIL&rAAV-Tet-On under the presence of inducer doxycycline resulted in a considerable cell death by apoptosis. Intravenous injection of the recombinant virus efficiently suppressed the growth of human breast carcinoma in nude mice when activated by doxycycline. CONCLUSION: These data suggest that rAAV-mediated soluble TRAIL expression under the control of the Tet-On system is a promising strategy for breast cancer therapy. PMID- 22530953 TI - RSA prediction of high failure rate for the uncoated Interax TKA confirmed by meta-analysis. AB - BACKGROUND AND PURPOSE: In a previous radiostereometric (RSA) trial the uncoated, uncemented, Interax tibial components showed excessive migration within 2 years compared to HA-coated and cemented tibial components. It was predicted that this type of fixation would have a high failure rate. The purpose of this systematic review and meta-analysis was to investigate whether this RSA prediction was correct. MATERIALS AND METHODS: We performed a systematic review and meta analysis to determine the revision rate for aseptic loosening of the uncoated and cemented Interax tibial components. RESULTS: 3 studies were included, involving 349 Interax total knee arthroplasties (TKAs) for the comparison of uncoated and cemented fixation. There were 30 revisions: 27 uncoated and 3 cemented components. There was a 3-times higher revision rate for the uncoated Interax components than that for cemented Interax components (OR = 3; 95% CI: 1.4-7.2). INTERPRETATION: This meta-analysis confirms the prediction of a previous RSA trial. The uncoated Interax components showed the highest migration and turned out to have the highest revision rate for aseptic loosening. RSA appears to enable efficient detection of an inferior design as early as 2 years postoperatively in a small group of patients. PMID- 22530954 TI - Comparison of dynamics of extracellular accesses to the beta(1) and beta(2) adrenoceptors binding sites uncovers the potential of kinetic basis of antagonist selectivity. AB - From the molecular mechanism of antagonist unbinding in the beta(1) and beta(2) adrenoceptors investigated by steered molecular dynamics, we attempt to provide further possibilities of ligand subtype and subspecies selectivity. We have simulated unbinding of beta(1)-selective Esmolol and beta(2)-selective ICI-118551 from both receptors to the extracellular environment and found distinct molecular features of unbinding. By calculating work profiles, we show different preference in antagonist unbinding pathways between the receptors, in particular, perpendicular to the membrane pathway is favourable in the beta(1) adrenoceptor, whereas the lateral pathway involving helices 5, 6 and 7 is preferable in the beta(2) adrenoceptor. The estimated free energy change of unbinding based on the preferable pathway correlates with the experimental ligand selectivity. We then show that the non-conserved K347 (6.58) appears to facilitate in guiding Esmolol to the extracellular surface via hydrogen bonds in the beta(1) adrenoceptor. In contrast, hydrophobic and aromatic interactions dominate in driving ICI-118551 through the easiest pathway in the beta(2) adrenoceptor. We show how our study can stimulate design of selective antagonists and discuss other possible molecular reasons of ligand selectivity, involving sequential binding of agonists and glycosylation of the receptor extracellular surface. PMID- 22530955 TI - Disulfide cross-linked micelles for the targeted delivery of vincristine to B cell lymphoma. AB - Vincristine (VCR) is a potent anticancer drug, but its clinical efficacy is limited by neurotoxicity. The field of drug delivery may provide an opportunity to increase the therapeutic index of VCR by delivering the drug specifically to tumor sites while sparing normal tissue. We have recently developed a telodendrimer (PEG(5k)-Cys(4)-L(8)-CA(8)) capable of forming disulfide cross linked micelles (DCMs) which can encapsulate a variety of chemotherapeutics. In the present study, we encapsulated VCR into these micelles (DCM-VCR) and used them to treat lymphoma bearing mice. DCM-VCR particles have a size of 16 nm, which has been shown to be optimal for their accumulation into tumor via the enhanced permeability and retention (EPR) effect. Compared to our first generation non-cross-linked micelles (NCMs), DCM-VCR demonstrated greater stability and slower drug release under physiological conditions. In addition, DCM-VCR exhibited a maximum tolerated dose (MTD) of 3.5 mg/kg while the MTD for conventional VCR was only 1.5 mg/kg. Using a near-infrared cyanine dye (DiD) as the surrogate drug, we showed that DCM-VCR accumulated at the tumor site starting 1 h after injection and persisted up to 72 h in lymphoma xenografted nude mice. In an in vivo efficacy study, high dose (2.5 mg/kg) DCM-VCR produced the greatest reduction in tumor volume. High dose DCM-VCR was well tolerated with no significant changes in complete blood count, serum chemistry and histology of the sciatic nerve. Mice treated with an equivalent dose (1 mg/kg) of conventional VCR and DCM-VCR controlled tumor growth equally; however, in combination with on demand addition of the reducing agent N-acetylcysteine, DCM-VCR exhibited a superior antitumor effect compared to conventional VCR. PMID- 22530956 TI - Plasma procalcitonin and the risk of cardiovascular events and death: a prospective population-based study. AB - OBJECTIVES: A number of inflammatory biomarkers such as C-reactive protein (CRP) are independent predictors of cardiovascular risk. The inflammatory biomarker procalcitonin (PCT) has previously been shown to be associated with coronary atherosclerosis and the metabolic syndrome. We evaluated the ability of PCT to predict future cardiovascular events in a population of apparently healthy individuals. DESIGN: We measured plasma PCT levels in 3713 subjects with no previous history of cardiovascular disease, randomly selected from the Malmo Diet and Cancer cohort. The correlation between PCT concentration and the incidence of coronary events, stroke and cardiovascular death over a median follow-up period of 13.7 years was studied using a Cox regression analysis corrected for age, sex, CRP level, traditional risk factors and renal function. RESULTS: Age and sex were strong determinants of PCT; the concentration of PCT was significantly higher in men than in women. PCT was associated with several of the established cardiovascular risk factors (CRP, hypertension, diabetes and renal function) as determined by multivariate linear regression. Of note, PCT was inversely correlated with HDL and smoking. We found significant correlations between PCT levels, coronary events and cardiovascular death. However, these relationships lost statistical significance when the analysis was corrected for CRP and the traditional risk factors. CONCLUSIONS: This is the largest population-based prospective study to demonstrate a positive association between plasma PCT levels and cardiovascular risk in subjects with no previous history of acute cardiovascular events. However, the high degree of covariation between PCT and other cardiovascular risk factors limits the value of PCT as an independent cardiovascular risk predictor. PMID- 22530957 TI - Breast cancer metastasising to the pelvis and abdomen: what the gynaecologist needs to know. AB - A small proportion of breast cancers metastasise within the peritoneal cavity. With increasing breast cancer incidence rates, gynaecologists and oncologists will encounter such women more frequently. Most women with intraperitoneal breast cancer are premenopausal. Although data are limited and are likely to be subject to selection bias, the median survival of women undergoing resection appears superior to those not undergoing surgery. Furthermore, survival is broadly similar to that for women undergoing advanced ovarian cancer surgery, particularly when tumour debulking is optimal. Obtaining data via randomised trials is unlikely to be feasible and therefore we recommend prospective data collection via the establishment of an international intraperitoneal breast cancer patient registry. For individual women where survival is anticipated to be more than a few months, we suggest considering referral to a gynaecological oncology team for discussion of surgical options. PMID- 22530958 TI - Bioactive rosette nanotube-hydroxyapatite nanocomposites improve osteoblast functions. AB - Inspired from biological systems, small synthetic organic molecules expressing the hydrogen bonding arrays of the DNA bases guanine and cytosine were prepared, and their self-assembly into rosette nanotubes (RNTs) was investigated. Due to their unique biological, physicochemical, and mechanical properties, RNTs could serve as the next generation of injectable orthopedic materials. In this study, a self-assembling module (termed twin base linkers or TBL) was synthesized, and the corresponding RNTs were used as bioactive components in composites of poly (2 hydroxyethyl methacrylate) (pHEMA) and hydroxyapatite (HA) nanoparticles (termed TBL/HA/pHEMA). The properties of these composites were characterized for solidification time, surface morphology, mechanical properties, and cytocompatibility. The experimental conditions were optimized to achieve solidification within 2-40 min, offering a range of properties for orthopedic applications. Composites with 20 wt% HA nanoparticles had a compressive strength (37.1 MPa) and an ultimate tensile stress (14.7 MPa) similar to that of a natural vertebral disc (5-30 MPa). Specifically, the TBL (0.01 mg/mL)/HA(20 wt%)/pHEMA composites improved long-term functions of osteoblasts (or bone-forming cells) in terms of collagen synthesis, alkaline phosphatase activity, and calcium deposition. Moreover, this composite inhibited fibroblast adhesion, thus decreasing the potential for undesirable fibrous tissue formation. In summary, this in vitro study provided evidence that TBL/HA/pHEMA composites are promising injectable orthopedic implant materials that warrant further mechanistic and in vivo studies. PMID- 22530959 TI - Asthma severity, exacerbation risk, and controller treatment burden in underweight and obese children. AB - OBJECTIVE: The relationship between weight status and asthma characteristics in children remains inadequately defined. Very little has been published on the risk of exacerbation, physician perception of severity, and the level controller treatment prescribed to underweight and obese children with asthma in a real world setting. METHODS: We assessed the diagnostic severity, pulmonary function, exacerbation prevalence, and controller treatment level in 10,559 new asthma patients seen at one of four pediatric asthma subspecialty clinics among three BMI groups. Participants were analyzed by body mass index (BMI)-percentile based on Centers for Disease Control & Prevention classification. Multivariable logistic regression models were used to assess the associations between BMI percentile cohort group and asthma outcomes. RESULTS. Underweight asthmatics were rare (2.5%) relative to obese asthmatics but appeared to have the greatest impairment in forced vital capacity and had the greatest controller treatment burden. Obese asthmatic children made up 26.2% of our cohort and were more likely to have severe disease (odds ratio (OR) 1.40, 95% confidence interval (CI) 1.06 1.85) and airflow obstruction (OR 1.36, 95% CI 1.16-1.59) compared to normal weight asthmatics. Obese asthmatics were not at greater risk for exacerbation (OR 1.41, 95% CI 0.64-3.11) or high treatment burden (OR 1.03, 95% CI 0.83-1.28). CONCLUSIONS. Obesity is more common than underweight status among children with asthma. Both underweight and obese children with asthma have worse lung function and asthma-related outcomes compared to similar normal weight children, though the phenotypic characteristics of underweight and obese asthmatics differed considerably. PMID- 22530961 TI - Automatic and controlled cognitive responses to intergroup threat as assessed using the process dissociation procedure: a study of a low-status group from China. AB - Xiang, L. & Zhao, Y. (2012). Automatic and controlled cognitive responses to intergroup threat as assessed using the process dissociation procedure: A study of a low-status group from China. Scandinavian Journal of Psychology 53, 280-285. Explicit and implicit methods are typically employed to investigate the respective controlled and automatic cognitive responses to intergroup threat. However, these may not be "process pure" measures of automatic or controlled responses. The present study used the process dissociation procedure to investigate the relative contributions of automatic and controlled cognitive responses to intergroup threat. Following exposure to a threat/no threat manipulation, fifty Chinese rural undergraduates who were regarded as low-status group members completed a recognition memory task, in which they were asked to identify all or select "old" (previously presented) trait words relating to an urban outgroup. The results showed that compared to the non-threat group, when rural members perceived threat from an urban group, their automatic response was a decrease in favoritism for this outgroup, but was not derogative, whereas the controlled response was neither positive nor negative. These findings are inconsistent with previous research using explicit and implicit methods. The reasons for this discrepancy are discussed. PMID- 22530960 TI - The immunohistochemical analysis of antigens such as RCAS1 and B7H4 in the cervical cancer nest and within the fibroblasts and macrophages infiltrating the cancer microenvironment. AB - INTRODUCTION: The presence of the aggressive phenotype of the tumor seems to be indicated by the local infiltration of cancer cells and by the development of metastases in the lymph nodes. This phenotype is related to the intensity of the suppressive profile of the tumor microenvironment. The aim of our study has been to gather information about the expression of both RCAS1 and B7H4 proteins in the macrophages and fibroblasts present within both the microenvironment of cervical cancer tumors and the cancer cells present on the front of the cancer nest. METHODS: We analyzed the immunoreactivity levels of such antigens as B7H4 and RCAS1 in the macrophages and fibroblasts of the cancer microenvironment and within the cancer nest in the tissue samples derived from patients on whom both a radical hysterectomy and a lymphadenectomy had been performed following a diagnosis of uterine cervical carcinoma. These patients were then divided into two subgroups according to the extent of the local and distant advancement of the cancer - that is, according to the FIGO stage and the presence or absence of lymph node metastases. RESULTS: RCAS1 immunoreactivity levels on the front of the cancer nest statistically significantly increase according to the FIGO stage or the extent of the local spread of the disease while B7H4 immunoreactivity levels on the tumor front increase in relation to the extent of the distant spread of the disease or the presence of lymph nodes metastases. CONCLUSION: The intensity of the suppressive profile of the cervical cancer microenvironment indicated by the presence of both RCAS1 and B7H4 on the front of the tumor and in the macrophages and fibroblasts infiltrating the cancer stroma seems to correlate with the extent of both the local and distant advancement of the disease. PMID- 22530962 TI - Molecular characterization of the microbial communities in the subcaudal gland secretion of the European badger (Meles meles). AB - Many mammals possess specialized scent glands, which convey information about the marking individual. As the chemical profile of scent marks is likely to be affected by bacteria metabolizing the primary gland products, the variation in bacterial communities between different individuals has been proposed to underpin olfactory communication. However, few studies have investigated the dependency of microbiota residing in the scent organs on the host's individual-specific parameters. Here, we used terminal restriction fragment length polymorphism analysis of the PCR-amplified 16S rRNA gene and clone library construction to investigate the microbial communities in the subcaudal gland secretion of the European badger (Meles meles). As the secretion has been shown to encode individual-specific information, we investigated the correlation of the microbiota with different individual-specific parameters (age, sex, body condition, reproductive status, and season). We discovered a high number of bacterial species (56 operational taxonomic units from four phyla: Actinobacteria, Firmicutes, Proteobacteria, and Bacteroidetes), dominated by Actinobacteria (76.0%). The bacterial communities of cubs and adults differed significantly. Cubs possessed considerably more diverse communities dominated by Firmicutes, while in adults the communities were less diverse and dominated by Actinobacteria, suggesting that the acquisition of a 'mature bacterial community' is an ontogenetic process related to physiological changes during maturation. PMID- 22530963 TI - Endothelium-dependent vascular relaxation induced by Globularia alypum extract is mediated by EDHF in perfused rat mesenteric arterial bed. AB - The vasodilatory effect of Globularia alypum L. (GA) extract was evaluated in rat mesenteric arterial bed pre-contracted by continuous infusion of phenylephrine (2 4 ng/mL). Bolus injections of GA elicited dose-response vasodilation, which was abolished after endothelium removal. Addition of a nitric oxide synthase inhibitor, N(G)-nitro-l-arginine methyl ester (100 umol/L), alone or in the presence of a cyclooxygenase inhibitor, indomethacin (10 umol/L), did not significantly affect the vasodilation of the mesenteric arterial bed in response to GA extract. These results suggest that GA-induced vasodilation is endothelium dependent but nitric oxide and prostacyclin independent. In the presence of high K(+) (60 mmol/L), the GA vasodilatory effect was completely abolished, suggesting that the vasodilation effect is mediated by hyperpolarization of the vascular cells. Also, pre-treatment with atropine (a muscarinic receptors antagonist) antagonized the GA-induced vasodilation, suggesting that the vasodilatory effect is mainly mediated by the endothelium-derived hyperpolarizing factor through activation of endothelial muscarinic receptors. PMID- 22530964 TI - Three different dimerizations of 2-bromo-3-methyl-1,4-naphthoquinones. AB - Three types of dimeric naphthoquinones, which possess structurally diverse skeletons, can be prepared in one step from 2-bromo-3-methyl-1,4-naphthoquinones. 2,2'-Dimeric naphthoquinones were prepared by a one-pot Stille-type reaction via vinylstannanes. Oxepines are formed by unexpected domino reactions via 1,4 dihydroxynaphthalene species. Epoxides are formed by a Michael/Darzens reaction via the o-quinone methides. PMID- 22530965 TI - Comparative genomics and transcriptomics of lineages I, II, and III strains of Listeria monocytogenes. AB - BACKGROUND: Listeria monocytogenes is a food-borne pathogen that causes infections with a high-mortality rate and has served as an invaluable model for intracellular parasitism. Here, we report complete genome sequences for two L. monocytogenes strains belonging to serotype 4a (L99) and 4b (CLIP80459), and transcriptomes of representative strains from lineages I, II, and III, thereby permitting in-depth comparison of genome- and transcriptome -based data from three lineages of L. monocytogenes. Lineage III, represented by the 4a L99 genome is known to contain strains less virulent for humans. RESULTS: The genome analysis of the weakly pathogenic L99 serotype 4a provides extensive evidence of virulence gene decay, including loss of several important surface proteins. The 4b CLIP80459 genome, unlike the previously sequenced 4b F2365 genome harbours an intact inlB invasion gene. These lineage I strains are characterized by the lack of prophage genes, as they share only a single prophage locus with other L. monocytogenes genomes 1/2a EGD-e and 4a L99. Comparative transcriptome analysis during intracellular growth uncovered adaptive expression level differences in lineages I, II and III of Listeria, notable amongst which was a strong intracellular induction of flagellar genes in strain 4a L99 compared to the other lineages. Furthermore, extensive differences between strains are manifest at levels of metabolic flux control and phosphorylated sugar uptake. Intriguingly, prophage gene expression was found to be a hallmark of intracellular gene expression. Deletion mutants in the single shared prophage locus of lineage II strain EGD-e 1/2a, the lma operon, revealed severe attenuation of virulence in a murine infection model. CONCLUSION: Comparative genomics and transcriptome analysis of L. monocytogenes strains from three lineages implicate prophage genes in intracellular adaptation and indicate that gene loss and decay may have led to the emergence of attenuated lineages. PMID- 22530967 TI - Expression, purification, and reconstitution of a diatom silicon transporter. AB - The synthesis and manipulation of silicon materials on the nanoscale are core themes in nanotechnology research. Inspiration is increasingly being taken from the natural world because the biological mineralization of silicon results in precisely controlled, complex silica structures with dimensions from the millimeter to the nanometer. One fascinating example of silicon biomineralization occurs in the diatoms, unicellular algae that sheath themselves in an ornate silica-based cell wall. To harvest silicon from the environment, diatoms have developed a unique family of integral membrane proteins that bind to a soluble form of silica, silicic acid, and transport it across the cell membrane to the cell interior. These are the first proteins shown to directly interact with silicon, but the current understanding of these specific silicon transport proteins is limited by the lack of in vitro studies of structure and function. We report here the recombinant expression, purification, and reconstitution of a silicon transporter from the model diatom Thalassiosira pseudonana. After using GFP fusions to optimize expression and purification protocols, a His(10)-tagged construct was expressed in Saccharomyces cerevisiae, solubilized in the detergent Fos-choline-12, and purified by affinity chromatography. Size-exclusion chromatography and particle sizing by dynamic light scattering showed that the protein was purified as a homotetramer, although nonspecific oligomerization occurred at high protein concentrations. Circular dichroism measurements confirmed sequence-based predictions that silicon transporters are alpha-helical membrane proteins. Silicic acid transport could be established in reconstituted proteoliposomes, and silicon uptake was found to be dependent upon an applied sodium gradient. Transport data across different substrate concentrations were best fit to the sigmoidal Hill equation, with a K(0.5) of 19.4 +/- 1.3 MUM and a cooperativity coefficient of 1.6. Sodium binding was noncooperative with a K(m)(app) of 1.7 +/- 1.0 mM, suggesting a transport silicic acid:Na(+) stoichiometry of 2:1. These results provide the basis for a full understanding of both silicon transport in the diatom and protein-silicon interactions in general. PMID- 22530968 TI - Transmission of electronic effects through the {closo-1-CB9} and {closo-1-CB11} cages: apparent dissociation constants for series of [closo-1-CB9H8-1-COOH-10-X] and [closo-1-CB11H10-1-COOH-12-X] acids. AB - The apparent ionization constants pK(a)' for series of carboxylic acids [closo-1 CB(9)H(8)-1-COOH-10-X](-) (1) and [closo-1-CB(11)H(10)-1-COOH-12-X](-) (2), where X = H, I, n-C(6)H(13), (+)NMe(3), (+)N(2), (+)SMe(2), OC(5)H(11), were measured in EtOH/H(2)O (1/1, v/v) at 24 degrees C. Correlation analysis of the pK(a)' values using Hammett substituent constants sigma(p)(X) gave the reaction constant rho = 0.87 +/- 0.04 for series 1 and rho = 1.00 +/- 0.09 for series 2. These values are higher than for derivatives of PhCH?CHCOOH (rho = 0.70 +/- 0.09 in 55% EtOH) and correspond to 56% and 65% efficiencies in transmission of electronic effects by [closo-1-CB(9)H(10)](-) (E) and [closo-1-CB(11)H(12)](-) (F), respectively, as compared to benzene (A). Experimental results were supported with DFT calculations of relative acidity for series of acids derived from A, E, and F in aqueous medium. PMID- 22530966 TI - Fibroblast growth factor 23 is associated with proteinuria and smoking in chronic kidney disease: an analysis of the MASTERPLAN cohort. AB - BACKGROUND: Fibroblast growth factor 23 (FGF23) has emerged as a risk factor for cardiovascular disease and mortality throughout all stages of chronic kidney disease (CKD), independent from established risk factors and markers of mineral homeostasis. The relation of FGF23 with other renal and non-renal cardiovascular risk factors is not well established. METHODS: Using stored samples, plasma FGF23 was determined in 604 patients with moderate to severe kidney disease that participated in the MASTERPLAN study (ISRCTN73187232). The association of FGF23 with demographic and clinical parameters was evaluated using multivariable regression models. RESULTS: Mean age in the study population was 60 years and eGFR was 37 (+/- 14) ml/min/1.73 m(2). Median proteinuria was 0.3 g/24 hours [IQR 0.1-0.9]. FGF23 level was 116 RU/ml [67-203] median and IQR. Using multivariable analysis the natural logarithm of FGF23 was positively associated with history of cardiovascular disease (B = 0.224 RU/ml; p = 0.002), presence of diabetes (B = 0.159 RU/ml; p = 0.035), smoking (B = 0.313 RU/ml; p < 0.001), phosphate level (B = 0.297 per mmol/l; p = 0.0024), lnPTH (B = 0.244 per pmol/l; p < 0.001) and proteinuria (B = 0.064 per gram/24 hrs; p = 0.002) and negatively associated with eGFR (B = -0.022 per ml/min/1.73 m(2); p < 0.001). CONCLUSIONS: Our study demonstrates that in patients with CKD, FGF23 is related to proteinuria and smoking. We confirm the relation between FGF23 and other cardiovascular risk factors. PMID- 22530970 TI - Detection and molecular characterization of adenoviruses in Korean children hospitalized with acute gastroenteritis. AB - Human adenoviruses (HAdVs) are an important cause of acute gastroenteritis in children. However, few studies on the epidemiology or types of HAdVs associated with acute gastroenteritis have been conducted in Korea. Therefore, in the present study, the incidence of HAdV in 2064 stool samples from Korean children hospitalized with acute gastroenteritis (2004-2006) was assessed and the types of viruses present determined. Polymerase chain reaction, sequencing, and phylogenic analyses revealed that 113 samples (5.5%) were HAdV-positive. While HAdVs were mainly detected during July to October, no seasonal difference between the enteric and non-enteric viruses in the incidence of HAdV was observed. HAdV-41 and HAdV-40 were found in 54 (47.8%) and 3 (2.6%) HAdV-positive samples, respectively. HAdV-3, HAdV-7, HAdV-2, HAdV-31, HAdV-4, and HAdV-37 were detected in 11 (9.7%), 5 (4.4%), 2 (1.7%), 2 (1.7%), 1 (0.8%), and 1 (0.8%) of sample(s), respectively. Thus, not only enteric, but also non-enteric, HAdVs may play an important role in acute gastroenteritis in Korean children. PMID- 22530969 TI - Site-specific hydration dynamics of globular proteins and the role of constrained water in solvent exchange with amphiphilic cosolvents. AB - The thermodynamic driving forces for protein folding, association, and function are often determined by protein-water interactions. With a novel covalently bound labeling approach, we have used sensitive vibrational probes, site-selectively conjugated to two lysozyme variants-in conjunction with ultrafast two-dimensional infrared (2D-IR) spectroscopy-to investigate directly the protein-water interface. By probing alternatively a topologically flat, rigid domain and a flexible domain, we find direct experimental evidence for spatially heterogeneous hydration dynamics. The hydration environment around globular proteins can vary from exhibiting bulk-like hydration dynamics to dynamically constrained water, which results from stifled hydrogen bond switching dynamics near extended hydrophobic surfaces. Furthermore, we leverage preferential solvation exchange to demonstrate that the liberation of dynamically constrained water is a sufficient driving force for protein-surface association reactions. These results provide an intuitive picture of the dynamic aspects of hydrophobic hydration of proteins, illustrating an essential function of water in biological processes. PMID- 22530971 TI - Triboelectricity: macroscopic charge patterns formed by self-arraying ions on polymer surfaces. AB - Tribocharged polymers display macroscopically patterned positive and negative domains, verifying the fractal geometry of electrostatic mosaics previously detected by electric probe microscopy. Excess charge on contacting polyethylene (PE) and polytetrafluoroethylene (PTFE) follows the triboelectric series but with one caveat: net charge is the arithmetic sum of patterned positive and negative charges, as opposed to the usual assumption of uniform but opposite signal charging on each surface. Extraction with n-hexane preferentially removes positive charges from PTFE, while 1,1-difluoroethane and ethanol largely remove both positive and negative charges. Using suitable analytical techniques (electron energy-loss spectral imaging, infrared microspectrophotometry and carbonization/colorimetry) and theoretical calculations, the positive species were identified as hydrocarbocations and the negative species were identified as fluorocarbanions. A comprehensive model is presented for PTFE tribocharging with PE: mechanochemical chain homolytic rupture is followed by electron transfer from hydrocarbon free radicals to the more electronegative fluorocarbon radicals. Polymer ions self-assemble according to Flory-Huggins theory, thus forming the experimentally observed macroscopic patterns. These results show that tribocharging can only be understood by considering the complex chemical events triggered by mechanical action, coupled to well-established physicochemical concepts. Patterned polymers can be cut and mounted to make macroscopic electrets and multipoles. PMID- 22530973 TI - Protection by polyphenols of postprandial human plasma and low-density lipoprotein modification: the stomach as a bioreactor. AB - Recent studies dramatically showed that the removal of circulating modified low density lipoprotein (LDL) results in complete prevention of atherosclerosis. The gastrointestinal tract is constantly exposed to food, some of it containing oxidized compounds. Lipid oxidation in the stomach was demonstrated by ingesting heated red meat in rats. Red wine polyphenols added to the rats' meat diet prevented lipid peroxidation in the stomach and absorption of malondialdehyde (MDA) in rat plasma. In humans, postprandial plasma MDA levels rose by 3-fold after a meal of red meat cutlets. MDA derived from meat consumption caused postprandial plasma LDL modification in human. The levels of plasma MDA showed a 75% reduction by consumption of red wine polyphenols during the meat meal. Locating the main biological site of action of polyphenols in the stomach led to a revision in the understanding of how antioxidants work in vivo and may help to elucidate the mechanism involved in the protective effects of polyphenols in human health. PMID- 22530974 TI - Metacognitive beliefs and psychological well-being in paranoia and depression. AB - INTRODUCTION: Despite the growing interest in the effects of metacognitive beliefs and psychological well-being on psychiatric conditions, little is known about how these two variables interact in clinical samples. The central aim of this study was to investigate the role of some metacognitive beliefs in the relationship between psychological well-being dimensions and psychopathology. METHODS: Fifty-five participants with persecutory delusions diagnosed with schizophrenia or other psychotic disorders, 38 participants with a major depressive episode, and 44 healthy controls completed the 30-item short form of the Metacognitions Questionnaire (MCQ-30) and the 54-item form of the Ryff Scales of Psychological Well-Being (PWB). RESULTS: MANCOVA analyses revealed group differences on four subscales of PWB (self-acceptance, autonomy, personal growth, and environmental mastery), as well as on three subscales of MCQ-30 (uncontrollability of worry, need to control thoughts, and lack of memory confidence). Moderation analyses showed the interaction between persecutory thinking and cognitive self-consciousness to be a predictor of psychological well being. CONCLUSIONS: These findings suggest that psychological well-being is particularly compromised in participants with a high level of persecutory thinking when they have low levels of cognitive self-consciousness. PMID- 22530975 TI - S-nitrosation: current concepts and new developments. AB - The S-nitrosation (also referred to as S-nitrosylation) of cysteine residues is an important post-translational protein modification that regulates protein function and cell signaling. The original research articles and reviews in this Forum cover important concepts in protein S-nitrosation and identify key developments and opportunities for progress in this area. Defining the mechanisms by which S-nitrosothiols (RSNOs) may be formed and decomposed in cells and tissues, the integration of the biological chemistry associated with nitric oxide (NO) and other derivatives such as nitrite, and the development of new methodologies merging proteomics and direct quantitation are all key issues that we believe would require detailed attention. PMID- 22530978 TI - Syntheses and structure-activity relationships of seven manganese-salen derivatives as anti-amyloidogenic and fibril-destabilizing agents against hen egg white lysozyme aggregation. AB - Accumulation of intra- and/or extracellular misfolded proteins as amyloid fibrils is a key hallmark in more than 20 amyloid-related diseases. In that respect, blocking or reversing amyloid aggregation via the use of small compounds is considered as two useful approaches in hampering the development of these diseases. In this research, we have studied the ability of different manganese salen derivatives to inhibit amyloid self-assembly as well as to dissolve amyloid aggregates of hen egg-white lysozyme, as an in vitro model system, with the aim of investigating their structure-activity relationships. By coupling several techniques such as thioflavin T and anilinonaphthalene-8-sulfonic acid fluorescence, congo red absorbance, far-UV circular dichroism, and transmission electron microscopy, we demonstrated that all compounds possessed anti amyloidogenic activities and were capable of dispersing the fibrillar aggregates. In addition, MTT assay of the treated SK-N-MC cells with the preformed fibrils formed in the presence of compounds at a drug-to-protein molar ratio of 5:1, indicated a significant increase in the viability of cells, compared to the fibrils formed in the absence of each of the compounds. Our spectroscopy, electron microscopy, and cellular studies indicated that EUK-15, with a methoxy group at the para position (group R(5)), had higher activity to either inhibit or disrupt the beta-sheet structures relative to other compounds. On the basis of these results, it can be concluded that in addition to aromatic rings of each of the derivatives, the type and position of the side group(s) contribute to lower lysozyme fibril accumulation. PMID- 22530980 TI - A close look at proteins: submolecular resolution of two- and three-dimensionally folded cytochrome c at surfaces. AB - Imaging of individual protein molecules at the single amino acid level has so far not been possible due to the incompatibility of proteins with the vacuum environment necessary for high-resolution scanning probe microscopy. Here we demonstrate electrospray ion beam deposition of selectively folded and unfolded cytochrome c protein ions on atomically defined solid surfaces in ultrahigh vacuum (10(-10) mbar) and achieve unprecedented resolution with scanning tunneling microscopy. On the surface folded proteins are found to retain their three-dimensional structure. Unfolded proteins are observed as extended polymer strands displaying submolecular features with resolution at the amino acid level. On weakly interacting surfaces, unfolded proteins refold into flat, irregular patches composed of individual molecules. This suggests the possibility of two dimensionally confined folding of peptides of an appropriate sequence into regular two-dimensional structures as a new approach toward functional molecular surface coatings. PMID- 22530979 TI - Patient and provider interventions for managing osteoarthritis in primary care: protocols for two randomized controlled trials. AB - BACKGROUND: Osteoarthritis (OA) of the hip and knee are among the most common chronic conditions, resulting in substantial pain and functional limitations. Adequate management of OA requires a combination of medical and behavioral strategies. However, some recommended therapies are under-utilized in clinical settings, and the majority of patients with hip and knee OA are overweight and physically inactive. Consequently, interventions at the provider-level and patient-level both have potential for improving outcomes. This manuscript describes two ongoing randomized clinical trials being conducted in two different health care systems, examining patient-based and provider-based interventions for managing hip and knee OA in primary care. METHODS / DESIGN: One study is being conducted within the Department of Veterans Affairs (VA) health care system and will compare a Combined Patient and Provider intervention relative to usual care among n = 300 patients (10 from each of 30 primary care providers). Another study is being conducted within the Duke Primary Care Research Consortium and will compare Patient Only, Provider Only, and Combined (Patient + Provider) interventions relative to usual care among n = 560 patients across 10 clinics. Participants in these studies have clinical and / or radiographic evidence of hip or knee osteoarthritis, are overweight, and do not meet current physical activity guidelines. The 12-month, telephone-based patient intervention focuses on physical activity, weight management, and cognitive behavioral pain management. The provider intervention involves provision of patient-specific recommendations for care (e.g., referral to physical therapy, knee brace, joint injection), based on evidence-based guidelines. Outcomes are collected at baseline, 6-months, and 12-months. The primary outcome is the Western Ontario and McMasters Universities Osteoarthritis Index (self-reported pain, stiffness, and function), and secondary outcomes are the Short Physical Performance Test Protocol (objective physical function) and the Patient Health Questionnaire-8 (depressive symptoms). Cost effectiveness of the interventions will also be assessed. DISCUSSION: Results of these two studies will further our understanding of the most effective strategies for improving hip and knee OA outcomes in primary care settings. TRIAL REGISTRATION: NCT01130740 (VA); NCT 01435109 (NIH). PMID- 22530982 TI - Asthma during pregnancy: the experiences, concerns and views of pregnant women with asthma. AB - OBJECTIVE: To investigate how pregnant women manage their asthma during pregnancy and factors influencing their behavior. METHODS: In-depth interviews (telephone or face-to-face) with a purposive sample of 23 asthmatic women at various stages of pregnancy and with varying severity of asthma. RESULTS: Five major themes were discerned relating to health behavior of pregnant women with asthma. Many of the participants decreased or discontinued their asthma medications themselves and refrained from taking doses when necessary during pregnancy without consulting their doctors. Reasons behind their decisions revolved around lack of support and information about what to do, concerns about the safety of the medications, past experiences, and desire for an "all natural" pregnancy. Asthma monitoring during pregnancy was seen as a low priority for some women and their doctors. Communication between pregnant women and health professionals regarding asthma management was poor. The health behavior of pregnant women with asthma could be explained using the Health Beliefs Model. CONCLUSIONS: Pregnant women are not well supported in managing asthma during pregnancy, despite being concerned about outcomes. Interventions, education, and more support are warranted and wanted by pregnant women with asthma to optimize pregnancy and neonatal outcomes. PMID- 22530983 TI - Leptin action on nonneuronal cells in the CNS: potential clinical applications. AB - Leptin, an adipocyte-derived cytokine, crosses the blood-brain barrier to act on many regions of the central nervous system (CNS). It participates in the regulation of energy balance, inflammatory processes, immune regulation, synaptic formation, memory condensation, and neurotrophic activities. This review focuses on the newly identified actions of leptin on astrocytes. We first summarize the distribution of leptin receptors in the brain, with a focus on the hypothalamus, where the leptin receptor is known to mediate essential feeding suppression activities, and on the hippocampus, where leptin facilitates memory, reduces neurodegeneration, and plays a dual role in seizures. We will then discuss regulation of the nonneuronal leptin system in obesity. Its relationship with neuronal leptin signaling is illustrated by in vitro assays in primary astrocyte culture and by in vivo studies on mice after pretreatment with a glial metabolic inhibitor or after cell-specific deletion of intracellular signaling leptin receptors. Overall, the glial leptin system shows robust regulation and plays an essential role in obesity. Strategies to manipulate this nonneuronal leptin signaling may have major clinical impact. PMID- 22530984 TI - Short form of the Changes in Outlook Questionnaire: translation and validation of the Chinese version. AB - BACKGROUND: The Changes in Outlook Questionnaire (CiOQ) is a self-report instrument designed to measure both positive and negative changes following the experience of severely stressful events. Previous research has focused on the Western context. The aim of this study is to translate the short form of the measure (CiOQ-S) into simplified Chinese and examine its validity and reliability in a sample of Chinese earthquake survivors. METHOD: The English language version of the 10-item CiOQ was translated into simplified Chinese and completed along with other measures in a sample of earthquake survivors (n = 120). Statistical analyses were performed to explore the structure of the simplified Chinese version of CiOQ-S (CiOQ-SCS), its reliability and validity. RESULTS: Principal components analysis (PCA) was conducted to test the structure of the CiOQ-SCS. The reliability and convergent validity were also assessed. The CiOQ-SCS demonstrated a similar factor structure to the English version, high internal consistency and convergent validity with measures of posttraumatic stress symptoms, anxiety and depression, coping and social support. CONCLUSION: The data are comparable to those reported for the original version of the instrument indicating that the CiOQ-SCS is a reliable and valid measure assessing positive and negative changes in the aftermath of adversity. However, the sampling method cannot permit us to know how representative our samples were of the earthquake survivor population. PMID- 22530985 TI - New insights for rapid evaluation of bactericidal activity: a semi-automated bioluminescent ATP assay. AB - AIMS: A new assay, much more rapid and efficient than the existing standardized tests, is introduced for the evaluation of bactericidal activity of chemical disinfectants and antiseptics under simulated practical conditions of use. METHODS AND RESULTS: The bactericidal activity of biocides was quantified using a novel semi-automated assay based on the European Norm (EN) standard suspension tests but determining bacterial cell viability by intracellular adenosine tri phosphate (ATP) content quantification instead of traditional culture-based microbiological techniques. The new test was validated by comparison to the standard suspension tests EN 1276 and EN 13727. During the validation, the linearity of the ATP detection system, limit of detection, specificity, sensitivity, relative accuracy and precision (repeatability and reproducibility) were determined. CONCLUSIONS: The validation study showed that the new assay evaluates the activity of biocides as well as the EN standard suspension tests, but it allows a large number of test conditions to be efficiently analysed. SIGNIFICANCE AND IMPACT OF THE STUDY: The new test can therefore be applied to accurately establish the lowest active concentration (MBCs) of disinfectants or antiseptics under simulated practical conditions of use and to compare the susceptibility of a large number of strains and conditions via inactivation curves. This is not possible in any reasonably practicable way with the EN standards considering the time and cost required for each determination. PMID- 22530986 TI - Validation of the theoretical domains framework for use in behaviour change and implementation research. AB - BACKGROUND: An integrative theoretical framework, developed for cross disciplinary implementation and other behaviour change research, has been applied across a wide range of clinical situations. This study tests the validity of this framework. METHODS: Validity was investigated by behavioural experts sorting 112 unique theoretical constructs using closed and open sort tasks. The extent of replication was tested by Discriminant Content Validation and Fuzzy Cluster Analysis. RESULTS: There was good support for a refinement of the framework comprising 14 domains of theoretical constructs (average silhouette value 0.29): 'Knowledge', 'Skills', 'Social/Professional Role and Identity', 'Beliefs about Capabilities', 'Optimism', 'Beliefs about Consequences', 'Reinforcement', 'Intentions', 'Goals', 'Memory, Attention and Decision Processes', 'Environmental Context and Resources', 'Social Influences', 'Emotions', and 'Behavioural Regulation'. CONCLUSIONS: The refined Theoretical Domains Framework has a strengthened empirical base and provides a method for theoretically assessing implementation problems, as well as professional and other health-related behaviours as a basis for intervention development. PMID- 22530987 TI - Amniotic fluid embolism: incidence, risk factors, and impact on perinatal outcome. AB - OBJECTIVE: To extend our previous work on AFE in Canada by including stricter criteria for case identification and by examining risks for stillbirth, neonatal mortality and serious maternal and neonatal morbidity. DESIGN: Population-based cohort study. SETTING: Canada. POPULATION OR SAMPLE: In all, 4,508,462 hospital deliveries from fiscal year 1991/92 to 2008/09. METHODS: To reduce false-positive diagnoses, we restricted our analysis to AFE cases with cardiac arrest, shock or severe hypertension, respiratory distress, mechanical ventilation, coma, seizure, or coagulation disorder. Linkage of maternal and neonatal records, available since 2001/02, enabled us to examine the effects of AFE on neonatal outcomes. Detailed demographic and clinical data facilitated control for a broad array of potential confounding variables. MAIN OUTCOME MEASURES: Amniotic fluid embolism, in-hospital neonatal death, asphyxia, mechanical ventilation, bacterial sepsis, seizure, nonimmune haemolytic or traumatic jaundice and length of hospital stay. RESULTS: A total of 292 AFE cases were identified, of which only 120 (40%) were confirmed after applying our additional diagnostic criteria, yielding an AFE incidence of 2.5 per 100,000 deliveries. Of the 120 confirmed cases, 33 (27%) were fatal. Significant modifiable risk factors included medical induction, caesarean delivery, instrumental vaginal delivery, and uterine or cervical trauma. Amniotic fluid embolism was associated with significantly increased risks of stillbirth and neonatal asphyxia, mechanical ventilation, sepsis, seizures and prolonged length of hospital stay. CONCLUSIONS: Amniotic fluid embolism remains a rare but serious obstetric outcome, with several important modifiable risk factors and major implications for maternal, fetal and neonatal health. PMID- 22530988 TI - Interaction of cetyltrimethylammonium bromide and its gemini homologue bis(cetyldimethylammonium)butane dibromide with xanthine oxidase. AB - The interaction of xanthine oxidase (XO), a key enzyme in purine metabolism, with cetyltrimethylammonium bromide (CTAB) and bis(cetyldimethylammonium)butane dibromide (C16C4C16Br2) has been studied using tensiometry, spectrofluorometry, spectrophotometry, and circular dichroism at pH 7.4 and 25 degrees C. The tensiometric profiles of CTAB and C16C4C16Br2 in the presence of XO exhibit a single break at a lower surfactant concentration termed as C1 compared to their CMC in the buffered solution and show the existence of interaction between the surfactants and the enzyme. The results of the multitechnique approach showed that, although both CTAB as well as C16C4C16Br2 interact with the XO, C16C4C16Br2 interacts more strongly than its conventional single chain counterpart. Fluorescence and absorption measurements revealed that, compared to CTAB, C16C4C16Br2 is more effective in unfolding the enzyme. Change in XO activity by the surfactants was in concurrence with the structural alterations monitored by circular dichroism and showed structural stabilization of XO at higher surfactant concentrations, consistent with the aggregation results. This stabilization has been explained in light of strong tendency of C16C4C16Br2 for micellar growth and membrane/water stabilization of proteins by membrane-like fragments provided by higher concentrations of C16C4C16Br2 . The results are related to the stronger electrostatic and hydrophobic forces in C16C4C16Br2, owing to the presence of two charged headgroups and two hydrophobic tails. PMID- 22530989 TI - Comparing the mitochondrial genomes of Wolbachia-dependent and independent filarial nematode species. AB - BACKGROUND: Many species of filarial nematodes depend on Wolbachia endobacteria to carry out their life cycle. Other species are naturally Wolbachia-free. The biological mechanisms underpinning Wolbachia-dependence and independence in filarial nematodes are not known. Previous studies have indicated that Wolbachia have an impact on mitochondrial gene expression, which may suggest a role in energy metabolism. If Wolbachia can supplement host energy metabolism, reduced mitochondrial function in infected filarial species may account for Wolbachia dependence. Wolbachia also have a strong influence on mitochondrial evolution due to vertical co-transmission. This could drive alterations in mitochondrial genome sequence in infected species. Comparisons between the mitochondrial genome sequences of Wolbachia-dependent and independent filarial worms may reveal differences indicative of altered mitochondrial function. RESULTS: The mitochondrial genomes of 5 species of filarial nematodes, Acanthocheilonema viteae, Chandlerella quiscali, Loa loa, Onchocerca flexuosa, and Wuchereria bancrofti, were sequenced, annotated and compared with available mitochondrial genome sequences from Brugia malayi, Dirofilaria immitis, Onchocerca volvulus and Setaria digitata. B. malayi, D. immitis, O. volvulus and W. bancrofti are Wolbachia-dependent while A. viteae, C. quiscali, L. loa, O. flexuosa and S. digitata are Wolbachia-free. The 9 mitochondrial genomes were similar in size and AT content and encoded the same 12 protein-coding genes, 22 tRNAs and 2 rRNAs. Synteny was perfectly preserved in all species except C. quiscali, which had a different order for 5 tRNA genes. Protein-coding genes were expressed at the RNA level in all examined species. In phylogenetic trees based on mitochondrial protein-coding sequences, species did not cluster according to Wolbachia dependence. CONCLUSIONS: Thus far, no discernable differences were detected between the mitochondrial genome sequences of Wolbachia-dependent and independent species. Additional research will be needed to determine whether mitochondria from Wolbachia-dependent filarial species show reduced function in comparison to the mitochondria of Wolbachia-independent species despite their sequence-level similarities. PMID- 22530991 TI - Feeding guild structure of beetles on Australian tropical rainforest trees reflects microhabitat resource availability. AB - 1. We tested the hypotheses that feeding guild structure of beetle assemblages changed with different arboreal microhabitats and that these differences were consistent across rainforest tree species. 2. Hand collection and beating techniques were used from the gondola of the Australian Canopy Crane to collect beetles from five microhabitats (mature leaves, flush leaves, flowers, fruit and suspended dead wood) within the rainforest canopy. A simple randomization procedure was implemented to test whether the abundances of each feeding guild on each microhabitat were different from that expected based on a null hypothesis of random distribution of individuals across microhabitats. 3. Beetles from different feeding guilds were not randomly distributed, but congregated on those microhabitats that are likely to provide the highest concentrations of their preferred food sources. Herbivorous beetles, in particular, were over-represented on flowers and flush foliage and under-represented on mature leaves and dead wood. Proportional numbers of species within each feeding guild were remarkably uniform across tree species for each microhabitat, but proportional abundances of feeding guilds were all significantly non-uniformly distributed between host tree species, regardless of microhabitat, confirming patterns previously found for arthropods in trees in temperate and tropical forests. 4. These results show that the canopy beetle community is partitioned into discrete assemblages between microhabitats and that this partitioning arises because of differences in feeding guild structure as a function of the diversity and the temporal and spatial availability of resources found on each microhabitat. PMID- 22530990 TI - Targeting the HGF/Met signaling pathway in cancer therapy. AB - INTRODUCTION: Under normal conditions, hepatocyte growth factor (HGF)-induced activation of its cell surface receptor, the Met tyrosine kinase (TK), is tightly regulated by paracrine ligand delivery, ligand activation at the target cell surface, and ligand-activated receptor internalization and degradation. Despite these controls, HGF/Met signaling contributes to oncogenesis and tumor progression in several cancers and promotes aggressive cellular invasiveness that is strongly linked to tumor metastasis. AREA COVERED: The prevalence of HGF/Met pathway activation in human malignancies has driven rapid growth in cancer drug development programs. The authors review Met structure and function, the basic properties of HGF/Met pathway antagonists now in preclinical and clinical development, as well as the latest clinical trial results. EXPERT OPINION: Clinical trials with HGF/Met pathway antagonists show that as a class these agents are well tolerated. Although widespread efficacy was not seen in several completed Phase II studies, promising results have been reported in lung, gastric, prostate and papillary renal cancer patients treated with these agents. The main challenges facing the effective use of HGF/Met-targeted antagonists for cancer treatment are optimal patient selection, diagnostic and pharmacodynamic biomarker development, and the identification and testing of optimal therapy combinations. The wealth of basic information, analytical reagents, and model systems available concerning HGF/Met oncogenic signaling will continue to be invaluable in meeting these challenges and moving expeditiously toward more effective disease control. PMID- 22530992 TI - Increased financial burden among patients with chronic myelogenous leukaemia receiving imatinib in Japan: a retrospective survey. AB - BACKGROUND: The financial burden of medical expenses has been increasing for cancer patients. We investigated the relationship between household income and financial burden among patients with chronic myelogenous leukaemia (CML) who have been treated with imatinib. METHODS: A questionnaire was distributed to 1200 patients between May and August 2009. We retrospectively surveyed their household incomes, out-of-pocket medical expenses, final co-payments after refunds, and the perceived financial burden of their medical expenses in 2000, 2005 and 2008. RESULTS: A total of 577 patients completed the questionnaire. Their median age was 61 years (range, 15-94). A financial burden was felt by 41.2 % (28 of 68) of the patients treated with imatinib in 2000, 70.8 % (201 of 284) in 2005, and 75.8 % (400 of 528) in 2008. Overall, 182 patients (31.7 %) considered its discontinuation because of the financial burden and 15 (2.6 %) temporarily stopped their imatinib prescription. In 2000, 2005 and 2008, the patients' median annual household incomes were 49,615 US Dollars (USD), 38,510 USD and 36,731 USD, respectively, with an average currency exchange rate of 104 Yen/USD in 2008. Their median annual out-of-pocket expenses were 11,548, 12,067 and 11,538 USD and their median final annual co-payments were 4,375, 4,327 and 3,558 USD, respectively. Older patients (OR = 0.96, 95 % CI: 0.95-0.98, p ? 0.0001 for 1 year increments), and patients with higher household incomes (OR = 0.92, 95 % CI: 0.85-0.99, p = 0.03 for 10,000 USD-increments) were less likely to have considered discontinuing their imatinib treatment. Conversely, patients with higher annual final co-payments (OR = 2.21, 95 % CI: 1.28-4.28, p = 0.004 for 10,000 USD-increments) were more likely to have considered discontinuing their imatinib treatment. CONCLUSIONS: The proportion of CML patients who sensed a financial burden increased between 2000 and 2008. During this period, their annual incomes fell by 13,000 USD, although their medical expenses did not change. Financial support for patients being treated with expensive drugs remains a major problem in Japan. PMID- 22530993 TI - MK-626, a dipeptidyl peptidase-4 inhibitor, does not improve the hyperglycemia or hyperinsulinemia of nonobese diabetic MKR mice. AB - Dipeptidyl peptidase-4 (DPP-4) inhibitors increase circulating levels of incretin hormones, which can enhance insulin secretion and beta cell function. The aim of this study was to evaluate the effectiveness of MK-626 (a novel DPP-4 inhibitor) to reduce the hyperglycemia and hyperinsulinemia of nonobese type 2 diabetic MKR mice. Twelve to 14-week-old hyperglycemic MKR mice were gavaged daily with MK-626 (3 mg/kg body weight) or vehicle (0.5% methyl cellulose (MC)) for 2 weeks. MK-626 treated mice displayed no change in body weight or adverse reactions, suggesting good tolerance of the drug. Fed blood glucose was significantly reduced over the 2-week experiment; however, it was also reduced in the MC group, suggesting an effect of gavage alone. Fed plasma insulin and glucagon levels and glucose tolerance of MK-626-treated mice were similar to those of MC mice. Therefore, treatment with MK-626 did not correct the prolonged hyperglycemia and impaired glucose tolerance of MKR mice. PMID- 22530994 TI - Rutile-TiO2 nanocoating for a high-rate Li4Ti5O12 anode of a lithium-ion battery. AB - Well-defined Li(4)Ti(5)O(12) nanosheets terminated with rutile-TiO(2) at the edges were synthesized by a facile solution-based method and revealed directly at atomic resolution by an advanced spherical aberration imaging technique. The rutile-TiO(2) terminated Li(4)Ti(5)O(12) nanosheets show much improved rate capability and specific capacity compared with pure Li(4)Ti(5)O(12) nanosheets when used as anode materials for lithium ion batteries. The results here give clear evidence of the utility of rutile-TiO(2) as a carbon-free coating layer to improve the kinetics of Li(4)Ti(5)O(12) toward fast lithium insertion/extraction. The carbon-free nanocoating of rutile-TiO(2) is highly effective in improving the electrochemical properties of Li(4)Ti(5)O(12), promising advanced batteries with high volumetric energy density, high surface stability, and long cycle life compared with the commonly used carbon nanocoating in electrode materials. PMID- 22530995 TI - Substitutional mechanism of Ni into the wide-band-gap semiconductor InTaO4 and its implications for water splitting activity in the wolframite structure type. AB - The mechanism of Ni substitution into the oxide semiconductor InTaO(4) has been studied through a combination of structural and spectroscopic techniques, providing insights into its previously reported photoactivity. Magnetic susceptibility and X-ray absorption near-edge spectroscopy (XANES) measurements demonstrate that nickel is divalent within the host lattice. The combined refinement of synchrotron X-ray and neutron powder diffraction data indicates that the product of Ni doping has the stoichiometry of (In(1 x)Ni(2x/3)Ta(x/3))TaO(4) with a solubility limit of x ~ 0.18, corresponding to 12% Ni on the In site. Single-phase samples were only obtained at synthesis temperatures of 1150 degrees C or higher due to the sluggish reaction mechanism that is hypothesized to result from small free energy differences between (In(1 x)Ni(2x/3)Ta(x/3))TaO(4) compounds with different x values. Undoped InTaO(4) is shown to have an indirect band gap of 3.96 eV, with direct optical transitions becoming allowed at photon energies in excess of 5.1 eV. Very small band-gap reductions (less than 0.2 eV) result from Ni doping, and the origin of the yellow color of (In(1-x)Ni(2x/3)Ta(x/3))TaO(4) compounds instead results from a weak (3)A(2g) -> (3)T(1g) internal d -> d transition not associated with the conduction or valence band that is common to oxide compounds with Ni(2+) in an octahedral environment. PMID- 22530997 TI - The effects of pH change and NO3- pulse on microbial community structure and function: a vernal pool microcosm study. AB - Forest vernal pools experience strong environmental fluctuations, such as changes in water chemistry, which are often correlated with changes in microbial community structure. However, very little is known about the extent to which these community changes influence ecosystem processes in vernal pools. This study utilized experimental vernal pool microcosms to simulate persistent pH alteration and a pulse input of nitrate (NO3 -), which are common perturbations to temperate vernal pool ecosystems. pH was manipulated at the onset and microbial respiration was monitored throughout the study (122 days). On day 29, NO3 - was added and denitrification rate was measured and bacterial, fungal, and denitrifier communities were profiled on day 30 and day 31. Microbial respiration and both bacterial and fungal community structure were altered by the pH treatment, demonstrating both structural and functional microbial responses. The NO3 - pulse increased denitrification rate without associated changes in community structure, suggesting that microbial communities responded functionally without structural shifts. The functioning of natural vernal pools, which experience both persistent and short-term environmental change, may thus depend on the type and duration of the change or disturbance. PMID- 22530996 TI - Early single-channel aEEG/EEG predicts outcome in very preterm infants. AB - AIM: To characterize early amplitude-integrated electroencephalogram (aEEG) and single-channel EEG (aEEG/EEG) in very preterm (VPT) infants for prediction of long-term outcome. PATIENTS: Forty-nine infants with median (range) gestational age of 25 (22-30) weeks. METHODS: Amplitude-integrated electroencephalogram/EEG recorded during the first 72 h and analysed over 0-12, 12-24, 24-48 and 48-72 h, for background pattern, sleep-wake cycling, seizures, interburst intervals (IBI) and interburst percentage (IB%). In total, 2614 h of single-channel EEG examined for seizures. Survivors were assessed at 2 years corrected age with a neurological examination and Bayley Scales of Infant Development-II. Poor outcome was defined as death or survival with neurodevelopmental impairment. Good outcome was defined as survival without impairment. RESULTS: Thirty infants had good outcome. Poor outcome (n = 19) was associated with depressed aEEG/EEG already during the first 12 h (p = 0.023), and with prolonged IBI and higher IB% at 24 h. Seizures were present in 43% of the infants and associated with intraventricular haemorrhages but not with outcome. Best predictors of poor outcome were burst suppression pattern [76% correctly predicted; positive predictive value (PPV) 63%, negative predictive value (NPV) 91%], IBI > 6 sec (74% correctly predicted; PPV 67%, NPV 79%) and IB% > 55% at 24 h age (79% correctly predicted; PPV 72%, NPV 80%). In 35 infants with normal cerebral ultrasound during the first 3 days, outcome was correctly predicted in 82% by IB% (PPV 82%, NPV 83%). CONCLUSION: Long-term outcome can be predicted by aEEG/EEG with 75-80% accuracy already at 24 postnatal hours in VPT infants, also in infants with no early indication of brain injury. PMID- 22530998 TI - Review of chemical and radiotoxicological properties of polonium for internal contamination purposes. AB - The discovery of polonium (Po) was first published in July, 1898 by P. Curie and M. Curie. It was the first element to be discovered by the radiochemical method. Polonium can be considered as a famous but neglected element: only a few studies of polonium chemistry have been published, mostly between 1950 and 1990. The recent (2006) event in which (210)Po evidently was used as a poison to kill A. Litvinenko has raised new interest in polonium. 2011 being the 100th anniversary of the Marie Curie Nobel Prize in Chemistry, the aim of this review is to look at the several aspects of polonium linked to its chemical properties and its radiotoxicity, including (i) its radiochemistry and interaction with matter; (ii) its main sources and uses; (iii) its physicochemical properties; (iv) its main analytical methods; (v) its background exposure risk in water, food, and other environmental media; (vi) its biokinetics and distribution following inhalation, ingestion, and wound contamination; (vii) its dosimetry; and (viii) treatments available (decorporation) in case of internal contamination. PMID- 22530999 TI - Villin 1 is a predictive factor for the recurrence of high serum alpha fetoprotein-associated hepatocellular carcinoma after hepatectomy. AB - The prognostic assessment of patients with hepatocellular carcinoma (HCC) after resection is an important clinical issue. The present study investigated those genes associated with high serum alpha-fetoprotein (AFP), and their clinical significance, including prognosis and recurrence after hepatectomy. Based on gene expression analysis of 110 training HCC cases, 20 genes whose mRNA expression levels were significantly upregulated and 50 genes that were downregulated correlated with high serum AFP-associated HCC patients. Gene expression profiles of Villin1 (Vil1) were obtained in high serum AFP-associated HCC tumor tissues. In the present analysis, only VIL1 was significantly correlated with the recurrence of HCC. The results were validated independently using Taqman gene expression assays and immunostaining analysis. Results showed that the upregulation of VIL1 mRNA was also correlated with high serum PIVKAII, vascular invasion (P < 0.05), poor differentiation, an advanced cancer stage (P < 0.01) and recurrence-free survival (P = 0.017). The upregulation of VIL1 mRNA was observed more frequently in the early recurrence patients as compared to the late recurrence patients. Cox regression univariate and multivariate analyses indicated that high serum AFP levels (overall survival, HR 1.675, P = 0.002; FRS, HR 1.359, P = 0.039) and Vil1 protein expression (overall survival, HR 0.253, P = 0.009; FRS, HR 0.401, P = 0.041) were independent, unfavorable prognostic factors for overall and recurrence-free survival of patients. We demonstrated that the VIL1 gene is a potential candidate molecular marker for high serum AFP-associated HCC and a predictive candidate for the postoperative recurrence and poorer prognosis of HCC. PMID- 22531000 TI - The N-terminal region of CXCL11 as structural template for CXCR3 molecular recognition: synthesis, conformational analysis, and binding studies. AB - The chemokines and their receptors play a key role in immune and inflammatory responses by promoting recruitment and activation of different subpopulations of leukocytes. The membrane receptor CXCR3 binds three chemokines, CXCL9, CXCL10, and CXCL11, and its involvement is recognized in many inflammatory diseases and cancers. Therefore, the inhibition of CXCR3 pathway through interactions with three ligands was indicated as putative therapeutic target for the treatment of these diseases, and some inhibitory compounds have already been described in the literature. Recently, we studied the interaction between CXCR3 and its three natural ligands and showed that three CXCR3 ligands bound the receptor mainly by their N-terminal regions using aromatic and electrostatic interactions, and, in particular, CXCL11 had the highest affinity for CXCR3. In light of these results, we focused our attention on what structural region(s) of CXCL11 interacted with CXCR3 and what were the structural features. Therefore, we have synthesized three peptides, corresponding to the N-terminal region of CXCL11, but with different aromatic amino acids, analyzed their conformations by circular dichroism, NMR, and molecular dynamics simulations, simulated their complexes with CXCR3 by docking methods, and validated these data by in vitro studies. The results showed that two peptides were able to bind CXCR3 and to mimic the molecular recognition of CXCL11 and demonstrated that N-terminal region of CXCL11 can be used as template and starting point to obtain new molecules by de novo design approaches. PMID- 22531002 TI - Thioredoxin and glutaredoxin systems in plants: molecular mechanisms, crosstalks, and functional significance. AB - Thioredoxins (Trx) and glutaredoxins (Grx) constitute families of thiol oxidoreductases. Our knowledge of Trx and Grx in plants has dramatically increased during the last decade. The release of the Arabidopsis genome sequence revealed an unexpectedly high number of Trx and Grx genes. The availability of several genomes of vascular and nonvascular plants allowed the establishment of a clear classification of the genes and the chronology of their appearance during plant evolution. Proteomic approaches have been developed that identified the putative Trx and Grx target proteins which are implicated in all aspects of plant growth, including basal metabolism, iron/sulfur cluster formation, development, adaptation to the environment, and stress responses. Analyses of the biochemical characteristics of specific Trx and Grx point to a strong specificity toward some target enzymes, particularly within plastidial Trx and Grx. In apparent contradiction with this specificity, genetic approaches show an absence of phenotype for most available Trx and Grx mutants, suggesting that redundancies also exist between Trx and Grx members. Despite this, the isolation of mutants inactivated in multiple genes and several genetic screens allowed the demonstration of the involvement of Trx and Grx in pathogen response, phytohormone pathways, and at several control points of plant development. Cytosolic Trxs are reduced by NADPH-thioredoxin reductase (NTR), while the reduction of Grx depends on reduced glutathione (GSH). Interestingly, recent development integrating biochemical analysis, proteomic data, and genetics have revealed an extensive crosstalk between the cytosolic NTR/Trx and GSH/Grx systems. This crosstalk, which occurs at multiple levels, reveals the high plasticity of the redox systems in plants. PMID- 22531001 TI - Genome-wide identification and characterization of replication origins by deep sequencing. AB - BACKGROUND: DNA replication initiates at distinct origins in eukaryotic genomes, but the genomic features that define these sites are not well understood. RESULTS: We have taken a combined experimental and bioinformatic approach to identify and characterize origins of replication in three distantly related fission yeasts: Schizosaccharomyces pombe, Schizosaccharomyces octosporus and Schizosaccharomyces japonicus. Using single-molecule deep sequencing to construct amplification-free high-resolution replication profiles, we located origins and identified sequence motifs that predict origin function. We then mapped nucleosome occupancy by deep sequencing of mononucleosomal DNA from the corresponding species, finding that origins tend to occupy nucleosome-depleted regions. CONCLUSIONS: The sequences that specify origins are evolutionarily plastic, with low complexity nucleosome-excluding sequences functioning in S. pombe and S. octosporus, and binding sites for trans-acting nucleosome-excluding proteins functioning in S. japonicus. Furthermore, chromosome-scale variation in replication timing is conserved independently of origin location and via a mechanism distinct from known heterochromatic effects on origin function. These results are consistent with a model in which origins are simply the nucleosome depleted regions of the genome with the highest affinity for the origin recognition complex. This approach provides a general strategy for understanding the mechanisms that define DNA replication origins in eukaryotes. PMID- 22531003 TI - Design, synthesis, and analysis of the quantitative structure-activity relationships of 4-phenyl-acyl-substituted 3-(2,5-dimethylphenyl)-4-hydroxy-1 azaspiro[4.5]dec-3-ene-2,8-dione derivatives. AB - A series of 4-phenyl-acyl-substituted 3-(2,5-dimethylphenyl)-4-hydroxy-1 azaspiro[4.5]dec-3-ene-2,8-dione derivatives were designed and synthesized, and their structures were characterized using (1)H NMR (or (13)C NMR), mass spectrometry, and elemental analysis. The bioactivities of the new compounds were evaluated. These compounds exhibited good inhibition activities against bean aphids (Aphis fabae) and carmine spider mite (Tetranychus cinnabarinus), and 4 phenyl acyl esters showed stronger bioactivity than 4-arylesterases and alkyl esters. The results showed that compound 8-I-e, which contains a para-methoxy group on the phenyl acyl, and compound 8-I-m, which contains a para trifluoromethyl group on the phenyl acyl, displayed potent insecticidal activity against A. fabae and T. cinnabarinus respectively. The insecticidal activity showed a clear structure-activity relationship, confirming the importance of the flexible bridge. The DFT/B3LYP/6-31(d) level method was used to calculate molecular geometries and electronic descriptors. These factors included total energy, charge distribution, and the linear orbital level of the title compounds. Quantitative structure-activity relationship studies were performed on these compounds using quantum-chemical and physicochemical parameters as independent variables and insecticidal activity as a dependent variable. Insecticidal activity was most closely correlated (r > 0.8) with quantum chemical and physicochemical parameters. PMID- 22531005 TI - Stage I seminoma: treatment outcome at King Hussein Cancer Center in Jordan. AB - BACKGROUND: The aim of this report is to address treatment outcomes of patients with early-stage seminoma in a single institution with special reference to patients with history of surgical violation of the scrotum. METHODS: Seventy four patients with pure seminoma were treated at King Hussein Cancer Center (Amman, Jordan) between 2003 and 2010. All patients underwent orchiectomy. All but 3 patients received adjuvant radiotherapy. Patients who underwent surgical violation of the scrotum prior to referral were managed by further excision or irradiation of the scrotal scar. The follow-up ranged from 1 to 200 months (mean, 33 months). RESULTS: At the time of follow-up; all but one patient remain alive. The 3-year relapse-free survival for the entire cohort was 95.9%. Three patients developed relapse, all of whom received adjuvant irradiation following inguinal orchiectomy and initially harbored tumors larger than 4 cm upon pathological examination. Median time to relapse was 14 months (range, 8-25 months). None were associated with elevated tumor markers prior to detection of relapse. All but one patient were successfully salvaged by chemotherapy. CONCLUSIONS: Our results confirm the excellent prognosis of patients with early-stage seminoma treated by orchiectomy and adjuvant radiotherapy in a developing country. Although all patients who developed relapse demonstrated adverse pathological findings upon initial assessment, no consistent predictor of relapse was found. Scrotal scar re excision or irradiation in patients with prior history of surgical violation of the scrotum are effective measures in preventing local failure. PMID- 22531004 TI - The PedsQLTM Oral Health Scale: feasibility, reliability and validity of the Brazilian Portuguese version. AB - BACKGROUND: Oral and orofacial problems may cause a profound impact on children's oral health-related quality of life (OHRQoL) because of symptoms associated with these conditions that may influence the physical, psychological and social aspects of their daily life. The OHRQoL questionnaires found in the literature are very specific and are not able to measure the impact of oral health on general health domains. Consequently, the objective of this study was to evaluate the psychometric properties of the Portuguese version for Brazilian translation of the Pediatric Quality of Life InventoryTM (PedsQLTM) Oral Health Scale in combination with the PedsQLTM 4.0 Generic Core Scales. METHODS: The PedsQLTM Oral Health Scale was forward-backward translated and cross-culturally adapted for the Brazilian Portuguese language. In order to assess the feasibility, reliability and validity of the Brazilian version of the instrument, a study was carried out in Belo Horizonte with 208 children and adolescents between 2 and 18 years-of-age and their parents. Clinical evaluation of dental caries, socioeconomic information and the Brazilian versions of the PedsQLTM Oral Health Scale, PedsQLTM 4.0 Generic Core Scales, Child Perceptions Questionnaire (CPQ11-14 and CPQ8-10) and Parental-Caregiver Perception Questionnaire (P-CPQ) were administered. Statistical analysis included feasibility (missing values), confirmatory factor analysis (CFA), internal consistency reliability, and test retest intraclass correlation coefficients (ICC) of the PedsQLTM Oral Health Scale. RESULTS: There were no missing data for both child self-report and parent proxy-report on the Brazilian version of the PedsQLTM Oral Health Scale. The CFA showed that the five items of child self-report and parent proxy-report loaded on a single construct. The Cronbach's alpha coefficients for child/adolescent and parent oral health instruments were 0.65 and 0.59, respectively. The test-retest reliability (ICC) for child self-report and parent proxy-report were 0.90 [95% confidence interval (CI) = 0.86-0.93] and 0.86 (95%CI = 0.81-0.90), respectively. The PedsQLTM Oral Health Scale demonstrated acceptable construct validity, convergent validity and discriminant validity. CONCLUSIONS: These results supported the feasibility, reliability and validity of the Brazilian version of the PedsQLTM Oral Health Scale for child self-report for ages 5-18 years-old and parent proxy-report for ages 2-18 years-old children. PMID- 22531006 TI - Powdered red yeast rice and plant stanols and sterols to lower cholesterol. AB - Elevated low-density lipoprotein (LDL) cholesterol is a significant risk factor for cardiovascular disease. It is estimated that 42% of females and 34% of males in the USA have elevated total cholesterol. The current mainstay of lipid lowering therapy utilizes 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (i.e., statin) medications that lower total cholesterol and LDL cholesterol by an average of 20% and 28%, respectively. However, due to the significant side effects of statin medications, many patients seek alternative therapies to help manage their hypercholesterolemia. Red yeast rice (Monascus purpureus) has been used as a food and as an herbal medication in China for centuries. Phytosterols are foods that are similar in structure and function to animal cholesterol. Both of these compounds have been shown in clinical studies to significantly lower LDL cholesterol. We report on a case series of 18 patients with hypercholesterolemia despite therapeutic lifestyle change through diet and exercise who took a proprietary product combining red yeast rice and phytosterols as a powdered shake in an effort to improve their cholesterol indices. Statistically significant reduction (p < .05) in the following mean variables was seen: total cholesterol 19% (46 mg/dL) and LDL 33% (53 mg/dL) after 6 weeks using the blend. There was no significant difference in body mass index (BMI), triglyceride, high-density lipoprotein (HDL) cholesterol levels, or systolic and diastolic blood pressure over the same period. This magnitude of reduction in LDL cholesterol is significantly greater than the 28% reduction observed in the 1999 Journal of the American Medical Association (JAMA) meta-analysis on the average effectiveness of statin medications in lowering cholesterol levels. None of the participants in our study reported any muscle pains, and no abnormal liver function tests were seen while taking the product. Though this case series is limited by small sample size, study duration, and lack of control group, the product's significant reduction in LDL cholesterol without severe side effects indicates that this product may be a clinically effective and well tolerated alternative treatment to using statin medications to treat hypercholesterolemia. PMID- 22531007 TI - Midbrain responses to micro-stimulation of the cochlea using high density thin film arrays. AB - A broader activation of auditory nerve fibres than normal using a cochlear implant contributes to poor frequency discrimination. As cochlear implants also deliver a restricted dynamic range, this hinders the ability to segregate sound sources. Better frequency coding and control over amplitude may be achieved by limiting current spread during electrical stimulation of the cochlea and positioning electrodes closer to the modiolus. Thin-film high density microelectrode arrays and conventional platinum ring electrode arrays were used to stimulate the cochlea of urethane-anaesthetized rats and responses compared. Neurophysiological recordings were taken at 197 multi-unit clusters in the central nucleus of the inferior colliculus (CIC), a site that receives direct monaural innervation from the cochlear nucleus. CIC responses to both the platinum ring and high density electrodes were recorded and differences in activity to changes in stimulation intensity, thresholds and frequency coding of neural activation were examined. The high density electrode array elicited less CIC activity at nonspecific frequency regions than the platinum ring electrode array. The high density electrode array produced significantly lower thresholds and larger dynamic ranges than the platinum ring electrode array when positioned close to the modiolus. These results suggest that a higher density of stimulation sites on electrodes that effectively 'aim' current, combined with placement closer to the modiolus would permit finer control over charge delivery. This may equate to improved frequency specific perception and control over amplitude when using future cochlear implant devices. PMID- 22531009 TI - Sertoli cell quiescence - new insights. AB - It is currently accepted that the Sertoli cells are proliferatively active only during the embryogenesis and early fetal development, seizing to divide after puberty, when the spermatogenic niche is prepared, and they become terminally differentiated. So far, only seasonal breeders from mammals have been reported as having season-dependent variations in adult Sertoli cells number and proliferation activity. In this review, we will try to shed light on testis somatic cell plasticity and discuss new evidence for some unique proliferative features Sertoli cells harbor. PMID- 22531008 TI - Meta-analysis of chicken--salmonella infection experiments. AB - BACKGROUND: Chicken meat and eggs can be a source of human zoonotic pathogens, especially Salmonella species. These food items contain a potential hazard for humans. Chickens lines differ in susceptibility for Salmonella and can harbor Salmonella pathogens without showing clinical signs of illness. Many investigations including genomic studies have examined the mechanisms how chickens react to infection. Apart from the innate immune response, many physiological mechanisms and pathways are reported to be involved in the chicken host response to Salmonella infection. The objective of this study was to perform a meta-analysis of diverse experiments to identify general and host specific mechanisms to the Salmonella challenge. RESULTS: Diverse chicken lines differing in susceptibility to Salmonella infection were challenged with different Salmonella serovars at several time points. Various tissues were sampled at different time points post-infection, and resulting host transcriptional differences investigated using different microarray platforms. The meta-analysis was performed with the R-package metaMA to create lists of differentially regulated genes. These gene lists showed many similarities for different chicken breeds and tissues, and also for different Salmonella serovars measured at different times post infection. Functional biological analysis of these differentially expressed gene lists revealed several common mechanisms for the chicken host response to Salmonella infection. The meta-analysis-specific genes (i.e. genes found differentially expressed only in the meta-analysis) confirmed and expanded the biological functional mechanisms. CONCLUSIONS: The meta-analysis combination of heterogeneous expression profiling data provided useful insights into the common metabolic pathways and functions of different chicken lines infected with different Salmonella serovars. PMID- 22531010 TI - Microelectronic-sensing assay to detect presence of Verotoxins in human faecal samples. AB - AIMS: To develop a novel Vero cell assay that implements a real-time cell electronic sensing (RT-CES) system for the determination of the presence of verotoxin-producing Escherichia coli (VTEC). The assay overcomes the major drawbacks in conventional Vero cell assay, for example, labour-intensive and time consuming. METHODS AND RESULTS: Cells were grown onto the surfaces of microelectronic sensors that are integrated into the bottom surfaces of the microtiter plate. Cellular viability was monitored in real-time and quantified based on changes in the sensor's electrical impedance. For cell viability measurement, the data generated on the RT-CES system correlated well with those obtained by the Vero cell assay for Verotoxins. To assess cytotoxicity, test cells growing on microelectronic sensors were treated with either supernatant from pure cultures, or stool samples. The specific neutralizing antibodies of VT1 and VT2 were used to identify specific toxins in the samples. CONCLUSIONS: The RT-CES assay provides a sensitive measurement comparable to conventional crystal violet assay. The assay has been successfully and specifically used to identify VTEC in human faecal samples. SIGNIFICANCE AND IMPACT OF THE STUDY: The RT-CES assay significantly shortens the testing time from 48 to 72 h required by the crystal violet assay to only 15 h with automated operation. PMID- 22531011 TI - A portable ultrasound based screening study on the prevalence and risk factors of cystic echinococcosis in primary school children in East Turkey. AB - The tapeworm Echinococcus granulosus constitutes a major public health concern, since its larval stage causes cystic echinococcosis (CE) which is a life threatening zoonotic disease in many parts of the world. The purpose of the present study was to perform a screening study in order to investigate the prevalence and risk factors of CE using a portable ultrasound (US) in a representative sample of 2500 primary school children aged 7-14 in East Turkey, where CE is known to be endemic. The students were scanned by portable US while standing, with special attention to the liver, spleen, pancreas, and kidneys. The US scan was followed by a physical examination. In addition, a questionnaire was distributed to all students for completion with the assistance of their teachers regarding their demographic and social characteristics as well as their hygienic habits possibly related to CE. Students found positive were subjected to serologic examination. The US based prevalence was 0.2%. Organ involvement was 0.12% for liver and 0.08% for kidney. The response rate of the questionnaire survey was 93%. The risk factors found to be significant (P<0.05) for CE infection were hand washing and family relative with CE. The results of this study indicate that CE infection is an important public health problem in East Turkey requiring appropriate control measures. PMID- 22531012 TI - Low concentration detergent sclerosants induce platelet activation but inhibit aggregation due to suppression of GPIIb/IIIa activation in vitro. AB - INTRODUCTION: Sclerotherapy is associated with thromboembolic and ischemic neurological adverse events but the effects of sclerosants on platelet function are unknown. The aim of this study was to investigate the in vitro effects of detergent sclerosants Sodium Tetradecyl Sulphate (STS) and Polidocanol (POL) on platelet activation and aggregation. MATERIALS AND METHODS: Whole blood and platelet rich plasma samples were incubated with sclerosants. Platelet and platelet microparticle (PMP) counts were measured by flow cytometry. Platelet activation was examined by ELISA for soluble factors (sP-selectin, von Willebrand factor, sCD40L and serotonin) and by flow cytometry for membrane-bound markers (CD62p, CD63) and cytoplasmic calcium. Platelet aggregation was assessed by PFA 100(r), light transmission and impedance (Multiplate(r)) aggregometry, and by flow cytometry for glycoprotein (GP) Ib and GPIIb/IIIa subunits, heterodimer expression and activation (PAC-1 binding). RESULTS: Both agents lysed platelets at high concentrations (>= 0.1%) but induced platelet activation at lower concentrations as evident by a rise in membrane-bound and soluble markers, cytoplasmic calcium and release of phosphatidylserine+PMP. Agonist-stimulated platelet aggregation was inhibited by both sclerosants. Membrane expression of GPIb and GPIIb/IIIa individual subunits or heterodimer was not affected by sclerosants but the activation of GPIIb/IIIa was suppressed. CONCLUSION: Low concentration sclerosants activated platelets and released microparticles but inhibited platelet aggregation due to suppression of GPIIb/IIIa activation. PMID- 22531013 TI - Developing theory-informed behaviour change interventions to implement evidence into practice: a systematic approach using the Theoretical Domains Framework. AB - BACKGROUND: There is little systematic operational guidance about how best to develop complex interventions to reduce the gap between practice and evidence. This article is one in a Series of articles documenting the development and use of the Theoretical Domains Framework (TDF) to advance the science of implementation research. METHODS: The intervention was developed considering three main components: theory, evidence, and practical issues. We used a four step approach, consisting of guiding questions, to direct the choice of the most appropriate components of an implementation intervention: Who needs to do what, differently? Using a theoretical framework, which barriers and enablers need to be addressed? Which intervention components (behaviour change techniques and mode(s) of delivery) could overcome the modifiable barriers and enhance the enablers? And how can behaviour change be measured and understood? RESULTS: A complex implementation intervention was designed that aimed to improve acute low back pain management in primary care. We used the TDF to identify the barriers and enablers to the uptake of evidence into practice and to guide the choice of intervention components. These components were then combined into a cohesive intervention. The intervention was delivered via two facilitated interactive small group workshops. We also produced a DVD to distribute to all participants in the intervention group. We chose outcome measures in order to assess the mediating mechanisms of behaviour change. CONCLUSIONS: We have illustrated a four step systematic method for developing an intervention designed to change clinical practice based on a theoretical framework. The method of development provides a systematic framework that could be used by others developing complex implementation interventions. While this framework should be iteratively adjusted and refined to suit other contexts and settings, we believe that the four-step process should be maintained as the primary framework to guide researchers through a comprehensive intervention development process. PMID- 22531016 TI - An overused phrase: interpreted with caution. PMID- 22531015 TI - View-invariance learning in object recognition by pigeons depends on error-driven associative learning processes. AB - A model hypothesizing that basic mechanisms of associative learning and generalization underlie object categorization in vertebrates can account for a large body of animal and human data. Here, we report two experiments which implicate error-driven associative learning in pigeons' recognition of objects across changes in viewpoint. Experiment 1 found that object recognition across changes in viewpoint depends on how well each view predicts reward. Analyses of generalization performance, spatial position of pecks to images, and learning curves all showed behavioral patterns analogous to those found in prior studies of relative validity in associative learning. In Experiment 2, pigeons were trained to recognize objects from multiple viewpoints, which usually promotes robust performance at novel views of the trained objects. However, when the objects possessed a salient, informative metric property for solving the task, the pigeons did not show view-invariant recognition of the training objects, a result analogous to the overshadowing effect in associative learning. PMID- 22531017 TI - Single-port laparoscopic colectomy versus conventional laparoscopic colectomy for colon cancer: a comparison of surgical results. AB - BACKGROUND: Single-port laparoscopic surgery is a new technique that leaves no visible scar. This new technique has generated strong interest among surgeons worldwide. However, single-port laparoscopic colon surgery has not yet been standardized. Our aim in this study was to evaluate the feasibility of single port laparoscopic colectomy compared with conventional laparoscopic colectomy for colon cancer. METHODS: We conducted a case-matched, controlled study comparing single-port laparoscopic colectomy to conventional laparoscopic colectomy for right-sided colon cancer. RESULTS: A total of ten patients were included for the single-port laparoscopic colectomy (S-LAC) group and ten patients for the conventional laparoscopic colectomy (C-LAC) group. The length of the skin incision in the S-LAC group was significantly shorter than that of the C-LAC group. CONCLUSION: Our early experiences indicated that S-LAC for right-sided colon cancer is a feasible and safe procedure and that S-LAC results in a better cosmetic outcome. PMID- 22531018 TI - Impact of soil matric potential on the fine-scale spatial distribution and activity of specific microbial degrader communities. AB - The impact of the soil matric potential on the relationship between the relative abundance of degraders and their activity and on the spatial distribution of both at fine scales was determined to understand the role of environmental conditions in the degradation of organic substrates. The mineralization of (13) C-glucose and (13) C-2,4-dichlorophenoxyacetic acid (2,4-D) was measured at different matric potentials (-0.001, -0.01 and -0.316 MPa) in 6 * 6 * 6 mm(3) cubes excised from soil cores. At the end of the incubation, total bacterial and 2,4-D degrader abundances were determined by quantifying the 16S rRNA and the tfdA genes, respectively. The mineralization of 2,4-D was more sensitive to changes in matric potential than was that of glucose. The amount and spatial structure of 2,4-D mineralization decreased with matric potential, whilst the spatial variability increased. On the other hand, the spatial variation of glucose mineralization was less affected by changes in matric potential. The relationship between the relative abundance of 2,4-D degraders and 2,4-D mineralization was significantly affected by matric potential: the relative abundance of tfdA needed to be higher to reach a given level of 2,4-D mineralization in dryer than in moister conditions. The data show how microbial interactions with their microhabitat can have an impact on soil processes at larger scales. PMID- 22531019 TI - Early menopause and risk of osteoporosis, fracture and mortality: a 34-year prospective observational study in 390 women. AB - OBJECTIVE: A prospective evaluation of the long-term effects of early menopause on mortality, risk of fragility fracture and osteoporosis. DESIGN: Prospective population-based observational study. SETTING: Malmo, Sweden. POPULATION: A total of 390 white north European women aged 48 years at the start of the study. METHODS: At baseline, bone mineral density (BMD) was measured by single-photon absorptiometry (SPA) in the distal forearm and menopausal status was noted. Menopause was determined according to the World Health Organization criterion of a minimum of 12 months of continuous amenorrhoea. Women were divided into early menopause (occurring before age 47 years) and late menopause (occurring at age 47 years or later). At age 77, forearm BMD was re-measured by SPA and proximal femur and lumbar spine BMD were measured by dual-energy X-ray absorptiometry (DXA). The prevalence of osteoporosis was determined using the DXA data. Mortality rate and the incidence of fractures were registered up until age 82. Data are presented as means with 95% confidence intervals (95% CI). MAIN OUTCOME MEASURES: Incidence of fragility fractures, mortality, prevalence of osteoporosis at age 77. RESULTS: Women with early menopause had a risk ratio of 1.83 (95% CI 1.22-2.74) for osteoporosis at age 77, a risk ratio of 1.68 (95% CI 1.05-2.57) for fragility fracture and a mortality risk of 1.59 (95% CI 1.04-2.36). CONCLUSIONS: Menopause before age 47 is associated with increased mortality risk and increased risk of sustaining fragility fractures and of osteoporosis at age 77. PMID- 22531020 TI - Porcine factor VIII. PMID- 22531022 TI - The challenging management of a child with type 3 von Willebrand disease and antibodies to von Willebrand factor. PMID- 22531023 TI - Successful immune tolerance induction in two boys with haemophilia B and inhibitory antibodies. PMID- 22531024 TI - Re-emergence of a low-titre factor VIII inhibitor after liver transplant. PMID- 22531025 TI - A study of 46 patients with acquired haemophilia A in Taiwan finds elevated LDH level and mucosal bleedings associated with reduced response to immunosuppressive therapy. PMID- 22531026 TI - Acquired haemophilia A treated with Rituximab in a patient with prostatic melioidosis. PMID- 22531027 TI - Synthesis and biological evaluation of triazole derivatives as potential antifungal agent. AB - A series of triazole antifungal agents with piperidine side chains were designed and synthesized. Results of preliminary antifungal tests against eight human pathogenic fungi in vitro showed that all the title compounds exhibited excellent activities with broad spectrum. Moreover, a molecular model for the binding between compound 12 and the active site of CACYP51 was provided based on the computational docking results. The side chain of the compound 12 is oriented into substrate access channel 2 (FG loop) and forms hydrophobic and van der waals interactions with surrounding hydrophobic residues. The phenyl group of the side chain can interact with the phenyl group of Phe380 through the formation of pi-pi face-to-edge interaction. PMID- 22531030 TI - Mediation of Drosophila autosomal dosage effects and compensation by network interactions. AB - BACKGROUND: Gene dosage change is a mild perturbation that is a valuable tool for pathway reconstruction in Drosophila. While it is often assumed that reducing gene dose by half leads to two-fold less expression, there is partial autosomal dosage compensation in Drosophila, which may be mediated by feedback or buffering in expression networks. RESULTS: We profiled expression in engineered flies where gene dose was reduced from two to one. While expression of most one-dose genes was reduced, the gene-specific dose responses were heterogeneous. Expression of two-dose genes that are first-degree neighbors of one-dose genes in novel network models also changed, and the directionality of change depended on the response of one-dose genes. CONCLUSIONS: Our data indicate that expression perturbation propagates in network space. Autosomal compensation, or the lack thereof, is a gene-specific response, largely mediated by interactions with the rest of the transcriptome. PMID- 22531033 TI - Translating evidence into practice: the role of health research funders. AB - BACKGROUND: A growing body of work on knowledge translation (KT) reveals significant gaps between what is known to improve health, and what is done to improve health. The literature and practice also suggest that KT has the potential to narrow those gaps, leading to more evidence-informed healthcare. In response, Canadian health research funders and agencies have made KT a priority. This article describes how one funding agency determined its KT role and in the process developed a model that other agencies could use when considering KT programs. DISCUSSION: While 'excellence' is an important criterion by which to evaluate and fund health research, it alone does not ensure relevance to societal health priorities. There is increased demand for return on investments in health research in the form of societal and health system benefits. Canadian health research funding agencies are responding to these demands by emphasizing relevance as a funding criterion and supporting researchers and research users to use the evidence generated.Based on recommendations from the literature, an environmental scan, broad circulation of an iterative discussion paper, and an expert working group process, our agency developed a plan to maximize our role in KT. Key to the process was development of a model comprising five key functional areas that together create the conditions for effective KT: advancing KT science; building KT capacity; managing KT projects; funding KT activities; and advocating for KT. Observations made during the planning process of relevance to the KT enterprise are: the importance of delineating KT and communications, and information and knowledge; determining responsibility for KT; supporting implementation and evaluation; and promoting the message that both research and KT take time to realize results. SUMMARY: Challenges exist in fulfilling expectations that research evidence results in beneficial impacts for society. However, health agencies are well placed to help maximize the use of evidence in health practice and policy. We propose five key functional areas of KT for health agencies, and encourage partnerships and discussion to advance the field. PMID- 22531032 TI - Correction: BTI-Tnao38, a new cell line derived from Trichoplusia ni, is permissive for AcMNPV infection and produces high levels of recombinant proteins. AB - After publication we discovered an error in the identification of the origin of the cell line reported in our article in BMC Biotechnology (2010, 10:50), entitled "Ao38, a new cell line from eggs of the black witch moth, Ascalapha odorata (Lepidoptera: Noctuidae), is permissive for AcMNPV infection and produces high levels of recombinant proteins". Upon analysis of primary A. odorata cultures, we found that they were contaminated with cells of Trichoplusia ni origin. The origin of the Ao38 cell line was determined as T. ni using three marker genes and the Ao38 cell line was renamed BTI-Tnao38. References to the origin of the cell line as Ascalapha odorata should be replaced with "a cell line of Trichoplusia ni origin". The absence of TNCL virus detection in the BTI-Tnao38 (Ao38) cell line was confirmed using a highly sensitive RT-PCR protocol capable of detecting TNCL virus RNA at approximately 0.018 copies/cell. Because of these observations, we have revised the title of the original article to "Correction: BTI-Tnao38, a new cell line derived from Trichoplusia ni, is permissive for AcMNPV infection and produces high levels of recombinant proteins" and two additional authors were added to reflect their contributions to the analysis of this cell line. PMID- 22531034 TI - Regulated intramembrane cleavage of the EGF receptor. AB - Following the addition of EGF or ionomycin to A431 cells, protease activity mediates cleavage of the EGF receptor producing a 60 kDa fragment that includes the intracellular domain (ICD). This fragment is located in both membrane and nuclear fractions. On the basis of sensitivity to chemical inhibitors and overexpression of cDNAs, the rhomboid intramembrane proteases, not gamma secretase proteases, are identified as responsible for the cleavage event. Agonist-initiated cleavage occurs slowly over 3-24 h. Inhibition of calpain protease activity significantly increased the detectable level of ICD fragment. PMID- 22531031 TI - Genome-wide analysis of Pax8 binding provides new insights into thyroid functions. AB - BACKGROUND: The transcription factor Pax8 is essential for the differentiation of thyroid cells. However, there are few data on genes transcriptionally regulated by Pax8 other than thyroid-related genes. To better understand the role of Pax8 in the biology of thyroid cells, we obtained transcriptional profiles of Pax8 silenced PCCl3 thyroid cells using whole genome expression arrays and integrated these signals with global cis-regulatory sequencing studies performed by ChIP-Seq analysis RESULTS: Exhaustive analysis of Pax8 immunoprecipitated peaks demonstrated preferential binding to intragenic regions and CpG-enriched islands, which suggests a role of Pax8 in transcriptional regulation of orphan CpG regions. In addition, ChIP-Seq allowed us to identify Pax8 partners, including proteins involved in tertiary DNA structure (CTCF) and chromatin remodeling (Sp1), and these direct transcriptional interactions were confirmed in vivo. Moreover, both factors modulate Pax8-dependent transcriptional activation of the sodium iodide symporter (Nis) gene promoter. We ultimately combined putative and novel Pax8 binding sites with actual target gene expression regulation to define Pax8-dependent genes. Functional classification suggests that Pax8-regulated genes may be directly involved in important processes of thyroid cell function such as cell proliferation and differentiation, apoptosis, cell polarity, motion and adhesion, and a plethora of DNA/protein-related processes. CONCLUSION: Our study provides novel insights into the role of Pax8 in thyroid biology, exerted through transcriptional regulation of important genes involved in critical thyrocyte processes. In addition, we found new transcriptional partners of Pax8, which functionally cooperate with Pax8 in the regulation of thyroid gene transcription. Besides, our data demonstrate preferential location of Pax8 in non promoter CpG regions. These data point to an orphan CpG island-mediated mechanism that represents a novel role of Pax8 in the transcriptional output of the thyrocyte. PMID- 22531035 TI - Key cellular components and interactive histocompatibility molecules regulating tolerance to the fetal allograft. AB - Implantation is a major landmark in life. It involves the correct apposition of the embryo in the maternal endometrium. The cellular environment influences placenta development, and direct contact of the fetus with maternal tissues is achieved through decidual cells. At the decidua, and at systemic level, the correct balance of cells potentially acting as antigen-presenting cells and histocompatibility products play a pivotal role in achieving feto-maternal tolerance. Here, we review some of the current issues associated with the interplay between cells and molecules needed for pregnancy development. PMID- 22531036 TI - [A woman with periocular swelling]. AB - We present a 37-year-old woman with an 8-year history of rosacea, who developed persistent swelling of the right lower eyelid, diagnosed as Morbihan's disease. Morbihan's disease is considered a rare complication of rosacea. PMID- 22531037 TI - [Many adults with congenital heart disease are lost to follow up]. AB - OBJECTIVE: Identification of adults with congenital heart disease (CHD) who were lost to cardiological follow-up. DESIGN: Cross-sectional study. METHOD: Adults with CHD and not under cardiological follow-up were asked via a nationwide publicity campaign to contact the CONCOR (CONgenital CORvitia) project group. RESULTS: A total of 593 patients with mild (85%) to moderate-severe (15%) CHD were registered via the nationwide campaign. Of these patients, 66% were examined within 1 year by a cardiologist. Additional cardiac follow-up was necessary within 1 year in 22% of these patients. In 16% of the patients, new residual lesions were found; and in three of these patients the pulmonary valve required replacement. CONCLUSION: During this comprehensive nationwide campaign it became clear that a considerable number of adults with CDH fail to receive regular cardiac care. However, after surgical correction of CHD in childhood, residual lesions are common in this population. Threatening residual lesions can be present asymptomatically. Cardiological follow-up is therefore almost always necessary, also in patients without symptoms. Patients with CHD as well as their medical care personnel need to be well informed of this. PMID- 22531038 TI - [Alexia without agraphia; not being able to read what you have just written]. AB - BACKGROUND: Alexia without agraphia is a neurological syndrome that is caused by a specific lesion in the left (or the dominant) cerebral hemisphere. It is characterised by a severe reading disorder with writing ability intact. CASE DESCRIPTION: We describe a patient who, after a fall from a staircase, could no longer read, even that which he had written shortly before. Initially, he also had problems with orientation and facial recognition. Two months after the accident, alexia without agraphia was still manifest while the other symptoms had disappeared. His ability to read showed a slow improvement; complete recovery occurred after two years. The absence of concomitant disorders was exceptional. CONCLUSION: The disorder alexia without agraphia seems improbable, but deserves serious attention to prevent diagnostic delay. PMID- 22531039 TI - [A child with convulsions of unknown origin: posterior reversible encephalopathy syndrome]. AB - BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is a rare complication in children with post-streptococcal glomerulonephritis (PSGN). CASE DESCRIPTION: An 8-year-old boy was brought to the emergency department with seizures preceded by acute headache attacks and vomiting. On examination the boy was hypertensive with periorbital edema. Further investigation showed proteinuria, haematuria and intra-cerebral abnormalities. Recent history indicated streptococcal tonsillitis for which oral amoxicillin was prescribed in the preceding week. The diagnosis 'PRES consequent to PSGN' was made, following which the patient was treated successfully with anticonvulsants and antihypertensives and he recovered without remaining problems. CONCLUSION: PRES is a rare syndrome which can occur in children as a complication of PSGN. By early recognition and adequate treatment, permanent neurological damage and possible death can be prevented. PMID- 22531040 TI - [Using rare disease as a research model]. AB - In Europe, a disease is considered to be rare when its prevalence is less than 5:10,000. With approximately 6000-7000 known rare diseases, 1 out of 20 individuals have such a disease. There is little interest in studying rare diseases because results of such research are only applicable to small groups of people. In addition, research into new drug development is considered not as relevant or financially lucrative as studies into more common diseases. We plead for a different manner of approaching rare diseases; namely, as a research model for human physiology and pathophysiology. The insights into pathophysiologic processes in rare diseases gained by research can subsequently be applied to more common diseases in which these same processes play a role. In addition, better collaboration between those involved in the field of science, such as patients and their support groups, academic hospitals and the pharmaceutical industry, is needed to stimulate research into rare diseases. PMID- 22531041 TI - [Orphan drugs: availability, reliability and reimbursement]. AB - Orphan drugs are drugs used in the treatment of life-threatening or chronic diseases that affect fewer than 1 out of 2000 persons in the European Union. Since the implementation of the European Regulation on Orphan Medicinal Products in 2000, 61 orphan drugs have been brought to market. One-third of these were granted their marketing authorisations based on non-comparative clinical research. Certain orphan drugs for extramural use will be transferred to the performance-based hospital financing system within the next few years. Unapproved orphan drugs are generally not reimbursed. In so-called compassionate use programmes, unauthorised orphan drugs can still become available to patients who do not participate in clinical trials. Compassionate use drugs are made available by the manufacturer. PMID- 22531042 TI - [A rapidly growing lump in the neck: anaplastic thyroid carcinoma]. AB - Anaplastic thyroid carcinoma (ATC) is a rapidly lethal disease. We present 3 patients with ATC. Patient A was a 68-year-old man, who died before radiotherapy could be started, 4 months after presentation. Patient B was a 74-year-old man who was treated by surgery and radiotherapy. He developed cervical metastasis, which was treated with palliative radiotherapy after which he was lost from follow-up. Patient C was a 55-year-old woman, treated with radiotherapy. She died by euthenasia 7 months after presentation. In adults with a rapidly growing neck lump, malignancy is a frequent cause and should be separated from infectious or reactive causes. Fine needle aspiration with neck ultrasonography are indicated in suspected malignant lumps. ATC is a rare cause of a neck lump. Due to the very fulminant course it should also be considered in an old patient presenting with a rapidly growing lump in the neck. PMID- 22531028 TI - Contributions of human enzymes in carcinogen metabolism. AB - Considerable support exists for the roles of metabolism in modulating the carcinogenic properties of chemicals. In particular, many of these compounds are pro-carcinogens that require activation to electrophilic forms to exert genotoxic effects. We systematically analyzed the existing literature on the metabolism of carcinogens by human enzymes, which has been developed largely in the past 25 years. The metabolism and especially bioactivation of carcinogens are dominated by cytochrome P450 enzymes (66% of bioactivations). Within this group, six P450s- 1A1, 1A2, 1B1, 2A6, 2E1, and 3A4--accounted for 77% of the P450 activation reactions. The roles of these P450s can be compared with those estimated for drug metabolism and should be considered in issues involving enzyme induction, chemoprevention, molecular epidemiology, interindividual variations, and risk assessment. PMID- 22531043 TI - Longevity and lifetime reproductive success of barn swallow offspring are predicted by their hatching date and phenotypic quality. AB - 1. Longevity is a major determinant of individual differences in Darwinian fitness. Several studies have analyzed the stochastic, time-dependent causes of variation in longevity, but little information exists from free-ranging animal populations on the effects that environmental conditions and phenotype early in ontogeny have on duration of life. 2. In this long-term (1993-2011) study of a migratory, colonial, passerine bird, the barn swallow (Hirundo rustica), we analyzed longevity and, in a subsample of individuals, lifetime reproductive success (LRS) of the offspring that reached sexual maturity in relation to hatching date, which can affect the rearing environment through a seasonal deterioration in ecological conditions. Moreover, we analyzed the consequences of variation in body size and, for the first time in any species, of a major component of immunity on longevity, both by looking at absolute phenotypic values and at deviations from the brood mean. 3. Accelerated failure time models showed that individuals of both sexes that hatched early in any breeding season enjoyed larger longevity and larger LRS, indicating directional selection for early breeding. Both male and female offspring with large T cell-mediated immune response relative to their siblings and female nestlings that dominated the brood size/age hierarchy had larger longevity than their siblings of inferior phenotypic quality/age. Conversely, absolute phenotypic values did not predict longevity. 4. Frailty modelling disclosed marked spatial heterogeneity in longevity among colonies of origin, again stressing the impact of rearing conditions on longevity. 5. This study therefore reinforces the notion that perinatal environment and maternal decisions over timing and site of breeding, and position in the brood hierarchy can have marked effects on progeny life history that extend well into adulthood. In addition, it provides the first evidence from any bird population in the wild that immune response when nestlings predicts individuals' longevity after sexual maturation. PMID- 22531045 TI - In vitro hepatotoxicity and cytochrome P450 induction and inhibition characteristics of carnosic acid, a dietary supplement with antiadipogenic properties. AB - Carnosic acid is a phenolic diterpene isolated from rosemary (Rosmarinus officinalis), which may have anticancer, antiadipogenic, and anti-inflammatory properties. Recently, carnosic acid was shown to prevent weight gain and hepatic steatosis in a mouse model of obesity and type II diabetes. Based on these results, carnosic acid has been suggested as a potential treatment for obesity and nonalcoholic fatty liver disease; however, little is known about the safety of carnosic acid at doses needed to elicit a pharmacological effect. For this reason, hepatotoxicity and cytochrome P450 inhibition and induction studies were performed in primary human hepatocytes and microsomes. Measuring cellular ATP, carnosic acid showed a dose-dependent increase in hepatotoxicity with an EC(50) value of 94.8 +/- 36.7 MUM in three human hepatocyte donors without a concurrent increase in the apoptosis markers caspase-3/7. In human liver microsomes, carnosic acid did not exhibit significant time-dependent inhibition for any of the cytochrome P450 enzymes investigated, although it did inhibit CYP2C9- and CYP3A4-catalyzed reactions with K(i) values of 9.2 and 4.3 MUM, respectively. Carnosic acid also induced CYP2B6 and CYP3A4 mRNA and enzyme activity in a dose dependent manner. At 10 MUM, carnosic acid increased CYP2B6 enzyme activity 61.6 and 49.3% in two donors compared with phenobarbital, and it increased CYP3A enzyme activity 82.6 and 142% compared with rifampicin. These results indicate the potential for drug interactions with carnosic acid and illustrate the need for an appropriate safety assessment before being used as a weight loss supplement. PMID- 22531044 TI - Atomic-resolution structures of horse liver alcohol dehydrogenase with NAD(+) and fluoroalcohols define strained Michaelis complexes. AB - Structures of horse liver alcohol dehydrogenase complexed with NAD(+) and unreactive substrate analogues, 2,2,2-trifluoroethanol or 2,3,4,5,6 pentafluorobenzyl alcohol, were determined at 100 K at 1.12 or 1.14 A resolution, providing estimates of atomic positions with overall errors of ~0.02 A, the geometry of ligand binding, descriptions of alternative conformations of amino acid residues and waters, and evidence of a strained nicotinamide ring. The four independent subunits from the two homodimeric structures differ only slightly in the peptide backbone conformation. Alternative conformations for amino acid side chains were identified for 50 of the 748 residues in each complex, and Leu-57 and Leu-116 adopt different conformations to accommodate the different alcohols at the active site. Each fluoroalcohol occupies one position, and the fluorines of the alcohols are well-resolved. These structures closely resemble the expected Michaelis complexes with the pro-R hydrogens of the methylene carbons of the alcohols directed toward the re face of C4N of the nicotinamide rings with a C-C distance of 3.40 A. The oxygens of the alcohols are ligated to the catalytic zinc at a distance expected for a zinc alkoxide (1.96 A) and participate in a low barrier hydrogen bond (2.52 A) with the hydroxyl group of Ser-48 in a proton relay system. As determined by X-ray refinement with no restraints on bond distances and planarity, the nicotinamide rings in the two complexes are slightly puckered (quasi-boat conformation, with torsion angles of 5.9 degrees for C4N and 4.8 degrees for N1N relative to the plane of the other atoms) and have bond distances that are somewhat different compared to those found for NAD(P)(+). It appears that the nicotinamide ring is strained toward the transition state on the path to alcohol oxidation. PMID- 22531047 TI - Editorial: Meeting the acute care needs of older people: the future is in our hands. PMID- 22531046 TI - Association of interleukin-18 gene polymorphism with body mass index in women. AB - BACKGROUND: Interleukin (IL)-18 is an important regulator of innate and acquired immune responses and has multiple roles in chronic inflammation and autoimmune disorders. Obesity is characterized by low- grade chronic inflammation. IL-18 has been suggested as an adipogenic cytokine that is associated with excess adiposity. The purpose of this study is to evaluate the relationship between IL 18 gene polymorphisms (-137 G/C and -607 C/A) and obesity. METHODS: All 680 subjects were genotyped for the polymorphisms of IL-18 gene promoters (at positions -137 G/C and -607 C/A) using a polymerase chain reaction (271 cases with BMI >=25 kg/m2 and 409 controls with BMI <25 kg/m2). A chi-square test was used to compare the genotype and allele frequencies between the cases and control populations. RESULTS: Analyses of the genotype distributions revealed that IL-18 607 C/A polymorphism was associated with an increase in body mass index in obese women in the Korean population (chi(2) = 12.301, df = 2, p = 0.015). CONCLUSION: Carriage of the A allele at position -607 in the promoter of the IL-18 gene may have a role in the development of obesity. PMID- 22531048 TI - 'Poppets and parcels': the links between staff experience of work and acutely ill older peoples' experience of hospital care. AB - BACKGROUND: Few empirical studies have directly examined the relationship between staff experiences of providing healthcare and patient experience. Present concerns over the care of older people in UK acute hospitals - and the reported attitudes of staff in such settings - highlight an important area of study. AIMS AND OBJECTIVES. To examine the links between staff experience of work and patient experience of care in a 'Medicine for Older People' (MfOP) service in England. METHODS: A mixed methods case study undertaken over 8 months incorporating a 149 item staff survey (66/192 - 34% response rate), a 48-item patient survey (26/111 23%), 18 staff interviews, 18 patient and carer interviews and 41 hours of non participant observation. RESULTS: Variation in patient experience is significantly influenced by staff work experiences. A high-demand/low-control work environment, poor staffing, ward leadership and co-worker relationships can each add to the inherent difficulties staff face when caring for acutely ill older people. Staff seek to alleviate the impact of such difficulties by finding personal satisfaction from caring for 'the poppets'; those patients they enjoy caring for and for whom they feel able to 'make a difference'. Other patients - noting dehumanising aspects of their care - felt like 'parcels'. Patients are aware of being seen by staff as 'difficult' or 'demanding' and seek to manage their relationships with nursing staff accordingly. CONCLUSIONS: The work experiences of staff in a MfOP service impacted directly on patient care experience. Poor ward and patient care climates often lead staff to seek job satisfaction through caring for 'poppets', leaving less favoured - and often more complex patients - to receive less personalised care. Implications for practice. Investment in staff well-being and ward climate is essential for the consistent delivery of high-quality care for older people in acute settings. PMID- 22531049 TI - RedeR: R/Bioconductor package for representing modular structures, nested networks and multiple levels of hierarchical associations. AB - Visualization and analysis of molecular networks are both central to systems biology. However, there still exists a large technological gap between them, especially when assessing multiple network levels or hierarchies. Here we present RedeR, an R/Bioconductor package combined with a Java core engine for representing modular networks. The functionality of RedeR is demonstrated in two different scenarios: hierarchical and modular organization in gene co-expression networks and nested structures in time-course gene expression subnetworks. Our results demonstrate RedeR as a new framework to deal with the multiple network levels that are inherent to complex biological systems. RedeR is available from http://bioconductor.org/packages/release/bioc/html/RedeR.html. PMID- 22531050 TI - Hypovitaminosis D and prevalent asymptomatic vertebral fractures in Moroccan postmenopausal women. AB - BACKGROUND: Hypovitaminosis D is associated to accentuated bone loss. However, association between osteoporotic vertebral fractures (VFs) and vitamin D status has not been clearly established. OBJECTIVE: To determine serum vitamin D status and to assess the association of vitamin D status with bone mineral density (BMD) and asymptomatic VFs prevalence using vertebral fracture assessment (VFA) in a cohort of Moroccan menopausal women. METHODS: from June to September 2010, 178 menopausal women 50 years old and over were enrolled in this cross-sectional study. The mean +/- SD (range) age, weight, height and BMI were 58.8 +/- 8.2 (50 to 79) years, 73.2 +/- 13.8 (35 to 119) Kgs, 1.56 +/- 0.06 (1.43 - 1.79) m and 29.8 +/- 5.9 (17.5 - 49.8) kg/m2, respectively. VFA images and scans of the lumbar spine and proximal femur were obtained using a GE Healthcare Lunar Prodigy densitometer. VFs were defined using a combination of Genant semiquantitative approach and morphometry. Serum levels of 25-hydroxyvitamin D (25(OH)D) were measured. RESULTS: Among the 178 women, 45 (25.2%) had densitometric osteoporosis, and on VFA, VFs (grade 2 or 3) were detected in 20.2% while grade 1 were identified in 33.1%. The mean values of serum levels of 25(OH)D were 15.8 +/ 11.6 ng/ml (range: 3.0 - 49.1) with 152 patients (85.3%) having levels <30 ng/ml (insufficiency) and 92 (51.6%) <10 ng/ml (deficiency). Stepwise regression analysis showed that presence of VFs was independently related to age, 25(OH)D and densitometric osteoporosis. CONCLUSION: our study shows that advanced age, hypovitaminosis D and osteoporosis are independent risk factors for asymptomatic VFs in Moroccan postmenopausal women. PMID- 22531051 TI - Effect of saponification on composition of unsaponifiable matter in rice bran oil. AB - Rice Bran Oil contains a variety of Unsaponifiable Constituents (USC) that are presumed to contribute to the high value of Unsaponifable Matter (USM). The objectives of the present study were to identify and quantify the constituents in USM. The changes that the unsaponifiables undergo during saponification were also quantitatively investigated. While analyzing the percentage of all constituents, the percentage of sterol get increased from 22.46 to 23.77 in USM of crude rice bran oil (CRBO) and 33.42 to 36.79 in USM of refined rice bran oil (RRBO). Oryzanol that comprised 34% of the unsaponifiable in the crude oil by direct estimation was almost eliminated in USM and same in refined oil. The results also revealed the presence of four additional classes of compounds that were quantified in USM (policosanol, fatty aldehydes, triterpene alcohols and potassium salt of oryzanols). Among the four classes of compounds, policosanol contributed high percentage in USM, (43.39% in CRBO and 28.46% in RRBO). Fatty aldehydes, triterpene alcohols and potassium salt of oryzanols together contributed 27.68% and 25.13% of USM from CRBO and RRBO respectively. The HPTLC method employed here thus, accounted for 96.75% by wt of the USM of CRBO and 92.00% by wt of the USM of RRBO. PMID- 22531052 TI - Soil removal from polyester fabric by laundering with frequency-modulated ultrasound. AB - The effectiveness of ultrasound in washing textiles was investigated using polyester woven fabrics soiled with model contaminants such as oleic acid/Sudan III mixture and carbon black. The soiled and original fabrics were washed together in aqueous solutions with shaking or frequency-modulated ultrasound. The detergency and the soil redeposition were evaluated from the change in the surface reflectance of the soiled and the original fabrics due to the washing. The results were strongly dependent on the type of mechanical action. Ultrasound removed the contaminants in a short time and at low bath ratios as compared with shaking. In addition, the ultrasound caused little damage to the fabric during washing. The detergency was much larger for the ultrasonic washing than for shake washing in aqueous solutions containing alkali, surfactants, and commercial detergent. However, uneven cleaning and soil redeposition were frequently observed during ultrasonic washing. This was the only observed limitation to this approach of textile washing. PMID- 22531053 TI - Production of ethoxylated fatty acids derived from Jatropha non-edible oil as a nonionic fat-liquoring agent. AB - Natural fatty derivatives (oleochemicals) have been used as intermediate materials in several industries replacing the harmful and expensive petrochemicals. Fatty ethoxylates are one of these natural fatty derivatives. In the present work Jatropha fatty acids were derived from the non edible Jatropha oil and used as the fat source precursor. The ethoxylation process was carried out on the derived fatty acids using a conventional cheap catalyst (K2CO3) in order to obtain economically and naturally valuable non-ionic surfactants. Ethoxylation reaction was proceeded using ethylene oxide gas in the presence of 1 or 2% K2CO3 catalyst at 120 and 145 degrees C for 5, 8 and 12 hours. The prepared products were evaluated for their chemical and physical properties as well as its application as non- ionic fat-liquoring agents in leather industry. The obtained results showed that the number of ethylene oxide groups introduced in the fatty acids as well as their EO% increased as the temperature and time of the reaction increased. The highest ethoxylation number was obtained at 145 degrees C for 8 hr. Also, the prepared ethoxylated products were found to be effective fat liquors with high HLB values giving stable oil in water emulsions. The fat liquored leather led to an improvement in its mechanical properties such as tensile strength and elongation at break. In addition, a significant enhancement in the texture of the treated leather by the prepared fat-liquors as indicated from the scanning electron microscope (SEM) images was observed. PMID- 22531054 TI - New lecithin organogels from lecithin/polyglycerol/oil systems. AB - New liquid substances that induce the formation of lecithin organogels composed of reverse worm-like micelles were studied. The phase behavior and rheological properties of lecithin/polyglycerol (PGL)/oil systems were investigated in detail; the polymerization degrees of the glycerol residues were 3, 4, 6, 10, 20, and 40. From the partial phase diagrams of the lecithin/PGL/n-decane systems, it was apparent that highly viscoelastic reverse worm-like micelles formed upon the addition of small amounts of the PGL, except in the case of the PGL with a polymerization degree of 40. Steady-flow viscosity measurements showed that the zero-shear viscosity (eta0) of the reverse worm-like micelles rapidly increased with the concentration and polymerization degree of the PGLs, reaching a maximum value that was 750,000 times the viscosity of n-decane and thus resulting in the growth of these micelles. It is noteworthy that the eta0 values of lecithin organogels formed using PGLs were higher than the eta0 value of the lecithin organogel formed using glycerol (GL). From dynamic viscoelasticity measurements, it was shown that the viscoelastic behavior of the reverse worm-like micelles was consistent with the single Maxwell model, which is the basic model of a viscoelastic body. It follows from this study that PGLs are useful liquids because they can induce the formation of lecithin organogels with high viscoelasticity, as do other liquids such as water, glycerol, ethylene glycol, and formamide. PMID- 22531055 TI - Lithography of self-assembled semiconductor quantum dots on templates fabricated from mixed Langmuir-Blodgett films. AB - In this paper, we discuss a useful technique to fabricate patterned single layers consisting of quantum dots on two-dimensional templates fabricated from phase separated mixed Langmuir-Blodgett (LB) films. The phase-separated structures are governed by two competing interactions-line tension and dipole-dipole interaction and are tunable by adjusting the intermolecular interactions between the film forming molecules and the fabrication conditions. The templates can be fabricated from mixed LB films containing silane-coupling agents, which form covalent bonds with Si wafers. The CdS- or CdSe/ZnS-nanoparticles were immobilized on the templates using a chemisorption technique. The samples were analyzed using ultraviolet-visible absorption spectroscopy, emission spectroscopy, atomic force microscopy, scanning electron microscopy, and fluorescence microscopy. The diameters of the CdS-NPs and CdSe/ZnS were estimated to be about 2.6 and 4.5 nm, respectively, using the Brus equation. We successfully obtained a patterned single layer consisting of quantum dots on the templates. The density of the immobilized-CdSe/ZnS-NPs on these templates can be controlled through variations in the concentration of the aqueous dispersion of CdSe/ZnS-NPs. Fluorescence observations indicate that the immobilized-CdSe/ZnS-NPs on the templates serve as light-emitting devices. These results indicate that patterned quantum dots can be formed only through self-assembly processes. PMID- 22531056 TI - Reverse vesicle formation from the yeast glycolipid biosurfactant mannosylerythritol lipid-D. AB - Mannosylerythritol lipids (MELs) are secreted by yeasts and are promising glycolipid biosurfactants. In our study on the non-aqueous phase behaviors of MEL homologues, we found that MEL-D (4-O-[2',3'-di-O-alka(e)noyl-beta-D mannopyranosyl]-(2R,3S)-erythritol) forms aggregates in decane. The microscopic observation and the X-ray scattering measurement of these aggregates revealed that they are reverse vesicles that consist of bilayers whose hydrophilic domains are located in the interior of the bilayers. In addition, MEL-D formed reverse vesicles without co-surfactants and co-solvents in various oily solutions, such as n-alkanes, cyclohexane, squalane, squalene, and silicone oils at a concentration below 10 mM. This is the first report on the reverse vesicle formation from biosurfactants. PMID- 22531057 TI - Antioxidant activities and essential oil composition of Herba Artemisiae Scopariae from China. AB - The essential oil in traditional Chinese medicine (TCM) Herba Artemisiae Scopariae (HAC) grown in China was obtained by hydrodistillation and studied by GC and GC-MS. Twenty compounds were identified representing 96.6% of the essential oil, of which the most prominent were n-hexadecanoic acid (33.1%), caryophyllene oxide (19.1%) and spathulenol (9.9%). The antioxidant activity of the essential oil (25-400 ug/ml) of HAC was evaluated by 1,1-diphenyl-2 picrylhydrazyl (DPPH) radical scavenging activity and ferric reducing/antioxidant power (FRAP) assay. The essential oil of HAC exhibited a strong antioxidant activity, which possess a good potential for use in the food and pharmaceutical industry. PMID- 22531058 TI - Optimization of reaction conditions for enzymatic synthesis of palm fatty hydrazides using response surface methodology. AB - Optimization of the enzymatic synthesis of palm fatty hydrazide by the response surface methodology (RSM) was conducted using the Design-Expert 6 software. The palm fatty hydrazide was synthesized from refined, bleached and deodorized palm olein (RBDPOo) and neutralized hydrazine monohydrate in the presence of Rhizomucor miehei lipase, Lipozyme RMIM, an immobilized lipase in n-hexane. The reaction conditions such as the percentage of enzyme, reaction temperature, stirring speed and reaction time were selected as independent variables or studied factors, while the amount of crude palm fatty hydrazide obtained was selected as a dependent variable or response. The study was conducted using a central composite design (CCD) at five coded levels and the experimental data were analyzed using a quadratic model. The analysis of variance (ANOVA) indicates that the model was significant at 95% confidence level with Prob>F of 0.0033, where the regression coefficient value, R2 was 0.8415 and lack-of-fit of 0.0984. A percentage of enzyme of 6%, a reaction temperature of 40 degrees C, a stirring speed of 350 rpm and a reaction time of 18 h were found to be the optimum conditions for the conversion of RBDPOo into palm fatty hydrazide. PMID- 22531059 TI - Comparison of frequency difference reconstruction algorithms for the detection of acute stroke using EIT in a realistic head-shaped tank. AB - Imaging of acute stroke might be possible using multi-frequency electrical impedance tomography (MFEIT) but requires absolute or frequency difference imaging. Simple linear frequency difference reconstruction has been shown to be ineffective in imaging with a frequency-dependant background conductivity; this has been overcome with a weighted frequency difference approach with correction for the background but this has only been validated for a cylindrical and hemispherical tank. The feasibility of MFEIT for imaging of acute stroke in a realistic head geometry was examined by imaging a potato perturbation against a saline background and a carrot-saline frequency-dependant background conductivity, in a head-shaped tank with the UCLH Mk2.5 MFEIT system. Reconstruction was performed with time difference (TD), frequency difference (FD), FD adjacent (FDA), weighted FD (WFD) and weighted FDA (WFDA) linear algorithms. The perturbation in reconstructed images corresponded to the true position to <9.5% of image diameter with an image SNR of >5.4 for all algorithms in saline but only for TD, WFDA and WFD in the carrot-saline background. No reliable imaging was possible with FD and FDA. This indicates that the WFD approach is also effective for a realistic head geometry and supports its use for human imaging in the future. PMID- 22531061 TI - Clinical efficacy and safety of focused-image ultrasonography: a 2-year experience. AB - BACKGROUND: Focused-image ultrasonography produces controlled waves that image dermal and subdermal structures in real time, with precise thermal coagulation points in a linear pattern, for eventual nonsurgical lifting. OBJECTIVES: The authors evaluate the effectiveness of single and dual planes of ultrasound treatment by varying the directions of treatment lines, depths, and cumulative joule energies and compare the safety and efficacy of treatment with these variations. METHODS: In this prospective, 2-part study, patients were treated by single- or dual-treatment depth with differing directions of treatment lines while the number of treatment lines and amount of energy delivered to brows or marionette lines remained constant (Study 1) or with lower or higher joule energy to opposing areas while the dual depths and number of vectored lines remained constant (Study 2). Lifting was measured using the matched-orientation function of specific mirroring software. Clinical outcomes were assessed with global aesthetic improvement scales. RESULTS: Vertical vectoring of 15 treatment lines in both tissue depths produced significant lifting over the 15 horizontally placed treatment lines in the opposing brows and marionette lines. Sites with more treatment lines and higher joule energy at dual depths resulted in significantly greater lifting (Study 2). Side effects were minimal. CONCLUSIONS: Focused-imaged ultrasound therapy to facial tissues is safe and effective when performed as described. PMID- 22531060 TI - Dosimetric consequences of translational and rotational errors in frame-less image-guided radiosurgery. AB - BACKGROUND: To investigate geometric and dosimetric accuracy of frame-less image guided radiosurgery (IG-RS) for brain metastases. METHODS AND MATERIALS: Single fraction IG-RS was practiced in 72 patients with 98 brain metastases. Patient positioning and immobilization used either double- (n = 71) or single-layer (n = 27) thermoplastic masks. Pre-treatment set-up errors (n = 98) were evaluated with cone-beam CT (CBCT) based image-guidance (IG) and were corrected in six degrees of freedom without an action level. CBCT imaging after treatment measured intra fractional errors (n = 64). Pre- and post-treatment errors were simulated in the treatment planning system and target coverage and dose conformity were evaluated. Three scenarios of 0 mm, 1 mm and 2 mm GTV-to-PTV (gross tumor volume, planning target volume) safety margins (SM) were simulated. RESULTS: Errors prior to IG were 3.9 mm +/- 1.7 mm (3D vector) and the maximum rotational error was 1.7 degrees +/- 0.8 degrees on average. The post-treatment 3D error was 0.9 mm +/- 0.6 mm. No differences between double- and single-layer masks were observed. Intra-fractional errors were significantly correlated with the total treatment time with 0.7 mm +/- 0.5 mm and 1.2 mm +/- 0.7 mm for treatment times <=23 minutes and >23 minutes (p<0.01), respectively. Simulation of RS without image guidance reduced target coverage and conformity to 75% +/- 19% and 60% +/- 25% of planned values. Each 3D set-up error of 1 mm decreased target coverage and dose conformity by 6% and 10% on average, respectively, with a large inter-patient variability. Pre-treatment correction of translations only but not rotations did not affect target coverage and conformity. Post-treatment errors reduced target coverage by >5% in 14% of the patients. A 1 mm safety margin fully compensated intra-fractional patient motion. CONCLUSIONS: IG-RS with online correction of translational errors achieves high geometric and dosimetric accuracy. Intra fractional errors decrease target coverage and conformity unless compensated with appropriate safety margins. PMID- 22531062 TI - IL-17 contributes to cardiac fibrosis following experimental autoimmune myocarditis by a PKCbeta/Erk1/2/NF-kappaB-dependent signaling pathway. AB - Myocarditis is a common clinical cardiovascular disease, and some patients progress to dilated cardiomyopathy (DCM) with chronic heart failure. Common viral infections are the most frequent cause of myocarditis, but other pathogens and autoimmune diseases have also been implicated. T(h)17 cells are novel IL-17 producing effector T helper cells that play an important role in the development of autoimmune myocarditis. Furthermore, IL-17 is also important in post myocarditis cardiac remodeling and progression to DCM. However, the mechanisms whereby IL-17 and IL-17-producing cells promote the progression of cardiac fibrosis remain unclear. We therefore investigated whether IL-17 directly induced cardiac fibrosis in experimental autoimmune myocarditis (EAM) and explored the possible molecular mechanisms. The EAM model was induced and serum IL-17 level was detected by ELISA; western blot, immunofluorescence and sirius red staining were used to analyze the collagen expression. PCR was used to assay the IL-17RA and IL-17RC. The results indicated that IL-17 induced cardiac fibrosis both in vitro and in vivo. The protein kinase C (PKC)beta/Erk1/2/NF-kappaB (Nuclear Factor kappaappa B) pathway was involved in the development of myocardial fibrosis and IL-17 contributed to cardiac fibrosis following EAM via this pathway. These results provide the first direct evidence for the involvement of the PKCbeta/Erk1/2/NF-kappaB signaling pathway in IL-17-induced myocardial fibrosis. PMID- 22531063 TI - Anti-CD3epsilon induces splenic B220lo B-cell expansion following anti-CD20 treatment in a mouse model of allosensitization. AB - Antibodies targeting T cells and B cells are increasingly used for immunosuppression in clinical transplantation. However, the impact of T-cell depletion by antibodies on B-cell homeostasis is poorly understood. Using a mouse model of allosensitization with skin allograft, we investigated whether targeting T cells by anti-CD3epsilon alters peripheral B-cell homeostasis and alloantibody responses following B-cell depletion by anti-CD20. We found that anti-CD3epsilon induced a discrete B220(lo), but not a conventional B220(hi) subset, in the spleens of the allosensitized mice 14 days after anti-CD20 treatment. The splenic B220(lo) cells were refractory to anti-CD20 depletion. Flow cytometry revealed that the splenic B220(lo) cells were phenotypically similar to the B220(lo) AA4.1(+) CD23(-) sIgM(lo) sIgD(-) developing B cells (pre-B to immature B) normally presented in the bone marrow. Despite the presence of the splenic B220(lo) cells, mice treated with combined anti-CD3epsilon/CD20 produced limited alloantibodies in response to the primary skin allografts. Alloantibody production increased significantly in the mice following re-immunization by donor specific splenocytes. We conclude that anti-CD3epsilon can induce an expansion of B220(lo) B cells in the spleens after B-cell depletion by anti-CD20. These B cells are not producing alloantibodies, but re-immunization of the mice with alloantigen leads to risk of alloantibody response. PMID- 22531065 TI - Playing it SAFE to improve diabetes care. PMID- 22531064 TI - Structure of Salmonella typhimurium OMP synthase in a complete substrate complex. AB - Dimeric Salmonella typhimurium orotate phosphoribosyltransferase (OMP synthase, EC 2.4.2.10), a key enzyme in de novo pyrimidine nucleotide synthesis, has been cocrystallized in a complete substrate E.MgPRPP.orotate complex and the structure determined to 2.2 A resolution. This structure resembles that of Saccharomyces cerevisiae OMP synthase in showing a dramatic and asymmetric reorganization around the active site-bound ligands but shares the same basic topology previously observed in complexes of OMP synthase from S. typhimurium and Escherichia coli. The catalytic loop (residues 99-109) contributed by subunit A is reorganized to close the active site situated in subunit B and to sequester it from solvent. Furthermore, the overall structure of subunit B is more compact, because of movements of the amino-terminal hood and elements of the core domain. The catalytic loop of subunit B remains open and disordered, and subunit A retains the more relaxed conformation observed in loop-open S. typhimurium OMP synthase structures. A non-proline cis-peptide formed between Ala71 and Tyr72 is seen in both subunits. The loop-closed catalytic site of subunit B reveals that both the loop and the hood interact directly with the bound pyrophosphate group of PRPP. In contrast to dimagnesium hypoxanthine-guanine phosphoribosyltransferases, OMP synthase contains a single catalytic Mg(2+) in the closed active site. The remaining pyrophosphate charges of PRPP are neutralized by interactions with Arg99A, Lys100B, Lys103A, and His105A. The new structure confirms the importance of loop movement in catalysis by OMP synthase and identifies several additional movements that must be accomplished in each catalytic cycle. A catalytic mechanism based on enzymic and substrate-assisted stabilization of the previously documented oxocarbenium transition state structure is proposed. PMID- 22531068 TI - CPR in older adults: what's the evidence? PMID- 22531072 TI - To a new generation of nurses. PMID- 22531070 TI - Newly licensed nurses: a look at their first 18 months. PMID- 22531074 TI - Benign prostatic hyperplasia. PMID- 22531076 TI - What's a peer-reviewed journal? PMID- 22531077 TI - Consider the accuracy of height and weight measurements. PMID- 22531078 TI - Cosmetic safety: is there any? PMID- 22531079 TI - Saving the brain with therapeutic hypothermia. PMID- 22531080 TI - Using genetic testing to guide warfarin therapy. PMID- 22531081 TI - Cauda equina syndrome. PMID- 22531082 TI - To whom do college women confide following sexual assault? A prospective study of predictors of sexual assault disclosure and social reactions. AB - A prospective methodology was used to explore predictors of sexual assault disclosure among college women, identify who women tell about sexual victimization, and examine the responses of informal support providers (N = 374). Women most often confided in a female peer. Increased coping via seeking emotional support, strong attachments, and high tendency to disclose stressful information predicted adolescent sexual assault disclosure and disclosure over the 7-month interim. Less acquaintance with the perpetrator predicted disclosure over the follow-up, including experiences of revictimization. Victim and perpetrator alcohol use at the time of the assault also predicted disclosure over the follow-up. Implications are presented. PMID- 22531083 TI - An intergenerational women's empowerment intervention to mitigate domestic violence: results of a pilot study in Bengaluru, India. AB - A growing body of literature has documented the global prevalence of domestic violence against women of reproductive age as well as the association between violence and an array of adverse reproductive, psychosocial, and child health outcomes. However, there is a dearth of research on domestic violence prevention interventions in the peer-reviewed literature to guide program planning and policy-making efforts. In this article, the authors describe the development and assessment of the feasibility, acceptability, and potential effectiveness of an intergenerational women's empowerment-based intervention to mitigate domestic violence and related adverse health outcomes in low-income urban communities in Southern India. PMID- 22531084 TI - Huangqi decoction inhibits apoptosis and fibrosis, but promotes Kupffer cell activation in dimethylnitrosamine-induced rat liver fibrosis. AB - BACKGROUND: Previously, Huangqi decoction (HQD) has been found to have a potential therapeutic effect on DMN-induced liver cirrhosis. Here, the mechanisms of HQD action against liver fibrosis were investigated in relation to hepatocyte apoptosis and hepatic inflammation regulation. METHODS: Liver fibrosis was induced by DMN administration for 2 or 4 weeks. Hepatocyte apoptosis and of Kupffer cells (KC) and hepatic stellate cells (HSC) interaction were investigated using confocal microscopy. The principle cytokines, fibrogenic proteins and apoptotic factors were investigated using western blot analysis. RESULTS: Compared with the DMN-water group, HQD showed decreased hepatocyte apoptosis and reduced expression of apoptotic effectors, cleaved-caspase-3, and fibrotic factors, such as smooth muscle alpha-actin (alpha-SMA), transforming growth factor beta-1 (TGF-beta1). However, the KC marker CD68 increased significantly in DMN-HQD liver. Confocal microscopy demonstrated widespread adhesion of KCs to HSCs in DMN-water and DMN-HQD rats liver. CONCLUSIONS: HQD exhibited positive protective effects against liver fibrosis; its mechanism of action was associated with protection from hepatocyte apoptosis and the promotion of CD68 expression in the devolopment of liver fibrosis to cirrhosis development. PMID- 22531085 TI - Obesity discrimination: the role of physical appearance, personal ideology, and anti-fat prejudice. AB - OBJECTIVE: Self-report measures of anti-fat prejudice are regularly used by the field, however, there is no research showing a relationship between explicit measures of anti-fat prejudice and the behavioral manifestation of them; obesity discrimination. The present study examined whether a recently developed measure of anti-fat prejudice, the universal measure of bias (UMB), along with other correlates of prejudicial attitudes and beliefs (that is, authoritarianism, social dominance orientation; SDO, physical appearance investment) predict obesity discrimination. METHOD: Under the guise of a personnel selection task, participants (n=102) gave assessments of obese and non-obese females applying for a managerial position across a number of selection criteria (for example, starting salary, likelihood of selecting). Participants viewed resumes that had attached either a photo of a pre-bariatric surgery obese female (body mass index (BMI)=38-41) or a photo of the same female post-bariatric surgery (BMI=22-24). Participants also completed measures of anti-fat prejudice (UMB) authoritarianism, SDO, physical appearance evaluation and orientation. RESULTS: Obesity discrimination was displayed across all selection criteria. Higher UMB subscale scores (distance and negative judgement), authoritarianism, physical appearance evaluation and orientation were associated with greater obesity discrimination. In regression models, UMB 'distance' was a predictor of obesity discrimination for perceived leadership potential, starting salary, and overall employability. UMB 'negative judgement' predicted discrimination for starting salary; and authoritarianism predicted likelihood of selecting an obese applicant and candidate ranking. Finally, physical appearance evaluation and appearance orientation predicted obesity discrimination for predicted career success and leadership potential, respectively. CONCLUSION: Self-report measures of prejudice act as surrogates for discrimination, but there has been no empirical support for the validity of explicit measures of anti-fat prejudice. Here, the UMB, authoritarianism, and physical appearance investment predicted obesity discrimination. The present results provide support for the use of these measures by researchers seeking to assess, understand, and reduce anti-fat prejudice and discrimination. PMID- 22531086 TI - MicroRNAs in adipose tissue: their role in adipogenesis and obesity. AB - MicroRNAs (miRNAs) are endogenous small RNAs that posttranscriptionally regulate gene expression and that have been shown to have important roles in numerous disease processes. There is growing evidence for an important role of miRNAs in regulating the pathways in adipose tissue that control a range of processes including adipogenesis, insulin resistance and inflammation. Several high throughput studies have identified differentially expressed miRNAs in adipose tissue pathology and during adipogenesis and a number of these have now been characterised functionally in terms of their actions and targets. This review will summarise the current literature on miRNAs in adipose tissue, as well as discussing the methodologies used in this area of research and the potential application of miRNAs as biomarkers and as therapeutic targets. PMID- 22531087 TI - Multilevel analysis of the Be Active Eat Well intervention: environmental and behavioural influences on reductions in child obesity risk. AB - BACKGROUND: The Be Active Eat Well (BAEW) community-based child obesity prevention intervention was successful in modestly reducing unhealthy weight gain in primary school children using a multi-strategy and multi-setting approach. OBJECTIVE: To (1) examine the relationship between changes in obesity-related individual, household and school factors and changes in standardised child body mass index (zBMI), and (2) determine if the BAEW intervention moderated these effects. METHODS: The longitudinal relationships between changes in individual, household and school variables and changes in zBMI were explored using multilevel modelling, with measurement time (baseline and follow-up) at level 1, individual (behaviours, n = 1812) at level 2 and households (n = 1318) and schools (n = 18) as higher levels (environments). The effect of the intervention was tested while controlling for child age, gender and maternal education level. RESULTS: This study confirmed that the BAEW intervention lowered child zBMI compared with the comparison group (-0.085 units, P = 0.03). The variation between household environments was found to be a large contributor to the percentage of unexplained change in child zBMI (59%), compared with contributions from the individual (23%) and school levels (1%). Across both groups, screen time (P = 0.03), sweet drink consumption (P = 0.03) and lack of household rules for television (TV) viewing (P = 0.05) were associated with increased zBMI, whereas there was a non-significant association with the frequency the TV was on during evening meals (P = 0.07). The moderating effect of the intervention was only evident for the relationship between the frequency of TV on during meals and zBMI, however, this effect was modest (P = 0.04). CONCLUSIONS: The development of childhood obesity involves multi-factorial and multi-level influences, some of which are amenable to change. Obesity prevention strategies should not only target individual behaviours but also the household environment and family practices. Although zBMI changes were modest, these findings are encouraging as small reductions can have population level impacts on childhood obesity levels. PMID- 22531088 TI - Weighing up the evidence -- a systematic review of measures used for the sensation of breathlessness in obesity. AB - Breathlessness on exertion is common in people with obesity. Assessments of breathlessness may include sensation (intensity, sensory quality or unpleasantness) and/ or the behavioral/emotional consequences of the sensation (respiratory-related functional impairment, disability or quality of life). This systematic review of primary studies published since 2005 evaluated how has the sensation of breathlessness been assessed in adults with increased adiposity. A total of 41 articles were retained from the systematic search strategy resulting in 20 instruments. The Modified Borg Scale (perceived exertion-intensity), the Medical Research Council (MRC) Scale and Baseline Dyspnea Index (BDI; both assess respiratory-related functional impairment) were, respectively, the most frequently reported instruments. Few instruments had been tested for reliability and validity in people with increased adiposity. Visual Analog Scale, Modified Borg Scale, descriptors of sensory quality, MRC and BDI can be recommended as instruments based on their psychometric properties (reliability (correlations >0.8) and concurrent validity (correlation with severity of airways obstruction and walking distance)). A greater number of instruments were identified that assessed the consequences of the breathlessness rather than breathlessness as a sensation. If sensation drives behavior, comprehensive data on the sensation of breathlessness might assist in understanding the behavioral consequences of interventions. PMID- 22531089 TI - Determination of the obesity-associated gene variants within the entire FTO gene by ultra-deep targeted sequencing in obese and lean children. AB - BACKGROUND: The Fat mass and obesity-associated gene (FTO) was the first gene reliably associated with body mass index in genome-wide association studies on a population level. At present, the genetic variations within the FTO gene are still the common variants that have the largest influence on body mass index. METHODS: In the current study, we amplified the entire FTO gene, in total 412 Kbp, in over 200 long-range PCR fragments from each individual, from 524 severely obese and 527 lean Swedish children, and sequenced the products as two DNA pools using massive parallel sequencing (SOLiD). RESULTS: The sequencing achieved very high coverage (median 18 000 reads) and we detected and estimated allele frequencies for 705 single nucleotide polymorphisms (SNPs) (19 novel) and 40 indels (24 novel) using a sophisticated statistical approach to remove false positive SNPs. We identified 19 obesity-associated SNPs within intron one of the FTO gene, and validated our findings with genotyping. Ten of the validated obesity-associated SNPs have a stronger obesity association (P<0.007) than the commonly studied rs9939609 SNP (P<0.012). CONCLUSIONS: This study provides a comprehensive obesity-associated variation map of FTO, identifies novel lead SNPs and evaluates putative causative variants. We conclude that intron one is the only region within the FTO gene associated with obesity, and finally, we establish next generation sequencing of pooled DNA as a powerful method to investigate genetic association with complex diseases and traits. PMID- 22531090 TI - Where are family theories in family-based obesity treatment?: conceptualizing the study of families in pediatric weight management. AB - Family-based approaches to pediatric obesity treatment are considered the 'gold standard,' and are recommended for facilitating behavior change to improve child weight status and health. If family-based approaches are to be truly rooted in the family, clinicians and researchers must consider family process and function in designing effective interventions. To bring a better understanding of family complexities to family-based treatment, two relevant reviews were conducted and are presented: (1) a review of prominent and established theories of the family that may provide a more comprehensive and in-depth approach for addressing pediatric obesity; and (2) a systematic review of the literature to identify the use of prominent family theories in pediatric obesity research, which found little use of theories in intervention studies. Overlapping concepts across theories include: families are a system, with interdependence of units; the idea that families are goal-directed and seek balance; and the physical and social environment imposes demands on families. Family-focused theories provide valuable insight into the complexities of families. Increased use of these theories in both research and practice may identify key leverage points in family process and function to prevent the development of or more effectively treat obesity. The field of family studies provides an innovative approach to the difficult problem of pediatric obesity, building on the long-established approach of family-based treatment. PMID- 22531091 TI - Effect of intrauterine growth retardation on liver and long-term metabolic risk. AB - Intrauterine growth retardation predisposes toward long-term morbidity from type 2 diabetes and cardiovascular disease. To explain this association, the concept of programming was introduced to indicate a process whereby a stimulus or insult at a critical period of development has lasting or lifelong consequences on key endocrine and metabolic pathways. Subtle changes in cell composition of tissues, induced by suboptimal conditions in utero, can influence postnatal physiological functions. There is increasing evidence, suggesting that liver may represent one of the candidate organs targeted by programming, undergoing structural, functional and epigenetic changes following exposure to an unfavorable intrauterine environment. The aim of this review is to provide insights into the molecular mechanisms underlying liver programming that contribute to increase the cardiometabolic risk in subjects with intrauterine growth restriction. PMID- 22531092 TI - Just as smart but not as successful: obese students obtain lower school grades but equivalent test scores to nonobese students. AB - OBJECTIVE: The obesity epidemic in industrialized nations has important implications for education, as research demonstrates lower academic achievement among obese students. The current paper compares the test scores and school grades of obese, overweight and normal-weight students in secondary and further education, controlling for demographic variables, personality, ability and well being confounds. PARTICIPANTS: This study included 383 eighth-grade students (49% female; study 1) and 1036 students from 24 community colleges and universities (64% female, study 2), both drawn from five regions across the United States. MEASURES: In study 1, body mass index (BMI) was calculated using self-reports and parent reports of weight and height. In study 2, BMI was calculated from self reported weight and height only. Both samples completed age-appropriate assessments of mathematics, vocabulary and the personality trait conscientiousness. Eighth-grade students additionally completed a measure of life satisfaction, with both self-reports and parent reports of their grades from the previous semester also obtained. Higher education students additionally completed measures of positive and negative affect, and self-reported their grades and college entrance scores. RESULTS: Obese students receive significantly lower grades in middle school (d=0.83), community college (d=0.34) and university (d=0.36), but show no statistically significant differences in intelligence or achievement test scores. Even after controlling for demographic variables, intelligence, personality and well-being, obese students obtain significantly lower grades than normal-weight students in the eighth grade (d=0.39), community college (d=0.42) and university (d=0.31). CONCLUSION: Lower grades may reflect peer and teacher prejudice against overweight and obese students rather than lack of ability among these students. PMID- 22531093 TI - Rate of weight gain predicts change in physical activity levels: a longitudinal analysis of the EPIC-Norfolk cohort. AB - OBJECTIVE: To investigate the relationship of body weight and its changes over time with physical activity (PA). DESIGN: Population-based prospective cohort study (Norfolk cohort of the European Prospective Investigation into Cancer and Nutrition, EPIC-Norfolk, United Kingdom). SUBJECTS: A total of 25 639 men and women aged 39-79 years at baseline. PA was self-reported. Weight and height were measured by standard clinical procedures at baseline and self-reported at 18 month and 10-year follow-ups (calibrated against clinical measures). Main outcome measure was PA at the 10-year follow-up. RESULTS: Body weight and PA were inversely associated in cross-sectional analyses. In longitudinal analyses, an increase in weight was associated with higher risk of being inactive 10 years later, after adjusting for baseline activity, 18-month activity, sex, baseline age, prevalent diseases, socioeconomic status, education, smoking, total daily energy intake and alcohol intake. Compared with stable weight, a gain in weight of >2 kg per year in the short-, medium- and long-term was consistently and significantly associated with greater likelihood of physical inactivity after 10 years, with the most pronounced effect for long-term weight gain, OR=1.89 (95% CI: 1.30-2.70) in fully adjusted analysis. Weight gain of 0.5-2 kg per year over long-term was substantially associated with physical inactivity after full adjustment, OR=1.26 (95% CI: 1.11-1.41). CONCLUSION: Weight gain (during short-, medium- and long-term) is a significant determinant of future physical inactivity independent of baseline weight and activity. Compared with maintaining weight, moderate (0.5-2 kg per year) and large weight gain (>2 kg per year) significantly predict future inactivity; a potentially vicious cycle including further weight gain, obesity and complications associated with a sedentary lifestyle. On the basis of current predictions of obesity trends, we estimate that the prevalence of inactivity in England would exceed 60% in the year 2020. PMID- 22531095 TI - Giant intercostal aneurysm complicated by Stanford type B acute aortic dissection in patients with type 1 neurofibromatosis. AB - Vascular involvement is rare in neurofibromatosis type 1 (NF1). It is often missed because it is usually asymptomatic. We report a case of a 42 years old male with neurofibromatosis type 1 who presented with left back discomfort. CT angiography revealed a massive 42 mm aneurysm of left 11th intercostal artery. After a discussion between radiologists and cardiothoracic surgeons, endovascular coil embolization was chosen to treat this patient. Percutaneous aneurysm embolization was successfully performed. However, the procedure was complicated by Stanford type B acute aortic dissection. Stanford type B acute aortic dissection was medically managed and patient remained well after discharge. Fragile vascular nature was thought to be one of the causes of this unreported complication. PMID- 22531094 TI - Association between obesity, hypertriglyceridemia and low hepatitis B viral load. AB - OBJECTIVE: This study aimed to investigate the metabolic risk factors of high hepatitis B viral load. DESIGN: Large-scale, community-based cross-sectional study. SUBJECTS: A total of 3587 hepatitis B virus (HBV)-infected participants without liver cirrhosis at study entry were investigated. High HBV viral load was defined as a serum level ?10(4) copies per ml for hepatitis B e antigen (HBeAg) seronegatives or ?10(8) copies per ml for HBeAg seropositives. RESULTS: Among HBeAg seropositives (n=545), high HBV viral load was reversely associated with extreme obesity (odds ratio (OR), 0.30; 95% confidence interval (CI), 0.13-0.68; P=0.004) or central obesity (OR, 0.53; 95% CI, 0.34-0.82; P=0.004) after adjustment for gender, hypertriglyceridemia, hyperuricemia and history of hypertension. High HBV viral load remained significantly inversely associated with extreme obesity (OR, 0.17; 95% CI, 0.05-0.63; P=0.008) and central obesity (OR, 0.44; 95% CI, 0.25-0.78; P=0.005) in male HBeAg-seropositive participants in stratification analyses by gender. Among HBeAg seronegatives (n=3042), however, high HBV viral load was inversely associated with hypertriglyceridemia (OR, 0.74; 95% CI, 0.61-0.89, P=0.002) after adjustment for age, gender, high serum alanine aminotransferase level, and extreme obesity or central obesity. High HBV viral load was still inversely associated with hypertriglyceridemia in both female (OR, 0.70; 95% CI, 0.50-0.97; P=0.041) and male (OR, 0.75; 95% CI, 0.60-0.94; P=0.011) HBeAg-seronegative participants. CONCLUSION: Extreme obesity and central obesity were associated with a low prevalence of high HBV viral load in HBeAg seropositives, especially in men; while hypertriglyceridemia was associated with a low prevalence of high viral load in HBeAg seronegatives in both women and men. PMID- 22531096 TI - Meta-analysis: probiotics in antibiotic-associated diarrhoea. AB - BACKGROUND: Diarrhoea is a common occurrence in association with antibiotic administration. Earlier studies and meta-analyses have suggested that probiotic administration reduces the incidence of antibiotic-associated diarrhoea (AAD). AIM: To estimate the reduction in risk of AAD with administration of probiotics in randomised placebo-controlled trials and to identify factors associated with such reduction. METHODS: Meta-analysis of randomised, double-blinded, placebo controlled trials including patients treated with antibiotics and administered a probiotic for at least the duration of the antibiotic treatment. The outcome was incidence of diarrhoea irrespective of the presence of Clostridium difficile or the development of pseudomembranous colitis. Meta-analysis and meta-regression methods were used to synthesise data and to assess influence of: mean age, duration of antibiotics, risk of bias and incidence of diarrhoea in the placebo group on outcomes. Subgroup analyses explored effects of different probiotic species, patient populations and treatment indications. RESULTS: A total of 34 studies were included with 4138 patients. The pooled relative risk (RR) for AAD in the probiotic group vs. placebo was 0.53 (95% CI 0.44-0.63), corresponding to a number needed to treat (NNT) of 8 (95% CI 7-11). The preventive effect of probiotics remained significant when grouped by probiotic species, population age group, relative duration of antibiotics and probiotics, study risk of bias and probiotic administered. The pooled RR for AAD during treatment for Helicobacter pylori (H. pylori) was 0.37 (95% CI 0.20-0.69), corresponding to a NNT of 5 (95% CI 4-10). CONCLUSIONS: This updated meta-analysis confirms earlier results supporting the preventive effects of probiotics in AAD. PMID- 22531098 TI - Addressing the computational cost of large EIT solutions. AB - Electrical impedance tomography (EIT) is a soft field tomography modality based on the application of electric current to a body and measurement of voltages through electrodes at the boundary. The interior conductivity is reconstructed on a discrete representation of the domain using a finite-element method (FEM) mesh and a parametrization of that domain. The reconstruction requires a sequence of numerically intensive calculations. There is strong interest in reducing the cost of these calculations. An improvement in the compute time for current problems would encourage further exploration of computationally challenging problems such as the incorporation of time series data, wide-spread adoption of three dimensional simulations and correlation of other modalities such as CT and ultrasound. Multicore processors offer an opportunity to reduce EIT computation times but may require some restructuring of the underlying algorithms to maximize the use of available resources. This work profiles two EIT software packages (EIDORS and NDRM) to experimentally determine where the computational costs arise in EIT as problems scale. Sparse matrix solvers, a key component for the FEM forward problem and sensitivity estimates in the inverse problem, are shown to take a considerable portion of the total compute time in these packages. A sparse matrix solver performance measurement tool, Meagre-Crowd, is developed to interface with a variety of solvers and compare their performance over a range of two- and three-dimensional problems of increasing node density. Results show that distributed sparse matrix solvers that operate on multiple cores are advantageous up to a limit that increases as the node density increases. We recommend a selection procedure to find a solver and hardware arrangement matched to the problem and provide guidance and tools to perform that selection. PMID- 22531097 TI - Predicting and preventing ovarian hyperstimulation syndrome (OHSS): the need for individualized not standardized treatment. AB - Ovarian hyperstimulation syndrome (OHSS) is the most serious complication of controlled ovarian stimulation (COS) as part of assisted reproductive technologies (ART). While the safety and efficacy of ART is well established, physicians should always be aware of the risk of OHSS in patients undergoing COS, as it can be fatal. This article will briefly present the pathophysiology of OHSS, including the key role of vascular endothelial growth factor (VEGF), to provide the foundation for an overview of current techniques for the prevention of OHSS. Risk factors and predictive factors for OHSS will be presented, as recognizing these risk factors and individualizing the COS protocol appropriately is the key to the primary prevention of OHSS, as the benefits and risks of each COS strategy vary among individuals. Individualized COS (iCOS) could effectively eradicate OHSS, and the identification of hormonal, functional and genetic markers of ovarian response will facilitate iCOS. However, if iCOS is not properly applied, various preventive measures can be instituted once COS has begun, including cancelling the cycle, coasting, individualizing the human chorionic gonadotropin trigger dose or using a gonadotropin-releasing hormone (GnRH) agonist (for those using a GnRH antagonist protocol), the use of intravenous fluids at the time of oocyte retrieval, and cryopreserving/vitrifying all embryos for subsequent transfer in an unstimulated cycle. Some of these techniques have been widely adopted, despite the scarcity of data from randomized clinical trials to support their use. PMID- 22531099 TI - Loop residues and catalysis in OMP synthase. AB - Residue-to-alanine mutations and a two-amino acid deletion have been made in the highly conserved catalytic loop (residues 100-109) of Salmonella typhimurium OMP synthase (orotate phosphoribosyltransferase, EC 2.4.2.10). As described previously, the K103A mutant enzyme exhibited a 10(4)-fold decrease in k(cat)/K(M) for PRPP; the K100A enzyme suffered a 50-fold decrease. Alanine mutations at His105 and Glu107 produced 40- and 7-fold decreases in k(cat)/K(M), respectively, and E101A, D104A, and G106A were slightly faster than the wild-type (WT) in terms of k(cat), with minor effects on k(cat)/K(M). Equilibrium binding of OMP or PRPP in binary complexes was affected little by loop mutation, suggesting that the energetics of ground-state binding have little contribution from the catalytic loop, or that a favorable binding energy is offset by costs of loop reorganization. Pre-steady-state kinetics for mutants showed that K103A and E107A had lost the burst of product formation in each direction that indicated rapid on-enzyme chemistry for WT, but that the burst was retained by H105A. Delta102Delta106, a loop-shortened enzyme with Ala102 and Gly106 deleted, showed a 10(4)-fold reduction of k(cat) but almost unaltered K(D) values for all four substrate molecules. The 20% (i.e., 1.20) intrinsic [1'-(3)H]OMP kinetic isotope effect (KIE) for WT is masked because of high forward and reverse commitment factors. K103A failed to express intrinsic KIEs fully (1.095 +/- 0.013). In contrast, H105A, which has a smaller catalytic lesion, gave a [1'-(3)H]OMP KIE of 1.21 +/- 0.0005, and E107A (1.179 +/- 0.0049) also gave high values. These results are interpreted in the context of the X-ray structure of the complete substrate complex for the enzyme [Grubmeyer, C., Hansen, M. R., Fedorov, A. A., and Almo, S. C. (2012) Biochemistry 51 (preceding paper in this issue, DOI 10.1021/bi300083p )]. The full expression of KIEs by H105A and E107A may result from a less secure closure of the catalytic loop. The lower level of expression of the KIE by K103A suggests that in these mutant proteins the major barrier to catalysis is successful closure of the catalytic loop, which when closed, produces rapid and reversible catalysis. PMID- 22531100 TI - Human bocavirus amongst an all-ages population hospitalised with acute lower respiratory infections in Cambodia. AB - BACKGROUND: Human bocavirus (HBoV) is a novel parvovirus that is associated with respiratory and gastrointestinal tract disease. OBJECTIVES: To investigate the prevalence and genetic diversity of HBoV amongst hospitalized patients with acute lower respiratory infection (ALRI) in Cambodia. STUDY DESIGN: Samples were collected from 2773 patients of all ages hospitalised with symptoms of ALRI between 2007 and 2009. All samples were screened by multiplex RT-PCR/PCR for 18 respiratory viruses. All samples positive for HBoV were sequenced and included in this study. RESULTS: Of the samples tested, 43 (1.5%) were positive for HBoV. The incidence of HBoV did not vary between the consecutive seasons investigated, and HBoV infections were detected year-round. The incidence of HBoV infection was highest in patients aged < 2 years, with pneumonia or bronchopneumonia the most common clinical diagnosis, regardless of age. A total of 19 patients (44%) were co-infected with HBoV and an additional respiratory pathogen. All isolates were classified as HBoV type 1 (HBoV-1). High conservation between Cambodian NP1 and V1V2 gene sequences was observed. CONCLUSIONS: Human bocavirus infection can result in serious illness, however is frequently detected in the context of viral co-infection. Specific studies are required to further understand the true pathogenesis of HBoV in the context of severe respiratory illness. PMID- 22531101 TI - Effect of mosapride on prednisolone-induced gastric mucosal injury and gastric emptying disorder in dog. AB - Previous report demonstrated that prokinetic agent mosapride has anti-ulcerogenic action in rat-indomethacin gastric mucosal injury model. Here, we assessed the prophylactic effect of mosapride on gastric mucosal injury and emptying disorder induced by prednisolone in dogs. Crossover study design was employed. Six healthy beagles were administered prednisolone alone (2 mg/kg, twice a day [BID] subcutaneously) and prednisolone with mosapride (1 mg/kg, BID, orally), followed by an interval of at least 6 weeks. In each treatment, gastric mucosal injury was scored endoscopically according to the modified Lanza scale, and gastric emptying was assessed with (13)C-octanoic acid breath test. The incidence of gastrointestinal adverse events was also investigated. Coadministration of mosapride with prednisolone significantly (P<0.05) reduced the gastric mucosal injury score (mean +/- SD, 17.67 +/- 6.96), compared with that of prednisolone treatment alone (25.50 +/- 13.03). Prednisolone treatment delayed the half emptying time (184 +/- 45 min) compared with that of controls (137 +/- 19 min), and coadministration of mosapride improved this gastric-emptying delay (143 +/- 29 min). Furthermore, the incidence of the gastrointestinal adverse event vomiting became less frequent upon coadministration with mosapride. In addition to its prokinetic action, our study suggests that mosapride has an anti ulcerogenic action in dogs. The use of mosapride in combination with prednisolone is effective for attenuating prednisolone-induced gastrointestinal adverse events. PMID- 22531102 TI - Clinical effects of bovine lactoferrin on two canine cases with familial neutrophil dysfunction. AB - This study reported detailed clinical effects of bovine lactoferrin on 2 canine littermates (1 female and 1 male) with familial neutrophil dysfunction and an investigation of their genetic background. Clinical signs caused by severe upper respiratory bacterial infections were observed in these dogs. Oral administration of bovine lactoferrin for a long duration improved their clinical signs (severe uveitis in the female dog and coughing from pneumonia in the male dog). Their backcross dogs that have the same father didn't show clinical signs of bacterial infection. Neutrophil function tests revealed that the backcross dogs didn't have any disorders. It is likely that abnormal clinical signs are associated with neutrophil dysfunction in the colony, and the mother dog of these cases might be the genetic carrier of this dysfunction. PMID- 22531103 TI - Porcine granulocyte-macrophage colony-stimulating factor improves the in vitro development of cloned porcine embryos. AB - We examined the effects of porcine granulocyte-macrophage colony-stimulating factor (pGM-CSF) on the in vitro development of porcine embryos produced by somatic cell nuclear transfer (SCNT) for the first time. We evaluated the effects of pGM-CSF on SCNT-derived blastocyst formation and investigated gene expression. A total of 522 cloned embryos in 6 replicates were treated with 10 ng/ml pGM-CSF during in vitro culture (IVC). This treatment significantly (P<0.05) increased blastocyst formation and total cell number in blastocysts compared with the control (12.3% and 41.4 vs. 9.0% and 34.7, respectively). However, there was no effect on cleavage rate. The numbers of cells in the inner cell mass and trophectoderm were significantly higher in the pGM-CSF treatment group (6.0 and 43.0, respectively) compared with the control (4.4 and 31.9, respectively). Treatment with 10 ng/ml pGM-CSF significantly increased POU5F1 and Cdx2 mRNA expression in blastocysts. In addition, Bcl-2, Dnmt1 and proliferating cell nuclear antigen (PCNA) mRNA expression were upregulated in blastocysts in the pGM CSF supplemented group compared with the control. These results suggest that pGM CSF improves the quality and developmental viability of porcine SCNT embryos by regulating transcription factor expression. PMID- 22531104 TI - Sleep disturbance among older adults in assisted living facilities. AB - OBJECTIVES: To evaluate whether objectively and subjectively measured sleep disturbances persist among older adults in assisted living facilities (ALFs) and to identify predictors of sleep disturbance in this setting. DESIGN: Prospective, observational cohort study. SETTING AND PARTICIPANTS: A total of 121 residents, age >= 65 years, in 18 ALFs in the Los Angeles area. MEASUREMENTS: Objective (actigraphy) and subjective (Pittsburgh Sleep Quality Index) sleep measures were collected at baseline and 3- and 6-month follow-up. Predictors of baseline sleep disturbance tested in bivariate analyses and multiple regression models included demographics, Mini-Mental State Examination score, number of comorbidities, nighttime sedating medication use, functional status (activities of daily living; instrumental activities of daily living), restless legs syndrome, and sleep apnea risk. RESULTS: Objective and subjective sleep measures were similar at baseline and 3- and 6-month follow-up (objective nighttime total sleep [hours] 6.3, 6.5, and 6.4; objective nighttime percent sleep 77.2, 77.7, and 78.3; and Pittsburgh Sleep Quality Index total score 8.0, 7.8, and 7.7, respectively). The mean baseline nighttime percent sleep decreased by 2% for each additional unit increase in baseline comorbid conditions (measured as the number of conditions), and increased by 4.5% for each additional unit increase in baseline activities of daily living (measured as the number of activities of daily living), in a multiple regression model. CONCLUSIONS: In this study, we found that objectively and subjectively measured sleep disturbances are persistent among ALF residents and are related to a greater number of comorbidities and poorer functional status at baseline. Interventions are needed to improve sleep in this setting. PMID- 22531106 TI - Make time to re-create yourself. PMID- 22531105 TI - Discrepancy between subjective and objective sleep disturbances in early- and moderate-stage Alzheimer disease. AB - OBJECTIVE: Sleep disturbances such as nocturnal awakenings frequently occur in demented elderly persons and can contribute to depression, cognitive impairment, and caregiver burden. Recognizing sleep disturbances at an early stage of the disease progress is a first prerequisite of intervention and monitoring of progress. This study aimed to investigate the reliability of subjective sleep reports in early- and moderate-stage Alzheimer dementia (AD), by investigating whether they differ from matched healthy normal comparison groups with respect to the discrepancy of subjective and objective sleep estimates. MEASUREMENTS: Subjective sleep was assessed using the Pittsburgh Sleep Quality Index, the Sleep Disorders Questionnaire, and the Athens Insomnia Scale. Objective sleep was estimated using actigraphy. RESULTS: As compared with the normal comparison group (N = 26), AD patients (N = 55) complained less of insomnia, while their objective sleep estimates indicated, in fact, more disturbed sleep, including a longer sleep onset latency and a lower sleep efficiency. Regression analyses aimed at predicting actigraphic sleep parameter estimates from their subjective counterparts showed significant predictive value of only very few subjective sleep parameters. Subjective reports of both patients and the normal comparison group had significant value in predicting actigraphic indices of total sleep time and bedtime. In addition, subjective reports of the normal comparison group, but not of patients, were of value to predict actigraphic indices of sleep onset latency, average sleep bout duration, and sleep efficiency. CONCLUSION: The results show that the value of sleep questionnaires is limited in early- and moderate-stage AD. Actigraphy may be essential to ensure that sleep problems do not go undetected and untreated. PMID- 22531108 TI - Current world literature. PMID- 22531107 TI - Evolving utility of sex hormone-binding globulin measurements in clinical medicine. AB - PURPOSE OF REVIEW: Sex hormone-binding globulin (SHBG) regulates the plasma levels and biological actions of the sex steroids: testosterone and estradiol. Advances in our understanding of how plasma SHBG levels are determined, and how SHBG functions, have provided insight into how SHBG should be used to assess the actions of its sex-steroid ligands, and as a biomarker of metabolic and endocrine abnormalities. RECENT FINDINGS: Plasma SHBG levels fluctuate throughout life in response to the changes in metabolic and physiologic states, and are altered by natural hormones and synthetic steroids. Interindividual differences in plasma SHBG levels and activity are also influenced by polymorphisms within the structural and regulatory regions of the SHBG gene. SUMMARY: Measurements of SHBG are widely used to predict plasma free testosterone levels in patients suffering from excess androgen exposures, but have broader utility in assessing the risk for endocrine diseases and clinical sequelae of the metabolic syndrome, namely, type 2 diabetes and cardiovascular disease. It is anticipated that new genetic and functional data regarding SHBG will reveal whether SHBG is simply a biomarker of these diseases or participants in their cause. PMID- 22531111 TI - Rickettsia massiliae in the Canary Islands. PMID- 22531110 TI - Isolation and biological activity of triglycerides of the fermented mushroom of Coprinus Comatus. AB - BACKGROUND: Although many physiological functions of Coprinus comatus have been reported, there has been no report on the antinociceptive activity of Coprinus comatus. Therefore, the objective of the present study is to demonstrate the production, isolation, and biological properties of triglycerides (TFC) of the fermented mushroom of Coprinus comatus. METHODS: The effects of TFC on cytokines levels, total antioxidant activity, antinociceptive effects in vivo, LD50 and tactile hyperalgesia were analyzed respectively. RESULTS: TFC treatment decreased the levels of cytokines and total antioxidant status (TAOS) and inhibited the acetic acid-induced abdominal constrictions in mice. In addition, TFC reduced CFA induced tactile hyperalgesia in a dose-dependent manner and the LD50 of TFC was determined to be 400 mg/kg. However, TFC did not significantly inhibit the reaction time to thermal stimuli in the hot-plate test. CONCLUSIONS: TFC showed anti-inflammatory, antioxidant, peripheral antinociceptive and antihyperalgesic activity in various models of inflammatory pain. The data suggest that TFC may be a viable treatment option for inflammatory pain. PMID- 22531112 TI - Bell-shaped and ultrasensitive dose-response in phosphorylation-dephosphorylation cycles: the role of kinase-phosphatase complex formation. AB - BACKGROUND: Phosphorylation-dephosphorylation cycles (PDCs) mediated by kinases and phosphatases are common in cellular signalling. Kinetic modelling of PDCs has shown that these systems can exhibit a variety of input-output (dose-response) behaviors including graded response, ultrasensitivity and bistability. In addition to proteins, there are a class of lipids known as phosphoinositides (PIs) that can be phosphorylated. Experimental studies have revealed the formation of an antagonistic kinase-phosphatase complex in regulation of phosphorylation of PIs. However, the functional significance of this type of complex formation is not clear. RESULTS: We first revisit the basic PDC and show that partial asymptotic phosphorylation of substrate limits ultrasensitivity. Also, substrate levels are changed one can obtain non-monotonic bell-shaped dose response curves over a narrow range of parameters. Then we extend the PDC to include kinase-phosphatase complex formation. We report the possibility of robust bell-shaped dose-response for a specific class of the model with complex formation. Also, we show that complex formation can produce ultrasensitivity outside the Goldbeter-Koshland zero-order ultrasensitivity regime through a mechanism similar to competitive inhibition between an enzyme and its inhibitor. CONCLUSIONS: We conclude that the novel PDC module studied here exhibits new dose response behaviour. In particular, we show that the bell-shaped response could result in transient phosphorylation of substrate. We discuss the relevance of this result in the context of experimental observations on PI regulation in endosomal trafficking. PMID- 22531113 TI - Impact of diabetes mellitus on life expectancy and health-adjusted life expectancy in Canada. AB - The objectives of this study were to estimate life expectancy (LE) and health adjusted life expectancy (HALE) for Canadians with and without diabetes and to evaluate the impact of diabetes on population health using administrative and survey data.Mortality data from the Canadian Chronic Disease Surveillance System (2004 to 2006) and Health Utilities Index data from the Canadian Community Health Survey (2000 to 2005) were used. Life table analysis was applied to calculate LE, HALE, and their confidence intervals using the Chiang and the adapted Sullivan methods.LE and HALE were significantly lower among people with diabetes than for people without the disease. LE and HALE for females without diabetes were 85.0 and 73.3 years, respectively (males: 80.2 and 70.9 years). Diabetes was associated with a loss of LE and HALE of 6.0 years and 5.8 years, respectively, for females, and 5.0 years and 5.3 years, respectively, for males, living with diabetes at 55 years of age. The overall gains in LE and HALE after the hypothetical elimination of prevalent diagnosed diabetes cases in the population were 1.4 years and 1.2 years, respectively, for females, and 1.3 years for both LE and HALE for males.The results of the study confirm that diabetes is an important disease burden in Canada impacting the female and male populations differently. The methods can be used to calculate LE and HALE for other chronic conditions, providing useful information for public health researchers and policymakers. PMID- 22531114 TI - Long-term, open-label trial: safety and efficacy of continuous maintenance treatment with pantoprazole for up to 15 years in severe acid-peptic disease. AB - BACKGROUND: To date, the safety and tolerability of proton pump inhibitors (PPIs) have been demonstrated in studies of up to 10 years. AIM: To report on the tolerability, safety and efficacy of up to 15 years' continuous treatment with pantoprazole in patients with severe acid-peptic disease. METHODS: Following healing of endoscopically confirmed peptic ulcer or reflux oesophagitis during 4 12 weeks' treatment with pantoprazole (40-80 mg/day), adult patients received open-label maintenance treatment with pantoprazole (40-160 mg/day) for up to 15 years in a single centre combined study (10-year initial study; 5-year extension study). Safety assessments were carried out using endoscopy, clinical examination, clinical laboratory investigations, serum gastrin determination, gastric mucosal histology and mucosal endocrine cell quantification. RESULTS: The safety set comprised 142 patients. At 12 weeks, healing rates were 95.8%. During long-term treatment, mean fasting gastrin levels rose from baseline to moderate levels throughout the study. Mean enterochromaffin-like cell density showed a moderate initial increase during the first 3 years, remaining stable thereafter. These changes were not associated with any clinically relevant changes of the gastric mucosa. Patients with successful Helicobacter pylori eradication showed long-term regression of antral and corpus gastritis during continued pantoprazole treatment. CONCLUSIONS: Daily pantoprazole maintenance therapy for up to 15 years for severe acid-peptic disease is effective and well tolerated, with no identified safety concerns. The longest study to date, these data provide reassuring evidence for the long-term safety of pantoprazole. PMID- 22531115 TI - Routes to copper zinc tin sulfide Cu2ZnSnS4 a potential material for solar cells. AB - Power generation through photovoltaics (PV) has been growing at an average rate of 40% per year over the last decade; but has largely been fuelled by conventional Si-based technologies. Such cells involve expensive processing and many alternatives use either toxic, less-abundant and or expensive elements. Kesterite Cu(2)ZnSnS(4) (CZTS) has been identified as a solar energy material composed of both less toxic and more available elements. Power conversion efficiencies of 8.4% (vacuum processing) and 10.1% (non-vacuum processing) from cells constructed using CZTS have been achieved to date. In this article, we review various deposition methods for CZTS thin films and the synthesis of CZTS nanoparticles. Studies of direct relevance to solar cell applications are emphasised and characteristic properties are collated. PMID- 22531116 TI - A method for rapid production of subject specific finite element meshes for electrical impedance tomography of the human head. AB - Finite element (FE) methods are widely used in electrical impedance tomography (EIT) to enable rapid image reconstruction of different tissues based on their electrical conductivity. For EIT of brain function, anatomically-accurate (head shaped) FE meshes have been shown to improve the quality of the reconstructed images. Unfortunately, given the lack of a computational protocol to generate patient-specific meshes suitable for EIT, production of such meshes is currently ad hoc and therefore very time consuming. Here we describe a robust protocol for rapid generation of patient-specific FE meshes from MRI or CT scan data. Most of the mesh generation process is automated and uses freely available user-friendly software. Other necessary custom scripts are provided as supplementary online data and are fully documented. The patient scan data is segmented into four surfaces: brain, cerebrospinal fluid, skull and scalp. The segmented surfaces are then triangulated and used to generate a global mesh of tetrahedral elements. The resulting meshes exhibit high quality when tested with different criteria and were validated in computational simulations. The proposed protocol provides a rapid and practicable method for generation of patient-specific FE meshes of the human head that are suitable for EIT. This method could eventually be extended to other body regions and might confer benefits with other imaging techniques such as optical tomography or EEG inverse source imaging. PMID- 22531117 TI - Asymmetric positive feedback loops reliably control biological responses. AB - Positive feedback is a common mechanism enabling biological systems to respond to stimuli in a switch-like manner. Such systems are often characterized by the requisite formation of a heterodimer where only one of the pair is subject to feedback. This ASymmetric Self-UpREgulation (ASSURE) motif is central to many biological systems, including cholesterol homeostasis (LXRalpha/RXRalpha), adipocyte differentiation (PPARgamma/RXRalpha), development and differentiation (RAR/RXR), myogenesis (MyoD/E12) and cellular antiviral defense (IRF3/IRF7). To understand why this motif is so prevalent, we examined its properties in an evolutionarily conserved transcriptional regulatory network in yeast (Oaf1p/Pip2p). We demonstrate that the asymmetry in positive feedback confers a competitive advantage and allows the system to robustly increase its responsiveness while precisely tuning the response to a consistent level in the presence of varying stimuli. This study reveals evolutionary advantages for the ASSURE motif, and mechanisms for control, that are relevant to pharmacologic intervention and synthetic biology applications. PMID- 22531120 TI - A direct look at RNAi screens. PMID- 22531119 TI - Single-cell analysis of population context advances RNAi screening at multiple levels. AB - Isogenic cells in culture show strong variability, which arises from dynamic adaptations to the microenvironment of individual cells. Here we study the influence of the cell population context, which determines a single cell's microenvironment, in image-based RNAi screens. We developed a comprehensive computational approach that employs Bayesian and multivariate methods at the single-cell level. We applied these methods to 45 RNA interference screens of various sizes, including 7 druggable genome and 2 genome-wide screens, analysing 17 different mammalian virus infections and four related cell physiological processes. Analysing cell-based screens at this depth reveals widespread RNAi induced changes in the population context of individual cells leading to indirect RNAi effects, as well as perturbations of cell-to-cell variability regulators. We find that accounting for indirect effects improves the consistency between siRNAs targeted against the same gene, and between replicate RNAi screens performed in different cell lines, in different labs, and with different siRNA libraries. In an era where large-scale RNAi screens are increasingly performed to reach a systems-level understanding of cellular processes, we show that this is often improved by analyses that account for and incorporate the single-cell microenvironment. PMID- 22531121 TI - Comparison between the gastric cancer cell line MKN-45 and the high-potential peritoneal dissemination gastric cancer cell line MKN-45P. AB - Peritoneal metastasis is the most common form of recurrence in gastric cancer, and is associated with a poor prognosis. It is clear that many agents are involved at the various stages of this process, however, many aspects of the progression remain unclear. In the present study we compared the gastric cancer cell line MKN-45 with the high-potential peritoneal dissemination gastric cancer cell line MKN-45P, established from MKN-45. The supernatant of culture medium of MKN-45 cells or MKN-45P cells was collected, and the concentrations of interleukin-1beta (IL-1beta), IL-6, IL-8, hepatocyte growth factor (HGF), Transforming growth factor beta-beta1 (TGF-beta1), vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2), MMP-9, and tissue inhibitor of metalloproteinase-1 (TIMP-1) proteins were measured using an enzyme-linked immuno sorbent assay (ELISA) method. Invasion, wound healing and adhesion assays were performed in vitro to examine interstitial invasion, migration and adhesion in the gastric cancer cell lines. Moreover, Western blotting was performed to determine the expression of cyclooxygenase-1 (COX-1) and COX-2 proteins in the culture media of the cell lines. The concentrations of IL-6, IL-8, VEGF and MMP-2 protein in the culture supernatant of MKN-45P were significantly higher than those of MKN-45. Percent adhesion of MKN-45P was significantly higher than that of MKN-45 in the fibronectin-coated group. There was no significant difference in invasion or migration between MKN-45 and MKN-45P. COX-1 and COX-2 proteins were observed in both cell lines. These results suggested that secretion of IL-6, IL 8, VEGF and MMP-2 from cancer cells, and adhesion of cancer cells to fibronectin, were related to the establishment of peritoneal dissemination. PMID- 22531122 TI - Recurrence of invasive micropapillary carcinoma of the breast with different ultrasound features according to lesion site: case report. AB - Invasive micropapillary carcinoma (IMPC) of the breast is a distinct variant of breast cancer. Extensive lymphatic penetration, lymph node metastasis, and local recurrence are seen at a relatively high frequency. On ultrasound (US) findings, IMPC has been reported to be an irregular or lobulated mass with hypoechoic internal areas, but as yet there is no consensus regarding typical findings. A 52 year-old female noticed a mass less than 3 cm in diameter in her left upper breast. US findings indicated an irregularly shaped, hypoechoic tumor with indistinct margins. The diagnosis according to fine-needle aspiration cytology was invasive ductal carcinoma. She underwent lymph node dissection with mastectomy of the left breast. Histological examination revealed mixed-type IMPC. Three years and three months after surgery, IMPC recurred under the skin of the surgical scar. US findings indicated a hyperechoic tumor in this region. Eight months after further surgery, a tumor in the anterior chest wall was observed. US findings indicated an oval hypoechoic tumor with posterior acoustic enhancement. US findings differed between primary and recurrent IMPC because of differences in the occupancy and distribution of IMPC. We describe here a comparison between US and histological findings, as well as differences in IMPC between primary, secondary and tertiary sites. PMID- 22531118 TI - A framework for mapping, visualisation and automatic model creation of signal transduction networks. AB - Intracellular signalling systems are highly complex. This complexity makes handling, analysis and visualisation of available knowledge a major challenge in current signalling research. Here, we present a novel framework for mapping signal-transduction networks that avoids the combinatorial explosion by breaking down the network in reaction and contingency information. It provides two new visualisation methods and automatic export to mathematical models. We use this framework to compile the presently most comprehensive map of the yeast MAP kinase network. Our method improves previous strategies by combining (I) more concise mapping adapted to empirical data, (II) individual referencing for each piece of information, (III) visualisation without simplifications or added uncertainty, (IV) automatic visualisation in multiple formats, (V) automatic export to mathematical models and (VI) compatibility with established formats. The framework is supported by an open source software tool that facilitates integration of the three levels of network analysis: definition, visualisation and mathematical modelling. The framework is species independent and we expect that it will have wider impact in signalling research on any system. PMID- 22531123 TI - Concurrent lung cancer in non-tuberculous mycobacteriosis: case report. AB - An 82-year-old woman was admitted to our hospital after multiple round opacities were detected in chest X-rays performed during a routine health screening. Mycobacterium avium complex (MAC) was found in sputum cultures, and compatible pathological findings on biopsy confirmed pulmonary MAC infection, whereas biopsies from another opacity revealed adenocarcinoma of the lung.Curative surgery for the lung cancer confirmed a concurrence of lung cancer and pulmonary MAC infection. Since the prevalence of both of these lung diseases is increasing, suspicion of concurrence is critical to provide appropriate care. PMID- 22531124 TI - Ectopic pregnancy occurred after oocyte intrauterine transfer (OUT)--a case report. AB - Although still an experimental procedure, it is hoped that oocyte intrauterine transfer (OUT) could become a convenient technique for initiating pregnancy. A 33 year old woman received OUT treatment after a period of infertility lasting for 3 years. Two weeks later the result of pregnancy test was positive, but shortly thereafter she complained of vaginal bleeding. Ultrasonography revealed a cystic lesion in her right adnexal area without any ascites. At laparotomy, a right side tubal pregnancy was confirmed. This is the first case report of ectopic pregnancy occurring after OUT. It was speculated that the OUT may have caused the tubal pregnancy. However, since the precise mechanism for embryonic implantation to the tubal epithelium is unknown, the causal relationship between OUT and tubal pregnancy remains unclear. PMID- 22531125 TI - Successful treatment of T4 renal cell carcinoma after a neoadjuvant targeted therapy using sunitinib: report of a case. AB - Since the introduction of targeted therapy, treatment of metastatic renal cell carcinoma (RCC) has undergone dramatic changes. Responses to targeted therapy within the primary tumor and metastatic lesions are novel findings not seen with immunotherapeutic-based strategies. We report here a case of T4 RCC in which cytoreductive nephrectomy became possible after a neoadjuvant targeted therapy using sunitinib. Our experience with the present case suggests that targeted therapy in the neoadjuvant setting may have a variety of potential applications. Further investigations should be encouraged. PMID- 22531126 TI - Cohort Profile: the Dongfeng-Tongji cohort study of retired workers. PMID- 22531127 TI - Body size and risk for colorectal cancers showing BRAF mutations or microsatellite instability: a pooled analysis. AB - BACKGROUND: How body size influences risk of molecular subtypes of colorectal cancer (CRC) is unclear. We investigated whether measures of anthropometry differentially influence risk of tumours according to BRAF c.1799T>A p.V600E mutation (BRAF) and microsatellite instability (MSI) status. METHODS: Data from The Netherlands Cohort Study (n = 120,852) and Melbourne Collaborative Cohort Study (n = 40,514) were pooled and included 734 and 717 colorectal cancer cases from each study, respectively. Hazard ratios (HRs) and 95% confidence intervals (CIs) for body mass index (BMI), waist measurement and height were calculated and compared for subtypes defined by BRAF mutation and MSI status, measured from archival tissue. RESULTS: Results were consistent between studies. When pooled, BMI modelled in 5 kg/m(2) increments was positively associated with BRAF wild type (HR: 1.16, 95% CI: 1.08-1.26) and MS-stable tumours (HR: 1.15, 95% CI: 1.06 1.24). Waist measurement was also associated with BRAF wild-type (highest vs lowest quartile, HR: 1.59, 95% CI: 1.33-1.90) and MS-stable tumours (highest vs lowest quartile HR: 1.68, 95% CI: 1.31-2.15). The HRs for BRAF mutation tumours and MSI tumours were smaller and non-significant, but differences between the HRs by tumour subtypes were not significant. Height, modelled per 5-cm increase, was positively associated with BRAF wild-type and BRAF mutation tumours, but the HR was greater for tumours with a BRAF mutation than BRAF wild-type (HR: 1.23, 95% CI: 1.11-1.37, P(heterogeneity) = 0.03). Similar associations were observed with respect to height and MSI tumours (HR: 1.26, 95% CI: 1.13-1.40, P(heterogeneity) = 0.02). CONCLUSIONS: Generally, overweight increases the risk of CRC. Taller individuals have an increased risk of developing a tumour with a BRAF mutation or MSI. PMID- 22531128 TI - Tamoxifen modulates cell migration and expression of angiogenesis-related genes in human endometrial endothelial cells. AB - The selective estrogen receptor modulator tamoxifen is used for the prevention and treatment of breast cancer. The adverse effects of tamoxifen include vaginal endometrial bleeding, endometrial hyperplasia, and cancer, conditions associated with angiogenesis. The aim of this study was to examine the effects of tamoxifen on cell migration and angiogenesis-related gene expression in human endometrial endothelial cells (HEECs). The regulatory effects of tamoxifen on endometrial stromal cells and HEECs were also examined. HEECs and stromal cells were isolated and grown in monocultures or co-cultures, and incubated with 0.1 to 100 MUmol/L tamoxifen for 48 hours. Quantitative PCR demonstrated that tamoxifen decreased the mRNA expression of vascular endothelial growth factor-A (VEGF-A) and increased the mRNA expression of VEGF receptor-1 and placental growth factor (PLGF) in HEECs. Tamoxifen's effects on VEGF-A were inhibited when HEECs were co cultured with stromal cells. In addition, tamoxifen reduced VEGF-induced HEEC migration. The tamoxifen-metabolizing enzymes CYP1A1 and CYP1B1 were detected by immunohistochemistry in and around endometrial blood vessels and by quantitative PCR in HEECs. Our data suggest that tamoxifen changes the regulation of angiogenesis in the endometrium, likely by reducing angiogenic activity. The results also indicate that endometrial stromal cells regulate some of tamoxifen's effects in HEECs, and the presence of tamoxifen-metabolizing enzymes suggests tamoxifen bioactivation in the endometrial vasculature in vivo. These findings may help to elucidate the mechanism of the bleeding disturbances associated with tamoxifen treatment. PMID- 22531129 TI - Retroviral integration profiles: their determinants and implications for gene therapy. AB - Retroviruses have often been used for gene therapy because of their capacity for the long-term expression of transgenes via stable integration into the host genome. However, retroviral integration can also result in the transformation of normal cells into cancer cells, as demonstrated by the incidence of leukemia in a recent retroviral gene therapy trial in Europe. This unfortunate outcome has led to the rapid initiation of studies examining various biological and pathological aspects of retroviral integration. This review summarizes recent findings from these studies, including the global integration patterns of various types of retroviruses, viral and cellular determinants of integration, implications of integration for gene therapy and retrovirus-mediated infectious diseases, and strategies to shift integration to safe host genomic loci. A more comprehensive and mechanistic understanding of retroviral integration processes will eventually make it possible to generate safer retroviral vector platforms in the near future. PMID- 22531130 TI - Systems biology of virus-host signaling network interactions. AB - Viruses have evolved to manipulate the host cell machinery for virus propagation, in part by interfering with the host cellular signaling network. Molecular studies of individual pathways have uncovered many viral host-protein targets; however, it is difficult to predict how viral perturbations will affect the signaling network as a whole. Systems biology approaches rely on multivariate, context-dependent measurements and computational analysis to elucidate how viral infection alters host cell signaling at a network level. Here we describe recent advances in systems analyses of signaling networks in both viral and non-viral biological contexts. These approaches have the potential to uncover virus- mediated changes to host signaling networks, suggest new therapeutic strategies, and assess how cell-to-cell variability affects host responses to infection. We argue that systems approaches will both improve understanding of how individual virus-host protein interactions fit into the progression of viral pathogenesis and help to identify novel therapeutic targets. PMID- 22531131 TI - Anticoagulant activities of curcumin and its derivative. AB - Curcumin, a polyphenol responsible for the yellow color of the curry spice turmeric, possesses antiinflammatory, antiproliferative and antiangiogenic activities. However, anticoagulant activities of curcumin have not been studied. Here, the anticoagulant properties of curcumin and its derivative (bisdemethoxycurcumin, BDMC) were determined by monitoring activated partial thromboplastin time (aPTT), prothrombin time (PT) as well as cell-based thrombin and activated factor X (FXa) generation activities. Data showed that curcumin and BDMC prolonged aPTT and PT significantly and inhibited thrombin and FXa activities. They inhibited the generation of thrombin or FXa. In accordance with these anticoagulant activities, curcumin and BDMC showed anticoagulant effect in vivo. Surprisingly, these anticoagulant effects of curcumin were better than those of BDMC indicating that methoxy group in curcumin positively regulated anticoagulant function of curcumin. Therefore, these results suggest that curcumin and BDMC possess antithrombotic activities and daily consumption of the curry spice turmeric might help maintain anticoagulant status. PMID- 22531132 TI - Translation elongation factor-1A1 (eEF1A1) localizes to the spine by domain III. AB - In vertebrates, there are two variants of eukaryotic peptide elongation factor 1A (eEF1A; formerly eEF-1alpha), eEF1A1 and eEF1A2, which have three well-conserved domains (D(I), D(II), and D(III)). In neurons, eEF1A1 is the embryonic type, which is expressed during embryonic development as well as the first two postnatal weeks. In the present study, EGFP-tagged eEF1A1 truncates were expressed in cortical neurons isolated from rat embryo (E18-19). Live cell images of transfected neurons showed that D(III)-containing EGFP-fusion proteins (EGFP D(III), -D(II)-III, -D(I)-III) formed clusters that were confined within somatodendritic domains, while D(III)-missing ones (EGFP-D(I), -D(II), -D(I)-II) and control EGFP were homogeneously D(I)spersed throughout the neuron incluD(I)ng axons. In dendrites, EGFP-D(III) was targeted to the heads of spine- and filopoD(I)a-like protrusions, where it was colocalized with SynGAPalpha, a postsynaptic marker. Our data inD(I)cate that D(III) of eEF1A1 meD(I)ates formation of clusters and localization to spines. PMID- 22531133 TI - Affinity chromatography and capillary electrophoresis for analysis of the yeast ribosomal proteins. AB - We present a top down separation platform for yeast ribosomal proteins using affinity chromatography and capillary electrophoresis which is designed to allow deposition of proteins onto a substrate. FLAG tagged ribosomes were affinity purified, and rRNA acid precipitation was performed on the ribosomes followed by capillary electrophoresis to separate the ribosomal proteins. Over 26 peaks were detected with excellent reproducibility (<0.5% RSD migration time). This is the first reported separation of eukaryotic ribosomal proteins using capillary electrophoresis. The two stages in this workflow, affinity chromatography and capillary electrophoresis, share the advantages that they are fast, flexible and have small sample requirements in comparison to more commonly used techniques. This method is a remarkably quick route from cell to separation that has the potential to be coupled to high throughput readout platforms for studies of the ribosomal proteome. PMID- 22531134 TI - Bacillus subtilis HmoB is a heme oxygenase with a novel structure. AB - Iron availability is limited in the environment and most bacteria have developed a system to acquire iron from host hemoproteins. Heme oxygenase plays an important role by degrading heme group and releasing the essential nutrient iron. The structure of Bacillus subtilis HmoB was determined to 2.0 A resolution. B. subtilis HmoB contains a typical antibiotic biosynthesis monooxygenase (ABM) domain that spans from 71 to 146 residues and belongs to the IsdG family heme oxygenases. Comparison of HmoB and IsdG family proteins showed that the C terminal region of HmoB has similar sequence and structure to IsdG family proteins and contains conserved critical residues for heme degradation. However, HmoB is distinct from other IsdG family proteins in that HmoB is about 60 amino acids longer in the N-terminus and does not form a dimer whereas previously studied IsdG family heme oxygenases form functional homodimers. Interestingly, the structure of monomeric HmoB resembles the dimeric structure of IsdG family proteins. Hence, B. subtilis HmoB is a heme oxygenase with a novel structural feature. PMID- 22531135 TI - Resveratrol and piperine enhance radiosensitivity of tumor cells. AB - The use of ionizing radiation (IR) is essential for treating many human cancers. However, radioresistance markedly impairs the efficacy of tumor radiotherapy. IR enhances the production of reactive oxygen species (ROS) in a variety of cells which are determinant components in the induction of apoptosis. Much interest has developed to augment the effect of radiation in tumors by combining it with radiosensitizers to improve the therapeutic ratio. In the current study, the radiosensitizing effects of resveratrol and piperine on cancer cells were evaluated. Cancer cell lines treated with these natural products exhibited significantly augmented IR-induced apoptosis and loss of mitochondrial membrane potential, presumably through enhanced ROS generation. Applying natural products as sensitizers for IR-induced apoptotic cell death offers a promising therapeutic approach to treat cancer. PMID- 22531136 TI - Smads, p38 and ERK1/2 are involved in BMP9-induced osteogenic differentiation of C3H10T1/2 mesenchymal stem cells. AB - Although previous studies have demonstrated that BMP9 is highly capable of inducing osteogenic differentiation of mesenchymal stem cells, the molecular mechanism involved remains to be fully elucidated. In this study, we showed that BMP9 simultaneously promotes the activation of Smad1/5/8, p38 and ERK1/2 in C3H10T1/2 cells. Knockdown of Smad4 with RNA interference reduced nuclear translocation of Smad1/5/8, and disrupted BMP9-induced osteogenic differentiation. BMP9-induced osteogenic differentiation was blocked by p38 inhibitor SB203580, whereas enhanced by ERK1/2 inhibitor PD98059. SB203580 decreased BMP9-activated Smads singling, and yet PD98059 stimulated Smads singling in C3H10T1/2 cells. The effects of inhibitor were reproduced with adenovirus expressing siRNA targeted p38 and ERK1/2, respectively. Taken together, our findings revealed that Smads, p38 and ERK1/2 are involved in BMP9 induced osteogenic differentiation. Also, it is noteworthy that p38 and ERK1/2 may play opposing regulatory roles in mediating BMP9-induced osteogenic differentiation of C3H10T1/2 cells. PMID- 22531138 TI - Characterisation of multiple substrate-specific (d)ITP/(d)XTPase and modelling of deaminated purine nucleotide metabolism. AB - Accumulation of modified nucleotides is defective to various cellular processes, especially those involving DNA and RNA. To be viable, organisms possess a number of (deoxy)nucleotide phosphohydrolases, which hydrolyze these nucleotides removing them from the active NTP and dNTP pools. Deamination of purine bases can result in accumulation of such nucleotides as ITP, dITP, XTP and dXTP. E. coli RdgB has been characterised as a deoxyribonucleoside triphosphate pyrophosphohydrolase that can act on these nucleotides. S. cerevisiae homologue encoded by YJR069C was purified and its (d)NTPase activity was assayed using fifteen nucleotide substrates. ITP, dITP, and XTP were identified as major substrates and kinetic parameters measured. Inhibition by ATP, dATP and GTP were established. On the basis of experimental and published data, modelling and simulation of ITP, dITP, XTP and dXTP metabolism was performed. (d)ITP/(d)XTPase is a new example of enzyme with multiple substrate-specificity demonstrating that multispecificity is not a rare phenomenon. PMID- 22531137 TI - Comparative secretome analysis of human follicular dermal papilla cells and fibroblasts using shotgun proteomics. AB - The dermal papilla cells (DPCs) of hair follicles are known to secrete paracrine factors for follicular cells. Shotgun proteomic analysis was performed to compare the expression profiles of the secretomes of human DPCs and dermal fibroblasts (DFs). In this study, the proteins secreted by DPCs and matched DFs were analyzed by 1DE/LTQ FTICR MS/MS, semi-quantitatively determined using emPAI mole percent values and then characterized using protein interaction network analysis. Among the 1,271 and 1,188 proteins identified in DFs and DPCs, respectively, 1,529 were further analyzed using the Ingenuity Pathway Analysis tool. We identified 28 DPC specific extracellular matrix proteins including transporters (ECM1, A2M), enzymes (LOX, PON2), and peptidases (C3, C1R). The biochemically- validated DPC specific proteins included thrombospondin 1 (THBS1), an insulin-like growth factor binding protein3 (IGFBP3), and, of particular interest, an integrin beta1 subunit (ITGB1) as a key network core protein. Using the shotgun proteomic technique and network analysis, we selected ITGB1, IGFBP3, and THBS1 as being possible hair-growth modulating protein biomarkers. PMID- 22531139 TI - Melanocortins as potential therapeutic agents in severe hypoxic conditions. AB - Melanocortin peptides with the adrenocorticotropin/melanocyte-stimulating hormone (ACTH/MSH) sequences and synthetic analogs have protective and life-saving effects in experimental conditions of circulatory shock, myocardial ischemia, ischemic stroke, traumatic brain injury, respiratory arrest, renal ischemia, intestinal ischemia and testicular ischemia, as well as in experimental heart transplantation. Moreover, melanocortins improve functional recovery and stimulate neurogenesis in experimental models of cerebral ischemia. These beneficial effects of ACTH/MSH-like peptides are mostly mediated by brain melanocortin MC(3)/MC(4) receptors, whose activation triggers protective pathways that counteract the main ischemia/reperfusion-related mechanisms of damage. Induction of signaling pathways and other molecular regulators of neural stem/progenitor cell proliferation, differentiation and integration seems to be the key mechanism of neurogenesis stimulation. Synthesis of stable and highly selective agonists at MC(3) and MC(4) receptors could provide the potential for development of a new class of drugs for a novel approach to management of severe ischemic diseases. PMID- 22531143 TI - Self-report questionnaires of nurses in Taiwan reveal that critical thinking ability and nursing competence are both at the middle level and there is a correlation between the two. PMID- 22531144 TI - The reciprocal relationship between physical activity and depression in older European adults. PMID- 22531140 TI - Outcomes of prolonged mechanic ventilation: a discrimination model based on longitudinal health insurance and death certificate data. AB - BACKGROUND: This study investigated prognosis among patients under prolonged mechanical ventilation (PMV) through exploring the following issues: (1) post-PMV survival rates, (2) factors associated with survival after PMV, and (3) the number of days alive free of hospital stays requiring mechanical ventilation (MV) care after PMV. METHODS: This is a retrospective cohort study based on secondary analysis of prospectively collected data in the national health insurance system and governmental data on death registry in Taiwan. It used data for a nationally representative sample of 25,482 patients becoming under PMV (> = 21 days) during 1998-2003. We calculated survival rates for the 4 years after PMV, and adopted logistic regression to construct prediction models for 3-month, 6-month, 1-year, and 2-year survival, with data of 1998-2002 for model estimation and the 2003 data for examination of model performance. We estimated the number of days alive free of hospital stays requiring MV care in the immediate 4-year period after PMV, and contrasted patients who had low survival probability with all PMV patients. RESULTS: Among these patients, the 3-month survival rate was 51.4%, and the 1-year survival rate was 31.9%. Common health conditions with significant associations with poor survival included neoplasm, acute and unspecific renal failure, chronic renal failure, non-alcoholic liver disease, shock and septicaemia (odd ratio < 0.7, p < 0.05). During a 4-year follow-up period for patients of year 2003, the mean number of days free of hospital stays requiring MV was 66.0 in those with a predicted 6-month survival rate < 10%, and 111.3 in those with a predicted 2-year survival rate < 10%. In contrast, the mean number of days was 256.9 in the whole sample of patients in 2003. CONCLUSIONS: Neoplasm, acute and unspecific renal failure, shock, chronic renal failure, septicemia, and non-alcoholic liver disease are significantly associated with lower survival among PMV patients. Patients with anticipated death in a near future tend to spend most of the rest of their life staying in hospital using MV services. This calls for further research into assessing PMV care need among patients at different prognosis stages of diseases listed above. PMID- 22531145 TI - Mindfulness meditation for women with irritable bowel syndrome--evidence of benefit from a randomised controlled trial. PMID- 22531146 TI - Pain in people with chronic obstructive pulmonary disease (COPD). AB - INTRODUCTION: The prevalence and characteristics of pain are not known in COPD patients. The purposes of this study were to determine if pain is more common in COPD patients than in healthy people and if it was related to self-reported physical activity, health related quality of life (HRQoL) and comorbidities. METHODS: Participants returned a mailed survey package that contained: 1) McGill Pain Questionnaire (MPQ) and Brief Pain Inventory (BPI) to evaluate pain severity and how pain interferes with activities; 2) Tampa Scale for Kinesiophobia (TSK) to evaluate fear of movement related to pain; 3) Short Form-36 (SF-36), to measure HRQoL; 4) Community Health Activities Model Program for Seniors (CHAMPS) to evaluate physical activity; 5) a form to list medications and comorbidities. RESULTS: Forty-seven COPD patients and 47 age- and gender-matched healthy people responded. People with COPD demonstrated more pain (MPQ and BPI, p = 0.000), a greater pain-related interference in their lives (BPI, p = 0.000), a higher pain related fear of movement, and lower frequency and energy expenditure of physical activities (CHAMPS, p = 0.000) than healthy people (TSK, p < 0.001). Pain severity (MPQ and BPI) was indirectly correlated to the Physical Component Score of the SF-36. COPD patients identified pain in the neck and trunk 3.1 times more often than healthy people. The number of comorbidities was the most consistent independent correlate of pain in COPD patients. CONCLUSIONS: COPD patients demonstrate more pain which interferes with activities more so than healthy people of similar age. Pain is also negatively associated with HRQoL in COPD. PMID- 22531147 TI - Plasmapheresis leading to remission of refractory nephrotic syndrome due to fibrillary glomerulonephritis: a case report. AB - INTRODUCTION: Fibrillary glomerulonephritis (FibGN) is characterized by extracellular deposition of Congo red-negative microfibrils within the glomerular mesangium and leads to gross proteinuria or nephrotic syndrome. After diagnosis of FibGN, end-stage renal disease occurs within four years in 50% of patients. CASE PRESENTATION: A 36-year-old Caucasian woman with proteinuria and intermittent nephrotic syndrome due to FibGN intermittently received immunosuppressive therapies, including glucocorticoids, mycophenolate mofetil, and rituximab, for 10 years. However, disease remission was not achieved and progressive kidney injury developed. Ultimately, in stage IV of chronic kidney disease (Kidney Disease: Improving Global Outcomes), three cycles of plasmapheresis of five to seven sessions each were performed every three to four months, reducing steady-state proteinuria from 7 to less than 1 g/day. Here, plasmapheresis led to a remission of nephrotic syndrome associated with FibGN. CONCLUSIONS: Plasmapheresis therapy is proposed as a further option for immunosuppressant-refractory FibGN. PMID- 22531148 TI - Tailoring magnetic properties of electrodeposited thin films of the molecule based magnet Cr5.5(CN)12 11.5H2O. AB - This paper reports on molecular-based magnetic thin films of Prussian blue analogues (PBA) with high critical temperatures composed of mixed-valence chromium cyanides. The thin films of PBA were synthesized by means of electrodeposition technique. Morphology and magnetic study are presented in a function of electrochemical deposition conditions. We present the electrochemical methods as a promising and effective tool for preparing molecular-based magnetic thin films of Prussian blue analogue. PMID- 22531149 TI - Parent's perceptions of health care providers actions around child ICU death: what helped, what did not. AB - PURPOSE: To describe parents' perspectives of health care provider actions that helped or did not around the time of infant/child's intensive care unit (ICU) death. Semistructured interviews with 63 parents (Black, White, and Hispanic) 7 months post infant/child death were audio-recorded, transcribed, analyzed, and themes identified. FINDINGS: What helped most: compassionate, sensitive staff; understandable explanations of infant's/child's condition; experienced, competent nurses; providers did everything to help infant/child; and parents' involvement in care decisions. What did not help: insensitive, nonsupportive staff; conflict between providers and parents; communication problems around the death; inexperienced nurses and doctors; parents not understanding child's disease, care, complications. CONCLUSIONS: Compassionate, sensitive staff and understandable explanations of children's conditions were most helpful; insensitive, nonsupportive staff least helpful by gender, racial group, or care setting. Conflict between providers and parents was most problematic for minority parents and mothers. PMID- 22531150 TI - Hospice and palliative care access issues in rural areas. AB - All individuals deserve to have access to quality end-of-life care. In rural communities within the United States, significant barriers limit access to hospice and palliative care. They include issues related to geography and supply, health care system eligibility criteria, limitations of the available workforce, educational deficits, and differences in cultural values. This article examines the barriers and potential solutions to address the gaps in hospice and palliative care services in rural communities. Strategies are proposed to strengthen hospice and palliative care delivery models to enhance earlier referrals and provide better facilitation and transition to hospice and palliative care. Future research should look at patient utilization questions specific to rural communities. PMID- 22531151 TI - Importance and timing of end-of-life care discussions among gynecologic oncology patients. AB - OBJECTIVES: To assess the importance and desired timing of end-of-life care (EOLC) discussions among women with gynecologic cancer. METHODS: A questionnaire related to EOLC issues was distributed to patients with gynecologic cancer. Answers were analyzed via SPSS using descriptive statistics. Contingency analysis was done to evaluate for differences among disease status and age regarding preferences for timing of discussions. RESULTS: Patients expressed that addressing EOLC is an important part of their treatment. Most patients were familiar with advanced directives (73.0%), do not resuscitate/do not intubate (88.5%), and hospice (97.5%). Designating someone to make decisions was significantly related to disease status (P = .03) and age (P = 0.02). CONCLUSIONS: Patients are familiar with basic EOLC with optimal timing for discussions at disease progression or when treatment is no longer available. PMID- 22531152 TI - A novel sensor of cysteine self-assembled monolayers over gold nanoparticles for the selective determination of epinephrine in presence of sodium dodecyl sulfate. AB - A novel sensor of cysteine self-assembled monolayers over gold nanoparticles modified gold electrode has been constructed for the determination of epinephrine in presence of sodium dodecyl sulfate (Au/Au(nano)-CysSDS). Electrochemical investigation and characterization of the modified electrode are achieved using cyclic voltammetry, linear sweep voltammetry, and scanning electron microscopy. The Au/Au(nano)-CysSDS electrode current signal is remarkably stable via repeated cycles and long term stability, due to the strong Au-S bond, compared to the Au/Au(nano) electrode. The catalytic oxidation peak currents obtained from linear sweep voltammetry (LSV) increased linearly with increasing epinephrine concentrations in the range of 2 to 30 MUmol L(-1) and 35 to 200 MUmol L(-1) with correlation coefficients of 0.9981 and 0.9999 and a limit of detection of 0.294 nmol L(-1) and 1.49 nmol L(-1), respectively. The results showed that Au/Au(nano) CysSDS can selectively determine epinephrine in the coexistence of a large amount of uric acid and glucose. In addition, a highly selective and simultaneous determination of tertiary mixture of ascorbic acid, epinephrine, and acetaminophen is explored at this modified electrode. Excellent recovery results were obtained for determination of epinephrine in spiked urine samples at the modified electrode. Au/Au(nano)-CysSDS can be used as a sensor with excellent reproducibility, sensitivity, and long term stability. PMID- 22531153 TI - Ionic galleries: a bilayered host-guest cocrystal of C-propyl pyrogallol[4]arene with an ionic liquid. AB - We report on a cocrystal between C-propyl pyrogallol[4]arene and the ionic liquid 1-ethyl-3-methylimidazolium ethylsulfate exhibiting a remarkable bilayer topology comprising two unique host-guest complexes resulting from the ionic liquid cation binding in two distinctive orientations relative to the macrocycle. PMID- 22531154 TI - A role for ubiquitinylation and the cytosolic proteasome in turnover of mitochondrial uncoupling protein 1 (UCP1). AB - In this study we show that mitochondrial uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) and thymus mitochondria can be ubiquitinylated and degraded by the cytosolic proteasome. Using a ubiquitin conjugating system, we show that UCP1 can be ubiquitinylated in vitro. We demonstrate that UCP1 is ubiquitinylated in vivo using isolated mitochondria from brown adipose tissue, thymus and whole brown adipocytes. Using an in vitro ubiquitin conjugating-proteasome degradation system, we show that the cytosolic proteasome can degrade UCP1 at a rate commensurate with the half-life of UCP1 (i.e. 30-72h in brown adipocytes and ~3h, in thymocytes). In addition, we demonstrate that the cytoplasmic proteasome is required for UCP1 degradation from mitochondria that the process is inhibited by the proteasome inhibitor MG132 and that dissipation of the mitochondrial membrane potential inhibits degradation of UCP1. There also appears to be a greater amount of ubiquitinylated UCP1 associated with BAT mitochondria from cold-acclimated animals. We have also identified (using immunoprecipitation coupled with mass spectrometry) ubiquitinylated proteins with molecular masses greater than 32kDa, as being UCP1. We conclude that there is a role for ubiquitinylation and the cytosolic proteasome in turnover of mitochondrial UCP1. This article is part of a Special Issue entitled: 17th European Bioenergetics Conference (EBEC 2012). PMID- 22531155 TI - Bioreducible nanogels/microgels easily prepared via temperature induced self assembly and self-crosslinking. AB - A facile temperature induced self-assembly and self-crosslinking method has been developed for preparing bioreducible nanogels/microgels without need of any stabilizer, catalyst or additional crosslinking agent. The size of formed nanogels/microgels can be easily tuned via the polymer concentration. PMID- 22531156 TI - Formation of CC-type palladacycles with assistance from an apparently innocent NH(CO) functional group. AB - A novel cyclometalation pathway to form CC-type palladacycles is reported. Unlike common donor-assisted cyclometalation, the NH(CO) auxiliary group undergoes a deprotonation step to form a palladalactam intermediate. The coordinating nitrogen atom functions as an intramolecular base promoting selective C-H bond cleavage. Without the NH proton, the ortho-N-phenyl C-H is activated instead. PMID- 22531157 TI - Leadership development for early career doctors. PMID- 22531158 TI - A thermoactive uropygial esterase from chicken: purification, characterisation and synthesis of flavour esters. AB - A lipolytic activity was located in the chicken uropygial glands, from which a carboxylesterase (CUE) was purified. Pure CUE has an apparent molecular mass of 50 kDa. The purified esterase displayed its maximal activity (200 U/mg) on short chain triacylglycerols (tributyrin) at a temperature of 50 degrees C. No significant lipolytic activity was found when medium chain (trioctanoin) or long chain (olive oil) triacylglycerols were used as substrates. The enzyme retained 75% of its maximal activity when incubated during 2h at 50 degrees C. The NH(2) terminal amino acid sequence showed similarities with the esterase purified recently from turkey pharyngeal tissue. Esterase activity remains stable after its incubation during 30 min in presence of organic solvents such as hexane or butanol. CUE is a serine enzyme since it was inactivated by phenylmethanesulphonyl fluoride (PMSF), a serine-specific inhibitor. The purified enzyme, which tolerates the presence of some organic solvent and a high temperature, can be used in non-aqueous synthesis reactions. Hence, the uropygial esterase immobilised onto CaCO(3) was tested to produce the isoamyl and the butyl acetate (flavour esters). Reactions were performed at 50 degrees C in presence of hexane. High synthesis yields of 91 and 67.8% were obtained for isoamyl and butyl acetate, respectively. PMID- 22531159 TI - Diagnosis of intestinal graft-versus-host disease and thrombotic microangiopathy after allogeneic stem cell transplantation. AB - Severe diarrhea is a serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). Acute graft-versus-host disease (GVHD) has been one of the major causes of diarrhea after HSCT, which is triggered by donor-derived cytotoxic T-lymphocytes. On the other hand, intestinal thrombotic microangiopathy (TMA) sometimes coexists with acute GVHD, and intensified immunosuppression to treat acute GVHD could exacerbate intestinal TMA, presumably through the vascular endothelial cell damage. The differential diagnosis between intestinal TMA and acute GVHD of the gut has mainly relied on the pathological findings, as clinical diagnosis of intestinal TMA has not been established. Therefore, we aimed to assess the feasibility of our clinical diagnosis for the patients with diarrhea after HSCT. We made tentative clinical criteria for intestinal TMA and acute GVHD of the gut, based on the clinical manifestations, laboratory data and colonoscopic findings, and started treatment before pathological diagnosis were made. Subsequently, a pathologist retrospectively assessed the accuracy of clinical diagnosis in a blind manner. In this study, we enrolled 19 patients complicating watery diarrhea after HSCT, and diagnosed as having acute GVHD (n = 10), intestinal TMA (n = 3), or both (n = 6) according to our criteria. We demonstrated that our clinical diagnosis for intestinal TMA and acute GVHD of the gut was overall correct, in terms of the response to the therapy and the pathological diagnosis. The present study may provide a clue on making clinical diagnosis of patients with watery diarrhea after HSCT, which enables us to start a prompt therapy. PMID- 22531160 TI - Paneth cells regulate both chemotaxis of immature dendritic cells and cytokine production from epithelial cells. AB - Paneth cells in the small intestine are able to sense luminal bacteria and secrete granules that contain antibacterial peptides. Human defensin (HD)-5 and 6 are antimicrobial peptides found in human Paneth cell granules, and are major bactericidal components. We investigated whether any constituents in the Paneth cell secretions showed chemotactic activity or stimulated cytokine secretion from intestinal epithelial cells, and assessed to what extent HD-5 and -6 were responsible for these activities. The secretions from human Paneth cells and recombinant HD-5 and -6 were evaluated to elucidate their effects on the chemotaxis of dendritic cells (DCs) in a migration assay. The Paneth cell secretions were chemotactic for immature DCs at concentrations ranging from 10 to 1,000 ug/ml. HD-6 was active at 100 ng/ml, but HD-5 was not. Next, the stimulation of cytokine production by the T84 intestinal cell line was assessed using ELISA and/or an antibody array. The secretions more strongly stimulated interleukin (IL)-8 production than did the defensin peptides, and induced production of various cytokines by the antibody array. The secretions were also analyzed by high performance liquid chromatography (HPLC) and mass spectrometry (MS) in order to determine the components. A large number of molecules was found in the secretions, and HD-5 was identified as an immature propeptide. In conclusion, some constituents other than defensin in human Paneth cell secretions activated the migration of DCs and induced the production of inflammatory cytokines. Therefore, Paneth cells may play a role in the innate immunity associated with adaptive immune responses. PMID- 22531162 TI - Vascular imaging in chronic kidney disease. AB - PURPOSE OF REVIEW: The chronic kidney disease (CKD) mineral bone disorder syndrome encompasses a number of metabolic, bone as well as vascular abnormalities of which vascular calcification is a prominent feature. Several noninvasive imaging techniques provide physicians with useful prognostic information beyond traditional cardiovascular and CKD-specific risk factors. We review the most recent evidence on vascular calcification screening as a tool for risk stratification in CKD patients. RECENT FINDINGS: Cardiovascular aging is accelerated and is associated with a poor prognosis in CKD patients. Numerous traditional and nontraditional risk factors have been associated with this outcome. Imaging markers and serological risk factors do not carry the same prognostic information. In fact, whereas serum biomarkers reflect the risk to which the individual is exposed at the time of measurement, imaging markers represent the cumulative result of prolonged exposure to one or multiple risk factors. As such, they have often been demonstrated to be better outcome predictors than serological markers. In some cases, imaging markers have been suggested as desirable targets of therapy or to guide treatment individualization. SUMMARY: Recent evidence suggests that cardiovascular imaging allows for cardiovascular risk stratification and treatment individualization in CKD patients. PMID- 22531161 TI - Bone disease in CKD. AB - PURPOSE OF REVIEW: Fractures are a common problem in chronic kidney disease (CKD). The 2009 KDIGO (Kidney Disease: Improving Global Outcomes) review of the bone and mineral disorders highlighted areas of uncertainty and stressed the importance of further research. This review includes studies published since that report with a focus on the bone. RECENT FINDINGS: Bone biopsies have shown a shift toward more adynamic bone, which may be associated with vascular calcifications. There are important racial differences in skeletal metabolism. Bone density may be helpful in identifying patients who have fractures, but neuromuscular tests perform better than radiographic ones. Even if bone density can predict fractures, it is still not clear what can be done in patients who have advanced stages of CKD. New data show interrelationships of fibroblast growth factor 23 (FGF23) secretion, parathyroid hormone, and wnt-signaling pathways. High FGF23 could have a negative impact on the bone. SUMMARY: These advances suggest that caution must be used prior to treatment with medications that inhibit bone turnover. Racial differences in response to vitamin D therapy need more careful delineation. Medications which inhibit wnt-signaling offer hope but development of new therapies to treat the bone disease will rely on further understanding of bone and vascular physiology. PMID- 22531163 TI - Fibroblast growth factor 23 and the heart. AB - PURPOSE OF REVIEW: Elevated serum levels of the phosphaturic hormone fibroblast growth factor 23 (FGF23) are strongly associated with chronic kidney disease (CKD) progression and mortality, and are also independently associated with left ventricular hypertrophy, a major contributor to cardiovascular disease (CVD) and death in CKD patients. As FGF23 levels rise long before serum phosphate in CKD, FGF23 is a more sensitive biomarker of disordered phosphate metabolism and its associated renal and CVD toxicity. RECENT FINDINGS: This review will address the novel possibility that FGF23 contributes directly to CVD in patients with CKD. We will summarize the basic principles of FGF-mediated signal transduction and review the current literature on effects of FGF family members on the heart as well as FGF23 signaling in 'classic' target cells, in order to flesh out the novelty underlying FGF23-induced cell signaling in the heart. By doing so we will speculate on why such a direct cardiac effect has not been described before, and suggest a novel target for pharmacological intervention. SUMMARY: By demonstrating direct pathological effects of FGF23 on the heart, novel findings from a recent translational study reposition FGF23 from biomarker of risk, to mechanism of disease. Therefore the pharmacological interference with FGF23 and/or its cardiac receptor in CKD patients could be beneficial to prevent or treat CVD. PMID- 22531164 TI - Process technology for multi-enzymatic reaction systems. AB - In recent years, biocatalysis has started to provide an important green tool in synthetic organic chemistry. Currently, the idea of using multi-enzymatic systems for industrial production of chemical compounds becomes increasingly attractive. Recent examples demonstrate the potential of enzymatic synthesis and fermentation as an alternative to chemical-catalysis for the production of pharmaceuticals and fine chemicals. In particular, the use of multiple enzymes is of special interest. However, many challenges remain in the scale-up of a multi-enzymatic system. This review summarizes and discusses the technology options and strategies that are available for the development of multi-enzymatic processes. Some engineering tools, including kinetic models and operating windows, for developing and evaluating such processes are also introduced. PMID- 22531165 TI - Response of poly-phosphate accumulating organisms to free nitrous acid inhibition under anoxic and aerobic conditions. AB - The response of free nitrous acid (FNA)-adapted poly-phosphate accumulating organisms (PAOs) to FNA inhibition under aerobic and anoxic conditions was studied. Anoxic P-uptake was 1-6 times more sensitive to the inhibition compared to aerobic P-uptake. The aerobic nitrite reduction rate increased with FNA concentration, accompanied by an equivalent decrease in the oxygen uptake rate, suggesting under high FNA concentration conditions, electrons were channeled to nitrite reduction from oxygen reduction. In contrast, the nitrite reduction rate decreased with increased FNA concentration under anoxic conditions. Anaerobic metabolism of PAO under both anoxic and aerobic conditions was observed at high FNA concentrations. Growth of PAOs decreased sharply with FNA concentration and stopped completely at FNA concentration of 10 MUg HNO(2)-N/L. This study, for the first time, investigated the function of nitrite/FNA in an aerobic denitrifying phosphate removal process by evaluating electron as well as energy balances, and provides explanation for FNA inhibition mechanisms. PMID- 22531166 TI - Simultaneous heterotrophic nitrification and aerobic denitrification by bacterium Rhodococcus sp. CPZ24. AB - Rhodococcus sp. CPZ24 was isolated from swine wastewater and identified. Batch (0.25 L flask) experiments of nitrogen removal under aerobic growth conditions showed complete removal of 50 mg L(-1) ammonium nitrogen within 20 h, while nitrate nitrogen removal reached 67%. A bioreactor (50 L) was used to further assess the heterotrophic nitrification and aerobic denitrification abilities of Rhodococcus sp. CPZ24. The results showed that 85% of the ammonium nitrogen (100 mg L(-1)) was transformed to nitrification products (NO(3)(-)-N and NO(2)(-)-N) (13%), intracellular nitrogen (24%), and gaseous denitrification products (48%) within 25 h. The ammonium nitrogen removal rate was 3.4 mg L(-1)h(-1). The results indicate that the strain CPZ24 carries out simultaneous nitrification and denitrification, demonstrating a potential use of the strain for wastewater treatment. PMID- 22531167 TI - Enhanced removal of carbon dioxide and alleviation of dissolved oxygen accumulation in photobioreactor with bubble tank. AB - Reduction of carbon loss from the effluent is one of the most important aspects of photobioreactors design. In this study, a novel gas sparger of bubble tank was adopted in a photobioreactor to enhance carbon dioxide (CO(2)) mass transfer rate as well as alleviate dissolved oxygen (DO) accumulation. The results showed that low DO level in the culture can be obtained due to the turbulent hydrodynamic condition provided by the bubble tank. The effects of CO(2) concentration, flow rate of influent, and light intensity on CO(2) removal efficiency were investigated. The maximum CO(2) removal efficiency was 94% at flow rate of 30 mL min(-1), light intensity of 179 MUmol m(-2) s(-1) and CO(2) concentration of 10%, implying that the novel gas sparger is a promising alternative for CO(2) removal from CO(2)-enriched air by cultivating microalgae in the photobioreactor. PMID- 22531168 TI - Electrode contact impedance sensitivity to variations in geometry. AB - Electrode contact impedance is a crucial factor in physiological measurements and can be an accuracy-limiting factor when performing electroencephalography and electrical impedance tomography. In this work, standard flat electrodes and micromachined multipoint spiked electrodes are characterized with a finite element method electromagnetic solver and the dependence of the contact impedance on geometrical factors is explored. It is found that flat electrodes are sensitive to changes in the outer skin layer properties related to hydration and thickness, while spike electrodes are not. The impedance as a function of the effective contact area, number of spikes and penetration depth has also been studied and characterized. PMID- 22531169 TI - Omega-3 biotechnology: errors and omissions. PMID- 22531170 TI - Application of a BRAF V600E mutation-specific antibody for the diagnosis of hairy cell leukemia. AB - In recent times BRAF V600E mutations have emerged as a genetic hallmark of hairy cell leukemia (HCL). This specific point mutation is present in virtually all cases of HCL but is exceedingly rare in other peripheral B-cell neoplasms. In this study we investigated the application of a BRAF V600E mutation-specific antibody (clone VE1) to differentiate HCL from HCL mimics, such as HCL variant and splenic marginal zone lymphoma. A total of 52 routinely processed formalin fixed paraffin-embedded tissue specimens were investigated (bone marrow, n=46; spleen, n=6) for expression of V600E-mutated BRAF protein. All 32 cases of HCL were scored positive, and all non-HCL cases were scored negative. In 28 of 30 HCL cases the presence of a BRAF V600E mutation could be confirmed by direct sequencing, whereas no BRAF mutations were detected among 20 HCL mimics. We further screened 228 mature B-cell neoplasms with VE1 and detected 1 positive case of chronic lymphocytic leukemia. Sequencing confirmed the presence of a BRAF V600E mutation. In conclusion, we demonstrate that VE1 immunohistochemistry can be used to reliably differentiate HCL from HCL-mimicking entities. This on-slide technique might be particularly helpful in interpreting challenging biopsies with low tumor content. PMID- 22531171 TI - Detection of human papillomavirus in small cell carcinomas of the anus and rectum. AB - Small cell carcinomas represent <1% of colorectal/anal carcinomas and have a poor prognosis. Anorectal squamous cell carcinomas are often associated with high-risk human papillomavirus (HPV) infection, similar to squamous and small cell carcinomas of the uterine cervix. In HPV infection, the oncoprotein E7 inactivates the tumor suppressor Rb, leading to p16 upregulation; however, in small cell carcinomas, the Rb pathway is often blocked by other mechanisms; thus, increased p16 may not indicate HPV infection. P16 immunohistochemistry (IHC) may have a limited role in evaluating small cell carcinomas for HPV infection. Formalin-fixed, paraffin-embedded tissue sections of previously diagnosed small cell carcinomas of the anus (n=5) and rectum (n=11) were subjected to IHC for p16, CDX2, and p63, followed by in situ hybridization for high-risk HPV. All (100%) cases of anal and rectal small cell carcinomas were positive for p16, and 100% of anal and 82% of rectal small cell carcinomas were positive for high-risk HPV. The majority of cases showed low or very low HPV copy numbers. In 6 cases, HPV was detected only by using the HPV-16 genotype-specific assay detecting very low copy numbers (1 to 2 viral copies). The majority of tumors expressed p63, which was more pronounced in the anal tumors. CDX2 expression was observed predominantly in rectal tumors. High-risk HPV can be detected using in situ hybridization in the majority of anorectal small cell carcinomas, which are uniformly p16 positive by IHC. HPV-targeted therapy could result in better control of these aggressive neoplasms. PMID- 22531172 TI - Neutrophilic infiltration in gluten-sensitive enteropathy is neither uncommon nor insignificant: assessment of duodenal biopsies from 267 pediatric and adult patients. AB - The histologic findings of celiac disease, that is, gluten-sensitive enteropathy (GSE), are dominated by increased intraepithelial lymphocytes, villous blunting, lymphoplasmacytic infiltration of lamina propria, and crypt hyperplasia. To date, neutrophils have not been thought to constitute a significant cell type in GSE, and their presence often invokes consideration of alternative diagnoses. Thus, we sought to determine the prevalence and severity of neutrophilic infiltration in duodenal biopsies from patients with GSE. The degree of neutrophilic infiltration and features characteristic of GSE were assessed in duodenal biopsies from 267 clinically confirmed GSE patients (116 adults and 151 children). These specimens were graded by the disease activity score (DAS) and the neutrophilic activity score (NAS). Gastric antral biopsies obtained from 195 patients were also evaluated for lymphocytic gastritis. NAS was correlated with DAS and other clinicopathologic features. We found that 56% of pediatric and 28% of adult GSE patients had significant duodenal neutrophilia. NAS was higher in children than in adults (2.3 vs. 1.2, P<0.001). Multivariate regression showed that DAS, eosinophilic infiltration, and foveolar metaplasia correlated positively, and age correlated negatively with NAS. Lymphocytic gastritis was seen in 21.5% of the gastric biopsies. The presence of lymphocytic gastritis correlated positively with NAS and DAS, and in the pediatric population it correlated negatively with age. Significant duodenal neutrophilia is often found in patients with celiac disease, especially in the pediatric population, and is associated with more active disease. Thus, the findings of duodenal neutrophilia in biopsies, otherwise consistent with GSE, should not preclude the diagnosis of GSE. PMID- 22531173 TI - Do adenocarcinomas of the prostate with Gleason score (GS) <=6 have the potential to metastasize to lymph nodes? AB - Although rare, there are cases within reported series of men with Gleason score (GS) <=6 on radical prostatectomies that show pelvic lymph node (LN) metastases. However, there are no studies on whether pelvic LN metastases occur in tumors with GS <=6 using the International Society of Urological Pathology (ISUP) updated GS system. We performed a search of the radical prostatectomy databases at 4 large academic centers for cases of GS <=6. Only prostatectomies submitted and embedded in entirety with pelvic LN dissections were included. A combined total of 14,123 cases were identified, of which 22 cases had a positive LN. Histopathologic review of 19 cases (3 cases unavailable for review) showed higher grade than originally reported by the pathologists in all cases. Of the 17 pre ISUP reviewed cases, 2 were upgraded to 4+3=7 with both cribriform and poorly formed glands. One case was upgraded to 4+3=7 with tertiary pattern 5 displaying cribriform glands, poorly formed glands, and cords of single cells. Eleven cases were upgraded to 3+4=7 with glomeruloid structures and small to large cribriform glands (1 of these also had features of ductal adenocarcinoma). Two cases had tertiary pattern 4 with small cribriform glands. One case had a prominent colloid component that would currently be graded as 4+5=9 because of large cribriform glands and solid sheets of cells within the mucin. Of the 2 post-ISUP cases, 1 demonstrated tertiary pattern 4, and the other showed GS 3+4=7 with irregular cribriform glands. Undergrading is the primary reason for LN positivity with GS <=6, which has decreased significantly since the adoption of the ISUP grading system in 2005. Of over 14,000 totally embedded radical prostatectomies from multiple institutions, there was not a single case of a GS <=6 tumor with LN metastases. In contrast to prevailing assumptions, GS <=6 tumors do not appear to metastasize to LNs. Rather, Gleason pattern 4 or 5, as better defined by the current ISUP updated grading system, is required for metastatic disease. PMID- 22531174 TI - Immunoreactivity for calretinin and keratins in desmoid fibromatosis and other myofibroblastic tumors: a diagnostic pitfall. AB - Calretinin is an intracellular calcium-binding EF-hand protein of the calmodulin superfamily. It plays a role in diverse cellular functions, including message targeting and intracellular calcium signaling. It is expressed in the mesothelium, mast cells, some neural cells, and fat cells, among others. Because of its relative specificity for mesothelial neoplasms, calretinin is widely used as one of the primary immunohistochemical markers for malignant mesothelioma and in differentiating it from adenocarcinoma. On the basis of our sporadic observation on calretinin immunoreactivity in desmoid fibromatosis, we systematically evaluated calretinin, keratin cocktail (AE1/AE3), and WT1 immunoreactivity in 268 fibroblastic/myofibroblastic neoplasms. Calretinin was observed in 75% (44/58) of desmoid fibromatosis, 50% (21/42) of proliferative fasciitis, 23% (8/35) of nodular fasciitis, 33% (13/40) of benign fibrous histiocytoma, 35% (22/62) of malignant fibrous histiocytoma, and 13% (4/31) of solitary fibrous tumors but not in normal connective tissue fibroblasts at various sites. Keratin AE1/AE3 immunoreactivity was also commonly (6/13) present in the large ganglion-like cells of proliferative fasciitis and sometimes in nodular fasciitis (3/35), solitary fibrous tumor (3/27), and malignant fibrous histiocytoma (9/62). Nuclear immunoreactivity for WT1 or keratin 5 positivity was not detected in myofibroblastic tumors. On the basis of these observations, it can be concluded that calretinin and focal keratin immunoreactivity is fairly common in benign and malignant fibroblastic and myofibroblastic lesions. Calretinin-positive and keratin-positive spindle cells in desmoid and nodular fasciitis or calretinin-positive ganglion-like cells in proliferative fasciitis should not be confused with elements of epithelioid or sarcomatoid mesothelioma. These diagnostic pitfalls can be avoided with careful observation of morphology, quantitative differences in keratin expression, and use of additional immunohistochemical markers such keratin 5 and WT1 to verify true epithelial and mesothelial differentiation typical of mesothelioma. PMID- 22531175 TI - Auto-regulatory RNA editing fine-tunes mRNA re-coding and complex behaviour in Drosophila. AB - Auto-regulatory feedback loops are a common molecular strategy used to optimize protein function. In Drosophila, many messenger RNAs involved in neuro transmission are re-coded at the RNA level by the RNA-editing enzyme, dADAR, leading to the incorporation of amino acids that are not directly encoded by the genome. dADAR also re-codes its own transcript, but the consequences of this auto regulation in vivo are unclear. Here we show that hard-wiring or abolishing endogenous dADAR auto-regulation dramatically remodels the landscape of re-coding events in a site-specific manner. These molecular phenotypes correlate with altered localization of dADAR within the nuclear compartment. Furthermore, auto editing exhibits sexually dimorphic patterns of spatial regulation and can be modified by abiotic environmental factors. Finally, we demonstrate that modifying dAdar auto-editing affects adaptive complex behaviours. Our results reveal the in vivo relevance of auto-regulatory control over post-transcriptional mRNA re coding events in fine-tuning brain function and organismal behaviour. PMID- 22531176 TI - Distinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons. AB - Human acute and inflammatory pain requires the expression of voltage-gated sodium channel Nav1.7 but its significance for neuropathic pain is unknown. Here we show that Nav1.7 expression in different sets of mouse sensory and sympathetic neurons underlies distinct types of pain sensation. Ablating Nav1.7 gene (SCN9A) expression in all sensory neurons using Advillin-Cre abolishes mechanical pain, inflammatory pain and reflex withdrawal responses to heat. In contrast, heat evoked pain is retained when SCN9A is deleted only in Nav1.8-positive nociceptors. Surprisingly, responses to the hotplate test, as well as neuropathic pain, are unaffected when SCN9A is deleted in all sensory neurons. However, deleting SCN9A in both sensory and sympathetic neurons abolishes these pain sensations and recapitulates the pain-free phenotype seen in humans with SCN9A loss-of-function mutations. These observations demonstrate an important role for Nav1.7 in sympathetic neurons in neuropathic pain, and provide possible insights into the mechanisms that underlie gain-of-function Nav1.7-dependent pain conditions. PMID- 22531177 TI - Stiffening hydrogels to probe short- and long-term cellular responses to dynamic mechanics. AB - Biological processes are dynamic in nature, and growing evidence suggests that matrix stiffening is particularly decisive during development, wound healing and disease; yet, nearly all in vitro models are static. Here we introduce a step wise approach, addition then light-mediated crosslinking, to fabricate hydrogels that stiffen (for example, ~3-30 kPa) in the presence of cells, and investigated the short-term (minutes-to-hours) and long-term (days-to-weeks) cell response to dynamic stiffening. When substrates are stiffened, adhered human mesenchymal stem cells increase their area from ~500 to 3,000 MUm(2) and exhibit greater traction from ~1 to 10 kPa over a timescale of hours. For longer cultures up to 14 days, human mesenchymal stem cells selectively differentiate based on the period of culture, before or after stiffening, such that adipogenic differentiation is favoured for later stiffening, whereas osteogenic differentiation is favoured for earlier stiffening. PMID- 22531178 TI - The C-terminal helical bundle of the tetrameric prokaryotic sodium channel accelerates the inactivation rate. AB - Most tetrameric channels have cytosolic domains to regulate their functions, including channel inactivation. Here we show that the cytosolic C-terminal region of NavSulP, a prokaryotic voltage-gated sodium channel cloned from Sulfitobacter pontiacus, accelerates channel inactivation. The crystal structure of the C terminal region of NavSulP grafted into the C-terminus of a NaK channel revealed that the NavSulP C-terminal region forms a four-helix bundle. Point mutations of the residues involved in the intersubunit interactions of the four-helix bundle destabilized the tetramer of the channel and reduced the inactivation rate. The four-helix bundle was directly connected to the inner helix of the pore domain, and a mutation increasing the rigidity of the inner helix also reduced the inactivation rate. These findings suggest that the NavSulP four-helix bundle has important roles not only in stabilizing the tetramer, but also in accelerating the inactivation rate, through promotion of the conformational change of the inner helix. PMID- 22531179 TI - Binary colloidal structures assembled through Ising interactions. AB - New methods for inducing microscopic particles to assemble into useful macroscopic structures could open pathways for fabricating complex materials that cannot be produced by lithographic methods. Here we demonstrate a colloidal assembly technique that uses two parameters to tune the assembly of over 20 different pre-programmed structures, including kagome, honeycomb and square lattices, as well as various chain and ring configurations. We programme the assembled structures by controlling the relative concentrations and interaction strengths between spherical magnetic and non-magnetic beads, which behave as paramagnetic or diamagnetic dipoles when immersed in a ferrofluid. A comparison of our experimental observations with potential energy calculations suggests that the lowest energy configuration within binary mixtures is determined entirely by the relative dipole strengths and their relative concentrations. PMID- 22531180 TI - Bilayer order in a polycarbazole-conjugated polymer. AB - One of the best performing semiconducting polymers used in bulk heterojunction devices is PCDTBT, a polycarbazole derivative with solar-conversion efficiencies as high as 7.2%. Here we report the formation of bilayer ordering in PCDTBT, and postulate that this structural motif is a direct consequence of the polymer's molecular design. This bilayer motif is composed of a pair of backbones arranged side-to-side where the alkyl tails are on the outer side. This is in stark contrast to the monolayer ordering found in other conjugated polymers. The crystalline bilayer phase forms at elevated temperatures and persists after cooling to room temperature. The existence of bilayer ordering, along with its high-packing fraction of conjugated moieties, may guide the synthesis of new materials with improved optoelectronic properties. PMID- 22531182 TI - VEGETATIVE1 is essential for development of the compound inflorescence in pea. AB - Unravelling the basis of variation in inflorescence architecture is important to understanding how the huge diversity in plant form has been generated. Inflorescences are divided between simple, as in Arabidopsis, with flowers directly formed at the main primary inflorescence axis, and compound, as in legumes, where they are formed at secondary or even higher order axes. The formation of secondary inflorescences predicts a novel genetic function in the development of the compound inflorescences. Here we show that in pea this function is controlled by VEGETATIVE1 (VEG1), whose mutation replaces secondary inflorescences by vegetative branches. We identify VEG1 as an AGL79-like MADS-box gene that specifies secondary inflorescence meristem identity. VEG1 misexpression in meristem identity mutants causes ectopic secondary inflorescence formation, suggesting a model for compound inflorescence development based on antagonistic interactions between VEG1 and genes conferring primary inflorescence and floral identity. Our study defines a novel mechanism to generate inflorescence complexity. PMID- 22531181 TI - Bats host major mammalian paramyxoviruses. AB - The large virus family Paramyxoviridae includes some of the most significant human and livestock viruses, such as measles-, distemper-, mumps-, parainfluenza , Newcastle disease-, respiratory syncytial virus and metapneumoviruses. Here we identify an estimated 66 new paramyxoviruses in a worldwide sample of 119 bat and rodent species (9,278 individuals). Major discoveries include evidence of an origin of Hendra- and Nipah virus in Africa, identification of a bat virus conspecific with the human mumps virus, detection of close relatives of respiratory syncytial virus, mouse pneumonia- and canine distemper virus in bats, as well as direct evidence of Sendai virus in rodents. Phylogenetic reconstruction of host associations suggests a predominance of host switches from bats to other mammals and birds. Hypothesis tests in a maximum likelihood framework permit the phylogenetic placement of bats as tentative hosts at ancestral nodes to both the major Paramyxoviridae subfamilies (Paramyxovirinae and Pneumovirinae). Future attempts to predict the emergence of novel paramyxoviruses in humans and livestock will have to rely fundamentally on these data. PMID- 22531183 TI - First enantioseparation and circular dichroism spectra of Au38 clusters protected by achiral ligands. AB - Bestowing chirality to metals is central in fields such as heterogeneous catalysis and modern optics. Although the bulk phase of metals is symmetric, their surfaces can become chiral through adsorption of molecules. Interestingly, even achiral molecules can lead to locally chiral, though globally racemic, surfaces. A similar situation can be obtained for metal particles or clusters. Here we report the first separation of the enantiomers of a gold cluster protected by achiral thiolates, Au(38)(SCH(2)CH(2)Ph)(24), achieved by chiral high-performance liquid chromatography. The chirality of the nanocluster arises from the chiral arrangement of the thiolates on its surface, forming 'staple motifs'. The enantiomers show mirror-image circular dichroism responses and large anisotropy factors of up to 4*10(-3). Comparison with reported circular dichroism spectra of other Au(38) clusters reveals that the influence of the ligand on the chiroptical properties is minor. PMID- 22531184 TI - Prominent electrochromism through vacancy-order melting in a complex oxide. AB - Electrochromes are materials that have the ability to reversibly change from one colour state to another with the application of an electric field. Electrochromic colouration efficiency is typically large in organic materials that are not very stable chemically. Here we show that inorganic Bi(0.9)Ca(0.1)FeO(3-0.05) thin films exhibit a prominent electrochromic effect arising from an intrinsic mechanism due to the melting of oxygen-vacancy ordering and the associated redistribution of carriers. We use a combination of optical characterization techniques in conjunction with high-resolution transmission electron microscopy and first-principles theory. The absorption change and colouration efficiency at the band edge (blue-cyan region) are 4.8*10(6) m(-1) and 190 cm(2) C(-1), respectively, which are the highest reported values for inorganic electrochromes, even exceeding values of some organic materials. PMID- 22531185 TI - Scalable architecture for a room temperature solid-state quantum information processor. AB - The realization of a scalable quantum information processor has emerged over the past decade as one of the central challenges at the interface of fundamental science and engineering. Here we propose and analyse an architecture for a scalable, solid-state quantum information processor capable of operating at room temperature. Our approach is based on recent experimental advances involving nitrogen-vacancy colour centres in diamond. In particular, we demonstrate that the multiple challenges associated with operation at ambient temperature, individual addressing at the nanoscale, strong qubit coupling, robustness against disorder and low decoherence rates can be simultaneously achieved under realistic, experimentally relevant conditions. The architecture uses a novel approach to quantum information transfer and includes a hierarchy of control at successive length scales. Moreover, it alleviates the stringent constraints currently limiting the realization of scalable quantum processors and will provide fundamental insights into the physics of non-equilibrium many-body quantum systems. PMID- 22531187 TI - Management of hypothermia: impact of lecture-based interactive workshops on training of pediatric nurses. AB - This study aimed to determine the efficacy of interactive workshop on the management of hypothermia and its impact on pediatric nurses' training. This is a pretest-to-posttest quasi-experimental descriptive study. Thirty pediatric nurses attended an interactive lecture-based interactive workshop on the management of hypothermia. Participants had to accept an invitation to the presentation before the training event. They completed the lecture, and a multiple-choice question test before and after the lecture was given. There was a significant improvement in mean test scores after the lecture when compared with those before the lecture (mean [SD], 15.5 [1.3] vs 5.0 [1.7], P < 0.001). The information gained in this study will be valuable as a baseline for further research and help guide improvements in the management of hypothermia with the ultimate goal of enhancing safe and quality patient care. PMID- 22531186 TI - Predictors of ventricular shunt infection among children presenting to a pediatric emergency department. AB - OBJECTIVES: Among a population of children with a ventricular shunt presenting to a pediatric emergency department (ED), and in whom cerebrospinal fluid (CSF) was obtained, we sought to (1) determine the rate of positive CSF bacterial culture and (2) identify clinical predictors of ventricular shunt infection. METHODS: We performed a retrospective cohort study of children 3 months to 21 years of age evaluated in a single pediatric tertiary ED from 1995 to 2008. All included children had CSF obtained within 24 hours of presentation to the ED. A shunt infection was defined by growth of bacteria in the CSF of a child who underwent shunt removal within 7 days of presentation. RESULTS: Nine hundred seventy-nine children met the inclusion criteria; 130 patients (13%) had growth of bacteria in CSF, of which 58 (5.9% of total) had a shunt infection. The median time since last shunt revision or replacement was shorter for patients with a shunt infection compared with children without shunt infection (44 vs 209 days, P = 0.001). After adjustment for patient age, the following factors were associated with shunt infection: shunt revision within the prior 90 days (adjusted odds ratio [aOR], 2.4; 95% CI, 1.3-4.4), presence of fever (aOR, 8.4; 95% CI, 4.3 16.3), and white blood cell count greater than 15,000/MUL (aOR, 3.2; 95% CI, 1.5 6.6). CONCLUSIONS: Among children with a ventricular shunt who had CSF obtained in the ED, the presence of recent shunt revision, fever, and leukocytosis was associated with ventricular shunt infection. PMID- 22531188 TI - REDUCE-PCP study: radiographs in the emergency department utilization criteria evaluation-pediatric chest pain. AB - BACKGROUND: Many emergency physicians order chest x-rays (CXRs) for pediatric patients who present with a chief complaint of chest pain despite a paucity of research to support this testing, which exposes patients to radiation, cost, and delays. OBJECTIVES: This study aimed to begin development of a decision making tool that will allow emergency physicians to selectively obtain CXR films in pediatric patients presenting with chest pain. METHODS: We performed a retrospective cohort study of 400 consecutive pediatric patients with a chief complaint of chest pain and reviewed charts to determine how many received a CXR and which clinical characteristics were present in all patients. Chest radiograph findings were graded for significance as follows: (1) no or minor clinical significance: normal result in the CXR film without effect on the immediate evaluation of a patient; (2) moderate clinical significance: only impact on plan for follow-up; and (3) major clinical significance: result in the CXR film directly affects immediate management. We then evaluated each chart for historical or examination findings that might identify criteria associated with positive radiographic findings to propose a set of criteria that could lead to the development of a decision rule that allows a reduced utilization while having a high sensitivity for clinically significant positive findings on CXR film. RESULTS: Of the 400 pediatric patients reviewed, 63.5% (n = 254) received a CXR in the emergency department (ED). Of those receiving a CXR, only 8.26% (n = 21) had a finding that affected either ED management or follow-up planning. The criteria that would have identified all patients with positive results in the CXR films were abnormal vital signs, shortness of breath, palpitations, presence of comorbidities, abnormal or unilateral breath sounds, history of trauma, murmur, or cough. CONCLUSIONS: This pilot study demonstrates the potential for a decision rule to eliminate both cost and radiation exposure by using defined criteria to determine the need for a CXR in pediatric ED patients. We identified 8 simple criteria that would have identified all children who benefited from a CXR in this study. The next phase of this study will prospectively evaluate the utility of each of the criteria as part of a draft decision rule. PMID- 22531189 TI - Pediatric all-terrain vehicle trauma: the epidemic continues unabated. AB - OBJECTIVES: The popularity of all-terrain vehicles (ATVs) continues to increase, but this form of recreation is not as well regulated and can impact children disproportionately. This study examines the epidemiology of ATV injuries in Arizona with emphasis on pediatric injuries and compares ATV injuries to those associated with motorcycle (MCC) and motor vehicle crashes (MVC). METHODS: The trauma registry of a level 1 trauma center was used to identify all ATV crashes during a 5-year period (2004-2008) in patients younger than 16 years. Registration data of ATV were obtained from the state DMV. All-terrain vehicle related injuries were compared with both MVC and MCC. RESULTS: A total of 250 pediatric ATV crashes were observed during the 5-year period, rising from 29 in 2004 to 53 in 2008. The median age of patients with ATV-related injuries was 13 years, which is higher than that of patients with MVC-related injuries (9 years). Only 34% of the patients with ATV-related injuries were helmeted, compared with 55% of patients with MCC-related injuries. All-terrain vehicle-related crashes were at least 30 times more likely than MVCs and almost 20 times more likely than MCCs. Statewide pediatric ATV deaths rose during the study period. CONCLUSIONS: All-terrain vehicle-related crashes have increased during this study period and have become a significant source of injuries. Public education and awareness of the dangers associated with ATV use need to be targeted toward both parents and children likely to use ATVs. PMID- 22531191 TI - Clinical manifestations in children with ruptured appendicitis. AB - OBJECTIVES: Appendicitis is the most common abdominal condition leading to urgent surgery in children. With the goal of identifying signs and symptoms that will allow prompt diagnosis of rupture of the appendix and thus decrease associated morbidities, our aim was to determine factors associated with ruptured appendicitis in children diagnosed with appendicitis. METHODS: The medical records of children aged 17 years or younger with a postoperative diagnosis of acute appendicitis treated at Cathay General Hospital, Taipei, Taiwan, from January 2002 and May 2009, were retrospectively reviewed. The patients were divided into with and without ruptured appendicitis. RESULTS: Of the 228 patients, 140 had a postoperative pathological diagnosis of a nonperforated appendix, and 88 had a diagnosis of perforated appendix, resulting in a perforation rate of 38.6%. Younger age, longer duration of abdominal pain, fever, muscle guarding, and elevated C-reactive protein level were significantly associated with a perforated appendix. CONCLUSIONS: Younger age, longer duration of abdominal pain, fever, muscle guarding, and elevated C-reactive protein level are significantly associated with a perforated appendix; these factors should be closely considered in the evaluation of individuals with suspected appendicitis. PMID- 22531190 TI - Flumazenil administration in poisoned pediatric patients. AB - OBJECTIVE: The goal of this retrospective cohort study of pediatric patients exposed to flumazenil was to identify the frequency of seizures. METHODS: Included patient were those aged 12 years or younger who received flumazenil, who had evidence of clinical poisoning as defined by an altered mental status, and who were reported to the California Poison Control System for the period 1999 to 2008. Data variables were age, sex, seizure, death, acute exposure to a benzodiazepine, drugs of exposure, long-term use of benzodiazepines, history of a seizure disorder, mental status before flumazenil administration, and poison center recommendation of flumazenil (yes/no). RESULTS: Eighty-three patients were included. Forty-eight (58%) of this subset were female. Median age was 2 years (range, 3 months-12 years). Seventy (84%) patients were younger than 5 years. Of the 83 patients, 68 (82%) were allegedly exposed to a benzodiazepine; whereas, 12 (15%) had been allegedly exposed to a proconvulsant drug. No flumazenil-related seizures occurred (0% with 95% confidence interval, 0%-4%). The California Poison Control System recommended flumazenil use in 60 (72%) of the 83 cases, and 48 of these had been allegedly exposed to a benzodiazepine. CONCLUSIONS: No flumazenil associated seizures occurred among allegedly benzodiazepine- and non benzodiazepine-poisoned pediatric patients aged 12 years or younger. PMID- 22531192 TI - Challenging assumptions about uninsured children in the pediatric emergency department. AB - OBJECTIVE: Emergency departments (EDs) are experiencing increased volumes and crowding problems. Although crowding is often blamed on uninsured patients, the role of uninsured children is unclear. We compared ED use by insured and uninsured children. METHODS: Parents of children presenting at a tertiary care pediatric hospital ED were surveyed to determine health insurance coverage and frequency of ED use. Hospital billing records were reviewed separately to validate our survey results. Results were compared with Census Bureau data on the prevalence of uninsured children. RESULTS: We enrolled 2024 participants in the survey arm. Of all children 48.4% (n = 972) were privately insured, 42.1% (n = 846) have government insurance, and 9.5% (n = 191) were uninsured. Billing records showed that 10.2% (n = 3825) of pediatric ED patients during the previous year were uninsured. Census data showed that 13% of children statewide were uninsured. Among survey subjects, uninsured children were more likely than privately insured children (53% vs 42%), but less likely than children with government insurance (67%), to have moderate ED use (>=1 additional ED visit in 12 months; P < 0.001) or frequent ED use (>=5 visits in 12 months; 4% vs 2% vs 8%; P < 0.001). When private and government insurance categories were combined, uninsured children showed no greater likelihood of moderate ED use (53% vs 53%, P = 0.89) or frequent ED use (4% vs 5%, P = 0.71) than insured children did. CONCLUSIONS: Uninsured pediatric patients were not disproportionately represented in the ED population. Moreover, uninsured children were not more likely than insured children to be moderate or frequent ED users. PMID- 22531193 TI - Induction dose of propofol for pediatric patients undergoing procedural sedation in the emergency department. AB - OBJECTIVE: This study aimed to determine if patient age is an independent predictor of the propofol dose required for the induction of sedation in pediatric patients for procedures performed in the emergency department (ED). METHODS: This is a retrospective study conducted in an academic, tertiary ED between May 2005 and October 2009. Medical records of patients younger than 18 years who received propofol for procedural sedation were evaluated. Data collected included patient demographics, procedure type, propofol doses administered, time to sedation induction, pain scores before procedure, opioid administration, and adverse effects. Factors predictive of propofol induction dose were analyzed using linear regression analyses. RESULTS: Eighty-eight patients were included in the final analyses. The mean age was 11 years (range, 1 17 years), and 75% were male. The mean induction dose required was 2.1 +/- 1.3 mg/kg using a median of 3 boluses (interquartile range, 2-4). The mean time to induction was 3.9 +/- 4.2 minutes. In the linear regression analyses (R = 0.07), patient age was inversely predictive of the induction dose (in milligram per kilogram) of propofol (coefficient = -0.074; P = 0.013). Sex, race, procedure type, pain score before procedure, and opioid administration were not predictive of induction dose. Transient respiratory depression occurred in 13.6% and hypotension occurred in 8% of patients, without further complications. CONCLUSIONS: In pediatric patients undergoing procedural sedation in the ED, age is an independent predictor of the dose of propofol required for induction of sedation. Therefore, younger patients may require higher doses by body weight (in milligram per kilogram). PMID- 22531195 TI - Ultrasound evaluation of skull fractures in children: a feasibility study. AB - OBJECTIVE: The objective of this study was to investigate feasibility and evaluate test characteristics of bedside ultrasound for the detection of skull fractures in children with closed head injury (CHI). METHODS: This was a prospective, observational study conducted in a pediatric emergency department of an urban tertiary care children's hospital. A convenience sample of children younger than 18 years were enrolled if they presented with an acute CHI, and a computed tomography (CT) scan was performed. Ultrasound was performed by pediatric emergency medicine physicians with at least 1 month of training in bedside ultrasound. Ultrasound interpretation as either positive or negative for the presence of skull fracture was compared with attending radiologist CT scan dictation. Test characteristics (sensitivity, specificity, and positive and negative predictive values) were calculated. RESULTS: Forty-six patients were enrolled. The median age was 2 years (range, 2 months to 17 years). Eleven patients (24%) were diagnosed with skull fractures on CT scan. Bedside ultrasound had a sensitivity of 82% (95% confidence interval [CI], 48%-97%), specificity of 94% (95% CI, 79%-99%), positive predictive value of 82% (95% CI, 48%-97%), and negative predictive value of 94% (95% CI, 79%-99%). CONCLUSIONS: Bedside ultrasonography can be used by pediatric emergency medicine physicians to detect skull fractures in children with acute CHI. Larger studies are needed to validate these findings. Future studies should investigate the role of this modality as an adjunct to clinical decision rules to reduce unnecessary CT scans in the evaluation of acute CHI in children. PMID- 22531194 TI - Utility of plain radiographs in detecting traumatic injuries of the cervical spine in children. AB - OBJECTIVE: The objective of this study was to estimate the sensitivity of plain radiographs in identifying bony or ligamentous cervical spine injury in children. METHODS: We identified a retrospective cohort of children younger than 16 years with blunt trauma-related bony or ligamentous cervical spine injury evaluated between 2000 and 2004 at 1 of 17 hospitals participating in the Pediatric Emergency Care Applied Research Network. We excluded children who had a single or undocumented number of radiographic views or one of the following injuries types: isolated spinal cord injury, spinal cord injury without radiographic abnormalities, or atlantoaxial rotary subluxation. Using consensus methods, study investigators reviewed the radiology reports and assigned a classification (definite, possible, or no cervical spine injury) as well as film adequacy. A pediatric neurosurgeon, blinded to the classification of the radiology reports, reviewed complete case histories and assigned final cervical spine injury type. RESULTS: We identified 206 children who met inclusion criteria, of which 127 had definite and 41 had possible cervical spine injury identified by plain radiograph. Of the 186 children with adequate cervical spine radiographs, 168 had definite or possible cervical spine injury identified by plain radiograph for a sensitivity of 90% (95% confidence interval, 85%-94%). Cervical spine radiographs did not identify the following cervical spine injuries: fracture (15 children) and ligamentous injury alone (3 children). Nine children with normal cervical spine radiographs presented with 1 or more of the following: endotracheal intubation (4 children), altered mental status (5 children), or focal neurologic findings (5 children). CONCLUSIONS: Plain radiographs had a high sensitivity for cervical spine injury in our pediatric cohort. PMID- 22531196 TI - C-reactive protein and procalcitonin are predictors of the severity of acute appendicitis in children. AB - OBJECTIVE: The aim of this study was to evaluate the use of procalcitonin (PCT) and C-reactive protein (CRP) on admission as predictors of the severity of appendicitis in children. METHODS: We prospectively studied 111 consecutive patients admitted with a diagnosis of acute appendicitis between July 2009 and February 2010 and recorded the following variables: age, sex, time since diagnosis, laboratory data, complications (abscess, intestinal obstruction), presence of hemodynamic instability, mortality, length of stay, and need for admission to the pediatric intensive care unit. Patients were divided into 2 groups according to the diagnosis confirmed during surgery (group 1, appendicitis; group 2, localized or generalized peritonitis). RESULTS: Group 1 comprised 69 patients, and group 2 comprised 42 patients. Procalcitonin and CRP values were significantly lower in group 1 than in group 2 (0.15 vs 4.95 ng/mL [P < 0.001] and 3 vs 14.3 mg/dL [P < 0.001]). For a diagnosis of peritonitis, a PCT cutoff of 0.18 ng/mL gave a sensitivity of 97%, specificity of 80%, positive predictive value of 72%, and negative predictive value of 89.3%. The equivalent values for a CRP cutoff of 3 mg/dL were 95%, 74%, 68%, and 96.2%. Complications and the need for admission to the pediatric intensive care unit were more common in patients with peritonitis. CONCLUSIONS: On admission, CRP and PCT predict the outcome of pediatric patients with appendicitis. Children with CRP greater than 3 mg/dL and/or PCT greater than 0.18 ng/mL have a greater risk of complications; thus, intervention should be early, and patients should be monitored closely. PMID- 22531197 TI - Serum procalcitonin concentration in the evaluation of febrile infants 2 to 60 days of age. AB - OBJECTIVE: Febrile infants younger than 60 days are at risk for serious bacterial infections (SBIs) and often undergo extensive laboratory investigation and hospitalization. We aim to determine the diagnostic value of serum procalcitonin (PCT) concentration for identification of febrile infants at low risk for SBI in comparison to the Rochester Criteria (RC). METHODS: Infants 2 to 60 days of age with rectal temperature 38 degrees C were enrolled between May 2004 and March 2007. Blood was obtained from each, and PCT was assessed using BRAHMS PCT LIA method. Information for identification of low-risk infants using RC was obtained. Negative predictive value, sensitivity, specificity, and likelihood ratio of PCT were compared with the RC. In univariate analysis, the components of RC and PCT were considered. Variables holding a significant association with the absence of SBI were included in a backward stepwise logistic regression model with SBI as the dependent variable, creating new low risk criteria. RESULTS: One hundred fifty-five patients were enrolled. Thirteen (8.4%) had an SBI. Procalcitonin concentration at a cutoff value of 0.26 ng/mL is similar in sensitivity (92%) and better in specificity (64%) than RC. A combination of urine white blood cell and PCT was the best model in the regression analysis. CONCLUSIONS: Procalcitonin concentration is a serological marker for identification of or exclusion of SBI in infants aged 2 to 60 days. The predictive value of PCT in combination with urinary white blood cell count may be clinically useful. A validation study is indicated. PMID- 22531198 TI - Decreasing adverse outcomes of unmodified electroconvulsive therapy: suggestions and possibilities. AB - Electroconvulsive therapy (ECT) is far and away the most effective treatment for depression and quite effective for a range of other psychiatric conditions that are unresponsive to medication. Electroconvulsive therapy in the developed world has been administered with anesthesia, muscle relaxants, and ventilation since the mid-1950s following 20 years of unmodified treatment. However, in much of the developing world, ECT continues to be administered unmodified because of lack of resources. We review the efficacy of unmodified compared with modified treatment. We also review the potential drawbacks of unmodified treatment including fear and anxiety, worse postictal confusion, fracture risk, and the negative effects of unmodified treatment on how ECT is perceived in the general community. Finally, we consider potential solutions in developing countries to minimize adverse outcomes of unmodified treatment by pretreating patients either with low-dose benzodiazepines or sedating, but not anesthetizing, dosages of anesthetic agents. Randomized controlled trials are necessary before either of these options could be considered an acceptable alternative to completely unmodified treatment when modified treatment is unavailable. PMID- 22531200 TI - Use of electroconvulsive therapy in Parkinson disease with residual axial symptoms partially unresponsive to L-dopa: a pilot study. AB - INTRODUCTION: Mental dysfunction and especially gait disorders, such as freezing and postural instability in "on phase," are partially unresponsive to dopaminergic therapy late in the course of Parkinson disease (PD). Some of them have been related to decreased sensitivity of postsynaptic dopaminergic receptors, and it is known that electroconvulsive therapy (ECT) enhances the sensitivity of these receptors. The aim of this study was to determine the efficacy and safety of ECT in patients with advanced Parkinson disease with symptoms partially unresponsive to L-dopa. METHODS: Neurologic (Parkinson's Disease Questionnaire, Unified Parkinson's Disease Rating Scale, Tinetti Scale, and the Sit-to-Stand test), psychiatric (structured interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and Hamilton Depression Rating Scale) and neuropsychological (Mini Mental State Examination, executive functions, declarative and procedural memory, visual processing, and reaction time) evaluation was performed on 9 patients with a diagnosis of L-dopa resistant PD by the Movement Disorders Working Group. This evaluation was done before and after 8 sessions of bitemporal ECT. Six patients completed the study. RESULTS: Statistically significant differences were found in the number of steps and freezing episodes in the on phase when they were compared before and after the ECT administration. However, no statistically significant differences were found in the "off" phenomena, motor fluctuations, or dyskinesias before and after ECT administration. No patient showed psychiatric symptoms before, during, or after the ECT. No statistically significant differences were observed in the neuropsychological results between the pretreatment and posttreatment evaluations. All patients showed transient amnesia after the ECT administration, which lasted for 48 hours. CONCLUSIONS: Electroconvulsive therapy could be a safe and effective therapeutic option in L-dopa-resistant patients with PD with predominantly axial "on" phenomena; nevertheless, it needs to be confirmed in later studies. PMID- 22531199 TI - Long-term follow-up of adolescents with resistant depression treated with repetitive transcranial magnetic stimulation. AB - OBJECTIVE: There is a paucity of information about repetitive transcranial magnetic stimulation (rTMS) as a treatment for adolescent depression, and there are no data about its long-term effectiveness and safety in this age group. The aim of this study was to evaluate symptoms of depression and cognitive functioning in young people who had been treated 3 years previously with rTMS for resistant depression. METHODS: Eight of 9 subjects who had participated in an open-label rTMS study were reassessed using the Child and Adolescent Depression Rating Scale-Revised and the Beck Depression Inventory II. Six of the subjects were also cognitively reassessed using the Cambridge Neuropsychological Test Automated Battery. The follow-up assessments were compared with the earlier pretreatment, inter-treatment and posttreatment assessments. RESULTS: At 3-year follow-up, there was no evidence of deterioration in symptoms of depression or cognitive functioning compared to the last assessment after rTMS. CONCLUSION: Preliminary evidence suggests that rTMS treatment of resistant depression in adolescents is not associated with long-term cognitive deterioration and that posttherapy clinical improvement can be maintained. It seems that some subjects may derive long-term benefit from the rTMS course. PMID- 22531201 TI - Long-term treatment strategies in major depression: a 2-year prospective naturalistic follow-up after successful electroconvulsive therapy. AB - OBJECTIVE: To describe a 2-year follow-up in a cohort of patients with major depressive disorder treated with pharmacotherapy plus a short-term course of electroconvulsive therapy (ECT) over the index episode. METHODS: This naturalistic study included 127 patients. After remission, the same pharmacotherapy regimen was maintained in all patients, whereas 44 also received continuation/maintenance ECT (C/M-ECT). Demographic and clinical data were reported for patients with pharmacotherapy and patients with pharmacotherapy and C/M-ECT. The clinical course of the disorder was compared two years before and after index episode remission. RESULTS: Continuation/maintenance ECT was more prescribed in men and in those patients with more previous episodes and admissions and higher treatment resistance. Longer duration of index episode and greater number of episodes in the previous 2 years were identified as risk factors for relapse/recurrence. Furthermore, in our sample, a significant improvement of the illness course after remission was observed after successful ECT. CONCLUSION: Both treatments were effective as maintenance strategies for depressive patients who showed complete response to an acute ECT course. According to our observations, pharmacotherapy both alone and plus C/M-ECT may potentially be considered as long-term treatments after successful ECT in patients with severe major depressive disorder. PMID- 22531202 TI - Exceptionally high initial seizure threshold in a patient treated with electroconvulsive therapy: a case report. AB - OBJECTIVES: Seizure threshold in electroconvulsive therapy (ECT) is defined as the smallest dose of electrical stimulus that produces a generalized seizure of at least 25 to 30 seconds as recorded by electroencephalography. Seizure thresholds vary considerably, with some patients demonstrating an exceptionally high initial seizure threshold. This case report describes a patient with schizoaffective disorder and an initial seizure threshold exceeding 1100 millicoulombs (mC), higher than can be delivered by the ECT device used. METHODS: A review of the literature was carried out to identify other reports of the phenomena. RESULTS: Six articles reporting on 9 patients with mental illness and exceptionally high initial seizure thresholds were identified. These reports were of mainly elderly patients treated for severe depression. The initial seizure thresholds ranged from 335 to 896 mC. In 6 of the 9 cases, ECT was given bilaterally; and in these cases, the median initial seizure threshold was 624 mC (interquartile range, 274 mC). CONCLUSIONS: Patients with exceptionally high initial seizure thresholds are rare, and few have been reported in the literature. The initial seizure threshold described in this case report is well in excess of others previously reported. The report highlights the potential for raised seizure thresholds in those taking mood-stabilizing antiepileptic medication. PMID- 22531203 TI - Electroconvulsive therapy in Bulgaria: a snapshot of past and present. AB - INTRODUCTION: Whereas the use of electroconvulsive therapy (ECT) has been frequently surveyed in Western Europe, information about the practice of ECT in Eastern Europe is limited. To date, there has been no information about the present state of ECT use in Bulgaria. OBJECTIVE: The aim of this project was to survey current ECT practice in Bulgaria. MATERIALS AND METHODS: A semi-structured questionnaire on the practice of ECT was mailed or e-mailed to all psychiatric inpatient facilities in Bulgaria seeking information about the year 2010. RESULTS: Only 4 inpatient facilities (all university departments) located in Sofia confirmed the use of ECT in 2010. The main indication of ECT was depression, and most of the patients were women. Three of the 4 centers used modern machines for electroencephalographic and electromyographic monitoring. DISCUSSION: This was the first nationwide survey of ECT practice in Bulgaria since 1982. The frequency of ECT use was similarly low as in other Eastern European countries. Approximately 12% of the psychiatric inpatient facilities in Bulgaria offered ECT in 2010, all in the capital city. The lack of availability of ECT outside the capital raises serious concerns about the accessibility of psychiatric care for patients with severe disorders responsive to ECT in other parts of the country. PMID- 22531204 TI - Effects of electroconvulsive stimulation on long-term potentiation and synaptophysin in the hippocampus of rats with depressive behavior. AB - OBJECTIVES: To evaluate the effects of electroconvulsive stimulation (ECS) on long-term potentiation (LTP) and synaptophysin (SYP) in the hippocampus of rats under chronic unpredictable mild stress (CUMS). METHODS: Sixty Sprague-Dawley rats were randomly divided into three groups (n=20 for each group): the control group (no intervention), the CUMS group (subjected to 28 days of CUMS exposure followed by 7 days of mock ECS treatment), and the CUMS+ECS group (subjected to 28 days of CUMS exposure followed by 7 days of ECS treatment). Depressive behavior was assessed by a sucrose preference test and an open-field test. The LTP levels in rat hippocampal slices were examined through electrophysiological experiments. The SYP mean density in the hippocampal CA3 region was detected by immunohistochemistry. Hippocampal SYP mRNA was assessed through reverse transcriptase-polymerase chain reaction. RESULTS: Chronic unpredictable mild stress diminished sucrose preference and reduced measures of locomotor activity. In addition, CUMS impaired LTP in the hippocampal CA1 region and significantly decreased SYP mean density in the hippocampal CA3 region and hippocampal SYP mRNA levels. Electroconvulsive stimulation improved these harmful behavioral effects and ameliorated LTP impairment, as well as stabilized SYP mean density in the hippocampal CA3 region and hippocampal SYP mRNA levels. CONCLUSIONS: These results suggest that ECS can reverse the harmful behavioral effects of CUMS in rats and that the behavioral alterations induced by ECS and/or CUMS may be associated with hippocampal neuroplasticity and SYP levels. PMID- 22531205 TI - Comparing efficacy of ECT with and without concurrent sodium valproate therapy in manic patients. AB - OBJECTIVES: There is mixed evidence as to the merits of continuing versus discontinuing medication with anticonvulsants before starting electroconvulsive therapy (ECT) in patients with manic episodes. The aim of the present study was therefore to compare, in a controlled double-blind randomized clinical trial, treatment improvements and treatment outcome in patients with current manic episodes while treated with ECT with and without concurrent sodium valproate therapy. METHODS: A total of 42 inpatients (mean [SD] age, 32.1 [9.6]; 88% men) with bipolar disorders and currently during a manic state took part in the study. They were randomly assigned either to the target group (continuation of sodium valproate administration; minimum, 750 mg/d) or to the control group (discontinuation of sodium valproate administration). All patients underwent bifrontal ECT for at least 6 sessions. Improvements were rated with the Young Mania Rating Scale and the Clinical Global Impression (CGI; CGI-Severity of Illness, and CGI-Improvement). RESULTS: Manic episodes as assessed by the Young Mania Rating Scale and CGI improved significantly over time and irrespective of group (target vs control group). CONCLUSIONS: The pattern of results from this double-blind randomized clinical trial suggests that continuing administration of the anticonvulsant sodium valproate does neither adversely affect nor enhance the efficacy of ECT inpatients with manic episodes. PMID- 22531206 TI - Remifentanil added to propofol for induction of anesthesia can reduce reorientation time after electroconvulsive therapy in patients with severe mania. AB - OBJECTIVES: To investigate the effect of adding remifentanil to propofol used in the induction of anesthesia in efficacy, and to investigate the cognitive adverse effects of electroconvulsive therapy (ECT) in the treatment of patients with severe mania. METHODS: Thirty-eight patients' condition was diagnosed as manic episode by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and were prescribed ECT by their physicians were included in a double-blind study and were randomly allocated to receive premedication with either remifentanil-atropine (study) or saline-atropine (control). Induction of anesthesia was done with propofol (1 mg/kg) and succinylcholine (0.5 mg/kg) in all patients. Assessments included seizure duration, Young Mania Rating Scale (YMRS), Mini-Mental State Examination (MMSE), and immediate cognitive adverse effects. RESULTS: Twenty-nine patients with 98 ECT sessions completed treatment. There were no differences between the 2 groups in relation to age, sex, duration of disease, weight, marital status, seizure duration, YMRS, and MMSE. However, immediate cognitive adverse effects were significantly lower in remifentanil group. PMID- 22531207 TI - Maintenance ECT as a therapeutic approach to medication-refractory epilepsy in an adult with mental retardation: case report and review of literature. AB - BACKGROUND: Electroconvulsive therapy (ECT) raises the seizure threshold. This physiological change may benefit patients with seizure disorders. Whereas ECT has recently been used to terminate medication-refractory status epilepticus, there is little current literature on its planned administration as a specific maintenance treatment for medication-refractory epilepsy. METHODS: We used maintenance ECT to treat an 18-year-old man with a long-standing generalized tonic-clonic seizure disorder who had shown poor response to several antiepileptic drugs administered in combination with antiepileptic medication compliance confirmed through drug level monitoring. RESULTS: A total of 52 ECTs were administered across nearly 20 months at a mean frequency of once in nearly 12 days. From the very outset, ECT dramatically decreased the frequency of spontaneous seizures from approximately 6 to 24 per week at baseline to approximately 1 to 2 per week after ECT initiation. The efficacy of maintenance ECT in spontaneous seizure prophylaxis was greater when the ECT treatment interval was narrower. Improvement with ECT was associated with improved behavior and improved psychosocial functioning on clinical report. No cognitive or other adverse effects were reported or clinically ascertained. The ECT charge administered at the last 10 treatment sessions was 1434 millicoulombs. This is probably the highest electrical stimulus dose recorded in literature. CONCLUSIONS: Maintenance ECT may reduce the frequency of breakthrough seizures in patients with seizure disorder that is inadequately responsive to antiepileptic medication regimes. Very high ECT seizure thresholds may be observed when many antiepileptic drugs are concurrently administered in high doses. PMID- 22531208 TI - Decreasing adverse outcomes associated with unmodified ECT: a commentary. PMID- 22531209 TI - One-year follow-up after discontinuing maintenance electroconvulsive therapy. AB - OBJECTIVES: Electroconvulsive therapy (ECT) has been established as an effective method in the treatment of severe depressive or psychotic disorders. Its efficacy is greatest in severe major depressive disorder (MDD) with or without psychotic symptoms. However, maintaining remission after a successful course of short-term ECT is often difficult owing to resistance to medication in these patients. Therefore, the relapse rate after short-term ECT is high; 40% to 60% of patients relapse even with adequate antidepressant continuation therapy. The risk of relapse is greatest during the first months after discontinuation of short-term ECT. Continuation/maintenance (c/m) ECT is an option in maintaining remission, but systematic data and clinical guidelines are lacking. The point at which to discontinue this treatment has not been adequately established. METHODS: Altogether 45 consecutive patients treated with c/mECT after short-term ECT to prevent relapse were followed up 1 year after discontinuation of this treatment. RESULTS: Twenty (44%) of 45 patients relapsed during follow-up, all within the first 8 months. Patients having a diagnosis other than MDD (bipolar disorder, depressive episode type I, schizophrenia, and schizoaffective disorder) were more likely to relapse than MDD patients. CONCLUSIONS: Almost half of the patients relapsed in 1 year after discontinuation of c/mECT, most of these within the first 3 months and all within the first 8 months. The risk of relapse is greater in the patients with diagnoses other than MDD. When discontinuing c/mECT, patients should be carefully followed up; and for those at risk of relapse, even permanent mECT should be considered. To the best of our knowledge, the present study is the first to report the prognosis of patients after discontinuing c/mECT. PMID- 22531210 TI - Evolving a photosynthetic organelle. AB - The evolution of plastids from cyanobacteria is believed to represent a singularity in the history of life. The enigmatic amoeba Paulinella and its 'recently' acquired photosynthetic inclusions provide a fascinating system through which to gain fresh insight into how endosymbionts become organelles.The plastids, or chloroplasts, of algae and plants evolved from cyanobacteria by endosymbiosis. This landmark event conferred on eukaryotes the benefits of photosynthesis--the conversion of solar energy into chemical energy--and in so doing had a huge impact on the course of evolution and the climate of Earth 1. From the present state of plastids, however, it is difficult to trace the evolutionary steps involved in this momentous development, because all modern-day plastids have fully integrated into their hosts. Paulinella chromatophora is a unicellular eukaryote that bears photosynthetic entities called chromatophores that are derived from cyanobacteria and has thus received much attention as a possible example of an organism in the early stages of organellogenesis. Recent studies have unlocked the genomic secrets of its chromatophore 23 and provided concrete evidence that the Paulinella chromatophore is a bona fide photosynthetic organelle 4. The question is how Paulinella can help us to understand the process by which an endosymbiont is converted into an organelle. PMID- 22531212 TI - Homonymous Quadrantanopsia as the First Manifestation of Cerebral Metastasis of Invasive Mole: a case report. AB - INTRODUCTION: Homonymous quadrantanopsia results from retrochiasmal lesions in the visual pathway. Invasive mole is a benign tumor that arises from myometrial invasion of a hydatidiform mole via direct extension through tissue or venous channels. Cerebral metastasis of invasive mole is rare and there has been no report demonstrating homonymous quadrantanopsia as the first manifestation of metastasis in any trophoblastic neoplasms. CASE PRESENTATION: We report the case of a 31-year-old Asian woman who presented with right homonymous inferior quadrantanopsia from the mass effect of a solitary cerebral metastasis from an invasive mole. A magnetic resonance image (MRI) of the brain showed a metastatic tumor in the left occipital lobe. The visual field improved slightly after chemotherapy. There was a reduction in the tumor size and the surrounding edema. This is the first case report demonstrating that homonymous quadrantanopsia should be included in the manifestations of the metastasis of an invasive mole. CONCLUSIONS: The presentation of homonymous quadrantanopsia must alert ophthalmologists to conduct a complete medical history and arrange specialist consultation. PMID- 22531211 TI - Using the spring constant method to analyze arterial elasticity in type 2 diabetic patients. AB - BACKGROUND: This study tests the validity of a newly-proposed spring constant method to analyze arterial elasticity in type 2 diabetic patients. METHODS: The experimental group comprised 66 participants (36 men and 30 women) ranging between 46 and 86 years of age, all with diabetes mellitus. In the experimental group, 21 participants suffered from atherosclerosis. All were subjected to the measurements of both the carotid-femoral pulse wave velocity (cfPWV) and the spring constant method. The comparison (control) group comprised 66 normal participants (37 men and 29 women) with an age range of 40 to 80 years who did not have diabetes mellitus. All control group members were subjected to measurement by the spring constant method. RESULTS: Statistical analysis of the experimental and control groups indicated a significant negative correlation between the spring constant and the cfPWV (P < .001; r = - 0.824 and - 0.71). Multivariate analysis similarly indicated a close relationship. The Student's t test was used to examine the difference in the spring constant parameter between the experimental and control groups. A P-value less than .05 confirmed that the difference between the 2 groups was statistically significant. In receiver operating characteristic curve (ROC), the Area Under Curve (AUC, = 0.85) indicates good discrimination. These findings imply that the spring constant method can effectively identify normal versus abnormal characteristics of elasticity in normal and diabetic participants. CONCLUSIONS: This study verifies the use of the spring constant method to assess arterial elasticity, and found it to be efficient and simple to use. The spring constant method should prove useful not only for improving clinical diagnoses, but also for screening diabetic patients who display early evidence of vascular disease. PMID- 22531213 TI - Label-free detection of proteins from dried-suspended droplets using surface enhanced Raman scattering. AB - A simple sample preparation method to obtain rich and reproducible surface enhanced Raman scattering (SERS) spectra from proteins regardless of their surface properties and dimensions for label-free detection and identification is reported. The method uses colloidal silver nanoparticles (AgNPs) as substrates and is based on suspending the droplet of a mixture containing AgNPs and proteins from a hydrophobic surface. Drying the droplet at this suspended configuration allows the accumulation and packing of AgNPs and protein molecules in the middle of the droplet area rather than getting jammed at the edges of drying droplets as the solvent evaporates. A detection limit of down to 0.05 MUg mL(-1) for some of the model proteins used in this study is obtained with this simple approach. The advantage of this method is its simplicity and improved sensitivity over other approaches reported in the literature. PMID- 22531214 TI - NuST: analysis of the interplay between nucleoid organization and gene expression. AB - Different experimental results suggest the presence of an interplay between global transcriptional regulation and chromosome spatial organization in bacteria. The identification and clear visualization of spatial clusters of contiguous genes targeted by specific DNA-binding proteins or sensitive to nucleoid perturbations can elucidate links between nucleoid structure and gene expression patterns. Similarly, statistical analysis to assess correlations between results from independent experiments can provide the integrated analysis needed in this line of research. NuST (Nucleoid Survey tools), based on the Escherichia coli genome, gives the non-expert the possibility to analyze the aggregation of genes or loci sets along the genome coordinate, at different scales of observation. It is useful to discover correlations between different sources of data (e.g. expression, binding or genomic data) and genome organization. A user can use it on datasets in the form of gene lists coming from his/her own experiments or bioinformatic analyses, but also make use of the internal database, which collects data from many published studies. AVAILABILITY AND IMPLEMENTATION: NuST is a web server (available at http://www.lgm.upmc.fr/nust/). The website is implemented in PHP, SQLite and Ajax, with all major browsers supported, while the core algorithms are optimized and implemented in C. NuST has an extensive help page and provides a direct visualization of results as well as different downloadable file formats. A template Perl code for automated access to the web server can be downloaded at http://www.lgm.upmc.fr/nust/downloads/, in order to allow the users to use NuST in systematic bioinformatic analyses. PMID- 22531215 TI - DelPhi web server v2: incorporating atomic-style geometrical figures into the computational protocol. AB - A new edition of the DelPhi web server, DelPhi web server v2, is released to include atomic presentation of geometrical figures. These geometrical objects can be used to model nano-size objects together with real biological macromolecules. The position and size of the object can be manipulated by the user in real time until desired results are achieved. The server fixes structural defects, adds hydrogen atoms and calculates electrostatic energies and the corresponding electrostatic potential and ionic distributions. AVAILABILITY AND IMPLEMENTATION: The web server follows a client-server architecture built on PHP and HTML and utilizes DelPhi software. The computation is carried out on supercomputer cluster and results are given back to the user via http protocol, including the ability to visualize the structure and corresponding electrostatic potential via Jmol implementation. The DelPhi web server is available from http://compbio.clemson.edu/delphi_webserver. PMID- 22531216 TI - Tachyon search speeds up retrieval of similar sequences by several orders of magnitude. AB - The usage of current sequence search tools becomes increasingly slower as databases of protein sequences continue to grow exponentially. Tachyon, a new algorithm that identifies closely related protein sequences ~200 times faster than standard BLAST, circumvents this limitation with a reduced database and oligopeptide matching heuristic. AVAILABILITY AND IMPLEMENTATION: The tool is publicly accessible as a webserver at http://tachyon.bii.a-star.edu.sg and can also be accessed programmatically through SOAP. PMID- 22531217 TI - Accurate extension of multiple sequence alignments using a phylogeny-aware graph algorithm. AB - MOTIVATION: Accurate alignment of large numbers of sequences is demanding and the computational burden is further increased by downstream analyses depending on these alignments. With the abundance of sequence data, an integrative approach of adding new sequences to existing alignments without their full re-computation and maintaining the relative matching of existing sequences is an attractive option. Another current challenge is the extension of reference alignments with fragmented sequences, as those coming from next-generation metagenomics, that contain relatively little information. Widely used methods for alignment extension are based on profile representation of reference sequences. These do not incorporate and use phylogenetic information and are affected by the composition of the reference alignment and the phylogenetic positions of query sequences. RESULTS: We have developed a method for phylogeny-aware alignment of partial-order sequence graphs and apply it here to the extension of alignments with new data. Our new method, called PAGAN, infers ancestral sequences for the reference alignment and adds new sequences in their phylogenetic context, either to predefined positions or by finding the best placement for sequences of unknown origin. Unlike profile-based alternatives, PAGAN considers the phylogenetic relatedness of the sequences and is not affected by inclusion of more diverged sequences in the reference set. Our analyses show that PAGAN outperforms alternative methods for alignment extension and provides superior accuracy for both DNA and protein data, the improvement being especially large for fragmented sequences. Moreover, PAGAN-generated alignments of noisy next-generation sequencing (NGS) sequences are accurate enough for the use of RNA-seq data in evolutionary analyses. AVAILABILITY: PAGAN is written in C++, licensed under the GPL and its source code is available at http://code.google.com/p/pagan-msa. PMID- 22531219 TI - Histaminergic pharmacology of homo-oligomeric beta3 gamma-aminobutyric acid type A receptors characterized by surface plasmon resonance biosensor technology. AB - A surface plasmon resonance biosensor assay was established for studying the interactions of 51 histaminergic and 15 GABAergic ligands with homo-oligomeric beta3 GABA(A) receptors. Detergent solubilized receptors were successfully immobilized via affinity-capture on biosensor surfaces. The interaction kinetics of both histaminergic and GABAergic ligands were very rapid but affinities could be determined by steady-state analysis. Binding of several GABAergic ligands was observed, in agreement with previous data. Histamine and 16 histaminergic ligands were detected to directly bind to beta3 GABA(A) receptors with micromolar affinity (K(D)<300 MUM), thus extending previous evidence that beta3 GABA(A) receptors can interact with histaminergic ligands. Histamine exhibited an affinity for these receptors comparable to that for human histamine type 1 (H1) or type 2 (H2) receptors. Furthermore, 13 of these histaminergic ligands appeared to compete with histamine. The discovery that H2, H3 and H4 receptor ligands interact with beta3 receptors indicates a unique histaminergic pharmacology of these receptors. Due to their low affinity for the homo-pentameric beta3 receptors these histaminergic drugs are not expected to modulate these receptors at clinically relevant concentrations. The results support the use of the new biosensor assay for the identification of drugs interacting with full length receptors and for fragment-based drug discovery of high affinity ligands for beta3 receptors. Drugs with high affinity and selectivity for these receptors can be used to clarify the question whether beta3 receptors do exist in the brain, and provide new avenues for the development of therapeutically active compounds targeting this novel histamine binding site. PMID- 22531218 TI - MMFPh: a maximal motif finder for phosphoproteomics datasets. AB - MOTIVATION: Protein phosphorylation, driven by specific recognition of substrates by kinases and phosphatases, plays central roles in a variety of important cellular processes such as signaling and enzyme activation. Mass spectrometry enables the determination of phosphorylated peptides (and thereby proteins) in scenarios ranging from targeted in vitro studies to in vivo cell lysates under particular conditions. The characterization of commonalities among identified phosphopeptides provides insights into the specificities of the kinases involved in a study. Several algorithms have been developed to uncover linear motifs representing position-specific amino acid patterns in sets of phosphopeptides. To more fully capture the available information, reduce sensitivity to both parameter choices and natural experimental variation, and develop more precise characterizations of kinase specificities, it is necessary to determine all statistically significant motifs represented in a dataset. RESULTS: We have developed MMFPh (Maximal Motif Finder for Phosphoproteomics datasets), which extends the approach of the popular phosphorylation motif software Motif-X (Schwartz and Gygi, 2005) to identify all statistically significant motifs and return the maximal ones (those not subsumed by motifs with more fixed amino acids). In tests with both synthetic and experimental data, we show that MMFPh finds important motifs missed by the greedy approach of Motif-X, while also finding more motifs that are more characteristic of the dataset relative to the background proteome. Thus MMFPh is in some sense both more sensitive and more specific in characterizing the involved kinases. We also show that MMFPh compares favorably to other recent methods for finding phosphorylation motifs. Furthermore, MMFPh is less dependent on parameter choices. We support this powerful new approach with a web interface so that it may become a useful tool for studies of kinase specificity and phosphorylation site prediction. AVAILABILITY: A web server is at www.cs.dartmouth.edu/~cbk/. PMID- 22531220 TI - G protein-coupled receptor signalling in astrocytes in health and disease: a focus on metabotropic glutamate receptors. AB - Work published over the past 10-15 years has caused the neuroscience community to engage in a process of constant re-evaluation of the roles of glial cells in the mammalian central nervous system. Recent emerging evidence suggests that, in addition to carrying out various homeostatic functions within the CNS, astrocytes can also engage in a two-way dialogue with neurons. Astrocytes possess many of the receptors, and some of the ion channels, present in neurons endowing them with an ability to sense and respond to an array of neuronal signals. In addition, an expanding number of small molecules and proteins have been shown to be released by astrocytes in both health and disease. In this commentary we will highlight advances in our understanding of G protein-coupled receptor signalling in astrocytes, with a particular emphasis on metabotropic glutamate (mGlu) receptors. Discussion will focus on the major mGlu receptors expressed in astrocytes, mGlu3 and mGlu5, how these receptors can influence different aspects of astrocyte physiology, and how signalling by these G protein-coupled receptors might change under pathophysiological circumstances. PMID- 22531221 TI - The integration of 3-D cell printing and mesoscopic fluorescence molecular tomography of vascular constructs within thick hydrogel scaffolds. AB - Developing methods that provide adequate vascular perfusion is an important step toward engineering large functional tissues. Meanwhile, an imaging modality to assess the three-dimensional (3-D) structures and functions of the vascular channels is lacking for thick matrices (>2 ~ 3 mm). Herein, we report on an original approach to construct and image 3-D dynamically perfused vascular structures in thick hydrogel scaffolds. In this work, we integrated a robotic 3-D cell printing technology with a mesoscopic fluorescence molecular tomography imaging system, and demonstrated the capability of the platform to construct perfused collagen scaffolds with endothelial lining and to image both the fluid flow and fluorescent-labeled living endothelial cells at high-frame rates, with high sensitivity and accuracy. These results establish the potential of integrating both 3-D cell printing and fluorescence mesoscopic imaging for functional and molecular studies in complex tissue-engineered tissues. PMID- 22531223 TI - Modulating the singlet oxygen generation property of meso-beta directly linked BODIPY dimers. AB - We report the synthesis, X-ray analysis and singlet oxygen generation properties of a set of meso-beta directly linked BODIPYs with the meso-aryl group (phi(1)) and meso-BODIPY component (phi(2)) free to rotate or constrained. PMID- 22531224 TI - Accumulation of disparity in physical activity in old age. AB - BACKGROUND AND AIMS: The level of physical activity often declines in old age, although many older people would like to be more active than what they are capable of. This leads to unmet physical activity need, the feeling that one's level of physical activity is inadequate, which is a manifestation of disparity in physical activity in old age. The accumulation of risk factors, including mobility limitations, low socioeconomic status (SES) and lack of social support may increase disparity in physical activity. The aim of this study was to investigate how the accumulation of risk factors is associated with unmet physical activity need in older community-living people. METHODS: The study was based on cross-sectional analyses of an observational study with 632 participants. Unmet physical activity need, SES, mobility limitations and availability of social support were self-reported by standardized questionnaires. RESULTS: Having mobility limitations increased the risk of unmet physical activity need almost four-fold compared to those with no mobility limitations; having mobility limitations and either low SES or not having social support increased the risk over four-fold and having mobility limitations, low SES and no social support further increased the risk over seven-fold. CONCLUSIONS: We found that accumulation of risk factors increases disparity in physical activity. PMID- 22531222 TI - A functional agarose-hydroxyapatite scaffold for osteochondral interface regeneration. AB - Regeneration of the osteochondral interface is critical for integrative and functional cartilage repair. This study focuses on the design and optimization of a hydrogel-ceramic composite scaffold of agarose and hydroxyapatite (HA) for calcified cartilage formation. The first study objective was to compare the effects of HA on non-hypertrophic and hypertrophic chondrocytes cultured in the composite scaffold. Specifically, cell growth, biosynthesis, hypertrophy, and scaffold mechanical properties were evaluated. Next, the ceramic phase of the scaffold was optimized in terms of particle size (200 nm vs. 25 MUm) and dose (0 6 w/v%). It was observed that while deep zone chondrocyte (DZC) biosynthesis and hypertrophy remained unaffected, hypertrophic chondrocytes measured higher matrix deposition and mineralization potential with the addition of HA. Most importantly, higher matrix content translated into significant increases in both compressive and shear mechanical properties. While cell hypertrophy was independent of ceramic size, matrix deposition was higher only with the addition of micron-sized ceramic particles. In addition, the highest matrix content, mechanical properties and mineralization potential were found in scaffolds with 3% micro-HA, which approximates both the mineral aggregate size and content of the native interface. These results demonstrate that the biomimetic hydrogel ceramic composite is optimal for calcified cartilage formation and is a promising design strategy for osteochondral interface regeneration. PMID- 22531225 TI - Electrical impedance tomography system based on active electrodes. AB - Electrical impedance tomography (EIT) can image the distribution of ventilated lung tissue, and is thus a promising technology to help monitor patient breathing to help selection of mechanical ventilation parameters. Two key difficulties in EIT instrumentation make such monitoring difficult: (1) EIT data quality depends on good electrode contact and is sensitive to changes in contact quality, and (2) EIT electrodes are difficult and time consuming to place on patients. This paper presents the design and initial tests of an active electrode-based system to address these difficulties. Our active electrode EIT system incorporates an active electrode belt, a central voltage-driven current source, central analog to digital converters and digital to analog converters, a central FPGA-based demodulator and controller. The electrode belt is designed incorporating 32 active electrodes, each of which contains the electronic amplifiers, switches and associated logic. Tests show stable device performance with a convenient ease of use and good imaging ability in volunteer tests. PMID- 22531226 TI - Morphological evidence of neurotoxicity in retina after methylmercury exposure. AB - The visual system is particularly sensitive to methylmercury (MeHg) exposure and, therefore, provides a useful model for investigating the fundamental mechanisms that direct toxic effects. During a period of 70 days, adult of a freshwater fish species Hoplias malabaricus were fed with fish prey previously labeled with two different doses of methylmercury (0.075 and 0.75 MUgg(-1)) to determine the mercury distribution and morphological changes in the retina. Mercury deposits were found in the photoreceptor layer, in the inner plexiform layer and in the outer plexiform layer, demonstrating a dose-dependent bioaccumulation. The ultrastructure analysis of retina revealed a cellular deterioration in the photoreceptor layer, morphological changes in the inner and outer segments of rods, structural changes in the plasma membrane of rods and double cones, changes in the process of removal of membranous discs and a structural discontinuity. These results lead to the conclusion that methylmercury is able to cross the blood-retina barrier, accumulate in the cells and layers of retina and induce changes in photoreceptors of H. malabaricus even under subchronic exposure. PMID- 22531227 TI - The similar neurotoxic effects of nanoparticulate and ionic silver in vivo and in vitro. AB - We compared the neurotoxic effects of 14 nm silver nanoparticles (AgNPs) and ionic silver, in the form of silver acetate (AgAc), in vivo and in vitro. In female rats, we found that AgNPs (4.5 and 9 mg AgNP/kg bw/day) and ionic silver (9 mg Ag/kg bw/day) increased the dopamine concentration in the brain following 28 days of oral administration. The concentration of 5-hydroxytryptamine (5-HT) in the brain was increased only by AgNP at a dose of 9 mg Ag/kg bw/day. Only AgAc (9 mg Ag/kg bw/day) was found to increase noradrenaline concentration in the brain. In contrast to the results obtained from a 28-day exposure, the dopamine concentration in the brain was decreased by AgNPs (2.25 and 4.5mg/kg bw/day) following a 14-day exposure. These data suggest that there are differential effects of silver on dopamine depending on the length of exposure. In vitro, AgNPs, AgAc and a 12 kDa filtered sub-nano AgNP fraction were used to investigate cell death mechanisms in neuronal-like PC12 cells. AgNPs and the 12 kDa filtered fraction decreased cell viability to a similar extent, whereas AgAc was relatively more potent. AgNPs did not induce necrosis. However, apoptosis was found to be equally increased in cells exposed to AgNPs and the 12kDa filtered fraction, with AgAc showing a greater potency. Both the mitochondrial and the death receptor pathways were found to be involved in AgNP- and AgAc-induced apoptosis. In conclusion, 14 nm AgNPs and AgAc affected brain neurotransmitter concentrations. AgNP affected 5-HT, AgAc affected noradrenaline, whereas both silver formulations affected dopamine. Furthermore, apoptosis was observed in neuronal-like cells exposed to AgNPs, a 12 kDa filtered fraction of AgNP, and AgAc. These findings suggest that ionic silver and a 14 nm AgNP preparation have similar neurotoxic effects; a possible explanation for this could be the release and action of ionic silver from the surface of AgNPs. PMID- 22531228 TI - 4-(2-Hydroxypropan-2-yl)-1-methylcyclohexane-1,2-diol prevents xenobiotic induced cytotoxicity. AB - Currently there is a great deal of interest in the study of natural compounds with free radical scavenging activity because of their potential role in maintaining human health and preventing diseases. In this paper, we report the antioxidant and cytoprotective properties of 4-(2-hydroxypropan-2-yl)-1 methylcyclohexane-1,2-diol (HPMCD) isolated from the aqueous extract of Decalepis hamiltonii roots. Our results show that HPMCD is a potent scavenger of superoxide (O(2)(*-)), hydroxyl ((*)OH), nitric oxide ((*)NO), and lipid peroxide (LOO(*)) physiologically relevant free radicals with IC(50) values in nmolar (56-582) range. HPMCD also exhibited concentration dependent secondary antioxidant activities like reducing power, metal chelating activity, and inhibition of protein carbonylation. Further, HPMCD at nmolar concentration prevented CuSO(4) induced human LDL oxidation. Apart from the in vitro free radical scavenging activity HPMCD demonstrated cytoprotective activity in primary hepatocytes and ehrlich ascites tumor (EAT) cells against oxidative stress inducing xenobiotics. The mechanism of cytoprotective action involved maintaining the intracellular glutathione (GSH), scavenging of reactive oxygen species (ROS), and inhibition of lipid peroxidation (LPO). Based on the results it is suggested that HPMCD is a novel bioactive molecule with health implications in both prevention and amelioration of diseases involving oxidative stress as well as in the general well being. PMID- 22531230 TI - High Ki67 expression is a risk marker of invasive relapse for classical lobular carcinoma in situ patients. AB - BACKGROUND: The clinical management of lobular carcinoma in situ lesions remains challenging. Our aim was to evaluate the risk of relapse for lobular carcinoma in situ (LCIS) patients, diagnosed on mammography performed for microcalcifications and according to proliferation assessed by Ki67 staining. METHODS: A series of 47 patient's files with LCIS and followed in our institution were retrospectively selected. All patients underwent lumpectomy without radiation therapy. The expression of E-cadherin, estrogen receptor (ER), progesterone receptor (PR), EGFR and Ki67 were determined. Four different classes were then defined with the following criteria: ER+ and Ki67 <= 10%; ER+, Ki67 >10%; ER-; ER-PR- and EGFR+. RESULTS: Patient's mean age was 51.3 yrs. The majority of the lesions were classical LCIS (97%). All cases were E-cadherin either negative (71%) or weak and incomplete (29%). Among the 44 evaluable cases, 34 cases were ER or PR positive with KI67 <= 10% (79%), 9 cases ER positive with KI67 > 10% (21%), 1 case was ER and PR negative and expressed EGFR. At five years, all patients were alive, 1/34 ER positive and Ki67 low experienced a relapse contrasting with 3 out of 9 ER positive and Ki67 high (3 invasive carcinomas including 2 ductal and 1 lobular) (p = 0.0054). CONCLUSION: In this retrospective study, we observed a higher risk of relapse associated with a high proliferative activity of classical LCIS. If confirmed in larger series, this observation suggests that radiation therapy or hormonotherapy could be discussed for patients with Ki67 high classical LCIS in order to decrease their risk of relapse. PMID- 22531231 TI - Use of the complete blood cell count in early-onset neonatal sepsis. AB - BACKGROUND: Early-onset sepsis (EOS) is an important cause of morbidity and mortality in neonates, and its diagnosis remains challenging. The complete blood cell count and differential have been previously evaluated as diagnostic tools for EOS in small, single-center reports. We evaluated the diagnostic accuracy of the complete blood cell count and differential in EOS in a large, multicenter population of neonates admitted to the neonatal intensive care unit. METHODS: Using a cohort of 166,092 neonates with suspected EOS with cultures admitted to 293 neonatal intensive care units, we calculated odds ratios and receiver operating characteristic curves for complete blood cell count indices and prediction of a positive culture. We determined sensitivity, specificity and likelihood ratios for various commonly used cutoff values from the complete blood cell count. RESULTS: Low white blood cell counts, low absolute neutrophil counts and high immature-to-total neutrophil ratios were associated with increasing odds of infection (highest odds ratios: 5.38, 6.84 and 7.97, respectively). Specificity and negative predictive values were high (73.7%-99.9% and >99.8%). However, sensitivities were low (0.3%-54.5%) for all complete blood cell count indices analyzed. CONCLUSION: Low white blood cell count, absolute neutrophil count and high immature-to-total neutrophil ratio were associated with increasing odds of infection, but no complete blood cell count-derived index possesses the sensitivity to rule out reliably EOS in neonates. PMID- 22531232 TI - Use of the complete blood cell count in late-onset neonatal sepsis. AB - BACKGROUND: Late-onset sepsis is an important cause of morbidity and mortality in infants. Diagnosis of late-onset sepsis can be challenging. The complete blood cell count and differential have been previously evaluated as diagnostic tools for late-onset sepsis in small, single-center reports. OBJECTIVE: We evaluated the diagnostic accuracy of the complete blood cell count and differential in late onset sepsis in a large multicenter population. STUDY DESIGN: Using a cohort of all infants with cultures and complete blood cell count data from a large administrative database, we calculated odds ratios for infection, as well as sensitivity, specificity, positive and negative predictive values and likelihood ratios for various commonly used cut-off values. RESULTS: High and low white blood cell counts, high absolute neutrophil counts, high immature-to-total neutrophil ratios and low platelet counts were associated with late-onset sepsis. Associations were weaker with increasing postnatal age at the time of the culture. Specificity was highest for white blood cell counts <1000/mm and >50,000/mm (>99%). Positive likelihood ratios were highest for white blood cell counts <1000/mm (4.1) and platelet counts <50,000/mm (3.5). CONCLUSION: No complete blood cell count index possessed adequate sensitivity to reliably rule out late-onset sepsis in this population. PMID- 22531233 TI - Serum hepcidin and ferritin to iron ratio in evaluation of bacterial versus viral infections in children: a single-center study. AB - BACKGROUND: Differential diagnosis of childhood infections is important. Several biochemical indices steer diagnosis toward bacterial agents, although the data are often not definitive. Hepcidin is a central component of blood iron, and ferritin alterations occur during infections. We measured hepcidin changes and evaluated ferritin to iron ratio (FIR) in patients with suspected infections. METHODS: We studied 69 children with infection and an equal number of matched controls during a 3-year period. A bacterial agent was demonstrated in 17 and a viral pathogen in 52 of the patients. Hematologic and biochemical tests were performed on all children including ferritin, iron and hepcidin. FIR was calculated and receiver operating characteristic curve analysis was performed to evaluate the best FIR cutoff value to discriminate between patients and controls and between patients with bacterial infections and viral infections. RESULTS: Hepcidin, ferritin and FIR were significantly higher and iron values significantly lower in febrile patients than its controls. Patients with bacterial infection had significantly lower iron and higher FIR than those with viral infection. FIR had high accuracy discriminating patients from controls but only moderate accuracy discriminating bacterial from viral infected patients. CONCLUSIONS: If further studies with larger samples confirm these observations, FIR could be used as an inexpensive, rapid and easily performed complementary index for diagnosis of bacterial infections. PMID- 22531234 TI - Epidemiology of respiratory syncytial virus infection in infants born at less than thirty-five weeks of gestational age. AB - BACKGROUND: The aims of this study were to observe the respiratory syncytial virus (RSV) hospitalization rate and to identify the risk factors for hospitalization for RSV infection among infants in Korea born at <35 weeks of gestational age and who had not previously received palivizumab. METHODS: We conducted a study over a 2.5-year period (between April 2007 and September 2009) that included premature infants (<35 weeks of gestational age) who underwent follow-up during 1 year after discharge from the neonatal intensive care unit. Demographic information was collected for each subject at baseline, and the reasons for hospitalization were obtained during the 1-year follow-up period. RESULTS: The study population included 1022 subjects who completed follow-up interviews. Eight hundred seventeen infants were included in analysis for RSV hospitalization. Excluded from the study were 167 subjects with chronic lung disease who had received palivizumab prophylaxis and 38 subjects who were not tested for RSV. The overall incidence of RSV hospitalization in the group that did not receive palivizumab was 4.5% (37 of 817 patients). Independent risk factors associated with RSV hospitalization were multiple gestation (P = 0.022) and longer duration of mechanical ventilation in the neonatal intensive care unit (P = 0.039). CONCLUSION: This study showed the epidemiology and risk factors of RSV hospitalization in preterm infants in Korea. RSV infection was one of the main causes of hospitalization after discharge from the neonatal intensive care unit in patients born at <35 weeks of gestational age. PMID- 22531235 TI - Successful treatment of pediatric latent tuberculosis infection in a community health center clinic. AB - OBJECTIVE: This study evaluates completion of treatment for latent tuberculosis infection (LTBI) in Mexican immigrant children aged 1-18 years in a Community Health Center (CHC). METHODS: Children were screened for LTBI at a CHC. All children with a tuberculin skin test (TST) >=10 mm had a chest radiograph (CXR). Those with negative CXR had nurse appointments to collect demographic information and to begin 9 months of INH treatment. A minimum 6 months of INH treatment defined completion. RESULTS: Between November 15, 2006 and March 15, 2009, 157 children had positive TSTs. Three never had a CXR, 2 had misdiagnosed LTBI and 2 had asymptomatic active tuberculosis. Of 150 with LTBI, 111 (74%) completed INH at CHC. Thirteen (9%) transferred care to school-based clinics or TB clinic (TBC) and 4 (3%) never started treatment. Twenty-two (15%) did not complete treatment at CHC. One developed INH hepatitis and 21 were lost to follow-up. Of 13 who transferred to school-based clinics/TBC, 10 completed therapy, with 121 (81%) completing treatment started at CHC. By logistic regression factors associated with not starting/incomplete LTBI treatment were older age, increased number of days between TST and CXR, and 0-1 well care visits versus >=2 visits before TST placement. A visit co-pay >=$15.00 was associated with transfer of care to school based clinics/TBC. CONCLUSIONS: Pediatric LTBI can be successfully treated by CHC nurses. Completion of treatment was associated with younger age, fewer days between TST reading and CXR, and being an established patient in the CHC. PMID- 22531236 TI - Frequency and trajectory of abnormalities in respiratory rate, temperature and oxygen saturation in severe pneumonia in children. AB - The frequency or trajectory of vital sign abnormalities in children with pneumonia has not been described. In a cohort of 2714 patients with severe pneumonia identified and treated as per the World Health Organization definition and recommendations, tachypnea, fever and hypoxia were found in 68.9%, 23.6% and 15.5% of children, respectively. Median oxygen saturation returned to a normal range by 10 hours following initiation of treatment, followed by temperature at 12 hours and respiratory rate at 22 hours for subjects <12 months and at 48 hours for those >= 12 months of age. PMID- 22531237 TI - Safety and immunogenicity of an investigational fully liquid hexavalent DTaP-IPV Hep B-PRP-T vaccine at two, four and six months of age compared with licensed vaccines in Latin America. AB - OBJECTIVE: This trial assessed the safety of a fully liquid investigational hexavalent DTaP-IPV-Hep B-PRP-T vaccine containing 10 MUg Hansenula polymorpha derived recombinant hepatitis B (hep B) antigen for primary vaccination of infants at 2, 4 and 6 months of age compared with licensed comparators. METHODS: Participants received the DTaP-IPV-Hep B-PRP-T vaccine (group 1, N = 1422) or licensed DTwP-Hep B//Hib (Tritanrix-Hep B/Hib) and oral poliovirus vaccines (group 2, N = 711). The incidence of severe fever (>= 39.6 degrees C rectal equivalent) in the 2 groups was compared statistically; reactogenicity was evaluated from parental reports. Anti-Hep B antibody titers were measured in a subset of participants (no hepatitis B vaccination at birth) 1 month after dose 3. RESULTS: The investigational vaccine was well tolerated. After any dose, fever (rectal equivalent temperature >= 38 degrees C) was observed in 74.8% and 92.7% of participants in groups 1 and 2; severe fever was observed in 4.0% and 5.5% of participants. Solicited injection site and systemic reactions were numerically less frequent in group 1 than group 2, although this difference was not assessed statistically. In both groups, all participants included in the immunogenicity analysis achieved anti-Hep B >= 10 mIU/mL and >= 96.2% of participants achieved anti-Hep B >= 100 mIU/mL, although geometric mean titer was approximately 3-fold lower for the investigational vaccine. CONCLUSION: This new, fully liquid acellular pertussis hexavalent vaccine demonstrated less reactogenicity than the licensed comparator whole cell pertussis vaccine and was highly immunogenic for the new Hep B valence. PMID- 22531238 TI - Outbreak of scarlet fever associated with emm12 type group A Streptococcus in 2011 in Shanghai, China. AB - BACKGROUND: An unprecedented, large outbreak of childhood scarlet fever occurred in Shanghai between April and July 2011. Investigation of the epidemiology could enhance our understanding of the factors related to the outbreak. METHODS: We retrospectively analyzed the demographic and seasonal characteristics of children with scarlet fever and the outcome. During the peak month of the 2011 outbreak, 45 GAS isolates recovered from pediatric patients and 13 (43.3%) GAS isolates recovered from 30 asymptomatic student contacts were characterized by emm typing, superantigen profiles, pulsed-field gel electrophoresis genotypes, mutilocus sequence typing and antimicrobial susceptibility. RESULTS: The 2011 outbreak of scarlet fever started in April and peaked in May and June. Boys outnumbered girls (65.1% versus 34.9%). Preschool and primary school children accounted for 96% of cases. No severe outcome was found. emm1, emm12 and emm75 were identified among 58 GAS isolates, and 53 (91.4%) isolates belonged to emm12, st36. Ten pulsed field gel electrophoresis genotypes were identified among emm12 GAS isolates, 43 (81.1%) shared SPYS16.001 genotype and the remaining 7 genotypes detected were related to SPYS16.001 closely or possibly. No streptococcal pyrogenic exotoxin A and streptococcal pyrogenic exotoxin M were detected in 58 isolates. All emm12 GAS isolates were resistant to azithromycin and clindamycin. CONCLUSIONS: emm12 GAS strain caused the large 2011 outbreak of scarlet fever in Shanghai. Antibiotic resistance to macrolides and clindamycin in GAS is prevalent in Shanghai. PMID- 22531240 TI - Invasive salmonellosis in urban Thai children: a ten-year review. AB - BACKGROUND: Invasive, extraintestinal salmonellosis carries a significant burden of childhood morbidity especially among infants and young children in developing countries. OBJECTIVES: To determine the clinical manifestations, outcomes, laboratory findings and antimicrobial susceptibility patterns in patients with invasive salmonellosis. METHODS: A retrospective chart review was conducted among children 0-18 years of age diagnosed with invasive salmonellosis receiving care at Queen Sirikit National Institute of Child Health, Bangkok, Thailand, from 2001 to 2010. RESULTS: We analyzed the records of 229 patients with culture-proven invasive salmonellosis. Sixty-three percent of cases had no documented underlying disease. Fever, diarrhea and respiratory symptoms were reported in 92%, 40% and 29% of cases, respectively. The spectrum of disease included isolated bacteremia (90%), clinical pneumonia (24.8%), bacteremia with meningitis (7.8%), septic arthritis (1.3%) and empyema thoracis (0.4%). Forty-seven of 57 cases presenting with clinical pneumonia had abnormal infiltrations on chest radiograph (20.5% of all cases). Despite the invasive nature of the illness, 53.1% of patients had a normal white blood cell count. Antimicrobial resistance was found among ampicillin (68.3%), chloramphenical (15.2%), trimethoprim-sulfamethoxazole (33.9%), ceftriaxone (17.4%) and ciprofloxacin (3%). The case fatality rate was 4.8%, 91% of whom had an underlying disease. Multivariate analysis indicated that age, underlying liver disease and presence of pneumonia were significant predictors of fatality. CONCLUSIONS: Fever, diarrhea and respiratory symptoms were among the most common presenting symptoms of invasive nontyphoidal salmonellosis. Older age, hepatobiliary disease and presence of pneumonia were associated with increased risk of fatality. Resistance to third-generation cephalosporins poses a major concern for its use as empiric antimicrobial therapy for this condition. PMID- 22531239 TI - Pediatric suppurative parotitis in Cambodia between 2007 and 2011. AB - The causes of suppurative parotitis in Cambodian children are not known. We describe 39 cases at the Angkor Hospital for Children, Siem Reap, between January 2007 and July 2011 (0.07/1000 hospital attendances). The median age was 5.7 years with no neonates affected. Burkholderia pseudomallei was cultured in 29 (74%) cases. No deaths occurred; 1 child developed facial nerve palsy. PMID- 22531241 TI - Enterobius vermicularis and risk factors in healthy Norwegian children. AB - BACKGROUND: The prevalence of Enterobius vermicularis in neighboring countries of Norway show large variation. The goal of this study was to investigate the prevalence among Norwegian children and possible risk factors. METHODS: The children were participants in "Environmental Triggers of Type 1 Diabetes: the MIDIA study." The study involved 2 groups with different genetic risks of type 1 diabetes: A high-risk group carries the Human Leukocyte Antigen genotype conferring the highest risk for type 1 diabetes and a nonhigh-risk group consisting of children without this genotype. Scotch tape samples were collected on 3 consecutive days and examined by light microscopy. RESULTS: A total of 18% (72/395) of children were positive for E. vermicularis. The highest prevalence (34%) was in children 6-11 years of age. Only 2 children were prior known positives. Increased number of siblings was linked to more infections, and there were fewer infections in the children with the high-risk genotype. CONCLUSION: E. vermicularis is a common parasite in Norwegian children. The likelihood of E. vermicularis infection depends on family size and prevalence increases with age. The reduced number of infections in the children carrying the high-risk genotype for type 1 diabetes is intriguing and should be investigated further. PMID- 22531242 TI - Cytokine expression profiles associated with distinct clinical courses in hepatitis A virus-infected children. AB - We determined the serum cytokine profiles during distinct hepatitis A virus induced clinical courses in children. A significant overexpression of interleukin 1, interleukin-6, tumor necrosis factor-alpha and monocyte chemotactic protein-2 was found in children with intermediate liver injury, whereas the patients with minor liver injury had a significant increase of interleukin-8 and transforming growth factor-beta values. PMID- 22531243 TI - Good agreement between parents and physician in the assessment of ear discharge in children. AB - Physicians often rely on parental observation of ear discharge in the follow-up after its treatment, but little is known about the reliability of this assessment. Follow-up data of trial participants treated for acute or chronic ear discharge showed a good agreement between parents' and physician's assessment, with high positive predictive values, but lower negative predictive values. PMID- 22531244 TI - Spectrum of respiratory viruses in children with community-acquired pneumonia. AB - BACKGROUND: Community-acquired pneumonia (CAP) remains a significant cause for childhood morbidity worldwide. We designed a study with the objective of describing the frequency of respiratory viruses, especially rhinovirus (RV), human metapneumovirus (HMPV) and human bocavirus (HBoV) in hospitalized children with CAP. METHODS: A 6-year prospective study was conducted in children <14 years old admitted to the Pediatrics Department of the Severo Ochoa Hospital (Spain) with CAP. We studied the frequency of 16 respiratory viruses in nasopharyngeal aspirates. Clinical characteristics of respiratory syncytial virus (RSV)-only infections were compared with those of RV, HMPV and HBoV single infections. RESULTS: A viral pathogen was identified in 649 (73.4%) of 884 hospitalized children with CAP. Viral coinfections were detected in 30%. The rate of viral detection was significantly greater in infants <18 months (83%) than in older children (67%) (P < 0.001). The most frequently detected virus was RSV with 41.6% of positive patients followed by RV (26.2%), HBoV (17.8%), adenovirus (17.8%), HMPV (7%) and parainfluenza (7%). RSV was the most frequent virus in children <18 months, but RV was most common in the eldest group (P < 0.001). After stratifying by age, we found some significant differences among RSV, RV, HBoV and HMPV associated infections. CONCLUSIONS: The high prevalence of viral infections supports the role of respiratory viruses, mainly RSV, RV, HBoV and HMPV in CAP of children requiring hospitalization. These findings help us to understand the etiologic disease burden and to guide research and public health policy. PMID- 22531249 TI - Ventilator-induced lung injury is mediated by the NLRP3 inflammasome. AB - BACKGROUND: The innate immune response is important in ventilator-induced lung injury (VILI) but the exact pathways involved are not elucidated. The authors studied the role of the intracellular danger sensor NLRP3 inflammasome. METHODS: NLRP3 inflammasome gene expression was analyzed in respiratory epithelial cells and alveolar macrophages obtained from ventilated patients (n = 40). In addition, wild-type and NLRP3 inflammasome deficient mice were randomized to low tidal volume (approximately 7.5 ml/kg) and high tidal volume (approximately 15 ml/kg) ventilation. The presence of uric acid in lung lavage, activation of caspase-1, and NLRP3 inflammasome gene expression in lung tissue were investigated. Moreover, mice were pretreated with interleukin-1 receptor antagonist, glibenclamide, or vehicle before start of mechanical ventilation. VILI endpoints were relative lung weights, total protein in lavage fluid, neutrophil influx, and pulmonary and systemic cytokine and chemokine concentrations. Data represent mean +/- SD. RESULTS: Mechanical ventilation up-regulated messenger RNA expression levels of NLRP3 in alveolar macrophages (1.0 +/- 0 vs. 1.70 +/- 1.65, P less than 0.05). In mice, mechanical ventilation increased both NLRP3 and apoptosis associated speck-like protein messenger RNA levels, respectively (1.08 +/- 0.55 vs. 3.98 +/- 2.89; P less than 0.001 and 0.95 +/- 0.53 vs. 6.0 +/- 3.55; P less than 0.001), activated caspase-1, and increased uric acid levels (6.36 +/- 1.85 vs. 41.9 +/- 32.0, P less than 0.001). NLRP3 inflammasome deficient mice displayed less VILI due to high tidal volume mechanical ventilation compared with wild-type mice. Furthermore, treatment with interleukin-1 receptor antagonist or glibenclamide reduced VILI. CONCLUSIONS: Mechanical ventilation induced a NLRP3 inflammasome dependent pulmonary inflammatory response. NLRP3 inflammasome deficiency partially protected mice from VILI. PMID- 22531245 TI - Malaria resurgence: a systematic review and assessment of its causes. AB - BACKGROUND: Considerable declines in malaria have accompanied increased funding for control since the year 2000, but historical failures to maintain gains against the disease underscore the fragility of these successes. Although malaria transmission can be suppressed by effective control measures, in the absence of active intervention malaria will return to an intrinsic equilibrium determined by factors related to ecology, efficiency of mosquito vectors, and socioeconomic characteristics. Understanding where and why resurgence has occurred historically can help current and future malaria control programmes avoid the mistakes of the past. METHODS: A systematic review of the literature was conducted to identify historical malaria resurgence events. All suggested causes of these events were categorized according to whether they were related to weakened malaria control programmes, increased potential for malaria transmission, or technical obstacles like resistance. RESULTS: The review identified 75 resurgence events in 61 countries, occurring from the 1930s through the 2000s. Almost all resurgence events (68/75 = 91%) were attributed at least in part to the weakening of malaria control programmes for a variety of reasons, of which resource constraints were the most common (39/68 = 57%). Over half of the events (44/75 = 59%) were attributed in part to increases in the intrinsic potential for malaria transmission, while only 24/75 (32%) were attributed to vector or drug resistance. CONCLUSIONS: Given that most malaria resurgences have been linked to weakening of control programmes, there is an urgent need to develop practical solutions to the financial and operational threats to effectively sustaining today's successful malaria control programmes. PMID- 22531252 TI - No clinical or electrophysiologic evidence proving intraneural injection is safe. PMID- 22531251 TI - Images in anesthesiology: Unexpected difficult intubation caused by a subglottic tracheal ring. PMID- 22531253 TI - Incidence of subclinical neuropathy after intraneural injection. PMID- 22531255 TI - Multiorifice catheters are required to maximize the benefits of intermittent bolus continuous regional techniques. PMID- 22531257 TI - Managing patients with abnormal placentation: what are the best anesthetic and transfusion strategies? PMID- 22531259 TI - Current and emerging approaches to address failure-to-rescue. PMID- 22531261 TI - Are faculties another brick in the wall? PMID- 22531262 TI - Likert or not, we are biased. PMID- 22531263 TI - Errors in assessment of resident performance. PMID- 22531265 TI - High end-expiratory airway pressures caused by internal obstruction of the Draeger Apollo(r) scavenger system that is not detected by the workstation self test and visual inspection. PMID- 22531271 TI - Efficacy of tranexamic acid in paediatric cardiac surgery: a systematic review and meta-analysis. AB - The benefit-to-risk ratio of using tranexamic acid (TXA) in paediatric cardiac surgery has not yet been determined. This systematic review evaluated studies that compared TXA to placebo in children undergoing cardiac surgery. A systematic search was conducted in all relevant randomized controlled trials. The following information was extracted from the studies and analysed if relevant: demographic data, TXA dose and regimen of administration, cardiopulmonary bypass time, blood loss and blood product transfusion at 24 h. From the studies screened, only 8 (848 patients) were included in the analysis. Most data were heterogeneously distributed and could not be analysed. Further, transfusion policies were not well defined for each study. TXA reduced the need for red blood cell transfusion by 6.4 ml kg(-1) day(-1) (I(2) = 0%, P = 0.45), platelet transfusion by 3.7 ml kg(-1) day(-1) (I(2) = 0%, P = 0.46) and fresh frozen plasma transfusion by 5.4 ml kg(-1) day(-1) (I(2) = 0%, P = 0.53). The number of children who avoided all blood product transfusions was not reported in most of the studies. Evaluation of the side effects associated with TXA use and the effects of the agent on postoperative morbidity and mortality was not possible from the data. There was marked variability in the dosage and infusion schemes used in different studies. This systematic review showed that in paediatric cardiac surgery, the benefit-to risk ratio associated with the use of TXA cannot be adequately defined. Evidence supporting the routine use of TXA in paediatric cardiac surgery remains weak. PMID- 22531272 TI - Editorial comment: The Borst elephant trunk technique is not lethal! PMID- 22531273 TI - Surgical treatment to increase the success rate of multidrug-resistant tuberculosis. AB - OBJECTIVE: Mycobacterium tuberculosis infects more than one-third of the world's population and causes an estimated 2-3 million deaths annually. The medical treatment of multidrug-resistant tuberculosis (MDR-TB) can cure 50-75% of cases. The median prevalence of new MDR-TB cases is 1.1%, while that of previously treated cases is 7%. METHODS: We carried out a retrospective study on 45 patients with MDR-TB who underwent surgical resection at the Leon Daniello Hospital (Regional Surgery Department) between January 1995 and December 2005. The number of MDR-TB cases has continued to increase despite the implementation of MDR-TB treatment strategies. Drug susceptibility tests showed that all our patients were resistant to at least isoniazid (hydrazide) and rifampicin. Therefore, individual drug regimens including at least five antibiotics were prescribed. Surgery under general anaesthesia (double-lumen endotracheal intubation) was performed by a team of thoracic surgeons. The patients had received anti-tuberculosis (TB) treatment for at least 1 month preoperatively as well as postoperatively. RESULTS: We collected and analysed patients' demographic data, clinical characteristics, place of origin, radiological findings, smear and culture status before surgery, TB localization, primary or secondary drug resistance, surgical procedures, complications, bacteriological smear and culture status after surgical treatment. The indications for surgery include medical treatment failure in 39 patients, persistent cavitary lesions with possible relapses in 3 patients and massive haemoptysis in 3 patients. Lobectomy was carried out in 30 cases, segmentectomy in four cases and cavernoplasty (speleoplasty) in 11 cases. Four weeks postoperatively, there were 83% smear-negative and 17% smear-positive patients. Only minor complications were registered: three patients had wound infections, two had minor haemorrhages and one presented a minor pneumothorax. Operative mortality was zero. CONCLUSIONS: The absolute indications for the surgical treatment of MDR-TB include failure of medical therapy (due to persistent cavitary disease and lung or lobar destruction) and massive haemoptysis. Proper patient selection and the timing of operations are crucial to avoid relapses and to provide a definitive cure. Good cooperation between chest physicians and thoracic surgeons as well as patients' adherence to pre- and post chemotherapy can increase the success rate of MDR-TB treatment. PMID- 22531275 TI - Small-bowel necrosis complicating a cytomegalovirus-induced superior mesenteric vein thrombosis in an immunocompetent patient: a case report. AB - INTRODUCTION: Superior mesenteric venous thrombosis as a result of acute cytomegalovirus infection is rare, with only a few cases reported in the literature. CASE PRESENTATION: We present the case of a 40-year-old Caucasian man who was admitted to our hospital with a 5-day history of fever. His serological test and pp65 antigen detection of cytomegalovirus were positive, suggesting acute infection. On the sixth day after his admission, the patient complained of acute, progressive abdominal pain. Abdominal computed tomography revealed acute superior mesenteric venous thrombosis. An emergency laparotomy showed diffuse edema and ischemic lesions of the small bowel and its associated mesentery with a 50-cm-long segmental infarction of the proximal jejunum. An extensive enterectomy of about 100 cm of jejunum that included the necrotic segment was performed, followed by an end-to-end anastomosis. Anti-coagulation therapy was administered pre-operatively in the form of small-fractionated heparin and continued postoperatively. The patient had an uneventful recovery and was discharged on the 11th postoperative day. CONCLUSION: Acute cytomegalovirus infection can contribute to the occurrence of mesenteric venous thrombosis in immunocompetent patients. It is important for physicians and internists to be aware of the possible thrombotic complications of cytomegalovirus infection. A high level of clinical suspicion is essential to successfully treat a potentially lethal condition such as superior mesenteric venous thrombosis. PMID- 22531274 TI - Quality of life in high-risk patients: comparison of transcatheter aortic valve implantation with surgical aortic valve replacement. AB - OBJECTIVES: To compare health-related quality of life (QoL) in patients undergoing transcatheter aortic valve implantation via transapical access (TA TAVI) with patients undergoing surgical aortic valve replacement (SAVR). METHODS: One hundred and forty-four high-risk patients referred for aortic valve replacement underwent TAVI screening and were assigned to either TA TAVI (n = 51, age 79.7 +/- 9.2 years, logistic EuroSCORE 26.5 +/- 16.1%, 51% males) or SAVR (n = 93, age 81.1 +/- 5.3 years, logistic EuroSCORE 12.1 +/- 9.3%, 42% males) by the interdisciplinary heart team. QoL was assessed using the Short Form 36 (SF-36) Health Survey Questionnaire and the Hospital Anxiety and Depression Scale. Furthermore, current living conditions and the degree of independence at home were evaluated. RESULTS: Patients undergoing TA TAVI were at higher risk as assessed by EuroSCORE (26.5 +/- 16 vs. 12.1 +/- 9, P < 0.001) and STS score (6.7 +/- 4 vs. 4.4 +/- 3, P < 0.001) compared with SAVR patients. At the 30-day follow up, the rate of mortality was similar and amounted to 7.8% for TA TAVI and 7.5% for SAVR patients and raised to 25.5% in TA TAVI and 18.3% in SAVR patients after a follow-up period of 15 +/- 10 months. Assessment of QoL revealed no differences in terms of anxiety and depression between TA TAVI and SAVR patients. The SF-36 mental health metascore was similar in both groups (65.6 +/- 19 vs. 68.8 +/- 22, P = 0.29), while a significant difference was observed in the physical health metascore (49.7 +/- 21 vs. 62.0 +/- 21, P = 0.015). After adjustment for baseline characteristics, this difference disappeared. However, every added point in the preoperative risk assessment with the STS score decreased the SF-36 physical health dimension by two raw points at the follow-up assessment. CONCLUSIONS: Selected high-risk patients undergoing TAVI by using a transapical access achieve similar clinical outcomes and QoL compared with patients undergoing SAVR. Increased STS scores predict worse QoL outcomes. PMID- 22531276 TI - Axonal and oligodendrocyte-localized IgM and IgG deposits in MS lesions. AB - BACKGROUND: Recent findings support the important role of antibodies in multiple sclerosis (MS) physiopathology. Thus, local IgG synthesis is a hallmark of the disease, and intrathecal IgM synthesis associates with a poor disease outcome. METHODOLOGY: The aim of this study was to investigate the presence of IgM and IgG in demyelinating lesions using high sensitivity immunohistochemistry techniques in necropsies from fourteen MS patients, four controls without neurological disease and four cases with non MS CNS inflammatory disease. RESULTS: IgG and IgM were absent in controls. Conversely, we found IgM in about 50% and IgG in 75% of MS patients. The presence of IgM and IgG antibodies was independent of disease duration, clinical disease type or lesion stage. IgM and IgG were present in acute, chronic active and chronic inactive lesions. Double immunofluorescence showed that IgM and IgG were detected on axons and oligodendrocytes in demyelinated areas. Moreover, we observed immunoglobulin deposits on oligodendrocytes in NAWM in some cases. IgG and IgM colocalized with complement C3b on demyelinated axons and oligodendrocytes and antibody-antigen immunocomplexes were detected in foamy macrophages in active lesion areas. These findings were absent from cases of non-neurological disease and cases with non-MS CNS inflammatory disease. SIGNIFICANCE OF THE STUDY: These observations provide further evidence on the role of antibodies, complement and macrophages in plaque development, and strongly suggest they can induce axonal injury, an important cause of disability in MS. They may provide novel therapeutic strategies to limit tissue degeneration in the disease. PMID- 22531277 TI - p70S6 kinase phosphorylation for pharmacodynamic monitoring. AB - Inhibitors of the mammalian target of rapamycin (mTOR) are administered as immunosuppressant as well as antineoplastic agents. Because of the narrow therapeutic index of mTOR inhibitors, drug monitoring is required, and this is usually done by measuring blood drug levels. Increasing knowledge of the signaling pathways of the mTOR protein kinase provides an opportunity for pharmacodynamic drug monitoring. With the different laboratory methods it is becoming possible to measure new biomarkers to control the influence of mTOR activity. One of these biomarkers is phospho-S6 kinase, with its isoform p70S6K. PMID- 22531278 TI - Highly selective and sensitive detection of Cu2+ with lysine enhancing bovine serum albumin modified-carbon dots fluorescent probe. AB - Based on the ability of lysine (Lys) to enhance the fluorescence intensity of bovine serum albumin modified-carbon dots (CDs-BSA) to decrease surface defects and quench fluorescence of the CDs-BSA-Lys system in the presence of Cu(2+) under conditions of phosphate buffer (PBS, pH = 5.0) at 45 degrees C for 10 min, a sensitive Lys enhancing CDs-BSA fluorescent probe was designed. The environment friendly, simple, rapid, selective and sensitive fluorescent probe has been utilized to detect Cu(2+) in hair and tap water samples and it achieved consistent results with those obtained by inductively coupled plasma mass spectroscopy (ICP-MS). The mechanism of the proposed assay for the detection of Cu(2+) is discussed. PMID- 22531279 TI - Beyond azide-alkyne click reaction: easy access to 18F-labelled compounds via nitrile oxide cycloadditions. AB - Radiofluorinated 4-fluorobenzonitrile oxide and N-hydroxy-4-fluorobenzimidoyl chloride rapidly react with different alkenes and alkynes under mild conditions. These cycloadditions are suitable for the preparation of low-molecular weight radiopharmaceuticals and, in a strain-promoted variant, can enable easy labelling of sensitive biopolymers. PMID- 22531280 TI - An electrical impedance tomography system for gynecological application GIT with a tiny electrode array. AB - The paper describes the development of an electrical impedance tomography (EIT) system for gynecologic research. The GIT (gynecological impedance tomography) system has 48 electrodes and is embedded on a small space (30 mm diameter and 20 mm height) inside of the vaginal probe. The system provides real-time (one shot per second) 3D visualization of the spatial distribution of the static electrical properties of the cervix tissue. History, advantages, disadvantages and aspects of the system development are also described. The algorithm for the tiny measuring array organization is given. New details of the backprojection method on the non-regular electrode array are discussed. Some pictures reconstructed from numerical simulated data are offered. 3D visualization of the test object and cervix is presented. PMID- 22531284 TI - Australian normative data for the Overall Assessment of the Speaker's Experience of Stuttering. AB - People who stutter often report negative impacts on their wellbeing as a result of their chronic fluency disorder. The need for a comprehensive assessment of the wellbeing and experience of stuttering should be a prime consideration when measuring treatment outcomes. One such measure designed to evaluate wellbeing and aspects of the individual's experience of his or her stuttering is the Overall Assessment of the Speaker's Experience of Stuttering (OASES). Normative data for the OASES Adult version (OASES-A; and hereafter referred to simply as the OASES) has begun to be collected over the past 10 years, though none are available for an Australian population. This paper presents Australian normative data for the OASES for 200 adult males and females who stutter, aged between 18 and 85 years. Additionally, the influence of age, sex, and frequency of stuttering on the Australian OASES scores are also presented. No significant relationships between OASES scores were found for sex and age, which is in keeping with the USA original dataset. However, those participants who had more severe stuttering were more likely to have higher negative impacts for 'General Information', Communication in Daily Situations,' and for the overall OASES score. Implications for further research are discussed. EDUCATIONAL OBJECTIVES: The reader will be able to: (i) describe the purpose of the Overall Experience of the Speaker's Experience of Stuttering for Adults (OASES), (ii) evaluate the relevance of the OASES to treatment planning and the evaluation of stuttering treatment outcomes in the adult population, and (iii) compare Australian normative dataset with the USA and Dutch normative datasets for the OASES. PMID- 22531283 TI - Recounting the K-12 school experiences of adults who stutter: a qualitative analysis. AB - This study qualitatively explored the primary and secondary (K-12) school experiences of adults who stutter. The primary investigator conducted semi structured interviews with 11 participants, a first focus group interview with 6 participants, and a second focus group interview with 4 participants. Participants discussed the various ways in which stuttering affected their personality; emotional and psychological experiences in the context of school; academic and learning experiences; classroom participation; teacher and peer relationships; speech therapy experiences; school activity involvement; and post educational experiences. Results suggest that school is a complex cultural environment in which students must engage on academic and social levels. People who stutter may experience observable and unobservable challenges as they navigate the complexity of school. EDUCATIONAL OBJECTIVES: After reading this article, the reader will be able to: (1) provide a rationale for the need to explore the school experiences of people who stutter; (2) describe the major themes associated with the school experiences of participants in the study; and (3) discuss how knowledge of school experiences can be useful to classroom teachers and speech-language pathologists. PMID- 22531285 TI - Phonological priming in adults who stutter. AB - The purpose of this study was to compare the speed of phonological encoding between adults who stutter (AWS) and adults who do not stutter (ANS). Fifteen male AWS and 15 age- and gender-matched ANS participated in the study. Speech onset latency was obtained for both groups and stuttering frequency was calculated for AWS during three phonological priming tasks: (1) heterogeneous, during which the participants' single-word verbal responses differed phonemically; (2) C-homogeneous, during which the participants' response words shared the initial consonant; and (3) CV-homogeneous, during which the participants' response words shared the initial consonant and vowel. Response words containing the same C and CV patterns in the two homogeneous conditions served as phonological primes for one another, while the response words in the heterogeneous condition did not. During each task, the participants produced a verbal response after being visually presented with a semantically related cue word, with cue-response pairs being learned beforehand. The data showed that AWS had significantly longer speech onset latency when compared to ANS in all priming conditions, priming had a facilitating effect on word retrieval for both groups, and there was no significant change in stuttering frequency across the conditions for AWS. This suggests that phonological encoding may play no role, or only a minor role, in stuttering. EDUCATIONAL OBJECTIVES: The reader will be able to: (1) describe previous research paradigms that have been used to assess phonological encoding in adults and children who stutter; (2) explain performance similarities and differences between adults who do and do not stutter during various phonological priming conditions; (3) compare the present findings to past research that examined the relationship between phonological encoding and stuttering. PMID- 22531286 TI - The impact of adolescent stuttering on educational and employment outcomes: evidence from a birth cohort study. AB - PURPOSE: In interview and survey studies, people who stutter report the belief that stuttering has had a negative impact on their own education and employment. This population study sought objective evidence of such disadvantage for people who stutter as a group, compared with people who do not stutter. METHOD: A secondary analysis of a British birth cohort dataset was used in the study. At age 16, there were 217 cohort members who were reported by their parents to stutter, and 15,694 cohort members with no known history of stuttering or other speech problems. Data were analysed concerning factors associated with report of stuttering at 16, school leaving age, highest qualification, unemployment early in working life, pay at age 23 and 50, and social class of job at age 23 and 50. RESULTS: Those who stuttered at 16 were statistically more likely than those who did not stutter to be male, to have poorer cognitive test scores, and to have been bullied. There were no significant effects of stuttering on educational outcomes. For employment outcomes, the only significant association with stuttering concerned socioeconomic status of occupation at 50, with those who had been reported to stutter having lower-status jobs. DISCUSSION: These findings fail to support the belief that stuttering has a negative impact on education and employment. The higher likelihood of those who stutter working in lower-status positions may reflect their preference for avoiding occupations perceived to require good spoken communication abilities. Therapeutic implications are discussed. EDUCATIONAL OBJECTIVES: The reader will be able to describe (a) prior work on the impact of stuttering on education and employment, (b) some characteristics of the National Child Development Study (NCDS), (c) the effect of stuttering on school leaving age and highest educational qualification in NCDS, (d) the effect of stuttering on employment outcomes in NCDS: unemployment by age 23, pay at 23 and 50, and socioeconomic status of occupation at 23 and 50. PMID- 22531287 TI - Immediate effects of AAF devices on the characteristics of stuttering: a clinical analysis. AB - The present study investigated the immediate effects of altered auditory feedback (AAF) and one Inactive Condition (AAF parameters set to 0) on clinical attributes of stuttering during scripted and spontaneous speech. Two commercially available, portable AAF devices were used to create the combined delayed auditory feedback (DAF) and frequency altered feedback (FAF) effects. Thirty adults, who stutter, aged 18-68 years (M=36.5; SD=15.2), participated in this investigation. Each subject produced four sets of 5-min of oral reading, three sets of 5-min monologs as well as 10-min dialogs. These speech samples were analyzed to detect changes in descriptive features of stuttering (frequency, duration, speech/articulatory rate, core behaviors) across the various speech samples and within two SSI-4 (Riley, 2009) based severity ratings. A statistically significant difference was found in the frequency of stuttered syllables (%SS) during both Active Device conditions (p=.000) for all speech samples. The most sizable reductions in %SS occurred within scripted speech. In the analysis of stuttering type, it was found that blocks were reduced significantly (Device A: p=.017; Device B: p=.049). To evaluate the impact on severe and mild stuttering, participants were grouped into two SSI-4 based categories; mild and moderate-severe. During the Inactive Condition those participants within the moderate-severe group (p=.024) showed a statistically significant reduction in overall disfluencies. This result indicates, that active AAF parameters alone may not be the sole cause of a fluency-enhancement when using a technical speech aid. EDUCATIONAL OBJECTIVES: The reader will learn and be able to describe: (1) currently available scientific evidence on the use of altered auditory feedback (AAF) during scripted and spontaneous speech, (2) which characteristics of stuttering are impacted by an AAF device (frequency, duration, core behaviors, speech & articulatory rate, stuttering severity), (3) the effects of an Inactive Condition on people who stutter (PWS) falling into two severity groups, and (4) how the examined participants perceived the use of AAF devices. PMID- 22531288 TI - The experiences of living with a sibling who stutters: a preliminary study. AB - Stuttering impacts on the child in a variety of ways, notably in terms of communicative impairment and psychosocial impact. In addition, the stuttering disorder has a holistic impact, affecting those with whom the child who stutters lives. Within the family constellation, the closest person to the individual who stutters is often their sibling. This study investigated the experiences of fluent siblings of children who stutter to examine the impact that stuttering may have on their lives. A mixed methods research design incorporated qualitative semi-structured interviews and quantitative questionnaires. The results of the qualitative investigation revealed four aspects of children's lives that were affected by having a sibling who stuttered: the relationship between siblings, the impact on the fluent sibling, the impact on the parent relationship with both children, and the impact on the sibling's relationship with others. Findings revealed that siblings of children who stutter exhibited strongly negative emotions, and differing levels of responsibility associated with their involvement in the actual stuttering management programme. Furthermore, for the fluent sibling, secondary to having a brother or sister who stuttered, communication with and attention from their parents was variable. The results of the quantitative component of the study revealed children who stutter and their siblings demonstrated significantly greater closeness, and concurrently, increased conflict and status disparity than did the control fluent sibling dyads. The parents of the experimental sibling dyads also demonstrated significantly greater partiality towards a child, namely the child who stuttered, than did the parents of the control sibling dyads. EDUCATIONAL OBJECTIVES: The reader will be able to: (1) identify the themes associated with having a sibling who stutters; (2) identify how the quality of the sibling relationship differs between sibling dyads that do and do not consist of a sibling who stutters; and (3) discuss the clinical implications of the results with regards to working with children who stutter and their families. PMID- 22531289 TI - Mobile and home-based vendors' contributions to the retail food environment in rural South Texas Mexican-origin settlements. AB - A growing concern with high rates of obesity and overweight among immigrant minority populations in the US has focused attention on the availability and accessibility to healthy foods in such communities. Small-scale vending in rural, impoverished and underserved areas, however, is generally overlooked; yet, this type of informal activity and source for food is particularly important in such environs, or "food desserts," where traditional forms of work and mainstream food outlets are limited or even absent. This exploratory study investigates two types of small-scale food vending that take place in rural colonias, or Mexican-origin settlements along the South Texas border with Mexico: mobile and home-based. Using a convenience sample of 23 vendors who live and work in Texas colonias, this study identifies the characteristics associated with mobile and home-based food vendors and their businesses and its contributions to the rural food environment. Findings reveal that mobile and home-based vending provides a variety of food and beverage options to colonia residents, and suggests that home based vendors contribute a greater assortment of food options, including some healthier food items, than mobile food vendors, which offer and sell a limited range of products. Findings may contribute to the development of innovative policy solutions and interventions aimed at increasing healthy food options or reducing health disparities in immigrant communities. PMID- 22531290 TI - Solvent dependence of helix stability in aromatic oligoamide foldamers. AB - A new helical aromatic oligoamide foldamer, bearing triethyleneglycol side chains for solubility in a broad range of media, was prepared. The stability of the helical conformation was assessed in various solvents and shown to vary greatly and unexpectedly. Stability was remarkably enhanced in methanol-water mixtures. PMID- 22531292 TI - Sex-specific influence of DRD2 on ADHD-type temperament in a large population based birth cohort. AB - Attention-deficit/hyperactivity disorder (ADHD) is a childhood-onset neurodevelopmental disorder with a significant public-health impact. Previously, we described a candidate gene study in a population-based birth cohort that demonstrated an association with ADHD-affected males and the dopamine receptor D2 (DRD2). The current study evaluates potential associations of dopamine receptor genes and Cloninger temperament traits within this same sample. Participants with stringent lifetime ADHD diagnoses were ascertained systematically from the genetically isolated Northern Finland 1986 Birth Cohort (n=9432), resulting in 178 cases and 157 controls. Markers in all known dopamine receptor genes were genotyped. We report an association of DRD2 with low Persistence in females (rs1079727 P=0.02, rs1124491 P=0.02, rs1800497 P=0.03). The associated DRD2 minor allelic haplotype (CAA, P=0.03) is the same haplotype we previously associated with ADHD in males in this birth cohort. The current study further supports previous results on the role of DRD2 in individuals with ADHD. Investigations suggest that DRD2 may have an impact on both males and females, but the particular outcome appears sex-specific, manifesting as ADHD in males and low Persistence in females. Furthermore, these findings suggest that the putative role of low Persistence as an endophenotype for ADHD deserves further investigation. PMID- 22531291 TI - The NALP3 inflammasome is involved in neurotoxic prion peptide-induced microglial activation. AB - BACKGROUND: Prion diseases are neurodegenerative disorders characterized by the accumulation of an abnormal disease-associated prion protein, PrPSc. In prion infected brains, activated microglia are often present in the vicinity of PrPSc aggregates, and microglial activation is thought to play a key role in the pathogenesis of prion diseases. Although interleukin (IL)-1beta release by prion induced microglia has been widely reported, the mechanism by which primed microglia become activated and secrete IL-1beta in prion diseases has not yet been elucidated. In this study, we investigated the role of the NACHT, LRR and PYD domains-containing protein (NALP)3 inflammasome in IL-1beta release from lipopolysaccharide (LPS)-primed microglia after exposure to a synthetic neurotoxic prion fragment (PrP106-126). METHODS: The inflammasome components NALP3 and apoptosis-associated speck-like protein (ASC) were knocked down by gene silencing. IL-1beta production was assessed using ELISA. The mRNA expression of NALP3, ASC, and pro-inflammatory factors was measured by quantitative PCR. Western blot analysis was used to detect the protein level of NALP3, ASC, caspase 1 and nuclear factor-kappaB. RESULTS: We found that that PrP106-126-induced IL 1beta release depends on NALP3 inflammasome activation, that inflammasome activation is required for the synthesis of pro-inflammatory and chemotactic factors by PrP106-126-activated microglia, that inhibition of NF-kappaB activation abrogated PrP106-126-induced NALP3 upregulation, and that potassium efflux and production of reactive oxygen species were implicated in PrP106-126 induced NALP3 inflammasome activation in microglia. CONCLUSIONS: We conclude that the NALP3 inflammasome is involved in neurotoxic prion peptide-induced microglial activation. To our knowledge, this is the first time that strong evidence for the involvement of NALP3 inflammasome in prion-associated inflammation has been found. PMID- 22531293 TI - Polymorphisms in the glutamate transporter gene SLC1A1 and obsessive-compulsive symptoms induced by second-generation antipsychotic agents. AB - BACKGROUND: A large subgroup of schizophrenic patients develops obsessive compulsive symptoms (OCS) during treatment with second-generation antipsychotics (SGA). A genetic risk factor for these secondary OCS was recently described in the gene SLC1A1 encoding the neuronal glutamate transporter excitatory amino acid carrier 1. The aim of this study was to replicate these findings in a European sample. METHODS: A total of 103 schizophrenic patients treated with SGAs were included. Three single nucleotide polymorphisms in SLC1A1 (rs2228622, rs3780412 and rs3780413), which had been associated with SGA-induced OCS, were investigated. Single marker and haplotype analyses were tested with logistic regressions using age, sex and medication type as covariates. RESULTS: Treatment with markedly antiserotonergic SGAs such as clozapine was more prevalent in the subgroup of patients with comorbid OCS (P<0.001). The dosage and duration of clozapine treatment correlated significantly with the severity of OCS. In contrast to the Asian sample, no genetic associations were found with OCS. CONCLUSION: Larger samples are necessary to unravel the interplay of pharmacological and genetic risk factors for OCS in schizophrenia. PMID- 22531294 TI - Retinal projections and neurochemical characterization of the pregeniculate nucleus of the common marmoset (Callithrix jacchus). AB - In mammals, the suprachiasmatic nucleus (SCN) and the intergeniculate leaflet (IGL) are the main components of the circadian timing system. The SCN is the site of the endogenous biological clock that generates rhythms and synchronizes them to environmental cues. The IGL is a key structure that modulates SCN activity and is responsible for the transmission of non-photic information to the SCN, thus participating in the integration between photic and non-photic stimuli. Both the SCN and IGL receive projections of retinal ganglion cells and the IGL is connected to the SCN through the geniculohypothalamic tract. Little is known about these structures in the primate brain and the pregeniculate nucleus (PGN) has been suggested to be the primate equivalent of the rodent IGL. The aim of this study was to characterize the PGN of a primate, the common marmoset (Callithrix jacchus), and to analyze its retinal afferents. Here, the marmoset PGN was found to be organized into three subsectors based on neuronal size, pattern of retinal projections, and the distribution of neuropeptide Y-, GAD-, serotonin-, enkephalin- and substance P-labeled terminals. This pattern indicates that the marmoset PGN is equivalent to the IGL. This detailed description contributes to the understanding of the circadian timing system in this primate species considering the importance of the IGL within the context of circadian regulation. PMID- 22531295 TI - Relegating malaria resurgences to history. AB - Progress in malaria control over the past decade has been striking, with malaria mortality rates falling by approximately one quarter globally and more than a third in the World Health Organization African Region. In the accompanying paper, Cohen et al. demonstrate the potential fragility of these gains, comprehensively describing malaria resurgences that have occurred over the past 80 or so years. They found that the vast majority of resurgences were due, at least in part, to the weakening of malaria control programmes; resource constraints were the most commonly identified factor. Their findings are timely and compelling, demonstrating that global efforts will be wasted if the required resources are not secured to achieve and maintain universal access to life-saving malaria prevention and control tools. The greatest threats to current malaria control efforts are not biological, but financial. The increases in funding for malaria over the past decade, while impressive, still fall far short of the nearly $6 billion dollars required annually. Domestic spending by endemic country governments on malaria specifically, and health more generally, could go a long way towards filling the projected funding gap. However, external funding is also essential, and the global community needs to work together to ensure full funding of the Global Fund to Fight AIDS, Tuberculosis, and Malaria, which has been the single largest source of malaria funding over the past decade. This year, on April 25th, World Malaria Day will be celebrated with the theme Sustain Gains, Save Lives: Invest in Malaria. The review by Cohen et al. suggests one possible future if such investment is not made. However, with sufficient support, malaria resurgences can be relegated to history. PMID- 22531296 TI - A distinct DNA methylation signature defines pediatric pre-B cell acute lymphoblastic leukemia. AB - Pre-B cell acute lymphoblastic leukemia (ALL) is the most prevalent childhood malignancy and remains one of the highest causes of childhood mortality. Despite this, the mechanisms leading to disease remain poorly understood. We asked if recurrent aberrant DNA methylation plays a role in childhood ALL and have defined a genome-scale DNA methylation profile associated with the ETV6-RUNX1 subtype of pediatric ALL. Archival bone marrow smears from 19 children collected at diagnosis and remission were used to derive a disease specific DNA methylation profile. The gene signature was confirmed in an independent cohort of 86 patients. A further 163 patients were analyzed for DNA methylation of a three gene signature. We found that the DNA methylation signature at diagnosis was unique from remission. Fifteen loci were sufficient to discriminate leukemia from disease-free samples and purified CD34+ cells. DNA methylation of these loci was recurrent irrespective of cytogenetic subtype of pre-B cell ALL. We show that recurrent aberrant genomic methylation is a common feature of pre-B ALL, suggesting a shared pathway for disease development. By revealing new DNA methylation markers associated with disease, this study has identified putative targets for development of novel epigenetic-based therapies. PMID- 22531298 TI - Dual action of NO synthases on blood flow and infarct volume consecutive to neonatal focal cerebral ischemia. AB - Research into neonatal ischemic brain damage is impeded by the lack of a complete understanding of the initial hemodynamic mechanisms resulting in a lesion, particularly that of NO-mediated vascular mechanisms. In a neonatal stroke rat model, we recently show that collateral recruitment contributes to infarct size variability. Non-specific and selective NO synthase (NOS) inhibition was evaluated on cerebral blood-flow changes and outcome in a P7 rat model of arterial occlusion (left middle cerebral artery electrocoagulation with 50 min occlusion of both common carotid arteries). Blood-flow changes were measured by using ultrasound imaging with sequential Doppler recordings in both internal carotid arteries and basilar trunk. Cortical perfusion was measured by using laser Doppler flowmetry. We showed that global NOS inhibition significantly reduced collateral support and cortical perfusion (collateral failure), and worsened the ischemic injury in both gender. Conversely, endothelial NOS inhibition increased blood-flows and aggravated volume lesion in males, whereas in females blood-flows did not change and infarct lesion was significantly reduced. These changes were associated with decreased phosphorylation of neuronal NOS at Ser(847) in males and increased phosphorylation in females at 24h, respectively. Neuronal NOS inhibition also increased blood-flows in males but not in females, and did not significantly change infarct volumes compared to their respective PBS-treated controls. In conclusion, both nNOS and eNOS appear to play a key role in modulating arterial blood flow during ischemia mainly in male pups with subsequent modifications in infarct lesion. PMID- 22531297 TI - Population genetic structure of Aedes polynesiensis in the Society Islands of French Polynesia: implications for control using a Wolbachia-based autocidal strategy. AB - BACKGROUND: Aedes polynesiensis is the primary vector of Wuchereria bancrofti in the South Pacific and an important vector of dengue virus. An improved understanding of the mosquito population genetics is needed for insight into the population dynamics and dispersal, which can aid in understanding the epidemiology of disease transmission and control of the vector. In light of the potential release of a Wolbachia infected strain for vector control, our objectives were to investigate the microgeographical and temporal population genetic structure of A. polynesiensis within the Society Islands of French Polynesia, and to compare the genetic background of a laboratory strain intended for release into its population of origin. METHODS: A panel of eight microsatellite loci were used to genotype A. polynesiensis samples collected in French Polynesia from 2005-2008 and introgressed A. polynesiensis and Aedes riversi laboratory strains. Examination of genetic differentiation was performed using F-statistics, STRUCTURE, and an AMOVA. BAYESASS was used to estimate direction and rates of mosquito movement. RESULTS: FST values, AMOVA, and STRUCTURE analyses suggest low levels of intra-island differentiation from multiple collection sites on Tahiti, Raiatea, and Maupiti. Significant pair-wise FST values translate to relatively minor levels of inter-island genetic differentiation between more isolated islands and little differentiation between islands with greater commercial traffic (i.e., Tahiti, Raiatea, and Moorea). STRUCTURE analyses also indicate two population groups across the Society Islands, and the genetic makeup of Wolbachia infected strains intended for release is similar to that of wild-type populations from its island of origin, and unlike that of A. riversi. CONCLUSIONS: The observed panmictic population on Tahiti, Raiatea, and Moorea is consistent with hypothesized gene flow occurring between islands that have relatively high levels of air and maritime traffic, compared to that of the more isolated Maupiti and Tahaa. Gene flow and potential mosquito movement is discussed in relation to trials of applied autocidal strategies. PMID- 22531299 TI - Re: Pontes HA, Pontes FS, Lameira AG, Salim RA, Carvalho PL, Guimaraes DM, Pinto Ddos S Jr.: Report of four cases of ameloblastic fibro-odontoma in mandible and discussion of the literature about the treatment. J Craniomaxillofac Surg 40(2): e59-e63, 2012 Feb. Epub 2011 Apr 15. PMID- 22531300 TI - Design and evaluation of cyclodextrin-based delivery systems to incorporate poorly soluble curcumin analogs for the treatment of melanoma. AB - Various analogs of curcumin show high in vitro cytotoxic activity and are potential candidates for treating a deadly skin disease, melanoma. Due to the low solubility of the drugs, a new delivery agent, namely a cationic gemini surfactant-conjugated beta-cyclodextrin, was designed to incorporate novel drug candidates of the 1,5-diaryl-3-oxo-1,4-pentadienyl family. Based on physicochemical parameters, such as particle size and zeta potential, a schematic model for the potential interaction of the drug with the delivery agent was developed. The drug formulations were highly efficient in inhibiting the growth of melanoma cells, with IC(50) values significantly lower than melphalan, the drug currently used for the treatment of in-transit melanoma. CDgemini formulations showed excellent cellular selectivity, triggering apoptosis in the A375 cell line while showing no cytotoxicity to healthy human epidermal keratinocytes. The goal is to develop this novel nanoparticle approach into a non invasive therapy for in-transit melanoma metastasis that lacks adequate treatment to date. PMID- 22531301 TI - Etiology of autistic features: the persisting neurotoxic effects of propionic acid. AB - BACKGROUND: Recent clinical observations suggest that certain gut and dietary factors may transiently worsen symptoms in autism. Propionic acid (PA) is a short chain fatty acid and an important intermediate of cellular metabolism. Although PA has several beneficial biological effects, its accumulation is neurotoxic. METHODS: Two groups of young Western albino male rats weighing about 45 to 60 grams (approximately 21 days old) were used in the present study. The first group consisted of oral buffered PA-treated rats that were given a neurotoxic dose of 250 mg/kg body weight/day for three days, n = eight; the second group of rats were given only phosphate buffered saline and used as a control. Biochemical parameters representing oxidative stress, energy metabolism, neuroinflammation, neurotransmission, and apoptosis were investigated in brain homogenates of both groups. RESULTS: Biochemical analyses of brain homogenates from PA-treated rats showed an increase in oxidative stress markers (for example, lipid peroxidation), coupled with a decrease in glutathione (GSH) and glutathione peroxidase (GPX) and catalase activities. Impaired energy metabolism was ascertained through the decrease of lactate dehydrogenase and activation of creatine kinase (CK). Elevated IL-6, TNFalpha, IFNgamma and heat shock protein 70 (HSP70) confirmed the neuroinflammatory effect of PA. Moreover, elevation of caspase3 and DNA fragmentation proved the pro-apoptotic and neurotoxic effect of PA to rat pups CONCLUSION: By comparing the results obtained with those from animal models of autism or with clinical data on the biochemical profile of autistic patients, this study showed that the neurotoxicity of PA as an environmental factor could play a central role in the etiology of autistic biochemical features. PMID- 22531303 TI - The antinociceptive effect of acetaminophen in a rat model of neuropathic pain. AB - Acetaminophen is one of the most popular and widely used analgesics for the treatment of pain and fever but few studies have evaluated its effects on neuropathic pain. This study examined the effect of acetaminophen on thermal hyperalgesia, mechanical and cold allodynia in a rat model of neuropathic pain. Male Sprague-Dawley rats were prepared by tightly ligating the left L5 and L6 spinal nerves to produce a model of neuropathic pain. Sixty neuropathic rats were assigned randomly into six groups. Normal saline and acetaminophen (25, 50, 100, 200 and 300 mg/kg) were administered intraperitoneally to these individual groups. Thermal hyperalgesia, mechanical and cold allodynia were examined at preadministration and at 15, 30, 60, 90, 120, 180, 240 and 360 min after administering the drug. Mechanical allodynia was quantified by measuring the paw withdrawal threshold to stimuli with von Frey filaments. Cold allodynia was quantified by measuring the frequency of foot lift after applying 100% acetone. Thermal hyperalgesia was quantified by measuring the thermal withdrawal threshold. The rotarod performance was measured to detect any drug-induced adverse effects, such as drowsiness. The hepatic and renal adverse effect was also assessed by measuring the serum levels of aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen and creatinine. The paw withdrawal thresholds to mechanical stimuli and the thermal withdrawal threshold were increased significantly and withdrawal frequencies to cold stimuli were reduced by acetaminophen administration in a dose-dependent manner. Acetaminophen reduces thermal hyperalgesia, mechanical and cold allodynia in a rat model of neuropathic pain, and might be useful for managing neuropathic pain. PMID- 22531302 TI - Molecular markers associated with nonepithelial ovarian cancer in formalin-fixed, paraffin-embedded specimens by genome wide expression profiling. AB - Nonepithelial ovarian cancer (NEOC) is a rare cancer that is often misdiagnosed as other malignant tumors. Research on this cancer using fresh tissues is nearly impossible because of its limited number of samples within a limited time provided. The study is to identify potential genes and their molecular pathways related to NEOC using formalin-fixed paraffin embedded samples. Total RNA was extracted from eight archived NEOCs and seven normal ovaries. The RNA samples with RNA integrity number >2.0, purity >1.7 and cycle count value <28 cycles were hybridized to the Illumina Whole-Genome DASL assay (cDNA-mediated annealing, selection, extension, and ligation). We analyzed the results using the GeneSpring GX11.0 and FlexArray software to determine the differentially expressed genes. Microarray results were validated using an immunohistochemistry method. Statistical analysis identified 804 differentially expressed genes with 443 and 361 genes as overexpressed and underexpressed in cancer, respectively. Consistent findings were documented for the overexpression of eukaryotic translation elongation factor 1 alpha 1, E2F transcription factor 2, and fibroblast growth factor receptor 3, except for the down-regulated gene, early growth response 1 (EGR1). The immunopositivity staining for EGR1 was found in the majority of cancer tissues. This finding suggested that the mRNA level of a transcript did not always match with the protein expression in tissues. The current gene profile can be the platform for further exploration of the molecular mechanism of NEOC. PMID- 22531305 TI - Carbon dioxide insufflation during withdrawal of the colonoscope improved postprocedure discomfort: a prospective, randomized, controlled trial. AB - In colonoscopy, the question of when and how to use carbon dioxide (CO(2)) insufflation remains uncertain. Inspection for the pathological changes during colonoscopy takes place during the withdrawal of the scope. This study aimed to determine whether CO(2) insufflation only at the withdrawal of the colonoscope has an effect comparable to that of CO(2) usage throughout the course of the procedure. Symptomatic patients were randomized in three groups: (1) patients given air insufflation (A; n = 33); (2) patients given CO(2) insufflation only at the time of scope withdrawal (CW; n = 33); and (3) patients given the CO(2) insufflation (C; n = 34) for the whole course of the colonoscopy. Patients were requested to answer questionnaires about their pain score during, at the end, and 1 h after the colonoscopy by using a pain numerical scale ranging from 0 to 10. The disparities of the pain score were noted at the end of the procedure and 1 h after the procedure (p = 0.026 and p < 0.001, respectively). We further analyzed the scores between two of the three groups. Both CW (vs. A; procedure end: p = 0.012, 1 h after: p = 0.001) and C (vs. A; procedure end: p = 0.072, 1 h after: p < 0.001) showed less postprocedure pain when compared with the group A. The pain score between CW and C were similar at each time segment (procedure end: p = 0.555, 1 h after: p = 0.491). CO(2) insufflation merely at the withdrawal of the colonoscope improved postprocedural abdominal discomfort and the effect was not inferior to that of full course CO(2) insufflation. PMID- 22531304 TI - Clinical study of ammonium acid urate urolithiasis. AB - Ammonium acid urate (AAU) urolithiasis is a rare condition; however, it is endemic in some countries, with an especially high incidence in Asia. This study was conducted to investigate the special presentation of patients with AAU urolithiasis in Taiwan. Reports of 3457 stones were retrospectively reviewed from January 2005 to January 2010 and 25 patients with urinary stones (0.7%) containing AAU crystals were identified. The clinical and biochemical presentation of all stones were compared to evaluate the specific comorbidities of AAU stones. AAU stones were observed in 11 males (44%) and 14 females (56%) with a mean age of 60.60 +/- 16.81 years and mean body mass index of 25.55 +/- 3.73 kg/m(2). AAU stones were frequently observed in the bladder (44%) and they were significantly larger (mean size 1.90 cm) than the non-AAU stones (mean size 1.22 cm). Other significant comorbidities of AAU stones included chronic kidney disease (CKD) (60%), urinary tract infections (UTIs) (52%), irritable bowel syndrome (IBS) (36%), and gout (28%). In addition, there were also three patients with coexisting urothelial carcinoma (12%) in the AAU-stone group. Patients with AAU urolithiasis were predominantly female, older in age, had increased bladder presentation, larger stones and a high percentage of coexisting CKD, UTIs, IBS, gout, and even urothelial carcinoma. Therefore, it is important for clinicians to evaluate and protect renal function in patients with AAU urolithiasis. PMID- 22531306 TI - Thermal welding versus cold knife tonsillectomy: a prospective randomized study. AB - This is a prospective randomized study conducted in a group of children who underwent two methods of tonsillectomy: thermal welding or cold knife tonsillectomy. Parameters, such as postoperative pain scores, intraoperative blood loss, operation time, and postoperative bleeding rates, were analyzed to find out which technique is better. Ninety-one children (aged between 2 years and 13 years) with recurrent tonsillitis, obstructive sleep apnea syndrome, or both were included in the study. According to the type of tonsillectomy procedure, the patients were divided into two groups: cold knife and thermal welding procedure. The two groups were compared on the basis of postoperative pain scores, intraoperative blood loss, operation time, and postoperative bleeding. Fifty seven patients underwent thermal welding tonsillectomy and 34 had cold knife tonsillectomy. The mean pain score in thermal welding group was significantly lower (p<0.001). There was no remarkable blood loss intraoperatively in the thermal welding procedure. The operation time was not significantly different between two groups. No postoperative bleeding was encountered in the thermal welding group. Compared with the cold knife technique, thermal welding was found to be a relatively new and safe technique for tonsillectomy as it results in significantly less postoperative pain and no remarkable blood loss. PMID- 22531307 TI - Tongue support of complete dentures in the elderly. AB - This study aimed to evaluate the tongue's role in supporting maxillary denture retention (MDR), in providing additional stabilization for the mandibular denture, and the tongue's relationship with the oral health-related well being in elderly complete denture patients. Four hundred elderly individuals, 263 males and 137 females, were enrolled in this study. All were older than 65 years, and wore complete dentures. Intraoral examinations were performed in accordance with the 10 criteria embedded in the Functional Assessment of Dentures (FAD). Participants also received personal interviews and completed the Oral Health Impact Profile-14 (OHIP-14) questionnaire. The associations between MDR (tongue support) with the mean OHIP-14 sum scores and FAD categories were analyzed using the t test or analysis of variance (ANOVA). Combinations of MDR (tongue support), MDR (resistance to vertical pull), and mandibular denture stability (anterior posterior movement) were also assessed with the remaining FAD criteria and OHIP 14 domain scores. Individuals with adequate MDR (tongue support) were significantly associated with denture articulation, denture occlusion, MDR (resistance to vertical pull), maxillary denture stability (pronounced rocking), and mandibular denture stability (anterior-posterior movement). When individuals with adequate MDR (tongue support) were analyzed in conjunction with adequate MDR (resistance to vertical pull) and adequate mandibular denture stability (anterior posterior movement), significant associations were observed with the mean OHIP-14 sum score and three individual OHIP-14 domains: functional limitation, physical pain, and physical disability (p < 0.05). The mean OHIP-14 sum score was lower among individuals with both adequate MDR (tongue support) and inadequate MDR (resistance to vertical pull) than among participants with both inadequate MDR (tongue support) and inadequate MDR (resistance to vertical pull). MDR (tongue support) demonstrated significant differences from denture occlusion, denture articulation, MDR (resistance to vertical pull), maxillary denture stability (pronounced rocking), and mandibular denture stability (anterior-posterior movement). MDR (tongue support), in conjunction with both adequate MDR (resistance to vertical pull) and adequate mandibular stability (anterior posterior movement), were significantly associated with the individuals' oral health-related well being. PMID- 22531308 TI - Quality of life of methylphenidate treatment-responsive adolescents with attention-deficit/hyperactivity disorder. AB - Quality of life (QOL) in methylphenidate treatment-responsive adolescents with attention deficit/hyperactivity disorder (ADHD) was assessed. Patients were 12- to 18-year-old adolescents with ADHD (total n = 45) who had been on methylphenidate treatment for at least 3 months and were clinically judged to be improved. The self-completed Taiwanese Quality of Life Questionnaire for Adolescents (TQOLQA) was used, and the resulting measures were compared between adolescents with ADHD and: (1) community adolescents (n = 2316); (2) treatment responsive adolescents with a chronic medical condition (i.e., adolescents with leukemia in its first and complete continuous remission for at least 3 years after chemotherapy) (n = 39). Patients' cognitive profile and their daily executive functioning were also obtained for analysis. The QOL of the treated adolescents with ADHD was reported to be worse than that of both the community healthy adolescents and the adolescent leukemia survivors in the self-reported TQOLQA domain of "psychological well-being". Treated adolescents with ADHD still had impaired executive skills in natural, everyday environments, and the scores for daily executive abilities could predict the QOL measures. Factors besides pharmacotherapy should be explored to further improve the QOL of medication treated adolescents with ADHD. PMID- 22531309 TI - Surgical treatment of melorheostosis: report of two cases. AB - Melorheostosis is a rare disease that usually burdens the patient with painful disability or soft tissue compromise. The treatment is usually symptomatic and conservative. Patients with severe and complicated forms of the disease may require surgery. Involvement of the distal part of a limb usually carries more morbidity, such as tumefaction pain, cosmetic and psychosocial or functional problems that render conservative treatment unsatisfactory to patients. In our series, surgical debulking or decompression of the mass effect provided prompt symptom relief. PMID- 22531310 TI - Metachronous brain and intramedullary spinal cord metastases from nonsmall-cell lung cancer: a case report. AB - A 44-year-old man had a brain tumor secondary to lung adenocarcinoma and underwent craniectomy to remove the brain tumor. After postoperative whole-brain radiation therapy, he underwent pneumonectomy followed by chemotherapy, mediastinal radiotherapy, and target therapy for lung cancer. Thirty-six months after the initial brain surgery, he suffered from neck pain and right upper limb numbness that rapidly progressed to upper extremity weakness and paralysis in 2 months. Magnetic resonance imaging demonstrated an intramedullary spinal cord lesion at the C4 level. Laminectomy and gross intramedullary tumor removal were performed. The patient's neurological function improved after the operation. Nevertheless, 4 months after the intramedullary tumor removal, he began to show multiple metastases. Unfortunately, the patient died from respiratory failure 8 months after diagnosis with intramedullary spinal cord metastasis. In this case, early diagnosis and aggressive surgical treatment combined with postoperative radiotherapy and chemotherapy might have provided this patient with a prolonged survival and better quality of life. PMID- 22531311 TI - Contractile peripapillary staphyloma mimicking morning-glory disc anomaly. PMID- 22531313 TI - Translating TRAIL-receptor targeting agents to the clinic. AB - The extrinsic apoptotic pathway can be activated by the endogenous ligand TRAIL (Tumor Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand) by binding to the death receptors TRAIL-R1 and TRAIL-R2 on the cell surface. This pathway is currently evaluated as an anticancer treatment strategy. Both recombinant human TRAIL and several agonistic antibodies against TRAIL-R1 and R2 have been studied in single agent and combination studies and proved to be safe and well tolerated. In this article, the clinical studies published to date will be reviewed. Also, future perspectives and biomarker studies for selecting patients that will benefit from these agents will be discussed. PMID- 22531312 TI - The imposition of, but not the propensity for, social subordination impairs exploratory behaviors and general cognitive abilities. AB - Imposed social subordination, such as that which accompanies physical defeat or alienation, has been associated with impaired cognitive function in both human and non-human animals. Here we examined whether domain-specific and/or domain general learning abilities (c.f. general intelligence) are differentially influenced by the imposition of social subordination. Furthermore, we assessed whether the impact of subordination on cognitive abilities was the result of imposed subordination per se, or if it reflected deficits intrinsically expressed in subjects that are predisposed to subordination. Subordinate and dominant behaviors were assessed in two groups of CD-1 male mice. In one group (Imposed Stratification), social stratification was imposed (through persistent physical defeat in a colonized setting) prior to the determination of cognitive abilities, while in the second group (Innate Stratification), an assessment of social stratification was made after cognitive abilities had been quantified. Domain specific learning abilities were measured as performance on individual learning tasks (odor discrimination, fear conditioning, spatial maze learning, passive avoidance, and egocentric navigation) while domain-general learning abilities were determined by subjects' aggregate performance across the battery of learning tasks. We observed that the imposition of subordination prior to cognitive testing decreased exploratory tendencies, moderately impaired performance on individual learning tasks, and severely impaired general cognitive performance. However, similar impairments were not observed in subjects with a predisposition toward a subordinate phenotype (but which had not experienced physical defeat at the time of cognitive testing). Mere colonization, regardless of outcome (i.e., stratification), was associated with an increase in stress-induced serum corticosterone (CORT) levels, and thus CORT elevations were not themselves adequate to explain the effects of imposed stratification on cognitive abilities. These findings indicate that absent the imposition of subordination, individuals with subordinate tendencies do not express learning impairments. This observation could have important ramifications for individuals in environments where social stratification is prevalent (e.g., schools or workplace settings). PMID- 22531314 TI - miR-409-3p inhibits HT1080 cell proliferation, vascularization and metastasis by targeting angiogenin. AB - Although the expression of angiogenin (ANG), an angiogenic and tumorigenic factor, is elevated in various types of cancers, its regulation mechanism remains unclear. In the present study, in silico search predicted that miR-409-3p targeted to the 3' untranslated region (3'UTR) of the ANG mRNA. Overexpression of miR-409-3p in fibrosarcoma HT1080 cells resulted in decreased steady-state level of ANG transcript and ANG production which were achieved through direct binding of this miRNA to the ANG 3'UTR. The suppressions of miR-409-3p to rRNA transcription, cell proliferation and vasculogenic mimicry could be partially restored by overexpression of ANG with a mutated binding site of miR-409-3p within the ANG 3'UTR. Ectopic expression of miR-409-3p in transplanted HT1080 cells led to the retardation of tumor growth, vascularization and lung metastasis in mouse tumor xenografts. In these xenografts tissues, the expression of miR-409 3p displayed an inverse correlation with ANG, which was also detected in human fibrosarcoma samples. In addition, the suppression effects of miR-409-3p on cell proliferation and angiogenesis in vitro were also found in human umbilical vein endothelial cells. Taken together, these data demonstrate that miR-409-3p inhibits tumor growth, vascularization and metastasis through down-regulating ANG expression. PMID- 22531316 TI - Hardware and software design for a National Instrument-based magnetic induction tomography system for prospective biomedical applications. AB - Magnetic induction tomography (MIT) is a new and emerging type of tomography technique that is able to map the passive electromagnetic properties (in particular conductivity) of an object. Excitation coils are used to induce eddy currents in the medium, and the magnetic field produced by the induced eddy current is then sensed by the receiver coils. Because of its non-invasive and contactless feature, it becomes an attractive technique for many applications (especially in biomedical area) compared to traditional contact electrode-based electrical impedance tomography. Due to the low contrast in conductivity between biological tissues, an accurate and stable hardware system is necessary. Most MIT systems in the literature employ external signal generators, power amplifiers and highly stable down-conversion electronics to obtain a satisfactory phase measurement. However, this would increase design complexity substantially. In this paper, a National Instrument-based MIT system is developed at the University of Bath, aiming for biomedical applications. The system utilizes National Instrument products to accomplish all signal driving, switching and data acquisition tasks, which ease the system design whilst providing satisfactory performance. This paper presents a full-scaled medical MIT system, from the sensor and system hardware design, eddy current model verification to the image reconstruction software: the performance of this MIT instrumentation system is characterized in detail, including the system accuracy and system stability. The methods of solving eddy current problem are presented. The reconstructed images of detecting the presence of saline solutions are also included in this paper, which show the capability of national instrument products to be developed into a full-scaled biomedical MIT system, by demonstrating the practical experimental results. PMID- 22531315 TI - Epigenetics in human gliomas. AB - Aberrant epigenetic landscapes and their involvement in genesis and progression of tumors, as well as in treatment responses and prognosis, indicate one of the most emerging fields in cancer research. In gliomas, the most common human primary brain tumors, and in particular in glioblastoma, the most malignant and devastating brain tumor entity in adults, the elucidation of distinct patterns of aberrant DNA methylation, histone modification, and miRNA expression and their interrelationship has fundamentally changed our point of view on these highly heterogeneous tumors. In the current review article, we address the basic principles of epigenetic control in gliomas, their current and putative future role in prognostic and predictive models and possible interactions within the epigenetic network. We discuss diagnostic and therapeutic opportunities appearing at horizon of epigenetic research. Moreover, we present current and propose future clinical workflow models for molecular characterization of malignant gliomas. PMID- 22531317 TI - Detection of perfusion abnormalities on coronary angiograms in hypertension by myocardium selective densitometric perfusion assessments. PMID- 22531318 TI - Tolerance: reversing diabetes in mice. PMID- 22531319 TI - Dendritic cells: actin a dangerous part. PMID- 22531323 TI - Innate immunity: the NLRP3 inflammasome--a good site for sore eyes. PMID- 22531324 TI - Dendritic cells: changing of the guard. PMID- 22531327 TI - Subjectivity and flow cytometric variability. PMID- 22531325 TI - Interferon-inducible effector mechanisms in cell-autonomous immunity. AB - Interferons (IFNs) induce the expression of hundreds of genes as part of an elaborate antimicrobial programme designed to combat infection in all nucleated cells - a process termed cell-autonomous immunity. As described in this Review, recent genomic and subgenomic analyses have begun to assign functional properties to novel IFN-inducible effector proteins that restrict bacteria, protozoa and viruses in different subcellular compartments and at different stages of the pathogen life cycle. Several newly described host defence factors also participate in canonical oxidative and autophagic pathways by spatially coordinating their activities to enhance microbial killing. Together, these IFN induced effector networks help to confer vertebrate host resistance to a vast and complex microbial world. PMID- 22531329 TI - Nurses' views of patient handoffs in Japanese hospitals. AB - Staff perceptions of risks associated with patient handoffs were investigated in a survey of nurses in 6 Japanese hospitals. A total of 1462 valid responses were collected from nurses with an overall response rate of 74%. Respondents are moderately satisfied with the transfer of information and responsibility during handoffs. However, the handoff system was identified as immature. Hospital, work setting, and work experience affected nurses' views of handoff quality. Strategies for improving patient handoffs in Japan are proposed. PMID- 22531330 TI - Nanostructured silicon surface modifications for as a selective matrix-free laser desorption/ionization mass spectrometry. AB - Matrix-assisted laser desorption/ionization mass spectrometry is an established soft ionization method that is widely applied to analyze biomolecules. The UV absorbing organic matrix is essential for biomolecule ionization; however, it also creates matrix background interference, which results in problematic analyses of biomolecules of less than 700 Da. Therefore, this study investigates hydrophilic, hydrophobic cationic, anionic and immobilized metal ion surface chemical modifications to advance nanostructured silicon mass spectrometry performance (nSi-MS). This investigation provides information required for a possible novel mass spectroscopy that combines surface-enhanced and nanostructured silicon surface-assisted laser desorption/ionization mass spectrometry for the selective detection of specific compounds of a mixture. PMID- 22531326 TI - Multipotent mesenchymal stromal cells and the innate immune system. AB - Multipotent mesenchymal stromal cells (MSCs) have unique immunoregulatory and regenerative properties that make them an attractive tool for the cellular treatment of autoimmunity and inflammation. Their underlying molecular mechanisms of action together with their clinical benefit - for example, in autoimmunity - are being revealed by an increasing number of clinical trials and preclinical studies of MSCs. However, autoimmunity and therapy-related alloimmunity are not only triggered and sustained by responses of the adaptive immune system; there is growing evidence that components of the innate immune system also have a key role. It is therefore important to study the crosstalk between MSCs and innate immunity, which ranges from the bone marrow niche to injured tissue. PMID- 22531332 TI - Variability in blood and blood component utilization as assessed by an anesthesia information management system. AB - BACKGROUND: Data can be collected for various purposes with anesthesia information management systems. The authors describe methods for using data acquired from an anesthesia information management system to assess intraoperative utilization of blood and blood components. METHODS: Over an 18 month period, data were collected on 48,086 surgical patients at a tertiary care academic medical center. All data were acquired with an automated anesthesia recordkeeping system. Detailed reports were generated for blood and blood component utilization according to surgical service and surgical procedure, and for individual surgeons and anesthesiologists. Transfusion hemoglobin trigger and target concentrations were compared among surgical services and procedures, and between individual medical providers. RESULTS: For all patients given erythrocytes, the mean transfusion hemoglobin trigger was 8.4 +/- 1.5, and the target was 10.2 +/- 1.5 g/dl. Variation was significant among surgical services (trigger range: 7.5 +/- 1.2-9.5 +/- 1.1, P = 0.0001; target range: 9.1 +/- 1.2 11.3 +/- 1.4 g/dl, P = 0.002), surgeons (trigger range: 7.2 +/- 0.7-9.8 +/- 1.0, P = 0.001; target range: 8.8 +/- 0.9-11.8 +/- 1.3 g/dl, P = 0.001), and anesthesiologists (trigger range: 7.2 +/- 0.8-9.6 +/- 1.2, P = 0.001; target range: 9.0 +/- 0.9-11.7 +/- 1.3 g/dl, P = 0.0004). The use of erythrocyte salvage, fresh frozen plasma, and platelets varied threefold to fourfold among individual surgeons compared with their peers performing the same surgical procedure. CONCLUSIONS: The use of data acquired from an anesthesia information management system allowed a detailed analysis of blood component utilization, which revealed significant variation among surgical services and surgical procedures, and among individual anesthesiologists and surgeons compared with their peers. Incorporating these methods of data acquisition and analysis into a blood management program could reduce unnecessary transfusions, an outcome that may increase patient safety and reduce costs. PMID- 22531331 TI - Adora2b signaling on bone marrow derived cells dampens myocardial ischemia reperfusion injury. AB - BACKGROUND: Cardiac ischemia-reperfusion (I-R) injury represents a major cause of cardiac tissue injury. Adenosine signaling dampens inflammation during cardiac I R. The authors investigated the role of the adenosine A2b-receptor (Adora2b) on inflammatory cells during cardiac I-R. METHODS: To study Adora2b signaling on inflammatory cells, the authors transplanted wild-type (WT) bone marrow (BM) into Adora2b(-/-) mice or Adora2b(-/-) BM into WT mice. To study the role of polymorphonuclear leukocytes (PMNs), neutrophil-depleted WT mice were treated with an Adora2b agonist. After treatments, mice were exposed to 60 min of myocardial ischemia and 120 min of reperfusion. Infarct sizes and troponin I concentrations were determined by triphenyltetrazolium chloride staining and enzyme-linked immunosorbent assay, respectively. RESULTS: Transplantation of WT BM into Adora2b(-/-) mice decreased infarct sizes by 19 +/- 4% and troponin I by 87.5 +/- 25.3 ng/ml (mean +/- SD, n = 6). Transplantation of Adora2b(-/-) BM into WT mice increased infarct sizes by 20 +/- 3% and troponin I concentrations by 69.7 +/- 17.9 ng/ml (mean +/- SD, n = 6). Studies on the reperfused myocardium revealed PMNs as the dominant cell type. PMN depletion or Adora2b agonist treatment reduced infarct sizes by 30 +/- 11% or 26 +/- 13% (mean +/- SD, n = 4); however, the combination of both did not produce additional cardioprotection. Cytokine profiling showed significantly higher cardiac tumor necrosis factor alpha concentrations in Adora2b(-/-) compared with WT mice (39.3 +/- 5.3 vs. 7.5 +/- 1.0 pg/mg protein, mean +/- SD, n = 4). Pharmacologic studies on human activated PMNs revealed an Adora2b-dependent tumor necrosis factor alpha release. CONCLUSION: Adora2b signaling on BM-derived cells such as PMNs represents an endogenous cardioprotective mechanism during cardiac I-R. The authors' findings suggest that Adora2b agonist treatment during cardiac I-R reduces tumor necrosis factor alpha release of PMNs, thereby dampening tissue injury. PMID- 22531334 TI - Spontaneous breathing during general anesthesia prevents the ventral redistribution of ventilation as detected by electrical impedance tomography: a randomized trial. AB - BACKGROUND: Positive-pressure ventilation causes a ventral redistribution of ventilation. Spontaneous breathing during general anesthesia with a laryngeal mask airway could prevent this redistribution of ventilation. We hypothesize that, compared with pressure-controlled ventilation, spontaneous breathing and pressure support ventilation reduce the extent of the redistribution of ventilation as detected by electrical impedance tomography. METHODS: The study was a randomized, three-armed, observational, clinical trial without blinding. With approval from the local ethics committee, we enrolled 30 nonobese patients without severe cardiac or pulmonary comorbidities who were scheduled for elective orthopedic surgery. All of the procedures were performed under general anesthesia with a laryngeal mask airway and a standardized anesthetic regimen. The center of ventilation (primary outcome) was calculated before the induction of anesthesia (AWAKE), after the placement of the laryngeal mask airway (BEGIN), before the end of anesthesia (END), and after arrival in the postanesthesia care unit (PACU). RESULTS: The center of ventilation during anesthesia (BEGIN) was higher than baseline (AWAKE) in both the pressure-controlled and pressure support ventilation groups (pressure control: 55.0 vs. 48.3, pressure support: 54.7 vs. 48.8, respectively; multivariate analysis of covariance, P < 0.01), whereas the values in the spontaneous breathing group remained at baseline levels (47.9 vs. 48.5). In the postanesthesia care unit, the center of ventilation had returned to the baseline values in all groups. No adverse events were recorded. CONCLUSIONS: Both pressure-controlled ventilation and pressure support ventilation induce a redistribution of ventilation toward the ventral region, as detected by electrical impedance tomography. Spontaneous breathing prevents this redistribution. PMID- 22531335 TI - Case scenario: respiratory variations in arterial pressure for guiding fluid management in mechanically ventilated patients. PMID- 22531336 TI - Two etomidate sites in alpha1beta2gamma2 gamma-aminobutyric acid type A receptors contribute equally and noncooperatively to modulation of channel gating. AB - BACKGROUND: Etomidate is a potent hypnotic agent that acts via gamma-aminobutyric acid receptor type A (GABA(A)) receptors. Evidence supports the presence of two etomidate sites per GABA(A) receptor, and current models assume that each site contributes equally and noncooperatively to drug effects. These assumptions remain untested. METHODS: We used concatenated dimer (beta2-alpha1) and trimer (gamma2-beta2-alpha1) GABA(A) subunit assemblies that form functional alpha1beta2gamma2 channels, and inserted alpha1M236W etomidate site mutations into both dimers (beta2-alpha1M236W) and trimers (gamma2-beta2-alpha1M236W). Wild type or mutant dimers (D(wt) or D(alphaM236W)) and trimers (T(wt) or T(alphaM236W)) were coexpressed in Xenopus oocytes to produce four types of channels: D(wt)T(wt), D(alphaM236W)T(wt), D(wt)T(alphaM236W), and D(alphaM236W)T(alphaM236W). For each channel type, two-electrode voltage clamp was performed to quantitatively assess GABA EC(50), etomidate modulation (left shift), etomidate direct activation, and other functional parameters affected by alphaM236W mutations. RESULTS: Concatenated wild-type D(wt)T(wt) channels displayed etomidate modulation and direct activation similar to alpha1beta2gamma2 receptors formed with free subunits. D(alphaM236W)T(alphaM236W) receptors also displayed altered GABA sensitivity and etomidate modulation similar to mutated channels formed with free subunits. Both single-site mutant receptors (D(alphaM236W)T(wt) and D(wt)T(alphaM236W)) displayed indistinguishable functional properties and equal gating energy changes for GABA activation (-4.9 +/- 0.48 vs. -4.7 +/- 0.48 kJ/mol, respectively) and etomidate modulation (-3.4 +/- 0.49 vs. -3.7 +/- 0.38 kJ/mol, respectively), which together accounted for the differences between D(wt)T(wt) and D(alphaM236W)T(alphaM236W) channels. CONCLUSIONS: These results support the hypothesis that the two etomidate sites on alpha1beta2gamma2 GABA(A) receptors contribute equally and noncooperatively to drug interactions and gating effects. PMID- 22531337 TI - Cell-based therapy for acute lung injury: are we there yet? PMID- 22531338 TI - Transfusion of stored autologous blood does not alter reactive hyperemia index in healthy volunteers. AB - BACKGROUND: Transfusion of human blood stored for more than 2 weeks is associated with increased mortality and morbidity. During storage, packed erythrocytes progressively release hemoglobin, which avidly binds nitric oxide. We hypothesized that the nitric oxide mediated hyperemic response after ischemia would be reduced after transfusion of packed erythrocytes stored for 40 days. METHODS AND RESULTS: We conducted a crossover randomized interventional study, enrolling 10 healthy adults. Nine volunteers completed the study. Each volunteer received one unit of 40-day and one of 3-day stored autologous leukoreduced packed erythrocytes, on different study days according to a randomization scheme. Blood withdrawal and reactive hyperemia index measurements were performed before and 10 min, 1 h, 2 h, and 4 h after transfusion. The reactive hyperemia index during the first 4 h after transfusion of 40-day compared with 3-day stored packed erythrocytes was unchanged. Plasma hemoglobin and bilirubin concentrations were higher after transfusion of 40-day than after 3-day stored packed erythrocytes (P = 0.02, [95% CI difference 10-114 mg/l] and 0.001, [95% CI difference 0.6-1.5 mg/dl], respectively). Plasma concentrations of potassium, lactate dehydrogenase, haptoglobin, and cytokines, as well as blood pressure, did not differ between the two transfusions and remained within the normal range. Plasma nitrite concentrations increased after transfusion of 40-day stored packed erythrocytes, but not after transfusion of 3-day stored packed erythrocytes (P = 0.01, [95% CI difference 0.446-0.66 MUM]). CONCLUSIONS: Transfusion of autologous packed erythrocytes stored for 40 days is associated with increased hemolysis, an unchanged reactive hyperemia index, and increased concentrations of plasma nitrite. PMID- 22531339 TI - "Triple low": murderer, mediator, or mirror. PMID- 22531341 TI - Laboratory identification of factor inhibitors: an update. AB - Coagulation factor inhibitors comprise antibodies that bind to and then neutralise specific pro-coagulant plasma proteins. Coagulation factor inhibitors can develop against any coagulation factor, although the most common are against factor VIII (FVIII). These can develop in individuals with inherited haemophilia A (HA) as an immune response to factor replacement therapy, or as auto-antibodies leading to the condition of acquired HA. Clinical suspicion for inhibitors may arise when individuals present with bleeding symptoms without any prior bleeding diathesis, or when a patient with known mild haemophilia presents with a bleeding diathesis more extreme to their usual presentation, or when there is failure of factor replacement therapy to arrest bleeding in a known haemophiliac. The laboratory identification of factor inhibitors requires a careful and systematic approach that excludes other possible causes of prolonged screening tests, most commonly the activated partial thromboplastin time (APTT), and sometimes prothrombin time (PT). Coagulation factor inhibitor studies, including the Bethesda assay, are then undertaken to measure inhibitor titre, which guides treatment. This paper overviews the laboratory investigation of factor inhibitors, and also briefly reviews recent cross-laboratory inhibitor studies and the most recent evidence related to differential inhibitor formation according to type of therapy. PMID- 22531340 TI - AZD-3043: a novel, metabolically labile sedative-hypnotic agent with rapid and predictable emergence from hypnosis. AB - BACKGROUND: Propofol can be associated with delayed awakening after prolonged infusion. The aim of this study was to characterize the preclinical pharmacology of AZD-3043, a positive allosteric modulator of the gamma-aminobutyric acid type A (GABA(A)) receptor containing a metabolically labile ester moiety. The authors postulated that its metabolic pathway would result in a short-acting clinical profile. METHODS: The effects of AZD-3043, propofol, and propanidid were studied on GABA(A) receptor-mediated chloride currents in embryonic rat cortical neurons. Radioligand binding studies were also performed. The in vitro stability of AZD 3043 in whole blood and liver microsomes was evaluated. The duration of the loss of righting reflex and effects on the electroencephalograph evoked by bolus or infusion intravenous administration were assessed in rats. A mixed-effects kinetic-dynamic model using minipigs permitted exploration of the clinical pharmacology of AZD-3043. RESULTS: AZD-3043 potentiated GABA(A) receptor-mediated chloride currents and inhibited [(35)S]tert-butylbicyclophosphorothionate binding to GABA(A) receptors. AZD-3043 was rapidly hydrolyzed in liver microsomes from humans and animals. AZD-3043 produced hypnosis and electroencephalograph depression in rats. Compared with propofol, AZD-3043 was shorter acting in rats and pigs. Computer simulation using the porcine kinetic-dynamic model demonstrated that AZD-3043 has very short 50 and 80% decrement times independent of infusion duration. CONCLUSIONS: AZD-3043 is a positive allosteric modulator of the GABA(A) receptor in vitro and a sedative-hypnotic agent in vivo. The esterase dependent metabolic pathway results in rapid clearance and short duration of action even for long infusions. AZD-3043 may have clinical potential as a sedative-hypnotic agent with rapid and predictable recovery. PMID- 22531342 TI - Approaches to routine handling of basal cell carcinoma re-excision specimens: a survey of Australian histopathologists. AB - AIMS: To investigate and assess variation in routine approaches to the handling of basal cell carcinoma (BCC) re-excision specimens by Australian histopathologists. METHODS: A questionnaire was sent to 440 Australian histopathologists requesting details of their routine approach to the handling of BCC re-excision specimens. Responses were collated and compared to demonstrate any variation in approach. RESULTS: Responses received from 208 pathologists indicated that variation was present in most aspects of specimen handling, including cut-up, examination of the specimen and reporting. CONCLUSIONS: Variation demonstrated in the routine handling of BCC re-excision specimens may have important academic and clinical implications. It is important for pathologists to communicate their specimen handling approach to the surgeon. Further study should be conducted to specifically compare the various specimen handling approaches that were identified in this study. The development of evidence-based guidelines for the routine handling of BCC re-excision specimens may be appropriate. PMID- 22531343 TI - Syndecan-4 and fibronectin in osteosarcoma. AB - AIMS: Syndecan-4 (SDC4) and fibronectin (FN), which belong to the cell adhesion molecules, have been reported to correlate with tumour growth and invasion in various carcinomas. We aimed to investigate the prognostic value of these molecules in osteosarcoma. METHODS: Using immunohistochemistry, we compared the expression of these molecules in high grade osteosarcoma to low grade central osteosarcoma, osteoid osteoma and normal bone. Further, the expression of SDC4 and FN were analysed with prognostic factors of high grade osteosarcoma. RESULTS: In high grade osteosarcoma, SDC4 was expressed in 50 of the 65 samples; of these, 32 of 65 showed strong expression profiles. FN was expressed in 46 of 65 samples, and 29 of 65 had evidence of strong expression of this molecule. SDC4 and FN expression were increased in high grade osteosarcoma as compared to other tissues. Strong SDC4 expression was associated with the occurrence of distant metastasis and a large tumour size, and strong FN expression was associated with the occurrence of distant metastasis. Strong expression of SDC4 or FN was associated with significantly shorter overall survival, respectively. CONCLUSIONS: [corrected] Increased expression of SDC4 and FN may be underlying molecular alteration of osteosarcoma which accounts for more aggressive clinical behaviour. PMID- 22531344 TI - A molecular tool to assess the pathological relevance of alpha-globin DNA variants. AB - AIM: While the phenotype for heterozygous beta-thalassaemia is straightforward, it is more difficult to confirm a causative relationship for mutations in the alpha-globin genes. The aim of this study was to generate an in vitro system to evaluate the pathological relevance of alpha-globin mutations. METHODS: The novel variant HBA1:c.301-3C>G was used as a model. In silico analysis predicted an aberrant acceptor splice site in the mutant sequence. Subsequent in vitro studies included generation of and transfection of an expression vector carrying the HBA1:c.301-3C>G mutation, RNA purification, reverse-transcription polymerase chain reaction (RT-PCR) and cDNA sequencing. Immunofluorochemistry (IFC) with antibodies specific to the N- and or C- terminal of the alpha-globin protein was used in protein detection. RESULTS: In vitro molecular characterisation of this point mutation confirmed the preferential utilisation of a cryptic splice site at intron 2 of the pre-mRNA, resulting in a shift in the reading frame causing a premature termination codon (PTC) at codons 101/102 and generation of a truncated protein. CONCLUSION: We have described here a molecular tool to study mutations that affect alpha-globin pre-mRNA splicing and translation. We confirm in silico predictions of the consequences of the HBA1:c.301-3C>G mutation, proving aberrant RNA splicing and the production of a truncated alpha-globin protein. PMID- 22531345 TI - Homozygous protein C deficiency with late onset venous thrombosis: identification and in vitro expression study of a novel Pro275Ser mutation. AB - AIMS: To identify the mutation and study the molecular mechanism of inherited protein C (PC) deficiency in a Chinese pedigree. METHODS: The plasma levels of PC activity (PC:A) and antigen (PC:Ag) were measured by chromogenic assay and ELISA, respectively. The PROC gene was amplified and sequenced for mutational screening. Wild type and Pro275Ser mutant PC cDNA expression plasmids were constructed and transfected into HEK 293T cells and COS 7 cells, respectively. The expression and transcription of PC were investigated by ELISA, Western blot and real time RT PCR. Immunofluorescence staining was utilised to analyse the intracellular distribution of PC, and pulse-chase experiments were used to detect the intracellular stability of the mutant PC. RESULTS: The proband's plasma PC:A and PC:Ag were 5% and 13.9%, respectively. A missense mutation (p.Pro275Ser) was identified in exon 9 of PROC gene. In vitro expression study showed that Pro275Ser variant was present at 22.6% and 78.9% of wild type levels in culture supernatants and cell lysates, respectively. No significant differences in the molecular weights, mRNA levels or intracellular stability were observed between the mutant and wild type PC. Immunofluorescence staining revealed that the mutant protein was mainly located in the endoplasmic reticulum. CONCLUSIONS: A homozygous Pro275Ser mutation was identified in a Chinese pedigree of PC deficiency. Impaired secretion of the mutant PC might be the molecular mechanism of PC deficiency caused by Pro275Ser mutation. PMID- 22531346 TI - Improved recovery of Clostridium difficile spores with the incorporation of synthetic taurocholate in cycloserine-cefoxitin-fructose agar (CCFA). AB - AIM: Culture remains important for the detection and typing of Clostridium difficile. Culture of C. difficile spores can be enhanced on media supplemented with a germinant. Despite this, unsupplemented media continues to be used in some laboratories. The aim of this study was to quantify the effect of the known germinant sodium taurocholate on recovery of C. difficile spores and to determine if the supplement impacts on the recovery of vegetative C. difficile. METHODS: The recovery on cycloserine-cefoxitin-fructose agar (CCFA) with and without taurocholate, of spore, vegetative, and total cell fractions of broth cultures of eight C. difficile isolates was compared. RESULTS: Taurocholate in CCFA did not inhibit growth of vegetative C. difficile and significantly increased recovery of spores (p = 0.04). CONCLUSIONS: The routine incorporation of taurocholate in CCFA is recommended for improved sensitivity in C. difficile culture from specimens. PMID- 22531347 TI - Total serum DNA and DNA integrity: diagnostic value in patients with hepatitis B virus-related hepatocellular carcinoma. AB - AIMS: This study aimed to test the diagnostic utility of the total serum cell free DNA (cfDNA) and DNA integrity index for detection of hepatitis B virus (HBV) related hepatocellular carcinoma (HCC). METHODS: We initially evaluated the sodium iodide (NaI) method, Triton/Heat/Phenol (THP) protocol and QIAamp Kit for cfDNA extraction. Then cfDNA was isolated from the sera of 80 patients with HBV related HCC, 80 patients with chronic HBV infection and 50 healthy subjects, and quantified by real-time quantitative polymerase chain reaction (qPCR) amplification of beta-actin genomic DNA fragments using two sets of primers of 100 and 400 bp. DNA integrity was calculated as the ratio of 400 bp to 100 bp beta-actin fragments. RESULTS: The THP approach was not only superior to the other two methods in terms of DNA quantity, but also was simpler, more rapid, and less costly. Serum DNA integrity in HCC patients was significantly higher than that in HBV patients or healthy controls. As for total cfDNA levels, although a significant difference was found between HCC patients and healthy individuals, no significant difference was found between HBV patients with and without HCC. DNA integrity was associated with tumour size, TNM stage, lymph node and distant metastasis. DNA integrity had a higher sensitivity and specificity in discriminating HCC from HBV patients than total DNA. CONCLUSIONS: The THP method is preferred for extraction of cfDNA. DNA integrity is a promising molecular biomarker for detecting HCC in patients with chronic HBV infection; it reflects the progression and metastatic potential of the tumour. PMID- 22531348 TI - Idiopathic diffuse dendriform pulmonary ossification in a dental technician. PMID- 22531349 TI - An evaluation of the VIDAS CDAB assay for the detection of Clostridium difficile infection in a clinical laboratory. PMID- 22531350 TI - Serum protein electrophoresis: a precautionary tale. PMID- 22531351 TI - Tenosynovitis with psammomatous calcification of the knee. PMID- 22531352 TI - Comparison of five CMV IgM immunoassays with CMV IgG avidity for diagnosis of primary CMV infection. PMID- 22531353 TI - A high-throughput method to detect Plasmodium falciparum clones in limiting dilution microplates. AB - BACKGROUND: Molecular and cellular studies of Plasmodium falciparum require cloning of parasites by limiting dilution cultivation, typically performed in microplates. The parasite's slow replication rate combined with laborious methods for identification of positive wells has limited these studies. A new high throughput method for detecting growth without compromising parasite viability is reported. METHODS: In vitro parasite cultivation is associated with extracellular acidification. A survey of fluorescent pH indicators identified 5-(and-6)-carboxy SNARF-1 as a membrane-impermeant dye with a suitable pKa value. Conditions for facile detection of viable parasites in 96-well microplates were optimized and used for limiting dilution cloning of genetic cross progeny and transfected parasites. RESULTS: 5-(and-6)-carboxy SNARF-1 is a two-emission wavelength dye that accurately reported extracellular pH in parasite cultures. It readily detected parasite growth in microplate wells and yielded results comparable to labour-intensive examination of Giemsa-stained smears. The dye is non-toxic, allowing parasite detection without transfer of culture material to additional plates for separate assays. This dye was used with high-throughput limiting dilution culture to generate additional progeny clones from the HB3 * Dd2 genetic cross. CONCLUSIONS: This fluorescence-based assay represents a low-cost, efficient method for detection of viable parasites in microplate wells; it can be easily expanded by automation. PMID- 22531354 TI - Thailandepsins are new small molecule class I HDAC inhibitors with potent cytotoxic activity in ovarian cancer cells: a preclinical study of epigenetic ovarian cancer therapy. AB - BACKGROUND: New treatment strategies are emerging to target DNA damage response pathways in ovarian cancer. Our group has previously shown that the class I biased HDAC inhibitor romidepsin (FK228) induces DNA damage response and has potent cytotoxic effects in ovarian cancer cells. Here, we investigated newly discovered HDAC inhibitors, thailandepsin A (TDP-A) and thailandepsin B (TDP-B), to determine the effects on cell viability, apoptosis and DNA damage response in ovarian cancer cells. METHODS: FK228, TDP-A and TDP-B were tested in five ovarian cancer cell lines. Cellular viability was measured by 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Immunofluorescence assays were used to assess activated caspase 3. Western blots were performed to detect protein expression of PARP cleavage, pH2AX, P-glycoprotein and tubulin acetylation. RESULTS: Treatment with TDPs decreased cell viability at nanonomolar concentrations in four of the five ovarian cancer cell lines studied. Similar to FK228, both TDP compounds exerted minimal effects on NCI/ADR-RES ovarian cancer cells. Across the four cell lines sensitive to the TDPs, TDP-B consistently had a greater inhibitory effect than TDP-A on cell viability. TDP-B also had relatively greater effects on promoting cell apoptosis and induction of pH2AX (a mark of DNA damage response), than TDP-A. These antitumor effects of TDP-B were of similar magnitude to those induced by an equal concentration of FK228. Similar to FK228, the nanomolar concentrations of the TDPs had little effect on tubulin acetylation (a mark of class II HDAC6 inhibition). CONCLUSIONS: The new small molecule HDAC inhibitors TDP-A and TDP-B are FK228 analogues that suppress cell viability and induce apoptosis at nanomolar drug concentrations. TDP-B showed the most similarity to the biological activity of FK228 with greater cytotoxic effects than TDP-A in vitro. Our results indicate that FK228-like small molecule class I HDAC-biased HDAC inhibitors have therapeutic potential for ovarian cancer. PMID- 22531356 TI - Alternative therapies: learning from patients who choose them. PMID- 22531355 TI - Losses of chromosome 5q and 14q are associated with favorable clinical outcome of patients with gastric cancer. AB - PURPOSE: To improve the clinical outcome of patients with gastric cancer, intensified combination strategies are currently in clinical development, including combinations of more extensive surgery, (neo)adjuvant chemotherapy, and radiotherapy. The present study used DNA copy number profiling to identify subgroups of patients with different clinical outcomes. We hypothesize that, by identification of subgroups, individual treatment strategies can be selected to improve clinical outcome and to reduce unnecessary treatment toxicity for patients with gastric cancer. EXPERIMENTAL DESIGN: DNA from 206 gastric cancer patients was isolated and analyzed by genomewide array comparative genomic hybridization. DNA copy number profiles were correlated with lymph node status and patient survival. In addition, heat shock protein 90 (HSP90) expression was analyzed and correlated with survival in 230 gastric cancer patients. RESULTS: Frequent (>20%) DNA copy number gains and losses were observed on several chromosomal regions. Losses on 5q11.2-q31.3 and 14q32.11-q32.33 (14% of patients) were correlated with good clinical outcome in univariate and multivariate analyses, with a median disease-free survival interval of 9.2 years. In addition, loss of expression of HSP90, located on chromosome 14q32.2, was correlated with better patient survival. CONCLUSION: Genomewide DNA copy number profiling allowed the identification of a subgroup of gastric cancer patients, marked by losses on chromosomes 5q11.2-q31.3 and 14q32.11-q32.33 or low HSP90 protein expression, with an excellent clinical outcome after surgery alone. We hypothesize that this subgroup of patients most likely will not benefit from (neo)adjuvant systemic treatment and/or radiotherapy, whereas anti-HSP90 therapy may have clinical potential in patients with HSP90-expressing gastric cancer, pending validation in an independent dataset. PMID- 22531358 TI - Beliefs and perceptions of women with newly diagnosed breast cancer who refused conventional treatment in favor of alternative therapies. AB - PURPOSE: Although breast cancer is a highly treatable disease, some women reject conventional treatment opting for unproven "alternative therapy" that may contribute to poor health outcomes. This study sought to understand why some women make this decision and to identify messages that might lead to greater acceptance of evidence-based treatment. PATIENTS AND METHODS: This study explored treatment decision making through in-depth interviews with 60 breast cancer patients identified by their treating oncologists. Thirty refused some or all conventional treatment, opting for alternative therapies, whereas 30 accepted both conventional and alternative treatments. All completed the Beck Anxiety Inventory and the Rotter Locus of Control scale. RESULTS: Negative first experiences with "uncaring, insensitive, and unnecessarily harsh" oncologists, fear of side effects, and belief in the efficacy of alternative therapies were key factors in the decision to reject potentially life-prolonging conventional therapy. Refusers differed from controls in their perceptions of the value of conventional treatment, believing that chemotherapy and radiotherapy were riskier (p < .0073) and less beneficial (p < .0001) than did controls. Controls perceived alternative medicine alone as riskier than did refusers because its value for treating cancer is unproven (p < .0001). Refusers believed they could heal themselves naturally from cancer with simple holistic methods like raw fruits, vegetables, and supplements. CONCLUSION: According to interviewees, a compassionate approach to cancer care plus physicians who acknowledge their fears, communicate hope, educate them about their options, and allow them time to come to terms with their diagnosis before starting treatment might have led them to better treatment choices. PMID- 22531357 TI - The risk for anemia with targeted therapies for solid tumors. AB - BACKGROUND: Anemia is a common manifestation in patients with cancer. Little is known about the frequency of and risk for anemia with targeted therapies used to treat solid tumors. METHODS: We performed a meta-analysis of randomized controlled trials of solid tumors by comparing targeted therapy (alone or in combination) with standard therapy alone to calculate the incidence and relative risk (RR) for anemia events associated with these agents. Overall, 24,310 patients were included in the analysis. RESULTS: The addition of targeted therapies to standard treatment (chemotherapy or placebo/best supportive care) increased the risk for all grades of anemia by 7%. The RR for all grades (incidence, 44%) and grades 1-2 (incidence, 38.9%) of anemia was higher with biological therapies alone but not when combined with chemotherapy. The risk was significant for erlotinib, trastuzumab, and sunitinib. Bevacizumab was associated with a lower risk for anemia. Anti-epidermal growth factor receptor, anti-human epidermal growth factor receptor 2, anti-vascular endothelial growth factor receptors, and tyrosine kinase inhibitors predicted RRs of 1.24, 1.20, 0.82, and 1.33, respectively, and all of these values were significant. CONCLUSION: Grade 1 2 anemia is frequently associated with biological agents. The risk is particularly associated with small-molecule tyrosine kinase inhibitors (gefitinib and erlotinib), breast cancer, and lung cancer. Erythropoiesis-stimulating agents are not labeled for use with targeted therapies (without chemotherapy) and the treatment is supportive only. PMID- 22531359 TI - Tamoxifen and CYP2D6: a contradiction of data. AB - Tamoxifen is an effective antiestrogen used in the treatment of hormone receptor positive breast cancer. Bioconversion of tamoxifen to endoxifen, its most abundant active metabolite, is primarily dependent on the activity of cytochrome P450 2D6 (CYP2D6), which is highly polymorphic. Over 20 published studies have reported on the potential association between CYP2D6 polymorphism and tamoxifen treatment outcome, with highly inconsistent results. The purpose of this review is to explore differences among 17 independent studies to identify factors that may have contributed to the discrepant findings. This report discusses six putative factors that are grouped into two categories: (a) clinical management criteria: hormone receptor classification, menopausal status, and tamoxifen combination therapy; (b) pharmacologic criteria: genotyping comprehensiveness, CYP2D6 inhibitor coadministration, and tamoxifen adherence. Comparison of these factors between the positive and negative studies suggests that tamoxifen combination therapy, genotyping comprehensiveness, and CYP2D6 inhibitor coadministration may account for some of the contradictory results. Future association studies on the link between CYP2D6 genotype and tamoxifen treatment efficacy should account for combination therapy and CYP2D6 inhibition, and interrogate as many CYP2D6 alleles as possible. PMID- 22531360 TI - Novel approaches of chemoradiotherapy in unresectable stage IIIA and stage IIIB non-small cell lung cancer. AB - Approximately one third of patients with non-small cell lung cancer have unresectable stage IIIA or stage IIIB disease, and appropriate patients are candidates for chemoradiotherapy with curative intent. The optimal treatment paradigm is currently undefined. Concurrent chemoradiotherapy, compared with sequential chemotherapy and thoracic radiation therapy (TRT), results in superior overall survival outcomes as a result of better locoregional control. Recent trials have revealed efficacy for newer chemotherapy combinations similar to that of older chemotherapy combinations with concurrent TRT and a lower rate of some toxicities. Ongoing phase III trials will determine the roles of cisplatin and pemetrexed concurrent with TRT in patients with nonsquamous histology, cetuximab, and the L-BLP25 vaccine. It is unlikely that bevacizumab will have a role in stage III disease because of its toxicity. Erlotinib, gefitinib, and crizotinib have not been evaluated in stage III patients selected based on molecular characteristics. The preliminary results of a phase III trial that compared conventionally fractionated standard-dose TRT (60 Gy) with high-dose TRT (74 Gy) revealed an inferior survival outcome among patients assigned to the high-dose arm. Hyperfractionation was investigated previously with promising results, but adoption has been limited because of logistical considerations. More recent trials have investigated hypofractionated TRT in chemoradiotherapy. Advances in tumor targeting and radiation treatment planning have made this approach more feasible and reduced the risk for normal tissue toxicity. Adaptive radiotherapy uses changes in tumor volume to adjust the TRT treatment plan during therapy, and trials using this strategy are ongoing. Ongoing trials with proton therapy will provide initial efficacy and safety data. PMID- 22531361 TI - Is age still the deciding factor? Commentary on "The effect of age on delay in diagnosis and stage of breast cancer" by Partridge et al. PMID- 22531362 TI - Tailored therapy in an unselected population of 91 elderly patients with DLBCL prospectively evaluated using a simplified CGA. AB - BACKGROUND: Elderly patients with diffuse large B-cell lymphoma (DLBCL) are a heterogeneous population; clinical trials have evaluated a minority of these patients. PATIENTS AND METHODS: Ninety-one elderly patients with DLBCL received tailored treatment based on a comprehensive geriatric assessment (CGA). Three groups were identified: I, fit patients; II, patients with comorbidities; III, frail patients. Group I received 21-day cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP-21), group II received R-CHOP-21 with liposomal doxorubicin, and group III received 21-day cycles of reduced-dose CHOP. Fifty-four patients (59%) were allocated to group I, 22 (25%) were allocated to group II, and 15 (16%) were allocated to group III. RESULTS: The complete response (CR) rates were 81.5% in group I, 64% in group II, and 60% in group III. With a median follow-up of 57 months, 42 patients are alive, with 41 in continuous CR: 31 patients (57%) in group I, seven patients (32%) in group II, and four patients (20%) in group III. The 5-year overall survival, event-free survival, and disease-free survival rates in all patients were 46%, 31%, and 41%, respectively. Multivariate analysis selected group I assignment as the main significant prognostic factor for outcome. CONCLUSIONS: This approach in an unselected population of elderly DLBCL patients shows that treatment tailored according to a CGA allows the evaluation of elderly patients who are currently excluded from clinical trials. PMID- 22531364 TI - Impaired aquaporin 3 expression in reepithelialization of cutaneous wound healing in the diabetic rat. AB - Impaired cutaneous wound healing is a serious complication of diabetes mellitus (DM). Currently, little is known about reepithelialization in DM. However, recent studies identified aquaporin 3 (AQP3), a transmembrane protein that functions as a pore-like passive transporter, to be a key molecule in cutaneous epidermal wound healing. AQP3 expression is downregulated in response to tumor necrosis factor-alpha (TNF- alpha). Given that systemic TNF-alpha levels are functionally connected to impaired healing in diabetic mice and that both diabetic and Aqp3 deficient animals exhibit impaired reepithelialization, the authors hypothesized that impaired AQP3 expression might contribute to diabetes-impaired wound healing. In the present study, the authors examined AQP3 expression in the regenerating epidermis during cutaneous full thickness wound healing and in intact skin of a streptozotocin-induced diabetic rat model. Aqp3 messenger RNA expression levels were decreased in wounds of DM rats compared to controls. Immunohistochemical analysis showed an absence of AQP3 in the stratum spinosum of the regenerating epidermis in the DM group, whereas the stratum basale was positive for AQP3 in both groups. In summary, these findings suggest that there may be a relationship between impaired AQP3 expression and diabetes-delayed reepithelialization. Thus, future nursing studies should focus on this mechanism in diabetic wound healing. PMID- 22531363 TI - White blood cell global methylation and IL-6 promoter methylation in association with diet and lifestyle risk factors in a cancer-free population. AB - Altered levels of global DNA methylation and gene silencing through methylation of promoter regions can impact cancer risk, but little is known about their environmental determinants. We examined the association between lifestyle factors and levels of global genomic methylation and IL-6 promoter methylation in white blood cell DNA of 165 cancer-free subjects, 18-78 years old, enrolled in the COMIR (Commuting Mode and Inflammatory Response) study, New York, 2009-2010. Besides self-administrated questionnaires on diet and physical activity, we measured weight and height, white blood cell (WBC) counts, plasma levels of high sensitivity C-reactive protein (hs-CRP), and genomic (LINE-1) and gene-specific methylation (IL-6) by pyrosequencing in peripheral blood WBC. Mean levels of LINE 1 and IL-6 promoter methylation were 78.2% and 57.1%, respectively. In multivariate linear regression models adjusting for age, gender, race/ethnicity, body mass index, diet, physical activity, WBC counts and CRP, only dietary folate intake from fortified foods was positively associated with LINE-1 methylation. Levels of IL-6 promoter methylation were not significantly correlated with age, gender, race/ethnicity, body mass index, physical activity or diet, including overall dietary patterns and individual food groups and nutrients. There were no apparent associations between levels of methylation and inflammation markers such as WBC counts and hs-CRP. Overall, among several lifestyle factors examined in association with DNA methylation, only dietary folate intake from fortification was associated with LINE-1 methylation. The long-term consequence of folate fortification on DNA methylation needs to be further evaluated in longitudinal settings. PMID- 22531365 TI - Heel blood flow during loading and off-loading in bedridden older adults with low and normal ankle-brachial pressure index: a quasi-experimental study. AB - The purpose of this study was to evaluate the differences in heel blood flow during loading and off-loading in bedridden adults older than 65 years. The patients were divided into three groups based on ankle-brachial pressure index (ABI) and transcutaneous oxygen tension (tcPO2): (1) patients with an ABI >= 0.8 (Group A); (2) patients with an ABI < 0.8 and heel tcPO2 >= 10 mmHg (Group B); and (3) patients with an ABI < 0.8 and heel tcPO2 < 10 mmHg (Group C). Heel blood flow was monitored using tcPO2 sensors. Data were collected with the heel (1) suspended above the bed surface (preload), (2) on the bed surface for 30 min (loading), and (3) again suspended above the bed surface for 60 min (off loading). Heel blood flow during off-loading was assessed using three parameters: oxygen recovery index (ORI), total tcPO2 for the first 10 min, and change in tcPO2 after 60 min of off-loading. ORI in Group C (n = 8) was significantly shorter than in Groups A (n = 22) and B (n = 15). Total tcPO2 for the first 10 min of off-loading in Group C was significantly less than that in Groups A and B. Change in tcPO2 after 60 min of off-loading in Group C was less than in Group A. Based on these findings, additional preventive care against heel blood flow decrease in older adults with an ABI < 0.8 and heel tcPO2 < 10 mmHg might be necessary after loading. PMID- 22531367 TI - Sleep stage assessment using power spectral indices of heart rate variability with a simple algorithm: limitations clarified from preliminary study. AB - Clinical researchers do not typically assess sleep with polysomnography (PSG) but rather with observation. However, methods relying on observation have limited reliability and are not suitable for assessing sleep depth and cycles. The purpose of this methodological study was to compare a sleep analysis method based on power spectral indices of heart rate variability (HRV) data to PSG. PSG and electrocardiography data were collected synchronously from 10 healthy women (ages 20-61 years) over 23 nights in a laboratory setting. HRV was analyzed for each 60 s epoch and calculated at 3 frequency band powers (very low frequency [VLF]-hi: 0.016-0.04 Hz; low frequency [LF]: 0.04-0.15 Hz; and high frequency [HF]: 0.15 0.4 Hz). Using HF/(VLF-hi + LF + HF) value, VLF-hi, and heart rate (HR) as indices, an algorithm to categorize sleep into 3 states (shallow sleep corresponding to Stages 1 & 2, deep sleep corresponding to Stages 3 & 4, and rapid eye movement [REM] sleep) was created. Movement epochs and time of sleep onset and wake-up were determined using VLF-hi and HR. The minute-by-minute agreement rate with the sleep stages as identified by PSG and HRV data ranged from 32 to 72% with an average of 56%. Longer wake after sleep onset (WASO) resulted in lower agreement rates. The mean differences between the 2 methods were 2 min for the time of sleep onset and 6 min for the time of wake-up. These results indicate that distinguishing WASO from shallow sleep segments is difficult using this HRV method. The algorithm's usefulness is thus limited in its current form, and it requires additional modification. PMID- 22531366 TI - Low-density lipoprotein cholesterol, apolipoprotein B, and risk of coronary heart disease: from familial hyperlipidemia to genomics. AB - Coronary heart disease (CHD) affects 17 million people in the United States and accounts for over a million hospital stays each year. Technological advances, especially in genetics and genomics, have changed our understanding of the risk factors for developing CHD. The purpose of this article is to review low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apo B), and risk of CHD. The article focuses on five topics: (1) a description of lipoprotein classes, normal lipoprotein metabolism, and the biological mechanism of atherosclerosis; (2) a review of selected epidemiologic and clinical trial studies examining the associations between elevated LDL-C and apo B with CHD; (3) a brief review of the familial forms of hyperlipidemia; (4) a description of variants in genes that have been associated with higher LDL-C levels in candidate gene studies and genome-wide association studies (GWAS); and (5) nursing implications, including a discussion on how genetic tests are evaluated and the current clinical utility and validity of genetic tests for CHD. PMID- 22531368 TI - Depressive symptoms and diurnal salivary cortisol patterns among female caregivers of stroke survivors. AB - Informal caregivers of stroke survivors experience elevated chronic stress and are at risk of developing depressive symptoms. The cumulative effects of chronic stress can increase allostatic load and dysregulate biological processes, thus increasing risk of stress-related disease. Stress-induced alterations in the pattern of cortisol secretion vary with respect to stressor onset, intensity, and chronicity. Little is known about the psychoendocrine response to stress in female caregivers of stroke survivors. The purpose of this study was to examine perceived stress, caregiver burden, and the association between caregiver depressive symptoms and diurnal cortisol in 45 females caring for a significant other who experienced a stroke within the past year. Women completed the Center for Epidemiologic Studies Depression Scale (CES-D) and collected saliva for cortisol upon awakening, 30 min postawakening, noon, and bedtime for 2 consecutive days. Results revealed that women had high levels of perceived stress and caregiver burden. In women with CES-D scores >= 16, salivary cortisol levels were significantly lower across the day relative to women with CES-D scores < 16. This difference persisted after adjusting for age, number of caregiving hours per week, perceived social support, and quality of sleep. Younger age was associated with more depressive symptoms as well as lower levels of cortisol at awakening and 30 min postawakening. Results demonstrate that the burden of caregiving increases risk of depressive symptoms and hypocortisolism across the day. Hypocortisolism may contribute to increased risk of depressive symptoms as a result of the loss of glucocorticoid attenuation of stress-induced inflammation. PMID- 22531371 TI - Ectopic ependymal cells in striatum accompany neurogenesis in a rat model of stroke. AB - Stroke-induced neurogenesis originates from a neural stem cell (NSC) niche in subventricular zone (SVZ). In mice, NSCs are concentrated in a so-called "neurogenic spot" in the lateral angle area of SVZ. We aimed to identify the "neurogenic spot" in the rat SVZ and to characterize the cellular changes in the ependymal cell compartment in this area at different time points after middle cerebral artery occlusion. The majority of ependymal cells outlining the ventricular wall did not proliferate, and their numbers in the "neurogenic spot" declined at 6 and 16weeks after stroke. Cells with the ultrastructural properties of ependymal cells were detected in the adjacent striatum. The number of these ectopic ependymal cells (EE cells) correlated positively with the magnitude of lateral ventricular enlargement and negatively with the ependymal cell number in the "neurogenic spot". EE cells were found along blood vessels, accumulated in the pericyst regions, and participated in scar formation but did not incorporate BrdU. We provide the first evidence for the occurrence of EE cells in the ischemic striatum following stroke. PMID- 22531369 TI - Tumor suppression by collagen XV is independent of the restin domain. AB - Non-fibrillar collagen XV is a chondroitin sulfate modified glycoprotein that is associated with the basement membrane zone in many tissues. Its precise functions remain to be fully elucidated though it clearly plays a critical role in the structural integrity of the extracellular matrix. Loss of collagen XV from the basement membrane zone precedes invasion of a number of tumor types and we previously showed that collagen XV functions as a dose-dependent suppressor of tumorigenicity in cervical carcinoma cells. The carboxyl terminus of another non fibrillar collagen (XVIII) is cleaved to produce endostatin, which has anti angiogenic effects and thus may act as a tumor suppressor in vivo. Since collagen XV has structural similarity with collagen XVIII, its C-terminal restin domain could confer tumor suppressive functions on the molecule, though our previous data did not support this. We now show that expression of collagen XV enhances the adhesion of cervical carcinoma cells to collagen I in vitro as does the N terminus and collagenous regions of collagen XV, but not the restin domain. Destruction of a cysteine residue in the collagenous region that is critical for intermolecular interactions of collagen XV abolished the enhanced adhesion to collagen I. Finally, we demonstrate that unlike full length collagen XV, expression of the restin domain alone does not suppress tumorigenicity of cervical carcinoma cells in vivo; hence, this process is dependent on functions and interactions of other parts of the protein. PMID- 22531370 TI - Inducible nitric oxide synthase is involved in the modulation of depressive behaviors induced by unpredictable chronic mild stress. AB - BACKGROUND: Experiences and inflammatory mediators are fundamental in the provocation of major depressive disorders (MDDs). We investigated the roles and mechanisms of inducible nitric oxide synthase (iNOS) in stress-induced depression. METHODS: We used a depressive-like state mouse model induced by unpredictable chronic mild stress (UCMS). Depressive-like behaviors were evaluated after 4 weeks of UCMS, in the presence and absence of the iNOS inhibitor N-(3-(aminomethyl)benzyl)acetamidine (1400 W) compared with the control group. Immunohistochemistry was used to check the loss of Nissl bodies in cerebral cortex neurons. The levels of iNOS mRNA expression in the cortex and nitrites in the plasma were measured with real-time reverse transcription PCR (RT PCR) and Griess reagent respectively. RESULTS: Results showed that the 4-week UCMS significantly induced depressive-like behaviors, including decreased sucrose preference in a sucrose preference test, increased duration of immobility in a forced swim test, and decreased hole-searching time in a locomotor activity test. Meanwhile, in the locomotor activity test, UCMS had no effect on normal locomotor activities, such as resting time, active time and total travel distance. Furthermore, the levels of iNOS mRNA expression in the cortex and nitrites in the plasma of UCMS-exposed mice were significantly increased compared with that of the control group. Neurons of cerebral cortex in UCMS-exposed mice were shrunken with dark staining, together with loss of Nissl bodies. The above-mentioned stress-related depressive-like behaviors, increase of iNOS mRNA expression in the cortex and nitrites in the plasma, and neuron damage, could be abrogated remarkably by pretreating the mice with an iNOS inhibitor (1400 W). Moreover, neurons with abundant Nissl bodies were significantly increased in the 1400 W + UCMS group. CONCLUSIONS: These results support the notion that stress-related NO (derived from iNOS) may contribute to depressive-like behaviors in a mouse model, potentially concurrent with neurodegenerative effects within the cerebral cortex. PMID- 22531372 TI - Effect of brain-derived neurotrophic factor on behavior and key members of the brain serotonin system in genetically predisposed to behavioral disorders mouse strains. AB - The effect of brain-derived neurotrophic factor (BDNF) on depressive-like behavior and serotonin (5-HT) system in the brain of antidepressant sensitive cataleptics (ASC)/Icg mouse strain, characterized by depressive-like behavior, in comparison with the parental nondepressive CBA/Lac mouse strain was examined. Significant decrease of catalepsy and tail suspension test (TST) immobility was shown 17days after acute central BDNF administration (300ng i.c.v.) in ASC mice. In CBA mouse strain, BDNF moderately decreased catalepsy without any effect on TST immobility time. Significant difference between ASC and CBA mice in the effect of BDNF on 5-HT system was revealed. It was shown that central administration of BDNF led to increase of 5-HT(1A) receptor gene expression but not 5-HT(1A) functional activity in ASC mice. Increased tryptophan hydroxylase-2 (Tph-2) and 5-HT(2A) receptor genes expression accompanied by 5-HT(2A) receptor sensitization was shown in BDNF-treated ASC but not in CBA mouse strain, suggesting BDNF-induced increase of the brain 5-HT system functional activity and activation of neurogenesis in "depressive" ASC mice. There were no changes found in the 5-HT transporter mRNA level in BDNF-treated ASC and CBA mice. In conclusion, central administration of BDNF produced prolonged ameliorative effect on depressive-like behavior accompanied by increase of the Tph-2, 5-HT(1A) and 5 HT(2A) genes expression and 5-HT(2A) receptor functional activity in animal model of hereditary behavior disorders. PMID- 22531374 TI - Xenon-induced inhibition of synchronized bursts in a rat cortical neuronal network. AB - Xenon (Xe) and other inert gases produce anesthesia via an inhibitory mechanism in neuronal networks. To better understand this mechanism, we measured the electrical signals from cultured rat cortical neuronal networks in a multi electrode array (MEA) under an applied Xe pressure. We used the MEA to measure the firing of the neuronal network with and without Xe gas pressurized to 0.3MPa. The MEA system monitored neuronal spikes on 16 electrodes (each 50*50MUm(2)) at a sampling rate of 20kHz. The embryo rat cortical cells were first cultured on MEAs without Xe for approximately 3weeks, at which time they produced synchronized bursts that indicate maturity. Then, with an applied Xe pressure, the synchronized bursts quickly ceased, whereas single spikes continued. The Xe induced inhibition-recovery of neuronal network firing was reversible: after purging Xe from the system, the synchronized bursts gradually resumed. Thus, Xe did not inhibit single neuron firing, yet reversibly inhibited the synaptic transmission. This finding agrees with the channel-blocker and a modified-hydrate hypothesis of anesthesia, but not the lipid-solubility hypothesis. PMID- 22531373 TI - Gene delivery of antioxidant enzymes inhibits human immunodeficiency virus type 1 gp120-induced expression of caspases. AB - Caspases are implicated in neuronal death in neurodegenerative and other central nervous system (CNS) diseases. In a rat model of human immunodeficiency virus type 1 (HIV-1) associated neurocognitive disorders (HAND), we previously characterized HIV-1 envelope gp120-induced neuronal apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. In this model, neuronal apoptosis occurred probably via gp120-induced reactive oxygen species (ROS). Antioxidant gene delivery blunted gp120-related apoptosis. Here, we studied the effect of gp120 on different caspases (3, 6, 8, 9) expression. Caspases production increased in the rat caudate-putamen (CP) 6h after gp120 injection into the same structure. The expression of caspases peaked by 24h. Caspases colocalized mainly with neurons. Prior gene delivery of the antioxidant enzymes Cu/Zn superoxide dismutase (SOD1) or glutathione peroxidase (GPx1) into the CP before injecting gp120 there reduced levels of gp120-induced caspases, recapitulating the effect of antioxidant enzymes on gp120-induced apoptosis observed by TUNEL. Thus, HIV-1 gp120 increased caspases expression in the CP. Prior antioxidant enzyme treatment mitigated production of these caspases, probably by reducing ROS levels. PMID- 22531375 TI - Substance P-induced changes in cell genesis following diffuse traumatic brain injury. AB - Inhibition of substance P (SP) activity through the use of NK1 receptor antagonists has been shown to be a promising neuroprotective therapy following traumatic brain injury (TBI). Conversely, recent research has implicated SP in the stimulation of neurogenesis, suggesting that the neuropeptide has the potential to promote recovery following TBI. This study characterised the effects of SP and the NK1 antagonist, n-acetyl tryptophan (NAT), on cell proliferation following diffuse TBI. Adult male Sprague-Dawley rats were injured using the impact acceleration model of TBI and randomly assigned to one of five treatment groups: sham, vehicle control, NAT alone, SP alone or SP with NAT. Cellular proliferation was assessed with immunostaining for bromodeoxyuridine (BrdU) and cell-specific markers. Infusion of SP (+/-NAT) promoted cellular proliferation in the subventricular zone and dentate gyrus following TBI. This increase was largely associated with microglial proliferation and did not correspond with functional improvements. These results suggest that NAT treatment results in neuroprotection following TBI, mediated in part via inhibition of microglia. PMID- 22531376 TI - Dynamics of phase-independent spectro-temporal tuning in primary auditory cortex of the awake ferret. AB - Tuning of cortical neurons is often measured as a static property, or during a steady-state regime, despite a number of studies suggesting that tuning depends on when it is measured during a neuron's response (e.g., onset vs. sustained vs. offset). We have previously shown that phase-locked tuning to feature transients evolves as a dynamic quantity from the onset of the sound. In this follow-up study, we examined the phase-independent tuning during feature transients. Based on previous results, we hypothesized phase-independent tuning should evolve on the same timescale as phase-locked tuning. We used stimuli of constant level, but alternating between flat spectro-temporal envelope and a modulated envelope with well-defined spectral density and temporal periodicity. This allowed the measure of changes in tuning to novel spectro-temporal content, as happens during running speech and other sounds with rapid transitions without a confounding change in sound level. For 95% of neurons, tuning changed significantly from the onset, over the course of the response. For a majority of these cells, the change occurred within the first 40ms following a feature onset, often even around 10 20ms. This solidifies the idea that tuning can change rapidly from onset tuning to the sustained, steady-state tuning. PMID- 22531377 TI - Transient expression of Xpn, an XLMR protein related to neurite extension, during brain development and participation in neurite outgrowth. AB - KIAA2022 has been implicated as a gene responsible for expressing X-linked mental retardation (XLMR) proteins in humans. However, the functional role of KIAA2022 in the human brain remains unclear. Here, we revealed that depletion of Kiaa2022 inhibits neurite outgrowth of PC12 cells, indicating that the gene participates in neurite extension. Thus, we termed Kiaa2022 as an XLMR protein related to neurite extension (Xpn). Using the mouse brain as a model and ontogenetic analysis of Xpn by real-time PCR, we clearly demonstrated that Xpn is expressed transiently during the late embryonic and perinatal stages. In situ hybridization histochemistry further revealed that Xpn-expressing neurons could be categorized ontogenetically into three types. The first type showed transient expression of Xpn during development. The second type maximally expressed Xpn during the late embryonic or perinatal stage. Thereafter, Xpn expression in this type of neuron decreased gradually throughout development. Nevertheless, a significant level of Xpn expression was detected even into adulthood. The third type of neurons initiated expression of Xpn during the embryonic stage, and continued to express the gene throughout the remaining developmental stages. Subsequent immunohistochemical analysis revealed that Xpn was localized to the nucleus and cytoplasm throughout brain development. Our findings indicate that Xpn may participate in neural circuit formation during developmental stages via nuclear and cytoplasmic Xpn. Moreover, disturbances of this neuronal circuit formation may play a role in the pathogenesis of mental retardation. PMID- 22531379 TI - ICLs: a chicken without an egg. PMID- 22531378 TI - Morphine and MK-801 administration leads to alternative N-methyl-D-aspartate receptor 1 splicing and associated changes in reward seeking behavior and nociception on an operant orofacial assay. AB - The NMDA receptor plays a large role in opioid-induced plastic changes in the nervous system. The expression levels of its NR1 subunit are altered dramatically by morphine but no changes in its alternative splicing have been reported. Changes in the splicing of the N1, C1, C2, and C2' cassettes can alter the pharmacology and regulation of this receptor. Western Blots run on brain tissue from rats made tolerant to morphine revealed altered splicing of the N1 cassettes in the accumbens and amygdala (AMY), and the C1 cassette in the AMY and the dorsal hippocampus (HIPP). After 3days of withdrawal C2'-containing NR1 subunits were down-regulated in each of these areas. These were not due to acute doses of morphine and may represent long-term alterations in drug-induced neuroplasticity. We also examined the effects of morphine tolerance on an operant orofacial nociception assay which forces an animal to endure an aversive heat stimulus in order to receive a sweet milk reward. Morphine decreased pain sensitivity as expected but also increased motivational reward seeking in this task. NMDAR antagonism potentiated this reward seeking behavior suggesting that instead of attenuating tolerance, MK-801 may actually alter the rewarding and/or motivational properties of morphine. When combined, MK-801 and morphine had an additive effect which led to altered splicing in the accumbens, AMY, and the HIPP. In conclusion, NR1 splicing may play a major role in the cognitive behavioral aspects especially in motivational reward-seeking behaviors. PMID- 22531380 TI - Synthesis of N6-alkyl(aryl)-2-alkyl(aryl)thioadenosines as antiplatelet agents. AB - A series of novel N(6)-alkyl(aryl)-2-alkyl(aryl)thioadenosines were synthesized, and their human antiplatelet aggregation activities were evaluated by the stimulation of adenosine 5'-diphosphate (ADP). Some of these compounds showed strong activity, among which compound 5b(11) displayed the highest activity with an IC(50) value of 29 +/- 3 MUM. Furthermore, five compounds were tested against arachidonic acid (AA)-induced human platelet aggregation. The results showed that compound 5b(10) exhibited the highest activity with an IC(50) value of 3 +/- 2 MUM. The adenosine derivatives substituted with a phenethyl group at the N(6) position and a methylthio or ethylthio group at the C-2 position displayed high antiplatelet aggregation activity. PMID- 22531381 TI - The effects of fluid injection on lesion size during bipolar radiofrequency treatment. AB - BACKGROUND: The effect of preinjected fluid on bipolar radiofrequency (RF) lesion characteristics has not been investigated with conventional pain medicine equipment. The purpose of the present study was to determine the effect of preinjected fluid composition on lesion parameters. METHODS: Bipolar RF lesioning was performed in ex vivo chicken samples without fluid preinjection or with 0.7 mL of fluid injected through the 2 RF cannulas (total volume, 1.4 mL). The preinjected fluids were sterile water, 0.9% NaCl, 3% NaCl, 1% lidocaine, and 6% hydroxyethyl starch (HES). For each condition, RF electrodes were incrementally separated, and the number of trials producing successful lesions was recorded. Maximum and minimum height, length, and depth of the lesions were measured, and volumes of the lesions were calculated. RESULTS: The preinjection of any fluid increased the odds of consistently achieving a continuous lesion between the electrodes that was at least 75% of the maximal height of tissue damaged; 3% NaCl increased the odds of achieving at least 75% maximum height significantly more than any other fluid except for HES. Injection of any fluid containing NaCl (including lidocaine and HES) significantly increased the mean volume of tissue lesioned over that observed with injection of water. CONCLUSIONS: Fluid composition influences success, alters lesion size, and could be an appropriate consideration when selecting treatment parameters for bipolar RF. The enhanced lesion size and improved odds of producing a successful lesion with increasing NaCl concentration suggest a method to enlarge lesion size in a controlled manner. PMID- 22531384 TI - Epidural technique for postoperative pain: gold standard no more? AB - Epidural analgesia is a well-established technique that has commonly been regarded as the gold standard in postoperative pain management. However, newer, evidence-based outcome data show that the benefits of epidural analgesia are not as significant as previously believed. There are some benefits in a decrease in the incidence of cardiovascular and pulmonary complications, but these benefits are probably limited to high-risk patients undergoing major abdominal or thoracic surgery who receive thoracic epidural analgesia with local anaesthetic drugs only. There is increasing evidence that less invasive regional analgesic techniques are as effective as epidural analgesia. These include paravertebral block for thoracotomy, femoral block for total hip and knee arthroplasty, wound catheter infusions for cesarean delivery, and local infiltration analgesia techniques for lower limb joint arthroplasty. Wound infiltration techniques and their modifications are simple and safe alternatives for a variety of other surgical procedures. Although pain relief associated with epidural analgesia can be outstanding, clinicians expect more from this invasive, high-cost, labour intensive technique. The number of indications for the use of epidural analgesia seems to be decreasing for a variety of reasons. The decision about whether to continue using epidural techniques should be guided by regular institutional audits and careful risk-benefit assessment rather than by tradition. For routine postoperative analgesia, epidural analgesia may no longer be considered the gold standard. PMID- 22531382 TI - Optical detection of peripheral nerves: an in vivo human study. AB - BACKGROUND AND OBJECTIVES: A critical challenge encountered in interventional pain medicine procedures is to accurately and efficiently identify transitions to peripheral nerve targets. Current methods, which include ultrasound guidance and nerve stimulation, are not perfect. In this pilot study, we investigated the feasibility of identifying tissue transitions encountered during insertions toward peripheral nerve targets using optical spectroscopy. METHODS: Using a custom needle stylet with integrated optical fibers, ultrasound-guided insertions toward peripheral nerves were performed in 20 patients, with the stylet positioned in the cannula of a 20-gauge stimulation needle. Six different peripheral nerves were represented in the study, with 1 insertion per patient. During each insertion, optical reflectance spectra were acquired with the needle tip in subcutaneous fat, skeletal muscle, and at the nerve target region. Differences in the spectra were quantified with 2 parameters that provide contrast for lipid and hemoglobin, respectively. RESULTS: The transition of the needle tip from subcutaneous fat to muscle was associated with lower lipid parameter values (P = 0.003) and higher hemoglobin parameter values (P = 0.023). The transition of the needle tip from the muscle to the nerve target region was associated with higher lipid parameter values (P = 0.008). CONCLUSIONS: The results indicate that the spectroscopic information provided by the needle stylet could potentially allow for reliable identification of transitions from subcutaneous fat to skeletal muscle and from the muscle to the nerve target region during peripheral nerve blocks. PMID- 22531385 TI - Carl Koller, cocaine, and local anesthesia: some less known and forgotten facts. AB - Modern-day local anesthesia began in 1884 with a discovery by a young unknown ophthalmologist from Vienna named Carl Koller, who placed a cocaine solution on the cornea, thus producing insensibility. The news of his discovery spread throughout the world in less than a month. "Not surprisingly," a controversial priority discussion emerged. There is little information about this "dark side" of Koller's discovery and only sparse data about the personalities involved in this controversy. In addition, Carl Koller's decision to leave Vienna is also surrounded in secrecy. The story surrounding the revelation of the local anesthetic effect of cocaine and the personalities involved is fascinating and relatively unknown. PMID- 22531386 TI - Orthopedic anesthesia subspecialization: the way forward to increase utilization of perineural infusions? PMID- 22531388 TI - Semantics, misnomer, or uncertainty: where is the epineurium on ultrasound? PMID- 22531390 TI - A room-temperature adenosine-based molecular beacon for highly sensitive detection of nucleic acids. AB - This study developed a simple, sensitive, and selective molecular beacon for detecting nucleic acids at room temperature based on coralyne induced conformational change of a MB through A(2)-coralyne-A(2) coordination. PMID- 22531391 TI - Highly selective reduction of nitroarenes by iron(0) nanoparticles in water. AB - Highly selective reduction of nitroarenes has been achieved using iron metal nanoparticles in water at room temperature. A wide spectrum of reducible functionalities remained inert under the reaction conditions. During the reaction a change in shape of Fe nanoparticles was observed. PMID- 22531392 TI - Paper spray: a simple and efficient means of analysis of different contaminants in foodstuffs. AB - A simple and efficient ambient ionization method based on paper spray combined with tandem mass spectrometry allows rapid detection and quantitation of various contaminants (clenbuterol, melamine, plasticizer and sudan red) in various foodstuffs (e.g., meat, milk, sports drinks and chili powder). PMID- 22531393 TI - Presidential Introduction: SESPRS. PMID- 22531394 TI - The Bikini Inset: a reliable method for postradiation breast reconstruction with transverse rectus abdominis myocutaneous and free abdominal tissue transfer. AB - The combination of radiation and mastectomy reduces the 3-dimensional topography of the breast into a relatively inelastic, 2-dimensional plane. This environment presents specific challenges to aesthetic breast reconstruction with autologous tissue transfer, and a relative sparsity of information exists in the surgical literature on how to address these challenges. Accordingly, this article details a formalized and reproducible approach for flap inset in postradiation breast reconstruction. We outline a novel technique for optimizing the recipient bed and present a sequential flow for contouring the autologous abdominal flap, so that it recreates the individual subunits of an aesthetic breast. PMID- 22531395 TI - Infectious complications associated with the use of acellular dermal matrix in implant-based bilateral breast reconstruction. AB - BACKGROUND: The use of acellular dermal matrix (ADM) has become a routine practice in implant-based breast reconstruction. Bilateral mastectomy is becoming more popular in cases of unilateral breast cancer. ADM has been associated with an increased incidence of complications. METHODS: We identified cases of bilateral implant-based breast reconstruction over a 5-year period. Data collection included medical comorbities, details of operative management, and details of postoperative cancer treatment. RESULTS: On univariate analysis, the use of ADM (31% vs. 7%, P = 0.018), smoking (37% vs. 13%, P = 0.045), and open wound (55% vs. 13%, P = 0.006) were significantly associated with increased risk of infection. Multivariate analysis revealed open wound as the strongest predictor of infection. CONCLUSIONS: The use of ADM is associated with an increased risk of infection in bilateral implant-based breast reconstruction. However, it does not appear to be an independent risk factor by itself. PMID- 22531396 TI - Outcome analysis of 541 women undergoing breast conservation therapy. AB - Breast conservation therapy (BCT) has evolved as a favorable approach to the management of early-stage breast cancer. Shortcomings of BCT include the potential need for re-excision in the event of positive tumor margins as well as the untoward sequelae of radiation therapy. Both of those factors have led to a substantial proportion of patients undergoing BCT who ultimately report suboptimal aesthetic outcomes. Application of plastic surgery principles to the management of this patient subset has been shown to be beneficial from both an oncologic and cosmetic perspective.The aim of this study was to identify factors that may predict which patients would benefit most from involvement of a plastic surgeon before BCT. A retrospective analysis was performed on 762 patients undergoing lumpectomy during a 10-year study period at a single institution. Younger women and patients with tumor size approaching 2 cm were noted to have a significantly higher likelihood of oncologic outcomes that ultimately required breast reconstruction. Integration of oncoplastic techniques in the surgical management of patients undergoing BCT would likely contribute to improvement in aesthetic outcomes and overall patient satisfaction. PMID- 22531397 TI - Improvement of success rates for abdominal component reconstructions using bovine fetal collagen. AB - Between February 2008 and December 2010, the author performed 15 standardized component repairs in patients reinforced with bovine fetal collagen. Of 15 repairs, 14 (93%) were intact at an average follow-up of 18 months. This success rate is a significant improvement from the author's previous success rate with this procedure (67%) and may represent a specific contribution of bovine fetal collagen reinforcement. PMID- 22531398 TI - Nipple-sparing mastectomy: technical aspects and aesthetic outcomes. AB - INTRODUCTION: Nipple-sparing mastectomy (NSM) is increasingly used to improve the results of immediate breast reconstruction. Technical aspects and aesthetic outcomes of this procedure are examined. METHODS: A study of a prospective institutional database of all cases of NSM between 2009 and 2010 was performed. Aesthetic outcomes (symmetry, inframammary fold, volume, contour, and nipple) are compared with patients undergoing skin-sparing mastectomy and immediate breast reconstruction by grading postoperative photographs. Technical refinements in incision types and nipple positioning are described. RESULTS: Twenty-six patients underwent 40 NSMs during the study period. Partial nipple necrosis occurred in 15 breasts (37.5%); of them, 14 healed uneventfully with local wound care, and 1 patient required delayed nipple reconstruction. Nipple necrosis by incision type was radial/circumareolar in 6 of 8 (75%) patients; radial, 3 of 9 (33.3%); inframammary fold, 6 of 22 (27.3%); and vertical, 0 of 1 (0%). The nipple aesthetic outcome was significantly better for NSM compared with nipple reconstruction after skin-sparing mastectomy (P = 0.01). CONCLUSIONS: The incidence of partial nipple necrosis was high and was related to circumareolar incisions. Most cases of nipple necrosis are superficial and heal uneventfully. Preservation of the nipple improves the aesthetic outcome of immediate breast reconstruction. PMID- 22531399 TI - Utilizing biologic assimilation of bovine fetal collagen in staged skin grafting. AB - Seven patients underwent 2-stage skin grafting with bovine fetal collagen (BFC) as an initial wound cover. Split-thickness skin grafts were successfully placed on the wounds after completion of interval management. BFC proved to be a resilient acellular dermal matrix that could proceed to assimilation and skin grafting under a variety of wound conditions. BFC may prove to be a valuable material, as the role of acellular dermal matrices in skin grafting becomes better defined. PMID- 22531400 TI - Screw fixation of dermal regeneration template for scalp reconstruction. AB - Despite many advances in reconstructive techniques, the full-thickness scalp defect remains a difficult problem for the reconstructive surgeon. Patient and disease-specific factors occasionally make reconstruction with a dermal regeneration template (DRT) an attractive option when other methods are less advised. Although the applicability of dermal regeneration templates has been well elucidated, the method of DRT immobilization has not been standardized. Given the difficulty of adherence and subsequent infiltration of host cells into the DRT from the underlying bone due to seroma, hematoma, or shearing forces, we propose a screw and bolster system for DRT immobilization. We present a series of 13 patients with full-thickness scalp loss who underwent reconstruction with DRT and a subsequent split-thickness skin graft. All 13 patients were treated with the screw-bolster method of DRT fixation before a vacuum-assisted closure dressing. The average surface area of the defect was 96 cm. The mean time interval between the application of DRT and skin graft was 28 days. At a mean of 9-month follow-up, all patients achieved a well-vascularized neodermis, and progressed to complete, stable wound healing following application of a split thickness skin graft. We propose that a screw-bolster system of fixation is a safe and effective method of immobilizing DRT in full-thickness scalp defects. PMID- 22531401 TI - Changing characteristics of facial fractures treated at a regional, level 1 trauma center, from 2005 to 2010: an assessment of patient demographics, referral patterns, etiology of injury, anatomic location, and clinical outcomes. AB - INTRODUCTION: Despite improvements in automotive safety, motor vehicle collision (MVC)-related facial fractures remain common and represent preventable injuries. This study examines the changing characteristics of facial fractures treated at a regional, level I trauma center, from 2005 to 2010. METHODS: We identified all patients with facial fractures admitted to our hospital, from 2005 to 2010, by querying the North Carolina Trauma Registry, using International Classification of Diseases, Ninth Revision codes. Prospectively collected data, sorted by year, were descriptively analyzed for demographics, referral patterns, etiology, anatomic location, and clinical outcomes. RESULTS: Number of patients with facial fractures increased from 201 per year to 263 per year (total n = 1508). Although transport distances remained constant at ~85 miles, standard deviation increased from 37 to 68 miles. Transport time increased from 87 to 119 minutes. Referrals came from 28 surrounding counties in 2005 and 43 counties in 2010. Regarding etiology, MVCs decreased from 40% to 27%, all-terrain vehicle crashes decreased from 6% to 2%, falls increased from 8% to 19%, and bicycle accidents increased from 3% to 6%. Regarding anatomic location, frontal sinus fractures increased from 8% to 37%, zygomaticomaxillary fractures increased from 9% to 18%, nasoethmoid fractures decreased from 12% to 6%, orbital floor fractures decreased from 6% to 3%, and mandible fractures decreased from 28% to 18%. Single-site fractures increased from 75% to 90%. Length of intensive care unit and hospital stay remained stable at 3 and 7 days, respectively. CONCLUSIONS: Despite a decrease in MVC-related facial fractures, the overall increase in facial fractures referred to our trauma center is due to a growing number of patient transfers from rural hospitals, where a paucity of qualified surgeons may exist. PMID- 22531402 TI - Incidence and management of zygomatic fractures at a level I trauma center. AB - PURPOSE: The purpose of this study is to evaluate current treatment of zygomatic fractures presenting at a level I trauma center. METHODS: Radiology records over a 1-year period were retrospectively reviewed to determine all patients diagnosed with fractures through the zygoma. A total of 1049 computed tomography maxillofacial scans were reviewed which identified 243 patients with fractures through the zygoma. Of these, 200 patients were identified as clinically relevant zygomatic fractures defined as having 3 or more major buttress fractures. RESULTS: Among the 200 patients identified with zygomatic fractures, 132 patients were treated nonoperatively and 68 patients required operative management. In the operative group 31% were treated with a limited (one-buttress) approach. CONCLUSIONS: Review of our management of zygomatic fractures at a level I trauma center found a high incidence of zygomatic fractures (66%) that can be managed nonoperatively without significant complications. There is a select group of zygomatic fractures that can be successfully managed by the experienced surgeon with a limited one-buttress approach. PMID- 22531403 TI - The impact of an independent transfer center on the evaluation and transport of patients with burn and maxillofacial injuries to definitive care at a level 1 trauma center. AB - OBJECTIVE: To assess the impact of an independent call center on facilitation of burn and maxillofacial trauma patient transfer to a level 1 trauma center. METHODS: All patients admitted to our level 1 trauma center for definitive management of either burn or maxillofacial injuries from September 1, 2004 to September 1, 2008, 2 years before and after transfer service initiation on September 1, 2006, were identified using the North Carolina Trauma Registry. Cohort demographics, referral patterns, transfer times/distances, and clinical outcomes were assessed. RESULTS: Burn patients increased from 1031 to 1208, from the 2 years before to after transfer center initiation. Average transport time increased from 113 to 165 minutes and average distance traveled increased from 84 to 86 miles. Out-of-state admissions increased from 24 to 46; number of referring counties increased from 58 to 60. Maxillofacial trauma patients increased from 390 to 576. Average transport time increased from 87 to 119 minutes, average distance increased from 84 to 89 miles, and number of referring counties jumped from 28 to 43. Length of stay did not change over the study period. CONCLUSIONS: The initiation of an independent call center, designed to facilitate the transfer of patients with burn and maxillofacial injuries to a level 1 trauma center, increased the number of referrals and expanded our geographic footprint, but did not decrease transport times. PMID- 22531404 TI - The transition from pedicle transverse rectus abdominis myocutaneous to perforator flap: what is the cost of opportunity? AB - PURPOSE: This study evaluates how the transition from pedicled transverse rectus abdominis myocutaneous (pTRAM) to perforator flaps at an academic center has affected outcome and reimbursement. METHODS: In 2006, our practice transitioned to almost exclusively perforator flaps for breast reconstruction. This study retrospectively compares pTRAM flaps performed from 2002 to 2006 (group 1) with perforator flaps from 2006 to 2010 (group 2). Operative time, complications, and reimbursement were compared between the 2 groups. RESULTS: We performed 93 pTRAM flaps in 69 patients in group 1 and 102 perforator flaps in 69 patients in group 2. Operative time was shorter in group 1 for unilateral breast reconstruction (399 vs. 543 minutes, P = 0.0001), but no significant difference was noted for bilateral cases (547 vs. 658 minutes, P = 0.1). Fat necrosis requiring reoperation (23.7% vs. 5.9%, P = 0.0004) and partial flap necrosis (20.6% vs. 7.2%, P = 0.045) were more frequent in group 1. There was a higher frequency of abdominal hernia (8.8% vs. 1.6%, P = 0.2) but fewer hematomas (1.5% vs. 10%, P = 0.06) in group 1, although statistical significance was not reached between the 2 groups. Mean adjusted payment per case was $3658.67 for group 1 versus $5256.48 for group 2 (P = 0.004), whereas payment per minute was $9.25 for group 1 versus $9.13 for group 2 (P = 0.9). Perforator flaps appear to be as profitable as pTRAM flaps with lower morbidity. CONCLUSIONS: The transition from pTRAM to perforator flap can be done successfully with appropriate resources and support. The development of a perforator flap practice represents an opportunity cost in optimizing patient care and should be an option to patients seeking breast reconstruction. PMID- 22531405 TI - Evaluation of host tissue integration, revascularization, and cellular infiltration within various dermal substrates. AB - Acellular dermal matrices are used in a variety of reconstructive and cosmetic procedures. There seems to be host tissue integration, revascularization, and recellularization into these products, but the exact timing and differences among these remain unknown. The purpose of this study is to determine and compare these properties of 4 different acellular dermal matrices (AlloDerm, DermACELL, DermaMatrix, and Integra) in an in vivo rat model. Tissue specimens were obtained at various time points. Histology and immunohistologic assays were used to quantify the extent of cellular infiltration and revascularization within the various matrices. A bimodal cellular response was observed in all products except for DermACELL. Cellular infiltration was highest in DermACELL and lowest in AlloDerm, and angiogenesis was evident by day 7. There were clear differences within the various products. It is undetermined whether these differences are advantageous or clinically significant. Future work is needed to define the specific roles for each. PMID- 22531406 TI - Efficacy of extrapolation from national burn data for estimating patient volume in a new burn unit. AB - In 2009, the JMS Burn Centers network opened as the only organized inpatient burn unit in Mississippi. Initial predictions of total annual state burn admissions (431 patients) and total annual state burn center admissions (239 patients) were made by extrapolating from national burn and census data. Actual JMS admissions for 2 years totaled 1016 patients, exceeding predicted total state burn admission by 18% and total predicted state burn center admissions by 113%. Demographic and professional characteristics may have contributed to the substantial inaccuracy of the original estimates of burn patients in this state. PMID- 22531407 TI - A simple technique for augmentation of axonal ingrowth into chondroitinase treated acellular nerve grafts using nerve growth factor. AB - BACKGROUND AND PURPOSE: Improvement in axonal regeneration may lead to the development of longer nerve grafts and improved outcomes for patients with peripheral nerve injury. Although the use of acellular nerve grafts has been well documented (Groves et al, Exp Neurol. 2005;195:278-292; Krekoski et al, J Neurosci. 2001;21:6206-6213; Massey et al, Exp Neurol. 2008;209:426-445; Neubauer et al, Exp Neurol. 2007;207:163-170; Zuo et al, Exp Neurol. 2002;176:221-228), less is known about the ability of neurotrophic factors to enhance axonal regeneration. This study evaluates axonal ingrowth augmentation using acellular, chondroitinase-treated nerve grafts doped with nerve growth factor (NGF). METHODS: Acellular chondroitinase-treated murine nerve grafts were placed in experimental (NGF-treated grafts) and control (carrier-only grafts) rats. Five days after implantation, axonal regeneration was assessed by immunocytochemistry along with digital image analysis. RESULTS: Higher axon count was observed throughout the length of the nerve in the NGF group (P < 0.0001), peaking at 3 mm from proximal repair (P = 0.02). Although the NGF group displayed a higher axon count per slice, the mean diameter of individual NGF axons was smaller (P < 0.0001), potentially consistent with induction of sensory axons (Rich et al, J Neurocytol. 1987;16:261-268; Sofroniew et al, Annu Rev Neurosci. 2001;24:1217 1128; Yip et al, J Neurosci. 1984;4:2986-2992). CONCLUSION: The simple technique of doping acellular, chondroitinase-treated nerve grafts with NGF can augment axonal ingrowth and possibly preferentially induce sensory axons. PMID- 22531408 TI - The impact of preoperative CT angiography on breast reconstruction with abdominal perforator flaps. AB - PURPOSE: Because of the anatomic variability of the deep inferior epigastric artery, preoperative CT angiography (pCTA) has gained popularity for planning abdominal perforator flap breast reconstruction. This study evaluates how pCTA has affected preoperative planning, operative time, and outcome. METHODS: We performed a retrospective study of abdominal free flap breast reconstruction at our institution over a 4-year period, with pCTA performed routinely after the first year. Operative time and outcomes were compared between procedures with and without pCTA. Incidental findings were recorded. RESULTS: Between 2006 and 2010, 102 abdominal perforator flap surgeries were performed on 69 patients; of whom, 51 patients had pCTA and 18 did not. pCTA changed preoperative planning in 50% of cases by identifying the best perforator in unilateral cases or perforators with long intramuscular course. Preoperative plan based on pCTA corresponded to operative procedures in 89% of cases. The sensitivity and positive predictive value of pCTA to localize perforators were 79% and 92%, respectively. Operative time was significantly reduced with pCTA for both unilateral (636 vs. 496 minutes, P = 0.017) and bilateral cases (746 vs. 629 minutes, P = 0.05). Rates of fat necrosis, partial flap necrosis, and complete flap loss were comparable between the 2 groups. Incidentalomas were found in 36% of patients. CONCLUSIONS: pCTA appears to reduce operative time by minimizing time spent identifying perforators, assisting in side selection for unilateral reconstruction, and optimizing planning when a long intramuscular course is identified. The effect of a learning curve cannot be excluded and is the chief limitation of this study. PMID- 22531409 TI - Thoracodorsal or internal mammary recipient vessels for microvascular breast reconstruction? PMID- 22531410 TI - The internal mammary artery and vein as recipient vessels for microvascular breast reconstruction. AB - Current recipient vessels for microvascular breast reconstruction include the internal mammary and the thoracodorsal systems. This review will focus on the advantages of the internal mammary artery and vein and reasons for their preference. PMID- 22531411 TI - The thoracodorsal vessels are advantageous, reliable, and safe recipient vessels for free abdominal flap breast reconstruction. PMID- 22531412 TI - Lack of evidence for a role of xenotropic murine leukemia virus-related virus in the pathogenesis of prostate cancer and/or chronic fatigue syndrome. AB - Since the discovery of xenotropic murine leukemia virus-related virus (XMRV) in 2006, one of the most controversial topics is whether it contributes to the pathogenesis of prostate cancer (PCa) and/or chronic fatigue syndrome (CFS). The debate began with the failure to detect XMRV in clinical PCa samples. Concerns about the potential health risk of XMRV exposure were reinforced by a study demonstrating the presence of XMRV in patients with CFS. However, serious concerns on whether XMRV plays a role in the development of PCa and/or CFS have been raised. However, inconsistent reports linking XMRV with PCa and/or CFS have led to conflicting views about the potential of XMRV as a human pathogen. Several recent studies suggest that contamination could account for the positive correlations between XMRV and PCa and/or CFS to date. At present, evidence does not indicate that XMRV plays any role in the pathogenesis of PCa or CFS. PMID- 22531413 TI - Cortical thinning in subcortical vascular dementia with negative 11C-PiB PET. AB - To determine the existence of cortical thinning in subcortical vascular dementia (SVaD) with a negative 11C-Pittsburgh compound B (PiB) positron emission tomography scan and to compare the topography of cortical thinning between PiB negative SVaD and Alzheimer's disease (AD), we enrolled 24 patients with PiB(-) SVaD, 81 clinically probable AD individuals, and 72 normal cognitive controls. Compared with controls, cortical thinning in PiB(-) SVaD was most profound in the perisylvian area, medial prefrontal area, and posterior cingulate gyri, while the precuneus and medial temporal lobes were relatively spared. When the cortical thickness of AD and PiB(-) SVaD were directly compared, PiB(-) SVaD demonstrated significant cortical thinning in the bilateral inferior frontal, superior temporal gyri, and right medial frontal and orbitofrontal lobes, while AD showed significant cortical thinning in the right medial temporal region. SVaD without amyloid burden may lead to substantial cortical atrophy. Moreover, characteristic topography of cortical thinning in PiB(-) SVaD suggests different mechanisms of cortical thinning in PiB(-) SVaD and AD. PMID- 22531414 TI - Urinary homocysteic acid levels correlate with mini-mental state examination scores in Alzheimer's disease patients. AB - Homocysteic acid (HA) has been suggested as a pathogen in a mouse model of Alzheimer's disease (AD), 3xTg-AD. However, it is not established whether HA is involved in humans. We investigated the relationship between urinary HA levels and Mini-Mental State Examination (MMSE) scores in AD patients (n = 70) and non AD controls (n = 34). We found a positive, statistically significant relationship between the two variables (the urinary HA level and MMSE score) (r = 0.31, p = 0.0008, n = 70). This relationship was stronger in females than males (r = 0.43, p = 0.005, n = 44 in females; r = 0.48, p = 0.02, n = 22 in males). The urinary HA levels were significantly different in AD patients than controls (AD: 8.7 +/- 7.5, n = 70; non-dementia control: 13.3 +/- 9.4, n = 34, p < 0.01). In addition, aging and smoking were found as lowering factors for urinary HA levels. Our preliminary study showed a negative, statistically significant relationship between blood HA (micromole) and urine HA levels (r = -0.6, p = 0.007, n = 19), and between blood HA levels and MMSE scores (r = -0.79, p = 0.0000518, n = 19). On the basis of these results, we speculate that reduced urinary excretion induces elevated HA levels in blood, resulting in cognitive dysfunctions. This study also suggests that HA may be a candidate of neurotoxins for uremic encephalopathy. Since amyloid-beta increases HA toxicity and HA is an agonist of N-methyl-D-aspartic acid (NMDA) receptor, we speculate that elevated blood HA affects the brain cognitive function through NMDA receptor-mediated toxicity in AD. PMID- 22531415 TI - Tumor diagnosis preceding Alzheimer's disease onset: is there a link between cancer and Alzheimer's disease? AB - Studies reporting an inverse association between Alzheimer's disease (AD) and cancer are scant. Available data are mostly based on ancillary findings of mortality data or obtained from studies evaluating frequency of neoplasms in AD patients independently if they occurred before or after AD. Moreover, some studies estimated frequencies of neoplasms in demented individuals, who were not necessarily AD patients. We estimated frequency of tumors preceding the onset of AD in AD patients and compared it to that of age- and gender-matched AD-free individuals. Occurrence of tumors preceding AD onset was assessed through a semi structured questionnaire. Tumors were categorized as benign, malignant, or of uncertain classification and as endocrine-related or not. Odds ratios (OR), used as measure of the association between the two diseases, were adjusted for tumor categories and known risk factors for AD and tumors. We included 126 AD patients and 252 matched controls. Tumor frequency before AD onset was 18.2% among cases and 24.2% among controls. There was a suggestive trend of an overall inverse association between the two diseases (adjusted OR 0.6; 95% CI 0.4-1.1; p = 0.11). Risk for neoplasms was significantly reduced only for women (adjusted OR, 0.5; 95% CI 0.3-0.9; p = 0.03) and for endocrine related tumors (adjusted OR, 0.5; 95% CI 0.2-1; p = 0.04). Our study confirms the inverse association reported in previous epidemiological studies. Though our findings might be explained by processes playing an opposite role in tumors development and neurodegeneration, they are also suggestive for a possible role of estrogen. PMID- 22531416 TI - Autosomal dominant Alzheimer's disease with early frontal lobe involvement associated with the Met239Ile mutation of Presenilin 2 gene. AB - Mutations in the Presenilin 2 gene (PSEN2) represent the less frequent genetic cause of familial Alzheimer's disease (FAD). Only eight PSEN2 mutations, reported in approximately 27 families, satisfied strict criteria of pathogenicity. We reported a patient with early-onset FAD and the PSEN2 p.Met239Ile mutation, presenting with severe executive dysfunction and myoclonic tremor, associated with memory loss. Brain SPECT study showed an early hypoperfusion of the frontal cortex. We confirmed the pathogenicity of PSEN2 p.Met239Ile mutation and its heterogeneous phenotypic expression. The modulating effect of the Apolipoprotein E and Prion Protein gene polymorphisms on the phenotypic variability was not confirmed. PMID- 22531417 TI - High prevalence of cerebral microbleeds at 7Tesla MRI in patients with early Alzheimer's disease. AB - The prevalence of microbleeds on magnetic resonance imaging (MRI) in patients with Alzheimer's disease (AD) is lower than that of its presumed pathological correlate, cerebral amyloid angiopathy. We examined 18 patients with early AD or mild cognitive impairment (MCI) and 18 non-demented controls with ultra-high field strength 7Tesla MRI, to assess if the actual prevalence of microbleeds could be higher than is currently reported. One or more microbleeds were visualized in 78% of the MCI/AD patients and in 44% of the controls (p = 0.04). 7Tesla MRI shows that presence of microbleeds may be the rule, rather than exception in patients with MCI/AD. PMID- 22531418 TI - Amyloid-beta(1-15/16) as a marker for gamma-secretase inhibition in Alzheimer's disease. AB - Amyloid-beta (Abeta) producing enzymes are key targets for disease-modifying Alzheimer's disease (AD) therapies since Abeta trafficking is at the core of AD pathogenesis. Development of such drugs might benefit from the identification of markers indicating in vivo drug effects in the central nervous system. We have previously shown that Abeta(1-15) is produced by concerted beta-and alpha secretase cleavage of amyloid-beta protein precursor (AbetaPP). Here, we test the hypothesis that this pathway is more engaged upon gamma-secretase inhibition in humans, and cerebrospinal fluid (CSF) levels of Abeta(1-15/16) represent a biomarker for this effect. Twenty healthy men were treated with placebo (n = 5) or the gamma-secretase inhibitor semagacestat (100 mg [n = 5], 140 mg [n = 5], or 280 mg [n = 5]). CSF samples were collected hourly over 36 hours and 10 time points were analyzed by immunoassay for Abeta(1-15/16), Abeta(x-38), Abeta(x-40), Abeta(x-42), sAbetaPPalpha, and sAbetaPPbeta. The CSF concentration of Abeta(1 15/16) showed a dose-dependent response over 36 hours. In the 280 mg treatment group, a transient increase was seen with a maximum of 180% relative to baseline at 9 hours post administration of semagacestat. The concentrations of Abeta(x 38), Abeta(x-40), and Abeta(x-42) decreased the first 9 hours followed by increased concentrations after 36 hours relative to baseline. No significant changes were detected for CSF sAbetaPPalpha and sAbetaPPbeta. Our data shows that CSF levels of Abeta(1-15/16) increase during treatment with semagacestat supporting its feasibility as a pharmacodynamic biomarker for drug candidates aimed at inhibiting gamma-secretase-mediated AbetaPP-processing. PMID- 22531419 TI - Stress hormone leads to memory deficits and altered tau phosphorylation in a model of Alzheimer's disease. AB - Several studies have linked stress with Alzheimer's disease (AD) vulnerability; however, the mechanism remains to be fully elucidated. In the current paper, we investigated the role of glucocortitcoids on the AD-like phenotype. We administered the glucocorticoid dexamethasone to Tg2576 mice for 4 weeks and then investigated its effect on memory, amyloid-beta and tau levels, and metabolism. At the end of the treatment period, we observed that mice receiving dexamethasone had a significant impairment in the fear conditioning paradigm compared with controls. Dexamethasone-treated animals showed a significant increase in the amount of brain soluble Abeta40 levels, but no alteration in the steady state levels of its precursor protein, AbetaPP, or in the major protease enzymes involved in its metabolism (i.e., ADAM-10, BACE-1, or gamma-secretase complex). While total tau protein levels were unaltered between the two groups, we found that dexamethasone significantly reduced tau phosphorylation at specific sites that were mediated by decreases in glycogen synthase kinase-3beta protein level activity. Finally, we observed a direct correlation between memory impairments and tau phosphorylation levels. Our study highlights the significant role that glucocorticoids play in exacerbating AD-like cognitive impairments via alteration of tau protein phosphorylation state. PMID- 22531421 TI - White matter hyperintensities, systemic inflammation, brain growth, and cognitive functions in children exposed to air pollution. AB - Air pollution exposures are linked to neuroinflammation and neuropathology in young urbanites. Forty percent of exposed children and young adults exhibit frontal tau hyperphosphorylation and 51% have amyloid-beta diffuse plaques compared to 0% in low pollution controls. In older adults, white matter hyperintensities (WMH) are associated with cognitive deficits while inflammatory markers correlate with greater atrophy than expected for age. We investigated patterns of WMH, magnetic resonance imaging (MRI) volume growth, blood inflammatory mediators, and cognition in matched children from two urban cohorts: one severely and one minimally exposed to air pollution. Baseline and one year follow-up measurements of cognitive abilities, brain MRI volumes, and blood were collected in 20 Mexico City (MC) children (10 with WMH+, and 10 without WMH-) and 10 matched controls (WMH-). MC WMH- children display the profile of classical pro inflammatory defensive responses: high interleukin 12, production of powerful pro inflammatory cytokines, and low concentrations of key cytokines and chemokines associated with neuroprotection. MC WMH+ children exhibit a response involved in resolution of inflammation, immunoregulation, and tissue remodeling. The MC WMH+ group responded to the air pollution-associated brain volumetric alterations with white and grey matter volume increases in temporal, parietal, and frontal regions and better cognitive performance compared to MC WMH-. We conclude that complex modulation of cytokines and chemokines influences children's central nervous system structural and volumetric responses and cognitive correlates resulting from environmental pollution exposures. Identification of biomarkers associating systemic inflammation to brain growth is critical for detecting children at higher risk for cognitive deficits and neurodegeneration, thereby warranting early implementation of neuroprotective measures. PMID- 22531420 TI - Multimodal comparative studies of neurodegenerative diseases. AB - Here we provide a brief description of our program to improve diagnostic accuracy in cases with phenotypically similar presentations that are due to distinct histopathologic abnormalities. We propose a staged approach to diagnosis, beginning with a screening assessment of specific, quantitative neuropsychological measures, and followed by assessments of imaging and biofluid biomarkers. Our goal is to determine the specific histopathologic abnormalities contributing to an individual's neurodegenerative condition. PMID- 22531422 TI - Molecular mechanisms of amyloid oligomers toxicity. AB - Amyloid oligomers have emerged as the most toxic species of amyloid-beta (Abeta). This hypothesis might explain the lack of correlation between amyloid plaques and memory impairment or cellular dysfunction. However, despite the numerous published research articles supporting the critical role Abeta oligomers in synaptic dysfunction and cell death, the exact definition and mechanism of amyloid oligomers formation and toxicity still elusive. Here we review the evidence supporting the many molecular mechanisms proposed for amyloid oligomers toxicity and suggest that the complexity and dynamic nature of amyloid oligomers may be responsible for the discrepancy among these mechanisms and the proposed cellular targets for amyloid oligomers. PMID- 22531423 TI - Amyloid-beta and cognition in aging and Alzheimer's disease: molecular and neurophysiological mechanisms. AB - Amyloid-beta (Abeta) deposition in the brain is one of the key pathological features of Alzheimer's disease (AD). Neither traditional clinical-pathological studies nor modern in vivo biomarker investigations of brain amyloid load, however, could reveal a convincing relationship between brain Abeta load and cognitive deficits and decline in patients with AD. Evidence suggests that pathophysiological Abeta dysregulation and accumulation are very early events that precede the onset of cognitive impairment reaching a plateau at the clinical stage of the beginning dementia syndrome. Therefore, research efforts have focused on the role of Abeta in asymptomatic older adults: the results of combined amyloid-PET and neuropsychological studies show a modest but significant correlation between brain fibrillar amyloid load and various subtle cognitive deficits, most notably in challenging episodic associative memory tasks. In order to elucidate the pathophysiological link between cognition and Abeta, a number of combined functional neuroimaging studies have been performed, resulting in early and complex functional alterations in cognitively relevant neural networks such as the default mode network and the largely overlapping episodic memory networks. Multimodal studies using amyloid-tracing imaging methods and neurodegeneration biomarkers strongly suggest that neural network discoordination is specifically related to Abeta-mediated functional and potentially reversible disruption of synaptic plasticity rather than a direct consequence to neurodegenerative pathological processes. These pathophysiological processes and mechanisms may dynamically and non-linearly evolve through fully reversible adaptive compensatory stages and through reactive decompensatory stages into fully irreversible neurodegenerative stages of AD. PMID- 22531424 TI - Trajectories of behavioral disturbance in dementia. AB - Predicting the progression of dementia is a challenge for clinicians yet this information is highly valued by patients' families. An informally observed 4 stage model of dementia can be helpful in educating caregivers and preparing them for what lies ahead. In the behavioral variant of frontotemporal dementia (bvFTD), this model describes the evolution of behavioral disturbances and is characterized by an inflection point between stage 2 (progressively severe behavioral aberration) and stage 3 (increasing apathy and remission of behavior problems). In this study, we sought evidence for this model using a database of serial Neuropsychiatric Inventory (NPI) scores for 45 patients with FTD and 47 patients with Alzheimer's disease (AD). We transformed the NPI scores into a single variable for each participant that represented the yearly rate of change in total NPI score and used this as the dependent variable in a multivariate linear regression. Age at onset of dementia, NPI score at initial visit, and duration of illness at first NPI all contributed significantly to the regression model in the bvFTD group. Participants with an initial NPI acquired before 6 years of disease duration tended to have a more positive rate of change in NPI total score (representing worsening behavioral disturbances) than those with an initial NPI performed after 6 years. None of the aforementioned variables were significantly associated with yearly change in NPI total score in the AD group. These results support a crescendo-decrescendo trajectory of behavioral symptoms in bvFTD but do not suggest that there is a similar pattern in AD, and further longitudinal data collection is necessary. PMID- 22531425 TI - Decreased accumulation of subcellular amyloid-beta with improved mitochondrial function mediates the neuroprotective effect of huperzine A. AB - A number of recent discoveries indicate that huperzine A, an active herbal medicine employed for the treatment of Alzheimer's disease (AD) in China, can afford neuroprotection on in vitro and in vivo models related to mitochondrial dysfunction. However, it is an intricate and highly debated research topic about whether another pharmacological mechanism is involved in the beneficial profiles of huperzine A, independent of its well-recognized potent acetycholinesterase (AChE) inhibitory effect. As an extension, this study for the first time verified the co-occurrence of the beneficial effects of huperzine A on mitochondrial dysfunction and memory deficits in AbetaPP/PS1 double transgenic mice, at a time point that AChE was not inhibited. Moreover, using isolated brain cortical mitochondria, we confirmed the ameliorating effect of huperzine A on oligomeric Abeta1-42-induced ATP reduction and mitochondrial swelling, as well as a decrease in the enzymatic activities of respiratory chain complexes, especially complex II III and complex IV, which may be attributed to the blockage of oligomeric Abeta1 42 from penetrating into mitochondria. These results shed more light on a potential direct target of huperzine A on isolated mitochondria, which may be largely different from its specific inhibition on AChE. This work describes a novel mechanism of neuroprotection by huperzine A and provides important clues for discovering novel therapeutic strategy for AD. PMID- 22531426 TI - Gene expression profiling in Alzheimer's disease brain microvessels. AB - The enigma that is Alzheimer's disease (AD) continues to present daunting challenges for effective therapeutic intervention. The lack of disease-modifying therapies may, in part, be attributable to the narrow research focus employed to understand this complex disease. Most studies into disease pathogenesis are based on a priori assumptions about the role of AD lesion-associated proteins such as amyloid-beta and tau. However, the complex disease processes at work may not be amenable to single-target therapeutic approaches. Genome-wide expression studies provide an unbiased approach for investigating the pathogenesis of complex diseases like AD. A growing literature suggests a role for cerebrovascular contributions to the pathogenesis of AD. The objective of the current study is to examine human brain microvessels isolated from AD patients and controls by microarray analysis. Differentially expressed genes with more than 2-fold change are used for further data analysis. Gene ontology analysis and pathway analysis algorithms within GeneSpringGX are employed to understand the regulatory networks of differentially expressed genes. Twelve matched pairs of AD and control brain microvessel samples are hybridized to Agilent Human 4 * 44 K arrays in replication. We document that more than 2,000 genes are differentially altered in AD microvessels and that a large number of these genes map to pathways associated with immune and inflammatory response, signal transduction, and nervous system development and function categories. These data may help elucidate heretofore unknown molecular alterations in the AD cerebromicrovasculature. PMID- 22531429 TI - Removal of Ni (II) ions from aqueous solutions by biosorption onto two strains of Yarrowia lipolytica. AB - The removal of Ni (II) ions from aqueous solutions by two strains of Yarrowia lipolytica (NCIM 3589 and NCIM 3590) under different environmental conditions was studied. Biosorption of Ni (II) was enhanced with an increase in pH, temperature, agitation, contact time and initial concentration of the metal ion. NCIM 3589 and NCIM 3590 at pH 7.5 in the presence of 1000 mg L(-1) Ni (II) at 35 degrees C exhibited a maximum uptake of 95.33 mg g(-1) and 85.44 mg g(-1), respectively. The experimental data fitted well to the Langmuir as well as the Freundlich isotherms. Dubinin-Radushkevich (D-R) isotherms suggested that a chemical ion exchange mechanism was involved in the biosorption process. The biosorption process followed the pseudo-second-order kinetic mechanism with liquid film diffusion being the rate limiting step. Fourier transform infra red (FTIR) spectroscopic studies suggested the possible involvement of hydroxyl, caboxyl, carbonyl and amino groups in process of biosorption. Scanning electron microscopy and energy dispersive spectra (SEM-EDS) confirmed biosorption of Ni (II). PMID- 22531427 TI - Assessment of Alzheimer's disease risk with functional magnetic resonance imaging: an arterial spin labeling study. AB - Functional magnetic resonance imaging (fMRI) of older adults at risk for Alzheimer's disease (AD) by virtue of their cognitive (i.e., mild cognitive impairment [MCI]) and/or genetic (i.e., apolipoprotein E [APOE] epsilon4 allele) status demonstrate divergent brain response patterns during memory encoding across studies. Using arterial spin labeling MRI, we examined the influence of AD risk on resting cerebral blood flow (CBF) as well as the CBF and blood oxygenation level dependent (BOLD) signal response to memory encoding in the medial temporal lobes (MTL) in 45 older adults (29 cognitively normal [14 APOE epsilon4 carriers and 15 noncarriers]; 16 MCI [8 APOE epsilon4 carriers, 8 noncarriers]). Risk groups were comparable in terms of mean age, years of education, gender distribution, and vascular risk burden. Individuals at genetic risk for AD by virtue of the APOE epsilon4 allele demonstrated increased MTL resting state CBF relative to epsilon4 noncarriers, whereas individuals characterized as MCI showed decreased MTL resting state CBF relative to their cognitively normal peers. For percent change CBF, there was a trend toward a cognitive status by genotype interaction. In the cognitively normal group, there was no difference in percent change CBF based on APOE genotype. In contrast, in the MCI group, APOE epsilon4 carriers demonstrated significantly greater percent change in CBF relative to epsilon4 noncarriers. No group differences were found for BOLD response. Findings suggest that abnormal resting state CBF and CBF response to memory encoding may be early indicators of brain dysfunction in individuals at risk for developing AD. PMID- 22531428 TI - Abnormal mitochondrial dynamics in the pathogenesis of Alzheimer's disease. AB - Mitochondrial dysfunction is one of the most early and prominent features in vulnerable neurons in the brain of Alzheimer's disease (AD) patients. Recent studies suggest that mitochondria are highly dynamic organelles characterized by a delicate balance of fission and fusion, a concept that has revolutionized our basic understanding of the regulation of mitochondrial structure and function which has far-reaching significance in studies of health and disease. Tremendous progress has been made in studying changes in mitochondrial dynamics in AD brain and models and the potential underlying mechanisms. This review highlights the recent work demonstrating abnormal mitochondrial dynamics and distribution in AD models and discusses how these abnormalities may contribute to various aspects of mitochondrial dysfunction and the pathogenesis of AD. PMID- 22531430 TI - Photocatalytic decolorization of Remazol Black 5 and Remazol Brilliant Orange 3R by mesoporous TiO2. AB - Mesoporous TiO2 microparticles (TiO2-11) were prepared through the micelle hydrothermal method using a 1:1 M ratio of 1-tetradecylamine:Ti(OiPr)4. TiO2-11 microparticles exhibited significantly higher decolorization percentage of Remazol Black 5 (RB5) and Remazol Brilliant Orange (3R) dyes than other TiO2 microparticles formed with different molar ratios of 1-tetradecylamine:Ti(OiPr)4, and P25 and anatase TiO2. The results showed that the decolorization of the dyes by the microparticles was affected by the different irradiation wavelengths, catalyst dosages, dye concentrations, initial pH values, as well as electron acceptors. The kinetic experiments with varying initial pH values were in accordance with the second-order model. In addition, the adsorption study of the dyes in the dark fitted well with the Langmuir isotherm model. With the addition of 20 mmol/mL of three electron acceptors, H2O2, KBrO3, and (NH4)2S2O8, the decolorization of the RB5 and 3R dyes increased by 54% and 35%, 59% and 41%, and 36% and 33%, respectively. Hence, this technique for the preparation of the mesoporous TiO2 microparticles can facilitate more efficient decolorization of dyes in an aqueous solution. PMID- 22531431 TI - VSX1 gene and keratoconus: genetic analysis in Korean patients. AB - PURPOSE: The visual system homeobox 1 (VSX1) gene variants have recently been shown to be associated with keratoconus. To replicate this finding, we performed a genetic analysis of the VSX1 gene in a Korean case-control sample. METHODS: Patients with keratoconus and healthy control subjects were recruited from Seoul National University Hospital. A diagnosis of keratoconus was made based on clinical examinations and the presence of characteristic topographic features. For all patients and controls, the whole coding region and the exon-intron junctions of the VSX1 gene were analyzed by direct sequencing. RESULTS: Fifty three patients with keratoconus and 100 healthy volunteers were included. We observed 2 novel missense substitutions (Leu17Val and Val199Leu) and 1 previously reported substitution (Gly160Val) in 6 of the 53 affected probands. Because these substitutions have been identified in unaffected individuals, they were not considered to be pathogenic. No intragenic polymorphism was associated with a significantly increased risk of keratoconus. CONCLUSIONS: We cannot confirm the previously reported association of the VSX1 gene variants with keratoconus. Our results suggest that the VSX1 gene and its mutations with amino acid changes do not play a major role in the pathogenesis of keratoconus. PMID- 22531432 TI - Fungal keratitis with the type 1 Boston keratoprosthesis: early Indian experience. AB - PURPOSE: To report 2 cases of fungal keratitis and endophthalmitis in patients with the type 1 Boston keratoprosthesis (KPro) in India. METHOD: Two patients underwent type 1 Boston KPro with uneventful intraoperative and early postoperative courses. The patients presented with keratitis and endophthalmitis within a few months after surgery. Both patients had soft bandage contact lenses in place and were on maintenance low-dose topical steroids and antibiotic eyedrops. Culture was positive for fungus in both the cases. RESULTS: Despite aggressive antifungal medical therapy and surgical management, one patient's eye was eviscerated and the other lost the potential for any useful vision. CONCLUSIONS: Fungal infection after KPro surgery can be devastating, negating the extraordinary visual recovery these patients achieve immediately after surgery. Chronic use of topical corticosteroids and broad-spectrum antibiotic and bandage contact lens, although indispensable, may enhance the risk of fungal infection especially in the endemic areas like India. The decision for KPro in such tropical climatic conditions should therefore be taken with absolute caution and frequent patient follow-up. A prophylactic antifungal regime may be mandatory when this procedure is undertaken in fungal endemic areas to improve outcomes. PMID- 22531433 TI - Corneal collagen cross-linking before Ferrara intrastromal corneal ring implantation for the treatment of progressive keratoconus. AB - PURPOSE: To evaluate the safety, efficacy, and stability of sequential corneal collagen cross-linking (CXL) and Ferrara intrastromal corneal ring segment (FR) implantation in selected patients with progressive keratoconus. METHODS: This prospective study involved 9 eyes with progressive keratoconus and a preoperative cylinder value equal to or greater than 5 diopters (D) diagnosed between June 2007 and October 2008. Preoperative and postoperative (6 months after the CXL procedure and 6 months after the FR implantation) biomicroscopy examinations, distance uncorrected and best-corrected visual acuities, refractive error, and topographic maps were evaluated and compared. RESULTS: Mean uncorrected visual acuity was 1.11 logarithm of the minimal angle of resolution (logMAR) preoperatively and 0.75 logMAR at 6 months after CXL (P = 0.03) and 0.23 logMAR at 6 months after FR implantation (P < 0.001). Mean best-corrected visual acuity was 0.26 logMAR preoperatively and 0.24 logMAR at 6 months after CXL (P = 0.87) and 0.12 logMAR at 6 months after FR (P = 0.05). Statistically significant reductions in the mean spherical equivalent (4.38 D; P < 0.001) and mean maximum (5.58 D; P < 0.001) and minimum (4.17 D; P < 0.001) keratometry values were present at 6 months after FR. CONCLUSIONS: FR implantation after CXL is a safe and efficacious treatment option for managing selected patients with progressive keratoconus. Good results in terms of visual acuity, postoperative residual refractive error, and keratometry values were obtained. Longer follow-up would be valuable to confirm the stability of these results. PMID- 22531434 TI - Phototherapeutic keratectomy for the treatment of subepithelial fibrosis and anterior corneal scarring after descemet stripping automated endothelial keratoplasty. AB - PURPOSE: To describe the use of phototherapeutic keratectomy (PTK) and transepithelial photorefractive keratectomy (PRK) for the treatment of subepithelial fibrosis and anterior corneal scarring after Descemet stripping automated endothelial keratoplasty (DSAEK). METHODS: The settings included the Department of Ophthalmology, Bascom Palmer Eye Institute, Miami, FL, and Carolina Cataract and Laser Center, Ladson, SC. Two patients with Fuchs endothelial dystrophy were noted to have anterior corneal opacities and corneal decompensation before DSAEK. Although both patients demonstrated improvement in corneal edema after DSAEK, they were left with residual anterior corneal opacities that were visually significant. The opacities were treated with excimer laser photoablation. RESULTS: Both patients demonstrated an improvement in best corrected visual acuity after elimination of the anterior corneal opacity using PTK or transepithelial PRK. CONCLUSIONS: Excimer laser ablation is an effective option for the treatment of residual subepithelial fibrosis and anterior corneal scarring after DSAEK. When appropriate, use of PTK or PRK can also eliminate residual refractive error. PMID- 22531435 TI - Femtosecond-assisted keratopigmentation double tunnel technique in the management of a case of Urrets-Zavalia syndrome. AB - PURPOSE: To describe the successful use of a double intrastromal tunnel femtosecond-assisted keratopigmentation technique to manage a case of unilateral Urrets-Zavalia syndrome. METHODS: A 33-year-old man was referred with a history of trauma in his right eye due to a labor-related accident. Because of myopic anisometropia, he had been previously implanted with an angle-supported phakic intraocular lens. The patient presented iris atrophy and a fixed dilated pupil. He complained of severe and incapacitating photophobia, glare, and decreased vision. To obtain a complete iris replica, the surgery involved creation of double keratopigmented intrastromal tunnels using femtosecond laser and micronized mineral pigments. The deepest layer was stained black first and then the superficial layer was stained with a contoured greenish blue-gray color, which matched the contralateral eye. RESULTS: In the immediate postoperative period, the patient reported a complete elimination of photophobia associated with the corrected distance visual acuity improvement. A very adequate cosmetic outcome was also achieved. Stability was observed during the 12-month follow-up. CONCLUSION: A femtosecond-assisted keratopigmentation technique using 2 pigmented intrastromal tunnels to achieve an intracorneal pigmented replica of the iris was effective in improving the patient's severe visual function disability and cosmetic appearance. To the best of our knowledge, this is the first report of severe visual function disability caused by atrophic iris and a fixed dilated pupil treated with double intrastromal layers of keratopigmentation by means of femtosecond-created tunnels. PMID- 22531436 TI - Protocol for vital dye staining of corneal endothelial cells. AB - PURPOSE: To describe a step-by-step methodology to establish a reproducible staining protocol for the evaluation of human corneal endothelial cells. METHODS: Four procedures were performed to determine the best protocol. (1) To determine the optimal trypan blue staining method, goat corneas were stained with 4 dilutions of trypan blue (0.4%, 0.2%, 0.1%, and 0.05%) and 1% alizarin red. (2) To determine the optimal alizarin red staining method, goat corneas were stained with 2 dilutions of alizarin red (1% and 0.5%) and 0.2% trypan blue. (3) To ensure that trypan blue truly stains damaged cells, goat corneas were exposed to either 3% hydrogen peroxide or to balanced salt solution, and then stained with 0.2% trypan blue and 0.5% alizarin red. (4) Finally, fresh human corneal buttons were examined; 1 group was stained with 0.2% trypan blue and another group with 0.4% trypan blue. RESULTS: For the 4 procedures performed, the results are as follows: (1) trypan blue staining was not observed in any of the normal corneal samples; (2) 0.5% alizarin red demonstrated sharper cell borders than 1% alizarin red; (3) positive trypan blue staining was observed in the hydrogen peroxide exposed tissue in damaged areas; (4) 0.4% trypan blue showed more distinct positive staining than 0.2% trypan blue. CONCLUSIONS: We were able to determine the optimal vital dye staining conditions for human corneal endothelial cells using 0.4% trypan blue and 0.5% alizarin red. PMID- 22531437 TI - Insights from Fc receptor biology: a route to improved antibody reagents. AB - Fc receptors and their interaction with antibodies will be a major theme at the forthcoming FASEB Science Research Conference on Immunoreceptors to be held in Snowmass this July (details available at www.faseb.org/src/home.aspx, follow the tabs for Immunoreceptors). Since its inception in the mid 1980s, this meeting series has maintained a focus on Fc receptors, and this year's meeting will be no exception. PMID- 22531438 TI - Femtomolar Fab binding affinities to a protein target by alternative CDR residue co-optimization strategies without phage or cell surface display. AB - In therapeutic or diagnostic antibody discovery, affinity maturation is frequently required to optimize binding properties. In some cases, achieving very high affinity is challenging using the display-based optimization technologies. Here we present an approach that begins with the creation and clonal, quantitative analysis of soluble Fab libraries with complete diversification in adjacent residue pairs encompassing every complementarity-determining region position. This was followed by alternative recombination approaches and high throughput screening to co-optimize large sets of the found improving mutations. We applied this approach to the affinity maturation of the anti-tumor necrosis factor antibody adalimumab and achieved ~500-fold affinity improvement, resulting in femtomolar binding. To our knowledge, this is the first report of the in vitro engineering of a femtomolar affinity antibody against a protein target without display screening. We compare our findings to a previous report that employed extensive mutagenesis and recombination libraries with yeast display screening. The present approach is widely applicable to the most challenging of affinity maturation efforts. PMID- 22531442 TI - Marketed therapeutic antibodies compendium. AB - Therapeutic monoclonal antibodies (mAbs) are currently being approved for marketing in Europe and the United States, as well as other countries, on a regular basis. As more mAbs become available to physicians and patients, keeping track of the number, types, production cell lines, antigenic targets, and dates and locations of approvals has become challenging. Data are presented here for 34 mAbs that were approved in either Europe or the United States (US) as of March 2012, and nimotuzumab, which is marketed outside Europe and the US. Of the 34 mAbs, 28 (abciximab, rituximab, basiliximab, palivizumab, infliximab, trastuzumab, alemtuzumab, adalimumab, tositumomab-I131, cetuximab, ibrituximab tiuxetan, omalizumab, bevacizumab, natalizumab, ranibizumab, panitumumab, eculizumab, certolizumab pegol, golimumab, canakinumab, catumaxomab, ustekinumab, tocilizumab, ofatumumab, denosumab, belimumab, ipilimumab, brentuximab) are currently marketed in Europe or the US. Data for six therapeutic mAbs (muromonab CD3, nebacumab, edrecolomab, daclizumab, gemtuzumab ozogamicin, efalizumab) that were approved but have been withdrawn or discontinued from marketing in Europe or the US are also included. PMID- 22531441 TI - Quantitative evaluation of fucose reducing effects in a humanized antibody on Fcgamma receptor binding and antibody-dependent cell-mediated cytotoxicity activities. AB - The presence or absence of core fucose in the Fc region N-linked glycans of antibodies affects their binding affinity toward FcgammaRIIIa as well as their antibody-dependent cell-mediated cytotoxicity (ADCC) activity. However, the quantitative nature of this structure-function relationship remains unclear. In this study, the in vitro biological activity of an afucosylated anti-CD20 antibody was fully characterized. Further, the effect of fucose reduction on Fc effector functions was quantitatively evaluated using the afucosylated antibody, its "regular" fucosylated counterpart and a series of mixtures containing varying proportions of "regular" and afucosylated materials. Compared with the "regular" fucosylated antibody, the afucosylated antibody demonstrated similar binding interactions with the target antigen (CD20), C1q and FcgammaRIa, moderate increases in binding to FcgammaRIIa and IIb, and substantially increased binding to FcgammaRIIIa. The afucosylated antibodies also showed comparable complement dependent cytotoxicity activity but markedly increased ADCC activity. Based on EC 50 values derived from dose-response curves, our results indicate that the amount of afucosylated glycan in antibody samples correlate with both FcgammaRIIIa binding activity and ADCC activity in a linear fashion. Furthermore, the extent of ADCC enhancement due to fucose depletion was not affected by the FcgammaRIIIa genotype of the effector cells. PMID- 22531440 TI - Lepidopteran cells, an alternative for the production of recombinant antibodies? AB - Monoclonal antibodies are used with great success in many different therapeutic domains. In order to satisfy the growing demand and to lower the production cost of these molecules, many alternative systems have been explored. Among them, the baculovirus/insect cells system is a good candidate. This system is very safe, given that the baculoviruses have a highly restricted host range and they are not pathogenic to vertebrates or plants. But the major asset is the speed with which it is possible to obtain very stable recombinant viruses capable of producing fully active proteins whose glycosylation pattern can be modulated to make it similar to the human one. These features could ultimately make the difference by enabling the production of antibodies with very low costs. However, efforts are still needed, in particular to increase production rates and thus make this system commercially viable for the production of these therapeutic agents. PMID- 22531443 TI - The birth pangs of monoclonal antibody therapeutics: the failure and legacy of Centoxin. AB - This paper examines the development and termination of nebacumab (Centoxin(r)), a human IgM monoclonal antibody (mAb) drug frequently cited as one of the notable failures of the early biopharmaceutical industry. The non-approval of Centoxin in the United States in 1992 generated major concerns at the time about the future viability of any mAb therapeutics. For Centocor, the biotechnology company that developed Centoxin, the drug posed formidable challenges in terms of safety, clinical efficacy, patient selection, the overall economic costs of health care, as well as financial backing. Indeed, Centocor's development of the drug brought it to the brink of bankruptcy. This article shows how many of the experiences learned with Centoxin paved the way for the current successes in therapeutic mAb development. PMID- 22531444 TI - Monoclonal antibodies: longitudinal prescribing information analysis of hypersensitivity reactions. AB - Monoclonal antibodies (mAbs) are known to cause hypersensitivity reactions (HSRs). The reactions pose a significant challenge to investigators, regulators, and health providers. Because HSRs cannot be predicted through the pharmacological basis of a therapy, clinical data are often relied upon to detect the reactions. Unfortunately, clinical studies are often unable to adequately characterize HSRs especially in therapies for orphan diseases. HSRs can go undetected until post-marketing safety surveillance when a large number of patients have been exposed to the therapy. The presented data demonstrates how hypersensitivity reaction warnings have changed over time in the prescribing information (PI), i.e., the drug package insert, through August 1, 2011 for 28 US marketed mAbs. Tracking all PI revisions for each mAb over time revealed that hypersensitivity warning statements were expanded to include more severe manifestations. Over the course of a mAb therapy's life cycle, the hypersensitivity warning is twice more likely to be upgraded than downgraded in priority. Approximately 85% of hypersensitivity-associated fatality warnings were added in PI revisions as a result of post-marketing experience. Over 60% (20/33) of revisions to hypersensitivity warnings occurred within 3-4 y of product approval. While HSRs are generally recognized and described in the initial PI of mAbs, fatal HSRs are most commonly observed in post-marketing surveillance. Results of this study suggest that initial product labeling information may not describe rare but clinically significant occurrences of severe or fatal HSRs, but subsequent label revisions include rare events observed during post-marketed product use. PMID- 22531445 TI - Development and validation of an antibody-dependent cell-mediated cytotoxicity reporter gene assay. AB - Humanized monoclonal antibodies (mAbs) are the fastest growing class of biological therapeutics that are being developed for various medical indications, and more than 30 mAbs are already approved and in the market place. Antibody dependent cell-mediated cytotoxicity (ADCC) is an important biological function attributed to the mechanism of action of several therapeutic antibodies, particularly oncology targeting mAbs. The ADCC assay is a complicated and highly variable assay. Thus, the use of an ADCC assay as a lot release test or a stability test for clinical trial batches of mAbs has been a substantial challenge to install in quality control laboratories. We describe here the development and validation of an alternate approach, an ADCC-reporter gene assay that is based on the key attributes of the PBMC-based ADCC assay. We tested the biological relevance of this assay using an anti-CD20 based model and demonstrated that this ADCC-reporter assay correlated well with standard ADCC assays when induced with the drugable human isotypes [IgG1, IgG2, IgG4, IgG4S > P (S228P) and IgG4PAA (S228P, F234A, L235A)] and with IgG1 isotype variants with varying amounts of fucosylation. This data demonstrates that the ADCC-reporter gene assay has performance characteristics (accuracy, precision and robustness) to be used not only as a potency assay for lot release and stability testing for antibody therapeutics, but also as a key assay for the characterization and process development of therapeutic molecules. PMID- 22531446 TI - Immunopotentiating properties of a multispecific alpha-anti-idiotype antibody. AB - Multispecificity is not a well-understood property of some antibodies. Different functions have been attributed to multispecific natural antibodies, commonly associated with the neutralization and clearance of antigens. Much less is known about the role of antibodies like these, based on their idiotypic connectivity. B7Y33 is a chimeric IgG1 version of a polyreactive alpha anti-idiotype antibody that is able to interact with different immunoglobulin and non-immunoglobulin antigens. Here we report the capacity of this antibody to enhance the immunogenicity of several autologous IgMs in adjuvant-free conditions. Our results suggest that the formation of immune complexes seems to be necessary, but not sufficient, to this activity. The potential involvement of the interaction of B7Y33 with the FcgammaRIIb is discussed. PMID- 22531447 TI - Targeting malignant B cells with an immunotoxin against ROR1. AB - The selective cell surface expression of receptor tyrosine kinase-like orphan receptor 1 (ROR1) in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) has made ROR1 a novel and promising target for therapeutic monoclonal antibodies (mAbs). Four mouse mAbs generated by hybridoma technology exhibited specific binding to human ROR1. Epitope mapping studies showed that two mAbs (2A2 and 2D11) recognized N-terminal epitopes in the extracellular region of ROR1 and the other two (1A1 and 1A7) recognized C-terminal epitopes. A ROR1- immunotoxin (BT-1) consisting of truncated Pseudomonas exotoxin A (PE38) and the VH and VL fragments of 2A2-IgG was made recombinantly. Both 2A2-IgG and BT-1 showed dose dependent and selective binding to primary CLL and MCL cells and MCL cell lines. Kinetic analyses revealed 0.12-nM (2A2-IgG) to 65-nM (BT-1) avidity/affinity to hROR1, depicting bivalent and monovalent interactions, respectively. After binding to cell surface ROR1, 2A2-IgG and BT-1 were partially internalized by primary CLL cells and MCL cell lines, and BT-1 induced profound apoptosis of ROR1 expressing MCL cell lines in vitro (EC 50 = 16 pM-16 nM), but did not affect ROR1 negative cell lines. Our data suggest that ROR1-immunotoxins such as BT-1 could serve as targeted therapeutic agents for ROR1-expressing B cell malignancies and other cancers. PMID- 22531448 TI - Solubility evaluation of murine hybridoma antibodies. AB - The successful development of antibody therapeutics depends on the molecules having properties that are suitable for manufacturing, as well as use by patients. Because high solubility is a desirable property for antibodies, screening for solubility has become an essential step during the early candidate selection process. In considering the screening process, we formed a hypothesis that hybridoma antibodies are filtered by nature to possess high solubility and tested this hypothesis using a large number of murine hybridoma-derived antibodies. Using the cross-interaction chromatography (CIC) method, we screened the solubility of 92 murine hybridoma-derived monoclonal antibodies and found that all of these molecules exhibited CIC profiles that are indicative of high solubility (> 100mg/mL). Further investigations revealed that variable region N linked glycosylation or isoelectric parameters are unlikely to contribute to the high solubility of these antibodies. These results support the general hypothesis that hybridoma monoclonal antibodies are highly soluble. PMID- 22531449 TI - Fluorescent IgG fusion proteins made in E. coli. AB - Antibodies are among the most powerful tools in biological and biomedical research and are presently the fastest growing category of new bio-pharmaceutics. The most common format of antibody applied for therapeutic, diagnostic and analytical purposes is the IgG format. For medical applications, recombinant IgGs are made in cultured mammalian cells in a process that is too expensive to be considered for producing antibodies for diagnostic and analytical purposes. Therefore, for such purposes, mouse monoclonal antibodies or polyclonal sera from immunized animals are used. While looking for an easier and more rapid way to prepare full-length IgGs for therapeutic purposes, we recently developed and reported an expression and purification protocol for full-length IgGs, and IgG based fusion proteins in E. coli, called "Inclonals." By applying the Inclonals technology, we could generate full-length IgGs that are genetically fused to toxins. The aim of the study described herein was to evaluate the possibility of applying the "Inclonals" technology for preparing IgG-fluorophore fusion proteins. We found that IgG fused to the green fluorescent proteins enhanced GFP (EGFP) while maintaining functionality in binding, lost most of its fluorescence during the refolding process. In contrast, we found that green fluorescent Superfolder GFP (SFGFP)-fused IgG and red fluorescent mCherry-fused IgG were functional in antigen binding and maintained fluorescence intensity. In addition, we found that we can link several SFGFPs in tandem to each IgG, with fluorescence intensity increasing accordingly. Fluorescent IgGs made in E. coli may become attractive alternatives to monoclonal or polyclonal fluorescent antibodies derived from animals. PMID- 22531450 TI - Galactosylation variations in marketed therapeutic antibodies. AB - There are currently ~25 recombinant full-length IgGs (rIgGs) in the market that have been approved by regulatory agencies as biotherapeutics to treat various human diseases. Most of these are based on IgG1k framework and are either chimeric, humanized or human antibodies manufactured using either Chinese hamster ovary (CHO) cells or mouse myeloma cells as the expression system. Because CHO and mouse myeloma cells are mammalian cells, rIgGs produced in these cell lines are typically N-glycosylated at the conserved asparagine (Asn) residues in the CH2 domain of the Fc, which is also the case with serum IgGs. The Fc glycans present in these rIgGs are for the most part complex biantennary oligosaccharides with heterogeneity associated with the presence or the absence of several different terminal sugars. The major Fc glycans of rIgGs contain 0 or 1 or 2 (G0, G1 and G2, respectively) terminal galactose residues as non-reducing termini and their relative proportions may vary depending on the cell culture conditions in which they were expressed. Since glycosylation is strongly associated with antibody effector functions and terminal galactosylation may affect some of those functions, a panel of commercially available therapeutic rIgGs expressed in CHO cells and mouse myeloma cells were examined for their galactosylation patterns. The results suggest that the rIgGs expressed in CHO cells are generally less galactosylated compared to the rIgGs expressed in mouse myeloma cells. Accordingly, rIgGs produced in CHO cells tend to contain higher levels of G0 glycans compared with rIgGs produced in mouse myeloma cell lines. Despite the apparent wide variability in galactose content, adverse events or safety issues have not been associated with specific galactosylation patterns of therapeutic antibodies. Nevertheless, galactosylation may have an effect on the mechanisms of action of some therapeutic antibodies (e.g., effector pathways) and hence further studies to assess effects on product efficacy may be warranted for such antibodies. For antibodies that do not require effector functions for biological activity, however, setting a narrow specification range for galactose content may be unnecessary. PMID- 22531451 TI - Impact of linker and conjugation chemistry on antigen binding, Fc receptor binding and thermal stability of model antibody-drug conjugates. AB - Antibody-drug conjugates (ADCs) with biotin as a model cargo tethered to IgG1 mAbs via different linkers and conjugation methods were prepared and tested for thermostability and ability to bind target antigen and Fc receptor. Most conjugates demonstrated decreased thermostability relative to unconjugated antibody, based on DSC, with carbohydrate and amine coupled ADCs showing the least effect compared with thiol coupled conjugates. A strong correlation between biotin-load and loss of stability is observed with thiol conjugation to one IgG scaffold, but the stability of a second IgG scaffold is relatively insensitive to biotin load. The same correlation for amine coupling was less significant. Binding of antibody to antigen and Fc receptor was investigated using surface plasmon resonance. None of the conjugates exhibited altered antigen affinity. Fc receptor FcgammaIIb (CD32b) interactions were investigated using captured antibody conjugate. Protein G and Protein A, known inhibitors of Fc receptor (FcR) binding to IgG, were also used to extend the analysis of the impact of conjugation on Fc receptor binding. H10NPEG4 was the only conjugate to show significant negative impact to FcR binding, which is likely due to higher biotin load compared with the other ADCs. The ADC aHISNLC and aHISTPEG8 demonstrated some loss in affinity for FcR, but to much lower extent. The general insensitivity of target binding and effector function of the IgG1 platform to conjugation highlight their utility. The observed changes in thermostability require consideration for the choice of conjugation chemistry, depending on the system being pursued and particular application of the conjugate. PMID- 22531452 TI - Risk factors and possible mechanisms of intravenous port catheter migration. AB - OBJECTIVE: To identify the risk factors for catheter migration and demonstrate possible mechanisms of this migration. DESIGN: Retrospective study. SETTING: Chang Gung Memorial Hospital, a tertiary medical centre in Taiwan. PATIENTS: Patients who underwent implantation of intravenous ports via the superior vena cava (SVC). INTERVENTIONS: Procedures involving catheter placement and re intervention for catheter migration. MAIN OUTCOME MEASURES: The anatomic location of the catheter tip was confirmed by plain chest X-rays (postero-anterior view). From these plain radiographs, the distance (in cm) between the carina and catheter tip and the angle (in degrees) between the locking nut and catheter were measured. METHODS: A total of 1542 procedures related to intravenous port implantation were retrospectively reviewed but only procedures involving implantation via the SVC were included in the analysis. The study group was composed of 31 interventions because of catheter migration, while the control group consisted of 1475 implantation and re-intervention procedures except those involving catheter migrations. RESULTS: Shallow catheter-tip location (p < 0.0001) and the presence of lung cancer (p = 0.006) were risk factors for catheter migration. CONCLUSIONS: Shallow catheter-tip location and the presence of lung cancer are risk factors for catheter migration. Strategies that ensure low catheter-tip location and avoid increased thoracic pressure may be useful preventive measures. PMID- 22531453 TI - ADSORB: a prospective randomised study on the efficacy of endovascular grafting vs. best medical treatment in uncomplicated acute dissection of the descending aorta. PMID- 22531454 TI - Applications of minimally invasive cardiac output monitors. AB - Because of the increasing age of the population, critical care and emergency medicine physicians have seen an increased number of critically ill patients over the last decade. Moreover, the trend of hospital closures in the United States t imposes a burden of increased efficiency. Hence, the identification of devices that facilitate accurate but rapid assessments of hemodynamic parameters without the added burden of invasiveness becomes tantamount. The purpose of this review is to understand the applications and limitations of these new technologies. PMID- 22531455 TI - Distribution of human CYP2C8*2 allele in three different African populations. AB - BACKGROUND: The aim of this study was to investigate cytochrome P450 2C8*2 (CYP2C8*2) distribution and allele frequency in three populations from West and East Africa exposed to Plasmodium falciparum malaria. CYP2C8 enzyme is involved in the metabolism of the anti-malarials amodiaquine and chloroquine. The presence of the CYP2C8*2 defective allele has been recently associated to higher rate of chloroquine-resistant malaria parasites. METHODS: A total of 503 young subjects were genotyped for the single nucleotide polymorphism rs11572103 (A/T). Eighty eight were from southern Senegal, 262 from eastern Uganda and 153 from southern Madagascar. The PCR-RFLP technique was used to discriminate the wild-type (A) from the defective allele (T). RESULTS: A CYP2C8*2 (T) allele frequency of 0.222 +/- 0.044 was detected in Senegal, 0.105 +/- 0.019 in Uganda and 0.150 +/- 0.029 in Madagascar. CONCLUSIONS: This study demonstrated that CYP2C8*2 allele is widespread in Africa. This allele occurs at different frequency in West and East Africa, being higher in Senegal than in Uganda and Madagascar. These data indicate that an important fraction of the populations analysed has a decreased enzymatic activity, thus being at higher risk for drug accumulation with two possible consequences: i) an exacerbation of drug-associated adverse side effects; ii) an increase of drug-resistance selection pressure on P. falciparum parasites. PMID- 22531456 TI - Vpx is critical for SIVmne infection of pigtail macaques. AB - BACKGROUND: Viral protein X (Vpx) of SIV has been reported to be important for establishing infection in vivo. Vpx has several different activities in vitro, promoting preintegration complex import into the nucleus in quiescent lymphocytes and overcoming a block in reverse transcription in macrophages. Vpx interacts with the DDB1-CUL4-DCAF1 E3 ligase complex, which may or may not be required for the ascribed functions. The goal of the current study was to determine whether these activities of Vpx are important in vivo. RESULTS: An infectious, pathogenic clone of SIVmne was used to examine correlations between Vpx functions in vitro and in vivo. Three previously described HIV-2 Vpx mutants that were shown to be important for nuclear import of the preintegration complex in quiescent lymphocytes were constructed in SIVmne: A vpx-deleted virus, a truncation of Vpx at amino acid 102 that deletes the C-terminal proline-rich domain (X(102)), and a mutant with tyrosines 66, 69, and 71 changed to alanine (X(y-a)). All mutant viruses replicated similarly to wild type SIVmne027 in primary pigtail macaque PBMCs, and were only slightly retarded in CEMx174 cells. However, all the vpx mutant viruses were defective for replication in both human and pigtail monocyte derived macrophages. PCR assays demonstrated that the efficiency of reverse transcription and the levels of viral integration in macrophages were substantially reduced for the vpx mutant viruses. In vitro, the X(y-a) mutant, but not the X(102) mutant lost interaction with DCAF1. The wild type SIVmne027 and the three vpx mutant SIVs were inoculated by the intra-rectal route into pigtail macaques. Peak levels of plasma viremia of the vpx mutant SIVs were variable, but consistently lower than that observed in macaques infected with wild type SIVmne. In situ hybridization for SIV demonstrated that compared to wild type SIVmne infected macaques five of the six animals inoculated with the vpx mutant SIVs had only low levels of SIV-expressing cells in the rectum, most intestinal epithelial tissues, spleen, and mesenteric and peripheral nodes. CONCLUSIONS: This work demonstrates that the activities of Vpx to overcome restrictions in culture in vitro are also likely to be important for establishment of infection in vivo and suggest that both the nuclear localization and DCAF1-interaction functions of Vpx are critical in vivo. PMID- 22531457 TI - Sequential elution of multiply and singly phosphorylated peptides with polar copolymerized mixed-mode RP18/SCX material. AB - Novel polar-copolymerized mixed-mode RP18/SCX material was developed for feasible phosphopeptide enrichment, in which multiply and singly phosphorylated peptides could be sequentially eluted and separated with high selectivity. PMID- 22531458 TI - Spine degeneration in a murine model of chronic human tobacco smokers. AB - OBJECTIVE: To investigate the mechanisms by which chronic tobacco smoking promotes intervertebral disc degeneration (IDD) and vertebral degeneration in mice. METHODS: Three month old C57BL/6 mice were exposed to tobacco smoke by direct inhalation (4 cigarettes/day, 5 days/week for 6 months) to model long-term smoking in humans. Total disc proteoglycan (PG) content [1,9-dimethylmethylene blue (DMMB) assay], aggrecan proteolysis (immunobloting analysis), and cellular senescence (p16INK4a immunohistochemistry) were analyzed. PG and collagen syntheses ((35)S-sulfate and (3)H-proline incorporation, respectively) were measured using disc organotypic culture. Vertebral osteoporosity was measured by micro-computed tomography. RESULTS: Disc PG content of smoke-exposed mice was 63% of unexposed control, while new PG and collagen syntheses were 59% and 41% of those of untreated mice, respectively. Exposure to tobacco smoke dramatically increased metalloproteinase-mediated proteolysis of disc aggrecan within its interglobular domain (IGD). Cellular senescence was elevated two-fold in discs of smoke-exposed mice. Smoke exposure increased vertebral endplate porosity, which closely correlates with IDD in humans. CONCLUSIONS: These findings further support tobacco smoke as a contributor to spinal degeneration. Furthermore, the data provide a novel mechanistic insight, indicating that smoking-induced IDD is a result of both reduced PG synthesis and increased degradation of a key disc extracellular matrix protein, aggrecan. Cleavage of aggrecan IGD is extremely detrimental as this results in the loss of the entire glycosaminoglycan attachment region of aggrecan, which is vital for attracting water necessary to counteract compressive forces. Our results suggest identification and inhibition of specific metalloproteinases responsible for smoke-induced aggrecanolysis as a potential therapeutic strategy to treat IDD. PMID- 22531459 TI - Musculoskeletal changes following non-invasive knee injury using a novel mouse model of post-traumatic osteoarthritis. AB - OBJECTIVE: Post-traumatic osteoarthritis (PTOA) is a common consequence of traumatic joint injury, with 50% of anterior cruciate ligament (ACL) rupture patients developing PTOA within 10-20 years. Currently accepted mouse models of PTOA initiate symptoms using various methods, none of which faithfully mimic clinically-relevant injury conditions. In this study we characterize a novel non invasive mouse model of PTOA that injures the ACL with a single load of tibial compression overload. We utilize this model to determine the time course of articular cartilage and subchondral bone changes following knee injury. DESIGN: Mice were euthanized 1, 3, 7, 14, 28, or 56 days after non-invasive knee injury. Knees were scanned using micro-computed tomography (MUCT) in order to quantify subchondral trabecular bone, subchondral bone plate, and non-native bone formation (heterotopic ossification). Development of osteoarthritis (OA) was graded using the osteoarthritis research society international (OARSI) scale on histological sections of injured and uninjured knees. RESULTS: Following injury we observed a rapid loss of trabecular bone in injured knees compared to uninjured knees by 7 days post-injury, followed by a partial recovery of trabecular bone to a new steady state by 28 days post-injury. We also observed considerable non-native bone formation by 56 days post-injury. Grading of histological sections revealed deterioration of articular cartilage by 56 days post-injury, consistent with development of mild OA. CONCLUSIONS: This study establishes a novel mouse model of PTOA, and describes the time course of musculoskeletal changes following knee injury, helping to establish the window of opportunity for preventative treatment. PMID- 22531460 TI - Mineralization of articular cartilage in the Sprague-Dawley rat: characterization and mechanical analysis. PMID- 22531461 TI - Vitamin D receptor activation in a diabetic-like environment: potential role in the activity of the endothelial pro-inflammatory and thioredoxin pathways. AB - High blood and tissue concentrations of glucose and advanced glycation end products (AGEs) are thought to play an important role in the development of diabetic vascular complications. Thioredoxin interacting protein (TXNIP) is up regulated in response to high levels of glucose and is an endogenous inhibitor of thioredoxin (TRX), and may play a contributory role in the occurrence of diabetic related vascular diseases. Vitamin D inhibits endothelial proliferation and is a cardiovascular protective agent. The present study evaluated the impact of paricalcitol and calcitriol on the endothelial inflammatory and TXNIP pathways in cultured endothelial cells exposed to a diabetic-like environment. Fresh human umbilical vein cord endothelial cells (HUVEC) were treated for 24h with 200 MUg/ml AGE-HSA and 250 mg/dl glucose concentrations, with paricalcitol or calcitriol. IL6, IL8, NFkappaB (p50/p65), receptor of AGE (RAGE), TXNIP, and TRX expressions were evaluated at the levels of mRNA, protein, and TRX activity. Calcitriol and paricalcitol significantly down-regulated the markers involved in the inflammatory responses. Only paricalcitol induced a significant decrease in TXNIP mRNA and protein expressions. Neither paricalcitol nor calcitriol affected TRX reductase activity or TRX mRNA and protein expressions. Our findings indicate that in an endothelial diabetic-like environment, paricalcitol and calcitriol significantly decreased the expression of genes involved in the inflammatory pathway. In this in vitro study, it seems that the TRX antioxidant system was not involved. The different effects found between paricalcitol and calcitriol might reflect the selectivity of vitamin D receptor (VDR) activation. PMID- 22531462 TI - Assessment of atherosclerotic plaques at coronary bifurcations with multidetector computed tomography angiography and intravascular ultrasound-virtual histology. AB - AIMS: We evaluated the distribution and composition of atherosclerotic plaques at bifurcations with intravascular ultrasound-virtual histology (IVUS-VH) and multidetector computed tomography (MDCT) in relation to the bifurcation angle (BA). METHODS AND RESULTS: In 33 patients (age 63+/-11 years, 79% male) imaged with IVUS-VH and MDCT, 33 bifurcations were matched and studied. The analysed main vessel was divided into a 5 mm proximal segment, the in-bifurcation segment, and a 5 mm distal segment. Plaque contours were manually traced on MDCT and IVUS VH. Plaques with >10% confluent necrotic core and <10% dense calcium on IVUS-VH were considered high risk, whereas plaque composition by MDCT was graded as non calcified, calcified, or mixed. The maximum BA between the main vessel and the side branch was measured on diastolic MDCT data sets. Overall the mean plaque area decreased from the proximal to the distal segment [8.5+/-2.8 vs. 6.0+/-3.0 mm2 (P<0.001) by IVUS-VH and 9.0+/-2.6 vs. 6.5+/-2.5 mm2 (P<0.001) by MDCT]. Similarly, the necrotic core area was higher in the proximal compared with the distal segment (1.12+/-0.7 vs. 0.71+/-0.7 mm2, P=0.001). The proximal segment had the higher percentage of high-risk plaques (13/25, 52%), followed by the in bifurcation (6/25, 24%), and the distal segment (6/25, 24%); these plaques were characterized by MDCT as non-calcified (72%) or mixed (28%). The presence of high risk and non-calcified plaques in the proximal segment was associated with higher BA values (71+/-19 degrees vs. 55+/-19 degrees , P=0.028 and 74+/-20 degrees vs. 50+/-14 degrees , P=0.001, respectively). CONCLUSION: The proximal segment of bifurcations is more likely to contain high-risk plaques, especially when the branching angle is wide. PMID- 22531463 TI - Multi-layer radial systolic strain vs. one-layer strain for confirming reperfusion from a significant non-occlusive coronary stenosis. AB - AIMS: The aim of this study was to investigate whether multi-layer radial strain and strain rate analysis is superior to one-layer strain analysis for confirming reperfusion following a non-occlusive coronary stenosis. METHODS AND RESULTS: In 10 anaesthetized pigs, an extracorporeal shunt was inserted from the brachiocephalic to the left anterior descending coronary artery. Microspheres were injected and left ventricular (LV) short- and long-axis echocardiographic views were recorded with the open shunt, during the 120 min of severe stenosis and 20 min (early) and 100 min (late) after reperfusion. The anterior wall was analysed for radial one-layer and three-layer tissue Doppler imaging (TDI) strain and strain rate, in addition to radial, circumferential, and longitudinal speckle tracking echocardiography (STE) strain. During stenosis, perfusion was reduced in the two inner wall layers (P< 0.01). All peak systolic strain and strain rate parameters were reduced, whereas post-systolic longitudinal strain and post systolic strain in the two inner layers increased (P< 0.001). At early reperfusion, hyperaemia was evident in all layers (P< 0.01). Peak systolic TDI strain and strain rate increased in the mid- and subendocardial layer, whereas post-systolic strain decreased (P< 0.05). Peak systolic STE strain increased in the circumferential and longitudinal direction, whereas post-systolic longitudinal strain decreased (P< 0.05). At late reperfusion, strain and strain rate were unchanged while perfusion returned to baseline values in the mid- and subendocardium. CONCLUSION: Both multi-layer radial TDI strain and strain rate and one-layer STE strain measurements in the circumferential and longitudinal direction can confirm reperfusion early after a non-occlusive coronary stenosis. An advantage of multi-layer analysis was not evident. PMID- 22531464 TI - Impact of gender differences on myocardial salvage and post-ischaemic left ventricular remodelling after primary coronary angioplasty: new insights from cardiovascular magnetic resonance. AB - AIMS: There is conflicting evidence on the impact of gender on reperfusion after primary coronary angioplasty (PPCI), and on left ventricular (LV) remodelling (LVR). In a cohort of patients with reperfused ST elevation myocardial infarction (STEMI), gender-related differences on myocardial reperfusion, and sex-related differences on LVR were assessed by using a comprehensive cardiac magnetic resonance (CMR) approach. METHODS AND RESULTS: In four tertiary referral centres, 283 (238 males and 45 females) consecutive STEMI patients, treated with PPCI within 12 h from symptoms onset underwent CMR 3 +/- 2 days after STEMI and at 4 month follow-up. By CMR, the area at risk, infarct size (IS), microvascular obstruction (MVO), and myocardial salvage index (MSI) were assessed. Women were older than men (P = 0.014), more hypertensive (P < 0.001) and more frequently presented with pre-infarct angina (P = 0.018). An MSI extent was significantly higher (P = 0.013), IS was significantly smaller at both time points (acute P < 0.001, follow-up P < 0.001), and the MVO extent was significantly smaller (P < 0.001) in women. At multivariate analysis, Killip class and female sex were independently associated with a higher MSI (P = 0.02, P = 0.05, respectively). A similar incidence of LVR in both sexes was observed at follow-up (P = 0.808). CONCLUSIONS: The better reperfusion pattern observed in women by CMR in our population of reperfused STEMI suggests sex-based differences exist. No gender differences were observed with respect to incidence of LV remodelling at the follow-up mainly occurring in the subset of patients with a larger IS. PMID- 22531465 TI - Dehiscence of Freestyle aortic valve visualized by real-time three-dimensional transoesophageal echocardiography and dual-source computed tomography: a rare cause of aortic regurgitation. PMID- 22531466 TI - Effects of some endocrine disruptors on cell cycle progression and murine dendritic cell differentiation. AB - Endocrine disruptor chemicals (EDCs), which are predominantly present in the environment, are able to mimic or antagonise the biological activity of hormones primarily through the interaction with specific receptors. The main consequences are adverse effects on the growth and development of reproductive organs, the induction of cancer and effects on neuronal differentiation. In this study, we investigated the ability of certain EDCs, Bisphenol A (BPA), Bisphenol B (BPB), Bisphenol F (BPF), 4-n Nonylphenol (NP) and Octylphenol (OP), belonging to a homogeneous group of phenol origin, to interfere with specific cellular processes, namely, proliferation, by using MCF-7 breast carcinoma cells, and differentiation, by using murine bone marrow dendritic cells. We correlated the data on cell growth with the stimulation of cell cycle progression, which could become a step in the development of cancer, and we established a proliferation ranking between the tested EDCs: NP>BPA>OP>BPB>BPF. In addition, we investigated the ability of NP, BPA and OP to induce the differentiation of dendritic cells, the powerful antigen-presenting cells of the immune system. The differentiation and activation of these cells could affect a well-regulated immune response and determine an allergic sensitisation. We found that BPA and NP were active in determining differentiation. PMID- 22531467 TI - Bovine large luteal cells show increasing de novo DNA methylation of the main ovarian CYP19A1 promoter P2. AB - Transformation of the estrogen producing large dominant follicle into a functional progesterone producing corpus luteum involves profound and well orchestrated changes in cell type-specific gene expression profiles, possibly involving epigenetic mechanisms of gene silencing. As an experimental paradigm to examine the involvement of de novo DNA methylation in the process of luteinization, the transcript abundance and promoter-specific DNA methylation levels of CYP19A1, which encodes the key enzyme for estrogen biosynthesis, were analyzed in enzymatically dispersed and purified large granulosa luteal cells of early- to mid-cycle bovine corpora lutea. To characterize the morphology and physiology of isolated corpora lutea, their weights and the respective plasma progesterone levels were analyzed. Transcript abundance of CYP19A1, HSD3B1, GHR, and of LHGCR was quantified by real-time PCR. Methylation levels were analyzed by bisulfite direct sequencing. The data indicated that corpora lutea weights and plasma progesterone levels significantly increased during the early luteal phase (days 3-6 of the cycle). The growth of small and large luteal cells was particularly pronounced between days 3 and 4. Large luteal cells are characterized by high HSD3B1 and GHR, but low LHCGR transcript abundance, whereas CYP19A1 expression was very low or undetectable. The DNA methylation levels of the main ovarian CYP19A1 promoter P2 significantly increased from day 5. In conclusion, the data indicated de novo DNA methylation approximately five days after the luteinizing hormone-induced down-regulation of CYP19A1 expression, suggesting that DNA methylation during the early luteal phase might play a role for permanent silencing of previously down-regulated genes. PMID- 22531468 TI - A method for model-free partial volume correction in oncological PET. AB - BACKGROUND: As is well known, limited spatial resolution leads to partial volume effects (PVE) and consequently to limited signal recovery. Determination of the mean activity concentration of a target structure is thus compromised even at target sizes much larger than the reconstructed spatial resolution. This leads to serious size-dependent underestimates of true signal intensity in hot spot imaging. For quantitative PET in general and in the context of therapy assessment in particular it is, therefore, mandatory to perform an adequate partial volume correction (PVC). The goal of our work was to develop and to validate a model free PVC algorithm for hot spot imaging. METHODS: The algorithm proceeds in two automated steps. Step 1: estimation of the actual object boundary with a threshold based method and determination of the total activity A measured within the enclosed volume V. Step 2: determination of the activity fraction B, which is measured outside the object due to the partial volume effect (spill-out). The PVE corrected mean value is then given by Cmean = (A+B)/V. For validation simulated tumours were used which were derived from real patient data (liver metastases of a colorectal carcinoma and head and neck cancer, respectively). The simulated tumours have characteristics (regarding tumour shape, contrast, noise, etc.) which are very similar to those of the underlying patient data, but the boundaries and tracer accumulation are exactly known. The PVE corrected mean values of 37 simulated tumours were determined and compared with the true mean values. RESULTS: For the investigated simulated data the proposed approach yields PVE corrected mean values which agree very well with the true values (mean deviation (+/- s.d.): (-0.8+/-2.5)%). CONCLUSIONS: The described method enables accurate quantitative partial volume correction in oncological hot spot imaging. PMID- 22531469 TI - Professional identity in nursing: are we there yet? AB - Nursing in the United Kingdom (UK) has been part of higher education for more than a decade and is now moving towards graduate status as a profession. Increasingly, through adherence to good practice guidelines and professional body regulation, the profession is incrementally involving communities of reference to help shape current and future identity. The desire to articulate the impact of nursing practice underscores the new undergraduate programmes and propels professional preparation beyond an existence at the fuzzy fringes of medicine towards a unique and fully fledged contemporary identity. PMID- 22531470 TI - Health-related quality of life and low back pain of patients surgically treated for scoliosis after 21 years or more of follow-up: comparison among nonidiopathic scoliosis, idiopathic scoliosis, and healthy subjects. AB - STUDY DESIGN: A case-control study. OBJECTIVE: To compare health-related quality of life and low back pain of healthy subjects with those of patients with nonidiopathic scoliosis (non-IS) and idiopathic scoliosis (IS) 21 years or more after surgery. SUMMARY OF BACKGROUND DATA: There have been a very small number of reports on long-term results of surgery for non-IS. There have not been any reports that compare non-IS, IS, and healthy subjects. METHODS: The subjects with scoliosis were 602 patients who had undergone surgery between 1968 and 1988. The Scoliosis Research Society Patient Questionnaire (SRS-22), Roland-Morris Disability Questionnaire (RDQ), and our institution's original questionnaire were used for evaluating long-term clinical outcomes. The 136 respondents consisted of 56 patients with non-IS (non-IS group) and 80 patients with IS (IS group). The control group (CTR group) consisted of 80 healthy volunteers who were age- and body mass index-matched to the scoliosis groups. RESULTS: In the SRS-22, the 3 groups had no significant differences in pain and mental health. For function and self-image, the non-IS group and the IS group had a significantly lower score than the CTR group. In the RDQ, the non-IS group had significantly more severe low back pain than the CTR group. There was no significant difference in low back pain between the non-IS group and IS group or between the IS group and CTR group. The non-IS group had a significantly lower marriage rate than the IS and CTR groups. CONCLUSION: The patients with non-IS and IS had similar health-related quality of life and low back pain. The patients with non-IS were found to have lower function and self-image in the SRS-22 questionnaire and more severe low back pain in the RDQ than healthy subjects. The patients with non-IS had a significantly lower marriage rate than the other 2 groups. PMID- 22531471 TI - Postlaminectomy stabilization of the spine in a rat model of neuropathic pain reduces pain-related behavior. AB - STUDY DESIGN: Spine deformity and pain-related behavior after laminectomy with and without spine stabilization were investigated. OBJECTIVE: We tested hypothesis that spine stabilization after extensive laminectomy can prevent spine deformation and consequent pain-related behavior. SUMMARY OF BACKGROUND DATA: Various ablative procedures requiring laminectomy have been tested for prevention or reversal of pain-related behavior in studies using experimental animals. However, there is no precise description indicating how laminectomy should be performed. Lack of standardized surgical techniques makes it difficult to achieve uniformity of result reporting and to compare results of different research groups meaningfully. METHODS: To test our hypothesis, extensive laminectomy with and without spine stabilization was performed in Sprague-Dawley rats. U-shaped surgical wire was used for stabilization of the spine. A validated test of mechanical hyperalgesia was used to test the development of neuropathic pain behavior after surgery. Deformity of the spine was evaluated by calculating deviation from the central axis on radiographs obtained in anteroposterior projection. RESULTS: Surgical stabilization of the spine after laminectomy prevented development of spinal deformity. Laminectomy without stabilization induced hyperalgesia on the 8th and 15th days after surgery. Group with stabilized spine exhibited significant reduction in pain-related behavior on the 8th and 15th postoperative days compared with the group without stabilization. CONCLUSION: Surgical stabilization of the spine after laminectomy prevented development of spinal deformity and pain-related behavior. Our results suggest that spine stabilization procedure should be used in all experimental pain models in which laminectomy is performed. PMID- 22531472 TI - Enhancing pedicle screw fixation in the aging spine with a novel bioactive bone cement: an in vitro biomechanical study. AB - STUDY DESIGN: A paired biomechanical study of pedicle screws augmented with bone cement in a human cadaveric and osteoporotic lumbar spine model. OBJECTIVES.: To evaluate immediate strength and stiffness of pedicle screw fixation augmented with a novel bioactive bone cement in an osteoporotic spine model and compare it with polymethylmethacrylate (PMMA) cement. SUMMARY OF BACKGROUND DATA: A novel bioactive bone cement, containing nanoscale particles of strontium and hydroxyapatite (Sr-HA), can promote new bone formation and osteointegration and provides a promising reinforcement to the osteoporotic spine. Its immediate mechanical performance in augmenting pedicle screw fixation has not been evaluated. METHODS: Two pedicle screws augmented with Sr-HA and PMMA cement were applied to each of 10 isolated cadaveric L3 vertebrae. Each screw was subjected to a toggling test and screw kinematics were calculated. The pedicle screw was subjected to a pullout test until failure. Finally, the screw coverage with cement was measured on computed tomographic images. RESULTS: Screw translations in the toggling test were consistently larger in the Sr-HA group than in the PMMA group (1.4 +/- 1.2 mm vs. 1.0 +/- 1.1 mm at 1000 cycles). The rotation center was located closer to the screw tip in the Sr-HA group (19% of screw length) than in the PMMA group (37%). The only kinematic difference between Sr-HA and PMMA cements was the screw rotation at 1000 cycles (1.5 degrees +/- 0.9 degrees vs. 1.3 degrees +/- 0.6 degrees ; P = 0.0026). All motion parameters increased significantly with more loading cycles. The pullout force was higher in the PMMA group than the Sr-HA group (1.40 +/- 0.63 kN vs. 0.93 +/- 0.70 kN), and this difference was marginally significant (P = 0.051). Sr-HA cement covered more of the screw length than PMMA cement (79 +/- 19% vs. 43 +/- 19%) (P = 0.036). CONCLUSION: This paired-design study identified some subtle but mostly nonsignificant differences in immediate biomechanical fixation of pedicle screws augmented with the Sr-HA cement compared with the PMMA cement. PMID- 22531473 TI - Development of a new technique for pedicle screw and Magerl screw insertion using a 3-dimensional image guide. AB - STUDY DESIGN: We developed a new technique for cervical pedicle screw and Magerl screw insertion using a 3-dimensional image guide. OBJECTIVE: In posterior cervical spinal fusion surgery, instrumentation with screws is virtually routine. However, malpositioning of screws is not rare. To avoid complications during cervical pedicle screw and Magerl screw insertion, the authors developed a new technique which is a mold shaped to fit the lamina. SUMMARY OF BACKGROUND DATA: Cervical pedicle screw fixation and Magerl screw fixation provide good correction of cervical alignment, rigid fixation, and a high fusion rate. However, malpositioning of screws is not a rare occurrence, and thus the insertion of screws has a potential risk of neurovascular injury. It is necessary to determine a safe insertion procedure for these screws. METHODS: Preoperative computed tomographic (CT) scans of 1-mm slice thickness were obtained of the whole surgical area. The CT data were imported into a computer navigation system. We developed a 3-dimensional full-scale model of the patient's spine using a rapid prototyping technique from the CT data. Molds of the left and right sides at each vertebra were also constructed. One hole (2.0 mm in diameter and 2.0 cm in length) was made in each mold for the insertion of a screw guide. We performed a simulated surgery using the bone model and the mold before operation in all patients. The mold was firmly attached to the surface of the lamina and the guide wire was inserted using the intraoperative image of lateral vertebra. The proper insertion point, direction, and length of the guide were also confirmed both with the model bone and the image intensifier in the operative field. Then, drilling using a cannulated drill and tapping using a cannulated tapping device were carried out. Eleven consecutive patients who underwent posterior spinal fusion surgery using this technique since 2009 are included. The screw positions in the sagittal and axial planes were evaluated by postoperative CT scan to check for malpositioning. RESULTS: The screw insertion was done in the same manner as the simulated surgery. With the aid of this guide the pedicle screws and Magerl screws could be easily inserted even at the level where the pedicle seemed to be very thin and sclerotic on the CT scan. Postoperative CT scan showed that there were no critical breaches of the screws. CONCLUSION: This method employing the device using a 3-dimensional image guide seems to be easy and safe to use. The technique may improve the safety of pedicle screw and Magerl screw insertion even in difficult cases with narrow sclerotic pedicles. PMID- 22531474 TI - In vivo functional performance of failed Prodisc-L devices: retrieval analysis of lumbar total disc replacements. AB - STUDY DESIGN: A retrieval analysis of wear modes and fixation of lumbar total disc replacements (TDRs). Explanted Prodisc-L TDRs were prospectively collected during a 7-year period (2005-2011) and analyzed. OBJECTIVE: To assess the in vivo modes of wear and fixation of lumbar TDR with the Prodisc-L device. SUMMARY OF BACKGROUND DATA: Inferior clinical outcomes and failure of lumbar TDR may occur because of suboptimal component fixation, wear properties, and impingement in a subset of patients. Posterior component TDR impingement has been demonstrated radiographically; however, despite its widespread use, the in vivo mechanical performance and fixation of the Prodisc-L device remain unknown. METHODS: Explanted polyethylene and metallic (CoCrMo) components of Prodisc-L devices were examined by light stereo-microscopy (6X-31X), scanning electron microscopy, and energy-dispersive x-ray analysis from an international retrieval registry, with 13 participating surgeons. RESULTS: Nineteen ProDisc-L devices from 18 patients (age, 44.7 +/- 2.9 yr) following an index TDR at L4-L5 (n = 6), L5-S1 (n = 11), and unknown level (n = 2) were explanted for pain (n = 8), prosthesis subluxation/migration (n = 4), end plate collapse/subsidence (n = 3), polyethylene dislodgement (n = 3), and unknown (n = 2) after a mean length of implantation of 13.0 +/- 3.9 months. Surface area of bony ongrowth was 9.6 +/- 2.9% (range, 0%-52.5%). TDR burnishing was observed posteriorly consistent with component impingement in extension in 53% (8/15) (P < 0.02), more commonly than anterior 20% (3/15) lateral 20% (n = 3) (3/15) patterns. Circumferential burnishing was not observed. Posterior impingement was associated with 6 degrees lordotic implants (P < 0.05) and 10-mm polyethylene size (P < 0.05). Backside wear occurred in 75% (9 of 12) of the disassembled implants and third-body wear was observed in 33% (5 of 15). CONCLUSION: Metallic end plate burnishing was evident in a large percentage of clinically failed Prodisc-L TDR devices, most commonly posteriorly, consistent with impingement in extension. Long-term follow up studies will evaluate the effects of the observed backside wear, third-body wear, and end plate impingement on clinical outcomes. PMID- 22531476 TI - Prevalence of neurocognitive and balance deficits in collegiate aged football players without clinically diagnosed concussion. AB - STUDY DESIGN: Prospective cohort. OBJECTIVES: To identify the prevalence of neurocognitive and balance deficits in collegiate football players 48 hours following competition. BACKGROUND: Neurocognitive testing, balance assessments, and subjective report of symptoms are a commonly used test battery in examining athletes when concussion is suspected. Previous literature suggests many concussions go unreported. Little research exists examining the prevalence of neurocognitive or balance deficits in athletes who do not report concussion-like symptoms to a health care provider. METHODS: Forty-five Division IA collegiate football players participated in this study. Preseason baseline scores using the Balance Error Scoring System, the Immediate Post-Concussion Assessment and Cognitive Testing, and the Postconcussion Symptom Scale were compared to posttest results obtained 48 hours following a game. Prevalence of symptoms was analyzed and reported. RESULTS: Thirty-two (71%) of the 45 athletes tested demonstrated at least 1 deficit in either the Postconcussion Symptom Scale, Balance Error Scoring System, or at least 1 composite score of the Immediate Post-Concussion Assessment and Cognitive Testing. Nineteen of the 32 subjects demonstrated a change in 2 or more categories of neurocognitive and balance function. CONCLUSION: In a cohort of football players tested 48 hours following their last game of the season, who did not seek medical attention related to a concussion, a significant number demonstrated limitations in neurocognitive and balance performance, suggesting that further research may need to be performed to improve recognition of an athlete's deficits and to improve the ability to assess concussion. LEVEL OF EVIDENCE: Differential diagnosis/symptom prevalence, level 3b. PMID- 22531475 TI - Different measures of "genome-wide" DNA methylation exhibit unique properties in placental and somatic tissues. AB - DNA methylation of CpGs located in two types of repetitive elements-LINE1 (L1) and Alu-is used to assess "global" changes in DNA methylation in studies of human disease and environmental exposure. L1 and Alu contribute close to 30% of all base pairs in the human genome and transposition of repetitive elements is repressed through DNA methylation. Few studies have investigated whether repetitive element DNA methylation is associated with DNA methylation at other genomic regions, or the biological and technical factors that influence potential associations. Here, we assess L1 and Alu DNA methylation by Pyrosequencing of consensus sequences and using subsets of probes included in the Illumina Infinium HumanMethylation27 BeadChip array. We show that evolutionary age and assay method affect the assessment of repetitive element DNA methylation. Additionally, we compare Pyrosequencing results for repetitive elements to average DNA methylation of CpG islands, as assessed by array probes classified into strong, weak and non islands. We demonstrate that each of these dispersed sequences exhibits different patterns of tissue-specific DNA methylation. Correlation of DNA methylation suggests an association between L1 and weak CpG island DNA methylation in some of the tissues examined. We caution, however, that L1, Alu and CpG island DNA methylation are distinct measures of dispersed DNA methylation and one should not be used in lieu of another. Analysis of DNA methylation data is complex and assays may be influenced by environment and pathology in different or complementary ways. PMID- 22531477 TI - Special issue on Challenges in Environmental Science and Engineering, CESE-2011: 25-30, September, Ever Green Plaza Hotel, Tainan City, Taiwan. PMID- 22531478 TI - Role of nutritional status in predicting quality of life outcomes in cancer--a systematic review of the epidemiological literature. AB - Malnutrition is a significant factor in predicting cancer patients' quality of life (QoL). We systematically reviewed the literature on the role of nutritional status in predicting QoL in cancer. We searched MEDLINE database using the terms "nutritional status" in combination with "quality of life" together with "cancer". Human studies published in English, having nutritional status as one of the predictor variables, and QoL as one of the outcome measures were included. Of the 26 included studies, 6 investigated head and neck cancer, 8 gastrointestinal, 1 lung, 1 gynecologic and 10 heterogeneous cancers. 24 studies concluded that better nutritional status was associated with better QoL, 1 study showed that better nutritional status was associated with better QoL only in high-risk patients, while 1 study concluded that there was no association between nutritional status and QoL. Nutritional status is a strong predictor of QoL in cancer patients. We recommend that more providers implement the American Society of Parenteral and Enteral Nutrition (ASPEN) guidelines for oncology patients, which includes nutritional screening, nutritional assessment and intervention as appropriate. Correcting malnutrition may improve QoL in cancer patients, an important outcome of interest to cancer patients, their caregivers, and families. PMID- 22531479 TI - Compositional dependence of the stability of AuCu alloy nanoparticles. AB - The oxidation of AuCu nanoparticles was studied as a function of composition and temperature. Oxidation rates at 110 degrees C were higher for NPs with higher Cu content, showing that Au stabilized the Cu. Electrochemistry measurements show that AuCu could be a promising catalyst for lowering the over potential of CO(2) reduction. PMID- 22531480 TI - From restless legs syndrome to Willis-Ekbom disease: a condition reaches full age. PMID- 22531481 TI - Platelet counts and coagulation tests prior to neuraxial anesthesia in patients with preeclampsia: a retrospective analysis. AB - This retrospective, descriptive study aimed to assess hematologic testing practices in 100 patients with preeclampsia undergoing neuraxial blockade (NB). Prior to NB, platelet (PLT) count was performed in 61 (98%) of 62 women in labor and in 37 (97%) of 38 women undergoing cesarean delivery (CD). No patients had a pre-NB PLT count <70 * 10(9)/L. Pre-NB tests for prothrombin time (PT) and activated partial thromboplastin time (APTT) were less common and varied among laboring patients (15 [24%] of 62) and patients prior to CD (18 [47%] of 38). Prior to NB, PT and APTT values were within normal limits in all patients. The time intervals between laboratory testing and NB ranged from <2 to >12 hours. The lack of consistency in pre-NB coagulation testing and the variable time intervals between laboratory tests and NB may be due to a lack of consensus among anesthesiologists for determining "safe" hemostatic conditions for NB placement in patients with preeclampsia. PMID- 22531482 TI - The purple toe syndrome in female with Factor V Leiden mutation successfully treated with enoxaparin. AB - Purple toe syndrome is a rare complication of warfarin therapy. It occurs usually after 3 to 8 weeks of therapy and it is caused by cholesterol emboli from atheromatous plaque. Sudden onset of pain in affected area, typically in toes and feet, is the main characteristic of the syndrome. We describe a case of a 65-year old female with purple toe syndrome after 6 weeks of warfarin. Indication of warfarin was a proximal deep venous thrombosis, which developed after prolonged immobilization. Factor V (FV) Leiden and persistent high FVIII activity were found as additional eliciting factors for venous thromboembolism. After warfarin withdrawal and enoxaparin treatment, symptoms disappeared promptly but a slight discoloration of the toe persists. PMID- 22531484 TI - Prediction of MHC class I binding peptides with a new feature encoding technique. AB - The recognition of specific peptides, bound to major histocompatibility complex (MHC) class I molecules, is of particular importance to the robust identification of T-cell epitopes and thus the successful design of protein-based vaccines. Here, we present a new feature amino acid encoding technique termed OEDICHO to predict MHC class I/peptide complexes. In the proposed method, we have combined orthonormal encoding (OE) and the binary representation of selected 10 best physicochemical properties of amino acids derived from Amino Acid Index Database (AAindex). We also have compared our method to current feature encoding techniques. The tests have been carried out on comparatively large Human Leukocyte Antigen (HLA)-A and HLA-B allele peptide binding datasets. Empirical results show that our amino acid encoding scheme leads to better classification performance on a standalone classifier. PMID- 22531483 TI - Active Hexose Correlated Compound promotes T helper (Th) 17 and 1 cell responses via inducing IL-1beta production from monocytes in humans. AB - The differentiation of T helper (Th) cells is critically dependent on cytokine milieu. The innate immune monocytes produce IL-1beta which can affect the development of Th17 and Th1 cells that predominantly produce IL-17 and IFN-gamma, respectively. Oligosaccharides from microorganisms, crops and mushrooms can stimulate innate immune cells. Active Hexose Correlated Compound (AHCC) that contains a large amount of oligosaccharides is a natural extract prepared from the mycelium of the edible Basidiomycete fungus. This compound is reported to modulate immune responses against pathogens although the mechanisms for this effect are largely unknown. Here we show that AHCC could induce high levels of IL 1beta production from human monocytes. Furthermore, AHCC-treated monocytes increased the production of IL-17 and IFN-gamma from autologous CD4(+) T cells, which was blocked by adding IL-1 receptor antagonist. These finding provide new insight into how food supplements like AHCC could enhance human immunity by modulating monocytes and Th cells. PMID- 22531485 TI - Lidocaine patch (5%) is no more potent than placebo in treating chronic back pain when tested in a randomised double blind placebo controlled brain imaging study. AB - BACKGROUND: The 5% Lidocaine patch is used for treating chronic neuropathic pain conditions such as chronic back pain (CBP), diabetic neuropathy and complex regional pain syndrome, but is effective in a variable proportion of patients. Our lab has reported that this treatment reduces CBP intensity and associated brain activations when tested in an open labelled preliminary study. Notably, effectiveness of the 5% Lidocaine patch has not been tested against placebo for treating CBP. In this study, effectiveness of the 5% Lidocaine patch was compared with placebo in 30 CBP patients in a randomised double-blind study where 15 patients received 5% Lidocaine patches and the remaining patients received placebo patches. Functional MRI was used to identify brain activity for fluctuations of spontaneous pain, at baseline and at two time points after start of treatment (6 hours and 2 weeks). RESULTS: There was no significant difference between the treatment groups in either pain intensity, sensory and affective qualities of pain or in pain related brain activation at any time point. However, 50% patients in both the Lidocaine and placebo arms reported a greater than 50% decrease in pain suggesting a marked placebo effect. When tested against an untreated CBP group at similar time points, the patch treated subjects showed significantly greater decrease in pain compared to the untreated group (n = 15). CONCLUSIONS: These findings suggest that although the 5% Lidocaine is not better than placebo in its effectiveness for treating pain, the patch itself induces a potent placebo effect in a significant proportion of CBP patients. PMID- 22531486 TI - Cell cycle regulation during development and dormancy in embryos of the annual killifish Austrofundulus limnaeus. AB - Embryos of the annual killifish Austrofundulus limnaeus can enter into a state of metabolic dormancy, termed diapause, as a normal part of their development. In addition, these embryos can also survive for prolonged sojourns in the complete absence of oxygen. Dormant embryos support their metabolism using anaerobic metabolic pathways, regardless of oxygen availability. Dormancy in diapause is associated with high ATP and a positive cellular energy status, while anoxia causes a severe reduction in ATP content and large reductions in adenylate energy charge and ATP/ADP ratios. Most cells are arrested in the G 1/G 0 phase of the cell cycle during diapause and in response to oxygen deprivation. In this paper, we review what is known about the physiological and biochemical mechanisms that support metabolic dormancy in this species. We also highlight the great potential that this model holds for identifying novel therapies for human diseases such as heart attack, stroke and cancer. PMID- 22531487 TI - Study of the effect of 26RF- and 43RF-amides on testosterone and prolactin secretion in the adult male rhesus monkey (Macaca mulatta). AB - RF-amides (RFa), a superfamily of evolutionary-conserved neuropeptides, are expressed in both invertebrates and vertebrates. While some endocrine functions have been attributed to these peptides in lower vertebrates and few mammalian models, not much is known about their actions in primates. Therefore, the present study was designed to examine the effects of peripheral administration of two recently cloned human RFa peptides, 26RFa and 43RFa, on testosterone and prolactin secretion in the adult male adult male rhesus monkey (Macaca mulatta). For control purposes, a scrambled sequence of 26RFa (Sc-26RFa) and normal saline (1ml) were injected. Three different doses of 26RFa and 43RFa (19-nmol, 38-nmol and 76-nmol) and a single dose (38-nmol) of Sc-26RFa were tested. A set of four chair-restraint habituated monkeys was used. Comparison of post-treatment T levels with respective pre levels showed that none of the doses of both 26RFa and 43RFa changed T release. Similarly, Sc-26RFa and saline administration also did not affect T levels. In contrast, all doses of 26RFa and 43RFa significantly (P<0.05) stimulated prolactin secretion. 43RFa dose dependently increased prolactin secretion while dose dependency was not observed for 26RFa. Saline and Sc-26RFa injection had no effect on prolactin concentrations. Thus, present study demonstrated that peripheral administration of 26RFa and 43RFa, in the doses tested, have no effect on T secretion, suggesting possible selective lack of their neuroendocrine role in controlling hypothalamic-pituitary-gonadal axis in the adult male primates. The prominent stimulation of prolactin suggests a neuroendocrine role of RFa peptides in regulation of prolactin release in primates. PMID- 22531489 TI - Tandem transplantation for follicular lymphoma: the best of both worlds? PMID- 22531488 TI - Non-opioid nociceptive activity of human dynorphin mutants that cause neurodegenerative disorder spinocerebellar ataxia type 23. AB - We previously identified four missense mutations in the prodynorphin gene that cause human neurodegenerative disorder spinocerebellar ataxia type 23 (SCA23). Three mutations substitute Leu(5), Arg(6), and Arg(9) to Ser (L5S), Trp (R6W) and Cys (R9C) in dynorphin A(1-17) (Dyn A), a peptide with both opioid activities and non-opioid neurodegenerative actions. It has been reported that Dyn A administered intrathecally (i.t.) in femtomolar doses into mice produces nociceptive behaviors consisting of hindlimb scratching along with biting and licking of the hindpaw and tail (SBL responses) through a non-opioid mechanism. We here evaluated the potential of the three mutant peptides to produce similar behaviors. Compared to the wild type (WT)-peptide, the relative potency of Dyn A R6W, L5S and R9C peptides for SBL responses was 50-, 33- and 2-fold higher, and Dyn A R6W and L5S induced the SBL responses at a 10-30-fold lower doses. Dyn A R6W was the most potent peptide. The SBL responses induced by Dyn A R6W were dose dependently inhibited by morphine (i.p.; 0.1-1 mg/kg) or MK-801, an NMDA ion channel blocker (i.t. co-administration; 5-7.5 nmol). CP-99,994, a tachykinin NK1 receptor antagonist (i.t. co-administration; 2 nmol) and naloxone (i.p.; 5 mg/kg) failed to block effects of Dyn A R6W. Thus, similarly to Dyn A WT, the SBL responses induced by Dyn A R6W may involve the NMDA receptor but are not mediated through the opioid and tachykinin NK1 receptors. Enhanced non-opioid excitatory activities of Dyn A mutants may underlie in part development of SCA23. PMID- 22531490 TI - Incidence and risk factors for early hepatotoxicity and its impact on survival in patients with myelofibrosis undergoing allogeneic hematopoietic cell transplantation. AB - Allogeneic hematopoietic cell transplantation (HCT) is commonly associated with hepatic complications. Patients with myelofibrosis (MF) often develop liver dysfunction in the early posttransplantation period; however, this has not yet been studied in a systematic fashion. We retrospectively evaluated 53 patients with MF who underwent HCT to assess the prevalence of acute liver toxicity and risk factors and the impact on survival. We compared the prevalence of acute hepatic complications in that group and a matched control group of 53 patients with myelodysplastic syndrome (MDS). In the MF group, during the first 6 weeks after HCT, the incidence of mild (34.2-102.6 MUM), moderate (102.6-342 MUM), and severe (>342 MUM) hyperbilirubinemia was 34%, 40%, and 4%, respectively (normal, <22 MUM). The incidence of mild/moderate transaminitis (2-10 times the upper limit of normal) was 23%, and that of severe transaminitis (>10 times the upper limit of normal) was 6%. Veno-occlusive disease as defined by the Baltimore criteria was observed in 19 patients (36%) in the MF group. Compared with MDS, MF was associated with a significantly higher incidence of moderate/severe hyperbilirubinemia (44% versus 21%; P = .02) and veno-occlusive disease (36% versus 19%; P = .05). A history of portal hypertension, biopsy-proven hepatic iron overload, or splanchnic vein thrombosis was a strong predictor of moderate/severe hyperbilirubinemia (P = .02). Acute hepatocellular injury with moderate/severe hyperbilirubinemia or transaminitis was associated with inferior survival at 12 months (P = .02) in the MF group. We conclude that patients with MF are at significant risk of early hepatotoxicity after HCT, which is associated with an adverse impact on survival. PMID- 22531492 TI - One-year experience with high-emergency lung transplantation in France. AB - BACKGROUND: The continuing significant number of patients who die while on a waiting list for lung transplantation (LTx) has led several countries to modify their lung allocation rules in recent years. France has implemented high emergency allocation rules to allow patients at imminent risk of death to undergo priority transplantation within several days. The aim of this study was to report on the early (2-year) experience of high-emergency LTx (HELTx) in France. METHODS: From July 1, 2007, to June 30, 2008, 186 patients underwent LTx in France in nine centers. Among them, 32 patients (17.2%) underwent HELTx (19 with cystic fibrosis, 7 pulmonary fibrosis, and 6 other diagnoses). The reasons for HELTx were risk of invasive mechanical ventilation (n=20), invasive mechanical ventilation (n=8), and extracorporeal membrane oxygenation (n=4). RESULTS: The median time between being placed on the HELTx waiting list and LTx was 3 days (interquartile range: 1-8 days). Survival rates in the HELTx group were 90.5%, 71%, 64.5%, 55%, and 51.5% at 1, 3, 6, 12, and 24 months, respectively, which were significantly lower than for 154 patients who underwent regular, nonurgent LTx during the study period (88.5%, 83%, 79%, 77%, and 71%, respectively). CONCLUSIONS: Our data demonstrate that the new LTx allocation rules implemented in France since 2007 allow for rapid organ procurement for patients at imminent high risk of death. HELTx is feasible but yields poorer survival than elective LTx. Further studies are needed to assess implications of this organ allocation policy on the long run. PMID- 22531491 TI - Human parainfluenza virus infection after hematopoietic stem cell transplantation: risk factors, management, mortality, and changes over time. AB - Human parainfluenza viruses (HPIVs) are uncommon, yet high-risk pathogens after hematopoietic stem cell transplant (HCT). We evaluated 5178 pediatric and adult patients undergoing HCT between 1974 and 2010 to determine the incidence, risk factors, response to treatment, and outcome of HPIV infection as well as any change in frequency or character of HPIV infection over time. HPIV was identified in 173 patients (3.3%); type 3 was most common (66%). HPIV involved upper respiratory tract infection (URTI; 57%), lower respiratory tract infection (LRTI; 9%), and both areas of the respiratory tract (34%), at a median of 62 days after transplantation. In more recent years, HPIV has occurred later after HCT, whereas the proportion with nosocomial infection and mortality decreased. Over the last decade, HPIV was more common in older patients and in those receiving reduced intensity conditioning (RIC). RIC was a significant risk factor for later (beyond day +30). HPIV infections, and this association was strongest in patients with URTI. HCT using a matched unrelated donor (MURD), mismatched related donor (MMRD), age 10 to 19 years, and graft-versus-host disease (GVHD) were all risk factors for HPIV infections. LRTI, early (<30 days), age 10 to 19 years, MMRD, steroid use, and coinfection with other pathogens were risk factors for mortality. The survival of patients with LRTI, especially very early infections, was poor regardless of ribavirin treatment. HPIV incidence remains low, but may have delayed onset associated with RIC regimens and improving survival. Effective prophylaxis and treatment for HPIV are needed. PMID- 22531493 TI - Clostridium difficile on the transplantation radar. PMID- 22531494 TI - Incidence, determinants, and outcome of chronic kidney disease after adult heart transplantation in the United Kingdom. AB - BACKGROUND: We investigated the incidence of chronic kidney disease (CKD) in the United Kingdom heart transplant population, identified risk factors for the development of CKD, and assessed the impact of CKD on subsequent survival. METHODS: Data from the UK Cardiothoracic Transplant Audit and UK Renal Registry were linked for 1732 adult heart transplantations, 1996 to 2007. Factors influencing time to CKD, defined as National Kidney Foundation CKD stage 4 or 5 or preemptive kidney transplantation, were identified using a Cox proportional hazards model. The effects of distinct CKD stages on survival were evaluated using time-dependent covariates. RESULTS: A total of 3% of patients had CKD at transplantation, 11% at 1-year and more than 15% at 6 years posttransplantation and beyond. Earlier transplantations, shorter ischemia times, female, older, hepatitis C virus positive, and diabetic recipients were at increased risk of developing CKD, along with those with impaired renal function pretransplantation or early posttransplantation. Significant differences between transplantation centers were also observed. The risk of death was significantly higher for patients at CKD stage 4, stage 5 (excluding dialysis), or on dialysis, compared with equivalent patients surviving to the same time point with CKD stage 3 or lower (hazard ratios of 1.66, 8.54, and 4.07, respectively). CONCLUSIONS: CKD is a common complication of heart transplantation in the UK, and several risk factors identified in other studies are also relevant in this population. By linking national heart transplantation and renal data, we have determined the impact of CKD stage and dialysis treatment on subsequent survival in heart transplant recipients. PMID- 22531496 TI - Extensive mandibular ameloblastoma in a pediatric patient. AB - Ameloblastoma is an infrequent tumor of the jaw with peak incidence generally in the third and fourth decade of life. Treatment commonly involves resection although recurrence rates remain high despite this modality. We present a unique case of a 6.5 cm ameloblastoma in an adolescent patient with who underwent successful excision of her tumor. This case demonstrates the extensive development of the ameloblastoma in a patient requiring transport to the United States before surgical intervention. PMID- 22531495 TI - A novel mtDNA large-scale mutation clinically exclusively presenting with refractory anemia: is there a chance to predict disease progression? AB - Because of the diversity of clinical symptoms, the diagnosis of mitochondrial DNA (mtDNA) deletion disorders can be difficult. Here, we describe an 8-month-old boy presenting clinically exclusively with refractory anemia. Mutation analysis in our patient revealed a large, novel deletion in his mtDNA encompassing ATPase 6, cytochrome oxidase subunit III, NADH dehydrogenase genes ND3 to ND6, and cytochrome b. Comparison with other cases from the literature showed that there is no genotype-phenotype correlation regarding hematologic features. It is not possible to predict whether our patient will develop additional features from Pearson syndrome or Kearns-Sayre syndrome, both syndromic mitochondrial disorders with hematological manifestations. PMID- 22531497 TI - Trissomy of chromosome 8 and juvenile myelomonocytic leukemia. PMID- 22531498 TI - Poly(ADP-ribose) regulates post-transcriptional gene regulation in the cytoplasm. AB - Since its discovery in 1963, poly(ADP-ribose) (pADPr) has been shown to play important functions in the nucleus of multicellular eukaryotes. Each of these functions centers upon DNA metabolism, including DNA-damage repair, chromatin remodeling, transcription and telomere functions. We recently described two novel functions for pADPr in the cytoplasm, both of which involve RNA metabolism - 1) the assembly of cytoplasmic stress granules, cellular macrostructures that aggregate translationally stalled mRNA/protein complexes, and 2) modulation of microRNA activities. Multiple stress granule-localized, post-transcriptional gene regulators, including microRNA-binding argonaute family members, are substrates for pADPr modification and are increasingly modified by pADPr upon stress. Interestingly, the cytoplasmic RNA regulatory functions for PARPs are likely mediated through activities of catalytically inactive PARP-13/ARTD13/ZC3HAV1/ZAP and mono/poly(ADP-ribose)-synthesizing enzymes, including PARP-5a/ARTD5/TNKS1, PARP-12/ARTD12/ZC3HDC1 and PARP-15/ARTD7/BAL3. These data are consistent with other recent work, which suggests that mono(ADP-ribosyl)ated residues can be poly(ADP-ribosyl)ated by different enzymes. PMID- 22531500 TI - Reducing canonical Wingless/Wnt signaling pathway confers protection against mutant Huntingtin toxicity in Drosophila. AB - Huntington's disease (HD) is a genetic neurodegenerative disease characterized by movement disorders, cognitive decline and neuropsychiatric symptoms. HD is caused by expanded CAG tract within the coding region of Huntingtin protein. Despite major insights into the molecular mechanisms leading to HD, no effective cure is yet available. Mutant Huntingtin (mHtt) has been reported to alter the stability and levels of beta-Catenin, a key molecule in cell adhesion and signal transduction in Wingless (Wg)/Wnt pathway. However it remains to establish whether manipulation of Wg/Wnt signaling can impact HD pathology. We here investigated the phenotypic interactions between mHtt and Wg/Wnt signaling by using the power of Drosophila genetics. We provide compelling evidence that reducing Armadillo/beta-Catenin levels confers protection and that this beneficial effect is correlated with the inactivation of the canonical Wg/Wnt signaling pathway. Knockdowns of Wnt ligands or of the downstream transcription factor Pangolin/TCF both ameliorate the survival of HD flies. Similarly, overexpression of one Armadillo/beta-Catenin destruction complex component (Axin, APC2 or Shaggy/GSK-3beta) increases the lifespan of HD flies. Loss of functional Armadillo/beta-Catenin not only abolishes neuronal intrinsic but also glia induced alterations in HD flies. Our findings highlight that restoring canonical Wg/Wnt signaling may be of therapeutic value. PMID- 22531501 TI - Poor performance of mandatory nutritional screening of in-hospital patients. AB - BACKGROUND & AIMS: Since 2006 it has been mandatory at Copenhagen University Hospital Gentofte to screen all patients for nutritional risk within 24 h of admittance. Audits conducted by department staff estimate that 70-80% of assessments are correctly executed, but the validity of this estimate is unknown. The aim of the present study was to discover the true proportion of hospitalized patients receiving nutritional risk screening within the stipulated time limit and to evaluate the validity of the screening by comparison with medical records. METHODS: Retrospective examination of medical records of all patients (N = 3278) hospitalized in September 2008 in 11 different medical specialities were analysed in 2009-2010. RESULTS: Of 2393 medical records 24% of the patients were screened, of these only 65% were screened within the stipulated time limit. Half of the conducted screenings were inaccurate, the most common error being underestimation of nutritional status. Forty-six percent of patients required a secondary nutritional risk screening and 30% were found to be nutritionally at risk. CONCLUSION: Only 8% of patients received the mandatory nutritional risk screening without procedural errors. We conclude that pre-scheduled, self-conducted audits are not viable as the basis of an assessment of the use of nutritional risk screening. PMID- 22531499 TI - A multicenter study confirms CD226 gene association with systemic sclerosis related pulmonary fibrosis. AB - INTRODUCTION: CD226 genetic variants have been associated with a number of autoimmune diseases and recently with systemic sclerosis (SSc). The aim of this study was to test the influence of CD226 loci in SSc susceptibility, clinical phenotypes and autoantibody status in a large multicenter European population. METHODS: A total of seven European populations of Caucasian ancestry were included, comprising 2,131 patients with SSc and 3,966 healthy controls. Three CD226 single nucleotide polymorphisms (SNPs), rs763361, rs3479968 and rs727088, were genotyped using Taqman 5'allelic discrimination assays. RESULTS: Pooled analyses showed no evidence of association of the three SNPs, neither with the global disease nor with the analyzed subphenotypes. However, haplotype block analysis revealed a significant association for the TCG haplotype (SNP order: rs763361, rs34794968, rs727088) with lung fibrosis positive patients (PBonf = 3.18E-02 OR 1.27 (1.05 to 1.54)). CONCLUSION: Our data suggest that the tested genetic variants do not individually influence SSc susceptibility but a CD226 three-variant haplotype is related with genetic predisposition to SSc-related pulmonary fibrosis. PMID- 22531504 TI - India-magical realism. PMID- 22531503 TI - Relationships between food consumption and living arrangements among university students in four European countries - a cross-sectional study. AB - BACKGROUND: The transition of young people from school to university has many health implications. Food choice at the university can differ because of childhood food consumption patterns, sex and the living arrangements. Food consumption may change especially if students are living away from home. We aimed to assess food consumption patterns among university students from four European countries and how they differ by their living arrangements. METHODS: We analysed data from a cross-country survey assessing health and health behaviours of students. The sample comprised a total of 2402 first year undergraduate students from one university in each of the countries of Germany, Denmark, Poland and Bulgaria. Food consumption was assessed by means of a food frequency questionnaire with 9 food groups (indicators). RESULTS: Students' food consumption patterns differed across the countries. Frequent consumption of unhealthy items was common. Bulgarian students reported most often frequent consumption of sweets and cakes and snacks (e.g. chips and fast food). Polish students reported the least frequent consumption of vegetables and a low consumption of fruits. Across all countries except Bulgaria, men reported substantially more often frequent consumption of snacks than women. Students living at parental home consumed more fruit, vegetables, and meat than those who resided outside of their family home in all studied countries. There was more variation with regard to cakes and salads with more frequent consumption of cakes among Bulgarian female students and Danish male students and more frequent consumption of salads among Danish female students not living at parental home, compared to students from other countries. CONCLUSIONS: Nutrition habits of university students differed across countries and by sex. Students living at parental home displayed more healthy nutrition habits, with some exceptions. PMID- 22531505 TI - Microarrays and cancer diagnosis. AB - Cancer can be considered a "developmental disorder" because it involves a disruption in the normal development of cells, in terms of both differentiation and proliferation (Dean M,1998). Cancer cells generally contain the full complement of biomolecules that are necessary for survival, proliferation, differentiation, cell death, and expression of cell type-specific function. Human Cancer diagnosis and classification by Microarray analysis has yet to be widely accepted despite the exponential increase in microarray studies reported in the literatures. Additionally, recent microarrays were inspired by the nucleotide based technology, which have created to better define the molecular basis of malignancy which have shown that microarray have clinical utility in cancer diagnosis, risk stratification, and patient management. PMID- 22531506 TI - Functional magnetic resonance imaging in cervical cancer: current evidence and future directions. AB - Carcinoma cervix is one of the most common cancers amongst Indian women. Though treatment strategies continue to evolve, there are no established predictive biomarkers of prognosis or therapeutic response. Novel imaging techniques using magnetic resonance (MR) and positron emission tomography (PET) can facilitate time resolved spatial evaluation of biological characteristics (perfusion, permeability, cellularity, proliferation, oxygenation, and apoptosis) thereby serving as early surrogate biomarkers for prognosis and therapeutic response. Several of these imaging modalities such as dynamic contrast-enhanced MRI (DCE MRI), diffusion-weighted MRI (DW-MRI), MR spectroscopy (MRS) and fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) are now being evaluated for gynecological oncology, with the majority of work being performed on cervical tumors. PUBMED database was searched for this review from January 1966 till February 2011. This review examines the basic principles of functional MR imaging for cervical cancer and its current status as a diagnostic and predictive biomarker for cervical cancer. PMID- 22531508 TI - Nano cancer therapy strategies. AB - Cancer is a leading cause of deaths. Millions of people are diagnosed with cancer every year. Many cancer cells have a protein all over their surface, while healthy cells typically do not express the protein as strongly. By conjugating, or binding, the gold nanoparticles to an antibody the researchers were able to get the nanoparticles to attach themselves to the cancer cells which may help us unravel the inner workings of a cancer cell and produce better treatments. In terms of drug delivery systems, nano particles enable unique approaches for cancer treatment. A large number of nanoparticle delivery systems have been developed for cancer therapy and currently they are in the preclinical stages of development. More recently developed nanoparticles are demonstrating the potential sophistication of these delivery systems by incorporating multifunctional capabilities and targeting strategies in an effort to increase the efficacy of these systems against the most difficult cancer challenges. This article reviews the available preclinical and clinical nanoparticle technology platforms and their impact on cancer therapy. PMID- 22531509 TI - Positron emission tomography scan for predicting clinical outcome of patients with recurrent cervical carcinoma following radiation therapy. AB - PURPOSE: To evaluate the role of positron emission tomography (PET) for predicting the clinical outcome of patients with recurrent cervical carcinoma following definitive radiation therapy (RT). MATERIALS AND METHODS: Twenty two patients of post irradiated recurrent cervical carcinoma (PIRCC) were enrolled in this prospective study. 18-fluorodeoxyglucose (FDG) PET imaging was performed in each patient before the salvage therapy. The maximum standardized uptake value (SUVmax) and metabolic tumor volume (MTV) were measured and correlated with cumulative progression free survival (PFS). RESULTS: Median age of patients was 42 years. Majority of patients had stage III disease at the initial presentation and all 22 patients had received prior definitive RT. The median recurrence free period was 11 months. Salvage therapy consisted of surgical resection or re irradiation depending upon the various clinical and radiological factors. Median SUVmax was 5.8 (range 1.8-50.6) and median MTV was 43 cm3 (range 5.8-243). The cumulative PFS for all patients was 20% at 30 months. The one-year PFS was 28% for patients with SUVmax value of >5.8 versus 42% for those with SUVmax value of <5.8 (P value 0.01). The one-year PFS was 43% for patients with MTV value of >43 cm3 versus 45% for those with MTV value of <43 cm3 (P value 0.8). CONCLUSION: Our preliminary experience has suggested that FDG uptake on PET scan can predict the clinical outcome of PIRCC patients. Further randomized studies may be conducted with large sample size and longer follow up to establish its definite predictive value. PMID- 22531510 TI - Transcriptome network analysis reveals candidate genes for renal cell carcinoma. AB - CONTEXT: Renal cell carcinoma (RCC) is a kidney cancer that originates in renal parenchyma and it is the most common type of kidney cancer with approximately 80% lethal cases. AIMS: To interpret the mechanism, explore the regulation of TF target genes and TF-pathway, and identify the potential key genes of renal cell carcinoma. SETTINGS AND DESIGN: After constructing a regulation network from differently expressed genes and transcription factors, pathway regulation network and gene ontology (GO) enrichment analysis were made. MATERIALS AND METHODS: The gene expression profile set GSE6344, a renal cell carcinoma sample set, was collected from NCBI, pathway data from KEGG, and regulationship data from database TRANSFAC and TRED. STATISTICAL ANALYSIS USED: Besides different expressed genes obtained by limma, impact analysis method and GO enrichment were applied to find the significant expressed pathways. RESULTS: Finally, we constructed a TF-target gene and TF-pathway regulation network of renal cell carcinoma. And some genes proved to be highly related to renal cell carcinoma were identified. CONCLUSIONS: This study illustrated that by incorporating significantly expressed pathway into a regulation network based analysis, one can derive greater insights into the underlying mechanisms of renal cell carcinoma. PMID- 22531511 TI - Conformal fields in prostate radiotherapy: a comparison between measurement, calculation and simulation. AB - AIMS: The objective of this study is to evaluate the accuracy of a treatment planning system (TPS) for calculating the dose distribution parameters in conformal fields (CF). Dosimetric parameters of CF's were compared between measurement, Monte Carlo simulation (MCNP4C) and TPS calculation. MATERIALS AND METHODS: Field analyzer water phantom was used for obtaining percentage depth dose (PDD) curves and beam profiles (BP) of different conformal fields. MCNP4C was used to model conformal fields dose specification factors and head of linear accelerator varian model 2100C/D. RESULTS: Results showed that the distance to agreement (DTA) and dose difference (DD) of our findings were well within the acceptance criteria of 3 mm and 3%, respectively. CONCLUSIONS: According to this study it can be revealed that TPS using equivalent tissue air ratio calculation method is still convenient for dose prediction in non small conformal fields normally used in prostate radiotherapy. It was also showed that, since there is a close correlation with Monte Carlo simulation, measurements and TPS, Monte Carlo can be further confirmed for implementation and calculation dose distribution in non standard and complex conformal irradiation field for treatment planning systems. PMID- 22531512 TI - CYP 2D6 polymorphism: a predictor of susceptibility and response to chemoradiotherapy in head and neck cancer. AB - AIMS: A major problem in cancer pharmacology is the unpredictability of the outcome of therapy, both in terms of tumor response and host toxicity. Pharmacogenetic variability associated with the drug metabolizing enzyme systems is a major determinant of variations in these outcomes. MATERIALS AND METHODS: A case-control study of 100 male cases of head and neck squamous cell carcinoma and equal number of healthy controls was conducted. Genomic DNA isolated from blood samples collected from controls and patients was studied by PCR-RFLP technique for CYP2D6 polymorphism. All patients received three cycles of cisplatinum-based sequential chemoradiotherapy. RESULTS: The increased frequency of variant genotypes was associated with a statistically significant increase in the risk in the cases both in CYP2D6*4 and *10. The effect of interaction of the risk modifiers such as cigarette smoking or tobacco chewing or alcohol drinking with the CYP2D6 genotypes in the controls and patients was found to be significant. Response to therapy in patients with variant genotypes of CYP2D6 (CYP2D6*4 and CYP2D6*10) and treated with radio and chemotherapy regimen was poor. CONCLUSIONS: Functional enzyme deficiencies due to polymorphism in CYPs are not only important in enhancing susceptibility to head and neck squamous cell carcinoma but also in determining chemotherapeutic response. PMID- 22531513 TI - A survey of breast cancer knowledge and attitude in Iranian women. AB - BACKGROUND: Breast cancer (BC) is the most common cancer among Iranian women. It is recommended that women be under national screening for early detection of cases to improve survival and decrease mortality. Because of shortage of facilities, breast self-examination (BSE) instead of clinical-based examination (CBE) and mammography is advocated as the first step of screening in developing countries including Iran. It is quite clear that the related knowledge, attitude, and practice (KAP) of the community is necessary to have a successful screening program particularly for BSE. MATERIALS AND METHODS: A community-based descriptive study on 650 females aged more than 18 years was carried out with a well-structured and valid questionnaire to demonstrate the knowledge and practice of women for BSE, CBE and mammography. RESULTS: The mean age of participants was 40.72 years with standard deviation (SD) of 9.58. Eighty-two point six percent (82.6%) were married and 48.4% were post graduates. A painless mass (60.8%) and bloody discharge (44.9%) were reported as the two important symptoms for BC. In this assay, 80.3% of participants knew females are at risk of BC and 70.6% of them perceived that early detection and operation in early stages are effective issues. Thirty point eight percent (30.8%) of respondents knew the BSE and this knowledge had significant association with their educational status. Fifty-nine point nine percent (59.9%) of participants were able to do BSE but only 12.9% of respondents practiced BSE regularly. CONCLUSION: Community awareness and education level are important elements in BSE as a substitute for traditional screening in BC for early detection. PMID- 22531514 TI - Survival outcome and neurotoxicity in patients of high-grade gliomas treated with conformal radiation and temozolamide. AB - BACKGROUND: To study the survival outcome and neurotoxicity grades in patients of high-grade glioma (HGG) treated with conformal radiation and temozolamide. MATERIALS AND METHODS: Forty-six patients of HGG received conformal post operative radiation and temozolamide in the period 2003 to 2007. Twenty seven patients had near total resection, 17 had subtotal resection and 2 had biopsy only. 33 patients (71.7%) were treated with IMRT and 13 (28.3%) received 3DCRT (conformal radiation). Median dose delivered to PTV2 was 61.58 Gy and PTV1 was 54.3 Gy. Neurotoxicity was assessed with sequential MRI and cognitive disturbance was evaluated and grading was done according to CTCAE version 2.0 and 3.0 respectively. RESULTS: At a median follow-up of 12 months, median progression free and overall survival was 9 months and 15 months respectively. At 6 months, MRI neurotoxicity of grade 1, 2, and 3 was seen in 34.3, 11.4 and 2.9% patients. At 24 months, 35.3 and 29.4% patients had grade 1 and 2 neurotoxicity respectively. Cognitive disturbance was grade 0, 1, 2 and 3 in 55, 34.4, 6.8 and 3.4% patients at 6 months and grade 0 and grade 1 in 51.1 and 42.8% patients respectively at 24 months. CONCLUSION: Conformal Radiation yields low grades of MRI assessed neurotoxicity and cognitive disturbance in patients of HGG with no adverse impact on local control and survival. PMID- 22531515 TI - Overexpression of interferon regulatory factor 1 enhances chemosensitivity to 5 fluorouracil in gastric cancer cells. AB - PURPOSE: To investigate the effects of interferon regulatory factor 1 (IRF-1) gene overexpression on chemotherapeutic sensitivity of gastric cancer cells. MATERIALS AND METHODS: An AGS cell system with tetracycline-inducible IRF-1 expression (AGS/IRF-1) was established. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting were used to detect the expression of the IRF-1 gene. Chemosensitivity to 5-fluorouracil (5-FU) was assessed by cell proliferation assay and cell apoptosis. RESULTS: IRF-1 mRNA and protein level were significantly increased in AGS/IRF-1 cells induced with tetracycline. Compared with control cells, the growth inhibition rate of cells with IRF-1 overexpression was significantly increased when treated with 5-FU (P<0.01). Treatment with 5 MUmol/l 5-FU resulted in 12.6% apoptotic cells, whereas such treatment after overexpression of IRF-1 resulted in 39.4% apoptotic cells. Moreover, more poly(adenosine diphosphate-ribose) polymerase (PARP) cleavage was seen in cells with IRF-1 overexpression. CONCLUSIONS: Overexpression of IRF-1 enhanced the chemosensitivity of gastric cancer cells to 5-FU through induction of apoptosis. PMID- 22531516 TI - Bone marrow involvement by lymphoproliferative disorders after renal transplantation: PTLD. Int. Survey. AB - CONTEXT: Renal graft recipients who develop post-transplant lymphoproliferative disorders (PTLD) that complicate bone marrow (BM). AIMS: To investigate features, predictors and prognosis of BM involvement by PTLD in renal transplant patients. SETTINGS AND DESIGN: A comprehensive search for the available data though PubMed and Google Scholar for reports of PTLD localization in BM in renal allograft recipients. MATERIALS AND METHODS: Data of 168 PTLD cases in renal transplant context who have developed bone marrow PTLD gathered from 18 studies and were pooled and analyzed. STATISTICAL ANALYSIS USED: Chi-square test, Student's t test and fissure's exact test were employed. RESULTS: Chi-square test showed that renal recipients with BM PTLD were significantly more likely to represent multi organ disease (P<0.001), and disseminated PTLD (P<0.001). BM PTLD was also more frequently seen among pediatric renal recipients who had developed PTLD (P=0.016). PTLD, in BM PTLD renal recipients more significantly complicated liver (P=0.008), but less commonly affected skin (P=0.045). BM PTLD lesions were relatively more likely to be of monomorph phenomenon (P=0.06). CONCLUSIONS: Renal recipients with BM PTLD represent worse outcome and more unfavorable histopathological phenomenon than in other organ involvements. Moreover, a concomitant PTLD involvement site in liver was found which necessitates full hepatic evaluation for a potential complication by the disease in renal recipients whose BM is involved. PMID- 22531517 TI - Evaluation of diffusion-weighted imaging as a predictive marker for tumor response in patients undergoing chemoradiation for postoperative recurrences of cervical cancer. AB - PURPOSE: To investigate diffusion-weighted imaging (DWI) as a response biomarker in patients undergoing chemoradiation for postoperative recurrences of cervical cancer. MATERIALS AND METHODS: From October 2008 to March 2011, 20 patients were included. All underwent T2-weighted (T2W) and DWI before and after chemoradiation. Gross tumor volume (GTV), lateral extent, apparent diffusion coefficient (ADC), and presence of regions of focally restricted diffusion were determined at baseline. Response to chemoradiation was categorized as either partial or complete. Receiver operator characteristics (ROC) curve identified thresholds of GTV and ADC that best predict for partial response. Univariate and multivariate analysis were performed on SPSS version 15. RESULTS: The median GTV was 24.5 cc (4.1-110 cc). Central and lateral disease was present in 8 and 12 patients, respectively. The median ADC was 1 * 10 -3 mm2 /s (0.8-1.3 * 10-3 mm2 /s) and 12/20 (60%) patients had focal restricted diffusion. Overall 10/20 patients had partial response. ROC analysis identified volume of 25 cc or higher [sensitivity = 80%, specificity = 80%, area under curve (AUC) = 0.76, P = 0.04] and ADC more than 1 * 10-3 mm2 /s (sensitivity = 70%, specificity = 50%, AUC = 0.62; P = 0.34) to best predict for partial response. On univariate analysis bulky disease (77.7% vs. 27%; P = 0.03), lateral disease (66.6% vs. 25%; P = 0.08), and focal regions of restricted diffusion (66.6% vs. 25%; P = 0.06) predicted for partial response to chemoradiation. All factors continued to be significant on multivariate analysis. On restricting analysis to bulky tumors ADC greater than 0.95 * 10-3 mm2 /s predicted partial response with high sensitivity (85.7%) and specificity (100%) (AUC 0.96; P = 0.05). On univariate analysis lateral disease (P = 0.04), high baseline ADC (P = 0.07) predicted for partial response. CONCLUSIONS: Baseline ADC and focal regions of ADC restriction predict for partial response with moderate sensitivity and specificity in patients with postoperative recurrences of cervical cancer and need to be validated in larger cohort. PMID- 22531518 TI - Cut margins and disease control in oral cancers. AB - AIM: This retrospective study was done to evaluate the impact of cut margins on disease-free survival in patients with previously untreated oral squamous cell cancers. MATERIALS AND METHODS: Records of 306 cases were reviewed for clinical details and status of margins at resection. The independent influence of margins on recurrence was analyzed. The impact of frozen section analysis on achieving free margins was also examined. RESULTS: 190 (62.1%) patients had negative margins of resection (>= 5 mm), 102 (33.3%) patients had close margins (1-5 mm), while 14 (4.6%) patients had positive margins (<= 1 mm). The median follow-up for the entire cohort was 26.5 months. There were 79 (25.8%) recurrences, of which, 46 (58.2%) were local, 9 (11.3%) were locoregional, 16 (20.2%) were regional, and 8 (10.1%) were distant metastasis. 42 (22.2%) cases with negative margins developed a recurrence as compared to 31 (30.4%) cases with close margins and 6 (42.8%) cases with positive margins (P value 0.01). Average time to recurrence in case of negative margins was 34.8 months, for close margins was 33.9 months, while in those with positive margins was 10.18 months (P value 0.002). Close and positive margins were found to be significantly associated with increased local recurrence (P values 0.01 and 0.03, respectively) and with overall recurrence (P values 0.003 and 0.003, respectively). Frozen section was seen to influence margins in 20.4% cases. CONCLUSION: Margins are an important predictor of disease control. The surgeon must aim for adequate margins at initial resection. PMID- 22531519 TI - Low voltage irreversible electroporation induced apoptosis in HeLa cells. AB - BACKGROUND: High-voltage electric field pulses can make cell membrane electroporated irreversibly and eliminate malignant cells via necrosis. However, low-voltage is not efficient as that. AIMS: This study determined the differential effects of high- and low-voltage electric field pulses on HeLa cells, when the power of low-voltage was enhanced by increasing quantity of pulses. MATERIALS AND METHODS: Pulses electric fields with permanent frequency (1 Hz) and pulse length (100 MUs) were performed on HeLa cells. Voltage and pulse sets (8 pulses/set) were various during treatment. CCK-8 assay was used to detect cell viability. The quantitative determination of apoptosis and necrosis were performed by flow cytometry with Annexin V and PI staining. Transmission electron microscopy was used to observe the ultrastructure of HeLa cells. Caspase-3 and caspase-8, the enzymes in apoptotic pathway, were determined by western blot. RESULTS: The data showed that low-voltage electric field pulses also could make cell irreversible electroporation (IRE) and ablate HeLa cells effectively by induction of apoptosis. The ablating effect due to low-voltage treatments delivered with a greater number of pulses may be as satisfactory as high-voltage, or even preferable because it causes less necrosis and more apoptosis. CONCLUSIONS: IRE induced by low voltage with more pulses could ablate HeLa cells effectively as high voltage, and it was preferable that less necrosis and more apoptosis occurred under such condition. PMID- 22531520 TI - Dosimetric validation of new semiconductor diode dosimetry system for intensity modulated radiotherapy. AB - INTRODUCTION: The new diode Isorad was validated for intensity modulated radiotherapy (IMRT) and the observations during the validation are reported. MATERIALS AND METHODS: The validation includes intrinsic precision, post irradiation stability, dose linearity, dose-rate effect, angular response, source to surface (SSD) dependence, field size dependence, and dose calibration. RESULTS: The intrinsic precision of the diode was more than 1% (1 sigma). The linearity found in the whole range of dose analyzed was 1.93% (R2 = 1). The minimum and maximum variation in the measured and calculated dose were found to be 0.78% (with 25 MU at ioscentre) and 4.8% (with 1000 MU at isocentre), respectively. The maximal variation in angular response with respect to arbitrary angle 0 degrees found was 1.31%. The diode exhibited a 51.7% and 35% decrease in the response in the 35 cm and 20 cm SSD range, respectively. The minimum and the maximum variation in the measured dose from the diode and calculated dose were 0.82% (5 cm * 5 cm) and 3.75% (30 cm * 30 cm), respectively. At couch 270 degrees , the response of the diode was found to vary maximum by 1.4% with +/- 60 gantry angle. Mean variation between measured dose with diode and planned dose by TPS was found to be 1.3% (SD 0.75) for IMRT patient-specific quality assurance. CONCLUSION: For the evaluation of IMRT, use of cylindrical diode is strongly recommended. PMID- 22531522 TI - Correlation of fluorodeoxyglucose uptake and tumor-proliferating antigen Ki-67 in lymphomas. AB - OBJECTIVE: To investigate the correlation between cellular proliferation and the fluorodeoxyglucose (FDG) uptake in positron emission tomography/computed tomography (PET/CT) imaging by comparing 50 cases of different subtypes of lymphoma. MATERIALS AND METHODS: Fifty cases of lymphomas were collected. Each case was labeled with Ki-67 stain, a marker of cellular proliferation, and a PET/CT examination was performed. All lymphoma cases were sorted according to the World Health Organization's classification, and the International Non-Hodgkin's Lymphoma Working Formulation was used to differentiate groups of large and small cell non-Hodgkin's lymphoma. The Ki-67 staining was described as slight, mild, middle, or strong according to the nuclear staining of positive cells. FDG uptake by lesions in PET/CT images was semi-quantitatively analyzed to calculate the average standard uptake value. The statistics software SPSS13.0 was used to calculate the mean and standard deviation of the FDG uptake value of the lymphoma subtypes, the difference between the large and small cell lymphoma group with a Student's t-test, and the correlation between the Ki-67 level and FDG uptake of lesion with a Spearman's analysis. RESULTS: The FDG uptake value of large cell origin lymphoma was significantly higher than that of small cell origin lymphoma (t = 6.19, P < 0.01). The correlation coefficients between the Ki-67 level and FDG uptake value in lymph nodal and extranodal lesions was 0.750 and 0.843, respectively. CONCLUSIONS: Ki-67 staining, a reflection of tumor-proliferation activity, was significantly related to the FDG uptake value in lymphoma lesions. PMID- 22531521 TI - Reconstruction of oncological oro-mandibular defects with double skin paddled free fibula flap: a prudent alternative to double flaps in resource-constrained centres. AB - OBJECTIVE: The free fibula flap is the choice flap for mandibular reconstruction following extensive tumor resections. While large defects are managed with a second flap [free or pedicle] in advanced centres, a free fibula flap with a large skin paddle that can be de-epithelised to provide outer skin and inner lining is the best alternative in resource- constrained centres. MATERIALS AND METHODS: From January 2005 to December 2009 a total of 386 free fibula flaps were used of which 307 flaps had de-epithelised double skin paddle in reconstructing complex oral and mandibular defects after tumor ablative surgeries. RESULTS: Complete flap survival was seen in 282/307 patients. Complete flap loss was seen in 9/307 patients. Partial flap loss was seen in 16 patients. Re - exploration was done in 30 patients and the flap was salvaged in 21 patients. CONCLUSION: The vascular supply of the free fibula osteo myocutaneous flap is reliable and a flap with a large skin paddle can be used to provide both inner lining and outer cover in resource-constrained centres. PMID- 22531523 TI - Radiologic and pathologic correlation of aneurysmal bone cysts at unusual sites. AB - Aneurysmal bone cyst (ABC) is a benign solitary lesion. It usually occurs in the long bones but uncommonly in the calcaneum, mandible, femur and clavicle. Its frequency of occurrence in skull and mandible is 4%, clavicle and ribs is 5%, femur is 13% and foot is 3%. Only a few cases of ABC of these unusual sites have been reported till date. Here we report four cases of ABC at unusual sites namely the calcaneum, mandible, femur and clavicle diagnosed primarily on the basis of different imaging modalities and later confirmed on histopathology. PMID- 22531524 TI - F-18 flourodeoxyglucose positron emission tomography/computed tomography findings in a case of hepatosplenic T-cell lymphoma. AB - T-cell lymphoma (TCL) is a biologically diverse and uncommon group of lymphoid malignant diseases. Compared with its B-cell counterparts, TCL is notably more difficult to diagnose and manage owing to its rarity and biologic heterogeneity. Hepatosplenic TCL is an extremely rare subtype of TCL. A 37-year-old Indian male presented to his physician with swelling and pain in left hypochondrium. Clinical examination revealed pallor, icterus and massive splenomegaly. His blood examination revealed pancytopenia. His bone marrow biopsy was suggestive of lymphoma. Whole body F-18 flourodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) scan revealed diffuse increased metabolic activity in massively enlarged spleen, liver and bone marrow. There was no evidence of metabolically active lymphadenopathy anywhere in the body. Guided by the FDG PET/CT findings, a liver biopsy was advised. Liver histopathology revealed the presence of hepatosplenic TCL. A final diagnosis of hepatosplenic TCL with liver, spleen and bone marrow involvement was made. Even though rare, hepatosplenic TCL should be considered as a possible diagnosis in patients presenting with similar clinical picture and FDG PET/CT scan findings. PMID- 22531525 TI - Primary leiomyosarcoma of epididymis. AB - Primary leiomyosarcomas rarely arise from epididymis. But they are the most common histopathological types of sarcoma arising from the epididymis. Primary epididymal leiomyosarcoma occurs usually in older patients. We report a young patient of 35 years presenting with leiomyosarcoma of left epididymis. He did not have any metastasis and underwent left high inguinal orchiectomy. He is on regular follow-up and disease free for last two years. PMID- 22531526 TI - Classic Kaposi's sarcoma with colonic involvement: a rare presentation with successful treatment with oral etoposide. AB - Kaposi's sarcoma (KS) is currently regarded as a low-grade vascular malignancy. KS is a multicentric and multisystem disease that involves the skin and less commonly visceral organs, such as the gastrointestinal system including colonic involvement. KS with colonic involvement in HIV-negative patients is a rare clinical manifestation. In this regard, we report an immunocompetent, HIV negative elderly female patient with classic KS presenting with colonic involvement. PMID- 22531528 TI - Malignant fibrous histiocytoma of the spleen: an extremely rare entity. AB - Primary malignant fibrous histiocytoma (MFH) of the spleen is extremely rare. Since the first description of primary splenic MFH reported by Govoni et al in 1982, to the best of our knowledge, only twelve cases of MFH of the spleen have been reported in the literature. We herein report a rare case of primary splenic MFH in a 30-year-old Indian male who presented with abdominal pain with a history of recurrent hydatid cyst of liver and spleen. A computed tomography (CT) scan was performed and a diagnosis of splenic hydatid cyst was made. Splenectomy was done. On histopathological examination, a diagnosis of malignant mesenchymal tumor, possibly storiform variant of malignant fibrous histiocytoma, was made. On immunohistochemistry, the tumor was positive for vimentin and CD68. The post operative period was uneventful. Compared with the twelve previously cases of MFH of the spleen, our patient is the youngest case reported so far. PMID- 22531527 TI - Complete response to chemotherapy in primary hepatic lymphoma. AB - Primary hepatic lymphoma is an uncommon lymphoid tumor with varied clinical presentations and treatment outcomes. The median age of involvement is 50 years (male preponderance) with median survival as 8-16 months. Here we report a 68 years-old female who presented with right hypochondriac pain and anorexia with hepatomegaly on physical examination. Ultrasonography (USG) with subsequent contrast enhanced computed tomography (CECT) of abdomen depicted a hypoechoic mass in the left lobe of liver. CECT of chest and neck showed no abnormality. Liver biopsy proved to be Non-Hodgkin lymphoma (NHL) diffuse large B cell type, CD20 positive. Bone marrow examination showed no infiltration by NHL. The patient was started on three weekly R-CHOP, given a total of 8 cycles. Patient attained a complete remission documented by negative computed tomography (CT) and positron emission tomography (PET) scans. PMID- 22531529 TI - Colorectal carcinoma in a ten-year-old girl: a case report. AB - Colorectal carcinoma is very rare in childhood. In this case report, we depict a ten-year-old girl who presented with features of intestinal obstruction which turned out to be due to poorly differentiated mucin secreting adenocarcinoma of descending colon. Only increased awareness of this malignancy in this age-group and a high index of suspicion can help when a child complains of persistent pain of abdomen, altered bowel habits or rectal bleeding, and may provide diagnosis at an earlier stage, thereby improving the prognosis. PMID- 22531530 TI - Chondrosarcoma of the distal phalanx of the right great toe: report of a rare malignancy and review of literature. AB - Foot is an uncommon site for chondrosarcoma and involvement of phalanges is extremely rare. Here, a case of low-grade chondrosarcoma of the distal phalanx of the right great toe in a 37-year-old male patient is being reported. The patient complained of gradual swelling of the right great toe and pain for last 2 years. X-ray showed a lytic lesion destroying the distal phalanx with soft tissue extension. Amputation of the great toe was done and specimen was sent for histopathological examination. Microscopical examination revealed grade 1 chodrosarcoma infiltrating the surrounding soft tissue and muscle. The patient is on 1-year follow-up which is uneventful. PMID- 22531531 TI - Lymphadenopathy resulting from acute toxoplasmosis mimicking relapse of non Hodgkin's lymphoma on fluorodeoxyglucose positron emission tomography/computed tomography. AB - We report a case documenting fluorodeoxyglucose (FDG) accumulation in cervical, supraclavicular and axillary lymph nodes resulting from acute toxoplasmosis. A 50 year-old Indian female with history of non-Hodgkin's lymphoma (NHL) of left breast, postchemotherapy status, was found to have hypermetabolic right cervical, supraclavicular and axillary lymph nodes on a surveillance FDG positron emission tomography/computed tomography (PET/CT) scan. Her previous two PET/CT scans were unremarkable with no evidence of metabolically active disease. Therefore, a differential diagnosis of relapse of NHL versus infectious/inflammatory pathology was raised in the report. Biopsy of axillary lymph node demonstrated features characteristic of toxoplasmosis. The serological test results were also compatible with acute toxoplasmosis infection. Infective and inflammatory diseases are known to accumulate FDG, resulting in false positives for malignancy. This case demonstrates lymph nodal toxoplasmosis as a potential cause of false positive FDG PET/CT findings in patients with known malignancy and highlights the importance of histopathological and laboratory correlation for the accurate interpretation of FDG PET/CT scans. PMID- 22531532 TI - Synchronous bilateral medullary carcinoma of breast: is it metastasis or second primary? AB - Bilateral breast cancer is a rare event accounting for 2-5% of all breast malignancies. A second tumor in contralateral breast may be either synchronous or metachronous lesion. Synchronous bilateral invasive ductal carcinoma is known but medullary carcinoma is rare. The etiology of bilateral breast cancer is uncertain and prognosis in these cases once thought to be poor but recent data suggest a similar survival compared to unilateral disease. We report a case of triple negative synchronous bilateral medullary carcinoma in a 38-year-old female who presented with lump in both the breasts for three months. Multidetector computed tomography breast scan revealed bilateral heterogeneously enhancing well-defined lesion in both the breasts. Fine needle aspiration cytology from both the breast lump was suggestive of malignancy. Patient underwent bilateral modified radical mastectomy with axillary clearance in a single sitting. Histopathology showed synchronous bilateral medullary carcinoma of breast with ER, PR and HER- 2/ neu negativity. Patient was treated with chemoradiation and she is on regular follow up for one year without any recurrence or metastasis. PMID- 22531533 TI - Acute leukemic appendicitis in a patient with acute promyelocytic leukemia. AB - Leukemic and lymphomatous infiltration of the appendix is a rare complication. We present the case of a 31-year-old male with acute promyelocytic leukemia who developed acute abdomen on day 11 of induction chemotherapy with idarubicin and cytarabine. After appropriate work-up, a clinical diagnosis of acute appendicitis was made. Despite severe pancytopenia, he successfully underwent laparoscopic appendectomy. The final pathology revealed leukemic infiltration of the appendix. It is hypothesized that the leukemic infiltration may play a role in the development of acute appendicitis. Further, this case demonstrates the need to maintain a high index of suspicion and prompt surgical intervention for surgical pathologies in neutropenic patients. PMID- 22531534 TI - Primary diffuse large B cell lymphoma of the base of tongue. AB - Primary non-Hodgkin's lymphoma of tongue is very rare. We report a case of an elderly female who presented with a mass lesion and pain primarily involving the tongue and was diagnosed with diffuse large B cell lymphoma. Computed tomography revealed a 3-cm enhanced mass localized to the right tongue base. The patient was treated with three cycles of combination rituximab and CHOP chemotherapy, followed by external beam radiotherapy. The patient had a complete response after treatment, and three years following treatment, the patient has no signs of recurrence. PMID- 22531535 TI - Long-term survival in a patient with metastatic oropharynx squamous cell carcinoma to liver. AB - The traditionally held view is that the patients with metastatic disease cannot be cured and should be treated palliatively as it was believed that the patients will eventually succumb to the disease progression due to lack of effective treatments for systemic disease. In this article, we report our experience in a patient who was diagnosed with metastatic oropharynx squamous cell carcinoma to the liver, who has now survived five years since the original diagnosis, and is three years disease free. This case report illustrates the curative potential in selected patients with limited burden of metastatic disease with aggressive local therapy to all known sites of disease. It underscores the importance of imaging modalities in monitoring progression of disease, and most importantly illustrates the importance of multidisciplinary care for oncology patients. PMID- 22531536 TI - Rare case of extraskeletal Ewings sarcoma of the sinonasal tract. AB - Ewings sarcoma (ES) and primitive neuroectodermal tumor are closely related family of small round cell tumors seen in childhood and adolescence. The incidence of these tumors occurring in the head and neck region is just 2-7%. Mandible and maxilla are the most common sites, whereas involvement of the sinonasal tract is very rare. We report a case of extraskeletal ES of the sinonasal tract in a 29-year-old female who presented with nasal obstruction and epistaxis. The patient was treated with 14 cycles of chemotherapy, combined with surgery and radiotherapy with complete recovery. We present this case due to its rarity, to analyze the clinical, histopathological and immunohistochemical findings, so as to differentiate from other small round cell tumors of the sinonasal tract for appropriate treatment. PMID- 22531537 TI - Meningioma with hemorrhagic onset: two case reports. AB - Haemorrhage is a rare complication of meningiomas that can occur spontaneously, after embolization, stereotactic radiation and perioperatively. Our first case was a 16 year old male, admitted with spastic quadriparesis, and retention of urine. Magnetic Resonance Imaging (MRI) revealed anteriorly placed cervical intradural extramedullary mass. Patient underwent emergency surgery following sudden worsening of neurological symptoms and intratumoral bleed was noted peroperatively. Tumor was labeled as angiomatous meningioma with hemorrhage. The second case was of a 45 year female who presented with history of sudden onset weakness in right upper and lower limb followed by unconsciousness. MRI revealed heterogeneous lesion in left parasagittal area with intratumoral bleed. Left frontal craniotomy with tumour decompression was performed. Tumour was labelled as meningothelial meningioma with haemorrhage. Meningiomas with hemorrhagic onset remain rare, and pathophysiology is still incompletely understood. Prevention and outcome of intratumoral haemorrhage highly depends on early diagnosis and adequate treatment. PMID- 22531538 TI - Squamotous-type sarcomatoid carcinoma of the lung with rhabdomyosarcomatous components. AB - Lung carcinosarcoma is an infrequently biphasic tumor composed of carcinomatous and sarcomatous components. It is divided into endobronchial (squamous-type) and peripheral (glandular type) categories. The carcinomatous component is usually a squamous carcinoma, and the sarcomatous component usually resembles a fibrosarcoma or a malignant fibrous histiocytoma. The presence of rhabdomyoblastic differentiation in such neoplasms is exceedingly rare. There are strong associations with smoking and asbestosis. In this study, we describe a unique case of a 43-year-old man with a 75 packet/year smoking history in whom a rare mixed malignant tumor of the lung was diagnosed and treated by left pneumonectomy. Histological examination of the resected specimen showed squamous cell carcinoma and rhabdomyosarcoma components. Although rare, the association of a sarcomatoid carcinoma of the lung with squamous cell carcinoma and rhabdomyosarcomatous component is possible and should be kept in mind when dealing with these unusual tumors. PMID- 22531539 TI - Obesity as the initial manifestation of central nervous system relapse of acute lymphoblastic leukemia: case report and literature review. AB - A 6-year-old boy with acute lymphoblastic leukemia in remission experienced hyperphagia, obesity, and emotional disorders. Cytomorphologic examination of cerebral spinal fluid (CSF) and cranial MRI did not help in differentiating between central nervous system leukemia (CNSL) and other CNS diseases including tuberculosis in this boy. Flow cytometric CSF analysis on repeated lumber puncture detected lymphoblasts, while microscopic CSF examination did not definitively show relapse disease. The diagnosis of CNSL was thus made and confirmed by the response to leukemia treatment. Obesity can be the first manifestation of CNSL and the diagnosis can be challenging. A combination of CSF cytomorphology, CSF flow cytometry, and cranial MRI can be useful in the diagnosis of the disease. Two mechanisms of CNSL-related obesity are discussed based on the literature review. PMID- 22531540 TI - Erlotinib-induced acute interstitial lung disease associated with extreme elevation of the plasma concentration in an elderly non-small-cell lung cancer patient. AB - We herein describe a case of drug-induced interstitial lung disease (ILD) following treatment with erlotinib. The plasma trough concentration of erlotinib at the time of the ILD diagnosis was extremely elevated compared with the plasma maximum concentration on day 1. We hypothesized that this phenomenon was associated with the pharmacodynamic interaction with a concomitant drug. The present case indicates that erlotinib-induced ILD was associated with a high plasma concentration of erlotinib. Oncologists should be aware of the possibility of ILD induced by erlotinib, especially for patients with co-morbidities. PMID- 22531541 TI - Giant lipoblastoma of the thigh: a rare soft tissue tumor in an infant. AB - Lipoblastoma is a rare lipomatous tumor encountered almost exclusively in infants and young children. It arises from embryonic white fat. The common site of involvement is the extremities. In spite of their potential for local invasion, they are benign tumors. We report a case of a lipoblastoma in an infant and review the literature pertaining to clinical management of these tumors. PMID- 22531542 TI - Branch chain amino acid supplementation for correction of ascites in liver cancer postembolization. PMID- 22531543 TI - Primary thyroid lymphoma arising from Hashimotos thyroiditis diagnosed by fine needle aspiration cytology. PMID- 22531544 TI - Isolated axillary lymph node metastasis at presentation in bronchogenic carcinoma. PMID- 22531546 TI - Arabs and kaposi sarcoma. PMID- 22531545 TI - The neurobiological basis of anti-cancer therapy induced cognitive dysfunction and the promising pharmacological modalities against the same. PMID- 22531547 TI - Lesson for management of cancerous patient in the big flooding. PMID- 22531548 TI - Mouthparts and stylet penetration of the lac insect Kerria lacca (Kerr) (Hemiptera:Tachardiidae). AB - Hitherto less known aspects on mouthpart morphology and penetration mechanism of the lac insect Kerria lacca have been explored. Unique details of the mouthparts, i.e. morphology of labium and stylets and salivary sheath have been brought out. The gross morphology of the mouthparts though resembled other plant sucking homopterans; a two-segmented labium with symmetrically distributed six pairs of contact-chemoreceptors on its surface was distinct; the mandibular stylets had serrations on its extreme apical region, while the maxillary stylets had their external surface smooth with parallel longitudinal grooves on their inner surface. Formation of flanges, salivary sheath and penetration pathway observed along with probing and penetration of the stylets intracellularly up to the phloem cells, as illustrated herein, are the addition to the existing knowledge on the structural details of the mouthparts and the feeding behavior thereupon. PMID- 22531550 TI - Cortical plasticity in the face of congenitally altered input into V1. PMID- 22531549 TI - The emergence of adolescent onset pain hypersensitivity following neonatal nerve injury. AB - BACKGROUND: Peripheral nerve injuries can trigger neuropathic pain in adults but cause little or no pain when they are sustained in infancy or early childhood. This is confirmed in rodent models where neonatal nerve injury causes no pain behaviour. However, delayed pain can arise in man some considerable time after nerve damage and to examine this following early life nerve injury we have carried out a longer term follow up of rat pain behaviour into adolescence and adulthood. RESULTS: Spared nerve injury (SNI) or sham surgery was performed on 10 day old (P10) rat pups and mechanical nociceptive reflex thresholds were analysed 3, 7, 14, 21, 28, 38 and 44 days post surgery. While mechanical thresholds on the ipsilateral side are not significantly different from controls for the first 2-3 weeks post P10 surgery, after that time period, beginning at 21 days post surgery (P31), the SNI group developed following early life nerve injury significant hypersensitivity compared to the other groups. Ipsilateral mechanical nociceptive threshold was 2-fold below that of the contralateral and sham thresholds at 21 days post surgery (SNI-ipsilateral 28 (+/- 5) g control groups 69 (+/- 9) g, p < 0.001, 3-way ANOVA, n = 6 per group). Importantly, no effect was observed on thermal thresholds. This hypersensitivity was accompanied by macrophage, microglial and astrocyte activation in the DRG and dorsal horn, but no significant change in dorsal horn p38 or JNK expression. Preemptive minocycline (daily 40 mg/kg, s.c) did not prevent the effect. Ketamine (20 mg/kg, s.c), on the other hand, produced a dose-dependent reversal of mechanical nociceptive thresholds ipsilateral to the nerve injury such that thresholds return to control levels at the highest doses of 20 mg/Kg. CONCLUSIONS: We report a novel consequence of early life nerve injury whereby mechanical hypersensitivity only emerges later in life. This delayed adolescent onset in mechanical pain thresholds is accompanied by neuroimmune activation and NMDA dependent central sensitization of spinal nociceptive circuits. This delayed onset in mechanical pain sensitivity may provide clues to understand the long term effects of early injury such as late onset phantom pain and the emergence of complex adolescent chronic pain syndromes. PMID- 22531551 TI - Role of visuo-spatial working memory in path integration disorders in neglect. AB - This paper investigates the relationship between memory deficits and navigational ability in neglect. In recent studies (Piccardi et al., 2008a, 2010; Bianchini et al., 2010), a dissociation was found in visuo-spatial memory for peripersonal/reaching space and visuo-spatial memory for navigational space, suggesting that the latter is processed by a specific system devoted to storing environmental information for navigational purposes (Piccardi et al., 2010). Specific deficits have also been described in neglect patients in navigational tasks requiring to memorize and retrieve a target location in a real environment. In order to analyze the relation between visuo-spatial memory for different type of space (reaching vs navigational) and its relation with navigational processes, in the present study, we compared the performance of right brain-damaged patients with and without neglect on visuo-spatial memory both in peripersonal/reaching (Corsi Block-Tapping test) and in navigational (Walking Corsi test Laser) space with performances on navigational tests (a human version of the Morris Water Maze). Results indicate that a specific deficit in navigational working memory affects navigational ability in neglect patients. Indeed, neglect patients' difficulty in using path integration to navigate in the environment is directly correlated with a deficit in visuo-spatial working memory. These results support the existence of a specific memory system devoted to representing environmental information for navigational purposes and separate from visuo-spatial memory systems, which stores information in peripersonal/reaching space. PMID- 22531552 TI - Vision of the body and the differentiation of perceived body side in touch. AB - Although tactile representations of the two body sides are initially segregated into opposite hemispheres of the brain, behavioural interactions between body sides exist and can be revealed under conditions of tactile double simultaneous stimulation (DSS) at the hands. Here we examined to what extent vision can affect body side segregation in touch. To this aim, we changed hand-related visual input while participants performed a go/no-go task to detect a tactile stimulus delivered to one target finger (e.g., right index), stimulated alone or with a concurrent non-target finger either on the same hand (e.g., right middle finger) or on the other hand (e.g., left index finger=homologous; left middle finger=non homologous). Across experiments, the two hands were visible or occluded from view (Experiment 1), images of the two hands were either merged using a morphing technique (Experiment 2), or were shown in a compatible vs incompatible position with respect to the actual posture (Experiment 3). Overall, the results showed reliable interference effects of DSS, as compared to target-only stimulation. This interference varied as a function of which non-target finger was stimulated, and emerged both within and between hands. These results imply that the competition between tactile events is not clearly segregated across body sides. Crucially, non-informative vision of the hand affected overall tactile performance only when a visual/proprioceptive conflict was present, while neither congruent nor morphed hand vision affected tactile DSS interference. This suggests that DSS operates at a tactile processing stage in which interactions between body sides can occur regardless of the available visual input from the body. PMID- 22531554 TI - Avian reovirus sigma C enhances the mucosal and systemic immune responses elicited by antigen-conjugated lactic acid bacteria. AB - Mucosal surfaces are common sites of pathogen colonization/entry. Effective mucosal immunity by vaccination should provide protection at this primary infection site. Our aim was to develop a new vaccination strategy that elicits a mucosal immune response. A new strain of Enterococcus faecium, a non pathogenic lactic acid bacteria (LAB) with strong cell adhesion ability, was identified and used as a vaccine vector to deliver two model antigens. Specifically, sigma (sigma) C protein of avian reovirus (ARV), a functional homolog of mammalian reovirus sigma1 protein and responsible for M-cell targeting, was administered together with a subfragment of the spike protein of infectious bronchitis virus (IBV). Next, the effect of immunization route on the immune response was assessed by delivering the antigens via the LAB strain. Intranasal (IN) immunization induced stronger humoral responses than intragastic (IG) immunization. IN immunization produced antigen specific IgA both systemically and in the lungs. A higher IgA titer was induced by the LAB with ARV sigmaC protein attached. Moreover, the serum of mice immunized with LAB displaying divalent antigens had much stronger immune reactivity against ARV sigmaC protein compared to IBV-S1. Our results indicate that ARV sigmaC protein delivered by LAB via the IN route elicits strong mucosal immunity. A needle-free delivery approach is a convenient and cost effective method of vaccine administration, especially for respiratory infections in economic animals. Furthermore, ARV sigmaC, a strong immunogen of ARV, may be able to serve as an immunoenhancer for other vaccines, especially avian vaccines. PMID- 22531553 TI - Serum BAFF and APRIL levels in patients with IgG4-related disease and their clinical significance. AB - INTRODUCTION: B cell-activating factor of the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) play a crucial role in B cell development, survival, and antibody production. Here we analyzed the serum levels of BAFF and APRIL and their respective clinical associations in patients with an immunoglobulin (Ig) G4-related disease (IgG4-RD). METHODS: We measured serum levels of BAFF and APRIL in patients with IgG4-RD, primary Sjogren's syndrome (pSS), and healthy individuals. Serum BAFF and APRIL levels in IgG4-RD were assessed for correlations with serological parameters, including Ig, particularly IgG4, and the number of affected organs. Serum BAFF and APRIL levels in IgG4-RD were monitored during glucocorticoid (GC) therapy. RESULTS: Serum BAFF and APRIL levels in patients with IgG4-RD were significantly higher (P < 0.01) than in healthy individuals. The BAFF levels of patients with IgG4-RD were comparable to those of patients with pSS. Although clinical parameters, such as serum IgG4 and the number of affected organs, were not correlated with the levels of BAFF, serum APRIL levels were inversely correlated with serum IgG4 levels (r = -0.626, P < 0.05). While serum BAFF levels decreased following GC therapy, serum APRIL levels increased during follow-up. CONCLUSION: These results indicate that BAFF and APRIL might be useful markers for predicting disease activity in IgG4-RD. Further studies are needed to elucidate the role of BAFF and APRIL in the pathogenesis of IgG4-RD. PMID- 22531555 TI - An efficient statistical algorithm for a temporal scan statistic applied to vaccine safety analyses. AB - In the US, the Vaccine Safety Datalink (VSD) project, sponsored by the Centers for Disease Control and Prevention, conducts near-real-time, population-based, active surveillance for vaccine safety. One of the steps in analyzing signals, if there are enough cases, is to apply temporal scan statistics. The purpose is to determine if the cases clustered in time within an overall a priori defined post vaccination observation interval. We presented a relatively efficient and accurate algorithm for the purely temporal scan statistic as applied to vaccine safety investigations. It only needs SAS/BASE((r)) software, and the algorithm is simple enough to be programmed in another software languages. Our present work is focused on incorporating the temporal scan statistic algorithm within our previous approach for finding an optimal risk window for studies of vaccine safety. PMID- 22531556 TI - Infected dendritic cells are sufficient to mediate the adjuvant activity generated by Venezuelan equine encephalitis virus replicon particles. AB - Replicon particles derived from Venezuelan equine encephalitis virus (VEE) are infectious non-propagating particles which act as a safe and potent systemic, mucosal, and cellular adjuvant when delivered with antigen. VEE and VEE replicon particles (VRP) can target multiple cell types including dendritic cells (DCs). The role of these cell types in VRP adjuvant activity has not been previously evaluated, and for these studies we focused on the contribution of DCs to the response to VRP. By analysis of VRP targeting in the draining lymph node, we found that VRP induced rapid recruitment of TNF-secreting monocyte-derived inflammatory dendritic cells. VRP preferentially infected these inflammatory DCs as well as classical DCs and macrophages, with less efficient infection of other cell types. DC depletion suggested that the interaction of VRP with classical DCs was required for recruitment of inflammatory DCs, induction of high levels of many cytokines, and for stable transport of VRP to the draining lymph node. Additionally, in vitro-infected DCs enhanced antigen-specific responses by CD4 and CD8 T cells. By transfer of VRP-infected DCs into mice we showed that these DCs generated an inflammatory state in the draining lymph node similar to that achieved by VRP injection. Most importantly, VRP-infected DCs were sufficient to establish robust adjuvant activity in mice comparable to that produced by VRP injection. These findings indicate that VRP infect, recruit and activate both classical and inflammatory DCs, and those DCs become mediators of the VRP adjuvant activity. PMID- 22531557 TI - Prophylactic treatment with Toll-like receptor ligands enhances host immunity to avian influenza virus in chickens. AB - Avian influenza viruses (AIV) pose a threat towards the health of both poultry and humans. To interrupt the transmission of the virus, novel prophylactic strategies must be considered which may reduce the shedding of AIV. One potential is the prophylactic use of Toll-like receptor (TLR) ligands. Many cells of the immune system express TLRs, and cellular responses to TLR stimulation include activation and the production of cytokines. TLR ligands have been employed as prophylactic treatments to enhance host resistance to pathogens both in mammals and chickens. Therefore, the present study was conducted to determine whether TLR ligands may be used prophylactically in chickens to enhance host immunity to AIV. Chickens received intramuscular injections of either low or high doses of the TLR ligands poly I:C, lipopolysaccharide (LPS) and CpG ODN. Twenty-four hours post treatment, chickens were infected with the low pathogenic avian influenza virus H4N6, and both oropharyngeal and cloacal virus shedding were assessed on days 4 and 7 post-infection. To identify potential correlates of immunity, spleen and lungs were collected on days 2, 4 and 7 post-infection for RNA extraction. The results suggested that all of the TLR ligand treatments induced a significant reduction in virus shedding, with the TLR3 ligand poly I:C conferring the greatest AIV immunity compared to control birds, followed by CpG ODN and LPS. Furthermore, transcriptional analysis of gene expression in the spleen and lungs suggest IFN-alpha and IL-8 as correlates of immunity conferred by poly I:C, and IFN-gamma for CpG ODN and LPS. In conclusion, TLR ligands, have the ability to enhance host immunity against AIV, and future studies should consider exploring the combinatory effects of poly I:C and CpG ODN prophylaxis in conjunction with AIV vaccination. PMID- 22531558 TI - Significance and anamnestic response in isolated hepatitis B core antibody positive individuals 18 years after neonatal hepatitis B virus vaccination in Taiwan. AB - AIM: To investigate the significance of isolated hepatitis B core antibody (anti HBc) and to analyze the response to hepatitis B virus (HBV) booster vaccination in young adults with isolated anti-HBc who had been fully vaccinated with HBV vaccine as infants. MATERIALS AND METHODS: We screened 1734 new university entrants who had been fully vaccinated against HBV in infancy for the presence of hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and anti-HBc upon university entry. Results positive for isolated anti-HBc were reconfirmed by testing for the presence of HBsAg and anti-HBc once more, and further evaluated for anti-HCV, anti-HIV, and HBV DNA status 6 months later. Students were also offered HBV booster vaccinations at that time. Geometric mean titers (GMT) of anti-HBs after one booster dose of HBV were compared between students with isolated anti-HBc and students with HBV naive status. RESULTS: The overall prevalence of isolated anti-HBc in our student cohort was 1.2% (21 of 1734). No evidence of occult HBV infection was observed. A "booster" anamnestic response (anti-HBs titer >= 10 mIU/mL) was noted in 95% (20 of 21) of subjects with isolated anti-HBc. After re-measurement of anti-HBc, 13 (62%) of the 21 subjects with isolated anti-HBc were reclassified as having resolved HBV infection with a loss of anti-HBs. In the remaining 8 subjects (38%), isolated anti-HBc was determined to be false positive. The HBV status of these 8 subjects was HBV naive due to the waning-off effect of anti-HBs of the neonatal HBV vaccination. There was no significant difference in anamnestic response to a single HBV booster dose of vaccine between students with isolated anti-HBc (n=13) and those with HBV naive (n=323) status (GMT 50.6 vs 47.7 mIU/mL, P=0.90). CONCLUSION: The presence of isolated anti-HBc 18 years after HBV vaccination can be attributed to post-HBV infection with a loss of anti-HBs and to a decline in anti-HBs elicited by vaccine. A single HBV booster dose of vaccine is recommended for subjects with isolated anti-HBc who were fully vaccinated with HBV vaccine as infants. This finding needs to be replicated in further studies with larger cohorts. PMID- 22531559 TI - Sigh improves gas exchange and respiratory mechanics in children undergoing pressure support after major surgery. AB - BACKGROUND: Children undergoing major surgery can develop lung de-recruitment and gas exchange impairment in the postoperative period. The aim of this study was to assess the effect of periodic sigh breaths (Sighs) during pressure support ventilation (PSV) on gas exchange and respiratory pattern in children after major surgery. METHODS: Twenty children were enrolled and received PSV alone and with Sighs in a randomized order. Sighs were administered once per minute by adding to baseline pressure support a pressure controlled breath set at 30 cm H2O of peak airway pressure. At the end of each study period air flow, pressure traces, and compliance of respiratory system, together with hemodynamic parameters and venous and arterial blood gas tensions, were recorded. RESULTS: PaO2/FiO2 improved from baseline to Sigh group (312.6 +/- 137.4 vs. 394.2 +/- 127.0; P<0.01) and PaCO2 decreased from baseline to Sigh group (39.3 +/- 3.3 vs. 34.3 +/- 4.6 mmHg; P<0.001), without any change in minute expiratory volume. Indexed to body weight compliance of respiratory system improved from baseline to Sigh group (0.85 +/- 0.35 vs. 1.01 +/- 0.30 mL/kg/cm H2O; P<0.01). There were no significant differences between the two groups for the hemodynamic parameters. CONCLUSION: The addition of one Sigh per minute during PSV in the post-operative period of children that underwent major surgery improved gas exchange and decreased respiratory drive without producing major short-term complications. Further long term studies are necessary to evaluate the efficacy and safety of Sigh in pediatric patients. PMID- 22531561 TI - Community acquired methicillin resistant Staphylococcus aureus pneumonia: an update for the emergency and intensive care physician. AB - Pneumonia caused by community-acquired (CA) methicillin-resistant Staphylococcus aureus (MRSA) among individuals without healthcare-associated (HA) risk factors was first recognized a decade ago. CA-MRSA has now been established as a pathogen responsible for rapidly progressive, frequently fatal disease manifesting as necrotizing pneumonia, severe sepsis and necrotizing fasciitis. The frequency of occurrence, risk factors, and optimal treatment of CA-MRSA pneumonia remain unclear and vary significantly across countries. CA-MRSA is resistant to beta lactam antimicrobials due to the acquisition of novel methicillin resistance genetic cassettes. Additionally many CA-MRSA strains produce Panton-Valentine leukocidin (PVL), due to which they probably exceed the virulence of hospital acquired MRSA isolates (HA-MRSA). CA-MRSA pneumonia requires early suspicion especially in young otherwise healthy individuals with rapidly evolving clinical picture presenting with cavitary consolidation, bilateral infiltrates, pleural effusion and hemoptysis. Prompt hospitalization and aggressive treatment with intravenous antibiotics is warranted to improve outcomes. Therapeutic approach for severe CA-MRSA infections and particularly pneumonia is generally the same as that for invasive HA-MRSA infections. New anti-MRSA agents and possible combinations are of great importance to be evaluated in the future. PMID- 22531562 TI - Adoption and implementation of the original strict glycemic control guideline is feasible and safe in adult critically ill patients. AB - BACKGROUND: Three trials of tight glucose control (TGC) found clinical benefit of normalization of blood glucose levels in the intensive care unit (ICU). Implementation of TGC was imperfect in subsequent trials, since attained blood glucose levels (BGLs) never reached the targets as in the original trials of TGC. We investigated whether implementation of the TGC guideline as used in the original trials of TGC is feasible and safe. METHODS: In this study 3 ICUs adopted and implemented the TGC guideline as used in the original trials of TGC using a multifaceted practice change strategy; 3 ICUs that did not change their blood glucose control guideline served as controls. TGC was practiced by physicians and nurses during the first 12-month (period-2), thereafter exclusively by nurses (period-3). Blood glucose metrics 12-month before (period 1) and 24-month after implementation of the guideline were compared. RESULTS: The analysis included 1321 in period-1, 1169 and 1006 patients in period-2, and -3, respectively, in the intervention ICUs, and 3110 patients in the control ICUs. After implementation of the new TGC guideline, patients in intervention ICUs had lower median BGLs (105 [IQR: 85-130] mg/dL vs. 119 [99-150] mg/dL in period-1, P<0.001; and vs. 113 [95-141] mg/dL in control ICUs, P<0.001). The incidence of severe hypoglycemia initially increased, but again decreased when exclusively nurses practiced TGC, and was not associated with increased mortality or morbidity. CONCLUSIONS: Implementation of the original TGC guideline is feasible and safe. Our study suggests a learning effect over time. PMID- 22531563 TI - Influence of different flow-triggering levels on the breathing effort of mechanically ventilated patients. AB - BACKGROUND: Although a sensitive flow triggering (FT) level is supposed to be associated with reduced breathing effort, the incidence of autotriggering (AT) is likely to be increased. The actual effects of various FT levels on the work of breathing and occurrence of AT in mechanically ventilated patients are unknown. We investigated the effects of different FT levels (1-8 L/min) on breathing effort and incidence of AT in mechanically ventilated patients under pressure support ventilation using a Puritan-Bennett 840 ventilator. METHODS: Eight FT levels were randomly studied in mechanically ventilated patients under pressure support ventilation. The triggering effort (pressure-time product of triggering, PTPtr) was assessed by quantitating a segment of the pressure-time product of the esophagus (PTPes). The total PTPes, inspiratory work of breathing (Wi) and P0.1 were determined. RESULTS: Nine patients with appropriately recorded signals were included. The incidence of AT significantly decreased with increasing FT level (FT1, 1 L/min: 30.7%, FT8: 0.2%). PTPtr significantly increased with increasing FT level (0.020 +/- 0.004 cmH2O * S in FT1 to 0.190 +/- 0.017 cmH2O * S in FT8), but P0.1 remained similar. PTPtr accounted for only1-3% of total PTPes. Wi and PTPes were significantly lower only at FT1, but there was no significant difference in Wi and PTPes at different FT levels when AT breaths were excluded. CONCLUSION: A higher FT level was associated with lower incidence of AT, but without a significant increase in breathing effort. A higher FT level may be more reasonable in mechanically ventilated patients with this particular ventilator. PMID- 22531564 TI - Ascites characterizes perioperative clinical indices better than preoperative body mass index. A study in orthotopic liver transplant candidates. AB - BACKGROUND: Preoperative body mass index (pre-BMI) affecting patients' recovery from orthotropic liver transplantation (OLT) is controversial. Pre-BMI measurements may be exaggerated by ascites. Aim of the study was the assessment of early outcome associated with pre-BMI and ascites. METHODS: Postoperative BMI values and ascites volumes of 206 patients undergoing OLT (2006-2007) were reviewed. RESULTS: There were 141 preoperatively "non-obese" patients (pre-BMI <= 30 kg/m2) and 65 "obese" patients (pre-BMI >30 kg/m2). Demographics and model for end-stage liver disease scores were similar for both groups. The mean volume of ascites removed from the "non-obese" patients was significantly larger compared to the "obese" ones (P=0.018). Seventeen "obese" patients became "non-obese" postoperatively. The duration of anesthesia, ischemia, surgery, hemodynamic parameters, estimated blood loss and transfused products were similar for both groups. Ascites volumes correlated significantly (P<0.05) with various intraoperative indices but not pre-BMI. At 24 h postoperatively, the extubation rate was better for the "obese" group (99%) versus the "non-obese" group (93%, P=0.03). However, "non-obese" patients were extubated earlier than the "obese" both by 6 h (45% versus 22%, respectively, P<0.01) and by 12 h (88% versus 74%, respectively, P=0.012). The postoperative, but not the preoperative BMI, correlated with extubation rate <= 6 h (r=0.924, P=0.0001). No "obese" patients died <1 month postoperatively, compared to 9 "non-obese" patients (P<0.01). Intensive Care Unit and hospital stay were ~25% longer for the "obese" group. CONCLUSION: Pre-OLT BMI does not correlate with ascites or postoperative BMI, nor does it affect duration of ventilation, especially <6 h after surgery. These results dissociate ascites from pre- and post-OLT. PMID- 22531565 TI - Ropivacaine-induced cardiac arrest and paraplegia after epidural anesthesia. PMID- 22531566 TI - High flow nasal oxygen in acute respiratory failure. AB - Use of high flow nasal cannula oxygen (HFNC) is increasingly popular in adult ICUs for patients with acute hypoxemic respiratory failure. This is the result of the successful long-term use of HFNC in the neonatal field and recent clinical data in adults indicating beneficial effects of HFNC over conventional facemask oxygen therapy. HFNC rapidly alleviates symptoms of respiratory distress and improves oxygenation by several mechanisms, including deadspace washout, reduction in oxygen dilution and in inspiratory nasopharyngeal resistance, a moderate positive airway pressure effect that may generate alveolar recruitment and an overall greater tolerance and comfort with the interface and the heated and humidified inspired gases. Indications of HFNC are broad, encompassing most if not all causes of acute hypoxemic respiratory failure. HFNC can also provide oxygen during invasive procedures, and be used to prevent or treat post extubation respiratory failure. HFNC may also alleviate respiratory distress in patients at a palliative stage. Although observational studies suggest that HFNC might reduce the need for intubation in acute hypoxemic respiratory failure; such a reduction has not yet been demonstrated. Beyond this potential additional effect on outcome, the evidence already published argues in favor of the large use of HFNC as first line therapy for acute respiratory failure. PMID- 22531569 TI - Transcutaneous electrical nerve stimulation on acupoints reduces fentanyl requirement for postoperative pain relief after total hip arthroplasty in elderly patients. AB - BACKGROUND: Transcutaneous electrical nerve stimulation (TENS) is regarded as an effective treatment for various types of pain. However, no randomized controlled trial has investigated TENS on acupoints for postoperative analgesia in elderly patients. This study aim to investigate whether TENS on acupoints has any favorable effect on complementary analgesia after total hip arthroplasty (THA) for elderly patients compared with a sham control treatment. METHODS: Sixty-eight elderly patients requiring THA surgery were enrolled and randomly allocated to one of two groups. Group Acu received true TENS on acupoints (bilateral P6, L14; ST36, GB31 ipsilateral to the surgery site) and Group Sham received sham treatment. All patients received patient-controlled analgesia for two days postoperatively. Analgesia was assessed by postoperative fentanyl requirement and pain intensity using a visual analogue scale (VAS-10 cm). The incidence of analgesia-related side effects, optional medication use and effects of patients' blinding were recorded. RESULTS: Fentanyl consumption in Group Acu was lower than that in Group Sham at 24 h (mean +/- SD; 360+/-117 vs. 572+/-132 MUg; P<0.001) and 48 h (712+/-184 vs. 1022+/-197 MUg; P<0.001) after surgery. Postoperative pain intensity measured by VAS was similar in both groups. The incidence of opioid-related side effects and rescue medication for postoperative analgesia was significantly higher in Group Sham than in Group Acu. Differences between the groups regarding the effects of patients' blinding were not significant. CONCLUSION: TENS on specific acupoints is an effective and complementary approach to reduce postoperative analgesic requirement in elderly patients after THA. PMID- 22531570 TI - Mg-Zr-Sr alloys as biodegradable implant materials. AB - Novel Mg-Zr-Sr alloys have recently been developed for use as biodegradable implant materials. The Mg-Zr-Sr alloys were prepared by diluting Mg-Zr and Mg-Sr master alloys with pure Mg. The impact of Zr and Sr on the mechanical and biological properties has been thoroughly examined. The microstructures and mechanical properties of the alloys were characterized using optical microscopy, X-ray diffraction and compressive tests. The corrosion resistance was evaluated by electrochemical analysis and hydrogen evolution measurement. The in vitro biocompatibility was assessed using osteoblast-like SaOS2 cells and MTS and haemolysis tests. In vivo bone formation and biodegradability were studied in a rabbit model. The results indicated that both Zr and Sr are excellent candidates for Mg alloying elements in manufacturing biodegradable Mg alloy implants. Zr addition refined the grain size, improved the ductility, smoothed the grain boundaries and enhanced the corrosion resistance of Mg alloys. Sr addition led to an increase in compressive strength, better in vitro biocompatibility, and significantly higher bone formation in vivo. This study demonstrated that Mg-xZr ySr alloys with x and y <=5 wt.% would make excellent biodegradable implant materials for load-bearing applications. PMID- 22531571 TI - Predictors of and health services utilization related to depressive symptoms among elderly Koreans. AB - While the prevalence, comorbidity, risk profile and health care utilization for late-life depression have been described for many Western countries, much less is known about the recent epidemiology of late-life depression in East Asian countries such as Korea. We investigated predictors for depressive symptoms and the association between depressive symptoms and the utilization of both medical care and preventive services in elderly Koreans. Data were obtained from a nationally representative sample of Koreans aged 60 and above (2226 men, 2911 women) who participated in the 2008 wave of the Korean Longitudinal Study of Ageing. Depressive symptoms were measured using the 10-item Center for Epidemiological Studies-Depression scale. Risk factors considered included sociodemographics, health behaviors, chronic diseases, and physical function. Health care utilization factors included hospitalization, outpatient clinic use and basic medical checkup. Being female, being unmarried, and having less education, lower household income, physical inactivity and lower weight were associated with depressive symptoms. Presence of chronic diseases and limited physical function also showed a significant association with depressive symptoms. Depressive symptoms were associated with increased odds of hospitalization and outpatient visits, but decreased the odds of utilization of basic medical checkup after controlling for potential confounders. Findings on most risk factors, except lower weight, were consistent with reports from Western countries. It is important to recognize the burden of depressive symptoms in the elderly. The interaction of such symptoms with chronic diseases should be acknowledged and considered in the clinical setting as well as in health care planning and policymaking. PMID- 22531572 TI - Linkages between maternal education and childhood immunization in India. AB - While correlations between maternal education and child health have been observed in diverse parts of the world, the causal pathways explaining how maternal education improves child health remain far from clear. Using data from the nationally representative India Human Development Survey of 2004-5, this analysis examines four possible pathways that may mediate the influence of maternal education on childhood immunization: greater human, social, and cultural capitals and more autonomy within the household. Data from 5287 households in India show the familiar positive relationship between maternal education and childhood immunization even after extensive controls for socio-demographic characteristics and village- and neighborhood-fixed effects. Two pathways are important: human capital (health knowledge) is an especially important advantage for mothers with primary education, and cultural capital (communication skills) is important for mothers with some secondary education and beyond. PMID- 22531573 TI - Feasibility of ecological momentary assessment of hearing difficulties encountered by hearing aid users. AB - OBJECTIVES: Measurement of outcomes has become increasingly important to assess the benefit of audiologic rehabilitation, including hearing aids, in adults. Data from questionnaires, however, are based on retrospective recall of events and experiences, and often can be inaccurate. Questionnaires also do not capture the daily variation that typically occurs in relevant events and experiences. Clinical researchers in a variety of fields have turned to a methodology known as ecological momentary assessment (EMA) to assess quotidian experiences associated with health problems. The objective of this study was to determine the feasibility of using EMA to obtain real-time responses from hearing aid users describing their experiences with challenging hearing situations. DESIGN: This study required three phases: (1) develop EMA methodology to assess hearing difficulties experienced by hearing aid users; (2) make use of focus groups to refine the methodology; and (3) test the methodology with 24 hearing aid users. Phase 3 participants carried a personal digital assistant 12 hr per day for 2 weeks. The personal digital assistant alerted participants to respond to questions four times a day. Each assessment started with a question to determine whether a hearing problem was experienced since the last alert. If "yes," then up to 23 questions (depending on contingent response branching) obtained details about the situation. If "no," then up to 11 questions obtained information that would help to explain why hearing was not a problem. Each participant completed the Hearing Handicap Inventory for the Elderly (HHIE) both before and after the 2 week EMA testing period to evaluate for "reactivity" (exacerbation of self perceived hearing problems that could result from the repeated assessments). RESULTS: Participants responded to the alerts with a 77% compliance rate, providing a total of 991 completed momentary assessments (mean = 43.1 per participant). A substantial amount of data were obtained with the methodology. It is important to note that participants reported a "hearing problem situation since the last alert" 37.6% of the time (372 responses). The most common problem situation involved "face-to-face conversation" (53.8% of the time). The next most common problem situation was "telephone conversation" (17.2%) followed by "TV, radio, iPod, etc." (15.3%), "environmental sounds" (9.7%), and "movies, lecture, etc." (4.0%). Comparison of pre- and post-EMA mean HHIE scores revealed no significant difference (p > 0.05), indicating that reactivity did not occur for this group. It should be noted, however, that 37.5% of participants reported a greater sense of awareness regarding their hearing loss and use of hearing aids. CONCLUSIONS: Results showed participants were compliant, gave positive feedback, and did not demonstrate reactivity based on pre- and post-HHIE scores. We conclude that EMA methodology is feasible with patients who use hearing aids and could potentially inform hearing healthcare (HHC) services. The next step is to develop and evaluate EMA protocols that provide detailed daily patient information to audiologists at each stage of HHC. The advantages of such an approach would be to obtain real-life outcome measures, and to determine within- and between-day variability in outcomes and associated factors. Such information at present is not available from patients who seek and use HHC services. PMID- 22531574 TI - Effects of frequency compression hearing aids for unilaterally implanted children with acoustically amplified residual hearing in the nonimplanted ear. AB - OBJECTIVES: The primary objective of this study is to evaluate the benefits of nonlinear frequency compression (NLFC) hearing aids in the nonimplanted ears of children with unilateral cochlear implants (CIs). It is hypothesized that speech perception performance will benefit from complementary auditory cues provided by the CI and the hearing aid, particularly with the increased access to high frequency sounds provided by NLFC. DESIGN: Eleven children using unilateral CIs with usable residual hearing in the nonimplanted ears were enrolled in the study and fitted with NLFC hearing aids. The test protocol included consonant-nucleus consonant words in quiet, the Hearing in Noise Test sentences presented in speech noise and two-talker maskers, and a consonant identification task. Subjects were tested in a CI-alone condition as well as bimodally, with and without NLFC enabled. RESULTS: The results support previous work in adults and children, demonstrating the beneficial effects of bimodal listening. Frequency compression did not significantly affect performance for the children enrolled in this study, although some preferred using NLFC. The results yield suggestions regarding test methods for pediatric bimodal listeners, and considerations regarding validation and audibility of the compressed signal. CONCLUSIONS: Hearing aid use in the contralateral ear of unilaterally implanted children is beneficial. Children and young adults who are fitted bimodally should be tested both in quiet and in complex listening situations to determine bimodal benefit. In the current test battery, the inclusion of frequency compression in the hearing aid fitting does not seem to provide significant improvement beyond standard hearing aid fittings or any bilateral interference symptoms for this group of bimodal listeners. PMID- 22531575 TI - Characteristics of noise exposure during solitary trumpet playing: immediate impact on distortion-product otoacoustic emissions and long-term implications for hearing. AB - OBJECTIVES: The objectives of this investigation were to quantify noise exposures generated during a 1 hr trumpet practice session and to determine whether distortion-product otoacoustic emissions (DPOAEs) are affected by such exposure, to describe the distribution of intensity levels and temporal characteristics of noise produced by trumpet practice, and to determine the effect of earplug use on generated noise levels and DPOAEs. DESIGN: In experiment 1, eight college-age trumpeters underwent an otoscopic inspection, tympanometry, and pure-tone threshold testing. Using a Grason-Stadler 60 DPOAE system, DPOAEs were recorded just before a 1 hr practice session, at 2 min after the practice session, 4 min after the session, and at 4 min intervals thereafter for a total period of 1 hr. A Hewlett-Packard 3569A Real-Time Frequency Analyzer was used to integrate noise levels to assess the overall level of exposure averaged over the course of the hour. In experiment 2, seven different trumpeters participated in two data collection sessions. The main difference between the sessions was that subjects wore E.A.R. earplugs during session 2. All other design parameters were similar to those of experiment 1. RESULTS: Noise levels generated during the practice sessions resulted in average Leqs of 95.96, 96.6, and 96.43 dB SPL. A sound distribution analysis revealed that noise levels exceeded 85 dB for an average of 43.73 min per session. Mean Leq values did not change when subjects wore earplugs (96.6 dB SPL versus 96.43 dB SPL.) Predictions (ISO 1999) of the increased risk of hearing loss that trumpeters would experience at 40, 50, and 60 years of age were made and indicated that trumpeters are at a significantly increased risk of hearing loss over that contributable to age alone. This increased risk is apparent with as little as 1 hr of exposure per day and suggests that 60-year-old male and female musicians exposed to trumpet noise for 4 hr per day for 40 years would be 85% and 300%, respectively, more likely to have hearing loss than their peers with negative noise exposure histories. Statistically significant decreases in DPOAE amplitudes from the prenoise exposure collection point to the 2 min post exposure point were observed only when subjects were not wearing earplugs during their practice session. Recovery of DPOAEs to baseline level varied in form for four test frequencies. CONCLUSION: During solitary play, trumpeters generate noise levels that temporarily decrease DPOAE amplitudes and that by themselves have the potential to result in permanent noise-induced hearing loss. Trumpeters who practice/perform over a period of years should be concerned about the implications of their craft on their hearing and should be offered personalized hearing conservation programs. The use of earplugs offers a practical and cost effective means of hearing protection and, for this group of trumpeters, did not lead to an increase in playing level. PMID- 22531576 TI - The formal potentials and electrode kinetics of the proton/hydrogen couple in various room temperature ionic liquids. AB - The Hydrogen evolution reaction has been quantitatively investigated at a Pt electrode in series of room temperature ionic liquids vs. Ag/Ag(+) redox couple. The measured formal potentials of the H(2)/H(+) (HNTf(2)) redox couple in each RTIL reveals a dependence on the nature of anion, suggesting significant interaction between proton and anion. PMID- 22531578 TI - The nursing home as a core site for educating residents and medical students. PMID- 22531577 TI - The crystal structure of the CRISPR-associated protein Csn2 from Streptococcus agalactiae. AB - The prokaryotic immune system, CRISPR, confers an adaptive and inheritable defense mechanism against invasion by mobile genetic elements. Guided by small CRISPR RNAs (crRNAs), a diverse family of CRISPR-associated (Cas) proteins mediates the targeting and inactivation of foreign DNA. Here, we demonstrate that Csn2, a Cas protein likely involved in spacer integration, forms a tetramer in solution and structurally possesses a ring-like structure. Furthermore, co purified Ca(2+) was found important for the DNA binding property of Csn2, which contains a helicase fold, with highly conserved DxD and RR motifs found throughout Csn2 proteins. We could verify that Csn2 binds ds-DNA. In addition molecular dynamics simulations suggested a Csn2 conformation that can "sit" on the DNA helix and binds DNA in a groove on the outside of the ring. PMID- 22531579 TI - Patient feedback via a national registry could improve physicians' CME. PMID- 22531581 TI - Bridging the leadership development gap: recommendations for medical education. PMID- 22531584 TI - Why course work in health policy and systems should be a premedical admission requirement. PMID- 22531585 TI - Teaching as a competency: practical suggestions. PMID- 22531586 TI - Commentary: Change we must: putting patients first with the institute model of academic health center organization. AB - In the traditional department-based organizational structure of an academic health center, patients can be neglected as a result of fragmented systems of care. Specialty-driven, provider-oriented, economically influenced organizations dominated by research and education missions might, paradoxically, promote too little concern for the patient. All three components (education, research, and patient care) of academic health centers' tripartite mission are sacred, but times have changed. Academic health centers must rethink their traditional approach to achieving their mission. The authors describe the evolution at the Cleveland Clinic of a unique, institute-based reorganization that is focused on integrated disease- and organ-system-based patient care, research, and education. The authors argue that this model better focuses on the patient as well as on the institution's academic charge. It is a concept that should be more widely adopted with deference to individual institutional culture and history. PMID- 22531589 TI - Teaching and learning moments: The hematomato: lessons from the ICU. PMID- 22531588 TI - Commentary: Institutes versus traditional administrative academic health center structures. AB - In the Point-Counterpoint section of this issue, Kastor discusses the pros and cons of a new, institute-based administrative structure that was developed at the Cleveland Clinic in 2008, ostensibly to improve the quality and efficiency of patient care. The real issue underlying this organizational transformation is not whether the institute model is better than the traditional model; instead, the issue is whether the traditional academic health center (AHC) structure is viable or whether it must evolve. The traditional academic model, in which the department and chair retain a great deal of autonomy and authority, and in which decision-making processes are legislative in nature, is too tedious and laborious to effectively compete in today's health care market. The current health care market is demanding greater efficiencies, lower costs, and thus greater integration, as well as more transparency and accountability. Improvements in both quality and efficiency will demand coordination and integration. Focusing on quality and efficiency requires organizational structures that facilitate cohesion and teamwork, and traditional organizational models will not suffice. These new structures must and will replace the loose amalgamation of the traditional AHC to develop the focus and cohesion to address the pressures of an evolving health care system. Because these new structures should lead to more successful clinical enterprises, they will, in fact, support the traditional academic missions of research and education more successfully than traditional organizational models can. PMID- 22531590 TI - Point-counterpoint: The Cleveland Clinic institute system is the right structure for academic health centers in the 21st century. PMID- 22531591 TI - Point-counterpoint: The traditional departmental model is the right structure for academic health centers in the 21st century. PMID- 22531592 TI - Teaching and learning moments: In midair. PMID- 22531593 TI - Medicine and the arts. Memoirs of a woman doctor: [excerpt] by Nawal El-Saadawi. Commentary. PMID- 22531595 TI - AM last page. Robert Gagne's nine events of instruction, revisited. AB - In 1965, Robert Gagne published The Conditions of Learning, which identified the mental conditions for learning. These were based on the information processing model of the mental events that occur when adults are presented with various stimuli.(1) PMID- 22531596 TI - Vascular compliance changes of the coronary vessel wall after bioresorbable vascular scaffold implantation in the treated and adjacent segments. AB - BACKGROUND: Implantation of a metallic prosthesis creates local stiffness with a subsequent mismatch in the compliance of the vessel wall, disturbances in flow and heterogeneous distribution of wall shear stress. Polymeric bioresorbable ABSORB scaffolds have less stiffness than metallic platform stents. We sought to analyze the mismatch in vascular compliance after ABSORB implantation and its long-term resolution with bioresorption. METHODS AND RESULTS: A total of 83 patients from the ABSORB trials underwent palpography investigations (30 and 53 patients from ABSORB Cohorts A and B, respectively) to measure the compliance of the scaffolded and adjacent segments at various time points (from pre implantation up to 24 months). The mean of the maximum strain values was calculated per segment by utilizing the Rotterdam Classification (ROC) score and expressed as ROC/mm. Scaffold implantation lead to a significant decrease in vascular compliance (median [IQR]) at the scaffolded segment (from 0.37 [0.24 0.45] to 0.14 [0.09-0.23], P<0.001) with mismatch in compliance in a paired analysis between the scaffolded and adjacent segments (proximal: 0.23 [0.12 0.34], scaffold: 0.12 [0.07-0.19], distal: 0.15 [0.05-0.26], P=0.042). This reported compliance mismatch disappears at short- and mid-term follow-up. CONCLUSIONS: The ABSORB scaffold decreases vascular compliance at the site of scaffold implantation. A compliance mismatch is evident immediately post implantation and in contrast to metallic stents disappears in the mid-term, likely leading to a normalization of the rheological behavior of the scaffolded segment. PMID- 22531597 TI - Did we misunderstand how to calculate total stroke work in mitral regurgitation by echocardiography? AB - BACKGROUND: Total stroke work (TSW) is used for the estimation of cardiac efficiency in mitral regurgitation (MR). We should be cautious about the interpretation of this parameter, especially when it is assessed by non-invasive methods such as echocardiography. METHODS AND RESULTS: For the calculation of regurgitant stroke work, regurgitant volume is usually multiplied by left atrial (LA) pressure. However, by considering the left ventricular (LV) pressure-volume loop, it would be more appropriate to multiply regurgitant volume and the LV pressure, not the atrial one. CONCLUSIONS: We might underestimate TSW when we use LA pressure for the estimation of regurgitant stroke work. PMID- 22531598 TI - Primary prevention with aspirin in type 2 diabetic patients. Searching for the right spot. PMID- 22531599 TI - In-vitro characterization of a cochlear implant system for recording of evoked compound action potentials. AB - BACKGROUND: Modern cochlear implants have integrated recording systems for measuring electrically evoked compound action potentials of the auditory nerve. The characterization of such recording systems is important for establishing a reliable basis for the interpretation of signals acquired in vivo. In this study we investigated the characteristics of the recording system integrated into the MED-EL PULSARCI100 cochlear implant, especially its linearity and resolution, in order to develop a mathematical model describing the recording system. METHODS: In-vitro setup: The cochlear implant, including all attached electrodes, was fixed in a tank of physiologic saline solution. Sinusoidal signals of the same frequency but with different amplitudes were delivered via a signal generator for measuring and recording on a single electrode.Computer simulations: A basic mathematical model including the main elements of the recording system, i.e. amplification and digitalization stage, was developed. For this, digital output for sinusoidal input signals of different amplitudes were calculated using in vitro recordings as reference. RESULTS: Using an averaging of 100 measurements the recording system behaved linearly down to approximately -60 dB of the input signal range. Using the same method, a system resolution of 10 MUV was determined for sinusoidal signals. The simulation results were in very good agreement with the results obtained from in-vitro experiments. CONCLUSIONS: The recording system implemented in the MED-EL PULSARCI100 cochlear implant for measuring the evoked compound action potential of the auditory nerve operates reliably. The developed mathematical model provides a good approximation of the recording system. PMID- 22531601 TI - Theories of behaviour change synthesised into a set of theoretical groupings: introducing a thematic series on the theoretical domains framework. AB - Behaviour change is key to increasing the uptake of evidence into healthcare practice. Designing behaviour-change interventions first requires problem analysis, ideally informed by theory. Yet the large number of partly overlapping theories of behaviour makes it difficult to select the most appropriate theory. The need for an overarching theoretical framework of behaviour change was addressed in research in which 128 explanatory constructs from 33 theories of behaviour were identified and grouped. The resulting Theoretical Domains Framework (TDF) appears to be a helpful basis for investigating implementation problems. Research groups in several countries have conducted TDF-based studies. It seems timely to bring together the experience of these teams in a thematic series to demonstrate further applications and to report key developments. This overview article describes the TDF, provides a brief critique of the framework, and introduces this thematic series.In a brief review to assess the extent of TDF based research, we identified 133 papers that cite the framework. Of these, 17 used the TDF as the basis for empirical studies to explore health professionals' behaviour. The identified papers provide evidence of the impact of the TDF on implementation research. Two major strengths of the framework are its theoretical coverage and its capacity to elicit beliefs that could signify key mediators of behaviour change. The TDF provides a useful conceptual basis for assessing implementation problems, designing interventions to enhance healthcare practice, and understanding behaviour-change processes. We discuss limitations and research challenges and introduce papers in this series. PMID- 22531602 TI - Chronic dietary toxicity and carcinogenicity study with ammonium perfluorooctanoate in Sprague-Dawley rats. AB - In order to assess the potential chronic toxicity and tumorigenicity of ammonium perfluorooctanoate (APFO), a 2-year dietary study was conducted with male and female rats fed 30 ppm or 300 ppm (approximately 1.5 and 15 mg/kg). In males fed 300 ppm, mean body weights were lower across most of the test period and survival in these rats was greater than that seen either in the 30 ppm or the control group. Non-neoplastic effects were observed in liver in rats fed 300 ppm and included elevated liver weight, an increase in the incidence of diffuse hepatocellular hypertrophy, portal mononuclear cell infiltration, and mild hepatocellular vacuolation without an increase in hepatocellular necrosis. Mean serum activities of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase were elevated up to three times the control means, primarily at the 300 ppm dose. A significant increase in Leydig cell tumors of the testes was seen in the males fed 300 ppm, and tumors of the liver and acinar pancreas, which are often observed in rats from chronic exposure to peroxisome proliferating agents, were not observed in this study. All other tumor types were those seen spontaneously in rats of this stock and age and were not associated with feeding of APFO. PMID- 22531603 TI - An efficient synthetic approach to 6,5'-(S)- and 6,5'-(R)-cyclouridine. AB - Here we present new routes for the efficient syntheses of 6,5'-(S)- and 6,5'-(R) cyclouridine. The syntheses utilize readily accessible uridine as a starting material. This route to the R diastereomer is significantly more efficient than previous synthetic efforts, allowing us to obtain large amounts of pure material for future biological testing. PMID- 22531600 TI - Early vascular deficits are correlated with delayed mammary tumorigenesis in the MMTV-PyMT transgenic mouse following genetic ablation of the NG2 proteoglycan. AB - INTRODUCTION: The neuron-glial antigen 2 (NG2) proteoglycan promotes pericyte recruitment and mediates pericyte interaction with endothelial cells. In the absence of NG2, blood vessel development is negatively impacted in several pathological models. Our goal in this study was to determine the effect of NG2 ablation on the early development and function of blood vessels in mammary tumors in the mammary tumor virus-driven polyoma middle T (MMTV-PyMT) transgenic mouse, and to correlate these vascular changes with alterations in mammary tumor growth. METHODS: Three different tumor paradigms (spontaneous tumors, transplanted tumors, and orthotopic allografts of tumor cell lines) were used to investigate the effects of NG2 ablation on breast cancer progression in the MMTV-PyMT transgenic mouse. In addition to examining effects of NG2 ablation on mammary tumor growth, we also investigated effects on the structure and function of tumor vasculature. RESULTS: Ablation of NG2 led to reduced early progression of spontaneous, transplanted, and orthotopic allograft mammary tumors. NG2 was not expressed by the mammary tumor cells themselves, but instead was found on three components of the tumor stroma. Microvascular pericytes, myeloid cells, and adipocytes were NG2-positive in both mouse and human mammary tumor stroma. The effect of NG2 on tumor progression therefore must be stromal in nature. Ablation of NG2 had several negative effects on early development of the mammary tumor vasculature. In the absence of NG2, pericyte ensheathment of endothelial cells was reduced, along with reduced pericyte maturation, reduced sprouting of endothelial cells, reduced assembly of the vascular basal lamina, and reduced tumor vessel diameter. These early deficits in vessel structure are accompanied by increased vessel leakiness, increased tumor hypoxia, and decreased tumor growth. NG2 ablation also diminishes the number of tumor-associated and TEK tyrosine kinase endothelial (Tie2) expressing macrophages in mammary tumors, providing another possible mechanism for reducing tumor vascularization and growth. CONCLUSIONS: These results emphasize the importance of NG2 in mediating pericyte/endothelial cell communication that is required for proper vessel maturation and function. In the absence of normal pericyte/endothelial cell interaction, poor vascular function results in diminished early progression of mammary tumors. PMID- 22531608 TI - Relationships between salivary free testosterone and the expression of force and power in elite athletes. AB - AIM: This study examined the predictive relationships between the salivary free testosterone (T) concentrations of elite athletes and the expression of force and power. METHODS: A group of elite male rugby players (N.=64) were assessed for peak force (PF), peak rate of force development (PRFD), force at 100 milliseconds (F100 ms) and 250 milliseconds (F250 ms) during an isometric mid-thigh pull (IMTP), and/or peak power (PP) and height during a countermovement jump (CMJ). Saliva samples were collected before testing and assayed for free T. Relationships between individual T concentrations and performance were assessed as a pooled group and 4 sub-groups of equal size. RESULTS: As pooled data sets, none of the IMTP and CMJ performance variables were significantly correlated with free T in either the PF or PP groups (r=0.01-0.23). The PF and PP abilities of the 4 sub-groups were significantly different, so that PF1>PF2>PF3>PF4 (P<0.001) and PP1>PP2>PP3>PP4 (P<0.01). When the 4 sub-groups were analysed, the T concentrations of the PF4 group were significantly (P<0.05-0.01) correlated to PRFD (r=0.69) and F100 ms (r=0.55) during the IMTP, as was F100 ms in the PF1 group (r=0.66). In the PP1 group, free T also correlated to CMJ height (r=0.62). CONCLUSION: The key conclusion is that the expression of force and power in an elite athletic group may be dependent, to some extent, on individual variation in salivary free T concentrations and existing strength or power levels. The current results also confirm that the grouping of elite athletes of mixed strength or power ability may bias predictive results in a manner not reflective of sub groups within this population. PMID- 22531609 TI - The evolutionary history of maternal plant-manipulation and larval feeding behaviours in attelabid weevils (Coleoptera; Curculionoidea). AB - Attelabid weevils manipulate specific structures of their host plants in a species-specific manner, e.g., cutting a shoot, cutting a leaf, rolling a leaf, or constructing sophisticated wrapped leaf rolls, presumably to secure the survivorship of eggs or larvae. To depict the evolutionary history of maternal plant-manipulation behaviours and larval feeding strategies of the family Attelabidae, molecular phylogenetic analyses were conducted by sequencing the nuclear 18S and 28S ribosomal DNA and the mitochondrial cytochrome oxidase subunit I genes. Our analyses indicated that the attelabid weevils form a monophyletic group, and that maternal plant-cutting behaviour originated in a common ancestor of Attelabidae, but was subsequently lost in several lineages. Monophyly of the subfamily Attelabinae was also recovered with high support, but the subfamily Rhynchitinae was not recovered as monophyletic. By employing maximum-likelihood-based ancestral state reconstructions, larval leaf-blade feeding was inferred to have evolved from boring of cut shoots/petioles. Moreover, maternal leaf-rolling behaviours likely originated independently in the Attelabinae and Byctiscini lineages, and in several Deporaini lineages. As the sophisticated behaviours constructing wrapped leaf rolls of Attelabinae originated only once and has not been lost from the lineage, these complex and innovative behaviours may have contributed to the success and diversification of the lineage. PMID- 22531610 TI - Phylogenetics and evolution of host-plant use in leaf-mining sawflies (Hymenoptera: Tenthredinidae: Heterarthrinae). AB - The habit of mining within leaves has evolved convergently in numerous plant feeding insect taxa. Many leaf-mining groups contain a large number of species with distinct feeding preferences, which makes them highly suitable for studies on the evolutionary history of host-plant use and on the role of niche shifts in speciation. We aimed to clarify the origin, classification, and ecological evolution of the tenthredinid sawfly subfamily Heterarthrinae, which contains c. 150 leaf-mining species that collectively feed on over 20 plant genera around the world. For this, we reconstructed the phylogeny of representative heterarthrine species and diverse outgroups from the superfamily Tenthredinoidea on the basis of DNA sequence data collected from two mitochondrial (CoI and Cytb) and two nuclear (EF-1alpha and NaK) genes. Thereafter, we inferred the history of niche diversification within Heterarthrinae by plotting larval host-plant associations on the trees, and by contrasting a time-calibrated leaf-miner phylogeny with the phylogeny of their host plants. The results show that: (1) heterarthrine leaf miners constitute a monophyletic group that arose from external-feeding blennocampine lineages within the Tenthredinidae c. 110-80 million years ago; (2) heterarthrines generally radiated well after their host taxa, and extant host plant associations therefore result from a combination of host conservatism and occasional shifts among available plant taxa; and (3) diversification in Heterarthrinae apparently occurs by multiple mechanisms, including sympatric or allopatric ecological speciation, non-ecological allopatric speciation, and possibly allochronic speciation. Overall, both present and historical host-use patterns within the Heterarthrinae exhibit striking similarities to patterns found in co-occurring herbivore taxa. PMID- 22531611 TI - The relationship between cerebral vascular disease and parkinsonism: The VADO study. AB - BACKGROUND: The observation of gait abnormalities, parkinsonism and vascular lesions in elderly patients is often reported as vascular parkinsonism (VP). However the status of striatal dopamine transporter (DAT) and the effects of brain vascular lesions on motor features and levodopa responsiveness are poorly defined. METHODS: We recorded clinical features, chronic response to levodopa and vascular risk factors in a cross-sectional cohort of consecutive elderly patients with possible Parkinson's disease (PD) or VP recruited in 20 centers in Italy. RESULTS: We included a total of 158 patients. Onset of motor symptoms was asymmetric in 93 (59%) and symmetric in 65 patients (41%). Symmetric motor onset was associated with greater disease severity. Chronic levodopa response was positive in 75 (47.8%) and negative in 82 patients (52.2%). A negative response to levodopa was associated with greater frequency of symmetric onset of motor symptoms, worst disease severity, absence of dyskinesia and greater number of vascular risk factors. Frontal lobe showed largest vascular load. Striatal DAT was normal in 48 (30.4%) and abnormal in 110 (69.6%) patients. Patients with normal DAT binding showed higher vascular load at MRI. Significant predictive factors of worst disease severity and negative response to levodopa were hypertension, vascular lesions in basal ganglia/periventricular regions, and normal DAT uptake. CONCLUSIONS: Multiple cerebral vascular lesions modify clinical presentation and severity in patients with parkinsonism and this is underlined by specific risk factors primarily hypertension. Striatal DAT assessment is helpful in identifying patients where therapy benefit is less likely. PMID- 22531612 TI - Drivers with Parkinson's disease: who participates in research studies? AB - BACKGROUND: Concern about the effects of Parkinson's disease (PD) on driving competence has precipitated many studies, although most have consisted of small samples. Findings are difficult to interpret and compare as researchers have employed different inclusion/exclusion criteria and rarely provide information on the number of PD patients who are no longer driving, fail to meet other criteria, or refuse to participate. METHODS: The present study examined barriers to participation and representativeness of research participants by screening PD patients at a movement disorder research center to develop a profile of patients who were currently driving versus those who had stopped driving, and to ascertain eligibility and willingness to participate in driving research. RESULTS: Over 13 months, 128 PD patients were screened (mean age 69.2 +/- 10.1; range 39-90); 62% men; with UPDRS motor scores ranging from 8.5 to 68 (mean 30.3 +/- 11.3). Only 66% were still driving, and compared to those who had stopped driving, current drivers were more likely to be men (p < .05), younger (p < .05), experienced less severe motor dysfunction (p < .001) and were less likely to report freezing symptoms (p < .05). Less than half (48%) who were eligible for the study agreed to participate. The primary reasons for refusal was having their driving assessed and fear of being reported to licensing authorities. CONCLUSIONS: Recruitment of women and participants from various ethnic, educational and socioeconomic backgrounds are important when considering the generalizability of study findings and are needed to develop fitness to drive guidelines in persons with PD. PMID- 22531613 TI - The effect of training at a specific time of day: a review. AB - This article focuses on physical performances after training at a specific time of day. To date, although the effect of time of day on aerobic performances appears to be equivocal, during anaerobic exercises, the effect of time of day has been well established with early morning nadirs and peak performances in the late afternoon. These diurnal rhythms can be influenced by several factors such as the regular training at a specific time of day. Indeed, regular training in the morning hours may increase the lower morning performances to the same or even higher level as their normal diurnal peak typically observed in the late afternoon by a greater increase of performance in the evening. However, regular training in the evening hours may increase the morning-evening (i.e., amplitude of the rhythm) difference by a greater increase of performance in the late afternoon. Therefore, adaptations to training are greater at the time of day at which training is regularly performed than at other times. Nevertheless, although modifications in resting hormones concentrations could explain this time-of-day specific adaptations, precise information on the underlying mechanisms is lacking. PMID- 22531614 TI - Anaerobic power in road cyclists is improved after 10 weeks of whole-body vibration training. AB - Whole-body vibration (WBV) training has previously improved muscle power in various athletic groups requiring explosive muscle contractions. To evaluate the benefit of including WBV as a training adjunct for improving aerobic and anaerobic cycling performance, road cyclists (n = 9) performed 3 weekly, 10 minute sessions of intermittent WBV on synchronous vertical plates (30 Hz) while standing in a static posture. A control group of cyclists (n = 8) received no WBV training. Before and after the 10-week intervention period, lean body mass (LBM), cycling aerobic peak power (Wmax), 4 mM lactate concentration (OBLA), VO2peak, and Wingate anaerobic peak and mean power output were determined. The WBV group successfully completed all WBV sessions but reported a significant 30% decrease in the weekly cycling training time (pre: 9.4 +/- 3.3 h.wk(-1); post: 6.7 +/- 3.7 h.wk(-1); p = 0.01) that resulted in a 6% decrease in VO2peak and a 4% decrease in OBLA. The control group reported a nonsignificant 6% decrease in cycling training volume (pre: 9.5 +/- 3.6 h.wk(-1); 8.6 +/- 2.9 h.wk(-1); p = 0.13), and all measured variables were maintained. Despite the evidence of detraining in the WBV group, Wmax was maintained (pre: 258 +/- 53 W; post: 254 +/- 57 W; p = 0.43). Furthermore, Wingate peak power increased by 6% (668 +/- 189 to 708 +/- 220 W; p = 0.055), and Wingate mean power increased by 2% (553 +/- 157 to 565 +/- 157 W; p = 0.006) in the WBV group from preintervention to postintervention, respectively, without any change to LBM. The WBV training is an attractive training supplement for improving anaerobic power without increasing muscle mass in road cyclists. PMID- 22531615 TI - Gas exchange threshold and VO2max testing for athletes: an update. AB - Standardized graded exercise test (GXT) protocols are ineffective for testing endurance athletes. Scientists have called for the abandonment of traditional techniques for corroborating "true" maximum oxygen uptake (VO2max), as measured during a GXT. Instead, a new technique, the verification bout subsequent to the GXT, has emerged for establishing the "true" VO2max. The addition of the verification bout reframes how the GXT should be viewed. In this article, we summarize the methods for developing custom GXT protocols, identifying threshold and interpolating power or outdoor running velocity, and implicating the verification bout. PMID- 22531616 TI - Changes in selected physical, motor performance and anthropometric components of university-level rugby players after one microcycle of a combined rugby conditioning and plyometric training program. AB - The purpose of this study was to determine the effects of a microcycle (4 weeks) combined rugby conditioning plyometric compared with a nonplyometric rugby conditioning program on selected physical and motor performance components and anthropometric measurements of university-level rugby players. Players (18.94 +/- 0.40 years) were assigned to either a control (n = 16) or experimental group (n = 19) from the U/19 rugby teams of the North-West University (South Africa). Twenty six direct and indirect anthropometric measurements were taken, and the players performed a battery of 5 physical and motor performance tests before and after a microcycle (4 week) combined rugby conditioning plyometric (experimental group) and a nonplyometric rugby conditioning program (control group). The dependent t test results showed that the control group's upper-body explosive power decreased significantly, whereas the stature, skeletal mass, and femur breadth increased significantly from pre- to posttesting. The experimental group showed significant increases in wrist breadth, speed over 20 m, agility, and power and work measurements of the Wingate anaerobic test (WAnT). Despite these results, the independent t-test revealed that speed over 20 m, average power output at 20 seconds, relative work of the WAnT, and agility were the only components of the experimental group that improved significantly more than the control group. A microcycle combined rugby conditioning plyometric program therefore leads to significantly bigger changes in selected physical and motor performance components of university-level rugby players than a nonplyometric rugby conditioning program alone. Based on these findings, coaches and sport scientists should implement 3 weekly combined rugby conditioning plyometric programs in rugby players' training regimens to improve the players' speed, agility, and power. PMID- 22531618 TI - Relationships between ground reaction impulse and sprint acceleration performance in team sport athletes. AB - Large horizontal acceleration in short sprints is a critical performance parameter for many team sport athletes. It is often stated that producing large horizontal impulse at each ground contact is essential for high short sprint performance, but the optimal pattern of horizontal and vertical impulses is not well understood, especially when the sprints are initiated from a standing start. This study was an investigation of the relationships between ground reaction impulses and sprint acceleration performance from a standing start in team sport athletes. Thirty physically active young men with team sport background performed 10-m sprint from a standing start, whereas sprint time and ground reaction forces were recorded during the first ground contact and at 8 m from the start. Associations between sprint time and ground reaction impulses (normalized to body mass) were determined by a Pearson's correlation coefficient (r) analysis. The 10 m sprint time was significantly (p < 0.01) correlated with net horizontal impulse (r = -0.52) and propulsive impulse (r = -0.66) measured at 8 m from the start. No significant correlations were found between sprint time and impulses recorded during the first ground contact after the start. These results suggest that applying ground reaction impulse in a more horizontal direction is important for sprint acceleration from a standing start. This is consistent with the hypothesis of training to increase net horizontal impulse production using sled towing or using elastic resistance devices, which needs to be validated by future longitudinal training studies. PMID- 22531619 TI - Reliability of a computer software angle tool for measuring spine and pelvic flexibility during the sit-and-reach test. AB - The purpose of this study was to determine the reliability of a computer software angle tool that measures thoracic (T), lumbar (L), and pelvic (P) angles as a means of evaluating spine and pelvic flexibility during the sit-and-reach (SR) test. Thirty adults performed the SR twice on separate days. The SR test was captured on video and later analyzed for T, L, and P angles using the computer software angle tool. During the test, 3 markers were placed over T1, T12, and L5 vertebrae to identify T, L, and P angles. Intraclass correlation coefficient (ICC) indicated a very high internal consistency (between trials) for T, L, and P angles (0.95-0.99); thus, the average of trials was used for test-retest (between days) reliability. Mean (+/-SD) values did not differ between days for T (51.0 +/ 14.3 vs. 52.3 +/- 16.2 degrees ), L (23.9 +/- 7.1 vs. 23.0 +/- 6.9 degrees ), or P (98.4 +/- 15.6 vs. 98.3 +/- 14.7 degrees ) angles. Test-retest reliability (ICC) was high for T (0.96) and P (0.97) angles and moderate for L angle (0.84). Both intrarater and interrater reliabilities were high for T (0.95, 0.94) and P (0.97, 0.97) angles and moderate for L angle (0.87, 0.82). Thus, the computer software angle tool is a highly objective method for assessing spine and pelvic flexibility during a video-captured SR test. PMID- 22531620 TI - Longitudinal interventions in elite swimming: a systematic review based on energetics, biomechanics, and performance. AB - Longitudinal information requires the notion of repeated measurements throughout time. Such data is important because it allows the determination of the effectiveness of an intervention program. Research in competitive swimming has given special emphasis to energetics and biomechanics as determinant domains to improve performance. The purpose of this systematic review was to summarize longitudinal evidences on the energetic, biomechanical, and performance status of elite swimmers. A computerized search was made in 6 databases, conference proceedings, and department files. The 28 studies that satisfied the inclusion criteria were selected for analysis. Studies' qualitative evaluation was made by 2 independent reviewers using the Quality Index. These studies were then gathered into 3 main categories according to their reported data: energetics (n = 18), biomechanics (n = 9), and performance (n = 8). The conclusions were as follows: (a) elite swimmers are able to demonstrate from slight to substantial changes in their performance and energetic and biomechanical profiles within and between seasons; (b) the magnitude of change is dependent on the characteristics of the training programs, the duration of the intervention, and subject's gender; and (c) future research should emphasize the use of more complex procedures to improve the quality of the interventions. PMID- 22531622 TI - Effects of a compression garment on shoulder external rotation force outputs during isotonic contractions. AB - The use of compression garments (CGs) has been advocated for performance enhancement and recovery in athletes. The effect of a CG on humeral rotation motor control has not been previously tested. The purpose of this study was to examine the isotonic contraction of external rotation (ER) of the glenohumeral joint at different force outputs to determine the effect of wearing a long sleeve CG on muscular performance. Twelve male college tennis players and 12 male college soccer players were tested for ER of the dominant shoulder during both concentric and eccentric isotonic contractions. The subjects performed 5 consecutive repetitions of both concentric and eccentric ER at 20-30% and 40-50% of maximum voluntary isometric contraction (MVIC) intensities. All subjects were tested with and without CG as well as with and without ongoing visual feedback information (OVFI). The order of CG wearing and the presence of OVFI were randomly assigned across all subjects. The results indicated a significant 3-way interaction between CG wearing and OVFI across 2 loads. Specifically, significantly different mean value of the completion time was found between OVFI and no-OVFI without CG wearing at 40-50% of MVIC, whereas no difference in the completion time was found with and without OVFI with CG wearing. Taken together, with CG wearing, athletes may have ER at 40-50% of MVIC more readily maintained by peripheral feedback without visuomotor control imposed on force outputs as compared without CG wearing. PMID- 22531623 TI - Chiral self-assembly of lactose functionalized perylene bisimides as multivalent glycoclusters. AB - A chiral self-assembly has been constructed from a d-lactose functionalized perylene bisimide derivative, showing right-handed supramolecular stacking induced by the chiral d-lactose moieties. Benefiting from the grafting of D lactose, the self-assembled multivalent glycoclusters exhibited specific binding with PNA lectin. PMID- 22531625 TI - Utilization of fluorescent chimeras for investigation of heterooligomeric complexes formed by human small heat shock proteins. AB - Fluorescent chimeras composed of enhanced cyan (or enhanced yellow) fluorescent proteins (ECFP or EYFP) and one of the four human small heat shock proteins (HspB1, HspB5, HspB6 or HspB8) were expressed in E. coli and purified. Fluorescent chimeras were used for investigation of heterooligomeric complexes formed by different small heat shock proteins (sHsp) and for analysis of their subunit exchange. EYFP-HspB1 and ECFP-HspB6 form heterooligomeric complex with apparent molecular weight of ~280 kDa containing equimolar quantities of both sHsp. EYFP-HspB5 and ECFP-HspB6 formed heterogeneous oligomeric complexes. Fluorescent proteins inside heterooligomeric complexes formed by HspB1/HspB6 and HspB5/HspB6 chimeras are closely located, making possible effective fluorescence resonance energy transfer (FRET). Neither the wild type HspB8 nor its fluorescent chimeras were able to form stable heterooligomeric complexes with the wild type HspB1 and HspB5. Homo- and hetero-FRET was used for analysis of subunit exchange of small heat shock proteins. The apparent rate constant of subunit exchange was temperature-dependent and was higher for HspB6 forming small oligomers than for HspB1 forming large oligomers. Replacement induced by homologous subunits was more rapid than the replacement induced by heterologous subunits of small heat shock proteins. Fusion of fluorescent proteins might affect oligomeric structure of small heat shock proteins, however fluorescent chimeras can be useful for investigation of heterooligomeric complexes formed by sHsp and for analysis of kinetics of their subunit exchange. PMID- 22531626 TI - Distinct alternative splicing patterns of mediator subunit genes during endothelial progenitor cell differentiation. AB - Mediator (MED) is a fundamental component of the RNA polymerase II-mediated transcription machinery playing a pivotal role in the regulation of eukaryotic mRNA synthesis. Human MED complexes contain at least 30 distinct MED subunits. Our previous study, aimed to analyse MED complex during the pattern of endothelial progenitor cells (EPCs) differentiation, found an alternative transcript of MED30 subunit expressed only in circulating immature progenitor cells. Here, we report two novel transcripts of MED12 and MED19 subunits both generated by alternative splicing and displaying similar expression patterns, thereby indicating their involvement during endothelial cell differentiation. PMID- 22531627 TI - Application of fusion protein 4D5 scFv-dibarnase:barstar-gold complex for studying P185HER2 receptor distribution in human cancer cells. AB - Overexpression of the P185(HER2) protein determines the malignancy and unfavorable prognosis of ovarian and breast tumors. In this work, the distribution of P185(HER2) in human cancer cells was studied by electron microscopy, using a novel approach. It is based on the interaction between barnase (a ribonuclease from Bacillus amyloliquefaciens) and its specific inhibitor barstar. The monoclonal antibody 4D5 scFv to extracellular P185(HER2) domain fused with two molecules of barnase was used as a recognizing agent, and the conjugate of colloidal gold with barstar, as an electron dense label for electron microscopic visualization. For labeling, we used supramolecular complexes 4D5 scFv-dibarnase:barstar-Au. The distribution of P185(HER2) in human ovarian carcinoma cells SKOV-3 and breast carcinoma cells BT-474 was studied at 4 degrees C and 37 degrees C. It was shown that at 4 degrees C the protein P185(HER2) occurs exclusively on the cell surface, mainly on protrusions or close to their bases. At 37 degrees C, the internalization of P185(HER2) caused by its interaction with 4D5 scFv-dibarnase was observed. Inside the cells, P185(HER2) was located in the coated pits and vesicles, endosomes and multivesicular bodies. The data obtained indicate that the supramolecular 4D5 scFv-dibarnase:barstar gold complex can be used as a new immunodetection system for exploring the P185(HER2) distribution. PMID- 22531628 TI - Correlation of bevacizumab-induced hypertension and outcome in the BOXER study, a phase II study of capecitabine, oxaliplatin (CAPOX) plus bevacizumab as peri operative treatment in 45 patients with poor-risk colorectal liver-only metastases unsuitable for upfront resection. AB - BACKGROUND: Bevacizumab is commonly used in combination with chemotherapy in the treatment of metastatic colorectal cancer, but to date, despite extensive research, no predictive or prognostic biomarkers for bevacizumab have been identified. The development of bevacizumab-induced arterial hypertension has recently been suggested as a potential predictive biomarker. METHODS: Blood pressure was recorded during the BOXER study, a phase II study of capecitabine, oxaliplatin (CAPOX) plus bevacizumab as peri-operative treatment in 45 patients with poor-risk colorectal liver-only metastases unsuitable for upfront resection. In this analysis, the development of bevacizumab-induced hypertension was correlated with clinical outcomes. RESULTS: Fifteen percent of patients developed >=grade 1 hypertension while receiving neoadjuvant chemotherapy, and 4% developed grade 3 hypertension. There was no correlation between the development of hypertension and radiological response rate (P=0.642), progression-free survival (P=0.644) or overall survival (P=0.480) in those who developed hypertension compared with those who did not. CONCLUSION: Bevacizumab-induced hypertension did not predict radiological response or survival in our study. The results highlight a number of important issues regarding the use of hypertension as a biomarker. PMID- 22531629 TI - Incidence and time trends of brain metastases admissions among breast cancer patients in Sweden. AB - BACKGROUND: While treatment for breast cancer has been refined and overall survival has improved, there is concern that the incidence of brain metastases has increased. METHODS: We identified patients in Sweden with incident breast cancer 1998-2006 in the National Cancer Register, and matched these to the National Patient Register to obtain information on hospital admissions for distant metastases. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed with Cox regression as estimates of relative risk. RESULTS: Among 50 528 breast cancer patients, 696 (1.4%) were admitted with brain metastases during median 3.5 years of follow-up. Admissions for other metastases were found in 3470 (6.9%) patients. Compared with the period 1998-2000, patients diagnosed with breast cancer 2004-2006 were at a 44% increased risk of being admitted with brain metastases (HR 1.44, 95% CI 1.13-1.85). CONCLUSION: The incidence of admissions with brain metastases in breast cancer patients was increasing in the mid-2000s in Sweden. These findings support a true increase in incidence of brain metastases among breast cancer patients. PMID- 22531630 TI - Incidence and possible pathogenesis of sentinel node micrometastases in ductal carcinoma in situ of the breast detected using molecular whole lymph node assay. AB - BACKGROUND: The pathogenesis of lymph node metastases in preinvasive breast cancer - ductal carcinoma in situ (DCIS) - remains controversial. The one-step nucleic acid amplification (OSNA) assay is a novel molecular method that can assess a whole node and detect clinically relevant metastases. In this retrospective cohort study, we determined the performance of the OSNA assay in DCIS and the pathogenesis of node-positive DCIS. METHODS: The subjects consisted of 623 patients with DCIS who underwent sentinel lymph node (SN) biopsy. Of these, 2-mm-sectioned nodes were examined using frozen-section (FS) histology in 338 patients between 2007 and 2009, while 285 underwent OSNA whole node assays between 2009 and 2011. The SN-positivity rate was compared between cohorts, and the characteristics of OSNA-positive DCIS were investigated. RESULTS: The OSNA detected more cases of SN metastases than FS histology (12 out of 285, 4.2% vs 1 out of 338, 0.3%). Most of the metastases were micrometastases. The characteristics of high-risk DCIS (i.e., mass formation, size, grade, and comedo) and preoperative breast biopsy (i.e., methods or time to surgery) were not valid for OSNA assay-positive DCIS. CONCLUSION: The OSNA detects more SN metastases in DCIS than FS histology. Further examination of the primary tumours and follow-up of node-positive DCIS are needed to elucidate the pathogenesis. PMID- 22531631 TI - The differential effects of statins on the metastatic behaviour of prostate cancer. AB - BACKGROUND: Although statins do not affect the incidence of prostate cancer (CaP), usage reduces the risk of clinical progression and mortality. Although statins are known to downregulate the mevalonate pathway, the mechanism by which statins reduce CaP progression is unknown. METHODS: Bone marrow stroma (BMS) was isolated with ethical approval from consenting patients undergoing surgery for non-malignant disease. PC-3 binding, invasion and colony formation within BMS was assessed by standardised in vitro co-culture assays in the presence of different statins. RESULTS: Statins act directly on PC-3 cells with atorvastatin, mevastatin, simvastatin (1 MUM) and rosuvastatin (5 MUM), but not pravastatin, significantly reducing invasion towards BMS by an average of 66.68% (range 53.93 77.04%; P<0.05) and significantly reducing both number (76.2+/-8.29 vs 122.9+/ 2.48; P=0.0055) and size (0.2+/-0.0058 mm(2) vs 0.27+/-0.012 mm(2); P=0.0019) of colonies formed within BMS. Statin-treated colonies displayed a more compact morphology containing cells of a more epithelial phenotype, indicative of a reduction in the migrational ability of PC-3 cells. Normal PC-3 phenotype and invasive ability was recovered by the addition of geranylgeranyl pyrophosphate (GGPP). CONCLUSION: Lipophilic statins reduce the migration and colony formation of PC-3 cells in human BMS by inhibiting GGPP production, reducing the formation and the spread of metastatic prostate colonies. PMID- 22531632 TI - Quiescence and gammaH2AX in neuroblastoma are regulated by ouabain/Na,K-ATPase. AB - BACKGROUND: Cellular quiescence is a state of reversible proliferation arrest that is induced by anti-mitogenic signals. The endogenous cardiac glycoside ouabain is a specific ligand of the ubiquitous sodium pump, Na,K-ATPase, also known to regulate cell growth through unknown signalling pathways. METHODS: To investigate the role of ouabain/Na,K-ATPase in uncontrolled neuroblastoma growth we used xenografts, flow cytometry, immunostaining, comet assay, real-time PCR, and electrophysiology after various treatment strategies. RESULTS: The ouabain/Na,K-ATPase complex induced quiescence in malignant neuroblastoma. Tumour growth was reduced by >50% when neuroblastoma cells were xenografted into immune deficient mice that were fed with ouabain. Ouabain-induced S-G2 phase arrest, activated the DNA-damage response (DDR) pathway marker gammaH2AX, increased the cell cycle regulator p21(Waf1/Cip1) and upregulated the quiescence-specific transcription factor hairy and enhancer of split1 (HES1), causing neuroblastoma cells to ultimately enter G0. Cells re-entered the cell cycle and resumed proliferation, without showing DNA damage, when ouabain was removed. CONCLUSION: These findings demonstrate a novel action of ouabain/Na,K-ATPase as a regulator of quiescence in neuroblastoma, suggesting that ouabain can be used in chemotherapies to suppress tumour growth and/or arrest cells to increase the therapeutic index in combination therapies. PMID- 22531633 TI - Tumour budding: a promising parameter in colorectal cancer. AB - In 2011, the Tumour Node Metastasis (TNM) staging system still remains the gold standard for stratifying colorectal cancer (CRC) patients into prognostic subgroups, and is considered a solid basis for treatment management. Nevertheless, there is still a challenge with regard to therapeutic strategy; stage II patients are not typically selected for postoperative adjuvant chemotherapy, although some stage II patients have a comparable outcome to stage III patients who, themselves do receive such treatment. Consequently, there has been an inundation of 'prognostic biomarker' studies aiming to improve the prognostic stratification power of the TNM staging system. Most proposed biomarkers are not implemented because of lack of reproducibility, validation and standardisation. This problem can be partially resolved by following the REMARK guidelines. In search of novel prognostic factors for patients with CRC, one might glance at a table in the book entitled 'Prognostic Factors in Cancer' published by the International Union against Cancer (UICC) in 2006, in which TNM stage, L and V classifications are considered 'essential' prognostic factors, whereas tumour grade, perineural invasion, tumour budding and tumour-border configuration among others are proposed as 'additional' prognostic factors. Histopathology reports normally include the 'essential' features and are accompanied by tumour grade, histological subtype and information on perineural invasion, but interestingly, the tumour-border configuration (i.e., growth pattern) and especially tumour budding are rarely reported. Although scoring systems such as the 'BRE' in breast and 'Gleason' in prostate cancer are solidly based on histomorphological features and used in daily practice, no such additional scoring system to complement TNM staging is available for CRC. Regardless of differences in study design and methods for tumour-budding assessment, the prognostic power of tumour budding has been confirmed by dozens of study groups worldwide, suggesting that tumour budding may be a valuable candidate for inclusion into a future prognostic scoring system for CRC. This mini-review therefore attempts to present a short and concise overview on tumour budding, including morphological, molecular and prognostic aspects underlining its inter-disciplinary relevance. PMID- 22531634 TI - Contrasting effects of diclofenac and ibuprofen on active imatinib uptake into leukaemic cells. AB - BACKGROUND: The human organic cation transporter-1 (OCT-1) is the primary active protein for imatinib uptake into target BCR-ABL-positive cells. Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used by chronic myeloid leukaemia (CML) patients on imatinib to manage musculoskeletal complaints. METHODS: Here we investigated the impact of NSAIDs on functional activity of the OCT-1 (OCT-1 activity; OA) in CML cells. RESULTS: Although ten of twelve NSAIDs tested had no significant impact on OA (P>0.05), we observed increased OA (27% increase in K562; 22% increase in KU812 cells, P<0.05) and reduced IC50(imatinib) when treated with diclofenac. Co-incubation with imatinib and diclofenac resulted in a significantly lower viable cell number compared with imatinib alone. In contrast, ibuprofen led to a significant decrease in OA, an increase in IC50(imatinib) and thus reduced the cytotoxicity of imatinib. In primary CML samples, diclofenac significantly increased OA, particularly in patients with low OA (<4 ng per 200 000 cells), and significantly decreased IC50(imatinib). Ibuprofen induced significant decreases in OA in CML samples and healthy donors. CONCLUSION: On the basis of the expected impact of these two drugs on OA, ibuprofen should be avoided in combination with imatinib. Further studies are warranted regarding the potential benefit of diclofenac to improve OA in a clinical setting. PMID- 22531636 TI - Cervical cancer incidence in young women: a historical and geographic controlled UK regional population study. AB - BACKGROUND: The commencing age of cervical screening in England was raised from 20 to 25 years in 2004. Cervical cancer incidence in young women of England is increasing. It is not clear if this is due to either greater exposure to population risk factors or reduced cervical screening. METHODS: We measured if the relative risk of cervical cancer in younger women (20-29 years) of the north east of England (NE) differed to that of women aged 30yrs and above since 2004. We also measured average annual percentage change (AAPC) in the 3 yr moving average incidence for all age-groups. Regional screening coverage rate and population risk factors were reviewed. Comparisons were made with Wales where screening continues to commence from the age of 20yrs. RESULTS: Cervical cancer incidence in women aged 20-29 increased annually by an average of 10.3% between 2000 and 2009. The rise in women aged 30-39 was less steep (3.5%/year) but no significant rise was observed in women aged 40-49. Socioeconomic factors remained stable or improved during the time period except for the incidence of chlamydia, herpes simplex and in particular, genital warts, which increased significantly in young women. Data from Wales show similar results. CONCLUSION: The incidence of cervical cancers in young women of the NE is increasing. The rise in incidence is unrelated to the change in screening policy in 2004. Close monitoring of incidence in young women and a greater attempt to reverse the current decline in screening coverage of women aged 25-29 years are recommended. PMID- 22531637 TI - Phase I study of saracatinib (AZD0530) in combination with paclitaxel and/or carboplatin in patients with solid tumours. AB - BACKGROUND: As a prelude to combination studies aimed at resistance reversal, this dose-escalation/dose-expansion study investigated the selective Src kinase inhibitor saracatinib (AZD0530) in combination with carboplatin and/or paclitaxel. METHODS: Patients with advanced solid tumours received saracatinib once-daily oral tablets in combination with either carboplatin AUC 5 every 3 weeks (q3w), paclitaxel 175 mg m(-2) q3w, paclitaxel 80 mg m(-2) every 1 week (q1w), or carboplatin AUC 5 plus paclitaxel 175 mg m(-2) q3w. The primary endpoint was safety/tolerability. RESULTS: A total of 116 patients received saracatinib 125 (N=20), 175 (N=44), 225 (N=40), 250 (N=9), or 300 mg (N=3). There were no clear dose-related trends within each chemotherapy regimen group in number or severity of adverse events (AEs). However, combining all groups, the occurrence of grade >=3 asthenic AEs (all causality) was dose-related (125 mg, 10%; 175 mg, 20%; >=225 mg, 33%), and grade >=3 neutropenia occurred more commonly at doses >=225 mg. There was no evidence that saracatinib affected exposure to carboplatin or paclitaxel, or vice versa. Objective responses were seen in 5 out of 44 patients (11%) receiving carboplatin plus paclitaxel q3w, and 5 out of 24 (21%) receiving paclitaxel q1w. CONCLUSION: Saracatinib doses up to 175 mg with paclitaxel with/without carboplatin showed acceptable toxicity in most patients, and are suitable for further trials. PMID- 22531639 TI - Assessment of the contribution of the IHC4+C score to decision making in clinical practice in early breast cancer. AB - BACKGROUND: The immunohistochemical (IHC) 4+C score is a cost-effective prognostic tool that uses clinicopathologic factors and four standard IHC assays: oestrogen receptor (ER), PR, HER2 and Ki67. We assessed its utility in personalising breast cancer treatment in a clinical practice setting, through comparison with Adjuvant! Online (AoL) and the Nottingham Prognostic Index (NPI). METHODS: We prospectively gathered clinicopathologic data for postmenopausal patients with hormone receptor-positive, HER2-negative, N0-3 resected early breast cancer treated consecutively at our institution. We retrospectively calculated and compared prognostic scores. The primary endpoint was the proportion of patients reclassified from AoL-defined intermediate-risk by application of the IHC4+C score. RESULTS: The median age of the 101 patients included in the analysis was 63. In all, 15 of the 26 patients classified as intermediate-risk by AoL were reallocated to a low-risk group by application of the IHC4+C score and no patient was reclassified as high-risk group. Of the 59 patients classified as intermediate-risk group by the NPI, 24 were reallocated to a low-risk group and 13 to a high-risk group. CONCLUSION: IHC4+C reclassifies more than half of the patients stratified as being in intermediate-risk group by the AoL and NPI. The use of IHC4+C may substantially improve decision-making on adjuvant chemotherapy. PMID- 22531638 TI - PPARgamma agonists regulate the expression of stemness and differentiation genes in brain tumour stem cells. AB - BACKGROUND: Brain tumour stem cells (BTSCs) are a small population of cancer cells that exhibit self-renewal, multi-drug resistance, and recurrence properties. We have shown earlier that peroxisome proliferator-activated receptor gamma (PPARgamma) agonists inhibit the expansion of BTSCs in T98G and U87MG glioma. In this study, we analysed the influence of PPARgamma agonists on the expression of stemness and differentiation genes in BTSCs. METHODS: The BTSCs were isolated from T98G and DB29 glioma cells, and cultured in neurobasal medium with epidermal growth factor+basic fibroblast growth factor. Proliferation was measured by WST-1 (4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2 H-5-tetrazolio]-1,3 benzene disulphonate) and 3H thymidine uptake assays, and gene expression was analysed by quantitative reverse--transcription PCR and Taqman array. The expression of CD133, SRY box 2, and nanog homeobox (Nanog) was also evaluated by western blotting, immunostaining, and flow cytometry. RESULTS: We found that PPARgamma agonists, ciglitazone and 15-deoxy-Delta(12,14)-ProstaglandinJ(2), inhibited cell viability and proliferation of T98G- and DB29-BTSCs. The PPARgamma agonists reduced the expansion of CD133(+) BTSCs and altered the expression of stemness and differentiation genes. They also inhibited Sox2 while enhancing Nanog expression in BTSCs. CONCLUSION: These findings highlight that PPARgamma agonists inhibit BTSC proliferation in association with altered expression of Sox2, Nanog, and other stemness genes. Therefore, targeting stemness genes in BTSCs could be a novel strategy in the treatment of glioblastoma. PMID- 22531640 TI - Avoidable deaths and random variation in patients' survival. AB - BACKGROUND: Random error in the numbers of avoidable deaths among cancer patients has not been considered in earlier studies. METHODS: Methods to obtain valid confidence intervals (CIs) for numbers of avoidable deaths were developed. The excess mortality rates were estimated for patients diagnosed with colon cancer in five cancer control regions in Finland during 2000-2007 using a relative survival regression model. Numbers of avoidable deaths due to colon cancer and other causes, respectively, were estimated in different scenarios. RESULTS: Altogether, 4139 and 1335 out of 10 772 patients under 90 years at diagnosis were estimated to have died due to colon cancer and other causes, respectively, during the first 5 years after diagnosis. If all the patients had shared the relative survival of the largest cancer control region to which the country capital belongs, the estimated number of avoidable deaths would have been 146 (95% CI 3-290). CONCLUSION: Random error in numbers of avoidable deaths, often substantial, can be quantified by realistic error margins, based on appropriate statistical methods. PMID- 22531642 TI - Near IR emitting BODIPY fluorophores with mega-Stokes shifts. AB - A novel Near Infra-Red emitting BODIPY derivative is presented which exhibits the largest Stokes shift thus far reported for a BODIPY compound. PMID- 22531641 TI - What helps and hinders midwives in engaging with pregnant women about stopping smoking? A cross-sectional survey of perceived implementation difficulties among midwives in the North East of England. AB - BACKGROUND: Around 5,000 miscarriages and 300 perinatal deaths per year result from maternal smoking in the United Kingdom. In the northeast of England, 22% of women smoke at delivery compared to 14% nationally. Midwives have designated responsibilities to help pregnant women stop smoking. We aimed to assess perceived implementation difficulties regarding midwives' roles in smoking cessation in pregnancy. METHODS: A self-completed, anonymous survey was sent to all midwives in northeast England (n = 1,358) that explores the theoretical explanations for implementation difficulties of four behaviours recommended in the National Institute for Health and Clinical Excellence (NICE) guidance: (a) asking a pregnant woman about her smoking behaviour, (b) referring to the stop smoking service, (c) giving advice about smoking behaviour, and (d) using a carbon monoxide monitor. Questions covering Michie et al.'s theoretical domain framework (TDF), describing 11 domains of hypothesised behavioural determinants (i.e., 'knowledge', 'skills', 'social/professional role/identity', 'beliefs about capabilities', 'beliefs about consequences', 'motivation and goals', 'memory', 'attention and decision processes', 'environmental context and resources', 'social influences', 'emotion', and 'self-regulation/action planning'), were used to describe perceived implementation difficulties, predict self-reported implementation behaviours, and explore relationships with demographic and professional variables. RESULTS: The overall response rate was 43% (n = 589). The number of questionnaires analysed was 364, following removal of the delivery-unit midwives, who are not directly involved in providing smoking-cessation services. Participants reported few implementation difficulties, high levels of motivation for all four behaviours and identified smoking-cessation work with their role. Midwives were less certain about the consequences of, and the environmental context and resources available for, engaging in this work relative to other TDF domains. All domains were highly correlated. A principal component analysis showed that a single factor ('propensity to act'), derived from all domains, explained 66% of variance in theoretical domain measures. The 'propensity to act' was predictive of the self-reported behaviour 'Refer all women who smoke......to NHS Stop Smoking Services' and mediated the relationship between demographic variables, such as midwives' main place of work, and behaviour. CONCLUSIONS: Our findings advance understanding of what facilitates and inhibits midwives' guideline implementation behaviours in relation to smoking cessation and will inform the development of current practice and new interventions. Using the TDF as a self-completion questionnaire is innovative, and this study supports previous research that the TDF is an appropriate tool to understand the behaviour of healthcare professionals. PMID- 22531647 TI - Priority setting in health care and higher order degree change in risk. AB - This paper examines how priority setting in health care expenditures is influenced by the presence of uncertainty about the severity of the illness and the effectiveness of medical treatment. We provide necessary and sufficient conditions on social preferences under which a social planner will allocate more health care resources to populations at higher risk. Changes in risk are defined by the concept of stochastic dominance up to order n. The shape of the social utility function and an equity weighting function are used to model the inequality aversion of the social planner. We show that for higher order risk changes, the usual conditions on preferences such as prudence or relative risk aversion are not necessarily required to prioritise health care when there are different levels of uncertainty associated with otherwise similar patient groups. PMID- 22531635 TI - Subjective cognitive complaints one year after ceasing adjuvant endocrine treatment for early-stage breast cancer. AB - BACKGROUND: In the BIG 1-98 trial objective cognitive function improved in postmenopausal women 1 year after cessation of adjuvant endocrine therapy for breast cancer. This report evaluates changes in subjective cognitive function (SCF). METHODS: One hundred postmenopausal women, randomised to receive 5 years of adjuvant tamoxifen, letrozole, or a sequence of the two, completed self reported measures on SCF, psychological distress, fatigue, and quality of life during the fifth year of trial treatment (year 5) and 1 year after treatment completion (year 6). Changes between years 5 and 6 were evaluated using the Wilcoxon signed-rank test. Subjective cognitive function and its correlates were explored. RESULTS: Subjective cognitive function and the other patient-reported outcomes did not change significantly after cessation of endocrine therapy with the exception of improvement for hot flushes (P=0.0005). No difference in changes was found between women taking tamoxifen or letrozole. Subjective cognitive function was the only psychosocial outcome with a substantial correlation between year 5 and 6 (Spearman's R=0.80). Correlations between SCF and the other patient reported outcomes were generally low. CONCLUSION: Improved objective cognitive function but not SCF occur following cessation of adjuvant endocrine therapy in the BIG 1-98 trial. The substantial correlation of SCF scores over time may represent a stable attribute. PMID- 22531648 TI - Validation of electronic data on chemotherapy and hormone therapy use in HMOs. AB - BACKGROUND: Most data regarding medical care for cancer patients in the United States comes from Surveillance, Epidemiology and End Results-linked Medicare analyses of individuals aged 65 years or older and typically excludes Medicare Advantage enrollees. OBJECTIVES: To assess the accuracy of chemotherapy and hormone therapy treatment data available through the Cancer Research Network's Virtual Data Warehouse (VDW). RESEARCH DESIGN: Retrospective, longitudinal cohort study. Medical record-abstracted, tumor registry-indicated treatments (gold standard) were compared with VDW-indicated treatments derived from health maintenance organization pharmacy, electronic medical record, and claim-based data systems. SUBJECTS: Enrollees aged 18 years and older diagnosed with incident breast, colorectal, lung, or prostate cancer from 2000 through 2007. MEASURES: Sensitivity, specificity, and positive predictive value were computed at 6 and 12 months after cancer diagnosis. RESULTS: Approximately 45% of all cancer cases (total N=23,800) were aged 64 years or younger. Overall chemotherapy sensitivity/specificities across the 3 health plans for incident breast, colorectal, lung, and prostate cancer cases were 95%/90%, 95%/93%, 93%/93%, and 85%/77%, respectively. With the exception of prostate cancer cases, overall positive predictive value ranged from 86% to 89%. Small variations in chemotherapy data accuracy existed due to cancer site and data source, whereas greater variation existed in hormone therapy capture across sites. CONCLUSIONS: Strong concordance exists between gold standard tumor registry measures of chemotherapy receipt and Cancer Research Network VDW data. Health maintenance organization VDW data can be used for a variety of studies addressing patterns of cancer care and comparative effectiveness research that previously could only be conducted among elderly Surveillance, Epidemiology and End Results-Medicare populations. PMID- 22531651 TI - Ambient temperature zincation of N-Boc pyrrolidine and its solvent dependency. AB - Sodium TMP-zincate, [(TMEDA)Na(TMP)((t)Bu)Zn((t)Bu)], can deproto-zincate N-Boc pyrrolidine at ambient temperature in hexane solution, whereas in toluene the captured alpha-carbanion of the heterocycle attacks the solvent setting off a cascade of reactions that ultimately produce a pyrrolidine-substituted enolate. PMID- 22531652 TI - [Renal dysfunction is a frequent complication in patients with advanced stage of Duchenne muscular dystrophy]. AB - Mechanical ventilation and cardioprotective therapy have significantly improved the prognosis and quality of life of patients with Duchenne muscular dystrophy (DMD). The incidence of congestive heart failure is on declining trend by meticulous care. Meanwhile, elongation of decreased cardiac function can provoke instability in circulation. Recently, we experienced six DMD patients who died from acute renal failure with preserved cardiac function (brain natriuretic peptide: BNP <100 pg/ml, fractional shortening: FS >15% and left ventricular diameter: LVD <50mm). In some patients, hypovolemia induced by low water intake, diarrhea or dose-up of diuretics was thought to be a trigger of renal failure. Since the value of creatinine (Crnn) decreased in amyotrophic patients, we evaluated renal function in 103 patients with DMD using cystatin C (CysC), which is a sensitive renal marker and unaffected by muscle volume. In addition, we assessed beta2-microglobulin (b2MG) in 24 patients, because it is also unaffected by muscle volume. The correlation between logarithm of CysC (LogCysC) and logarithm of b2MG was quite high (r=0.954), though that between LogCysC and logarithm of Crnn was not adequate (r=0.623). The average of CysC increased along with age, and more than 30% of patients over 30 years old showed abnormal values. Hemoglobin and logCysC was also negatively associated (r=-0.519), and patients with hemoglobin less than 10 g/dl showed elevated values of CysC. Cardiac indices such as FS (r=-0.250) and logarithm of BNP (r=0.319) showed weak correlations with logCysC, though significant correlation was not detected between LVD and LogCysC. Since renal dysfunction is a common complication in advanced stage of DMD patients, proper managements of water balance and anemia is important. In the medical managements for DMD, we should pay attention to cardiac-renal-anemia association. PMID- 22531649 TI - Consumer governance and the provision of enabling services that facilitate access to care at community health centers. AB - BACKGROUND: Federally qualified health centers (FQHCs) are primary care clinics, governed by a consumer majority, which accept patients regardless of ability to pay and provide nonclinical enabling services that facilitate patients' access to care. Understanding how FQHCs decide which services to provide is important, because enabling services are not typically reimbursed. OBJECTIVE: To model enabling service provision as a function of FQHC board composition. METHODS: FQHC level data were drawn from multiple years of the Uniform Data System (UDS) (2002 2007), and merged with county-level data from the Area Resource File (ARF) (2002 2007) and board data from FQHC grant applications (2003-2006). The scope and volume of enabling services an FQHC provides are modeled as a function of board composition, executive committee composition, the interaction between them, general time trends, and other FQHC and county-level controls. RESULTS: The proportion of consumers on the board does not affect the scope of enabling services, but the proportion of descriptive consumers (who resemble typical FQHC patients) on the executive committee is associated with a significant increase in the scope of enabling services a health center provides. Neither the proportion of consumers on the board nor the proportion of consumers on the executive committee affected the volume of enabling services provided. CONCLUSIONS: Consumer governance, specifically on the executive committee, plays a small role in determining which enabling services an FQHC provides, but more work is needed to identify factors associated with variation in the scope and volume of enabling services across FQHCs. PMID- 22531653 TI - [Eye movement disturbance in multiple system atrophy: chronological study of 50 patients]. AB - To clarify the features of the eye movement disturbance in the patients with multiple system atrophy (MSA), we retrospectively examined chronological changes of 9 oculomotor parameters as described below in 50 MSA patients including 12 autopsied cases. Patients with MSA were consisted of 35 patients with cerebellar ataxia-preceding type and 15 patients with parkinsonism-preceding type. Nine parameters include saccade test, eye tracking test, positioning/positional/gaze/caloric nystagmus tests, and visual suppression test. Each parameter was evaluated by three categories; normal and the two abnormal findings according to their characteristic features. In all of the 9 parameters, no significant differences were found between the cerebellar ataxia- and the parkinsonism-preceding types of MSA both in the early (disease duration less than 3 years) and in the advanced stages (duration between 8 to 11 years). From the chronological analysis, 9 oculomotor parameters could be divided into three groups: the first group with the higher frequency of the abnormality from the early stage, the second with gradual increase of the frequency, and the third with less increased frequency even in the advanced stage. We here focused on the three representatives corresponding with the above-described each group; positioning nystagmus test mainly showing downbeat nystagmus as a first group, visual suppression test showing a qualitative change from depressed into increased response as the second, and the caloric nystagmus test showing decreased response as the third. Based on these chronological changes of the oculomotor parameters, we supposed that in MSA the dorsal vermis is involved at first, followed by the flocculus in the cerebellum, and then the degenerative lesions might expand to the vestibular nucleus, and the cerebral cortex including the vestibular cortex. PMID- 22531654 TI - [A case of myositis associated with clonal expansion of gammadelta T cells in peripheral blood and bone marrow]. AB - We report a 45-year-old man with myositis associated with clonal expansion of gammadelta T cells. He was referred to our hospital because of slowly progressive (over 10 years) muscle weakness. On neurological examination, weakness and muscle atrophy were noted in the proximal upper and lower limbs. The level of creatinine kinase (CK) was 1,436 U/L. Neutropenia and monoclonal gammopathy were found in the peripheral blood. Flow cytometric analysis of peripheral blood and bone marrow revealed proliferation of CD3(+)CD4(-)CD8(+) and CD3(+)CD4(-)CD8(-) gammadelta T cells, and Southern blotting demonstrated a clonally rearranged T cell receptor Jgamma gene in peripheral blood and bone marrow. A biopsy of the right quadriceps muscle showed variations in muscle fiber size, and endomysial mononuclear cell infiltration. The expression of MHC Class I antigen was increased on the surfaces of most of muscle fibers, and TCRdelta1 positive lymphocytes invaded nonnecrotic muscle fiber. After starting treatment with cyclosporin A and steroids, his muscle weakness gradually ameliorated, the CK level decreased and neutrophils increased. Although reports of myositis associated with clonal expansion of gammadelta T cells are extremely rare, the present case suggests that gammadelta T cells might play a role in mediating myositis. PMID- 22531655 TI - [Atypical distribution of muscular atrophy in a 29-year-old man with polymyositis and anti-SRP antibodies]. AB - A 29-year-old man developed muscle weakness in the neck at age 27. An increasing serum creatine kinase (CK) activity was detected. The first examination at our hospital revealed severe muscular atrophy at the front of the neck. Subsequently, muscular atrophy and weakness developed in the shoulders and upper extremities with an increasing serum CK level, which reached 9,159 IU/l. Needle electromyography (EMG) was not able to reveal typical myopathic change represented low-amplitude motor unit potentials (MUPs) in the proximal parts of the upper and lower extremities at the first examination, but in the course of the disease, the MUPs amplitude decrease in the same muscles. Serum examination gave a positive result for anti-signal recognition particle (SRP) antibodies. A biopsy of the deltoid muscle revealed necrotizing myopathy including small angular fiber-like atrophy without inflammatory cell infiltration or fibrotic proliferation. He was treated with prednisolone and tacrolimus with the diagnosis of polymyositis. The characteristic feature in this patient is that muscular atrophy and weakness were mainly observed in the neck. Moreover, the neurogenic changes on EMG in the early stage are also observed on atypical. Polymyositis with anti-SRP antibodies has the distinctive feature of typical polymyositis with cellular infiltration clinically and pathologically. In this respect, this case has striking and suggestive features of polymyositis with anti-SRP antibodies. PMID- 22531656 TI - [A 56-year-old woman with adult-onset ophthalmoplegic migraine presenting with recurrent bilateral abducens nerve palsy]. AB - A 56-year-old woman had been experiencing episodic left eye pain followed within 3 days by double vision and adduction of the left eye since the age of 30. The episodes occurred once per month, and her symptoms spontaneously resolved within 3 days. The patient was diagnosed with ophthalmoplegic migraine (OM) with left abducens nerve palsy at the age of 53 years. In May 2011, she developed bilateral retro-orbital pain followed by double vision and limitation of abduction of the right eye. She recalled having a cold and high fever 10 days before the onset of the headache. MRI showed no thickening or enhancement of the right abducens nerve. Constructive interference in steady-state (CISS) MRI showed neurovascular contact between the right abducens nerve and anterior inferior cerebellar artery. Right abducens nerve palsy accompanied by OM was diagnosed after other diseases that can cause ophthalmoplegia were excluded. The patient's eye symptoms gradually improved following steroid treatment. There have been a few similar case reports of adult patients with OM showing left and right abducens nerve palsy at different time points. In this case report, we discuss the possible mechanisms related to OM. PMID- 22531657 TI - [Primary clivus diffuse large B cell lymphoma presenting with posterior neck pain and bilateral abducens nerve palsy]. AB - Bilateral abducens nerve palsy is an unusual clinical presentation, which could be caused by stroke, aneurysm, trauma and malignant neoplasm. We describe here a patient with bilateral abducens nerve palsy caused by large B cell lymphoma originated from clivus. An 83-year-old woman admitted to our hospital because of diplopia and severe posterior neck pain. Her diplopia developed one month before and progressed to her admission. Neurological examination revealed bilateral abducens nerve palsy. Brain MRI with enhancement lesion in the clivus, suggesting that bilateral petroclival segment of the abducens nerves were affected by the lesion. Biopsied was performed via a transsphenoidal approach, and histological diagnosis was made as diffuse large B cell lymphoma. She received oral corticosteroid administration combined with radiation therapy. After initiation of the treatment, posterior neck pain was resolved and tumor size was reduced in the repeated brain MRI. However, diplopia and bilateral abducens nerve palsy were still unresolved. Although malignant lymphoma originated at the clivus is uncommon, according to a presenting case as well as previously reported cases, lymphoma can present as an isolated involvement in the clivus associated with headache, and bilateral abducens nerve palsy. It is suggested that the clivus tumor affected the petroclival segment of abducent nerve in our case. PMID- 22531658 TI - [Late-onset leukoencephalopathy induced by long-term chemotherapy with capecitabine and cyclophosphamide for liver metastasis from breast cancer]. AB - A 55-year-old woman with a 3-year and 4-month history of liver metastasis from breast cancer underwent chemotherapy with capecitabine and cyclophosphamide for following 10-months. She did not have hypertension and was not pregnant. She showed dysarthria and mild somnolence, and her conscious level developed to semicoma after 6 days. She had pyrexia. Cerebrospinal fluid (CSF) demonstrated increased cell-count and elevated protein but no evidence of positive cytological finding and cultivation of bacteria was found in the CSF. Brain magnetic resonance imaging (MRI) revealed multiple lesions with hyperintensity in the brain stem, bilateral middle cerebellar peduncles, left splenium of corpus callosum, bilateral basal ganglia, bilateral thalami, bilateral corona radiata, and bilateral subcortical white matters of parietal lobes on the T(2) weighted and fluid attenuated inversion recovery (FLAIR) images. These lesions demonstrated mild hyperintensity on the diffusion weighted images but did not demonstrate hypointensity on the T(1) weighted images. Capecitabine and cyclophosphamide were discontinued at 4th day after onset of symptoms, and her conscious disturbance showed improvement slowly since day 12 after cessation of these drugs and hyperintensity areas detected on FLAIR image of MRI showed decreasing intensity after three weeks of onset. Capecitabine is an oral prodrug converted to 5-fluorouracil (5-FU). 5-FU and cyclophosphamide are known to induce leukoencephalopathy. Reversible multiple lesions with leukoencephalopathy on brain MRI which is called as a posterior reversible encephalopathy syndrome (PRES). Capecitabine is also reported to induce PRES in rare cases. Combination of these drugs was considered for the possible cause to induce leukoencephalopathy like PRES. Usually leukoencephalopathy occurs in relatively early time after start of chemotherapy with capecitabine or cyclophosphamide, but we consider that late-onset leukoencephalopathy can be induced by long-term chemotherapy with these drugs. It is necessary to observe leukoencephalopathy by brain MRI regularly when these drugs are used. PMID- 22531659 TI - [Case report of transthyretin Val30Met familial amyloid polyneuropathy presenting hydrocephalus]. AB - A 70-year-old man was admitted to our hospital with visual loss, dysesthesia, gait disturbance, and urinary retention. A pacemaker was implanted 1 year ago for atrioventricular conduction block. Neurologic examination revealed mild cognitive impairment, near blindness with vitreous opacity, diffuse muscle weakness, loss of all sensory modalities with areflexia, and orthostatic hypotension. Head CT showed hydrocephalus. The Congo red staining of vitrectomized specimen and the biopsied sural nerve showed amyloid depositions. Gene analysis disclosed Val30Met missense mutation of transthyretin, which is responsible for familial amyloid polyneuropathy. His bed-ridden brother also had severe urinary dysfunction and orthostatic hypotension with hydrocephalus on MRI. These two sibling cases suggest correlation of the transthyretin Val30Met mutation with hydrocephalus, a rare phenotype of this disease. PMID- 22531660 TI - [Dantrolene sodium may not be effective in the treatment of status epileptics]. PMID- 22531662 TI - Clinical indicators of ineffective airway clearance for patients in the cardiac postoperative period. AB - BACKGROUND: The accuracy of an indicator determines the direct relationship between a defining characteristic and the presence or absence of a specific nursing diagnosis. AIMS: To analyse the accuracy of the clinical indicators of ineffective airway clearance in patients during the postoperative period of cardiac surgery. METHODS: A total of 98 patients recruited from a postoperative unit were included in the study. An analysis of sensitivity, specificity, predictive value, likelihood ratio, diagnostic odds ratio, accuracy, and area under the ROC curve was used to determine the accuracy of these clinical indicators. RESULTS: Four clinical indicators showed the highest levels of accuracy by statistical measure: dyspnoea, adventitious breath sounds, ineffective cough, and retained secretions. The indicators retained secretions and ineffective cough showed high diagnostic odds ratios (62.8 and 28.1, respectively). CONCLUSION: The results suggest that there are differences between the ineffective airway clearance indicators as accuracy measures. PMID- 22531663 TI - 45,X/46,XX karyotype mitigates the aberrant craniofacial morphology in Turner syndrome. AB - The aim of this project was to study the impact on craniofacial morphology from Turner syndrome (TS) karyotype, number of intact X chromosomal p-arms, and age as well as to compare craniofacial morphology in TS with healthy females. Lateral radiographs from 108 females with TS, ranging from 5.4 to 61.6 years, were analysed. The TS females were divided into four karyotype groups: 1. monosomy (45,X), 2. mosaic (45,X/46,XX), 3. isochromosome, and 4. other, as well as according to the number of intact X chromosomal p-arms. The karyotype was found to have an impact on craniofacial growth, where the mosaic group, with presence of 46,XX cell lines, seems to exhibit less mandibular retrognathism as well as fewer statistically significant differences compared to the reference group than the 45,X karyotype. Isochromosomes had more significant differences versus the reference group than 45,X/46,XX but fewer than 45,X. To our knowledge, this is the first time the 45,X/46,XX and isochromosome karyotypes are divided into separate groups studying craniofacial morphology. Impact from p-arm was found on both maxillary and mandibular length. Compared to healthy females, TS expressed a shorter posterior and flattened cranial base, retrognathic, short and posteriorly rotated maxilla and mandible, increased height of ramus, and relatively shorter posterior facial height. The impact of age was found mainly on mandibular morphology since mandibular retrognathism and length were more discrepant in older TS females than younger. PMID- 22531664 TI - Negative self-perception of smile associated with malocclusions among Brazilian adolescents. AB - This study estimated the prevalence of negative self-perception of smile because of occlusion abnormalities and investigated their association according to standard clinical criteria. The sample consisted of 1290 randomly selected Brazilian adolescent boys and girls aged 12-16 years. The outcome of interest was dissatisfaction with smile, and data were collected using a standardized questionnaire. Occlusion characteristics were assessed using the dental aesthetic index (DAI). The other study variables were gender, age, and use of dental services. A chi-square test and Poisson multiple regression were used for statistical analysis. Of the 1290 students interviewed and examined, 539 (41.8 per cent) were dissatisfied with their smile; of these, 373 (69.2 per cent) assigned their dissatisfaction to the presence of an occlusal abnormality, and 166 (30.8 per cent) reported reasons other than occlusal abnormalities for their negative self-perception of their smile. In multivariate analysis, the following variables were associated with the outcome of interest: maxillary anterior irregularity [prevalence ratio (PR) = 1.40; 95 per cent confidence interval (CI) = 1.29-1.80], incisal spacing (PR = 1.37; 95 per cent CI = 1.19-1.57), vertical open bite (PR = 1.34; 95 per cent CI = 1.15-1.55), mandibular anterior irregularity (PR = 1.29; 95 per cent CI = 1.14-1.46), permanent anterior teeth missing (PR = 1.21; 95 per cent CI = 1.05-1.39), and incisal diastema (PR = 1.14; 95 per cent CI = 1.01-1.31). The negative self-perception of smile was statistically associated with severity of occlusal disorders according to the DAI scores, which suggests that self-perception should be used together with standard clinical criteria when decisions about orthodontic treatments are made in public health care systems. PMID- 22531665 TI - Long-term periodontal response to orthodontic treatment of palatally impacted maxillary canines. AB - One of the most important aspects to take into consideration when evaluating the outcome of treatment of impacted maxillary canines is the final periodontal status. The aim of the present study was to evaluate the long-term periodontal response of palatally impacted maxillary canines aligned using a codified procedure and the 'Easy Cuspid' compared with contralateral spontaneously erupted teeth. The periodontal conditions of the adjacent teeth were also considered. From an initial sample of 124 patients, 33 patients (24 females and 9 males) were selected. All patients who had undergone surgical orthodontic treatment conducted in accordance with a standardized protocol were recalled for follow-up at an average of 4.6 years after the end of treatment. The average treatment time was 29 months and the mean eruption time of the previously impacted tooth was 3.1 months. The average probing depth values showed no significant clinical differences. Probing depths recorded at the vestibular surface of the lateral incisor (P < 0.05) and at the midpalatal/midlingual aspect of the first premolar were statistically significant in comparison with the control elements. Student's t-test was used to compare the test and control group values. Coefficient of reliability was set at P < 0.05. The use of a closed-flap surgical technique in association with a codified orthodontic traction system (Easy Cuspid) allowed alignment of palatally impacted canines without damage to the periodontium. PMID- 22531666 TI - Secular trends in Swedish hip fractures 1987-2002: birth cohort and period effects. AB - BACKGROUND: Recently, a leveling off in hip-fracture incidence has been reported in several settings, but the annual number is nonetheless predicted to increase due to the growing elderly population. METHODS: Using Swedish national data for 1987-2002 for all inpatients 50 years or older, we examined the annual number and incidence of hip fractures and explored age, period, and cohort effects. Age adjustment was done by direct standardization, time-trend analysis by linear regression, changes in linear trends by joinpoint regression, and age-period cohort effects by log-likelihood estimates in Poisson regression models. RESULTS: Before 1996, the age-standardized hip fracture incidence was stable (0.1% per year [95% confidence interval = -0.2% to 0.5%]), and the annual number of hip fractures increased (2.1% per year [1.8% to 2.4%]). After 1996, both the age standardized hip fracture incidence (-2.2% per year [-2.8% to -1.6%]) and the number of hip fractures (-0.9% per year [-1.5% to -0.4%]) decreased. The period + cohort effects were more marked among women than men, with a major reduction in hip fracture incidence in subsequent birth cohorts (estimated incidence rate ratio = 2.2 comparing women born 1889-1896 with 1945-1952) or periods (estimated incidence rate ratio = 1.1 comparing women living 1987-1990 with 1999-2002). CONCLUSION: The age-standardized hip fracture incidence has decreased since 1996, more than counteracting the effects of the aging population and resulting in a decline in the annual number of hip fractures through 2002. The magnitude of the combined period and cohort effects in women seems to be of biologic importance. If this persists into older age, the annual number of hip fractures will be lower than has been projected. PMID- 22531667 TI - PM10-induced hospital admissions for asthma and chronic obstructive pulmonary disease: the modifying effect of individual characteristics. AB - BACKGROUND: Evidence suggests that oxidative stress is a unifying feature underlying the toxic actions of particulate matter (PM). We have investigated whether individual plasma antioxidant concentrations (uric acid and vitamins C, A, and E) and 10 antioxidant genes modify the response to PM with respect to hospital admissions for chronic obstructive pulmonary disease (COPD) or asthma. METHODS: Using a bidirectional, hospital-based, case-crossover study, 209 patients admitted for asthma or COPD to the Chelsea and Westminster Hospital (London), with 234 admissions, were recruited between May 2008 and July 2010. PM10 levels in the area of Kensington and Chelsea at the time of admission were compared with the levels 14 days before and 14 days after the event. Conditional logistic regression was used to estimate the effect of PM10 at several temporal lags, while controlling for confounders. RESULTS: An increase in asthma/COPD admission rate was related to a 10 MUg/m increase in PM10, with the highest effect noted 0-3 days before the exacerbation (for lag 0-3, odds ratio = 1.35 [95% confidence interval = 1.04-1.76]). Serum vitamin C modified the effect of PM10 on asthma/COPD exacerbations. A similar (although weaker) influence was observed for low levels of uric acid and vitamin E, whereas vitamin A showed no effect modification. GSTP1 (rs1695), SOD2 (rs4880), and Nrf2 (rs1806649) were associated with a trend toward an increased risk of hospital admissions during periods of high PM10 levels. CONCLUSIONS: Our study suggests that the concentration of antioxidants in patients' serum modifies the short-term effects of PM10 on asthma and COPD exacerbations. PMID- 22531668 TI - Ambient temperature and cardiorespiratory morbidity: a systematic review and meta analysis. AB - BACKGROUND: The effect of extreme temperature has become an increasing public health concern. Evaluating the impact of ambient temperature on morbidity has received less attention than its impact on mortality. METHODS: We performed a systematic literature review and extracted quantitative estimates of the effects of hot temperatures on cardiorespiratory morbidity. There were too few studies on effects of cold temperatures to warrant a summary. Pooled estimates of effects of heat were calculated using a Bayesian hierarchical approach that allowed multiple results to be included from the same study, particularly results at different latitudes and with varying lagged effects. RESULTS: Twenty-one studies were included in the final meta-analysis. The pooled results suggest an increase of 3.2% (95% posterior interval = -3.2% to 10.1%) in respiratory morbidity with 1 degrees C increase on hot days. No apparent association was observed for cardiovascular morbidity (-0.5% [-3.0% to 2.1%]). The length of lags had inconsistent effects on the risk of respiratory and cardiovascular morbidity, whereas latitude had little effect on either. CONCLUSIONS: The effects of temperature on cardiorespiratory morbidity seemed to be smaller and more variable than previous findings related to mortality. PMID- 22531669 TI - Neurotransmitter segregation: functional and plastic implications. AB - Synaptic cotransmission is the ability of neurons to use more than one transmitter to convey synaptic signals. Cotransmission was originally described as the presence of a classic transmitter, which conveys main signal, along one or more cotransmitters that modulate transmission, later on, it was found cotransmission of classic transmitters. It has been generally accepted that neurons store and release the same set of transmitters in all their synaptic processes. However, some findings that show axon endings of individual neurons storing and releasing different sets of transmitters, are not in accordance with this assumption, and give support to the hypothesis that neurons can segregate transmitters to different synapses. Here, we review the studies showing segregation of transmitters in invertebrate and mammalian central nervous system neurons, and correlate them with our results obtained in sympathetic neurons. Our data show that these neurons segregate even classic transmitters to separated axons. Based on our data we suggest that segregation is a plastic phenomenon and responds to functional synaptic requirements, and to 'environmental' cues such as neurotrophins. We propose that neurons have the machinery to guide the different molecules required in synaptic transmission through axons and sort them to different axon endings. We believe that transmitter segregation improves neuron interactions during cotransmission and gives them selective and better control of synaptic plasticity. PMID- 22531670 TI - SCA1-phosphorylation, a regulator of Ataxin-1 function and pathogenesis. AB - Spinocerebellar ataxia type 1 (SCA1) is one an intriguing set of nine neurodegenerative diseases caused by the expansion of a unstable trinucleotide CAG repeat where the repeat is located within the coding of the affected gene, i.e. the polyglutamine (polyQ) diseases. A gain-of-function mechanism for toxicity in SCA1, like the other polyQ diseases, is thought to have a major role in pathogenesis. Yet, the specific nature of this gain-of-function is a matter of considerable discussion. An issue concerns whether toxicity stems from the native or normal function of the affected protein versus a novel function induced by polyQ expansion. For SCA1 considerable evidence is accumulating that pathology is mediated by a polyQ-induced exaggeration of a native function of the host protein Ataxin-1 (ATXN1) and that phosphorylation of S776 regulates its interaction with other cellular protein and thereby function. In addition, this posttranslational modification modulates toxicity of ATXN1 with an expanded polyglutamine. PMID- 22531671 TI - Novel electrorheological properties of a metal-organic framework Cu3(BTC)2. AB - A metal-organic framework, Cu(3)(BTC)(2), was synthesized and applied as an electro-responsive electrorheological material dispersed in insulating oil. Powder of crystalline Cu(3)(BTC)(2) exhibited excellent chain-like structures and controllable rheological properties in an applied electric field. PMID- 22531672 TI - Impact of fertilisation practices on soil respiration, as measured by the metabolic index of short-term nitrogen input behaviour. AB - The main objective of this study was the evaluation of the impact of different sources of organic waste (used as an N source) on soil quality (as measured by CO(2) release) and N transformation processes (available inorganic N forms) in a short-term field study of an almond tree plantation. Three compost types were used as organic fertilisers: EC compost constituted from organic agriculture farm (vegetables and manure), SC compost formed from sewage sludge and pruning waste composted, and XC compost comprised a mixture of composted sewage sludge plus slurry and manure from an intensive pig farm. The two compost doses were compared according to N content, and a high dose (H), corresponding to 210 kg N ha(-1), and a low dose (L), equivalent to 105 kg N ha(-1), were used. In addition, an N rate corresponding to 130 kg N ha(-1), which resulted from the supplementation of NPK mineral fertiliser with compost application at a low dose (mixed fertilisation), was compared in a parallel study. Generally, almost all organically treated soils demonstrated an improvement in the levels of C, N and P, compared to controls (unfertilised soils). In addition, the nitrate content increased, predominating over ammonium content, with the highest values in the soils with the low dose application of SC. Furthermore, soil respiration improved in organically treated soils, which showed different responses according to the organic-exogenous source of the incorporated matter. In contrast, a mineral supplement promoted a decrease in biological activity and resulted in lower CO(2) production in soils with XC and mineral fertiliser. Contrary to the organically treated soil, in soils with mix fertilisation the NH(4)(+)-N was the primary available form of nitrogen. However, the application of SC plus mineral fertiliser to soil caused a positive effect on CO(2) emissions compared to the control soil. Soil respiration behaviour was closely related to the form of inorganic N available in the soils due to the fertilisation practice type (organic or mixed), where both parameters seemed to depend on the mobilisations of cations (Na(+) and Ca(2+)) to the soil solution. PMID- 22531673 TI - Effect of female sex on cardiac arrhythmias. AB - We performed a systematic literature review to examine the effect of female sex on cardiac electrophysiology and arrhythmias. Women have faster resting heart rates yet longer QTc intervals. Women also have shorter PR and QRS intervals; these are presumed to be due to the small heart size of women and hormonal effects on ion channels. Women are two times more likely to experience atrioventricular nodal re-entry tachycardia than men. In contrast to atrioventricular nodal re-entry tachycardia, accessory-pathway-mediated atrial arrhythmias are less common in women, and women have more concealed and fewer manifest accessory pathways. Supraventricular tachycardia in women varies with the menstrual cycle and is more frequent in the luteal phase and inversely correlated with estrogen levels. Atrial fibrillation (AF) is less prevalent in women, but the absolute number of women with AF is higher because AF prevalence increases with age and women live longer. Also, complications of AF are greater in women. Women are generally less prone to ventricular arrhythmias, but they comprise a higher percentage of symptomatic subjects with congenital long QT syndrome and are more often affected by drugs that prolong the QT. Women are less prone to arrhythmias during pregnancy although they commonly complain of palpitations, which are sometimes related to the increase in heart rate during pregnancy. Clinicians should explore the relationship of arrhythmias to the menstrual cycle in female patients and should know that the menstrual cycle may affect the induction of arrhythmias during electrophysiological testing. Clinicians should also be aware that the arrhythmia and the result of clinical trials examining arrhythmia treatment may have different implications in women than in men. PMID- 22531674 TI - Oxygen treatment attenuates systemic inflammation via cholinergic pathways. PMID- 22531675 TI - Mitogen-activated protein kinase pathway activation correlates with adverse outcomes in trauma patients. PMID- 22531677 TI - Compensation of CH4 emissions during tunneling works in Asturias: a proposal with benefits both for local councils and for the affected population. AB - The appearance of methane during the excavation of tunnels through Carboniferous strata has always been a significantly frequent event. The occurrence of methane in tunnels poses a twofold problem. On the one hand, there are the associated hazards for the safety of personnel: methane is both an inflammable and an explosive gas. It therefore becomes very important to estimate the methane flow reaching the tunnel as it advances in order to minimize risks and the negative effects of methane-related incidents. A number of calculation methods have been developed to estimate methane emissions in these specific underground workings. At the same time, methane is a potent greenhouse gas, with environmentally harmful effects and a pollutant potential more than 20 times that of carbon dioxide. The immediate consequence is that the aforementioned calculations methods should enable methane emissions to be predicted and allow the environmental impact of these methane emissions into the atmosphere to be assessed using the values thus estimated. In the present paper, a research study into CH(4) emissions in the Variante de Pajares tunnels has been used to estimate the equivalent emission of CO(2) to the atmosphere. Some significant compensatory actions are accordingly proposed to mitigate the environmental effects of tunnels excavated through methane-prone coalbeds and to contribute to the sustainable development of the affected areas. The results obtained would apply directly to the strata where they have been validated; however, it is not difficult to extrapolate the proposed methodology to other coal basins and other tunnels in similar conditions. PMID- 22531676 TI - Perceptions and expectations of cardiothoracic residents and attending surgeons. AB - BACKGROUND: With our specialty going through a critical phase of re-evaluation and adaptation, our aim was to evaluate and compare the perceptions and expectations among residents and faculty regarding cardiothoracic training. METHODS: A content-validated, 13-item survey was distributed electronically from August 14 to August 24, 2010 to 728 cardiothoracic surgery residents, recent program graduates (on or after June 2006), cardiothoracic surgery chairpersons, and program directors identified in the Cardiothoracic Surgery Network database. RESULTS: The response rate was 34% (244 of 728). Of the respondents, 76% reported being "satisfied" or "very satisfied" with their program. Faculty willingness to teach in the operating room was ranked as the most valuable aspect of a training program, and strict adherence to the 80-h work week ranked as least valuable. Most respondents believed that a resident performing at least 75% of a case was acceptable for low-complexity procedures (92% of residents, 77% of attending physicians) and at least 25% for high-complexity procedures (91% of residents, 73% of attending physicians). However, residents wanted to perform more of the operations than the attending physicians considered necessary (P < 0.05). Finally, 63% of respondents (73% of residents, 56% of attending physicians) indicated that the increasing scrutiny of outcomes has adversely affected training. Other differences between the residents' and attending physicians' perceptions regarded the importance of participation in preoperative and postoperative care, what constitutes "scut work," and the value of auxiliary staff. CONCLUSIONS: Reconciling residents' expectations with the realities of duty-hour restrictions and high-stakes procedures will require the development of novel educational approaches to improve resident learning. PMID- 22531678 TI - Distinguishing malaria and influenza: early clinical features in controlled human experimental infection studies. AB - During the H1N1 influenza pandemic (pH1N1/09) diagnostic algorithms were developed to guide antiviral provision. However febrile illnesses are notoriously difficult to distinguish clinically. Recent evidence highlights the importance of incorporating travel history into diagnostic algorithms to prevent the catastrophic misdiagnosis of life-threatening infections such as malaria. We applied retrospectively the UK pH1N1/09 case definition to a unique cohort of healthy adult volunteers exposed to Plasmodium falciparum malaria or influenza to assess the predictive value of this case definition, and to explore the distinguishing clinical features of early phase infection with these pathogens under experimental conditions. For influenza exposure the positive predictive value of the pH1N1/09 case definition was only 0.38 (95% CI: 0.06-0.60), with a negative predictive value of 0.27 (95% CI: 0.02-0.51). Interestingly, 8/11 symptomatic malaria-infected adults would have been inappropriately classified with influenza by the pH1N1/09 case definition, while 5/8 symptomatic influenza exposed volunteers would have been classified without influenza (P = 0.18 Fisher's exact). Cough (P = 0.005) and nasal symptoms (P = 0.001) were the only clinical features that distinguished influenza-exposed from malaria-exposed volunteers. An open mind regarding the clinical cause of undifferentiated febrile illness, particularly in the absence of upper respiratory tract symptoms, remains important even during influenza pandemic settings. These data support incorporating travel history into pandemic algorithms. PMID- 22531679 TI - Expression of estrogen and androgen receptors in differentiated thyroid cancer: an additional criterion to assess the patient's risk. AB - Estrogen receptor (ER) and androgen receptor (AR) may be expressed in thyroid tumors, but their prognostic role is controversial. We investigated whether ER and AR expressions could confer a more aggressive phenotype to thyroid tumors. We enrolled 91 patients (13 males and 78 females, mean age 49.3+/-14.8 years) bearing small (T1 in the 2006 TNM system) differentiated thyroid cancers (DTC). Thirty-eight tumors were incidental histological findings. Using immunohistochemistry, we evaluated ERalpha, ERbeta, and AR expressions in tumors and in its correspondent extra-tumor parenchyma. In tumors, 13 (16.7%) women and one (7.7%) man expressed ERalpha; 42 (53.8%) women and six (46%) men expressed ERbeta; and 16 (20.5%) women and three (23.1%) men expressed AR. In normal thyroid parenchymas, ERbeta was expressed in 52 (66.7%) women and nine (69.2%) men, ERalpha in three (3.8%) women, and AR in 13 (16.7%) women. Compared with normal thyroid parenchyma, tumors gained ERalpha and lost ERbeta expressions. Incidental cancers were more commonly ERalpha(-) than ERalpha(+) (47.7 vs 14.3%, P=0.037). Postsurgical serum thyroglobulin was higher in ERalpha(+) tumors than in the ERalpha(-) tumors (P=0.04). ERbeta(-) tumors showed vascular invasion more frequently than the ERbeta(+) tumors (26.2 vs 4.1%, P=0.005). AR(+) tumors showed capsular invasion more frequently than the AR(-) tumors (77.8 vs 46.6%, P=0.014). In conclusion, ERalpha positivity, ERbeta negativity, and AR expressions are associated with a more aggressive phenotype of small T1-DTC. ER and AR expressions may represent an additional criterion in deciding whether to perform radioiodine ablation in these tumors. PMID- 22531680 TI - The role of discovery DMPK scientists in industry: where do we go from here? PMID- 22531681 TI - Relationships between immunophenotype, Ki-67 index, microvascular density, Ep CAM/P-cadherin, and MMP-2 expression in early-stage invasive ductal breast cancer. AB - There is still a lack of complete consensus on immunohistochemical surrogate markers for luminal A (LA) and luminal B (LB), HER2, and basal-like subtypes of breast carcinomas and their correlation with cancer cell adhesion and invasion promoting factors. Therefore, early-stage invasive ductal breast cancer patients (N=209) were recruited to the study and divided into 4 subtypes, on the basis of the expression of the estrogen/progesterone receptor and HER2 (LA: 74.4% of cases; LB: 7.8%; HER2: 5.6%; and triple-negative phenotype: 12.2%). Regardless of the above-mentioned classification, we divided all carcinomas into 2 groups: carcinomas expressing at least 1 basal marker [cytokeratine (CK)5/6, CK5, vimentin, epidermal growth factor receptor, or aberrant CK8/18 expression membranous or in <10% of cells] versus carcinomas negative for basal markers. Then we studied the relationships between the above subtypes (2 classifications) and (i) the expression of adhesion molecules (Ep-CAM, P-cadherin), (ii) matrix metalloproteinases (MMP)-2, (iii) the proliferation index (MIB-1 LI), and (iv) the microvascular density. We confirmed that triple-negative phenotypes are characterized by basal marker expression, a high tumor grade, and high MIB-1 LI. In this subtype, we found MMP-2 expression in stromal leukocytes less frequently. Both LA carcinomas and carcinomas negative for basal markers were more often negative for epithelial cell adhesion molecule (Ep-CAM) and P-cadherin. Moreover, we noted a higher mean value of microvascular density in CK5/6 and Ep-CAM immunopositive tumors, carcinomas with aberrant CK8/18 expression, and carcinomas with no or strong expression of MMP-2 in stromal fibroblast-like cells. These results might suggest that mechanisms of stroma remodeling and carcinogenesis (Ep CAM is the suggested marker of breast progenitors) may differ between breast cancer subtypes. PMID- 22531682 TI - Simultaneous immunofluorescent labeling using anti-BrdU monoclonal antibody and a melanocyte-specific marker in formalin-fixed paraffin-embedded human skin samples. AB - Immunolabeling of tissue sections requires careful optimization of protocols in order to achieve accurate and consistent data. Multiple immunolabeling is desirable when determining the exact location and phenotype of cell populations in the same cellular compartment. 5-bromodeoxyuridine (BrdU)-immunolabeling is commonly used to assess cellular proliferation in vitro. However, the technical limitations of standard methods preclude multiple antigen immunolabeling. The aim was therefore to develop a robust protocol for simultaneous labeling using anti BrdU and a melanocyte-specific marker in formalin-fixed paraffin-embedded (FFPE) skin samples. Human skin samples were obtained from patients undergoing elective plastic surgery. The tissue was incubated with BrdU, and a standard sample procedure for FFPE tissue was used. Heat-induced antigen retrieval was performed in a conventional pressure cooker, followed by immunolabeling with anti-BrdU and anti-Melan A/MART-1 antibodies. Fluorescent-conjugated secondary antibodies were used for signal detection. We have demonstrated both proliferating cells (BrdU immunopositive) and melanocytes (Melan A/MART-1-immunopositive) in the basal compartment of the epidermis in our skin samples. Successful double labeling requires heat-induced epitope retrieval to replace the harsh pretreatment protocols of standard BrdU immunolabeling methods. We have optimized a robust protocol for the double labeling of proliferating cells and cells bearing melanocyte-specific antigens (melanocytes and/or melanoblasts) in FFPE human skin samples. PMID- 22531683 TI - Immunoexpression of claudin-1 and Nm23-H1 in metastatic and nonmetastatic lower lip squamous-cell carcinoma. AB - The aim of this study was to evaluate the immunoexpression of claudin-1 and Nm23 H1 in metastatic and nonmetastatic lower lip squamous-cell carcinoma (LLSCC). Twenty LLSCCs with regional nodal metastasis and 20 LLSCCs without metastases were selected. The percentage of claudin-1 staining and the staining intensity and percentage of Nm23-H1 staining in each tumor core were assessed. Metastatic tumors exhibited higher expression of claudin-1 than nonmetastatic tumors (P = 0.030). Similarly, stage III and IV LLSCCs showed higher expression of claudin-1 than stages I and II (P = 0.026). The percentage of claudin-1 staining was scored as 2 in most well-differentiated and moderately differentiated tumors, whereas poorly differentiated tumors showed a relatively similar distribution of scores 2, 1, and 0 (P = 0.648). Regarding Nm23-H1, there was a predominance of negative cases for both metastatic and nonmetastatic tumors (P = 0.235). In addition, no significant differences in the percentage of Nm23-H1-negative and Nm23-H1 positive cases were observed regarding the clinical staging (P = 0.430) and the histologic grading of malignancy (P = 0.702). The results of this study suggest an important role of claudin-1 in the development of metastasis in LLSCCs. In contrast, the present findings do not support a significant role of Nm23-H1 in metastasis suppression of LLSCC. PMID- 22531684 TI - Reduced expression of argininosuccinate lyase is closely associated with postresectional survival in hepatocellular carcinoma: an immunohistochemistry study of 61 cases. AB - Argininosuccinate lyase (ASL) is an important enzyme in the hepatic urea cycle, and catalyzes the reversible reaction of argininosuccinate to arginine and fumarate. Its expression is significantly reduced in some hepatocellular carcinomas (HCC). In this study, we aimed to investigate the correlation of reduced ASL expression and clinicopathologic features and prognosis in HCC patients. Immunohistochemistry was used to determine the expression of ASL in HCC tissues from 61 patients who had undergone hepatic tumor resection. The correlation of ASL expression in HCC with background liver status, viral status, tumor size, portal vein invasion, histopathologic differentiation, early tumor recurrence, sex, and age were assessed with the chi(2) test. Patient survival and survival differences were determined by the Kaplan-Meier method and log-rank test. Cox regression (proportional hazard model) was used for multivariate analysis of prognostic factors. Strong positive staining was found in 39/61 HCCs and normal liver tissues, and reduced ASL staining was found in 22/61 HCCs (36.1%). Patients with low ASL expression had a significantly poorer overall survival and disease-free survival (both P<0.001). Reduced ASL expression in carcinoma tissues was also significantly associated with the tumor-node metastasis stage and early tumor recurrence, and histopathologic differentiation and portal vein invasion (P<0.05). Cox regression analysis showed that ASL is an independent prognostic marker for HCC. Therefore, reduced ASL expression may be a novel maker for poor prognosis in HCC patients. PMID- 22531685 TI - Plasmacytoid dendritic cells in lymph nodes of patients with human immunodeficiency virus. AB - Circulating plasmacytoid dendritic cells (PDC) decrease in human immunodeficiency virus (HIV) infection, either from loss or redistribution to lymph nodes (LN). Limited animal and human studies variably showed increased or decreased nodal PDC. CD123 immunostaining was performed on 28 archived LN biopsies (20 reactive) from 25 HIV patients. PDC clustering was graded (1: none; 2: rare small; 3: medium-sized, loose; and 4: large tight clusters) and correlated with HIV lymphadenitis stage, blood CD4 counts, time since HIV diagnosis, and treatment duration. Increased PDC clustering was seen with decreasing CD4 counts (P = 0.001), shorter treatment duration (P = 0.0268), and advancing HIV-lymphadenitis stage (P = 0.06). No correlation with time since HIV diagnosis was noted. To our knowledge, this is the first human study assessing relationship of nodal PDC in HIV to CD4 counts, treatment duration, and lymphadenitis pattern. Our findings suggest that PDC redistribute to LN with advancing immunodeficiency and stage of HIV infection. PMID- 22531686 TI - Thyroid transcription factor-1 is not expressed in squamous cell carcinomas of the lung: an immunohistochemical study with review of the literature. AB - Thyroid transcription factor-1 (TTF-1) is one of the peripheral airway epithelial markers that, because it is commonly expressed in lung adenocarcinomas, but not in squamous cell carcinomas, is regarded as being useful in distinguishing between these 2 malignancies, especially in those instances in which the diagnosis cannot be made on routine histology. Even though it is generally believed that TTF-1 is not expressed in squamous cell carcinomas of the lung, a significant number of studies have reported positivity for this marker in up to 38% of the cases investigated. To determine the causes of these discrepancies, 85 pulmonary and 50 nonpulmonary squamous cell carcinomas (17 skin, 8 esophagus, 5 uterine cervix, and 20 from the head-and-neck region) were investigated by immunohistochemistry for TTF-1. None of the 85 squamous cell carcinomas of the lung showed reactivity in the neoplastic cells; however, because strong TTF-1 positivity was observed in the hyperplastic type II pneumocytes that were sometimes seen entrapped within the tumor, it is concluded that the presence of these entrapped cells was one of the most likely causes of the discrepancies. In addition, after a careful review of all of the previous publications on TTF-1 expression in squamous cell carcinomas of the lung, it was found that other factors, such as the type of antibody used and the selection of the cases, may have been the cause of the discrepancies. PMID- 22531687 TI - Mucinous epithelial lesions in endometrial curettage material: a diagnostic challenge. AB - AIM: To evaluate the immunohistochemical expression of several benign or malignant mucinous lesions that can be encountered in endometrial curettage material. MATERIALS AND METHODS: Nineteen well-differentiated mucinous endometrial carcinomas, 12 papillary mucinous metaplasias, 11 cervical microglandular hyperplasias, 11 endocervical adenocarcinomas, 2 goblet cell metaplasias, 1 minimal-deviation adenocarcinoma, and 1 lobular endocervical glandular hyperplasia entered the study. Immunohistochemistry was performed with the following antibodies against: estrogen receptors, progesterone receptors, vimentin, p16, p63, carcinoembryonic antigen, and Ki-67. RESULTS: Immunohistochemistry could easily distinguish endocervical adenocarcinoma of usual type from all other lesions under study. A Vim(-)/p16(-)/p63(high) signature was found to favor a cervical microglandular hyperplasia, whereas both mucinous endometrial carcinoma and mucinous papillary metaplasia would be preferentially characterized by a Vim(+)/p16(+)/p63(low) immunophenotype. A high Ki-67 expression would be of help in differentiating the latter 2 conditions. Statistically, the expression of estrogen receptors, progesterone receptors, and carcinoembryonic antigen did not aid in the differential diagnosis of these 3 conditions. For the 4 cases representing goblet cell metaplasia, minimal deviation adenocarcinoma and lobular endocervical glandular hyperplasia, no results could be drawn. CONCLUSIONS: In endometrial curettage material, the differential diagnosis of lesions comprising mucinous epithelium might be rendered by combining the immunohistochemical expression of vimentin, p16, p63, and Ki-67. Of all lesions, endocervical adenocarcinoma of usual type is the most easily identified. PMID- 22531688 TI - Value of thyroid transcription factor-1 immunostaining in tumor diagnosis: a review and update. AB - Thyroid transcription factor-1 (TTF-1) is a tissue-specific transcription factor that plays a critical role in the normal development of embryonic epithelial cells of the thyroid and lung. Because TTF-1 expression is highly restricted to epithelial tumors arising in these organs, it is, at present, one of the immunohistochemical markers most commonly used to assist in the differential diagnosis of carcinomas of the lung and thyroid. Recent studies, however, have reported that TTF-1 is not as specific for lung and thyroid carcinomas as was previously thought as it can be found to be expressed, although much less frequently, in some carcinomas arising in other organs, such as the ovaries, endometrium, colon, and breast, as well as in some tumors of the central nervous system. Even though this unexpected TTF-1 positivity has been reported more frequently with the recently available SPT24 anti-TTF-1 monoclonal antibody, it has also been shown to occur with the commonly used 8G7G3/1 clone, albeit in a lower percentage of cases. Despite these findings, TTF-1 remains a very useful immunohistochemical marker in diagnostic pathology. PMID- 22531689 TI - The role of lipophilicity in transmembrane anion transport. AB - The transmembrane anion transport activity of a series of synthetic molecules inspired by the structure of tambjamine alkaloids can be tuned by varying the lipophilicity of the receptor, with carriers within a certain log P range performing best. PMID- 22531692 TI - Enantioselective synthesis of substituted pyrans via amine-catalyzed Michael addition and subsequent enolization/cyclisation. AB - An organocatalytic construction of optically enriched substituted pyran derivatives via amine-catalyzed Michael addition and subsequent enolization/cyclisation has been described starting from electronically poor alkenes. Functionalized pyrans were obtained in high enantioselectivities (up to 96%) and good yields (up to 90%) having three contiguous chiral centers. PMID- 22531694 TI - Variability in bleach kinetics and amount of photopigment between individual foveal cones. AB - PURPOSE: To study the bleaching dynamics of individual foveal cone photoreceptors using an adaptive optics ophthalmoscope. METHODS: After dark adaptation, cones were progressively bleached and imaged by a series of flashes of 545-nm to 570-nm light at 12 Hz. Intensity measurements were made within the foveal avascular zone (FAZ) to avoid confounding signals from the inner retinal blood supply. Over 1300 cones in this region were identified and tracked through the imaging sequences. A single subject was used who demonstrated the necessary steady fixation, wide FAZ, and resolvability of cones close to the foveal center. RESULTS: The mean intensity of all cones was well-described by first-order kinetics. Individual cones showed marked differences from the mean, both in rate of bleach and amount of photopigment; there was an inverse correlation between these two parameters. A subset of the cones showed large oscillations in intensity consistent with interference from light scattered within the cone outer segment. These cones also bleached more quickly, implying that rapid bleaching induces greater amounts of scatter. CONCLUSIONS: Neighboring cones in the fovea display high variability in their optical properties. PMID- 22531693 TI - Oxidative balance and colon and rectal cancer: interaction of lifestyle factors and genes. AB - Pro-oxidant and anti-oxidant genetic and lifestyle factors can contribute to an individual's level of oxidative stress. We hypothesize that diet, lifestyle and genetic factors work together to influence colon and rectal cancer through an oxidative balance mechanism. We evaluated nine markers for eosinophil peroxidase (EPX), two for myeloperoxidase (MPO), four for hypoxia-inducible factor-1A (HIFIA), and 16 for inducible nitric oxide synthase (NOS2A) in conjunction with dietary antioxidants, aspirin/NSAID use, and cigarette smoking. We used data from population-based case-control studies (colon cancer n=1555 cases, 1956 controls; rectal cancer n=754 cases, 959 controls). Only NOS2A rs2297518 was associated with colon cancer (OR 0.86 95% CI 0.74, 0.99) and EPX rs2302313 and MPO rs2243828 were associated with rectal cancer (OR 0.75 95% CI 0.59, 0.96; OR 0.81 95% CI 0.67, 0.99 respectively) for main effects. However, after adjustment for multiple comparisons we observed the following significant interactions for colon cancer: NOS2A and lutein, EPX and aspirin/NSAID use, and NOS2A (4 SNPs) and cigarette smoking. For rectal cancer we observed the following interactions after adjustment for multiple comparisons: HIF1A and vitamin E, NOS2A (3SNPs) with calcium; MPO with lutein; HIF1A with lycopene; NOS2A with selenium; EPX and NOS2A with aspirin/NSAID use; HIF1A, MPO, and NOS2A (3 SNPs) with cigarette smoking. We observed significant interaction between a composite oxidative balance score and a polygenic model for both colon (p interaction 0.0008) and rectal cancer (p=0.0018). These results suggest the need to comprehensively evaluate interactions to assess the contribution of risk from both environmental and genetic factors. PMID- 22531695 TI - Shape perception is altered by normal aging. AB - PURPOSE: To compare the effects of aging on two shape-discrimination tasks: a closed shape task (radial frequency [RF] patterns) and a Glass pattern coherence task (discrimination of global shape signal from textured noise). We hypothesized that aging would impair the extraction of shape from texture more than the discrimination of closed shapes, consistent with evidence that aging impairs the ability to suppress irrelevant information when segmenting contours from noise. METHODS: Fourteen younger (19-38 years) and 14 older (62-72 years) adults participated. Contrast-detection thresholds were measured for the RF and Glass stimuli, and then shape-discrimination tasks were performed using stimuli of 5 fold each individual's contrast threshold. The threshold sinusoidal amplitude for the discrimination of an RF3 (triangular) versus an RF4 (square) was measured, in addition to the threshold signal coherence level for the discrimination of concentric from radial Glass patterns. RESULTS: Older adults had elevated shape discrimination thresholds: RF: mean older = 27 second arc, younger = 18 second arc, t(26) = -3.14, P < 0.01; Glass patterns mean coherence: older = 29%, younger = 16%, t(26) = -5.67, P < 0.01. Relative to younger adult performance, the Z scores for older adult performance on the Glass task were higher than the RF task (paired t-test; P < 0.05). CONCLUSIONS: Shape perception is not robust to the effects of aging. Greater deficits were manifest for the discrimination of shape from texture than for the discrimination of closed contours. PMID- 22531696 TI - Abnormal radial deformation hyperacuity in children with strabismic amblyopia. AB - PURPOSE: In infants and toddlers, letter acuity is not a useful option, and grating acuity may underestimate the depth of strabismic amblyopia. Here, as a first step to establish the effectiveness of the paradigm as a clinical test, we assessed if radial deformation hyperacuity, known to be severely disrupted in adults with strabismic amblyopia, could be a potential test to detect and monitor strabismic amblyopia in young children. METHODS: Fifty-one strabismic children and 130 normal controls ages 3 to 17 years participated. Radial deformation hyperacuity with three different radial frequency (RF) patterns (1 degrees radius 8 RF, 0.5 degrees radius 8 RF, and 1 degrees radius 16 RF), optotype acuity, and grating acuity were measured. For strabismic children, hyperacuity and grating acuity were identified as normal/amblyopic based on age-matched norms. The normal/abnormal classification was compared with amblyopia diagnosis by gold standard early treatment diabetic retinopathy study (ETDRS) optotype visual acuity. RESULTS: The 0.5 degrees radius 8 RF pattern had 83% sensitivity and 71% positive predictive value (PPV) for strabismic amblyopia. In comparison, the 1 degrees radius 8 RF and 1 degrees radius 16 RF patterns had poorer sensitivity (27%-12%) and PPV (57%-50%) for amblyopia, similar to grating acuity (sensitivity = 38%, PPV = 31%). Amblyopic deficits using the 0.5 degrees radius 8 RF pattern were directly proportional to optotype visual acuity deficits. CONCLUSIONS: The demonstrated feasibility of radial deformation stimuli for forced-choice preferential looking testing and the sensitivity and specificity of the small radius radial deformation hyperacuity stimulus for amblyopia support the potential to utilize this test to detect and monitor amblyopia in infants and preschool children. PMID- 22531697 TI - Two-photon immunofluorescence characterization of the trabecular meshwork in situ. AB - PURPOSE: To develop an in situ model to study biological responses and glaucoma pathology in the human trabecular meshwork (TM). Characteristic TM cell- and glaucoma-associated markers were localized in situ in relation to the tissue's autofluorescent structural extracellular matrix (ECM) by two-photon excitation fluorescence optical sectioning (TPEF). METHODS: Human donor corneoscleral (CS) tissue containing the intact aqueous drainage tract was incubated with dexamethasone (Dex) or TGF-beta1, and immunostained for epifluorescence (EF) microscopy with antibodies to myocilin and alpha smooth muscle (alpha-SMA). Separate specimens were labeled for Type-IV collagen and fibronectin. Nuclei were stained with Hoechst 33342. Multimodal TPEF was used to visualize EF, intravital dyes, and autofluorescence (AF) in situ. Three-dimensional (3D) localization of fluorescence within the TM was analyzed using reconstruction software. RESULTS: Autofluorescent beams, perforated sheets, and fibers, consistent with the uveal (UV), CS, and juxtacanalicular (JCT) meshwork, respectively, were captured at different depths of the TM. Type-IV collagen EF distinctly outlined the AF beams in a location consistent with basement membrane. Fibronectin EF showed a diffuse reticular pattern throughout the TM. TGF-beta1-induced alpha-SMA expression, which was distributed perinuclearly in cells among autofluorescent structures. Dex-induced myocilin expression had both cytosolic and extracellular distributions. CONCLUSIONS: The authors have localized markers that are characteristic of TM cells and relevant to glaucoma pathogenesis in situ using multimodal TPEF without conventional histological embedding and sectioning. Protein expression was inducible in situ and could be analyzed with respect to cells and the ECM within the 3D environment of the human TM. PMID- 22531698 TI - Meta-analysis of sex differences in presbyopia. AB - PURPOSE: Uncorrected presbyopia is a significant cause of visual disability globally. Greater comprehension of the etiology of presbyopia and its contributing factors among medical and vision care providers could lead to changes in correction methods and account for sex differences in near-vision requirements. METHODS: A meta-analysis was performed using nine cross-sectional studies that provided sufficient data to compare the prevalence and magnitude of presbyopia among men and women. This analysis was further subdivided into measurement methods to determine what differences in presbyopia might exist between men and women. RESULTS: Studies of presbyopia including sex as a contributing factor were highly heterogenic (P = 0.01) but overall found female sex to be statistically significant in predicting earlier onset for presbyopia with an adjusted confidence interval (CI) using the Shore method of 95% CI [1.02, 1.45]. When limited to studies only measuring accommodative amplitude, female sex was not associated with presbyopia in a fixed effects model with a 95% CI [0.49, 1.07]. CONCLUSIONS: While an association between female sex and presbyopia for subjective measurements (near spectacle prescriptions and add powers) was indicated, measurements of accommodative amplitude show a weak tendency toward the opposite. CONCLUSION: This suggests that increased association of presbyopia for women is not due to a physiologic difference in accommodation but rather due to other sex differences, such as tasks performed and viewing distances. Age based correction nomograms for presbyopia should therefore consider these sex differences when prescribing add powers for near tasks. PMID- 22531699 TI - Demodex-associated Bacillus proteins induce an aberrant wound healing response in a corneal epithelial cell line: possible implications for corneal ulcer formation in ocular rosacea. AB - PURPOSE: The aim of the work presented here was to establish the response of a corneal epithelial cell line (hTCEpi) to protein extracted from a bacterium (Bacillus oleronius) previously isolated from a Demodex mite from a rosacea patient. METHODS: The response of the corneal epithelial cell line to Bacillus proteins was measured in terms of alterations in cell migration and invasiveness. Changes in the expression of metalloproteinase genes and proteins were also assessed. RESULTS: The results indicated increased cell migration (14.5-fold, P = 0.001) as measured using 8-MUm PET inserts (BD Falcon) in a transwell assay and invasiveness (1.7-fold, P = 0.003) as measured using 8-MUm Matrigel (BD Biocoat) invasion inserts in a 24-well plate assay format, following exposure to the Bacillus proteins. Cells exposed to the Bacillus protein showed a dose-dependent increase in expression of genes coding for matrix metalloprotease (MMP)-3 (61 fold) and MPP-9 (301-fold). This dose-dependent increase in gene expression was also reflected in elevated levels of MMP-9 protein (1.34-fold, P = 0.033) and increased matrix metalloprotease activity (1.96-fold, P = 0.043) being present in the culture supernatant. Cells also displayed reduced levels of beta-integrin (1.25-fold, P = 0.01), indicative of increased motility and elevated levels of vinculin (2.7-fold, P = 0.0009), suggesting altered motility. CONCLUSIONS: The results indicate that exposure of corneal epithelial cells to Bacillus proteins results in an aberrant wound healing response as visualized using a scratch wound assay. These results suggest a possible link between the high density of Demodex mites on the eyelashes of ocular rosacea patients and the development of corneal ulcers. PMID- 22531700 TI - Quantitative retinal protein analysis after optic nerve transection reveals a neuroprotective role for hepatoma-derived growth factor on injured retinal ganglion cells. AB - PURPOSE: Retinal ganglion cell (RGC) degeneration is an important cause of visual impairment and can be modeled by optic nerve transection, which causes the death of 90% of RGCs within 14 days postaxotomy. We performed a proteomic study to identify and quantify proteins in the rat retina after optic nerve transection. Our goal was to isolate potential targets for therapeutic intervention to prevent RGC degeneration. METHODS: iTRAQ proteomics was used to analyze adult rat retinas at 1, 3, 4, 7, 14, and 21 days postaxotomy. Hepatoma-derived growth factor (HDGF), a target identified by iTRAQ, was delivered by intraocular injections. Wortmannin or PD98059 were coadministered with HDGF to determine if the protective effects of HDGF are dependent on PI3 kinase or MAP kinase activity, respectively. RESULTS: At a false-discovery rate of 5%, 216 proteins were identified by iTRAQ proteomics, 71 of which showed changes in expression (<0.7* or >1.3*) at one time point after injury: 52 proteins had expression peaks, whereas 19 showed downward expression spikes. Levels of GAPDH did not change after axotomy. Among these differentially expressed proteins was HDGF. HDGF delivery significantly increased RGC survival compared with control treatments, and increased Akt phosphorylation in the retina at 24 hours after intraocular injection. RGC rescue by HDGF was dependent on both MAP kinase and PI3 kinase activity in the retina. CONCLUSIONS: We have identified numerous proteins that are differentially regulated at key time points after axotomy, and how the temporal profiles of their expression parallel RGC death. Using these data, we showed that HDGF is a potent neuroprotective factor for injured adult RGCs. PMID- 22531701 TI - Evaluation and quantitation of intact wax esters of human meibum by gas-liquid chromatography-ion trap mass spectrometry. AB - PURPOSE: Wax esters (WE) of human meibum are one of the largest group of meibomian lipids. Their complete characterization on the level of individual intact lipid species has not been completed yet. We obtained detailed structural information on previously uncharacterized meibomian WE. METHODS: Intact WE were separated and analyzed by means of high-temperature capillary gas-liquid chromatography (GLC) in combination with low voltage (30 eV) electron ionization ion trap mass spectrometry (ITMS). 3D (mass-to-charge ratio [m/z] versus lipid sample weight versus signal intensity) calibration plots were used for quantitation of WE. RESULTS: We demonstrated that GLC-ITMS was suitable for analyzing unpooled/underivatized WE collected from 14 individual donors. More than 100 of saturated and unsaturated WE (SWE and UWE, respectively) were detected. On average, UWE represented about 82% of the total WE pool. About 90% of UWE were based on oleic acid, while less than 10% were based on palmitoleic acid. The amounts of poly-UWE were <3% of their mono-UWA counterparts. SWE were based primarily on C(16)-C(18) fatty acids (FA) in overall molar ratios of 22:65:13. A pool of C(16:0)-FA was comprised of a 20:80 (mol/mol) mixture of straight chain and iso-branched isomers, while the corresponding ratio for C(18:0)-FA was 43:57. Interestingly, C(17:0)-FA was almost exclusively branched, with anteiso- and iso-isomers found in a ratio of 93:7. CONCLUSIONS: GLC-ITMS can be used successfully to analyze more than 100 individual species of meibomian WE, which were shown to comprise 41 +/- 8% (wt/wt) of meibum, which made them the largest group of lipids in meibum. PMID- 22531703 TI - Are there any left-right asymmetries in saccade parameters? Examination of latency, gain, and peak velocity. AB - PURPOSE: Hemispheric specialization in saccadic control is still under debate. Here we examine the latency, gain, and peak velocity of reactive and voluntary leftward and rightward saccades to assess the respective roles of eye and hand dominance. METHODS: Participants with contrasting hand and eye dominance were asked to make saccades toward a target displayed at 5 degrees , 10 degrees , or 15 degrees left or right of the central fixation point. In separate sessions, reactive and voluntary saccades were elicited by Gap-200, Gap-0, Overlap-600, and Antisaccade procedures. RESULTS: Left-right asymmetries were not found in saccade latencies but appeared in saccade gain and peak velocity. Regardless of the dominant hand, saccades directed to the ipsilateral side relative to the dominant eye had larger amplitudes and faster peak velocities. CONCLUSIONS: Left-right asymmetries can be explained by naso-temporal differences for some subjects and by eye dominance for others. Further investigations are needed to examine saccadic parameters more systematically in relation to eye dominance. Indeed, any method that allows one to determine ocular dominance from objective measures based on saccade parameters should greatly benefit clinical applications, such as monovision surgery. PMID- 22531702 TI - Ethnic difference of the anterior chamber area and volume and its association with angle width. AB - PURPOSE: To compare the anterior chamber area/volume (ACA/ACV) and their relationship with the drainage angle between adult Caucasians and Chinese. METHODS: Study groups were comprised of four age- and sex-matched cohorts: American Caucasians, American Chinese, southern mainland Chinese, and northern mainland Chinese. All subjects were consecutively recruited from general ophthalmology clinics except for southern mainland Chinese participants who were drawn from an ongoing population-based study. Anterior segment optical coherence tomography (ASOCT) images were obtained under dark conditions. Customized software was used to analyze structural indices including ACA/ACV, angle opening distance (AOD), anterior chamber depth (ACD), anterior chamber width (ACW), lens vault (LV), corneal arc depth (CAD), iris thickness (IT), iris curvature (ICurv), and iris area (IArea). RESULTS: Data from 121, 124, 121, and 120 participants were obtained of American Caucasians, American Chinese, and southern and northern mainland Chinese, respectively. After multiple linear regression analysis, adjusting for age, sex, pupil diameter (PD), and axial length (AL), ACA/ACV was positively associated with ACD, ACW, CAD, and corneal radius of curvature (CR) but negatively related with ICurv and IArea. Ethnic Chinese had significantly smaller ACA (beta = -0.18, P = 0.022) and ACV (beta = -3.9, P = 0.001) than Caucasians. ACV contributes the most to AOD variation for both Chinese (standardized regression coefficient [SRC] = 0.47, P < 0.001) and Caucasians (SRC = 0.59, P < 0.001). CONCLUSIONS: Compared with Caucasians, ethnic Chinese had smaller ACA/ACV independent of ACD, ACW, ICurv, IArea, PD, CR, and AL. ACA/ACV is the most prominent contributor to angle width variation for both Chinese and Caucasians in this study. PMID- 22531705 TI - Associations of IL-23 with polypoidal choroidal vasculopathy. AB - PURPOSE: To determine the relationship between the levels of intraocular inflammatory cytokines and polypoidal choroidal vasculopathy (PCV). METHODS: Prospective cohort study. Sixty-two patients with PCV and 36 control subjects were studied. The levels of cytokines, chemokines, and growth factors in the aqueous humor samples from PCV patients and control subjects were assessed for significant associations with PCV. Logistic regression analysis was used to compute the odds ratios (ORs) and 95% confidence intervals (CIs) after the study populations were divided into quartiles. RESULTS: In PCV patients, IL-4, IL-10, and IL-23 were significantly higher than in the controls. Logistic analyses showed a significantly high risk for IL-23 (OR for the highest quartile compared with the lowest quartile: 16.3; 95% CI: 3.5-75.2), VEGF (5.7; 1.2-26.1), and IL-4 (4.0; 1.3-12.7). IL-10 and IL-4, but not IL-23, were significantly correlated with the VEGF levels in PCV patients (IL-10: rho = 0.477, IL-4: rho = 0.281). The elevated levels of IL-5, IL-10, IL-4, IL-23, and IL-1alpha were found to be significantly associated with exudative lesion(s) in the fluorescein angiograms. CONCLUSIONS: The significant associations between elevated levels of IL-23 with PCV and its activity strongly suggest an involvement of inflammatory processes in the etiology of PCV, presumably independent of VEGF. (www.umin.ac.jp/ctr number, UMIN000003854.). PMID- 22531704 TI - Racemization of two proteins over our lifespan: deamidation of asparagine 76 in gammaS crystallin is greater in cataract than in normal lenses across the age range. AB - PURPOSE: Long-lived proteins are widespread in man, yet little is known about the processes that affect their function over time, or their role in age-related diseases. METHODS: Racemization of two proteins from normal and cataract human lenses were compared with age using tryptic digestion and LC/mass spectrometry. Asp 151 in alphaA crystallin and Asn 76 in gammaS crystallin were studied. RESULTS: Age-dependent profiles for the two proteins from normal lenses were different. In neither protein did the modifications increase linearly with age. For alphaA crystallin, racemization occurred most rapidly during the first 15 years of life, with approximately half of L-Asp 151 converted to D-isoAsp, L isoAsp, and D-Asp in a ratio of 3:1:0.5. Values then changed little. By contrast, racemization of Asn 76 in gammaS crystallin was slow until age 15, with isoAsp accounting for only 5%. Values remained relatively constant until age 40 when a linear increase (1%/year) took place. When cataract lenses were compared with age matched normal lenses, there were marked differences in the time courses of the two crystallins. For alphaA crystallin, there was no significant difference in Asp 151 racemization between cataract and normal lenses. By contrast, in gammaS crystallin the degree of conversion of Asn 76 to isoAsp in cataract lenses was approximately double that of normals at every age. CONCLUSIONS: Modification of Asn and Asp over time may contribute to denaturation of proteins in the human lens. An accelerated rate of deamidation/racemization at selected sites in proteins, such as gammaS crystallin, may contribute to cataract formation. PMID- 22531706 TI - Mutations in RD3 are associated with an extremely rare and severe form of early onset retinal dystrophy. AB - PURPOSE: To identify the underlying mutation and describe the phenotype in a consanguineous Kurdish family with Leber's congenital amaurosis (LCA)/early onset severe retinal dystrophy (EOSRD). METHODS: Members of the index family were followed up to 22 years by ophthalmological examinations, including best corrected visual acuity (BCVA), Goldmann visual field (GVF), two-color-threshold perimetry (2CTP) and Ganzfeld electroretinogram (ERG), fundus photographs, fundus autofluorescence (FAF), and optical coherence tomography (OCT). After excluding seven of nine known LCA/EOSRD genes in the index patient, linkage analysis was performed in the family using a microarray followed by microsatellite fine mapping and direct sequencing of candidate genes. RD3 was screened by direct sequencing of 85 independent patients with LCA/EOSRD presenting with a BCVA >= 1.0 LogMAR before the age of 2 years to assess the prevalence of RD3 mutations in LCA/EOSRD. Since RD3 and RetGC1 have a functional relation, study authors screened for a modifying effect of RD3 mutations in 17 independent patients with mutations in GUCY2D. RESULTS: BCVA was severely reduced from the earliest examinations (as early as 3 months), never exceeding 1.3 LogMAR. The disease presented as cone-rod dystrophy with dystrophic changes in the macula and bone spicules in the periphery on progression. Linkage analysis narrowed the region of interest towards the LCA12 locus. Direct sequencing of RD3 revealed a homozygous nonsense mutation (c.180C > A) in all affected members tested. Screening of additional unrelated LCA/EOSRD patients revealed only polymorphisms in RD3. CONCLUSIONS: This is the second family reported so far with mutations in RD3. Mutations in RD3 are a very rare cause of LCA associated with an extremely severe form of retinal dystrophy. PMID- 22531708 TI - GABA-induced relaxation of porcine retinal arterioles in vitro depends on inhibition from the perivascular retina and is mediated by GABAC receptors. AB - PURPOSE: To study the dependence of gamma-aminobutyric acid (GABA)-induced relaxation of retinal arterioles on the glutamate agonist N-methyl-D-aspartate (NMDA), adenosine triphosphate (ATP), prostaglandin E2 (PGE2), and adenosine, and to characterize the type and location of GABA-receptor(s) mediating GABA-induced relaxation of retinal arterioles. METHODS: Porcine retinal arterioles were mounted in a wire myograph, and the effects of agonists and antagonists to NMDA, ATP, PGE2, and adenosine on GABA-induced relaxation were studied. Additionally, experiments were conducted to study relaxation induced by agonists to specific GABA receptors, and GABA-induced relaxation in the presence of specific GABA antagonists. Finally, immunohistochemistry was performed to identify the location of GABA(C) receptors in the porcine retina. RESULTS: GABA induced vasorelaxation during blocking of the glutamate NMDA receptor, PGE2 receptor, and ATP synthesis degradation, but not during blocking of the adenosine receptor or by agonists to any of these compounds. The vasorelaxing effect of GABA could be elicited by a specific GABA(C) agonist, but not by specific GABA(A) or GABA(B) agonists, and could be blocked by a specific GABA(C) antagonist, but not by specific GABA(A) or GABA(B) antagonists. GABA(C) receptor subunits could be identified in the ganglion cell layer, and at the border between the outer plexiform and inner nuclear layers. CONCLUSIONS: GABA-induced relaxation of porcine retinal vessels is mediated by the GABA(C) receptor in the perivascular retinal tissue, and depends on blocking of the glutamate NMDA receptor, prostaglandin E2 receptor, or ATP degradation. PMID- 22531709 TI - Microcalorimetry of oxygen adsorption on fcc Co{110}. AB - The coverage dependent heats of adsorption and sticking probabilities for oxygen on fcc Co{110} have been measured at 300 K using single crystal adsorption calorimetry (SCAC). Initial adsorption is consistent with dissociative chemisorption at low coverage followed by oxide formation above 0.6 ML coverage. The initial heat of adsorption of 633 kJ mol(-1) is similar to heat values calorimetrically measured on other ferromagnetic metal surfaces, such as nickel and iron. As the coverage increases, the heat of adsorption and sticking probability drop very rapidly up to the onset of oxidation. As already observed for other oxygen-metal surface systems, strong lateral adatom repulsions are responsible for the transition from the chemisorption regime to oxide film formation at higher coverage. The heat of oxide formation at the onset is 475 kJ mol(-1), which is consistent with the formation of CoO crystallites. The oxide film formation is discussed in terms of nucleation and island growth, and the Mott-Cabrera mechanisms, the latter being evidenced by the relatively constant heat of adsorption and sticking probability in contrast to the nickel and iron oxidation cases. PMID- 22531707 TI - Chemical chaperone TUDCA preserves cone photoreceptors in a mouse model of Leber congenital amaurosis. AB - PURPOSE: Mutations in either retinoid isomerase (RPE65) or lecithin-retinol acyltransferase (LRAT) lead to Leber congenital amaurosis (LCA). By using the Lrat(-/-) mouse model, previous studies have shown that the rapid cone degeneration in LCA was caused by endoplasmic reticulum (ER) stress induced by S opsin aggregation. The purpose of this study is to examine the efficacy of an ER chemical chaperone, tauroursodeoxycholic acid (TUDCA), in preserving cones in the Lrat(-/-) model. METHODS: Lrat(-/-) mice were systemically administered with TUDCA and vehicle (0.15 M NaHCO(3)) every 3 days from P9 to P28. Cone cell survival was determined by counting cone cells on flat-mounted retinas. The expression and subcellular localization of cone-specific proteins were analyzed by western blotting and immunohistochemistry, respectively. RESULTS: TUDCA treatment reduced ER stress and apoptosis in Lrat(-/-) retina. It significantly slowed down cone degeneration in Lrat(-/-) mice, resulting in a ~3-fold increase in cone density in the ventral and central retina as compared with the vehicle treated mice at P28. Furthermore, TUDCA promoted the degradation of cone membrane associated proteins by enhancing the ER-associated protein degradation pathway. CONCLUSIONS: Systemic injection of TUDCA is effective in reducing ER stress, preventing apoptosis, and preserving cones in Lrat(-/-) mice. TUDCA has the potential to lead to the development of a new class of therapeutic drugs for treating LCA. PMID- 22531710 TI - Highly oriented nanoplates of layered double hydroxides as an ultra slow release system. AB - A novel controlled molecular release based on highly oriented nanoplates of layered double hydroxide was fabricated on indium tin oxide substrates by electrophoretic deposition of exfoliated LDH nanosheets. The LDH particle coating exhibited a superior release performance of the order of hours. PMID- 22531711 TI - Effects of indomethacin test on intracranial pressure and cerebral hemodynamics in patients with refractory intracranial hypertension: a feasibility study. AB - BACKGROUND: Intracranial hypertension is the final pathway of many neurocritical entities, such as spontaneous intracerebral hemorrhage (sICH) and severe traumatic brain injury (sTBI). OBJECTIVE: This study aimed to (1) determine alterations in intracranial pressure (ICP) and cerebral hemodynamics after an indomethacin (INDO) infusion test and the related association with survival in patients with refractory intracranial hypertension (RICH) secondary to sICH or sTBI and (2) assess the safety profile after INDO. METHODS: INDO was administered in a loading dose (0.8 mg/kg/15 min), followed by a 2-hour continuous infusion (0.5 mg/kg/h) in RICH patients with ICP greater than 20 mm Hg who did not respond to first-line therapies. Changes in ICP, cerebral perfusion pressure (CPP), and cerebrovascular variables (assessed by transcranial Doppler and jugular bulb saturation) were observed. Clinical outcome was assessed at 1 and 6 months according to the Glasgow Outcome Scale and correlated with INDO infusion test response. Analysis of INDO safety profile was conducted. RESULTS: Thirteen sICH and 10 sTBI patients were studied. The median GCS score at admission was 6. Within 30 minutes of INDO infusion, ICP decreased (42.0 +/- 13.5 vs 27.70 +/- 12.7 mm Hg; Delta%: -48.4%; P < .001), and both CPP (57.7 +/- 4.8 vs 71.9 +/- 7.0 mm Hg; Delta%: +26.0%; P < .001) and middle cerebral artery velocity (35.2 +/- 5.6 vs 42.0 +/- 5.1 cm.s(-1); Delta%: +26.1%; P < .001) increased. The CPP response to a 2-hour INDO infusion test was correlated (R2 = 0.72, P < .001) with survival. No adverse events were observed after INDO. CONCLUSION: Our findings support the effectiveness and feasibility of an INDO test in decreasing ICP and improving cerebral hemodynamics in surviving RICH patients. Future studies to evaluate different doses, lengths of infusion, and longer term effects are needed. PMID- 22531712 TI - A hierarchically assembled mesoporous ZnO hemisphere array and hollow microspheres for photocatalytic membrane water filtration. AB - A mesoporous ZnO hemisphere array has been prepared via a topotactic transition of Zn(4)(OH)(6)CO(3).H(2)O (ZCHH) by chemical bath deposition. Each hemisphere is comprised of a radially oriented nanoflake shell grown on the hemispherical interior. Reaction time-dependent SEM analysis shows that the morphological formation of ZCHH involves a deposition-growth-secondary growth-redeposition procedure. Upon calcination, ZCHH readily decomposes to nanocrystalline wurtzite phase ZnO without significant change in morphology, and the release of CO(2) and H(2)O from ZCHH creates an additional mesoporous structure in both hemispherical interior and nanoflake shell. A similar process but without using a substrate has been developed for synthesis of mesoporous ZnO hollow microspheres in powder form. Both the elaborated superstructured photocatalysts consisting of mesoporous nanoflakes have been demonstrated to exhibit excellent performances in the photocatalytic membrane filtration. PMID- 22531715 TI - Identification of OASL d, a splice variant of human OASL, with antiviral activity. AB - The 2',5'-oligoadenylate synthetases (OASs) are IFN-induced antiviral proteins and are upregulated by infection of viral and some bacterial pathogens. There are at least 2 transcripts of approximately 1.8 and 2.0 kb in interferon-beta treated samples that are recognized by a probe for human OASL in Northern blot assay. By RT-PCR amplification we have isolated a previously undescribed splice variant of human OASL, named OASL d. The new variant was derived from deletion of exons 4 and 5 and encodes a protein of 384 aa residues that shares the N-terminal 219 aa residues with OASL a. Sequence analysis indicates that OASL d also contains the entire ubiquitin-like domain identified in human OASL a. OASL d was strongly induced by IFNgamma in THP-1 monocytic cells and in A549 epithelial cells by interferon-beta as detected by immunoblotting assay. Ectopic expression of OASL a or OASL d, but not OASL b that shares the N-terminus with OASL a and d, partially inhibited EV71 and VSV infection. No effect against HSV-2 infection was observed. Therefore, OASL d is a novel isoform of human OASL that possesses antiviral activity against RNA viruses. PMID- 22531714 TI - The zinc finger transcription factor ZKSCAN3 promotes prostate cancer cell migration. AB - In our previous studies, ZKSCAN3 was demonstrated to be over-expressed in invasive colonic tumor cells and their liver metastases, but minimally expressed in adjacent non-transformed tissues. Further preliminary data showed that ZKSCAN3 was expressed in a majority of prostate cancer patient samples, but not in normal prostate tissues. Moreover, the ZKSCAN3 protein is highly expressed in the PC3 prostate cancer cell line, which has high metastatic potential, but little expression was observed in non-metastatic prostate cancer cell lines. Thus, we hypothesized that ZKSCAN3 could participate in tumor metastasis by regulating tumor cell migration. To test this hypothesis, ZKSCAN3 mRNA was knocked down by ZKSCAN3 specific shRNA in PC3 cells and a significant decrease in cell motility was observed. In contrast, when ZKSCAN3 cDNA was overexpressed in PC3 cells, cell detachment was observed and suspension culture induced apoptosis was greatly decreased, suggesting that ZKSCAN3 is able to enhance PC3 cell survival under anoikis stress. Additional wound healing and invasion assays showed that cell migration was enhanced by ZKSCAN3 expression. Interestingly, the ZKSCAN3 gene was amplified in 26% (5/19) of metastatic prostate cancers and 20% (1/5) of lymph node metastases, but there was no amplification found in primary prostate cancers, further supporting the role of ZKSCAN3 in tumor cell migration. In vivo studies using orthotopic tumor models indicated that overexpression of ZKSCAN3 significantly enhanced tumorigenicity. Taken together, we provide evidence that ZKSCAN3, a zinc finger transcription factor, plays a critical role in promoting prostate cancer cell migration. PMID- 22531716 TI - Psychometric properties of a revised version of the Visual Analog Mood Scales. AB - OBJECTIVE: To assess the internal consistency, validity and factor structure of a revised version of the Visual Analog Mood Scales (VAMS-R) in healthy older adults and aphasic stroke patients. DESIGN: Cross-sectional study. PARTICIPANTS: Fifty healthy older people and 71 aphasic stroke patients. SETTING: Community and hospital. MEASURES: The healthy participants were asked to complete the Hospital Anxiety and Depression Scale (HADS) and the VAMS-R. The aphasic stroke patients completed the VAMS-R and Visual Analogue Self Esteem Scale (VASES) and the Stroke Aphasic Depression Questionnaire 21 (SADQH-21) was completed by a nurse or carer. RESULTS: The internal consistency of the scale was high (healthy adults alpha 0.74, aphasic stroke patients alpha 0.80). The VAMS-R correlated significantly with the HADS in healthy participants (HADS Anxiety r (s) = 0.59, P < 0.001, HADS Depression r (s) = 0.49, P = 0.001) and the VASES (r (s) = -0.69, P < 0.001) and SADQH-21 (r (s) = 0.43, P = 0.001) in stroke patients. Exploratory factor analysis identified three factors in the scale: negative mood states, energy levels and happiness. The three factors accounted 73% of the variance in healthy participants and 70% of the variance in aphasic stroke patients. CONCLUSIONS: The VAMS-R showed better psychometric properties than the original VAMS. Reversing the happy and energetic items improved the ability of the scale to assess mood states. PMID- 22531713 TI - Antiviral therapies: focus on hepatitis B reverse transcriptase. AB - Hepatitis B virus (HBV) is the etiologic agent of mankind's most serious liver disease. While the availability of a vaccine has reduced the number of new HBV infections, the vaccine does not benefit the approximately 350 million people already chronically infected by the virus. Most of the drugs approved by the FDA for the treatment of hepatitis B target the reverse transcriptase (RT or P gene product) and are nucleoside RT inhibitors (NRTIs) that suppress viral replication. However, prolonged monotherapies directed against a single target result in the emergence of viral resistance. HBV genotypic differences affect NRTI resistance, and because the reading frames of the S (surface antigen) and P genes partially overlap, genomic differences that affect the surface of the virus may also alter the viral polymerase sequence, function and drug susceptibility. The scope of this review is to assess the effects of HBV genotypic variation on the development of drug resistance to NRTIs. Some RT residues that vary among different genotypes are in the vicinity of residues that mutate and give rise to NRTI resistance. Interactions between these amino acids can help explain the effect of HBV genotype on the development of NRTI resistance during antiviral therapies, and might help in the design of improved therapeutic strategies. PMID- 22531717 TI - Inter-rater reliability of the Nottingham Neurological Driving Assessment for people with dementia - a preliminary evaluation. AB - OBJECTIVE: The purpose was to examine the inter-rater reliability of the Nottingham Neurological Driving Assessment. PARTICIPANTS: Six drivers with dementia (mean age 78 years, 5 men). INTERVENTIONS: Participants were assessed for their safety to drive on a set route while being observed by two driving assessors, who were experienced in assessing safety to drive in people with dementia. MAIN MEASURES: Performance was rated in terms of overall safety to drive and 25 items were recorded as correct, minor error (not compromising safety) and major error (compromising safety). RESULTS: Four drivers were found to be probably safe to drive and two definitely unsafe to drive. There was perfect agreement in the overall decisions about safety to drive. There were significant discrepancies between correct or minor error and major error on six of the 25 items of the road test involving three participants. CONCLUSIONS: Two experienced driving assessors agreed on the overall safety to drive of six participants with dementia. There were discrepancies about safety on six out of 150 observations (4%). PMID- 22531718 TI - Gamma-glutamyl transferase: risk and prognosis of cancer. PMID- 22531719 TI - CXCR7 expression is associated with disease-free and disease-specific survival in cervical cancer patients. AB - BACKGROUND: The CXC chemokine receptor (CXCR)7 is involved in tumour development and metastases formation. The aim of the present study was to determine protein expression of CXCR7, its putative co-receptors epidermal growth factor receptor (EGFR) and CXCR4, its predominant ligand CXCL12, their co-dependency and their association with survival in cervical cancer patients. METHODS: CXC chemokine receptor 7, EGFR, CXCR4 and CXCL12 expression were determined immunohistochemically in 103 paraffin-embedded, cervical cancers. Subsequently, associations with patient characteristics were assessed and survival analyses were performed. RESULTS: CXC chemokine receptor 7 was expressed by 43% of tumour specimens, in a large majority of cases together with either EGFR or CXCR4 (double positive), or both (triple positive). The CXCR7 expression was associated with tumour size (P=0.013), lymph node metastasis (P=0.001) and EGFR expression (P=0.009). CXC chemokine receptor 7 was independently associated with disease free survival (hazard ratio (HR)=4.3, 95% confidence intervals (CI) 1.7-11.0, P=0.002), and strongly associated with disease-specific survival (HR=3.9, 95% CI 1.5-10.2, P=0.005). CONCLUSION: CXC chemokine receptor 7 expression predicts poor disease-free and disease-specific survival in cervical cancer patients, and might be a promising new therapeutic marker. In a large majority of cases, CXCR7 is co expressed with CXCR4 and/or EGFR, supporting the hypothesis that these receptors assist in CXCR7 signal transduction. PMID- 22531720 TI - PI3K/Akt signalling is required for the attachment and spreading, and growth in vivo of metastatic scirrhous gastric carcinoma. AB - BACKGROUND: PI3K/Akt (PKB) pathway has been shown in several cell types to be activated by ligands to cell surface integrins, leading to the metastasis of tumour cells. The signalling pathways involved in the metastatic spread of human scirrhous gastric carcinoma cells have not been defined. METHODS: The role of the PI3K/Akt pathway in an extensive peritoneal-seeding cell line, OCUM-2MD3 and a parental cell line, OCUM-2M, was investigated by assessing in vitro adhesion and spreading assay, and in vivo peritoneal metastatic model. We also examined the correlation of PI3K/Akt pathway with integrin signals by immunoprecipitations, using cells by transfection with mutant p85 (Deltap85). RESULTS: Adhesiveness and spreading of OCUM-2MD3 cells on collagen type IV was significantly decreased by PI3K inhibitors and expression of mutant p85, but not by inhibitors of protein kinase C (PKC) or extracellular signal-regulated kinase (ERK). Immunoprecipitation studies indicated that the PI3K/Akt pathway was associated with integrin signalling through Src and vinculin. In an in vivo experimental metastasis model, p85 inhibition reduced peritoneal metastasis of OCUM-2MD3 cells. CONCLUSION: PI3K/Akt signalling may be required for integrin-dependent attachment and spreading of scirrhous gastric carcinoma cells, and would be translated into generating better strategies to optimise their use in cancer clinical trials. PMID- 22531722 TI - Recent findings in mouse models for human atopic dermatitis. AB - Atopic dermatitis (AD) is a chronic inflammatory skin disease, with its major clinical feature being persistent itch sensation in the skin. There are extremely few animal models to reproduce the complicated condition of a patient with AD; therefore researchers have been confronted with some difficulties in pathologic analysis and drug development for AD. Although various models have been proposed and developed, there is no doubt that the spontaneous mouse model, NC mice, gave the greatest impact. NC mice enabled us to analyze pathogenesis of allergic skin abnormalities as well as development of new drugs for AD. However, many questions still remain in the pathogenesis of AD. In recent years, the study of the itch has attracted our attention because itch is one of the most unbearable symptoms of AD. For development of an effective treatment to overcome the itch, not only a precise animal model but also an accurate evaluation protocol are needed. This review summarizes some mouse models of AD, particularly focusing on NC mice, together with a novel evaluation system for scratching behavior of mice to help the understanding of researchers. PMID- 22531724 TI - Sequence determination of the heavy-chain constant region in four immunoglobulin classes of Mongolian gerbils (Meriones unguiculatus). AB - We determined partial cDNA sequences of four immunoglobulin (Ig) classes-IgM, IgG1, IgE, and IgA-of Mongolian gerbil (Meriones unguiculatus). Each deduced Ig heavy-chain constant (IGHC) region-Cu, Cgamma1, Cepsilon, and Calpha-is structurally similar to its counterparts in the mouse and rat, and phylogenetic analysis suggests that the gerbil Igs are evolutionarily close to their counterparts. In spite of the high sequence homology to the other rodent Cgamma sequences, the gerbil Cgamma1 sequence differs from our previously reported Cgamma2. This result indicates that the gerbil has at least two IgG subclasses. These four gerbil IGHC cDNA sequences will be useful for determining gerbil Ig isotypes and examining the expression of gerbil Ig mRNAs in response to parasitic and bacterial infections. PMID- 22531721 TI - Downregulation of membrane complement inhibitors CD55 and CD59 by siRNA sensitises uterine serous carcinoma overexpressing Her2/neu to complement and antibody-dependent cell cytotoxicity in vitro: implications for trastuzumab-based immunotherapy. AB - BACKGROUND: We evaluated the expression of CD46, CD55 and CD59 membrane-bound complement-regulatory proteins (mCRPs) in primary uterine serous carcinoma (USC) and the ability of small interfering RNA (siRNA) against these mCRPs to sensitise USC to complement-dependent cytotoxicity (CDC) and antibody (trastuzumab) dependent cellular cytotoxicity (ADCC) in vitro. METHODS: Membrane-bound complement-regulatory proteins expression was evaluated using real-time PCR (RT PCR) and flow cytometry, whereas Her2/neu expression and c-erbB2 gene amplification were assessed using immunohistochemistry, flow cytometry and fluorescent in-situ hybridisation. The biological effect of siRNA-mediated knockdown of mCRPs on HER2/neu-overexpressing USC cell lines was evaluated in CDC and ADCC 4-h chromium-release assays. RESULTS: High expression of mCRPs was found in USC cell lines when compared with normal endometrial cells (P<0.05). RT-PCR and FACS analyses demonstrated that anti-mCRP siRNAs were effective in reducing CD46, CD55 and CD59 expression on USC (P<0.05). Baseline complement-dependent cytotoxicity (CDC) against USC cell lines was low (mean +/- s.e.m.=6.8 +/- 0.9%) but significantly increased upon CD55 and CD59 knockdown (11.6 +/- 0.8% and 10.7 +/- 0.9%, respectively, P<0.05). Importantly, in the absence of complement, both CD55 and CD59, but not CD46, knockdowns significantly augmented ADCC against USC overexpressing Her2/neu. CONCLUSION: Uterine serous carcinoma express high levels of the mCRPs CD46, CD55 and CD59. Small interfering RNA inhibition of CD55 and CD59, but not CD46, sensitises USC to both CDC and ADCC in vitro, and if specifically targeted to tumour cells, may significantly increase trastuzumab mediated therapeutic effect in vivo. PMID- 22531723 TI - Advantages of a mouse model for human hearing impairment. AB - Hearing is a major factor in human quality of life. Mouse models are important tools for discovering the genes that are responsible for genetic hearing loss, and these models often allow the processes that regulate the onset of deafness in humans to be analyzed. Thus far, in the study of hearing and deafness, at least 400 mutants with hearing impairments have been identified in laboratory mouse populations. Analysis of through a combination of genetic, morphological, and physiological studies is revealing valuable insights into the ontogenesis, morphogenesis, and function of the mammalian ear. This review discusses the advantages of the mouse models of human hearing impairment and highlights the identification of the molecules required for stereocilia development in the inner ear hair cells by analysis of various mouse mutants. PMID- 22531725 TI - Color preferences of laboratory mice for bedding materials: evaluation using radiotelemetry. AB - Preferences for different housing conditions in mice were evaluated by radiotelemetry. Male C57BL/6J and ICR mice were used. Preference for bedding materials in mice was compared among three materials, wood shavings (WS), paper (CF) and cloth (AG), using the length of stay in cages as a parameter. The results indicated that mice stayed longer in a cage with AG than in cages with other bedding materials. The present study confirmed our previous results and thereby indicated that radiotelemetry is a useful method to evaluate impacts of housing conditions on animal welfare. In the second part of this study, we used radiotelemetry to evaluate color preference of the mice for cloth bedding material. In C57BL/6J mice, staying time in black cloth was significantly longer than that in white cloth. In ICR mice, staying time in white cloth was significantly longer than that in black cloth. The mice preferred the environment with the same color as their fur, which may be important for animal welfare. PMID- 22531726 TI - Involvement of protein kinase C in reduction of aggregated protein and phosphorylation of CREB in glomeruli. AB - We previously demonstrated the cAMP-PKA pathway to be associated with the reduction in aggregated proteins such as immune complex in glomeruli. The aim of this study was to clarify whether PKC is involved in the reduction of aggregated protein and phosphorylation of CREB in aggregated protein-loaded glomeruli. Mice were injected with aggregated bovine serum albumin (a-BSA), and glomeruli were isolated. The a-BSA-injected mice produced more cyclic AMP and had more phosphorylated serine and phosphorylated CREB in their glomeruli than the controls. The expression of phospho-CREB increased with the accumulation of a BSA. KT5720 and H7 suppressed the increase in phosphorylated CREB in a-BSA-loaded glomeruli and the decrease in accumulated a-BSA in the glomeruli. These findings suggest that PKC is associated with the reduction of aggregated protein and phosphorylation of CREB in aggregated protein-loaded glomeruli. PMID- 22531727 TI - Impairment of alpha(2)-macroglobulin synthesis in experimental hepatopathic rats treated with turpentine oil. AB - The aim of this study was to investigate the synthesis of alpha(2)-macroglobulin (alpha2M) in hepatopathic rats injected with turpentine oil to induce acute inflammation. Hepatopathy was induced by oral administration of acetaminophen at a dose of 1 g/kg daily for 2 weeks or a 25% solution of carbon tetrachloride (CCl(4)) at 2 ml/kg body weight three times per week for 7 weeks. Acute inflammation was induced by intramuscular injection of turpentine oil at a dose of 1.0 ml/kg body weight. Serum concentrations of alpha2M were measured by enzyme linked immunosorbent assay. Aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and total protein differed significantly between acetaminophen or CCl(4)-induced hepatopathic rats and acetaminophen control (AA control) or CCl(4) control (CC-control) rats. Furthermore, pathological examination confirmed hepatopathy in rat livers. Peak serum concentrations and area under the time-concentration curve for alpha2M showed significant differences between hepatopathic rats and AA-control or CC-control rats. Thus, serum concentrations of alpha2M did not increase when compared with nontreated rats. PMID- 22531728 TI - A-type natriuretic peptide level in angiotensin II type 1a receptor knockout mice. AB - A-type (atrial) natriuretic peptide (ANP) levels in the heart and plasma were examined by immunohistochemistry, electron microscopy, and radioimmunoassay (RIA) in angiotensin II type 1a receptor knockout (Agtr1a KO) mice. Additionally, the ANP mRNA level in the heart was measured using a real-time polymerase chain reaction (PCR) assay. The blood pressure in Agtr1a KO mice was significantly lower than that in wild-type (WT) mice. The number of ANP granules and ANP immunoreactivity in the auricular cardiocytes were significantly lower in Agtr1a KO mice than in WT mice. Ultrastructurally, the ventricular cardiocytes in Agtr1a KO mice occasionally had ANP-like granules, which were not present in WT mice. The plasma, auricular, and ventricular ANP and plasma cyclic guanosine monophosphate (cGMP) concentrations were significantly higher in Agtr1a KO mice than in WT mice. The ANP mRNA levels of the auricular and ventricular cardiocytes in the Agtr1a KO mice were almost twice as large as those in WT mice. The present data suggest that a notable increase in the ANP biosynthesis and release in the heart of Agtr1a KO mice may account for the reduction in blood pressure together with the lack of an AGTR1A receptor in this model. PMID- 22531729 TI - An attempt of cryopreservation of mouse embryos at the ACTREC laboratory animal facility in India. AB - Cryopreservation is the long-term storage of viable cells/tissue in liquid nitrogen. The present study was conducted to freeze 8-cell- to morula-stage mouse embryos from the ACTREC Laboratory Animal Facility using a "slow freezing and fast revival" method. In all, 4,088 embryos were collected from 495 donor female mice of ten different strains. An average recovery of 8 embryos per donor mouse were recorded. Of the 4,088 embryos, 3,946 embryos of normal morphology were frozen in 173 straws. They were cooled down using a controlled-rate freezing assembly, and the straws were directly plunged into liquid nitrogen for long-term storage. Out of these 3,946 frozen embryos, 2,650 were found to be viable after fast revival. The highest survival rate, 81%, was recorded in B6D2F1 hybrid mice, whereas the lowest rate, 51%, was recorded in the S/RV/Cri-ba mutant strain. Out of 2,650 viable embryos, 2,359 embryos (89%) developed to the blastocyst stage after 24 h of incubation in a CO(2) incubator. The developed blastocysts were transferred surgically into 101 pseudopregnant female mice, of which 49 (48.5%) females were found to be pregnant. The highest percentage of pregnancy, 75%, was recorded in C57BL/6NCrl and NIH-III mice, whereas no pregnant recipients were recorded in Ptch, C3H/HeNCrl and NOD SCID mice. Based on the deliveries of these 49 females, an average of 4 young were delivered per female. Improvement in efficiency of freezing, thawing, and surgical transfer of embryos into pseudopregnant females is one of the challenges in such studies. PMID- 22531730 TI - Evaluation of the skin blanching of topically applied steroids using a chroma meter in animals. AB - We evaluated the utility of animal skins for determining the skin blanching of steroids. A Chroma Meter was used to determine the skin blanching of steroids. Hydrophilic creams containing clobetasol propionate (CP) or prednisolone (PS) were selected as model steroid formulations. Skin blanching, a*, was determined using a Chroma Meter after the application of 0.005, 0.01, 0.1, or 1.0% CP or PS hydrophilic cream to the back skin of guinea pigs and hairless rats for 24 h. The relationships between Deltaa*(6h) and the skin concentrations of the steroids were determined at 6 h after removal of the cream. Deltaa*(6h) was markedly decreased after the application of CP hydrophilic cream to guinea pigs, and a good linear relationship was observed between Deltaa*(6h) and skin concentration (r=0.98). In contrast, no relationship was observed between these parameters after the application of CP cream to the hairless rats. Although skin blanching was observed after PS cream application in guinea pigs, no relationship was observed between Deltaa*(6h) and skin concentration of PS in each animal. These results suggest that the skin blanching effect of CP in guinea pigs is greater than that of PS and that its blanching effect in guinea pigs was stronger than that in hairless rats. Guinea pigs were found to be a good animal model for determining the skin blanching produced by steroid creams. In addition, Chroma Meters can be effectively used in skin vasoconstrictive tests in guinea pigs. PMID- 22531731 TI - New method of manganese-enhanced Magnetic Resonance Imaging (MEMRI) for rat brain research. AB - Manganese (Mn(2+))-enhanced MRI (MEMRI) is known to provide insight into functional and anatomical biology. However, this method, which uses Mn(2+) as a MRI-detectable contrast agent, has drawbacks such as the toxicity to cells beyond a certain level of Mn(2+). In this study, we attempt to determine a new method of ICV administration, the optimal concentration of administered Mn(2+) and the optimal MEMRI acquisition time following administration. Male Sprague-Dawley rats were used in the following experimental sessions: (1) intracerebroventricular (ICV) cannula implantation in the region of the cisterna magna, (2) serial dilution of MnCl(2) (20-80 mM), (3) ICV administration of MnCl(2) through the cannula, and (4) T(1)-weighted MRI measurements. We confirmed that cannula implantation in the region of the cisterna magna was a new ICV injection method for the administration of a contrast agent. The optimal concentration for MEMRI was 20/50 mM/ul of MnCl(2). The MEMRI data acquired at different time points indicate that most signal enhancement is maintained during 14-48 h after contrast agent injection, and 24 h was the optimal time to acquire images of the rat brain. The present study offers optimized parameters for contrast agent injection that would be a good basis for studies using MEMRI to research the rat brain. PMID- 22531732 TI - Pentobarbital decreased nitric oxide release in the rat striatum but ketamine increased the release independent of cholinergic regulation. AB - Pentobarbital (PB) and ketamine (Ket) influence the concentration of neurotransmitters in the brain. PB has been reported to decrease the extracellular nitric oxide (NO) concentration through a decrease in acetylcholine (ACh) release, while Ket has been shown to increase the NO concentration via an increase in ACh release. Here, we investigated effects of PB and Ket on NO release and the relationship between NO and ACh in the rat striatum by in vivo microdialysis experiments. Male Sprague-Dawley rats were used. A microdialysis probe was inserted into the right striatum and perfused with modified Ringer's solution. Samples were collected every 15 min and injected into an HPLC system. The rats were freely moving, and PB and Ket were administered intraperitoneally. Neostigmine (1 and 10 uM) and mecamylamine (100 uM) were added to the perfusate. Calcium and magnesium concentrations were modified for each anesthetic to influence ACh release. PB decreased NO products (NOx) while Ket increased them. While perfusion with neostigmine showed no effect on baseline NOx concentrations, it diminished the PB-induced NOx reduction at low concentrations and abolished it at high concentrations. Magnesium-free perfusion had no effect on baseline NOx concentrations, whereas perfusion at a low magnesium concentration antagonized the PB-induced NOx reduction. Mecamylamine and calcium-free perfusion had no effect on baseline NOx concentrations and Ket-induced NOx increases. PB may decrease NO release through reduction in ACh release, whereas Ket may increase NO release independent of ACh regulation. PMID- 22531733 TI - Data on Wistar Hannover rats from an immunotoxicity study. AB - The aim of this study was to collect data on immunological parameters from Wistar Hannover rats at 8, 10, 19, and 32 weeks of age. Low leukocyte parameter cell counts, serum globulin concentration, and T, B, and NK lymphocyte counts in peripheral blood at each time point; low T, B, and NK splenocyte counts; and high, or tendencies toward high, thymocyte counts at 10 weeks of age were noted in females when compared with males. KLH-specific antibody production increased gradually with age in both sexes. The immunological data noted for leukocyte parameters, the serum globulin concentration, and immunophenotyping (peripheral blood, spleen, and thymus) relating to chronological changes and sex differences may be useful in assessing drug-related immunotoxicity in this strain. PMID- 22531734 TI - Current status of memorial services for laboratory animals in Japan: a questionnaire survey. AB - In this study, we found that almost all institutions conducting animal experiments, such as universities, corporations, and research laboratories, also conducted memorial services for the animals sacrificed during animal experimentation. A questionnaire survey was conducted among 120 institutions. A total of 83 (69.1%) valid responses were obtained from the participating institutions. Memorial services were held at 79 institutions (95.1%). Memorial services for laboratory animals have been mainly conducted to show appreciation, comfort the spirit, and console the souls. PMID- 22531735 TI - The correlation between postmenopausal osteoporosis and inflammatory periodontitis regarding bone loss in experimental models. AB - We have invented a mouse model of periodontitis associated with alveolar bone loss induced by lipopolysaccharide. Ovariectomized (OVX) animals are widely used as a model for osteoporosis due to estrogen deficiency. To define the relationship between periodontitis and osteoporosis, we examined the influence of estrogen deficiency on the mouse alveolar bone mass. In OVX mice, bone loss was detected not only in the femur, but also in the alveolar bone, indicating that estrogen deficiency could induce resorption in alveolar bone. In experiments using a combination of osteoporosis and periodontitis models, OVX significantly enhanced the alveolar bone loss in the model of periodontitis. Therefore, postmenopausal osteoporosis may enhance the risk of periodontitis associated with inflammatory alveolar bone resorption. PMID- 22531736 TI - Asymmetric aldol reaction via memory of chirality. AB - Asymmetric aldol reactions of alpha-amino acid derivatives via memory of chirality were developed. Chiral oxazolidones with contiguous tetra- and trisubstituted chiral centers were obtained in 78-94% ee by the asymmetric aldol reaction followed by intramolecular acylation. PMID- 22531738 TI - Statistically reliable and fast direct estimation of phase-amplitude cross frequency coupling. AB - There is growing interest in phase-amplitude cross-frequency coupling (PAC), which is widely observed in human and animal brain recordings. The choice of the estimation method is vital while extracting accurate PAC parameters from data. Two desired properties of PAC estimators are reliability and computational efficiency. This study offers a methodology called normalized direct PAC (ndPAC) for the rapid and statistically reliable estimation of PAC strength. A plain confidence limit formula, depending solely on data length and confidence level, is derived. Confidence level derivation is validated numerically. It is shown through simulations that ndPAC exhibits high specificity and sensitivity performances. The suggested methodology is also demonstrated on monkey electrocorticogram recorded during a visual task. PMID- 22531737 TI - Evaluation of a smartphone platform as a wireless interface between tongue drive system and electric-powered wheelchairs. AB - Tongue drive system (TDS) is a new wireless assistive technology (AT) for the mobility impaired population. It provides users with the ability to drive powered wheelchairs (PWC) and access computers using their unconstrained tongue motion. Migration of the TDS processing unit and user interface platform from a bulky personal computer to a smartphone (iPhone) has significantly facilitated its usage by turning it into a true wireless and wearable AT. After implementation of the necessary interfacing hardware and software to allow the smartphone to act as a bridge between the TDS and PWC, the wheelchair navigation performance and associated learning was evaluated in nine able-bodied subjects in five sessions over a 5-week period. Subjects wore magnetic tongue studs over the duration of the study and drove the PWC in an obstacle course with their tongue using three different navigation strategies; namely unlatched, latched, and semiproportional. Qualitative aspects of using the TDS-iPhone-PWC interface were also evaluated via a five-point Likert scale questionnaire. Subjects showed more than 20% improvement in the overall completion time between the first and second sessions, and maintained a modest improvement of ~9% per session over the following three sessions. PMID- 22531739 TI - Fusion of magnetometer and gradiometer sensors of MEG in the presence of multiplicative error. AB - Novel neuroimaging techniques have provided unprecedented information on the structure and function of the living human brain. Multimodal fusion of data from different sensors promises to radically improve this understanding, yet optimal methods have not been developed. Here, we demonstrate a novel method for combining multichannel signals. We show how this method can be used to fuse signals from the magnetometer and gradiometer sensors used in magnetoencephalography (MEG), and through extensive experiments using simulation, head phantom and real MEG data, show that it is both robust and accurate. This new approach works by assuming that the lead fields have multiplicative error. The criterion to estimate the error is given within a spatial filter framework such that the estimated power is minimized in the worst case scenario. The method is compared to, and found better than, existing approaches. The closed-form solution and the conditions under which the multiplicative error can be optimally estimated are provided. This novel approach can also be employed for multimodal fusion of other multichannel signals such as MEG and EEG. Although the multiplicative error is estimated based on beamforming, other methods for source analysis can equally be used after the lead-field modification. PMID- 22531740 TI - Galvanic vestibular stimulation elicits consistent head-neck motion in seated subjects. AB - Humans actively stabilize the head-neck system based on vestibular, proprioceptive and visual information. Galvanic vestibular stimulation (GVS) has been used previously to demonstrate the role of vestibular feedback in standing balance. This study explores the effect of GVS on head-neck kinematics and evaluates the approach to investigate the vestibular contribution to head-neck stabilization. GVS was applied to 11 seated subjects using seven different stimuli (single sinusoids and multisines) at amplitudes of 0.5-2 mA and frequencies of 0.4-5.2 Hz using a bilateral bipolar configuration while 3-D head and torso kinematics were recorded using motion capture. System identification techniques were used evaluating coherence and frequency response functions (FRFs). GVS resulted in significant coherence in roll, yaw and lateral translation, consistent with effects of GVS while standing as reported in the literature. The gain of the FRFs varied with frequency and no modulation was observed across the stimulus amplitudes, indicating a linear system response for the stimulations considered. Compared to single sine stimulation, equivalent FRFs were observed during unpredictable multisine stimulation, suggesting the responses during both stimuli to be of a reflexive nature. These results demonstrate the potential of GVS to investigate the vestibular contribution to head-neck stabilization. PMID- 22531741 TI - Characterization and experimental results of a novel sensor for measuring the contact force from myenteric contractions. AB - The intraluminal pressures and traction forces associated with the migrating motor complex are well understood; however, the contact forces directly exerted by the bowel wall on a solid, or near solid, bolus have not previously been measured. Quantifying contact forces is an important component to understanding the net force experienced by an in vivo robotic capsule endoscope. In this paper, we develop a novel sensor, the migrating motor complex force sensor (MFS), for measuring the contact force generated by the contracting myenteron of the small intestine. The MFS consists of a perfused manometer connected to four torus shaped balloons custom formed of natural latex rubber and embedded with temperature and pressure sensors. Force exerted on the balloon causes sensor pressure change. In vivo, the MFS measures the magnitude and axial location of contact pressure exerted by the myenteron. The device is tested in vivo in a live porcine model on the middle small bowel. The mean total force per centimeter of axial length of intestine that occurred over a 16-min interval in vivo was 1.04 N.cm (-1) in the middle region of the small intestine; the measured force is in the range of theoretical values. PMID- 22531742 TI - flexTMS--a novel repetitive transcranial magnetic stimulation device with freely programmable stimulus currents. AB - Transcranial magnetic stimulation (TMS) is able to noninvasively excite neuronal populations due to brief magnetic field pulses. The efficiency and the characteristics of stimulation pulse shapes influence the physiological effect of TMS. However, commercial devices allow only a minimum of control of different pulse shapes. Basically, just sinusoidal and monophasic pulse shapes with fixed pulse widths are available. Only few research groups work on TMS devices with controllable pulse parameters such as pulse shape or pulse width. We describe a novel TMS device with a full-bridge circuit topology incorporating four insulated gate bipolar transistor (IGBT) modules and one energy storage capacitor to generate arbitrary waveforms. This flexible TMS (flexTMS ) device can generate magnetic pulses which can be adjusted with respect to pulse width, polarity, and intensity. Furthermore, the equipment allows us to set paired pulses with a variable interstimulus interval (ISI) from 0 to 20 ms with a step size of 10 MUs. All user-defined pulses can be applied continually with repetition rates up to 30 pulses per second (pps) or, respectively, up to 100 pps in theta burst mode. Offering this variety of flexibility, flexTMS will allow the enhancement of existing TMS paradigms and novel research applications. PMID- 22531747 TI - Association study between two novel single nucleotide polymorphisms and sporadic Parkinson's disease in Chinese Han population. AB - Two novel single nucleotide polymorphisms (SNPs) (rs6812193 and rs11868035) were recently identified to be associated with Parkinson's disease (PD) in a Web Based Genome-Wide Association Study. Herein, we conducted a case-control study to evaluate the possible associations between these two SNPs and PD in Chinese Han population. All subjects (501 sporadic PD patients and 502 normal controls) were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis with these two SNPs. Chi-square test revealed no significant difference in either genotype frequencies or allele frequencies, even after being stratified by age. But we found that the genotype and allele frequency of rs6812193 shows difference between male patients and male controls (p=0.031, OR=0.584; p=0.037, OR=0.606) but none in the female. Our findings suggest that rs11868035 may have no association with PD in Chinese population and rs6812193 may have marginal association with PD in male Chinese population. However, due to the limited data in the present study, replication studies in larger sample and other populations are required. PMID- 22531748 TI - Anodal tDCS of dorsolateral prefontal cortex during an Implicit Association Test. AB - Anodal stimulation of dorsolateral prefrontal cortex by transcranial Direct Current Stimulation (tDCS) has been shown to enhance performance on working memory tasks. However, it is not yet known precisely which aspects of working memory - a broad theoretical concept including short-term memory and various executive functions - are involved in such effects. In the current study, we aimed to determine whether tDCS would reduce bias effects on an Implicit Association Test, in which subjects must respond either congruently or incongruently to pre-existing evaluative associations. Such biases reflect a conflict between automatic associations and executive function, and tDCS was hypothesized to cause a shift in this balance in favor of executive function. The results clearly contradicted this hypothesis: tDCS did improve reaction times, but in the congruent rather than incongruent mapping condition. We conclude that DLPFC tDCS does not directly improve the ability to overcome bias; previous findings concerning working memory enhancement appear to reflect effects on a different component of executive function. PMID- 22531749 TI - Sympathetic nerves bridge the cross-transmission in hemifacial spasm. AB - The pathophysiologic basis of hemifacial spasm is abnormal cross-transmission between facial nerve fibers. The author hypothesized that the demyelinated facial nerve fibers were connected with the sympathetic nerve fibers on the offending artery wall, and thus the latter function as a bridge in the cross-transmission circuit. This hypothesis was tested using a rat model of hemifacial spasm. A facial muscle response was recorded while the offending artery wall was electrically stimulated. The nerve fibers on the offending artery wall were blocked with lidocaine, or the superior cervical ganglion, which innervates the offending artery, was resected, and meanwhile the abnormal muscle response was monitored and analyzed. A waveform was recorded from the facial muscle when the offending artery wall was stimulated, named as "Z-L response". The latency of Z-L response was different from that of abnormal muscle response. When the nerve fibers on the offending artery wall were blocked by lidocaine, the abnormal muscle response disappeared gradually and recovered in 2h. The abnormal muscle response disappeared permanently after the sympathetic ganglion was resected. Our findings indicate that cross-transmission between the facial nerve fibers is bridged by the nerve fibers on the offending artery wall, probably sympathetic nerve fibers. PMID- 22531750 TI - Involvement of spinal monocyte chemoattractant protein-1 (MCP-1) in cancer induced bone pain in rats. AB - In this study, we examined the involvement of chemokine monocyte chemoattractant protein-1 (MCP-1) in the spinal cord of a rat model of cancer-induced bone pain (CIBP). In this model, CIBP was established by an intramedullary injection of Walker 256 cells into the tibia of rats. We observed a significant increase in expression levels of MCP-1 and its receptor CCR2 in the spinal cord of CIBP rats. Furthermore, the intrathecal administration of an anti-MCP-1 neutralizing antibody attenuated the mechanical allodynia established in CIBP rats. Likewise, an intrathecal injection of exogenous recombinant MCP-1 induced a striking mechanical allodynia in naive rats. These results suggest that increases in spinal MCP-1 and CCR2 expression are involved in the development of mechanical allodynia associated with bone cancer rats. PMID- 22531752 TI - Wildfires, fuel treatment and risk mitigation in Australian eucalypt forests: insights from landscape-scale simulation. AB - Wildfires pose significant risks to people and human infrastructure worldwide. The treatment of fuel in landscapes may alter these risks but the magnitude of this effect on risk is poorly understood. Evidence from Australian Eucalyptus forests suggests that mitigation of risk using prescribed burning as a fuel treatment is partial because weather and fuel dynamics are conducive to regular high intensity fires. We further examine the response of risk to treatment in eucalypt forests using landscape simulation modelling. We model how five key measures of wildfire activity that govern risk to people and property may respond to variations in rate and spatial pattern of prescribed fire. We then model effects of predicted climate change (2050 scenarios) to determine how the response of risk to treatment is likely to be altered in the future. The results indicate that a halving of risk to people and property in these forests is likely to require treatment rates of 7-10% of the area of the landscape per annum. Projections of 2050 weather conditions under climate change further substantially diminished the effect of rate of treatment. A large increase in rates of treatment (i.e. circa. 50% over current levels) would be required to counteract these effects of climate change. Such levels of prescribed burning are unlikely to be financially feasible across eucalypt dominated vegetation in south eastern Australia. Despite policy imperatives to expand fuel treatment, a reduction rather than an elimination of risk will result. Multi-faceted strategies will therefore be required for the management of risk. PMID- 22531751 TI - Selective activation of either mGlu2 or mGlu3 receptors can induce LTD in the amygdala. AB - Group II metabotropic glutamate (mGlu) receptors are known to induce a long-term depression (LTD) of synaptic transmission in many brain regions including the amygdala. However the roles of the individual receptor subtypes, mGlu2 and mGlu3, in LTD are not well understood. In particular, it is unclear whether activation of mGlu3 receptors is sufficient to induce LTD at synapses in the CNS. In the present study, advantage was taken of a Wistar rat strain not expressing mGlu2 receptors (Ceolin et al., 2011) to investigate the function of mGlu3 receptors in the amygdala. In this preparation, the group II agonist, DCG-IV induced an LTD of the cortical, but not the intra-nuclear, synaptic input to the lateral amygdala. This LTD was concentration dependent and was blocked by the group II mGlu receptor antagonist, LY341495. To investigate further the role of mGlu3 receptors, we used LY395756 (an mGlu2 agonist and mGlu3 antagonist), which acts as a pure mGlu3 receptor antagonist in this rat strain. This compound alone had no effect on basal synaptic transmission, but blocked the LTD induced by DCG-IV. Furthermore, we found that DCG-IV also induces LTD in mGlu2 receptor knock-out (KO) mice to a similar extent as in wild-type mice. This confirms that the activation of mGlu3 receptors alone is sufficient to induce LTD at this amygdala synapse. To address whether mGlu2 activation alone is also sufficient to induce LTD at this synapse we used LY541850 (the active enantiomer of LY395756) in wild type mice. LY541850 induced a substantial LTD showing that either receptor alone is capable of inducing LTD in this pathway. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. PMID- 22531753 TI - PbS/CdS-sensitized mesoscopic SnO2 solar cells for enhanced infrared light harnessing. AB - Metal oxide semiconductors with lower lying conduction band minimum and superior electron mobility are essential for efficient charge separation and collection in PbS-sensitized solar cells. In the present study, mesoscopic SnO(2) was investigated as an alternative photoanode to the commonly used TiO(2) and examined comprehensively in PbS-sensitized liquid junction solar cells. To exploit the capability of PbS in an optimized structure, cascaded nPbS/nCdS and alternate n(PbS/CdS) layers deposited by a successive ionic layer adsorption and reaction method were systematically scrutinized. It was observed that the surface of SnO(2) has greater affinity to the growth of PbS compared with TiO(2), giving rise to much enhanced light absorption. In addition, the deposition of a CdS buffer layer and a ZnS passivation layer before and after a PbS layer was found to be beneficial for efficient charge separation. Under optimized conditions, cascaded PbS/CdS-sensitized SnO(2) exhibited an unprecedented photocurrent density of 17.38 mA cm(-2) with pronounced infrared light harvesting extending beyond 1100 nm, and a power conversion efficiency of 2.23% under AM 1.5, 1 sun illumination. In comparison, TiO(2) cells fabricated under similar conditions showed much inferior performance owing to the less efficient light harnessing of long wavelength photons. We anticipate that the systematic study of PbS sensitized solar cells utilizing different metal oxide semiconductors as electron transporters would provide useful insights and promote the development of semiconductor-sensitized mesoscopic solar cells employing panchromatic sensitizers. PMID- 22531754 TI - Identification of reduced-order thermal therapy models using thermal MR images: theory and validation. AB - In this paper, we develop and validate a method to identify computationally efficient site- and patient-specific models of ultrasound thermal therapies from MR thermal images. The models of the specific absorption rate of the transduced energy and the temperature response of the therapy target are identified in the reduced basis of proper orthogonal decomposition of thermal images, acquired in response to a mild thermal test excitation. The method permits dynamic reidentification of the treatment models during the therapy by recursively utilizing newly acquired images. Such adaptation is particularly important during high-temperature therapies, which are known to substantially and rapidly change tissue properties and blood perfusion. The developed theory was validated for the case of focused ultrasound heating of a tissue phantom. The experimental and computational results indicate that the developed approach produces accurate low dimensional treatment models despite temporal and spatial noises in MR images and slow image acquisition rate. PMID- 22531755 TI - Nonrigid 2D/3D registration of coronary artery models with live fluoroscopy for guidance of cardiac interventions. AB - A 2D/3D nonrigid registration method is proposed that brings a 3D centerline model of the coronary arteries into correspondence with bi-plane fluoroscopic angiograms. The registered model is overlaid on top of interventional angiograms to provide surgical assistance during image-guided chronic total occlusion procedures, thereby reducing the uncertainty inherent in 2D interventional images. The proposed methodology is divided into two parts: global structural alignment and local nonrigid registration. In both cases, vessel centerlines are automatically extracted from the 2D fluoroscopic images, and serve as the basis for the alignment and registration algorithms. In the first part, an energy minimization method is used to estimate a global affine transformation that aligns the centerline with the angiograms. The performance of nine general purpose optimizers has been assessed for this problem, and detailed results are presented. In the second part, a fully nonrigid registration method is proposed and used to compensate for any local shape discrepancy. This method is based on a variational framework, and uses a simultaneous matching and reconstruction process to compute a nonrigid registration. With a typical run time of less than 3 s, the algorithms are fast enough for interactive applications. Experiments on five different subjects are presented and show promising results. PMID- 22531756 TI - Episodes of HIV viremia and the risk of non-AIDS diseases in patients on suppressive antiretroviral therapy. AB - BACKGROUND: Several studies reported an association between immunodeficiency and non-AIDS-defining diseases. We investigated whether nonstructured treatment interruptions and episodes of viremia during suppressive combination antiretroviral therapy were independently associated with non-AIDS diseases. METHODS: Six thousand four hundred forty patients with viral suppression (<50 copies/mL) within 48 weeks of starting combination antiretroviral therapy were selected from the Dutch ATHENA cohort. In proportional hazards models, associations between treatment interruptions, viral suppression, low-level (50 400 copies/mL), and high-level viremia (>400), and serious non-AIDS diseases (cardiovascular disease, chronic renal failure, liver fibrosis/cirrhosis) were investigated by including time-updated cumulative exposure to either viremia and interruptions or HIV RNA >400 copies per milliliter. RESULTS: During 24,603 person-years, of which 88.5% occurred during viral suppression, 102 patients developed cardiovascular disease, 54 chronic renal failure, and 70 liver fibrosis/cirrhosis. Overall incidence of non-AIDS diseases ranged from 1.41 (95% confidence interval: 0.73 to 2.46) per 100 person-years for CD4 counts <200 to 0.71 (0.49 to 1.00) for CD4 >=500 cells per cubic millimeter. Compared with viral suppression, high-level viremia was associated only with cardiovascular disease (relative hazard: 1.37, 1.04 to 1.81 per year longer), whereas interruptions and low-level viremia were not associated with non-AIDS diseases. Relative hazards for cumulative exposure to RNA >400 versus <=400 copies per milliliter were 1.32 (1.01 to 1.73) for cardiovascular disease, 1.13 (0.66 to 1.92) for renal failure, and 0.86 (0.51 to 1.44) for fibrosis/cirrhosis. CONCLUSIONS: Lower CD4 counts are associated with increased risk of non-AIDS diseases, whereas high-level viremia seems to be independently associated with cardiovascular disease. However, the power to detect associations with viremia or interruptions may have been limited as most events occurred during viral suppression. PMID- 22531757 TI - Using tuberculin skin test as an entry point to screen for latent and active tuberculosis in Thai people living with HIV. AB - BACKGROUND: Tuberculin skin test (TST) identifies patients highly likely to benefit from isoniazid preventive therapy and tuberculosis (TB) prevalence may differ by TST status. We evaluated latent and active TB screening and diagnosis strategies among people living with HIV (PLHIV) incorporating TST as the initial screening step. METHODS: PLHIV attending services at the Thai Red Cross Anonymous Clinic during September 2006 to January 2008 were enrolled. TB disease was defined as any positive Mycobacterium tuberculosis (MTB) specimen culture from sputum, urine, stool, lymph node aspiration, and blood. The performance of symptom screening (>1 of: any cough, any fever, night sweats lasting 3 or more weeks in the preceding 4 weeks) and laboratory screening (sputum smear followed by chest radiography and CD4 count) for active TB disease were evaluated according to TST status. RESULTS: We enrolled 604 PLHIV. TST was positive in 151 PLHIV (25.0%). TB disease was diagnosed in 33 PLHIV, including 22 (14.6%) TST positive and 11 (2.4%) TST-negative PLHIV. We found that an approach of performing MTB culture for all TST-positive PLHIV and symptom screening followed by laboratory screening for all TST-negative PLHIV would identify 196 (32.4%) of 604 PLHIV who would need MTB culture to correctly diagnose 29 (87.9%) of 33 active TB cases. CONCLUSIONS: TST can be used as an initial screening test among PLHIV to identify those at highest risk of active TB disease. Access to MTB culture or other sensitive tests to exclude TB disease is urgently needed to improve TB screening and prevention in resource-limited settings. PMID- 22531758 TI - Establishment, retention, and loss to follow-up in outpatient HIV care. AB - BACKGROUND: For optimal clinical benefit, HIV-infected patients should receive periodic outpatient care indefinitely. However, initially establishing HIV care and subsequent retention in care are problematic. This study examines establishment, retention, and loss to follow-up (LTFU) in a large multi-site cohort over a 2-8 year period. METHODS: Medical record data were reviewed for 22,984 adult HIV patients receiving care at 12 clinics in the HIV Research Network between 2001 and 2009. Three dichotomous outcome measures were based on each patient's history of outpatient visits. Establishment reflects whether the patient made outpatient visits for longer than 6 months after initial enrollment. The retention measure reflects whether the patient had at least 2 outpatient visits separated by 90 days in each year in care. LTFU reflects whether the patient had no outpatient visits for more than 12 months without returning. Multiple logistic regression examined demographic and clinical correlates of each outcome and the combined outcome of meeting all 3 measures. RESULTS: Overall, 21.7% of patients never established HIV care after an initial visit. Among established patients, 57.4% did not meet the retention criterion in all years, and 34.9% were LTFU. Only 20.4% of all patients met all 3 criteria. The odds of successfully meeting all 3 criteria were higher for women, for older patients, for Hispanics compared with whites, and for those with CD4 levels <=50 cells per cubic millimeter. CONCLUSIONS: These data highlight the need to improve establishment and retention in HIV care. PMID- 22531760 TI - Overall well focused catadioptric image acquisition with multi-focal images: a model based method. AB - When a catadioptric imaging system suffers from limited depth of field, a single image can not capture all the objects with clear focus. To solve this problem, a set of multi-focal images can be used to extend the depth of field by fusing the best focused image regions to an overall well focused composite image. In this paper, we proposed a novel model based method that avoids the computational cost problem of previous extended-depth-of-field algorithms. Based on the special optical geometry properties of catadioptric systems, the proposed model describes the shapes of the best focused image regions in multi-focal images by a series of neighboring concentric annuluses. Then we proposed a method to estimate the model parameters. Based on this model, an overall well focused image is obtained by combining the best focused regions with a fast and reliable online operation. Experiments on catadioptric images of a variety of different scenes and camera settings verify the validity of the model and the robust performance of the proposed method. PMID- 22531759 TI - High diagnostic yield of tuberculosis from screening urine samples from HIV infected patients with advanced immunodeficiency using the Xpert MTB/RIF assay. AB - We determined the diagnostic yield of the Xpert MTB/RIF assay for tuberculosis (TB) when testing small volumes of urine from ambulatory HIV-infected patients before starting antiretroviral therapy in South Africa. Compared with a gold standard of sputum culture, the sensitivity of urine Xpert among those with CD4 cell counts of <50, 50-100, and >100 cells per microliter were 44.4%, 25.0%, and 2.7% (P = 0.001), respectively. Urine Xpert testing provides a means of rapid TB diagnosis in patients with advanced immunodeficiency and poor prognosis. These data are indicative of high rates of TB dissemination and renal involvement in this clinical population. PMID- 22531761 TI - Robust pairwise matching of interest points with complex wavelets. AB - We present a matching framework to find robust correspondences between image features by considering the spatial information between them. To achieve this, we define spatial constraints on the relative orientation and change in scale between pairs of features. A pairwise similarity score which measures the similarity of features based on these spatial constraints is considered. The pairwise similarity scores for all pairs of candidate correspondences are then accumulated in a 2D similarity space. Robust correspondences can be found by searching for clusters in the similarity space, since actual correspondences are expected to form clusters that satisfy similar spatial constraints in this space. As it is difficult to achieve reliable and consistent estimates of scale and orientation, an additional contribution is that these parameters do not need to be determined at the interest point detection stage, which differs from conventional methods. Polar matching of dual-tree complex wavelet transform features is used, since it fits naturally into the framework with the defined spatial constraints. Our tests show that the proposed framework is capable of producing robust correspondences with higher correspondence ratios and reasonable computational efficiency, compared to other well-known algorithms. PMID- 22531762 TI - Weighted similarity-invariant linear algorithm for camera calibration with rotating 1D objects. AB - In this paper, a weighted similarity-invariant linear algorithm for camera calibration with rotating 1D objects is proposed. First, we propose a new estimation method for computing the relative depth of the free endpoint on the 1D object and prove its robustness against noise compared with those used in previous literature. The introduced estimator is invariant to image similarity transforms, resulting in a similarity-invariant linear calibration algorithm which is slightly more accurate than the well-known normalized linear algorithm. Then, we use the reciprocals of the standard deviations of the estimated relative depths from different images as the weights on the constraint equations of the similarity-invariant linear calibration algorithm, and propose a weighted similarity-invariant linear calibration algorithm with higher accuracy. Experimental results on synthetic data as well as on real image data show the effectiveness of our proposed algorithm. PMID- 22531763 TI - Conjunctive patches subspace learning with side information for collaborative image retrieval. AB - Content-Based Image Retrieval (CBIR) has attracted substantial attention during the past few years for its potential practical applications to image management. A variety of Relevance Feedback (RF) schemes have been designed to bridge the semantic gap between the low-level visual features and the high-level semantic concepts for an image retrieval task. Various Collaborative Image Retrieval (CIR) schemes aim to utilize the user historical feedback log data with similar and dissimilar pairwise constraints to improve the performance of a CBIR system. However, existing subspace learning approaches with explicit label information cannot be applied for a CIR task, although the subspace learning techniques play a key role in various computer vision tasks, e.g., face recognition and image classification. In this paper, we propose a novel subspace learning framework, i.e., Conjunctive Patches Subspace Learning (CPSL) with side information, for learning an effective semantic subspace by exploiting the user historical feedback log data for a CIR task. The CPSL can effectively integrate the discriminative information of labeled log images, the geometrical information of labeled log images and the weakly similar information of unlabeled images together to learn a reliable subspace. We formally formulate this problem into a constrained optimization problem and then present a new subspace learning technique to exploit the user historical feedback log data. Extensive experiments on both synthetic data sets and a real-world image database demonstrate the effectiveness of the proposed scheme in improving the performance of a CBIR system by exploiting the user historical feedback log data. PMID- 22531764 TI - Regularization parameter selection for nonlinear iterative image restoration and MRI reconstruction using GCV and SURE-based methods. AB - Regularized iterative reconstruction algorithms for imaging inverse problems require selection of appropriate regularization parameter values. We focus on the challenging problem of tuning regularization parameters for nonlinear algorithms for the case of additive (possibly complex) Gaussian noise. Generalized cross validation (GCV) and (weighted) mean-squared error (MSE) approaches (based on Steinfs Unbiased Risk Estimate. SURE) need the Jacobian matrix of the nonlinear reconstruction operator (representative of the iterative algorithm) with respect to the data. We derive the desired Jacobian matrix for two types of nonlinear iterative algorithms: a fast variant of the standard iterative reweighted least squares method and the contemporary split-Bregman algorithm, both of which can accommodate a wide variety of analysis- and synthesis-type regularizers. The proposed approach iteratively computes two weighted SURE-type measures: Predicted SURE and Projected-SURE (that require knowledge of noise variance D2), and GCV (that does not need D2) for these algorithms. We apply the methods to image restoration and to magnetic resonance image (MRI) reconstruction using total variation (TV) and an analysis-type .1-regularization. We demonstrate through simulations and experiments with real data that minimizing Predicted-SURE and Projected-SURE consistently lead to near-MSE-optimal reconstructions. We also observed that minimizing GCV yields reconstruction results that are near-MSE optimal for image restoration and slightly suboptimal for MRI. Theoretical derivations in this work related to Jacobian matrix evaluations can be extended, in principle, to other types of regularizers and reconstruction algorithms. PMID- 22531766 TI - Conclusions and outlook. PMID- 22531765 TI - Motion-based structure separation for label-free, high-speed, 3D cardiac microscopy. AB - Capturing the dynamics of individual structures in the embryonic heart is an essential step for studying its function and development. Label-free brightfield (BF) microscopy allows for higher acquisition frame-rates than techniques requiring molecular labeling, without interfering with embryo viability or needing complex equipment. However, since different structures contribute similarly to image contrast, label-free microscopy lacks specificity. Here we mitigate this problem by separating a single-channel image series into multiple channels specific to different cardio-vascular structures, based only on their motion patterns. The technique combines images from multiple cardiac cycles and z sections after non-uniform temporal registration to produce 3D+time image volumes of one full cardiac cycle with separate channels for static, transient and periodically moving structures. The resulting data is well-suited for velocity analysis and 3D-visualization. We characterize the separating capabilities of our technique on a synthetic cardiac dataset and demonstrate its practical applicability, by reconstructing three-channel views of the beating embryonic zebrafish heart with an effective frame rate of 1000 volumes (256*256*20 voxels each) per second. This technique enables quantitative characterization of dynamic heart function during cardiogenesis. PMID- 22531767 TI - Distribution and sources of aliphatic hydrocarbons in surface sediments of Sergipe River estuarine system. AB - The assessment of aliphatic hydrocarbons was performed in the Sergipe River estuarine system, northeastern Brazil. Aliphatic hydrocarbons concentration ranged from 9.9 ug g-1 up to 30.8 ug g-1 of dry sediment. The carbon preference index (CPI, based on nC24 to nC34 range), indicated predominance of petrogenic input in two of the sites analyzed (P4 and P5). The unresolved complex mixture (UCM) was found to be present in seven of the nine sites sampled (except for P4 and P5). Overall, the results of this work suggest that there is a mix of organic matter sources to the sediment. Although the coast of Sergipe has an intense off shore petroleum exploration and the Sergipe River crosses the entire city of Aracaju, the capital city of Sergipe, non-significant anthropogenic fingerprint was assessed. PMID- 22531768 TI - Aromaticity and pi-bond covalency: prominent intermolecular covalent bonding interaction of a Kekule hydrocarbon with very significant singlet biradical character. AB - An anthracene-linked bisphenalenyl Kekule molecule with very significant singlet biradical character has shown a prominent covalent bonding interaction between molecules in a molecular aggregate. High aromatic stabilization energy in the anthracene linker is responsible for the significant singlet biradical character. PMID- 22531770 TI - Addressing LGBT healthcare needs. PMID- 22531769 TI - Predicting the risk of lymph node invasion during radical prostatectomy using the European Association of Urology guideline nomogram: a validation study. AB - BACKGROUND: The 2011 European Association of Urology (EAU) guidelines for prostate cancer recommend a pelvic lymph node dissection (PLND) at radical prostatectomy (RP) in all individuals with a nomogram predicted lymph node invasion (LNI) risk of >7%. METHODS: To test the performing characteristics for several thresholds (1-14%) and to examine the overall accuracy and calibration plot of the EAU nomogram at our institution. The study population consisted of 3081 patients treated with RP and PLND limited to the obturator fossa and the external iliac vein between 2008 and 2010 at a single European institution from Germany. More extensive PLNDs were performed at the surgeon's discretion. RESULTS: Overall, 260 patients (9.2%) had LNI. The 7% threshold would have avoided 30% of PLNDs, at the cost of missing 8% of patients with LNI. The use of 8% and 9% threshold would have allowed the avoidance of respectively 39% and 48% of PLNDs, at the cost of missing respectively 12% and 14% of patients with LNI. The accuracy of the LNI nomogram was 78%, and the unadjusted departure from ideal calibration was 5.3%. CONCLUSIONS: We confirmed adequate accuracy and calibration of the LNI nomogram. The 7% cut-off may be overly conservative. Better trade-offs between avoided PLNDs and missed LNI cases may be achieved with a limit of 8 or even 9%. PMID- 22531772 TI - The EBP rollout process. PMID- 22531773 TI - Shifting gears: guiding your facility to knowledge-driven nursing. PMID- 22531774 TI - Reconceptualizing patient safety attendants. PMID- 22531776 TI - The path to staff appreciation. PMID- 22531777 TI - ED navigators: steering patients through the system. PMID- 22531778 TI - Are you confidently competent? PMID- 22531779 TI - To hire and be hired. PMID- 22531780 TI - Remarkable dependence of electrochemical performance of SrCo0.8Fe0.2O(3-delta) on A-site nonstoichiometry. AB - SrCo(0.8)Fe(0.2)O(3-delta) is a controversial material whether it is used as an oxygen permeable membrane or as a cathode of solid oxide fuel cells. In this paper, carefully synthesized powders of perovskite-type Sr(x)Co(0.8)Fe(0.2)O(3 delta) (x = 0.80-1.20) oxides are utilized to investigate the effect of A-site nonstoichiometry on their electrochemical performance. The electrical conductivity, sintering property and stability in ambient air of Sr(x)Co(0.8)Fe(0.2)O(3-delta) are critically dependent on the A-site nonstoichiometry. Sr(1.00)Co(0.8)Fe(0.2)O(3-delta) has a single-phase cubic perovskite structure, but a cobalt-iron oxide impurity appears in A-site cation deficient samples and Sr(3)(Co, Fe)(2)O(7-delta) appears when there is an A-site cation excess. It was found that the presence of the cobalt-iron oxide improves the electrochemical performance. However, Sr(3)(Co, Fe)(2)O(7-delta) has a significant negative influence on the electrochemical activity for intermediate temperature solid oxide fuel cells (IT-SOFCs). The peak power densities with a single-layer Sr(1.00)Co(0.8)Fe(0.2)O(3-delta) cathode are 275, 475, 749 and 962 mW cm(-2) at 550, 600, 650 and 700 degrees C, respectively, values which are slightly lower than those for Sr(0.95)Co(0.8)Fe(0.2)O(3-delta) (e.g. 1025 mW cm( 2) at 700 degrees C) but much higher than those for Sr(1.05)Co(0.8)Fe(0.2)O(3 delta) (e.g. only 371 mW cm(-2) at 700 degrees C). This remarkable dependence of electrochemical performance of the Sr(x)Co(0.8)Fe(0.2)O(3-delta) cathode on the A site nonstoichiometry reveals that lower values of electrochemical activity reported in the literature may be induced by an A-site cation excess. Therefore, to obtain a high performance of Sr(x)Co(0.8)Fe(0.2)O(3-delta) cathode for IT SOFCs, an A-site cation excess must be avoided. PMID- 22531781 TI - CTC1 deletion results in defective telomere replication, leading to catastrophic telomere loss and stem cell exhaustion. AB - The proper maintenance of telomeres is essential for genome stability. Mammalian telomere maintenance is governed by a number of telomere binding proteins, including the newly identified CTC1-STN1-TEN1 (CST) complex. However, the in vivo functions of mammalian CST remain unclear. To address this question, we conditionally deleted CTC1 from mice. We report here that CTC1 null mice experience rapid onset of global cellular proliferative defects and die prematurely from complete bone marrow failure due to the activation of an ATR dependent G2/M checkpoint. Acute deletion of CTC1 does not result in telomere deprotection, suggesting that mammalian CST is not involved in capping telomeres. Rather, CTC1 facilitates telomere replication by promoting efficient restart of stalled replication forks. CTC1 deletion results in increased loss of leading C strand telomeres, catastrophic telomere loss and accumulation of excessive ss telomere DNA. Our data demonstrate an essential role for CTC1 in promoting efficient replication and length maintenance of telomeres. PMID- 22531782 TI - A new non-catalytic role for ubiquitin ligase RNF8 in unfolding higher-order chromatin structure. AB - The ubiquitin ligases RNF8 and RNF168 orchestrate DNA damage signalling through the ubiquitylation of histone H2A and the recruitment of downstream repair factors. Here, we demonstrate that RNF8, but not RNF168 or the canonical H2A ubiquitin ligase RNF2, mediates extensive chromatin decondensation. Our data show that CHD4, the catalytic subunit of the NuRD complex, interacts with RNF8 and is essential for RNF8-mediated chromatin unfolding. The chromatin remodelling activity of CHD4 promotes efficient ubiquitin conjugation and assembly of RNF168 and BRCA1 at DNA double-strand breaks. Interestingly, RNF8-mediated recruitment of CHD4 and subsequent chromatin remodelling were independent of the ubiquitin ligase activity of RNF8, but involved a non-canonical interaction with the forkhead-associated (FHA) domain. Our study reveals a new mechanism of chromatin remodelling-assisted ubiquitylation, which involves the cooperation between CHD4 and RNF8 to create a local chromatin environment that is permissive to the assembly of checkpoint and repair machineries at DNA lesions. PMID- 22531783 TI - Differential effects of viral silencing suppressors on siRNA and miRNA loading support the existence of two distinct cellular pools of ARGONAUTE1. AB - Plant viruses encode RNA silencing suppressors (VSRs) to counteract the antiviral RNA silencing response. Based on in-vitro studies, several VSRs were proposed to suppress silencing through direct binding of short-interfering RNAs (siRNAs). Because their expression also frequently hinders endogenous miRNA-mediated regulation and stabilizes labile miRNA* strands, VSRs have been assumed to prevent both siRNA and miRNA loading into their common effector protein, AGO1, through sequestration of small RNA (sRNA) duplexes in vivo. These assumptions, however, have not been formally tested experimentally. Here, we present a systematic in planta analysis comparing the effects of four distinct VSRs in Arabidopsis. While all of the VSRs tested compromised loading of siRNAs into AGO1, only P19 was found to concurrently prevent miRNA loading, consistent with a VSR strategy primarily based on sRNA sequestration. By contrast, we provide multiple lines of evidence that the action of the other VSRs tested is unlikely to entail siRNA sequestration, indicating that in-vitro binding assays and in vivo miRNA* stabilization are not reliable indicator of VSR action. The contrasted effects of VSRs on siRNA versus miRNA loading into AGO1 also imply the existence of two distinct pools of cellular AGO1 that are specifically loaded by each class of sRNAs. These findings have important implications for our current understanding of RNA silencing and of its suppression in plants. PMID- 22531784 TI - Activity-dependent phosphorylation of GABAA receptors regulates receptor insertion and tonic current. AB - The expression of GABA(A) receptors and the efficacy of GABAergic neurotransmission are subject to adaptive compensatory regulation as a result of changes in neuronal activity. Here, we show that activation of L-type voltage gated Ca(2+) channels (VGCCs) leads to Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) phosphorylation of S383 within the beta3 subunit of the GABA(A) receptor. Consequently, this results in rapid insertion of GABA(A) receptors at the cell surface and enhanced tonic current. Furthermore, we demonstrate that acute changes in neuronal activity leads to the rapid modulation of cell surface numbers of GABA(A) receptors and tonic current, which are critically dependent on Ca(2+) influx through L-type VGCCs and CaMKII phosphorylation of beta3S383. These data provide a mechanistic link between activity-dependent changes in Ca(2+) influx through L-type channels and the rapid modulation of GABA(A) receptor cell surface numbers and tonic current, suggesting a homeostatic pathway involved in regulating neuronal intrinsic excitability in response to changes in activity. PMID- 22531786 TI - A transcriptional repressor co-regulatory network governing androgen response in prostate cancers. AB - Transcriptional corepressors are frequently aberrantly over-expressed in prostate cancers. However, their crosstalk with the Androgen receptor (AR), a key player in prostate cancer development, is unclear. Using ChIP-Seq, we generated extensive global binding maps of AR, ERG, and commonly over-expressed transcriptional corepressors including HDAC1, HDAC2, HDAC3, and EZH2 in prostate cancer cells. Surprisingly, our results revealed that ERG, HDACs, and EZH2 are directly involved in androgen-regulated transcription and wired into an AR centric transcriptional network via a spectrum of distal enhancers and/or proximal promoters. Moreover, we showed that similar to ERG, these corepressors function to mediate repression of AR-induced transcription including cytoskeletal genes that promote epithelial differentiation and inhibit metastasis. Specifically, we demonstrated that the direct suppression of Vinculin expression by ERG, EZH2, and HDACs leads to enhanced invasiveness of prostate cancer cells. Taken together, our results highlight a novel mechanism by which, ERG working together with oncogenic corepressors including HDACs and the polycomb protein, EZH2, could impede epithelial differentiation and contribute to prostate cancer progression, through directly modulating the transcriptional output of AR. PMID- 22531785 TI - Caspase-2 is an initiator caspase responsible for pore-forming toxin-mediated apoptosis. AB - Bacterial pathogens modulate host cell apoptosis to establish a successful infection. Pore-forming toxins (PFTs) secreted by pathogenic bacteria are major virulence factors and have been shown to induce various forms of cell death in infected cells. Here we demonstrate that the highly conserved caspase-2 is required for PFT-mediated apoptosis. Despite being the second mammalian caspase to be identified, the role of caspase-2 during apoptosis remains enigmatic. We show that caspase-2 functions as an initiator caspase during Staphylococcus aureus alpha-toxin- and Aeromonas aerolysin-mediated apoptosis in epithelial cells. Downregulation of caspase-2 leads to a strong inhibition of PFT-mediated apoptosis. Activation of caspase-2 is PIDDosome-independent, and endogenous caspase-2 is recruited to a high-molecular-weight complex in alpha-toxin-treated cells. Interestingly, prevention of PFT-induced potassium efflux inhibits the formation of caspase-2 complex, leading to its inactivation, thus resisting apoptosis. These results revealed a thus far unknown, obligatory role for caspase 2 as an initiator caspase during PFT-mediated apoptosis. PMID- 22531787 TI - Integrating instance selection, instance weighting, and feature weighting for nearest neighbor classifiers by coevolutionary algorithms. AB - Cooperative coevolution is a successful trend of evolutionary computation which allows us to define partitions of the domain of a given problem, or to integrate several related techniques into one, by the use of evolutionary algorithms. It is possible to apply it to the development of advanced classification methods, which integrate several machine learning techniques into a single proposal. A novel approach integrating instance selection, instance weighting, and feature weighting into the framework of a coevolutionary model is presented in this paper. We compare it with a wide range of evolutionary and nonevolutionary related methods, in order to show the benefits of the employment of coevolution to apply the techniques considered simultaneously. The results obtained, contrasted through nonparametric statistical tests, show that our proposal outperforms other methods in the comparison, thus becoming a suitable tool in the task of enhancing the nearest neighbor classifier. PMID- 22531788 TI - Tracking control of a closed-chain five-bar robot with two degrees of freedom by integration of an approximation-based approach and mechanical design. AB - The trajectory tracking problem of a closed-chain five-bar robot is studied in this paper. Based on an error transformation function and the backstepping technique, an approximation-based tracking algorithm is proposed, which can guarantee the control performance of the robotic system in both the stable and transient phases. In particular, the overshoot, settling time, and final tracking error of the robotic system can be all adjusted by properly setting the parameters in the error transformation function. The radial basis function neural network (RBFNN) is used to compensate the complicated nonlinear terms in the closed-loop dynamics of the robotic system. The approximation error of the RBFNN is only required to be bounded, which simplifies the initial "trail-and-error" configuration of the neural network. Illustrative examples are given to verify the theoretical analysis and illustrate the effectiveness of the proposed algorithm. Finally, it is also shown that the proposed approximation-based controller can be simplified by a smart mechanical design of the closed-chain robot, which demonstrates the promise of the integrated design and control philosophy. PMID- 22531789 TI - Effect of a rye B chromosome and its segments on homoeologous pairing in hybrids between common wheat and Aegilops variabilis. AB - Rye B chromosomes, which are supernumerary chromosomes dispensable for the host but increase in number by non-disjunction after meiosis, have been reported to affect meiotic homoeologous pairing in wheat-rye hybrids. The effect of a rye B chromosome (B) and its segments (B-9 and B-10) on homoeologous pairing was studied in hybrids between common wheat (2n=42) and Aegilops variabilis (2n=28), with reference to the Ph1 gene located on wheat chromosome 5B. The B-9 and B-10 chromosomes are derived from reciprocal translocations between a wheat and the B chromosomes, and the former had the B pericentromeric segment and the latter had the B distal segment. Both the B and B-9 chromosomes suppressed homoeologous pairing when chromosome 5B was absent. On the other hand, the B-9 and B-10 chromosomes promoted homoeologous pairing when 5B was present. On pairing suppression, B-9 had a greater effect in one dose than in two doses, and B-9 had a greater effect than B-10 had in one dose. These results suggested that the effect of the B chromosomes on homoeologous pairing was not confined to a specific region and that the intensity of the effect varied depending on the presence or absence of 5B and also on the segment and dose of the B chromosome. The mean chiasma frequency (10.23) in a hybrid (2n=36) possessing 5B and one B-9 was considerably higher than that (2.78) of a hybrid (2n=35) possessing 5B alone, and was comparable with that (14.09) of a hybrid (2n=34) lacking 5B. This fact suggested that the B chromosome or its segment can be used in introducing alien genes into wheat by inducing homoeologous pairing between wheat and alien chromosome. PMID- 22531790 TI - Variation in abscisic acid responsiveness of Aegilops tauschii and hexaploid wheat synthetics due to the D-genome diversity. AB - Common wheat (Triticum aestivum L.) is an allohexaploid that originated from natural hybridization between tetraploid wheat (Triticum turgidum) and diploid Aegilops tauschii. Ae. tauschii is considered one of the potential sources of new genetic variation in abiotic stress tolerance for improving common wheat. Abscisic acid (ABA) plays an important role in plant adaptation to environmental stresses. In this study, ABA responsiveness of 67 Ae. tauschii accessions and their synthetic hexaploid wheat lines, derived from crosses between T. turgidum cv. Langdon and the Ae. tauschii accessions, was evaluated based on growth inhibition by 20 uM ABA. Wide variation was found in ABA responsiveness for both synthetic wheat lines and their parental Ae. tauschii accessions. The variations due to D-genome found at the diploid level were also expressed in a hexaploid genetic background. Two pairs of synthetic wheat lines differing in ABA responsiveness were then selected for gene expression analysis and to test abiotic stress tolerance, because their parental Ae. tauschii accessions similarly exhibited the differential response to ABA. Gene expression of ABA inducible transcription factor, WABI5, and the downstream Cor/Lea genes (Wrab17, Wdhn13 and Wrab18) were analysed. In one pair, the highly responsive line exhibited higher induction of Wrab17 by ABA treatment, but no significant difference in dehydration or salinity tolerance was observed between these lines. In contrast, in the second pair, the highly ABA-responsive line showed higher levels of Wdhn13 expression and dehydration and salinity tolerance. In synthetic wheat lines, the difference in the ABA responsiveness of the lines appeared to be determined by the different sets of D-genome genes. Our findings suggest that highly ABA-responsive Ae. tauschii accessions should be valuable genetic resources for improving the abiotic stress tolerance of common wheat. PMID- 22531791 TI - The identification of quantitative trait loci that control the paternal inheritance of a mitochondrial plasmid in rapeseed (Brassica napus L.). AB - Some varieties of Brassica napus (rapeseed) and B. rapa contain a liner mitochondrial plasmid that is unique in that it can be inherited from the male parent through the pollen. We found that two rapeseed cultivars, Norin 16 and Westar, showed different rates of plasmid inheritance from the paternal parent (78.8% and 27.5%, respectively). To identify nuclear genes controlling the inheritance of the plasmid, we carried out quantitative trait locus (QTL) analyses using F(2) populations derived from a cross between these two cultivars. The F1 plants transmitted the plasmid from the paternal plant at a frequency of approximately 60%; the transmission rates of the F2 lines varied greatly, from 0 to 100%, with an average of 68.2%. A genetic map was constructed based on the segregation of 175 loci in the 102 F2 plants. A total of 22 linkage groups were obtained, all of which could be assigned to the 19 rapeseed chromosomes. The total map length was 1374.7 cM, with an average distance of 7.9 cM between the markers. We found that three quantitative trait loci for plasmid paternal transfer, qPpt1, qPpt2 and qPpt3, located on chromosomes A5, C2 and C9, respectively, were significantly linked to the transmission frequency, whose the logarithm of odds (LOD) score were 4.97, 3.49 and 3.57, respectively. Their explained phenotypic variances were 25.0%, 22.2% and 37.1%, respectively. These results suggest that the paternal inheritance of the mitochondrial plasmid is controlled by a relatively small number of nuclear genes. PMID- 22531792 TI - Genetic characterization of Okinawan black rats showing coat color polymorphisms of white spotting and melanism. AB - We examined pelage color variation in wild populations of black rats (the Rattus rattus species complex) in the Yambaru forest area, northern Okinawa Island, Ryukyu Archipelago, Japan. Our field study revealed that 8.7% (38/438) and 0.2% (4/2500) of rats exhibited two types of coat color: white spotting and melanism, respectively. Using 34 representative animals, the phylogeography of the population was inferred using a nuclear gene marker, i.e., sequences (954 bp) of the melanocortin-1 receptor (Mc1r) gene responsible for the melanistic form in black rats. Four sequences from Okinawa were characterized as R. tanezumi, the Asian strain of black rat. Notably, neither of the phenotypic characters of white spotting or melanism was associated with the Mc1r haplotypes. Analysis of mitochondrial cytochrome b (Cytb) sequences (1140 bp) revealed that four haplotypes recovered from Okinawa clustered with the clade of R. tanezumi and differed by one or more bases from haplotypes at other localities in Japan and Asian countries. Thus, both variants may have arisen in the native rat population of Okinawa without interaction with the lineage of R. rattus, which exhibits a worldwide distribution and displays such coat color variants. The Yambaru population of black rats has thus experienced its own evolutionary history in allopatry for a substantial period of time (e.g., 10,000 years), which has preserved valuable genetic polymorphisms and will be useful for assessing the ecological consequences of genetic variation in natural populations. PMID- 22531793 TI - Mitochondrial genomes and divergence times of crocodile newts: inter-islands distribution of Echinotriton andersoni and the origin of a unique repetitive sequence found in Tylototriton mt genomes. AB - Crocodile newts, which constitute the genera Echinotriton and Tylototriton, are known as living fossils, and these genera comprise many endangered species. To identify mitochondrial (mt) genes suitable for future population genetic analyses for endangered taxa, we determined the complete nucleotide sequences of the mt genomes of the Japanese crocodile newt Echinotriton andersoni and Himalayan crocodile newt Tylototriton verrucosus. Although the control region (CR) is known as the most variable mtDNA region in many animal taxa, the CRs of crocodile newts are highly conservative. Rather, the genes of NADH dehydrogenase subunits and ATPase subunit 6 were found to have high sequence divergences and to be usable for population genetics studies. To estimate the inter-population divergence ages of E. andersoni endemic to the Ryukyu Islands, we performed molecular dating analysis using whole and partial mt genomic data. The estimated divergence ages of the inter-island individuals are older than the paleogeographic segmentation ages of the islands, suggesting that the lineage splits of E. andersoni populations were not caused by vicariant events. Our phylogenetic analysis with partial mt sequence data also suggests the existence of at least two more undescribed species in the genus Tylototriton. We also found unusual repeat sequences containing the 3' region of cytochrome apoenzyme b gene, whole tRNA-Thr gene, and a noncoding region (the T-P noncoding region characteristic in caudate mtDNAs) from T. verrucosus mtDNA. Similar repeat sequences were found in two other Tylototriton species. The Tylototriton taxa with the repeats become a monophyletic group, indicating a single origin of the repeat sequences. The intra and inter-specific comparisons of the repeat sequences suggest the occurrences of homologous recombination-based concerted evolution among the repeat sequences. PMID- 22531794 TI - Conservation of genomic imprinting at the NDN, MAGEL2 and MEST loci in pigs. AB - Imprinted genes have important effects on the regulation of fetal growth, development, and postnatal behavior. However, the study of imprinted genes has been limited in mammalian species other than human and mouse. Therefore, the study of porcine imprinted genes is useful for defining the extent of conservation of genomic imprinting among different species. In this study, the imprinting status of porcine NDN, MAGEL2 and MEST genes was determined by direct sequencing of the cDNAs and detection of single nucleotide polymorphisms (SNPs) identified in individuals from reciprocal crosses between Meishan and Large White pigs for allele discrimination. The analysis was carried out in 13 different tissues (skeletal muscle, fat, pituitary gland, heart, lung, liver, kidney, spleen, stomach, small intestine, uterus, ovary and testis) from 12 two-month-old piglets. Imprinting analysis showed that NDN and MAGEL2 were paternally expressed in all tissues where the genes were expressed as in human and mouse. Interestingly, MEST showed tissue-specific imprinting, being paternally expressed in skeletal muscle, fat, pituitary gland, heart, kidney, lung, stomach and uterus, and maternally expressed in spleen and liver. PMID- 22531795 TI - No gender differences in the frequencies of HLA-DRB3/B4/B5 heterozygotes in newborns and adults in Koreans. AB - HLA class II haplotypes often contain a second expressed HLA-DRB locus tightly linked to the classical HLA-DRB1 locus on the haplotype, which can be either HLA DRB3, -DRB4 or -DRB5. These encode the HLA-DR51, -DR52 or -DR53 supertypic specificities and mark the ancestral lineages. HLA-DRB3/B4/B5 heterozygote excess in Welsh male newborns has been reported, suggesting a possibility of male specific major histocompatibility complex (MHC)-mediated prenatal selection. However, it has not been confirmed in newborns of other ethnic groups or in adult populations. We analyzed the HLA-DRB1 and HLA-DRB3/B4/B5 genes in Korean newborns and healthy adults to examine whether MHC-mediated prenatal or postnatal selection exists. A total of 1,038 newborns (cord blood registry, 516 males and 522 females) and 2,082 healthy adults (hematopoietic stem cell donor registry, 1,111 males and 971 females) were HLA typed. HLA-DRB1/B3/B4/B5 DNA typing was performed using Dynal RELI HLA-DRB SSO Kit (Dyanl Biotech, Wirral, U.K.). Genotype frequencies and homozygosity and heterozygosity rates for DRB3/B4/B5 supertypic loci were compared between males and females in newborns and adults. There were no significant differences in the HLA-DRB3/B4/B5 homozygosity and heterozygosity rates between males and females in both newborns and adults. In the comparison between newborns and adults, homozygosity rate was significantly higher in newborn females than in adult females (31.0% vs 25.0%, p=0.01). Whether there is an age-related change from newborns toward adults has not been well studied in other populations, and further studies are warranted. In conclusion, male-specific heterozygosity excess reported in Welsh newborns has not been observed in Korean population, and there might be some ethnic differences in the gender-specific prenatal selection events. PMID- 22531796 TI - A selective reaction-based fluorescent probe for detecting cobalt in living cells. AB - A reaction-based strategy exploiting cobalt-mediated oxidative C-O bond cleavage affords a selective turn-on fluorescent probe for paramagnetic Co(2+) in water and in living cells. PMID- 22531798 TI - Don't forget the vasculitides. PMID- 22531799 TI - The riddle of the male obstetric patients: solved. PMID- 22531797 TI - Angiotensin receptor blockers and risk of cancer: cohort study among people receiving antihypertensive drugs in UK General Practice Research Database. AB - OBJECTIVES: To investigate whether there is an association between use of angiotensin receptor blockers and risk of cancer. DESIGN: Cohort study of risk of cancer in people treated with angiotensin receptor blockers compared with angiotensin converting enzyme (ACE) inhibitors. Effects were explored with time updated covariates in Cox models adjusted for age, sex, body mass index (BMI), diabetes and metformin/insulin use, hypertension, heart failure, statin use, socioeconomic status, alcohol, smoking, and calendar year. Absolute changes in risk were predicted from a Poisson model incorporating the strongest determinants of risk from the main analysis. SETTING: UK primary care practices contributing to the General Practice Research Database. PARTICIPANTS: 377,649 new users of angiotensin receptor blockers or ACE inhibitors with at least one year of initial treatment. MAIN OUTCOME MEASURES: Adjusted hazard ratios for all cancer and major site specific cancers (breast, lung, colon, prostate) by exposure to angiotensin receptor blockers and by cumulative duration of use. RESULTS: Follow-up ended a median of 4.6 years after the start of treatment; 20,203 cancers were observed. There was no evidence of any increase in overall risk of cancer among those ever exposed to angiotensin receptor blockers (adjusted hazard ratio 1.03, 95% confidence interval 0.99 to 1.06, P = 0.10). For specific cancers, there was some evidence of an increased risk of breast and prostate cancer (1.11, 1.01 to 1.21, P = 0.02; and 1.10, 1.00 to 1.20, P = 0.04; respectively), which in absolute terms corresponded to an estimated 0.5 and 1.1 extra cases, respectively, per 1000 person years of follow-up among those with the highest baseline risk. Longer duration of treatment did not seem to be associated with higher risk (P>0.15 in each case). There was a decreased risk of lung cancer (0.84, 0.75 to 0.94), but no effect on colon cancer (1.02, 0.91 to 1.16). CONCLUSIONS: Use of angiotensin receptor blockers was not associated with an increased risk of cancer overall. Observed increased risks for breast and prostate cancer were small in absolute terms, and the lack of association with duration of treatment meant that non causal explanations could not be excluded. PMID- 22531800 TI - Why the victims were silent. PMID- 22531801 TI - A narrow distal phalanx may be the cause. PMID- 22531802 TI - Increased awareness cuts time to attend. PMID- 22531803 TI - Must be trained in geriatric medicine. PMID- 22531804 TI - Guidance offers little in the way of ethics or transparency. PMID- 22531805 TI - No better than less expensive drugs. PMID- 22531806 TI - Report was overpositive about their benefits. PMID- 22531807 TI - Prescribed with gusto despite "uncertain" benefits. PMID- 22531809 TI - Clinicians and trusts have a role in data quality. PMID- 22531810 TI - An alternative set of principles for consideration. PMID- 22531811 TI - Malaria resurges when complacency over control sets in or funding collapses, study concludes. PMID- 22531812 TI - Blackout at PFI hospital forces surgeon to operate by torchlight. PMID- 22531814 TI - Cross-database evaluation of a multilead heartbeat classifier. AB - In this paper, we studied the improvement in heartbeat classification achieved by including information from multilead ECG recordings in a previously developed and validated classification model. This model includes features from the RR interval series and morphology descriptors for each lead calculated from the wavelet transform. The experiments were carried out in the INCART database, available in Physionet, and the generalization was corroborated in private and public databases. In all databases, the AAMI recommendations for class labeling and results presentation were followed. Different strategies to integrate the additional information available in the 12-leads were studied. The best performing strategy consisted in performing principal component analysis to the wavelet transform of the available ECG leads. The performance indices obtained for normal beats were sensitivity (S) 98%, positive predictive value (P(+)) 93%; for supraventricular beats, (S) 86%, (P(+)) 91%; and for ventricular beats (S) 90%, (P(+)) 90%. The generalization capability of the chosen strategy was confirmed by applying the classifier to other databases with different number of leads with comparable results. In conclusion, the performance of the reference two-lead classifier was improved by taking into account additional information from the 12-leads. PMID- 22531815 TI - Anonymous indexing of health conditions for a similarity measure. AB - A health social network is an online information service which facilitates information sharing between closely related members of a community with the same or a similar health condition. Over the years, many automated recommender systems have been developed for social networking in order to help users find their communities of interest. For health social networking, the ideal source of information for measuring similarities of patients is the medical information of the patients. However, it is not desirable that such sensitive and private information be shared over the Internet. This is also true for many other security sensitive domains. A new information-sharing scheme is developed where each patient is represented as a small number of (possibly disjoint) d-words (discriminant words) and the d-words are used to measure similarities between patients without revealing sensitive personal information. The d-words are simple words like "food,'' and thus do not contain identifiable personal information. This makes our method an effective one-way hashing of patient assessments for a similarity measure. The d-words can be easily shared on the Internet to find peers who might have similar health conditions. PMID- 22531813 TI - Impact of environmental exposures on ovarian function and role of xenobiotic metabolism during ovotoxicity. AB - The mammalian ovary is a heterogeneous organ and contains oocyte-containing follicles at varying stages of development. The most immature follicular stage, the primordial follicle, comprises the ovarian reserve and is a finite number, defined at the time of birth. Depletion of all follicles within the ovary leads to reproductive senescence, known as menopause. A number of chemical classes can destroy follicles, thus hastening entry into the menopausal state. The ovarian response to chemical exposure can determine the extent of ovotoxicity that occurs. Enzymes capable of bioactivating as well as detoxifying xenobiotics are expressed in the ovary and their impact on ovotoxicity has been partially characterized for trichloroethylene, 7,12-dimethylbenz[a]anthracene, and 4 vinylcyclohexene. This review will discuss those studies, as well as illustrate where knowledge gaps remain for chemicals that have also been established as ovotoxicants. PMID- 22531816 TI - ReTrust: attack-resistant and lightweight trust management for medical sensor networks. AB - Wireless medical sensor networks (MSNs) enable ubiquitous health monitoring of users during their everyday lives, at health sites, without restricting their freedom. Establishing trust among distributed network entities has been recognized as a powerful tool to improve the security and performance of distributed networks such as mobile ad hoc networks and sensor networks. However, most existing trust systems are not well suited for MSNs due to the unique operational and security requirements of MSNs. Moreover, similar to most security schemes, trust management methods themselves can be vulnerable to attacks. Unfortunately, this issue is often ignored in existing trust systems. In this paper, we identify the security and performance challenges facing a sensor network for wireless medical monitoring and suggest it should follow a two-tier architecture. Based on such an architecture, we develop an attack-resistant and lightweight trust management scheme named ReTrust. This paper also reports the experimental results of the Collection Tree Protocol using our proposed system in a network of TelosB motes, which show that ReTrust not only can efficiently detect malicious/faulty behaviors, but can also significantly improve the network performance in practice. PMID- 22531820 TI - Renal efflux transporter expression in pregnant mice with Type I diabetes. AB - Prior research suggests that sex hormones and metabolic changes, such as obesity and hyperglycemia, can alter renal transporter expression in rodents. The purpose of this study was to characterize the expression of kidney efflux transporters and regulatory transcription factors in response to Type I diabetes and pregnancy. Female C57BL/6 mice were treated with multiple low doses of streptozotocin (STZ) to induce hyperglycemia and then mated with normoglycemic male mice. Transporter mRNA and protein expression were quantified in kidneys from vehicle- and STZ-treated non-pregnant and pregnant mice on gestation day 14. Pregnancy decreased the expression of Mdr1b, Mrp4, and 5 proteins and increased the mRNA and protein expression of Mrp3 by 50-60%. STZ treatment elevated Mrp1, 2, 4, and 5 and reduced Mrp3, 6, and Mdr1b mRNA and/or protein in non-pregnant mice. Pregnancy had little effect on STZ-mediated changes in renal efflux transporter expression. Transcriptional profiles of Hnf1alpha, PXR, AhR, and Nrf2 were altered in patterns similar to some efflux transporters suggesting potential involvement in their regulation. Taken together, these results suggest that renal drug efflux transporters and regulatory signaling pathways are altered by endocrine and metabolic changes that occur during pregnancy and Type I diabetes. PMID- 22531819 TI - Cocaine use in the past year is associated with altitude of residence. AB - OBJECTIVES: Recently, increased rates of suicide in US counties at higher altitudes have been noted. Because of the documented association between cocaine use and suicide, we hypothesized that there would be a correlation between incidence of cocaine use and altitude of residence. METHODS: Cocaine use data were obtained from the Substate Substance Abuse Estimates from the 1999-2001 National Surveys on Drug Use and Health. Data related to the percentages of people 12 years or older who used cocaine in the past year. Average elevation for US counties was calculated using the Shuttle Radar Topography Mission elevation data set, and subject region elevation was calculated by averaging the weighted elevations of each region's relevant counties. The correlation between elevation of a substate region and incidence of cocaine use in that region was calculated using Pearson correlation coefficients. RESULTS: A significant correlation exists between mean altitude of a substate region and incidence of cocaine use in that region (r = 0.34; P < 0.0001). Regression analysis controlling for age, sex, race, education level, income, unemployment, and population density was performed. Altitude remained a significant factor (P = 0.007), whereas male sex (P = 0.008) and possessing less than a college education (P < 0.0001) were also significant predictors of self-reported cocaine use in the past year. It is important to note that cocaine use was assessed in isolation of other drugs of abuse, an additional confounding variable. CONCLUSIONS: This study demonstrates a significant correlation between altitude of substate region of residence and incidence of cocaine use. It is possible that stress response due to hypoxia is responsible; however, this requires further investigation. However, because other substance use was not assessed, specificity of this association is unknown. In addition, this correlation may help explain the increased rate of suicide in areas of higher elevation. PMID- 22531822 TI - Learning, retention, and slacking: a model of the dynamics of recovery in robot therapy. AB - Quantitative descriptions of the process of recovery of motor functions in impaired subjects during robot-assisted exercise might help to understand how to use these devices to make recovery faster and more effective. Linear dynamical models have been used to describe the dynamics of sensorimotor adaptation. Here, we extend this formalism to characterize the neuromotor recovery process. We focus on a robot therapy experiment that involved chronic stroke survivors, based on a robot-assisted arm extension task. The results suggest that modeling the recovery process with dynamical models is feasible, and could allow predicting the long-term outcome of a robot-assisted rehabilitation treatment. PMID- 22531821 TI - Induction of carbonyl reductase 1 (CBR1) expression in human lung tissues and lung cancer cells by the cigarette smoke constituent benzo[a]pyrene. AB - Carbonyl reductase 1 (CBR1) reduces various xenobiotic carbonyl substrates to corresponding alcohol metabolites. Here we demonstrated that benzo[a]pyrene (B[a]P), a potent pro-carcinogen and predominant polycyclic aromatic hydrocarbon (PAH) compound in cigarette smoke and air pollutants, upregulates CBR1 gene expression in vitro and in vivo, and that a proximal xenobiotic response element (XRE) motif (-122XRE) mediates the induction effect of B[a]P. First, we observed 46% and 50% increases in CBR1 mRNA and CBR1 protein levels, respectively, in human lung tissue samples from smokers compared to never-smokers. Second, we detected 3.0-fold (p<0.0001) induction of CBR1 mRNA and 1.5-fold (p<0.01) induction of CBR1 protein levels in cells of the human lung cancer cell line A549 incubated with 2.5 MUM B[a]P for 24h. Third, results from experiments with CBR1 promoter constructs indicated that a proximal XRE motif -122XRE) mediates induction of reporter activity in response to B[a]P. Furthermore, we detected enhanced nuclear translocation of aryl hydrocarbon receptor (AhR) following B[a]P exposure in A549 cells. Finally, we demonstrated increased binding of specific protein complexes to -122XRE in nuclear extracts from B[a]P-treated cells and the presence of the AhR/Arnt complex in the specific nuclear protein -122XRE complexes. PMID- 22531823 TI - Experimental study to improve the focalization of a figure-eight coil of rTMS by using a highly conductive and highly permeable medium. AB - A method to improve the focalization of the repetitive transcranial magnetic stimulation figure-eight coil in a magnetic stimulation is presented in this paper. For the purpose of reducing the half width of the distribution curve, while improving the ratio of positive to negative electric field, a shield plate with a window and a magnetic conductor were adopted. The shield plate, which was made of highly conductive copper, focused the magnetic field into a smaller area. The magnetic inductor, which was made of highly permeable soft magnetic ferrite, strengthened the magnetic field. A group of experiments was conducted to validate the focalizing effect. Experimental results showed that the negative peak and the half width of the distribution curve reduced by using the shield plate and the magnetic conductor. Especially for to the Magstim 70 mm double coil, when the shield window was 30 * 60 mm, the ratio of positive to negative electric field could be increased 109%, while the half width of the distribution curve could be reduced about 55%. PMID- 22531824 TI - An optical flow-based method to predict infantile cerebral palsy. AB - Cerebral palsy (CP) is a perinatally acquired nonprogressive brain damage resulting in motor impairment affecting mobility and posture. Early identification of infants with CP is desired to target early interventions and follow-up. During early infancy, distinct motion patterns occur which are highly predictive for later disability. These motor patterns can be observed and recorded. In this paper, a method to predict later CP based on early video recordings of the infants' spontaneous movements, applying optical flow and statistical pattern recognition, is presented. We extract motion information from video recordings of young infants using a total variation related optical flow method. By using wavelet analysis features from motion trajectories of points initiated on a regular grid were extracted and classified using a support vector machine. PMID- 22531825 TI - Breaking it down is better: haptic decomposition of complex movements aids in robot-assisted motor learning. AB - Training with haptic guidance has been proposed as a technique for learning complex movements in rehabilitation and sports, but it is unclear how to best deliver guidance-based training. Here, we hypothesized that breaking down a complex movement, similar to a tennis backhand, into simpler parts and then using haptic feedback from a robotic exoskeleton would help the motor system learn the movement. We also examined how the particular form of the decomposition affected learning. Three groups of unimpaired participants trained with the target arm movement broken down in three ways: 1) elbow flexion/extension and the unified shoulder motion independently ("anatomical" decomposition), 2) three component shoulder motions in Euler coordinates and elbow flexion/extension ("Euler" decomposition), or 3) the motion of the tip of the elbow and motion of the hand with respect to the elbow, independently ("visual" decomposition). A control group practiced the same number of movements, but experienced the target motion only, achieving eight times more direct practice with this motion. Despite less experience with the target motion, part training was better, but only when the arm trajectory was decomposed into anatomical components. Varying robotic movement training to include practice of simpler, anatomically-isolated motions may enhance its efficacy. PMID- 22531826 TI - Microstructural impact of anodic coatings on the electrochemical chlorine evolution reaction. AB - Sol-gel Ru(0.3)Sn(0.7)O(2) electrode coatings with crack-free and mud-crack surface morphology deposited onto a Ti-substrate are prepared for a comparative investigation of the microstructural effect on the electrochemical activity for Cl(2) production and the Cl(2) bubble evolution behaviour. For comparison, a state-of-the-art mud-crack commercial Ru(0.3)Ti(0.7)O(2) coating is used. The compact coating is potentially durable over a long term compared to the mud-crack coating due to the reduced penetration of the electrolyte. Ti L-edge X-ray absorption spectroscopy confirms that a TiO(x) interlayer is formed between the mud-crack Ru(0.3)Sn(0.7)O(2) coating and the underlying Ti-substrate due to the attack of the electrolyte. Meanwhile, the compact coating shows enhanced activity in comparison to the commercial coating, benefiting from the nanoparticle nanoporosity architecture. The dependence of the overall electrode polarization behaviour on the local activity and the bubble evolution behaviour for the Ru(0.3)Sn(0.7)O(2) coatings with different surface microstructure are evaluated by means of scanning electrochemical microscopy and microscopic bubble imaging. PMID- 22531827 TI - Conformations of individual quadruplex units studied in the context of extended human telomeric DNA. AB - G-quadruplex conformations within a sequence of three quadruplex units of human telomeric DNA were studied by two-frequency pulsed electron paramagnetic resonance (EPR) spectroscopy. In contrast to some individual G-quadruplexes, within the higher-order human telomeric sequence a (3+1) hybrid structure is formed. PMID- 22531828 TI - Predictors of initial 18F-fluorodeoxyglucose-positron emission tomography indication among patients with colorectal cancer. AB - OBJECTIVES: To evaluate the determinants of initial F-fluorodeoxyglucose (F-FDG) PET indication following primary colorectal cancer diagnosis among patients who underwent surgery between January 2000 and December 2007 and who were observed at a single institution for at least 2 years after diagnosis. METHODS: Of the 530 patients who underwent colorectal cancer resection, 113 patients received at least one F-FDG-PET following diagnosis. Outcome variables included indication and time of the first F-FDG-PET following diagnosis. Potential predictors included disease-level and patient-level characteristics. Univariate and multivariate regression analyses were performed. RESULTS: Patients diagnosed later in the study period and patients with higher-stage disease were more likely to receive their first F-FDG-PET for initial staging (P<0.001 and P=0.016, respectively). Patients with lower-stage disease were more likely to receive their initial F-FDG-PET for suspected recurrence on conventional imaging. When performed more than 2 years after diagnosis, F-FDG-PET was more likely to be ordered for suspected recurrence either on the basis of conventional imaging or on the basis of patient symptoms/tumor markers (P=0.003 and 0.031, respectively). F-FDG-PET demonstrated disease progression in at least 50% of patients referred for each indication (P=0.037). CONCLUSION: Higher utilization of F-FDG-PET may be appropriate among patients referred for a number of indications including: initial staging, particularly among those with higher-stage disease; suspected recurrence on conventional imaging among patients with lower-stage disease; and suspected recurrence more than 2 years after diagnosis. Further research is needed to verify these findings. PMID- 22531829 TI - Prospective evaluation of 68Ga-DOTA-NOC PET-CT in patients with recurrent medullary thyroid carcinoma: comparison with 18F-FDG PET-CT. AB - OBJECTIVE: To prospectively evaluate the role of Ga-labelled [1,4,7,10 tetraazacyclododecane-1,4,7,10-tetraacetic acid]-1-NaI-octreotide (Ga-DOTA-NOC) PET-CT in patients with recurrent medullary thyroid carcinoma (MTC) and compare the same with F-fluorodeoxyglucose (F-FDG) PET-CT. MATERIALS AND METHODS: Fifty two consecutive patients with recurrent MTC based on raised serum calcitonin levels underwent Ga-DOTA-NOC PET-CT. In addition, 41 patients also underwent F FDG PET-CT. PET-CT images were evaluated by two experienced nuclear medicine physicians both qualitatively and quantitatively (standardized uptake value). Histopathology (when available), correlation with conventional imaging modalities (ultrasonography/CT/MRI) and subsequent clinical/imaging follow-up were used as reference standard. Serum calcitonin levels were correlated with findings of PET CT. RESULTS: Overall, Ga-DOTA-NOC PET-CT showed a sensitivity of 80.7% [95% confidence interval (CI) 67.4-90.3] and a positive predictive value of 100% (95% CI 91.5-100) for detecting recurrent MTC. When both were available (n=41), Ga DOTA-NOC PET-CT proved superior to F-FDG PET-CT with a higher sensitivity (75.61 vs. 63.4%). However, the difference was statistically not significant (P=0.179). Ga-DOTA-NOC PET-CT was superior to F-FDG PET-CT for detecting recurrence in cervical lymph nodes (P<0.001). Both modalities were concordant in 75% of cases. No significant cut-off level of calcitonin could be derived for either Ga-DOTA NOC or F-FDG PET-CT. CONCLUSION: Both Ga-DOTA-NOC PET-CT and F-FDG PET-CT are able to localize disease recurrence in patients with MTC, and their role appears to be complementary for this purpose. PMID- 22531830 TI - Introducing RFID technology in dynamic and time-critical medical settings: requirements and challenges. AB - We describe the process of introducing RFID technology in the trauma bay of a trauma center to support fast-paced and complex teamwork during resuscitation. We analyzed trauma resuscitation tasks, photographs of medical tools, and videos of simulated resuscitations to gain insight into resuscitation tasks, work practices and procedures. Based on these data, we discuss strategies for placing RFID tags on medical tools and for placing antennas in the environment for optimal tracking and activity recognition. Results from our preliminary RFID deployment in the trauma bay show the feasibility of our approach for tracking tools and for recognizing trauma team activities. We conclude by discussing implications for and challenges to introducing RFID technology in other similar settings characterized by dynamic and collocated collaboration. PMID- 22531831 TI - A query integrator and manager for the query web. AB - We introduce two concepts: the Query Web as a layer of interconnected queries over the document web and the semantic web, and a Query Web Integrator and Manager (QI) that enables the Query Web to evolve. QI permits users to write, save and reuse queries over any web accessible source, including other queries saved in other installations of QI. The saved queries may be in any language (e.g. SPARQL, XQuery); the only condition for interconnection is that the queries return their results in some form of XML. This condition allows queries to chain off each other, and to be written in whatever language is appropriate for the task. We illustrate the potential use of QI for several biomedical use cases, including ontology view generation using a combination of graph-based and logical approaches, value set generation for clinical data management, image annotation using terminology obtained from an ontology web service, ontology-driven brain imaging data integration, small-scale clinical data integration, and wider-scale clinical data integration. Such use cases illustrate the current range of applications of QI and lead us to speculate about the potential evolution from smaller groups of interconnected queries into a larger query network that layers over the document and semantic web. The resulting Query Web could greatly aid researchers and others who now have to manually navigate through multiple information sources in order to answer specific questions. PMID- 22531832 TI - Determining relative rates of cellulose dissolution in ionic liquids through in situ viscosity measurement. AB - Using in situ viscosity measurement, the rate of cellulose dissolution in a number of ionic liquids has been determined allowing their performance as solvents to be quantitatively assessed. 1-Butyl-3-methylimidazolium ethanoate was shown to dissolve cellulose faster than analogous ionic liquids with chloride or dimethylphosphate anions. Analysis of the data highlights the influence of both anion basicity and relative concentration on the rate of dissolution. PMID- 22531833 TI - Supramolecular hydrogels formed by pyrene-terminated poly(ethylene glycol) star polymers through inclusion complexation of pyrene dimers with gamma-cyclodextrin. AB - Novel supramolecular hydrogels were formed between pyrene-terminated poly(ethylene glycol) star polymers and gamma-cyclodextrin (gamma-CD), through the inclusion complexation of dimers of the pyrene terminals with gamma-CD, where gamma-CD was directly used as a supramolecular cross-linking reagent without any modification. PMID- 22531835 TI - Effect of temperature on the diffusion mechanism of xylene isomers in a FAU zeolite: a molecular dynamics study. AB - The diffusion of o-, m-, and p-xylene in a FAU zeolite at 300-900 K was investigated using molecular dynamics simulations. Calculated self-diffusion coefficients of xylene isomers showed that the mobility of p-xylene was the fastest, m-xylene the second fastest, and o-xylene the slowest in the FAU zeolite at the same temperature. The diffusion activation energy of o-xylene, m-xylene and p-xylene was, respectively, determined to be 9.04, 7.45 and 6.44 kJ mol(-1) within the temperature range of 400 to 900 K, while to be 14.12, 13.59 and 15.47 kJ mol(-1) within the temperature range of 300 to 400 K. Xylene density profiles and orientational analysis suggested that this can be attributed to the xylene molecules that diffuse in the FAU zeolite by two different mechanisms at high and low temperatures. The behavior of motion for xylene in the FAU zeolite exhibits a "fluid-like" mode at high temperatures and exhibits a "jump-like" mode at low temperatures. PMID- 22531838 TI - Free-standing graphene on microstructured silicon vertices for enhanced field emission properties. AB - Controlled deposition of graphene in different orientations relative to the substrate is challenging and majority of existing deposition methods lead to sheets that lay flat on the substrate surface, limiting the potential applications in which the exposed sheet surface area and the atomically thin edges of graphene are exploited. Here we describe a simple and general solution based methodology for the fabrication of random arrays of free-standing few-layer graphene (FLG) flakes on micro-spikes engraved on Si substrates. This should greatly benefit applications using free-standing graphene, such as in energy storage/conversion devices and bright electron sources. As a proof of concept, it is shown that the FLG sheets protruding on the top of micro-spikes are good electron emitters with turn-on fields as low as 2.3 V MUm(-1) and field enhancement of few thousands. The emission performance and long-term stability achieved by this hierarchical deposition process are superior to that of planar graphene sheets and demonstrate promise for applications. Mechanisms leading to formation of free-standing FLG flakes are discussed. PMID- 22531836 TI - Repairing proximal and middle lower-leg wounds with retrograde sartorius myocutaneous flap pedicled by perforating branches of medial inferior genicular artery or posterior tibial artery. AB - BACKGROUND AND OBJECTIVES: The blood supply of the lower one-third of the sartorius muscle is mainly provided by the descending genicular artery (saphenous artery). The terminal branches of the saphenous artery, together with the perforators of the posterior tibial artery and medial inferior genicular artery, form a stable and rich anastomotic network in the genus inferior medialis. Based on this anatomy, we designed a retrograde sartorius myocutaneous flap to repair wounds in the proximal and middle thirds of the lower leg. METHODS: A sartorius myocutaneous flap with the posterior tibial (or medial inferior genicular) artery perforators as the pedicle was designed. The flap was based on a retrograde flow route: medial inferior genicular and posterior tibial artery perforators, the vascular network at the inferomedial knee, the saphenous artery, saphenous artery perforators, to the sartorius muscle. With this design, the flap can be transferred to the middle and proximal tibia. Between January 2007 and June 2010, 12 patients with middle/proximal lower-leg wounds were successfully treated with this method. RESULTS: Ten of 12 myocutaneous flaps survived with primary healing of wounds. Two cases developed a small degree of distal superficial skin necrosis but with normal muscular blood supply and healed after conservative treatment. CONCLUSION: Retrograde sartorius myocutaneous pedicle flaps from the perforating branches of the medial inferior genicular artery or posterior tibial artery have advantages in terms of reliable blood supply, ease of operation and minimal amount of damage, and can be used to repair proximal and middle lower-leg wounds. They are especially applicable when lower-leg flaps are unavailable due to poor soft-tissue conditions following trauma or multiple operations. However, the safety flap size needs to be determined in future studies. PMID- 22531839 TI - Dissipation and decontamination of bifenthrin residues in tomato (Lycopersicon esculentum Mill). AB - A field experiment was conducted at the Research Farm of CCS HAU, Hisar to study the dissipation and decontamination behavior of bifenthrin on tomato crop following the application of 25 g a.i ha(-1) (T(1)) and 50 g a.i ha(-1) (T(2)). Samples were collected periodically on the sampling days after applications. Residues were reached below detectable level of 0.005 mg kg(-1) on 10(th) day after application showing half-life period of 1.83 and 2.05 days at room temperature and 2.02 and 2.32 days under refrigerated condition for single and double dose, respectively. Processing was found effective in reducing the residues of bifenthrin in tomato fruits. Maximum reduction (42.10-45.23 %) was observed by washing + boiling followed by washing (16.66-19.04 %). Reduction was slightly less when samples were stored under refrigerated conditions as compared to room temperature conditions. PMID- 22531840 TI - Protective role of gallic acid on sodium fluoride induced oxidative stress in rat brain. AB - Gallic acid is known as a potent antioxidant active compound of the edible and medicinal plant Peltiphyllum peltatum. The main objective of this study was to evaluate the neuroprotective effects of gallic acid against sodium fluoride induced oxidative stress in rat brain. Gallic acid (10 and 20 mg/kg) and vitamin C (10 mg/kg) were intraperitoneally administrated for 1 week prior to sodium fluoride intoxication. After the treatment period, brain tissues were collected and homogenized, and antioxidant parameters were measured in the homogenates. The level of thiobarbituric acid reactive substances in sodium fluoride intoxicated rats (42.04 +/- 2.14 nmol MDA eq/g tissue, p < 0.01 vs. normal) increased compared to the normal rats (35.99 +/- 1.08 nmol MDA eq/g tissue). Pretreatment with gallic acid at 20 mg/kg was exhibited significant reduction in the thiobarbituric acid reactive substances level (37.06 +/- 1.4 nmol MDA eq/g tissue, p > 0.05 vs. normal). This increasing in thiobarbituric acid reactive substances level was accompanied with a decrease in the level of reduced glutathione (6.74 +/- 0.28 MUg/mg of protein, p < 0.001 vs. normal), superoxide dismutase (53.24 +/- 1.62 U/mg of protein, p < 0.001 vs. normal) and catalase (70.73 +/- 2.94 MUmol/min/mg of protein p < 0.001 vs. normal) activities in sodium fluoride intoxicated rat. Gallic acid at 20 mg/kg was significantly modified the level of reduced glutathione (11.02 +/- 0.53 MUg/mg of protein, p < 0.05 vs normal) and catalase activity (89.22 +/- 3.67 MUmol/min/mg of protein, p > 0.05 vs. normal) in rat brain. However, gallic acid at 20 mg/kg was significantly more effective in retrieving superoxide dismutase (124.78 +/- 5.7 U/mg of protein) activity than vitamin C (115.5 +/- 4.97 U/mg of protein). PMID- 22531841 TI - Lead bioaccumulation and toxicity in tissues of economically fish species from river and marine water. AB - Bioaccumulation of lead was determined in muscle and liver of Barbus xanthopterus, Liza abu, Barbus grypus, Acanthopagrus latus, Platycephalus indicus, Otolithes ruber exposed to lead contaminated river and marine in Khouzestan. Significant variations in metal values were evaluated using student's t test at p < 0.05. In river fish, liver was polluted in comparison with muscle and high level was in B. xanthopterus (2.80 mg kg(-1) wet weight) except for B. grypus in Karkhe River (1.73 mg kg(-1)wet weight). In marine fish, muscle was contaminated than liver and high level was in O. ruber (47.18 mg kg(-1)wet weight) except for O. ruber in Mahshahr seaport (17.85 mg kg(-1) wet weight). PMID- 22531842 TI - Nucleophile recognition as an alternative inhibition mode for benzoic acid based carbonic anhydrase inhibitors. AB - A series of hydroxybenzoic acid derivatives have shown inhibitory activity against carbonic anhydrase (CA). X-ray crystallography shows that these molecules inhibit not by binding the active site metal ion but by strong hydrogen bonding to the metal-bound water nucleophile. The binding mode observed for these molecules is distinct when compared to other non-metal-binding CA inhibitors. PMID- 22531843 TI - A split luciferase complementation assay for studying in vivo protein-protein interactions in filamentous ascomycetes. AB - Protein-protein interactions play important roles in controlling many cellular events. To date, several techniques have been developed for detection of protein protein interactions in living cells, among which split luciferase complementation has been applied in animal and plant cells. Here, we examined whether the split luciferase assay could be used in filamentous ascomycetes, such as Gibberella zeae and Cochliobolus heterostrophus. The coding sequences of two strongly interacting proteins (the F-box protein, FBP1, and its partner SKP1) in G. zeae, under the control of the cryparin promoter from Cryphonectria parasitica, were translationally fused to the C- and N-terminal fragments of firefly luciferase (luc), respectively. Each fusion product inserted into a fungal transforming vector carrying the gene for resistance to either geneticin or hygromycin B, was transformed into both fungi. We detected complementation of split luciferase proteins driven by interaction of the two fungal proteins with a high luminescence intensity-to-background ratio only in the fungal transformants expressing both N-luc and C-luc fusion constructs. Using this system, we also confirmed a novel protein interaction between transcription factors, GzMCM1 and FST12 in G. zeae, which could hardly be proven by the yeast two-hybrid method. This is the first study demonstrating that monitoring of split luciferase complementation is a sensitive and efficient method of studying in vivo protein protein interactions in filamentous ascomycetes. PMID- 22531844 TI - Assessment of metabolic syndrome in patients with primary biliary cirrhosis. AB - BACKGROUND: Primary biliary cirrhosis (PBC) is a chronic, progressive liver disease with elevated serum lipids. It remains unclear if hyperlipidemia increases the risk for atherosclerosis in PBC patients. Metabolic syndrome (MS) promotes the development of atherosclerotic cardiovascular disease due to abdominal obesity and insulin resistance. AIMS: The aim of this study was to assess incidence and parameters of MS, as well as subcutaneous and visceral fat using noninvasive ultrasonographic measurement in patients with PBC in our population. METHODS: We included 55 patients with PBC and 44 age- and sex-matched healthy controls (CG-control group). Anthropometric measurements (weight, height, and waist circumference), age, sex, and body mass index were recorded for patients and controls. Laboratory tests for assessing MS and liver function tests were analyzed. We used ultrasonography to determine subcutaneous and visceral fat diameter and area (SF, VF and SA, VA, respectively), as well as perirenal fat diameter (PF). RESULTS: Patients with PBC had significantly higher levels of cholesterol and liver function tests. There were no statistically significant difference in serum insulin and HOMA levels, as well as incidence of MS was diagnosed in 30.9 % (17/55) PBC patients and 43.2 % (19/44) controls. We registered lower amount of VF (PBC:10.92 +/- 3.63 mm, CG:16.84 +/- 5.51 mm,p < 0.001), VA (PBC:403.64 +/- 166.97 mm(2), CG:720.57 +/- 272.50 mm(2),p < 0.001), and PF (PBC:7.03 +/- 1.82 mm, CG 10.49 +/- 2.70 mm,p < 0.001) in patients with PBC. CONCLUSION: MS is not more frequent in patients with PBC compared with healthy volunteers in our population. Lower amount of VF could be related to lower risk for cardiovascular events in PBC patients. PMID- 22531845 TI - Centrifugal air-assisted melt agglomeration for fast-release "granulet" design. AB - Conventional melt pelletization and granulation processes produce round and dense, and irregularly shaped but porous agglomerates respectively. This study aimed to design centrifugal air-assisted melt agglomeration technology for manufacture of spherical and yet porous "granulets" for ease of downstream manufacturing and enhancing drug release. A bladeless agglomerator, which utilized shear-free air stream to mass the powder mixture of lactose filler, polyethylene glycol binder and poorly water-soluble tolbutamide drug into "granulets", was developed. The inclination angle and number of vane, air impermeable surface area of air guide, processing temperature, binder content and molecular weight were investigated with reference to "granulet" size, shape, texture and drug release properties. Unlike fluid-bed melt agglomeration with vertical processing air flow, the air stream in the present technology moved centrifugally to roll the processing mass into spherical but porous "granulets" with a drug release propensity higher than physical powder mixture, unprocessed drug and dense pellets prepared using high shear mixer. The fast-release attribute of "granulets" was ascribed to porous matrix formed with a high level of polyethylene glycol as solubilizer. The agglomeration and drug release outcomes of centrifugal air-assisted technology are unmet by the existing high shear and fluid-bed melt agglomeration techniques. PMID- 22531846 TI - A novel surface modified nitrendipine nanocrystals with enhancement of bioavailability and stability. AB - In this study, chitosan, a cationic polymer with positive charge, was introduced to modify the nanocrystals of nitrendipine with negative charge. The nanocrystals were prepared via precipitation-high pressure homogenization method. Then the nanocrystals were dispersed into chitosan solution, and the free chitosan was removed by centrifugation to obtain the chitosan modified nanocrystals, which remained the same particle size. However, the zeta-potential changed to positive after modification. The physical stability of the chitosan modified nanocrystals was remarkably improved under ambient conditions. During the in vitro dissolution test, the modified nanocrystals showed a certain degree of slow-release property. In the in vivo study, the C(max) of nitrendipine remained the same, however, the T(max) delayed from 0.75 h to 1.5 h with the chitosan modified nanocrystals. The surface modification by chitosan improved the bioavailability compared with the initial nanocrystals, which had demonstrated significant improvement of bioavailability compared to the traditional coarse powder form. Based on the experimental results, modification of the nanocrystals with certain polymer was supposed to be a good method to control the in vitro and in vivo behaviors of the nanocrystals, which could further increase the bioavailability of the water insoluble drug. PMID- 22531847 TI - Development of drug delivery systems for the dermal application of therapeutic DNAzymes. AB - DNAzymes are potent novel drugs for the treatment of inflammatory diseases such as atopic dermatitis. DNAzymes represent a novel class of pharmaceuticals that fulfil a causal therapy by interruption of the inflammation cascade at its origin. There are two challenges regarding the dermal application of DNAzymes: the large molecular weight and the sensitivity to DNases as part of the natural skin flora. To overcome these limitations suitable carrier systems have to be considered. Nano-sized drug carrier systems (submicron emulsions, microemulsions) are known to improve the skin uptake of drugs due to their ability to interact with the skin's lipids. To protect the drug against degradation, the hydrophilic drug may be incorporated into the inner aqueous phase of carrier systems, such as water-in-oil-in-water multiple emulsions. In the present study various emulsions of pharmaceutical grade were produced. Their physicochemical properties were determined and the influence of preservation systems on stability was tested. Drug release and skin uptake studies using various skin conditions and experimental set-ups were conducted. Furthermore, cellular uptake was determined by flow cytometric analysis. The investigations revealed that the developed multiple emulsion is a suitable and promising drug carrier system for the topical application of DNAzyme. PMID- 22531848 TI - Suppression of tumor growth in xenograft model mice by small interfering RNA targeting osteopontin delivery using biocompatible poly(amino ester). AB - Gene therapy using small interfering RNA (siRNA) is a novel strategy for effective anticancer therapies. However, low gene transfection efficiency and technical difficulties linked to siRNA delivery limit their practical application for gene delivery. Therefore, development of effective siRNA carriers is required. Overexpression of osteopontin (OPN) and its association with tumorigenesis has been reported in a majority of breast cancers. In this study, we used siRNA against OPN (siOPN) and investigated the possible OPN-dependent signaling pathway and the potential use of poly(amino ester) (PAE) based on glycerol propoxylate triacrylate (GPT) and spermine (SPE) for siRNA delivery. The GPT-SPE could effectively condense siRNA and protect the siRNA from RNaseA enzyme degradation. GPT-SPE/siRNA complexes showed good intracellular uptake and high gene silencing efficiency in vitro. Furthermore, in the breast cancer xenograft model, intratumoral injection of GPT-SPE/siOPN significantly inhibited tumor growth. These results demonstrated that silencing of OPN effectively suppressed the growth of breast cancer cells and further suggested that delivery of siRNA using GPT-SPE may act as an effective gene carrier for cancer therapy. PMID- 22531850 TI - Diffusion and binding of 5-fluorouracil in non-ionic hydrogels with interpolymer complexation. AB - Hydrogen-bonded interpolymer complexes can be used for development of novel dosage forms. In this study, two types of crosslinked hydrogels, copolymer networks of N-vinyl pyrrolidone and acrylamide (PVP-co-PAM) and interpenetrating polymer networks (IPN) composed of crosslinked PVP-co-PAM and poly(vinyl alcohol) (PVA), were synthesized at three different degrees of crosslinking. The side chain groups in such polymers can form non-ionic complexes through H-bonding, resulting in additional "crosslinks" in the hydrogels. Both kinds of hydrogels have significantly larger swelling sensitivities than the networks formed with ionizable side chains. In the IPNs, introduction of the PVA chains into the PVP co-PAM networks raises the permeability, indicating more open pores. The permeability decreases with the increasing degree of crosslinking of the copolymer. For probing the drug binding in the hydrogels, Fourier transform infrared spectra (FTIR) difference spectroscopy indicated the presence of significant H-bonding interactions between 5-fluorouracil (5-FU) and the side chains of the polymers. Such interactions are larger in the PVP-co-PAM copolymers than in the IPN hydrogels, thereby causing an additional source of the slower release kinetics in the copolymer hydrogels as revealed by the Peppas model, albeit both types of the networks followed a non-Fickian transport mechanism. PMID- 22531849 TI - Enhanced cell uptake of superparamagnetic iron oxide nanoparticles through direct chemisorption of FITC-Tat-PEG600-b-poly(glycerol monoacrylate). AB - Magnetic nanoparticles (MNPs) functionalized with specific ligands are emerging as a highly integrated platform for cancer targeting, drug delivery, and magnetic resonance imaging applications. In this study, we describe a multifunctional magnetic nanoparticle system (FITC-Tat MNPs) consisting of a fluorescently labeled cell penetrating peptide (FITC-Tat peptide), a biocompatible block copolymer PEG(600)-b-poly(glycerol monoacrylate) (PEG(600)-b-PGA), and a superparamagnetic iron oxide (SPIO) nanoparticle core. The particles were prepared by direct chemisorption of PEG(600)-b-PGA conjugated with FITC-Tat peptide on the SPIO nanoparticles. FITC-MNPs without Tat were prepared for comparison. Flow cytometry assays revealed significantly higher uptake of FITC Tat MNPs compared to FITC-MNPs in Caco-2 cells. These results were confirmed using confocal laser scanning microscopy (LSCM), which further demonstrated that the FITC-Tat MNPs accumulated in the cytoplasm and nucleus while the FITC-MNPs were localized in the cell membrane compartments. The FITC-Tat MNPs did not exhibit observable cytotoxicity in MTS assays. PMID- 22531851 TI - Improving the stability of the EC1 domain of E-cadherin by thiol alkylation of the cysteine residue. AB - The objective of this work was to improve chemical and physical stability of the EC1 protein derived from the extracellular domain of E-cadherin. In solution, the EC1 protein has been shown to form a covalent dimer via a disulfide bond formation followed by physical aggregation and precipitation. To improve solution stability of the EC1 protein, the thiol group of the Cys13 residue in EC1 was alkylated with iodoacetate, iodoacetamide, and maleimide-PEG-5000 to produce thioether derivatives called EC1-IA, EC1-IN, and EC1-PEG. The physical and chemical stabilities of the EC1 derivatives and the parent EC1 were evaluated at various pHs (3.0, 7.0, and 9.0) and temperatures (0, 3, 70 degrees C). The structural characteristics of each molecule were analyzed by circular dichroism (CD) and fluorescence spectroscopy and the derivatives have similar secondary structure as the parent EC1 protein at pH 7.0. Both EC1-IN and EC1-PEG derivatives showed better chemical and physical stability profiles than did the parent EC1 at pH 7.0. EC1-PEG had the best stability profile compared to EC1-IN and EC1 in solution under various conditions. PMID- 22531853 TI - The in vivo antitumor activity of LHRH targeted methotrexate-human serum albumin nanoparticles in 4T1 tumor-bearing Balb/c mice. AB - The use of targeted drug delivery systems is a growing trend in cancer treatment to decrease the adverse effect of anti-cancer drugs. In this study, we sought to conjugate methotrexate-human serum albumin nanoparticles (MTX-HSA NPs) with luteinizing-hormone releasing hormone (LHRH). The LHRH was intended to target LHRH receptors overexpressed on the several types of tumors. The expression of LHRH receptors on the 4T1 breast cancer cells was confirmed by FITC conjugated LHRH receptor antibody using fluorescence microscopy. Female Balb/c mice bearing 4T1 breast cancer tumor were treated with a single i.v. injection of free MTX, non-targeted MTX-HSA NPs and LHRH targeted MTX-HSA NPs. LHRH targeted MTX-HSA nanoparticles showed stronger anti-tumor activity in vivo. By 7 days after treatment, average tumor volume in the LHRH targeted MTX-HSA NPs treated group decreased to 8.67% of the initial tumor volume when the number of attached LHRH molecules on MTX-HSA NPs was the highest, while the average tumor volume in non targeted MTX-HSA NPs treated mice grew rapidly and reached 250.7% of the initial tumor volume 7 days after the treatment. LHRH targeted MTX-HSA NPs could significantly extend the survival time of tumor bearing mice compared with the non-targeted MTX-HSA NPs and free MTX formulations. PMID- 22531852 TI - Evaluation of subcutaneous forms in the improvement of pharmacokinetic profile of warfarin. AB - We attempted to prepare a subcutaneous pharmaceutical form of warfarin based on a suspension or poly(epsilon-caprolactone) microparticles to improve patient adherence. The warfarin suspension had a mean particle size of 20.0 MUm and in vitro release close to 100% in 72 h. Microparticle size and encapsulation efficiencies ranged from 54.0 to 80.0 MUm and 37.0 to 47.0%, respectively. After 72 h, warfarin microparticles exhibited in vitro drug release ranging from 62.0 to 80.0%. Warfarin subcutaneous dosage forms were administered to rabbits. Plasma concentration of warfarin was determined and biological activity was measured by prothrombin time monitoring. The observed relative bioavailabilities calculated from plasma concentrations and prothrombin times were 54.2 and 92.1%, and 61.8 and 61.4% for suspension and microparticles, respectively. PMID- 22531854 TI - Preparation and evaluation of granules with pH-dependent release by melt granulation. AB - This study had two objectives: (1) to prepare, by melt granulation in a high shear mixer, granules containing acetaminophen (APAP) as a model drug and aminoalkyl methacrylate copolymer E (AMCE) as a pH-sensitive polymer that readily dissolves at pH values lower than 5, and (2) to investigate the effects of AMCE loading (5-15%) on granule properties and the in vitro release profile of drug from the granules. Compared with polymer-free granules, the granules containing 5% and 10% AMCE were found to have higher median diameters and wider particle size distributions. For the formulation containing 15% AMCE, on the other hand, the diameters and distribution were similar to those for polymer-free granules. From compression testing, load-displacement curves revealed that AMCE enhanced particle strength at ambient temperature and induced plastic strain, while suppressing fragmentation of the granules. In addition, from dissolution testing using media with pH 4.0 and pH 6.5, granules containing AMCE, except 15% AMCE loading, exhibited drug release with significant pH dependence. When the pH 4.0 and pH 6.5 dissolution profiles were further compared by calculating the difference factor (f(1)), the 5% AMCE granules showed the strongest pH dependence of drug release among all formulations in this study. Large cracks and breakage were observed on the surface of 10% AMCE granules after they were used in dissolution testing. The obtained results are attributed to the plastic strain properties of AMCE above its glass transition temperature, and to the irregular distribution of AMCE within granules. Hence, this study has demonstrated for the first time that the combination of melt granulation and AMCE incorporation enables the formulation of novel functional granules that exhibit pH-dependent release of the active ingredient. PMID- 22531855 TI - Application of a ternary HP-beta-CD-complex approach to improve the dissolution performance of a poorly soluble weak acid under biorelevant conditions. AB - Over the last decades the poor solubility of new drugs has become an important issue, with one of the main challenges being to develop oral dosage forms with acceptable bioavailability for such compounds. The specific purpose of our study was to combine the advantages of cyclodextrins with those of solid dispersion approaches to improve the bioavailability of poorly soluble weak acids. Glyburide, an antidiabetic, was used as a model drug. First, binary drug inclusion complexes were prepared with 2-hydroxypropyl-beta-cyclodextrin. Next, solid glyburide dispersions were prepared with polyvinylpyrrolidone (PVP) and a relatively new hydrophilic copolymer, Kollicoat IR. Finally, to check for potential synergistic effects of the two types of excipients, ternary inclusion complexes were formulated by keeping the 1:2 drug:CD ratio constant but varying the polymer concentration (5-20%). The formulations were analyzed by differential scanning calorimetry and subjected to solubility and dissolution experiments in compendial and biorelevant media. The results of the study clearly indicate that all formulations result in better in vitro performance of the drug. Best results were obtained with the ternary inclusion complexes containing 10% Kollicoat IR or 20% PVP K30. This formulation approach, particularly with the new polymer, appears to be promising in terms of enhancing the bioavailability of BCS class II drugs. PMID- 22531856 TI - Intracellular delivery of redox cycler-doxorubicin to the mitochondria of cancer cell by folate receptor targeted mitocancerotropic liposomes. AB - Cancer cells reflect higher level of ROS in comparison to the normal cell, so they become more vulnerable to further oxidative stress induced by exogenous ROS generating agents. Through this a novel therapeutic strategy has evolved, which involves the delivery of redox cycler-doxorubicin (DOX) to the mitochondria of cancer cell where it acts as a source of exogenous ROS production. The purpose of this study is to develop a liposomal preparation which exhibits a propensity to selectively target cancer cell along with the potential of delivering drug to mitochondria of cell. We have rendered liposomes mitocancerotropic (FA-MTLs) by their surface modification with dual ligands, folic acid (FA) for cancer cell targeting and triphenylphosphonium (TPP) cations for mitochondria targeting. The cytotoxicity, ROS production and cell uptake of doxorubicin loaded liposomes were evaluated in FR (+) KB cells and found to be increased considerably with FA-MTLs in comparison to folic acid appended, mitochondria targeted and non-targeted liposomes. As confirmed by confocal microscopy, the STPP appended liposomes delivered DOX to mitochondria of cancer cell and also showed higher ROS production and cytotoxicity in comparison to folic acid appended and non-targeted liposomes. Most importantly, mitocancerotropic liposomes showed superior activity over mitochondria targeted liposomes which confirm the synergistic effect imparted by the presence of dual ligands - folic acid and TPP on the enhancement of cellular and mitochondrial delivery of doxorubicin in KB cells. PMID- 22531857 TI - Enhanced antitumor efficacy of cisplatin by tirapazamine-transferrin conjugate. AB - Combination of tirapazamine (TPZ) with cisplatin has been studied extensively in clinical trial for tumor therapy. However, in phase III clinical trial, the combination therapy did not show overall survival improvement in patients. To decrease the side effects and increase the efficacy of the combination therapy, TPZ was conjugated with transferrin (Tf-G-TPZ) for targeted delivery and co administered with cisplatin. In vitro toxicity study showed that the combination of Tf-G-TPZ with cisplatin induced substantially higher cytotoxicity of tumor cells than the combination of TPZ and cisplatin. After Tf-G-TPZ was intravenously injected into tumor-bearing mice, its total accumulation in tumor was 2.3 fold higher than that of the unmodified TPZ, suggesting transferrin-mediated target delivery of TPZ into the tumor tissue. With the increased accumulation of Tf-G TPZ in tumor, the synergistic anti-tumor effects of Tf-G-TPZ and cisplatin were also enhanced as showed by the 53% tumor inhibition rate. Meanwhile, the side effects such as body weight lost were not significantly increased. Therefore, Tf G-TPZ holds great promise to a better substitute for TPZ in the combination therapy with cisplatin. PMID- 22531858 TI - [Impact of late treatment-related radiotherapy toxicity, depression, and anxiety on quality of life in long-term breast cancer survivors]. AB - INTRODUCTION: This study aimed to assess the impact of late treatment toxicity (especially radiotherapy toxicity), chemoradiotherapy treatment type (concurrent or sequential), depression and anxiety on overall, physical and emotional quality of life (QoL) in long-term breast cancer survivors. Method. We assessed 117 patients (mean follow-up since the end of treatment = 8.1 years) for late radiotherapy toxicity (LENT-SOMA scale), patient and doctor ratings of breast cosmetic outcomes, QoL (EORTC QLQ-C30), depression and anxiety (Hospital and Anxiety Depression scale). RESULTS: In univariate analyses, factors associated with significantly decreased QoL were: use of sequential treatment and decreased overall QoL (P = 0.002) and emotional QoL (P = 0.02) ; few radiotherapy late toxicity symptoms (pain and decreased physical QoL, P = 0.01 ; fibrosis and decreased emotional QoL, P = 0.04) ; probable depression or probable anxiety and decreased overall, physical and emotional QoL (P <= 0.005). In multivariate analyses, probable depression and probable anxiety were the most stronger predictors for decreased QoL in the overall, physical and emotional domains (P <= 0.02). CONCLUSION: Improving screening for and treatment of depression and anxiety might improve QoL in long-term breast cancer survivors. PMID- 22531859 TI - Docetaxel rechallenge after a first response in non-resistant metastatic breast cancer: significant activity with manageable toxicity. AB - Docetaxel is a major drug in metastatic breast cancer (MBC) treatment. At progression, rechallenge with docetaxel can be discussed, according to previous efficacy and tolerance, as long as it was stopped for reasons other than progression. Currently, no data are available outlining outcomes after this pragmatic approach in MBC. We retrospectively identified 72 patients with the following criteria: (i) objective response or stable disease with a previous line of treatment with docetaxel in the metastatic setting, (ii) discontinuation for a reason other than progression, (iii) rechallenge with docetaxel after a minimal docetaxel-free interval of 3 months. The main objectives were to evaluate overall response (ORR), time to progression (TTP), overall survival (OS) and toxicity at reintroduction of docetaxel. Median patient age was 57 years (range: 34-84). Docetaxel was reintroduced as a 2nd, 3rd, or >=4th line of chemotherapy in the metastatic setting in 21, 46 and 33% of cases, respectively. Previous agents used included capecitabine, anthracycline, and vinorelbine in 54, 40 and 21% of cases, respectively. The median number of docetaxel cycles was 6 (range: 1-18). Among the 33 patients with disease assessed according to RECIST criteria, 14 (42.5%) had a partial response and 11 (33.5%) a stable disease>6 weeks. Among the 46 patients with an initial CA 15-3 increase, 34 (74%) had a >=50% decrease of the value. Globally, 55 patients (76%) obtained a benefit from the treatment. The median TTP and OS were 5.7 months (95% CI: 5.0-6.3) and 10.2 months (95% CI: 8.6 11.8), respectively. Forty-six patients (64%) reported grade 1/2 toxicity, 23 patients (32%) experienced grade 3/4 toxicity, mostly neutropenia (17%) and fluid retention (10%). There was no difference in median TTP after subsequent docetaxel in subgroup analyses. This retrospective analysis supports the pragmatic strategy to retreat patients with MBC with docetaxel when this drug has shown previous activity and was stopped for other causes than progression. PMID- 22531860 TI - A comparison of the effects of symmetry and magnetoanisotropy on paramagnetic relaxation in related dysprosium single ion magnets. AB - Dysprosium complexes of the tmtaa(2-) ligand were synthesized and characterized by X-band EPR and magnetism studies. Both complexes demonstrate magnetoanisotropy and slow paramagnetic relaxation. Comparison of these compounds with the seminal phthalocyanine complex [Dy(Pc)(2)](-) shows the azaannulide complexes are more susceptible to relaxation through non-thermal pathways. PMID- 22531863 TI - The effect of oral presentation on salivary 3-methoxy-4-hydroxy-phenylglycol (MHPG) and cortisol concentrations in training doctors: a preliminary study. PMID- 22531864 TI - Glucose intolerance and primary hyperparathyroidism: an unresolved relationship. AB - Primary hyperparathyroidism (PHPT) can be characterized as either symptomatic or asymptomatic, or, most recently, as normocalcemic. In the current issue of the journal, Cakir et al. report that insulin resistance and glucose intolerance is not an aspect of normocalcemic PHPT. However, both the current study as well as the literature are compromised by the lack of appropriate classification of normocalcemic PHPT subjects. Rigorously characterized cohorts are necessary to determine whether glucose intolerance is in fact present in normocalcemic PHPT. PMID- 22531865 TI - Early changes in the fatty acid composition of photosynthetic membrane lipids from Populus nigra grown on a metallurgical landfill. AB - We compared the fatty acid composition of leaves taken from poplars on a metal contaminated landfill, and on the uncontaminated roadside bordering this site. For the first time, it is shown that the percentage of linolenic acid, which is mainly associated with thylakoid lipids, was significantly lower in tree species within the landfill than within the control area. A correlation study was carried out to investigate relationships between the C18:3/(C18:0 + C18:1 + C18:2) fatty acid ratios and the metal contents in soils and leaves. Lead and chromium leaf contents were significantly negatively correlated to this fatty acid ratio. The impact of each of these metals remains difficult to evaluate, but chromium in leaf likely plays a major role in toxicity. In addition, the decrease in the C18:3/(C18:0 + C18:1 + C18:2) fatty acid ratio occurred at low leaf metal content, and therefore it is shown that this ratio can be used as an early indicator of the effect of metals. PMID- 22531866 TI - Highly bright tunable blue-violet photoluminescence in SiC nanocrystal-sodium dodecyl sulfonate crosslinked network. AB - We report strong photoluminescence in an ultra-small surface oxidized SiC quantum dot-sodium dodecyl sulfonate crosslinked network. The peak emission wavelength is tunable spanning a wide blue-violet spectral region showing clear quantum confinement effects. The photoluminescence decay exhibits triple recombination dynamics with an average lifetime of 13.65 ns. PMID- 22531867 TI - Flavor avoidance learning based on missing calories but not on palatability reduction. AB - Avoidance of a target flavor can be produced by providing rats with a highly nutritious solution of 20 % maltodextrin (20 %Malto) in some sessions and a 3 % maltodextrin (3 %Malto) solution containing the target flavor in intermixed sessions. Since 20 %Malto is both more nutritious and more palatable than 3 %Malto, flavor avoidance could arise because the flavor signals either a reduction in calories or reduced palatability, or both. Pilot testing established that rats strongly preferred 3 %Malto plus 0.1 % saccharin to both unflavored 3 %Malto and unflavored 20 %Malto. The two main experiments tested whether the palatability difference, which the pilot data had suggested was larger than the difference between 20 %Malto and 3 %Malto, could produce flavor avoidance. In both experiments, one group of rats were given 3 %Malto plus 0.1 % saccharin on some days, intermixed with other days on which this group was given 3 %Malto plus the target flavor, almond. Neither when trained and tested under conditions of food deprivation (Experiment 1) nor when trained and tested sated (Experiment 2) did palatability reduction produce almond avoidance. In contrast, calorie reduction produced almond avoidance under both conditions. These results suggest that flavor avoidance can be produced by intermixed training involving solutions that differ in nutritious value and palatability, but not when they differ only in palatability. PMID- 22531868 TI - What can we learn from asthma in elite athletes? PMID- 22531869 TI - Diagnostic value of single complete compression ultrasonography in pregnant and postpartum women with suspected deep vein thrombosis: prospective study. AB - OBJECTIVE: To assess the safety of using single complete compression ultrasonography in pregnant and postpartum women to rule out deep vein thrombosis. DESIGN: Prospective outcome study. SETTING: Two tertiary care centres and 18 private practices specialising in vascular medicine in France and Switzerland. PARTICIPANTS: 226 pregnant and postpartum women referred for suspected deep vein thrombosis. METHODS: A single proximal and distal compression ultrasonography was performed. All women with a negative complete compression ultrasonography result did not receive anticoagulant therapy and were followed up for a three month period. MAIN OUTCOME MEASURES: Symptoms of venous thromboembolism, second compression ultrasonography or chest imaging, a thromboembolic event, and anticoagulant treatment. RESULTS: 16 women were excluded, mainly because of associated suspected pulmonary embolism. Deep vein thrombosis was diagnosed in 22 out of the 210 included women (10.5%). 10 patients received full dose anticoagulation despite a negative test result during follow up. Of the 177 patients without deep vein thrombosis and who did not receive full dose anticoagulant therapy, two (1.1%, 95% confidence interval 0.3% to 4.0%) had an objectively confirmed deep vein thrombosis during follow-up. CONCLUSIONS: The rate of venous thromboembolic events after single complete compression ultrasonography in pregnant and postpartum women seems to be within the range of that observed in studies in the non-pregnant population. These data suggest that a negative single complete compression ultrasonography result may safely exclude the diagnosis of deep vein thrombosis in this setting. TRIAL REGISTRATION: clinicaltrials.gov NCT00740454. PMID- 22531870 TI - Intrathyroidal thymic tissue mimicking a thyroid nodule in a 4-year-old child. AB - A 4 year-old girl was referred for CT of her neck for suspected submental lymphadenopathy and was found to have an incidental low-attenuation thyroid mass. Subsequent thyroid ultrasound showed a heterogeneous thyroid mass with punctate areas of increased echogenicity. Cytologic examination was consistent with ectopic intrathyroidal thymic nodule. We review the presentation of ectopic thymic tissue, especially in the thyroid gland. PMID- 22531871 TI - Gastric pH and gastric residence time in fasted and fed conscious beagle dogs using the Bravo pH system. AB - To further characterize the time course of gastric pH with respect to meals and gastric residence times (GRTs) in dogs, continuous pH measurements were recorded with Bravo capsules, which were attached to the dogs' stomach mucosa or administered as free capsules, respectively. Experiments took place in home or study cages, and meals were administered at designated times. Up until 2 h prior to mealtime, the fasted gastric pH remained constantly acidic (~2.0) regardless whether the dogs were in the study or home cages. However, as feeding time became imminent, the pH was typically elevated for dogs in home cages, whereas the pH remained acidic for dogs in study cages. For both monitoring locations, the gastric pH remained acidic during meal consumption and for at least 10 h after meals. The GRT between fasted (25 +/- 32 min) and fed (686 +/- 352 min) conditions was significantly different with considerable inter- and intrasubject variability. Fasted gastric pH was similar to that of literature monkey and human values but differed after meals as the dog gastric pH remained acidic unlike monkey and human. In dogs, the fasted GRT was remarkably rapid and under fed conditions, longer than that observed in humans. PMID- 22531872 TI - [Patient participation to patient safety in radiotherapy: a reality to be developed]. AB - BACKGROUND: Patient safety during radiotherapy has become a central priority for public policy further to the various accidents arisen at Epinal, Toulouse and Grenoble for the most symbolic. In this context, patients' involvement in the management of their own safety can be a way to improve the quality of care in general. OBJECTIVE AND METHOD: This study was carried out in the radiotherapy department of the Georges-Pompidou European Hospital and aimed at analyzing the role of patients in the management of patient safety. Interviews have been conducted with patients and with professionals in order to understand if patients could have a role in the safety of their treatment and to describe the possible forms of participation. RESULTS: The results describe two main forms of patient participation. On one hand, active participation, which refers to preventive and corrective actions carried out spontaneously by the patients. On the other hand, compliance, which consists in the respect of the recommended or prescribed behavior. CONCLUSION: Patient participation is a reality which remains almost invisible for professionals and which needs to be encouraged insofar as it is a means to improve healthcare safety by a cooperative risk management. However, it must be a possibility offered to the patients and not an obligation, a source of additional stress. PMID- 22531873 TI - Binge eating during pregnancy and birth outcomes: a cohort study in a disadvantaged population in Brazil. AB - OBJECTIVE: To assess the impact of binge eating behavior (BE) during pregnancy on birth outcomes among 697 Brazilian women who attended primary care. METHOD: Pregnant women answered a questionnaire on sociodemographic data, obstetric history, and The Eating Disorder Examination Questionnaire (EDE-Q). Perinatal outcomes were obtained from birth records. Birth weight, prematurity, caesarean delivery, being small or large for gestational age were compared among women reporting BE (N = 119) and those without BE (N = 578). Poisson regression was used to estimate the association between BE during pregnancy and birth outcomes. RESULTS: BE during pregnancy was not significantly associated with the birth outcomes analyzed. Gestational weight gain was significantly higher among those who reported BE. DISCUSSION: Binge eating behavior during pregnancy may not influence birth outcomes as binge eating disorder does but affects gestational weight gain. Women reporting binge eating during pregnancy should undergo a diagnostic assessment for eating disorders. PMID- 22531874 TI - Assembly of trinuclear and tetranuclear building units of Cu2+ towards two 1D magnetic systems: synthesis and magneto-structural correlations. AB - Two new 1D coordination polymers, [Cu(3)(MU(3)-OH)(ppk)(3)(MU-N(CN)(2))(OAc)](n) (1) and {[Cu(4)(pdmH)(2)(pdm)(2)(MU(2)-OH)(H(2)O)].ClO(4)}(n) (2) based on two different blocking ligands phenyl-2-pyridylketoxime (ppk) and pyridine-2,6 dimethanol (pdmH(2)) have been synthesized and were characterized by X-ray single crystal structural analysis. In compound 1, the hydroxido-bridged trinuclear core, {Cu(3)(MU(3)-OH)(ppk)(3)(OAc)}, acts as secondary building units and are connected by the N(CN)(2)(-) anions resulting in a one dimensional (1D) coordination polymer. The 1D coordination chains undergo pi-pi interactions giving rise to a 3D supramolecular framework. In compound 2, tetrameric [Cu(4)(pdmH)(2)(pdm)(2)(H(2)O)](2+) cores are linked via hydroxido groups forming a zigzag 1D coordination chain where non-coordinated ClO(4)(-) ions are intercalated between the chains. Variable temperature magnetic susceptibility study of suggests that Cu(II) ions in the trinuclear Cu(3)(MU(3)-OH) cores are antiferromagnetically coupled with J = -459.7 cm(-1) and g = 2.11 and the trinuclear cores are further weakly coupled antiferromagnetically (zj' = -5.25 cm(-1)) through the N(CN)(2)(-) bridging ligand. Investigation of the magnetic properties of reveals that Cu(II) ions are coupled antiferromagnetically in the tetranuclear core with J = -27.1 cm(-1) and g = 2.17; the Cu(II)(4) building units are further coupled antiferromagnetically with zj' = -9.65 cm(-1). The experimental magnetic behaviours of 1 and 2 are correlated by first principle DFT calculations which provide a qualitative understanding of the origin of antiferromagnetic interactions in both cases. PMID- 22531876 TI - Oral bacteria and yeasts in relationship to oral ulcerations in hematopoietic stem cell transplant recipients. AB - BACKGROUND: Oral mucositis is a serious and debilitating side effect of conditioning regimens for hematopoietic stem cell transplant (HSCT). Through HSCT, the homeostasis in the oral cavity is disrupted. The contribution of the oral microflora to mucositis remains to be clarified. The aim of our study was to investigate the relationship between yeasts, bacteria associated with periodontitis, and oral ulcerations in HSCT recipients. METHODS: This prospective observational study included 49 adult HSCT recipients. Twice weekly, oral ulcerations were scored, and oral rinsing samples were obtained. Samples were evaluated for the total bacterial load; the Gram-negative bacteria: Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, Parvimonas micra, Fusobacterium nucleatum, Tannerella forsythia, and Treponema denticola; and the yeasts: Candida albicans, Candida glabrata, Candida kefyr, Candida krusei, Candida parapsilosis, and Candida tropicalis using real time polymerase chain reaction with specific primers and probes. Explanatory variables for oral ulcerations were calculated using the multilevel generalized estimated equations (GEE) technique. RESULTS: None of the samples was positive for A. actinomycetemcomitans, while F. nucleatum was found most often (66 % of samples). C. albicans was the most isolated yeast (88 % of samples), whereas C. parapsilosis was found in only 8 % of the samples. Multivariate GEE analyses identified P. gingivalis, P. micra, T. denticola, F. nucleatum, C. glabrata, and C. kefyr as significant explanatory variables of oral ulcerations. CONCLUSIONS: Our data indicate that P. gingivalis in particular, but also P. micra, T. denticola, F. nucleatum, C. glabrata, and C. kefyr may play a role in ulcerative oral mucositis in patients undergoing HSCT. PMID- 22531877 TI - Identifying the informational and psychosocial needs of Chinese immigrant cancer patients: a focus group study. AB - PURPOSE: The Chinese immigrant community faces multiple barriers to quality cancer care and cancer survivorship. Psychosocial interventions can positively impact quality of life, anxiety, and distress in cancer patients. In this study, we explored the informational and psychosocial needs of Chinese cancer patients to inform the development of culturally targeted support and survivorship interventions. METHODS: We conducted four focus groups with a total of 28 Chinese cancer patients to elucidate their cancer informational and psychosocial needs. The groups were conducted using standard methodology and guided by community based participatory research principles. Sessions were audio recorded, transcribed, and translated into English. The research team conducted the analysis. RESULTS: Frequently occurring themes included (1) the need for accurate information on cancer and treatment options, (2) the role of language barriers in accessing cancer care, (3) the role of food in cancer and the need for nutritional information, and (4) the role of Chinese medicine in cancer treatment. Participants expressed significant dissatisfaction with the amount, reliability, and/or comprehensibility of available information. CONCLUSIONS: Support groups and programs should be developed to address participants' needs for more information on cancer and its treatment. Programs should educate and empower patients on how to find further Chinese language information and resources and effectively communicate their questions and needs to providers in an interpreted encounter. System-level approaches should be implemented to ensure provision of interpretation services. Additionally, programs should incorporate the unique cultural needs of this population related to food/nutrition and Chinese medicine. PMID- 22531878 TI - Using mixed methods to assess how cancer patients' needs in relation to their relatives are met in the Danish health care system: a report from the population based study "The Cancer Patient's World". AB - AIM: The aims of this paper were to validate four items assessing how patients' needs regarding support to and from their relatives are met and to investigate patients' evaluation of this support. METHOD: Items were validated by patient observer agreement and cognitive interviews. Adequacy of support was assessed in a cross-sectional study of 1,490 Danish cancer patients; 147 of these also answered an open-ended question. RESULTS: All items performed well in the validation. Only 4 % reported lack of support from their relatives, whereas 9 and 11 % had lacked support from the health care professionals regarding how to tell the relatives about the disease and regarding the relatives in general, respectively. Although the patients' expectations are not unequivocal, a large proportion (35 %) reported that the health care professionals had shown little interest in how the relatives were doing. This was most pronounced for female patients and patients sampled in urban areas. Compared to older patients, younger patients lacked more support with respect to the relatives in general and regarding how to tell them about the disease. Divorced patients were less satisfied than married patients on all measures. CONCLUSION: While most patients felt well-supported by their relatives, the oldest, the divorced, and those without children may be a vulnerable group. Many patients reported that the health care staff showed insufficient interest in the well-being of the relatives. Thus, it may be beneficial for both the patient and the relatives if health care professionals acknowledge and support the relatives in fulfilling their important role as caregiver and companion. PMID- 22531880 TI - Thermally stable polymer composites with improved transparency by using colloidal mesoporous silica nanoparticles as inorganic fillers. AB - The colloidal mesoporous silica nanoparticles with small particle sizes (namely, CMS) are used as inorganic fillers of polymers (i.e. epoxy and silicone). From simple calculation, almost all polymers are estimated to be confined in the mesopores. To clarify the superiority of CMS over nonporous silica particles and mesoporous silica particles with much larger size (TMPS-4) as inorganic fillers, a systematic study on mechanical strength and transparency of polymer-silica nanocomposites was conducted. Compared with nonporous silica particles, similar to TMPS-4, CMS shows a greater effect on lowering the CTE. In addition, obtained polymer-CMS nanocomposites show improved transparency than polymer-TMPS-4 nanocomposites. PMID- 22531881 TI - Manifold beneficial effects of acetyl salicylic acid and nonsteroidal anti inflammatory drugs on sepsis. AB - INTRODUCTION: Acetyl salicylic acid (ASA) and nonsteroidal anti-inflammatory drugs (NSAIDs) may have potential as adjunctive agents for sepsis. MATERIALS: This review considers the large body of literature that indicates a basis for sepsis therapy with ASA and suggests an agenda for future intervention studies in sepsis prevention and treatment. ASA and NSAIDs have beneficial effects in numerous experimental models of sepsis. Low doses of ASA of 100 mg/day or less trigger synthesis of lipoxins that are anti-inflammatory and aid in resolution of inflammation. Higher doses of ASA and NSAIDs act to reduce NF-kappaB stimulation and inhibit numerous septic pathways. While a previous randomised controlled trial of ibuprofen failed to show a reduction in mortality in sepsis, it did reduce clinical manifestations of sepsis. More recent observational studies have shown reduction in sepsis or acute lung injury leading to lower mortality in ICU patients treated with ASA. CONCLUSIONS: Low-dose ASA appears to be beneficial in the prevention and treatment of sepsis and SIRS. If proven, this intervention would have a major, cost-effective impact on sepsis care. PMID- 22531882 TI - Frequency of extended-spectrum beta-lactamase (ESBL)-producing Gram-negative bacilli in a 200-bed multi-specialty hospital in Vellore district, Tamil Nadu, India. AB - PURPOSE: Extended-spectrum beta-lactamase (ESBL) producers were reported only from hospital settings previously, but, nowadays, its common presence in community settings is evident from reports. Our primary aim was to assess the frequency of ESBL-producing Gram-negative bacteria (GNB) and their antibiogram pattern among the clinical isolates received during an 8-month time period. METHODS: The clinical isolates which belonged to the family Enterobacteriaceae from the clinical specimens were included in the study. These clinical isolates were tested for ESBL production using the double-disk synergy test. RESULTS: In total, 301 patients were included in this study, of which 146 (48.50 %) were found to harbor strains of ESBL producers. The acquisition of ESBL in relation to age, sex, inhabitancy, inpatients, and outpatients was also analyzed. In our study, 50.29 % of inpatients and 45.86 % of outpatients were found to harbor ESBL producers. The difference between the two groups was not statistically significant. We found five meropenem-resistant ESBL-producing strains among the 146 ESBL producers. Rural inhabitants were found to contain more ESBLs when compared to peri-urban inhabitants. CONCLUSION: The study showed a high frequency of ESBLs in both community-acquired and hospital-acquired infections. The frequency of ESBLs was higher among isolates from patients who were from rural populations than those from peri-urban populations. The data on ESBL frequency suggests the need for a rational antibiotic use which would reduce the spread of ESBL-producing members of the family Enterobacteriaceae. PMID- 22531883 TI - Liver involvement in HIV-infected patients diagnosed with syphilis. AB - PURPOSE: Liver involvement in syphilis has been studied in cohorts of human immunodeficiency virus (HIV)-negative individuals despite the scarcity of data on such HIV-infected patients. Th aim of this study was to assess hepatic involvement of HIV-infected patients diagnosed with syphilis. METHODS: Patients with syphilis and liver involvement, including all stages of syphilis, were systematically identified in our HIV cohort between 2004 and 2008. RESULTS: Of the 1,599 HIV-infected patients identified during the study period, 100 were diagnosed with acute syphilis, all of whom were male. Of these 100 patients, 84% were men who have sex with men. Laboratory parameters of liver involvement were present in 19 of the 100 HIV-infected patients with syphilis; these resolved after successful antibiotic treatment. Among these 19 patients, six were diagnosed to be in the latent stage, with elevated liver enzymes and parameters of inflammation representing the only distinctive feature. CONCLUSIONS: Based on our results, syphilis should be included in the differential diagnosis of increased liver enzymes in HIV-infected patients. PMID- 22531884 TI - Adenylyl cyclases: expression in the developing rat thalamus and their role in absence epilepsy. AB - Adenylyl cyclases (ACs) synthesize the second messenger cyclic AMP (cAMP) which influences the function of multiple ion channels. Former studies point to a malfunction of cAMP-dependent ion channel regulation in thalamocortical relay neurons that contribute to the development of the absence epileptic phenotype of a rat genetic model (WAG/Rij). Here, we provide detailed information about the thalamic gene and protein expression of Ca(2+)/calmodulin-activated AC isoforms in rat thalamus. Data from WAG/Rij were compared to those from non-epileptic controls (August-Copenhagen Irish rats) to elucidate whether differential expression of ACs contributes to the dysregulation of thalamocortical activity. At one postnatal stage (P21), we found the gene expression of two specific Ca(2+) activated AC isoforms (AC-1 and AC-3) to be significantly down-regulated in epileptic tissue, and we identified the isoform AC-1 to be the most prominent one in both strains. However, Western blot data and analysis of enzymatic AC activity revealed no differences between the two strains. While basal AC activity was low, cAMP production was boosted by application of a forskolin derivative up to sevenfold. Despite previous hints pointing to a major contribution of ACs, the presented data show that there is no apparent causality between AC activity and the occurrence of the epileptic phenotype. PMID- 22531885 TI - Revising the M235T polymorphism position for the AGT gene and reporting a modifying variant in the Brazilian population with potential cardiac and neural impact. AB - There is a growing need to curate the overwhelming amount of sequencing data which is available in many public databases. For instance, new information shows that the M235T polymorphism at the angiotensinogen gene (AGT) is actually positioned at the position corresponding to the amino acid 268 and not 235. This polymorphism is filled as rs699 in the NCBI SNP database and results in the synthesis of a threonine (T) instead of a methionine (M). It has been widely studied and associated as an important risk factor for several vascular and neuropsychiatric conditions. We faced this new situation during the targeted sequencing of 360 chromosomes from Brazilian subjects studied for the M235T polymorphism, leading to the identification of a novel variation (rs141900991). This report explores the potential impact of such a dinucleotide variation, which promotes the change of alanine (A) to serine (S) at the AGT protein structure (A237S). Considering the previous M268T variation at the four possible haplotypes combined (MA, MS, TA and TS), we performed a comparative hydrophobicity simulation, using the Kyte-Doolittle algorithm, available at the CLB Bio workbench, in the four possible haplotypes. Additional simulations were performed using the programs PolyPhen, I-Mutant and SIFT, in order to evaluate the pathogenicity of both mutations. The predicted hydrophobicity decreases of a similar magnitude, with both MS and TA haplotypes, but the presence of both variations induces a major decrease in hydrophobicity, suggesting a cumulative effect, with possible modifying effect since that this variation per se would limit the hydrophobicity range and the latter chances in finding significant phenotype differences. A better characterization of this kind of variant is particularly important because the current genome wide scan analyses in complex disorders with cardiac or neural etiology are not generating reliable findings, especially if we consider the huge investment with such approach. Additional and unknown variations like this one, with potential modifying effect, might be more common than previously expected. PMID- 22531886 TI - Signal mechanisms underlying low-dose endothelial monocyte-activating polypeptide II-induced opening of the blood-tumor barrier. AB - Our previous studies have demonstrated that both the RhoA/Rho kinase and the protein kinase C (PKC) signaling pathways are involved in the low-dose endothelial monocyte-activating polypeptide-II (EMAP-II)-induced blood-tumor barrier (BTB) opening. In the present study, an in vitro BTB model was used to investigate which isoforms of PKC were involved in this process as well as the interactions between the RhoA/Rho kinase and the PKC signaling pathways. Our results showed that EMAP-II-activated PKC-alpha, beta, and zeta and induced translocations of them from the cytosolic to the membrane fractions of rat brain microvascular endothelial cells. The EMAP-II-induced alterations in BTB permeability and tight junction (TJ) protein expression were partially blocked by GO6976, the inhibitor of PKC-alpha/beta, and PKC-zeta pseudosubstrate inhibitor (PKC-zeta-PI). Meanwhile, we observed that GO6976 partly inhibited the EMAP-II induced rearrangement of actin cytoskeleton as well as phosphorylation of myosin light chain and cofilin, whereas PKC-zeta-PI had no effect on these above mentioned changes induced by EMAP-II. Also, our data revealed that inhibition of RhoA or inhibition of Rho kinase significantly diminished the activities and the translocations of PKC-alpha and PKC-beta induced by EMAP-II, whereas PKC-zeta was unaffected. However, inhibition of PKC-alpha/beta or inhibition of PKC-zeta did not cause any changes in the RhoA and Rho kinase activities. The effects of EMAP II on BTB permeability and TJ proteins expression were completely blocked by inhibition of both RhoA and PKC-zeta, whereas inhibition of both RhoA and PKC alpha/beta had an effect similar to that of inhibition of RhoA alone. In summary, this study demonstrates for the first time that three PKC isoforms, PKC-alpha, beta, and zeta, are involved in the EMAP-II-induced BTB opening. It is PKC alpha/beta, but not PKC-zeta, which serves as the downstream target for RhoA and Rho kinase, suggesting that EMAP-II induces BTB opening via the RhoA/Rho kinase/PKC-alpha/beta signaling pathways. However, PKC-zeta is involved in this process by other mechanisms. PMID- 22531888 TI - Synthesis of the unique angular tricyclic chromone structure proposed for aspergillitine, and its relationship with alkaloid TMC-120B. AB - The synthesis of the tricyclic angular chromone structure originally assigned to aspergillitine is reported. The synthesis was achieved in 11 steps and 15% overall yield from 2,4-dihydroxypropiophenone, through the intermediacy of 2,3 dimethyl-7-hydroxychromen-4-one. Construction of the nitrogen-bearing heterocyclic ring entailed a Stille cross-coupling reaction with n Bu(3)SnCH(2)CH=CH(2), followed by double bond isomerization, oximation of the chromone carbonyl, and a final microwave-assisted electrocyclization of the thus formed 6pi-electron aza-triene system. PMID- 22531887 TI - Relation of interleukin-6 in rheumatoid arthritis patients to systemic bone loss and structural bone damage. AB - IL-6 plays a key role in local and systemic manifestation of RA. IL-6 is not only a pro-inflammatory cytokine, but also interacts in complex ways with the cells involved in bone remodeling. In RA, IL-6 may indirectly promote osteoclastogenesis by increasing the release of RANK-L by osteoblasts, and it diminishes the proliferation of osteoblasts at late differentiation stages. The aims of this work were to evaluate the level of serum IL-6 and to correlate it with the activity, severity, early development of osteoporosis, and early structural bone damage in RA patients. The following parameters were investigated in 40 RA patients and 20 healthy controls: IL-6 level, BMI, ESR, CRP, CBCs, serum ionized calcium, blood urea, serum creatinine, AST, ALT, anti-CCP, and RF. Bone mineral density was measured by dual-energy X-ray absorptiometry at lumbar spines and femoral neck. Drug history was taken stressing on steroid therapy. Data were processed and analyzed using computer-based program. IL-6 was significantly positively correlated with HAQ1, PTGA, grade of pain, ESR, platelet count, blood urea, AST level, and anti-CCP level; IL-6 showed an inverse significant correlation with T-score. IL-6 was positively correlated with TGC, DAS-28 score, and RF level. No correlation was found between T-score and morning stiffness duration, BMI, CRP, RBC, serum creatinine, and ALT. There was an inverse significant correlation between T-score and HAQ1, SJC, pain grade, DAS-28 score, PTGA, ESR, RF, anti-CCP, and IL-6. Patients with RA on steroid therapy had significantly higher TJC, SJC, and DAS-28 score, anti-CCP, and IL-6 than patients with RA not on steroid therapy. Patients with RA on steroid therapy had significantly lower T-score and lower serum ionized calcium than patients with RA not on steroid therapy. IL-6 has an important role in increasing osteoclastic activity and subsequent bone resorption in the patients with RA. Blocking IL-6 by using IL-6 inhibitors and anti-RANK-L therapy may be effective in inhibiting the inflammatory process and preventing the bone complications of RA disease. PMID- 22531889 TI - Moxibustion inhibits apoptosis and tumor necrosis factor-alpha/tumor necrosis factor receptor 1 in the colonic epithelium of Crohn's disease model rats. AB - BACKGROUND: Previous studies have shown that moxibustion on Tianshu (ST25) and Qihai (CV6) is effective for treating Crohn's disease. However, the mechanism of moxibustion has not been clearly elucidated. AIM: The purpose of this study was to investigate the effect of moxibustion on the inhibition of colonic epithelial cell apoptosis and on tumor necrosis factor alpha (TNF-alpha) and tumor necrosis factor receptor TNF receptor-1 (TNFR1) and TNFR2 and to determine the mechanism of its protective effect using Crohn's disease (CD) model rats. METHODS AND RESULTS: The experimental CD rat models were established by the administration of trinitrobenzene sulfonic acid. In the herbs-partitioned moxibustion (HPM) and mild-warm moxibustion (MWM) groups, moxibustion was administered to Tianshu (ST25) and Qihai (CV6) acupoints once daily for 14 days. In the salicylazosulfapyridine (SASP) group, SASP was administered twice daily for 14 days. A normal control (NC) group and a model control (MC) group were also studied. The levels of TNF-alpha and its mRNA, TNFR1 as well as the rate of colonic epithelial cell apoptosis were significantly decreased in the HPM, MWM and SASP groups compared with the MC group. The HPM and MWM groups had lower mRNA expression and lower protein levels of TNF-alpha compared to the SASP group. The HPM and MWM groups exhibited less apoptosis than the SASP group. CONCLUSIONS: Moxibustion may inhibit colonic epithelial cell apoptosis by reducing the high expression of TNF-alpha and TNFR1 to protect the defective colonic epithelial barrier in CD model rats. PMID- 22531890 TI - Is diabetes a risk factor for colorectal cancer? PMID- 22531892 TI - [Disseminated and circulating tumor cells in gastrointestinal oncology]. AB - Circulating (CTC) and disseminated tumor cells (DTC) represent two different steps of the metastatic process. As with other types of cancer, the recent development of techniques for the detection of CTC and DTC respectively in the blood and bone marrow of patients generated many results in digestive cancers. However, the interpretation of these results and of the prognostic value of CTC/DTC is often limited by the small cohort size and the heterogeneity of detection methods. The aim of this article is to review the different results and their clinical impact, and discuss the possible use of CTC and DTC as new biomarkers. First of all, it is important to take into account the variability of epithelial markers used for the initial stage of immunoselection of CTC/DTC as well as that of molecular or cytological markers used for the second stage of detection. In esophageal, gastric, pancreatic and hepatocellular carcinomas, and in the ileal and pancreatic neuroendocrine tumors, some studies showed a correlation between the detection of CTC and/or DTC and a clinical pejorative course, whether these tumors were at localized or metastatic stages. On colorectal cancer in the adjuvant setting, a recent meta-analysis showed an association between the detection of CTC in peripheral blood and disease-free survival or overall survival. These results are consistent with those of a study that identified detection of CTC as a prognostic factor for relapse in stage II. This last study concluded that it was necessary to achieve long-term evaluation of CTC as a biomarker to guide the decisions of chemotherapy for stage II. In metastatic colorectal cancer, the FDA approved in 2007 the use of pretherapeutic levels of CTC and its variations per-treatment, determined by CellSearch((r)) technology, as a tool in treatments management. However, the modalities of this monitoring have to be specified and clinical benefit or the cost-effectiveness of a treatment based on this new biomarker has to be evaluated. Finally, the qualitative and quantitative monitoring of CTC could be a non-invasive tool to monitor changes in tumor biology throughout the disease, and thereby improve the understanding of the processes of dissemination and therapeutic resistance. PMID- 22531894 TI - Temporary occipito-cervical stabilization of a unilateral occipital condyle fracture. AB - INTRODUCTION: Injuries of the occipital condyles are rare. While the majority of occipital condyle fractures can be treated conservatively, surgery is recommended in craniocervical misalignment and instability. Open reduction and temporary occipito-cervical stabilization might be an alternative to fusion or halo treatment. MATERIALS AND METHODS: This Grand Round case presentation describes temporary C0-C3 stabilization in a 29-year-old man who was involved in a car accident. Radiological examination revealed a rotational burst fracture (type AO C3.1) of C7, and a slight displaced right occipital condyle fracture (Anderson/Montesano type III) with rotational misalignment of the C0-C2 complex. RESULTS: The C7 fracture was stabilized and fused from anterior and posterior. The occipital condyle fracture was reduced and temporarily stabilized from C0-C3 from posterior. Bony healing occurred after 6 months and consequently the internal fixator was removed to preserve upper cervical mobility. PMID- 22531895 TI - Injection of a polymerized hyaluronic acid/collagen hydrogel matrix in an in vivo porcine disc degeneration model. AB - INTRODUCTION: Disc degeneration and re-herniation after nucleotomy procedures are common problems. Simultaneous application of hyaluronic acid (HA)-based matrix has been proposed to limit disc degeneration. This, however, is hampered by loss of the substituted matrix out of the disc. Hence, in situ polymerization of the injected matrix with ultraviolet light (UVL) directly used after injection may be useful. Therefore, this study evaluates a new HA/collagen hydrogel matrix with in situ polymerization after implantation in an established porcine nucleotomy model. MATERIALS AND METHODS: 12 mature minipigs were used. A total of 60 lumbar discs were analyzed. 36 discs underwent partial nucleotomy with a 16G biopsy needle. Of those, 24 discs received matrix (porcine nucleus pulposus collagenous scaffold component and chemically modified HA) which was in situ polymerized using UVL immediately after transplantation. 12 nucleotomized discs and 24 non nucleotomized discs served as controls. After 24 weeks, animals were killed. X rays, MRIs, histology, and gene expression analysis were done. RESULTS: Disc height was reduced equally after sole nucleotomy and nucleotomy with HA treatment and in MRIs signal intensity decreased. For both nucleotomy groups, the nucleus histo-degeneration score showed a significant increase compared to controls. In histology, HA treatment resulted in more scarring and inflammation in the annulus. Gene expression of catabolic MMPs was up-regulated, whereas IFN-gamma, IL-6, and IL-1b were unchanged. CONCLUSION: Although nucleotomy and administration of the implant material did not cause generalized inflammation of the disc, localized annular damage with annulus inflammation and scarring resulted in detrimental degenerative disc changes. As a result, therapeutic strategies should strongly focus on the prevention of annular damage or techniques for annular repair to remain disc integrity. PMID- 22531896 TI - Isolated atypical spinal tuberculosis mistaken for neoplasia: case report and literature review. AB - INTRODUCTION: We report a case of isolated intra-spinal tuberculosis in a 45 year old woman. The uncommon findings in MRI were more suggestive of tumor lesion. MATERIALS AND METHODS: After 3 month history of low back pain and 2 weeks radiated pain of right lower extremity, an operation was performed and the total intra-spinal mass was resected. Histological examination revealed a granulomatous necrosis with caseum. Symptoms were greatly improved postoperatively and then the patient was treated with four anti-tuberculosis drugs. CONCLUSION: This case indicated the complexity of differentiating atypical spinal tuberculosis from disease which could cause spinal cord and cauda equina compression. PMID- 22531897 TI - Lack of uniform diagnostic criteria for cervical radiculopathy in conservative intervention studies: a systematic review. AB - PURPOSE: Cervical radiculopathy (CR) is a common diagnosis. It is unclear if intervention studies use uniform definitions and criteria for patient selection. Our objective was to assess the uniformity of diagnostic criteria and definitions used in intervention studies to select patients with CR. METHODS: We electronically searched the Cochrane Controlled Trials Register, MEDLINE, EMBASE and CINAHL. Studies were included when evaluating conservative interventions in randomised clinical trials (RCTs) in patients with CR. Selection criteria and definitions for patients with CR were extracted and evaluated on their uniformity. RESULTS: Thirteen RCTs were included. Pain was used as an inclusion criterion in 11 studies. Inclusion based on the duration and location of pain varied between studies. Five studies used sensory symptoms in the arm as inclusion criterion. Four studies used cervical range of motion and motor disturbances as inclusion criteria, while reflex changes were used in two studies. Three studies included patients with a positive Spurling's test and two studies used it within a cluster of provocation tests. CONCLUSIONS: Criteria used to select patients with CR vary widely between different intervention studies. Selection criteria and test methods used are poorly described. There is consensus on the presence of pain, but not on the exact location of pain. PMID- 22531898 TI - Spontaneous lumbar curve correction in selective anterior instrumentation and fusion of idiopathic thoracic scoliosis of Lenke type C. AB - BACKGROUND: Posterior pedicle screw instrumented correction and fusion have become the gold standard in the surgical treatment of thoracic scoliosis. However, in thoracic Lenke type C curves selective posterior fusion of the thoracic curve may lead to spinal imbalance. The aim of the study was to analyse the radiological results of selective anterior thoracic fusion using a standard open dual rod technique with special respect to spontaneous lumbar curve correction (SLCC). METHODS: Twenty-eight patients (26 patients with Lenke 1C and 2 patients with Lenke 2C curves) with an average age of 15 years were surgically treated with an anterior dual rod system through a standard open double thoracotomy approach. Average clinical and radiological follow-up was 4 years (24 84 months). RESULTS: Fusion was carried out mostly from end-to-end vertebra. The primary curve was corrected from 61.6 degrees (average correction on reverse bending films 42.9 %) to 27.1 degrees (56.0 % correction) with an average loss of correction of 2.2 degrees . The secondary lumbar curve measured 47.7 degrees preoperatively (40-56 degrees , average correction on reverse bending films 66.2 %) and corrected spontaneously to 30.1 degrees (36 % SLCC) and remained stable without any cases of deterioration or decompensation during follow-up. Lumbar apical vertebral translation increased minimally by an average of 4 mm directly, postoperatively, and returned to an average of preoperative values during follow up. All but two curves remained as type C lumbar modifier at follow-up. Preoperatively, three patients showed a marked coronal imbalance of more than 3 cm (all left, average 4.0 cm); at follow-up, two patients were still out of balance by more than 3 cm (all to the left, average 3.4 cm). Preoperatively, a marked shoulder imbalance of more than 1.0 cm was found in 11 patients; this was corrected in all patients to <1.0 cm at follow-up. The apical vertebral rotation measured according to Perdriolle was corrected from 23.5 degrees to 15.0 degrees in the thoracic spine (36.2 % correction) with an average clinical reduction of the rib hump of 63.2 %. In the lumbar spine, there was no relevant radiological derotation; however, clinically, the lumbar hump corrected spontaneously by 44.3 %. Thoracic kyphosis measured 28.5 degrees preoperatively and 32.3 degrees at follow-up. All six patients with a preoperative hypokyphosis (<20 degrees ) of an average of 9.5 degrees were successfully corrected to an average thoracic kyphosis of 23.8 degrees at follow-up. There were no cases of junctional thoracolumbar kyphosis. There were neither reoperations nor implant failures with pseudarthrosis. CONCLUSION: Selective anterior correction and fusion in primary thoracic curves with lumbar modifier type Lenke C resulted in a reliable and satisfactory SLCC. Advantages of anterior versus posterior techniques are the true segmental derotation with excellent rib hump correction and a superior restoration of thoracic kyphosis. PMID- 22531899 TI - Pedicle screw instrumentation and spinal deformities: have we gone too far? AB - INTRODUCTION: Placement of pedicle screws within the thoracic and lumbar spine has become the "state of the art" for the treatment of spinal deformities. Newly trained surgeons are often trained only with the placement of pedicle screws within the thoracic and lumbar spine and not with hooks or other means of fixation. However, if the benefits of pedicle screw instrumentation in terms of correction ability cannot be questioned on some issues pertaining to their safety, their rationale for all situations as well as their long-term adverse consequence and or early or late complications start to arise. MATERIALS AND METHODS: We therefore present four case examples that illustrate the advantages, questions and complications inherent to pedicle screw instrumentation in spinal deformities. These four cases serve as discussion supported by a review of the literature. The literature search was performed to include pedicle screws associated risks, costs and complications. Articles focusing on instrumentation of the thoracic and lumbar spine for the treatment of adult and pediatric scoliosis were reviewed. RESULTS: Pedicle screw instrumentation in the treatment of spinal deformity is here to stay, however a fair number of issues have come up since their widespread use that started 10 years ago: these include their misplacement with the inherent risks to the vascular or neurologic structures, the rate of misplaced pedicle screw not per number of screws inserted, but per patient operated, the number of screws really necessary to achieve a satisfactory outcome while maintaining costs, their contraindications in some very challenging deformities where the risks clearly outweigh their advantage compared to hooks. At last, the use of pedicle screw instrumentation has driven many centers in increasing the safety of such procedures using intraoperative spinal cord monitoring as well as improved imaging technologies. CONCLUSION: To answer our provocative title "Pedicle screw instrumentation have we gone too far?" Definitively we can answer that for some spinal deformities instrumented with all pedicle-screw instrumentation, we have observed cases where the surgeons have gone way too far; in other cases, where such instrumentation was used in a comprehensive and rational manner, the answer to "Have we gone too far" is no, and such use of pedicle screw has improved outcome with minimum complications. PMID- 22531900 TI - Kinematic evaluation of one- and two-level Maverick lumbar total disc replacement caudal to a long thoracolumbar spinal fusion. AB - PURPOSE: Adjacent level degeneration that occurs above and/or below long fusion constructs is a documented clinical problem that is widely believed to be associated with the considerable change in stiffness caused by the fusion. Some researchers have suggested that early degeneration at spinal joints adjacent to a fusion could be treated by implanting total disc replacements at these levels. It is thought that further degeneration could be prevented through the disc replacement's design aims to reproduce normal disc heights, kinematics and tissue loading. For this reason, there is a clinical need to evaluate if a total disc replacement can maintain both the quantity of motion (i.e. range) and the quality of motion (i.e. center of rotation and coupling) at segments adjacent to a long spinal fusion. The purpose of this study was to experimentally evaluate range of motion (ROM-the intervertebral motion measured) and helical axis of motion (HAM) changes due to one- and two-level Maverick total disc replacement (TDR) adjacent to a long spinal fusion. METHODS: Seven spine specimens (T8-S1) were used in this study (66 +/- 19 years old, 3F/4 M). A continuous pure moment of +/-5.0 Nm was applied to the specimen in flexion-extension (FE), lateral bending (LB) and axial rotation (AR), with a compressive follower preload of 400 N. The 5.0 Nm data were analyzed to evaluate the operated segment biomechanics at the level of the disc replacements. The data were also analyzed at lower moments using a modified version of Panjabi's proposed "hybrid" method to evaluate adjacent segment kinematics (intervertebral motion at the segments adjacent to the fusion) under identical overall (T8-S1) specimen rotations. The motion of each vertebra was monitored with an optoelectronic camera system. The biomechanical test was completed for (1) the intact condition and repeated after each surgical technique was applied to the specimen, (2) capsulotomy at L4-L5 and L5-S1, (3) T8-L4 fusion and capsulotomy at L4-L5 and L5-S1, (4) Maverick at L4-L5, and (5) Maverick at L5 S1. The capsulotomy was performed to allow measurement of facet joint loads in a companion study. Paired t tests were used to determine if differences in the kinematic parameters measured were significant. Holm-Sidak corrections for multiple comparisons were applied where appropriate. RESULTS: Under the 5.0 Nm loads, L4-L5 ROMs tended to decrease in all directions following L4-L5 Maverick replacement (mean = 22 %, compared to the fused condition). Two-level Maverick implantation also tended to reduce L4-S1 ROM (mean 18, 7 and 31 % in FE, LB and AR, respectively, compared to the fused condition without TDR). Following TDR replacement, the HAM location tended to shift posteriorly in FE (at L5-S1), anteriorly in AR, and inferiorly in LB. However, although the above-mentioned trends were observed, neither one- nor two-level TDR replacement showed statistically significant ROM or HAM change in any of the three directions. At the identical T8-S1 posture identified by the modified hybrid analysis, the L4-L5 and L5-S1 levels underwent significant larger motions, relative to the overall specimen rotation, after fusion. In the hybrid analysis, there were no significant differences between the ROM after fusion with intact natural discs at L4-L5 and L5-S1 and the motions at those levels with one or two TDRs implanted. CONCLUSIONS: The present results demonstrated that one or two Maverick discs implanted subjacent to a long thoracolumbar fusion preserved considerable and intact-like ranges of motion and maintained motion patterns similar to the intact specimen, in this ex vivo study with applied pure moments and compressive follower preload. The hybrid analysis demonstrated that, after fusion, the TDR implanted levels are required to undergo large rotations, relative to those necessary before fusion, in order to achieve the same motion between T8 and S1. Additional clinical and biomechanical research is necessary to determine if such a kinematic demand would be made on these levels clinically and the biomechanical performance of these implants if it were. PMID- 22531901 TI - Use of polar organic chemical integrative samplers to assess the effects of chronic pesticide exposure on biofilms. AB - The responses of aquatic organisms to chronic exposure to environmental concentrations of toxicants, often found in mixtures, are poorly documented. Here passive sampler extracts were used in experimental contamination of laboratory channels, to investigate their effects on natural biofilm communities. A realistic mixture of pesticides extracted from Polar Organic Chemical Integrative Samplers was used to expose biofilms in laboratory channels to total pesticide concentrations averaging 0.5 +/- 0.1 MUg l-1. The level of exposure was representative of field conditions in terms of relative proportions of the substances but the exposure concentration was not maintained (decreasing concentrations between contamination occasions). The impact on the structural as well as the functional characteristics of the autotrophic and heterotrophic components was determined, using biofilm grown in uncontaminated conditions (reference site) and in sites exposed to pesticides (contaminated site). The exposure imposed did not significantly modify the structure or functions of reference biofilms, nor did it modify tolerance as measured by mixture EC50 (EC50 mix). In contrast, the communities from the more contaminated downstream section lost tolerance following decreased dose exposure, but community composition remained fairly stable. Overall, these results indicate that low levels of contamination did not lead to strong changes in community structure, and 14-day changes in tolerance seemed to depend mainly on physiological adaptation, suggesting that other environmental factors or longer-lasting processes prevailed. This study reports the first attempt to use passive sampler extracts as a realistic composite contaminant for experimental exposure of biofilms, with promising perspectives in further ecotoxicology studies. PMID- 22531902 TI - The role of imaging in the management of non-metastatic cervical cancer. AB - The role of the physician is to choose the best treatment in terms of survival benefits with the lowest toxicity. Surgery is indicated for early disease, but insufficient pretreatment evaluation may result in an unnecessary procedure or the need for adjuvant therapy. Appropriate imaging may aid in these decisions. Involvement of imaging in radiotherapy allows more accurate and localized irradiation. Confirmation of correct patient positioning is an integral part of radiotherapy, and in the era of modern imaging, newer image-guided techniques are used to ensure adequate positioning of the target. It seems that the evolution of radiotherapy in the era of advanced imaging and the field of adaptive radiotherapy in uterine cervical cancer is a result of the availability of these novel modalities. This review discusses the role of imaging in the treatment planning of cervical cancer. PMID- 22531907 TI - Dutch immunology: vibrant throughout the years. PMID- 22531908 TI - Taurine: energy drink for T cells. AB - The activation of T cells causes many cellular changes, including alterations in cell morphology, motility, and size. While all immunologists know that T cells increase their size and become "blasted" upon activation, little attention has been paid to the question of how cell size is regulated and how this process influences T-cell responses. In this issue of the European Journal of Immunology, Kaesler et al. [Eur. J. Immunol. 2012. 42: 831-841] demonstrate that the organic osmolyte taurine and its transporter Taut are instrumental in driving cell-volume regulation and therefore the T-cell response. In the absence of Taut, effector and memory T-cell responses in mice are severely impaired, mainly due to increased apoptosis of effector cells. Hence, this paper provides an important link between the regulation of cell size and effector T-cell responses. PMID- 22531909 TI - Complement, Candida, and cytokines: the role of C5a in host response to fungi. AB - Complement is the central host defense system that clears invading microbes and balances homeostasis. Pathogenic microbes such as Candida albicans have to breach this efficient and important immune defense layer in order to propagate within the host and to establish an infection. Knowing exactly how the activated complement cascade responds to and attacks microbial invaders is central to understanding the immune battle and the infection process. This also allows a better understanding of how Candida counteracts the individual steps of host innate immunity. Ultimately this knowledge will allow the design of appropriate therapeutic molecules. In this issue Cheng et al. [Eur. J. Immunol. 2012. 42: 993 1004] identify a new cellular effect of the activated human complement system in the defense against the fungal pathogen C. albicans. The authors show that the complement activation fragment C5a, which is formed in response to Candida infection, induces the cellular release of the inflammatory cytokines IL-6 and IL 1beta. PMID- 22531910 TI - Effective T-cell recall responses require the taurine transporter Taut. AB - T-cell activation and the subsequent transformation of activated T cells into T cell blasts require profound changes in cell volume. However, the impact of cell volume regulation for T-cell immunology has not been characterized. Here we studied the role of the cell-volume regulating osmolyte transporter Taut for T cell activation in Taut-deficient mice. T-cell mediated recall responses were severely impaired in taut(-/-) mice as shown with B16 melanoma rejection and hapten-induced contact hypersensitivity. CD4(+) and CD8(+) T cells were unequivocally located within peripheral lymph nodes of unprimed taut(-/-) mice but significantly decreased in taut(-/-) compared with taut(+/+) mice following in vivo activation. Further analysis revealed that Taut is critical for rescuing T cells from activation-induced cell death in vitro and in vivo as shown with TCR, superantigen, and antigen-specific activation. Consequently, reduction of CD4(+) and CD8(+) T cells in taut(-/-) mice upon antigen challenge resulted in impaired in vivo generation of T-cell memory. These findings disclose for the first time that volume regulation in T cells is an element in the regulation of adaptive immune responses and that the osmolyte transporter Taut is crucial for T cell survival and T-cell mediated immune reactions. PMID- 22531911 TI - Melanoma cells present high levels of HLA-A2-tyrosinase in association with instability and aberrant intracellular processing of tyrosinase. AB - Short-lived protein translation products are proposed to be a major source of substrates for major histocompatibility complex (MHC) class I antigen processing and presentation; however, a direct link between protein stability and the presentation level of MHC class I-peptide complexes has not been made. We have recently discovered that the peptide Tyr((369-377)) , derived from the tyrosinase protein is highly presented by HLA-A2 on the surface of melanoma cells. To examine the molecular mechanisms responsible for this presentation, we compared characteristics of tyrosinase in melanoma cells lines that present high or low levels of HLA-A2-Tyr((369-377)) complexes. We found no correlation between mRNA levels and the levels of HLA-A2-Tyr((369-377)) presentation. Co-localization experiments revealed that, in cell lines presenting low levels of HLA-A2-Tyr((369 377)) complexes, tyrosinase co-localizes with LAMP-1, a melanosome marker, whereas in cell lines presenting high HLA-A2-Tyr((369-377)) levels, tyrosinase localizes to the endoplasmic reticulum. We also observed differences in tyrosinase molecular weight and glycosylation composition as well as major differences in protein stability (t(1/2) ). By stabilizing the tyrosinase protein, we observed a dramatic decrease in HLA-A2-tyrosinase presentation. Our findings suggest that aberrant processing and instability of tyrosinase are responsible for the high presentation of HLA-A2-Tyr((369-377)) complexes and thus shed new light on the relationship between intracellular processing, stability of proteins, and MHC-restricted peptide presentation. PMID- 22531912 TI - Loss of central and peripheral CD8+ T-cell tolerance to HFE in mouse models of human familial hemochromatosis. AB - HFE, an MHC class Ib molecule that controls iron metabolism, can be directly targeted by cytotoxic TCR alphabeta T lymphocytes. Transgenic DBA/2 mice expressing, in a Rag 2 KO context, an alphabeta TCR that directly recognizes mouse HFE (mHFE) were created to further explore the interface of HFE with the immune system. TCR-transgenic mHfe WT mice deleted mHFE-reactive T cells in the thymus, but a fraction of reprogrammed cells were able to escape deletion. In contrast, TCR-transgenic mice deprived of mHFE molecules (mHfe KO mice) or expressing a C282->Y mutated mHFE molecule - the most frequent mutation associated with human hereditary hemochromatosis - positively selected mHFE reactive CD8(+) T lymphocytes and were not tolerant toward mHFE. By engrafting these mice with DBA/2 WT (mHFE(+)) skin, it was established, as suspected on the basis of similar engraftments performed on DBA/2 mHfe KO mice, that mHFE behaves as an autonomous skin-associated histocompatibility antigen, even for mHFE-C282 >Y mutated mice. By contrast, infusion of DBA/2 mHFE(+) mice with naive mHFE reactive transgenic CD8(+) T lymphocytes did not induce GVHD. Thus, tolerance toward HFE in mHfe WT mice can be acquired at either thymic or peripheral levels but is disrupted in mice reproducing human familial hemochromatosis. PMID- 22531913 TI - Universal vaccine against influenza virus: linking TLR signaling to anti-viral protection. AB - A vaccine protecting against all influenza strains is a long-sought goal, particularly for emerging pandemics. As previously shown, vaccines based on the highly conserved extracellular domain of M2 (M2e) may protect against all influenza A strains. Here, we demonstrate that M2e-specific monoclonal antibodies (mAbs) protect mice from a lethal influenza infection. To be protective, antibodies had to be able to bind to Fc receptors and fix complement. Furthermore, mAbs of IgG2c isotype were protective in mice, while antibodies of identical specificity, but of the IgG1 isotype, failed to prevent disease. These findings readily translated into vaccine design. A vaccine targeting M2 in the absence of a toll-like receptor (TLR) 7 ligand primarily induced IgG1, whilst the same vaccine linked to a TLR7 ligand yielded high levels of IgG2c antibodies. Although both vaccines protected mice from a lethal challenge, mice treated with the vaccine containing a TLR7 ligand showed significantly lower morbidity. In accordance with these findings, vaccination of TLR7(-/-) mice with a vaccine containing a TLR7 ligand did not result in protection from a lethal challenge. Hence, the innate immune system is required to direct isotype switching toward the more protective IgG2a/c antibodies. PMID- 22531914 TI - CBA/J mice generate protective immunity to soluble Ag85 but fail to respond efficiently to Ag85 during natural Mycobacterium tuberculosis infection. AB - In CBA/J mice, susceptibility to Mycobacterium tuberculosis (M.tb) is associated with low interferon-gamma (IFN-gamma) responses to antigens (Antigen 85 (Ag85) and early secreted antigenic target-6 (ESAT-6)) that have been defined as immunodominant. Here, we asked whether the failure of CBA/J mice to recognize Ag85 is a consequence of M.tb infection or whether CBA/J mice have a general defect in generating specific T-cell responses to this protein antigen. We compared CBA/J mice during primary M.tb infection, Ag85 vaccination followed by M.tb challenge, or M.tb memory immune mice for their capacity to generate Ag85 specific IFN-gamma responses and to control M.tb infection. CBA/J mice did not respond efficiently to Ag85 in the context of natural infection or re-infection. In contrast, CBA/J mice could generate Ag85-specific IFN-gamma responses and protective immunity when this antigen was delivered as a soluble protein. Our data indicate that although M.tb infection of CBA/J mice does not drive an Ag85 response, these mice can fully and protectively respond to Ag85 if it is delivered as a vaccine. The data from this experimental model suggest that the Ag85-containing vaccines in clinical trials should protect M.tb susceptible humans. PMID- 22531915 TI - NOD2 enhances the innate response of alveolar macrophages to Mycobacterium tuberculosis in humans. AB - A role for the nucleotide-binding oligomerization domain 2 (NOD2) receptor in pulmonary innate immune responses has recently been explored. In the present study, we investigated the role that NOD2 plays in human alveolar macrophage innate responses and determined its involvement in the response to infection with virulent Mycobacterium tuberculosis. Our results showed that NOD2 was expressed in human alveolar macrophages, and significant amounts of IL-1beta, IL-6, and TNF alpha were produced upon ligand recognition with muramyldipeptide (MDP). NOD2 ligation induced the transcription and protein expression of the antimicrobial peptide LL37 and the autophagy enzyme IRGM in alveolar macrophages, demonstrating a novel function for this receptor in these cells. MDP treatment of alveolar macrophages improved the intracellular growth control of virulent M. tuberculosis; this was associated with a significant release of TNF-alpha and IL 6 and overexpression of bactericidal LL37. In addition, the autophagy proteins IRGM, LC3 and ATG16L1 were recruited to the bacteria-containing autophagosome after treatment with MDP. In conclusion, our results suggest that NOD2 can modulate the innate immune response of alveolar macrophages and play a role in the initial control of respiratory M. tuberculosis infections. PMID- 22531916 TI - Pituitary adenylate cyclase-activating peptide and vasoactive intestinal polypeptide bias Langerhans cell Ag presentation toward Th17 cells. AB - Epidermal Langerhans cells (LCs) are dendritic APCs that play an important role in cutaneous immune responses. LCs are associated with epidermal nerves and the neuropeptides vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) inhibit LC Ag presentation for Th1-type immune responses. Here, we examined whether PACAP or VIP modulates LC Ag presentation for induction of IL-17A-producing CD4(+) T cells. Treatment with VIP or PACAP prior to in vitro LC Ag presentation to CD4(+) T cells enhanced IL 17A, IL-6, and IL-4 production, decreased interferon (IFN)-gamma and interleukin (IL)-22 release, and increased RORgammat and Gata3 mRNA expression while decreasing T-bet expression. The CD4(+) T-cell population was increased in IL 17A- and IL-4-expressing cells and decreased in IFN-gamma-expressing cells. Addition of anti-IL-6 mAb blocked the enhanced IL-17A production seen with LC preexposure to VIP or PACAP. Intradermal administration of VIP or PACAP prior to application of a contact sensitizer at the injection site, followed by harvesting of draining lymph node CD4(+) T cells and stimulation with anti-CD3/anti-CD28 mAbs, enhanced IL-17A and IL-4 production but reduced production of IL-22 and IFN gamma. PACAP and VIP are endogenous mediators that likely regulate immunity and immune-mediated diseases within the skin. PMID- 22531917 TI - Prostaglandin E2 modulates IL-8 expression through formation of a multiprotein enhanceosome in human colonic epithelial cells. AB - Gastrointestinal inflammation is mediated by the pro-inflammatory mediators interleukin-8 (IL-8) and prostaglandin E(2) (PGE(2) ). PGE(2) binding and coupling through EP2/4 receptor subtypes on colonic epithelial cells stimulates cyclic adenosine monophosphate (cAMP) and IL-8 production. Here we determined the mechanisms whereby PGE(2) regu-lates IL-8 in Caco2 colonic epithelial cells and in cells over-expressing the EP2/4 receptors (EP2S/EP4S). PGE(2) coupling through EP2 activated the transcription factor inducible cAMP early repressor (ICER), whereas coupling through EP4 receptors activated the cyclic AMP-responsive element-binding protein (CREB). Activation of CREB in Caco2/EP2S was protein kinase A (PKA) dependent, whereas in EP4S cells, activation of CREB occurred through the PKA and phosphatidylinositol 3-kinase pathways. Since ICER lacks the transactivation domain, it functions as a transcription repressor as opposed to CREB. PGE(2) coupling through EP2/4 receptors can therefore acts in an opposing manner to either decrease (EP2) or promote IL-8 expression by recruiting CREB binding protein (CBP) (EP4), which formed a multiprotein IL-8 enhanceosome. A novel half CRE (167CRE) and a composite NFAT1-AP1-like site in the IL-8 promoter participated in binding and complex formation as confirmed by mutagenesis and expression studies. These data unravel the mechanisms by which expression of IL-8 is controlled by different signalling pathways that are activated by PGE(2) but acting through different EP receptors. PMID- 22531918 TI - Targeting of macrophage galactose-type C-type lectin (MGL) induces DC signaling and activation. AB - Dendritic cells (DCs) sense the microenvironment through several types of receptors recognizing pathogen-associated molecular patterns. In particular, C type lectins, expressed by distinct subsets of DCs, recognize and internalize specific carbohydrate antigen in a Ca(2+) -dependent manner. Targeting of these receptors is becoming an efficient strategy of delivering antigens in DC-based anticancer immunotherapy. Here we investigated the role of the macrophage galactose type C-lectin receptor (MGL), expressed by immature DCs (iDCs), as a molecular target for alpha-N-acetylgalactosamine (GalNAc or Tn)-carrying tumor associated antigens to improve DC performance. MGL expressed by ex vivo-generated iDCs from healthy donors was engaged by a 60-mer MUC1(9Tn) -glycopeptide as a Tn carrying tumor-associated antigen, and an anti-MGL antibody, as a specific MGL binder. We demonstrated that MGL engagement induced homotrimers and homodimers, triggering the phosphorylation of extracellular signal-regulated kinase 1,2 (ERK1,2) and nuclear factor-kappaB activation. Analysis of DC phenotype and function demonstrated that MGL engagement improved DC performance as antigen presenting cells, promoting the upregulation of maturation markers, a decrease in phagocytosis, an enhancement of motility, and most importantly an increase in antigen-specific CD8(+) T-cell activation. These results demonstrate that the targeting of MGL receptor on human DCs has an adjuvant effect and that this strategy can be used to design novel anticancer vaccines. PMID- 22531919 TI - MxA expression induced by alpha-defensin in healthy human periodontal tissue. AB - Although periodontal tissue is continually challenged by microbial plaque, it is generally maintained in a healthy state. To understand the basis for this, we investigated innate antiviral immunity in human periodontal tissue. The expression of mRNA encoding different antiviral proteins, myxovirus resistance A (MxA), protein kinase R (PKR), oligoadenylate synthetase (OAS), and secretory leukocyte protease inhibitor (SLPI) were detected in both healthy tissue and that with periodontitis. Immunostaining data consistently showed higher MxA protein expression in the epithelial layer of healthy gingiva as compared with tissue with periodontitis. Human MxA is thought to be induced by type I and III interferons (IFNs) but neither cytokine type was detected in healthy periodontal tissues. Treatment in vitro of primary human gingival epithelial cells (HGECs) with alpha-defensins, but not with the antimicrobial peptides beta-defensins or LL-37, led to MxA protein expression. alpha-defensin was also detected in healthy periodontal tissue. In addition, MxA in alpha-defensin-treated HGECs was associated with protection against avian influenza H5N1 infection and silencing of the MxA gene using MxA-targeted-siRNA abolished this antiviral activity. To our knowledge, this is the first study to uncover a novel pathway of human MxA induction, which is initiated by an endogenous antimicrobial peptide, namely alpha-defensin. This pathway may play an important role in the first line of antiviral defense in periodontal tissue. PMID- 22531920 TI - Transcript profiling of CD16-positive monocytes reveals a unique molecular fingerprint. AB - CD16-positive (CD14(++) CD16(+) and CD14(+) CD16(++) ) monocytes have unique features with respect to phenotype and function. We have used transcriptional profiling for comparison of CD16-positive monocytes and classical monocytes. We show herein that 187 genes are greater than fivefold differentially expressed, including 90 genes relevant to immune response and inflammation. Hierarchical clustering of data for monocyte subsets and CD1c(+) myeloid blood dendritic cells (DCs) demonstrate that CD16-positive cells are more closely related to classical monocytes than to DCs. Reverse transcriptase polymerase chain reaction for ten genes with the strongest differential expression confirmed the pattern including a lower messenger RNA level for CD14, CD163, and versican in CD16 positive monocytes. The pattern was similar for CD16-positive monocytes at rest and after exercise mobilization from the marginal pool. By contrast, alveolar macrophages, small sputum macrophages, breast milk macrophages, and synovial macrophages all showed a different pattern. When monocyte-derived macrophages (MDMs) were generated from CD16-positive monocytes by culture with macrophage colony-stimulating factor in vitro, then the MDMs maintained properties of their progeny with lower expression of CD14, CD163, and versican compared with CD14(++) CD16(-) MDMs. Furthermore, CD16-positive MDMs showed a higher phagocytosis for opsonized Escherichia coli. The data demonstrate that CD16-positive monocytes form a distinct type of cell, which gives rise to a distinct macrophage phenotype. PMID- 22531921 TI - Human polymorphonuclear neutrophils express RANK and are activated by its ligand, RANKL. AB - The receptor activator of NF-kappaB (RANK) is especially well studied in the context of bone remodeling, and RANK and its ligand, RANKL, are key molecules in the induction of bone resorbing osteoclasts. We now report that polymorphonuclear neutrophils (PMNs) contain preformed RANK, stored in secretory vesicles and in specific granules. Upon stimulation of PMNs in vitro, RANK was translocated to the cell membrane. In patients with persistent bacterial infections, RANK surface expression was enhanced compared with that of healthy individuals. The functional activity of RANK was assessed by determining migration of PMNs toward RANKL. A time- and dose-dependent migration was seen, leading to the conclusion that RANK on PMNs is functional. We presume that regulated RANK expression contributes to the fine tuning of PMN migration, for example, on and through inflamed endothelium that is known to express RANKL. PMID- 22531922 TI - Novel functions of murine B1 cells: active phagocytic and microbicidal abilities. AB - B1 cells are evolutionarily conserved innate-like cells that share many features with macrophages. It has also been established that B1 cells have a close developmental relationship with macrophages. However, whether B1 cells are able to act as professional phagocytic cells is not clear. In this study, we report that mouse peritoneal cavity (PerC) B cells demonstrate in vivo and in vitro phagocytic activities for Staphylococcus aureus, Escherichia coli, and polystyrene fluorescent microspheres. Approximately 5% of PerC B cells, mainly B1b cells, showed phagocytic activity. Ingested microbes were killed efficiently in the phagolysosome. The antigen-specific B-cell antigen receptor promoted B cell phagocytosis, resulting in antigen presentation to T cells after uptake of bacteria. Our results reveal for the first time that mouse B1 cells have active phagocytic capabilities and thereby act as a bridge linking innate and adaptive immunity. PMID- 22531923 TI - Complement plays a central role in Candida albicans-induced cytokine production by human PBMCs. AB - In experimental studies, the role of complement in antifungal host defense has been attributed to its opsonizing capability. In this study, we report that in humans an activated complement system mainly augments Candida albicans-induced host proinflammatory cytokine production via C5a-C5aR signaling, while phagocytosis and intracellular killing of Candida are not influenced. By blocking the C5a-C5aR signaling pathway, either with anti-C5a antagonist antibodies or with the C5aR antagonist W-54001, C. albicans-induced IL-6 and IL-1beta levels were significantly reduced. Recombinant C5a augmented cytokine production. In addition, using serum from patients with various complement deficiencies, we demonstrated a crucial role of C5, but not C6 or the membrane attack complex, in C. albicans-induced IL-6 and IL-1beta production in monocytes. These findings reveal a central role of anaphylatoxin C5a in augmenting host proinflammatory cytokine production upon contact with C. albicans, and define the role of the complement system in anti-Candida host defense in humans. PMID- 22531924 TI - Modulation of PKC-alpha promotes lineage reprogramming of committed B lymphocytes. AB - During hematopoietic lineage development, hematopoietic stem cells sequentially commit toward myeloid or lymphoid lineages in a tightly regulated manner, which under normal circumstances is irreversible. However, studies have established that targeted deletion of the B-lineage specific transcription factor, paired box gene 5 (Pax5), enables B cells to differentiate toward other hematopoietic lineages, in addition to generating progenitor B-cell lymphomas. Our previous studies showed that subversion of protein kinase C (PKC)-alpha in developing B cells transformed B-lineage cells. Here, we demonstrate that PKC-alpha modulation in committed CD19(+) B lymphocytes also promoted lineage conversion toward myeloid, NK-, and T-cell lineages upon Notch ligation. This occurred via a reduction in Pax5 expression resulting from a downregulation of E47, a product of the E2A gene. T-cell lineage commitment was indicated by the expression of T-cell associated genes Ptcra, Cd3e, and gene rearrangement at the Tcrb gene locus. Importantly, the lineage-converted T cells carried Igh gene rearrangements reminiscent of their B-cell origin. Our findings suggest that modulation of PKC alpha induces hematopoietic-lineage plasticity in committed B-lineage cells by perturbing expression of critical B-lineage transcription factors, and deregulation of PKC-alpha activity/expression represents a potential mechanism for lineage trans-differentiation during malignancies. PMID- 22531926 TI - FOXO3 as a new IKK-epsilon-controlled check-point of regulation of IFN-beta expression. AB - Cell survival transcription factor FOXO3 has been recently implicated in moderating pro-inflammatory cytokine production by dendritic cells (DCs), but the molecular mechanisms are unclear. It was suggested that FOXO3 could antagonize NF kappaB activity, while IKK-beta was demonstrated to inactivate FOXO3, suggesting a cross-talk between the two pathways. Therefore, FOXO3 activity must be tightly regulated to allow for an appropriate inflammatory response. Here, we show that in human monocyte-derived DCs (MDDCs), FOXO3 is able to antagonize signaling intermediates downstream of the Toll-like receptor (TLR) 4, such as NF-kappaB and interferon regulatory factors (IRFs), resulting in inhibition of interferon (IFN) beta expression. We also demonstrate that the activity of FOXO3 itself is regulated by IKK-epsilon, a kinase involved in IFN-beta production, which phosphorylates and inactivates FOXO3 in response to TLR4 agonists. Thus, we identify FOXO3 as a new IKK-epsilon-controlled check-point of IRF activation and regulation of IFN-beta expression, providing new insight into the role of FOXO3 in immune response control. PMID- 22531925 TI - Immunoglobulin class switching appears to be regulated by B-cell antigen receptor specific T-cell action. AB - Antigen affinity is commonly viewed as the driving force behind the selection for dominant clonotypes that can occur during the T-cell-dependent processes of class switch recombination (CSR) and immune maturation. To test this view, we analyzed the variable gene repertoires of natural monoclonal antibodies to the hapten 2 phenyloxazolone (phOx) as well as those generated after phOx protein carrier induced thymus-dependent or Ficoll-induced thymus-independent antigen stimulation. In contrast to expectations, the extent of IgM heterogeneity proved similar and many IgM from these three populations exhibited similar or even greater affinities than the classic Ox1 clonotype that dominates only after CSR among primary and memory IgG. The population of clones that were selected during CSR exhibited a reduced VH/VL repertoire that was enriched for variable domains with shorter and more uniform CDR-H3 lengths and almost completely stripped of variable domains encoded by the large VH1 family. Thus, contrary to the current paradigm, T-cell-dependent clonal selection during CSR appeared to select for VH family and CDR-H3 loop content even when the affinity provided by alternative clones exhibited similar to increased affinity for antigen. PMID- 22531927 TI - Overexpression of Snai3 suppresses lymphoid- and enhances myeloid-cell differentiation. AB - The altered expression of transcription factors in hematopoietic stem cells and their subsequent lineages can alter the development of lymphoid and myeloid lineages. The role of the transcriptional repressor Snai3 protein in the derivation of cells of the hemato-poietic system was investigated. Snai3 is expressed in terminal T-cell and myeloid lineages, therefore, we chose to determine if expressing Snai3 in the early stages of hematopoietic development would influence cell-lineage determination. Expression of Snai3 by retroviral transduction of hematopoietic stem cells using bone marrow chimera studies demonstrated a block in lymphoid-cell development and enhanced expansion of myeloid-lineage cells. Analysis of Snai3-expressing hematopoietic precursor cells showed normal numbers of immature cells, but a block in the development of cells committed to lymphoid lineages. These data indicate that the overexpression of Snai3 does alter bone marrow cell development and that the identification of genes whose expression is altered by the presence of Snai3 would aid in our understanding of these developmental pathways. PMID- 22531928 TI - Multiple phosphorylation sites are important for RUNX1 activity in early hematopoiesis and T-cell differentiation. AB - RUNX1 is essential for definitive hematopoiesis and T-cell differentiation. It has been shown that RUNX1 is phosphorylated at specific serine and threonine residues by several kinase families. However, it remains unclear whether RUNX1 phosphorylation is absolutely required for its biological functions. Here, we evaluated hematopoietic activities of RUNX1 mutants with serine (S)/threonine (T) to alanine (A), aspartic acid (D), or glutamic acid (E) mutations at phosphorylation sites using primary culture systems. Consistent with the results of knockin mice, RUNX1-2A, carrying two phospho-deficient mutations at S276 and S293, retained hematopoietic activity. RUNX1-4A, carrying four mutations at S276, S293, T300, and S303, showed impaired T-cell differentiation activity, but retained the ability to rescue the defective early hematopoiesis of Runx1 deficient cells. Notably, RUNX1-5A, carrying five mutations at S276, S293, T300, S303, and S462, completely lost its hematopoietic activity. In contrast, the phospho-mimic proteins RUNX1-4D/E and RUNX1-5D/E exhibited normal function. Our study identifies multiple phosphorylation sites that are indispensable for RUNX1 activity in hematopoiesis. PMID- 22531929 TI - Chronic smoke exposure induces rheumatoid factor and anti-heat shock protein 70 autoantibodies in susceptible mice and humans with lung disease. AB - The impact of cigarette smoke (CS), a risk factor for rheumatoid arthritis (RA), on sauto-antibody production was studied in humans and mice with and without chronic lung disease (LD). Rheumatoid factor (RF), anti-cyclic citrullinated peptides (CCPs), and anti-HSP70 autoantibodies were measured in several mouse strains and in cohorts of smokers and nonsmokers with and without autoimmune disease. Chronic smoking-induced RFs in AKR/J mice, which are most susceptible to LD. RFs were identified in human smokers, preferentially in those with LD. Anti HSP70 auto-antibodies were identified in CS-exposed AKR/J mice but not in ambient air exposed AKR/J controls. Whereas inflammation could induce anti-HSP70 IgM, smoke exposure promoted the switch to anti-HSP70 IgG autoantibodies. Elevated anti-CCP autoantibodies were not detected in CS-exposed mice or smokers. AKR/J splenocytes stimulated in vitro by immune complexes (ICs) of HSP70/anti-HSP70 antibodies produced RFs. The CD91 scavenger pathway was required as anti-CD91 blocked the HSP70-IC-induced RF response. Blocking Toll-like receptors did not influence the HSP70-IC-induced RFs. These studies identify both anti-HSP70 and RFs as serological markers of smoke-related LD in humans and mice. Identification of these autoantibodies could suggest a common environmental insult, namely CS, in a number of different disease settings. PMID- 22531931 TI - Monitoring of ozone in selected forest ecosystems in Southern Carpathian and Romanian Intensive Monitoring Network (level II). AB - In the Romanian forest ecosystems, the first measurements of ambient ozone (O(3)) concentrations started in 1997 in 6 of 26 locations established in a trans Carpathian Network. Furthermore, three additional ozone and other phytotoxic pollutant (NO(x), SO(2) and NH(3)) monitoring networks were installed in 2000 in Retezat (11 locations) and during 2006-2009 in Bucegi-Piatra Craiului (22 locations) LTER Sites. Since 2007, in four Intensive Forest Monitoring plots (level II), measurements of ozone concentrations were developed. Measurements were made using the Ogawa(r) passive sampler system during the growing season (April to October). In the Bucegi LTER Site, the seasonal means of 42.5-47.2 ppb in 2006 and 2008 were higher than those determined in the Carpathian Network in the 1997-1999 period (39.0-42.0 ppb), while the 2009 mean of 40.0 ppb was in the range of these values. The O(3) levels were slightly higher than those measured in Retezat LTER Site. In the Intensive Forest Monitoring Network (level II), no significant differences in ozone concentrations between individual core plots were noticed. The seasonal means for each plot range between 36.8 and 49.8 ppb in 2008. An influence of ozone concentrations on crown condition and tree volume growth was not determined. PMID- 22531932 TI - Association between BoLA-DRB3 and somatic cell count in Holstein cattle from Argentina. AB - Different studies have proved that the resistance/susceptibility to mastitis is genetically determined. The major histocompatibility complex in cows is known as bovine lymphocyte antigen (BoLA). Genes from the BoLA have been associated with the occurrence of infectious diseases such as mastitis and leukosis, especially the BoLA-DRB gene. The object of the present study was to detect associations between BoLA-DRB3 alleles and somatic cell count (SCC), as an indicator of resistance/susceptibility to mastitis in Holstein cattle (N = 123) from La Pampa, Argentina. Fisher's exact test and Woolf-Haldane odds ratio were applied to study the association between SCC and BoLA-DRB3 allele frequencies. Significant association was noted between BoLA-DRB3.2*23 and *27 alleles (p < 0.05) and protective or susceptibility effects, respectively. In addition, alleles BoLA DRB3.2*20 and *25 exhibit suggestive association with high SCC (p < 0.1). These results were partially in agreement with data reported from Japanese Holstein cattle, but differed from those published by other authors. A possible explanation for the contrasting results could be that the mastitis is a multifactor disease caused by different pathogens. Moreover, most of the studies were carried out using PCR-RFLP method, which has less resolution than PCR-SBT because PCR-RFLP defined alleles included more than one sequenced alleles. PMID- 22531933 TI - Cloning and function analysis of a drought-inducible gene associated with resistance to Curvularia leaf spot in maize. AB - ZmDIP was cloned and its function against Curvularia lunata was analyzed, according to a previous finding on a drought-inducible protein in resistant maize identified through MALDI-TOF-MS/MS. The ZmDIP expression varied in roots, leaf sheaths, and young, as well as old, leaves of different maize inbred lines. The ZmDIP transcript level changed in leaves over the course of time after inoculation with C. lunata. A prokaryotic expression analysis demonstrated that the gene can regulate the salt stress tolerance of Escherichia coli. The ZmDIP transient expression in the maize leaf showed that the gene was also linked to leaf resistance against the C. lunata infection. ZmDIP-mediated ROS and ABA signaling pathways were inferred to be closely associated with maize leaf resistance to the pathogen infection. PMID- 22531934 TI - Molecular characterization and expression analysis of sodium pump genes in the marine red alga Porphyra yezoensis. AB - Sodium pumps (EC 3.6.3.9, Na(+)-ATPase), which mediate excretion of Na(+) from the cell, play a crucial role in Na(+) homeostasis in eukaryotic cells. The objective of this study is to understand the Na(+) efflux system in a marine red alga. We identified a novel sodium pump gene, PyKPA2, from the marine red alga Porphyra yezoensis. The amino acid sequence of PyKPA2 shares 65 % identity with PyKPA1, a previously identified P. yezoensis sodium pump. Similar to PyKPA1, PyKPA2 contains conserved sequences for functions such as phosphorylation, ATP binding, and cation binding. Phylogenetic analysis revealed that the two genes cluster with sodium pumps from algae. Reverse-transcription polymerase chain reaction (RT-PCR) analysis showed that PyKPA1 is expressed preferentially in sporophytes, whereas PyKPA2 is expressed specifically in gametophytes. RT-PCR and quantitative real-time PCR analysis revealed that PyKPA1 and PyKPA2 transcripts were upregulated and downregulated, respectively, in gametophytes during exposure to alkali stress. In addition, transcription of both genes in gametophytes was also induced by cold stress. These results suggest that PyKPA1 and PyKPA2 play an important role in alkali and cold stress tolerance. PMID- 22531935 TI - Influence of different nitrogen inputs on the members of ammonium transporter and glutamine synthetase genes in two rice genotypes having differential responsiveness to nitrogen. AB - Two aromatic rice genotypes, Pusa Basmati 1 (PB1) and Kalanamak 3119 (KN3119) having 120 and 30 kg/ha optimum nitrogen requirement respectively, to produce optimal yield, were chosen to understand their differential nitrogen responsiveness. Both the genotypes grown under increasing nitrogen inputs showed differences in seed/panicle, 1,000 seed weight, %nitrogen in the biomass and protein content in the seeds. All these parameters in PB1 were found to be in the increasing order in contrast to KN3119 which showed declined response on increasing nitrogen dose exceeding the normal dose indicating that both the genotypes respond differentially to the nitrogen inputs. Gene expression analysis of members of ammonium transporter gene family in flag leaves during active grain filling stage revealed that all the three members of OsAMT3 family genes (OsAMT1;1-3), only one member of OsAMT2 family i.e., OsAMT2;3 and the high affinity OsAMT1;1 were differentially expressed and were affected by different doses of nitrogen. In both the genotypes, both increase and decline in seed protein contents matched with the expressions levels of OsAMT1;1, OsGS1;1 and OsGS1;2 in the flag leaves during grain filling stage indicating that high nitrogen nutrition in KN3119 probably causes the repression of these genes which might be important during grain filling. PMID- 22531936 TI - Effects of retrograde gene transfer of brain-derived neurotrophic factor in the rostral spinal cord of a compression model in rat. AB - Recovery after spinal cord injury (SCI) is rare in humans and experimental animals. Following SCI in adults, changes in gene expression and the regulation of these genes are associated with the pathological development of the injury. High levels of brain-derived neurotrophic factor (BDNF) in the injury area during the post-injury period contribute to enhanced neuroprotection and axonal regeneration. Intervention at the level of gene regulation has the potential to promote SCI repair. In this study, the injection of adenovirus-mediated BDNF in the lesion area (rostral spinal cord) up-regulated the expression of BDNF in the injury zone of a compression model in rat, thereby protecting neurons and enhancing behavioral function. PMID- 22531937 TI - Molecular cloning and characterization of a nonsymbiotic hemoglobin gene (GLB1) from Malus hupehensis Rehd. with heterologous expression in tomato. AB - Nonsymbiotic hemoglobins (nsHbs) are involved in a variety of cellular processes in plants. Previous studies indicate that nsHb expression improves plant tolerance during waterlogging and hypoxia. In the present work, the nsHb class-1 coding sequence was cloned from Malus hupehensis Rehd. var. pinyiensis Jiang and subsequently named MhGLB1. The results elucidated the expressed characteristics and physiological effects of MhGLB1. The full-length cDNA contained a 477 bp open reading frame encoding a protein with a molecular mass of 17.8 KDa with 158 amino acids. Quantitative real-time PCR analysis showed that MhGLB1 expresses in roots, stems and leaves growing under normal and nitrate-induced conditions. Hypoxic stress induced accumulation of MhGLB1 within 12 h, and abscisic acid significantly induced expression of MhGLB1 in roots. The photosynthetic, transpiration and stomatal conductance rates of transgenic MhGLB1 tomato plants decreased more slowly than that of wild-type plants under waterlogging treatment. These results indicated that the MhGLB1 gene has an important role in hypoxia. PMID- 22531938 TI - Pathway analysis of genome-wide association study for bone mineral density. AB - The aim of this study was to identify the candidate causal single nucleotide polymorphisms (SNPs) and candidate causal mechanisms that contribute to bone mineral density (BMD) and to generate a SNP to gene to pathway hypothesis using an analytical pathway-based approach. We used hip BMD GWAS data of the genotypes of 301,019 SNPs in 5,715 Europeans. ICSNPathway (identify candidate causal SNPs and pathways) analysis was applied to the BMD GWAS dataset. The first stage involved the pre-selection of candidate causal SNPs by linkage disequilibrium analysis and the functional SNP annotation of the most significant SNPs found. The second stage involved the annotation of biological mechanisms for the pre selected candidate causal SNPs using improved-gene set enrichment analysis. ICSNPathway analysis identified seven candidate SNPs, eight candidate pathways, and seven hypothetical biological mechanisms. Eight pathways are as follows; gamma-hexachlorocyclohexane degradation (nominal p-value < 0.001, false discovery rate (FDR) <0.001), regulation of the smoothened signaling pathway (nominal p value < 0.001, FDR = 0.016), TACI and BCMA stimulation of B cell immune response (nominal p-value < 0.001, FDR = 0.021), endonuclease activity (nominal p-value = 0.001, FDR = 0,026), regulation of defense response to virus (nominal p-value = 0.001, FDR = 0.028), serine_type_endopeptidase_inhibitor_activity (nominal p value = 0.001, FDR = 0.044), endoribonuclease activity (nominal p-value = 0.002, FDR = 0.045), and myeloid leukocyte differentiation (nominal p-value = 0.001, FDR = 0.050). The most significant causal pathway was gamma-hexachlorocyclohexane degradation. CYP3A5, PON2, PON3, CMBL, PON1, ALPL, CYP3A43, CYP3A7, ACP6, ACPP, and ALPI (p < 0.05) are involved in the pathway of gamma-hexachlorocyclohexane degradation. Further examination of the gene contents revealed that DBR1, DICER1, EXO1, FEN1, POP1, POP4, RPP30, and RPP38 were involved in 2 of the 8 pathways (p < 0.05). By applying ICSNPathway analysis to BMD GWAS data, we identified seven candidate SNPs and eight pathways involving gamma-hexachlorocyclohexane degradation, which may contribute to low BMD. PMID- 22531939 TI - Association of multi-pathogenic infections with BAT2, CXCL12, Mx1 and EHMT2 variations in pigs. AB - Porcine reproductive and respiratory syndrome virus (PRRSV), Haemophilus parasuis and Pseudorabies become a widespread problem causing great economic losses associated with reproductive disturbance, respiratory diseases, neonatal mortality, fibrinous polyserositis, meningitis and arthritis in the pig industry. The important candidate genes are assumed to play crucial roles in host defense against the diseases. The aims of this study were to evaluate the variants in HLA B associated transcript 2 (BAT2), CXCL12, myxovirus resistance protein 1 (Mx1) and EHMT2 genes and their effects on the risk of infection PRRSV and H. parasuis in a case-control (diseased-healthy pigs) population of Duroc * Landrace * LargeWhite. The results showed that the mutations in BAT2, Mx1 and EHMT2 genes were significantly associated with the antibody and the reisk of infection PRRSV and H. parasuis. Those individuals with AA genotype of BAT2 had significantly higher Pseudorabies virus antibody than that with GG and GA (P < 0.05), and the individuals with TT genotype of EHMT2 generated higher Hog Cholera and Pseudorabies virus antibody than that wtih GG and GA (P < 0.01). These results indicated that the polymorphisms in Mx1, BAT2 and EHMT2 genes changed the diseases susceptibility and could be the potential markers assisting the pig breeding selection and disease resistance. PMID- 22531940 TI - Antifactor Xa levels versus activated partial thromboplastin time for monitoring unfractionated heparin. AB - Intravenous unfractionated heparin (UFH) remains an important therapeutic agent, particularly in the inpatient setting, for anticoagulation. Historically, the activated partial thromboplastin time (aPTT) has been the primary laboratory test used to monitor and adjust UFH. The aPTT test has evolved since the 1950s, and the historical goal range of 1.5-2.5 times the control aPTT, which first gained favor in the 1970s, has fallen out of favor due to a high degree of variability in aPTT readings from one laboratory to another, and even from one reagent to another. As a result, it is now recommended that the aPTT goal range be based on a corresponding heparin concentration of 0.2-0.4 unit/ml by protamine titration or 0.3-0.7 unit/ml by antifactor Xa assay. Given that several biologic factors can influence the aPTT independent of the effects of UFH, many institutions have transitioned to monitoring heparin with antifactor Xa levels, rather than the aPTT. Clinical data from the last 10-20 years have begun to show that a conversion from aPTT to antifactor Xa monitoring may offer a smoother dose response curve, such that levels remain more stable, requiring fewer blood samples and dosage adjustments. Given the minimal increased acquisition cost of the antifactor Xa reagents, it can be argued that the antifactor Xa is a cost effective method for monitoring UFH. In this review, we discuss the relative advantages and disadvantages of the aPTT, antifactor Xa, and protamine titration tests, and provide a clinical framework to guide practitioners who are seeking to optimize UFH monitoring within their own institutions. PMID- 22531941 TI - [Managing EHEC in hospital routine]. AB - BACKGROUND: During May and June 2011 an outbreak of enterohemorrhagic Escherichia coli (EHEC) occurred in Germany. More than 4000 patients were infected of which 800 developed hemolytic uremic syndrome (HUS) as a severe complication. Reports in the press led to great concern in the general population. Many people with diarrhea reported to hospitals in order to exclude EHEC infections. METHODS: We describe the management of patients with suspected infectious diarrhea at the university hospital of Essen. A hospital with a significant number of immunocompromised patients. RESULTS: One important measure to handle the surge of contagious patients was to establish a multidisciplinary coordination team under leadership and guidance of the Department of Nephrology and the Department of Hospital Hygiene. Suspected infectious patients were separated in a modified emergency room. A new ward for infectious diseases was established to isolate in patients. CONCLUSION: In our hospital the management of EHEC outbreak enabled us to treat these additional infectious patients without hampering the treatment of the other patients. As a result we plan the implementation of a coordination team for future epidemics. PMID- 22531942 TI - [Gallbladder agenesis, a rare congenital disorder]. AB - HISTORY AND ADMISSION FINDINGS: A 51-year-old woman presented with right upper abdominal discomfort for three weeks. Her medical history revealed a lower abdominal gynecological laparoscopy and an ileocaecal resection 7 years ago. INVESTIGATIONS: Blood samples including liver enzymes were within normal limits. An upper abdominal ultrasound failed to reveal a gallbladder. An MRI with MR cholangiography confirmed the abscence of a gallbladder, thus the diagnosis of a gallbladder agenesis. TREATMENT AND COURSE: The patient was informed about the benign nature of her diagnosis and was discharged. The right upper abdominal discomfort was mild and untypical, and most probably not caused by the gallbladder agenesis. CONCLUSION: Gallbladder agenesis is rare. The congenital disorder has to be taken into account if no gallbladder can be found during imaging or surgery. Sonography is not the adequate method for diagnosing gallbladder agenesis. PMID- 22531943 TI - [52-year-old man with pain of the neck]. PMID- 22531944 TI - [Need for differentiating decompression illness]. PMID- 22531946 TI - Understanding the glass-forming ability of active pharmaceutical ingredients for designing supersaturating dosage forms. AB - Amorphous solid dispersions have great potential for enhancing oral absorption of poorly soluble drugs. Crystallization behavior during storage and after exposure to aqueous media must be examined in detail for designing stable and effective amorphous formulations, and it is significantly affected by the intrinsic properties of an amorphous drug. Many attempts have been made to correlate various thermodynamic parameters of pharmaceutical glasses with their crystallization behavior; however, variations in model drugs that could be used for such investigation has been limited because the amorphous characteristics of drugs possessing a high crystallization tendency are difficult to evaluate. In this study, high-speed differential scanning calorimetry, which could inhibit their crystallization using high cooling rates up to 2000 degrees C/s, was employed for assessing such drugs. The thermodynamic parameters of the glasses, including glass transition temperature (T(g)) and fragility, were obtained to show that their crystallization tendency cannot be explained simply by the parameters, although there have been general thought that fragility may be correlated with crystallization tendency. Also investigated was correlation between the thermodynamic parameters and crystallization tendency upon contact with water, which influences in vivo efficacy of amorphous formulations. T(g) was correlated well with the crystallization tendency upon contact with water. PMID- 22531950 TI - On the origins of diastereoselectivity in the conjugate additions of the antipodes of lithium N-benzyl-(N-alpha-methylbenzyl)amide to enantiopure cis- and trans-dioxolane containing alpha,beta-unsaturated esters. AB - "Matching" and "mismatching" effects in the doubly diastereoselective conjugate additions of the antipodes of lithium N-benzyl-(N-alpha-methylbenzyl)amide to enantiopure cis- and trans-dioxolane containing alpha,beta-unsaturated esters have been investigated. High levels of substrate control were established first upon conjugate addition of achiral lithium N-benzyl-N-isopropylamide to both tert butyl (S,S,E)-4,5-O-isopropylidene-4,5-dihydroxyhex-2-enoate and tert-butyl (4R,5S,E)-4,5-O-isopropylidene-4,5-dihydroxyhex-2-enoate. However, upon conjugate addition of lithium (R)-N-benzyl-(N-alpha-methylbenzyl)amide and lithium (S)-N benzyl-(N-alpha-methylbenzyl)amide to these substrates, neither reaction pairing reinforced the apparent sense of substrate control. These reactions do not, therefore, conform to the classical doubly diastereoselective "matching" or "mismatching" pattern usually exhibited by this class of reaction. A comparison of these reactions with the previously reported doubly diastereoselective conjugate addition reactions of lithium amide reagents to analogous substrates is also discussed. PMID- 22531947 TI - Specific bile acids inhibit hepatic fatty acid uptake in mice. AB - Bile acids are known to play important roles as detergents in the absorption of hydrophobic nutrients and as signaling molecules in the regulation of metabolism. We tested the novel hypothesis that naturally occurring bile acids interfere with protein-mediated hepatic long chain free fatty acid (LCFA) uptake. To this end, stable cell lines expressing fatty acid transporters as well as primary hepatocytes from mouse and human livers were incubated with primary and secondary bile acids to determine their effects on LCFA uptake rates. We identified ursodeoxycholic acid (UDCA) and deoxycholic acid (DCA) as the two most potent inhibitors of the liver-specific fatty acid transport protein 5 (FATP5). Both UDCA and DCA were able to inhibit LCFA uptake by primary hepatocytes in a FATP5 dependent manner. Subsequently, mice were treated with these secondary bile acids in vivo to assess their ability to inhibit diet-induced hepatic triglyceride accumulation. Administration of DCA in vivo via injection or as part of a high fat diet significantly inhibited hepatic fatty acid uptake and reduced liver triglycerides by more than 50%. CONCLUSION: The data demonstrate a novel role for specific bile acids, and the secondary bile acid DCA in particular, in the regulation of hepatic LCFA uptake. The results illuminate a previously unappreciated means by which specific bile acids, such as UDCA and DCA, can impact hepatic triglyceride metabolism and may lead to novel approaches to combat obesity-associated fatty liver disease. PMID- 22531949 TI - Selection of internal reference genes for normalization of quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis in the canine brain and other organs. AB - Quantitative reverse transcription polymerase chain reaction (qRT-PCR) is a specific and sensitive technique for quantifying gene expression. To analyze qRT PCR data accurately, suitable reference genes that show consistent expression patterns across different tissues and experimental conditions should be selected. The objective of this study was to obtain the most stable reference genes in dogs, using samples from 13 different brain tissues and 10 other organs. 16 well known candidate reference genes were analyzed by the geNorm, NormFinder, and BestKeeper programs. Brain tissues were derived from several different anatomical regions, including the forebrain, cerebrum, diencephalon, hindbrain, and metencephalon, and grouped accordingly. Combination of the three different analyses clearly indicated that the ideal reference genes are ribosomal protien S5 (RPS5) in whole brain, RPL8 and RPS5 in whole body tissues, RPS5 and RPS19 in the forebrain and cerebrum, RPL32 and RPS19 in the diencephalon, GAPDH and RPS19 in the hindbrain, and MRPS7 and RPL13A in the metencephalon. These genes were identified as ideal for the normalization of qRT-PCR results in the respective tissues. These findings indicate more suitable and stable reference genes for future studies of canine gene expression. PMID- 22531951 TI - Irreducible procidentia due to multiple bladder calculi mimicking impacted faecal mass. AB - A case of massive irreducible procidentia with a hard palpable mass in the anterior vaginal wall mimicking an impacted faecal mass in a 57-year-old multiparous, post-menopausal woman is reported. Inability to walk, constipation and urinary incontinence were her primary complaints. Routine CT of the abdomen and pelvis excluded intestinal pathology, but failed to reveal multiple vesical calculi as the procidentia was lying outside the imaging zone of the pelvic CT. However, targeted plain X-ray and ultrasound of the prolapsed mass disclosed the existence of multiple vesical calculi. The patient was managed with single-stage laparotomy and vaginal hysterectomy. Hysterectomy permitted the reduction of the prolapse and facilitated extraperitoneal vesicolithotomy. Laparotomy excluded bowel pathology. No reconstructive surgical steps for repair and reconstruction were combined. Currently, the patient is relieved of all symptoms and her asymptomatic stage II vault prolapse is managed conservatively. PMID- 22531952 TI - Two-year follow-up of an open-label multicenter study of polyacrylamide hydrogel (Bulkamid(r)) for female stress and stress-predominant mixed incontinence. AB - INTRODUCTION AND HYPOTHESIS: Polyacrylamide hydrogel (PAHG, Bulkamid(r)) is a promising urethral bulking agent. This article presents the 2-year follow-up results of a multicenter study of PAHG injections for treating stress and stress predominant mixed urinary incontinence. METHODS: Submucosal injection of PAHG was performed in 135 women with urinary incontinence, with subjective and objective assessment of the efficacy and safety 24 months postinjection. RESULTS: At 24 months, the subjective responder rate was 64 % (a statistically non-significant reduction from 67 % at 12 months). The decreased number of incontinence episodes and urine leakage were maintained compared with the result from the 12-month evaluations, as were objective result rates and quality of life data. No safety issues occurred. CONCLUSIONS: PAHG is an effective and safe treatment option for women with stress-predominant mixed urinary incontinence, with maintained medium term responder rates. PMID- 22531953 TI - Bladder polyps following Avaulta anterior mesh vaginal wall repair. AB - We present the case of a postmenopausal woman who developed bladder polyps leading to serious abdominal pain, dysuria with mucus and blood, and urinary incontinence after anterior vaginal wall repair using Avaulta anterior mesh (Bard). All of these symptoms resolved after mesh removal. This case emphasizes that not all complications of mesh are known. PMID- 22531954 TI - Urologic complications of laparoscopic radical hysterectomy and lymphadenectomy. AB - INTRODUCTION AND HYPOTHESIS: The purpose of this study was to evaluate the intra- and postoperative urologic complications and management in patients with cervical or endometrial cancer treated with laparoscopic radical hysterectomy and lymphadenectomy. METHODS: We retrospectively reviewed the medical records of 146 patients with cervical or endometrial cancer who underwent total laparoscopic radical hysterectomy with lymphadenectomy between August 2002 and April 2011. The intra- and postoperative urologic complications were analyzed. RESULTS: Double ureteral stents were inserted prophylactically in 13 patients (8.9 %), 2 of whom had postoperative urologic complications. Nine patients (6.2 %) had postoperative urologic complications. Of four patients with ureterovaginal fistulas, two were treated conservatively with cystoscopic placement of ureteral stents and two underwent ureteroneocystostomies. Vesicovaginal fistulas occurred in two patients, both of whom underwent vesicovaginal fistula repairs. One patient noted to have a bladder injury intraoperatively had a laparoscopic repair, and one patient noted to have a ureteral injury postoperatively was treated conservatively with cystoscopic placement of ureteral stents. CONCLUSIONS: Iatrogenic lower urinary tract injuries during laparoscopic radical hysterectomy are relatively common complications. Intraoperative prophylactic ureteral stent insertion and the early detection of urologic complications postoperatively is advised for patients who undergo laparoscopic radical hysterectomies. PMID- 22531955 TI - Dynamic magnetic resonance imaging to quantify pelvic organ prolapse: reliability of assessment and correlation with clinical findings and pelvic floor symptoms. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to assess the interobserver agreement of magnetic resonance imaging (MRI)-based staging of pelvic organ prolapse (POP) and to quantify associations between MRI-based POP staging, findings at pelvic examination, and pelvic floor symptoms. METHODS: This was a cross-sectional study of ten symptomatic POP patients, ten symptomatic patients without POP, and ten nulliparous asymptomatic women. Three different observers performed MRI-based POP staging using the pubococcygeal line (PCL), midpubic line (MPL), perineal line, and H line as references. RESULTS: The interobserver agreement of MRI-based staging of the anterior and middle compartment was good to excellent. In symptomatic women without prolapse, MRI based and pelvic-examination-based POP staging were poorly correlated. In none of the women were MRI-based POP Quantification (POP-Q) staging and pelvic floor symptoms strongly associated. CONCLUSION: The interobserver agreement of MRI based POP staging is excellent, but the added clinical value of such staging is questionable due to poor association with clinical findings and pelvic floor symptoms. PMID- 22531956 TI - Minimal mesh repair for apical and anterior prolapse: initial anatomical and subjective outcomes. AB - INTRODUCTION AND HYPOTHESIS: Here we describe anatomic and quality of life (QOL) outcomes of an anterior and apical compartment prolapse repair involving a reduced mesh implant size and apex-only fixation. METHODS: One hundred and fifteen patients undergoing the repair at a single urogynecology center were assessed using the Pelvic Organ Prolapse Quantification (POP-Q) and inpatient chart reviews. A horizontal incision eliminated overlap with the mesh, and each sacrospinous ligament was approached anteriorly by blunt dissection. Recurrence was defined as apical (C), or anterior (Aa or Ba) >=0, and secondary analyses were performed using POP-Q >= -1 as the anatomic threshold. Pelvic Floor Distress Inventory (PFDI), Surgical Satisfaction Questionnaires (SSQ) and a dyspareunia symptom scale were analyzed pre- and postoperatively. RESULTS: Fifty-three women with uterus in situ demonstrated a combined anterior-apical recurrence rate of 1.89 %, including no anterior (Ba >= -1) and one apical (C >= -1) recurrence. Forty-seven women undergoing repair for vault prolapse had recurrence rates ranging from 0 % in those with prior hysterectomy to 4.2 % in those undergoing concurrent hysterectomy. The rate of mesh exposure was 3/115 (2.6 %), including two in women with concurrent hysterectomy. Self-reported dyspareunia was more common preoperatively (13.4 %) than postoperatively (9.3 %). PFDI scores improved in all domains, and 93 % completing the SSQ reported they were satisfied and would choose the surgery again. CONCLUSIONS: This technique resulted in successful outcomes within both anterior and apical compartments with a low rate of mesh complication, and no cases required mesh removal or hospital readmission. High rates of satisfaction and improved condition-specific QOL were observed. PMID- 22531957 TI - The prevalence of detrusor overactivity amongst patients with symptoms of overactive bladder: a retrospective cohort study. AB - INTRODUCTION AND HYPOTHESIS: Overactive bladder (OAB) is a symptom-based condition consisting of urgency, with or without incontinence, usually with frequency and nocturia. There are many potential causes of OAB, yet many patients are prescribed anticholinergic medications empirically. This study aimed to determine what proportion of patients presenting for urogynecologic assessment with symptoms of OAB had urodynamic detrusor overactivity (DO). METHODS: Retrospective chart review was performed for 220 consecutive patient referrals. Demographic data, physical exam information, and urodynamic results were collected. The t test and Fisher's exact test were used for statistical analyses. RESULTS: The prevalence of DO was 11.8 % in this population. Urogenital atrophy and incomplete emptying were more common. Patients with DO were older and more often menopausal than those without DO. Significant prolapse was a common finding amongst patients with OAB symptoms. CONCLUSIONS: Patients with symptoms of OAB should undergo pelvic examination and assessment of post-void residuals before being initiated on anticholinergic medication. PMID- 22531958 TI - Sexual dysfunction among young married women in southern India. AB - INTRODUCTION AND HYPOTHESIS: This study aimed to identify the nature, prevalence, and factors associated with female sexual disorders (FSD). METHODS: We assessed 150 women using the following instruments: Diagnostic and Statistical Manual IV (DSM IV), Sexual Disorders, Female Sexual Function Index, World Health Organization Quality of Life BREF (WHOQOL-BREF), an abbreviated version of the WHOQOL-100, and a pro forma to record sociodemographic and clinical details. Descriptive statistics were calculated and multivariable logistic regression models used to adjust for confounders. RESULTS: A third of the 150 women met DSM IV criteria for FSD. The common disorders were hypoactive desire (16.67 %) and arousal (14.67) and orgasmic disorders (18 %). Women with any DSM IV diagnosis of sexual disorder had a poorer QOL (t = -3.1; df = 148; p = 0.002) in general and had impaired social relationships (t = -3.5; df = 148; p = 0.001) and lower environmental scores (t = -2.8; df = 148; p = 0.005) in particular. CONCLUSIONS: A minority of women reported sexual dysfunction. Hypoactive desire and arousal and orgasmic disorders were the common conditions. The presence of dysfunction was associated with poor QOL. PMID- 22531959 TI - Restoration of miR-34a in p53 deficient cells unexpectedly promotes the cell survival by increasing NFkappaB activity. AB - Upregulation of miR-34a by p53 is recently believed to be a key mediator in the pro-apoptotic effects of this tumor suppressor. We sought to determine whether restoration of miR-34a levels in p53 deficient cells could rescue the response to DNA damage. Compared with the p53 wildtype U2OS cells, miR-34a expression was much lower in p53 deficient Saos2 cells upon cisplatin treatment. Unexpectedly, delivery of miR-34a in Saos2 cells does not increase the cell sensitivity to apoptosis. This effect was mediated by direct downregulation of SirT1 expression by miR-34a, which in turn increased the NFkappaB activity. Inhibition of NFkappaB activity in Saos2 cells by Aspirin sensitized the miR-34a overexpressing cells to cell death. Thus, in tumors with p53 deficiency, miR-34a restoration alone confers drug resistance through Sirt1-NFkappaB pathway and combination of miR-34a and NFkappaB inhibitor could be considered as a promising therapeutic strategy. PMID- 22531960 TI - Reduction of RANTES expression in lesional psoriatic skin after narrow band ultraviolet therapy: a possible marker of therapeutic efficacy. AB - BACKGROUND: The regulated upon activation, normal T cell expressed and secreted (RANTES) production in psoriatic lesions may amplify the inflammation in these lesions. Narrow band ultraviolet B (NB-UVB), a therapeutic modality for psoriasis, affects the expression of inflammatory cytokines and chemokines. OBJECTIVE: Our aim was to evaluate RANTES mRNA expression in skin lesions of psoriasis before and after NB-UVB phototherapy. METHODS: This study included 25 psoriatic patients who received 24 sessions of NB-UVB. Skin biopsies were taken before and after phototherapy for real time PCR evaluation of RANTES mRNA. RESULTS: The relative quantitation values (RQ) of RANTES mRNA expression was significantly reduced after treatment. A significant negative correlation was found between pre-treatment RQ RANTES mRNA expression and post-treatment PASI score. We found a significant negative correlation between dRQ RANTES mRNA expression (difference between RQ RANTES mRNA expression before and after phototherapy) and PASI score after phototherapy. We found significant negative correlations between pre-treatment RQ RANTES mRNA expression and both initial response session number and total NB-UVB dose at the end of phototherapy. CONCLUSION: NB-UVB reduces RANTES mRNA expression in psoriatic lesions. Pre treatment RQ RANTES mRNA expression could be considered as a marker for clinical improvement and NB-UVB phototherapy efficacy. PMID- 22531961 TI - Solvent-modulated metamagnetism in an Fe(II) system exhibiting a two-step field induced magnetic transition. AB - A one-dimensional iron(II) coordination polymer, [Fe(3)(hpdc)(2)(H(2)O)(6)].2H(2)O (H(3)hpdc = 2-hydroxypyrimidine-4,6 dicarboxylic acid) has been synthesized and characterized. The compound exhibits field-induced two-step magnetic phase transitions and a coexistence of spin canting and metamagnetism, and undergoes a structural transformation from single crystalline to amorphous state upon dehydration, accompanied by significantly enhanced spontaneous magnetization and critical temperature. PMID- 22531962 TI - Cystic pilomatrixoma of the wrist mimicking a ganglion cyst in a child. AB - We describe a patient with a cystic pilomatrixoma mimicking a ganglion cyst on ultrasound. A 9-year-old boy had a subcutaneous mass on his left wrist. Ultrasound displayed a well-defined, multilobulated anechoic mass containing a few internal septa between the extensor pollicis longus and the extensor carpi radialis longus tendons. Sonographic findings suggested that the mass was a ganglion cyst. After excisional biopsy, histopathologic examination confirmed the diagnosis of pilomatrixoma. PMID- 22531963 TI - Surgical technique for trigeminal microvascular decompression. AB - BACKGROUND: Microvascular decompression (MVD) is a non-ablative technique designed to resolve the neurovascular conflict responsible for typical idiopathic trigeminal neuralgia (TN). METHOD: With the patient in a supine position, a small elliptical retrosigmoid craniectomy is used to approach the cerebellopontine angle and the trigeminal nerve. After careful exploration of the trigeminal root entry zone, the offending vessel is identified and moved away. Oxidized regenerated cellulose is used to keep the vessel in its new position far from the nerve. CONCLUSION: MVD represents the gold standard first line treatment for TN; its aim is to free the nerve from any contact. PMID- 22531964 TI - Application of the endoscopic transsphenoidal approach to true type transsellar transsphenoidal meningoencephalocele in an adult: a case report and literature review. AB - Of the transsellar transsphenoidal meningoencephaloceles (TTSMEs), the true type presents with the hernial sac extending from the intracranium to the epipharynx through the sellar floor. The true type is the most serious and difficult to manage, especially when the hernial sac contains vital structures, such as the anterior cerebral artery, pituitary gland, optic nerve, hypothalamus, and third ventricle. Surgical outcome for true type TTSME is reported to be poor. We describe a successful case of endoscopic repair for a 36-year-old man with true type TTSME. Our success with endoscopic repair for true type TTSME in an adult is the first reported case. We believe that the endoscopic transsphenoidal approach allows less invasive surgery and provides an acceptable operative outcome in comparison with other microsurgical approaches. PMID- 22531965 TI - Response to "benefit effect of naloxone in benzodiazepines intoxication: findings of a preliminary study". PMID- 22531967 TI - Fixed drug eruption induced by topical olopatadine ophthalmic solution. AB - Fixed drug eruption (FDE) usually develops after oral administration and is described as a cutaneous reaction recurring at the same location each time the drug is taken. Olopatadine is both a H1 histamine receptor antagonist and a mast cell stabilizer, indicated for the treatment of allergic conjunctivitis. Here, we report a 14-year-old male patient who developed FDE localised on the lateral side of periorbital rim bilaterally, whilst applying olopatadine 0.1% ophthalmic solution for the treatment of allergic conjunctivitis. As far as we know, FDE due to olopatadine has not been previously reported in the literature. We deem it appropriate to report this case because FDE that results from the application of topical drugs is a rare event in the literature. PMID- 22531966 TI - Relative trends in hospitalizations and mortality among infants by the number of vaccine doses and age, based on the Vaccine Adverse Event Reporting System (VAERS), 1990-2010. AB - In this study, the Vaccine Adverse Event Reporting System (VAERS) database, 1990 2010, was investigated; cases that specified either hospitalization or death were identified among 38,801 reports of infants. Based on the types of vaccines reported, the actual number of vaccine doses administered, from 1 to 8, was summed for each case. Linear regression analysis of hospitalization rates as a function of (a) the number of reported vaccine doses and (b) patient age yielded a linear relationship with r(2) = 0.91 and r(2) = 0.95, respectively. The hospitalization rate increased linearly from 11.0% (107 of 969) for 2 doses to 23.5% (661 of 2817) for 8 doses and decreased linearly from 20.1% (154 of 765) for children aged <0.1 year to 10.7% (86 of 801) for children aged 0.9 year. The rate ratio (RR) of the mortality rate for 5-8 vaccine doses to 1-4 vaccine doses is 1.5 (95% confidence interval (CI), 1.4-1.7), indicating a statistically significant increase from 3.6% (95% CI, 3.2-3.9%) deaths associated with 1-4 vaccine doses to 5.5% (95% CI, 5.2-5.7%) associated with 5-8 vaccine doses. The male-to-female mortality RR was 1.4 (95% CI, 1.3-1.5). Our findings show a positive correlation between the number of vaccine doses administered and the percentage of hospitalizations and deaths. Since vaccines are given to millions of infants annually, it is imperative that health authorities have scientific data from synergistic toxicity studies on all combinations of vaccines that infants might receive. Finding ways to increase vaccine safety should be the highest priority. PMID- 22531968 TI - Curcumin and resveratrol in combination modulates benzo(a)pyrene-induced genotoxicity during lung carcinogenesis. AB - The present study attempted to explore the efficacy of curcumin and resveratrol in modulating mitotic catastrophe and apoptosis during lung carcinogenesis. The mice were segregated into five groups, which included normal control, benzo(a)pyrene (BP)-treated, BP + curcumin (C)-treated, BP + resveratrol (R) treated and BP + C + R-treated groups. The BP treatment resulted in a significant increase in the formation of micronuclei as well as in the protein expression of bcl-2 in the lungs of mice. On the other hand, a significant decrease was observed in the number of apoptotic cells and protein expression of bax in the lungs of BP-treated mice. Supplementation of curcumin and resveratrol individually to BP-treated animals resulted in a decrease in the micronuclei formation; however, it was not statistically significant. Interestingly, combination of curcumin and resveratrol resulted in a statistically significant decrease in micronuclei formation. Moreover, phytochemicals in combination significantly reduced the protein expression of bcl-2 in BP-treated mice. Furthermore, supplementation of phytochemicals in combination brought a noticeable improvement in the number of apoptotic cells as well as in the protein expression of bax. The present study, therefore, concludes that the combined treatment with curcumin and resveratrol modulates mitotic catastrophe by stimulating apoptosis in BP-treated mice. PMID- 22531969 TI - Protective effect of omega-3 polyunsaturated fatty acids on L-arginine-induced nephrotoxicity and oxidative damage in rat kidney. AB - L-Arginine (ARG), an essential amino acid, is the endogenous source of the deleterious nitric oxide. Dietary omega-3 polyunsaturated fatty acid (PUFA) enriched fish oil (FO) has been shown to reduce the severity of certain types of cancers, cardiovascular disease, and renal disease. Present study examined whether feeding of FO/flaxseed oil (FXO) would have protective effect against ARG induced nephrotoxicity. ARG-induced nephrotoxicity was recorded by increased serum creatinine and blood urea nitrogen. ARG significantly altered the activities of metabolic and brush border membrane (BBM) enzymes. ARG caused significant imbalances in the antioxidant system. These alterations were associated with increased lipid peroxidation (LPO) and altered antioxidant enzyme activities. Feeding of FO and FXO with ARG ameliorated the changes in various parameters caused by ARG. Nephrotoxicity parameters lowered and enzyme activities of carbohydrate metabolism, BBM and inorganic phosphate (32Pi) transport were improved to near control values. ARG-induced LPO declined and antioxidant defense mechanism was strengthened by both FO and FXO alike. The results of the present study suggest that omega-3 PUFA-enriched FO and FXO from seafoods and plant sources, respectively, are similarly effective in reducing ARG-induced nephrotoxicity and oxidative damage. Thus, vegetarians who cannot consume FO can have similar health benefits from plant-derived omega-3 PUFA. PMID- 22531970 TI - Safrole-modulated immune response is mediated through enhancing the CD11b surface marker and stimulating the phagocytosis by macrophages in BALB/c mice. AB - Safrole, a component of piper betle inflorescence, is a documented rodent hepatocarcinogen and inhibits bactericidal activity and the release of superoxide anion (O(2-)) by polymorphonuclear leukocytes (PMNs). In the present study, we investigated the effects of safrole on immune responses, including natural killer (NK) cell cytotoxicity, phagocytic activity and population distribution of leukocytes from normal BALB/c mice. The cells population (cell surface markers) and phagocytosis by macrophages and monocytes from the peripheral blood mononuclear cells (PBMCs) were determined, and NK cell cytotoxicity from splenocytes of mice after oral treatment with safrole was performed using flow cytometric assay. Results indicated that safrole did not affect the weights of body, spleen and liver when compared with the normal mice group. Safrole also promoted the levels of CD11b (monocytes) and Mac-3 (macrophages) that might be the reason for promoting the activity of phagocytosis. However, safrole reduced the cell population such as CD3 (T cells) and CD19 (B cells) of safrole-treated normal mice by oral administration. Furthermore, safrole elevated the uptake of Escherichia coli-labelled fluorescein isothiocyanate (FITC) by macrophages from blood and significantly stimulated the NK cell cytotoxicity in normal mice in vivo. In conclusions, alterations of the cell population (the increase in monocytes and macrophages, respectively) in safrole-treated normal BALB/c mice might indirectly influence the immune responses in vivo. PMID- 22531971 TI - Involvement of fatty acid metabolism in the hepatotoxicity induced by divalproex sodium. AB - Divalproex sodium is an antiepileptic drug. Hepatotoxicity is one of the most common side effects induced by divalproex sodium. Impaired fatty acid metabolism is considered to play an important role in the drug-induced hepatotoxicity. The sterol regulatory element-binding protein 1c (SREBP-1c) and peroxisome proliferator-activated receptor alpha (PPARalpha) are two key transcription factors involved, respectively, in fatty acid synthesis and degradation in liver. In the present study, we investigated the hepatotoxicity induced by divalproex sodium and its potential mechanism. The results indicated that divalproex sodium significantly decreased the cell viability and increased lactate dehydrogenase leakage in hepatocytes. The activities of alanine aminotransferase and aspartate transaminase were increased in hepatocytes treated with divalproex sodium. Furthermore, divalproex sodium activated SREBP-1c and increased the mRNA expressions of acetyl-CoA carboxylase 1, fatty acid synthase and stearoyl-CoA desaturase 1. Divalproex sodium also inhibited PPARalpha and decreased the messenger RNA expressions of 3-hydroxy-3-methylglutaryl-CoA synthase 2 and carnitine palmitoyltransferase 1A. These results suggest that the hepatotoxicity induced by divalproex sodium may be related with fatty acid synthesis and degradation mediated by SREBP-1c and PPARalpha in hepatocytes. PMID- 22531972 TI - Effects of regular exercise on adult asthma. AB - Although many guidelines recommend regular exercise for adults with asthma, the empirical evidence on the effect of exercise on adult asthma has been inconsistent and there are no previous systematic reviews on this topic. To fill in this gap of knowledge, we synthesized the data on the effects of regular exercise on physical fitness, asthma control and quality of life of adult asthmatics. We performed a Medline search from 1980 through June 2011. In the systematic review we included all clinical trials that provided information on the effects of regular exercise on adult asthma. We conducted meta-analyses of maximal oxygen consumption (VO(2)max) and forced expiratory volume in 1 s (FEV(1)) based on 9 studies. A total of 11 studies were included in the analyses, but only 6 of them had a non-exercising reference group of asthmatics. The meta analyses of randomized controlled trials showed that regular exercise significantly improved VO(2)max. There was no obvious improvement in lung function measurements. Some individual studies showed evidence of improvement in quality of life and asthma control. Meta-analyses provided evidence that regular physical exercise improves physical fitness of adult asthmatics. The results on effects on lung function were inconclusive. There is insufficient evidence to assess the effects of exercise on asthma control and quality of life. PMID- 22531973 TI - The effect of reminders in a web-based intervention study. AB - Knowledge on effective strategies to encourage participation in epidemiological web-based research is scant. We studied the effects of reminders on overall participation. 3,876 employees were e-mailed a baseline web-based lifestyle questionnaire. Nine months later, a follow-up questionnaire was sent. To encourage study participation, 4-5 and 11 e-mail reminders were sent at baseline and follow-up, respectively. Additional reminders (media articles, flyers, SMS etc) were also administered. Reminders (e-mails + additional) were given in low (<= 6 reminders), medium (7-9 reminders) or high amounts (>9 reminders). Participation was examined with respect to participant characteristics (i.e. age, sex, Body Mass Index, occupation), type/number of reminders, and time of participation. Most participants were males, 35-49 years, and field workers (non office based). About 29 % responded before any e-mail reminder, following 26 and 45 % after 1 respective >= 2 e-mail reminders. Participant characteristics were not related to when the participants responded. The 4-5 e-mail reminders increased total response rate by 15 %, the eleven by 21 % (greatest increases in September). Those receiving medium amounts of reminders (reference) had the highest response rate (75 %), likewise office workers (54 %) compared to field workers (33 %). High amounts of reminders were particularly effective on office workers. The participants' characteristics were not related to when they responded in this web-based study. Frequent reminders were effective on response rates, especially for those with high Internet availability. The highest increases in response rates were found in September. PMID- 22531974 TI - CopAb, the second N-terminal soluble domain of Bacillus subtilis CopA, dominates the Cu(I)-binding properties of CopAab. AB - The Cu(I)-detoxifying P-type ATPase CopA from Bacillus subtilis contains two N terminal soluble domains, CopAa and CopAb, connected by a short linker. This arrangement is extremely common in prokaryotic Cu(I) transporters and is also found amongst the multiple soluble domains of eukaryotic homologues. Previous studies of a protein containing only these domains (CopAab) revealed complex Cu(I)-binding properties: both domains are able to bind Cu(I) extremely tightly and, at levels of Cu(I) > 1 per CopAab, the protein undergoes dimerisation, yielding a highly luminescent multi-Cu(I) bound species (Singleton and Le Brun, Dalton Trans., 2009, 688-696). To investigate this complex Cu(I)-binding behaviour and, in particular, to determine the contributions of the two domains to the overall behaviour of the N-terminal part, we generated and purified each domain in isolation. Here, we report studies of the second domain, CopAb. The protein was found to bind Cu(I) with an extremely high affinity (K = ~1 * 10(18) M(-1)) and remained as a monomer up to a level of 1 Cu(I) per protein. Above this level, the protein dimerised, generating a weakly luminescent species. Studies of the acid-base properties of the binding motif Cys residues revealed pK(a) values of < ~5 and ~6.3, adding further support to the proposal that high Cu(I)-affinity is correlated with low proton affinity. Exchange of Cu(I) between the protein and a high affinity chelator was found to occur rapidly via Cu(I)-mediated association, a process that is relevant to in vivo Cu(I) trafficking. Overall, the Cu(I)-binding properties of CopAb are very similar to those of the two-domain protein CopAab, indicating that this domain plays a dominant role in determining the binding properties of CopAab. PMID- 22531976 TI - Use of alternative time scales in Cox proportional hazard models: implications for time-varying environmental exposures. AB - Issues surrounding choice of time scales in Cox proportional hazard regression models have received limited attention in the literature. Although the choice between time on study and 'attained' age time scales has been examined, the calendar time scale may be of interest when modeling health effects of environmental exposures with noteworthy secular trends such as ambient particulate matter air pollution in large epidemiological cohort studies. The authors use simulation studies to examine performance (bias, mean squared error, coverage probabilities, and power) of models using all three time scales when the primary exposure of interest depends on calendar time. Results show that performance of models fit to the calendar time scale varies inversely with the strength of the linear association between the time-varying primary exposure and calendar time. Although models fit to attained age and time on study that do not adjust for calendar time were relatively robust, the authors conclude that care should be exercised when using time scales that are highly correlated with exposures of interest. PMID- 22531977 TI - Protein binding on stepped calcite surfaces: simulations of ovocleidin-17 on calcite {31.16} and {31.8}. AB - Simulations using classical molecular dynamics are reported on the binding of the protein Ovocleidin-17 to calcite stepped surfaces. vicinal surfaces ({31.8} and {31.16}) are used to obtain acute and obtuse steps. The simulations demonstrate that binding is greater at the obtuse step. A range of analytical methods is used to show the importance of surface and local water structure for protein binding. We discuss the general features of molecular binding in the light of these results. Our analysis shows that it is unlikely that Ovocleidin-17 is important in controlling crystal morphology; its main role is likely to be in controlling calcite nucleation. PMID- 22531978 TI - Cryptococcus and cryptococcosis in the twenty-first century. PMID- 22531979 TI - Cryptococcus neoformans/Cryptococcus gattii species complex in southern Italy: an overview on the environmental diffusion of serotypes, genotypes and mating-types. AB - Given the lack of comprehensive molecular epidemiology studies in Reggio Calabria and Messina, Italy, we decided to perform an extensive environmental sampling to describe the current molecular epidemiology of C. neoformans/C. gattii species complex in southern Italy. In this study, we report the occurrence of serotypes, genotypes and mating-types of isolates of the C. neoformans/C. gattii species complex recovered from environmental sources. In addition, a number of environmental C. neoformans var. grubii strains, isolated in 1997 by our laboratory, were also retrospectively examined in order to compare their genotypes with those recently found and to infer the possible epidemiological changes in our country. One hundred and twenty-two isolates were identified as being C. neoformans, whereas only one was found to belong to C. gattii serotype B, genotype VGI and mating-type alpha. Our data revealed that all environmental isolates of C. neoformans recovered here as well as those previously isolated in 1997 belong to serotype A and genotype VNI and posses a mating-type alpha allele. PMID- 22531980 TI - Retinoids ameliorate insulin resistance in a leptin-dependent manner in mice. AB - Transgenic mice expressing dominant-negative retinoic acid receptor (RAR) alpha specifically in the liver exhibit steatohepatitis, which leads to the development of liver tumors. Although the cause of steatohepatitis in these mice is unknown, diminished hepatic expression of insulin-like growth factor-1 suggests that insulin resistance may be involved. In the present study, we examined the effects of retinoids on insulin resistance in mice to gain further insight into the mechanisms responsible for this condition. Dietary administration of all-trans retinoic acid (ATRA) significantly improved insulin sensitivity in C57BL/6J mice, which served as a model for high-fat, high-fructose diet-induced nonalcoholic fatty liver disease (NAFLD). The same effect was observed in genetically insulin resistant KK-A(y) mice, occurring in concert with activation of leptin-signaling pathway proteins, including signal transducer and activator of transcription 3 (STAT3) and Janus kinase 2. However, such an effect was not observed in leptin deficient ob/ob mice. ATRA treatment significantly up-regulated leptin receptor (LEPR) expression in the livers of NAFLD mice. In agreement with these observations, in vitro experiments showed that in the presence of leptin, ATRA directly induced LEPR gene expression through RARalpha, resulting in enhancement of STAT3 and insulin-induced insulin receptor substrate 1 phosphorylation. A selective RARalpha/beta agonist, Am80, also enhanced hepatic LEPR expression and STAT3 phosphorylation and ameliorated insulin resistance in KK-A(y) mice. CONCLUSION: We discovered an unrecognized mechanism of retinoid action for the activation of hepatic leptin signaling, which resulted in enhanced insulin sensitivity in two mouse models of insulin resistance. Our data suggest that retinoids might have potential for treating NAFLD associated with insulin resistance. PMID- 22531981 TI - Nonanesthesiologist administration of propofol: it's all about money. PMID- 22531982 TI - Endoscopist-directed propofol administration versus anesthesiologist assistance for colorectal cancer screening: a cost-effectiveness analysis. AB - BACKGROUND: Propofol for colonoscopy is largely administered by anesthesiologists or anesthesiology nurses in the United States (US) and Europe. Endoscopist directed administration of propofol (EDP) by nonanesthesiologists has recently been proposed, with potential savings of anesthetist reimbursement costs. We aimed to assess potential EDP-related benefit in a screening setting. METHODS: In a Markov model the total number of screening and follow-up colonoscopies in a cohort of 100 000 US subjects were estimated. Anesthetist-assisted colonoscopy was compared with an EDP strategy. Model outputs were projected onto the 50 - 80 year-old US population, assuming 27 % as the current uptake for colonoscopy screening. Anesthetist costs were estimated using the mean reimbursement for the corresponding Medicare code (>= 65-year-olds) and from commercial insurance information (50 - 64-year-olds). The proportion of colonoscopies with anesthesiologist assistance was estimated from the Medicare database. Mean nurse salary was used to estimate the cost of a 2-week EDP training. The absolute number of US endoscopists was estimated by inflating by 33 % the number of board certified gastroenterologists. No EDP mortality was assumed in the reference scenario, and 0.0008 % mortality in the sensitivity analysis. US census data were adopted. Analogous inputs were used for France to assess EDP-related benefit in a European country. RESULTS: EDP training for 17 166 nurses (one for each US endoscopist) showed a cost of $ 47 million. Cost estimates for anesthesiologist assistance for colonoscopy were $ 95 (Medicare) and $ 450 (non-Medicare commercial insurance), with 34.8 % of colonoscopies requiring anesthesiologist assistance. US implementation of an EDP policy showed a 10-year saving of $ 3.2 billion (Monte Carlo analysis 5 - 95 % percentiles $ 2.7 - $ 11.9 billion). In the sensitivity analysis, assuming 50 % of colonoscopies were anesthetist assisted showed an EDP benefit of $ 4.6 billion. Assuming a 0.0008 % mortality rate, the incremental cost - effectiveness of anesthetist-assisted colonoscopy versus an EDP policy was $ 1.5 million per life-year gained, supporting EDP as the optimal choice. A 31-fold increase of EDP-related mortality or a 17-fold cost reduction for anesthetist-assisted colonoscopy was required for EDP to become not cost-effective in this scenario. Implementation of an EDP policy in France, within a guaiac-fecal occult blood test (g-FOBT) screening program, was estimated to save ? 0.8 billion in 10 years. CONCLUSIONS: The absolute economic benefit of EDP implementation in a screening setting is probably substantial with 10-year savings of $3.2 billion in the US and ?0.8 billion in France. The impact of an eventual EDP-related mortality on EDP cost - effectiveness seems marginal. The huge economic and medical resources entailed by anesthetist-assisted colonoscopy could be more efficiently invested in other clinical fields. PMID- 22531983 TI - Withdrawal time as a quality indicator for colonoscopy - a nationwide analysis. AB - BACKGROUND AND STUDY AIMS: A withdrawal time of at least 6 min has been recommended as a quality indicator for colonoscopy. One drawback of many of the studies that have investigated withdrawal time and produced conflicting results has been their single-center design involving few endoscopists. Therefore, the validity of withdrawal time as a quality measure remains unclear. This study explores the value of individual withdrawal time in a nationwide analysis. PATIENTS AND METHODS: This prospective cohort study comprised data from outpatient colonoscopies performed at 19 Norwegian centers from January to September 2009 and registered in the Norwegian Gastronet Quality Assurance (QA) program. The participating endoscopists were characterized by their median withdrawal time for visual colonoscopies (diagnostic colonoscopies without biopsy or therapy) and categorized into two visual withdrawal time (VWT) groups (< 6 min or >= 6 min) to analyze the predictive value of VWT for detection of one or more polyps >= 5 mm in diameter using multiple logistic regression models. RESULTS: The study included 4429 consecutive colonoscopies performed by 67 endoscopists. The adjusted odds ratio for the detection of polyps >= 5 mm was 1.21 (95 %CI 0.94 - 1.56, P = 0.14) for endoscopists with a median VWT >= 6 min compared with endoscopists with a median VWT < 6 min. CONCLUSION: Withdrawal time using 6 min as the threshold is not a strong predictor of the likelihood of finding a polyp during colonoscopy and should not be used as a quality indicator. PMID- 22531984 TI - Transgastric endoscopic gastroenterostomy using a partially covered occluder: a canine feasibility study. AB - BACKGROUND AND STUDY AIMS: The use of natural orifice transluminal endoscopic surgery (NOTES) for gastroenterostomy has been previously reported, but it remains technically challenging and additional assistance is often needed. The aim of this study was to develop and evaluate a novel method for the creation of a gastroenterostomy using NOTES with an occluder. METHODS: Transgastric endoscopic gastroenterostomy was performed in 12 healthy female dogs using a therapeutic upper gastrointestinal endoscope and a partially covered occluder. The occluder was removed with a snare 1 week later. The patency of the gastroenterostomy was confirmed by endoscopy, contrast radiological study, necropsy, and histological examination after 2 weeks. RESULTS: NOTES gastroenterostomy with an occluder was successful in all 12 dogs. The mean operative time was 32.3 +/- 10.3 min (range 20.3 - 53.5). One dog (the first; 8.3 %) died 4 days after the operation of severe intra-abdominal infection due to incorrect deployment of the occluder and poor bowel preparation. Minor bleeding occurred at the anastomosis after removal of the occluder in two of the remaining dogs (18.2 %). Necropsy revealed postoperative adhesions that had developed at the anastomotic site in one dog (9.1 %). No anastomotic leakage or intestinal obstruction was observed. Complete healing of the anastomosis was confirmed on histological evaluation. CONCLUSION: Gastroenterostomy performed entirely by NOTES using an occluder was technically feasible in this survival animal model. PMID- 22531985 TI - Endoscopic ultrasound-guided gastroenterostomy using novel tools designed for transluminal therapy: a porcine study. AB - BACKGROUND AND STUDY AIMS: Surgical gastroenterostomy is associated with appreciable morbidity and mortality. We evaluated the technical feasibility and outcomes of a new method of endoscopic ultrasound (EUS)-guided gastroenterostomy using novel tools designed for transluminal therapy. METHODS: In one acute and four survival female pigs, a gastroenterostomy was created under EUS guidance. Novel tools used included: (i) an anchor wire; (ii) an access device; (iii) a fully covered metal stent with bilateral lumen-apposing anchors. The anchor guide wire was inserted through a standard 19-G fine needle aspiration (FNA) needle to appose the small-bowel and stomach walls. The access device created a 3.5-mm fistula opening for insertion of the stent delivery catheter. The stent lumen was dilated to 10 mm to pass a gastroscope into the small bowel. RESULTS: The procedure was technically successful in all animals. No bleeding occurred. In one acute animal, necropsy showed good stent position and no tissue injury. In four survival animals, the stents remained fully patent and all animals showed normal eating behavior without signs of infection. Stents were easily removed without tissue trauma at 4.5 weeks (n = 3) or 5.5 weeks (n = 1). After stent removal, the tracts appeared mature and were easily intubated with the gastroscope. Necropsy and histopathology showed complete fusion of the stomach and small-bowel wall layers at the site of gastroenterostomy. CONCLUSIONS: EUS-guided gastroenterostomy is feasible using novel tools with no adverse outcomes in a survival porcine model. Further study of this is indicated as an alternative to surgical bypass for the palliation of malignant gastric outlet obstruction in appropriately selected patients. PMID- 22531986 TI - UEGW 2011 report: putting endoscopy into perspective. PMID- 22531987 TI - Carbon dioxide insufflation vs. conventional saline irrigation for peroral video cholangioscopy. PMID- 22531990 TI - A novel mutation in lysophosphatidic acid receptor 6 gene in autosomal recessive hypotrichosis and evidence for a founder effect. AB - Mutations in the lysophosphatidic acid receptor 6 (LPAR6) gene cause localized autosomal recessive hypotrichosis. We report six consanguineous families from Pakistan with segregating hypotrichosis localized to the scalp. Genetic investigation using polymorphic microsatellite markers revealed homozygosity spanning the LAH3 locus on chromosome 13 in affected individuals of all six families. Sequence analysis of the LPAR6 gene showed a novel insertion resulting in a frameshift and a premature termination (p.I194FfsX11) in affected members of one family. In the remaining five families we identified a previously described missense mutation (p.G146R) in a homozygous state in affected members. The closest flanking polymorphic marker showed an identical allele size in the five families segregating with the p.G146R mutation, supporting a single origin of this variation. These findings extend the spectrum of known LPAR6 mutations and suggest a founder effect of the p.G146R mutation in the Pakistani population. PMID- 22531991 TI - Fabrication, properties and applications of Janus particles. AB - Although the concept of Janus particles was raised in the early 1990s, the related research has not attracted considerable interest until recently due to the special properties and applications of these colloidal particles as well as the advances in new fabrications. Janus particles can be divided into three categories: polymeric, inorganic, and polymeric-inorganic, and each kind of Janus particles can be spherical, dumbbell-like, half raspberry-like, cylindrical, disk like, or any of a variety of other shapes. Different Janus particles may share common preparation principles or require specific fabrication processes, and may have different assembly behaviours and properties. This critical review discusses the main fabrication methods of the three kinds of Janus particles, and then highlights the important properties and applications of these Janus particles developed in recent years, and finally proposes some perspectives on the future of Janus particle research and development. PMID- 22531992 TI - Production of PEGylated nanocapsules through solvent displacement in confined impinging jet mixers. AB - The growth of importance of nanocapsules (and other particulate systems) in different fields requires fast and reproducible methods for their production. Confined impinging jet mixers were successfully used for the production of nanospheres and are now tested for the first time for the production of nanocapsules. This work focuses on the understanding of formation mechanisms and on the quantification of the effect of the most important operating parameters involved in their production. Solvent displacement is employed here for the assembly of the nanocapsules by using a PEGylated derivative of cyanoacrylate as copolymer. A comparison with nanospheres obtained under the same operating conditions is also reported. Results show that the oil-to-copolymer mass ratio (MR) is the main factor affecting the final size distribution and that small nanocapsules are obtained only at low oil-to-copolymer MR. The effect of mixing is significant, proving that mixing of solvent and antisolvent also affects the final size distribution; this depends mainly on the inlet jet velocity, but the size of the mixer is also important. The Reynolds number may be useful to take this into account for geometrically similar systems. Quenching by dilution allows to stabilize the nanocapsules, evidencing the role of aggregation and ripening. PMID- 22531993 TI - Molecular characterization of eight segments of Scylla serrata reovirus (SsRV) provides the complete genome sequence. AB - Scylla serrata reovirus (SsRV) is one of the most prevalent viral pathogens of mud crabs (S. serrata). Of the 12 double-stranded RNA (dsRNA) genomic segments (S1-S12), the three largest (S1-S3) and S7 were sequenced previously and were shown to have no or only low sequence homology to known members within the family Reoviridae. The sequences of the remaining segments, S4-S6 and S8-S12, are reported here. With the exception of S4, all have single open reading frames (ORFs) on their positive strands, and the terminal sequences 5'-AUAAA(U)/(C) (A)/(U)...G(A)/(G) (A)/(U) (A)/(C)AAC(G)/(U)AU-3' are conserved among currently and previously sequenced segments. S4 contains two out-of-phase ORFs on the positive strand, suggesting that this segment is bicistronic. The ORFs of segments S4-S6 and S8-S12 have low or no homology to other reovirus genes, with the exception that all of the SsRV segments have high sequence similarity to those of mud crab reovirus (MCRV) and share the same 5'- and 3'-terminal nucleotide sequences, suggesting that the two viruses belong to the same species in the family Reoviridae. Analysis of virion proteins revealed that SsRV contains at least eight structural proteins, with sizes ranging from 25 to 160 kDa. PMID- 22531994 TI - Belief in a just world, teacher justice, and bullying behavior. AB - The relation between school students' belief in a just world (BJW) and their bullying behavior was investigated in a questionnaire study. The mediating role of teacher justice was also examined. Data were obtained from a total of N = 458 German and Indian high school students. Regression analyses revealed that the more strongly students believed in a personal just world and the more they evaluated their teachers' behavior toward them personally to be just, the less bullying behavior they reported. Moreover, students with a strong BJW tended to evaluate their teachers' behavior toward them personally to be more just, and the experience of teacher justice mediated the relation between BJW and less bullying perpetration. This pattern of results was as expected and consistent across different cultural contexts. It persisted when neuroticism, sex, and country were controlled. The adaptive functions of BJW and implications for future school research are discussed. PMID- 22531995 TI - Social aggression and resource conflict across the female life-course in the Bolivian Amazon. AB - This work explores sources of conflict among forager-horticulturalist women in Amazonian Bolivia, and applies life history theory as a tool for understanding competitive and cooperative social networking behaviors among women. In this study, 121 Tsimane women and girls were interviewed regarding current and past disagreements with others in their community to identify categories of contested resources that instigate interpersonal conflicts, often resulting in incidences of social aggression. Analysis of frequency data on quarrels (N = 334) reveals that women target several diverse categories of resources, with social types appearing as frequently as food and mates. It was also found that the focus of women's competition changes throughout the life-course, consistent with the notion that current vs. future reproduction and quantity-quality trade-offs might have different influences on competition and social conflict over resources within women's social networks across different age groups. PMID- 22531997 TI - Locus of control as a contributing factor in the relation between self-perception and adolescent aggression. AB - Researchers continue to debate the role of self-esteem in aggression, but research has shown a consistent association between narcissism and aggression in adults and adolescents [e.g., Barry et al., 2007; Bushman and Baumeister, 1998; Stucke, 2007]. The primary aim of the current study was to examine whether locus of control (LOC) moderated the relation between self-perception variables (i.e., self-esteem and narcissism) and aggression in adolescents. Participants were 174 youth (145 males, 26 females) between the ages of 16 and 19 who were enrolled in a voluntary residential program for youth who have dropped out of school. The results showed that LOC moderated the association between self-esteem and aggression such that low self-esteem was associated with higher levels of aggression for individuals with an external LOC. Contrary to expectations, LOC failed to moderate the narcissism-aggression relation. The implications of this study for understanding how self-perception is related to adolescent aggression are discussed. PMID- 22531996 TI - 2D:4D in men is related to aggressive dominance but not to sociable dominance. AB - It has been shown that a smaller ratio between the length of the second and fourth digit (2D:4D) is an indicator of the exposure to prenatal testosterone (T). This study measured the 2D:4D of men and assessed dominance as a personality trait to investigate indirectly if the exposure to prenatal T is related to a dominant personality later in life. Results showed that men had a more aggressive dominant personality when having a more masculine (lower) 2D:4D, while there was no relationship between sociable dominance and 2D:4D. Findings from this study indicate that it is important to distinguish different forms of dominance since other studies failed to find relationships between dominance and 2D:4D. PMID- 22531998 TI - Child sex moderates the association between negative parenting and childhood conduct problems. AB - Although multiple dimensions of negative parenting behavior are associated with childhood conduct problems (CP), there is relatively little research on whether the association is equally robust in boys and girls. To improve the specificity of current models of negative parenting and offspring CP, we explored the potential moderating role of child sex in a sample of 179 5- to 10-year-old ethnically diverse boys and girls with and without attention deficit/hyperactivity disorder (ADHD) who were assessed using multiple methods (i.e., rating scales, semistructured interviews) and informants (i.e., parents, teachers). Controlling for children's age, race-ethnicity, and ADHD diagnostic status (i.e., ADHD vs. non-ADHD), inconsistent discipline was positively associated with offspring aggression and rule-breaking behavior, whereas harsh punishment was positively associated with aggression, rule-breaking behavior, and oppositional defiant disorder symptoms. Furthermore, child sex significantly moderated the association of inconsistent discipline and aggression and rule breaking behavior, such that inconsistent discipline was positively associated with CP for boys, but not for girls. Given the centrality of negative parenting to theories of and efficacious interventions for aggression and CP, we discuss these findings within a developmental psychopathology framework and consider their implications for intervention. PMID- 22531999 TI - Fracture rate in patients with myasthenia gravis: the general practice research database. AB - SUMMARY: The aim of this study was to evaluate fracture risk after onset of myasthenia gravis using the UK General Practice Research Database. Overall fracture risk is not statistically increased compared with age- and gender matched controls irrespective of glucocorticoid use, but was increased in those using antidepressants, anxiolytics or anticonvulsants. INTRODUCTION: Myasthenia gravis (MG) is a neuromuscular disease which has been associated with an increased falls risk and glucocorticoid-induced osteoporosis, recognized determinants of increased fracture risk. The aim of this study was to evaluate the risk of fracture after onset of MG. METHODS: We conducted a retrospective cohort study using the UK General Practice Research Database (1987-2009). Each MG patient was matched by age, sex, calendar time and practice to up to six patients without a history of MG and we identified all fractures and those associated with osteoporosis. RESULTS: Compared to the control cohort, there was no statistically significant increased risk observed in patients with MG for any fracture (adjusted hazard ratio [AHR] 1.11; 95 % confidence interval [CI], 0.84-1.47) or osteoporotic fractures (AHR 0.98 [95 % CI 0.67-1.41]). Further, use of oral glucocorticoids up to a cumulative dose exceeding 5 g prednisolone equivalents did not increase risk of osteoporotic fracture (AHR 0.99 [95 % CI, 0.31-3.14]) compared with MG patients without glucocorticoid exposure. However, fracture risk was higher in patients with MG prescribed antidepressants (AHR 3.27 [95 % CI, 1.63-6.55]), anxiolytics (AHR 2.18 [95 % CI, 1.04-4.57]) and anticonvulsants (AHR 6.88 [95 % CI, 2.91-16.27]). CONCLUSION: Overall risk of fracture in patients with MG is not statistically increased compared with age- and gender-matched controls irrespective of glucocorticoid use but was increased in those using antidepressants, anxiolytics or anticonvulsants. These findings have implications in strategies preserving bone health in patients with MG. PMID- 22532000 TI - Secondhand smoke exposure and osteoporosis in never-smoking postmenopausal women: the Fourth Korea National Health and Nutrition Examination Survey. AB - SUMMARY: The association between secondhand smoke (SHS) exposure and lumbar and femoral neck osteoporosis was assessed in postmenopausal never-smoking Korean women. The presence of family members who actively smoked was associated with femoral neck osteoporosis. The number of cigarettes consumed by cohabitant smokers was positively associated with lumbar and femoral neck osteoporosis. INTRODUCTION: This study aimed to assess the association between SHS and postmenopausal osteoporosis. METHODS: Of 2,067 postmenopausal women (age, >=55 years) participating in the Fourth Korea National Health and Nutrition Examination Survey, 925 never-smokers identified through interviews and urinary cotinine level verification were enrolled. Cross-sectional relationships between self-reported SHS exposure and osteoporosis of the lumbar vertebrae and femoral neck (defined using the World Health Organization T-score criteria) were investigated by bone densitometry. RESULTS: Participants having actively smoking family members showed increased adjusted odds ratio (aOR) for femoral neck osteoporosis compared with participants not exposed to SHS (aOR, 3.68; 95 % confidence interval [CI], 1.23-10.92). Participants whose cohabitant smokers consumed any number of cigarettes per day showed increased occurrences for lumbar and femoral neck osteoporosis compared with the nonexposed group. Participants whose cohabitant smokers consumed >=20 cigarettes/day showed increased aORs for lumbar (aOR, 5.40; 95 % CI, 1.04-28.04) and femoral neck (aOR, 4.35; 95 % CI, 1.07-17.68) osteoporosis compared with participants not exposed to SHS. CONCLUSIONS: In postmenopausal never-smoking Korean women, exposure to SHS was positively associated with osteoporosis. This finding further emphasizes a need to identify vulnerable groups exposed to SHS to increase bone health. PMID- 22532001 TI - Amphiphilic alpha-helix mimetics based on a benzoylurea scaffold. AB - The design and synthesis of amphiphilic benzoylurea alpha-helix mimetics is described. These conformationally constrained molecules allow for the correct angular and spatial projection of hydrophobic and hydrophilic groups and thus the reproduction of side-chains on both faces of an alpha-helix. PMID- 22532005 TI - Does affective valence during and immediately following a 10-min walk predict concurrent and future physical activity? AB - BACKGROUND: Affect may be important for understanding physical activity behavior. PURPOSE: To examine whether affective valence (i.e., good/bad feelings) during and immediately following a brief walk predicts concurrent and future physical activity. METHODS: At months 6 and 12 of a 12-month physical activity promotion trial, healthy low-active adults (N=146) reported affective valence during and immediately following a 10-min treadmill walk. Dependent variables were self reported minutes/week of lifestyle physical activity at months 6 and 12. RESULTS: Affect reported during the treadmill walk was cross-sectionally (month 6: beta=28.6, p=0.008; month 12: beta=26.6, p=0.021) and longitudinally (beta=14.8, p=0.030) associated with minutes/week of physical activity. Affect reported during a 2-min cool down was cross-sectionally (month 6: beta=21.1, p=0.034; month 12: beta=30.3, p<0.001), but not longitudinally associated with minutes/week of physical activity. Affect reported during a postcool-down seated rest was not associated with physical activity. CONCLUSIONS: During-behavior affect is predictive of concurrent and future physical activity behavior. PMID- 22532006 TI - Glycomics using mass spectrometry. AB - Mass spectrometry plays an increasingly important role in structural glycomics. This review provides an overview on currently used mass spectrometric approaches such as the characterization of glycans, the analysis of glycopeptides obtained by proteolytic cleavage of proteins and the analysis of glycosphingolipids. The given examples are demonstrating the application of mass spectrometry to study glycosylation changes associated with congenital disorders of glycosylation, lysosomal storage diseases, autoimmune diseases and cancer. PMID- 22532007 TI - Direct and indirect organogenesis of Clivia miniata and assessment of DNA methylation changes in various regenerated plantlets. AB - Clivia miniata is an important indoor ornamental plant and has been reported to have medicinal value. We developed an efficient in vitro micropropagation protocol from young leaves (indirect organogenesis), young petals (indirect organogenesis) and shoot tips (direct organogenesis) of this plant. Using young leaves and shoot tips as explants, the regeneration frequencies were much higher than those in previous investigation and the regeneration was dependent upon less nutrition. We speculated that the leaf-derived callus can generate amino acids necessary for protein synthesis by itself. We employed the methylation-sensitive amplified polymorphism (MSAP) method to assess cytosine methylation variation in various regenerated plantlets and between organs. The MSAP profiles indicated that the frequency of somaclonal variation in the form of cytosine methylation was highest in petal-derived plantlets followed by secondary leaf-derived, primary leaf-derived and shoot tip-derived plantlets, but the methylation variation in petal-derived plantlets was lower than between petals and leaves of a single plant. The results indicated that the methylation variation in regenerated plantlets was related to the types of explants, regeneration pathways and number of regeneration generations. Two possible factors for the highest somaclonal variation rate in petal-derived plantlets are the callus phase and petal-specific set of epigenetic regulators. The property of meristem integrity can account for the lowest variation rate in shoot tip-derived plantlets. Moreover, the secondary plantlets underwent a longer total period of in vitro culture, which can explain why the methylation variation rate in the secondary plantlets is higher than in the primary ones. KEY MESSAGE: Methylation variation in regenerated plantlets of C. miniata was found to be related to the types of explants, regeneration pathways and number of regeneration generations. PMID- 22532009 TI - Diagnosis and management of bone stress injuries of the lower limb in athletes. PMID- 22532008 TI - Involvement of heme oxygenase-1 in beta-cyclodextrin-hemin complex-induced cucumber adventitious rooting process. AB - Our previous results showed that beta-cyclodextrin-hemin complex (CDH) exhibited a vital protective role against cadmium-induced oxidative damage and toxicity in alfalfa seedling roots by the regulation of heme oxygenase-1 (HO-1) gene expression. In this report, we further test whether CDH exhibited the hormonal like response. The application of CDH and an inducer of HO-1, hemin, were able to induce the up-regulation of cucumber HO-1 gene (CsHO1) expression and thereafter the promotion of adventitious rooting in cucumber explants. The effect is specific for HO-1 since the potent HO-1 inhibitor zinc protoporphyrin IX (ZnPP) blocked the above responses triggered by CDH, and the inhibitory effects were reversed further when 30% saturation of CO aqueous solution was added together. Further, molecular evidence showed that CDH triggered the increases of the HO-1 mediated target genes responsible for adventitious rooting, including one DnaJ like gene (CsDNAJ-1) and two calcium-dependent protein kinase (CDPK) genes (CsCDPK1 and CsCDPK5), and were inhibited by ZnPP and reversed by CO. The calcium (Ca2+) chelator ethylene glycol-bis (2-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA) and the Ca2+ channel blocker lanthanum chloride (LaCl3) not only compromised the induction of adventitious rooting induced by CDH but also decreased the transcripts of above three target genes. However, the application of ascorbic acid (AsA), a well-known antioxidant in plants, failed to exhibit similar inducible effect on adventitious root formation. In short, above results illustrated that the response of CDH in the induction of cucumber adventitious rooting might be through HO-1-dependent mechanism and calcium signaling. KEY MESSAGE: Physiological, pharmacological and molecular evidence showed that beta cyclodextrin-hemin complex (CDH) was able to induce cucumber adventitious rooting through heme oxygenase-1 (HO-1)-dependent mechanism and calcium signaling. PMID- 22532010 TI - Agencies renew pledge to tackle measles after target to reduce deaths by 90% is missed. PMID- 22532011 TI - Novartis takes legal action over trusts' advice to use bevacizumab for wet AMD. PMID- 22532012 TI - Attacks on doctors rise as rules of conduct in conflict zones are abandoned. PMID- 22532014 TI - Coordinate lentiviral expression of Cre recombinase and RFP/EGFP mediated by FMDV 2A and analysis of Cre activity. AB - The site-specific recombination mediated by Cre recombinase has been utilized extensively in genetic engineering and gene function studies. Efficient delivery of a Cre enzyme with enzymatic activity and the ability to monitor the enzyme expression are required in applications, and lentiviral constructs with a fluorescent protein (FP) to report the Cre expression are suitable for most studies. However, the current lentiviral vector systems have some deficiencies in precise reporting the Cre expression through fluorescence. To solve the problem, we generated a lentiviral system with Cre and RFP or EGFP bridged by an FMDV 2A sequence in an open reading frame expressed by a CMV promoter. We then examined the capabilities of the constructs to package with VSVG into infectious virus and to mediate expression of the Cre enzyme and fluorescent reporter. Furthermore, we monitored the bioactivities of the expressed products. We demonstrated the coordinate expression of the enzyme and the reporter. The expressed Cre was efficient at removing LoxP-flanked fragments in cells and did not show obvious cellular toxicity, and the expressed FPs allowed direct observation under fluorescent microscope. Therefore, the conjugation of CMV-Cre-2A-FP represents a significant improvement to the current lentiviral Cre delivery systems for obtaining a required Cre activity while accurately monitoring its presence. Our study also provides information concerning application of the established vector system. PMID- 22532015 TI - Community pharmacists' attitudes relating to patients' use of health products in Japan. AB - BACKGROUND: There is little information about Japanese pharmacists' perceived facilitators and barriers to communication with patients about orally taken health products, including herbs and dietary supplements. OBJECTIVE: To explore Japanese pharmacists' attitudes relating to patients' use of health products. METHOD: Qualitative study involving focus group interviews with pharmacists was conducted. Data were analyzed using the constant comparative method. SETTING: Focus group interviews with community pharmacists were conducted in Japan. Main outcome measure Pharmacists' views and experiences about patients' health product use and their perceived facilitators and barriers to communication. RESULTS: Sixteen pharmacists participated and were asked to describe their views and experiences about patients' health product use. Some were uncomfortable inquiring about and being asked about patients' health product use, due to lack of scientific evidence for their efficacy and safety, lack of knowledge to advise patients properly, and fear that they could not answer patients' questions. Other pharmacists had similar views or experiences, but those who were proactive in communicating with patients were motivated by certain predisposing factors, such as their professional responsibility for ensuring patients' health and safety. CONCLUSION: This study showed that differences in opinion about their roles might create differences in pharmacists' attitudes toward patients' health product use. This highlights the importance of reconsidering pharmacists' roles in community settings. Further studies and debate are needed in order to clarify the pharmacists' roles and to ensure the design of educational objectives that would enable pharmacists to support their patients in using health products and prescription drugs safely. PMID- 22532016 TI - A multivariate meta-analysis approach for reducing the impact of outcome reporting bias in systematic reviews. AB - Multivariate meta-analysis allows the joint synthesis of multiple correlated outcomes from randomised trials, and is an alternative to a separate univariate meta-analysis of each outcome independently. Usually not all trials report all outcomes; furthermore, outcome reporting bias (ORB) within trials, where an outcome is measured and analysed but not reported on the basis of the results, may cause a biased set of the evidence to be available for some outcomes, potentially affecting the significance and direction of meta-analysis results. The multivariate approach, however, allows one to 'borrow strength' across correlated outcomes, to potentially reduce the impact of ORB. Assuming ORB missing data mechanisms, we aim to investigate the magnitude of bias in the pooled treatment effect estimates for multiple outcomes using univariate meta analysis, and to determine whether the 'borrowing of strength' from multivariate meta-analysis can reduce the impact of ORB. A simulation study was conducted for a bivariate fixed effect meta-analysis of two correlated outcomes. The approach is illustrated by application to a Cochrane systematic review. Results show that the 'borrowing of strength' from a multivariate meta-analysis can reduce the impact of ORB on the pooled treatment effect estimates. We also examine the use of the Pearson correlation as a novel approach for dealing with missing within study correlations, and provide an extension to bivariate random-effects models that reduce ORB in the presence of heterogeneity. PMID- 22532017 TI - Mass spectrometry based tools to investigate protein-ligand interactions for drug discovery. AB - The initial stages of drug discovery are increasingly reliant on development and improvement of analytical methods to investigate protein-protein and protein ligand interactions. For over 20 years, mass spectrometry (MS) has been recognized as providing a fast, sensitive and high-throughput methodology for analysis of weak non-covalent complexes. Careful control of electrospray ionization conditions has enabled investigation of the structure, stability and interactions of proteins and peptides in a solvent free environment. This critical review covers the use of mass spectrometry for kinetic, dynamic and structural studies of proteins and protein complexes. We discuss how conjunction of mass spectrometry with related techniques and methodologies such as ion mobility, hydrogen-deuterium exchange (HDX), protein footprinting or chemical cross-linking can provide us with structural information useful for drug development. Along with other biophysical techniques, such as NMR or X-ray crystallography, mass spectrometry provides a powerful toolbox for investigation of biological problems of medical relevance (204 references). PMID- 22532019 TI - Xanthatin induces G2/M cell cycle arrest and apoptosis in human gastric carcinoma MKN-45 cells. AB - Xanthatin, a natural bioactive compound of sesquiterpene lactones, was isolated and purified from air-dried aerial part of Xanthium sibiricum Patrin ex Widder. In the present study, we demonstrated the significant antiproliferative and proapoptotic effects of xanthatin on human gastric carcinoma MKN-45 cells. MTS assay showed that xanthatin produced obvious cytotoxicity in MKN-45 cells with IC50 values of 18.6, 9.3, and 3.9 uM for 12, 24, and 48 h, respectively. Results of flow cytometry analysis indicated that the antiproliferative activity induced by xanthatin might be executed via G2/M cell cycle arrest and proapoptosis in MKN 45 cells. Western blot analysis elucidated that: a) xanthatin downregulated expression of Chk1 and Chk2 and phosphorylation of CDC2, which are known as key G2/M transition regulators; b) xanthatin increased p53 activation, decreased the bcl-2/bax ratio and the levels of downstream procaspase-9 and procaspase-3, which are key regulators in the intrinsic apoptosis pathway; c) xanthatin blocked phosphorylation of NF-kappaB (p65 subunit) and of IkappaBalpha, which might contribute to its proapoptotic effects on MKN-45 cells. In conclusion, our results suggest that xanthatin may have therapeutic potential against human gastric carcinoma. PMID- 22532020 TI - Simultaneous determination of the absolute configuration of twelve monosaccharide enantiomers from natural products in a single injection by a UPLC-UV/MS method. AB - In natural product chemistry, it is often crucial to determine sugar composition as well as the absolute configuration of each monosaccharide in glycosides. An ultra-performance liquid chromatography method using both photodiode array (PDA) and mass spectrometry detectors (UPLC-UV/MS) was developed for qualitative analysis of the absolute configuration of monosaccharide enantiomers. Within a single injection, 16 monosaccharide derivatives including 6 pairs of aldose enantiomers (D/L-glucose, D/L-galactose, D/L-allose, D/L-arabinose, D/L-xylose, and D/L-fucose) and 4 other monosaccharides (L-rhamnose, 2-deoxy-D-glucose, 6 deoxy-D-glucose, and 2-deoxy-D-glalactose) were identified in less than 25 minutes. It was found that the structures of derivatives of sugar enantiomers correlated with retention time. Among derivatives of sugar enantiomers in the current study, the stereoisomer of R-configuration at C-3' retained longer than the corresponding S-configuration isomer. The UPLC-MS method can increase sensitivity of detection of the saccharides by more than 10 times compared to previously reported methods. The one-pot reaction of monosaccharide with L cysteine methyl ester and phenyl isothiocyanate is easily reproduced, clean, and relatively simple in a screw-capped reaction vial. The developed method was successfully applied for the analysis of different types of glycosides, viz., glycosides of triterpenes, steroids, and flavonoids, that commonly exist in nature. The absolute configurations of composed monosaccharides are clearly characterized from tested samples. PMID- 22532021 TI - Effect of Coffea canephora aqueous extract on microbial counts in ex vivo oral biofilms: a case study. AB - In the present study, the ex vivo antimicrobial effect of brewed coffee was tested on oral biofilms. For this, unsweetened and sweetened (10 % sucrose) brewed light-roasted Coffea canephora at 20 % was used in biofilms formed by non stimulated saliva from three volunteers. After 30 min contact with unsweetened and sweetened brews, the average microorganism count in the biofilms reduced by 15.2 % and 12.4 %, respectively, with no statistical difference among them. We also observed a drop of microorganisms in the biofilms after treatment with sucrose solution at 5 % compared to control (saline) and to sucrose at 1 % and 3 %. In conclusion, Coffea canephora extract reduces the microbial count in oral biofilm, and our data suggest that sucrose concentration in coffee brew can influence its antimicrobial property against the referred biofilm. PMID- 22532022 TI - The effect of silymarin on telomerase activity in the human leukemia cell line K562. AB - Telomerase has been proposed as a novel and potentially selective target in cancer therapy. Silymarin, which is a standardized mixture of flavonolignans from the medical plant Silybum marianum, has potent effects against various types of cancer cells, but its effect on telomerase activity in the human leukemia cell line K562 has not been investigated. The aim of this study was to examine the mechanism of silymarin-induced apoptosis in K562 cells, with particular emphasis on its effect on telomerase activity. The antiproliferation effect of silymarin on K562 cells was evaluated by the MTT assay. To measure apoptosis, Hoechst 33342 staining and flow cytometry were used. The telomerase activity was determined using the telomeric repeat amplification protocol (TRAP)-ELISA assay. The treatment of the K562 cells with silymarin resulted in a significant inhibition of cell growth and telomerase activity. Also, a positive correlation was found between telomerase inhibition and induction of apoptosis in silymarin-treated K562 cells. These results suggest a novel mechanism in the anticancer activity of silymarin in human leukemia K562 cells and may provide a basis for future development of anti-telomerase therapies. PMID- 22532023 TI - Oxysophoridine through intrathecal injection induces antinociception and increases the expression of the GABAAalpha1 receptor in the spinal cord of mice. AB - Our researches in recent years have shown that oxysophoridine (OSR), an alkaloid extracted from Siphocampylus verticillatus, presents antinociception through systemic and intracerebroventricular (icv) administration, and that OSR can also increase the GABA-immunopositive cells number in the central nervous system in rats. The purpose of the present study was to investigate the antinociception produced by OSR administered spinally, the interaction between OSR and GABAA receptor (GABAAR) agonists or antagonists on acute thermal nociceptive models (tail-flick test), and the possible alterations on the mRNA and protein expression of GABAAalpha1 receptors in the spinal cord. ICR mice were tested for their tail withdrawal response to thermal stimulation (tail-flick test). Quantitative real-time PCR and Western blot were used to inspect the influence of OSR administered by intrathecal injection (i. t.) on mRNA and protein expression of the GABAAalpha1 receptor in mice spinal cord by the formalin test. The experiments showed that OSR (0.13-0.25 mg/site, i. t.) significantly increased the tail withdrawal threshold with a peak effect of 68.35 % MPE at 20 min (p < 0.01). When OSR (0.06 mg/site, i. t.) was administered with gamma aminobutyric acid (GABA) (30.0 ug/site, icv) or muscimol (MUS) (0.10 ug/site, icv), the value of tail-flick latency was remarkably larger than with OSR alone (at 10 min, 45.67 % or 31.45 %, p < 0.01). Picrotoxin (PTX) and bicuculine (BIC) can significantly antagonize the antinociception of OSR. OSR (0.25 mg/site, i. t.) can increase the expression of mRNA and protein of the GABAAalpha1 receptor in the spinal cord (L5 L6). The results reveal that i. t. administered OSR presents effective antinociception whose action is mainly located in the spinal cord. The antinociception of OSR results from the activation of the GABAA receptor and from the regulation of the GABAAalpha1 receptor-mediated neurotransmission. PMID- 22532024 TI - Hazard identification of inhaled nanomaterials: making use of short-term inhalation studies. AB - A major health concern for nanomaterials is their potential toxic effect after inhalation of dusts. Correspondingly, the core element of tier 1 in the currently proposed integrated testing strategy (ITS) is a short-term rat inhalation study (STIS) for this route of exposure. STIS comprises a comprehensive scheme of biological effects and marker determination in order to generate appropriate information on early key elements of pathogenesis, such as inflammatory reactions in the lung and indications of effects in other organs. Within the STIS information on the persistence, progression and/or regression of effects is obtained. The STIS also addresses organ burden in the lung and potential translocation to other tissues. Up to now, STIS was performed in research projects and routine testing of nanomaterials. Meanwhile, rat STIS results for more than 20 nanomaterials are available including the representative nanomaterials listed by the Organization for Economic Cooperation and Development (OECD) working party on manufactured nanomaterials (WPMN), which has endorsed a list of representative manufactured nanomaterials (MN) as well as a set of relevant endpoints to be addressed. Here, results of STIS carried out with different nanomaterials are discussed as case studies. The ranking of different nanomaterials potential to induce adverse effects and the ranking of the respective NOAEC are the same among the STIS and the corresponding subchronic and chronic studies. In another case study, a translocation of a coated silica nanomaterial was judged critical for its safety assessment. Thus, STIS enables application of the proposed ITS, as long as reliable and relevant in vitro methods for the tier 1 testing are still missing. Compared to traditional subacute and subchronic inhalation testing (according to OECD test guidelines 412 and 413), STIS uses less animals and resources and offers additional information on organ burden and progression or regression of potential effects. PMID- 22532025 TI - Safety assessment of intraportal liver cell application in New Zealand white rabbits under GLP conditions. AB - Liver cell transplantation (LCT) is considered a new therapeutic strategy for the treatment of acute liver failure and inborn metabolic defects of the liver. Although minimally invasive, known safety risks of the method include portal vein thrombosis and pulmonary embolism. Since no systematic data on these potential side effects exist, we investigated the toxicological profile of repeated intraportal infusion of allogeneic liver cells in 30 rabbits under GLP conditions. Rabbit liver cells were administered once daily for 6 consecutive days at 3 different dose levels, followed by a 2-week recovery period. No test item-related mortality was observed. During cell infusion, clinical findings such as signs of apathy and hyperventilation, moderate elevations of liver enzymes ALT and AST and a slight decrease in AP were observed, all fully reversible. Cell therapy-related macroscopic and histological findings, especially in liver and lungs, were observed in animals of all dose groups. In conclusion, the liver and lungs were identified as potential toxicological target organs of intraportal allogeneic liver cell infusion. A NOAEL (no observed adverse effect level) was not defined because of findings observed also in the low-dose group. No unexpected reactions became apparent in this GLP study. Overall, LCT at total doses up to 12 % (2 % daily over 6 days) of the total liver cell count were tolerated in rabbits. Observed adverse effects are not considered critical for treatment in the intended patient populations provided that a thorough monitoring of safety relevant parameters is in place during the application procedure. PMID- 22532026 TI - Rs11892031[A] on chromosome 2q37 in an intronic region of the UGT1A locus is associated with urinary bladder cancer risk. AB - Recently, rs11892031[A] has been identified in a genome-wide association study (GWAS) to confer increased risk of urinary bladder cancer (UBC). To confirm this association and additionally study a possible relevance of exposure to urinary bladder carcinogens, we investigated the IfADo UBC study group, consisting of eight case-control series from different regions including 1,805 cases and 2,141 controls. This analysis was supplemented by a meta-analysis of all published data, including 13,395 cases and 54,876 controls. Rs11892031 A/A was significantly associated with UBC risk in the IfADo case-control series adjusted to cigarette smoking, gender, age and ethnicity (OR = 1.18; 95% CI = 1.02-1.37; P = 0.026). In the meta-analysis, a convincing association with UBC risk was obtained (OR = 1.19; 95% Cl = 1.12-1.26; P < 0.0001). Interestingly, the highest odds ratios were obtained for individual case-control series with a high degree of occupational exposure to polycyclic aromatic hydrocarbons and aromatic amines: cases with suspected occupational UBC (OR = 1.41) and cases from the highly industrialized Ruhr area (OR = 1.98) compared with Ruhr area controls (all combined OR = 1.46). Odds ratios were lower for study groups with no or a lower degree of occupational exposure to bladder carcinogens, such as the Hungary (OR = 1.02) or the ongoing West German case-control series (OR = 1.06). However, the possible association of rs11892031[A] with exposure to bladder carcinogens still should be interpreted with caution, because in contrast to the differences between the individual study groups, interview-based data on occupational exposure were not significantly associated with rs11892031. In conclusion, the association of rs11892031[A] with UBC risk could be confirmed in independent study groups. PMID- 22532027 TI - NADPH oxidase-produced superoxide mediates EGFR transactivation by c-Src in arsenic trioxide-stimulated human keratinocytes. AB - Arsenic is a well-known poison and carcinogen in humans. However, it also has been used to effectively treat some human cancers and non-carcinogenic ailments. Previously, we demonstrated in keratinocytes that arsenic trioxide (ATO)-induced p21(WAF1/CIP1) (p21) expression leading to cellular cytotoxicity through the c Src/EGFR/ERK pathway and generation of reactive oxygen species (ROS). In this study, we found that EGFR-Y845 and EGFR-Y1173 could be phosphorylated by ATO. Using confocal microscopy and flow cytometry, we found that pretreatment with apocynin, DPI, and tiron could remove ATO-induced ROS production. Furthermore, to increase NADPH oxidase activity, ATO could induce cytosolic p67(phox) expression and translocation to membrane. In addition, knockdown of p67(phox) could abolish ATO-induced ROS production. Therefore, we suggest that NADPH oxidase-produced superoxide was a major source of ATO-induced ROS production. Conversely, ATO induced NADPH oxidase activation and superoxide generation could be inhibited by the c-Src inhibitor PP1, but not by the EGFR inhibitor PD153035. In addition, overexpression of c-Src as well as treatment with ATO could stimulate EGFR Y845/ERK phosphorylation, p21 expression, and cellular arrest/apoptosis, which could be attenuated by pretreatment with apocynin or knockdown of p67(phox). Collectively, we suggest that NADPH oxidase was involved in the ATO-induced arrest/apoptosis of keratinocytes, which was regulated by c-Src activation. PMID- 22532028 TI - Hepatitis B in the United States: a major health disparity affecting many foreign born populations. PMID- 22532029 TI - Endoscopy and role of endoscopic resection in gastric cancer. AB - Patient selection for endoscopic resection is based on meticulous endoscopic examination and histological assessment so as to avoid performing this procedure on patients with a high risk of lymph node involvement or metastatic disease. Currently, endoscopic mucosal resection (EMR) is used for tumors <2 cm, and endoscopic submucosal dissection (ESD) should be considered for tumors >2 cm. The advantage of ESD is that it achieves en-bloc resection of larger tumors, potentially reducing the risk of disease recurrence. PMID- 22532030 TI - N-acetylcysteine reduces inflammation in the small intestine by regulating redox, EGF and TLR4 signaling. AB - This study determined whether N-acetylcysteine (NAC) could affect intestinal redox status, proinflammatory cytokines, epidermal growth factor (EGF), EGF receptor (EGFR), Toll-like receptor-4 (TLR4), and aquaporin-8 in a lipopolysaccharide (LPS)-challenged piglet model. Eighteen piglets (35-day-old) were randomly allocated into one of the three treatments (control, LPS and NAC). The control and LPS groups were fed a basal diet, and the NAC group received the basal diet +500 mg/kg NAC. On days 10, 13, and 20 of the trial, the LPS- and NAC treated piglets received intraperitoneal administration of LPS (100 MUg/kg BW), whereas the control group received the same volume of saline. On days 10 and 20, venous blood samples were obtained at 3 h post LPS or saline injection. On day 21 of the trial, piglets were killed to obtain the intestinal mucosa for analysis. Compared with the control group, LPS challenge reduced (P < 0.05) the activities of superoxide dismutase, catalase, and glutathione peroxidase in jejunal mucosae, while increasing (P < 0.05) the concentrations of malondialdehyde, H2O2, O2 (.-) and the ratio of oxidized to reduced glutathione in jejunal mucosae, and concentrations of TNF-alpha, cortisol, interleukin-6, and prostaglandin E2 in both plasma and intestinal mucosae. These adverse effects of LPS were attenuated (P < 0.05) by NAC supplementation. Moreover, NAC prevented LPS-induced increases in abundances of intestinal HSP70 and NF-kappaB p65 proteins and TLR4 mRNA. NAC supplementation enhanced plasma EGF concentration and intestinal EGFR mRNA levels. Collectively, these results indicate that dietary NAC supplementation alleviates LPS-induced intestinal inflammation via regulating redox, EGF, and TLR4 signaling. PMID- 22532031 TI - Apelin-APJ induces ICAM-1, VCAM-1 and MCP-1 expression via NF-kappaB/JNK signal pathway in human umbilical vein endothelial cells. AB - Apelin receptor (APJ) deficiency has been reported to be preventive against atherosclerosis. However, the mechanism of this effect remains unknown. In this study, quantitative real-time RT-PCR, Western blotting and ELISA analyses revealed a significant increase in the expression of intercellular adhesion molecule-1(ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) in human umbilical vein endothelial cells (HUVECs) treated with apelin. Inhibitors of cellular signal transduction molecules were used to demonstrate involvement of nuclear factor kappa-B (NF kappaB) and c-Jun N-terminal kinase (JNK) pathways in apelin-APJ-induced activation of adhesion molecules and chemokines. Inhibition of APJ expression by RNA interference abrogated apelin-induced expression of adhesion molecules and chemokines and apelin-stimulated cellular signal transduction in HUVECs. The apelin-APJ system in endothelial cells is involved in the expression of adhesion molecules and chemokines, which are important for the initiation of endothelial inflammation-related atherosclerosis. Therefore, apelin-APJ and the cell signaling pathways activated by this system in endothelial cells may represent targets for therapy of atherosclerosis. PMID- 22532032 TI - Synthetic curcumin analog EF31 inhibits the growth of head and neck squamous cell carcinoma xenografts. AB - Objectives are to examine the efficacy, pharmacokinetics, and toxicology of a synthetic curcumin analog EF31 in head and neck squamous cell carcinoma. The synthesis of EF31 was described for the first time. Solubility of EF24 and EF31 was compared using nephelometric analysis. Human head and neck squamous cell carcinoma Tu212 xenograft tumors were established in athymic nude mice and treated with EF31 i.p. once daily five days a week for about 5-6 weeks. The long term effect of EF31 on the NF-kappaB signaling system in the tumors was examined by Western blot analysis. EF31 at 25 mg kg(-1), i.p. inhibited tumor growth almost completely. Solubilities of EF24 and EF31 are <10 and 13 MUg mL(-1) or <32 and 47 MUM, respectively. The serum chemistry profiles of treated mice were within the limits of normal, they revealed a linear increase of C(max). EF31 decreased the level of phosphorylation of NF-kappaB p65. In conclusion, the novel synthetic curcumin analog EF31 is efficacious in inhibiting the growth of Tu212 xenograft tumors and may be useful for treating head and neck squamous cell carcinoma. The long term EF31 treatment inhibited NF-kappaB p65 phosphorylation in xenografts, implicating downregulation of cancer promoting transcription factors such as angiogenesis and metastasis. PMID- 22532034 TI - Green tea and lung cancer: a systematic review. AB - BACKGROUND: Green tea is a beverage widely used by lung cancer patients and the public for its purported anticancer properties. The authors conducted a systematic review of green tea for the treatment and prevention of lung cancer. METHODOLOGY: Six electronic databases were searched from inception until November 2011 for human interventional and preclinical evidence pertaining to the safety and efficacy of green tea for lung cancer. RESULTS: A total of 84 articles met inclusion criteria: two Phase I trials, three reports of one surrogate study, and 79 preclinical studies. There is a lack of controlled trials investigating green tea for lung cancer. Two Phase I studies showed no objective tumor responses at the maximum tolerated dose, ranging from 3 to 4.2 g/m(2) green tea extract (GTE) per day. Four cups of green tea daily decreased DNA damage (8OH-dG) in smokers. Human studies indicate that 800mg of green tea catechins daily does not alter activity of the CYP2D6, CYP1A2, CYP3A4 and CYP2C9 enzymes, however in vitro evidence suggests that green tea may bind to and reduce the effectiveness of bortezomib. Green tea applied topically may improve the healing time of radiation burns. CONCLUSIONS: Although some evidence suggests that chemopreventative benefits can be accrued from green tea, there is currently insufficient evidence to support green tea as a treatment or preventative agent for lung cancer. Green tea should not be used by patients on bortezomib therapy. Further research is warranted to explore this natural agent for lung cancer treatment and prevention. PMID- 22532035 TI - Synergistic and additive effects of modified citrus pectin with two polybotanical compounds, in the suppression of invasive behavior of human breast and prostate cancer cells. AB - AIM: The objective of this study was to evaluate the combined effect of a known galectin-3 inhibitor, PectaSol-C modified citrus pectin (MCP), and 2 novel integrative polybotanical compounds for breast and prostate health, BreastDefend (BD) and ProstaCaid (PC), on invasive behavior in human breast and prostate cancer cells in vitro, respectively. METHODS: The effect of MCP and BD and of MCP and PC on invasiveness was assessed by cell adhesion, cell migration, and cell invasion assays. Secretion of urokinase plasminogen activator (uPA) was determined by Western blot analysis. RESULTS: Although low concentrations of MCP (0.25-1.0 mg/mL) do not suppress cell adhesion of breast or prostate cancer cells, the combination of MCP with BD or PC synergistically inhibits adhesion of these cells. Dose-dependent inhibition of breast and prostate cancer cell migration by MCP (0.25-1.0 mg/mL) is synergistically enhanced by BD (20 ug/mL) and PC (10 ug/mL), respectively. BD or PC did not further inhibit the invasion of breast and prostate cancer cells by MCP; however, the combination of MCP with BD or PC suppressed secretion of uPA from breast and prostate cancer cells, respectively. CONCLUSION: The combination of MCP with BD and of MCP with PC synergistically inhibits the metastatic phenotypes of human breast and prostate cancer cells, respectively. Further studies confirming these observations in animal models of breast and prostate cancer metastasis are warranted. PMID- 22532036 TI - Flow synthesis using gaseous ammonia in a Teflon AF-2400 tube-in-tube reactor: Paal-Knorr pyrrole formation and gas concentration measurement by inline flow titration. AB - Using a simple and accessible Teflon AF-2400 based tube-in-tube reactor, a series of pyrroles were synthesised in flow using the Paal-Knorr reaction of 1,4 diketones with gaseous ammonia. An inline flow titration technique allowed measurement of the ammonia concentration and its relationship to residence time and temperature. PMID- 22532037 TI - Anticoagulation techniques in apheresis: from heparin to citrate and beyond. AB - Anticoagulation is essential for maintaining the fluidity of extravascular blood on the apheresis circuit. Although both citrate and heparin are used as an anticoagulant during apheresis, citrate is preferred for the majority of exchange procedures because of its safety and effectiveness. Complications of citrate are primarily due to physiologic effects of hypocalcemia. Symptoms of hypocalcemia and other citrate-induced metabolic abnormalities affect neuromuscular and cardiac function and range in severity from mild dysesthesias (most common) to tetany, seizures, and cardiac arrhythmias. Oral or intravenous calcium supplementation is advised for decreased ionized calcium levels and/or symptomatic management of hypocalcemia. Heparin-based anticoagulation is limited to certain apheresis procedures (membrane-based plasma exchange, LDL apheresis, or photopheresis) or is used in combination with citrate to reduce citrate load. While effective, heparin anticoagulation is associated with an increased frequency of bleeding complications and heparin-induced thrombocytopenia. J. Clin. Apheresis 2012. (c) 2012 Wiley Periodicals, Inc. PMID- 22532038 TI - [Navigated focal retinal laser therapy using the NAVILAS(r) system for diabetic macula edema]. AB - PURPOSE: The aim of this study was to investigate the accuracy of a navigated laser photocoagulator in clinically significant macular edema (CSME). METHODS: Focal laser treatment for diabetic macular edema (DME) in 36 patients was digitally planned on fundus images and performed with navigation using NAVILAS(r) (OD-OS, Teltow, Germany). Treatment intensity was controlled visually during treatment so the laser spots applied were barely directly visible after treatment. Using color images (CI) and optical coherence tomography (OCT) 4,137 laser spots (mean 115 per eye) were analyzed at 1 month follow-up and accuracy of spot placement was determined. RESULTS: In total 79% of laser spots were visible on CI of which 96% were within 100 um of the planned target position. On an intention-to-treat (ITT) basis, 76% of the laser spots were placed and visible within the 100 um target and OCT confirmed that laser effects were limited to the outer retina. The mean time for focal treatment was < 7 min (+/-3 min). CONCLUSIONS: After NAVILAS treatment for DME a high percentage of laser effects could be visualized on post-treatment color images and the location showed high concordance with the preplanning target. PMID- 22532039 TI - [Immunological graft rejection after autologous contralateral keratoplasty]. AB - Autologous keratoplasty from an amblyopic eye to the fellow oculus ultimus is a rarely used procedure. This is due to the relatively uncommon constellation of pathology. The following article reports the case of a graft rejection after autologous keratoplasty, while the homologous graft on the amblyopic fellow eye remained clear. PMID- 22532040 TI - [Traumatic proptosis]. AB - The emergency consultation of a female patient revealed a left-sided prolapse of the eyeball with visual loss. The patient had fallen against an object hitting the left eye 40 min prior to the consultation. Motility of the eye was severely restricted and retinoscopy was impossible due to a corneal edema. The pupil was moderately dilated and non-reactive. The ocular pressure was 50 mmHg. Spontaneous repositioning was unsuccessful and an immediate lateral canthotomy was performed. The follow-up control showed that the patient had recovered good visual acuity with a reduction of intraocular pressure and pain. The latest findings were uneventful. PMID- 22532041 TI - [Ping-pong transmission of herpes simplex virus 1 following corneal transplantation]. AB - BACKGROUND: Primary corneal graft failure (PCGF) after penetrating keratoplasty (PKP) despite good endothelial cell count of the transplant in organ culture rarely occurs in young patients. A herpes simplex virus type I (HSV-1) infection (transmission through the donor or reactivation by the patient) can lead to PCGF. METHODS: We report on a 43-year-old man with pellucid marginal corneal degeneration and neurodermitis, who was underwent penetrating keratoplasty (PKP) on the left eye after acute corneal hydrops in both eyes. A repeat keratoplasty (re-PKP) had to be performed 15 days after the first PKP due to a primary graft failure. A re-re-PKP with simultaneous amniotic membrane transplantation (as a patch) and partial lateral tarsorrhaphy became necessary 4 months after the re PKP due to melting on the edge of the graft with persistent epithelial defects. RESULTS: After intensive cooperation between ophthalmologists and pathologists the histopathological findings showed keratocytes which reacted immunohistochemically positive for HSV-1 antigens in the deep corneal stroma of both corneal grafts. The excised own cornea of the patient was histopathologically negative but the DNA-PCR for HSV-1 was weakly positive. After adequate topical and systemic antiviral therapy the third graft has remained clear for 12 months. CONCLUSION: In cases of PCGF after normal risk corneal transplantation the possibility of HSV infection should always be considered. After confirmation of the diagnosis with the help of the immunohistochemical tests and/or PCR, an adequate treatment with antiviral medication (acyclovir tablets 2 * 400 mg for more than 1 year) should be administered to the patient after repeat PKP. PMID- 22532042 TI - [Ptosis surgery. Current aspects]. AB - Ptosis can be congenital but is more commonly an acquired condition occurring in particular as involutional forms. In addition to the aesthetic aspects ptosis mostly also leads to functional problems. Congenital ptosis in particular carries a high risk of amblyopia in childhood, therefore competent and close-knit pediatric ophthalmological treatment is important. Correction of ptosis is surgical and direct or indirect procedures are available depending on the conditions. Transcutaneous levator surgery has proven to be the universally applicable method for ptosis of all degrees of severity and can be combined with other corrective measures, such as temporal canthopexy or blepharoplasty, particularly for eyelids of elderly patients. In cases of severely impaired levator function and poor Bell phenomenon the indirect frontalis suspension method can be used. Congenital ptosis in childhood should be surgically treated at an early stage because of a substantial risk of amblyopia even if the central visual axis is still clear. The results of ptosis surgery are generally good and serious complications are rare. PMID- 22532043 TI - [Blepharoplasty of the upper and lower eyelid. Strategic considerations for incisions]. AB - Blepharoplasty of the upper and the lower eyelid is a very common aesthetic procedure of the face and is carried out by different types of surgeons. Before starting the procedure it is very important to analyze all pathogenetic factors. The position of the skin incision is dependent on the extent and position of the element to be corrected and age, sex and racial characteristics should be taken into consideration. PMID- 22532044 TI - [Lower lid entropion and ectropion. Indication, technique and key points of "classical" surgical methods]. AB - Lower lid malposition is common, increases with age and leads to impaired optical function of the ocular surface through chronic irritation of the conjunctiva and cornea. Numerous techniques have been described to reposition the lid margin to the globe and secure this position while maintaining intact motility. Some of these techniques have passed the test of time and have reached the status of "classic" standard procedures that need to be in the armamentarium of every oculoplastic surgeon. The aim of this article is to consider the merits of a selection of standard methods for the correction of lower lid entropion and ectropion by describing their indication, technique and key points. PMID- 22532045 TI - [Poorly healing periorbital wounds. Therapeutic use of maggots]. AB - The treatment of poorly healing wounds, although not a typical problem in the periorbital area, has been enriched by the option of biosurgery, the therapeutic application of larvae of the blow fly (Lucilia sericata). PMID- 22532047 TI - [Comparison of endobronchial ultrasound (EBUS) and mediastinoscopy (MS) for staging lung cancer]. AB - Diagnostic findings of mediastinal metastasis are an important factor for the prognosis of and therapy for lung cancer. In this retrospective study we examined the role of endobronchial ultrasound with transbronchial needle aspiration (EBUS) and mediastinoscopy (MS) in patients with confirmed lung cancer. Between 01/2009 and 07/2011 we performed 111 EBUS procedures [partly in combination with transoesophageal endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA)] and 88 mediastinoscopies. The diagnostic accuracy of EBUS (94%) was superior to that of MS (86%) (p < 0.05). The negative predictive value of EBUS and MS was 83% for both, the sensitivity was 94% vs. 58%, the prevalence of N2 /N3 was 84% vs. 32% and the rate of complications was 0% vs. 3%. Due to the at least similar accuracy the EBUS should be the first diagnostic procedure for histological staging of the mediastinum in patients with lung cancer. PMID- 22532046 TI - An open-label extension study evaluating the safety and efficacy of romiplostim for up to 3.5 years in thrombocytopenic Japanese patients with immune thrombocytopenic purpura (ITP). AB - Long-term use of the thrombopoietin mimetic romiplostim was examined in Japanese patients with chronic immune thrombocytopenic purpura (ITP) in this open-label extension. The starting dose of romiplostim was the previous trial dose or 3 MUg/kg/week, which was titrated up to 10 MUg/kg/week to maintain platelet counts between 50 and 200 * 10(9)/L. As of April 2010, 44 patients had enrolled; 71 % women, median age 55.5 years, with five patients discontinuing romiplostim due to patient request (2), administrative decision (2), or not achieving study-defined platelet response (1). Median treatment duration was 100 weeks; median average weekly dose was 3.8 MUg/kg. Twenty-eight patients (64 %) self-injected romiplostim. The most frequent adverse events were nasopharyngitis and headache. Nine patients (20 %) had a total of 14 serious adverse events (0.31/100 patient weeks); of these, only oral hemorrhage was considered treatment related. Fifty hemorrhagic adverse events were reported in 20 patients (46 %) (1.12/100 patient weeks). Ninety-six percent of patients had a platelet response (doubling of baseline platelet count and platelet count >= 50 * 10(9)/L). Of the 25 patients receiving concurrent ITP therapy at baseline, all reduced or discontinued the therapy. Eight patients (18 %) received rescue medications. Administration of up to 3.5 years of romiplostim increased platelet counts and was well tolerated in Japanese patients with chronic ITP. PMID- 22532048 TI - [Personalized, individualized, stratified - Thoracic oncology quo vadis?]. PMID- 22532051 TI - Gone and forgotten: where has the "literature" gone? PMID- 22532049 TI - [Catch me if you can--a case of endobronchial lipoma]. AB - Incidentally, a lesion in the right upper pulmonary lobe was found in a 74-year old male patient. The flexible bronchoscopy revealed an endobrochial lipoma in the right lower lobe as the only pathological finding. Due to multiple co morbidities, no intervention was performed initially. Since the endobronchial lipoma increased in size during follow-up, it was removed by cryoextraction. This case report on an endobronchial lipoma includes a short summary of this rare benign lung tumor. PMID- 22532052 TI - Simulation of massive public health data by power polynomials. AB - Situations in which multiple outcomes and predictors of different distributional types are collected are becoming increasingly common in public health practice, and joint modeling of mixed types has been gaining popularity in recent years. Evaluation of various statistical techniques that have been developed for mixed data in simulated environments necessarily requires joint generation of multiple variables. Most massive public health data sets include different types of variables. For instance, in clustered or longitudinal designs, often multiple variables are measured or observed for each individual or at each occasion. This work is motivated by a need to jointly generate binary and possibly non-normal continuous variables. We illustrate the use of power polynomials to simulate multivariate mixed data on the basis of a real adolescent smoking study. We believe that our proposed technique for simulating such intensive data has the potential to be a handy methodological addition to public health researchers' toolkit. PMID- 22532053 TI - Trajectories of long-term outcomes for postnatally depressed mothers treated with group interpersonal psychotherapy. AB - There is evidence that psychological treatments for postnatal depression are effective in the short-term; however, whether the effects are enduring over time remains an important empirical question. The aim of this study was to investigate the depressive symptoms and interpersonal functioning of participants in a randomised controlled trial (RCT) of group interpersonal psychotherapy (IPT-G) at 2 years posttreatment. The study also examined long-term trajectories, such as whether participants maintained their recovery status, achieved later recovery, recurrence or persistent symptoms. Approximately 2 years posttreatment, all women in the original RCT (N = 50) were invited to participate in a mailed follow-up. A repeated measures analysis of variance assessed differences between the treatment and control conditions on depression and interpersonal scores across five measurement occasions: baseline, mid-treatment, end of treatment and 3-month and 2-year follow-up. Chi-square tests were used to analyse the percentage of participants in the four recovery categories. Mothers who received IPT-G improved more rapidly in the short-term and were less likely to develop persistent depressive symptoms in the long-term. Fifty seven percent of IPT-G mothers maintained their recovery over the follow-up period. Overall, IPT-G participants were significantly less likely to require follow-up treatment. Limitations include the use of self-report questionnaires to classify recovery. The positive finding that fewer women in the group condition experienced a persistent course of depression highlights its possible enduring effects after treatment discontinuation. Further research is needed to improve our long-term management of postnatal depression for individuals who are vulnerable to a recurrent or chronic trajectory. PMID- 22532054 TI - The effect of vitamin D therapy on hematological indices in children with vitamin D deficiency. AB - We investigated the effect of vitamin D on hematological indices, blood pressure (BP) and heart rate (HR) in children with vitamin D deficiency before and after treatment. Vitamin D deficiency does not have a significant effect on red blood cell count and indices, total and differential white blood cell count, or on BP and HR. A mega-dose vitamin D therapy did not have a significant effect on all these parameters in children. PMID- 22532055 TI - The prevalence of cirrhosis and hepatocellular carcinoma in patients with human immunodeficiency virus infection. AB - Cirrhosis is a leading cause of death among patients infected with human immunodeficiency virus (HIV). We sought to determine risk factors for and time trends in the prevalence of cirrhosis, decompensated cirrhosis, and hepatocellular carcinoma (HCC) among patients diagnosed with HIV who received care in the Veterans Affairs (VA) health care system nationally between 1996 and 2009 (n = 24,040 in 2009). Among patients coinfected with HIV and hepatitis C virus (HCV), there was a dramatic increase in the prevalence of cirrhosis (3.5% 13.2%), decompensated cirrhosis (1.9%-5.8%), and HCC (0.07%-1.6%). Little increase was observed among patients without HCV coinfection in the prevalence of cirrhosis (1.7%-2.2%), decompensated cirrhosis (1.1%-1.2%), and HCC (0.03% 0.13%). In 2009, HCV infection was present in the majority of patients with HIV who had cirrhosis (66%), decompensated cirrhosis (62%), and HCC (80%). Independent risk factors for cirrhosis included HCV infection (adjusted odds ratio [AOR], 5.82; 95% confidence interval [CI], 5.0-6.7), hepatitis B virus (HBV) infection (AOR, 2.40; 95% CI, 2.0-2.9), age (AOR, 1.03; 95% CI, 1.02-1.04), Hispanic ethnicity (AOR, 1.76; 95% CI, 1.4-2.2), diabetes (AOR, 1.79; 95% CI, 1.6 2.1), and alcohol abuse (AOR, 1.78; 95% CI, 1.5-2.1), whereas black race (AOR, 0.56; 95% CI, 0.48-0.64) and successful eradication of HCV (AOR, 0.61; 95% CI, 0.4-0.9) were protective. Independent risk factors for HCC included HCV infection (AOR, 10.0; 95% CI, 6.1-16.4), HBV infection (AOR, 2.82; 95% CI, 1.7-4.7), age (AOR, 1.05; 95% CI, 1.03-1.08), and low CD4+ cell count (AOR, 2.36; 95% CI, 1.3 4.2). Among 5999 HIV/HCV-coinfected patients, 994 (18%) had ever received HCV antiviral treatment, of whom 165 (17%) achieved sustained virologic response. CONCLUSION: The prevalence of cirrhosis and HCC has increased dramatically among HIV-infected patients driven primarily by the HCV epidemic. Potentially modifiable risk factors include HCV infection, HBV infection, diabetes, alcohol abuse, and low CD4+ cell count. PMID- 22532056 TI - Guest editorial: fetal growth restriction and its consequences. PMID- 22532057 TI - Robotic adrenalectomy. AB - Over the last decade, there has been a significant progress in general surgical applications of robotic surgery. Multiple groups have reported safe and effective techniques for robotic adrenalectomy. Our aim in this review is to describe these techniques and summarize the literature on outcomes. PMID- 22532058 TI - Characterisation of heterogeneous molybdate and chromate phase assemblages in model nuclear waste glasses by multinuclear magnetic resonance spectroscopy. AB - A series of sodium borosilicate glasses containing cesium, molybdenum, and chromium was prepared to investigate the partitioning of chromium amongst the glass and phase-separated crystalline molybdates. The precipitates were examined by (133)Cs, (23)Na, and (95)Mo MAS NMR, revealing a phase assemblage consisting of Na(2)MoO(4), Na(2)MoO(4).2H(2)O, Cs(2)MoO(4), Cs(2)CrO(4), CsNaMoO(4).2H(2)O, and Cs(3)Na(MoO(4))(2). (133)Cs MAS NMR indicates random substitution of Cr into the Mo sites of Cs(3)Na(MoO(4))(2) and provides a quantitative assessment of Cr incorporation. The sample compositions were verified by various analytical techniques and highlight the centrality of NMR in the identification and quantification of heterogeneous crystalline composites, including sensitivity to cationic substitution. The observation and facile interconversion of hydrated phases invites careful consideration of these materials for nuclear waste disposal. PMID- 22532059 TI - Hydrogen bonding and reactivity of water to azines in their S1 (n,pi*) electronic excited states in the gas phase and in solution. AB - A unified picture is presented of water interacting with pyridine, pyridazine, pyrimidine, and pyrazine on the S(1) manifold in both gas-phase dimers and in aqueous solution. As (n,pi*) excitation to the S(1) state removes electrons from the ground-state hydrogen bond, this analysis provides fundamental understanding of excited-state hydrogen bonding. Traditional interpretations view the excitation as simply breaking hydrogen bonds to form dissociated molecular products, but reactive processes such as photohydrolysis and excited-state proton coupled electron transfer (PCET) are also possible. Here we review studies performed using equations-of-motion coupled-cluster theory (EOM-CCSD), multireference perturbation theory (CASPT2), time-dependent density-functional theory (TD-DFT), and excited-state Monte Carlo liquid simulations, adding new results from symmetry-adapted-cluster configuration interaction (SAC-CI) and TD DFT calculations. Invariably, gas-phase molecular dimers are identified as stable local minima on the S(1) surface with energies less than those for dissociated molecular products. Lower-energy biradical PCET minima are also identified that could lead to ground-state recombination and hence molecular dissociation, dissociation into radicals or ions, or hydration reactions leading to ring cleavage. For pyridine.water, the calculated barriers to PCET are low, suggesting that this mechanism is responsible for fluorescence quenching of pyridine.water at low energies rather than accepted higher-energy Dewar-benzene based "channel three" process. Owing to (n,pi*) excitation localization, much higher reaction barriers are predicted for the diazines, facilitating fluorescence in aqueous solution and predicting that the as yet unobserved fluorescence from pyridazine.water and pyrimidine.water should be observable. Liquid simulations based on the assumption that the solvent equilibrates on the fluorescence timescale quantitatively reproduce the observed spectral properties, with the degree of (n,pi*) delocalization providing a critical controlling factor. PMID- 22532060 TI - Ultra-trace determination of mercury in river waters after online UV digestion of humic matter. AB - A fully automated online ultraviolet (UV) digestion method for subsequent mercury (Hg) quantification in humic matter containing river waters is reported. The new developed flow injection analysis system (FIAS) consists basically of a UV lamp, a meander-form quartz glass reaction tube for online irradiation of the sample, and a nano-gold collector for preconcentration of dissolved mercury species. The FIAS is coupled to an atomic fluorescence spectrometer (AFS) for Hg detection. The optimized procedure allows accurate mercury quantification in water samples with up to 15 mg CL(-1) as dissolved organic carbon by addition of only 1% (v/v) of hydrogen peroxide solution and online UV irradiation for 6 min. Addition of strong oxidants and any other reagents is avoided due to the use of the catalytic active nano-gold collector. Here, preconcentration of Hg species, release of mercury as Hg(0), and AFS measurement are performed without addition of any reagents. Hence, the proposed approach offers significant advantages over existing methods. Analytical figures of merit showed the good performance of the developed method: The limit of quantification was found to be as low as 0.14 ng Hg L(-1). The linear working range is from 0.1 to 200 ng Hg L(-1) and relative standard deviation is <6.0% (n = 9). The system was successfully validated by comparison of the mercury concentrations found in model and real water samples obtained by the reference method EPA 1631 and the proposed method. Furthermore, application to six real river waters confirmed the feasibility of the proposed approach. PMID- 22532061 TI - Objective chemical fingerprinting of oil spills by partial least-squares discriminant analysis. AB - An objective method based on partial least-squares discriminant analysis (PLS-DA) was used to assign an oil lump collected on the coastline to a suspected source. The approach is an add-on to current US and European oil fingerprinting standard procedures that are based on lengthy and rather subjective visual comparison of chromatograms. The procedure required an initial variable selection step using the selectivity ratio index (SRI) followed by a PLS-DA model. From the model, a "matching decision diagram" was established that yielded the four possible decisions that may arise from standard procedures (i.e., match, non-match, probable match, and inconclusive). The decision diagram included two limits, one derived from the Q-residuals of the samples of the target class and the other derived from the predicted y of the PLS model. The method was used classify 45 oil lumps collected on the Galician coast after the Prestige wreckage. The results compared satisfactorily with those from the standard methods. PMID- 22532062 TI - Cathodic electrochemiluminescence and reversible electrochemistry of [Ru(bpy)3](2+/1+) in aqueous solutions on tricresyl phosphate-based carbon paste electrode with extremely high hydrogen evolution potential. AB - Many cathodic electrochemiluminescence (ECL) systems require very negative potentials; it is difficult to achieve stable cathodic ECL in aqueous solutions because of hydrogen evolution and instability of intermediates. In this study, tricresyl phosphate-based carbon paste electrode (CPE) was used to achieve cathodic ECL. It exhibits no obvious hydrogen evolution even at a potential up to -1.6 V and dramatically stabilizes electrogenerated [Ru(bpy)3](+). Therefore, a reversible wave of [Ru(bpy)3](2+/1+) in aqueous solutions at carbon electrode has been observed for the first time, and cathodic ECL of [Ru(bpy)3](2+)/S2O8(2-) has been achieved. Under the optimum conditions, the plots of the ECL versus the concentration of S2O8(2-) are linear in the range of 10(-6) to 10(-2) M with the detection limit of 3.98 * 10(-7) M. Common anions have no effect on the ECL intensity of the [Ru(bpy)3](2+)/S2O8(2-) system. Since CPEs have been widely used, CPEs with high hydrogen evolution potential are versatile platforms for electrochemical study and cathodic ECL study. PMID- 22532063 TI - Ageing population is not a drain on economy or NHS, says report. PMID- 22532064 TI - Study finds possible role for aspirin as treatment for colon cancer. PMID- 22532065 TI - Regulation of morphogenesis and neural differentiation of human mesenchymal stem cells using carbon nanotube sheets. AB - In order to successfully utilize stem cells for therapeutic applications in regenerative medicine, efficient differentiation into a specific cell lineage and guidance of axons in a desired direction is crucial. Here, we used aligned multi walled carbon nanotube (MWCNT) sheets to differentiate human mesenchymal stem cells (hMSCs) into neural cells. Human MSCs present a preferential adhesion to aligned CNT sheets with longitudinal stretch parallel to the CNT orientation direction. Cell elongation was 2-fold higher than the control and most of the cells were aligned on CNT sheets within 5 degrees from the CNT orientation direction. Furthermore, a significant, synergistic enhancement of neural differentiation was observed in hMSCs cultured on the CNT sheets. Axon outgrowth was also controlled using nanoscale patterning of CNTs. This CNT sheet provides a new cellular scaffold platform that can regulate morphogenesis and differentiation of stem cells, which could open up a new approach for tissue and stem cell regeneration. PMID- 22532066 TI - A highly efficient solvent system containing functionalized diglycolamides and an ionic liquid for americium recovery from radioactive wastes. AB - Three room temperature ionic liquids (RTILs), viz. C(4)mim(+).PF(6)(-), C(6)mim(+).PF(6)(-) and C(8)mim(+).PF(6)(-), were evaluated as diluents for the extraction of Am(III) by N,N,N',N'-tetraoctyl diglycolamide (TODGA). At 3 M HNO(3), the D(Am)-values by 0.01 M TODGA were found to be 102, 34 and 74 for C(4)mim(+).PF(6)(-), C(6)mim(+).PF(6)(-) and C(8)mim(+).PF(6)(-), respectively. The extraction of Am(III) decreased with increasing feed acidity for all three diluents, indicating an ion exchange mechanism for the extraction. The stoichiometry of the extracted species suggested that two TODGA molecules were associated with Am(III) during the extraction for all three RTILs and the conditional extraction constants have been determined. The D(M)-values for different metal ions followed the order: 75 (Am(III)) > 30.7 (Pu(IV)) > 3.9 (Np(IV)) > 1.19 (Pu(VI)) > 0.52 (U(VI)) > 0.12 (Cs(I)) > 0.024 (Sr(II)). The distribution behaviour of Am(III) was also studied with a recently synthesized calix[4]arene-4DGA (C4DGA) extractant dissolved in C(8)mim(+).PF(6)(-). Using this extractant diluent combination, the D(Am)-value was 194 at 3 M HNO(3) using 5 * 10(-5) M C4DGA, suggesting a very high distribution coefficient at very low extractant concentrations. The stoichiometry of the extracted species containing Am was found to be 1:2 (M:L) in C(8)mim(+).PF(6)(-). The thermodynamics of the extraction was also studied for both extractants in C(8)mim(+).PF(6)(-). The use of RTILs gives rise to significantly improved extraction properties than the commonly used n-dodecane and an unusual increase in separation factor values was seen for the first time which can lead to selective separation of Am from wastes containing a mixture of U, Pu and Am. PMID- 22532067 TI - Review of a simple noise simulation technique in digital radiography. AB - Reduction of exposure dose and improvement in image quality can be expected to result from advances in the performance of imaging detectors. A number of researchers have reported on methods for simulating reduced dose images. The simplest method provides reduced dose images by adding white Gaussian noise with a certain standard deviation to the original image. Our aim in this study was to develop and validate a system with a graphic user interface for simulating reduced dose images by a simple method. Here, we describe a technical approach with the use of a flat-panel detector system, and we validated the simulation performance in reducing the dose objectively and subjectively. In addition, the technical limitations and possible solutions to the simple method are suggested based on the validation results presented in this paper. PMID- 22532070 TI - Retroperitoneal tumors that may be confused as adrenal pathologies. AB - There are a number of retroperitoneal pathologies that may be confused with adrenal tumors. It is important to suspect and recognize these conditions as their management and work up might be different than adrenal tumors. This review will go in to the differential diagnosis and unique features of these conditions. A management strategy will also be provided. PMID- 22532069 TI - Cognitive defects are reversible in inducible mice expressing pro-aggregant full length human Tau. AB - Neurofibrillary lesions of abnormal Tau are hallmarks of Alzheimer disease and frontotemporal dementias. Our regulatable (Tet-OFF) mouse models of tauopathy express variants of human full-length Tau in the forebrain (CaMKIIalpha promoter) either with mutation DeltaK280 (pro-aggregant) or DeltaK280/I277P/I308P (anti aggregant). Co-expression of luciferase enables in vivo quantification of gene expression by bioluminescence imaging. Pro-aggregant mice develop synapse loss and Tau-pathology including missorting, phosphorylation and early pretangle formation, whereas anti-aggregant mice do not. We correlated hippocampal Tau pathology with learning/memory performance and synaptic plasticity. Pro-aggregant mice at 16 months of gene expression exhibited severe cognitive deficits in Morris water maze and in passive-avoidance paradigms, whereas anti-aggregant mice were comparable to controls. Cognitive impairment of pro-aggregant mice was accompanied by loss of hippocampal LTP in CA1 and CA3 areas and by a reduction of synaptic proteins and dendritic spines, although no neuronal loss was observed. Remarkably, memory and LTP recovered when pro-aggregant Tau was switched-OFF for ~4 months, Tau phosphorylation and missorting were reversed, and synapses recovered. Moreover, soluble and insoluble pro-aggregant hTau40 disappeared, while insoluble mouse Tau was still present. This study links early Tau pathology without neurofibrillary tangles and neuronal death to cognitive decline and synaptic dysfunction. It demonstrates that Tau-induced impairments are reversible after switching-OFF pro-aggregant Tau. Therefore, our mouse model may mimic an early phase of AD when the hippocampus does not yet suffer from irreversible cell death but cognitive deficits are already striking. It offers potential to evaluate drugs with regard to learning and memory performance. PMID- 22532072 TI - Worms under cover: relationships between performance in learning tasks and personality in great tits (Parus major). AB - In animals, individual differences in learning ability are common and are in part explained by genetic differences, developmental conditions and by general experience. Yet, not all variations in learning are well understood. Individual differences in learning may be associated with elementary individual characteristics that are consistent across situations and over time, commonly referred to as personality or temperament. Here, we tested whether or not male great tits (Parus major) from two selection lines for fast or slow exploratory behaviour, an operational measure for avian personality, vary in their learning performance in two related consecutive tasks. In the first task, birds had to associate a colour with a reward whereas in the second task, they had to associate a new colour with a reward ignoring the previously rewarded colour. Slow explorers had shorter latencies to approach the experimental device compared with fast explorers in both tasks, but birds from the two selection lines did not differ in accomplishing the first task, that is, to associate a colour with a reward. However, in the second task, fast explorers had longer latencies to solve the trials than slow explorers. Moreover, relative to the number of trials needed to reach the learning criteria in the first task, birds from the slow selection line took more trials to associate a new colour with a reward while ignoring the previously learned association compared with birds from the fast selection line. Overall, the experiments suggest that personality in great tits is not strongly related to learning per se in such an association task, but that birds from different selection lines might express different learning strategies as birds from the different selection lines were differently affected by their previous learning performance. PMID- 22532071 TI - On the active site of mononuclear B1 metallo beta-lactamases: a computational study. AB - Metallo-beta-lactamases (MbetaLs) are Zn(II)-based bacterial enzymes that hydrolyze beta-lactam antibiotics, hampering their beneficial effects. In the most relevant subclass (B1), X-ray crystallography studies on the enzyme from Bacillus Cereus point to either two zinc ions in two metal sites (the so-called '3H' and 'DCH' sites) or a single Zn(II) ion in the 3H site, where the ion is coordinated by Asp120, Cys221 and His263 residues. However, spectroscopic studies on the B1 enzyme from B. Cereus in the mono-zinc form suggested the presence of the Zn(II) ion also in the DCH site, where it is bound to an aspartate, a cysteine, a histidine and a water molecule. A structural model of this enzyme in its DCH mononuclear form, so far lacking, is therefore required for inhibitor design and mechanistic studies. By using force field based and mixed quantum classical (QM/MM) molecular dynamics (MD) simulations of the protein in aqueous solution we constructed such structural model. The geometry and the H-bond network at the catalytic site of this model, in the free form and in complex with two common beta-lactam drugs, is compared with experimental and theoretical findings of CphA and the recently solved crystal structure of new B2 MbetaL from Serratia fonticola (Sfh-I). These are MbetaLs from the B2 subclass, which features an experimentally well established mono-zinc form, in which the Zn(II) is located in the DCH site. From our simulations the epsilonepsilondelta and deltaepsilondelta protomers emerge as possible DCH mono-zinc reactive species, giving a novel contribution to the discussion on the MbetaL reactivity and to the drug design process. PMID- 22532073 TI - Are monkeys able to plan for future exchange? AB - Whether or not non-human animals can plan for the future is a hotly debated issue. We investigate this question further and use a planning-to-exchange task to study future planning in the cooperative domain in two species of monkeys: the brown capuchin (Cebus apella) and the Tonkean macaque (Macaca tonkeana). The rationale required subjects to plan for a future opportunity to exchange tokens for food by collecting tokens several minutes in advance. Subjects who successfully planned for the exchange task were expected to select suitable tokens during a collection period (5/10 min), save them for a fixed period of time (20/30 min), then take them into an adjacent compartment and exchange them for food with an experimenter. Monkeys mostly failed to transport tokens when entering the testing compartment; hence, they do not seem able to plan for a future exchange with a human partner. Three subjects did however manage to solve the task several times, albeit at very low rates. They brought the correct version of three possible token types, but rarely transported more than one suitable token at a time. Given that the frequency of token manipulation predicted transport, success might have occurred by chance. This was not the case, however, since in most cases subjects were not already holding the token in their hands before they entered the testing compartment. Instead, these results may reflect subjects' strengths and weaknesses in their time-related comprehension of the task. PMID- 22532074 TI - The role of user control in adherence to and knowledge gained from a website: randomized comparison between a tunneled version and a freedom-of-choice version. AB - BACKGROUND: Internet-delivered interventions can effectively change health risk behaviors and their determinants, but adherence to these interventions once they are accessed is very low. Therefore, it is relevant and necessary to systematically manipulate website characteristics to test their effect on website use. This study focuses on user control as a website characteristic. OBJECTIVE: To test whether and how user control (the freedom of choice to skip pages) can increase website use and knowledge gained from the website. METHODS: Participants older than 18 years were drawn from the Dutch Internet population (in June 2011) and completed a hepatitis knowledge questionnaire. Subsequently, they were randomly assigned to three groups: (1) a tunneled version of the website with less user control; (2) a high user control version of the website where visitors had the freedom of choice to skip pages; and (3) a control group that was not exposed to the website. Participants completed (1) a questionnaire of validated measures regarding user perceptions immediately after exposure to the website (except for the control group), and (2) a hepatitis knowledge questionnaire after one week to test whether participants in the experimental groups only clicked through the website or actually processed and learned its content. Server registrations were used to assess website use. Analyses of covariance (ANCOVA) using all available data were conducted to determine whether user control increases website use. Structural equation models (SEM) using all available data were constructed to test how user control increases website use-a latent variable derived from number of pages visited and time on website. RESULTS: Of the 1044 persons invited to participate, 668 took part (668/1044, 64.0%). One half of participants (332/668 49.7%) were female and the mean age was 49 years (SD 16). A total of 571 participants completed the one-week follow-up measure regarding hepatitis knowledge (571/668, 85.5%). The findings demonstrate that having less user control (ie, a tunneled version of the website) had a negative effect on users' perception of efficiency (F(1,452) = 97.69, P < .001), but a positive effect on number of pages visited (F(1,452) = 171.49, P < .001), time on the website (F(1,452) = 6.32, P = .01), and knowledge gained from the website (F(1,452) = 134.32, P < .001). The direct effect of having less user control appeared to surpass the effect mediated by efficiency, because website use was higher among participants exposed to the tunneled version of the website in comparison with those having the freedom of choice to skip pages. CONCLUSIONS: The key finding that visitors demonstrated increased website use in the tunneled version of the website indicates that visitors should be carefully guided through the intervention for future intervention websites. PMID- 22532075 TI - Chemokines and mitochondrial products activate neutrophils to amplify organ injury during mouse acute liver failure. AB - Acetaminophen (APAP) is a safe analgesic and antipyretic drug. However, APAP overdose leads to massive hepatocyte death. Cell death during APAP toxicity occurs by oncotic necrosis, in which the release of intracellular contents can elicit a reactive inflammatory response. We have previously demonstrated that an intravascular gradient of chemokines and mitochondria-derived formyl peptides collaborate to guide neutrophils to sites of liver necrosis by CXC chemokine receptor 2 (CXCR2) and formyl peptide receptor 1 (FPR1), respectively. Here, we investigated the role of CXCR2 chemokines and mitochondrial products during APAP induced liver injury and in liver neutrophil influx and hepatotoxicity. During APAP overdose, neutrophils accumulated into the liver, and blockage of neutrophil infiltration by anti-granulocyte receptor 1 depletion or combined CXCR2-FPR1 antagonism significantly prevented hepatotoxicity. In agreement with our in vivo data, isolated human neutrophils were cytotoxic to HepG2 cells when cocultured, and the mechanism of neutrophil killing was dependent on direct contact with HepG2 cells and the CXCR2-FPR1-signaling pathway. Also, in mice and humans, serum levels of both mitochondrial DNA (mitDNA) and CXCR2 chemokines were higher during acute liver injury, suggesting that necrosis products may reach remote organs through the circulation, leading to a systemic inflammatory response. Accordingly, APAP-treated mice exhibited marked systemic inflammation and lung injury, which was prevented by CXCR2-FPR1 blockage and Toll-like receptor 9 (TLR9) absence (TLR9(-/-) mice). CONCLUSION: Chemokines and mitochondrial products (e.g., formyl peptides and mitDNA) collaborate in neutrophil-mediated injury and systemic inflammation during acute liver failure. Hepatocyte death is amplified by liver neutrophil infiltration, and the release of necrotic products into the circulation may trigger a systemic inflammatory response and remote lung injury. PMID- 22532077 TI - GnRH-1 mRNA, LH surges, steroid hormones, egg production, and intersequence pause days alter in birds exposed to longer wavelength of light in the later stages of production in Gallus gallus domesticus. AB - The objective of this was to establish the effects of red spectrum of light (650 nm, treated n = 12) and normal spectrum of light (450 nm control = 12) on GnRH-I mRNA expression, amplitude and frequency of luteinizing hormone (LH), and egg production from 72-82 weeks of age in white leghorn hens. Birds exposed to red spectrum of wavelength significantly improved (P < 0.01) steroid hormone, and egg production improved over old laying 72 to 82 weeks. Weekly interval profiles followed the same pattern. At 77th weeks of age blood, samples from both the groups were collected at every 3 h for 36 h to study the pulsatile secretion of LH surges. Plasma LH concentration was higher (P < 0.01) in treated birds with more number of frequencies and amplitude LH surges in plasma of treated birds. LH frequencies were more pronounced and advanced during 36 h of sampling at 3 h interval in treated birds. Weekly interval of plasma LH, E2beta, and P(4) concentrations increased (P < 0.01) in treated birds from 72 to 82 weeks of age. GnRH-I mRNA concentration was significantly (P < 0.01) higher in birds exposed to red spectrum of light compared to controls. It is hypothesized that exposure of birds to red spectrum of light-enhanced (P < 0.01) GnRH-I mRNA with more number of yellow yolky follicles was found in birds exposed to red spectrum of light during 77 days (72-82 weeks of age) of experimental period. It is concluded that higher levels of GnRH-I mRNA, LH, E2beta, and P(4) concentration with lower incidence of pause days enabled the birds to lay more eggs even later in the productive period by modulating the wavelengths of light under normal husbandry conditions. PMID- 22532076 TI - Torque teno sus virus infection in suckling piglets from Brazilian pig herds. AB - Torque teno sus virus (TTSuV) is responsible for the infection of pig herds around the world. The aim of this study was to analyse the presence of natural infection by both species of TTSuV in suckling piglets from major pig-producing regions of Brazil. Faecal samples (n = 135) from 1 to 3-week-old suckling piglets from the Southern, Southeast and Midwest regions of Brazil were analysed by PCR assay to detect TTSuV1 and 2. TTSuV1 and 2 DNA was identified in 65 (48.1 %) and 23 (17 %) of piglet faecal samples, respectively. Co-infection by both species of TTSuV was detected in 17 (12.6 %) samples. Detection of TTSuV1 was significantly higher than that of TTSuV2 in the three Brazilian regions together (p < 0.05). Based on age of animals, TTSuV1 infection was statistically higher than TTSuV2 in each age group (p < 0.05). For all of the age groups together, no statistical difference was detected in the number of TTSuV1 and 2 positive results (p > 0.05). These findings revealed that TTSuV infection has disseminated in pig herds from different geographic Brazilian regions, and the presence of TTSuV in suckling piglet faecal samples suggested the early infection by the virus and the potential of these animals in spreading the virus. PMID- 22532078 TI - Inhibitory effects of Broccolini leaf flavonoids on human cancer cells. AB - Broccolini (Brassica oleracea Italica * Alboglabra) is a hybrid between broccoli and Gai Lan, also known as Chinese broccoli and Chinese kale. The aim of this study was to assess the antitumor activity of Broccolini leaf flavonoids (BLF). Cell growth inhibition was evaluated using a standard colorimetric MTT assay, cellular morphology was observed using phase contrast microscopy and flow cytometry was introduced to further investigate cells apoptosis effect. The results showed that BLF possess a dose-dependent antiproliferative effects on four human cancer cell lines (SW480, HepG2, Hela, and A549) and apoptosis induction activity on SW480 cell line. Thus, the hybrid species Broccolini could be considered as a functional vegetable with potential in assisting for the treatment of four human cancers examined here. PMID- 22532079 TI - SEM sample preparation for cells on 3D scaffolds by freeze-drying and HMDS. AB - Common dehydration methods of cells on biomaterials for scanning electron microscopy (SEM) include air drying, hexamethyldisilazane (HMDS) or tetramethysilane (TMS) treatment and critical point drying (CPD). On the other side, freeze-drying has been widely employed in dehydrating biological samples and also in preparing porous biomaterial scaffolds but not in preparing cells on three-dimensional (3D) biomaterials for SEM examination. In this study, we compare cells on porous hydroxyapatite (HA) prepared by air drying, HMDS and freeze-drying. The effects of fixation and using phosphate buffered saline (PBS) in the fixation were also assessed on three porous calcium phosphate (CaP) materials, namely, HA, alpha-tricalcium phosphate (alpha-TCP) and beta-tricalcium phosphate (beta-TCP) samples. There is no significant difference in samples prepared by HMDS treatment and freeze-drying viewed at low magnification. Besides, it is better not to use phosphate buffer in the fixation step for CaP materials to avoid undesirable spontaneous precipitation of CaPs. On the other hand, fewer exchanges of liquids are required for freeze-drying and hence chemical fixation may not be absolutely required for samples prepared by freeze drying. Other technical details of the preparation were also investigated and discussed. This study suggests both HMDS and freeze-drying can be employed to dehydrate cells on 3D scaffolds for SEM examination. PMID- 22532080 TI - The study of nanoscratch and nanomachining on hard multilayer thin films using atomic force microscope. AB - In this study, nanoscratching and nanomachining were conducted using an atomic force microscope (AFM) equipped with a doped diamond-coated probe (DDESP-10; VEECO) to evaluate the fabrication of nanopatterns on hard, Cr2N/Cu multilayer thin films. The influence of normal force, scratch speed, and repeated scratches on the properties of hard multilayer thin films was also investigated. The nanoscratch experiments led researchers to establish a probe preparation and selection criteria (PPS criteria) to enhance the stability and accuracy of machining hard materials. Experimental results indicate that the depth of grooves produced by nanoscratching increased with an increase in normal force, while an increase in the number of scratches in a single location increased the groove depth but decreased friction. Therelationships among normal force and groove depth more closely resembled a logarithmic form than other mathematical models, as did the relationship between repeated scratching and its effect on groove depth and friction. The influence of scratch speed on friction was divided into two ranges. Between 0.1 and 2 um/s, friction decreased logarithmically with an increase in scratch speed; however, when the speed exceeded 2 um/s, the friction appeared stable. In this study, multilayered coatings were successfully machined, demonstrating considerable promise for the fabrication of nanopatterns in multilayered coatings at the nanoscale. PMID- 22532082 TI - Balancing continuous and categorical baseline covariates in sequential clinical trials using the area between empirical cumulative distribution functions. AB - Covariate adaptive allocation is often adopted in sequential clinical trials to maintain the balance of baseline covariates that could potentially confound the outcome of a trial. Several allocation methods exist in the literature that can handle both continuous and categorical covariates. We propose a minimization approach to maintaining the balance of multiple continuous and categorical covariates in sequential clinical trials, which uses the area between the empirical cumulative distribution functions of the observed covariate values as the imbalance metric. Numerical results based on extensive simulation studies and a real dataset show that the proposed approach produces more accurate estimates of the treatment effect and leads to more powerful trials than the existing approaches for trials with binary, continuous, and time-to-event outcomes. PMID- 22532081 TI - [Effect of noninvasive first trimester diagnosis on indications and results of chorion villi sampling]. AB - AIM: In this explorative study it should be evaluated how the introduction of non invasive first trimester diagnosis (nuchal translucency measurement, Combined Test, first trimester ultrasound screening) has influenced the indications and cytogenetic results of chorion villi samplings. MATERIALS AND METHODS: Between 1989 and 2008 3337 pregnancies with CVS between 11 and 14 weeks of gestation were examined retrospectively. They were divided in two groups: CVS 1989 - 2001 before introduction of non invasive first trimester diagnosis (n = 1698) and CVS 2002 - 2008 after introducing non invasive testing at the end of 2001 (n = 1639). In both groups the indications for CVS (maternal age, sonographic findings, past history, maternal anxiety, and abnormal results of the Combined Test only in the second group) and the cytogenetic results were evaluated. RESULTS: In the first group (1989 - 2001, n = 1698) 85,6% (n = 1454) of all CVS were performed because of maternal age and only 3% (n = 51) due to sonographic findings. In the second group (2002 - 2008, n = 1639) there was a distinct increase of sonographic findings leading to CVS (33,9%, n = 555) with a clear decrease of maternal age to 37,9% (n = 621). Abnormal cytogenetic results were found in 10,5% (n = 172) in the second group, in the first group only in 4,5% (n = 76), respectively. The parameter with the highest rate of chromosomal disorders was fetal hydrops (66,1%), follwed by hygroma colli (48,2%), malformations (12,9%) and increased nuchal translucency (11,2%). Regarding maternal age alone the rate of abnormal chromosomes was 3,1%. CONCLUSIONS: It could be shown that non invasive first trimester diagnosis has lead to a more specific indication for invasive fetal testing (sonographic findings 33,9 vs. 3%, maternal age 37,9 vs. 85,6%) with a higher rate of chromosomal disorder in this group (10,5 vs. 4,5%). PMID- 22532083 TI - A needs assessment and instrument comparison for a therapeutic apheresis medicine service. AB - This article outlines a needs assessment process for developing or updating a therapeutic apheresis medicine (TAM) service. The TAM service brings together administrative, medical, laboratory, and pharmacy services. As these services jointly respond to needs assessment questions, the TAM service evolves. Discussions identifying patient populations impact the types of procedures to be offered and subsequent instrument choices. This article will also review and compare current TAM devices using centrifugation-based or column-based methods for treatments. The TAM service is unique in regard to both the multiservice involvement and spectrum of patients served. PMID- 22532084 TI - Microcavity effect on the pump-probe intersubband response of multiple-quantum well structures. AB - We study theoretically the coherent pump-probe intersubband response of a multiple quantum well (MQW) embedded in a semiconductor microcavity. An n-type doped MQW structure with two subbands in the conduction band is considered. Self consistent numerical calculations are performed for realistic systems employing a semiclassical approach based on the transfer matrix formalism and the so-called sheet model. They show that in the strong coupling limit the pumping of the system leads to evolution of the intersubband cavity polariton doublet into a Mollow-type spectrum. By using appropriate angles, both the pump and the probe light can be tuned into resonance with the cavity mode. In this double-resonance case, simultaneously with a dramatic enhancement of the Rabi flopping frequency, a strong selective enhancement of distinct parts of the Rabi sidebands is possible. PMID- 22532085 TI - Quality assurance challenge 10. PMID- 22532086 TI - Solution to Plato's elements challenge. PMID- 22532087 TI - The Static-99R: are there really differences between the normative groups? AB - A sample of 348 high-risk sexual offenders was divided into two groups based on the level of preselection (detained, n = 211, and nondetained, n = 137) and the groups were compared on a number of measures which were related to dynamic risk. The hypothesis was that the detained group would score as being higher need on these instruments than the nondetained group. This hypothesis was supported with the detained group reporting greater levels of hostility, cognitive distortions supportive of offending, sexual obsessions, and sexually deviant behaviours. They also scored as being less assertive and as having a more extensive psychiatric history. These findings were interpreted as being supportive of the assertion that the new Static-99R normative groups are related to preselection based on the differences on dynamic factors. PMID- 22532088 TI - A plant virus substrate induces early upregulation of BMP2 for rapid bone formation. AB - Many nanoscale materials have been developed to investigate the effects on stem cell differentiations via topographical and chemical cues for applications in tissue engineering and regenerative medicine. The use of plant viruses as cell supporting substrates has been of particular interest due to the rapid induction of bone marrow derived mesenchymal stem cells (BMSCs) towards osteogenic cells. In this study, the role of Tobacco mosaic virus (TMV) and its early effects on osteoinduction with particular emphasis on the regulation of bone morphogenetic protein-2 (BMP2) was examined. We observed that the cells on the virus substrate immediately aggregated and formed bone-like nodules within 24 hours. An immediate increase in BMP2 gene and protein expression for cells on the TMV substrate was observed within 8 hours of osteoinduction. Moreover, BMP2 expression was highly localized to cells within the cell aggregates. This enhanced differentiation only occurred when TMV was coated on a solid support but not upon adding the virus to the media solution. Taken together, the results from this study highlight the potential of virus-based nanomaterials to promote endogenous BMP2 production which may prove to be a unique approach to studying the regulatory mechanisms involved in early osteoblastic differentiation. PMID- 22532089 TI - 3D-Endometrial volume and outcome of cryopreserved embryo replacement cycles. AB - PURPOSE: The success of artificial reproductive techniques not only depends on the quality of oocytes and spermatozoa but also on the receptivity of the endometrium. The aim of this study was to assess the value of measurement of endometrial volume by three-dimensional (3D) in comparison to 2D-ultrasound in the prediction of implantation in women having transfer of cryopreserved embryos. METHODS: One hundred and eight couples were included in this prospective study. All patients underwent the IVF or ICSI program and had transfer of cryopreserved embryos. Sixty-eight transfers were done in a spontaneous cycle and 40 in an artificial cycle. Endometrial thickness, pattern and three-dimensional volume were measured immediately before embryo transfer. RESULTS: Twenty clinical pregnancies were achieved (PR 18.5 % per transfer), the PR being similar in spontaneous (22.1 %) and artificial (12.5 %, ns) cycles. Three to five days after ovulation (spontaneous cycles) or after the endometrium reached a thickness of at least 8 mm (artificial cycles), a median of three embryos were replaced. In spontaneous cycles, there were no significant differences in endometrial thickness or volume between pregnant (11.9 mm, 2.9 ml) and non-pregnant women (10.7 mm, 3.4 ml). In artificial cycles, the endometrial volume (3.9 vs. 2.5 ml, p < 0.05), but not endometrial thickness (10.7 vs. 10.2 mm, ns) was significantly higher in pregnant than in non-pregnant women. CONCLUSIONS: In artificial cycles, a low endometrial volume is associated with a poor likelihood of implantation. Endometrial volume measured by 3D-ultrasound is an objective parameter to predict endometrial receptivity. PMID- 22532090 TI - The use of spa and phage typing for characterization of clinical isolates of methicillin-resistant Staphylococcus aureus in the University Clinical Center in Gdansk, Poland. AB - The emergence of spa types and spa-clonal complexes (CC) among clinical methicillin-resistant Staphylococcus aureus isolates collected from the University Clinical Center in Gdansk between 2008 and 2009 were investigated. Phage typing was used as the initial screening in the study. The basic set of phages and the additional set of phages were used. Most of the isolates (56 %) belonged to the phage group III. With the additional set of phages, eight types were found, with predominant one MR8 (50 %). Sixteen distinct spa types were observed. The most frequent were t003 (22 %), t151 (16 %), and t008 (12 %). The spa types were clustered into two spa-CC and eight singletons. The predominant CC010 (50 %) consisted of six types, with the most common t003 (36.7 %) and t151(26.7 %), and in 80 % was identified as staphylococcal chromosomal casette mec (SCCmec) type II. The second cluster has no founder (12 %) with only two spa types: t037 belonging to SCCmec type III and t029. In the most frequent singleton, spa type t008 alone was clustered in 12 % of the isolates. All singletons correspond to SCCmec type IV. The CC010 was distributed in most of the hospital wards, corresponded to Multilocus sequence typing type ST5/ST225 and was constantly present throughout the observed period. The isolates of CC010 generally belonged to the phage group III, and most of them (53.3 %) were resistant to erythromycin, clindamycin, and ciprofloxacin. The concordance between spa-clone and phage type was very high, but the same phage type MR8 was observed within different spa types of the predominant clone. PMID- 22532091 TI - Illusions and delusions in anosognosia for hemiplegia: from motor predictions to prior beliefs. PMID- 22532092 TI - Effective Hamiltonian of strained graphene. AB - Based on the symmetry properties of the graphene lattice, we derive the effective Hamiltonian of graphene under spatially nonuniform acoustic and optical strains. Comparison with the published results of the first-principles calculations allows us to determine the values of some Hamiltonian parameters, and suggests the validity of the derived Hamiltonian for acoustical strain up to 10%. The results are generalized for the case of graphene with broken plane reflection symmetry, which corresponds, for example, to the case of graphene placed on a substrate. Here, essential modifications to the Hamiltonian give rise, in particular, to the gap opening in the spectrum in the presence of the out-of-plane component of optical strain, which is shown to be due to the lifting of the sublattice symmetry. The developed effective Hamiltonian can be used as a convenient tool for analysis of a variety of strain-related effects, including electron-phonon interaction or pseudo-magnetic fields induced by the nonuniform strain. PMID- 22532093 TI - The inverse sandwich complex [(K(18-crown-6))2Cp][CpFe(CO)2]--unpredictable redox reactions of [CpFe(CO)2]I with the silanides Na[SiRtBu2] (R = Me, tBu) and the isoelectronic phosphanyl borohydride K[PtBu2BH3]. AB - The dimeric iron carbonyl [CpFe(CO)(2)](2) and the iodosilanes tBu(2)RSiI were obtained from the reaction of [CpFe(CO)(2)]I with the silanides Na[SiRtBu(2)] (R = Me, tBu) in THF. By the reactions of [CpFe(CO)(2)]I and Na[SiRtBu(2)] (R = Me, tBu) the disilanes tBu(2)RSiSiRtBu(2) (R = Me, tBu) were additionally formed using more than one equivalent of the silanide. In this context it should be noted that reduction of [CpFe(CO)(2)](2) with Na[SitBu(3)] gives the disilanes tBu(3)SiSitBu(3) along with the sodium ferrate [(Na(18-crown 6))(2)Cp][CpFe(CO)(2)]. The potassium analogue [(K(18-crown 6))(2)Cp][CpFe(CO)(2)] (orthorhombic, space group Pmc2(1)), however, could be isolated as a minor product from the reaction of [CpFe(CO)(2)]I with [K(18-crown 6)][PtBu(2)BH(3)]. The reaction of [CpFe(CO)(2)](2) with the potassium benzophenone ketyl radical and subsequent treatment with 18-crown-6 yielded the ferrate [K(18-crown-6)][CpFe(CO)(2)] in THF at room temperature. The crown ether complex [K(18-crown-6)][CpFe(CO)(2)] was analyzed using X-ray crystallography (orthorhombic, space group Pna2(1)) and its thermal behaviour was investigated. PMID- 22532094 TI - A new partition testing strategy for multiple endpoints. AB - To evaluate efficacy in multiple endpoints in confirmatory clinical trials is a challenging problem in multiple hypotheses testing. The difficulty comes from the different importance of each endpoint and their underlying correlation. Current approaches to this problem, which test the efficacy in certain dose-endpoint combinations and collate the results, are based on closed testing or partition testing. Despite their different formulations, all current approaches test their dose-endpoint combinations as intersection hypotheses and apply various union intersection tests. Likelihood ratio test is seldom used owing to the extensive computation and lack of consistent inferences. In this article, we first generalize the formulation of multiple endpoints problem to include the cases of alternative primary endpoints and co-primary endpoints. Then we propose a new partition testing approach that is based on consonance-adjusted likelihood ratio test. The new procedure provides consistent inferences, and yet, it is still conservative and does not rely on the estimation of endpoint correlation or independence assumptions that might be challenged by regulatory agencies. PMID- 22532095 TI - Blood banking and transfusion medicine for the apheresis medicine practitioner. AB - This article provides a concise overview of blood banking and transfusion medicine (BBTM) for the therapeutic apheresis medicine practitioner. It addresses the complete pathway from blood donor qualification to blood collection, to processing and storing blood components, to patient testing, to ordering blood components for therapeutic apheresis (TA) procedures, to preparing the component for transfusion, and finally to transfusion. The nurses, technologists, and physicians orchestrate these activities in concert to best serve patients undergoing TA procedures. Enhancing knowledge of these processes may improve the quality of patient care and the utilization of blood products. PMID- 22532096 TI - Biosynthesis of highly pure poly-gamma-glutamic acid for biomedical applications. AB - The remarkable properties of poly-aminoacids, mainly their biocompatibility and biodegradability, have prompted an increasing interest in these polymers for biomedical applications. Poly-gamma-glutamic acid (gamma-PGA) is one of the most interesting poly-aminoacids with potential applications as a biomaterial. Here we describe the production and characterization of gamma-PGA by Bacillus subtilis natto. The gamma-PGA was produced with low molecular weight (10-50 kDa), high purity grade (>99 %) and a D: -/L: -glutamate ratio of 50-60/50-40 %. To evaluate the feasibility of using this gamma-PGA as a biomaterial, chitosan (Ch)/gamma-PGA nanoparticles were prepared by the coacervation method at pH ranging from 3.0 to 5.0, with dimensions in the interval 214-221 nm with a poly-dispersion index of ca. 0.2. The high purity of gamma-PGA produced by this method, which is firstly described here, renders this biopolymer suitable for biomedical applications. Moreover, the Ch/gamma-PGA nanocomplexes developed in this investigation can be combined with biologically active substances for their delivery in the organism. The fact that the assembly between Ch and gamma-PGA relies on electrostatic interactions enables addition of other molecules that can be released into the medium through changes from acidic to physiological pH, without loss in biological activity. PMID- 22532097 TI - Bioactive glass-derived trabecular coating: a smart solution for enhancing osteointegration of prosthetic elements. AB - In this work, the use of foam-like glass-ceramic scaffolds as trabecular coatings on ceramic prosthetic devices to enhance implant osteointegration is proposed. The feasibility of this innovative device was explored in a simplified, flat geometry: glass-ceramic scaffolds, prepared by polymeric sponge replication and mimicking the trabecular architecture of cancellous bone, were joined to alumina square substrates by a dense glass coating (interlayer). The role played by different formulations of starting glasses was examined, with particular care to the effect on the mechanical properties and bioactivity of the final coating. Microindentations at the coating/substrate interface and tensile tests were performed to evaluate the bonding strength between the sample's components. In vitro bioactive behaviour was assessed by soaking in simulated body fluid and evaluating the apatite formation on the surface and inside the pores of the trabecular coating. The concepts disclosed in the present study can have a significant impact in the field of implantable devices, suggesting a valuable alternative to traditional, often invasive bone-prosthesis fixation. PMID- 22532098 TI - Ion migration from fluoride-releasing dental restorative materials into dental hard tissues. AB - This study was carried out in order to determine the extent to which ions released from fluoride-containing dental restoratives migrated through the enamel and dentine of extracted teeth. A total of 40 permanent human 3rd molars were used. They were extracted for orthodontic reasons, and employed within 1 month of extraction. A cervical (Class V) cavity was prepared in each tooth, then filled with one of: a conventional glass-ionomer, a resin-modified glass-ionomer, a polyacid-modified composite resin ("compomer") or a fluoride-releasing resin composite. Ten samples were prepared per material. After 1 month, five specimens per material were prepared and examined under SEM/EDX. Concentrations of sodium, aluminium, strontium, fluorine, magnesium, silicon, phosphorus and calcium were determined within the tooth. After 18 months, the remaining five specimens for each material were prepared and studied in the same way. The greatest extent of ion migration into the tooth was found with the conventional glass-ionomer and least migration was found for the fluoride-releasing composite, which showed no evidence of fluoride migration at all. Levels of migrating ions were generally higher in the 18 month specimens than in the 1 month specimens, and also higher in the dentine than in the enamel. Ions released by restorative dental materials have been shown conclusively for the first time to be capable of migrating into the enamel and dentine surrounding the restoration. The conventional glass ionomer showed the highest level of ion migration whereas the fluoridated composite resin showed little if any ion migration. This suggests that the conventional glass-ionomer has the greatest caries inhibiting effects of all the materials tested, and the fluoridated composite the least. PMID- 22532100 TI - Synthesis of mesoporous silica nanobamboo with highly dispersed tungsten carbide nanoparticles. AB - By controlling the interaction between cationic surfactant micelles and ammonium metatungstate during the formation of mesoporous silica structure, highly dispersed tungsten carbide (WC) nanoparticles of 2.0 nm in diameter on mesoporous silica nanospheres were synthesized at lower concentration of ammonium metatungstate. With additional ammonium metatungstate, a novel mesoporous silica nanobamboo structure was formed with bimodal size-distributed WC nanoparticles, in which 2.0 nm WC was homogeneously distributed in nanobamboo's mesoporous silica wall and those with larger diameter (10.0-20.0 nm) were only formed on the nanobamboo's inner surface and at its internodes. The mesoporous silica nanobamboo also had a very high tensile strength due to its bamboo-like structure. PMID- 22532099 TI - Impact of infrared laser light-induced ablation at different wavelengths on bovine intervertebral disc ex vivo: evaluation with magnetic resonance imaging and histology. AB - BACKGROUND AND OBJECTIVE: Percutaneous laser disc decompression is commonly used to lower high pressure in the nucleus pulposus in degenerative disc diseases. The aim of this study was to investigate the impact of diode laser disc decompression at different wavelengths (980-nm vs. 1,470-nm, i.e., different water absorption characteristics). MATERIALS AND METHODS: To model decompression, a flexible laser quartz fiber inserted into the nucleus pulposus of ex vivo bovine spines using computer-assisted surgical navigation was utilized to vaporize tissue. The same energy (500 J) was delivered using both 980-nm and 1,470-nm wavelength lasers. To determine the different impact of the wavelengths before and after the procedure we evaluated the discs with MRI (T(1), T(2), diffusion maps) and with histopathology. RESULTS: There were no visible changes on T(1) and T(2) maps after 1,470-nm wavelength laser irradiation; however, the 980-nm wavelength caused significant changes on T(1) (decrease) and T(2) (increase) in the vaporization zone at the site of the quartz fiber. Pathological findings showed carbonization and steam-bubble formation in addition to the T(1) and T(2) changes. No significant changes were detected in the value of apparent diffusion coefficient (ADC) measurements in intervertebral disc with the 980-nm wavelength, but significant ADC and T(1) signal increase was detected with the 1,470-nm wavelength when the whole nucleus pulposus was considered. CONCLUSION: The 1,470 nm laser light had an effect in the whole nucleus pulposus and not only at the site of the quartz fiber, whereas with the 980-nm laser irradiation, significant changes were demonstrated only at the application site. PMID- 22532101 TI - The effect of humidity on the ozonolysis of unsaturated compounds in aerosol particles. AB - Atmospheric aerosol particles are important in many atmospheric processes such as: light scattering, light absorption, and cloud formation. Oxidation reactions continuously change the chemical composition of aerosol particles, especially the organic mass component, which is often the dominant fraction. These ageing processes are poorly understood but are known to significantly affect the cloud formation potential of aerosol particles. In this study we investigate the effect of humidity and ozone on the chemical composition of two model organic aerosol systems: oleic acid and arachidonic acid. These two acids are also compared to maleic acid an aerosol system we have previously studied using the same techniques. The role of relative humidity in the oxidation scheme of the three carboxylic acids is very compound specific. Relative humidity was observed to have a major influence on the oxidation scheme of maleic acid and arachidonic acid, whereas no dependence was observed for the oxidation of oleic acid. In both, maleic acid and arachidonic acid, an evaporation of volatile oxidation products could only be observed when the particle was exposed to high relative humidities. The particle phase has a strong effect on the particle processing and the effect of water on the oxidation processes. Oleic acid is liquid under all conditions at room temperature (dry or elevated humidity, pure or oxidized particle). Thus ozone can easily diffuse into the bulk of the particle irrespective of the oxidation conditions. In addition, water does not influence the oxidation reactions of oleic acid particles, which is partly explained by the structure of oxidation intermediates. The low water solubility of oleic acid and its ozonolysis products limits the effect of water. This is very different for maleic and arachidonic acid, which change their phase from liquid to solid upon oxidation or upon changes in humidity. In a solid particle the reactions of ozone and water with the organic particle are restricted to the particle surface and hence different regimes of reactivity are dictated by particle phase. The potential relevance of these three model systems to mimic ambient atmospheric processes is discussed. PMID- 22532102 TI - Web-based, computer-tailored, pedometer-based physical activity advice: development, dissemination through general practice, acceptability, and preliminary efficacy in a randomized controlled trial. AB - BACKGROUND: Computer tailoring is a relatively innovative and promising physical activity intervention approach. However, few computer-tailored physical activity interventions in adults have provided feedback based on pedometer use. OBJECTIVES: To (1) describe the development of a Web-based, pedometer-based, computer-tailored step advice intervention, (2) report on the dissemination of this tool through general practice, (3) report on its perceived acceptability, and (4) evaluate the preliminary efficacy of this tool in comparison with a standard intervention. METHODS: We recruited 92 participants through general practitioners and randomly assigned them to a standard condition (receiving a pedometer-only intervention, n = 47) and a tailored condition (receiving a pedometer plus newly developed, automated, computer-tailored step advice intervention, n = 45). Step counts, self-reported data obtained via telephone interview on physical activity, time spent sitting, and body mass index were assessed at baseline and postintervention. The present sample was mostly female (54/92, 59%), highly educated (59/92, 64%), employed (65/92, 71%), and in good health (62/92, 67%). RESULTS: Recruitment through general practitioners was poor (n = 107, initial response rate 107/1737, 6.2%); however, the majority of participants (50/69, 73%) believed it is useful that general practitioners help patients find ways to increase physical activity. In the tailored condition, 30/43 (70%) participants requested the computer-tailored step advice and the majority found it understandable (21/21, 100%), credible (17/18, 94%), relevant (15/18, 83%), not too long (13/18, 72%), instructive (13/18, 72%), and encouraging to increase steps (16/24, 67%). Daily step counts increased from baseline (mean 9237, SD 3749 steps/day) to postintervention (mean 11,876, SD 4574 steps/day) in the total sample (change of 2639, 95% confidence interval 105-5172; F(1 )= 5.0, P = .04). No interaction or other time effects were found. CONCLUSIONS: The majority of participants in the tailored condition accepted the step advice and indicated it was useful. However, in this selected sample of adults, the tailored condition did not show superior effects compared with the standard condition. PMID- 22532104 TI - Hemichorea-hemiballism syndrome following a thrombo-embolic striatal infarction. PMID- 22532103 TI - Neuropeptide PACAP in mouse liver ischemia and reperfusion injury: immunomodulation by the cAMP-PKA pathway. AB - Hepatic ischemia and reperfusion injury (IRI), an exogenous antigen-independent local inflammation response, occurs in multiple clinical settings, including liver transplantation, hepatic resection, trauma, and shock. The immune system and the nervous system maintain extensive communication and mount a variety of integrated responses to danger signals through intricate chemical messengers. This study examined the function and potential therapeutic potential of neuropeptide pituitary adenylate cyclase-activating polypeptides (PACAP) in a murine model of partial liver "warm" ischemia (90 minutes) followed by reperfusion. Liver IRI readily triggered the expression of intrinsic PACAP and its receptors, whereas the hepatocellular damage was exacerbated in PACAP deficient mice. Conversely, PACAP27, or PACAP38 peptide monotherapy, which elevates intracellular cyclic adenosine monophosphate/protein kinase A (cAMP-PKA) signaling, protected livers from IRI, as evidenced by diminished serum alanine aminotransferase levels and well-preserved tissue architecture. The liver protection rendered by PACAP peptides was accompanied by diminished neutrophil/macrophage infiltration and activation, reduced hepatocyte necrosis/apoptosis, and selectively augmented hepatic interleukin (IL)-10 expression. Strikingly, PKA inhibition readily restored liver damage in otherwise IR-resistant, PACAP-conditioned mice. In vitro, PACAP treatment not only diminished macrophage tumor necrosis factor alpha/IL-6/IL-12 levels in a PKA dependent manner, but also prevented necrosis and apoptosis in primary mouse hepatocyte cultures. CONCLUSION: Our novel findings document the importance of PACAP-mediated cAMP-PKA signaling in hepatic homeostasis and cytoprotection in vivo. Because the enhancement of neural modulation differentially regulates local inflammation and prevents hepatocyte death, these results provide the rationale for novel approaches to manage liver inflammation and IRI in transplant patients. PMID- 22532105 TI - Management of advanced carcinoma of the base of tongue. AB - BACKGROUND AND OBJECTIVE: Base-of-tongue carcinoma is a relatively rare disease with aggressive behavior and poor prognosis. Up to date no consensus exists regarding the ideal management strategy for each stage of the disease. This study aims to evaluate the experience of a single head and neck oncology center in the management of advanced stage base-of-tongue cancer. METHODS: A retrospective evaluation of cases primarily treated for stage III/IV(A-B) base-of-tongue carcinoma, between 1980 and 2007, at a tertiary referral center. RESULTS: A total of 366 cases were studied. Five-year disease specific survival (DSS) was 42% and local control (LC) 80%. Regional and distal control estimates were 91.3 and 84%, respectively. Prognosis was significantly superior for cases receiving surgery plus adjuvant treatment compared to cases solely managed with non-surgical modalities. Positive surgical margins and regional disease significantly worsened prognosis. Satisfactory retention of pharyngeal function and no fatal complications were noted in surgical cases. CONCLUSION: Although no consensus exists regarding ideal therapy for advanced base-of-tongue carcinoma, combined strategies with the use of surgery and adjuvant chemoradiotherapy (CRT) seem to offer the best possibility for a positive outcome. PMID- 22532106 TI - [Autistic disorders - the state of the art and recent findings: epidemiology, aetiology, diagnostic criteria, and therapeutic interventions]. AB - This review article is based on a state-of-the-art lecture given at the 32nd meeting of the German Child Psychiatry Association in March 2011. It summarizes recent findings from epidemiological studies (comorbid disorders, risk factors), early diagnosis, classification, and evidence-based therapeutic interventions (psychopharmacology, early intervention, group-based behavioural interventions). Intensive research over the last years has led to a better understanding of, and improved therapeutic options for, autism spectrum disorders. PMID- 22532107 TI - Subjective and biological weight-related parameters in adolescents and young adults with schizophrenia spectrum disorder under clozapine or olanzapine treatment. AB - OBJECTIVE: Administration of atypical antipsychotics often induces significant weight gain and metabolic changes. Little is known about subjective weight related parameters in adolescent patients. Therefore, this cross-sectional, explorative study aimed to assess these parameters and their relationship with biological weight-related parameters. METHOD: 74 patients (mean age: 19.9 [SD +/- 2.3] years; 66.2% male) with schizophrenia under clozapine or olanzapine treatment were examined. Subjective well-being, eating behavior, body perception and social functioning were assessed, using the Three-Factor-Eating Questionnaire, FKB-20 Body Perception Questionnaire, Subjective Well-being under Neuroleptics, Short Form and Global Assessment of Functioning. Patients' biological weight-related parameters were measured as well. Gender differences as well as associations between subjective and biological weight-related parameters were evaluated. RESULTS: Female patients reported significantly worse negative body appraisal and physical functioning than males. An elevated BMI was associated with impaired physical functioning in females and with negative body appraisal and hunger in males. CONCLUSIONS: In our sample of young patients with schizophrenia unter treatment with atypical antipsychotics, an elevated BMI was associated with impaired physical functioning and negative body appraisal, respectively. Bearing in mind the high risk of obesity in this population, the mentioned impairments should be accounted for, especially in terms of compliance and quality of life. PMID- 22532108 TI - [Depression screening in pediatric patients - a comparison of the concurrent validity of the German version of the Children's Depression Inventory, the German Depression Test for Children, and the new Children's Depression Screener]. AB - OBJECTIVE: We compared the concurrent validity of several tests for screening depression in pediatric care with respect to ICD-10 depression diagnoses in medically ill children: the German version of the Children's Depression Inventory (Depressionsinventar fur Kinder und Jugendliche, DIKJ), the scale Dysphoria of the Depression Test for Children (Depressionstest fur Kinder, DTK), and the Children's Depression Screener (ChilD-S). METHOD: Data of 9- to 12-year-old patients (N = 228) were analyzed with receiver operating characteristics. Validity measures like area under the curve (AUC), sensitivity (SE), and specificity (SP) were calculated for each instrument and subsequently compared. ICD-10 depression diagnoses according to a structured clinical interview served as the gold standard. RESULTS: The concurrent validity was high for the 26-item DIKJ (AUC = 92.6 %), satisfactory for the 25-item scale Dysphoria (AUC = 86.2 %), and very high for the 8-item ChilD-S (AUC = 97.5 %); the ChilD-S was significantly superior to the DIKJ. According to the Youden-Index the following cutoff scores are recommended: DIKJ >= 12 (SE = 91.7 %, SP = 81.9 %), scale Dysphoria >= 10 (SE = 75.0 %, SP = 89.8 %) and ChilD-S >= 10 (SE = 100 %, SP = 86.6 %). CONCLUSIONS: DIKJ and ChilD-S showed excellent concurrent validity for depression screening in pediatric patients, while the scale Dysphoria achieved lower values. For implementation in time-limited pediatric settings, the economic ChilD-S is the preferred instrument. PMID- 22532109 TI - [Evaluation of the Marburg Spelling Training (MRT) in 2nd- and 3rd-grade students with spelling difficulties]. AB - OBJECTIVE: Children with severe dyslexia are substantially impaired because reading and writing are key competencies necessary for a successful academic and occupational career. METHODS: In this evaluation study, a cohort of 2nd- and 3rd grade students from a variety of Hamburg primary schools was trained with the Marburger Rechtschreibtraining (MRT) by supervised university graduates. The research questions focused on the feasibility of the MRT as a within-school training, the improvement of spelling and reading skills of the participants, subjective assessments of success, as well as potential predictors. Besides established performance tests, we also considered the subjective appraisals of parents, teachers, and coaches. RESULTS: The results demonstrate that standardized spelling training methods like the MRT can be consistently used during morning hours at schools. Within a year of starting MRT exercises, mean effect sizes in writing and reading were observed in performance tests using test norms. However, parent, teacher, and coach reports failed to replicate these improvements. Changes in writing performance were mainly associated with school class level; improvements in reading ability were dependent on initial writing performance. CONCLUSIONS: The results provide starting points for optimizing current training practices in elementary schools and for posing questions regarding the effectiveness of the MRT, as well as for training programs in general. PMID- 22532110 TI - [Changes in comorbid symptoms and subjective interference in a habit reversal therapy in children with chronic tic disorder - a pilot study]. AB - OBJECTIVE: This pilot study investigates the effects of habit reversal training in a German-speaking population of children and young adults with chronic tic disorders on comorbid symptoms and subjective interference. METHODS: 16 children were treated using a manualized program. Comorbid-symptoms (ADHD, anxiety and OCD, depression) were assessed using parent and self-ratings. Additionally, the correlation of tic symptoms with comorbid symptoms at the beginning of the therapy was analyzed. RESULTS: We obtained positive results in reducing comorbid symptoms during a primary treatment of tic symptoms. We further found a correlation of tic symptoms and comorbid symptoms especially in parent ratings. CONCLUSIONS: These first findings show that a primary treatment of tics may be indicated in patients with comorbid symptoms, because a therapy of tic symptoms has also positive effects on comorbid symptoms. PMID- 22532111 TI - [The performance of children with AD(H)D according to the HAWIK-IV]. AB - The focus of the present study were performances of N = 433 children and adolescents with AD(H)D on the German version of the Wechsler Intelligence Scale for children (HAWIK-IV). Furthermore, we investigated whether test results depend on comorbid disorders based on subgroups (n = 212, n = 262, n = 217) composed by excluding individuals based on comorbidities on either (a) the first, (b) the second, and (c) the first and the second axis of the multiaxial classification scheme for mental disorders in childhood and adolescents. The specificity of the AD(H)D profile was investigated by comparing it against a clinical control group of children with anxiety or other emotional disorders (N = 41). As expected, a significant deficit in the Speed Index was shown not only in the total sample of all AD(H)D children, but also in the subsample cleared of comorbidities. There was also a deficit in Working Memory, although this result was no longer found in the subsample of AD(H)D children without comorbidities. The profile of the AD(H)D only group was not significantly different from the profile of the clinical control group. The results support the assumption that AD(H)D is associated with deficits in Processing Speed. Working Memory deficits seem to occur only if comorbid disorders are present. PMID- 22532114 TI - IR and IR + UV spectroscopy of isolated [Al-AcPheOMe]n+ cluster cations (n = 1, 3). AB - Singly and triply charged cationic clusters of aluminium and the protected amino acid AcPheOMe are investigated in a supersonic beam by using a combination of a thermic and a laser ablation ion source. For the singly charged species UV- and IR photodissociation spectroscopy is applied. In the case of the triply charged clusters a variant of combined IR + UV spectroscopy is used to obtain information in the NH-stretching region. By comparison with DFT calculations structural assignments are suggested and it turns out that both clusters prefer a helical arrangement with aluminium being aggregated to both carbonyl groups. For the triply charged cluster a globular structure is formed in which aluminium is captured both by the carbonyl groups and the phenyl ring. PMID- 22532115 TI - Zinc sulfate therapy of vocal process granuloma. AB - Vocal process granuloma is a benign lesion that occurs on the arytenoid cartilage. It tends to recur locally, and there is a great diversity of methods to treat it. Here, we reviewed the effects of zinc sulfate therapy program in 16 patients with vocal process granulomas. Eleven patients had a history of trauma or laryngeal intubation and five patients had unknown origin. Eleven had recurrence after one to three failed surgeries, and the others had no prior treatment. Symptoms included hoarseness, sore throat, lump sensation in the throat and cough that apparently improved. The granulomas did not recur for at least 1 year. No complications occurred. For vocal process granuloma, zinc sulfate therapy is good either as an initial or compensatory treatment. PMID- 22532117 TI - Disorder and optical gaps in strained dense amorphous carbon and diamond nanocomposites. AB - We employ empirical tight-binding simulations on strained tetrahedral amorphous carbon and diamond nanocomposite networks. For each applied strain, the optoelectronic properties are monitored through the absorption coefficient and the dielectric function. These lead to the optical gaps and are able to quantify the amount of disorder in the structures. We compare our results to those of unstrained nanostructured diamond and amorphous carbon (a-C) phases and link the degree of disorder in these materials to their structural details as a function of the external load. The atomic rearrangements and distortions imposed by the external strain in these structures are directly observable in their optoelectronic properties. We thoroughly discuss the interplay between increased external strain, structural and topological disorder, atomic rearrangements and their effect on the calculated optoelectronic properties. PMID- 22532116 TI - The role of nuclear receptors in the kidney in obesity and metabolic syndrome. AB - Nuclear receptors are ligand-activated transcriptional regulators of several key aspects of renal physiology and pathophysiology. As such, nuclear receptors control a large variety of metabolic processes, including kidney lipid metabolism, drug clearance, inflammation, fibrosis, cell differentiation, and oxidative stress. Derangement of nuclear receptor regulation, that is, mainly due to obesity may induce metabolic syndrome, may contribute to the pathogenesis and progression of chronic renal disease and may result in end-stage renal disease. This places nuclear receptors at the forefront of novel therapeutic approaches for a broad range of kidney disorders and diseases, including glomerulosclerosis, tubulointerstitial disease, renal lipotoxicity, kidney fibrosis, and hypertension. This review focuses on the importance of the transcription factors peroxisome proliferator-activated receptor alpha, peroxisome proliferator activated receptor beta, peroxisome proliferator-activated receptor gamma, liver X receptors, farnesoid X receptor, and the pregnane X receptor/steroid and xenobiotic receptor (PXR) on the physiology and pathophysiology of renal diseases associated with obesity and metabolic syndrome. PMID- 22532118 TI - Modelling the adsorption of mercury onto natural and aluminium pillared clays. AB - INTRODUCTION: The removal of heavy metals by natural adsorbent has become one of the most attractive solutions for environmental remediation. Natural clay collected from the Late Cretaceous Aleg formation, Tunisia was used as a natural adsorbent for the removal of Hg(II) in aqueous system. METHODS: Physicochemical characterization of the adsorbent was carried out with the aid of various techniques, including chemical analysis, X-ray diffraction, Fourier transform infrared and scanning electron micrograph. Batch sorption technique was selected as an appropriate technique in the current study. Method parameters, including pH, temperature, initial metal concentration and contact time, were varied in order to quantitatively evaluate their effects on Hg(II) adsorption onto the original and pillared clay samples. Adsorption kinetic was studied by fitting the experimental results to the pseudo-first-order and pseudo-second-order kinetic models. The adsorption data were also simulated with Langmuir, Freundlich and Temkin isotherms. RESULTS: Results showed that the natural clay samples are mainly composed of silica, alumina, iron, calcium and magnesium oxides. The sorbents are mainly mesoporous materials with specific surface area of <250 m(2) g(-1). From the adsorption of Hg(II) studies, experimental data demonstrated a high degree of fitness to the pseudo-second-order kinetics with an equilibration time of 240 min. The equilibrium data showed the best model fit to Langmuir model with the maximum adsorption capacities of 9.70 and 49.75 mg g(-1) for the original and aluminium pillared clays, respectively. The maximum adsorption of Hg(II) on the aluminium pillared clay was observed to occur at pH 3.2. The calculated thermodynamic parameters (?G degrees , ?H degrees and ?S degrees ) showed an exothermic adsorption process. The entropy values varied between 60.77 and 117.59 J mol(-1) K(-1), and those of enthalpy ranged from 16.31 to 30.77 kJ mol(-1). The equilibrium parameter (R (L)) indicated that the adsorption of Hg(II) on Tunisian smectitic clays was favourable under the experimental conditions of this study. CONCLUSION: The clay of the Aleg formation, Tunisia was found to be an efficient adsorbent for Hg(II) removal in aqueous systems. PMID- 22532119 TI - Evaluation of environmental impact produced by different economic activities with the global pollution index. AB - INTRODUCTION: The paper analyses the environment pollution state in different case studies of economic activities (i.e. co-generation electric and thermal power production, iron profile manufacturing, cement processing, waste landfilling, and wood furniture manufacturing), evaluating mainly the environmental cumulative impacts (e.g. cumulative impact against the health of the environment and different life forms). MATERIALS AND METHODS: The status of the environment (air, water resources, soil, and noise) is analysed with respect to discharges such as gaseous discharges in the air, final effluents discharged in natural receiving basins or sewerage system, and discharges onto the soil together with the principal pollutants expressed by different environmental indicators corresponding to each specific productive activity. The alternative methodology of global pollution index (I (GP)*) for quantification of environmental impacts is applied. RESULTS AND DISCUSSION: Environmental data analysis permits the identification of potential impact, prediction of significant impact, and evaluation of cumulative impact on a commensurate scale by evaluation scores (ES(i)) for discharge quality, and global effect to the environment pollution state by calculation of the global pollution index (I (GP)*). CONCLUSIONS: The I (GP)* values for each productive unit (i.e. 1.664 2.414) correspond to an 'environment modified by industrial/economic activity within admissible limits, having potential of generating discomfort effects'. The evaluation results are significant in view of future development of each productive unit and sustain the economic production in terms of environment protection with respect to a preventive environment protection scheme and continuous measures of pollution control. PMID- 22532120 TI - Glutathione, glutathione S-transferase, and glutathione conjugates, complementary markers of oxidative stress in aquatic biota. AB - Contaminants are ubiquitous in the environment and their impacts are of increasing concern due to human population expansion and the generation of deleterious effects in aquatic species. Oxidative stress can result from the presence of persistent organic pollutants, metals, pesticides, toxins, pharmaceuticals, and nanomaterials, as well as changes in temperature or oxygen in water, the examined species, with differences in age, sex, or reproductive cycle of an individual. The antioxidant role of glutathione (GSH), accompanied by the formation of its disulfide dimer, GSSG, and metabolites in response to chemical stress, are highlighted in this review along with, to some extent, that of glutathione S-transferase (GST). The available literature concerning the use and analysis of these markers will be discussed, focusing on studies of aquatic organisms. The inclusion of GST within the suite of biomarkers used to assess the effects of xenobiotics is recommended to complement that of lipid peroxidation and mixed function oxygenation. Combining the analysis of GSH, GSSG, and conjugates would be beneficial in pinpointing the role of contaminants within the plethora of causes that could lead to the toxic effects of reactive oxygen species. PMID- 22532122 TI - Heterogeneous reaction of acetic acid on MgO, alpha-Al2O3, and CaCO3 and the effect on the hygroscopic behaviour of these particles. AB - Mixtures of organic compounds with mineral dust are ubiquitous in the atmosphere, whereas the formation pathways and hygroscopic behavior of these mixtures are not well understood. In this study, in situ DRIFTS, XRD, and a vapor sorption analyzer were used to investigate the heterogeneous reaction of acetic acid on alpha-Al(2)O(3), MgO, and CaCO(3) particles under both dry and humid conditions while the effect of reactions on the hygroscopic behavior of these particles was also measured. In all cases, formation of acetate is significantly enhanced in the presence of surface water. However, the reaction extent varied with the mineral phase of these particles. For alpha-Al(2)O(3), the reaction is limited to the surface with the formation of surface coordinated acetate under both dry and humid conditions. For MgO, the bulk of the particle is involved in the reaction and Mg(CH(3)COO)(2) is formed under both dry and humid conditions, although it exhibits a saturation effect under dry conditions. In the case of CaCO(3), acetic acid uptake is limited to the surface under dry conditions while it leads to the decomposition of the bulk of CaCO(3) under humid conditions. While coordinated surface acetate species increased the water adsorption capacity slightly, the formation of bulk acetate promoted the water absorption capacity greatly. This study demonstrated that heterogeneous reaction between CH(3)COOH and mineral dust is not only an important sink for CH(3)COOH, but also has a significant effect on the hygroscopic behavior of mineral dust. PMID- 22532121 TI - Combination of beehive matrices analysis and ant biodiversity to study heavy metal pollution impact in a post-mining area (Sardinia, Italy). AB - Mining activities represent a major source of environment contamination. The aim of this study was to evaluate the use of bees and ants as bioindicators to detect the heavy metal impact in post-mining areas. A biomonitoring programme involving a combination of honeybee hive matrices analysis and ant biodiversity survey was conducted over a 3-year period. The experimental design involved three monitoring stations where repeated sampling activities focused on chemical detection of cadmium (Cd), chrome (Cr) and lead (Pb) from different matrices, both from hosted beehives (foraging bees, honey and pollen) and from the surrounding environment (stream water and soil). At the same time, ant biodiversity (number and abundance of species) was determined through a monitoring programme based on the use of pitfall traps placed in different habitats inside each mining site. The heavy metal content detected in stream water from the control station was always below the analytical limit of quantification. In the case of soil, the content of Cd and Pb from the control was lower than that of mining sites. The mean heavy metal concentrations in beehive matrices from mining sites were mainly higher than the control, and as a result of regression and discriminant analysis, forager bee sampling was an efficient environmental pollution bioindicator. Ant collection and identification highlighted a wide species variety with differences among habitats mostly associated with vegetation features. A lower variability was observed in the polluted landfill characterised by lack of vegetation. Combined biomonitoring with forager bees and ants represents a reliable tool for heavy metal environmental impact studies. PMID- 22532123 TI - Dynamics of monocyte count: a good predictor for timing of peripheral blood stem cell collection. AB - To investigate potential predictive parameters for successful collection of autologous peripheral blood stem cells (PBSC), 60 consecutive first mobilization attempts and 145 leukapheresis procedures for patients with hematologic malignancies (multiple myeloma: n = 20; acute leukemia: n = 27; lymphoma: n = 13) were analyzed. All patients underwent chemotherapy and granulocyte-colony stimulating factor combined mobilization protocols. PBSC collection began when white blood cell (WBC) count rebounded to >1.0 * 10(9)/L. Poor mobilization (PM) was defined as <2.0 * 10(6)/kg of ideal body weight CD34+ cells were collected from at least three leukapheresis procedures. PM incidence was 15% (9/60). On the first apheresis day, CD34+ cell yield was closely associated with the final yield. Failure to reach the first-day target of 0.7 * 10(6) CD34+ cells/kg was perfectly matched with PM. Circulating WBC and monocyte (MO) counts preleukapheresis had a positive correlation with final CD34+ cell yield. For the first-day apheresis target, receiver operator characteristic (ROC) curve analysis showed that MO count had an area under the curve (AUC) of 0.806 (P = 0.004). An optimal predictive cutoff value for MO count was 1.455 * 10(9)/L with both high sensitivity and specificity of 0.739 and 0.899, respectively. Patients who began leukapheresis with an MO count of >=1.455 * 10(9)/L accomplished more successful first-day collections than those of their counterparts (P = 0.021). ROC analysis also showed preapheresis WBC count had a high AUC of 0.768 (P = 0.012). However, we could not find a WBC indicator to initiate leukapheresis. In conclusion, circulating MO count after mobilization is a helpful parameter to determine the optimal time point for starting a PBSC collection. PMID- 22532124 TI - High NIR-purity index single-walled carbon nanotubes for electrochemical sensing in microfluidic chips. AB - Single-walled carbon nanotubes (SWCNTs) should constitute an important natural step towards the improvement of the analytical performance of microfluidic electrochemical sensing. SWCNTs inherently offer lower detection potentials, higher surfaces and better stability than the existing carbon electrodes. However, pristine SWCNTs contain some carbonaceous and metallic impurities that influence their electrochemical performance. Thus, an appropriate processing method is important for obtaining high purity SWCNTs for analytical applications. In this work, a set of 0.1 mg mL(-1) SWCNT dispersions with different degrees of purity and different dispersants (SDBS; pluronic F68 and DMF) was carefully characterized by near infrared (NIR) spectroscopy giving a Purity Index (NIR-PI) ranging from 0.039 to 0.310. The highest purity was obtained when air oxidized SWCNTs were dispersed in SDBS, followed by centrifugation. The SWCNT dispersions were utilized to modify microfluidic chip electrodes for the electrochemical sensing of dopamine and catechol. In comparison with non-SWCNT-based electrodes, the sample with the highest NIR-PI (0.310) exhibited the best analytical performance in terms of improved sensitivity (3-folds higher), very good signal to-noise ratio, high resistance-to-fouling in terms of relative standard deviation (RSD 7%; n = 15), and enhanced resolution (2-folds higher). In addition, very well-defined concentration dependence was also obtained with excellent correlation coefficients (r >= 0.990). Likewise, a good analytical sensitivity, suitable detection limits (LODs) and a very good precision with independence of the concentration assayed (RSDs <= 5%) was achieved. These valuable features indicate the suitability of this material for quantitative analysis. NIR-PI and further TEM and XRD characterization demonstrated that the analytical response was driven and controlled by the high NIR-PI of the SWCNTs used. The significance of this work is the demonstration for the first time of the sensitivity-purity relationship in SWCNT microfluidic chips. A novel and valuable analytical tool for electrochemical sensing has been developed: SWCNTs with high purity and a rich surface chemistry with functional groups, both essential for analytical purposes. Also, this work helps to better understand the analytical potency of SWCNTs coupled to microfluidic chips and it opens new gates for using these unique dispersions in real-world applications. PMID- 22532125 TI - A qualitative analysis of influences on recovery following a first episode of psychosis. AB - BACKGROUND: Understanding perceived influences on recovery following a first episode of psychosis could help improve services. MATERIAL: Thematic analysis was used to examine important influences on early recovery identified by 30 individuals receiving services in an early intervention programme. DISCUSSION: Social support, medication, meaningful activities and lifestyle modification were identified as helpful, and stigma, substance abuse and medication side effects as harmful. Perceptions of benefits of social support and the negative effects of stigma were particularly prominent. CONCLUSIONS: Results suggest the importance of assistance with engagement in valued activities and relationships, and provision of messages of worth and hope for recovery. PMID- 22532126 TI - Reduction of the background magnetic field inhibits ability of Drosophila melanogaster to survive ionizing radiation. AB - The effects of exposure to an environment where the background magnetic field (BMF) has been reduced were studied on wild-type Drosophila melanogaster by measuring its ability to survive a single exposure to ionizing radiation (IR) during its larval stage. The experimental design presented shows a timeframe, IR dose, and BMF parameters that will cause a significant and reproducible reduction of survival on this insect model. These results suggest that BMFs may play a fundamental role in the recovery or harm of a biological system that is exposed to single doses of IR. PMID- 22532127 TI - A population-based study of human papillomavirus genotype prevalence in the United States: baseline measures prior to mass human papillomavirus vaccination. AB - Currently, two prophylactic human papillomavirus (HPV) vaccines targeting HPV 16 and 18 have been shown to be highly efficacious for preventing precursor lesions although the effectiveness of these vaccines in real-world clinical settings must still be determined. Toward this end, an ongoing statewide surveillance program was established in New Mexico to assess all aspects of cervical cancer preventive care. Given that the reduction in cervical cancer incidence is expected to take several decades to manifest, a systematic population-based measurement of HPV type-specific prevalence employing an age- and cytology-stratified sample of 47,617 women attending for cervical screening was conducted prior to widespread HPV vaccination. A well-validated polymerase chain reaction (PCR) method for 37 HPV genotypes was used to test liquid-based cytology specimens. The prevalence for any of the 37 HPV types was 27.3% overall with a maximum of 52% at age of 20 years followed by a rapid decline at older ages. The HPV 16 prevalences in women aged <= 20 years, 21-29 years or >= 30 years were 9.6, 6.5 and 1.8%, respectively. The combined prevalences of HPV 16 and 18 in these age groups were 12.0, 8.3 and 2.4%, respectively. HPV 16 and/or HPV 18 were detected in 54.5% of high-grade squamous intraepithelial (cytologic) lesions (HSIL) and in 25.0% of those with low-grade SIL (LSIL). These baseline data enable estimates of maximum HPV vaccine impact across time and provide critical reference measurements important to assessing clinical benefits and potential harms of HPV vaccination including increases in nonvaccine HPV types (i.e., type replacement). PMID- 22532128 TI - Selective editing of Val and Leu methyl groups in high molecular weight protein NMR. AB - The development of methyl-TROSY approaches and specific (13)C-(1)H labeling of Ile, Leu and Val methyl groups in highly deuterated proteins has made it possible to study high molecular weight proteins, either alone or in complexes, using solution nuclear magnetic resonance (NMR) spectroscopy. Here we present 2 dimensional (2D) and 3-dimensional (3D) NMR experiments designed to achieve complete separation of the methyl resonances of Val and Leu, labeled using the same precursor, alpha-ketoisovalerate or acetolactate. The 2D experiment can further select the methyl resonances of Val or Leu based on the C(alpha) or C(beta) chemical shift values of Val or Leu, respectively. In the 3D spectrum, the methyl cross peaks of Val and Leu residues have opposite signs; thus, not only can the residue types be easily distinguished, but the methyl pairs from the same residue can also be identified. The feasibility of this approach, implemented in both 2D and 3D experiments, has been demonstrated on an 82 kDa protein, malate synthase G. The methods developed in this study will reduce resonance overlaps and also facilitate structure-guided resonance assignments. PMID- 22532129 TI - Hyperthermia synergizes with tissue factor knockdown to suppress the growth and hepatic metastasis of colorectal cancer in orthotopic tumor model. AB - BACKGROUND: Tissue factor (TF) is a significant risk factor for tumor growth and hepatic metastasis in patients with colorectal cancer (CRC). This study aimed to investigate whether hyperthermia has synergistic anti-tumor effects with TF knockdown in suppressing CRC progression and metastasis in vitro and in vivo. METHODS: Human colorectal cancer LOVO cells were treated by hyperthermia at 44 degrees C for 2 hr or/and TF siRNA. Then the cells were subjected to colony formation assay. Apoptosis was analyzed by flow cytometry, confocal microscopy, and transmission electron microscopy. The cell migration and invasion abilities were analyzed by wound healing and matrigel assay. In addition, orthotopic nude mice model of CRC was established. RESULTS: Hyperthermia synergized with TF knockdown to reduce colony formation ability, induce apoptosis, and suppress the migration and invasion of LOVO cells in vitro. Moreover, hyperthermia in combination with TF depletion inhibited the growth and hepatic metastasis of CRC in orthotopic nude mice model. Mechanistically, the synergistic effects were at least partly mediated by inducing JNK mediated apoptosis and suppressing matrix metalloproteinases (MMPs) mediated invasion. CONCLUSIONS: Hyperthermia in combination with TF-targeted therapy could be a potential approach for CRC treatment. PMID- 22532130 TI - Alcohol abuse and glycoconjugate metabolism. AB - The relationship between alcohol consumption and glycoconjugate metabolism is complex and multidimensional. This review summarizes the advances in basic and clinical research on the molecular and cellular events involved in the metabolic effects of alcohol on glycoconjugates (glycoproteins, glycolipids, and proteoglycans). We summarize the action of ethanol, acetaldehyde, reactive oxygen species (ROS), nonoxidative metabolite of alcohol--fatty acid ethyl esters (FAEEs), and the ethanol-water competition mechanism, on glycoconjugate biosynthesis, modification, transport and secretion, as well as on elimination and catabolism processes. As the majority of changes in the cellular metabolism of glycoconjugates are generally ascribed to alterations in synthesis, transport, glycosylation and secretion, the degradation and elimination processes, of which the former occurs also in extracellular matrix, seem to be underappreciated. The pathomechanisms are additionally complicated by the fact that the effect of alcohol intoxication on the glycoconjugate metabolism depends not only on the duration of ethanol exposure, but also demonstrates dose- and regional sensitivity. Further research is needed to bridge the gap in transdisciplinary research and enhance our understanding of alcohol- and glycoconjugate-related diseases. PMID- 22532131 TI - The role of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in the development of esophageal cancer. AB - Esophageal cancer (EC) is one of the most aggressive malignant tumors of the gastrointestinal tract. There are two distinct histological types of EC: esophageal squamous cell carcinoma and adenocarcinoma of the esophagus. Etiologic factors and the patterns of incidence of both subtypes are different. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play an important role in esophageal carcinogenesis. Gellatinases MMP-2 and MMP-9 are able to degrade collagen IV from basement membranes and extracellular matrix which is related to tumor progression, including invasion, metastasis, growth and angiogenesis. It has been shown that increased expression of MMPs plays a crucial role in the development of several human malignancies, including esophageal cancer. The activity of MMPs is regulated by their endogenous natural inhibitors (TIMPs). Among these, the roles of TIMP-1 and TIMP-2 in EC development, tumor progression and formation of metastases have been most extensively characterized and best recognized. PMID- 22532132 TI - Role of cathepsin A and cathepsin C in the regulation of glycosidase activity. AB - Increased tissue activity of cathepsin A and cathepsin C can be observed in many pathological conditions. It is associated with an enhanced degradation of glycosaminoglycans, proteoglycans, and glycoproteins, and results in their decreased tissue content. Cathepsin C releases the glycosidases from complexes formed with cathepsin A, and reinstates their activity. In this review a current state of knowledge is presented concerning the regulation of selected glycosidases activity by cathepsin A (EC 3.4.16.1) and C (EC 3.4.14.1). PMID- 22532133 TI - The anticancer activity of propolis. AB - Propolis and its compounds have been the subject of many studies due to their antimicrobial and antiinflammatory activity; however, it is now known that they also possess antitumor properties. This review aims to summarize the results of studies on the mechanism of activity of propolis and its active compounds such as CAPE and chrysin in the apoptotic process, and their influence on the proliferation of cancer cells. Our review shows that propolis and its presented compounds induce apoptosis pathways in cancer cells. The antiproliferative effects of propolis, CAPE or chrysin in cancer cells are the result of the suppression of complexes of cyclins, as well as cell cycle arrest. The results of in vitro and in vivo studies suggest that propolis, CAPE and chrysin may inhibit tumor cell progression and may be useful as potential chemotherapeutic or chemopreventive anticancer drugs. PMID- 22532134 TI - Postnatal changes in testicular development and androgen receptors immunolocalization in D'Man ram lambs. AB - The purpose of this study was to characterize testicular development in D'Man ram lambs, focusing primarily on androgen receptors (ARs) immunolocalization in the adenohypophysis and testis that is not still known in the D'Man ram lamb. Lambs (n = 12) were divided into four groups (three lambs per group). Adenohypophysis and testis were fixed and paraffin embedded; cross-section (3 MUm) were stained and evaluated with immunohistochemistry. Testis weight increased at a greater rate between two and five months after birth, which was associated with remarkable changes in testicular histology, including significant increases in the diameter of seminiferous tubules. Spermatogenesis started between three and five months after birth; lumen and elongated spermatids were observed for the first time in three and four months-old animals respectively. ARs detected with immunohistochemistry were located in the nuclei and cytoplasm of adenohypophysis cells, and only in nuclei of testis cells (Leydig, Sertoli, peritubular myoid and germ cells). PMID- 22532135 TI - Susceptibility, phenotypes of resistance, and extended-spectrum beta-lactamases in Acinetobacter baumannii strains. AB - Acinetobacter baumannii plays an increasing role in the pathogenesis of infections in humans. The bacilli are frequently isolated from patients treated in intensive care units. A growing resistance to antibiotics is leading to the emergence of strains that are multidrug-resistant and resistant to all available agents. The objective of this study was to assess susceptibility to antibiotics and to determine the presence and current level of the extended-spectrum beta lactamases (ESBLs) and attempt to isolate the Acinetobacter baumannii strain carrying the blaPER gene. A total of 51 strains of A. baumannii identified by phenotypic features were examined. That the strains belonged to the species was confirmed by the presence of the blaOXA-51-like; gene. A broth microdilution method was used for antibacterial susceptibility testing. The occurrence of ESBLs was determined using phenotypic double-disk synergy tests. The PCR technique was used to confirm the presence of the blaPER-1; gene encoding ESBL. The most active antibiotics were meropenem, cefepime and ampicillin/sulbactam, with susceptibility shown by 76.5%, 60.8% and 56.9% of the strains, respectively. The strains exhibited the highest resistance (> 75%) to piperacillin, tetracycline, ciprofloxacin and cefotaxime. Phenotypic tests revealed ESBL mechanism of resistance in approximately 20% of Acinetobacter baumannii isolates. However, the PCR technique did not confirm the presence of the blaPER-1; gene in any of the Acinetobacter baumannii strains examined in our hospital. Acinetobacter baumannii strains demonstrate considerable resistance to many groups of antibiotics. Our findings indicate the involvement of enzymes belonging to families other than PER beta-lactamase in resistance to beta-lactams in A. baumannii. PMID- 22532136 TI - The effect of the juvenile hormone analog, fenoxycarb, on ecdysone receptor B1 expression in the midgut of Bombyx mori during larval-pupal metamorphosis. AB - The Bombyx mori (Lepidoptera: Bombycidae) midgut undergoes remodeling during the larval-pupal metamorphosis. All metamorphic events in insects are controlled by mainly two hormones: 20-hydroxyecdysone (20E) and juvenile hormone (JH). Fenoxycarb, O-ethyl N-(2-(4-phenoxyphenoxy)-ethyl) carbamate, has been shown to be one of the most potent juvenile hormone analogs against a variety of insect species. In this study, the effect of fenoxycarb on EcR-B1 protein expression in the midgut of Bombyx mori during the remodeling processwas investigated. Fenoxycarb was topically treated to the beginning of the fifth instar Bombyx larvae. Its application prolonged the last instar and prevented metamorphic events. Analyses were performed from day 6 of the fifth instar to 24 hr after pupation in controls and to day 14 of the fifth instar in the fenoxycarb treated group. According to our results, the presence of EcR-B1 in the midguts of the fenoxycarb treated group during the feeding period suggested that EcR-B1 was involved in the functioning of larval cells and during this period fenoxycarb did not affect EcR-B1 status. Immediately after termination of the feeding stage, the amount of EcR-B1 protein increased, which indicated that it may strengthen the ecdysone signal for commitment of remodeling process. In the fenoxycarb treated group, its upregulation was delayed, which may be related to the inhibition of ecdysone secretion from the prothoracic gland. PMID- 22532137 TI - Expression of cyclin B1 after induction of senescence and cell death in non-small cell lung carcinoma A549 cells. AB - The purpose of this study was to evaluate the level of mitotic cyclin B1 in the context of senescence and cell death in A549 non-small cell lung carcinoma cells. This was performed through analysis of the cell cycle, the percentage of SA-beta galactosidase-positive, as well as TUNEL-positive cells. Morphological alterations were studied using a transmission electron microscope. Changes in the intracellular level and the presence of cyclin B1 in the nucleus and cytoplasm areas were detected by flow cytometry and confocal fluorescence microscopy, respectively. In the cells exposed to various concentrations of doxorubicin, different kinds of cell death and senescent phenotype were observed. Alterations in the cell cycle and increased polyploidy may be indicative of mitotic catastrophe execution. Changes in cyclin B1 may also be strictly related to its different regulation at mitotic catastrophe and senescence programs. PMID- 22532138 TI - Characteristics of Klebsiella pneumoniae harboring QnrB32, Aac(6')-Ib-cr, GyrA and CTX-M-22 genes. AB - Quinolone resistance in members of the Enterobacteriaceae family is mostly due to mutations in the quinolone resistance-determining regions of topoisomerase genes. CTX-M-22 is a member of the CTX-M family which can reduce extended-spectrum beta lactamase (ESBL) production and modulate antibiotic resistance, resulting in low ceftazidime minimum inhibitory concentrations (MICs). There are four different genes in Klebsiella pneumoniae (KP4707) including qnrB32 (novel qnr allele gene, HQ704413), aac(6')-Ib-cr (novel aac(6')-Ib allele gene, HQ680690), gyrA (novel gyrA allele gene, HQ680691) and CTX-M-22 gene. Five point amino acid mutations Arn(N)27 -> Leu(L), Val(V)129 -> Ala(A), Iie(I)142 -> Met(M), Gly(G)188 -> Arg(R), Val(V)212 -> Iie(I) were observed in the qnr32 gene when compared to qnrB1. Of all qnrB alleles, a novel variant of the qnrB32 gene, with qnrB31, had the highest amino acid homology. Three point amino acid mutations including Trp(W)105 -> Arg(R), Asp(D)182 -> Tyr(Y) and Val(V)201 -> Asp(D) were observed in aac(6')-Ib-cr gene, when compared to GenBank number AF479774. New variants of qnr32, aac(6')-Ib-cr, gyrA and CTX-M-22 or other genotype determinants continuously appear in different genomic sites and also outside the Enterobacteriaceae family. PMID- 22532139 TI - Evaluation of CD40, its ligand CD40L and Bcl-2 in psoriatic patients. AB - Psoriasis is a chronic, recurrent, inflammatory disease. Recent investigations indicate an autoimmune pathogenesis of the disease. Apoptosis plays an important role in the regulation of immune mechanisms in many autoimmune diseases. Although CD40, CD40L, and Bcl-2 have already been studied in psoriatic skin lesions, little is known about their circulating forms. The aim of the present study was to evaluate the serum concentrations of Bcl-2, soluble CD40 and CD40L in psoriatic patients. The study was performed using ELISA kits in 39 psoriatic patients before treatment and after two weeks of topical ointment. Data was analyzed with respect to severity of psoriasis, duration of the disease, and coexisting psoriatic arthritis. Our results revealed that serum concentrations of soluble CD40 and CD40L before and after treatment were significantly higher (p < 0.01 and p < 0.001) in patients with psoriasis compared to the control group. Topical treatment of psoriatic lesions with dithranol ointment failed to decrease serum of CD40 and CD40L, which has not been described until now. There was no significant difference in serum Bcl-2 concentration between the compared groups. We did not find significant differences in serum concentrations of Bcl-2, CD40 or CD40L between patients with mild or severe psoriasis, nor any correlation between disease duration and the presence of psoriatic arthritis symptoms. Our data indicates upregulation of the CD40/CD40L system in psoriatic patients despite topical treatment and suggests their possible role in the pathogenesis of psoriasis. PMID- 22532140 TI - Predictive value of ERCC1 single-nucleotide polymorphism in patients receiving platinum-based chemotherapy for locally-advanced and advanced non-small cell lung cancer--a pilot study. AB - Platinum-based chemotherapy is the main type of I-line treatment of advanced and non-operative NSCLC patients without EGFR gene mutation. The excision repair cross-complementation group 1 (ERCC1) is an enzyme that executes the incision of the damaged DNA strand and removes platinum-induced DNA adducts. We investigated whether ERCC1 gene polymorphism has an effect on the response to chemotherapy and survival in 43 patients with NSCLC treated with platinum-based chemotherapy. ERCC1 19007 T>C SNPs were assessed using a PCR-RFLP methods in DNA isolated from peripheral blood lymphocytes. Disease control occurred significantly (p = 0.045) more frequently in patients with CC or CT genotype compared to patients with TT genotype. Median PFS and OS for CC homozygous were 4 and 10.5 months, 4 and 12.5 months for CT heterozygous, but only 0.3 and 1.5 months for TT homozygous patients, respectively. The probability of PFS was significantly higher (HR = 0.438, 95% CI: 0.084-0.881, p = 0.03) and probability of OS was insignificantlyhigher (HR = 0.503, 95% CI: 0.129-1.137, p = 0.084) in patients with CC or CT genotype than in patients with TT genotype. Uncommon TT genotype of ERCC1 19007 T>C polymorphism could predict poor response and shortening of progression free survival in NSCLC patients treated with platinum-based I-line chemotherapy. The analysis of this polymorphism may serve as a promising tool in the qualification of advanced NSCLC patients for appropriate chemotherapy. PMID- 22532141 TI - Morphological, histochemical and immunohistochemical studies of polar fox kidney. AB - The aim of the present study was to evaluate the morphology and intermediate filaments cytokeratin, desmin and vimentin expression in the kidneys of the polar fox (Alopex lagopus). Routine morphological, histochemical and immunohistochemical techniques of examinations of the kidneys of adult male and female polar foxes were used. We found different localizations and different levels of immunoexpression of cytokeratin in epithelia of calyxes, distal tubules and Henle's loops, and also in endothelial cells. We also noted immunolocalization and immunoexpression of vimentin in mesangial cells, interstitial tissue and distal tubules. Desmin reactivity was revealed for muscle cells of arteries and mesangial cells. Our study is the first attempt to localize cytoskeletal intermediate filaments performed on polar fox kidneys. It is worth noting that our observations concerning the distribution of vimentin in the polar fox kidney may suggest that protein as being useful as a marker of distal tubules in the polar fox kidney. PMID- 22532142 TI - Tubular NF-κB is overexpressed in proteinuric patients with IgA nephropathy. AB - Increasing evidence suggests that nuclear factor kappaB (NF-kappaB) plays a pivotal role in many glomerulopathies. Therefore, the aim of the present study was to determine the tubular immunoexpression of NF-kappaB in non-proteinuric (n = 22) and proteinuric patients (n = 16) with IgA nephropathy (IgAN). Another purpose of this study was to examine the possible relationship between NF-kappaB immunoexpression and proteinuria, interstitial fibrosis as well as interstitial infiltrates. Tubular immunoexpression of NF-kappaB, interstitial monocytes/macrophages, T lymphocytes, B lymphocytes and interstitial area were determined using a computer image analysis system. The mean values of the tubular immunoexpression of NF-kappaB, interstitial area and interstitial monocytes/macrophages were in proteinuric IgAN patients significantly increased compared to non-proteinuric IgAN cases, whereas interstitial T and B lymphocytes did not differ between these groups. In proteinuric patients, tubular immunoexpression of NF-kappaB was highly significantly positively correlated with the degree of proteinuria. Moreover, in both the non-proteinuric and the proteinuric groups with IgAN, tubular immunoexpression of NF-kappaB was positively correlated with the interstitial area and interstitial monocytes/macrophages. Our findings raise the possibility that proteinuria causes tubular overexpression of NF-kappaB and, in the process, recruitment of monocytes/macrophages and tubulointerstitial injury in IgAN patients. PMID- 22532143 TI - Atrial expression of the CCN1 and CCN2 proteins in chronic heart failure. AB - Previous studies have reported the upregulation of CCN proteins early after acute heart injury. The aim of the present work was to evaluate the expression of the CCN1 and CCN2 proteins and their regulation by angiotensin II in the atrial myocardium of a chronically failing heart. Male adult mice were subjected to ligation of the left coronary artery to produce myocardial infarction (the MI group), and 16 of them were treated for 12 weeks with the AT1 receptor antagonist telmisartan (the MI-Tel group). Sham-operated mice served as controls. The expression of proteins was evaluated by immunohistochemistry 12 weeks after the operation. In shamoperated mice, stainings for CCN1 and CCN2 proteins were positive within atrial cardiomyocytes. CCN1-positive reaction revealed diffused cytoplasmic localization, while CCN2 was present mainly within the perinuclear cytoplasm. CCN1 was upregulated in the MI group, while CCN2 remained at basal level. Telmisartan prevented the upregulation of CCN1 and decreased CCN2 level. We compared the experimental data with the expression of CCN1 and CCN2 proteins in human right atrial appendages. We found an inverse, but not significant, relation between the level of either protein and the left ventricular ejection fraction. This suggests a similar atrial regulation of CCN1 and CCN2 expression also in humans. We conclude that in the murine atria, CCN1 and CCN2 proteins are expressed constitutively. In chronic heart failure, CCN proteins tend to be upregulated, which may be related to the action of angiotensin II. PMID- 22532144 TI - Cytological response of palatal epithelium to TiN-coated CoCr alloy denture. AB - The aim of this study was to assess the impact of titanium nitride coatings on CoCr alloy metal parts in framework dentures on human palatal epithelium cytology compared to framework dentures made with the same alloy but without titanium nitride coating, and to acrylic dentures. Every prosthetic restoration introduced into the oral cavity and remaining in direct contact with the palate exhibits a varied and harmful effect on the state of the palatal epithelium by disturbing its keratinization. CoCr alloy dentures produce a significantly greater perturbation of keratinization compared to acrylic dentures. There is no evidence showing that a titanium nitride coating of the CoCr alloy plays a protective role in the environment of the oral cavity. PMID- 22532145 TI - Effects of CP 55,940--agonist of CB1 cannabinoid receptors on ghrelin and somatostatin producing cells in the rat pancreas. AB - Cannabinoids participate in the modulation of numerous functions in the human organism, increasing the sense of hunger, affecting carbohydrate and lipid metabolism, and controlling systemic energy balance mechanisms. Moreover, they influence the endocrine system functions, acting via two types of receptors, CB1 and CB2. The aim of the present study was to examine the number, distribution and activity of ghrelin and somatostatin producing endocrine cells in the pancreas of rats after a single administration of selective CP 55,940 agonist of CB1 receptor. The study was performed on 20 rats. Neuroendocrine cells were identified by immunohistochemical reactions, involving specific antibodies against ghrelin and somatostatin. The distribution and number of ghrelin- and somatostatin-immunoreactive cells were separately studied in five pancreas islets of each section. A performed analysis showed a decreased number of somatostatin immunoreactive cells and a weak immunoreactivity of ghrelin and somatostatin containing neuroendocrine cells in the pancreatic islets of experimental rats, compared to control animals. The obtained results suggest that a single administration of a selective CP 55,940 agonist of CB1 receptor influences the immunoreactivity of endocrine cells with ghrelin and somatostatin expression in the pancreas islets. PMID- 22532146 TI - Increased apoptotic activity on inflammatory human placentas in spontaneous abortions during the first and second trimester of gestation: a histochemical and immunohistochemical study. AB - The aim of this study was to investigate the role of apoptotic markers on inflammatory human placentas from spontaneous abortions during the first and second trimester of gestation and compare them to those without inflammation. Paraffin-embedded specimens from 76 placentas were investigated by conventional histology and immunohistochemistry using monoclonal antibodies against M30, Caspase 3, Caspase 8 and Caspase 9, as well as the terminal deoxynucleotidyl tranferase-mediated deoxyuridine triphosphate nick end labeling method. A higher prevalence of expression of apoptotic markers (94.4%) was observed in placentas associated with chorioamnionitis in comparison with those without inflammation. Our observations confirm that apoptosis is strikingly prevalent in placentas diagnosed with histologic chorioamnionitis, while the inflammation induces cell death. PMID- 22532147 TI - Discrepancy between clinical and histological effects of DHA supplementation in a rat model of pouchitis. AB - Docosahexaenoic acid (DHA) potentially modulates inflammatory processes. Therefore, the aim of this study was to determine the influence of DHA supplementation on the expression of intestinal inflammation and nutritional status in rats which have undergone restorative proctocolectomy. Twenty-four Wistar rats were operated. After the induction of pouchitis, animals were randomly divided into a control group (CG) and supplementation groups receiving respectively a semi-synthetic diet without or with DHA (in a lower or higher dose, respectively known as the lower dose, LD, and higher dose, HD, groups) for six weeks. Selected nutritional parameters were assessed. Histopathological and immunohistochemical analysis of pouch mucosa specimens was also performed. The effectiveness of feeding and quality of stools were significantly better in the HD group than in the CG. The intensity of inflammation (Moskovitz scale) was higher in HD and LD than in CG (p = 0.03 and p = 0.0006, respectively). Nevertheless, pouch adaptation (Laumonier scale) was more significant in LD than in CG (p = 0.007). On the other hand, tissue expression of IL-1alpha and IL-10 was higher in HD and LD than in CG (IL-1alpha, p = 0.009 and p = 0.05, respectively; IL-10, p = 0.04 for both). DHA supplementation has no impact on body weight gain. Yet it seems that it may improve the effectiveness of nutrition and stool quality in rats which have undergone restorative proctocolectomy. Simultaneously, it increases the intensity of pouch adaptation and inflammation. The specificity of observed changes is not clear. However, it may imply potential modulation of inflammatory processes of pouch mucosa. PMID- 22532148 TI - Surface Plasmon Resonance Imaging biosensor for cystatin determination based on the application of bromelain, ficin and chymopapain. AB - A Surface Plasmon Resonance Imaging (SPRI) sensor based on bromelain or chymopapain or ficin has been developed for specific cystatin determination. Cystatin was captured from a solution by immobilized bromelain or chymopapain or ficin due to the formation of an enzyme-inhibitor complex on the biosensor surface. The influence of bromelain, chymopapain or ficin concentration, as well as the pH of the interaction on the SPRI signal, was investigated and optimized. Sensor dynamic response range is between 0-0.6 MUg/ml and the detection limit is equal to 0.1 MUg/ml. In order to demonstrate the sensor potential, cystatin was determined in blood plasma, urine and saliva, showing good agreement with the data reported in the literature. PMID- 22532149 TI - Increased apoptosis in human knee osteoarthritis cartilage related to the expression of protein kinase B and protein kinase Cα in chondrocytes. AB - Protein kinase B (Akt) and protein kinase Calpha (PKCalpha) play important roles in the regulation of cell apoptosis. The aim of this study was to investigate the expression of Akt and PKCa in chondrocytes of human knee osteoarthritic (OA) cartilage, further evaluating their role in chondrocyte apoptosis during OA progression. Human knee OA cartilages were obtained from 38 patients undergoing knee arthroplasty, which is the medium-late stage of OA. Healthy knee cartilages were obtained from 11 amputees. The samples taken from the condyle of femur were collected routinely for morphological, immunohistochemical and Western blot detection, respectively. Light microscopy and laser-scanning confocal microscopy were used for morphological observation. The optical density with computer image analysis evaluated the intensity of immunohistochemical reaction of Akt and PKCalpha in OA cartilage. Western blot detected the protein expression levels. The results indicated that Akt and PKCa were involved in OA progression, along with the increase of cell apoptosis. In OA cartilage, Akt decreased (p < 0.05) and PKCalpha increased (p < 0.05). There was a negative correlation and interaction between Akt and PKCalpha (r = -0.8). These results demonstrated that both Akt and PKCalpha are related to increased chondrocyte apoptosis in human OA cartilage. The correlation between human OA progression, the role of Akt and PKCalpha, and chondrocyte apoptosis allows for new therapeutic strategies to be considered. PMID- 22532150 TI - Mouse gastrocnemius muscle regeneration after mechanical or cardiotoxin injury. AB - The goal of our study was to compare the skeletal muscle regeneration induced by two types of injury: either crushing, that causes muscle degeneration as a result of mechanical devastation of myofibers, or the injection of a cardiotoxin that is a myotoxic agent causing myolysis of myofibers leading to muscle degeneration. Regenerating muscles were analyzed at selected intervals, until the 14th day following the injury. We analyzed their weight and morphology. We also studied the expression of different myosin heavy chain isoforms as a molecular marker of the regeneration progress. Histological analysis revealed that inflammatory response and myotube formation in crushed muscles was delayed compared to cardiotoxin-injected ones. Moreover, the expression of myosin heavy chain isoforms was observed earlier in cardiotoxin-injured versus crushed muscles. We conclude that the dynamics of skeletal muscle regeneration depends on the method of injury. PMID- 22532151 TI - Handling the limit of detection by extrapolation. AB - A general method of estimation with a variable observed subject to a limit of detection is introduced. It is based on extrapolation of the estimates obtained by increasing the limit of detection. Theoretical arguments support the method in some special cases, and it is explored by simulations. Several examples are presented and adaptations for other kinds of censoring explored. PMID- 22532153 TI - Criterion validity of the neuropsychological assessment battery after traumatic brain injury. AB - The performance of 54 patients with complicated mild-severe traumatic brain injury (TBI) was evaluated on the Attention, Executive Functions, and Memory modules of the Neuropsychological Assessment Battery (NAB) and compared with that of 54 demographically matched healthy controls. All three NAB indices demonstrated statistically significant group differences and negative covariances with the duration of coma, with large effect sizes. The Numbers and Letters and Mazes subtests had the most consistent evidence for sensitivity to brain injury. The findings provide preliminary support for the criterion validity of the NAB in the assessment of patients with complicated mild-severe TBI. PMID- 22532152 TI - Degradation of zopiclone during storage of spiked and authentic whole blood and matching dried blood spots. AB - Z-drugs such as zopiclone are increasingly involved in forensic cases. Its degradation occurs in solvents and biological fluids. It is assumed that hydrolysis largely accounts for the breakdown of zopiclone in aqueous media. Therefore, a stability study in blood at different storage conditions (-20, 4, 20, and 40 degrees C) was performed to establish changes of the drug's concentration with time, also including its degradation product 2-amino-5 chloropyridine (ACP). As removal of the aqueous phase may stabilize molecules that are prone to hydrolysis, it was assessed whether the use of dried blood spots (DBS) may be an alternative for storing and analyzing zopiclone and ACP. Spiked and authentic blood samples and corresponding DBS were analyzed using fully validated LC-MS/MS assays. There was agreement between the measurement of zopiclone from either blood or matching DBS in freshly prepared samples. Results showed that zopiclone was unstable in blood at all storage temperatures except at -20 degrees C. Stability of zopiclone in spiked and authentic blood was increased in DBS compared to matching blood samples stored at the same condition. About 85 % of the initial concentration of zopiclone was still intact in DBS on day 8 at 20 degrees C. ACP was formed from zopiclone in equimolar amounts in both media. Therefore, determination of both zopiclone and ACP may be helpful to estimate the initial concentration in both media. Pre-analytical conditions have a major impact on the recovery of zopiclone from blood. With respect to its known advantages, DBS can be recommended as a valuable alternative for the determination of zopiclone from blood. PMID- 22532154 TI - Is serum C-reactive protein a reliable predictor of abdomino-pelvic CT findings in the clinical setting of the non-traumatic acute abdomen? AB - The aim of this study was to determine if serum C-reactive protein (CRP), an acute phase reactant which exhibits a rapid rise in serum in inflammatory conditions, is a reliable predictor of abdomino-pelvic CT findings in the clinical setting of the non-traumatic acute abdomen. All patients presenting with symptoms of acute abdominal pain to a level-1 emergency department over a 12 month period were included. Patients with serum CRP measured on admission and within 24 h of the abdomino-pelvic CT scan were subselected and those with a history of recent surgery, malignancy, and inflammatory bowel disease were excluded (n = 241). CT findings were graded in consensus by two radiologists and visceral adipose volume and severity of adipose stranding were also assessed. Statistical analysis was performed using SPSS v17. Positive imaging findings were evident on 176 CTs (73 %). There were equal numbers of positive and negative CT scans in patients with low serum level of CRP (0-5 mg/L). As CRP level increased the proportion of positive CTs increased (p < 0.001, Chi-square test for trend). The likelihood ratio for positive CT findings in patients with a CRP level greater than 130 mg/L was 3.45 with reported specificity and sensitivity of 90.9 and 31.4 %, respectively. A low CRP level (0-5 mg/L) does not out rule positive findings on CT in the clinical setting of the acute abdomen. Increasing levels of CRP predict, with increasing likelihood, positive findings on CT. PMID- 22532155 TI - Musculoskeletal: what's different in children? Stubbed toe; pain for 2 days. PMID- 22532157 TI - Coexistence of spin glass and antiferromagnetic orders in Ba3Fe2.15W0.85O8.72. AB - Ba(3)Fe(2.15)W(0.85)O(8.72) has been grown as large single crystals using the floating-zone method, permitting very precise characterization of the nuclear and magnetic structures by neutron and synchrotron diffraction methods. The results of our structural investigation are combined with dc and ac magnetization and heat capacity measurements to give an unusually complete and detailed picture of a complex magnetic system. The compound crystallizes in the hexagonal perovskite structure (space group P6(3)/mmc) and reveals antiferromagnetic order below T(N) = 290 K. Frequency-dependent ac susceptibility and the presence of magnetic viscosity suggest the onset of a spin glass component in this material below T(f) = 60 K. These findings are discussed on the basis of detailed analysis of the crystalo-chemical properties, supported by ab initio (density functional theory) calculations. PMID- 22532156 TI - The immunobiology of colitis and cholangitis in interleukin-23p19 and interleukin 17A deleted dominant negative form of transforming growth factor beta receptor type II mice. AB - Dominant negative form of transforming growth factor beta receptor type II (dnTGFbetaRII) mice, expressing a dominant negative form of TGFbeta receptor II under control of the CD4 promoter, develop autoimmune colitis and cholangitis. Deficiency in interleukin (IL)-12p40 lead to a marked diminution of inflammation in both the colon and the liver. To distinguish whether IL-12p40 mediates protection by the IL-12 or IL-23 pathways, we generated an IL-23p19(-/-) dnTGFbetaRII strain deficient in IL-23, but not in IL-12; mice were longitudinally followed for changes in the natural history of disease and immune responses. Interestingly, IL-23p19(-/-) mice demonstrate dramatic improvement in their colitis, but no changes in biliary pathology; mice also manifest reduced T helper (Th)17 cell populations and unchanged IFN-gamma levels. We submit that the IL-12/Th1 pathway is essential for biliary disease pathogenesis, whereas the IL 23/Th17 pathway mediates colitis. To further assess the mechanism of the IL-23 mediated protection from colitis, we generated an IL-17A(-/-) dnTGFbetaRII strain deficient in IL-17, a major effector cytokine produced by IL-23-dependent Th17 cells. Deletion of the IL-17A gene did not affect the severity of either cholangitis or colitis, suggesting that the IL-23/Th17 pathway contributes to colon disease in an IL-17-independent manner. These results affirm that the IL 12/Th1 pathway is critical to biliary pathology in dnTGFbetaRII mice, whereas colitis is caused by a direct effect of IL-23. PMID- 22532158 TI - Plasma exchange and immunoadsorption effectively remove antiphospholipid antibodies in pregnant patients with antiphospholipid syndrome. AB - Conventional therapy with aspirin and/or heparin is at times incapable of preventing complications in high risk pregnancies of patients with antiphospholipid syndrome (APS). In those cases, a so-called second-line treatment protocol is used in addition to conventional therapy strategies. This manuscript is a report on three APS pregnant patients who were successfully treated with plasma exchange (PE) (two cases) or with immunoadsorption (IA) (one case) as a second-line treatment strategy. The efficacy of these procedures in removing anticardiolipin (aCL) and anti-beta(2)glycoprotein I (abeta(2)GPI) antibodies from blood was evaluated. Serum samples were collected before and after 87 apheretic treatment sessions. Serum IgG/M aCL and IgG/M abeta(2)GPI antibodies were determined using an "in-house" enzyme-linked immunosorbent assay and showed that all three patients had medium/high IgG aCL and abeta(2)GPI titers. All three women had a successful pregnancy. A significant decrease in IgG aCL (P = 0.0001) and abeta(2)GPI (P = 0.0001) antibody titers was observed after PE and IA sessions. There was moreover a significant, steady fall in serum IgG aCL pretreatment levels during the course of all three pregnancies (P = 0.0001, P = 0.0001, P = 0.001). The fall in IgG abeta(2)GPI was significant in two of the patients (P = 0.0001, P = 0.0001) both with high antibody titers, but not in one with medium antibody titers, who was treated with PE (P = 0.17). PMID- 22532159 TI - Pioglitazone therapy in progressive differentiated thyroid carcinoma. AB - AIM: Rosiglitazone achieved promising results in progressive differentiated thyroid carcinoma (DTC) with redifferentiative and antiproliferative effects, but has been taken off the market. Thus we evaluated another glitazone, pioglitazone, expecting similar positive results. PATIENT, MATERIALS, METHODS: Five patients with progressive DTC and no or only negligible iodine uptake were enrolled. Oral pioglitazone treatment was applied for 6 months. The re-differentiative effect was assessed by 124I-NaI PET/CT dosimetry and the anti-proliferative effect by 18F-FDG PET/CT imaging. RESULTS: A redifferentiative effect of pioglitazone could not be shown. Lesion dosimetry indicated that 3/5 patients had unchanged no lesion absorbed dose per administered activity (LDpA) in any tumour lesion, 2/5 patients had a deterioration of LDpA within some lesions, thus radioiodine therapy was not performed in any patient. Volumetric analysis, using RECIST criteria, revealed progressive disease in 3/5 patients and stable disease in 2/5 patients. Metabolic changes, using EORTC criteria, revealed 3/5 patients with progressive metabolic disease, 1/5 patient with stable metabolic disease and 1/5 patients with partial metabolic response. The medication was well-tolerated, and no patient developed clinically important toxicity associated with the treatment. CONCLUSION: Pioglitazone revealed some positive effects in radioiodine negative and progressive DTC patients but it did not fulfill the expectations given by the results of rosiglitazone therapy. PMID- 22532160 TI - Preparation of supramolecular chromophoric assemblies using a DNA duplex. AB - Organization of supramolecular assemblies of chromophores with precisely controlled orientation and sequence remains challenging. Nucleic acids with complementary base sequences spontaneously form double-helical structures. Therefore, covalent attachment of chromophores to DNA or RNA can be used to control assembly and orientation of chromophores. In this perspective, we first review our recent work on the assemblies of fluorophores (pyrene and perylene) by using natural base pairs. The interaction between dyes can be strictly controlled by means of cluster and interstrand wedge motifs. We then discuss novel artificial base pairs that can suppress the interaction between fluorophores and nucleobases. We incorporated a cyclohexane moiety into DNA, and showed that these artificial base pairs suppressed the electron-hole transfer between fluorophores and nucleobases and enhanced the quantum yields of fluorophores. These base pairs can potentially be used to accumulate fluorophores inside DNA duplexes without decreasing quantum yields. PMID- 22532161 TI - Possible clinical cure of metastatic breast cancer: lessons from our 30-year experience with oligometastatic breast cancer patients and literature review. AB - BACKGROUND: Metastatic breast cancer (MBC) is generally incurable. However, 10-20 year relapse-free survival of MBC is approximately 2%, implying that at least a small subset of MBC patients achieve prolonged survival. We therefore analyzed long-term outcome in a particular subset, i.e., oligometastatic breast cancer (OMBC). METHODS: Data of OMBC subjects (N = 75) treated in our institution from April 1980 to March 2010 were retrospectively analyzed. OMBC was identified as: one or 2 organs involved with metastatic lesions (excluding the primary lesion resectable by surgery), fewer than 5 lesions per metastasized organ, and lesion diameter less than 5 cm. Patients were generally treated with systemic chemotherapy first, and those who achieved complete response (CR) or partial response (PR) were further treated, if applicable, with local therapy (surgical or radiation therapy) to maintain CR or to induce no evidence of clinical disease (NED), with additional systemic therapy. RESULTS: Median follow-up duration was 103 (6-329) months. Single or 2 organs were involved in, respectively, 44 (59%) and 31 (41%) cases with metastatic lesions, 48% of which were visceral. In cases where effects of systemic therapy, possibly in combination with other treatments, were evaluated (N = 68), CR or PR was achieved in 33 (48.5%) or 32 (47.1%), respectively, with overall response rate (ORR: CR + PR) of 95.6% (N = 65). In cases receiving multidisciplinary treatment (N = 75), CR or NED (CR/NED), or PR was induced in 48 (64.0%) or 23 (30.7%) cases, respectively, with ORR (CR/NED + PR) of 94.7% (N = 71). CR rates (60.5%) with systemic therapy and CR/NED rates (79.5%) with multidisciplinary treatment were significantly better in subjects with a single involved organ than in those with two involved organs (P = 0.047 and 0.002, systemic only or multidisciplinary treatments, respectively). Medians estimated by Kaplan-Meier method were: overall survival (OS) of 185.0 months and relapse-free interval (RFI) of 48.0 months. Estimated outcomes were: OS rates (OSR) of 59.2% at 10 years and 34.1% at 20 years, and relapse-free rates (RFR) of 27.4% at 10 years and 20 years. No disease progression was observed after 101.0 months as RFR. Cases with single organ involvement (N = 44) showed significantly better outcomes (OSR of 73% at 10 years and 52% at 20 years, RFR of 42% at 10 years and 20 years). Those who received local therapies (N = 35) also showed better prognosis: OSR of 82% at 10 years and 53% at 20 years, RFR of 38% at 10 years and 20 years. Three cases (4%) survived for their lifetime without relapse after achieving CR or NED, our definition of clinical cure. Multivariate analysis revealed factors favoring better prognosis as: none for OS, and single organ involvement with metastasis, administration of local treatment, and shorter disease-free interval (DFI) (P = 0.030, 0.039, and 0.042, respectively) for RFR. Outcomes in OMBC in literature were OSR of 35-73% at 10 years and 26-52% at 20 years, and RFR of 27-42% at 10 years and 26-42% at 20 years. CONCLUSIONS: The present analyses clearly indicate that OMBC is a distinct subgroup with long-term prognosis superior to MBC, with reasonable provability for clinical cure. Further prospective studies to better characterize OMBC are warranted to improve prognosis in MBC. PMID- 22532162 TI - Quantitative color analysis for capillaroscopy image segmentation. AB - This communication introduces a novel approach for quantitatively evaluating the role of color space decomposition in digital nailfold capillaroscopy analysis. It is clinically recognized that any alterations of the capillary pattern, at the periungual skin region, are directly related to dermatologic and rheumatic diseases. The proposed algorithm for the segmentation of digital capillaroscopy images is optimized with respect to the choice of the color space and the contrast variation. Since the color space is a critical factor for segmenting low contrast images, an exhaustive comparison between different color channels is conducted and a novel color channel combination is presented. Results from images of 15 healthy subjects are compared with annotated data, i.e. selected images approved by clinicians. By comparison, a set of figures of merit, which highlights the algorithm capability to correctly segment capillaries, their shape and their number, is extracted. Experimental tests depict that the optimized procedure for capillaries segmentation, based on a novel color channel combination, presents values of average accuracy higher than 0.8, and extracts capillaries whose shape and granularity are acceptable. The obtained results are particularly encouraging for future developments on the classification of capillary patterns with respect to dermatologic and rheumatic diseases. PMID- 22532164 TI - Increased primary motor cortical excitability by a single-pulse transcranial magnetic stimulation over the supplementary motor area. AB - The supplementary motor area (SMA) is a secondary motor area that is involved in various complex hand movements. In animal studies, short latency and probably direct excitatory inputs from SMA to the primary motor cortex (M1) have been established. Although human imaging studies revealed functional connectivity between SMA and M1, its electrophysiological nature has been less studied. This study explored the connection between SMA and M1 in humans using a single-pulse transcranial magnetic stimulation (TMS) over SMA. First, TMS over SMA did not alter the corticospinal tract excitability measured by the size of motor evoked potential elicited by single-pulse TMS over M1. Next, we measured short-interval intracortical facilitation (SICF), which reflects the function of a facilitatory circuit within M1, with or without a single-pulse TMS over SMA. When the intensity of the second pulse in the SICF paradigm (S2) was as weak as 1.0 active motor threshold for a hand muscle, SMA stimulation significantly enhanced the SICF. Furthermore, this enhancement by SMA stimulation was spatially confined and had a limited time window. On the other hand, SMA stimulation did not alter short interval intracortical inhibition or contralateral silent period duration, which reflects the function of an inhibitory circuit mediated by gamma-aminobutyric acid A (GABA(A)) or GABA(B) receptors, respectively. We conclude that a single pulse TMS over SMA modulates a facilitatory circuit within M1. PMID- 22532165 TI - Modulating behavioral inhibition by tDCS combined with cognitive training. AB - Cognitive training is an effective tool to improve a variety of cognitive functions, and a small number of studies have now shown that brain stimulation accompanying these training protocols can enhance their effects. In the domain of behavioral inhibition, little is known about how training can affect this skill. As for transcranial direct current stimulation (tDCS), it was previously found that stimulation over the right inferior frontal gyrus (rIFG) facilitates behavioral inhibition performance and modulates its electrophysiological correlates. This study aimed to investigate this behavioral facilitation in the context of a learning paradigm by giving tDCS over rIFG repetitively over four consecutive days of training on a behavioral inhibition task (stop signal task (SST)). Twenty-two participants took part; ten participants were assigned to receive anodal tDCS (1.5 mA, 15 min), 12 were assigned to receive training but not active stimulation. There was a significant effect of training on learning and performance in the SST, and the integration of the training and rIFG-tDCS produced a more linear learning slope. Better performance was also found in the active stimulation group. Our findings show that tDCS-combined cognitive training is an effective tool for improving the ability to inhibit responses. The current study could constitute a step toward the use of tDCS and cognitive training as a therapeutic tool for cognitive control impairments in conditions such as attention-deficit hyperactivity disorder (ADHD) or schizophrenia. PMID- 22532166 TI - Stat3 activation in urothelial stem cells leads to direct progression to invasive bladder cancer. AB - Two subtypes of human bladder cancer, noninvasive papillary and muscle-invasive cancer, develop through independent pathologic and molecular pathways. Human invasive bladder cancer frequently develops without prior clinical evidence of a noninvasive tumor stage. However, an animal model that recapitulates this unique clinical progression of invasive bladder cancer has not yet been developed. In this study, we created a novel transgenic mouse model of invasive bladder cancer by targeting an active dimerized form of Stat3 to the basal cells of bladder epithelium. When exposed to the carcinogen nitrosamine, Stat3-transgenic mice developed invasive cancer directly from carcinoma in situ (CIS), bypassing the noninvasive papillary tumor stage. Remarkably, invasive bladder cancer driven by active Stat3 was predominantly composed of stem cells, which were characterized by cytokeratin 14 (CK14) staining and enhanced tumor sphere-forming ability. Active Stat3 was also shown to localize to the nucleus of human invasive bladder cancers that were primarily composed of CK14+ stem cells. Together, our findings show that Stat3-induced stem cell expansion plays a critical role in the unique clinical progression of invasive bladder cancer through the CIS pathway. PMID- 22532167 TI - An NQO1 substrate with potent antitumor activity that selectively kills by PARP1 induced programmed necrosis. AB - Agents, such as beta-lapachone, that target the redox enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1), to induce programmed necrosis in solid tumors have shown great promise, but more potent tumor-selective compounds are needed. Here, we report that deoxynyboquinone kills a wide spectrum of cancer cells in an NQO1 dependent manner with greater potency than beta-lapachone. Deoxynyboquinone lethality relies on NQO1-dependent futile redox cycling that consumes oxygen and generates extensive reactive oxygen species (ROS). Elevated ROS levels cause extensive DNA lesions, PARP1 hyperactivation, and severe NAD+ /ATP depletion that stimulate Ca2+ -dependent programmed necrosis, unique to this new class of NQO1 "bioactivated" drugs. Short-term exposure of NQO1+ cells to deoxynyboquinone was sufficient to trigger cell death, although genetically matched NQO1- cells were unaffected. Moreover, siRNA-mediated NQO1 or PARP1 knockdown spared NQO1+ cells from short-term lethality. Pretreatment of cells with BAPTA-AM (a cytosolic Ca2+ chelator) or catalase (enzymatic H2O2 scavenger) was sufficient to rescue deoxynyboquinone-induced lethality, as noted with beta-lapachone. Investigations in vivo showed equivalent antitumor efficacy of deoxynyboquinone to beta lapachone, but at a 6-fold greater potency. PARP1 hyperactivation and dramatic ATP loss were noted in the tumor, but not in the associated normal lung tissue. Our findings offer preclinical proof-of-concept for deoxynyboquinone as a potent chemotherapeutic agent for treatment of a wide spectrum of therapeutically challenging solid tumors, such as pancreatic and lung cancers. PMID- 22532169 TI - Accuracy of subjective and objective handwriting assessment for differentiating Parkinson's disease from tremulous subjects without evidence of dopaminergic deficits (SWEDDs): an FP-CIT-validated study. AB - Handwriting examinations are commonly performed in the analysis of tremor and Parkinson's disease (PD). We analyzed the accuracy of subjective and objective assessment of handwriting samples for distinguishing 27 PD cases, 22 with tremulous PD, and five with akinetic-rigid PD, from 39 movement-disorder patients with normal presynaptic dopamine imaging (subjects without evidence of dopamine deficiency or SWEDDs; 31 with dystonic tremor (DT), six indeterminate tremor syndrome, one essential tremor, one vascular parkinsonism). All handwriting analysis was performed blind to clinical details. Subjective classification was made as: (1) micrographia, (2) normal, or (3) macrographia. In addition, a range of objective metrices were measured on standardized handwriting specimens. Subjective assessments found micrographia more frequently in PD than SWEDDs (p = 0.0352) and in akinetic-rigid than tremulous PD (p = 0.0259). Macrographia was predominantly seen in patients with dystonic tremor and not other diagnoses (p = 0.007). Micrographia had a mean sensitivity of 55 % and specificity of 84 % for distinguishing PD from SWEDDs and mean sensitivity of 90 % and specificity of 55 % for distinguishing akinetic-rigid PD from tremulous PD. Macrographia had a sensitivity of 26 % and specificity of 96 % for distinguishing DT from all other diagnoses. The best of the objective metrices increased sensitivity for the distinction of SWEDDs from PD with a reduction in specificity. We conclude that micrographia is more indicative of PD than SWEDDs and more characteristic of akinetic-rigid than tremulous PD. In addition, macrographia strongly suggests a diagnosis of dystonic tremor. PMID- 22532168 TI - Induction of the RNA regulator LIN28A is required for the growth and pathogenesis of RESTless breast tumors. AB - The transcription factor RE1 silencing transcription factor (REST) is lost in approximately 20% of breast cancers. Although it is known that these RESTless tumors are highly aggressive and include all tumor subtypes, the underlying tumorigenic mechanisms remain unknown. In this study, we show that loss of REST results in upregulation of LIN28A, a known promoter of tumor development, in breast cancer cell lines and human breast tumors. We found that LIN28A was a direct transcriptional target of REST in cancer cells and that loss of REST resulted in increased LIN28A expression and enhanced tumor growth both in vitro and in vivo, effects that were dependent on heightened LIN28A expression. Tumors lacking REST expression were locally invasive, consistent with the increased lymph node involvement observed in human RESTless tumors. Clinically, human RESTless breast tumors also displayed significantly enhanced LIN28A expression when compared with non-RESTless tumors. Our findings therefore show a critical role for the REST-LIN28A axis in tumor aggression and suggest a causative relationship between REST loss and tumorigenicity in vivo. PMID- 22532170 TI - Clinical and biochemical improvement following HSCT in a patient with MNGIE: 1 year follow-up. PMID- 22532171 TI - Impulse control disorders in Parkinson's disease: the role of personality and cognitive status. AB - This study reviews empirical findings on two debated issues related to the phenomenon of impulse control disorders (ICD) in patients with Parkinson's disease (PD) treated with dopamine agonists: the role of "premorbid" or "baseline" personality traits and the role of cognitive status. A review of both these issues may help clinicians to understand why only some PD patients, when treated with dopamine agonists, develop an ICD: besides the treatment, which other neuropsychiatric characteristics represent a risk factor to develop an ICD? A literature review was performed on studies of ICD in PD patients, in electronic databases ISI Web of Knowledge, Medline and PsychInfo, conducted in January 2011. In the general population, impulsivity, depression and difficulties with executive functions, especially of inhibitory control, are factors associated with ICD development. As regards cognitive functions, PD patients present executive difficulties, and patients with ICD present more difficulties in comparison to patients without ICD. As regards personality characteristics, PD patients present a trait of negative affect, which could predispose them to affective disorders and could represent an affective risk factor for the development of ICD; as regards impulsivity, preliminary findings support the hypothesis that premorbid "baseline" levels may moderate the decrease of impulsivity because of the progressive dopaminergic deficit in PD patients and therefore also moderate the development of ICD. Longitudinal psychometric and cognitive studies, following PD patients since the clinical diagnosis and during dopaminergic treatment, are needed to confirm the role of personality traits and cognitive status on ICD development in this clinical population. PMID- 22532172 TI - Frontotemporal lobar degeneration: current knowledge and future challenges. AB - Frontotemporal lobar degeneration (FTLD) is one of the most frequent neurodegenerative disorders with a presenile onset. It presents with a spectrum of clinical manifestations, ranging from behavioral and executive impairment to language disorders and motor dysfunction. New diagnostic criteria identified two main cognitive syndromes: behavioral variant frontotemporal dementia (bvFTD) and primary progressive aphasia. Regarding bvFTD, new criteria include the use of biomarkers. According to them, bvFTD can be classified in "possible" (clinical features only), "probable" (inclusion of imaging biomarkers) and "definite" (in the presence of a known causal mutation or at autopsy). Familial aggregation is frequently reported in FTLD, and about 10 % of cases have an autosomal dominant transmission. Microtubule-associated protein tau gene mutations have been the first ones identified, and are generally associated with early onset (40-50 years) and with the bvFTD phenotype. More recently, progranulin gene mutations were recognized in association with the familial form of FTLD and a hexanucleotide repetition in C9ORF72 has been shown to be responsible for familial FTLD and amyotrophic lateral sclerosis. In addition, other genes are linked to rare cases of familiar FTLD. Lastly, a number of genetic risk factors for sporadic forms have also been identified. PMID- 22532173 TI - Is pre-existing dementia an independent predictor of outcome after stroke? A propensity score-matched analysis. AB - With an aging population, patients are increasingly likely to present with stroke and pre-existing dementia, which may lead to greater death and disability. The aim of this work was to assess the risk of all-cause mortality and poor functional outcomes after ischemic stroke in patients with and without pre existing dementia. We conducted a multicenter cohort study of all patients presenting to 12 tertiary care institutions participating in the Registry of the Canadian Stroke Network (RCSN) with a first ischemic stroke between 2003 and 2008. Individuals with pre-existing dementia were matched using propensity-score methods with patients without dementia during their index hospitalization based on the following characteristics: age (within 3 years), sex, stroke severity, stroke subtype (lacunar vs. non-lacunar), level of consciousness, vascular risk factors, dysphagia, glucose and creatinine on admission, Charlson index, residence prior to hospitalization (home vs. other), pre-admission dependency, hospital arrival via ambulance, admission to stroke unit, thrombolysis, and palliative care. A propensity score for all-cause mortality and clinical outcomes was developed. Registry of the Canadian Stroke Network (RCSN) and Registered Persons Database (RPDB). The primary outcome was all-cause mortality at 30 days. Secondary outcomes included mortality at discharge and at 1 year, disability at discharge (modified Rankin scale >= 3), medical complications (pneumonia), and discharge disposition. A subgroup analysis assessing the risk of intracerebral hemorrhage among those receiving thrombolysis was also conducted. We matched 877 patients with an acute ischemic stroke and pre-existing dementia to 877 stroke patients without dementia. Patients were well matched. The mean age was 82 years and 58 % were women. Mortality at discharge, 30 days, and 1 year after stroke was similar in patients with and without dementia [for mortality at discharge RR 0.88 [95 % confidence interval (CI) 0.74-1.05]; mortality at 30-days: RR 0.88 (95 % CI 0.75-1.03) and mortality at 1 year: RR 1.01 (95 % CI 0.92-1.11). Patients with pre-existing dementia had similar disability at discharge and home disposition. In the subgroup of patients who received thrombolysis, there were no differences between those with and without dementia in the risk of intracerebral hemorrhage (RR 1.27; 95 % CI 0.69-2.35) and no differences in mortality or disability at discharge. Pre-existing dementia is not independently associated with mortality, disability, or institutionalization after ischemic stroke. Pre-existing dementia may not necessarily preclude access to thrombolytic therapy and specialized stroke care. PMID- 22532174 TI - Role of radiation therapy in the management of pancreatic cancer. AB - Local failure remains a major issue for patients with both resectable and locally advanced pancreatic cancer. The role of radiation therapy in the management of this disease is less clear and represents an area of some controversy. The objective of this review is to present the rationale for radiation therapy in pancreatic cancer, as well as to discuss the potential limitations and caveats of the currently available studies. PMID- 22532175 TI - Breast cancer mortality in Norway after the introduction of mammography screening. AB - An organized mammography screening program was gradually implemented in Norway during the period 1996-2004. Norwegian authorities have initiated an evaluation of the program. Our study focused on breast cancer mortality. Using Poisson regression, we compared the change in breast cancer mortality from before to during screening in four counties starting the program early controlling for change in breast cancer mortality during the same time in counties starting the program late. A follow-up model included death in all breast cancers diagnosed during the follow-up period. An evaluation model included only breast cancers diagnosed in ages where screening was offered. The study group had been invited for screening one to three times and followed for on average of 5.9 years. In the follow-up model, 314 breast cancer deaths were observed in the study group, and 523, 404 and 638, respectively, in the four control groups. The ratio between the changes in breast cancer mortality between early and late starting counties was 0.93 (95% confidence interval [CI] 0.77-1.12). In the evaluation model, this ratio was 0.89 (95% CI: 0.71-1.12). In Norway, where 40% of women used regular mammography prior to the program, the implementation of the organized mammography screening program was associated with a statistically nonsignificant decrease in breast cancer mortality of around 11%. PMID- 22532176 TI - CBe5E- (E = Al, Ga, In, Tl): planar pentacoordinate carbon in heptaatomic clusters. AB - A series of clusters with the general formula CBe(5)E(-) (E = Al, Ga, In, Tl) are theoretically shown to have a planar pentacoordinate carbon atom. The structures show a simple and rigid topological framework-a planar EBe(4) ring surrounding a C center, with one of the ring Be-Be bonds capped in-plane by a fifth Be atom. The system is stabilized by a network of multicenter sigma bonds in which the central C atom is the acceptor, and pi systems as well by which the C atom donates charge to the Be and E atoms that encircle it. PMID- 22532177 TI - Effects of Ficus exasperata vahl. (moraceae) leaf aqueous extract on the renal function of streptozotocin-treated rats. AB - The present study was undertaken to evaluate the possible reno-protective effect of Ficus exasperata leaf aqueous extract (FEE) in a rat experimental paradigm of diabetes mellitus. Forty Wistar rats (weighing 200-230 g) were divided into four (A, B, C, and D) groups, each group consisting of 10 rats. Group A rats served as 'control' animals and received citrate buffer (pH 6.3) solution in quantities equivalent to intraperitoneally-administered volumes of streptozotocin (STZ) and FEE. Diabetes mellitus was induced in Groups B and C rats by intraperitoneal injections of STZ (75 mg/kg). Group C rats were additionally treated with FEE (100 mg/kg/day, p.o.) 4 weeks post STZ injections, for 4 consecutive weeks. Group D rats received FEE (100 mg/kg/day p.o.) only for 4 weeks. Post-euthanisation, kidney tissues were excised for histopathological evaluation and processed for light microscopy. Plasma malondialdehyde and tissue nitric oxide were determined. Serum creatinine, blood urea nitrogen, nitrite, and albumin concentrations were measured for the evaluation of renal function. The diabetic rats significantly lost more weight and their blood glucose levels were significantly elevated as compared to the 'control' group of animals. Renal dysfunction was evidenced by kidney hypertrophy, decreased renal blood flow, and increased serum creatinine and nitrite concentrations. Furthermore, vascular dysfunction, as evidenced by decreased carotid blood flow, was observed in the diabetic rats. FEE treatment positively ameliorated the alterations in the biochemical variables in the STZ + FEE-treated rats. In conclusion, our findings suggest that FEE treatment ameliorates STZ-induced nephrotoxicity. PMID- 22532178 TI - The arterial anatomy of the saphenous flap: a cadaveric study. AB - The saphenous flap is a fasciocutaneous flap generally used for knee and upper third of the leg coverage. Due to various descriptions of the saphenous flap, such as venous, sensory, and free flap, the origin and distributing characteristics of the saphenous artery are important for plastic surgeons. The aim of this cadaveric study was to evaluate the anatomical features of the saphenous flap. The pedicles of the saphenous flap were dissected under 4 x loop magnification in thirty-two legs of 16 formalin-fixed adult cadavers. The findings of this anatomic study were as follows: Descending genicular artery originated from the femoral artery in all of the cases. The first musculoarticular branch, which arose from descending genicular, to the vastus medialis muscle existed in all dissections. The second branch was the saphenous artery which separately originated from the descending genicular artery in all of the cases. At the level of origin the mean diameter of the saphenous artery was found to be 1.61 mm. The muscular branches to the anterior or posterior sides of the sartorious muscle existed in all of the dissections. Two vena comitantes and a saphenous nerve were accompanying the saphenous artery in all cadavers. The mean distance between the origin of the artery and interepicondylar line of tibia was 115 mm. The muscular branches of the saphenous artery to the gracilis muscle were encountered 6.66% of the cases. The cutaneous branches numbered between one and four, and arose 3.5 to 9.5 cm from the site of origin of the saphenous artery. The distal end of the saphenous artery reached approximately 122 mm distally to the knee joint in all cases. Due to variations of the arterial anatomy and limited number of anatomic studies of the saphenous flap, we studied the topography and anatomy of the saphenous artery for increasing reliability of the saphenous flap. PMID- 22532179 TI - Variant origin of the lateral circumflex femoral artery in a black Kenyan population. AB - Variant origin of lateral circumflex femoral artery (FA) is important during harvesting of anterolateral thigh flaps, aortopopliteal by-pass, coronary artery grafting, and vascularised iliac transplant. The frequencies of variant origins display ethnic variations, but reports from black Africans are scarce. This study, therefore, aimed to describe the variant origins of lateral circumflex FA in a black Kenyan population. Eighty-four (42 right and 42 left) lateral femoral circumflex arteries from 42 cadavers (31 male and 11 female) were exposed by dissection of the femoral triangles at the Department of Human Anatomy, University of Nairobi. The arteries were then traced proximally to their parent trunks. Sites of origin were recorded and representative images of the variations taken using a high-resolution digital camera. Data were analysed using Statistical Program for Social Scientists version 16.0 for Windows and presented in tables and macrographs. The lateral circumflex artery was a branch of the profunda femoris in only 65.5% of cases. Variant origins included from a common trunk with medial circumflex artery (14.3%), with profunda femoris (10.7%), as a trifurcation with profunda femoris and medial circumflex FA (7.1%), and from FA (2.4%). Variant origin of the lateral circumflex FA occurred in nearly 35% of the Kenyan population studied, much lower than in oriental populations. The most frequent variant origin is as a common trunk with medial circumflex femoral and profunda femoris, with a very low prevalence of origin from FA. The unusual origins make the artery more vulnerable to iatrogenic injury during surgery and catheterisation. Preoperative angiographic evaluation of the femoral arterial system is recommended. PMID- 22532180 TI - Sternal foramina and variant xiphoid morphology in a Kenyan population. AB - Sternal foramina may pose a great hazard during sternal puncture, due to inadvertent cardiac or great vessel injury. They can also be misinterpreted as osteolytic lesions in cross-sectional imaging of the sternum. On the other hand, variant xiphoid morphology such as bifid, duplicated, or trifurcated may be mistaken for fractures during imaging. The distribution of these anomalies differs between populations, but data from Africans is scarcely reported. This study therefore aimed to investigate the distribution and frequency of sternal foramina and variant xiphoid morphology in a Kenyan population. Eighty formalin fixed adult sterna (42 males [M], 38 females [F]) of age range 18-45 years were studied during dissection at the Department of Human Anatomy, University of Nairobi. Soft tissues were removed from the macerated sterna by blunt dissection and foramina recorded in the manubrium, body, and xiphoid process. The xiphisternal ending was classified as single, bifurcated (2 xiphoid processes with a common stem), or duplicated (2 xiphoid processes with separate stems). Results were analysed using SPSS version 17.0. Foramina were present in 11 specimens (13.8%): 7 M, 4 F. The highest frequency was in the sternal body (n = 9), where they predominantly occurred at the 5th intercostal segment. Xiphoid foramina were present in 2 specimens (both males) (2.5%), while manubrial foramen was not encountered. The xiphisternum ended as a single process in 64 cases (34 M, 30 F) (80%). It bifurcated in 10 cases (5 M, 5 F) (12.5%), and duplicated in 6 cases (4 M, 2 F) (7.5%). There were no cases of trifurcation. Sternal foramina in Kenyans vary in distribution and show higher frequency than in other populations. These variations may complicate sternal puncture, and due caution is recommended. The variant xiphisternal morphology may raise alarm for xiphoid fractures and may therefore be considered a differential. PMID- 22532181 TI - Sex variations in the structure of human atrioventricular annuli. AB - Atrioventricular annuli are important in haemodynamic flexibility, competence, and support for tricuspid and mitral valves. The anatomical features of the annuli, such as circumference, organisation of connective tissue fibres, myocardium, and cellularity, may predispose to annular insufficiency and valvular incompetence. These pathologies occur more commonly in females, although the anatomical basis for this disparity is unclear. Sex variation in the structure of the annuli is important in providing a morphological basis for the patterns of these diseases. This study therefore aimed to determine the sex variations in the structure of human atrioventricular annuli. One hundred and one hearts (48 males, 53 females) obtained from the Department of Human Anatomy of the University of Nairobi were studied. Annular circumferences were measured using a flexible ruler and corrected for heart weight. Results were analysed using SPSS version 17.0 and sex differences determined using student's t-test. A p-value of less than 0.05 was considered significant. For light microscopy, specimens were harvested within 48 hours post-mortem, processed, sectioned, and stained with Masson's trichrome and Weigert's elastic stain with van Gieson counterstaining. Females had significantly larger annular circumferences than males after correcting for heart weight (p <= 0.05). Histologically, myocardium was consistently present in all male annuli while this was absent in females except in one specimen. The annuli were more elastic and cellular in males especially in the annulo-myocardial and annulo-valvular zones, respectively. The corrected larger annular circumference in females may limit heart valve coaptation during cardiac cycle and may be a risk factor for valvular insufficiency. The predominance of myocardium, annular cellularity, and elasticity may be more protective against heart valve incompetence in males than in females. PMID- 22532182 TI - Variations in the formation of the median nerve and its clinical correlation. AB - Variations in the formation of the median nerve are of interest to anatomists, radiologists, and surgeons. These variations may be vulnerable to damage in surgical operations, but their knowledge also helps in the interpretation of a nervous compression having unexplained clinical symptoms. We studied the variation in the formation of the median nerve in 87 cadavers, i.e. 174 upper limbs of formalin preserved cadavers at the department of Anatomy, Subharti medical college. We observed an additional root taking part in the formation of the median nerve in 26.4% of upper limbs, unusual low formation of the median nerve in the arm in front of the brachial artery in 18.4% of upper limbs, and median nerve formation medial to the axillary artery in 10.3% of upper limbs. Knowledge of such anatomical variations is of interest to the anatomist and clinician alike. Surgeons who perform procedures involving neoplasm or trauma repair need to be aware of these variations. PMID- 22532183 TI - Transforming growth factor beta1/Smad signalling pathway of aortic disorders: histopathological and immunohistochemical studies. AB - BACKGROUND: The aim of the present study was to evaluate the expressions and biological functions of the TGF-beta(1)/Smad signalling pathway of aortic disorders by way of histopathological and immunohistochemical studies. MATERIAL AND METHODS: Aortic specimens of 20 patients with aortic dissection, 9 patients with aortic aneurysm, 9 patients with coronary artery disease, and 5 deceased healthy adults were collected. The samples were stained with haematoxylin -eosin, Masson's trichrome, van Gieson, and alcian blue, and with immunohistochemical stainings to detect TGF-beta(1), type I receptor (TbetaRI), Smad2/3, Smad4, and Smad7. RESULTS: Masson's trichrome and van Gieson stainings showed attenuated collagens in the aorta of the patients with aortic dissection and aortic aneurysm. TGF-beta(1), TbetaRI, and Smad2/3 mainly showed a cytoplasmic immunoreactivity in the aortic media, Smad4 immunoreactivity was predominantly located in the cytoplasm and/or the nucleus of the aortic media, and Smad7 immunoreactivity was present in the nucleus of the aortic media and intima. The TGF-beta(1) signalling pathway proteins were similarly expressed in the aorta of aortic dissection and aortic aneurysm patients, while they were less pronounced in the aorta of coronary artery disease patients, and weak or negative in the aorta of healthy control individuals. CONCLUSIONS: These observations support the notion that there is an association between the TGF-beta(1)/Smad pathway and the pathological events of the aorta. Dysregulation of the TGF-beta(1)/Smad pathway may predispose the pathologenesis of aortic disorders. PMID- 22532184 TI - Immunohistochemical identification and localisation of gastrin and somatostatin in endocrine cells of human pyloric gastric mucosa. AB - The detailed description of the distribution of endocrine cells G and D producing important hormones that regulate activation of other cells in the human stomach may be a valuable source of information for opinions about mucosa changes in different diseases of the alimentary tract. The density and distribution of immunoreactive G and D cells in the pylorus of humans (donors of organs) were evaluated. The pylorus samples were collected after other organs were harvested for transplantation. The number of G cells in the pyloric mucosa of healthy people was higher than the number of D cells. G and D cells were distributed between columnar cells of epithelium mucosa. Multiform endocrine cells generally occurred: gastrin in the middle third of the mucosa and somatostatin cells in the basal half of the pyloric mucosa. The investigation of the pyloric part of the healthy human stomach showed a characteristic distribution of cells that reacted with antisera against gastrin and somatostatin. PMID- 22532185 TI - Intrapancreatic accessory spleen. AB - A case of accessory spleen located in the tail of the pancreas in a stillbirth male foetus is reported. The congenital anomaly was revealed at autopsy. The intrapancreatic spleen was well demarcated and was composed of red and white pulp; however, same pancreatic ducts were intermingled with the splenic parenchyma. As well as the intrapancreatic lesion another minute accessory spleen was also found at the hilum of the proper organ. Since a lack of morphological features of trisomy 13 syndrome were found in the foetus, the ectopic spleens were regarded as incidental findings. PMID- 22532186 TI - Bilateral superficial ulnar artery with high origin from the axillary artery: its anatomy and clinical significance. AB - The superficial ulnar artery (SUA) is a rare anatomical variant that usually arises either in the axilla or the arm and runs a superficial course in the forearm, enters the hand, and participates in the formation of superficial palmar arch. During the routine dissection of cadavers in the department of anatomy, whilst preparing the specimen for medical students, an unusual bilateral branch of the axillary artery was found in one of the cadavers: a rare variant of the artery known as SUA, which originates from the 2nd part of the axillary arteries of both sides. The SUA is a known anatomical variant, but the bilateral high origin from the 2nd part of the axillary artery is extremely unusual. Its occurrence is of great clinical importance to the surgical and radiological departments. PMID- 22532187 TI - Bilateral reversed palmaris longus muscle: a rare anatomical variation. AB - We report a case of bilateral reversed palmaris longus muscle (PLM). The muscle was tendinous in its upper portion and muscular in its lower portion in both arms. This rare variation has been mentioned only once in the literature as a surgical finding. According to the literature, a reversed PLM may cause a compartment syndrome in the wrist area, carpal tunnel, and Guyon's syndrome. The described variation is also useful to the hand surgeon as a tendon graft, a tendon for transfer, or as an anatomical landmark for operations at this area. PMID- 22532188 TI - Professor Janina Sokolowska-Pituchowa--a legend in Polish anatomy (1915-2011). PMID- 22532189 TI - Design and dosimetric analysis of a 385 MHz TETRA head exposure system for use in human provocation studies. AB - A new head exposure system for double-blind provocation studies investigating possible effects of terrestrial trunked radio (TETRA)-like exposure (385 MHz) on central nervous processes was developed and dosimetrically analyzed. The exposure system allows localized exposure in the temporal brain, similar to the case of operating a TETRA handset at the ear. The system and antenna concept enables exposure during wake and sleep states while an electroencephalogram (EEG) is recorded. The dosimetric assessment and uncertainty analysis yield high efficiency of 14 W/kg per Watt of accepted antenna input power due to an optimized antenna directly worn on the subject's head. Beside sham exposure, high and low exposure at 6 and 1.5 W/kg (in terms of maxSAR10g in the head) were implemented. Double-blind control and monitoring of exposure is enabled by easy to-use control software. Exposure uncertainty was rigorously evaluated using finite-difference time-domain (FDTD)-based computations, taking into account anatomical differences of the head, the physiological range of the dielectric tissue properties including effects of sweating on the antenna, possible influences of the EEG electrodes and cables, variations in antenna input reflection coefficients, and effects on the specific absorption rate (SAR) distribution due to unavoidable small variations in the antenna position. This analysis yielded a reasonable uncertainty of <+/-45% (max to min ratio of 4.2 dB) in terms of maxSAR10g in the head and a variability of <+/-60% (max to min ratio of 6 dB) in terms of mass-averaged SAR in different brain regions, as demonstrated by a brain region-specific absorption analysis. PMID- 22532190 TI - Natural killer p46High expression defines a natural killer cell subset that is potentially involved in control of hepatitis C virus replication and modulation of liver fibrosis. AB - Natural killer (NK) cells play a role in the early control and natural course of hepatitis C virus (HCV) infection. NK cell function is regulated by a multitude of receptors, including activating NKp46 receptor. However, reports on NKp46 in hepatitis C are controversial. Therefore, we investigated the hepatic recruitment and function of NKp46(+) NK cells, considering differential surface expression of NKp46 resulting in NKp46(High) and NKp46(Dim) subsets. Intra- and extrahepatic NK cell subsets from HCV-infected patients were characterized by flow cytometry. Cytotoxic activity and interferon-gamma (IFN-gamma) secretion were studied using K-562, P815, and primary hepatic stellate cells as targets. Anti-HCV activity of NK-cell subsets was studied using the replicon system. Density of NKp46 surface expression clearly segregated NKp46(Dim) and NKp46(High) subsets, which differed significantly with respect to the coexpression of maturation markers and NK-cell receptors. More important, NKp46(High) NK cells showed a higher cytolytic activity and stronger IFN-gamma secretion than NKp46(Dim) NK cells. Accordingly, NKp46(High) NK cells efficiently blocked HCV replication in vitro. Blocking experiments confirmed an important role for the NKp46 receptor. Furthermore, we found an intrahepatic accumulation of NKp46(High) NK cells. Of note, high cytolytic activity of NKp46(High) NK cells was also confirmed in the intrahepatic NK-cell population, and the frequency of intrahepatic NKp46(High) NK cells was inversely correlated with HCV-RNA levels and fibrosis stage. CONCLUSIONS: NKp46(High) expression defines a specific NK-cell subset that may be involved in both the suppression of HCV replication and HCV-associated liver damage underpinning the role of NK cells in the immunopathogenesis of HCV. PMID- 22532191 TI - Joint trajectories of victimization and marijuana use and their health consequences among urban African American and Puerto Rican young men. AB - We examined the joint trajectories of violent victimization and marijuana use from emerging adulthood to the early thirties and their health consequences in the early thirties among urban African American and Puerto Rican men. Data were collected from a community sample of young men (N = 340) when they were 19, 24, 29, and 32 years old. The joint trajectories of violent victimization and marijuana use were extracted using growth mixture modeling. Three distinct joint trajectory groups of violent victimization and marijuana use were identified: high violent victimization/consistently high marijuana use; low violent victimization/increasingly high marijuana use, and low violent victimization/low marijuana use. Group comparisons using regression analyses showed that men who had experienced high levels of violent victimization and were high frequency marijuana over time users experienced the most adverse psychological and physical health outcomes, including more health problems, psychological maladjustment, and substance use disorders. PMID- 22532192 TI - Effects of repeated "benign" noise exposures in young CBA mice: shedding light on age-related hearing loss. AB - Temporary hearing threshold shift (TTS) resulting from a "benign" noise exposure can cause irreversible auditory nerve afferent terminal damage and retraction. While hearing thresholds and acute tissue injury recover within 1-2 weeks after a noise overexposure, it is not clear if multiple TTS noise exposures would result in cumulative damage even though sufficient TTS recovery time is provided. Here, we tested whether repeated TTS noise exposures affected permanent hearing thresholds and examined how that related to inner ear histopathology. Despite a peak 35-40 dB TTS 24 hours after each noise exposure, a double dose (2 weeks apart) of 100 dB noise (8-16 kHz) exposures to young (4-week-old) CBA mice resulted in no permanent threshold shifts (PTS) and abnormal distortion product otoacoustic emissions (DPOAE). However, although auditory brainstem response (ABR) thresholds recovered fully in once- and twice-exposed animals, the growth function of ABR wave 1( p-p ) amplitude (synchronized spiral ganglion cell activity) was significantly reduced to a similar extent, suggesting that damage resulting from a second dose of the exposure was not proportional to that observed after the initial exposure. Estimate of surviving inner hair cell afferent terminals using immunostaining of presynaptic ribbons revealed ribbon loss of ~ 40 % at the ~ 23 kHz region after the first round of noise exposure, but no additional loss of ribbons after the second exposure. In contrast, a third dose of the same noise exposure resulted in not only TTS, but also PTS even in regions where DPOAEs were not affected. The pattern of PTS seen was not entirely tonotopically related to the noise band used. Instead, it resembled more to that of age-related hearing loss, i.e., high frequency hearing impairment towards the base of the cochlea. Interestingly, after a 3rd dose of the noise exposure, additional loss of ribbons (another ~ 25 %) was observed, suggesting a cumulative detrimental effect from individual "benign" noise exposures, which should result in a significant deficit in central temporal processing. PMID- 22532194 TI - A commentary on "Recruiting researchers in psychiatry: the influence of residency vs. early motivation". PMID- 22532193 TI - Plasma exchange as a therapeutic option in patients with neurologic symptoms due to antibodies to voltage-gated potassium channels: a report of five cases and review of the literature. AB - Antibodies to voltage-gated potassium channels (VGKC) are associated with acquired neuromyotonia, limbic encephalitis, and Morvan's syndrome. The antibodies are often not associated with malignancy and have shown good clinical response to immunomodulatory therapies. A record review identified five patients with laboratory evidence of antibodies to VGKC who underwent plasma exchange (PE) as part of their immunosuppressive therapy for neurologic disease. Four of the patients presented with limbic encephalitis and one with neuromyotonia. Symptoms included memory impairment, seizures, and personality changes. All PE were 1.0 volume and were performed on an every-other-day schedule. Replacement fluid was 5% normal serum albumin except when a bleeding risk was identified and then fresh frozen plasma was added. Four of five patients were also receiving concurrent immunosuppressive therapy including corticosteroids. Of the five patients treated with PE, three had sustained improvement in symptoms for 6-17 months following PE. Two patients did not have signs of improvement at a limited follow-up. One patient had recurrence of her symptoms, which responded to additional PE. These cases, as well as the reports in the literature, suggest that PE could be a useful adjunctive therapy for patients with VGKC antibodies and neurologic symptoms. PMID- 22532195 TI - Recruiting researchers in psychiatry: the influence of residency vs. early motivation. AB - BACKGROUND: The declining numbers of clinician-researchers in psychiatry and other medical specialties has been a subject of growing concern. Residency training has been cited as an important factor in recruiting new researchers, but there are essentially no data to support this assertion. This study aimed to explore which factors have influenced motivation to conduct research among senior psychiatry residents. METHODS: The authors surveyed senior residents, inquiring about their level of interest in research, demographics, background, research experiences, and factors influencing motivation for research. The authors had confirmed participation from 16 of 33 residency programs with a class size of 10 or more. They received 127 responses, a 67% response rate, from participating programs. RESULTS: Residents with high stated interest in research differed from those with low and moderate interest in their research-intense post-residency plans. They were more likely to have graduate degrees. Those planning research careers had a consistent pattern of interest and involvement in research, starting well before residency. The majority of residents had had research exposure in college, but research involvement of those with very high versus lower interest diverged sharply thereafter. Those with high research interest were overwhelmingly male and tended to have lower debt than those with less interest. CONCLUSION: The great majority of residents appear to have decided whether or not to pursue a research career by the time they reached residency, and few of those with less than the highest research interest were enrolled in research tracks. Efforts to increase recruitment into research should center on identifying early developmental influences, eliminating barriers specific to women, and ensuring adequate funding to provide secure careers for talented potential researchers. PMID- 22532196 TI - An approach to integrating interprofessional education in collaborative mental health care. AB - OBJECTIVE: This article describes an evaluation of a curriculum approach to integrating interprofessional education (IPE) in collaborative mental health practice across the pre- to post-licensure continuum of medical education. METHODS: A systematic evaluation of IPE activities was conducted, utilizing a combination of evaluation study designs, including: pretest-posttest control group; one-group pre-test-post-test; and one-shot case study. Participant satisfaction, attitudes toward teamwork, and self-reported teamwork abilities were key evaluative outcome measures. RESULTS: IPE in collaborative mental health practice was well received at both the pre- and post-licensure levels. Satisfaction scores were very high, and students, trainees, and practitioners welcomed the opportunity to learn about collaboration in the context of mental health. Medical student satisfaction increased significantly with the introduction of standardized patients (SPs) as an interprofessional learning method. Medical students and faculty reported that experiential learning in practice-based settings is a key component of effective approaches to IPE implementation. At a post-licensure level, practitioners reported significant improvement in attitudes toward interprofessional collaboration in mental health care after participation in IPE. CONCLUSION: IPE in collaborative mental health is feasible, and mental health settings offer practical and useful learning experiences for students, trainees, and practitioners in interprofessional collaboration. PMID- 22532197 TI - Communication profiles of psychiatric residents and attending physicians in medication-management appointments: a quantitative pilot study. AB - OBJECTIVE: The authors quantitatively examined differences in psychiatric residents' and attending physicians' communication profiles and voice tones. METHODS: Audiotaped recordings of 49 resident-patient and 35 attending-patient medication-management appointments at four ambulatory sites were analyzed with the Roter Interaction Analysis System (RIAS). Nonparametric tests were used to compare differences in proportions of speech devoted to relationship-building, activating, and partnering in decision-making processes, and data gathering/counseling/patient education. Differences in affect expressed by psychiatrists' voice tones were also examined. RESULTS: Residents' visits were twice as long as Attendings' visits (28.2 versus 14.1 minutes), and residents devoted a significantly greater proportion of their talk to relationship-building (23% versus 20%) and activating/partnering (36% versus 28%) aspects of communication, whereas Attendings devoted a greater proportion to biomedically related data-gathering/counseling/patient education (31% versus 20%). Analysis of voice tones revealed that residents were perceived as sounding significantly friendlier and more sympathetic, versus Attendings, who were rated as sounding more dominant and rushed. CONCLUSION: These findings show distinct communication profiles and voice-tone differences. Future psychiatric communication research should address the influence of appointment length, psychiatrist/patient characteristics, and other potential confounders on psychiatrist-patient communication. PMID- 22532198 TI - Evidence-based decision-making as a practice-based learning skill: a pilot study. AB - OBJECTIVES: As physicians are being trained to adapt their practices to the needs and experience of patients, initiatives to standardize care have been gaining momentum. The resulting conflict can be addressed through a practice-based learning and improvement (PBL) program that develops competency in using treatment guidelines as decision aids and incorporating patient-specific information into treatment recommendations. This article describes and tests a program that is consistent with the ACGME's multilevel competency-based approach, targets students at four levels of training, and features progressive learning objectives and assessments. METHODS: The program was pilot-tested with 22 paid volunteer psychiatric residents and fellows. They were introduced to a schizophrenia treatment guideline and reviewed six case vignettes of varying complexity. PBL assessments were based on how treatment recommendations were influenced by clinical and patient-specific factors. The task permitted separate assessments of learning objectives all four training levels. RESULTS: Among the key findings at each level, most participants found the treatment guideline helpful in making treatment decisions. Recommendations were influenced by guideline-based assessment criteria and other clinical features. They were also influenced by patients' perceptions of their illness, patient-based progress assessments, and complications such as stressors and coping patterns. Recommendations were strongly influenced by incongruence between clinical facts and patient experience. CONCLUSION: Practical understanding of how patient experience joins with clinical knowledge can enhance the use of treatment guidelines as decision tools and enable clinicians to appreciate more fully how and why patients' perceptions of their illness should influence treatment recommendations. This PBL program can assist training facilities in preparing students to cope with contradictory demands to both standardize and adapt their practice. The program can be modified to accommodate various disorders and a range of clinical factors and patient-specific complications. PMID- 22532199 TI - Neurology didactic curricula for psychiatry residents: a review of the literature and a survey of program directors. AB - OBJECTIVE: Minimal literature exists on neurology didactic instruction offered to psychiatry residents, and there is no model neurology didactic curriculum offered for psychiatry residency programs. The authors sought to describe the current state of neurology didactic training in psychiatry residencies. METHODS: The authors electronically surveyed 172 directors of U.S. psychiatric residency training programs to examine the types and extent of neurology didactic instruction offered to their residents. RESULTS: Fifty-seven program directors (33%) responded. The majority of these psychiatry residency programs offer neurology didactic instruction to their residents, as provided by both neurology and psychiatry faculty, in a number of different settings and covering many topics. However, room for improvement likely remains. CONCLUSIONS: The authors hope this report will guide psychiatry residencies in optimizing their neurology didactic curricula. Further research should explore tools for assessing resident knowledge in neurology and measure the effectiveness of neurology curricula in increasing knowledge and improving clinical outcomes. PMID- 22532200 TI - Teaching critical appraisal of articles on psychopharmacology. AB - OBJECTIVE: Psychiatrists and other physicians sometimes read publications superficially, relying excessively on abstracts. The authors addressed this problem by teaching critical appraisal of individual articles. METHOD: The authors developed a 23-item appraisal instrument to assess articles in the area of psychopharmacology. The results were collected with an electronic voting system. A discussion of each of the item followed; tutors shared their views and provided key ratings. RESULTS: Six publications were evaluated in the course of three workshops by a total of 58 trainees. Evaluation of the papers yielded varying results, reflecting variations of the participants' theoretical background as well as varied quality of the publications. The authors present detailed analysis of one paper as an illustrative example. CONCLUSION: The discussion format and voting stimulated active participation of the trainees. Active involvement, facilitated by the structured assessment tool, followed by feedback with discussion, may enhance the learning process. PMID- 22532201 TI - Impact of a metabolic screening bundle on rates of screening for metabolic syndrome in a psychiatry resident outpatient clinic. AB - OBJECTIVE: Although it is widely acknowledged that second-generation antipsychotics are associated with cardiometabolic side effects, rates of metabolic screening have remained low. The authors created a quality-improvement (QI) intervention in an academic medical center outpatient psychiatry resident clinic with the aim of improving rates of screening for metabolic syndrome in patients being prescribed antipsychotic medications. METHODS: The core components of the QI intervention included resident education and creation of a metabolic screening bundle for the electronic medical record. Quarterly audits of individual patient electronic medical records assessed whether a patient was currently prescribed antipsychotics and whether metabolic-syndrome screening had been documented at any time in the preceding 12 months. RESULTS: In each audit period, from 131 to 156 patients (30%-36% of total clinic sample) were prescribed antipsychotic medication. After the intervention, rates of documentation of the components of the metabolic screening bundle increased between 3.5- and 10-fold (final rates: 39% for blood pressure, 44% for BMI, and 55% for glucose and lipid panel). Rates of documenting the full bundle increased nearly 30-fold (final rate: 31%). CONCLUSION: Provider-education combined with introduction of a documentation bundle in the electronic medical record increased rates of documented metabolic screening in patients being prescribed antipsychotic medications by psychiatry residents. PMID- 22532202 TI - Clinical skills verification, formative feedback, and psychiatry residency trainees. AB - OBJECTIVE: The authors describe the implementation of Clinical Skills Verification (CSV) in their program as an in-training assessment intended primarily to provide formative feedback to trainees, strengthen the supervisory experience, identify the need for remediation of interviewing skills, and secondarily to demonstrating resident competence for American Board of Psychiatry and Neurology (ABPN) certification in Psychiatry. METHODS: The authors review the background and context of the implementation of CSV, and describe how the experience is structured within their residency program. RESULTS: The authors have embedded CSV experiences into clinical rotations across all years of residency training, aiming to complete 6-12 evaluations for each resident in each year. The authors provide training to faculty regarding supervision and formative feedback, including interrater reliability sessions for the CSV assessment. CONCLUSION: Effective incorporation of the CSV assessment into regular clinical settings can improve clinical supervision, residents' training experience, and the field's ability to consistently produce qualified, competent psychiatrists. PMID- 22532203 TI - Evaluation of professional role competency during psychiatry residency. AB - OBJECTIVE: The authors sought to determine psychiatry residents' perceptions on the current method of evaluating professional role competency and the use of multi-source feedback (MSF) as an assessment tool. METHOD: Authors disseminated a structured, anonymous survey to 128 University of Toronto psychiatry residents, evaluating the current mode of assessment of the professional role and the use of MSF. RESULTS: The overall response rate was 86%. Fewer than half (44%) of residents felt that their professional role is adequately evaluated, and 84% were in favor of incorporating MSF for the evaluation of this competency. Respondents believed their primary supervisor should have the largest proportional impact on the evaluation (50%), followed by allied heath staff (19%), patients (16%), co residents (12%), self (11%), and administrative staff (9%). CONCLUSION: On the basis of this needs assessment and the Royal College recommendations, MSF may be considered a potential assessment tool for evaluating psychiatry residents in their professional role. PMID- 22532204 TI - A comparison of psychiatry and internal medicine: a bibliometric study. AB - OBJECTIVE: Psychiatric education needs to expose students to a broad range of topics. One resource for psychiatric education, both during initial training and in later continuing medical education, is the scientific literature, as published in psychiatric journals. The authors assessed current research trends in psychiatric journals, as compared with internal-medicine counterparts and examined their relevance to psychiatric education. METHODS: The authors classified abstracts and original articles as biological or non-biological, based on methodology, from 2008 in Archives of General Psychiatry and The American Journal of Psychiatry, as compared with The Archives of Internal Medicine and Annals of Internal Medicine. RESULTS: Biological and non-biological studies were similarly frequent in psychiatric journals (48.2% and 51.8%, respectively). Internal-medicine journals had a non-biological and epidemiological predominance (22.2% biological, 77.8% non-biological: epidemiological, 59.9%; reviews, 21.4%; clinical, 13.2%; other, 5.4%). CONCLUSION: Psychiatric journals publish more biological studies than internal-medicine journals. This tendency may influence psychiatric education and practice in a biological direction, with less attention to psychosocial or clinical approaches to psychiatry. PMID- 22532205 TI - Countertransference experienced by junior faculty in the care of V.I.P. patients. PMID- 22532206 TI - Comprehensive trauma training curriculum for psychiatry residents. PMID- 22532207 TI - Crisis as a classroom: use of a health systems crisis to teach ethics and professionalism. PMID- 22532208 TI - The transition to practice in psychiatry: a practical guide. PMID- 22532209 TI - Interactive virtual-patient scenarios: an evolving tool in psychiatric education. PMID- 22532210 TI - Encouraging collaboration. PMID- 22532211 TI - Teaching statistical literacy to psychiatry residents: a pilot study of training directors. PMID- 22532212 TI - The downside of teaching psychopathology with film. PMID- 22532213 TI - Magnetic phase diagrams of R2RhIn8 (R = Tb, Dy, Ho, Er and Tm) compounds. AB - We have grown and characterized single crystals of R(2)RhIn(8) (R=Tb, Dy, Ho, Er and Tm) compounds crystallizing in the tetragonal Ho(2)CoGa(8)-type crystal structure. Their magnetic properties were studied by specific heat and magnetization measurements. All the investigated compounds order antiferromagnetically with Neel temperatures of 43.6, 25.1, 10.9, 3.8 and 4.1 K, respectively. Magnetic phase diagrams were constructed. PMID- 22532214 TI - [A new approach to the Alzheimer's disease diagnosis with biomarkers: description of the AD-CSF-Index]. AB - INTRODUCTION: Studies with cerebrospinal fluid (CSF) biomarkers in patients with confirmed Alzheimer's disease (AD) pathology have shown that decreased levels of Abeta(1-42) and increased levels of tau and p-tau, are a specific feature of the AD type pathology. AIM: To describe a new method for determining the AD-CSF Index, through the values obtained with CSF biomarkers and thus optimize AD diagnosis. SUBJECTS AND METHODS: We recruited a total of 61 subjects in the Alzheimer's unit and other cognitive disorders of the Hospital Clinic of Barcelona, of which 42 were cognitively healthy controls and 19 were diagnosed with AD according to the new research criteria proposed by Dubois et al: episodic memory impairment and atrophy of medial temporal areas using the Scheltens scale. The AD-CSF-Index was constructed from the addition of normalized values between the minimum and maximum values of amyloid and tau proteins. RESULTS: Subjects diagnosed with AD presented a significantly higher AD-CSF-Index (1.17) than healthy subjects (0.72) (p < 0.001; 95% CI of the difference = 0.32-0.57). In the ROC analysis, the AD-CSF-Index obtained the best results of all, showing the cut off point of 0.93 a sensitivity of 92% and a specificity of 89%. CONCLUSION: The AD-CSF-Index represents a novel approach that combines optimally the observed CSF biomarkers alterations, which allows establishing the diagnosis of AD with high sensitivity and specificity. PMID- 22532216 TI - [Incidence and characteristics of tumours of the central nervous system among the paediatric population of Asturias. New data about an incidence on the rise]. AB - INTRODUCTION: Tumours of the central nervous system (CNS) are one of the most common causes of child mortality, second only to accidents. In the last few decades we have witnessed an increase in the incidence of these tumours, which now stands at 2.5-3.2 cases/100,000 children/year in the population under 15 years of age. AIMS: To determine the real incidence of tumours affecting the CNS in Asturias and to describe their characteristics. PATIENTS AND METHODS: Data were collected on patients under 15 years of age who had been diagnosed with a CNS tumour in any of the hospitals in the Community during the ten-year period 1999-2008. RESULTS: The mean annual incidence of CNS tumours was 4.4 cases/100,000 children/year (range: 3.1-5.7). The mean time elapsed before a diagnosis was reached was 2.03 months. The clinical features at onset were focal neurological deficit in 58% of cases, followed by cerebellar symptoms (42%), headache (32%) and behavioural disorders (32%). CONCLUSIONS: The incidence of tumours affecting the CNS found in children in Asturias is the highest of those recorded for this age bracket, the clinical features of these patients being similar to those in other studies. We seem to be before new data that confirms the claims of a growing incidence of these tumours. PMID- 22532217 TI - [Evolution of the incidence of migraine in Alava over the period 2004-2008]. AB - INTRODUCTION: Few studies have been conducted on the incidence of migraine in Spain, and those that have been carried out have some shortcomings, such as the lack of a clear population base. AIMS: To examine the evolution of the incidence of migraine over the period 2004-2008 in the province of Alava (Basque Country, Spain). PATIENTS AND METHODS: Data concerned persons aged 15 or over who were registered in the Basque Health Service/Osakidetza database as new cases diagnosed with migraine. The tendency of the incidence of migraine was evaluated by means of linear regression. RESULTS: The incidence of migraine was significantly higher in females than in males, at any age. No significant changes in the incidence of migraine were observed over the period 2004-2008 in the population of Avala as a whole (p = 0.189). Nevertheless, there have been both a decrease in the incidence of migraine in females over the age of 64 (p = 0.014) and an increase in those aged 15-24 years (p = 0.052) and 35-44 years (p = 0.057). The new cases of migraine that are diagnosed tended to appear at younger ages over this period. CONCLUSIONS: These results suggest an absence of changes in the tendency in the incidence of migraine throughout the period 2004-2008, except for a decrease in the case of females over 64 years of age and an increase in young females. This evolution is similar to that of other regions in Europe. PMID- 22532215 TI - [Compliance with the measures for preventing vascular risk factors in hospitalised patients with acute stroke. Analysis of a national multi-centre registry: EPICES registry (III)]. AB - INTRODUCTION: Pharmacological and dietary measurements, as well as life style, to control risk factors are efficient procedures to prevent cerebrovascular diseases, though their implementation in the clinics seems not optimal. AIM: To identify the fulfillment of preventive measurements on a sample of 6197 hospitalized stroke patients, attended by neurologists. PATIENTS AND METHODS: Analysis of a secondary objective of the EPICES registry. Primary prevention was considered in patients without previous record of transitory ischemic attack, stroke, coronary diseases and/or peripheral arterial disease (n = 3977); secondary prevention was considered in patients with record of coronary and/or peripheral arterial disease, but without record of cerebrovascular disease (n = 1047); neurological secondary prevention was considered in patients with a record of transitory ischemic attack and/or stroke, independently of the presence of coronary and/or peripheral arterial disease (n = 1173). RESULTS: Secondary prevention and neurological secondary prevention were more efficient than primary prevention (p = 0.028 and p < 0.0001, respectively). Control was higher in centers with some type of structure to assist stroke patients (p < 0.0001). Influence of age in the taking of therapeutic decisions followed a similar pattern in all three types of prevention, with a significant reduction on anticoagulation for patients older than 80 years. CONCLUSION: The EPICES registry confirms the poor control of risk factors for cerebrovascular diseases. Globally it demonstrated that the objectives that imply the modification of lifestyle are fulfilled worse than pharmacological preventive measurements. PMID- 22532218 TI - [Neuronal ceroid lipofuscinosis: diagnostic algorithm and clinical description of the Finnish (CLN5) and Turkish (CLN7) variants late infantile]. AB - INTRODUCTION: The neuronal ceroid lipofuscinosis are classified based on age at onset into four main clinical forms in child-hood: infantile, late infantile, juvenile and congenital (CLN1, CLN2, CLN3 and CLN10). The variant late infantile forms (CLN5, CLN6, CLN7 and CLN8) are characterized by a wide variability of the clinical phenotypes and the most patients are originated from Finland and Turkey (Finnish, CLN5, and Turkish, CLN7 variants). CASE REPORTS: We describe three unrelated patients with Finnish variant and another patient with Turkish variant. We describe an algorithm to facility the diagnosis of these low prevalence diseases. Patients with Finnish variant started with behaviour disorder between 2.6 and 4.6 years of age followed by learning difficulties and visual failure at an age of 6 years. Generalised tonic-clonic and myoclonic seizures were observed at 7 years of age with myoclonic jerks later on. Patients developed ataxia and blindness within 9 years and increasingly disability at 11 years of age. The patient with Turkish variant started with refractory epilepsy at age of 2, followed by a severe neurodegeneration manifested by ataxia, loss of walking ability within 2-3 years and vegetative state at 11 years of age. CONCLUSIONS: The clinical spectrum of the variant late infantile forms shows a wide geographical distribution. We report three novel mutations in the CLN5 gene and a diagnostic algorithm to facility the correlation genotype-phenotype studies. PMID- 22532219 TI - [Eslicarbazepine acetate: a novel therapeutic alternative in the treatment of focal seizures]. AB - Epilepsy is one of the most common neurological diseases. In recent years an important number of drugs have been added to the therapeutic options we have available to us. With the aim of offering an optimal clinical effectiveness, the mechanisms of action or chemical structures of the antiepileptic drugs recently introduced onto the market have been modified with respect to the first, so called classical or conventional, antiepileptics. Eslicarbazepine acetate belongs to this group of recently incorporated pharmaceuticals and is a novel single daily dose voltage-gated sodium channel blocker, which acts selectively in groups of rapid-activation neurons. It has been approved for indication in associated therapy in adults with partial onset seizures, with or without secondary generalisation. It is widely metabolised to eslicarbazepine and, to a lesser extent, to R-licarbazepine and oxcarbazepine. In 800 mg and 1200 mg doses it has been shown to bring about a significant reduction in a high percentage of patients with refractory epilepsy in simultaneous treatment with up to three antiepileptic drugs, and this effectiveness is maintained in open follow-up studies lasting up to a year. It is generally speaking well-tolerated; most of the adverse side-effects range in intensity from mild to moderate, and the percentage of patients who withdraw from treatment for this reason is low. Eslicarbazepine acetate is an alternative treatment in associated therapy in patients with partial epilepsy who do not respond adequately to treatment in monotherapy. PMID- 22532220 TI - [Optical coherence tomography in multiple sclerosis]. AB - Optical coherence tomography (OCT) is a non-invasive imaging technique that allows the different layers of the retina to be visualised in vivo. One of them is the so-called retinal nervous fibre layer (RNFL), which is made up of amyelinic axons from the ganglionic cells, and therefore part of the central nervous system. Recent studies have begun to examine possible applications of OCT in the field of neurology and, more specifically, the usefulness of measuring the thickness of the RNFL in multiple sclerosis (MS). In both cross-sectional and longitudinal studies it has been shown that a decrease in the RNFL is produced in eyes that are affected and unaffected by optic neuritis in MS patients, compared with controls. Several studies have found evidence of an inverse relation between the thickness of the nerve fibre layer and the neurological disability or cerebral atrophy parameters in magnetic resonance imaging of the brain in these same patients. The correlations are, however, weak and sometimes contradictory. Although there are still many doubts that need settling, the role OCT may play in gaining a better understanding of the disease and its follow-up and monitoring seems promising. A review of the different studies published on the thickness of the RNFL in patients with MS will also be conducted. PMID- 22532221 TI - [Locked-in syndrome in literature, cinema and television]. AB - INTRODUCTION: Many diseases have been dealt with in literature, cinema or television, including epilepsy, cancer, mental disorders, movement disorders or infectious diseases. Among the many pathologies that have been considered, locked in syndrome is one that has been of particular interest to writers and film makers. AIM: To review how locked-in syndrome has been portrayed in literature, cinema and television. DEVELOPMENT: Locked-in syndrome is a state that is generally secondary to a brainstem lesion with involvement of the corticobulbar and corticospinal tracts, thereby impeding the patient from producing any kind of motor response. Patients remain conscious, maintain their higher functions and can both see and hear. Yet, they are quadriplegic with paralysis of the lower cranial nerves and cannot move or speak. They only conserve the capacity to move their eyes vertically and their eyelids, which they can use as a way to communicate. This pathology has come to the attention of writers and film and television directors, who have described characters with this syndrome. Likewise, there are also stories told in the first person by patients who have experienced this condition and who have written their story using eye movements as a means to communicate. CONCLUSIONS: Literature, cinema and television have shown an interest in locked-in syndrome and have placed special attention on the problems these patients have to communicate with others. PMID- 22532223 TI - [Some considerations on the analysis of publications in clinical neurology in different European countries over the period 2000-2009. Reply]. PMID- 22532225 TI - Mutational analysis of MED12 exon 2 in uterine leiomyoma and other common tumors. AB - Recurrent somatic mutations in MED12 exon 2 have recently been reported in uterine leiomyomas. The recurrent nature of the mutations strongly suggests that the mutations may play important roles in the pathogenesis of uterine leiomyomas. The aim of our study was to see whether MED12 exon 2 mutations occur in other human tumors besides uterine leiomyomas. We also attempted to confirm occurrence of the MED12 mutations in uterine leiomyomas of Korean patients. For this, we analyzed 1,862 tumor tissues, including a variety of carcinomas, leukemias and stromal tumors by single-strand conformation polymorphism analysis. We found MED12 mutations in 35 uterine leiomyomas (35/67; 52.2%) and one colon carcinoma (0.3%), but none in other tumors. The MED12 mutations consisted of missense (77%) and inframe insertion-deletion (23%) mutations, the pattern of which was similar to the earlier report. Our data indicate that MED12 exon 2 mutations may be tissue-specific to uterine leiomyoma and rare in other tumors. Our study suggests that the MED12 mutations play unique roles in the pathogenesis of uterine leiomyomas and mutated MED12 could be therapeutically targeted in uterine leiomyomas. PMID- 22532226 TI - The C-terminal fragment of the immunoproteasome PA28S (Reg alpha) as an early diagnosis and tumor-relapse biomarker: evidence from mass spectrometry profiling. AB - This study reports on the C-terminal fragment of the 11S proteasome activator complex (PA28 or Reg alpha), a novel ovarian-specific biomarker of early and late stages of ovarian cancer (OVC) relapse, in patient biopsies after chemotherapy. A total of 179 tissue samples were analyzed: 8 stage I, 55 stage III-IV, 10 relapsed serous carcinomas, 25 mucinous carcinomas and 12 borderline and 68 benign ovarian tissue samples. This fragment was detected by MALDI mass spectrometry profiling in conjunction with a novel extraction method using hexafluoroisopropanol (1,1,1,3,3,3-hexafluoro-2-propanol; HFIP) solvents for protein solubilization and by immunohistochemistry using a specific antibody directed against the C-terminal fragment of PA28. Due to its specific cellular localization, this fragment is a suitable candidate for early OVC diagnosis, patient prognosis and follow-up during therapy and discriminating borderline cancers. Statistical analyses performed for this marker at different OVC stages reflect a prevalence of 77.66 +/- 8.77 % (with a correlation coefficient value p < 0.001 of 0.601 between OVC and benign tissue). This marker presents a prevalence of 88 % in the case of tumor relapse and is detected at 80.5 % in stage I and 81.25 % +/- 1.06 in stage III-IV of OVC. The correlation value for the different OVC stages is p < 0.001 of 0.998. Taken together, this report constitutes the first evidence of a novel OVC-specific marker. PMID- 22532227 TI - A model-based decision support system for critiquing mechanical ventilation treatments. AB - A computerized system for critiquing mechanical ventilation treatments is presented that can be used as an aide to the intensivist. The presented system is based on the physiological model of the subject's respiratory system. It uses modified versions of previously developed models of adult and neonatal respiratory systems to simulate the effects of different ventilator treatments on the patient's blood gases. The physiological models that have been used for research and teaching purposes by many researchers in the field include lungs, body tissue, and the brain tissue. The lung volume is continuously time-varying and the effects of shunt in the lung, changes in cardiac output and cerebral blood flow, and the arterial transport delays are included in the system. Evaluation tests were done on adult and neonate patients with different diagnoses. In both groups combined, the differences between the arterial partial pressures of CO(2) predicted by the system and the experimental values were 1.86 +/- 1.6 mmHg (mean +/- SD), and the differences between the predicted arterial hemoglobin oxygen saturation values, S(aO2), and the experimental values measured by using pulse oximetry, S(pO2), were 0.032 +/- 0.02 (mean +/- SD). The proposed system has the potential to be used alone or in combination with other decision support systems to set ventilation parameters and optimize treatment for patients on mechanical ventilation. PMID- 22532229 TI - Exposure classification of MRI workers in epidemiological studies. AB - We estimate that there are about 100,000 workers from different disciplines, such as radiographers, nurses, anesthetists, technicians, engineers, etc., who can be exposed to substantial electromagnetic fields (compared to normal background levels) around magnetic resonance imaging (MRI) scanners. There is a need for well-designed epidemiological studies of MRI workers but since the exposure from MRI equipment is a very complex mixture of static magnetic fields, switched gradient magnetic fields, and radiofrequency electromagnetic fields (RF EMF), it is necessary to discuss how to assess the exposure in epidemiological studies. As an alternative to the use of job title as a proxy of exposure, we propose an exposure categorization for the different professions working with MRI equipment. Specifically, we propose defining exposure in three categories, depending on whether people are exposed to only the static field, to the static plus switched gradient fields or to the static plus switched gradient plus RF fields, as a basis for exposure assessment in epidemiological studies. PMID- 22532228 TI - The role of fibrin glue instillation under skin flaps in the prevention of seroma formation and related morbidities following breast and axillary surgery for breast cancer: a meta-analysis. AB - A systematic review of randomised, controlled trials investigating the effectiveness of fibrin glue (FG) in reducing the postoperative seroma and seroma related morbidities following breast and axillary surgery was conducted. FG failed to influence the incidence of postoperative seroma, average volume of seroma, wound infection, complications and length of hospital stay in patients undergoing breast cancer surgery. However, a major multicentre and high quality randomised, controlled trial is required to validate these findings. PMID- 22532230 TI - Novel H2 activation by a tris[3,5-bis(trifluoromethyl)phenyl]borane frustrated Lewis pair. AB - Tris[3,5-bis(trifluoromethyl)phenyl]borane (1, BArF(18)), has been synthesised on a practical scale for the first time. According to the Gutmann-Beckett method it is a more powerful Lewis acid than B(C(6)F(5))(3). It forms a 'frustrated Lewis pair' with 2,2,6,6-tetramethylpiperidine which cleaves H(2) to form a salt containing the novel anion [MU-H(BArF(18))(2)](-). PMID- 22532231 TI - Influence of estrogen replacement and aging on the expression of nerve growth factor in the urethra of female rats. AB - OBJECTIVE: To evaluate the expression of nerve growth factor (NGF) in the urethra of adult female rats in different hormonal status using immunohistochemical assay. METHODS: Forty-eight rats (Rattus norvegicus albinus, Rodentia, Mammalia) from the CEDEME-UNIFESP laboratory animal facility were used in the study. Rats were divided into four groups: group A, 12 non-neutered rats; group B, 12 oophorectomized rats; group C, 12 castrated rats treated with 17beta-estradiol for 30 days; and group D, 12 aging rats. Animals were killed by lethal injection and their urethra was removed. NGF expression was evaluated by means of immunohistochemistry using mouse monoclonal primary IgG antibody anti-NGF diluted 1:600, and read under 400* magnification. Digital analysis of the images was done by Imagelab software. The intensity of the dark brown color was used as a measure of NGF cytoplasmatic expression, and was used to quantify the percentage of epithelial and muscular layer cells showing this neurotrophin. RESULTS: After oophorectomy, rats showed a significant increase in NGF expression in the periurethral muscular layer. Compared with oophorectomized rats, NGF expression increased in the epithelial layer and diminished in the periurethral smooth muscle following estrogen administration. In 18-month-old rats, NGF expression was diminished in both epithelial and muscular layers. CONCLUSIONS: Hormonal status led to significant differences in NGF protein expression in urethral epithelium and periurethral smooth muscle. PMID- 22532232 TI - Oral alendronate use and risk of cancer in postmenopausal women with osteoporosis: A nationwide study. AB - The association between use of oral bisphosphonates and cancer development in elderly women is still uncertain, and previous studies have shown controversial results. We used a nationwide, population-based database to explore the relationship between the use of alendronate, an oral bisphosphonate agent used for the treatment of osteoporosis, and the risk of all malignancies in women with osteoporosis and age over 55 years. In the study group, we included 6906 women with osteoporosis (age, mean +/- SD, 73.4 +/- 8.4 years) taking oral alendronate, who were selected from a 1,000,000 sample cohort dataset collected between January 1998 and December 2009. Another 20,697 age- and comorbidity-matched women (73.5 +/- 8.4 years) without bisphosphonates treatment were included in the control group. No subjects had any history of being diagnosed with cancer before inclusion. We used a log-rank test to analyze the differences in accumulated cancer-free survival rates between these two groups. A Cox proportional-hazard model, adjusted for confounding factors, was used to evaluate the association between alendronate use and the development of all cancer events in postmenopausal women with osteoporosis. During the mean follow-up period of 4.8 years, 821 patients from the study group and 2646 patients from the control group had new cancers. There was no significant difference in cancer incidence between alendronate users and controls (11.9% versus 12.8%, p = 0.054). The person-year incidence of newly-developed cancer in alendronate users and controls was 28.0 and 29.4 per 1000 person-years, respectively. Alendronate use was not associated with increased risk of cancer development in women with osteoporosis (adjusted hazard ratio, 1.05; 95% confidence interval [CI], 0.97-1.13; p = 0.237). However, due to the limited study size and underpowered results, further larger prospective studies or meta-analysis are suggested to further confirm our findings. PMID- 22532233 TI - Prenatal diagnosis of fetal skeletal dysplasia with 3D CT. AB - BACKGROUND: Clinical use of 3D CT for fetal skeletal malformations is controversial. OBJECTIVE: The purpose of this study was to evaluate the efficacy of fetal 3D CT using three protocols with different radiation doses and through comparing findings between fetal CT and conventional postnatal radiographic skeletal survey. MATERIALS AND METHODS: Seventeen fetuses underwent CT for suspected skeletal dysplasia. A relay of three CT protocols with stepwise dose reduction were used over the study period. The concordance between the CT diagnosis and the final diagnosis was assessed. Ninety-three radiological findings identifiable on radiographs were compared with CT. RESULTS: Fetal CT provided the correct diagnosis in all 17 fetuses, the detectability rate of cardinal findings was 93.5 %. In 59 % of the fetuses an US-based diagnosis was changed prenatally due to CT findings. The estimated fetal radiation dose in the final protocol was 3.4 mSv (50 %) of the initial protocol, and this dose reduction did not result in degraded image quality. CONCLUSION: The capability of fetal CT to delineate the skeleton was almost the same as that of postnatal skeletal survey. The perinatal management was altered due to these more specific CT findings, which aided in counseling and in the management of the pregnancy. PMID- 22532234 TI - Color Doppler US of normal cerebral venous sinuses in neonates: a comparison with MR venography. AB - BACKGROUND: Color Doppler US (CDUS) has been used for evaluation of cerebral venous sinuses in neonates. However, there is very limited information available regarding the appearance of superficial and deep normal cerebral venous sinuses using CDUS and the specificity of the technique to rule out disease. OBJECTIVE: To determine the specificity, inter-modality and inter-reader agreement of color Doppler US (CDUS). To evaluate normal cerebral venous sinuses in neonates in comparison to MR venography (MRV). MATERIALS AND METHODS: Newborns undergoing a clinically indicated brain MRI were prospectively evaluated. All underwent a dedicated CDUS of the cerebral venous sinuses within 10 h (mean, 3.5 h, range, and 2-7.6 h) of the MRI study using a standard protocol. RESULTS: Fifty consecutive neonates participated in the study (30 males [60%]; 25-41 weeks old; mean, 37 weeks). The mean time interval between the date of birth and the CDUS study was 19.1 days. No cases showed evidence of thrombosis. Overall agreement for US reading was 97% (range, 82-100%), for MRV reading, 99% (range, 96-100%) and for intermodality, 100% (range, 96-100%). Excellent US-MRI agreement was noted for superior sagittal sinus, cerebral veins, straight sinus, torcular Herophili, sigmoid sinus, superior jugular veins (94-98%) and transverse sinuses (82-86%). In 10 cases (20%), MRV showed flow gaps whereas normal flow was demonstrated with US. Visualization of the inferior sagittal sinus was limited with both imaging techniques. CONCLUSION: Excellent reading agreement was noted for US, MRV and intermodality. CDUS is highly specific to rule out cerebral venous thrombosis in neonates and holds potential for clinical application as part of clinical-laboratory-imaging algorithms of pre/post-test probabilities of disease. PMID- 22532235 TI - Synthesis and anticonvulsant activities of some triazolothiadiazole derivatives. AB - The present study describes the synthesis and anticonvulsant activity evaluation of 6-substituted-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives (4a-4x) and their partially dehydrogenated products 5,6-dihydro-6-substituted [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives (5a-5n). The bioevaluation demonstrated that most compounds in the series of 4a-4x exhibited potent anticonvulsant activity in the maximal electroshock test. Among which, 6-(4 chlorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (4h) emerged as the most promising candidate on the basis of its favorable ED(50) value of 23.7 mg/kg and PI value of 10.8. In addition, the potency of compound 4h against seizures induced by pentylenetetrazole, 3-mercaptopropionic acid, and bicuculline in the chemical-induced seizure tests suggested that compound 4h displayed broad spectrum activity in several models, and it may exert its anticonvulsant activity through affecting the GABAergic system. PMID- 22532236 TI - The impact of time cost of physical exercise on health outcomes by older adults: the DR's EXTRA Study. AB - When the motivation for exercise is high and people are retired, the cost of time used for physical exercise may be lower and individuals may exercise more compared to individuals with a low motivational level and in working life. The aim was to study the effect of time cost of physical exercise on the amount of physical exercise and on health-related quality of life. We used 2-year data (n = 1,292) from a 4-year randomised controlled trial in a population-based sample of Eastern Finnish men and women, 57-78 years of age at baseline, in 2005-2006. In the statistical analysis, physical exercise and health outcomes were assumed to be endogenous variables explained with a set of exogenous variables. The statistical modelling was done by panel data instrumental variable regressions. Health-related quality of life was evaluated by the RAND 36-item survey and motives for exercise with a questionnaire. Joy as the motivation for physical exercise and retirement increased the amount of physical exercise per week (p < 0.001). A higher amount of exercise was associated with physical (p < 0.001) and mental (p < 0.001) components of quality of life. Moreover, a higher amount of physical exercise decreased the metabolic risk factor score (p < 0.001). The motivation and extra time, i.e. retirement, have a significant impact on the time spent on physical exercise (p < 0.001). Our data agree with the theory that high motivation and retirement lower the time cost of physical exercise. The results emphasise that motivation and the labour market position are important in determining the cost of physical exercise. PMID- 22532237 TI - [Chronic migraine, a new and necessary concept]. PMID- 22532238 TI - [Chronic migraine: pathophysiology]. AB - Chronic migraine is considered a complication of episodic migraine. Several risk factors, which may be modifiable or non-modifiable, make varying contributions to the progression towards chronification. Every year 2.5% of patients with episodic migraine go on to suffer chronic migraine. Experimental studies point to a dysfunction in the descending pain modulatory system that would facilitate nociceptive afferents, in the absence of damage to tissues, and so chronic migraine would share a pathogenesis that is similar to that of fibromyalgia, irritable bowel syndrome or chronic tension-type headache (conditions that frequently coexist). This paper reviews the risk factors and the scientific evidence of the possible pathogenic mechanisms involved in the progression towards chronification. PMID- 22532239 TI - [Chronic migraine: clinical manifestations and differential diagnosis]. AB - Chronic migraine is a condition that has been present since the dawn of medicine, although only recently has progress been made in characterising it nosologically. It is the result of the evolution of episodic migraine which, at one particular moment and in relation to certain risk factors, changes its characteristics. The diagnostic criteria of chronic migraine, which were initially very restrictive and based on the specific type of patient from the most important headache units, are gradually being adjusted to match the real situation experienced in most neurology departments. The consideration of medication abuse criteria has also evolved and this has made it possible to perform a prospective diagnosis of these cases, instead of requiring withdrawal from the abuse, which is not also feasible in practice. The influence of medication abuse in the development of chronic migraine remains a controversial issue. In our opinion, abuse is an important risk factor for the chronification of migraine, but it is not a necessary or a sufficient condition for it to become chronic. Like other authors, we recommend the use of the term 'chronic migraine' indistinctly for patients with or without abuse. The diagnosis of chronic migraine is not always a simple matter; the anamnesis is our best weapon, although in our patients with headache we must get used to taking into account not only the most striking bouts of pain but also the intercritical periods. The differential diagnosis has to be considered in cases of chronic headaches with prolonged episodes of pain. We draw special attention to its differentiation from tension-type headache and we recommend avoiding whenever possible the use of the term 'mixed headache'. PMID- 22532240 TI - [Chronic migraine: its epidemiology and impact]. AB - Chronic migraine (that is to say, cases where migraine is suffered on 15 or more days per month) is an illness that affects approximately 0.5-2.5% of the population, depending on the statistics that are analysed and the definition of chronic migraine used. The incidence of transformation from episodic to chronic migraine is 3% per year, and 6% go from low-frequency (1-9 days/month) to high frequency migraine (10-14 days/month). The risk factors for developing chronic migraine are genetic, frequent use of painkillers, being female, having poor hygienic-dietary habits, developing anxiety/depression, having a low socioeconomic status, suffering from obesity and being divorced or widowed. Despite the modification of the risk factors, it has still not been proved that the chances of developing chronic migraine can be lowered. Chronic migraine has an important impact on patients' quality of life, as measured on disability, quality of life and impact on daily activities scales. These patients have twice the chance of suffering from depression, anxiety and chronic pain, which means they therefore need greater health care. Many have still to be diagnosed and treated, however. In a Spanish epidemiological study, a follow-up was carried out on patients with chronic daily headache after undergoing a therapeutic intervention and up to 60% of the patients showed improvement. In other words, with increased interest and diagnosis of this illness, many patients would benefit from suitable treatments. PMID- 22532241 TI - [Chronic migraine: treatment]. AB - We define chronic migraine as that clinical situation in which migraine attacks appear 15 or more days per month. Until recently, and in spite of its negative impact, patients with chronic migraine were excluded of the clinical trials. This manuscript revises the current treatment of chronic migraine. The first step should include the avoidance of potential precipitating/aggravating factors for chronic migraine, mainly analgesic overuse and the treatment of comorbid disorders, such as anxiety and depression. The symptomatic treatment should be based on the use of nonsteroidal anti-inflammatory agents and triptans (in this case < 10 days per month). It is necessary to avoid the use of combined analgesics, opioids and ergotamine-containing medications. Preventive treatment includes a 'transitional' treatment with nonsteroidal anti-inflammatory agents or steroids, while preventive treatment exerts its actions. Even though those medications efficacious in episodic migraine prevention are used, the only drugs with demonstrated efficacy in the preventive treatment of chronic migraine are topiramate and pericranial infiltrations of Onabotulinumtoxin A. PMID- 22532242 TI - [Onabotulinumtoxin A in the treatment of chronic migraine]. AB - INTRODUCTION. Chronic migraine is the most frequent complication of migraine. Its management is complex and difficult, and is based essentially on preventive measures. AIM. To analyse the development of the use of Onabotulinumtoxin A (OnabotA) in migraine, especially in its chronic form, the method of administration, its mechanism of action, its safety profile and its possible indications in clinical practice. DEVELOPMENT. The study conducts a thorough review of all the clinical trials in the literature that have used OnabotA in the prevention of migraine, both in its episodic and its chronic forms, and the outcomes in the chronic form are analysed in detail. CONCLUSIONS. In studies in phase III, OnabotA has proved to be effective in the treatment of patients with chronic migraine, with significant reductions in the mean frequency of days with headaches, the number of headache episodes, the days with migraine or the proportion of patients with severe disability, in addition to other parameters. It is also effective in the subgroup of patients with symptomatic headache due to medication abuse. OnabotA has proved to be safe and well tolerated in this indication, with foreseeable, usually mild or moderate, transitory side effects. In sum, OnabotA is a safe, well-tolerated alternative in the preventive treatment of chronic migraine. PMID- 22532243 TI - SOCS-1 gene delivery cooperates with cisplatin plus pemetrexed to exhibit preclinical antitumor activity against malignant pleural mesothelioma. AB - Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis for which an effective therapy remains to be established. This study investigated the therapeutic potential of gene delivery using suppressor of cytokine signaling 1 (SOCS-1), an endogenous inhibitor of intracellular signaling pathways, for the treatment of MPM. We infected MPM cells (MESO-4, H28 and H226) with adenovirus expressing SOCS-1 vector to examine the effect of SOCS-1 overexpression on MPM cells. We evaluated the antitumor effect of SOCS-1 gene delivery combined with cisplatin plus pemetrexed by cell proliferation, apoptosis and invasion assay. We also investigated the regulation of NF-kappaB and STAT3 signaling related to apoptotic pathways. Furthermore, we evaluated the inhibition of tumor growth by SOCS-1 gene delivery combined with cisplatin plus pemetrexed in vivo. SOCS-1 gene delivery cooperated with cisplatin plus pemetrexed to inhibit cell proliferation, invasiveness and induction of apoptosis in MPM cells. SOCS-1 regulated NF-kappaB and STAT3 signaling to induce apoptosis in MESO-4 and H226 cells. Furthermore, SOCS-1 gene delivery cooperated with cisplatin plus pemetrexed to regulate NF kappaB signaling and significantly inhibit tumor growth of MPM in vivo. These results suggest that SOCS-1 gene delivery has a potent antitumor effect against MPM and a potential for clinical use in combination with cisplatin plus pemetrexed. PMID- 22532244 TI - Immunohistochemical study of epiretinal membranes in patients with uveitis. AB - BACKGROUND: The purpose of this study is to report two cases of idiopathic uveitis with secondary epiretinal membrane (ERM) formation in order to describe histologic and immunohistochemical features that may help distinguish uveitic from idiopathic ERMs. METHODS: The study utilized a clinical case series and histopathological and immunohistochemical findings. RESULTS: There was no identifiable etiology of inflammation in either case. Histology and immunohistochemistry demonstrated a mixture of abundant inflammatory cells, including lymphocytes, histiocytes, plasma cells, and occasional eosinophils, among a stromal matrix composed of glial elements and condensed vitreous, but no retinal pigment epithelium (RPE) was present. The relative proportions of the various inflammatory cell types were assessed with immunohistochemistry, and among the lymphocyte population, T cells predominated over B cells. In one of the cases, there was an abundance of histiocytes, consistent with granulomatous uveitis, which was later confirmed on histology of the enucleated globe. CONCLUSIONS: Idiopathic ERM formation is thought to be secondary to glial cell migration that may require some involvement of RPE cells. The absence of RPE and abundance of inflammatory cells may be used to identify ERMs as secondary to uveitis. PMID- 22532245 TI - Hormaphis hamamelidis fundatrices benefit by manipulating phenolic metabolism of their host. AB - We investigated the pattern and potential adaptive value of phenolic concentrations in galls induced by the aphid Hormaphis hamamelidis on leaves of Hamamelis virginiana. By the time that founding females began reproduction, galls had higher concentrations of condensed tannins and lower concentrations of hydrolyzable tannins than leaves. Galled and ungalled leaf laminas never differed significantly in any phenolic measure. Condensed tannin concentrations also were positively related to the number of offspring per gall when gall dry weight, another important correlate of fecundity, was accounted for. This could indicate the prior sink strength of the gall. Polyphenols may act as a repository for excess carbon drawn to the gall by increased sink strength, or be an indication of the fundatrix' ability to manipulate host physiology. This study is the first to demonstrate a tangible, quantitative association between phenolic accumulation in galls and gall-former reproductive performance, and illustrates that condensed tannins may play roles other than plant defense. PMID- 22532246 TI - Chiral hetero- and carbocyclic compounds from the asymmetric hydrogenation of cyclic alkenes. AB - Several types of chiral hetero- and carbocyclic compounds have been synthesized by using the asymmetric hydrogenation of cyclic alkenes. N,P-Ligated iridium catalysts reduced six-membered cyclic alkenes with various substituents and heterofunctionality in good to excellent enantioselectivity, whereas the reduction of five-membered cyclic alkenes was generally less selective, giving modest enantiomeric excesses. The stereoselectivity of the hydrogenation depended more strongly on the substrate structure for the five- rather than the six membered cyclic alkenes. The major enantiomer formed in the reduction of six membered alkenes could be predicted from a selectivity model and isomeric alkenes had complementary enantioselectivity, giving opposite optical isomers upon hydrogenation. The utility of the reaction was demonstrated by using it as a key step in the preparation of chiral 1,3-cis-cyclohexane carboxylates. PMID- 22532247 TI - Fabrication of composite photocatalyst g-C3N4-ZnO and enhancement of photocatalytic activity under visible light. AB - The g-C(3)N(4)-ZnO composite photocatalysts with various weight percents of ZnO were synthsized by a simple calcination process. The photocatalysts were characterized by powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HR-TEM), UV-vis diffuse reflection spectroscopy (UV-vis), X-ray photoelectron spectroscopy (XPS) and thermogravimetric analysis (TGA). The PXRD and HR-TEM results show that the composite materials consist of hexagonal wurzite phase ZnO and g-C(3)N(4). The solid-state UV-vis diffuse reflection spectra show that the absorption edge of the composite materials shifts toward the lower energy region and to longer wavelengths in comparison with pure ZnO and g-C(3)N(4). Remarkably, the photocatalytic activity of g-C(3)N(4)-ZnO composites has been demonstrated, via photodegradation of Methyl Orange (MO) and p-nitrophenol experiments. The photocatalytic activity of g-C(3)N(4)-ZnO for photodegradation of Methyl Orange and p-nitrophenol under visible light irradiation was increased by over 3 and 6 times, respectively, to be much higher than that of single-phase g-C(3)N(4), clearly demonstrating a synergistic effect between ZnO and g-C(3)N(4). The concentrations of Zn(2+) in g-C(3)N(4)-ZnO system after a photocatalytic reaction at various reaction times were found to be much lower than those for a ZnO system under the same reaction conditions, indicating that the g-C(3)N(4)-ZnO composite possesses excellent long-term stability for a photocatalytic reaction in aqueous solutions. Furthermore, a synergistic photocatalysis mechanism between ZnO and g C(3)N(4) was proposed based on the photodegradation results. Such obviously improved performance of g-C(3)N(4)-ZnO can be ascribed mainly to the enhancement of electron-hole separations at the interface of ZnO and g-C(3)N(4). PMID- 22532248 TI - Enhanced interpretability of the PFDI-20 with establishment of reference scores among women in the general population. AB - AIMS: To enhance the interpretability of the PFDI-20 by establishing a score distribution for women in the general population and to determine whether scores correspond with urinary and anal incontinence (UI and AI). METHODS: Subjects recruited during Twins Day Festivals from 2004 to 2009 completed a survey assessing for stress and urgency urinary incontinence (SUI and UUI) and AI of flatus and stool. Score distributions for the PFDI-20 and each of its subscales were determined for all subjects and for women with isolated forms of incontinence. Scores were compared between continent and incontinent women and between incontinent subtypes by Wilcoxon rank-sum tests. RESULTS: One thousand three hundred seventy-six women completed the survey with PFDI-20 (Median = 8.9, IQR 31.3), POPDI-6 (Median = 0, IQR = 8.3), CRADI-8 (Median = 0, IQR = 10.7), and UDI-6 (Median = 0, IQR = 16.7). PFDI-20, POPDI-6, CRADI-8, and UDI-6 scores were significantly greater among women reporting isolated SUI (P < 0.0001, P = 0.04, P < 0.0001, P < 0.0001, respectively), UUI (P < 0.0001, P = 0.02, P < 0.0001, P < 0.0001, respectively), mixed UI (P < 0.0001 each), AI flatus (P < 0.0001 each), and AI stool (P < 0.0001 each) compared to those denying incontinence. Women with mixed UI had significantly greater PFDI-20 and UDI-6 scores compare to those with SUI (P < 0.0001) or UUI (P < 0.0001). Subjects with AI stool had significantly greater PFDI-20 and CRADI-8 scores compared to those with AI flatus (P = 0.01). CONCLUSIONS: PFDI-20 scores from a sample of the general population correspond with the presence or absence of UI and AI. These normative and symptom-specific score distributions for the PFDI-20 provide reference points to gauge the effect of disease and intervention on quality of life for women with incontinence. PMID- 22532249 TI - Aloe-emodin suppresses prostate cancer by targeting the mTOR complex 2. AB - Phosphatidylinositol 3-kinase (PI3-K) amplification and phosphatase and tensin homolog (PTEN) deletion-caused Akt activation contribute to the development of prostate cancer. Mammalian target of rapamycin complex 2 (mTORC2) is a kinase complex comprised of mTOR, Rictor, mSin1, mLST8/GbetaL and PRR5 and functions in the phosphorylation of Akt at Ser473. Herein, we report that mTORC2 plays an important role in PC3 androgen refractory prostate cell proliferation and anchorage-independent growth. Aloe-emodin, a natural compound found in aloe, inhibited both proliferation and anchorage-independent growth of PC3 cells. Protein content analysis suggested that activation of the downstream substrates of mTORC2, Akt and PKCalpha, was inhibited by aloe-emodin treatment. Pull-down assay and in vitro kinase assay results indicated that aloe-emodin could bind with mTORC2 in cells and inhibit its kinase activity. Aloe-emodin also exhibited tumor suppression effects in vivo in an athymic nude mouse model. Collectively, our data suggest that mTORC2 plays an important role in prostate cancer development and aloe-emodin suppresses prostate cancer progression by targeting mTORC2. PMID- 22532250 TI - Integrated analysis of genetic and epigenetic alterations reveals CpG island methylator phenotype associated with distinct clinical characters of lung adenocarcinoma. AB - DNA methylation affects the aggressiveness of human malignancies. Cancers with CpG island methylator phenotype (CIMP), a distinct group with extensive DNA methylation, show characteristic features in several types of tumors. In this study, we initially defined the existence of CIMP in 41 lung adenocarcinomas (AdCas) through genome-wide DNA methylation microarray analysis. DNA methylation status of six CIMP markers newly identified by microarray analysis was further estimated in a total of 128 AdCas by bisulfite pyrosequencing analysis, which revealed that 10 (7.8%), 40 (31.3%) and 78 (60.9%) cases were classified as CIMP high (CIMP-H), CIMP-low and CIMP-negative (CIMP-N), respectively. Notably, CIMP-H AdCas were strongly associated with wild-type epidermal growth factor receptor (EGFR), males and heavy smokers (P = 0.0089, P = 0.0047 and P = 0.0036, respectively). In addition, CIMP-H was significantly associated with worse prognosis; especially among male smokers, CIMP-H was an independent prognostic factor (hazard ratio 1.7617, 95% confidence interval 1.0030-2.9550, P = 0.0489). Compellingly, the existence of CIMP in AdCas was supported by the available public datasets, such as data from the Cancer Genome Atlas. Intriguingly, analysis of AdCa cell lines revealed that CIMP-positive AdCa cell lines were more sensitive to a DNA methylation inhibitor than CIMP-N ones regardless of EGFR mutation status. Our data demonstrate that CIMP in AdCas appears to be a unique subgroup that has distinct clinical traits from other AdCas. CIMP classification using our six-marker panel has implications for personalized medical strategies for lung cancer patients; in particular, DNA methylation inhibitor might be of therapeutic benefit to patients with CIMP-positive tumors. PMID- 22532251 TI - A transcriptome signature of endothelial lymphatic cells coexists with the chronic oxidative stress signature in radiation-induced post-radiotherapy breast angiosarcomas. AB - Radiation-induced breast angiosarcomas are rare but recognized complication of breast cancer radiotherapy and are of poor prognosis. Little is known about the genetic abnormalities present in these secondary tumors. Herein, we investigated the differences in the genome and in the transcriptome that discriminate these tumors as a function of their etiology. Seven primary breast angiosarcomas and 18 secondary breast angiosarcomas arising in the irradiation field of a radiotherapy were analyzed. Copy number alterations and gene expression were analyzed using Affymetrix SNP 6.0 Array and Affymetrix Exon Arrays, respectively. We showed that two transcriptome signatures of the radiation tumorigenesis coexisted in these tumors. One was histology specific and correctly discriminated 100% of the primary tumors from the radiation-induced tumors. The deregulation of marker genes, including podoplanin (PDPN), prospero homeobox 1 (PROX-1), vascular endothelial growth factor 3 (VEGFR3) and endothelin receptor A (EDNRA), suggests that the radiation-induced breast angiosarcomas developed from radiation stimulated lymphatic endothelial cells. None of the genes of the histology specific signature were present in our previously published signature of the radiation tumorigenesis which shows the presence of a chronic oxidative stress in radiation-induced sarcomas of various histologies. Nevertheless, this oxidative stress signature classified correctly 88% of the breast angiosarcomas as a function of the etiology. In contrast, MYC amplification, which is observed in all radiation-induced tumors but also at a low rate in primary tumors, was not a marker of the radiation tumorigenesis. PMID- 22532252 TI - PET/CT for staging and follow-up of pediatric nasopharyngeal carcinoma. AB - PURPOSE: While FDG PET/CT for the evaluation of nasopharyngeal carcinoma (NPC) in adult patients has documented advantages and disadvantages compared with conventional imaging, to our knowledge, no studies of FDG PET/CT for the evaluation of NPC in pediatric patients have been performed. In this investigation, we studied the utility of FDG PET/CT in children with NPC. METHODS: The study group comprised 18 children with biopsy-proven NPC who underwent FDG PET/CT and MRI (total 38 pairs of images). All baseline and follow up FDG PET/CT and MRI studies were independently reviewed for restaging of disease. RESULTS: The concordance between FDG PET/CT and MRI in T, N, and overall staging was 29%, 64%, and 43%, respectively. Compared with MRI, FDG PET/CT yielded lower T and overall staging and showed less cervical and retropharyngeal lymphadenopathy. The concordance between follow-up FDG PET/CT and MRI was 79% overall and 100% 9 months after therapy. In patients who achieved complete remission, FDG PET/CT showed disease clearance 3-6 months earlier than MRI. There were no false-positive or false-negative FDG PET/CT scans during follow-up. CONCLUSION: FDG PET/CT may underestimate tumor extent and regional lymphadenopathy compared with MRI at the time of diagnosis, but it helps to detect metastases and clarify ambiguous findings. FDG PET/CT is sensitive and specific for follow-up and enables earlier determination of disease remission. FDG PET/CT is a valuable imaging modality for the evaluation and monitoring of NPC in pediatric patients. PMID- 22532253 TI - LV dyssynchrony as assessed by phase analysis of gated SPECT myocardial perfusion imaging in patients with Wolff-Parkinson-White syndrome. AB - PURPOSE: The purpose of this study was to evaluate left ventricular (LV) mechanical dyssynchrony in patients with Wolff-Parkinson-White (WPW) syndrome pre and post-radiofrequency catheter ablation (RFA) using phase analysis of gated single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI). METHODS: Forty-five WPW patients were enrolled and had gated SPECT MPI pre and 2-3 days post-RFA. Electrophysiological study (EPS) was used to locate accessory pathways (APs) and categorize the patients according to the AP locations (septal, left and right free wall). Electrocardiography (ECG) was performed pre- and post-RFA to confirm successful elimination of the APs. Phase analysis of gated SPECT MPI was used to assess LV dyssynchrony pre- and post-RFA. RESULTS: Among the 45 patients, 3 had gating errors, and thus 42 had SPECT phase analysis. Twenty-two patients (52.4%) had baseline LV dyssynchrony. Baseline LV dyssynchrony was more prominent in the patients with septal APs than in the patients with left or right APs (p < 0.05). RFA improved LV synchrony in the entire cohort and in the patients with septal APs (p < 0.01). CONCLUSION: Phase analysis of gated SPECT MPI demonstrated that LV mechanical dyssynchrony can be present in patients with WPW syndrome. Septal APs result in the greatest degree of LV mechanical dyssynchrony and afford the most benefit after RFA. This study supports further investigation in the relationship between electrical and mechanical activation using EPS and phase analysis of gated SPECT MPI. PMID- 22532255 TI - Heterocycles 27. Microwave assisted synthesis and antitumour activity of novel phenothiazinyl-thiazolyl-hydrazine derivatives. AB - A series of new phenothiazinyl-thiazolyl-hydrazine derivatives were synthesized by Hantzsch cyclization of 1-(10-ethyl-10H-phenothiazin-3-yl)-methylidene thiosemicarbazide with alpha-halocarbonyl derivatives. Comparison between classical and microwave assisted synthesis emphasizes the great advantages induced by microwaves irradiation which afforded high reaction yields in much shorter reaction time. Structural assignments were based on spectroscopic methods (high resolution NMR, FTIR, MS). The new compounds were tested in vitro for their antiproliferative activity against tumor cell lines using spectrometric methods. Most of the compounds exhibit cytotoxicity against hepatic and colon tumor cells in a dose-dependent mode and a relationship between the structure and their biological activity was observed. PMID- 22532254 TI - Use of pretreatment metabolic tumour volumes to predict the outcome of pharyngeal cancer treated by definitive radiotherapy. AB - PURPOSE: The aim of the study was to investigate the predictive role of pretreatment metabolic volume (MTV) in pharyngeal cancer (PC) patients treated with definitive (chemo) radiotherapy. METHODS: This retrospective analysis enrolled 64 patients with PC treated with (chemo) radiotherapy. All patients received pretreatment fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT. Four PET segmentation methods were used, namely applying an isocontour at a standardized uptake value (SUV) of either 2.5 or 3.0 (MTV2.5 and MTV3.0) or using fixed thresholds of either 40 or 50 % (MTV40 %, MTV50 %) of the maximum intratumoural FDG activity. Disease-free survival (DFS) and primary relapse-free survival (PRFS) were examined according to cutoffs of the median values for each MTV and the gross tumour volume (GTVp). Independent prognosticators were identified by Cox regression analysis. RESULTS: With a median follow-up of 24 months, 19 patients died, and 26 patients experienced tumour relapse at primary sites. Multivariate analysis of the DFS showed that MTV2.5 > 13.6 ml was the only predictor of relapse [p = 0.011, hazard ratio = 2.69, 95 % confidence interval (CI) 1.25-5.76]. The independent predictor for PRFS was MTV2.5 > 13.6 ml (p = 0.003, hazard ratio = 3.76, 95 % CI 1.57-8.92), whereas GTVp > 15.5 ml had a marginal impact on PRFS (p = 0.06, hazard ratio = 3.54, 95 % CI 0.97-11.85). Patients having tumours with MTV2.5 > 13.6 ml had a significantly inferior 2-year PRFS compared with patients who had lower MTV2.5 tumours (39 vs 72 %, respectively, p = 0.001). CONCLUSION: For PC patients treated with definitive (chemo)radiotherapy, pretreatment MTV2.5 volume achieved the best predictive value for primary recurrence, and the same value was also a prognosticator for DFS. PMID- 22532256 TI - Supratrigonal cystectomy with Hautmann pouch as treatment for neurogenic bladder in spinal cord injury patients: long-term functional results. AB - AIMS: To study clinical and urodynamic data along with immediate and long-term morbidity of surgical management of neurogenic bladder in spinal cord injury (SCI) patients METHODS: Single-center retrospective study of 61 SCI patients with neurogenic detrusor overactivity (NDO) related urinary incontinence and/or sphincter weakness incontinence who underwent supratrigonal cystectomy with Hautmann pouch +/- concomitant stress incontinence procedure (27.9%; n = 17). RESULTS: With a mean follow-up of 5.84 years (range 1-20.5) an improved or total continence rate was achieved in 89.7% and 74.1%, respectively. Surgery failed (incontinence persisted) for six (10.3%) patients, three of which had a simultaneous procedure for stress incontinence. On urodynamics, maximum cystometric capacity (MCC) (ml) increased from 305.2 to 509.4 (P < 0.05), mean compliance (ml/cmH(2) O) increased from 15 to 42.7 (P < 0.05) and mean detrusor pressure at MCC (cmH(2) O) fell from 54.1 to 19.1 (P < 0.05). Persisent NDO occurred in 20.7% compared to 59% pre-operatively (P < 0.05). The overall complication rate was 37.7% but <=Clavien grade 2 in 82.6%. Notably, the incidence of bowel dysfunction, namely diarrhea and/or fecal incontinence was 27.5%. Concomitant outlet surgery was associated with increased morbidity as three (17.6%) complications led to re-intervention. CONCLUSIONS: Supratrigonal cystectomy with Hautmann pouch is an excellent surgical treatment for SCI patients suffering from refractory NDO incontinence. It achieves the main goals of achieving continence (74% complete), reducing rates of infection and preserving upper tract function, which is reflected in the improvement on urodynamics. The incidence of secondary bowel dysfunction and potential risk of a simultaneous procedure for stress incontinence needs to be discussed. PMID- 22532257 TI - Relevance of hand dominance to the bilateral deficit phenomenon. AB - During maximal voluntary contractions, the sum of forces exerted by homonymous muscles when activated unilaterally (UL) is, typically, larger than the sum of forces when activated bilaterally (BL). This phenomenon is known as the bilateral deficit (BLD). Our purpose was to determine if the dominant limb would be inhibited to a greater degree in the BL condition, thereby reducing any disparity in force output between the limbs. Maximum voluntary handgrip strength was measured in 40 left-handed and 40 right-handed individuals under both BL and UL conditions. The right-handers displayed 10.4 % greater right hand strength in both conditions; the left-handers exhibited 5.5 % greater left hand strength in the UL and 4.3 % in the BL condition. A BLD (-1.30 %) was present in the left handed group only but a reduction in the force disparity between the hands was not evident. It was observed, however, that seven individuals from each group exhibited greater UL force with their non-dominant hand. Accordingly, we re analyzed the data after rearranging the groups based on unilateral hand grip strength dominance. A significant reduction in force disparity between the hands occurred for the left-handed group only, the result of a significant inhibition of the stronger left hand. A trend towards a similar reduction occurred for the right-handers because of a significant force reduction of the stronger right hand. Consequently, it appears that for maximum handgrip contractions, the BLD may be related to preferential inhibition of the stronger hand, especially for individuals who are left-hand-strength-dominant in terms of unilateral force output. PMID- 22532258 TI - Pseudoaneurysm of the superior thyroid artery following revision tracheostomy. AB - This case report describes the presentation and management of a rare complication of pseudoaneurysm of the superior thyroid artery following tracheostomy. The majority of post-tracheostomy bleeding is managed either with packing or surgical re-exploration. However, angiography can pinpoint an arterial source of bleeding and allow the surgeon to address it via either a traditional open surgical approach or with minimally invasive endovascular embolization. PMID- 22532259 TI - Purification, characterization of a CkChn134 protein from Cynanchum komarovii seeds and synergistic effect with CkTLP against Verticillium dahliae. AB - Cynanchum komarovii Al Iljinski is a desert plant that has been used as analgesic, anthelminthic, and antidiarrheal, but also as herbal medicine to treat cholecystitis in people. In this work, an antifungal protein with sequence homology to chitinase was isolated from C. komarovii seeds and named CkChn134. The three-dimensional structure prediction of CkChn134 indicated that the protein has a loop domain formed a thin cleft, which is able to bind molecules and substrates. The protein and CkTLP synergistically inhibited the fungal growth of Verticillium dahliae, Fusarium oxysporum, Rhizoctonia solani, Botrytis cinerea, and Valsa mali in vitro. The full-length cDNA was cloned by RT-PCR and RACE-PCR according to the partial protein sequences obtained by nanoESI-MS/MS. The real time PCR showed that the transcription level of CkChn134 had a significant increase under the stress of ethylene, NaCl, low temperature, drought, and pathogen infection, which indicates that CkChn134 may play an important role in response to abiotic and biotic stresses. The CkChn134 protein was located in the extracellular space/cell wall by CkChn134::GFP fusion protein in transgenic Arabidopsis. Furthermore, overexpression of CkChn134 significantly enhanced the resistance of transgenic Arabidopsis against V. dahliae. Interestingly, the coexpression of CkChn134 and CkTLP showed substantially greater protection against the fungal pathogen V. dahliae than either transgene alone. The results suggest that the CkChn134 is a good candidate protein or gene, and it had a potential synergistic effect with CkTLP for contributing to the development of disease-resistant crops. PMID- 22532260 TI - Joint hypermobility syndrome: a risk factor for fixed dystonia? PMID- 22532261 TI - [Skin infections with MRSA. Epidemiology and clinical features]. AB - Staphylococcus aureus is the most prevalent pathogen in dermatology causing a broad array of pyogenic, community-acquired (CA) and health care-associated (HA), acute and chronic, superficial and deep skin infections which can progress to life-threatening systemic infections. The pathogen causes also toxin-mediated diseases with cutaneous symptoms. Methicillin-resistant S. aureus (MRSA) strains are not sensitive to the beta-lactam antibiotics available in Germany. Even though they cause the same skin infections as methicillin -sensitive strains, they are associated with greater morbidity and mortality because of their resistance to therapy. In addition to HA-MSRA in hospitalized patients with well known and defined risk factors, there are new CA-MSRA strains which arise in the community or from, animal husbandry sources. These MSRA strains are also a problem in hospitals today. CA-MRSA strains often have special virulence factors, such as Panton Valentine leukocidin), and are often associated with specific often recurrent skin and soft tissue infections (furuncles, abscesses, necrotizing entities). PMID- 22532262 TI - [Vacation and tropical dermatoses]. AB - Besides fever and diarrhea, skin diseases are the third most common cause of morbidity in returning travelers after a stay in a tropical country. Approximately one- quarter of these dermatological symptoms can be referred to a classical tropical disease. The majority are of infectious origin. Often only the clinical appearance leads to the diagnosis of a tropical disease as myiasis, cutaneous larva migrans, tungiasis or cutaneous leishmaniasis. Not infrequently the dermatological symptoms lead to the diagnosis of a primarily systemic tropical disease. For example, an eschar with or without a rash might lead to the diagnosis of a South African tick bite fever caused by Rickettsia africae days before serology may turn positive. Less common tropical skin diseases such as lymphatic filariasis and loiasis need to be considered in returning long-term travelers and immigrants. PMID- 22532263 TI - [New apects in the diagnosis and therapy of dermatomycoses]. AB - Recent observations indicate that Arthroderma benhamiae can cause bullous tinea, that onychomycosis increasingly occurs in children and that molds can cause tinea like lesions. If a mycotic infection is suspected, the pathogen needs to be identified. The first genetic assays for the detection of dermatophytes have successfully been tested under routine conditions. Using appropriate techniques, genetic diagnosis is faster and more sensitive than a culture. Laboratory standards that would facilitate widespread implementation of genetic identification of dermatophytes have not yet been established. For the identification of yeasts, MALDI-TOF has already been established in many laboratories. This method is being refined for the diagnosis of hyphomycetes too. Newer antimycotics that are approved for certain systemic mycoses such as the triazoles voriconazole and posaconazole and the echinocandines caspofungin, micafungin und anidulafungin may be considered for dermatomycoses that cannot be treated by other therapies. Thermotherapy and photodynamic therapy are additional options in particularly difficult cases. PMID- 22532264 TI - Progress in radiotherapy for pediatric sarcomas. AB - Pediatric sarcoma includes a diverse group of pathologies classified, based on the cell of origin, as primary bone or soft tissue sarcomas. Radiotherapy plays an integral role in the multidisciplinary approach required for optimal therapy in these patients. The particular challenges faced by the radiation oncologist while treating these patients include the age of the patient and the location of these tumors, as they are very often adjacent to critical or growing organs. Technical advances in radiation oncology, including highly conformal planning and improved tumor delineation, may allow a reduction in radiation related toxicities with excellent tumor control. In this chapter, the role of radiotherapy will be reviewed as well as modern technologies that are currently available and under development, with an emphasis on the application of these strategies in the pediatric and young adult population. PMID- 22532265 TI - The double edged sword of bleeding and clotting from VEGF inhibition in renal cancer patients. AB - Vascular endothelial growth factor (VEGF) inhibitors have significantly improved outcomes in patients with advanced renal cell carcinoma (RCC). Multiple VEGF inhibiting orally administered tyrosine kinase inhibitors (TKIs) have been approved including sunitinib, sorafenib, pazopanib and most recently, axitinib. One VEGF inhibiting monoclonal antibody, bevacizumab, is approved in combination with interferon. However, these agents, besides the known progression-free survival benefits, are associated with a small but real risk of potentially life threatening and contrasting toxicities of thrombosis (both venous and arterial) and bleeding. Appropriate patient selection for VEGF inhibitors and prevention as well as prompt intervention to manage thrombosis and bleeding are necessary to forestall serious morbidities and mortality. PMID- 22532266 TI - Incidence and management of gastrointestinal perforation from bevacizumab in advanced cancers. AB - Bevacizumab (AvastinTM, Genentech) is a monoclonal antibody that deactivates the vascular endothelial growth factor leading to disruption of vital cancer signaling pathways and inhibition of angiogenesis which results in its anti-tumor activity. The use of bevacizumab in treating cancers has steadily increased since it was initially approved by the Food and Drug Administration for metastatic colorectal cancer. Clinical trials have revealed that bevacizumab has serious side effects, including spontaneous bowel perforation, which can occur in patients who have no involvement of the gastrointestinal tract by cancer. Although risk factors for bevacizumab-associated bowel perforation have been identified, it is still unclear which patients are specifically at risk for this complication. The management of bevacizumab-induced bowel perforation depends on the clinical presentation and the goals of care set by the treating physicians and the patient. PMID- 22532267 TI - Cancer incidence in professional flight crew and air traffic control officers: disentangling the effect of occupational versus lifestyle exposures. AB - Flight crew are occupationally exposed to several potentially carcinogenic hazards; however, previous investigations have been hampered by lack of information on lifestyle exposures. The authors identified, through the United Kingdom Civil Aviation Authority medical records, a cohort of 16,329 flight crew and 3,165 air traffic control officers (ATCOs) and assembled data on their occupational and lifestyle exposures. Standardised incidence ratios (SIRs) were estimated to compare cancer incidence in each occupation to that of the general population; internal analyses were conducted by fitting Cox regression models. All-cancer incidence was 20-29% lower in each occupation than in the general population, mainly due to a lower incidence of smoking-related cancers [SIR (95% CI) = 0.33 (0.27-0.38) and 0.42 (0.28-0.60) for flight crew and ATCOs, respectively], consistent with their much lower prevalence of smoking. Skin melanoma rates were increased in both flight crew (SIR = 1.87; 95% CI = 1.45 2.38) and ATCOs (2.66; 1.55-4.25), with rates among the former increasing with increasing number of flight hours (p-trend = 0.02). However, internal analyses revealed no differences in skin melanoma rates between flight crew and ATCOs (hazard ratio: 0.78, 95% CI = 0.37-1.66) and identified skin that burns easily when exposed to sunlight (p = 0.001) and sunbathing to get a tan (p = 0.07) as the strongest risk predictors of skin melanoma in both occupations. The similar site-specific cancer risks between the two occupational groups argue against risks among flight crew being driven by occupation-specific exposures. The skin melanoma excess reflects sun-related behaviour rather than cosmic radiation exposure. PMID- 22532268 TI - Whither lung EIT: where are we, where do we want to go and what do we need to get there? AB - Breathing moves volumes of electrically insulating air into and out of the lungs, producing conductivity changes which can be seen by electrical impedance tomography (EIT). It has thus been apparent, since the early days of EIT research, that imaging of ventilation could become a key clinical application of EIT. In this paper, we review the current state and future prospects for lung EIT, by a synthesis of the presentations of the authors at the 'special lung sessions' of the annual biomedical EIT conferences in 2009-2011. We argue that lung EIT research has arrived at an important transition. It is now clear that valid and reproducible physiological information is available from EIT lung images. We must now ask the question: How can these data be used to help improve patient outcomes? To answer this question, we develop a classification of possible clinical scenarios in which EIT could play an important role, and we identify clinical and experimental research programmes and engineering developments required to turn EIT into a clinically useful tool for lung monitoring. PMID- 22532270 TI - Changing the regioselectivity of a P450 from C15 to C11 hydroxylation of progesterone. AB - CYP106A2 is known as a 15beta-hydroxylase, but also shows minor 11alpha hydroxylase activity for progesterone. 11alpha-Hydroxyprogesterone is an important pharmaceutical compound with anti-androgenic and blood-pressure regulating activity. This work therefore focused on directing the regioselectivity of the enzyme towards hydroxylation at position 11 in the C ring of the steroid through a combination of saturation mutagenesis and rational site directed mutagenesis. With the aid of data from a homology model of CYP106A2 containing docked progesterone, together with site-directed mutagenesis of active site residues (Lisurek et al. ChemBioChem 2008, 9, 1439-1449), a saturation mutagenesis library at positions A395 and G397 was created. Screening of the library identified the mutants A395I and A395W/G397K as having 11alpha hydroxylase activities 8.9 and 11.5 times higher than that of the wild type (WT). In the next step, additional mutations were integrated by a rational site directed mutagenesis approach to increase the catalytic efficiency. Of the 40 candidates analyzed, the mutants A106T/A395I, A106T/A395I/R409L, and T89N/A395I turned out to display increased 11alpha-hydroxylase selectivities and activities relative to the WT (14.3-, 12.6-, and 11.8-fold increases in selectivity and 39.3 , 108-, and 24.4- in k(cat)/K(m)). In the last step of the study, the best mutants were applied in a whole-cell biotransformation. In these experiments the production (percentage) of 15beta-hydroxyprogesterone decreased from 50.4 % (wild type) to 4.8 % (mutant T89N/A395I), whereas that of 11alpha-hydroxyprogesterone increased from 27.7 to 80.9 %, thus demonstrating an impressive regioselectivity. PMID- 22532271 TI - Emulsion reactors: a new technique for the preparation of molecular imaging probes. PMID- 22532269 TI - Relationship between adipose tissue insulin resistance and liver histology in nonalcoholic steatohepatitis: a pioglitazone versus vitamin E versus placebo for the treatment of nondiabetic patients with nonalcoholic steatohepatitis trial follow-up study. AB - The PIVENS (Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis [NASH]) trial demonstrated that pioglitazone and vitamin E improved liver histology to varying degrees, but the mechanisms are unknown. We conducted a study to examine the changes in adipose tissue insulin resistance (Adipo-IR) during the PIVENS trial and its relationship to histological endpoints. Adipo-IR (fasting nonesterified fatty acids [NEFAs] * fasting insulin) was calculated at baseline and after 16 and 96 weeks of therapy. Compared to placebo, the baseline Adipo-IR was not different in either the vitamin E group (P = 0.34) or the pioglitazone group (P = 0.29). Baseline Adipo-IR was significantly associated with fibrosis score (P = 0.02), but not with other histological features or nonalcoholic fatty liver disease (NAFLD) activity score (NAS). After 16 weeks, compared to placebo, the pioglitazone group had a significant reduction in Adipo-IR (-15.7 versus -1.91; P = 0.02), but this effect did not persist at 96 weeks (-3.25 versus -4.28; P = 0.31). Compared to placebo, Adipo-IR in the vitamin E group did not change significantly either after 16 weeks (P = 0.70) or after 96 weeks (P = 0.85). Change in Adipo-IR at week 16 was not associated with changes in any histological parameters at week 96, but improvement in Adipo-IR at week 96 was significantly associated with improvement in ballooning (P = 0.03), fibrosis (P = 0.004), and NAS (P = 0.01). CONCLUSION: Vitamin E improved liver histology independent of changes in Adipo-IR, and pioglitazone treatment acutely improved Adipo-IR, but this was not sustained. Changes in Adipo-IR were associated with changes in liver histology, including fibrosis. PMID- 22532273 TI - Cardiovascular variability in Parkinson's disease and extrapyramidal motor slowing. AB - OBJECTIVE: Parkinson's disease (PD) is a degenerative neurological condition, associated with cardiovascular dysfunction. Many studies have utilised heart rate variability (HRV) to assess the autonomic nervous system in PD, but blood pressure variability (BPV) has received less attention. The purpose of the present study was to compare HRV and BPV between participants with established PD, extrapyramidal motor slowing (EPMS) (not reaching clinical criteria for PD), older healthy controls (OHC), and young healthy controls (YHC), in order to ascertain whether either of these measures can be used as an early marker of non motor symptoms in PD. METHODS: HRV was assessed at rest and during 2 min of slow deep breathing in 97 participants, divided into four groups: YHC (20-30 years; n = 19); OHC (67-83 years; n = 28); EPMS (59-91 years; n = 25) and PD (61-84 years; n = 25). RESULTS: Spectral analysis of blood pressure was performed on stable non invasive recordings of blood pressure obtained in 76 of the participants. Low frequency (LF) and high frequency (HF) components, and the LF/HF ratio, were measured. Significant differences were only seen between the YHC and the three older groups. For HRV this was seen at rest and during 2 min of slow deep breathing, whereas for BPV this was only seen during 2 min of slow deep breathing. INTERPRETATION: These data indicate that there are only age-related changes in HRV and BPV, and that neither technique is sensitive enough to provide an index of pre-clinical PD. PMID- 22532274 TI - Bortezomib-induced severe autonomic neuropathy. AB - Peripheral neuropathy is a known side effect of bortezomib therapy. Acute autonomic neuropathy may also follow treatment with this cytotoxic agent used for treatment of multiple myeloma. Here, we report clinical characteristics and patterns of autonomic involvement in a 75-year-old patient who presented with recurring syncopes. PMID- 22532275 TI - Correlation of magnetic AC field on cardiac myocyte Ca(2+) transients at different magnetic DC levels. AB - The purpose of this study was to determine the effect of extremely low frequency and weak magnetic fields (WMF) on cardiac myocyte Ca(2+) transients, and to explore the involvement of potassium channels under the WMF effect. In addition, we aimed to find a physical explanation for the effect of WMF on cardiac myocyte Ca(2+) transients. Indo-1 loaded cells, which were exposed to a WMF at 16 Hz and 40 nT, demonstrated a 75 +/- 4% reduction in cytosolic Ca(2+) transients versus control. Treatment with the K(ATP) channel blocker, glibenclamide, followed by WMF at 16 Hz exposure, blocked the reduction in cytosolic calcium transients while treatment with pinacidil, a K(ATP) channel opener, or chromanol 293B, a selective potassium channel blocker of the delayed rectifier K(+) channels, did not inhibit the effect. Based on these finding and the ion cyclotron resonance frequency theory, we further investigated the effect of WMF by changing the direct current (DC) magnetic field (B(0) ). When operating different DC magnetic fields we showed that the WMF value changed correspondingly: for B(0) = 44.5 uT, the effect was observed at 17.05 Hz; for B(0) = 46.5 uT, the effect was observed at 18.15 Hz; and for B(0) = 49 uT the effect was observed at 19.1 Hz. We can conclude that the effect of WMF on Ca(2+) transients depends on the DC magnetic field level. PMID- 22532276 TI - Genetic counseling for the orthodox jewish couple undergoing preimplantation genetic diagnosis. AB - Orthodox Jewish patients who seek genetic counseling are often placed in a difficult position of having to choose between their desire to follow Jewish religious instruction (halacha) and following the advice of the genetic counselor. In this article we will present the work of the Puah Institute based in Jerusalem that is dedicated to assisting and guiding such couples to navigate through the medical system and medical recommendations and create a harmony between modern genetic counseling and the Orthodox Jewish tradition. In light of the expanding use of preimplantation genetic diagnosis (PGD) for a variety of medical and non-medical conditions, this dilemma is even more poignant. There is an ethical debate regarding PGD and the correct parameters for its use. Here we present the Orthodox Jewish view of the use and abuse of PGD. We present three case studies that sought the assistance and guidance of the Puah Institute. Each of these cases raises ethical dilemmas for the genetic counselor and for the rabbinic counselor. We discuss; the status of the embryo, the status of a carrier of a genetic abnormality and whether PGD is an obligation or good practice. In addition we deal with whether PGD and the search for the desired traits can be defined as eugenics or not. PMID- 22532277 TI - Re: Harding C, Horsburgh B, Dorkin TJ, Thorpe AC. Quantifying the effect of urodynamic catheters on urine flow rate measurement. Neurourol Urodyn 2012;31:139 42. PMID- 22532278 TI - [Guillain-Barre syndrome with dysphagia after frontal sinusitis]. AB - One week after an acute sinusitis, a male patient developed a hypernasal voice, dysphagia, diplopic images, ataxia and paresthesias. He had paresis of the glossopharyngeal and abducens nerves, weakness of the arms and legs, and reflex deficiency. The neurography showed a motor axonal demyelinating neuropathy, so that the diagnosis of Guillain-Barre syndrome was made. After five courses of plasmapheresis, the symptoms improved rapidly. PMID- 22532279 TI - [Jugular vein thrombosis caused by hypercoagulability following in-vitro fertilization-activated protein C resistance and immobilization]. AB - Jugular vein thrombosis (JVT) is extremely difficult to diagnose clinically because of its rarity, the wide range of possible symptoms and the variety of differential diagnoses. A rapid diagnosis is important in order to avoid or prevent imminent life-threatening complications. This study reports a clinical case of extensive JVT due to increased thrombophilia in conjunction with ovarian hyperstimulation syndrome (OHSS) after in vitro fertilization, increased APC resistance and immobilization. It also discusses the current literature that forms the basis for recommendations regarding the diagnosis, therapy and interdisciplinary management. PMID- 22532280 TI - [The significance of the emergency department of the Jena ENT Clinic in outpatient health care]. AB - BACKGROUND: The impact of outpatient clinics on emergency health care has not yet been analyzed satisfactorily. This study aims to determine the importance of the Jena University Outpatient ENT Clinic in emergency health care. METHODS: In a retrospective study, all 1,884 emergency cases from 2008 were gathered and analyzed. RESULTS: The patients' average age was 38.2 years; half of them were female. A total of 1,379 patients (73%) went to the outpatient clinic without having previously consulted another doctor, and more than half of the emergency treatments took place on weekends or public holidays. Seven hundred nineteen patients (38%) had medical diagnoses indicating the need for emergency treatment. DISCUSSION: The University of Jena's Emergency Department ENT Clinic provides much more than just emergency health care. As only 38% of the cases analyzed were emergencies, the ENT Clinic complements outpatient health care outside business hours. PMID- 22532281 TI - [Mechanism of action of nasal glucocorticosteroids in the treatment of allergic rhinitis. Part 1: Pathophysiology, molecular basis]. AB - Allergic rhinitis (AR) is a common airway disease characterized by mucosal swelling leading to congestion, mucosal hyperreactivity and increased secretions. Inflammatory processes in the mucosa are responsible for most symptoms and are characterized by mucosal remodeling after longer time periods. The early phase response, which is characterized by sneezing, rhinorrhea and nasal congestion, is the response of the sensory nerve terminals and blood vessels in the nasal mucosa to chemical mediators such as histamine, prostaglandins and leukotrienes. Nasal exposure to allergens leads to infiltration of inflammatory cells, such as activated eosinophils and T helper type 2 (TH2) cells, into the nasal mucosa by chemoattractant factors such as cytokines including interleukin 5 (IL-5), chemical mediators including cysLTs and chemokines including eotaxin. Edema of the nasal mucosa develops as a secondary reaction with inflammatory cells. This inflammation, referred to as the late-phase response, develops 6-10 h after allergen challenge and causes prolonged nasal congestion. In addition, a neurogenic mechanism is activated after liberation of substance P and others. Therefore, allergic rhinitis is a complex immunogenic disease that also activates mechanisms of the immune system in general. Antiallergic and antiinflammatory medications such as nasal glucocorticosteroids (nGCS) are thought to be the most effective treatment for controlling the symptoms and inflammatory mechanisms of AR. The antiinflammatory action of nGCS depends on at least two different mechanisms: transactivation and transrepression. Moreover, they regulate immune functions by inducing regulatory cytokines and forkhead box P3 (Foxp3). Foxp3 is of upmost importance as a transcription factor of regulatory t-cells, allowing the inhibition of effector function and proliferation of other CD4+ cells. PMID- 22532283 TI - [Leiomyoma. A rare neoplasia of the parotid gland]. AB - Leiomyomas are benign neoplasias consisting of smooth muscle tissue, with the most common localization being the uterus. Less often incidence is observed in other regions such as the blood vessels, esophagus and lower urinary tract. Leiomyomas occur only rarely in the head and neck area. We report about a female patient being treated because of progredient swelling and enlargement of the left parotid gland. The histological specimen revealed a regressive transformed tumor. PMID- 22532282 TI - [Mechanism of action of nasal glucocorticosteroids in the treatment of allergic rhinitis. Part 2: Practical aspects of application]. AB - Allergic rhinitis (AR) is the single most common allergic disease and one of the most common chronic diseases. It affects approximately 25-30% of the population, and can substantially worsen patients' medical conditions, reduce quality of life, and contribute to absenteeism from work or school. It is also responsible for substantial direct and indirect economic burdens on the health care system. The medical management of allergic rhinitis includes several available pharmacotherapies, such as alpha-sympathomimetics, anticholinergic drugs, natural saline or other nasal rinses, mast cell-stabilizing agents, topical and systemic antihistamines, topical and systemic glucocorticosteroids, leukotriene-receptor antagonists and the new monoclonal antibodies following a stepwise approach. Allergen-specific immunotherapy is the only treatment option that interferes with the natural course of the disease and, besides allergen elimination, is thought to be the only causative treatment option. Nasal glucocorticosteroids (nGCS) are thought to be the most effective treatment choice for controlling the symptoms of AR. Double-blind, randomized clinical trials have demonstrated greater efficacy of nGCSs versus placebo, antihistamines or montelukast for relief of all nasal symptoms, especially congestion. Therefore, especially in the management of AR related nasal inflammation and congestion, nGCSs are considered the most appropriate treatment. Patients should be informed that symptom improvement can be expected after 2-4 days for intermittent rhinitis and after up to 2-3 weeks for persistent rhinitis. The medication has to be taken regularly and not as "on demand" treatment. Adherence to treatment also affects outcomes, and this may be influenced by patient preferences for the sensory attributes of an individual drug and the awareness of possible side effects. More recently, safety studies have shown that the newer nGCS agents have improved safety profiles compared with older nGCS agents. The newer nGCS drugs have been found to have minimal adverse effects on growth and hypothalamic-pituitary-adrenal-axis function in children. This review will discuss the pathophysiology of allergic inflammation in the nasal mucosa and the mechanism of action of nGCSs; also the efficacy and safety of nGCSs will be discussed by focusing on clinical evidence. PMID- 22532284 TI - [Palliative medicine]. AB - INTRODUCTION: This paper investigates the qualitative and quantitative situation of palliative care medicine in Germany. The challenge of palliative care is the improvement of the quality of life of patients who are expected to die within months. In head and neck surgery most of these patients are suffering from cancer. Palliative care may incorporate symptom control and may support self determination, including psychological, social and spiritual aspects. Treatment is not intended to cure the patients. Palliative care focuses on care of the patient and family rather than on the underlying disease. MATERIALS AND METHODS: A databank search was performed using key words such as palliative medicine, palliative care, hospice, AAPV, SAPV and PCT. RESULTS: The search demonstrates the restoration of quality of life as a guiding principle of palliative care in Germany. This may be achieved by symptom control and support of self determination as well as psychosocial or spiritual support. Furthermore, relatives including children receive emotional support. A further principle is the proactive coordination of palliative procedures. CONCLUSION: Improved legal conditions for realistic specialized ambulatory palliative care (spezialisierte ambulante Palliativversorgung, SAPV) as well as strengthening of general palliative care (allgemeine ambulante Palliativversorgung, AAPV) should be encouraged so that a sustainable palliative care net with cooperation of SAPV and AASP can be developed throughout Germany. PMID- 22532285 TI - Imaging of patients after the Lap-Band System application. AB - OBJECTIVE: We describe the use of imaging in the management of adjustable gastric banding patients, and describe complications of banding that are diagnosed by imaging. MATERIALS & METHODS: Using a four-year period as an example of complications of this type of laparoscopic approach, we have retrospectively identified all patients with laparoscopic bands who were imaged in the radiology department at our large multispecialty hospital. Included are patients who had their bands placed by the hospital's surgeons as well as patients referred for consultation from other practices. RESULTS: Twenty-two of 165 patients who had banding as their sole weight loss surgery had 23 complications diagnosed by imaging. Complications included band slip (3), device issues (4), esophageal dilation (8), esophageal dysmotility (5), symptomatic gallstones (2) and a gastroesphageal diverticulum (1). Complications were detected by fluoroscopy (17), CT (4) or ultrasound (2). 17 patients had banding as one of multiple bariatric surgeries, with 13 complications: band slip (4), port infection (1), esophageal dilation (1), esophageal dysmotility (5), anastomotic leak (1) and internal hernia (2). Complications were detected with fluoroscopy (12) and CT (1). CONCLUSIONS: Fluoroscopy is generally the primary imaging modality used to diagnose complications of gastric banding. Esophageal dilation and dysmotility, which appear to be long-term sequelae of banding, were the most common complications identified by imaging. PMID- 22532286 TI - A possible involvement of autophagy in amyloplast degradation in columella cells during hydrotropic response of Arabidopsis roots. AB - Seedling roots display not only gravitropism but also hydrotropism, and the two tropisms interfere with one another. In Arabidopsis (Arabidopsis thaliana) roots, amyloplasts in columella cells are rapidly degraded during the hydrotropic response. Degradation of amyloplasts involved in gravisensing enhances the hydrotropic response by reducing the gravitropic response. However, the mechanism by which amyloplasts are degraded in hydrotropically responding roots remains unknown. In this study, the mechanistic aspects of the degradation of amyloplasts in columella cells during hydrotropic response were investigated by analyzing organellar morphology, cell polarity and changes in gene expression. The results showed that hydrotropic stimulation or systemic water stress caused dramatic changes in organellar form and positioning in columella cells. Specifically, the columella cells of hydrotropically responding or water-stressed roots lost polarity in the distribution of the endoplasmic reticulum (ER), and showed accelerated vacuolization and nuclear movement. Analysis of ER-localized GFP showed that ER redistributed around the developed vacuoles. Cells often showed decomposing amyloplasts in autophagosome-like structures. Both hydrotropic stimulation and water stress upregulated the expression of AtATG18a, which is required for autophagosome formation. Furthermore, analysis with GFP-AtATG8a revealed that both hydrotropic stimulation and water stress induced the formation of autophagosomes in the columella cells. In addition, expression of plastid marker, pt-GFP, in the columella cells dramatically decreased in response to both hydrotropic stimulation and water stress, but its decrease was much less in the autophagy mutant atg5. These results suggest that hydrotropic stimulation confers water stress in the roots, which triggers an autophagic response responsible for the degradation of amyloplasts in columella cells of Arabidopsis roots. PMID- 22532287 TI - Small cell lung cancer tumour cells induce regulatory T lymphocytes, and patient survival correlates negatively with FOXP3+ cells in tumour infiltrate. AB - Small cell lung cancer (SCLC) kills at least one person every 2 hr in the United Kingdom. Some patients do relatively well but most have rapidly progressive disease. There is no effective treatment and overall 2-year survival is less than 5%. Patients with SCLC have poorly understood local and systemic immune defects and can be immunocompromised. As CD4(+) T lymphocytes coordinate and regulate immunity, a better understanding of interactions between SCLC tumour cells and CD4(+) T cells may lead to effective molecular immunotherapy. We show that some, but not all, SCLC tumour cell lines secrete molecules that induce IL-10 secretion by and de novo differentiation of functional CD4(+)CD25(+)FOXP3(+)CD127(lo)Helios(-) regulatory T (Treg) cells in healthy blood lymphocytes. FOXP3(+) T cells were found in SCLC tumour biopsies, and patients with higher ratios of FOXP3(+) cells in tumour infiltrates have a worse survival rate. The inhibitory effect of SCLC tumour cells was not affected by blocking IL-10 receptor or TGF-beta signalling but was partially reversed by blocking IL-15, which is reported to be involved in human Treg cells induction. IL-15 was secreted by SCLC cells that inhibited CD4(+) T-cell proliferation and was present in SCLC biopsy tumour cells. These novel findings demonstrate that SCLC tumour cells can induce CD4(+) T-cell-mediated immunosuppression. This gives a potential mechanism by which SCLC tumour cells may downregulate local and systemic immune responses and contribute to poor patient survival. Our data suggest that IL-15 and Treg cells are potential new therapeutic targets to improve immune response and patient survival in SCLC. PMID- 22532288 TI - What have genome-wide studies told us about psoriatic arthritis? AB - There is convincing evidence to suggest a strong genetic component to psoriatic arthritis (PsA), with studies reporting a 40-fold risk to first-degree relatives of patients with disease. However, compared with rheumatoid arthritis, our understanding of the genetic etiology of PsA is less well-developed. Only three modestly sized genome-wide association studies of PsA have been undertaken to date, but they have identified the HLA-C region, IL12B, TRAF3IP2, and FBXL19 genes as being associated with PsA susceptibility. Results of genome-wide association studies of psoriasis and rheumatoid arthritis have been used to identify candidate genes for subsequent testing in PsA and have led to the identification of additional susceptibility factors for PsA. Most show overlap with psoriasis, whereas the overlap with rheumatoid arthritis is less pronounced. However, two loci show strong evidence for association with PsA but not psoriasis: HLA-B27 and the IL-13 gene locus. PMID- 22532289 TI - Some chronic rhinosinusitis patients have elevated populations of fungi in their sinuses. AB - OBJECTIVES/HYPOTHESIS: To measure the populations of 36 fungi in the homes and sinuses of chronic rhinosinusitis (CRS) and non-CRS patients. STUDY DESIGN: Single-blind cross-sectional study. METHODS: Populations of 36 fungi were measured in sinus samples and in the home vacuum cleaner dust of CRS (n = 73) and non-CRS patients (n = 16) using quantitative polymerase chain reaction. Etest strips containing amphotericin B, anidulafungin, caspofungin, fluconazole, and voriconazole were used to test the susceptibility of seven potentially relevant fungi. RESULTS: Seven fungi (Alternaria alternata, Cladosporium cladosporioides types 1 and 2, Cladosporium herbarum, Penicillium brevicompactum, Penicillium crustosum, and Penicillium chrysogenum type 2) were discovered at very high concentrations in some CRS patients. In vitro antifungal susceptibility testing of these seven fungi demonstrated species specific sensitivities. Four CRS patients with marked elevations of fungal populations in their sinus samples underwent endoscopic sinus surgery. After surgical treatment, the fungal populations were reduced by several orders of magnitude. CONCLUSIONS: Seven fungi were found in very high concentrations in the sinuses of some CRS patients. Not one of the five common antifungal agents could control all seven of these fungi based on in vitro tests. PMID- 22532291 TI - A review on electrical impedance tomography for pulmonary perfusion imaging. AB - Although electrical impedance tomography (EIT) for ventilation monitoring is on the verge of clinical trials, pulmonary perfusion imaging with EIT remains a challenge, especially in spontaneously breathing subjects. In anticipation of more research on this subject, we believe a thorough review is called for. In this paper, findings related to the physiological origins and electrical characteristics of this signal are summarized, highlighting properties that are particularly relevant to EIT. The perfusion impedance change signal is significantly smaller in amplitude compared with the changes due to ventilation. Therefore, the hardware used for this purpose must be more sensitive and more resilient to noise. In previous works, some signal- or image-processing methods have been required to separate these two signals. Three different techniques are reviewed in this paper, including the ECG-gating method, frequency-domain filtering-based methods and a principal-component-analysis-based method. In addition, we review a number of experimental studies on both human and animal subjects that employed EIT for perfusion imaging, with promising results in the diagnosis of pulmonary embolism (PE) and pulmonary arterial hypertension as well as other potential applications. In our opinion, PE is most likely to become the main focus for perfusion EIT in the future, especially for heavily instrumented patients in the intensive care unit (ICU). PMID- 22532290 TI - Regulation of Schwann cell differentiation and proliferation by the Pax-3 transcription factor. AB - Pax-3 is a paired domain transcription factor that plays many roles during vertebrate development. In the Schwann cell lineage, Pax-3 is expressed at an early stage in Schwann cells precursors of the embryonic nerve, is maintained in the nonmyelinating cells of the adult nerve, and is upregulated in Schwann cells after peripheral nerve injury. Consistent with this expression pattern, Pax-3 has previously been shown to play a role in repressing the expression of the myelin basic protein gene in Schwann cells. We have studied the role of Pax-3 in Schwann cells and have found that it controls not only the regulation of cell differentiation but also the survival and proliferation of Schwann cells. Pax-3 expression blocks both the induction of Oct-6 and Krox-20 (K20) by cyclic AMP and completely inhibits the ability of K20, the physiological regulator of myelination in the peripheral nervous system, to induce myelin gene expression in Schwann cells. In contrast to other inhibitors of myelination, we find that Pax-3 represses myelin gene expression in a c-Jun-independent manner. In addition to this, we find that Pax-3 expression alone is sufficient to inhibit the induction of apoptosis by TGFbeta1 in Schwann cells. Expression of Pax-3 is also sufficient to induce the proliferation of Schwann cells in the absence of added growth factors and to reverse K20-induced exit from the cell cycle. These findings indicate new roles for the Pax-3 transcription factor in controlling the differentiation and proliferation of Schwann cells during development and after peripheral nerve injury. PMID- 22532292 TI - Re: Kanai A, et al. mechanisms of action of botulinum neurotoxins, beta3 adrenergic receptor agonists, and PDE5 inhibitors in modulating detrusor function in overactive bladders: ICI-RS 2011. Neurourol urodyn 2012;31:300-308. PMID- 22532294 TI - Iron borohydride pincer complexes for the efficient hydrogenation of ketones under mild, base-free conditions: synthesis and mechanistic insight. AB - The new, structurally characterized hydrido carbonyl tetrahydridoborate iron pincer complex [(iPr-PNP)Fe(H)(CO)(eta(1)-BH(4))] (1) catalyzes the base-free hydrogenation of ketones to their corresponding alcohols employing only 4.1 atm hydrogen pressure. Turnover numbers up to 1980 at complete conversion of ketone were reached with this system. Treatment of 1 with aniline (as a BH(3) scavenger) resulted in a mixture of trans-[(iPr-PNP)Fe(H)(2)(CO)] (4a) and cis-[(iPr PNP)Fe(H)(2)(CO)] (4b). The dihydrido complexes 4a and 4b do not react with acetophenone or benzaldehyde, indicating that these complexes are not intermediates in the catalytic reduction of ketones. NMR studies indicate that the tetrahydridoborate ligand in 1 dissociates prior to ketone reduction. DFT calculations show that the mechanism of the iron-catalyzed hydrogenation of ketones involves alcohol-assisted aromatization of the dearomatized complex [(iPr PNP*)Fe(H)(CO)] (7) to initially give the Fe(0) complex [(iPr-PNP)Fe(CO)] (21) and subsequently [(iPr-PNP)Fe(CO)(EtOH)] (38). Concerted coordination of acetophenone and dual hydrogen-atom transfer from the PNP arm and the coordinated ethanol to, respectively, the carbonyl carbon and oxygen atoms, leads to the dearomatized complex [(iPr-PNP*)Fe(CO)(EtO)(MeCH(OH)Ph)] (32). The catalyst is regenerated by release of 1-phenylethanol, followed by dihydrogen coordination and proton transfer to the coordinated ethoxide ligand. PMID- 22532293 TI - Novel methylation panel for the early detection of neoplasia in high-risk ulcerative colitis and Crohn's colitis patients. AB - BACKGROUND: Patients with ulcerative colitis and Crohn's colonic disease are at increased risk of developing colorectal cancer (CRC). The aim of the study was to analyze the methylation status of selected genes as a risk marker for CRC in inflammatory bowel disease (IBD) patients. METHODS: We evaluated the methylation status of four genes (TGFB2, SLIT2, HS3ST2, and TMEFF2) in biopsies of four groups of patients: 60 patients with sporadic CRC, 32 patients with IBD associated neoplasia, 85 patients with IBD without associated neoplasia (20 at high risk and 65 at low risk), and 28 healthy controls. Methylation-specific melting curve analysis (MS-MCA) was used. Methylation status of these genes was also assessed in stool DNA from 60 IBD patients without neoplasia. RESULTS: Methylation of the panel of genes analyzed was a very common phenomenon (78%) in IBD-associated neoplasia. The prevalence of methylation in adjacent nonneoplastic mucosa was also high (12/30). This prevalence was higher than in mucosa from healthy controls (2/28;7.1%; P < 0.05). Methylation of SLIT2 and TMEFF2 was more frequently detected in the mucosa of IBD patients at high risk of dysplasia or cancer (15/20) than patients at low risk (32/63) (P = 0.05 and P = 0.03, respectively). When stool samples were assessed, only SLIT2 gene methylation was more frequently methylated in the group of patients at high risk of dysplasia or cancer (4/16) compared to low risk (0/37) (P = 0.006). CONCLUSIONS: Analysis of a panel of methylation markers may help in the early identification of colorectal dysplasia or cancer in high-risk IBD patients. PMID- 22532295 TI - Synthesis and evaluation of 5-benzylidenethiazolidine-2,4-dione derivatives for the treatment of non-alcoholic fatty liver disease. AB - Twenty-two 5-benzylidenethiazolidine-2,4-dione derivatives (TZDs) were synthesized and evaluated for their potency on adipogenesis of 3T3-L1 adipocytes by measuring the expression of adiponectin protein. Among them, compared to rosiglitazone, 3V was found to upregulate the adiponectin protein expression and downregulate the secretion of leptin protein in 3T3-L1 adipocytes at a respective concentration of 10 uM. With respect to high-fat/high-calorie (HF/HC) diet induced non-alcoholic fatty liver disease (NAFLD) in Wistar rats, oral administration of 3V could reduce liver weight, visceral fat, and improve serum levels of biochemical markers. H&E staining of liver sections validated 3V as a potent hepatoprotective agent for reducing fat deposition against NAFLD. PMID- 22532296 TI - von Willebrand factor as new noninvasive predictor of portal hypertension, decompensation and mortality in patients with liver cirrhosis. AB - von Willebrand factor antigen (vWF-Ag) is elevated in patients with liver cirrhosis, but the clinical significance is unclear. We hypothesized that vWF-Ag levels may correlate with portal pressure, measured by hepatic venous pressure gradient (HVPG), and predict clinically significant portal hypertension (CSPH; HVPG >= 10 mmHg), decompensation and mortality. Portal hemodynamics were assessed by HVPG measurement, whereas vWF-Ag levels were measured by enzyme-linked immunosorbent assay. During follow-up, complications of liver cirrhosis, death or transplantation were recorded. Two hundred and eighty-six patients (205 male and 81 female; mean age, 56 years) with liver cirrhosis were included. vWF-Ag correlated with HVPG (r = 0.69; P < 0.0001) and predicted CSPH independently of Child Pugh score. Higher vWF-Ag levels were associated with varices (odds ratio [OR] = 3.27; P < 0.001), ascites (OR = 3.93; P < 0.001) and mortality (hazard ratio: 4.41; P < 0.001). Using a vWF-Ag cut-off value of >= 241%, the AUC for detection of CSPH in compensated patients was 0.85, with a positive predictive value and negative predictive value of 87% and 80%, respectively. Compensated patients had 25% mortality after 53 months if the vWF-Ag was <315% compared to 15 months in patients with vWF-Ag >315% (P < 0.001). Decompensated patients had a mortality of 25% after 37 and 7 months if their vWF-Ag was <315% and >315%, respectively (P = 0.002). In compensated patients with a vWF-Ag >315% median time to decompensation or death was 32 months compared with 59 months in patients with vWF-Ag <315%. vWF-Ag equals Model for End-Stage Liver Disease (MELD) in mortality prediction (area under the curve [AUC] = 0.71 for vWF-Ag versus AUC = 0.65 for MELD; P = 0.2). CONCLUSION: vWF-Ag is a new, simple and noninvasive predictor of CSPH. A vWF-Ag cut-off value at 315% can clearly stratify patients with compensated and decompensated liver cirrhosis in two groups with completely different survival. vWF-Ag may become a valuable marker for the prediction of mortality in patients with liver cirrhosis in clinical practice. PMID- 22532297 TI - Subcellular localization and activity of gambogic acid. AB - The natural product gambogic acid (GA) has shown significant potential as an anticancer agent as it is able to induce apoptosis in multiple tumor cell lines, including multidrug-resistant cell lines, as well as displaying antitumor activity in animal models. Despite the fact that GA has entered phase I clinical trials, the primary cellular target and mode of action of this compound remain unclear, although many proteins have been shown to be affected by it. By thorough analysis of several cellular organelles, at both the morphological and functional levels, we demonstrate that the primary effect of GA is at the mitochondria. We found that GA induces mitochondrial damage within minutes of incubation at low micromolar concentrations. Moreover, a fluorescent derivative of GA was able to localize specifically to the mitochondria and was displaced from these organelles after competition with unlabeled GA. These findings indicate that GA directly targets the mitochondria to induce the intrinsic pathway of apoptosis, and thus represents a new member of the mitocans. PMID- 22532298 TI - Understanding the needs of lung cancer patients during the pre-diagnosis phase. AB - Patients with lung cancer have numerous and varying needs spanning across the cancer trajectory; however, only limited research has focused specifically on the pre-diagnosis phase. A multicentre cross-sectional survey was conducted to explore the experience of lung cancer patients during the pre-diagnosis phase. High levels of anxiety were reported by many participants (45.6 %). Informational (32.1 %), and emotional (24.1 %) needs were reported as most important; the majority (89.0 %) reported these needs were met. Most participants sought information throughout, with many (38.6 %) rating their oncology health care providers to be the best source of information. The majority (70.0 %) reported that they were not directed to any resources to help address their anxiety. During pre-diagnosis, informational and emotional needs appear most important, and for the majority, these were reportedly met. Although many experienced high levels of anxiety, few were directed to resources to address it. PMID- 22532299 TI - The role of acculturation and family functioning in predicting HIV risk behaviors among Hispanic delinquent youth. AB - The present study examined the relationship between Berry's acculturation typology and HIV risk behaviors and whether family functioning mediated any such effects. A total of 235 high risk Hispanic adolescents were categorized into one of Berry's four acculturation typologies through the use of cut-off scores on measures of Hispanicism and Americanism. Structural equation modeling was used to examine the effects of acculturation typology on HIV risk behaviors and the indirect effects of acculturation typology on HIV risk behaviors through family functioning. Acculturation typology was related to HIV risk behaviors. Family functioning partially mediated the effects of acculturation typology on the HIV risk behavior outcomes. These findings suggest that both Americanism and Hispanicism play an important role in the etiology of HIV risk behaviors among Hispanic youth and that both, along with family functioning, are important to consider when designing preventive interventions for this population. PMID- 22532300 TI - ELF magnetic fields in electric and gasoline-powered vehicles. AB - We conducted a pilot study to assess magnetic field levels in electric compared to gasoline-powered vehicles, and established a methodology that would provide valid data for further assessments. The sample consisted of 14 vehicles, all manufactured between January 2000 and April 2009; 6 were gasoline-powered vehicles and 8 were electric vehicles of various types. Of the eight models available, three were represented by a gasoline-powered vehicle and at least one electric vehicle, enabling intra-model comparisons. Vehicles were driven over a 16.3 km test route. Each vehicle was equipped with six EMDEX Lite broadband meters with a 40-1,000 Hz bandwidth programmed to sample every 4 s. Standard statistical testing was based on the fact that the autocorrelation statistic damped quickly with time. For seven electric cars, the geometric mean (GM) of all measurements (N = 18,318) was 0.095 uT with a geometric standard deviation (GSD) of 2.66, compared to 0.051 uT (N = 9,301; GSD = 2.11) for four gasoline-powered cars (P < 0.0001). Using the data from a previous exposure assessment of residential exposure in eight geographic regions in the United States as a basis for comparison (N = 218), the broadband magnetic fields in electric vehicles covered the same range as personal exposure levels recorded in that study. All fields measured in all vehicles were much less than the exposure limits published by the International Commission on Non-Ionizing Radiation Protection (ICNIRP) and the Institute of Electrical and Electronics Engineers (IEEE). Future studies should include larger sample sizes representative of a greater cross-section of electric-type vehicles. PMID- 22532302 TI - Perils of the information highway: we need better road maps. PMID- 22532301 TI - Muscle excursion does not correlate with increased serial sarcomere number after muscle adaptation to stretched tendon transfer. AB - Chronic skeletal muscle stretch typically increases serial muscle fiber sarcomere number. Since serial sarcomere number correlates with functional excursion in normal muscle, observed changes in sarcomere number are often extrapolated to their new assumed function. However, this has not been well demonstrated experimentally. Thus, we measured the functional properties of muscles stretched due to tendon transfer surgery. Muscle active and passive length-tension curves were measured 1 week and 4 weeks after surgery, and then each muscle was further examined to determine structural adaptation as well as single fiber and fiber bundle passive mechanical properties. We found a disconnect between the functional and structural muscle properties. Specifically, muscle excursion was significantly lower in the transferred muscle compared to controls, even though serial sarcomere number had increased. Furthermore, maximum tetanic tension was significantly reduced, though the two groups had similar physiological cross sectional areas. Passive tension increased in the transferred muscle, which was deemed to be due to proliferation of extracellular matrix. These data are the first to report that muscle morphological adaptation after chronic stretch does not accurately predict the muscle's functional properties. These data have significant implications for examining muscle physiological properties under surgical interventions. PMID- 22532303 TI - The Hirudo medicinalis species complex. AB - Recently, Hildebrandt and Lemke (Naturwissenschaften 98:995-1008, 2011) argued that the taxonomic status of the three European medicinal leeches, Hirudo medicinalis Linnaeus 1758, Hirudo verbana Carena 1820, and Hirudo orientalis Utevsky and Trontelj (Parasitol Res 98:61-66, 2005) is "questionable" since "all three species interbreed in the laboratory". This statement is in conflict with data published by Elliott and Kutschera (Freshwater Reviews 4:21-41, 2011), indicating that these leeches, which are reciprocally copulating hermaphrodites, represent reproductively isolated biospecies. Here, I summarize evidence indicating that these three European taxa, plus the North African "dragon leech" (Hirudo troctina Johnson 1816), must be interpreted as a complex of closely related species, and that the economically most important taxon H. verbana is polymorphic. PMID- 22532304 TI - Regional and cell-type specific distribution of HDAC2 in the adult mouse brain. AB - The effects of epigenetics on brain functions are not completely understood, but histone deacetylases (HDACs) are known to affect brain function and dysfunction by mediating the acetylation status of target proteins, thereby affecting gene expression. The current study used immunochemistry to illuminate the regional distribution of one member of the HDAC family, HDAC2, in the C57BL/6J mouse brain. Our data show that HDAC2 is ubiquitously expressed throughout the mouse brain and is localized primarily within the cell nucleus. Using double immunofluorescence, we demonstrated HDAC2 expression in neuronal cells, including cholinergic, serotonergic and catecholaminergic neurons, as well as postsynaptic glutamatergic and GABAergic neurons. HDAC2 was also observed in oligodendrocytes, but not in astrocytes or microglia. These detailed immunological studies illuminate the distribution of HDAC2 throughout the mouse brain and will facilitate investigation of the roles of HDAC2 in brain function and neurological disorders. PMID- 22532305 TI - Prognostic significance of alpha-fetoprotein status in the outcome of hepatocellular carcinoma after treatment of transarterial chemoembolization. AB - BACKGROUND: Alpha-fetoprotein (AFP) has been used as a diagnostic biomarker for hepatocellular carcinoma (HCC), but its prognostic significance is not well defined. This study was performed to classify the prognostic significance of AFP status in HCC patients after transarterial chemoembolization (TACE). METHODS: Four hundred forty-one HCC patients from a prospective maintained database with pathologic confirmation including 139 with normal AFP levels and 302 with elevated AFP levels were retrospectively studied for prognostic significance of AFP in treatment response and survival after TACE. Univariate and multivariate analyses were used to identify the prognostic factors. RESULTS: There were significant differences in overall survival (OS) after TACE between AFP-negative and AFP-positive HCC patients when the AFP cutoff value was defined as 20 ng/ml (P < 0.0001). Among the AFP-positive patients, different AFP levels had no significantly prognostic effects on OS after TACE (P = 0.093). Multivariate analysis revealed that AFP status for AFP-negative or positive was an independent prognostic factor for HCC patients after TACE (P = 0.001), along with gamma glutamyltransferase (GGT) level (P = 0.004) and tumor diameter (P < 0.0001). In addition, there were significant differences in clinicopathologic features between AFP-positive and AFP-negative patients with regard to age, gender, alanine transferase level, GGT level, tumor diameter, and Barcelona Clinic Liver Cancer stage. CONCLUSIONS: Compared with AFP-positive HCC patients, patients with AFP-negative status have a better treatment response and prognosis after TACE. PMID- 22532306 TI - Gastric stump cancer after distal gastrectomy for benign gastric ulcer in a population-based study. AB - The risk of cancer in the gastric remnant after distal gastrectomy for benign ulcer disease has been assessed mainly in studies of small sample size, selected series and limited follow-up time. This was a population-based cohort study of patients who had undergone distal gastrectomy for benign ulcer disease in 1964 2008 in Sweden. Data for follow-up for cancer and censoring for death were obtained from nationwide registries of Cancer and Population, respectively. The number of observed cancer cases in the gastrectomy cohort was divided by the expected number, calculated from the cancer incidence of the Swedish population of corresponding age, sex and calendar year. Relative risks were presented as standardized incidence ratios (SIRs) with 95% confidence intervals (CIs). The distal gastrectomy cohort included 18,912 patients and 323,676 person-years at risk. The observed total number of gastric stump cancers (n = 140) was not higher than expected (SIR 0.84, 95% CI 0.71-0.99). There was no increased SIR with latency periods shorter than 30 years; increase was seen only among patients who had undergone gastric resection over 30 years earlier (SIR 2.29, 95% CI 1.38 3.57). Sex, age, ulcer location and type of surgical reconstruction were not associated with any considerable differences in SIR. In conclusion, this large population-based study revealed an increased risk of cancer in the gastric remnant only 30 years or longer after gastric resection for benign disease, whereas other factors did not influence this risk. PMID- 22532307 TI - Human papillomavirus DNA strongly correlates with a poorer prognosis in oral cavity carcinoma. AB - OBJECTIVES/HYPOTHESIS: The prevalence of human papillomavirus (HPV) in a clinical series of 162 patients with oral squamous cell carcinoma (OSCC) was studied. Furthermore, we analyzed the correlation between the immunohistochemical expression of p16, p53, epidermal growth factor receptor (EGFR), and HPV status to predict survival in OSCC patients. STUDY DESIGN: Retrospective study. METHODS: Paraffin-embedded samples from OSCC patients (n = 162) were evaluated for the presence of HPV DNA using both GP5+/GP6+ consensus polymerase chain reaction (PCR) and type-specific E6/E7 PCR to detect HPV types 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 67, and 68. Immunohistochemical staining for p16, p53, and EGFR was also performed. RESULTS: The type-specific E6/E7 PCR demonstrated that 65 of the 147 OSCC patients (44%) presented with high-risk (hr) HPV types and that 38 of the 147 OSCC patients (26%) presented with low-risk (lr) HPV types. Comparable p53 and EGFR expression levels were observed in the hr HPV+ group (41.5% p53+, 92% EGFR+) and the lr HPV+ group (57% p53+, 92% EGFR+). Conversely, a slight increase in the proportion of p16+ tumors was observed in the hr HPV+ group (65%) compared with the lr HPV+ group (44%). In regard to patient outcome, the presence of HPV was correlated with a worse prognosis (P = .007). CONCLUSIONS: A high prevalence of hr and lr HPV infections was detected in the OSCC patients included in the study. Moreover, hr HPV positivity was correlated with a decreased 5-year disease-free survival rate compared with HPV- and lr HPV+. PMID- 22532308 TI - Recent advancements in medical simulation: patient-specific virtual reality simulation. AB - BACKGROUND: Patient-specific virtual reality simulation (PSVR) is a new technological advancement that allows practice of upcoming real operations and complements the established role of VR simulation as a generic training tool. This review describes current developments in PSVR and draws parallels with other high-stake industries, such as aviation, military, and sports. METHODS: A review of the literature was performed using PubMed and Internet search engines to retrieve data relevant to PSVR in medicine. All reports pertaining to PSVR were included. Reports on simulators that did not incorporate a haptic interface device were excluded from the review. RESULTS: Fifteen reports described 12 simulators that enabled PSVR. Medical procedures in the field of laparoscopy, vascular surgery, orthopedics, neurosurgery, and plastic surgery were included. In all cases, source data was two-dimensional CT or MRI data. Face validity was most commonly reported. Only one (vascular) simulator had undergone face, content, and construct validity. Of the 12 simulators, 1 is commercialized and 11 are prototypes. Five simulators have been used in conjunction with real patient procedures. CONCLUSIONS: PSVR is a promising technological advance within medicine. The majority of simulators are still in the prototype phase. As further developments unfold, the validity of PSVR will have to be examined much like generic VR simulation for training purposes. Nonetheless, similar to the aviation, military, and sport industries, operative performance and patient safety may be enhanced by the application of this novel technology. PMID- 22532309 TI - Impact of preoperative alpha-fetoprotein level on disease-free survival after liver transplantation for hepatocellular carcinoma. AB - BACKGROUND: Preoperative alpha-fetoprotein (AFP) levels may have an influence on disease-free survival (DFS) of patients after liver transplantation for hepatocellular carcinoma (HCC) located on a cirrhotic liver. METHODS: Between 2000 and 2009, two groups were distinguished according to preoperative AFP level: normal-level group (<10 ng/ml) and increased-level group (>10 ng/ml). The increased-level group was further divided into three levels of preoperative AFP: 10-150, 150-500, and >= 500 ng/ml. DFS and recurrence rates were compared. All patients underwent transplantation using the preoperative 5/5 criteria. RESULTS: Of the 122 patients in this study, 63 had normal and 59 had increased preoperative AFP. There were no differences between the two groups concerning perioperative or pathologic data. Those with an increased preoperative AFP level had a significantly shorter 5-year DFS, and their recurrence rate was higher than that of the normal AFP group. The 5-year DFS and recurrence rates were 71 and 4 %, respectively, for those with normal AFP; 57 and 10 %, respectively, for those with AFP 10-150 ng/ml; 46 and 24 %, respectively, for those with AFP 150-500 ng/ml; and 28 and 62 %, respectively, for those with AFP >= 500 ng/ml. CONCLUSIONS: This study shows the prognostic value of preoperative AFP levels on DFS after a liver transplant for HCC in a population of patients undergoing transplantation with the same preoperative criteria. PMID- 22532311 TI - Site-selected doping of upconversion luminescent Er3+ into SrTiO3 for visible light-driven photocatalytic H2 or O2 evolution. AB - A series of upconversion luminescent erbium-doped SrTiO(3) (ABO(3)-type) photocatalysts with different initial molar ratios of Sr/Ti have been prepared by a facile polymerized complex method. Er(3+) ions, which were gradually transferred from the A to the B site with increasing Sr/Ti, enabled the absorption of visible light and the generation of high-energy excited states populated by upconversion processes. The local internal fields arising from the dipole moments of the distorted BO(6) octahedra promoted energy transfer from the high-energy excited states of Er(3+) with B-site occupancy to the host SrTiO(3) and thus enhanced the band-to-band transition of the host SrTiO(3). Consequently, the erbium-doped SrTiO(3) species with B-site occupancy showed higher photocatalytic activity than those with A-site occupancy for visible-light-driven H(2) or O(2) evolution in the presence of the corresponding sacrificial reagents. The results generally suggest that the introduction of upconversion luminescent agents into host semiconductors is a promising approach to simultaneously harnessing low-energy photons and maintaining redox ability for photocatalytic H(2) and O(2) evolution and that the site occupancy of doped elements in ABO(3) type perovskite oxides greatly determines the photocatalytic activity. PMID- 22532310 TI - Ratio of cesarean sections to total procedures as a marker of district hospital trauma capacity. AB - BACKGROUND: There are few established metrics to define surgical capacity in resource-limited settings. Previous work hypothesizes that the relative frequency of cesarean sections (CS) at a hospital, expressed as a proportion of total operative procedures (%CS), may serve as a proxy measure of surgical capacity. We attempted to evaluate this hypothesis as it specifically relates to hospital capacity for emergency interventions for injury. METHODS: We conducted a WHO survey of emergency surgical capacity at 40 Rwandan district hospitals in November 2010 and extracted annual operative volume for 2010 from the Ministry of Health centralized statistical system. We dichotomized the 40 hospitals into low and high %CS groups below and above the median proportion of CS performed. We compared low and high %CS groups across self-reported capabilities related to facility characteristics, trauma supplies, procedural capacity, and surgical training using bivariate chi(2) statistics with significance indicated at p <= 0.05. We evaluated herniorrhaphy proportion of total procedures (%Hernia) as a representative general surgery procedure in the same manner. RESULTS: High %CS hospitals were less likely to report capability related to blood banking (p = 0.05), amputation (p = 0.04), closed fracture repair (p = 0.04), inhalational anesthesia (p = 0.05), and chest tube insertion (p = 0.05). Availability of reliable electricity was the only measure that showed statistical significance with the %Hernia measure (p = 0.02). CONCLUSIONS: Cesarean section proportion shows some utility as a marker for district hospital injury-care capacity in resource-limited settings. PMID- 22532312 TI - International Children's Continence Society's recommendations for initial diagnostic evaluation and follow-up in congenital neuropathic bladder and bowel dysfunction in children. AB - PURPOSE: The objective of this ICCS standardization document is to report the initial diagnostic evaluation and subsequent work-up of children with neuropathic bladder dysfunction. MATERIALS AND METHODS: Due to a paucity of level I or level II, "levels of evidence" publications, these recommendations are actually a compilation of best practices because they seem to be effective and reliable, although not with any control. RESULTS: Throughout the document, the emphasis is on promoting early, comprehensive evaluation of lower urinary tract function that is thorough but with a minimum of unnecessary testing. This includes what tests to order, when to order them and what to do with the results. Some of the recommendations may not be practical in various worldwide locations but the suggested testing should be considered the ideal approach to completely diagnosing and then promulgating treatments based on the full knowledge of the condition and its effect on urinary tract function. Once the findings are delineated, those lower urinary tract patterns of dysfunction that put the kidneys at risk for deterioration, that are barriers to attaining eventual continence, and that have long-term consequence to the lower urinary track can be obviated by specific management recommendations. The indications and timing of investigations to achieve these objectives are clearly defined in each diagnostic category and during follow-up. RECOMMENDATIONS: This document should be used as a basis for appropriate evaluation and timely surveillance of the various neuro urologic conditions that affect children. PMID- 22532314 TI - Determination of abdominal fat thickness using dual electrode separation in the focused impedance method (FIM). AB - Subcutaneous fat layer thickness in the abdomen is a risk indicator of several diseases and disorders like diabetes and heart problems and could be used as a measure of fitness. Skinfold measurement using mechanical calipers is simple but prone to error. Ultrasound scanning techniques are yet to be established as accurate methods for this purpose. magnetic resonance imaging (MRI) and computed tomography (CT) scans can provide the answer but are expensive and not available widely. Some initiatives were made earlier to use electrical impedance to this end, but had inadequacies. In the first part of this paper, a 4-electrode focused impedance method (FIM) with different electrode separations has been studied for its possible use in the determination of abdominal fat thickness in a localized region. For this, a saline phantom was designed to provide different electrode separations and different layers of resistive materials adjacent to the electrodes. The background saline simulated the internal organs having low impedance while the resistive layers simulated the subcutaneous fat. The plot of the measured impedance with electrode separation had different 'slopes' for different thicknesses of resistive layers, which offered a method to obtain an unknown thickness of subcutaneous fat layer. In the second part, measurements were performed on seven human subjects using two electrode separations. Fat layer thickness was measured using mechanical calipers. A plot of the above 'slope' against fat thickness could be fitted using a straight line with an R(2) of 0.93. Then this could be used as a calibration curve for the determination of unknown fat thickness. Further work using more accurate CT and MRI measurements would give a better calibration curve for practical use of this non-invasive and low cost technique in abdominal fat thickness measurement. PMID- 22532313 TI - Passive range of motion characteristics in the overhead baseball pitcher and their implications for rehabilitation. AB - BACKGROUND: Repetitive overhead throwing motion causes motion adaptations at the glenohumeral joint that cause injury, decrease performance, and affect throwing mechanics. It is essential to define the typical range of motion (ROM) exhibited at the glenohumeral joint in the overhead thrower. QUESTIONS/PURPOSES: We (1) assessed the glenohumeral joint passive range of motion (PROM) characteristics in professional baseball pitchers; and (2) applied these findings clinically in a treatment program to restore normal PROM and assist in injury prevention. METHODS: From 2005 to 2010, we evaluated 369 professional baseball pitchers to assess ROM parameters, including bilateral passive shoulder external rotation (ER) at 45 degrees of abduction, external and internal rotation (IR) at 90 degrees abduction while in the scapular plane, and supine horizontal adduction. RESULTS: The mean ER was greater for the throwing and nonthrowing shoulders at 45 degrees of abduction, 102 degrees and 98 degrees , respectively. The throwing shoulder ER at 90 degrees of abduction was 132 degrees compared with 127 degrees on the nonthrowing shoulder. Also, the pitcher's dominant IR PROM was 52 degrees compared with 63 degrees on the nondominant side. We found no statistically significant differences in total rotational motion between the sides. CONCLUSIONS: Although we found side-to-side differences for rotational ROM and horizontal adduction, the total rotational ROM was similar. CLINICAL RELEVANCE: The clinician can use these PROM values, assessment techniques, and treatment guidelines to accurately examine and develop a treatment program for the overhead-throwing athlete. PMID- 22532315 TI - Large increase of the lifetime of a charge-separated state in a molecular triad induced by hydrogen-bonding solvent. PMID- 22532316 TI - Prophylaxis versus preemptive therapy for cytomegalovirus disease in high-risk liver transplant recipients. AB - Cytomegalovirus (CMV) infection is an opportunistic infection frequently found after solid organ transplantation, and it contributes significantly to mortality and morbidity. CMV-seronegative recipients of grafts from CMV-seropositive donors have the highest risk of CMV disease. The most appropriate strategy for preventing CMV disease in this population is a matter of active debate. In this study, we compared prophylaxis and preemptive therapy for the prevention of CMV disease in donor-seropositive/recipient-seronegative (D+ /R-) liver recipients. To this end, we selected a retrospective cohort of liver recipients (1992-2009) for analysis. D+ /R- patients were identified from the liver transplant program database. Eighty of 878 consecutive liver recipients (9%) were D+ /R-. Six of these patients died within 30 days of transplantation and were excluded. Thirty five of the remaining D+ /R- patients (47%) received prophylaxis, and 39 patients (53%) followed a preemptive strategy based on CMV antigenemia surveillance. Fifty four (73%) were men, the median age was 49 years (range = 15-68 years), and the mean follow-up was 68 months (range = 8-214 months). The baseline characteristics and the initial immunosuppressive regimens were similar for the 2 groups. Ganciclovir or valganciclovir was the antiviral drug used initially in both strategy groups. CMV disease occurred more frequently among D+ /R- liver recipients receiving preemptive therapy (33.3% versus 8.6% for the prophylaxis group, P = 0.01), whereas late-onset CMV disease was found only in patients receiving prophylaxis (5.7% versus 0% for the preemptive therapy group, P = 0.22). No significant differences in acute allograft rejection, other opportunistic infections, or case fatality rates were observed. According to our data, prophylaxis was more effective than preemptive therapy in preventing CMV disease in high-risk liver transplant recipients. PMID- 22532317 TI - Design, synthesis, and antibacterial activity of novel pleuromutilin derivatives bearing an amino thiazolyl ring. AB - A series of novel pleuromutilin derivatives containing the amino thiazolyl ring were designed, synthesized, and evaluated for their antibacterial activities in vitro against Gram-positive clinical bacteria. All the target compounds showed better aqueous solubility compared with the lead compound (10). Most compounds displayed strong antibacterial activities against both susceptible and resistant bacteria, particularly for the compound (12f) which showed extraordinary antibacterial properties superior to amoxicillin and tiamulin. Molecular docking studies revealed that the amino thiazolyl ring, the side chains of the pleuromutilin derivatives, can be adopted in the binding pocket of the 50S ribosomal subunit near the mutilin core. Therefore, our novel findings may provide new insights into the design of novel pleuromutilin derivatives and lay the basis for further studies on these promising antibiotics for human clinical use. PMID- 22532318 TI - The prognosis of perihilar cholangiocarcinoma after radical treatments. PMID- 22532319 TI - Sixty-year study of incidence of childhood ulcerative colitis finds eleven-fold increase beginning in 1990s. AB - BACKGROUND: We sought to define the point at which a recently noted marked increase in the incidence of ulcerative colitis (UC) had occurred in children in Victoria, Australia. METHODS: A 60-year retrospective review (1950-2009) of children age 16 years or less diagnosed with UC in the state's major pediatric centers was performed. RESULTS: In all, 342 children were diagnosed with UC (male to female ratio of 1.25:1.0, median age 10.9 years, interquartile range [IQR] 7.0, 13.2). The overall median annual incidence of UC was 0.36/10(5) children <= 16 years of age (IQR 0.18, 0.66). The number of reported cases increased by 11 fold during the study period (P < 0.001). This marked increase appeared to occur from the early 1990s and has yet to plateau. Children diagnosed during the last two decades were older at diagnosis (median 10 years vs. 11.6, P < 0.0001), and had higher weight- and height-for-age z scores than those diagnosed during the first 40 years (mean weight-for-age [standard deviation] 1950-1989: -0.80 [1.56] vs. 1990-2009: -0.11 [1.17], P < 0.001; mean height-for-age 1950-1989: -0.50 [1.15] vs. 1990-2009: -0.13 [1.12], P < 0.05). More recently diagnosed children also had more extensive disease (1950-1989: 52% vs. 1990-2009: 71%, P < 0.01). CONCLUSIONS: The incidence of UC has increased markedly in Victorian children since 1990. Although some of this change may be attributable to earlier diagnosis, it is unlikely that this can provide a complete explanation for this still-increasing condition. PMID- 22532320 TI - Fluid flow-induced calcium response in early or late differentiated osteoclasts. AB - Intracellular calcium oscillation caused by receptor activator of nuclear factor kappa-B ligand has been demonstrated to promote the differentiation of osteoclasts. Osteoclasts are recruited on the surface of trabeculae, and are exposed to fluid flow caused by the deformation of the bone matrix. However, the roles of fluid shear stress (FSS) on calcium response during the differentiation process of osteoclasts are still unknown. In the current study, the formation of tartrate-resistant acid phosphatase-positive, multinucleated osteoclasts from RAW264.7 macrophage cells were induced by co-culturing them with the conditioned medium from MC3T3-E1 osteoblasts. The in situ observations showed a high correlation between the area and the nuclear number of osteoclasts. The cells were stimulated by FSS at different levels (1 or 10 dyne/cm(2)) before (0 day) or after being induced for 4 or 8 days. The mechanically-induced calcium response was recorded and analyzed. The results indicated a different property of calcium oscillation for the osteoclasts in different fusion stages (i.e., more calcium responsive peaks appeared in small osteoclasts than those in the larger ones). The rates of calcium influx decreased and the time of recovery in osteoclast cytosol increased along with the fusion of osteoclasts. In addition, increasing the FSS level enhanced the calcium oscillation of osteoclasts at early induction (4 days). However, this effect was weakened at the late induction (8 days). The present work could help provide understanding regarding the mechanism of the involvement of calcium in mechanically induced bone remodeling. PMID- 22532322 TI - Development of a simultaneous cryo-anchoring and radiofrequency ablation catheter for percutaneous treatment of mitral valve prolapse. AB - Mitral valve prolapse (MVP) is one subtype of mitral valve (MV) disease and is often characterized by enlarged leaflets that are thickened and have disrupted collagen architecture. The increased surface area of myxomatous leaflets with MVP leads to mitral regurgitation, and there is need for percutaneous treatment options that avoid open-chest surgery. Radiofrequency (RF) ablation is one potential therapy in which resistive heating can be used to reduce leaflet size via collagen contracture. One challenge of using RF ablation to percutaneously treat MVP is maintaining contact between the RF ablation catheter tip and a functioning MV leaflet. To meet this challenge, we have developed a RF ablation catheter with a cryogenic anchor for attachment to leaflets in order to apply RF ablation. We demonstrate the effectiveness of the dual-energy catheter in vitro by examining changes in leaflet biaxial compliance, thermal distribution with infrared (IR) imaging, and cryogenic anchor strength. We report that 1250 J of RF energy with cryo-anchoring reduced the determinant of the deformation gradient tensor at systolic loading by 23%. IR imaging revealed distinct regions of cryo anchoring and tissue ablation, demonstrating that the two modalities do not counteract one another. Finally, cryogenic anchor strength to the leaflet was reduced but still robust during the application of RF energy. These results indicate that a catheter having combined RF ablation and cryo-anchoring provides a novel percutaneous treatment strategy for MVP and may also be useful for other percutaneous procedures where anchored ablation would provide more precise spatial control. PMID- 22532321 TI - Voxelized computational model for convection-enhanced delivery in the rat ventral hippocampus: comparison with in vivo MR experimental studies. AB - Convection-enhanced delivery (CED) is a promising local delivery technique for overcoming the blood-brain barrier (BBB) and treating diseases of the central nervous system (CNS). For CED, therapeutics are infused directly into brain tissue and the drug agent is spread through the extracellular space, considered to be highly tortuous porous media. In this study, 3D computational models developed using magnetic resonance (MR) diffusion tensor imaging data sets were used to predict CED transport in the rat ventral hippocampus using a voxelized modeling previously developed by our group. Predicted albumin tracer distributions were compared with MR-measured distributions from in vivo CED in the ventral hippocampus up to 10 MUL of Gd-DTPA albumin tracer infusion. Predicted and measured tissue distribution volumes and distribution patterns after 5 and 10 MUL infusions were found to be comparable. Tracers were found to occupy the underlying landmark structures with preferential transport found in regions with less fluid resistance such as the molecular layer of the dentate gyrus. Also, tracer spread was bounded by high fluid resistance layers such as the granular cell layer and pyramidal cell layer of dentate gyrus. Leakage of tracers into adjacent CSF spaces was observed towards the end of infusions. PMID- 22532323 TI - Targeted cancer therapy by immunoconjugated gold-gold sulfide nanoparticles using Protein G as a cofactor. AB - Gold-gold sulfide nanoparticles (GGS-NPs) fabricated from chloroauric acid and sodium thiosulfate show unique near infrared (NIR) absorption that renders them as a promising candidate for photothermal cancer therapy. To improve targeting efficiency, we developed a versatile method to allow ordered immunoconjugation of antibodies on the surfaces of these nanoparticles via a PEGylated recombinant Protein G (ProG). The PEGylated ProG was prepared with orthopyridyldisulfide polyethylene glycol-succinimidyl valerate, average MW 2000 (OPSS-PEG-SVA), to first allow the self-assembly of ProG on the nanoparticles, subsequently antibodies were added to this construct to enable active targeting. The bioconjugated GGS-NPs were characterized by TEM, NIR-spectra, dynamic light scattering and modified immunoassay. In in vitro studies, the ProG-conjugated GGS NPs with bound mouse anti c-erbB-2 (HER-2) immunoglobulin G (IgG) successfully targeted the HER-2 overexpressing breast cancer cell, SK-BR-3. Extensive cell death was observed for the targeted SK-BR-3 line at a low laser power of 540 J (3 W cm(-2) for 3 min) while the control breast cancer cell (low expressing HER-2), HTB-22 survived. Using PEGylated ProG as a cofactor for immobilization of antibodies offers a promising strategy to functionalize various IgGs on nanoparticles for engineering their biomedical applications in cancer therapeutics. PMID- 22532324 TI - Automatic neck plane detection and 3D geometric characterization of aneurysmal sacs. AB - Geometric indices defined on intracranial aneurysms have been widely used in rupture risk assessment and surgical planning. However, most indices employed in clinical settings are currently evaluated based on two-dimensional images that inevitably fail to capture the three-dimensional nature of complex aneurysmal shapes. In addition, since measurements are performed manually, they can suffer from poor inter and intra operator repeatability. The purpose of the current work is to introduce objective and robust techniques for the 3D characterization of intracranial aneurysms, while preserving a close connection to the way aneurysms are currently characterized in clinical settings. Techniques for automatically identifying the neck plane, key aneurysm dimensions, shape factors, and orientations relative to the parent vessel are demonstrated in a population of 15 sidewall and 15 terminal aneurysms whose surface has been obtained by two trained operators using both level-set segmentation and thresholding, the latter reflecting typical clinical practice. Automatically-identified neck planes are shown to be in concordance with those manually positioned by an expert neurosurgeon, and automatically-derived geometric indices are shown to be largely insensitive to segmentation method or operator. By capturing the 3D nature of aneurysmal sacs and by minimizing observer variability, our approach allows large retrospective and prospective studies on aneurysm geometric risk factors to be performed using routinely acquired clinical images. PMID- 22532326 TI - [Psychiatric care for subjects with bipolar disorder: results of the new German S3 guidelines]. AB - Bipolar affective disorders are frequent and have severe consequences. The German S3 guidelines outline the principles of evidence-based treatment of this condition. Based on a partnership with service users and their families accessibility to illness-specific therapy including psychotherapy/psychoeducation, self-help groups for family members and for users are important. Other significant service aspects include assertive outreach and specific rehabilitation (including work). Psychiatric services in Germany remain scattered; therefore there is a need for more coordination. PMID- 22532325 TI - Progastrin overexpression imparts tumorigenic/metastatic potential to embryonic epithelial cells: phenotypic differences between transformed and nontransformed stem cells. AB - We recently reported that overexpression of progastrin (PG) in embryonic epithelial cells (HEKmGAS cells) increased proliferation of the cells compared to that of control HEKC cells. Here, we report the novel finding that tumorigenic and metastatic potential of HEKmGAS cells is also increased significantly compared to that of HEKC cells. Cell surface-associated annexinA2 (CS-ANXA2) binds PG and is overexpressed on cancer cells, allowing us to successfully use fluorescently labeled PG peptide for enumerating metastatic lesions of transformed/cancer cells in vivo. Next, we examined the hypothesis that increased tumorigenic/metastatic potential of isogenic HEKmGAS versus HEKC cells maybe due to transformed phenotype of stem cells. FACSorting/FACScanning of cells demonstrated significant increases in percent doublecortin-CAM-kinase-like1 (DCLK1)/Lgr5-positive stem cells, coexpressing cluster of differentiation44 (CD44)/CS-ANXA2, in HEKmGAS versus HEKC cells. Distinct differences were noted in the morphology of HEKC versus HEKmGAS spheroidal growths on nonadherent cultures (selective for stem cells). HEKC spheroids were rounded with distinct perimeters (e.g., basement membranes), whereas HEKmGAS spheroids were amorphous with no perimeters. Relative levels of DCLK1/Lgr5/CD44 and ANXA2/beta catenin/pNFkappaBp65/metalloproteinases were significantly increased in HEKmGAS versus HEKC cells, growing as monolayer cultures, 3D spheroids (in vitro), or xenografts (in vivo). Interestingly, HEKC cells enriched for CS-ANXA2 developed amorphous spheroids, whereas downregulation of ANXA2 in HEKmGAS clones resulted in loss of matrixmetalloproteinases (MMPs) and re-formation of rounded spheroids, suggesting that high levels of CS-ANXA2/MMPs may impact spheroid morphology. Downregulation of DCLK1 significantly attenuated activation of beta-catenin, with loss of proliferation of HEKmGAS and HEKC cells, suggesting that DCLK1 is required for maintaining proliferation of cells. Our results suggest the novel possibility that transformed stem cells, unlike nontransformed stem cells, coexpress stem cell markers DCLK1 and CD44 with CS-ANXA2. PMID- 22532327 TI - Does phacoemulsification under topical anesthesia affect retrobulbar blood flow? AB - PURPOSE: To investigate with color Doppler imaging the effects of phacoemulsification surgery under topical anesthesia on retrobulbar vessels hemodynamics. METHODS: In this prospective study, color Doppler imaging was used to measure the maximum (Vmax) and minimum flow velocity (Vmin) of the central retinal vein, and the Vmax and Vmin, pulsatility index and resistance index of the central retinal artery, nasal, and temporal posterior ciliary arteries, and ophthalmic artery blood flow before and 1 day after phacoemulsification surgery under topical anesthesia. RESULTS: After phacoemulsification surgery under topical anesthesia, Vmin of the central retinal artery increased (p <= 0.05), whereas the other variables showed no significant change. CONCLUSIONS: Phacoemulsification surgery under topical anesthesia has a minor effect on retrobulbar blood flow. Therefore topical anesthesia should be suitable for patients with ocular perfusion disorders (eg, glaucoma). PMID- 22532328 TI - Serum and urine acute kidney injury biomarkers in asphyxiated neonates. AB - BACKGROUND: We evaluated serum (s) cystatin C (CysC) and neutrophil gelatinase associated lipocalin (NGAL) and urine (u) CysC, NGAL and kidney injury molecule-1 (KIM-1) as markers of acute kidney injury (AKI) in asphyxiated neonates. METHODS: AKI biomarkers were measured in 13 asphyxiated neonates born at >= 36 weeks gestational age (eight with AKI and five without AKI) and 22 controls. AKI was defined as serum creatinine >= 1.5 mg/dl for >24 h or rising values >0.3 mg/dl from day of life (DOL) 1. Biomarkers were measured on DOL 1, 3, and 10. RESULTS: Asphyxiated neonates had significantly higher sCysC on DOL 1 as well as sNGAL and uCysC and uNGAL (standardized to urine creatinine and absolute values) than controls at all time points. Compared to controls, significantly higher sNGAL, uCysC, and uNGAL values were observed in the asphyxia-AKI and asphyxia-no AKI subgroups. Regarding uKIM-1, only the absolute values were significantly higher in asphyxiated neonates (DOL 10). sNGAL, uCyst, and uNGAL had a significant diagnostic performance as predictors AKI on DOL 1. CONCLUSIONS: sNGAL, uCysC, and uNGAL are sensitive, early AKI biomarkers, increasing significantly in asphyxiated neonates even in those not fulfilling AKI criteria. Their measurement on DOL 1 is predictive of post-asphyxia-AKI. PMID- 22532330 TI - LRRC8 proteins share a common ancestor with pannexins, and may form hexameric channels involved in cell-cell communication. AB - Leucine-rich repeat-containing 8 (LRRC8) proteins are composed of four transmembrane helices and 17 leucine-rich repeats (LRR). Although LRRC8 proteins have been associated with important processes, like maturation of B cells or adipocyte differentiation, their biology and molecular function are largely unknown. We found that LRRC8 proteins originated from the combination of a pannexin and an LRR domain (most likely related to the SHOC2, LAP, RSU1 and LRRIQ4 protein families) before the diversification of chordates. We propose that, like pannexins, LRRC8 proteins form hexameric channels, which participate in cell-cell communication processes. According to the inferred topological model, and contrary to what was previously assumed, the six LRR domains are located in the cytoplasm, and could participate in the organisation of signalling cascades. By compiling available proteomics and gene expression data, and on the basis of the LRRC8 proposed hexameric channel structure, we present clues to the function of this family. PMID- 22532329 TI - Safety in glomerular numbers. AB - A low nephron number is, according to Brenner's hyperfiltration hypothesis, associated with hypertension, glomerular damage and proteinuria, and starts a vicious cycle that ends in renal failure over the long term. Nephron endowment is set during foetal life, and there is no formation of nephrons after 34-36 weeks of gestation, indicating that many factors before that time-point may have an impact on kidney development and reduce nephron numbers. Such factors include maternal malnutrition, stress, diseases, such as diabetes, uteroplacental insufficiency, maternal and neonatal drugs and premature birth. However, other congenital anomalies, such as renal hypoplasia, unilateral renal agenesis or multicystic dysplastic kidney, may also lead to a reduced nephron endowment, with an increased risk for hypertension, renal dysfunction and the need for renal replacement therapy. This review focuses on the causes and consequences of a low nephron endowment and will illustrate why there is safety in glomerular numbers. PMID- 22532331 TI - Effect of head-group chemistry on surface-mediated molecular self-assembly. AB - Surface molecular self-assembly is a fast advancing field with broad applications in sensing, patterning, device assembly, and biochemical applications. A vast number of practical systems utilize alkane thiols supported on gold surfaces. Whereas a strong Au-S bond facilitates robust self-assembly, the interaction is so strong that the surface is reconstructed, leaving etch pits that render the monolayers susceptible to degradation. By using different head group elements to adcust the molecule-surface interaction, a vast array of new systems with novel properties may be formed. In this paper we use a carefully chosen set of molecules to make a direct comparison of the self-assembly of thioether, selenoether, and phosphine species on Au(111). Using the herringbone reconstruction of gold as a sensitive readout of molecule-surface interaction strength, we correlate head-group chemistry with monolayer (ML) properties. It is demonstrated that the hard/soft rules of inorganic chemistry can be used to rationalize the observed trend of molecular interaction strengths with the soft gold surface, that is, P>Se>S. We find that the structure of the monolayers can be explained by the geometry of the molecules in terms of dipolar, quadrupolar, or van der Waals interactions between neighboring species driving the assembly of distinct ordered arrays. As this study directly compares one element with another in simple systems, it may serve as a guide for the design of self-assembled monolayers with novel structures and properties. PMID- 22532333 TI - Hepatocellular carcinoma supplied from the short gastric artery: treatment with chemoembolization. AB - We report a case of transcatheter arterial chemoembolization (TACE) to treat hepatocellular carcinoma (HCC) that was supplied by the short gastric artery. A 67-year-old woman with two nodular HCCs underwent repeated TACE. One of the nodules was supplied by the short gastric artery. PMID- 22532332 TI - Photodissociation of charge tagged peptides. AB - Tris(2,4,6-trimethoxyphenyl) phosphonium acetyl (TMPP-Ac) was previously introduced to improve the mass spectrometric sequence analysis of peptides by fixing a permanent charge at the N-termini. However, peptides containing arginine residues did not fragment efficiently after TMPP-Ac modification. In this work, we combine charge derivatization with photodissociation. The fragmentation of TMPP-derivatized peptides is greatly improved and a series of N-terminal fragments is generated with complete sequence information. Arginine has a special effect on the fragmentation of the TMPP tagged peptides when it is the N-terminal peptide residue. Theoretical and experimental results suggest that this is due to hydrogen transfer from the charged N-terminus to the hydrogen-deficient peptide sequence. PMID- 22532334 TI - Retrograde percutaneous transmetatarsal artery access: new approach for extreme revascularization in challenging cases of critical limb ischemia. PMID- 22532335 TI - Importance of a patient dosimetry and clinical follow-up program in the detection of radiodermatitis after long percutaneous coronary interventions. AB - PURPOSE: Complex percutaneous interventions often require high radiation doses likely to produce skin radiation injuries. We assessed the methodology used to select patients with potential skin injuries in cardiac procedures and in need of clinical follow-up. We evaluated peak skin dose and clinical follow-up in a case of radiodermatitis produced during a total occlusion recanalization. MATERIALS AND METHODS: This prospective study followed CIRSE and ACC/AHA/SCAI recommendations for patient radiation dose management in interventional procedures carried out in a university hospital with a workload of 4200 interventional cardiac procedures per year. Patient dose reports were automatically transferred to a central database. Patients exceeding trigger levels for air kerma area product (500 Gy cm(2)) and cumulative skin dose (5 Gy) were counseled and underwent follow-up for early detection of skin injuries, with dermatologic support. The Ethical Committee and the Quality Assurance and Radiation Safety Committee approved the program. RESULTS: During 2010, a total of 13 patients (3.0/1,000 that year) received dose values exceeding trigger levels in the cardiovascular institute. Only one patient, who had undergone two consecutive procedures resulting in 970 Gy cm(2) and 13.0 Gy as cumulative skin dose, showed signs of serious radiodermatitis that resolved in 3.7 months. The remaining patients did not manifest skin lesions during follow-up, and whenever patient examination was not feasible as part of the follow-up, neither patients nor families reported any skin injuries. CONCLUSIONS: Peak skin dose calculation and close clinical follow-up were feasible and appropriate, with a moderate additional workload for the staff and satisfaction for the patient. PMID- 22532336 TI - Transforming frozen self-assemblies of amphiphilic block copolymers into dynamic pH-sensitive micelles. AB - The self-assembly in water of an amphiphilic P(nBMA(50%) -stat-DMAEMA(50%) )(100) b-PDMAEMA(235) diblock copolymer based on hydrophilic dimethylaminoethylmethacrylate (DMAEMA) units and hydrophobic n-butylmethacrylate (nBMA) ones is reported. DMAEMA units have been incorporated into the hydrophobic block of this copolymer to moderate its hydrophobic character. Light scattering experiments revealed the formation of micelles whose apparent aggregation number varied reversibly with the ionization degree of the DMAEMA units. Incorporating hydrophilic units into the hydrophobic block of an amphiphilic block copolymer is thus a way to generate dynamic aggregates in aqueous medium. As this strategy was also successful using other types of hydrophilic units, we believe it to be universal. PMID- 22532337 TI - Asymmetric cyclization reactions of allenoates with imines or alpha,beta unsaturated ketones catalyzed by organocatalysts derived from cinchona alkaloids. AB - Lewis base-catalyzed cyclization reactions of allenoates with electron-deficient olefins and imines have been demonstrated by the preparation of biologically active natural products and pharmaceutically interesting substances and have emerged as powerful synthetic tools in the rapid construction of cyclic molecular complexity. In contrast to phosphine-containing Lewis bases, nitrogen-containing Lewis base amines display markedly different reaction profiles; however, this area is not well-developed. Herein we summarize the recent progress in this emerging field and outline the challenges ahead. PMID- 22532339 TI - Anatomically accurate hard priors for transrectal electrical impedance tomography (TREIT) of the prostate. AB - Current prostate biopsy procedures entail sampling tissues at template-based locations that are not patient specific. Ultrasound (US)-coupled transrectal electrical impedance tomography (TREIT), featuring an endorectal US probe retrofitted with electrodes, has been developed for prostate imaging. This multi modal imaging system aims to identify suspicious tumor regions based on their electrical properties and ultimately provide additional patient-specific locations where to take biopsy samples. Unfortunately, the open-domain geometry associated with TREIT results in a severely ill-posed problem due to the small number of measurements and unbounded imaging domain. Furthermore, reconstructing contrasts within the prostate volume is challenging because the conductivity differences between the prostate and surrounding tissues are much larger than the conductivity differences between benign and malignant tissues within the prostate. To help overcome these problems, anatomically accurate hard priors can be employed to limit estimation of the electrical property distribution to within the prostate volume; however, this requires the availability of structural information. Here, a method that extracts the prostate surface from US images and incorporates this surface into the image reconstruction algorithm has been developed to enable estimation of electrical parameters within the prostate volume. In this paper, the performance of this algorithm is evaluated against a more traditional EIT algorithm that does not use anatomically accurate structural information, in the context of numerical simulations and phantom experiments. The developed anatomically accurate hard-prior algorithm demonstrably identifies contrasts within the prostate volume while an algorithm that does not rely on anatomically accurate structural information is unable to localize these contrasts. While inclusions are identified in the correct locations, they are found to be smaller in size than the actual object due to the rapid decay in sensitivity at increasing distances from the probe surface. Despite this, identifying the size of the inclusion accurately may not be essential for biopsy guidance in a clinical setting; instead, knowledge of the general vicinity of a cancerous lesion may be sufficient for suggesting and guiding clinicians to extract additional biopsy cores. PMID- 22532338 TI - Complexes of Ir(III)-octaethylporphyrin with peptides as probes for sensing cellular O2. AB - Ir(III)-porphyrins are a relatively new group of phosphorescent dyes that have potential for oxygen sensing and labeling of biomolecules. The requirement of two axial ligands for the Ir(III) ion permits simple linkage of biomolecules by a one step ligand-exchange reaction, for example, using precursor carbonyl chloride complexes and peptides containing histidine residue(s). Using this approach, we produced three complexes of Ir(III)-octaethylporphyrin with cell-penetrating (Ir1 and Ir2) and tumor-targeting (Ir3) peptides and studied their photophysical properties. All of the complexes were stable and possessed bright, long-decay (unquenched lifetimes exceeding 45 MUs) phosphorescence at around 650 nm, with moderate sensitivity to oxygen. The Ir1 and Ir2 complexes showed positive staining of a number of mammalian cell types, thus demonstrating localization similar to endoplasmic reticulum and ATP- and temperature-independent intracellular accumulation (direct translocation mechanism). Their low photo- and cytotoxicity allows intracellular oxygen to be probed. PMID- 22532341 TI - Variability of standard liver volume estimation versus software-assisted total liver volume measurement. AB - The estimation of the standard liver volume (SLV) is an important component of the evaluation of potential living liver donors and the surgical planning for resection for tumors. At least 16 different formulas for estimating SLV have been published in the worldwide literature. More recently, several proprietary software-assisted image postprocessing (SAIP) programs have been developed to provide accurate volume measurements based on the actual anatomy of a specific patient. Using SAIP, we measured SLV in 375 healthy potential liver donors and compared the results to SLV values that were estimated with the previously published formulas and each donor's demographic and anthropomorphic data. The percentage errors of the 16 SLV formulas versus SAIP varied by more than 59% (from -21.6% to +37.7%). One formula was not statistically different from SAIP with respect to the percentage error (-1.2%), and another formula was not statistically different with respect to the absolute liver volume (18 mL). More than 75% of the estimated SLV values produced by these 2 formulas had percentage errors within +/-15%, and the formulas provided good predictions within acceptable agreement (+/-15%) on scatter plots. Because of the wide variability, care must be taken when a formula is being chosen for estimating SLV, but the 2 aforementioned formulas provided the most accurate results with our patient demographics. PMID- 22532340 TI - 2-Benzazepine nitrones protect dopaminergic neurons against 6-hydroxydopamine induced oxidative toxicity. AB - A number of C-3 spirocyclic 2-benzazepine analogs of alpha-phenyl-N-tert-butyl nitrone (PBN) were synthesized and tested for their activity in protecting rat brain mitochondria and dopaminergic (DA) neurons against 6-hydroxydopamine (6 OHDA), a toxin inducing destruction of the DA nigro-striatal pathway in rodent models of Parkinson's disease. The newly synthesized nitrone derivatives were firstly investigated for their activity in decreasing the level of hydroxyl radicals generated during 6-OHDA oxidation, and inhibit lipid peroxidation (TBARS assay) and protein carbonyl content (PCC) in rat brain mitochondria. Most of the studied 2-benzazepine nitrones showed inhibitory potencies in both TBARS and PCC assays at least two magnitude orders higher than that of PBN. The data obtained usefully complemented the known structure-activity relationships. In particular, 5 and 10, bearing C-3 spiro cyclopentyl and tetrahydropyranyl moieties, respectively, at 8 uM concentration proved to be significantly more effective than PBN in protecting cultured DA neurons exposed to 6-OHDA, which alone causes about 45% cell loss in 24 h. In addition, we found that 5 inhibited butyrylcholinesterase with an IC(50) value of 16.8 uM, which would enhance its potential as neuroprotective agent in Alzheimer's neurodegeneration. These findings extend the utility of benzazepine-based PBN analogs in the treatment of age-related free radical-mediated disorders. PMID- 22532342 TI - Systems of care as asset-building communities: implementing strengths-based planning and positive youth development. AB - Using a strength-based approach is one of the hallmarks of the system of care (SOC) initiative, and is consistent with the foundations of community psychology. However, while strengths-based planning is recommended and child and family teams often list child and family strengths, the care plans often do not incorporate the strengths in strategies and interventions. The research base regarding strength implementation and effectiveness is summarized, and needed research is outlined. Steps are offered for promoting the use of strengths in SOCS. Implementing programs from the field of positive youth development is advocated as a way that the educational and criminal justice systems could be more actively engaged in implementing strength-based strategies in SOCs. Promoting SOCs to focus more attentively to asset-building (at the child, family, and community level) is compatible with a public health model that addresses mental health concerns in the context of a full range of supports and services so that all children might experience good mental health and realize their potential. PMID- 22532343 TI - Defense-related polyphenol oxidase from Hevea brasiliensis cell suspension: purification and characterization. AB - Polyphenol oxidase (PPO) was examined from the extract of leaf, seed, and cell suspension of Hevea brasiliensis, a rubber plant. The defense-related isozyme from Hevea cell suspension induced by culture filtrate of Phytophthora palmivora or by agitation stress was isolated through anion exchange and affinity chromatography, respectively. A 104-purification fold, migrated as a single band of 70 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis of PPO, was obtained after further purified by the preparative gel electrophoresis. Based on reaction with catechol and dopamine but not with p-cresol and guaiacol, it is a diphenol-type PPO. The values of V(max)/K(m) ratio indicated that catechol was the most specific substrate. The optimal activity of the purified PPO was observed at pH 6.0. The PPO activity was retained at pH 4.0-10.0 and temperature 10-60 degrees C. The inhibitors which completely inhibited the activity were ascorbic acid, dithiothreitol, and beta-mercaptoethanol while sodium azide was a poor inhibitor. The PPO obtained from Hevea cell suspension possesses high specific activity and is stable at wide range of pH and temperature. It is therefore suitable for extreme condition uses and may lead to an alternative source of PPO in various industrial applications. PMID- 22532344 TI - HPLC-MS/MS enantioseparation of triazole fungicides using polysaccharide-based stationary phases. AB - The enantiomeric separation of 21 triazole fungicides was carried out on four polysaccharide-derived chiral stationary phases in the reversed phase separation mode using high performance liquid chromatography coupled with tandem mass spectrometry. All fungicides were detected in electrospray ionization (ESI) positive mode with selected reaction monitoring (SRM). Complete enantioseparation was achieved for 21 fungicides except for difenoconazole based on cellulose tris (3,5-dimethylphenylcarbamate) and cellulose tris (3-chloro-4-methylphenyl carbamate) columns by optimizing experimental conditions including mobile phase and column temperature. Mobile phase was 0.1% formic acid aqueous solution mixed with methanol or acetonitrile in different proportions. Among all the fungicides, 15 with two enantiomers and three with four stereoisomers (bitertanol, bromuconazole, and cyproconazole) were successfully separated at 25 degrees C. Enantioseparation for the other three fungicides (propiconazole, triadimenol, and difenoconazole) with four stereoisomers could be achieved by changing the column temperature from 10 to 40 degrees C. Propiconazole and triadimenol were enantioseparated on baseline at 40 and at 35 degrees C, respectively, and difenoconazole was enantioseparated partially with the R(s) > 1.1 at 25 degrees C. Moreover, linearities and limits of detection (LODs) of 21 fungicides except for difenoconazole were studied, showing coefficients of determination (R(2)) higher than 0.99 and LODs lower than 2.5 MUg/L. PMID- 22532345 TI - Identification of the okadaic acid-based toxin profile of a marine dinoflagellate strain Prorocentrum lima by LC-MS/MS and NMR spectroscopic data. AB - The marine dinoflagellate Prorocentrum lima can produce toxins of okadaic acid and its congeners, which are mainly responsible for diarrhetic shellfish poisoning syndrome. Since 1990s, cells of P. lima have been reported as epiphytes to seaweeds distributed along the coast of Hainan Island. However, its toxin profile has not hitherto been investigated. We report herein the first description and unequivocal evidence of diarrhetic shellfish poisoning toxin production in a cultured strain of P. lima isolated from the coast of Sanya, Hainan Island. Okadaic acid and its two longest diol esters, viz. okadaic acid D10a and okadaic acid-D10b, have been characterized as the main diarrhetic shellfish poisoning toxin congeners of this strain by liquid chromatography tandem mass spectrometry and NMR spectroscopic data. Okadaic acid-D10a and okadaic acid-D10b are first identified by NMR spectroscopic data from the dinoflagellate P. lima. The simultaneous presence of okadaic acid-D10a and okadaic acid-D10b in P. lima enlarges the range of target molecules that must be considered in future diarrhetic shellfish poisoning monitoring programs of Hainan Island, China. PMID- 22532346 TI - Isolation of the minor and rare constituents from fruits of Peucedanum alsaticum L. using high-performance counter-current chromatography. AB - A high-performance counter-current chromatography (HPCCC) method was applied for the first time for the preparative separation and purification of three rare compounds which occur as minor constituents in the fruits of Peucedanum alsaticum L.: 5-substituted coumarin notoptol and two dihydropyranochromones: divaricatol and ledebouriellol. A scale-up process from analytical to preparative in a very short time was developed. In order to purify a range of rare and minor compounds with different polarity two separate experiments were performed, one in reverse phase, the other in normal phase, using the same crude extract. A two-phase solvent system composed of n-hexane/ethyl acetate/methanol/water (1:1:1:1) was developed. The components purified and collected were analyzed by high performance liquid chromatography. The method yielded 0.7 mg of notoptol, 1.46 mg of ledebouriellol at purity of 99.5%, and 10 mg of mixtures of divaricatol, alsaticol and alsaticocoumarin, where divaricatol present 22% by peak area. These amounts were obtained from 1 g of the crude extract in a single run. This is the first time when minor notoptol, ledebouriellol, and divaricatol were isolated in a single run using HPCCC method and first time when these were identified in plant from Peucedanum genus. PMID- 22532347 TI - Rapid determination of ambrisentan enantiomers by enantioselective liquid chromatography using cellulose-based chiral stationary phase in reverse phase mode. AB - A sensitive, specific, and rapid high-performance liquid chromatography (HPLC) method for the determination of ambrisentan enantiomers has been developed and validated. Six chiral columns were tested in a reversed-phase system. Excellent enantioseparation with the resolution more than 2.5 was achieved on Chiralcel OZ 3R (cellulose 3-chloro-4-methylphenylcarbamate) using mixture of 20 mM sodium formate (pH 3.0) with acetonitrile (55:45; v/v). Validation of the HPLC method including linearity, limit of detection, limit of quantification, precision, accuracy, and selectivity was performed according to the International Conference on Harmonisation (ICH) guidelines. The method has an advantage of a very quick chromatographic separation (less than 6 min) and therefore is highly suitable for routine determination of (R)-ambrisentan in enantiopure active pharmaceutical ingredient (S)-ambrisentan. PMID- 22532348 TI - Impact of substituent position in monosubstituted alpha-cyclodextrins on enantioselectivity in capillary electrophoresis. AB - In this study, our three recently synthesized regiospecifically monosubstituted carboxymethyl-alpha-cyclodextrins (CMACDs) were successfully applied for the enantiomeric separation of several biologically important low-molecular weight compounds by capillary electrophoresis. The enantioselectivity of the individual monosubstituted CMACDs added into the background electrolyte (BGE) was studied and compared with the mixture of three monosubstituted CMACDs and with native alpha-cyclodextrin at pH of the BGE ranging from 2.5 to 11. Our experiments revealed a significant influence of the position of the carboxymethyl group on the alpha-cyclodextrin skeleton on the enantioselectivity for all the studied analytes. Interestingly, the least common 3(I)-O regioisomer was revealed as the most effective chiral selector. PMID- 22532349 TI - Selectivity of two types of sulfadimidine-imprinted monolithic polymer-based fibers. AB - Molecularly imprinted polymeric monolithic fiber is a new technique of solid phase microextraction that focuses on selectivity. However, the inner mechanism of increasing the selectivity is not well understood. Here, a new approach to improve the selectivity is shown through controlling the surface of a molecular imprinted polymeric monolithic fiber. Sulfadimidine-imprinted polymeric monolithic fibers were fabricated using two kinds of molds, the polytetrafluoroethylene capillary and the silica capillary. A mixture of sulfadimidine, sulfamerazine, sulfadiazine, and sulfametoxypirydazine was used to test the selectivity of the fibers to sulfadimidine. This paper demonstrates that the extraction ratio for sulfadimidine in mixture is increased to more than 150% in sulfadimidine-imprinted polymeric monolithic fiber compared to nonimprinted polymeric monolithic fiber. The extraction ratio is increased to about 30% in sulfadimidine-imprinted polymeric monolithic fiber fabricated from silica capillary than in the counterpart from nonimprinted polymeric monolithic fiber. The sulfadimidine-imprinted polymeric monolithic fibers were also applied to extract standard mixtures spiked into Pearl River water and milk. The results indicated that polytetrafluoroethylene-sulfadimidine imprinted polymeric monolithic fiber showed highest selectivity to sulfadimidine in complex samples. PMID- 22532350 TI - Determination of (fluoro)quinolones in environmental water using online preconcentration with column switching linked to large sample volumes and fluorescence detection. AB - An analytical method based on online enrichment using coupled-column liquid chromatography with fluorescence detection has been developed to determine marbofloxacin, ciprofloxacin, danofloxacin, enrofloxacin, norfloxacin, lomefloxacin, oxolinic acid, and nalidixic acid at trace levels in surface water. The sample containing the pharmaceuticals was pumped through a short C18 column in such a way that the analytes were retained on the column, whereas polar interferences, eluting at the first of the chromatogram, were discarded to waste. Then, the analytes were transferred by the chromatographic mobile phase to a second C18 analytical column, where they were separated following a conventional chromatography. The optimized approach allowed to preconcentrate 15 mL of sample volume adjusted at acid pH with phosphoric acid and modified with 5% of methanol, at a flow rate of 1.5 mL/min in 10 min. R(2) values were between 0.994 and 0.998, detection and quantitation limits ranged between 0.001 and 0.080 and between 0.002 and 0.100 MUg/L, respectively, and the interday precision was below 9.8%. Recoveries in three different surface water samples, spiked at concentration levels between 0.002 and 0.500 MUg/L (n = 3 for each spiking level), ranged from 82.1 to 125.8% with the relative standard deviation lower than 12%. PMID- 22532351 TI - Comparison of three solid-phase extraction processes in quantification of ciprofloxacin and enrofloxacin in pork meat. AB - Due to strong implications for food safety, control of fluoroquinolones residues in swine meat should be undertaken to verify compliance of the contamination levels with the maximum residue limits recently updated by Commission Regulation (EU) No. 37/2010 of 22 December 2009. Solid-phase extraction is widely used in antibiotic analysis in food of animal origin. In this study, the results of a comparative study using different types of solid-phase extraction columns, HLB, MCX, and MAX, for ciprofloxacin and enrofloxacin analysis, in pork meat, are presented. In addition, diverse sample treatments for defatting, precipitate proteins, eliminate cations, and increase the ionic strength, were used to obtain the most suitable method of analysis. Only the MCX's use followed by liquid chromatography with fluorescence detection resulted in chromatograms that allow the quantification at maximum residue limits. The validation method, in terms of CCalpha and CCbeta, recovery and precision determination, was according to the EU Decision 2002/657/EC. This procedure was used in the analysis of 50 samples of pork meat of Portuguese origin. Only two samples presented residues of enrofloxacin at 30 and 42 MUg/kg, values under the legal maximum residue limit. PMID- 22532352 TI - A simple HPLC method for the simultaneous determination of two selective serotonin reuptake inhibitors and two serotonin-norepinephrine reuptake inhibitors in hair, nail clippings, and cerebrospinal fluid. AB - A novel and simple high-performance liquid chromatography method has been developed for the simultaneous determination of two selective serotonin reuptake inhibitors (fluoxetine and paroxetine) and two serotonin-norepinephrine reuptake inhibitors (venlafaxine and duloxetine) in alternative samples of toxicological interest such as hair, nail clippings, and cerebrospinal fluid (CSF). The separation was achieved on a Hichrom Kromasil 100-5C(18) (250 * 4.6 mm) 5 MUm column by using ammonium acetate (0.05 M)-acetonitrile (59:41% v/v) as the mobile phase, delivered isocratically at a flow rate of 1.3 mL/min, within ca. 10 min. Ultraviolet detection at 235 nm was used for monitoring the eluting analytes. Validation was performed in terms of linearity, selectivity, accuracy, precision, and stability. Correlation coefficients were greater than 0.9954. The limits of quantitation ranged between 0.3 and 2.1 ng/MUL for all analytes in the liquid matrix (CSF), while the respective values were in the range of 0.3-3.6 ng/mg for solid matrices (hair and nail clippings), with an injection volume of 20 MUL. Repeatability and intermediate precision (relative standard deviation, RSD%) were less than 16.6%. The method was successfully applied to actual hair and nail samples from a patient under fluoxetine treatment. PMID- 22532353 TI - Determination of trace indium in urine after preconcentration with a chelating resin-packed minicolumn. AB - A simple and rapid chelating-resin-packed column has been developed for preconcentration of trace indium in biological samples. A large-sized urine sample was pumped through a minicolumn at a flow rate of 1.0 mL/min by using a peristaltic pump, and the eluents were analyzed using graphite furnace atomic absorption spectrometry (GFAAS). Four commercially available chelating resins including Chelex-100, Amberlite IRC-50, Duolite GT-73, and Celite 545-AW were studied for evaluating the indium sorption performance. Several parameters, such as pH, resin amount, eluent volume, eluent flow rate, and the volume of sample, were investigated and optimized. A 100-200 mL of the sample was loaded into a column containing 1.2 g of wet Chelex-100 and subjected to the ion-exchange procedure. The retained analytes were eluted with 5.0 mL of 0.1 M HNO(3) and quantified by GFAAS. The correlation coefficient in the range 10-250 ng/mL was of 0.9994. The limit of detection of the proposed method was 2.75 ng/mL. The method developed was successfully applied to analysis of spiked urine samples with good recoveries of 93-103% (n = 6) and reproducibility (relative standard deviation < 4.9%). The accuracy of procedure was confirmed by indium determination in spiked certified reference materials. PMID- 22532354 TI - Optimization of matrix solid-phase dispersion conditions for organic fungicides determination in soil samples. AB - A simplified sample preparation method, based on the matrix solid-phase dispersion technique, is proposed for the sensitive determination of 15 organic fungicides in vineyard soils by gas chromatography-mass spectrometry (GC-MS). Under final working conditions, sieved samples (0.5 g) were blended and dispersed with 2 g of C18 and transferred to a polypropylene syringe containing 1 g of diatomaceous earth. Analytes were recovered using 10 mL of ethyl acetate, this extract was concentrated to 1 mL and fungicides determined by GC-MS, without additional cleanup. The method provided recoveries in the range from 74 to 122% for soils with total carbon contents up to 5.5% and it allowed the use of external standard as quantification technique. Inter-day precision, given as relative standard deviations, stayed between 3 and 13%, and the limits of quantification were comprised between 0.6 and 15 ng g(-1). Several fungicides were found in the top layer of vineyard soils with the highest detection frequency and maximum concentration corresponding to iprovalicarb. Some real samples were also submitted to pressurized liquid extraction. Measured concentrations were in excellent agreement with those obtained by matrix solid phase dispersion, which reinforces the accuracy of the latter methodology. PMID- 22532355 TI - Comparison of several extraction procedures for the determination of biopesticides in soil samples by ultrahigh pressure LC-MS/MS. AB - A new procedure has been proposed for the determination of biopesticides (nicotine, sabadine, veratridine, rotenone, azadirachtin, cevadine, deguelin, spynosad D, and pyrethrins) and piperonyl butoxide in agricultural soils. Several extraction procedures such as solid-liquid extraction using mechanical shaking, sonication, pressurized liquid extraction, and modified QuEChERS (quick, easy, cheap, effective, rugged, and safe) have been tested, obtaining better results when QuEChERS procedure without further cleanup steps was applied. The determination of the compounds was carried out by ultra high pressure liquid chromatography coupled to tandem mass spectrometry, using methanol and aqueous solution of ammonium formate 5 mM as mobile phase. The method was validated for all compounds at concentrations ranging from 10 to 100 MUg/kg and recoveries ranged from 68 to 116%, except for nicotine and sabadine, with recoveries lower than 50%. Precision was estimated through intra- and inter-day studies, obtaining intra-day precision lower than 20% for most of the compounds, and inter-day precision was lower than 25%. Limits of detection and quantification were also estimated, obtaining limits of quantification equal or lower than 10 MUg/kg. Finally, the method was applied to the analysis of 20 real agricultural soil samples and no biopesticide residues were found over the limit of quantification. PMID- 22532356 TI - Isolation of bioactive components from Flaveria bidentis (L.) Kuntze using high speed counter-current chromatography and time-controlled collection method. AB - Semipreparative high-speed counter-current chromatography (HSCCC) by time controlled collection method was successfully applied for isolation and purification of alpha-terthienyl, 5-(3-buten-1-ynyl)-2,2'-bithienyl, and 5-(3 penten-1-ynyl)-2,2'-bithienyl from Flaveria bidentis (L.) Kuntze for the first time. The two-phase solvent system composed of n-hexane and acetonitrile at the volume ratio of 1:1 (v/v) was used for the semipreparative HSCCC. The 5.2 mg alpha-terthienyl, 2.2 mg 5-(3-buten-1-ynyl)-2,2'-bithienyl, and 4.3 mg 5-(3 penten-1-ynyl)-2,2'-bithienyl with the purity of 99.9, 90.2, and 92.1% were produced from 265.6 mg crude extract, respectively, and 5-(3-penten-1-ynyl)-2,2' bithienyl was first isolated from Flaveria bidentis (L.) Kuntze. The structures of the separated compounds were identified by electrospray-ionization mass spectrometry and proton and carbon nuclear magnetic resonance ((1)H- and (13)C NMR). PMID- 22532357 TI - Determination of pharmaceuticals in wastewaters using solid-phase extraction liquid chromatography-tandem mass spectrometry. AB - Four different commercial sorbents for solid-phase extraction have been evaluated for the extraction of a group of acidic pharmaceuticals in terms of selectivity and capacity: Oasis hydrophilic-lipophilic balance (HLB), Oasis MAX (strong anion exchange), Oasis WAX (weak anion exchange) and a commercial available molecularly imprinted polymer specific for non-steroidal anti-inflammatory drugs. Among the sorbents studied, molecularly imprinted polymer proved to be very effective in the reduction of matrix interferences and the selective extraction of acidic pharmaceuticals, such as salicylic acid, ibuprofen, fenoprofen, diclofenac and naproxen, among others, from effluent wastewater samples. Moreover, molecularly imprinted solid-phase extraction protocol was applied to liquid chromatography coupled to tandem mass spectrometry (MS/MS) with the purpose of evaluating the clean-up effect on ion suppression/enhancement when the complexity of the samples increases and a reduction of this effect was observed. Molecularly imprinted solid-phase extraction followed by liquid chromatography coupled to ultraviolet detection and liquid chromatography coupled to tandem mass spectrometry validation methodologies with effluent wastewaters were developed, obtaining recoveries between 70 and 85% and limits of detection at low levels of MUg/L (0.15-1 MUg/L) and ng/L (0.5-2 ng/L), respectively. The final application of molecularly imprinted solid-phase extraction and liquid chromatography coupled to MS/MS detection showed the presence of acidic pharmaceuticals studied in this work in effluent wastewaters (3)-alpha-L-rhamnopyranosyl-(1->6)-beta-D galactopyranoside, kaempferol 3-O-alpha-L-rhamnopyranosyl-(1->3)-(4-O-acetyl alpha-L-rhamnopyranosyl)-(1->6)-beta-D-galactopyranoside and kaempferol 3-O-alpha L-rhamnopyranosyl-(1->3)-(2,4-di-O-acetyl-alpha-L-rhamnopyranosyl)-(1->6)-beta-D galactopyranoside, were obtained. The purities of the separated compounds were all over 95% as determined by HPLC area normalization method. Their chemical structures were confirmed by UV, MS, NMR, and the standards. PMID- 22532359 TI - Preparation of agarose/chitosan composite supermacroporous monolithic cryogels for affinity purification of glycoproteins. AB - Supermacroporous agarose/chitosan composite monolithic (AC CM) cryogels were prepared for affinity purification of the major egg white glycoproteins, ovalbumin (OVA), and ovotransferrin (OVT). The supermacroporous AC CM cryogels were produced by cryocopolymerization of agarose/chitosan blend solutions using glutaraldehyde as the cross-linker. The 3-aminophenlyboronic acid ligand was immobilized by covalent binding to epoxy-group-coupled supermacroporous AC CM cryogels. The microstructure morphologies of these cryogels were analyzed by scanning electron microscopy. The supermacroporous AC CM cryogels contained a continuous interpenetrating polymer network matrix with interconnected pores of 10-100 MUm in size. The composite cryogels offered high mechanical stability and had specific recognition for glycoproteins. The maximum binding capacity of OVA adsorption from aqueous solutions was 55.6 mg/g. The matrix could be reused 11 times without significant loss in OVA adsorption capacity. The recovery yields of OVA and OVT from egg white were estimated to be 89 and 93%, respectively. PMID- 22532360 TI - Separation and purification of furanocoumarins from Toddalia asiatica (L.) Lam. using microwave-assisted extraction coupled with high-speed counter-current chromatography. AB - A method of microwave-assisted extraction coupled with high-speed counter-current chromatography was established for separation and purification of isopimpinellin, pimpinellin and phellopterin from Toddalia asiatica (L.) Lam. The conditions of MAE including the extraction solvent, size of sample, solid/liquid ratio, extraction temperature and extraction time were optimized by a mono-factor test. That is, 2.0 g dried powder of T. asiatica (L.) Lam of 0.30-0.15 mm size was extracted with 20 mL (solid/liquid ratio of 1:10, g/mL) methanol under 50 degrees C for 1 min. The crude extract was separated and purified by high-speed counter-current chromatography with hexane-ethyl acetate-methanol-water (5:5:5.5:4.5, v/v/v/v) solvent system. 0.85 mg/g of isopimpinellin, 2.55 mg/g of pimpinellin and 0.95 mg/g of phellopterin were obtained from original sample in one-step within 240 min, the purity determined by high performance liquid chromatography was 95.0%, 99.1% and 96.4%, respectively. Their chemical structures were further identified by mass spectroscopy and nuclear magnetic resonance spectroscopy. The results demonstrated that microwave-assisted extraction coupled with high-speed counter-current chromatography was a feasible, economical and efficient technique for rapid extraction, separation and purification of effective compounds from natural products. PMID- 22532363 TI - [Prevention of uro-oncological diseases]. AB - During the last decade consideration of the role of vitamins and minerals in primary prevention of genitourinary tumors has changed dramatically. Despite all efforts the efficacy of a specific compound has not yet been proven and as a consequence recommendations for the use of vitamins or other supplements for tumor prevention should no longer be given. In contrast life style modification might be helpful as recent investigations suggested that smoking not only promotes the development of bladder cancer but is also involved in prostate and renal cell carcinogenesis. In addition there is some evidence that moderate food consumption, reduction of dairy product consumption and an Asian or Mediterranean diet can prevent prostate cancer and also harbor additional beneficial effects for general health. These observations should be the starting point of future epidemiological research. This may be considered as a change of paradigm in prostate cancer prevention. In contrast there is clear evidence of the efficacy of chemoprevention using 5alpha-reductase inhibitors as the use of finasteride and dutasteride significantly reduces the detection of prostate cancer. However, translation of these findings into urological practice remains a matter of controversial discussion. PMID- 22532364 TI - [Radical cystectomy - pro laparoscopic]. AB - Although the technical feasibility of laparoscopic radical cystectomy (LRC) has been proven and the procedure has been accepted in the EAU guidelines 2011 as a valid alternative, its actual position has to be determined. On the one hand the advantages of LRC (less blood loss, lower transfusion rates, shorter analgesia time) have been proven in retrospective studies; however, the technical difficulties of purely laparoscopic urinary diversion result in very long operating times and in cases of a laparoscopic-assisted creation of a neobladder, the question of the advantage of this approach remains doubtful. Despite case reports of port metastases and peritoneal carcinosis following laparoscopic and robot-assisted radical cystectomy, there is no difference in terms of oncological long-term data (up to 10 years) between laparoscopy and open surgery performed at centres of excellence. Evidently, the curative options for the patients do not depend on the type of surgery (open versus minimally invasive) but on the efficacy of adjuvant treatment strategies (polychemotherapy). Currently it is believed that LRC should be considered for patients with low risk of progression (pT1-2). The final position of laparoscopic radical cystectomy can only be evaluated in a multicentric randomized controlled trial. PMID- 22532365 TI - [Comments on radical prostatectomy - laparoscopic versus robotic]. PMID- 22532366 TI - [Comments on retroperitoneal lymphadenectomy - laparoscopic versus robotic]. AB - Retroperitoneal lymph node dissection (RPLND) in high risk clinical stage I nonseminomatous germ cell tumors (NSGCT) plays a limited role in modern uro oncology due to the superior therapeutic efficacy of even one cycle of PEB (cysplatin, etoposide, bleomycin) chemotherapy. There might be an indication for the rare case of pure mature teratoma with unfavorable prognostic risk factors. If RPLND is performed for clinical stage I NSGCT it always has to be performed in a nerve-sparing technique and within the well-defined boundaries of an anatomically adequate template in order to avoid unnecessary adjuvant systemic chemotherapy. In this aspect, laparoscopic RPLND is inferior to open RPLND as basically all patients with lymph node positive disease receive adjuvant chemotherapy. The evidence for robotic-assisted RPLND is too weak to draw any clinically useful conclusions. Currently, it is an experimental procedure.Postchemotherapy RPLND (PC-RPLND) remains a surgery for tertiary referral centres due to the complexity of the surgical intervention and the high probability of adjunctive visceral and/or vascular surgery. In accordance with international guidelines it remains a domain for an open surgical approach. Laparoscopic PC-RPLND is reserved for small residual masses with the option of a unilateral modified template resection in very experienced laparoscopic centres. With regard to robotic-assisted PC-RPLND there is no evidence in the literature with regard to morbidity and complications, short-term and long-term oncological results being in favor of this experimental approach. PMID- 22532367 TI - Remembering Joanne Angle, 1941-2012. PMID- 22532368 TI - International Children's Continence Society's recommendations for therapeutic intervention in congenital neuropathic bladder and bowel dysfunction in children. AB - PURPOSE: We present a consensus view of members of the International Children's Continence Society on the therapeutic intervention in congenital neuropatic bladder and bowel dysfunction in children. MATERIAL AND METHODS: Discussions were held by a group of pediatric urologists and gastroenterologists appointed by the board. The following draft review document was open to all the ICCS members via the ICCS web site. Feedback was considered by the core authors and by agreement, amendments were made as necessary. The final document is not a systematic literature review. It includes relevant research when available as well as expert opinion on the current understanding of therapeutic intervention in congenital neuropatic bladder and bowel dysfunction in children. RESULTS: Guidelines on pharmalogical and surgical intervention are presented. First the multiple modalities for intervention that do not involve surgical reconstruction are summarized concerning pharmacological agents, medical devices, and neuromodulation. The non-surgical intervention is promoted before undertaking major surgery. Indicators for non-surgical treatments depend on issues related to intravesical pressure, upper urinary tract status, prevalence of urinary tract infections, and the degree of incontinence. The optimal age for treatment of incontinence is also addressed. This is followed by a survey of specific treatments such as anticholinergics, botulinum-A toxin, antibiotics, and catheters. Neuromodulation of the bladder via intravesical electrical stimulation, sacral nerve stimulation, transcutaneous stimulation, and biofeedback is scrutinized. Then follows surgical intervention, which should be tailored to each individual, based on careful consideration of urodynamic findings, medical history, age, and presence of other disability. Treatments mentioned are: urethral dilation, vesicostomy, bladder, augmentation, fascial sling, artificial urinary sphincters, and bladder neck reconstruction and are summarized with regards to success rates and complications. Finally, the treatment on neuropathic bowel dysfunction with rectal suppositories irrigation and transrectal stimulation are scrutinized. PMID- 22532369 TI - Protein arginine methyltransferase 1 regulates hepatic glucose production in a FoxO1-dependent manner. AB - Postprandial insulin plays a critical role in suppressing hepatic glucose production to maintain euglycemia in mammals. Insulin-dependent activation of protein kinase B (Akt) regulates this process, in part, by inhibiting FoxO1 dependent hepatic gluconeogenesis by direct phosphorylation and subsequent cytoplasmic exclusion. Previously, it was demonstrated that protein arginine methyltransferase 1 (PRMT1)-dependent arginine modification of FoxO1 interferes with Akt-dependent phosphorylation, both in cancer cells and in the Caenorhabditis elegans model, suggesting that this additional modification of FoxO1 might be critical in its transcriptional activity. In this study, we attempted to directly test the effect of arginine methylation of FoxO1 on hepatic glucose metabolism. The ectopic expression of PRMT1 enhanced messenger RNA levels of FoxO1 target genes in gluconeogenesis, resulting in increased glucose production from primary hepatocytes. Phosphorylation of FoxO1 at serine 253 was reduced with PRMT1 expression, without affecting the serine 473 phosphorylation of Akt. Conversely, knockdown of PRMT1 promoted an inhibition of FoxO1 activity and hepatic gluconeogenesis by enhancing the phosphorylation of FoxO1. In addition, genetic haploinsufficiency of Prmt1 reduced hepatic gluconeogenesis and blood-glucose levels in mouse models, underscoring the importance of this factor in hepatic glucose metabolism in vivo. Finally, we were able to observe an amelioration of the hyperglycemic phenotype of db/db mice with PRMT1 knockdown, showing a potential importance of this protein as a therapeutic target for the treatment of diabetes. CONCLUSION: Our data strongly suggest that the PRMT1 dependent regulation of FoxO1 is critical in hepatic glucose metabolism in vivo. PMID- 22532370 TI - Are increased carotid artery pulsatility and resistance indexes early signs of vascular abnormalities in young obese males? AB - PURPOSE: To provide insight into the factors by which obesity in itself may directly lead to early arterial damage, we aimed to determine early sonographic markers of obesity-related vascular dysfunction in young obese males. METHODS: Thirty-five young obese males and 23 age-matched healthy male volunteers were recruited into the study. Common carotid artery pulsatility index and resistance index were calculated from blood flow velocities curves obtained by pulsed Doppler ultrasonography. RESULTS: The mean pulsatility index, resistance index, body mass index, waist circumference, systolic and diastolic blood pressure, homeostasis model assessment for insulin resistance, plasma fasting glucose, insulin, C-peptide, triglycerides, low-density lipoprotein cholesterol, and high sensitivity C-reactive protein were statistically higher in obese subjects than in healthy controls. CONCLUSIONS: Our results suggest that depressed vessel compliance and increased vascular resistance are features of young, obese, normotensive subjects independently of and in addition to cardiovascular risk factors. As changes in arterial wall properties may be incipient in young obese subjects, future studies will be required to demonstrate whether early intervention such as diet and exercise in this population can improve vascular functions. PMID- 22532371 TI - International trends in the incidence of malignant melanoma 1953-2008--are recent generations at higher or lower risk? AB - The incidence of cutaneous malignant melanoma has steadily increased over the past 50 years in predominately fair-skinned populations. This increase is reported to have leveled off recently in several Northern and Western European countries, Australia, New Zealand and in North America. We studied the global patterns and time trends in incidence of melanoma by country and sex, with a focus on and age- and cohort-specific variations. We analyzed the incidence data from 39 population-based cancer registries, examining all-ages and age-truncated standardized incidence rates of melanoma, estimating the annual percentage change and incidence rate ratios from age-period-cohort models. Incidence rates of melanoma continue to rise in most European countries (primarily Southern and Eastern Europe), whereas in Australia, New Zealand, the U.S., Canada, Israel and Norway, rates have become rather stable in recent years. Indications of a stabilization or decreasing trend were observed mainly in the youngest age group (25-44 years). Rates have been rising steadily in generations born up to the end of the 1940s, followed by a stabilization or decline in rates for more recently born cohorts in Australia, New Zealand, the U.S., Canada and Norway. In addition to the birth cohort effect, there was a suggestion of a period-related influence on melanoma trends in certain populations. Although our findings provide support that primary and secondary prevention can halt and reverse the observed increasing burden of melanoma, they also indicate that those prevention measures require further endorsement in many countries. PMID- 22532372 TI - Diffusion sensitivity of turbo spin echo sequences. AB - This article introduces an effective b-factor b(TSE) for turbo spin echo (TSE) sequences to quantify their inherent diffusion sensitivity. b(TSE) is investigated for a broad variety of two-dimensional- and three-dimensional-TSE sequences using constant and varying flip angles (transitions between pseudo steady states, SPACE, VISTA, Cube, etc.). The inherent TSE diffusion sensitivity becomes important for high-resolution protocols, which can lead to subtle contrast modifications or even fluid suppressions in a clinical setting or animal imaging regime. The b(TSE) values obtained considerably depend on the relaxation times and diffusion coefficient and, thus, on the tissue under observation. The fractional b(TSE) contributions per TSE imaging encoding axis are highly anisotropic. Further noteworthy effects such as decreasing b-factors along a TSE train are pointed out and explained. The results are also discussed in combination with recent findings regarding contrast properties and possible diffusion sensitivity of TSE sequences. Identical but well more pronounced b(TSE) effects are observed in the animal imaging regime due to smaller field of view and higher resolutions. PMID- 22532373 TI - Infliximab treatment induces levels of the active azathioprine metabolite TGTP in Crohn's disease. PMID- 22532374 TI - "DNA traffic lights": concept of wavelength-shifting DNA probes and application in an aptasensor. AB - Add it and see it: The concept of "DNA traffic lights" for wavelength-shifting DNA probes has a great potential in the application of biosensors, for example, in DNA aptamers. A visual color change in the DNA aptasensor fluorescence from green to red occurs after specific target binding. PMID- 22532375 TI - Feasibility of computer-assisted surgery for trapeziometacarpal prosthesis: a preliminary experimental study. AB - BACKGROUNDS: The main complication of trapeziometacarpal replacement is trapezial cup loosening due to an imperfect positioning of the trapezial component. This problem is quite similar to those related to other arthroplasties. Hip surgery was progressed toward computer-assisted surgery (CAS) for the improvement of acetabular cup positioning. In this study, we propose an analysis of the feasibility of CAS in trapeziometacarpal replacement. METHODS: We implanted the hand of a cadaver with a trapeziometacarpal prosthesis (Elektra, by SBI). The surgical procedure and the analysis of motion with CAS were carried out in 6 steps: incision, bone morphing preparation and initialisation, trapezial and metacarpal recordings, first kinematic analysis, prosthesis insertion, and second kinematic analysis. The evaluation of the results was carried out as the comparison of the 2 curves sequences before and after prosthesis insertion. RESULTS: We did not notice any dislocation of the prosthesis. The comparison of 2 curves showed differences regarding motion. For instance, as for abduction adduction movements, before prosthesis insertion, an opposed-phase automatic rotation was clearly observed whereas after prosthesis insertion, no rotation was observed. CONCLUSION: CAS makes it possible to analyze the trapeziometacarpal joint motion in terms of biomechanics rather than in terms of anatomy. Such progress should result in measurement standardization that in turn should improve the positioning of prostheses and perhaps the lengthening of their life expectancy by decreasing the rates of prosthesis loosening. PMID- 22532376 TI - Axial ligand and spin-state influence on the formation and reactivity of hydroperoxo-iron(III) porphyrin complexes. AB - The present study focuses on the formation and reactivity of hydroperoxo iron(III) porphyrin complexes formed in the [Fe(III)(tpfpp)X]/H(2)O(2)/HOO(-) system (TPFPP=5,10,15,20-tetrakis(pentafluorophenyl)-21H,23H-porphyrin; X=Cl(-) or CF(3) SO(3)(-)) in acetonitrile under basic conditions at -15 degrees C. Depending on the selected reaction conditions and the active form of the catalyst, the formation of high-spin [Fe(III)(tpfpp)(OOH)] and low-spin [Fe(III)(tpfpp)(OH)(OOH)] could be observed with the application of a low temperature rapid-scan UV/Vis spectroscopic technique. Axial ligation and the spin state of the iron(III) center control the mode of O-O bond cleavage in the corresponding hydroperoxo porphyrin species. A mechanistic changeover from homo- to heterolytic O-O bond cleavage is observed for high- [Fe(III)(tpfpp)(OOH)] and low-spin [Fe(III)(tpfpp)(OH)(OOH)] complexes, respectively. In contrast to other iron(III) hydroperoxo complexes with electron-rich porphyrin ligands, electron deficient [Fe(III)(tpfpp)(OH)(OOH)] was stable under relatively mild conditions and could therefore be investigated directly in the oxygenation reactions of selected organic substrates. The very low reactivity of [Fe(III)(tpfpp)(OH)(OOH)] towards organic substrates implied that the ferric hydroperoxo intermediate must be a very sluggish oxidant compared with the iron(IV)-oxo porphyrin pi-cation radical intermediate in the catalytic oxygenation reactions of cytochrome P450. PMID- 22532377 TI - Taurine postponed the replicative senescence of rat bone marrow-derived multipotent stromal cells in vitro. AB - The aging of many mammalian tissues is associated with replicative decline in somatic stem cells. Postponing this decline is a direct way of anti-aging. Bone marrow-derived multipotent stromal cells (BMSCs) hold promise for an increasing list of therapeutic uses due to their multilineage potential. Clinical application of BMSCs requires abundant cells that can be overcome by ex vivo expansion of cells, but often facing the replicative senescence problem. We demonstrated that taurine exhibited anti-replicative senescence effect on rat BMSCs by promoting colony forming unit-fibroblast formation and cell proliferation, shortening cell population doubling time, enormously inhibiting senescence-associated beta-galactosidase activity and slowing the loss of differentiation potential, while having no significant effect on the maximum passage number and total culture time, and slight influences on the cell surface CD molecules expressions. Taurine is a quite safe antioxidant and nutrient extensively used in food addition and clinical treatment. These suggested that taurine is a promising anti-replicative senescence additive for ex vivo expansion of BMSCs in experimental and clinical cell therapies. PMID- 22532378 TI - Synthesis and biological evaluation of phenyl substituted 1H-1,2,4-triazoles as non-steroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 2. AB - A series of disubstituted-1H-1,2,4-triazole derivatives was synthesized with the aim of developing new non-steroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 2 (17betaHSD2) - a novel and attractive target for the treatment of osteoporosis. 17betaHSD2 catalyzes the oxidation of the highly active estrogen 17beta-estradiol (E2) and androgen testosterone (T) into the weak estrone and androstenedione, respectively. Inhibition of this enzyme will locally in the bone lead to an increase in E2 and T levels, two key players in the maintenance of the balance between bone resorption and bone formation. In this study, a new class of 17betaHSD2 inhibitors with a 1H-1,2,4-triazole scaffold was identified; the three best compounds 8b, 8f, and 13a showed moderate 17betaHSD2 inhibitory activity and a good selectivity toward 17betaHSD1. They could be a useful tool to map the unexplored enzyme active site. PMID- 22532379 TI - Level-set-based reconstruction algorithm for EIT lung images: first clinical results. AB - We show the first clinical results using the level-set-based reconstruction algorithm for electrical impedance tomography (EIT) data. The level-set-based reconstruction method (LSRM) allows the reconstruction of non-smooth interfaces between image regions, which are typically smoothed by traditional voxel-based reconstruction methods (VBRMs). We develop a time difference formulation of the LSRM for 2D images. The proposed reconstruction method is applied to reconstruct clinical EIT data of a slow flow inflation pressure-volume manoeuvre in lung healthy and adult lung-injury patients. Images from the LSRM and the VBRM are compared. The results show comparable reconstructed images, but with an improved ability to reconstruct sharp conductivity changes in the distribution of lung ventilation using the LSRM. PMID- 22532380 TI - Cardioversion for atrial fibrillation in the real world: there is room for improvement. PMID- 22532382 TI - Coordination studies on supramolecular chiral ligands and application in asymmetric hydroformylation. AB - In this study we introduce a series of monodentate pyridine-based ligands for which the phosphorus coordination mode to rhodium can be controlled by the binding of Zn(II)-templates to the pyridyl group. A series of monodentate phosphoroamidite and phosphite ligands have been prepared and studied under hydroformylation conditions by in situ high-pressure NMR and IR techniques. These studies reveal the exclusive formation of rhodium hydride complexes in which the phosphorus atom of the ligand resides in an axial position, trans to the hydride, but only after addition of Zn(II)-template. In the absence of these templates the usual mono-coordinated rhodium hydrido complexes are formed, with the phosphorus ligated in the equatorial plane, cis to the hydride. The catalytic performance of these complexes is evaluated in asymmetric hydroformylation of unfunctionalised internal alkenes in which the supramolecular change is reflected in higher activity and selectivity. PMID- 22532381 TI - Periprocedural anticoagulation therapy for devices and atrial fibrillation ablation. AB - This EP Wire surveyed clinical practice with regard to the use of antithrombotic therapy in relation to device implantation (pacemakers, ICT, resynchronization therapy) and atrial fibrillation ablation in 71 centres-members of the European Heart Rhythm Association research network. The results of this survey show variation in clinical practice, but reassuringly some consistency with guidelines and consensus recommendations on the management of periprocedure (devices, ablation) antithrombotic therapy. PMID- 22532383 TI - Rapid and simple determination of psychotropic phenylalkylamine derivatives in urine by direct injection liquid chromatography-electrospray ionization-tandem mass spectrometry. AB - A direct injection liquid chromatography-electrospray ionization-tandem mass spectrometric method (LC-ESI-MS/MS) was developed and validated for the rapid and simple determination of 13 phenylalkylamine derivatives. Eight deuterium-labeled compounds were prepared for use as internal standards (ISs) to quantify the analytes. Urine samples mixed with ISs were centrifuged, filtered through 0.22 um filters and then injected directly into the LC-ESI-MS/MS system. The mobile phase was composed of 0.2% formic acid and 2 mM ammonium formate in distilled water and 0.2% formic acid and 2 mM ammonium formate in acetonitrile. The analytical column was a Capcell Pak MG-II C(18) (150 * 2.0 mm i.d., 5 um, Shiseido). Separation and detection of the analytes were accomplished within 10 min. The linear ranges were 5-750 ng/mL (ephedrine and fenfluramine), 10-750 ng/mL (3,4 methylenedioxyamphetamine, phendimetrazine, methamphetamine, 3,4 methylenedioxyethylamphetamine and benzphetamine), 20-750 ng/mL (norephedrine, amphetamine, phentermine and ketamine) and 30-1000 ng/mL (3,4 methylenedioxymethamphetamine and norketamine), with determination coefficients, R(2) , >= 0.9967. The intra-day and inter-day precisions were within 19.1%. The intra-day and inter-day accuracies ranged from -16.0 to 18.7%. The lower limits of quantification for all the analytes were lower than 26.5 ng/mL. The applicability of the method was examined by analyzing urine samples from drug abusers (n = 30). PMID- 22532384 TI - Familiarity does not affect the unilateral field advantage for repetition detection. AB - We have previously reported evidence that repetitions of letters, colors, sizes, and common motion paths are more rapidly detected when they are presented unilaterally (i.e., both in the same visual field) versus bilaterally (one element in each visual field; Butcher and Cavanagh (Attention, Perception, & Psychophysics 70:714-724, 2008). Here, we report evidence that this unilateral field advantage (UFA) for repetition detection does not depend on prior experience with the elements that comprise the repetition. In Experiment 1, native English, Persian, and Japanese speakers were tested on a repetition detection task involving characters from Western, Arabic, and Japanese character sets. The character sets were tested in blocks, in each of which subjects were presented with four characters for 16 ms and asked to report whether any two of the characters were identical. The subjects were faster detecting repetitions that were presented unilaterally rather than bilaterally, and there was no interaction with stimulus familiarity. A second experiment replicated this finding with native English speakers only, using a longer stimulus duration (150 ms). We had previously proposed that the UFA arises because the low-level processes that group physically identical items operate more efficiently within than across hemifields. Our data now indicate that this grouping process is insensitive to item familiarity, supporting the claim that the process is low level. PMID- 22532385 TI - Cue-integration and context effects in speech: evidence against speaking-rate normalization. AB - Listeners are able to accurately recognize speech despite variation in acoustic cues across contexts, such as different speaking rates. Previous work has suggested that listeners use rate information (indicated by vowel length; VL) to modify their use of context-dependent acoustic cues, like voice-onset time (VOT), a primary cue to voicing. We present several experiments and simulations that offer an alternative explanation: that listeners treat VL as a phonetic cue rather than as an indicator of speaking rate, and that they rely on general cue integration principles to combine information from VOT and VL. We demonstrate that listeners use the two cues independently, that VL is used in both naturally produced and synthetic speech, and that the effects of stimulus naturalness can be explained by a cue-integration model. Together, these results suggest that listeners do not interpret VOT relative to rate information provided by VL and that the effects of speaking rate can be explained by more general cue integration principles. PMID- 22532386 TI - Low charge density cationic polymers for gene delivery: exploring the influence of structural elements on in vitro transfection. AB - A series of end-functionalized poly(trimethylene carbonate) DNA carriers, characterized by low cationic charge density and pronounced hydrophobicity, is used to study structural effects on in vitro gene delivery. As the DNA-binding moieties are identical in all polymer structures, the differences observed between the different polymers are directly related to the functionality and length of the polymer backbone. The transfection efficiency and cytotoxicity of the polymer/DNA complexes are thus found to be dependent on a combination of polymer charge density and functionality, highlighting the importance of such structural considerations in the development of materials for efficient gene delivery. PMID- 22532387 TI - Rewiring and dosing of systems modules as a design approach for synthetic mammalian signaling networks. AB - Modularly structured signaling networks coordinate the fate and function of complex biological systems. Each component in the network performs a discrete computational operation, but when connected to each other intricate functionality emerges. Here we study such an architecture by connecting auxin signaling modules and inducible protein biotinylation systems with transcriptional control systems to construct synthetic mammalian high-detect, low-detect and band-detect networks that translate overlapping gradients of inducer molecules into distinct gene expression patterns. Guided by a mathematical model we apply fundamental computational operations like conjunction or addition to rewire individual building blocks to qualitatively and quantitatively program the way the overall network interprets graded input signals. The design principles described in this study might serve as a conceptual blueprint for the development of next generation mammalian synthetic gene networks in fundamental and translational research. PMID- 22532389 TI - Inhibition of acetyl-CoA carboxylase 2 enhances skeletal muscle fatty acid oxidation and improves whole-body glucose homeostasis in db/db mice. AB - AIMS/HYPOTHESIS: Excessive ectopic lipid deposition contributes to impaired insulin action in peripheral tissues and is considered an important link between obesity and type 2 diabetes mellitus. Acetyl-CoA carboxylase 2 (ACC2) is a key regulatory enzyme controlling skeletal muscle mitochondrial fatty acid oxidation; inhibition of ACC2 results in enhanced oxidation of lipids. Several mouse models lacking functional ACC2 have been reported in the literature. However, the phenotypes of the different models are inconclusive with respect to glucose homeostasis and protection from diet-induced obesity. METHODS: Here, we studied the effects of pharmacological inhibition of ACC2 using as a selective inhibitor the S enantiomer of compound 9c ([S]-9c). Selectivity was confirmed in biochemical assays using purified human ACC1 and ACC2. RESULTS: (S)-9c significantly increased fatty acid oxidation in isolated extensor digitorum longus muscle from different mouse models (EC(50) 226 nmol/l). Accordingly, short term treatment of mice with (S)-9c decreased malonyl-CoA levels in skeletal muscle and concomitantly reduced intramyocellular lipid levels. Treatment of db/db mice for 70 days with (S)-9c (10 and 30 mg/kg, by oral gavage) resulted in improved oral glucose tolerance (AUC -36%, p < 0.05), enhanced skeletal muscle 2 deoxy-2-[(18)F]fluoro-D-glucose (FDG) uptake, as well as lowered prandial glucose (-31%, p < 0.01) and HbA(1c) (-0.7%, p < 0.05). Body weight, liver triacylglycerol, plasma insulin and pancreatic insulin content were unaffected by the treatment. CONCLUSIONS/INTERPRETATION: In conclusion, the ACC2-selective inhibitor (S)-9c revealed glucose-lowering effects in a mouse model of diabetes mellitus. PMID- 22532391 TI - Comment on "A Prospective Study on Electrocardiographic Findings of Patients with Organophosphorus Poisoning". PMID- 22532388 TI - Current status of functional imaging in eating disorders. AB - Eating Disorders are complex psychiatric problems that involve biologic and psychological factors. Brain imaging studies provide insights about how functionally connected brain networks may contribute to disturbed eating behavior, resulting in food refusal and altered body weight, but also body preoccupations and heightened anxiety. In this article, we review the current state of brain imaging in eating disorders, and how such techniques may help identify pathways that could be important in the treatment of those often detrimental disorders. PMID- 22532392 TI - CuO/ZnO nanocomposite gas sensors developed by a plasma-assisted route. AB - CuO/ZnO nanocomposites were synthesized on Al(2)O(3) substrates by a hybrid plasma-assisted approach, combining the initial growth of ZnO columnar arrays by plasma-enhanced chemical vapor deposition (PE-CVD) and subsequent radio frequency (RF) sputtering of copper, followed by final annealing in air. Chemical, morphological, and structural analyses revealed the formation of high-purity nanosystems, characterized by a controllable dispersion of CuO particles into ZnO matrices. The high surface-to-volume ratio of the obtained materials, along with intimate CuO/ZnO intermixing, resulted in the efficient detection of various oxidizing and reducing gases (such as O(3), CH(3)CH(2)OH, and H(2)). The obtained data are critically discussed and interrelated with the chemical and physical properties of the nanocomposites. PMID- 22532395 TI - Janus-like squaramide-based hosts: dual mode of binding and conformational transitions driven by ion-pair recognition. AB - New tripodal squaramide-based hosts have been synthesised and structurally characterised by spectroscopic methods. In 2.5 % (v/v) [D(6)]DMSO in CDCl(3), compound 4 formed dimeric assemblies [log K(dim)=3.68(8)] as demonstrated by (1)H NMR spectroscopy and UV dilution experiments. AFM and SEM analyses revealed the formation of a network of bundled fibres, which indicates a preferential mechanism for aggregation. These C(3)-symmetric tripodal hosts exhibited two different and mutually exclusive modes of binding, each one easily accessible by simultaneous reorientation of the squaramide groups. In the first, a convergent disposition of the NH squaramide protons allowed the formation of an array of N H???X(-) hydrogen bonds with anions. In the second mode, reorientation of carbonyl squaramide groups allowed multiple C=O???H interactions with ammonium cations. The titration of 4 with different tetraalkylammonium iodides persistently showed the formation of 1:1 complexes, as well as 1:2 and 1:3 complexes. The corresponding stoichiometries and binding affinities of the complexes were evaluated by multi-regression analysis. The formation of high order complexes, supported by ROESY, NOESY and mass spectrometry experiments, has been attributed to the insertion of NR(4)I ion pairs between the carbonyl and NH protons of the squaramide groups located in adjacent arms of 4. The observed effects reflect the induction of significant conformational changes in the hosts, mainly in relation to the relative orientation of the squaramide groups adapting their geometries to incoming ion-pair complementary substrates. The results presented herein identify and fully describe two different modes of ion-pair recognition aimed at directing conformational transitions in the host, therefore establishing a base for controlling more elaborate movements of molecular devices through ion-pair recognition. PMID- 22532397 TI - Breast EIT using a new projected image reconstruction method with multi-frequency measurements. AB - We propose a new method to produce admittivity images of the breast for the diagnosis of breast cancer using electrical impedance tomography(EIT). Considering the anatomical structure of the breast, we designed an electrode configuration where current-injection and voltage-sensing electrodes are separated in such a way that internal current pathways are approximately along the tangential direction of an array of voltage-sensing electrodes. Unlike conventional EIT imaging methods where the number of injected currents is maximized to increase the total amount of measured data, current is injected only twice between two pairs of current-injection electrodes attached along the circumferential side of the breast. For each current injection, the induced voltages are measured from the front surface of the breast using as many voltage sensing electrodes as possible. Although this electrode configurational lows us to measure induced voltages only on the front surface of the breast,they are more sensitive to an anomaly inside the breast since such an injected current tends to produce a more uniform internal current density distribution. Furthermore, the sensitivity of a measured boundary voltage between two equipotential lines on the front surface of the breast is improved since those equipotential lines are perpendicular to the primary direction of internal current streamlines. One should note that this novel data collection method is different from those of other frontal plane techniques such as the x-ray projection and T-scan imaging methods because we do not get any data on the plane that is perpendicular to the current flow. To reconstruct admittivity images using two measured voltage data sets, a new projected image reconstruction algorithm is developed. Numerical simulations demonstrate the frequency-difference EIT imaging of the breast. The results show that the new method is promising to accurately detect and localize small anomalies inside the breast. PMID- 22532396 TI - Effect of the volume-to-surface ratio of cultures on Escherichia coli growth: an experimental and theoretical analysis. AB - The growth dynamics of bacterial populations are usually represented by the classical S-shaped profiles composed of lag, exponential and stationary growth phases. Although exceptions to this classical behavior occur, they are normally produced under non-standard conditions such as supply of two carbohydrates as sole carbon source. However, we here report variations in the classic S-shaped growth profiles of Escherichia coli under standard culturing conditions; explicitly, we found growth during transition to the stationary phase wherein the bacterial growth rate inversely depended on the volume-to-surface ratio of cultures (V/S); the reasons for this behavior were experimentally explored. To complement our experimental analysis, a theoretical model that rationalizes the bacterial response was developed; simulations based on the developed model essentially reproduced experimental growth curves. We consequently conclude that the effect of V/S on E. coli growth reflects an interplay between auto-catalytic bacterial growth, bacterial growth auto-inhibition, and, the relief of that inhibition. PMID- 22532398 TI - Iridium-catalyzed enantioselective hydrogenation of alkenylboronic esters. PMID- 22532390 TI - Double incontinence in a cohort of nulliparous pregnant women. AB - AIMS: To estimate the frequency of double incontinence, and to identify associated risk factors during pregnancy and postpartum in previously continent nulliparous women. METHODS: A cohort study in healthy, nulliparous, continent pregnant women, attending the public healthcare system of Catalonia (Spain) was designed. The field work was conducted during the control visits of pregnancy, at the time of delivery, and in the postpartum. Double incontinence was defined as a situation in which participants reported simultaneously urinary incontinence (UI) and anal incontinence with the help of a self-administered questionnaire. Prevalence rates, and their corresponding confidence intervals (95% CI), were calculated, as well as the impact on daily life. Multivariable logistic regressions in pregnancy and postpartum were estimated to assess the association of potential risk factors. RESULTS: The prevalence rate of double incontinence during pregnancy was 8.6% (95% CI: 7.0-10.3). Age over 35 years, and family history of UI were associated to a higher risk of double incontinence. After delivery, the prevalence rate decreased to 3.5% (95% CI: 2.4-4.6); only 6.7% of women with double incontinence in pregnancy had a persistency of their symptoms in early postpartum. Instrumental vaginal deliveries carried 2.2 times more risk of double incontinence than spontaneous ones. Episiotomy implied a higher risk for double incontinence. CONCLUSIONS: Symptoms of double incontinence are prevalent during first pregnancy; age and other intrinsic factors may favor the occurrence of double incontinence throughout gestation, while instrumental delivery and episiotomy increase the risk of double incontinence in the postpartum period. PMID- 22532399 TI - Asparaginase-associated myelosuppression and effects on dosing of other chemotherapeutic agents in childhood acute lymphoblastic leukemia. AB - Although L-asparaginase (ASP) is associated with several toxicities, its myelosuppressive effect has not been well characterized. On DFCI ALL Consortium Protocol 05-01 for children with newly diagnosed acute lymphoblastic leukemia, the Consolidation phase and the initial portion of the Continuation phase were identical for standard risk patients, except ASP was given only during Consolidation. Comparing the two treatment phases revealed that low blood counts during Consolidation with ASP resulted in more dosage reductions of 6 mercaptopurine and methotrexate. The myelosuppressive effect of ASP should be considered when designing treatment regimens to avoid excessive toxicity and dose reductions of other critical chemotherapy agents. PMID- 22532400 TI - Prediction of successful labor induction using transvaginal sonographic cervical measurements. AB - PURPOSE: To predict the success of labor induction by sonographic cervical measurements, maternal/obstetrical factors, and the Bishop's score. METHODS: Between February 2008 and February 2010, 190 consecutive pregnant women underwent clinical examination to assess the Bishop's score and transvaginal sonographic cervical measurements (cervical length, fetal head stage, and cervical dilatation) before labor induction. The following outcomes were analyzed: overall vaginal delivery and vaginal delivery up to 24 hours after labor induction. RESULTS: Overall vaginal delivery occurred in 133 (70.0%) patients and vaginal delivery 24 hours after labor induction happened in 119 (62.6%) patients. The sonographic cervical measurements were significantly associated with all outcomes (p < 0.01). The areas under the ROC curve (AUC) of all ultrasound cervical parameters to predict the two events were 68.9% and 72.0% (cervical length); 71.6% and 73.6% (fetal head stage); and 72.0% and 73.4% (cervical dilatation). Mathematical equations were obtained to calculate the probability for each event considering the sonographic cervical measurements in association with clinical factors after regression analysis, which increased the AUC for both events (80.1% and 79.3%). CONCLUSIONS: Transvaginal sonographic cervical measurements can predict the successful labor induction, especially when associated to clinical analysis (Bishop's score). PMID- 22532401 TI - Synthesis and evaluation of 2(3H)-thiazole thiones as tyrosinase inhibitors. AB - A series of 2(3H)-thiazole thiones 3-5 was synthesized and evaluated for tyrosinase inhibition and DPPH radical scavenging activities. Among them, 3 methyl-4-phenyl-2(3H)-thiazole thione (4a) showed good tyrosinase inhibitory activity, even better than that of the well-known tyrosinase inhibitor, namely, kojic acid. From the structure-activity point of view, although it was found that the phenolic hydroxyl group in prototype 3-5 might contribute to the scavenging activity against DPPH radicals, there was no correlation between the potency of tyrosinase inhibition and the presence of the phenolic moiety. The in silico ADME Tox screening revealed that the drug-likeness and drug-score values of the most potent compound 4a were significantly higher than those of kojic acid. PMID- 22532402 TI - Preferences for receiving information among frail older adults and their informal caregivers: a qualitative study. AB - BACKGROUND: Patient involvement in clinical decision making is increasingly advocated. Although older patients may be more reluctant to become involved, most do appreciate being informed. However, knowledge about their experiences with and preferences for receiving information is limited, and even less is known about these topics for frail older people. OBJECTIVE: To explore the experiences of frail older people and informal caregivers with receiving information from health care professionals as well as their preferences for receiving information. METHODS: We conducted semi-structured interviews with frail older people (n = 11, 65-90 years) and informal caregivers (n = 11, 55-87 years). Interviews were transcribed verbatim and analysed using a grounded theory approach. RESULTS: Frail older people and informal caregivers varied in their information needs and discussed both positive and negative experiences with receiving information. They preferred receiving verbal information from their physician during the consultation; yet would appreciate receiving brief, clearly written information leaflets in addition. They employed several strategies to enhance the information provided, i.e. advocacy, preparing for a consultation and searching their own information. Contextual factors for receiving information, such as having enough time and having a good relationship with professionals involved, were considered of great importance. CONCLUSIONS: Participants described a wide range of experiences with and preferences for receiving information. However, even if the information provided would meet all their preferences, this would be of limited significance if not provided within the context of an ongoing trusting relationship with a professional, such as a GP or practice nurse, who genuinely cared for them. PMID- 22532403 TI - Simultaneous quantification of fat content and fatty acid composition using MR imaging. AB - Not only the fat content but also the composition of fatty acids (FAs) in stored triglycerides might be of interest in the research on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. In this study, a novel reconstruction approach is proposed that uses theoretical knowledge of the chemical structure of FAs to simultaneously quantify the fat fraction (FF) and the FAs composition (chain length cl, number of double bonds ndb, and number of methylene-interrupted double bonds nmidb) from multiple gradient echo images. Twenty phantoms with various fat contents (FF = 9-100%) and FA compositions (cl = 12.1-17.9, ndb = 0.23-5.10, and nmidb = 0.04-2.39) were constructed and imaged in a 3-T Siemens scanner. In addition, spectra were acquired in each phantom. Slopes and "standard deviations from true values" were used to investigate the accuracy of the two methods. The imaging method holds well in a comparison to the previously suggested spectroscopy method and showed similar overall accuracy. The in vivo feasibility was demonstrated in the thigh adipose tissue of a healthy volunteer. In conclusion, our developed method is a promising tool for FF and FA composition quantification. PMID- 22532404 TI - B-type natriuretic peptide as an independent correlate of nocturnal voiding in Japanese women. AB - AIMS: To investigate whether objective cardiovascular parameters have an independent association with nocturnal voiding in women. METHODS: Thirty-two parameters derived from questionnaires, and anthropometric, physiological and biochemical measures of 5,980 women were applied for analysis. Nocturnal voiding was assessed by the International Prostate Symptom Score and the Overactive Bladder Symptom Score. We measured variables including previously reported correlates of nocturnal voiding, such as age, a history of hypertension, and a history of diabetes, as well as those focusing on cardiovascular function, such as the cardio-ankle vascular index, the augmentation index, the ankle-brachial index, plasma B-type natriuretic peptide (BNP), and C-reactive protein (CRP). RESULTS: Age [odds ratio (OR): 1.058, P < 0.001], length of sleep (OR: 1.194, P < 0.001), sleeplessness (OR: 2.841, P < 0.001), urgency (OR: 1.528, P < 0.001), log(BNP) (OR: 2.031, P < 0.001), waist circumference (OR: 1.037, P = 0.002), body mass index (OR: 0.935, P = 0.007), menopause (OR: 1.503, P = 0.043), and history of hypertension (OR: 1.225, P = 0.029) were independently associated with nocturnal voiding >=2 times. Age (beta = 0.256, P < 0.001), urgency (beta = 0.195, P < 0.001), sleeplessness (beta = 0.181, P < 0.001), length of sleep (beta = 0.088, P < 0.001), log(BNP) (beta = 0.072, P < 0.001), waist circumference (beta = 0.086, P < 0.001), and low-density lipoprotein-cholesterol (beta = 0.038, P = 0.003) were significantly correlated with the severity of nocturnal voiding. CONCLUSIONS: Plasma BNP, which represents cardiac load, is strongly associated with the prevalence and severity of nocturnal voiding in Japanese women, as well as previously known correlates including age, urgency, quality and quantity of sleep, and obesity. PMID- 22532405 TI - Metabolic profiling of an alcoholic fatty liver in zebrafish (Danio rerio). AB - Zebrafish (Danio rerio) is becoming a popular developmental biology model to study diseases and for drug discovery. In this study, we performed proton nuclear magnetic resonance spectroscopy ((1)H-NMR)- and gas chromatography-mass spectrometry (GC/MS)-based metabolic profiling of an alcoholic fatty liver using a zebrafish disease model. We examined metabolic differences between the control and alcoholic fatty liver groups in zebrafish to determine how metabolism in an alcoholic fatty liver is regulated. Multivariate statistical analysis showed a significant difference between the control and alcoholic fatty liver groups. The alcoholic fatty liver group showed increased excretion of isoleucine, acetate, succinate, choline, creatine, acetoacetate, 3-hydroxybutyrate (3HB), ethyl glucuronide (EtG), lactate/pyruvate ratio, fatty acids, and cholesterol, and decreased excretion of citrate, aspartate, tyrosine, glycine, glucose, alanine, betaine, and maltose. Metabolites identified in the fatty liver groups were associated with long-term alcohol consumption, which causes both oxidation reduction (redox) changes and oxidative stress. This study suggests that global metabolite profiling in a zebrafish model can provide insights into the metabolic changes in an alcoholic fatty liver. PMID- 22532406 TI - Why are hydrophobic/water interfaces negatively charged? PMID- 22532407 TI - Synthesis and characterization of ZnS:Mn/ZnS core/shell nanoparticles for tumor targeting and imaging in vivo. AB - Fluorescence imaging technique has been used for imaging of biological cells and tissues in vivo. The Cd-free luminescent quantum dots conjugating with a cancer targeting ligand has been taken as a promising biocompatibility and low cytotoxicity system for targeted cancer imaging. This work reports the synthesis of fluorescent-doped core/shell quantum dots of water-soluble manganese-doped zinc sulfide. Quantum dots of manganese-doped zinc sulfide were prepared by nucleation doping strategy, with 3-mercaptopropionic acid as stabilizer at 90 in aqueous solution. The manganese-doped zinc sulfide nanoparticles exhibit strong orange fluorescence under UV irradiation, resistance to photo-bleaching, and low cytotoxicity to HeLa cells. The structure and optical properties of nanoparticles were characterized by scanning electron microscope, X-ray diffraction, dynamic light scattering, and photoluminescence emission spectroscopy. Manganese-doped zinc sulfide nanoparticles conjugated with folic acid using 2,2'-(ethylenedioxy) bis-(ethylamine) as the linker. The covalent binding of both 2,2'-(ethylenedioxy) bis-(ethylamine) and folic acid on the surface of manganese-doped zinc sulfide nanoparticles probed by Fourier transform infrared spectroscopy detection. Furthermore, in vitro cytotoxicity assessment of manganese-doped zinc sulfide folic acid probes use HeLa cells. The obtained fluorescent probes (manganese doped zinc sulfide) were used for tumor targeting and imaging in vivo. The manganese-doped zinc sulfide-folic acid fluorescent probes which targeting the tumor cells in the body of nude mouse tumor model would emit orange fluorescence, when exposed to a 365 nm lamp. We investigate the biodistribution of the manganese-doped zinc sulfide-folic acid fluorescent probes in tumor mouse model by measuring zinc concentration in tissues. These studies demonstrate the practicality of manganese-doped zinc sulfide-folic acid fluorescent probes as promising platform for tumor targeting and imaging in vivo. PMID- 22532408 TI - Modifying three-dimensional scaffolds from novel nanocomposite materials using dissolvable porogen particles for use in liver tissue engineering. AB - BACKGROUND: Although hepatocytes have a remarkable regenerative power, the rapidity of acute liver failure makes liver transplantation the only definitive treatment. Attempts to incorporate engineered three-dimensional liver tissue in bioartificial liver devices or in implantable tissue constructs, to treat or bridge patients to self-recovery, were met with many challenges, amongst which is to find suitable polymeric matrices. We studied the feasibility of utilising nanocomposite polymers in three-dimensional scaffolds for hepatocytes. MATERIALS AND METHODS: Hepatocytes (HepG2) were seeded on a flat sheet and in three dimensional scaffolds made of a nanocomposite polymer (Polyhedral Oligomeric Silsesquioxane [POSS]-modified polycaprolactone urea urethane) alone as well as with porogen particles, i.e. glucose, sodium bicarbonate and sodium chloride. The scaffold architecture, cell attachment and morphology were studied with scanning electron microscopy, and we assessed cell viability and functionality. RESULTS: Cell attachment to the scaffolds was demonstrated. The scaffold made with glucose particles as porogen showed a narrower range of pore size with higher porosity and better inter-pore communications and seemed to encourage near normal cell morphology. There was a steady increase of albumin secretion throughout the experiment while the control (monolayer cell culture) showed a steep decrease after day 7. At the end of the experiment, there was no significant difference in viability and functionality between the scaffolds and the control. CONCLUSION: In this initial study, porogen particles were used to modify the scaffolds produced from the novel polymer. Although there was no significance against the control in functionality and viability, the demonstrable attachment on scanning electron microscopy suggest potential roles for this polymer and in particular for scaffolds made with glucose particles in liver tissue engineering. PMID- 22532409 TI - Technique for internal channelling of hydroentangled nonwoven scaffolds to enhance cell penetration. AB - An important requirement in thick, high-porosity scaffolds is to maximise cellular penetration into the interior and avoid necrosis during culture in vitro. Hitherto, reproducible control of the pore structure in nonwoven scaffolds has proved challenging. A new, channelled scaffold manufacturing process is reported based on water jet entanglement of fibres (hydroentangling) around filamentous template to form a coherent scaffold that is subsequently removed. Longitudinally-oriented channels were introduced within the scaffold in controlled proximity using 220 um diameter cylindrical templates. In this case study, channelled scaffolds composed of poly(l-lactic acid) were manufactured and evaluated in vitro. Environmental scanning electron microscope and uCT (X-ray microtomography) confirmed channel openings in the scaffold cross-section before and after cell culture with human dermal fibroblasts up to 14 weeks. Histology at week 11 indicated that the channels promoted cell penetration and distribution within the scaffold interior. At week 14, cellular matrix deposition was evident in the internal channel walls and the entrances remained unoccluded by cellular matrix suggesting that diffusion conduits for mass transfer of nutrient to the scaffold interior could be maintained. PMID- 22532410 TI - Phase stability and rapid consolidation of hydroxyapatite-zirconia nano coprecipitates made using continuous hydrothermal flow synthesis. AB - A rapid and continuous hydrothermal route for the synthesis of nano-sized hydroxyapatite rods co-precipitated with calcium-doped zirconia nanoparticles using a superheated water flow at 450 degrees C and 24.1 MPa as a crystallizing medium is described. Hydroxyapatite and calcium-doped zirconia phases in the powder mixtures could be clearly identified based on particle size and morphology under transmission electron microscopy. Retention of a nanostructure after sintering is crucial to load-bearing applications of hydroxyapatite-based ceramics. Therefore, rapid consolidation of the co-precipitates was investigated using a spark plasma sintering furnace under a range of processing conditions. Samples nominally containing 5 and 10 wt% calcium-doped zirconia and hydroxyapatite made with Ca:P solution molar ratio 2.5 showed excellent thermal stability (investigated using in situ variable temperature X-ray diffraction) and were sintered via spark plasma sintering to >96% sintered densities at 1000 degrees C resulting in hydroxyapatite and calcium-doped zirconia as the only two phases. Mechanical tests of spark plasma sintering sintered samples (containing 10 wt% calcium-doped zirconia) revealed a three-pt flexural strength of 107.7 MPa and Weibull modulus of 9.9. The complementary nature of the spark plasma sintering technique and continuous hydrothermal flow synthesis (which results in retention of a nanostructure even after sintering at elevated temperatures) was hence showcased. PMID- 22532411 TI - The Yale-Brown-Cornell eating disorders scale self-report questionnaire: a new, efficient tool for clinicians and researchers. AB - OBJECTIVE: The YBC-EDS is a semistructured interview assessing core preoccupations and rituals related to eating disorders. METHOD: We developed and conducted an examination of the reliability and validity of a self-report questionnaire (SRQ) version of the YBC-EDS. Convergent validity of YBC-EDS-SRQ with the YBC-EDS was examined for 112 eating disordered patients. RESULTS: All subscales and total scores were significantly intercorrelated. Thirty-one additional patients completed YBC-EDS-SRQ at admission and again 1 week later. All correlations revealed significant test-retest reliability. Discriminant validity of the SRQ was evaluated for a smaller subset of participants who completed the Beck Depression Inventory (BDI) and State Trait Anxiety Inventory (STAI). There were no significant correlations between various symptom dimensions of the YBC-EDS-SRQ and the BDI and STAI. DISCUSSION: Taken together, these findings indicate that the self-report form of the YBC-EDS is both valid and reliable. The SRQ can serve as a useful and efficient assessment of eating disorder patients for clinicians and researchers. PMID- 22532412 TI - Editorial: The latest in imaging technology. AB - "Seeing is believing" - this issue of Biotechnology Journal features a collection of articles on the latest in imaging technologies. PMID- 22532415 TI - PEGylated protein separations: challenges and opportunities. AB - PEGylation, the covalent attachment of polyethylene glycol (PEG) chains to protein, isa promising method for making an efficient protein drug. Several PEGylated protein drugs, such as PEGylated interferons, are already on the market and others are presently in their clinical trials. However, the PEGylation reaction is very product specific so that generalized or platform processes for both reaction and purification have not yet been established. In the current issue of Biotechnology Journal, Gunter Allmaier and colleagues report a modified microchip capillary gel electrophoresis (MCGE), which allows for a rapid separation (one minute) of PEGylated proteins of different degrees of PEGylation. PMID- 22532420 TI - Sustainable Heck-Matsuda reaction with catalytic amounts of diazonium salts: an experimental and theoretical study. AB - The palladium-catalyzed Heck-Matsuda reaction with a catalytic amount of an in situ-generated diazonium salt proceeded under mild and sustainable conditions. The reaction proceeded at room temperature, under base-free conditions, and only generated tBuOH, H(2)O, and N(2) as by-products. Ortho-substituted diazonium salts were more-efficiently coupled to methyl acrylate than their corresponding para isomers, which required the addition of anisole as an additive. In support of these experimental data, we carried out theoretical studies to gain a deeper understanding of these reaction outcomes. PMID- 22532419 TI - Comparative study of flavins binding with human serum albumin: a fluorometric, thermodynamic, and molecular dynamics approach. AB - Flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) are derivatives of riboflavin (RF), a water-soluble vitamin, more commonly known as vitamin B(2). Flavins have attracted special attention in the last few years because of the recent discovery of a large number of flavoproteins. In this work, these flavins are used as extrinsic fluorescence markers for probing the microheterogeneous environment of a well-known transport protein, human serum albumin (HSA). Steady state and time-resolved fluorescence experiments confirm that both FMN and FAD bind to the Sudlow's site-1 (SS1) binding pocket of HSA, where Trp214 resides. In the case of RF, a fraction of RF molecules binds at the SS1, whereas the major fraction of RF molecules remains unbound or surface bound to the protein. Moreover, flavin(s)-HSA interactions are monitored with the help of isothermal titration calorimetry, which provides free energy, enthalpy, and entropy changes of binding along with the binding constants. The molecular picture of binding interaction between flavins and HSA is well explored by docking and molecular dynamics studies. PMID- 22532421 TI - The role of pendant amines in the breaking and forming of molecular hydrogen catalyzed by nickel complexes. AB - We present the results of a comprehensive theoretical investigation of the role of pendant amine ligands in the oxidation of H(2) and formation of H(2) by [Ni(P(R)(2)N(R')(2))(2)](2+) electrocatalysts (P(R)(2)N(R')(2) is the 1,5-R'-3,7 R derivative of 1,5-diaza-3,7-diphosphacyclooctane, in which R and R' are aryl or alkyl groups). We focus our analysis on the thermal steps of the catalytic cycle, as they are known to be rate-determining for both H(2) oxidation and production. We find that the presence of pendant amine functional groups greatly facilitates the heterolytic H(2) bond cleavage, resulting in a protonated amine and a Ni hydride. Only one single positioned pendant amine is required to serve this function. The pendant amine can also effectively shuttle protons to the active site, making the redistribution of protons and the H(2) evolution a very facile process. An important requirement for the overall catalytic process is the positioning of at least one amine in close proximity to the metal center. Indeed, only protonation of the pendant amines on the metal center side (endo position) leads to catalytically active intermediates, whereas protonation on the opposite side of the metal center (exo position) leads to a variety of isomers, which are detrimental to catalysis. PMID- 22532422 TI - CTC1 Mutations in a patient with dyskeratosis congenita. AB - Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome caused by mutations in seven genes involved in telomere biology, with approximately 50% of cases remaining genetically uncharacterized. We report a patient with classic DC carrying a compound heterozygous mutation in the CTC1 (conserved telomere maintenance component 1) gene, which has recently implicated in the pleiotropic syndrome Coats plus. This report confirms a molecular link between DC and Coats plus and expands the genotype-phenotype complexity observed in telomere-related genetic disorders. PMID- 22532423 TI - Noncontrast-enhanced three-dimensional (3D) intracranial MR angiography using pseudocontinuous arterial spin labeling and accelerated 3D radial acquisition. AB - Pseudocontinuous arterial spin labeling (PCASL) can be used to generate noncontrast magnetic resonance angiograms of the cerebrovascular structures. Previously described PCASL-based angiography techniques were limited to two dimensional projection images or relatively low-resolution three-dimensional (3D) imaging due to long acquisition time. This work proposes a new PCASL-based 3D magnetic resonance angiography method that uses an accelerated 3D radial acquisition technique (VIPR, spoiled gradient echo) as the readout. Benefiting from the sparsity provided by PCASL and noise-like artifacts of VIPR, this new method is able to obtain submillimeter 3D isotropic resolution and whole head coverage with a 8-min scan. Intracranial angiography feasibility studies in healthy (N = 5) and diseased (N = 5) subjects show reduced saturation artifacts in PCASL-VIPR compared with a standard time-of-flight protocol. These initial results show great promise for PCASL-VIPR for static, dynamic, and vessel selective 3D intracranial angiography. PMID- 22532424 TI - High-performance electrocatalysis on palladium aerogels. PMID- 22532425 TI - Scanning ion conductance microscopy studies of amyloid fibrils at nanoscale. AB - Atomic force microscopy (AFM) has developed to become a very versatile nano-scale technique to reveal the three-dimensional (3D) morphology of amyloid aggregates under physiological conditions. However, the imaging principle of AFM is based on measuring the 'force' between a sharp tip and a given nanostructure, which may cause mechanical deformation of relatively soft objects. To avoid the deformation, scanning ion conductance microscopy (SICM) is an alternative scanning probe microscopy technique, operating with alternating current mode. Here we can indeed reveal the 3D morphology of amyloid fibrils and it is capable of exploring proteins with nanoscale resolution. Compared with conventional AFM, we show that SICM can provide precise height measurements of amyloid protein aggregates, a feature that enables us to obtain unique insight into the detailed nucleation and growth mechanisms behind amyloid self-assembly. PMID- 22532426 TI - Thermodynamic aspects of the synthesis of thin-film materials for solar cells. AB - A simple and useful thermodynamic approach to the prediction of reactions taking place during thermal treatment of layers of multinary semiconductor compounds on different substrates has been developed. The method, which uses the extensive information for the possible binary compounds to assess the stability of multinary phases, is illustrated with the examples of Cu(In,Ga)Se(2) and Cu(2)ZnSnSe(4) as well as other less-studied ternary and quaternary semiconductors that have the potential for use as absorbers in photovoltaic devices. PMID- 22532429 TI - The spermatid individualization complex of Drosophila melanogaster. PMID- 22532430 TI - A microphone array system for automatic fall detection. AB - More than a third of elderly fall each year in the United States. It has been shown that the longer the lie on the floor, the poorer is the outcome of the medical intervention. To reduce delay of the medical intervention, we have developed an acoustic fall detection system (acoustic-FADE) that automatically detects a fall and reports it promptly to the caregiver. Acoustic-FADE consists of a circular microphone array that captures the sounds in a room. When a sound is detected, acoustic-FADE locates the source, enhances the signal, and classifies it as "fall" or "nonfall." The sound source is located using the steered response power with phase transform technique, which has been shown to be robust under noisy environments and resilient to reverberation effects. Signal enhancement is performed by the beamforming technique based on the estimated sound source location. Height information is used to increase the specificity. The mel-frequency cepstral coefficient features computed from the enhanced signal are utilized in the classification process. We have evaluated the performance of acoustic-FADE using simulated fall and nonfall sounds performed by three stunt actors trained to behave like elderly under different environmental conditions. Using a dataset consisting of 120 falls and 120 nonfalls, the acoustic-FADE achieves 100% sensitivity at a specificity of 97%. PMID- 22532431 TI - En route to dinitroacetylene: nitro(trimethylsilyl)acetylene and nitroacetylene harnessed by dicobalt hexacarbonyl. AB - Dinitroacetylene and other nitroacetylenes are attractive stoichiometric precursors to high energy-density materials, but suffer from high reactivity and thermal instability. Herein, we report that nitroacetylenes can be dramatically stabilized in the form of their dicobalt hexacarbonyl complexes. In particular, we describe the syntheses and characterization of the first two transition-metal complexes of nitroalkynes, [MU-1-nitro-2-(trimethylsilyl)ethyne-1,2 diyl]bis(tricarbonylcobalt)(Co-Co) and [MU-1-nitroethyne-1,2 diyl]bis(tricarbonylcobalt)(Co-Co). The chemistry of these compounds reveals their potential as reaction partners in [2+2+2] cyclotrimerizations, furnishing nitroindane, nitrotetralin, and trinitrobenzene products. The X-ray crystal structure of 1,3,5-trinitro-2,4,6-tris(trimethylsilyl)benzene presents a distorted, yet planar, aromatic ring. PMID- 22532432 TI - Silicon-containing formal 4pi-electron four-membered ring systems: antiaromatic, aromatic, or nonaromatic? AB - Density functional theory calculations (B3LYP) have been carried out to investigate the 4pi-electron systems of 2,4-disila-1,3-diphosphacyclobutadiene (compound 1) and the tetrasilacyclobutadiene dication (compound 2). The calculated nucleus-independent chemical shift (NICS) values for these two compounds are negative, which indicates that the core rings of compounds 1 and 2 have a certain amount of aromaticity. However, deep electronic analysis reveals that neither of these two formal 4pi-electron four-membered ring systems is aromatic. Compound 1 has very weak, almost negligible antiaromaticity, and the amidinate ligands attached to the Si atoms play an important role in stabilizing this conjugated 4pi-electron system. The monoanionic bidentate ligand interacts with the conjugated pi system to cause pi-orbital splitting. This ligand-induced pi-orbital splitting effect provides an opportunity to manipulate the gap between occupied and unoccupied pi orbitals in conjugated systems. Conversely, compound 2 is nonaromatic because its core ring does not have a conjugated pi ring system and does not fulfill the requirements of a Huckel system. PMID- 22532433 TI - Informed consent for whole genome sequencing: a qualitative analysis of participant expectations and perceptions of risks, benefits, and harms. AB - Scientific evidence on the extent to which ethical concerns about privacy, confidentiality, and return of results for whole genome sequencing (WGS) are effectively conveyed by informed consent (IC) is lacking. The aim of this study was to learn, via qualitative interviews, about participant expectations and perceptions of risks, benefits, and harms of WGS. Participants in two families with Miller syndrome consented for WGS were interviewed about their experiences of the IC process and their perceptions of risks, benefits, and harms of WGS. Interviews were transcribed and analyzed for common themes. IC documents are included in the Supplementary Materials. Participants expressed minimal concerns about privacy and confidentiality with regard to both their participation and sharing of their WGS data in restricted access databases. Participants expressed strong preferences about how results should be returned, requesting both flexibility of the results return process and options for the types of results to be returned. Participant concerns about risks to privacy and confidentiality from broad sharing of WGS data are likely to be strongly influenced by social and medical context. In these families with a rare Mendelian syndrome, the perceived benefits of participation strongly trumped concerns about risks. Individual preferences, for results return, even within a family, varied widely. This underscores the need to develop a framework for results return that allows explicitly for participant preferences and enables modifications to preferences over time. Web-based tools that facilitate participant management of their individual research results could accommodate such a framework. PMID- 22532434 TI - Highly stable silver nanoplates for surface plasmon resonance biosensing. PMID- 22532436 TI - Effects of ammonium hydroxide on the structure and gas adsorption of nanosized Zr MOFs (UiO-66). AB - Several zirconium-based metal-organic frameworks (Zr-MOFs) have been synthesized using ammonium hydroxide as an additive in the synthesis process. Their physicochemical properties have been characterized by N(2) adsorption/desorption, XRD, SEM, FTIR, and TGA, and their application in CO(2) adsorption was evaluated. It was found that addition of ammonium hydroxide produced some effects on the structure and adsorption behavior of Zr-MOFs. The pore size and pore volume of Zr MOFs were enhanced with the additive, however, specific surface area of Zr-MOFs was reduced. Using an ammonium hydroxide additive, the crystal size of Zr-MOF was reduced with increasing amount of the additive. All the samples presented strong thermal stability. Adsorption tests showed that capacity of CO(2) adsorption on the Zr-MOFs under standard conditions was reduced due to decreased micropore fractions. However, modified Zr-MOFs had significantly lower adsorption heat. The adsorption capacity of carbon dioxide was increased at high pressure, reaching 8.63 mmol g(-1) at 987 kPa for Zr-MOF-NH(4)-2. PMID- 22532435 TI - Perfusion phantom: An efficient and reproducible method to simulate myocardial first-pass perfusion measurements with cardiovascular magnetic resonance. AB - The aim of this article is to describe a novel hardware perfusion phantom that simulates myocardial first-pass perfusion allowing comparisons between different MR techniques and validation of the results against a true gold standard. MR perfusion images were acquired at different myocardial perfusion rates and variable doses of gadolinium and cardiac output. The system proved to be sensitive to controlled variations of myocardial perfusion rate, contrast agent dose, and cardiac output. It produced distinct signal intensity curves for perfusion rates ranging from 1 to 10 mL/mL/min. Quantification of myocardial blood flow by signal deconvolution techniques provided accurate measurements of perfusion. The phantom also proved to be very reproducible between different sessions and different operators. This novel hardware perfusion phantom system allows reliable, reproducible, and efficient simulation of myocardial first-pass MR perfusion. Direct comparison between the results of image-based quantification and reference values of flow and myocardial perfusion will allow development and validation of accurate quantification methods. PMID- 22532437 TI - Photoanodes based on nanostructured WO3 for water splitting. AB - Anodically grown WO(3) photoelectrodes prepared in an N-methylformamide (NMF) electrolyte have been investigated with the aim of exploring the effects induced by anodization time and water concentration in the electrochemical bath on the properties of the resulting photoanodes. An n-type WO(3) semiconductor is one of the most promising photoanodes for hydrogen production from water splitting and the electrochemical anodization of tungsten allows very good photoelectrodes, which are characterized by a low charge-transfer resistance and an increased spectral response in the visible region, to be obtained. These photoanodes were investigated by a combination of steady state and transient photoelectrochemical techniques and a correlation between photocurrent produced, morphology, and charge transport has been evaluated. PMID- 22532438 TI - Kinase inhibitor scaffolds against neurodegenerative diseases from a Southern Australian ascidian, Didemnum sp. AB - Screening a library of Southern Australian and Antarctic marine invertebrates and algae for inhibitors of neurodegenerative disease kinase targets casein kinase 1 (CK1delta), cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3beta (GSK3beta) identified a Western Australian Didemnum species (CMB-02127) as a high priority specimen. Chemical fractionation returned the known aromatic alkaloids ningalins B-D as the major metabolites, together with six minor metabolites, the new ningalins E-G and the known hexacyclic pyrrole alkaloids lamellarins Z, G and A6. All structures were assigned by detailed spectroscopic analysis and literature comparisons, and the structural assignments were supported by biosynthetic considerations. The ningalins showed potent and broad inhibition across the three kinases, while the lamellarins were generally more selective for CDK5. Docking studies using published X-ray crystal structures of CDK5 revealed both scaffolds target the ATP binding pocket. PMID- 22532439 TI - Endoplasmic reticulum stress is involved in granulosa cell apoptosis during follicular atresia in goat ovaries. AB - Follicular atresia is primarily induced by granulosa cell apoptosis, but description of the apoptotic pathway in granulosa cells is incomplete. In this study, we explored the possibility that endoplasmic reticulum (ER) stress could be involved in granulosa cell apoptosis during goat follicular atresia. Immunohistochemical analysis revealed that DNA damage-inducible transcript 3 (DDIT3) and glucose-regulated protein 78 (Grp78) were observed in scattered apoptotic granulosa cells of atretic follicles. Grp78 and DDIT3 mRNA and protein were upregulated in granulosa cells during follicular atresia, although DDIT3 was not significantly different between early atretic and progressed atretic follicles. Spontaneous apoptosis was also observed in vitro in granulosa cells induced by serum deprivation or by the ER stress agent tunicamycin, both inducing similar increases in DDIT3 mRNA. Activating transcription factor-6 (ATF6) and ATF4 mRNAs were significantly increased during granulosa cell apoptosis in vivo; in contrast to ATF6, ATF4 mRNA was attenuated after 16 hr of culture despite the persistence of ER stress. Taken together, ER stress-dependent DDIT3 pathways may play an important role in the regulation of selective granulosa cell apoptosis in goat ovaries during early follicular atresia. Serum deprivation could also increase apoptosis of cultured granulosa cells through the ER stress pathway as both ATF6 and PERK/eIF2alpha/ATF4 signaling have been implicated in the granulosa cell apoptosis of atretic follicles. PMID- 22532440 TI - Innate immune agonist, dsRNA, induces apoptosis in ovarian cancer cells and enhances the potency of cytotoxic chemotherapeutics. AB - Ovarian cancer is the most lethal gynecological cancer. Here we show that innate immune agonist, dsRNA, directly induces ovarian cancer cell death and identify biomarkers associated with responsiveness to this targeted treatment. Nuclear staining and MTT assays following dsRNA stimulation revealed two subpopulations, sensitive (OVCAR-3, CAOV-3; patient samples malignant 1 and 2) and resistant (DOV 13, SKOV-3). Microarray analysis identified 75 genes with differential expression that further delineated these two subpopulations. qPCR and immunoblot analyses showed increased dsRNA receptor expression after stimulation as compared to resistant and immortalized ovarian surface epithelial cells (e.g., 70-fold with malignant 2, 43-fold with OVCAR-3). Using agonists, antagonists, and shRNA mediated knockdown of dsRNA receptors, we show that TLR3, RIG-I, and mda5 coordinated a caspase 8/9- and interferon-dependent cell death. In resistant cells, dsRNA receptor overexpression restored dsRNA sensitivity. When dsRNA was combined with carboplatin or paclitaxel, cell viability significantly decreased over individual treatments (1.5- to 7.5-fold). Isobologram analyses showed synergism in dsRNA combinations (CI=0.4-0.82) vs. an additive effect in carboplatin/paclitaxel treatment (CI=1.5-2). Our data identify a predictive marker, dsRNA receptor expression, to target dsRNA responsive populations and show that, in dsRNA-sensitive cells, dsRNA induces apoptosis and enhances the potency of cytotoxic chemotherapeutics. PMID- 22532442 TI - Signaling through the neuropeptide GPCR PAC1 induces neuritogenesis via a single linear cAMP- and ERK-dependent pathway using a novel cAMP sensor. AB - Both cAMP and ERK are necessary for neuroendocrine cell neuritogenesis, and pituitary adenylate cyclase-activating polypeptide (PACAP) activates each. It is important to know whether cAMP and ERK are arranged in a novel, linear pathway or in two parallel pathways using known signaling mechanisms. Native cellular responses [cAMP elevation, ERK phosphorylation, cAMP responsive element binding (CREB) phosphorylation, and neuritogenesis] and promoter-reporter gene activation after treatment with forskolin, cAMP analogs, and PACAP were measured in Neuroscreen-1 (NS-1) cells, a PC12 variant enabling simultaneous morphological, molecular biological, and biochemical analysis. Forskolin (25 MUM) and cAMP analogs (8-bromo-cAMP, dibutyryl-cAMP, and 8-chlorophenylthio-cAMP) stimulated ERK phosphorylation and neuritogenesis in NS-1 cells. Both ERK phosphorylation and neuritogenesis were MEK dependent (blocked by 10 MUM U0126) and PKA independent (insensitive to 30 MUM H-89 or 100 nM myristoylated protein kinase A inhibitor). CREB phosphorylation induced by PACAP was blocked by H-89. The exchange protein activated by cAMP (Epac)-selective 8-(4-chlorophenylthio)-2'-O Me-cAMP (100-500 MUM) activated Rap1 without affecting the other cAMP-dependent processes. Thus, PACAP-38 potently stimulated two distinct and independent cAMP pathways leading to CREB or ERK activation in NS-1 cells. Drug concentrations for appropriate effect were derived from control data for all compounds. In summary, a novel PKA- and Epac-independent signaling pathway: PACAP -> adenylate cyclase > cAMP -> ERK -> neuritogenesis has been identified. PMID- 22532443 TI - Additional base-pair formation in DNA duplexes by a double-headed nucleotide. AB - We have designed and synthesised a double-headed nucleotide that presents two nucleobases in the interior of a dsDNA duplex. This nucleotide recognises and forms Watson-Crick base pairs with two complementary adenosines in a Watson-Crick framework. Furthermore, with judicious positioning in complementary strands, the nucleotide recognises itself through the formation of a T:T base pair. Thus, two novel nucleic acid motifs can be defined by using our double-headed nucleotide. Both motifs were characterised by UV melting experiments, CD and NMR spectroscopy and molecular dynamics simulations. Both motifs leave the thermostability of the native dsDNA duplex largely unaltered. Molecular dynamics calculations showed that the double-headed nucleotides are accommodated in the dsDNA by entirely local perturbations and that the modified duplexes retain an overall B-type geometry with the dsDNA unwound by around 25 or 60 degrees , respectively, in each of the modified motifs. Both motifs can be accommodated twice in a dsDNA duplex without incurring any loss of stability and extrapolating from this observation and the results of modelling, it is conceivable that both can be multiplied several times within a dsDNA duplex. These new motifs extend the DNA recognition repertoire and may form the basis for a complete series of double headed nucleotides based on all 16 base combinations of the four natural nucleobases. In addition, both motifs can be used in the design of nanoscale DNA structures in which a specific duplex twist is required. PMID- 22532441 TI - MicroRNA-31 targets FIH-1 to positively regulate corneal epithelial glycogen metabolism. AB - Corneal epithelium relies on abundant glycogen stores as its primary energy source. MicroRNA-31 (miR-31), a corneal epithelial-preferred miRNA, negatively regulates factor inhibiting hypoxia-inducible factor-1 (FIH-1). Since HIF-1alpha is involved in anaerobic energy production, we investigated the role that miR-31 and FIH-1 play in regulating corneal epithelial glycogen. We used antagomirs (antago) to reduce the level of miR-31 in primary human corneal epithelial keratinocytes (HCEKs), and a miR-31-resistant FIH-1 to increase FIH-1 levels. Antago-31 raised FIH-1 levels and significantly reduced glycogen stores in HCEKs compared to irrelevant-antago treatment. Similarly, HCEKs retrovirally transduced with a miR-31-resistant FIH-1 had markedly reduced glycogen levels compared with empty vector controls. In addition, we observed no change in a HIF-1alpha reporter or known genes downstream of HIF-1alpha indicating that the action of FIH-1 and miR-31 on glycogen is HIF-1alpha-independent. An enzyme-dead FIH-1 mutation failed to restore glycogen stores, indicating that FIH-1 negatively regulates glycogen in a hydroxylase-independent manner. FIH-1 overexpression in HCEKs decreased AKT signaling, activated GSK-3beta, and inactivated glycogen synthase. Treatment of FIH-1-transduced HCEKs with either a myristolated Akt or a GSK-3beta inhibitor restored glycogen stores, confirming the direct involvement of Akt/GSK-3beta signaling. Silencing FIH-1 in HCEKs reversed the observed changes in Akt-signaling. Glycogen regulation in a HIF-1alpha-independent manner is a novel function for FIH-1 and provides new insight into how the corneal epithelium regulates its energy requirements. PMID- 22532444 TI - Coating Pt(0) nanoparticles with methyl groups: the reaction between methyl radicals and Pt(0)-NPs suspended in aqueous solutions. PMID- 22532445 TI - Engineering of osmium(II)-based light absorbers for dye-sensitized solar cells. PMID- 22532446 TI - OMIP-010: a new 10-color monoclonal antibody panel for polychromatic immunophenotyping of small hematopoietic cell samples. PMID- 22532447 TI - Reducing localized signal fluctuation in fMRI using spectral-spatial fat saturation. AB - Conventional 1D, spatially nonselective fat saturation can generate uncrushed fat signals in areas far outside the imaging slice where crushers are weak because of reduced gradient linearity. These fat signals can corrupt in-slice water signal, and in functional MRI, they can manifest themselves as artifacts such as clouds in image background or localized signal fluctuation over time. In this article, a spectral-spatial radiofrequency pulse is proposed to replace the conventional, spatially nonselective fat saturation pulse. The advantage of the proposed method is that fat protons far outside the image slice would not be excited because of the spatial selectivity, thereby removing the root cause of the fat aliasing artifacts. The proposed method also preserves thin slice capability, pulse duration, and fat suppression performance of the conventional method. Bloch simulation and human volunteer results show that the method is effective in reducing the fat aliasing artifacts seen in functional MRI. PMID- 22532448 TI - One-pot synthesis and characterization of subnanometre-size benzotriazolate protected copper clusters. AB - A simple one-pot method for the preparation of subnanometre-size benzotriazolate (BTA) protected copper clusters, Cu(n)BTA(m), is reported. The clusters were analyzed by optical and infrared spectroscopy, mass spectrometry and transmission electron microscopy together with computational methods. We suggest a structural motif where the copper core of the Cu(n)BTA(m) clusters is protected by BTA-Cu(i) BTA units. PMID- 22532449 TI - Ultrafast photoinduced electron transfer at electrodes: the general case of a heterogeneous electron-transfer reaction. AB - The general case of a heterogeneous electron-transfer reaction is realized by ultrafast electron transfer from a light-absorbing molecule to a wide continuum of electronic acceptor states, realizing the so-called wide band limit. Experimental data obtained for perylene dye/TiO(2) systems confirm the predictions of fully quantum mechanical model calculations of the dynamics. The energy distribution of the injected electron shows an energy loss due to excitations of high-energy (quantum) vibrational modes in the ionized perylene moiety. The electron-transfer mechanism is non-adiabatic and the reaction is ultrafast, for example, with a time constant of 9 fs for the COOH anchor-bridge group. The underlying strong coupling of the electronic states to high-energy vibrational modes is a characteristic feature of sensitizer molecules. PMID- 22532450 TI - Differential proteomics of human seminal plasma: A potential target for searching male infertility marker proteins. AB - The clinical fertility tests, available in the market, fail to define the exact cause of male infertility in almost half of the cases and point toward a crucial need of developing better ways of infertility investigations. The protein biomarkers may help us toward better understanding of unknown cases of male infertility that, in turn, can guide us to find better therapeutic solutions. Many clinical attempts have been made to identify biomarkers of male infertility in sperm proteome but only few studies have targeted seminal plasma. Human seminal plasma is a rich source of proteins that are essentially required for development of sperm and successful fertilization. This viewpoint article highlights the importance of human seminal plasma proteome in reproductive physiology and suggests that differential proteomics integrated with functional analysis may help us in searching potential biomarkers of male infertility. PMID- 22532451 TI - S100A9, GIF and AAT as potential combinatorial biomarkers in gastric cancer diagnosis and prognosis. AB - PURPOSE: We have mined the gastric fluid proteome for potential gastric cancer (GC) biomarkers that may enhance disease detection and facilitate prognostic monitoring. EXPERIMENTAL DESIGN: In biomarker discovery, a total of 12 patient gastric fluid samples (stages I, III, IV and gastritis) were analysed by 2DE for expression changes that correlated with GC status or disease progression. Gastric fluid proteins showing differential expression with GC were identified by MALDI TOF/TOF MS as putative biomarkers. Levels of these potential biomarker candidates were independently validated by Western blotting in further 60 gastritis and GC patients. A targeted approach that recruits biomarker candidates for panel consideration was adopted to test if two or more biomarkers in combination improved diagnostic power. RESULTS: From the 15 differentially regulated proteins identified, expression levels of S100A9, GIF and AAT in the gastric fluid clearly correlated with GC status. S100A9/AAT (AUC = 0.81) and S100A9/GIF (AUC = 0.92) were revealed as promising biomarker pairs for early GC diagnosis and disease monitoring, respectively. CONCLUSION AND CLINICAL RELEVANCE: Early diagnosis, accurate staging and constant disease monitoring remain the prerequisites for effective treatment against GC. As current biomarkers like CA19-9 and carcinoembryonic antigen (CEA) lack sensitivity and specificity, there is a pressing need for novel GC detection and monitoring methods. To this end, S100A9, GIF and AAT from the gastric fluid may significantly augment existing methods of GC detection and monitoring, and eliminate the need for invasive tissue biopsies. PMID- 22532452 TI - Characterization of cerebrospinal fluid aminoterminally truncated and oxidized amyloid-beta peptides. AB - PURPOSE: Carboxyterminally elongated and aminoterminally truncated Abeta peptides as well as their pyroglutamate and oxidized derivates are major constituents of human amyloid plaques. The objective of the present study was to characterize aminoterminally truncated or oxidized Abeta38, Abeta40, and Abeta42 peptide species in immunoprecipitated human cerebrospinal fluid (CSF). EXPERIMENTAL DESIGN: We invented a novel sequential aminoterminally and carboxyterminally specific immunoprecipitation protocol and used the Abeta-SDS-PAGE/immunoblot for subsequent analysis of CSF Abeta peptide patterns. RESULTS: In the present study, we identified the aminoterminally truncated Abeta peptides 2-40 and 2-42 as well as oxidized forms of Abeta1-38 and Abeta1-42 in CSF. Our protocol allowed the quantification of a pattern of Abeta peptides 1-38(ox), 2-40, and 2-42 in addition to the well known panel of Abeta 1-37, 1-38, 1-39, 1-40, 1-40(ox), and 1 42 in a group of seven patients with peripheral polyneuropathy. CONCLUSIONS AND CLINICAL RELEVANCE: In the present approach, we could broaden the range of quantifiable Abeta peptides described in previous studies (i.e., 1-37, 1-38, 1 39, 1-40, 1-40(ox), and 1-42) by Abeta 1-38(ox), 2-40, and 2-42. An exact analysis of CSF Abeta peptides regarding their carboxy- and aminoterminus as well as posttranslational modification seems promising with respect to diagnostic and pathogenic aspects. PMID- 22532453 TI - Identification of ovarian cancer-associated proteins in symptomatic women: A novel method for semi-quantitative plasma proteomics. AB - PURPOSE: To evaluate the utility of an enhanced biomarker discovery approach in order to identify potential biomarkers relevant to ovarian cancer detection. EXPERIMENTAL DESIGN: We combined immuno-depletion, liquid-phase IEF, 1D-DIGE, MALDI-TOF/MS and LC-MS/MS to identify differentially expressed proteins in the plasma of symptomatic ovarian cancer patients, stratified by stage, compared to samples obtained from normal subjects. RESULTS: We demonstrate that this approach is a practical alternative to traditional 2D gel techniques and that it has some advantages, most notably increased protein capacity. Proteins were identified in all 76 bands excised from the gels in this project and confirmed the cancer associated expression of several well-established biomarkers of ovarian cancer. These included C-reactive protein (CRP), haptoglobin, alpha-2 macroglobulin and A1A2. We also identified new ovarian cancer candidate biomarkers, Protein S100-A9 (S100A9) and multimerin-2. The cancer-associated differential expression of CRP and S100A9 was further confirmed by Western blot and ELISA. CONCLUSIONS: The methods developed in this study allow for the increased loading of plasma proteins into the analytical stream when compared to traditional 2D-DIGE. This increased protein identification sensitivity allowed us to identify new putative ovarian cancer biomarkers. PMID- 22532454 TI - Candidate biomarker verification: Critical examination of a serum protein pattern for human colorectal cancer. AB - PURPOSE: We critically examine a candidate serum protein pattern for human colorectal cancer (CRC) with respect to reproducibility, sample handling, and disease specificity. EXPERIMENTAL DESIGN: Serum samples from CRC patients, patients with benign colon tumors and healthy individuals, were obtained at two collection sites and analyzed by SELDI-TOF MS on 8 days, over a period of 5 weeks. The spectra were subjected to multivariate analysis. Tissues from normal colon and CRC were analyzed by SELDI-TOF MS. Selected mass peaks were identified. RESULTS: Using an elaborate experimental design we developed a multivariate classifier that correctly classified CRC and control serum measured on an independent day. The classifier did not discriminate between samples from CRC patients and patients with benign colon tumors, and, secondly, did not correctly classify serum from an independent collection site. All discriminatory mass peaks were identified as high abundant plasma proteins. Tissue profiling provided support of increased proteolytic activity in CRC tissue. CONCLUSION AND CLINICAL RELEVANCE: Critical verification did not justify advancing the identified CRC serum protein pattern into clinical validation without improvement. We believe that proteomics biomarker research could benefit if the presented, or a similar, verification scheme was more commonly employed in explorative biomarker studies. PMID- 22532455 TI - Discrimination of ischemic and hemorrhagic strokes using a multiplexed, mass spectrometry-based assay for serum apolipoproteins coupled to multi-marker ROC algorithm. AB - PURPOSE: Typically, apolipoproteins are individually measured in blood by immunoassay. In this report, we describe the development of a multiplexed selected reaction monitoring (SRM) based assay for a panel of apolipoproteins and its application to a clinical cohort of samples derived from acute stroke patients. EXPERIMENTAL DESIGN: An SRM assay for a panel of nine apolipoproteins was developed on a triple quadrupole mass spectrometer. Quantitative data for each apolipoprotein were analyzed to determine expression ratio and receiver operating characteristic (ROC) values for ischemic versus hemorrhagic stroke. RESULTS: The optimized SRM assay was used to interrogate a small cohort of well characterized plasma samples obtained from patients with acute ischemic and hemorrhagic strokes. The ROC analyses demonstrated good classification power for several single apolipoproteins, most notably apoC-III and apoC-I. When a novel multi-marker ROC algorithm was applied, the ischemic versus hemorrhagic groups were best differentiated by a combination of apoC-III and apoA-I with an area under the curve (AUC) value of 0.92. CONCLUSIONS AND CLINICAL RELEVANCE: This proof-of-concept study provides interesting and provocative data for distinguishing ischemic versus hemorrhage within first week of symptom onset. However, the observations are based on one cohort of patient samples and further confirmation will be required. PMID- 22532461 TI - Computational design of cyclic nitroxides as efficient redox mediators for dye sensitized solar cells. AB - Cyclic nitroxide radicals represent promising alternatives to the iodine-based redox mediator commonly used in dye-sensitized solar cells (DSSCs). To date DSSCs with nitroxide-based redox mediators have achieved energy conversion efficiencies of just over 5 % but efficiencies of over 15 % might be achievable, given an appropriate mediator. The efficacy of the mediator depends upon two main factors: it must reversibly undergo one-electron oxidation and it must possess an oxidation potential in a range of 0.600-0.850 V (vs. a standard hydrogen electrode (SHE) in acetonitrile at 25 degrees C). Herein, we have examined the effect that structural modifications have on the value of the oxidation potential of cyclic nitroxides as well as the reversibility of the oxidation process. These included alterations to the N-containing skeleton (pyrrolidine, piperidine, isoindoline, azaphenalene, etc.), as well as the introduction of different substituents (alkyl-, methoxy-, amino-, carboxy-, etc.) to the ring. Standard oxidation potentials were calculated using high-level ab initio methodology that was demonstrated to be very accurate (with a mean absolute deviation from experimental values of only 16 mV). An optimal value of 1.45 for the electrostatic scaling factor for UAKS radii in acetonitrile solution was obtained. Established trends in the values of oxidation potentials were used to guide molecular design of stable nitroxides with desired E(ox) degrees , and a number of compounds were suggested for potential use as enhanced redox mediators in DSSCs. PMID- 22532456 TI - Analysis of a membrane-enriched proteome from postmortem human brain tissue in Alzheimer's disease. AB - PURPOSE: The present study is a discovery mode proteomics analysis of the membrane-enriched fraction of postmortem brain tissue from Alzheimer's disease (AD) and control cases. This study aims to validate a method to identify new proteins that could be involved in the pathogenesis of AD and potentially serve as disease biomarkers. EXPERIMENTAL DESIGN: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to analyze the membrane-enriched fraction of human postmortem brain tissue from five AD and five control cases of similar age. Biochemical validation of specific targets was performed by immunoblotting. RESULTS: One thousand seven hundred and nine proteins were identified from the membrane-enriched fraction of frontal cortex. Label-free quantification by spectral counting and G-test analysis identified 13 proteins that were significantly changed in disease. In addition to Tau (MAPT), two additional proteins found to be enriched in AD, ubiquitin carboxy-terminal hydrolase 1 (UCHL1), and syntaxin-binding protein 1 (Munc-18), were validated through immunoblotting. DISCUSSION AND CLINICAL RELEVANCE: Proteomic analysis of the membrane-enriched fraction of postmortem brain tissue identifies proteins biochemically altered in AD. Further analysis of this subproteome may help elucidate mechanisms behind AD pathogenesis and provide new sources of biomarkers. PMID- 22532463 TI - Use of hydrogen peroxide as a biocide: new consideration of its mechanisms of biocidal action. AB - Hydrogen peroxide is extensively used as a biocide, particularly in applications where its decomposition into non-toxic by-products is important. Although increasing information on the biocidal efficacy of hydrogen peroxide is available, there is still little understanding of its biocidal mechanisms of action. This review aims to combine past and novel evidence of interactions between hydrogen peroxide and the microbial cell and its components, while reflecting on alternative applications that make use of gaseous hydrogen peroxide. It is currently believed that the Fenton reaction leading to the production of free hydroxyl radicals is the basis of hydrogen peroxide action and evidence exists for this reaction leading to oxidation of DNA, proteins and membrane lipids in vivo. Investigations of DNA oxidation suggest that the oxidizing radical is the ferryl radical formed from DNA-associated iron, not hydroxyl. Investigations of protein oxidation suggest that selective oxidation of certain proteins might occur, and that vapour-phase hydrogen peroxide is a more potent oxidizer of protein than liquid-phase hydrogen peroxide. Few studies have investigated membrane damage by hydrogen peroxide, though it is suggested that this is important for the biocidal mechanism. No studies have investigated damage to microbial cell components under conditions commonly used for sterilization. Despite extensive studies of hydrogen peroxide toxicity, the mechanism of its action as a biocide requires further investigation. PMID- 22532462 TI - Intensive care unit dissemination of multiple clones of linezolid-resistant Enterococcus faecalis and Enterococcus faecium. AB - OBJECTIVES: Outbreaks caused by linezolid-resistant (LR) enterococci remain rare. We report the epidemiological and molecular characteristics of the multiclonal dissemination of LR enterococci in the intensive care unit (ICU) of a Greek hospital. METHODS: All LR enterococcal isolates recovered from patients hospitalized in the ICU of the University Hospital of Larissa, Greece, between January 2007 and October 2008 were included. Isolates were tested by PFGE and PCR followed by sequence analysis of the entire 23S rRNA gene. Patient records were retrieved to access patterns of acquisition and outcome. RESULTS: Sixteen separate patients were infected and/or colonized by 22 LR enterococcal isolates (17 Enterococcus faecium and 5 Enterococcus faecalis). Linezolid MICs varied from 8 to 16 mg/L; 12 isolates showed cross-resistance to vancomycin. Genotyping revealed as many as seven and three PFGE types among E. faecium and E. faecalis isolates, respectively, indicating multiclonal spread of LR enterococci. Nine patients had received linezolid prior to the recovery of LR enterococci, while the remaining seven patients were not exposed to the drug. All isolates carried the mutation G2576T; the mutated position was heterogeneous in 12 isolates and homogeneous in 10. CONCLUSIONS: The multiclonal composition of LR enterococci indicates that linezolid resistance possibly occurred on several independent occasions. Its acquisition was often not related to linezolid administration; patients might have acquired their LR isolate from another patient that had received linezolid or, alternatively, resistance may have arisen by mutation that occurred independently. PMID- 22532464 TI - Inhibitory activity of garenoxacin against DNA gyrase of Mycoplasma pneumoniae. AB - OBJECTIVES: Garenoxacin, a des-fluoro(6)-quinolone, exhibits potent activity against Mycoplasma pneumoniae, including macrolide-resistant strains. There has been no report on the inhibitory activity of garenoxacin against the target enzyme of M. pneumoniae. METHODS: Subunits of DNA gyrase (GyrA and GyrB) proteins of M. pneumoniae FH were separately expressed as His-tagged proteins in Escherichia coli Chaperone Competent Cell BL21 by IPTG induction of plasmids containing the respective gyrA and gyrB genes. The inhibitory activities of garenoxacin, moxifloxacin, gatifloxacin and levofloxacin against DNA gyrase were evaluated by the inhibition of supercoiling activity (n = 3). RESULTS: Against M. pneumoniae FH, garenoxacin showed 2- to 16-fold more potent activity than the other quinolones. The mean IC(50) of garenoxacin for DNA gyrase of M. pneumoniae was 2.5 mg/L. Garenoxacin showed the most potent inhibitory activity against M. pneumoniae DNA gyrase among the quinolones tested. The IC(50) values of the quinolones for DNA gyrase roughly correlated with each MIC value. CONCLUSIONS: The antimycoplasmal activity of the quinolones was almost certainly due to inhibition of the supercoiling activity of DNA gyrase. Garenoxacin was considered a valuable quinolone in the treatment of infectious diseases caused by M. pneumoniae. PMID- 22532466 TI - Efficacy of linezolid versus a pharmacodynamically optimized vancomycin therapy in an experimental pneumonia model caused by methicillin-resistant Staphylococcus aureus. AB - OBJECTIVES: The British Thoracic Society, American Thoracic Society and Infectious Diseases Society of America guidelines recommend vancomycin for methicillin-resistant Staphylococcus aureus (MRSA) pneumonia, based on evidence suggesting that a vancomycin AUC0-24/MIC ratio of 400 predicts clinical success against MRSA pneumonia. The aim of this study was the evaluation of an optimized dose of vancomycin in the treatment of MRSA experimental pneumonia versus linezolid. METHODS: In vitro activities of vancomycin and linezolid were tested using time-kill curves. Experimental pneumonia in neutropenic C57BL/6 mice was achieved using two clinical MRSA strains, MR30 and MR33 (vancomycin and linezolid MICs of 1 and 4 mg/L, respectively). In vivo dosages were 30 and 110 mg/kg vancomycin (obtaining an AUC0-24/MIC ratio lower and higher than 400, respectively), and 30 mg/kg linezolid. RESULTS: Survival rates in controls, and in the groups treated with 120 mg/kg/day vancomycin, 440 mg/kg/day vancomycin and 120 mg/kg/day linezolid were 85.7%, 92.9%, 76.9% and 100%, and 66.7%, 100%, 75% and 100% for MR30 and MR33, respectively. Sterile blood cultures occurred at rates of 21.4%, 64.3%, 100% and 93.8%, and 40%, 66.7%, 100% and 93.3% for MR30 and MR33 strains, respectively. Finally, the respective bacterial lung concentrations (log10 cfu/g) were 8.93 +/- 0.78, 6.67 +/- 3.01, 3.25 +/- 1.59 and 2.87 +/- 1.86 for MR30, and 8.62 +/- 0.72, 5.76 +/- 2.43, 3.97 +/- 1.52 and 1.59 +/- 1.40 for MR33. CONCLUSIONS: These results support that a vancomycin AUC0 24/MIC ratio >400 is necessary to obtain a high bacterial lung reduction in MRSA pneumonia, comparable to that achieved with linezolid and better than that with the low dose of vancomycin tested. Linezolid was more efficacious than the pharmacodynamically optimized vancomycin dose in the pneumonia caused by the most virulent strain (MR33). PMID- 22532467 TI - Characterization of Enterobacteriaceae producing OXA-48-like carbapenemases in the UK. AB - OBJECTIVES: To characterize UK clinical isolates of Enterobacteriaceae producing OXA-48-like carbapenemases and to compare their resistance plasmids. METHODS: Twenty-six enterobacteria producing OXA-48-like enzymes were studied. These were from 22 diverse hospitals in the UK. Isolates of Escherichia coli and Klebsiella pneumoniae were assigned to clonal lineages by multilocus sequence typing. Carbapenemase genes and their genetic environments were characterized by PCR and sequencing. Resistance plasmids were transferred by transformation or conjugation and compared by restriction analysis and PCR for genes encoding critical plasmid functions. RESULTS: Thirteen isolates of K. pneumoniae, 10 E. coli and 2 Enterobacter cloacae harboured a classical bla(OXA-48) gene; the K. pneumoniae isolates belonged to 11 sequence types (STs) and the E. coli to 7 STs, including ST131 and ST38. The bla(OXA-48) genes were located within either Tn1999 or Tn1999.2 transposons on related ~ 50 kb or ~ 62 kb plasmids, which lacked other resistance genes or, in one isolate, on an ~ 140 kb plasmid that also encoded OXA 9 and CTX-M group-9 beta-lactamases. One India-linked K. pneumoniae isolate had a bla(OXA-181) gene in association with an ISEcp1 insertion sequence on a 7 kb plasmid. CONCLUSIONS: Horizontal transfer of related plasmids has facilitated the spread of OXA-48 carbapenemase into multiple strains of several Enterobacteriaceae species. The clonal diversity of the producers suggests repeated introduction into the UK. Low carbapenem MICs for some producers complicates detection and creates a risk for unrecognized spread. PMID- 22532468 TI - An NDM-1-producing Escherichia coli obtained in Denmark has a genetic profile similar to an NDM-1-producing E. coli isolate from the UK. PMID- 22532469 TI - Palladium-catalyzed asymmetric quaternary stereocenter formation. AB - An efficient palladium catalyst is presented for the formation of benzylic quaternary stereocenters by conjugate addition of arylboronic acids to a variety of beta,beta-disubstituted carbocyclic, heterocyclic, and acyclic enones. The catalyst is readily prepared from PdCl(2), PhBOX, and AgSbF(6), and provides products in up to 99% enantiomeric excess, with good yields. Based on this strategy, (-)-alpha-cuparenone has been prepared in only two steps. PMID- 22532470 TI - Asymmetric hydrogenation of 2,4-disubstituted 1,5-benzodiazepines using cationic ruthenium diamine catalysts: an unusual achiral counteranion induced reversal of enantioselectivity. PMID- 22532471 TI - Dynamic expression of Pax6 in the shark olfactory system: evidence for the presence of Pax6 cells along the olfactory nerve pathway. AB - Pax6 is involved in the control of neuronal specification, migration, and differentiation in the olfactory epithelium and in the generation of different interneuron subtypes in the olfactory bulb. Whether these roles are conserved during evolution is not known. Cartilaginous fish are extremely useful models for assessing the ancestral condition of brain organization because of their phylogenetic position. To shed light on the evolution of development of the olfactory system in vertebrates and on the involvement of Pax6 in this process, we analyzed by in situ hybridization and immunohistochemistry the expression pattern of Pax6 in the developing olfactory system in a basal vertebrate, the lesser spotted dogfish Scyliorhinus canicula. This small shark is becoming an important fish model in studies of vertebrate development. We report Pax6 expression in cells of the olfactory epithelium and olfactory bulb, and present the first evidence in vertebrates of strings of Pax6-expressing cells extending along the developing olfactory nerve. The results indicate the olfactory epithelium as the origin of these cells. These data are compatible with a role for Pax6 in the development of the olfactory epithelium and fibers, and provide a basis for future investigations into the mechanisms that regulate development of the olfactory system throughout evolution. PMID- 22532465 TI - Efficacy and safety of rilpivirine in treatment-naive, HIV-1-infected patients with hepatitis B virus/hepatitis C virus coinfection enrolled in the Phase III randomized, double-blind ECHO and THRIVE trials. AB - OBJECTIVES: The efficacy and hepatic safety of the non-nucleoside reverse transcriptase inhibitors rilpivirine (TMC278) and efavirenz were compared in treatment-naive, HIV-infected adults with concurrent hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection in the pooled week 48 analysis of the Phase III, double-blind, randomized ECHO (NCT00540449) and THRIVE (NCT00543725) trials. METHODS: Patients received 25 mg of rilpivirine once daily or 600 mg of efavirenz once daily, plus two nucleoside/nucleotide reverse transcriptase inhibitors. At screening, patients had alanine aminotransferase/aspartate aminotransferase levels <=5* the upper limit of normal. HBV and HCV status was determined at baseline by HBV surface antigen, HCV antibody and HCV RNA testing. RESULTS: HBV/HCV coinfection status was known for 670 patients in the rilpivirine group and 665 in the efavirenz group. At baseline, 49 rilpivirine and 63 efavirenz patients [112/1335 (8.4%)] were coinfected with either HBV [55/1357 (4.1%)] or HCV [57/1333 (4.3%)]. The safety analysis included all available data, including beyond week 48. Eight patients seroconverted during the study (rilpivirine: five; efavirenz: three). A higher proportion of patients achieved viral load <50 copies/mL (intent to treat, time to loss of virological response) in the subgroup without HBV/HCV coinfection (rilpivirine: 85.0%; efavirenz: 82.6%) than in the coinfected subgroup (rilpivirine: 73.5%; efavirenz: 79.4%) (rilpivirine, P = 0.04 and efavirenz, P = 0.49, Fisher's exact test). The incidence of hepatic adverse events (AEs) was low in both groups in the overall population (rilpivirine: 5.5% versus efavirenz: 6.6%) and was higher in HBV/HCV coinfected patients than in those not coinfected (26.7% versus 4.1%, respectively). CONCLUSIONS: Hepatic AEs were more common and response rates lower in HBV/HCV-coinfected patients treated with rilpivirine or efavirenz than in those who were not coinfected. PMID- 22532472 TI - Pax6 expression during retinogenesis in sharks: comparison with markers of cell proliferation and neuronal differentiation. AB - Pax6 is a highly conserved transcription factor that appears involved in the entire process of retinogenesis, including maintenance of proliferation of retinal progenitors and differentiation of particular neuron fates. To gain insight into the retinogenesis in fish, we study the dynamics of Pax6 expression in the developing and mature retina of two sharks that inhabit in particular environments, and compare it with the dynamics of a marker of cell proliferation (proliferating cell nuclear antigen, PCNA) and markers of neuronal differentiation, such as glutamic acid decarboxylase (GAD), calretinin (CR), tyrosine-hydroxylase, and serotonin (5-HT). Our results reveal that Pax6 is expressed in PCNA-immunoreactive cells within the nonlayered retina, suggesting a role for Pax6 in proliferating progenitors. Pax6 expression decays as development proceeds and eventually remains in some postmitotic cells, which points to additional roles of Pax6 following neurogenesis. Double immunofluorescence reveals Pax6/CR colocalization in the ganglion cell layer, Pax6/5-HT in the inner part of the inner nuclear layer (INLi), and Pax6/GAD in the INLi and horizontal cell layer. Our results suggest that Pax6 may contribute to neuron diversification in the neural retina. PMID- 22532474 TI - Extracellular Ca2+ influx is crucial for the early embryonic development of the sea urchin Echinometra lucunter. AB - The involvement of Ca(2+) in the activation of eggs and in the first steps of the embryonic development of several species is a well-known phenomenon. An association between Ca(2+) sources with the fate of the blastopore during embryonic development has been investigated by several authors. Ca(2+) influx mediated by voltage-gated channels and Ca(2+) mobilization from intracellular stores are the major sources of Ca(2+) to egg activation and succeeding cell divisions. Studies on sea urchins embryonic development show that intracellular Ca(2+) stores are responsible for egg activation and early embryogenesis. In the present work we investigated the involvement of extracellular Ca(2+) in the first stages of the embryonic development of the sea urchin Echinometra lucunter. Divalent cation chelators EDTA and EGTA strongly blocked the early embryonic development. Adding to this, we demonstrated the involvement of voltage-gated Ca(2+) channels in E. lucunter embryogenesis since Ca(2+) channel blockers powerfully inhibited the early embryonic development. Our data also revealed that Ca(2+) influx is crucial for embryonic development during only the first 40 min postfertilization. However, intracellular Ca(2+) remains mandatory to embryonic development 40 min postfertilization, seen that both the intracellular Ca(2+) chelator BAPTA-AM and calmodulin antagonists trifluoperazine and chlorpromazine inhibited the first stages of development when added to embryos culture 50 min postfertilization. Our work highlights the crucial role of extracellular Ca(2+) influx through voltage-gated Ca(2+) channels for the early embryonic development of the sea urchin E. lucunter and characterizes an exception in the phylum Echinodermata. PMID- 22532475 TI - Variation in anthropoid vertebral formulae: implications for homology and homoplasy in hominoid evolution. AB - Variation in vertebral formulae within and among hominoid species has complicated our understanding of hominoid vertebral evolution. Here, variation is quantified using diversity and similarity indices derived from population genetics. These indices allow for testing models of hominoid vertebral evolution that call for disparate amounts of homoplasy, and by inference, different patterns of evolution. Results are interpreted in light of "short-backed" (J Exp Zool (Mol Dev Evol) 302B:241-267) and "long-backed" (J Exp Zool (Mol Dev Evol) 314B:123 134) ancestries proposed in different models of hominin vertebral evolution. Under the long-back model, we should expect reduced variation in vertebral formulae associated with adaptively driven homoplasy (independently and repeatedly reduced lumbar regions) and the relatively strong directional selection presumably associated with it, especially in closely related taxa that diverged relatively recently (e.g., Pan troglodytes and Pan paniscus). Instead, high amounts of intraspecific variation are observed among all hominoids except humans and eastern gorillas, taxa that have likely experienced strong stabilizing selection on vertebral formulae associated with locomotor and habitat specializations. Furthermore, analyses of interspecific similarity support an evolutionary scenario in which the vertebral formulae observed in western gorillas and chimpanzees represent a reasonable approximation of the ancestral condition for great apes and humans, from which eastern gorillas, humans, and bonobos derived their unique vertebral profiles. Therefore, these results support the short-back model and are compatible with a scenario of homology of reduced lumbar regions in hominoid primates. Fossil hominin vertebral columns are discussed and shown to support, rather than contradict, the short-back model. PMID- 22532473 TI - Unilateral and bilateral expression of a quantitative trait: asymmetry and symmetry in coronal craniosynostosis. AB - Bilateral symmetry in vertebrates is imperfect and mild asymmetries are found in normal growth and development. However, abnormal development is often characterized by strong asymmetries. Coronal craniosynostosis, defined here as consisting of premature suture closure and a characteristic skull shape, is a complex trait. The premature fusion of the coronal suture can occur unilaterally associated with skull asymmetry (anterior plagiocephaly) or bilaterally associated with a symmetric but brachycephalic skull. We investigated the relationship between coronal craniosynostosis and skull bilateral symmetry. Three dimensional landmark coordinates were recorded on preoperative computed tomography images of children diagnosed with coronal nonsyndromic craniosynostosis (N = 40) and that of unaffected individuals (N = 20) and analyzed by geometric morphometrics. Our results showed that the fusion pattern of the coronal suture is similar across individuals and types of coronal craniosynostosis. Shape analysis showed that skulls of bilateral coronal craniosynostosis (BCS) and unaffected individuals display low degrees of asymmetry, whereas right and left unilateral coronal craniosynostosis (UCS) skulls are asymmetric and mirror images of one another. When premature fusion of the coronal suture (without taking into account cranial dysmorphology) is scored as a qualitative trait, the expected relationship between trait frequency and trait unilateral expression (i.e. negative correlation) is confirmed. Overall, we interpret our results as evidence that the same biological processes operate on the two sides in BCS skulls and on the affected side in UCS skulls, and that coronal craniosynostosis is a quantitative trait exhibiting a phenotypic continuum with BCS displaying more intense shape changes than UCS. PMID- 22532476 TI - Uterine epithelial morphology and progesterone receptors in a mifepristone treated viviparous lizard Pseudemoia entrecasteauxii (Squamata: Scincidae) during gestation. AB - Structural and functional changes to the uterus associated with maintenance of pregnancy are controlled primarily by steroid hormones such as progesterone. We tested the hypothesis that progesterone regulates uterine structural changes during pregnancy in the viviparous skink, Pseudemoia entrecasteauxii, by treating pregnant females with the progesterone receptor antagonist mifepristone at different stages of pregnancy. Expression and distribution of progesterone receptor was determined using Western blot and immunohistochemistry. During early pregnancy, mifepristone treatment resulted in altered uterine epithelial cell surface morphology and high embryo mortality, but did not affect females at mid and late stages of pregnancy. Females treated with mifepristone in early pregnancy exhibited abnormal uterine epithelial cell morphology such as lateral blebbing and presence of wide gaps between cells indicating loss of intercellular attachment. Chorioallantoic membranes of the embryo were not affected by mifepristone treatment. Two isoforms (55 kDa and 100 kDa) of progesterone receptor were identified using immunoblots and both isoforms were localized to the nucleus of uterine epithelial cells. The 55 kDa isoform was expressed throughout pregnancy, whereas the 100 kDa isoform was expressed during mid and especially late pregnancy. In P. entrecasteauxii, mifepristone may prevent successful embryo attachment in early pregnancy through its effects on uterine epithelial cells but may have little effect on pregnancy once the maternal-embryo structural relationship is established. PMID- 22532478 TI - Single yeast cell vacuolar milieu viscosity assessment by fluorescence polarization microscopy with computer image analysis. AB - This study was undertaken to evaluate the apparent viscosity within the vacuoles of single Saccharomyces cerevisiae cells by steady-state fluorescence anisotropy measurements of quinacrine, using wide-field fluorescence polarization microscopy combined with computer image analysis. Quinacrine was shown to be rather specifically accumulated within the vacuoles of the cells. This accumulation was effectively reversed by ATP depletion of the cells, with no detectable binding of the dye within the vacuoles. Quinacrine fluorescence anisotropy in the sucrose solutions of various viscosities obeyed the Perrin equation. The fluorescence anisotropy of quinacrine was measured in the vacuoles of 39 cells. From cell to cell, this parameter changed in the range 0.032-0.086. Using the Perrin plot as a calibration curve, apparent viscosity values of the vacuolar milieu were calculated for each cell. The population of the cells studied was heterogeneous with regard to vacuolar viscosity, which was in the range 3.5 +/- 0.4-14.06 +/- 0.64 cP. There was a characteristic distribution of the frequencies of cells with apparent viscosities within certain limits, and cells with viscosity values in the range 5-6 cP were the most frequent. No relationship was found between the sizes of the vacuoles and their apparent viscosities. PMID- 22532479 TI - A highly stable anode, carbon-free, catalyst support based on tungsten trioxide nanoclusters for proton-exchange membrane fuel cells. AB - Durability is an important issue in proton-exchange membrane fuel cells (PEMFCs). One of the major challenges lies in the degradation caused by the oxidation of the carbon support under high anode potentials (under fuel starvation conditions). Herein, we report highly stable, carbon-free, WO(3) nanoclusters as catalyst supports. The WO(3) nanoclusters are synthesized through a hard template method and characterized by means of electron microscopy and electrochemical analysis. The electrochemical studies show that the WO(3) nanoclusters have excellent electrochemical stability under a high potential (1.6 V for 10 h) compared to Vulcan XC-72. Pt nanoparticles supported on these nanoclusters exhibit high and stable electrocatalytic activity for the oxidation of hydrogen. The catalyst shows negligible loss in electrochemically active surface area (ECA) after an accelerated durability test, whereas the ECA of the Pt nanoparticles immobilized on conventional carbon decreases significantly after the same oxidation condition. Therefore, Pt/WO(3) could be considered as a promising alternative anode catalyst for PEMFCs. PMID- 22532481 TI - A first-principles study on the interaction between alkyl radicals and graphene. AB - The interaction between alkyl radicals and graphene was studied by means of dispersion-corrected density functional theory. The results indicate that isolated alkyl radicals are not likely to be attached onto perfect graphene. It was found that the covalent binding energies are low, and because of the large entropic contribution, DeltaG(298) degrees is positive for methyl, ethyl, isopropyl, and tert-butyl radicals. Although the alkylation may proceed by moderate heating, the desorption barriers are low. For the removal of the methyl and tert-butyl radicals covalently bonded to graphene, 15.3 and 2.4 kcal mol(-1) are needed, respectively. When alkyl radicals are agglomerated, the binding energies are increased. For the addition in the ortho position and on opposite sides of the sheet, the graphene-CH(3) binding energy is increased by 20 kcal mol(-1), whereas for the para addition on the same side of the sheet, the increment is 9.4 kcal mol(-1). In both cases, the agglomeration turns the DeltaG(298) degrees <0. For the ethyl radical, the ortho addition on opposite sides of the sheet has a negative DeltaG(298) degrees , whereas for isopropyl and tert-butyl radicals the reactions are endergonic. The attachment of the four alkyl radicals under consideration onto the zigzag edges is exergonic. The noncovalent adsorption energies computed for ethyl, isopropyl, and tert-butyl radicals are significantly larger than the graphene-alkyl-radical covalent binding energies. Thus, physisorption is favored over chemisorption. As for the DeltaG(298) degrees for the adsorption of isolated alkyl radicals, only the tert butyl radical is likely to be exergonic. For the phenalenyl radical we were not able to locate a local minimum for the chemisorbed structure since it moves to the physisorbed structure. An important conclusion of this work is that the consideration of entropic effects is essential to investigate the interaction between graphene and free radicals. PMID- 22532480 TI - Interfering with Fos expression in rat perirhinal cortex impairs recognition memory. AB - Previous work has shown that immunohistochemical imaging of Fos protein is a reliable marker for changes in activity related to recognition memory in the perirhinal (PRH) cortex of the medial temporal lobe; however, whether PRH Fos expression is necessary for recognition memory had not been established. To investigate this potential requirement, antisense Fos oligodeoxynucleotide (ODN) was infused locally into PRH cortex to interfere with Fos production. As in previous studies, differential Fos expression produced by viewing novel or familiar visual stimuli was measured by immunohistochemistry: antisense Fos ODN infusion into PRH cortex disrupted the normal pattern of differential Fos expression in PRH cortex. The effect of antisense Fos ODN infusion into PRH cortex was therefore sought on recognition memory. Infusion before or immediately after acquisition impaired recognition memory for objects when the memory delay was 3 or 24 h, but not when the delay was 20 min, or when the ODN was infused before retrieval after a 24-h delay. The findings indicate a role for Fos in consolidation processes underlying long-term recognition memory for objects and establish that interfering with its expression impairs recognition memory. Antisense Fos ODN infusion also impaired object-in-place recognition memory. The results demonstrate that Fos is necessary for neuronal mechanisms in PRH cortex essential to recognition memory. PMID- 22532482 TI - Synthesis of acrylonitriles through an FeCl3-catalyzed domino propargylic substitution/aza-Meyer-Schuster rearrangement sequence. PMID- 22532483 TI - Orally active peptidic bradykinin B1 receptor antagonists engineered from a cyclotide scaffold for inflammatory pain treatment. PMID- 22532484 TI - The hand that feeds you. PMID- 22532485 TI - Healthcare financing in Yemen. AB - Yemen is a low-middle-income country where more than half of the population live in rural areas and lack access to the most basic health care. At US$40 per capita, Yemen's annual total health expenditure (THE) is among the lowest worldwide. This study analyses the preconditions and options for implementing basic social health protection in Yemen. It reveals a four-tiered healthcare system characterised by high geographic and financial access barriers mainly for the poor. Out-of-pocket payments constitute 55% of THE, and cost-sharing exemption schemes are not well organised. Resource-allocation practices are inequitable because about 30% of THE gets spent on treatment abroad for a small number of patients, mainly from better-off families. Against the background of a lack of social health protection, a series of small-scale and often informal solidarity schemes have developed, and a number of public and private companies have set up health benefit schemes for their employees. Employment-based schemes usually provide reasonable health care at an average annual cost of YR44 000 (US$200) per employee. In contrast, civil servants contribute to a mandatory health-insurance scheme without receiving any additional health benefits in return. A number of options for initiating a pathway towards a universal health insurance system are discussed. PMID- 22532488 TI - Analysis of tetrahydrocannabinol and its metabolite, 11-nor-Delta9 tetrahydrocannabinol-9-carboxylic acid, in oral fluid using liquid chromatography with tandem mass spectrometry. AB - This paper describes the determination of tetrahydrocannabinol (THC) and its metabolite, 11-nor-Delta9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH) in oral fluid using solid-phase extraction and liquid chromatography with tandem mass spectral detection (LC-MS-MS) and its application to proficiency specimens. The method employs collection of oral fluid with the QuantisalTM device, base hydrolysis, solid-phase extraction and LC-MS-MS in positive ion electrospray mode. Because the concentration of the metabolite in oral fluid is quite low, extremely sensitive analytical methods are necessary. The requisite sensitivity was achieved by a simple, rapid derivatization of the compound after extraction. The derivatization conditions did not affect parent THC. The method was fully validated using standard parameters including linearity, sensitivity, accuracy, intra-day and inter-day imprecision, drug recovery from the collection pad, limit of quantitation, limit of detection and matrix effects. The procedure was applied to oral fluid proficiency specimens previously analyzed to assess the stability of THC-COOH. PMID- 22532489 TI - Voices of donors: case reports of body donation in Hong Kong. AB - Body donation is important for medical education and academic research. However, it is relatively rare in Hong Kong when compared with many Western countries. Comprehensive research has been performed on the motivation for body donation in Western countries; however, there is still insufficient research on body donation in Hong Kong to provide information on how to increase the body-donation rate. To understand the factors involved in the decision to donate one's body, the authors interviewed a registered donor and the daughter of another donor in Hong Kong. The authors interpreted the information collected in light of the available published reports, which mostly focus on body donation in Western countries. Despite the consistency of some demographic factors and motivations between the participants in our study and those investigated in the published reports from Western countries, there are differences in education level and socioeconomic status between the donors in our study and those from Western studies. The authors also suggest that Confucianism and Buddhism in Chinese culture may motivate potential body donors in Hong Kong. Other important factors that influence the body-donation decision may include family members' body donation, registration as organ donors, and good doctor-patient relationships. Although case report studies have their limitations, this study allows us to explore the complexity of events and establish the interconnectivity of factors involved in body donation, which could not be achieved in previous survey-based studies. PMID- 22532490 TI - Firefly chemiluminescence and bioluminescence: efficient generation of excited states. AB - Firefly luciferase catalyzes a light-emitting reaction in which an excited-state product is formed. Both experimental and theoretical methodologies are used to study this system, and the reactions catalyzed by luciferase are relatively well characterized. However, the mechanism by which an excited-state product is formed is still unknown. This Minireview deals with the current understanding of firefly bioluminescence and chemiluminescence. Thermal decomposition of simple 1,2 dioxetanes is also discussed, due to their role in formation of the excited-state bioluminophore. PMID- 22532491 TI - Suitability of ivy extract for the treatment of paediatric cough. AB - Two galenical formulations of an ivy herbal extract, syrup and cough drops, were tested for their efficacy and safety in the paediatric treatment of cough and bronchitis in two independent open, non-interventional studies with identical design. Two-hundred and sixty-eight children aged 0-12 yr were treated with one of the two preparations for up to 14 days. The effects on cough-related symptoms were addressed on a verbal rating scale. At the end of the study the major symptoms rhinitis, cough and viscous mucus, were found to be only mildly expressed or absent in 93, 94.2 and 97.7% of cases. The global effect was rated as 'good' or 'very good' in 96.5% of cases. Tolerability and compliance were found 'good' to 'very good' in 99% (syrup) and 100% (drops) of patients on completion of the study. A subgroup analysis according to four different age and dosing groups did not reveal differences in treatment response. Safety was confirmed and corresponded to literature findings. Five adverse events classified as mild and non-serious were reported (1.9%). In conclusion, ivy leaf extract in the form of syrup and of cough drops was confirmed as an effective and safe treatment of cough in children. PMID- 22532492 TI - Enantioselective synthesis of anti-beta-hydroxy-alpha-amido esters by asymmetric transfer hydrogenation in emulsions. AB - Herein, we present two methods for an asymmetric transfer hydrogenation through the dynamic kinetic resolution of alpha-amido-beta-ketoesters. These procedures yield the corresponding anti-beta-hydroxy-alpha-amido esters in good yields and with good diastereo- and enantioselectivities. First, the scope of the reduction of alpha-amido-beta-ketoesters by using triethylammonium formate azeotrope is examined. Then, an emulsion technology with sodium formate is explored, which allows for broader substrate scope, faster reaction times, and lower catalyst loading. Furthermore, these reactions are operationally simple and can be set up in air. PMID- 22532493 TI - Histological differentiation grade and microvascular invasion of hepatocellular carcinoma predicted by dynamic contrast-enhanced MRI. AB - PURPOSE: To explore the potential use of magnetic resonance imaging (MRI) in predicting the outcome for patients with hepatocellular carcinoma (HCC), imaging characteristics were correlated with pathological findings and clinical outcome. MATERIALS AND METHODS: With permission from the Ethical Board, clinical data and tissues of resected HCC patients were collected, including the preoperative MRI. The role of MRI characteristics on recurrence and survival were evaluated with univariate and multivariate analyses. RESULTS: Between January 2000 and December 2008, 87 patients with 104 HCCs were operated on. Microvascular invasion was present in 55 lesions (53%). HCC was characterized as well differentiated in 15 lesions (14%), as moderate in 50 lesions (48%), and as poorly differentiated in 34 lesions (33%). Due to preoperative treatment in five lesions (5%) no vital tumor was left. In 85 lesions (88%) washout of contrast was noted. Of the 87 patients, 28 (32%) with 37 lesions developed HCC recurrence; these patients had microvascular invasion significantly more often and a moderate or poorly differentiated tumor (P < 0.001 and P = 0.025, respectively). MRI more often showed washout when HCC was moderately or poorly differentiated (P < 0.001) or microvascular invasion was present (P = 0.032). CONCLUSION: Differentiation grade and microvascular invasion are significantly associated with the presence of washout demonstrated on dynamic contrast-enhanced MRI. PMID- 22532494 TI - The prevalence of osteoporosis in Korean adults aged 50 years or older and the higher diagnosis rates in women who were beneficiaries of a national screening program: the Korea National Health and Nutrition Examination Survey 2008-2009. AB - For the prevention of osteoporotic fracture, adequate screening and treatment are important. However, there are few published data on diagnosis and treatment rates of osteoporosis in Asia. We used data from the fourth Korea National Health and Nutrition Examination Survey 2008-2009 to estimate the nationwide prevalence, physician diagnosis rate, and treatment rate of osteoporosis in adults aged 50 years and older. The bone mineral density (BMD) measurements of central skeletal sites (lumbar spine, femoral neck, and total hip) were obtained using dual-energy X-ray absorptiometry (DXA) (Discovery-W; Hologic Inc., Waltham, MA, USA). Diagnosis of osteopenia or osteoporosis was defined by the World Health Organization (WHO) T-score criteria. The prevalence of osteoporosis in adults aged 50 years or older was 35.5% in women and 7.5% in men. The prevalence of osteoporosis in Korea was similar to other East Asian countries but higher than that in Caucasians. Lumbar spine bone density T-scores tended to be lower than those of the femoral neck or hip. The estimated diagnosis rate was 26.2% (women 29.9%, men 5.8%) and the treatment rate was 12.8% (women 14.4%, men 4.0%). The physician diagnosis rate was significantly higher in females aged 66 to 68 years who were the beneficiaries of the national screening program than that in females of other ages (43.6% versus 28.1%, p < 0.05). The national screening program for osteoporosis may have contributed to an increased diagnosis rate in older Korean women. However, it was evident that treatment following a diagnosis of osteoporosis was still inadequate. PMID- 22532495 TI - Rhodium-catalyzed intramolecular cyclization of naphthol- or phenol-linked 1,6 enynes through the cleavage and formation of sp2 C-O bonds. PMID- 22532496 TI - Adverse outcomes associated with gastroesophageal reflux disease are rare following an apparent life-threatening event. AB - OBJECTIVE: To evaluate for adverse outcomes associated with gastroesophageal reflux disease (GERD) following an apparent life-threatening event (ALTE) and potential risk factors of these outcomes. STUDY DESIGN: Retrospective cohort study of well-appearing infants (<12 months) admitted for ALTE. Patients were followed for adverse outcomes associated with GERD (including aspiration pneumonia, failure-to-thrive, or anti-reflux surgery), second ALTE, or death. Risk factors evaluated included: age, prematurity, gender, previous event, diagnosis of GERD, gastrointestinal (GI) testing positive for gastroesophageal reflux, length of stay (LOS), and neurologic impairment diagnosed in follow-up. RESULTS: Four hundred sixty-nine patients met inclusion criteria, mean age was 45 days, 110 (22%) were premature. Patients were followed for an average of 7.8 years; 3.8% of all patients had an adverse outcome associated with GERD. The only significant risk factors were a longer LOS, and development of neurological impairment. A diagnosis of GERD and positive reflux testing during the initial hospitalization were not associated with adverse outcomes associated with GERD. CONCLUSIONS: Adverse outcomes associated with GERD are rare following an ALTE. Patients who developed neurological impairment and a longer initial LOS were at higher risk for developing these outcomes. Positive testing for gastroesophageal reflux during hospitalization for ALTE did not predict adverse outcomes associated with GERD. PMID- 22532497 TI - Perceptions of anatomy: critical components in the clinical setting. AB - The evolution in undergraduate medical school curricula has significantly impacted anatomy education. This study investigated the perceived role of clinical anatomy and evaluated perceptions of medical students' ability to apply anatomical knowledge in the clinic. The aim of this study was to develop a framework to enhance anatomical educational initiatives. Unlike previous work, multiple stakeholders (clinicians, medical students, and academic anatomists) in anatomy education were evaluated. Participants completed an eleven-point Likert scale survey written by the investigators. Responses from both clinical educators and medical students at Penn State Milton S. Hershey Medical Center and College of Medicine suggest that medical students are perceived as ill-prepared to transfer anatomy to the clinic. Although some areas of patient management differ in relevancy to anatomical education, there are areas of clinical care which were uniformly ranked as relying heavily on anatomical knowledge (imaging and diagnostic studies, physical examination, and arrival at correct diagnosis) by a variety of clinical specialists. Our results suggest a need for advanced anatomy courses to be taught coincidental with medical students' clinical education. Development of these courses would optimally rely on input from both clinicians and academic anatomists, as both cohorts rated clinical anatomy similarly (P >= 0.05). Additionally, we hypothesize that preclinical students' application of anatomy would be enhanced if clinical context was derived from areas of clinical care which rely heavily on anatomy, whereas courses designed for advanced medical students will benefit from anatomical context focused on specialty specific aspects of clinical care identified in this study. PMID- 22532498 TI - Successful treatment of aortic root rupture following transcatheter aortic valve implantation in a heavily calcified aorta: a novel approach to a serious complication. AB - Aortic root rupture during transcatheter aortic valve implantation (TAVI) is an uncommon but almost uniformly fatal complication. We describe a novel surgical management of this complication using a combination of pledgeted sutures and prolonged direct digital compression with biomatrix and lattice adjuncts. Furthermore, our patient underwent percutaneous coronary intervention with endothelial progenitor cell-capturing stents, which facilitated TAVI to be performed off clopidogrel therapy. We believe the use of these stents reduced the severity of hemorrhage following aortic root rupture and helped maintain vessel patency following prolonged hypotension. PMID- 22532499 TI - Effect of water extracts from edible Myrtaceae plants on uptake of 2-(n-(7 nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose in TNF-alpha-treated FL83B mouse hepatocytes. AB - This study investigated the glucose uptake activity of the water extracts from the leaves and fruit of edible Myrtaceae plants, including guava (Psidium guajava Linn.), wax apples [Syzygium samarangense (Blume) Merr. and L.M. Perry], Pu-Tau [Syzygium jambo (L.) Alston], and Kan-Shi Pu-Tau (Syzygium cumini Linn.) in FL83B mouse hepatocytes. The fluorescent dye 2-(n-(7-nitrobenz-2-oxa-1,3-diazol-4 yl)amino)-2-deoxyglucose was used to estimate the uptake ability of the cells. Glucose uptake test showed that pink wax apple fruit extract (PWFE) exhibits the highest glucose uptake activity, at an increment of 21% in the insulin-resistant FL83B mouse hepatocytes as compared with the TNF-alpha-treated control group. Vescalagin was isolated using column chromatography of PWFE. This compound, at the concentration of 6.25 ug/mL, exhibits the same glucose uptake improvement in insulin-resistant cells as PWFE at a 100-ug/mL dose. We postulate that vescalagin is an active component in PWFE that may alleviate the insulin resistance in mouse hepatocytes. PMID- 22532500 TI - Optically transparent hydrogels from an auxin-amino-acid conjugate super hydrogelator and its interactions with an entrapped dye. AB - Low-molecular-weight organic hydrogelators (LMHGs) that can rigidify water into soft materials are desirable in various applications. Herein, we report the excellent hydrogelating properties of a simple synthetic auxin-amino-acid conjugate, naphthalene-1-acetamide of L-phenylalanine (1-NapF, M(w)=333.38 Da), which gelated water even at 0.025 wt %, thereby making it the most-efficient LMHG known. Optically transparent gels that exhibited negligible scattering in the range 350-900 nm were obtained. A large shift from the theoretical pK(a) value of the gelator was observed. The dependence of the minimum gelator concentration (MGC) and the gel-melting temperatures on the pH value indicated the importance of H-bonding between the carboxylate groups on adjacent phenylalanine molecules in the gelator assembly. FTIR spectroscopy of the xerogels showed a beta-sheet like assembly of the gelator. Variable-temperature (1)H NMR spectroscopy demonstrated that pi stacking of the aromatic residues was also partly involved in the gelator assembly. TEM of the xerogel showed the presence of a dense network of thin, high-aspect-ratio fibrillar assemblies with diameters of about 5 nm and lengths that exceeded a few microns. Rheology studies showed the formation of stable gels. The entrapment of water-soluble dyes afforded extremely fluorescent gels that involved the formation of J-aggregates by the dye within gel. A strong induced-CD band established that the RhoB molecules were interacting closely with the chiral gelator aggregates. H-bonding and electrostatic interactions, rather than intercalation, seemed to be involved in RhoB binding. The addition of chaotropic reagents, as well as increasing the pH value, disassembled the gel and promoted the release of the entrapped dye with zero-order kinetics. PMID- 22532501 TI - Tumor-induced osteomalacia: an important cause of adult-onset hypophosphatemic osteomalacia in China: Report of 39 cases and review of the literature. AB - Tumor-induced osteomalacia (TIO) is an acquired form of hypophosphatemia. Tumor resection leads to cure. We investigated the clinical characteristics of TIO, diagnostic methods, and course after tumor resection in Beijing, China, and compared them with 269 previous published reports of TIO. A total of 94 patients with adult-onset hypophosphatemic osteomalacia were seen over a 6-year period (January, 2004 to May, 2010) in Peking Union Medical College Hospital. After physical examination (PE), all patients underwent technetium-99m octreotide scintigraphy ((99) Tc(m) -OCT). Tumors were removed after localization. The results demonstrated that 46 of 94 hypophosphatemic osteomalacia patients had high uptake in (99) Tc(m) -OCT imaging. Forty of them underwent tumor resection with the TIO diagnosis established in 37 patients. In 2 patients, the tumor was discovered on PE but not by (99) Tc(m) -OCT. The gender distribution was equal (M/F = 19/20). Average age was 42 +/- 14 years. In 35 patients (90%), the serum phosphorus concentration returned to normal in 5.5 +/- 3.0 days after tumor resection. Most of the tumors (85%) were classified as phosphaturic mesenchymal tumor (PMT) or mixed connective tissue variant (PMTMCT). Recurrence of disease was suggested in 3 patients (9%). When combined with the 269 cases reported in the literature, the mean age and sex distribution were similar. The tumors were of bone (40%) and soft tissue (55%) origins, with 42% of the tumors being found in the lower extremities. In summary, TIO is an important cause of adult-onset hypophosphatemia in China. (99) Tc(m) -OCT imaging successfully localized the tumor in the overwhelming majority of patients. Successful removal of tumors leads to cure in most cases, but recurrence should be sought by long-term follow up. PMID- 22532502 TI - Rhodium(II)-catalyzed cyclization of bis(N-tosylhydrazone)s: an efficient approach towards polycyclic aromatic compounds. PMID- 22532503 TI - MR prediction of liver fibrosis using a liver-specific contrast agent: Superparamagnetic iron oxide versus Gd-EOB-DTPA. AB - PURPOSE: To examine whether the uptake of a liver-specific contrast agent in the liver parenchyma was correlated with the degree of liver fibrosis. MATERIALS AND METHODS: This retrospective study included 54 and 63 patients who underwent superparamagnetic iron oxide (SPIO)- and gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI before liver surgery, respectively. For each patient, we calculated DeltaR2* and DeltaR2, which represent differences in R2* and R2 values of the liver parenchyma before and after administration of SPIO; and the increase rate of liver-to-spleen signal intensity ratio (LSR) on the hepatobiliary phase compared with the precontrast image. The correlation of each MR parameter with the degree of liver fibrosis (F0 to F4) was assessed using Spearman's rank correlation test. RESULTS: The increase rate of LSR was best correlated with the degree of liver fibrosis and significantly decreased as the liver fibrosis progressed (rho = -0.641; P < 0.0001). It showed sensitivity of 76.9% and specificity of 83.3% in differentiating F3 or greater fibrosis when 1.126 or less was set up as a cut-off value. No significant correlation was obtained between DeltaR2* or DeltaR2 and the degree of liver fibrosis. CONCLUSION: The uptake of Gd-EOB-DTPA in the liver parenchyma decreased as the liver fibrosis progressed. J. Magn. Reson. Imaging 2012;36:664-671. (c) 2012 Wiley Periodicals, Inc. PMID- 22532504 TI - Ischemic colitis after transcatheter aortic valve implantation. AB - Transcatheter aortic valve implantation is a novel therapeutic approach for high risk patients with severe symptomatic aortic stenosis. The success rate of this new procedure is high; however, it is associated with issues such as vascular access site complications and embolization related to the advancement of a large bore delivery catheter through the femoral and iliac arteries and aortic arch. Using the Edwards SAPIEN transcatheter heart valve, we describe a case of transfemoral catheter aortic valve implantation complicated by a mobile mass attached to the valve, probable due to atherosclerotic plaque from the aorta. Shortly thereafter, the patient presented with ischemic colitis and subsequently died. PMID- 22532505 TI - Extracts of Scutellaria baicalensis reduced body weight and blood triglyceride in db/db Mice. AB - Scutellaria baicalensis has been extensively employed for the clinical treatment of hyperlipidemia, atherosclerosis, hypertension, dysentery, inflammatory diseases, and the common cold. The present study was performed to investigate the anti-obesity and anti-dyslipidemia effect of Scutellaria baicalensis extracts (SBE) in type 2 diabetic db/db mice. Male db/db mice were divided into three groups (n = 5) and orally administrated vehicle (control), SBE 10, and 100 mg/kg body weight/day for 4 weeks everyday. Administration of SBE improves weight gain, hypertriglyceridemia, and hyperinsulinemia in db/db mice. In obese db/db mice, SBE treatment also reduced plasma alanine aminotransferase levels. In the livers of db/db mice, SBE promoted 5' AMP-activated protein kinase activity and restored metabolic process and insulin signaling pathways. Our data demonstrate that SBE exerts potent anti-obesity and anti-hypertriglyceride effects suggesting its useful potential function as adjuvant therapeutic agent for the treatment of weight gain and hypertriglyceridemia. PMID- 22532506 TI - Manganese catalysts with C1-symmetric N4 ligand for enantioselective epoxidation of olefins. PMID- 22532508 TI - OPN and SPN: small molecules with great potential. PMID- 22532507 TI - The amount of periosteal apposition required to maintain bone strength during aging depends on adult bone morphology and tissue-modulus degradation rate. AB - Although the continued periosteal apposition that accompanies age-related bone loss is a biomechanically critical target for prophylactic treatment of bone fragility, the magnitude of periosteal expansion required to maintain strength during aging has not been established. A new model for predicting periosteal apposition rate for men and women was developed to better understand the complex, nonlinear interactions that exist among bone morphology, tissue-modulus, and aging. Periosteal apposition rate varied up to eightfold across bone sizes, and this depended on the relationship between cortical area and total area, which varies with external size and among anatomical sites. Increasing tissue-modulus degradation rate from 0% to -4%/decade resulted in 65% to 145% increases in periosteal apposition rate beyond that expected for bone loss alone. Periosteal apposition rate had to increase as much as 350% over time to maintain stiffness for slender diaphyses, whereas robust bones required less than a 32% increase over time. Small changes in the amount of bone accrued during growth (ie, adult cortical area) affected periosteal apposition rate of slender bones to a much greater extent compared to robust bones. This outcome suggested that impaired bone growth places a heavy burden on the biological activity required to maintain stiffness with aging. Finally, sex-specific differences in periosteal apposition were attributable in part to differences in bone size between the two populations. The results indicated that a substantial proportion of the variation in periosteal expansion required to maintain bone strength during aging can be attributed to the natural variation in adult bone width. Efforts to identify factors contributing to variation in periosteal expansion will benefit from developing a better understanding of how to adjust clinical data to differentiate the biological responses attributable to size-effects from other genetic and environmental factors. PMID- 22532509 TI - Accuracy of pharmacy and coded-diagnosis information in identifying tuberculosis in patients with rheumatoid arthritis. AB - PURPOSE: Previous studies suggest that disease-modifying anti-rheumatic drugs (DMARDs) increase tuberculosis (TB) risk. The accuracy of pharmacy and coded diagnosis information to identify persons with TB is unclear. METHODS: Within a cohort of rheumatoid arthritis (RA) patients (2000-2005) enrolled in Tennessee Medicaid, we identified those with potential TB using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD9-CM) diagnosis codes and/or pharmacy claims. Using the Tennessee TB registry as the gold standard for identification of TB, we estimated the sensitivity, specificity, predictive values, and the respective 95% confidence intervals for each TB case-ascertainment strategy. RESULTS: Ten of 18,094 RA patients had confirmed TB during 61,461 person-years of follow-up (16.3 per 100,000 person years). The sensitivity and positive predictive value (PPV) and respective 95% confidence intervals were low for confirmed TB based on ICD9-CM codes alone (60.0% (26.2-87.8) and 1.3% (0.5-2.9)), pharmacy data alone (20% (2.5-55.6) and 4.1% (0.5-14.3)), and both (20% (2.5-55.6) and 25.0% (3.2-65.1)). CONCLUSIONS: Algorithms that use administrative data alone to identify TB have a poor PPV that results in a high false positive rate of TB detection. PMID- 22532510 TI - Substrate-baited nanoparticles: a catch and release strategy for enzyme recognition and harvesting. AB - The isolation of a single type of protein from a complex mixture is vital for the characterization of the function, structure, and interactions of the protein of interest and is typically the most laborious aspect of the protein purification process. In this work, a model system is utilized to show the efficacy of synthesizing a "baited" nanoparticle to capture and recycle enzymes (proteins that catalyze chemical reactions) from crude cell lysate. Enzyme trapping and recycling is illustrated with the carbazole 1,9a-dioxygenase (CARDO) system, an enzyme important in bioremediation and natural product synthesis. The enzymes are baited with azide-modified carbazolyl moieties attached to poly(propargyl acrylate) nanoparticles through a click transformation. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis indicates the single-step procedure to immobilize the enzymes on the particles is capable of significantly concentrating the protein from raw lysate and sequestering all required components of the protein to maintain bioactivity. These results establish a universal model applicable to concentrating and extracting known substrate-protein pairs, but it can be an invaluable tool in recognizing unknown protein-ligand affinities. PMID- 22532511 TI - Risk factors and outcome of Ventilator Associated Tracheitis (VAT) in pediatric trauma patients. AB - We sought to investigate the risk factors and outcome of Ventilator Associated Tracheitis (VAT) according to the Center for Disease Control (CDC) definition in pediatric trauma patients who were ventilated for >=48 hr. In a retrospective cohort study, medical records of all pediatric trauma patients admitted to our Pediatric Intensive Care Unit (PICU) between April 2002 and April 2007 were reviewed. Medical records were reviewed for patients' demographics, Trauma Injury Severity Score (TISS), Glasgow Coma Scale (GCS), type of trauma, and other potential risk factors prior to the development of VAT (such as hyperglycemia, rate of re-intubation and tracheotomy, presence of chest tubes and central lines, urinary tract infection, seizures, need for cardiopulmonary resuscitation, use of total parental nutrition, transfusion, use of H(2) blockers, steroids, and pressors/inotropes). Medical records were also reviewed for days of mechanical ventilation, PICU length of stay, and PICU mortality. During the study period, 217 trauma patients were admitted to the PICU, 113 patients met our inclusion criteria and 21.2% (24/113) developed VAT. On average patients with VAT (in comparison to patients without VAT), had a higher TISS score on admission [38.6 +/- 16.9 vs. 24.2 +/- 10.6; respectively (P < 0.01)], longer days of ventilation and PICU length of stay [11.5 +/- 6.2 vs. 3.7 +/- 2.3 days (P < 0.001) and 16.4 +/- 8.3 vs. 5.4 +/- 2.8 days (P < 0.001), respectively]. There was no difference in mortality between the two groups. In a logistic regression model adjusting for possible confounders, the TISS score (adjusted OR 7.53; CI: 2.01-28.14; P = 0.03 and use of pressors/inotropes (adjusted OR 4.64; CI: 1.28-16.86; P = 0.01) were the only independent risk factors associated with VAT. We conclude that the severity of illness and use of pressors/inotropes are associated with VAT in pediatric trauma patients. We also conclude that VAT is associated with an increase in days of mechanical ventilation and PICU length of stay in pediatric trauma patients. PMID- 22532513 TI - Electrochemiluminescent determination of cancer cells based on aptamers, nanoparticles, and magnetic beads. AB - Herein we report a polymerase chain reaction (PCR)-free electrochemiluminescence (ECL) approach that uses ECL nanoprobes for the determination of cancer cells with high sensitivity. The ECL nanoprobe consists of gold nanoparticles (AuNPs), linker DNA, and tris(2,2'-bipyridyl)ruthenium (TBR)-labeled signal DNA. The linker DNA and signal DNA were modified on the surface of the AuNPs through Au-S bonds. The linker DNA can partly hybridize with the aptamers of cancer cells loaded onto the magnetic beads (MB1) to construct the magnetic biocomplexes. In the presence of the cancer cells, the aptamers conjugated with the cancer cells with higher affinity. The ECL nanoprobe was released from the biocomplexes and subsequently hybridized with the capture DNA loaded onto another magnetic bead (MB2) to form the magnetic nanocomposite. The nanocomposites can be easily separated and firmly attached to an electrode on account of their excellent magnetic properties. The ECL intensity of the TBR loaded onto the nanocomposites directly reflected the amount of cancer cells. By using cell lines of Burkitt's lymphoma (Ramos cells) as a model, the ECL response was proportional to the cell concentration in the range from 5 to 100 cells ml(-1); a limit of detection as low as 5 cells ml(-1) of Ramos cells could be achieved. The proposed method described here is ideal for the diagnosis of cancers due to its high sensitivity, simplicity, and low cost. PMID- 22532512 TI - Disparity between angiographic coronary lesion complexity and lipid core plaques assessed by near-infrared spectroscopy. AB - OBJECTIVE: The purpose of this study was to determine if there was a relationship between angiographic lesion complexity and the extent of lipid core plaque (LCP) identified by catheter-based near-infrared spectroscopy (NIRS). BACKGROUND: The angiographic complexity of coronary artery disease (CAD) is used to predict outcomes in patients undergoing percutaneous coronary intervention (PCI). The SYNTAX score, an angiographic tool quantifying the complexity of CAD, is associated with PCI outcomes. Recently, a novel catheter-based imaging technique using NIRS can identify LCP, which also is associated with PCI periprocedural myocardial infarction (MI). However, it is unknown whether these events are related to distinct adverse event prone pathobiology, such as a LCP within a complex angiographic lesion. Thus, we hypothesized that LCP identified by NIRS would be associated with high SYNTAX score. METHODS: Seventy-eight patients who underwent coronary angiography and target-vessel NIRS were selected from the Chemometric Observations of Lipid Core Containing Plaques of Interest in Native Coronary Arteries Registry, an industry sponsored registry to collate clinical findings in all patients undergoing NIRS evaluation. A lipid core burden index (LCBI) was obtained from the scan of the proximal 50 mm of the target vessel. Three vessel SYNTAX (total, tSYN) and target single vessel (only NIRS interrogated vessel) SYNTAX (1vSYN) scores were calculated and compared to LCBI. High LCBI was defined as (>110) and was compared to tertile scores for 1vSYN score (low 0-5, intermediate 6-10, high >=11) and previously established tertiles for tSYN score (low 0-22, intermediate 23-32, high >=33). RESULTS: Patients had mean age of 63 years with prevalence of females (10%), diabetes mellitus (28%), hypertension (88%), and smoking history (72%); 1vSYN and tSYN scores correlated poorly with LCBI [(r(2) = 0.25; P = 0.02; n = 78) and (r(2) = 0.24; P = 0.04; n = 78), respectively]. Mean LCBI did not differ significantly across all tertiles of 1vSYN or tSYN scores. CONCLUSIONS: Angiographic SYNTAX score only weakly correlated with LCBI. It is of interest as well that high LCBI was also present in cases of low SYNTAX scores. The disparity between the degree of angiographic complexity and the amount of LCP supports postulated mechanisms of the adverse event propensity even in patients who demonstrate low angiographic complexity. Future studies are necessary to address the clinical significance of high LCBI in patients with low-to-intermediate angiographic complexity and their potential for PCI-related complications. PMID- 22532514 TI - Total synthesis of rhizopodin. PMID- 22532515 TI - Relationship of changes in total hip bone mineral density to vertebral and nonvertebral fracture risk in women with postmenopausal osteoporosis treated with once-yearly zoledronic acid 5 mg: the HORIZON-Pivotal Fracture Trial (PFT). AB - Measurements of change in bone mineral density (BMD) are thought to be weak predictors of treatment effect on the reduction of fracture risk. In this study we report an alternative year-on-year approach for the estimation of treatment effect explained by BMD in which we examine the relationship between fracture risk and the most recent change in BMD. We studied 7736 postmenopausal women (ages 65 to 89 years) who were participants in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT) and were randomized to either intravenous administration of zoledronic acid or placebo. The percentage of treatment effect explained by change in total hip BMD was estimated using the alternative year-on-year approach and the standard approach of looking at change over 3 years. We also studied a subset of 1132 women in whom procollagen type 1 amino-terminal propeptide (PINP) was measured at baseline and 12 months, to estimate the percentage of treatment effect explained by change in PINP. Regardless of the method used, the change in total hip BMD explained a large percentage of the effect of zoledronic acid in reducing new vertebral fracture risk (40%; 95% CI, 30% to 54%; for the 3-year analysis). The treatment effects for nonvertebral fracture were not statistically significant for the year-on-year analysis but 3-year change in BMD explained 61% (95% CI, 24% to 156%) of treatment effect. Change in PINP explained 58% (95% CI, 15% to 222%) of the effect of zoledronic acid in reducing new vertebral fracture risk. We conclude that our estimates of the percentage of treatment effect explained may be higher than in previous studies because of high compliance with zoledronic acid (due to its once-yearly intravenous administration). Previous studies may have underestimated the relationship between BMD change and the effect of treatment on fracture risk. PMID- 22532516 TI - Detection of fluoroquinolone-induced tendon disorders using a hospital database in Japan. AB - PURPOSE: Tendinitis and tendon rupture are well-known side effects of fluoroquinolones (FQs) in Western countries. In Japan, some case reports have been reported; however, the incidence of FQ-induced tendon disorders has not been investigated. The aims of this study were to measure the occurrence of tendon disorders associated with FQs in Japanese patients and to compare the observed risk with that of previous reports. Moreover, the observed risk in FQ-prescribed patients was compared with that in cephalosporin-prescribed patients. METHODS: The Hamamatsu University Hospital database was examined to determine the risk of tendon disorders that occurred in all inpatients and outpatients between the first day of prescription of an oral FQ or cephalosporins to the calculated end date plus 30 days. The risk of tendon disorders, the risk ratio, and their 95% confidence intervals (CIs) were evaluated. RESULTS: From April 1996 to December 2009, FQs were prescribed to 17 147 patients, 14 of whom had tendon disorders (risk: 0.082%, 95%CI: 0.049-0.137). The risk of a tendon disorder in FQ prescribed patients was significantly higher than that in cephalosporin prescribed patients (five tendon disorders in 38 517 patients, risk: 0.013%, 95%CI: 0.006-0.030, and p < 0.001). The risk ratio of a tendon disorder in FQ prescribed patients in relation to cephalosporin-prescribed patients was 6.29 (95%CI: 2.27-17.46). A large discrepancy in the risk of tendon disorders was not observed between our findings and previous reports. CONCLUSION: A hospital database search revealed that the risk of tendon disorders in Japanese patients administered with FQs was higher than in those administered with cephalosporins. PMID- 22532517 TI - Synthesis and effect of Ce and Mn co-doping on photoluminescence characteristics of Ca6AlP5O20:Eu novel phosphors. AB - A series of Ca6AlP5O20 doped with rare earths (Eu and Ce) and co-doped (Eu, Ce and Eu,Mn) were prepared by combustion synthesis. Under Hg-free excitation, Ca6AlP5O20:Eu exhibited Eu(2+) (486 nm) emission in the blue region of the spectrum and under near Hg excitation (245 nm), Ca6AlP5O20:Ce phosphor exhibited Ce(3+) emission (357 nm) in the UV range. Photoluminescence (PL) peak intensity increased in Ca6AlP5O20:Eu,Ce and Ca6AlP5O20:Eu, Mn phosphors due to co activators of Ce(3+) and Mn(2+) ions. As a result, these ions played an important role in PL emission in the present matrix. Ca6AlP5O20:Eu, Ce and Ca6AlP5O20:Eu, Mn phosphors provided energy transfer mechanisms via Ce(3+) -> Eu(2+) and Eu(2+) > Mn(2+), respectively. Eu ions acted as activators and Ce ions acted as sensitizers. Ce emission energy was well matched with Eu excitation energy in the case of Ca6AlP5O20:Eu, Ce and Eu ions acted as activators and Mn ions acted as sensitizers in Ca6AlP5O20:Eu, Mn. This study included synthesis of new and efficient phosphate phosphors. The impact of doping and co-doping on photoluminescence properties and energy transfer mechanisms were investigated and we propose a feasible interpretation. PMID- 22532519 TI - Activating internal tandem duplication mutations of the fms-like tyrosine kinase 3 (FLT3-ITD) at complete response and relapse in patients with acute myeloid leukemia. AB - FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations are among the most frequent molecular aberrations in patients with acute myeloid leukemia. We retrospectively analyzed 324 patients with acute myeloid leukemia treated with front-line induction chemotherapy between October 2004 and March 2010. Fifty-six patients had FLT3-ITD mutation at diagnosis. Fifty-one (91%) patients with FLT3-ITD achieved complete remission. Thirteen patients had FLT3 analysis at complete remission. None had FLT3-ITD. Twenty-five (49%) patients with FLT3-ITD relapsed. Of these, 13 (52%) had FLT3-ITD at relapse (3 negative and 9 not done). Among the 201 patients without FLT3-ITD at diagnosis who achieved complete remission, 77 (38%) relapsed among whom 8 (10%) patients acquired FLT3-ITD clone. We conclude that FLT3-ITD mutations are unstable at follow up and may occur for the first time at relapse. Therefore, FLT3-ITD is not a reliable marker for minimal residual disease in acute myeloid leukemia. PMID- 22532518 TI - RHAMM/HMMR (CD168) is not an ideal target antigen for immunotherapy of acute myeloid leukemia. AB - BACKGROUND: Criteria for good candidate antigens for immunotherapy of acute myeloid leukemia are high expression on leukemic stem cells in the majority of patients with acute myeloid leukemia and low or no expression in vital tissues. It was shown in vaccination trials that Receptor for Hyaluronic Acid Mediated Motility (RHAMM/HMMR) generates cellular immune responses in patients with acute myeloid leukemia and that these responses correlate with clinical benefit. It is not clear however whether this response actually targets the leukemic stem cell, especially since it was reported that RHAMM is expressed maximally during the G2/M phase of the cell cycle. In addition, tumor specificity of RHAMM expression remains relatively unexplored. DESIGN AND METHODS: Blood, leukapheresis and bone marrow samples were collected from both acute myeloid leukemia patients and healthy controls. RHAMM expression was assessed at protein and mRNA levels on various sorted populations, either fresh or after manipulation. RESULTS: High levels of RHAMM were expressed by CD34(+)CD38(+) and CD34(-) acute myeloid leukemia blasts. However, only baseline expression of RHAMM was measured in CD34(+)CD38(-) leukemic stem cells, and was not different from that in CD34(+)CD38(-) hematopoietic stem cells from healthy controls. RHAMM was significantly up-regulated in CD34(+) cells from healthy donors during in vitro expansion and during in vivo engraftment. Finally, we demonstrated an explicit increase in the expression level of RHAMM after in vitro activation of T cells. CONCLUSIONS: RHAMM does not fulfill the criteria of an ideal target antigen for immunotherapy of acute myeloid leukemia. RHAMM expression in leukemic stem cells does not differ significantly from the expression in hematopoietic stem cells from healthy controls. RHAMM expression in proliferating CD34+ cells of healthy donors and activated T cells further compromises RHAMM-specific T-cell-mediated immunotherapy. PMID- 22532521 TI - Platelet dysfunction associated with ponatinib, a new pan BCR-ABL inhibitor with efficacy for chronic myeloid leukemia resistant to multiple tyrosine kinase inhibitor therapy. PMID- 22532520 TI - The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantation. AB - BACKGROUND: We have previously shown that bortezomib induces a depletion of alloreactive T cells and allows the expansion of T cells with suppressive properties. In the current study, we analyzed the potential synergistic effect of bortezomib in conjunction with sirolimus in order to reduce-graft-versus-host disease without hampering graft-versus-leukemia effect in the allogeneic transplant setting. DESIGN AND METHODS: We evaluated the effect of sirolimus, bortezomib or the combination of both in the proliferation and activation of in vitro stimulated T lymphocytes. Pathways involved in this synergy were also analyzed using Western blot assays. Finally, BALB/c mice receiving C57BL/6 allogeneic donor bone marrow with splenocytes were used to measure in vivo the effect of this novel combination on the risk of graft-versus-host disease. RESULTS: The combination of both drugs synergistically inhibited both activation and proliferation of stimulated T cells. Also, the production of Th1 cytokines (IFN gamma, IL-2 and TNF) was significantly inhibited. This effect was due, at least in part, to the inhibition of Erk and Akt phosphorylation. In vivo, the combination reduced the risk of graft-versus-host disease without hampering graft versus-leukemia effect, as shown in mice receiving graft-versus-host disease prophylaxis with sirolimus plus bortezomib being infused with tumor WEHI cells plus C57BL/6 donor BM and splenocytes. CONCLUSIONS: The current study reveals a synergistic effect of the combination sirolimus and bortezomib to prevent graft versus-host disease while maintaining the graft-versus-leukemia effect. PMID- 22532524 TI - A native chemical ligation approach for combinatorial assembly of affibody molecules. AB - Affinity molecules labeled with different reporter groups, such as fluorophores or radionuclides, are valuable research tools used in a variety of applications. One class of engineered affinity proteins is Affibody molecules, which are small (6.5 kDa) proteins that can be produced by solid phase peptide synthesis (SPPS), thereby allowing site-specific incorporation of reporter groups during synthesis. The Affibody molecules are triple-helix proteins composed of a variable part, which gives the protein its binding specificity, and a constant part, which is identical for all Affibody molecules. In the present study, native chemical ligation (NCL) has been applied for combinatorial assembly of Affibody molecules from peptide fragments produced by Fmoc SPPS. The concept is demonstrated for the synthesis of three different Affibody molecules. The cysteine residue introduced at the site of ligation can be used for directed immobilization and does not interfere with the function of the investigated proteins. This strategy combines a high-yield production method with facilitated preparation of proteins with different C-terminal modifications. PMID- 22532522 TI - Clinical features and course of refractory anemia with ring sideroblasts associated with marked thrombocytosis. AB - BACKGROUND: Refractory anemia with ring sideroblasts associated with marked thrombocytosis was proposed as a provisional entity in the 2001 World Health Organization classification of myeloid neoplasms and also in the 2008 version, but its existence as a single entity is contested. We wish to define the clinical features of this rare myelodysplastic/myeloproliferative neoplasm and to compare its clinical outcome with that of refractory anemia with ring sideroblasts and essential thrombocythemia. DESIGN AND METHODS: We conducted a collaborative retrospective study across Europe. Our database included 200 patients diagnosed with refractory anemia with ring sideroblasts and marked thrombocytosis. For each of these patients, each patient diagnosed with refractory anemia with ring sideroblasts was matched for age and sex. At the same time, a cohort of 454 patients with essential thrombocythemia was used to compare outcomes of the two diseases. RESULTS: In patients with refractory anemia with ring sideroblasts and marked thrombocytosis, depending on the Janus Kinase 2 V617F mutational status (positive or negative) or platelet threshold (over or below 600 * 10(9)/L), no difference in survival was noted. However, these patients had shorter overall survival and leukemia-free survival with a lower risk of thrombotic complications than did patients with essential thrombocythemia (P<0.001) but better survival (P<0.001) and a higher risk of thrombosis (P=0.039) than patients with refractory anemia with ring sideroblasts. CONCLUSIONS: The clinical course of refractory anemia with ring sideroblasts and marked thrombocytosis is better than that of refractory anemia with ring sideroblasts and worse than that of essential thrombocythemia. The higher risk of thrombotic events in this disorder suggests that anti-platelet therapy might be considered in this subset of patients. From a clinical point of view, it appears to be important to consider refractory anemia with ring sideroblasts and marked thrombocytosis as a distinct entity. PMID- 22532526 TI - A putative role for the immunoproteasome in the maintenance of pluripotency in human embryonic stem cells. AB - The function of the proteasome is essential for maintenance of cellular homeostasis, and in pluripotent stem cells, this has been extended to the removal of nascent proteins in a manner that restricts differentiation. In this study, we show enhanced expression of genes encoding subunits of the 20S proteasome in human embryonic stem cells (hESCs) coupled to their downregulation as the cells progress into differentiation. The decrease in expression is particularly marked for the alternative catalytic subunits of the 20S proteasome variant known as the immunoproteasome indicating the possibility of a hitherto unknown function for this proteasome variant in pluripotent cells. The immunoproteasome is normally associated with antigen-presenting cells where it provides peptides of an appropriate length for antibody generation; however, our data suggest that it may be involved in maintaining the pluripotency in hESCs. Selective inhibition of two immunoproteasome subunits (PSMB9 and PSMB8) results in downregulation of cell surface and transcriptional markers that characterize the pluripotent state, subtle cell accumulation in G1 at the expense of S-phase, and upregulation of various markers characterizing the differentiated primitive and definitive lineages arising from hESC. Our data also support a different function for each of these two subunits in hESC that may be linked to their selectivity in driving proteasome-mediated degradation of cell cycle regulatory components and/or differentiation inducing factors. PMID- 22532527 TI - Electrochemically reduced single-layer MoS2 nanosheets: characterization, properties, and sensing applications. AB - The electrochemical study of single-layer, 2D MoS2 nanosheets reveals a reduction peak in the cyclic voltammetry in NaCl aqueous solution. The electrochemically reduced MoS2 (rMoS2) shows good conductivity and fast electron transfer rate in the [Fe(CN)6]3-/4- and [Ru(NH3)6]2+/3+ redox systems. The obtained rMoS2 can be used for glucose detection. In addition, it can selectively detect dopamine in the presence of ascorbic acid and uric acid. This novel material, rMoS2, is believed to be a good electrode material for electrochemical sensing applications. PMID- 22532528 TI - Loss of Cdk2 and Cdk4 induces a switch from proliferation to differentiation in neural stem cells. AB - During neurogenesis, cell cycle regulators play a pivotal role in ensuring proper proliferation, cell cycle exit, and differentiation of neural precursors. However, the precise role of cyclin-dependent kinases (Cdks) in these processes is not well understood. We generated Cdk2 and Cdk4 double knockout (DKO) mice and found a striking ablation of the intermediate zone and cortical plate in mouse embryonic brain. When neural stem cells (NSCs) were isolated and analyzed, DKO NSCs proliferated comparable to wild type as Cdk1 now binds to cyclin D1 and E1 and assumes the role vacated by the loss of Cdk2 and Cdk4 in phosphorylating Rb. Although compensation was sufficient for the maintenance of self-renewal and multilineage potential, DKO NSCs displayed an altered cell cycle profile and were more prone to neuronal differentiation. This was manifested in vivo as a marked reduction in S-phase length and an increased tendency for neurogenic divisions that prevented proper expansion of the basal progenitor pool. Our data thus demonstrate the induction of neurogenic divisions in the absence of critical mediators of G1/S transition-Cdk2 and Cdk4, and highlight their evolutionary importance in the determination of cortical thickness. PMID- 22532529 TI - Complete genome sequence of the rearranged porcine circovirus type 2. AB - We first report here the genome sequences of 4 rearranged porcine circovirus type 2 strains, JSTZ, ZJQDH1, ZJQDH2, and JSHM, isolated from porcine sera in China. The complete circular genomes of these isolates are 578, 483, 574, and 772 nucleotides in length, respectively. They are predicted to be defective interfering particles of porcine circovirus type 2. The findings will help us to understand molecular evolution of porcine circovirus type 2 and the relationship between porcine circovirus type 2 and diseases. PMID- 22532530 TI - Complete genome sequences of a Korean virulent porcine epidemic diarrhea virus and its attenuated counterpart. AB - A virulent porcine epidemic diarrhea virus (PEDV) strain, DR13, was obtained from suckling pigs suspected of having porcine epidemic diarrhea in 1999 in Korea, and its attenuated counterpart was derived from virulent strain DR13 by serial propagation in Vero cells. This report describes the first complete genome sequences of virulent PEDV and its attenuated counterpart, which will provide important insights into the molecular basis of the attenuation of PEDV. PMID- 22532531 TI - Complete genomic sequence of Chinese virulent duck enteritis virus. AB - The Chinese virulent (CHv) strain of duck enteritis virus (DEV) has a genome of approximately 162,175 nucleotides with a GC content of 44.89%. Here we report the complete genomic sequence and annotation of DEV CHv, which offer an effective platform for providing authentic research experiences to novice scientists. In addition, knowledge of this virus will extend our general knowledge of DEV and will be useful for further studies of the mechanisms of virus replication and pathogenesis. PMID- 22532532 TI - Complete genome sequence of canine papillomavirus type 9. AB - Papillomaviruses are nonenveloped, double-stranded DNA viruses that are associated with both benign and malignant tumors in animals and humans. We report the complete genome sequence of canine papillomavirus type 9 isolated from a solitary pigmented plaque on a mixed-breed bloodhound. PMID- 22532533 TI - The genome sequence of bluetongue virus type 2 from India: evidence for reassortment between eastern and western topotype field strains. AB - Bluetongue virus type 2, isolated in India in 1982 (IND1982/01), was obtained from the Orbivirus Reference Collection at IAH Pirbright (http://www.reoviridae.org/dsRNA_virus_proteins/ReoID/btv-2.htm#IND1982/01). Full genome sequencing and phylogenetic analyses show that IND1982/01 is a reassortant virus containing genome segments derived from both eastern and western topotypes. These data will help to identify further reassortment events involving this or other virus lineages in the subcontinent. PMID- 22532535 TI - The genome sequence of bluetongue virus type 10 from India: evidence for circulation of a western topotype vaccine strain. AB - Bluetongue virus is the type species of the genus Orbivirus in the family Reoviridae. We report the first complete genome sequence of an isolate (IND2004/01) of bluetongue virus serotype 10 (BTV-10) from Andhra Pradesh, India. This isolate, which is stored in the Orbivirus Reference Collection (ORC) at IAH Pirbright, shows >99% nucleotide identity in all 10 genome segments with a vaccine strain of BTV-10 from the United States. PMID- 22532534 TI - Complete genome sequences of Newcastle disease virus strains circulating in chicken populations of Indonesia. AB - Eight highly virulent Newcastle disease virus (NDV) strains were isolated from vaccinated commercial chickens in Indonesia during outbreaks in 2009 and 2010. The complete genome sequences of two NDV strains and the sequences of the surface protein genes (F and HN) of six other strains were determined. Phylogenetic analysis classified them into two new subgroups of genotype VII in the class II cluster that were genetically distinct from vaccine strains. This is the first report of complete genome sequences of NDV strains isolated from chickens in Indonesia. PMID- 22532536 TI - Clinical features and genetic analysis of children with hyperekplexia in Korea. AB - Hyperekplexia is a rare inherited neurologic disorder that is characterized by hypertonia and an exaggerated startle response to sudden external stimuli. Until now, 5 genes are known to be associated with hyperekplexia: GLRA1, SLC6A5, GLRB, GPHN, and ARHGEF9. In this report, we performed a clinical and genetic analysis of 4 Korean children with hyperekplexia. Two patients had typical clinical manifestations of hyperekplexia that initially were misdiagnosed as epilepsy. Direct sequencing of the GLRB and GLRA1 genes revealed 2 novel mutations, GLRB c.298-1G>A and c.1028C>T (p.S343F), in patient 1 and 1 novel mutation, GLRA1 c.895C>T (p.R299X), in patient 2. The other 2 familial cases, patients 3 and 4, exhibited startle responses, which appeared at the age of 1 year, and had global developmental delay. Those patients showed negative results for the 5 genes. PMID- 22532537 TI - Mesial temporal sclerosis in a cohort of children with SCN1A gene mutation. AB - Mesial temporal sclerosis is uncommon in childhood but has been associated with febrile status epilepticus. SCN1A gene mutations are linked to multiple epilepsy syndromes with patients frequently presenting with prolonged febrile seizures. After observing mesial temporal sclerosis in a child with SCN1A gene mutation, we retrospectively reviewed magnetic resonance imaging (MRI) findings in all patients with SCN1A gene mutation identified between 2005 and 2010. We identified 20 patients with SCN1A mutations. Six patients had evidence of definite mesial temporal sclerosis with 2 patients having bilateral abnormalities. Another 4 patients were defined as having possible mesial temporal sclerosis. This patient group revealed that 50% had findings consistent with definite or possible mesial temporal sclerosis and many did not have a history of prolonged febrile seizures. We conclude that mesial temporal sclerosis is a common finding in children with SCN1A mutations. Many of these children will have Dravet syndrome but not all. PMID- 22532538 TI - Nonketotic hyperglycinemia: a cause of encephalopathy in children. AB - Nonketotic hyperglycinemia is a rare metabolic disorder with severe, frequently fatal, neurologic manifestations. Reliable and accurate diagnosis depends on careful interpretation of laboratory findings. The clinical suspicion should lead to determination of glycine in plasma and cerebrospinal fluid. Amino acid analysis presents diagnostic values for classic nonketotic hyperglycinemia, but it also should be performed in suspected cases of atypical nonketotic hyperglycinemia and in children with seizures, failure to thrive, behavior problems, and uncoordinated movements. Clinical assessment should be reinforced by demonstration of elevated cerebrospinal fluid-to-plasma glycine ratio. Confirmatory diagnosis requires enzymatic and genetic investigation of glycine cleavage system. An early diagnosis, though not affecting clinical outcome, allows proper genetic counseling, with the possibility of prenatal diagnosis. We report 3 cases of nonketotic hyperglycinemia, 2 typical neonatal and 1 atypical, diagnosed in Pediatric Hospital of Coimbra, Portugal, and investigated at Laboratory of Biochemical Genetics in 2004 to 2010 (incidence 1:47 455; prevalence 1:782 951). PMID- 22532539 TI - Intramedullary spinal cord primitive neuroectodermal tumor presenting with hydrocephalus. AB - Spinal primitive neuroectodermal tumors are exceedingly rare. Herewith, we present the first case of an intramedullary spinal cord tumor associated with hydrocephalus in a 2-month-old boy that presented with left hemiparesis. The patient had been diagnosed on prenatal ultrasound with enlarged ventricular system. At his current admission, a brain magnetic resonance imaging (MRI) revealed hydrocephalus and an intramedullary lesion extending from the second cervical to the first thoracic vertebrae. Dissemination of the tumor was revealed intracranially and in the spinal canal. After a ventriculoperitoneal shunt placement a radical resection of the tumor was performed, however some small tumor remnants could not be safely removed. Postoperative there was no neurologic deterioration. The tumor was diagnosed as a central nervous system primitive neuroectodermal tumor (World Health Organization grade IV). Spinal intramedullary primitive neuroectodermal tumors are extremely rare. In such rare tumors, multiinstitutional studies are needed for treatment guidelines to be established. PMID- 22532540 TI - Mumps virus-associated acute encephalopathy: case report and review of the literature. AB - We describe a fatal case of mumps virus-associated acute encephalopathy. In terms of the clinical course and cytokine as well as chemokine profiles, the pathogenesis in our case was different from that of mumps meningoencephalitis but was similar to that of influenza virus-associated acute encephalopathy. PMID- 22532541 TI - Long-term follow-up of children treated with the modified Atkins diet. AB - The modified Atkins diet has been studied in mostly short-term clinical trials and case series. No studies have systematically examined the long-term benefits and side effects. The modified Atkins diet was started without prior ketogenic diet use in 87 children at the Johns Hopkins Hospital since 2002, of which 54 continued for more than 6 months. Children who had not been seen within the past 2 years were contacted by phone and email. At their most recent point during the modified Atkins diet (mean 19.9 months), 30 of 54 (55%) children with diet durations of more than 6 months achieved >50% improvement; 19 (35%) were seizure free. Using an intent-to-treat analysis, at 12 months, 33 of 87 (38%) had >50% seizure reduction; 16 (18%) were seizure-free. These results are similar to published data for short-term modified Atkins diet and long-term ketogenic diet use. Side effects were predominantly elevations in lipid profile and gastrointestinal upset. PMID- 22532542 TI - Case report: spontaneous resolution of an established iatrogenic vertebral arteriovenous fistula. AB - Vertebral artery injuries can complicate attempted cannulation of the internal jugular vein including arteriovenous fistula formation. Such a fistula may occlude spontaneously in the acute phase but once established, spontaneous occlusion is extremely unusual. To the best of our knowledge, this has not been reported in the medical literature. We present a case of a patient who developed a right-sided vertebral arteriovenous fistula following instrumentation of the neck vessels but formal angiography/intervention was declined. The reason to report this case is that follow-up magnetic resonance angiography was performed, with spontaneous resolution of the right-sided vertebral arteriovenous fistula occurring postoperatively between days 30 and 135. Endovascular treatment options are available but for those who decline intervention, this report highlights the fact that spontaneous resolution of vertebral arteriovenous fistulae can occur. PMID- 22532543 TI - Classification of childhood epilepsies in a tertiary pediatric neurology clinic using a customized classification scheme from the international league against epilepsy 2010 report. AB - In its 2010 report, the International League Against Epilepsy Commission on Classification and Terminology had made a number of changes to the organization, terminology, and classification of seizures and epilepsies. This study aims to test the usefulness of this revised classification scheme on children with epilepsies aged between 0 and 18 years old. Of 527 patients, 75.1% only had 1 type of seizure and the commonest was focal seizure (61.9%). A specific electroclinical syndrome diagnosis could be made in 27.5%. Only 2.1% had a distinctive constellation. In this cohort, 46.9% had an underlying structural, metabolic, or genetic etiology. Among the important causes were pre-/perinatal insults, malformation of cortical development, intracranial infections, and neurocutaneous syndromes. However, 23.5% of the patients in our cohort were classified as having "epilepsies of unknown cause." The revised classification scheme is generally useful for pediatric patients. To make it more inclusive and clinically meaningful, some local customizations are required. PMID- 22532545 TI - Reversible diffusion weighted imaging changes in propionic acidemia. AB - Propionic acidemia is an inborn error of metabolism with neurologic manifestations. We describe a 3-year-old boy with propionic acidemia presenting with a metabolic crisis including headache, vomiting, and altered mental status with metabolic acidosis. Electroencephalography showed focal slowing in right temporal region. Magnetic resonance imaging (MRI) of the brain showed restricted diffusion with apparent diffusion coefficient correlate in the right parietooccipital region. Correction of metabolic acidosis led to clinical improvement and normalization of MRI diffusion weighted imaging/apparent diffusion coefficient changes. This article suggests that restricted diffusion resulting from metabolic crises in propionic acidemia may be reversible in some cases. PMID- 22532546 TI - No such thing as a "blind culture". AB - Cochlear implant technology has altered the landscape for the Deaf and for those who provide services to the profoundly hearing impaired. As indicated by Teagle in one of the companion articles, cochlear implants afford the profoundly hearing impaired child the ability to circumvent the effects of deafness. Cochlear implants, as indicated by Lee in the other companion article, are regarded differently by members of the Deaf Community where some see the technology as a threat to Deaf Culture. Members of a different community, which comprises the visually impaired, cite lack of a common language as the main argument against the existence of a "Blind Culture." As indicated by Pierce "We [the blind] often enjoy each other's company, and we certainly spend time together working on the problems that face what we often call the 'blind community,' but I would argue that this community is different from an actual culture." PMID- 22532547 TI - Cerebral vasculopathy in children with neurofibromatosis type 1. AB - Cerebral vasculopathy is an important but underrecognized complication of neurofibromatosis type 1. Over a 10-year period, we retrospectively assessed the prevalence, clinical manifestations, management, and outcome of cerebral vasculopathy in children with neurofibromatosis type 1. Magnetic resonance imaging (MRI) of the brain was performed on 78% of the patients (312/398) of which 46% (143/312) had magnetic resonance angiography of the intracranial arteries; 4.8% (15/312) had cerebral vasculopathy. Approximately half were asymptomatic at presentation; none had neurologic deficits. Cerebral vasculopathy included moyamoya changes (7) and stenosis/occlusion of major intracranial arteries (8). On follow-up (mean 4 years), 2 patients developed radiologic progression; 1 was treated with aspirin alone, whereas another underwent revascularization surgery. Although cerebral vasculopathy in neurofibromatosis type 1 may be asymptomatic at presentation, there may be radiologic and clinical progression leading to morbidity and mortality. Magnetic resonance angiography should be considered with brain MRI for early detection and timely intervention of cerebral vasculopathy. PMID- 22532548 TI - Cobblestone lissencephaly in Schinzel-Giedion syndrome. AB - The brain of a 5-year-old boy with Schinzel-Giedion syndrome displayed a cobblestone appearance of orbital and lateral aspects of frontal lobes due to widespread glioneuronal meningeal heterotopia. Meningeal heterotopia consisted of scattered neurons, neurofilament positive axons, and myelinated fibers accompanied by striking astrocytic gliosis. The underlying cortex showed gaps in the pial basal lamina, distorted neuronal layering, and focal polymicrogyria. The number of capillaries appeared increased throughout the brain. Mild hydrocephalus was associated with a slight atrophy of corpus callosum as well as villous hyperplasia and marked stromal degeneration of the choroid plexus. Our findings suggest that Schinzel-Giedion syndrome may represent One more entity within enlarging spectrum of lissencephalic cortical dysplasia syndromes. PMID- 22532549 TI - Patients with electrical status epilepticus in sleep share similar clinical features regardless of their focal or generalized sleep potentiation of epileptiform activity. AB - The study objective was to compare qualitatively the clinical features of patients with electrical status epilepticus in sleep with focal versus generalized sleep potentiated epileptiform activity. We enrolled patients 2 to 20 years of age, studied between 2001 and 2009, and with sleep potentiated epileptiform activity defined as an increase of epileptiform activity of 50% or more during non-rapid eye movement sleep compared with wakefulness. Eighty-five patients met the inclusion criteria, median age was 7.3 years, and 54 (63.5%) were boys. Sixty-seven (78.8%) patients had focal sleep potentiated epileptiform activity, whereas 18 (21.2%) had generalized sleep potentiated epileptiform activity. The 2 groups did not differ with respect to sex, age, presence of a structural brain abnormality, epilepsy, or other qualitative cognitive, motor, or behavioral problems. Our data suggest that there are no qualitative differences in the clinical features of patients with focal versus generalized sleep potentiated epileptiform activity. PMID- 22532550 TI - Valproic acid enhances glucose transport in the cultured brain astrocytes of glucose transporter 1 heterozygous mice. AB - Glucose transporter 1 facilitates glucose transport across the blood-brain barrier. By increasing histone acetylation at the SLC2A1 promotor, valproic acid could increase SLC2A1 gene expression. This study was designed to evaluate the effects of valproic acid on glucose transport in astrocyte cultures derived from SLC2A1 heterozygous mice. Primary astrocyte cultures were prepared from the cerebral cortex of 1-day-old neonatal mice. Cultured astrocytes were incubated with valproic acid (0.05, 0.5, and 5 mM) for 48 hours. On day 3, the glucose uptake capacity of the astrocytes was measured by using (14)C-2-Deoxy-d-glucose under zero-trans conditions. The heterozygous astrocyte glucose uptake treated with valproic acid (0.05 and 0.5 mM) for 48 hours was significantly increased compared with the untreated control heterozygous astrocytes. Our findings demonstrate that valproic acid increased glucose transport capacity in SLC2A1 heterozygous cerebral astrocytes. PMID- 22532551 TI - Deafness and cochlear implants: a deaf scholar's perspective. AB - During the past 3 decades, cochlear implants have dramatically influenced Deaf education and the Deaf Community. They have also served as catalysts for discord between some members of the Deaf Community and advocates of the technology. In this article, I do not intend to support either side of the spoken English versus sign language debate. Instead, I will discuss ethical and practical issues related to cochlear implants. More specifically, I will address the nature and notion of deafness and the purpose of Deaf education. Although many authors have discussed these issues, they have mostly done so from the perspective of hearing scholars and the hearing parents of deaf children. It is important to recognize that understanding deafness and the experience of life from a Deaf individual's perspective has important implications for further educational policy and practice. PMID- 22532552 TI - Synaptogenesis in the fetal corpus striatum, globus pallidus, and substantia nigra: correlations with striosomes of Graybiel and dyskinesias in premature infants. AB - Synaptogenesis can be detected in tissue sections by immunoreactivity for synaptophysin, a synaptic vesicle glycoprotein that serves as a marker of synaptic maturation. Reactivity was prospectively studied postmortem in sections of the striatum, globus pallidus, and substantia nigra in 172 normal human fetuses and neonates of 6 to 41 weeks' gestation. Caudate nucleus and putamen show patchy reactivity beginning at 13 weeks' gestation around some intracapsular neurons; the pattern is well developed in all regions before midgestation. Near uniform reactivity throughout the striatum is achieved by 34 weeks, but subtle patchiness is still perceived at term. The globus pallidus shows uniform reactivity without stria from 13 weeks and the substantia nigra from 9 weeks. Synaptic patchiness in the fetal corpus striatum appears to correspond to the "striosomes of Graybiel" that define adjacent neurotransmitter-rich and neurotransmitter-poor zones. Clinical correlation is proposed with dystonic postures and athetoid movements observed in normal preterm neonates of 26 to 32 weeks. PMID- 22532553 TI - Postictal psychosis in a 3-year-old child. AB - A case of a 3½-year-old with clinical and correlated electroencephalographic (EEG) features of postictal psychosis is described. The clinical course and sequence of EEG changes parallel the evolution of changes well described in the adult population. Although well established and defined in the adults, postictal psychosis is rarely characterized and diagnosed in the pediatric population. The true incidence of postictal psychosis in children may be underestimated because of lack of awareness as well as biological differences in presentation of clinical symptoms. To our knowledge, this is the youngest reported case of postictal psychosis in the pediatric population. PMID- 22532554 TI - Mutation in an mtDNA protein-coding gene: prenatal diagnosis aided by fetal muscle biopsy. AB - Prenatal diagnosis of disorders due to mitochondrial DNA (mtDNA) tRNA gene mutations is problematic. Experience in families harboring the protein-coding ATPase 6 m.8993T>G mutation suggests that the mutant load is homogeneous in different tissues, thus allowing prenatal diagnosis. We have encountered a novel protein-coding gene mutation, m.10198C>T in MT-ND3. A baby girl homoplasmic for this mutation died at 3 months after severe psychomotor regression and respiratory arrest. The mother had no detectable mutation in accessible tissues. The product of a second pregnancy showed only wild-type mt genomes in amniocytes, chorionic villi, and biopsied fetal muscle. This second girl is now 18 months old and healthy. Our observations support the concept that the pathogenic mutation in this patient appeared de novo and that fetal muscle biopsy is a useful aide in prenatal diagnosis. PMID- 22532555 TI - Park Spearin Gerald: a tribute. PMID- 22532556 TI - The very low density lipoprotein receptor-associated pontocerebellar hypoplasia and dysmorphic features in three Turkish patients. AB - Pontocerebellar hypoplasia consists of a rare heterogeneous group of congenital neurodevelopmental disorders characterized by hypoplasia and atrophy of the cerebellar cortex, dentate and pontine nuclei, and inferior olives. The very low density lipoprotein receptor protein is an integral part of the reelin signaling pathway, which guides neuroblast migration in the cerebral cortex and cerebellum. Mutations in this receptor cause nonprogressive cerebellar ataxia, mental retardation, and cerebellar hypoplasia. In this report, we present 3 patients from 2 different families displaying very low density lipoprotein receptor associated pontocerebellar hypoplasia, cortical dysplasia, mental retardation, and bipedal gait. One of the siblings has also displayed dysmorphic features, as we previously reported before the identification of the genetic defect in this family. PMID- 22532557 TI - Nontypeable pneumococci can be divided into multiple cps types, including one type expressing the novel gene pspK. AB - Although virulence of Streptococcus pneumoniae is associated with its capsule, some pathogenic S. pneumoniae isolates lack capsules and are serologically nontypeable (NT). We obtained 64 isolates that were identified as NT "pneumococci" (i.e., bacteria satisfying the conventional definition but without the multilocus sequence typing [MLST]-based definition of S. pneumoniae) by the traditional criteria. All 64 were optochin sensitive and had lytA, and 63 had ply. Twelve isolates had cpsA, suggesting the presence of a conventional but defective capsular polysaccharide synthesis (cps) locus. The 52 cpsA-negative isolates could be divided into three null capsule clades (NCC) based on aliC (aliB-like ORF1), aliD (aliB-like ORF2), and our newly discovered gene, pspK, in their cps loci. pspK encodes a protein with a long alpha-helical region containing an LPxTG motif and a YPT motif known to bind human pIgR. There were nine isolates in NCC1 (pspK(+) but negative for aliC and aliD), 32 isolates in NCC2 (aliC(+) aliD(+) but negative for pspK), and 11 in NCC3 (aliD(+) but negative for aliC and pspK). Among 52 cpsA-negative isolates, 41 were identified as S. pneumoniae by MLST analysis. All NCC1 and most NCC2 isolates were S. pneumoniae, whereas all nine NCC3 and two NCC2 isolates were not S. pneumoniae. Several NCC1 and NCC2 isolates from multiple individuals had identical MLST and cps regions, showing that unencapsulated S. pneumoniae can be infectious among humans. Furthermore, NCC1 and NCC2 S. pneumoniae isolates could colonize mice as well as encapsulated S. pneumoniae, although S. pneumoniae with an artificially disrupted cps locus did not. Moreover, an NCC1 isolate with pspK deletion did not colonize mice, suggesting that pspK is critical for colonization. Thus, PspK may provide pneumococci a means of surviving in the nasopharynx without capsule. IMPORTANCE The presence of a capsule is critical for many pathogenic bacteria, including pneumococci. Reflecting the pathogenic importance of the pneumococcal capsule, pneumococcal vaccines are designed to elicit anticapsule antibodies. Additional evidence for the pathogenic importance of the pneumococcal capsule is the fact that in pneumococci all the genes necessary for capsule production are together in one genetic locus, which is called the cps locus. However, there are occasional pathogenic pneumococci without capsules, and how they survive in the host without the capsule is unknown. Here, we show that in these acapsular pneumococci, the cps loci have been replaced with various novel genes and they can colonize mouse nasopharynges as well as capsulated pneumococci. Since the genes that replace the cps loci are likely to be important in host survival, they may show new and/or alternative capsule-independent survival mechanisms used by pneumococci. PMID- 22532558 TI - The origins of cooperative bacterial communities. AB - Bacteria live in complex multispecies communities. Intimately interacting bacterial cells are ubiquitous on biological and mineral surfaces in all habitats. Molecular and cellular biologists have unraveled some key mechanisms that modulate bacterial interactions, but the ecology and evolution of these associations remain poorly understood. One debate has focused on the relative importance of cooperation among cells in bacterial communities. Some researchers suggest that communication and cooperation, both within and among bacterial species, have produced emergent properties that give such groups a selective advantage. Evolutionary biologists have countered that the appearance of group level traits should be viewed with caution, as natural selection almost invariably favors selfishness. A recent theory by Morris, Lenski, and Zinser, called the Black Queen Hypothesis, gives a new perspective on this debate (J. J. Morris, R. E. Lenski, and E. R. Zinser, mBio 3(2):e00036-12, 2012). These authors present a model that reshapes a decades-old idea: cooperation among species can be automatic and based upon purely selfish traits. Moreover, this hypothesis stands in contrast to the Red Queen Hypothesis, which states that species are in constant evolutionary conflict. Two assumptions serve as the core of the Black Queen model. First, bacterial functions are often leaky, such that cells unavoidably produce resources that benefit others. Second, the receivers of such by-products will tend to delete their own costly pathways for those products, thus building dependency into the interactions. Although not explicitly required in their model, an emergent prediction is that the initiation of such dependency can favor the spread of more obligate coevolved partnerships. This new paradigm suggests that bacteria might often form interdependent cooperative interactions in communities and moreover that bacterial cooperation should leave a clear genomic signature via complementary loss of shared diffusible functions. PMID- 22532560 TI - Cannabinoid receptors CB1 and CB2 form functional heteromers in brain. AB - Exploring the role of cannabinoid CB(2) receptors in the brain, we present evidence of CB(2) receptor molecular and functional interaction with cannabinoid CB(1) receptors. Using biophysical and biochemical approaches, we discovered that CB(2) receptors can form heteromers with CB(1) receptors in transfected neuronal cells and in rat brain pineal gland, nucleus accumbens, and globus pallidus. Within CB(1)-CB(2) receptor heteromers expressed in a neuronal cell model, agonist co-activation of CB(1) and CB(2) receptors resulted in a negative cross talk in Akt phosphorylation and neurite outgrowth. Moreover, one specific characteristic of CB(1)-CB(2) receptor heteromers consists of both the ability of CB(1) receptor antagonists to block the effect of CB(2) receptor agonists and, conversely, the ability of CB(2) receptor antagonists to block the effect of CB(1) receptor agonists, showing a bidirectional cross-antagonism phenomenon. Taken together, these data illuminate the mechanism by which CB(2) receptors can negatively modulate CB(1) receptor function. PMID- 22532561 TI - Chaperone gp96-independent inhibition of endotoxin response by chaperone-based peptide inhibitors. AB - HSP90 chaperones a large number of proteins, and it plays essential roles in multiple signaling pathways to maintain protein homeostasis in the cytosol. In addition, HSP90 has been implicated in mediating recognition of lipopolysaccharide (LPS). However, no pharmacologic agents have been developed to interrogate this pathway. Herein we demonstrate that a peptide-based inhibitor that was previously reported to inhibit the master Toll-like receptor-chaperone gp96, an endoplasmic reticulum paralog of HSP90, in fact blocks HSP90-LPS interaction. It inhibited the binding of LPS to the cell surface of both wild type and gp96-null cells and thereby abrogated the cellular response to LPS but not to other Toll-like receptor ligands. We also generated a series of peptide derivatives (named peptide inhibitors of endotoxin responsiveness (PIERs)) from the N-terminal helix structure of HSP90 and demonstrated their effectiveness in blocking LPS activity. PIER inhibition of LPS signaling was partially reversed by CD14 expression. Moreover, we found that a cell-permeable PIER abrogated HSP90 function and caused degradation of multiple known HSP90 client proteins in cancer cells. Thus, targeting HSP90 is a promising modality for treatment of both LPS mediated pathology and cancer. PMID- 22532562 TI - Neutrophils express distinct RNA receptors in a non-canonical way. AB - RNAs are capable of modulating immune responses by binding to specific receptors. Neutrophils represent the major fraction of circulating immune cells, but receptors and mechanisms by which neutrophils sense RNA are poorly defined. Here, we analyzed the mRNA and protein expression patterns and the subcellular localization of the RNA receptors RIG-I, MDA-5, TLR3, TLR7, and TLR8 in primary neutrophils and immortalized neutrophil-like differentiated HL-60 cells. Our results demonstrate that both neutrophils and differentiated HL-60 cells express RIG-I, MDA-5, and TLR8 at the mRNA and protein levels, whereas TLR3 and TLR7 are not expressed at the protein level. Subcellular fractionation, flow cytometry, confocal laser scanning microscopy, and immuno-transmission electron microscopy provided evidence that, besides the cytoplasm, RIG-I and MDA-5 are stored in secretory vesicles of neutrophils and showed that RIG-I and its ligand, 3p-RNA, co-localize at the cell surface without triggering neutrophil activation. In summary, this study demonstrates that neutrophils express a distinct pattern of RNA recognition receptors in a non-canonical way, which could have essential implications for future RNA-based therapeutics. PMID- 22532563 TI - Basic helix-loop-helix transcription factor Twist1 inhibits transactivator function of master chondrogenic regulator Sox9. AB - Canonical Wnt signaling strongly inhibits chondrogenesis. Previously, we identified Twist1 as a critical downstream mediator of Wnt in repression of chondrocyte differentiation. However, the mechanistic basis for the antichondrogenic activity of Twist1 has not heretofore been established. Here, we show that Twist1 suppresses cartilage development by directly inhibiting the transcriptional activity of Sox9, the master regulator of chondrogenesis. Twist1, through its carboxyl-terminal Twist-box, binds to the Sox9 high mobility group DNA-binding domain, inhibiting Sox9 transactivation potential. In chondrocyte precursor cells, Twist1, in a Twist-box-dependent manner, inhibits Sox9-dependent activation of chondrocyte marker gene expression by blocking Sox9-enhancer DNA association. These findings identify Twist1 as an inhibitor of Sox9 and further suggest that the balance between Twist1 and Sox9 may determine the earliest steps of chondrogenesis. PMID- 22532564 TI - Protein kinase Calpha and Src kinase support human prostate-distributed dihydrotestosterone-metabolizing UDP-glucuronosyltransferase 2B15 activity. AB - Because human prostate-distributed UDP-glucuronosyltransferase (UGT) 2B15 metabolizes 5alpha-dihydrotestosterone (DHT) and 3alpha-androstane-5alpha,17beta diol metabolite, we sought to determine whether 2B15 requires regulated phosphorylation similar to UGTs already analyzed. Reversible down-regulation of 2B15-transfected COS-1 cells following curcumin treatment and irreversible inhibition by calphostin C, bisindolylmaleimide, or rottlerin treatment versus activation by phorbol 12-myristate 13-acetate indicated that 2B15 undergoes PKC phosphorylation. Mutation of three predicted PKC and two tyrosine kinase sites in 2B15 caused 70-100 and 80-90% inactivation, respectively. Anti-UGT-1168 antibody trapped 2B15-His-containing co-immunoprecipitates of PKCalpha in 130-140- and >150-kDa complexes by gradient SDS-PAGE analysis. Complexes bound to WT 2B15-His remained intact during electrophoresis, whereas 2B15-His mutants at phosphorylation sites differentially dissociated. PKCalpha siRNA treatment inactivated >50% of COS-1 cell-expressed 2B15. In contrast, treatment of 2B15 transfected COS-1 cells with the Src-specific activator 1,25-dihydroxyvitamin D(3) enhanced activity; treatment with the Src-specific PP2 inhibitor or Src siRNA inhibited >50% of the activity. Solubilized 2B15-His-transfected Src-free fibroblasts subjected to in vitro [gamma-(33)P]ATP-dependent phosphorylation by PKCalpha and/or Src, affinity purification, and SDS gel analysis revealed 2-fold more radiolabeling of 55-58-kDa 2B15-His by PKCalpha than by Src; labeling was additive for combined kinases. Collectively, the evidence indicates that 2B15 requires regulated phosphorylation by both PKCalpha and Src, which is consistent with the complexity of synthesis and metabolism of its major substrate, DHT. Whether basal cells import or synthesize testosterone for transport to luminal cells for reduction to DHT by 5alpha-steroid reductase 2, comparatively low activity luminal cell 2B15 undergoes a complex pattern of regulated phosphorylation necessary to maintain homeostatic DHT levels to support occupation of the androgen receptor for prostate-specific functions. PMID- 22532565 TI - Perilipin 5, a lipid droplet-binding protein, protects heart from oxidative burden by sequestering fatty acid from excessive oxidation. AB - Lipid droplets (LDs) are ubiquitous organelles storing neutral lipids, including triacylglycerol (TAG) and cholesterol ester. The properties of LDs vary greatly among tissues, and LD-binding proteins, the perilipin family in particular, play critical roles in determining such diversity. Overaccumulation of TAG in LDs of non-adipose tissues may cause lipotoxicity, leading to diseases such as diabetes and cardiomyopathy. However, the physiological significance of non-adipose LDs in a normal state is poorly understood. To address this issue, we generated and characterized mice deficient in perilipin 5 (Plin5), a member of the perilipin family particularly abundant in the heart. The mutant mice lacked detectable LDs, containing significantly less TAG in the heart. Particulate structures containing another LD-binding protein, Plin2, but negative for lipid staining, remained in mutant mice hearts. LDs were recovered by perfusing the heart with an inhibitor of lipase. Cultured cardiomyocytes from Plin5-null mice more actively oxidized fatty acid than those of wild-type mice. Production of reactive oxygen species was increased in the mutant mice hearts, leading to a greater decline in heart function with age. This was, however, reduced by the administration of N acetylcysteine, a precursor of an antioxidant, glutathione. Thus, we conclude that Plin5 is essential for maintaining LDs at detectable sizes in the heart, by antagonizing lipase(s). LDs in turn prevent excess reactive oxygen species production by sequestering fatty acid from oxidation and hence suppress oxidative burden to the heart. PMID- 22532566 TI - Generation of Alzheimer disease-associated amyloid beta42/43 peptide by gamma secretase can be inhibited directly by modulation of membrane thickness. AB - Pathogenic generation of amyloid beta-peptide (Abeta) by sequential cleavage of beta-amyloid precursor protein (APP) by beta- and gamma-secretases is widely believed to causally underlie Alzheimer disease (AD). beta-Secretase initially cleaves APP thereby generating a membrane-bound APP C-terminal fragment, from which gamma-secretase subsequently liberates 37-43-amino acid long Abeta species. Although the latter cleavages are intramembranous and although lipid alterations have been implicated in AD, little is known of how the gamma-secretase-mediated release of the various Abeta species, in particular that of the pathogenic longer variants Abeta(42) and Abeta(43), is affected by the lipid environment. Using a cell-free system, we have directly and systematically investigated the activity of gamma-secretase reconstituted in defined model membranes of different thicknesses. We found that bilayer thickness is a critical parameter affecting both total activity as well as cleavage specificity of gamma-secretase. Whereas the generation of the pathogenic Abeta(42/43) species was markedly attenuated in thick membranes, that of the major and rather benign Abeta(40) species was enhanced. Moreover, the increased production of Abeta(42/43) by familial AD mutants of presenilin 1, the catalytic subunit of gamma-secretase, could be substantially lowered in thick membranes. Our data demonstrate an effective modulation of gamma-secretase activity by membrane thickness, which may provide an approach to lower the generation of the pathogenic Abeta(42/43) species. PMID- 22532567 TI - Androgen receptor splice variants activate androgen receptor target genes and support aberrant prostate cancer cell growth independent of canonical androgen receptor nuclear localization signal. AB - Synthesis of truncated androgen receptor (AR) splice variants has emerged as an important mechanism of prostate cancer (PCa) resistance to AR-targeted therapy and progression to a lethal castration-resistant phenotype. However, the precise role of these factors at this stage of the disease is not clear due to loss of multiple COOH-terminal AR protein domains, including the canonical nuclear localization signal (NLS) in the AR hinge region. Despite loss of this NLS, we show that diverse truncated AR variant species have a basal level of nuclear localization sufficient for ligand-independent transcriptional activity. Whereas full-length AR requires Hsp90 and importin-beta for active nuclear translocation, basal nuclear localization of truncated AR variants is independent of these classical signals. For a subset of truncated AR variants, this basal level of nuclear import can be augmented by unique COOH-terminal sequences that reconstitute classical AR NLS activity. However, this property is separable from ligand-independent transcriptional activity. Therefore, the AR splice variant core consisting of the AR NH(2)-terminal domain and DNA binding domain is sufficient for nuclear localization and androgen-independent transcriptional activation of endogenous AR target genes. Indeed, we show that truncated AR variants with nuclear as well as nuclear/cytoplasmic localization patterns can drive androgen-independent growth of PCa cells. Together, our data demonstrate that diverse truncated AR species with varying efficiencies of nuclear localization can contribute to castration-resistant PCa pathology by driving persistent ligand-independent AR transcriptional activity. PMID- 22532568 TI - Neutralizing aspartate 83 modifies substrate translocation of excitatory amino acid transporter 3 (EAAT3) glutamate transporters. AB - Excitatory amino acid transporters (EAATs) terminate glutamatergic synaptic transmission by removing glutamate from the synaptic cleft into neuronal and glial cells. EAATs are not only secondary active glutamate transporters but also function as anion channels. Gating of EAAT anion channels is tightly coupled to transitions within the glutamate uptake cycle, resulting in Na(+)- and glutamate dependent anion currents. A point mutation neutralizing a conserved aspartic acid within the intracellular loop close to the end of transmembrane domain 2 was recently shown to modify the substrate dependence of EAAT anion currents. To distinguish whether this mutation affects transitions within the uptake cycle or directly modifies the opening/closing of the anion channel, we used voltage clamp fluorometry. Using three different sites for fluorophore attachment, V120C, M205C, and A430C, we observed time-, voltage-, and substrate-dependent alterations of EAAT3 fluorescence intensities. The voltage and substrate dependence of fluorescence intensities can be described by a 15-state model of the transport cycle in which several states are connected to branching anion channel states. D83A-mediated changes of fluorescence intensities, anion currents, and secondary active transport can be explained by exclusive modifications of substrate translocation rates. In contrast, sole modification of anion channel opening and closing is insufficient to account for all experimental data. We conclude that D83A has direct effects on the glutamate transport cycle and that these effects result in changed anion channel function. PMID- 22532569 TI - Prostate cancer cells and bone stromal cells mutually interact with each other through bone morphogenetic protein-mediated signals. AB - Functional interactions between cancer cells and the bone microenvironment contribute to the development of bone metastasis. Although the bone metastasis of prostate cancer is characterized by increased ossification, the molecular mechanisms involved in this process are not fully understood. Here, the roles of bone morphogenetic proteins (BMPs) in the interactions between prostate cancer cells and bone stromal cells were investigated. In human prostate cancer LNCaP cells, BMP-4 induced the production of Sonic hedgehog (SHH) through a Smad dependent pathway. In mouse stromal MC3T3-E1 cells, SHH up-regulated the expression of activin receptor IIB (ActR-IIB) and Smad1, which in turn enhanced BMP-responsive reporter activities in these cells. The combined stimulation with BMP-4 and SHH of MC3T3-E1 cells cooperatively induced the expression of osteoblastic markers, including alkaline phosphatase, bone sialoprotein, collagen type II alpha1, and osteocalcin. When MC3T3-E1 cells and LNCaP cells were co cultured, the osteoblastic differentiation of MC3T3-E1 cells, which was induced by BMP-4, was accelerated by SHH from LNCaP cells. Furthermore, LNCaP cells and BMP-4 cooperatively induced the production of growth factors, including fibroblast growth factor (FGF)-2 and epidermal growth factor (EGF) in MC3T3-E1 cells, and these may promote the proliferation of LNCaP cells. Taken together, our findings suggest that BMPs provide favorable circumstances for the survival of prostate cancer cells and the differentiation of bone stromal cells in the bone microenvironment, possibly leading to the osteoblastic metastasis of prostate cancer. PMID- 22532570 TI - Murine protein serine-threonine kinase 38 activates p53 function through Ser15 phosphorylation. AB - Murine protein serine-threonine kinase 38 (MPK38) is a member of the AMP activated protein kinase-related serine/threonine kinase family. In this study, we show that MPK38 physically associates with p53 via the carboxyl-terminal domain of MPK38 and the central DNA-binding domain of p53. This interaction is increased by 5-fluorouracil or doxorubicin treatment and is responsible for Ser(15) phosphorylation of p53. Ectopic expression of wild-type Mpk38, but not kinase-dead Mpk38, stimulates p53-mediated transcription in a dose-dependent manner and up-regulates p53 targets, including p53, p21, MDM2, and BAX. Consistently, knockdown of MPK38 shows an opposite trend, inhibiting p53-mediated transcription. MPK38 functionally enhances p53-mediated apoptosis and cell cycle arrest in a kinase-dependent manner by stimulating p53 nuclear translocation. We also demonstrate that MPK38-mediated p53 activation is induced by removing MDM2, a negative regulator of p53, from the p53-MDM2 complex as well as by stabilization of interaction between p53 and its positive regulators, including NM23-H1, serine/threonine kinase receptor-associated protein, and 14-3-3. This leads to the enhancement of p53 stability. Together, these results suggest that MPK38 may act as a novel regulator for promoting p53 activity through direct phosphorylation of p53 at Ser(15). PMID- 22532571 TI - Astrocytes secrete exosomes enriched with proapoptotic ceramide and prostate apoptosis response 4 (PAR-4): potential mechanism of apoptosis induction in Alzheimer disease (AD). AB - Amyloid protein is well known to induce neuronal cell death, whereas only little is known about its effect on astrocytes. We found that amyloid peptides activated caspase 3 and induced apoptosis in primary cultured astrocytes, which was prevented by caspase 3 inhibition. Apoptosis was also prevented by shRNA-mediated down-regulation of PAR-4, a protein sensitizing cells to the sphingolipid ceramide. Consistent with a potentially proapoptotic effect of PAR-4 and ceramide, astrocytes surrounding amyloid plaques in brain sections of the 5xFAD mouse (and Alzheimer disease patient brain) showed caspase 3 activation and were apoptotic when co-expressing PAR-4 and ceramide. Apoptosis was not observed in astrocytes with deficient neutral sphingomyelinase 2 (nSMase2), indicating that ceramide generated by nSMase2 is critical for amyloid-induced apoptosis. Antibodies against PAR-4 and ceramide prevented amyloid-induced apoptosis in vitro and in vivo, suggesting that apoptosis was mediated by exogenous PAR-4 and ceramide, potentially associated with secreted lipid vesicles. This was confirmed by the analysis of lipid vesicles from conditioned medium showing that amyloid peptide induced the secretion of PAR-4 and C18 ceramide-enriched exosomes. Exosomes were not secreted by nSMase2-deficient astrocytes, indicating that ceramide generated by nSMase2 is critical for exosome secretion. Consistent with the ceramide composition in amyloid-induced exosomes, exogenously added C18 ceramide restored PAR-4-containing exosome secretion in nSMase2-deficient astrocytes. Moreover, isolated PAR-4/ceramide-enriched exosomes were taken up by astrocytes and induced apoptosis in the absence of amyloid peptide. Taken together, we report a novel mechanism of apoptosis induction by PAR-4/ceramide enriched exosomes, which may critically contribute to Alzheimer disease. PMID- 22532572 TI - The differential effects of prenatal and/or postnatal rapamycin on neurodevelopmental defects and cognition in a neuroglial mouse model of tuberous sclerosis complex. AB - Tuberous sclerosis complex (TSC) is caused by heterozygous mutations in either the TSC1 (hamartin) or the TSC2 (tuberin) gene. Among the multisystemic manifestations of TSC, the neurodevelopmental features cause the most morbidity and mortality, presenting a considerable clinical challenge. Hamartin and tuberin form a heterodimer that inhibits the mammalian target of rapamycin complex 1 (mTORC1) kinase, a major cellular regulator of protein translation, cell growth and proliferation. Hyperactivated mTORC1 signaling, an important feature of TSC, has prompted a number of preclinical and clinical studies with the mTORC1 inhibitor rapamycin. Equally exciting is the prospect of treating TSC in the perinatal period to block the progression of brain pathologies and allow normal brain development to proceed. We hypothesized that low-dose rapamycin given prenatally and/or postnatally in a well-established neuroglial (Tsc2-hGFAP) model of TSC would rescue brain developmental defects. We developed three treatment regimens with low-dose intraperitoneal rapamycin (0.1 mg/kg): prenatal, postnatal and pre/postnatal (combined). Combined rapamycin treatment resulted in almost complete histologic rescue, with a well-organized cortex and hippocampus almost identical to control animals. Other treatment regimens yielded less complete, but significant improvements in brain histology. To assess how treatment regimens affected cognitive function, we continued rapamycin treatment after weaning and performed behavioral testing. Surprisingly, the animals treated with the combined therapy did not perform as well as postnatally-treated animals in learning and memory tasks. These results have important translational implications in the optimization of the timing and dosage of rapamycin treatment in TSC affected children. PMID- 22532575 TI - Everyday, everywhere: alcohol marketing and social media--current trends. AB - AIMS: To provide a snapshot content analysis of social media marketing among leading alcohol brands in the UK, and to outline the implications for both regulatory policies and further research. METHODS: Using screengrab technology, the complete Facebook walls and Twitter timelines for 12 leading UK alcohol brands in November 2011 were captured and archived. A total of 701 brand-authored posts were identified and categorized using a thematic coding frame. Key strategic trends were identified and analysed in the light of contextual research into recent developments in marketing practice within the alcohol industry. RESULTS: A number of dominating trends were identified. These included the use of real-world tie-ins, interactive games, competitions and time-specific suggestions to drink. These methods reflect a strategy of branded conversation-stimulus which is favoured by social media marketing agencies. CONCLUSION: A number of distinct marketing methods are deployed by alcohol brands when using social media. These may undermine policies which seek to change social norms around drinking, especially the normalization of daily consumption. Social media marketing also raises questions regarding the efficacy of reactive regulatory frameworks. Further research into both the nature and impact of alcohol marketing on social media is needed. PMID- 22532574 TI - Identification of a novel percent mammographic density locus at 12q24. AB - Percent mammographic density adjusted for age and body mass index (BMI) is one of the strongest risk factors for breast cancer and has a heritable component that remains largely unidentified. We performed a three-stage genome-wide association study (GWAS) of percent mammographic density to identify novel genetic loci associated with this trait. In stage 1, we combined three GWASs of percent density comprised of 1241 women from studies at the Mayo Clinic and identified the top 48 loci (99 single nucleotide polymorphisms). We attempted replication of these loci in 7018 women from seven additional studies (stage 2). The meta analysis of stage 1 and 2 data identified a novel locus, rs1265507 on 12q24, associated with percent density, adjusting for age and BMI (P = 4.43 * 10(-8)). We refined the 12q24 locus with 459 additional variants (stage 3) in a combined analysis of all three stages (n = 10 377) and confirmed that rs1265507 has the strongest association in the 12q24 region (P = 1.03 * 10(-8)). Rs1265507 is located between the genes TBX5 and TBX3, which are members of the phylogenetically conserved T-box gene family and encode transcription factors involved in developmental regulation. Understanding the mechanism underlying this association will provide insight into the genetics of breast tissue composition. PMID- 22532576 TI - Slow fitness recovery in a codon-modified viral genome. AB - Extensive synonymous codon modification of viral genomes appears to be an effective way of attenuating strains for use as live vaccines. An assumption of this method is that codon changes have individually small effects, such that codon-attenuated viruses will be slow to evolve back to high fitness (and thus to high virulence). The major capsid gene of the bacterial virus T7 was modified to have varying levels of suboptimal synonymous codons in different constructs, and fitnesses declined linearly with the number of changes. Adaptation of the most extreme design, with 182 codon changes, resulted in a slow fitness recovery by standards of previous experimental evolution with this virus, although fitness effects of substitutions were higher than expected from the average effect of an engineered codon modification. Molecular evolution during recovery was modest, and changes evolved both within the modified gene and outside it. Some changes within the modified gene evolved in parallel across replicates, but with no obvious explanation. Overall, the study supports the premise that codon-modified viruses recover fitness slowly, although the evolution is substantially more rapid than expected from the design principle. PMID- 22532577 TI - Article withdrawal: Proanthocyanidins from grape seeds inhibit expression of matrix metalloproteinases in human prostate carcinoma cells, which is associated with the inhibition of activation of MAPK and NFkappaB. PMID- 22532573 TI - The role of genetic breast cancer susceptibility variants as prognostic factors. AB - Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and the prognosis in a different patient group. One of the 11 SNPs, rs3803662 (TOX3) and none of the 62 candidate/GWAS SNPs were associated with OS and/or BCS at P<0.01. The genotypic-specific survival for rs3803662 suggested a recessive mode of action [hazard ratio (HR) of rare homozygous carriers=1.21; 95% CI: 1.09-1.35, P=0.0002 and HR=1.29; 95% CI: 1.12-1.47, P=0.0003 for OS and BCS, respectively]. This association was seen similarly in all analyzed tumor subgroups defined by nodal status, tumor size, grade and estrogen receptor. Breast tumor expression of these genes was not associated with prognosis. With the exception of rs3803662 (TOX3), there was no evidence that any of the SNPs associated with BC susceptibility were associated with the BC survival. Survival may be influenced by a distinct set of germline variants from those influencing susceptibility. PMID- 22532584 TI - Concordance among gene expression-based predictors for ER-positive breast cancer treated with adjuvant tamoxifen. AB - BACKGROUND: ER-positive (ER+) breast cancer includes all of the intrinsic molecular subtypes, although the luminal A and B subtypes predominate. In this study, we evaluated the ability of six clinically relevant genomic signatures to predict relapse in patients with ER+ tumors treated with adjuvant tamoxifen only. METHODS: Four microarray datasets were combined and research-based versions of PAM50 intrinsic subtyping and risk of relapse (PAM50-ROR) score, 21-gene recurrence score (OncotypeDX), Mammaprint, Rotterdam 76 gene, index of sensitivity to endocrine therapy (SET) and an estrogen-induced gene set were evaluated. Distant relapse-free survival (DRFS) was estimated by Kaplan-Meier and log-rank tests, and multivariable analyses were done using Cox regression analysis. Harrell's C-index was also used to estimate performance. RESULTS: All signatures were prognostic in patients with ER+ node-negative tumors, whereas most were prognostic in ER+ node-positive disease. Among the signatures evaluated, PAM50-ROR, OncotypeDX, Mammaprint and SET were consistently found to be independent predictors of relapse. A combination of all signatures significantly increased the performance prediction. Importantly, low-risk tumors (>90% DRFS at 8.5 years) were identified by the majority of signatures only within node-negative disease, and these tumors were mostly luminal A (78%-100%). CONCLUSIONS: Most established genomic signatures were successful in outcome predictions in ER+ breast cancer and provided statistically independent information. From a clinical perspective, multiple signatures combined together most accurately predicted outcome, but a common finding was that each signature identified a subset of luminal A patients with node-negative disease who might be considered suitable candidates for adjuvant endocrine therapy alone. PMID- 22532585 TI - Survival analysis and prognostic nomogram for patients undergoing resection of extrahepatic cholangiocarcinoma. AB - BACKGROUND: Tumor location of extrahepatic cholangiocarcinoma (CCA) might influence survival after resection. METHODS: A consecutive series of 175 patients who had undergone a potentially curative resection of extrahepatic CCA was analyzed. We calculated concordance indices of different constructed prognostic models for survival including TNM (tumour-node-metastasis) staging and developed a nomogram of the most sensitive model. RESULTS: Overall cancer-specific survival rates were 83%, 58%, and 26% at 1, 2, and 5 years, respectively. Cancer-specific survival according to location was 42% for proximal, 23% for mid, and 19% for distal CCA after 5 years. Tumor location was not an independent significant predictor (P = 0.06). A prognostic model using all potential prognostic variables predicted survival better compared with TNM staging (concordance index 0.65 versus 0.63). A reduced model containing only lymph node status, microscopically residual tumor status, and tumor differentiation grade, also outperformed TNM staging (concordance index 0.66). CONCLUSIONS: Tumor location of extrahepatic CCA does not independently predict cancer-specific survival after resection. We developed a nomogram, based on a prognostic model with lymph node status, microscopically residual tumor status of resection margins, and tumor differentiation grade, that predicted survival better than TNM staging. PMID- 22532586 TI - Basal-like breast cancer cells induce phenotypic and genomic changes in macrophages. AB - Basal-like breast cancer (BBC) is an aggressive subtype of breast cancer that has no biologically targeted therapy. The interactions of BBCs with stromal cells are important determinants of tumor biology, with inflammatory cells playing well recognized roles in cancer progression. Despite the fact that macrophage-BBC communication is bidirectional, important questions remain about how BBCs affect adjacent immune cells. This study investigated monocyte-to-macrophage differentiation and polarization and gene expression in response to coculture with basal-like versus luminal breast cancer cells. Changes induced by coculture were compared with changes observed under classical differentiation and polarization conditions. Monocytes (THP-1 cells) exposed to BBC cells in coculture had altered gene expression with upregulation of both M1 and M2 macrophage markers. Two sets of M1 and M2 markers were selected from the PCR profiles and used for dual immunofluorescent staining of BBC versus luminal cocultured THP-1s, and cancer-adjacent, benign tissue sections from patients diagnosed with BBCs or luminal breast cancer, confirming the differential expression patterns. Relative to luminal breast cancers, BBCs also increased differentiation of monocytes to macrophages and stimulated macrophage migration. Consistent with these changes in cellular phenotype, a distinct pattern of cytokine secretion was evident in macrophage-BBC cocultures, including upregulation of NAP-2, osteoprotegerin, MIG, MCP-1, MCP-3, and interleukin (IL) 1beta. Application of IL-1 receptor antagonist (IL-1RA) to cocultures attenuated BBC-induced macrophage migration. These data contribute to an understanding of the BBC-mediated activation of the stromal immune response, implicating specific cytokines that are differentially expressed in basal-like microenvironments and suggesting plausible targets for modulating immune responses to BBCs. PMID- 22532588 TI - Analysis of inorganic cations in honey by capillary zone electrophoresis with indirect UV detection. AB - An indirect UV detection method based on capillary electrophoresis was developed to separate eleven metal cations completely, including alkali, alkaline earth and transition metal, which are related to evaluate the quality of honey. The background electrolyte contains 15 mmol/L chromophore imidazole, and acetic acid (pH = 3.7), which functioned as pH adjustor and complexing reagent. The selected cations can be completely separated within 8 min under hydrodynamic mode injection with a running voltage of 20 kV at 25 degrees C. Limit of detection, linearity, reproducibility relative standard deviation of migration time and recoveries are in the range of 0.01-0.21 mg/L, 0.06-60.0 mg/L, 2.1-3.4% and 95.4 104.1%, respectively. The applicability of the method is shown by the analysis of honey samples, including a comparison with results of pretreatment and unpretreatment of eight samples. The results demonstrate that the developed method can conveniently be used in routine analysis of honey. PMID- 22532587 TI - Mouse tissues that undergo neoplastic progression after K-Ras activation are distinguished by nuclear translocation of phospho-Erk1/2 and robust tumor suppressor responses. AB - Mutation of K-Ras is a frequent oncogenic event in human cancers, particularly cancers of lungs, pancreas, and colon. It remains unclear why some tissues are more susceptible to Ras-induced transformation than others. Here, we globally activated a mutant oncogenic K-Ras allele (K-Ras(G12D)) in mice and examined the tissue-specific effects of this activation on cancer pathobiology, Ras signaling, tumor suppressor, DNA damage, and inflammatory responses. Within 5 to 6 weeks of oncogenic Ras activation, mice develop oral and gastric papillomas, lung adenomas, and hematopoietic hyperproliferation and turn moribund. The oral, gastric, and lung premalignant lesions display activated extracellular signal regulated kinases (Erk)1/2 and NF-kappaB signaling as well as activated tumor suppressor and DNA damage responses. Other organs such as pancreas, liver, and small intestine do not exhibit neoplastic progression within 6 weeks following K Ras(G12D) activation and do not show a potent tumor suppressor response. Even though robust Erk1/2 signaling is activated in all the tissues examined, the pErk1/2 distribution remains largely cytoplasmic in K-Ras(G12D)-refractory tissues (pancreas, liver, and intestines) as opposed to a predominantly nuclear localization in K-Ras(G12D)-induced neoplasms of lung, oral, and gastric mucosa. The downstream targets of Ras signaling, pElk-1 and c-Myc, are elevated in K Ras(G12D)-induced neoplastic lesions but not in K-Ras(G12D)-refractory tissues. We propose that oncogenic K-Ras-refractory tissues delay oncogenic progression by spatially limiting the efficacy of Ras/Raf/Erk1/2 signaling, whereas K-Ras responsive tissues exhibit activated Ras/Raf/Erk1/2 signaling, rapidly form premalignant tumors, and activate potent antitumor responses that effectively prevent further malignant progression. PMID- 22532589 TI - Role of different salts on cloud-point extraction of isoprocarb and promecarb insecticides followed by high-performance liquid chromatography. AB - The influence of salt additive on cloud point extraction (CPE) of isoprocarb and promecarb insecticides is described. Types of salt (Na(2)CO(3), CaCl(2), MgSO(4), Na(2)SO(4), NaHCO(3) and NaCl) and concentrations were studied. The extracted target compounds were analyzed using reversed phase high-performance liquid chromatography. Among the salts studied, Na(2)CO(3) was found to be the most effective salt for salting out of both insecticides, resulting in high extraction efficiency (>95%) and high enrichment factor of up to 18 compared to extraction without preconcentration. The optimum CPE conditions were 1.5% (w/v) Triton X 114, 3.0% (w/v) Na(2)CO(3), and 20-min equilibration at 45 degrees C. Under the selected conditions, the linear range of 0.05 to 3.0 mg/L was found for both analytes. The limits of detection for isoprocarb and promecarb were 10 and 20 ug/L, respectively. High intra-day (n = 9) and inter-day (n = 3 * 4 days) precisions with relative standard deviations <1% and <8% were obtained for retention time and peak area, respectively. The proposed method was successfully applied for the residue analysis of target compounds in beverages (i.e., fruit juice, vegetable juice and wine samples), which provided high recoveries (>80%, on average) for spiked samples at three levels (0.05, 0.10 and 0.50 mg/L). PMID- 22532590 TI - Molecularly imprinted stationary phase prepared by reverse micro-emulsion polymerization for selective recognition of gatifloxacin in aqueous media. AB - A new stationary phase for selectively recognizing gatifloxacin in aqueous media based on molecularly imprinted microspheres (MIMs) has been prepared by water/oil reverse micro-emulsion polymerization. The MIMs were prepared using gatifloxacin as the template, N, N'-methylenebisacrylamide as cross-linker and acrylamide and acryloyl-beta-CD (beta-CD-A, synthesized by ester reaction of acrylic acid with beta-CD) as combinatorial functional monomers. The surface morphology of MIMs was characterized by scanning electron microscopy. The properties of MIMs recognition for gatifloxacin in water were studied by adsorption kinetics, adsorption isotherms combined with Scatchard analysis and selective recognition experiments. The results showed that the synthesized MIMs had an excellent ability to selectively recognize gatifloxacin in aqueous media. MIMs were employed as the chromatographic stationary phase to successfully separate the template gatifloxacin from its analogues. Discovering the mechanism of the MIMs recognition revealed that the memory cavities in the surface of the MIMs and hydrophobic effects between the template and the cavities of the beta-CD residues were the primary contributions to the special recognition process. PMID- 22532591 TI - Determination of tryptophan in raw materials, rat brain and human plasma by RP HPLC technique. AB - This paper describes tryptophan (TRP) estimation in raw human plasma and rat brain by reversed-phase high-performance liquid chromatography (RP-HPLC). Estimation was carried out on a Purospher STAR C18 column using water acetonitrile (90:10 v/v, at pH 2.7) mixture at a rate of 1.5 mL/min as mobile phase. Eluents were monitored at 273 nm by an ultraviolet detector. The method was linear (R(2) > 0.999), precise (intra-day and inter-day precision <2%) in the range of 0.25-20 ug/mL. The detection and quantification limits were 0.0144 ug/mL and 0.0437 ug/mL, respectively. In human plasma, Day 1 and Day 2 precision were 0.054-2.29% and 1.66-3.7%; whereas precisions in rat brain were 1.23-2.3% and 0.677-4.2%, respectively. The method was applied to study TRP level in human smokers and in arthritic rat brain. An efficient RP-HPLC method was developed for TRP determination that worked for clinical and research purposes. PMID- 22532592 TI - On the need for a universal prospective ECG database. PMID- 22532593 TI - Risk of arrhythmia and sudden death in patients with asymptomatic preexcitation: a meta-analysis. AB - BACKGROUND: The incidence of sudden cardiac death (SCD) and the management of this risk in patients with asymptomatic preexcitation remain controversial. The purpose of this meta-analysis was to define the incidence of SCD and supraventricular tachycardia in patients with asymptomatic Wolff-Parkinson-White ECG pattern. METHODS AND RESULTS: We performed a systematic search of prospective, retrospective, randomized, or cohort English-language studies in EMBASE and Medline through February 2011. Studies reporting asymptomatic patients with preexcitation who did not undergo ablation were included. Twenty studies involving 1869 patients met our inclusion criteria. Participants were primarily male with a mean age ranging from 7 to 43 years. Ten SCDs were reported involving 11 722 person-years of follow-up. Seven studies originated from Italy and reported 9 SCDs. The risk of SCD is estimated at 1.25 per 1000 person-years (95% confidence interval [CI], 0.57-2.19). A total of 156 supraventricular tachycardias were reported involving 9884 person-years from 18 studies. The risk of supraventricular tachycardia was 16 (95% CI, 10-24) events per 1000 person years of follow-up. Children had numerically higher SCD (1.93 [95% CI, 0.57-4.1] versus 0.86 [95% CI, 0.28-1.75]; P=0.07) and supraventricular tachycardia (20 [95% CI, 12-31] versus 14 [95% CI, 6-25]; P=0.38) event rates compared with adults. CONCLUSION: The low incidence of SCD and low risk of supraventricular tachycardia argue against routine invasive management in most asymptomatic patients with the Wolff-Parkinson-White ECG pattern. PMID- 22532594 TI - Cannabinoid stability in authentic oral fluid after controlled cannabis smoking. AB - BACKGROUND: Defining cannabinoid stability in authentic oral fluid (OF) is critically important for result interpretation. There are few published OF stability data, and of those available, all employed fortified synthetic OF solutions or elution buffers; none included authentic OF following controlled cannabis smoking. METHODS: An expectorated OF pool and a pool of OF collected with QuantisalTM devices were prepared for each of 10 participants. Delta9 tetrahydrocannabinol (THC), 11-nor-9-carboxy-THC (THCCOOH), cannabidiol (CBD), and cannabinol (CBN) stability in each of 10 authentic expectorated and Quantisal collected OF pools were determined after storage at 4 degrees C for 1 and 4 weeks and at -20 degrees C for 4 and 24 weeks. Results within +/-20% of baseline concentrations analyzed within 24 h of collection were considered stable. RESULTS: All Quantisal OF cannabinoid concentrations were stable for 1 week at 4 degrees C. After 4 weeks at 4 degrees C, as well as 4 and 24 weeks at -20 degrees C, THC was stable in 90%, 80%, and 80% and THCCOOH in 89%, 40%, and 50% of Quantisal samples, respectively. Cannabinoids in expectorated OF were less stable than in Quantisal samples when refrigerated or frozen. After 4 weeks at 4 and -20 degrees C, CBD and CBN were stable in 33%-100% of Quantisal and expectorated samples; by 24 weeks at -20 degrees C, CBD and CBN were stable in <= 44%. CONCLUSIONS: Cannabinoid OF stability varied by analyte, collection method, and storage duration and temperature, and across participants. OF collection with a device containing an elution/stabilization buffer, sample storage at 4 degrees C, and analysis within 4 weeks is preferred to maximize result accuracy. PMID- 22532595 TI - A unique approach to business strategy as a means to enable change in global healthcare: a case study. PMID- 22532596 TI - Immunotherapy of cancer with 4-1BB. AB - 4-1BB (CD137), a member of the TNF receptor superfamily, is an activation-induced T-cell costimulatory molecule. Signaling via 4-1BB upregulates survival genes, enhances cell division, induces cytokine production, and prevents activation induced cell death in T cells. The importance of the 4-1BB pathway has been underscored in a number of diseases, including cancer. Growing evidence indicates that anti-4-1BB monoclonal antibodies possess strong antitumor properties, which in turn are the result of their powerful CD8+ T-cell activating, IFN-gamma producing, and cytolytic marker-inducing capabilities. In addition, combination therapy of anti-4-1BB with other anticancer agents, such as radiation, has robust tumor-regressing abilities against nonimmunogenic or poorly immunogenic tumors. Furthermore, the adoptive transfer of ex vivo anti-4-1BB-activated CD8+ T cells from previously tumor-treated animals efficiently inhibits progression of tumors in recipient mice that have been inoculated with fresh tumors. In addition, targeting of tumors with variants of 4-1BBL directed against 4-1BB also have potent antitumor effects. Currently, a humanized anti-4-1BB is in clinical trials in patients with solid tumors, including melanoma, renal carcinoma, and ovarian cancer, and so far seems to have a favorable toxicity profile. In this review, we discuss the basis of the therapeutic potential of targeting the 4-1BB-4-1BBL pathway in cancer treatment. PMID- 22532597 TI - STAT3 inhibition overcomes temozolomide resistance in glioblastoma by downregulating MGMT expression. AB - Glioblastoma multiforme (GBM) is one of the most aggressive human tumors with a poor prognosis. Current standard treatment includes chemotherapy with the DNA alkylating agent temozolomide concomitant with surgical resection and/or irradiation. However, a number of cases are resistant to temozolomide-induced DNA damage due to elevated expression of the DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT). Here, we show that upregulation of both MGMT and STAT3 was accompanied with acquisition of temozolomide resistance in the GBM cell line U87. Inactivation of STAT3 by inhibitor or short hairpin RNA (shRNA) downregulated MGMT expression in GBM cell lines. MGMT upregulation was not observed by the treatment of interleukin (IL)-6 which is a strong activator of STAT3. Contrarily, forced expressed MGMT could be downregulated by STAT3 inhibitor which was partially rescued by the proteasome inhibitor, MG132, suggesting the STAT3-mediated posttranscriptional regulation of the protein levels of MGMT. Immunohistochemical analysis of 44 malignant glioma specimens showed significant positive correlation between expression levels of MGMT and phosphorylated STAT3 (p-STAT3; P < 0.001, r = 0.58). Importantly, the levels of both MGMT and p-STAT3 were increased in the recurrence compared with the primary lesion in paired identical tumors of 12 cases. Finally, we showed that STAT3 inhibitor or STAT3 knockdown potentiated temozolomide efficacy in temozolomide resistant GBM cell lines. Therefore, STAT3 inhibitor might be one of the candidate reagents for combination therapy with temozolomide for patients with temozolomide-resistant GBM. PMID- 22532598 TI - Inhibition of ATR-dependent signaling by protoapigenone and its derivative sensitizes cancer cells to interstrand cross-link-generating agents in vitro and in vivo. AB - DNA damage caused during cancer treatment can rapidly activate the ataxia telangiectasia-mutated (ATM) and ATM and Rad3-related (ATR)-dependent phosphorylation of Chk2 and Chk1 kinases, which are hallmarks of the DNA damage response (DDR). Pharmacologic inhibition of ATR causes a synthetic lethal effect on ATM- or p53-defective cancers, suggesting that such inhibition is an effective way to improve the sensitivity of cancers to DNA-damaging agents. Here, both the natural compound protoapigenone (WYC02) and its synthetic derivative WYC0209 exhibited cytotoxic effects on various cancer cell lines. WYC02 causes chromosomal aberration in the mitotic spreads of Chinese hamster ovary cells. Interestingly, cancer cells did not exhibit typical DDR markers upon exposure to WYC02 and WYC0209 (WYCs). Further investigation into the molecular mechanisms of WYCs function revealed that they have a potential ability to inhibit DDR, particularly on activation of Chk1 and Fanconi anemia group D2 protein (FANCD2), but not Chk2. In this way, WYCs inhibited ATR-mediated DNA damage checkpoint and repair. Furthermore, when combined with the DNA cross-linking agent cisplatin, treatment with WYCs resulted in increased tumor sensitivity to interstrand cross link-generating agents both in vitro and in vivo. Our results therefore especially implicate WYCs in enhancing tumor chemosensitivity when the ATR checkpoint is constitutively active in states of oncogene-driven replicative stress or tolerance to DNA-interfering agents. PMID- 22532599 TI - Inducible silencing of protein kinase D3 inhibits secretion of tumor-promoting factors in prostate cancer. AB - Protein kinase D (PKD) acts as a major mediator of several signaling pathways related to cancer development. Aberrant PKD expression and activity have been shown in multiple cancers, and novel PKD inhibitors show promising anticancer activities. Despite these advances, the mechanisms through which PKD contributes to the pathogenesis of cancer remain unknown. Here, we establish a novel role for PKD3, the least studied member of the PKD family, in the regulation of prostate cancer cell growth and motility through modulation of secreted tumor-promoting factors. Using both a stable inducible knockdown cell model and a transient knockdown system using multiple siRNAs, we show that silencing of endogenous PKD3 significantly reduces prostate cancer cell proliferation, migration, and invasion. In addition, conditioned medium from PKD3-knockdown cells exhibits less migratory potential compared with that from control cells. Further analysis indicated that depletion of PKD3 blocks secretion of multiple key tumor-promoting factors including matrix metalloproteinase (MMP)-9, interleukin (IL)-6, IL-8, and GROalpha but does not alter mRNA transcript levels for these factors, implying impairment of the secretory pathway. More significantly, inducible depletion of PKD3 in a subcutaneous xenograft model suppresses tumor growth and decreases levels of intratumoral GROalpha in mice. These data validate PKD3 as a promising therapeutic target in prostate cancer and shed light on the role of secreted tumor-promoting factors in prostate cancer progression. PMID- 22532600 TI - Modulation of Akt/mTOR signaling overcomes sunitinib resistance in renal and prostate cancer cells. AB - Tyrosine kinase inhibitors exhibit impressive activity against advanced renal cell carcinoma. However, recent clinical studies have shown an equivocal response to sunitinib in patients with castration-resistant prostate cancer. The tumor suppressor PTEN acts as a gatekeeper of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR cell-survival pathway. Our experiments showed that PTEN expression inversely correlates with sunitinib resistance in renal and prostate cancer cells. Restoration of PTEN expression markedly increases sensitivity of tumor cells to sunitinib both in vitro and in vivo. In addition, pharmacologic manipulation of PI3K/Akt/mTOR signaling with PI3K/mTOR inhibitor, GDC-0980, mTOR inhibitor, temsirolimus, or pan-Akt inhibitor, GSK690693, was able to overcome sunitinib resistance in cancer cells. Our findings underscore the importance of PTEN expression in relation to sunitinib resistance and imply a direct cytotoxic effect by sunitinib on tumor cells in addition to its antiangiogenic actions. PMID- 22532601 TI - Thermal targeting of an acid-sensitive doxorubicin conjugate of elastin-like polypeptide enhances the therapeutic efficacy compared with the parent compound in vivo. AB - Elastin-like polypeptides (ELP) aggregate in response to mild hyperthermia, but remain soluble under normal physiologic conditions. ELP macromolecules can accumulate in solid tumors because of the enhanced permeability and retention effect. Tumor retention of ELPs can be further enhanced through hyperthermia induced aggregation of ELPs by local heating of the tumor. We evaluated the therapeutic potential of ELPs in delivering doxorubicin in the E0771 syngeneic mouse breast cancer model. The ELP-Dox conjugate consisted of a cell-penetrating peptide at the N-terminus and the 6-maleimidocaproyl hydrazone derivative of doxorubicin at the C-terminus of ELP. The acid-sensitive hydrazone linker ensured release of doxorubicin in the lysosomes/endosomes after cellular uptake of the drug conjugate. ELP-Dox dosed at 5 mg doxorubicin equivalent/kg, extended the plasma half-life of doxorubicin to 5.5 hours. In addition, tumor uptake of ELP Dox increased 2-fold when hyperthermia was applied, and was also enhanced compared to free doxorubicin. Although high levels of doxorubicin were found in the heart of animals treated with free doxorubicin, no detectable levels of doxorubicin were found in ELP-Dox-treated animals, indicating a correlation between tumor targeting and reduction of potential cardiac toxicity by ELP-Dox. At an optimal dose of 12 mg doxorubicin equivalent/kg, ELP-Dox in combination with hyperthermia induced a complete tumor growth inhibition, which was distinctly superior to free drug that only moderately inhibited tumor growth. In summary, our findings show that thermal targeting of ELP increases the potency of doxorubicin underlying the potential of exploiting ELPs to enhance the therapeutic efficacy of conventional anticancer drugs. PMID- 22532602 TI - CDK-4 inhibitor P276 sensitizes pancreatic cancer cells to gemcitabine-induced apoptosis. AB - Despite advances in molecular pathogenesis, pancreatic cancer remains a major unsolved health problem. It is a rapidly invasive, metastatic tumor that is resistant to standard therapies. The phosphatidylinositol-3-kinase/Akt and mTOR signaling pathways are frequently dysregulated in pancreatic cancer. Gemcitabine is the mainstay treatment for metastatic pancreatic cancer. P276 is a novel CDK inhibitor that induces G(2)/M arrest and inhibits tumor growth in vivo models. Here, we determined that P276 sensitizes pancreatic cancer cells to gemcitabine induced apoptosis, a mechanism-mediated through inhibition of Akt-mTOR signaling. In vitro, the combination of P276 and gemcitabine resulted in a dose- and time dependent inhibition of proliferation and colony formation of pancreatic cancer cells but not with normal pancreatic ductal cells. This combination also induced apoptosis, as seen by activated caspase-3 and increased Bax/Bcl2 ratio. Gene profiling studies showed that this combination downregulated Akt-mTOR signaling pathway, which was confirmed by Western blot analyses. There was also a downregulation of VEGF and interleukin-8 expression suggesting effects on angiogenesis pathway. In vivo, intraperitoneal administration of the P276-Gem combination significantly suppressed the growth of pancreatic cancer tumor xenografts. There was a reduction in CD31-positive blood vessels and reduced VEGF expression, again suggesting an effect on angiogenesis. Taken together, these data suggest that P276-Gem combination is a novel potent therapeutic agent that can target the Akt-mTOR signaling pathway to inhibit both tumor growth and angiogenesis. PMID- 22532603 TI - Proteasome inhibition blocks NF-kappaB and ERK1/2 pathways, restores antigen expression, and sensitizes resistant human melanoma to TCR-engineered CTLs. AB - Adoptive cell transfer (ACT) of ex vivo engineered autologous lymphocytes encoding high-affinity MART-1/HLA-A*0201-specific T-cell receptor (TCR)alpha/beta chains (F5 CTL), densely infiltrate into sites of metastatic disease, mediating dramatic but partial clinical responses in patients with melanoma. We hypothesized that MART-1 downmodulation in addition to aberrant apoptotic/survival signaling could confer resistance to death signals delivered by transgenic CTLs. To explore this hypothesis, we established an in vitro model of resistant (R) lines from MART-1(+)/HLA-A*0201(+) F5 CTL-sensitive parental (P) lines under serial F5 CTL-selective pressure. We have recently reported that several melanoma R lines, while retaining MART-1 expression, exhibited constitutive NF-kappaB activation and overexpression of NF-kappaB-dependent resistance factors. Another established melanoma cell line M244, otherwise sensitive to F5 CTL, yielded R lines after serial F5 CTL-selective pressure, which had both reduced MART-1 expression levels, thus, could not be recognized, and were resistant to CTL-delivered apoptotic death signals. The proteasome inhibitor bortezomib blocked NF-kappaB activity, decreased phospho-ERK1/2, increased phospho-c-jun-NH(2)-kinase (p-JNK) levels, reduced expression of resistance factors, restored MART-1 expression to sufficient levels, which in combination allowed M244R lines be sensitized to F5 CTL killing. These findings suggest that proteasome inhibition in immune resistant tumors can restore proapoptotic signaling and improve tumor antigen expression. PMID- 22532604 TI - The leaf reticulate mutant dov1 is impaired in the first step of purine metabolism. AB - A series of reticulated Arabidopsis thaliana mutants were previously described. All mutants show a reticulate leaf pattern, namely green veins on a pale leaf lamina. They have an aberrant mesophyll structure but an intact layer of bundle sheath cells around the veins. Here, we unravel the function of the previously described reticulated EMS-mutant dov1 (differential development of vascular associated cells 1). By positional cloning, we identified the mutated gene, which encodes glutamine phosphoribosyl pyrophosphate aminotransferase 2 (ATase2), an enzyme catalyzing the first step of purine nucleotide biosynthesis. dov1 is allelic to the previously characterized cia1-2 mutant that was isolated in a screen for mutants with impaired chloroplast protein import. We show that purine derived total cytokinins are lowered in dov1 and crosses with phytohormone reporter lines revealed differential reporter activity patterns in dov1. Metabolite profiling unraveled that amino acids that are involved in purine biosynthesis are increased in dov1. This study identified the molecular basis of an established mutant line, which has the potential for further investigation of the interaction between metabolism and leaf development. PMID- 22532605 TI - Signaling role of sucrose metabolism in development. PMID- 22532606 TI - Effects of combined epidermal growth factor, brain-derived neurotrophic factor and insulin-like growth factor-1 on human oocyte maturation and early fertilized and cloned embryo development. AB - BACKGROUND: Human cloned blastocysts generated from oocytes following in vitro maturation (IVM) are a potential resource for embryonic stem cells (ESC) with homologous immune systems. The purpose of this study was to evaluate the effects of multiple growth factors [epidermal growth factor (EGF), brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1)] on human oocyte maturation, early embryo development, blastocyst formation and ESC line generation. METHODS: Patients (n= 344) undergoing IVF owing to male factor infertility were enrolled in this study. Metaphase II oocytes were separated into four grades based on their morphology. Spindle assembly from IVM oocytes with or without growth factor treatment was assessed by immunostaining. Piezo-assisted micromanipulation technology was used to produce fertilized (ICSI) and cloned [(somatic cell nuclear transfer (SCNT)] embryos. Embryos received four different growth factor treatments; embryo development rates from pronuclear to blastocyst stage and embryo grading (for quality) at the 8-cell stage were analyzed. The presence of receptors on human cumulus cells and IVM oocytes was assessed by immunofluorescence. The blastocysts generated from fertilized and cloned embryos were used for ESC derivation. RESULTS: The combination of EGF, BDNF and IGF-1 can effectively increase oocyte maturation rate in vitro, and significantly improve the oocyte quality in terms of morphology and normal spindle levels (P< 0.05). Also, the developmental competence of fertilized oocytes to 8-cell and blastocyst stages was improved by the addition of growth factors (P< 0.05). However, there were no significant differences among the four groups in 8-cell grading. Blastocyst formation in cloned embryos cultured with the three growth factors was higher than the control group (23.1 versus 4.3%, P< 0.05). Receptors for the three growth factors were present in cumulus cells and IVM oocytes, and four human ESC lines were derived from fertilized blastocysts but none from cloned blastocysts. CONCLUSION: This study demonstrated that EGF, BDNF and IGF-1 can improve oocyte maturation rate and quality in vitro, and consequently increase early embryo development and blastocyst formation, which is very beneficial in improving the reprogramming efficiency of SCNT. The present study has identified a valuable culture system for IVM and cloned human embryos, potentially using these embryos to derive human therapeutic ESC. PMID- 22532607 TI - Deep phylogeny and character evolution in Thecostraca (Crustacea: Maxillopoda). AB - The thecostracans include the Facetotecta, Ascothoracida, and Cirripedia and show great diversity in both morphology and biology. This makes them ideal models for studying evolutionary adaptations of the larval and adult body-plan, lifestyle, and reproduction. Surprisingly, despite all the work published since Darwin's seminal monographs, few studies have tested evolutionary hypotheses about Thecostraca within a phylogenetic context. In this review, we combine a Bayesian phylogenetic method and multilocus sequence data to reconstruct the evolutionary history of 12 key thecostracan phenotypic traits associated with their lifecycle, larval biology, reproduction, and adult morphology. Our analyses show that thecostracan biological diversity resulted both from unique innovations and from events of convergence. This provides an opportunity to reevaluate previous classifications of the Thecostraca and the theories relating to the origin and diversification of this taxon. PMID- 22532608 TI - Rapid identification of high-confidence taxonomic assignments for metagenomic data. AB - Determining the taxonomic lineage of DNA sequences is an important step in metagenomic analysis. Short DNA fragments from next-generation sequencing projects and microbes that lack close relatives in reference sequenced genome databases pose significant problems to taxonomic attribution methods. Our new classification algorithm, RITA (Rapid Identification of Taxonomic Assignments), uses the agreement between composition and homology to accurately classify sequences as short as 50 nt in length by assigning them to different classification groups with varying degrees of confidence. RITA is much faster than the hybrid PhymmBL approach when comparable homology search algorithms are used, and achieves slightly better accuracy than PhymmBL on an artificial metagenome. RITA can also incorporate prior knowledge about taxonomic distributions to increase the accuracy of assignments in data sets with varying degrees of taxonomic novelty, and classified sequences with higher precision than the current best rank-flexible classifier. The accuracy on short reads can be increased by exploiting paired-end information, if available, which we demonstrate on a recently published bovine rumen data set. Finally, we develop a variant of RITA that incorporates accelerated homology search techniques, and generate predictions on a set of human gut metagenomes that were previously assigned to different 'enterotypes'. RITA is freely available in Web server and standalone versions. PMID- 22532609 TI - Solution-state structure of an intramolecular G-quadruplex with propeller, diagonal and edgewise loops. AB - We herein report on the formation and high-resolution NMR solution-state structure determination of a G-quadruplex adopted by d[G(3)ATG(3)ACACAG(4)ACG(3)] comprised of four G-tracts with the third one consisting of four guanines that are intervened with non-G streches of different lengths. A single intramolecular antiparallel (3+1) G-quadruplex exhibits three stacked G-quartets connected with propeller, diagonal and edgewise loops of different lengths. The propeller and edgewise loops are well structured, whereas the longer diagonal loop is more flexible. To the best of our knowledge, this is the first high-resolution G quadruplex structure where all of the three main loop types are present. PMID- 22532611 TI - Seeking other sources of information. PMID- 22532612 TI - Re: Franz T, Vogelin E. Aseptic tissue necrosis and chronic inflammation after irrigation of penetrating hand wounds using Octenisept(R). J Hand Surg Eur. 2012, 37: 61-4. PMID- 22532610 TI - The DNA dioxygenase ALKBH2 protects Arabidopsis thaliana against methylation damage. AB - The Escherichia coli AlkB protein (EcAlkB) is a DNA repair enzyme which reverses methylation damage such as 1-methyladenine (1-meA) and 3-methylcytosine (3-meC). The mammalian AlkB homologues ALKBH2 and ALKBH3 display EcAlkB-like repair activity in vitro, but their substrate specificities are different, and ALKBH2 is the main DNA repair enzyme for 1-meA in vivo. The genome of the model plant Arabidopsis thaliana encodes several AlkB homologues, including the yet uncharacterized protein AT2G22260, which displays sequence similarity to both ALKBH2 and ALKBH3. We have here characterized protein AT2G22260, by us denoted ALKBH2, as both our functional studies and bioinformatics analysis suggest it to be an orthologue of mammalian ALKBH2. The Arabidopsis ALKBH2 protein displayed in vitro repair activities towards methyl and etheno adducts in DNA, and was able to complement corresponding repair deficiencies of the E. coli alkB mutant. Interestingly, alkbh2 knock-out plants were sensitive to the methylating agent methylmethanesulphonate (MMS), and seedlings from these plants developed abnormally when grown in the presence of MMS. The present study establishes ALKBH2 as an important enzyme for protecting Arabidopsis against methylation damage in DNA, and suggests its homologues in other plants to have a similar function. PMID- 22532613 TI - Cochrane corner: water for wound cleansing. AB - BACKGROUND: Although various solutions have been recommended for cleansing wounds, normal saline is favoured as it is an isotonic solution and does not interfere with the normal healing process. Tap water is commonly used in the community for cleansing wounds because it is easily accessible, efficient and cost effective; however, there is an unresolved debate about its use. OBJECTIVES: The objective of this review was to assess the effects of water compared with other solutions for wound cleansing. SEARCH STRATEGY: For this update we searched the Cochrane Wounds Group Specialised Register (Searched 22 February 2010); The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2010 Issue 1); Ovid MEDLINE - 2007 to February Week 2 2010; Ovid MEDLINE - In Process & Other Non-Indexed Citations (Searched19 February 2010); Ovid EMBASE - 2007 to 2010 Week 06; EBSCO CINAHL - 2007 to 22 February 2010. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials that compared the use of water with other solutions for wound cleansing were eligible for inclusion. Additional criteria were outcomes that included objective or subjective measures of wound infection or healing. DATA COLLECTION AND ANALYSIS: Two review authors independently carried out trial selection, data extraction and quality assessment. We settled differences in opinion by discussion. We pooled some data using a random-effects model. PMID- 22532614 TI - Competitive flow between a vein and an arterial graft at transit-time flow measurement. AB - We report the intraoperative finding, at a transit-time flow measurement, of competitive flow between a venous and an arterial graft in a 72-year old woman who underwent uncomplicated coronary artery bypass grafting 3. The blood flow in the left internal mammary artery (LIMA) improved only after temporary occlusion of the saphenous vein graft (SVG) anastomosed to the first diagonal (D1), demonstrating the presence of competitive flow from the SVG-D1 anastomosis into the LIMA-left anterior descending coronary artery (LAD) system. Interestingly the two target vessels suffered from separate critical lesions. The patient's haemodynamics remained stable throughout and no further action was taken. Her recovery was uneventful and the patient was discharged home on postoperative day 6. This case raised questions about the cost benefit of grafting a diagonal target even when it appeared to be disconnected from the LAD on a coronary angiogram. PMID- 22532615 TI - Familial Mediterranean FeVer gene (MEFV) mutations as a modifier of systemic lupus erythematosus. AB - The objective of this study was to assess the prevalence of the Mediterranean FeVer (MEFV) gene mutations in systemic lupus erythematosus (SLE) patients and their effect on organ involvement, as well as disease activity and severity. The frequencies of three familial Mediterranean fever-related MEFV gene mutations (M694V, V726A and E148Q) were investigated in 70 SLE patients. Organ involvement, Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores were correlated with mutation carriage. Eleven of 70 patients (15.7%) were found to carry an MEFV mutation. A single patient harbored two mutations, E148Q and V726A, without overt familial Mediterranean fever while the rest were heterozygous carriers. Four of the 11 carried an M694V mutation, four carried V726A and two carried E148Q. The majority of MEFV mutation carriers were Sephardic while non-carriers were mainly of Ashkenazi origin (72.7% vs. 45.7% and 47.4% vs. 9.1%, respectively, p = 0.02). SLE onset was significantly earlier in MEFV carriers (27.6 +/- 9.7 vs. 38.2 +/- 15.5 years, in carriers vs. non-carriers, p = 0.02). Hematologic and serologic parameters were comparable among mutation carriers and non-carriers. Febrile episodes were more common among MEFV mutation carriers (45.4% vs. 15.2%, p = 0.035) and there was a trend for excess episodes of pleuritis as well (54.5% vs. 23.7%, p = 0.06 in carriers vs. non-carriers, respectively). The frequency of secondary anti phospholipid antibody syndrome was equivalent among the groups. Conversely, compound urinary abnormalities and renal failure was not observed among MEFV carriers yet was present in 33.4% and 18.6% of non-carriers (p = 0.027 and 0.19, respectively). SLICC damage index and SLEDAI activity index did not differ significantly between the groups. MEFV mutation carriage appears to modify the SLE disease phenotype in that it contributes to an excess of inflammatory manifestations such as fever and pleuritis on the one hand, while thwarting more severe renal involvement on the other. PMID- 22532616 TI - Contrast-enhanced ultrasound with SonoVue could accurately assess the renal microvascular perfusion in diabetic kidney damage. AB - OBJECTIVE: The aim of this study was to investigate the clinical significance of real-time gray-scale contrast-enhanced ultrasound (CEUS) through evaluating renal microvascular perfusion in diabetic kidney damage. METHODS: Diabetic patients (aged: 62.5+/-7.2, n=33) were divided into Group A with chronic kidney disease (CKD) Stages I and II (n=19) and Group B (n=14) with CKD Stages IV and V. Twenty one healthy adults were selected as control group. The real-time and dynamic imaging from renal cortex was performed using contrast-enhanced ultrasound with SonoVue. The outage time-intensity curves (TICs) with >85% goodness-of-fit index were chosen for the analysis of basic intensity, intensity increment (A1), arriving time (AT), time to peak (TTP), mean transit time, peak intensity (PI) and total area under the curve (AUC). RESULTS: (i) After intravenous injection of a contrast agent, the renal artery, cortex, pyramid and renal vein were clearly displayed in sequence. (ii) TIC of renal cortical Perfusion in all groups showed an asymmetrical single-peak curve, which has an obvious ascending slope, peak and descending slope. The ascending slope was steep, whereas the descending slope was flat. However, the ascending slope in Group A and B was flatter than that in the control group. (iii) Compared to the control group, AT and TTP were all markedly prolonged but A1 and PI were significantly decreased in Group A and B (P<0.05). In Group A, the AUC had a trend of increase; however, the area under the ascending slope (AUC1), area under the descending slope (AUC2) and AUC were all decreased in Group B (P<0.05). (iv) AUC positively correlated with glomerular filtration rate (GFR) (r=0.472, P=0.01), but TTP did not correlate well with GFR (r=0.262, P=0.177). CONCLUSIONS: CEUS could accurately assess renal microvascular perfusion in a real-time and dynamic manner. PI, TTP and AUC could be used for the diagnosis of the renal microvascular damage in early and late stage diabetic patients. CEUS is a safe, noninvasive and simple technique to detect the severity of kidney microvascular perfusion deficits. PMID- 22532617 TI - Translating chronic kidney disease epidemiology into patient care--the individual/public health risk paradox. AB - BACKGROUND: Applying the Kidney Disease Outcomes Quality Initiative definitions of chronic kidney disease (CKD), it appears that CKD is common. The increased recognition of CKD has brought with it the clinical challenge of translating into practice the implications for the patient and for service planning. To understand the clinical relevance and translate that into information to support individual patient care and service planning, we explored clinical outcomes in a large British CKD cohort, identified through routine opportunistic testing, with a 6 year follow-up (~ 13,000 patient-years). METHODS: A cohort had previously been identified with CKD-sustained reduced eGFR over at least 3 months and case note review. Six-year (13,339 patient-years) follow-up for renal replacement therapy (RRT) initiation and death was achieved through data linkage. Age- and sex specific mortality rates were compared to the general population. RESULTS: Of 3414 individuals (most Stage 3b-5), median age 78.6 years, followed for 13 339 patient-years, 170 (5%) initiated RRT and 2024 (59%) died without initiating RRT. RRT initiation rates decreased with age from 14.33 to 0.65 per 100 patient-years among those aged 15-25 and 75-85 years at baseline but the actual numbers initiating RRT increased from 6 to 34, respectively. RRT initiation rates were lower for female sex, absence of macroalbuminuria and less advanced CKD stage. Mortality rates increased with age from 2 to 34 per 100 patient-years for those aged 15-45 and > 85 years at baseline, an excess of 2 and 17 per 100 patient years over that of the general population, respectively. However, the increase in relative risk was 19-fold for those aged 15-45 years and just 2-fold in those > 85 years. These data have been converted into simple tools for considering individual patients' risk and informing service planning. CONCLUSIONS: The contrast between relative and absolute risk for both RRT initiation and mortality by age group illustrates the difficulties for planning services. The challenge that now faces clinicians is how to appropriately identify which elderly patients with CKD are at high risk of poor outcome. PMID- 22532618 TI - Perioperative pain relief by a COX-2 inhibitor affects ileal repair and provides a model for anastomotic leakage in the intestine. AB - The authors examined the potential of the cyclooxygenase 2 (COX-2) inhibitor carprofen to reproducibly induce anastomotic leakage. In experiment 1, an anastomosis was constructed in both ileum and colon of 20 rats, and they were given carprofen (5 mg/kg subcutaneously every 24 hours) or buprenorphine (0.02 mg/kg subcutaneously every 12 hours). In another 20 rats an anastomosis was constructed in either ileum or colon, and all received carprofen (experiment 2). Animals were sacrificed after 3 days. In experiment 1, the ileal dehiscence rate was 60% in the carprofen group and 0% in the buprenorphine group (P = .0108). Colonic anastomoses in both groups remained patent. In experiment 2, the anastomotic leakage rate was 80% in ileum and 0% in colon. Thus, COX-2 inhibitors can severely interfere with intestinal healing, particularly in the ileum. Perioperative administration of carprofen yields a unique model for anastomotic leakage, which allows translational research on the effectiveness of perisuture line reinforcement. PMID- 22532625 TI - Splicing variant of AIMP2 as an effective target against chemoresistant ovarian cancer. AB - Chemoresistance is a main cause for the failure of cancer management and intensive investigation is on-going to control chemoresistant (CR) cancers. Although NF-kappaB has been suggested as one of the potential targets to alleviate chemoresistance of epithelial ovarian cancer (EOC), direct targeting of NF-kappaB may result in an unexpected effect due to the complex regulatory network via NF-kappaB. Here we show that AIMP2-DX2, a splicing variant of tumor suppressor AIMP2, can be a therapeutic target to control CR EOC. AIMP2-DX2 was often highly expressed in CR EOC both in vitro and in vivo. AIMP2-DX2 compromised the tumor necrosis factor alpha-dependent pro-apoptotic activity of AIMP2 via the competitive inhibition of AIMP2 binding to TRAF2 that plays a pivotal role in the regulation of NF-kappaB. The direct delivery of siRNA against AIMP2-DX2 into abdominal metastatic tumors of ovarian cancer using a microneedle converged on microendoscopy significantly suppressed the growth rate of tumors. The treated cancer tissues showed an enhanced apoptosis and the decreased TRAF2 level. Thus, we suggest that the downregulation of AIMP2-DX2 can be a potent adjuvant therapeutic approach for CR EOC that resulted from an aberrant activity of NF kappaB. PMID- 22532626 TI - Regulation of the distribution and function of [(125)I]epibatidine binding sites by chronic nicotine in mouse embryonic neuronal cultures. AB - Chronic nicotine produces up-regulation of alpha4beta2* nicotinic acetylcholine receptors (nAChRs) (* denotes that an additional subunit may be part of the receptor). However, the extent of up-regulation to persistent ligand exposure varies across brain regions. The aim of this work was to study the cellular distribution and function of nAChRs after chronic nicotine treatment in primary cultures of mouse brain neurons. Initially, high-affinity [(125)I]epibatidine binding to cell membrane homogenates from primary neuronal cultures obtained from diencephalon and hippocampus of C57BL/6J mouse embryos (embryonic days 16-18) was measured. An increase in alpha4beta2*-nAChR binding sites was observed in hippocampus, but not in diencephalon, after 24 h of treatment with 1 MUM nicotine. However, a nicotine dose-dependent up-regulation of approximately 3.5- and 0.4-fold in hippocampus and diencephalon, respectively, was found after 96 h of nicotine treatment. A significant fraction of total [(125)I]epibatidine binding sites in both hippocampus (45%) and diencephalon (65%) was located on the cell surface. Chronic nicotine (96 h) up-regulated both intracellular and surface binding in both brain regions without changing the proportion of those binding sites compared with control neurons. The increase in surface binding was not accompanied by an increase in nicotine-stimulated Ca(2+) influx, suggesting persistent desensitization or inactivation of receptors at the plasma membrane occurred. Given the differences observed between hippocampus and diencephalon neurons exposed to nicotine, multiple mechanisms may play a role in the regulation of nAChR expression and function. PMID- 22532627 TI - Pyroglutamyl peptidase II inhibition enhances the analeptic effect of thyrotropin releasing hormone in the rat medial septum. AB - Thyrotropin-releasing hormone (TRH; pGlu-His-Pro-NH(2)) has multiple, but transient, homeostatic functions in the brain. It is hydrolyzed in vitro by pyroglutamyl peptidase II (PPII), a narrow specificity ectoenzyme with a preferential localization in the brain, but evidence that PPII controls TRH communication in the brain in vivo is scarce. We therefore studied in male Wistar rats the distribution of PPII mRNA in the septum and the consequence of PPII inhibition on the analeptic effect of TRH injected into the medial septum. Twelve to 14% of cell profiles expressed PPII mRNA in the medial septum-diagonal band of Broca; in this region the specific activity of PPII was relatively high. Twenty to 35% of PPII mRNA-labeled profiles were positive for TRH-receptor 1 (TRH-R1) mRNA. The intramedial septum injection of TRH reduced, in a dose-dependent manner, the duration of ethanol-induced loss of righting reflex (LORR). Injection of the PPII inhibitor pGlu-Asn-Pro-7-amido-4-methylcoumarin into the medial septum enhanced the effect of TRH. The injection of a phosphinic TRH analog, a higher-affinity inhibitor of PPII, diminished the duration of LORR by itself. In contrast, the intraseptal injection of pGlu-Asp-Pro-NH(2), a peptide that did not inhibit PPII activity, or an inhibitor of prolyl oligopeptidase did not change the duration of LORR. We conclude that in the medial septum PPII activity may limit TRH action, presumably by reducing the concentration of TRH in the extracellular fluid around cells coexpressing PPII and TRH-R1. PMID- 22532628 TI - Prevalence of coronary heart disease and cardiovascular risk factors in a national cross-sectional cohort study of systemic sclerosis. AB - OBJECTIVES: To determine the prevalence of coronary heart disease (CHD) and cardiovascular risk factors in a well-characterised cohort of systemic sclerosis (SSc) patients, and to compare this with the general population. METHODS: A cross sectional study of the prevalence of CHD and cardiovascular risk factors in participants in the Australian Scleroderma Cohort Study was performed. Controls were drawn from the 2007-8 National Health Survey (NHS) and the Australian Diabetes, Obesity and Lifestyle Study (AusDiab). OR and 95% CI were calculated to determine the prevalence of CHD and cardiovascular risk factors in SSc patients compared with controls. RESULTS: Data were available for 850 SSc patients (86% female), 15 787 NHS participants (53% female) and 8802 AusDiab participants (56% female). Adjusted for age and gender, the OR of CHD in SSc patients was 1.9 (95% CI 1.4 to 2.4) compared with controls from AusDiab and 2.0 (95% CI 1.5 to 2.5) compared with controls from the NHS. The OR of CHD increased to 3.2 (95% CI 2.3 to 4.5) for SSc patients compared with controls from AusDiab after further adjustment for cardiovascular risk factors. Hypercholesterolaemia, diabetes mellitus and obesity were significantly less prevalent in the SSc cohort than in AusDiab. Within the SSc cohort, the presence of pulmonary arterial hypertension was associated with CHD. CONCLUSIONS: This is the first report of an increased prevalence of CHD in SSc patients. Further studies are required to determine the relative contribution of scleroderma-specific factors such as microvascular disease to the development of CHD. PMID- 22532629 TI - Cardiovascular comorbidities in patients with psoriatic arthritis: a systematic review. AB - OBJECTIVE: Data regarding cardiovascular comorbidity and cardiovascular risk factors in patients with psoriatic arthritis (PsA) are limited. To evaluate the cardiovascular risk profile, a systematic literature search was performed to provide an extensive summary of all studies available on cardiovascular risk in PsA. METHODS: Medline, EMBASE and the Cochrane library were searched from January 1966 to April 2011 for English language articles on data concerning cardiovascular diseases and cardiovascular risk factors in PsA. Review articles, case reports and studies on psoriasis alone were excluded. RESULTS: Twenty-eight articles were included in this review. Studies on all-cause mortality revealed mixed results. Available data on cardiovascular disease appeared more consistent, indicating an increased cardiovascular mortality and morbidity in PsA. Commensurate with this, surrogate markers of subclinical atherosclerosis, arterial stiffness and cardiovascular risk factors, for example hypertension, dyslipidaemia, obesity and metabolic-related factors, were more prominent in PsA compared with controls. Suppression of inflammation was linked with a favourable effect on cardiovascular surrogate markers, for example carotid intima media thickness and endothelial dysfunction, in several (un)controlled studies. CONCLUSION: Most studies point towards an increased cardiovascular risk in PsA, broadly on a par with the risk level in rheumatoid arthritis, emphasising the need for similar cardiovascular risk management in both conditions. Further studies are needed to indicate whether inflammatory suppression or modification of traditional cardiovascular risk factors, or both, will reduce cardiovascular risk. PMID- 22532630 TI - Rapid radiological progression in the first year of early rheumatoid arthritis is predictive of disability and joint damage progression during 8 years of follow up. AB - OBJECTIVE: Several prediction models for rapid radiological progression (RRP) in the first year of rheumatoid arthritis have been designed to aid rheumatologists in their choice of initial treatment. The association was assessed between RRP and disability and joint damage progression in 8 years. METHODS: Patients from the BeSt cohort were used. RRP was defined as an increase of >=5 points in the Sharp/van der Heijde score (SHS) in year 1. Functional ability over 8 years, measured with the health assessment questionnaire (HAQ), was compared for patients with and without RRP using linear mixed models. Joint damage progression from years 1 to 8 was compared using logistic regression analyses. RESULTS: RRP was observed in 102/465 patients. Over 8 years, patients with RRP had worse functional ability: difference in HAQ score 0.21 (0.14 after adjustment for disease activity score (over time)). RRP was associated with joint damage progression >=25 points in SHS in years 1-8: OR 4.6. CONCLUSION: RRP in year 1 is a predictor of worse functional ability over 8 years, independent of baseline joint damage and disease activity. Patients with RRP have more joint damage progression in subsequent years. RRP is thus a relevant outcome on which to base the initial treatment decision. PMID- 22532631 TI - IL-17 and tumour necrosis factor alpha combination induces a HIF-1alpha-dependent invasive phenotype in synoviocytes. AB - OBJECTIVES: To examine the effect of interleukin-17 (IL-17) on rheumatoid arthritis (RA) synoviocyte migration and invasiveness. METHODS: IL-17A and tumour necrosis factor alpha (TNFalpha)-induced messenger RNA expression in RA synoviocytes was analysed using Affymetrix U133A microarrays. The capacity of IL 17 alone or in combination with TNFalpha to induce synoviocyte migration and invasion was tested using Boyden and transwell Matrigel invasion chambers. A functional DNA binding assay was used to evaluate the regulation of the key hypoxia-related gene hypoxia-inducible factor 1 (HIF-1alpha) expression and activation. The role of metalloproteinase 2 (MMP2) in IL-17-induced invasiveness was assessed using small interfering RNA. Hypoxia pathway gene expression was measured in the blood of RA patients and healthy volunteers using Affymetrix microarrays. RESULTS: Among the genes induced by IL-17A in RA synoviocytes, a molecular pattern of inflammation hypoxia-related genes, including CXC chemokine receptor 4 (CXCR4) and MMP2 was identified. Using immunofluorescence microscopy, the expression of CXCR4 was confirmed on synoviocytes. IL-17A and TNFalpha induced synoviocyte migration and invasion through a CXCR4-dependent mechanism with a synergistic effect. Their combination activated HIF-1alpha through the nuclear factor kappaB pathway. IL-17 enhanced invasion through MMP2 induction as demonstrated using siRNA. Finally, hypoxia genes were overexpressed in the blood of RA patients. CONCLUSION: IL-17A, specifically when combined with TNFalpha may contribute to the progression of RA, notably through their effect on synoviocyte aggressiveness. Part of this effect results from activation of the CXCR4/stromal cell-derived factor 1 and hypoxia-mediated pathways. PMID- 22532632 TI - Adiponectin isoforms: a potential therapeutic target in rheumatoid arthritis? AB - OBJECTIVES: Several clinical studies have suggested the adipocytokine adiponectin is involved in the progression of rheumatoid arthritis (RA). From this point of view, adiponectin might present a new therapeutic target. However, as adiponectin also exerts beneficial effects in the human organism, a strategy that would allow its detrimental effects to be abolished while maintaining the positive effects would be highly favourable. To elucidate such a strategy, the authors analysed whether the different adiponectin isoforms induce diverging effects, especially with regard to rheumatoid arthritis synovial fibroblasts (RASF), a central cell type in RA pathogenesis capable of invading into and destroying cartilage. METHODS: Affymetrix microarrays were used to screen for changes in gene expression of RASF. Messenger RNA levels were quantified by real-time PCR, protein levels by immunoassay. The migration of RASF and primary human lymphocytes was analysed using a two-chamber migration assay. RESULTS: In RASF, the individual adiponectin isoforms induced numerous genes/proteins relevant in RA pathogenesis to clearly different extents. In general, the most potent isoforms were the high molecular weight/middle molecular weight isoforms and the globular isoform, while the least potent isoform was the adiponectin trimer. The chemokines secreted by RASF upon adiponectin stimulation resulted in an increased migration of RASF and lymphocytes. CONCLUSION: The results clearly suggest a pro inflammatory and joint-destructive role of all adiponectin isoforms in RA pathophysiology, indicating that in chronic inflammatory joint diseases the detrimental effects outweigh the beneficial effects of adiponectin. PMID- 22532633 TI - Risk of skin and soft tissue infections (including shingles) in patients exposed to anti-tumour necrosis factor therapy: results from the British Society for Rheumatology Biologics Register. AB - INTRODUCTION: Anti-tumour necrosis factor (TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). In 2001, BSRBR was established to evaluate the safety of these agents. This paper addresses the safety of anti-TNF therapy in RA with specific reference to serious skin and soft tissue infections (SSSI) and shingles. METHODS: A cohort of anti-TNF-treated patients was recruited alongside a comparator group with active RA treated with non-biological disease modifying antirheumatic drugs (nbDMARD). 11 881 anti-TNF and 3673 nbDMARD patients were analysed. Follow-up was by 6-monthly questionnaires to patients and clinicians. Analyses considered SSSI and shingles separately. Incidence rates (IR) were calculated and then compared using survival analyses. RESULTS: The crude IR for SSSI were: anti-TNF 1.6/100 patient-years (95% CI 1.4 to 1.8); nbDMARD 0.7/100 patient-years (95% CI 0.5 to 1.0) and shingles: anti-TNF 1.6/100 patient-years (95% CI 1.3 to 2.0); nbDMARD 0.8/100 patient-years (95% CI 0.6 to 1.1). Adjusted HR were SSSI 1.4 (95% CI 0.9 to 2.4), shingles 1.8 (95% CI 1.2 to 2.8). For SSSI, no significant differences were seen between anti-TNF agents. For shingles, the lowest risk was observed for adalimumab (adjusted HR vs nbDMARD) 1.5 (95% CI 1.1 to 2.0) and highest for infliximab (HR 2.2; 95% CI 1.4 to 3.4)). CONCLUSION: A significantly increased risk of shingles was observed in the anti TNF-treated cohort. The risk of SSSI tended towards being greater with anti-TNF treatment but was not statistically significant. As with any observational dataset cause and effect cannot be established with certainty as residual confounding may remain. This finding would support the evaluation of zoster vaccination in this population. PMID- 22532634 TI - A CD4 T cell gene signature for early rheumatoid arthritis implicates interleukin 6-mediated STAT3 signalling, particularly in anti-citrullinated peptide antibody negative disease. AB - OBJECTIVE: We sought clinically relevant predictive biomarkers present in CD4 T cells, or in serum, that identified those patients with undifferentiated arthritis (UA) who subsequently develop rheumatoid arthritis (RA). METHODS: Total RNA was isolated from highly purified peripheral blood CD4 T cells of 173 early arthritis clinic patients. Paired serum samples were also stored. Microarray analysis of RNA samples was performed and differential transcript expression among 111 'training cohort' patients confirmed using real-time quantitative PCR. Machine learning approaches tested the utility of a classification model among an independent validation cohort presenting with UA (62 patients). Cytokine measurements were performed using a highly sensitive electrochemiluminescence detection system. RESULTS: A 12-gene transcriptional 'signature' identified RA patients in the training cohort and predicted the subsequent development of RA among UA patients in the validation cohort (sensitivity 68%, specificity 70%). STAT3-inducible genes were over-represented in the signature, particularly in anti-citrullinated peptide antibody-negative disease, providing a risk metric of similar predictive value to the Leiden score in seronegative UA (sensitivity 85%, specificity 75%). Baseline levels of serum interleukin 6 (IL-6) (which signals via STAT3) were highest in anti-citrullinated peptide antibodies-negative RA and distinguished this subgroup from non-RA inflammatory synovitis (corrected p<0.05).Paired serum IL-6 measurements correlated strongly with STAT3-inducible gene expression. CONCLUSION: The authors have identified IL-6-mediated STAT-3 signalling in CD4 T cells during the earliest clinical phase of RA, which is most prominent in seronegative disease. While highlighting potential biomarker(s) for early RA, the role of this pathway in disease pathogenesis awaits clarification. PMID- 22532635 TI - Smoking, rheumatoid factor status and responses to rituximab. PMID- 22532636 TI - Impact of tumour necrosis factor inhibitor treatment on radiographic progression in rheumatoid arthritis patients in clinical practice: results from the nationwide Danish DANBIO registry. AB - OBJECTIVES: To compare radiographic progression during treatment with disease modifying antirheumatic drugs (DMARD) and subsequent treatment with tumour necrosis factor alpha inhibitors (TNF-I) in rheumatoid arthritis (RA) patients in clinical practice. METHODS: Conventional radiographs (x-rays) of hands and wrists were obtained ~2 years before start (prebaseline), at baseline and ~2 years after start (follow-up) of TNF-I. Clinical data were obtained from the DANBIO registry and the patient files. x-Rays were scored blinded to chronology according to the Sharp/van der Heijde method. Annual radiographic progression rates during the DMARD (prebaseline to baseline x-ray) and TNF-I (baseline to follow-up x-ray) periods were calculated. RESULTS: 517 RA patients (76% women, 80% IgM rheumatoid factor positive, 65% anticyclic citrullinated peptide positive, 40% current smokers, age 54 years (range 21-86), median disease duration 5 years (range 0 57)) were included. Patients were treated with infliximab (61%), etanercept (15%) or adalimumab (24%). During the DMARD period 85% of patients received methotrexate, 51% sulphasalazine and 78% prednisolone. The median DMARD period was 733 days (IQR 484-1002) and the median TNF-I period was 562 days (IQR 405 766). The median radiographic progression rate decreased from 0.7 (IQR 0-2.9) total Sharp score units/year (dTSS) in the DMARD period to 0 (0-0.9) units/year in the TNF-I period (p<0.0001, Wilcoxon). Corresponding mean dTSS values were 2.1 (SD 3.7) versus 0.7 (SD 2.3) units/year (p<0.0001, paired t test). 305 patients progressed (dTSS >0) in the DMARD period compared with 158 patients in the TNF-I period (p<0.0001, chi(2)). CONCLUSION: This nationwide observational study of RA patients documented significantly reduced radiographic progression during TNF-I treatment compared with the previous period of DMARD treatment. PMID- 22532637 TI - Serum IL-6 and IL-21 are associated with markers of B cell activation and structural progression in early rheumatoid arthritis: results from the ESPOIR cohort. AB - OBJECTIVE: To identify a specific pattern of serum cytokines that correlates with the diagnosis, activity and severity of rheumatoid arthritis (RA) in patients with early RA as well as with the level of serum markers of B cell activation. METHODS: Serum interleukin (IL)-1beta, IL-1 receptor antagonist (IL1-Ra), IL-2, IL-4, IL-6, IL-10, IL-17, IL-21, monocyte chemotactic protein 1 (MCP-1), tumour necrosis factor alpha and interferon gamma levels were measured in the (ESPOIR) Etude et Suivi des POlyarthrites Indifferenciees Recentes early arthritis cohort, which included patients with at least two swollen joints for >6 weeks and <6 months, and no previous corticosteroids or disease-modifying antirheumatic drugs. Serum cytokine levels were compared between patients who met the 1987 American College of Rheumatology criteria for RA (n=578) or had undifferentiated arthritis (UA, n=132) at the 1-year follow-up visit. RESULTS: Serum IL-6 and IL-21 were the only cytokines that discriminated RA from UA on univariate analysis. IL-6 level was associated with RA, whereas erythrocyte sedimentation rate and C-reactive protein were not. Higher proportions of rheumatoid factor and anticyclic citrullinated protein (CCP) positivity, levels of markers of B cell activation, and a higher frequency of rapid radiographic progression were observed in patients with RA with detectable IL-6 or IL-21. Multivariate analysis associated IL-6 and anti-CCP levels with radiographic erosions at enrolment with 1-year radiographic progression. CONCLUSION: Serum IL-6 concentration is greater in RA than in UA. Increase in serum IL-6 and IL-21 levels is associated with markers of B cell activation, and IL-6 is associated with radiographic progression in patients with RA. PMID- 22532639 TI - Continuous NSAID use reverts the effects of inflammation on radiographic progression in patients with ankylosing spondylitis. AB - OBJECTIVES: The aim was to compare continuous and on-demand NSAID treatment with respect to their ability to suppress radiographic progression in subgroups of patients with high/elevated CRP-levels, ESR, ASDAS-levels or BASDAI-levels in comparison to patients with normal levels. METHODS: Post-hoc analyses were performed in a randomized trial comparing continuous and on-demand NSAID treatment. Relevant high/elevated subgroups were created based on time-averaged (ta) CRP (>5mg/L), ta-ESR (>12mm/hr), ta-BASDAI (>4), ta-ASDAS-CRP (>2.1) and ta ASDAS-ESR (>2.1). Subgroups were further split according to NSAID-use (continuous vs. on-demand). Radiological progression was presented in probability plots. Statistical interactions were tested using multiple and logistic regression analysis. Differences in radiological progression were analysed using the Chi square and Mann-Whitney U test. RESULTS: 150 participants randomized to either the continuous-treatment group (n=76), or the on-demand group (n=74) had complete radiographs and were included. The effect of slowing radiological progression with continuous NSAID therapy was more pronounced in patients with elevated ta CRP-levels, elevated ta-ESR, high ta-ASDAS-CRP or high ta-ASDAS-ESR versus patients with low/normal values. No such effect was found for participants with high vs. low BASDAI. Also, in participants with elevated ta-ESR (irrespective of treatment), there appeared to be a higher rate of structural progression than in participants with normal ta-ESR. Regression analyses showed that continuous NSAID treatment neutralizes the negative effect of inflammation (high ta-ESR). CONCLUSIONS: Patients with elevated acute phase reactants seem to benefit most from continuous treatment with NSAIDs. Continuous NSAID-therapy in patients with elevated acute phase reactants may lead to an improved benefit-risk-ratio of these drugs. PMID- 22532638 TI - Patient's global assessment of disease activity and patient's assessment of general health for rheumatoid arthritis activity assessment: are they equivalent? AB - OBJECTIVES: To assess (A) determinants of patient's global assessment of disease activity (PTGL) and patient's assessment of general health (GH) scores of rheumatoid arthritis (RA) patients; (B) whether they are equivalent as individual variables; and (C) whether they may be used interchangeably in calculating common RA activity assessment composite indices. METHODS: Data of 7023 patients from 30 countries in the Quantitative Standard Monitoring of Patients with RA (QUEST-RA) was analysed. PTGL and GH determinants were assessed by mixed-effects analyses of covariance models. PTGL and GH equivalence was determined by Bland-Altman 95% limits of agreement (BALOA) and Lin's coefficient of concordance (LCC). Concordance between PTGL and GH based Disease Activity Score 28 (DAS28), Clinical Disease Activity Index (CDAI) and Routine Assessment of Patient Index Data 3 (RAPID3) indices were calculated using LCC, and the level of agreement in classifying RA activity in four states (remission, low, moderate, high) using kappa statistics. RESULTS: Significant differences in relative and absolute contribution of RA and non-RA related variables in PTGL and GH ratings were noted. LCC of 0.64 and BALOA of -4.41 to 4.54 showed that PTGL and GH are not equivalent. There was excellent concordance (LCC 0.95-0.99) for PTGL and GH based DAS28, CDAI and RAPID3 indices, and >80% absolute agreement (kappa statistics 0.75-0.84) in RA activity state classification for all three indices. CONCLUSIONS: PTGL and GH ratings differ in their determinants. Although they are individually not equivalent, they may be used interchangeably for calculating composite indices for RA activity assessment. PMID- 22532641 TI - Congratulations, APS! 125 and counting. PMID- 22532640 TI - A systematic literature review of strategies promoting early referral and reducing delays in the diagnosis and management of inflammatory arthritis. AB - BACKGROUND: Despite the importance of timely management of patients with inflammatory arthritis (IA), delays exist in its diagnosis and treatment. OBJECTIVE: To perform a systematic literature review to identify strategies addressing these delays to inform an American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) taskforce. METHODS: The authors searched literature published between January 1985 and November 2010, and ACR and EULAR abstracts between 2007-2010. Additional information was obtained through a grey literature search, a survey conducted through ACR and EULAR, and a hand search of the literature. RESULTS: (1) From symptom onset to primary care, community case-finding strategies, including the use of a questionnaire and autoantibody testing, have been designed to identify patients with early IA. Several websites provided information on IA but were of varying quality and insufficient to aid early referral. (2) At a primary care level, education programmes and patient self-administered questionnaires identified patients with potential IA for referral to rheumatology. Many guidelines emphasised the need for early referral with one providing specific referral criteria. (3) Once referred, early arthritis clinics provided a point of early access for rheumatology assessment. Triage systems, including triage clinics, helped prioritise clinic appointments for patients with IA. Use of referral forms standardised information required, further optimising the triage process. Wait times for patients with acute IA were also reduced with development of rapid access systems. CONCLUSIONS: This review identified three main areas of delay to care for patients with IA and potential solutions for each. A co-ordinated effort will be required by the rheumatology and primary care community to address these effectively. PMID- 22532642 TI - Radical change for the fetus. PMID- 22532643 TI - Vasovagal syncope--the electricity, the pump or the input pressure? PMID- 22532644 TI - Resolution and concordance in dissecting the compound inhibitory junction potential. PMID- 22532645 TI - A TRP that makes us feel hyper. PMID- 22532646 TI - New insights from the measurement of loop gain in obstructive sleep apnoea. PMID- 22532647 TI - Waveless mammalian muscle. PMID- 22532648 TI - Protein ingestion after endurance exercise: the 'evolving' needs of the mitochondria? PMID- 22532649 TI - Guiding the moral vision of medicine. PMID- 22532650 TI - GRIST: Growing Recruitment in Interventional and Surgical Trials. PMID- 22532651 TI - Avicenna and the Canon Medicinae. PMID- 22532652 TI - Two sides of a coin. PMID- 22532653 TI - Where are all the bioethicists when you need them? PMID- 22532654 TI - 'Sans teeth, sans eyes, sans taste, sans everything:' resourcing mental health services for older people. PMID- 22532655 TI - The link between child abuse and psychopathology: a review of neurobiological and genetic research. AB - Childhood abuse is associated with later psychopathology, including conduct disorder, antisocial personality disorder, anxiety and depression as well as a heightened risk of health and social problems. However, the neurobiological mechanisms by which childhood adversity increases vulnerability to psychopathology remain poorly understood. There is likely to be a complex interaction between environmental experiences (such as abuse) and individual differences in risk versus protective genes, which influences the neurobiological circuitry underpinning psychological and emotional development. Neuroendocrine studies indicate an association between early adversity and atypical development of the hypothalamic-pituitary-adrenal (HPA) axis stress response, which may predispose to psychiatric vulnerability in adulthood. Brain imaging research in children and adults is providing evidence of several structural and functional brain differences associated with early adversity. Structural differences have been reported in the corpus callosum, cerebellum and prefrontal cortex. Functional differences have been reported in regions implicated in emotional and behavioural regulation, including the amygdala and anterior cingulate cortex. These differences at the neurobiological level may represent adaptations to early experiences of heightened stress that lead to an increased risk of psychopathology. We also consider the clinical implications of future neurobiological and genetic research. PMID- 22532656 TI - Doctors who considered but did not pursue specific clinical specialties as careers: questionnaire surveys. AB - OBJECTIVES: To report doctors' rejection of specialties as long-term careers and reasons for rejection. DESIGN: Postal questionnaires. SETTING: United Kingdom. PARTICIPANTS: Graduates of 2002, 2005 and 2008 from all UK medical schools, surveyed one year after qualification. MAIN OUTCOME MEASURES: Current specialty choice; any choice that had been seriously considered but not pursued (termed 'rejected' choices) with reasons for rejection. RESULTS: 2573 of 9155 respondents (28%) had seriously considered but then not pursued a specialty choice. By comparison with positive choices, general practice was under-represented among rejected choices: it was the actual choice of 27% of respondents and the rejected choice of only 6% of those who had rejected a specialty. Consideration of 'job content' was important in not pursuing general practice (cited by 78% of those who considered but rejected a career in general practice), psychiatry (72%), radiology (69%) and pathology (68%). The surgical specialties were the current choice of 20% of respondents and had been considered but rejected by 32% of doctors who rejected a specialty. Issues of work-life balance were the single most common factor, particularly for women, in not pursuing the surgical specialties, emergency medicine, the medical hospital specialties, paediatrics, and obstetrics and gynaecology. Competition for posts, difficult examinations, stressful working conditions, and poor training were mentioned but were mainly minority concerns. CONCLUSIONS: There is considerable diversity between doctors in their reasons for finding specialties attractive or unattractive. This underlines the importance of recruitment strategies to medical school that recognize diversity of students' interests and aptitudes. PMID- 22532657 TI - Observations of unprecedented remissions following novel treatment for acute leukemia in children in 1948. PMID- 22532661 TI - Randomized controlled trial of high concentration oxygen in suspected community acquired pneumonia. AB - OBJECTIVE: To determine whether high concentration oxygen increases the PaCO(2) in the treatment of community-acquired pneumonia. DESIGN: Randomized controlled clinical trial in which patients received high concentration oxygen (8 L/min via medium concentration mask) or titrated oxygen (to achieve oxygen saturations between 93 and 95%) for 60 minutes. Transcutaneous CO(2) (PtCO(2)) was measured at 0, 20, 40 and 60 minutes. SETTING: The Emergency Departments at Wellington, Hutt and Kenepuru Hospitals. PARTICIPANTS: 150 patients with suspected community acquired pneumonia presenting to the Emergency Department. Patients with chronic obstructive pulmonary disease (COPD) or disorders associated with hypercapnic respiratory failure were excluded. MAIN OUTCOME VARIABLES: The primary outcome variable was the proportion of patients with a rise in PtCO(2) >=4 mmHg at 60 minutes. Secondary outcome variables included the proportion of patients with a rise in PtCO(2) >=8 mmHg at 60 minutes. RESULTS: The proportion of patients with a rise in PtCO(2) >=4 mmHg at 60 minutes was greater in the high concentration oxygen group, 36/72 (50.0%) vs 11/75 (14.7%), relative risk (RR) 3.4 (95% CI 1.9 to 6.2), P < 0.001. The high concentration group had a greater proportion of patients with a rise in PtCO(2) >=8 mmHg, 11/72 (15.3%) vs 2/75 (2.7%), RR 5.7 (95% CI 1.3 to 25.0), P = 0.007. Amongst the 74 patients with radiological confirmation of pneumonia, the high concentration group had a greater proportion with a rise in PtCO(2) >=4 mmHg, 20/35 (57.1%) vs 5/39 (12.8%), RR 4.5 (95% CI 1.9 to 10.6) P < 0.001. CONCLUSIONS: We conclude that high concentration oxygen therapy increases the PtCO(2) in patients presenting with suspected community acquired pneumonia. This suggests that the potential increase in PaCO(2) with high concentration oxygen therapy is not limited to COPD, but may also occur in other respiratory disorders with abnormal gas exchange. PMID- 22532662 TI - Two distinct overstretched DNA structures revealed by single-molecule thermodynamics measurements. AB - Double-stranded DNA is a dynamic molecule whose structure can change depending on conditions. While there is consensus in the literature about many structures DNA can have, the state of highly-stretched DNA is still not clear. Several groups have shown that DNA in the torsion-unconstrained B-form undergoes an "overstretching" transition at a stretching force of around 65 pN, which leads to approximately 1.7-fold elongation of the DNA contour length. Recent experiments have revealed that two distinct structural transitions are involved in the overstretching process: (i) a hysteretic "peeling" off one strand from its complementary strand, and (ii) a nonhysteretic transition that leads to an undetermined DNA structure. We report the first simultaneous determination of the entropy (DeltaS) and enthalpy changes (DeltaH) pertaining to these respective transitions. For the hysteretic peeling transition, we determined DeltaS ~ 20 cal/(K.mol) and DeltaH ~ 7 kcal/mol. In the case of the nonhysteretic transition, DeltaS ~ -3 cal/(K.mol) and DeltaH ~ 1 kcal/mol. Furthermore, the response of the transition force to salt concentration implies that the two DNA strands are spatially separated after the hysteretic peeling transition. In contrast, the corresponding response after the nonhysteretic transition indicated that the strands remained in close proximity. The selection between the two transitions depends on DNA base-pair stability, and it can be illustrated by a multidimensional phase diagram. Our results provide important insights into the thermodynamics of DNA overstretching and conformational structures of overstretched DNA that may play an important role in vivo. PMID- 22532663 TI - Photo-inducible cell ablation in Caenorhabditis elegans using the genetically encoded singlet oxygen generating protein miniSOG. AB - We describe a method for light-inducible and tissue-selective cell ablation using a genetically encoded photosensitizer, miniSOG (mini singlet oxygen generator). miniSOG is a newly engineered fluorescent protein of 106 amino acids that generates singlet oxygen in quantum yield upon blue-light illumination. We transgenically expressed mitochondrially targeted miniSOG (mito-miniSOG) in Caenorhabditis elegans neurons. Upon blue-light illumination, mito-miniSOG causes rapid and effective death of neurons in a cell-autonomous manner without detectable damages to surrounding tissues. Neuronal death induced by mito-miniSOG appears to be independent of the caspase CED-3, but the clearance of the damaged cells partially depends on the phagocytic receptor CED-1, a homolog of human CD91. We show that neurons can be killed at different developmental stages. We further use this method to investigate the role of the premotor interneurons in regulating the convulsive behavior caused by a gain-of-function mutation in the neuronal acetylcholine receptor acr-2. Our findings support an instructive role for the interneuron AVB in controlling motor neuron activity and reveal an inhibitory effect of the backward premotor interneurons on the forward interneurons. In summary, the simple inducible cell ablation method reported here allows temporal and spatial control and will prove to be a useful tool in studying the function of specific cells within complex cellular contexts. PMID- 22532664 TI - Conserved and essential transcription factors for cellulase gene expression in ascomycete fungi. AB - Rational engineering of filamentous fungi for improved cellulase production is hampered by our incomplete knowledge of transcriptional regulatory networks. We therefore used the model filamentous fungus Neurospora crassa to search for uncharacterized transcription factors associated with cellulose deconstruction. A screen of a N. crassa transcription factor deletion collection identified two uncharacterized zinc binuclear cluster transcription factors (clr-1 and clr-2) that were required for growth and enzymatic activity on cellulose, but were not required for growth or hemicellulase activity on xylan. Transcriptional profiling with next-generation sequencing methods refined our understanding of the N. crassa transcriptional response to cellulose and demonstrated that clr-1 and clr 2 were required for the bulk of that response, including induction of all major cellulase and some major hemicellulase genes. Functional CLR-1 was necessary for expression of clr-2 and efficient cellobiose utilization. Phylogenetic analyses showed that CLR-1 and CLR-2 are conserved in the genomes of most filamentous ascomycete fungi capable of degrading cellulose. In Aspergillus nidulans, a strain carrying a deletion of the clr-2 homolog (clrB) failed to induce cellulase gene expression and lacked cellulolytic activity on Avicel. Further manipulation of this control system in industrial production strains may significantly improve yields of cellulases for cellulosic biofuel production. PMID- 22532666 TI - RNA unwinding by the Trf4/Air2/Mtr4 polyadenylation (TRAMP) complex. AB - Many RNA-processing events in the cell nucleus involve the Trf4/Air2/Mtr4 polyadenylation (TRAMP) complex, which contains the poly(A) polymerase Trf4p, the Zn-knuckle protein Air2p, and the RNA helicase Mtr4p. TRAMP polyadenylates RNAs designated for processing by the nuclear exosome. In addition, TRAMP functions as an exosome cofactor during RNA degradation, and it has been speculated that this role involves disruption of RNA secondary structure. However, it is unknown whether TRAMP displays RNA unwinding activity. It is also not clear how unwinding would be coordinated with polyadenylation and the function of the RNA helicase Mtr4p in modulating poly(A) addition. Here, we show that TRAMP robustly unwinds RNA duplexes. The unwinding activity of Mtr4p is significantly stimulated by Trf4p/Air2p, but the stimulation of Mtr4p does not depend on ongoing polyadenylation. Nonetheless, polyadenylation enables TRAMP to unwind RNA substrates that it otherwise cannot separate. Moreover, TRAMP displays optimal unwinding activity on substrates with a minimal Mtr4p binding site comprised of adenylates. Our results suggest a model for coordination between unwinding and polyadenylation activities by TRAMP that reveals remarkable synergy between helicase and poly(A) polymerase. PMID- 22532667 TI - A scissor blade-like closing mechanism implicated in transmembrane signaling in a Bacteroides hybrid two-component system. AB - Signaling across the membrane in response to extracellular stimuli is essential for survival of all cells. In bacteria, responses to environmental changes are predominantly mediated by two-component systems, which are typically composed of a membrane-spanning sensor histidine kinase and a cytoplasmic response regulator. In the human gut symbiont Bacteroides thetaiotaomicron, hybrid two-component systems are a key part of the bacterium's ability to sense and degrade complex carbohydrates in the gut. Here, we identify the activating ligand of the hybrid two-component system, BT4663, which controls heparin and heparan sulfate acquisition and degradation in this prominent gut microbe, and report the crystal structure of the extracellular sensor domain in both apo and ligand-bound forms. Current models for signal transduction across the membrane involve either a piston-like or rotational displacement of the transmembrane helices to modulate activity of the linked cytoplasmic kinases. The structures of the BT4663 sensor domain reveal a significant conformational change in the homodimer on ligand binding, which results in a scissor-like closing of the C-termini of each protomer. We propose this movement activates the attached intracellular kinase domains and represents an allosteric mechanism for bacterial transmembrane signaling distinct from previously described models, thus expanding our understanding of signal transduction across the membrane, a fundamental requirement in many important biological processes. PMID- 22532668 TI - Structural basis of species-specific endotoxin sensing by innate immune receptor TLR4/MD-2. AB - Lipopolysaccharide (LPS), also known as endotoxin, activates the innate immune response through toll-like receptor 4 (TLR4) and its coreceptor, MD-2. MD-2 has a unique hydrophobic cavity that directly binds to lipid A, the active center of LPS. Tetraacylated lipid IVa, a synthetic lipid A precursor, acts as a weak agonist to mouse TLR4/MD-2, but as an antagonist to human TLR4/MD-2. However, it remains unclear as to how LPS and lipid IVa show agonistic or antagonistic activities in a species-specific manner. The present study reports the crystal structures of mouse TLR4/MD-2/LPS and TLR4/MD-2/lipid IVa complexes at 2.5 and 2.7 A resolutions, respectively. Mouse TLR4/MD-2/LPS exhibited an agonistic "m" shaped 2:2:2 complex similar to the human TLR4/MD-2/LPS complex. Mouse TLR4/MD 2/lipid IVa complex also showed an agonistic structural feature, exhibiting architecture similar to the 2:2:2 complex. Remarkably, lipid IVa in the mouse TLR4/MD-2 complex occupied nearly the same space as LPS, although lipid IVa lacked the two acyl chains. Human MD-2 binds lipid IVa in an antagonistic manner completely differently from the way mouse MD-2 does. Together, the results provide structural evidence of the agonistic property of lipid IVa on mouse TLR4/MD-2 and deepen understanding of the ligand binding and dimerization mechanism by the structurally diverse LPS variants. PMID- 22532669 TI - Covalent attachment of pyridoxal-phosphate derivatives to 14-3-3 proteins. PMID- 22532670 TI - Comparable polyfunctionality of ectromelia virus- and vaccinia virus-specific murine T cells despite markedly different in vivo replication and pathogenicity. AB - Vaccinia virus (VACV) stimulates long-term immunity against highly pathogenic orthopoxvirus infection of humans (smallpox) and mice (mousepox [ectromelia virus {ECTV}]) despite the lack of a natural host-pathogen relationship with either of these species. Previous research revealed that VACV is able to induce polyfunctional CD8(+) T-cell responses after immunization of humans. However, the degree to which the functional profile of T cells induced by VACV is similar to that generated during natural poxvirus infection remains unknown. In this study, we monitored virus-specific T-cell responses following the dermal infection of C57BL/6 mice with ECTV or VACV. Using polychromatic flow cytometry, we measured levels of degranulation, cytokine expression (gamma interferon [IFN-gamma], tumor necrosis factor alpha [TNF-alpha], and interleukin-2 [IL-2]), and the cytolytic mediator granzyme B. We observed that the functional capacities of T cells induced by VACV and ECTV were of a similar quality in spite of the markedly different replication abilities and pathogenic outcomes of these viruses. In general, a significant fraction (>=50%) of all T-cell responses were positive for at least three functions both during acute infection and into the memory phase. In vivo killing assays revealed that CD8(+) T cells specific for both viruses were equally cytolytic (~80% target cell lysis after 4 h), consistent with the similar levels of granzyme B and degranulation detected among these cells. Collectively, these data provide a mechanism to explain the ability of VACV to induce protective T-cell responses against pathogenic poxviruses in their natural hosts and provide further support for the use of VACV as a vaccine platform able to induce polyfunctional T cells. PMID- 22532671 TI - Single and coexpression of CXCR4 and CXCR5 identifies CD4 T helper cells in distinct lymph node niches during influenza virus infection. AB - Influenza virus infection results in strong, mainly T-dependent, extrafollicular and germinal center B cell responses, which provide lifelong humoral immunity against the homotypic virus strain. Follicular T helper cells (T(FH)) are key regulators of humoral immunity. Questions remain regarding the presence, identity, and function of T(FH) subsets regulating early extrafollicular and later germinal center B cell responses. This study demonstrates that ICOS but not CXCR5 marks T cells with B helper activity induced by influenza virus infection and identifies germinal center T cells (T(GC)) as lymph node-resident CD4(+) ICOS(+) CXCR4(+) CXCR5(+) PSGL-1(lo) PD-1(hi) cells. The CXCR4 expression intensity further distinguished their germinal center light and dark zone locations. This population emerged strongly in regional lymph nodes and with kinetics similar to those of germinal center B cells and were the only T(FH) subsets missing in influenza virus-infected, germinal center-deficient SAP(-/-) mice, mice which were shown previously to lack protective memory responses after a secondary influenza virus challenge, thus indicting the nonredundant functions of CXCR4- and CXCR5-coexpressing CD4 helper cells in antiviral B cell immunity. CXCR4-single-positive T cells, present in B cell-mediated autoimmunity and regarded as "extrafollicular" helper T cells, were rare throughout the response, despite prominent extrafollicular B cell responses, revealing fundamental differences in autoimmune- and infection-induced T-dependent B cell responses. While all ICOS(+) subsets induced similar antibody levels in vitro, CXCR5-single positive T cells were superior in inducing B cell proliferation. The regulation of T cell localization, marked by the single and coexpression of CXCR4 and CXCR5, might be an important determinant of T(FH) function. PMID- 22532672 TI - Sequence in the influenza A virus nucleoprotein required for viral polymerase binding and RNA synthesis. AB - Many proposed mechanisms for influenza A viral RNA synthesis include an interaction of the nucleoprotein (NP) with the viral polymerase. To identify an NP sequence required for this interaction, we used the cryoelectron microscopic structure of an influenza virus miniribonucleoprotein as a guide for choosing promising surface-exposed sequences. We show that three amino acids (R204, W207, and R208) located in a loop at the top of the head domain of NP are required for functional interaction with the viral polymerase. Quantitative reverse transcription-PCR (RT-PCR) measurements of RNAs synthesized in minigenome assays established that each of these NP amino acids is required for viral RNA synthesis. The mutation of these three amino acids does not affect nuclear localization or RNA-binding and oligomerization activities of NP. In vitro binding experiments with purified virus polymerase and NPs established that these three amino acids are required for NP binding to the viral polymerase. PMID- 22532673 TI - Mutations conferring resistance to viral DNA polymerase inhibitors in camelpox virus give different drug-susceptibility profiles in vaccinia virus. AB - Cidofovir or (S)-HPMPC is one of the three antiviral drugs that might be used for the treatment of orthopoxvirus infections. (S)-HPMPC and its 2,6-diaminopurine counterpart, (S)-HPMPDAP, have been described to select, in vitro, for drug resistance mutations in the viral DNA polymerase (E9L) gene of vaccinia virus (VACV). Here, to extend our knowledge of drug resistance development among orthopoxviruses, we selected, in vitro, camelpox viruses (CMLV) resistant to (S) HPMPDAP and identified a single amino acid change, T831I, and a double mutation, A314V+A684V, within E9L. The production of recombinant CMLV and VACV carrying these amino acid substitutions (T831I, A314V, or A314V+A684V) demonstrated clearly their involvement in conferring reduced sensitivity to viral DNA polymerase inhibitors, including (S)-HPMPDAP. Both CMLV and VACV harboring the A314V change showed comparable drug-susceptibility profiles to various antivirals and similar impairments in viral growth. In contrast, the single change T831I and the double change A314V+A684V in VACV were responsible for increased levels of drug resistance and for cross-resistance to viral DNA polymerase antivirals that were not observed with their CMLV counterparts. Each amino acid change accounted for an attenuated phenotype of VACV in vivo. Modeling of E9L suggested that the T >I change at position 831 might abolish hydrogen bonds between E9L and the DNA backbone and have a direct impact on the incorporation of the acyclic nucleoside phosphonates. Our findings demonstrate that drug-resistance development in two related orthopoxvirus species may impact drug-susceptibility profiles and viral fitness differently. PMID- 22532674 TI - Replication of herpes simplex virus: egress of progeny virus at specialized cell membrane sites. AB - In the final stages of the herpes simplex virus 1 (HSV-1) life cycle, a viral nucleocapsid buds into a vesicle of trans-Golgi network (TGN)/endosome origin, acquiring an envelope and an outer vesicular membrane. The virus-containing vesicle then traffics to the plasma membrane where it fuses, exposing a mature virion. Although the process of directed egress has been studied in polarized epithelial cell lines, less work has been done in nonpolarized cell types. In this report, we describe a study of HSV-1 egress as it occurs in nonpolarized cells. The examination of infected Vero cells by electron, confocal, and total internal reflection fluorescence (TIRF) microscopy revealed that HSV-1 was released at specific pocket-like areas of the plasma membrane that were found along the substrate-adherent surface and cell-cell-adherent contacts. Both the membrane composition and cytoskeletal structure of egress sites were found to be modified by infection. The plasma membrane at virion release sites was heavily enriched in viral glycoproteins. Small glycoprotein patches formed early in infection, and virus became associated with these areas as they expanded. Glycoprotein-rich areas formed independently from virion trafficking as confirmed by the use of a UL25 mutant with a defect in capsid nuclear egress. The depolymerization of the cytoskeleton indicated that microtubules were important for the trafficking of virions and glycoproteins to release sites. In addition, the actin cytoskeleton was found to be necessary for maintaining the integrity of egress sites. When actin was depolymerized, the glycoprotein concentrations dispersed across the membrane, as did the surface-associated virus. Lastly, viral glycoprotein E appeared to function in a different manner in nonpolarized cells compared to previous studies of egress in polarized epithelial cells; the total amount of virus released at egress sites was slightly increased in infected Vero cells when gE was absent. However, gE was important for egress site formation, as Vero cells infected with gE deletion mutants formed glycoprotein patches that were significantly reduced in size. The results of this study are interpreted to indicate that the egress of HSV-1 in Vero cells is directed to virally induced, specialized egress sites that form along specific areas of the cell membrane. PMID- 22532675 TI - Envelope variable region 4 is the first target of neutralizing antibodies in early simian immunodeficiency virus mac251 infection of rhesus monkeys. AB - A major goal of AIDS vaccine development is to design vaccination strategies that can elicit broad and potent protective antibodies. The initial viral targets of neutralizing antibodies (NAbs) early after human or simian immunodeficiency virus (HIV/SIV) infection are not known. The identification of early NAb epitopes that induce protective immunity or retard the progression of disease is important for AIDS vaccine development. The aim of this study was to determine the Env residues targeted by early SIV NAbs and to assess the influence of prior vaccination on neutralizing antibody kinetics and specificity during early infection. We previously described stereotypic env sequence variations in SIVmac251-infected rhesus monkeys that resulted in viral escape from NAbs. Here, we defined the early viral targets of neutralization and determined whether the ability of serum antibody from infected monkeys to neutralize SIV was altered in the setting of prior vaccination. To localize the viral determinants recognized by early NAbs, a panel of mutant pseudoviruses was assessed in a TZM-bl reporter gene neutralization assay to define the precise changes that eliminate recognition by SIV Env-specific NAbs in 16 rhesus monkeys. Changing R420 to G or R424 to Q in V4 of Env resulted in the loss of recognition by NAbs in vaccinated monkeys. In contrast, mutations in the V1 region of Env did not alter the NAb profile. These findings indicate that early NAbs are directed toward SIVmac251 Env V4 but not the V1 region, and that this env vaccination regimen did not alter the kinetics or the breadth of NAbs during early infection. PMID- 22532676 TI - Kaposi's sarcoma-associated herpesvirus inhibits expression and function of endothelial cell major histocompatibility complex class II via suppressor of cytokine signaling 3. AB - Endothelial cells (EC) can present antigen to either CD8(+) T lymphocytes through constitutively expressed major histocompatibility complex class I (MHC-I) or CD4(+) T lymphocytes through gamma interferon (IFN-gamma)-induced MHC-II. Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), an EC neoplasm characterized by dysregulated angiogenesis and a substantial inflammatory infiltrate. KSHV is understood to have evolved strategies to inhibit MHC-I expression on EC and MHC-II expression on primary effusion lymphoma cells, but its effects on EC MHC-II expression are unknown. Here, we report that the KSHV infection of human primary EC inhibits IFN-gamma induced expression of the MHC-II molecule HLA-DR at the transcriptional level. The effect is functionally significant, since recognition by an HLA-DR-restricted CD4(+) T-cell clone in response to cognate antigen presented by KSHV-infected EC was attenuated. Inhibition of HLA-DR expression was also achieved by exposing EC to supernatant from KSHV-inoculated EC before IFN-gamma treatment, revealing a role for soluble mediators. IFN-gamma-induced phosphorylation of STAT-1 and transcription of CIITA were suppressed in KSHV-inoculated EC via a mechanism involving SOCS3 (suppressor of cytokine signaling 3). Thus, KSHV infection resulted in transcriptional upregulation of SOCS3, and treatment with RNA interference against SOCS3 relieved virus-induced inhibition of IFN-gamma-induced STAT-1 phosphorylation. Since cell surface MHC-II molecules present peptide antigens to CD4(+) T lymphocytes that can function either as direct cytolytic effectors or to initiate and regulate adaptive immune responses, inhibition of this antigen-presenting pathway would provide a survival advantage to the virus. PMID- 22532677 TI - RNA structural elements determine frequency and sites of nonhomologous recombination in an animal plus-strand RNA virus. AB - For highly variable RNA viruses, RNA recombination significantly contributes to genetic variations which may lead to changes of virulence, adaptation to new hosts, escape from the host immune response, and emergence of new infectious agents. Using a system based on transfection of cells with synthetic nonreplicable subgenomic transcripts derived from bovine viral diarrhea virus (family Flaviviridae), the existence of a replication-independent mechanism of RNA recombination, in addition to the commonly accepted replicative copy-choice recombination, has been previously proven (A. Gallei et al., J. Virol. 78:6271 6281, 2004). To identify RNA signals involved in efficient joining of RNA molecules, RNA recombination in living cells was targeted to the 3' nontranslated region. Molecular characterization of 40 independently emerged recombinant viruses revealed that the majority of recombination sites are located in single stranded regions of the RNA molecules. Furthermore, the results of this study showed that the frequency of RNA recombination directly correlated with the RNA amounts of both recombination partners. The frequency can be strongly increased by modification of the 5' triphosphates and 3' hydroxyls of the recombining RNA molecules to 5' hydroxyl and 3' monophosphoryl ends, respectively. Analysis of recombinants that emerged after transfection with such modified RNA molecules revealed a complete integration and efficient end-to-end joining of the recombination partner(s) in at least 80% of recombinants, while unmodified RNA molecules recombined exclusively at internal positions. These results are in line with the hypothesis that endoribonucleolytic cleavage and a subsequent ligation reaction can cause RNA recombination. PMID- 22532678 TI - Base pairing between hepatitis C virus RNA and microRNA 122 3' of its seed sequence is essential for genome stabilization and production of infectious virus. AB - MicroRNA 122 (miR-122) facilitates hepatitis C virus (HCV) replication by recruiting an RNA-induced silencing complex (RISC)-like complex containing argonaute 2 (Ago2) to the 5' end of the HCV genome, thereby stabilizing the viral RNA. This requires base pairing between the miR-122 "seed sequence" (nucleotides [nt] 2 to 8) and two sequences near the 5' end of the HCV RNA: S1 (nt 22 to 28) and S2 (nt 38 to 43). However, recent reports suggest that additional base pair interactions occur between HCV RNA and miR-122. We searched 606 sequences from a public database (genotypes 1 to 6) and identified two conserved, putatively single-stranded RNA segments, upstream of S1 (nt 2 and 3) and S2 (nt 30 to 34), with potential for base pairing to miR-122 (nt 15 and 16 and nt 13 to 16, respectively). Mutagenesis and genetic complementation experiments confirmed that HCV nt 2 and 3 pair with nt 15 and 16 of miR-122 bound to S1, while HCV nt 30 to 33 pair with nt 13 to 16 of miR-122 at S2. In genotype 1 and 6 HCV, nt 4 also base pairs with nt 14 of miR-122. These 3' supplementary base pair interactions of miR-122 are functionally important and are required for Ago2 recruitment to HCV RNA by miR-122, miR-122-mediated stabilization of HCV RNA, and production of infectious virus. However, while complementary mutations at HCV nt 30 and 31 efficiently rescued the activity of a 15C,16C miR-122 mutant targeting S2, similar mutations at nt 2 and 3 failed to rescue Ago2 recruitment at S1. These data add to the current understanding of miR-122 interactions with HCV RNA but indicate that base pairing between miR-122 and the 5' 43 nt of the HCV genome is more complex than suggested by existing models. PMID- 22532679 TI - Pathogenic Old World arenaviruses inhibit TLR2/Mal-dependent proinflammatory cytokines in vitro. AB - Lymphocytic choriomeningitis virus (LCMV), the prototype arenavirus, and Lassa virus (LASV), the causative agent of Lassa fever (LF), have extensive strain diversity and significant variations in pathogenicity for humans and experimental animals. The WE strain of LCMV (LCMV-WE), but not the Armstrong (Arm) strain, induces a fatal LF-like disease in rhesus macaques. We also demonstrated that LASV infection of human macrophages and endothelial cells resulted in reduced levels of proinflammatory cytokines. Here we have shown that cells infected with LASV or with LCMV-WE suppressed Toll-like receptor 2 (TLR2)-dependent proinflammatory cytokine responses. The persisting isolate LCMV clone 13 (CL13) also failed to stimulate interleukin-6 (IL-6) in macrophages. In contrast, nonpathogenic Mopeia virus, which is a genetic relative of LASV and LCMV-Arm induced robust responses that were TLR2/Mal dependent, required virus replication, and were enhanced by CD14. Superinfection experiments demonstrated that the WE strain of LCMV inhibited the Arm-mediated IL-8 response during the early stage of infection. In cells transfected with the NF-kappaB-luciferase reporter, infection with LCMV-Arm resulted in the induction of NF-kappaB, but cells infected with LCMV-WE and CL13 did not. These results suggest that pathogenic arenaviruses suppress NF-kappaB-mediated proinflammatory cytokine responses in infected cells. PMID- 22532680 TI - The influenza A virus PB2, PA, NP, and M segments play a pivotal role during genome packaging. AB - The genomes of influenza A viruses consist of eight negative-strand RNA segments. Recent studies suggest that influenza viruses are able to specifically package their segmented genomes into the progeny virions. Segment-specific packaging signals of influenza virus RNAs (vRNAs) are located in the 5' and 3' noncoding regions, as well as in the terminal regions, of the open reading frames. How these packaging signals function during genome packaging remains unclear. Previously, we generated a 7-segmented virus in which the hemagglutinin (HA) and neuraminidase (NA) segments of the influenza A/Puerto Rico/8/34 virus were replaced by a chimeric influenza C virus hemagglutinin/esterase/fusion (HEF) segment carrying the HA packaging sequences. The robust growth of the HEF virus suggested that the NA segment is not required for the packaging of other segments. In this study, in order to determine the roles of the other seven segments during influenza A virus genome assembly, we continued to use this HEF virus as a tool and analyzed the effects of replacing the packaging sequences of other segments with those of the NA segment. Our results showed that deleting the packaging signals of the PB1, HA, or NS segment had no effect on the growth of the HEF virus, while growth was greatly impaired when the packaging sequence of the PB2, PA, nucleoprotein (NP), or matrix (M) segment was removed. These results indicate that the PB2, PA, NP, and M segments play a more important role than the remaining four vRNAs during the genome-packaging process. PMID- 22532681 TI - Mutagenesis of the DI/DIII linker in dengue virus envelope protein impairs viral particle assembly. AB - The dengue virus (DV) envelope (E) protein is important in mediating viral entry and assembly of progeny virus during cellular infection. Domains I and III (DI and DIII, respectively) of the DV E protein are connected by a highly conserved but poorly ordered region, the DI/DIII linker. Although the flexibility of the DI/DIII linker is thought to be important for accommodating the structural rearrangements undergone by the E protein during viral entry, the function of the linker in the DV infectious cycle is not well understood. In this study, we performed site-directed mutagenesis on conserved residues in the DI/DIII linker of the DV2 E protein and showed that the resulting mutations had little or no effect on the entry process but greatly affected virus assembly. Biochemical fractionation and immunofluorescence microscopy experiments performed on infectious virus as well as in a virus-like particle (VLP) system indicate that the DI/DIII linker mutants express the DV structural proteins at the sites of particle assembly near the ER but fail to form infectious particles. This defect is not due to disruption of E's interaction with prM and pr in immature and mature virions, respectively. Serial passaging of the DV2 mutant E-Y299F led to the identification of a mutation in the membrane-proximal stem region of E that fully compensates for the assembly defect of this DI/DIII linker mutant. Together, our results suggest a critical and previously unidentified role for the E protein DI/DIII linker region during the DV2 assembly process. PMID- 22532682 TI - HIV-1 infection ex vivo accelerates measles virus infection by upregulating signaling lymphocytic activation molecule (SLAM) in CD4+ T cells. AB - Measles virus (MV) infection in children harboring human immunodeficiency virus type 1 (HIV-1) is often fatal, even in the presence of neutralizing antibodies; however, the underlying mechanisms are unclear. Therefore, the aim of the present study was to examine the interaction between HIV-1 and wild-type MV (MVwt) or an MV vaccine strain (MVvac) during dual infection. The results showed that the frequencies of MVwt- and MVvac-infected CD4(+) T cells within the resting peripheral blood mononuclear cells (PBMCs) were increased 3- to 4-fold after HIV 1 infection, and this was associated with a marked upregulation of signaling lymphocytic activation molecule (SLAM) expression on CD4(+) T cells but not on CD8(+) T cells. SLAM upregulation was induced by infection with a replication competent HIV-1 isolate comprising both the X4 and R5 types and to a lesser extent by a pseudotyped HIV-1 infection. Notably, SLAM upregulation was observed in HIV-infected as well as -uninfected CD4(+) T cells and was abrogated by the removal of HLA-DR(+) cells from the PBMC culture. Furthermore, SLAM upregulation did not occur in uninfected PBMCs cultured together with HIV-infected PBMCs in compartments separated by a permeable membrane, indicating that no soluble factors were involved. Rather, CD4(+) T cell activation mediated through direct contact with dendritic cells via leukocyte function-associated molecule 1 (LFA 1)/intercellular adhesion molecule 1 (ICAM-1) and LFA-3/CD2 was critical. Thus, HIV-1 infection induces a high level of SLAM expression on CD4(+) T cells, which may enhance their susceptibility to MV and exacerbate measles in coinfected individuals. PMID- 22532683 TI - Arenavirus nucleoprotein targets interferon regulatory factor-activating kinase IKKepsilon. AB - Arenaviruses perturb innate antiviral defense by blocking induction of type I interferon (IFN) production. Accordingly, the arenavirus nucleoprotein (NP) was shown to block activation and nuclear translocation of interferon regulatory factor 3 (IRF3) in response to virus infection. Here, we sought to identify cellular factors involved in innate antiviral signaling targeted by arenavirus NP. Consistent with previous studies, infection with the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) prevented phosphorylation of IRF3 in response to infection with Sendai virus, a strong inducer of the retinoic acid inducible gene I (RIG-I)/mitochondrial antiviral signaling (MAVS) pathway of innate antiviral signaling. Using a combination of coimmunoprecipitation and confocal microscopy, we found that LCMV NP associates with the IkappaB kinase (IKK)-related kinase IKKepsilon but that, rather unexpectedly, LCMV NP did not bind to the closely related TANK-binding kinase 1 (TBK-1). The NP-IKKepsilon interaction was highly conserved among arenaviruses from different clades. In LCMV-infected cells, IKKepsilon colocalized with NP but not with MAVS located on the outer membrane of mitochondria. LCMV NP bound the kinase domain (KD) of IKKepsilon (IKBKE) and blocked its autocatalytic activity and its ability to phosphorylate IRF3, without undergoing phosphorylation. Together, our data identify IKKepsilon as a novel target of arenavirus NP. Engagement of NP seems to sequester IKKepsilon in an inactive complex. Considering the important functions of IKKepsilon in innate antiviral immunity and other cellular processes, the NP IKKepsilon interaction likely plays a crucial role in arenavirus-host interaction. PMID- 22532684 TI - Comparison of the host immune response to herpes simplex virus 1 (HSV-1) and HSV 2 at two different mucosal sites. AB - A study was undertaken to compare the host immune responses to herpes simplex virus 1 (HSV-1) and HSV-2 infection by the ocular or genital route in mice. Titers of HSV-2 from tissue samples were elevated regardless of the route of infection. The elevation in titers of HSV-2, including cell infiltration and cytokine/chemokine levels in the central nervous system relative to those found following HSV-1 infection, was correlative with inflammation. These results underscore a dichotomy between the host immune responses to closely related alphaherpesviruses. PMID- 22532685 TI - The IE180 protein of pseudorabies virus suppresses phosphorylation of translation initiation factor eIF2alpha. AB - We have previously shown that the porcine alphaherpesvirus pseudorabies virus (PRV) efficiently interferes with phosphorylation of the eukaryotic translation initiation factor eIF2alpha. Inhibition of phosphorylation of eIF2alpha has been reported earlier for the closely related alphaherpesvirus herpes simplex virus 1 (HSV-1) through its ICP34.5 and US11 proteins. PRV, however, does not encode an ICP34.5 or US11 orthologue. Assays using cycloheximide, UV-inactivated PRV, or phosphonoacetic acid (PAA) showed that de novo expression of one or more (immediate) early viral protein(s) is required for interference with eIF2alpha phosphorylation. In line with this, a time course assay showed that eIF2alpha phosphorylation was abolished within 2 h after PRV inoculation. PRV encodes only one immediate-early protein, IE180, the orthologue of HSV-1 ICP4. As reported earlier, a combinational treatment of cells with cycloheximide and actinomycin D allowed expression of IE180 without detectable expression of the US3 early protein in PRV-infected cells. This led to a substantial reduction in eIF2alpha phosphorylation levels, indicative for an involvement of IE180. In support of this, transfection of IE180 also potently reduced eIF2alpha phosphorylation. IE180-mediated interference with eIF2alpha phosphorylation was not cell type dependent, as it occurred both in rat neuronal 50B11 cells and in swine testicle cells. Inhibition of the cellular phosphatase PP1 impaired PRV-mediated interference with eIF2alpha phosphorylation, indicating that PP1 is involved in this process. In conclusion, the immediate-early IE180 protein of PRV has the previously uncharacterized ability to suppress phosphorylation levels of the eukaryotic translation initiation factor eIF2alpha. PMID- 22532686 TI - Isoflavone agonists of IRF-3 dependent signaling have antiviral activity against RNA viruses. AB - There is a growing need for novel antiviral therapies that are broad spectrum, effective, and not subject to resistance due to viral mutations. Using high throughput screening methods, including computational docking studies and an interferon-stimulated gene 54 (ISG54)-luciferase reporter assay, we identified a class of isoflavone compounds that act as specific agonists of innate immune signaling pathways and cause activation of the interferon regulatory factor (IRF 3) transcription factor. The isoflavone compounds activated the ISG54 promoter, mediated nuclear translocation of IRF-3, and displayed highly potent activity against hepatitis C virus (HCV) and influenza virus. Additionally, these agonists efficiently activated IRF-3 in the presence of the HCV protease NS3-4A, which is known to blunt the host immune response. Furthermore, genomic studies showed that discrete innate immune pathways centered on IRF signaling were regulated following agonist treatment without causing global changes in host gene expression. Following treatment, the expression of only 64 cellular genes was significantly induced. This report provides the first evidence that innate immune pathways dependent on IRF-3 can be successfully targeted by small-molecule drugs for the development of novel broad-spectrum antiviral compounds. PMID- 22532687 TI - Inhibition of interferon regulatory factor 3 activation by paramyxovirus V protein. AB - The V protein of Sendai virus (SeV) suppresses innate immunity, resulting in enhancement of viral growth in mouse lungs and viral pathogenicity. The innate immunity restricted by the V protein is induced through activation of interferon regulatory factor 3 (IRF3). The V protein has been shown to interact with melanoma differentiation-associated gene 5 (MDA5) and to inhibit beta interferon production. In the present study, we infected MDA5-knockout mice with V-deficient SeV and found that MDA5 was largely unrelated to the innate immunity that the V protein suppresses in vivo. We therefore investigated the target of the SeV V protein. We previously reported interaction of the V protein with IRF3. Here we extended the observation and showed that the V protein appeared to inhibit translocation of IRF3 into the nucleus. We also found that the V protein inhibited IRF3 activation when induced by a constitutive active form of IRF3. The V proteins of measles virus and Newcastle disease virus inhibited IRF3 transcriptional activation, as did the V protein of SeV, while the V proteins of mumps virus and Nipah virus did not, and inhibition by these proteins correlated with interaction of each V protein with IRF3. These results indicate that IRF3 is important as an alternative target of paramyxovirus V proteins. PMID- 22532688 TI - Multiple antigenic sites are involved in blocking the interaction of GII.4 norovirus capsid with ABH histo-blood group antigens. AB - Noroviruses are major etiological agents of acute viral gastroenteritis. In 2002, a GII.4 variant (Farmington Hills cluster) spread so rapidly in the human population that it predominated worldwide and displaced previous GII.4 strains. We developed and characterized a panel of six monoclonal antibodies (MAbs) directed against the capsid protein of a Farmington Hills-like GII.4 norovirus strain that was associated with a large hospital outbreak in Maryland in 2004. The six MAbs reacted with high titers against homologous virus-like particles (VLPs) by enzyme-linked immunoassay but did not react with denatured capsid protein in immunoblots. The expression and self-assembly of newly developed genogroup I/II chimeric VLPs showed that five MAbs bound to the GII.4 protruding (P) domain of the capsid protein, while one recognized the GII.4 shell (S) domain. Cross-competition assays and mutational analyses showed evidence for at least three distinct antigenic sites in the P domain and one in the S domain. MAbs that mapped to the P domain but not the S domain were able to block the interaction of VLPs with ABH histo-blood group antigens (HBGA), suggesting that multiple antigenic sites of the P domain are involved in HBGA blocking. Further analysis showed that two MAbs mapped to regions of the capsid that had been associated with the emergence of new GII.4 variants. Taken together, our data map antibody and HBGA carbohydrate binding to proximal regions of the norovirus capsid, showing that evolutionary pressures on the norovirus capsid protein may affect both antigenic and carbohydrate recognition phenotypes. PMID- 22532689 TI - Dynamic interactions between Bombyx mori nucleopolyhedrovirus and its host cells revealed by transcriptome analysis. AB - Although microarray and expressed sequence tag (EST)-based approaches have been used to profile gene expression during baculovirus infection, the response of host genes to baculovirus infection and the interaction between baculovirus and its host remain largely unknown. To determine the host response to Bombyx mori nucleopolyhedrovirus infection and the dynamic interaction between the virus and its host, eight digital gene expression libraries were examined in a Bm5 cell line before infection and at 1.5, 3, 6, 12, 24, 48, and 96 h postinfection. Gene set enrichment analysis of differentially expressed genes at each time point following infection showed that gene sets including cytoskeleton, transcription, translation, energy metabolism, iron ion metabolism, and the ubiquitin-proteasome pathway were altered after viral infection. In addition, a time course depicting protein-protein interaction networks between the baculovirus and the host were constructed and revealed that viral proteins interact with a multitude of cellular machineries, such as the proteasome, cytoskeleton, and spliceosome. Several viral proteins, including IE2, CG30, PE38, and PK-1/2, were predicted to play key roles in mediating virus-host interactions. Based on these results, we tested the role of the ubiquitin-proteasome pathway and iron ion metabolism in the viral infection cycle. Treatment with a proteasome inhibitor and deferoxamine mesylate in vitro and in vivo confirmed that these pathways regulate viral infection. Taken together, these findings provide new insights into the interaction between the baculovirus and its host and identify molecular mechanisms that can be used to block viral infection and improve baculovirus expression systems. PMID- 22532690 TI - Loss of cytoskeletal transport during egress critically attenuates ectromelia virus infection in vivo. AB - Egress of wrapped virus (WV) to the cell periphery following vaccinia virus (VACV) replication is dependent on interactions with the microtubule motor complex kinesin-1 and is mediated by the viral envelope protein A36. Here we report that ectromelia virus (ECTV), a related orthopoxvirus and the causative agent of mousepox, encodes an A36 homologue (ECTV-Mos-142) that is highly conserved despite a large truncation at the C terminus. Deleting the ECTV A36R gene leads to a reduction in the number of extracellular viruses formed and to a reduced plaque size, consistent with a role in microtubule transport. We also observed a complete loss of virus-associated actin comets, another phenotype dependent on A36 expression during VACV infection. ECTV DeltaA36R was severely attenuated when used to infect the normally susceptible BALB/c mouse strain. ECTV DeltaA36R replication and spread from the draining lymph nodes to the liver and spleen were significantly reduced in BALB/c mice and in Rag-1-deficient mice, which lack T and B lymphocytes. The dramatic reduction in ECTV DeltaA36R titers early during the course of infection was not associated with an augmented immune response. Taken together, these findings demonstrate the critical role that subcellular transport pathways play not only in orthopoxvirus infection in an in vitro context but also during orthopoxvirus pathogenesis in a natural host. Furthermore, despite the attenuation of the mutant virus, we found that infection nonetheless induced protective immunity in mice, suggesting that orthopoxvirus vectors with A36 deletions may be considered another safe vaccine alternative. PMID- 22532691 TI - Antiviral antibodies and T cells are present in the foreskin of simian immunodeficiency virus-infected rhesus macaques. AB - No information exists regarding immune responses to human immunodeficiency virus (HIV) infection in the foreskin or glans of the human penis, although this is a key tissue for HIV transmission. To address this gap, we characterized antiviral immune responses in foreskin of male rhesus macaques (RMs) inoculated with simian immunodeficiency virus (SIV) strain SIVmac251 by penile foreskin exposure. We found a complete population of immune cells in the foreskin and glans of normal RMs, although B cells were less common than CD4(+) and CD8(+) T cells. IgG secreting cells were detected by enzyme-linked immunospot (ELISPOT) assay in cell suspensions made from the foreskin. In the foreskin and glans of SIV-infected RMs, although B cells were less common than CD4(+) and CD8(+) T cells, SIV specific IgG antibody was present in foreskin secretions. In addition, cytokine secreting SIV-specific CD8(+) T cells were readily found in cell suspensions made from the foreskin. Although potential HIV target cells were found in and under the epithelium covering all penile surfaces, the presence of antiviral effector B and T cells in the foreskin suggests that vaccines may be able to elicit immunity in this critical site to protect men from acquiring HIV. PMID- 22532692 TI - Hepatitis C virus attachment mediated by apolipoprotein E binding to cell surface heparan sulfate. AB - Viruses are known to use virally encoded envelope proteins for cell attachment, which is the very first step of virus infection. In the present study, we have obtained substantial evidence demonstrating that hepatitis C virus (HCV) uses the cellular protein apolipoprotein E (apoE) for its attachment to cells. An apoE specific monoclonal antibody was able to efficiently block HCV attachment to the hepatoma cell line Huh-7.5 as well as primary human hepatocytes. After HCV bound to cells, however, anti-apoE antibody was unable to inhibit virus infection. Conversely, the HCV E2-specific monoclonal antibody CBH5 did not affect HCV attachment but potently inhibited HCV entry. Similarly, small interfering RNA mediated knockdown of the key HCV receptor/coreceptor molecules CD81, claudin-1, low-density lipoprotein receptor (LDLr), occludin, and SR-BI did not affect HCV attachment but efficiently suppressed HCV infection, suggesting their important roles in HCV infection at postattachment steps. Strikingly, removal of heparan sulfate from the cell surface by treatment with heparinase blocked HCV attachment. Likewise, substitutions of the positively charged amino acids with neutral or negatively charged residues in the receptor-binding region of apoE resulted in a reduction of apoE-mediating HCV infection. More importantly, mutations of the arginine and lysine to alanine or glutamic acid in the receptor binding region ablated the heparin-binding activity of apoE, as determined by an in vitro heparin pulldown assay. HCV attachment could also be inhibited by a synthetic peptide derived from the apoE receptor-binding region. Collectively, these findings demonstrate that apoE mediates HCV attachment through specific interactions with cell surface heparan sulfate. PMID- 22532693 TI - Enhanced mammalian transmissibility of seasonal influenza A/H1N1 viruses encoding an oseltamivir-resistant neuraminidase. AB - Between 2007 and 2009, oseltamivir resistance developed among seasonal influenza A/H1N1 (sH1N1) virus isolates at an exponential rate, without a corresponding increase in oseltamivir usage. We hypothesized that the oseltamivir-resistant neuraminidase (NA), in addition to being relatively insusceptible to the antiviral effect of oseltamivir, might confer an additional fitness advantage on these viruses by enhancing their transmission efficiency among humans. Here we demonstrate that an oseltamivir-resistant clinical isolate, an A/Brisbane/59/2007(H1N1)-like virus isolated in New York State in 2008, transmits more efficiently among guinea pigs than does a highly similar, contemporaneous oseltamivir-sensitive isolate. With reverse genetics reassortants and point mutants of the two clinical isolates, we further show that expression of the oseltamivir-resistant NA in the context of viral proteins from the oseltamivir sensitive virus (a 7:1 reassortant) is sufficient to enhance transmissibility. In the guinea pig model, the NA is the critical determinant of transmission efficiency between oseltamivir-sensitive and -resistant Brisbane/59-like sH1N1 viruses, independent of concurrent drift mutations that occurred in other gene products. Our data suggest that the oseltamivir-resistant NA (specifically, one or both of the companion mutations, H275Y and D354G) may have allowed resistant Brisbane/59-like viruses to outtransmit sensitive isolates. These data provide in vivo evidence of an evolutionary mechanism that would explain the rapidity with which oseltamivir resistance achieved fixation among sH1N1 isolates in the human reservoir. PMID- 22532694 TI - Two crucial early steps in RNA synthesis by the hepatitis C virus polymerase involve a dual role of residue 405. AB - The hepatitis C virus (HCV) NS5B protein is an RNA-dependent RNA polymerase essential for replication of the viral RNA genome. In vitro and presumably in vivo, NS5B initiates RNA synthesis by a de novo mechanism and then processively copies the whole RNA template. Dissections of de novo RNA synthesis by genotype 1 NS5B proteins previously established that there are two successive crucial steps in de novo initiation. The first is dinucleotide formation, which requires a closed conformation, and the second is the transition to elongation, which requires an opening of NS5B. We also recently published a combined structural and functional analysis of genotype 2 HCV-NS5B proteins (of strains JFH1 and J6) that established residue 405 as a key element in de novo RNA synthesis (P. Simister et al., J. Virol. 83:11926-11939, 2009; M. Schmitt et al., J. Virol 85:2565-2581, 2011). We hypothesized that this residue stabilizes a particularly closed conformation conducive to dinucleotide formation. Here we report similar in vitro dissections of de novo synthesis for J6 and JFH1 NS5B proteins, as well as for mutants at position 405 of several genotype 1 and 2 strains. Our results show that an isoleucine at position 405 can promote both dinucleotide formation and the transition to elongation. New structural results highlight a molecular switch of position 405 with long-range effects, resolving the implied paradox of how the same residue can successively favor both the closed conformation of the dinucleotide formation step and the opening necessary to the transition step. PMID- 22532696 TI - Antibodies against the gH/gL/UL128/UL130/UL131 complex comprise the majority of the anti-cytomegalovirus (anti-CMV) neutralizing antibody response in CMV hyperimmune globulin. AB - Anti-cytomegalovirus (anti-CMV) hyperimmune globulin (HIG) has demonstrated efficacy in preventing CMV disease in solid-organ transplant patients as well as congenital disease when administered to pregnant women. To identify the neutralizing component of cytomegalovirus hyperimmune globulin (CMV-HIG), we performed serial depletions of CMV-HIG on cell-surface-expressed CMV antigens as well as purified antigens. Using this approach, we demonstrate that the major neutralizing antibody response is directed at the gH/gL/UL128/UL130/UL131 complex, suggesting little role for anti-gB antibodies in CMV-HIG neutralization. PMID- 22532695 TI - Implication of inflammatory macrophages, nuclear receptors, and interferon regulatory factors in increased virulence of pandemic 2009 H1N1 influenza A virus after host adaptation. AB - While pandemic 2009 H1N1 influenza A viruses were responsible for numerous severe infections in humans, these viruses do not typically cause corresponding severe disease in mammalian models. However, the generation of a virulent 2009 H1N1 virus following serial lung passage in mice has allowed for the modeling of human lung pathology in this species. Genetic determinants of mouse-adapted 2009 H1N1 viral pathogenicity have been identified, but the molecular and signaling characteristics of the host response following infection with this adapted virus have not been described. Here we compared the gene expression response following infection of mice with A/CA/04/2009 (CA/04) or the virulent mouse-adapted strain (MA-CA/04). Microarray analysis revealed that increased pathogenicity of MA-CA/04 was associated with the following: (i) an early and sustained inflammatory and interferon response that could be driven in part by interferon regulatory factors (IRFs) and increased NF-kappaB activation, as well as inhibition of the negative regulator TRIM24, (ii) early and persistent infiltration of immune cells, including inflammatory macrophages, and (iii) the absence of activation of lipid metabolism later in infection, which may be mediated by inhibition of nuclear receptors, including PPARG and HNF1A and -4A, with proinflammatory consequences. Further investigation of these signatures in the host response to other H1N1 viruses of various pathogenicities confirmed their general relevance for virulence of influenza virus and suggested that lung response to MA-CA/04 virus was similar to that following infection with lethal H1N1 r1918 influenza virus. This study links differential activation of IRFs, nuclear receptors, and macrophage infiltration with influenza virulence in vivo. PMID- 22532697 TI - Reovirus variants with mutations in genome segments S1 and L2 exhibit enhanced virion infectivity and superior oncolysis. AB - Reovirus preferentially replicates in transformed cells and is being explored as a cancer therapy. Immunological and physical barriers to virotherapy inspired a quest for reovirus variants with enhanced oncolytic potency. Using a classical genetics approach, we isolated two reovirus variants (T3v1 and T3v2) with superior replication relative to wild-type reovirus serotype 3 Dearing (T3wt) on various human and mouse tumorigenic cell lines. Unique mutations in reovirus lambda2 vertex protein and sigma1 cell attachment protein were associated with the large plaque-forming phenotype of T3v1 and T3v2, respectively. Both T3v1 and T3v2 exhibited higher infectivity (i.e., a higher PFU-to-particle ratio) than T3wt. A detailed analysis of virus replication revealed that virus cell binding and uncoating were equivalent for variant and wild-type reoviruses. However, T3v1 and T3v2 were significantly more efficient than T3wt in initiating productive infection. Thus, when cells were infected with equivalent input virus particles, T3v1 and T3v2 produced significantly higher levels of early viral RNAs relative to T3wt. Subsequent steps of virus replication (viral RNA and protein synthesis, virus assembly, and cell death) were equivalent for all three viruses. In a syngeneic mouse model of melanoma, both T3v1 and T3v2 prolonged mouse survival compared to wild-type reovirus. Our studies reveal that oncolytic potency of reovirus can be improved through distinct mutations that increase the infectivity of reovirus particles. PMID- 22532698 TI - Engineered regulation of lysozyme by the SH3-CB1 binding interaction. AB - The ability to design proteins with desired properties by using protein structural information will allow us to create high-value therapeutic and diagnostic products. Using the protein structures of lambda lysozyme and the SH3 domain of human Crk, we designed a synthetic protein switch that controls the activity of lysozyme by sterically hindering its active cleft through the binding of SH3 to its CB1 peptide-binding partner. First, several fusion protein designs with lysozyme and CB1 were modeled to determine the one with greatest steric effect in the presence of SH3. Next, the selected fusion protein was created and tested in vitro. In the absence of SH3, the lysozyme-CB1 fusion protein functioned normally. In the presence of SH3, the lysozyme activity was inhibited and with the addition of excess CB1 peptides to compete for SH3 binding, the lysozyme activity was restored. Lastly, this structure-based strategy can be used to engineer synthetic regulation by peptide-domain-binding interfaces into a variety of proteins. PMID- 22532699 TI - Predictors of outcomes of total knee replacement surgery. AB - OBJECTIVE: To identify pre-operative predictors of patient-reported outcomes of primary total knee replacement (TKR) surgery. METHODS: The Elective Orthopaedic Centre database is a large prospective cohort of 1991 patients receiving primary TKR in south-west London from 2005 to 2008. The primary outcome is the 6-month post-operative Oxford Knee Score (OKS). To classify whether patients had a clinically important outcome, we calculated a patient acceptable symptom state (PASS) for the 6-month OKS related to satisfaction with surgery. Potential predictor variables were pre-operative OKS, age, sex, BMI, deprivation, surgical side, diagnosis, operation type, American Society of Anesthesiologists grade and EQ5D anxiety/depression. Regression modelling was used to identify predictors of outcome. RESULTS: The strongest determinants of outcome include pre-operative pain/function-those with less severe pre-operative disease obtain the best outcomes; diagnosis in relation to pain outcome-patients with RA did better than those with OA; deprivation-those living in poorer areas had worse outcomes; and anxiety/depression-worse pre-operative anxiety/depression led to worse pain. Differences were observed between predictors of pain and functional outcomes. Diagnosis of RA and anxiety/depression were associated with pain, whereas age and gender were specifically associated with function. BMI was not a clinically important predictor of outcome. CONCLUSION: This study identified clinically important predictors of attained pain/function post-TKR. Predictors of pain were not necessarily the same as functional outcomes, which may be important in the context of a patient's expectations of surgery. Other predictive factors need to be identified to improve our ability to recognize patients at risk of poor TKR outcomes. PMID- 22532700 TI - INT6 interacts with MIF4GD/SLIP1 and is necessary for efficient histone mRNA translation. AB - The INT6/EIF3E protein has been implicated in mouse and human breast carcinogenesis. This subunit of the eIF3 translation initiation factor that includes a PCI domain exhibits specific features such as presence in the nucleus and ability to interact with other important cellular protein complexes like the 26S proteasome and the COP9 signalosome. It has been previously shown that INT6 was not essential for bulk translation, and this protein is considered to regulate expression of specific mRNAs. Based on the results of a two-hybrid screen performed with INT6 as bait, we characterize in this article the MIF4GD/SLIP1 protein as an interactor of this eIF3 subunit. MIF4GD was previously shown to associate with SLBP, which binds the stem-loop located at the 3' end of the histone mRNAs, and to be necessary for efficient translation of these cell cycle-regulated mRNAs that lack a poly(A) tail. In line with the interaction of both proteins, we show using the RNA interference approach that INT6 is also essential to S-phase histone mRNA translation. This was observed by analyzing expression of endogenous histones and by testing heterologous constructs placing the luciferase reporter gene under the control of the stem-loop element of various histone genes. With such a reporter plasmid, silencing and overexpression of INT6 exerted opposite effects. In agreement with these results, INT6 and MIF4GD were observed to colocalize in cytoplasmic foci. We conclude from these data that INT6, by establishing interactions with MIF4GD and SLBP, plays an important role in translation of poly(A) minus histone mRNAs. PMID- 22532701 TI - Evaluation of normalization methods in mammalian microRNA-Seq data. AB - Simple total tag count normalization is inadequate for microRNA sequencing data generated from the next generation sequencing technology. However, so far systematic evaluation of normalization methods on microRNA sequencing data is lacking. We comprehensively evaluate seven commonly used normalization methods including global normalization, Lowess normalization, Trimmed Mean Method (TMM), quantile normalization, scaling normalization, variance stabilization, and invariant method. We assess these methods on two individual experimental data sets with the empirical statistical metrics of mean square error (MSE) and Kolmogorov-Smirnov (K-S) statistic. Additionally, we evaluate the methods with results from quantitative PCR validation. Our results consistently show that Lowess normalization and quantile normalization perform the best, whereas TMM, a method applied to the RNA-Sequencing normalization, performs the worst. The poor performance of TMM normalization is further evidenced by abnormal results from the test of differential expression (DE) of microRNA-Seq data. Comparing with the models used for DE, the choice of normalization method is the primary factor that affects the results of DE. In summary, Lowess normalization and quantile normalization are recommended for normalizing microRNA-Seq data, whereas the TMM method should be used with caution. PMID- 22532702 TI - Intermediate phenotype analysis of patients, unaffected siblings, and healthy controls identifies VMAT2 as a candidate gene for psychotic disorder and neurocognition. AB - Psychotic disorders are associated with neurocognitive alterations that aggregate in unaffected family members, suggesting that genetic vulnerability to psychotic disorder impacts neurocognition. The aim of the present study was to investigate whether selected schizophrenia candidate single nucleotide polymorphisms (SNPs) are associated with (1) neurocognitive functioning across populations at different genetic risk for psychosis (2) and psychotic disorder. The association between 152 SNPs in 43 candidate genes and a composite measure of neurocognitive functioning was examined in 718 patients with psychotic disorder. Follow-up analyses were carried out in 750 unaffected siblings and 389 healthy comparison subjects. In the patients, 13 associations between SNPs and cognitive functioning were significant at P < .05, situated in DRD1, DRD3, SLC6A3, BDNF, FGF2, SLC18A2, FKBP5, and DNMT3B. Follow-up of these SNPs revealed a significant and directionally similar association for SLC18A2 (alternatively VMAT2) rs363227 in siblings (B = -0.13, P = .04) and a trend association in control subjects (B = 0.10, P = .12). This association was accompanied by a significantly increased risk for psychotic disorder associated with the T allele (linear OR = 1.51, 95% CI 1.10-2.07, P = .01), which was reduced when covarying for cognitive performance (OR = 1.29, 95% CI 0.92-1.81, P = .14), suggesting mediation. Genetic variation in VMAT2 may be linked to alterations in cognitive functioning underlying psychotic disorder, possibly through altered transport of monoamines into synaptic vesicles. PMID- 22532704 TI - An intact social cognitive process in schizophrenia: situational context effects on perception of facial affect. AB - BACKGROUND: Impaired facial affect recognition is the most consistent social cognitive finding in schizophrenia. Although social situations provide powerful constraints on our perception, little is known about how situational context modulates facial affect recognition in schizophrenia. METHODS: Study 1 was a single-site study with 34 schizophrenia patients and 22 healthy controls. Study 2 was a 2-site study with 68 schizophrenia patients and 28 controls. Both studies administered a Situational Context Facial Affect Recognition Task with 2 conditions: a situational context condition and a no-context condition. For the situational context condition, a briefly shown face was preceded by a sentence describing either a fear- or surprise-inducing event. In the no-context condition, a face was presented without a sentence. For both conditions, subjects rated how fearful or surprised the face appeared on a 9-point Likert scale. RESULTS: For the situational context condition of study 1, both patients and controls rated faces as more afraid when they were paired with fear-inducing sentences and as more surprised when they were paired with surprise-inducing sentences. The degree of modulation was comparable across groups. For the no context condition, patients rated faces comparably to controls. The findings of study 2 replicated those from study 1. CONCLUSIONS: Despite previous abnormalities in other types of context paradigms, this study found intact situational context processing in schizophrenia, suggesting that patients benefit from situational context when interpreting ambiguous facial expression. This area of relative social cognitive strength in schizophrenia has implications for social cognitive training programs. PMID- 22532705 TI - Does differential predation permit invasive and native mosquito larvae to coexist in Florida? AB - 1. The hypothesis that selective predation on larvae of the invasive Aedes albopictus (Skuse) could account for its stable coexistence with the native mosquito species and inferior competitor Ochlerotatus triseriatus (Say) in Florida treeholes and container systems was tested experimentally.2. Functional responses of the two dipteran predators Toxorhynchites rutilus (Coquillett) and Corethrella appendiculata (Grabham) were evaluated separately for A. albopictus and O. triseriatus prey. Both predators exhibited type II functional responses and consistently consumed more of the invasive species. Handling time of T. rutilus feeding upon O. triseriatus was significantly longer than when preying upon the invasive species.3. When either predator species was offered varying ratios of the two prey species, A. albopictus was consumed preferentially. The absence of a prey ratio effect on preference indicated that switching probably does not occur.4. The higher maximum feeding rate upon, and preference for, A. albopictus suggests that differential predation may foster coexistence of the invasive and native mosquito prey species in Florida. PMID- 22532703 TI - Glutamate dysfunction in hippocampus: relevance of dentate gyrus and CA3 signaling. AB - Synaptic glutamate signaling in brain is highly complex and includes multiple interacting receptors, modulating cotransmitters and distinct regional dynamics. Medial temporal lobe (MTL) memory structures receive excitatory inputs from neocortical sensory and associational projections: afferents from neocortex pass to parahippocampal cortex, then to layers II/III of entorhinal cortex, and then onto hippocampal subfields. Principles of Hebbian plasticity govern synaptic encoding of memory signals, and homeostatic plasticity processes influence the activity of the memory system as a whole. Hippocampal imaging studies in schizophrenia have identified 2 alterations in MTL--increases in baseline blood perfusion and decreases in task-related activation. These observations along with converging postsynaptic hippocampal protein changes suggest that homeostatic plasticity mechanisms might be altered in schizophrenia hippocampus. If hippocampal pattern separation is diminished due to partial dentate gyrus failure (resulting in 'spurious associations') and also if pattern completion is accelerated and increasingly inaccurate due to increased CA3 associational activity, then it is conceivable that associations could be false and, especially if driven by anxiety or stress, could generate psychotic content, with the mistaken associations being laid down in memory, despite their psychotic content, especially delusions and thought disorder. PMID- 22532706 TI - Introduction: dealing with what is. PMID- 22532707 TI - Climate change: the evidence and our options. AB - Glaciers serve as early indicators of climate change. Over the last 35 years, our research team has recovered ice-core records of climatic and environmental variations from the polar regions and from low-latitude high-elevation ice fields from 16 countries. The ongoing widespread melting of high-elevation glaciers and ice caps, particularly in low to middle latitudes, provides some of the strongest evidence to date that a large-scale, pervasive, and, in some cases, rapid change in Earth's climate system is underway. This paper highlights observations of 20th and 21st century glacier shrinkage in the Andes, the Himalayas, and on Mount Kilimanjaro. Ice cores retrieved from shrinking glaciers around the world confirm their continuous existence for periods ranging from hundreds of years to multiple millennia, suggesting that climatological conditions that dominate those regions today are different from those under which these ice fields originally accumulated and have been sustained. The current warming is therefore unusual when viewed from the millennial perspective provided by multiple lines of proxy evidence and the 160-year record of direct temperature measurements. Despite all this evidence, plus the well-documented continual increase in atmospheric greenhouse gas concentrations, societies have taken little action to address this global-scale problem. Hence, the rate of global carbon dioxide emissions continues to accelerate. As a result of our inaction, we have three options: mitigation, adaptation, and suffering. PMID- 22532708 TI - The recycling solution: how I increased recycling on dilworth road. PMID- 22532709 TI - Buying green. PMID- 22532710 TI - I'll Save the World from Global Warming-Tomorrow: Using Procrastination Management to Combat Global Warming. PMID- 22532711 TI - Helping for change. PMID- 22532712 TI - Virtual rewards for driving green. PMID- 22532713 TI - The power of cooperation. PMID- 22532714 TI - TerraKids: An Interactive Web Site Where Kids Learn about Saving the Environment. PMID- 22532715 TI - Climate change: meeting the challenge. PMID- 22532716 TI - Functions of research in radical behaviorism for the further development of behavior analysis. AB - The experimental analysis of behavior began as an inductively oriented, empirically based scientific field. As the field grew, its distinctive system of science-radical behaviorism-grew with it. The continuing growth of the empirical base of the field has been accompanied by the growth of the literature on radical behaviorism and its implications. In this article the case is made that radical behaviorism is more than an abstract description of the assumptions and practices of the field; it is an active area of research within the field itself, and that such theoretical research is of great importance to the development of the field. Some of the characteristics of radical behaviorism are described in brief, along with the functions of organization, clarification, and extension of various aspects of behavior-analytic science. Research examples are given from the areas of work on the system itself, behavior-analytic theory, and implications of behavior analysis for issues and findings in other fields. The unique characteristics of radical behaviorism provide an integrative and generative scientific framework for the continuing development of behavior analysis. PMID- 22532717 TI - On the use of fluency training in the behavioral treatment of autism: a commentary. AB - The substantial demand for behavior-analytic treatment of early childhood autism has been associated with rapid dissemination of treatment procedures to practitioners and caregivers. This level of demand could plausibly induce premature dissemination of treatments that do not yet have sufficient empirical support. We argue that this might have happened with the use of fluency training for learners with autism and identify four areas of research that are necessary to ensure that dissemination efforts are better matched to the available empirical support for this instructional strategy. PMID- 22532718 TI - A Response to Stewart, McElwee, and Ming. PMID- 22532719 TI - Getting It Wrong: Comment on Moore's "Behaviorism and the Stages of Scientific Activity". PMID- 22532720 TI - Getting it right: a reply to baum. AB - In this reply to Baum, I emphasize that the failure to understand the processes associated with scientific verbal behavior may result in scientific statements like the generalized matching law that do not accurately reflect cause-and-effect relations. PMID- 22532721 TI - Dragon Training and Changing Culture: A Review of DreamWorks' How to Train Your Dragon. AB - DreamWorks' How to Train Your Dragon is an animated coming-of-age story in which the hero uses behavioral techniques to befriend and then to train an adversary. This movie provides an example of the successful dissemination of behavioral principles and technologies to the general population. Although it does not represent best practices in every instance, the movie may be an indication of a broader social acceptance of behavioral approaches to conflict resolution. PMID- 22532722 TI - Editorial. PMID- 22532724 TI - Is translation the problem? Some reactions to critchfield (2011). PMID- 22532723 TI - Translational contributions of the experimental analysis of behavior. AB - It has been argued that to increase societal impact behavioral researchers must do more to address problems of obvious practical importance. The basic science wing of behavior analysis has been described as especially detached from this goal, but is it really necessary that basic science demonstrate social relevance? If so, why hasn't this occurred more often, and what can be done to improve the status quo? To address these questions and to stimulate discussion about the future of basic behavior science, I describe two widely embraced arguments in favor of pure basic science (that which is undertaken without concern for practical applications); explain why a translational research agenda is likely to better recruit tangible support for basic science; propose that addressing practical problems does not require basic science to abandon its focus on fundamental principles; and identify some possible impediments to translational innovation that may need to be addressed for basic behavior science to increase its translational footprint. PMID- 22532725 TI - Translational Research: It's not 1960s Behavior Analysis. PMID- 22532726 TI - Reach out. PMID- 22532727 TI - Three variations of translational research: comments on critchfield (2011). PMID- 22532728 TI - Translational behavior analysis and practical benefits. PMID- 22532729 TI - The aesthetics of intervention in defense of the esoteric. PMID- 22532730 TI - Tuberculosis detection by giant african pouched rats. AB - In recent years, operant discrimination training procedures have been used to teach giant African pouched rats to detect tuberculosis (TB) in human sputum samples. This article summarizes how the rats are trained and used operationally, as well as their performance in studies published to date. Available data suggest that pouched rats, which can evaluate many samples quickly, are sufficiently accurate in detecting TB to merit further investigation as a diagnostic tool. PMID- 22532731 TI - Applied behavior analysis is ideal for the development of a land mine detection technology using animals. AB - The detection and subsequent removal of land mines and unexploded ordnance (UXO) from many developing countries are slow, expensive, and dangerous tasks, but have the potential to improve the well-being of millions of people. Consequently, those involved with humanitarian mine and UXO clearance are actively searching for new and more efficient detection technologies. Remote explosive scent tracing (REST) using trained dogs has the potential to be one such technology. However, details regarding how best to train, test, and deploy dogs in this role have never been made publicly available. This article describes how the key characteristics of applied behavior analysis, as described by Baer, Wolf and Risley (1968, 1987), served as important objectives for the research and development of the behavioral technology component of REST while the author worked in humanitarian demining. PMID- 22532732 TI - A Quantitative Analysis and Natural History of B. F. Skinner's Coauthoring Practices. AB - This paper describes and analyzes B. F. Skinner's coauthoring practices. After identifying his 35 coauthored publications and 27 coauthors, we analyze his coauthored works by their form (e.g., journal articles) and kind (e.g., empirical); identify the journals in which he published and their type (e.g., data-type); describe his overall and local rates of publishing with his coauthors (e.g., noting breaks in the latter); and compare his coauthoring practices with his single-authoring practices (e.g., form, kind, journal type) and with those in the scientometric literature (e.g., majority of coauthored publications are empirical). We address these findings in the context of describing the natural history of Skinner's coauthoring practices. Finally, we describe some limitations in our methods and offer suggestions for future research. PMID- 22532733 TI - A resource on behavioral terminology: an annotated bibliography of on terms articles in the behavior analyst. AB - An annotated bibliography that summarizes the On Terms articles on behavior analytic terminology from The Behavior Analyst is provided. Thirty-five articles published between 1979 and 2010 were identified, annotated, and classified using common behavior analysis course-content frameworks. PMID- 22532734 TI - The association for behavior analysis international position statement on restraint and seclusion. AB - A task force authorized by the Executive Council of the Association for Behavior Analysis International (ABAI) generated the statement below concerning the techniques called restraint and seclusion. Members of the task force independently reviewed the scientific literature concerning restraint and seclusion and agreed unanimously to the content of the statement. The Executive Council accepted the statement, and it was subsequently approved by a two-thirds majority vote of the general membership. It now constitutes official ABAI policy. The position statement is posted on the ABAI Web site (www.abainternational.org/ABA/statements/RestraintSeclusion.asp). The purpose of the position statement is to provide guidance to behavior analysts and other professionals interested in the position of ABAI on these controversial topics. In extreme cases, abuses of procedures erroneously used in the name of behavior analysis are not defensible. On the other hand, behavior analysts acting ethically and in good faith are provided with guidelines for sound and acceptably safe practice. To the extent that behavior-analytic positions influence public policy and law, this statement can be presented to officials and lawmakers to guide informed decision making. At the conclusion of the document, a bibliography is provided of articles and presentations considered by one or more task force members in developing the position statement. PMID- 22532735 TI - Editorial. PMID- 22532736 TI - To a young basic scientist, about to embark on a program of translational research. AB - From recent commentaries about the role of basic behavior scientists in translational research, I distill some advice to young investigators who seek to apply their basic science training to translational studies. Among the challenges are (a) devising use-inspired research programs that complement, and are not redundant with, existing efforts in basic and applied behavior analysis; and (b) making tactical decisions, such as the selection of methods and collaborators, based on the research topic rather than, necessarily, the existing traditions in behavioral research. Finally, it must be recognized that although use-inspired basic research has the potential to attract support to basic laboratories and contribute to "saving the world," neither of these outcomes is guaranteed. I discuss the relative risks for basic scientists who proceed with use-inspired basic research rather than ignore such translational questions. PMID- 22532737 TI - Observing ben wyckoff: from basic research to programmed instruction and social issues. AB - L. Benjamin Wyckoff's seminal contributions to both psychological theory and application are the subject of this review. Wyckoff started his academic career as a graduate student at Indiana University, where he developed the observing response procedure under the guidance of B. F. Skinner and C. J. Burke. At the University of Wisconsin-Madison, Wyckoff refined his mathematical theory of secondary reinforcement. This theory was the impetus for his creation of an electronic simulation of a rat running a T maze, one of the first "computer models" of learning. Wyckoff next went to Emory University, leaving there to help create two of the most successful companies dedicated to the advancement of programmed instruction and teaching machines: Teaching Machines, Inc. and the Human Development Institute. Wyckoff's involvement in these companies epitomizes the application of basic behavior-analytic principles in the development of technology to improve education and human relationships. The emergent picture of Wyckoff is that of a man who, through his research, professional work in educational applications of behavioral principles, and active involvement in the civil rights movement of the 1960s, was strongly committed to applying behavioral science to positively influence human behavior change. PMID- 22532739 TI - Introduction: private events in a natural science of behavior. PMID- 22532738 TI - Contributions of contingencies in modern societies to "privacy" in the behavioral relations of cognition and emotion. AB - The aim of this paper is to examine specific features of modern individualistic societies that contribute to "emotions" and "cognitions" becoming a matter of privacy. Although some behavior analysts identify emotions and cognitions as "private events," we argue with Skinner (1945) that cognitions and emotions are relations among events and that their origin is in public events in the contingencies of reinforcement maintained by other people. Guided by Elias (1939/1996), we suggest that the shift from feudal economies to market economies involved the increasing individualization of society's members. This individualizing process includes the socially maintained contingencies that bring some verbal responses under control of private stimulation and reduce the magnitude of some verbal responses to a covert level. Behavioral relations in which either stimuli or responses (or both) cannot be observed by others set the stage for a concept of "privacy." Changes in societal contingencies that gave rise to individualization and the attribution of privacy to cognitions and emotions are suggested to include the following: (a) increasing frequency of individual consequences that have no apparent or direct relevance to the group; (b) increasing numbers of concurrent contingencies and choice requirements; (c) conflicts between immediate and delayed consequences for the individual; and (d) conflicts between consequences for the individual and for the group. PMID- 22532740 TI - Behaviorism, private events, and the molar view of behavior. AB - Viewing the science of behavior (behavior analysis) to be a natural science, radical behaviorism rejects any form of dualism, including subjective-objective or inner-outer dualism. Yet radical behaviorists often claim that treating private events as covert behavior and internal stimuli is necessary and important to behavior analysis. To the contrary, this paper argues that, compared with the rejection of dualism, private events constitute a trivial idea and are irrelevant to accounts of behavior. Viewed in the framework of evolutionary theory or for any practical purpose, behavior is commerce with the environment. By its very nature, behavior is extended in time. The temptation to posit private events arises when an activity is viewed in too small a time frame, obscuring what the activity does. When activities are viewed in an appropriately extended time frame, private events become irrelevant to the account. This insight provides the answer to many philosophical questions about thinking, sensing, and feeling. Confusion about private events arises in large part from failure to appreciate fully the radical implications of replacing mentalistic ideas about language with the concept of verbal behavior. Like other operant behavior, verbal behavior involves no agent and no hidden causes; like all natural events, it is caused by other natural events. In a science of behavior grounded in evolutionary theory, the same set of principles applies to verbal and nonverbal behavior and to human and nonhuman organisms. PMID- 22532741 TI - Consideration of Private Events is Required in a Comprehensive Science of Behavior. PMID- 22532742 TI - Baum's Private Thoughts. PMID- 22532743 TI - Has radical behaviorism lost its right to privacy? PMID- 22532744 TI - Private versus Inner in Multiscaled Interpretation. PMID- 22532745 TI - On Baum's Public Claim That He Has No Significant Private Events. PMID- 22532746 TI - No need for private events in a science of behavior: response to commentaries. PMID- 22532747 TI - Can we consume our way out of climate change? A call for analysis. AB - The problem of climate change is analyzed as a manifestation of economic growth, and the steady-state economy of ecological economics is proposed as a system-wide solution. Four classes of more specific solutions are described. In the absence of analysis, cultural inertia will bias solutions in favor of green consumption as a generalized solution strategy. By itself, green consumption is a flawed solution to climate change because it perpetuates or even accelerates economic growth that is incompatible with a sustainable culture. Addressing climate change requires an integration of regulatory, energy efficiency, skill-based, and dissemination solutions. Behavioral scientists are encouraged to work with others in ecological economics and other social sciences who recognize cultural reinvention as a means of achieving sustainability. PMID- 22532748 TI - The personal life of the behavior analyst. AB - The human species faces crises of critical proportions. Excessive population, global warming, and the anticipated descent from peak fossil-fuel extraction promise to change our future in far-reaching ways. Operant conditioning prepares the individual for a world similar to the selecting past, but our world is changing more rapidly than our adaptation. As individuals, we cannot make substantial changes in the world at large because we do not control enough reinforcers, but we can turn to the sources of our personal behavior and manipulate them. We will need help. Better organized social networks and the self management techniques they support can promote immediate changes in consumption at home, work, and moving about in our personal worlds. Surprisingly, consuming less can lead to more satisfying and happier lives, but a better understanding of reinforcement contingencies is necessary. We can recover the strengthening effects of personal daily accomplishments that are eroded when conditioned generalized reinforcers intervene. When we get our own personal lives in order we can reduce our carbon footprints, restore the connections between our behavior and its strengthening effects, and become models worthy of imitation. PMID- 22532749 TI - Beyond freedom and dignity at 40: comments on behavioral science, the future, and chance (2007). AB - Forty years after the publication of Beyond Freedom and Dignity (Skinner, 1971) and the continuing growth of behavior analysis, the future of humanity and the role of behavioral science in that future remain uncertain. A recent paper by Chance (2007) documented a shift in Skinner's views during the last years of his life. Skinner had long advocated a science and technology of behavior for finding and engineering solutions to cultural and global problems and advancing human development. This optimism had given way under a gradual realization that the science of behavior was in fact showing how such problems were unlikely to be solved in time to avert a variety of possible disasters. Chance described nine behavioral phenomena that appear to interfere with effective problem-solving behavior on a large scale and in effective time frames. These phenomena are reviewed toward an analysis of common themes. Research is also reviewed that involves nonverbal, verbal, and cultural contingencies that may lead to applications designed to address the common themes. Problems and strategies of implementation are also discussed. The challenges are daunting, but may nevertheless be regarded as technical problems best suited for a science and technology of behavior. PMID- 22532750 TI - Interesting times: practice, science, and professional associations in behavior analysis. AB - Neither practitioners nor scientists appear to be fully satisfied with the world's largest behavior-analytic membership organization. Each community appears to believe that initiatives that serve the other will undermine the association's capacity to serve their own needs. Historical examples suggest that such discord is predicted when practitioners and scientists cohabit the same association. This is true because all professional associations exist to address guild interests, and practice and science are different professions with different guild interests. No association, therefore, can succeed in being all things to all people. The solution is to assure that practice and science communities are well served by separate professional associations. I comment briefly on how this outcome might be promoted. PMID- 22532751 TI - Editorial: Where should we go from here. PMID- 22532752 TI - The multiple control of verbal behavior. AB - Amid the novel terms and original analyses in Skinner's Verbal Behavior, the importance of his discussion of multiple control is easily missed, but multiple control of verbal responses is the rule rather than the exception. In this paper we summarize and illustrate Skinner's analysis of multiple control and introduce the terms convergent multiple control and divergent multiple control. We point out some implications for applied work and discuss examples of the role of multiple control in humor, poetry, problem solving, and recall. Joint control and conditional discrimination are discussed as special cases of multiple control. We suggest that multiple control is a useful analytic tool for interpreting virtually all complex behavior, and we consider the concepts of derived relations and naming as cases in point. PMID- 22532753 TI - Intraverbal behavior and verbal conditional discriminations in typically developing children and children with autism. AB - Individuals with autism often experience difficulty acquiring a functional intraverbal repertoire, despite demonstrating strong mand, tact, and listener skills. This learning problem may be related to the fact that the primary antecedent variable for most intraverbal behavior involves a type of multiple control identified as a verbal conditional discrimination (VC(D)). The current study is a descriptive analysis that sought to determine if there is a general sequence of intraverbal acquisition by typically developing children and for children with autism, and if this sequence could be used as a framework for intraverbal assessment and intervention. Thirty-nine typically developing children and 71 children with autism were administered an 80-item intraverbal subtest that contained increasingly difficult intraverbal questions and VC(D)s. For the typically developing children the results showed that there was a correlation between age and correct intraverbal responses. However, there was variability in the scores of children who were the same age. An error analysis revealed that compound VC(D)s were the primary cause of errors. Children with autism made the same types of errors as typically developing children who scored at their level on the subtest. These data suggest a potential framework and sequence for intraverbal assessment and intervention. PMID- 22532754 TI - Analyzing stimulus-stimulus pairing effects on preferences for speech sounds. AB - Several studies have demonstrated effects of stimulus-stimulus pairing (SSP) on children's vocalizations, but numerous treatment failures have also been reported. The present study attempted to isolate procedural variables related to failures of SSP to condition speech sounds as reinforcers. Three boys diagnosed with autism-spectrum disorders participated. Phase 1 was designed to assess SSP effects on production of auditory stimuli via button pressing. When SSP failed to produce a preference for the target stimulus, we instituted a series of procedural manipulations intended to address potential reasons for failure. One participant preferred the target stimulus when given the opportunity to select preferred items for pairing prior to each session, but a subsequent reversal attempt produced ambiguous results. Two participants showed no consistent preference in Phase 1 and underwent a within-session reinforcer evaluation in Phase 2, in which alternative controlling variables were demonstrated by delivering preferred stimuli contingent on button pressing. PMID- 22532755 TI - Effects of multiple exemplar training on the emergence of derived relations in preschool children learning a second language. AB - We evaluated the facilitative effects of multiple exemplar training (MET) on the establishment of derived tact relations in typically developing children. A multiple-probe design across stimulus sets was implemented to introduce MET. Participants were first taught to conditionally relate dictated names in English to their corresponding objects (listener behavior; A-B relations), followed by tests for derived tacts (B-A relations). If participants failed these tests, MET was implemented whereby tact relations were explicitly taught with novel stimulus sets, followed by test probes with the original training set. MET continued with novel stimuli until participants met criterion for the emergence of derived tact relations or after exposure to three MET sets. Results indicated failed tests for tact relations following direct training in listener relations, and marked improvements in derived tact relations following MET across all participants. PMID- 22532756 TI - Further evaluation of prompting tactics for establishing intraverbal responding in children with autism. AB - We compared prompting tactics to establish intraverbal responding (question answering) in four boys with autism. Based on the results of intraverbal, textual, echoic, and tact pretests, we compared vocal and picture prompts with three participants, and textual, vocal, and picture prompts with one participant. We also evaluated repeated acquisition with different question sets, and included a concurrent-chains arrangement, in which initial link selections determined which prompting procedure occurred in the terminal link. All the prompting procedures were effective in establishing intraverbal responding, but vocal prompts resulted in the fewest trials to criterion for all four participants during the initial prompt comparison. However, the results were less consistent for the second comparison. The concurrent chains arrangement revealed a clear preference for picture prompts for one participant, but the results for the others were inconclusive. PMID- 22532757 TI - Acquisition of mands, tacts, and intraverbals through sign exposure in an individual with autism. AB - Many children with autism communicate through the use of alternative communication systems, such as sign language. Limited research has been conducted on the situations under which sign language will be acquired across verbal operants without direct teaching. The purpose of the current study was to evaluate exposure to sign language on the acquisition of signed mands, tacts, and intraverbals in a male child with autism. Results indicated fast acquisition of mands, tacts, and intraverbals without direct teaching. Results are discussed in the context of future research investigating exposure without direct teaching in individuals who communicate with alternative communication systems. PMID- 22532758 TI - Effects of conditioning voices as reinforcers for listener responses on rate of learning, awareness, and preferences for listening to stories in preschoolers with autism. AB - We used a delayed non-concurrent pre- and post-intervention probe design to test the effects of a voice conditioning protocol (VCP) with 3 preschoolers with autism on (a) rate of acquisition of listener curricular objectives, (b) observing voices and the presence of adults across 3 settings, (c) selecting to listen to adults tell stories in free play setting, and (d) the occurrence of stereotypy in the story setting. The VCP conditioned voices as reinforcers for listening to recordings of voices via stimulus-stimulus pairing, which resulted in the children listening to audio recordings of voices in 90% of intervals in 5 min concurrent-operant preference tests. After voices became conditioned reinforcers, all 3 children's learning accelerated; 2 children's observing responses increased in the 3 settings; and 2 children selected to listen to stories and also showed decreased stereotypy in the story setting. The data suggest that conditioned reinforcement for observing responses may be a verbal behavior developmental cusp that acts to accelerate learning that involves listening, and that the cusp may be induced using the VCP. PMID- 22532759 TI - Rule-governed behavior: teaching a preliminary repertoire of rule-following to children with autism. AB - Rule-governed behavior is generally considered an integral component of complex verbal repertoires but has rarely been the subject of empirical research. In particular, little or no previous research has attempted to establish rule governed behavior in individuals who do not already display the repertoire. This study consists of two experiments that evaluated multiple exemplar training procedures for teaching a simple component skill, which may be necessary for developing a repertoire of rule-governed behavior. In both experiments, children with autism were taught to respond to simple rules that specified antecedents and the behaviors that should occur in their presence. In the first study, participants were taught to respond to rules containing "if/then" statements, where the antecedent was specified before the behavior. The second experiment was a replication and extension of the first. It involved a variation on the manner in which rules were presented. Both experiments eventually demonstrated generalization to novel rules for all participants; however variations to the standard procedure were required for several participants. Results suggest that rule-following can be analyzed and taught as generalized operant behavior and implications for future research are discussed. PMID- 22532760 TI - The emergence of autoclitic frames in atypically and typically developing children as a function of multiple exemplar instruction. AB - In two experiments, we tested the effect of multiple exemplar instruction (MEI) for training sets on the emergence of autoclitic frames for spatial relations for novel tacts and mands. In Experiment 1, we used a replicated pre- and post intervention probe design with four students with significant learning disabilities to test for acquisition of four autoclitic frames with novel tacts and mands before and after MEI. The untaught topographies emerged for all participants. In Experiment 2, we used a multiple probe design to test the effects of the MEI procedures on the same responses in four typically developing, bilingual students. The novel usage emerged for all participants. In the latter experiment, the children demonstrated untaught usage of mand or tact frames regardless of whether they were taught to respond in either listener or speaker functions alone or across listener and speaker functions. The findings are discussed in terms of the role of MEI in the formation of abstractions. PMID- 22532761 TI - Establishing naming in typically developing two-year-old children as a function of multiple exemplar speaker and listener experiences. AB - Naming is a verbal developmental capability and cusp that allows children to acquire listener and speaker functions without direct instruction (e.g., incidental learning of words for objects). We screened 19 typically developing 2- and 3-year-old children for the presence of Naming for 3-dimensional objects. All 9 3-year-olds had Naming, and 8 of 10 2-year-olds lacked Naming. For the 2-year old children who lacked Naming, we used multiple-probe designs (2 groups of 4 children) to test the effect of multiple exemplar instruction (MEI) across speaker and listener responses on the emergence of Naming. Prior to the MEI, the children could not emit untaught listener or speaker responses following match-to sample instruction with novel stimuli, during which they had heard the experimenter tact the stimuli. After MEI with a different set of novel stimuli, the children emitted listener and speaker responses when probed with the original stimuli, in the absence of any further instruction with those stimuli. Seven of 8 children acquired the speaker and listener responses of Naming at 83% to 100% accuracy. We discuss the basic and applied science implications. PMID- 22532762 TI - Teaching a child with autism to mand for information using "how". AB - Children with autism often do not learn to mand for information without structured teaching. Studies have demonstrated that manipulation of establishing operations (EOs), prompts, prompt fading, and differential reinforcement are effective in teaching children with autism to ask "wh" questions such as "what," "who," and "where." To date, no studies have evaluated procedures to teach children with autism to mand for information using "how." Teaching the mand, "how" is uniquely challenging because once the information regarding how to do something is provided, the EO may no longer be present. The following study evaluated a procedure to teach one child with autism to mand for information using "how" to obtain information to complete multiple activities. The results have implications for clinical application and future research on contriving EOs to teach the mand, "how." PMID- 22532763 TI - A functional analysis of gestural behaviors emitted by young children with severe developmental disabilities. AB - Many children with severe developmental disabilities emit idiosyncratic gestures that may function as verbal operants (Sigafoos et al., 2000). This study examined the effectiveness of a functional analysis methodology to identify the variables responsible for gestures emitted by 2 young children with severe developmental disabilities. Potential verbal operants for each participant were functionally analyzed using a multi-element design. Results indicate that gestures were maintained by access to tangible items or the delivery of information about novel stimuli. This study extends the use of functional analysis to identify conditions under which children with developmental disabilities emit gestural verbal behavior. PMID- 22532764 TI - Understanding observational learning: an interbehavioral approach. AB - Observational learning is an important area in the field of psychology and behavior science more generally. Given this, it is essential that behavior analysts articulate a sound theory of how behavior change occurs through observation. This paper begins with an overview of seminal research in the area of observational learning, followed by a consideration of common behavior analytic conceptualizations of these findings. The interbehavioral perspective is then outlined, shedding light on some difficulties with the existing behavior analytic approaches. The implications of embracing the interbehavioral perspective for understanding the most complex sorts of behavior, including those involved in observational learning are considered. PMID- 22532766 TI - Endovascular revascularization of symptomatic infrapopliteal arteriosclerotic occlusive disease: comparison of atherectomy and angioplasty. AB - The preferred method for revascularization of symptomatic infrapopliteal arterial occlusive disease (IPAD) has traditionally been open vascular bypass. Endovascular techniques have been increasingly applied to treat tibial disease with mixed results. We evaluated the short-term outcome of percutaneous infrapopliteal intervention and compared the different techniques used. A retrospective analysis of consecutive patients undergoing endovascular treatment for infrapopliteal arterial occlusive lesions between 2003 and 2007 in a tertiary teaching hospital was performed. Patient demographic data, indication for intervention, and periprocedural complications were recorded. Periprocedural and short-term outcomes were measured and compared. Forty-nine infrapopliteal arteries in 35 patients were treated. Twenty vessels (15 patients) underwent angioplasty and 29 vessels (20 patients) were treated with atherectomy. Demographic and angiographic characteristics were similar between the groups. Twenty-six patients had concurrent femoral and/or popliteal artery interventions. Overall, technical success was 90% and similar between angioplasty and atherectomy groups (85% versus 93%, p = NS). The vessel-specific complication rate was 10% and was similar between both groups (angioplasty 5% versus atherectomy 14%, p = NS). One dissection occurred in the angioplasty group; one perforation and three thromboembolic events occurred in the atherectomy group. Limb salvage and freedom from reintervention at 6 months were 81% and 68%, respectively, and were not significantly different between the angioplasty and atherectomy groups. Endovascular intervention for IPAD had acceptable periprocedural and short-term success rates in our high-risk patient population. Both atherectomy and angioplasty can be used successfully to treat symptomatic IPAD. PMID- 22532767 TI - Risk factors predictive of carotid artery stenting-associated subclinical microemboli. AB - Subclinical microemboli documented on diffusion-weighted magnetic resonance imaging (DWI) are common following carotid artery stenting (CAS) procedures despite absence of neurological symptoms. This study was to evaluate risk factors predictive of microemboli in patients undergoing protected CAS with a distal embolic protection device. All CAS patients who received pre- and postprocedural magnetic resonance imaging (MRI) evaluations for carotid interventions at a single academic institution from July 2004 to December 2008 were examined. Microemboli were defined by new hyperintensities on postoperative DWI with corresponding decreased diffusion. Risk factors including patient demographics, medical comorbidities, clinical symptoms, lesion morphologies, and perioperative information were examined, and logistic regression analyses were utilized to determine predictors of CAS-related microemboli. A total of 204 patients underwent carotid interventions (76 CAS and 128 carotid endarterectomies) during the study period; 167 of them, including 67 CAS patients, received both preoperative and postoperative MRIs. Among those who underwent protected CAS, the incidence of microemboli was 46.3% despite a relative low incidence of associated neurological symptoms (2.9%). Univariate and multivariate regression analyses showed that date of procedure (odds ratio [OR] 30.6 and p = 0.019) and preoperative transient ischemic attack symptoms (OR 9.24 and p = 0.009) were independent predictors of developing postoperative changes on DWI in the ipsilateral hemisphere, and age >76 years was predictive of having new lesions on DWI in the contralateral hemisphere (OR 6.11 and p = 0.026). Our study underscores that certain risk factors are significantly associated with CAS related microemboli and that physician experience and patient selection are essential in improving outcome of CAS procedures. PMID- 22532768 TI - Coexistence of left main and right coronary artery ostial stenosis: demographic and angiographic features. AB - This study was designed to evaluate ostial left main coronary artery (LMCA) stenosis and investigate concomitant stenotic lesions of LMCA and right coronary arteries (RCA) and their demographic and angiographic features. We evaluated 11,283 patients who underwent coronary angiography. Patients were placed into four groups according to having ostial or nonostial LMCA or RCA stenosis. Significant LMCA stenosis was observed in 242 (8.3%) of the patients, and only 68 (28.1%) of them had significant ostial LMCA stenosis. There was a significant correlation between ostial stenosis of LMCA and RCA (p = 0.03). The frequency of female gender was greater in ostial LMCA and ostial RCA stenosis groups compared with the other groups (p = 0.01). Ostial LMCA and RCA stenosis were related significantly. Both female predominance and coexistence of ostial LMCA and RCA stenosis might have suggest a different pathological ground for this disease. PMID- 22532765 TI - Antiplatelet drugs: mechanisms and risks of bleeding following cardiac operations. AB - Preoperative antiplatelet drug use is common in patients undergoing coronary artery bypass grafting (CABG). The impact of these drugs on bleeding and blood transfusion varies. We hypothesize that review of available evidence regarding drug-related bleeding risk, underlying mechanisms of platelet dysfunction, and variations in patient response to antiplatelet drugs will aid surgeons as they assess preoperative risk and attempt to limit perioperative bleeding. The purpose of this review is to (1) examine the role that antiplatelet drugs play in excessive postoperative blood transfusion, (2) identify possible mechanisms to explain patient response to antiplatelet drugs, and (3) formulate a strategy to limit excessive blood product usage in these patients. We reviewed available published evidence regarding bleeding risk in patients taking preoperative antiplatelet drugs. In addition, we summarized our previous research into mechanisms of antiplatelet drug-related platelet dysfunction. Aspirin users have a slight but significant increase in blood product usage after CABG (0.5 U of nonautologous blood per treated patient). Platelet adenosine diphosphate (ADP) receptor inhibitors are more potent antiplatelet drugs than aspirin but have a half-life similar to aspirin, around 5 to 10 days. The American Heart Association/American College of Cardiology and the Society of Thoracic Surgeons guidelines recommend discontinuation, if possible, of ADP inhibitors 5 to 7 days before operation because of excessive bleeding risk, whereas aspirin should be continued during the entire perioperative period in most patients. Individual variability in response to aspirin and other antiplatelet drugs is common with both hyper- and hyporesponsiveness seen in 5 to 25% of patients. Use of preoperative antiplatelet drugs is a risk factor for increased perioperative bleeding and blood transfusion. Point-of-care tests can identify patients at high risk for perioperative bleeding and blood transfusion, although these tests have limitations. Available evidence suggests that multiple blood conservation techniques benefit high-risk patients taking antiplatelet drugs before operation. Guidelines for patients who take aspirin and/or thienopyridines before cardiac procedures include some or all of the following: (1) preoperative identification of high-risk patients using point-of-care testing; (2) withdrawal of aspirin or other antiplatelet drugs for a few days and delay of operation in patients at high risk for bleeding if clinical circumstances permit; (3) selective perioperative use of evidence-based blood conservation interventions (e.g., short course erythropoietin, off-pump procedures, and use of intraoperative blood conservation techniques), especially in high-risk patients; and (4) platelet transfusions if clinical bleeding occurs. PMID- 22532769 TI - Effectiveness of tunneled pleural catheter placement in patients with malignant pleural effusions. AB - Pleural effusions (PE) occur frequently among patients with various types of advanced malignancies, resulting in remarkably decreased quality of life. Treatment of malignant PE includes placement of a chest tube with subsequent placement of a tunneled pleural catheter. We reviewed our experience with tunneled pleural catheter use to assess outcomes and resource utilization of this intervention. A retrospective study of consecutive patients (n = 163, including 41 outpatients) who were treated between July 2001 and April 2008 with tunneled pleural catheters was performed to evaluate operative and discharge outcomes. The average age of the patients was 59.32 years (range: 24 to 89). Lung cancer, breast cancer, and ovarian cancer were common primary diseases in this patient population. The mean hospital stay after tunneled pleural catheter placement was 3.19 days (range: 0 to 56), with 41 patients treated as outpatients. Thirteen inpatient deaths were related to the patients' primary diseases, but no deaths were due to drain placement itself. Eight patients (4.91%) required reoperation to replace a nonfunctioning drain or to add an additional drain, and six patients underwent a second procedure to place a contralateral drain. One hundred twenty six patients (77.30%) were discharged home following the procedure and hospital stay. Fifty-five people achieved spontaneous pleurodesis. Tunneled pleural catheter placement is a safe and effective approach to the treatment of PE. The advantages of tunneled pleural catheter placement include symptomatic relief and improved quality of life. This method allows patients to spend time at home with their family and avoid prolonged hospitalization. PMID- 22532770 TI - High-sensitivity C-reactive protein and ankle brachial index in a finnish cardiovascular risk population. AB - High-sensitivity C-reactive protein (hsCRP) has been previously linked to different forms of vascular disease. However, some studies have not found any relationship between hsCRP and atherosclerosis. Also, studies investigating correlation between hsCRP and ankle brachial index (ABI) are scarce. We studied hsCRP in a cardiovascular risk population with a special interest in correlation between hsCRP and ABI. All men and women aged 45 to 70 years from a rural town Harjavalta, Finland were invited to participate in a population survey. Diabetics and people with known vascular disease were excluded. Seventy-three percent (n = 2085) of the invited persons participated and 70% of the respondents (n = 1496) had at least one risk factor to cardiovascular diseases. These subjects were invited to further examinations. From them we measured ABI, hsCRP, leukocyte count, glucose tolerance, systemic coronary risk evaluation (SCORE), body mass index (BMI), and waist circumference. Mean hsCRP was 1.9 mg/L. Smokers had higher hsCRP (mean 2.2 mg/L) than nonsmokers (mean 1.8 mL/L). hsCRP in women was higher than in men (mean 2.0 mg/L versus 1.8 mg/L). Mean ABI was 1.10, and the prevalence of peripheral arterial disease was 3.1%. ABI correlated weakly with hsCRP (r = -0.077, p = 0.014), leukocyte count (r = -0.107, p = 0.001), and SCORE (r = -0.116, p = 0.001). It did not have correlation between age, weight, BMI, or waist circumference. hsCRP correlated with BMI (r = 0.208, p < 0.0001) and waist circumference (r = 0.325, p < 0.0001). When we excluded subjects with hsCRP >10 mg/L, ABI no longer correlated with hsCRP. In a cardiovascular risk population, hsCRP has only a weak correlation with ABI, and this correlation disappeared when we excluded subject with hsCRP >10 mg/L. Instead, hsCRP was correlated to the measures of obesity (waist circumference and BMI), indicating its role as a marker of adipose tissue-driven inflammation. hsCRP does not seem to be a suitable screening method for peripheral arterial disease. PMID- 22532771 TI - Inverse Association between Cardiac Troponin-I and Soluble Receptor for Advanced Glycation End Products in Patients with Non-ST-Segment Elevation Myocardial Infarction. AB - Interaction of advanced glycation end products (AGEs) with the receptor for advanced AGEs (RAGE) results in activation of nuclear factor kappa-B, release of cytokines, expression of adhesion molecules, and induction of oxidative stress. Oxygen radicals are involved in plaque rupture contributing to thromboembolism, resulting in acute coronary syndrome (ACS). Thromboembolism and the direct effect of oxygen radicals on myocardial cells cause cardiac damage that results in the release of cardiac troponin-I (cTnI) and other biochemical markers. The soluble RAGE (sRAGE) compete with RAGE for binding with AGE, thus functioning as a decoy and exerting a cytoprotective effect. Low levels of serum sRAGE would allow unopposed serum AGE availability for binding with RAGE, resulting in the generation of oxygen radicals and proinflammatory molecules that have deleterious consequences and promote myocardial damage. sRAGE may stabilize atherosclerotic plaques. It is hypothesized that low levels of sRAGE are associated with high levels of serum cTnI in patients with ACS. The main objective of the study was to determine whether low levels of serum sRAGE are associated with high levels of serum cTnI in ACS patients. The serum levels of sRAGE and cTnI were measured in 36 patients with non-ST-segment elevation myocardial infarction (NSTEMI) and 30 control subjects. Serum levels of sRAGE were lower in NSTEMI patients (802.56 +/- 39.32 pg/mL) as compared with control subjects (1311.43 +/- 66.92 pg/mL). The levels of cTnI were higher in NSTEMI patients (2.18 +/- 0.33 MUg/mL) as compared with control subjects (0.012 +/- 0.001 MUg/mL). Serum sRAGE levels were negatively correlated with the levels of cTnI. In conclusion, the data suggest that low levels of serum sRAGE are associated with high serum levels of cTnI and that there is a negative correlation between sRAGE and cTnI. PMID- 22532772 TI - Successful retrieval of a coronary stent dislodged in the brachial artery by means of improvised snare and guiding catheter. AB - This is a case report regarding the retrieval, by means of an improvised snare and guiding catheter, of a stent dislodged in the brachial artery during a transradial coronary intervention. A full-length guiding catheter could not be used to approach the lost stent, which was a mere 30 to 35 cm away from the sheath insertion site at the radial artery, and a commercial snare was not available at the time. Thus, we had to improvise a shortened guiding catheter and a snare, which was formed by folding an angioplasty Whisper guide wire (Abbott Laboratories, Abbott Park, IL) and was used successfully to snare the stent and retrieve it. PMID- 22532773 TI - Isolated necrotizing aortitis presenting as incidental thoracoabdominal aortic aneurysm: a case report. AB - Noninfectious aortitis is frequently asymptomatic yet often leads to the development of ascending aortic aneurysms requiring repair. We present the case of a 64-year-old Caucasian woman who presented to our medical center with an incidentally discovered thoracoabdominal aneurysm. She had previously been in good health and had not complained of chest pain or been otherwise symptomatic. At presentation to our clinic, her ascending aorta measured 5 cm at the sinotubular junction (STJ) with dilation of her descending thoracic aorta to 6 cm. Her coronary angiogram was normal. Cross-sectional imaging was notable for thickening of the aortic wall along its length. The entity of isolated noninfectious aortitis is increasingly being recognized as an identifiable factor leading to ascending aneurysmal disease. In reviewing this case, we outline current understanding and guidelines for management and follow-up of this pathology. Operative repair of the ascending arch was conducted using an interpositional graft. The aortic valve apparatus was normal and the proximal anastomosis was created at the STJ. Intraoperatively, an inflammatory obliteration of the aortopulmonary window was noted. It was not possible to completely excise the posterior aortic wall. Our patient had an uneventful recovery and final pathology revealed necrotizing aortitis (NA). She is currently undergoing routine surveillance of her descending thoracoabdominal aneurysm. Recent case series indicate that NA is a histologically distinct process, which is associated commonly with development of ascending aneurysm, and although it is most commonly an isolated finding, it may be associated with other vascular abnormalities including stenoses of branch vessels. There is a growing body of literature suggesting that NA represents a distinct clinical entity, associated with the development of ascending aortic aneurysms. Further research is required to determine the optimal follow-up and value of medical therapies. PMID- 22532774 TI - The small leucine-rich proteoglycan, biglycan, is highly expressed in adipose tissue of Psammomys obesus and is associated with obesity and type 2 diabetes. AB - We have previously demonstrated that the small leucine-rich proteoglycan decorin may play a role in adipose tissue homeostasis and the pathophysiology of obesity. Biglycan is highly similar in structure to decorin, therefore we hypothesized it would have a similar expression profile and role to decorin in adipose tissue. Real time polymerase chain reaction was used to measure biglycan mRNA levels in adipose tissue from normal glucose tolerant and impaired glucose tolerant and type 2 diabetic (T2D) Psammomys obesus. Biglycan mRNA was found to be highly expressed in adipose tissue, and gene expression was significantly higher in visceral compared to subcutaneous adipose tissue, with elevated levels in obese, T2D compared to lean normal glucose tolerant P. obesus (P < 0.04). Biglycan mRNA was predominantly expressed by stromal/vascular cells of fractionated adipose tissue (P = 0.023). Biglycan expression in adipose tissue, particularly in the obese state, was markedly upregulated. Collectively, our data suggest that the small leucine-rich proteoglycan family proteins biglycan and decorin may play a role in the development of obesity and T2D, possibly by facilitating expansion of adipose tissue mass. PMID- 22532776 TI - NK cell count as predictor of clinical response in patients with rheumatoid arthritis treated with rituximab. AB - PURPOSE: The relationship between antiCD20 therapy with rituximab and the lymphocytes phenotype in patients with rheumatoid arthritis was investigated, with an attempt to establish a relationship between commonly used clinical activity indices and variations in leukocyte count, in particular natural killer (NK) lymphocytes. METHODS: Patients with seropositive (cyclic citrullinated peptides and rheumatoid factor positive) rheumatoid arthritis (according to the American College of Rheumatology 1987 criteria) refractory to conventional and antitumor necrosis factor-alpha agents who were subsequently treated with rituximab, a chimeric monoclonal antibody directed against CD20, were enrolled between January 2009 and September 2009. All subjects were treated with rituximab standard rheumatologic dose of 1.0 g on days 1 and 15 every 6 months for at least 2 years. A clinical evaluation was performed at baseline and subsequently every 3 months thereafter. At each assessment activated NK (CD56+/CD16+/CD54bright) cell count was collected and disease activity was assessed using Disease Activity Score in 28 Joints and the Simplified Disease Activity Index (SDAI). RESULTS: Thirty-four patients were enrolled (mean age +/- standard deviation: 54.8 +/- 12.8 years). Basal SDAI was 21.75 +/- 5.4 and NK cell count mean value was 157.6 +/- 90. After 24 months, SDAI was 14 +/- 1.2 and NK cell count mean value was 301.7 +/- 21 (P < 0.05). An inverted correlation between SDAI and NK count was observed at 3 months (r = -0.36, P < 0.05), 6 months (r = -0.48, P < 0.45), 9 months (r = -0.47, P < 0.05), 12 months (r = -0.41, P < 0.01), 15 months (r = 0.58, P < 0.05), 18 months (r = -0.53, P < 0.05), 21 months (r = -0.68, P < 0.05), and 24 months (r = -0.61, P < 0.05). A linear regression model between all variables collected and SDAI/Disease Activity Score in 28 Joints at 6 months and 12 months confirmed a significant relationship between SDAI/Disease Activity Score in 28 Joints and NK cell count. CONCLUSION: The data confirm the clinical efficacy of rituximab and suggests the use of NK cells as a predictor of clinical response in patients with rheumatoid arthritis. PMID- 22532775 TI - Natural killer cells: role in local tumor growth and metastasis. AB - Historically, the name of natural killer (NK) cells came from their natural ability to kill tumor cells in vitro. From the 1970s to date, accumulating data highlighted the importance of NK cells in host immune response against cancer and in therapy-induced antitumor response. The recognition and the lysis of tumor cells by NK cells are regulated by a complex balance of inhibitory and activating signals. This review summarizes NK cell mechanisms to kill cancer cells, their role in host immune responses against tumor growth or metastasis, and their implications in antitumor immunotherapies via cytokines, antibodies, or in combination with other therapies. The regulatory role of NK cells in autoimmunity is also discussed. PMID- 22532777 TI - Role of denosumab in the management of skeletal complications in patients with bone metastases from solid tumors. AB - Skeletal-related events (SREs) including pain, fractures, and hypercalcemia are a major source of morbidity for cancer patients with bone metastases. The receptor activator of NF-kappaB ligand (RANKL) is a key mediator of osteoclast formation and activity in normal bone physiology as well as cancer-induced bone resorption. The first commercially available drug that specifically targets and inhibits the RANKL pathway is denosumab, a fully human monoclonal antibody that binds and neutralizes RANKL, thereby inhibiting osteoclast function. In this review, we summarize the major studies leading to the US Food and Drug Administration approval of denosumab for the prevention of SREs in patients with bone metastases from solid tumors. Further, we discuss the role of denosumab in the prevention and treatment of SREs and bone loss in cancer patients. As a monoclonal antibody, denosumab has several advantages over bisphosphonates, including improved efficacy, better tolerability, and the convenience of administration by subcutaneous injection. In addition, as denosumab has no known renal toxicity, it may be the preferred choice over bisphosphonates in patients with baseline renal insufficiency or receiving nephrotoxic therapies. However, other toxicities, including osteonecrosis of the jaw and hypocalcemia, appear to be class effects of agents that potently inhibit osteoclast activity and are associated with both denosumab and bisphosphonate use. The data presented highlight the differences associated with intravenous bisphosphonate and denosumab use as well as confirm the essential role bone-modifying agents play in maintaining the quality of life for patients with bone metastases. PMID- 22532779 TI - Examining human rights and mental health among women in drug abuse treatment centers in Afghanistan. AB - Denial of human rights, gender disparities, and living in a war zone can be associated with severe depression and poor social functioning, especially for female drug abusers. This study of Afghan women in drug abuse treatment (DAT) centers assesses (a) the extent to which these women have experienced human rights violations and mental health problems prior to entering the DAT centers, and (b) whether there are specific risk factors for human rights violations among this population. A total of 176 in-person interviews were conducted with female patients admitted to three drug abuse treatment centers in Afghanistan in 2010. Nearly all women (91%) reported limitations with social functioning. Further, 41% of the women indicated they had suicide ideation and 27% of the women had attempted suicide at least once 30 days prior to entering the DAT centers due to feelings of sadness or hopelessness. Half of the women (50%) experienced at least one human rights violation in the past year prior to entering the DAT centers. Risk factors for human rights violations among this population include marital status, ethnicity, literacy, employment status, entering treatment based on one's own desire, limited social functioning, and suicide attempts. Conclusions stemming from the results are discussed. PMID- 22532778 TI - Exacerbation of collagen induced arthritis by Fcgamma receptor targeted collagen peptide due to enhanced inflammatory chemokine and cytokine production. AB - Antibodies specific for bovine type II collagen (CII) and Fcgamma receptors play a major role in collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis (RA). Our aim was to clarify the mechanism of immune complex-mediated inflammation and modulation of the disease. CII pre-immunized DBA/1 mice were intravenously boosted with extravidin coupled biotinylated monomeric CII-peptide epitope (ARGLTGRPGDA) and its complexes with biotinylated FcgammaRII/III specific single chain Fv (scFv) fragment. Disease scores were monitored, antibody titers and cytokines were determined by ELISA, and binding of complexes was detected by flow cytometry and immune histochemistry. Cytokine and chemokine secretion was monitored by protein profiler microarray. When intravenously administered into collagen-primed DBA/1 mice, both CII-peptide and its complex with 2.4G2 scFv significantly accelerated CIA and increased the severity of the disease, whereas the monomeric peptide and monomeric 2.4G2 scFv had no effect. FcgammaRII/III targeted CII-peptide complexes bound to marginal zone macrophages and dendritic cells, and significantly elevated the synthesis of peptide-specific IgG2a. Furthermore, CII-peptide containing complexes augmented the in vivo secretion of cytokines, including IL-10, IL-12, IL-17, IL-23, and chemokines (CXCL13, MIP-1, MIP-2). These data indicate that complexes formed by the CII-peptide epitope aggravate CIA by inducing the secretion of chemokines and the IL-12/23 family of pro-inflammatory cytokines. Taken together, these results suggest that the in vivo emerging immune complexes formed with autoantigen(s) may trigger the IL 12/23 dependent pathways, escalating the inflammation in RA. Thus blockade of these cytokines may be beneficial to downregulate immune complex-induced inflammation in autoimmune arthritis. PMID- 22532780 TI - Clinical utility of risedronate in postmenopausal osteoporosis: patient considerations with delayed-release formulation. AB - Bisphosphonates are the most widely prescribed treatment for postmenopausal osteoporosis, secondary osteoporosis, and male osteoporosis. Notwithstanding their high effectiveness and favorable safety profile, the adherence to bisphosphonate treatment remains low. Different treatment strategies aim to improve the clinical effectiveness of bisphosphonate therapy. This review paper assesses the clinical utility of oral intermittent risedronate in the treatment of postmenopausal osteoporosis. The new delayed-release risedronate formulation is a safer and easy to use alternative to other risedronate therapy. Oral risedronate, a potent nitrogen-containing bisphosphonate, has been extensively studied using daily regimens. A new intermittent (weekly) dosing regimen confirmed its clinical effectiveness in relation to vertebral and nonvertebral fracture prevention. The absence of significant differences in the incidence of adverse effects confirmed the favorable tolerability of the weekly dosage. In efforts to improve patient adherence to treatment, an innovative, delayed-release formulation of risedronate, which ensures adequate bioavailability of the active compound when taken with food, was introduced. The once-weekly delayed-release formulation of risedronate proved to be noninferior to the daily dosage of risedronate in terms of bone mineral density and markers of bone turnover. In addition, the incidence of new morphometric vertebral fractures was comparable in both treatment regimens. The new delayed-release formulation of risedronate showed a favorable safety profile. Delayed-release risedronate is a promising, new, effective, and convenient alternative to current bisphosphonate treatments. It appears to allow better patient adherence to antiresorptive treatment. PMID- 22532781 TI - Effect of a hormone-releasing intrauterine system (Mirena((r))) on aromatase and Cox-2 expression in patients with adenomyosis submitted or not, to endometrial resection. AB - OBJECTIVE: To investigate the effect of a levonorgestrel-releasing intrauterine system (Mirena((r))) on aromatase and cyclooxygenase-2 (Cox-2) expression in the endometrium of patients with adenomyosis who were submitted to endometrial resection at the time of insertion, compared to a group not submitted to endometrial resection and a group of controls with adenomyosis not submitted to any previous hormonal treatment. PATIENTS AND METHODS: Patients with adenomyosis (n = 89) were included in this study. Twenty- two patients had been using Mirena((r)) for 5 years but had not been submitted to endometrial resection prior to insertion of the device. Twenty-four patients were submitted to endometrial resection at the time of Mirena((r)) insertion. The remaining 43 patients with adenomyosis had undergone no previous hormonal treatment and served as a control group. Cox-2 and aromatase expression were determined in the endometrium by immunohistochemistry. RESULTS: Use of Mirena((r)) for 5 years reduced aromatase expression in the endometrium; however, this reduction was significantly greater in the uteri previously submitted to endometrial resection. The reduction in Cox 2 expression was significant only in the uteri submitted to endometrial resection followed by the insertion of Mirena((r)). CONCLUSION: Endometrial resection followed by the insertion of Mirena((r)) was associated with greater rates of amenorrhea in patients with adenomyosis, which in turn were associated with a more effective inhibition of aromatase and Cox-2 expression in the endometrium. PMID- 22532782 TI - Wernerius inyoensis, an elusive new scorpion from the Inyo Mountains of California (Scorpiones, Vaejovidae). AB - A new scorpion species is described from the Inyo Mountains of California (USA). The presence of a strong subaculear spine, along with other characters, places the new species within Wernerius, an incredibly rare genus that until now consisted of only two species. Wernerius inyoensissp. n. can be most easily distinguished from the other members of the genus by smaller adult size, femur and pedipalp dimensions, and differences in hemispermatophore morphology. Previous studies have suggested that the elusive nature of this genus may be attributed to low densities and sporadic surface activity. Herein, we provide another hypothesis, that Wernerius are primarily subterranean. Mitochondrial sequence data are provided for the holotype. PMID- 22532783 TI - Six new species of the genus Laena Dejean from China (Coleoptera, Tenebrionidae, Lagriinae). AB - Six new species of Laena Dejean, Laena quadratasp. n. and Laena motoganasp. n.(China: Xizang), Laena chiloriluxasp. n., Laena dentatasp. n. and Laena liangisp. n. (China: Yunnan), Laena dentatocrassasp. n. (China: Hainan Island, representing new province record of the genus) are described, complemented with photos of habitus, illustrations of legs, antenna, aedeagus and last abdominal ventrite of male and female. Type specimens are deposited in both the Museum of Hebei University, Baoding, China and the Natural History Museum of Stuttgart, Germany.A key to the 102 Chinese species of genus Laena is provided. PMID- 22532784 TI - One the genus Tocama Reitter (Coleoptera, Scarabaeidae, Melolonthinae), with descriptions of two new species from Indochina. AB - Two new species of the Oriental scarab genus Tocama Reitter, 1902, Tocama laosensissp. n. and Tocama procerasp. n., are described from Indochina with diagnoses, distributions, remarks and illustrations. A key to the species of the genus is provided with a checklist with several nomenclatural changes: Hoplosternus tonkinensis Moser, 1913 is transferred to Tocama; Hoplosternus pygidialis Moser, 1915 syn. n., Tocama atra atra Keith, 2006 syn. n. and Tocama atra reichenbachi Keith, 2007 syn. n. = Tocama tonkinensis (Moser). PMID- 22532785 TI - Megalara garuda, a new genus and species of larrine wasps from Indonesia (Larrinae, Crabronidae, Hymenoptera). AB - A new genus and species, Megalara garuda is described from Sulawesi (Indonesia). The new species is one the largest known members of the crabronid subfamily Larrinae. It has a unique suite of putatively apomorphic morphological characters and is most closely related to the genus Paraliris. We found indications of a significant allometric variation in body size and mandibular length and shape in male Megalara, and the presence of acarinaria at least in females of the new genus. Allometric variation and acarinaria have previously been shown to occur in Paraliris, which is another indication for a close relationship of Megalara and Paraliris. PMID- 22532786 TI - The genus Meiothrips Priesner (Thysanoptera, Phlaeothripidae, Idolothripinae) with a key and a new species from China. AB - The genus Meiothrips Priesneris reviewed, with Meiothrips fuscicrussp. n., and Meiothrips nepalensis Kudo & Ananthakrishnan recorded and described from China, and a key provided to the five known species. COI sequences of the new species and Meiothrips nepalensis are also provided. PMID- 22532787 TI - Isoalantolactone induces reactive oxygen species mediated apoptosis in pancreatic carcinoma PANC-1 cells. AB - Isoalantolactone, a sesquiterpene lactone compound possesses antifungal, antibacteria, antihelminthic and antiproliferative activities. In the present study, we found that isoalantolactone inhibits growth and induces apoptosis in pancreatic cancer cells. Further mechanistic studies revealed that induction of apoptosis is associated with increased generation of reactive oxygen species, cardiolipin oxidation, reduced mitochondrial membrane potential, release of cytochrome c and cell cycle arrest at S phase. N-Acetyl Cysteine (NAC), a specific ROS inhibitor restored cell viability and completely blocked isoalantolactone-mediated apoptosis in PANC-1 cells indicating that ROS are involved in isoalantolactone-mediated apoptosis. Western blot study showed that isoalantolactone increased the expression of phosphorylated p38 MAPK, Bax, and cleaved caspase-3 and decreased the expression of Bcl-2 in a dose-dependent manner. No change in expression of phosphorylated p38 MAPK and Bax was found when cells were treated with isoalantolactone in the presence of NAC, indicating that activation of these proteins is directly dependent on ROS generation. The present study provides evidence for the first time that isoalantolactone induces ROS dependent apoptosis through intrinsic pathway. Furthermore, our in vivo toxicity study demonstrated that isoalantolactone did not induce any acute or chronic toxicity in liver and kidneys of CD1 mice at dose of 100 mg/kg body weight. Therefore, isoalantolactone may be a safe chemotherapeutic candidate for the treatment of human pancreatic carcinoma. PMID- 22532788 TI - Data mining in networks of differentially expressed genes during sow pregnancy. AB - Small to moderate gains in Pig fertility can mean large returns in overall efficiency, and developing methods to improve it is highly desirable. High fertility rates depend on completion of successful pregnancies. To understand the molecular signals associated with pregnancy in sows, expression profiling experiments were conducted to identify differentially expressed genes in ovary and myometrium at different pregnancy periods using the Affymetrix Porcine GeneChip(TM). A total of 974, 1800, 335 and 710 differentially expressed transcripts were identified in the myometrium during early pregnancy (EP) and late pregnancy (LP), and in the ovary during EP and LP, respectively. Self Organizing Map (SOM) clusters indicated the differentially expressed genes belonged to 7 different functional groups. Based on BLASTX searches and Gene Ontology (GO) classifications, 129 unique genes closely related to pregnancy showed differential expression patterns. GO analysis also indicated that there were 21 different molecular function categories, 20 different biological process categories, and 8 different cellular component categories of genes differentially expressed during sow pregnancy. Gene regulatory network reconstruction provided us with an interaction model of known genes such as insulin-like growth factor 2 (IGF2) gene, estrogen receptor (ESR) gene, retinol-binding protein-4 (RBP4) gene, and several unknown candidate genes related to reproduction. Several pitch point genes were selected for association study with reproduction traits. For instance, DPPA5 g.363 T>C was found to associate with litter born weight at later parities in Beijing Black pigs significantly (p < 0.05). Overall, this study contributes to elucidating the mechanism underlying pregnancy processes, which maybe provide valuable information for pig reproduction improvement. PMID- 22532789 TI - Characterization of the complete mitochondrial genomes of Cnaphalocrocis medinalis and Chilo suppressalis (Lepidoptera: Pyralidae). AB - The complete mitochondrial genomes (mitogenomes) of Cnaphalocrocis medinalis and Chilo suppressalis (Lepidoptera: Pyralidae) were determined and analyzed. The circular genomes were 15,388 bp long for C. medinalis and 15,395 bp long for C. suppressalis. Both mitogenomes contained 37 genes, with gene order similar to that of other lepidopterans. Notably, 12 protein-coding genes (PCGs) utilized the standard ATN, but the cox1 gene used CGA as the initiation codon; the cox1, cox2, and nad4 genes in the two mitogenomes had the truncated termination codons T, T, and TA, respectively, but the nad5 gene was found to use T as the termination codon only in the C. medinalis mitogenome. Additionally, the codon distribution and Relative Synonymous Codon Usage of the 13 PCGs in the C. medinalis mitogenome were very different from those in other pyralid moth mitogenomes. Most of the tRNA genes had typical cloverleaf secondary structures. However, the dihydrouridine (DHU) arm of the trnS1(AGN) gene did not form a stable stem-loop structure. Forty-nine helices in six domains, and 33 helices in three domains were present in the secondary structures of the rrnL and rrnS genes of the two mitogenomes, respectively. There were four major intergenic spacers, except for the A+T-rich region, spanning at least 12 bp in the two mitogenomes. The A+T-rich region contained an 'ATAGT(A)'-like motif followed by a poly-T stretch in the two mitogenomes. In addition, there were a potential stem-loop structure, a duplicated 25-bp repeat element, and a microsatellite '(TA)(13)' observed in the A+T-rich region of the C. medinalis mitogenome. A poly-T motif, a duplicated 31 bp repeat element, and a 19-bp triplication were found in the C. suppressalis mitogenome. However, there are many differences in the A+T-rich regions between the C. suppressalis mitogenome sequence in the present study and previous reports. Finally, the phylogenetic relationships of these insects were reconstructed based on amino acid sequences of mitochondrial 13 PCGs using Bayesian inference and maximum likelihood methods. These molecular-based phylogenies support the traditional morphologically based view of relationships within the Pyralidae. PMID- 22532790 TI - Genome-wide association analysis of meat quality traits in a porcine Large White * Minzhu intercross population. AB - Pork quality is an economically important trait and one of the main selection criteria for breeding in the swine industry. In this genome-wide association study (GWAS), 455 pigs from a porcine Large White * Minzhu intercross population were genotyped using the Illumina PorcineSNP60K Beadchip, and phenotyped for intramuscular fat content (IMF), marbling, moisture, color L*, color a*, color b* and color score in the longissimus muscle (LM). Association tests between each trait and the SNPs were performed via the Genome Wide Rapid Association using the Mixed Model and Regression-Genomic Control (GRAMMAR-GC) approach. From the Ensembl porcine database, SNP annotation was implemented using Sus scrofa Build 9. A total of 45 SNPs showed significant association with one or multiple meat quality traits. Of the 45 SNPs, 36 were located on SSC12. These significantly associated SNPs aligned to or were in close approximation to previously reported quantitative trait loci (QTL) and some were located within introns of previously reported candidate genes. Two haplotype blocks ASGA0100525-ASGA0055225 ALGA0067099-MARC0004712-DIAS0000861, and ASGA0085522-H3GA0056170 were detected in the significant region. The first block contained the genes MYH1, MYH2 and MYH4. A SNP (ASGA0094812) within an intron of the USP43 gene was significantly associated with five meat quality traits. The present results effectively narrowed down the associated regions compared to previous QTL studies and revealed haplotypes and candidate genes on SSC12 for meat quality traits in pigs. PMID- 22532791 TI - Non-additive coupling enables propagation of synchronous spiking activity in purely random networks. AB - Despite the current debate about the computational role of experimentally observed precise spike patterns it is still theoretically unclear under which conditions and how they may emerge in neural circuits. Here, we study spiking neural networks with non-additive dendritic interactions that were recently uncovered in single-neuron experiments. We show that supra-additive dendritic interactions enable the persistent propagation of synchronous activity already in purely random networks without superimposed structures and explain the mechanism underlying it. This study adds a novel perspective on the dynamics of networks with nonlinear interactions in general and presents a new viable mechanism for the occurrence of patterns of precisely timed spikes in recurrent networks. PMID- 22532792 TI - Exploration of multi-state conformational dynamics and underlying global functional landscape of maltose binding protein. AB - An increasing number of biological machines have been revealed to have more than two macroscopic states. Quantifying the underlying multiple-basin functional landscape is essential for understanding their functions. However, the present models seem to be insufficient to describe such multiple-state systems. To meet this challenge, we have developed a coarse grained triple-basin structure-based model with implicit ligand. Based on our model, the constructed functional landscape is sufficiently sampled by the brute-force molecular dynamics simulation. We explored maltose-binding protein (MBP) which undergoes large-scale domain motion between open, apo-closed (partially closed) and holo-closed (fully closed) states responding to ligand binding. We revealed an underlying mechanism whereby major induced fit and minor population shift pathways co-exist by quantitative flux analysis. We found that the hinge regions play an important role in the functional dynamics as well as that increases in its flexibility promote population shifts. This finding provides a theoretical explanation of the mechanistic discrepancies in PBP protein family. We also found a functional "backtracking" behavior that favors conformational change. We further explored the underlying folding landscape in response to ligand binding. Consistent with earlier experimental findings, the presence of ligand increases the cooperativity and stability of MBP. This work provides the first study to explore the folding dynamics and functional dynamics under the same theoretical framework using our triple-basin functional model. PMID- 22532793 TI - Ligand-dependent conformations and dynamics of the serotonin 5-HT(2A) receptor determine its activation and membrane-driven oligomerization properties. AB - From computational simulations of a serotonin 2A receptor (5-HT(2A)R) model complexed with pharmacologically and structurally diverse ligands we identify different conformational states and dynamics adopted by the receptor bound to the full agonist 5-HT, the partial agonist LSD, and the inverse agonist Ketanserin. The results from the unbiased all-atom molecular dynamics (MD) simulations show that the three ligands affect differently the known GPCR activation elements including the toggle switch at W6.48, the changes in the ionic lock between E6.30 and R3.50 of the DRY motif in TM3, and the dynamics of the NPxxY motif in TM7. The computational results uncover a sequence of steps connecting these experimentally-identified elements of GPCR activation. The differences among the properties of the receptor molecule interacting with the ligands correlate with their distinct pharmacological properties. Combining these results with quantitative analysis of membrane deformation obtained with our new method (Mondal et al, Biophysical Journal 2011), we show that distinct conformational rearrangements produced by the three ligands also elicit different responses in the surrounding membrane. The differential reorganization of the receptor environment is reflected in (i)-the involvement of cholesterol in the activation of the 5-HT(2A)R, and (ii)-different extents and patterns of membrane deformations. These findings are discussed in the context of their likely functional consequences and a predicted mechanism of ligand-specific GPCR oligomerization. PMID- 22532794 TI - Persisting viral sequences shape microbial CRISPR-based immunity. AB - Well-studied innate immune systems exist throughout bacteria and archaea, but a more recently discovered genomic locus may offer prokaryotes surprising immunological adaptability. Mediated by a cassette-like genomic locus termed Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), the microbial adaptive immune system differs from its eukaryotic immune analogues by incorporating new immunities unidirectionally. CRISPR thus stores genomically recoverable timelines of virus-host coevolution in natural organisms refractory to laboratory cultivation. Here we combined a population genetic mathematical model of CRISPR-virus coevolution with six years of metagenomic sequencing to link the recoverable genomic dynamics of CRISPR loci to the unknown population dynamics of virus and host in natural communities. Metagenomic reconstructions in an acid-mine drainage system document CRISPR loci conserving ancestral immune elements to the base-pair across thousands of microbial generations. This 'trailer-end conservation' occurs despite rapid viral mutation and despite rapid prokaryotic genomic deletion. The trailer-ends of many reconstructed CRISPR loci are also largely identical across a population. 'Trailer-end clonality' occurs despite predictions of host immunological diversity due to negative frequency dependent selection (kill the winner dynamics). Statistical clustering and model simulations explain this lack of diversity by capturing rapid selective sweeps by highly immune CRISPR lineages. Potentially explaining 'trailer-end conservation,' we record the first example of a viral bloom overwhelming a CRISPR system. The polyclonal viruses bloom even though they share sequences previously targeted by host CRISPR loci. Simulations show how increasing random genomic deletions in CRISPR loci purges immunological controls on long-lived viral sequences, allowing polyclonal viruses to bloom and depressing host fitness. Our results thus link documented patterns of genomic conservation in CRISPR loci to an evolutionary advantage against persistent viruses. By maintaining old immunities, selection may be tuning CRISPR-mediated immunity against viruses reemerging from lysogeny or migration. PMID- 22532795 TI - Computational design of a PDZ domain peptide inhibitor that rescues CFTR activity. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) is an epithelial chloride channel mutated in patients with cystic fibrosis (CF). The most prevalent CFTR mutation, DeltaF508, blocks folding in the endoplasmic reticulum. Recent work has shown that some DeltaF508-CFTR channel activity can be recovered by pharmaceutical modulators ("potentiators" and "correctors"), but DeltaF508 CFTR can still be rapidly degraded via a lysosomal pathway involving the CFTR associated ligand (CAL), which binds CFTR via a PDZ interaction domain. We present a study that goes from theory, to new structure-based computational design algorithms, to computational predictions, to biochemical testing and ultimately to epithelial-cell validation of novel, effective CAL PDZ inhibitors (called "stabilizers") that rescue DeltaF508-CFTR activity. To design the "stabilizers", we extended our structural ensemble-based computational protein redesign algorithm K* to encompass protein-protein and protein-peptide interactions. The computational predictions achieved high accuracy: all of the top-predicted peptide inhibitors bound well to CAL. Furthermore, when compared to state-of-the-art CAL inhibitors, our design methodology achieved higher affinity and increased binding efficiency. The designed inhibitor with the highest affinity for CAL (kCAL01) binds six-fold more tightly than the previous best hexamer (iCAL35), and 170-fold more tightly than the CFTR C-terminus. We show that kCAL01 has physiological activity and can rescue chloride efflux in CF patient-derived airway epithelial cells. Since stabilizers address a different cellular CF defect from potentiators and correctors, our inhibitors provide an additional therapeutic pathway that can be used in conjunction with current methods. PMID- 22532796 TI - Inference of genotype-phenotype relationships in the antigenic evolution of human influenza A (H3N2) viruses. AB - Distinguishing mutations that determine an organism's phenotype from (near-) neutral 'hitchhikers' is a fundamental challenge in genome research, and is relevant for numerous medical and biotechnological applications. For human influenza viruses, recognizing changes in the antigenic phenotype and a strains' capability to evade pre-existing host immunity is important for the production of efficient vaccines. We have developed a method for inferring 'antigenic trees' for the major viral surface protein hemagglutinin. In the antigenic tree, antigenic weights are assigned to all tree branches, which allows us to resolve the antigenic impact of the associated amino acid changes. Our technique predicted antigenic distances with comparable accuracy to antigenic cartography. Additionally, it identified both known and novel sites, and amino acid changes with antigenic impact in the evolution of influenza A (H3N2) viruses from 1968 to 2003. The technique can also be applied for inference of 'phenotype trees' and genotype-phenotype relationships from other types of pairwise phenotype distances. PMID- 22532797 TI - Systematic review of mucosal immunity induced by oral and inactivated poliovirus vaccines against virus shedding following oral poliovirus challenge. AB - Inactivated poliovirus vaccine (IPV) may be used in mass vaccination campaigns during the final stages of polio eradication. It is also likely to be adopted by many countries following the coordinated global cessation of vaccination with oral poliovirus vaccine (OPV) after eradication. The success of IPV in the control of poliomyelitis outbreaks will depend on the degree of nasopharyngeal and intestinal mucosal immunity induced against poliovirus infection. We performed a systematic review of studies published through May 2011 that recorded the prevalence of poliovirus shedding in stool samples or nasopharyngeal secretions collected 5-30 days after a "challenge" dose of OPV. Studies were combined in a meta-analysis of the odds of shedding among children vaccinated according to IPV, OPV, and combination schedules. We identified 31 studies of shedding in stool and four in nasopharyngeal samples that met the inclusion criteria. Individuals vaccinated with OPV were protected against infection and shedding of poliovirus in stool samples collected after challenge compared with unvaccinated individuals (summary odds ratio [OR] for shedding 0.13 (95% confidence interval [CI] 0.08-0.24)). In contrast, IPV provided no protection against shedding compared with unvaccinated individuals (summary OR 0.81 [95% CI 0.59-1.11]) or when given in addition to OPV, compared with individuals given OPV alone (summary OR 1.14 [95% CI 0.82-1.58]). There were insufficient studies of nasopharyngeal shedding to draw a conclusion. IPV does not induce sufficient intestinal mucosal immunity to reduce the prevalence of fecal poliovirus shedding after challenge, although there was some evidence that it can reduce the quantity of virus shed. The impact of IPV on poliovirus transmission in countries where fecal-oral spread is common is unknown but is likely to be limited compared with OPV. PMID- 22532798 TI - The arbuscular mycorrhizal symbiosis: origin and evolution of a beneficial plant infection. PMID- 22532799 TI - CD8+ T-cells expressing interferon gamma or perforin play antagonistic roles in heart injury in experimental Trypanosoma cruzi-elicited cardiomyopathy. AB - In Chagas disease, CD8(+) T-cells are critical for the control of Trypanosoma cruzi during acute infection. Conversely, CD8(+) T-cell accumulation in the myocardium during chronic infection may cause tissue injury leading to chronic chagasic cardiomyopathy (CCC). Here we explored the role of CD8(+) T-cells in T. cruzi-elicited heart injury in C57BL/6 mice infected with the Colombian strain. Cardiomyocyte lesion evaluated by creatine kinase-MB isoenzyme activity levels in the serum and electrical abnormalities revealed by electrocardiogram were not associated with the intensity of heart parasitism and myocarditis in the chronic infection. Further, there was no association between heart injury and systemic anti-T. cruzi CD8(+) T-cell capacity to produce interferon-gamma (IFNgamma) and to perform specific cytotoxicity. Heart injury, however, paralleled accumulation of anti-T. cruzi cells in the cardiac tissue. In T. cruzi infection, most of the CD8(+) T-cells segregated into IFNgamma(+) perforin (Pfn)(neg) or IFNgamma(neg)Pfn(+) cell populations. Colonization of the cardiac tissue by anti T. cruzi CD8(+)Pfn(+) cells paralleled the worsening of CCC. The adoptive cell transfer to T. cruzi-infected cd8(-/-) recipients showed that the CD8(+) cells from infected ifngamma(-/-)pfn(+/+) donors migrate towards the cardiac tissue to a greater extent and caused a more severe cardiomyocyte lesion than CD8(+) cells from ifngamma(+/+)pfn(-/-) donors. Moreover, the reconstitution of naive cd8(-/-) mice with CD8(+) cells from naive ifngamma(+/+)pfn(-/-) donors ameliorated T. cruzi-elicited heart injury paralleled IFNgamma(+) cells accumulation, whereas reconstitution with CD8(+) cells from naive ifngamma(-/-)pfn(+/+) donors led to an aggravation of the cardiomyocyte lesion, which was associated with the accumulation of Pfn(+) cells in the cardiac tissue. Our data support a possible antagonist effect of CD8(+)Pfn(+) and CD8(+)IFNgamma(+) cells during CCC. CD8(+)IFNgamma(+) cells may exert a beneficial role, whereas CD8(+)Pfn(+) may play a detrimental role in T. cruzi-elicited heart injury. PMID- 22532800 TI - Modelling the evolutionary dynamics of viruses within their hosts: a case study using high-throughput sequencing. AB - Uncovering how natural selection and genetic drift shape the evolutionary dynamics of virus populations within their hosts can pave the way to a better understanding of virus emergence. Mathematical models already play a leading role in these studies and are intended to predict future emergences. Here, using high throughput sequencing, we analyzed the within-host population dynamics of four Potato virus Y (PVY) variants differing at most by two substitutions involved in pathogenicity properties. Model selection procedures were used to compare experimental results to six hypotheses regarding competitiveness and intensity of genetic drift experienced by viruses during host plant colonization. Results indicated that the frequencies of variants were well described using Lotka Volterra models where the competition coefficients beta(ij) exerted by variant j on variant i are equal to their fitness ratio, r(j)/r(i). Statistical inference allowed the estimation of the effect of each mutation on fitness, revealing slight (s = -0.45%) and high (s = -13.2%) fitness costs and a negative epistasis between them. Results also indicated that only 1 to 4 infectious units initiated the population of one apical leaf. The between-host variances of the variant frequencies were described using Dirichlet-multinomial distributions whose scale parameters, closely related to the fixation index F(ST), were shown to vary with time. The genetic differentiation of virus populations among plants increased from 0 to 10 days post-inoculation and then decreased until 35 days. Overall, this study showed that mathematical models can accurately describe both selection and genetic drift processes shaping the evolutionary dynamics of viruses within their hosts. PMID- 22532801 TI - AMP-activated kinase restricts Rift Valley fever virus infection by inhibiting fatty acid synthesis. AB - The cell intrinsic innate immune responses provide a first line of defense against viral infection, and often function by targeting cellular pathways usurped by the virus during infection. In particular, many viruses manipulate cellular lipids to form complex structures required for viral replication, many of which are dependent on de novo fatty acid synthesis. We found that the energy regulator AMPK, which potently inhibits fatty acid synthesis, restricts infection of the Bunyavirus, Rift Valley Fever Virus (RVFV), an important re-emerging arthropod-borne human pathogen for which there are no effective vaccines or therapeutics. We show restriction of RVFV both by AMPK and its upstream activator LKB1, indicating an antiviral role for this signaling pathway. Furthermore, we found that AMPK is activated during RVFV infection, leading to the phosphorylation and inhibition of acetyl-CoA carboxylase, the first rate-limiting enzyme in fatty acid synthesis. Activating AMPK pharmacologically both restricted infection and reduced lipid levels. This restriction could be bypassed by treatment with the fatty acid palmitate, demonstrating that AMPK restricts RVFV infection through its inhibition of fatty acid biosynthesis. Lastly, we found that this pathway plays a broad role in antiviral defense since additional viruses from disparate families were also restricted by AMPK and LKB1. Therefore, AMPK is an important component of the cell intrinsic immune response that restricts infection through a novel mechanism involving the inhibition of fatty acid metabolism. PMID- 22532802 TI - Induction of strain-transcending antibodies against Group A PfEMP1 surface antigens from virulent malaria parasites. AB - Sequence diversity in pathogen antigens is an obstacle to the development of interventions against many infectious diseases. In malaria caused by Plasmodium falciparum, the PfEMP1 family of variant surface antigens encoded by var genes are adhesion molecules that play a pivotal role in malaria pathogenesis and clinical disease. PfEMP1 is a major target of protective immunity, however, development of drugs or vaccines based on PfEMP1 is problematic due to extensive sequence diversity within the PfEMP1 family. Here we identified the PfEMP1 variants transcribed by P. falciparum strains selected for a virulence-associated adhesion phenotype (IgM-positive rosetting). The parasites transcribed a subset of Group A PfEMP1 variants characterised by an unusual PfEMP1 architecture and a distinct N-terminal domain (either DBLalpha1.5 or DBLalpha1.8 type). Antibodies raised in rabbits against the N-terminal domains showed functional activity (surface reactivity with live infected erythrocytes (IEs), rosette inhibition and induction of phagocytosis of IEs) down to low concentrations (<10 ug/ml of total IgG) against homologous parasites. Furthermore, the antibodies showed broad cross reactivity against heterologous parasite strains with the same rosetting phenotype, including clinical isolates from four sub-Saharan African countries that showed surface reactivity with either DBLalpha1.5 antibodies (variant HB3var6) or DBLalpha1.8 antibodies (variant TM284var1). These data show that parasites with a virulence-associated adhesion phenotype share IE surface epitopes that can be targeted by strain-transcending antibodies to PfEMP1. The existence of shared surface epitopes amongst functionally similar disease associated P. falciparum parasite isolates suggests that development of therapeutic interventions to prevent severe malaria is a realistic goal. PMID- 22532803 TI - Epigenome-wide scans identify differentially methylated regions for age and age related phenotypes in a healthy ageing population. AB - Age-related changes in DNA methylation have been implicated in cellular senescence and longevity, yet the causes and functional consequences of these variants remain unclear. To elucidate the role of age-related epigenetic changes in healthy ageing and potential longevity, we tested for association between whole-blood DNA methylation patterns in 172 female twins aged 32 to 80 with age and age-related phenotypes. Twin-based DNA methylation levels at 26,690 CpG-sites showed evidence for mean genome-wide heritability of 18%, which was supported by the identification of 1,537 CpG-sites with methylation QTLs in cis at FDR 5%. We performed genome-wide analyses to discover differentially methylated regions (DMRs) for sixteen age-related phenotypes (ap-DMRs) and chronological age (a DMRs). Epigenome-wide association scans (EWAS) identified age-related phenotype DMRs (ap-DMRs) associated with LDL (STAT5A), lung function (WT1), and maternal longevity (ARL4A, TBX20). In contrast, EWAS for chronological age identified hundreds of predominantly hyper-methylated age DMRs (490 a-DMRs at FDR 5%), of which only one (TBX20) was also associated with an age-related phenotype. Therefore, the majority of age-related changes in DNA methylation are not associated with phenotypic measures of healthy ageing in later life. We replicated a large proportion of a-DMRs in a sample of 44 younger adult MZ twins aged 20 to 61, suggesting that a-DMRs may initiate at an earlier age. We next explored potential genetic and environmental mechanisms underlying a-DMRs and ap DMRs. Genome-wide overlap across cis-meQTLs, genotype-phenotype associations, and EWAS ap-DMRs identified CpG-sites that had cis-meQTLs with evidence for genotype phenotype association, where the CpG-site was also an ap-DMR for the same phenotype. Monozygotic twin methylation difference analyses identified one potential environmentally-mediated ap-DMR associated with total cholesterol and LDL (CSMD1). Our results suggest that in a small set of genes DNA methylation may be a candidate mechanism of mediating not only environmental, but also genetic effects on age-related phenotypes. PMID- 22532804 TI - Differing requirements for RAD51 and DMC1 in meiotic pairing of centromeres and chromosome arms in Arabidopsis thaliana. AB - During meiosis homologous chromosomes pair, recombine, and synapse, thus ensuring accurate chromosome segregation and the halving of ploidy necessary for gametogenesis. The processes permitting a chromosome to pair only with its homologue are not fully understood, but successful pairing of homologous chromosomes is tightly linked to recombination. In Arabidopsis thaliana, meiotic prophase of rad51, xrcc3, and rad51C mutants appears normal up to the zygotene/pachytene stage, after which the genome fragments, leading to sterility. To better understand the relationship between recombination and chromosome pairing, we have analysed meiotic chromosome pairing in these and in dmc1 mutant lines. Our data show a differing requirement for these proteins in pairing of centromeric regions and chromosome arms. No homologous pairing of mid-arm or distal regions was observed in rad51, xrcc3, and rad51C mutants. However, homologous centromeres do pair in these mutants and we show that this does depend upon recombination, principally on DMC1. This centromere pairing extends well beyond the heterochromatic centromere region and, surprisingly, does not require XRCC3 and RAD51C. In addition to clarifying and bringing the roles of centromeres in meiotic synapsis to the fore, this analysis thus separates the roles in meiotic synapsis of DMC1 and RAD51 and the meiotic RAD51 paralogs, XRCC3 and RAD51C, with respect to different chromosome domains. PMID- 22532805 TI - Patterns of cis regulatory variation in diverse human populations. AB - The genetic basis of gene expression variation has long been studied with the aim to understand the landscape of regulatory variants, but also more recently to assist in the interpretation and elucidation of disease signals. To date, many studies have looked in specific tissues and population-based samples, but there has been limited assessment of the degree of inter-population variability in regulatory variation. We analyzed genome-wide gene expression in lymphoblastoid cell lines from a total of 726 individuals from 8 global populations from the HapMap3 project and correlated gene expression levels with HapMap3 SNPs located in cis to the genes. We describe the influence of ancestry on gene expression levels within and between these diverse human populations and uncover a non negligible impact on global patterns of gene expression. We further dissect the specific functional pathways differentiated between populations. We also identify 5,691 expression quantitative trait loci (eQTLs) after controlling for both non genetic factors and population admixture and observe that half of the cis-eQTLs are replicated in one or more of the populations. We highlight patterns of eQTL sharing between populations, which are partially determined by population genetic relatedness, and discover significant sharing of eQTL effects between Asians, European-admixed, and African subpopulations. Specifically, we observe that both the effect size and the direction of effect for eQTLs are highly conserved across populations. We observe an increasing proximity of eQTLs toward the transcription start site as sharing of eQTLs among populations increases, highlighting that variants close to TSS have stronger effects and therefore are more likely to be detected across a wider panel of populations. Together these results offer a unique picture and resource of the degree of differentiation among human populations in functional regulatory variation and provide an estimate for the transferability of complex trait variants across populations. PMID- 22532806 TI - Competition between replicative and translesion polymerases during homologous recombination repair in Drosophila. AB - In metazoans, the mechanism by which DNA is synthesized during homologous recombination repair of double-strand breaks is poorly understood. Specifically, the identities of the polymerase(s) that carry out repair synthesis and how they are recruited to repair sites are unclear. Here, we have investigated the roles of several different polymerases during homologous recombination repair in Drosophila melanogaster. Using a gap repair assay, we found that homologous recombination is impaired in Drosophila lacking DNA polymerase zeta and, to a lesser extent, polymerase eta. In addition, the Pol32 protein, part of the polymerase delta complex, is needed for repair requiring extensive synthesis. Loss of Rev1, which interacts with multiple translesion polymerases, results in increased synthesis during gap repair. Together, our findings support a model in which translesion polymerases and the polymerase delta complex compete during homologous recombination repair. In addition, they establish Rev1 as a crucial factor that regulates the extent of repair synthesis. PMID- 22532807 TI - Genome-wide patterns of Arabidopsis gene expression in nature. AB - Organisms in the wild are subject to multiple, fluctuating environmental factors, and it is in complex natural environments that genetic regulatory networks actually function and evolve. We assessed genome-wide gene expression patterns in the wild in two natural accessions of the model plant Arabidopsis thaliana and examined the nature of transcriptional variation throughout its life cycle and gene expression correlations with natural environmental fluctuations. We grew plants in a natural field environment and measured genome-wide time-series gene expression from the plant shoot every three days, spanning the seedling to reproductive stages. We find that 15,352 genes were expressed in the A. thaliana shoot in the field, and accession and flowering status (vegetative versus flowering) were strong components of transcriptional variation in this plant. We identified between ~110 and 190 time-varying gene expression clusters in the field, many of which were significantly overrepresented by genes regulated by abiotic and biotic environmental stresses. The two main principal components of vegetative shoot gene expression (PC(veg)) correlate to temperature and precipitation occurrence in the field. The largest PC(veg) axes included thermoregulatory genes while the second major PC(veg) was associated with precipitation and contained drought-responsive genes. By exposing A. thaliana to natural environments in an open field, we provide a framework for further understanding the genetic networks that are deployed in natural environments, and we connect plant molecular genetics in the laboratory to plant organismal ecology in the wild. PMID- 22532808 TI - dyschronic, a Drosophila homolog of a deaf-blindness gene, regulates circadian output and Slowpoke channels. AB - Many aspects of behavior and physiology are under circadian control. In Drosophila, the molecular clock that regulates rhythmic patterns of behavior has been extensively characterized. In contrast, genetic loci involved in linking the clock to alterations in motor activity have remained elusive. In a forward genetic screen, we uncovered a new component of the circadian output pathway, which we have termed dyschronic (dysc). dysc mutants exhibit arrhythmic locomotor behavior, yet their eclosion rhythms are normal and clock protein cycling remains intact. Intriguingly, dysc is the closest Drosophila homolog of whirlin, a gene linked to type II Usher syndrome, the leading cause of deaf-blindness in humans. Whirlin and other Usher proteins are expressed in the mammalian central nervous system, yet their function in the CNS has not been investigated. We show that DYSC is expressed in major neuronal tracts and regulates expression of the calcium-activated potassium channel SLOWPOKE (SLO), an ion channel also required in the circadian output pathway. SLO and DYSC are co-localized in the brain and control each other's expression post-transcriptionally. Co-immunoprecipitation experiments demonstrate they form a complex, suggesting they regulate each other through protein-protein interaction. Furthermore, electrophysiological recordings of neurons in the adult brain show that SLO-dependent currents are greatly reduced in dysc mutants. Our work identifies a Drosophila homolog of a deaf blindness gene as a new component of the circadian output pathway and an important regulator of ion channel expression, and suggests novel roles for Usher proteins in the mammalian nervous system. PMID- 22532809 TI - Long-range chromosome organization in E. coli: a site-specific system isolates the Ter macrodomain. AB - The organization of the Escherichia coli chromosome into a ring composed of four macrodomains and two less-structured regions influences the segregation of sister chromatids and the mobility of chromosomal DNA. The structuring of the terminus region (Ter) into a macrodomain relies on the interaction of the protein MatP with a 13-bp target called matS repeated 23 times in the 800-kb-long domain. Here, by using a new method that allows the transposition of any chromosomal segment at a defined position on the genetic map, we reveal a site-specific system that restricts to the Ter region a constraining process that reduces DNA mobility and delays loci segregation. Remarkably, the constraining process is regulated during the cell cycle and occurs only when the Ter MD is associated with the division machinery at mid-cell. The change of DNA properties does not rely on the presence of a trans-acting mechanism but rather involves a cis-effect acting at a long distance from the Ter region. Two specific 12-bp sequences located in the flanking Left and Right macrodomains and a newly identified protein designated YfbV conserved with MatP through evolution are required to impede the spreading of the constraining process to the rest of the chromosome. Our results unravel a site-specific system required to restrict to the Ter region the consequences of anchoring the Ter MD to the division machinery. PMID- 22532810 TI - Portal vein thrombosis after restorative proctocolectomy for familial adenomatous polyposis and sigmoid cancer. AB - Postoperative portal vein thrombosis (PVT) is rare, but has been described after various open as well as minimal access abdominal operations, especially splenectomy and colorectal surgical procedures. We report the case of a 39-year old female who underwent restorative proctocolectomy and ileal pouch-anal anastomosis for familial adenomatous polyposis with sigmoid cancer. She presented 14 days later with vague upper abdominal pain, nausea, vomiting and high output stoma. Doppler ultrasonography confirmed PVT and therefore anticoagulant therapy was started. Her condition improved dramatically and she underwent closure of ileostomy after finishing adjuvant chemotherapy. She remained well at 3-year follow-up with good pouch function and no local or distant recurrence. A high index of suspicion is essential for early diagnosis and prompt treatment of postoperative PVT after restorative proctocolectomy. Early anticoagulation is essential to avoid subsequent complications. PMID- 22532811 TI - Additional resection of the pancreas body prevents postoperative pancreas fistula in patients with portal annular pancreas who undergo pancreaticoduodenectomy. AB - Portal annular pancreas (PAP) is a rare variant in which the uncinate process of the pancreas extends to the dorsal surface of the pancreas body and surrounds the portal vein or superior mesenteric vein. Upon pancreaticoduodenectomy (PD), when the pancreas is cut at the neck, two cut surfaces are created. Thus, the cut surface of the pancreas becomes larger than usual and the dorsal cut surface is behind the portal vein, therefore pancreatic fistula after PD has been reported frequently. We planned subtotal stomach-preserving PD in a 45-year-old woman with underlying insulinoma of the pancreas head. When the pancreas head was dissected, the uncinate process was extended and fused to the dorsal surface of the pancreas body. Additional resection of the pancreas body 1 cm distal to the pancreas tail to the left side of the original resection line was performed. The new cut surface became one and pancreaticojejunostomy was performed as usual. No postoperative complications such as pancreatic fistula occurred. Additional resection of the pancreas body may be a standardized procedure in patients with PAP in cases of pancreas cut surface reconstruction. PMID- 22532812 TI - Achalasia--a disease of unknown cause that is often diagnosed too late. AB - INTRODUCTION: Many physicians are inadequately familiar with the clinical features of achalasia. Often, it is not diagnosed until years after the symptoms arise. This is unfortunate, because a delay in diagnosis worsens the prognosis. METHODS: Selective review of the literature. RESULTS: Achalasia has a lifetime prevalence of 1:10 000. It is a neurodegenerative disorder in which the neurons of the myenteric plexus are lost, leading to dysfunction of the lower esophageal sphincter and to a derangement of esophageal peristalsis. In the final stage of achalasia, esophageal motility is irreversibly impaired, and complications ensue because of the retention of food that is no longer transported into the stomach. Aspiration causes pulmonary disturbances in up to half of all patients with achalasia. There may also be inflammation of the esophageal mucosa (retention esophagitis); this, in turn, is a risk factor for esophageal cancer, which arises in 4% to 6% of patients. The cause of achalasia is not fully known, but autoimmune processes appear to be involved in patients with a genetic susceptibility to the disease. CONCLUSION: Achalasia should be diagnosed as early as possible, so that complications can be prevented. In addition, guidelines should be established for cancer prevention in achalasia patients. Currently ongoing studies of the molecular causes of achalasia will probably help us understand its pathophysiology. PMID- 22532813 TI - The frequency of prescription of immediate-release nifedipine for elderly patients in Germany: utilization analysis of a substance on the PRISCUS list of potentially inappropriate medications. AB - BACKGROUND: Immediate-release nifedipine is on the PRISCUS list of drugs that should not be given to elderly patients. We studied the use of this calcium channel blocker under real-life conditions. METHODS: In 2009, we carried out a cross-sectional study based on the Statutory Health Insurance Sample AOK Hesse/KV Hesse with a sample size of 260 672 insurees. We used an anatomic-therapeutic chemical classification (C08) to identify prescriptions for calcium-channel blockers. We determined from brand names and dosage forms whether nifedipine was prescribed in an immediate-release or sustained-release formulation. RESULTS: Among insurees over age 65, the prevalence of treatment with immediate-release and sustained-release nifedipine was 0.9% and 1.0%, respectively. Immediate release nifedipine was usually (75%) given in a single administration. 46% of patients receiving immediate-release nifedipine also received another calcium channel blocker. Patients who received immediate-release nifedipine tended to take more cardiovascular drugs than those who received sustained-release nifedipine (6 or more cardiovascular drugs were taken by 30% and 16%, respectively). Among all medical diagnoses related to hypertension, two were significantly more common among patients taking immediate-release nifedipine than among those taking sustained-release nifedipine: hypertensive crisis (OR 4.26, 95% CI 2.45-7.40) and hypertensive heart disease (OR 1.82, 95% CI 1.04-3.19). CONCLUSION: Our analysis demonstrates that immediate-release nifedipine is being prescribed to elderly patients in Germany, albeit mostly in a single administration. In view of the risks and the availability of alternative drugs, stricter adherence to the PRISCUS recommendations in this case should be stressed in continuing medical education. PMID- 22532814 TI - Fertility preservation in women with malignant tumors and gonadotoxic treatments. AB - BACKGROUND: Because of improved survival rates and recent advances in reproductive medicine, fertility preservation methods in women of reproductive age with malignant or autoimmune diseases have risen in importance. METHODS: Selective literature review based on the authors' clinical and scientific experience. RESULTS: Fertility-preserving techniques are recommended for all girls and women up to age 40 who are at high risk of ovarian failure. As these techniques are complex, special expertise in counseling and treatment is needed; in the German-speaking countries, such expertise is available in centers belonging to the FertiPROTEKT network (www.fertiprotekt.eu). Most of these techniques carry a very low risk and can be performed in two weeks or less. Success rates depend on the patient's age, the experience of the center, and the particular technique used. The highest attainable likelihood of pregnancy after the use of a combination of cryopreservation techniques is estimated at 40% to 50%. Fertility preservation is generally not covered by health insurance; its cost ranges from several hundred to several thousand euros. CONCLUSION: Girls and women up to age 40 who are about to undergo gonadotoxic treatment should be counseled about the availability of fertility-preserving techniques and, if appropriate, should be treated with such techniques in a specialized center. PMID- 22532815 TI - Aneurysms of the ascending aorta. AB - BACKGROUND: Aneurysms of the ascending aorta present a special challenge to primary care physicians, internists, and cardiac surgeons because they remain asymptomatic until they present with either dissection or rupture. METHOD: This review article is based on a selective search of the literature. RESULTS: In the elderly, aneurysms of the ascending aorta are mainly caused by atherosclerosis. In younger patients, the most common cause is Marfan syndrome; less commonly, younger patients may have Loeys-Dietz syndrome, non-syndromic familial aortic aneurysms, or aortic valve malformations. Genetic variants predisposing to the development of sporadic aortic aneurysms have recently been identified. The risk of rupture and dissection depends on the aortic diameter: when the diameter exceeds 55 mm, surgery improves the outcome, as the risk of surgical complications is lower than the mortality due to rupture or dissection. A more accurate prognosis can be obtained by normalizing the aortic diameter to the body surface area. For patients with Marfan syndrome or a bicuspid aortic valve, the indications for surgery should be determined on an individual basis, depending on additional risk factors. Randomized treatment trials are lacking. The medical management of aneurysms of the ascending aorta consists of monitoring the size of the aneurysm, controlling blood pressure, and treating any cardiovascular risk factors. Patients with Marfan syndrome benefit from preventive treatment with beta-blockers. Advances in the pathophysiological understanding of aortic aneurysms have led to the testing of new types of treatment, e.g., with AT1 antagonists. CONCLUSION: With the aid of a risk-based treatment strategy, surgery can be properly timed to prevent dissection, which is usually lethal when it occurs. More research is needed on the pathogenesis of this condition so that better preventive treatments can be developed. PMID- 22532816 TI - Competence lies with the emergency physician. PMID- 22532817 TI - Economic concerns. PMID- 22532819 TI - Exercise tolerance in genetic cardiac disorders. PMID- 22532821 TI - Insect stings: clinical features and management. AB - BACKGROUND: In human beings, local and systemic reactions can be caused both by blood-sucking insects and by venomous insect stings. In Central Europe, the insects that most commonly cause such reactions are honeybees, certain social wasps, mosquitoes, and flies. METHODS: This article is based on a selective literature review, including guidelines from Germany and abroad. RESULTS: Insect venom induces a toxic reaction at the site of the sting. Large local reactions are due to allergy and occur in up to 25% of the population; as many as 3.5% develop IgE-mediated, potentially life-threatening anaphylaxis, of which about 20 people die in Germany each year. Mastocytosis is found in 3% to 5% of patients with sting anaphylaxis, rendering these patients prone to very severe reactions. Blood-sucking by hematophagous insects can elicit a local allergic reaction, presenting as a wheal or papule, in at least 75% of the population. Large local reactions may ensue, but other diseases are rare. The acute symptoms of an insect sting are treated symptomatically. Patients who have had a systemic reaction or a large local reaction due to insect allergy must take permanent measures to avoid further allergen contact, and to make sure they can treat themselves adequately if stung again. Most patients with systemic anaphylactic reactions to bee or wasp stings need specific immunotherapy. CONCLUSION: Insect stings can cause severe disease. Anaphylaxis due to bee or wasp stings is not a rare event; specific immunotherapy protects susceptible persons from further, potentially life threatening reactions. PMID- 22532824 TI - Pregnancy incidence and correlates during the HVTN 503 Phambili HIV vaccine trial conducted among South African women. AB - BACKGROUND: HIV prevention trials are increasingly being conducted in sub-Saharan Africa. Women at risk for HIV are also at risk of pregnancy. To maximize safety, women agree to avoid pregnancy during trials, yet pregnancies occur. Using data from the HVTN 503/"Phambili" vaccine trial, we report pregnancy incidence during and after the vaccination period and identify factors, measured at screening, associated with incident pregnancy. METHODS: To enrol in the trial, women agreed and were supported to avoid pregnancy until 1 month after their third and final vaccination ("vaccination period"), corresponding to the first 7 months of follow up. Unsterilized women, pooled across study arms, were analyzed. Poisson regression compared pregnancy rates during and after the vaccination period. Cox proportional hazards regression identified associations with first pregnancy. RESULTS: Among 352 women (median age 23 yrs; median follow-up 1.5 yrs), pregnancy incidence was 9.6/100 women-years overall and 6.8/100 w-yrs and 11.3/100 w-yrs during and after the vaccination period, respectively [Rate Ratio = 0.60 (0.32 1.14), p = 0.10]. In multivariable analysis, pregnancy was reduced among women who: enrolled at sites providing contraception on-site [HR = 0.43, 95% CI (0.22 0.86)]; entered the trial as injectable contraceptive users [HR = 0.37 (0.21 0.67)] or as consistent condom users (trend) [HR = 0.54 (0.28-1.04)]. Compared with women with a single partner of HIV-unknown status, pregnancy rates were increased among women with: a single partner whose status was HIV-negative [HR = 2.34(1.16-4.73)] and; 2 partners both of HIV-unknown status [HR = 4.42(1.59 12.29)]. Women with 2 more of these risk factors: marijuana use, heavy drinking, or use of either during sex, had increased pregnancy incidence [HR = 2.66 (1.24 5.72)]. CONCLUSIONS: It is possible to screen South African women for pregnancy risk at trial entry. Providing injectable contraception for free on-site and supporting consistent condom use may reduce incident pregnancy. Screening should determine the substance use, partnering, and HIV status of both members of the couple for both pregnancy and HIV prevention. TRIAL REGISTRATION: SA National Health Research Database DOH-27-0207-1539; Clinicaltrials.gov NCT00413725. PMID- 22532825 TI - Chiral speciation in terrestrial pulmonate snails. AB - On the basis of data in the literature, the percentages of dextral versus sinistral species of snails have been calculated for western Europe, Turkey, North America (north of Mexico), and Japan. When the family of Clausiliidae is represented, about a quarter of all snail species may be sinistral, whereas less than one per cent of the species may be sinistral where that family does not occur. The number of single-gene speciation events on the basis of chirality, resulting in the origin of mirror image species, is not closely linked to the percentage of sinistral versus dextral species in a particular region. Turkey is nevertheless exceptional by both a high percentage of sinistral species and a high number of speciation events resulting in mirror image species. Shell morphology and genetic background may influence the ease of chirality-linked speciation, whereas sinistrality may additionally be selected against by internal selection. For the Clausiliidae, the fossil record and the recent fauna suggest that successful reversals in coiling direction occurred with a frequency of once every three to four million years. PMID- 22532826 TI - The acute phase protein Serum Amyloid A induces lipolysis and inflammation in human adipocytes through distinct pathways. AB - BACKGROUND: The acute phase response (APR) is characterized by alterations in lipid and glucose metabolism leading to an increased delivery of energy substrates. In adipocytes, there is a coordinated decrease in Free Fatty acids (FFAs) and glucose storage, in addition to an increase in FFAs mobilization. Serum Amyloid A (SAA) is an acute phase protein mainly associated with High Density Lipoproteins (HDL). We hypothesized that enrichment of HDL with SAA, during the APR, could be implicated in the metabolic changes occurring in adipocytes. METHODOLOGY/PRINCIPAL FINDINGS: In vitro differentiated human adipocytes (hMADS) were treated with SAA enriched HDL or recombinant SAA and the metabolic phenotype of the cells analyzed. In hMADS, SAA induces an increased lipolysis through an ERK dependent pathway. At the molecular level, SAA represses PPARgamma2, C/EBPalpha and SREBP-1c gene expression, three transcription factors involved in adipocyte differentiation or lipid synthesis. In addition, the activation of the NF-kappaB pathway by SAA leads to the induction of pro inflammatory cytokines and chemokines, as in the case of immune cells. These latter findings were replicated in freshly isolated mature human adipocytes. CONCLUSIONS/SIGNIFICANCE: Besides its well-characterized role in cholesterol metabolism, SAA has direct metabolic effects on human adipocytes. These metabolic changes could be at least partly responsible for alterations of adipocyte metabolism observed during the APR as well as during pathophysiological conditions such as obesity and conditions leading to insulin resistant states. PMID- 22532827 TI - Phosphofructo-2-kinase/fructose-2,6-bisphosphatase modulates oscillations of pancreatic islet metabolism. AB - Pulses of insulin from pancreatic beta-cells help maintain blood glucose in a narrow range, although the source of these pulses is unclear. It has been proposed that a positive feedback circuit exists within the glycolytic pathway, the autocatalytic activation of phosphofructokinase-1 (PFK1), which endows pancreatic beta-cells with the ability to generate oscillations in metabolism. Flux through PFK1 is controlled by the bifunctional enzyme PFK2/FBPase2 (6 phosphofructo-2-kinase/fructose-2,6-bisphosphatase) in two ways: via (1) production/degradation of fructose-2,6-bisphosphate (Fru2,6-BP), a potent allosteric activator of PFK1, as well as (2) direct activation of glucokinase due to a protein-protein interaction. In this study, we used a combination of live cell imaging and mathematical modeling to examine the effects of inducibly expressed PFK2/FBPase2 mutants on glucose-induced Ca(2+) pulsatility in mouse islets. Irrespective of the ability to bind glucokinase, mutants of PFK2/FBPase2 that increased the kinase:phosphatase ratio reduced the period and amplitude of Ca(2+) oscillations. Mutants which reduced the kinase:phosphatase ratio had the opposite effect. These results indicate that the main effect of the bifunctional enzyme on islet pulsatility is due to Fru2,6-BP alteration of the threshold for autocatalytic activation of PFK1 by Fru1,6-BP. Using computational models based on PFK1-generated islet oscillations, we then illustrated how moderate elevation of Fru-2,6-BP can increase the frequency of glycolytic oscillations while reducing their amplitude, with sufficiently high activation resulting in termination of slow oscillations. The concordance we observed between PFK2/FBPase2-induced modulation of islet oscillations and the models of PFK1 driven oscillations furthermore suggests that metabolic oscillations, like those found in yeast and skeletal muscle, are shaped early in glycolysis. PMID- 22532828 TI - Depletion of trypanosome CTR9 leads to gene expression defects. AB - The Paf complex of Opisthokonts and plants contains at least five subunits: Paf1, Cdc73, Rtf1, Ctr9, and Leo1. Mutations in, or loss of Paf complex subunits have been shown to cause defects in histone modification, mRNA polyadenylation, and transcription by RNA polymerase I and RNA polymerase II. We here investigated trypanosome CTR9, which is essential for trypanosome survival. The results of tandem affinity purification suggested that trypanosome CTR9 associates with homologues of Leo1 and Cdc73; genes encoding homologues of Rtf1 and Paf1 were not found. RNAi targeting CTR9 resulted in at least ten-fold decreases in 131 essential mRNAs: they included several that are required for gene expression and its control, such as those encoding subunits of RNA polymerases, exoribonucleases that target mRNA, RNA helicases and RNA-binding proteins. Simultaneously, some genes from regions subject to chromatin silencing were derepressed, possibly as a secondary effect of the loss of two proteins that are required for silencing, ISWI and NLP1. PMID- 22532829 TI - Single endemic genotype of measles virus continuously circulating in China for at least 16 years. AB - The incidence of measles in China from 1991 to 2008 was reviewed, and the nucleotide sequences from 1507 measles viruses (MeV) isolated during 1993 to 2008 were phylogenetically analyzed. The results showed that measles epidemics peaked approximately every 3 to 5 years with the range of measles cases detected between 56,850 and 140,048 per year. The Chinese MeV strains represented three genotypes; 1501 H1, 1 H2 and 5 A. Genotype H1 was the predominant genotype throughout China continuously circulating for at least 16 years. Genotype H1 sequences could be divided into two distinct clusters, H1a and H1b. A 4.2% average nucleotide divergence was found between the H1a and H1b clusters, and the nucleotide sequence and predicted amino acid homologies of H1a viruses were 92.3%-100% and 84.7%-100%, H1b were 97.1%-100% and 95.3%-100%, respectively. Viruses from both clusters were distributed throughout China with no apparent geographic restriction and multiple co-circulating lineages were present in many provinces. Cluster H1a and H1b viruses were co-circulating during 1993 to 2005, while no H1b viruses were detected after 2005 and the transmission of that cluster has presumably been interrupted. Analysis of the nucleotide and predicted amino acid changes in the N proteins of H1a and H1b viruses showed no evidence of selective pressure. This study investigated the genotype and cluster distribution of MeV in China over a 16-year period to establish a genetic baseline before MeV elimination in Western Pacific Region (WPR). Continuous and extensive MeV surveillance and the ability to quickly identify imported cases of measles will become more critical as measles elimination goals are achieved in China in the near future. This is the first report that a single endemic genotype of measles virus has been found to be continuously circulating in one country for at least 16 years. PMID- 22532830 TI - Cysteamine suppresses invasion, metastasis and prolongs survival by inhibiting matrix metalloproteinases in a mouse model of human pancreatic cancer. AB - BACKGROUND: Cysteamine, an anti-oxidant aminothiol, is the treatment of choice for nephropathic cystinosis, a rare lysosomal storage disease. Cysteamine is a chemo-sensitization and radioprotection agent and its antitumor effects have been investigated in various tumor cell lines and chemical induced carcinogenesis. Here, we investigated whether cysteamine has anti-tumor and anti-metastatic effects in transplantable human pancreatic cancer, an aggressive metastatic disease. METHODOLOGY/PRINCIPAL FINDINGS: Cysteamine's anti-invasion effects were studied by matrigel invasion and cell migration assays in 10 pancreatic cancer cell lines. To study mechanism of action, we examined cell viability and matrix metalloproteinases (MMPs) activity in the cysteamine-treated cells. We also examined cysteamine's anti-metastasis effect in two orthotopic murine models of human pancreatic cancer by measuring peritoneal metastasis and survival of animals. Cysteamine inhibited both migration and invasion of all ten pancreatic cancer cell lines at concentrations (<25 mM) that caused no toxicity to cells. It significantly decreased MMPs activity (IC(50) 38-460 uM) and zymographic gelatinase activity in a dose dependent manner in vitro and in vivo; while mRNA and protein levels of MMP-9, MMP-12 and MMP-14 were slightly increased using the highest cysteamine concentration. In vivo, cysteamine significantly decreased metastasis in two established pancreatic tumor models, although it did not affect the size of primary tumors. Additionally, cysteamine prolonged survival of mice in a dose-dependent manner without causing any toxicity. Similar to the in vitro results, MMP activity was significantly decreased in animal tumors treated with cysteamine. Cysteamine had no clinical or preclinical adverse effects in the host even at the highest dose. CONCLUSIONS/SIGNIFICANCE: Our results suggest that cysteamine, an agent with a proven safety profile, may be useful for inhibition of metastasis and prolonging the survival of a host with pancreatic cancer. PMID- 22532831 TI - Molecular characterization of a 21.4 kilobase antibiotic resistance plasmid from an alpha-hemolytic Escherichia coli O108:H- human clinical isolate. AB - This study characterizes the 21.4 kilobase plasmid pECTm80 isolated from Escherichia coli strain 80, an alpha hemolytic human clinical diarrhoeal isolate (serotype O108:H-). DNA sequence analysis of pECTm80 revealed it belonged to incompatibility group X1, and contained plasmid partition and toxin-antitoxin systems, an R6K-like triple origin (ori) replication system, genes required for replication regulation, insertion sequences IS1R, ISEc37 and a truncated transposase gene (Tn3-like DeltatnpA) of the Tn3 family, and carried a class 2 integron. The class 2 integron of pECTm80 contains an intact cassette array dfrA1 sat2, encoding resistance to trimethoprim and streptothricin, and an aadA1 gene cassette truncated by the insertion of IS1R. The complex plasmid replication system includes alpha, beta and gamma origins of replication. Pairwise BLASTn comparison of pECTm80 with plasmid pE001 reveals a conserved plasmid backbone suggestive of a common ancestral lineage. Plasmid pECTm80 is of potential clinical importance, as it carries multiple genes to ensure its stable maintenance through successive bacterial cell divisions and multiple antibiotic resistance genes. PMID- 22532832 TI - Neonatal brain injury and neuroanatomy of memory processing following very preterm birth in adulthood: an fMRI study. AB - Altered functional neuroanatomy of high-order cognitive processing has been described in very preterm individuals (born before 33 weeks of gestation; VPT) compared to controls in childhood and adolescence. However, VPT birth may be accompanied by different types of adverse neonatal events and associated brain injury, the severity of which may have differential effects on brain development and subsequent neurodevelopmental outcome. We conducted a functional magnetic resonance imaging (fMRI) study to investigate how differing degrees of neonatal brain injury, detected by neonatal ultrasounds, affect the functional neuroanatomy of memory processing in VPT young adults. We used a verbal paired associates learning task, consisting of four encoding, four cued-recall and four baseline condition blocks. To further investigate whether differences in neural activation between the groups were modulated by structural brain changes, structural MRI data were also collected. We studied 12 VPT young adults with a history of periventricular haemorrhage with associated ventricular dilatation, 17 VPT individuals with a history of uncomplicated periventricular haemorrhage, 12 individuals with normal ultrasonographic findings, and 17 controls. Results of a linear trend analysis demonstrated that during completion of the paired associates learning task right frontal and right parietal brain activation decreased as the severity of neonatal brain injury increased. There were no statistically significant between-group differences in on-line task performance and participants' intelligence quotient (IQ) at assessment. This pattern of differential activation across the groups was observed particularly in the right middle frontal gyrus during encoding and in the right posterior cingulate gyrus during recall. Structural MRI data analysis revealed that grey matter volume in the right superior temporal gyrus, right cerebellum, left middle temporal gyrus, right globus pallidus and right medial frontal gyrus decreased with increasing severity of neonatal brain injury. However, the significant between-group functional neuroanatomical differences were not directly attributable to the detected structural regional differences. PMID- 22532833 TI - Loss of maternal CTCF is associated with peri-implantation lethality of Ctcf null embryos. AB - CTCF is a highly conserved, multifunctional zinc finger protein involved in critical aspects of gene regulation including transcription regulation, chromatin insulation, genomic imprinting, X-chromosome inactivation, and higher order chromatin organization. Such multifunctional properties of CTCF suggest an essential role in development. Indeed, a previous report on maternal depletion of CTCF suggested that CTCF is essential for pre-implantation development. To distinguish between the effects of maternal and zygotic expression of CTCF, we studied pre-implantation development in mice harboring a complete loss of function Ctcf knockout allele. Although we demonstrated that homozygous deletion of Ctcf is early embryonically lethal, in contrast to previous observations, we showed that the Ctcf nullizygous embryos developed up to the blastocyst stage (E3.5) followed by peri-implantation lethality (E4.5-E5.5). Moreover, one-cell stage Ctcf nullizygous embryos cultured ex vivo developed to the 16-32 cell stage with no obvious abnormalities. Using a single embryo assay that allowed both genotype and mRNA expression analyses of the same embryo, we demonstrated that pre-implantation development of the Ctcf nullizygous embryos was associated with the retention of the maternal wild type Ctcf mRNA. Loss of this stable maternal transcript was temporally associated with loss of CTCF protein expression, apoptosis of the developing embryo, and failure to further develop an inner cell mass and trophoectoderm ex vivo. This indicates that CTCF expression is critical to early embryogenesis and loss of its expression rapidly leads to apoptosis at a very early developmental stage. This is the first study documenting the presence of the stable maternal Ctcf transcript in the blastocyst stage embryos. Furthermore, in the presence of maternal CTCF, zygotic CTCF expression does not seem to be required for pre-implantation development. PMID- 22532835 TI - Counting mycobacteria in infected human cells and mouse tissue: a comparison between qPCR and CFU. AB - Due to the slow growth rate and pathogenicity of mycobacteria, enumeration by traditional reference methods like colony counting is notoriously time-consuming, inconvenient and biohazardous. Thus, novel methods that rapidly and reliably quantify mycobacteria are warranted in experimental models to facilitate basic research, development of vaccines and anti-mycobacterial drugs. In this study we have developed quantitative polymerase chain reaction (qPCR) assays for simultaneous quantification of mycobacterial and host DNA in infected human macrophage cultures and in mouse tissues. The qPCR method cannot discriminate live from dead bacteria and found a 10- to 100-fold excess of mycobacterial genomes, relative to colony formation. However, good linear correlations were observed between viable colony counts and qPCR results from infected macrophage cultures (Pearson correlation coefficient [r] for M. tuberculosis = 0.82; M. a. avium = 0.95; M. a. paratuberculosis = 0.91). Regression models that predict colony counts from qPCR data in infected macrophages were validated empirically and showed a high degree of agreement with observed counts. Similar correlation results were also obtained in liver and spleen homogenates of M. a. avium infected mice, although the correlations were distinct for the early phase (< day 9 post-infection) and later phase (>= day 20 post-infection) liver r = 0.94 and r = 0.91; spleen r = 0.91 and r = 0.87, respectively. Interestingly, in the mouse model the number of live bacteria as determined by colony counts constituted a much higher proportion of the total genomic qPCR count in the early phase (geometric mean ratio of 0.37 and 0.34 in spleen and liver, respectively), as compared to later phase of infection (geometric mean ratio of 0.01 in both spleen and liver). Overall, qPCR methods offer advantages in biosafety, time-saving, assay range and reproducibility compared to colony counting. Additionally, the duplex format allows enumeration of bacteria per host cell, an advantage in experiments where variable cell death can give misleading colony counts. PMID- 22532834 TI - Intracellular spatial localization regulated by the microtubule network. AB - The commonly recognized mechanisms for spatial regulation inside the cell are membrane-bounded compartmentalization and biochemical association with subcellular organelles. We use computational modeling to investigate another spatial regulation mechanism mediated by the microtubule network in the cell. Our results demonstrate that the mitotic spindle can impose strong sequestration and concentration effects on molecules with binding affinity for microtubules, especially dynein-directed cargoes. The model can recapitulate the essence of three experimental observations on distinct microtubule network morphologies: the sequestration of germ plasm components by the mitotic spindles in the Drosophila syncytial embryo, the asymmetric cell division initiated by the time delay in centrosome maturation in the Drosophila neuroblast, and the diffusional block between neighboring energids in the Drosophila syncytial embryo. Our model thus suggests that the cell cycle-dependent changes in the microtubule network are critical for achieving different spatial regulation effects. The microtubule network provides a spatially extensive docking platform for molecules and gives rise to a "structured cytoplasm", in contrast to a free and fluid environment. PMID- 22532836 TI - Identification and characterization of novel genotoxic stress-inducible nuclear long noncoding RNAs in mammalian cells. AB - Whole transcriptome analyses have revealed a large number of novel transcripts including long and short noncoding RNAs (ncRNAs). Currently, there is great interest in characterizing the functions of the different classes of ncRNAs and their relevance to cellular processes. In particular, nuclear long ncRNAs may be involved in controlling various aspects of biological regulation, such as stress responses. By a combination of bioinformatic and experimental approaches, we identified 25 novel nuclear long ncRNAs from 6,088,565 full-length human cDNA sequences. Some nuclear long ncRNAs were conserved among vertebrates, whereas others were found only among primates. Expression profiling of the nuclear long ncRNAs in human tissues revealed that most were expressed ubiquitously. A subset of the identified nuclear long ncRNAs was induced by the genotoxic agents mitomycin C or doxorubicin, in HeLa Tet-off cells. There were no commonly altered nuclear long ncRNAs between mitomycin C- and doxorubicin-treated cells. These results suggest that distinct sets of nuclear long ncRNAs play roles in cellular defense mechanisms against specific genotoxic agents, and that particular long ncRNAs have the potential to be surrogate indicators of a specific cell stress. PMID- 22532837 TI - Lestaurtinib inhibits histone phosphorylation and androgen-dependent gene expression in prostate cancer cells. AB - BACKGROUND: Epigenetics is defined as heritable changes in gene expression that are not based on changes in the DNA sequence. Posttranslational modification of histone proteins is a major mechanism of epigenetic regulation. The kinase PRK1 (protein kinase C related kinase 1, also known as PKN1) phosphorylates histone H3 at threonine 11 and is involved in the regulation of androgen receptor signalling. Thus, it has been identified as a novel drug target but little is known about PRK1 inhibitors and consequences of its inhibition. METHODOLOGY/PRINCIPAL FINDING: Using a focused library screening approach, we identified the clinical candidate lestaurtinib (also known as CEP-701) as a new inhibitor of PRK1. Based on a generated 3D model of the PRK1 kinase using the homolog PKC-theta (protein kinase c theta) protein as a template, the key interaction of lestaurtinib with PRK1 was analyzed by means of molecular docking studies. Furthermore, the effects on histone H3 threonine phosphorylation and androgen-dependent gene expression was evaluated in prostate cancer cells. CONCLUSIONS/SIGNIFICANCE: Lestaurtinib inhibits PRK1 very potently in vitro and in vivo. Applied to cell culture it inhibits histone H3 threonine phosphorylation and androgen-dependent gene expression, a feature that has not been known yet. Thus our findings have implication both for understanding of the clinical activity of lestaurtinib as well as for future PRK1 inhibitors. PMID- 22532838 TI - Parkinson's disease DJ-1 L166P alters rRNA biogenesis by exclusion of TTRAP from the nucleolus and sequestration into cytoplasmic aggregates via TRAF6. AB - Mutations in PARK7/DJ-1 gene are associated to autosomal recessive early onset forms of Parkinson's disease (PD). Although large gene deletions have been linked to a loss-of-function phenotype, the pathogenic mechanism of missense mutations is less clear. The L166P mutation causes misfolding of DJ-1 protein and its degradation. L166P protein may also accumulate into insoluble cytoplasmic aggregates with a mechanism facilitated by the E3 ligase TNF receptor associated factor 6 (TRAF6). Upon proteasome impairment L166P activates the JNK/p38 MAPK apoptotic pathway by its interaction with TRAF and TNF Receptor Associated Protein (TTRAP). When proteasome activity is blocked in the presence of wild-type DJ-1, TTRAP forms aggregates that are localized to the cytoplasm or associated to nucleolar cavities, where it is required for a correct rRNA biogenesis. In this study we show that in post-mortem brains of sporadic PD patients TTRAP is associated to the nucleolus and to Lewy Bodies, cytoplasmic aggregates considered the hallmark of the disease. In SH-SY5Y neuroblastoma cells, misfolded mutant DJ 1 L166P alters rRNA biogenesis inhibiting TTRAP localization to the nucleolus and enhancing its recruitment into cytoplasmic aggregates with a mechanism that depends in part on TRAF6 activity. This work suggests that TTRAP plays a role in the molecular mechanisms of both sporadic and familial PD. Furthermore, it unveils the existence of an interplay between cytoplasmic and nucleolar aggregates that impacts rRNA biogenesis and involves TRAF6. PMID- 22532839 TI - Neuromagnetic index of hemispheric asymmetry prognosticating the outcome of sudden hearing loss. AB - The longitudinal relationship between central plastic changes and clinical presentations of peripheral hearing impairment remains unknown. Previously, we reported a unique plastic pattern of "healthy-side dominance" in acute unilateral idiopathic sudden sensorineural hearing loss (ISSNHL). This study aimed to explore whether such hemispheric asymmetry bears any prognostic relevance to ISSNHL along the disease course. Using magnetoencephalography (MEG), inter hemispheric differences in peak dipole amplitude and latency of N100m to monaural tones were evaluated in 21 controls and 21 ISSNHL patients at two stages: initial and fixed stage (1 month later). Dynamics/Prognostication of hemispheric asymmetry were assessed by the interplay between hearing level/hearing gain and ipsilateral/contralateral ratio (I/C) of N100m latency and amplitude. Healthy side dominance of N100m amplitude was observed in ISSNHL initially. The pattern changed with disease process. There is a strong correlation between the hearing level at the fixed stage and initial I/C(amplitude) on affected-ear stimulation in ISSNHL. The optimal cut-off value with the best prognostication effect for the hearing improvement at the fixed stage was an initial I/C(latency) on affected ear stimulation of 1.34 (between subgroups of complete and partial recovery) and an initial I/C(latency) on healthy-ear stimulation of 0.76 (between subgroups of partial and no recovery), respectively. This study suggested that a dynamic process of central auditory plasticity can be induced by peripheral lesions. The hemispheric asymmetry at the initial stage bears an excellent prognostic potential for the treatment outcomes and hearing level at the fixed stage in ISSNHL. Our study demonstrated that such brain signature of central auditory plasticity in terms of both N100m latency and amplitude at defined time can serve as a prognostication predictor for ISSNHL. Further studies are needed to explore the long-term temporal scenario of auditory hemispheric asymmetry and to get better psychoacoustic correlates of pathological hemispheric asymmetry in ISSNHL. PMID- 22532840 TI - Association of serum albumin with markers of nutritional status among HIV infected and uninfected Rwandan women. AB - INTRODUCTION: The objectives of this study are to address if and how albumin can be used as an indication of malnutrition in HIV infected and uninfected Africans. METHODS: In 2005, 710 HIV-infected and 226 HIV-uninfected women enrolled in a cohort study. Clinical/demographic parameters, CD4 count, albumin, liver transaminases; anthropometric measurements and Bioelectrical Impedance Analysis (BIA) were performed. Malnutrition outcomes were defined as body mass index (BMI), Fat-free mass index (FFMI) and Fat mass index (FMI). Separate linear predictive models including albumin were fit to these outcomes in HIV negative and HIV positive women by CD4 strata (CD4>350,200-350 and <200 cells/ul). RESULTS: In unadjusted models for each outcome in HIV-negative and HIV positive women with CD4>350 cells/ul, serum albumin was not significantly associated with BMI, FFMI or FMI. Albumin was significantly associated with all three outcomes (p<0.05) in HIV+ women with CD4 200-350 cells/ul, and highly significant in HIV+ women with CD4<200 cells/ul (P<0.001). In multivariable linear regression, albumin remained associated with FFMI in women with CD4 count<200 cells/ul (p<0.01) but not in HIV+ women with CD4>200. DISCUSSION: While serum albumin is widely used to indicate nutritional status it did not consistently predict malnutrition outcomes in HIV- women or HIV+ women with higher CD4. This result suggests that albumin may measure end stage disease as well as malnutrition and should not be used as a proxy for nutritional status without further study of its association with validated measures. PMID- 22532841 TI - Risk of Foot-and-Mouth Disease spread due to sole occupancy authorities and linked cattle holdings. AB - Livestock movements in Great Britain are well recorded, have been extensively analysed with respect to their role in disease spread, and have been used in real time to advise governments on the control of infectious diseases. Typically, livestock holdings are treated as distinct entities that must observe movement standstills upon receipt of livestock, and must report livestock movements. However, there are currently two dispensations that can exempt holdings from either observing standstills or reporting movements, namely the Sole Occupancy Authority (SOA) and Cattle Tracing System (CTS) Links, respectively. In this report we have used a combination of data analyses and computational modelling to investigate the usage and potential impact of such linked holdings on the size of a Foot-and-Mouth Disease (FMD) epidemic. Our analyses show that although SOAs are abundant, their dynamics appear relatively stagnant. The number of CTS Links is also abundant, and increasing rapidly. Although most linked holdings are only involved in a single CTS Link, some holdings are involved in numerous links that can be amalgamated to form "CTS Chains" which can be both large and geographically dispersed. Our model predicts that under a worst case scenario of "one infected - all infected", SOAs do pose a risk of increasing the size (in terms of number of infected holdings) of a FMD epidemic, but this increase is mainly due to intra-SOA infection spread events. Furthermore, although SOAs do increase the geographic spread of an epidemic, this increase is predominantly local. Whereas, CTS Chains pose a risk of increasing both the size and the geographical spread of the disease substantially, under a worse case scenario. Our results highlight the need for further investigations into whether CTS Chains are transmission chains, and also investigations into intra-SOA movements and livestock distributions due to the lack of current data. PMID- 22532842 TI - Allosteric analysis of glucocorticoid receptor-DNA interface induced by cyclic Py Im polyamide: a molecular dynamics simulation study. AB - BACKGROUND: It has been extensively developed in recent years that cell-permeable small molecules, such as polyamide, can be programmed to disrupt transcription factor-DNA interfaces and can silence aberrant gene expression. For example, cyclic pyrrole-imidazole polyamide that competes with glucocorticoid receptor (GR) for binding to glucocorticoid response elements could be expected to affect the DNA dependent binding by interfering with the protein-DNA interface. However, how such small molecules affect the transcription factor-DNA interfaces and gene regulatory pathways through DNA structure distortion is not fully understood so far. METHODOLOGY/PRINCIPAL FINDINGS: In the present work, we have constructed some models, especially the ternary model of polyamides+DNA+GR DNA-binding domain (GRDBD) dimer, and carried out molecular dynamics simulations and free energy calculations for them to address how polyamide molecules disrupt the GRDBD and DNA interface when polyamide and protein bind at the same sites on opposite grooves of DNA. CONCLUSIONS/SIGNIFICANCE: We found that the cyclic polyamide binding in minor groove of DNA can induce a large structural perturbation of DNA, i.e. a >4 A widening of the DNA minor groove and a compression of the major groove by more than 4 A as compared with the DNA molecule in the GRDBD dimer+DNA complex. Further investigations for the ternary system of polyamides+DNA+GRDBD dimer and the binary system of allosteric DNA+GRDBD dimer revealed that the compression of DNA major groove surface causes GRDBD to move away from the DNA major groove with the initial average distance of ~4 A to the final average distance of ~10 A during 40 ns simulation course. Therefore, this study straightforward explores how small molecule targeting specific sites in the DNA minor groove disrupts the transcription factor-DNA interface in DNA major groove, and consequently modulates gene expression. PMID- 22532843 TI - Role of Homer proteins in the maintenance of sleep-wake states. AB - Sleep is an evolutionarily conserved process that is linked to diurnal cycles and normal daytime wakefulness. Healthy sleep and wakefulness are integral to a healthy lifestyle; this occurs when an organism is able to maintain long bouts of both sleep and wake. Homer proteins, which function as adaptors for group 1 metabotropic glutamate receptors, have been implicated in genetic studies of sleep in both Drosophila and mouse. Drosophila express a single Homer gene product that is upregulated during sleep. By contrast, vertebrates express Homer as both constitutive and immediate early gene (H1a) forms, and H1a is up regulated during wakefulness. Genetic deletion of Homer in Drosophila results in fragmented sleep and in failure to sustain long bouts of sleep, even under increased sleep drive. However, deletion of Homer1a in mouse results in failure to sustain long bouts of wakefulness. Further evidence for the role of Homer1a in the maintenance of wake comes from the CREB alpha delta mutant mouse, which displays a reduced wake phenotype similar to the Homer1a knockout and fails to up regulate Homer1a upon sleep loss. Homer1a is a gene whose expression is induced by CREB. Sustained behaviors of the sleep/wake cycle are created by molecular pathways that are distinct from those for arousal or short bouts, and implicate an evolutionarily-conserved role for Homer in sustaining these behaviors. PMID- 22532844 TI - The role of sphingosine kinase 1/sphingosine-1-phosphate pathway in the myogenic tone of posterior cerebral arteries. AB - AIMS: The goal of the current study was to determine whether the sphingosine kinase 1 (SK1)/sphingosine-1-phosphate (S1P) pathway is involved in myogenic vasoconstriction under normal physiological conditions. In the present study, we assessed whether endogenous S1P generated by pressure participates in myogenic vasoconstriction and which signaling pathways are involved in SK1/S1P-induced myogenic response under normal physiological conditions. METHODS AND RESULTS: We measured pressure-induced myogenic response, Ca(2+) concentration, and 20 kDa myosin light chain phosphorylation (MLC(20)) in rabbit posterior cerebral arteries (PCAs). SK1 was expressed and activated by elevated transmural pressure in rabbit PCAs. Translocation of SK1 by pressure elevation was blocked in the absence of external Ca(2+) and in the presence of mechanosensitive ion channel and voltage-sensitive Ca(2+) channel blockers. Pressure-induced myogenic tone was inhibited in rabbit PCAs treated with sphingosine kinase inhibitor (SKI), but was augmented by treatment with NaF, which is an inhibitor of sphingosine-1-phosphate phosphohydrolase. Exogenous S1P further augmented pressure-induced myogenic responses. Pressure induced an increase in Ca(2+) concentration leading to the development of myogenic tone, which was inhibited by SKI. Exogenous S1P further increased the pressure-induced increased Ca(2+) concentration and myogenic tone, but SKI had no effect. Pressure- and exogenous S1P-induced myogenic tone was inhibited by pre-treatment with the Rho kinase inhibitor and NADPH oxidase inhibitors. Pressure- and exogenous S1P-induced myogenic tone were inhibited by pre-treatment with S1P receptor blockers, W146 (S1P1), JTE013 (S1P2), and CAY10444 (S1P3). MLC(20) phosphorylation was increased when the transmural pressure was raised from 40 to 80 mmHg and exogenous S1P further increased MLC(20) phosphorylation. The pressure-induced increase of MLC(20) phosphorylation was inhibited by pre-treatment of arteries with SKI. CONCLUSIONS: Our results suggest that the SK1/S1P pathway may play an important role in pressure-induced myogenic responses in rabbit PCAs under normal physiological conditions. PMID- 22532845 TI - Programmed death-1 and its ligand are novel immunotolerant molecules expressed on leukemic B cells in chronic lymphocytic leukemia. AB - Programmed death-1 (PD-1) is an immunoreceptor predominantly expressed on exhausted T cells, which through an interaction with its ligand (PD-L1), controls peripheral tolerance by limiting effector functions of T lymphocytes. qRT-PCR for PD-1, PD-L1 and their splicing forms as well as flow cytometric assessment of surface expression was performed in a cohort of 58 chronic lymphocytic leukemia (CLL) patients. In functional studies, we assessed the influence of the proliferative response of leukemic B-cells induced by IL-4 and CD40L on PD-1 transcripts and expression on the protein level. The median level of PD-1, but not PD-L1, transcripts in CLL patients was higher in comparison to healthy volunteers (HVs, n = 43, p = 0.0057). We confirmed the presence of PD-1 and PD-L1 on the CLL cell surface, and found the expression of PD-1, but not PD-L1, to be higher among CLL patients in comparison to HVs (47.2% vs. 14.8%, p<0.0001). The Kaplan-Meier curves for the time to progression and overall survival in groups with high and low surface expression of PD-1 and PD-L1 revealed no prognostic value in CLL patients. After stimulation with IL-4 and CD40L, protein expression of PD-1 was significantly increased in samples that responded and up-regulated CD38. PD-1, which is aberrantly expressed both at mRNA and cell surface levels in CLL cells might represent a novel immunotolerant molecule involved in the pathomechanism of the disease, and could provide a novel target for future therapies. PMID- 22532846 TI - Expert opinion on laparoscopic surgery for colorectal cancer parallels evidence from a cumulative meta-analysis of randomized controlled trials. AB - BACKGROUND: This study sought to synthesize survival outcomes from trials of laparoscopic and open colorectal cancer surgery, and to determine whether expert acceptance of this technology in the literature has parallel cumulative survival evidence. STUDY DESIGN: A systematic review of randomized trials was conducted. The primary outcome was survival, and meta-analysis of time-to-event data was conducted. Expert opinion in the literature (published reviews, guidelines, and textbook chapters) on the acceptability of laparoscopic colorectal cancer was graded using a 7-point scale. Pooled survival data were correlated in time with accumulating expert opinion scores. RESULTS: A total of 5,800 citations were screened. Of these, 39 publications pertaining to 23 individual trials were retained. As well, 414 reviews were included (28 guidelines, 30 textbook chapters, 20 systematic reviews, 336 narrative reviews). In total, 5,782 patients were randomized to laparoscopic (n = 3,031) and open (n = 2,751) colorectal surgery. Survival data were presented in 16 publications. Laparoscopic surgery was not inferior to open surgery in terms of overall survival (HR = 0.94, 95% CI 0.80, 1.09). Expert opinion in the literature pertaining to the oncologic acceptability of laparoscopic surgery for colon cancer correlated most closely with the publication of large RCTs in 2002-2004. Although increasingly accepted since 2006, laparoscopic surgery for rectal cancer remained controversial. CONCLUSIONS: Laparoscopic surgery for colon cancer is non-inferior to open surgery in terms of overall survival, and has been so since 2004. The majority expert opinion in the literature has considered these two techniques to be equivalent since 2002-2004. Laparoscopic surgery for rectal cancer has been increasingly accepted since 2006, but remains controversial. Knowledge translation efforts in this field appear to have paralleled the accumulation of clinical trial evidence. PMID- 22532848 TI - Mild hypothermia attenuates mitochondrial oxidative stress by protecting respiratory enzymes and upregulating MnSOD in a pig model of cardiac arrest. AB - Mild hypothermia is the only effective treatment confirmed clinically to improve neurological outcomes for comatose patients with cardiac arrest. However, the underlying mechanism is not fully elucidated. In this study, our aim was to determine the effect of mild hypothermia on mitochondrial oxidative stress in the cerebral cortex. We intravascularly induced mild hypothermia (33 degrees C), maintained this temperature for 12 h, and actively rewarmed in the inbred Chinese Wuzhishan minipigs successfully resuscitated after 8 min of untreated ventricular fibrillation. Cerebral samples were collected at 24 and 72 h following return of spontaneous circulation (ROSC). We found that mitochondrial malondialdehyde and protein carbonyl levels were significantly increased in the cerebral cortex in normothermic pigs even at 24 h after ROSC, whereas mild hypothermia attenuated this increase. Moreover, mild hypothermia attenuated the decrease in Complex I and Complex III (i.e., major sites of reactive oxygen species production) activities of the mitochondrial respiratory chain and increased antioxidant enzyme manganese superoxide dismutase (MnSOD) activity. This increase in MnSOD activity was consistent with the upregulation of nuclear factor erythroid 2 related factor 2 (Nrf2) mRNA and protein expressions, and with the increase of Nrf2 nuclear translocation in normothermic pigs at 24 and 72 h following ROSC, whereas mild hypothermia enhanced these tendencies. Thus, our findings indicate that mild hypothermia attenuates mitochondrial oxidative stress in the cerebral cortex, which may be associated with reduced impairment of mitochondrial respiratory chain enzymes, and enhancement of MnSOD activity and expression via Nrf2 activation. PMID- 22532847 TI - Pooled sample-based GWAS: a cost-effective alternative for identifying colorectal and prostate cancer risk variants in the Polish population. AB - BACKGROUND: Prostate cancer (PCa) and colorectal cancer (CRC) are the most commonly diagnosed cancers and cancer-related causes of death in Poland. To date, numerous single nucleotide polymorphisms (SNPs) associated with susceptibility to both cancer types have been identified, but their effect on disease risk may differ among populations. METHODS: To identify new SNPs associated with PCa and CRC in the Polish population, a genome-wide association study (GWAS) was performed using DNA sample pools on Affymetrix Genome-Wide Human SNP 6.0 arrays. A total of 135 PCa patients and 270 healthy men (PCa sub-study) and 525 patients with adenoma (AD), 630 patients with CRC and 690 controls (AD/CRC sub-study) were included in the analysis. Allele frequency distributions were compared with t tests and chi(2)-tests. Only those significantly associated SNPs with a proxy SNP (p<0.001; distance of 100 kb; r(2)>0.7) were selected. GWAS marker selection was conducted using PLINK. The study was replicated using extended cohorts of patients and controls. The association with previously reported PCa and CRC susceptibility variants was also examined. Individual patients were genotyped using TaqMan SNP Genotyping Assays. RESULTS: The GWAS selected six and 24 new candidate SNPs associated with PCa and CRC susceptibility, respectively. In the replication study, 17 of these associations were confirmed as significant in additive model of inheritance. Seven of them remained significant after correction for multiple hypothesis testing. Additionally, 17 previously reported risk variants have been identified, five of which remained significant after correction. CONCLUSION: Pooled-DNA GWAS enabled the identification of new susceptibility loci for CRC in the Polish population. Previously reported CRC and PCa predisposition variants were also identified, validating the global nature of their associations. Further independent replication studies are required to confirm significance of the newly uncovered candidate susceptibility loci. PMID- 22532849 TI - Telephone cognitive-behavioral therapy for subthreshold depression and presenteeism in workplace: a randomized controlled trial. AB - BACKGROUND: Subthreshold depression is highly prevalent in the general population and causes great loss to society especially in the form of reduced productivity while at work (presenteeism). We developed a highly-structured manualized eight session cognitive-behavioral program with a focus on subthreshold depression in the workplace and to be administered via telephone by trained psychotherapists (tCBT). METHODS: We conducted a parallel-group, non-blinded randomized controlled trial of tCBT in addition to the pre-existing Employee Assistance Program (EAP) versus EAP alone among workers with subthreshold depression at a large manufacturing company in Japan. The primary outcomes were depression severity as measured with Beck Depression Inventory-II (BDI-II) and presenteeism as measured with World Health Organization Health and Work Productivity Questionnaire (HPQ). In the course of the trial the follow-up period was shortened in order to increase acceptability of the study. RESULTS: The planned sample size was 108 per arm but the trial was stopped early due to low accrual. Altogether 118 subjects were randomized to tCBT+EAP (n = 58) and to EAP alone (n = 60). The BDI-II scores fell from the mean of 17.3 at baseline to 11.0 in the intervention group and to 15.7 in the control group after 4 months (p<0.001, Effect size = 0.69, 95%CI: 0.32 to 1.05). However, there was no statistically significant decrease in absolute and relative presenteeism (p = 0.44, ES = 0.15, -0.21 to 0.52, and p = 0.50, ES = 0.02, -0.34 to 0.39, respectively). CONCLUSION: Remote CBT, including tCBT, may provide easy access to quality-assured effective psychotherapy for people in the work force who present with subthreshold depression. Further studies are needed to evaluate the effectiveness of this approach in longer terms. The study was funded by Sekisui Chemicals Co. Ltd. TRIAL REGISTRATION: ClinicalTrials.gov NCT00885014. PMID- 22532850 TI - MiR-133b targets antiapoptotic genes and enhances death receptor-induced apoptosis. AB - Despite the importance of microRNAs (miRs) for regulation of the delicate balance between cell proliferation and death, evidence for their specific involvement during death receptor (DR)-mediated apoptosis is scarce. Transfection with miR 133b rendered resistant HeLa cells sensitive to tumor necrosis factor-alpha (TNFalpha)-induced cell death. Similarly, miR-133b caused exacerbated proapoptotic responses to TNF-related apoptosis-inducing ligand (TRAIL) or an activating antibody to Fas/CD95. Comprehensive analysis, encompassing global RNA or protein expression profiling performed by microarray experiments and pulsed stable isotope labeling with amino acids in cell culture (pSILAC), led to the discovery of the antiapoptotic protein Fas apoptosis inhibitory molecule (FAIM) as immediate miR-133b target. Moreover, miR-133b impaired the expression of the detoxifying protein glutathione-S-transferase pi (GSTP1). Expression of miR-133b in tumor specimens of prostate cancer patients was significantly downregulated in 75% of the cases, when compared with matched healthy tissue. Furthermore, introduction of synthetic miR-133b into an ex-vivo model of prostate cancer resulted in impaired proliferation and cellular metabolic activity. PC3 cells were also sensitized to apoptotic stimuli after transfection with miR-133b similar to HeLa cells. These data reveal the ability of a single miR to influence major apoptosis pathways, suggesting an essential role for this molecule during cellular transformation, tumorigenesis and tissue homeostasis. PMID- 22532851 TI - Alterations of gene expression and glutamate clearance in astrocytes derived from an MeCP2-null mouse model of Rett syndrome. AB - Rett syndrome (RTT) is a neurodevelopmetal disorder associated with mutations in the methyl-CpG-binding protein 2 (MeCP2) gene. MeCP2-deficient mice recapitulate the neurological degeneration observed in RTT patients. Recent studies indicated a role of not only neurons but also glial cells in neuronal dysfunction in RTT. We cultured astrocytes from MeCP2-null mouse brain and examined astroglial gene expression, growth rate, cytotoxic effects, and glutamate (Glu) clearance. Semi quantitative RT-PCR analysis revealed that expression of astroglial marker genes, including GFAP and S100beta, was significantly higher in MeCP2-null astrocytes than in control astrocytes. Loss of MeCP2 did not affect astroglial cell morphology, growth, or cytotoxic effects, but did alter Glu clearance in astrocytes. When high extracellular Glu was added to the astrocyte cultures and incubated, a time-dependent decrease of extracellular Glu concentration occurred due to Glu clearance by astrocytes. Although the shapes of the profiles of Glu concentration versus time for each strain of astrocytes were grossly similar, Glu concentration in the medium of MeCP2-null astrocytes were lower than those of control astrocytes at 12 and 18 h. In addition, MeCP2 deficiency impaired downregulation of excitatory amino acid transporter 1 and 2 (EAAT1/2) transcripts, but not induction of glutamine synthetase (GS) transcripts, upon high Glu exposure. In contrast, GS protein was significantly higher in MeCP2-null astrocytes than in control astrocytes. These findings suggest that MeCP2 affects astroglial genes expression in cultured astrocytes, and that abnormal Glu clearance in MeCP2-deficient astrocytes may influence the onset and progression of RTT. PMID- 22532852 TI - Real-time cytotoxicity assay for rapid and sensitive detection of ricin from complex matrices. AB - BACKGROUND: In the context of a potential bioterrorist attack sensitive and fast detection of functionally active toxins such as ricin from complex matrices is necessary to be able to start timely countermeasures. One of the functional detection methods currently available for ricin is the endpoint cytotoxicity assay, which suffers from a number of technical deficits. METHODOLOGY/FINDINGS: This work describes a novel online cytotoxicity assay for the detection of active ricin and Ricinus communis agglutinin, that is based on a real-time cell electronic sensing system and impedance measurement. Characteristic growth parameters of Vero cells were monitored online and used as standardized viability control. Upon incubation with toxin the cell status and the cytotoxic effect were visualized using a characteristic cell index-time profile. For ricin, tested in concentrations of 0.06 ng/mL or above, a concentration-dependent decrease of cell index correlating with cytotoxicity was recorded between 3.5 h and 60 h. For ricin, sensitive detection was determined after 24 h, with an IC50 of 0.4 ng/mL (for agglutinin, an IC50 of 30 ng/mL was observed). Using functionally blocking antibodies, the specificity for ricin and agglutinin was shown. For detection from complex matrices, ricin was spiked into several food matrices, and an IC50 ranging from 5.6 to 200 ng/mL was observed. Additionally, the assay proved to be useful in detecting active ricin in environmental sample materials, as shown for organic fertilizer containing R. communis material. CONCLUSIONS/SIGNIFICANCE: The cell-electrode impedance measurement provides a sensitive online detection method for biologically active cytotoxins such as ricin. As the cell status is monitored online, the assay can be standardized more efficiently than previous approaches based on endpoint measurement. More importantly, the real-time cytotoxicity assay provides a fast and easy tool to detect active ricin in complex sample matrices. PMID- 22532853 TI - How contemporary human reproductive behaviors influence the role of fertility related genes: the example of the p53 gene. AB - Studies on human fertility genes have identified numerous risk/protective alleles involved in the occurrence of reproductive system diseases causing infertility or subfertility. Investigations we carried out in populations at natural fertility seem to suggest that the clinical relevance that some fertility genes are now acquiring depends on their interaction with contemporary reproductive behaviors (birth control, delayed childbearing, and spacing birth order, among others). In recent years, a new physiological role in human fertility regulation has emerged for the tumor- suppressor p53 gene (P53), and the P53 Arg72Pro polymorphism has been associated with recurrent implantation failure in humans. To lend support to our previous observations, we examined the impact of Arg72Pro polymorphism on fertility in two samples of Italian women not selected for impaired fertility but collected from populations with different (premodern and modern) reproductive behaviors. Among the women at near-natural fertility (n = 98), the P53 genotypes were not associated with different reproductive efficiency, whereas among those with modern reproductive behaviors (n = 68), the P53 genotypes were associated with different mean numbers of children [Pro/Pro = 0.75 .05). CONCLUSION: In consideration of the short observation period, the clinical use of AdheSE One in stress-bearing posterior cavities reached acceptable clinical results with a 1.1% cumulative failure rate after 2 years. The use of a flowable composite resin did not show an improved clinical performance. PMID- 22532942 TI - Machined and sandblasted human dental implants retrieved after 5 years: a histologic and histomorphometric analysis of three cases. AB - OBJECTIVE: Human retrieved implants with an intact bone-implant interface play a pivotal role in validating data obtained from in vitro studies and animal experiments. This study presents a histologic and histomorphometric analysis of peri-implant tissue reactions and of the bone-titanium interface in three machined and sandblasted dental implants retrieved after a 5-year loading period. METHOD AND MATERIALS: Three implants, with an intact bone-implant interface, were found in the Archives of the Implant Retrieval Center of the Dental School of the University of Chieti-Pescara, Chieti, Italy. The three implants had been used in a two-stage submerged procedure and loaded as part of a small prosthetic restoration. One implant had been retrieved because of an abutment fracture, while there was a fracture of the connecting screw in the other two. One implant was in the maxilla (sandblasted surface), and two were in the mandible (one with a machined surface and the other with a sandblasted surface). All implants had been processed for histology. RESULTS: All three implants presented mature, compact, lamellar bone at the interface. Many remodeling areas were present in the peri-implant bone, especially inside the implant threads. The bone was always in close contact with the implant surface. The bone-implant contact percentage of the machined implant was 92.7%, while the two sandblasted implants showed bone implant contact percentages of 85.9% and 76.6%. CONCLUSION: The present histologic results confirmed that these implants with different surfaces maintained a good level of osseointegration over a 5-year loading period, with continuous remodeling at the interface, and showed high bone-implant contact percentages. PMID- 22532943 TI - Placement of Branemark Mk IV implants in compromised and grafted bone: radiographic outcome of 61 sites in 27 patients with 3- to 7-year follow-ups. AB - OBJECTIVE: Sites in which bone is reduced in quality or height create challenges in esthetic reconstruction and loading support, which leads to a higher risk of failure. The Mk IV system with a TiUnite surface was designed specifically for placement in soft bone. This paper describes postloading outcomes of 103 Mk IV implants, with a focus on bone preservation in compromised bone sites during early remodeling, stability after abutment connection, and a 3- to 7-year follow up from implant placement. METHOD AND MATERIALS: A series of 103 4-mm (diameter), <= 10-mm (length) Mk IV implants were placed in the maxillae of 25 females and 14 males. Twenty-three patients also received staged bone grafts, and two underwent socket augmentation as well as grafts. Areas of previous infection were prepared mechanically and chemically. To ensure primary implant stability, the size of the osteotomy and the number of entries were minimized. Following a delayed loading protocol, all patients were restored with fixed partial dentures. For analysis of bone stability, the marginal levels on the mesial and distal aspects of the implants were measured at 7x magnification by a radiologist not involved in the treatment. RESULTS: Three implants were lost, 1 implant was never loaded although it integrated, 14 implants were not available for follow-up after abutment correction, and 5 had poor-quality radiographs. The mean marginal bone loss between implant insertion and loading was 1.21 +/- 0.86 mm (n = 80). The differences in bone-remodeling levels in grafted and nongrafted sites were not significant. Data are reported on 103 implants in 39 consecutive patients through abutment connection, with radiographic follow-up from 3 to 7 years postimplant placement on 27 patients. CONCLUSION: It is critical to ensure optimal three dimensional orientation and minimize site preparation, particularly when placing implants in compromised bone. With bone of poor preoperative density using a customized site preparation technique, excellent short-term implant survival and long-term bone stability have been demonstrated. Further follow-up will determine whether the Mk IV implant is the optimal design for compromised bone, including associated soft tissue stability. PMID- 22532944 TI - Laboratory-made composite resin restorations in children and adolescents with hypoplasia or hypomineralization of teeth. AB - Management of children and adolescents with qualitative or quantitative defects of enamel or dentin are often impeded by patient compliance, rare prevalence of disease, lack of evidence, and cost. The aim for all patients in this case series was to develop a suitable treatment strategy that required little chair time and was applicable to several conditions. Thirty-four laboratory-made composite resin restorations were placed in differently affected permanent posterior teeth of eight young patients. The ages of the patients ranged from 6 to 15 years. All restorations were adhesively inserted with the etch-and-rinse technique and are still in situ. The longevity of the restorations at present is 2 to 48 months. This treatment method allowed relatively comfortable treatment for children and adolescents who required extensive dental treatment. The outcome has been favorable with good patient compliance, brief chair time, and functional and esthetic restorations. PMID- 22532945 TI - The effect of Breezy candy on halitosis: a double-blind, controlled, and randomized study. AB - Halitosis (bad breath) is a common condition that is socially crippling for vast parts of the population and results from malodorous volatile sulfur compounds, which are by-products of oral bacteria. In this doubled-blind, randomized study, 75 subjects with halitosis were evaluated. The participants were treated with or without abrasive microcapsules (candy) containing zinc gluconate 0.5%, propolis 2%, and a combination of both (zinc 0.25% and propolis 1%). The halitosis was assessed by a Halimeter, a portable instrument that measures the emission of volatile sulfur compounds at different time exposures to the treatments. Breezy candy (which is sugar-free) was found effective in the treatment of halitosis for up to 4 hours. While treatment with regular candy (group 1, traditional candy without abrasive particles) showed reduction in malodor of 10%, Breezy candy showed reduction of up to 60% in malodor (P < .0001). Since this was not a longitudinal study, the total duration of the effect was not assessed. Breezy candy in the abrasive form with zinc additive had the best potential to positively affect malodor when treating patients with halitosis. The combined effect of abrasion by microcapsules with zinc supplement represents a novel and successful approach for the treatment of halitosis. PMID- 22532946 TI - Familial white sponge nevus of the oral mucosa: report of occurrence in three generations. AB - White sponge nevus is a rare, inherited disorder that usually presents as nonpainful white plaque primarily involving the buccal mucosa, gingiva, and palate. Extraoral lesions most often occur in the esophagus or anogenital area, but almost invariably follow the development of typical buccal lesions. This article presents a familial case of white sponge nevus in which oral lesions were found in patients in three generations of the same family. Histologic findings include hyperkeratosis, acanthosis, and perinuclear eosinophilic condensation of epithelial cell cytoplasm, which serve to confirm white sponge nevus as the diagnosis. Clinical presentation and histopathology of white sponge nevus are discussed in relation to the differential diagnosis of other oral leukokeratoses. PMID- 22532947 TI - Energy dispersive x-ray analysis of corrosion products in nondiscolored dentin and a dye-extraction study of Class 2 composite restorations following amalgam removal. AB - OBJECTIVE: To evaluate the effect of corrosion products on the microleakage of composite placed adjacent to nondiscolored dentin after amalgam removal. METHOD AND MATERIALS: Sixty Class 2 cavities were prepared on extracted premolars, which were divided into four equal groups according to the manner in which they were restored: group 1, light-cured packable composite (Elite LS) to establish a microleakage baseline; group 2, a high-copper amalgam (World Work) previously stored in 37 degrees C normal saline for 6 months to create amalgam corrosion products; group 3, identical to group 2, but the amalgam was later replaced with composite, leaving the cavity walls intact; and group 4, identical to group 3 except the cavity walls were extended 0.5 mm after amalgam removal prior to insertion of the composite. Groups 1, 3, and 4 were kept in a 37 degrees C normal saline for 1 week. Ten specimens from each of these three groups were randomly selected for dye-extraction testing, while dentin elemental microanalysis of five specimens from all four experimental groups was also conducted. Data were analyzed using ANOVA and the Tukey tests (alpha = .05). RESULTS: Corrosion products were not detected in group 4, and no statistically significant difference (P > .05) in microleakage was found between this group and group 1. The highest dye absorbance was associated with group 3 (P < .05). CONCLUSION: After amalgam removal, a 0.5-mm extension of the cavity walls could improve the dentinal marginal seal to replicate that of an initial composite restoration. PMID- 22532948 TI - Sporadic Burkitt lymphoma of the jaw: case report and review of the literature. AB - Sporadic Burkitt lymphoma of the jaw is a rare neoplasm with an exceedingly fast doubling rate. This article presents a case of sporadic Burkitt lymphoma initially managed as an odontogenic infection. The early radiographic features and histologic criteria are discussed. Burkitt lymphoma should be considered in the differential diagnosis of any rapidly expanding or swelling jaw masses in young patients. PMID- 22532949 TI - Dental treatment of an adult patient with a history of biliary atresia. AB - OBJECTIVE: Biliary atresia is a congenital disease treated by liver transplantation. Adults may have oral consequences of the medical therapy. Green teeth are oral manifestations of the induced hyperbilirubinemia. Gingival enlargement is associated with the immunosuppressive drug. This case report describes the successful treatment of an 18-year-old patient displaying severe green teeth and gingival enlargement. METHOD AND MATERIALS: The gingival enlargement was treated by reducing the pathogenic oral microflora through scaling and root planing of the teeth, gingival excision surgeries, and conversion from cyclosporin to tacrolimus. RESULTS: Gingival enlargement and inflammation had completely disappeared after nonsurgical treatment for the maxilla and after surgical treatment for the mandible. The green coloration of the teeth was masked using composite restorations. CONCLUSION: This case report indicates that a patient's quality of life can be improved by a team approach combining pharmacologic and dental therapies. PMID- 22532950 TI - The microtensile bond strengths of four resin core materials and fiber posts and their micromorphologic characteristics. AB - OBJECTIVE: To evaluate the morphologies of D.T. Light-Post (LP), JFP-II quartz (JQ), and JFP-II glass (JG) fiber posts and their microtensile bond strengths to light- or dual-cured resin core materials. METHOD AND MATERIALS: The resin core materials that were used for the core buildup included three dual-cure core materials (Clearfil DC, Rebilda DC, and Luxacore Z) and a light-cured core material (Z100). The microtensile bond strength of each group was tested, and the morphology of each post and fractured surface was evaluated using scanning electron microscopy. Two-way ANOVA and Tukey or Dunnett T3 tests were used for statistical analyses. RESULTS: LP exhibited wider fibers and less matrix than the JFP-II posts, and JQ exhibited a similar surface texture to JG. The bond strength of the JQ group was significantly less than that of the other groups, but for each of the resin core materials that were used in this study, there were no statistical differences between JQ and JG. The results also showed that the microtensile bond strengths of the Luxacore Z/LP and Z100/JG groups were significantly higher than those of the other groups. Cohesive failure was the exclusive mode of failure in the Z100 group, and the other fractured surfaces exhibited adhesive failure. CONCLUSION: The bonding between fiber posts and resin core materials is affected by the fiber type, but the type of dual-cure resin has no effect on the post and core bonds for any of the three posts used in this study. PMID- 22532951 TI - The heights of dental education. PMID- 22532953 TI - CAD/CAM-generated high-density polymer restorations for the pretreatment of complex cases: a case report. AB - Complex rehabilitations represent a particular challenge for the restorative team, especially if the vertical dimension of occlusion (VDO) needs to be reconstructed or redefined. The use of provisional acrylic or composite materials allows clinicians to evaluate the treatment objective over a certain period of time and therefore generates a high predictability of the definitive rehabilitation in terms of esthetics and function. CAD/CAM technology enables the use of prefabricated polymer materials, which are fabricated under industrial conditions to form a highly homogeneous structure compared with those of direct fabrication. This increases long-term stability, biocompatibility, and resistance to wear. Furthermore, they offer more suitable CAD/CAM processing characteristics and can be used in thinner thicknesses than ceramic restorative materials. Also, based on the improved long-term stability, the transfer into the definitive restoration can be divided into multiple treatment steps. This article presents different clinical cases with minimally invasive indications for CAD/CAM fabricated temporary restorations for the pretreatment of complex cases. PMID- 22532952 TI - Clinical and radiographic evaluation of immediately loaded one-piece implants placed into fresh extraction sockets. AB - OBJECTIVE: To assess clinical survival and success rates of one-piece implants placed at the time of tooth extraction with immediate provisionalization and to evaluate radiographic peri-implant bone loss around one-piece implants 1 year after functional loading. METHOD AND MATERIALS: Forty-six patients (20 men and 26 women) with a mean age of 45.5 years (range, 24 to 74 years) were recruited from four centers for this case series report. Immediately following the extraction of untreatable teeth, all patients received one-piece implants. The implants were immediately restored and placed into function with no occlusal contact. Outcome assessments included clinical and radiographic evaluations. RESULTS: Of the one piece implants placed after extraction in the maxilla and mandible, 95.7% integrated successfully. The mean marginal bone loss after 1 year was 0.80 mm (SD, 0.53 mm). Overall peri-implant bone loss at maxillary sites was compared with overall bone loss at mandibular sites. At the 1-year follow-up, no statistically significant difference was found. The deeper the implants were placed below the crest, the more marginal bone loss was observed. However, no difference in marginal bone loss was observed as a consequence of the following three variables: implant length (10, 11.5, or 13 mm), implant diameter (3, 3.7, or 4.7 mm); and 3- and 6-month time periods after implant prosthesis placement. CONCLUSION: Based on data obtained from this sample size study, it can be concluded that one-piece implants can be successfully placed immediately after extraction with minimal peri-implant bone loss. PMID- 22532954 TI - Sinus augmentation with intra- vs extraorally harvested bone grafts for the provision of dental implants: clinical long-term results. AB - OBJECTIVE: To report the long-term outcome of sinus augmentation with intra- vs extraorally harvested autogenous bone grafts. METHOD AND MATERIALS: Between January 1993 and August 2009, 146 patients (86 women and 60 men) were consecutively treated with sinus elevation procedures. In February 2010, 127 patients were re-evaluated. Bone grafts were harvested from the iliac crest (54 patients, group 1) and from the mandibular symphysis (73 patients, group 2). A total of 179 sinus augmentation procedures were performed (105 in group 1 and 74 in group 2). All patients received fixed prostheses. RESULTS: A total of 456 Frialit II implants were placed in the 127 patients: 244 implants in extraorally harvested bone (group 1) and 212 in intraorally harvested bone (group 2). Patients had a mean bone graft consolidation period of 5.8 months in group 1 and of 5.2 months in group 2. During a minimum 3-month healing phase following implant placement, 35 of 456 implants failed (12.0% of group 1 and 4.5% of group 2) to become integrated in grafted bone. A total of 421 implants proceeded to occlusal loading with a fixed prosthesis. After a mean follow-up period of 110.2 months (range, 6 to 204 months), 34 implants were lost (25 in group 1 and 9 in group 2, for a total of 387 implants (91.9%) still functioning. CONCLUSION: Sinus augmentation procedures using intra- and extraorally harvested bone grafts can provide implant stability in the long term. However, major preoperative discomfort and more bone loss was seen when bone was harvested from the iliac crest. If autogenous bone is mandatory in sinus elevation procedures, extraorally harvested bone grafts can still be recommended, especially when bilateral procedures are indicated. PMID- 22532955 TI - Hereditary gingival hyperplasia associated with amelogenesis imperfecta: a case report. AB - Hereditary gingival fibromatosis (HGF) and amelogenesis imperfecta (AI) are two rare oral conditions with genetic etiologies. The case of a 17-year-old boy affected by HGF, AI, anterior open bite, and pyramidal impaction of the maxillary molars is reported. Internal bevel gingivectomies were carried out to reduce gingival overgrowth. Clinical examination of the family revealed the presence of HGF and AI in his 12-year-old sister (both in milder forms) and of HGF in his older half brother. Genetic sequencing analyses were performed to detect any of the known mutations leading to HGF and AI. Histologic analysis revealed the presence of fibroepithelial hyperplasia, consistent with a diagnosis of GF. Sequencing genetic analysis failed to identify any of the common mutations leading to HGF (SOS-1) or AI (enamelin and amelogenin genes). This phenotype, similar to what has been described in other families, may represent a new syndrome caused by an as-yet unknown genotype. PMID- 22532956 TI - Bacterial and inflammatory behavior of implants in the early healing phase of chronic periodontitis. AB - OBJECTIVE: To assess the pattern of early bacterial colonization at implants and teeth in patients with a history of chronic periodontitis compared with a group of healthy subjects. Furthermore, the presence of host-derived markers at teeth and implants in the two subject groups was determined. METHOD AND MATERIALS: Subgingival and submucosal plaque and gingival crevicular fluid samples from 37 nonsubmerged healing dental implants and the deepest tooth sites per quadrant were analyzed 2 to 5 months after implant insertion. The presence of periodontal pathogens was assessed by means of real-time polymerase chain reaction. Further, the levels of interleukin (IL)-1Beta, IL-8, and IL-10; secretory leukocyte protease inhibitor; and the neutrophil elastase activity were determined. RESULTS: Eleven patients with chronic periodontitis and 13 subjects without periodontitis were recruited for this study. Bacterial species associated with periodontitis were detectable at both the teeth and implants. The presence was always higher in the chronic periodontitis group; the difference was significant for Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans at both the implants and teeth. The levels of IL-1Beta were higher at teeth than at implants; in contrast, more IL-10 was measured at the implants. CONCLUSION: The present results indicate that (1) dental implants inserted in periodontally compromised patients are colonized with periodontal pathogens within the first weeks of healing; (2) inflammatory markers (IL-1Beta) are present in higher levels at teeth as compared with implants, whereas at implants, anti-inflammatory cytokines (IL-10) might play the important role; and (3) the importance of periodontal treatment prior to implant insertion to reduce bacterial load and inflammation should be emphasized. PMID- 22532957 TI - Early childhood caries and feeding practices in kindergarten children. AB - OBJECTIVE: To determine the prevalence and severity of early childhood caries (ECC) and its relation to feeding practices in Syria. METHOD AND MATERIALS: A total of 400 children aged 3 to 5 years (mean age +/- SD, 4.2 +/- 0.5) were screened from 20 randomly selected kindergartens in Latakia, Syria. Dental examinations were carried out by a specialist in pediatric dentistry using DMFT and DMFS indices and an ECC scoring system. Information regarding feeding practices during early childhood was also collected. RESULTS: Caries was seen in 70% of the children, with a total mean DMFT value of 4.25 +/- 4.2 per child. The mean values increased from 2.4 +/- 3.2 DMFT at age 3 to 5.6 +/- 4.9 at age 5 (4.1 +/- 6.3 and 12.8 +/- 12.0 DMFS, respectively). Age and feeding practices showed statistically significant associations with caries (P < .001). The mean DMFT in the bottlefed children was 5.33 +/- 4.6 compared with only 3.27 +/- 3.5 in predominantly breastfed children. Forty-eight percent of the children had ECC, and 24% showed a severe degree with carious defects and open caries lesions. A significantly higher prevalence and severity of ECC was observed in children who were bottlefed (z-statistic, -2.1; P = .036) compared with breastfed children. CONCLUSION: In addition to a high prevalence of caries and ECC in preschool children, bottlefeeding led to even higher caries rates in Syria. Since the caries was largely untreated, preventive and restorative dental programs should be implemented. PMID- 22532958 TI - Increased gingival blood vessel density in SLE patients. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) is a serious multisystem disease with a variety of cutaneous and oral manifestations. It is an autoimmune disorder whereby patients develop autoantibodies to many of their cells, cell components, and tissue. The microvascular changes in SLE play a role in the pathogenesis of this disease. The aim of this study was to investigate the gingival microcirculation in SLE patients. METHOD AND MATERIALS: Fifteen SLE patients and 15 healthy subjects were recruited for this study. Gingival microcirculation was investigated using videocapillaroscopy, a noninvasive technique that permits the in vivo evaluation of microvascular patterns. RESULTS: Significant differences between patients and controls for the capillary density were seen. An increase of mean capillary density was observed in SLE patients (105.5 +/- 3.41) (P < .05). CONCLUSION: This study showed significant modifications of gingival microcirculation in SLE patients. PMID- 22532960 TI - Brushing skills and plaque reduction using single- and triple-headed toothbrushes. AB - OBJECTIVE: To evaluate the effect of toothbrush design on brushing skills and plaque removal among young healthy adults. METHOD AND MATERIALS: A population of 200 healthy young adults was approached. Patients were randomly assigned to one of two research groups: one used a manual single-headed toothbrush, while the other used a manual triple-headed toothbrush. At the start of the study, participants were asked to brush their teeth using the provided toothbrush with no prior guidance or instructions. Plaque Index (PI) was measured. Immediately afterward, participants were personally instructed on how to brush their teeth using the provided toothbrush. Toothbrushing performance skill was evaluated and scored using the toothbrushing performance skill index (TB-PS-I/Ashkenazi index) following the first brushing, as well as on a recall visit 1 week later. RESULTS: Following the first, uninstructed brushing, PI values ranged from 0.41 to 1.33, with higher plaque scores for the single-headed toothbrush group. One week after receiving brushing instructions, PI decreased in the both toothbrush groups and ranged between 0.12 and 0.81, with higher PI scores for the single-headed toothbrush group. Following the first, uninstructed brushing, total TB-PS-I scores, as well as component scores ("reaching" and "staying") showed no difference between the two toothbrush groups. One week after receiving brushing instructions, the TB-PS-I in the triple-headed toothbrush group was significantly higher than that in the single-headed toothbrush group. CONCLUSION: The triple headed toothbrush was found to promote easier toothbrushing and plaque removal both before and after receiving toothbrushing instructions. PMID- 22532959 TI - Influence of pulpotomy medicaments on the ultrastructure and shear bond strength of a self-etch adhesive to primary tooth dentin. AB - OBJECTIVE: To compare the effect of the pulpotomy medicaments glutaraldehyde, ferric sulfate, and formocresol on the structure and shear bond strength of a self-etch adhesive to the dentin of primary teeth. METHOD AND MATERIALS: Forty human primary molars were sectioned mesiodistally and divided into four groups: group I (control group), dentin specimens were soaked in distilled water for 48 hours; group II, dentin specimens were soaked in 2% glutaraldehyde; group III, dentin specimens were soaked in formocresol; and group IV, dentin specimens were soaked in 15.5% ferric sulfate. All specimens were rinsed with tap water and dried with air. AdheSE One (a self-etch adhesive) and Valux Plus composite resin were applied to the dentin surfaces. The molecular structure of the adhesive itself and adhesive with composite resin were tested using an FTIR spectrometer. Shear bond strength was tested with a universal testing machine. Failure modes analyses were performed with a scanning electron microscope (SEM). RESULTS: Glutaraldehyde showed little changes in the molecular structure of the adhesive itself and adhesive with composite. However, ferric sulfate and formocresol affected the molecular structure of the adhesive alone and the adhesive with composite. The highest mean value of shear bond strength was for the glutaraldehyde group (11.17 +/- 4.87 MPa). Ferric sulfate and formocresol significantly reduced shear bond strength after the application of pulpotomy medicaments (7.45 +/- 3.73 and 5.31 +/- 3.30 MPa, respectively). SEM analysis revealed that most of the specimens failed in cohesive and mixed modes. CONCLUSION: This study revealed that formocresol and ferric sulfate adversely affect the shear bond strength and molecular structure of the adhesive system to primary dentin. PMID- 22532961 TI - Influence of three scan spray systems on human gingival fibroblasts. AB - OBJECTIVE: CAD/CAM is based on optical or mechanical scanning of tooth surfaces. The aim of this in vitro study was to investigate the influence of three different scan sprays on the proliferation, viability, and adenylate kinase (ADK) release of human fibroblasts. METHOD AND MATERIALS: Three different scan sprays (ScanDry, ScanSpray Luer Classic, and CEREC Optispray) were tested in vitro to determine their effects on proliferation, viability, and ADK release of human periodontal fibroblasts. A defined amount of the test material was sprayed into 96 multiwell plates, dried, and incubated with fibroblasts. The LIVE/DEAD Viability Assay, a two-color fluorescence-based method, was used to determine the cytotoxic potential (the AlamarBlue Assay for the proliferation rate and the ToxiLight BioAssay for the release of ADK). RESULTS: There were differences between the scan sprays concerning inhibition of the proliferation and viability of fibroblasts. All materials inhibited the fibroblast proliferation and viability compared with the control group (P < .001), and there were also significant differences among the scan spray groups. The scan sprays led to a greater release of ADK, but a significant difference could be found only between ScanSpray Luer Classic and CEREC Optispray (P < .009). CONCLUSION: The results of this study proved that the scan sprays do not induce a significantly higher ADK release than the control group. The inhibiting effect on the fibroblast proliferation can be attributed to a material-independent phenomenon. Further experiments are necessary to validate the present data. PMID- 22532963 TI - The reverse environmental gender gap in China: evidence from "The China Survey". AB - Objectives This article explores gender differences in attitudes about the seriousness of the environment as a problem in China using the "2008 China Survey." Methods We use generalized ordered logit models to analyze survey respondents' environmental attitudes. Results Our results indicate that there is indeed a "gender gap" in environmental attitudes in China, but the pattern is reversed from what has been generally found in previous work conducted in the United States and Europe. Chinese men, not women, show a greater concern about environmental problems and the seriousness of the environmental degradation in China. Further, we find that this gender gap is based largely in the substantial economic and educational differences between men and women in contemporary China. Conclusions This study emphasizes the mediating influence of socioeconomic variables in explaining gender attitudes toward the environment in China. Our findings suggest that in different contexts, women may be faced with difficult decisions between immediate economic necessities and long-term environmental concerns. The observed environmental gender gap in China will likely persist unless further economic development results in improved access to education and economic conditions for Chinese women. PMID- 22532962 TI - Influence of treatment modalities of prepared teeth on retention of cast metal copings bonded with self-adhesive resin cements. AB - OBJECTIVE: To evaluate the influence of different conditioning methods of prepared teeth on the retention of cast metal copings bonded with two self adhesive resin cements. METHOD AND MATERIALS: Mandibular first molars (n = 80) were prepared to receive metal copings. Sixteen molars were stored in water without interim copings as a control group (CG), while 64 molars were covered with interim copings. Eighty cast copings were laboratory fabricated from Ni-Cr alloy. Interim copings were removed, and 64 molars were cleaned and divided into four groups (n = 16) according to pretreatment methods of prepared molars: no pretreatment (T-NT) and conditioning with self-etching adhesive (T-SE), polyacrylic acid (T-PA), or ethylenediaminetetraacetic acid (EDTA) (T-ED). Each group was further subdivided into two subgroups (n = 8) according to luting cements. RelyX Unicem and seT self-adhesive resin cements were used for cementation of copings. Specimens were stored in water at 37 degrees C for 6 months and then cyclically loaded and thermal cycled. Retentive stress in N was recorded for each specimen. Statistical analyses were conducted with two- and one way ANOVA and Tukey HSD test. RESULTS: Retentive stress ranged from 526.7 to 692.9 N for RelyX Unicem and 339.8 to 492.3 N for seT. There were no statistically significant differences between the mean retentive stress of the CG, T-SE, and T-PA groups (P > .05). The mean retentive stress of group CG was significantly higher than mean retentive stress of groups T-NT and T-ED (P < .05). The mean retentive stress of the control and test groups bonded with RelyX Unicem was significantly higher than the mean retentive stress of the same groups bonded with seT. CONCLUSION: Conditioning of prepared teeth using polyacrylic acid or self-etching adhesive significantly increased the retentive stress of cast metal copings. PMID- 22532964 TI - The effect of child support enforcement on abortion in the United States. AB - OBJECTIVES: This project aims to answer a critically important question of public policy: Does effective child support enforcement lead to a change in the incidence of abortion across the United States? METHODS: Using state-level data collected from 1978-2003 from a variety of sources, we employ fixed effects regression analysis to examine whether financial security as measured by five types of child support enforcement effectiveness impacts abortion outcomes. RESULTS: We find that child support enforcement effectiveness decreases the incidence of abortion as measured by the abortion rate, but not the abortion ratio. CONCLUSIONS: Income transfer policies such as child support enforcement can affect certain fertility outcomes such as abortion rates across the states. PMID- 22532965 TI - Social energy and racial segregation in the university context. AB - OBJECTIVES: Universities often promote their diversity as a selling point, but are students of different races at these universities integrated socially? Using theories on social energy, I examine racial segregation among university students. METHODS: Quantitative data were collected on student residence patterns and social groupings formed at lunch tables at a case study university. In addition, interviews were conducted with 25 students. RESULTS: Students are substantially more segregated than chance predicts. Blacks and Hispanics are particularly segregated. Interviews reveal that these students spend large amounts of social energy coping with prejudice and discrimination as well as functioning in a student culture they find unwelcoming and foreign. CONCLUSIONS: Social energy drains on minority students from discrimination and an unwelcoming campus culture reduce energy left for interracial interaction, making these racial groups more segregated. The study highlights the need for understanding segregation as a function of the interaction of out-group preferences, in-group preferences, and the larger social context. PMID- 22532966 TI - Combined effects of melatonin and all-trans retinoic acid and somatostatin on breast cancer cell proliferation and death: molecular basis for the anticancer effect of these molecules. AB - Melatonin has been shown to inhibit breast cancer cell growth in numerous studies. However, our understanding of the therapeutic effects of this hormone is still marginal and there is little information concerning its combination with other antitumor agents to achieve additional potential benefits. All-trans retinoic acids or somatostatin have been used in combination with melatonin in several pre-clinical and clinical trials, but they have never been combined altogether as an anti-breast cancer treatment. In the present study, we investigated whether the association of melatonin, all-trans retinoic acid and somatostatin leads to an enhanced anticancer activity in MCF-7 breast cancer cells. In such conditions, MCF-7 cells were investigated for cell growth/viability and proliferation, as well as for the expression of cyclin A, and components of the Notch and EGFR pathways, by Western blotting and confocal immunofluorescence. Electrophysiological, morphological, and biochemical analysis were also performed to reveal signs of cell damage and death. We found that melatonin in combination with all-trans retinoic acid and somatostatin potentiated the effects of melatonin alone on MCF-7 cell viability and growth inhibition; this phenomenon was associated with altered conductance through Ca2+ and voltage-activated K+ (BK) channels, and with substantial impairments of Notch 1 and epidermal growth factor (EGF)-mediated signaling. The combined treatment also caused a marked reduction in mitochondrial membrane potential and intracellular ATP production as well as induction of necrotic cell death. Taken together our results indicate that co-administration of melatonin with all-trans retinoic acid and somatostatin may be of significant therapeutic benefit in breast cancer. PMID- 22532967 TI - Vasorelaxation to capsaicin and its effects on calcium influx in arteries. AB - Capsaicin, an activator of the transient potential vanilloid receptor type 1 (TRPV1), is a commonly used pharmacological tool for desensitising sensory nerves. Capsaicin can induce vasorelaxation of isolated blood vessels by activating perivascular TRPV1 receptors, causing the release of vasoactive neuropeptides. This study attempted to characterise the vascular effects of capsaicin in the rat isolated aorta and porcine coronary arteries. Capsaicin elicited concentration-dependent vasorelaxation of both rat aortae and porcine coronary arteries. Capsaicin-induced vasorelaxation of rat aorta was unaffected by a chronic pre-treatment of vessels with capsaicin. Moreover, relaxation was insensitive to the presence of capsazepine, a competitive TRPV1 antagonist, in both the rat aorta and porcine coronary artery. It was hypothesised that capsaicin may be inhibiting calcium influx into smooth muscle cells. Indeed, in vessels incubated in a Ca2+-free high-k+ buffer, the presence of 30 MUM capsaicin significantly inhibited the contractile response to the re-introduction of Ca2+. In porcine coronary arteries 100 MUM capsaicin completely abolished the contractile response to the re-introduction of Ca2+. In addition, capsaicin also abolished the concentration-dependent contraction of porcine coronary arteries induced by the L-type calcium activator Bay-K 8644. Therefore, we suggest that capsaicin causes vascular responses in arteries through the inhibition of L-type Ca2+ channels. In summary,we have identified a potential mechanism underlying TRPV1-independent capsaicin-induced vasorelaxation. Our results also question the use of chronic capsaicin pre-treatment in experimental pharmacology in order to elucidate the role of sensory nerves in vascular responses. PMID- 22532968 TI - The influence of ageing in the cerebrospinal fluid concentrations of proteins that are derived from the choroid plexus, brain, and plasma. AB - Studies have shown that ageing alone can cause increases in the concentrations of many cerebrospinal fluid (CSF) proteins. Therefore, CSF protein concentrations must be interpreted with caution before concluding that the increased concentrations of certain proteins can be used as disease-specific biomarkers. Age-related reduction in CSF turnover has been shown to have a significant concentrating effect on CSF proteins from young to old. As a result, CSF protein concentrations need to be corrected with age-specific turnovers first before performing any data comparisons between different ages. This study applied the concept of CSF/plasma concentration ratios of plasma-derived proteins that is frequently used in the investigation of brain barrier integrity to calculate the amount of protein that enters the CSF from the plasma side in different age groups. Based on our calculations, proteins with molecular weights greater than 91.92 kDa for the young, 109.51 kDa for the middle-aged and 120 kDa for the old should not be able to cross the brain barriers of the blood-brain and blood-CSF barriers to enter the CSF from the plasma side. For proteins that can be derived from the choroid plexus (CP), brain, and plasma, the amount that crosses the barriers to enter the CSF from the plasma side will contribute to their measured total protein concentrations in the CSF. CP and brain production of these proteins can be calculated when turnover corrected CSF protein concentrations are further corrected by the amount of protein that crosses the barriers. In this study, CP and brain produced concentrations of transthyretin, retinol binding protein, alpha-1-antitrypsin, gelsolin, and lactotransferrin were calculated. The production of these proteins decreased with age with alpha-1-antitrypsin protein revealing the most substantial decrease of 86% from young (0.14+/-0.01 mg.dL(-1)) to old (0.02 mg.dL(-1)). In conclusion, measured CSF protein concentrations for proteins that can be derived from the CP, brain, and plasma need to be corrected by age-specific CSF turnovers and by the amount of protein that crosses the brain barriers first before their concentrations can be compared logically between different ages. PMID- 22532969 TI - Equine disease surveillance: quarterly summary. PMID- 22532970 TI - Translating research into therapies. PMID- 22532971 TI - [Abstracts of the Meeting of the French Society for Diabetes. Nice, France. March 20-23, 2012]. PMID- 22532972 TI - Abstracts of the Annual Meeting of the Society for Investigative Dermatology. May 9-12, 2012. Raleigh, North Carolina, USA. PMID- 22532973 TI - Retraction. InvA protein is a Nudix hydrolase required for infection by pathogenic Leptospira in cell lines and animals. PMID- 22532974 TI - Abstracts of the 52nd Annual Scientific Meeting of the British Society for Haematology. April 16-18, 2012. Glasgow, United Kingdom. PMID- 22532975 TI - Abstracts of the Urological Society of Australia and New Zealand 65th Annual Scientific Meeting. April 21-24, 2012. Darwin, Australia. PMID- 22532976 TI - Abstracts of the 18th Annual Conference of the British HIV Association (BHIVA). Birmingham, United Kingdom. April 18-20, 2012. PMID- 22532977 TI - Abstracts of the RACP (Royal Australasian College of Physicians) Future Directions in Health Congress 2012. May 6-9, 2012. Brisbane, Queensland, Australia. PMID- 22532978 TI - Abstracts of the 3rd European Lung Cancer Conference. April 18-21, 2012. Geneva, Switzerland. PMID- 22532979 TI - Isolipidic diets differing in their essential fatty acid profiles affect the deposition of unsaturated neutral lipids in the intestine, liver and vascular system of Senegalese sole larvae and early juveniles. PMID- 22532980 TI - [Not Available]. PMID- 22532981 TI - [Not Available]. PMID- 22532982 TI - [Not Available]. PMID- 22532983 TI - Ser medico ...as a physician and professor at the University of Chicago. PMID- 22532985 TI - The role of vitamin D in asthma. AB - Vitamin D metabolites are important immune-modulatory hormones and are able to suppress Th2-mediated allergic airway disease. Some genetic factors that may contribute to asthma are regulated by vitamin D, such as vitamin D receptor (VDR), human leukocyte antigen genes (HLA), human Toll-like receptors (TLR), matrix metalloproteinases (MMPs), a disintegrin and metalloprotein-33 (ADAM-33), and poly(ADP-ribosyl) polymerase- 1 (PARP-1). Vitamin D has also been implicated in asthma through its effects on the obesity, bacillus Calmettee Guerin (BCG) vaccination and high vitamin D level, vitamin D supplement, checkpoint protein kinase 1 (Chk1), plasminogen activator inhibitor-1 (PAI-1) and gamma delta T cells (gdT). Vitamin D plays a role in asthma and exerts its action through either genomic and/or non-genomic ways. PMID- 22532984 TI - [Diagnosis and treatment of lupus nephritis: the way to consensus]. PMID- 22532986 TI - Rituximab as potential therapy for paraneoplastic cerebellar degeneration in pediatric Hodgkin disease. AB - Paraneoplastic cerebellar degeneration (PCD) is a rare neurological syndrome associated with lung cancer, breast adenocarcinoma,ovarian adenocarcinoma, and Hodgkin disease. It is rarely seen in pediatrics. We report a case of a 10-year old boy with a 2-year prodrome that led to a diagnosis of PCD in association with stage IV Hodgkin disease. He received radiation and chemotherapy for his Hodgkin disease with resolution of his lymphoma. Based on promising data in adults on the efficacy of rituximab over other immuno suppressive agents in paraneoplastic disorders, he was treated with rituximab with marked improvement of the cerebellar syndrome. PMID- 22532987 TI - Fenretinide cytotoxicity is independent of both constitutive and pharmacologically modulated glutathione levels in pediatric acute lymphoblastic leukemia cells cultured at hypoxia. AB - Fenretinide (4-HPR) cytotoxicity relative to glutathione levels in pediatric acute lymphoblastic leukemia cell lines cultured at bone marrow level hypoxia (5% O2) is evaluated. 4-HPR cytotoxicity correlated with reactive oxygen species generation (P < 0.001),but not with levels of intracellular glutathione, g glutamylcysteine synthase, or glutathione peroxidase. Buthionine sulfoximine (BSO)reduced glutathione levels in 10 cell lines (P < 0.001), but 4-HPR p BSO was markedly synergistic in only 1 of 10 lines. Pretreatment with N-acetylcysteine increased glutathione (P < 0.02)but did not alter 4-HPR cytotoxicity. Our data suggest that 4-HPR cytotoxicity is independent of glutathione under physiologic oxygen tension. PMID- 22532988 TI - Inborn errors of metabolism: psychosocial challenges and proposed family systems model of intervention. AB - Inborn errors of metabolism result in psychosocial crises that challenge individual and familial modes of functioning across the life cycle. Increased stress, mood disorders, interpersonal challenges, decreased quality of life, and grief reactions are all common for patients and their families. To effectively care for these patients, a holistic approach to their care, which incorporates their social context, is essential. Patients and their families need support as they focus on immediate practical demands, grieve over illness-related losses, and reorient future expectations. A family systems based model provides a flexible and individualized approach to care that allows for optimal psychosocial adjustment throughout the disease process. PMID- 22532990 TI - ["I only write to amuse myself": on gender differences in 19th-century autobiographies and diaries]. PMID- 22532989 TI - Enriched experience and recovery from amblyopia in adult rats: impact of motor, social and sensory components. AB - Amblyopia is one of the most common forms of visual impairment, arising from an early functional imbalance between the two eyes. It is currently accepted that, due to a lack of neural plasticity,amblyopia is an untreatable pathology in adults. Environmental enrichment (EE) emerged as a strategy highly effective in restoring plasticity in adult animals, eliciting recovery from amblyopia through a reduction of intracortical inhibition. It is unknown whether single EE components are able to promote plasticity in the adult brain, crucial information for designing new protocols of environmental stimulation suitable for amblyopic human subjects. Here, we assessed the effects of enhanced physical exercise,increased social interaction, visual enrichment or perceptual learning on visual function recovery in adult amblyopic rats. We report a complete rescue of both visual acuity and ocular dominance in exercised rats, in animals exposed to visual enrichment and in animals engaged in perceptual learning.These effects were accompanied by a reduced inhibition/excitation balance in the visual cortex. In contrast, we did not detect any sign of recovery in socially enriched rats or in animals practicing a purely associative visual task. These findings could have a bearing in orienting clinical research in the field of amblyopia therapy. PMID- 22532991 TI - [Maria Toet and other stories: the nationality of married women and the construction of the nation-state]. PMID- 22532992 TI - [The management of disability: the political debate on the Workmen's Compensation Act and the development of the medical market]. PMID- 22532993 TI - [From threat to partner: the transformation of the pharmaceutical industry in the Netherlands, 1880-1940]. PMID- 22532994 TI - [Silence as murderer: domestic violence and the juridical position of married women in 19th-century Belgium]. PMID- 22532995 TI - [New wine in old bottles? The place and function of associations in the society of the ancien regime]. PMID- 22532996 TI - [Portrait of the anthropologist as a young woman: Jane Ellen Harrison's reviews for "The Athenaeum"]. PMID- 22532997 TI - A dynamic bumiputera commercial and industrial class? A mismatch with market rationality. PMID- 22532998 TI - [Rural transformation and women's labor in North Vietnam: the case of Trang Liet village, Bac Ninh Province]. PMID- 22532999 TI - [An account of a fermented food, "cao," in the daily life of a fishing community: changes of activities for subsistence on "Island B" in the Makassar Straits]. PMID- 22533000 TI - Physical and economic change in Bangkok, 1851-1925. PMID- 22533002 TI - [Confraternities in late medieval Utrecht at the intersection of religion, work, friendship, and politics]. PMID- 22533004 TI - [Coffeehouses and spies: social control in the mid-19th-century Ottoman Empire]. PMID- 22533006 TI - [Poor relief in the Ottoman Empire, 1839-1918]. PMID- 22533008 TI - [Health politics and border setting: the Ottoman example, 18th and 19th centuries]. PMID- 22533009 TI - Performance: There will be no respite in the face of relentless pressure. PMID- 22533007 TI - [Peripheral population groups in the Ottoman reform period]. PMID- 22533010 TI - Operating framework: Pressure piles up on acute hospital sector. PMID- 22533011 TI - Operating framework: 'Managers need help and motivation'. PMID- 22533012 TI - Operating framework: 'Price competition' back on the cards. PMID- 22533013 TI - Keogh: Time for the NHS to move on weekend working. PMID- 22533014 TI - Patients to see GP records online. PMID- 22533015 TI - On life after the Francis report. PMID- 22533016 TI - Boards must be braver to be better. PMID- 22533017 TI - Authorisation: Making the sums add up. PMID- 22533018 TI - Bribery: Beware of those bearing gifts. PMID- 22533019 TI - Recruitment: Steering clear of the hot seat. PMID- 22533020 TI - Timely tests save lives. PMID- 22533021 TI - Telehealth: Remote chance for virtual care. PMID- 22533022 TI - Leadership: Trust in a cold climate. PMID- 22533023 TI - Stability of pharyngeal airway dimensions: tongue and hyoid changes after treatment with a functional appliance. AB - Because stability is known as the fundamental key of the successful outcome of orthodontics treatment, this study investigated the stability of tongue, hyoid bone and airway dimensions at least two years after active treatment with Faramand functional appliance in patients with class II div 1 malocclusion. CONCLUSION: The present findings indicate that treatment with functional appliance has the potential to increase pharyngeal airway dimensions and changes in tongue and hyoid position. Importantly, these achieved changes seemed to be maintained in long-term, up to 4 years on average. PMID- 22533024 TI - Class III bilateral posterior crossbite with three horizontally impacted maxillary anterior teeth. AB - What's in a pretty face? In our world, unfortunately, too much. As orthodontists our goal should be to provide our patients with a stable, functional occlusion. Consider, however, the importance of changing our patients' future by significantly improving their facial esthetics. The combination of a very narrow maxillary arch, three absent upper left incisors, and a protrusive lower jaw provide a platform for dramatic improvement in our patients' facial esthetics. PMID- 22533025 TI - Guiding atypical facial growth back to normal. Part 2: Causative factors, patient assessment, and treatment planning. AB - It has been well-documented that the most common factors associated with atypical facial growth involve the airway, which when compromised, leads to mouth breathing and associated aberrant tongue function. The most common changes include downward and backward rotation of the mandible, deficient nasomaxillary complex, a vertical growth pattern, posterior displacement of the TMJ, narrow maxillary arch, dental malocclusions, and dental crowding. It is imperative that clinicians recognize, diagnose, and begin treatment as early as possible when facial growth deviates from normal. Several specific diagnostic tools, coupled with traditional diagnostic records, assist the clinician in determining the degree and direction of atypical growth. Such a clear-cut diagnostic process sets in motion the treatment plan requirements necessary to accomplish the goal of returning facial growth to normal. Diagnosis and treatment planning requires that each practitioner has a broad base of knowledge, a good power of observation, and insight into the complex subject of facial growth and development. PMID- 22533026 TI - Correlation of different cephalometric measurements to define facial type. AB - The aim of this study was to analyze a possible correlation of different cephalometric measurements to define facial type and to evaluate the best measurement for diagnosis. The sample consisted of 95 lateral cephalograms of caucasian patients with normal occlusion, aged between 15 years and two months and 21 years and four months, of which 54 were male and 41 female. The facial types were divided into dolichofacial, mesofacial and brachyfacial, according to the standards stated by different authors, and a relationship among them was investigated using the Kappa and Total agreement methods. The highest agreement found was between FMA and SN.GoGn; the lowest was between SN. Gn and VERT index. According to literature review and the interpretation of the results, SN.GoGn appears to be the best measurement to define facial type. PMID- 22533027 TI - Class III malocclusion with missing maxillary central incisor and facial asymmetry treated with orthodontics and intraoral vertical ramus osteotomy. AB - A 28-year-old female with a Class III malocclusion and facial asymmetry was treated with orthodontics combined with intraoral vertical ramus osteotomy (IVRO). She had severe skeletal Class III (Wits: -9.7 mm). She was missing her maxillary left central incisor and had a fixed three-unit bridge on her maxillary anterior teeth. The patient presented a concave profile with a protrusive mandible. Her dental and mandibular midline was shifted 3 mm toward the left. After presurgical orthodontic treatment, IVRO was performed. The total active treatment time was 16 months including surgery. Both occlusion and facial appearance were significantly improved by the surgical-orthodontic treatment. Posttreatment records after 2 years showed excellent results with good, stable occlusion, facial balance and harmony, and long-term stability. PMID- 22533028 TI - Diagnosis and interceptive treatment of palatally displaced canines: a literature review. AB - This paper presents a literature review of palatally displaced canines, their prevalence, etiology and associated theories. Clinical and radiographic diagnostic techniques are discussed as well as some interceptive treatment approaches and implications for orthodontic treatment. PMID- 22533029 TI - Assessment of computer customized brackets and positioning jigs. AB - An in-practice assessment of Ormco's CAD CAM Insignia Orthodontic system is reviewed Investigation included an in-vitro and in-vivo analysis of the accuracy of bracket placement, and measurement of the accuracy of slot and torque manufacturing specifications were addressed. The possible role of these systems in general dental practice is discussed. Examination of the Insignia system has led us to believe that changes in the way that orthodontic cases are being planned, treated, and delivered to the patient are changing with the increased use of computer technology. The ability to customize brackets and wires for the individual tooth in the individual patient should lead to better and easier finishing. PMID- 22533030 TI - Treatment of "white spot lesions" after removal of fixed orthodontic appliances. PMID- 22533031 TI - A technique for placement of direct bonded lingual retainer. AB - Different methods of bonding lingual retainers have evolved over the past three decades, both direct and indirect methods. The indirect method involves certain laboratory procedures to hold the retainer wire on the teeth, whereas the direct technique involves bonding the prefabricated retainer wire. The present article describes a new technique for direct-bonded lingual retainer. PMID- 22533032 TI - Is your team on board with your dental practice? PMID- 22533033 TI - Searching for otherness: the view of a novel. AB - The ethical issues concerning the use of PGD (Preimplantation Genetic Diagnosis) to select embryos of a particular HLA (Human Leukocyte Antigen) type are numerous. They arise from the potentially conflicting interests between those of the pre-existing child, the subject of a treatment which may be curative, and those of the sibling to be created, who cannot give consent to the donation, together with the problem of the destruction of potentially healthy embryos. This essay focuses on the web of vulnerabilities affecting the parents, the sick child and the "saviour sibling," while addressing three areas: science, bioethics and literature. The novel My Sister's Keeper, by Jodi Picoult, provides the reader with an in-depth view of the conflicting interests and emotional problems that affect the Fitzgeralds, a family experiencing the pain of seeing one of their children dying while facing the tragic consequences of trying to save this child by having another offspring. PMID- 22533034 TI - Reshaping human intelligence: the debate about genetic enhancement of cognitive functions. AB - Given the technical feasibility, not only scientists but also moral philosophers approve of an intervention in the genetic basis of our intellectual dispositions. Among the features not related to illnesses, intelligence seems to be an especially promising candidate for genetic enhancement, for intelligence is valued in every culture. The paper presents some of the arguments for and against genetic enhancement of intelligence. The author analyses what kind of good increased intelligence is: an instrumental good for the wellbeing of mankind, a positional good for a given society or an individual, or something that is appreciated by the individual subject because of the positive experience the subject has by making use of it. Since such experiences are not bad in themselves the means of genetic enhancement have to be assessed and compared with accepted practices like education. The author comes to the conclusion that there are morally significant differences between genetic enhancement and accepted practices to enhance intelligence. PMID- 22533035 TI - Should UK law reconsider the initial threshold of legal personality? A critical analysis. AB - At present UK Law states that the unborn child only becomes a legal person invested with legal rights and full protections, like other human persons, at birth. This article critiques the present legal position of setting the threshold for legal personality at birth, showing its inconsistencies and fundamentally pragmatic basis. Against this background, it is argued that a principled approach towards unborn life is necessary, which reflects in law the reality that the unborn child is a type of human person deserving protection as it develops through the continuum of human personhood--from embryonic personhood, to infant personhood and ultimately into adult personhood Human personhood is defined as a union of a material and immaterial self meaning that at every stage of their development they are never a "potential person," but rather a "person with potential" even if it is not actualized through miscarriage, premature death, or disability. This moral and philosophical reasoning is what justifies protecting the sanctity of unborn life in law. The rest of the article explores and critiques the alternative static legal threshold for ascribing legal personality, at conception, implantation and viability. Having considered the practical moral, legal and philosophical problems of these alternatives; the final proposal for law reform combines all three of these thresholds in a proposal for a "dynamic" threshold for legal personality commencing at conception, which would render birth as an irrelevant threshold for moral and legal reasoning about the unborn. PMID- 22533036 TI - Gender, infertility, motherhood, and assisted reproductive technology (ART) in Turkey. AB - In Turkey, as in many other countries, infertility is generally regarded as a negative phenomenon in a woman's life and is associated with a lot of stigma by society. In other words, female infertility and having a baby using Assisted Reproductive Technologies (ART) have to be taken into consideration with respect to gender motherhood, social factors, religion and law. Yet if a woman chooses to use ART she has to deal with the consequences of her decision, such as being ostracized by society. Other types of procedures in this area, such as sperm and ova donation or surrogate motherhood, are not permitted in law. However; both before and after the development of this techonology, society has been finding its own solutions which are rarely questioned and are still performed This article will discuss what these practices are and try to reach some pragmatic conclusions concerning female infertility, the concept of motherhood and some traditional practices in Turkey. PMID- 22533037 TI - Balancing consciences: how our obsession with autonomy sacrifices our duty to our patients. PMID- 22533038 TI - Trauma informed child welfare practice--remembering Robert. PMID- 22533039 TI - Effectively addressing the impact of child traumatic stress in child welfare. PMID- 22533040 TI - Addressing trauma to promote social and emotional well-being: a child welfare imparative. PMID- 22533042 TI - Trauma-informed forensic child maltreatment investigations. AB - Trauma-informed child welfare systems (CWSs) are the focus of several recent national and state initiatives. Since 2005 social work publications have focused on systemic and practice changes within CW which seek to identify and reduce trauma to children and families experiencing child maltreatment or other distressing events, as well as to the agency personnel working with these clients. Within the body of trauma-informed literature, little attention has been devoted specifically to the initial investigative response and its role in controlling for system induced trauma to the child, family, and caseworker. Training child protection services (CPS) workers on the impact of trauma in child maltreatment forensic investigations and the worker's role in anticipating and mitigating the effects of trauma during the investigative process is rarely addressed in the trauma-informed literature. This article reports on a training strategy to infuse trauma information into an existing forensic child maltreatment investigation curriculum with the goal of enhancing CPS caseworker's knowledge, skills, and values concerning the importance of viewing investigations and their associated tasks through a trauma lens. PMID- 22533041 TI - Trauma adapted family connections: reducing developmental and complex trauma symptomatology to prevent child abuse and neglect. AB - Families living in urban poverty, enduring chronic and complex traumatic stress, and having difficulty meeting their children's basic needs have significant child maltreatment risk factors. There is a paucity of family focused, trauma-informed evidence-based interventions aimed to alleviate trauma symptomatology, strengthen family functioning, and prevent child abuse and neglect. Trauma Adapted Family Connections (TA-FC) is a manualized trauma-focused practice rooted in the principles of Family Connections (FC), an evidence supported preventive intervention developed to address the glaring gap in services for this specific, growing, and underserved population. This paper describes the science based development of TA-FC, its phases and essential components, which are based on theories of attachment, neglect, trauma, and family interaction within a comprehensive community-based family focused intervention framework. PMID- 22533043 TI - Addressing the impact of trauma before diagnosing mental illness in child welfare. AB - Congress set requirements for child welfare agencies to respond to emotional trauma associated with child maltreatment and removal. In meeting these requirements, agencies should develop policies that address child trauma. To assist in policy development, this study analyzes more than 14,000 clinical assessments from child welfare in Illinois. Based on the analysis, the study recommends child welfare agencies adopt policies requiring that (1) mental health screenings and assessments of all youth in child welfare include measures of traumatic events and trauma-related symptoms; (2) evidence-based, trauma-focused treatment begin when a youth in child welfare demonstrates a trauma-related symptom; and (3) a clinician not diagnose a youth in child welfare with a mental illness without first addressing the impact of trauma. The study also raises the issue of treatment reimbursement based on diagnosis. PMID- 22533044 TI - Complex trauma and mental health in children and adolescents placed in foster care: findings from the National Child Traumatic Stress Network. AB - Many children in the child welfare system (CWS) have histories of recurrent interpersonal trauma perpetrated by caregivers early in life often referred to as complex trauma. Children in the CWS also experience a diverse range of reactions across multiple areas of functioning that are associated with such exposure. Nevertheless, few CWSs routinely screen for trauma exposure and associated symptoms beyond an initial assessment of the precipitating event. This study examines trauma histories, including complex trauma exposure (physical abuse, sexual abuse, emotional abuse, neglect, domestic violence), posttraumatic stress, and behavioral and emotional problems of 2,251 youth (age 0 to 21; M = 9.5, SD = 4.3) in foster care who were referred to a National Child Traumatic Stress Network site for treatment. High prevalence rates of complex trauma exposure were observed: 70.4% of the sample reported at least two of the traumas that constitute complex trauma; 11.7% of the sample reported all 5 types. Compared to youth with other types of trauma, those with complex trauma histories had significantly higher rates of internalizing problems, posttraumatic stress, and clinical diagnoses, and differed on some demographic variables. Implications for child welfare practice and future research are discussed. PMID- 22533045 TI - Screening for trauma exposure, and posttraumatic stress disorder and depression symptoms among mothers receiving child welfare preventive services. AB - The role of parental trauma exposure and related mental health symptoms as risk factors for child maltreatment for parents involved with the child welfare (CW) system has received limited attention. In particular, little is known about the extent to which mothers receiving CW services to prevent maltreatment have experienced trauma and suffered trauma-related psychopathology. This study examined screening data collected from 127 mothers receiving CW preventive services. There were high levels of trauma exposure among screened mothers and their young children. Among mothers, 91.6% experienced at least one traumatic event (M = 2.60) and 92.2% reported their children had been exposed to one or more traumas (M = 4.85). Mothers reported high levels of trauma-related symptoms: 54.3% met probable criteria for posttraumatic stress disorder (PTSD) or depression (61.7%). Nearly half (48.8%) met criteria for co-morbid PTSD and depression. The large majority of the clients with trauma-related disorders were not receiving mental health services. Latina women had significantly more severe PTSD symptoms than African American women. Case planners reported that the screening process was useful and feasible. These findings underscore the feasibility and importance of trauma screening among parents receiving CW preventive services. PMID- 22533046 TI - Linking child welfare and mental health using trauma-informed screening and assessment practices. AB - An abundance of research suggests that children in the child welfare system (CWS) have experienced numerous traumatic events and are exhibiting traumatic stress symptoms. Therefore, it is critical that the CWS work closely with the mental health system to ensure that these children receive the appropriate trauma screening, trauma-focused assessment, and referral to the appropriate trauma focused mental health services. This paper will begin by providing a concrete definition of trauma-focused screening and highlighting how that differs from a more comprehensive trauma-focused assessment process and a psychological evaluation. From there, the authors will highlight existing trauma-focused screening and assessment tools that are used widely within CWSs and the challenges related to integrating trauma-focused screening practices into CWSs. The authors will provide recommendations for ways in which child welfare jurisdictions can integrate trauma-focused screening practices into their daily practice. PMID- 22533047 TI - Secondary traumatic stress and burnout in child welfare workers: a comparative analysis of occupational distress across professional groups. AB - This study describes predictors of secondary traumatic stress and burnout in a national sample of helping professionals, with a specific focus on the unique responses of child welfare (CW) workers. Specific worker and exposure characteristics are examined as possible predictors of these forms of occupational distress in a sample of 669 professionals from across the country who responded to mailed (e-mail and post) invitations to participate in an online survey. E-mail and home mailing addresses were secured from licensure boards and professional membership organizations in six states from across the country that had high rates of child related deaths in 2009. Respondents completed the Professional Quality of Life IV (Stamm, 2005) to ascertain compassion fatigue (CF) and burnout symptoms. Being male, young, Hispanic, holding rural residence, and endorsing a lack of religious participation were significant predictors of secondary traumatic stress. Similarly, being male and young predicted high burnout rates, while actively participating in religious services predicted lower burnout. CW worker job status as a professional was significantly more likely to predict CF and burnout compared to all other types of behavioral healthcare professionals. Based on the findings from this study, this paper proposes strategies for enhancing self-care for CW workers, and describes the essential elements of a trauma-informed CW agency that addresses secondary traumatic stress and burnout. PMID- 22533048 TI - A grassroots prototype for trauma-informed child welfare system change. AB - The development of trauma-informed child welfare systems (TICWSs) that advance individual agency practice to target transformation of the system as a whole has been conceptualized but not documented. A grassroots effort to build a TICWS with key participants (e.g., Department of Human Services, Community Mental Health, Family Court, schools) in nine Michigan communities provides a field tested model for implementation. This article described what emerged as the core elements for a TICWS, which includes (1) development and support of a project champion, (2) trauma identification, (3) comprehensive assessment of traumatic impact, (4) evidence based trauma treatment, (5) establishing a common trauma language, and (6) trauma-informed decision-making. Several new instruments for assessing aTICWS are identified. Lessons learned are highlighted for consideration of communities seeking to develop TICWSs. PMID- 22533049 TI - Creating trauma-informed child welfare systems using a community assessment process. AB - This article describes a community assessment process designed to evaluate a specific child welfare jurisdiction based on the current definition of trauma informed child welfare and its essential elements. This process has recently been developed and pilot tested within three diverse child welfare systems in the United States. The purpose of the assessment is to identify strengths and barriers related to trauma and child welfare in each site, to make tailored recommendations to help the sites better understand, and to address the impact of trauma on the families served and on the child welfare system itself. The specific components of the assessment process will be explained, and a summary of some of the findings that were common across sites will be provided. Recommendations for future work will also be discussed. PMID- 22533050 TI - Promising practices and strategies for using trauma-informed child welfare practice to improve foster care placement stability: a breakthrough series collaborative. AB - This paper will provide information on a recent Breakthrough Series Collaborative (BSC) conducted by the National Child Traumatic Stress Network on Using Trauma Informed Child Welfare Practice to Improve Foster Care Placement Stability. Information on this particular BSC will be provided, followed by initial findings gathered from an evaluation of the BSC and metrics gathered by each of the nine participating teams throughout the BSC process. Specific trauma-informed promising strategies adopted by teams are presented along with recommendations for next steps. PMID- 22533051 TI - From mother goose to cultural humility and beyond. PMID- 22533052 TI - Benefits of mother goose: influence of a community-based program on parent-child attachment relationships in typical families. AB - An estimated 50 to 60% of children from typical families develop secure attachment relationships with their parents (Ainsworth, Blehar, Waters, & Wall, 1978; Van IJzendoorn & Kroonenberg, 1988); however, intervention research has focused primarily on interventions for high-risk clinical samples (Berlin, Zeanah, & Lieberman, 2008). In this project, the influence of a popular community based parent-child program was assessed in a non-clinical sample of families. Families participating in a 10-week Parent-Child Mother Goose Program (n.d.) and families on the waitlist for the program were asked to complete questionnaires to assess parenting efficacy and satisfaction as well as parents' perception of their own and their child's attachment styles at the beginning of the program, the end of the program, and six months later. Mothers in the program group reported significantly more positive change in their reports of parenting efficacy over time and also reported significantly more change in their children's attachment category. Specifically, children in the program group were significantly more likely to be classified as secure over time (55% at T1 to 81% at T3) as compared to the waitlist participants (45% at T1 to 62% at T2). In this popular 10-week, community-based program, parents learned skills that continued to influence their relationship with their children six months after the conclusion of the program. PMID- 22533053 TI - Training child welfare workers from an intersectional cultural humility perspective: a paradigm shift. AB - The increasing diversity of the populations encountered and served by child welfare workers challenges cultural competence models. Current concerns focus on the unintentional over-emphasis on shared group characteristics, undervaluing unique differences of individuals served, and privileging worker expertise about the client's culture, thereby exacerbating the power imbalance between them. This article promotes cultural humility in child welfare service delivery as a compliment to cultural competence, to liberate workers from expectations of cultural expertise about others, and to actively engage the clients, inclusive of their cultural differences, in the service delivery process. Skills and practice principles are discussed. PMID- 22533054 TI - The role of therapeutic mentoring in enhancing outcomes for youth in foster care. AB - Effective service interventions greatly enhance the well-being of foster youth. A study of 262 foster youth examined one such intervention, therapeutic mentoring. Results showed that mentored youth improved significantly in the areas of family and social functioning, school behavior, and recreational activities, as well as in the reduction of expressed symptoms of traumatic stress. Study results suggest that therapeutic mentoring shows promise for enhancing treatment interventions. PMID- 22533055 TI - Posttraumatic stress disorder among foster care alumni: the role of race, gender, and foster care context. AB - Little is known about the prevalence of posttraumatic stress disorder (PTSD) in adult alumni of foster care and its demographic and contextual correlates. This is one of the first studies to report on racial/ethnic and gender differences and the influence of foster care experiences (i.e., revictimization during foster care, placement change rate, and placement in kinship care) on past year PTSD. Findings revealed significant gender disparities and a moderating influence of kinship care on the relationship between gender and PTSD, as well as increased risk associated with a history of emotional and sexual abuse. Recommendations are made for clinical and systemic intervention. PMID- 22533056 TI - Adolescent fathers involved with child protection: social workers speak. AB - This study examined adolescent paternity through structured interviews with their social workers. It adds to the literature by exploring if there were young men involved with the child protection services (CPS) system who are fathers, identifying their unique needs, and beginning discussions on working with these young men. CPS social workers from six area offices and one juvenile detention facility completed surveys for each father on their caseload. A 3.5% rate of adolescent paternity was observed across these offices. Information about the nature of the young men's involvement with CPS, their involvement with their children, and their unique needs as fathers are provided. This paper also identifies some practice and policy implications for adolescent fathers and CPS charged with their care. PMID- 22533057 TI - A care coordination program for substance-exposed newborns. AB - The Vulnerable Infants Program of Rhode Island (VIP-RI) was established as a care coordination program to promote permanency for substance-exposed newborns in the child welfare system. Goals of VIP-RI were to optimize parents' opportunities for reunification and increase the efficacy of social service systems involved with families affected by perinatal substance use. Findings from VIP-RI's final four years show that by 12 months, 86% of substance-exposed newborns had identified permanent placements and 77% were placed with biological parents or relatives. PMID- 22533058 TI - [The beginnings of genetics in Italy (1903-1940). A reconnaissance]. AB - The spreading of Mendelism in Italy produced a sort of "Mendelization" of already existing studies and research on the subject of heredity, which received a new impetus. This was the origin of genetics. There followed a "Morganization" process of the field, when the mere formal-genealogical analysis became substituted by laboratory research. The first phase began with the rediscovery of Mendel's laws, and its strong point ever since the beginning was in agrarian research. The second phase began after 1925, following upon the conclusion of a heated pre-war debate on the subject of nuclear cytology. Various Italian scholars raised strong objections against the so-called Sutton-Boveri hypothesis, of which the successive Morgan et al. chromosomal theory of inheritance was initially understood, or misunderstood, to be a specious extension. The resulting controversy is that which most characterized the history of genetics in Italy during the first part of the twentieth century, and conditioned its development. PMID- 22533059 TI - [Alfred Binet and the first 'measures' of intelligence (1905-1908)]. AB - Alfred Binet (1857-1911) is considered the most representative exponent of the second generation of French experimental psychologists. His scientific work was inspired both by the experimentalism that Theodule Ribot and Hippolyte Taine introduced in France at the end of the 1870s, and by that of Wundt. Drawing from numerous sources, Binet was able to elaborate a psychology that focused on experiments and a controlled observation of pathological phenomena, with the objective of differentiating them from normal phenomena. His scientific production was moreover characterized by the emphasis placed upon the experimental study of "superior" psychic phenomena and, in particular, on their measurement. The aim of this paper is to describe the stages and sources of the "psychological" study of intelligence, which constituted precisely the fil rouge that had indispensably to be followed in order to fully understand the originality of all of Binet's research, whose most mature product was undoubtedly represented by the development of the Echelle metrique de l'intelligence, the first intelligence test in the history of psychology. PMID- 22533060 TI - [The measurement of time and its instruments: the program of experimental psychology of Gabriele Buccola]. AB - Gabriele Buccola is remembered as the first Italian psychologist to have developed a rigorous program of laboratory research. The careful examination of the instruments and experimental planning of his psychochronometric investigations reveals the indissoluble bond between theory and experimentation that defines a scientific conception of psychology on the basis of a differential methodology. For Buccola it is important to demonstrate that there exist "laws" that govern the mental processes, and that there exists a time that regulates human reactions and behaviour, considering however the individual differences and various factors that can bear influence to increase or decrease it. The use of 'intelligent' instruments proves to be fundamental within a model of experimentation directed towards pointing out individual differences and not just identifying the general laws of mental functioning. Buccola in this way imparts a psychological characterization to the study of mental illness--placing him as an initiator of experimental psychopathology, which will have a significant development in Europe thanks precisely to the work of Kraepelin--along with a differential and clinical-experimental bent to the emerging Italian scientific psychology. Lastly, the attention directed to the study of complex mental processes leads Buccola to lay the foundation in Italy for the study of the subjective experience of time. PMID- 22533061 TI - [The letters preserved by Vittorio Benussi 'Fund Sante de Sanctis']. AB - Through the publication of a previously unpublished exchange of letters, this paper examines the relations between the Italian psychologists Sante De Sanctis and Vittorio Benussi. The collaboration between the two scholars, which emerges from the 23 letters presented here, was solid and long-lasting both on the scientific plane and on the personal one. It began in 1905 on the occasion of the Fifth International Congress of Psychology held in Rome, and it terminated more than 20 years later, in 1927, with the death of Benussi, who took his own life. The Benussi-De Sanctis correspondence (1905-1927) is part of a archive, denominated the "Sante De Sanctis (1893-1935) Archive," which has been recently constituted on the basis of commonly shared archival criteria. In order to facilitate a better understanding of the general context of Sante De Sanctis's scientific relations, the Appendix contains an analytical list, divided into 170 files, of all those who sent letters to him between 1893 and 1935. PMID- 22533062 TI - [Psychoanalysis is a precious thread, fragile but precious": Vittorio Benussi and the Inventory of psychoanalysis (1926-1927)]. AB - The lessons of psychoanalysis held by Vittorio Benussi in Padua between 1926 and 1927 reveal the other aspect of his interests: that which regards psychoanalysis and its method. These unpublished lessons, which we are printing here for the first time, are preserved in the historical Archives of Italian psychology of the Universita di Milano-Bicocca. I have assigned to them the title of Inventario di psicanalisi (Inventory of Psychoanalysis) for their character, unprecedented in the Italy of the 1920s, of a first record of the lexical and theoretical world of psychoanalysis. Since they were not intended for publication, the lessons were written without the urgency of ordering facts and interpretations, and without resorting to the rhetoric of linguistic conventions. A reading of them makes evident how the Benussian attempt to integrate experimental psychology and analytic method is still unresolved. In these pages everything is shown in an incipient stage, in a contracted and intricate prose; while things are complicated by the hermetism of the style, the terminological oscillations, the theoretical density; and yet, these unpublished notes should be read like a palimpsest in which each word has been written, erased, and rewritten, in a work that remains unique in twentieth-century European psychology. PMID- 22533063 TI - [Ecology: the creation of a science]. AB - This paper synthetically outlines the process that from the botanical researches, evolutionary theories, and mineral-cycles discoveries, beginning from the second half of the nineteenth century, has led to the development of ecology as an autonomous scientific discipline. At the beginning of the twentieth century, this development intersected the studies on thermodynamics and systems theories, which together with a great variety of natural, technical, and social sciences, became integrated in the constituting ecological science. From the 1950s onward, systems theory has notably constituted an important contribution in the shaping of ecology, some of whose most influential and controversial approaches, namely ecosystems ecology and global ecology, are deeply characterised by the systems theorists' influence. PMID- 22533064 TI - [Signs of upper airways digestive tract cancers and the general practitionner. Study of the practices by a Script Test Concordance]. AB - INTRODUCTION: Upper Airways digestive tract cancers are the 4th more frequent cancer. They are responsible for non specific symptoms. The examination of this antomical region is very difficult for a general practitioner. The precoce diagnosis of these cancers is based on the good recognition of the clinical situations by the general practitioner. The aim of this study was to test the practice of the general practitioner in front of clinical situations typical of head and neck cancers by a Script test concordance. METHOD: The study was performed on 107 parisian general practitioners who answered a questionnaire based on a Script Concordance Test (SCT). The SCT is a questionnaire that test the clinical way of thinking comparing the use of an information of experts versus non experts. RESULTS: The answers of the practitioners tested were quite in accordance with the panel of experts' anwers. They were particularly good concerning the risk factors and the buccal and oropharyngeal cancers. The scores were lower concerning the nasopharyngeal, laryngeal and paranasal sinuses cancers. The scores were significantly better for the most experimented practitioners. DISCUSSION: The fact that the rhinopharygeal, the laryngeal and the paranasal sinuses cancers are less frequent and the fact that these cancers can not be seen directly during a standard physical examination of general practitioner can explain the lower scores for these types of head and neck cancers. That is why practitioners have to be particularly aware of the symptoms and have to ask a specialized advice in case of doubt. PMID- 22533065 TI - [Rhinoplasty and reconstruction of the nasal dorsum: role of an autologous graft of the concha media]. AB - BACKGROUND: Aesthetic and functional rhinoplasty can improve facial beauty. Surgical procedure may require autogenous grafts. These bone or cartilage grafts are harvested from different parts of the body. The objective of our study is to evaluate the use of nasal concha media as a new type of graft in rhinoplasty. MATERIALS AND METHODS: Patients consulted for aesthetic as well as for functional problems. They had dorsum deformities. The inclusion criteria had been the achievement of a harmonization surgery of the nasal dorsum, associated or not with another aesthetic or functional rhinoplastic intervention. The grafts are quickly and easily removed by endoscopic endonasal approach under optical control. The removed graft is then shaped and inserted by hidden approach during a rhinoplastic operation. Complications have been noticed for harvesting site and recipient site. RESULTS: Ten patients have benefited from this new technique from 2002 to 2007. They consulted for aesthetic as well as for functional problems in 9 cases. One person consulted for aesthetic matters only. The removal of these grafts has led to no complication. One case of infection has been noticed, and one dorsum irregularitie has been noticed. Aesthetic and functional results have been analysed over an average step back of two years and show at least comparable results to techniques already published. CONCLUSION: The concha media seems to serve well as graft material in some indications of rhinoplasty. The primary indication of this type of graft is in the harmonization surgery of the nasal dorsum. These grafts do not replace the other existent autologous grafts, but advantageously complete the technical arsenal of the rhinoplastician. A study involving a wider population should be done to validate the interest of this new type of filling graft in rhinoplasty. PMID- 22533066 TI - [Exophthalmos arising from paranasal sinuses]. AB - INTRODUCTION: Proptosis due to intraorbital process is frequent and secondary to various aetiologies. Its findings in ENT practice is the sign of a serious complication. The purpose of this study is to review a series of patients who presented an exophtalmy. MATERIAL AND METHODS: We conducted a retrospective analysis of 15 patients with exophthalmos complicating a rhinosinusal benign disease, diagnosed and treated in our department between January 2003 and December 2010. As their management is different, we excluded all cases of orbital cellulitis. RESULTS: Average age of presentation was 38 years, without sex predominance. Exophthalmos was unilateral, non axial and irreductible in all cases. The average duration of symptoms installation was 18 months. The most common aetiology was fronto-ethmoidal osteomas (9 cases), followed by fronto ethmoidal mucoceles (5 cases) and spheno-orbito-frontal fibrous dysplasia (1 case). The functional prognosis of the affected eye depended on the aetiology and the degree of ocular injury. CONCLUSION: In our experience, sinusal causes of exophthalmos comprise osteomas and ethmoidal mucoceles. Medical history, clinical and radiological data as provide the diagnostic. In case of benign tumours, surgery is the curative treatment. PMID- 22533067 TI - [Role of hypnotherapy in the treatment of debilitating tinnitus]. AB - OBJECTIVE: Hypnotherapy is currently used for tinnitus therapy in our university hospital. The aim of this study was to evaluate its efficacy. MATERIAL AND METHODS: This study was performed on 110 patients suffering from distressing tinnitus. They were treated during five sessions with hypnotherapy, supplemented by instruction on self-hypnotherapy. A subjective evaluation was done by the practitioner at the end of the sessions of hypnotherapy. Then a questionnaire on psychologic distress (Wilson 1991) was sent retrospectively to the patients. RESULTS: We received 65 responses which were used for this study. Before treatment, the mean value of the Wilson score was 54 (28-104). After treatment, it was: 31 (0-86). 69% of the patients felt an improvement > or = 5 points Wilson score. These results were compared with the evaluation carried out by the practitioner at the end of the sessions of hypnosis. There was a "significant correlation" between the evaluation of the felt benefice, analyzed by the practitioner at the end of the sessions of hypnosis, and by the patient questioned long after the treatment. These results had significant correlation with the evaluation made by the therapist at the end of the five sessions of hypnotherapy. They show, how effective (68% improvement) this therapeutic approach can be. CONCLUSION: Hypnotherapy can be regarded as an effective treatment against distressing tinnitus. PMID- 22533068 TI - Hyperglycemia after intratympanic dexamethasone treatment in a diabetic patient. AB - The treatment of patients with idiopathic sudden sensorineural hearing loss must be performed as an emergency measure in order to prevent long term hearing deficit. Steroids in monotherapy provide the best outcome. There is some controversy regarding the most efficient route but in order to prevent side effects, intratympanic treatment is the preferred choice, especially in diabetic patients. We here present the case of a patient that developed hyperglycemia after systemic and intratympanic dexamethasone treatment for sudden hearing loss. We conclude that after intratympanic treatment great caution must be taken. PMID- 22533069 TI - Medial displacement of T-tubes: case report. AB - Medial displacement of T-tubes is rare and only 6 cases have been reported in literature. We report a case of a medial displacement of a T-tube in the middle ear behind an intact tympanic membrane with normal mobility. No treatment was undergone as the patient was asymptomatic and no hearing problems were detected. A brief overview of this unusual complication of tympanostomy tubes is presented and the management strategy is discussed. PMID- 22533070 TI - Middle ear osteoma: a rare cause of conductive hearing loss with normal tympanic membrane. AB - Osteomas of the temporal bone are benign osseous tumors usually located to the external auditory canal. Osteomas involving the middle ear are very rare. We report the case of a patient presenting with a progressive hearing loss caused by a middle ear osteoma involving the incus and contiguous to the tympanic segment of the facial nerve. This report highlights the value of CT scan in the work-up of conductive or mixed hearing loss with normal tympanic membrane. The management of middle ear osteoma is discussed. PMID- 22533071 TI - [Submental flap for auricule reconstruction]. AB - OBJECTIVE: We present our experience in the use of submental flap in reconstruction of post-auricular excision defects. MATERIAL AND METHODS: Three patients underwent reconstruction with submental flap. RESULTS: The submental flap has been used in 3 patients for auricular defect reconstruction. All patients had a carcinoma involving the auricle. All the donor site defects were closed primarily. Outcomes were simple. In one case, we noticed a partial necrosis of the flap extremity. CONCLUSION: The submental flap produces excellent skin color and contour. It leaves a very well-hidden donor site. The operative technique makes it easy to use. So, the submental flap has definite advantages over distant flaps and it is a useful addition to the reconstruction in head and neck surgery. PMID- 22533072 TI - [Chondrocalcinosis of the temporomandibular joint revealed by a hearing loss: a case report]. AB - INTRODUCTION: Chondrocalcinosis is a microcrystalline arthropathy that principally affects the knee. It is a rare disorder, usually asymptomatic, that occurs mainly in the elderly people. PURPOSE: To report a case of a temporomandibular joint chondrocalcinosis with ossicular contact revealed by a conductive hearing loss. CASE REPORT: We describe the case of a 57-year-old man with a right conductive sudden hearing loss of 15 dB. The CT scan revealed a lytic lesion in the right attic extended to the middle cerebral fossa in contact with the ossicles with a suspicion of lysis of the head of the malleus. MRI showed a lesion enhancing after gadolinium injection on T1 weighted images. A biopsy revealed a chondrocalcinosis of the temporomandibular joint. Due to the complexity of surgical excision and the benin character of the lesion, a medical treatment and a radiologic follow-up every six months were proposed. CONCLUSION: Chondrocalcinosis of the temporo-mandibular joint is rare especially when it is revealed by a hearing loss. We present here a review of the literature. PMID- 22533073 TI - Melanotic neuroectodermal tumor of infancy: case report and review of the literature. AB - Melanotic Neuroectodermal Tumor of Infancy (MNTI) is a rare but distinct neoplastic entity in infancy. Diagnosis is usually made before the age of 12 months. The common clinical presentation is a rapidly growing mass of the pre maxillary area. Its surface is unevenly pigmented. To affirm the diagnosis a biopsy is necessary. Few cases of malignancy have been described (5% of cases). Adequate surgical excision is the treatment of choice. Recurrence rate is about 10 to 15% within 5 years. We report in this article the case of a newborn with MNTI illustrating that an R0 surgical excision can be correlated to a favourable prognosis. In this case the 5 years follow up didn't show any local or distant recurrence. PMID- 22533074 TI - Cemento-ossifying fibroma involving paranasal sinuses and skull base. AB - INTRODUCTION: Ossifying fibroma is a rare benign fibro-osseous lesion that usually affects mandible and maxillary bone. Their localisation to paranasal sinus and skull base is uncommon. MATERIAL AND METHOD: We report a huge recurrence of ossifying fibroma of the ethmoid paranasal sinus involving the skull base. CASE REPORT: Ten years after the removal of ossifying of the ethmoid 34 year old man presented headache with diplopia. Computed tomography (CT) and magnetic resonance imagery (MRI) showed a recurrent tumour witch extended to the nasal cavity, the sphenoid and the posterior ethmoid sinuses, and the skull base. The tumour was totally removed using an anterior subcranial approach with removal of the orbital rim. Histopathology confirmed an ossifying fibroma. Two years later a subdural empyema with frontal suppuration necessited to remove the frontal bone flap, which was re-constructed 12 months later using a synthetic material. CONCLUSION: Ossifying fibroma is a rare, benign tumour witch may recur if incomplete resection is performed. A long follow up with CT scan and MRI is required. PMID- 22533075 TI - [Ectopic thyroid: a report of a case and review of the literature]. AB - Ectopic thyroid is the presence of thyroid tissue outside its normal cervical seat. It results from abnormal embryological development. We report the case of an ectopic lingual thyroid found during maneuvers of intubation in a patient of 56 years old. The examination found a rhonchopathy with sleep apnea syndrome and sleep in a sitting position. Endoscopy showed a posterior lingual tumour. The cervical echography showed an absent thyroid in the normal place. Scintigraphy, computed tomography and magnetic resonance imaging confirmed the diagnosis of ectopic lingual thyroid position. The treatment consisted of surgical excision by cervical route after a safety tracheotomy. PMID- 22533076 TI - New records of Anopheles homunculus in central and Serra do Mar biodiversity corridors of the Atlantic Forest, Brazil. AB - Two new records of Anopheles homunculus in the eastern part of the Atlantic Forest are reported. This species was found for the first time in Barra do Ouro district, Maquine municipality, Rio Grande do Sul state, located in the southern limit of the Atlantic Forest. The 2nd new record was in the Serra Bonita Reserve, Camacan municipality, southeast Bahia state. These records extend the geographical distribution of An. homunculus, suggesting that the species may be widely distributed in coastal areas of the Atlantic Forest. It is hypothesized that the disjunct distribution of the species may be caused by inadequate sampling, and also difficulties in species identification based only on female external characteristics. Species identification was based on morphological characters of the male, larva, and pupa, and corroborated by DNA sequence analyses, employing data from both 2nd internal transcribed spacer of nuclear ribosomal DNA and of mitochondrial cytochrome c oxidase subunit I. PMID- 22533077 TI - The mosquitoes and chaoborids of Glacier and Yellowstone National Parks with new records and Ochlerotatus nevadensis, a new state record for Montana. AB - The known mosquito fauna of Glacier National Park, Montana, and Yellowstone National Park, Wyoming, is reported with new records, including a list of the species of Chaoboridae known from both parks. Ochlerotatus nevadensis (= Aedes nevadensis) from Glacier National Park is a new record for the state of Montana. PMID- 22533078 TI - Description of Himalayan mosquito pupae III, Ochlerotatus albolateralis and Ochlerotatus deccanus. AB - The pupae of Ochlerotatus albolateralis and Oc. deccanus are described and illustrated for the first time from specimens collected in the Himalayan Mountains in Nepal, breeding in tree holes and bamboo stumps. Chaetotaxal tables and illustrations show the morphology of their setae. Characters to recognize each species are explained. PMID- 22533079 TI - Potential of the bush mint, Hyptis suaveolens essential oil for personal protection against mosquito biting. AB - We studied the potential of the essential oil extract from the bush mint, Hyptis suaveolens, for use against mosquito biting under both laboratory and field conditions. In the laboratory, the repellency of various concentrations (1-6%) of the essential oil was assessed against Anopheles gambiae, based on a 15-min landing and biting on treated forearms of volunteers. In the laboratory, the percentage of mosquitoes landing on the forearm was 42, 33, 23, 23, 9, and 2 for 1%, 2%, 3%, 4%, 5%, and 6% essential oil concentration, respectively; and 92 and 91 for the solvent (isopropanol) and untreated control, respectively. The percentage of mosquitoes taking a blood meal was 22, 12, 13, 12, 5, and 3 for 1%, 2%, 3%, 4%, 5%, and 6% essential oil, respectively; and 52 and 51 for the solvent and control, respectively. In the field, the 6% essential oil repelled all mosquitoes immediately postapplication; this activity declined to 75% after 5 h. The repellent action of the 8% essential oil concentration was higher, 97% after 5 h. Based on these data, the essential oil of H. suaveolens appears to be a good candidate for use in the integrated management of mosquito vectors of disease. PMID- 22533080 TI - Irritant and repellent responses of Anopheles harrisoni and Anopheles minimus upon exposure to bifenthrin or deltamethrin using an excito-repellency system and a live host. AB - Feeding responses of Anopheles harrisoni and An. minimus were evaluated following exposure to 2 pyrethroid insecticides, bifenthrin or deltamethrin, using an excito-repellency test system in the presence and absence of live host cues. The results demonstrated that contact irritancy was the primary action of bifenthrin or deltamethrin in both mosquito species. There was no noncontact repellency effect elicited by either insecticide. Anopheles minimus showed rapid escape response with high mortality rates following direct contact with deltamethrin in the absence of a host and delayed escape responses when a host was present. Similarly, exposure of An. minimus to bifenthrin also elicited a delayed escape response in the presence of a host but with lower mortality rates. In experiments using An. harrisoni, the presence or absence of a host had no significant effect on behavioral responses to either insecticide (P > 0.05). We conclude that deltamethrin elicited stronger irritant chemical effects than bifenthrin but that behavioral responses in vector populations are dampened in the presence of an available host. This information is useful for estimating probability of pathogen transmission when using irritant chemicals in proximity to a blood-meal source. PMID- 22533081 TI - Discriminating lethal concentrations and efficacy of six pyrethroids for control of Aedes aegypti in Thailand. AB - Establishing baseline insecticide discriminating doses is crucial in accurately determining susceptibility status and changing temporal patterns of physiological response in mosquito populations. Pyrethroids are the predominant chemicals used for controlling adult Aedes aegypti and Ae. albopictus, both vectors of dengue viruses, in Thailand. Presently, only 2 pyrethroids, permethrin and lambda cyhalothrin, have published diagnostic dose rates for monitoring Ae. aegypti. This study established the diagnostic lethal concentrations for 6 different pyrethroids available in Thailand for dengue vector control. United States Department of Agriculture insecticide-susceptible strain of Ae. aegypti was used to establish the baseline concentrations for subsequent susceptibility testing of field populations. Our findings showed lower discriminating concentrations for lambda-cyhalothrin and permethrin than those recommended by the World Health Organization (WHO), at 2.5- and 1.7-fold lower dosing, respectively. The susceptibility status of 3 different geographical populations of field-collected Ae. aegypti were tested using the standard WHO procedures. All 3 field strains demonstrated varying levels of physiological resistance to each compound. We conclude that establishing the baseline diagnostic concentration of an insecticide is of paramount importance in accurately determining the susceptibility status in field-collected mosquitoes. If possible, discriminating doses should be established for all insecticides and test assays run concurrently with a known susceptible strain for more accurate monitoring of resistance in mosquito populations in Thailand. PMID- 22533082 TI - First report of Aedes japonicus in natural and artificial habitats in northeastern Arkansas. AB - During the summers of 2010 and 2011, Aedes japonicus larvae were collected from 2 sites in northeastern Arkansas while collecting mosquito larvae for a study on the presence of gut-inhabiting fungal symbionts. This is the first report of Ae. japonicus in the state of Arkansas. No identifiable specimens of gut-inhabiting fungi were collected from dissected Ae. japonicus larvae. PMID- 22533083 TI - First record of Aedes japonicus japonicus in Mississippi. AB - In July 2011, 7 late-stage larvae of Aedes japonicus japonicus were collected from a 5-gal bucket located behind a house in Fulton, MS. Three of the larvae were reared to the adult stage, with the remaining retained in 70% ethanol. Fifteen subsequent attempts over the next month to collect specimens by larval dipping in artificial containers at the property and surrounding towns in 3 adjacent counties all failed to produce any additional Ae. j. japonicus. PMID- 22533084 TI - Mosquitoes and other arthropod macro fauna associated with tank bromeliads in a Peruvian cloud forest. AB - Mosquitoes and other macro arthropods were collected in September 2008 from bucket bromeliads in the vicinity of the Wayqecha Cloud Forest Research Center in southeastern Peru, an area for which there are no published data. Range extensions of culicid species are reported. PMID- 22533085 TI - Selection of oviposition sites by female Aedes aegypti exposed to two larvicides. AB - The selection of oviposition sites by female mosquitoes involves the ability to choose less dangerous larval habitats. The aim of the present study was to evaluate the ovipositional behavior of female Aedes aegypti in selecting sites treated with 2 different larvicides. The study was conducted in metal cages with plastic cups containing paper strips and either spinosad or temephos, or dechlorinated water (control). After exposing all treated and control cups to ovipositing female mosquitoes for 3 days, the paper strips were removed and examined for egg laying. Based on the number of eggs laid per treatment, the oviposition index was found positive for spinosad (0.66) but negative for temephos (-0.49), indicating that the natural product spinosad acted as an attractant and temephos as a repellent. PMID- 22533086 TI - Pyriproxyfen for the control of Australian salt-marsh mosquito, Aedes vigilax. AB - The efficacy of pyriproxyfen against the Australian salt-marsh mosquito, Aedes vigilax, was examined in 2 laboratory and 1 semi-field study using both technical grade and formulated products. In a dose-response study, the median emergence inhibition (EI50) and EI95 values were determined to be 0.019 and 0.076 ppb, respectively, for pyriproxyfen technical grade, 0.021 and 0.092 ppb for a microencapsulated formulation (Sumilarv 90CS), and 0.054 and 0.236 ppb for the formulated s-methoprene product, Altosid Liquid Larvicide. A further laboratory comparison of the microencapsulated formulation of pyriproxyfen and Altosid, at the nominal field rate for Altosid, showed that both products provided 100% emergence inhibition and this was confirmed in a semi-field study, which also included a granular formulation of pyriproxyfen (Sumilarv 0.5G). PMID- 22533087 TI - Does the monomolecular film aquatain mosquito formula provide effective control of container-breeding mosquitoes in Australia? AB - The mosquito control potential of the silicone-based monomolecular film Aquatain Mosquito Formula (AMF) was investigated in field tests against the backyard mosquitoes Aedes notoscriptus and Culex quinquefasciatus. Plastic tubs, with and without emergent aquatic vegetation (Cyperus alternifolius), were sampled weekly for 2 wk prior to an application of Aquatain and up to 6 wk postapplication. The mean abundance of mosquito larvae and pupae was compared between pre- and postapplication periods as well as between treatment and control tubs. There was a significant reduction in the abundance of immature stages of both Ae. notoscriptus and Cx. quinquefasciatus within 48 h of application, and the mean weekly abundance of larvae of both species was significantly lower in treatment tubs compared with control tubs for up to 6 wk postapplication. Egg rafts, larvae, and pupae were not detected in treatment tubs until 5 wk postapplication. The results indicate that AMF holds great potential for mosquito control in backyard habitats. PMID- 22533088 TI - QCal: a software application for the calculation of dose-response curves in insecticide resistance bioassays. AB - We describe a novel software application (QCal) that was developed for calculation of dose-response curves in insecticide resistance bioassays. QCal uses a logistic regression model to generate values for lethal dose/knockdown dose based on data from a bioassay entered into the application user interface. The application can be freely distributed to interested parties. PMID- 22533089 TI - An innovative mosquito trap for testing attractants. AB - We describe a simple trap modification for testing volatile attractants to collect flying mosquitoes. The trap uses a standard Centers for Disease Control and Prevention trap modified for release of test chemicals. Test chemicals and other materials can be added and removed easily without spills or cross contamination. In preliminary studies using lactic acid and octenol, modified traps collected 40% more mosquitoes than controls (n = 164 and n = 117, respectively). Modifications cost less than $2.00 per trap. PMID- 22533090 TI - Aspirator gun for high-throughput mosquito bioassays. AB - We describe an innovative aspirator gun designed to transfer individual anesthetized mosquitoes directly into glass bioassay tubes. The gun has been used for thousands of transfers with extremely low associated mortality and is the central component of a high-throughput bioassay system. The gun is constructed using readily obtainable materials and can be modified for a range of insects. PMID- 22533091 TI - The art of engagement: nurses, ANA work to address conflict. PMID- 22533092 TI - Safe streets, clean air: new report, public health nurses on what makes people healthy. PMID- 22533093 TI - Advocacy at the state level: why it's important. PMID- 22533094 TI - Zalon steps down from ANF, but always steps up for the profession. PMID- 22533095 TI - It is not what you leave behind...it is what you take with you that counts! PMID- 22533096 TI - Critical care nurses' information-seeking behaviour during an unfamiliar patient care task. AB - Critical care nurses complete tasks during patient care to promote the recovery or maintain the health of their patients. These tasks can be routine or non routine to the nurse. Non-routine tasks are characterized by unfamiliarity, requiring nurses to seek additional information from a variety of sources to effectively complete the tasks. Critical care units are dynamic environments where decisions are often made by nurses under stress and time pressure because patient status changes rapidly. A non-routine task (e.g., administration of an unfamiliar medication) to the critical care nurse can impact patient care outcomes (e.g., increased time to complete task has consequences for the patient). In this article, the authors discuss literature reviewed on nurses' information-seeking and explore an information-seeking conceptual model that will be used as a guide to examine the main concepts found through the empirical evidence. PMID- 22533097 TI - Journal club in a critical care unit: an innovative design triggering learning through reading and dialogue. AB - Journal club has been used for decades to incorporate reading clinical and research articles into professional practice of numerous health care providers to disseminate knowledge and to bridge the gap between research and clinical practice. In this article, the authors describe how such activity was implemented by and for the nursing team of an intensive care unit. This journal club was designed to trigger dialogue among the nurses related to cardiac surgery topics, while providing an organizational support for them aimed to facilitate the incorporation of reading in their professional habits. More specifically, the design of this journal club was intended to create an opportunity for these nurses to keep their practice updated, to review physiological or pathological processes related to the cardiac surgery population, and to explore if how and why the results described in those research reports should be implemented in their own intensive care unit. The authors describe the phases of this project: the co-development of the journal club, the implementation of the activity and its results. The authors detail how this journal club format incorporated additional teaching aids during each session and used narrative pedagogy as a conceptual framework. PMID- 22533098 TI - Charting a new course in knowledge: creating life-long critical care thinkers. AB - The Registered Nurses Professional Development Centre's Critical Care Nursing Program situated in Halifax, Nova Scotia, aspires to provide evidence-based critical care nursing education. Using a didactic traditional lecture-based teaching method, the faculty noted that some learners were not prepared for class, preferred memorization of content and were not engaged in their learning. In 2008, faculty acknowledged the need to change their principal teaching method in the full-time program to a method that would foster student engagement and active learning while inspiring registered nurses to become life-long critical thinkers. After consulting with colleagues, attending conferences and reviewing the literature, team-based learning (TBL) was chosen as the strategy to achieve this goal. Although some challenges were experienced during the adoption of TBL, the faculty believed that TBL enhanced the learners' critical thinking abilities and teamwork skills. PMID- 22533099 TI - MyPlate--make it great! PMID- 22533100 TI - Lead in your lipstick and other scary stories. PMID- 22533101 TI - Decreasing public health funding and public health nursing. PMID- 22533102 TI - The art of holistic self-care: a journey within. PMID- 22533103 TI - Help me make it through the night (shift). PMID- 22533104 TI - Eating at work and healthy living. Interview by Kelly Trautner. PMID- 22533105 TI - Louisiana Birth Outcomes Initiative: improving birth outcomes with interventions before, during, and after pregnancy. AB - The costs of poor birth outcomes to the United States in both human and fiscal terms are large and a continuing concern. Louisiana has among the worst birth outcomes in our nation, which include preterm and low birth weight births, and maternal and infant mortality. In response to these poor birth outcomes, the Louisiana Department of Health and Hospitals is implementing a statewide, multi faceted Birth Outcomes Initiative at the level of the secretary. The Birth Outcomes Initiative aims to adopt evidence-based and best practices along the continuum of care for women and infants. Of particular importance is ending all non-medically indicated deliveries prior to 39 weeks, administration of the hormone 17-hydroxyprogesterone to eligible women for prematurity prevention, optimal behavioral health counseling and referral for reproductive aged women, and ensuring optimal health for women between pregnancies. Opportunities exist to improve outcomes for primary care and obstetrical providers. Louisiana is the first state to aim at improving birth outcomes with interventions before, during, and after pregnancy. PMID- 22533106 TI - Risk factors for suboptimal vitamin D levels among adults with HIV attending an inner-city clinic of New Orleans, Louisiana. AB - BACKGROUND: Vitamin D insufficiency and deficiency are highly prevalent in populations with HIV, but there is limited data on predictors for suboptimal levels. METHODS: To determine risk factors for Vitamin D insufficiency/deficiency, 185 charts were retrospectively reviewed. RESULTS: Proportions with Vitamin D levels < 10 ng/ml, 10 - 20 ng/ml, 20 - 30 ng/ml and > 30 ng/ml were 14.6%, 44.8%, 24.9%, and 15.7%, respectively. Bivariate analysis showed that Vitamin D levels < 20 ng/ml were associated with a lower albumin level (p =.02), female gender (p = .0003), and African-American (AA) race (p = .0001). Tenofovir exposure showed borderline significance (p = .09). AA race was the only significant factor in multivariate modeling. CONCLUSIONS: Vitamin D insufficiency/deficiency was high. AA race was an independent risk factor. Although not significant, obese persons with a poorer nutritional status and possibly those on tenofovir may also be at higher risk. PMID- 22533107 TI - Hepatocellular carcinoma mimicking primary peritoneal carcinomatosis. PMID- 22533108 TI - Environmental risk factors for epidemic typhus in the United States: wintertime is typhus time. PMID- 22533109 TI - Mediastinal pleomorphic sarcoma in an immunodeficient patient: case report and review of the literature. AB - Pleomorphic sarcoma, widely known as malignant fibrous histiocytoma (MFH), is a soft tissue sarcoma. The occurrence of this malignancy in the mediastinum is rare. To our knowledge, only 13 cases of MFH of the mediastinum have been previously reported. Furthermore, only three cases of MFH in patients infected with human immunodeficiency virus (HIV) have been previously described. Here we present a 44-year-old African-American male who complained of epigastric pain radiating to the right chest. On admission, a chest radiograph revealed a widened mediastinum, and chest computerized tomography (CT) identified a large mass in the posterior mediastinum. Histologic diagnosis revealed a high-grade MFH. He was also incidentally diagnosed with HIV infection. The rarity of this malignancy and uncommon site of presentation in association with an immunodeficient state makes this case unique. This is the first report in the literature of an HIV-infected patient presenting with this uncommon tumor in the mediastinum. PMID- 22533110 TI - Paraganglioma of the Organ of Zuckerkandl. AB - Paragangliomas are tumors of the sympathetic and parasympathetic paraganglia. While most paraganglioma are of parasympathetic origin and present as benign palpable masses of the neck, sympathetic paraganglioma are often secretory, presenting with symptoms related to excess catecholamines. Such symptoms include hypertension, headache, palpitations, and diaphoresis. Most sympathetic paraganglioma form within the adrenal medulla, the largest sympathetic paraganglia, and are commonly known as pheochromocytomas. However, sympathetic paragangliomas may present extra-adrenally, carrying a significantly higher risk of malignancy. In this manuscript, we examine a case of a young man with an extra adrenal sympathetic paraganglioma of the Organ of Zuckerkandl. Furthermore, we discuss appropriate diagnostic workup and treatment of pheochromocytomas and sympathetic paragangliomas. PMID- 22533111 TI - Large cell lymphoma associated with prosthetic joint debris. AB - Soft tissue reactions to materials in joint prostheses include discoloration, fibrosis, florid histiocytic reaction, and granulomatous inflammation with foreign body giant cell reaction. Clinical manifestations include pain and swelling. We report a case of temporomandibular joint Proplast-Teflon prosthesis, followed by the development of large cell lymphoma in the left parotid gland 10 years after joint replacement. While it is unclear whether the implant directly contributed to the development of lymphoma, this association has not been previously documented, prompting this report. PMID- 22533112 TI - Louisiana physician population trends: will increase in supply meet demand? AB - Physician shortages in the United States are now recognized broadly and widespread by specialty and geography. While supply is increasing, demand inexorably rises. This situation will probably be further stressed post implementation of healthcare reform. The variations by region and by state are many and significant; this complexity is not fully understood nor yet characterized. Trends similar to the averages of the US have been identified in Louisiana, including the aging of physicians. Lack of physicians, both specialists and generalists, has been reported to compromise quality and effectiveness of healthcare. Thus, the importance of matching up supply and demand is evident. The supply of physicians is increasing in absolute number and in the physicians-to-population ratio. Variations in population, aging, geography, and specialties indicate, in some areas, that this may not be enough to deal with the increasing demand. This paper aims to assess historically how physician shortages may affect the balance of supply and demand in future healthcare delivery, particularly in Louisiana. PMID- 22533113 TI - Breast MRI: patterns of utilization and impact on patient management in the community hospital setting. AB - OBJECTIVE: The objective of our study was to investigate the indications for breast magnetic resonance imaging, or MRI, in our community hospital, determine how many probably benign MRI findings were malignant at follow-up, determine how many cancers were identified by MRI in screening patients, and evaluate the utility of MRI for surgical planning and problem-solving. MATERIALS AND METHODS: Five hundred twenty-eight contrast-enhanced MRI's of the breast in 434 patients were retrospectively reviewed. MRI images/reports were compared to surgical pathology reports and the results of follow-up studies. RESULTS: Screening was the most common indication for breast MRI in our patient population. Five percent of findings termed "probably benign" on MRI proved to be malignant at follow-up. Eight malignancies were detected in six of 202 screened patients. Ten malignancies were diagnosed in 66 patients referred to MRI for problem-solving. In two of 74 patients with known breast cancer, an unsuspected ipsilateral cancer was identified on MRI. CONCLUSION: MRI proved useful in the community hospital setting for screening high-risk patients and problem-solving. The rate of malignancy in probably benign MRI findings was higher than the corresponding rate in mammography. The detection of additional ipsilateral and contralateral cancers in pre-operative patients with known breast cancer was not as high as expected, based on prior studies. PMID- 22533114 TI - A family cluster of tuberculosis cases, including a case of acquired multidrug resistant tuberculosis. AB - Although the number of tuberculosis cases in the US is at an all-time low, with progressive declines seen for the past 17 years, many goals in the tuberculosis elimination process remain unrealized. This report describes a cluster of four tuberculosis cases in a family, including one case of acquired multidrug resistant tuberculosis. It also underscores some important issues in tuberculosis control today, including significant disparities in the foreign-born population with multidrug resistant tuberculosis as a looming problem, as well as utilization of therapeutic drug level monitoring in complicated cases. PMID- 22533115 TI - ECG of the month. Weakness and near syncope in a 79-year-old woman. Sinus bradycardia and arrhythmia, high-grade second degree atrioventricular (AV) block. PMID- 22533116 TI - Radiology case of the month. Knee pain after a heated racquetball match. Meniscal flounce. PMID- 22533118 TI - Program resources--how much is enough? Building the case for environmental health program credibility. PMID- 22533117 TI - A 35-year-old immunocompromised man with cough of three weeks duration. Pneumocystis pneumonia. PMID- 22533119 TI - The dilemma of promoting green products: what we know and don't know about biobased metalworking fluids. AB - Advocates of "green products" argue that promoting these products can protect the environment, workers, and public health. Biobased metalworking fluids (MWFs) are among the products promoted as "green products." The main question is, what constitutes a green product? To answer this question, the authors compared and contrasted the health and safety aspects of biobased and petroleum-based MWFs in terms of their additives. These two product categories of MWFs derived from various feedstocks were investigated through interviews and literature review. Three classes of biobased MWFs and four classes of petroleum-based MWFs were identified and compared. The little information available on the individual constituents for biobased MWFs indicates that they had biocides and preservatives, corrosion inhibitors, extreme pressure, and antiwear components, which are also common additives in petroleum-based MWFs. Precautionary approaches should be taken when promoting biobased MWFs as "green products" until individual components are evaluated for their health and safety impacts. PMID- 22533120 TI - A survey of California public school districts' ant and weed management practices and a review of their use of IPM. AB - The U.S. Environmental Protection Agency encourages school officials to adopt integrated pest management (IPM) to reduce children's exposure to potentially harmful pesticides. In California, the Healthy Schools Act of 2000 (HSA) establishes right-to-know requirements for pesticide use in public schools; requires school districts to designate an IPM coordinator; and requires the California Department of Pesticide Regulation (DPR) to collect pesticide-use information from pest control businesses, conduct IPM training workshops, and promote least-toxic pest management practices. DPR periodically surveys school districts statewide to measure compliance with the HSA and the use of least-toxic management practices compatible with IPM and to guide DPR's training and outreach efforts. Results from three surveys, conducted in 2001, 2002, and 2004, show that an increasing number of districts use ant management practices compatible with IPM; however, fewer districts use IPM-compatible weed management practices. DPR's California School IPM program plans to develop technical materials and to conduct training workshops that will provide districts with more information about how to use an IPM program to prevent and manage weeds. PMID- 22533121 TI - Fish consumption and advisory awareness among the Philadelphia Asian community: a pilot study. AB - Difficulties in the risk communication of fish consumption arise from the concept that this consumption can have both harmful and beneficial effects. This is particularly an issue among populations for which seafood is a major dietary and cultural component. Fish advisories are an important tool in preventing overconsumption of fish that have elevated concentrations of toxic contaminants. The exploratory pilot study described in this article examined fish consumption patterns and knowledge of the potential health risks associated with overconsumption of mercury-contaminated fish within a limited (N = 34) sample of the Philadelphia Asian-American population. Study data were used to evaluate the efficacy of state-issued advisories designed to encourage safe levels of fish consumption within the study population. Results indicate that while advisory awareness levels among study participants were greater than previously observed in Asian-American populations, consumption levels remained high. The limited findings of the authors' study, in combination with existing evidence, suggest the need for the development of more effective methods of disseminating advisory information. PMID- 22533122 TI - Public health performance management: opportunities for environmental public health. PMID- 22533123 TI - 28 major trends for 2012 and beyond: Part 1. PMID- 22533124 TI - Public health records that stand up in court. PMID- 22533125 TI - Wisdom from the wise old owl. PMID- 22533127 TI - Surfacing safety hazards using standardized operating room briefings and debriefings at a large regional medical center. AB - BACKGROUND: Briefings and debriefings, previously shown to be a practical and feasible strategy to improve interdisciplinary communication and teamwork in the operating room (OR), was then assessed as a strategy to prospectively surface clinical and operational defects in surgical care--and thereby prevent patient harm. METHODS: A one-page, double-sided briefing and debriefing tool was used by surgical teams during cases at the William Beaumont Hospital Royal Oak (Royal Oak, Michigan) campus to surface clinical and operational defects during the study period (October 2006-May 2010). Defects were coded into six categories (with each category stratified by briefing or debriefing period) during the first six months, and refinement of coding resulted in expansion to 16 defect categories and no further stratification. A provider survey was used in January 2008 to interview a sample of 40 caregivers regarding the perceived effectiveness of the tool in surfacing defects. FINDINGS: The teams identified a total of 6,202 defects--an average of 141 defects per month--during the entire study period. Of 2,760 defects identified during the six-defect coding period, 1,265 (46%) surfaced during briefings, and the remaining 1,495 (54%) during debriefings. Equipment (48%) and communication (31%) issues were most prominent. Of 3,442 defects identified during the 16-defect coding period, the most common were Central Processing Department (CPD) instrumentation (22%) and Communication/Safety (15%). Overall, 70 (87%) of the 80 responses were in agreement that briefings were effective for surfacing defects, as were 59 (76%) of the 78 responses for debriefings. CONCLUSIONS: Briefings and debriefings were a practical and effective strategy to surface potential surgical defects in the operating rooms of a large medical center. PMID- 22533126 TI - Building hospital management capacity to improve patient flow for cardiac catheterization at a cardiovascular hospital in Egypt. AB - BACKGROUND: Quality improvement (QI) has been shown to be effective in improving hospital care in high-income countries, but evidence of its use in low- and middle-income countries has been limited to date. The impact of a QI intervention to reduce patient waiting time and overcrowding for cardiac catheterization-the subset of procedures associated with the most severe bottlenecks in patient flow at the National Heart Institute in Cairo-was investigated. METHODS: A pre-post intervention study was conducted to examine the impact of a new scheduling system on patient waiting time and overcrowdedness for cardiac catheterization. The sample consisted of 628 consecutive patients in the pre-intervention period (July August 2009) and 1,607 in the postintervention period (September-November 2010). RESULTS: The intervention was associated with significant reductions in waiting time and patient crowdedness. On average, total patient waiting time from arrival to beginning the catheterization procedure decreased from 208 minutes to 180 minutes (13% decrease, p < .001). Time between arrival at registration and admission to inpatient ward unit decreased from 33 minutes to 24 minutes (27% decrease, p < .001). Patient waiting time immediately prior to the catheterization laboratory procedure decreased from 79 minutes to 58 minutes (27% decrease, p < .001). The percentage of patients arriving between 7:00 A.M. and 9:00 A.M. decreased from 88% to 44% (50% decrease, p < .001), reducing patient crowding. CONCLUSION: With little financial investment, the patient scheduling system significantly reduced waiting time and crowdedness in a resource-limited setting. The capacity-building effort enabled the hospital to sustain the scheduling system and data collection after the Egyptian revolution and departure of the mentoring team in January 2011. PMID- 22533128 TI - Patient perceptions of missed nursing care. AB - BACKGROUND: A series of studies involving nursing staff perception have shown that a significant amount of standard nursing care is being "missed"-that is, aspects of required patient care are omitted or significantly delayed. A study was conducted to (1) determine the elements of nursing care that patients are able to report on and (2) to gain insight into the extent and type of missed nursing care experienced by a group of patients. METHODS: In-depth, semistructured, face-to-face interviews, guided by open-ended and interactive questions, were conducted with 38 inpatients on seven different patient care units in an acute care hospital. FINDINGS: For Question 1, elements were categorized as fully reportable (for example, mouth care, bathing, and pain medication), partially reportable (hand washing, vital signs, and patient education), or not reportable (nursing assessment, skin assessment, intravenous site care). For Question 2, patients identified mouth care, ambulation, discharge planning, patient education, listening to them, and being kept informed as frequently missing. Patients sometimes missed response to call lights and alarms, meal assistance, pain medication and follow-up, other medication administration, and repositioning. Nursing care identified as rarely missed were bathing, vital signs, and hand washing. CONCLUSIONS: There is a large area of care for which patients can give an account if they are cognizant of their surroundings and mentally able to do so. For certain aspects of care, patients' perceptions of missed care were similar to those of nursing staff. There is a need to link specific aspects of nursing care to patient outcomes to assist in determining how essential specific elements of nursing care are and the cost-benefit balance of completing them or not. PMID- 22533129 TI - "But what does it mean for me?" Primary care patients' communication preferences for test results notification. AB - BACKGROUND: The best ways to communicate test results in primary care to achieve patient satisfaction and assist patients to incorporate results into their personal health decision making are unknown. A study was conducted to determine the factors that patients believe are important in achieving those goals. METHODS: Semistructured interviews were conducted with a convenience sample of 12 adults, at least half with a chronic disease requiring regular testing, who shared experiences about receiving test results from physicians' offices and how they used them in their health decision making. In addition, "think aloud" interviewing techniques were used to assess participants' satisfaction and stated understanding with six different formats for receiving a hypothetical test result (a mildly elevated lipid profile). The interviews were analyzed using the editing technique to determine important factors in test results notification. FINDINGS: Three themes were found to be important in satisfaction with and stated understanding and use of test results: (1) the information shared (test result, clinician interpretation and guidance), (2) significance of the results (testing purpose, abnormal or normal result) and (3) personal preferences for communication (timeliness, interpersonal connection, and hard copy). Participants' stated understanding was highest, among several potential formats, for actual values with desired/normal values, a low-literacy description of the test's purpose, and a simple graph. CONCLUSIONS: A results notification algorithm includes (1) communication elements (the purpose of the test, the actual results with desired values, clinician guidance, and a graphical representation) and (2) appropriate choice of notification technique (phone/visit for diagnostic tests and all significantly abnormal results and mail/e-mail/Web for all others). PMID- 22533130 TI - Detecting unapproved abbreviations in the electronic medical record. AB - BACKGROUND: At an emergency department (ED) in a tertiary care children's hospital with a level 1 pediatric trauma designation, unapproved abbreviations (UAAs) within electronic medical records (EMRs) were identified, and feedback was provided to providers regarding their types and use rates. METHODS: Existing EMRs, including the ED physicians' patient notes were used as templates to develop a UAA list and an abbreviation detector. The detector was validated against human-screened samples of electronic ED notes from 2003 and then applied to all existing data to generate baseline rates of UAA, before intervention/implementation. Next, the validated abbreviation detector was applied prospectively in screening all EMRs monthly during a six-month period. RESULTS: In validation, the abbreviation detector had a sensitivity of 89%, a specificity of 99.9%, and a positive predictive value of 89%. Some 475,613 EMRs were screened, with UAAs identified at a rate of 26.4 +/- 4 per 1,000 EMRs. The most common nonmedication UAA was "qd" [11.8/1,000 EMRs], and the most common medication UAA was "PCN" [4.2/1,000 EMRs]. A total of 27,282 patient notes from 74 physicians were screened between January 1, 2007, and June 30, 2007, and 392 monthly reports were generated. Aggregate UAA use decreased by 8% (95% confidence interval [CI]: 6%-14%) per month-from 19.3 to > 12.1/100 charts, for a 37.3% decrease in UAA use in the six-month period. The estimated monthly decrease per physician was 0.9/100 (95% CI: 0.86-0.94, p < .001.) After adjusting for secular trends, the decrease was 29% in the six-month study period (95% CI: 14%-44%, p < .0001). CONCLUSIONS: Use of the abbreviation detector for surveillance of newly created EMRs, followed by consistent education and feedback, led to a significant decrease in UAA use in the study period. PMID- 22533131 TI - Beyond the focus group: understanding physicians' barriers to electronic medical records. AB - BACKGROUND: Although electronic medical records (EMRs) have potential to improve quality of care, physician adoption remains low. Rhode Island physicians' perceptions of barriers to EMRs and the association between these barriers and physician characteristics were examined. It was hypothesized that physicians with and without EMRs would differ in the types and magnitude of barriers identified. METHODS: Data were drawn from the Rhode Island Department of Health's mandatory 2009 Physician Health Information Technology (HIT) survey of physicians licensed and in active practice in Rhode Island or an adjacent state. Some 1,888 (58.1% of the target population of 3,248 physicians) responded. Respondents, who were invited to provide open-ended comments, were asked to consider 11 issues as barriers to EMR use: Access to technical support, lack of computer skills, availability of a computer in the appropriate location, impact of a computer on doctor-patient interaction, lack of interoperability, privacy or security concerns, start-up financial costs, ongoing financial costs, technic limitations of systems, training and productivity impact, and lack of uniform industry standards. RESULTS: Respondents with EMRs consistently perceived significantly fewer barriers than those without them (p < .0001). For example, 78.9% of physicians without EMRs viewed start-up financial costs as a major barrier versus only 45.8% of physicians with EMRs. CONCLUSIONS: An understanding of physicians' reluctance to use EMRs is critical for developing adoption strategies. Policies to increase EMR adoption should be tailored to different physician groups to achieve maximum effectiveness. Further research into the differences between current EMR users' and nonusers' perceptions of barriers may help elucidate how to facilitate subsequent adoption. PMID- 22533132 TI - Lessons from The Bad News Bears. PMID- 22533133 TI - ICD-10 implementation deadlines: no time to relax. PMID- 22533134 TI - Between hospital and home. PMID- 22533135 TI - Time to build? Health reform and tight margins crimp new construction plans. PMID- 22533136 TI - Care, health and cost: 'The triple aim on steroids'. PMID- 22533137 TI - Governance: Forging better CEO-trustee bonds. PMID- 22533138 TI - Supply chain needs improvement. AB - Other businesses rely on information technology to make the supply chain more efficient and dependable. Hospitals should follow suit. PMID- 22533139 TI - Teamswork! AB - The physician-centric approach to patient care is giving way to a team-based model in which nurses, pharmacists, social workers and others truly share responsibility. The goal: Higher quality, enhanced efficiency. PMID- 22533140 TI - Affordable care ruling awaits. Interview by Bob Kehoe. PMID- 22533141 TI - Focus on the C-suite: Influencer-in-chief. PMID- 22533142 TI - The changing role of nurses. PMID- 22533143 TI - ICD-10 implementation: no time to delay. AB - Whatever the ICD-10 launch date, hospitals must keep up their complex preparations. This foldout offers tips and case studies. PMID- 22533144 TI - The quest for quality: excellence in the new era of care delivery. PMID- 22533145 TI - Rooms with a view. PMID- 22533146 TI - A statistical snapshot of health care. AB - More Americans get hospice care at the end of life. Hospitalist numbers surge. The need for new knees doubles in a decade. PMID- 22533147 TI - Managing construction costs. PMID- 22533148 TI - [History and the development of the studies on HIV and AIDS]. AB - The article describes the progress of medical knowledge which has been observed since the finding and discovery of the first case of the immune deficiency syndrome in the world in 1981. During this period the methods of diagnosis and treatment of HIV/AIDS has changed significantly. The progress in this area of examinations which is presently achieved allows unambiguous diagnosis of the virus and the disease. The recognition of the pathogenesis of the HIV and AIDS enabled the beginning of the studies on the medicines having antiretroviral properties. The utilization of the potential of the currently used medicines inhibits the progress of the disease and, in consequence, the elongation of the patients' life span. However, despite excessive clinical experiments in numerous research centres world-wide, until now there has not been found an effective medicine which could totally eradicate this virus from the body nor the vaccine which could prevent the further spread of this virus in the world. PMID- 22533149 TI - [Duties of institutions and heads of health care centers in the area of infection control, information, assessment, registration and financing of benefits provided to TB patients]. AB - The Act on preventing and counteracting infections and infectious diseases in humans effective in Poland provides for the duty of the heads of health care outlets and institutions to counteract spreading of TB in units under their management. They are, by all means, responsible for monitoring infections in their respective units, involving development, implementation and monitoring of practical implementation of procedures aiming at limiting dissemination of TB in hospitals and outpatient clinics. Medical service unit managers are also responsible for providing members of their staffs with means of individual protection against infection with Mycobacterium tuberculosis bacillus. Their duties also include notification of all recognized TB cases in their respective units. TB is an infectious diseases included in the occupational disease list. Assessment of TB as occupational disease is the responsibility of provincial TB prevention clinics. The Act also provides for principles of financing of individual benefits available for the insured TB patients and those not insured. PMID- 22533150 TI - [The assessment of cynacalcet (Mimpara) accompanied by alfacalcidol treatment efficacy in haemodialysis patients with different secondary hyperparathyroidism severity recognized by iPTH]. AB - INTRODUCTION: Calcimimetics are highly efficient drugs in treatment of secondary hyperparathyroidism (sHPT) in patients on haemodialysis. The effect and the dose of cinacalcet may depend on severity of sHPT, and alfacalcidol supplementation helps in the treatment optimization. The study evaluated cinacalcet and alfacalcidol treatment efficacy in haemodialysis patients with different secondary hyperparathyroidism severity recognized by iPTH. MATERIAL AND METHODS: The study group comprised of 82 participants (male 67 and 34 female) in aged from 36 to 75 years, on haemodialysis. All patients were divided into two groups: the study group--40 participants treated with cinacalcet accompanied by alfacalcidol started after 8 months of the study (0.25 to 0.5 microg/day) and the control group--42 patients. The study group comprises of two subgroups: I--moderate sHPT with iPTH 500 to 800 pg/ml and II--severe sHPT with iPTH > 800 pg/ml. The basic phosphate binder treatment throughout the study period in all groups was calcium carbonate. RESULTS: In the subgroup I initial mean iPTH 700 +/- 129 pg/ml was reduced to 550 +/- 61 pg/ml (p < 0.05) in the third month with no need of the Mimpara dose change. No further iPTH decrease up to eighth month of the treatment was observed despite the cinacalcet dose increase to 53 mg (p < 0.05). The alfacalcidol supplementation decreased iPTH to 331 +/-55 pg/ml (p < 0.05) and the cynacalcet dose to 42 mg (p < 0.05). In the II subgroup iPTH was reduced from 1035 +/- 149 pg/ml to 885 +/- 101 pg/ml (p < 0.05) in the third month of the treatment and Mimpara dose changed to 90 mg. Up to eighth month iPTH did not change (790 +/- 92 pg/ml; p > 0.05) despite the cinacalcet dose increase to 122 mg (p < 0.05). The alfacalcidol supplementation induced iPTH reduction to 622 +/- 71 pg/ml (p < 0.05) and the cinacalcet dose to 100 mg (p < 0.05). CONCLUSIONS: Cinacalcet convinced its effectiveness in the iPTH serum concentration control in haemodialysis patients independently of secondary hyperparathyroidism severity and alfacalcidol supplementation enhanced its efficacy. Still in case of the late introduction of Mimpara this drug was recognized as potent however the efficient dose was mandatory multiply. PMID- 22533151 TI - [Coexistence of resistance to thyroid hormone with pituitary incidentaloma]. AB - Contrary to generalized resistance, pituitary resistance to thyroid hormones is characterized by features of hyperthyroidism. Its clinical manifestation resembles that of thyrotropin (TSH)-secreting adenomas, tumors constituting about 1-2% of all pituitary lesions. Both patients with resistance to thyroid hormone and thyrotropin-secreting tumors have increased plasma thyroid hormone levels and raised or inappropriately normal thyrotropin levels. However, their treatment is different and therefore differentiation of these entities is very important. The significant progress made in recent years in the field of high-resolution imaging procedures led to a situation during which hormonally inactive adenomas not posing a risk to a patient's health, referred to as incidentalomas, are discovered in endocrine organs including the pituitary. In our paper, we report a case of a young man with predominant pituitary resistance to thyroid hormone. Because of coexisting pituitary incidentaloma the patient was initially misdiagnosed as having a TSH-secreting tumor. We describe in details diagnostic and treatment strategies applied in our patient. The described case of our patient illustrates the need for clinical awareness of the possible presence of resistance to thyroid hormones in subjects with central hyperthyroidism and focal lesions in the pituitary. PMID- 22533152 TI - [The effect of oxcarbamazepine on the clinical effectiveness of dopamine agonists in the treatment of prolactinoma]. AB - The CYP450 enzyme family plays a very important role in the biotransformation of many drugs with a different chemical structure. Therefore, the inhibition or induction of CYP enzymes may be responsible for the development of numerous drug interactions. Moreover, a peculiarity of constitution causes that some persons in particular situations may respond differently to a drug or treatment than do most people. In this article, we show a case of a young woman diagnosed with prolactinoma who was initially successfully treated with bromocriptine. Two years later she developed epilepsy secondary to brain trauma and as a result, she started receiving oxcarbamazepine treatment. Unfortunately, the treatment led to a deterioration of prolactinoma control. To normalize plasma prolactin levels, bromocriptine dose had to be increased and then replaced, initially with cabergoline and later with quinagolide. Only the latter drug effectively reduced plasma prolactin levels and tumor size. This case shows for the first time the existence of a drug interaction between dopamine agonists and any anti-epileptic drug in patients with prolactinoma. PMID- 22533153 TI - [Toxic epidermal necrolysis during therapy with sulphasalazine in a patient with arthritis. Case report]. AB - Toxic epidermal necrolysis (TEN) is a severe, life-threatening disease appearing after certain drugs, characterized by keratinocyte necrosis, which shows with painful cutaneous and mucosal exfoliation and systemic involvement. TEN mortality rate is between 30% to 70%, so patients need early administration of medical care. We report a case of a 40-year old woman with TEN-like symptoms, who received treatment with sulphasalazine for 3 weeks because of arthritis. Various diagnostic procedures were performed which caused many doubts about diagnosis. In differential diagnosis we thought about: firstly TEN after treatment with sulphasalazine--patient with systemic lupus erythematosus, secondly toxic epidermal necrolisis like lupus erythematosus, finally TEN and LE after treatment with sulpasalazine--patient with rheumatoid arthritis. Final diagnosis needs more investigation and further diagnostic procedures. The patient stays under our control. PMID- 22533154 TI - [Burn shock, diagnostics, monitoring and fluid therapy of severe burns--new look]. AB - Pathomechanism of burn shock is associated with an important endocrine disorder and cytokines storm. As a result of the burns are released to bloodstream kinins such as: histamine, serotonin and bradykinin and also inflammatory mediators such as: tromboxans, prostacyclins, prostaglandins and leukotrienes. Arises temporary endothelial failure. Comes to the escape of liquid blood to the tissues and a sudden decrease in the quantity of the fluid in the vessels and appear symptoms of burn shock. Offset of fluids by vascular wall to the extravascular space described mathematically with Landis-Starling law. Treatment of burn shock relies on intensive fluid therapy to fill vessels. Fluid rules are based on infusion crystalloids, colloids, hypersaline or plasma. Effect of fluid resuscitation after severe burn are edemas of whole body. Severe burn receives up to 25 000 ml of fluids intravenous in the first 48 hours after injury. The quantity of water defaulting tissue after 48 hours is even 13 000-18 500 ml which is 300-400% of the volume of blood flow. From 3rd day after burn this may produce symptoms of acute circulatory insufficiency or polycompartment syndrom. Enforces this restrictive fluid treatment and removing significant quantities of water from the bloodstream. In East Poland Burn Center and Reconstructive Surgery we remove even 300-350 ml fluid/h by ultrafiltration during CVVHD CiCa. Additional application hemodynamic monitoring such Vigileo-Flotrac has considerably reduce the amount of complications such as: intra-abdominal hypertension IAH, acute heart syndrome, cerebral edema and pulmonary edema. PMID- 22533155 TI - [Role of the polymorphisms within genes encoding proteins related to endothelial dysfunction in coronary artery disease]. AB - Endothelial dysfunction is crucial in the development of atherosclerotic lesions. There is number of factors involved in this process, e.g. hypercholesterolemia, hyperhomocysteinemia, free radicals, hypertension, obesity or overweight, smoking. Polymorphisms of the genes encoding products involved in the atherosclerotic process play significant role in the etiology of atherosclerosis and coronary artery disease (CAD). The aim of the present study was to show the role of the factors and markers of endothelial dysfunction e.g. methylenetetrahydrofolate reductase (MTHFR), E-selectin (CD62E) and intercellular adhesion molecule-1 (ICAM-1) and common polymorphisms within genes encoding these molecules in the etiology of CAD. MTHFR catalyzes a reduction of 5,10 methylenetetrahydrofolate to 5-methyletetrahydrofolate that is the carbon donor for the remethylation ofhomocysteine (Hcys) to methionine. The 677C>T polymorphism in the MTHFR gene influences enzyme thermolability that leads to its decreased activity and in consequence to elevated level of plasma Hcys. E selectin is synthesized by the endothelium after the activation of inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF alpha). The C allele of the 561A>C polymorphism within CD62E is suggested to be a risk factor for restenosis in CAD patients. Another polymorphism in CD62E gene, 98G>T polymorphism is suggested to be a marker of the 561A>C polymorphism and both of these changes are likely to control the E-selectin expression. The 1405A>G polymorphism in ICAM1 gene may affect mRNA splicing patterns that modify cell-cell interactions and influence inflammatory response. PMID- 22533156 TI - [Definition and epidemiology of sarcoidosis]. AB - Sarcoidosis is a systemic inflammatory disease of undetermined etiology with unexplained predilection for the lung. The definition of disease has been evaluated in many clinical centers but final results are still under discussion. Some historical facts of sarcoidosis presented in the paper show that histological and x-ray examinations are key diagnostic tools. Sarcoidosis occurs worldwide, with a high prevalence in Afro-Americans and Caribbeans, and in people of Nordic countries. Prevalence varies with geography and is dependent from environmental factors and immunogenetic mechanisms. PMID- 22533157 TI - [Rhodococcus equi infections in animals and humans]. AB - Little is known about the occurrence of R. equi infection in humans at the present time. However, an increasing number of R. equi infections mainly in immunocompromised patients has been reported recently and R. equi is now considered an emerging zoonotic pathogen. Nevertheless sources and routes of human infection are not fully understood. Recently R. equi was detected in tissues of animals intended for human consumption. Clinical course of infection is often diversified and atypical. The physicians are frequently unaware of R. equi pathogenic potential due to little epidemiological and risk factors data. PMID- 22533158 TI - [Patients's with aphasia communication problems]. AB - Aphasia is a speech disorder caused by disorders of speech centre in brain cortex. Patient with aphasia compensates communication disorders by communication strategy, witch are spontaneous mechanisms, and uses individual rehabilitation methods. Compensation mechanisms are divided in to: phonetic, inflective, formative, semantic, discursive and structural. Patients with aphasia early therapy have to be individual and consists in not only articulation correction, but in establish over verbal contact or verbal, and improvement this contacts, to create patients ability of communication with society. Later therapy is oriented on improvement of cognitive functions for possibility of participation in social live and if it is possible for return to work. PMID- 22533159 TI - [Searching for new wound healing strategies--problems and pitfalls]. AB - Authors present the most recent and prospective trends in wound healing procedures, which are expected to solve problems with acute and chronic wounds management. While searching for new strategies to optimize the would healing process, reduce the complication probability, and support or replace the classical treatment procedures, researchers are faced with many diagnostic and therapeutic problems and pitfalls. That leads to creating highly complicated and expensive treatment procedures which, however, have not yet been proven to exceed the effectiveness of the moist wound therapy. PMID- 22533160 TI - [The analysis of the clinical symptoms and social conditionings of the tic disorder in children]. AB - A tic is a rapid, involuntary and stereotypical motor movement or vocalization. The exact cause of tic disorder is unknown, but it is well established that both genetic and environmental factors are involved. Tic occurence in population was estimated on 5-100/10 000. AIM: The purpose of the research was to analyze the clinical symptoms and social conditionings of tic disorder in children. MATERIAL AND METHOD: The analysis was conducted on a group of 42 patients (8 girls, 34 boys) at the age of 3 to 15 years, admitted to Department of Neuropediatric of Medical University of Silesia to diagnose and treatment of tic disorder. The children's family history was analyzed. The patients were physically, neurogically, radiologically and psychologically examined. RESULTS: The majority group were boys and the time of the symptoms appearance was an early school age. The tics were associated with emotional and anxiety disorders, compulsive behavior, psychological obsession. 9% of patients had family history of tic disorder. Pregnancy-birth history was complicated in 24% of cases. There were not abnormalities in physical, neurological and radiological examination in most cases. The majority group (83%) lives in the cities. The most parents have vocational training. CONCLUSION: In case of appearance of twitching during suspicious behavior of child, we need to carry out a inquiring research targeted to widely understated social issues. PMID- 22533161 TI - A new hypothetical factor responsible for occurrence and changes in incidence of rheumatoid arthritis in Europe in historical perspective. PMID- 22533162 TI - TB and diabetes--the dual epidemic: is it a matter of concern? PMID- 22533163 TI - Tuberculosis--challenges and opportunities. PMID- 22533164 TI - Bronchial thermoplasty. AB - Even with the use of maximum pharmacological treatment, asthma still remains uncontrolled in some cases. For such cases of uncontrolled asthma, a novel therapy--Bronchial Thermoplasty (BT)--has shown some promising results over the past few years. BT is application of controlled radiofrequency heat via catheter inserted through a flexible bronchoscope, to the bronchial walls. It reduces the smooth muscle mass in bronchial wall and thus results in decreased contractility. Three major trials of BT show that it does not cause any improvement in FEV1. However, BT causes improvement the quality of life and decreases the future exacerbations and emergency hospital visits due to asthma. But the benefit observed was too small to be clinically significant. Follow up (two to five years) results of these BT trials did not show any significant long-term adverse event related to BT. However, further independent large randomized controlled trials and results of application of BT in real hospital settings are needed to define its role in asthma management. PMID- 22533165 TI - A pilot study of same day sputum smear examination, its feasibility and usefulness in diagnosis of pulmonary TB. AB - INTRODUCTION: A large number of tuberculosis cases are continuously being reported from India and other developing countries leading to high morbidity and mortality. In spite of many newer tests available for diagnosing a case of tuberculosis, smear microscopy of sputum is still the preferred test under programmatic conditions. The current national and international guidelines recommend two sputum smear examinations in two days for diagnosing cases of tuberculosis, which is time-consuming, tedious, needs multiple visits, leading to high dropout of infectious cases. In the background of existing limitations of smear microscopy, we attempted to complete the diagnosis of tuberculosis on same day by serial collection of the spot sputum specimen and analyze its advantages, feasibility and viability. MATERIAL & METHODS: The study was undertaken by the Department of Microbiology, Lala Ram Sarup Institute of Tuberculosis and Respiratory Diseases during May 2010 to April 2011. Sputum specimens were collected from 330 randomly selected tuberculosis suspects who attended OPD of hospital, patients submitted spot and home collected morning sputum sample in a standard method and spot and additional spot sputum (X- spot) collected one hour after the first spot sample as per the proposed front loading method. All the samples received were stained by acid fast Ziehl-Neelsen (ZN) stain and examined on the same day. The sputum sample was pooled and cultured in Lowenstein Jensen (LJ) media in duplicate set of bottles. The results of two different microscopic methods were compared with the gold standard culture test. RESULTS: Out of the total 330 TB suspects, 70.60% were males and 29.39% females. The most common complaint was of cough with sputum (88.18%), chest pain (70.21%), fever (55.15%) and loss of appetite (43.03%). Upon examining the total sputum slides, 18.48 % were positive for acid fast bacilli. The smear positivity was 61/330 (18.48%) by standard methods and in proposed new method 43/330 (13.03%). Sensitivity of the standard and proposed new method smear microscopy was 58.25% and 40.07% respectively and specificity was 99.55% in both the methods. CONCLUSION: Same day smear microscopy for diagnosing tuberculosis by a proposed new method of smear examination in the case of suspected tuberculosis seems not a promising step towards improving the quality of sputum smear examination. The results of sensitivity and specificity of the two approaches were not similar. More than eighty per cent responded in favour of same day sputum delivery system and getting result on same day. This study can be confirmed on larger scale and preference of patients can be examined in peripheral laboratory also before taking it up for consideration in the national tuberculosis programme. PMID- 22533166 TI - A comparative assessment of KAP regarding tuberculosis and RNTCP among government and private practitioners in District Gwalior, India: an operational research. AB - BACKGROUND: Tuberculosis is one of the oldest diseases known to mankind. However, still practitioners are unaware of various facts associated with it. OBJECTIVES: (1) To assess the knowledge, attitude and practices adopted by practitioners of both government and private sectors in diagnosis and management of TB patients. (2) To assess the views of practitioners in strengthening the RNTCP programme. METHODOLOGY: 200 allopathic practitioners from both government and private sectors providing their services in Gwalior District were interviewed using pre designed pre-tested structured questionnaire. RESULTS: The mean score of knowledge related to tuberculosis and RNTCP was higher among government practitioners (9.8) compared to private practitioners (6.1). All practitioners were having positive attitude towards regular up gradation of knowledge while statistically significant differences were noted on issues related to management of TB patients as per RNTCP guidelines. X-ray was the most preferred modality for diagnosis and follow up among private practitioners compared to sputum examination among government practitioners. Referral of poor and serious patients was also very low among private practitioners. CONCLUSION: The present study hereby concludes that there is a large gap in Knowledge, Attitude and Practices on TB and RNTCP among the practitioners of both the sectors. There is an urgent need for upgrading the knowledge on various issues and regular Continuing Medical Education (CME) involving various professional bodies. PMID- 22533167 TI - Determinants for the retreatment groups of pulmonary tuberculosis patients treated in a DOTS programme in Sikkim, India. AB - OBJECTIVE: To assess knowledge, attitude and different health-seeking behaviours among 250 cured and 250 category-II tuberculosis patients. METHODS: A case control study was conducted in different health settings in Sikkim, a part of the Indian continent. A questionnaire was filled for the purpose. RESULTS: Results showed significant differences in overcrowding, smoking and alcohol intake. There was a general unawareness with the disease and its treatment between the two groups. 45% of the respondents reported that tuberculosis is caused by germs. 81.4% stated that tuberculosis presents only as cough. 94.8% of the case group and 90.8% of the control group stated that it is a transmissible disease. Sharing food with tuberculosis patients (64% of case group, 55% of the control group; p < 0.05), inadequate diet (16.4% of case group, 9.6% of the control group; p < 0.03) were mentioned as modes of transmission. Sixty six per cent of the case group and 56.8% of the control group mentioned the use of DOTS for prevention and control (p < 0.05). Sixty three per cent of the control group regarded tuberculosis as a life threatening condition (p < 0.00) [(adjusted OR = 2.04, (95% CI: 1.43, 2.93)]. Tuberculosis was considered as a completely curable disease by 96.4% of the case group (p < 0.05). 40.6% of the respondents agreed to be in contact with a tuberculosis infected person. 64% of the retreatment group discontinued their treatment due to frequent travelling for work. CONCLUSION: The study revealed lack of knowledge, positive attitude and inappropriate health seeking behaviours among of the tuberculosis patients, irrespective of their categorization. PMID- 22533169 TI - Ophthalmic manifestations of central nervous system tuberculosis--two case reports. AB - In this report, we present two unusual ocular manifestations due to CNS tuberculosis. One of the cases is a 7 years' old boy with brain stem tuberculoma who presented with horizontal gaze palsy. The other is a 14 years' old girl with temporal lobe tuberculoma who presented with unilateral sixth nerve paresis and papilledema. Both responded well to treatment with antitubercular drugs. It highlights the importance of gaze palsy as a rare manifestation of CNS tuberculosis. PMID- 22533168 TI - Scrofuloderma--a case series from rural India. AB - Cutaneous tuberculosis is the rarest presentation of all the forms of tuberculosis. Scrofuloderma is a frequent manifestation of cutaneous tuberculosis in Indian scenario. Males are affected one and half times more than females. The most common affected age group showing clinical infection is within the first three decades of life. A series of cases mostly malnourished children attending a tertiary care centre in a rural area of central India is being reported. They have presented with a wide spectrum of clinical features, forcing us to establish the final diagnosis by Mantoux test, fine needle aspiration cytology and histopathological examination. The mainstay of treatment remains medical therapy but the underlying cause for severe immunosuppression needs to be ruled out and treated. PMID- 22533170 TI - Status report on RNTCP. PMID- 22533171 TI - Determinants of childhood tuberculosis--a case control study among children registered under revised National Tuberculosis Control Programme in a district of South India. AB - AIM: To study the determinants of Tuberculosis (TB) in children between the age group of 0-14 years receiving treatment under Revised National TB Control Programme (RNTCP). METHODS: A case (registered under RNTCP) control study was undertaken with 41 cases and 82 controls. RESULTS: Factors found to have significance according to binary logistic regression were low-birth weight (LBW) [Odd's ratio = 3.56],Malnutrition [Odd's ratio = 3.96], Passive smoking [Odd's ratio=6.28] and exposure to fire-wood smoke [Odd's ratio = 6.91]. CONCLUSION: LBW, malnutrition, passive smoking and fire-wood smoke are the risk factors to be addressed to prevent pediatric TB. PMID- 22533172 TI - Factors associated with low utilization of x-ray facilities among the sputum negative chest symptomatics in Jalpaiguri district (West Bengal) 2009. AB - New sputum negative (NSN) tuberculosis case detection in Jalpaiguri district has been consistently low. Availability and accessibility of health facilities with chet x-rays is key for the diagnosis of NSN cases. To identify factors associated with utilisation of x-ray facilities in the district, we interviewed 4,875 chest symptomatics who were sputum negative on two occasions with an antibiotics course in between. Chest radiography was available in only three public health facilities in the district. Low income, long distance from the public health facilities with chest radiography and high cost of x-rays at private hospitals were key factors associated with symptomatics not undergoing X-ray. It is necessary to increase facilities for radiological diagnosis and provide mobility support for the symptomatics in Jalpaiguri. PMID- 22533173 TI - In the balance: With the drama of Supreme Court arguments over, providers are left to worry what will happen if the individual mandate is struck down. AB - After last week's U.S. Supreme Court arguments on the landmark healthcare reform case, providers are left to wait and wonder what will happen. "If I were a betting person ... I would come away and think they would throw out the mandate," says William Petasnick, of Froedtert Health. "But I think there is some case law and precedent that might move them in a different way because of the consequences." PMID- 22533174 TI - 'Complete nonsense': participants defend pay-for-performance project. PMID- 22533175 TI - IOM: integrate 'communities': reuniting public health, primary care critical. PMID- 22533176 TI - Challenging the FTC: ProMedica to test merger guidelines in federal court. PMID- 22533178 TI - Familiar arguments: debate over device user-fee act reflects FDA's record. PMID- 22533177 TI - Domino effect: companies challenged to step up privacy efforts. PMID- 22533180 TI - Local lessons: improving regional scorecards requires working together. PMID- 22533181 TI - Marketing prevention: making procedures less distressing, offering unbiased info could boost testing. PMID- 22533179 TI - Past, present and future: old civil rights-era case offers perspective on health reform legal fight. PMID- 22533182 TI - Partnering up: As consolidation begins to sweep through healthcare, hospitalists expect to see the trend accelerate in their sector. PMID- 22533183 TI - Feeling a subtle impact: 2.5 million young adults gain coverage, while insurers barely register a change in costs. PMID- 22533184 TI - Less morbidity with flapless implant. AB - Flapless implant placement requires punch removal of the gingiva without flap reflection, suggesting this technique will be less invasive, and with less tissue destruction, than comparable alternative techniques. METHODS: Eleven implants were placed with flapless (FL) technique and 11 implants were placed with full thickness flap (FT) technique in split mouth technique. FL technique was done with dermal tissue puncture, while FT was performed with crestal incision, including the papillae. Patients were followed-up postoperatively for clinical and morbidity evaluation in both groups. RESULTS: There was no pain, and there were only mild signs of inflammation, at the sites of flapless implant placement in the 11 patients studied. In contrast, there were complaints of mild to moderate pain and signs of inflammation at the site of full-thickness flap implant placement in the 11 patients studied. In addition, there was gingival overgrowth over the healing cap noted in this group. CONCLUSIONS: FL technique may be recommended for the apprehensive or hyperalgesic patient because of the absence of pain it conveys, as well as the decreased postoperative swelling. Periosteal disruption is responsible for the patient's morbidity postoperatively. PMID- 22533185 TI - Managing failure: The fate of unsustainable services back in the hands of the centre. PMID- 22533186 TI - Vital support services 'on the cusp of failing'. PMID- 22533187 TI - On the right person for the job. PMID- 22533188 TI - At the heart of safer surgery. PMID- 22533189 TI - Structure: Taking baby steps to effect major change. PMID- 22533190 TI - 'A stronger, shared vision'. PMID- 22533191 TI - Workforce: Moving in the right direction. PMID- 22533192 TI - Innovation: Hospitals tune in to radio tracking systems. PMID- 22533193 TI - Court tells United--pay up. PMID- 22533194 TI - "Filling my bucket". PMID- 22533195 TI - Building the medical home: after-hours access. PMID- 22533197 TI - The supporting cast. Strong, focused committees and task forces are essential to overall governance excellence. AB - The best committees improve board decision-making and efficiency. PMID- 22533196 TI - Arkansas Department of Health 2011 report. PMID- 22533198 TI - A new voice at the table. The chief nursing officer provides a valuable perspective on quality, safety and the bottom line. AB - The chief nursing officer's perspective on quality and outcomes should be heard at each board meeting. PMID- 22533199 TI - Physicians in the C-suite. Hospitals are looking for a new kind of leader, but are today's docs ready? AB - M.D. Hospitals seeking physician executives first must provide leadership learning opportunities. PMID- 22533200 TI - The patient-centered medical home. PMID- 22533201 TI - Making the right match. These eight lessons can help boards explore the strategic partnership decision. AB - Working through eight lessons can help boards clarify the strategic partnership decision. PMID- 22533202 TI - Distress signals. Asking these tough questions will help boards to head off potential crises. AB - To look beyond financial metrics when assessing hospital performance, trustees should ask questions in key areas. PMID- 22533203 TI - Reinventing rural care. In the move from volume to value, ensuring rural health care's viability will benefit all providers. AB - It's time to rethink the way rural health care is funded and delivered. PMID- 22533204 TI - Governing with competency. Assessing trustees' strengths and opportunities for improvement helps boards prepare for the future. AB - Boards have several options for applying competencies to governance. PMID- 22533205 TI - Leaders and long-term planning. AB - A long-term planning committee focuses on emerging trends. PMID- 22533206 TI - Hieronymus Bosch and ergotism. PMID- 22533208 TI - Two sides of the same coin. PMID- 22533207 TI - The medical school situation. 1910. PMID- 22533209 TI - Community connections free clinic providing health care and more to uninsured. PMID- 22533210 TI - Face mask use by patients in primary care. AB - CONTEXT: Face masks are recommended for patients with respiratory symptoms to reduce influenza transmission. Little knowledge exists regarding actual utilization and acceptance of face masks in primary care. OBJECTIVE: Compare distribution of face masks to clinic and community trends in respiratory infection (RI) and influenza-like illness (ILI); estimate the annual need for face masks in primary care. DESIGN: Retrospective observational study of practice data from a 31-week period starting in October 2009. SETTING: Family practice clinic in Madison, Wis. PATIENTS: Patients with fever, cough, or other respiratory symptoms as evaluated by reception staff. MAIN OUTCOME MEASURES: Age, sex, and weekly counts of individuals receiving a face mask, as well as counts of RI and ILI patients based on ICD-9 coding from 27 statewide clinics. RESULTS: Face mask counts were 80% of RI counts for the clinic and reflected the demographics of the clinic population. Distribution was correlated to prevalence of RI (R = 0.783, P < 0.001) and ILI (R = 0.632, P < 0.001). Annually, 8% of clinic visits were for RI. CONCLUSIONS: The high percentage of face mask use among RI patients reflects the feasibility of this intervention to help control influenza transmission in a primary care setting. Using the present data, clinics can estimate the annual need for face masks. PMID- 22533211 TI - Use of broad-spectrum antibiotics and the development of irritable bowel syndrome. AB - BACKGROUND: Irritable bowel syndrome (IBS) is a functional bowel disorder with an estimated prevalence of 9% to 22% in the United States. It is responsible for 28% of gastroenterology visits, with associated health care costs of $8 billion annually. Yet, IBS etiology is the subject of much debate. OBJECTIVES: Our study examines a possible relationship between IBS and exposure to broad-spectrum antibiotics. It is known that antibiotics alter the colonic flora; we hypothesize that this can create the manifestations seen in IBS patients. METHODS: Following approval by the Gundersen Clinic, Ltd Human Subjects Committee/IRB, the medical records of adults who were started on a broad-spectrum antibiotic at Gundersen Lutheran Health System between January 1, 2008, and December 31, 2008, were reviewed retrospectively. From this population, we identified those who developed IBS within 12 months and compared their demographic and clinical characteristics with the characteristics of those who did not. RESULTS: Of the 26,107 adult patients exposed to broad-spectrum antibiotics during the study period, 115 received an IBS diagnosis within 12 months. Most were women (84%; n = 97), and they had a higher prevalence of associated comorbidities than those who did not develop IBS. Patients indicated for macrolide or tetracycline use had a higher proportion of IBS development within 12 months; indication for tetracycline use maintained significance even after controlling for sex and comorbid conditions (odds ratio; 1.48; P = .046). CONCLUSION: Use of broad-spectrum antibiotics- particularly macrolides or tetracyclines--may be associated with IBS development. To date, we know of no other study that has associated these antibiotics with IBS development. Further studies are necessary. PMID- 22533212 TI - An update on the diagnosis and management of concussion. AB - Concussion is a common medical problem with significant morbidity and sometimes devastating consequences. Awareness of this injury has increased dramatically in recent years, and our understanding of its pathophysiology and treatment is rapidly evolving. This article reviews the current concepts of concussion pathophysiology and epidemiology, and will provide an overview of proper diagnosis and management. Complications and risk reduction also will be reviewed. By understanding the essentials of concussion medicine, health care professionals will be equipped to manage this injury, including common complications. PMID- 22533213 TI - Immunoglobulin A nephropathy associated with mesothelioma. AB - Immunoglobulin A nephropathy (IgAN) has been identified in patients with various malignancies. Although membranous glomerulonephritis and minimal change disease have been described in patients with mesothelioma, to our knowledge IgAN associated with mesothelioma has not been reported. We present a case of IgAN, characterized by progressive deterioration of renal function from normal and confirmed by kidney biopsy. Despite improvement of renal function following treatment with cyclophosphamide and prednisone, the patient succumbed to acute respiratory failure 8 months later. We conclude that IgAN may be a potential complication of mesothelioma. PMID- 22533214 TI - Increasing medical team cohesion and leadership behaviors using a 360-degree evaluation process. AB - Current national health care issues of affordability, quality, and accessibility have prompted the development of Accountable Care Organizations (ACOs) and Patient-Centered Medical Homes (PCMHs). Components of ACOs and PCMHs call for increased capacities in areas of teamwork, engagement, and physician leadership skills and behaviors. Three hundred sixty degree feedback evaluation processes have been established in corporate environments as effective for increasing capacities in these areas. Recently, health care organizations have begun to adopt the use of such tools with positive outcomes. This article presents a case study of the development and implementation of a 360-degree evaluation process at a family medicine clinic. We also discuss the challenges, successes, and lessons learned along the way. PMID- 22533215 TI - Shedding light on what the Sunshine Act will mean for physicians. PMID- 22533216 TI - Community-based medical school expansion holds potential for addressing physician shortage. PMID- 22533217 TI - How much is it worth? PMID- 22533218 TI - The decline and fall of the neighborhood drugstore. PMID- 22533220 TI - Geriatric Neurology Conference, November 2011: it is time to be old. PMID- 22533219 TI - Introduction to the aging brain, Part 1. PMID- 22533221 TI - "Normal" and pathological changes with age in the brain. PMID- 22533222 TI - An evidence-based approach to stroke prevention: important advances in the last decade. PMID- 22533223 TI - Epilepsy concerns in older patients. AB - Epilepsy incidence is higher in the elderly than in younger adults. Diagnosis and management of the elderly with epilepsy presents several specific demands. A variety of other mimics can confound the diagnosis in this age group. Treatment choices should consider issues of metabolism, co-morbidities, and side effect profiles. Drug-drug interactions are prevalent and need to be minimized and/ or anticipated. PMID- 22533224 TI - Gait disorders in the elderly. PMID- 22533225 TI - Idiopathic normal pressure hydrocephalus--neurosurgical management of dementia! PMID- 22533226 TI - Sleep and aging. PMID- 22533227 TI - Less than optimal dental care among Rhode Island adults with diabetes: the need to assure oral health care for all adults with diabetes. PMID- 22533228 TI - Physician's lexicon: causes, cases and casuistries. PMID- 22533229 TI - Peptidoglycan from Staphylococcus aureus induces T(H)2 immune response in mice. AB - BACKGROUND AND OBJECTIVE: Atopic dermatitis patients have an increased number of type 2 helper (T(H)2) cells in their peripheral blood and superficial Staphylococcus aureus colonization. The purpose of this study was to clarify the effects of peptidoglycan (PEG) from S aureus on the induction of the TH2 immune response in mice. METHODS: Mice were primed with PEG- and ovalbumin (OVA)-pulsed Langerhans cells (LCs) and given a booster OVA injection 2 days later via the hind footpad. Five days later, the cytokine response in the draining popliteal lymph nodes was investigated by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA). IL-12 production from cultured LCs was detected by ELISA and Western blot analysis. RESULTS: Administration of PEG- and OVA-pulsed LCs into the hind footpads of the mice induced a T(H)2-prone immune response as represented by the enhanced interleukin (IL) 4 expression in the lymph nodes. We further showed that higher levels of IL-12 p40 production by PEG-stimulated LCs relative to IL-12 p70 (p35/p40) production were associated with the induction of the T(H)2 immune response.The LC-derived IL-12 p40 protein induced by PEG stimulation was detected mainly as monomeric and homodimeric IL-12 p40 subunits; other heterodimers including the L-12 p40 subunit, such as IL-23, were undetected. CONCLUSION: These results suggest that PEG may have the ability to induce the development of T(H)2 cells through insufficient production of IL-12 p70 and excessive production by LCs of homodimeric IL-12 p40, a known antagonist of bioactive IL-12 p70, offering a possible explanation for the role of S aureus colonization in patients with atopic dermatitis. PMID- 22533230 TI - Different rates of autoreactivity in patients with recurrent idiopathic angioedema associated or not with wheals. AB - BACKGROUND: The pathophysiology and triggers of idiopathic nonhistaminergic angioedema are unclear. This study aimed to assess autoreactivity in recurrent idiopathic angioedema associated or not with wheals. METHODS: The study population comprised 19 patients with recurrent idiopathic nonhistaminergic angioedema without wheals, 38 patients with angioedema and chronic urticaria (CU), and 52 patients with CU without angioedema. Twenty healthy individuals served as controls. Autoreactivity was evaluated in vivo using the autologous serum skin test (ASST) and in vitro by measuring serum-induced basophil histamine release (BHR). RESULTS: ASST results were negative in all patients with idiopathic angioedema without wheals and in healthy controls and positive in 29 of the 38 patients with angioedema and CU (76.3%) and in 26 of the 52 patients with CU without angioedema (50%) (P < .0001 for both CU groups). BHR was negative in the healthy controls and positive in 2 of the 19 patients with idiopathic angioedema without wheals (10.5%), in 18 of the 38 patients with angioedema and CU (47.3%) (P < .0001), and in 11 of the 52 patients with CU without angioedema (21.1%) (P < .03). CONCLUSION: The different rates of autoreactivity observed in patients with idiopathic nonhistaminergic angioedema without wheals and in patients with CU either with or without angioedema suggest that these disorders have a different pathophysiology. The failure to detect circulating vasoactive factors and histamine-releasing autoantibodies explains why H1 antihistamines are scarcely effective in most patients with idiopathic angioedema without wheals. However, they represent the cornerstone of CU treatment. PMID- 22533231 TI - A prospective study in children with a severe form of atopic dermatitis: clinical outcome in relation to cytokine gene polymorphisms. AB - BACKGROUND AND OBJECTIVE: The course of atopic dermatitis (AD) in childhood is characterized by typical changes in phenotype, including a shift from skin involvement to respiratory allergy usually around the third year of age. We thus designed a prospective study to monitor the outcome of severe AD and to investigate the association between cytokine gene polymorphisms and clinical manifestations. METHODS: Clinical and laboratory follow-up of 94 patients with severe AD and 103 healthy controls was performed using routine methodology. Allele, genotype, and haplotype frequencies of single nucleotide polymorphisms of 13 selected cytokine/receptor genes were analyzed using PCR with sequence specific primers. RESULTS: In our study, genotypes of 7 polymorphisms--LL-4 1098G/T and -590C/T, IL-6 -174C/G and nt565A/G, and IL-10 -1082A/G, -819C/T, and 592A/C were significantly associated with atopic AD (P < .05). A significant association was also found for TNF-alpha AA and IL-4 GC haplotypes and AD. We confirm the progressive clinical improvement of AD together with a decrease in the severity index SCORAD (SCORing atopic dermatitis) during childhood (P < .05). We found significant differences between IL-4Ralpha +1902 A/G and positivity of tree pollen-specific IgE (P < .05) in the AD group. Moreover, a weak association was also found between IL-10 -819C/T and IL-10 -590A/C and the appearance of allergic rhinitis (P < 0.1). CONCLUSIONS: We confirmed a clinical shift in allergic phenotype in the first 3 years of life, and showed an association between IL-4, IL-6, and IL-10 polymorphisms and AD. Our data indicate that IL 4alpha and IL-10 polymorphisms may be considered predictive factors of respiratory allergy in children with AD. PMID- 22533232 TI - Nasal nitric oxide measurements in the assessment of nasal allergen challenge. AB - BACKGROUND: Several objective methods are used to assess the result of nasal allergen challenge. OBJECTIVE: The aim of this study was to compare the diagnostic value of nasal nitric oxide (nNO) measurements with that of peak nasal inspiratory flow (PNIF), nasal lavage fluid beta-tryptase levels, and changes in cell count after nasal challenge with grass pollen. METHODS: The study population comprised 24 patients allergic to grass pollen and 24 healthy controls. All participants underwent grass allergen challenge preceded by administration of placebo. A visual analog scale was administered. nNO and PNIF were determined, and nasal lavage fluid was collected before and 30 minutes after administration of placebo and allergen. The study was performed outside the pollen season. RESULTS: Significant changes in nNO, PNIF, nasal lavage fluid beta-tryptase level, and cell count were observed only in allergic patients after administration of the allergen. Receiver operating characteristic (ROC) curves were drawn for each determination. A change in nNO levels of -11.987% was indicated as the best cutoff point for differentiating between allergic patients and healthy participants with a sensitivity of 60.9%, specificity of 100%, negative predictive value of 71%, and positive predictive value of 100%. Comparison of the area under the ROC curve did not show significant differences between the diagnostic value of changes in nNO levels and other objective methods of assessing the outcome of the challenge. CONCLUSION: Changes in nNO levels do not differ significantly from other methods used to objectively assess the outcome of nasal challenge. Given their insufficient sensitivity, nNO measurements have limited value as the sole diagnostic tool when assessing the outcome of nasal challenge. PMID- 22533233 TI - Accidental allergic reactions in children allergic to hen's egg. AB - BACKGROUND: Hen's egg is one of the main causes of food allergy in children. Accidental exposure is common in food-allergic patients. However, the few studies that analyze this problem focus mainly on peanut allergy. We sought to calculate the frequency of accidental exposure reactions in children allergic to hen's egg during a 12-month period, to analyze the clinical characteristics and circumstances surrounding the reactions, and to identify risk factors for the most severe reactions. METHODS: Ninety-two egg-allergic children (55 boys; median age, 52 months) were included in the study. A systematic questionnaire about accidental exposure was administered. Reactions were classified as mild, moderate, and severe. Egg white-specific immunoglobulin (Ig) E antibody titers were determined. RESULTS: Nineteen (21%) children had 24 reactions in the previous year (42% mild, 50% moderate, and 8% severe). Most reactions took place at home (50%) under routine circumstances (83%). Children with severe or moderate reactions had higher specific IgE levels to egg white (adjusted odds ratio for every 0.1-unit increase in the decimal logarithm, 1.15; 95% CI, 1.03-1.28; P = .008) and lower serum total IgE (adjusted odds ratio for every 1-unit increase in the decimal logarithm, 0.16; 95% CI, 0.05-0.54; P = .001) than those children with mild or no reactions. CONCLUSIONS: Reactions to accidental exposure are frequent in children with egg allergy. The proportion of severe or moderate reactions was 58%. The risk factors for such reactions included high titers of specific IgE to egg white and low titers of serum total IgE. PMID- 22533234 TI - Risk factors for infantile atopic dermatitis and recurrent wheezing. AB - BACKGROUND: The pathogenic mechanisms of atopic dermatitis (AD) and recurrent wheezing (RW) during infancy are not fully understood. OBJECTIVE: We evaluated immunological markers associated with AD and RW during infancy. METHODS: We followed a cohort (n = 314) from birth to 14 months of age. Some of the participants underwent a physical examination and blood test at 6 and 14 months of age. Univariate and multivariate logistic regression analysis and receiver operating characteristic curve analysis were performed to find which immunological markers could be risk factors for AD and RW. RESULTS: Of 16 immunological markers found in cord blood, only immunoglobulin (Ig) E was associated with AD at 6 months of age (adjusted OR [aOR], 1.607). None of the markers was associated with AD or RW at 14 months of age. Of 23 immunological markers at 6 months of age, total IgE (aOR, 1.018) and sensitization to egg white (aOR, 23.246) were associated with AD at 14 months of age. Phytohemagglutinin (PHA)-induced production of interleukin (IL) 4 from peripheral blood mononuclear cells (PBMCs) (aOR, 1.043) was associated with RW at 14 months of age. CONCLUSION: Cord blood IgE was a risk factor for AD at 6 months of age. Total IgE and sensitization to egg white at 6 months of age were risk factors for AD at 14 months of age. PHA-induced IL-4 production in PBMCs at 6 months of age was a risk factor for RW at 14 months of age. PMID- 22533235 TI - Analysis of polymorphisms in T(H)2-associated genes in Russian patients with atopic bronchial asthma. AB - BACKGROUND: Bronchial asthma is a chronic respiratory disorder characterized by airway inflammation, airway hyperresponsiveness, and periodic reversible airway obstruction. Subtype 2 helperT cell (T(H)2) cytokines play an important role in the development of allergic airway inflammation in patients with bronchial asthma. OBJECTIVE: To investigate whether the single-nucleotide polymorphisms (SNPs) Ile75Val and Gln576Arg in the IL4RA gene, -33C>T in the IL4 gene, and Gly237Glu in the FCER1B gene contribute to the development and severity of atopic bronchial asthma in Russian patients from Moscow. METHODS: We analyzed DNA samples from 224 patients with atopic bronchial asthma and 172 healthy individuals. Genotyping was performed by primer extension followed by matrix assisted laser desorption/ionization-time of flight mass spectrometry. RESULTS: We observed a moderate association between the Arg/Arg genotype of Gln576Arg and protection against asthma (odds ratio [OR], 0.16; P < .012) and a strong association between the T allele and TT genotype of -33C> and atopic bronchial asthma (OR, 1.91 and 4.65, respectively; P < .0001). Carriers of the C allele had a reduced risk of asthma (OR, 0.53; P < .0001). Furthermore, we found that the TT genotype of -33C>T correlated with higher concentrations of total serum immunoglobulin E and interleukin 4 than the CC and CT genotypes. CONCLUSION: We found an association between atopic bronchial asthma and the SNPs Gln576Arg in IL4RA and -33C>T in IL4. IL4RA and IL4 seem to be involved in the pathogenesis of asthma. PMID- 22533236 TI - Malignancy phenotype in common variable immunodeficiency. PMID- 22533237 TI - Importance of controlled sting challenge and component-resolved diagnosis in the success of venom immunotherapy. PMID- 22533238 TI - Differences between general practitioners and allergists in treating moderate to severe persistent rhinitis. PMID- 22533239 TI - Necrobiotic cutaneous granulomas in Nijmegen breakage syndrome. PMID- 22533240 TI - Allergy to red currant: immunoglobulin E-mediated hypersensitivity to lipid transport proteins (Pru p 3). PMID- 22533241 TI - Occupational allergic contact urticaria to crustacean in a cook. PMID- 22533242 TI - Hyperimmunoglobulin E syndrome presenting with renal abscess. PMID- 22533243 TI - A case of allergic bronchopulmonary aspergillosis treated with omalizumab. PMID- 22533244 TI - Threshold doses in specific oral tolerance induction in children with egg allergy. PMID- 22533245 TI - Diagnosis of autosomal-dominant hyperimmunoglobulin E syndrome. PMID- 22533246 TI - Different patterns of sensitization in allergy to dry fermented sausage. PMID- 22533247 TI - [The establishment of the hospital-system in the Byzantine Empire]. AB - Byzantine hospitals developed out of Christian institutions for the poor and homeless. Philanthropy provided the initial impulse to create hospices (xenons) and to expand these institutions into specialized medical centers (iatreons or nosokomeions). However the Byzantine nosocomeions resemble more closely modern hospitals than they do any of the institutions of Greek-Roman antiquity or any of the houses of charity in the Latin West during the Middle Ages. Since the 4th century the Byzantine hospitals have stressed the central position of the nosocomeion in Byzantine society at the intersection of state, ecclesiastical and professional interest. In the great cities and in the capital, more than hundred hospitals worked in the East-Roman Empire. The Byzantine hospital rules guaranted patients private beds, required physicians to wash their hands after each examination and arranged the physical plant to keep all the sick warm. The Byzantine hospitals had separate sections (in modern terms: surgery-trauma surgery, internal medicine, ophthalmology, etc.) and at the beginning of the sixth century a separate institution for women. From the sixth century at least, bathing facilities normally adjoined Byzantine nosocomeia. By the twelfth century Byzantine hospitals also set aside a room or perhaps a separate building to treat outpatients. In addition to the main dormitories the surgery, baths and outpatient clinic, the large parts of hospitals also had separate rooms (or adjoining buildings) for library, for lecture hall, for administrative functions and record keeping for storage and for other services. PMID- 22533248 TI - [David Gruby -- a legend in medical history]. PMID- 22533249 TI - [Jozsef Brandt, school-founding professor of surgery -- for the centennary of his death]. AB - The present article outlines the biography of the great Transylvanian surgeon Jozsef Brandt and appraises his professional work. After his medical training in Vienna and specialisation in surgery Brandt returned to Kolozsvar (now: Cluj/Romania) in 1867 to teach surgery and ophthalmology at the Medical-Surgical Institute of this town. As soon as the Royal Hungarian University in Kolozsvar was opened in 1872, Brandt was appointed as professor of the Department of Surgery. He was elected vice-dean of the medical school and rector of the university. More than 100 of his students specialized in surgery taught and mentored by the school-founding professor. Brandt retired in 1904. Brandt was the medical president of the first Kolozsvar Ambulance Service (1891) and the initiator, then director of the Red Cross Hospital in Kolozsvar (1895) where he worked until his death (1912). He is considered to be the first great surgeon in Transylvania, although he had to work under poor conditions, since the first modern surgical clinic was opened in the town only in 1899. Brandt was the first to perform successful ovariectomy in Transylvania (1869), and the second in Europe who performed nephrectomy (1873). He accepted Lister's antiseptic theory; in 1890 the university sent him to Berlin to study Koch's vaccine. The Appendix of the present article lists Brandt's assistants and students. PMID- 22533250 TI - [Dostoevsky's epileptic experiences and his descriptions of epilepsy in the mirror of modern neurology]. AB - The aim of the study is to present Fyodor Mihailovich Dostoevsky's epilepsy through the results of the related historical and contemporary medical literature, further, to show how the illness is reflected in the writer's biographical data and in the famous patient characters displayed in his great romans. Nowadays it is well presumed that the writer could have had temporal lobe epilepsy with secondary generalized seizures, the symptoms of which he by no means was producing throughout his life. This can be tracked easily by his own descriptions of his seizures, from the memories of his wife and his contemporaries, as well as the symptoms of his epileptic characters in his novels. This theme has been widely dealt with by neurologists, epileptologists and literary experts all over the world. Author details the literature research, the related works and establishes her own concept concerning Dostoevsky's epilepsy. PMID- 22533251 TI - [Attitudes of intellectuals, public life, science. Medical public life and publicity in the 19th century]. AB - The professional publicity of medical society of the 19th century was assured partly by the medical press partly by different associations. At the end of the century the scientific thinking's accent was put on the prevention, and as a result of this, the physicians' activity focused on informing the public. Contemporary physicians still believed in strong connection between science and everyday life, so they were convinced, that every single individual of the society might and should be addressed. The message this time was mediated mostly by printed media. This program of the medical society attempted to involve the school as well. Anyway, despite some successes, till the end of 19th century health education in schools hasn't been introduced. The oeuvre of Doctor Dubay was an excellent example of this process, since he was also convinced, that media was the possible tool of reaching his professional objectives. His main aim was to raise the level of Hungarian public health. Present article describes Dubay's struggle for using media on behalf of wet nurses, mothers and of their children. PMID- 22533252 TI - [Health care of the students at the Elisabeth University in Pecs between 1924 and 1950]. AB - In this study, we present the arrangements of the Erzsebet University, seated in Pecs since 1923, on student health protection via analyzing the archive resources. Due to the scattered resources, we cannot give an account on the preceding Pozsony (1914-20) or Budapest (1920-23) era. In this period, the resources mention only the boarding-students' medical attendance by an internist teaching assistant. After the University moved to Pecs, Dr. Janos Angyan was the one, who considered the (health protection) issue significant. In his proposition, he suggested the University should set up a hospital association and the pre-examination of the boarding-students. The actual examination of the students was introduced along with the compulsory physical education. While it was compulsory for male students, female students could participate voluntarily since the fall of 1927. From 1923, the cost of medical arrangements of the students of the fourth faculty, of the Evangelical Theological Faculty, was covered by a separate fund financed by university students. In the early 1930s, it was Dr. Janos Angyan again who made a proposition that the examinations should be institutionalized, which in the new settings took place in the school year of 1936-37. In three consecutive years all the students were subject to examinations. The participation rate differed among the faculties. It was high among the freshmen of the Medical Faculty and of the Humanities, however, it was 22 percent of the Faculty of Law at the beginning and even later, in the fall of 1948 it was only 48 percent. Besides the management of the University, other universities and non-governmental organizations of the country stood up to fight against contagions of the era, such as the Tuberculosis and venereal diseases. These initiatives were carefully considered by the management of the university, which took proper action in each and every case. In the 1940s the examinations continued, which were suspended during the war. The management planned to restart the examinations in 1947, however, no data survived from this period. PMID- 22533253 TI - [A historiographical overview of the historical literature of dentistry]. AB - Historiographical works of dentistry present cultural, intellectual, technical, institutional aspects of dentistry as well. They evaluate and reconstruct the past of the profession from the prehistoric times till the end of the 20th century. Present article sketching the history of dental historiography summarizes the most important works, reference books and articles published on the field of history of dentistry, evaluates and annotates the single publica tions, grouping them by their (French, German, English and Hungarian) languages. PMID- 22533254 TI - Empty threat: Hospitals could see more vacancies as demand for outpatient care grows and financial pressure builds to curb inpatient admissions. AB - Markets with too many hospital beds could see trouble as providers seek to control spending and avoid expensive hospitalizations. "You'll need a lot fewer hospitals and hospital beds" because providers will do more to keep patients healthy enough not to need them, says Frank Trembulak, of Geisinger Health System. PMID- 22533255 TI - Can a GPO deliver? Ascension backs plan as others study own strategies. PMID- 22533256 TI - Battle royal ends: Tenet's lawsuit against Community dismissed. PMID- 22533257 TI - 'Dramatic change': meeting emphasized evolution of healthcare. PMID- 22533259 TI - Ready to hit the road? Communities need to address geographic disparities in care access, quality. PMID- 22533258 TI - Making it personal: grass-roots appeal aims to boost S.C. town's health. PMID- 22533260 TI - No credit due: lower spending increases are rooted in a bad economy. PMID- 22533262 TI - How do they measure up? Program gauges surgery services at rural hospitals. PMID- 22533261 TI - Looking for an oasis: large sections of rural America continue to suffer from a drought of general surgeons. PMID- 22533263 TI - What do great leaders have in common? They're authentic. PMID- 22533265 TI - Squeezing drug costs: Rx spending targeted in Dems' deficit-cutting plans. PMID- 22533264 TI - 'Shift work': 24-hour workdays are out as residents, hospitals deal with changes, mixed feelings on restrictions. AB - Shorter work hours for first-year residents are causing a big shift as hospitals adapt to the new limits. It has meant a hiring boom for hospitalists and a need to pack more tasks into shorter shifts. And physicians are now finding themselves performing more basic tasks that used to be handled by residents, causing something of a professional identity crisis, says Dr. Bradley Sharpe, of the University of California at San Francisco. PMID- 22533267 TI - Looking for equality: campaign shines spotlight on reducing disparities. PMID- 22533266 TI - Express Scripts deal draws fire: only one other large competitor would remain. PMID- 22533268 TI - Partner confusion? AMA says it's not part of new AHA doc effort. PMID- 22533269 TI - Joint effort: NRC wants teamwork for home-health regs. PMID- 22533270 TI - Eye to eye: industry officials applaud FDA's mobile medical app guidelines. PMID- 22533271 TI - 'Ripple effect': Medicare reimbursement cuts would be unfair, harmful: SNF reps. PMID- 22533272 TI - IOM focuses on prevention. PMID- 22533273 TI - Hard times: politicos aim to slash health programs, but Modern Healthcare is on a roll. PMID- 22533274 TI - Seeing clearly: public reporting on processes, outcomes shows clinicians where they can improve. PMID- 22533275 TI - What's the agenda? PMID- 22533276 TI - Seeking approval: for new drugs and devices, a faster track to market often found in Europe. PMID- 22533277 TI - In the right direction: way-finding isn't just about signage any longer. PMID- 22533278 TI - [The visiting nurse, an essential player in public health]. PMID- 22533279 TI - [The efficiency of the French health system is in doubt]. PMID- 22533280 TI - [Sophrology in geriatrics, an innovative approach to reducing pain and anxiety]. AB - Sophrology is a non medication-based method which involves both the body and mind. It combines relaxing the muscles, increasing awareness of breathing and positive thinking, and leads to the search for improved well-being through the integration of the body percept. It generates a feeling of "letting go" and helps to relieve physical, psychological and spiritual suffering, in particular in geriatrics. PMID- 22533281 TI - [Diabetes in elderly people]. AB - The treatment of elderly diabetic people concerns not only doctors but also paramedical professionals. As these patients represent a heterogeneous group, treatment must be adapted to each person. The frequent occurrence of physical, sensory and cognitive disabilities must be taken into account in order to define the objectives and method of treatment. Therapeutic education must enable the patient or the carers to have a better understanding of the pathology and the therapy in order to avoid the occurrence of complications and accidents. The paramedical guide for the care of elderly diabetic people brings together all the information enabling caregivers to improve their knowledge and their practices. PMID- 22533282 TI - [Chronic wounds, for wound healing without delay]. PMID- 22533283 TI - [Traumatic head injuries. A long and complex journey]. PMID- 22533284 TI - [Epidemiology of traumatic head injuries]. AB - Head injuries are a major public health problem the incidence of which is difficult to compare across the world. Accidents on the public highway, falls and assaults are the most frequent etiologies. The financial and social cost is significant and underestimated. PMID- 22533285 TI - [Head trauma, anatomy and physiopathology, clinical and paraclinical diagnoses]. AB - The brain, situated in the skull, can suffer a trauma through direct or indirect shocks. Primary and secondary lesions determine the evolution of the trauma. The initial clinical assessment and repeated clinical examinations are the basis of the monitoring. The diagnosis of any head lesion is made by CT-scan. A head injury must always be considered to be associated with other lesions until there is evidence to the contrary. PMID- 22533286 TI - [From emergency services to neurosurgical intensive care, the role of the nurse in neurosurgery]. AB - Treating a patient with a head injury requires a full general assessment, a rigorous evaluation of the severity of the trauma and the prevention of brain insults of systemic origin. Monitoring by the nurse is essential and determines the carrying out of additional tests. She must look out for neurological deterioration and prepare the patient and his or her family for potential sequelae. PMID- 22533287 TI - [Mild head trauma, from assessment to treatment]. AB - In adults, 80% to 90% of head injuries are mild. They are mainly due to road accidents, falls and sports activities. They represent, due to their potential consequences and their incidence, a major health problem. Victims are most often young men, teenagers or children, as well as elderly people. PMID- 22533288 TI - [Care of the tracheostomy in brain injury patients]. AB - The evolution of a patient suffering from a serious head injury can require the placement of a tracheotomy. This helps with respirator weaning and usually enables the patient to be moved from the neurosurgical intensive care ward to the neurosurgery ward. Patients fitted with a tracheotomy will therefore be cared for by post-intensive care neurological rehabilitation departments. PMID- 22533289 TI - [The multi-disciplinary treatment of adult head trauma, from treatment to reintegration]. AB - The treatment of patients with head trauma in neurological rehabilitation units must implement a coordinated care approach, involving rehabilitation and early reintegration. This integration is overseen by a specialised and multi disciplinary team. PMID- 22533290 TI - [Psychological support for victims of head trauma]. AB - Patients who are victims of a head trauma are affected throughout their whole person. The reconstruction of their identity is complicated by the implication of neuropsychological disorders. The support takes into account the nature and the severity of the modifications generated by such an event with regard to personal, family, social and professional implications. It is integrative and can be modified over time. PMID- 22533291 TI - [A medical-social program to support head trauma victims]. AB - The Mutualite Francaise Finistere/Morbihan has developed measures for the reintegration, orientation and provision of residential care for victims of brain injuries. Such measures thereby provide support for the person's life project. PMID- 22533292 TI - [Health and social work personnel at the center of re-integration of the traumatic brain injury patient]. PMID- 22533293 TI - [The role of the family of a patient with a head injury]. AB - When someone suffers a head injury, it is not always easy for the family to find its place and adopt a suitable attitude. The French national association of families and victims of head injuries and brain-damaged people (UNAFTC) was created in 1986 in order to support families and to assist in the patient's social and/or professional reintegration. PMID- 22533295 TI - [Bibliography. Traumatic brain injuries]. PMID- 22533294 TI - [A novel diagnostic tool for victims of traumatic brain injuries]. PMID- 22533296 TI - [Organizing patient education programs]. PMID- 22533297 TI - Preparing to lead... the NCNA Leadership Academy embarks. PMID- 22533298 TI - Young whipper-snappers and old warhorses: understanding generational differences and finding common ground. PMID- 22533299 TI - Mobilization and transport of naturally occurring enterococci in beach sands subject to transient infiltration of seawater. AB - This study explores the transport of enterococci (ENT) from naturally contaminated beach sands to the groundwater table via infiltrating seawater using field, laboratory, and modeling experiments. ENT were readily mobilized and transported through the unsaturated zone during infiltration events in both the field and laboratory column experiments. Detachment mechanisms were investigated using a modified version of HYDRUS-1D. Three models for detachment kinetics were tested. Detachment kinetics that are first order with respect to the rate of change in the water content and attached surface bacterial concentrations were found to provide a best fit between predicted and observed data. From these experimental and model results we conclude that detachment mechanisms associated with the rapid increases in pore water content such as air-water interface scouring and thin film expansion are likely drivers of ENT mobilization in the investigated system. These findings suggest that through-beach transport of ENT may be an important pathway through which ENT from beach sands are transported to beach groundwater where they may be discharged to coastal waters via submarine groundwater discharge. PMID- 22533300 TI - Effect of particle properties of powders on the generation and transmission of Raman scattering. AB - Transmission Raman measurements of a 1 mm thick sulfur-containing disk were made at different positions as it was moved through 4 mm of aspirin (150-212 MUm) or microcrystalline cellulose (Avicel) of different size ranges (<38, 53-106, and 150-212 MUm). The transmission Raman intensity of the sulfur interlayer at 218 cm(-1) was lower when the disk was placed at the top or bottom of the powder bed, compared to positions within the bed and the difference between the sulfur intensity at the outer and inner positions increased with Avicel particle size. Also, the positional intensity difference was smaller for needle-shaped aspirin than for granular Avicel of the same size. The attenuation coefficients for the propagation of the exciting laser and transmitted Raman photons through the individual powders were the same but decreased as the particle size of Avicel increased; also, the attenuation coefficients for propagation through 150-212 MUm aspirin were almost half of those through similar sized Avicel particles. The study has demonstrated that particulate size and type affect transmitted Raman intensities and, consequently, such factors need to be considered in the analysis of powders, especially if particle properties vary between the samples. PMID- 22533301 TI - A semisynthetic fluorescent sensor protein for glutamate. AB - We report the semisynthesis of a fluorescent glutamate sensor protein on cell surfaces. Sensor excitation at 547 nm yields a glutamate-dependent emission spectrum between 550 and 700 nm that can be exploited for ratiometric sensing. On cells, the sensor displays a ratiometric change of 1.56. The high sensitivity toward glutamate concentration changes of the sensor and its exclusive extracellular localization make it an attractive tool for glutamate sensing in neurobiology. PMID- 22533309 TI - Trends in attitudes toward people living with HIV, homophobia, and HIV transmission knowledge in Quebec, Canada (1996, 2002, and 2010). AB - People living with HIV (PWHIV) face negative attitudes that isolate and discourage them from accessing services. Understanding negative attitudes and the social environment can lead to more effective health promotion strategies and programs. However, a scale to measure attitudes has been lacking. We developed and validated attitudes toward PWHIV Scale to examine trends in attitudes toward PWHIV in Quebec in 1996, 2002, and 2010. We also examined the relationship between negative attitudes toward PWHIV, homophobia, and knowledge about HIV transmission. The scale included 16 items and had a five-factor structure: F1 (fear of being infected), F2 (fear of contact with PWHIV), F3 (prejudicial beliefs toward groups at high risk of HIV), F4 (tolerance regarding sexual mores and behaviors), and F5 (social support for PWHIV). The validity and reliability of the scale were assessed and found to be high. Overall, Quebecers had positive attitudes toward PWHIV, with more negative attitudes observed in subgroups defined as male, >=50 years of age, <14 years of education, higher levels of homophobia, and below-average knowledge about HIV transmission. Scores were stable between 1996 and 2002, and increased in 2010. Negative attitudes were correlated with higher levels of homophobia and lesser knowledge about HIV transmission. The lowest scores for each factor were observed in the same subgroups that had low overall scores on the Attitudes Scale. The findings from this study can be used to intensify interventions that promote compassion for PWHIV, address attitudes toward homosexuality, and encourage greater knowledge about the transmission of HIV in these subgroups. PMID- 22533310 TI - Determination of contact angles, silane coverage, and hydrophobicity heterogeneity of methylated quartz surfaces using ToF-SIMS. AB - Methylated quartz surfaces are extensively used in colloid science for wettability studies and the control and impact of hydrophobicity in key physicochemical processes. In this study, time-of-flight secondary ion mass spectrometry (ToF-SIMS) has been used to correlate the surface chemistry of trimethylchlorosilane-methylated quartz surfaces with the contact angle. Models have been developed for the calculation of both advancing and receding contact angles based on measurements of the ToF-SIMS signals for SiC(3)H(9)(+) (TMCS) and Si(+) (quartz). These models enable the contact angle across surfaces and, more importantly, that of individual particles to be determined on a micrometer scale. Distributions of contact angles in large ensembles of particles, therefore, can now be determined. In addition, from the ToF-SIMS analysis, the surface coverage of the methylated species can be quantitatively determined, in line with the Cassie equation. Moreover, advancing and receding contact angle maps can be calculated from ToF-SIMS images, and hence the variation in microscopic hydrophobicity (e.g., at the particle level) can be extracted directly from the images. PMID- 22533311 TI - Dietary supplementation of Zingiber officinale and Zingiber zerumbet to heat stressed broiler chickens and its effect on heat shock protein 70 expression, blood parameters and body temperature. AB - The present study was conducted to assess the effects of dietary supplementation of Zingiber officinale and Zingiber zerumbet and to heat-stressed broiler chickens on heat shock protein (HSP) 70 density, plasma corticosterone concentration (CORT), heterophil to lymphocyte ratio (HLR) and body temperature. Beginning from day 28, chicks were divided into five dietary groups: (i) basal diet (control), (ii) basal diet +1%Z. zerumbet powder (ZZ1%), (iii) basal diet +2%Z. zerumbet powder (ZZ2%), (iv) basal diet +1%Z. officinale powder (ZO1%) and (v) basal diet +2%Z. officinale powder (ZO2%). From day 35-42, heat stress was induced by exposing birds to 38+/-1 degrees C and 80% RH for 2 h/day. Irrespective of diet, heat challenge elevated HSP70 expression, CORT and HLR on day 42. On day 42, following heat challenge, the ZZ1% birds showed lower body temperatures than those of control, ZO1% and ZO2%. Neither CORT nor HLR was significantly affected by diet. The ZO2% and ZZ2% diets enhanced HSP70 expression when compared to the control groups. We concluded that dietary supplementation of Z. officinale and Z. zerumbet powder may induce HSP70 reaction in broiler chickens exposed to heat stress. PMID- 22533312 TI - Prescription drug mayhem and rural America. PMID- 22533315 TI - Lignin structural variation in hardwood species. AB - A comprehensive lignin structure analysis of ten industrially relevant hardwood species is presented. Milled wood lignin (MWL) was isolated from each species using a modified protocol and all milled wood lignin preparations were analyzed through quantitative (13)C NMR spectroscopy, elemental analysis, methoxyl analysis, sugar analysis, and nitrobenzene oxidation. Nitrobenzene oxidation and ozonation were carried out on extractive-free wood, alkali-extracted wood, milled wood lignin, and alkali-extracted lignin. Milled wood lignin isolated by the modified protocol was found to be representative of the total lignin in alkali extracted wood. Significant variations in lignin structures, such as syringylpropane/guaiacylpropane ratio (S/G ratio), arylglycerol-beta-aryl ether (beta-O-4), degree of condensation, and elemental and methoxyl contents, were found among the hardwood species studied. These structural variations among species appear to be correlated to a single factor, the syringyl/guaiacyl ratio. A new method to predict the S/G ratio of total lignin in wood was developed, using a calibration line established by the syringaldehyde/vanillin (S/V) ratio (nitrobenzene oxidation) and the S/G ratio ((13)C NMR) of milled wood lignin (MWL). PMID- 22533316 TI - Cytotoxic effects of combination of oxidosqualene cyclase inhibitors with atorvastatin in human cancer cells. AB - Ten oxidosqualene cyclase inhibitors with high efficacy as cholesterol-lowering agents and of different chemical structure classes were evaluated as potential anticancer agents against human cancer cells from various tissue origins and nontumoral human-brain-derived endothelial cells. Inhibition of cancer cell growth was demonstrated at micromolar concentrations, comparable to the concentrations of statins necessary for antitumor effect. Human glioblastoma cells were among the most sensitive cells. These compounds were also able to decrease the proliferation of angiogenic brain-derived endothelial cells, as a model of tumor-induced neovasculation. Additive effects in human glioblastoma cells were also demonstrated for oxidosqualene cyclase inhibitors in combination with atorvastatin while maintaining selectivity against endothelial cells. Thus, not only statins targeting the 3-hydroxy-3-methylglutaryl coenzyme A reductase but also inhibitors of oxidosqualene cyclase decrease tumor growth, suggesting new therapeutic opportunities of combined anti-cholesterol agents for dual treatment of glioblastoma. PMID- 22533318 TI - What is "theory of mind"? Concepts, cognitive processes and individual differences. AB - Research on "theory of mind" has traditionally focused on a narrow participant group (preschool children) using a narrow range of experimental tasks (most notably, false-belief tasks). Recent work has greatly expanded the age range of human participants tested to include human infants, older children, and adults, has devised new tasks, and has adopted methods from cognitive psychology and neuroscience. However, theoretical work has not kept pace with these changes, with the result that studies using one kind of method or participant group often inherit assumptions about the nature of theory of mind from other research, with little regard for whether these assumptions are appropriate. I argue that three distinct approaches to thinking about theory of mind are already implicit in research practice, and that future work, whether with infants, children, or adults, will benefit from articulating these approaches more clearly and following their different implications for what theory of mind is and how it should be studied. PMID- 22533317 TI - Potent inhibition of CYP1A2 by Frutinone A, an active ingredient of the broad spectrum antimicrobial herbal extract from P. fruticosa. AB - 1. Frutinone is an active ingredient extracted from the lipophilic fraction of the Polygala Fruticosa demonstrating various antibacterial and fungal properties. The aim of this study was to characterize its metabolism in an effort to understand metabolism based drug-herb interactions. 2. In vitro metabolic clearance and metabolite identification studies were done using cryopreserved hepatocytes. Reaction phenotyping and inhibition studies were done using human liver microsomes and recombinant cytochrome P450s (CYPs). Frutinone A-CYP1A2 interactions were rationalized using docking simulations. 3. Hepatic clearance was predicted to be low (7.17 mL/min/kg), with reaction phenotyping studies indicating no clearance by the enzymes tested. Frutinone was identified as a potent inhibitor of CYP1A2 with moderate effects on CYP2C19, 2C9, 2D6 and 3A4. CYP1A2 inhibition was reversible and characterised by an IC(50) of 0.56 uM. Inhibition was differential showing mixed (K(i) = 0.48 uM) and competitive (K(i) = 0.31 uM) inhibition with 3-cyano-7-ethoxycoumarin and ethoxyresorufin, respectively. Two binding sites, one for inhibitors and the other for substrates were identified in silico. 4. The potent CYP1A2 inhibition by Frutinone A could be predictive of the potential drug-herb interaction risk in the use of herbal extracts from P. fruticosa. The data suggest future pharmacological research on this chromocoumarin should take metabolic properties into account. PMID- 22533319 TI - Do print journals have a future? PMID- 22533320 TI - Assessment of the value of quantitative thyroid scintigraphy for determination of thyroid function in dogs. AB - OBJECTIVE: To assess the value of thyroid scintigraphy to determine thyroid status in dogs with hypothyroidism and various non-thyroidal illnesses. METHODS: Thyroid hormone concentrations were measured and quantitative thyroid scintigraphy performed in 21 dogs with clinical and/or clinicopathological features consistent with hypothyroidism. RESULTS: In 14 dogs with technetium thyroidal uptake values consistent with euthyroidism, further investigations supported non-thyroidal illness. In five dogs with technetium thyroidal uptake values within the hypothyroid range, primary hypothyroidism was confirmed as the only disease in four. The remaining dog had pituitary-dependent hyperadrenocorticism. Two dogs had technetium thyroidal uptake values in the non diagnostic range. One dog had iodothyronine concentrations indicative of euthyroidism. In the other, a dog receiving glucocorticoid therapy, all iodothyronine concentrations were decreased. Markedly asymmetric technetium thyroidal uptake was present in two dogs. All iodothyronine concentrations were within reference interval but canine thyroid stimulating hormone concentration was elevated in one. Non-thyroidal illness was identified in both cases. CLINICAL SIGNIFICANCE: In dogs, technetium thyroidal uptake is a useful test to determine thyroid function. However, values may be non-diagnostic, asymmetric uptake can occur and excess glucocorticoids may variably suppress technetium thyroidal uptake and/or thyroid hormone concentrations. Further studies are necessary to evaluate quantitative thyroid scintigraphy as a gold standard method for determining canine thyroid function. PMID- 22533322 TI - Evidence for increased probability of cardiac death in dogs with pulmonic stenosis questionable. PMID- 22533321 TI - Severe dermatophytosis due to Trichophyton mentagrophytes var. interdigitale in flocks of green iguanas (Iguana iguana). AB - OBJECTIVE: To describe the clinical, mycological, histopathological and molecular findings in green iguanas (Iguana iguana) affected with severe dermatophytosis in selected flocks near Tehran, Iran. MATERIALS AND METHODS: Samples were collected from the scales of skin lesions and tested with standard mycological methods and dermatophyte-specific PCR amplification analysis using the primer pair for the chitin synthase 1(CHS1) gene. RESULTS: All iguanas were definitively diagnosed with dermatophytosis using both traditional and molecular diagnostic methods. PCR fingerprinting profiles using simple repetitive (GACA)4 primers showed that all diagnosed iguanas had the same pattern profile. Intraspecific variability was not observed for these isolates. Oligonucleotide sequencing of CHS1 gene PCR products confirmed Trichophyton mentagrophytes var. interdigitale as the infectious agent. CLINICAL SIGNIFICANCE: These results suggest that (GACA)4-based PCR has utility both as a simple and rapid method for identification of dermatophyte species and for differentiation of T. mentagrophytes variants. PMID- 22533323 TI - Primary pyonephrosis in a young dog. PMID- 22533325 TI - Physical health and mental illness: a silent scandal. PMID- 22533327 TI - Should we or shouldn't we? Mental health nurses' views on physical health care of mental health consumers. AB - People diagnosed with a mental illness experience poorer physical health than the general population. Nurses have been identified for their potential role in addressing physical health needs of consumers of mental health services. This paper reports on preliminary findings of a qualitative study on health-care services for physical and mental health in a regional area in Australia. A key purpose of the study was to explore the perceptions of nurses working in mental health settings of their physical care with consumers. A qualitative, exploratory approach was undertaken. Semi-structured focus groups were conducted with 38 nurses from one mental health service. Nurse participants described a common co occurrence of physical problems and mental illness and expressed the importance of health-care services to treatment and prevention. Participants expressed divergent views on nurses' capacity to contribute to better health-care processes. PMID- 22533326 TI - Role of the mental health nurse towards physical health care in serious mental illness: an integrative review of 10 years of UK literature. AB - People with serious mental illness have significantly poorer physical health compared to the general population. Mental health nurses are in a prime position to help reduce unacceptable death in this population. A literature search was undertaken to identify the role of the mental health nurse in regards to physical health care, intervention, and attaining the necessary knowledge to address the physical health needs of people in the UK with serious mental illness. Of 254 papers identified, nine met the inclusion criteria. An integrative literature review found that mental health nurses are not routinely supported by physical health-care education and training, with many expressing role ambiguity. Inpatient setting correlated to a less positive role attitude; poor primary secondary care interface communication compounded the problem of this vulnerable population having their physical health needs identified and met. PMID- 22533328 TI - Minding our own bodies: reviewing the literature regarding the perceptions of service users diagnosed with serious mental illness on barriers to accessing physical health care. AB - International studies consistently demonstrate that individuals diagnosed with severe mental illness (SMI) have an increased risk of co-morbid physical health problems and premature death. During the past decade, government policy in the UK has focused on improving the physical health of those with SMI. Despite this, international research has continued to report barriers to accessing appropriate services. These have been identified as emanating from service users and professionals alike, and also from institutional bureaucracy. Most of this research has reported difficulties from the perspective of various professional groups, with little attention being paid to the service user voice. Studies from the service user perspective undertaken in the past 10 years equate to six qualitative and three quantitative studies, and it appears that poor physical health care remains a problem in the developed world. The quality of this care is compromised by practical problems and interpersonal difficulties between service users and health-care providers and between providers of mental health services and those providing physical health care. This paper presents a review of the nine international studies and discusses the implications for developing policy and practices that could lead to improved physical health-care services for people experiencing SMI. PMID- 22533329 TI - Dietary habits of patients with schizophrenia: a self-reported questionnaire survey. AB - The present study was carried out to determine the dietary habits of patients with schizophrenia and the influence of these habits on the degree of obesity. The study was developed in a sample of 159 patients, who were given a self reported questionnaire, to ascertain the influence of socio-familiar aspects, pharmacological treatment, and dietary habits. Anthropometric measurements (body mass index (BMI) and waist circumference (WC)) were also taken. Patients with schizophrenia presented unhealthy dietary habits, as indicated by the finding that 51% of the patients took no longer than 15 min to eat, 40.8% did not eat fruit daily, and 63.1% did not eat fish. Women were three times more likely to be obese than men (odds ratio (OR) = 2.91, P = 0.021). Patients classified as having unhealthy dietary habits have a 2.33-fold higher risk of obesity than patients with good dietary habits (OR = 2.33, P = 0.034). In summary, this paper highlights the fact that patients with schizophrenia have a detrimental dietary pattern that is associated with an increase in BMI and WC, with the consequent development of obesity and related metabolic alterations, regardless of the pharmacological treatment being followed. Future research directions will include exploring the need for nutritional education programmes to improve the dietary habits of such patients. PMID- 22533330 TI - Evaluation of service users' experiences of participating in an exercise programme at the Western Australian State Forensic Mental Health Services. AB - Approximately 210 patients are admitted each year to the Western Australian State Forensic Mental Health Service, and most present with psychotic illness, along with other physical and mental comorbidities. In 2010, a healthy lifestyle programme, which included a formal exercise programme coordinated by an exercise physiologist, was introduced at the service. A self-report questionnaire was developed to obtain feedback on the programme, and 56 patients completed the questionnaire during the 6-month evaluation period. As well as providing patients with access to regular physical activity, the programme also supports the recovery philosophy, where patients work in partnership with forensic mental health staff. Overall, patients reported that the programme assisted them to manage their psychiatric symptoms, as well as improving their level of fitness, confidence, and self-esteem. In addition, patients received education about the importance of regular exercise to their mental health, and the role exercise plays in preventing chronic illness and obesity. While the benefits of exercise on mental health outcomes for people with depression and anxiety are well established, this evaluation adds to the evidence that such programmes provide similar benefits to people who have a psychotic illness and are hospitalized in an acute secure setting. PMID- 22533331 TI - Health behaviour interventions to improve physical health in individuals diagnosed with a mental illness: a systematic review. AB - Individuals diagnosed with mental illness experience high rates of morbidity and mortality as a result of poor physical health and unhealthy lifestyle behaviours. The aim of this paper is to systematically review the literature on health behaviour interventions to improve the physical health of individuals diagnosed with a mental illness. A systematic search strategy was undertaken using four of the major electronic databases. Identified articles were screened for inclusion, included articles were coded, and data were extracted and critically reviewed. A total of 42 articles were identified for inclusion. The most commonly targeted physical health behaviour was weight management. The majority of studies reported improvements in health behaviours following interventions. The findings provide evidence for the positive effect of health behaviour interventions in improving the physical health of individuals diagnosed with a serious mental illness. A focus on health behaviour interventions within the mental health nursing profession might lead to improvements in health behaviours and general health in consumers of mental health services. PMID- 22533332 TI - Meeting the physical health-care needs of people with substance misuse problems: evaluation of a nurse-led blood-borne virus programme. AB - People who inject substances are at high risk of many physical health problems. The Blood-Borne Virus Programme (BBVP) is a nurse-led health screening programme for blood-borne conditions in substance misusers. The aim of this study was to evaluate the service delivery, organization, and outcomes of the BBVP. The researchers used a case study with three units of analysis: BBVP clinical activities during 1 year using a prospective audit; service users' (n = 20) and professional stakeholders' (n = 10) experiences of the BBVP using semistructured interviews; and service users' (n = 132) satisfaction with the BBVP using a satisfaction measure. The BBVP conducted 4450 consultations with 1940 service users; 847 of whom were new, and presented with many health problems compromising their physical health. The BBVP provided a range of interventions meeting its users' physical health needs. Users and other stakeholders were very satisfied with the service, and suggested ways in which the service might improve. The BBVP appeared to meet the physical health-care needs of people dependent on drugs. Nurse-led services, such as the BBVP, offer a solution that, in the view of users and professional stakeholders, is impacting significantly on the physical health and well-being of people dependent on drugs. PMID- 22533333 TI - Training practice nurses to improve the physical health of patients with severe mental illness: effects on beliefs and attitudes. AB - Annual health checks are recommended for patients with severe mental illness (SMI) as they are at high risk of cardiovascular disease. Ideally, these health checks should be carried out in primary care. Practice nurses are already competent in carrying out physical health checks, but might have misconceptions about mental illness, which is a barrier to offering the service. We used a mirror imaging study to establish the effectiveness of a training package for practice nurses that aims to address common misconceptions about the physical health of people with SMI. This 2-hour training package (Northampton Physical Health and Wellbeing Project) was delivered to eight practice nurses. Their misconceptions and beliefs were assessed before and after training. Motivation to work with community mental health workers was assessed after training. The practice nurses involved in the study rejected commonly held misconceptions about the physical health of people with SMI after training. Their attitudes towards their role in providing health checks appeared to be modified in a positive direction. Their motivation to work with community mental health workers also seemed to be enhanced. The Northampton Physical Health and Wellbeing Project training was effective in modifying practice nurses' misconceptions about physical health in people with SMI. PMID- 22533334 TI - Evolving role of mental health nurses in the physical health care of people with serious mental health illness. AB - Life expectancy in members of the general population has steadily improved in most countries since 1960. However, during the same period, the life expectancy of people with serious mental illness (SMI) has actually reduced. The majority of premature deaths result from natural causes, such as coronary heart disease. Obesity, a key risk factor for heart disease in this client group, might be caused both by unhealthy lifestyle behaviours and the side-effects of antipsychotic medication. Mental health nurses (MHN) nurses have an important role to play in improving the physical health of people with SMI. Evidence, however, suggests that they are often ambivalent about this role, and might perceive themselves as being inadequately trained and lacking in confidence. In this paper, we will argue that MHN need to re-evaluate their practice and recognize that the provision of physical health care is as important as other roles they occupy in relation to the care of people with SMI. We will also consider examples of best practice in physical health care, and discuss how these might be adopted by MHN and other professionals, in order to begin to improve services and to reduce health inequalities in this client group. PMID- 22533335 TI - Physical health and wellbeing of emerging and young adults with mental illness: an integrative review of international literature. AB - Physical health in people with mental illness is often compromised. Chronic physical conditions and disease risk factors occur at higher rates than in the general population. Although substantial research exists regarding mental physical comorbidities in middle to older-aged adults and mental illness consequential to childhood physical illness, research addressing physical health in young people/emerging adults of 16-24 years with primary mental illnesses is minimal. Health problems often track from youth to adulthood, indicating a need to better recognize and understand the overall health of young people with mental illness. This paper reports findings from an integrative review of published research investigating physical health of emerging/young adults with mental illness. A total of 18 research papers were systematically analysed. The review found that comorbid mental-physical illness/conditions were evident across a wide age span. Specific physical health problems, including pain, gastrointestinal, and respiratory disorders, were apparent in those 16 years to those in their mid late 20s, and/or with first episode psychosis. Lifestyle risk factors for cardiometabolic disorders occurred with some frequency and originated prior to adulthood. These findings highlight the need for targeted health screening and illness prevention strategies for emerging/young adults with mental health problems and draws attention to the need for young people to be supported in their health-care behaviours. PMID- 22533336 TI - Mental and physical health comordibity: political imperatives and practice implications. AB - Insufficient priority is being given to meet the physical health-care needs of people with mental illness. Mental health nurses, as the largest professional group working in mental health care, have a pivotal role in improving the physical health and well-being of people with mental illness. Through health promotion strategies, alongside recovery-focused support aimed at avoiding deteriorating physical health, mental health nurses can significantly contribute to improving the current rate of premature death experienced by people with enduring mental illness. Drawing from contemporary policy, alongside practical examples taken from the published literature, this paper considers what constitutes recommended best practice in dealing with the physical health-care needs of people with mental illness. The role that UK-based health-care policy plays in shaping care delivery that meets the needs of people with mental illness is explored and placed within the context of global health concerns. Recommendations are made on how mental health nursing can work to provide evidence for a reassertion that nurses are well placed to work across organizational and professional boundaries to deliver person-centred care and a holistic approach to population health and well-being. PMID- 22533337 TI - Marked genetic heterogeneity in familial myelodysplasia/acute myeloid leukaemia. AB - The myelodysplastic syndromes (MDS) are heterogeneous and can evolve into acute myeloid leukaemia (AML). Rare familial cases are reported in which five disease genes have been identified to date (RUNX1, CEBPA, TERC, TERT and GATA2). Here we report the genetic categorization of 27 families with familial MDS/AML. All of these families were screened for RUNX1, CEBPA, TERC, TERT and GATA2 as well as TET2 and NPM1. Five of the 27 families had telomerase mutations; one had a RUNX1 mutation, while none were found to have TET2, CEBPA or NPM1 mutations. We identified four families with heterozygous GATA2 mutations, each associated with a different phenotype. While one of these mutations is novel, three have been previously reported: one has been described in dendritic cell, monocyte, B and NK lymphoid (DCML) deficiency and one is in a family that has been reported in a series with primary lymphoedema with a predisposition to AML (Emberger syndrome). In summary, genetic characterization was shown in 10 (four GATA2, three TERT, two TERC, one RUNX1) of these families; however 17 remain uncharacterized, highlighting marked genetic heterogeneity in familial MDS/AML and the scope for further functional pathways that could give rise to this group of disorders. PMID- 22533338 TI - Ionic parachor and its application II. Ionic liquid homologues of 1-alkyl-3 methylimidazolium propionate {[C(n)mim][Pro] (n = 2-6)}. AB - Five propionic acid ionic liquids (PrAILs) [C(n)mim][Pro] (n = 2-6) (1-alkyl-3 methylimidazolium propionate) have been prepared by the neutralization method and characterized by (1)H NMR spectroscopy and differential scanning calorimetry (DSC). Their density, rho, surface tension, gamma, and refractive index, n(D), were measured at (298.15 +/- 0.05) K, and the experimental values of parachor for the PrAILs were calculated. Using the parachor values of [C(n)mim](+) obtained by Guan et al., the anionic parachor values of [C(n)mim][Pro] (n = 2-6), [C(2)mim][RBF(3)] (R = N-C(n)H(2n+1) (n = 1-5)), [C(n)mim][Gly] (n = 2-6), and [C(n)mim][PF(3)(CF(2)CF(3))(3)] (n = 1-6) were determined. Then, the parachor, surface tension, and refractive index of the ILs investigated in this work were estimated. The estimated values correlate quite well with the corresponding experimental values. PMID- 22533340 TI - Editorial comment for Maurice et al. PMID- 22533339 TI - Sex differences in cardiovascular drug-induced adverse reactions causing hospital admissions. AB - AIMS: Cardiovascular disease in women is often underestimated. The effects of cardiovascular drugs differ between the sexes because of pharmacokinetic and pharmacodynamic differences. Adverse drug reactions (ADRs) within these drug classes may have serious consequences, leading to hospital admission. We aimed to study differences between men and women in hospital admissions for ADRs due to cardiovascular drugs. METHODS: We conducted a nationwide study of all hospital admissions between 2000 and 2005 with data from the Dutch National Medical Register. Relative risks were calculated of hospital admissions due to ADRs to the different cardiovascular drug groups for women compared with men. By an ecological design, risks were adjusted for the total number of Dutch inhabitants and the total number of prescriptions. RESULTS: In total, 14 207 of the hospital admissions (34% of all ADR-related admissions) were attributed to cardiovascular drugs [7690 in women (54%; 95% confidence interval 53-55%)]. 'Anticoagulants and salicylates' (n= 8988), 'high- and low-ceiling diuretics' (n= 2242) and 'cardiotonic glycosides' (n= 932) were responsible for the majority of the ADR related hospital admissions. The most pronounced sex differences were seen in users of low-ceiling diuretics (relative risk 4.02; 95% confidence interval 3.12 5.19), cardiotonic glycosides (relative risk 2.38; 95% confidence interval 2.06 2.74), high-ceiling diuretics (relative risk 2.10; 95% confidence interval 1.91 2.32) and coronary vasodilators (relative risk 0.77; 95% confidence interval 0.65 0.91). CONCLUSIONS: Clear sex differences exist in ADRs requiring hospital admission for different cardiovascular drug groups. Sex differences should be taken into account in the prescription and evaluation of drugs. PMID- 22533341 TI - Reinforcing cerclage in the prevention of preterm birth in women at high risk: a retrospective case-controlled study. AB - BACKGROUND: Transvaginal ultrasound measurement of cervical length is useful after suture insertion in predicting preterm delivery. However, there is little evidence to guide practice in the clinical scenario when fetal membranes are seen on ultrasound to be prolapsing distal to a cervical suture. AIM: To determine whether a reinforcing cerclage reduced preterm delivery in those women with ultrasound evidence of fetal membranes prolapsing distal to the first suture. METHODS: A retrospective cohort study was conducted on women with a cervical suture in situ plus ultrasound evidence of fetal membranes prolapsing through the first suture. Exposed patients were those managed with a reinforcing cerclage. The unexposed group were women who were managed expectantly, without a reinforcing cerclage. RESULTS: Those women with a reinforcing cerclage were significantly more likely to deliver at an earlier gestation compared with those managed expectantly: 26(+0) (+/-5(+1) ) compared with 31(+1) (+/-7(+0) ) weeks, P = 0.047. More women in the reinforcing cerclage group delivered at <32 completed weeks' gestation: 12/13 (92%) versus 5/12 (42%), P = 0.01. There was no significant difference in the rate of second-trimester miscarriages between the expectant management group and those with a reinforcing cerclage: 2/12 (17%) versus 5/13 (38%), P = 0.38. CONCLUSION: Our study found that a reinforcing cerclage following primary cerclage failure hastened preterm delivery. The role of transvaginal ultrasound measurement of cervical length postsuture is debatable if the possible intervention is not beneficial and may be detrimental. PMID- 22533342 TI - The Physalis peruviana leaf transcriptome: assembly, annotation and gene model prediction. AB - BACKGROUND: Physalis peruviana commonly known as Cape gooseberry is a member of the Solanaceae family that has an increasing popularity due to its nutritional and medicinal values. A broad range of genomic tools is available for other Solanaceae, including tomato and potato. However, limited genomic resources are currently available for Cape gooseberry. RESULTS: We report the generation of a total of 652,614 P. peruviana Expressed Sequence Tags (ESTs), using 454 GS FLX Titanium technology. ESTs, with an average length of 371 bp, were obtained from a normalized leaf cDNA library prepared using a Colombian commercial variety. De novo assembling was performed to generate a collection of 24,014 isotigs and 110,921 singletons, with an average length of 1,638 bp and 354 bp, respectively. Functional annotation was performed using NCBI's BLAST tools and Blast2GO, which identified putative functions for 21,191 assembled sequences, including gene families involved in all the major biological processes and molecular functions as well as defense response and amino acid metabolism pathways. Gene model predictions in P. peruviana were obtained by using the genomes of Solanum lycopersicum (tomato) and Solanum tuberosum (potato). We predict 9,436 P. peruviana sequences with multiple-exon models and conserved intron positions with respect to the potato and tomato genomes. Additionally, to study species diversity we developed 5,971 SSR markers from assembled ESTs. CONCLUSIONS: We present the first comprehensive analysis of the Physalis peruviana leaf transcriptome, which will provide valuable resources for development of genetic tools in the species. Assembled transcripts with gene models could serve as potential candidates for marker discovery with a variety of applications including: functional diversity, conservation and improvement to increase productivity and fruit quality. P. peruviana was estimated to be phylogenetically branched out before the divergence of five other Solanaceae family members, S. lycopersicum, S. tuberosum, Capsicum spp, S. melongena and Petunia spp. PMID- 22533343 TI - Isocitrate dehydrogenase 1 is downregulated during early skin tumorigenesis which can be inhibited by overexpression of manganese superoxide dismutase. AB - Isocitrate dehydrogenase 1 (IDH1), a cytosolic enzyme that converts isocitrate to alpha-ketoglutarate, has been shown to be dysregulated during tumorigenesis. However, at what stage of cancer development IDH1 is dysregulated and how IDH1 may affect cell transformation and tumor promotion during early stages of cancer development are unclear. We used a skin cell transformation model and mouse skin epidermal tissues to study the role of IDH1 in early skin tumorigenesis. Our studies demonstrate that both the tumor promoter TPA and UVC irradiation decreased expression and activity levels of IDH1, not IDH2, in the tumor promotable JB6 P+ cell model. Skin epidermal tissues treated with dimethylbenz[alpha]anthracene/TPA also showed decreases in IDH1 expression and activity. In non-promotable JB6 P-cells, IDH1 was upregulated upon TPA treatment, whereas IDH2 was maintained at similar levels with TPA treatment. Interestingly, IDH1 knockdown enhanced, whereas IDH1 overexpression suppressed, TPA-induced cell transformation. Finally, manganese superoxide dismutase overexpression suppressed tumor promoter induced decreases in IDH1 expression and mitochondrial respiration, while intracellular alpha-ketoglutarate levels were unchanged. These results suggest that decreased IDH1 expression in early stage skin tumorigenesis is highly correlated with tumor promotion. In addition, oxidative stress might contribute to IDH1 inactivation, because manganese superoxide dismutase, a mitochondrial antioxidant enzyme, blocked decreases in IDH1 expression and activity. PMID- 22533344 TI - Non drowsy obstructive sleep apnea as a potential cause of resistant hypertension: a case report. AB - BACKGROUND: Obstructive sleep apnea (OSA) and arterial hypertension (AH) are common and underrecognized medical disorders. OSA is a potential risk factor for the development of AH and/or may act as a factor complicating AH management. The symptoms of excessive daytime sleepiness (EDS) are considered essential for the initiation of continuous positive airway pressure (CPAP) therapy, which is a first line treatment of OSA. The medical literature and practice is controversial about the treatment of people with asymptomatic OSA. Thus, OSA patients without EDS may be left at increased cardiovascular risk. CASE PRESENTATION: The report presents a case of 42 year old Asian woman with symptoms of heart failure and angina like chest pain upon admission. She didn't experience symptoms of EDS, and the Epworth Sleepiness Scale was seven points. Snoring was reported on direct questioning. The patient had prior medical history of three unsuccessful pregnancies complicated by gestational AH and preeclampsia with C-section during the last pregnancy. The admission blood pressure (BP) was 200/120 mm Hg. The patients treatment regimen consisted of five hypotensive medications including diuretic. However, a target BP wasn't achieved in about one and half month. The patient was offered to undergo a polysomnography (PSG) study, which she rejected. One month after discharge the PSG study was done, and this showed an apnea hypopnea index (AHI) of 46 events per hour. CPAP therapy was initiated with a pressure of 11 H20 cm. After 2 months of compliant CPAP use, adherence to pharmacologic regimen and lifestyle modifications the patients BP decreased to 134/82 mm Hg. CONCLUSIONS: OSA and AH are common and often underdiagnosed medical disorders independently imposing excessive cardiovascular risk on a diseased subject. When two conditions coexist the cardiovascular risk is likely much greater. This case highlights a possible clinical phenotype of OSA without EDS and its association with resistant AH. Most importantly a good hypotensive response to medical treatment in tandem with CPAP therapy was achieved in this patient. Thus, it is reasonable to include OSA in the differential list of resistant AH, even if EDS is not clinically obvious. PMID- 22533345 TI - Volunteer satisfaction and program evaluation at a pediatric hospice. AB - RATIONALE: Volunteers are essential to the functioning of palliative care programs and serve as important members of the hospice team. They devote much time, effort, and diverse skills and talent to enhance the quality of care at Roger's House--a pediatric palliative care hospice. OBJECTIVES: To evaluate volunteering in a pediatric palliative care hospice and to assess the level of satisfaction from the perspective of hospice volunteers. METHODS: A survey was sent to all active Roger's House volunteers. Questions were related to their demographics, their overall impression of their volunteering experience, and 47 closed (fixed-choice) statements, divided into 6 parts: 1) Orientation; 2) Training; 3) Feedback/Performance; 4) Communication; 5) Social Contacts; and 6) Value and Respect. Each statement was rated by the participants using a six-point Likert rating scale. RESULTS: Volunteers fully completing the survey were 159 online and 4 on paper, giving a response rate of 66%. The greater number (66, 40.5%) of respondents were 50 years or older and they were mostly female (141, 86.5%). Successes identified included the volunteers' orientation, training, and feedback and performance. Challenges identified included certain aspects of communication, social contacts, and respect/value for the volunteer. CONCLUSION: Volunteers at Roger's House are generally satisfied with their volunteer position and the environment in which they work. Greater insight into volunteer satisfaction and factors that bring feelings of reward and/or dissatisfaction to the volunteers have allowed Roger's House to identify informed and effective interventions to improve the quality of and satisfaction with the hospice volunteer program. PMID- 22533347 TI - Chair yoga: benefits for community-dwelling older adults with osteoarthritis. AB - The aim of this pilot study was to examine whether chair yoga was effective in reducing pain level and improving physical function and emotional well-being in a sample of community-dwelling older adults with osteoarthritis. One-way repeated measures analysis of variance was performed to examine the effectiveness of chair yoga at baseline, midpoint (4 weeks), and end of the intervention (8 weeks). Although chair yoga was effective in improving physical function and reducing stiffness in older adults with osteoarthritis, it was not effective in reducing pain level or improving depressive symptoms. Future research planned by this team will use rigorous study methods, including larger samples, randomized controlled trials, and follow up for monitoring home practice after the interventions. PMID- 22533346 TI - MicroRNA-143 targets MACC1 to inhibit cell invasion and migration in colorectal cancer. AB - BACKGROUND: MicroRNAs (miRNAs) have been suggested to play a vital role in tumor initiation and progression by negatively regulating oncogenes and tumor suppressors. Quite recently, studies have identified some miRNAs operating to promote or suppress tumor invasion or metastasis via regulating metastasis related genes, providing potential therapeutic targets on anti-metastasis strategy. Metastasis-associated in colon cancer-1 (MACC1) has been newly identified to express highly in colorectal cancer (CRC) and promote tumor metastasis through transactivating metastasis-inducing HGF/MET signaling pathway. In this study, we investigated whether miRNA 143 is involved in the regulation of MACC1 and thus plays a functional role in CRC. RESULTS: Using both in silico prediction and western blot assay, we found the previously reported tumor suppressive miR-143 targeted MACC1 in CRC. The direct interaction between them was confirmed by 3' UTR luciferase reporter gene. In concordance with the inhibitory effects induced by siRNA mediated knockdown of MACC1, restoration of miR-143 by mimics in SW620 cells significantly attenuated cell growth, migration and invasion. It is notable that combined treatment of miR-143 mimics and MACC1 siRNA induced synergistic inhibitory effects compared to either miR-143 mimics or MACC1 siRNA treatment alone. Conversely, reduction of miR-143 by inhibitors in SW480 cells apparently stimulated these phenotypes. Furthermore, we observed that miR-143 level was inversely correlated with MACC1 mRNA expression in CRC tissues. CONCLUSIONS: Our findings newly described miR-143/MACC1 link and provided a potential mechanism for MACC1 dysregulation and contribution to CRC cell invasion. It may help to estimate the therapeutic utility of miR-143 in CRC. PMID- 22533348 TI - Nighttime activity in individuals with dementia: understanding the problem and identifying solutions. AB - Sleep disturbances may occur in more than 50% of individuals with dementia, and nighttime activity can lead to unsafe situations and serious consequences for both the person and his or her caregivers. Nighttime awakenings expose individuals with dementia to two major dangers: falls and unattended home exits. This article is a review of the current research on the causes of sleep disturbances and interventions for nighttime activity in individuals with dementia living at home. PMID- 22533349 TI - Does the insufficient supply of physicians worsen their urban-rural distribution? A Hiroshima-Nagasaki comparison. AB - INTRODUCTION: Studies have suggested that a rapid increase in physicians does not necessarily change an urban-rural inequity in their distribution. However, it is unknown whether an insufficient supply of physicians worsens an inequity. Spatial competition and attraction-repulsion hypotheses were applied to the geographic distribution of physicians during a time of insufficient physician supply in Japan. METHODS: Trends of physician distribution as well as urban-rural physician flow were compared using Hiroshima Prefecture which had the lowest increase in physician-to-population ratios between 2002 and 2008 (2.7%), and Nagasaki Prefecture where the increase was one of the highest (12.0%) among the 47 Japanese prefectures. RESULTS: The Gini coefficient of physicians compared with population in Hiroshima increased by 4.1%. Movement toward inequity was greater in Hiroshima compared with Nagasaki where the increase was 2.5%. Approximately 245 physicians or 18.8% moved from rural to urban locations in Hiroshima compared with 143 (14.6%) for Nagasaki (p=0.01). In contrast, 228 (7.6%) urban physicians moved to rural areas in Hiroshima compared with 175 (11.6%) in Nagasaki (p<0.001). CONCLUSIONS: In a time of insufficient supply of physicians, a region with a smaller increase in physicians may experience worsening of the urban-rural distribution of physicians compared with a region where there is a more rapid increase in physicians. One strategy for achieving a more equitable distribution of physicians is to increase in the physician supply relative to demand in order to stimulate competition among urban physicians and maintain the power equilibrium between attraction-to and repulsion-from urban areas. PMID- 22533350 TI - Cost and affordability of healthy food in rural South Australia. AB - INTRODUCTION: As in many other countries, Australian consumers have recently had to accommodate increases in costs of basic food, and during the financial year 2007-2008 overall food prices rose by nearly 4%. Food costs are mediating factors in food choice, especially for low-income groups, where food security is often tenuous. There are reports that rural populations may have higher levels of food insecurity, although the evidence is often contradictory. METHODS: To assess cost and affordability of food in rural areas this study used the Healthy Food Basket (HFB) methodology, which has been applied in a number of settings. The HFBs were costed at supermarkets and stores in different locations with different degrees of rurality. RESULTS: Compared with metropolitan areas, healthy food is more expensive in rural areas; costs are even higher in more remote areas. The overall affordability of HFB in rural areas was not significantly different from metro areas. The main difference concerned low socio-economic status (SES) groups, where the proportion of household income spent on the HFB was three times that of higher SES groups. CONCLUSIONS: The unaffordability of healthy food, or 'food stress' in low SES groups is a concern, especially when this group carries the greatest burden of diet-related disease. Findings suggest that there is a need to consider both rurality and SES when developing policy responses to decrease the cost and increase the affordability of healthy foods in rural and remote areas. PMID- 22533352 TI - Evaluation of the effectiveness of an outreach clinical mentoring programme in support of paediatric HIV care scale-up in Botswana. AB - Clinical mentoring by providers skilled in HIV management has been identified as a cornerstone of scaling-up antiretroviral treatment in Africa, particularly in settings where expertise is limited. However, little data exist on its effectiveness and impact on improving the quality-of-care and clinical outcomes, especially for HIV-infected children. Since 2008, the Botswana-Baylor Children's Clinical Centre of Excellence (COE) has operated an outreach mentoring programme at clinical sites around Botswana. This study is a retrospective review of 374 paediatric charts at four outreach mentoring sites (Mochudi, Phutadikobo, Molepolole and Thamaga) evaluating the effectiveness of the programme as reflected in a number of clinically-relevant areas. Charts from one visit prior to initiation of mentoring and from one visit after approximately one year of mentoring were assessed for statistically-significant differences (p<0.05) in the documentation of clinically-relevant indicators. Mochudi showed notable improvements in all indicators analysed, with particular improvements in documentation of pill count, viral load (VL) results, correct laboratory monitoring and correct antiretroviral therapy (ART) dosing (p<0.0001, p<0.0001, p<0.0001 and p<0.0001, respectively). Broad and substantial improvements were also seen in Molepolole, with the most improvement in disclosure documentation of all four sites. At Thamaga, improvements were restricted to CD4 documentation (p<0.001), recent VL and documented pill count (p<0.05 and p<0.05, respectively). Phuthadikobo showed the least amount of improvement across indicators, with only VL documentation and correct ART dosing showing statistically-significant improvements (p<0.05 and p<0.0001, respectively). These findings suggest that clinical mentoring may assist improvements in a number of important areas, including ART dosing and monitoring; adherence assessment and assurance; and disclosure. Clinical mentoring may be a valuable tool in scale-up of quality paediatric HIV care-and-treatment outside specialised centres. Further study will help refine approaches to clinical mentoring, including assuring mentoring translates into improved clinical outcomes for HIV-infected children. PMID- 22533353 TI - Exploring key parameters to detect subtle ligand-induced protein conformational changes using traveling wave ion mobility mass spectrometry. AB - Evidencing subtle conformational transitions in proteins occurring upon small modulator binding usually requires atomic resolution techniques (X-ray crystallography or NMR). Recently, hyphenation of ion mobility and mass spectrometry (IM-MS) has greatly enlarged the potentials for biomolecular assembly structural characterization. Using the well 3D-characterized Bcl-xL/ABT 737 protein model, we explored in the present report whether IM-MS can be used to differentiate close conformers and monitor collision cross section (CCS) differences correlating with ligand-induced conformational changes. Because comparing CCS derived from IM-MS data with 3D-computed CCS is critical for thorough data interpretation, discussing pitfalls related to protein construct similarity and missing sequence sections in PDB files was of primary importance to avoid misinterpretation. The methodic exploration of instrument parameters showed enhanced IM separation of Bcl-xL conformers by combining high wave heights and velocities with low helium and nitrogen flow rates while keeping a high He/N(2) flow rate ratio (>3). The robustness of CCS measurements was eventually improved with a modified IM calibration method providing constant CCS values regardless of instrument settings. Altogether, optimized IM-MS settings allowed a 0.4 nm(2) increase (i.e., 2%) of Bcl-xL CCS to be evidenced upon ABT-737 binding. PMID- 22533359 TI - Influence of mercury and chlorine content of coal on mercury emissions from coal fired power plants in China. AB - China is the largest mercury emitter in the world and coal combustion is the most important mercury source in China. This paper updates the coal quality database of China and evaluates the mercury removal efficiency of air pollution control devices (APCDs) based on 112 on-site measurements. A submodel was developed to address the relationship of mercury emission factor to the chlorine content of coal. The mercury emissions from coal-fired power plants (CFPPs) in China were estimated using deterministic mercury emission factor model, nonchlorine-based and chlorine-based probabilistic emission factor models, respectively. The national mercury emission from CFPPs in 2008 was calculated to be 113.3 t using the deterministic model. The nonchlorine-based probabilistic emission factor model, which addresses the log-normal distribution of the mercury content of coal, estimates that the mercury emission from CFPPs is 96.5 t (P50), with a confidence interval of 57.3 t (P10) to 183.0 t (P90). The best estimate by the chlorine-based probabilistic emission factor model is 102.5 t, with a confidence interval of 71.7 to 162.1 t. The chlorine-based model addresses the influence of chlorine and reduces the uncertainties of mercury emission estimates. PMID- 22533360 TI - Lysine-specific histone demethylase 1 inhibitors control breast cancer proliferation in ERalpha-dependent and -independent manners. AB - Lysine specific demethylase 1 (LSD1, also known as KDM1) is a histone modifying enzyme that regulates the expression of many genes important in cancer progression and proliferation. It is present in various transcriptional complexes including those containing the estrogen receptor (ER). Indeed, inhibition of LSD1 activity and or expression has been shown to attenuate estrogen signaling in breast cancer cells in vitro, implicating this protein in the pathogenesis of cancer. Herein we describe experiments that utilize small molecule inhibitors, phenylcyclopropylamines, along with small interfering RNA to probe the role of LSD1 in breast cancer proliferation and in estrogen-dependent gene transcription. Surprisingly, whereas we have confirmed that inhibition of LSD1 strongly inhibits proliferation of breast cancer cells, we have determined that the cytostatic actions of LSD1 inhibition are not impacted by ER status. These data suggest that LSD1 may be a useful therapeutic target in several types of breast cancer; most notably, inhibitors of LSD1 may have utility in the treatment of ER-negative cancers for which there are minimal therapeutic options. PMID- 22533361 TI - Retrograde intrarenal surgery in patients with spinal deformities. AB - PURPOSE: To present our experience with retrograde intrarenal surgery (RIRS) for managing renal stones in patients with spinal deformities. PATIENTS AND METHODS: We retrospectively reviewed the records of eight patients with congenital scoliosis (n=6), ankylosing spondylitis (n=1), or spina bifida (n=1) who had undergone RIRS for renal stones. Stone-free status was determined by CT 30 days after the procedure and was defined as the absence of stones in the kidney or residual fragments <= 1 mm. RESULTS: Mean patient age was 32.5 years (8-51 years), and mean stone size was 15.8 mm (9-20 mm). The average operative time was 46.5 minutes (25-75 min), and postoperative hospital stay was 1.12 days (1-2 days). A stone-free status was obtained in six (75%) patients, and two patients were considered to have treatment failure. A Double-J stent was placed at the end of the procedure in five (62.5%) patients. Double- J stent discomfort was reported by one (20%) patient who was treated conservatively. No severe complications, either from anesthesia or the surgical procedure, were observed, and no blood transfusion was reported. CONCLUSIONS: The good clearance rate with a low incidence of complications shown by the present study has demonstrated that RIRS is a safe and effective procedure for renal stones in patients with spinal deformities. PMID- 22533362 TI - Comparison of isolated cranberry (Vaccinium macrocarpon Ait.) proanthocyanidins to catechin and procyanidins A2 and B2 for use as standards in the 4 (dimethylamino)cinnamaldehyde assay. AB - The 4-(dimethylamino)cinnamaldehyde (DMAC) assay is currently used to quantify proanthocyanidin (PAC) content in cranberry products. However, this method suffers from issues of accuracy and precision in the analysis and comparison of PAC levels across a broad range of cranberry products. Current use of procyanidin A2 as a standard leads to an underestimation of PACs content in certain cranberry products, especially those containing higher molecular weight PACs. To begin to address the issue of accuracy, a method for the production of a cranberry PAC standard, derived from an extraction of cranberry (c-PAC) press cake, was developed and evaluated. Use of the c-PAC standard to quantify PAC content in cranberry samples resulted in values that were 2.2 times higher than those determined by procyanidin A2. Increased accuracy is critical for estimating PAC content in relationship to research on authenticity, efficacy, and bioactivity, especially in designing clinical trials for determination of putative health benefits. PMID- 22533363 TI - Hormonal therapy of intrinsic aging. AB - Intrinsic skin aging represents the biological clock of the skin cells per se and reflects the reduction processes that are common in internal organs. The reduced secretion of the pituitary, adrenal glands, and the gonads contributes to characteristic aging-associated body and skin phenotypes as well as behavior patterns. Our knowledge of whether there is a direct or indirect connection between hormonal deficiency and skin aging still remains limited. In females, serum levels of 17beta-estradiol, dehydroepiandrosterone, progesterone, growth hormone (GH), and its downstream hormone insulin-like growth factor I (IGF-I) are significantly decreased with increasing age. In males, serum levels of GH and IGF I decrease significantly, whereas it can decrease in late age in a part of the population. Hormones have been shown to influence skin morphology and functions, skin permeability, wound healing, sebaceous lipogenesis, and the metabolism of skin cells. Prevention of skin aging by estrogen/progesterone replacement therapy is effective if administered early after menopause and influences intrinsically aged skin only. Vitamin D substitution and antioxidant treatment may also be beneficial. Replacement therapy with androgens, GH, IGF-I, progesterone, melatonin, cortisol, and thyroid hormones still remains controversial. PMID- 22533365 TI - Aging-related changes in cutaneous corticotropin-releasing hormone system reflect a defective neuroendocrine-stress response in aging. AB - BACKGROUND AND OBJECTIVE: Skin, being a mirror of the body, is a major target for aging research. Aging is a complex process that involves the decline of function or dysfunction of many systems. The corticotropin-releasing hormone (CRH) system is involved in skin inflammation. In addition, CRH has a suggested role in age associated conditions and in animal aging models. However, a consistent logic interaction between the different CRH system components and the aging process has, to our knowledge, never been examined before. METHODS: The expression of CRH, CRH-binding protein (CRHBP), CRH receptor 1 (CRHR1), and CRH receptor 2 (CRHR2) in healthy skin samples of 42 patients of different ages (18-92 years) was evaluated by immunohistochemistry, and the age-related changes were assessed. RESULTS: Compared with young skin, the aged skin displayed an upregulation of CRH in sebaceous glands and CRHR1 in hair follicles and the epidermis. Moreover, age associated downregulation of CRHBP in the sebaceous and sweat glands was detected, whereas the CRHR2 showed no age-related changes. CONCLUSION: Our findings suggest that the age-associated changes in the expression of CRH system components reflect an exaggerated stress response reaction, putting the aged skin continuously in a stress-like situation. PMID- 22533366 TI - Point-of-care beta-hydroxybutyrate measurement for the diagnosis of feline diabetic ketoacidaemia. AB - OBJECTIVES: To evaluate accuracy and precision of a hand-held ketone meter measuring beta-hydroxybutyrate and to determine its diagnostic performance to rule out ketoacidaemia in diabetic cats. METHODS: The ketone meter was validated by calculating within-day precision at different beta-hydroxybutyrate concentrations and by comparison with a laboratory method. To determine its diagnostic performance to diagnose ketoacidaemia, 217 sets of data (venous blood gas analysis and beta-hydroxybutyrate measurements) were retrospectively analysed. Sensitivities and specificities were calculated with the help of receiver-operating characteristic curves. RESULTS: The ketone meter reliably detected beta-hydroxybutyrate at concentrations >0.1 mmol/L and reproducibility was acceptable. Measurements highly correlated with laboratory results (r=0.97; P<0.001), but a significant negative bias was found at high concentrations. A beta-hydroxybutyrate concentration of >2.55 mmol/L had a sensitivity of 94% and a specificity of 68% for diagnosing ketoacidaemia. Many cats with high beta hydroxybutyrate concentrations and normal blood pH had an elevated chloride gap suggestive of superimposed hypochloraemic metabolic alkalosis. CLINICAL SIGNIFICANCE: The commercially available point-of-care ketone meter Precision Xtra is a valid tool to measure beta-hydroxybutyrate in diabetic cats. Concentration <2.55 mmol/L enable ketoacidaemia to be excluded and should lead to redirection of differential diagnoses. PMID- 22533364 TI - Polygenic effects of common single-nucleotide polymorphisms on life span: when association meets causality. AB - Recently we have shown that the human life span is influenced jointly by many common single-nucleotide polymorphisms (SNPs), each with a small individual effect. Here we investigate further the polygenic influence on life span and discuss its possible biological mechanisms. First we identified six sets of prolongevity SNP alleles in the Framingham Heart Study 550K SNPs data, using six different statistical procedures (normal linear, Cox, and logistic regressions; generalized estimation equation; mixed model; gene frequency method). We then estimated joint effects of these SNPs on human survival. We found that alleles in each set show significant additive influence on life span. Twenty-seven SNPs comprised the overlapping set of SNPs that influenced life span, regardless of the statistical procedure. The majority of these SNPs (74%) were within genes, compared to 40% of SNPs in the original 550K set. We then performed a review of current literature on functions of genes closest to these 27 SNPs. The review showed that the respective genes are largely involved in aging, cancer, and brain disorders. We concluded that polygenic effects can explain a substantial portion of genetic influence on life span. Composition of the set of prolongevity alleles depends on the statistical procedure used for the allele selection. At the same time, there is a core set of longevity alleles that are selected with all statistical procedures. Functional relevance of respective genes to aging and major diseases supports causal relationships between the identified SNPs and life span. The fact that genes found in our and other genetic association studies of aging/longevity have similar functions indicates high chances of true positive associations for corresponding genetic variants. PMID- 22533367 TI - Regional differences in symptomatic fever management among paediatricians in Switzerland: the results of a cross-sectional Web-based survey. AB - AIMS: In symptomatic fever management, there is often a gap between everyday clinical practice and current evidence. We were interested to see whether the three linguistic regions of Switzerland differ in the management of fever. METHODS: A close-ended questionnaire, sent to 900 Swiss paediatricians, was answered by 322 paediatricians. Two hundred and fourteen respondents were active in the German speaking, 78 in the French speaking and 30 in the Italian speaking region. RESULTS: Paediatricians from the French and Italian speaking regions identify a lower temperature threshold for initiating a treatment and more frequently reduce it for children with a history of febrile seizures. A reduced general appearance leads more frequently to a lower threshold for treatment in the German speaking than in the French and Italian speaking areas. Among 1.5 and 5-year-old children the preference for the rectal route is more pronounced in the German than in the French speaking region. French speaking respondents more frequently prescribe ibuprofen and an alternating regimen with two drugs than German speaking respondents. Finally, the stated occurrence of exaggerated fear of fever was higher in the German and Italian speaking regions. CONCLUSIONS: Switzerland offers the opportunity to compare three different regions with respect to management of febrile children. This inquiry shows regional differences in symptomatic fever management and in the perceived frequency of exaggerated fear of fever. The gap between available evidence and clinical practice is more pronounced in the French and in the Italian speaking regions than in the German speaking region. PMID- 22533368 TI - Tissue microarray analysis reveals protein expression patterns and potential biomarkers of clinical benefit to bortezomib in relapsed/refractory non-Hodgkin lymphoma. PMID- 22533369 TI - Fabrication of highly transparent superhydrophobic coatings from hollow silica nanoparticles. AB - We herein report a simple and effective method to fabricate excellent transparent superhydrophobic coatings. 3-Aminopropytriethoxysilane (APTS)-modified hollow silica nanoparticle sols were dip-coated on slide glasses, followed by thermal annealing and chemical vapor deposition with 1H,1H,2H,2H perfluorooctyltrimethoxysilane (POTS). The largest water contact angle (WCA) of coating reached as high as 156 degrees with a sliding angle (SA) of <=2 degrees and a maximum transmittance of 83.7%. The highest transmittance of coated slide glass reached as high as 92% with a WCA of 146 degrees and an SA of <=6 degrees . A coating simultaneously showing both good transparency (90.2%) and superhydrophobicity (WCA: 150 degrees , SA: 4 degrees ) was achieved through regulating the concentration of APTS and the withdrawing speed of dip-coating. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), and atomic force microscopy (AFM) were used to observe the morphology and structure of nanoparticles and coating surfaces. Optical properties were characterized by a UV-visible spectrophotometer. Surface wettability was studied by a contact angle/interface system. The effects of APTS concentration and the withdrawing speed of dip-coating were also discussed on the basis of experimental observations. PMID- 22533370 TI - Genome-wide identification of novel small RNAs in Pseudomonas aeruginosa. AB - Bacterial small regulatory RNAs (sRNAs) function in post-transcriptional control of gene expression and control a variety of processes including metabolic reactions, stress responses and pathogenesis in response to environmental signals. A variety of approaches have been used previously to identify 44 sRNAs in the opportunistic human pathogen Pseudomonas aeruginosa. In this work, RNA sequencing (RNA-seq) is used to identify novel transcripts in P.aeruginosa involving a combination of three different sequencing libraries. Almost all known sRNAs and over 500 novel intergenic sRNAs are identified with this approach. Although the use of three libraries increased the number of novel transcripts identified, there were significant differences in the subset of transcripts detected in each library, underscoring the importance of library preparation strategy and relative sRNA abundance for successful sRNA detection. Nearly 90% of the novel sRNAs have no orthologous bacterial sequences outside of P.aeruginosa, supporting a limited degree of sequence conservation and rapid evolution of sRNAs at the species level. We anticipate that the data will be useful for the study of regulatory sRNAs in bacteria and that the approach described here may be applied to identify sRNAs in any bacterium under different growth and stress conditions. PMID- 22533371 TI - Service user involvement in nurse education: perceptions of mental health nursing students. AB - Increasingly providers of mental health nurse education are required to demonstrate user involvement in all aspects of these programmes including student selection, programme design and student assessment. There has been limited analysis of how nursing students perceive user involvement in nurse education programmes. The aim of this study has been to explore mental health nursing student's perceptions of involving users in all aspects of pre-registration mental health nursing programme. Researchers completed a number of focus group interviews with 12 ex-mental health nursing students who had been recruited by purposeful sampling. Each focus group interview was recorded and analysed using a series of data reduction, data display and verification methods. The study confirms many of the findings reported in earlier user participation in education studies. Three main themes related to user involvement have been identified: the protection of users, enhanced student learning and the added value benefits associated with user involvement. PMID- 22533372 TI - Comments on the paper "A statistical assessment of differences and equivalences between genetically modified and reference plant varieties" by van der Voet et al. 2011. AB - van der Voet et al. (2011) describe statistical methodology that the European Food Safety Authority expects an applicant to adopt when making a GM crop regulatory submission. Key to their proposed methodology is the inclusion of reference varieties in the experimental design to provide a measure of natural variation amongst commercially grown crops. While taking proper account of natural variation amongst commercial varieties in the safety assessment of GM plants makes good sense, the methodology described by the authors is shown here to be fundamentally flawed and consequently cannot be considered fit for purpose in its current form. PMID- 22533373 TI - High prevalence of Panton-Valentine leukocidin among methicillin-sensitive Staphylococcus aureus colonization isolates in rural Iowa. AB - Recent studies have shown that livestock can carry Staphylococcus aureus and transmit it to human caretakers. We conducted a pilot study to determine the prevalence and molecular epidemiology of S. aureus among rural Iowans, including individuals with livestock contact. Nasal and throat swabs were collected and plated onto selective media to isolate methicillin-susceptible and methicillin resistant S. aureus (MRSA), followed by antibiotic resistance testing and molecular analysis of the isolates. While no MRSA was detected, overall, 23.7% (31/131) of participants were found to harbor S. aureus in their nose, throat, or both. Fifteen isolates displayed resistance to one or more tested antibiotics, and the Panton-Valentine leukocidin (PVL) genes were present at a high level (29% [9/31] of S. aureus-positive participants). Younger age and tobacco use were associated with increased risk of S. aureus carriage. Our results suggest that carriage of PVL-positive S. aureus is common among rural Iowans, even in the absence of detectable MRSA colonization. PMID- 22533374 TI - Virulence and plasmid transferability of KPC Klebsiella pneumoniae at the Veterans Affairs Healthcare System of New Jersey. AB - Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae infections are associated with high mortality; however, little is known about the virulence determinants of KPC-producing K. pneumoniae. At the Veterans Affairs New Jersey Healthcare System (VA NJHCS), we investigated the virulence and plasmid transferability of 60 clinically unique KPC-containing K. pneumoniae isolates. All 60 isolates were negative for known virulence factors K1, K2, and K5 capsular antigens; rmpA; and the aerobactin gene by polymerase chain reaction. Isolates varied in their susceptibility to neutrophil phagocytosis, but were less resistant than the virulent serotype K1 isolate. Additionally, no deaths were seen on murine lethality studies. Conjugation results of this study showed that the bla(KPC) gene can be transferred into an Escherichia coli J-53 strain but not to E. coli JP-995. However, the stability is very limited as E. coli J-53 does not retain bla(KPC)-containing plasmids for any period of time. The lack of virulence factors in the set of KPC-producing K. pneumoniae studied suggests that morbidity and mortality may be due to detection issues or lack of effective antibiotics. PMID- 22533375 TI - Malassezia-derived indoles activate the aryl hydrocarbon receptor and inhibit Toll-like receptor-induced maturation in monocyte-derived dendritic cells. AB - BACKGROUND: The aryl hydrocarbon receptor (AhR) is a nuclear receptor and transcriptional regulator with pleiotropic effects. The production of potent AhR ligands by Malassezia yeasts, such as indirubin, indolo[3,2-b]carbazole (ICZ), tryptanthrin and malassezin, has been associated with the pathogenesis of seborrhoeic dermatitis and pityriasis versicolor. Antigen-presenting cells in the skin can encounter microbes in the presence of these bioactive metabolites that could potentially modulate their function. OBJECTIVES: To study the effects of the aforementioned naturally occurring ligands on AhR activation and Toll-like receptor (TLR)-induced maturation in human monocyte-derived dendritic cells (moDCs). METHODS: These indoles were screened for AhR activation capacity in moDCs employing CYP1A1 and CYP1B1 induction as read out and for their effects on the function of moDCs after TLR-ligand stimulation. RESULTS: Indirubin and ICZ were the most potent AhR ligands and were selected for subsequent experiments. Concurrent exposure of moDCs to indirubin or ICZ together with TLR agonists significantly augmented the AhR-mediated CYP1A1 and CYP1B1 gene expression. Additionally, mature DCs that were subsequently stimulated with AhR ligands showed increased AhR target gene expression. Moreover, these ligands limited TLR induced phenotypic maturation (CD80, CD83, CD86, MHC II upregulation) of moDCs, reduced secretion of the inflammatory cytokines interleukin (IL)-6 and IL-12, and decreased their ability to induce alloreactive T-lymphocyte proliferation. CONCLUSIONS: These results demonstrate that AhR agonists of yeast origin are able to inhibit moDC responses to TLR ligands and that moDCs can adapt through increased transcription of metabolizing enzymes such as CYP1A1 and CYP1B1. PMID- 22533376 TI - Mice do not require auditory input for the normal development of their ultrasonic vocalizations. AB - BACKGROUND: Transgenic mice have become an important tool to elucidate the genetic foundation of the human language faculty. While learning is an essential prerequisite for the acquisition of human speech, it is still a matter of debate whether auditory learning plays any role in the development of species-specific vocalizations in mice. To study the influence of auditory input on call development, we compared the occurrence and structure of ultrasonic vocalizations from deaf otoferlin-knockout mice, a model for human deafness DFNB9, to those of hearing wild-type and heterozygous littermates. RESULTS: We found that the occurrence and structure of ultrasonic vocalizations recorded from deaf otoferlin knockout mice and hearing wild-type and heterozygous littermates do not differ. Isolation calls from 16 deaf and 15 hearing pups show the same ontogenetic development in terms of the usage and structure of their vocalizations as their hearing conspecifics. Similarly, adult courtship 'songs' produced by 12 deaf and 16 hearing males did not differ in the latency to call, rhythm of calling or acoustic structure. CONCLUSION: The results indicate that auditory experience is not a prerequisite for the development of species-specific vocalizations in mice. Thus, mouse models are of only limited suitability to study the evolution of vocal learning, a crucial component in the development of human speech. Nevertheless, ultrasonic vocalizations of mice constitute a valuable readout in studies of the genetic foundations of social and communicative behavior. PMID- 22533377 TI - Therapeutic approaches to muscular dystrophies. PMID- 22533378 TI - Use of cell-penetrating-peptides in oligonucleotide splice switching therapy. AB - The hydrophobic plasma membrane constitutes an indispensable barrier for cells, allowing influx of essential molecules while preventing access to other macromolecules. Although pivotal for the maintenance of cells, the inability to cross the plasma membrane is one of the major obstacles toward current drug development. Oligonucleotides (ONs) are a group of substances that display great therapeutic potential to interfere with gene expression. Several classes of ONs have emerged either based on double stranded RNAs, such as short interfering RNAs that are utilized to confer gene silencing, or single stranded ONs of various chemistries for antisense targeting of small regulatory micro RNAs or mRNAs. In particular the use of splice switching oligonucleotides (SSOs) to manipulate alternative splicing, by targeting pre-mRNA, has proven to be a highly promising therapeutic strategy to treat various genetic disorders, including Duchenne muscular dystrophy and spinal muscular atrophy. Despite being efficient compounds to alter splicing patterns, their hydrophilic macromolecular nature prohibits efficient cellular internalization.Various chemical drug delivery vehicles have been developed aiming at improving the bioavailability of nucleic acid-based drugs. In the context of SSOs, one group of peptidebased delivery vectors, i.e. cell-penetrating peptides (CPPs), display extremely high potency. CPPs have a remarkable ability to convey various, otherwise impermeable, macromolecules across the plasma membrane of cells in a relatively non-toxic fashion. This review provides insight into the application of CPPs and ONs in gene regulation with particular focus on CPP-assisted delivery of therapeutic SSOs. PMID- 22533380 TI - Antisense oligonucleotide-mediated exon skipping for Duchenne muscular dystrophy: progress and challenges. AB - Duchenne muscular dystrophy (DMD) is the most common childhood neuromuscular disorder. It is caused by mutations in the DMD gene that disrupt the open reading frame (ORF) preventing the production of functional dystrophin protein. The loss of dystrophin ultimately leads to the degeneration of muscle fibres, progressive weakness and premature death. Antisense oligonucleotides (AOs) targeted to splicing elements within DMD pre-mRNA can induce the skipping of targeted exons, restoring the ORF and the consequent production of a shorter but functional dystrophin protein. This approach may lead to an effective disease modifying treatment for DMD and progress towards clinical application has been rapid. Less than a decade has passed between the first studies published in 1998 describing the use of AOs to modify the DMD gene in mice and the results of the first intramuscular proof of concept clinical trials. Whilst phase II and III trials are now underway, the heterogeneity of DMD mutations, efficient systemic delivery and targeting of AOs to cardiac muscle remain significant challenges. Here we review the current status of AO-mediated therapy for DMD, discussing the preclinical, clinical and regulatory hurdles and their possible solutions to expedite the translation of AO-mediated exon skipping therapy to clinic. PMID- 22533381 TI - Adipose tissue biglycan as a potential anti-inflammatory target of sodium salicylate in mice fed a high fat diet. AB - BACKGROUND: Inflammation in adipose tissue (AT) during obesity causes impaired AT function. Although multiple extracellular matrix (ECM) proteins are expressed in AT their potential role in adipose tissue inflammation is unclear. Biglycan, a pro-inflammatory ECM gene, is highly enriched in adipose tissue. However, whether it is correlated with adipose tissue inflammation is unknown. We provide evidence in support of a strong association between biglycan expression and inflammatory status of adipose tissue. METHODS: C57BL6 mice were fed either a control (10% fat calories) or a high fat diet (HFD) (60% fat calories) for 8 weeks. Adipose tissue was analyzed for the expression of biglycan, IL-6 and TNFalpha. Biglycan knockout or wild type were also fed a high fat diet for 8 weeks and the expression of inflammatory genes in the mesenteric adipose tissue was examined. To test anti inflammatory treatment on biglycan expression, a group of mice were fed either the low fat or high fat diet for eight weeks supplemented with either saline or sodium salicylate @ 25mg/100ml in their drinking water. RESULTS: Mice on HFD had an increase in ECM genes (BGN and COL1A1), inflammatory genes (IL-6 and TNFalpha) in both the subcutaneous and epididymal depots. However, correlation analysis only shows a positive correlation between biglycan, IL-6 and TNFalpha expression. In addition, lower expression of IL-6 and CD68 was found in the mesenteric adipose tissue of biglycan knockout mice compared to the wild type. Sodium salicylate treatment reduced subcutaneous adipose tissue expression of BGN, COL1A1, and COL6A1 and a concurrent downregulation of TNFalpha and IL-6 and TLR4 expression. Salicylate also lowered the serum TGFbeta1 levels. CONCLUSION: Biglycan expression correlates with adipose tissue inflammation, especially in the subcutaneous depot compared to the epididymal depot. This is supported by the greater effect of sodium salicylate in attenuating both inflammatory and ECM gene expression the subcutaneous adipose depot compared to the epididymal depot. These results show that inflammatory state may explain the induction of biglycan, and perhaps, other ECM genes in adipose tissue. PMID- 22533379 TI - Gene replacement therapies for duchenne muscular dystrophy using adeno-associated viral vectors. AB - The muscular dystrophies collectively represent a major health challenge, as few significant treatment options currently exist for any of these disorders. Recent years have witnessed a proliferation of novel approaches to therapy, spanning increased testing of existing and new pharmaceuticals, DNA delivery (both anti sense oligonucleotides and plasmid DNA), gene therapies and stem cell technologies. While none of these has reached the point of being used in clinical practice, all show promise for being able to impact different types of muscular dystrophies. Our group has focused on developing direct gene replacement strategies to treat recessively inherited forms of muscular dystrophy, particularly Duchenne and Becker muscular dystrophy (DMD/BMD). Both forms of dystrophy are caused by mutations in the dystrophin gene and all cases can in theory be treated by gene replacement using synthetic forms of the dystrophin gene. The major challenges for success of this approach are the development of a suitable gene delivery shuttle, generating a suitable gene expression cassette able to be carried by such a shuttle, and achieving safe and effective delivery without elicitation of a destructive immune response. This review summarizes the current state of the art in terms of using adeno-associated viral vectors to deliver synthetic dystrophin genes for the purpose of developing gene therapy for DMD. PMID- 22533382 TI - Antioxidation status and histidine dipeptides content in broiler blood and muscles depending on protein sources in feed. AB - One-day-old chickens were fed mixtures containing different raw materials (fish by-products meal, porcine blood cells meal, blood meal, wheat gluten, fodder yeast), as a source of histidine and beta-alanine - components of carnosine. Control birds were administered a feed mixture, in which soy bean meal was the main protein source. The bodyweight, feed consumption and conversion, antioxidant characteristics and histidine dipeptides content in blood and muscles, and also amino acid composition of chicken meat on day 34 post-hatch were recorded. The best (p < 0.05) performance and feed conversion were observed in chickens fed mixture containing porcine blood cells meal. In blood plasma of control chickens, a significantly (p < 0.01) higher ability to scavenge DPPH radicals was found. However, the highest catalase activity in erythrocytes was determined in chickens fed mixtures with blood by-products. Insignificant differences in both carnosine and anserine levels in plasma between treatments were noted. Breast muscles from control birds were characterized by lower activity of glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) (p < 0.05; p < 0.01), than those from chickens fed blood by-products. Improved ability to reduce ferric ions (FRAP) (p < 0.01) and carnosine content in meat from chickens fed blood cell meal were recorded. No direct relations between amino acids content in feed mixtures and in meat were observed. PMID- 22533383 TI - Sulfate aerosol as a potential transport medium of radiocesium from the Fukushima nuclear accident. AB - To date, areas contaminated by radionuclides discharged from the Fukushima Dai ichi nuclear power plant accident have been mapped in detail. However, size of the radionuclides and their mixing state with other aerosol components, which are critical in their removal from the atmosphere, have not yet been revealed. We measured activity size distributions of (134)Cs and (137)Cs in aerosols collected 47 days after the accident at Tsukuba, Japan, and found that the activity median aerodynamic diameters of (134)Cs and (137)Cs in the first sample (April 28-May 12) were 0.54 and 0.53 MUm, respectively, and those in the second sample (May 12 26) were both 0.63 MUm. The activity size distributions of these radiocesium were within the accumulation mode size range and almost overlapped with the mass size distribution of non-sea-salt sulfate aerosol. From the analysis of other aerosol components, we found that sulfate was the potential transport medium for these radionuclides, and resuspended soil particles that attached radionuclides were not the major airborne radioactive substances at the time of measurement. This explains the relatively similar activity sizes of radiocesium measured at various sites during the Chernobyl accident. Our results can serve as basic data for modeling the transport/deposition of radionuclides. PMID- 22533384 TI - Ankle-foot orthotic management in neuromuscular disorders: recommendations for future research. AB - PURPOSE: To describe research evidence supporting clinical recommendations for ankle-foot orthotic (AFO) prescription and examine common limitations in current research among individuals with stroke and cerebral palsy. METHOD: Three databases and one journal website were searched for articles reporting AFO interventions on gait and functional mobility outcome measures in participants with stroke or cerebral palsy. The International Society for Prosthetics and Orthotics (ISPO) best practice recommendations from consensus conferences were reviewed. Data extracted from the articles include participant characteristics, AFO intervention details, evaluation methods, and outcome measures. RESULTS: Sixty articles were included; twenty-seven on stroke and thirty-three on cerebral palsy participants. Many articles reported insufficient detail on severity of lower limb impairment. Type of interventions included nineteen nonarticulating AFO studies, twelve articulating AFO studies and twenty-three studies testing both. Confounding factors, such as compliance, activity level and footwear, need to be considered in longitudinal studies. CONCLUSIONS: Most studies demonstrated improvement in walking speed and ankle dorsiflexion, whereas the indirect effect on knee stability remains unclear. Future research needs to provide detailed information on type and severity of lower limb impairment of participants and design features of the AFO intervention. PMID- 22533385 TI - Selective digestive tract decontamination in critically ill patients. AB - INTRODUCTION: Selective decontamination of the digestive tract (SDD) has been proposed to prevent endogenous and exogenous infections and to reduce mortality in critically ill patients. Although the efficacy of SDD has been confirmed by randomized controlled trials (RCTs) and systematic reviews, SDD has been the subject of intense controversy, based mainly on an insufficient evidence of efficacy and on concerns about resistance. AREAS COVERED: This article reviews the philosophy, the current evidence on the efficacy of SDD and the issue of emergence of resistance. All SDD RCTs were searched using Embase and Medline, with no restriction of language, gender or age. Personal archives were also explored, including abstracts from major scientific meetings; references in papers and published meta-analyses on SDD were crosschecked. Up-to-date evidence of the impact of SDD on carriage, infections and mortality is presented, and the efficacy of SDD in selected patient groups was investigated, along with the problem of the emergence of resistance. EXPERT OPINION: SDD significantly reduces the number of infections of the lower respiratory tract and bloodstream, multiple organ failure and mortality. It also controls resistance, particularly when the full protocol of parenteral and enteral antimicrobials is used. PMID- 22533388 TI - Cardiopulmonary and sedative effects of the peripheral alpha2-adrenoceptor antagonist MK 0467 administered intravenously or intramuscularly concurrently with medetomidine in dogs. AB - OBJECTIVE: To evaluate the cardiopulmonary and sedative effects of the peripheral alpha(2)-adrenoceptor antagonist MK 0467 when administered IM or IV concurrently with medetomidine in dogs. ANIMALS: 8 adult dogs. PROCEDURES: Dogs received 20 MUg of medetomidine/kg, IM, alone or concurrently with MK 0467 (0.4 mg/kg, IM), and 10 MUg of medetomidine/kg, IV, alone or concurrently with MK 0467 (0.2 mg/kg, IV), in a randomized crossover study. Sedation characteristics were scored and hemodynamic measurements and arterial and mixed-venous blood samples for blood gas analysis were obtained before (time 0; baseline) and for 90 minutes after treatment. RESULTS: Heart rate (HR), mixed-venous partial pressure of oxygen (Pvo(2)), and cardiac index (CI) were significantly lower and mean arterial blood pressure (MAP), systemic vascular resistance (SVR), and oxygen extraction ratio (ER) were significantly higher after administration of medetomidine IM or IV, compared with baseline values. Administration of medetomidine and MK 0467 IM caused a significantly higher heart rate, CI, and Pvo(2) and significantly lower MAP, SVR, and ER for 60 to 90 minutes than did IM administration of medetomidine alone. Administration of medetomidine and MK 0467 IV caused a significantly higher CI and Pvo(2) and significantly lower MAP, SVR, and ER for 45 to 90 minutes than did IV administration of medetomidine alone. There was no significant difference in sedation scores among treatments. CONCLUSIONS AND CLINICAL RELEVANCE: In dogs, MK 0467 administered concurrently with medetomidine IV or IM reduced the cardiovascular effects of medetomidine but had no detectable effect on sedation scores. PMID- 22533389 TI - Effects of acepromazine maleate on platelet function assessed by use of adenosine diphosphate activated- and arachidonic acid- activated modified thromboelastography in healthy dogs. AB - OBJECTIVE: To evaluate the effect of acepromazine maleate administered IV on platelet function assessed in healthy dogs by use of a modified thromboelastography assay. ANIMALS: 6 healthy adult mixed-breed dogs. PROCEDURES: Dogs received each of 3 treatments (saline [0.9% NaCl] solution [1 to 2 mL, IV] and acepromazine maleate [0.05 and 0.1 mg/kg, IV]) in a randomized crossover study with a minimum 3-day washout period between treatments. From each dog, blood samples were collected via jugular venipuncture immediately before and 30 and 240 minutes after administration of each treatment. A modified thromboelastography assay, consisting of citrated kaolin-activated (baseline assessment), reptilase-ADP-activated (ADP-activated), and reptilase-arachidonic acid (AA)-activated (AA-activated) thromboelastography, was performed for each sample. Platelet inhibition was evaluated by assessing the percentage change in maximum amplitude for ADP-activated or AA-activated samples, compared with baseline values. Percentage change in maximum amplitude was analyzed by use of Skillings-Mack tests with significance accepted at a family-wise error rate of P < 0.05 by use of Bonferroni corrections for multiple comparisons. RESULTS: No significant differences were found in the percentage change of maximum amplitude from baseline for ADP-activated or AA-activated samples among treatments at any time. CONCLUSIONS AND CLINICAL RELEVANCE: Platelet function in dogs, as assessed by use of a modified thromboelastography assay, was not inhibited by acepromazine at doses of 0.05 or 0.1 mg/kg, IV. This was in contrast to previous reports in which it was suggested that acepromazine may alter platelet function via inhibition of ADP and AA. PMID- 22533390 TI - Effects of isoflurane anesthesia with and without dexmedetomidine or remifentanil on quantitative electroencephalographic variables before and after nociceptive stimulation in dogs. AB - OBJECTIVE: To evaluate the influence of various anesthetic protocols and 3 multiples of isoflurane minimum alveolar concentration (MAC) before and after supramaximal stimulation on electroencephalographic (EEG) variables in dogs. ANIMALS: 6 healthy adult Beagles (mean +/- SD body weight, 16.3 +/- 1.0 kg). PROCEDURES: All dogs underwent 3 anesthesia sessions with a minimum of 1 week separating sessions: isoflurane alone, isoflurane and a constant rate infusion of dexmedetomidine (3 MUg/kg/h, IV; ID), and isoflurane and a constant rate infusion of remifentanil (18 MUg/kg/h, IV; IR). The MAC of isoflurane was determined via supramaximal electrical stimulation. Quantitative variables (frequency bands and their ratios, median frequency, 95% spectral edge frequency [SEF], and an EEG index) were determined directly before and after supramaximal stimulation at 0.75, 1.0, and 1.5 times the MAC for each session of 20-second epochs. RESULTS: Mean +/- SD isoflurane MACs for isoflurane alone, ID, and IR were 1.7 +/- 0.3%, 1.0 +/- 0.1%, and 1.0 +/- 0.1%, respectively. Prestimulation 95% SEF decreased significantly with increasing MAC during the isoflurane alone and ID sessions. Significant decreases in delta frequency band (0.5 to 3.5 Hz) presence and significant increases in beta frequency band (> 12.5 Hz) presence, median frequency, and 95% SEF after stimulation were dependent on the MAC and anesthetic protocol. The EEG index had the strongest correlation with increasing MAC during the isoflurane-alone session (rho = -0.89) and the least in the IR session (rho = -0.15). CONCLUSIONS AND CLINICAL RELEVANCE: Anesthesia with isoflurane alone resulted in the greatest overall EEG depression of all protocols. Use of remifentanil depressed the EEG response to nociceptive stimulation more strongly than did dexmedetomidine. The EEG variables evaluated did not appear useful when used alone as indicators of anesthetic depth in dogs. PMID- 22533391 TI - Effect of ketamine hydrochloride on the analgesic effects of tramadol hydrochloride in horses with signs of chronic laminitis-associated pain. AB - OBJECTIVE: To investigate the effects of ketamine hydrochloride on the analgesic effects of tramadol hydrochloride in horses with signs of pain associated with naturally occurring chronic laminitis. ANIMALS: 15 client-owned adult horses with chronic laminitis. PROCEDURES: Each horse received tramadol alone or tramadol and ketamine in a randomized, crossover study (>= 2 months between treatments). Tramadol (5 mg/kg) was administered orally every 12 hours for 1 week. When appropriate, ketamine (0.6 mg/kg/h) was administered IV for 6 hours on each of the first 3 days of tramadol administration. Noninvasive systemic blood pressure values, heart and respiratory rates, intestinal sounds, forelimb load and off loading frequency (determined via force plate system), and plasma tumor necrosis factor-alpha and thromboxane B(2) concentrations were assessed before (baseline) during (7 days) and after (3 days) each treatment. RESULTS: Compared with baseline data, arterial blood pressure decreased significantly both during and after tramadol-ketamine treatment but not with tramadol alone. Forelimb off loading frequency significantly decreased during the first 3 days of treatment with tramadol only, returning to baseline frequency thereafter. The addition of ketamine to tramadol treatment reduced off-loading frequency both during and after treatment. Forelimb load did not change with tramadol alone but increased with tramadol-ketamine treatment. Plasma concentrations of tumor necrosis factor alpha and thromboxane B(2) were significantly reduced with tramadol-ketamine treatment but not with tramadol alone. CONCLUSIONS AND CLINICAL RELEVANCE: In horses with chronic laminitis, tramadol administration induced limited analgesia, but this effect was significantly enhanced by administration of subanesthetic doses of ketamine. PMID- 22533392 TI - Pharmacokinetics of a single intramuscular injection of ceftiofur crystalline free acid in American black ducks (Anas rubripes). AB - OBJECTIVE: To determine the pharmacokinetic properties of 1 IM injection of ceftiofur crystalline-free acid (CCFA) in American black ducks (Anas rubripes). ANIMALS: 20 adult American black ducks (6 in a preliminary experiment and 14 in a primary experiment). PROCEDURES: Dose and route of administration of CCFA for the primary experiment were determined in a preliminary experiment. In the primary experiment, CCFA (10 mg/kg, IM) was administered to ducks. Ducks were allocated into 2 groups, and blood samples were obtained 0.25, 0.5, 1, 2, 4, 8, 12, 48, 96, 144, 192, and 240 hours or 0.25, 0.5, 1, 2, 4, 8, 24, 72, 120, 168, and 216 hours after administration of CCFA. Plasma concentrations of ceftiofur free acid equivalents (CFAEs) were determined by use of high-performance liquid chromatography. Data were evaluated by use of a naive pooled-data approach. RESULTS: The area under the plasma concentration versus time curve from 0 hours to infinity was 783 h*MUg/mL, maximum plasma concentration observed was 13.1 MUg/mL, time to maximum plasma concentration observed was 24 hours, terminal phase half-life was 32.0 hours, time that concentrations of CFAEs were higher than the minimum inhibitory concentration (1.0 MUg/mL) for many pathogens of birds was 123 hours, and time that concentrations of CFAEs were higher than the target plasma concentration (4.0 MUg/mL) was 73.3 hours. CONCLUSIONS AND CLINICAL RELEVANCE: On the basis of the time that CFAE concentrations were higher than the target plasma concentration, a dosing interval of 3 days can be recommended for future multidose CCFA studies. PMID- 22533393 TI - Evaluation of intramuscularly administered sodium pentosan polysulfate for treatment of experimentally induced osteoarthritis in horses. AB - OBJECTIVE: To assess clinical, radiographic, histologic, and biochemical effects of sodium pentosan polysulfate (NaPPS) administered IM for treatment of experimentally induced osteoarthritis in horses. ANIMALS: 18 horses. PROCEDURES: Osteoarthritis was induced arthroscopically in 1 middle carpal joint of all horses. Nine horses received NaPPS (3 mg/kg, IM) on study days 15, 22, 29, and 36. Nine control horses received the same volume of saline (0.9% NaCl) solution IM on study days 15, 22, 29, and 36. Clinical, radiographic, gross, histologic, histochemical, and biochemical findings as well as findings of synovial fluid analysis were evaluated. RESULTS: No adverse treatment-related events were detected. Induced osteoarthritis caused a substantial increase in lameness, response to flexion, joint effusion, radiographic findings, synovial membrane inflammation, and articular cartilage fibrillation. Articular cartilage fibrillation was substantially reduced by NaPPS treatment, and concentrations of chondroitin sulfate 846 epitope were significantly increased in the synovial fluid of osteoarthritic and non-osteoarthritic joints of treated horses. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that NaPPS has some beneficial disease-modifying effects and may be a therapeutic option for osteoarthritis in horses. PMID- 22533394 TI - Ultrasonographic anatomy of the coelomic organs of boid snakes (Boa constrictor imperator, Python regius, Python molurus molurus, and Python curtus). AB - OBJECTIVE: To determine the ultrasonographic features of the coelomic organs of healthy snakes belonging to the Boidae and Pythonidae families. ANIMALS: 16 ball pythons (Python regius; 7 males, 8 females, and 1 sexually immature), 10 Indian rock pythons (Python molurus molurus; 5 males, 4 females, and 1 sexually immature), 12 Python curtus (5 males and 7 females), and 8 boa constrictors (Boa constrictor imperator; 4 males and 4 females). PROCEDURES: All snakes underwent complete ultrasonographic evaluation of the coelomic cavity; chemical restraint was not necessary. A dorsolateral approach to probe placement was chosen to increase image quality and to avoid injury to the snakes and operators. Qualitative and quantitative observations were recorded. RESULTS: The liver, stomach, gallbladder, pancreas, small and large intestines, kidneys, cloaca, and scent glands were identified in all snakes. The hemipenes were identified in 10 of the 21 (48%) male snakes. The spleen was identified in 5 of the 46 (11%) snakes, and ureters were identified in 6 (13%). In 2 sexually immature snakes, the gonads were not visible. One (2%) snake was gravid, and 7 (15%) had small amounts of free fluid in the coelomic cavity. A significant positive correlation was identified between several measurements (diameter and thickness of scent glands, gastric and pyloric walls, and colonic wall) and body length (snout to vent) and body weight. CONCLUSIONS AND CLINICAL RELEVANCE: The study findings can be used as an atlas of the ultrasonographic anatomy of the coelomic cavity in healthy boid snakes. Ultrasonography was reasonably fast to perform and was well tolerated in conscious snakes. PMID- 22533395 TI - Comparison of four ventilatory protocols for computed tomography of the thorax in healthy cats. AB - OBJECTIVE: To identify ventilatory protocols that yielded good image quality for thoracic CT and hemodynamic stability in cats. Animals-7 healthy cats. PROCEDURES: Cats were anesthetized and ventilated via 4 randomized protocols (hyperventilation, 20 seconds [protocol 1]; single deep inspiration, positive inspiratory pressure of 15 cm H(2)O [protocol 2]; recruitment maneuver [protocol 3]; and hyperventilation, 20 seconds with a positive end-expiratory pressure of 5 cm H(2)O [protocol 4]). Thoracic CT was performed for each protocol; images were acquired during apnea for protocols 1 and 3 and during positive airway pressure for protocols 2 and 4. Heart rate; systolic, mean, and diastolic arterial blood pressures; blood gas values; end-tidal isoflurane concentration; rectal temperature; and measures of atelectasis, total lung volume (TLV), and lung density were determined before and after each protocol. RESULTS: None of the protocols eliminated atelectasis; the number of lung lobes with atelectasis was significantly greater during protocol 1 than during the other protocols. Lung density and TLV differed significantly among protocols, except between protocols 1 and 3. Protocol 2 TLV exceeded reference values. Arterial blood pressure after each protocol was lower than before the protocols. Mean and diastolic arterial blood pressure were higher after protocol 3 and diastolic arterial blood pressure was higher after protocol 4 than after protocol 2. CONCLUSIONS AND CLINICAL RELEVANCE: Standardization of ventilatory protocols may minimize effects on thoracic CT images and hemodynamic variables. Although atelectasis was still present, ventilatory protocols 3 and 4 provided the best compromise between image quality and hemodynamic stability. PMID- 22533396 TI - Urinary recovery of orally administered chromium 51-labeled EDTA, lactulose, rhamnose, d-xylose, 3-O-methyl-d-glucose, and sucrose in healthy adult male Beagles. AB - Objective-To provide values for gastrointestinal permeability and absorptive function tests (GIPFTs) with chromium 51 ((51)Cr)-labeled EDTA, lactulose, rhamnose, d-xylose, 3-O-methyl-d-glucose, and sucrose in Beagles and to evaluate potential correlations between markers. Animals-19 healthy adult male Beagles. Procedures-A test solution containing 3.7 MBq of (51)Cr-labeled EDTA, 2 g of lactulose, 2 g of rhamnose, 2 g of d-xylose, 1 g of 3-O-methyl-d-glucose, and 8 g of sucrose was administered intragastrically to each dog. Urinary recovery of each probe was determined 6 hours after administration. Results-Mean +/- SD (range) percentage urinary recovery was 6.3 +/- 1.6% (4.3% to 9.7%) for (51)Cr labeled EDTA, 3.3 +/- 1.1% (1.7% to 5.3%) for lactulose, 25.5 +/- 5.0% (16.7% to 36.9%) for rhamnose, and 58.8% +/- 11.0% (40.1% to 87.8%) for 3-O-methyl-d glucose. Mean (range) recovery ratio was 0.25 +/- 0.06 (0.17 to 0.37) for (51)Cr labeled EDTA to rhamnose, 0.13 +/- 0.04 (0.08 to 0.23) for lactulose to rhamnose, and 0.73 +/- 0.09 (0.60 to 0.90) for d-xylose to 3-O-methyl-d-glucose. Median (range) percentage urinary recovery was 40.3% (31.6% to 62.7%) for d-xylose and 0% (0% to 0.8%) for sucrose. Conclusions and Clinical Relevance-Reference values in healthy adult male Beagles for 6 of the most commonly used GIPFT markers were determined. The correlation between results for (51)Cr-labeled EDTA and lactulose was not as prominent as that reported for humans and cats; thus, investigators should be cautious in the use and interpretation of GIPFTs performed with sugar probes in dogs with suspected intestinal dysbiosis. PMID- 22533397 TI - Effect of a zinc L-carnosine compound on acid-induced injury in canine gastric mucosa ex vivo. AB - OBJECTIVE: To examine whether a zinc L-carnosine compound used for treatment of suspected gastric ulcers in dogs ameliorates acid-induced injury in canine gastric mucosa. SAMPLE: Gastric mucosa from 6 healthy dogs. PROCEDURES: Mucosa from the gastric antrum was harvested from 6 unadoptable shelter dogs immediately after euthanasia and mounted on Ussing chambers. The tissues were equilibrated for 30 minutes in neutral Ringer's solution prior to incubation with acidic Ringer's solution (HCl plus Ringer's solution [final pH, 1.5 to 2.5]), acidic Ringer's solution plus zinc L-carnosine compound, or zinc L-carnosine compound alone. Tissues were maintained for 180 minutes in Ussing chambers, during which permeability was assessed by measurement of transepithelial electrical resistance. After the 180-minute treatment period, tissues were removed from Ussing chambers and labeled with immunofluorescent anti-active caspase-3 antibody as an indicator of apoptosis. RESULTS: Permeability of the gastric mucosa was significantly increased in a time-dependent manner by addition of HCl, whereas control tissues maintained viability for the study period. Change in permeability was detected within the first 15 minutes after acid application and progressed over the subsequent 150 minutes. The zinc L-carnosine compound had no significant effect on this increase in permeability. Apoptosis was evident in acid-treated tissues but not in control tissues. The zinc L-carnosine compound did not protect against development of apoptosis. CONCLUSIONS AND CLINICAL RELEVANCE: Addition of HCl caused a dose-dependent increase in gastric permeability over time and apparent induction of apoptosis as determined on the basis of immunofluorescence. However, there was no significant protective effect of a zinc L-carnosine compound. Nonetheless, results suggested the utility of this method for further studies of canine gastric injury. PMID- 22533398 TI - Evaluation of oral administration of firocoxib for the management of musculoskeletal pain and lameness associated with osteoarthritis in horses. AB - OBJECTIVE: To generate data on the effects of firocoxib administration to horses with osteoarthritis. ANIMALS: Client-owned horses with signs of lameness and joint pain associated with osteoarthritis. PROCEDURES: Firocoxib was administered as an oral paste (0.1 mg/kg, q 24 h) for 14 days. Assessments were performed on day 0 (baseline) and days 7 and 14. RESULTS: 390 of 429 horses from 80 sites in 25 states met the criteria for analysis. Quarter Horse and Thoroughbred were the 2 most commonly represented breeds, comprising half of the study population. Signs of musculoskeletal pain or lameness attributed to osteoarthritis were diagnosed in a single joint in 197 (197/390 [50.5%]) horses and in multiple joints in 193 (193/390 [49.5%]) horses. In those with involvement of a single joint, the tarsus was the most frequently affected joint (79/197 [40.1 %]). Among the 390 horses with complete lameness data, improvement was reported in approximately 80% by day 14. Investigators rated 307 (78.7%) horses as improved, whereas owners or handlers rated 316 (81.0%) horses as improved at the termination of the study. Horses treated with firocoxib paste had significant improvement in lameness scores from baseline values. Improvement was most rapid within the first 7 days after starting treatment and continued, albeit at a slower rate, through treatment day 14. CONCLUSIONS AND CLINICAL RELEVANCE: Firocoxib significantly improved lameness scores throughout the 14-day period with few adverse effects. Firocoxib can be a safe cyclooxygenase-2-specific NSAID for the treatment of musculoskeletal pain and lameness associated with osteoarthritis. PMID- 22533399 TI - In vitro evaluation of the relationship between the semitendinosus muscle and cranial cruciate ligament in canine cadavers. AB - OBJECTIVE: To evaluate the role of the semitendinosus muscle in stabilization of the canine stifle joint. SAMPLE: Left stifle joints collected from cadavers of 8 healthy Beagles. PROCEDURES: Left hind limbs, including the pelvis, were collected. To mimic the tensile force of the quadriceps, gastrocnemius, and semitendinosus muscles, wires were placed under strain between the ends of each muscle. A sensor was used to measure the tensile force in each wire. Specimens were tested in the following sequence: cranial cruciate ligament (CrCL) intact, CrCL transected, released (tensile force of semitendinosus muscle was released in the CrCL-transected stifle joint), and readjusted (tensile force of semitendinosus muscle was reapplied in the CrCL-transected stifle joint). Specimens were loaded at 65.3% of body weight, and tensile force in the wires as well as the cranial tibial displacement were measured. RESULTS: Tensile force for the CrCL-transected condition increased significantly, compared with that for the CrCL-intact condition. Mean +/- SD cranial tibial displacement for the CrCL transected condition was 2.1 +/- 1.3 mm, which increased to 7.2 +/- 2.3 mm after release of the tensile force in the semitendinosus muscle. CONCLUSIONS AND CLINICAL RELEVANCE: Results supported the contention that the semitendinosus muscle is an agonist of the CrCL in the stifle joint of dogs. Moreover, the quadriceps and gastrocnemius muscles may be antagonists of the CrCL. These findings suggested that the risk of CrCL rupture may be increased by diseases (such as cauda equina syndrome) associated with a decrease in activity of the semitendinosus muscle. PMID- 22533400 TI - Evaluation of a B-cell leukemia-lymphoma 2-specific radiolabeled peptide nucleic acid-peptide conjugate for scintigraphic detection of neoplastic lymphocytes in dogs with B-cell lymphoma. AB - OBJECTIVE: To evaluate use of a radiolabeled peptide nucleic acid-peptide conjugate (RaPP) targeting B-cell leukemia-lymphoma 2 (BCL2) mRNA for scintigraphic detection of neoplastic lymphocytes in dogs with B-cell lymphoma and to assess associations among RaPP uptake, time to tumor progression (TTP), and BCL2 mRNA expression. ANIMALS: 11 dogs with B-cell lymphoma and 1 clinically normal dog. PROCEDURES: Scintigraphic images were acquired 1 hour after IV injection of the RaPP. Regions of interest (ROIs) were drawn around lymph nodes, liver, and spleen; ROI intensity (relative to that of an equally sized region of muscle in the same image) was measured. Each ROI was also subjectively categorized as positive or negative for increased RaPP uptake. Expression of BCL2 mRNA was determined via quantitative reverse transcriptase PCR assay of a lymph node sample from dogs with lymphoma. Associations among imaging results, TTP, and BCL2 mRNA expression were evaluated. RESULTS: Increased RaPP uptake was detected in affected tissues of dogs with lymphoma. Dogs with superficial cervical lymph node ROIs categorized as negative (n = 8) for increased RaPP uptake had a significantly longer TTP than did dogs for which this ROI was considered positive (2). Measured intensity of mandibular and superficial cervical lymph node ROIs was negatively associated with TTP. Associations among BCL2 mRNA and ROI intensity or TTP were not significant. CONCLUSIONS AND CLINICAL RELEVANCE: Increased RaPP uptake at mandibular or superficial cervical lymph node ROIs may be a negative prognostic indicator in dogs with lymphoma. A larger investigation is needed to determine clinical value of the RaPP for disease detection and prognostication. PMID- 22533401 TI - Matrix metalloproteinase-9 expression in mammary gland tumors in dogs and its relationship with prognostic factors and patient outcome. AB - OBJECTIVE: To immunohistochemically evaluate matrix metalloproteinase (MMP)-9 expression in benign and malignant mammary gland tumors (MMTs) in dogs and relate expression to prognostic factors and patient outcome. ANIMALS: 118 female dogs with naturally occurring mammary gland tumors and 8 dogs without mammary gland tumors. PROCEDURES: 24 benign mammary gland tumors and 94 MMTs (1/affected dog) were obtained during surgical treatment; control mammary gland tissue samples were collected from unaffected dogs after euthanasia for reasons unrelated to the study. Tumors were evaluated for proliferation, invasive growth, histologic grade, and metastatic capacity; expression of MMP-9 was determined immunohistochemically, and its relationship with clinical and histologic findings was investigated. For dogs with MMTs, follow-up continued for 2 years; data were used to compute overall survival time and disease-free interval and construct survival curves. RESULTS: MMTs had significantly higher MMP-9 expression in stromal cells and in neo-plastic cells than did the benign neoplasms. Stromal MMP 9 expression was also higher in highly proliferative tumors and in tumors with invasive growth, high histologic grade, and metastatic capacity. Furthermore, tumors from patients with shorter overall survival times and disease-free intervals had higher expression of MMP-9 in stromal cells. CONCLUSIONS AND CLINICAL RELEVANCE: In dogs with MMTs, level of MMP-9 expression by stromal cells was related to factors of poor prognosis and shorter overall survival times and disease-free intervals. These results suggested that MMP-9 produced by tumor adjacent stromal cells contributed to MMT progression in female dogs and that assessment of MMP-9 expression may be a valuable prognostic factor. PMID- 22533402 TI - Comparison of the effects of IV administration of meloxicam, carprofen, and flunixin meglumine on prostaglandin E(2) concentration in aqueous humor of dogs with aqueocentesis-induced anterior uveitis. AB - OBJECTIVE: To compare the effects of meloxicam, carprofen, and flunixin meglumine administered IV on the concentration of prostaglandin E(2) (PGE(2)) in the aqueous humor of dogs with aqueocentesis-induced anterior uveitis. ANIMALS: 15 adult dogs with ophthalmically normal eyes. PROCEDURES: Each dog was assigned to 1 of 4 treatment groups. Treatment groups were saline (0.9% NaCl) solution (1 mL, IV), meloxicam (0.2 mg/kg, IV), carprofen (4.4 mg/kg, IV), and flunixin meglumine (0.5 mg/kg, IV). Each dog was anesthetized, treatment was administered, and aqueocentesis was performed on each eye at 30 and 60 minutes after treatment. Aqueous humor samples were frozen at -80 degrees C until assayed for PGE(2) concentration with an enzyme immunoassay kit. RESULTS: For all 4 treatment groups, PGE(2) concentration was significantly higher in samples obtained 60 minutes after treatment, compared with that in samples obtained 30 minutes after treatment, which indicated aqueocentesis-induced PGE(2) synthesis. For aqueous humor samples obtained 60 minutes after treatment, PGE(2) concentration did not differ significantly among groups treated with saline solution, meloxicam, and carprofen; however, the PGE(2) concentration for the group treated with flunixin meglumine was significantly lower than that for each of the other 3 treatment groups. CONCLUSIONS AND CLINICAL RELEVANCE: Flunixin meglumine was more effective than meloxicam or carprofen for minimizing the PGE(2) concentration in the aqueous humor of dogs with experimentally induced uveitis. Flunixin meglumine may be an appropriate pre-medication for use prior to intraocular surgery in dogs. PMID- 22533403 TI - Evaluation of the aqueous humor flow rate in the eyes of clinically normal cats by use of fluorophotometry. AB - OBJECTIVE: To evaluate aqueous humor flow rate in the eyes of clinically normal cats by use of a noninvasive technique successfully used in other species. ANIMALS: 20 domestic shorthair cats. PROCEDURES: 1 drop of 10% fluorescein sodium was instilled into both eyes of 5 cats every 5 minutes until 3 drops had been administered. Fluorophotometry was performed at 2, 4, 5, 6, 7, 8, 9, and 10 hours after fluorescein application to monitor fluorescein removal and determine aqueous humor flow rate. The 3-drop protocol was used for the remaining 15 cats, and fluorophotometry was performed at 5, 6, 7, and 8 hours after fluorescein application. Aqueous humor flow rates were calculated manually by use of established equations with minor adjustments to constant values to reflect feline anatomic features. Correlation coefficients and slope ratios were calculated to assess the legitimacy of the flow rate data. Paired t tests were calculated to assess for differences between the right and left eyes. RESULTS: Mean +/- SD calculated aqueous humor flow rate in the right, left, and both eyes of the 20 cats was 5.94 +/- 2.30 MUL/min, 5.05 +/- 2.06 MUL/min, and 5.51 +/- 2.21 MUL/min, respectively. Correlation coefficients and slope ratios revealed that the aqueous humor flow rates were accurate. No significant differences in values for the right and left eyes were detected. CONCLUSIONS AND CLINICAL RELEVANCE: Accurate aqueous humor flow values for cats can be determined by use of the fluorophotometric technique evaluated in this study. PMID- 22533404 TI - Evaluation of intraocular pressure measurements obtained by use of a rebound tonometer and applanation tonometer in dogs before and after elective phacoemulsification. AB - OBJECTIVE: To determine whether an applanation tonometer and rebound tonometer can be used to detect similar intraocular pressure (IOP) measurements in eyes of dogs undergoing phacoemulsification. ANIMALS: 24 dogs (40 eyes) undergoing elective phacoemulsification. PROCEDURES: IOP measurements were obtained from each eye by use of both the rebound tonometer and applanation tonometer. Central corneal thickness was measured by use of an ultrasonic pachymeter 3 hours before surgery and 2 and 24 hours after surgery. Statistical analysis was performed by use of paired t tests. RESULTS: Mean +/- SD IOP 3 hours before surgery, 2 hours after surgery, and 24 hours after surgery was 11.9 +/- 4.7 mm Hg, 15.5 +/- 11.7 mm Hg, and 10.9 +/- 6.7 mm Hg, respectively, as measured with the rebound tonometer and 12.2 +/- 5.3 mm Hg, 15.7 +/- 12.5 mm Hg, and 12.4 +/- 5.4 mm Hg, respectively, as measured with the applanation tonometer. Measured IOP did not differ significantly between the 2 tonometers 3 hours before surgery and 2 hours after surgery, but measured IOP differed significantly between the tonometers 24 hours after surgery. CONCLUSIONS AND CLINICAL RELEVANCE: Use of a rebound tonometer underestimated IOP, relative to results for use of an applanation tonometer, by 1.65 mm Hg in eyes 24 hours after phacoemulsification. Caution should be used when IOP measurements obtained with a rebound tonometer are in the high part of the reference range, and verification of these values with an applanation tonometer would be advised. PMID- 22533405 TI - Pharmacokinetic behavior of doxycycline after intramuscular injection in sheep. AB - OBJECTIVE: To determine the pharmacokinetics of a commercial formulation of doxycycline hyclate after IM administration of a single dose to sheep. ANIMALS: 11 healthy domestic sheep. PROCEDURES: For each sheep, doxycycline was administered as a single dose of 20 mg/kg, IM. Blood samples were obtained prior to and for 84 hours after doxycycline administration. Plasma concentrations of doxycycline were determined via high-performance liquid chromatography with UV detection. Pharmacokinetic data were analyzed with noncompartmental methods. RESULTS: Mean +/- SD values for pharmacokinetic parameters included maximum plasma concentration (2.792 +/- 0.791 MUg/mL), time to reach maximum plasma concentration (0.856 +/- 0.472 hours), mean residence time (91.1 +/- 40.78 hours), elimination half-life (77.88 +/- 28.45 hours), and area under the curve (65.67 +/- 9.877 MUg*h/mL). CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that doxycycline had prolonged absorption and elimination in sheep after IM administration. A daily dose of 20 mg/kg would be sufficient to reach effective plasma concentrations against Chlamydia spp (minimum inhibitory concentration, 0.008 to 0.031 MUg/mL) and Staphylococcus aureus (minimum inhibitory concentration, 0.12 MUg/mL). Doxycycline administered IM could be an option for therapeutic use in sheep, although further studies are needed. PMID- 22533406 TI - Evaluation of coronary band temperatures in healthy horses. AB - OBJECTIVE: To measure coronary band temperature (CBT) in healthy horses fed high fructan or low-carbohydrate diets and to analyze the association of CBT with diet, time of day, and ambient temperature. ANIMALS: 6 healthy horses. PROCEDURES: Horses were fed 3 diets (treatment 1, 1 g of fructan/kg fed daily in the morning; treatment 2, 1 g of fructan/kg fed daily in the afternoon; and treatment 3, a low-carbohydrate [7.2%] diet) in a 3 * 3 Latin square study design. For each horse, the CBT of all 4 limbs as well as rectal and ambient temperatures were recorded by use of infrared thermometry and standard thermometers hourly from 8 am to 10 pm for 4 consecutive days after the initiation of each diet. Each horse received each diet, and there was a 10-day washout period between each diet change. Data were analyzed by use of a mixed linear model. RESULTS: 4,320 CBTs were obtained from the 6 horses. The CBT ranged from 9.6 degrees to 35.5 degrees C. Coronary band temperature followed a diurnal pattern and was positively associated with ambient temperature but was not associated with diet. CONCLUSIONS AND CLINICAL RELEVANCE: CBT of healthy horses varied significantly during the day and among limbs. These results should be considered whenever increased CBT is used as an indication of incipient laminitis or in other clinical investigations. PMID- 22533407 TI - Comparison of hydroxyapatite-coated and uncoated pins for transfixation casting in horses. AB - OBJECTIVE: To determine the extent to which a hydroxyapatite coating promotes pin stability in the third metacarpal bone during transfixation casting in horses. ANIMALS: 14 adult horses. PROCEDURES: 7 horses each were assigned to either an uncoated or hydroxyapatite-coated pin group. Three transcortical pins were placed in the third metacarpal bone of each horse and incorporated into a cast for 8 weeks. Insertion and extraction torque were measured, and torque reduction was calculated. Radiography was performed at 0, 4, and 8 weeks. Lameness evaluation was performed at 2, 4, 6, and 8 weeks. Bacteriologic culture of pins and pin holes was performed at pin removal. RESULTS: All horses used casts without major complication throughout the study. Insertion torque was higher in uncoated pins. There was no effect of group on extraction torque. Hydroxyapatite-coated pins had lower torque reduction. Five of 15 hydroxyapatite-coated pins maintained or increased stability, whereas all uncoated pins loosened. Pin hole radiolucency, lameness grades, and positive bacteriologic culture rates were not different between groups. CONCLUSIONS AND CLINICAL RELEVANCE: Hydroxyapatite coating increased pin stability within the third metacarpal bone of horses during 8 weeks of transfixation casting but did not improve pin performance on clinical assessments. Clinical use of hydroxyapatite-coated transfixation pins may result in greater pin stability; however, further research is necessary to improve the consistency of pin osteointegration and elucidate whether clinical benefits will ultimately result from this approach in horses. PMID- 22533408 TI - Efficacy of vaccination of cattle with the Leptospira interrogans serovar hardjo type hardjoprajitno component of a pentavalent Leptospira bacterin against experimental challenge with Leptospira borgpetersenii serovar hardjo type hardjo bovis. AB - OBJECTIVE: To evaluate the efficacy of vaccination with the Leptospira interrogans serovar hardjo type hardjoprajitno component of a pentavalent Leptospira bacterin against a virulent experimental challenge with Leptospira borgpetersenii serovar hardjo type hardjo-bovis strain 203 in cattle. ANIMALS: Fifty-five 6-month-old Holstein heifers. PROCEDURES: Heifers that were negative for persistent infection with bovine viral diarrhea virus determined via immunohistochemical testing and negative for Leptospira interrogans serovar pomona, Leptospira interrogans serovar hardjo, Leptospira interrogans serovar grippotyphosa, Leptospira interrogans serovar bratislava, Leptospira interrogans serovar canicola, and Leptospira interrogans serovar icterohaemorrhagiae determined via microscopic agglutination assay were enrolled in the study. Two heifers were separated and used for the challenge passage. The remaining heifers were vaccinated twice with a commercial pentavalent bacterin or a sham vaccine 21 days apart and subsequently challenged with L borgpetersenii serovar hardjo type hardjo-bovis strain 203. Urinary shedding, antibody titers, and clinical signs of leptospirosis infection were recorded for 8 weeks after challenge. RESULTS: Heifers that received the pentavalent bacterin did not shed the organism in urine after challenge and did not have renal colonization at necropsy. Heifers that were sham vaccinated shed the organism in urine and had renal colonization. CONCLUSIONS AND CLINICAL RELEVANCE: Results provided evidence that a pentavalent Leptospira vaccine containing L interrogans serovar hardjo type hardjoprajitno can provide protection against challenge with L borgpetersenii serovar hardjo type hardjo-bovis strain 203. It is important to demonstrate cross-protection that is vaccine specific against disease-causing strains of organisms that are prevalent under field conditions. PMID- 22533409 TI - Efficacy of an avirulent live vaccine against Lawsonia intracellularis in the prevention of proliferative enteropathy in experimentally infected weanling foals. AB - OBJECTIVE: To determine the efficacy of an avirulent Lawsonia intracellularis vaccine in preventing proliferative enteropathy in weanling foals. ANIMALS: 12 healthy weanling foals. PROCEDURES: Foals were randomly assigned to a vaccinated, nonvaccinated, or control group. Vaccinated foals received an avirulent porcine L intracellularis frozen-thawed vaccine intrarectally 60 and 30 days prior to experimental challenge. On day 1, vaccinated and nonvaccinated foals were challenged via nasogastric intubation with a virulent heterologous isolate of L intracellularis. Control foals were not challenged. Clinical observation and ultrasonographic evaluation of the small intestine were performed, and body weight, serum concentration of total solids, fecal excretion of L intracellularis, and seroconversion were measured for each foal until day 56. Diseased foals were treated with antimicrobials and supportive care. RESULTS: None of the 4 vaccinated foals developed clinical disease following challenge with virulent L intracellularis. Three of 4 nonvaccinated foals developed moderate to severe clinical signs compatible with proliferative enteropathy, hypoproteinemia, and thickened small intestinal loops. Vaccinated foals had significantly less fecal shedding of L intracellularis than nonvaccinated foals. Serologic responses between vaccinated and nonvaccinated foals after challenge were similar. Control foals remained clinically unaffected with no evidence of fecal shedding and seroconversion. CONCLUSIONS AND CLINICAL RELEVANCE: Intrarectal administration of a commercial avirulent porcine vaccine against L intracellularis resulted in complete protection against proliferative enteropathy in the foals in this study and may also reduce environmental contamination with the organism on endemic farms. PMID- 22533410 TI - Proteomic characterization of Aspergillus fumigatus treated with an antifungal coumarin for identification of novel target molecules of key pathways. AB - A synthetic coumarin, N,N,N-triethyl-11-(4-methyl-2-oxo-2H-chromen-7-yloxy)-11 oxoundecan-1-aminium bromide (SCD-1), having potent activity against pathogenic Aspergilli (MIC90 15.62 MUg/mL), was investigated to identify its molecular targets in the pathogen. The proteome of Aspergillus fumigatus was developed after treatment with sublethal doses of compound and analyzed. The results demonstrated 143 differentially expressed proteins on treatment with SCD-1. The expression of four proteins, namely cell division control protein, ubiquitin-like activating enzyme, vacuolar ATP synthase catalytic subunit A, and UTP-glucose-1 phosphate uridylyltransferase of A. fumigatus, was completely inhibited, whereas there were 13 newly expressed and 96 overexpressed proteins, mainly belonging to stress pathway. The treatment of A. fumigatus with SCD-1 also led to attenuation of proteins involved in cell replication and other important biosynthetic processes, including riboflavin biosynthesis, which has been pathogen-specific. In addition to key enzymatic players and antioxidants, nine hypothetical proteins were also identified, seven of which have been novel, being described for the first time. As no cellular functions have yet been described for these hypothetical proteins, their alteration in response to SCD-1 provides significant information about their putative roles in pathogen defense. PMID- 22533411 TI - Mutagenesis of isopentenyl phosphate kinase to enhance geranyl phosphate kinase activity. AB - Isopentenyl phosphate kinase (IPK) catalyzes the ATP-dependent phosphorylation of isopentenyl phosphate (IP) to form isopentenyl diphosphate (IPP) during biosynthesis of isoprenoid metabolites in Archaea. The structure of IPK from the archeaon Thermoplasma acidophilum (THA) was recently reported and guided the reconstruction of the IP binding site to accommodate the longer chain isoprenoid monophosphates geranyl phosphate (GP) and farnesyl phosphate (FP). We created four mutants of THA IPK with different combinations of alanine substitutions for Tyr70, Val73, Val130, and Ile140, amino acids with bulky side chains that limited the size of the side chain of the isoprenoid phosphate substrate that could be accommodated in the active site. The mutants had substantially increased GP kinase activity, with 20-200-fold increases in k(cat)(GP) and 30-130-fold increases in k(cat)(GP)/K(M)(GP) relative to those of wild-type THA IPK. The mutations also resulted in a 10(6)-fold decrease in k(cat)(IP)/K(M)(IP) compared to that of wild-type IPK. No significant change in the kinetic parameters for the cosubstrate ATP was observed, signifying that binding between the nucleotide binding site and the IP binding site was not cooperative. The shift in substrate selectivity from IP to GP, and to a lesser extent, FP, in the mutants could act as a starting point for the creation of more efficient GP or FP kinases whose products could be exploited for the chemoenzymatic synthesis of radiolabeled isoprenoid diphosphates. PMID- 22533412 TI - The many-level value of proofs of concept. PMID- 22533413 TI - A bioinformatics analysis of Lamin-A regulatory network: a perspective on epigenetic involvement in Hutchinson-Gilford progeria syndrome. AB - Hutchinson-Gilford progeria syndrome (HGPS) is a rare human genetic disease that leads to premature aging. HGPS is caused by mutation in the Lamin-A (LMNA) gene that leads, in affected young individuals, to the accumulation of the progerin protein, usually present only in aging differentiated cells. Bioinformatics analyses of the network of interactions of the LMNA gene and transcripts are presented. The LMNA gene network has been analyzed using the BioGRID database (http://thebiogrid.org/) and related analysis tools such as Osprey (http://biodata.mshri.on.ca/osprey/servlet/Index) and GeneMANIA ( http://genemania.org/). The network of interaction of LMNA transcripts has been further analyzed following the competing endogenous (ceRNA) hypotheses (RNA cross talk via microRNAs [miRNAs]) and using the miRWalk database and tools (www.ma.uni heidelberg.de/apps/zmf/mirwalk/). These analyses suggest particular relevance of epigenetic modifiers (via acetylase complexes and specifically HTATIP histone acetylase) and adenosine triphosphate (ATP)-dependent chromatin remodelers (via pBAF, BAF, and SWI/SNF complexes). PMID- 22533415 TI - Postponing aging and prolonging life expectancy with the knowledge-based economy. AB - People are interested in the aging phenomenon and hope that scientists are doing as much as they can to solve the mysteries of aging. However, this is not the case. A lot of knowledge is produced for local interests in curing specific disorders; aging is studied much less. Today's economy is undergoing a transition to a knowledge-based economy. Knowledge of aging should be integrated into the economies of contemporary societies. Aging research and intervention can ensure better health, primarily among middle-aged and older people, and prolong life. There are many reasons why postponing aging and rejuvenation research is not as widespread as it should be. Developed countries should create economic stimuli for such studies and intervention. PMID- 22533414 TI - Hormone supplementation during aging: how much and when? AB - Circulating levels of dehydroepiandrosterone, a major adrenal steroid, show a marked age-related decrease in both humans and nonhuman primates. Because this decrease has been implicated in age-related cognitive decline, we administered supplementary dehydroepiandrosterone to perimenopausal rhesus macaques (Macaca mulatta) to test for cognitive benefits. Although recognition memory improved, there was no benefit to spatial working memory. To address the limitations of this study we developed a hormone supplementation regimen in aged male macaques that more accurately replicates the 24-hr androgen profiles of young animals. We hypothesize that this more comprehensive physiological hormone replacement paradigm will enhance cognitive function in the elderly. PMID- 22533416 TI - The last recession was good for life expectancy. AB - Most people think that economic growth and a good economy are prerequisites for good health and high life expectancy. As such, a recession should decrease life expectancy or stop it from rising. In fact, recessions can boost life expectancy. This was the case during the Great Depression in the United States from 1929 to 1932 and during the recession in the European Union in 2009. In 2009, life expectancy increased most rapidly in European countries where the decrease in gross domestic product was greatest-Estonia, Latvia, and Lithuania. Studies of life expectancy increasing during recessions can yield valuable information regarding extending average life expectancy without essential costs. PMID- 22533417 TI - Acetyl-L-carnitine activates the peroxisome proliferator-activated receptor-gamma coactivators PGC-1alpha/PGC-1beta-dependent signaling cascade of mitochondrial biogenesis and decreases the oxidized peroxiredoxins content in old rat liver. AB - The behavior of the peroxisome proliferator-activated receptor-gamma coactivators PGC-1alpha/PGC-beta-dependent mitochondrial biogenesis signaling pathway, as well as the level of some antioxidant enzymes and proteins involved in mitochondrial dynamics in the liver of old rats before and after 2 months of acetyl-L-carnitine (ALCAR) supplementation, was tested. The results reveal that ALCAR treatment is able to reverse the age-associated decline of PGC-1alpha, PGC-1beta, nuclear respiratory factor 1 (NRF-1), mitochondrial transcription factor A (TFAM), nicotinamide adenine dinucleotide (NADH) dehydrogenase subunit 1 (ND1), and cytochrome c oxidase subunit IV (COX IV) protein levels, of mitochondrial DNA (mtDNA) content, and of citrate synthase activity. Moreover, it partially reverses the mitochondrial superoxide dismutase 2 (SOD2) decline and reduces the cellular content of oxidized peroxiredoxins. These data demonstrate that ALCAR treatment is able to promote in the old rat liver a new mitochondrial population that can contribute to the cellular oxidative stress reduction. Furthermore, a remarkable decline of Drp1 and of Mfn2 proteins is reported here for the first time, suggesting a reduced mitochondrial dynamics in aging liver with no effect of ALCAR treatment. PMID- 22533418 TI - Survival study of metallothionein-1 transgenic mice and respective controls (C57BL/6J): influence of a zinc-enriched environment. AB - The role of metallothioneins (MTs) in aging is not completely understood. Several studies have shown evidence that these proteins could represent a defense system against oxidative damage, but survival studies on mice overexpressing MTs are poor. Here we describe a survival study performed on old MT-1-overexpressing mice (MT-TG) and their respective controls (C57BL/6J) fed a standard or zinc (Zn) supplemented diet. MT-TG mice had significantly increased survival compared with control. Zn supplementation affects the survival curves of MT-TG and C57BL/6J mice differently. This study poses the basis for intervention based on gene therapy with MTs to enhance the health span of laboratory mice. PMID- 22533419 TI - Identification and characterization of an abeta oligomer precipitating peptide that may be useful to explore gene therapeutic approaches to Alzheimer disease. AB - A key feature of Alzheimer disease (AD) is the pathologic self-association of the amyloid-beta (Abeta) peptide, leading to the formation of diffusible toxic Abeta oligomers and extracellular amyloid plaques. Next to extracellular Abeta, intraneuronal Abeta has important pathological functions in AD. Agents that specifically interfere with the oligomerization processes either outside or inside of neurons are highly desired for the elucidation of the pathologic mechanisms of AD and might even pave the way for new AD gene therapeutic approaches. Here, we characterize the Abeta binding peptide L3 and its influence on Abeta oligomerization in vitro. Preliminary studies in cell culture demonstrate that stably expressed L3 reduces cell toxicity of externally added Abeta in neuroblastoma cells. PMID- 22533421 TI - A phytochemical approach to experimental metabolic syndrome-associated renal damage and oxidative stress. AB - The aim of this study was to evaluate the effect of DTS-phytocompound on oxidant antioxidant balance and protein damage in the kidneys of rats administered high doses of fructose. Adult male Wistar rats were divided into four groups. Group A received a control diet, whereas groups B and C were fed a high-fructose diet (60 g/100 g), the latter with additional DTS (50 mg/kg per day) for 60 days. Lipo- and nitro-peroxidation together with alpha-smooth muscle actin (alpha-SMA) expression in the glomerular and interstitial tissue of the kidneys were measured after 60 days. Fructose-fed rats showed significantly higher lipoperoxidation, 2,4-dinitrophenol and 3-nitrotyrosine protein adducts, and upregulation of alpha SMA in the kidney. DTS significantly decreased such redox unbalance in renal tissue, while partially downregulating alpha-SMA (p<0.01). These data suggest the potential clinical benefit of DTS in protecting the kidneys from metabolic syndrome-associated changes; gender-related analysis is under way. PMID- 22533420 TI - In silico drug screen in mouse liver identifies candidate calorie restriction mimetics. AB - Calorie restriction (CR) extends life span in mammals and delays the onset of age related diseases, including cancer and diabetes. Drugs that target the same genes and pathways as CR may have enormous therapeutic potential. Recently, genome scale data on the responses of human cell lines to over 1,000 drug treatments have become available. Here we integrate these data with gene expression signatures of CR in mouse liver to generate a prioritized list of candidate CR mimetics. We identify 14 drugs that reproduce the effects of CR at the transcriptional level. PMID- 22533422 TI - Biomarine extracts significantly protect from ultraviolet A-induced skin photoaging: an ex vivo study. AB - We tested the activity of the marine nutraceutical CL-1222 added with a coenzyme Q10 (CoQ10)-lutein-selenium component (Celergen((r)), Laboratoires-Dom, Switzerland) to protect human fibroblasts against ultraviolet A (UVA)-induced photoaging. Cells obtained from 22- to 39-year-old healthy donors were pretreated with CL-1222 before UV irradiation, as compared with same quantity of the CoQ10 lutein-selenium component. As compared to untreated control, UVA-irradiated samples exhibited a significant increase of secreted matrix metalloproteinase-1 (MMP-1) (p<0.001) with over four-fold MMP-1 upregulation (p<0.001). Samples treated with CL-1222, but not with the CoQ10-lutein-selenium component, showed a significant decrease of MMP-1 secretion (p<0.01) and expression decrease (>60%, p<0.01) with >54% elastase activity inhibition (p<0.01). This preliminary study shows that such marine nutraceuticals can significantly protect against UV irradiation irrespective of the CoQ10-lutein-selenium component with a specific protective gene expression modulation amenable to novel clinical applications. PMID- 22533423 TI - POLI-mix functional food enhances steady-state bioenergetic status independently of age: an experimental study. AB - BALB/c mice were divided into young, middle-aged, and aged groups, and each group was given 3 weeks of oral treatments: (1) 1 mL of VBC1-99 (a mixture of 42 fruits and vegetables extracts) or (2) 1 mL of same amount of antioxidant vitamins as control. Steady-state hepatic adenosine triphosphate (ATP) was assessed by phosphorus-31 nuclear magnetic resonance ((31)P-NMR) spectroscopy as: beta ATP/reference peak, inorganic phosphorus (Pi)/peak and beta-ATP/Pi. As compared to untreated control, VBC1-99 significantly enhanced beta-ATP/peak and beta ATP/Pi ratios (p<0.01) in all age groups and throughout the observation period (p<0.05) together with a significant decrease of Pi/ref peak ratio (p<0.05). However, this value in middle-aged and aged mice was comparable to antioxidant control mice. These NMR data demonstrate that VBC1-99 has a beneficial effect on hepatic energy metabolism, irrespective of age. PMID- 22533424 TI - Vascular and neuronal ischemic damage in cryonics patients. AB - Cryonics technology seeks to cryopreserve the anatomical basis of the mind so that future medicine can restore legally dead cryonics patients to life, youth, and health. Most cryonics patients experience varying degrees of ischemia and reperfusion injury. Neurons can survive ischemia and reperfusion injury more than is generally believed, but blood vessels are more vulnerable, and such injury can impair perfusion of vitrifying cryoprotectant solution intended to eliminate ice formation in the brain. Forms of vascular and neuronal damage are reviewed, along with means of mitigating that damage. Recommendations are also made for preventing such damage. PMID- 22533425 TI - Is the mean blood leukocyte telomere length a predictor for sporadic thoracic aortic aneurysm? Data from a preliminary study. AB - Telomeres have been postulated as a universal clock that shortens in parallel with cellular aging. They are specialized DNA-protein structures at the ends of chromosome with remarkable functions--preventing their recognition as double stranded DNA breaks, protecting their recombination and degradation, and avoiding a DNA damage cellular response. Telomere shortening is currently considered the best aging marker, but is also a predictor for age-related diseases, including cardiovascular diseases. Biological age clearly seems to be a better predictor of vascular risk rather than chronological age. This concept is supported by key assumptions that peripheral blood leukocyte telomere content accurately reflects that of the vascular wall and its decrease is associated with premature vascular disease. Thus, we are analyzing whether the mean of blood leukocyte telomere length might also be a predictor for sporadic thoracic aortic aneurysm (S-TAA). The preliminary results seem to be promising. Shorter telomeres were detected in patients than in controls. Thus, mean of blood leukocyte telomere length could contribute to identify individuals at S-TAA risk. PMID- 22533426 TI - Beneficial modulation from a high-purity caviar-derived homogenate on chronological skin aging. AB - This study tested the activity of LD-1227, which contains a caviar-derived homogenate added with coenzyme Q(10) (CoQ(10))-selenium component (CaviarLieri((r)), Lab-Dom, Switzerland), in aged human skin and its potential role on skin mitochondria function. Human dermal fibroblasts were obtained from healthy donors over 70 years old and treated with LD-1227 for 72 hr. As compared to baseline, LD-1227 caused a robust (>67%) collagen type I synthesis (p<0.001) and decreased fibronectin synthesis (p<0.05) with significant fibronectin messenger RNA (mRNA) downregulation (p<0.05, r=0.78). A significant collagen mRNA overexpression occurred with LD-1227 treatment (p<0.05). Mitochondria cytosolic adenosine triphosphate (ATP) level decreased in aged skin samples (p<0.05 vs. young control), but this phenomenon was reversed by LD-1227 (p<0.01). These data show that LD-1227 may modify the extracellular matrix milieu in aged skin and also beneficially affect mitochondrial function. PMID- 22533428 TI - Aging of budding yeast. AB - Accumulation of insoluble (i.e., aggregated, cross-linked) protein is proposed to be a major cause of aging of the budding yeast cell Saccharomyces cerevisiae. This may give rise to the Lansing effect--precocious aging of parthenogenetically propagated daughters from old mothers--and to the genomic instability observed in old cells. PMID- 22533427 TI - Cardioprotective effect of a biofermented nutraceutical on endothelial function in healthy middle-aged subjects. AB - We tested a biofermented nutraceutical (FPP) that has been previously shown to positively modulate nitric oxide (NO). Forty-two healthy middle-aged subjects were given 3 grams of FPP three times a day for 6 weeks, and tests were repeated at 3 and 6 weeks; the control group was given a placebo. Flow-mediated dilation (FMD) was measured together with NO compounds (nitrogen oxides [NOx]: NO(2)( )+NO(3)(-)) plasma levels and asymmetrical dimethylarginine (ADMA). In the interventional group, overall FMD significantly increased from 4.2% to 7.3% (p<0.05 vs. placebo). A significant increase in plasma NO and a decrease in ADMA were detected after consumption of FPP (p<0.01). Although larger studies are awaited, it appears that, at least in healthy individuals, such nutraceutical intervention by positively acting on significant cardiovascular parameters can be considered in the armamentarium of a proactive age-management strategy. PMID- 22533429 TI - Mediterranean diet and longevity in Sicily: survey in a Sicani Mountains population. AB - Over the past several years, increasing evidence suggests that the Mediterranean diet has a beneficial influence on several age-related diseases, showing protective effect on health and longevity. Mediterranean diet refers to dietary patterns found in olive-growing regions of the Mediterranean countries. Previous data reported that in Sicily, Italy, the largest Mediterranean island, there are some mountainous regions where there is a high frequency of male centenarians with respect to the Italian average. The aim of the present study was to characterize centenarians living in one of this region, the Sicani Mountains, located in western Sicily. Present data shows that in this zone there are more centenarians with respect to the Italian average. In fact, in the three villages of the Sicani Mountains, there were 15 people ranging from 100 to 107 years old, of the total population of about 10,000 inhabitants. This centenarian number was more than six-fold higher the national average (15.0 vs. 2.4/10,000); the female/male ratio was 1.5 in the study area, whereas the national ratio is 4.54. Centenarians living in these villages had anthropometric measurements within normal limits and moderate sensory disability without any sign of age-related diseases, including cognitive deterioration and dementia. In addition, their clinical chemistry profile was similar to young controls and far better than that of old controls. Unequivocally, their nutritional assessment showed a high adherence to the Mediterranean nutritional profile, with low glycemic index food consumed. Overall, close adherence to Mediterranean diet seems to play a key role in age-related disease prevention and in attaining longevity. PMID- 22533431 TI - Approach to assessing the walking motion of elderly males based on kinetic parameters of young males. AB - The objectives of this study were to explore a method of evaluating the walking motion of elderly males using mainly kinetic parameters and to determine how to maintain their level of walking motion to equal that of the young. We employed the coefficient of variation (CV) (=standard deviation[SD]/MEAN * 100), z-score, and weighted z-score (WZ) (=z-score/CV) and examined the relationship between the WZ of each parameter and age by regression analysis. Finally, we used the regression line to estimate "gait age" and determined the critical factors of gait decay in elderly individuals. PMID- 22533430 TI - Positive lysosomal modulation as a unique strategy to treat age-related protein accumulation diseases. AB - Lysosomes are involved in degrading and recycling cellular ingredients, and their disruption with age may contribute to amyloidogenesis, paired helical filaments (PHFs), and alpha-synuclein and mutant huntingtin aggregation. Lysosomal cathepsins are upregulated by accumulating proteins and more so by the modulator Z-Phe-Ala-diazomethylketone (PADK). Such positive modulators of the lysosomal system have been studied in the well-characterized hippocampal slice model of protein accumulation that exhibits the pathogenic cascade of tau aggregation, tubulin breakdown, microtubule destabilization, transport failure, and synaptic decline. Active cathepsins were upregulated by PADK; Rab proteins were modified as well, indicating enhanced trafficking, whereas lysosome-associated membrane protein and proteasome markers were unchanged. Lysosomal modulation reduced the pre-existing PHF deposits, restored tubulin structure and transport, and recovered synaptic components. Further proof-of-principle studies used Alzheimer disease mouse models. It was recently reported that systemic PADK administration caused dramatic increases in cathepsin B protein and activity levels, whereas neprilysin, insulin-degrading enzyme, alpha-secretase, and beta-secretase were unaffected by PADK. In the transgenic models, PADK treatment resulted in clearance of intracellular amyloid beta (Abeta) peptide and concomitant reduction of extracellular deposits. Production of the less pathogenic Abeta(1-38) peptide corresponded with decreased levels of Abeta(1-42), supporting the lysosome's antiamyloidogenic role through intracellular truncation. Amelioration of synaptic and behavioral deficits also indicates a neuroprotective function of the lysosomal system, identifying lysosomal modulation as an avenue for disease modifying therapies. From the in vitro and in vivo findings, unique lysosomal modulators represent a minimally invasive, pharmacologically controlled strategy against protein accumulation disorders to enhance protein clearance, promote synaptic integrity, and slow the progression of dementia. PMID- 22533432 TI - Kinetics of advanced glycation end products formation on bovine serum albumin with various reducing sugars and dicarbonyl compounds in equimolar ratios. AB - Reducing sugars and reactive dicarbonyl compounds play a major role in glycation of proteins in vivo. Glycation of proteins is the first step in of a nonenzymatic reaction, resulting in advanced glycation end products (AGEs). AGEs can inactivate proteins or modify their biological activities. Therefore, it is important to understand the mechanism of AGE formation. Here, we systematically analyzed the kinetics of AGE formation in vitro by fluorescence and absorption measurements utilizing a microplate reader system and bovine serum albumin (BSA) as a model protein. Comparing different concentrations of BSA, we applied various reducing sugars and reactive dicarbonyl compounds as AGE-inducing agents at different concentrations. In summary, this experimental setup enabled us to measure the kinetics of AGE formation in an efficient and defined way. PMID- 22533433 TI - Telomerase expression in adult and old mouse Purkinje neurons. AB - Telomerase promotes tissue regeneration by delaying the entrance of cells into senescence. Studies performed on cells or animals overexpressing telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase, have revealed that TERT exhibits antiapoptotic effects in neurons. However, it is not clear whether endogenous TERT possesses these functions as well. Here we demonstrate the presence of active telomerase in the cytoplasm and nucleus of cerebellar Purkinje neurons of adult and old mice. TERT protein levels are reduced with age, whereas in the nucleus TERT activity is increased. These findings suggest that telomerase plays a role in the aging of nondividing cells. PMID- 22533434 TI - Bile acids, chaperones, and mammalian longevity. AB - Bile acids are detergent molecules derived from cholesterol in the liver that are important for the metabolism and absorption of lipids in the intestine. Bile acids are also steroid hormones activating specific nuclear receptors and G protein-coupled receptors. Conjugated bile acids are cytoprotective and anticarcinogenic. Bile acid synthesis and bile flow decreases markedly during aging. The housekeeping molecular chaperones are stress response proteins, important for the processes of folding, maintenance, and repair of proteins, RNA, and DNA, as well as for the structure and function of the steroid hormone receptors. The level of expression of the molecular chaperones correlates with mammalian longevity as well as with the life span of differentiated cells. The functions of the chaperone machinery are progressively impaired during aging, and the progressive age-related impairment of these housekeeping mechanisms probably contributes to the phenotype of aging. This review presents evidence that the bile acids are chemical chaperones, improving the general chaperone defense, and thus serve to support an epigenetic mechanism of possible significance for the evolution of mammalian longevity, as well as for the attainment of healthy aging. PMID- 22533435 TI - Detection of alpha-synuclein aggregates by fluorescence microscopy. AB - Parkinson disease (PD) is one of the most common age-related neurodegenerative diseases associated with motor deficiencies in humans. The symptoms are caused by the death of dopaminergic neurons in the brain, which is accompanied by the misfolding and aggregation of the protein alpha-synuclein. Diagnosis is based on the incidence of clinical symptoms, although they only appear as a result of the irreversible damage of neurons during the disease. Identification of a suitable biomarker would allow preclinical diagnosis. We an approach to quantify single alpha-synuclein aggregates as a possible biomarker for PD. PMID- 22533436 TI - Can Alzheimer disease be a form of type 3 diabetes? AB - Alzheimer disease (AD) and metabolic syndrome are two highly prevalent pathological conditions of Western society due to incorrect diet, lifestyle, and vascular risk factors. Recent data have suggested metabolic syndrome as an independent risk factor for AD and pre-AD syndrome. Furthermore, biological plausibility for this relationship has been framed within the "metabolic cognitive syndrome" concept. Due to the increasing aging of populations, prevalence of AD in Western industrialized countries will rise in the near future. Thus, new knowledge in the area of molecular biology and epigenetics will probably help to make an early molecular diagnosis of dementia. An association between metabolic syndrome and specific single-nucleotide polymorphisms (SNPs) in the gene INPPL1, encoding for SHIP2, a SH2 domain-containing inositol 5 phosphatase involved in insulin signaling, has been described. According to recent data suggesting that Type 2 diabetes represents an independent risk factor for AD and pre-AD, preliminary results of a case-control study performed to test the putative association between three SNPs in the SHIP2 gene and AD show a trend toward association of these SNPs with AD. PMID- 22533437 TI - Plasmonic photothermic and stem cell therapy of atherosclerotic plaque as a novel nanotool for angioplasty and artery remodeling. AB - BACKGROUND: Some modern angioplasty techniques drastically affect the geometry of the plaque and the lumen, but have some inherent clinical and technical limitations. METHODS: A total of 101 Yucatan miniature swine were allocated to the three following groups (34 pigs into 60/15- to 70/40-nm silica-gold nanoparticles (NPs), 34 swine into ferromagnetic group with iron-bearing NPs and delivery in hand of magnetic fields, and 33 in a sirolimus stenting control). Animals in the nanogroup were subdivided further into four subsets according to the delivery approach: (1) Intracoronary infused circulating stem progenitor cells (SPCs), including SP(+) (side population) cells, (2) intracoronary infused, ultrasound-mediated, albumin-coated, gas-filled microbubbles, (3) CD73(+)105(+) SPCs in the composition of a bioengineered on-artery patch (cardiac surgery), (4) CD73(+)CD105(+) SPCs engrafted by manual subadventitial injection (cardiac surgery). NPs were detonated with a microwatt near-infrared (NIR) laser (821 nm, 35-44 W/cm(2) for 7 min of exposure). RESULTS: Changes of the total atheroma volume (TAV; mm(3)) immediately after the laser irradiation at month 6 in the nanoshell, ferromagnetic, and control groups were -7.54%/-22.92%, -9.7%/-16.84%, and -10.5%/-7.06% (p<0.01), respectively, and in the subsets reached -2.79%/ 21.92%, -6.26%/-15.24%, -4.6%/-31.21%, -16.5%/-23.3% (p<0.05), respectively. Some cases of atherothrombosis and distal embolism (23.5%) were documented only in the microbubbles subset. The impact of the therapy on the nonorganic part of the plaque-antiinflammative and antiapoptotic effects, signs of neovascularization, and restoration of artery function-were predominant in the observed subsets with SPCs (p<0.01). CONCLUSION: Nanoburning, especially in combination with stem cell technologies, is a very challenging technique for altering advanced plaque and holds the promise of revolutionizing state-of-the-art interventional cardiology, assuring destruction of plaque and functional restoration of the vessel wall. It could potentially become the current mechanical and pharmacological treatment. PMID- 22533438 TI - Early impairment of long-term depression in the perirhinal cortex of a mouse model of Alzheimer's disease. AB - Visual recognition memory is early impaired in Alzheimer's disease. Long-term depression of synaptic transmission in the perirhinal cortex is critically involved in this form of memory. We found that synaptic transmission was impaired in perirhinal cortex slices obtained from 3-month-old Tg2576 mice, and that 3,000 pulses at 5 Hz induced long-term depression in perirhinal cortex slices from age matched control mice, but not in those from Tg2576 mice. To our knowledge, these data provide the first evidence of synaptic transmission and long-term depression impairment in the perirhinal cortex in an animal model of Alzheimer's disease, and the earliest synaptic deficit in Tg2576 mice. PMID- 22533440 TI - Accelerated aging versus rejuvenation of the immune system in heterochronic parabiosis. AB - The emergence of immune disorders in aging is explained by many factors, including thymus dysfunction, decrease in the proportion and function of naive T cells, and so forth. There are several approaches to preventing these changes, such as thymus rejuvenation, stem cells recovery, modulation of hormone production, and others. Our investigations of heterochronic parabiosis have shown that benefits of a young immune system, e.g., actively working thymus and regular migration of young hematopoietic stem cells between parabiotic partners, appeared unable to restore the immune system of the old partner. At the same time, we have established a progressive immune impairment in the young heterochronic partners. The mechanism of age changes in the immune system in this model, which may lead to reduced life expectancy, has not been fully understood. The first age-related manifestation in the young partners observed 3 weeks after the surgery was a dramatic increase of CD8(+)44(+) cells population in the spleen. A detailed analysis of further changes revealed a progressive decline of most immunological functions observable for up to 3 months after the surgery. This article reviews possible mechanisms of induction of age-related changes in the immune system of young heterochronic partners. The data obtained suggest the existence of certain factors in the old organisms that trigger aging, thus preventing the rejuvenation process. PMID- 22533439 TI - Impairments of synaptic plasticity in aged animals and in animal models of Alzheimer's disease. AB - Aging is associated with a gradual decline in cognitive functions, and more dramatic cognitive impairments occur in patients affected by Alzheimer's disease (AD). Electrophysiological and molecular studies performed in aged animals and in animal models of AD have shown that cognitive decline is associated with significant modifications in synaptic plasticity (i.e., activity-dependent changes in synaptic strength) and have elucidated some of the cellular mechanisms underlying this process. Morphological studies have revealed a correlation between the quality of memory performance and the extent of structural changes of synaptic contacts occurring during memory consolidation. We briefly review recent experimental evidence here. PMID- 22533441 TI - Scientific excellence in biomedical research: new opportunities and challenges in Kazakhstan. AB - Kazakhstan is the ninth largest country in the world by territory, having a land mass similar to Western Europe and a population of 16 million. Oil and gas reserves rank it among the top 10 countries in the world and have fueled an average growth rate of 9.4% as well as a doubling of Kazakhstan's per capita gross domestic product since 2001. A strategic goal of Kazakhstan is to diversify the economy in other sectors such as construction, heavy machinery, agriculture, tourism, and education. PMID- 22533443 TI - Toxicogenomic analysis of chlorine vapor-induced porcine skin injury. AB - Chlorine is an industrial chemical that can cause cutaneous burns. Understanding the molecular mechanisms of tissue damage and wound healing is important for the selection and development of an effective post-exposure treatment. This study investigated the effect of cutaneous chlorine vapor exposure using a weanling swine burn model and microarray analysis. Ventral abdominal sites were exposed to a mean calculated chlorine vapor concentration of 2.9 g/L for 30 min. Skin samples were harvested at 1.5 h, 3 h, 6 h, and 24 h post-exposure and stored in RNAlater((r)) until processing. Total RNA was isolated, processed, and hybridized to Affymetrix GeneChip((r)) Porcine Genome Arrays. Differences in gene expression were observed with respect to sampling time. Ingenuity Pathways Analysis revealed seven common biological functions among the top ten functions of each time point, while canonical pathway analysis revealed 3 genes (IL-6, IL1A, and IL1B) were commonly shared among three significantly altered signaling pathways. The transcripts encoding all three genes were identified as common potential therapeutic targets for Phase II/III clinical trial, or FDA-approved drugs. The present study shows transcriptional profiling of cutaneous wounds induced by chlorine exposure identified potential targets for developing therapeutics against chlorine-induced skin injury. PMID- 22533444 TI - Comparison of the determination of a low-concentration active ingredient in pharmaceutical tablets by backscatter and transmission Raman spectrometry. AB - A total of 383 tablets of a pharmaceutical product were analyzed by backscatter and transmission Raman spectrometry to determine the concentration of an active pharmaceutical ingredient (API), chlorpheniramine maleate, at the 2% m/m (4 mg) level. As the exact composition of the tablets was unknown, external calibration samples were prepared from chlorpheniramine maleate and microcrystalline cellulose (Avicel) of different particle size. The API peak at 1594 cm(-1) in the second derivative Raman spectra was used to generate linear calibration models. The API concentration predicted using backscatter Raman measurements was relatively insensitive to the particle size of Avicel. With transmission, however, particle size effects were greater and accurate prediction of the API content was only possible when the photon propagation properties of the calibration and sample tablets were matched. Good agreement was obtained with HPLC analysis when matched calibration tablets were used for both modes. When the calibration and sample tablets are not chemically matched, spectral normalization based on calculation of relative intensities cannot be used to reduce the effects of differences in physical properties. The main conclusion is that although better for whole tablet analysis, transmission Raman is more sensitive to differences in the photon propagation properties of the calibration and sample tablets. PMID- 22533445 TI - Inhibition of quorum sensing (QS) in Yersinia enterocolitica by an orange extract rich in glycosylated flavanones. AB - Flavanones, flavonoids abundant in Citrus , have been shown to interfere with quorum sensing (QS) and affect related physiological processes. We have investigated the QS-inhibitory effects of an orange extract enriched in O glycosylated flavanones (mainly naringin, neohesperidin, and hesperidin). The QS inhibitory capacity of this extract and its main flavanone components was first screened using the bacteriological monitoring system Chromobacterium violaceum . We next examined the ability of the orange extract and of some of the flavanones to (i) reduce the levels of the QS mediators produced by Y. enterocolitica using HPLC-MS/MS, (ii) inhibit biofilm formation, and (iii) inhibit swimming and swarming motility. Additionally, we evaluated changes in the expression of specific genes involved in the synthesis of the lactones (yenI, yenR) and in the flagellar regulon (flhDC, fleB, fliA) by RT-PCR. The results showed that the orange extract and its main flavanone components inhibited QS in C. violaceum, diminished the levels of lactones secreted by Y. enterocolitica to the media, and decreased QS-associated biofilm maturation without affecting bacterial growth. Among the tested compounds, naringin was found to inhibit swimming motility. Exposure to the orange extract and (or) to naringin was also found to be associated with induction of the transcription levels of yenR, flhDC, and fliA. This work shows the in vitro QS-inhibitory effects of an orange extract enriched in flavanones against a human enteropathogen at doses that can be achieved through the diet and suggests that consumption of these natural extracts may have a beneficial antipathogenic effect. PMID- 22533446 TI - Setbacks in diet adherence and emotional distress: a study of older patients with type 2 diabetes and their spouses. AB - OBJECTIVES: We investigated patients' difficulties in managing their diet (i.e. diet setbacks) and associations with change in disease-specific and general emotional distress (diabetes distress and depressive symptoms) among patients with type 2 diabetes and their spouses. METHOD: Data for this study were collected in couples' homes (N=115 couples) using structured interviews and self administered questionnaires at three time points: baseline (T1), six months after baseline (T2) and 12 months after baseline (T3). RESULTS: Patients' diet setbacks were associated with an increase in their diabetes distress in the shorter-term (over six months). Patients' diet setbacks were not associated with longer-term change in diabetes distress or with change in depressive symptoms at either time point (six months or one year). In contrast, spouses' perceptions of patients' diet setbacks were associated with increases in their own diabetes distress at both time points (over six months and one year), and also with an increase in their depressive symptoms in the longer-term (over one year). CONCLUSION: Findings reveal detrimental consequences of patients' diet nonadherence for emotional well-being that extend to the well-being of their spouses. PMID- 22533447 TI - A randomized, double-blind, placebo-controlled study to evaluate the addition of methotrexate to etanercept in patients with moderate to severe plaque psoriasis. AB - BACKGROUND: Etanercept plus methotrexate combination therapy has not been adequately investigated in psoriasis. OBJECTIVES: To evaluate etanercept plus methotrexate vs. etanercept monotherapy in patients with moderate to severe plaque psoriasis who had not failed prior methotrexate or tumour necrosis factor inhibitor therapy. METHODS: Patients received etanercept 50 mg twice weekly for 12 weeks followed by 50 mg once weekly for 12 weeks and were randomized 1 : 1 to receive methotrexate (7.5-15 mg weekly) or placebo. The primary endpoint was the proportion of patients achieving >=75% improvement in Psoriasis Area and Severity Index (PASI 75) at week 24. RESULTS: In total, 239 patients were enrolled in each arm. PASI 75 was significantly higher at week 24 for the combination therapy group compared with the monotherapy group (77.3% vs. 60.3%; P < 0.0001). Other PASI improvement scores at week 12 [PASI 75, 70.2% vs. 54.3% (P = 0.01); PASI 50, 92.4% vs. 83.8% (P = 0.01); and PASI 90, 34.0% vs. 23.1% (P = 0.03)] showed similar results as did week 24 PASI 50 (91.6% vs. 84.6%; P = 0.01) and PASI 90 (53.8% vs. 34.2%; P = 0.01). Significantly more patients receiving combination therapy than monotherapy had static Physician's Global Assessment of clear/almost clear at week 12 (65.5% vs. 47.0%; P = 0.01) and week 24 (71.8% vs. 54.3%; P = 0.01). Adverse events (AEs) were reported in 74.9% and 59.8% of combination therapy and monotherapy groups, respectively; three serious AEs were reported in each arm. CONCLUSIONS: Combination therapy with etanercept plus methotrexate had acceptable tolerability and increased efficacy compared with etanercept monotherapy in patients with moderate to severe psoriasis. PMID- 22533448 TI - Nitrofurantoin reveals good in vitro antimicrobial activity against methicillin resistant staphylococci isolated from dogs with topic infections. PMID- 22533449 TI - Betaproteobacterial symbionts of the ciliate Euplotes: origin and tangled evolutionary path of an obligate microbial association. AB - The Polynucleobacter-Euplotes association is an obligatory symbiotic system between a monophyletic group of ciliate species belonging to the genus Euplotes and bacteria of the species Polynucleobacter necessarius (Betaproteobacteria). Both organisms are unable to survive independently. Several studies revealed the existence of free-living populations of Polynucleobacter bacteria which are phylogenetically closely related to the endosymbiotic ones, but never share associations with Euplotes in the natural environment. Hence, following the most parsimonious explanation on the origin of the association, this symbiosis should represent a synapomorphic character for the hosts' clade. Nevertheless, phylogenetic analyses performed on an increased number of strains here presented suggest that Euplotes species, during their evolution, recruited Polynucleobacter bacteria as symbionts more than once. Moreover, in three cases, we observed different bacteria as obligate symbionts. These symbionts are the first characterized representatives of a phylogenetic lineage branching in a basal position with respect to the genus Polynucleobacter. The hypothesis that the original obligate symbionts belonged to this newly discovered clade and that, only subsequently, in most cases they have been replaced by Polynucleobacter bacteria recruited from the environment is proposed and discussed. The evolutionary path of this association seems anyway to have been more complex than so far supposed. PMID- 22533450 TI - Optimal poly(L-lysine) grafting density in hydrogels for promoting neural progenitor cell functions. AB - Recently, we have developed a photopolymerizable poly(L-lysine) (PLL) that can be covalently incorporated into poly(ethylene glycol) diacrylate (PEGDA) hydrogels to improve their bioactivity by providing positive charges. To explore the potential of these PLL-grafted PEGDA hydrogels as a cell delivery vehicle and luminal filler in nerve guidance conduits for peripheral and central nerve regeneration, we varied the number of pendent PLL chains in the hydrogels by photo-cross-linking PEGDA with weight compositions of PLL (phi(PLL)) of 0, 1, 2, 3, and 5%. We further investigated the effect of PLL grafting density on E14 mouse neural progenitor cell (NPC) behavior including cell viability, attachment, proliferation, differentiation, and gene expression. The amount of actually grafted PLL and charge densities were characterized, showing a proportional increase with the feed composition phi(PLL). NPC viability in 3D hydrogels was significantly improved in a PLL grafting density-dependent manner at days 7 and 14 postencapsulation. Similarly, NPC attachment and proliferation were promoted on the PLL-grafted hydrogels with increasing phi(PLL) up to 2%. More intriguingly, NPC lineage commitment was dramatically altered by the amount of grafted PLL chains in the hydrogels. NPC differentiation demonstrated a parabolic or nonmonotonic dependence on phi(PLL), resulting in cells mostly differentiated toward mature neurons with extensive neurite formation and astrocytes rather than oligodendrocytes on the PLL-grafted hydrogels with phi(PLL) of 2%, whereas the neutral hydrogels and PLL-grafted hydrogels with higher phi(PLL) of 5% support NPC differentiation less. Gene expression of lineage markers further illustrated this trend, indicating that PLL-grafted hydrogels with an optimal phi(PLL) of 2% could be a promising cell carrier that promoted NPC functions for treatment of nerve injuries. PMID- 22533452 TI - Cardiac tamponade related to a coronary injury by a pericardial calcification: an unusual complication. AB - BACKGROUND: Cardiac tamponade is a rare but severe complication of pericardial effusion with a poor prognosis. Prompt diagnosis using transthoracic echocardiography allows guiding initial therapeutic management. Although etiologies are numerous, cardiac tamponade is more often due to a hemopericardium. Rarely, a coronary injury may result in such a hemopericardium with cardiac tamponade. Coronary artery aneurysm are the main etiologies but blunt, open chest trauma or complication of endovascular procedures have also been described. CASE PRESENTATION: A 83-year-old hypertensive man presented for dizziness and hypotension. The patient had oliguria and mottled skin. Transthoracic echocardiography disclosed a circumferential pericardial effusion with a compressed right atrium, confirmed by contrast-enhanced thoracic CT scan. A pig-tail catheter allowed to withdraw 500 mL of blood, resulting in a transient improvement of hemodynamics. Rapidly, recurrent hypotension prompted a reoperation. An active bleeding was identified at the level of the retroventricular coronary artery. The pericardium was thickened with several "sharping" calcified plaques in the vicinity of the bleeding areas. On day 2, vasopressors were stopped and the patient was successfully extubated. Final diagnosis was a spontaneous cardiac tamponade secondary to a coronary artery injury attributed to a "sharping"calcified pericardial plaque. CONCLUSION: Cardiac tamponade secondary to the development of a hemopericardium may develop as the result of a myocardial and coronary artery injury induced by a calcified pericardial plaque. PMID- 22533454 TI - Corn ethanol production, food exports, and indirect land use change. AB - The approximately 100 million tonne per year increase in the use of corn to produce ethanol in the U.S. over the past 10 years, and projections of greater future use, have raised concerns that reduced exports of corn (and other agricultural products) and higher commodity prices would lead to land-use changes and, consequently, negative environmental impacts in other countries. The concerns have been driven by agricultural and trade models, which project that large-scale corn ethanol production leads to substantial decreases in food exports, increases in food prices, and greater deforestation globally. Over the past decade, the increased use of corn for ethanol has been largely matched by the increased corn harvest attributable mainly to increased yields. U.S. exports of corn, wheat, soybeans, pork, chicken, and beef either increased or remained unchanged. Exports of distillers' dry grains (DDG, a coproduct of ethanol production and a valuable animal feed) increased by more than an order of magnitude to 9 million tonnes in 2010. Increased biofuel production may lead to intensification (higher yields) and extensification (more land) of agricultural activities. Intensification and extensification have opposite impacts on land use change. We highlight the lack of information concerning the magnitude of intensification effects and the associated large uncertainties in assessments of the indirect land use change associated with corn ethanol. PMID- 22533453 TI - Separating the fish from the sharks: a longitudinal study of preschool response inhibition. AB - The development of response inhibition was investigated using a computerized go/no-go task, in a lagged sequential design where 376 preschool children were assessed repeatedly between 3.0 and 5.25 years of age. Growth curve modeling was used to examine change in performance and predictors of individual differences. The most pronounced change was observed between 3 and 3.75 years. Better working memory and general cognitive ability were related to more accurate performance at all ages, but relations with speed changed with age, where better cognitive skills were initially related to slower responding, but faster responding at later ages. Boys responded more quickly and were more accurate on go trials, whereas girls were better able to withhold responding on no-go trials. PMID- 22533455 TI - Treatment trends for haemophilia A and haemophilia B in the United States: results from the 2010 practice patterns survey. AB - Frequent evaluation of haemophilia treatment is necessary to improve patient care. The 2010 Practice Patterns Survey (PPS) investigated current trends in haemophilia treatment in the United States, as reported by nurses. The aim was to document practice patterns for haemophilia A and haemophilia B Survey questionnaires were sent to nurses at haemophilia treatment centres (HTCs) across the United States. Seventy-one of 126 HTCs (56%) responded to the survey. Factor dosage across treatment modalities ranged from 20 to 50 IU kg(-1) for severe haemophilia A. Dosage for severe haemophilia B was more variable (<40 to >100 IU kg(-1)). On-demand dosing regimens were inconsistent for haemophilia A and more so for haemophilia B. Rates of adherence to prescribed treatment were similar for both haemophilia types (~80%). The main barrier to adherence was identified as inconvenience. More bleeding episodes occurred in adults (16.6 bleeding episodes per year) with severe haemophilia A than in younger patients (11.3 bleeding episodes per year) before switching patients to prophylaxis. For both haemophilia types, most patients who switched from prophylaxis to on-demand treatment were aged 13-24 years; these patients also had the lowest adherence (60-71%). More paediatric patients with severe haemophilia A and inhibitors (53%) received prophylactic bypassing therapy than their haemophilia B counterparts (38%). Adults with severe haemophilia A faced challenges in relation to co-morbidities and long-term care. This PPS provides insights into previously unexplored aspects of haemophilia care that will serve to increase awareness and promote discussion of current issues affecting haemophilia patient care. PMID- 22533456 TI - Developing a useful, user-friendly website for cancer patient follow-up: users' perspectives on ease of access and usefulness. AB - UK cancer survival has improved, leading to an increase in review patients and pressure on clinics. Use of the Internet for information exchange between patients and healthcare staff may provide a useful adjunct or alternative to traditional follow-up. This study aimed to develop and evaluate a website for use in follow-up cancer care in terms of usability, feasibility and acceptability. A website was developed and underwent iterative amendment following patient usability testing in focus groups. Patients on follow-up completed a Computer and Internet Usage Questionnaire. Internet users consented to a randomised crossover study to complete paper and online questionnaires, browse the website and participate in a website evaluation interview. Patient website use was tracked. Usability: Website changes were made following patient testing (n= 21). Patients would have liked a 'personalized' website with links to their clinical team, out with the scope of this study. Feasibility: The majority of participants (65%) had Internet access. Age remained a differentiating factor. Acceptability: Final evaluation (n= 103) was positive although many would like to maintain face-to face hospital contact. User involvement in website design can ensure patient needs are met. A website model for follow-up will suit some patients but others will prefer clinical contact. PMID- 22533457 TI - Effect of monensin and vitamin E on milk production and composition of lactating dairy cows. AB - Feeding unsaturated oils to lactating dairy cows impair ruminal biohydrogenation (BH) of unsaturated fatty acids (USFA) and increase ruminal outflow of BH intermediates such as trans-10, cis-12 CLA that are considered to be potent inhibitors of milk fat synthesis. Supplementing lactating dairy cow's rations containing plant origin oils with monensin and/or vitamin E may minimise the formation of trans-10 isomers in the rumen, thereby preventing milk fat depression. Therefore, this study was conducted to evaluate the effects of monensin and vitamin E supplementation in the diets of lactating dairy cows containing whole cottonseed, as the main source of FA on feed intake, milk production and composition, milk fatty acid profile, efficiency of nitrogen (N) utilisation, efficiency of net energy (NE) utilisation and nutrients digestibilities. Four multiparous Holstein lactating dairy cows (86+/-41 days in milk) were assigned to a balanced 4 * 4 Latin square design. Each experimental period lasted 21 days with a 14 days of treatment adaptation and a 7 days of data collection. The control diet was a total mixed ration (TMR) consisted of 430 g/kg forage and 570 g/kg of a concentrate mixture on dry matter (DM) basis. Cows were randomly assigned to one of the four dietary treatments including control diet (C), control diet supplemented with 150 mg of vitamin E/kg of DM (E), control diet supplemented with 24 mg of monensin/kg of DM (M) and control diet supplemented with 150 mg of vitamin E and 24 mg of monensin/kg of DM (EM). Dry matter intake (DMI) ranged from 19.1 to 19.5 kg/d and was similar among the dietary treatments. Dietary supplementation with vitamin E or monensin had no effect on milk production, milk fat, protein and lactose concentrations, efficiency of utilisation of nitrogen and net energy for lactation (NEL ). Digestibility of DM, organic matter (OM), crude protein (CP) and ether extract (EE) was not affected by the dietary treatments. Digestibility of neutral detergent fibre (NDF) was higher in cows fed with the M and EM diets in relation to those fed the C and E diets. The concentrations of C4:0, C6:0, C8:0, C10:0, C12:0, C14:0, C15:0, trans-10-16:1, cis-9-16:1, 17:0, 18:0, trans-11-18:1, cis-9 18:1, cis-9, trans-11 conjugated linoleic acid (CLA), trans-10, cis-12 CLA, and 18:3n-3 FA in milk fat were not affected by the dietary supplementations. While feeding the M diet tended to decrease milk fat concentration of C16:0, the milk fat concentration of C18:2n-6 FA tended to be increased. Dietary supplementation with vitamin E or monensin had no effect on milk fat concentrations of saturated, unsaturated, monounsaturated, polyunsaturated, short chain and long chain FA, but feeding the M diet numerically decreased milk fat concentration of medium chain fatty acids (MCFA). The results showed that vitamin E and/or monensin supplementations did not improve milk fat content and did not minimise the formation of trans-10 FA isomers in the rumen when whole cottonseed was included in the diet as the main source of fatty acids. PMID- 22533458 TI - Development of a potential functional food prepared with pigeon pea (Cajanus cajan), oats and Lactobacillus reuteri ATCC 55730. AB - The purpose of this study was to investigate the survival of Lactobacillus reuteri ATCC 55730 in creams, prepared with pigeon peas and oat. Products were analysed to determine their content of protein, fibre, fat, carbohydrates and degree of likeness. Viable numbers of L. reuteri and pH were determined after 1, 7, 14, 21 and 28 days of storage at 4 degrees C. Results showed significant differences (P < 0.05) in protein, fat, fibre and carbohydrate content between creams. No significant differences (P > 0.05) were found on sensory quality between control and creams with L. reuteri. After 28 days, the cell viability was above 7 log cfu/g in all creams. L. reuteri ATCC 55730 had the highest viability in cream with 40% pigeon pea and 20% oat (8.16 log cfu/g). In conclusion, due to its acceptability and highly nutritious value, the product could be used so as to support the growth of L. reuteri. PMID- 22533459 TI - Effects of human and porcine bile on the proteome of Helicobacter hepaticus. AB - BACKGROUND: Helicobacter hepaticus colonizes the intestine and liver of mice causing hepatobiliary disorders such as hepatitis and hepatocellular carcinoma, and has also been associated with inflammatory bowel disease in children. In its habitat, H. hepaticus must encounter bile which has potent antibacterial properties. To elucidate virulence and host-specific adaptation mechanisms of H. hepaticus modulated by human or porcine bile, a proteomic study of its response to the two types of bile was performed employing two-dimensional gel electrophoresis (2-DE) and mass spectrometry. RESULTS: The 2-DE and mass spectrometry analyses of the proteome revealed that 46 proteins of H. hepaticus were differentially expressed in human bile, 18 up-regulated and 28 down regulated. In the case of porcine bile, 32 proteins were differentially expressed of which 19 were up-regulated, and 13 were down-regulated. Functional classifications revealed that identified proteins participated in various biological functions including stress response, energy metabolism, membrane stability, motility, virulence and colonization. Selected genes were analyzed by RT-PCR to provide internal validation for the proteomic data as well as provide insight into specific expressions of motility, colonization and virulence genes of H. hepaticus in response to human or porcine bile. CONCLUSIONS: Overall, the data suggested that bile is an important factor that determines virulence, host adaptation, localization and colonization of specific niches within host environment. PMID- 22533460 TI - Water tetramer, pentamer, and hexamer in inert matrices. AB - The infrared spectrum of water, isolated in inert matrices, has been studied in the interval from 60 to 4000 cm(-1). Experiments with partially deuterated water combined with DFT (density functional theory) calculations have been used to investigate the structure of matrix-isolated water tetramer. A few, strong intermolecular fundamentals of the water tetramer have been observed. Mid infrared bands due to deuterated pentamers and hexamers have been observed and are used to discuss the assignments of these water clusters. PMID- 22533461 TI - New therapeutic options for onychomycosis. AB - INTRODUCTION: Onychomycosis is a fungal infection of the nail apparatus that affects 10 - 30% of the global population. Current therapeutic options for onychomycosis have a low to moderate efficacy and result in a 20 - 25% rate of relapse and reinfection. New therapeutic options are needed to broaden the spectrum of treatment options and improve the efficacy of treatment. AREAS COVERED: This review discusses the emerging pharmacotherapeutics; including topical reformulations of terbinafine, new azole molecules for systemic and topical administration, topical benzoxaboroles and topical polymer barriers. The paper also discusses device-based options, which may be designed to activate a drug or to improve drug delivery, such as photodynamic therapy and iontophoresis; laser device systems have also begun to receive regulatory approval for onychomycosis. EXPERT OPINION: Device-based therapeutic options for onychomycosis are expanding more rapidly than pharmacotherapy. Systemic azoles are the only class of pharmacotherapy that has shown a comparable efficacy to systemic terbinafine; however terbinafine remains the gold standard. The most notable new topical drugs are tavaborole, efinaconazole and luliconazole, which belong to the benzoxaborole and azole classes of drugs. Photodynamic therapy, iontophoresis and laser therapy have shown positive initial results, but randomized controlled trials are necessary to determine the long-term success of these devices. PMID- 22533462 TI - Juvenile and adult-onset ALS/MND among Africans: incidence, phenotype, survival: a review. AB - AIM: We reviewed the epidemiology of ALS among subjects of African origin, considering incidence, phenotype and prognosis. METHODS: We searched Medline, Scopus, Science direct, Bibliotheque Virtuelle de Neurologie Africaine (BVNA), ( http://www-ient.unilim.fr/ ) and African journal OnLine databases using the following search terms "amyotrophic lateral sclerosis (ALS)", "motor neuron disease (MND)" or "Charcot disease", in combination with "Africa", "ethnic groups", "blacks" or "epidemiology". Of 1264 references examined, 35 were included in this review. RESULTS AND DISCUSSION: Among the 35 references, 19 studies were performed in the African continent and dealt with MND/ALS; four other studies focused on ALS-like syndromes; finally, 12 studies were not performed in Africa but focused on either incidence and mortality or survival of ALS in subjects of African origin. Several characteristics of ALS among Africans or subjects of African origin were identified: (i) lower incidence rates among people of African origin living in western countries, (ii) higher incidence of classic ALS among men, (iii) presence of juvenile form, (iv) younger age at onset of classic ALS. We cannot draw firm conclusions about (i) the prognosis in African ALS patients, (ii) prognostic factors, (iii) genetic or behavioral factors affecting incidence or clinical phenotype. CONCLUSION: Further multicenter prospective studies with homogeneous methodological approaches need to be performed in Africa to clarify the situation. PMID- 22533463 TI - Predictors of emergent feeding tubes and tracheostomies in amyotrophic lateral sclerosis (ALS). AB - Predictable decline in ALS makes unplanned gastrostomy and tracheostomy avoidable. We determined whether gastrostomy or tracheostomy insertion during emergent hospitalization is associated with patient or hospital characteristics, changed Medicare policy in 2001, or proximity to specialized ALS care. We performed a retrospective analysis of hospitalizations and procedures for ALS/MND patients in Pennsylvania between 1996 and 2009. We identified predictors of gastrostomy/tracheostomy during emergent hospitalization and trends over time. Patients underwent 1748 gastrostomies and 373 tracheostomies. Thirty-two percent of gastrostomies and 67% of tracheostomies were placed emergently. Emergent hospitalizations involving gastrostomy were more expensive with fewer home discharges. Black patients and Medicaid patients had higher odds of emergent gastrostomy placement. Conversely, academic hospital affiliation decreased odds of emergent gastrostomy or tracheostomy placement (AOR 0.49, AOR 0.37, p < 0.001). After Medicare policy changes, gastrostomy use increased, while emergent gastrostomies decreased. Surprisingly, proximity to specialized care was associated with increased emergent gastrostomy placement. In conclusion, black patients and Medicaid patients were more likely to undergo emergent gastrostomy insertion. Patients receiving gastrostomy during emergent admissions had fewer home discharges and higher costs. Academic hospital affiliation decreased odds of emergent gastrostomy or tracheostomy. After Medicare changes broadening access, while gastrostomy use increased, the proportion of emergent procedures decreased. PMID- 22533465 TI - Ethnic groups' perception of physicians' attentiveness: implications for health and obesity. AB - Variables from the Health Tracking Household Survey 2007 were mapped to fit the "integrative model" of patient-doctor communication proposed by Ashton et al. (2003) to describe how communication patterns between patients and doctors influence patients' health outcomes. Patients' perceptions of their physician's attentiveness were examined to determine if perceived attentiveness mediated the relationship between physicians' recommendations (to diet and exercise) and health. Ethnic group differences related to these variables were explored. Overall, patient perception of physician attentiveness did significantly mediate the relationship between recommendations and patients' general health status. Hispanics and African Americans perceived their physicians as significantly less attentive to them, compared to Caucasians' perception of attentiveness. Across all ethnic groups, there was no evidence that doctors' recommendations to diet and exercise had an effect on patients' body mass index. The findings support previous research regarding the importance of physicians' communication skills and cultural sensitivity in promoting patient adherence to health recommendations. PMID- 22533466 TI - Opportunities for using lipoprotein subclass profile by nuclear magnetic resonance spectroscopy in assessing insulin resistance and diabetes prediction. AB - The incidence of type 2 diabetes mellitus (T2DM) has reached epidemic levels, and current trends indicate that its prevalence will continue to rise. The development of T2DM can be delayed by several years, and may even be prevented, by identifying individuals at risk for T2DM and treating them with lifestyle modification and/or pharmacological therapies. There are a number of methods available for assessing the insulin resistance (IR) that characterizes, and is the precursor to, T2DM. However, current clinical methods for assessing IR, based on measures of plasma glucose and/or insulin are either laborious and time consuming or show a low specificity. IR manifests its earliest measurable abnormalities through changes in lipoproteins, and thus we propose that by examining lipoprotein subclass profile, it may be possible to alert physicians and patients to a heightened risk of developing diabetes. This will allow us to institute appropriate lifestyle changes and treatment potentially to delay the onset or possibly prevent the progression to diabetes. PMID- 22533467 TI - Preconditioning enhances the paracrine effect of mesenchymal stem cells in preventing oxygen-induced neonatal lung injury in rats. AB - Bronchopulmonary dysplasia (BPD) remains a main complication of extreme prematurity. Bone marrow derived-mesenchymal stem cells (BM-MSC) prevent lung injury in an O(2)-induced model of BPD. The low level of lung BM-MSC engraftment suggests alternate mechanisms-beyond cell replacement-to account for their therapeutic benefit. We hypothesized that BM-MSC prevent O(2)-induced BPD through a paracrine-mediated mechanism and that preconditioning of BM-MSC would further enhance this paracrine effect. To this end, conditioned medium (CM) from BM-MSC (MSCcm) or preconditioned CM harvested after 24 h of BM-MSC exposure to 95% O(2) (MSC-O2cm) were administrated for 21 days to newborn rats exposed to 95% O(2) from birth until postnatal day (P)14. Rat pups exposed to hyperoxia had fewer and enlarged air spaces and exhibited signs of pulmonary hypertension (PH), assessed by echo-Doppler, right ventricular hypertrophy, and pulmonary artery medial wall thickness. Daily intraperitoneal administration of both CM preserved alveolar growth. MSC-O2cm exerted the most potent therapeutic benefit and also prevented PH. CM of lung fibroblasts (control cells) had no effect. MSCcm had higher antioxidant capacity than control fibroblast CM. Preconditioning did not increase the antioxidant capacity in MSC-O2cm but produced higher levels of the naturally occurring antioxidant stanniocalcin-1 in MSC-O2cm. Ex vivo preconditioning enhances the paracrine effect of BM-MSC and opens new therapeutic options for cell-based therapies. Ex vivo preconditioning may also facilitate the discovery of MSC-derived repair molecules. PMID- 22533468 TI - A model for quantitative evaluation of skin damage at adhesive wound dressing removal. AB - The removal of adhesive wound dressings from the wound surface involves a risk of damaging the intact stratum corneum and regenerating epithelium. Pain associated with the removal of wound dressings is a major issue for patients and medical personnel. Recently, wound dressings coated with a silicone adhesive have been developed to reduce such skin damage and pain on removal and they have received good evaluation in various clinical settings. However, there is neither a standard method to quantify whether or not the integrity of the stratum corneum and regenerating epithelium is retained or if both structures are damaged by the removal of wound dressings, nor are there standardised values with which to assess skin damage. We applied six different types of adhesive wound dressing on plain copy paper printed with black ink by a laser printer, removed the dressings, examined the adhesive-coated surface of the wound dressings using a high-power videoscope, and examined the stripped areas. Wound dressings coated with a silicone adhesive showed significantly less detachment of the stratum corneum and regenerating epithelium, followed by those coated with polyurethane, hydrocolloid, and acrylic adhesives. The assessment method utilised in this study revealed distinct differences between wound dressing types, but less variation in the evaluation outcome of each type. This assessment method may be useful for the evaluation of adhesive wound dressings, particularly during product development. However, further studies will be needed to examine the effectiveness of this assessment method in the clinical setting because the adherent properties of polyurethane and hydrocolloid adhesives may be altered by the absorption of water from the skin. PMID- 22533470 TI - HIV-1 Vpu and BST-2/tetherin: enemies at the gates. PMID- 22533471 TI - Intracellular logistics of BST-2/tetherin. AB - Bone marrow stromal antigen 2 (BST-2) is a type II membrane protein with two targeting signals, one of which is located in the cytoplasmic domain and contains a non-canonical dual tyrosine-based motif responsible for its endocytosis from the plasma membrane, and the other is a C-terminal glycosylphosphatidylinositol anchor that facilitates its association with detergent-resistant membranes/lipid rafts and targeting to the apical domain in polarized epithelial cells. Due to its unusual topology at the membrane, BST-2 takes unique and complicated trafficking routes in cells. Recently, a physiological role for BST-2 as the "tetherin" molecule for viruses, especially for HIV-1, has been extensively examined. These studies have shown that the biosynthesis, intracellular trafficking, localization, and structure of human BST-2 are closely related to its antiviral activity. This review provides an overview of the intracellular logistics of human BST-2. PMID- 22533472 TI - Toward self-constructing materials: a systems chemistry approach. AB - To design the next generation of so-called "smart" materials, researchers will need to develop chemical systems that respond, adapt, and multitask. Because many of these features occur in living systems, we expect that such advanced artificial systems will be inspired by nature. In particular, these new materials should ultimately combine three key properties of life: metabolism, mutation, and self-replication. In this Account, we discuss our endeavors toward the design of such advanced functional materials. First, we focus on dynamic molecular libraries. These molecular and supramolecular chemical systems are based on mixtures of reversibly interacting molecules that are coupled within networks of thermodynamic equilibria. We will explain how the superimposition of combinatorial networks at different length scales of structural organization can provide valuable hierarchical dynamics for producing complex functional systems. In particular, our experimental results highlight why these libraries are of interest for the design of responsive materials and how their functional properties can be modulated by various chemical and physical stimuli. Then, we introduce examples in which these dynamic combinatorial systems can be coupled to kinetic feedback loops to produce self-replicating pathways that amplify a selected component from the equilibrated libraries. Finally, we discuss the discovery of highly functional self-replicating supramolecular assemblies that can transfer an electric signal in space and time. We show how these wires can be directly incorporated within an electronic nanocircuit by self-organization and functional feedback loops. Because the network topologies act as complex algorithms to process information, we present these systems in this order to provide context for their potential for extending the current generation of responsive materials. We propose a general description for a potential autonomous (self-constructing) material. Such a system should self-assemble among several possible molecular combinations in response to external information (input) and possibly self-replicate to amplify its structure. Ultimately, its functional response (output) can drive the self-assembly of the system and also serve a mechanism to transfer this initial information. Far from equilibrium, such synergistic processes could give rise to evolving, "information gaining" systems which become increasingly complex because internal self-organization rapidly reduces the potential energy surrounding the system. PMID- 22533474 TI - Using saliency maps to separate competing processes in infant visual cognition. AB - This article presents an eye-tracking study using a novel combination of visual saliency maps and "area-of-interest" analyses to explore online feature extraction during category learning in infants. Category learning in 12-month olds (N = 22) involved a transition from looking at high-saliency image regions to looking at more informative, highly variable object parts. In contrast, 4 month-olds (N = 27) exhibited a different pattern displaying a similar decreasing impact of saliency accompanied by a steady focus on the object's center, indicating that targeted feature extraction during category learning develops across the 1st year of life. These results illustrate how the effects of lower and higher level processes may be disentangled using a combined saliency map and area-of-interest analysis. PMID- 22533473 TI - Modulation of activation-associated host cell gene expression by the apicomplexan parasite Theileria annulata. AB - Infection of bovine leucocytes by Theileria annulata results in establishment of transformed, infected cells. Infection of the host cell is known to promote constitutive activation of pro-inflammatory transcription factors that have the potential to be beneficial or detrimental. In this study we have compared the effect of LPS activation on uninfected bovine leucocytes (BL20 cells) and their Theileria-infected counterpart (TBL20). Gene expression profiles representing activated uninfected BL20 relative to TBL20 cells were also compared. The results show that while prolonged stimulation with LPS induces cell death and activation of NF-kappaB in BL20 cells, the viability of Theileria-infected cells was unaffected. Analysis of gene expression networks provided evidence that the parasite establishes tight control over pathways associated with cellular activation by modulating reception of extrinsic stimuli and by significantly altering the expression outcome of genes targeted by infection-activated transcription factors. Pathway analysis of the data set identified novel candidate genes involved in manipulation of cellular functions associated with the infected transformed cell. The data indicate that the T. annulata parasite can irreversibly reconfigure host cell gene expression networks associated with development of inflammatory disease and cancer to generate an outcome that is beneficial to survival and propagation of the infected leucocyte. PMID- 22533475 TI - Dehydration polycondensation of dicarboxylic acids and diols using sublimating strong bronsted acids. AB - We investigated catalytic activities of strong bronsted acids for dehydration polycondensations of dicarboxylic acids and diols, which were carried out at low temperature (<100 degrees C) under reduced pressure (0.3-3 mmHg). Strong Bronsted acids, bis(perfluoroalkanesulfonyl)imide and perfluoroalkanesulfonic acid, showed higher activity than p-toluenesulfonic acid or rare-earth catalysts at 60 degrees C. In particular, bis(nonafluorobutanesulfonyl)imide (Nf(2)NH) showed the highest activity to synthesize not only aliphatic polyester (M(n) > 19000) but also aromatic polyester (M(n) > 7000). The used Nf(2)NH was sublimated from the reaction flask during polycondensation, and the sublimate, Nf(2)NH, was extra pure so that we can reuse the catalyst without loss of the activity in the dehydration polycondensations. PMID- 22533476 TI - Evaluating short-term and working memory in older adults: French normative data. AB - Short-term and working memory (WM) capacities are subject to change with ageing, both in normal older adults and in patients with degenerative or non-degenerative neurological disease. Few normative data are available for comparisons of short term and WM capacities in the verbal, spatial and visual domains. To provide researchers and clinicians with a set of standardised tasks that assess short term and WM using verbal and visuospatial materials, and to present normative data for that set of tasks. The present study compiled normative French data for three short-term memory tasks (verbal, visual and spatial simple span tasks) and two WM tasks (verbal and spatial complex span tasks) obtained from 445 healthy older adults aged between 55 and 85 years. Our data reveal main effects of age, education level and gender on older adults' short-term and WM performances. Equation-based normalisation can therefore be used to take these factors into account. The results provide a set of cut-off scores for five standardised tasks that can be used to determine the presence of short-term or WM impairment in older adults. PMID- 22533477 TI - Disposition kinetics of albendazole and metabolites in laying hens. AB - An increasing prevalence of roundworm parasites in poultry, particularly in litter-based housing systems, has been reported. However, few anthelmintic drugs are commercially available for use in avian production systems. The anthelmintic efficacy of albendazole (ABZ) in poultry has been demonstrated well. The goal of this work was to characterize the ABZ and metabolites plasma disposition kinetics after treatment with different administration routes in laying hens. Twenty-four laying hens Plymouth Rock Barrada were distributed into three groups and treated with ABZ as follows: intravenously at 10 mg/kg (ABZ i.v.); orally at the same dose (ABZ oral); and in medicated feed at 10 mg/kg.day for 7 days (ABZ feed). Blood samples were taken up to 48 h posttreatment (ABZ i.v. and ABZ oral) and up to 10 days poststart feed medication (ABZ feed). The collected plasma samples were analyzed using high-performance liquid chromatography. ABZ and its albendazole sulphoxide (ABZSO) and ABZSO2 metabolites were recovered in plasma after ABZ i.v. administration. ABZ parent compound showed an initial concentration of 16.4 +/- 2.0 MUg/mL, being rapidly metabolized into the ABZSO and ABZSO2 metabolites. The ABZSO maximum concentration (Cmax ) (3.10 +/- 0.78 MUg/mL) was higher than that of ABZSO2 Cmax (0.34 +/- 0.05 MUg/mL). The area under the concentration vs time curve (AUC) for ABZSO (21.9 +/- 3.6 MUg.h/mL) was higher than that observed for ABZSO2 and ABZ (7.80 +/- 1.02 and 12.0 +/- 1.6 MUg.h/mL, respectively). The ABZ body clearance (Cl) was 0.88 +/- 0.11 L.h/kg with an elimination half-life (T1/2el ) of 3.47 +/- 0.73 h. The T1/2el for ABZSO and ABZSO2 were 6.36 +/- 1.50 and 5.40 +/- 1.90 h, respectively. After ABZ oral administration, low ABZ plasma concentrations were measured between 0.5 and 3 h posttreatment. ABZ was rapidly metabolized to ABZSO (Cmax , 1.71 +/- 0.62 MUg/mL) and ABZSO2 (Cmax , 0.43 +/- 0.04 MUg/mL). The metabolite systemic exposure (AUC) values were 18.6 +/- 2.0 and 10.6 +/- 0.9 MUg.h/mL for ABZSO and ABZSO2 , respectively. The half-life values after ABZ oral were similar (5.91 +/- 0.60 and 5.57 +/- 1.19 h for ABZSO and ABZSO2 , respectively) to those obtained after ABZ i.v. administration. ABZ was not recovered from the bloodstream after ABZ feed administration. AUC values of ABZSO and ABZSO2 were 61.9 and 92.4 MUg.h/mL, respectively. The work reported here provides useful information on the pharmacokinetic behavior of ABZ after both i.v. and oral administrations in hens, which is a useful first step to evaluate its potential as an anthelmintic tool for use in poultry. PMID- 22533478 TI - The protective effects of ginsenoside Rg1 against hypertension target-organ damage in spontaneously hypertensive rats. AB - BACKGROUND: Although a number of medicines are available for the management of hypertension, the organ damage induced by hypertension is not resolved. The aim of this study was to investigate the protection of ginsenoside Rg1 (Rg1) against vascular remodeling and organ damage in spontaneously hypertensive rats (SHR). METHODS: Male SHR were treated with 5, 10 or 20 mg/kg Rg1 through intraperitoneal injection per day for 1 month. SHR or Wistar-Kyoto rats (WKY) receiving vehicle (saline) was used as control. Blood pressure detection and pathological stain, transmission electron microscope, immunohistochemical assay were used to elucidate the protection of Rg1. RESULTS: Blood pressures were not different between control SHR rats and Rg1 treated SHR rats, but Rg1 improved the aortic outward remodeling by lowering the lumen diameter and reducing the media thickness according the histopathological and ultrastructural detections. Rg1 also protected the retinal vessels against inward remodeling detected by immunohistochemical assay. Furthermore, Rg1 attenuated the target heart and kidney damage with improvement on cardiac and glomerular structure. CONCLUSIONS: These results suggested that Rg1 held beneficial effects on vascular structure and further protected against the organ-damage induced by hypertension. These findings also paved a novel and promising approach to the treatment of hypertensive complications. PMID- 22533479 TI - Multidimensional identification of tissue biomarkers of gastric cancer. AB - Gastric cancer remains highly fatal due to a dearth of diagnostic biomarkers for early stage disease and molecular targets for therapy. Plasma membrane proteins, including cluster of differentiation (CD) proteins and receptor tyrosine kinases (RTKs), are a rich reservoir of biomarkers. Recognizing that interrogating plasma membrane proteins individually overlooks extensive interactions among them, we have systematically investigated the membrane proteomes and transcriptomes of six gastric cancer cell lines. Our data revealed aberrantly high expression of proteins whose functions accurately reflect the clinical phenotype of gastric cancer, and prioritized critical RTKs and CD proteins in gastric cancer. Expression of selected surface proteins was confirmed by flow cytometry and immunostaining of clinical gastric cancer tissues. Close to 90% of the gastric cancer tissues in a cohort showed up-regulation of at least one of four proteins, that is, MET, EPHA2, FGFR2, and CD104/ITGB4. All intestinal type gastric cancer tumors in this cohort overexpressed at least one of a panel of three proteins, MET, FGFR2, and EPHA2. This study reports the first quantitative global landscape of the surface proteome of gastric cancer cells and provides a shortlist of gastric cancer biomarkers. PMID- 22533481 TI - Dietitian-coached management in combination with annual endocrinologist follow up improves global metabolic and cardiovascular health in diabetic participants after 24 months. AB - This 24 month study evaluated the effect of dietitian coaching combined with minimal endocrinologist follow up on the glycemic control and cardiovascular risks of diabetic participants, compared with conventional endocrinologist follow up. Participants with type 1 or type 2 diabetes were assigned to either the control group with conventional endocrinologist follow up (C; n = 50) or the dietitian-coached group (DC; n = 51) with on-site diabetes self-management education every 3 months combined with annual endocrinologist followup. Over the 24 month intervention, weight (-0.7 vs. +2.1 kg; p = 0.04), BMI (+0.3 vs. +0.7 kg/m(2); p = 0.009), and waist circumference (-1.3 vs. +2.4 cm; p = 0.01) significantly differed between the DC and control groups. HbA(1C) dropped significantly in participants of the DC versus the control group (-0.6% vs.-0.3%; p = 0.04). This was accompanied by improved overall energy intake (-548 vs. -74 kcal/day; p = 0.04). However, no link associated glycemic control to nutrient intake or intensiveness of pharmacotherapy. Coaching by a dietitian improves glycemic control and reduces certain cardiovascular risk factors in diabetic subjects, demonstrating that a joint dietitian-endocrinologist model of care provides a convenient strategy for cardiovascular risk management in the diabetic population. PMID- 22533480 TI - Associations among different functional and structural arterial wall properties and their relations to traditional cardiovascular risk factors in healthy subjects: a cross-sectional study. AB - BACKGROUND: The arterial wall possesses several functional and structural properties that define arterial health. Once they become impaired, cardiovascular risk increases. We aimed to ascertain the pattern of correlations among different arterial wall properties and to explore their relations to traditional risk factors and cardiovascular risk stratification. To allow such an investigation a middle-aged healthy population was recruited. METHODS: This cross-sectional study included 100 healthy males (aged 41.9 +/- 6.4 years). Pulse wave velocity (PWV), beta-stiffness and intima-media thickness (IMT) of the carotid artery, and brachial artery flow-mediated dilation (FMD) were measured by a standardized ultrasound approach. RESULTS: No correlation between FMD and IMT was found; only relatively poor correlations between PWV (or beta-stiffness) and FMD existed, as well as between PWV (or beta-stiffness) and IMT. PWV and beta-stiffness highly correlated. Unexpectedly, only weak associations between PWV, beta-stiffness, FMD, IMT and traditional risk factors were revealed. Hence, traditional risk factors (mainly age) explained only 10-50% of variability for PWV, beta stiffness, FMD and IMT. Although the subjects had low cardiovascular risk according to their Framingham score, their arterial wall properties were already impaired, particularly FMD. CONCLUSIONS: In healthy middle-age males we found: i) absent or poor correlations among arterial stiffness, IMT and endothelial function; ii) a low impact of traditional risk factors on the studied variables, and iii) the presence of impaired arterial wall properties despite low calculated cardiovascular risk. These results provide a deepened understanding of arterial wall properties and could help to improve cardiovascular risk stratification. PMID- 22533482 TI - The context of perceived and desired social support among Korean older adults. AB - Social support has multiple dimensions, the context of which can be explored by qualitative methods. In this study, face-to-face interviews were conducted with 21 local senior center members (9 men and 12 women aged 65 and older) in Seoul, South Korea, in order to explore how they perceive and desire social support in an aging society. The qualitative methods in this study also included thematic analysis and constant comparison to identify three main themes: "no or denied support," "not to be greedy and shameless," and "justification and hopelessness." In the interviews, perceived and desired support did not emerge immediately as the participants were reluctant to share personal concerns with or to seek support from others. Nevertheless, they would turn to spouses and children for both emotional and instrumental support when in dire need. A shared norm among the participants was that seeking support would be an embarrassing and shameless act for themselves and a burden to others. They justified the discrepancy between the perceived and desired support as part of aging and felt hopelessness about it. The findings of this study have implications that implicit, individual social support may be effective than explicit, group support activities for those who are passive in recognizing the need for and seeking social support. In assessing and interpreting social support in old age, both perceived and desired support should be included and contextual approaches can be useful in so doing. The senior centers should be a more active advocate of successful aging that would offset hopelessness, negative attitude toward life, and social disconnection. Future research should focus on identifying effective strategies to bridge the gap between perceived and desired social support in older adults in this society of changing values and social norms. PMID- 22533483 TI - Unexpected geometrical effects on paramagnetic spin-orbit and spin-dipolar 2J(FF) couplings. AB - The second-rank tensor character of the paramagnetic spin-orbit and spin-dipolar contributions to nuclear spin-spin coupling constants is usually ignored when NMR measurements are carried out in the isotropic phase. However, in this study it is shown that isotropic (2)J(FF) couplings strongly depend on the relative orientation of the C-F bonds containing the coupling nuclei and the eigenvectors of such tensors. Predictions about such effect are obtained using a qualitative approach based on the polarization propagator formalism at the RPA, and results are corroborated performing high-level ab initio spin-spin coupling calculations at the SOPPA(CCSD)/EPR-III//MP2/EPR-III level in a model system. It is highlighted that no calculations at the RPA level were carried out in this work. The quite promising results reported in this paper suggest that similar properties are expected to hold for the second-rank nuclear magnetic shielding tensor. PMID- 22533484 TI - Cell surface hydrophobicity of oral Candida dubliniensis isolates following limited exposure to sub-therapeutic concentrations of chlorhexidine gluconate. AB - Candidal adhesion has been implicated as the initial step in the pathogenesis of oral candidiasis and cell surface hydrophobicity (CSH) has been implicated in adhesion to mucosal surfaces. Candida dubliniensis is an opportunistic pathogen associated with recurrent oral candidiasis. Chlorhexidine gluconate is by far the commonest antiseptic mouth wash prescribed in dentistry. At dosage intervals the intraoral concentration of this antiseptic fluctuates considerably and reaches sub-therapeutic levels due to the dynamics of the oral cavity. Hence, the organisms undergo only a limited exposure to the antiseptic during treatment. The impact of this antiseptic following such exposure on CSH of C. dubliniensis isolates has not been investigated. Hence, the main objective of this study was to investigate the effect of brief exposure to sub-therapeutic concentrations of chlorhexidine gluconate on the CSH of C. dubliniensis isolates. Twelve oral isolates of C. dubliniensis were briefly exposed to three sub-therapeutic concentrations of 0.005%, 0.0025% and 0.00125% chlorhexidine gluconate for 30 min. Following subsequent removal of the drug, the CSH of the isolates was determined by a biphasic aqueous-hydrocarbon assay. Compared with the controls, exposure to 0.005% and 0.0025% chlorhexidine gluconate suppressed the relative CSH of the total sample tested by 44.49% (P < 0.001) and 21.82% (P < 0.018), respectively, with all isolates being significantly affected. Although exposure to 0.00125% of chlorhexidine gluconate did not elicit a significant suppression on the total sample tested (7.01%; P > 0.05), four isolates of the group were significantly affected. These findings imply that exposure to sub-therapeutic concentrations of chlorhexidine gluconate may suppress CSH of C. dublinienis isolates, thereby reducing its pathogenicity and highlights further the pharmacodynamics of chlorhexidine gluconate. PMID- 22533485 TI - Novel erythropoietin-loaded nanoparticles with prolonged in vivo response. AB - The aim of this study was to incorporate human recombinant erythropoietin (EPO) in biodegradable polymeric nanoparticles targeting a prolonged-release effect. EPO-loaded poly(DL-lactide-co-glycolide) nanoparticles were prepared using double emulsion method (w/o/w) with least process-related stress on the encapsulated drug. The nanoparticles have been fully characterized including in vitro release profile. The biological activity was assessed in vivo using BALB-c mice. The produced particles appeared spherical in shape with smooth regular surfaces and had an average particle size of 225.9 +/- 3.8 nm. The entrapment efficiency was 33.3%. The in vitro release profile exhibited a biphasic mode with a burst of 50% cumulative drug release, followed by a slow rate of release over 24 h, reaching a maximum of 82%. The bioassay results showed that EPO-loaded nanoparticles were able to maintain the physiological activity of EPO for 14 days after single subcutaneous injection compared with pure and marketed EPO formulae (EPREX(r)). PMID- 22533486 TI - Preparation and evaluation of andrographolide-loaded microemulsion. AB - Andrographolide has a low aqueous solubility and oral bioavailability, which limits its clinical application. Reform the dosage forms of andrographolide to improve its aqueous solubility and oral bioavailability. The formulation, characterisation, stability, anti-inflammatory effect, pharmacokinetics and oral toxicity of andrographolide-loaded microemulsion, were studied. An formulation of O/W microemulsion consisting of an oil phase of isopropyl myristate, a surfactant phase of Tween 80, a co-surfactant of alcohol, and water was found to be ideal, with mean droplet size of 15.9 nm, a high capacity of solubilisation for andrographolide (8.02 mg mL(-1)). Such an andrographolide-loaded microemulsion is stable by monitoring the time, temperature and gravity-dependent change, and has a much better anti-inflammatory effect and a higher biological availability than andrographolide tablets. Besides, it also shows a very low acute oral toxicity. The andrographolide-loaded microemulsion is a promising dosage form of andrographolide. PMID- 22533487 TI - Nanoliter hemolymph sampling and analysis of individual adult Drosophila melanogaster. AB - The fruit fly (Drosophila melanogaster) is an extensively used and powerful, genetic model organism. However, chemical studies using individual flies have been limited by the animal's small size. Introduced here is a method to sample nanoliter hemolymph volumes from individual adult fruit-flies for chemical analysis. The technique results in an ability to distinguish hemolymph chemical variations with developmental stage, fly sex, and sampling conditions. Also presented is the means for two-point monitoring of hemolymph composition for individual flies. PMID- 22533488 TI - The potential role of synovial thrombomodulin in the pathophysiology of joint bleeds in haemophilia. AB - Haemophilic arthropathy (HA) is one of the main complications of recurrent bleeding episodes in patients with severe haemophilia. However, the precise reasons making joints the predilected site of bleeding in patients with haemophilia are not fully understood. The objective of this project was to study the potential effect of synovium-derived thrombomodulin (TM) on the pathophysiology of haemarthroses. The concentration of TM and tissue factor pathway inhibitor (TFPI) was measured in knee synovial fluid of patients with haemophilia and controls. We used these concentrations of TM and TFPI in a thrombin generation (TG) model to analyse their in vitro effects on coagulation in plasma of six male controls and six severe haemophiliacs. The expression of TM in synovial tissue was also studied in controls and haemophiliacs. Patients with HA had significantly higher synovial fluid TFPI and TM levels, with a mean of 47 +/- 27 ng/mL (P = 0.033) and 56 +/- 25 ng/mL (P = 0.031), respectively, compared to the control group which presented lower levels of synovial fluid TFPI (26 +/- 9 ng/mL) and TM concentrations (39 +/- 21 ng/mL). TG capacity was significantly reduced in the presence of TM 56 ng/mL (P = 0.02), concentration observed in the synovial fluid of patients with HA. The concomitant addition of TM 56 ng/mL and TFPI 47 ng/mL induced a highly significant inhibition of TG in the same samples (P = 0.008).No significant inhibition of TG capacity was observed in the presence of control synovial concentration of TM (P > 0.05). Our results showed increased TM levels in synovial fluid and dramatically impaired expression of TM on synovial cells, suggesting a massive release of TM into the synovial fluid induced by a concerted action of neutrophils and cytokines on synovial cells as previously described in patients with rheumatoid arthritis. PMID- 22533489 TI - Origin of leaf rust adult plant resistance gene Rph20 in barley. AB - Rph20 is the only reported, simply inherited gene conferring moderate to high levels of adult plant resistance (APR) to leaf rust (Puccinia hordei Otth) in barley (Hordeum vulgare L.). Key parental genotypes were examined to determine the origin of Rph20 in two-rowed barley. The Dutch cultivar 'Vada' (released in the 1950s) and parents, 'Hordeum laevigatum' and 'Gull' ('Gold'), along with the related cultivar 'Emir' (a derivative of 'Delta'), were assessed for APR to P. hordei in a disease screening nursery. The marker bPb-0837-PCR, co-located with Rph20 on the short arm of chromosome 5H (5HS), was used to screen genotypes for the resistance allele, Rph20.ai. Results from phenotypic assessment and DNA analysis confirmed that Rph20 originated from the landrace 'H. laevigatum' (i.e., Hordeum vulgare subsp. vulgare). Tracing back this gene through the pedigrees of two-rowed barley cultivars, indicated that Rph20 has contributed APR to P. hordei for more than 60 years. Although there have been no reports of an Rph20-virulent pathotype, the search for alternative sources of APR should continue to avoid widespread reliance upon a single resistance factor. PMID- 22533490 TI - Treatment of infantile haemangioma with captopril. AB - BACKGROUND: Infantile haemangioma (IH) has recently been reported as an aberrant proliferation and differentiation of a primitive mesoderm-derived haemogenic endothelium regulated by the renin-angiotensin system (RAS), leading us to propose angiotensin converting enzyme (ACE) as a potential therapeutic target. OBJECTIVES: To present initial results of our open-labelled observational clinical trial using captopril, an ACE inhibitor (ACEi), in the treatment of problematic proliferating IH. METHODS: After initial screening investigations, infants with problematic IH were admitted for initiation of captopril with a 0.1 mg kg(-1) test dose orally, followed by 0.15 8-hourly over 24 h. This was then followed by dose escalation to 0.3 mg kg(-1) 8-hourly for another 24 hours. The dosage was increased to 0.5 mg kg(-1) 8-hourly 1 week later, if a noticeable involution had not already occurred. The response of IH to captopril was documented clinically and photographically before and after treatment and any side-effect was recorded. RESULTS: Two boys and six girls aged 5-22 weeks (mean 12.9) with problematic IH were recruited with the lesions located in nasal tip (n = 1), cervicofacial (n = 3), periorbital (n = 1) and perineal (n = 2) areas, and shoulder (n = 1). Transient mild renal impairment occurred in one subject but resolved spontaneously. No other complication was observed. The IHs in all patients responded to captopril at a dosage of 1.5 mg kg(-1) daily which led to a dramatic response in three, moderate response in two, and slow response in three patients. Continued involution of IHs was observed during the follow-up period of 8-19 months (mean 15.8) in all subjects. Treatment was ceased at 14 months of age in seven patients with no rebound growth. In the remaining patient, rapid healing occurred with ongoing gradual reduction in the size and colour of a large ulcerated retroauricular lesion following 5.5 months of treatment. The lesion was excised to address its persistent distortion of the ear. CONCLUSIONS: The response of IH to an ACEi supports a critical role for the RAS in IH and represents a paradigm shift in the understanding and treatment of this enigmatic condition. PMID- 22533491 TI - Production of extracellular water-insoluble polysaccharide from Pseudomonas sp. AB - Curdlan is a microbial polysaccharide composed exclusively of beta-(1,3)-linked glucose residues. Until now only bacteria belonging to the Alcaligenes and Agrobacterium species have been reported to produce Curdlan. In this study, a bacterium capable of producing extracellular Curdlan, identified as Pseudomonas sp. on the basis of 16S rDNA gene sequencing, was isolated from soil samples. From the HPLC, permethylation linkage analysis, (13)C NMR, and FT-IR analytical data, the polysaccharide consisted exclusively of glucose; the most prominent sugar was 1,3-linked glucose, and most glycosidic bonds joining these sugar residues were of the beta-type. This also supported that the exopolysaccharide produced by Pseudomonas sp. was actually Curdlan. In addition, the Pseudomonas sp. was studied for the production of Curdlan by conventional "one-factor-at-a time technique" and response surface methodology (RSM). It was observed that glucose and yeast extract were the most suitable carbon source and nitrogen source for Curdlan production, respectively. By using RSM, Curdlan production was increased significantly by 188%, from 1.25 to 2.35 g/L, when the strain was cultivated in the optimal condition developed by RSM, and the highest Curdlan production rate of 0.81 g/(L h) was obtained. To the best of the authors' knowledge, this is the first report on Curdlan production by Pseudomonas sp. PMID- 22533492 TI - Magnetic nanoparticles sensitize MCF-7 breast cancer cells to doxorubicin-induced apoptosis. AB - BACKGROUND: Resistance of breast cancer cells to the available chemotherapeutics is a major obstacle to successful treatment. Recent studies have shown that magnetic nanoparticles might have significant application in different medical fields including cancer treatment. The goal of this study is to verify the ability of magnetic nanoparticles to sensitize cancer cells to the clinically available chemotherapy. METHODS: The role of iron oxide nanoparticles, static magnetic field, or a combination in the enhancement of the apoptotic potential of doxorubicin against the resistant breast cancer cells, MCF-7 was evaluated using the MTT assay and the propidium iodide method. RESULTS: In the present study, results revealed that pre-incubation of MCF-7 cells with iron oxide nanoparticles before the addition of doxorubicin did not enhance doxorubicin-induced growth inhibition. Pre-incubation of MCF-7 cells with iron oxide nanoparticles followed by a static magnetic field exposure significantly (P < 0.05) increased doxorubicin-induced cytotoxicity. Sensitization with pre-exposure to the magnetic field was dose-dependent where the highest cytotoxicity was seen at 1 tesla. Further experiments revealed that the anti-proliferative effect of this treatment procedure is due to induction of apoptotic cell death. CONCLUSIONS: These results might point to the importance of combining magnetic nanoparticles with a static magnetic field in treatment of doxorubicin-refractory breast cancer cells. PMID- 22533493 TI - Characterizing biofuel combustion with patterns of real-time emission data (PaRTED). AB - Emission properties and quantities from combustion sources can vary significantly during operation, and this characteristic variability is hidden in the traditional presentation of emission test averages. As a complement to the emission test averages, we introduce the notion of statistical pattern analysis to characterize temporal fluctuations in emissions, using cluster analysis and frequency plots. We demonstrate this approach by comparing emissions from traditional and improved wood-burning cookstoves under in-field conditions, and also to contrast laboratory and in-field cookstove performance. Compared with traditional cookstoves, improved cookstoves eliminate emissions that occur at low combustion efficiency. For cookstoves where the only improvement is an insulated combustion chamber, this change results in emission of more light-absorbing (black) particles. When a chimney is added, the stoves produce more black particles but also have reduced emission factors. Laboratory tests give different results than in-field tests, because they fail to reproduce a significant fraction of low-efficiency events, spikes in particulate matter (PM) emissions, and less-absorbing particles. These conditions should be isolated and replicated in future laboratory testing protocols to ensure that stove designs are relevant to in-use operation. PMID- 22533494 TI - Cognitive behavioural therapy from the perspective of clients with mild intellectual disabilities: a qualitative investigation of process issues. AB - BACKGROUND: Clinicians working with clients who have mild intellectual disabilities (IDs) have shown growing enthusiasm for using a cognitive behavioural approach, amid increasing evidence of good treatment outcomes for this client group. However, very little is known about the views and experiences of clients with IDs who have undergone cognitive behavioural therapy. This study aims to explore the perspective of these clients. METHODS: Fifteen participants with borderline to mild IDs and problems of anxiety, depression and anger were interviewed regarding their experience of cognitive behavioural therapy (CBT). Two semi-structured interviews were carried out in the first phase of therapy between session four and session nine. An interpretive phenomenological approach was taken to seek out themes from participants' own personal accounts. RESULTS: Participants valued the opportunity to talk about problems with their therapist and benefitted from therapeutic relationships characterised by warmth, empathy and validation. Participants identified areas of positive change; however, many thought that this may be short lived or not maintained beyond discharge. CONCLUSIONS: The supportive aspects of therapeutic relationships were particularly important to participants undergoing CBT. The clinical implications are considered. PMID- 22533495 TI - Cytotoxicity of silver dressings on diabetic fibroblasts. AB - A large number of silver-based dressings are commonly used in the management of chronic wounds that are at risk of infection, including diabetic foot ulcers. However, there are still controversies regarding the toxicity of silver dressings on wound healing. The purpose of this study was to objectively test the cytotoxicity of silver dressings on human diabetic fibroblasts. Human diabetic fibroblasts were obtained from the foot skin of four diabetic foot ulcer patients and cultured. The effect of five silver-containing dressing products (Aquacel Ag, Acticoat*Absorbent, Medifoam Ag, Biatain Ag and PolyMem Ag) and their comparable silver-free dressing products on morphology, proliferation and collagen synthesis of the cultured human diabetic fibroblasts were compared in vitro. In addition, extracts of each dressing were tested in order to examine the effect of other chemical components found in the dressings on cytotoxicity. The diabetic fibroblasts cultured with each silver-free dressing adopted the typical dendritic and fusiform shape. On the other hand, the diabetic fibroblasts did not adopt this typical morphology when treated with the different silver dressings. All silver dressings tested in the study reduced the viability of the diabetic fibroblasts and collagen synthesis by 54-70 and 48-68%, respectively, when compared to silver-free dressings. Silver dressings significantly changed the cell morphology and decreased cell proliferation and collagen synthesis of diabetic fibroblasts. Therefore, silver dressings should be used with caution when treating diabetic wounds. PMID- 22533496 TI - A bedtime dose of ARB was better than a morning dose in improving baroreflex sensitivity and urinary albumin excretion--the J-TOP study. AB - The hypothesis that the bedtime dosing of angiotensin receptor blocker (ARB) is superior to morning dose in improving baroreflex sensitivity (BRS) and urinary albumin/creatinine ratio (UACR) was tested in this study. Baroreflex sensitivity was measured at baseline and at 6th month (N = 109) and was found to increase in the bedtime-dose group (P = .004), but not in the morning-dose group. The correlations between the change in BRS and the change in UACR were insignificant in the morning-dose group (r = 0.17, P = .26), but were significant in the bedtime-dose group (r = -0.29, P = .04). In conclusion, the improvement of BRS could be one of the mechanisms by which bedtime dosing of ARB confers renal protection. PMID- 22533497 TI - Successful and unsuccessful clinical nursing students. AB - This study describes the characteristics of successful and unsuccessful clinical performance in prelicensure nursing students. Clinical evaluation is an important role of nurse educators; however, many feel uncomfortable with its subjective nature, and commonly used criteria for successful and unsuccessful clinical performance are not available in the literature. Using a qualitative descriptive design, we analyzed telephone interviews with 24 nurse educators. Educators indicated successful students were positive and eager to learn, built relationships, communicated well, think critically, prepared for the clinical experience and showed progress, accepted feedback, and adapted to the clinical setting. Unsuccessful students were unprepared for the clinical experience, were unable to function in the clinical area, were unsafe, violated legal-ethical principles, and had difficulty with communication skills. Specific characteristics differentiated students who are considered satisfactory in the clinical area and those who are not. These behaviors may identify students at risk of failure in clinical courses. PMID- 22533498 TI - Life of a caregiver simulation: teaching students about frail older adults and their family caregivers. AB - The number of older adults with caregiving needs is rapidly escalating, and the majority of these adults are cared for at home by unpaid family members. Nurse educators must better prepare nurse graduates to meet the needs of this population, as well as to include family caregivers as part of the health care team. This article describes the design, implementation, and preliminary outcomes of a unique learning experience, the Life of a Caregiver Simulation, which uses narrative pedagogy to increase students' awareness and understanding of the needs of older adults, their family caregivers, and the community services they use. Subjective data from students (N = 25) indicated the simulation served as an effective catalyst for students to experience first-hand and understand the stress and burdens of caregiving. PMID- 22533499 TI - Developing and piloting an online graduate nursing course focused on experiential learning of qualitative research methods. AB - Despite the turmoil of a worldwide economic crisis, the health sector remains largely understaffed, and the nursing shortage represents a major issue that jeopardizes graduate nursing education. Access to education remains a challenge, particularly in rural and remote areas. This article reports the process of developing an asynchronous online qualitative research course. This online course was piloted among 16 interdisciplinary students. Participants agreed that experiential learning was useful to understand the intricacies of qualitative research. Within this constructivist approach, students were immersed in real life experiences, which focused on the development of skills applicable to qualitative research. Based on the findings, we suggest that constructivism and the Four-Component Instructional Design (4C/ID) model (a four-part approach for fostering the development of complex skills) represent valuable ontological and pedagogical approaches that can be used in online courses. Triangulating these two approaches is also congruent with the student-centered philosophy that underpins nursing graduate programs. PMID- 22533500 TI - Learning in simulated environments: effect on learning transfer and clinical skill acquisition in nurse practitioner students. AB - This research study examined whether a transfer of learning (i.e., growth in clinical competency) occurred from the simulation laboratory to the clinical bedside and if it did occur, how. The study design was descriptive research, using 14 acute care nurse practitioner students. Observations were done in the simulation laboratory with a standardized patient and then in the clinical setting with an actual patient. The results showed significant growth in overall clinical competency from the simulation laboratory to the clinical bedside (M(diff) = 0.08, SE = 0.02, t(13) = 3.03, p = 0.01, r = 0.64). A statistically significant correlation was noted between the overall competency scores of students in the simulation laboratory and the overall competency scores in the clinical setting, with r(12) = 0.63, p < 0.01. Three themes emerged from the students' responses regarding how the simulation experience affected their clinical competency. PMID- 22533501 TI - Measuring critical thinking dispositions of novice nursing students using human patient simulators. AB - This study assessed the influence of human patient simulator (HPS) practice on critical thinking dispositions in a sample of novice baccalaureate nursing students. Eighty-five second-year nursing students were randomly assigned to an experimental (n = 42) or a control (n = 43) group based on exposure to a 2-hour HPS practice session prior to a course competency examination. The California Critical Thinking Disposition Inventory (CCTDI) was administered before and after the competency examination. No between-group differences were found on overall or subscale CCTDI mean scores. Within-group differences for the HPS practice group were significant for overall scores (p < 0.05) and the truth-seeking (p < 0.01) and judiciousness or maturity of judgment (p < 0.01) subscales. This preliminary data analysis suggests disposition gains for individual students practicing critical assessment skills using HPS. The cohort will be followed for 2 years to assess long-term critical thinking outcomes following practice with HPS. PMID- 22533502 TI - Paraspinal ganglioneuroma in the proband of a large family with mild cutaneous manifestations of NF1, carrying a deep NF1 intronic mutation. PMID- 22533503 TI - Tuning the properties of elastin mimetic hybrid copolymers via a modular polymerization method. AB - We have synthesized elastin mimetic hybrid polymers (EMHPs) via the step-growth polymerization of azide-functionalized poly(ethylene glycol) (PEG) and alkyne terminated peptide (AKAAAKA)(2) (AK2) that is abundant in the cross-linking domains of the natural elastin. The modular nature of our synthesis allows facile adjustment of the peptide sequence to modulate the structural and biological properties of EMHPs. Therefore, EMHPs containing cell-binding domains (CBDs) were constructed from alpha,omega-azido-PEG and two types of alkyne-terminated AK2 peptides with sequences of DGRGX(AKAAAKA)(2)X (AK2-CBD1) and X(AKAAAKA)(2)XGGRGDSPG (AK2-CBD2, X = propargylglycine) via a step-growth, click coupling reaction. The resultant hybrid copolymers contain an estimated five to seven repeats of PEG and AK2 peptides. The secondary structure of EMHPs is sensitive to the specific sequence of the peptidic building blocks, with CBD containing EMHPs exhibiting a significant enhancement in the alpha-helical content as compared with the peptide alone. Elastomeric hydrogels formed by covalent cross-linking of the EMHPs had a compressive modulus of 1.06 +/- 0.1 MPa. Neonatal human dermal fibroblasts (NHDFs) were able to adhere to the hydrogels within 1 h and to spread and develop F-actin filaments 24 h postseeding. NHDF proliferation was only observed on hydrogels containing RGDSP domains, demonstrating the importance of integrin engagement for cell growth and the potential use of these EMHPs as tissue engineering scaffolds. These cell instructive, hybrid polymers are promising candidates as elastomeric scaffolds for tissue engineering. PMID- 22533505 TI - Epoxidation of olefins with a silica-supported peracid in supercritical carbon dioxide under flow conditions. AB - Anhydrous 2-percarboxyethyl-functionalized silica (2b), a recyclable supported peracid, is a suitable reagent to perform the epoxidation of alkenes 1 in supercritical carbon dioxide at 250 bar and 40 degrees C under flow conditions. This procedure simplifies the isolation of the reaction products and uses only carbon dioxide as a solvent under mild conditions. The solid reagent 2b can be easily recycled by a reaction with 30% hydrogen peroxide in an acid medium. PMID- 22533504 TI - The expression of the glucocorticoid receptor in human erythroblasts is uniquely regulated by KIT ligand: implications for stress erythropoiesis. AB - Studies in mice indicated that activation of the erythroid stress pathway requires the presence of both soluble KIT ligand (KITL) and the glucocorticoid receptor (GR). To clarify the relative role of KITL and GR in stress erythropoiesis in humans, the biological activities of soluble full length- (fl-, 26-190 aa), carboxy-terminus truncated (tr-, 26-162 aa) human (hKITL) and murine (mKITL) KITL in cultures of cord blood (CB) mononuclear cells (MNCs) and CD34(pos) cells that mimic either steady state (growth factors alone) or stress (growth factors plus dexamethasone [DXM]) erythropoeisis were investigated. In steady state cultures, the KITLs investigated were equally potent in sustaining growth of hematopoietic colonies and expansion of megakaryocytes (MK) and erythroid precursors (EBs). By contrast, under stress erythropoiesis conditions, fl-hKITL generated greater numbers of EBs (fold increase [FI]=140) than tr-hKITL or mKITL (FI=20-40). Flow cytometric analyses indicated that only EBs generated with fl-hKITL remained immature (>70% CD36(pos)/CD235a(neg/low)), and therefore capable to proliferate, until day 8-12 in response to DXM. Signaling studies indicated that all KITLs investigated induced EBs to phosphorylate signal transducer and activator of transcription 5 (STAT5) but that extracellular signaling-regulated-kinases (ERK) activation was observed mainly in the presence of fl-hKITL. EBs exposed to fl-hKITL also expressed higher levels of GRalpha than those exposed to mKITL (and tr-hKITL) which were reduced upon exposure to the ERK inhibitor U0126. These data reveal a unique requirement for fl-hKITL in the upregulation of GRalpha and optimal EB expansion in cultures that mimic stress erythropoiesis. PMID- 22533506 TI - Immunohistochemical alterations in invasive adenocarcinoma in endoscopically resected adenoma and factors associated with risk of residual or recurrent disease. AB - AIM: We determined the pattern of immunohistochemical expression in invasive adenocarcinoma in endoscopically resected adenoma, its relationship with the risk of residual or recurrent disease and the related factors. METHOD: We included individuals with malignant polyps resected endoscopically in the period 1999 2009. Clinical and endoscopic data were collected. All histological specimens were re-analysed. CD44, matrix metalloproteinase 9 (MMP-9), vascular endothelial growth factor-beta (VEGF-beta), beta-catenin, laminin and cyclooxygenase 2 (COX 2) expression were determined by immunohistochemistry. A multivariate logistic regression was performed to determine variables independently associated with the risk of residual or recurrent disease. RESULTS: One-hundred and fifty-one malignant polyps (114 pedunculated; mean size +/- SD=22.61 +/- 10.86 mm) were resected endoscopically. Resection was fragmented and incomplete in 26.5% and 8.6% of patients, respectively. Surgical resection was performed on 71 (47%) patients. After a median follow-up of 44 months, residual (n=12) or recurrent (n=6) disease was detected in 17 patients. Conventional histology showed that 32.1% met high-risk histological criteria. Immunohistochemical expression was positive for CD44, MMP-9, VEGF-beta, beta-catenin, laminin and COX-2 in 63.3%, 25.3%, 45%, 38.8%, 79% and 34.5% of specimens, respectively, with no differences between both groups. Variables associated with residual or recurrent disease in the univariate analysis were: nonpedunculated morphology (P=0.07); fragmented (P<0.001) or incomplete resection (P<0.001); margin infiltration (P=0.04); and histological high-risk lesion (P=0.003). Finally, incomplete resection (OR=12.16, 95% CI=3.15-46.98; P<0.001) and histological high risk (OR=4.73, 95% CI=1.33 16.74; P=0.002) were independently associated with the risk of residual or recurrent disease. CONCLUSION: Immunohistochemistry could not predict residual or recurrent disease. Only incomplete excision and histological high risk did so. The factors independently associated were histological high-risk lesion and incomplete resection. PMID- 22533507 TI - Identification of methicillin-resistant Staphylococcus aureus within the nation's Veterans Affairs medical centers using natural language processing. AB - BACKGROUND: Accurate information is needed to direct healthcare systems' efforts to control methicillin-resistant Staphylococcus aureus (MRSA). Assembling complete and correct microbiology data is vital to understanding and addressing the multiple drug-resistant organisms in our hospitals. METHODS: Herein, we describe a system that securely gathers microbiology data from the Department of Veterans Affairs (VA) network of databases. Using natural language processing methods, we applied an information extraction process to extract organisms and susceptibilities from the free-text data. We then validated the extraction against independently derived electronic data and expert annotation. RESULTS: We estimate that the collected microbiology data are 98.5% complete and that methicillin-resistant Staphylococcus aureus was extracted accurately 99.7% of the time. CONCLUSIONS: Applying natural language processing methods to microbiology records appears to be a promising way to extract accurate and useful nosocomial pathogen surveillance data. Both scientific inquiry and the data's reliability will be dependent on the surveillance system's capability to compare from multiple sources and circumvent systematic error. The dataset constructed and methods used for this investigation could contribute to a comprehensive infectious disease surveillance system or other pressing needs. PMID- 22533508 TI - Proteomic identification of a novel hsp90-containing protein-mineral complex which can be induced in cells in response to massive calcium influx. AB - Fetuin-A is known for limiting the expansion and formation of hydroxyapatite crystals from calcium phosphate aggregates in circulation by forming a soluble fetuin-mineral complex. This study was aimed to uncover potential proteins involved in the regulation of calcium phosphate precipitation within cells. We found that a novel protein-mineral complex (PMC) can be generated after introduction of calcium chloride and sodium phosphate into the porcine brain protein extract prepared in Tris-HCl buffer. Selectively enriched proteins in the pellet were confirmed by immunoblotting, including heat shock protein 90 (Hsp90), annexin A5, calreticulin, nucleolin, and other proteins. In addition, purified native Hsp90 directly bound both amorphous calcium phosphate and hydroxyapatite and underwent conformational changes and oligomerization in the presence of excess calcium and phosphate. The morphology of the PMC prepared from Hsp90, calcium, and phosphate was distinctly different from that of hydroxyapatite under transmission electron microscope observation. When cultured SiHa cells were treated with a calcium ionophore or damaged by scratch to induce the massive calcium influx, a complex was formed and observed at discrete sites near the plasma membrane as revealed by antibodies against Hsp90, annexin A5, calreticulin, nucleolin, and other proteins. This complex could also be probed in situ with fetuin-A suggesting the existence of calcium phosphate aggregates in this complex. Inhibition of the complex formation by bisphosphonates hindered cell recovery from A23187 assault. Our results show that following membrane damage amorphous calcium phosphate develops at sites near membrane rupture where saturated calcium phosphate concentration is achieved. As a result, Hsp90 and other proteins are recruited, and the cytosolic PMC is formed. Inhibition of the cytosolic PMC formation may in part contribute to the cellular toxicity and in vivo side effects of bisphosphonates, particularly in cells prone to membrane damage under physiological conditions such as gastrointestinal epithelial and oral cavity epithelial cells. PMID- 22533509 TI - Nitrergic response to Clostridium perfringens infection in the rat brain regions: effect of red light irradiation. AB - A single intraperitoneal injection of a gram-positive pathogen Clostridium perfringens (Cp) causes a remarkable down-regulation the constitutive nitric oxide synthase (cNOS) with a simultaneous increase in the activity of inducible NOS (iNOS) and the level of reactive nitrogen species in the rat brain major regions (cortex, striatum, hippocampus and hypothalamus) at 48 h post administration of Cp. Treatment by both a semiconductor laser (SCL) and/or a light-emitting diode (LED) with same wavelength, energy density and time exposure (continuous wave, lambda=654 nm, fluence=1.27 J/cm(2), time exposure=600 s) could modulate brain nitrergic response following Cp-infection. Besides, unlike the LED, the SCL-irradiation prevents the cNOS inhibition in all the studied brain regions and might be useful in restoring its function in neurotransmission and cerebral blood flow, along with providing a protective effect against nitrosative stress-induced iNOS-mediated injury in the brain regions. PMID- 22533510 TI - Central nervous system acting drugs in treatment of migraine headache. AB - Migraine is a primary headache disorder with an unknown pathophysiology. The growing evidence in recent years indicates migraine being a brain disorder, a sensory dysmodulation, and a system failure of normal sensory processing of the brainstem that involves the vascular tone and pain. At the moment, triptan family and NSAIDs are the first choice drugs for the treatment of acute migraine. There are several prophylactic drugs including the antiepileptic drugs (AEDs), betablockers, and Ca2+ channel blockers that are used for the treatment of migraine. Although many drugs including the triptans, NSAIDs, and others target the peripheral sites of activation, several novel drugs are being developed to target neural sites of action in the central nervous system (CNS). The first trigeminal synapses in the brain stem as well as the ascending and descending pathways and higher brain centers are involved in the transmission of pain and therefore be the main targets of several drugs some of which are in clinical trials. Central sensitization may also aggravate the headache and some drugs tend to alleviate pain by targeting neurotransmitters, receptors, or signalling molecules involved in this phenomenon. This article discusses the CNS acting novel drugs and those that are currently in use for the treatment of migraine. PMID- 22533511 TI - GEMSP: a new therapeutic approach to multiple sclerosis. AB - A new therapeutic approach called Endotherapia (GEMSP) for the treatment of Multiple Sclerosis (MS) is suggested. Endotherapia is the result of an immunopathological strategy addressing chronic incurable diseases with a multifactorial etiology. This approach combines a biomedical evaluation of circulating immunoglobulins directed against specific self-antigens and self antigens modified by free radicals. GEMSP is a "tailor-made" combination of small molecules (fatty acids, antioxidants, radical scavengers, amino acids) linked to a non-immunogenic linear chain of poly-L.lysine (PLL). Each individual linkage or PLL derivative offers great advantages, such as an increase in the half-life of the active small molecules. GEMSP inhibits brain leukocyte infiltration and abolishes episodes of experimental autoimmune encephalomyelitis. In a clinical trial with 102 MS patients treated with GEMSP Endotherapia, 28% of them showed a worsening of their state; 20% showed a decrease in the progression of the disease; 17% showed disease stabilization; and 35% showed a reversal of the evolution of disease; i.e., an improvement in their disease state. In 72% of the cases, a positive evolution of the state of the MS patients treated with Endotherapia was observed (a decrease or stabilization of disease evolution or an improvement). Endotherapia is very safe and no side-effects were reported for GEMSP. Moreover, GEMSP showed no toxicity either in experimental animals or in humans. It seems that Endotherapia is a promising therapy for MS, with no side effects, which should be considered in the management of long-term pathologies. PMID- 22533513 TI - Commentary on proposed new classification system for BRONJ. PMID- 22533512 TI - Bioequivalence in dogs of a meloxicam formulation administered as a transmucosal oral mist with an orally administered pioneer suspension product. AB - A mucosal mist formulation of meloxicam, administered as a spray into the mouth (test article), was compared for bioequivalence to a pioneer meloxicam suspension for oral administration (reference article). Pharmacokinetic profiles and average bioequivalence were investigated in 20 dogs. The study design comprised a two period, two-sequence, two-treatment cross-over design, with maximum concentration (C(max)) and area under plasma concentration-time curve to last sampling time (AUC(last)) used as pivotal bioequivalence variables. Bioequivalence of the products was confirmed, based on relative ratios of geometric mean concentrations (and 90% confidence intervals within the range 0.80-1.25) for C(max) of 101.9 (97.99-106.0) and for AUC(last) of 97.24 (94.44-100.1). The initial absorption of meloxicam was more rapid for the test article, despite virtually identical C(max) values for the two products. Mean elimination half-lives were 29.6 h (test article) and 30.0 h (reference article). The meloxicam plasma concentration-time profiles were considered in relation to published data on the inhibition of the cyclooxygenase-1 (COX-1) and COX-2 isoenzymes by meloxicam. PMID- 22533514 TI - Interactions in the B(+)-RG complexes and comparison with Be(+)-RG (RG = He-Rn): evidence for chemical bonding. AB - Potential energy curves for the interaction of B(+) ((1)S) with RG ((1)S), RG = He-Rn, have been calculated at the CCSD(T) level of theory employing quadruple zeta and quintuple-zeta quality basis sets. The interaction energies from these curves were subsequently point-by-point extrapolated to the basis set limit. Rovibrational energy levels have been calculated for each extrapolated curve, from which spectroscopic parameters are determined. These are compared to previously determined experimental and theoretical values. The potentials have also been employed to calculate the transport coefficients for B(+) traveling through a bath of RG atoms. We also investigate the interactions between B(+) and the rare gases via contour plots, natural population analysis (NPA), and molecular orbital diagrams. In addition, we consider the atoms-in-molecules (AIM) parameters. The interactions here are compared and contrasted with those for Li(+)-He and Be(+)-RG; it is concluded that there is significant and increasing dative covalent bonding for the Be(+)-RG and B(+)-RG complexes for RG = Ar-Rn, while the other species are predominantly physically bound. PMID- 22533515 TI - Editor's Choice. Hope and living with long-term conditions. PMID- 22533516 TI - The effect of spiritual therapy for improving the quality of life of women with breast cancer: a randomized controlled trial. AB - Diagnosis of breast cancer is a devastating psychological experience for a woman. Also, treatments such as radiation therapy may cause psychosocial distress in these patients and threaten their quality of life (QOL). Among several approaches, spirituality has been shown to be significantly associated with improving the QOL. The aim of this study was to assess the role of spiritual therapy intervention in improving the QOL of patients with breast cancer undergoing radiation therapy. This was a randomized controlled trial study undertaken in a radiotherapy clinic, Isfahan, Iran. Between October 2010 and February 2011, 68 patients under radiation therapy were randomized to either spiritual therapy intervention group or control group who received routine management and educational programs. Before and after six weeks of spiritual therapy sessions, the QOL was evaluated using Cancer quality-of-life questionnaire (QLQ)-C30 and breast cancer-specific questionnaire (BR-23). Multivariate, repeated-measures ANOVA, t-test, and Paired t-test were used for analysis using Predictive Analytic Soft Ware (PASW, version 18) for windows. In all, 65 patients actually completed the six-week intervention and were evaluated for the outcome. The mean Global health status score/QOL reached from 44.37 (SD = 13.03) to 68.63 (SD = 10.86), (p = 0.00). There was a statistically significant difference in all functional scales of QLQ-C30 after intervention (p < 0.05). The results of this trial showed that the spiritual therapy program can improve the overall QOL of women with breast cancer; therefore, it could be adopted in comprehensive care programs for women with breast cancer. PMID- 22533517 TI - Bigger weights may not beget bigger muscles: evidence from acute muscle protein synthetic responses after resistance exercise. AB - It is often recommended that heavier training intensities (~70%-80% of maximal strength) be lifted to maximize muscle growth. However, we have reported that intensities as low as 30% of maximum strength, when lifted to volitional fatigue, are equally effective at stimulating muscle protein synthesis rates during resistance exercise recovery. This paper discusses the idea that high-intensity contractions are not the exclusive driver of resistance exercise-induced changes in muscle protein synthesis rates. PMID- 22533518 TI - Lymph-node ratio is an independent prognostic factor in patients with stage III colorectal cancer: a retrospective study from the Middle East. AB - BACKGROUND: In this retrospective study, we evaluated the prognostic effect of positive lymph-node ratio (pLNR) on patients with stage III colorectal cancer (CRC). Our paper is the first analysis, to our knowledge, to deal with such data from the Middle East. METHODS: We analyzed the clinicopathological data of 535 patients diagnosed with colorectal cancer at our institution between 1983 and 2003. The 164 patients diagnosed with stage III disease were divided into two categories based on lymph-node ratio (LNR) being the ratio of positive lymph nodes over total lymph nodes dissected: LNR <= 0.4 and LNR >0.4. We used Kaplan Meier and Cox proportional hazard models to evaluate the prognostic effect of pLNR. RESULTS: The 10-year survival rate for the patients with stage IIIA, IIIB and IIIC cancers were 76%, 56% and 0% respectively (P = 0.014). Using pLNR of 0.4 as the cutoff point was found to yield clinically and significant results, with a significant difference in the outcomes of patients with pLNR <= 0.4 compared to those with pLNR >0.4 (hazard ratio = 5.25, 95% confidence interval = 1.2 to 22.1, P = 0.02). CONCLUSION: The ratio-based staging (pLNR) of CRC is a more accurate and clinically useful prognostic method than the number of positive LNs resected or the total number of LNs retrieved for predicting the course of patients with stage III CRC. PMID- 22533519 TI - Role of pK(a) of nucleobases in the origins of chemical evolution. AB - The formation of canonical base pairs through Watson-Crick hydrogen bonding sits at the heart of the genetic apparatus. The specificity of the base pairing of adenine with thymine/uracil and guanine with cytosine preserves accurate information for the biochemical blueprint and replicates the instructions necessary for carrying out biological function. The chemical evolution question of how these five canonical nucleobases were selected over various other possibilities remains intriguing. Since these and alternative nucleobases would have been available for chemical evolution, the reasons for the emergence of this system appear to be primarily functional. While investigating the base-pairing properties of structural nucleic acid analogs, we encountered a relationship between the pK(a) of a series of nonstandard (and canonical) nucleobases and the pH of the aqueous medium. This relationship appeared to correspond with the propensity of these molecules to self-assemble via Watson-Crick-type base-pairing interactions. A simple correlation of the "magnitude of the difference between the pK(a) and pH" (pK(a)-pH correlation) enables a general prediction of which types of heterocyclic recognition elements form hydrogen-bonded base pairs in aqueous media. Using the pK(a)-pH relationship, we can rationalize why nature chose the canonical nucleobases in terms of hydrophobic and hydrophilic interactions, and further extrapolate its significance within the context of chemical evolution. The connection between the physicochemical properties of bioorganic compounds and the interactions with their aqueous environment directly affects structure and function, at both a molecular and a supramolecular level. A general structure-function pattern emerges in biomolecules and biopolymers in aqueous media near neutral pH. A pK(a) - pH < 2 generally prompts catalytic functions, central to metabolism, but a difference in pK(a) - pH > 2 seems to result in the emergence of structure, central to replication. While this general trend is observed throughout extant biology, it could have also been an important factor in chemical evolution. PMID- 22533520 TI - The prognostic importance of a history of hypertension in patients with symptomatic heart failure is substantially worsened by a short mitral inflow deceleration time. AB - BACKGROUND: Hypertension is a common comorbidity in patients with heart failure and may contribute to development and course of disease, but the importance of a history of hypertension in patients with prevalent heart failure remains uncertain. METHODS: 3078 consecutively hospitalized heart failure patients (NYHA classes II-IV) were screened for the EchoCardiography and Heart Outcome Study (ECHOS). The left ventricular ejection fraction (LVEF) was estimated by 2 dimensional transthoracic echocardiography in all patients and a subgroup of 878 patients had additional data on pulsed wave Doppler assessment of transmitral flow available. A restrictive filling (RF) was defined as a mitral inflow deceleration time <=140 ms. Patients were followed for a median of 6.8 (Inter Quartile Range 6.6-7.0) years and multivariable Cox regression models were used to assess the risk of all-cause mortality associated with hypertension. RESULTS: The study population had a mean age of 73 +/- 11 years. 39% were female, 27% had a history of hypertension and 48% had a RF. Over the study period, 64% of the population died. Hypertension was not associated with increased risk of mortality, hazard ratio (HR) 0.95 (0.85-1.05). LVEF did not modify this relationship (p for interaction = 0.7), but RF pattern substantially influenced the outcomes associated with hypertension (p for interaction < 0.001); HR 0.75 (0.57-0.99) and 1.41 (1.08-1.84) in patients without and with RF, respectively. CONCLUSIONS: In patients with symptomatic heart failure, a history of hypertension is associated with a substantially increased relative risk of mortality among patients with a restrictive transmitral filling pattern. PMID- 22533521 TI - Off-label use of sunitinib in patients with advanced, epithelial thyroid cancer: a retrospective analysis. AB - Tyrosine kinase receptors play an important role in tumor angiogenesis and, their implication in epithelial thyroid tumor growth has been highlighted. Sunitinib is a novel tyrosine kinase inhibitor, approved in 2006 by Food and Drug Administration for the treatment of advanced renal cell and gastrointestinal stromal tumors. Preliminary promising results have been also obtained in patients with RAI-resistant thyroid neoplasia. In the current study, our experience on 9 patients with advanced thyroid epithelial cancer is analyzed and discussed in relation to the new patents in this field. According to RECIST criteria, partial response was obtained in 5/9 (55.5%) patients at 3 months and in 6/9 (66.6%) at 6 months. Median treatment follow-up was 13.0 months and median overall survival and progression-free survival were 20 [95% confidence interval (CI) 9.3 - 30.6] and 21 months (95% CI 6.9 - 35.1), respectively. One case of severe thoracic hemorrhage was observed, the most common adverse events being represented by fatigue, (44.4% ), skin rash (33.3% ), headache (33.3% ), and one case each of hypertension, macrocytosis and acute pneumonia. These results confirm sunitinib as a potential useful tool for the treatment of advanced thyroid cancers and may open the way for new patents of molecules with more specific target selectivity. PMID- 22533522 TI - Potential role of Rho-associated protein kinase inhibitors for glaucoma treatment. AB - Rho kinase inhibitors are widely considered as a new treatment for glaucoma. Rho kinase inhibition has been shown in vitro and in vivo to lower intraocular pressure. Furthermore in the first clinical reports involving healthy human subjects, the results were quite promising. The potential of this new class of medicines is enormous in a field where there were not many developments lately. The inhibition of Rho kinase lowers the intraocular pressure by increasing the outflow through the trabecular meshwork. Increased blood flow to the optic nerve and a possible delay of optic nerve cell death has also been reported. As a consequence, the exploration of pharmacological inhibitors of Rho kinase signaling is actively being pursued by a number of pharmaceutical companies such as Senju Pharmaceuticals, Novartis, Kowa, Santen, Aerie, Inspire and others. In this article, we review the latest patents in this field, with their corresponding literature, regarding Rho kinase inhibitors for the treatment of intraocular pressure and summarize the many roles of Rho kinase signaling in the eye. PMID- 22533523 TI - Usefulness of sentinel lymph node biopsy for extramammary Paget disease. PMID- 22533524 TI - The burden of immune thrombocytopenia in adults: evaluation of the thrombopoietin receptor agonist romiplostim. AB - BACKGROUND: Immune thrombocytopenia (ITP) is a chronic, immune-mediated disease characterized by a transient or long-lasting decrease in platelet counts. ITP is associated with numerous serious clinical consequences. Discussed here are clinical aspects of ITP, the humanistic and economic burden of ITP, and current treatment options with a focus on romiplostim, a thrombopoietin (TPO) receptor agonist. The aim of this review is to provide decision-makers with the background information necessary to evaluate the value of romiplostim. SCOPE: PubMed was searched for relevant, English-language papers published from January 2006 through November 2011 relating to the epidemiology and treatment options of chronic ITP, and, focusing on the TPO mimetic romiplostim, patient-reported outcomes (PRO) and economic burden. Recent select conference abstracts were also reviewed. FINDINGS: The initial clinical management of ITP (e.g., corticosteroids, immunoglobulins) is often associated with adverse events and recommended for short-term use only. Splenectomy, a potentially curative second line treatment, is associated with increased risks of bleeding and infection, and patients often require additional long-term drug intervention. ITP and its sequelae are associated with a substantial burden on patients' health-related quality-of-life (HRQoL) and increased medical costs. Use of TPO receptor agonists in ITP patients may represent a more efficient use of healthcare resources than existing therapies. CONCLUSION: While this literature review is not a systematic review, e.g., it considers only approved therapies and published literature written in English, it provides a comprehensive overview of the clinical, humanistic, and economic factors that should be considered in treating ITP, particularly with new agents such as romiplostim. Among the limited number of safe and effective therapies currently available for chronic ITP, highly effective and well-tolerated medications such as romiplostim may reduce the healthcare resource utilization associated with ITP while improving patients' HRQoL. PMID- 22533525 TI - Derivation of severity index for rheumatoid arthritis and its association with healthcare outcomes. AB - OBJECTIVES: To develop a claims-based severity index for rheumatoid arthritis (RA) using the Veterans Health Administration (VHA) database. METHODS: Adult patients with at least two RA diagnoses 2 months apart were identified between 10/1/2008-09/30/2009. Patients were required to have at least 12 months continuous health plan enrollment before and after the index date (first RA diagnosis date) for an overall study period of 10/1/2007-09/30/2010. A severity index for rheumatoid arthritis (SIFRA, a proprietary algorithm of SIMR, Inc. [STATinMED Research]) was developed by calculating a weighted sum of 34 RA related indicators assessed by an expert Delphi panel of six rheumatologists, including laboratory, clinical, and functional status, extra-articular manifestations, surgical history, and medications, during a 1-year pre-index period. Separate SIFRA versions were derived for patients with and without laboratory information. Correlations between SIFRA and previously validated claims-based indexes for RA severity (CIRAS), and other traditional comorbidity indexes were calculated during the pre-index period. The relationship between SIFRA and follow-up healthcare outcomes was also examined using histograms. RESULTS: The Spearman's rank correlations between SIFRA and CIRAS were 0.525 for SIFRA without and 0.539 with laboratory data. The correlations between SIFRA and the Charlson Comorbidity Index (CCI) (0.1503 without, 0.1135 with laboratory data), Elixhauser Index (ELIX) (0.105 without, 0.079 with laboratory data), and Chronic Disease Score (CDS) (0.255 without, 0.239 with laboratory data) were low. Histograms showed that patients in the upper tercile of SIFRA incurred $9123 more all-cause and $1326 more RA-related healthcare costs during the 1-year post-index period than patients in the lower tercile. Using SIFRA in combination with CCI, CDS, or ELIX significantly increased the percentage of variation explained in outcomes measures. LIMITATIONS: Patients in the VHA database may not represent typical RA patients since the database generally contains older, economically disadvantaged men with a high disease burden. Validity of the score is indirectly based on disease activity score 28 (DAS28), which measures disease activity rather than severity. CONCLUSIONS: SIFRA was found to have moderate correlations with the previously validated CIRAS score, and demonstrated evidence of being a significant determinant of total and RA-related healthcare costs for RA patients. This study suggests that SIFRA could be an important methodological tool to control for severity in RA-related outcomes research. The algorithm can be applied to any claims dataset. PMID- 22533526 TI - Economic outcomes of exenatide vs liraglutide in type 2 diabetes patients in the United States: results from a retrospective claims database analysis. AB - OBJECTIVE: The safety and efficacy of the GLP-1 receptor agonists exenatide BID (exenatide) and liraglutide for treating type 2 diabetes mellitus (T2DM) have been established in clinical trials. Effective treatments may lower overall treatment costs. This study examined cost offsets and medication adherence for exenatide vs liraglutide in a large, managed care population in the US. METHODS: This was a retrospective cohort analysis comprising adult patients with T2DM who initiated exenatide or liraglutide between 1/1/2010 and 6/30/2010 and had 6 months pre-index and post-index continuous eligibility. Patients were propensity score-matched to controls for baseline differences. Medication adherence was measured by proportion of days covered (PDC). Paired t-test and McNemar's test were used to compare outcomes. RESULTS: Matched exenatide and liraglutide cohorts (n=1347 pairs) had similar average total 6-month follow-up costs ($6688 vs $7346). However, exenatide patients had significantly lower mean pharmacy costs ($2925 vs $3272, p<0.001). Among liraglutide patients, patients receiving the 1.8 mg dose had significantly higher average total costs compared to those receiving the 1.2 mg dose ($8031 vs $6536, p=0.026), with higher mean pharmacy costs in the 1.8 mg cohort ($3935 vs $3146, p<0.001). There were no significant differences in inpatient or outpatient costs or medication adherence between groups (mean PDC: exenatide 56% vs liraglutide 57%, p=0.088). LIMITATIONS: The study assumed that all information needed for case classification and matching of cohorts was present and not differential across cohorts. The study did not control for covariates that were unavailable, such as HbA1c and duration of diabetes. CONCLUSIONS: Patients initiating exenatide vs liraglutide for T2DM had similar medication adherence and total healthcare costs; however, exenatide patients had significantly lower total pharmacy costs. Patients prescribed 1.8 mg liraglutide had significantly higher costs compared to those on 1.2 mg. PMID- 22533527 TI - Cost effectiveness analysis of immunotherapy in patients with grass pollen allergic rhinoconjunctivitis in Germany. AB - OBJECTIVES: An economic evaluation was conducted to assess the outcomes and costs as well as cost-effectiveness of the following grass-pollen immunotherapies: OA (Oralair; Stallergenes S.A., Antony, France) vs GRZ (Grazax; ALK-Abello, Horsholm, Denmark), and ALD (Alk Depot SQ; ALK-Abello) (immunotherapy agents alongside symptomatic medication) and symptomatic treatment alone for grass pollen allergic rhinoconjunctivitis. METHODS: The costs and outcomes of 3-year treatment were assessed for a period of 9 years using a Markov model. Treatment efficacy was estimated using an indirect comparison of available clinical trials with placebo as a common comparator. Estimates for immunotherapy discontinuation, occurrence of asthma, health state utilities, drug costs, resource use, and healthcare costs were derived from published sources. The analysis was conducted from the insurant's perspective including public and private health insurance payments and co-payments by insurants. Outcomes were reported as quality-adjusted life years (QALYs) and symptom-free days. The uncertainty around incremental model results was tested by means of extensive deterministic univariate and probabilistic multivariate sensitivity analyses. RESULTS: In the base case analysis the model predicted a cost-utility ratio of OA vs symptomatic treatment of ?14,728 per QALY; incremental costs were ?1356 (95%CI: ?1230; ?1484) and incremental QALYs 0.092 (95%CI: 0.052; 0.140). OA was the dominant strategy compared to GRZ and ALD, with estimated incremental costs of -?1142 (95%CI: ?1255; -?1038) and -?54 (95%CI: -?188; ?85) and incremental QALYs of 0.015 (95%CI: -0.025; 0.056) and 0.027 (95%CI: -0.022; 0.075), respectively. At a willingness-to-pay threshold of ?20,000, the probability of OA being the most cost-effective treatment was predicted to be 79%. Univariate sensitivity analyses show that incremental outcomes were moderately sensitive to changes in efficacy estimates. The main study limitation was the requirement of an indirect comparison involving several steps to assess relative treatment effects. CONCLUSION: The analysis suggests OA to be cost-effective compared to GRZ and ALD, and a symptomatic treatment. Sensitivity analyses showed that uncertainty surrounding treatment efficacy estimates affected the model outcomes. PMID- 22533528 TI - One-pot, three-component synthesis of a library of spirooxindole-pyrimidines catalyzed by magnetic nanoparticle supported dodecyl benzenesulfonic acid in aqueous media. AB - Dodecyl benzenesulfonic acid functionalized silica-coated magnetic nanoparticles (gamma-Fe2O3@SiO2-DDBSA) were readily prepared and identified as an efficient catalyst for the synthesis of a library of spirooxindole-pyrimidine derivatives by three-component condensation reaction of barbituric acids, isatins and cyclohexane-1,3-diones. The aqueous reaction medium, easy recovery of the catalyst using an external magnet, and high yields make the protocol sustainable and economic. PMID- 22533530 TI - Association of insomnia symptoms with kidney disease quality of life reported by patients on maintenance dialysis. AB - Results of many studies indicate that sleep disorders can reduce quality of life (QoL) in patients with chronic kidney disease. This study aimed to investigate therelation of insomnia symptoms to QoL among haemodialysis (HD) and peritoneal dialysis patients. A sample of 144 patients was recruited from three General Hospitals in the broader area of Athens, consisting of 84 patients undergoing in centre HD and 60 patients in continuous ambulatory peritoneal dialysis. Measurements were conducted with the following instruments: The World Health Organization Quality of Life (WHOQOL) instrument, the General Health Questionnaire, the State-Trait Anxiety In nu entory and the Center for Epidemiologic Studies Depression Scale. The results indicated that insomnia symptoms had negative association with all the domains of WHOQOL questionnaire (physical health, psychological well-being, social relationships and environment). Insomnia symptoms were also related positively to depression as well as state and trait anxiety. The findings provide evidence that the presence of insomnia symptoms relates significantly to the negative evaluation of mental health and QoL in patients with chronic kidney disease. PMID- 22533529 TI - Classification of co-occurring depression and substance abuse symptoms predicts suicide attempts in adolescents. AB - Although both depression and substance use have been found to contribute to suicide attempts, the synergistic impact of these disorders has not been fully explored. Additionally, the impact of subthreshold presentations of these disorders has not been researched. We utilized the Quadrant Model of Classification (a matrix of severity of two disorders) to assess for suicide attempt risk among adolescents. Logistic regression was used to examine the impact of co-occurring disorder classification on suicide risk attempts. Results indicate that quadrant classification had a dramatic impact on suicide attempt risk, with individuals with high severity co-occurring disorders at greatest risk. PMID- 22533531 TI - The involvement of parents in healthcare decisions where adult children are at risk of lacking decision-making capacity: a qualitative study of treatment decisions in epilepsy. AB - BACKGROUND: Patients with intellectual disabilities (ID) receive health care by proxy. It is family members and/or paid support staff who must recognise health problems, communicate with clinicians, and report the benefits, if any, of a particular treatment. At the same time international and national statutes protect and promote the right of people with disabilities to access the highest attainable standards of health on the basis of free and informed consent. METHODS: To consider the role of parent-proxies in the management of epilepsy in adult children with ID who are at risk of lacking capacity to make decisions about their health care we interviewed 21 mothers. FINDINGS: These mothers are not pursuing changes in treatment that might improve their son or daughter's epilepsy, nor are they willing to countenance changes in treatment. Clinicians concerned to build and sustain therapeutic alliances with these mothers, our evidence suggests, may well avoid going against their wishes. DISCUSSION: Our research highlights the interactional contingencies of a hitherto neglected three way clinical relationship comprising parent-proxy, an adult at risk of lacking decision-making capacity, and a treating clinician. This is a relationship, our findings suggest, where little importance is attached to either patient consent, or involvement in treatment decisions. PMID- 22533532 TI - In situ infrared spectroscopic study of brucite carbonation in dry to water saturated supercritical carbon dioxide. AB - In geologic carbon sequestration, whereas part of the injected carbon dioxide will dissolve into host brine, some will remain as neat to water saturated supercritical CO(2) (scCO(2)) near the well bore and at the caprock, especially in the short term life cycle of the sequestration site. Little is known about the reactivity of minerals with scCO(2) containing variable concentrations of water. In this study, we used high-pressure infrared spectroscopy to examine the carbonation of brucite (Mg(OH)(2)) in situ over a 24 h reaction period with scCO(2) containing water concentrations between 0% and 100% saturation, at temperatures of 35, 50, and 70 degrees C, and at a pressure of 100 bar. Little or no detectable carbonation was observed when brucite was reacted with neat scCO(2). Higher water concentrations and higher temperatures led to greater brucite carbonation rates and larger extents of conversion to magnesium carbonate products. The only observed carbonation product at 35 degrees C was nesquehonite (MgCO(3).3H(2)O). Mixtures of nesquehonite and magnesite (MgCO(3)) were detected at 50 degrees C, but magnesite was more prevalent with increasing water concentration. Both an amorphous hydrated magnesium carbonate solid and magnesite were detected at 70 degrees C, but magnesite predominated with increasing water concentration. The identity of the magnesium carbonate products appears strongly linked to magnesium water exchange kinetics through temperature and water availability effects. PMID- 22533534 TI - Performance improvement in health care--seizing the moment. PMID- 22533533 TI - Regioselective, borinic acid-catalyzed monoacylation, sulfonylation and alkylation of diols and carbohydrates: expansion of substrate scope and mechanistic studies. AB - Synthetic and mechanistic aspects of the diarylborinic acid-catalyzed regioselective monofunctionalization of 1,2- and 1,3-diols are presented. Diarylborinic acid catalysis is shown to be an efficient and general method for monotosylation of pyranoside derivatives bearing three secondary hydroxyl groups (7 examples, 88% average yield). In addition, the scope of the selective acylation, sulfonylation, and alkylation is extended to 1,2- and 1,3-diols not derived from carbohydrates (28 examples); the efficiency, generality, and operational simplicity of this method are competitive with those of state-of-the art protocols including the broadly applied organotin-catalyzed or -mediated reactions. Mechanistic details of the organoboron-catalyzed processes are explored using competition experiments, kinetics, and catalyst structure-activity relationships. These experiments are consistent with a mechanism in which a tetracoordinate borinate complex reacts with the electrophilic species in the turnover-limiting step of the catalytic cycle. PMID- 22533535 TI - Implications for ACOs of variations in spending growth. PMID- 22533536 TI - Statins: is it really time to reassess benefits and risks? PMID- 22533537 TI - Salivary cortisol, 17beta-estradiol, progesterone, dehydroepiandrosterone, and alpha-amylase in patients with burning mouth syndrome. AB - OBJECTIVE: The aim of this study was to investigate salivary markers related with burning mouth syndrome (BMS). MATERIALS AND METHODS: Thirty female patients with BMS and twenty female control subjects were included. Unstimulated (UWS) and stimulated whole saliva samples (SWS) were collected, and their flow rates were determined. Salivary levels of cortisol, 17beta-estradiol, progesterone, dehydroepiandrosterone (DHEA), and enzymatic activity of alpha-amylase were determined. Salivary transferrin level was measured to determine the level of blood contamination in saliva samples. RESULTS: The levels of all analytes in UWS were significantly correlated with those of SWS. The levels of 17beta estradiol, progesterone, and DHEA in UWS were significantly correlated with age. Age-matched comparisons revealed that the patient group had significantly higher levels of cortisol in UWS and of 17beta-estradiol in SWS. When the patients were divided into older (>=60years) and younger (<60years) groups, the older group showed a significantly lower level of progesterone in UWS. There were no significant relationships between treatment efficacy and levels of salivary analytes. CONCLUSIONS: In conclusion, patients with BMS showed significantly higher levels of cortisol in UWS and of 17beta-estradiol in SWS compared with controls. PMID- 22533538 TI - Population health status of South Asian and African-Caribbean communities in the United Kingdom. AB - BACKGROUND: Population health status scores are routinely used to inform economic evaluation and evaluate the impact of disease and/or treatment on health. It is unclear whether the health status in black and minority ethnic groups are comparable to these population health status data. The aim of this study was to evaluate health-status in South Asian and African-Caribbean populations. METHODS: Cross-sectional study recruiting participants aged >= 45 years (September 2006 to July 2009) from 20 primary care centres in Birmingham, United Kingdom.10,902 eligible subjects were invited, 5,408 participated (49.6%). 5,354 participants had complete data (49.1%) (3442 South Asian and 1912 African-Caribbean). Health status was assessed by interview using the EuroQoL EQ-5D. RESULTS: The mean EQ-5D score in South Asian participants was 0.91 (standard deviation (SD) 0.18), median score 1 (interquartile range (IQR) 0.848 to 1) and in African-Caribbean participants the mean score was 0.92 (SD 0.18), median 1 (IQR 1 to 1). Compared with normative data from the UK general population, substantially fewer African Caribbean and South Asian participants reported problems with mobility, usual activities, pain and anxiety when stratified by age resulting in higher average health status estimates than those from the UK population. Multivariable modelling showed that decreased health-related quality of life (HRQL) was associated with increased age, female gender and increased body mass index. A medical history of depression, stroke/transient ischemic attack, heart failure and arthritis were associated with substantial reductions in HRQL. CONCLUSIONS: The reported HRQL of these minority ethnic groups was substantially higher than anticipated compared to UK normative data. Participants with chronic disease experienced significant reductions in HRQL and should be a target for health intervention. PMID- 22533540 TI - XCMS Online: a web-based platform to process untargeted metabolomic data. AB - Recently, interest in untargeted metabolomics has become prevalent in the general scientific community among an increasing number of investigators. The majority of these investigators, however, do not have the bioinformatic expertise that has been required to process metabolomic data by using command-line driven software programs. Here we introduce a novel platform to process untargeted metabolomic data that uses an intuitive graphical interface and does not require installation or technical expertise. This platform, called XCMS Online, is a web-based version of the widely used XCMS software that allows users to easily upload and process liquid chromatography/mass spectrometry data with only a few mouse clicks. XCMS Online provides a solution for the complete untargeted metabolomic workflow including feature detection, retention time correction, alignment, annotation, statistical analysis, and data visualization. Results can be browsed online in an interactive, customizable table showing statistics, chromatograms, and putative METLIN identities for each metabolite. Additionally, all results and images can be downloaded as zip files for offline analysis and publication. XCMS Online is available at https://xcmsonline.scripps.edu. PMID- 22533539 TI - Age-related treatment strategy and long-term outcome in acute myocardial infarction patients in the PCI era. AB - BACKGROUND: Older age, as a factor we cannot affect, is consistently one of the main negative prognostic values in patients with acute myocardial infarction. One of the most powerful factors that improves outcomes in patients with acute coronary syndromes is the revascularization preferably performed by percutaneous coronary intervention. No data is currently available for the role of age in large groups of consecutive patients with PCI as the nearly sole method of revascularization in AMI patients. The aim of this study was to analyze age related differences in treatment strategies, results of PCI procedures and both in-hospital and long-term outcomes of consecutive patients with acute myocardial infarction. METHODS: Retrospective multicenter analysis of 3814 consecutive acute myocardial infarction patients divided into two groups according to age (1800 patients <= 65 years and 2014 patients > 65 years). Significantly more older patients had a history of diabetes mellitus and previous myocardial infarctions. RESULTS: The older population had a significantly lower rate of coronary angiographies (1726; 95.9% vs. 1860; 92.4%, p < 0.0001), PCI (1541; 85.6% vs. 1505; 74.7%, p < 0.001), achievement of optimal final TIMI flow 3 (1434; 79.7% vs. 1343; 66.7%, p < 0.001) and higher rate of unsuccessful reperfusion with final TIMI flow 0-1 (46; 2.6% vs. 78; 3.9%, p = 0.022). A total of 217 patients (5.7%) died during hospitalization, significantly more often in the older population (46; 2.6% vs. 171; 8.5%, p < 0.001). The long-term mortality (data for 2847 patients from 2 centers) was higher in the older population as well (5 years survival: 86.1% vs. 59.8%). Though not significantly different and in contrast with PCI, the presence of diabetes mellitus, previous MI, final TIMI flow and LAD, as the infarct-related artery, had relatively lower impact on the older patients. Severe heart failure on admission (Killip III-IV) was associated with the worst prognosis in the whole group of patients, though its significance was higher in the youngers (HR 6.04 vs. 3.14, p = 0.051 for Killip III and 12.24 vs. 5.65, p = 0.030 for Killip IV). We clearly demonstrated age as a strong discriminator for the whole population of AMI patients. CONCLUSIONS: In a consecutive AMI population, the older group (>65 years) was associated with a less pronounced impact of risk factors on long-term outcome. To ascertain the coronary anatomy by coronary angiography and proceed to PCI if suitable regardless of age is crucial in all patients, though the primary success rate of PCI in the older age is lower. Age, when viewed as a risk factor, was a dominant discriminating factor in all patients. PMID- 22533541 TI - Enzymatic hydrolysis of heat-induced aggregates of whey protein isolate. AB - The effects of heat-induced denaturation and subsequent aggregation of whey protein isolate (WPI) solutions on the rate of enzymatic hydrolysis was investigated. Both heated (60 degrees C, 15 min; 65 degrees C, 5 and 15 min; 70 degrees C, 5 and 15 min, 75 degrees C, 5 and 15 min; 80 degrees C, 10 min) and unheated WPI solutions (100 g L(-1) protein) were incubated with a commercial proteolytic enzyme preparation, Corolase PP, until they reached a target degree of hydrolysis (DH) of 5%. WPI solutions on heating were characterized by large aggregate formation, higher viscosity, and surface hydrophobicity and hydrolyzed more rapidly (P < 0.001) than the unheated. The whey proteins exhibited differences in their susceptibility to hydrolysis. Both viscosity and surface hydrophobicity along with insolubility declined as hydrolysis progressed. However, microstructural changes observed by light and confocal laser scanning microscopy (CLSM) provided insights to suggest that aggregate size and porosity may be complementary to denaturation in promoting faster enzymatic hydrolysis. This could be clearly observed in the course of aggregate disintegration, gel network breakdown, and improved solution clarification. PMID- 22533543 TI - Fluoride-mediated elimination of allyl sulfones: application to the synthesis of a 2,4-dimethyl-A-ring vitamin D3 analogue. AB - A coupling strategy for the synthesis of 2,4-dimethyl-1alpha,25(OH)(2)D(3) is achieved which involves methylation of a pro-A ring vinyl sulfone and in situ traping of the allyl sulfonyl anion with a CD ring allyl chloride. TBAF-promoted 1,2-eliminative desulfonylation and concomitant silyl ether deprotection gives the vitamin D(3) analogue. PMID- 22533542 TI - Atypical presentation and a novel mutation in ALMS1: implications for clinical and molecular diagnostic strategies for Alstrom syndrome. PMID- 22533545 TI - Remote preconditioning improves hepatic oxygenation after ischaemia reperfusion injury. AB - Hepatic ischaemia reperfusion injury (IRI) lowers hepatic oxygenation and induces tissue acidosis. Remote ischaemic preconditioning (RIPC) reduces hepatic IRI through increased hepatic blood flow but its effect on hepatic oxygenation and acidosis is not known. This study investigates these effects through near infrared spectroscopy (NIRS). Twenty-four NZ rabbits were grouped into four: sham, RIPC, IRI alone, RIPC + IRI. RIPC was induced through three cycles of 10 min ischaemia and reperfusion to the limb. Total hepatic ischaemia was produced by complete portal inflow occlusion for 25 min. Serum transaminases, bicarbonate and hepatic venous nitrite/nitrate (NO(x) ) levels were measured 2 h postreperfusion. Hepatic oxygenation was monitored with NIRS. At 2 h post reperfusion, IRI alone resulted in reduced mitochondrial oxygenation (CytOx CuA Redox), serum bicarbonate, hepatic venous NO(x) with an increase in serum transaminases and hepatic deoxyhaemoglobin levels. RIPC before IRI caused significant improvement in mitochondrial oxygenation (P = 0.01), increased serum bicarbonate (P = 0.02), hepatic venous NO(x) (P = 0.025) with a decrease in serum transaminases (P = 0.04) and hepatic deoxyhaemoglobin levels (P = 0.03). There was a positive correlation (P = 0.02) between hepatic venous NO(x) levels and mitochondrial oxygenation. RIPC before IRI improves hepatic mitochondrial oxygenation and reduces acidosis and currently undergoing clinical study. PMID- 22533544 TI - Temporary antiretroviral treatment during primary HIV-1 infection has a positive impact on health-related quality of life: data from the Primo-SHM cohort study. AB - OBJECTIVES: The aim of the study was to compare health-related quality of life (HRQL) over 96 weeks in patients receiving no treatment or 24 or 60 weeks of combination antiretroviral therapy (cART) during primary HIV-1 infection (PHI). METHODS: A multicentre prospective cohort study of PHI patients, with an embedded randomized trial, was carried out. HRQL was assessed with the Medical Outcomes Study Health Survey for HIV (MOS-HIV) and a symptom checklist administered at weeks 0, 8, 24, 36, 48, 60, 72, 84 and 96. Mixed linear models were used for the analysis of differences in HRQL among the three groups. RESULTS: A total of 112 patients were included in the study: 28 received no treatment, 45 received 24 weeks of cART and 39 received 60 weeks of cART. Over 96 weeks of follow-up, the groups receiving 24 and 60 weeks of cART had better cognitive functioning than the no-treatment group (P = 0.005). Patients receiving 60 weeks of cART had less pain (P = 0.004), better role functioning (P = 0.001), better physical functioning (P = 0.02) and a better physical health summary score (P = 0.006) than the groups receiving no treatment or 24 weeks of cART. Mental health was better in patients receiving 24 weeks of cART than in patients in the no treatment group or the group receiving 60 weeks of cART (P = 0.02). At week 8, patients in the groups receiving 24 and 60 weeks of cART reported more nausea (P = 0.002), diarrhoea (P < 0.001), abdominal pain (P = 0.02), stomach pain (P = 0.049) and dizziness (P = 0.01) than those in the no-treatment group. These differences had disappeared by week 24. CONCLUSIONS: Temporary cART during PHI had a significant positive impact on patients' HRQL as compared with no treatment, despite the initial, short-term occurrence of more physical symptoms, probably related to drug toxicity. PMID- 22533546 TI - Three-year safety and effectiveness of fixed-dose losartan/hydrochlorothiazide combination therapy in Japanese patients with hypertension under clinical setting (PALM-1 Extension Study). AB - Concerns about metabolic complications often disturb prolonged use of diuretics in Japan. We investigated 3-year safety and efficacy in Japanese patients with hypertension who were uncontrolled with angiotensin receptor blocker or angiotensin-converting enzyme inhibitor regimens and then switched to losartan (50 mg)/hydrochlorothiazide (12.5 mg; HCTZ) combinations. Blood pressure decreased favorably and maintained a steady state for 3 years (157 +/- 16/88 +/- 11 mm Hg to 132 +/- 13/75 +/- 9 mm Hg, P < .0001). Metabolic parameters maintained a limited range of changes after 3 years, and adverse events were markedly decreased after 1-year treatment. The losartan/HCTZ combination minimized diuretic-related adverse effects and thus may be useful for the treatment of Japanese patients with hypertension. PMID- 22533547 TI - Impact of natural organic matter on uranium transport through saturated geologic materials: from molecular to column scale. AB - The risk stemming from human exposure to actinides via the groundwater track has motivated numerous studies on the transport of radionuclides within geologic environments; however, the effects of waterborne organic matter on radionuclide mobility are still poorly understood. In this study, we compared the abilities of three humic acids (HAs) (obtained through sequential extraction of a peat soil) to cotransport hexavalent uranium (U) within water-saturated sand columns. Relative breakthrough concentrations of U measured upon elution of 18 pore volumes increased from undetectable levels (<0.001) in an experiment without HAs to 0.17 to 0.55 in experiments with HAs. The strength of the HA effect on U mobility was positively correlated with the hydrophobicity of organic matter and NMR-detected content of alkyl carbon, which indicates the possible importance of hydrophobic organic matter in facilitating U transport. Carbon and uranium elemental maps collected with a scanning transmission X-ray microscope (STXM) revealed uneven microscale distribution of U. Such molecular- and column-scale data provide evidence for a critical role of hydrophobic organic matter in the association and cotransport of U by HAs. Therefore, evaluations of radionuclide transport within subsurface environments should consider the chemical characteristics of waterborne organic substances, especially hydrophobic organic matter. PMID- 22533548 TI - Apoptosis modulated by oxidative stress and inflammation during obstructive nephropathy. AB - Kidney apoptosis and fibrosis are an inevitable outcome of progressive chronic kidney diseases where congenital obstructive nephropathy is the primary cause of the end-stage renal disease in children, and is also a major cause of renal failure in adults. The injured tubular cells linked to interstitial macrophages, and myofibroblasts produce cytokines and growth factors that promote an inflammatory state in the kidney, induce tubular cell apoptosis, and facilitate the accumulation of extracellular matrix. Angiotensin II plays a central role in the renal fibrogenesis at a very early stage leading to a rapid progression in chronic kidney disease. The increasing levels of angiotensin II induce pro inflammatory cytokines, NF-kappaB activation, adhesion molecules, chemokines, growth factors, and oxidative stress. Furthermore, growing evidence reports that angiotensin II (a pro-inflammatory hormone) increases the mitochondrial oxidative stress regulating apoptosis induction. This review summarizes our understanding about possible mechanisms that contribute to apoptosis modulated by inflammation and/or oxidative stress during obstructive nephropathy. The new concept of antiinflammatory tools regulating mitochondrial oxidative stress will directly affect the inflammatory process and apoptosis. This idea could have attractive consequences in the treatment of renal and other inflammatory pathologies. PMID- 22533549 TI - Interleukin-21 in immune and allergic diseases. AB - Interleukin-21 (IL-21), a cytokine produced by various subsets of activated CD4+ T cells, plays a major role in the control of innate and adaptive immune responses. IL-21 biological activity is mediated by binding of the cytokine to a heterodimeric receptor, composed of a specific subunit, termed IL-21 receptor (IL 21R), and the common gamma-chain, that is shared with IL-2, IL-4, IL-7, IL-9 and IL-15 receptors. IL-21 stimulates the proliferation of CD4+ and CD8+ T lymphocytes and regulates the profile of cytokines secreted by these cells, drives the differentiation of B cells into memory cells and Ig-secreting plasma cells, and enhances the activity of natural killer cells. IL-21 controls also the activity of non-immune cells, such as epithelial cells and stromal cells. The demonstration that IL-21 is involved in the immune responses occurring in chronic inflammatory and allergic diseases suggests that either disrupting or enhancing IL-21 signalling may be useful in specific clinical settings. PMID- 22533550 TI - Microwave-assisted synthesis of N-isobutyl-4,5-epoxy-2(E)-decenamide. AB - A new and efficient synthesis of a naturally occurring amide alkaloid, N-isobutyl 4,5-epoxy-2(E)-decenamide isolated from the roots of Piper nigrum has been described involving a total of nine steps. Octanal and 2-bromoacetic acid have been used as the starting materials. PMID- 22533551 TI - Stem cells and alopecia: a review of pathogenesis. AB - Recent work has focused on the hair follicle as the main source of multipotent stem cells in the skin. The hair follicle bulge contains multipotent stem cells that can form the epidermis, hair follicles and sebaceous glands and help in repopulation of the epidermis after injury. The localization of these stem cells to the bulge area may explain why some types of inflammatory alopecia cause permanent loss of hair (cicatricial alopecia) (such as lichen planopilaris and discoid lupus erythematosus), while others (such as alopecia areata) are reversible (noncicatricial alopecia). The lack of distinctive bulge morphology in human hair follicles has hampered studies of bulge cells. To date, the best marker for bulge stem cells in human hair is cytokeratin (CK) 15; human bulge cells have been reported to express CK15 selectively throughout all stages of the hair cycle in different types of follicles. There is direct evidence in the mouse, and indirect evidence in the human, that compromising the integrity of the sebaceous gland and/or bulge is important in the development of alopecia. Several interesting studies have been done in the last few years to investigate the role of stem cells in alopecia, especially nonscarring types. This is a review about the role of stem cells in the pathogenesis of alopecia (scarring and nonscarring). PMID- 22533552 TI - Serum levels of apelin, salusin-alpha and salusin-beta in normal pregnancy and preeclampsia. AB - OBJECTIVE: The purpose of this study was to investigate the relationship between the serum apelin, salusin-alpha and salusin-beta levels and preeclampsia. METHOD: Twenty-one healthy pregnant women (control group) and 48 patients with preeclampsia (study group) were included in the study between August 2010 and February 2011. Serum apelin, salusin-alpha and salusin-beta levels of the groups were compared. RESULTS: The patients in the study group were divided into two categories: mild preeclampsia and severe preeclampsia. The mild preeclampsia group consisted of 31 patients, and the severe preeclampsia group consisted of 17 patients. Serum salusin-alpha and salusin-beta levels of the control and study groups were not significantly different (p > 0.05). Apelin levels were statistically significantly higher in the study group. No statistically significant difference was detected between the mild and severe preeclampsia groups in terms of the mean serum apelin levels. CONCLUSION: The serum levels of apelin were higher in the pregnant women with preeclampsia; however, there was no positive relationship between serum salusin-alpha and salusin-beta levels and the disease. Larger prospective studies are needed to validate our findings. PMID- 22533553 TI - Direct experimental evidence of metal-mediated etching of suspended graphene. AB - Atomic resolution high angle annular dark field imaging of suspended, single layer graphene, onto which the metals Cr, Ti, Pd, Ni, Al, and Au atoms had been deposited, was carried out in an aberration-corrected scanning transmission electron microscope. In combination with electron energy loss spectroscopy, employed to identify individual impurity atoms, it was shown that nanoscale holes were etched into graphene, initiated at sites where single atoms of all the metal species except for gold come into close contact with the graphene. The e-beam scanning process is instrumental in promoting metal atoms from clusters formed during the original metal deposition process onto the clean graphene surface, where they initiate the hole-forming process. Our observations are discussed in the light of calculations in the literature, predicting a much lowered vacancy formation in graphene when metal ad-atoms are present. The requirement and importance of oxygen atoms in this process, although not predicted by such previous calculations, is also discussed, following our observations of hole formation in pristine graphene in the presence of Si-impurity atoms, supported by new calculations which predict a dramatic decrease of the vacancy formation energy, when SiO(x) molecules are present. PMID- 22533554 TI - Aptameric peptide for one-step detection of protein kinase. AB - Protein kinases are significant regulators in the cell signal pathway, and it is difficult to achieve quick kinase detection because traditional kinase assays normally rely on a time-consuming kinase phosphorylation process. Herein, we present a novel one-step strategy to detect protein kinase by using a kinase specific aptameric peptide-functionalized quartz crystal microbalance (QCM) electrode, in which the detection can be finished in less than 10 min. A peptide kinase inhibitor (IP(20)) was used as the aptameric peptide because of its selective and strong interaction with the target protein kinase (cyclic adenosine monophosphate-dependent protein kinase A, PKA), high stability, and ease of inexpensive synthesis, presenting a new direct recognition element for kinase. The aptameric peptide was immobilized on the Au-coated quartz electrode through dual-thiol anchoring and the binding of His-tagged peptide with a nitrilotriacetic acid/Ni(II) complex, fabricating a highly specific and stable detection platform. The interaction of aptameric peptide with kinase was monitored with the QCM in real time, and the concentration of protein kinase was sensitively measured by the frequency response of the QCM with the low detection limit for PKA at 0.061 mU MUL(-1) and a linear range from 0.64 to 22.33 mU MUL( 1). This method is rapid and reagentless and does not require a phosphorylation process. The versatility of our aptameric peptide-based strategy has also been demonstrated by the application in kinase assay using electrochemical impedance spectroscopy. Moreover, this method was successfully applied to detect the forskolin/3-isobutyl-1-methylxanthine-stimulated activation of PKA in cell lysate. PMID- 22533555 TI - The relationship between body dysmorphic disorder behaviors and the acquired capability for suicide. AB - In a sample of 200 individuals diagnosed with body dysmorphic disorder (BDD), we utilized the interpersonal-psychological theory for suicide as a framework to examine BDD behaviors that might be associated with suicide risk, insofar as they might increase the acquired capability for suicide. We predicted that physically painful BDD behaviors (e.g., cosmetic surgery, restrictive eating) would be associated with suicide attempts but not suicide-related ideation because these behaviors increase capability for, but not thoughts about, suicide. Our hypothesis was partially confirmed, as BDD-related restrictive food intake was associated with suicide attempts (but not suicide-related ideation) even after controlling for numerous covariates. PMID- 22533556 TI - Inhibitory activity of liposomal flavonoids during oxidative metabolism of human neutrophils upon stimulation with immune complexes and phorbol ester. AB - CONTEXT AND OBJECTIVE: The massive production of reactive oxygen species by neutrophils during inflammation may cause damage to tissues. Flavonoids act as antioxidants and have anti-inflammatory effects. In this study, liposomes loaded with these compounds were evaluated as potential antioxidant carriers, in attempt to overcome their poor solubility and stability. MATERIALS AND METHODS: Liposomes containing quercetin, myricetin, kaempferol or galangin were prepared by the ethanol injection method and analyzed as inhibitors of immune complex (IC) and phorbol ester-stimulated neutrophil oxidative metabolism by luminol (CLlum) and lucigenin-enhanced (CLluc) chemiluminescence (CL) assays. The mechanisms involved this activity of liposomal flavonoids, such as cytotoxicity and superoxide anion scavenging capacity, and their effect on phagocytosis of ICs were also investigated. RESULTS AND DISCUSSION: The results showed that the inhibitory effect of liposomal flavonoids on CLlum and CLluc is inversely related to the number of hydroxyl groups in the flavonoid B ring. Moreover, phagocytosis of liposomes by neutrophils does not seem to necessarily promote such activity, as the liposomal flavonoids are also able to reduce CL when the cells are pretreated with cytochalasin B. Under assessed conditions, the antioxidant liposomes are not toxic to the human neutrophils and do not interfere with IC-induced phagocytosis. CONCLUSION: The studied liposomes can be suitable carriers of flavonoids and be an alternative for the treatment of diseases in which a massive oxidative metabolism of neutrophils is involved. PMID- 22533557 TI - Bioanalysis of biotherapeutic proteins and peptides: immunological or MS approach? PMID- 22533558 TI - Fast chromatography in the regulated bioanalytical environment: sub-2-um versus fused-core particles. AB - Increased throughput and rapid data turnaround have necessitated the need for faster LC separations in the regulated bioanalytical environment; sub-2-MUm and fused-core chromatography are two viable approaches to accomplish this. Sub-2-MUm columns offer high efficiency and resolution separations at the cost of high system backpressure and are best suited for preclinical sample analysis, whereas fused-core columns offer slightly lower efficiency and resolution, but are more tolerant to dirty extracts (such as those seen in clinical samples) that may clog the inlet filter. For clinical sample analyses, sub-2-MUm columns should be restricted to sample extracts obtained via LLE or SLE, whereas fused-core columns can be used with sample preparations techniques ranging from protein precipitation to SLE. PMID- 22533559 TI - European Medicines Agency guideline on bioanalytical method validation: what more is there to say? PMID- 22533561 TI - Bioanalysis young investigator: Michael Groessl. PMID- 22533562 TI - Bioanalysis young investigator: Eugene Ciccimaro. PMID- 22533563 TI - Profiling phospholipid elution in reversed-phase LC-MS/MS bioanalytical methods in order to avoid matrix effects. AB - BACKGROUND: Endogenous phospholipids have a profound matrix effect in bioanalytical LC-MS methods and considerable effort is invested in strategies to minimize their impact either by removal during sample processing or chromatographic separation during the analytical run. The aim of the research presented in this article was to investigate the latter approach, under reversed phase conditions. RESULTS: The retention of glycerophosphocholines (GPCs) in mobile phases employing acetonitrile demonstrated a complex 'U-shaped' relationship with the percentage of organic. Conversely, in mobile phases employing methanol, the relationship between retention and percentage of organic was entirely predictive and unaffected by changes in the mobile phase pH. The GPC elution profile was also qualitatively equivalent irrespective of the species from which the plasma was derived. CONCLUSION: The predictive nature of GPC retention, under reversed-phase chromatography and with MeOH as organic modifier, is an important finding that should allow for a more streamlined and simplified strategy in the development of bioanalytical assays. PMID- 22533564 TI - Confirmation of no impact from different anticoagulant counter ions on bioanalytical method. AB - BACKGROUND: In the past several years, the impact of changing counter ions while keeping the same anticoagulant in bioanalytical LC-MS/MS methods has become a highly discussed topic. In order to confirm that there is no impact from counter ions, matrix effect and stability evaluations were performed on bicalutamide LC MS/MS bioanalytical methods. RESULTS: Independently from the anticoagulant counter ion used, the matrix effect evaluation met acceptance criteria, even when using conditions expected to increase matrix effect, such as protein precipitation with an analog internal standard. Freeze-thaw along with storage stabilities, namely short- and long-term, demonstrated less than 8% deviation regardless of the counter ion used. CONCLUSION: Differences in the anticoagulant counter ion used has no impact on the bicalutamide bioanalytical LC-MS/MS method. PMID- 22533565 TI - Development of a method by UPLC-MS/MS for the quantification of tizoxanide in human plasma and its pharmacokinetic application. AB - BACKGROUND: Nitazoxanide (NTZ) is used for the treatment of gastrointestinal tract colonization by anaerobic bacteria, viruses and other pathogens that represent a major cause of morbidity in Latin America. The aim of the present work was to develop and validate a UPLC-MS/MS method for the selective quantification of tizoxanide (TZN, the major metabolite of NTZ) in human plasma using niclosamide as internal standard; and examine its pharmacokinetic application in healthy volunteers. Nine male subjects received a single oral dose of a NTZ 500-mg tablet under fasting conditions. RESULTS: The method was linear between 0.1 and 10 ug/ml and capable of separating signals from free-TZN and those delivered by in-source collision-induced dissociation of TZN-glucuronide, quantifying it with accuracy and precision. Mean maximum plasma concentration was 6.79 ug/ml and was reached at 2.4 h post-dose. CONCLUSION: The method was validated, fulfilling regulatory guidelines. Results suggest low pharmacokinetic variability in the assayed population. PMID- 22533566 TI - Metabolomic investigations of human infections. AB - Metabolomics has a special place among other 'omics' disciplines (genomics, transcriptomics and proteomics) as it describes the most dynamic level of biological regulation and, as such, provides the most direct reflection of the physiological status of an organism. Quick development of the analytical technologies in the first place - MS and NMR - has enabled the metabolomics analysis of such complex biological phenomena as host-pathogen interactions in the development of infection. In this review, an overview of the metabolomics studies of infectious diseases carried out on human material is provided. The relevant papers on the metabolomics of human infectious diseases are comprehensively summarized in a table, including, for example, information on the study design, number of subjects, employed technology and metabolic discriminator. Future considerations, such as importance of the time-resolved study designs and the embedment of metabolomics in large-scale epidemiological studies are discussed. PMID- 22533567 TI - Recent advances in multiplex immunoassays. AB - The present review reports on the lastest developments in multiplex immunoassays. The selected examples are classified through their detection strategy (fluorescence, chemiluminescence, colorimetry or labeless) and their assay format (standard microtiter plate, polymeric membranes and glass slides). Finally, the degree of integration in a complete system, incorporating fluid handling and detection was also taken into account. PMID- 22533568 TI - Recent advances in metabolite identification and quantitative bioanalysis by LC-Q TOF MS. AB - The need for rapid, sensitive and effective identification and quantitation of drugs and metabolites to accelerate drug discovery and development has given MS its central position in drug metabolism and pharmacokinetic research. This review attempts to orient the readers with respect to hybrid Q-TOF MS, which enables accurate mass measurement and generates information-rich datasets. The key properties of the Q-TOF MS system, including mass accuracy, resolution, scan speed and dynamic range, are herein discussed. Developments on tandem separation techniques (e.g., UHPLC((r)) and ion mobility spectrometry), data acquisition and data-mining methods (e.g., mass defect, product/neutral loss, isotope pattern filters and background subtraction) that facilitate qualitative and quantitative analysis are then examined. The performance and versatility of LC-Q-TOF MS are thoroughly illustrated by its applications in metabolite identification and quantitative bioanalysis. Future perspectives are also discussed. PMID- 22533569 TI - Atypical antipsychotics: trends in analysis and sample preparation of various biological samples. AB - Atypical antipsychotics are increasingly popular and increasingly prescribed. In some countries, they can even be obtained over-the-counter, without a prescription, making their abuse quite easy. Although atypical antipsychotics are thought to be safer than typical antipsychotics, they still have severe side effects. Intoxications are not rare and some of them have a fatal outcome. Drug interactions involving atypical antipsychotics complicate patient management in clinical settings and the determination of the cause of death in fatalities. In view of the above, analytical strategies that can efficiently isolate atypical antipsychotics from a variety of biological samples and quantify them accurately, sensitively and reliably, are of utmost importance both for the clinical, as well as for the forensic toxicologist. In this review, we will present and discuss novel analytical strategies that have been developed from 2004 to the present day for the determination of atypical antipsychotics in various biological samples. PMID- 22533570 TI - CO2 in 1-butyl-3-methylimidazolium acetate. 2. NMR investigation of chemical reactions. AB - The solvation of CO(2) in 1-butyl-3-methylimidazolium acetate (Bmim Ac) has been investigated by (1)H, (13)C, and (15)N NMR spectroscopy at low CO(2) molar fraction (mf) (x(CO(2)) ca. 0.27) corresponding to the reactive regime described in part 1 of this study. It is shown that a carboxylation reaction occurs between CO(2) and Bmim Ac, leading to the formation of a non-negligible amount (~16%) of 1-butyl-3-methylimidazolium-2-carboxylate. It is also found that acetic acid molecules are produced during this reaction and tend to form with elapsed time stable cyclic dimers existing in pure acid. A further series of experiments has been dedicated to characterize the influence of water traces on the carboxylation reaction. It is found that water, even at high ratio (0.15 mf), does not hamper the formation of the carboxylate species but lead to the formation of byproduct involving CO(2). The evolution with temperature of the resonance lines associated with the products of the reactions confirms that they have a different origin. The main byproduct has been assigned to bicarbonate. All these results confirm the existence of a reactive regime in the CO(2)-Bmim Ac system but different from that reported in the literature on the formation of a reversible molecular complex possibly accompanied by a minor chemical reaction. Finally, the reactive scheme interpreting the carboxylation reaction and the formation of acetic acid proposed in the literature is discussed. We found that the triggering of the carboxylation reaction is necessarily connected with the introduction of carbon dioxide in the IL. We argue that a more refined scheme is still needed to understand in details the different steps of the chemical reaction in the dense phase. PMID- 22533571 TI - Co-morbidity of complex genetic disorders and hypersomnias of central origin: lessons from the underlying neurobiology of wake and sleep. AB - Appropriate wake and sleep cycles are important to physical well-being, and are modulated by neuronal networks in the brain. A variety of medical conditions can disrupt sleep or cause excessive daytime sleepiness. Clinical diagnostic classification schemes have historically lumped genetic disorders together into a category that considers the sleep dysfunction to be secondary to a medical condition. The unique nature of sleep endophenotypes that occur more frequently in particular genetic disorders has been underappreciated. Increased understanding of the pathophysiology of wake/sleep dysfunction in rare genetic disorders could inform studies of the neurological mechanisms that underlie more common forms of wake and sleep dysfunction. In this review, we highlight genetic developmental disorders in which sleep endophenotypes have been described, and then consider genetic neurodegenerative disorders with sleep characteristics that set them apart from the disruptions to sleep that are typically associated with aging and dementia. PMID- 22533572 TI - Role of lipocalin 2 and its complex with matrix metalloproteinase-9 in oral cancer. AB - OBJECTIVES: Recent evidence demonstrated that lipocalin (LCN)2 is induced in many types of human cancer, while the detection of its complex with matrix metalloproteinase (MMP)-9 is correlated with the cancer disease status. We attempted to evaluate plasma expressions of LCN2, MMP-9, and their complex (LCN2/MMP-9) during the diagnostic work-up of patients with oral squamous cell carcinoma (OSCC) and investigated their correlations with disease progression. METHODS: In total, 195 patients with OSCC and 81 healthy controls were recruited. Expression levels of LCN2, MMP-9, and LCN2/MMP-9 were determined with immunoenzymatic assays. RESULTS: Patients with OSCC exhibited significantly higher levels of LCN2, MMP-9, and LCN2/MMP-9 compared with healthy controls (LCN2: P < 0.001; MMP-9: P < 0.001; LCN2/MMP-9: P < 0.01). Plasma levels of LCN2, MMP-9, and LCN2/MMP-9 in patients with OSCC were significantly correlated with each other and were associated with more-advanced clinical stages (P < 0.05) and/or a larger tumor size (P < 0.05), but were not associated with positive lymph-node metastasis or distal metastasis. CONCLUSION: Our results suggest that plasma levels of LCN2 and the LCN2/MMP-9 complex may be useful in non-invasively monitoring OSCC progression, while supporting their potential role as biomarkers of oral cancer disease status. PMID- 22533573 TI - Hypothalamic-pituitary-adrenal (HPA) axis activity in adults with intellectual disabilities: a preliminary investigation. AB - BACKGROUND: Cortisol is a marker of physiological arousal, exhibiting a characteristic pattern of diurnal activity. The daily cortisol profile has been xamined extensively and is atypical in a number of clinical disorders. However, there are very few studies focussing on the cortisol profile in adults with intellectual disabilities (ID). This paper reports a preliminary investigation into the nature of the cortisol profile in adults with mild or moderate ID and provides reflections on the challenges of psychophysiological research in this population. METHODS: On two consecutive days, 39 adults with mild or moderate ID each donated saliva samples for cortisol analysis, at multiple times between waking and evening. A comparison between these data and the published literature permitted a descriptive assessment of the cortisol awakening response (CAR) and diurnal profile. A variety of psychometric measures and an assessment of behavioural history were also collected in order to describe aspects of the participants' emotional and behavioural states. RESULTS: Individuals with ID exhibit a diurnal cortisol secretion profile, qualitatively similar to that of the typical, healthy, adult population. However, the findings also suggested a blunted CAR, warranting further investigation. There was also some evidence that cortisol secretion was affected by anxiety and a recent history of aggression. CONCLUSION: While further work is required to characterise the CAR fully, there was no indication that the diurnal cortisol profile among people with ID differs from that of the typical population. This study also demonstrates that, although challenging, it is feasible, and acceptable to participants, to collect repeated physiological measures from men and women with mild and moderate ID. PMID- 22533574 TI - Transformations of summary statistics as input in meta-analysis for linear dose response models on a logarithmic scale: a methodology developed within EURRECA. AB - BACKGROUND: To derive micronutrient recommendations in a scientifically sound way, it is important to obtain and analyse all published information on the association between micronutrient intake and biochemical proxies for micronutrient status using a systematic approach. Therefore, it is important to incorporate information from randomized controlled trials as well as observational studies as both of these provide information on the association. However, original research papers present their data in various ways. METHODS: This paper presents a methodology to obtain an estimate of the dose-response curve, assuming a bivariate normal linear model on the logarithmic scale, incorporating a range of transformations of the original reported data. RESULTS: The simulation study, conducted to validate the methodology, shows that there is no bias in the transformations. Furthermore, it is shown that when the original studies report the mean and standard deviation or the geometric mean and confidence interval the results are less variable compared to when the median with IQR or range is reported in the original study. CONCLUSIONS: The presented methodology with transformations for various reported data provides a valid way to estimate the dose-response curve for micronutrient intake and status using both randomized controlled trials and observational studies. PMID- 22533575 TI - Moving boundaries--the Nightingale twins and transplantation science. PMID- 22533576 TI - Low-dose abdominal CT for evaluating suspected appendicitis. AB - BACKGROUND: Computed tomography (CT) has become the predominant test for diagnosing acute appendicitis in adults. In children and young adults, exposure to CT radiation is of particular concern. We evaluated the rate of negative (unnecessary) appendectomy after low-dose versus standard-dose abdominal CT in young adults with suspected appendicitis. METHODS: In this single-institution, single-blind, noninferiority trial, we randomly assigned 891 patients with suspected appendicitis to either low-dose CT (444 patients) or standard-dose CT (447 patients). The median radiation dose in terms of dose-length product was 116 mGy.cm in the low-dose group and 521 mGy.cm in the standard-dose group. The primary end point was the percentage of negative appendectomies among all nonincidental appendectomies, with a noninferiority margin of 5.5 percentage points. Secondary end points included the appendiceal perforation rate and the proportion of patients with suspected appendicitis who required additional imaging. RESULTS: The negative appendectomy rate was 3.5% (6 of 172 patients) in the low-dose CT group and 3.2% (6 of 186 patients) in the standard-dose CT group (difference, 0.3 percentage points; 95% confidence interval, -3.8 to 4.6). The two groups did not differ significantly in terms of the appendiceal perforation rate (26.5% with low-dose CT and 23.3% with standard-dose CT, P=0.46) or the proportion of patients who needed additional imaging tests (3.2% and 1.6%, respectively; P=0.09). CONCLUSIONS: Low-dose CT was noninferior to standard-dose CT with respect to negative appendectomy rates in young adults with suspected appendicitis. (Funded by GE Healthcare Medical Diagnostics and others; ClinicalTrials.gov number, NCT00913380.). PMID- 22533578 TI - Images in clinical medicine. Torsion of undescended testis. PMID- 22533577 TI - Insulin-pump therapy for type 1 diabetes mellitus. PMID- 22533579 TI - Case records of the Massachusetts General Hospital. Case 13-2012. A 62-year-old man with paresthesias, weight loss, jaundice, and anemia. PMID- 22533581 TI - Bevacizumab in neoadjuvant treatment for breast cancer. PMID- 22533582 TI - Bevacizumab in neoadjuvant treatment for breast cancer. PMID- 22533583 TI - Bevacizumab in neoadjuvant treatment for breast cancer. PMID- 22533585 TI - Antenatal thyroid screening and childhood cognitive function. PMID- 22533587 TI - Lifetime risks of cardiovascular disease. PMID- 22533588 TI - Lifetime risks of cardiovascular disease. PMID- 22533589 TI - Lifetime risks of cardiovascular disease. PMID- 22533591 TI - IgG4-related disease. PMID- 22533592 TI - IgG4-related disease. PMID- 22533593 TI - IgG4-related disease. PMID- 22533594 TI - IgG4-related disease. PMID- 22533595 TI - IgG4-related disease. PMID- 22533597 TI - Case 2-2012: Dyspnea and rapidly progressive respiratory failure. PMID- 22533598 TI - Resolution of recurrent focal segmental glomerulosclerosis after retransplantation. PMID- 22533601 TI - Images in clinical medicine. Pneumoperitoneum. PMID- 22533602 TI - Profiling of hydroxycinnamoyl tartrates and acylated anthocyanins in the skin of 34 Vitis vinifera genotypes. AB - The diversity of berry skin flavonoids in grape genotypes has been previously widely investigated with regard to major compounds (nonacylated anthocyanins and flavonols), but much less with regard to acylated anthocyanins and hydroxycinnamoyl tartrates (HCTs). In this study, the composition of the phenolic fraction of the berry skin (free and acylated anthocyanins, flavonols, and HCTs) was assessed on 34 grapevine genotypes grown in a collection vineyard in northwestern Italy. The phenolic fraction was profiled on berries collected in the same vineyard, at the same ripening level across two successive vintages. The anthocyanin, HCT, and flavonol profiles were specific of each genotype, and the first two were relatively little affected by the vintage. A wide diversity in the polyphenolic fraction was shown among cultivars. Besides expected discriminatory effects of free anthocyanins and flavonol profiles, principal component analyses allowed a good discrimination of cultivars on the basis of coumaroylated anthocyanins and of the HCT profile. Anthocyanins were mostly acylated by aromatic acids, and acylation was independent from the anthocyanin substrate. HCTs were present mostly as coumaroyl and caffeoyl derivatives, and no correlation was observed between the same acylation patterns of tartrate and of anthocyanins. The results of this study are discussed in the light of new hypotheses on still unknown biosynthetic steps of phenolic substances and of the potential use of these substances in discrimination and identification of different grape cultivars in wines. PMID- 22533603 TI - Say 'trouble's gone': chronic illness and employability in job training programmes. AB - The concept of biographical disruption has unique relevance for socioeconomically disadvantaged groups who participate in entry-level job training programmes. In these programmes trainees often suffer from various forms of chronic illness and must arrange these illnesses into a picture of employability. In this article I use ethnographic data and narrative analysis to examine closely two trainees' illness-related experiences, expressions and talk, and find that their ability to present their illnesses in ways that are consistent with programmatic goals is strongly influenced by family support, responsibilities and roles, as well as particular aspects of illness, like the interpretability of symptoms. I also find that the concept of biographical disruption has a curious traction in the world of job training, particularly among job training programme staff who would like to see trainees mobilise a variety of resources to help manage their illness. However, for trainees, many of whom have lived with chronic illness for years, the concept of biographical disruption may be more limited as a tool for understanding the experiences of illness. A more meaningful disruptive force in the lives of trainees appears to be the programme itself and the strategies for dealing with illness that programme staff may extend. PMID- 22533605 TI - Episodic transdermal delivery of testosterone. AB - Film-forming lotions, precast films and adhesive patches containing testosterone (T) were prepared by compounding vinylic, acrylic and cellulosic polymers with a variety of excipients in order to achieve distribution of T in domains of heterogeneity within multicomponent matrices. The feasibility of this approach in achieving episodic transdermal delivery of testosterone (T) was investigated. Composition-dependent differences in extent of in vitro drug release and periodicity were observed. Representative formulations showing the most pronounced episodic T release in vitro were tested in female rats. Whereas intravenously administered T decayed exponentially, three maxima of T in serum were observed upon application of selected formulations. Thus, peak serum concentrations of 240, 36, and 29 ng/dL were observed at 0.2, 5, and 16.8 h after application of the preferred lotion formulation, and 89, 65, and 64 ng/dL at 1, 16.4, and 48.8 h after patches. Deconvolution, noncompartment pharmacokinetic analysis and multiple peak fitting also indicated episodicity. These results suggest the feasibility of using transdermal systems for pulsatile T delivery in a variety of clinical applications, including hormone supplementation and male contraception. PMID- 22533604 TI - Strategies to work with HLA data in human populations for histocompatibility, clinical transplantation, epidemiology and population genetics: HLA-NET methodological recommendations. AB - HLA-NET (a European COST Action) aims at networking researchers working in bone marrow transplantation, epidemiology and population genetics to improve the molecular characterization of the HLA genetic diversity of human populations, with an expected strong impact on both public health and fundamental research. Such improvements involve finding consensual strategies to characterize human populations and samples and report HLA molecular typings and ambiguities; proposing user-friendly access to databases and computer tools and defining minimal requirements related to ethical aspects. The overall outcome is the provision of population genetic characterizations and comparisons in a standard way by all interested laboratories. This article reports the recommendations of four working groups (WG1-4) of the HLA-NET network at the mid-term of its activities. WG1 (Population definitions and sampling strategies for population genetics' analyses) recommends avoiding outdated racial classifications and population names (e.g. 'Caucasian') and using instead geographic and/or cultural (e.g. linguistic) criteria to describe human populations (e.g. 'pan-European'). A standard 'HLA-NET POPULATION DATA QUESTIONNAIRE' has been finalized and is available for the whole HLA community. WG2 (HLA typing standards for population genetics analyses) recommends retaining maximal information when reporting HLA typing results. Rather than using the National Marrow Donor Program coding system, all ambiguities should be provided by listing all allele pairs required to explain each genotype, according to the formats proposed in 'HLA-NET GUIDELINES FOR REPORTING HLA TYPINGS'. The group also suggests taking into account a preliminary list of alleles defined by polymorphisms outside the peptide-binding sites that may affect population genetic statistics because of significant frequencies. WG3 (Bioinformatic strategies for HLA population data storage and analysis) recommends the use of programs capable of dealing with ambiguous data, such as the 'gene[rate]' computer tools to estimate frequencies, test for Hardy-Weinberg equilibrium and selective neutrality on data containing any number and kind of ambiguities. WG4 (Ethical issues) proposes to adopt thorough general principles for any HLA population study to ensure that it conforms to (inter)national legislation or recommendations/guidelines. All HLA NET guidelines and tools are available through its website http://hla-net.eu. PMID- 22533606 TI - Genome-wide miRNA signatures of human longevity. AB - Little is known about the functions of miRNAs in human longevity. Here, we present the first genome-wide miRNA study in long-lived individuals (LLI) who are considered a model for healthy aging. Using a microarray with 863 miRNAs, we compared the expression profiles obtained from blood samples of 15 centenarians and nonagenarians (mean age 96.4 years) with those of 55 younger individuals (mean age 45.9 years). Eighty miRNAs showed aging-associated expression changes, with 16 miRNAs being up-regulated and 64 down-regulated in the LLI relative to the younger probands. Seven of the eight selected aging-related biomarkers were technically validated using quantitative RT-PCR, confirming the microarray data. Three of the eight miRNAs were further investigated in independent samples of 15 LLI and 17 younger participants (mean age 101.5 and 36.9 years, respectively). Our screening confirmed previously published miRNAs of human aging, thus reflecting the utility of the applied approach. The hierarchical clustering analysis of the miRNA microarray expression data revealed a distinct separation between the LLI and the younger controls (P-value < 10(-5) ). The down-regulated miRNAs appeared as a cluster and were more often reported in the context of diseases than the up-regulated miRNAs. Moreover, many of the differentially regulated miRNAs are known to exhibit contrasting expression patterns in major age-related diseases. Further in silico analyses showed enrichment of potential targets of the down-regulated miRNAs in p53 and other cancer pathways. Altogether, synchronized miRNA-p53 activities could be involved in the prevention of tumorigenesis and the maintenance of genomic integrity during aging. PMID- 22533607 TI - Raman microspectroscopy-based identification of individual fungal spores as potential indicators of indoor contamination and moisture-related building damage. AB - We present an application of Raman microspectroscopy (RMS) for the rapid characterization and identification of individual spores from several species of microfungi. The RMS-based methodology requires minimal sample preparation and small sample volumes for analyses. Hence, it is suitable for preserving sample integrity while providing micrometer-scale spatial resolution required for the characterization of individual cells. We present the acquisition of unique Raman spectral signatures from intact fungal spores dispersed on commercially available aluminum foil substrate. The RMS-based method has been used to compile a reference library of Raman spectra from several species of microfungi typically associated with damp indoor environments. The acquired reference spectral library has subsequently been used to identify individual microfungal spores through direct comparison of the spore Raman spectra with the reference spectral signatures in the library. Moreover, the distinct peak structures of Raman spectra provide detailed insight into the overall chemical composition of spores. We anticipate potential application of this methodology in the fields of public health, forensic sciences, and environmental microbiology. PMID- 22533608 TI - Seasonal screening of AChE, GSH and gonad histology, in European sea bass Dicentrarchus labrax L. reared in three different fish farms. AB - The aim of this work was to do a preliminary seasonal screening of ecotoxicological biomarkers in European sea bass Dicentrarchus labrax in three different fish farms, to know if the different location and typology can discriminate them. A set of selected biomarkers of xenobiotic exposure, such as acetylcholinesterase (AChE) activity, Glutathione (GSH) and gonad morphology were investigated seasonally in male European sea bass D. labrax (L.) reared in three different intensive farms: a land-based farm of cement tanks (T), an in-shore sea cages farm (C1) and an off-shore sea cages farm (C2). The results showed that both location and typology can discriminate AChE activity, GSH content and gonad morphology. Further investigation is needed to propose these biomarkers in the protocol of fish farm quality control. PMID- 22533609 TI - "I know it's bad for me and yet I do it": exploring the factors that perpetuate smoking in Aboriginal Health Workers--a qualitative study. AB - BACKGROUND: Aboriginal Health Workers (AHWs) have a mandate to deliver smoking cessation support to Aboriginal people. However, a high proportion of AHWs are smokers and this undermines their delivery of smoking cessation programs. Smoking tobacco is the leading contributor to the burden of disease in Aboriginal Australians and must be prevented. Little is known about how to enable AHWs to quit smoking. An understanding of the factors that perpetuate smoking in AHWs is needed to inform the development of culturally relevant programs that enable AHWs to quit smoking. A reduction of smoking in AHWs is important to promote their health and also optimise the delivery of smoking cessation support to Aboriginal clients. METHODS: We conducted a fundamental qualitative description study that was nested within a larger mixed method participatory research project. The individual and contextual factors that directly or indirectly promote (i.e. perpetuate) smoking behaviours in AHWs were explored in 34 interviews and 3 focus groups. AHWs, other health service staff and tobacco control personnel shared their perspectives. Data analysis was performed using a qualitative content analysis approach with collective member checking by AHW representatives. RESULTS: AHWs were highly stressed, burdened by their responsibilities, felt powerless and undervalued, and used smoking to cope with and support a sense of social connectedness in their lives. Factors directly and indirectly associated with smoking were reported at six levels of behavioural influence: personal factors (e.g. stress, nicotine addiction), family (e.g. breakdown of family dynamics, grief and loss), interpersonal processes (e.g. socialisation and connection, domestic disputes), the health service (e.g. job insecurity and financial insecurity, demanding work), the community (e.g. racism, social disadvantage) and policy (e.g. short term and insecure funding). CONCLUSIONS: An extensive array of factors perpetuated smoking in AHWs. The multitude of personal, social and environmental stressors faced by AHWs and the accepted use of communal smoking to facilitate socialisation and connection were primary drivers of smoking in AHWs in addition to nicotine dependence. Culturally sensitive multidimensional smoking cessation programs that address these factors and can be tailored to local needs are indicated. PMID- 22533611 TI - Reactivation of an aversive memory modulates learning strategy preference in male rats. AB - Reminders of an aversive event adversely impact retrieval of hippocampus dependent memories and exacerbate stress-induced levels of anxiety. Interestingly, stress and anxiety shift control over learning away from the hippocampus and toward the striatum. The aims of the current study were to determine whether spatial memory and learning strategy are impacted by reminders of a stressor. Adult male Long-Evans rats (N = 47) were subjected to an inhibitory avoidance (IA) training trial in which 32 rats were exposed (3 s) to a single inescapable electrical footshock (0.6 mA). Prior to the retention trial of a Y-maze task and the probe trials of two different learning strategy tasks, some of the rats that were exposed to the footshock (n = 17) were reminded of the stressor on an IA retrieval trial. Both groups of rats exposed to the initial stressor exhibited hypoactivity, but no impairment in spatial memory, on the Y maze task conducted 1 week after exposure to the footshock. One month after exposure to footshock, both groups of rats exposed to the initial stressor tended to prefer a striatum-dependent learning strategy on a water T-maze task. However, 2 months after exposure to footshock, only shocked rats that were reminded of the stressor exhibited a preference for a striatum-dependent learning strategy on a visible-platform water maze task, which corresponded with lower levels of activity in an open field. The results indicate that reminders of a stressor perpetuate the deleterious effects of stress on affective and cognitive processes. PMID- 22533610 TI - A novel immunogenic CS1-specific peptide inducing antigen-specific cytotoxic T lymphocytes targeting multiple myeloma. AB - The CS1 antigen provides a unique target for the development of an immunotherapeutic strategy to treat patients with multiple myeloma (MM). This study aimed to identify HLA-A2(+) immunogenic peptides from the CS1 antigen, which induce peptide-specific cytotoxic T lymphocytes (CTL) against HLA-A2(+) MM cells. We identified a novel immunogenic HLA-A2-specific CS1(239-247) (SLFVLGLFL) peptide, which induced CS1-specific CTL (CS1-CTL) to MM cells. The CS1-CTL showed a distinct phenotype, with an increased percentage of effector memory and activated CTL and a decreased percentage of naive CTL. CS1(239-247) peptide-specific CD8(+) T cells were detected by DimerX analyses and demonstrated functional activities specific to the peptide. The CTL displayed HLA A2-restricted and antigen-specific cytotoxicity, proliferation, degranulation and gamma-interferon (IFN-gamma) production against both primary MM cells and MM cell lines. In addition, the effector memory cells subset (CD45RO(+) CCR7(-) /CD3(+) CD8(+) ) within CS1-CTL showed a higher level of CD107a degranulation and IFN gamma production as compared to effector cells (CD45RO(-) CCR7(-) /CD3(+) CD8(+) ) against HLA-A2(+) primary MM cells or MM cell lines. In conclusion, this study introduced a novel immunogenic HLA-A2-specific CS1(239-247) peptide capable of inducing antigen-specific CTL against MM cells that will provide a framework for its application as a novel MM immunotherapy. PMID- 22533612 TI - Sterically congested adamantylnaphthalene quinone methides. AB - Five new (2-adamantyl)naphthol derivatives (5-9, quinone methide precursors, QMP) were synthesized and their photochemical reactivity was investigated by preparative photolyses, fluorescence spectroscopy, and laser flash photolysis (LFP). Excitation of QMP 5 to S(1) leads to efficient excited state intramolecular proton transfer (ESIPT) coupled with dehydration, giving quinone methide QM5 which was characterized by LFP (in CH(3)CN-H(2)O, lambda(max) = 370 nm, tau = 0.19 ms). On irradiation of QMP 5 in CH(3)OH-H(2)O (4:1), the quantum yield of methanolysis is Phi = 0.70. Excitation of naphthols QMP 6-8 to S(1) in CH(3)CN leads to photoionization and formation of naphthoxyl radicals. In a protic solvent, QMP 6-8 undergo solvent-assisted PT giving QM6 or zwitterion QM8 that react with nucleophiles delivering adducts, but with a significantly lower quantum efficiency. QMP 9 in a protic solvent undergoes two competitive processes, photosolvolysis via QM9 and solvent-assisted PT to carbon atom of the naphthalene giving zwitterion. QM9 has been characterized by LFP (in CH(3)CN H(2)O, lambda(max) > 600 nm, tau = 0.9 ms). In addition to photogenerated QMs, two stable naphthalene QMs, QM10 and QM11 were synthesized thermally and characterized by X-ray crystallography. QM10 and QM11 do not react with H(2)O but undergo acid-catalyzed fragmentation or rearrangement. Antiproliferative activity of 5-9 was investigated on three human cancer cell lines. Exposure of MCF-7 cells treated with 5 to 300 nm irradiation leads to an enhanced antiproliferative effect, in accordance with the activity being due to the formation of QM5. PMID- 22533613 TI - Inflammatory lymphangiogenesis in a rat transplant model of interstitial fibrosis and tubular atrophy. AB - We have previously reported de novo lymphangiogenesis in human renal allograft nephrectomy specimens that exhibited interstitial fibrosis and tubular atrophy (IFTA). This study examined whether a similar pathology developed in an experimental model of renal transplantation in the rat. Renal transplants were carried out in rats comprising both isografts (Lewis kidneys -> Lewis rats) and allografts (Fisher kidneys -> Lewis rats). Animals were immunosuppressed in the immediate postoperative period and sacrificed at 12 months. Experimental readouts included lymphatic vessel number and location, inflammatory cell infiltration, interstitial fibrosis, renal function, blood pressure and proteinuria. Rat allografts demonstrated the characteristic features of IFTA with increased macrophage and T cell infiltration and scattered B cells aggregates. Rat allografts exhibited impaired renal function and proteinuria. Although there was no difference in the number of perivascular lymphatic vessels, there was a striking 18-fold increase in the number of interstitial lymphatic vessels in renal allografts. Furthermore, the lymphatic vessel number correlated with the extent of interstitial fibrosis. This rat allograft model of IFTA demonstrates a marked increase in the number of interstitial lymphatic vessels and mirrors previous work in failing human renal allografts. PMID- 22533614 TI - Dual enzyme-like activities of iron oxide nanoparticles and their implication for diminishing cytotoxicity. AB - Iron oxide nanoparticles (IONPs) are frequently used in biomedical applications, yet their toxic potential is still a major concern. While most studies of biosafety focus on cellular responses after exposure to nanomaterials, little is reported to analyze reactions on the surface of nanoparticles as a source of cytotoxicity. Here we report that different intracellular microenvironment in which IONPs are located leads to contradictive outcomes in their abilities to produce free radicals. We first verified pH-dependent peroxidase-like and catalase-like activities of IONPs and investigated how they interact with hydrogen peroxide (H(2)O(2)) within cells. Results showed that IONPs had a concentration-dependent cytotoxicity on human glioma U251 cells, and they could enhance H(2)O(2)-induced cell damage dramatically. By conducting electron spin resonance spectroscopy experiments, we showed that both Fe(3)O(4) and gamma Fe(2)O(3) nanoparticles could catalyze H(2)O(2) to produce hydroxyl radicals in acidic lysosome mimic conditions, with relative potency Fe(3)O(4) > gamma Fe(2)O(3), which was consistent with their peroxidase-like activities. However, no hydroxyl radicals were observed in neutral cytosol mimic conditions with both nanoparticles. Instead, they decomposed H(2)O(2) into H(2)O and O(2) directly in this condition through catalase-like activities. Transmission electron micrographs revealed that IONPs located in lysosomes in cells, the acidic environment of which may contribute to hydroxyl radical production. This is the first study regarding cytotoxicity based on their enzyme-like activities. Since H(2)O(2) is continuously produced in cells, our data indicate that lysosome escaped strategy for IONP delivery would be an efficient way to diminish long term toxic potential. PMID- 22533616 TI - Editorial: cell processes in bacterial diseases. PMID- 22533615 TI - Low fidelity bypass of O(2)-(3-pyridyl)-4-oxobutylthymine, the most persistent bulky adduct produced by the tobacco specific nitrosamine 4-(methylnitrosamino)-1 (3-pyridyl)-1-butanone by model DNA polymerases. AB - 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the most important human carcinogens. It is metabolized to produce a variety of methyl and 4-(3 pyridyl)-4-oxo-butyl (POB) DNA adducts. A potentially important POB adduct is O(2)-[4-(3-pyridyl)-4-oxobut-1-yl]thymidine (O(2)-POB-dT) because it is the most abundant POB adduct in NNK-treated rodents. To evaluate the mutagenic properties of O(2)-POB-dT, we measured the rate of insertion of dNTPs opposite and extension past both O(2)-POB-dT and O(2)-methylthymidine (O(2)-Me-dT) by two model polymerases, E. coli DNA polymerase I (Klenow fragment) with the proofreading exonuclease activity inactivated (Kf) and Sulfolobus solfataricus DNA polymerase IV (Dpo4). We found that the size of the alkyl chain only marginally affected the reactivity and that the specificity of adduct bypass was very low. The k(cat)/K(m) for the Kf catalyzed incorporation opposite and extension past the adducts was reduced ~10(6)-fold when compared to undamaged DNA. Dpo4 catalyzed the incorporation opposite and extension past the adducts approximately 10(3) fold more slowly than undamaged DNA. The dNTP specificity was less for Dpo4 than for Kf. In general, dA was the preferred base pair partner for O(2)-Me-dT and dT the preferred base pair partner for O(2)-POB-dT. With enzyme in excess over DNA, the time courses of the reactions showed a biphasic kinetics that indicates the formation inactive binary and ternary complexes. PMID- 22533617 TI - Bacterial lipopolysaccharides in plant and mammalian innate immunity. AB - This mini-review gives a structural view on the lipopolysaccharides (LPSs), the endotoxin from Gram negative bacteria, paying attention on the features that are relevant for their activity as elicitors of the innate immune system of humans, animals and plants. PMID- 22533618 TI - Impact of structural domains of the heparin binding hemagglutinin of Mycobacterium tuberculosis on function. AB - Among the few well characterized virulence factors of Mycobacterium tuberculosis (Mtb) is the heparinbinding hemagglutinin (HBHA). HBHA is a 21-kDa protein that localizes to the mycobacterial surface where it can interact with host components. Interaction with epithelial cells and components of the extracellular matrix is mediated by the methylated lysine-rich C-terminal domain of the protein. The N-terminal end of HBHA contains a coiled coil motif which is involved in protein oligomerization and bacterial-bacterial aggregation. In this report, we will focus our attention on what is known about the structure of the HBHA protein and the protein function and role in TB pathogenesis. PMID- 22533619 TI - Resuscitation-promoting factors (Rpf): in search of inhibitors. AB - Resuscitation promoting factors (Rpf) are a family of proteins secreted by actively growing actinobacteria, including Mycobacterium tuberculosis. Experimental evidence suggests that Rpfs play a distinct role in bacterial resuscitation and re-growth as well as reactivation of chronic tuberculosis in mice. The striking similarity of the Rpfs structure to cell wall hydrolysing enzymes has provided a basis for the development of novel low molecular weight inhibitors of Rpfs activity. In particular, recently characterised nitrophenylthiocyanate compounds could be considered as a promising scaffold for generation of therapeutic agents targeting reactivation of latent tuberculosis. This review describes recent progress in understanding of molecular mechanisms of Rpf biological activity. PMID- 22533620 TI - Structural and dynamic properties of incomplete immunoglobulin-like fold domains. AB - The immunoglobulin fold (Ig-fold) is a widespread structural motif that is detected in a variety of proteins involved in diversified biological processes. The Ig-fold contains 70-110 residues that are assembled in a characteristic sandwich-like structure formed by two facing beta-sheets each made of antiparallel beta-strands. A number of variations on this common theme have been detected and described (Ig-like fold). One of the most intriguing variants is characterized by the lack of a strand compared to the canonical motif (incomplete Ig-like fold). Interestingly, proteins exhibiting incomplete Ig-like fold have been shown to play an important role in mediating either protein-protein or domain-domain interactions. Protein-protein interactions mediated by incomplete Ig-like folds play a key structural role in the chaperone-usher pathway, a process that generates multi-protein assemblies essential for the adhesion of gram negative bacteria. Domains with incomplete Ig-like fold have also been discovered in the mechanism of action of adhesins belonging to the family of MSCRAMMs (microbial surface components recognizing adhesive matrix molecules). Recently, a stable incomplete Iglike fold has been detected in the peptidoglycan binding extra-cellular portion of Staphylococcus aureus PrkC, an important Ser/Thr membrane kinase involved in bacterial growth and revival from latency. It is important to note that the occurrence of proteins with incomplete Ig-like fold is often related to cell adhesion and infectivity of bacterial pathological agents. We here report a survey of the structural data available on this peculiar structural motif highlighting analogies and differences of incomplete Ig-like fold involved in different processes. The dynamical behavior of these domains, investigated by molecular dynamics techniques, will be also commented. PMID- 22533621 TI - Eight stranded beta -barrel and related outer membrane proteins: role in bacterial pathogenesis. AB - Gram negative bacteria have evolved many mechanisms of attaching to and invading host epithelial and immune cells. In particular, many outer membrane proteins (OMPs) are involved in this initial interaction between the pathogen and their host. This review focuses on a number of small pore-forming OMPs that are all composed of eightstranded beta- barrel proteins and include members of the OmpA, OmpW and OmpX families of proteins. These proteins, together with the related OmpA-like peptidoglycan associated lipoproteins, are involved in interactions with host cells and are mediators of virulence. In many cases, these proteins interact with host immune cells and can be considered as pathogen associated molecular patterns (PAMPS) due to their ability to signal via Toll like receptor molecules and other pattern recognition receptors. The role of these proteins in pathogenesis is discussed here, together with the potential for these proteins to be used as immunoprophylactic agents to protect against infection. PMID- 22533622 TI - A generalized linear model for peak calling in ChIP-Seq data. AB - Chromatin immunoprecipitation followed by massively parallel sequencing (ChIP Seq) has become a routine for detecting genome-wide protein-DNA interaction. The success of ChIP-Seq data analysis highly depends on the quality of peak calling (i.e., to detect peaks of tag counts at a genomic location and evaluate if the peak corresponds to a real protein-DNA interaction event). The challenges in peak calling include (1) how to combine the forward and the reverse strand tag data to improve the power of peak calling and (2) how to account for the variation of tag data observed across different genomic locations. We introduce a new peak calling method based on the generalized linear model (GLMNB) that utilizes negative binomial distribution to model the tag count data and account for the variation of background tags that may randomly bind to the DNA sequence at varying levels due to local genomic structures and sequence contents. We allow local shifting of peaks observed on the forward and the reverse stands, such that at each potential binding site, a binding profile representing the pattern of a real peak signal is fitted to best explain the observed tag data with maximum likelihood. Our method can also detect multiple peaks within a local region if there are multiple binding sites in the region. PMID- 22533623 TI - Practical research-based guidance for motor imagery practice in neurorehabilitation. AB - PURPOSE: The purpose of this appraisal is to offer guidance to clinicians on applying motor imagery in neurorehabilitation and provide guidance to support this process. METHOD: We used evidence from a variety of fields as well as clinical experience with motor imagery to develop guidance for employing motor imagery during neurorehabilitation. RESULTS: Motor imagery is a relatively new intervention for neurorehabilitation supported by evidence from areas such as cognitive neuroscience and sports psychology. Motor imagery has become a very popular intervention modality for clinicians but there is insufficient information available on how to administer it in clinical practice and make deliberate decisions during its application. CONCLUSIONS: We provide evidence based guidance for employing motor imagery in neurorehabilitation and use the principles of motor learning as the framework for clinical application. PMID- 22533624 TI - Assessing changes in oral health-related quality of life and its factors in community-dwelling older Brazilians. AB - OBJECTIVE: To describe changes in oral health-related quality of life and to evaluate the associations of these changes in community-dwelling older people. MATERIALS AND METHODS: In this longitudinal study a representative sample of 872 older people, living in Brazil, was evaluated during 2004. The follow-up was carried out during 2008, with 587 older persons evaluated. A questionnaire assessing socio-demographic information, health history, oral health-impact profile and number of natural teeth was used. Changes in oral health-related quality of life were categorized as improvement or deterioration. Data analysis was performed using a hierarchical approach based in a conceptual framework. A hierarchal approach was carried out using Poisson regressions. RESULTS: Older persons living in rural areas, those who reported brushing once a day or less and older persons with fewer natural teeth had an increased chance of reporting deterioration in oral health-related quality of life. Women and participants who received a minimum wage of less than US $219.50 were more likely to report improvement in oral health-related quality of life. CONCLUSION: The results of this study suggest that changes in the oral health-related quality of life are influenced by many of the variables that were included in the conceptual framework. PMID- 22533625 TI - Prognostic value of tumour-associated macrophages in canine mammary tumours. AB - Tumour-associated macrophages (TAMs) have already been associated in human breast cancer to a poor prognosis. As a part of a tumoural microenvironment, TAMs have an important contribution influencing neoplastic progression. Hitherto, in canine mammary tumours (CMT) the prognostic value of TAMs has not been reported. In this study, MAC387 immunohistochemical expression was evaluated in 59 CMTs (20 benign and 39 malignant). The TAM value was significantly higher in malignant than benign CMT (P = 0.011). In malignant CMT, TAMs were associated with skin ulceration (P = 0.022), histological type (P = 0.044), nuclear grade (P = 0.031) and tubular differentiation (P = 0.042). The survival analysis revealed a significant association between tumours with higher levels of TAMs and the decrease in overall survival (P = 0.030). TAMs have proven to have a prognostic value. These findings suggest the future possibility of using TAMs as a novel therapeutic target in CMT. PMID- 22533626 TI - Sensitive method for determination of protein and cell concentrations based on competitive adsorption to nanoparticles and time-resolved luminescence resonance energy transfer between labeled proteins. AB - A sensitive mix-and-measure method for the determination of protein and cell concentrations was developed. It is based on the competitive adsorption between the analyte and donor- and acceptor-labeled proteins to carboxylate-modified polystyrene nanoparticles. A high time-resolved luminescence resonance energy transfer (TR-LRET) signal is detected in the absence of the analyte due to the close proximity of the nanoparticle-adsorbed labeled proteins. The increased concentration of the analyte decreases the adsorption of the labeled proteins, leading to the loss of proximity and thus a decrease in the TR-LRET. The detection limit of the assay was 2.6 ng of proteins, which is higher than that of the most sensitive commercial methods. The method was also applied to cell counting, and 200 eukaryotic cells were measured in a microtiter well under the optimized conditions. The average coefficient of variation for both developed assays was approximately 10%, and the protein-to-protein variability for 11 different proteins was no more than 20%. The developed method requires no labeled particles, making the concept optimally applicable to varying targets as the material of the particle may be selected according to the application. PMID- 22533627 TI - Accuracy and precision of variance components in occupational posture recordings: a simulation study of different data collection strategies. AB - BACKGROUND: Information on exposure variability, expressed as exposure variance components, is of vital use in occupational epidemiology, including informed risk control and efficient study design. While accurate and precise estimates of the variance components are desirable in such cases, very little research has been devoted to understanding the performance of data sampling strategies designed specifically to determine the size and structure of exposure variability. The aim of this study was to investigate the accuracy and precision of estimators of between-subjects, between-days and within-day variance components obtained by sampling strategies differing with respect to number of subjects, total sampling time per subject, number of days per subject and the size of individual sampling periods. METHODS: Minute-by-minute values of average elevation, percentage time above 90 degrees and percentage time below 15 degrees were calculated in a data set consisting of measurements of right upper arm elevation during four full shifts from each of 23 car mechanics. Based on this parent data, bootstrapping was used to simulate sampling with 80 different combinations of the number of subjects (10, 20), total sampling time per subject (60, 120, 240, 480 minutes), number of days per subject (2, 4), and size of sampling periods (blocks) within days (1, 15, 60, 240 minutes). Accuracy (absence of bias) and precision (prediction intervals) of the variance component estimators were assessed for each simulated sampling strategy. RESULTS: Sampling in small blocks within days resulted in essentially unbiased variance components. For a specific total sampling time per subject, and in particular if this time was small, increasing the block size resulted in an increasing bias, primarily of the between-days and the within-days variance components. Prediction intervals were in general wide, and even more so at larger block sizes. Distributing sampling time across more days gave in general more precise variance component estimates, but also reduced accuracy in some cases. CONCLUSIONS: Variance components estimated from small samples of exposure data within working days may be both inaccurate and imprecise, in particular if sampling is laid out in large consecutive time blocks. In order to estimate variance components with a satisfying accuracy and precision, for instance for arriving at trustworthy power calculations in a planned intervention study, larger samples of data will be required than for estimating an exposure mean value with a corresponding certainty. PMID- 22533628 TI - Electrophysiological characterization of sodium-activated potassium channels in NG108-15 and NSC-34 motor neuron-like cells. AB - AIMS: The electrical properties of Na(+) -activated K(+) current (I(K(Na)) ) and its contribution to spike firing has not been characterized in motor neurons. METHODS: We evaluated how activation of voltage-gated K(+) current (I(K) ) at the cellular level could be coupled to Na(+) influx through voltage-gated Na(+) current (I(N) (a) ) in two motor neuron-like cells (NG108-15 and NSC-34 cells). RESULTS: Increasing stimulation frequency altered the amplitudes of both I(Na) and I(K) simultaneously. With changes in stimulation frequency, the kinetics of both I(Na) inactivation and I(K) activation were well correlated at the same cell. Addition of tetrodotoxin or ranolazine reduced the amplitudes of both I(Na) and I(K) simultaneously. Tefluthrin (Tef) increased the amplitudes of both I(Na) and I(K) throughout the voltages ranging from -30 to + 10 mV. In cell attached recordings, single-channel conductance from a linear current-voltage relation was 94 +/- 3 pS (n = 7). Tef (10 MUm) enhanced channel activity with no change in single-channel conductance. Tef increased spike firing accompanied by enhanced facilitation of spike-frequency adaptation. Riluzole (10 MUm) reversed Tef-stimulated activity of K(Na) channels. In motor neuron-like NSC-34 cells, increasing stimulation frequency altered the kinetics of both I(Na) and I(K) . Modelling studies of motor neurons were simulated to demonstrate that the magnitude of I(K(Na)) modulates AP firing. CONCLUSIONS: There is a direct association of Na(+) and K(Na) channels which can provide the rapid activation of K(Na) channels required to regulate AP firing occurring in motor neurons. PMID- 22533629 TI - Validation of the attitudes toward intellectual disability: ATTID questionnaire. AB - BACKGROUND: Individuals with an intellectual disability (ID) continue to experience major obstacles towards social, educational and vocational integration. Negative attitudes toward persons with ID has remained relevant over time and has led to discrimination and stigma. OBJECTIVE: The present study describes the development of a new questionnaire for tapping into the general population's attitudes toward individuals with ID and addresses its psychometric properties. METHODS: Adopting a multidimensional perspective, the Attitudes Toward Intellectual Disability Questionnaire (ATTID) was developed from a series of previously validated instruments and principles from the Montreal Declaration on Intellectual Disability (2004). The ATTID was administered by phone to 1605 randomly selected adult men and women, stratified by region in the Province of Quebec, Canada. RESULTS: The ATTID yielded a five-factor structure overlapping the tri-partite model of attitudes. The cognitive component was represented by two factors: knowledge of capacity and rights and knowledge of causes of ID. The affective component tapped into two factors: discomfort and sensitivity/compassion. Finally, the behavioural component emerged as a single factor. The ATTID had good internal consistency with Cronbach's alpha coefficients ranging from 0.59 to 0.89 for the five factors and of 0.92 for the overall questionnaire. Test-retest reliability yielded correlations from 0.62 to 0.83 for the five factors. CONCLUSION: The ATTID can be used to measure attitudes among different populations and allows comparisons over time within the same population as a function of various intervention strategies for de-stigmatising ID. PMID- 22533630 TI - Pyropheophorbide A and c(RGDyK) comodified chitosan-wrapped upconversion nanoparticle for targeted near-infrared photodynamic therapy. AB - Near-infrared (NIR)-to-visible upconversion nanoparticle (UCNP) has shown promising prospects in photodynamic therapy (PDT) as a drug carrier or energy donor. In this work, a photosensitizer pyropheophorbide a (Ppa) and RGD peptide c(RGDyK) comodified chitosan-wrapped NaYF(4):Yb/Er upconversion nanoparticle UCNP Ppa-RGD was developed for targeted near-infrared photodynamic therapy. The properties of UCNP-Ppa-RGD, such as morphology, stability, optical spectroscopy and singlet oxygen generation efficiency, were investigated. The results show that covalently linked pyropheophorbide a molecule not only is stable but also retains its spectroscopic and functional properties. In vitro studies confirm a stronger targeting specificity of UCNP-Ppa-RGD to integrin alpha(v)beta(3) positive U87-MG cells compared with that in the corresponding negative group. The photosensitizer-attached nanostructure exhibited low dark toxicity and high phototoxicity against cancer cells upon 980 nm laser irradiation at an appropriate dosage. These results represent the first demonstration of a highly stable and efficient photosensitizer modified upconversion nanostructure for targeted near-infrared photodynamic therapy of cancer cells. The novel UCNP-Ppa RGD nanoparticle may provide a powerful alternative for near-infrared photodynamic therapy with an improved tumor targeting specificity. PMID- 22533631 TI - The health services burden of heart failure: an analysis using linked population health data-sets. AB - BACKGROUND: The burden of patients with heart failure on health care systems is widely recognised, although there have been few attempts to quantify individual patterns of care and differences in health service utilisation related to age, socio-economic factors and the presence of co-morbidities. The aim of this study was to assess the typical profile, trajectory and resource use of a cohort of Australian patients with heart failure using linked population-based, patient level data. METHODS: Using hospital separations (Admitted Patient Data Collection) with death registrations (Registry of Births, Deaths and Marriages) for the period 2000-2007 we estimated age- and gender-specific rates of index admissions and readmissions, risk factors for hospital readmission, mean length of stay (LOS), median survival and bed-days occupied by patients with heart failure in New South Wales, Australia. RESULTS: We identified 29,161 index admissions for heart failure. Admission rates increased with age, and were higher for males than females for all age groups. Age-standardised rates decreased over time (256.7 to 237.7/100,000 for males and 235.3 to 217.1/100,000 for females from 2002-3 to 2006-7; p = 0.0073 adjusted for gender). Readmission rates (any cause) were 27% and 73% at 28-days and one year respectively; readmission rates for heart failure were 11% and 32% respectively. All cause mortality was 10% and 28% at 28 days and one year. Increasing age was associated with more heart failure readmissions, longer LOS and shorter median survival. Increasing age, increasing Charlson comorbidity score and male gender were risk factors for hospital readmission. Cohort members occupied 954,888 hospital bed-days during the study period (any cause); 383,646 bed-days were attributed to heart failure admissions. CONCLUSIONS: The rates of index admissions for heart failure decreased significantly in both males and females over the study period. However, the impact on acute care hospital beds was substantial, with heart failure patients occupying almost 200,000 bed-days per year in NSW over the five year study period. The strong age-related trends highlight the importance of stabilising elderly patients before discharge and community-based outreach programs to better manage heart failure and reduce readmissions. PMID- 22533633 TI - A new lignan with anti-tumour activity from Polygonum perfoliatum L. AB - The methanol extract of the tubers of Polygonum perfoliatum L. afforded a new lignan: 8-oxo-pinoresinol (1), and five known compounds 3',5-dihydroxy-3,4',5',7 tetramethoxy-flavone (2), catechin (3), quercetin (4), quercetin-3-O-beta-D glucuronide (5) and rutin (6). Their structures were established by MS, one- and two-dimensional NMR experiments. Compound 1 showed cytotoxicity against human mammary carcinoma (Bcap-37), human colon carcinoma (RKO), human hepatocellular carcinoma (SMMC-7721), human prostate carcinoma (PC3) and human erythroleukaemia (K562) cells. PMID- 22533632 TI - An FMRI study of auditory orienting and inhibition of return in pediatric mild traumatic brain injury. AB - Studies in adult mild traumatic brain injury (mTBI) have shown that two key measures of attention, spatial reorienting and inhibition of return (IOR), are impaired during the first few weeks of injury. However, it is currently unknown whether similar deficits exist following pediatric mTBI. The current study used functional magnetic resonance imaging (fMRI) to investigate the effects of semi acute mTBI (<3 weeks post-injury) on auditory orienting in 14 pediatric mTBI patients (age 13.50+/-1.83 years; education: 6.86+/-1.88 years), and 14 healthy controls (age 13.29+/-2.09 years; education: 7.21+/-2.08 years), matched for age and years of education. The results indicated that patients with mTBI showed subtle (i.e., moderate effect sizes) but non-significant deficits on formal neuropsychological testing and during IOR. In contrast, functional imaging results indicated that patients with mTBI demonstrated significantly decreased activation within the bilateral posterior cingulate gyrus, thalamus, basal ganglia, midbrain nuclei, and cerebellum. The spatial topography of hypoactivation was very similar to our previous study in adults, suggesting that subcortical structures may be particularly affected by the initial biomechanical forces in mTBI. Current results also suggest that fMRI may be a more sensitive tool for identifying semi-acute effects of mTBI than the procedures currently used in clinical practice, such as neuropsychological testing and structural scans. fMRI findings could potentially serve as a biomarker for measuring the subtle injury caused by mTBI, and documenting the course of recovery. PMID- 22533634 TI - GeoChip-based analysis of microbial functional gene diversity in a landfill leachate-contaminated aquifer. AB - The functional gene diversity and structure of microbial communities in a shallow landfill leachate-contaminated aquifer were assessed using a comprehensive functional gene array (GeoChip 3.0). Water samples were obtained from eight wells at the same aquifer depth immediately below a municipal landfill or along the predominant downgradient groundwater flowpath. Functional gene richness and diversity immediately below the landfill and the closest well were considerably lower than those in downgradient wells. Mantel tests and canonical correspondence analysis (CCA) suggested that various geochemical parameters had a significant impact on the subsurface microbial community structure. That is, leachate from the unlined landfill impacted the diversity, composition, structure, and functional potential of groundwater microbial communities as a function of groundwater pH, and concentrations of sulfate, ammonia, and dissolved organic carbon (DOC). Historical geochemical records indicate that all sampled wells chronically received leachate, and the increase in microbial diversity as a function of distance from the landfill is consistent with mitigation of the impact of leachate on the groundwater system by natural attenuation mechanisms. PMID- 22533635 TI - Inhibitor incidence after intensive FVIII replacement for surgery in mild and moderate haemophilia A: a prospective national study in the Netherlands. AB - Inhibitor development is currently the most severe complication in mild/moderate haemophilia A patients, causing increased bleeding tendency, hospitalization and mortality. It has been suggested that receiving high doses of factor VIII (FVIII) concentrates for surgical procedures is an important risk factor for inhibitor development in these patients. The current multicentre study aimed to determine prospectively the incidence of inhibitor development after intensive FVIII replacement therapy for surgical procedures in patients with mild/moderate haemophilia A. All consecutive patients with mild/moderate haemophilia A were included when they required at least 10 000 iu of FVIII concentrates (or 250 iu/kg) for 5 or more days for a surgical procedure. Potential clinical risk factors for inhibitor development and results of inhibitor tests were collected. Forty-six patients with a median age of 54 years (interquartile range, 40-59 years) were included in the study. F8 genotyping revealed 20 different missense mutations. Patients received either recombinant (65%) or plasma-derived FVIII concentrates (35%) by intermittent bolus injections (41%) or continuous infusion (57%). Two patients developed a low titre inhibitor post-operatively. The incidence of inhibitor development following intensive treatment for surgery in this unselected prospective cohort of mild/moderate haemophilia A patients was 4% (95% confidence interval, 0.5-14.8). PMID- 22533636 TI - Understanding the origins and prevalence of AIDS conspiracy beliefs in the United States and South Africa. AB - The human immunodeficiency virus (HIV) originated from cross-species transmission of the simian immunodeficiency virus from primates to humans. Yet a significant minority of people in the United States (US) and South Africa believe that HIV was deliberately created by scientists as a bioweapon. Scholars in the humanities emphasise the historical context, socially situated character and psycho-social dimensions of such aetiological narratives. This is important, but so is the role of individual agents participating in the cultic milieu in which oppositional ideas such as HIV conspiracy theories are borrowed across national, ideological and political divides. This article discusses the origins of the legend of 'HIV as bioweapon' and summarises the available evidence on the prevalence of acquired immune deficiency syndrome (AIDS) conspiracy beliefs in the US and South Africa. This is followed by a discussion of the history of biowarfare and racial oppression which renders the legend (and its local South African variants) believable for many people. The article then moves beyond socio-historical analysis to argue that analytical space needs to be created to critique the political leaders who promoted AIDS conspiracy beliefs. PMID- 22533637 TI - Sociodemographic and risk behavior characteristics associated with unprotected sex with women among black men who have sex with men and women in New York City. AB - The objectives of this cross-sectional study were to compare sociodemographic and risk behavior characteristics between black men who have sex with both men and women (MSMW) and those who have sex with men only (MSMO) and assess factors associated with having any unprotected vaginal and/or anal intercourse (UVAI) with women in the last 3 months. Data from 326 black men who reported recent unprotected anal intercourse with a man in an HIV behavioral intervention study in New York City were analyzed. Baseline characteristics were compared between MSMW and MSMO, and factors associated with having any UVAI in the past 3 months with women among MSMW were evaluated. In total, 26.8% reported having sex with both men and women in the last 3 months. MSMW were less likely to be HIV infected, use amyl nitrates, and have unprotected receptive anal sex with most recent male partner. MSMW were more likely to be over 40 years old and use heroin. A total of 55.6% of MSMW reported having UVAI with women in the last 3 months. Compared to MSMW having only protected sex, MSMW having any UVAI with women were less likely to be HIV infected and to disclose having sex with men to female partners; they were more likely to have greater than four male sex partners in the last 3 months. In conclusion, HIV prevention interventions among black MSMW should directly address the risk of HIV transmission to both their female and male partners. Disclosure of bisexuality to female partners may be an important component of future prevention efforts. PMID- 22533638 TI - Characterization of rumen bacterial diversity and fermentation parameters in concentrate fed cattle with and without forage. AB - AIMS: To determine the effects of the removal of forage in high-concentrate diets on rumen fermentation conditions and rumen bacterial populations using culture independent methods. METHODS AND RESULTS: Detectable bacteria and fermentation parameters were measured in the solid and liquid fractions of digesta from cattle fed two dietary treatments, high concentrate (HC) and high concentrate without forage (HCNF). Comparison of rumen fermentation conditions showed that duration of time spent below pH 5.2 and rumen osmolality were higher in the HCNF treatment. Simpson's index of 16S PCR-DGGE images showed a greater diversity of dominant species in the HCNF treatment. Real-time qPCR showed populations of Fibrobacter succinogenes (P = 0.01) were lower in HCNF than HC diets. Ruminococcus spp., F. succinogenes and Selenomonas ruminantium were at higher (P <= 0.05) concentrations in the solid vs the liquid fraction of digesta regardless of diet. CONCLUSIONS: The detectable bacterial community structure in the rumen is highly diverse. Reducing diet complexity by removing forage increased bacterial diversity despite the associated reduction in ruminal pH being less conducive for fibrolytic bacterial populations. Quantitative PCR showed that removal of forage from the diet resulted in a decline in the density of some, but not all fibrolytic bacterial species examined. SIGNIFICANCE AND IMPACT OF THE STUDY: Molecular techniques such as DGGE and qPCR provide an increased understanding of the impacts of dietary changes on the nature of rumen bacterial populations, and conclusions derived using these techniques may not match those previously derived using traditional laboratory culturing techniques. PMID- 22533639 TI - Multicomponent synthesis of Ugi-type ceramide analogues and neoglycolipids from lipidic isocyanides. AB - Unique types of ceramide and glycolipid architectures were obtained by means of Ugi reactions incorporating lipidic isocyanides as surrogates of sphingolipids. The multicomponent nature of this approach allowed for a highly efficient assembly process, wherein two of the components provided the lipidic tails while a third one incorporated either the functionality suitable for the conjugation to sugar or the sugar moiety itself. Two dissimilar strategies were implemented: (i) the initial assembly of ceramide analogues followed by glycosylation to produce a glycolipid skeleton and (ii) the one-pot construction of glycolipid frameworks by condensation of lipidic isocyanides either with lipidic amines and oligosaccharidic acids or with fatty acids and oligosaccharidic amines. Whereas both approaches are amenable for accessing analogues of anticancer glycolipids, the latter one proved to have greater potential owing to its more straightforward and efficient character. Overall, the methodology developed shows great promise toward the massive (eventually combinatorial) production of neoglycolipids suitable for biological screening. PMID- 22533640 TI - Multidimensional epistasis and fitness landscapes in enzyme evolution. AB - The conventional analysis of enzyme evolution is to regard one single salient feature as a measure of fitness, expressed in a milieu exposing the possible selective advantage at a given time and location. Given that a single protein may serve more than one function, fitness should be assessed in several dimensions. In the present study we have explored individual mutational steps leading to a triple-point-mutated human GST (glutathione transferase) A2-2 displaying enhanced activity with azathioprine. A total of eight alternative substrates were used to monitor the diverse evolutionary trajectories. The epistatic effects of the mutations on catalytic activity were variable in sign and magnitude and depended on the substrate used, showing that epistasis is a multidimensional quality. Evidently, the multidimensional fitness landscape can lead to alternative trajectories resulting in enzymes optimized for features other than the selectable markers relevant at the origin of the evolutionary process. In this manner the evolutionary response is robust and can adapt to changing environmental conditions. PMID- 22533641 TI - Meanings, motivations, and strategies for engaging in physical activity among women with multiple sclerosis. AB - PURPOSE: The aim of the current study was to better understand the adoption and maintenance of physical activity from the perspective of women with multiple sclerosis (MS). METHODS: Participants (N = 11) were women with MS who had low levels of disability and who engaged in varying levels of physical activity. Participants completed two semi-structured, audio taped interviews focusing on their beliefs, motivators, and experiences of physical activity. RESULTS: Across all activity levels participants reported similar beliefs and motivations related to being physically active including the desire to be "normal", savoring current health, enjoyment of the activity, "feeling good" after activity, weight control, and maintenance of physical function. Active and inactive participants differed in the practical strategies they reportedly used to adopt and maintain physical activity, such as prioritizing and scheduling physical activity, managing disease specific barriers, and building social support networks. CONCLUSIONS: A consideration of these beliefs, motivations, and strategies may be useful for designing behavioral interventions to increase physical activity that are sensitive to the needs and preferences of women with MS. PMID- 22533642 TI - The system epilepsies: a pathophysiological hypothesis. AB - We postulate that "system epilepsies" (SystE) are due to an enduring propensity to generate seizures of functionally characterized brain systems. Data supporting this hypothesis-that some types of epilepsy depend on the dysfunction of specific neural systems-are reviewed. The SystE hypothesis may drive pathophysiologic and clinical studies that can advance our understanding of epilepsies and can open up new therapeutic perspectives. PMID- 22533644 TI - Consistent message? PMID- 22533643 TI - Abnormalities of granule cell dendritic structure are a prominent feature of the intrahippocampal kainic acid model of epilepsy despite reduced postinjury neurogenesis. AB - PURPOSE: Aberrant plastic changes among adult-generated hippocampal dentate granule cells are hypothesized to contribute to the development of temporal lobe epilepsy. Changes include formation of basal dendrites projecting into the dentate hilus. Innervation of these processes by granule cell mossy fiber axons leads to the creation of recurrent excitatory circuits within the dentate. The destabilizing effect of these recurrent circuits may contribute to hyperexcitability and seizures. Although basal dendrites have been identified in status epilepticus models of epilepsy associated with increased neurogenesis, we do not know whether similar changes are present in the intrahippocampal kainic acid model of epilepsy, which is associated with reduced neurogenesis. METHODS: In the present study, we used Thy1-YFP-expressing transgenic mice to determine whether hippocampal dentate granule cells develop hilar-projecting basal dendrites in the intrahippocampal kainic acid model. Brain sections were examined 2 weeks after treatment. Tissue was also examined using ZnT-3 immunostaining for granule cell mossy fiber terminals to assess recurrent connectivity. Adult neurogenesis was assessed using the proliferative marker Ki-67 and the immature granule cell marker calretinin. KEY FINDINGS: Significant numbers of cells with basal dendrites were found in this model, but their structure was distinct from basal dendrites seen in other epilepsy models, often ending in complex tufts of short branches and spines. Even more unusual, a subset of cells with basal dendrites had an inverted appearance; they completely lacked apical dendrites. Spines on basal dendrites were found to be apposed to ZnT-3 immunoreactive puncta, suggestive of recurrent mossy fiber input. Finally, YFP-expressing abnormal granule cells did not colocalize Ki-67 or calretinin, indicating that these cells were more than a few weeks old, but were found almost exclusively in proximity to the neurogenic subgranular zone, where the youngest granule cells are located. SIGNIFICANCE: Recent studies have demonstrated in other models of epilepsy that dentate pathology develops following the aberrant integration of immature, adult-generated granule cells. Given these findings, one might predict that the intrahippocampal kainic acid model of epilepsy, which is associated with a dramatic reduction in adult neurogenesis, would not exhibit these changes. Herein we demonstrate that hilar basal dendrites are a common feature of this model, with the abnormal cells likely resulting from the disruption of juvenile granule cell born in the weeks before the insult. These studies demonstrate that postinjury neurogenesis is not required for the accumulation of large numbers of abnormal granule cells. PMID- 22533645 TI - HLA-B*1502 allele screening: determination of carbamazepine-induced cutaneous reactions. PMID- 22533647 TI - How infants die in neonatal intensive care units - a European perspective. PMID- 22533648 TI - Embracing complexity: deciphering origins and transformations of atmospheric organics through speciated measurements. PMID- 22533649 TI - Phenotypes of antibody-mediated rejection in organ transplants. AB - Antibody-mediated hyperacute rejection was the first rejection phenotype observed in human organ transplants. This devastating phenotype was eliminated by reliable crossmatch technologies. Since then, the focus was on T-cell-mediated rejection and de novo donor-specific antibodies were considered an epiphenomenon of cognate T-cell activation. The immune theory was that controlling the T-cell response would entail elimination of antibody-mediated rejection (ABMR). With modern immunosuppressive drugs, T-cell-mediated rejection is essentially treatable. However, this did not prevent ABMR from emerging as a significant phenotype in all types of organ transplants. It became obvious that both rejection types require distinct treatment and thus reliable diagnosis. This is the current challenge. ABMR, depending on stage, grade, time course, organ type or prior treatment, can present with a wide spectrum of phenotypes. This review summarizes the current diagnostic consensus for ABMR, describes unmet needs and challenges in diagnostics, and proposes new approaches for consideration. PMID- 22533651 TI - Low molecular weight carbohydrates in pine nuts from Pinus pinea L. AB - Low molecular weight carbohydrates in pine nuts from Pinus pinea L. (n = 7) have been studied by gas chromatography-mass spectrometry as their trimethylsilyl oximes. Besides previously reported components, such as glucose, fructose, sucrose, and raffinose, several soluble carbohydrates have been identified for the first time in this product, including saccharides (galactose, maltose, and planteose) and cyclitols (pinitol, galactinol, galactopinitol A1, fagopyritol B1, and other glycosyl-inositols). Most abundant cyclitols were chiro-inositol, fagopyritol B1, and pinitol, with concentrations ranging from 126.7 to 222.1 mg (100 g)(-1), 94.2 to 177.1 mg (100 g)(-1), and 51.2 to 282.8 mg (100 g)(-1), respectively. PMID- 22533650 TI - Increased insulin secretion and decreased glucose concentrations, but not allostatic load, are associated with stress-related exhaustion in a clinical patient population. AB - Allostatic load (AL) has been shown to be a useful marker of physiological strain during chronic stress and burnout in non-clinical working populations. The usability of the AL index for a clinical population with severe stress-related exhaustion was tested in this study. Thirteen biomarkers assembled as an AL index were analysed using blood samples from 90 patients with stress-related exhaustion (43 men and 47 women, age 31-61 years) and 90 healthy controls (46 men and 44 women, age 25-56 years). The AL scores did not differ between patients and controls. For men, some indication of higher cardiovascular risk was seen in the patient group: male patients had higher body mass index and waist-hip ratio and a poorer blood lipid status than male controls. We found lower plasma glucose concentrations in both female and male patients than those in controls. The male patients also showed increased fasting serum insulin concentrations. Further analysis using homeostasis model assessment for insulin resistance and beta-cell function showed indications of insulin resistance in the patient group, particularly in the males, and an increased insulin secretion in both male and female patients. In conclusion, AL index does not seem to capture plausible physiological strain in patients diagnosed with stress-related exhaustion. The finding of lower plasma glucose concentrations, probably due to higher insulin secretion, in patients with severe stress-related exhaustion, needs to be further investigated, including mechanisms and the clinical relevance. PMID- 22533652 TI - Guidelines for use of diuretics: a view from a member of JNC 7. PMID- 22533653 TI - Hypertension control among newly treated patients before and after publication of the main ALLHAT results and JNC 7 guidelines. AB - Medication prescribing practice changed following the publications of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) in 2002 and the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) in 2003. Few data are available on changes in hypertension control rates for patients initiating antihypertensive treatment before and after these publications. The authors compared systolic and diastolic blood pressure (SBP and DBP) levels and hypertension control (SBP <140 mm Hg and DBP <90 mm Hg) rates in patients initiating antihypertensive treatment in a large managed care organization during 2 time periods: July 1, 2001, to June 30, 2002 (n=322); and July 1, 2003, to June 30, 2004 (n=323). The blood pressure reduction associated with antihypertensive medication initiation was similar in 2001-2002 and 2003 2004 (-11.9 and -10.5 mm Hg, respectively, P=.251 for SBP; -6.9 and -5.9 mm Hg, respectively, P=.160 for DBP). The mean SBP and DBP prior to treatment were significantly lower in 2003-2004 vs 2001-2002 (145.4 vs 151.3 mm Hg, P<.001 for SBP; 87.6 vs 90.1 mm Hg, P<.002 for DBP). Hypertension control rates increased from 38.0% to 50.2% (P=.005) from 2001-2002 to 2003-2004. Lower pretreatment SBP and DBP explained hypertension control improvement over time. In this real-world clinic population, antihypertensive treatment was initiated at lower blood pressure levels following publication of ALLHAT and JNC 7, resulting in substantial improvements in hypertension control rates. PMID- 22533654 TI - Blood pressure-lowering efficacy of the fixed-dose combination of azilsartan medoxomil and chlorthalidone: a factorial study. AB - This study compared the efficacy and safety of fixed-dose combinations (FDCs) of the angiotensin II receptor blocker azilsartan medoxomil (AZL-M) and the thiazide like diuretic chlorthalidone (CLD) with the individual monotherapies in a double blind factorial study. A total of 1714 patients with clinic systolic blood pressure (SBP) 160 mm Hg to 190 mm Hg inclusive were randomized to AZL-M 0 mg, 20 mg, 40 mg, or 80 mg and/or chlorthalidone 0 mg, 12.5 mg, or 25 mg. The primary efficacy end point was change from baseline to 8 weeks in trough (hour 22-24) SBP by ambulatory blood pressure (BP) monitoring (ABPM). Patients' mean age was 57 years; 47% were men and 20% were black. Baseline trough BP was approximately 165/95 mm Hg and 151/91 mm Hg by clinic and ABPM measurements, respectively. For the pooled AZL-M/CLD 40/25-mg and 80/25-mg FDC groups, SBP reduction by ABPM at trough was 28.9 mm Hg and exceeded AZL-M 80 mg and CLD 25 mg monotherapies by 13.8 mm Hg and 13 mm Hg, respectively (P<.001 for both comparisons). Discontinuation rates and elevations in serum creatinine were dose-dependent and occurred more often in the AZL-M/CLD groups. In patients with stage 2 hypertension, treatment with the combination of AZL-M and CLD resulted in substantially greater SBP reduction compared with either agent alone. PMID- 22533655 TI - Effect of the rs168924 single-nucleotide polymorphism in the SLC6A2 catecholamine transporter gene on blood pressure in Caucasians. AB - The NG_016969.1:g.5003A>G promoter polymorphism (rs168924) in the SLC6A2 norepinephrine transporter gene was found to be predictive of the hypertensive status in a Japanese population, but no data are available for Caucasians. Genotyping for rs168924 was performed in 282 young men with normal blood pressure (BP), grade 1 or 2 hypertension. In addition to casual BP, 24-hour ABPM and echocardiography were performed. Multiple regression analysis revealed a significant association of rs168924 genotype with diagnosis of hypertension (P=.044), casual systolic BP (SBP) levels (P=.028), and daytime ambulatory SBP (P=.02). The finding that rs168924 was also significantly associated with diastolic posterior wall thickness (P=.041), an echocardiographic index of hypertensive cardiac target organ damage, further supports the notion that the rs168924 SNP in SLC6A2 in fact might influence BP. Unlike previous findings in a Japanese population, in our Caucasian study cohort the presence of the minor rs168924 G allele was associated with lower prevalence of hypertension. PMID- 22533656 TI - Comparative efficacy of aliskiren/valsartan vs valsartan in nocturnal dipper and nondipper hypertensive patients: a pooled analysis. AB - This pooled analysis of ambulatory blood pressure (BP) monitoring data from two 8 week randomized controlled trials compared the antihypertensive efficacy and safety of combination aliskiren/valsartan vs valsartan alone in hypertensive patients (nocturnal dippers or nondippers). At study end, patients were taking aliskiren/valsartan 300/320 mg or valsartan 320 mg. In dippers (n=138) and nondippers (n=132), aliskiren/valsartan provided significantly (P<.05) greater reductions from baseline to week 8 than valsartan in 24-hour, daytime, and last-4 hour mean ambulatory systolic BP (maSBP). Treatment differences were more pronounced in nondippers. Nighttime maSBP reductions with aliskiren/valsartan were significantly greater vs valsartan in nondippers (-17.0 mm Hg vs -8.9 mm Hg; P<.05) but not dippers (-7.6 mm Hg vs -4.5 mm Hg; P=.16). In all time periods, combination therapy was generally associated with BP reductions that were greater in nondippers than dippers. Conversion from nondipper to dipper status was 32% vs 22% for aliskiren/valsartan vs valsartan (P=.48). Both treatments were similarly well tolerated. Although the addition of aliskiren to valsartan did not significantly alter dipper status, our data suggest an increased contribution of the renin-angiotensin-aldosterone system to the nondipper status of hypertensive patients. PMID- 22533657 TI - Small pheochromocytomas: significance, diagnosis, and outcome. AB - To address the unique challenges in the diagnosis and management of small pheochromocytomas, the authors performed a retrospective study of 24 patients with small pheochromocytomas (<= 3 cm) treated between 1995 and 2011, using 51 patients with larger pheochromocytomas (> 3 cm) as controls. Patient demographics were similar between the two groups. Small pheochromocytomas presented mainly as adrenal mass and hypertension and their major complication was hypertensive crisis during unrelated procedures in 4 patients (17%). Hypertension was improved in a quarter of the patients after pheochromocytoma resection. The biochemical marker levels in patients with small pheochromocytomas were generally lower than those with larger tumors and half of the patients exhibited modestly elevated or normal levels. The authors conclude that small pheochromocytomas are frequent and may not contribute to baseline hypertension, but can cause hypertensive crisis during unrelated medical procedures. Small pheochromocytomas should be removed to prevent hypertensive crisis and future complications of pheochromocytoma. PMID- 22533658 TI - Prediction of primary vs secondary hypertension in children. AB - Despite current guidelines, variability exists in the workup of hypertensive children due to physician preferences. The study evaluates primary vs secondary hypertension diagnosis from investigations routinely performed in hypertensive children. This retrospective study included children 5 to 19 years with primary and secondary hypertension. The proportions of abnormal laboratory and imaging tests were compared between primary and secondary hypertension groups. Risk factors for primary vs secondary hypertension were evaluated by logistic regression and likelihood function analysis. Patients with secondary hypertension were younger (5-12 years) and had a higher proportion of abnormal creatinine, renal ultrasound, and echocardiogram findings. There was no significant difference in abnormal results of thyroid function, urine catecholamines, plasma renin, and aldosterone. Abnormal renal ultrasound findings and age were predictors of secondary hypertension by regression and likelihood function analysis. Children aged 5 to 12 years with abnormal renal ultrasound findings and high diastolic blood pressures are at higher risk for secondary hypertension that requires detailed evaluation. PMID- 22533659 TI - Reducing clinical inertia in hypertension treatment: a pragmatic randomized controlled trial. AB - Clinical inertia is a major contributor to poor blood pressure (BP) control. The authors tested the effectiveness of an intervention targeting physician, patient, and office system factors with regard to outcomes of clinical inertia and BP control. A total of 591 adult primary care patients with elevated BP (mean systolic BP >= 140 mm Hg or mean diastolic BP >= 90 mm Hg) were randomized to intervention or usual care. An outreach coordinator raised patient and provider awareness of unmet BP goals, arranged BP-focused primary care clinic visits, and furnished providers with treatment decision support. The intervention reduced clinical inertia (-29% vs -11%, P=.001). Nonetheless, change in BP did not differ between intervention and usual care (-10.1/-4.1 mm Hg vs -9.1/-4.5 mm Hg, P=.50 and 0.71 for systolic and diastolic BP, respectively). Future primary care focused interventions might benefit from the use of specific medication titration protocols, treatment adherence support, and more sustained patient follow-up visits. PMID- 22533660 TI - TLR2 and TLR4 gene expression in peripheral monocytes in nondiabetic hypertensive patients: the effect of intensive blood pressure-lowering. AB - The activation of innate immune receptors, such as Toll-like receptors (TLRs), participates in the pathogenesis of cardiovascular diseases. The authors evaluated TLR2 and TLR4 gene expression in the peripheral monocytes of nondiabetic hypertensive patients compared with normotensive individuals and investigated the effect of intensive systolic blood pressure (SBP)-lowering. Included were 43 nondiabetic hypertensive patients with essential hypertension who were randomly assigned to an intensive treatment arm, with an SBP target of <130 mm Hg, or a standard arm, with an SBP target of <140 mm Hg. TLR2 and TLR4 messenger RNA (mRNA) levels in monocytes were estimated before and 12 weeks after therapy initiation. Sixteen healthy individuals were included for comparison. Hypertensives revealed significantly higher TLR4 mRNA levels compared with normotensives (985 +/- 885 vs 554 +/- 234, P=.005). In contrast, no statistically significant difference was found in TLR2. Compared with standard treatment, intensive treatment significantly downregulated TLR2 and TLR4 mRNAs, expressed as fold induction (0.66 +/- 0.49 vs 1.38 +/- 1.65 and 0.62 +/- 0.3 vs 1.9 +/- 1.2, respectively; P<.001 for both). In conclusion, TLR4 mRNA levels in peripheral monocytes are significantly elevated in nondiabetic hypertensive patients. Intensive control of SBP results in attenuation of TLR2 and TLR4 gene expression in those patients. Our findings suggest that a strict SBP target in nondiabetic hypertensive patients may offer additional benefits. PMID- 22533661 TI - Community-based approaches to prevention and management of hypertension and cardiovascular disease. AB - Community hypertension (HTN) outreach seeks to improve public health by identifying HTN and cardiovascular disease (CVD) risks. In the 1980s, the National Heart, Lung, and Blood Institute (NHLBI) funded multiple positive community studies. Additionally, the Centers for Disease Control and Prevention's (CDC's) Racial and Ethnic Approaches to Community Health (REACH) program addresses CVD risks. In 1978, in Baltimore, MD, the Association of Black Cardiologists (ABC), organized barbershops and churches as HTN control centers, as in New Orleans, LA, since 1993, the Healthy Heart Community Prevention Project (HHCPP). Also, the NHLBI Community Health Workers and Promotores de Salud are beneficial. The American Society of Hypertension (ASH) Hypertension Community Outreach program provides free HTN and CVD screenings, digital BP monitors, multilingual and literacy-appropriate information, and videos. Contemporary major federal programs, such as the Million Hearts Initiative, are ongoing. Overall, the evidence-based Logic Model should enhance planning, implementation, and dissemination. PMID- 22533662 TI - Value of combined thiazide-loop diuretic therapy in chronic kidney disease: heart failure and renin-angiotensin-aldosterone blockade. PMID- 22533663 TI - Logic operations based on magnetic-vortex-state networks. AB - Logic operations based on coupled magnetic vortices were experimentally demonstrated. We utilized a simple chain structure consisting of three physically separated but dipolar-coupled vortex-state Permalloy disks as well as two electrodes for application of the logical inputs. We directly monitored the vortex gyrations in the middle disk, as the logical output, by time-resolved full field soft X-ray microscopy measurements. By manipulating the relative polarization configurations of both end disks, two different logic operations are programmable: the XOR operation for the parallel polarization and the OR operation for the antiparallel polarization. This work paves the way for new-type programmable logic gates based on the coupled vortex-gyration dynamics achievable in vortex-state networks. The advantages are as follows: a low-power input signal by means of resonant vortex excitation, low-energy dissipation during signal transportation by selection of low-damping materials, and a simple patterned array structure. PMID- 22533664 TI - Three distinct water structures at a zwitterionic lipid/water interface revealed by heterodyne-detected vibrational sum frequency generation. AB - Lipid/water interfaces and associated interfacial water are vital for various biochemical reactions, but the molecular-level understanding of their property is very limited. We investigated the water structure at a zwitterionic lipid, phosphatidylcholine, monolayer/water interface using heterodyne-detected vibrational sum frequency generation spectroscopy. Isotopically diluted water was utilized in the experiments to minimize the effect of intra/intermolecular couplings. It was found that the OH stretch band in the Imchi((2)) spectrum of the phosphatidylcholine/water interface exhibits a characteristic double-peaked feature. To interpret this peculiar spectrum of the zwitterionic lipid/water interface, Imchi((2)) spectra of a zwitterionic surfactant/water interface and mixed lipid/water interfaces were measured. The Imchi((2)) spectrum of the zwitterionic surfactant/water interface clearly shows both positive and negative bands in the OH stretch region, revealing that multiple water structures exist at the interface. At the mixed lipid/water interfaces, while gradually varying the fraction of the anionic and cationic lipids, we observed a drastic change in the Imchi((2)) spectra in which spectral features similar to those of the anionic, zwitterionic, and cationic lipid/water interfaces appeared successively. These observations demonstrate that, when the positive and negative charges coexist at the interface, the H-down-oriented water structure and H-up-oriented water structure appear in the vicinity of the respective charged sites. In addition, it was found that a positive Imchi((2)) appears around 3600 cm(-1) for all the monolayer interfaces examined, indicating weakly interacting water species existing in the hydrophobic region of the monolayer at the interface. On the basis of these results, we concluded that the characteristic Imchi((2)) spectrum of the zwitterionic lipid/water interface arises from three different types of water existing at the interface: (1) the water associated with the negatively charged phosphate, which is strongly H-bonded and has a net H-up orientation, (2) the water around the positively charged choline, which forms weaker H-bonds and has a net H-down orientation, and (3) the water weakly interacting with the hydrophobic region of the lipid, which has a net H-up orientation. PMID- 22533666 TI - Using record linkage to monitor equity and variation in screening programmes. AB - BACKGROUND: Ecological or survey based methods to investigate screening uptake rates are fraught with many limitations which can be circumvented by record linkage between Census and health services datasets using variations in breast screening attendance as an exemplar. The aim of this current study is to identify the demographic, socio-economic factors associated with uptake of breast screening. METHODS: Record linkage study: combining 2001 Census data within the Northern Ireland Longitudinal Study (NILS) with data relating to validated breast screening histories from the National Breast Screening System. A cohort was identified of 37,059 women aged 48-64 at the Census who were invited for routine breast screening in the three years following the Census. All cohort attributes were as recorded on the Census form. RESULTS: The record linkage methodology enabled the records of almost 40,000 of those invited for screening to be analysed at an individual level, exceeding the largest published survey by a factor of ten. This produced a more robust analysis and demonstrated (in fully adjusted models) the lower uptake amongst non-married women and those in the lowest social class (OR 0.74; 95%CI 0.66, 0.82), factors that had not been reported earlier in the UK. In addition, with the availability of both individual and area information it was possible to show that the much lower screening uptake in urban areas is not due to differences in population composition suggesting unrecognised organisational problems. CONCLUSIONS: Linkage of screening data to Census-based longitudinal studies is an efficient and powerful way to increase the evidence base on sources of variation in screening uptake within the UK. PMID- 22533665 TI - The association of leptin and C-reactive protein with the cardiovascular risk factors and metabolic syndrome score in Taiwanese adults. AB - BACKGROUND: Serum C-reactive protein (CRP) and leptin levels have been independently associated with the cardiovascular risk factors. The aim of the present study was to determine if their serum levels were associated with cardiovascular risk factors or metabolic syndrome as well as their correlation in the Taiwanese population. METHODS: This retrospective study included 999 subjects (> 18 y), who underwent a physical examination in Chang-Gung Memorial Hospital Linkou and Chiayi in Taiwan. The associations between CRP and/or leptin levels and cardiovascular risk factors and metabolic syndrome were determined using independent two sample t-tests to detect gender differences and chi-square tests to evaluate differences in frequencies. To compare the means of the variables measured among the four groups (high and low leptin and high and low CRP), analysis of variance (ANOVA) was used. RESULTS: Both CRP and leptin levels were independently associated with several cardiovascular risk factors, including diabetes, hypercholesterolemia and metabolic syndrome in both men and women (P < 0.05). In addition, a positive correlation between leptin and CRP levels was observed in both genders. Both high-CRP and high-leptin were associated with high blood glucose, waist circumference and serum triglyceride. Whereas increased metabolic syndrome incidence was observed in males with elevated leptin regardless of CRP levels, females with elevated CRP or leptin had increased incidence of metabolic syndrome. CONCLUSION: Both leptin and CRP levels were associated with cardiovascular risk factors as well as metabolic syndrome score in both men and women although gender-specific differences were observed. Thus, CRP and leptin may represent useful biomarkers for predicting the onset of cardiovascular disease or metabolic syndrome in Taiwanese adults. TRIAL REGISTRATION: IRB/CGMH 100-3514B. PMID- 22533667 TI - A 'learning platform' approach to outcome measurement in fragile X syndrome: a preliminary psychometric study. AB - BACKGROUND: Clinical trials of medications to alleviate the cognitive and behavioural symptoms of individuals with fragile X syndrome (FXS) are now underway. However, there are few reliable, valid and/or sensitive outcome measures available that can be directly administered to individuals with FXS. The majority of assessments employed in clinical trials may be suboptimal for individuals with intellectual disability (ID) because they require face-to-face interaction with an examiner, taxing administration periods, and do not provide reinforcement and/or feedback during the test. We therefore examined the psychometric properties of a new computerised 'learning platform' approach to outcome measurement in FXS. METHOD: A brief computerised test, incorporated into the Discrete Trial Trainer(c)- a commercially available software program designed for children with ID - was administered to 13 girls with FXS, 12 boys with FXS and 15 matched ID controls aged 10 to 23 years (mental age = 4 to 12 years). The software delivered automated contingent access to reinforcement, feedback, token delivery and prompting procedures (if necessary) on each trial to facilitate responding. The primary outcome measure was the participant's learning rate, derived from the participant's cumulative record of correct responses. RESULTS: All participants were able to complete the test and floor effects appeared to be minimal. Learning rates averaged approximately five correct responses per minute, ranging from one to eight correct responses per minute in each group. Test-retest reliability of the learning rates was 0.77 for girls with FXS, 0.90 for boys with FXS and 0.90 for matched ID controls. Concurrent validity with raw scores obtained on the Arithmetic subtest of the Wechsler Intelligence Scale for Children-III was 0.35 for girls with FXS, 0.80 for boys with FXS and 0.56 for matched ID controls. The learning rates were also highly sensitive to change, with effect sizes of 1.21, 0.89 and 1.47 in each group respectively following 15 to 20, 15-min sessions of intensive discrete trial training conducted over 1.5 days. CONCLUSIONS: These results suggest that a learning platform approach to outcome measurement could provide investigators with a reliable, valid and highly sensitive measure to evaluate treatment efficacy, not only for individuals with FXS but also for individuals with other ID. PMID- 22533668 TI - How 'preventable' are lower extremity amputations? A qualitative study of patient perceptions of precipitating factors. AB - PURPOSE: Clinicians commonly believe that lower extremity amputations are potentially preventable with coordinated care and motivated patient self management. We used in-depth interviews with recent amputees to assess how patients viewed their initial amputation risk and causes. METHOD: We interviewed 22 patients at a rehabilitation hospital 2-6 weeks after an incident amputation. We focused on patients' representations of amputation cause and methods of coping with prior foot and leg symptoms. RESULTS: Patients reported unexpected onset and rapid progression of ulceration, infection, progressive vascular disease, foot trauma and complications of comorbid illness as precipitating events. Fateful delays of care were common. Many had long histories of painful prior treatments. A fatalistic approach to self-management, difficulties with access and communication with providers and poor understanding of medical conditions were common themes. Few patients seemed aware of the role of smoking as an amputation risk factor. CONCLUSIONS: Most patients felt out of control and had a poor understanding of the events leading to their initial amputations. Prevention of subsequent amputations will require rehabilitation programs to address low health literacy and psychosocial obstacles to self-management. PMID- 22533669 TI - Frequency of VKORC1 (C1173T) and CYP2C9 genetic polymorphisms in Egyptians and their influence on warfarin maintenance dose: proposal for a new dosing regimen. AB - INTRODUCTION: Warfarin is one of the most widely used anticoagulants, yet interindividual differences in drug response, a narrow therapeutic range and a high risk of bleeding or stroke complicate its use. We aimed to determine the allele and genotype frequency of VKORC1 1173 C>T, CYP2C9*2 and CYP2C9*3 variant polymorphisms in the Egyptian population and to evaluate their influence on the interindividual differences in warfarin dosage. METHODS: A total of 154 unrelated healthy adult patients and 46 warfarin-treated patients were included. SYBR Green based real-time polymerase chain reaction (PCR) assay was used for studying VKORC1 (C1173T) and CYP2C9*3 polymorphisms. Mutagenically separated PCR assay was used to detect the CYP2C9*2 allele. RESULTS: VKORC1 genotype frequencies were 11%, 24% and 65% for CC, CT and TT, respectively. The prevalence of CYP2C9 haplotypes was 81% (*1?*1), 3.3% (*1?*2), 9.7% (*1?*3), 4.5% (*2?*2) and 0.65% (2?*3 and *3?*3). VKORC1 TT and CYP2C9*2?*2 were associated with a significantly lower warfarin dose. VKORC1 and CYP2C9 accounted for 31.7% and 15.6% of warfarin dose variability, respectively, and together with clinical factors explained 61.3% of total variability. CONCLUSION: VKORC1-TT and CYP2C9 *1/*1 are the most prevalent genotypes among Egyptians. Patients with VKORC1-TT genotype required a lower warfarin dose. PMID- 22533670 TI - SIRT3, a pivotal actor in mitochondrial functions: metabolism, cell death and aging. AB - SIRT3 is a member of the sirtuin family of protein deacetylases that is preferentially localized to mitochondria. Prominent among the proteins targeted by SIRT3 are enzymes involved in energy metabolism processes, including the respiratory chain, tricarboxylic acid cycle, fatty acid beta-oxidation and ketogenesis. Through these actions, SIRT3 controls the flow of mitochondrial oxidative pathways and, consequently, the rate of production of reactive oxygen species. In addition, SIRT3-mediated deacetylation activates enzymes responsible for quenching reactive oxygen species, and thereby exerts a profound protective action against oxidative stress-dependent pathologies, such as cardiac hypertrophy and neural degeneration. SIRT3 also plays a role in multiple additional metabolic processes, from acetate metabolism to brown adipose tissue thermogenesis, often by controlling mitochondrial pathways through the deacetylation of target enzymes. In general, SIRT3 activity and subsequent control of enzymes involved in energy metabolism is consistent with an overall role of protecting against age-related diseases. In fact, experimental and genetic evidence has linked SIRT3 activity with increased lifespan. In the coming years, the identification of drugs and nutrients capable of increasing SIRT3 expression or modulating SIRT3 activity can be expected to provide promising strategies for ameliorating the metabolic syndrome and other oxidative stress related diseases that appear preferentially with aging, such as cancer, cardiac dysfunction and neural degeneration. PMID- 22533671 TI - Gibberellin biosynthesis and its regulation. AB - The GAs (gibberellins) comprise a large group of diterpenoid carboxylic acids that are ubiquitous in higher plants, in which certain members function as endogenous growth regulators, promoting organ expansion and developmental changes. These compounds are also produced by some species of lower plants, fungi and bacteria, although, in contrast to higher plants, the function of GAs in these organisms has only recently been investigated and is still unclear. In higher plants, GAs are synthesized by the action of terpene cyclases, cytochrome P450 mono-oxygenases and 2-oxoglutarate-dependent dioxygenases localized, respectively, in plastids, the endomembrane system and the cytosol. The concentration of biologically active GAs at their sites of action is tightly regulated and is moderated by numerous developmental and environmental cues. Recent research has focused on regulatory mechanisms, acting primarily on expression of the genes that encode the dioxygenases involved in biosynthesis and deactivation. The present review discusses the current state of knowledge on GA metabolism with particular emphasis on regulation, including the complex mechanisms for the maintenance of GA homoeostasis. PMID- 22533672 TI - Building a better sphingosine kinase-1 inhibitor. AB - Sphingosine 1-phosphate (S1P) is currently one of the most intensely studied lipid mediators. Interest in S1P has been propelled by the development of fingolimod, an S1P receptor agonist prodrug, which revealed both a theretofore unsuspected role of S1P in lymphocyte trafficking and that such modulation of the immune system achieves therapeutic benefit in multiple sclerosis patients. S1P is synthesized from sphingosine by two SphKs (sphingosine kinases) (SphK1 and SphK2). Manipulation of SphK levels using molecular biology and mouse genetic tools has implicated these enzymes, particularly SphK1, in a variety of pathological processes such as fibrosis, inflammation and cancer progression. The results of such studies have spurred interest in SphK1 as a drug target. In this issue of the Biochemical Journal, Schnute et al. describe a small molecule inhibitor of SphK1 that is both potent and selective. Such chemical tools are essential to learn whether targeting S1P signalling at the level of synthesis is a viable therapeutic strategy. PMID- 22533673 TI - Effects of vegetation cover, presence of a native ant species, and human disturbance on colonization by Argentine ants. AB - The spread of non-native invasive species is affected by human activity, vegetation cover, weather, and interaction with native species. We analyzed data from a 17-year study of the distribution of the non-native Argentine ant (Linepithema humile) and the native winter ant (Prenolepis imparis) in a preserve in northern California (U.S.A.). We conducted logistic regressions and used model selection to determine whether the following variables were associated with changes in the distribution of each species: presence of conspecifics at neighboring sites, distance to development (e.g., roads, buildings, and landscaped areas), proportion of vegetation cover taller than 0.75 m, elevation, distance to water, presence of both species at a site, temperature, and rainfall. Argentine ants colonized unoccupied sites from neighboring sites, but the probability of appearance and persistence decreased as distance to development, vegetation cover, and elevation increased. Winter ants appeared and persisted in sites with relatively high vegetation cover (i.e., highly shaded sites). Presence of the 2 species was negatively associated in sites with high vegetation cover (more winter ants) and sites near development (more Argentine ants). Probability of colonization of Argentine ants decreased where winter ants were most persistent. At sites near development within the preserve, abundant Argentine ant populations may be excluding winter ants. The high abundance of Argentine ants at these sites may be due to immigration from suburban areas outside the preserve, which are high-quality habitat for Argentine ants. In the interior of the preserve, distance from development, low-quality habitat, and interaction with winter ants may in combination exclude Argentine ants. Interactions among the variables we examined were associated with low probabilities of Argentine ant colonization in the preserve. PMID- 22533675 TI - Impacts of silver nanoparticle coating on the nitrification potential of Nitrosomonas europaea. AB - Silver nanoparticles (AgNPs) are increasingly used as bacteriostatic agents to prevent microbial growth. AgNPs are manufactured with a variety of coatings, and their potential impacts on wastewater treatment in general are poorly understood. In the present study, Nitrosomonas europaea, a model ammonia oxidizing bacterium, was exposed to AgNPs with citrate, gum arabic (GA), and polyvinylpyrrolidone (PVP). GA and citrate AgNPs inhibited nitrification most strongly (67.9 +/- 3.6% and 91.4 +/- 0.2%, respectively at 2 ppm). Our data indicate that Ag(+) dissolution and colloid stability of AgNPs were the main factors in AgNP toxicity. In general, low amounts of dissolved Ag initially caused a post transcriptional interruption of membrane-bound nitrifying enzyme function, reducing nitrification by 10% or more. A further increase in dissolved Ag resulted in heavy metal stress response (e.g., merA up-regulation) and ultimately led to membrane disruption. The highest effect on membrane disruption was observed for citrate AgNPs (64 +/- 11% membranes compromised at 2 ppm), which had high colloidal stability. This study demonstrates that coating plays a very important role in determining Ag dissolution and ultimately toxicity to nitrifiers. More research is needed to characterize these parameters in complex growth media such as wastewater. PMID- 22533676 TI - Detection of mitochondrial DNA mutations in nonmuscle invasive bladder cancer. AB - BACKGROUND: Mitochondrial DNA (mtDNA) mutations have been recently described in various tumors; however, data focusing on bladder cancer are scarce. To understand the significance of mtDNA mutations in bladder cancer development, we investigated the mtDNA alterations in bladder cancer cases. METHODS: We studied the mtDNA in 38 bladder tumors and 21 microdissected normal bladder tissue samples. Mitochondrial genes ATPase6, CytB, ND1, and D310 region were amplified by polymerase chain reaction and then sequenced. RESULTS: We detected 40 mutations in our patient population. Our findings indicate that G8697A, G14905A, C15452A, and A15607G mutations are frequent in bladder cancers (p<0.05). In addition, the incidence of A3480G, T4216C, T14798C, and G9055A mutations were higher in patients with bladder tumors. CONCLUSIONS: In conclusion, the high incidence of mtDNA mutations in bladder cancer suggests that mitochondria could play an important role in carcinogenesis and mtDNA could be a valuable marker for early bladder cancer diagnosis. PMID- 22533677 TI - HIV/AIDS knowledge, contraceptive knowledge, and condom use among unmarried youth in China. AB - This study aims to describe HIV/AIDS knowledge, contraceptive knowledge, and their relationships to condom use among unmarried youth in China, especially the mediating effect of consciousness. The first nationally representative survey data on sexual and reproductive health of unmarried Chinese youth was used and analysis was carried out according to the AIDS Risk Reduction Model. Among the sexually active respondents, about 30% had not used a condom during their most recent intercourse. Levels of both types of knowledge were low. HIV/AIDS knowledge was not significantly associated with condom use, even through the mediation of HIV/AIDS consciousness. And, communication about contraception between sexual partners played a key role in the disconnection between HIV/AIDS consciousness and condom use. By contrast, contraceptive knowledge and consciousness exhibited a larger effect on condom use. In conclusion, to increase condom use among unmarried youth in China, interventions and policies should provide more information to help youth build a store of systematic HIV/AIDS knowledge and help them realize the personal vulnerability to HIV/AIDS. Contraceptive knowledge and consciousness are also important factors to promote condom use. Besides, more of an effort should be made to improve youth's skill on communication and negotiation about condom use during sex. These conclusions are also useful to other countries with similar situation with China. PMID- 22533678 TI - Multiple myeloma and its therapies: to what extent do they contribute to the increased incidence of second malignant neoplasms? AB - BACKGROUND: The high risk of another cancer once one has been diagnosed is well known. Furthermore, a clear association exists between the use of some cytotoxic agents and chemotherapy-induced malignancies. METHODS: This review is set to explore the relationship between multiple myeloma, its modern therapies and the development of second cancers due to various genetic, immune, and environmental (including iatrogenic) factors. Most relevant publications were identified through the PubMed database and by reviewing the drug information released by the US Federal Drug Administration. FINDINGS: Our comprehensive analysis identified several retrospective population studies, cohort group analyses and a number of case reports linking myeloma with other cancers in the world literature. A majority of these studies suggest that incidence of second solid and hematologic malignancies is significantly increased in patients with multiple myeloma and its precursor lesion, monoclonal gammopathy of unknown significance. In addition, incidence of second malignancies has been found increased in the family members of these individuals, especially in their first-degree relatives. CONCLUSIONS: Analysis of the existing literature cohorts does not discriminate between the burden of second cancers in treated myeloma patients as opposed to the patients followed with the wait-and-watch approach. Notably, the rate of second malignant neoplasms in multiple myeloma may be further increased by certain myeloma therapies. These cancers include, for the most part, hematologic malignancies such as acute leukemias and certain lymphomas. While there is no question about the role of alkylating agents and topoisomerase II inhibitors in this regard, further research is necessary to determine whether the excess of second cancers represents a direct consequence of lenalidomide use. PMID- 22533679 TI - Epoetin theta: efficacy and safety of subcutaneous administration in anemic pre dialysis patients in the maintenance phase in comparison to epoetin beta. AB - OBJECTIVE: To compare the efficacy and safety of epoetin theta and epoetin beta in anemic patients with chronic kidney disease (CKD) not yet receiving dialysis and previously on stable maintenance therapy with epoetin beta. METHODS: In this multicenter, randomized, controlled, double-blind, non-inferiority study, 288 patients were treated subcutaneously (s.c.) for 24 weeks with epoetin theta (n = 193) or epoetin beta (n = 95). The primary efficacy endpoint was change in hemoglobin (Hb) from a 2-week baseline period to end of treatment (12-week efficacy evaluation period [EEP], weeks 15-26). The non-inferiority limit was 1.0 g/dL (2-sided alpha = 0.05). Weekly doses of epoetin required to maintain Hb levels, dose changes, safety, tolerability, and immunogenicity were also evaluated. CLINICAL TRIAL REGISTRATION: EudraCT No. 2005-000142-37. RESULTS: Mean Hb values were comparable in both groups at baseline and during the 24-week treatment period. The estimated treatment difference between groups from baseline to EEP was 0.01 g/dL (95% confidence interval: -0.20, 0.22; p = 0.9207 (ANCOVA)), indicating that epoetin theta was non-inferior to epoetin beta. The weekly doses of epoetin theta or epoetin beta were nearly the same and the change from baseline to EEP in patients who switched to epoetin theta (36.6 to 30.0 IU/kg(BW)) was comparable to those continuing epoetin beta therapy (37.7 to 28.3 IU/kg(BW)). The profile and the frequency of adverse drug reactions (ADRs) were comparable in both groups (17.1% epoetin theta; 14.7% epoetin beta). The most common ADR was hypertension. No patient developed anti-erythropoietin antibodies. CONCLUSIONS: Epoetin theta (s.c.) has efficacy comparable with epoetin beta (s.c.) in pre-dialysis patients with renal anemia based on Hb changes from baseline to end of treatment (non-inferiority). The safety profile was also comparable. Patients could be switched from maintenance treatment with epoetin beta to epoetin theta without relevant dose changes. PMID- 22533680 TI - Long-term benefits of preventing venous thromboembolic events. AB - BACKGROUND: Venous thromboembolism (VTE) and its long-term secondary complications are major health problems associated with high rates of morbidity and mortality and considerable costs for healthcare systems. Many patients receive suboptimal therapy, despite the availability of established and effective agents (including low molecular weight heparins, unfractionated heparin, fondaparinux and vitamin K antagonists) and evidence-based, internationally recognised guidelines. Limited knowledge of guidelines, concerns about bleeding risks and the inconvenience of parenteral administration and routine coagulation monitoring contribute to non-adherence to guidelines. Newer oral anticoagulants such as rivaroxaban, dabigatran etexilate, apixaban and edoxaban, which do not have the limitations of established anticoagulants, have been developed. METHOD: Phase III randomised controlled trials for the treatment of acute VTE or for secondary prevention of recurrent VTE were identified in the PubMed and ClinicalTrials.gov databases. The search was limited to phase III studies and performed up to 26 March 2012 with the terms 'rivaroxaban OR Xarelto', 'dabigatran OR Pradaxa', 'apixaban OR Eliquis' and 'edoxaban OR DU-176b OR Lixiana'. FINDINGS: A total of ten phase III studies, four published (three rivaroxaban, one dabigatran), three completed with results presented at recent congresses (dabigatran), and three ongoing (two apixaban, one edoxaban) were identified. Published and completed studies showed that rivaroxaban and dabigatran provided effective and convenient short-term treatment for deep vein thrombosis and VTE, respectively, when compared with standard of care, and showed superiority for long-term prevention of recurrent VTE when compared with placebo. Currently, rivaroxaban is the only newer anticoagulant that has been approved in Europe for the treatment of deep vein thrombosis and prevention of recurrent VTE. CONCLUSIONS: Based on results of completed trials, rivaroxaban and dabigatran both may reduce the incidence of secondary complications of VTE and associated socioeconomic costs. Introduction of these newer anticoagulants is likely to have a substantial impact on clinical practice. PMID- 22533682 TI - Differential effects of microorganism-invertebrate interactions on benthic nitrogen cycling. AB - Infaunal invertebrate activity can fundamentally alter physicochemical conditions in sediments and influence nutrient cycling. However, despite clear links between invertebrate activity and microbially mediated processes such as nitrification, the mechanisms by which bioturbating macrofauna affect microbial communities have received little attention. This study provides strong evidence for differential stimulation of microbial nitrogen transformations by three functionally contrasting species of macrofauna (Hediste diversicolor, Corophium volutator, Hydrobia ulvae). Despite increased nitrification, abundance of ammonia-oxidising bacteria (AOB) and ammonia-oxidising archaea (AOA) at the sediment-water interface did not significantly change in the presence of macrofauna. However, species-specific differences in macrofaunal activity did influence ammonia oxidiser community structure, increasing AOB abundance relative to AOA in the presence of C. volutator or H. ulvae, but with no change in H. diversicolor and no-macrofauna treatments. Denaturing gradient gel electrophoresis profiles were similar between macrofaunal treatments, although one AOB band increased in relative intensity in the presence of C. volutator, decreased in the H. diversicolor treatment and was unchanged in the H. ulvae treatment. These data suggest that links between bioturbating macrofauna and nutrient cycling are not expressed through changes in the abundance of ammonia oxidisers in surface sediments, but are associated with changes in the AOA : AOB ratio depending on the invertebrate species. PMID- 22533683 TI - Chemotherapy-induced neuropathic pain and its relation to cluster symptoms in breast cancer patients treated with paclitaxel. AB - The majority of patients with breast cancer receiving chemotherapy report multiple symptoms. Compelling evidence has shown that subgroups of patients can be clustered by the severity of symptoms. Recent studies demonstrate that chemotherapy with such substances as paclitaxel can cause neuropathic pain (CINP) and consequently neural damage. OBJECTIVES: the present study examined the relationship between symptom clusters and CINP among 40 patients with breast cancer. The study was based on 2 sessions conducted before and during paclitaxel treatment. In each session, neuropathic pain was assessed by the DN4 Questionnaire. In the second session, the Lee Fatigue Scale, the General Sleep Disturbance Scale, and the Center for Epidemiological Studies-Depression Scale were also administered, and the worst pain intensity was assessed. Using cluster analysis, 2 symptom clusters were identified on the basis of the severity of the 4 symptoms scores. Patients in the High Cluster (37%) experienced a high level of all symptoms, whereas patients in the Low Cluster (63%) experienced a low level of all symptoms. Twenty patients (50%) were diagnosed with CINP. A subgroup of patients (23%) from the High Cluster was identified as having CINP; 35% were in the Low Cluster and free of CINP. In conclusion, there appears to be a specific subgroup of patients with hypersensitive cancer who need greater attention to symptom management. Early detection of symptoms, together with careful dose selection and assessment of early stages in the development of neuropathic pain, are essential for preventing the simultaneous occurrence of severe multiple symptoms and CINP. PMID- 22533681 TI - Halofuginone inhibits multiple myeloma growth in vitro and in vivo and enhances cytotoxicity of conventional and novel agents. AB - Multiple Myeloma (MM), a malignancy of plasma cells, remains incurable despite the use of conventional and novel therapies. Halofuginone (HF), a synthetic derivative of quinazolinone alkaloid, has recently been shown to have anti-cancer activity in various preclinical settings. This study demonstrated the anti-tumour activity of HF against a panel of human MM cell lines and primary patient-derived MM cells, regardless of their sensitivity to conventional therapy or novel agents. HF showed anti-MM activity in vivo using a myeloma xenograft mouse model. HF suppressed proliferation of myeloma cells alone and when co-cultured with bone marrow stromal cells. Similarly, HF induced apoptosis in MM cells even in the presence of insulin-like growth factor 1 or interleukin 6. Importantly, HF, even at high doses, did not induce cytotoxicity against CD40 activated peripheral blood mononuclear cells from normal donors. HF treatment induced accumulation of cells in the G(0) /G(1) cell cycle and induction of apoptotic cell death associated with depletion of mitochondrial membrane potential; cleavage of poly (ADP-ribose) polymerase and caspases-3, 8 and 9 as well as down-regulation of anti-apoptotic proteins including Mcl-1 and X-IAP. Multiplex analysis of phosphorylation of diverse components of signalling cascades revealed that HF induced changes in P38MAPK activation; increased phosphorylation of c-jun, c-jun NH(2)-terminal kinase (JNK), p53 and Hsp-27. Importantly, HF triggered synergistic cytotoxicity in combination with lenalidomide, melphalan, dexamethasone, and doxorubicin. Taken together, these preclinical studies provide the preclinical framework for future clinical studies of HF in MM. PMID- 22533684 TI - Adverse childhood experiences are associated with migraine and vascular biomarkers. AB - OBJECTIVES: Migraine is a risk factor for stroke in young women. Biomarker studies implicate endothelial activation as a possible mechanism. Emerging relationships of childhood adversity with migraine, and with inflammation, a component of endothelial activation, suggest that it may play a role in the migraine-stroke association. Our objective is to evaluate the relationship between adverse childhood experiences (ACEs), migraine, and vascular biomarker levels in premenopausal women. METHODS: Vascular and metabolic biomarkers from women 18-50 years, including 125 with migraine (interictal) and 50 without migraine, were evaluated. An ACE questionnaire was later collected by mail (response rate 80.6%, 100 migraineurs, 41 controls). RESULTS: Migraineurs and controls were demographically similar. Migraineurs reported adversity more commonly than controls (71% vs 46%, odds ratio [OR] = 1.53, 95% confidence interval 1.07-2.17). Average ACE scores were elevated in migraineurs as compared with controls (2.4 vs 0.76, P < .001). ACE scores correlated with headache frequency (0.37, P = .001) and younger age of headache onset (-0.22, P = .04). It also correlated with body mass index (r = 0.43, P = .0001), von Willebrand factor activity (r = 0.21, P = .009), tissue plasminogen activator antigen (r = 0.28, P = .004), prothrombin activation fragment (r = 0.36, P = .001), high-sensitivity C reactive protein (r = 0.98, P = .0001), transforming growth factor-beta1 (r = 0.28, P = .003), tissue necrosis factor-alpha (r = 0.20, P = .03), interleukin-6 (r = 0.22, P = .03), adiponectin (r = -0.29, P = .003), and nitrate/nitrite concentration (r = -314, P = .001). Logistic regression analyses (adjusted for vascular risk factors and migraine) demonstrated an association of childhood adversity with inflammatory factors (high-sensitivity C-reactive protein, interleukin-6, and tissue necrosis factor-alpha). CONCLUSIONS: In young women, adverse childhood events are associated with migraine, particularly chronic and transformed migraine, and with vascular biomarkers, especially inflammatory biomarkers. These findings implicate early life stress as a link between migraine and endothelial activation. PMID- 22533686 TI - Light emission in silicon from carbon nanotubes. AB - The use of optics in microelectronic circuits to overcome the limitation of metallic interconnects is more and more considered as a viable solution. Among future silicon compatible materials, carbon nanotubes are promising candidates thanks to their ability to emit, modulate, and detect light in the wavelength range of silicon transparency. We report the first integration of carbon nanotubes with silicon waveguides, successfully coupling their emission and absorption properties. A complete study of this coupling between carbon nanotubes and silicon waveguides was carried out, which led to the demonstration of the temperature-independent emission from carbon nanotubes in silicon at a wavelength of 1.3 MUm. This represents the first milestone in the development of photonics based on carbon nanotubes on silicon. PMID- 22533685 TI - Uncoupling protein 2 gene polymorphisms are associated with obesity. AB - BACKGROUND: Uncoupling protein 2 (UCP2) gene polymorphisms have been reported as genetic risk factors for obesity and type 2 diabetes mellitus (T2DM). We examined the association of commonly observed UCP2 G(-866)A (rs659366) and Ala55Val (C > T) (rs660339) single nucleotide polymorphisms (SNPs) with obesity, high fasting plasma glucose, and serum lipids in a Balinese population. METHODS: A total of 603 participants (278 urban and 325 rural subjects) were recruited from Bali Island, Indonesia. Fasting plasma glucose (FPG), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) were measured. Obesity was determined based on WHO classifications for adult Asians. Participants were genotyped for G(-866)A and Ala55Val polymorphisms of the UCP2 gene. RESULTS: Obesity prevalence was higher in urban subjects (51%) as compared to rural subjects (23%). The genotype, minor allele (MAF), and heterozygosity frequencies were similar between urban and rural subjects for both SNPs. All genotype frequencies were in Hardy-Weinberg equilibrium. A combined analysis of genotypes and environment revealed that the urban subjects carrying the A/A genotype of the G(-866)A SNP have higher BMI than the rural subjects with the same genotype. Since the two SNPs showed strong linkage disequilibrium (D' = 0.946, r2 = 0.657), a haplotype analysis was performed. We found that the AT haplotype was associated with high BMI only when the urban environment was taken into account. CONCLUSIONS: We have demonstrated the importance of environmental settings in studying the influence of the common UCP2 gene polymorphisms in the development of obesity in a Balinese population. PMID- 22533688 TI - An evaluation of the quality of statistical design and analysis of published medical research: results from a systematic survey of general orthopaedic journals. AB - BACKGROUND: The application of statistics in reported research in trauma and orthopaedic surgery has become ever more important and complex. Despite the extensive use of statistical analysis, it is still a subject which is often not conceptually well understood, resulting in clear methodological flaws and inadequate reporting in many papers. METHODS: A detailed statistical survey sampled 100 representative orthopaedic papers using a validated questionnaire that assessed the quality of the trial design and statistical analysis methods. RESULTS: The survey found evidence of failings in study design, statistical methodology and presentation of the results. Overall, in 17% (95% confidence interval; 10-26%) of the studies investigated the conclusions were not clearly justified by the results, in 39% (30-49%) of studies a different analysis should have been undertaken and in 17% (10-26%) a different analysis could have made a difference to the overall conclusions. CONCLUSION: It is only by an improved dialogue between statistician, clinician, reviewer and journal editor that the failings in design methodology and analysis highlighted by this survey can be addressed. PMID- 22533689 TI - Description of HLA-A*33:49 in a Spanish cord blood unit. AB - A*33:49 has one nucleotide change regarding A*33:01:01 at exon 3, producing an amino acid replacement at codon 97, M97 to I97. PMID- 22533690 TI - Using land to mitigate climate change: hitting the target, recognizing the trade offs. AB - Land can be used in several ways to mitigate climate change, but especially under changing environmental conditions there may be implications for food prices. Using an integrated global system model, we explore the roles that these land-use options can play in a global mitigation strategy to stabilize Earth's average temperature within 2 degrees C of the preindustrial level and their impacts on agriculture. We show that an ambitious global Energy-Only climate policy that includes biofuels would likely not achieve the 2 degrees C target. A thought experiment where the world ideally prices land carbon fluxes combined with biofuels (Energy+Land policy) gets the world much closer. Land could become a large net carbon sink of about 178 Pg C over the 21st century with price incentives in the Energy+Land scenario. With land carbon pricing but without biofuels (a No-Biofuel scenario) the carbon sink is nearly identical to the case with biofuels, but emissions from energy are somewhat higher, thereby results in more warming. Absent such incentives, land is either a much smaller net carbon sink (+37 Pg C - Energy-Only policy) or a net source (-21 Pg C - No-Policy). The significant trade-off with this integrated land-use approach is that prices for agricultural products rise substantially because of mitigation costs borne by the sector and higher land prices. Share of income spent on food for wealthier regions continues to fall, but for the poorest regions, higher food prices lead to a rising share of income spent on food. PMID- 22533691 TI - Analyzing disease risks associated with translocations. AB - Translocations of species are expected to be used increasingly to counter the undesirable effects of anthropogenic changes to ecosystems, including loss of species. Methods to assess the risk of disease associated with translocations have been compiled in a comprehensive manual of disease-risk analysis for movement of domestic animals. We used this manual to devise a qualitative method for assessing the probability of the occurrence of disease in wild animals associated with translocations. We adapted the method such that we considered a parasite (any agent of infectious or noninfectious disease) a hazard if it or the host had crossed an ecological or geographical barrier and was novel to the host. We included in our analyses hazards present throughout the translocation pathway derived from the interactions between host immunity and the parasite, the effect of parasites on populations, the effect of noninfectious disease agents, and the effect of stressors on host-parasite interactions. We used the reintroduction of Eurasian Cranes (Grus grus) to England to demonstrate our method. Of the 24 hazards identified, 1 was classified as high risk (coccidia) and 5 were medium risk (highly pathogenic avian influenza virus, Mycobacterium avium, Aspergillus fumigatus, tracheal worms [Syngamus sp. and Cyathostoma sp.], and Tetrameres spp.). Seventeen other hazards were considered low or very low risk. In the absence of better information on the number, identity, distribution, and pathogenicity of parasites of wild animals, there is uncertainty in the risk of disease to translocated animals and recipient populations. Surveys of parasites in source and destination populations and detailed health monitoring after release will improve the information available for future analyses of disease risk. We believe our method can be adapted to assess the risks of disease in other translocated populations. PMID- 22533692 TI - Sex differences in adherence to highly active antiretroviral therapy: a meta analysis. AB - Observational studies have found that women tend to have lower adherence to highly active antiretroviral therapy (HAART) than men do, though no meta-analysis has yet investigated this trend. The aims of the current meta-analysis are to determine if and to what degree the percentage of men versus women maintaining >=90% adherence to prescribed HAART differs, and if the external variables moderating adherence differs by gender. Eight electronic databases were searched to locate all relevant studies available by May 2011. Fifty-six observational studies were eligible for inclusion in the meta-analysis. A random effect model was assumed for the global percentage estimation and to explain the heterogeneity. Across these studies, the difference between men and women in the proportion of individuals with >=90% adherence to HAART was marginally significant (p<0.1; 67% and 62%, respectively). A greater proportion of men maintaining >=90% adherence to HAART was more likely in studies with higher proportions of men who have sex with men (MSM), lower proportions of male alcohol users or lower proportions of men in a methadone program. In women, higher rates of adherence were found in studies conducted in Africa, Asia, and South America, when the sample included more widows or when the sample had a lower basal CD4 count. That both the percentage of adherent individuals and the variables associated with such adherence differ between men and women are suggestive of the need for improving gender-tailored interventions for adherence to HAART. PMID- 22533693 TI - Family functioning in families with a child with Down syndrome: a mixed methods approach. AB - BACKGROUND: This study aimed to explore the factors that predict functioning in families with a child with Down syndrome using a mixed methods design. The quantitative component examined the effect of maladaptive and autism-spectrum behaviours on the functioning of the family while the qualitative component explored the impact of having a child with Down syndrome on family holidays, family activities and general family functioning. METHODS: Participants in this study were 224 primary caregivers of children with Down syndrome aged 4-25 years (57.1% male; 42.9% female) currently residing in Western Australia (74.0% in metropolitan Perth and 26.0% in rural Western Australia). RESULTS: Maladaptive and autism-spectrum behaviour were associated with poorer family functioning. Mean total scores on the measures of family functioning and marital adjustment were comparable to that of families of typically developing children. Consistent with the quantitative findings, normality was the most common theme to emerge in the qualitative data. Child problem behaviours were also identified by parents/carers as having a negative impact on the family. CONCLUSIONS: This study has implications for the development of programs to support families with a child with Down syndrome and may dispel some of the myths surrounding the impact of intellectual disability on the family. PMID- 22533694 TI - The challenges of incorporating genetic testing in the unified national health system in Brazil. AB - Genetic diseases and congenital anomalies are the second most common cause of infant mortality in Brazil. In 2009, the Ministry of Health established the National Policy for Integral Attention in Clinical Genetics in the Brazilian Unified National Health System (UNHS). This policy is not yet regulated, and there is a fear that, in the name of the comprehensiveness of health care, genetic testing might be carried out without due care and criteria, increasing costs to the UNHS. Currently, only a small population has access to genetic testing, through teaching hospitals or private health care. The biggest challenge in Brazil, in this area, is to be able to set the right standards and assessment processes about clinical utility, testing priorities, dispersal of resources, and distribution of skilled professionals. Expanding access to users of the Brazilian UNHS will mean mining the technical, social, and ethical aspects about medical genetics services. PMID- 22533695 TI - The nurse education imperative. PMID- 22533696 TI - Postsimulation: use of wikis for designing care plans. PMID- 22533697 TI - Candidate gene polymorphisms and the risk for pregnancy-related venous thrombosis. AB - Venous thrombosis (VT) is one of the leading causes of maternal death in the western world, but the genetic causes of pregnancy-related VT are insufficiently understood. The aim of this study was to investigate the association between common genetic variations in candidate genes and pregnancy-related VT. We undertook a hospital based case-control study of women with VT during pregnancy or puerperium; controls were women giving birth without having VT. Single nucleotide polymorphisms (SNPs) were selected in 49 pre-specified candidate genes involved in coagulation, inflammation, and hormonal metabolism in 313 cases and 353 controls. We found new associations between SNPs and total pregnancy-related VT in the genes encoding coagulation factors V and VIII, and p-selectin. Additional new associations between SNPs and antenatal VT were found in the genes encoding the epidermal growth factor receptor, the pregnane X receptor, and protein S. Of 21 SNPs previously associated with thrombotic disease, rs2289252 in F11 and rs3917643 in F3 were associated with pregnancy-related VT, while rs4524 in F5 was associated with antenatal VT. PMID- 22533698 TI - (Val-)Ganciclovir prophylaxis reduces Epstein-Barr virus primary infection in pediatric renal transplantation. AB - Epstein-Barr virus (EBV) primary infection constitutes a serious risk for pediatric transplant recipients, particularly as regards the development of EBV related post-transplant lymphoproliferative disease (PTLD). Currently, there is no established prophylactic regimen. We investigated the association between chemoprophylaxis with valganciclovir (VGCV) or ganciclovir (GCV) and the incidence of EBV viremia in EBV-naive pediatric renal transplant recipients (R-) who had received a graft from an EBV-positive donor (D+) and are therefore at high risk of EBV primary infection. In a prospective, multicenter trial (n = 114), we compared a cohort on chemoprophylaxis (n = 20) with a similar control cohort without chemoprophylaxis (n = 8). Over the 1-year study period, antiviral prophylaxis with VGCV/GCV was associated with a significantly decreased incidence of EBV primary infection: 9/20 patients (45%) in the prophylaxis group experienced an EBV primary infection compared to 8/8 controls (100%) (P < 0.0001). Chemoprophylaxis was associated with a significantly lower EBV viral load (P < 0.001). Type or intensity of immunosuppressive therapy did not influence the occurrence of EBV primary infection or the level/persistence of EBV viral load. Chemoprophylaxis with VGCV/GCV is associated with a reduced incidence of EBV viremia in high-risk pediatric kidney allograft recipients in the first year post-transplant. (ClinicalTrials.gov number: NCT00963248). PMID- 22533699 TI - The multi-faceted nature of HLA class I dimer molecules. AB - The canonical role of major histocompatibility complex class I (MHCI) molecules in antigen presentation involves the recognition of a short peptide of intracellular origin, bound to the upper surface of the class I molecule, by CD8(+) T lymphocytes. Assembly and loading of the MHCI is a highly regulated, chaperone-mediated process and only when the fully folded MHCI molecule is correctly loaded with peptide is it released from the endoplasmic reticulum for trafficking to the cell surface. Current models of the interactions of MHCI molecules with their cognate receptors visualize them functioning as monomeric entities. However, in recent years, new data have revealed MHCI molecules with the ability to form disulphide-linked dimeric structures, with several distinct dimer entities being elucidated. We describe here three types of MHCI dimers; HLA B27 dimers formed predominantly through the possession of an unpaired cysteine within the peptide-binding groove; HLA-G dimers, which form through a cysteine on its external surface; and a novel population we term redox-induced dimers, which can form between cysteine residues in the cytoplasmic tail domains. The characteristics of these dimeric MHCI molecules and their role in both normal immune responses and in disease pathogenesis are reviewed in this article. PMID- 22533700 TI - Electronic impurity doping in CdSe nanocrystals. AB - We dope CdSe nanocrystals with Ag impurities and investigate their optical and electrical properties. Doping leads not only to dramatic changes but surprising complexity. The addition of just a few Ag atoms per nanocrystal causes a large enhancement in the fluorescence, reaching efficiencies comparable to core-shell nanocrystals. While Ag was expected to be a substitutional acceptor, nonmonotonic trends in the fluorescence and Fermi level suggest that Ag changes from an interstitial (n-type) to a substitutional (p-type) impurity with increased doping. PMID- 22533701 TI - Parents of children with and without intellectual disability: couple relationship and individual well-being. AB - BACKGROUND: Research on parents of children with intellectual disability (ID) has identified a range of risk and protective factors for parental well-being. In family research, the association between marital quality and depression is a vital field of investigation. Still little research has addressed how aspects of the couple relationship affect the adaptation of parents of children with ID. The present study examined predictive links between couple relationship factors (marital quality and coparenting quality) and individual well-being. METHODS: Data were obtained through self-report questionnaires completed by parents of children with ID (mothers, n = 58; and fathers, n = 46) and control children (mothers, n = 178; and fathers, n = 141). To test the hypothesis that couple relationship factors predicted individual well-being, multiple regression analyses were performed controlling for the following risk factors identified by previous research: child self-injury/stereotypic behaviour, parenting stress, and economic risk. RESULTS: Marital quality predicted concurrent well-being, and coparenting quality predicted prospective well-being. Mothers of children with ID reported lower well-being than other parents. CONCLUSIONS: There is a continued need for investigation of the details of the links between couple relationship and individual well-being in parents of children with ID. Couple relationship factors should be given consideration in clinical interventions. PMID- 22533702 TI - Western mental health training for traditional Chinese medicine practitioners. AB - OBJECTIVE: To investigate the impact of a Western mental health training course for Traditional Chinese Medicine (TCM) practitioners. METHOD: A combined qualitative and quantitative approach was applied to examine the changes in the TCM practitioners' clinical practice characteristics and attitudes. Focus groups and structured questionnaire surveys were conducted to compare their responses before and after the Course. RESULTS: After a 10-week training course conducted by psychiatrists and family physicians, there were significant changes in confidence of the TCM practitioners for diagnosis (33% being confident before the Course vs. 76% after the Course) and management (24% vs. 55%) of common mental health problems. The causal effects of better classifications to recognition of mental health problems were explained by the qualitative responses. Proportion of TCM practitioners being confident of referring mental health patients to other healthcare professionals doubled from 25% to 50% after the Course. Nonetheless, there was no significant change in percentage of these patients being recommended to Western doctors owing to a lack of formal referral channel. CONCLUSIONS: Western mental health training for TCM practitioners has positive impact on their clinical practice. However, the practical barriers in making referrals highlight the need of closer collaboration between conventional and traditional medicine. PMID- 22533703 TI - Polymer-like conformation and growth kinetics of Bi2S3 nanowires. AB - One-dimensional inorganic crystals (i.e., crystalline nanowires) are one of the most intensely investigated classes of materials of the past two decades. Despite this intense effort, an important question has yet to be answered: do nanowires display some of the unique characteristics of polymers as their diameter is progressively decreased? This work addresses this question with three remarkable findings on the growth and form of ultrathin Bi(2)S(3) nanowires. (i) Their crystallization in solution is quantitatively describable as a form of living step-growth polymerization: an apparently exclusive combination of addition of "monomer" to the ends of the nanowires and coupling of fully formed nanowires "end-to-end", with negligible termination and initiation. (ii) The rate constants of these two main processes are comparable to those of analogous processes found in polymerization. (iii) The conformation of these nanowires is quantitatively described as a worm-like conformation analytically analogous to that of semiflexible polymers and characterized by a persistence length of 17.5 nm (shorter than that of double-stranded DNA) and contour lengths of hundreds of micrometers (longer than those of most synthetic polymers). These findings do not prove a chemical analogy between crystals and polymers (it is unclear if the monomer is a molecular entity tout court) but demonstrate a physical analogy between crystallization and polymerization. Specifically, they (i) show that the crystallization of ensembles of nanoscale inorganic crystals can be conceptually analogous to polymerization and can be described quantitatively with the same experimental and mathematical tools, (ii) demonstrate that one-dimensional nanocrystals can display topological characteristics of polymers (e.g., worm-like conformation in solution), (iii) establish a unique experimental model system for the investigation of polymer-like topological properties in inorganic crystals, and (iv) provide new heuristic guidelines for the synthesis of polymer-like nanowires. PMID- 22533704 TI - Fluorinated and pegylated polyaspartamide derivatives to increase solubility and efficacy of Flutamide. AB - New fluorinated amphiphilic copolymers based on a biocompatible polyaspartamide have been prepared in order to obtain polymeric micelles useful for delivering anticancer drugs. In particular, alpha,beta-poly(N-2-hydroxyethyl)-d,l aspartamide (PHEA) has been derivatized with polyethylene glycol (PEG(2000)) and ethylendiamine (EDA). Both these portions form the hydrophilic part of the copolymer, while the hydrophobic moiety is given by 1,2,4-oxadiazoles: 5 pentafluorophenyl-3-perfluoroheptyl-1,2,4-oxadiazole (PPOX) or 3-carboxyethyl-5 pentadecafluoroheptyl-1,2,4-oxadiazole (CPOX). Copolymers named PHEA-PEG(2000) EDA-PPOX and PHEA-PEG(2000)-EDA-CPOX have been prepared with various degrees of derivatization and characterized by spectroscopic analyses. Size exclusion chromatography, pyrene colorimetric assay, light scattering analysis and scanning electron microscopy have evidenced the occurrence of a self-association process in aqueous medium. The ability of these aggregates to incorporate a hydrophobic drug and increase its solubility has been evaluated by using Flutamide, a fluorinated anticancer agent. Moreover, the activity of Flutamide-loaded micelles on proliferation of dihydrotestosterone stimulated LNCaP cells has been determined and compared to that of free drug. PMID- 22533705 TI - Non-physician providers of obstetric care in Mexico: Perspectives of physicians, obstetric nurses and professional midwives. AB - BACKGROUND: In Mexico 87% of births are attended by physicians. However, the decline in the national maternal mortality rate has been slower than expected. The Mexican Ministry of Health's 2009 strategy to reduce maternal mortality gives a role to two non-physician models that meet criteria for skilled attendants: obstetric nurses and professional midwives. This study compares and contrasts these two provider types with the medical model, analyzing perspectives on their respective training, scope of practice, and also their perception and/or experiences with integration into the public system as skilled birth attendants. METHODOLOGY: This paper synthesizes qualitative research that was obtained as a component of the quantitative and qualitative study that evaluated three models of obstetric care: professional midwives (PM), obstetric nurses (ON) and general physicians (GP). A total of 27 individual interviews using a semi-structured guide were carried out with PMs, ONs, GPs and specialists. Interviews were transcribed following the principles of grounded theory, codes and categories were created as they emerged from the data. We analyzed data in ATLAS.ti. RESULTS: All provider types interviewed expressed confidence in their professional training and acknowledge that both professional midwives and obstetric nurses have the necessary skills and knowledge to care for women during normal pregnancy and childbirth. The three types of providers recognize limits to their practice, namely in the area of managing complications.We found differences in how each type of practitioner perceived the concept and process of birth and their role in this process. The barriers to incorporation as a model to attend birth faced by PMs and ONs are at the individual, hospital and system level. GPs question their ability and training to handle deliveries, in particular those that become complicated, and the professional midwifery model particularly as it relates to a clinical setting, is also questioned. CONCLUSIONS: Hospitals in the Mexican public health sector have a heavy obstetric workload; physicians carry the additional burden of non-obstetric cases. The incorporation of a non- physician model at the primary health center level to attend low-risk, normal deliveries would contribute to the reduction of non-necessary referrals. There is also a role for these providers at the hospital level. PMID- 22533706 TI - Effect of multiple adduct fullerenes on microstructure and phase behavior of P3HT:fullerene blend films for organic solar cells. AB - The bis and tris adducts of [6,6]phenyl-C(61)-butyric acid methyl ester (PCBM) offer lower reduction potentials than PCBM and are therefore expected to offer larger open-circuit voltages and more efficient energy conversion when blended with conjugated polymers in photovoltaic devices in place of PCBM. However, poor photovoltaic device performances are commonly observed when PCBM is replaced with higher-adduct fullerenes. In this work, we use transmission electron microscopy (TEM), steady-state and ultrafast time-resolved photoluminescence spectroscopy (PL), and differential scanning calorimetry (DSC) to probe the microstructural properties of blend films of poly(3-hexylthiophene-2,5-diyl) (P3HT) with the bis and tris adducts of PCBM. TEM and PL indicate that, in as-spun blend films, fullerenes become less soluble in P3HT as the number of adducts increases. PL indicates that upon annealing crystallization leads to phase separation in P3HT:PCBM samples only. DSC studies indicate that the interactions between P3HT and the fullerene become weaker with higher-adduct fullerenes and that all systems exhibit eutectic phase behavior with a eutectic composition being shifted to higher molar fullerene content for higher-adduct fullerenes. We propose two different mechanisms of microstructure development for PCBM and higher-adduct fullerenes. P3HT:PCBM blends, phase segregation is the result of crystallization of either one or both components and is facilitated by thermal treatments. In contrast, for blends containing higher adducts, the phase separation is due to a partial demixing of the amorphous phases. We rationalize the lower photocurrent generation by the higher-adduct fullerene blends in terms of film microstructure. PMID- 22533707 TI - The value of repetitive sequences in chloroplast DNA for phylogeographic inference: a comment on Vachon & Freeland 2011. AB - In a recent Technical Advance article, Vachon and Freeland (2011, Molecular Ecology Resources, 11, 279-285.) evaluate the utility of repetitive and non repetitive variation in the chloroplast genome for phylogeographic inference, using variation in Phragmites australis as an example. While we agree that repetitive and nonrepetitive regions evolve at different rates and homoplasy can impact results, we disagree with the conclusion that repetitive regions are inappropriate for large-scale phylogeographic studies. Here we describe limitations to the study dataset and analysis, and provide an alternative viewpoint on the utility of repetitive regions for phylogeographic studies. PMID- 22533708 TI - Influence of plant polyphenols and medicinal plant extracts on antibiotic susceptibility of Escherichia coli. AB - AIMS: To investigate the influence of polyphenols and plant extracts on the susceptibility of Escherichia coli to antibiotics. METHODS AND RESULTS: Susceptibility of E. coli to antibiotics in the presence of extracts and polyphenols was estimated by the determination of the minimum inhibitory concentrations (MICs). To study gene expression, we used strains of E. coli carrying fusions between promoters of genes katG, sodA, iucC and structural beta galactosidase gene. Treatment with polyphenols and some plant extracts significantly decreased the antibacterial effects of antibiotics, to a larger extent, ciprofloxacin. The most remarkable protective effect was observed for the extracts of Chamerion (Epilobium) angustifolium, Filipendula vulgaris, Tanacetum vulgare and Serratula coronata. These extracts increased the MICs of ciprofloxacin by four and more times. In case of kanamycin, extracts of Artemisia austriaca and Artemisia pontica increased MICs by four and eight times, respectively. Polyphenol quercetin also caused protective effect against ciprofloxacin, increasing the MIC by four times. A positive correlation was found between protective effects of polyphenols and extracts and their antioxidant activity. CONCLUSION: Medicinal plant extracts and polyphenols may protect cells of E. coli against antibiotic toxicity. SIGNIFICANCE AND IMPACT OF THE STUDY: The results of this study may be used to enhance the efficiency of antibacterial therapies. PMID- 22533709 TI - The CTGF gene -945 G/C polymorphism is not associated with cardiac or kidney complications in subjects with type 2 diabetes. AB - BACKGROUND: Connective tissue growth factor (CTGF) has been implicated in the cardiac and kidney complications of type 2 diabetes, and the CTGF -945 G/C polymorphism is associated with susceptibility to systemic sclerosis, a disease characterised by tissue fibrosis. This study investigated the association of the CTGF -945 G/C promoter variant with cardiac complications (left ventricular (LV) hypertrophy (LVH), diastolic and systolic dysfunction) and chronic kidney disease (CKD) in type 2 diabetes. METHODS: The CTGF -945 G/C polymorphism (rs6918698) was examined in 495 Caucasian subjects with type 2 diabetes. Cardiac structure and function were assessed by transthoracic echocardiography. Kidney function was assessed using estimated glomerular filtration rate (eGFR) and albuminuria, and CKD defined as the presence of kidney damage (decreased kidney function (eGFR <60 ml/min/1.73 m2) or albuminuria). RESULTS: The mean age +/- SD of the cohort was 62 +/- 14 years, with a body mass index (BMI) of 31 +/- 6 kg/m2 and median diabetes duration of 11 years [25th, 75th interquartile range; 5, 18]. An abnormal echocardiogram was present in 73% of subjects; of these, 8% had LVH alone, 74% had diastolic dysfunction and 18% had systolic +/- diastolic dysfunction. CKD was present in 42% of subjects. There were no significant associations between the CTGF -945 G/C polymorphism and echocardiographic parameters of LV mass or cardiac function, or kidney function both before and after adjustment for covariates of age, gender, BMI, blood pressure and hypertension. CTGF -945 genotypes were not associated with the cardiac complications of LVH, diastolic or systolic dysfunction, nor with CKD. CONCLUSIONS: In Caucasians with type 2 diabetes, genetic variation in the CTGF 945 G/C polymorphism is not associated with cardiac or kidney complications. PMID- 22533710 TI - Proactive and integrated primary care for frail older people: design and methodological challenges of the Utrecht primary care PROactive frailty intervention trial (U-PROFIT). AB - BACKGROUND: Currently, primary care for frail older people is reactive, time consuming and does not meet patients' needs. A transition is needed towards proactive and integrated care, so that daily functioning and a good quality of life can be preserved. To work towards these goals, two interventions were developed to enhance the care of frail older patients in general practice: a screening and monitoring intervention using routine healthcare data (U-PRIM) and a nurse-led multidisciplinary intervention program (U-CARE). The U-PROFIT trial was designed to evaluate the effectiveness of these interventions. The aim of this paper is to describe the U-PROFIT trial design and to discuss methodological issues and challenges. METHODS/DESIGN: The effectiveness of U-PRIM and U-CARE is being tested in a three-armed, cluster randomized trial in 58 general practices in the Netherlands, with approximately 5000 elderly individuals expected to participate. The primary outcome is the effect on activities of daily living as measured with the Katz ADL index. Secondary outcomes are quality of life, mortality, nursing home admission, emergency department and out-of-hours General Practice (GP), surgery visits, and caregiver burden. DISCUSSION: In a large, pragmatic trial conducted in daily clinical practice with frail older patients, several challenges and methodological issues will occur. Recruitment and retention of patients and feasibility of the interventions are important issues. To enable broad generalizability of results, careful choices of the design and outcome measures are required. Taking this into account, the U-PROFIT trial aims to provide robust evidence for a structured and integrated approach to provide care for frail older people in primary care. TRIAL REGISTRATION: NTR2288. PMID- 22533711 TI - ABCC8 polymorphisms are associated with triglyceride concentration in type 2 diabetics on sulfonylurea therapy. AB - BACKGROUND: The failure of therapy with oral hypoglycemic drugs leads to not only poorly regulated glycemic status, but also dyslipidemia and increased body weight and body mass index (BMI). Sulfonylureas act as insulin secretagogues by binding to the sulfonylurea receptor (SUR-1) encoded by the gene ABCC8. The aim of this study was to explore whether there is an association of ABCC8 polymorphisms SUR1 exon 16 (-3C/T), SUR-1 exon 31 (Arg1273Arg), and SUR-1 exon 33 (S1369A) with lipid concentration and BMI in type 2 diabetics on sulfonylurea therapy. MATERIALS AND METHODS: This study included 251 unrelated type 2 diabetics on sulfonylurea therapy. Height and weight were measured for BMI calculation. All polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism methods. Lipid concentrations and BMI were measured at inclusion into the study and after 6 months of follow-up. RESULTS: Wild-type allele carriers for the SUR-1 exon 31 polymorphism (Arg1273Arg) had a significantly higher triglyceride (TG) concentration when compared with the carriers of two variant alleles (p=0.023). Polymorphic allele carriers of the SUR 1 exon 16 (-3C/T) polymorphism were more frequent in the subgroup of patients with the TG concentration increase after 6 months (p for genotype and allelic differences: 0.024 and 0.015, respectively). CONCLUSION: ABCC8 polymorphisms in exon 16 and 31 are associated with the TG concentration in type 2 diabetics on sulfonylurea therapy. PMID- 22533712 TI - Vacuum cup placement during delivery--a suggested obstetric quality assessment measure. AB - OBJECTIVE: To establish standards for the deviation of vacuum cup placement from the ideal location during operative delivery in an academic center. METHODS: Data on 92 vacuum deliveries were prospectively obtained. The actual point on the newborns head was determined and both midline and anterior-posterior line deviations from the ideal point of placement were calculated. RESULTS: The most common indication for vacuum extraction was a nonreassuring fetal heart rate (66.7%). The average deviation on the mid anterior-posterior line was 3.72 +/- 1.46 cm; the average midline-lateral deviation was 1.92 +/- 1.33 cm. There was no statistically significant difference in the cup placement deviations between deliveries performed by residents and consultants. The vacuum procedure failed in 8.6% of the cases. CONCLUSIONS: Accurate placement of the vacuum cup on the fetal head is considered to be clinically important. This assumption requires scientific clinical proof. Our local standard for deviation was established and will serve for audit. If safer neonatal and maternal outcomes are demonstrated, the deviation from the ideal placement location ought to become a universal quality measure for vacuum deliveries. PMID- 22533714 TI - Detecting suboptimal cognitive effort: classification accuracy of the Conner's Continuous Performance Test-II, Brief Test Of Attention, and Trail Making Test. AB - Many cognitive measures have been studied for their ability to detect suboptimal cognitive effort; however, attention measures have not been extensively researched. The current study evaluated the classification accuracy of commonly used attention/concentration measures, the Brief Test of Attention (BTA), Trail Making Test (TMT), and the Conners' Continuous Performance Test (CPT-II). Participants included 413 consecutive patients who completed a comprehensive neuropsychological evaluation. Participants were separated into two groups, identified as either unbiased responders or biased responders as determined by performance on the TOMM. Based on Mann-Whitney U results, the two groups differed significantly on all attentional measures. Classification accuracy of the BTA (.83), CPT-II omission errors (OE; .76) and TMT B (.75) were acceptable; however, classification accuracy of CPT-II commission errors (CE; .64) and TMT A (.62) were poor. When variables were combined in different combinations, sensitivity did not significantly increase. Results indicated for optimal cut-off scores, sensitivity ranged from 48% to 64% when specificity was at least 85%. Given that sensitivity rates were not adequate, there remains a need to utilize highly sensitive measures in addition to these embedded measures. Results were discussed within the context of research promoting the need for multiple measures of cognitive effort. PMID- 22533713 TI - Specific psychiatric correlates of acute care utilization among unstably housed HIV-positive adults. AB - The role of specific psychiatric diagnoses in emergency department use and/or inpatient hospitalizations (acute care) has not been extensively examined among HIV-infected, unstably housed persons. A community-recruited sample of 284 HIV infected, unstably housed adults completed the Diagnostic Interview Schedule for DSM-IV. One-third of participants screened positive for major depression and stimulant use disorders. Sleeping on the street [adjusted odds ratio (AOR) = 4.21], major depression (AOR = 2.88) and stimulant use disorders (AOR = 4.45) were associated with greater odds of acute care use. Housing and effective treatment of depression and stimulant use disorders may decrease use of acute care services in this population. PMID- 22533716 TI - Acanthomatous ameloblastoma masquerading as a squamous cell carcinoma. PMID- 22533715 TI - Haematopoietic stem cell transplantation (HSCT) in severe autoimmune diseases: analysis of UK outcomes from the British Society of Blood and Marrow Transplantation (BSBMT) data registry 1997-2009. AB - The British Society of Blood and Marrow Transplantation Data Registry was used to analyse outcomes of haematopoietic stem cell transplantation (HSCT) in severe autoimmune diseases (SADs) from 1997 to 2009. 55 autologous and 15 allogeneic HSCT were registered (0.22% of overall UK HSCT activity). Sustained responses were observed following HSCT, although toxicity was significant. This is the first reported national analysis of long-term outcomes of HSCT in SADs, and should be viewed in the context of translational and developmental phases of HSCT in poor prognosis and refractory SADs. Treatment of poor-risk but reversible SADs with adequate fitness for HSCT in accordance with current guidelines is warranted. PMID- 22533717 TI - Gold nanoparticles coated with semi-fluorinated oligo(ethylene glycol) produce sub-100 nm nanoparticle vesicles without templates. AB - Gold nanoparticles (NPs) with diameters of 5, 10, and 20 nm coated with semifluorinated oligo(ethylene glycol) ligands were formed into sub-100 nm hollow NP assemblies (NP vesicles) in THF without the use of a template. The NP vesicles maintained their structure even after the solvent was changed from THF to other solvents such as butanol or CH(2)Cl(2). NMR analyses indicated that the fluorinated ligands are bundled on the NPs and that the solvophobic feature of the fluorinated bundles is the driving force for NP assembly. The formed NP vesicles were surface-enhanced Raman scattering-active capsules. PMID- 22533719 TI - Plasmonic planet-satellite analogues: hierarchical self-assembly of gold nanostructures. AB - In the past few years, a remarkable progress has been made in unveiling novel and unique optical properties of strongly coupled plasmonic nanostructures, known as plasmonic molecules. However, realization of such plasmonic molecules using nonlithographic approaches remains challenging largely due to the lack of facile and robust assembly methods. Previous attempts to achieve plasmonic nanoassemblies using molecular ligands were limited to dipolar assembly of nanostructures, which typically results in polydisperse linear and branched chains. Here, we demonstrate that core-satellite structures comprised of shape controlled plasmonic nanostructures can be achieved through self-assembly using simple molecular cross-linkers. Prevention of self-conjugation and promotion of cross-conjugation among cores and satellites plays a key role in the formation of core-satellite heteroassemblies. The in-built electromagnetic hot-spots and Raman reporters of core-satellite structures make them excellent candidates for surface enhanced Raman scattering probes. PMID- 22533718 TI - Cyclosporin A and tacrolimus reduce T-cell polyfunctionality but not interferon gamma responses directed at cytomegalovirus. AB - Cytomegalovirus (CMV) -specific immunity is often estimated by the number of in vitro CMV antigen-inducible interferon-gamma-positive (IFN-gamma(+) ) T cells. However, recent work indicates that simultaneous production of IFN-gamma, tumour necrosis factor-alpha (TNF-alpha) and interleukin-2 (IL-2) (referred to as 'polyfunctionality') is more relevant for anti-viral protection. Here, we compared polyfunctionality of CMV-specific T cells (pp65 and IE-1 proteins) in 23 solid-organ transplant patients and seven healthy controls by flow cytometry. The proportions of TNF-alpha(+) /IFN-gamma(+) /IL-2 cells among the activated cells were significantly reduced in transplant patients but not the frequencies of IFN gamma(+) CD8(+) T cells. Immunosuppression reduces polyfunctionality, which reflects the increased infection risk in this patient group. PMID- 22533720 TI - Work experiences among nurses and physicians in the beginning of their professional careers - analyses using the effort-reward imbalance model. AB - The aim of the study was to scrutinise how nurses and physicians, employed by the county councils in Sweden, assess their work environment in terms of effort and reward at the start of their career. The aim was also to estimate associations between work satisfaction and the potential outcomes from the effort-reward imbalance (ERI) questionnaire. The study group, 198 nurses and 242 physicians who graduated in 1999, is a subsample drawn from a national cross-sectional survey. Data were collected in the third year after graduation among the nurses and in the fourth year after graduation among registered physicians. The effort-reward imbalance questionnaire, together with a question on work satisfaction, was used to evaluate psychosocial factors at work. The results reveal that nurses scored higher on effort, lower on reward and experienced higher effort-reward imbalance, compared with physicians. Women scored higher on work-related overcommitment (WOC) compared with men. Among the physicians, logistic regression analysis revealed a statistically significant association between WOC and ERI, sex, effort and reward. Logistic regression analysis also revealed a statistically significant association between WOC and ERI and between WOC and effort among the nurses. Dissatisfaction with work was significantly higher among those who scored worst on all three ERI subscales (effort, reward and WOC) and also among those with the highest ERI ratios compared with the other respondents. In conclusion, to prevent future work-related health problems and work dissatisfaction among nurses and physicians in the beginning of their professional careers, signs of poor psychosocial working conditions have to been taken seriously. In future work related stress research among healthcare personnel, gender-specific aspects of working conditions must be further highlighted to develop more gender-sensitive analyses. PMID- 22533722 TI - Reanalysis of methamphetamine dependence treatment trial. PMID- 22533723 TI - AQP4 knockout aggravates ischemia/reperfusion injury in mice. AB - BACKGROUND AND PURPOSE: The glial water channel aquaporin-4 (AQP4) has been shown to be involved in a wide range of brain disorders. Although its important role in stroke has already been documented, the underlying mechanism was not clarified yet. Therefore, this study was designed to investigate the impacts of AQP4 deletion in ischemia/reperfusion (I/R). METHODS AND RESULTS: Herein we found a higher mortality and more severe neurological deficits in AQP4 knockout (AQP4(-/ )) mice after transient middle cerebral artery occlusion while no difference was observed in water content variation during I/R between two genotypes except a higher basal water content developed in AQP4(-/-) mouse brain, implying the same increment of water content over a higher basal level may provoke an even more elevated intracranial pressure, which might be an important cause of increased mortality in AQP4(-/-) mice. Moreover, AQP4 knockout aggravated I/R injury with enlarged infarct size and a more serious loss of CA1 neurons accompanied by a striking hypertrophy of astrocytes, suggesting an involvement of AQP4 in astrocytic dysfunction. CONCLUSIONS: Our findings provide direct evidence that AQP4 plays a crucial role in the pathogenesis of I/R injury, which may confer a new option for stroke treatment. PMID- 22533724 TI - Kallikrein gene transfer induces angiogenesis and further improves regional cerebral blood flow in the early period after cerebral ischemia/reperfusion in rats. AB - AIMS: The aims of this study were to find out whether kallikrein could induce angiogenesis and affect the cerebral blood flow (rCBF) in the early period after cerebral ischemia/reperfusion (CI/R). METHODS: The adenovirus carried human tissue kallikrein (HTK) gene was administrated into the periinfarction region after CI/R. At 12, 24, and 72 h after treatments, neurological deficits were evaluated; expression of HTK and vascular endothelial growth factor (VEGF) were detected by immunohistochemistry staining; the infarction volume was measured; and rCBF was examined by( 14) C-iodoantipyrine microtracing technique. RESULTS: The expression of VEGF was enhanced significantly in pAdCMV-HTK group than controls over all time points (P < 0.05). Furthermore, the rCBF in pAdCMV-HTK group increased markedly than controls at 24 and 72 h after treatment (P < 0.05), and the improved neurological deficit was accompanied by reduced infarction volume in pAdCMV-HTK group 24 and 72 h posttreatment. CONCLUSION: In the early period after CI/R, kallikrein could induce the angiogenesis and improve rCBF in periinfarction region, and further reduce the infarction volume and improve the neurological deficits. PMID- 22533725 TI - Effect of nisoldipine and olmesartan on endothelium-dependent vasodilation in essential hypertensive patients. AB - AIMS: To investigate whether nisoldipine and olmesartan improve endothelial function, decrease asymmetric dimethylarginine (ADMA) and alleviate the inflammatory and oxidative process. METHODS: Fifty-five essential hypertensive patients were randomized to receive nisoldipine or olmesartan for 8 weeks according to a parallel-group, active-controlled, single blind study, and 28 matched normotensive subjects served as healthy controls. Flow-mediated dilation (FMD), and plasma levels of nitric oxide (NO), endothelin-1 (ET-1), high sensitive C-reactive protein (hs-CRP), 8-isoprostane (also named 8-isoPGF2alpha), and ADMA were determined. RESULTS: At baseline, the plasma levels of ADMA, ET-1, hs-CRP, and 8-isoPGF2alpha were markedly higher in patients with essential hypertension than in normotensive subjects (P < 0.05). A significant positive correlation was observed between plasma levels of ET-1 and ADMA in patients with essential hypertension, but not in normotensive subjects. The NO plasma concentrations were significantly lower in patients with essential hypertension than in normotensive subjects. Furthermore, hypertensive subjects demonstrated significantly lower FMD than healthy control (P < 0.05). Nisoldipine and olmesartan significantly and similarly reduced blood pressure in patients with essential hypertension (P < 0.001). At the end of the 8-week treatment, plasma ADMA and ET-1 levels were decreased significantly (P < 0.01). FMD increased significantly in nisoldipine or olmesartan-treated patients (P < 0.05). A significant decrease in plasma hs-CRP contents was observed in patients receiving nisoldipine (P < 0.05). CONCLUSION: The findings demonstrate that nisoldipine and olmesartan both improve FMD in patients with essential hypertension. This may be associated with decreased circulating levels of CRP, ET-1, and ADMA. PMID- 22533726 TI - Combination of low-dose bupivacaine and opioids provides satisfactory analgesia with less intraoperative hypotension for spinal anesthesia in cesarean section. AB - AIMS: This meta-analysis was undertaken to compare the three most common drug regimens of bupivacaine in spinal anesthesia for cesarean section: high-dose bupivacaine (>=10 mg, HB), low-dose bupivacaine (<10 mg, LB) and combination of low-dose bupivacaine and opioids (LBO). METHODS: Databases of MEDLINE, EMBASE, and Cochrane Library were searched (updated on October 30, 2011). Primary endpoints were the incidence of intraoperative hypotension and analgesia efficacy. Pooled risk ratio (RR) or standard mean difference and their 95% confidence intervals (95% CI) were calculated. A RR <1 indicates that LB or LBO regimen is associated with less intraoperative complications and better anesthesia or analgesia efficacy. RESULTS: A total of 11 randomized controlled trials including 605 parturients were analyzed. Results of this meta-analysis showed that compared with HB regimen, LB regimen decreased the incidence of intraoperative hypotension (RR = 0.64, 95% CI: 0.42-0.96) with less satisfactory analgesia (fixed model, RR = 1.50, 95% CI: 1.14-1.98). LBO regimen significantly reduced the incidence of intraoperative hypotension (RR = 0.52, 95% CI: 0.33 0.82) with reliable analgesia efficacy (RR = 2.56, 95% CI: 0.77-8.48). CONCLUSION: Compared with conventional HB regimen and LB regimen, LBO regimen not only reduced intraoperative hypotension but also provided reliable analgesia. Therefore, LBO regimen should be considered as the preferred drug combination for spinal anesthesia in cesarean section. PMID- 22533727 TI - Safety and efficacy of stent-supported thrombolysis in acute ischemic stroke. PMID- 22533728 TI - Tanshinones increase fibrinolysis through inhibition of plasminogen activator inhibitor-1. PMID- 22533729 TI - Infection with Wolbachia protects mosquitoes against Plasmodium-induced mortality in a natural system. AB - In recent years, there has been a shift in the one host-one parasite paradigm with the realization that, in the field, most hosts are coinfected with multiple parasites. Coinfections are particularly relevant when the host is a vector of diseases, because multiple infections can have drastic consequences for parasite transmission at both the ecological and evolutionary timescales. Wolbachia pipientis is the most common parasitic microorganism in insects, and as such, it is of special interest for understanding the role of coinfections in the outcome of parasite infections. Here, we investigate whether Wolbachia can modulate the effect of Plasmodium on what is, arguably, the most important component of the vectorial capacity of mosquitoes: their longevity. For this purpose, and in contrast to recent studies that have focused on mosquito-Plasmodium and/or mosquito-Wolbachia combinations not found in nature, we work on a Wolbachia mosquito-Plasmodium triad with a common evolutionary history. Our results show that Wolbachia protects mosquitoes from Plasmodium-induced mortality. The results are consistent across two different strains of Wolbachia and repeatable across two different experimental blocks. To our knowledge, this is the first time that such an effect has been shown for Plasmodium-infected mosquitoes and, in particular, in a natural Wolbachia-host combination. We discuss different mechanistic and evolutionary explanations for these results as well as their consequences for Plasmodium transmission. PMID- 22533731 TI - Dynamic analysis of Th1/Th2 cytokine concentration during antiretroviral therapy of HIV-1/HCV co-infected patients. AB - BACKGROUND: Co-infection with hepatitis C (HCV) is very common in human immunodeficiency virus 1 (HIV-1) infected patients. Although HIV co-infection clearly accelerates progression of HCV-related fibrosis and liver disease, controversy remains as to the impact of HCV on HIV disease progression in co infected patients. HIV can cause immune dysfunction, in which the regulatory function of T helper (Th) cells is very essential. Moreover, cytokines derived from Th cells play a prominent role in viral infection. Investigating the functional changes of Th1 and Th2 cells in cytokine level can improve the understanding of the effect of co-infected HCV on HIV infection. METHODS: In this study, we measured the baseline Th1/Th2 cytokine concentration in sera by using flow cytometry in HIV/HCV co-infection, HIV mono-infection, HCV mono-infection, and healthy control group, as well as the dynamic changes of these cytokine levels after receiving highly active antiretroviral therapy (HAART). RESULTS: The ratio of Th1 and Th2 cytokine concentration in HIV/HCV co-infection was higher than HCV mono-infection and healthy control group, while lower than HIV mono infection group. After HAART was initiated, the Th1/Th2 ratio of HIV/HCV co infection group decreased to the same level of healthy control, while HIV mono infection group was still higher than the control group. CONCLUSIONS: There was no significant evidence showing co-infected with HCV had negative effect on HIV related diseases. However, co-infected with HCV can decrease Th1/Th2 ratio by affecting Th1 cytokine level, especially the secretion of IFN-gamma. With the initiation of HAART, Th1 and Th2 cytokine levels were progressively reduced. HIV was the main stimulating factor of T cells in HIV/HCV co-infection group. PMID- 22533732 TI - Molecular architecture: construction of self-assembled organophosphonate duplexes and their electrochemical characterization. AB - Self-assembled monolayers of phosphonates (SAMPs) of 11-hydroxyundecylphosphonic acid, 2,6-diphosphonoanthracene, 9,10-diphenyl-2,6-diphosphonoanthracene, and 10,10'-diphosphono-9,9'-bianthracene and a novel self-assembled organophosphonate duplex ensemble were synthesized on nanometer-thick SiO(2)-coated, highly doped silicon electrodes. The duplex ensemble was synthesized by first treating the SAMP prepared from an aromatic diphosphonic acid to form a titanium complex terminated one; this was followed by addition of a second equivalent of the aromatic diphosphonic acid. SAMP homogeneity, roughness, and thickness were evaluated by AFM; SAMP film thickness and the structural contributions of each unit in the duplex were measured by X-ray reflection (XRR). The duplex was compared with the aliphatic and aromatic monolayer SAMPs to determine the effect of stacking on electrochemical properties; these were measured by impedance spectroscopy using aqueous electrolytes in the frequency range 20 Hz to 100 kHz, and data were analyzed using resistance-capacitance network based equivalent circuits. For the 11-hydroxyundecylphosphonate SAMP, C(SAMP) = 2.6 +/- 0.2 MUF/cm(2), consistent with its measured layer thickness (ca. 1.1 nm). For the anthracene-based SAMPs, C(SAMP) = 6-10 MUF/cm(2), which is attributed primarily to a higher effective dielectric constant for the aromatic moieties (epsilon = 5 10) compared to the aliphatic one; impedance spectroscopy measured the additional capacitance of the second aromatic monolayer in the duplex (2ndSAMP) to be C(Ti/2ndSAMP) = 6.8 +/- 0.7 MUF/cm(2), in series with the first. PMID- 22533733 TI - Survey for asymptomatic malaria cases in low transmission settings of Iran under elimination programme. AB - BACKGROUND: In malaria endemic areas, continuous exposure to Plasmodium parasites leads to asymptomatic carriers that provide a fundamental reservoir of parasites, contributing to the persistence of malaria transmission. Therefore, in the present investigation, the presence and prevalence of malaria asymptomatic cases were determined to evaluate the reservoir of infection in two malaria endemic areas with a previous history of malaria transmission in the south of Iran, Bashagard and Ghale-Ganj districts of Hormozgan and Kerman provinces, respectively, where malaria transmission has been drastically reduced in the recent years. METHODS: The population samples (n = 500 from each of the studied areas) were randomly collected from non-febrile, long-term residing, aged two to over 60 years, during 20092010. Three identical surveys were carried out in both study areas and in each phase all the consent participants were interviewed and clinically examined. In all, three surveys to detect hidden parasite reservoirs (both Plasmodium falciparum and Plasmodium vivax), thick and thin blood smears and a highly sensitive nested-PCR were applied. In addition, the sero-prevalence survey for detecting malaria exposure was done by using a serological marker. RESULTS: In this study, P. vivax and P. falciparum parasites were not detected by light microscopy and nested-PCR assay in all three surveys of samples. Antibody responses against P. vivax and P. falciparum were detected in 1% and 0.2% of the total examined individuals, respectively, in Bashagard district. Regarding to Ghale-Ganj district, about 0.9% of the individuals had IgG -specific antibody to P. vivax at the first and second surveys, but at the third survey 0.45% of the participants had positive antibody to P. vivax parasite. IgG -specific antibody to P. falciparum was detected in 0.2% of the participants at the first and follow up surveys. The overall regional differences were not statistically significant (P > 0.05). CONCLUSION: Taken together, the lack of asymptomatic carrier with the evidence of extremely low sero-positive to both P. vivax and P. falciparum among examined individuals supported the limited recent transmission in the studied areas and, therefore, these parts of Iran have potential to eliminate the disease in the next few years. However, continued follow up and action are still needed in both studied areas and also in their neighbouring province, Sistan and Baluchistan, which has the highest reported cases of malaria in Iran and also, has the largest border line with Afghanistan and Pakistan, with no elimination activities. This data will provide useful information for managing elimination activities in Iran. PMID- 22533735 TI - Structural imaging techniques in schizophrenia. AB - OBJECTIVE: The aim of this overview study is to translate the technical terminology regarding structural Magnetic Resonance Imaging (sMRI) post processing analysis into a clinical clear description. METHOD: We resumed and explained the most popular post-processing methods for structural MRI (sMRI) data applied in psychiatry and their main contributions to the comprehension of the biological basis of schizophrenia. RESULTS: The region-of-interest (ROI) technique allows to investigate specific brain region size by manual tracing; it is anatomically precise and requires a priori hypothesis, but also it is time consuming and operator-dependent. The voxel-based morphometry (VBM) detects gray matter density across the whole brain by comparing voxel to voxel; it is operator independent, does not require a priori hypothesis, and is relatively fast; however, it is limited by multiple comparisons and poor anatomical definition. Finally, computational neuroanatomical analyses have recently been applied to automatically discriminate subjects with schizophrenia from healthy subjects on the basis of MRI images. CONCLUSION: Structural MRI represents a useful tool in understanding the biological underpinnings of schizophrenia and in planning focused interventions, thus assisting clinicians especially in the early phases of the illness. PMID- 22533734 TI - Ribosomal protein l13a as a reference gene for human bone marrow-derived mesenchymal stromal cells during expansion, adipo-, chondro-, and osteogenesis. AB - In the field of human mesenchymal stromal cell (MSC) research, quantitative real time reverse transcription-polymerase chain reaction (qPCR) is the method of choice to study changes in gene expression patterns upon differentiation, application of stimuli, or of factors such as inhibitors or siRNAs. To reliably detect small changes, the use of a reference gene (RG) that is stably expressed under all conditions is essential. The large number of different RGs used in the field and the lack of validation of their suitability make the comparison between studies impossible. Therefore, this work aims to establish one single RG for mesodermal differentiation studies that use MSCs. Seven commonly used RGs (glyceraldehyde-3-phosphate dehydrogenase [GAPDH], ribosomal protein L13a [RPL13a], beta-actin [ACTB], tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta-polypeptide [YWHAZ], eukaryotic translational elongation factor 1 alpha [EF1alpha], beta2-microglobulin [B2M], and 18S ribosomal RNA [18S]) were investigated concerning their mRNA expression stability during expansion of bone marrow-derived MSCs up to four passages as well as during their adipo-, chondro-, and osteogenenic differentiation on days 9, 16, and 22 after induction. RPL13a was validated for qPCR studies of MSCs (bone marrow- and placenta-derived) and, additionally, for primary human bone cells (HBCs) and the osteosarcoma cell line MG-63. GAPDH and ACTB, the two most frequently used RGs, showed the highest expression variance. The superior performance of RPL13a should make it the RG of choice for all MSC studies addressing mesodermal differentiation. PMID- 22533736 TI - Antiretroviral therapy (ART) adherence and correlates to nonadherence among people on ART in Estonia. AB - There are little data on antiretroviral therapy (ART) adherence among patients in Eastern Europe, despite the high incidence of HIV infection and the growing number of HIV-infected individuals who are being prescribed ART. The aim of this study was to measure rates of adherence to ART and factors associated with nonadherence among patients receiving care at an outpatient HIV clinic in Estonia. The study was based on cross-sectional data from a convenience sample of 144 patients receiving outpatient HIV care. Data were obtained via interviewer administered surveys and data abstraction from clinical records. Adherence was measured from a 3-day patient self-report. Among 144 participants (mean age 33.8 years), two-thirds (63%) had been infected with HIV through intravenous drug use. Most (74%) were co-infected with hepatitis C (HCV). Perfect adherence over the last 3 days was commonly reported (88% [95% CI 81-92%]) with nonperfect adherence associated with greater concerns about the potential adverse consequences of taking ART (adjusted odds ratio [AOR] 4.8, 95% CI 1.2-34.0) and average (versus good/very good) self-reported health status (AOR 4.7, 95% CI 1.2-31.4). Self reported ART adherence in this sample of Estonian HIV-positive patients in clinical care was similar to rates observed in Western Europe and other developed countries. Results suggest that adherence education and support may be most helpful if they specifically target the development of positive beliefs, reduction of negative expectancies towards ART. PMID- 22533737 TI - CCR5 inhibitors: emergence, success, and challenges. AB - INTRODUCTION: The discovery of CC-chemokine receptor 5 (CCR5) as a human immunodeficiency virus type 1 (HIV-1) coreceptor opened a new avenue to exploit CCR5 as a potential target for the intervention of HIV-1's cellular entry. AREAS COVERED: Various small-molecule CCR5 inhibitors were identified in the last decade; however, maraviroc (MVC) is the only CCR5 inhibitor currently used in the clinic. Concerns and challenges that exist for wider clinical use of CCR5 inhibitors are discussed. EXPERT OPINION: Although MVC-containing regimens have been recommended for treatment-naive patients, MVC appears to have been used as one of drugs for salvage therapy rather than for treating drug-naive patients. This is apparently due to MVC's twice-daily dosing schedule. Another significant disadvantage is that a costly tropism assay must be performed prior to MVC treatment. The access to inexpensive, sensitive, and rapid tropism tests should be made easily available. Only a few novel CCR5 inhibitors are presently in the pipeline. Development of potent and metabolically-stable novel CCR5 inhibitors allowing once-daily dosing regimens is needed. Development of CXCR4 inhibitors should greatly improve the treatment options available to patients infected with X4- and/or dual-tropic HIV-1 strains in combination with a CCR5 inhibitor. PMID- 22533738 TI - Skp2 expression unfavorably impacts survival in resectable esophageal squamous cell carcinoma. AB - BACKGROUND: The correlation of S-phase kinase-associated protein 2 (Skp2) with metastasis and prognosis in esophageal squamous cell carcinoma (ESCC) is controversial. The purpose of this study was to explore whether there was a correlation between the expression of Skp2 evaluated by immunohistochemistry and the clinical outcome of patients with operable ESCC, and to further determine the possible mechanism of the impact of Skp2 on survival. METHODS: Tissue microarrays that included 157 surgically resected ESCC specimens was successfully generated for immunohistochemical evaluation. The clinical/prognostic significance of Skp2 expression was analyzed. Kaplan-Meier analysis was used to compare the postoperative survival between groups. The prognostic impact of clinicopathologic variables and Skp2 expression was evaluated using a Cox proportional hazards model. A cell proliferation assay and a colony formation assay were performed in ESCC cell lines to determine the function of Skp2 on the progression of ESCC in vitro. RESULTS: Skp2 expression correlated closely with the T category (p = 0.035) and the pathological tumor-node-metastasis (TNM) stage (p = 0.027). High expression of Skp2 was associated with poor overall survival in resectable ESCC (p = 0.01). The multivariate Cox regression analysis demonstrated that pathological T category, pathological N category, cell differentiation, and negative Skp2 expression were independent factors for better overall survival. In vitro assays of ESCC cell lines demonstrated that Skp2 promoted the proliferative and colony-forming capacity of ESCCs. CONCLUSIONS: Negative Skp2 expression in primary resected ESCC is an independent factor for better survival. Skp2 may play a pro-proliferative role in ESCC cells. PMID- 22533739 TI - The risk status, screening history and health concerns of Aboriginal and Torres Strait Islander people attending an Aboriginal Community Controlled Health Service. AB - INTRODUCTION AND AIMS: Primary health-care services need to maximise prevention activities to improve the health of Aboriginal and Torres Strait Islander people. This study determined Aboriginal and Torres Strait Islander people's risk status and screening history for cardiovascular, diabetes and cancer, and identified opportunities for prevention based on patient's health concerns. DESIGN AND METHODS: Consenting adult patients attending an Aboriginal Community Controlled Health Service completed interview surveys. Outcome measures were: patient's self reported rates of smoking, at-risk alcohol consumption, body mass index and screening rates for cholesterol, diabetes, blood pressure, cervical and breast cancer, the proportion of patients with multiple risk factors and health information patients prioritise to receive from their doctor. RESULTS: We surveyed 587 patients giving a consent rate of 77%. Patient's self-reported being at risk due to smoking (51%), harmful alcohol consumption in both short term (10%) and long term (10%), and overweight (28%) and obese (49%) body mass index. The proportion of patients who had not been screened within the recommended guidelines was 27% for cholesterol, 24% for diabetes, 40% for blood pressure, 47% for cervical cancer and 54% for breast cancer. The majority (73%) of patients had multiple risk factors. Patients prioritised receiving health information on diabetes (45%), weight (43%) and heart disease (43%). DISCUSSION AND CONCLUSIONS: Many patients were at high risk, and were concerned about the health risks they experience. Strategies are needed to help clinic staff identify risks, and maximise prevention activities according to best-practice guidelines, particularly to patients who experience multiple risk factors. PMID- 22533740 TI - Outcome disparities in multiple myeloma: a SEER-based comparative analysis of ethnic subgroups. AB - Studies of ethnic disparities in malignancies have revealed variation in clinical outcomes. In multiple myeloma (MM), previous literature has focused only on patients of Caucasian and African-American (AA) descent. We present a Surveillance Epidemiology and End Results (SEER)-based outcome analysis of MM patients from a broader range of ethnicities, representing current United States demographics. The SEER 17 Registry data was utilized to analyse adult MM patients diagnosed since 1992 (n = 37,963), as patients of other ethnicities were not well represented prior to that. Overall survival (OS) and myeloma-specific survival (MSS) were compared across different ethnicities stratified by year of diagnosis, registry identification, age, sex and marital-status. Hispanics had the youngest median age at diagnosis (65 years) and Whites had the oldest (71 years) (P < 0.001). Increased age at diagnosis was an independent predictor of decreased OS and MSS. Asians had the best median OS (2.7 years) and MSS (4.1 years), while Hispanics had the worst median OS (2.4 years). These trends were more pronounced in patients >= 75 years. Cumulative survival benefit over successive years was largest among Whites (1.3 years) and smallest among Asians (0.5 years). These disparities may be secondary to multifactorial causes that need to be explored and should be considered for optimal triaging of healthcare resources. PMID- 22533741 TI - On how nucleus-endplate integration is achieved at the fibrillar level in the ovine lumbar disc. AB - The intervertebral disc nucleus has traditionally been viewed as a largely unstructured amorphous gel having little obvious integration with the cartilaginous endplates (CEPs). However, recent work by the present authors has provided clear evidence of structural cohesion across the nucleus-endplate junction via a distinctive microanatomical feature termed insertion nodes. The aim of this study was to explore the nature of these insertion nodes at the fibrillar level. Specially prepared vertebra-nucleus-vertebra composite samples from ovine lumbar motion segments were extended axially and chemically fixed in this stretched state, and then decalcified. Sections taken from the samples were prepared for examination by scanning electron microscopy. A close morphological correlation was obtained between previously published optical microscopic images of the nodes and those seen using low magnification SEM. Progressively high magnifications provided insight into the fibrillar-level modes of structural integration across the nucleus-endplate junction. The closely packed fibrils of the CEP were largely parallel to the vertebral endplate and formed a dense, multi layer substrate within which the nodal fibrils appeared to be anchored. Our idealised structural model proposes a mechanism by which this integration is achieved. The nodal fibrils, in curving into the CEP, are locked in place within its close-packed layers of transversely aligned fibrils, and probably at multiple levels. Secondly, there appears to be a subtle interweaving of the strongly aligned nodal fibrils with the multi-directional endplate fibrils. It is suggested that this structural integration provides the nucleus with a form of tethered mobility that supports physiological functions quite distinct from the primary strength requirements of the disc. PMID- 22533743 TI - Proceedings of the Endoscopy Forum Japan 2011. Preface. PMID- 22533742 TI - Evaluation of four protocols for the detection and isolation of thermophilic Campylobacter from different matrices. AB - AIMS: To identify the optimal method for detection of thermophilic Campylobacter at various stages in the food chain, three culture-dependent (direct plating, Bolton and Preston enrichment) and one molecular method (qPCR) were compared for three matrices: poultry faeces (n = 38), neck skin (n = 38) and packed fresh meat (n = 38). METHODS AND RESULTS: Direct plating was compared to enrichment with either Bolton broth (ISO 10272:2006-1) or Preston broth, followed by culture on two selective agars: modified charcoal cefoperazone desoxycholate agar (mCCDA) and Campyfood agar (CFA). Direct plating on CFA provided the highest number of positive samples for faeces and neck skin samples. Enrichment of meat samples in Preston followed by plating on mCCDA gave significantly higher number of positives than the recommended ISO method. Real-time qPCR yielded the highest number of positive samples. CONCLUSION: Direct plating on CFA is optimal for Campylobacter isolation from highly contaminated samples such as faeces or neck skin. When enrichment is required for less-contaminated samples such as poultry meat, Preston broth is the best choice. The maximum of detectable cells predicted by qPCR is a sensitive and powerful evaluation tool. SIGNIFICANCE AND IMPACT OF THE STUDY: The recommended ISO protocol had the least sensitivity, and application of this method could result in underreporting. We detected a high prevalence of Campylobacter on packed meat to be distributed, which suggests this is still a significant risk for consumers. PMID- 22533744 TI - The 2011 Great East Japan earthquake: a report of a regional hospital in Fukushima Prefecture coping with the Fukushima nuclear disaster. AB - A catastrophic undersea megathrust earthquake of magnitude 9.0 off the coast of Japan occurred at 14:46 JST on Friday, 11 March 2011. The earthquake triggered powerful tsunami waves, and the tsunami precipitated Fukushima nuclear accidents. After the terrible earthquake, many people fled from the nuclear accident and arrived at places far from the nuclear power plant. In this article, I present a story of one measure devised to deal with the problem of the Fukushima nuclear accident at a regional hospital of Fukushima prefecture, Aizu General Hospital, which is located far from the Fukushima nuclear plant. In addition, I briefly report the current situation of Fukushima prefecture after the 2011 Great East Japan earthquake. In our hospital, the countermeasure headquarters was established to supply medical care for those who had been injured by tsunami waves and the Fukushima nuclear accident. Especially, the screening for radioactive exposure using a dosimeter to take decontamination measures for cases of external exposure was extremely important task. Nevertheless, because the accurate knowledge related to radioactive contamination didn't provide, most medical staff fell into confusion. Fukushima prefecture has been 'shrinking' since the nuclear accident. However, today, although some hot spots remain in residential areas, the radioactive contamination is decreasing little by little. Many people in Fukushima Prefecture advance as one, facing forward. Recently, decontamination projects started. Efforts must be continued over a long period. PMID- 22533745 TI - Management of benign strictures of the extrahepatic bile duct due to chronic pancreatitis and surgical intervention. AB - In the Endoscopic Forum Japan 2011 (EFJ 2011), we focused on the management of biliary strictures derived from chronic pancreatitis and surgical intervention. We concluded that regardless of causes of strictures, a large bore single plastic stent is better as a first choice of stenting. As a next step, multiple plastic stents may be preferable compared to a covered self-expandable metallic stent in case of unexpected adverse events and cost of stent. In the near future, we believe that not only progress of treatment technique and accessories but also good understanding of the pathology of biliary strictures will lead to the best management. PMID- 22533746 TI - Endoscopic treatment for biliary stricture secondary to chronic pancreatitis. AB - The causes of benign biliary stricture include chronic pancreatitis, primary/immunoglobulin G4-related sclerosing cholangitis and complications of surgical procedures. Biliary stricture due to fibrosis as a result of inflammation is sometimes encountered in patients with chronic pancreatitis. Frey's procedure, which can provide pancreatic duct drainage with decompression of biliary stricture, can be an initial treatment for chronic pancreatitis with pancreatic and bile duct strictures with upstream dilation. When patients are high-risk surgical candidates or hesitate to undergo surgery, endoscopic treatment appears to be a potential second-line therapy. Placement of multiple plastic stents is currently considered to be the best choice as endoscopic treatment for biliary stricture due to chronic pancreatitis. Temporary placement with a fully covered metal stent has become an attractive option due to the lesser number of endoscopic retrograde cholangiopancreatography (ERCP) sessions and its large diameter. Further clinical trials comparing multiple placement of plastic stents with placement of a covered metal stent for biliary stricture secondary to chronic pancreatitis are awaited. PMID- 22533747 TI - Transpapillary biliary forceps biopsy to distinguish benign biliary stricture from malignancy: how many tissue samples should be obtained? AB - BACKGROUND: The sensitivity of transpapillary biliary forceps biopsy for malignancy has been reported as varying from 43-81%. Therefore, there are false negatives in more than 20% of patients, which makes it difficult to diagnose benign biliary stricture as benignancy in a clinical setting. METHODS: To clarify the number of tissue samples that should be obtained during transpapillary forceps biopsy to distinguish benign biliary stricture from malignancy, patients undergoing transpapillary biliary forceps biopsy at our institute were examined retrospectively in this study. RESULTS: Seventy-two biliary forceps biopsy procedures were performed on 61 patients. The final diagnoses were malignant biliary stricture in 34 patients and benign stricture in 27 patients. The overall sensitivity and specificity for malignancy in this study were 76.5% and 100%, respectively. There were zero out of 10 (0%) false-negative patients when three or more tissue samples were obtained. In contrast, when four or more tissue samples were obtained, eight out of eight (100%) patients had negative diagnoses for malignancy and were finally diagnosed with benignancy. CONCLUSION: We suggest that three or more tissue samples are recommended for the diagnosis of biliary malignant stricture. PMID- 22533748 TI - Temporary placement of covered self-expandable metallic stents in the management of benign biliary strictures. AB - BACKGROUND AND AIM: Currently, endoscopic intervention is widely attempted as the first-line treatment of benign biliary strictures because of its convenience and low morbidity. Plastic tube stents (PS) are usually used for such treatment; however, covered self-expandable metallic stents (C-SEMS) are becoming more commonly used at some institutions. The temporary placement of C-SEMS may lead to better outcomes because of their larger diameter and, therefore, better dilation of the stricture, especially in refractory cases. The aim of the present study was to evaluate the efficacy of the temporary placement of C-SEMS in the management of benign biliary strictures. METHODS: We retrospectively reviewed our endoscopic retrograde cholangiopancreatography (ERCP) database (May 1996 to December 2010), and extracted the data of patients who underwent endoscopic treatment for benign biliary strictures. Then, the follow-up data from patient charts were reviewed to determine the long-term outcomes of those procedures. RESULTS: All patients (n = 56) initially had a PS placed, with or without balloon dilation. However, C-SEMS placement was later attempted in 12 patients because the stricture was refractory to placement of the PS. During their follow-up periods, two patients died of unrelated diseases after 15 and 17 months, and another two still had the C-SEMS in place after 9 and 50 months. In the remaining eight patients, the C-SEMS was removed after a median placement period of 6 months (range, 2-15). Seven patients in this group have not experienced a recurrence at a median follow-up time of 48 months. However, in one patient, stenosis did recur 8 months after the C-SEMS was removed. CONCLUSIONS: Temporary placement of C-SEMS can be a treatment option for benign biliary strictures, especially in refractory cases. PMID- 22533749 TI - Endoscopic ultrasound-guided biliary drainage performed for refractory bile duct stenosis due to chronic pancreatitis: a case report. AB - We report a case of the patient who underwent endoscopic ultrasound-guided biliary drainage (EUS-BD) for refractory bile duct stenosis due to chronic pancreatitis. The patient had repeatedly undergone endoscopic biliary stenting for bile duct stenosis due to chronic pancreatitis. Because of repeated relapses of cholangitis and jaundice, transpapillary treatment was judged to have reached its limits. Surgical bypass was attempted but had to be abandoned due to adhesions. Thus, EUS-BD was performed. The procedure was successful, and placement of a covered expandable metallic stent (C-EMS) relieved cholangitis. Two months after placement, the C-EMS was removed, and the patient became stent free but closure of the fistula subsequently occurred. PMID- 22533750 TI - Role of endoscopic stenting for biliary strictures in chronic pancreatitis. AB - AIM: To review the published work concerning the role of biliary stenting for chronic pancreatitis-related strictures. METHODS: A case study in which multiple plastic stents are used to manage a chronic pancreatitis biliary stricture is presented, and the published work reviewed. RESULTS: There has been a gradual evolution in the endoscopic management of distal biliary strictures secondary to chronic pancreatitis. Most early series used single (usually 10 F) plastic stents for varying time periods. Long-term stricture resolution occurred in only approximately 25% of patients and stent-related complications were high if stent exchanges were not performed routinely every 3-4 months. Recent studies using multiple (>= 3) 10 F stents placed sequentially every few months for approximately 12 months have resulted in resolution of biliary strictures in up to 90% of patients. In general, the use of both uncovered and partially covered self-expandable metal stents for biliary strictures due to chronic pancreatitis have been disappointing due to problems with epithelial hyperplasia involving the uncovered portions of the self-expandable metal stents resulting in late stent occlusion and other problems. Similarly, early published data does not at this stage support the routine use of fully covered self-expandable metal stents because of unacceptable stent-related complications. CONCLUSION: Chronic pancreatitis-related biliary strictures should be managed initially with sequentially-placed multiple 10 F plastic stents for approximately 12 months. PMID- 22533751 TI - Successful treatment of benign biliary stricture by a covered self-expandable metallic stent in a patient with chronic pancreatitis. AB - The patient was a 73 year old man for whom surgery under general anesthesia was difficult to perform because of pulmonary emphysema. In April 2003, he visited our hospital complaining of epigastralgia and dorsal pain, and was admitted under a diagnosis of acute exacerbation of chronic pancreatitis. In 2005, acute cholangitis concomitantly developed with acute exacerbation of chronic pancreatitis, for which a plastic stent was placed in the common bile duct. Cholangitis repeatedly developed every 2-3 months thereafter, and admission was required each time to exchange the stent. Surgery was considered but not applicable because of his poor respiratory function, and a partially covered self expandable metallic stent was inevitably placed in the bile duct. Ten months later, an aberration of the metallic stent in the bile duct occurred, but it was dealt with by placing an additional metallic stent, and no cholangitis or pancreatitis developed until the patient died of respiratory insufficiency 3 years later. Placement of a covered self-expandable metallic stent might be an option for the treatment of benign biliary stricture, especially in patients at high risk from surgery. PMID- 22533753 TI - Use of a partially covered self-expandable metallic stent to treat a biliary stricture secondary to chronic pancreatitis complicated by recurrent cholangitis: a case report. AB - The patient was a 69 year old man who had been diagnosed with alcoholic chronic pancreatitis and lower common bile duct (CBD) stricture. He subsequently developed cholangitis 2-3 times a year, and we replaced the endoscopic biliary stent (EBS) each time. In April 2010, he was admitted because of complication by a liver abscess and acute cholangitis. We performed percutaneous transhepatic liver abscess drainage. The inflammatory findings then rapidly improved, but the patient developed acute cholangitis due to the sludge and the stones. Then, we placed a partially covered self-expandable metallic stent (C-SEMS) in the lower CBD and performed endoscopic lithotripsy through the C-SEMS, and the cholangitis subsequently improved. Two weeks after, we removed the C-SEMS endoscopically and replaced it with a 10 Fr plastic stent; since then there have been no recurrences of cholangitis. Our experience in this case suggested that when a plastic stent is placed long-term to treat a biliary stricture associated with chronic pancreatitis, it might be useful to also control biliary sludge and stones using a C-SEMS. PMID- 22533752 TI - Covered metallic stent for ischemic hilar biliary stricture. AB - Compared with surgery, endoscopic treatment is safe and highly effective for a postoperative hilar benign bile duct stricture (BDS). However, the long-term outcome of conventional placement of a single biliary stent for hilar benign BDS is generally poor. Although the placement of multiple biliary stents is preferred, multiple stenting in a BDS is difficult. Alternatively, single or multiple stent placement above the papilla ('inside stent') or fully-covered self expandable metallic stents (SEMS) are feasible approaches for benign BDS. Nevertheless, controversy remains regarding whether and how to perform endoscopic biliary drainage for a hilar benign BDS. In patients with hilar benign BDS, endoscopic biliary drainage can be performed by placing conventional plastic stents across the papilla, plastic stents above the papilla or fully-covered SEMS. Individualized treatment should be considered. We report the placement of a fully-covered SEMS for a hilar benign biliary stricture after extended left hepatectomy. PMID- 22533754 TI - Endoscopic management with inside stent for proximal benign biliary stricture after laparoscopic cholecystectomy. AB - Endoscopic placement of a plastic stent is the standard drainage for a symptomatic benign biliary stricture. Although a removable fully covered self expandable metal stent has been applied for distal benign biliary stricture, placement of a plastic stent remains the standard treatment for proximal benign biliary stricture. Placement of a plastic stent above the papilla (inside stent) is an alternative to the conventional method because of its preventive effect against the dysfunction of the stent in patients with proximal benign biliary stricture. PMID- 22533755 TI - Case of immunoglobulin G4-related cholangitis accompanying autoimmune pancreatitis: diagnosis by peroral cholangioscopy and treatment by endoscopic biliary stenting. AB - Recently, the progress of endoscopy has made it possible to evaluate bile duct mucosa by peroral cholangioscopy. Herein, we report a case of immunoglobulin G4 related sclerosing cholangitis accompanying autoimmune pancreatitis in a patient who improved with treatment by steroid therapy and endoscopic biliary stenting, and observed the bile duct mucosa by peroral cholangioscopy before and after treatment. PMID- 22533756 TI - Current status of colorectal endoscopic submucosal dissection in Japan and other Asian countries: progressing towards technical standardization. AB - AIM: The primary purpose of this questionnaire survey study was to determine the current status of colorectal endoscopic submucosal dissection (ESD) in specialized Japanese referral centers before and after introduction of a government-approved advanced medical treatment system; and, secondly, to determine the current status of colorectal ESD in other Asian specialized referral centers. METHODS: A total of 1321 colorectal ESDs were performed in 11 institutions including two Asian centers outside Japan. RESULTS: Overall en-bloc resection, curative resection, R0 resection, perforation, delayed bleeding and emergency surgery rates were 95.4%, 89.1%, 87.2%, 2.9%, 2.5% and 0.2%, respectively. Similar clinical results were reported in the two Asian centers. CONCLUSION: There were no significant differences with regards to clinical results between the two periods although the perforation rate decreased from 3.3% to 2.4%. In addition, colorectal ESD has become increasingly standardized technically at specialized referral centers not only in Japan, but several other Asian referral institutions as well. PMID- 22533757 TI - Current status and future perspectives of endoscopic submucosal dissection for colorectal tumors. AB - Endoscopic submucosal dissection (ESD) allows for en bloc tumor resection irrespective of the size of the lesion. In Japan, ESD has been established as a standard method for endoscopic ablation of malignant tumors in the upper gastrointestinal tract. Although the use of colorectal ESD has been gradually spreading with the development of numerous devices, ESD has not yet been fully established as a standard therapeutic method for colorectal lesions. Currently, colorectal ESD is performed as an 'advanced medical treatment' without national health insurance coverage. With the recent accumulation of numerous cases, the safety and simplicity of colorectal ESD have improved remarkably. Currently in Japan, a prospective multicenter cohort study organized by the Japan Gastroenterological Endoscopy Society is ongoing to clarify the safety and efficacy of colorectal ESD to obtain remuneration from national health insurance. In this report, we showed the outcome regarding safety and efficacy of colorectal ESD through a review of the published work. Of 2719 cases with colorectal ESD at 13 institutions, the complete en bloc resection and perforation rates were 82.8% (61-98.2%, 2082/2516) and 4.7% (1.4-8.2%, 127/2719), respectively. Additional surgery for perforation was very rare because perforations were tiny enough to be closed endoscopically by clips in most of the cases and treated conservatively. In the near future, colorectal ESD will be a common therapeutic method for early colorectal carcinoma. PMID- 22533758 TI - Colorectal endoscopic submucosal dissection in Japan and Western countries. AB - Various studies by Japanese endoscopists have demonstrated that colorectal endoscopic submucosal dissection (ESD) can overcome technical limitations of the endoscopic mucosal resection (EMR) technique such as piecemeal resection for flat lesions larger than 20 mm, resection of lesions involving the dentate line or the ileocecal valve and lesions with the non-lifting sign, and achieve higher en bloc resection rate. However, it is infrequently performed in Western countries in comparison with Japan, despite the advantages explained above. There are some differences between Japan and Western countries in environments and clinical settings for performing ESD in the colorectum. Endoscopists who perform colorectal ESD around the world are considering that refinements in ESD techniques, devices and training will be necessary to further reduce a higher risk of complications and longer procedure times before adoption of ESD can be recommended on a widespread international scale. PMID- 22533759 TI - Effective training system in colorectal endoscopic submucosal dissection. AB - Although colorectal endoscopic submucosal dissection (ESD) is superior to endoscopic mucosal resection (EMR) in en bloc resection rate, it is technically quite difficult because of the anatomical and histological characteristics of the colorectal wall. This difficulty prevents wide spread of the technique. Establishment of the training system for colorectal ESD is necessary to standardize training and to achieve wider acceptance of this technique. Herein, we describe our training system for colorectal ESD, and assess the validity of the training system for colorectal ESD, based on the clinical outcomes and learning curve of trainees. Our training system for colorectal ESD would help the spread of this procedure. PMID- 22533760 TI - Usefulness and safety of SB knife Jr in endoscopic submucosal dissection for colorectal tumors. AB - Use of a Dual knife has become commonplace for endoscopic submucosal dissection (ESD) of colorectal tumors at Hiroshima University Hosipital. A Hook knife has been also used in combination with the Dual knife, depending on the location of the lesion. We have had recent opportunities to use a scissors-type SB knife Jr. We retrospectively compared outcomes of colorectal ESD performed with the Dual knife in combination with the SB knife Jr versus the Hook knife. In conclusion, although the Hook knife was shown to be a very useful auxiliary device for colorectal ESD, the SB knife Jr. yielded better results than the Hook knife in terms of complete en block resection and avoidance of perforation. Use of the Dual knife with the SB Knife Jr shows good potential for improving complete en bloc resection rate and safety of technically difficult colorectal ESD. PMID- 22533761 TI - Endoscopic submucosal dissection for large colorectal tumors using a cross counter technique and a novel large-diameter balloon overtube. AB - BACKGROUND AND AIM: Endoscopic submucosal dissection (ESD) in early gastric cancer (EGC), which provides a higher complete resection rate than conventional endoscopic mucosal resection (EMR), has rapidly come into widespread use. However, colorectal ESD is not widely used because of its technical difficulty and complications such as perforation, and the procedure time is longer than that of conventional EMR. Development of safer and more reliable devices as well as technique modifications are therefore required. The aim of our study is to compare safety and efficacy of a new traction method, the cross-counter technique, for large colorectal tumors combined with a balloon overtube. METHODS: A total of 30 patients with large colorectal tumors were analyzed retrospectively; 15 patients for the cross-counter technique group (CC group) and 15 patients for the no-traction group (NT group). Procedure time, complete resection rate, perforation rate and bleeding rate were assessed. RESULTS: The procedure time was 126 +/- 42.2 min and 165 +/- 61.3 min in the CC and NT groups, respectively, and there was a significant difference between the two groups (P < 0.05). There were no significant differences in complete resection rate, perforation rate and bleeding rate between the two groups. CONCLUSION: The cross counter technique shortened the treatment time in colorectal ESD without any complication. PMID- 22533762 TI - Indication, strategy and outcomes of endoscopic submucosal dissection for colorectal neoplasm. AB - Although endoscopic submucosal dissection (ESD) for colorectal neoplasm is a promising endoscopic therapy with a high rate of successful en bloc resection, ESD for colorectal neoplasm is not a health-care service provided by Japanese public heath insurance, yet. Now, ESD for colorectal neoplasm has been approved as an 'advanced medical treatment' system, which is a partial-care service provided by Japanese public health insurance with individual payment of medical expenses, and the indication for ESD for colorectal neoplasm has been under debate. In our hospital, a total of 348 colorectal neoplasms underwent ESD using the FlexKnife and the FlushKnife, and 317 lesions (91%) were resected en bloc. Perforation occurred in eight cases (2%) and they were not critical and did not require emergent surgery. Delayed bleeding occurred in 16 cases (4%) and they were able to be controlled without transfusion and were not critical. The major impact of the advanced medical treatment system on clinical practice in our hospital was the increased incidence of adenocarcinoma and increased tumor size in the lesions that underwent ESD. It is thought that the application of the advanced medical treatment system resulted in careful selection of lesions for ESD while maintaining the principle of en bloc resection. We expect that a new, revised indication that covers recurrent carcinoma after endoscopic therapy will be indicated when ESD for colorectal neoplasm becomes a health-care service provided by Japanese public health insurance. PMID- 22533763 TI - Clinical outcomes of 200 colorectal endoscopic submucosal dissections. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) is an outstanding endoscopic technique in which a colonic lesion can be resected en-bloc. However, the procedure requires a high level of skill and the procedure has yet to be standardized. At the present time, colorectal ESD is only permitted in Japanese institutions that have been certified for advanced medical treatments. METHODS: We examined 200 cases of colorectal ESD that were performed in our hospital. RESULTS: Over time, it was found that there was a continuous improvement in the treatment outcomes along with advances in both the procedures and the peripheral equipment utilized. CONCLUSION: Current results suggest that the colorectal ESD procedure is relatively stable. To ensure colorectal ESD continues to be safe, indications for its use need to be more fully investigated and medical personnel must be trained to carefully perform the procedure. PMID- 22533764 TI - Current opinions for endoscopic submucosal dissection for colorectal tumors from our experiences: indications, technical aspects and complications. AB - Endoscopic submucosal dissection (ESD) was first applied in the resection of large colorectal tumors 10 years ago. Frequent complications and technical difficulties were serious problems at first, but were gradually improved with experience. Here, we describe the indications, technical aspects and management of complications of ESD for colorectal tumors. In 2009, we introduce the use of small tip insulation-tipped diathermic (IT) knife. Features separating it from the IT knife and IT Knife2 are a smaller ceramic tip and small round disk at the root of the tip. During submucosal dissection, the small tip IT knife could dissect large pieces of tissue intact. This allows us to shorten the procedure time, particularly the submucosal dissection component. A total of 146 ESD for 140 patients were performed between January 2009 and July 2011. En bloc, and en bloc and R0 resection rates were 92.5% and 83.6%, respectively. Median procedural time was 48.5 min for 40.5 mm specimens. Perforation and delayed bleeding occurred in 2.1% and 1.4%, respectively. We successfully performed ESD for colorectal tumors with a shortened procedure time while preserving quality and safety. PMID- 22533765 TI - Efficacy of novel SB knife Jr examined in a multicenter study on colorectal endoscopic submucosal dissection. AB - BACKGROUND AND AIM: Secure manipulation of forceps in endoscopic submucosal dissection (ESD) for colorectal tumors is sometimes hindered by the characteristics of that organ. SB knife Jr, which are scissor forceps using a mono-pole high frequency, were developed to avoid the difficulty of ESD operation in the colorectum. The aim of the present study was to examine the effectiveness of the SB knife Jr in colorectal ESD in 11 hospitals, mostly in northeastern Japan. MATERIALS: One hundred and two colorectal tumors (49 non-granular laterally spreading tumor [LST] lesions, 39 granular LST lesions and 14 other lesions) that were resected by ESD operations using SB knife Jr between October 2009 and March 2010. RESULTS: All tumors (102/102) were resected en bloc and could be observed in detail. The mean size of the resected pieces was 40.3 mm. The mean operation time was 54.2 min. Of the complications, one case of micro perforation occurred during the manipulation of submucosal dissection, and this case was treated with clips in that operation. The rates of resection carried out only with SB knife Jr were 74.5% (76/102). CONCLUSION: The novel ESD using SB knife Jr in the colorectum offers a breakthrough in resection techniques for not only expert endoscopists but also general endoscopists. PMID- 22533766 TI - Desirable training and roles of Japanese endoscopists towards the further penetration of endoscopic submucosal dissection in Asia. AB - Endoscopic submucosal dissection (ESD) was invented in Japan and is now permeating into the rest of the world. Therefore, it is necessary to elucidate the desirable ESD training by knowing the current status of ESD training in Japan. After this, we mainly discussed the following three topics: (i) requirements for preceptees to start ESD training; (ii) requirements for competent endoscopists in ESD; and (iii) requirements for preceptors in the first half of the upper gastrointestinal tract session at the Endoscopic Forum Japan 2011. Additionally, we discussed what Japanese endoscopists can do for further permeation of ESD outside Japan, especially in Asia in the second half. The session was wrapped up by the conclusions that it was absolutely necessary to establish official training courses authorized by the Japan Gastroenterological Endoscopy Society with certification for trainees and trainers and our Japanese endoscopists had a responsibility to spread ESD safely and reliably by collaborating with enthusiastic endoscopists in each country which have different backgrounds in terms of incidences and screening systems of target diseases, accessibility to endoscopy, medical economics, national characters, and so on. PMID- 22533767 TI - Current situation of endoscopic submucosal dissection for superficial neoplasms in the upper digestive tract in East Asian countries: a questionnaire survey. AB - AIM: This study was carried out to understand the current practice and learning of endoscopic submucosal dissection (ESD) for superficial esophageal and gastric cancers in East Asian countries. METHODS: A questionnaire survey was used to investigate differences in upper gastrointestinal (GI) ESD among East Asian countries. RESULTS: ESD is used by many endoscopists in not only tertiary centers but also secondary care hospitals in China, Korea and Japan. By contrast, it is less used by doctors in tertiary centers in Hong Kong and Taiwan. However, the general trend appears to be the same; ESD, which is a highly advanced endoscopic technique, is being transmitted from preceptors to preceptees in tertiary centers, then from doctors in tertiary centers to experienced doctors in secondary hospitals. The speed of learning and uptake in the practice of this procedure will depend on the volume of cases. Upper GI ESD can be expected to spread at a similar rate across different districts or hospitals in East Asia because of similarities in disease prevalence. Also, endoscopists in this region can easily learn from each other by attending international conferences or visiting endoscopy units to learn the procedure. CONCLUSION: Efforts to establish a standardized protocol for ESD practice and training are important, and may help endoscopists around the world develop this technique further. PMID- 22533768 TI - Learning curve for endoscopic submucosal dissection of early gastric cancer based on trainee experience. AB - BACKGROUND AND AIM: There have been few previous reports on endoscopic submucosal dissection (ESD) learning curve for early gastric cancer (EGC) so we retrospectively assessed this subject based on experience of our trainees. METHODS: Trainees in our center start performing ESDs for lesions in lower third of stomach with hands-on support by experts during first 10 cases and then perform ESDs by themselves primarily with verbal guidance from experts. They are gradually assigned to perform ESDs in middle and upper thirds of stomach. From January 1999 to December 2008, 464 EGC patients, who underwent ESD performed by 13 trainees, were assessed by dividing ESD cases into five training periods (A, 1 10; B, 11-20; C, 21-30; D, 31-40; and E, 41-50). We compared data from B to C, D and E. RESULTS: Lesions in lower third were A/59%, B/57%, C/55%, D/36% and E/40% with B significantly higher than D (p<0.01) and E (p<0.05). Mean tumor sizes were A/13.9 +/- 7.5mm, B/18.3 +/- 11.4mm, C/19.0 +/- 12.5mm, D/19.3 +/- 11.7 mm and E/16.8 +/- 10.3mm. En-bloc resection rate was 100% in every period. Delayed bleeding / perforation rates were A/0%/1.8%, B/2.8%/1.9%, C/1.9%/2.9%, D/1.1%/0% and E/2.1%/2.1%, respectively. Lower third procedure times were A/76 +/- 39, B/90 +/- 61, C/70 +/- 48, D/60 +/- 50 and E/55 +/- 26 minutes with B significantly longer than D and E (p<0.05). Middle and upper third procedure times were A/104 +/- 80, B/115 +/- 68, C/106 +/- 67, D/134 +/- 86 and E/96 +/- 55 minutes. CONCLUSION: Step-by-step training was highly effective with 100% en-bloc resection rate and few complications. Learning curve point for our trainees to acquire performing ESD in lower third of stomach was 30 cases. PMID- 22533769 TI - Terminology for training of endoscopic submucosal dissection. AB - Like many other advanced endoscopic skills, to master the skill of endoscopic submucosal dissection (ESD) requires training for a novice. The general medical terminology should be used similarly even in case of ESD training. However, it is not common for everyone to recall the same meaning from one medical term. Therefore, it is necessary to unify the meaning of medical terms and review their usage in a meeting to achieve a consensus. For this purpose, terms used in the upper gastrointestinal session, Endoscopic Forum Japan 2011, entitled 'Towards further penetration of ESD techniques - what is the role of Japanese ESD experts?', were determined beforehand as shown. Additionally, the present educational approach of ESD in Japan is simply outlined in this article. PMID- 22533770 TI - How to teach and learn endoscopic submucosal dissection for upper gastrointestinal neoplasm in Japan. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) is an innovative and promising procedure. However, ESD experience is mostly limited to Japan and a few countries in Asia. An appropriate training system should be proposed from Japan to promote a permeation of ESD technique. We conducted questionnaire survey to representative Japanese experts to reveal their training method of ESD for upper gastrointestinal neoplasm. MATERIALS AND METHODS: We sent the questionnaire on gastric and esophageal ESD to 9 Japanese experts in ESD. The questionnaire results were discussed in a session of Endoscopic Forum Japan 2011 held in Tokyo. RESULTS: The inception criteria consisted of two main elements, diagnostic ability and primary endoscopy technique of preceptees. Preceptees should observe and attend as many ESD cases as possible. Most of the experts recommend training with isolated or live animal stomach or esophagus. Lesion in the distal stomach is the most suitable for the first real ESD by a preceptee. Being proficient in a gastric ESD is needed before starting esophageal ESD. Preceptor should have significantly high level of diagnostic ability and proficient ESD techniques in the colorectum as well as the stomach and esophagus. CONCLUSION: The present questionnaire survey seems to reveal basic elements required for ESD training program. We believe that this is also helpful in other countries where ESD would be initiated and penetrated safely and properly. PMID- 22533771 TI - Determining early gastric cancer lesions appropriate for endoscopic submucosal dissection trainees: a proposal related to curability. AB - Endoscopic submucosal dissection (ESD) was introduced worldwide as a new treatment option for early gastric cancer. Our objective was to discuss the limited ESD reports available and to determine the lesions suitable for use in training endoscopists on which lesions are appropriate for ESD. We reviewed a series of ESD reports that have been written on various risk factors related to the resectability or curability of a variety of lesions. These published studies show that certain risk factors such as tumor size and location and the presence of ulceration are closely related to both resectability and curability. Because the combination of these risk factors resulted in a much higher risk than did any single factor, we recently established a 'risk assessment chart' to determine an individual's total risk of treatment failure for early gastric cancer that has been treated using ESD. This risk chart provides a clear indication that small, non-ulcerated lesions located in the lower third of the stomach have a high rate of curative resection and are technically less challenging if ESD is used. We suggest that trainees should gain ESD experience with such lesions before they start to perform ESD on more difficult lesion types that have a lower probability of curative resection. In addition, we suggest that this risk assessment chart is suitable for the pretreatment assessment of curability and the likelihood of successful en bloc resection. PMID- 22533772 TI - Current status of training for endoscopic submucosal dissection for gastric epithelial neoplasm at Cancer Institute Hospital, Japanese Foundation for Cancer Research, a famous Japanese hospital. AB - AIM: Endoscopic submucosal dissection (ESD) is relatively difficult compared with endoscopic mucosal resection (EMR), thus, proper training is essential for the safe performance of the procedure. The aim of this study is to clarify the current status of training for ESD for gastric epithelial neoplasm by following the performance of 13 preceptees. METHODS: We performed ESD for 1520 lesions between March 2005 and April 2011 and conducted ESD training of 13 preceptees who were supervised by experts. We classified the samples into four groups according to the number of ESD performed by the preceptees to chart their progress by comparing the procedural outcomes. Group A included cases 1-40 performed by all 13 preceptees, group B consisted of cases 41-80 performed by 10 of the preceptees and group C included cases 81 onwards executed by five of the preceptees. Group D comprised the cases that were performed by experts during the same period as group C. RESULTS: The procedural outcomes of group A were similar to those of group B with regard to operation time, complete en bloc resection and complications. However, the results of group B included significantly more lesions of the middle or upper third of the stomach, resected specimen and lesions were larger in diameter, lesions with positive ulcer finding were more frequent and a higher frequency of lesions were of expanded, non-indication type. Group B outcomes were similar to those of group C but differed in location of lesions and specimen size. Group C outcomes were similar to group D's in all parameters. CONCLUSION: Preceptees were able to safely perform ESD for gastric epithelium neoplasms under appropriate supervision by expert endoscopists. The number of cases in which preceptees successfully extracted guideline-indication lesions and expanded-indication lesions by ESD were approximately 40 and 80 cases, respectively. The procedural outcomes of ESD performed by preceptees who had experience in over 80 cases were similar to those by expert endoscopists. Thus, these findings show that the minimal amount of training for achieving preceptorship of ESD is performance of at least 80 of the procedures. PMID- 22533773 TI - Safety and efficacy of colorectal endoscopic submucosal dissection by the trainee endoscopists. AB - The colorectum is known to be the most difficult organ to perform endoscopic submucosal dissection (ESD), however, the training has not been sufficiently established. In our hospital, the essential condition to start colorectal ESD was to experience at least 30 gastric ESD and to have sufficient knowledge and techniques beforehand. Rectal ESD were initially performed under supervision of ESD experts. According to their technical acquisition, the ESD experts allocated lesions to the trainees from smaller lesions in the distal colon to larger lesions in the proximal colon. We retrospectively investigated the outcomes of 92 and 23 colorectal ESD performed by two trainee endoscopists (A/B) who gained experience on our training scheme. The rates of en bloc/complete resection for A and B were 92.4%/73.9% and 95.7%/65.2%, respectively. The rates of bleeding/perforation, which occurred only with A, were 1.1%/3.3%, respectively. Intraoperative perforation occurred in one case (4.3%) in the later period. In the later period, en bloc resection rate remained high in spite of the difficult lesions. Our training scheme enabled trainees to perform colorectal ESD effectively and safely from the initial period. Step-by-step accumulation of cases such as from the rectum to the colon may be desirable for the introduction of colorectal ESD. PMID- 22533774 TI - Endoscopic resection for early gastric cancer: current status in Korea. AB - Endoscopic mucosal resection (EMR) was introduced in the 1990s, and endoscopic submucosal dissection (ESD) in 2003. Currently, ESD is becoming the main procedure for the resection of early gastric cancer (EGC), and provides safer and curative outcomes. Endoscopic resection (ER) showed excellent long-term survival in Korea. The number of ESD has doubled over 5 years. ESD might be better than EMR in terms of en bloc resection, complete resection and long-term outcome. Novel techniques including endoscopic full-thickness resection with lymph node dissection will be positioned for some EGC. PMID- 22533775 TI - Current status of endoscopic resection in China. AB - The early diagnosis of early gastrointestinal (GI) diseases is becoming easier than ever before, due to the rapid development of all kinds of endoscopic techniques, including chromoendoscopy, narrowband imaging, magnifying endoscopy, confocal microscopy and autofluorescence imaging. Endoscopic resection is gradually becoming the optimal choice, which is significantly less invasive than conventional surgical interventions. In China, endoscopic resection techniques have been developed very quickly after several pioneers learned from Japanese gastroenterologists. Endoscopic submucosal dissection (ESD) has achieved remarkable initial outcomes, however, large-scale, multicenter, retrospective studies of the long-term follow up of ESD outcomes in China are still lacking. New endoscopic interventions are also being developed from the ESD technique, namely, endoscopic full-thickness resection of gastric submucosal tumors, peroral endoscopic myotomy and submucosal tunneling endoscopic resection techniques. Here, we discuss the current status of endoscopic resection in China and several problems: (i) the lack of guideline or consensus from academic society; (ii) approximately half of the ESD are performed on benign submucosal tumors, so the diagnosis of mucosal cancers needs to be increased; (iii) the standard technique used, results, management of complications and follow-up should be standardized; and (iv) the minimum training requirements, the step-by-step approach should also need to be standardized. PMID- 22533776 TI - Making endoscopy mobile: the journey. AB - In spite of the economic development through the past six decades post independence, nearly 70% of the Indian population still live in villages, and these people very often have limited access to the advanced health-care technology. In an attempt to render cost-effective gastrointestinal care to the rural dwellers, we have initiated a Rural Health Care Project. We have tailor made and converted a bus into a mobile hospital equipped with basic diagnostic facilities including a custom-made endoscopy unit. This bus travels to rural areas and renders basic diagnostic and therapeutic services including endoscopy. A telemedicine van accompanies the mobile hospital and endoscopy unit and transmits all procedures and data to the main telemedicine center at our parent institute. We have so far performed over 30,000 endoscopic procedures in 4837 villages with a population of over 10 million people. Both the rural dwellers and the staff involved in this project have reported a high level of satisfaction. This project runs on philanthropic donations. PMID- 22533777 TI - Closing remarks. PMID- 22533779 TI - Association of S549N and IVS8-5T splice variants with bronchial asthma and its severity in Indian children. AB - BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) is an asthma susceptibility gene. Individuals heterozygous for CFTR gene mutation may develop obstructive pulmonary disease like bronchial asthma. AIM AND OBJECTIVE: To find out the association of S549N and IVS8-5T variants of the CFTR gene with bronchial asthma and its severity and to assess the combinational effect of S549N and IVS8-5T variants on severity of disease. MATERIALS AND METHODS: Included were 250 clinically diagnosed bronchial asthma cases aged 5 months to 15 years and 250 age- and sex-matched controls. All cases were further categorized into four different categories as per Global Initiative for Asthma criteria (GINA) guidelines: mild intermittent (83), mild persistent (96), moderate persistent (52), and severe persistent (19). Screening for S549N and 5T variants was done using the polymerase chain reaction-restriction fragment length polymorphism method. RESULT: The proportion of IVS8-5T variant was found significantly higher in cases (10.8%) as compared with controls (2.4%) (p=0.001); however, no significant difference in the proportion of S549N was observed among cases (2.0%) and controls (0.8%) (p=0.447). Individuals mutant for IVS8-5T variant had increased risk for persistent asthma (p=0.000). DISCUSSION: We conclude that IVS8 5T variant is associated with bronchial asthma and can also increase severity of the disease. PMID- 22533780 TI - Lysyl oxidase G473A polymorphism is associated with increased risk of ovarian cancer. AB - Despite the knowledge of many genetic alterations present in ovarian cancer, the complexity of this disease precludes placing its biology into a simple conceptual framework. Lysyl oxidase (LOX) is an extracellular matrix enzyme that catalyzes the cross-linking of collagens or elastin in the extracellular compartment. A novel polymorphism in the LOX gene, G473A (rs1800449), has been reported as being a risk factor for different diseases. The objective of this study was to investigate the association between the LOX G473A polymorphism and the susceptibility to ovarian cancer in the Chinese population. The LOX variant G473A was detected by a polymerase chain reaction-restriction fragment length polymorphism in 233 ovarian cancer cases and 246 age-matched controls. Data were analyzed using the chi-square test. Data showed that frequencies of the LOX 473AA genotype and the A allele were significantly higher in ovarian cancer patients than in controls (odds ratio [OR]=2.52, 95% confidence interval [CI] 1.28-4.96, p=0.006; and OR=1.62, 95% CI 1.18-2.20, p=0.002). In addition, the prevalence of the GA genotype, AA genotype, and A allele were significantly increased in recurrent ovarian cancer cases compared with primary ovarian cancer cases. Our data suggest that the G473A polymorphism of the LOX gene is associated with increased susceptibility to ovarian cancer. PMID- 22533781 TI - Progress toward the syntheses of (+)-GB 13, (+)-himgaline, and himandridine. new insights into intramolecular imine/enamine aldol cyclizations. AB - A full account of our total synthesis of the galbulimima alkaloids GB 13 and himgaline is provided. Using a strategy adapted from the proposed biosynthesis of the GB alkaloid family, a linear precursor underwent successive intramolecular Diels-Alder, Michael, and imine aldol cyclizations to form the polycyclic alkaloid core. We now show that modification of this strategy can also deliver an advanced intermediate en route to the related alkaloid himandridine. The success of the key imine aldol cyclization is acutely sensitive to substrate structure and solvent, including a case in which cyclization was spontaneous in protic solvents. A detailed computational investigation of the course of the reaction closely correlates with, and suggests a rationale for, the observed patterns of imine aldol reactivity. PMID- 22533778 TI - Intra-individual variability across neurocognitive domains in chronic hepatitis C infection: elevated dispersion is associated with serostatus and unemployment risk. AB - Approximately one-third of persons infected with the hepatitis C virus (HCV) evidence mild cognitive impairment that is consistent with frontostriatal systems dysfunction, including cognitive dyscontrol, and impacts everyday functioning. The present study examined the effects of HCV on neurocognitive dispersion, or within-person variability in neurocognitive performance across domains, which may be a function of poor sustained cognitive control. High dispersion was also hypothesized to increase risk for unemployment. The study sample included 37 individuals with HCV infection (HCV+) and 45 demographically comparable uninfected comparison participants (HCV-). Dispersion was operationalized as an intra-individual standard deviation (ISD) calculated across the demographically adjusted T-scores of 13 standard neuropsychological tests. Multiple linear regression and logistic regression approaches were used to evaluate associations between dispersion and HCV serostatus and employment status, respectively. HCV serostatus was significantly associated with higher dispersion, independent of mean level of neurocognitive ability, psychiatric factors, and liver disease severity. Within the HCV+ group, higher dispersion was associated with an increased risk of unemployment among individuals with higher overall mean neurocognitive ability. Increased neurocognitive dispersion among HCV+ individuals may indicate vulnerability to cognitive dyscontrol expressed as poor regulation of performance across tasks. Higher dispersion may manifest as functional difficulties in daily life, particularly among neurocognitively normal HCV-infected persons, which speaks to the potential clinical value of considering intra-individual variability when evaluating risk for everyday function problems in this population. PMID- 22533782 TI - A reappraisal of the medical therapy with steroidogenesis inhibitors in Cushing's syndrome. AB - OBJECTIVE: To evaluate the outcome of preoperative therapy with ketoconazole (KTZ) and/or metyrapone (MTP) in previously untreated patients with Cushing's syndrome (CS). DESIGN AND PATIENTS: Sixty-two patients with CS (85% ACTH dependent), treated with steroidogenesis inhibitors prior to surgery between 1983 and 2010, were retrospectively studied. T(0) and t(1) defined baseline and end of preoperative medical treatment. RESULTS: Outcomes were based upon clinical and biochemical (normal UFC) control of hypercortisolism at t(1) : group CO (controlled) included 20 patients (32%) with eucortisolism and significant clinical improvement; group NC (not controlled) 30 (48%) with persistent hypercortisolism and no control of symptoms; and group PC (partially controlled) 12 patients (19%) who despite eucortisolism had no real clinical improvement. Median duration of treatment was 4 months (range: 1-30.7), and median cumulative dose of KTZ and MTP was 57 g (range: 3.6-240) and 120 g (range: 7.5-1215). CO patients were treated more with KTZ alone than the other groups (P < 0.05). MTP alone was administered more in PC than in CO patients (P < 0.01). No clinical differences were observed between groups at baseline. Systolic blood pressure at t(1) was higher in PC than in NC patients (P < 0.05). Hypertension persisted more in PC patients than in the other groups (P < 0.05) after a median postsurgery follow-up of 108 months (range: 4-276). CONCLUSIONS: Preoperative administration of KTZ, MTP or both normalized UFC in 52% of patients with CS, but concomitant clinical improvement did not always follow. Larger, multicentre studies are needed to individualize preoperative medical treatment and improve outcome in patients with CS. PMID- 22533783 TI - Two-color antibunching from band-gap engineered colloidal semiconductor nanocrystals. AB - Photon antibunching is ubiquitously observed in light emitted from quantum systems but is usually associated only with the lowest excited state of the emitter. Here, we devise a fluorophore that upon photoexcitation emits in either one of two distinct colors but exhibits strong antibunching between the two. This work demonstrates the possibility of creating room-temperature quantum emitters with higher complexity than effective two level systems via colloidal synthesis. PMID- 22533784 TI - Mental health and physical activity interventions: a review of the qualitative literature. AB - BACKGROUND: Interventions based on physical activity are of proven efficacy as adjunctive interventions in mental health, but less is known about how these benefits come about. AIMS: This review summarises the qualitative research on the perspectives of service users so as to shed light on possible psychological and social mechanisms of therapeutic change. METHOD: Thirteen published studies were identified by a detailed search of the peer-reviewed literature employing a variety of methodologies across a range of physical activity contexts for participants with severe and enduring mental health difficulties. The results are grouped thematically, and the studies were compared and contrasted with respect to methodology and findings. FINDINGS: There was a high degree of congruence in support of the themes of social interaction and social support; feeling safe; improved symptoms; a sense of meaning, purpose and achievement; identity and the role of the facilitating personnel. CONCLUSIONS: Exercise interventions deserve greater emphasis both theoretically and clinically, as many service users experience them as socially inclusive, non-stigmatising and, above all, effective in aiding recovery. PMID- 22533785 TI - The use of magnetic resonance imaging in evaluating horses with spinal ataxia. AB - To determine the accuracy of magnetic resonance imaging for diagnosing cervical stenotic myelopathy in horses, 39 horses with spinal ataxia and 20 control horses underwent clinical and neurologic examinations, cervical radiographs, euthanasia, magnetic resonance (MR) imaging of the cervical spine and necropsy. Twenty-four horses were diagnosed with cervical stenotic myelopathy, 5 with cervical vertebral stenosis, 7 with idiopathic ataxia, 3 horses had other causes of ataxia, and 20 were controls. The MR images were assessed for spinal cord intensity changes, presence of spinal cord compression, spinal cord compression direction, shape of spinal cord, and the presence of synovial cysts, joint mice, and degenerative joint disease. The height, width, and area of the spinal cord, dural tube and vertebral canal were measured. The identification of spinal cord compression on MR images was significantly different in horses with cervical stenotic myelopathy (P < 0.02), but in the cervical stenotic myelopathy group the identification of spinal cord compression on MR images had poor to slight agreement with histopathologic evidence of compression (kappa = 0.05). Horses with cervical stenotic myelopathy were more likely to have a T2 hyperintensity in the spinal cord (P < 0.05). Horses with cervical stenotic myelopathy or cervical vertebral stenosis were more likely to have degenerative joint disease than control horses or horses with other or idiopathic ataxia. PMID- 22533786 TI - Continual transcranial Doppler in the monitoring of hemodynamic change following aneurysmal subarachnoid hemorrhage. AB - AIMS: To analyze and compare the value of different treatment methods for acute aneurysmal subarachnoid hemorrhage (aSAH)-related vasospasm. Cerebral hemodynamic variables' changes were evaluated by transcranial Doppler (TCD) in aSAH patients within 14 days after onset. METHODS: Thirty aSAH patients were enrolled in the study within 72 h after onset. Baseline CT and TCD were used for assessment. Patients were divided into three groups according to SAH severity and patients' discretion: nonsurgical group, endovascular coiling, and neurosurgical clipping. TCD hemodynamic parameters were measured and Lindegaard index was calculated daily from onset to 14th day after SAH. The group mean cerebral blood velocity (MBFV) and Lindegaard index were compared using repeated measures analysis of variance (reANOVA). Least Significant Difference (LSD) test was used for post hoc comparison. All 30 patients were followed for 90 days after onset for outcome assessment. RESULTS: The values of MBFV and Lindegaard index of anterior cerebral artery (ACA)/middle cerebral artery (MCA) from high to low is nonsurgical group, clipping and coiling (ACA: P= 0.0001/P= 0.006; MCA: P= 0.243/P= 0.317). CONCLUSIONS: These results indicate that both neurosurgical clipping and endovascular coiling management may relieve the severity of cerebral vasospasm in acute aSAH. PMID- 22533787 TI - Preparation of composite membranes with bicontinuous structure. AB - Composite membranes with a hierarchical structure comprising thin regions with a bicontinuous structure and thick regions providing mechanical strength have been prepared by casting inorganic zeolite particles and mixtures that yield organic polymers onto substrates that were decorated with sessile droplets of aqueous solutions. Analysis by scanning electron microscopy (SEM) showed a membrane structure with well-ordered imprints caused by the sessile template droplets. These imprints were open at the bottom and covered on the top with a thin sheet composed of particles and polymer. The particles protruded out of the polymer sheet at the top and bottom of the membrane in the thin regions. A significant number of the particles protruded out of both interfaces at the same time. Thus, these parts of the membrane can be considered to be bicontinuous. The imprints are surrounded by thick regions. These regions act as a supporting structure. Thus, the membranes are stable enough to be handled without special precautions and might be applicable to membrane separation processes. PMID- 22533788 TI - Production and characterization of a single-chain variable fragment linked alkaline phosphatase fusion protein for detection of O,O-diethyl organophosphorus pesticides in a one-step enzyme-linked immunosorbent assay. AB - A single-chain variable fragment (scFv) linked alkaline phosphatase (AP) fusion protein for detection of O,O-diethyl organophosphorus pesticides (O,O-diethyl OPs) was produced and characterized. The scFv gene was prepared by cloning V(L) and V(H) genes from hybridoma cells secreting monoclonal antibody with broad specificity for O,O-diethyl OPs. The amplified V(L) and V(H) regions were assembled using a linker (Gly(4)Ser)(3) by means of splicing overlap extension polymerase chain reaction to obtain the scFv gene, which was cloned into the expression vector pLIP6/GN containing an AP gene to produce the scFv-AP fusion protein in Escherichia coli strain BL21. The protein was purified by antigen conjugated immunoaffinity chromatography and characterized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, Western blotting, and competitive direct enzyme-linked immunosorbent assay (cdELISA). The fusion protein is bifunctional, retaining both antigen binding specificity and AP enzymatic activity. Analysis of spiked and blind river water and Chinese cabbage samples demonstrated that the fusion protein based cdELISA(FP) exhibited good sensitivity and reproducibility. PMID- 22533789 TI - Assessment of the effect of insecticide-treated nets and indoor residual spraying for malaria control in three rural kebeles of Adami Tulu District, South Central Ethiopia. AB - BACKGROUND: In the Adami Tulu District, indoor residual spraying (IRS) and insecticide-treated nets (ITNs) has been the main tool used to control malaria. The purpose of this study was to assess the effect of IRS and ITNs control strategies in Aneno Shisho kebele (lowest administrative unit of Ethiopia) compared with Kamo Gerbi (supplied ITN only) and Jela Aluto (no IRS and ITNs), with regards to the prevalence of malaria and mosquito density. METHODS: Cross sectional surveys were conducted after heavy rains (October/November, 2006) and during the sporadic rains (April, 2007) in the three kebeles of Adami Tulu District. Malaria infection was measured by means of thick and thin film. Monthly collection of adult mosquitoes from October-December 2006 and April-May 2007 and sporozoite enzyme-linked immunosorbent assay (ELISA) on the collected mosquitoes were detected. Data related to the knowledge of mode of malaria transmission and its control measures were collected. Data collected on parasitological and knowledge, attitude and practice (KAP) surveys were managed and analysed using a statistical computer program SPSS version 13.0. A P-value <0.05 was considered to be statistically significant. RESULTS: The overall prevalence of malaria was 8.6% in Jela Aluto, 4.4% in Kamo Gerbi and 1.3% in Aneno Shisho in the two season surveys. The vector, Anopheles gambiae s.l., Anopheles pharoensis and Anopheles coustani were recorded. However, sporozoite ELISA on mosquito collections detected no infection. The difference in overall malaria prevalence and mosquito density between the three kebeles was significant (P<0.05). CONCLUSIONS: The present study has provided some evidence for the success of ITNs/IRS combined malaria control measures in Aneno Shisho kebele in Adami Tulu District. Therefore, the combined ITNs/IRS malaria control measures must be expanded to cover all kebeles in the District of Ethiopia. PMID- 22533790 TI - Synthesis, chemical reactivity as Michael acceptors, and biological potency of monocyclic cyanoenones, novel and highly potent anti-inflammatory and cytoprotective agents. AB - Novel monocyclic cyanoenones examined to date display unique features regarding chemical reactivity as Michael acceptors and biological potency. Remarkably, in some biological assays, the simple structure is more potent than pentacyclic triterpenoids (e.g., CDDO and bardoxolone methyl) and tricycles (e.g., TBE-31). Among monocyclic cyanoenones, 1 is a highly reactive Michael acceptor with thiol nucleophiles. Furthermore, an important feature of 1 is that its Michael addition is reversible. For the inhibition of NO production, 1 shows the highest potency. Notably, its potency is about three times higher than CDDO, whose methyl ester (bardoxolone methyl) is presently in phase III clinical trials. For the induction of NQO1, 1 also demonstrated the highest potency. These results suggest that the reactivity of these Michael acceptors is closely related to their biological potency. Interestingly, in LPS-stimulated macrophages, 1 causes apoptosis and inhibits secretion of TNF-alpha and IL-1beta with potencies that are higher than those of bardoxolone methyl and TBE-31. PMID- 22533791 TI - Myocardial strains from 3D displacement encoded magnetic resonance imaging. AB - BACKGROUND: The ability to measure and quantify myocardial motion and deformation provides a useful tool to assist in the diagnosis, prognosis and management of heart disease. The recent development of magnetic resonance imaging methods, such as harmonic phase analysis of tagging and displacement encoding with stimulated echoes (DENSE), make detailed non-invasive 3D kinematic analyses of human myocardium possible in the clinic and for research purposes. A robust analysis method is required, however. METHODS: We propose to estimate strain using a polynomial function which produces local models of the displacement field obtained with DENSE. Given a specific polynomial order, the model is obtained as the least squares fit of the acquired displacement field. These local models are subsequently used to produce estimates of the full strain tensor. RESULTS: The proposed method is evaluated on a numerical phantom as well as in vivo on a healthy human heart. The evaluation showed that the proposed method produced accurate results and showed low sensitivity to noise in the numerical phantom. The method was also demonstrated in vivo by assessment of the full strain tensor and to resolve transmural strain variations. CONCLUSIONS: Strain estimation within a 3D myocardial volume based on polynomial functions yields accurate and robust results when validated on an analytical model. The polynomial field is capable of resolving the measured material positions from the in vivo data, and the obtained in vivo strains values agree with previously reported myocardial strains in normal human hearts. PMID- 22533792 TI - Editorial comment to first report of idiopathic segmental ureteritis successfully treated by steroid therapy. PMID- 22533793 TI - Prevalence and correlates of insecticide-treated bednet use among HIV-1-infected adults in Kenya. AB - HIV-1-infected adults are at increased risk for malaria. Insecticide-treated bednets protect individuals from malaria. Little is known about correlates of ownership and use of bednets among HIV-1-infected individuals. We conducted a cross-sectional survey of 388 HIV-1-infected adults recruited from three sites in Kenya (Kilifi, Kisii, and Kisumu) to determine factors associated with ownership and use of optimal bednets. We defined an optimal bednet as an untorn, insecticide-treated bednet. Of 388 participants, 134(34.5%) reported owning an optimal bednet. Of those that owned optimal bednets, most (76.9%) reported using it daily. In a multivariate model, higher socioeconomic status as defined as postsecondary education [OR = 2.8 (95% CI: 1.3-6.4), p = 0.01] and living in a permanent home [OR = 1.7(1.03-2.9), p = 0.04] were significantly associated with optimal bednet ownership. Among individuals who owned bednets, employed individuals were less likely [OR = 0.2(0.04-0.8), p = 0.01] and participants from Kilifi were more likely to use bednets [OR = 2.9 (95% CI 1.04-8.1), p = 0.04] in univariate analysis. Participants from Kilifi had the least education, lowest income, and lowest rate of employment. Our findings suggest that lower socioeconomic status is a barrier to ownership of an optimal bednet. However, consistent use is high once individuals are in possession of an optimal bednet. Increasing access to optimal bednets will lead to high uptake and use. PMID- 22533795 TI - Emerging targets for the treatment of scleroderma. AB - INTRODUCTION: Scleroderma is an often-fatal autoimmune connective tissue disease. Recommendations for treating digital ulcers and pulmonary hypertension in scleroderma have recently been established by the European League Against Rheumatism. Conversely, although many valuable insights have been generated into the molecular mechanism underlying the persistent fibrotic phenotype in scleroderma, no safe, clinically proven effective treatment has been found for this aspect of the disease. AREAS COVERED: Recent evidence suggests that, based on genome-wide molecular profiling, scleroderma can be loosely divided into 'fibroproliferative' and 'inflammatory' cohorts. The latter cohort contains patients with localized and 'limited' disease, as well as a small subset of those with 'diffuse' disease. Drugs targeting either B cells or ILs might be useful to treat patients who possess an 'inflammatory' gene expression signature. EXPERT OPINION: In the future, a 'personalized medicine' approach might be used to treat patients with scleroderma: individuals with an 'inflammatory' gene expression signature may be successfully treated with drugs specifically targeting the immune system. Indeed, drugs currently approved for other rheumatic disease might also be used to treat scleroderma patients bearing an 'inflammatory' gene expression profile. PMID- 22533794 TI - Conversion to sirolimus in pediatric renal transplant patients: a single-center experience. AB - We studied efficacy and safety of conversion from CNI- to SRL-based immunosuppression in 92 kidney TX recipients, mainly due to CAN (69%). Median time of conversion was 31 months (r: 0.3-165); median time of follow-up: 36 months (r: 2-102). In the whole group mean eGFR increased from 53 +/- 22 to 67 +/ 26mL/min/1.73 m(2) at three months (p = 0.02) and did not change subsequently. Patients with grade I CAN had higher eGFR than those with grade II CAN. Patient and graft survival was 96% and 70% 10 yr after conversion. Patients with grade I CAN had better graft survival than those with grade II CAN: 89% vs. 65% at six yr (p = 0.02) post conversion. There were two episodes of BPAR. Baseline proteinuria >20 mg/kg/day (HR: 10) and baseline eGFR <50 mL/min/1.73 m(2) (HR: 8) were independent predictors of graft loss. Sixty-seven of 92 subjects had >=1 AEs: diarrhea (n = 52), urinary tract infections (n = 35), and lower respiratory tract infections (n = 12) were the most frequent. Patients with >2 AEs had SRL blood levels >9 ng/mL at month 3 (p = 0.01). In conclusion, patients converted from CNI to SRL had good graft survival and tolerable but frequent AEs. Independent predictors of graft loss were baseline proteinuria and eGFR. PMID- 22533796 TI - Lean oncology: a new model for oncologists. AB - The history of the term Lean is relatively recent and originates from the Toyota Production System (TPS). The term "Lean" means "thin", which refers to a mental process, operational, productive, no-frills, quick but not hasty, consequential to the previous event. The Lean process flows seamlessly into the result, eliminates unnecessary complications to the effect, prevents unnecessary equipment processes. The idea is to 'do more with less', like using the (few) available resources in the most productive way possible, through the elimination of all types of waste that inevitably accompanies every stage of a production process. Lean management is primarily a management philosophy, a system of values and behaviors that goes beyond the mere application of the instrument and that, once internalized, will form the nucleus of the corporate culture. "Lean Oncology" is a term coined to identify a methodology of care and treatment to cancer patients, consisting on process simplification, streamlining of the organizational and routes of drug treatment, detection and elimination of waste. Its main objective is the centrality of the patient. PMID- 22533797 TI - Equivalent comfort contours for vertical seat vibration: effect of vibration magnitude and backrest inclination. AB - This study determined how backrest inclination and the frequency and magnitude of vertical seat vibration influence vibration discomfort. Subjects experienced vertical seat vibration at frequencies in the range 2.5-25 Hz at vibration magnitudes in the range 0.016-2.0 ms(-2) r.m.s. Equivalent comfort contours were determined with five backrest conditions: no backrest, and with a stationary backrest inclined at 0 degrees (upright), 30 degrees , 60 degrees and 90 degrees . Within all conditions, the frequency of greatest sensitivity to acceleration decreased with increasing vibration magnitude. Compared to an upright backrest, around the main resonance of the body, the vibration magnitudes required to cause similar discomfort were 100% greater with 60 degrees and 90 degrees backrest inclinations and 50% greater with a 30 degrees backrest inclination. It is concluded that no single frequency weighting provides an accurate prediction of the discomfort caused by vertical seat vibration at all magnitudes and with all backrest conditions. PRACTITIONER SUMMARY: Vertical seat vibration is a main cause of vibration discomfort for drivers and passengers of road vehicles. A frequency weighting has been standardised for the evaluation of vertical seat vibration when sitting upright but it was not known whether this weighting is suitable for the reclined sitting postures often adopted during travel. PMID- 22533798 TI - Association between thyroid function, thyroid autoimmunity, and state and trait factors of depression. AB - OBJECTIVE: The aim of this study was to investigate whether thyroid function and thyroid peroxidase antibodies (TPOAb) are associated with depression, when using both state and trait parameters of depression. METHOD: In 1125 participants of the Nijmegen Biomedical Study, thyroid-stimulating hormone (TSH), free thyroxine (FT4), and TPOAb were measured twice. The Beck Depression Inventory (BDI), a self reported lifetime diagnosis of depression, and the neuroticism scale of the Eysenck Personality Questionnaire Revised Short Scale (EPQ-RSS) were used to evaluate the presence of state and trait features of depression. RESULTS: We found no association between TSH and FT4 levels and BDI score, current depression, lifetime diagnosis of depression, and EPQ-RSS neuroticism score. Subjects with TPOAb had higher EPQ-RSS neuroticism scores in comparison with subjects without TPOAb, mean score 4.1 vs. 3.2 (regression coefficient 0.70; 95% CI 0.1-1.3; P-value 0.02 after adjustment for confounders). The prevalence of a lifetime diagnosis of depression was higher in subjects with positive TPOAb in comparison with participants without TPOAb: 24.2% vs. 16.7% (relative risk 1.4; 95% CI 1.0-2.1; P-value 0.04 after adjustment for confounders). CONCLUSION: Thyroid peroxidase antibodies are positively associated with trait markers of depression. The presence of TPOAb may be a vulnerability marker for depression. PMID- 22533799 TI - The potential benefits of sugar-free chewing gum on the oral health and quality of life of older people living in the community: a randomized controlled trial. AB - OBJECTIVES: To determine the effects of prescribing sugar-free chewing gum on the oral health and quality of life of dentate older people living in the community and attending for routine dental care. METHODS: A randomized controlled trial was conducted on 186 older people who were not regular chewers of gum, (aged 60 years and over with >= 6 teeth) recruited from primary care clinics. Participants were randomly allocated to a gum-chewing group (chewing xylitol-containing gum twice a day for 15 min; n = 95) or a control group (no gum; n = 91). Both groups were examined at baseline and at the end of the study (6 months later). The primary outcome measure for the study was increased in stimulated saliva flow rate. Secondary measures included improvements in Plaque and Gingival Indices, and self perceived change in oral health. RESULTS: The retention rate for the study was 78.5% (n = 146 at follow-up); reported compliance with the protocol was 84% (ranged between 12% and 100%). There was no significant change in the saliva flow of the gum-chewing group (1.20-1.17 ml/min), while the control group experienced an increase in flow rate (1.06-1.32 ml/min; P = 0.001). The gum-chewing group, however, demonstrated significant improvement in Plaque and Gingival Index scores over the control group. For the Plaque Index, the mean scores (+/-SD) were 0.29 (+/-0.29) and 0.56 (+/-0.46) for the gum-chewing group and control groups, respectively (P < 0.001), at the second examination, which remained significant after controlling for age and saliva flow rate. For the Gingival Index, the scores were 0.73 (+/-0.30) and 0.92 (+/-0.32), respectively (P < 0.001), which persisted after controlling for age. A significantly higher proportion of participants in the gum-chewing group perceived that their oral health had improved during the study period in comparison with the control group (40% cf 21%; P = 0.016). CONCLUSIONS: Prescription of sugar-free chewing gum to dentate older people living in the community and attending routine dental services was not associated with a significant increase in stimulated saliva flow. There were, however, significant improvements in Plaque and Gingival Index scores, and in self-perceived oral health. PMID- 22533800 TI - Processing speed mediates gender differences in memory in schizophrenia. AB - The primary aim of this study was to examine whether processing speed mediates the association between gender and episodic memory in schizophrenia. Participants were 51 female and 51 male outpatients comparable on demographic, clinical, and cognitive variables. Memory tests included both verbal and visual measures. Both groups scored below the normative mean of the memory and processing speed tests, except that females performed slightly above the mean on face recognition. Females outperformed males on verbal memory, visual recognition, and processing speed. Mediation regression analyses showed processing speed mediated immediate and delayed recall for both verbal and visual memory measures. Thus processing speed appears to be a critical variable for understanding cognitive deficits in schizophrenia and may be an important target for cognitive rehabilitation. PMID- 22533801 TI - Efficacy of a reading and language intervention for children with Down syndrome: a randomized controlled trial. AB - BACKGROUND: This study evaluates the effects of a language and literacy intervention for children with Down syndrome. METHODS: Teaching assistants (TAs) were trained to deliver a reading and language intervention to children in individual daily 40-min sessions. We used a waiting list control design, in which half the sample received the intervention immediately, whereas the remaining children received the treatment after a 20-week delay. Fifty-seven children with Down syndrome in mainstream primary schools in two U.K. locations (Yorkshire and Hampshire) were randomly allocated to intervention (40 weeks of intervention) and waiting control (20 weeks of intervention) groups. Assessments were conducted at three time points: pre-intervention, after 20 weeks of intervention, and after 40 weeks of intervention. RESULTS: After 20 weeks of intervention, the intervention group showed significantly greater progress than the waiting control group on measures of single word reading, letter-sound knowledge, phoneme blending and taught expressive vocabulary. Effects did not transfer to other skills (nonword reading, spelling, standardised expressive and receptive vocabulary, expressive information and grammar). After 40 weeks of intervention, the intervention group remained numerically ahead of the control group on most key outcome measures; but these differences were not significant. Children who were younger, attended more intervention sessions, and had better initial receptive language skills made greater progress during the course of the intervention. CONCLUSIONS: A TA delivered intervention produced improvements in the reading and language skills of children with Down syndrome. Gains were largest in skills directly taught with little evidence of generalization to skills not directly taught in the intervention. PMID- 22533802 TI - Structure/processing/properties relationships in nanoporous nanoparticles as applied to catalysis of the cathodic oxygen reduction reaction. AB - We present a comprehensive experimental study of the formation and activity of dealloyed nanoporous Ni/Pt alloy nanoparticles for the cathodic oxygen reduction reaction. By addressing the kinetics of nucleation during solvothermal synthesis we developed a method to control the size and composition of Ni/Pt alloy nanoparticles over a broad range while maintaining an adequate size distribution. Electrochemical dealloying of these size-controlled nanoparticles was used to explore conditions in which hierarchical nanoporosity within nanoparticles can evolve. Our results show that in order to evolve fully formed porosity, particles must have a minimum diameter of ~15 nm, a result consistent with the surface kinetic processes occurring during dealloying. Nanoporous nanoparticles possess ligaments and voids with diameters of approximately 2 nm, high surface area/mass ratios usually associated with much smaller particles, and a composition consistent with a Pt-skeleton covering a Ni/Pt alloy core. Electrochemical measurements show that the mass activity for the oxygen reduction reaction using carbon-supported nanoporous Ni/Pt nanoparticles is nearly four times that of commercial Pt/C catalyst and even exceeds that of comparable nonporous Pt skeleton Ni/Pt alloy nanoparticles. PMID- 22533803 TI - Acute stroke management in patients taking dabigatran. AB - Dabigatran etexilate is emerging as an alternative for vitamin K antagonists, but evidence-based guidelines for management of intracerebral hemorrhage and acute ischemic stroke in patients taking this drug are nonexistent. This review summarizes current knowledge on key pharmacological features and the assessment of dabigatran activity. Pragmatic approaches are provided for individualized decision taking with regard to hemostatic therapy and reperfusion strategies in acute stroke patients. PMID- 22533804 TI - Endothelial feedback and the myoendothelial projection. AB - The endothelium plays a critical role in controlling resistance artery diameter, and thus blood flow and blood pressure. Circulating chemical mediators and physical forces act directly on the endothelium to release diffusible relaxing factors, such as NO, and elicit hyperpolarization of the endothelial cell membrane potential, which spreads to the underlying smooth muscle cells via gap junctions (EDH). It has long been known that arterial vasoconstriction in response to agonists is limited by the endothelium, but the question of how contraction of smooth muscle cells leads to activation of the endothelium (myoendothelial feedback) has, until recently, received little attention. Initial studies proposed the permissive movement of Ca(2+) ions from smooth muscle to endothelial cells to elicit release of NO. However, more recent evidence supports the notion that flux of IP(3) leading to localized Ca(2+) events within spatially restricted myoendothelial projections and activation of EDH may underlie myoendothelial feedback. In this perspective, we review recent data which supports the functional role of myoendothelial projections in smooth muscle to endothelial communication. We also discuss the functional evidence supporting the notion that EDH, as opposed to NO, is the primary mediator of myoendothelial feedback in resistance arteries. PMID- 22533805 TI - Improving the understanding of medication non-adherence among mental health professionals: findings from a series of UK training workshops. AB - BACKGROUND: Medication non-adherence has far-reaching consequences. Before utilising specialized interventions to target this problem, there is a need to improve the detection, understanding and management of non-adherence in routine clinical practice. AIMS AND METHOD: This study explored whether a 1-day workshop targeting attitudes, skills and knowledge about medication adherence could modify any aspect of clinical practice of mental health professionals. RESULTS: Five workshops were held with 134 participants. Baseline general knowledge in all professional groups was poor and interventions used not ideal. Post-workshop knowledge improved significantly. At 3-month follow-up, participants reported identifying more new cases of non-adherence and use of more effective strategies. Lack of time and support were identified as persisting barriers to change. CONCLUSIONS: It is possible to raise awareness, teach a model and simple techniques to effect change in clinical practice. This brief training was well received, although ongoing support is required to increase interventions for as well as identification of individuals at risk of medication non-adherence. PMID- 22533806 TI - Fluoreno[4,3-c]fluorene: a closed-shell, fully conjugated hydrocarbon. AB - The synthesis and optoelectronic properties of 24 pi-electron, formally antiaromatic 4,11-di-t-butyl-1,8-dimesitylfluoreno[4,3-c]fluorene (FF) are presented. The solid-state structure shows that the outer rings are aromatic, while the central four rings possess a bond-localized 2,6-naphthoquinone dimethide motif (in red). The biradical character of FF is assessed experimentally and computationally; the results of which implicate a closed-shell ground state. PMID- 22533811 TI - Diagnosis and management of chronic graft-versus-host disease. AB - A joint working group established by the Haemato-oncology subgroup of the British Committee for Standards in Haematology (BCSH) and the British Society for Bone Marrow Transplantation (BSBMT) has reviewed the available literature and made recommendations for the diagnosis and management of chronic graft-versus-host disease (GvHD). This guideline includes recommendations for the diagnosis and staging of chronic GvHD as well as primary treatment and options for patients with steroid-refractory disease. The goal of treatment should be the effective control of GvHD while minimizing the risk of toxicity and relapse. PMID- 22533807 TI - Metabolic engineering of recombinant protein secretion by Saccharomyces cerevisiae. AB - The yeast Saccharomyces cerevisiae is a widely used cell factory for the production of fuels and chemicals, and it is also provides a platform for the production of many heterologous proteins of medical or industrial interest. Therefore, many studies have focused on metabolic engineering S. cerevisiae to improve the recombinant protein production, and with the development of systems biology, it is interesting to see how this approach can be applied both to gain further insight into protein production and secretion and to further engineer the cell for improved production of valuable proteins. In this review, the protein post-translational modification such as folding, trafficking, and secretion, steps that are traditionally studied in isolation will here be described in the context of the whole system of protein secretion. Furthermore, examples of engineering secretion pathways, high-throughput screening and systems biology applications of studying protein production and secretion are also given to show how the protein production can be improved by different approaches. The objective of the review is to describe individual biological processes in the context of the larger, complex protein synthesis network. PMID- 22533814 TI - Pore networks and polymer rearrangement on a drug-eluting stent as revealed by correlated confocal Raman and atomic force microscopy. AB - Drug release from and coating morphology on a CYPHER sirolimus-eluting coronary stent (SES) during in vitro elution were studied by correlated confocal Raman and atomic force microscopy (CRM and AFM, respectively). Chemical surface and subsurface maps of the SES were generated in the same region of interest by CRM and were correlated with surface topography measured by AFM at different elution times. For the first time, a direct correlation between drug-rich regions and the coating morphology was made on a drug-eluting medical device, linking drug release with pore formation, pore throats, and pore networks. Drug release was studied on a drug-eluting stent (DES) system with a multicomponent carrier matrix (poly(n-butyl methacrylate) [PBMA] and poly(ethylene-co-vinyl acetate) [PEVA]). The polymer was found to rearrange postelution because confluence of the carrier polymer matrix reconstituted the voids created by drug release. PMID- 22533815 TI - Partial identification of antifungal compounds from Punica granatum peel extracts. AB - Aqueous extracts of pomegranate peels were assayed in vitro for their antifungal activity against six rot fungi that cause fruit and vegetable decay during storage. The growth rates of Alternaria alternata , Stemphylium botryosum , and Fusarium spp. were significantly inhibited by the extracts. The growth rates were negatively correlated with the levels of total polyphenolic compounds in the extract and particularly with punicalagins, the major ellagitannins in pomegranate peels. Ellagitannins were also found to be the main compounds in the bioactive fractions using bioautograms, and punicalagins were identified as the main bioactive compounds using chromatographic separation. These results suggest that ellagitannins, and more specifically punicalagins, which are the dominant compounds in pomegranate peels, may be used as a control agent of storage diseases and to reduce the use of synthetic fungicides. PMID- 22533816 TI - Possible association of the Plasmodium falciparum T1526C resa2 gene mutation with severe malaria. AB - BACKGROUND: Plasmodium falciparum exports proteins that remodel the erythrocyte membrane. One such protein, called Pf155/RESA (RESA1) contributes to parasite fitness, optimizing parasite survival during febrile episodes. Resa1 gene is a member of a small family comprising three highly related genes. Preliminary evidence led to a search for clues indicating the involvement of RESA2 protein in the pathophysiology of malaria. In the present study, cDNA sequence of resa2 gene was obtained from two different strains. The proportion of P. falciparum isolates having a non-stop T1526C mutation in resa2 gene was evaluated and the association of this genotype with severity of malaria was investigated. METHODS: Resa2 cDNAs of two different strains (a patient isolate and K1 culture adapted strain) was obtained by RT-PCR and DNA sequencing was performed to confirm its gene structure. The proportion of isolates having a T1526C mutation was evaluated using a PCR-RFLP methodology on groups of severe malaria and uncomplicated patients recruited in 1991-1994 in Senegal and in 2009 in Benin. RESULTS: A unique ORF with an internal translation stop was found in the patient isolate (Genbank access number : JN183870), while the K1 strain harboured the T1526C mutation (Genbank access number : JN183869) which affects the internal stop codon and restores a full length coding sequence. About 14% of isolates obtained from Senegal and Benin harboured mutant T1526C parasites. Some isolates had both wild and mutant resa alleles. The analysis excluding those mixed isolates showed that the resa2 T1526C mutation was found more frequently in severe malaria cases than in uncomplicated cases (p = 0.008). The association of the presence of the mutant allele and parasitaemia >4% was shown in multivariate analysis (p = 0.03) in the group of Beninese children. CONCLUSIONS: All T1526C mutant parasites theoretically have the ability to give rise to a full-length RESA2 protein. This study raises the hypothesis that the RESA2 protein could favour high-density infections. Other studies in various geographic settings and probably including more patients are now required to replicate these results and to answer the questions raised by these results. PMID- 22533817 TI - Comparison of pre-cryopreserved and post-thaw-and-wash-nucleated cell count on major outcomes following unrelated cord blood transplant in children. AB - Engraftment and OS after umbilical CBT is highly dependent on the TNC. The contribution of the wash step to cell loss and ultimately the dose of cells available for transplant is not well described. To investigate the amount of cell loss after washing and its impact on major outcomes compared to pre-cryopreserved TNC, we analyzed data from patients prospectively enrolled on a National Heart, Lung and Blood Institute sponsored cord blood transplant study between 1999 and 2003. There were 310 patients <=18 yr of age with malignant (N = 218) or non malignant (N = 92) disease enrolled on this trial. Only single CBU were used. All CBU were thawed and washed using an identical process. The median TNC after thawing and washing (PTW) was 5.43 * 10(7) /kg (79% recovery of cells). The cumulative incidence of neutrophil engraftment was significantly higher in patients receiving a PTW TNC >=2.5 * 10(7) /kg (p = 0.01). The cumulative incidence of TRM was higher among patients receiving post-thaw-and-wash TNC <2.5 * 10(7) /kg (p = 0.039). In conclusion, receiving a PTW TNC of <2.5 * 10(7) /kg resulted in worse neutrophil engraftment and increased transplant-related mortality compared to a PTW TNC of >=2.5 * 10(7) /kg. PMID- 22533818 TI - Identification of glycogen synthase kinase-3 inhibitors with a selective sting for glycogen synthase kinase-3alpha. AB - The glycogen synthase kinase-3 (GSK-3) has been linked to the pathogenesis of colorectal cancer, diabetes, cardiovascular disease, acute myeloid leukemia (AML), and Alzheimer's disease (AD). The debate on the respective contributions of GSK-3alpha and GSK-3beta to AD pathology and AML is ongoing. Thus, the identification of potent GSK-3alpha-selective inhibitors, endowed with favorable pharmacokinetic properties, may elucidate the effect of GSK-3alpha inhibition in AD and AML models. The analysis of all available crystallized GSK-3 structures provided a simplified scheme of the relevant hot spots responsible for ligand binding and potency. This resulted in the identification of novel scorpion shaped GSK-3 inhibitors. It is noteworthy, compounds 14d and 15b showed the highest GSK 3alpha selectivity reported so far. In addition, compound 14d did not display significant inhibition of 48 out of 50 kinases in the test panel. The GSK-3 inhibitors were further profiled for efficacy and toxicity in the wild-type (wt) zebrafish embryo assay. PMID- 22533819 TI - Dynamical analysis in real time: detecting perturbations to team communication. AB - Dynamical systems methods characterise patterns of change over time. Typically, such methods are applied only after data collection is complete. However, brief disturbances - perturbations - can occur as a process unfolds and can result in undesirable outcomes if not acted on. The application of dynamics in real time would be useful for detecting these sudden changes. Real-time analysis was accomplished by updating dynamical estimates simultaneously across different window sizes. We calculated the largest Lyapunov exponent, a measure of dynamical stability, to detect a perturbation to team communication in a simulated uninhabited air vehicle (UAV) reconnaissance mission. The perturbation consisted of information demands from a confederate that occurred unexpectedly during performance of a UAV mission. We demonstrate the use of real-time methods in detecting that perturbation as it occurred. In application, this technique would have enabled real-time intervention. Extensions of the real-time dynamical method to other domains of psychological inquiry are discussed. PRACTITIONER SUMMARY: A real-time dynamical analysis method that was developed to detect unexpected perturbations in team communication is described. The use of the method is demonstrated on perturbed communication from a three-person uninhabited air vehicle command-and-control team. The generalisability of the method is considered with respect to physiological and motor coordination dynamics. PMID- 22533820 TI - Electron transfer triggered by optical excitation of phenothiazine-tris(meta phenylene-ethynylene)-(tricarbonyl)(bpy)(py)rhenium(I). AB - We have investigated excited-state electron transfer in a donor-bridge-acceptor complex containing phenothiazine (PTZ) linked via tris(meta-phenylene-ethynylene) to a tricarbonyl(bipyridine)(pyridine)Re(I) unit. Time-resolved luminescence experiments reveal two excited-state (*Re) decay regimes, a multiexponential component with a mean lifetime of 2.7 ns and a longer monoexponential component of 530 ns in dichloromethane solution. The faster decay is attributed to PTZ -> *Re electron transfer in a C-shaped PTZ-bridge-Re conformer (PTZ-Re ~ 7.5 A). We assign the longer lifetime, which is virtually identical to that of free *Re, to an extended conformer (PTZ-Re > 20 A). The observed biexponential *Re decay requires that interconversion of PTZ-bridge-Re conformers be slower than 10(6) s( 1). PMID- 22533822 TI - Generation of an isolable, monomeric manganese(V)-oxo complex from O2 and visible light. AB - The direct conversion of a Mn(III) complex [(TBP(8)Cz)Mn(III) (1)] to a Mn(V)-oxo complex [(TBP(8)Cz)Mn(V)(O) (2)] with O(2) and visible light is reported. Complex 1 is also shown to function as an active photocatalyst for the oxidation of PPh(3) to OPPh(3). Mechanistic studies indicate that the photogeneration of 2 does not involve singlet oxygen but rather likely occurs via a free-radical mechanism upon photoactivation of 1. PMID- 22533821 TI - Nitric oxide augments mesenchymal stem cell ability to repair liver fibrosis. AB - BACKGROUND: Liver fibrosis is a major health problem worldwide and poses a serious obstacle for cell based therapies. Mesenchymal stem cells (MSCs) are multipotent and important candidate cells for future clinical applications however success of MSC therapy depends upon their homing and survival in recipient organs. This study was designed to improve the repair potential of MSCs by transplanting them in sodium nitroprusside (SNP) pretreated mice with CCl(4) induced liver fibrosis. METHODS: SNP 100 mM, a nitric oxide (NO) donor, was administered twice a week for 4 weeks to CCl(4)-injured mice. MSCs were isolated from C57BL/6 wild type mice and transplanted in the left lateral lobe of the liver in experimental animals. After 4 weeks, animals were sacrificed and liver improvement was analyzed. Analysis of fibrosis by qRT-PCR and sirius red staining, homing, bilirubin and alkaline phosphatase (ALP) serum levels between different treatment groups were compared to control. RESULTS: Liver histology demonstrated enhanced MSCs homing in SNP-MSCs group compared to MSCs group. The gene expression of fibrotic markers; alphaSMA, collagen 1alpha1, TIMP, NFkappaB and iNOS was down regulated while cytokeratin 18, albumin and eNOS was up regulated in SNP-MSCs group. Combine treatment sequentially reduced fibrosis in SNP-MSCs treated liver compared to the other treatment groups. These results were also comparable with reduced serum levels of bilirubin and ALP observed in SNP MSCs treated group. CONCLUSION: This study demonstrated that NO effectively augments MSC ability to repair liver fibrosis induced by CCl(4) in mice and therefore is a better treatment regimen to reduce liver fibrosis. PMID- 22533823 TI - Drugs in the medical treatment of Cushing's syndrome--an update on mifepristone and pasireotide. PMID- 22533824 TI - HIV risk perceptions among adolescents attending family planning clinics: an integrated perspective. AB - Abstract The current study assessed the impact of individual, interpersonal, and contextual factors on HIV risk perception. A total of 426 female adolescents attending family planning clinics took part in this study. The majority, 60.1% were African-American and 39.9% were Hispanic. The results indicated that the majority of participants perceived themselves to be at no or low risk for contracting HIV. Individual, interpersonal as well as contextual factors correlated with HIV risk perception in the study. Adolescents who perceived themselves to be at no or low risk were more likely to be Hispanic, be married and had children. They also felt that they can control situations where they have to refuse sex or insist on condom use, had more frequent communication with sexual partners about condom use and held perceptions that peer norms support condom use. The findings in this study have important implications for risk reduction education for female adolescents. Risk reduction education should strengthen adolescents' personal skills to help them avoid HIV risk despite the various pressures they experience in their life. PMID- 22533826 TI - Validation of the repeatable battery for the assessment of neuropsychological status--effort index in a veteran sample. AB - The RBANS Effort Index (RBANS-EI; Silverberg, Wertheimer, & Fichtenberg, 2007) is an embedded measure of effort within a frequently employed neuropsychological screening battery. While it has been criticized for inadequate specificity in older non-litigating samples (Hook, Marquine, & Hoelzle, 2009; Warren et al., 2010), the RBANS-EI has yet to be investigated in a non-geriatric veteran sample. Archival data were collected from 85 veterans who completed the RBANS and WMT within either a routine neuropsychological evaluation (n = 66) or compensation evaluation (n = 19). At a cutoff of >3 RBANS-EI exhibited strong specificity (.94) yet limited sensitivity (.31) in the prediction of WMT performance. Examination of RBANS-EI component subtests found that List Recognition <17 had strong specificity (.90) and moderate sensitivity (.52) in discriminating WMT performance groups. In contrast, Digit Span performance was comparable between those passing and failing the WMT. Present findings indicate that both the RBANS EI and List Recognition subtest may be useful in detecting suboptimal effort yet raise questions regarding the Digit Span component of the RBANS-EI. PMID- 22533825 TI - Functional single nucleotide polymorphism in C20orf54 modifies susceptibility to esophageal squamous cell carcinoma. AB - The aim of this study was to explore the association of C20orf54 functional single nucleotide polymorphism (SNP) with the susceptibility to esophageal squamous cell carcinoma (ESCC) in a northern China population. The C20orf54 SNP was genotyped by direct sequencing in 240 cancer patients and 198 controls in northern China. The results showed that drinking status, family history of ESCC, and body mass index have great influence on the risk of developing ESCC. The overall genotype frequencies of C20orf54 in ESCC patients have a significant difference with healthy controls (chi(2) = 8.06, P = 0.018). By using C/C genotype as the reference, the C/T genotype showed a significantly decreased risk to the development of ESCC. Thus, compared with the C/C genotype, smokers, drinkers with C/T genotype significantly decreased the risk of developing ESCC. A positive family history of ESCC with C/T and T/T genotype both increased the risk of developing ESCC. Body mass index between 18.5 and 24 with C/T genotype significantly decreased the risk of developing ESCC. The present study suggests that the C20orf54 functional SNP might be associated with a risk of development in ESCC. PMID- 22533827 TI - Introduction of a competency based haemodialysis education programme: 5 years experience. AB - The quality of care that patients receive is fundamentally related to the knowledge and skills of the staff providing the care. To ensure that all staff within our dialysis clinic network has the knowledge and competence to provide the care, support and education that patients require, a competency based education programme was developed. Roll-out of the programme commenced in 129 clinics in our dialysis clinic network during 2006-2007. Activity with this programme has continued. It is now translated into 12 languages and fully implemented in 11 countries. At the end of December 2010, 3,099 staff had completed the Basic Dialysis Programme and 3,125 staff had completed the Orientation Programme component of the education programme. Results of quality activities have enabled further programme development and have shown that the investment in staff education has benefited our organisation, staff and patients. PMID- 22533828 TI - Juxtaglomerular apparatus hyperplasia under dual angiotensin blockade. A footprint of adequate RAS inhibition or a concern for renal fibrosis? AB - BACKGROUND: Dual renin-angiotensin system blockade with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers has been advocated to minimize proteinuria. However, recent trials have questioned the renal safety of this approach. Our understanding on the molecular effects of dual blockade in humans is incomplete. CASE PRESENTATION: We present a patient with corticoid resistant nephrotic syndrome who developed marked juxtaglomerular apparatus hyperplasia and renin expression in the context of dual angiotensin system blockade. CONCLUSIONS: Although renin may have profibrotic effects mediated by (pro)renin receptor activation, this report raises questions on the potential consequences of local renin activation on chronic kidney disease in patients with dual angiotensin blockade. PMID- 22533829 TI - Subsurface influence on the structure of protein adsorbates as revealed by in situ X-ray reflectivity. AB - The adsorption process of proteins to surfaces is governed by the mutual interactions among proteins, the solution, and the substrate. Interactions arising from the substrate are usually attributed to the uppermost atomic layer. This actual surface defines the surface chemistry and hence steric and electrostatic interactions. For a comprehensive understanding, however, the interactions arising from the bulk material also have to be considered. Our protein adsorption experiments with globular proteins (alpha-amylase, bovine serum albumin, and lysozyme) clearly reveal the influence of the subsurface material via van der Waals forces. Here, a set of functionalized silicon wafers enables a distinction between the effects of surface chemistry and the subsurface composition of the substrate. Whereas the surface chemistry controls whether the individual proteins are denatured, the strength of the van der Waals forces affects the final layer density and hence the adsorbed amount of proteins. The results imply that van der Waals forces mainly influence surface processes, which govern the structure formation of the protein adsorbates, such as surface diffusion and spreading. PMID- 22533830 TI - Enantioselective preparation of cis-beta-azidocyclopropane esters by cyclopropanation of azido alkenes using a chiral dirhodium catalyst. AB - A diastereo- and enantiocontrolled preparation of the conformationally restricted cis-beta-azidocyclopropane esters have been developed. The Rh(2)(S-DOSP)(4) was found to be an efficient catalyst in hexane for the cyclopropanation of azido alkenes with diazo esters, and 19 cis-beta-azidocyclopropane esters were prepared in excellent yields. The value of the diastereomer ratio was up to 99:1, and the enantiomeric excess was up to 95%. Furthermore, the relative and absolute configuration was confirmed by X-ray analysis. PMID- 22533831 TI - Diagnosis and management of acute graft-versus-host disease. AB - A joint working group established by the Haemato-oncology subgroup of the British Committee for Standards in Haematology (BCSH) and the British Society for Bone Marrow Transplantation (BSBMT) has reviewed the available literature and made recommendations for the diagnosis and management of acute graft-versus-host disease. This guideline includes recommendations for the diagnosis and grading of acute graft-versus-host disease as well as primary treatment and options for patients with steroid-refractory disease. The goal of treatment should be effective control of graft-versus-host disease while minimizing risk of toxicity and relapse. PMID- 22533837 TI - Respiratory syncytial virus lower respiratory tract infection in a pediatric liver transplant recipient treated with oral ribavirin. AB - The mainstay of therapy for RSV disease is supportive care, although aerosolized ribavirin has been used to treat infants and young children with severe lower respiratory tract infections. Aerosolized ribavirin has adverse effects, high cost and teratogenic potential. We report the case of a pediatric liver transplant recipient diagnosed with lower respiratory RSV infection, who was successfully treated with oral ribavirin. PMID- 22533832 TI - Evidence for in vitro and in vivo expression of the conserved VAR3 (type 3) plasmodium falciparum erythrocyte membrane protein 1. AB - BACKGROUND: Members of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) adhesion antigen family are major contributors to the pathogenesis of P. falciparum malaria infections. The PfEMP1-encoding var genes are among the most diverse sequences in nature, but three genes, var1, var2csa and var3 are found conserved in most parasite genomes. The most severe forms of malaria disease are caused by parasites expressing a subset of antigenically conserved PfEMP1 variants. Thus the ubiquitous and conserved VAR3 PfEMP1 is of particular interest to the research field. Evidence of VAR3 expression on the infected erythrocyte surface has never been presented, and var3 genes have been proposed to be transcribed and expressed differently from the rest of the var gene family members. METHODS: In this study, parasites expressing VAR3 PfEMP1 were generated using anti-VAR3 antibodies and the var transcript and PfEMP1 expression profiles of the generated parasites were investigated. The IgG reactivity by plasma from children living in malaria-endemic Tanzania was tested to parasites and recombinant VAR3 protein. Parasites from hospitalized children were isolated and the transcript level of var3 was investigated. RESULTS: Var3 is transcribed and its protein product expressed on the surface of infected erythrocytes. The VAR3 expressing parasites were better recognized by children's IgG than a parasite line expressing a Group B var gene. Two in 130 children showed increased recognition of parasites expressing VAR3 and to the recombinant VAR3 protein after a malaria episode and the isolated parasites showed high levels of var3 transcripts. CONCLUSIONS: Collectively, the presented data suggest that var3 is transcribed and its protein product expressed on the surface of infected erythrocytes in the same manner as seen for other var genes both in vitro and in vivo. Only very few children exhibit seroconversion to VAR3 following a malaria episode requiring hospitalization, supporting the previous conclusion drawn from var3 transcript analysis of parasites collected from children hospitalized with malaria, that VAR3 is not associated with severe anaemia or cerebral malaria syndromes in children. PMID- 22533839 TI - Liquid state elasticity and the onset of activated transport in glass formers. AB - We show that the crossover temperature to activated transport in glass-forming liquids can be predicted using their finite-frequency elastic constants and the fusion entropy. The latter quantities determine the size of the vibrational motions of chemically rigid molecular units in the liquid as a function of temperature. Using the notion that, at the crossover, the "Lindemann ratio" of this vibrational displacement to the corresponding lattice spacing is nearly system-independent, one can estimate the crossover temperature. For nine specific substances, the resulting predictions are consistent with experimental estimates of the dynamical crossover temperature and also with the predictions of the random first order transition (RFOT) theory for the onset of barrierless transport owing to fractal correlated rearrangements that occur at a critical configurational entropy. In particular, the fragility index is found to inversely correlate with the ratio of the crossover and glass transition temperatures. This prediction agrees with most observations except for boron oxide B2O3, which deviates from the common trend. This exception is argued to result from additional local ordering with lowering temperature in B2O3. Finally, we show that taking into account the temperature dependence of the elastic constants is crucial for accurate estimates of the crossover temperature. PMID- 22533838 TI - Organic anion transporting polypeptides OATP1B1 and OATP1B3 and their genetic variants influence the pharmacokinetics and pharmacodynamics of raloxifene. AB - BACKGROUND: Raloxifene, a selective estrogen receptor modulator, exhibits quite large and unexplained interindividual variability in pharmacokinetics and pharmacodynamics. The aim of this study was to determine the role of organic anion transporting polypeptides OATP1B1 and OATP1B3 and their genetic variants in the pharmacokinetics and pharmacodynamics of raloxifene. METHODS: To test the role of OATP1B1 and OATP1B3 transporters on hepatic uptake of raloxifene and its metabolites an in vitro model of Chinese Hamster Ovary cells expressing OATP1B1 or OATP1B3 was employed. The influence of OATP1B1 and OATP1B3 genetic variants on in vivo pharmacokinetics and pharmacodynamics was evaluated in 53 osteoporotic postmenopausal women treated with raloxifene. RESULTS: Our in vitro results showed that raloxifene and two of the three metabolites, raloxifene-4'-beta glucuronide (M2) and raloxifene-6,4'-diglucuronide (M3), interact with OATP1B1 and OATP1B3. Higher M3 and total raloxifene serum concentrations in patients correlated with lower serum levels of bone resorption marker, serum C-terminal telopeptide fragments of type I collagen, indicating a higher antiresorptive effect of raloxifene. Higher concentrations of M2 correlated with higher increase of lumbar spine bone mineral density supporting the raloxifene vertebral fracture specific protection effect. Finally, raloxifene, M3 and total raloxifene serum concentrations were significantly higher in patients with SLCO1B1 c.388A > G polymorphism and *1b haplotype implicating a considerable genetic effect on pharmacokinetics and pharmacodynamics of raloxifene. CONCLUSIONS: These findings indicate that SLCO1B1 c.388A > G polymorphism could play an important role in pharmacokinetics and pharmacodynamics of raloxifene. PMID- 22533840 TI - From dinner table to digital tablet: technology's potential for reducing loneliness in older adults. AB - Statistics estimate that close to 35% of our nation's older individuals experience loneliness. Feelings of loneliness have been associated with physical and psychological illness in several research studies. As technology advances and connectivity through tablet devices becomes increasingly user friendly, the potential for tablets to reduce loneliness among older adults is substantial. This article discusses the issue of loneliness among older adults and suggests tablet technology as a tool to improve connectivity and reduce loneliness in the older adult population. As nurses, we have the opportunity to help enhance the quality of life for our clients. Tablet technology offers a new option that should be fully explored. PMID- 22533841 TI - Changing attitudes about self-injury prevention management: lessons learned. AB - In the behavioral health environment, nurses often use continuous staff monitoring and, at times, physical restraints, to manage the severity of patients' self-injury. Both options put staff in control, are the most restrictive in nature, and can be financially draining on the hospital's budget. This can result in negative reactions by both patients and staff. It is important to develop a program that will empower patients to control their behavior and allow staff to be aware of their perceptions and attitudes toward patients who self-injure. This article describes the leadership initiative that drove the development, training, and implementation of a self-injury prevention project and the lessons learned by staff. PMID- 22533842 TI - Enclosed versus open nursing stations in adult acute care psychiatric settings: does the design affect the therapeutic milieu? AB - Specific efforts by hospital accreditation organizations encourage renovation of nursing stations, so nurses can better see, attend, and care for their patients. The purpose of this study was to examine the effect of nursing station design on the therapeutic milieu in an adult acute care psychiatric unit. A repeated cross sectional, pretest-posttest design was used. Data were collected from a convenience sample of 81 patients and 25 nursing staff members who completed the Ward Atmosphere Scale. Pretest data were collected when the unit had an enclosed nursing station, and posttest data were collected after renovations to the unit created an open nursing station. No statistically significant differences were found in patient or staff perceptions of the therapeutic milieu. No increase in aggression toward staff was found, given patients' ease of access to the nursing station. More research is needed about the impact of unit design in acute care psychiatric settings. PMID- 22533843 TI - Making it real: using standardized patients to bring case studies to life. AB - With increases in the overall number of individuals with posttraumatic stress disorder (PTSD), nurse educators must provide experiences that help nursing students learn how to better communicate and care for individuals with this disorder. This article describes how two learning strategies-case studies and standardized patients-were combined to facilitate the development of therapeutic communication and assessment skills. Two case studies on PTSD were written, and actors were trained to portray the individuals in the case studies. Fourteen baccalaureate nursing students enrolled in a senior-level psychiatric nursing clinical course participated in this pilot alternative learning activity. This article describes the learning activity and presents student evaluations of the assignment. PMID- 22533844 TI - The challenges of clinical psychopharmacological management. AB - Collaboration among health care providers in the treatment of mental health patients with comorbid medical and neurological conditions can be very challenging, especially with pharmacotherapy management where medications are prescribed by multiple providers. An individual example of a patient with a number of comorbid conditions taking multiple concurrent medical and psychotropic medications is described to highlight how challenging such situations can be. Medical conditions or medical medications might trigger or exacerbate symptoms of mental disorders. Psychotropic drugs may cause adverse effects that come to the attention of medical providers. Accurate communication among providers-and between the patient and providers-is important to avoid misinformation or misunderstandings in the care of patients with complicated problems. PMID- 22533845 TI - Brain-computer interface (BCI) and ergonomics. PMID- 22533850 TI - Synthesis and biological evaluation of fatty acyl ester derivatives of (-)-2',3' dideoxy-3'-thiacytidine. AB - A number of fatty acyl derivatives of (-)-2',3'-dideoxy-3'-thiacytidine (lamivudine, 3TC, 1) were synthesized and evaluated for their anti-HIV activity. The monosubstituted 5'-O-fatty acyl derivatives of 3TC (EC(50) = 0.2-2.3 MUM) were more potent than the corresponding monosubstituted N(4)-fatty acyl (EC(50) = 0.4-29.4 MUM) and 5'-O-N(4)-disubstituted (EC(50) = 72.6 to >154.0 MUM) derivatives of the nucleoside. 5'-O-Myristoyl (16) and 5'-O-12-azidododecanoyl derivatives (17) were found to be the most potent compounds (EC(50) = 0.2-0.9 MUM) exhibiting at least 16-36-fold higher anti-HIV activity against cell-free virus than 1 (EC(50) = 11.4-32.7 MUM). The EC(90) values for 16 against B-subtype and C-subtype clinical isolates were several folds lower than those of 1. The cellular uptake studies confirmed that compound 16 accumulated intracellularly after 1 h of incubation with CCRF-CEM cells and underwent intracellular hydrolysis. 5'-O-Fatty acyl derivatives of 1 showed significantly higher anti-HIV activity than the corresponding physical mixtures against the B-subtype virus. PMID- 22533849 TI - Electron tunneling pathways and role of adenine in repair of cyclobutane pyrimidine dimer by DNA photolyase. AB - Electron tunneling pathways in enzymes are critical to their catalytic efficiency. Through electron tunneling, photolyase, a photoenzyme, splits UV induced cyclobutane pyrimidine dimer into two normal bases. Here, we report our systematic characterization and analyses of photoinitiated three electron transfer processes and cyclobutane ring splitting by following the entire dynamical evolution during enzymatic repair with femtosecond resolution. We observed the complete dynamics of the reactants, all intermediates and final products, and determined their reaction time scales. Using (deoxy)uracil and thymine as dimer substrates, we unambiguously determined the electron tunneling pathways for the forward electron transfer to initiate repair and for the final electron return to restore the active cofactor and complete the catalytic photocycle. Significantly, we found that the adenine moiety of the unusual bent flavin cofactor is essential to mediating all electron-transfer dynamics through a superexchange mechanism, leading to a delicate balance of time scales. The cyclobutane ring splitting takes tens of picoseconds, while electron-transfer dynamics all occur on a longer time scale. The active-site structural integrity, unique electron tunneling pathways, and the critical role of adenine ensure the synergy of these elementary steps in this complex photorepair machinery to achieve maximum repair efficiency which is close to unity. Finally, we used the Marcus electron-transfer theory to evaluate all three electron-transfer processes and thus obtained their reaction driving forces (free energies), reorganization energies, and electronic coupling constants, concluding that the forward and futile back-electron transfer is in the normal region and that the final electron return of the catalytic cycle is in the inverted region. PMID- 22533852 TI - Harmful drinking and talking about alcohol in primary care: New Zealand population survey findings. AB - OBJECTIVE: Existing evidence suggests low recognition of alcohol problems in primary care. This study aimed to determine the 12-month prevalence of harmful or hazardous drinking (HHD) in a population sample and to measure the relationship between HHD and talking about alcohol in primary care consultations in that period. METHOD: A New Zealand population survey of 12 488 adults. Alcohol use in the past 12 months was assessed by the Alcohol Use Disorders Identification Test (AUDIT), with HHD defined as a total score of eight or above. Talking about alcohol was self-reported. RESULTS: HHD was present in 17.7% and was commoner in men and in younger age groups, with the highest prevalence 53.6% in men aged 18 24. Three per cent of those who attended their usual primary care provider in the past 12 months reported being talked to about alcohol. Talking about alcohol increased with AUDIT score, but was not commoner in young people despite their higher prevalence of HHD. Overall, 9.4% of attendees with HHD reported talking about alcohol. CONCLUSION: HHD is common but largely not detected in primary care. Improved detection would permit the delivery of effective treatments such as brief interventions. PMID- 22533853 TI - Colorimetric and ultrasensitive bioassay based on a dual-amplification system using aptamer and DNAzyme. AB - Rapid detection of ultralow amount of biomarkers in a biologically complex mixture remains a major challenge. Herein, we report a novel aptamer-based protein detection assay that integrates two signal amplification processes, namely, polymerase-mediated rolling-circle amplification (RCA) and DNA enzyme catalyzed colorimetric reaction. The target biomarker is captured in a sandwich assay by primary aptamer-functionalized microbeads (MBs) and a secondary aptamer that is connected to a RCA primer/circular template complex. RCA reaction, which amplifies the single biomarker binding events by a factor of hundreds to thousands (the first amplification) produces a long DNA molecule containing multiple DNAzyme units. The peroxidase-like DNAzyme catalyzes the oxidation of 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (the second amplification), which generates a blue-green colorimetric signal. This new biosensing platform permits the ultrasensitive, label-free, colorimetric detection of biomarker in real time. Using platelet-derived growth factor B-chain (PDGF-BB) as a model system, we demonstrated that our assay can detect a protein marker specifically in a serum-containing medium, at a concentration as low as 0.2 pg/mL in ~2 h, which rivals traditional assays such as ELISA. We anticipate this simple methodology for biomarker detection can find utility in point-of-care applications. PMID- 22533854 TI - Conditional monogyny: female quality predicts male faithfulness. AB - INTRODUCTION: Male monogyny in the absence of paternal investment is arguably one of the most puzzling mating systems. Recent evidence suggests that males of monogynous species adjust their life-history and their mating decision to shifting spatial and temporal selection regimes. In the cannibalistic wasp spider Argiope bruennichi males can be either monogynous or mate with a maximum of two females. We studied factors underlying male mating decisions in a natural population over a whole mating season. We documented all matings and categorized the males into single-mated and double-mated monogynous as well as bigynous males. RESULTS: We found that all categories were continuously present with relatively stable frequencies despite changes in the operational sex ratio. Males were more likely monogynous when copulating with relatively heavy and old females and otherwise bigynous. CONCLUSION: Our results imply that males make conditional mating decisions based on the quality of the first female they encounter but do not adjust their mating tactic to the local selection regime. PMID- 22533851 TI - Recent developments on immunotherapy for brain cancer. AB - INTRODUCTION: Brain tumors are a unique class of cancers since they are anatomically shielded from normal immunosurveillance by the blood-brain barrier, lack a normal lymphatic drainage system and reside in a potently immunosuppressive environment. Of the primary brain cancers, glioblastoma multiforme (GBM) is the most common and aggressive in adults. Although treatment options include surgery, radiation and chemotherapy, the average lifespan of GBM patients remains at only 14.6 months post-diagnosis. AREAS COVERED: A review of key cellular and molecular immune system mediators in the context of brain tumors including TGF-beta, cytotoxic T cells, Tregs, CTLA-4, PD-1 and IDO is discussed. In addition, prognostic factors, currently utilized immunotherapeutic strategies, ongoing clinical trials and a discussion of new or potential immunotherapies for brain tumor patients are considered. EXPERT OPINION: Current drugs that improve the quality of life and overall survival in patients with brain tumors, especially for GBM, are poorly effective. This disease requires a reanalysis of currently accepted treatment strategies, as well as newly designed approaches. Here, we review the fundamental aspects of immunosuppression in brain tumors, new and promising immunotherapeutic drugs as well as combinatorial strategies that focus on the simultaneous inhibition of immunosuppressive hubs, both in immune and brain tumor cells, which is critical to consider for achieving future success for the treatment of this devastating disease. PMID- 22533855 TI - Absence of association between ex vivo susceptibility to doxycycline and pftetQ and pfmdt copy numbers in Plasmodium falciparum isolates from Dakar, Senegal. AB - The objective of this study was to validate the use of pftetQ and pfmdt genes as molecular markers of decreased in vitro susceptibility to doxycycline in 113 Plasmodium falciparum isolates from Dakar, Senegal. The results show that copy numbers of pftetQ and pfmdt, estimated by TaqMan real-time PCR, are not significantly associated with reduced susceptibility to doxycycline in vitro; however, the number of samples with a high doxycycline IC(50) was likely to be too low to derive statistically significant results. Thus, no definitive conclusions could be drawn. The markers should be further tested by analysing more isolates. PMID- 22533856 TI - Membrane-perturbing properties of two Arg-rich paddle domains from voltage-gated sensors in the KvAP and HsapBK K(+) channels. AB - Voltage-gated K(+) channels are gated by displacement of basic residues located in the S4 helix that together with a part of the S3 helix, S3b, forms a "paddle" domain, whose position is altered by changes in the membrane potential modulating the open probability of the channel. Here, interactions between two paddle domains, KvAPp from the K(v) channel from Aeropyrum pernix and HsapBKp from the BK channel from Homo sapiens, and membrane models have been studied by spectroscopy. We show that both paddle domains induce calcein leakage in large unilamellar vesicles, and we suggest that this leakage represents a general thinning of the bilayer, making movement of the whole paddle domain plausible. The fact that HsapBKp induces more leakage than KvAPp may be explained by the presence of a Trp residue in HsapBKp. Trp residues generally promote localization to the hydrophilic-hydrophobic interface and disturb tight packing. In magnetically aligned bicelles, KvAPp increases the level of order along the whole acyl chain, while HsapBKp affects the morphology, also indicating that KvAPp adapts more to the lipid environment. Nuclear magnetic resonance (NMR) relaxation measurements for HsapBKp show that overall the sequence has anisotropic motions. The S4 helix is well-structured with restricted local motion, while the turn between S4 and S3b is more flexible and undergoes slow local motion. Our results indicate that the calcein leakage is related to the flexibility in this turn region. A possibility by which HsapBKp can undergo structural transitions is also shown by relaxation NMR, which may be important for the gating mechanism. PMID- 22533860 TI - Pd- and Cu-catalyzed one-pot multicomponent synthesis of hetero alpha,alpha' dimers of heterocycles. AB - A novel palladium- and copper-catalyzed one-pot multicomponent synthesis of hetero alpha,alpha'-dimers of heterocycles via Sonogashira coupling and double cyclization cascade involving imine formation has been developed. This reaction cascade proceeded under mild conditions, providing a powerful synthetic tool for the assembly of pi-conjugated systems with a combination of palladium-catalyzed post-direct C-H bond arylations. PMID- 22533861 TI - Photoinduced electron transfer and nonlinear absorption in poly(carbazole-alt-2,7 fluorene)s bearing perylene diimides as pendant acceptors. AB - This paper reports the synthesis, photophysical behavior, and use in nanosecond optical-pulse suppression of a poly(2,7-carbazole-alt-2,7-fluorene) and a poly(3,6-carbazole-alt-2,7-fluorene) in which the carbazole N-positions are linked by an alkyl chain to one of the nitrogen atoms of a perylene-3,4,9,10 tetracarboxylic diimide (PDI) acceptor. It was found that the PDI pendants on the polymer side chain aggregated even in dilute solution, which extended the onset of PDI absorption into the near-infrared (NIR). Transient-absorption spectra of these polymers provide evidence for efficient electron transfer following either donor or acceptor photoexcitation to form long-lived charge-separated species, which exhibit strong absorption in the NIR. The spectral overlap between the transient species and the long-wavelength absorption edge of the aggregated PDI leads to reverse saturable absorption at 680 nm that can be used for optical pulse suppression. Additionally, at high input energies, two-photon absorption mechanisms may also contribute to the suppression. PDI-grafted polymers exhibit enhanced optical-pulse suppression compared with blends of model materials composed of unfunctionalized poly(carbazole-alt-2,7-fluorene)s and PDI small molecules. PMID- 22533862 TI - Success of allogeneic marrow transplantation for children with severe aplastic anaemia. AB - Allogeneic marrow transplantation offers curative therapy for children with severe aplastic anaemia (SAA). We report the outcomes of 148 children with SAA who received human leucocyte antigen (HLA)-matched related marrow grafts between 1971 and 2010. Patients were divided into three groups, reflecting changes in conditioning and graft-versus-host disease (GVHD) prophylaxis regimens that occurred over time. Patients in Group 1 were conditioned with cyclophosphamide (CY; 200 mg/kg) followed by 'long' (102 d) methotrexate (MTX). Patients in Groups 2 and 3 received CY alone (Group 2) or combined with anti-thymocyte globulin (Group 3) followed by 'short' (days 1, 3, 6, and 11) MTX and ciclosporin (until day 180). With a median follow-up of 25 years, the 5-year survivals were 66%, 95%, and 100% for Groups 1, 2, and 3, respectively (overall P < 0.0001). The 3 year estimates of graft rejection were 22%, 32%, and 7%, respectively. The probabilities of grades III-IV acute and 2-year chronic GVHD were 15%, 0%, and 3%, and 21%, 21%, and 10%, respectively. Advances in preparative and GVHD prophylaxis regimens, and supportive care during the past 40 years have led to improved outcomes for children with SAA. These results confirm the use of allogeneic marrow transplantation for children with SAA who have HLA-matched related donors. PMID- 22533864 TI - Flexible transparent PES/silver nanowires/PET sandwich-structured film for high efficiency electromagnetic interference shielding. AB - We have developed a kind of high-yield synthesis strategy for silver nanowires by a two-step injection polyol method. Silver nanowires and polyethylene oxide (PEO) (M(w) = 900,000) were prepared in a homogeneous-coating ink. Wet composite films with different thicknesses were fabricated on a PET substrate by drawn-down rod coating technology. Silver nanowires on PET substrates present a homogeneous distribution under the assistance of PEO. Then PEO was thermally removed in situ at a relatively low temperature attributed to its special thermal behavior under atmospheric conditions. As-prepared metallic nanowire films on PET substrates show excellent stability and a good combination of conductivity and light transmission. A layer of transparent poly(ethersulfones) (PESs) was further coated on silver nanowire networks by the same coating method to prevent the shedding and corrosion of silver nanowires. Sandwich-structured flexible transparent films were obtained and displayed excellent electromagnetic interference (EMI) shielding effectiveness. PMID- 22533863 TI - A qualitative investigation of attitudes towards aerobic and resistance exercise amongst overweight and obese individuals. AB - BACKGROUND: Most people are not meeting the minimal requirements for physical activity participation, particularly people who are overweight or obese. Numerous initiatives have been developed which aim to increase levels of physical activity in this group, yet little is known about their feelings towards different types of exercise. In particular, resistance exercise may offer unique benefits to people seeking to lose weight, yet no study to date has examined views of resistance exercise amongst the overweight and obese. This qualitative study examined the views and attitudes towards aerobic and resistance exercise amongst overweight and obese individuals engaged in a weight management clinic. METHODS: 30 overweight and obese patients comprised of 25 females and 5 males, with a mean age of 40.7 years (SD = 15.2) and mean BMI of 33.8 kg/m2 (SD = 7.9) were recruited from a dietetic clinic to take part in baseline focus groups and interviews to assess their views on physical activity. After selecting and participating in a 12 week aerobic- or resistance-exercise program, the participants took part in follow-up interviews. Thematic analysis was then performed on the transcribed focus group and interview data. RESULTS: For the overweight and obese women in this study, weight loss was the primary motivation for physical activity participation. Subsequently, these women perceived a failure to lose weight as strongly affecting their motivation to continue or re engage in physical activity. Only 3 participants selected the resistance exercise option. The view of resistance exercise as a masculine activity was a dominant theme amongst all participants. A lack of knowledge of how to perform certain exercises emerged as a barrier, but was seen by the participants as surmountable given appropriate instruction. CONCLUSIONS: The females in this study cited weight loss as a primary motivation for physical activity participation. This view must be reconciled with the existing knowledge base of physical activity requirements for successful weight loss and maintenance. Participants in this study had little awareness or experience of resistance exercise, and many were fearful of the potential risks. PMID- 22533865 TI - Mismatch between shape changes and ecological shifts during the post-settlement growth of the surgeonfish, Acanthurus triostegus. AB - BACKGROUND: Many coral reef fishes undergo habitat and diet shifts during ontogeny. However, studies focusing on the physiological and morphological adaptations that may prepare them for these transitions are relatively scarce. Here, we explored the body shape variation related to ontogenetic shifts in the ecology of the surgeonfish Acanthurus triostegus (Acanthuridae) from new settler to adult stages at Moorea Island (French Polynesia). Specifically, we tested the relationship between diet and habitat shifts and changes in overall body shape during the ontogeny of A. triostegus using a combination of geometric morphometric methods, stomach contents and stable isotope analysis. RESULTS: After reef settlement, stable isotope composition of carbon and nitrogen revealed a change from a zooplanktivorous to a benthic algae diet. The large amount of algae (> 75% of stomach contents) found in the digestive tract of small juveniles (25-30 mm SL) suggested the diet shift is rapid. The post-settlement growth of A. triostegus is highly allometric. The allometric shape changes mainly concern cephalic and pectoral regions. The head becomes shorter and more ventrally oriented during growth. Morphological changes are directly related to the diet shift given that a small mouth ventrally oriented is particularly suited for grazing activities at the adult stage. The pectoral fin is more anteriorely and vertically positioned and its basis is larger in adults than in juveniles. This shape variation had implications for swimming performance, manoeuvrability, turning ability and is related to habitat shift. Acanthurus triostegus achieves its main transformation of body shape to an adult-like form at size of 35-40 mm SL. CONCLUSION: Most of the shape changes occurred after the reef colonization but before the transition between juvenile habitat (fringing reef) and adult habitat (barrier reef). A large amount of allometric variation was observed after diet shift from zooplankton to benthic algae. Diet shift could act as an environmental factor favouring or inducing morphological changes. On the other hand, the main shape changes have to be achieved before the recruitment to adult populations and start negotiating the biophysical challenges of locomotion and feeding in wave- and current-swept outer reef habitat. PMID- 22533866 TI - Prognostic significance of MyD88 expression by human epithelial ovarian carcinoma cells. AB - BACKGROUND: MyD88 is an adaptor protein for TLR-4 signaling known to mediate paclitaxel resistance in epithelial ovarian carcinoma (EOC). This study examined the clinical significance of MyD88 expression in EOC. METHODS: MyD88 and TLR-4 expression were examined by immunocytochemistry in 109 specimens of ovarian tissues, comprising EOC (N = 83), borderline tumors (N = 9), benign cysts (N = 9) and normal ovarian tissue (N = 8), and clinical data collected by a retrospective chart review. The correlations between MyD88 expression and clinicopathological factors and outcomes were analyzed. RESULTS: TLR-4 expression was detected frequently in all the ovarian tissues. Distinct MyD88 expression was showed in EOC (64 of 83, 77.1 %), in borderline tumors (5 of 9, 55.6 %) and in benign cysts (3 of 9, 33.3 %), and normal ovarian tissue showed no MyD88 expression. Positive MyD88 expression significantly correlated with shorter disease-free and overall survival for EOC (P < 0.0001 and P = 0.0031), and high MyD88 expression was significantly correlated with tumor metastasis (P = 0.0012) for EOC. Univariate and multivariate analyses revealed that MyD88 expression was an independent prognostic factor for disease-free survival and overall survival for EOC. CONCLUSION: Our data indicate that MyD88 expression is a significantly poor prognostic factor for EOC. A better understanding of the role of MyD88 expression in disease progression and outcome may be helpful for development of novel chemotherapies for patients with EOC. PMID- 22533867 TI - The use and accuracy of manual and electronic gestational age calculators. AB - OBJECTIVES: The accuracy of gestational age (GA) wheels has been shown to be poor, yet they remain commonly used. We surveyed their use within our institution and determined the inter-observer and inter-device variability of a range of devices. We have devised a procedure for validating device accuracy. METHODS: All clinicians within our maternity unit were asked their most recent method of calculating GA and whether they felt this was accurate to within one day. Ten clinicians assessed 16 devices: 14 manual, 2 electronic. Five dates represented the last menstrual period (LMP) and were used to calculate the estimated date of delivery (EDD) of the 5 dates for each device compared to a 280 day control. ANOVA was used for statistical analysis. RESULTS: 73% last used a manual device to calculate GA. Seventy-two per cent believed their method was accurate. There was a significant bias (difference in the mean) between device-calculated and control EDD for all manual devices except one, with individual differences of up to 4 days. Variability altered throughout the year. Electronic devices consistently had no error. Inter-observer variability was insignificant. CONCLUSIONS: Clinicians should be aware of the inaccuracy of manual devices. Electronic devices are recommended. Manual devices should be validated before use by comparing the device-calculated EDD with a 280 day control at five points throughout the year. PMID- 22533868 TI - Qualitative analysis of heterosexual women's experience of sexual pain and discomfort. AB - In this qualitative analysis, the author explored heterosexual women's accounts of the lived experience of sexual pain and discomfort. The author's aim was to expand theoretical and empirical knowledge in the area of female sexual dysfunction by providing a detailed description of the subjective experience of female sexual concerns. The author used empirical phenomenological methodology to analyze the data generated during semi-structured in-depth interviews conducted with 9 women and generated 42 themes that were woven into a common story of the experience, its preconditions, coping strategies, and aftereffects. The limitations of the study and implications for research and clinical practice are discussed. PMID- 22533869 TI - Romantic attachment insecurity predicts sexual dissatisfaction in couples seeking marital therapy. AB - Researchers and practitioners have noted the importance of considering individual characteristics as well as couple dynamics when attempting to understand couples and sexual difficulties. Using a dyadic approach, this study examined the links between 2 forms of romantic attachment insecurity (anxiety and avoidance) and sexual dissatisfaction among members of couples seeking couple therapy. A large clinical sample of 242 French-speaking couples completed the Experiences in Close Relationships Scale and the Index of Sexual Satisfaction. Analyses based on the actor-partner interdependence model revealed that both attachment anxiety and avoidance predicted individuals' own sexual dissatisfaction (actor effects). The authors also observed 2 partner effects: (a) anxiety in men predicted female partners' sexual dissatisfaction and (b) avoidance in women predicted male partners' sexual dissatisfaction. The results support attachment theory and have clinical implications for emotion-focused couple therapy and other approaches to couple therapy. PMID- 22533870 TI - Intimacy, sexual desire and differentiation in couplehood: a theoretical and methodological review. AB - The scientific community underlines that one of the main challenges for couples is the effect of time on sexual desire. Some studies suggest that although some dimensions associated with intimacy tend to increase during the relationship, sexual desire and the related constructs tend to decrease. Some researchers have recently suggested that couples' relationships with high degrees of sharing and fusion might be particularly detrimental for the sustenance of sexual desire. However, the authors found no empirical or theoretical studies that investigate the relations between intimacy and desire. Recovering the concept of differentiation as a possible influencing variable between intimacy and desire, this article develops reflections on this theme, which is of paramount relevance for the couple viability. PMID- 22533875 TI - Mitigating heterocycle metabolism in drug discovery. PMID- 22533871 TI - Strategies for the treatment of antipsychotic-induced sexual dysfunction and/or hyperprolactinemia among patients of the schizophrenia spectrum: a review. AB - There is limited evidence for the management of sexual dysfunction and/or hyperprolactinemia resulting from use of antipsychotics in patients with schizophrenia and spectrum. The aim of this study was to review and describe the strategies for the treatment of antipsychotic-induced sexual dysfunctions and/or hyperprolactinemia. The research was carried out through Medline/PubMed, Cochrane, Lilacs, Embase, and PsycINFO, and it included open labels or randomized clinical trials. The authors found 31 studies: 25 open-label noncontrolled studies and 6 randomized controlled clinical trials. The randomized, double-blind controlled studies that were conducted with adjunctive treatment that showed improvement of sexual dysfunction and/or decrease of prolactin levels were sildenafil and aripiprazole. The medication selegiline and cyproheptadine did not improve sexual function. The switch to quetiapine was demonstrated in 2 randomized controlled studies: 1 showed improvement in the primary outcome and the other did not. This reviewed data have suggested that further well-designed randomized controlled trials are needed to provide evidence for the effects of different strategies to manage sexual dysfunction and/or hyperprolactinaemia resulting from antipsychotics. These trials are necessary in order to have a better compliance and reduce the distress among patients with schizophrenia. PMID- 22533876 TI - So near and yet so far: the specific case of Ralstonia Solanacearum populations from Cote d'Ivoire in Africa. AB - The genetic and phenotypic diversity of Cote d'Ivoire Ralstonia solanacearum strains was assessed on a 168-strain collection sampled on Solanaceae both in the southern lowlands and western highlands. Phylotypes I, II, and III were prevalent, though at unexpected frequencies. Phylotype I strains (87.5%) were genetically diverse and overrepresented in all agroecological areas, including highlands (AEZ III). Phylotype II strains (10.7%) only belonged to one tropical lowland-adapted broad host range lineage (IIA-35), whereas no highland-adapted potato brown rot (IIB-1) or Moko strains were detected. African phylotype III strains were rare (1.8%). They originated from a single Burkina Faso lineage (III 23) and were only found in lowlands. Three phylotype I strains were found harboring pRSC35, a plasmid identified in phylotype III strains in Cameroon. From pathogenicity tests performed on commercial varieties and tomato/eggplant/pepper references, the virulence diversity observed was high, with five pathoprofiles described. Eggplant accessions MM152 and EG203 and tomato HW7996 displayed the largest resistance spectrum and highest level. Two highly virulent phylotype I strains were able to bypass resistance of HW7996 and the eggplant reference AG91 25. Collectively, these points lead to the conclusion that the situation in Cote d'Ivoire is specific towards other African countries, and specifically from the Cameroon reference, and that within phylotype I can exist a high virulence diversity. This calls for similar studies in neighboring West African countries, linking R. solanacearum pathogen genetic diversity to strain virulence at the regional level, for the rationalization of regional resistance deployment strategies and future resistance durability studies. PMID- 22533877 TI - Effects of Simplicillium lanosoniveum on Phakopsora pachyrhizi, the soybean rust pathogen, and its use as a biological control agent. AB - The fungus Simplicillium lanosoniveum was isolated from soybean leaves infected with Phakopsora pachyrhizi, the soybean rust pathogen, in Louisiana and Florida. The fungus did not grow or become established on leaf surfaces until uredinia erupted, but when soybean rust signs and symptoms were evident, S. lanosoniveum colonized leaves within 3 days and sporulated within 4 days. Development of new uredinia was suppressed by about fourfold when S. lanosoniveum colonized uredinia. In the presence of S. lanosoniveum, uredinia became increasingly red brown, and urediniospores turned brown and germinated at very low rates. Assays using quantitative real time polymerase chain reaction revealed that the fungus colonized leaf surfaces when plants were infected with P. pachyrhizi, either in a latent stage of infection or when symptoms were present. However, when plants were inoculated before infection, there was no increase of DNA of S. lanosoniveum, suggesting that the pathogen must be present in order for the antagonist to become established on soybean leaf surfaces. We documented significantly lower amounts of DNA of P. pachyrhizi and lower disease severity when soybean leaves were colonized with S. lanosoniveum. These studies documented the mycophilic and disease-suppressive nature of S. lanosoniveum. PMID- 22533879 TI - Reporting new cases of anaemia in primary care settings in Crete, Greece: a rural practice study. AB - BACKGROUND: Early diagnosis of anaemia represents an important task within primary care settings. This study reports on the frequency of new cases of anaemia among patients attending rural primary care settings in Crete (Greece) and to offer an estimate of iron deficiency anaemia (IDA) frequency in this study group. METHODS: All patients attending the rural primary health care units of twelve general practitioners (GPs) on the island of Crete for ten consecutive working days were eligible to participate in this study. Hemoglobin (Hb) levels were measured by portable analyzers. Laboratory tests to confirm new cases of anaemia were performed at the University General Hospital of Heraklion. RESULTS: One hundred and thirteen out of 541 recruited patients had a low value of Hb according to the initial measurement obtained by the use of the portable analyzer. Forty five (45.5%) of the 99 subjects who underwent laboratory testing had confirmed anaemia. The mean value of the Hb levels in the group with confirmed anaemia, as detected by the portable analyzer was 11.1 g/dl (95% Confidence Interval (CI) from 10.9 to 11.4) and the respective mean value of the Hb levels obtained from the full blood count was 11.4 g/dl (95% CI from 11.2 to 11.7) (P = 0.01). Sixteen out of those 45 patients with anaemia (35.6%) had IDA, with ferritin levels lower than 30 ng/ml. CONCLUSION: Keeping in mind that this paper does not deal with specificity or sensitivity figures, it is suggested that in rural and remote settings anaemia is still invisible and point of care testing may have a place to identify it. PMID- 22533880 TI - Thermodynamic contribution to the regulation of electron transfer in the Na(+) pumping NADH:quinone oxidoreductase from Vibrio cholerae. AB - The Na(+)-pumping NADH:quinone oxidoreductase (Na(+)-NQR) is a fundamental enzyme of the oxidative phosphorylation metabolism and ionic homeostasis in several pathogenic and marine bacteria. To understand the mechanism that couples electron transfer with sodium translocation in Na(+)-NQR, the ion dependence of the redox potential of the individual cofactors was studied using a spectroelectrochemical approach. The redox potential of one of the FMN cofactors increased 90 mV in the presence of Na(+) or Li(+), compared to the redox potentials measured in the presence of other cations that are not transported by the enzyme, such as K(+), Rb(+), and NH(4)(+). This shift in redox potential of one FMN confirms the crucial role of the FMN anionic radicals in the Na(+) pumping mechanism and demonstrates that the control of the electron transfer rate has both kinetic (via conformational changes) and thermodynamic components. PMID- 22533881 TI - [Agressive fibromatosis: genetic and biological correlations]. AB - Aggressive fibromatosis, also known as desmoid tumor, is specific and relatively rarely occuring disease. It belongs to heterogenous group of soft tissue tumors. Originally, it arises from fibroblasts with monoclonal proliferation derived from fibro-aponeurotic tissue with typical local invasive spreading without metastatic tendency. Increased amount of knowledge about the role of the APC gene and its protein product in FAP play an important role in revealing the molecular nature of desmoid tumors. In general, we can conclude that the beta-catenin dysregulation is the key player of the FAP associated desmoid tumor onset. The Wingless/Wnt cascade plays a crucial role in the pathogenesis of aggressive fibromatosis. However, it has not been definitely proven that the mutations of APC or beta-catenin genes are the trigger mechanisms. The research outcome can pave the way for using target biological therapy in routine practice in patients with aggressive fibromatosis in the future. PMID- 22533882 TI - [Aggressive fibromatosis: clinical aspects]. AB - The clinical picture of desmoids is unpredictable, which is a feature of different tumor specific associations. Anatomic location, age, sex, association with FAP as well as other factors determine biological behavior of the tumor. Negative prognosis is linked with the intraabdominal area and as many as 80% of desmoids are associated with FAP. Currently, biological targeting therapy is used in the treatment of many cancer diseases. It is only the question of time when and by which of these therapies we will be able to treat the patients with aggressive fibromatosis as well. A disadvantage is heterogenity and rare occurrence of desmoids. The efficacy of tailoring treatment still depends on knowledge and study of particular disease biological markers, which is currently the most important issue. . PMID- 22533883 TI - [Changes in immune reactivity in cancer patients]. AB - It appears that the long-accepted paradigm that cytostatic and radiation therapy cause only immunosuppression, is not so clearly true. With regard to new knowledge in cancer immunology field, it seems that not only cytostatic and radiation therapy plays an important role in the alteration of immune system. There are many other factors influencing immunity like tumour environment itself, the use of immunomodulatory drugs or even the mental condition of cancer patients. The aim of review is to familiarize physicians with possible alterations of the immune system in cancer patients. PMID- 22533884 TI - [Prognostic significance of morphology in multiple myeloma]. AB - BACKGROUNDS: Multiple myeloma is the second most common hematological disease caused by clonal proliferation of B cells. Evaluation of number of plasmocytes in the bone marrow is still one of the basic diagnostic criteria. The aim of this study was to verify if this evaluation has prognostic value even in the era of new drugs. MATERIAL AND METHODS: Two groups of MM patients were enrolled in this study. The group T - 45 newly diagnosed MM patients who underwent treatment with thalidomide. Group B - 86 patients in first relapse of MM without autologous transplantation of bone marrow that were treated with thalidomide and bortezomib in various combinations. Percentage of subtypes of plasmocytes in the bone marrow was evaluated based on progressive analysis of nucleus, chromatin and nucleo cellular ratio (N/C). RESULTS: Mature plasma cells were found in 53.3% (group T) and 53.5% (group B) of patients; proplasmocytes I were found in 22.2% (group T) and 24.4% (group B) of patients; proplasmocytes II were found in 22.2% (group T) and 22.1% (group B) of patients and plasmablasts in 1% (group T) and 0% (group B). Patients who reached treatment response after first treatment had statistically significant number of proplasmocytes II when compared to group without treatment response (median 37% vs. 11%, p = 0.033). Group B patients with mature plasmocytes below 10% had significantly shorter overall survival than other patients when comparison of quartiles was performed. Group B patients with higher infiltration of proplasmocytes I than median of 15% had lower overall survival (median 50.3 months vs. 74.9 months, p = 0,024); the same was true for evaluation of proplasmocytes II (median OS 41.3 months vs. 74.9 months, p = 0,011). CONCLUSION: Numerical evaluations of plasma cells in the bone marrow remain basic diagnostic criteria of MM even in the era of new genomics analyses. More precise morphological evaluation of 8 subtypes of plasma cells brings important prognostic information that is necessary for new protocols for immunomodulatory drugs and proteasome inhibitors. PMID- 22533885 TI - Radiation-induced long-term alterations in hippocampus under experimental conditions. AB - BACKGROUNDS: The aim of the present study was to investigate the effect of ionizing radiation on the cell population that co-forms hippocampal formation in an adult rat brain. MATERIALS AND METHODS: Adult male Wistar rats were exposed to whole-body irradiation with fractionated doses of gamma rays (the total dose of 4 Gy). Thirty, 60 and 90 days after irradiation the cell-specific types housed in the CA1, CA3 subregions and adjacent layers were labelled using immunohistochemistry for specific cell phenotypes; Ki-67 marker was used for proliferating cells and GFAP for detection of astrocytes. RESULTS: During the 30th day post-exposure, a considerable increase in the numbers of Ki-67-positive cells was seen. Moreover, significant decline in the density of neurons, mostly in the CA1 subregion, was observed on the 60th day. Slight overaccumulation of Ki 67-positive cells was seen in CA1 area 90 days after radiation treatment. Temporary decrease of GFAP-positive astrocytes was seen thirty days after irradiation, followed by their subsequent increase 60 days after exposure. Secondary decrease of GFAP-positive cells in both of regions was found in the group surviving 90 days post-irradiation. CONCLUSION: Results showed that radiation response of neurons and astrocytes that form the adult hippocampus may play contributory role in the development of prognostically unfavourable adverse radiation-induced late effect. PMID- 22533886 TI - [Palliative surgical treatment of tumors of pancreas and periampullary region]. AB - BACKGROUNDS: Pancreatic cancer is an aggressive malignant disease with increasing incidence. Radical resection, the only potentially curative method, is possible in only 20-30% of patients. The main symptoms of advanced non-resectable pancreatic head tumors include obstructive jaundice, caused by stenosis of distal common bile duct, duodenal obstruction and pain, especially in the epigastric region and back. The aim of palliative treatment is to relieve these complaints. This paper evaluates our own palliative surgical treatment results in patients with pancreatic head and periampullary region cancer. PATIENTS AND METHODS: This study included all patients with pancreatic head and periampullary region cancer who underwent surgery at the Department of Surgery, University Hospital in Hradec Kralove from 1st January 2006 to 31st December 2010. The aim of the surgery in all patients was to resect the tumor. Palliative surgical procedure was performed in patients witn an inoperable tumor. We performed gastro-entero anastomosis in all the patients. When perioperative situation allowed, hepatico-jejuno anastomosis was performed in patients with obstructive jaundice. Surgical splanchnicectomy was performed in patients with back pain. RESULTS: Over five years, we performed a surgery in 94 patients for malignant disease of pancreas and periampullary region. Radical resection was performed in 45 patients. Palliative bypass procedure was performed in 42 patients. Exploration only was performed in 7 patients. Postoperative complications after palliative bypass procedures were noted in 15 patients (30.6%), the majority of these complications were minor. CONCLUSION: The advantage of surgical hepatico-jejuno anastomosis over endoscopically placed stent is particulary in superior long-term patency. Therefore, it is advisable to perform these procedures in patients with longer expected survival. Morbidity associated with palliative surgical procedures was relatively low and there was no mortality. PMID- 22533887 TI - [Thyroid disorders in women with breast cancer]. AB - AIM: Increasing prevalence of non-malignant thyroid disorders in women with breast cancer has been known for several decades; it is said to be associated with a better prognosis of the cancerous disease. The aim of this work was to analyse associations between thyropathies found in women with breast cancer and particular prognostic factors. PATIENTS AND METHODS: A group of 110 women with breast cancer were tested for autoimmune thyroiditis (AIT) and functional changes of the thyroid gland. Presence of thyroid-peroxidase autoantibodies (TPOAb), serum levels of thyroid-stimulating hormone (TSH) and free thyroxine (FT3, FT4) were determined after the surgery but before adjuvant cancer treatment (radiotherapy, chemotherapy or hormone therapy) initiation. Conventionally evaluated prognostic factors of breast cancer, including histological grading and molecular predictive factors (i.e. the status of the hormone receptors and the human epidermal growth factor receptor) were assessed - these were divided into four basic categories. RESULTS AND CONCLUSIONS: The incidence of AIT and subclinical hypothyroidism in the study group was 37.3% and 20%, respectively, i.e. higher than in the general population. The only correlation found was between thyropathies and the specific prognostic factors was that with G1 breast cancer grading. PMID- 22533888 TI - Duodenal gastrointestinal stromal tumor presenting with acute upper gastrointestinal bleeding treated with segmental resection. AB - Gastrointestinal stromal tumours (GISTs) are considered to derive from the interstitial cells of Cajal or their precursors and are defined by their expression of c-kit protein (CD117) that is positive in 95% percent of cases. These are rare mesenchymatous tumours, while they represent the most common mesenchymal tumours of the alimentary tract. The majority of GISTs develop in the stomach and small intestine and more rarely in the rectum, colon, esophagus and mesentery; only 3-5% of all GISTs are located in the duodenum. The presenting symptoms include early satiation, dysphagia, bloating, abdominal pain and gastrointestinal bleeding, either acute or chronic. Surgery remains the mainstay of treatment for localized, non-metastatic, resectable GISTs. We present a case of duodenal gastrointestinal stromal tumour of the third portion of the duodenum that presented with acute upper gastrointestinal bleeding treated with segmental duodenal resection. PMID- 22533889 TI - Organ-specific management and supportive care in chronic graft-versus-host disease. AB - A joint working group established by the Haemato-oncology subgroup of the British Committee for Standards in Haematology and the British Society for Bone Marrow Transplantation has reviewed the available literature and made recommendations for the supportive care and management of organ-specific complications of chronic graft-versus-host disease (cGvHD). This guideline includes recommendations for the specific therapy of skin, oral, liver, gut, lung, ocular and genital manifestations of cGvHD and for the supportive care of these patients, including vaccinations and prophylaxis against infection. The goal of treatment should be effective control of GvHD while minimizing the risk of toxicity and relapse. PMID- 22533893 TI - Evolutionary constraints and expression analysis of gene duplications in Rhodobacter sphaeroides 2.4.1. AB - BACKGROUND: Gene duplication is a major force that contributes to the evolution of new metabolic functions in all organisms. Rhodobacter sphaeroides 2.4.1 is a bacterium that displays a wide degree of metabolic versatility and genome complexity and therefore is a fitting model for the study of gene duplications in bacteria. A comprehensive analysis of 234 duplicate gene-pairs in R. sphaeroides was performed using structural constraint and expression analysis. RESULTS: The results revealed that most gene-pairs in in-paralogs are maintained under negative selection (omega <= 0.3), but the strength of selection differed among in-paralog gene-pairs. Although in-paralogs located on different replicons are maintained under purifying selection, the duplicated genes distributed between the primary chromosome (CI) and the second chromosome (CII) are relatively less selectively constrained than the gene-pairs located within each chromosome. The mRNA expression patterns of duplicate gene-pairs were examined through microarray analysis of this organism grown under seven different growth conditions. Results revealed that ~62% of paralogs have similar expression patterns (cosine >= 0.90) over all of these growth conditions, while only ~7% of paralogs are very different in their expression patterns (cosine < 0.50). CONCLUSIONS: The overall findings of the study suggest that only a small proportion of paralogs contribute to the metabolic diversity and the evolution of novel metabolic functions in R. sphaeroides. In addition, the lack of relationships between structural constraints and gene-pair expression suggests that patterns of gene-pair expression are likely associated with conservation or divergence of gene-pair promoter regions and other coregulation mechanisms. PMID- 22533894 TI - In situ molecular spectroscopic evidence for CO2 intercalation into montmorillonite in supercritical carbon dioxide. AB - The interaction of anhydrous supercritical CO(2) (scCO(2)) with both kaolinite and ~1W (i.e., close to but less than one layer of hydration) calcium-saturated montmorillonite was investigated under conditions relevant to geologic carbon sequestration (50 degrees C and 90 bar). The CO(2) molecular environment was probed in situ using a combination of three novel high-pressure techniques: X-ray diffraction, magic angle spinning nuclear magnetic resonance spectroscopy, and attenuated total reflection infrared spectroscopy. We report the first direct evidence that the expansion of montmorillonite under scCO(2) conditions is due to CO(2) migration into the interlayer. Intercalated CO(2) molecules are rotationally constrained and do not appear to react with waters to form bicarbonate or carbonic acid. In contrast, CO(2) does not intercalate into kaolinite. The findings show that predicting the seal integrity of caprock will have complex dependence on clay mineralogy and hydration state. PMID- 22533895 TI - The Economic impact of Non-communicable Diseases on households in India. AB - BACKGROUND: In India, Non Communicable Diseases (NCDs) and injuries account for an estimated 62% of the total age-standardized burden of forgone Disability Adjusted Life Years (DALYs). Public and private financing of clinical services to reduce the NCD burden is a major challenge. METHODS: We used National Sample Survey Organization (NSSO) survey data from 1995-96 and 2004 covering nearly 200 thousand households to assess healthcare utilization patterns and out of pocket health spending by disease category. For this purpose, self-reported diseases and conditions were categorized into NCDs and non-NCDs. Survey data were used to assess how households financed their overall health expenditures and related this pattern to specific health conditions. We measured catastrophic spending on NCD related hospitalization, defined as occurring when health expenditures exceeded 40% of a household's ability to pay, that is, household consumption spending less combined survival consumption expenditure; and impoverishment when per capita expenditure within the household decreased to below the poverty line once health spending was netted out. RESULTS: The share of NCDs in out of pocket health expenses incurred by households increased over time, from 31.6 percent in 1995-96 to 47.3 percent in 2004. In both years, own savings and income were the most important source of financing for many health conditions, typically between 40-60 percent of all spending, whereas 30-35 percent was from borrowing. The odds of catastrophic hospitalization expenditures for cancer was nearly 170% greater and for CVD and injuries 22 percent greater than the odds due to communicable diseases. Impoverishment patterns were similar. CONCLUSIONS: Out of pocket expenses for treating NCDs rose sharply over the period from 1995-96 to 2004. When NCDs are present, the financial risks to which Indians households are exposed are significant. PMID- 22533896 TI - Interactive relations among maternal depressive symptomatology, nutrition, and parenting. AB - Theoretical models linking maternal nutrition, depressive symptomatology, and parenting are underdeveloped. However, existing literature suggests that iron status and depressive symptomatology interact in relation to problematic parenting styles (authoritarian, permissive). Therefore, in the current study the authors investigate these interactive relations in a sample of breastfeeding mothers (n = 105) interviewed at three months postpartum. Participants completed questionnaires (from December 2008 to January 2011) regarding their depressive symptomatology and parenting styles. Iron status (i.e., hemoglobin, soluble transferrin receptors, and serum ferritin concentrations) was assessed from blood samples. Significant interactions were found between iron status and depressive symptomatology in relation to authoritarian parenting style (low warmth, high punishment and directiveness). For those women with hemoglobin below 14.00 g/dL, depressive symptomatology was positively related to authoritarian parenting style (p < 0.001). Thus, screening for poor iron status and depressive sympatomology in postpartum women may help to identify those at risk for problematic parenting. Dietary interventions may help to eliminate relations between depressive symptoms and problematic parenting. PMID- 22533897 TI - Gender and mental health aspects of living with HIV disease and its longer-term outcomes for UK heterosexual patients. AB - Gender is important in the experience of illness generally and HIV specifically. In this study the authors compare 183 HIV positive women with 76 HIV positive heterosexual men attending United Kingdom HIV clinics on clinical, treatment, and mental health factors. Participants completed a questionnaire on mental health and HIV-related factors. Laboratory measures of HIV viral load and CD4 cell count were obtained at baseline and 6-18 months later. After adjusting for age, employment, and treatment status, men were significantly less likely than women to suffer from high psychological [adjusted odds ratio (OR) = 0.38, 95% confidence interval (CI): 0.17, 0.86] and global symptom distress (adjusted OR = 0.42, 95% CI: 0.19, 0.92). However, men were more likely than women to report having suicidal thoughts (adjusted OR = 1.85, 95% CI: 0.95, 3.58). Relational, sexual behavior, and quality of life factors were similar for men and women. Adherence levels did not differ by gender but were sub-optimal in 56% of patients. Men had significantly lower CD4 counts than women at baseline, but not at follow-up. No differences were observed in the proportions with viral suppression. The groups had generally similar HIV experiences with high psychological distress. Adherence monitoring and gender appropriate psychological support are needed for these groups. PMID- 22533898 TI - Women's perceptions of the relationship between recent life events, transitions, and diet in midlife: findings from a focus group study. AB - Research indicates that history and early life events and trajectories influence women's dietary behaviors. Yet the social context in which recent life changes occur requires greater understanding, particularly regarding changes that embody the interconnectedness of women and their families, and how those changes affect women's dietary decisions and behaviors. The data presented here were the product of eight focus groups conducted in one Maryland county in the fall of 2009. The participants were 43 women with limited financial resources aged 40-64 years. In this analysis, the researchers focus on women's perceptions of the relation of recent life transitions and events to the dietary decisions they made for themselves and their families. The findings suggested that transitions and events related to household structure, health status, phases of motherhood, and shifts in financial and employment status all had the potential to have profound and immediate effects on women's dietary decisions and resulting dietary behaviors. The focus group data was used to consider implications for developing intervention strategies designed to improve self-efficacy and negotiation skills around dietary issues as a means of promoting healthy decision making among women in midlife, particularly in times of familial upheaval and in circumstances where financial resources are limited. PMID- 22533899 TI - Mothers of IVF twins: the mediating role of employment and social coping resources in maternal stress. AB - Twin pregnancies and births resulting from assisted reproductive technologies have been associated with adverse perinatal outcomes and maternal health complications leading to psychologically complex parenting. In the current study the authors assess the prevalence of clinical levels of maternal stress among mothers of twins resulting from in vitro fertilization and examine the association of social coping resources with three maternal stress sub-scales. During the years 2003-2005, 88 primiparous Israeli mothers of in vitro fertilization-conceived twins provided socio-demographic data during their third trimester of pregnancy, and at 6 months after birth provided data on delivery and medical condition of infants, coping resources (social support and marital quality), and a maternal stress scale. Forty-one percent of the mothers reached a clinically significant level of maternal stress. Social support and maternal employment were the most significant variables associated with experience of the stress in the early stages of adaptation to mothering in vitro fertilization twins. Primiparous mothers of in vitro fertilization twins are vulnerable to maternal stress in early stages of adaptation to the maternal role, some of whom reach clinical levels that may require professional interventions. Unemployed mothers with low social support were the most susceptible to the deleterious effects of in vitro fertilization treatment. PMID- 22533901 TI - The relationship between religiosity and cancer screening among Vietnamese women in the United States: the moderating role of acculturation. AB - In this study the authors explore the relationship between intrinsic, personal extrinsic, and social extrinsic religiosity to breast and cervical cancer screening efficacy and behavior among Vietnamese women recruited from a Catholic Vietnamese church and a Buddhist temple in the Richmond, Virginia metropolitan area. The potential moderating effect of acculturation was of interest. Participants were 111 Vietnamese women who participated in a larger cancer screening intervention. Data collection began early fall of 2010 and ended in late spring 2011. High levels of acculturation were associated with increased self-efficacy for Pap tests and having received a Pap test. Acculturation moderated the relationships between religiosity and self-efficacy for breast and cervical cancer screening. Higher levels of social extrinsic religiosity were associated with increased efficacy for cancer screening among less acculturated women. Acculturation also moderated the relationship between religiosity and breast cancer screening. Specifically, for less acculturated women, increasing levels of intrinsic religiosity and personal extrinsic religiosity were associated with lower likelihood probability of Pap testing. For highly acculturated women, increasing levels of intrinsic religiosity and personal extrinsic religiosity were associated with higher likelihood probability of Pap testing. The authors' findings demonstrate the need for further investigation of the dynamic interplay of multi-level factors that influence cancer screening. PMID- 22533900 TI - Baseline results from Hawaii's Na Mikimiki Project: a physical activity intervention tailored to multiethnic postpartum women. AB - During the postpartum period, ethnic minority women have higher rates of inactivity/under-activity than white women. The Na Mikimiki ("the active ones") Project is designed to increase moderate-to-vigorous physical activity over 18 months among multiethnic women with infants 2-12 months old. The study was designed to test, via a randomized controlled trial, the effectiveness of a tailored telephone counseling of moderate-to-vigorous physical activity intervention compared to a print/website materials-only condition. Healthy, underactive women (mean age = 32 +/- 5.6 years) with a baby (mean age = 5.7 +/- 2.8 months) were enrolled from 2008-2009 (N = 278). Of the total sample, 84% were ethnic minority women, predominantly Asian-American and Native Hawaiian. Mean self-reported baseline level of moderate-to-vigorous physical activity was 40 minutes/week with no significant differences by study condition, ethnicity, infant's age, maternal body mass index, or maternal employment. Women had high scores on perceived benefits, self-efficacy, and environmental support for exercise but low scores on social support for exercise. This multiethnic sample's demographic and psychosocial characteristics and their perceived barriers to exercise were comparable to previous physical activity studies conducted largely with white postpartum women. The Na Mikimiki Project's innovative tailored technology-based intervention and unique population are significant contributions to the literature on moderate-to-vigorous physical activity in postpartum women. PMID- 22533903 TI - Mechanical properties of freely suspended semiconducting graphene-like layers based on MoS2. AB - We fabricate freely suspended nanosheets of molybdenum disulphide (MoS2) which are characterized by quantitative optical microscopy and high-resolution friction force microscopy. We study the elastic deformation of freely suspended nanosheets of MoS2 using an atomic force microscope. The Young's modulus and the initial pre tension of the nanosheets are determined by performing a nanoscopic version of a bending test experiment. MoS2 sheets show high elasticity and an extremely high Young's modulus (0.30 TPa, 50% larger than steel). These results make them a potential alternative to graphene in applications requiring flexible semiconductor materials.PACS, 73.61.Le, other inorganic semiconductors, 68.65.Ac, multilayers, 62.20.de, elastic moduli, 81.40.Jj, elasticity and anelasticity, stress-strain relations. PMID- 22533904 TI - Sleep disturbances in Korean pregnant and postpartum women. AB - This was a prospective, cohort study in Korean pregnant and postpartum women, to estimate the prevalence and patterns of sleep disturbances. The survey was composed of the following validated sleep questionnaires: the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), Women's Health Initiative Insomnia Rating Scale, Berlin Questionnaire for sleep disordered breathing, the international restless leg syndrome (IRLS) Study Group criteria, and the Johns Hopkins Telephone Diagnostic Interview Form (JHTDIF) for RLS. Statistical analyses were performed using SPSS version 18.0. Six hundred eighty-nine women completed sleep surveys. The overall percentage of women with very poor sleep quality (a PSQI score greater than 10), clinically significant insomnia (a total score of 9 or more), excessive daytime sleepiness (a total ESS score of 10 or more), short sleep duration (less than 7 hours per night) were 80.7%, 50.5%, 34.0% and 29.5%, respectively, and all of three parameters became increased as pregnancy progressed and after delivery ( p = 0.002, 0.001, and 0.001, respectively). The overall positive rates in Berlin and RLS questionnaires were 25.4% and 19.4%. In conclusion, sleep disturbances are prevalent among Korean pregnant and postpartum women, and increase significantly as pregnancy progresses and after delivery. PMID- 22533905 TI - Chalcogenopyrylium compounds as modulators of the ATP-binding cassette transporters P-glycoprotein (P-gp/ABCB1) and multidrug resistance protein 1 (MRP1/ABCC1). AB - Twenty-seven chalcogenopyrylium derivatives varying in the heteroatom of the pyrylium core and substituents at the 2-, 4-, and 6-positions were examined for their effect on human MRP1-mediated uptake of tritiated estradiol glucuronide into inside-out membrane vesicles, their affinity for and ability to stimulate the ATPase activity of purified human P-glycoprotein (P-gp)-His(10), and their ability to promote uptake of calcein AM and vinblastine in multidrug-resistant cells. Differences in their effects on MRP1 and P-gp activity were noted, and a second set of thiopyrylium compounds with systematic substituent changes was examined to refine these differences further. Derivatives with tert-butyl substituents in the 2- and 6-positions had the lowest inhibitory activity toward both transporters. Derivatives with thioamide functionality in the 4-position were more active against MRP1 than derivatives with amide functionality. Conversely, derivatives with amide functionality in the 4-position were more active in P-gp than derivatives with thioamide functionality. PMID- 22533907 TI - Gas chromatography coupled to mass spectrometry analysis of volatiles, sugars, organic acids and aminoacids in Valencia Late orange juice and reliability of the Automated Mass Spectral Deconvolution and Identification System for their automatic identification and quantification. AB - Neutral volatiles and non-volatile polar compounds (sugars, organics acids and aminoacids) present in Valencia Late orange juice have been analysed by Gas Chromatography coupled to Mass Spectrometry (GC-MS). Before analysis, the neutral volatiles have been extracted by Headspace-Solid Phase Microextraction (HS-SPME), and the non-volatile polar compounds have been transformed to their corresponding volatile trimethylsilyl (TMS) derivatives. From the resulting raw GC-MS data files, the reliability of the Automated Mass Spectral Deconvolution and Identification System (AMDIS) to perform accurate identification and quantification of the compounds present in the sample has been tested. Hence, both raw GC-MS data files have been processed automatically by using AMDIS and manually by using XcaliburTM, the manufacturer's data processing software for the GC-MS platform used. Results indicate that the reliability of AMDIS for accurate identification and quantification of the compounds present in the sample strongly depends on a number of operational settings, for both the MS and AMDIS, which must be optimized for the particular type of assayed sample. After optimization of these settings, AMDIS and XcaliburTM yield practically the same results. A total of 85 volatiles and 22 polar compounds have been identified and quantified in Valencia Late orange juice. PMID- 22533908 TI - Development and comparison of three liquid chromatography-atmospheric pressure chemical ionization/mass spectrometry methods for determining vitamin D metabolites in human serum. AB - Liquid chromatographic methods with atmospheric pressure chemical ionization mass spectrometry were developed for the determination of the vitamin D metabolites 25 hydroxyvitamin D2 (25(OH)D2), 25-hydroxyvitamin D3 (25(OH)D3), and 3-epi-25 hydroxyvitamin-D3 (3-epi-25(OH)D3) in the four Levels of SRM 972, Vitamin D in Human Serum. One method utilized a C18 column, which separates 25(OH)D2 and 25(OH)D3, and one method utilized a CN column that also resolves the diastereomers 25(OH)D3 and 3-epi-25(OH)D3. Both methods utilized stable isotope labeled internal standards for quantitation of 25(OH)D2 and 25(OH)D3. These methods were subsequently used to evaluate SRM 909c Human Serum, and 25(OH)D3 was the only vitamin D metabolite detected in this material. However, SRM 909c samples contained matrix peaks that interfered with the determination of the [2H6]-25(OH)D3 peak area. The chromatographic conditions for the C18 column were modified to remove this interference, but conditions that separated the matrix peaks from [2H6]-25(OH)D3 on the CN column could not be identified. The alternate internal standard [2H3]-25(OH)D3 did not suffer from matrix interferences and was used for quantitation of 25(OH)D3 in SRM 909c. During the evaluation of SRM 909c samples, a third method was developed using a pentafluorophenylpropyl column that also separates the diastereomers 25(OH)D3 and 3-epi-25(OH)D3. The 25(OH)D3 was measured in SRM 909c using all three methods, and the results were compared. PMID- 22533909 TI - Analysis of multiple quaternary ammonium compounds in the brain using tandem capillary column separation and high resolution mass spectrometric detection. AB - Endogenous quaternary ammonium compounds are involved in various physiological processes in the central nervous system. In the present study, eleven quaternary ammonium compounds, including acetylcholine, choline, carnitine, acetylcarnitine and seven other acylcarnitines of low polarity, were analyzed from brain extracts using a two dimension capillary liquid chromatography-Fourier transform mass spectrometry method. To deal with their large difference in hydrophobicities, tandem coupling between reversed phase and hydrophilic interaction chromatography columns was used to separate all the targeted quaternary ammonium compounds. Using high accuracy mass spectrometry in selected ion monitoring mode, all the compounds could be detected from each brain sample with high selectivity. The developed method was applied for the relative quantification of these quaternary ammonium compounds in three different brain regions of tree shrews: prefrontal cortex, striatum, and hippocampus. The comparative analysis showed that quaternary ammonium compounds were differentially distributed across the three brain areas. The analytical method proved to be highly sensitive and reliable for simultaneous determination of all the targeted analytes from brain samples. PMID- 22533910 TI - Feasability of neat carbon dioxide packed column comprehensive two dimensional supercritical fluid chromatography. AB - The design and implementation of comprehensive two dimensional supercritical fluid chromatography (SFC) using neat carbon dioxide as the mobile phase is described. Two conventional supercritical fluid chromatographs were hyphenated via an on line comprehensive 2D liquid chromatography like interface; it consisted of a two loop switching valve allowing the collection of the first dimension column effluent, the second dimension separation of a fraction being performed during the time allowed for the collection of the subsequent fraction of the first dimension eluent. Both dimension separations were monitored via UV detection; for the second dimension, the main flow was diverted to implement flame ionisation detection for the detection of hydrocarbons and the construction of the corresponding colour plots. Some key parameters related to the interfacing of the two dimensions and the chromatographic conditions used in both dimensions are discussed. In this preliminary report, the feasibility of comprehensive 2D SFC is demonstrated on synthetic mixtures of hydrocarbons and its potential on real sample analysis is illustrated by the separation of coal derived vacuum distillate. PMID- 22533911 TI - Determination of alkylphenols and phthalate esters in vegetables and migration studies from their packages by means of stir bar sorptive extraction coupled to gas chromatography-mass spectrometry. AB - This paper describes a method for the determination of three alkylphenols (APs), 4-tert-octylphenol (tOP), 4-n-octylphenol (OP) and 4-nonylphenol (NP), and six phthalate esters (PEs), dimethylphthalate (DMP), diethylphthalate (DEP), di-n butylphthalate (DBP), n-butylbenzylphthalate (BBP), di-2-ethylhexylphthalate (DEHP) and di-n-octylphthalate (DOP), in vegetables using stir bar sorptive extraction (SBSE) in combination with thermal desorption-gas chromatography-mass spectrometry (TD-GC-MS). Ultrasonic radiation was used to extract the analytes from the solid food matrix, and the extract obtained was preconcentrated by SBSE. The different parameters affecting both stages were carefully optimized. The method was applied to analyze commercial vegetables, in the form of plastic packed salads and canned greens, as well as the corresponding filling liquids of the canned food. Quantification of the samples was carried out against aqueous standards using an internal standard (anthracene). The analysis of a 2 g vegetable sample provided detection limits between 12.7 and 105.8 pg g-1 for OP and DEHP, respectively. Migration studies from the plastic packages of the vegetables samples analyzed were carried out. DEP, DBP and DEHP were found to have migrated from the bags to the simulant and the same compounds were quantified in lettuce, corn salad, arugula, parsley and chard, at concentration levels in the 8-51 ng g-1 range. However, OP and NP were found in only two vegetable samples and one filling liquid, but neither was detected in any package. The proposed method provided recoveries of 83-118%. PMID- 22533912 TI - Recent developments in the detailed characterization of polymers by multidimensional chromatography. AB - Synthetic polymers as well as biopolymers reveal complex structures, such as variations in functionality, chain length and architecture. Therefore, combinations of different chromatographic techniques are a prerequisite for a detailed characterization. One possible approach is the combination of high performance liquid chromatography at critical conditions (LCCC) and size exclusion chromatography, also named as two-dimensional chromatography, which allows the separation of the polymers according to different properties, like molar mass, chemical composition or functionality. In addition, LCCC hyphenated with different mass spectrometry techniques, e.g. MALDI-TOF or ESI-TOF, leads to additional information about molecular details of the polymeric structure. We summarize in this article the recent developments in two-dimensional chromatography of synthetic polymers and biopolymers since 2005. PMID- 22533915 TI - Fabrication of palladium/graphene oxide composite by plasma reduction at room temperature. AB - Pd nanoparticles were fabricated on graphene oxide (GO) using a deposition precipitation method with a glow discharge plasma reduction at room temperature. Argon was employed as the plasma-generating gas. The novel plasma method selectively reduces the metal ions. The graphene oxide has no change with this plasma reduction according to the Fourier transform infrared analysis. The Pd nanoparticles on the GO were uniformly distributed with an average diameter of 1.6 nm. The functional groups on the GO not only prevent Pd nanoparticles from further aggregation but also provide a strong hydrophilic property to the Pd/GO composite, which can form stable colloidal dispersions in water. PMID- 22533913 TI - DNA binding regulates the self-association of the ETS domain of PU.1 in a sequence-dependent manner. AB - The current paradigm of ETS transcription factors holds that their DNA-binding (ETS) domain binds to a single sequence-specific site with strict 1:1 stoichiometry. PU.1 (Spi-1) is a lineage-restricted member of the ETS family that is essential in normal hematopoietic development. Characterization of the binding properties of the ETS domain of PU.1 by isothermal titration calorimetry revealed that it binds a single sequence-specific binding site with 1:1 and 2:1 stoichiometry in a discrete, sequential, and negatively cooperative manner. While both high-affinity- and low-affinity-specific sites exhibit this behavior, the thermodynamics for each complex are highly differentiated. In the unbound state, the PU.1 ETS domain exists as a weak noncovalent homodimer that dissociates and unfolds cooperatively. Thus, the PU.1 ETS domain exists as a monomeric and dimeric species in both DNA-bound and free states. Structural characterization of the protein-DNA interface by quantitative DNA footprinting revealed new minor groove contacts and changes in the core consensus suggestive of increased DNA distortion in the 2:1 complex. Together, the structural and thermodynamic data support a model in which DNA binding dissociates a PU.1 ETS dimer to a 1:1 protein-DNA complex followed by, at higher concentrations, an asymmetric 2:1 complex. The implications of distinct monomeric and dimeric states on the known structural biology of ETS domains as well as potential ETS-protein interactions are discussed. PMID- 22533916 TI - Preparation of alpha- and beta-D-glucoseptanose pentaacetates. AB - The alpha- and beta-D-glucoseptanose pentaacetates have been prepared by treatment of ethyl 1-thio-beta-D-glucoseptanoside tetraacetate with mercury(II) acetate in acetic acid. The solid state structure of the beta-isomer has been determined by X-ray diffraction. PMID- 22533917 TI - Tetraisopropyldisiloxane-1,3-diyl as a versatile protecting group for pentopyranosides. AB - The protecting group tetraisopropyldisiloxane-1,3-yl has been investigated for simultaneous protection of two hydroxyls on pentopyranosides. Methyl alpha-D xylopyranoside is protected in excellent regioselectivity and high yield to form the 2,3-protected xylopyranoside whereas methyl beta-D-xylopyranoside gives the 3,4-protected product also with excellent regioselectivity. PMID- 22533918 TI - Low molecular mass dermatan sulfate modulates endothelial cells proliferation and migration. AB - Low molecular mass dermatan sulfate, obtained by depolymerization, induced the entrance in S phase of mitosis, enhanced the activity of matrix metalloproteinase 2, and could modulate cell migration of endothelial cells, through mechanisms independent of TNF-alpha autocrine regulation. LMMDS located at the injured sites could influence early stages of angiogenesis. PMID- 22533919 TI - Clostridium difficile carbohydrates: glucan in spores, PSII common antigen in cells, immunogenicity of PSII in swine and synthesis of a dual C. difficile-ETEC conjugate vaccine. AB - Clostridium difficile is responsible for severe diarrhea in humans that may cause death. Spores are the infectious form of C. difficile, which germinate into toxin producing vegetative cells in response to bile acids. Recently, we discovered that C. difficile cells possess three complex polysaccharides (PSs), named PSI, PSII, and PSIII, in which PSI was only associated with a hypervirulent ribotype 027 strain, PSII was hypothesized to be a common antigen, and PSIII was a water insoluble polymer. Here, we show that (i) C. difficile spores contain, at least in part, a D-glucan, (ii) PSI is not a ribotype 027-unique antigen, (iii) common antigen PSII may in part be present as a low molecular weight lipoteichoic acid, (iv) selective hydrolysis of PSII yields single PSII repeat units, (v) the glycosyl diester-phosphate linkage affords high flexibility to PSII, and (vi) that PSII is immunogenic in sows. Also, with the intent of creating a dual anti diarrheal vaccine against C. difficile and enterotoxin Escherichia coli (ETEC) infections in humans, we describe the conjugation of PSII to the ETEC-associated LTB enterotoxin. PMID- 22533920 TI - Tuning methyl 4,6-O-benzylidene alpha-D-glucopyranosides' gelation ability by minor group modifications. AB - Ten methyl 4,6-O-benzylidene alpha-D-glucopyranosides were synthesized for the purpose of studying systematically the effect of small group changes at position 4 of the aromatic ring on the ability to gelate organic solvents. The gelation properties are discussed on the basis of small angle X-ray scattering (SAXS), Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) measurements, and scanning electron microscopy (SEM) observations. Sol-gel transition temperatures were determined simultaneously by DSC and temperature dependent FTIR measurements. The current study emphasizes that carbohydrates furnish not only valuable information about structural requirements for organogelator design, but also for molecular assembly systems in general. PMID- 22533921 TI - Enzymatic synthesis of cellulose II-like substance via cellulolytic enzyme mediated transglycosylation in an aqueous medium. AB - The enzymatic synthesis of cellulose-like substance via a non-biosynthetic pathway has been achieved by transglycosylation in an aqueous system of the corresponding substrate, cellotriose for cellulolytic enzyme endo-acting endoglucanase I (EG I) from Hypocrea jecorina. A significant amount of water insoluble product precipitated out from the reaction system. MALDI-TOF mass analysis showed that the resulting precipitate had a degree of polymerization (DP) of up to 16 from cellotriose. Solid-state (13)C NMR spectrum of the resulting water-insoluble product revealed that all carbon resonance lines were assigned to two kinds of anhydroglucose residues in the corresponding structure of cellulose II. X-ray diffraction (XRD) measurement as well as (13)C NMR analysis showed that the crystal structure corresponds to cellulose II with a high degree of crystallinity. We propose the multiple oligomers form highly crystalline cellulose II as a result of self-assembly via oligomer-oligomer interaction when they precipitate. PMID- 22533922 TI - Plasma levels of TNF-alpha, IFN-gamma, IL-4 and IL-10 during a course of experimental contagious bovine pleuropneumonia. AB - BACKGROUND: Contagious Bovine Pleuropneumonia (CBPP), caused by Mycoplasma mycoides subsp. mycoides, is widespread in sub-Saharan Africa. The current live vaccine T1/44 has limited efficacy and occasionally leads to severe side effects in the animals. A better understanding of the immune responses triggered by Mycoplasma mycoides subsp. mycoides and their role in disease progression will help to facilitate the design of a rational vaccine. Currently, knowledge of cytokines involved in immunity and immunopathology in CBPP is rather limited. The aim of this study was to characterize the in vivo plasma concentrations of the cytokines TNF-alpha, IFN-gamma, IL-4, IL-10 and the overall role of CD4+ T cells in the development of cytokine levels during a primary infection. Plasma cytokine concentrations in two groups of cattle (CD4+ T cell-depleted and non-depleted cattle) experimentally infected with Mycoplasma mycoides subsp. mycoides were measured and their relationship to the clinical outcomes was investigated. RESULTS: Plasma cytokine concentrations varied between animals in each group. Depletion of CD4+ T cells did not induce significant changes in plasma levels of TNF-alpha, IL-4, and IL-10, suggesting a minor role of CD4+ T cells in regulation or production of the three cytokines during the time window of depletion (1-2 weeks post depletion). Unexpectedly, the IFN-gamma concentrations were slightly, but statistically significantly higher in the depleted group (p < 0.05) between week three and four post infection. Three CD4+ T cell-depleted animals that experienced severe disease, had high levels of TNF-alpha and IFN-gamma. Only one severely diseased non-depleted animal showed a high serum concentration of IL-4 post infection. CONCLUSIONS: Comparison of most severely diseased animals, which had to be euthanized prior to the expected date, versus less severe diseased animals, irrespective of the depletion status, suggested that high TNF-alpha levels are correlated with more severe pathology in concomitance with high IFN gamma levels. PMID- 22533923 TI - Methicillin-resistant staphylococcal contamination of cellular phones of personnel in a veterinary teaching hospital. AB - BACKGROUND: Hospital-associated infections are an increasing cause of morbidity and mortality in veterinary patients. With the emergence of multi-drug resistant bacteria, these infections can be particularly difficult to eradicate. Sources of hospital-associated infections can include the patients own flora, medical staff and inanimate hospital objects. Cellular phones are becoming an invaluable feature of communication within hospitals, and since they are frequently handled by healthcare personnel, there may be a potential for contamination with various pathogens. The objective of this study was to determine the prevalence of contamination of cellular phones (hospital issued and personal) carried by personnel at the Ontario Veterinary College Health Sciences Centre with methicillin-resistant Staphylococcus pseudintermedius (MRSP) and methicillin resistant Staphylococcus aureus (MRSA). RESULTS: MRSP was isolated from 1.6% (2/123) and MRSA was isolated from 0.8% (1/123) of cellular phones. Only 21.9% (27/123) of participants in the study indicated that they routinely cleaned their cellular phone. CONCLUSIONS: Cellular phones in a veterinary teaching hospital can harbour MRSP and MRSA, two opportunistic pathogens of significant concern. While the contamination rate was low, cellular phones could represent a potential source for infection of patients as well as infection of veterinary personnel and other people that might have contact with them. Regardless of the low incidence of contamination of cellular phones found in this study, a disinfection protocol for hospital-issued and personal cellular phones used in veterinary teaching hospitals should be in place to reduce the potential of cross-contamination. PMID- 22533925 TI - Cutaneous Castleman disease. PMID- 22533924 TI - EnzML: multi-label prediction of enzyme classes using InterPro signatures. AB - BACKGROUND: Manual annotation of enzymatic functions cannot keep up with automatic genome sequencing. In this work we explore the capacity of InterPro sequence signatures to automatically predict enzymatic function. RESULTS: We present EnzML, a multi-label classification method that can efficiently account also for proteins with multiple enzymatic functions: 50,000 in UniProt. EnzML was evaluated using a standard set of 300,747 proteins for which the manually curated Swiss-Prot and KEGG databases have agreeing Enzyme Commission (EC) annotations. EnzML achieved more than 98% subset accuracy (exact match of all correct Enzyme Commission classes of a protein) for the entire dataset and between 87 and 97% subset accuracy in reannotating eight entire proteomes: human, mouse, rat, mouse ear cress, fruit fly, the S. pombe yeast, the E. coli bacterium and the M. jannaschii archaebacterium. To understand the role played by the dataset size, we compared the cross-evaluation results of smaller datasets, either constructed at random or from specific taxonomic domains such as archaea, bacteria, fungi, invertebrates, plants and vertebrates. The results were confirmed even when the redundancy in the dataset was reduced using UniRef100, UniRef90 or UniRef50 clusters. CONCLUSIONS: InterPro signatures are a compact and powerful attribute space for the prediction of enzymatic function. This representation makes multi label machine learning feasible in reasonable time (30 minutes to train on 300,747 instances with 10,852 attributes and 2,201 class values) using the Mulan Binary Relevance Nearest Neighbours algorithm implementation (BR-kNN). PMID- 22533926 TI - The mechanism of propagation of variation potentials in wheat leaves. AB - Here we examined the mechanism of propagation of variation potential (VP) induced by burning in wheat leaves. Participation of hydraulic and chemical mechanisms in VP transmission was analyzed by optical coherent tomography and a radioactive tracer method, respectively. The speed of the hydraulic signal considerably exceeded the VP velocity. Investigation of a chemical substance spreading from the zone of local wounding was based on experimental data for radioactive marker transmission derived with a one-dimensional diffusion equation. The speed of the marker transmission was in accordance with VP velocity. The elimination of the potential transmission of a chemical signal by a timed severing of the leaf between the burn site and the recorded site blocked VP propagation. We suggest that a VP is formed by the transmission of a wound substance, the velocity of which is likely increased by hydraulic wave propagation. PMID- 22533928 TI - [Occurrence of obesity: stagnation of the increase]. PMID- 22533929 TI - [Use of clinical databases and central health registries for description of disease courses]. AB - In Denmark, the linkage between national clinical databases and central health administrative and socio-demographic registries provides unique opportunities for describing and analysing disease courses in ways that can be applied for quality improvement purposes, in the evaluation of new organisational initiatives, and for research. This status article presents an overview of the possibilities and discusses the potentials and challenges. PMID- 22533927 TI - The role of nutrition in integrated programs to control neglected tropical diseases. AB - There are strong and direct relationships between undernutrition and the disease caused by infectious organisms, including the diverse pathogens labeled as neglected tropical diseases (NTDs). Undernutrition increases the risk of infection, the severity of disease and the risk that children will die, while the physical damage, loss of appetite, and host responses during chronic infection can contribute substantially to undernutrition. These relationships are often synergistic. This opinion article examines the role of nutrition in controlling NTDs and makes the point that mass drug treatment--the major strategy currently proposed to control several diseases--is crucial to controlling disease and transmission, but is only the start of the process of physical recovery. Without adequate energy and nutrients to repair damaged tissues or recover lost growth and development, the benefits of treatment may not be evident quickly; the effects of control programs may be not appreciated by beneficiaries; while vulnerability to reinfection and disease may not be reduced. There is substantial potential for nutritional interventions to be added to large-scale programs to deliver drug treatments and thereby contribute, within a broad strategy of public health interventions and behavior change activities, to controlling and preventing NTDs in populations, and to restoring their health. PMID- 22533930 TI - [Multiple self-healing squamous epithelioma is an inherited self-healing skin cancer condition]. AB - Multiple self-healing squamous epithelioma - Ferguson-Smith disease (MSSE) is an autosomal dominant inherited disease with multiple, recurrent, histologically malignant tumours that undergo spontaneous regression. The gene for MSSE has recently been identified as the transforming growth factor-beta receptor 1 (TGFBR1). Although rare, MSSE constitutes an important model of tumour-biology research. The discovery of the genetic background for MSSE paves the way for further elucidating the mechanisms involved in this peculiar self-healing cancer syndrome. PMID- 22533931 TI - [Genetic causes of infantile spasms--a systematic review]. AB - Infantile spasms are a symptom of a severe epileptic encephalopathy. It is important to determine the aetiology for a child's disease. When a standard programme for evaluating the aetiology of the infantile spasms is unsuccessful genetic causes should be considered. We suggest array CGH as the first-line analysis and present an overview of relevant present possibilities for genetic testing. PMID- 22533932 TI - [High standards of educational climate in Danish anaesthesiological departments]. AB - For the first time since the implementation of the Danish national medical educational reform in 2004 the effects on the educational programme are investigated by means of a nation-wide questionnaire. Mandatory concepts introduced with the educational reform such as supervisor involvement, appraisal meetings and personal learning plans are almost completely implemented in the anaesthesiological departments. Doctors, who do not currently undertake specialist training, were also contented with the implementation. The educational climate is reported to be of high standards. Hopefully, this survey can inspire other specialities to identify how education can be improved. PMID- 22533933 TI - [Improved prognosis in light chain nephropathy due to multiple myeloma]. AB - A 64 year-old woman with acute renal failure and cast nephropathy due to excessive production of lambda free light chains received chemotherapy (using bortezomib and dexamethason) and haemodialysis with a high cut off-filter. The concentration of free light chains was markedly reduced after a fortnight. Nine months after admission, the patient's kidney function had improved and dialysis was stopped. Three months later, she got an autologous stem cell transplantation. One year later, estimated glomerular filtration rate was 25 ml/min, and the production of free light chains was under control. PMID- 22533934 TI - [Relevant trauma in a haemodynamic stable patient should be computed tomographed in spite of pregnancy]. AB - A 37 year-old pregnant woman, gestational age 32 weeks, was involved in a motor vehicle accident. Abdominal ultrasound revealed no pathological findings, and the woman was discharged after 24 hours of observation. Three weeks later a healthy girl was delivered by emergency caesarean section due to placental abruption. During surgery a large amount of blood was detected and signs of previous trauma and haematoma to the spleen were revealed. Post-operative abdominal computed tomography scan was performed, revealing a 5 * 7 cm intrasplenic haematoma. PMID- 22533935 TI - [Bilateral sarcoidosis of parotid glands]. AB - We describe an unusual case of sarcoidosis in which the patient presented with a bilateral swelling of the parotid salivary glands and no other manifestation of the disease. Sarcoidosis is a multisystem granulomatous disorder of unknown cause in which there may be multiple exocrine involvement, including the salivary glands. This case emphasises the importance of including sarcoidosis in the differential diagnosis of bilateral parotid swelling. PMID- 22533936 TI - [Extravasation of contrast following coronary angiography can be misinterpretated as subarachnoid haemorrhage]. AB - Brain parenchymal extravasation of contrast has been described after infusion of larger amounts of iodinated X-ray contrast agent. We describe a case in which a patient after infusion of 500 ml iomeprole 350 mg/ml developed neurological symptoms and a subsequent cerebral computed tomography (CT) scan was interpreted as subarachnoid haemorrhage. The patient was fully recovered within 48 hours, and a follow-up CT scan 26 hours later showed no signs of haemorrhage. In patients with sudden onset of neurological symptoms after infusion of large quantities of contrast media and a CT scan showing signs of subarachnoid haemorrhage, spinal puncture or magnetic resonance imaging should be considered prior to interventional procedures in order to verify the diagnosis. PMID- 22533937 TI - [The clinical course of a three year-old girl after overdose of valproic acid]. AB - Valproic acid (VA) is an antiepileptic drug, and frequently prescribed in pediatrics. VA overdose results in central nervous system depression, insufficient respiration, tachycardia, hypotension, hepatotoxicity, and electrolyte derangement. We describe the clinical course of a three year-old girl after accidental intake of 6,000 mg VA. Treatment included activated charcoal. Clinical observation included measurements of blood pressure, cardiac telemetry, and measurements of serum VA and metabolic parameters every 4-6 hrs. The girl was discharged successfully after 72 hrs with her usual dose of VA. PMID- 22533939 TI - Kisspeptins and the reproductive axis: potential applications to manage reproduction in farm animals. AB - Kisspeptins (Kp) are a family of neuropeptides produced mainly by two hypothalamic neuronal cell populations. They have recently emerged as a major regulator of the gonadotropin axis and their action is located upstream of the gonadotropin-releasing hormone (GnRH) cell population. In less than 10 yr a growing body of literature has demonstrated the involvement of these peptides in most, if not all, aspects of reproductive axis maturation and function. In contrast to these abundant basic research studies, few experiments have evaluated the potential application of Kp as tools to manipulate reproduction in domestic animals. In mammals, exogenous Kp administration potently stimulates gonadotropin secretion. This action is exerted mainly, if not exclusively, through the stimulation of GnRH release. Intravenous, intraperitoneal, or subcutaneous administration of Kp induced a robust and rapid increase in plasma gonadotropins (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]). However, this stimulatory effect is of short duration. Prolonged LH and FSH release over several hours can be achieved only when Kp are given as repeated multiple bolus or as an infusion. Kp administration was used in two experimental models, ewe and pony mare, with the aim of inducing well-timed and synchronized ovulations. During the breeding season, progesterone-synchronized ewes were given an intravenous infusion of Kp starting 30 h after the removal of progesterone implants. An LH surge was induced in all Kp-treated animals within 2 h of infusion onset. In contrast, in pony mares a constant infusion of Kp for 3 d in the the late follicular phase was unable to induce synchronized ovulation. Another set of studies showed that Kp could be used to activate reproductive function in acyclic animals. Pulsatile administration of Kp in prepubertal ewe lambs was shown to activate ovarian function, leading to enhanced ovarian steroidogenesis, stimulation of LH preovulatory surge, and ovulation. In anestrous ewes, an intravenous infusion of a low dose of Kp induced an immediate and sustained release of gonadotropins, followed a few hours later by an LH surge. This hormonal pattern mimicked hormonal changes normally observed during the estrous cycle follicular phase and was associated with a high percentage of ovulating animals (80%). In summary, exogenous administration of Kp appears to be a new tool to manipulate reproduction. However, optimal doses and periods of treatment should be defined for each species, and the development of powerful analogs or long-term release formulations is necessary before large-scale applications in domestic animals could be envisaged. PMID- 22533938 TI - Obesity and long term functional outcomes following elective total hip replacement. AB - INTRODUCTION: Obesity rates continue to rise and more total hip arthroplasty procedures are being performed in progressively younger, obese patients. Hence, maintenance of long term physical function will become very important for quality of life, functional independence and hip prosthesis survival. Presently, there are no reviews of the long term efficacy of total hip arthroplasty on physical function. This review: 1) synopsized available data regarding obesity effects on long term functional outcomes after total hip arthroplasty, and 2) suggested future directions for research. METHODS: A literature search was conducted from 1965 to January of 2011 for studies that evaluated long term functional outcomes at one year or longer after THA in obese (body mass index values >= 30 kg/m2) and non-obese patients (body mass index <30 kg/m2). RESULTS: Five retrospective studies and 18 prospective studies were identified as those that assessed physical function before surgery out to >= one year after total hip arthroplasty. Study sample sizes ranged from 108-18,968 and followed patients from one to twenty years. Total hip arthroplasty confers significant pain reduction and improvement in quality of life irrespective of body mass index. Functional improvement occurred after total hip arthroplasty among all studies, but obese patients generally did not attain the same level of physical function by the follow-up time point. DISCUSSION: Uncontrolled obesity after total hip arthroplasty is related to worsening of comorbidities and excessive health care costs over the long term. Aggressive and sustainable rehabilitation strategies that include physical exercise, psychosocial components and behavior modification may be highly useful in maximizing and maintaining weight loss after total hip arthroplasty. PMID- 22533940 TI - Sociosexual stimuli and gonadotropin-releasing hormone/luteinizing hormone secretion in sheep and goats. AB - Sociosexual stimuli have a profound effect on the physiology of all species. Sheep and goats provide an ideal model to study the impact of sociosexual stimuli on the hypothalamic-pituitary-gonadal axis because we can use the robust changes in the pulsatile secretion of luteinizing hormone as a bioassay of gonadotropin releasing hormone secretion. We can also correlate these changes with neural activity using the immediate early gene c-fos and in real time using changes in electrical activity in the mediobasal hypothalamus of female goats. In this review, we will update our current understanding of the proven and potential mechanisms and mode of action of the male effect in sheep and goats and then briefly compare our understanding of sociosexual stimuli in ungulate species with the "traditional" definition of a pheromone. PMID- 22533941 TI - Care for residents with dementia in an assisted living facility. AB - The purpose of this prospective, ethnographic study was to describe and analyze the care of residents with dementia in an assisted living facility (ALF) providing dementia care. Participant observation and interviews with 20 employees were used to obtain data. Data were collected and analyzed over a period of 6 months. Four major themes emerged from the data: (a) Caregivers' Level of Knowledge of Dementia, (b) Caregivers' Lack of Knowledge in Preventing or Assessing Acute Illnesses, (c) Limitations in Monitoring and Reporting Resident Changes, and (d) Inappropriate Medication Administration. Forty percent of the residents (N = 35) were admitted to the hospital over 6 months. The problems in providing quality care in this facility demonstrate the need for gerontological nurses in ALFs, who would improve care by assessing and monitoring the residents and by supervising and educating the caregivers. PMID- 22533942 TI - The role of emerging information technologies in frailty assessment. AB - Frailty has an insidious impact on multiple systems, resulting in increased disability, morbidity, and mortality among community-dwelling older adults. Notwithstanding the burden that frailty imposes on individuals, there is still a lack of consensus on its operational and conceptual definitions, leading research groups to invest efforts into developing a more comprehensive model of frailty. A number of screening models have been proposed to objectively measure the magnitude of the frailty process and to assess its long-term consequences. Each model incorporates a distinct set of physiological parameters stemming from the combination of a number of clinical domains. Emerging information technologies (ITs) could provide an effective, flexible, and integrative solution for monitoring and measuring the different aspects of the frailty construct in real life settings. The purpose of this article is to discuss how various ITs can be used to measure the core characteristics of frailty identified from an integrative systematic review. We discuss the actual and potential integration of ITs in frailty research, strengths and limitations of various methods, and areas for future work. PMID- 22533943 TI - Preclinical in vivo research in implant dentistry. Consensus of the eighth European workshop on periodontology. AB - Guidelines for improving the reporting in preclinical in vivo research (ARRIVE) have been recently proposed. AIM: The aim was to assess to what extent the ARRIVE guidelines were considered in preclinical in vivo studies in implant dentistry. MATERIAL AND METHODS: Four comprehensive systematic reviews evaluated to what extent the ARRIVE guidelines were considered in preclinical in vivo studies in implant dentistry. Studies on the influence of implant material, surface and design on tissue integration to implants placed in pristine bone, in locally compromised sites and/or systemically compromised animals, as well as on peri implant mucositis and peri-implantitis were evaluated. The four reviews introduced different modifications to the ARRIVE guidelines dedicated to the specific assignment of the review. RESULTS: A large variation in the frequency of reporting with regard to the items of the modified ARRIVE guidelines was observed. The reviews revealed that relevant information, e.g. sample size calculation, blinding of the assessor etc., was often not reported. It was also identified that several items in the ARRIVE guidelines may be less--if at all- applicable to research in implant dentistry. CONCLUSION: It is suggested that researchers implement, whenever relevant, the ARRIVE guidelines during planning and reporting of preclinical in vivo studies related to dental implants. PMID- 22533944 TI - Quality of reporting of experimental research in implant dentistry. Critical aspects in design, outcome assessment and model validation. AB - OBJECTIVE: The aim was to assess the quality of reporting of experimental research in implant dentistry by a critical evaluation of study design, outcome assessments and model validation. MATERIAL & METHODS: An online search was performed using the MEDLINE. Experimental studies performed in both animals and humans were included. A’stratified random sample of the included studies was extracted and used for quantitative and qualitative analyses. Modified versions of the ARRIVE guidelines were used for quality assessment. RESULTS: A total of 982 papers were eligible and used for quantitative analyses. A’stratified random sample of 193 publications was extracted. The dog model was the most used experimental model whereas experimental studies on humans were few. Intra-oral experimental sites dominated in human, monkey, dog and mini-pig studies. Extra oral sites dominated in rabbit, rodent and goat/sheep studies. Studies on the pathogenesis and treatment of peri-implant diseases were few. CONCLUSION: Different animal models, experimental protocols and methods of analysis have been used to address different areas of experimental research in implant dentistry. Standardized designs for investigations within this type of experimental research seem to be lacking. Furthermore, in many of these studies there were limitations in reporting on methodology and statistical methods. PMID- 22533945 TI - Systematic review of animal models for the study of implant integration, assessing the influence of material, surface and design. AB - OBJECTIVES: The aim of this systematic review was to assess the scientific literature in terms of pre-clinical studies evaluating the influence of material, surface and design on the integration of an implant by hard and soft tissues. The included publications were analysed with regard to the frequency of reporting of criteria being derived from the ARRIVE guidelines. This served to trace elements within animal studies, where the quality of reporting needs to improve. MATERIAL AND METHODS: The literature search was performed in Ovid Medline and included English literature from January 1990 to July 2011. A list of 24 criteria derived from the ARRIVE guidelines for animal research was adjusted to implant studies on osseointegration in pristine bone and was applied to all included study manuscripts. Each criteria was graded by "0" (not reported) or "1" (reported) and the frequency of reporting for each criteria was recorded. RESULTS: A total of 271 studies were included into this review. Generally the quality of reporting increased with time. Low frequencies of reporting were achieved for criteria like "randomisation of animals", "reasons for the animal model" and "relevance to humans". CONCLUSIONS: The frequency of reporting showed high percentages for most criteria. However, the quality of reporting in pre-clinical studies needs to improve in areas like the reporting of statistical information, study setup and the possible translation of the results to humans. PMID- 22533946 TI - Systematic review of pre-clinical models assessing implant integration in locally compromised sites and/or systemically compromised animals. AB - OBJECTIVE: The aim was to systematically search the dental literature for pre clinical models assessing implant integration in locally compromised sites (part 1) and systemically compromised animals (part 2), and to evaluate the quality of reporting of included publications. METHODS: A Medline search (1966-2011) was performed, complimented by additional hand searching. The quality of reporting of the included publications was evaluated using the 20 items of the ARRIVE (Animals in Research In Vivo Experiments) guidelines. RESULTS: One-hundred and seventy-six (part 1; mean ARRIVE score = 15.6 +/- 2.4) and 104 (part 2; 16.2 +/- 1.9) studies met the inclusion criteria. The overall mean score for all included studies amounted to 15.8 +/- 2.2. Housing (38.3%), allocation of animals (37.9%), numbers analysed (50%) and adverse events (51.4%) of the ARRIVE guidelines were the least reported. Statistically significant differences in mean ARRIVE scores were found depending on the publication date (p < 0.05), with the highest score of 16.7 +/- 1.6 for studies published within the last 2 years. CONCLUSIONS: A large number of studies met the inclusion criteria. The ARRIVE scores revealed heterogeneity and missing information for selected items in more than 50% of the publications. The quality of reporting shifted towards better-reported pre-clinical trials within recent years. PMID- 22533947 TI - Quality assessment of reporting of animal studies on pathogenesis and treatment of peri-implant mucositis and peri-implantitis. A systematic review using the ARRIVE guidelines. AB - OBJECTIVES: To address the following focused question: What is the quality of reporting of pre-clinical research for the study and treatment of mucositis/peri implantitis? MATERIALS AND METHODS: Electronic databases of the PubMed and the Cochrane Library were searched for animal studies reporting on pathogenesis or therapy of either peri-implant mucositits or peri-implantitis and completed by dual manual searches in duplicate between 1992 and May 2011. Quality assessment (i.e. grading of a checklist of 20 items in different categories) of selected full-text articles was performed according to the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines. RESULTS: Following screening, 75 publications were eligible for the review. For publications reporting on pathogenesis (n = 7) and therapy (n = 1) of peri-implant mucositis, minimum gradings were assigned to items 5 (Methods/Ethical Statement), 9 (Methods/Housing and husbandry), 11 (Methods/Allocation animals to experimental groups), 14 (Results/Baseline data), and 17 (Results/Adverse events). For publications reporting on pathogenesis (n = 34) and therapy (n = 33) of peri-implantitis, minimum grades were mainly assigned to items 9, 11, 14, and 17. CONCLUSIONS: This systematic review has identified missing information in the publications on pre clinical research for the study and treatment of mucositis/peri-implantitis. PMID- 22533948 TI - Clinical research in implant dentistry: study design, reporting and outcome measurements: consensus report of Working Group 2 of the VIII European Workshop on Periodontology. AB - AIMS: The objective of this working group was to assess and make specific recommendations to improve the quality of reporting of clinical research in implant dentistry and discuss ways to reach a consensus on choice of outcomes. MATERIAL AND METHODS: Discussions were informed by three systematic reviews on quality of reporting of observational studies (case series, case-control and cohort) and experimental research (randomized clinical trials). An additional systematic review provided information on choice of outcomes and analytical methods. In addition, an open survey among all workshop participants was utilized to capture a consensus view on the limits of currently used survival and success based outcomes as well as to identify domains that need to be captured by future outcome systems. RESULTS: The Workshop attempted to clarify the characteristics and the value in dental implant research of different study designs. In most areas, measurable quality improvements over time were identified. The Workshop recognized important aspects that require continued attention by clinical researchers, funding agencies and peer reviewers to decrease potential bias. With regard to choice of outcomes, the limitations of currently used systems were recognized. Three broad outcome domains that need to be captured by future research were identified: (i) patient reported outcome measures, (ii) peri implant tissue health and (iii) performance of implant supported restorations. Peri-implant tissue health can be measured by marginal bone level changes and soft tissue inflammation and can be incorporated in time to event analyses. CONCLUSIONS: The Workshop recommended that collaboration between clinicians and epidemiologists/clinical trials specialists should be encouraged. Aspects of design aimed at limitation of potential bias should receive attention by clinical researchers, funding agencies and journal editors. Adherence to appropriate reporting guidelines such as STROBE and CONSORT are necessary standards. Research on outcome measure domains is an area of top priority and should urgently inform a proper process leading to a consensus on outcome measures in dental implant research. PMID- 22533949 TI - Quality of reporting of randomized clinical trials in implant dentistry. A systematic review on critical aspects in design, outcome assessment and clinical relevance. AB - BACKGROUND: The aim of this systematic review (SR) was to assess the quality of reporting randomized clinical trials (RCTs) in the field of implant dentistry, its evolution over time and the possible relations between quality items and reported outcomes. MATERIAL AND METHODS: RCTs in implant dentistry were retrieved through electronic and hand searches. Risk of bias in individual studies was assessed focusing on study design, outcome assessment and clinical relevance. Associations between quality items and year of publication of RCTs or reporting of statistically significant outcomes were tested. RESULTS: Among the 495 originally screened manuscripts published from 1989 to April 2011, 276 RCTs were assessed in this SR; 59% of them were published between 2006 and 2011. RCTs were mainly parallel (65%), with a single centre (83%) and a superiority design (88%). Trials in implant dentistry showed several methodological flaws: only 37% showed a random sequence generation at low risk of bias, 75% did not provide information on allocation concealment, only 12% performed a correct sample size calculation, the examiner was blind solely in 42% of studies where blinding was feasible. In addition, only 21% of RCTs declared operator experience and 31% reported patient related outcomes. Many quality items improved over time. Allocation concealment at high risk of bias (p = 0.0125), no information on drop-out (p = 0.0318) and lack of CONSORT adherence (p = 0.0333) were associated with statistically significant reported outcomes. CONCLUSIONS: The overall quality of reporting of RCTs in implant dentistry is poor and only partially improved in the last years. Caution is suggested when interpreting these RCTs since risk of bias was associated with higher chance of reporting of statistically significant results. PMID- 22533950 TI - Quality of reporting of descriptive studies in implant dentistry. Critical aspects in design, outcome assessment and clinical relevance. AB - OBJECTIVES: The aim of this study was to conduct a review on quality of reporting on descriptive studies in implant dentistry using the STROBE Statement and to analyse possible changes in quality of reporting on descriptive studies in implant dentistry over time. MATERIAL AND METHODS: A hand search to select descriptive studies was carried out in seven dental journals, which were thought to have interest in the field of dental implants. Issues of the years 1990, 1995, 2000, 2005 and 2010 were screened. The STROBE Statement with 22 criteria to match was used to determine the quality of an article. RESULTS: Totally 4657 titles and abstracts were screened; 260 of them were found to be reporting on a descriptive study. Percentages of properly addressed items were 46% in 1990, 56% in 1995, 54% in 2000, 59% in 2005 and 70% in 2010. CONCLUSION: From this review can be concluded that quality of reporting on descriptive studies in implant dentistry is low; there is some improvement from 1990 to 2010, but it does not exceed 70% coverage of the possible to address items. PMID- 22533951 TI - A review assessing the quality of reporting of risk factor research in implant dentistry using smoking, diabetes and periodontitis and implant loss as an outcome: critical aspects in design and outcome assessment. AB - AIM: To assess, using a structured review, the quality of reporting (design and outcome assessment) of risk factor research using the STROBE statements. The outcome was implant loss, and the risk factors assessed were smoking, diabetes and periodontitis. MATERIALS AND METHODS: Literature search was performed individually for each of the risk factors and the outcome using three sets of database: (a) MEDLINE, (b) references derived from relevant reviews and (c) references derived from identified manuscripts. Only case-control and cohort studies were included and assessed using the STROBE statements. RESULTS: A total of 104 papers were retrieved, three of which were found to be cohort studies (one in the diabetes and two in the periodontitis review) and none was a case-control study. A total of 101 of 104 papers were case series or cross-sectional study. CONCLUSIONS: Risk factor research in implant dentistry is mostly comprised of case series studies. These are used to generate hypotheses, but are the wrong tool to test these hypotheses. In the near future, well-designed observational studies are needed and should be reported according to the proposed checklist. PMID- 22533952 TI - Systematic review of outcome measurements and reference group(s) to evaluate and compare implant success and failure. AB - BACKGROUND: There is a lack of consensus on measures to assess implant performance in clinical research. OBJECTIVES: To investigate the outcomes measures and reference groups employed to evaluate and compare implant success and failure. DATA SOURCES: MEDLINE (OVID) and Web of Science with searching reference lists of included papers. STUDY ELIGIBILITY CRITERIA: Inclusion: root form, titanium implants in dentate or edentulous individuals. Longitudinal studies reporting survival or success outcomes on at least 20 participants >= mean 5 years. STUDY APPRAISAL AND SYNTHESIS METHODS: Descriptive statistics. RESULTS: Two-hundred and sixteen studies were included. Implant survival was the most commonly reported primary outcome (60%) with success at 15.7%. Success constituted a wide variety of measures with little consistency. A percentage of 98.6% of studies employed the implant as the unit of analysis with little consideration of clustering within patients. The status of periodontal and general heath of study groups was unclear for more than 80% studies. The proportion of studies comprising randomized trials or using appropriate analytical methods increased from 1980 to 2011. LIMITATIONS: Considers only English language and there was no author contact. CONCLUSION: In view of the disparate outcome measures employed to assess dental implant performance, agreement is needed both on a core set of implant outcomes and their statistical management. PMID- 22533953 TI - Clinical research in implant dentistry: evaluation of implant-supported restorations, aesthetic and patient-reported outcomes. AB - The articles discussed in working group 3 dealt with specific aspects of clinical research. In this context, the literature reporting on survival and complication rates of implant-supported or implant-tooth supported restorations in longitudinal studies of at least 5 years were discussed. The second aspect dealt with the evaluation of aesthetic outcomes in clinical studies and the related index systems available. Finally, the third aspect discussed dealt with patient reported outcome measures (PROMs). A detailed appraisal of the available methodology was presented. PMID- 22533954 TI - Quality of reporting of clinical studies to assess and compare performance of implant-supported restorations. AB - OBJECTIVES: The objective of this analysis was to assess and compare the 5- and 10-year survival of different types of tooth-supported and implant-supported fixed dental prostheses (FDPs) and single crowns (SCs), and to describe the incidence of biological and technical complications with emphasis on quality of reporting. MATERIAL AND METHODS: The analysis was based on six systematic review identifying prospective and retrospective cohort studies and case-series on FDPs and SCs with a mean follow-up time of at least 5 years. Patients had to have been examined clinically at the follow-up visit. Failure and complication rates were analysed using random-effects Poisson regression models to obtain summary estimates of 5- and 10-year survival proportions. RESULTS: Meta-analyses of the included studies indicated that the 5-year survival rates ranged from 89.2% to 95.5% for different types of restorations. Investigating the relative failure rates using implant-supported SCs as reference, conventional and cantilever tooth supported FDPs and resin-bonded prosthesis (RBPs) showed higher failure rates. Moreover, for RBPs, this difference reached statistical significance (p = 0.018). Analysing the studies with 10 years follow-up time, the survival ranged from 65% to 89.4%. After a 10-year observation period, the lowest annual failure rates were seen for implant-supported SCs (1.12%), conventional tooth-supported FDPs (1.14%) and implant-supported FDPs (1.43%). Cantilever tooth-supported FDPs, combined tooth-implant-supported FDPs and RBPs had significantly (p < 0.001) higher annual failure rates of 2.20%, 2.51% and 4.31%, respectively. According to presently recommended standards for reporting cohort studies (STROBE Statement), it was evident that the included studies did not fulfil the present standards to a great extent. Information on study design, methods of selecting study participants, percentage and reason for participants lost to follow-up was often not reported. Furthermore, the included studies rarely discussed possible limitations and potential sources of bias. Moreover, funding sources were generally not reported. CONCLUSION: Based on the present analysis treatment planning in a mutilated dentition in need of oral reconstructions should base on the results of the systematic reviews performed. In this context, the choice of reconstructions on teeth with end abutments, of reconstructions on implants (both FDPs and SCs) should be given first priority, while combined tooth-implant supported reconstructions, cantilever reconstructions on teeth and RBPs represent options of second priority. Future studies on performance of implant-supported restorations should be prospective in design and should follow the present recommendation for reporting cohort studies (The STROBE statement). PMID- 22533955 TI - Systematic review of parameters and methods for the professional assessment of aesthetics in dental implant research. AB - OBJECTIVE: The purpose of the present systematic review was to evaluate the scientific literature regarding the professional assessment of aesthetics in implant dentistry. MATERIAL AND METHODS: An electronic search of Medline database and Cochrane Central Register of Controlled Trials was performed, and complemented by a manual search. Clinical or validation studies (Part 1) and randomized-controlled trials (RCTs) (Part 2) reporting parameters and methods for the assessment of aesthetics were included. The information regarding the assessment of aesthetics was extracted. The methodological quality of RCTs was evaluated by means of the Cochrane Collaboration's Tool for assessing risk of bias. RESULTS: The search yielded 149 and 32 publications in Part 1 and Part 2, respectively. A great diversity with regard to parameters, methods and measurement units used for the assessment of aesthetics was found among the included studies. With respect to time points of assessment there were significant differences between the RCTs. Only two RCTs fulfilled all the criteria of the The Cochrane Collaboration's Tool for assessing risk of bias. CONCLUSIONS: Due to the differences of the study designs, parameters and methods used for the assessment of aesthetics, comparisons between studies should be interpreted with caution. Only a limited number of RCTs offer sound evidence on aesthetic outcomes in implant dentistry. PMID- 22533956 TI - An evidence-based review of patient-reported outcome measures in dental implant research among dentate subjects. AB - AIM: To conduct an evidence-based review of patient-reported outcome measures (PROMs) in dental implant research among dentate patients so as to gain an understanding of the use of such measures, and the potential evidence that can be gleaned from such studies. MATERIAL AND METHODS: A structured literature search was carried out in the MEDLINE database. Patient-related end-points in dental implant research were categorized with respect to type of outcome and reviewed. RESULTS: The initial search identified 3397 publications; full texts were obtained for 133 papers, and ultimately 31 'effective papers'. PROMs were primarily concerned with assessment of patient satisfaction/preference (71%, 22). A range of prosthetic treatments associated with dental implants were identified. Few studies were prospective studies that included pre-treatment assessments. There was a lack of standardization in the assessment of patient-related outcomes. CONCLUSIONS: There is an increasing use of PROMs in dental implant research among dentate patients for a range of prosthetic treatments. For the most part studies have been concerned with the assessment of patient satisfaction/preference but fail to employ standardized outcome assessment methods, which hampers understanding of the benefit of dental implant therapy from patients' perspectives. PMID- 22533957 TI - Clinical research on peri-implant diseases: consensus report of Working Group 4. AB - BACKGROUND: Two systematic reviews have evaluated the quality of research and reporting of observational studies investigating the prevalence of, the incidence of and the risk factors for peri-implant diseases and of experimental clinical studies evaluating the efficacy of preventive and therapeutic interventions. MATERIALS AND METHODS: For the improvement of the quality of reporting for both observational and experimental studies, the STROBE and the Modified CONSORT recommendations were encouraged. RESULTS: To improve the quality of research in peri-implant diseases, the following were recommended: the use of unequivocal case definitions; the expression of outcomes at the subject rather than the implant level; the implementation of study validation tools; the reporting of potential sources of bias; and the use of appropriate statistical methods. CONCLUSIONS: In observational studies, case definitions for peri-implantitis were agreed. For risk factor determination, the progressive use of cross-sectional and case-control studies (univariate analyses), to prospective cohorts (multilevel modelling for confounding), and ultimately to intervention studies were recommended. For preventive and interventional studies of peri-implant disease management, parallel arm RCTs of at least 6-months were encouraged. For studies of non-surgical and surgical management of peri-implantitis, the use of a composite therapeutic end point was advocated. The development of standard control therapies was deemed essential. PMID- 22533958 TI - Clinical research of peri-implant diseases--quality of reporting, case definitions and methods to study incidence, prevalence and risk factors of peri implant diseases. AB - AIM: To review the quality of reporting and the methodology of clinical research on the incidence, prevalence and risk factors of peri-implant diseases. METHODS: A MEDLINE search was conducted for cross-sectional, case-control and prospective longitudinal studies reporting on peri-implant diseases. To evaluate the quality of reporting of the selected studies the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) checklist was utilized. RESULTS: The search provided 306 titles and abstracts, out of which 40 were selected for full text analysis. Finally, 16 studies were included out of which five assessed prevalence and only two the incidence of peri-implant diseases. 13 articles studied risk indicators for peri-implant diseases. None of the scrutinized articles adhered fully to the STROBE criteria. The large majority of articles did not (i) clearly state the applied study design, (ii) describe any effort to address potential sources of bias, (iii) explain how missing data were addressed, (iv) perform any kind of sensitivity analysis, (v) indicate the number of participants with missing data for each variable of interest. CONCLUSION: Collectively, the findings of this review indicate a need for improved reporting of epidemiological studies on peri-implant diseases. PMID- 22533959 TI - Systematic review of quality of reporting, outcome measurements and methods to study efficacy of preventive and therapeutic approaches to peri-implant diseases. AB - AIM: To systematically review the literature and to assess the quality of reporting, outcome measurements and methods in both preventive and therapeutic approaches to peri-implant mucositis (PM) and peri-implantitis (PI). MATERIALS AND METHODS: Randomized (RCT) and Controlled Clinical Trials (CCT), evaluating preventive or therapeutic interventions in patients with PM or PI, were identified through searching in electronic databases and in relevant journals. Reporting and methods were evaluated through an analysis of the risk of biases and quality score. Sub-analysis was performed in four subgroups: prevention of PM and PI, treatment of PM, and non-surgical and surgical treatment of PI. RESULTS: Thirty-two trials (29 RCT) were identified as accomplishing inclusion criteria after full-text reading. Seven focused on prevention, and among those dealing with therapy, six were related to PM and 19 related to PI therapy (10 non surgical and 9 surgical). Analysis found that quality of reporting and methods was generally low and surrogate outcomes were often chosen. CONCLUSIONS: Current literature on PM and PI prevention and treatment does not allow extracting applicable clinical information. Quality of methods and reporting guidelines should be encouraged. In particular, ad hoc guidelines should be designed for peri-implant diseases. PMID- 22533961 TI - Management of stiffness following total knee arthroplasty: a systematic review. AB - AIM: The aim of the study was to systematically evaluate the outcome of four main modalities of treatment for arthrofibrosis that develops subsequent to a total knee arthroplasty (TKA), namely manipulation under anesthesia (MUA), arthroscopic debridement, open surgical release and revision TKA. MATERIALS AND METHODS: A computerised search was conducted for relevant studies published from 1975 onwards in all the major databases and various search engines. A total of twenty five studies were selected, representing a total of 798 patients. Studies that passed the inclusion criteria were then subjected to quality assessment using the Newcastle-Ottawa Scale. On assessment, the 25 studies scored a total of 77 stars out of a possible 125. Two studies were prospective in design, while the remaining case series were retrospective in nature. The primary outcome measures assessed were increase in range of movement (ROM) and the Knee Society Score (KSS) at final follow-up. RESULTS: Our results showed that manipulation under anesthesia (MUA) had a mean increase in ROM of 38.4 degrees , arthroscopic release had a mean increase of 36.2 degrees , open surgical release had a mean increase of 43.4 degrees and revision TKA had a mean increase of 24.7 degrees . No significant differences were found in the KSS of the four treatment modalities. Our analysis suggests that open surgical release would be the most beneficial option for patients who are fit to undergo secondary surgery if their lifestyle requires a higher ROM for activities of daily living. However, there were methodological limitations as majority of the papers were case series, which decreased the quality of the evidence available. PMID- 22533962 TI - Long-term survivorship of a unicondylar knee replacement--a case report. AB - Unicondylar knee arthroplasty (UKA) was introduced in the 1970s as a treatment option for isolated knee compartment gonarthrosis. Early results were discouraging secondary to poor patient selection, suboptimal surgical technique, and inferior prosthetic design. In recent years, there has been resurgence in the use of the UKA. Improvements in implant design, surgical technique, and patient selection have led to multiple studies demonstrating 94-98% survivorship of the implants at a 10 year follow-up. However, there still remains a paucity of evidence with regard to this treatment option for young, active patients. This case report presents the longest recorded follow-up (31 years) of a UKA in a young, active patient and it highlights that with appropriate patient selection and meticulous surgical technique, UKA may have a role as a long term treatment option in patients with isolated unicompartmental disease. PMID- 22533963 TI - Type I interferons impair BDNF-induced cell signaling and neurotrophic activity in differentiated human SH-SY5Y neuroblastoma cells and mouse primary cortical neurons. AB - Type I interferons (IFNs) have been shown to act on neurons and to cause neuronal damage through mechanisms not completely defined. Here, we investigated the effects of type I IFNs on brain-derived neurotrophic factor (BDNF)-induced TrkB receptor signaling and neurotrophic activity. In retinoic acid-treated human SH SY5Y neuroblastoma cells and mouse primary cortical neurons, long-term exposure to IFNs curtailed BDNF-induced activation of phosphatidylinositol 3-kinase, phospholipase Cgamma and extracellular-regulated kinases 1 and 2 signaling. Moreover, IFN-beta inhibited BDNF-induced cell survival, neurite outgrowth, and expression of neuronal markers, such as neurofilament proteins, growth-associated protein-43 and glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor subunit GluR1. The IFN inhibitory effects were associated with down regulation of TrkB and inhibition of TrkB autophosphorylation. In SH-SY5Y cells, blockade of either Janus kinase with pyridone 6 or signal transducer and activator of transcription (STAT) 1 with siRNA transfection attenuated IFN-beta induced TrkB down-regulation. Quantitative real time RT-PCR indicated that IFN beta significantly reduced TrkB mRNA levels. Moreover, blockade of protein kinase R counteracted IFN-beta-induced inhibition of TrkB expression and signaling. These data indicate that in neuronal cells IFNs negatively regulate BDNF signaling and neurotrophic activity through inhibition of TrkB activation and Janus kinase/Signal transducer and activator of transcription-dependent down regulation of TrkB. PMID- 22533964 TI - The direct anterior approach: initial experience of a minimally invasive technique for total hip arthroplasty. AB - BACKGROUND: Less invasive approaches for hip arthroplasty have been developed in order to decrease traumatisation of soft tissue and shorten hospital stay. However, the benefits with a new technique can be at the expense of a new panorama of problems. This manuscript describes, with emphasis on postoperative complications, our experience from the first 200 cases of unilateral hip replacement using the direct anterior minimally invasive (MIS) approach. METHODS: A straight incision in front of the greater trochanter was used and the tensor muscle was approached subfascially and retracted laterally. The joint was opened and the femoral head was removed. Usually excellent acetabular exposure was obtained. In order to get access to the proximal femur, the hip capsule was released posterolaterally so that the femur could be lifted using a special retractor behind the tip of the trochanter. After insertion of the prostheses, the wound was closed using running sutures in the fascia overlying the tensor, sub- and intracutaneously. RESULTS: There was a small influence of BMI on the duration of surgery, and obese patients tended to have the cup positioned at a higher degree of deviation. There were in total 17 complications of which 5 necessitated revision surgery; 3 peroperative femoral fractures and 2 dislocations. Another 4 dislocations were treated with closed reduction and did not recur. 3 cases of nerve injury were noted, all resolved within 12 months. Three cases of DVT were diagnosed as well as 2 cases of postoperative infection; none of these led to chronic disability. CONCLUSIONS: The technique is perhaps more technically demanding than the lateral approaches used today due to the somewhat limited surgical exposure. Morbidly obese or very muscular patients as well as patients with a short femoral neck or acetabular protrusion can represent particular problems. Our results indicate that there are certain risks when adopting this procedure but the complications noted are avoidable. PMID- 22533965 TI - Exploring the applications of invertebrate host-pathogen models for in vivo biofilm infections. AB - In the natural environment, microorganisms exist together in self-produced polymeric matrix biofilms. Often, several species, which can belong to both bacterial and fungal kingdoms, coexist and interact in ways which are not completely understood. Biofilm infections have become prevalent largely in medical settings because of the increasing use of indwelling medical devices such as catheters or prosthetics. These infections are resistant to common antimicrobial therapies because of the inherent nature of their structure. In terms of infectious biofilms, it is important to understand the microbe-microbe interactions and how the host immune system reacts in order to discover therapeutic targets. Currently, single infection immune response studies are thriving with the use of invertebrate models. This review highlights the advances in single microbial-host immune response as well as the promising aspects of polymicrobial biofilm study in five invertebrate models: Lemna minor (duckweed), Arabidopsis thaliana (thale cress), Dictyostelium discoideum (slime mold), Drosophila melanogaster (common fruit fly), and Caenorhabditis elegans (roundworm). PMID- 22533966 TI - Neuroprotection by inhibiting the c-Jun N-terminal kinase pathway after cerebral ischemia occurs independently of interleukin-6 and keratinocyte-derived chemokine (KC/CXCL1) secretion. AB - BACKGROUND: Cerebral ischemia is associated with the activation of glial cells, infiltration of leukocytes and an increase in inflammatory mediators in the ischemic brain and systemic circulation. How this inflammatory response influences lesion size and neurological outcome remains unclear. D-JNKI1, an inhibitor of the c-Jun N-terminal kinase pathway, is strongly neuroprotective in animal models of stroke. Intriguingly, the protection mediated by D-JNKI1 is high even with intravenous administration at very low doses with undetectable drug levels in the brain, pointing to a systemic mode of action, perhaps on inflammation. FINDINGS: We evaluated whether D-JNKI1, administered intravenously 3 h after the onset of middle cerebral artery occlusion (MCAO), modulates secretion of the inflammatory mediators interleukin-6 and keratinocyte-derived chemokine in the plasma and from the spleen and brain at several time points after MCAO. We found an early release of both mediators in the systemic circulation followed by an increase in the brain and went on to show a later systemic increase in vehicle-treated mice. Release of interleukin-6 and keratinocyte-derived chemokine from the spleen of mice with MCAO was not significantly different from sham mice. Interestingly, the secretion of these inflammatory mediators was not altered in the systemic circulation or brain after successful neuroprotection with D-JNKI1. CONCLUSIONS: We demonstrate that neuroprotection with D-JNKI1 after experimental cerebral ischemia is independent of systemic and brain release of interleukin-6 and keratinocyte-derived chemokine. Furthermore, our findings suggest that the early systemic release of interleukin-6 and keratinocyte-derived chemokine may not necessarily predict an unfavorable outcome in this model. PMID- 22533967 TI - The impact of pretransplant 25-hydroxy vitamin D deficiency on subsequent graft function: an observational study. AB - BACKGROUND: In addition to its canonical role in musculoskeletal health, several reports have demonstrated that serum vitamin D level may influence kidney function. However, the effect of pretransplant serum vitamin D level on subsequent graft function has not been explored. Therefore, this study was undertaken to examine the effect of serum vitamin D level at the time of kidney transplantation (KT) on subsequent graft function. METHODS: We analyzed 106 patients who underwent KT and for whom 25-hydroxy vitamin D (25-OHD) levels were measured during hospitalization prior to transplantation. We measured estimated glomerular filtration rates (eGFR) using the Modification of Diet in Renal Disease (MDRD) formula at baseline and at six-month intervals up to 36 months after KT. RESULTS: 38.7% of the patients were diagnosed with 25-OHD deficiency defined as less than 10 ng/mL. Recipient gender (female vs. male, odds ratio [OR] 3.30, 95% CI 1.33-8.21, P=0.010), serum albumin level (per 1 mg/dl increase, OR 0.35, 95% CI 0.13-0.98, P=0.047), and predominant renal replacement therapy modality before KT (P<0.001) were found to be independent pretransplant risk factors for 25-OHD deficiency by multivariate logistic regression analysis. Subsequent repeated measures analysis of covariance revealed that 25-OHD level had the only significant main effect on eGFR during the 36-month follow-up period [F (1, 88)=12.07, P=0.001]. CONCLUSIONS: Pretransplant 25-OHD deficiency was significantly associated with a lower post-transplant eGFR, suggesting that 25 OHD may play an important role in maintaining graft function after KT. PMID- 22533968 TI - Carotenoid profiling and biosynthetic gene expression in flesh and peel of wild type and hp-1 tomato fruit under UV-B depletion. AB - Although light is recognized as one of the main factors influencing fruit carotenogenesis, the specific role of UV-B radiation has been poorly investigated. The present work is addressed to assess the molecular events underlying carotenoid accumulation in presence or absence of ultraviolet-B (UV-B) light in tomato fruits of wild-type and high pigment-1 (hp-1), a mutant characterized by exaggerated photoresponsiveness and increased fruit pigmentation. Gene expression analyses indicated that in wild-type fruits UV-B radiation mainly negatively affects the carotenoid biosynthetic genes encoding enzymes downstream of lycopene both in flesh and peel, suggesting that the down regulation of genes CrtL-b and CrtL-e and the subsequent accumulation of lycopene during tomato ripening are determined at least in part by UV-B light. In contrast to wild-type, UV-B depletion did not greatly affect carotenoid accumulation in hp 1 and generally determined minor differences in gene expression between control and UV-B-depleted conditions. PMID- 22533969 TI - Nitric oxide inhibits androgen receptor-mediated collagen production in human gingival fibroblasts. AB - Lin S-J, Lu H-K, Lee H-W, Chen Y-C, Li C-L, Wang L-F. Nitric oxide inhibits androgen receptor-mediated collagen production in human gingival fibroblasts. J Periodont Res 2012; 47: 701-710. (c) 2012 John Wiley & Sons A/S Background and Objective: In our previous study, we found that flutamide [an androgen receptor (AR) antagonist] inhibited the up-regulation of collagen induced by interleukin (IL)-1beta and/or nifedipine in gingival fibroblasts. The present study attempted to verify the role of nitric oxide (NO) in the IL-1beta/nifedipine-AR pathway in gingival overgrowth. MATERIAL AND METHODS: Confluent gingival fibroblasts derived from healthy individuals (n = 4) and those with dihydropyridine-induced gingival overgrowth (DIGO) (n = 6) were stimulated for 48 h with IL-1beta (10 ng/mL), nifedipine (0.34 MUm) or IL-1beta + nifedipine. Gene and protein expression were analyzed with real-time RT-PCR and western blot analyses, respectively. Meanwhile, Sircol dye-binding and the Griess reagent were, respectively, used to detect the concentrations of total soluble collagen and nitrite in the medium. RESULTS: IL-1beta and nifedipine simultaneously up regulated the expression of the AR and type-I collagen alpha1 [Colalpha1(I)] genes and the total collagen concentration in DIGO cells (p < 0.05). IL-1beta strongly increased the expression of inducible nitric oxide synthase (iNOS) mRNA and the nitrite concentration in both healthy and DIGO cells (p < 0.05). However, co-administration of IL-1beta and nifedipine largely abrogated the expression of iNOS mRNA and the nitrite concentration with the same treatment. Spearman's correlation coefficients revealed a positive correlation between the AR and total collagen (p < 0.001), but they both showed a negative correlation with iNOS expression and the NO concentration (p < 0.001). The iNOS inhibitor, 1400W, enhanced IL-1beta-induced AR expression; furthermore, the NO donor, NONOate, diminished the expression of the AR to a similar extent in gingival fibroblasts derived from both healthy patients and DIGO patients (p < 0.05). CONCLUSION: IL 1beta-induced NO attenuated AR-mediated collagen production in human gingival fibroblasts. The iNOS/NO system down-regulated the axis of AR/Colalpha1(I) mRNA expression and the production of AR/total collagen proteins by DIGO cells. PMID- 22533970 TI - Wafer-scale fabrication of nanofluidic arrays and networks using nanoimprint lithography and lithographically patterned nanowire electrodeposition gold nanowire masters. AB - Wafer scale (cm(2)) arrays and networks of nanochannels were created in polydimethylsiloxane (PDMS) from a surface pattern of electrodeposited gold nanowires in a master-replica process and characterized with scanning electron microscopy (SEM), atomic force microscopy (AFM), and fluorescence imaging measurements. Patterns of gold nanowires with cross-sectional dimensions as small as 50 nm in height and 100 nm in width were prepared on silica substrates using the process of lithographically patterned nanowire electrodeposition (LPNE). These nanowire patterns were then employed as masters for the fabrication of inverse replica nanochannels in a special formulation of PDMS. SEM and AFM measurements verified a linear correlation between the widths and heights of the nanowires and nanochannels over a range of 50 to 500 nm. The PDMS replica was then oxygen plasma-bonded to a glass substrate in order to create a linear array of nanofluidic channels (up to 1 mm in length) filled with solutions of either fluorescent dye or 20 nm diameter fluorescent polymer nanoparticles. Nanochannel continuity and a 99% fill success rate was determined from the fluorescence imaging measurements, and the electrophoretic injection of both dye and nanoparticles in the nanochannel arrays was also demonstrated. Employing a double LPNE fabrication method, this master-replica process was also used to create a large two-dimensional network of crossed nanofluidic channels. PMID- 22533971 TI - Immunoglobulins against the surface of Plasmodium falciparum-infected erythrocytes increase one month after delivery. AB - BACKGROUND: The risk of Plasmodium falciparum malaria increases during pregnancy and at early postpartum. Immunological and physiological alterations associated with pregnancy that persist after delivery may contribute to the susceptibility to P. falciparum during early postpartum period. METHODS: To determine changes in antibody-mediated responses after pregnancy, levels of Immunoglobulin G (IgGs) specific for P. falciparum were compared in 200 pairs of plasmas collected from Mozambican women at delivery and during the first two months postpartum. IgGs against the surface of erythrocytes infected with a P. falciparum chondroitin sulphate A binding line (CS2) and a paediatric isolate (MOZ2) were measured by flow cytometry. RESULTS: IgG levels against CS2 and MOZ2 were higher at postpartum than at delivery (p = 0.033 and p = 0.045, respectively) in women without P. falciparum infection. The analysis stratified by parity and period after delivery showed that this increase was significant in multi-gravid women (p = 0.023 for CS2 and p = 0.054 for MOZ2) and during the second month after delivery (p = 0.018 for CS2 and p = 0.015 for MOZ2). CONCLUSIONS: These results support the view that early postpartum is a period of recovery from physiological or immunological changes associated with pregnancy. PMID- 22533972 TI - PI16 is expressed by a subset of human memory Treg with enhanced migration to CCL17 and CCL20. AB - The peptidase inhibitor PI16 was shown previously by microarray analysis to be over-expressed by CD4-positive/CD25-positive Treg compared with CD4-positive/CD25 negative Th cells. Using a monoclonal antibody to the human PI16 protein, we found that PI16-positive Treg have a memory (CD45RO-positive) phenotype and express higher levels of FOXP3 than PI16-negative Treg. PI16-positive Treg are functional in suppressor assays in vitro with potency similar to PI16-negative Treg. Further phenotyping of the PI16-positive Treg revealed that the chemokine receptors CCR4 and CCR6 are expressed by more of the PI16-positive/CD45RO positive Treg compared with PI16-negative/CD45RO-positive Treg or Th cells. PI16 positive Treg showed enhanced in vitro migration towards the inflammatory chemokines CCL17 and CCL20, suggesting they can migrate to sites of inflammation. We conclude that PI16 identifies a novel distinct subset of functional memory Treg which can migrate to sites of inflammation and regulate the pro-inflammatory response at those sites. PMID- 22533973 TI - Mentored AuD student research at Washington University School of Medicine in St. Louis. PMID- 22533974 TI - Optimization of programming parameters in children with the advanced bionics cochlear implant. AB - BACKGROUND: Cochlear implants provide access to soft intensity sounds and therefore improved audibility for children with severe-to-profound hearing loss. Speech processor programming parameters, such as threshold (or T-level), input dynamic range (IDR), and microphone sensitivity, contribute to the recipient's program and influence audibility. When soundfield thresholds obtained through the speech processor are elevated, programming parameters can be modified to improve soft sound detection. Adult recipients show improved detection for low-level sounds when T-levels are set at raised levels and show better speech understanding in quiet when wider IDRs are used. Little is known about the effects of parameter settings on detection and speech recognition in children using today's cochlear implant technology. PURPOSE: The overall study aim was to assess optimal T-level, IDR, and sensitivity settings in pediatric recipients of the Advanced Bionics cochlear implant. RESEARCH DESIGN: Two experiments were conducted. Experiment 1 examined the effects of two T-level settings on soundfield thresholds and detection of the Ling 6 sounds. One program set T levels at 10% of most comfortable levels (M-levels) and another at 10 current units (CUs) below the level judged as "soft." Experiment 2 examined the effects of IDR and sensitivity settings on speech recognition in quiet and noise. STUDY SAMPLE: Participants were 11 children 7-17 yr of age (mean 11.3) implanted with the Advanced Bionics High Resolution 90K or CII cochlear implant system who had speech recognition scores of 20% or greater on a monosyllabic word test. DATA COLLECTION AND ANALYSIS: Two T-level programs were compared for detection of the Ling sounds and frequency modulated (FM) tones. Differing IDR/sensitivity programs (50/0, 50/10, 70/0, 70/10) were compared using Ling and FM tone detection thresholds, CNC (consonant-vowel nucleus-consonant) words at 50 dB SPL, and Hearing in Noise Test for Children (HINT-C) sentences at 65 dB SPL in the presence of four-talker babble (+8 signal-to-noise ratio). Outcomes were analyzed using a paired t-test and a mixed-model repeated measures analysis of variance (ANOVA). RESULTS: T-levels set 10 CUs below "soft" resulted in significantly lower detection thresholds for all six Ling sounds and FM tones at 250, 1000, 3000, 4000, and 6000 Hz. When comparing programs differing by IDR and sensitivity, a 50 dB IDR with a 0 sensitivity setting showed significantly poorer thresholds for low frequency FM tones and voiced Ling sounds. Analysis of group mean scores for CNC words in quiet or HINT-C sentences in noise indicated no significant differences across IDR/sensitivity settings. Individual data, however, showed significant differences between IDR/sensitivity programs in noise; the optimal program differed across participants. CONCLUSIONS: In pediatric recipients of the Advanced Bionics cochlear implant device, manually setting T-levels with ascending loudness judgments should be considered when possible or when low-level sounds are inaudible. Study findings confirm the need to determine program settings on an individual basis as well as the importance of speech recognition verification measures in both quiet and noise. Clinical guidelines are suggested for selection of programming parameters in both young and older children. PMID- 22533976 TI - Inheritance patterns of noise vulnerability and "protectability" in (C57BL/6J * CBA/J) F1 hybrid mice. AB - BACKGROUND: Interindividual variation in cochlear vulnerability to noise and ototoxins must in part reflect allelic variation in genes that largely remain unknown. Work in our laboratory has shown that young adult CBA/J mice are more vulnerable to cochlear noise injury than are similar-aged mice of other well studied strains such as C57BL/6J (B6). Conversely, young CBA/J mice are dramatically protected against noise exposure by low-dose kanamycin (KM) treatment, while B6 mice are not. Genetic differences that distinguish these two strains may include genes that help establish the early "sensitive period" in mammals, as well as genes that shape innate protective responses to stress. These genes may have human homologs that exert similar influences and thereby partly govern individual risk of acquired hearing loss. PURPOSE: We hypothesize that young CBA/J and B6 mice carry different alleles at unknown loci that mediate their characteristic sensitivities to noise and responses to kanamycin. The first step in any experimental genetic analysis of two divergent populations is to examine F1 hybrids formed from these. Accordingly, we evaluated both noise vulnerability and the extent of protection from noise by low-dose KM in 6-wk-old F1 hybrids derived from a B6 * CBA/J cross. STUDY SAMPLE: The study included 52 CBA/J, 59 C57BL/6J (B6), and 45 (B6 * CBA/J) F1 hybrid mice, aged 6 wk at time of noise exposure. Both genders were included. INTERVENTION: For experiments aimed at noise vulnerability, B6 and F1 mice were exposed to loud broadband noise (4-45 kHz, 110 dB SPL) for varying durations, and the resulting noise-induced permanent threshold shifts (NIPTSs, measured 2 wk postnoise) were compared with previous data from CBA/J mice. For experiments aimed at KM-based "protectability," CBA/J, B6, and F1 mice received either kanamycin (300 mg/kg, sc) or saline twice daily for 10 days and then were noise exposed for 30 min, followed by measurement of NIPTS at 2 wk postnoise. DATA COLLECTION AND ANALYSIS: Data comprised auditory brainstem response (ABR) thresholds examined by two-way ANOVA (threshold * frequency, group) and derived metrics for NIPTS, plotted versus noise duration. RESULTS: The "threshold" noise exposure duration for NIPTS in F1 hybrid mice was similar to that in CBA/J. Like CBA/J mice, F1 mice were also significantly protected from noise by KM although the protection appeared less robust than in the CBA/J parent strain. B6 mice appeared harmed by KM alone, even without noise exposure. None of the experimental groups provided any evidence for synergistic interactions between noise and KM. CONCLUSIONS: Our data support the hypothesis that young CBA/J and B6 mice carry different alleles that underlie their divergent responses to KM and sensitivities to noise exposure. While the number and type of genes remain unknown, they are worth pursuing because they establish completely novel hearing phenotypes with potential relevance to humans. Our results lay the foundation for mapping of the underlying genes, and ultimately gene identification. PMID- 22533975 TI - Evaluation of TIMIT sentence list equivalency with adult cochlear implant recipients. AB - BACKGROUND: Current measures used to determine sentence recognition abilities in cochlear implant recipients often include tests with one talker and one rate of speech. Performance with these measures may not accurately represent the speech recognition abilities of the listeners. Evaluation of cochlear implant performance should include measures that reflect realistic listening conditions. For example, the use of multiple talkers who vary in gender, rate of speech, and regional dialects represent varied communication interactions that people encounter daily. The TIMIT sentences, which use multiple talkers and incorporate these variations, provide additional test material for evaluating speech recognition. Dorman and colleagues created 34 lists of TIMIT sentences that were normalized for equal intelligibility using simulations of cochlear implant processing with normal-hearing listeners. Adults with sensorineural hearing loss who listen with cochlear implants represent a different population. Further study is needed to determine if these lists are equivalent for adult cochlear implant recipients and, if not, to identify a subset of lists that may be used with this population. PURPOSE: To evaluate the speech recognition equivalence of 34 TIMIT sentence lists with adult cochlear implant recipients. RESEARCH DESIGN: A prospective study comparing test-retest results within the same group of listeners. STUDY SAMPLE: Twenty-two adult cochlear implant recipients who met the inclusion criteria of at least 3 mo device use and a monosyllabic word score of 30% or greater participated in the study. DATA COLLECTION AND ANALYSIS: Participants were administered 34 TIMIT sentence lists (20 sentences per list) at each of two test sessions several months apart. List order was randomized and results scored as percent of words correct. Test-retest correlations and 95% confidence intervals for the means were used to identify equivalent lists with high test-retest reliability. RESULTS: Mean list scores across participants ranged from 66 to 81% with an overall mean of 73%. Twenty-nine lists had high test-retest reliability. Using the overall mean as a benchmark, the 95% confidence intervals indicated that 25 of the remaining 29 lists were equivalent (e.g., the benchmark of 73% fell within the 95% confidence interval for both test and retest). CONCLUSIONS: Twenty-five of the TIMIT lists evaluated are equivalent when used with adult cochlear implant recipients who have open-set word recognition abilities. These lists may prove valuable for monitoring progress, comparing listening conditions or treatments, and developing aural rehabilitation plans for cochlear implant recipients. PMID- 22533977 TI - A longitudinal study of speech perception skills and device characteristics of adolescent cochlear implant users. AB - BACKGROUND: For pediatric cochlear implant (CI) users, CI processor technology, map characteristics, and fitting strategies are known to have a substantial impact on speech perception scores at young ages. It is unknown whether these benefits continue over time as these children reach adolescence. PURPOSE: To document changes in CI technology, map characteristics, and speech perception scores in children between elementary grades and high school, and to describe relations between map characteristics and speech perception scores over time. RESEARCH DESIGN: A longitudinal design with participants 8-9-yr-old at session 1 and 15-18-yr-old at session 2. STUDY SAMPLE: Participants were 82 adolescents with unilateral CIs, who are a subset of a larger longitudinal study. Mean age at implantation was 3.4 yr (range: 1.7-5.4), and mean duration of device use was 5.5 yr (range: 3.8-7.5) at session 1 and 13.3 yr (range: 10.9-15) at session 2. DATA COLLECTION AND ANALYSIS: Speech perception tests at sessions 1 and 2 were the Lexical Neighborhood Test (LNT) presented at 70 dB SPL (LNT-70) and Bamford-Kowal Bench sentences in quiet (BKB-Q) presented at 70 dB SPL. At session 2, the LNT was also administered at 50 dB SPL (LNT-50), and BKB sentences were administered in noise with a +10 dB SNR (BKB-N). CI processor technology type and CI map characteristics (coding strategy, number of electrodes, threshold levels, and comfort levels) were obtained at both sessions. Electrical dynamic range was computed, and descriptive statistics, correlations, and repeated-measures ANOVAs were employed. RESULTS: Participants achieved significantly higher LNT and BKB scores, at 70 dB SPL, at ages 15-18 than at ages 8-9 yr. Forty-two participants had 1-3 electrodes either activated or deactivated in their map between test sessions, and 40 had no change in number of active electrodes (mean change: -0.5; range: -3 to +2). After conversion from arbitrary clinical map units to charge per-phase in nanocoulombs (nC), no significant difference was found for T levels across time. Average comfort levels (C levels) decreased by 19 nC. Seventy-three participants (89%) upgraded their CI processor technology type. At both sessions, significant correlations were found between electrical dynamic range (EDR) and all speech perception measures except LNT-50 (r range: .31 to .47; p < 0.01). Similarly, significant correlations were also found between C levels and all speech perception measures (r range: .29 to .49; p < 0.01). At session 2, a significant correlation was found between processor technology type and the LNT 50 scores (r = .38; p < 0.01). CONCLUSIONS: Significant improvement in speech scores was observed between elementary grades and high school for children who had used a CI since preschool. On average, T levels (nC) and electrode function remained stable for these long-term pediatric users. Analyses of maps did not allow for the determination of the exact cause of C level reductions, though power limitations in new processor systems and changes in perceived loudness over time are possible. Larger EDRs and higher C levels were associated with better speech scores. Newer speech processor technology was associated with better speech scores at a softer level. PMID- 22533979 TI - Difference between the default telecoil (t-coil) and programmed microphone frequency response in behind-the-ear (BTE) hearing aids. AB - BACKGROUND: A telecoil (t-coil) is essential for hearing aid users when listening on the telephone because using the hearing aid microphone when communicating on the telephone can cause feedback due to telephone handset proximity to the hearing aid microphone. Clinicians may overlook the role of the t-coil due to a primary concern of matching the microphone frequency response to a valid prescriptive target. Little has been published to support the idea that the t coil frequency response should match the microphone frequency response to provide "seamless" and perhaps optimal performance on the telephone. If the clinical goal were to match both frequency responses, it would be useful to know the relative differences, if any, that currently exist between these two transducers. PURPOSE: The primary purpose of this study was to determine if statistically significant differences were present between the mean output (in dB SPL) of the programmed microphone program and the hearing aid manufacturer's default t-coil program as a function of discrete test frequencies. In addition, pilot data are presented on the feasibility of measuring the microphone and t-coil frequency response with real-ear measures using a digital speech-weighted noise. RESEARCH DESIGN: A repeated-measures design was utilized for a 2-cc coupler measurement condition. Independent variables were the transducer (microphone, t-coil) and 11 discrete test frequencies (15 discrete frequencies in the real-ear pilot condition). STUDY SAMPLE: The study sample was comprised of behind-the-ear (BTE) hearing aids from one manufacturer. Fifty-two hearing aids were measured in a coupler condition, 39 of which were measured in the real-ear pilot condition. Hearing aids were previously programmed and verified using real-ear measures to the NAL-NL1 (National Acoustic Laboratories-Non-linear 1) prescriptive target by a licensed audiologist. DATA COLLECTION AND ANALYSIS: Hearing aid output was measured with a Fonix 7000 hearing aid analyzer (Frye Electronics, Inc.) in a HA-2 2-cc coupler condition using a pure-tone sweep at an input level of 60 dB SPL with the hearing aid in the microphone program and 31.6 mA/M in the t-coil program. A digital speech weighted noise input signal presented at additional input levels was used in the real-ear pilot condition. A mixed-model repeated-measures analysis of variance (ANOVA) and the Tukey Honestly Significant Difference (HSD) post hoc test were utilized to determine if significant differences were present in performance across treatment levels. RESULTS: There was no significant difference between mean overall t-coil and microphone output averaged across 11 discrete frequencies (F(1,102) = 0, p < 0.98). A mixed-model repeated-measures ANOVA revealed a significant transducer by frequency interaction (F(10,102) = 13.0, p < 0.0001). Significant differences were present at 200 and 400 Hz where the mean t coil output was less than the mean microphone output, and at 4000, 5000, and 6300 Hz where the mean t-coil output was greater than the mean microphone output. CONCLUSIONS: The mean t-coil output was significantly lower than the mean microphone output at 400 Hz, a frequency that lies within the typical telephone bandwidth of 300-3300 Hz. This difference may partially help to explain why some patients often complain the t-coil fails to provide sufficient loudness for telephone communication. PMID- 22533978 TI - Music perception and appraisal: cochlear implant users and simulated cochlear implant listening. AB - BACKGROUND: The inability to hear music well may contribute to decreased quality of life for cochlear implant (CI) users. Researchers have reported recently on the generally poor ability of CI users to perceive music, and a few researchers have reported on the enjoyment of music by CI users. However, the relation between music perception skills and music enjoyment is much less explored. Only one study has attempted to predict CI users' enjoyment and perception of music from the users' demographic variables and other perceptual skills (Gfeller et al, 2008). Gfeller's results yielded different predictive relationships for music perception and music enjoyment, and the relationships were weak, at best. PURPOSE: The first goal of this study is to clarify the nature and relationship between music perception skills and musical enjoyment for CI users, by employing a battery of music tests. The second goal is to determine whether normal hearing (NH) subjects, listening with a CI simulation, can be used as a model to represent actual CI users for either music enjoyment ratings or music perception tasks. RESEARCH DESIGN: A prospective, cross-sectional observational study. Original music stimuli (unprocessed) were presented to CI users, and music stimuli processed with CI-simulation software were presented to 20 NH listeners (CIsim). As a control, original music stimuli were also presented to five other NH listeners. All listeners appraised 24 musical excerpts, performed music perception tests, and filled out a musical background questionnaire. Music perception tests were the Appreciation of Music in Cochlear Implantees (AMICI), Montreal Battery for Evaluation of Amusia (MBEA), Melodic Contour Identification (MCI), and University of Washington Clinical Assessment of Music Perception (UW CAMP). STUDY SAMPLE: Twenty-five NH adults (22-56 yr old), recruited from the local and research communities, participated in the study. Ten adult CI users (46 80 yr old), recruited from the patient population of the local adult cochlear implant program, also participated in this study. DATA COLLECTION AND ANALYSIS: Musical excerpts were appraised using a seven-point rating scale, and music perception tests were scored as designed. Analysis of variance was performed on appraisal ratings, perception scores, and questionnaire data with listener group as a factor. Correlations were computed between musical appraisal ratings and perceptual scores on each music test. RESULTS: Music is rated as more enjoyable by CI users than by the NH listeners hearing music through a simulation (CIsim), and the difference is statistically significant. For roughly half of the music perception tests, there are no statistically significant differences between the performance of the CI users and of the CIsim listeners. Generally, correlations between appraisal ratings and music perception scores are weak or nonexistent. CONCLUSIONS: NH adults listening to music that has been processed through a CI simulation program are a reasonable model for actual CI users for many music perception skills, but not for rating musical enjoyment. For CI users, the apparent independence of music perception skills and music enjoyment (as assessed by appraisals) indicates that music enjoyment should not be assumed and should be examined explicitly. PMID- 22533980 TI - Virulence factors in Proteus bacteria from biofilm communities of catheter associated urinary tract infections. AB - More than 40% of nosocomial infections are those of the urinary tract, most of these occurring in catheterized patients. Bacterial colonization of the urinary tract and catheters results not only in infection, but also various complications, such as blockage of catheters with crystalline deposits of bacterial origin, generation of gravels and pyelonephritis. The diversity of the biofilm microbial community increases with duration of catheter emplacement. One of the most important pathogens in this regard is Proteus mirabilis. The aims of this study were to identify and assess particular virulence factors present in catheter-associated urinary tract infection (CAUTI) isolates, their correlation and linkages: three types of motility (swarming, swimming and twitching), the ability to swarm over urinary catheters, biofilm production in two types of media, urease production and adherence of bacterial cells to various types of urinary tract catheters. We examined 102 CAUTI isolates and 50 isolates taken from stool samples of healthy people. Among the microorganisms isolated from urinary catheters, significant differences were found in biofilm-forming ability and the swarming motility. In comparison with the control group, the microorganisms isolated from urinary catheters showed a wider spectrum of virulence factors. The virulence factors (twitching motility, swimming motility, swarming over various types of catheters and biofilm formation) were also more intensively expressed. PMID- 22533981 TI - Serum and urine bone resorption markers and pharmacokinetics of the cathepsin K inhibitor ONO-5334 after ascending single doses in post menopausal women. AB - AIMS: To investigate the safety, pharmacokinetics and pharmacodynamics of the new cathepsin K inhibitor, ONO-5334. METHODS: A double-blind, placebo-controlled, randomized study was carried out in 52 healthy post menopausal females. Single ascending doses of ONO-5334 (3-600 mg) were evaluated in six cohorts. The effect of food was studied at ONO-5334 100 mg. RESULTS: Across the doses tested, mean ONO-5334 C(max) occurred 0.5-1.0 h after dosing and the the t(1/2) ranged from 9.1 to 22 h. Linear increases in C(max) and AUC(0,infinity) were observed in the 3-300 mg and 3-600 mg dose range, respectively. After food, the geometric mean ratio (95% CI) C(max) and AUC(0,infinity) for ONO-5334 were 0.78 (0.31, 1.94) and 0.95 (0.67, 1.35)-fold greater than fasted, respectively. ONO-5334 significantly reduced serum bone resorption markers within 4 h vs. placebo. Statistical significance was achieved for ONO-5334 doses >=30 mg for C-terminal telopeptide of type 1 collagen (CTX) and >=300 mg for N-terminal telopeptide of type 1 collagen (NTX). Statistical significance was still evident at 24 h for ONO-5334 100 mg with serum CTX and 600 mg with serum NTX. The maximum suppression in serum CTX occurred at 4 h post dose with difference compared with placebo of -32%, 59%, -60% and -66% for 30, 100, 300 and 600 mg ONO-5334, respectively. Second morning urine void 24 h post dose showed statistically significant suppression of urinary CTX and NTX at 100 mg and above vs. placebo. ONO-5334 600 mg showed statistically significant suppression up to 72 h for serum CTX, urinary CTX and urinary NTX and 48 h for serum NTX vs. placebo. Adverse events were transient with no evidence of dose relationship. CONCLUSIONS: ONO-5334 displayed linear plasma pharmacokinetics over the (predicted therapeutic) dose range, 3-300 mg, with clear suppression of urinary bone resorption markers at doses >=100 mg for serum markers at 24 h. ONO-5334 was well tolerated up to 600 mg day(-1) when administered to healthy post menopausal women. PMID- 22533982 TI - Distribution of resveratrol metabolites in liver, adipose tissue, and skeletal muscle in rats fed different doses of this polyphenol. AB - This study aimed to characterize resveratrol metabolite profiles in liver, skeletal muscle, and adipose tissue in rats treated for 6 weeks with 6, 30, or 60 mg of trans-resveratrol/kg body weight/d. Resveratrol metabolites were quantified by liquid chromatography-tandem mass spectrometry. The greatest number of metabolites was found in liver followed by adipose tissue. A great number of metabolites in muscle was below the limit of detection. The amounts of sulfate conjugates tended to increase when resveratrol dosage was enhanced, while the glucuronide ones increased only between 6 and 30 mg/kg/d. Microbiota metabolites were detected in higher amounts than resveratrol conjugates in liver, while the opposite occurred in adipose tissue and muscle. So, the largest amounts of resveratrol metabolites were found in liver, intermediate amounts in adipose tissue, and the lowest amounts in muscle. Sulfate conjugates, but not glucuronides, showed a dose-response pattern. Microbiota metabolites were predominant in liver. PMID- 22533984 TI - Pure flat epithelial atypia is uncommon in subsequent breast excisions for atypical epithelial proliferation. AB - The management of atypical intraductal lesions of the breast remains controversial. In the present study, the subsequent surgical excision results and follow-up data on 86 (3.65%) atypical intraductal lesions and 78 (3.31%) low grade ductal carcinoma in situ (DCIS) from a cohort of 2358 needle biopsies were examined. There were 17 cases (0.72%) of pure flat epithelial atypia (FEA), 44 (1.87%) pure atypical ductal hyperplasia (ADH), three (0.13%) pure atypical lobular hyperplasia (ALH), 18 (0.76%) combined ADH + FEA, three (0.13%) combined ALH + FEA and one (0.04%) combined ALH + FEA + ADH. Subsequent surgical excisions were done in 53 cases and revealed the following incidences of malignancy: pure FEA (1/8); pure ADH (17/31); FEA + ADH (7/10); FEA + ALH (2/3); and FEA + ALH + ADH (0/1), with pure FEA showing significantly lower incidence of malignancy. In this cohort, there were 703 carcinomas including 155 DCIS with 78 cases (50.3%) being low-grade. FEA with ADH (and/or ALH) was present in 22 (28.2%) of these 78 cases of low-grade DCISs at surgical excisions. Pure FEA was not detected in any of the subsequently excised surgical materials of the atypical intraductal lesions nor the low-grade DCISs. Thus, pure FEA was very unusual in surgical specimens. When pure FEA is detected at needle biopsy, a wait and see approach can be adopted. However, when the FEA is associated with other concomitant atypical intraductal lesions, especially ADH, further excision should be contemplated. PMID- 22533983 TI - In vitro growth inhibition of human cancer cells by novel honokiol analogs. AB - Honokiol possesses many pharmacological activities including anti-cancer properties. Here in, we designed and synthesized honokiol analogs that block major honokiol metabolic pathway which may enhance their effectiveness. We studied their cytotoxicity in human cancer cells and evaluated possible mechanism of cell cycle arrest. Two analogs, namely 2 and 4, showed much higher growth inhibitory activity in A549 human lung cancer cells and significant increase of cell population in the G0-G1 phase. Further elucidation of the inhibition mechanism on cell cycle showed that analogs 2 and 4 inhibit both CDK1 and cyclin B1 protien levels in A549 cells. PMID- 22533985 TI - Hemodynamic effects of peri-operative statin therapy in on-pump cardiac surgery patients. AB - BACKGROUND: Peri-operative statin therapy in cardiac surgery cases is reported to reduce the rate of mortality, stroke, postoperative atrial fibrillation, and systemic inflammation. Systemic inflammation could affect the hemodynamic parameters and stability. We set out to study the effect of statin therapy on perioperative hemodynamic parameters and its clinical outcome. METHODS: In a single center study from 2006 to 2007, peri-operative hemodynamic parameters of 478 patients, who underwent cardiac surgery with cardiopulmonary bypass, were measured. Patients were divided into those who received perioperative statin therapy (n = 276; statin group) and those who did not receive statin therapy (n = 202; no-statin group). The two groups were compared together using Kolmogorov Smirnov-Test, Fisher's-Exact-Test, and Student's-T-test. A p value < 0.05 was considered as significant. RESULTS: There was no significant difference in the preoperative risk factors. Onset of postoperative atrial fibrillation was not affected by statin therapy. Extended hemodynamic measurements revealed no significant difference between the two groups, apart from Systemic Vascular Resistance Index (SVRI). The no-statin group had a significantly higher SVRI (882 +/- 206 vs. 1050 +/- 501 dyn s/cm5/m2, p = 0.022). Inotropic support was the same in both groups and no significant difference in the mortality rate was noticed. Also, hemodynamic parameters were not affected by different types and doses of statins. CONCLUSIONS: Perioperative statin therapy for patients undergoing on pump coronary bypass grafting or valvular surgery, does not affect the hemodynamic parameters and its clinical outcome. PMID- 22533987 TI - Anatomical departments in Bavaria and the corpses of executed victims of National Socialism. AB - While it is known that the bodies of executed victims of National Socialism (NS) were used for anatomical research and teaching, detailed studies are still missing for many anatomical departments. This analysis focuses on the institutes in Bavaria. From 1933 on the institutes of Munich, Wurzburg and Erlangen were actively involved in and competed over the procurement of bodies of NS victims, particularly between 1937 and 1941. While the body supply was sufficient thereafter it became again critical in the first years after the war. During that period, anatomists complained about a lack of bodies for dissection courses and tended to use the corpses remaining from the NS-period for teaching purposes. Their position was supported by the popular view that resistance fighters were seen as traitors to the Fatherland and not as honorable political victims. At the same time, relatives and aid organizations were in search of the dead victims of German terror. These conflicting interests created a situation full of tension, in which Philipp Auerbach, state commissioner for religious, political and racial victims of the Nazis in Bavaria, played a crucial role. PMID- 22533988 TI - Reversible surface electronic traps in PbS quantum dot solids induced by an order disorder phase transition in capping molecules. AB - The electronic properties of semiconductor quantum dots (QDs) are critically dependent on the nature of the ligand molecules on their surfaces. Here we show the reversible formation of surface electronic trap states in the model system of solid thin films of PbS QDs capped with thiol molecules. As the temperature was increased from cryogenic to room temperature, we discovered a phase transition in the fluorescence spectra from excitonic emission to trap emission. The critical temperature (T(c)) of the phase transition scales with molecular length and in each case is close to the bulk melting temperature of the capping molecules. We conclude that an order-disorder transition in the molecular monolayer above T(c) introduces surface mobility and the formation of a disordered atomic lead layer at the QD/capping molecule interface, leading to electronic trap formation. PMID- 22533986 TI - Discovery and optimization of a series of 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2 yl)pyridin-2-amines: orally bioavailable, selective, and potent ATP-independent Akt inhibitors. AB - This paper describes the implementation of a biochemical and biophysical screening strategy to identify and optimize small molecule Akt1 inhibitors that act through a mechanism distinct from that observed for kinase domain ATP competitive inhibitors. With the aid of an unphosphorylated Akt1 cocrystal structure of 12j solved at 2.25 A, it was possible to confirm that as a consequence of binding these novel inhibitors, the ATP binding cleft contained a number of hydrophobic residues that occlude ATP binding as expected. These Akt inhibitors potently inhibit intracellular Akt activation and its downstream target (PRAS40) in vitro. In vivo pharmacodynamic and pharmacokinetic studies with two examples, 12e and 12j, showed the series to be similarly effective at inhibiting the activation of Akt and an additional downstream effector (p70S6) following oral dosing in mice. PMID- 22533990 TI - Sequencing of a porcine enterovirus strain prevalent in swine groups in China and recombination analysis. PMID- 22533989 TI - Role of C-C chemokine receptor type 7 and its ligands during neuroinflammation. AB - For decades, chemokines and their receptors have received a great deal of attention for their multiple roles in controlling leukocyte functions during inflammation and immunity. The ability of chemokines to convey remarkably versatile but context-specific signals identifies them as powerful modulators of immune responses generated in response to diverse pathogenic or non-infectious insults. A number of recent studies have speculated that the C-C chemokine receptor type 7 (CCR7), plays important roles in immune-cell trafficking in various tissue compartments during inflammation and in immune surveillance. Using computational modeling and microfluidics-based approaches, recent studies have explored leukocyte migration behavior in response to CCR7 ligands in a complex chemokine environment existing with other coexisting chemokine fields. In this review, we summarize the current understanding of the effects of soluble versus immobilized ligands and of the downstream signaling pathways of CCR7 that control leukocyte motility, directionality, and speed. This review also integrates the current knowledge about the role of CCR7 in coordinating immune responses between secondary lymphoid organs and peripheral tissue microenvironments during primary or secondary antigen encounters. CCR7 seems to influence distinct immunological events during inflammatory responses in the central nervous system (CNS) including immune-cell entry and migration, and neuroglial interactions. The clinical and pathological outcome may vary depending on its contribution in the inflamed CNS microenvironment. Understanding these mechanisms has direct implications for therapeutic developments favoring more protective and efficient immune responses. PMID- 22533992 TI - Mohs frozen tissue sections in comparison to similar paraffin-embedded tissue sections in identifying perineural tumor invasion in cutaneous squamous cell carcinoma. AB - BACKGROUND: Perineural invasion (PNInv) in cutaneous squamous cell carcinoma (cSCC) increases the risk of recurrence, possibly because of suboptimal identification on frozen or paraffin-embedded tissue sections. Perineural inflammation (PNInf) may portend PNInv. OBJECTIVE: We sought to correlate identification of PNInv and PNInf in hematoxylin-eosin-stained Mohs frozen sections with PNInv and PNInf identified in similarly oriented paraffin-embedded sections obtained in cases of cSCC. METHODS: We reviewed same patient Mohs frozen and paraffin-embedded tissue sections for all patients presenting within a 2-year period to our Mohs micrographic surgical unit for removal of cSCC with PNInv or PNInf identified on either type of tissue section. RESULTS: Of 537 patients undergoing surgical resection of cSCC, 21 (3.9%) had either PNInv (n = 11) or PNInf (n = 10) on frozen sections. PNInv on Mohs frozen sections was identified in 11 cases and confirmed on paraffin-embedded sections in 9 cases (82%). Paraffin-embedded sections failed to identify PNInv present in Mohs frozen sections in two (2/11), or 18% of cases. PNInf on Mohs frozen sections was confirmed on paraffin-embedded sections in 3 cases (30%), but PNInv was identified in 5 cases (50%). LIMITATIONS: Our results are a retrospective case review from a specific time period by one institution. Furthermore, it is impossible to compare identical tissue specimens using two sequential tissue processing techniques. CONCLUSION: PNInv can be accurately identified with Mohs frozen sections. PNInf on Mohs frozen sections suggests the presence of PNInv and requires further histologic investigation. PMID- 22533991 TI - Carnitine palmitoyltransferase 1A (CPT1A): a transcriptional target of PAX3-FKHR and mediates PAX3-FKHR-dependent motility in alveolar rhabdomyosarcoma cells. AB - BACKGROUND: Alveolar rhabdomyosarcoma (ARMS) has a high propensity to metastasize, leading to its aggressiveness and a poor survival rate among those with the disease. More than 80% of aggressive ARMSs harbor a PAX3-FKHR fusion transcription factor, which regulates cell migration and promotes metastasis, most likely by regulating the fusion protein's transcriptional targets. Therefore, identifying druggable transcription targets of PAX3-FKHR that are also downstream effectors of PAX3-FKHR-mediated cell migration and metastasis may lead to novel therapeutic approaches for treating ARMS. METHODS: To identify genes whose expression is directly affected by the level of PAX3-FKHR in an ARMS cellular-context, we first developed an ARMS cell line in which PAX3-FKHR is stably down-regulated, and showed that stably downregulating PAX3-FKHR in ARMS cells significantly decreased the cells' motility. We used microarray analysis to identify genes whose expression level decreased when PAX3-FKHR was downregulated. We used mutational analysis, promoter reporter assays, and electrophoretic mobility shift assays to determine whether PAX3-FKHR binds to the promoter region of the target gene. We used siRNA and pharmacologic inhibitor to downregulate the target gene of PAX3-FKHR and investigated the effect of such downregulation on cell motility. RESULTS: We found that when PAX3-FKHR was downregulated, the expression of carnitine palmitoyltransferase 1A (CPT1A) decreased. We showed that PAX3-FKHR binds to a paired-domain binding-site in the CPT1A promoter region, indicating that CPT1A is a novel transcriptional target of PAX3-FKHR. Furthermore, downregulating CPT1A decreased cell motility in ARMS cells, indicating that CPT1A is a downstream effector of PAX3-FKHR-mediated cell migration and metastasis. CONCLUSIONS: Taken together, we have identified CPT1A as a novel transcriptional target of PAX3-FKHR and revealed the novel function of CPT1A in promoting cell motility. CPT1A may represent a novel therapeutic target for the treatment of ARMS. PMID- 22533993 TI - Solitary mycosis fungoides: a distinct clinicopathologic entity with a good prognosis: a series of 15 cases and literature review. AB - BACKGROUND: Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma (CTCL), accounting for almost 50% of all primary cutaneous lymphomas. The occurrence of solitary lesions, which are clinically and histopathologically indistinguishable from classic MF has been described. OBJECTIVE: We describe 15 cases of solitary MF and discuss the relationship to classic MF, "reactive" processes and to other, rarer forms of CTCL that may present with solitary lesions. METHODS: We conducted a retrospective chart review and a PubMed search to identify all reported cases of solitary MF to date, as well as information about other CTCLs presenting as a solitary lesion. RESULTS: Fifteen patients were identified. Follow-up data were available on 10 patients with a median follow-up of 10 months (range, 1 to 48 months). Clinical, pathological, immunocytochemical, and molecular-genetic features were analyzed. Five cases were diagnosed as folliculotropic MF (FMF). Of the 10 cases with follow-up, 2 were treated with topical steroids, 2 were completely excised, 5 received radiotherapy, and 1 received tacrolimus. One hundred twenty-eight cases of solitary MF were identified in the literature and reviewed for commonalities to and differences with our cases and other CTCLs. LIMITATIONS: This study was retrospective; follow up data were not available in some cases and were only short term in others. CONCLUSIONS: Solitary MF appears to have a good prognosis. In lesions that are not completely excised, curative radiotherapy can be used. Long-term follow up is advised. PMID- 22533994 TI - Coexistence of lichen sclerosus and morphea: a retrospective analysis of 472 patients with localized scleroderma from a German tertiary referral center. AB - BACKGROUND: The coexistence of lichen sclerosus (LiS) and localized scleroderma (LoS) has sporadically been reported in the literature. Recently, a prospective multicenter study demonstrated a surprisingly high percentage of genital LiS in patients with morphea. OBJECTIVE: The aim of this study was to determine the prevalence of LiS in a cohort of patients with LoS who presented at a tertiary referral medical center for connective tissue diseases in Germany. METHODS: We retrospectively evaluated the prevalence of genital and extragenital LiS in adult and pediatric patients with different subtypes of LoS. Secondary outcome measures included demographic characteristics and prevalence of other concomitant autoimmune diseases. RESULTS: Of the 472 patients (381 adults, 91 children; mean age: 46 years; range, 4-88 years; female to male ratio: 3.5:1 in adults and 8:1 in children) with LoS, 27 (5.7%) also presented with LiS (19 extragenital and 8 genital lesions). LiS exclusively occurred in patients with plaque-type (morphea) and generalized LoS. Twenty-six of the 27 (96.2%) patients with concomitant LoS and LiS were adults. Compared with LiS in the general population, LiS was significantly more frequent in LoS as indicated by an odds ratio of 18.1 (95% confidence interval 2.6-134.2; P < .0001). In all, 38 (8.1%) patients with LoS had other autoimmune disorders (most frequently Hashimoto thyroiditis, rheumatoid arthritis, and alopecia areata). LIMITATIONS: This was a retrospective study. CONCLUSIONS: This large retrospective analysis confirms recent reports of a high prevalence of LiS in patients with LoS. Based on these findings, patients with LoS, especially those with morphea, should be carefully screened for concomitant LiS, including inspection of the anogenital region. PMID- 22533995 TI - Oil-in-water emulsification using confined impinging jets. AB - A confined impinging jet mixing device has been used to investigate the continuous sunflower oil/water emulsification process under turbulent flow conditions with oil contents between 5% (v/v) and 10% (v/v). Various emulsifiers (Tween20, Span80, Whey Protein, Lecithin and Sodium Dodecylsulphate) varying in molecular weights have been studied. Mean droplet sizes varied with the emulsifiers used and smallest droplets were obtained under fully turbulent flow regime, i.e. at the highest jet flow rate and highest jet Reynolds Number conditions. Sodium Dodecylsulfate (SDS) produced droplets in the range of 3.8 MUm while 6 MUm droplets were obtained with Whey Protein. Similar droplet sizes were obtained under fully turbulent flow conditions (610 mL/min; Reynolds Number=13,000) for oil content varying between 5% (v/v) and 10% (v/v). To investigate the smallest droplet size possible in the device, the emulsion was passed through the geometry multiple times. Multi-pass emulsification resulted in reduction in droplet size indicating that longer residence in the flow field under high shear condition allowed for breakage of droplets as well as the time for the emulsifier to stabilize the newly formed droplets, decreasing the impact of coalescence. This was confirmed by timescale analysis of the involved process steps for the droplet data obtained via experiments. Dependence of mean droplet size on the o/w interfacial tension and peak energy dissipation was also investigated. PMID- 22533996 TI - Solute distribution and stability in emulsion-based delivery systems: an EPR study. AB - Oil-in-water emulsions and related systems are often used to deliver hydrophobic solutes in foods, personal care products, and pharmaceuticals. Recent work has considered the use of crystalline lipid carrier particles (i.e., solid lipid nanoparticles, SLN) to control the availability of the solute; however, there is little direct evidence for the localization of small molecules in these systems. Alkanes (10 wt.% tetradecane or eicosane) containing the spin probe 4-phenyl 2,2,5,5-tetramethyl-3-imidazoline-1-oxyl (PTMIO, 200 ppm) were homogenized into sodium caseinate solution (1 wt.%) to produce fine or coarse droplets (0.2 MUm or 1.3 MUm, respectively) and cooled to 21.5 degrees C where eicosane is crystalline and tetradecane is liquid. Analysis of the resulting EPR spectra revealed populations of probe in two discrete environments (i.e., aqueous and lipid). PTMIO is largely hydrophobic with 77% and 70% present in the coarse and fine liquid lipid droplets (i.e., tetradecane droplets), respectively. In the solid droplets (i.e., eicosane), all of the probe was excluded from the droplets into the aqueous environment. In all cases, the mobility of the probe in both lipid and aqueous environments was affected by the droplet surface; thus, we hypothesize that the majority of the probe molecules are associated with the droplet interface. The PTMIO was reduced to an EPR-silent form by the addition of iron/ascorbate to the aqueous phase, and the apparent rate constant of the reaction was proportional to the fraction of the spin probe in the aqueous phase. Based on these findings, we propose that droplet crystallization excludes solute molecules from the droplet core to the aqueous environment where they interact with the droplet surface. PMID- 22533997 TI - Conductive properties of TiO2/bacterial cellulose hybrid fibres. AB - Conductive properties of TiO(2) nanoparticles and TiO(2)/BC hybrid inorganic/organic fibres were investigated by electrostatic force microscopy (EFM). TiO(2)/BC hybrid composites were prepared based on bacterial cellulose produced by Gluconobacterxylinum, being the bacterial cellulose as a hydrophilic substrate for TiO(2) nanoparticles synthesized via sol-gel. Taken into account hydrophilic nature of the cellulose, TiO(2) nanoparticles were located on the surface of the fibres due to hydrogen bonding interactions. EFM was used to determine qualitatively conductive properties of TiO(2) nanoparticles and their TiO(2)/BC hybrid inorganic/organic fibres. Results indicate that TiO(2)/BC hybrid fibres respond to applied bias regardless of the sign of the applied voltage. PMID- 22533998 TI - Adoption of laparoscopy for elective colorectal resection: a report from the Surgical Care and Outcomes Assessment Program. AB - BACKGROUND: The purpose of this study was to evaluate the adoption of laparoscopic colon surgery and assess its impact in the community at large. STUDY DESIGN: The Surgical Care and Outcomes Assessment Program (SCOAP) is a quality improvement benchmarking initiative in the Northwest using medical record-based data. We evaluated the use of laparoscopy and a composite of adverse events (ie, death or clinical reintervention) for patients undergoing elective colorectal surgery at 48 hospitals from the 4th quarter of 2005 through 4th quarter of 2010. RESULTS: Of the 9,705 patients undergoing elective colorectal operations (mean age 60.6 +/- 15.6 years; 55.2% women), 38.0% were performed laparoscopically (17.8% laparoscopic procedures converted to open). The use of laparoscopic procedures increased from 23.3% in 4th quarter of 2005 to 41.6% in 4th quarter of 2010 (trend during study period, p < 0.001). After adjustment (for age, sex, albumin levels, diabetes, body mass index, comorbidity index, cancer diagnosis, year, hospital bed size, and urban vs rural location), the risk of transfusions (odds ratio [OR] = 0.52; 95% CI, 0.39-0.7), wound infections (OR = 0.45; 95% CI, 0.34-0.61), and composite of adverse events (OR = 0.58; 95% CI, 0.43-0.79) were all significantly lower with laparoscopy. Within those hospitals that had been in SCOAP since 2006, hospitals where laparoscopy was most commonly used also had a substantial increase in the volume of all types of colon surgery (202 cases per hospital in 2010 from 112 cases per hospital in 2006, an 80.4% increase) and, in particular, the number of resections for noncancer diagnoses and right-sided pathology. CONCLUSIONS: The use of laparoscopic colorectal resection increased in the Northwest. Increased adoption of laparoscopic colectomies was associated with greater use of all types of colorectal surgery. PMID- 22533999 TI - Decision makers calibrate behavioral persistence on the basis of time-interval experience. AB - A central question in intertemporal decision making is why people reverse their own past choices. Someone who initially prefers a long-run outcome might fail to maintain that preference for long enough to see the outcome realized. Such behavior is usually understood as reflecting preference instability or self control failure. However, if a decision maker is unsure exactly how long an awaited outcome will be delayed, a reversal can constitute the rational, utility maximizing course of action. In the present behavioral experiments, we placed participants in timing environments where persistence toward delayed rewards was either productive or counterproductive. Our results show that human decision makers are responsive to statistical timing cues, modulating their level of persistence according to the distribution of delay durations they encounter. We conclude that temporal expectations act as a powerful and adaptive influence on people's tendency to sustain patient decisions. PMID- 22534000 TI - Measles: the burden of preventable deaths. PMID- 22534001 TI - Assessment of the 2010 global measles mortality reduction goal: results from a model of surveillance data. AB - BACKGROUND: In 2008 all WHO member states endorsed a target of 90% reduction in measles mortality by 2010 over 2000 levels. We developed a model to estimate progress made towards this goal. METHODS: We constructed a state-space model with population and immunisation coverage estimates and reported surveillance data to estimate annual national measles cases, distributed across age classes. We estimated deaths by applying age-specific and country-specific case-fatality ratios to estimated cases in each age-country class. FINDINGS: Estimated global measles mortality decreased 74% from 535,300 deaths (95% CI 347,200-976,400) in 2000 to 139,300 (71,200-447,800) in 2010. Measles mortality was reduced by more than three-quarters in all WHO regions except the WHO southeast Asia region. India accounted for 47% of estimated measles mortality in 2010, and the WHO African region accounted for 36%. INTERPRETATION: Despite rapid progress in measles control from 2000 to 2007, delayed implementation of accelerated disease control in India and continued outbreaks in Africa stalled momentum towards the 2010 global measles mortality reduction goal. Intensified control measures and renewed political and financial commitment are needed to achieve mortality reduction targets and lay the foundation for future global eradication of measles. FUNDING: US Centers for Disease Control and Prevention (PMS 5U66/IP000161). PMID- 22534002 TI - Silicosis. AB - Silicosis is a fibrotic lung disease caused by inhalation of free crystalline silicon dioxide or silica. Occupational exposure to respirable crystalline silica dust particles occurs in many industries. Phagocytosis of crystalline silica in the lung causes lysosomal damage, activating the NALP3 inflammasome and triggering the inflammatory cascade with subsequent fibrosis. Impairment of lung function increases with disease progression, even after the patient is no longer exposed. Diagnosis of silicosis needs carefully documented records of occupational exposure and radiological features, with exclusion of other competing diagnoses. Mycobacterial diseases, airway obstruction, and lung cancer are associated with silica dust exposure. As yet, no curative treatment exists, but comprehensive management strategies help to improve quality of life and slow deterioration. Further efforts are needed for recognition and control of silica hazards, especially in developing countries. PMID- 22534003 TI - Retention on buprenorphine treatment reduces emergency department utilization, but not hospitalization, among treatment-seeking patients with opioid dependence. AB - Drug users are marginalized from typical primary care, often resulting in emergency department (ED) usage and hospitalization due to late-stage disease. Though data suggest methadone decreases such fragmented healthcare utilization (HCU), the impact of buprenorphine maintenance treatment (BMT) on HCU is unknown. Chart review was conducted on opioid dependent patients seeking BMT, comparing individuals (n=59) who left BMT<=7days with those retained on BMT (n=150), for ED use and hospitalization. Using negative binomial regressions, including comparison of time before BMT induction, ED utilization and hospitalization were assessed. Overall, ED utilization was 0.93 events per person year and was significantly reduced by BMT, with increasing time (retention) on BMT. BMT had no significant effect on hospitalizations or average length of stay. PMID- 22534005 TI - Dermatitis associated with cetuximab and radiotherapy: the potential benefit with recombinant human epidermal growth factor and a concern regarding the use of steroids. PMID- 22534006 TI - Effects of multidisciplinary care on the survival of patients with oral cavity cancer in Taiwan. AB - OBJECTIVES: The incidence of oral cavity cancer is high in Taiwan. To improve patient survival, multidisciplinary team (MDT) care was implemented. This research compared the survival of MDT care participants/non-participants and examined the effect of MDT care on patient characteristics. MATERIALS AND METHODS: In this study, 19,513 patients with newly diagnosed oral cavity cancer were recruited from 2004 to 2007 in Taiwan. Matching based on the propensity of receiving MDT care was used. In total, 9297 patients were observed until 2008. A Cox proportional hazards model was applied to elucidate the relative risks of death. RESULTS: The relative risk of death was lower for patients with MDT care than for those without such care (HR=0.84; 95% CI=0.78-0.90). Males had a higher risk of death than females (HR=1.20; 95% CI=1.04-1.38). Older age, lower income, and more severe comorbidity were associated with a higher risk of death. The effect of MDT care was stronger for older patients than for younger patients. Patients treated in public hospitals had a 1.24-fold (95% CI=1.13-1.36) higher risk of death than patients treated in private hospitals. Patients treated in hospitals or by attending physicians with higher service volumes had a lower relative risk of death (HR=0.89 and 0.78, respectively). The effect of MDT care was strong among patients with less severe comorbidities and patients without catastrophic illnesses. CONCLUSION: The relative risk of death was lower for MDT care participants. The effect of MDT care was stronger among older patients and patients with fewer comorbidities. PMID- 22534004 TI - Complex organochlorine pesticide mixtures as determinant factor for breast cancer risk: a population-based case-control study in the Canary Islands (Spain). AB - BACKGROUND: All the relevant risk factors contributing to breast cancer etiology are not fully known. Exposure to organochlorine pesticides has been linked to an increased incidence of the disease, although not all data have been consistent. Most published studies evaluated the exposure to organochlorines individually, ignoring the potential effects exerted by the mixtures of chemicals. METHODS: This population-based study was designed to evaluate the profile of mixtures of organochlorines detected in 103 healthy women and 121 women diagnosed with breast cancer from Gran Canaria Island, and the relation between the exposure to these compounds and breast cancer risk. RESULTS: The most prevalent mixture of organochlorines among healthy women was the combination of lindane and endrin, and this mixture was not detected in any affected women. Breast cancer patients presented more frequently a combination of aldrin, dichlorodiphenyldichloroethylene (DDE) and dichlorodiphenyldichloroethane (DDD), and this mixture was not found in any healthy woman. After adjusting for covariables, the risk of breast cancer was moderately associated with DDD (OR = 1.008, confidence interval 95% 1.001-1.015, p = 0.024). CONCLUSIONS: This study indicates that healthy women show a very different profile of organochlorine pesticide mixtures than breast cancer patients, suggesting that organochlorine pesticide mixtures could play a relevant role in breast cancer risk. PMID- 22534007 TI - Activation of COL1A2 promoter in human fibroblasts by Escherichia coli. AB - The relationship between bacterial infection and collagen production was investigated using human fibroblasts transfected with the promoter of COL1A2 , which encodes the alpha1 chain of human type I collagen, linked to a luciferase reporter. The cells were used to assess the gene promoter activity of COL1A2 following bacterial stimulation. The COL1A2 promoter was activated by stimulation with fixed Escherichia coli in a dose-dependent manner, but not by fixed Staphylococcus aureus. Enhancement of collagen production was observed in the E. coli-stimulated fibroblasts compared to those without stimulation. Both anti human Toll-like receptor (TLR) 4 antibody and polymyxin B clearly blocked the COL1A2 promoter activity stimulated by E. coli, while antibodies against human TLR2 and human transforming growth factor-beta (TGF-beta) receptor type II did not. These results indicate that E. coli can directly interact with TLR4 expressed on the surface of fibroblasts and can further induce human type I collagen gene expression and collagen production in these cells. These data also suggest that infection by gram-negative bacteria may cause fibrosis. PMID- 22534008 TI - Population genetic analysis of Enterocytozoon bieneusi in humans. AB - Genotyping based on sequence analysis of the ribosomal internal transcribed spacer has revealed significant genetic diversity in Enterocytozoonbieneusi. Thus far, the population genetics of E. bieneusi and its significance in the epidemiology of microsporidiosis have not been examined. In this study, a multilocus sequence typing of E. bieneusi in AIDS patients in Lima, Peru was conducted, using 72 specimens previously genotyped as A, D, IV, EbpC, WL11, Peru7, Peru8, Peru10 and Peru11 at the internal transcribed spacer locus. Altogether, 39 multilocus genotypes were identified among the 72 specimens. The observation of strong intragenic linkage disequilibria and limited genetic recombination among markers were indicative of an overall clonal population structure of E. bieneusi. Measures of pair-wise intergenic linkage disequilibria and a standardised index of association (IAS) based on allelic profile data further supported this conclusion. Both sequence-based and allelic profile-based phylogenetic analyses showed the presence of two genetically isolated groups in the study population, one (group 1) containing isolates of the anthroponotic internal transcribed spacer genotype A, and the other (group 2) containing isolates of multiple internal transcribed spacer genotypes (mainly genotypes D and IV) with zoonotic potential. The measurement of linkage disequilibria and recombination indicated group 2 had a clonal population structure, whereas group 1 had an epidemic population structure. The formation of the two sub-populations was confirmed by STRUCTURE and Wright's fixation index (FST) analyses. The data highlight the power of MLST in understanding the epidemiology of E. bieneusi. PMID- 22534009 TI - Disease progression model in subjects with mild cognitive impairment from the Alzheimer's disease neuroimaging initiative: CSF biomarkers predict population subtypes. AB - AIM: The objective is to develop a semi-mechanistic disease progression model for mild cognitive impairment (MCI) subjects. The model aims to describe the longitudinal progression of ADAS-cog scores from the Alzheimer's disease neuroimaging initiative trial that had data from 198 MCI subjects with cerebrospinal fluid (CSF) information who were followed for 3 years. METHOD: Various covariates were tested on disease progression parameters and these variables fell into six categories: imaging volumetrics, biochemical, genetic, demographic, cognitive tests and CSF biomarkers. RESULTS: CSF biomarkers were associated with both baseline disease score and disease progression rate in subjects with MCI. Baseline disease score was also correlated with atrophy measured using hippocampal volume. Progression rate was also predicted by executive functioning as measured by the Trail B-test. CONCLUSION: CSF biomarkers have the ability to discriminate MCI subjects into sub-populations that exhibit markedly different rates of disease progression on the ADAS-cog scale. These biomarkers can therefore be utilized for designing clinical trials enriched with subjects that carry the underlying disease pathology. PMID- 22534010 TI - Characterization of Ffh of Mycobacterium tuberculosis and its interaction with 4.5S RNA. AB - Signal recognition particle (SRP) mediates targeting of proteins to appropriate cellular compartments, which is an important process in all living organisms. In prokaryotes, SRP consists of Ffh, a protein, and 4.5S RNA that recognizes signal peptide emerging from ribosomes. The SRP (Ffh) of one the most successful intracellular pathogen, Mycobacterium tuberculosis, has been investigated with respect to biochemical properties. In the present study, Ffh of M. tuberculosis was overexpressed and was confirmed to be a GTPase using thin layer chromatography and malachite green assay. The GTP binding ability was confirmed by GTP overlay assay. The 4.5S RNA sequence of M. tuberculosis was synthesized by in vitro transcription assay. The interaction between Ffh and 4.5S RNA was confirmed by overlay assay and RNA gel shift assay. The results show that the biochemical properties of M. tuberculosis Ffh have been conserved, and this is the first report that shows the interaction of components of SRP in M. tuberculosis, namely Ffh protein and 4.5S RNA. PMID- 22534011 TI - Screening of postharvest agricultural wastes as alternative sources of peroxidases: characterization and kinetics of a novel peroxidase from lentil ( Lens culinaris L.) stubble. AB - Aqueous crude extracts of a series of plant wastes (agricultural, wild plants, residues from sports activities (grass), ornamental residues (gardens)) from 17 different plant species representative of the typical biodiversity of the Iberian peninsula were investigated as new sources of peroxidases (EC 1.11.1.7). Of these, lentil (Lens culinaris L.) stubble crude extract was seen to provide one of the highest specific peroxidase activities, catalyzing the oxidation of guaiacol in the presence of hydrogen peroxide to tetraguaiacol, and was used for further studies. For the optimum extraction conditions found, the peroxidase activity in this crude extract (110 U mL(-1)) did not vary for at least 15 months when stored at 4 degrees C (k(inact) = 0.146 year(-1), t(1/2 inact) = 4.75 year), whereas, for comparative purposes, the peroxidase activity (60 U mL(-1)) of horseradish (Armoracia rusticana L.) root crude extract, obtained and stored under the same conditions, showed much faster inactivation kinetics (k(inact) = 2.2 * 10(-3) day(-1), t(1/2 inact) = 315 days). Using guaiacol as an H donor and a universal buffer (see above), all crude extract samples exhibited the highest peroxidase activity in the pH range between 4 and 7. Once semipurified by passing the crude extract through hydrophobic chromatography on phenyl-Sepharose CL-4B, the novel peroxidase (LSP) was characterized as having a purity number (RZ) of 2.5 and three SDS-PAGE electrophoretic bands corresponding to molecular masses of 52, 35, and 18 kDa. The steady-state kinetic study carried out on the H(2)O(2) mediated oxidation of guaiacol by the catalytic action of this partially purified peroxidase pointed to apparent Michaelian kinetic behavior (K(m)(appH(2)O(2)) = 1.87 mM; V(max)(appH(2)O(2)) = 6.4 mM min(-1); K(m)(app guaicol) = 32 mM; V(max)(app guaicol) = 9.1 mM min(-1)), compatible with the two-substrate ping pong mechanism generally accepted for peroxidases. Finally, after the effectiveness of the crude extracts of LSP in oxidizing and removing from solution a series of last-generation dyes present in effluents from textile industries (1) had been checked, a steady-state kinetic study of the H(2)O(2) mediated oxidation and decolorization of Green Domalan BL by the catalytic action of the lentil stubble extract was carried out, with the observation of the same apparent Michaelian kinetic behavior (K(m)(appGD) = 471 MUM; V(max)(appGD)= 23 MUM min(-1)). Further studies are currently under way to address the application of this LSP crude extract for the clinical and biochemical analysis of biomarkers. PMID- 22534012 TI - Magnetic resonance tumor targeting imaging using gadolinium labeled human telomerase reverse transcriptase antisense probes. AB - To develop a molecular probe for MRI detection of human tumor telomerase reverse transcriptase (hTERT) mRNA expression. Uniformly phosphorothioate-modified hTERT antisense oligonucleotide (ASON) homing hTERT mRNA was labeled with gadolinium (Gd) through the bifunctional chelator 1,4,7, 10-tetraazacyclododecane-N, N', N'', N'''-tetraacetic acid (DOTA) stirred within 45 minutes at 60 degrees C. The Gd labeled probes were characterized in vitro. The cellular uptake rate and biodistribution of (99m) Tc-DOTA-ASON was measured instead of that of Gd-DOTA ASON. A549 lung adenocarcinoma model was established in BALB/c nude mice and Gd DOTA-ASON was injected intraperitoneally and MR images were acquired using 7.0T Micro-MRI (Bruker Biospec, Ettlingen, Germany) at different time points. Immunohistochemical analysis of telomerase activity of each xenograft was operated two days after in vivo imaging. The binding efficiency of Gd-DOTA-ASON reached as high as 71.7 +/- 4.5% (n = 6). Gd-DOTA-ASON displayed perfect stability in fresh human serum at 37 degrees C for 24 h. Compared with normal lung cells, A549 cells showed an obviously higher uptake of (99m) Tc-DOTA-ASON than that of lung cells (10.5 +/- 2.7% vs. 4.8 +/- 2.6%, P < 0.05). The signal intensity of A549 xenografts can be enhanced by Gd-DOTA-ASON and the signal to noise ratio (SNR) of tumor to muscle reached 2.37 and maintained a relatively high level within 6 h after injection. The activity of hTERT in A549 tumors can be suppressed by Gd-DOTA-ASON in pathological slices. The results of this study show that Gd-DOTA-ASON can be a promising intracellular MR contrast probe for targeting telomerase-positive carcinomas. PMID- 22534014 TI - The traceability chain of 131I measurements for nuclear medicine in Cuba. AB - The national traceability chain for (131)I activity measurements performed in nuclear medicine in Cuba is described. At the highest (primary) level, liquid scintillation counting employing the CIEMAT/NIST method is used; at the secondary level, a secondary standard radionuclide calibrator is utilized that allows for a quick and simple transference of the measurement unit to the tertiary level of end-users' instruments. The equivalence of Cuban standards and the assessment of measurement uncertainties at the end-user level are determined through the results of measurement comparisons. PMID- 22534013 TI - Trace elements as tumor biomarkers and prognostic factors in breast cancer: a study through energy dispersive x-ray fluorescence. AB - BACKGROUND: The application and better understanding of traditional and new breast tumor biomarkers and prognostic factors are increasing due to the fact that they are able to identify individuals at high risk of breast cancer, who may benefit from preventive interventions. Also, biomarkers can make possible for physicians to design an individualized treatment for each patient. Previous studies showed that trace elements (TEs) determined by X-Ray Fluorescence (XRF) techniques are found in significantly higher concentrations in neoplastic breast tissues (malignant and benign) when compared with normal tissues. The aim of this work was to evaluate the potential of TEs, determined by the use of the Energy Dispersive X-Ray Fluorescence (EDXRF) technique, as biomarkers and prognostic factors in breast cancer. METHODS: By using EDXRF, we determined Ca, Fe, Cu, and Zn trace elements concentrations in 106 samples of normal and breast cancer tissues. Cut-off values for each TE were determined through Receiver Operating Characteristic (ROC) analysis from the TEs distributions. These values were used to set the positive or negative expression. This expression was subsequently correlated with clinical prognostic factors through Fisher's exact test and chi square test. Kaplan Meier survival curves were also evaluated to assess the effect of the expression of TEs in the overall patient survival. RESULTS: Concentrations of TEs are higher in neoplastic tissues (malignant and benign) when compared with normal tissues. Results from ROC analysis showed that TEs can be considered a tumor biomarker because, after establishing a cut-off value, it was possible to classify different tissues as normal or neoplastic, as well as different types of cancer.The expression of TEs was found statistically correlated with age and menstrual status. The survival curves estimated by the Kaplan-Meier method showed that patients with positive expression for Cu presented a poor overall survival (p < 0.001). CONCLUSIONS: This study suggests that TEs expression has a great potential of application as a tumor biomarker, once it was revealed to be an effective tool to distinguish different types of breast tissues and to identify the difference between malignant and benign tumors. The expressions of all TEs were found statistically correlated with well known prognostic factors for breast cancer. The element copper also showed statistical correlation with overall survival. PMID- 22534015 TI - Changes in detrusor muscle oxygenation during detrusor overactivity contractions. AB - OBJECTIVE: To investigate changes in the oxygenated and deoxygenated haemoglobin (Hb) of the bladder wall during voluntary and involuntary detrusor contractions. STUDY DESIGN: Women with lower urinary tract symptoms were recruited from a urodynamics clinic. Near infra-red spectroscopy, a non-invasive optical technique which monitors changes in tissue oxygenation, was used to measure oxygenated and deoxygenated haemoglobin simultaneously while the women underwent urodynamics. All data were compared using paired sample t-test. RESULTS: Fifty-five women with a mean age of 52 years were enrolled into the study. In the 23 women with detrusor overactivity (15 with isolated detrusor overactivity and 8 with mixed urinary incontinence) there was a statistically significant rise in deoxygenated Hb during involuntary detrusor contractions at maximum detrusor pressure compared to the start of filling (p=0.02). There was no statistically significant change between Hb parameters measured at the start of the filling phase and those measured during voluntary detrusor contraction at pdetQmax (detrusor pressure at maximum flow rate). The mean detrusor pressure measured during voiding, however, was significantly higher than the maximum pressure during involuntary detrusor contractions (p=0.03). CONCLUSION: There is a significant rise in the deoxygenated Hb in the detrusor muscle during detrusor overactivity, which is not seen during voiding even when the pdetQmax was higher than the peak detrusor pressure during involuntary contractions. These interesting changes in detrusor muscle oxygenation during involuntary detrusor contraction need to be explored further to assess if deoxygenation plays a role in the pathogenesis of detrusor overactivity. PMID- 22534016 TI - Rectosigmoid deep infiltrating endometriosis and ureteral involvement with loss of renal function. AB - Endometriosis is a complex disease with unclear pathogenesis, defined as the presence of endometrial tissue (glands and stroma) outside its usual location in the uterine cavity. Ureteral involvement is rare, with an estimated frequency of 10-14% in cases of deep endometriosis with nodules of 3 cm or larger. An important complication of ureteral involvement is asymptomatic loss of renal function. In a patient with asymptomatic renal failure the relevance of extrinsic ureteral involvement by deep endometriosis has been taken to account. CASE REPORT: A 32-year-old nulliparous woman presented with chronic pelvic pain associated with severe dysmenorrhea, dyspareunia and digestive problems including diarrhea, occasional constipation and rectal bleeding. She reported no urological symptoms. Magnetic resonance imaging (MRI) identified a 4 cm nodule in the recto vaginal septum, compressing and infiltrating the rectal wall, and chronic left hydronephrosis. Isotope renogram revealed 91% function in the right kidney and 9% in the left kidney. A multidisciplinary surgical team including consultants from the departments of digestive surgery and urology assessed the patient. The treatment recommended was a joint approach of laparoscopic surgery to perform adhesiolysis, ureterolysis, freeing of the uterus and appendages, resection of the rectovaginal septum nodule, and left nephrectomy. COMMENT: Diagnosis and treatment of deep endometriosis should be performed in specialized centers and in the context of multidisciplinary collaboration. We must be aware of the potential risk of ureteral involvement and the asymptomatic loss of renal function in any patient with endometriosis nodules of 3 cm or larger. PMID- 22534018 TI - Advanced gallbladder cancer misdiagnosis. PMID- 22534019 TI - Cation-size-mismatch tuning of photoluminescence in oxynitride phosphors. AB - Red or yellow phosphors excited by a blue light-emitting diode are an efficient source of white light for everyday applications. Many solid oxides and nitrides, particularly silicon nitride-based materials such as M(2)Si(5)N(8) and MSi(2)O(2)N(2) (M = Ca, Sr, Ba), CaAlSiN(3), and SiAlON, are useful phosphor hosts with good thermal stabilities. Both oxide/nitride and various cation substitutions are commonly used to shift the emission spectrum and optimize luminescent properties, but the underlying mechanisms are not always clear. Here we show that size-mismatch between host and dopant cations tunes photoluminescence shifts systematically in M(1.95)Eu(0.05)Si(5-x)Al(x)N(8-x)O(x) lattices, leading to a red shift when the M = Ba and Sr host cations are larger than the Eu(2+) dopant, but a blue shift when the M = Ca host is smaller. Size mismatch tuning of thermal quenching is also observed. A local anion clustering mechanism in which Eu(2+) gains excess nitride coordination in the M = Ba and Sr structures, but excess oxide in the Ca analogues, is proposed for these mismatch effects. This mechanism is predicted to be general to oxynitride materials and will be useful in tuning optical and other properties that are sensitive to local coordination environments. PMID- 22534017 TI - Proteomic analysis of HIV-1 Nef cellular binding partners reveals a role for exocyst complex proteins in mediating enhancement of intercellular nanotube formation. AB - BACKGROUND: HIV-1 Nef protein contributes to pathogenesis via multiple functions that include enhancement of viral replication and infectivity, alteration of intracellular trafficking, and modulation of cellular signaling pathways. Nef stimulates formation of tunneling nanotubes and virological synapses, and is transferred to bystander cells via these intercellular contacts and secreted microvesicles. Nef associates with and activates Pak2, a kinase that regulates T cell signaling and actin cytoskeleton dynamics, but how Nef promotes nanotube formation is unknown. RESULTS: To identify Nef binding partners involved in Pak2 association dependent Nef functions, we employed tandem mass spectrometry analysis of Nef immunocomplexes from Jurkat cells expressing wild-type Nef or Nef mutants defective for the ability to associate with Pak2 (F85L, F89H, H191F and A72P, A75P in NL4-3). We report that wild-type, but not mutant Nef, was associated with 5 components of the exocyst complex (EXOC1, EXOC2, EXOC3, EXOC4, and EXOC6), an octameric complex that tethers vesicles at the plasma membrane, regulates polarized exocytosis, and recruits membranes and proteins required for nanotube formation. Additionally, Pak2 kinase was associated exclusively with wild-type Nef. Association of EXOC1, EXOC2, EXOC3, and EXOC4 with wild-type, but not mutant Nef, was verified by co-immunoprecipitation assays in Jurkat cells. Furthermore, shRNA-mediated depletion of EXOC2 in Jurkat cells abrogated Nef mediated enhancement of nanotube formation. Using bioinformatic tools, we visualized protein interaction networks that reveal functional linkages between Nef, the exocyst complex, and the cellular endocytic and exocytic trafficking machinery. CONCLUSIONS: Exocyst complex proteins are likely a key effector of Nef mediated enhancement of nanotube formation, and possibly microvesicle secretion. Linkages revealed between Nef and the exocyst complex suggest a new paradigm of exocyst involvement in polarized targeting for intercellular transfer of viral proteins and viruses. PMID- 22534021 TI - Androcoll-E large selects a subset of live stallion spermatozoa capable of producing ROS. AB - The aim of this study was to elucidate if SLC after 24 h storage selects the subpopulation of spermatozoa that better withstands osmotic shock. To test this hypothesis, viability, mitochondrial membrane potential (MMP) and superoxide anion (O(2)(.-)) production of uncentrifuged (UC) and single layer centrifugation (SLC) - selected spermatozoa were analyzed following SLC after storage of the semen. An aliquot of the extended ejaculate (100*10(6) spermatozoa/mL) was centrifuged through a single layer of a silane-coated silica based colloid formulation optimized for equine spermatozoa (Androcoll-E large, SLU, Sweden) and the rest was used as control. UC and SLC-sperm samples were subjected to osmotic challenges (75 and 900 mOsm) with a subsequent return to isosmolarity (300 mOsm) using Biggers-Whitten-Whittingham (BWW) medium. Viability and MMP decreased after the different osmotic stress in UC and SLC spermatozoa, and return to isosmolarity did not reverse these effects. O(2)(.-) production was enhanced after SLC in all osmolarities tested. Interestingly, the percentage of living spermatozoa showing O(2)(.-) production was increased after 900 mOsm stress in UC spermatozoa, this increase being more evident in SLC spermatozoa. Returning spermatozoa to 300 mOsm enhanced this percentage in UC viable cells but not in SLC spermatozoa. The scenario observed for UC spermatozoa shows that O(2)(.-) is produced in response to isolated hyperosmolarities and subsequent osmotic excursions. As the viability, MMP and cell volume remained the same between SLC and UC spermatozoa, we conclude that Androcoll-E large is likely selecting a higher percentage of physiologically O(2)(.-) producing spermatozoa. PMID- 22534020 TI - The I2020T Leucine-rich repeat kinase 2 transgenic mouse exhibits impaired locomotive ability accompanied by dopaminergic neuron abnormalities. AB - BACKGROUND: Leucine-rich repeat kinase 2 (LRRK2) is the gene responsible for autosomal-dominant Parkinson's disease (PD), PARK8, but the mechanism by which LRRK2 mutations cause neuronal dysfunction remains unknown. In the present study, we investigated for the first time a transgenic (TG) mouse strain expressing human LRRK2 with an I2020T mutation in the kinase domain, which had been detected in the patients of the original PARK8 family. RESULTS: The TG mouse expressed I2020T LRRK2 in dopaminergic (DA) neurons of the substantia nigra, ventral tegmental area, and olfactory bulb. In both the beam test and rotarod test, the TG mice exhibited impaired locomotive ability in comparison with their non transgenic (NTG) littermates. Although there was no obvious loss of DA neurons in either the substantia nigra or striatum, the TG brain showed several neurological abnormalities such as a reduced striatal dopamine content, fragmentation of the Golgi apparatus in DA neurons, and an increased degree of microtubule polymerization. Furthermore, the tyrosine hydroxylase-positive primary neurons derived from the TG mouse showed an increased frequency of apoptosis and had neurites with fewer branches and decreased outgrowth in comparison with those derived from the NTG controls. CONCLUSIONS: The I2020T LRRK2 TG mouse exhibited impaired locomotive ability accompanied by several dopaminergic neuron abnormalities. The TG mouse should provide valuable clues to the etiology of PD caused by the LRRK2 mutation. PMID- 22534022 TI - Etiology of unilateral hearing loss in a national hereditary deafness repository. AB - PURPOSE: The aim of this study was to characterize the genetic, audiologic, and epidemiologic characteristics of unilateral hearing loss (HL) in a national hereditary deafness repository. MATERIALS AND METHODS: This is a prospective clinical study involving 34 subjects identified in a national hereditary deafness repository. Clinical data and family history of HL were obtained on enrollment. Candidate deafness genes were screened by single-stranded conformation polymorphism, and mutations were confirmed with sequencing. RESULTS: Thirty-four subjects (19 males, 15 females) with unilateral HL were identified, ranging in age from 2 months to 36 years. The mean age at diagnosis was 7 years, and the left ear was affected in 62% of the cases. The racial distribution of our sample was 62% white, 23% African American, and 15% Hispanic. Imaging results were available in 47%, and most (69%) were considered normal. Nineteen percent had enlarged vestibular aqueducts, 2 had ipsilateral Mondini dysplasia, and 1 had a common cavity deformity. Twenty subjects (59%) had a family history of HL, with 26% specifically reporting familial unilateral HL. Mutational screening revealed sequence variants in the GJB2 (connexin 26), GJB3 (connexin 31), TECTA, and COCH genes. Two novel mutations were detected in COCH and TECTA. CONCLUSIONS: Sequence variants in known deafness genes were detected in more than one-third of our study population, suggesting that gene/gene or gene/environmental interactions may indeed play a role in the etiology of some cases of unilateral deafness. Further prospective studies including congenital cytomegalovirus screening at birth and molecular screening of deafness genes in children with congenital unilateral HL will be required to establish the etiology of unilateral deafness with certainty. PMID- 22534023 TI - Pattern of expression of cyclooxygenase-2 in malignant transformation of sinonasal inverted papilloma. AB - OBJECTIVE: Cyclooxygenases (COXs) are enzymes that catalyze the conversion of arachidonic acid to prostaglandins. Many studies have suggested that COX-2, the inducible form of COX, is important in carcinogenesis. However, little is known about the pattern of expression of COX-2 in a multistep process of malignant transformation of sinonasal inverted papilloma (IP). In this study, we investigated COX-2 expression in IPs, IPs with dysplasia, IPs with squamous cell carcinoma (SCC), and primary SCCs of sinonasal tract. STUDY DESIGN: A retrospective study was conducted. SETTING: The setting was a tertiary care referral center. SUBJECTS AND METHODS: The expression of COX-2 was evaluated by immunohistochemistry in 56, 7, 18, and 17 cases of IPs, IPs with dysplasia, IPs with SCC, and primary SCCs, respectively. Furthermore, we investigated the possible correlation between the expression of COX-2 and clinicopathologic variables in patients with IPs with SCC and primary SCC patients. RESULTS: Positive immunoreactivity for COX-2 was observed in 3 (5.4%) of 56 IPs, 7 (38.9%) of 18 IPs with SCC, and 7 (41.2%) of 17 primary SCCs, whereas it was not observed in IPs with dysplasia. The percentage of tumors with COX-2-positive immunostaining was significantly higher in IPs with SCC and primary SCCs compared with benign IPs. There was no significant correlation between the expression of COX-2 and clinicopathologic variables, such as tumor stage, histologic differentiation, and the proportion of malignant areas in patients with IPs with SCC. CONCLUSION: Cyclooxygenase-2 may play an important role in the process of malignant transformation from IP to SCC. PMID- 22534024 TI - Selective partitioning of cholesterol and a model drug into liposomes of varying size. AB - The resistance of a lipid bilayer with respect to a bending deformation generally depends on the presence of membrane additives such as sterols, cosurfactants, peptides, and drugs. As a consequence, the partitioning of membrane additives into liposomes becomes selective with respect to liposome size; i.e., membrane rigidification depletes the membrane additives in the smaller (more strongly curved) liposomes. We have measured this liposome size-selective partitioning for two membrane additives - cholesterol and the porphyrin-based photosensitizer temoporfin - using asymmetrical flow field-flow fractionation (AF4) of liposomes and radioactive labeling of the membrane additive and lipid. The method yields either the molar cholesterol-to-lipid or the temoporfin-to-lipid ratio as a function of liposome size, from which we calculate the corresponding change of the membrane bending stiffness. For small unilamellar fluid-phase liposomes composed of palmitoyloleoylphosphatidylcholine (POPC) and palmitoyloleoylphosphatidylglycerol (POPG), we find that cholesterol rigidifies the host membrane in a manner consistent with previously reported measurements. In contrast, temoporfin softens this membrane. Partitioning results for gel-phase liposomes composed of dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylglycerol (DPPG) are also curvature-sensitive but cannot be interpreted on the basis of the bending stiffness alone. PMID- 22534025 TI - Pathology and biofilm formation in a porcine model of staphylococcal osteomyelitis. AB - A porcine model was used to examine the potential of human and porcine Staphylococcus aureus isolates to induce haematogenously spread osteomyelitis. Pigs were inoculated in the right femoral artery with one of the following S. aureus strains: S54F9 (from a porcine lung abscess; n = 3 animals), NCTC-8325-4 (a laboratory strain of human origin; n = 3 animals) and UAMS-1 (a human osteomyelitis isolate; n = 3 animals). Two pigs were sham inoculated with saline. At 11 or 15 days post infection the animals were scanned by computed tomography before being killed and subjected to necropsy examination. Osteomyelitis lesions were present in the right hind limb of all pigs inoculated with strain S54F9 and in one pig inoculated with strain NCTC-8325-4. Microscopically, there was extensive loss of bone tissue with surrounding granulation tissue. Sequestrated bone trabeculae were intermingled with colonies of S. aureus as demonstrated immunohistochemically. By peptide nucleic acid fluorescence in situ hybridization bacterial aggregates were demonstrated to be embedded in an opaque matrix, indicating that the bacteria had formed a biofilm. Development of experimental osteomyelitis was therefore dependent on the strain of bacteria inoculated and on the formation of a biofilm. PMID- 22534026 TI - Modeling the residential infiltration of outdoor PM(2.5) in the Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air). AB - BACKGROUND: Epidemiologic studies of fine particulate matter [aerodynamic diameter <= 2.5 MUm (PM(2.5))] typically use outdoor concentrations as exposure surrogates. Failure to account for variation in residential infiltration efficiencies (F(inf)) will affect epidemiologic study results. OBJECTIVE: We aimed to develop models to predict F(inf) for > 6,000 homes in the Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air), a prospective cohort study of PM(2.5) exposure, subclinical cardiovascular disease, and clinical outcomes. METHODS: We collected 526 two-week, paired indoor-outdoor PM(2.5) filter samples from a subset of study homes. PM(2.5) elemental composition was measured by X-ray fluorescence, and F(inf) was estimated as the indoor/outdoor sulfur ratio. We regressed F(inf) on meteorologic variables and questionnaire-based predictors in season-specific models. Models were evaluated using the R2 and root mean square error (RMSE) from a 10-fold cross-validation. RESULTS: The mean +/- SD F(inf) across all communities and seasons was 0.62 +/- 0.21, and community-specific means ranged from 0.47 +/- 0.15 in Winston-Salem, North Carolina, to 0.82 +/- 0.14 in New York, New York. F(inf) was generally greater during the warm (> 18 degrees C) season. Central air conditioning (AC) use, frequency of AC use, and window opening frequency were the most important predictors during the warm season; outdoor temperature and forced-air heat were the best cold-season predictors. The models predicted 60% of the variance in 2-week F(inf), with an RMSE of 0.13. CONCLUSIONS: We developed intuitive models that can predict F(inf) using easily obtained variables. Using these models, MESA Air will be the first large epidemiologic study to incorporate variation in residential F(inf) into an exposure assessment. PMID- 22534027 TI - Participation bias in postal surveys among older adults: the role played by self reported health, physical functional decline and frailty. AB - Postal survey is a simple and efficient way to collect information in large study samples. The purpose of this study was to find out differences between older adults who responded to a postal survey on health outcomes and those who did not, and to examine the importance of frailty, physical functional decline and poor self-reported health in determining non-response. We mailed out a questionnaire on general health twice at a year's interval to 1000 individuals >=60 years, and members of the medical insurance scheme of the French national education system. At Year1, 535 persons responded to the questionnaire (65% women, 70.9 +/- 8.4 years). A year later (Year2), we obtained 384 responses (63.3% women, 70.5 +/- 7.8 years). Compared to respondents, non-respondents at Year2 were more frequently categorized as frail, reported more often to be in bad health, and had more physical functional declines. Frailty, physical functional decline and poor self-reported health increased the likelihood of not responding to Year2 questionnaire, with poor self-reported health weakening the association of physical functional decline and non-response. Respondents of this postal survey are fitter and healthier than non-respondents. This participation bias precludes the generalization of postal surveys results. PMID- 22534028 TI - Development and content validity of a patient reported outcomes measure to assess symptoms of major depressive disorder. AB - BACKGROUND: Although many symptoms of Major Depressive Disorder (MDD) are assessed through patient-report, there are currently no patient-reported outcome (PRO) instruments that incorporate documented evidence of patient input in PRO instrument development. A review of existing PROs used in MDD suggested the need to conduct qualitative research with patients with MDD to better understand their experience of MDD and develop an evaluative instrument with content validity. The aim of this study was to develop a disease-specific questionnaire to assess symptoms important and relevant to adult MDD patients. METHODS: The questionnaire development involved qualitative interviews for concept elicitation, instrument development, and cognitive interviews to support content validity. For concept elicitation, ten MDD severity-specific focus group interviews with thirty-eight patients having clinician-confirmed diagnoses of MDD were conducted in January 2009. A semi-structured discussion guide was used to elicit patients' spontaneous descriptions of MDD symptoms. Verbatim transcripts of focus groups were coded and analyzed to develop a conceptual framework to describe MDD. A PRO instrument was developed by operationalizing concepts elicited in the conceptual framework. Cognitive interviews were carried out in patients (n = 20) to refine and test the content validity of the instrument in terms of item relevance and comprehension, instructions, recall period, and response categories. RESULTS: Concept elicitation focus groups identified thirty-five unique concepts falling into several domains: i) emotional, ii) cognitive, iii) motivation, iv) work, v) sleep, vi) appetite, vii) social, viii) activities of daily living, ix) tired/fatigue, x) body pain, and xi) suicidality. Concept saturation, the point at which no new relevant information emerges in later interviews, was achieved for each of the concepts. Based on the qualitative findings, the PRO instrument developed had 15 daily and 20 weekly items. The cognitive interviews confirmed that the instructions, item content, and response scales were understood by the patients. CONCLUSIONS: Rigorous qualitative research resulted in the development of a PRO measure for MDD with supported content validity. The MDD PRO can assist in understanding and assessing MDD symptoms from patients' perspectives as well as evaluating treatment benefit of new targeted therapies. PMID- 22534029 TI - Durability of open repair of juxtarenal abdominal aortic aneurysms. AB - OBJECTIVE: As branched/fenestrated endografts expand endovascular options for juxtarenal abdominal aortic aneurysms (JAAAs), long-term durability will be compared to that of open JAAA repair, which has not been documented in large contemporary series. The goal of this study was to assess the late clinical and anatomic outcomes after open JAAA repair. METHODS: From July 2001 to December 2007, 199 patients underwent open elective JAAA repair, as defined by a need for suprarenal clamping. End points included perioperative and late survival, long term follow-up of renal function, and freedom from graft-related complications. Factors predictive of survival were determined by multivariate analysis. RESULTS: The mean patient age was 74 years, 71% were men, and 20% had baseline renal insufficiency (Cr >1.5). Thirty-seven renal artery bypasses, for anatomic necessity or ostial stenosis, were performed in 36 patients. Overall 30-day mortality was 2.5%. Four patients (2.0%) required early dialysis; one patient recovered by discharge. Two additional patients progressed to dialysis over long term follow-up. There was one graft infection involving one limb of a bifurcated graft. Surveillance imaging was obtained in 101 patients (72% of survivors) at a mean follow-up of 41 +/- 28 months. Renal artery occlusion occurred in four patients (3% of imaged renal arteries; one native/three grafts). Two patients (2.0%) had aneurysmal degeneration of the aorta either proximal or distal to the repaired segment, but there were no anastomotic pseudoaneurysms. Remote aneurysms were found in 29 patients (29% of imaged patients), 14 of whom had descending thoracic aneurysm or TAAA. Four patients underwent subsequent thoracic endovascular aneurysm repair (TEVAR). Actuarial survival was 74 +/- 3.3% at 5 years. Negative predictors of survival included increasing age at the time of operation (relative risk [RR], 1.05; P = .01), steroid use (RR, 2.20; P = .001), and elevated preoperative creatinine (RR, 1.73; P = .02). CONCLUSIONS: Open JAAA repair yields excellent long-term anatomic durability and preserves renal function. Perioperative renal insufficiency occurs in 8.5% of patients, but few of them progress to dialysis. Graft-related complications are rare (2% at 40 months); however, axial imaging revealed descending thoracic aneurysms in 14% of imaged patients, making continued surveillance for remote aneurysms prudent. These data provide a benchmark against which fenestrated/branched endovascular aneurysm repair (EVAR) outcomes can be compared. PMID- 22534030 TI - Synthesis, in vitro and in vivo characterization of novel 99mTc-'4+1'-labeled 5 nitroimidazole derivatives as potential agents for imaging hypoxia. AB - The evaluation of oxygenation status of solid tumors is an important field of radiopharmaceutical research. With the aim to develop new potential 99mTc radiopharmaceuticals for imaging hypoxia, we have synthesized two novel isocyanide derivatives of metronidazole, which has demonstrated high affinity for hypoxic tumors in vitro and in vivo. METHODS: Metronidazole derivatives 4 isocyano-N-[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl]butanamide (M1) and 1-(4 isocyanobutanoyl)-4-[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl]piperazine (M2) were synthesized, and labeling was performed through preparation of their corresponding 99mTc-(4+1) complexes, 99mTc-NS3M1 and 99mTc-NS3M2. The structure of the technetium complexes was corroborated by preparation and characterization of the corresponding rhenium complexes. We have studied the main physicochemical properties (stability, lipophilicity and plasma protein binding). Biological behavior in HCT-15 cells both in oxia and in hypoxia was assessed. Biodistribution in normal mice and in animals bearing induced 3LL Lewis murine lung carcinoma was also studied. RESULTS: Metronidazole derivatives were successfully synthesized. Labeling with high radiochemical purity was achieved for both ligands. 99mTc complexes were stable in labeling milieu and human plasma. However, presence of the piperazine linker in M2 resulted in higher lipophilicity and protein binding. Although cell uptake in hypoxic conditions was observed for both radiotracers, 99mTc-NS3M2 biodistribution was considered unsuitable for a potential radiopharmaceutical due to high liver uptake and poor blood clearance. However, 99mTc-NS3M1 demonstrated a very favorable in vivo profile both in normal mice and in mice bearing induced tumors. CONCLUSION: Selective uptake and retention in tumor together with favorable tumor/muscle ratio make 99mTc-NS3M1 a promising candidate for further evaluation as potential hypoxia imaging agent in tumors. PMID- 22534031 TI - Understanding the in vivo uptake kinetics of a phosphatidylethanolamine-binding agent (99m)Tc-Duramycin. AB - INTRODUCTION: (99m)Tc-Duramycin is a peptide-based molecular probe that binds specifically to phosphatidylethanolamine (PE). The goal was to characterize the kinetics of molecular interactions between (99m)Tc-Duramycin and the target tissue. METHODS: High level of accessible PE is induced in cardiac tissues by myocardial ischemia (30 min) and reperfusion (120 min) in Sprague-Dawley rats. Target binding and biodistribution of (99m)Tc-duramycin were captured using SPECT/CT. To quantify the binding kinetics, the presence of radioactivity in ischemic versus normal cardiac tissues was measured by gamma counting at 3, 10, 20, 60 and 180 min after injection. A partially inactivated form of (99m)Tc Duramycin was analyzed in the same fashion. A compartment model was developed to quantify the uptake kinetics of (99m)Tc-Duramycin in normal and ischemic myocardial tissue. RESULTS: (99m)Tc-duramycin binds avidly to the damaged tissue with a high target-to-background radio. Compartment modeling shows that accessibility of binding sites in myocardial tissue to (99m)Tc-Duramycin is not a limiting factor and the rate constant of target binding in the target tissue is at 2.2 ml/nmol/min/g. The number of available binding sites for (99m)Tc-Duramycin in ischemic myocardium was estimated at 0.14 nmol/g. Covalent modification of D15 resulted in a 9-fold reduction in binding affinity. CONCLUSION: (99m)Tc-Duramycin accumulates avidly in target tissues in a PE-dependent fashion. Model results reflect an efficient uptake mechanism, consistent with the low molecular weight of the radiopharmaceutical and the relatively high density of available binding sites. These data help better define the imaging utilities of (99m)Tc-Duramycin as a novel PE-binding agent. PMID- 22534032 TI - The impact of mood, anxiety, and sleep disorders on fibromyalgia. AB - INTRODUCTION: Several studies carried out mainly in North America revealed high rates of mood, anxiety and sleep disorders in patients with fibromyalgia (FM), while the information in other countries is scant. Therefore, we aimed at investigating the prevalence and the impact of such conditions on the health related quality of life (HRQoL) and the severity of pain in a sample of Italian FM patients. METHODS: One-hundred and sixty-seven women suffering from primary FM were consecutively enrolled. Psychiatric diagnoses were made by means of DSM-IV criteria. The HRQoL and the severity of pain were measured through the Medical Outcomes Study 36-item Short-Form Health Survey (MOS-SF-36) and the FM Impact Questionnaire (FIQ). RESULTS: Fibromyalgia patients showed a high rate (80.8%) of lifetime and/or current comorbidity with mood and anxiety disorders. Patients with psychiatric comorbidity resulted significantly more impaired on the Mental Component Summary score of the MOS-SF-36 and showed a higher FIQ total score than those suffering from FM only. The severity of pain was associated with current psychiatric comorbidity. Patients with current mood disorders showed significantly lower Mental and Physical Component Summary scores of the MOS-SF-36 and higher FIQ total scores than those with current anxiety disorders or those without psychiatric comorbidity. Finally, patients with sleep disorders reported a lower HRQoL than those with a normal sleep, and specifically those with difficulty in falling in sleep had higher severity of pain. CONCLUSION: Psychiatric comorbidity, in particular with mood disorders, provokes a significant impairment of the HRQoL and, when current, a higher severity of pain in FM patients. PMID- 22534033 TI - Work and social adjustment in patients with anorexia nervosa. AB - OBJECTIVE AND METHODS: The Work and Social Adjustment Scale (WSAS) assesses patients' perceptions of impairment in everyday functioning and has been reported as a simple and reliable self-report measure in different psychiatric disorders. This study compared WSAS data from an anorexia nervosa (AN) patient group with that from healthy controls (HCs) and published data from other patient groups. A total of 160 female participants (AN, 77; HC, 83) completed the WSAS as well as measures of eating disorder symptom severity and brief assessments of anxiety and depression. RESULTS: Work and Social Adjustment Scale scores for the AN group were found to be in the severely impaired range, whereas the scores for those within the HC group indicated very little, or no impairment. Total WSAS scores in the AN group were significantly correlated with severity of clinical symptoms, and eating disorder-specific symptoms were the best predictor of social and occupational functional impairment. The greatest impairment in the AN group was reported in the realm of social leisure. CONCLUSIONS: Consistent with reports in other clinical populations, it is suggested that the WSAS could be an extremely useful and meaningful measure to assess social and occupational functioning in people with eating disorders, in addition to eating disorder-specific assessments. PMID- 22534034 TI - Patient satisfaction and clinical parameters in psychiatric inpatients--the prevailing role of symptom severity and pharmacologic disturbances. AB - OBJECTIVE: A high degree of satisfaction is probably one of the most important aims for each patient during medical treatment. However, database on the influencing variables in a general psychiatric inpatient sample is still small. Therefore, the objective of this study is to identify clinical variables related to patients' treatment satisfaction. METHODS: In 113 patients (59 females; mean age, 48.3 +/- 16.6 years; mean treatment duration, 1.4 +/- 1.2 months) admitted to a psychiatric hospital, data were assessed on treatment satisfaction using the ZUF-8 questionnaire ("Fragebogen zur Patientenzufriedenheit"; questionnaire of patient satisfaction) at discharge and on general treatment variables as well as the psychosocial functioning using the "Basisdokumentation" (basic documentation) questionnaire including Clinical Global Impression scale (CGI) and Global Assessment of Functioning scale (GAF) at admission and discharge. Student t tests, univariate variance analyses, and Pearson correlations were performed. RESULTS: ZUF-8 sum score correlated significantly negatively with CGI score at discharge (part 1: P = .036), positively with GAF at discharge (P = .011), and as a trend with the reduction of CGI during the treatment (CGI change; P = .050). Patients with pharmacologic disturbances (P = .003) and with a schizophrenia spectrum disorder or a personality disorder were less content (trend; P = .071). Satisfaction did not differ in dependency of the variables age, sex, native language, number of inpatient treatments, therapeutic setting of the ward, duration of disorder or treatment, level of school education, bodily impairment, number of somatic diagnoses, psychopharmacologic treatment (vs none), antidepressants, body weight, or body weight change. CONCLUSION: The results of the study suggest that patient satisfaction is dependent on symptom severity and global functioning at discharge, on pharmacologic disturbances during treatment, and on the diagnostic group. Therefore, symptom relief and reduction of adverse side effects as far as possible should be the primary aim of an inpatient treatment. PMID- 22534035 TI - Birthweight and cytochrome P4503A4/5 activity in obese women. PMID- 22534036 TI - Eukaryotic assimilatory nitrate reductase fractionates N and O isotopes with a ratio near unity. AB - In order to (i) establish the biological systematics necessary to interpret nitrogen (N) and oxygen (O) isotope ratios of nitrate ((15)N/(14)N and (18)O/(16)O) in the environment and (ii) investigate the potential for isotopes to elucidate the mechanism of a key N cycle enzyme, we measured the nitrate N and O isotope effects ((15)epsilon and (18)epsilon) for nitrate reduction by two assimilatory eukaryotic nitrate reductase (eukNR) enzymes. The (15)epsilon for purified extracts of NADPH eukNR from the fungus Aspergillus niger and the (15)epsilon for NADH eukNR from cell homogenates of the marine diatom Thalassiosira weissflogii were indistinguishable, yielding a mean (15)epsilon for the enzyme of 26.6 +/- 0.20/00. Both forms of eukNR imparted near equivalent fractionation on N and O isotopes. The increase in (18)O/(16)O versus the increase in (15)N/(14)N (relative to their natural abundances) was 0.96 +/- 0.01 for NADPH eukNR and 1.09 +/- 0.03 for NADH eukNR. These results are the first reliable measurements of the coupled N and O isotope effects for any form of eukNR. They support the prevailing view that intracellular reduction by eukNR is the dominant step in isotope fractionation during nitrate assimilation and that it drives the (18)epsilon:(15)epsilon ~ 1 observed in phytoplankton cultures, suggesting that this O-to-N isotope signature will apply broadly in the environment. Our measured (15)epsilon and (18)epsilon may represent the intrinsic isotope effects for eukNR-mediated N-O bond rupture, a potential constraint on the nature of the enzyme's transition state. PMID- 22534037 TI - The influence of glutathione on redox regulation by antioxidant proteins and apoptosis in macrophages exposed to 2-hydroxyethyl methacrylate (HEMA). AB - Resin monomers like 2-hydroxyethyl methacrylate (HEMA) disturb cell functions including responses of the innate immune system, mineralization and differentiation, or induce cell death via apoptosis. These phenomena are associated with oxidative stress and a reduction in the concentration of the antioxidant glutathione (GSH), resulting in imbalanced redox homeostasis. Thus far, the precise mechanism of how resin monomers interfere with cellular redox regulation is unknown. The present study provides insight into the induction of apoptosis and the differential expression of antioxidant enzymes depending on the availability of GSH. Buthionine sulfoximine (BSO) was used to inhibit GSH synthesis, while 2-oxothiazolidine-4-carboxylate (OTC), and N-acetylcysteine (NAC) as prodrugs supported GSH synthesis in RAW264.7 mouse macrophages exposed to HEMA (0-8 mm) for 24 h. The level of GSH was significantly decreased after cells were preincubated with BSO, and the formation of reactive oxygen species (ROS) increased in cultures subsequently exposed to HEMA. Apoptosis was drastically increased by BSO in HEMA-exposed cell cultures as well, but OTC and NAC retracted HEMA-induced cell death. These results show that dental monomer induced apoptosis is causally related to the availability of GSH. The hydrogen peroxide decomposing enzymes glutathione peroxidase (GPx1/2) and catalase were differentially regulated in HEMA-exposed cultures. Expression of GPx1/2 was inhibited by HEMA and further reduced in the presence of BSO. SOD1 (superoxide dismutase) expression was inhibited in the presence of HEMA, and was decreased to an even greater extent by BSO, possibly due to H(2)O(2)-feedback inhibition. The expression of catalase was considerably up-regulated in HEMA-exposed cultures, implying that H(2)O(2) is the type of ROS that is significantly increased in monomer-exposed cells. OTC and NAC counteracted the effect of HEMA on GPx1/2, SOD1, and catalase expression. HO-1 (heme oxygenase) expression was strongly enhanced by HEMA, suggesting the need for further antioxidants like bilirubin to support enzyme activities that directly regulate H(2)O(2) equilibrium. Expression of the oxidoreductase thioredoxin (TRX1), the second major thiol-dependent antioxidant system in eukaryotic cells, was slightly reduced, while the oxygen sensing protein HIF-1alpha was downregulated in HEMA-exposed cell cultures. These results indicate that cells and tissues actively respond to monomer-induced oxidative stress by the differential expression of enzymatic antioxidants. PMID- 22534038 TI - [Urinary tract duplication]. AB - OBJECTIVES: Review the clinical and radiological characteristics of the different kinds of urinary tract duplications, assessing the outcome of the cases and the incidence of renal parenchymal injury. MATERIAL AND METHODS: A retrospective study was performed including 301 children diagnosed of renal duplication by urological ultrasound, voiding cystourethrogram (VCUG) and 99-technetium renal scintigraphy (DMSA). RESULTS: They were classified in four groups. The first consisted of 166 (55.1%) cases that had complete ureteral duplication without an obstructive component (CD). The cases that had an upper system obstruction due to an ectopic ureter (EU), 19 (6.3%), or an ureterocele (UTC), 35 (11.6%), were divided into two different groups. The fourth group 81 (26.9%) had incomplete ureteral duplication. The nephro-urological study was performed in 181/301 after a urinary tract infection; in 100/301 after a prenatal finding of hydronephrosis. It was a casual diagnosis in 20/301. The percentage upper kidney dilation in the diagnostic ultrasound was significantly higher in those with EU 16/19 (84%) and in those with UTC 33/35 (94%), compared with the upper pole dilations found in the CD 35/166 (21%) and ID 21/81 (25%). Surgery was performed in 96/166 (41%) of the CD, 7/81 of the ID, 16/19 (84%) of the EU, and 34/35 (97%) of the UTC. Three cases with EU and 8 with UTC needed a second surgery, and 3 a third one. No scintigraphy changes were observed in 58% of the patients in the CD group, 87% in the ID group, 29% in the EU group, and 5% in the UTC group. As regards the renal duplications who did not have surgery, it was found that there were 98 refluxing units in the CD, and 74 in the ID. The spontaneous resolution of the vesicoureteral reflux (VUR) was 80% in the CD, and 90% in the ID (McNemar test P<.001). The average healing time ranged from 1 year to 5 years (Mean: 3 years and 3 months). CONCLUSION: The patients with higher risk of having renal injury are those who presented with a duplication with upper kidney obstruction due to ectopic insertion of the ureter, particularly due to an ureterocele. PMID- 22534040 TI - Mental health among adults with asthma and chronic bronchitis. A population-based study in Spain. AB - OBJECTIVES: To analyze the conditions of psychological dysfunction and positive mental health in patients with asthma and chronic bronchitis (CB), as compared to healthy individuals, and to identify the factors associated with these mental health indicators. METHODS: Cross-sectional study based on data obtained from the European Health Interview Survey for Spain (EHISS, 2009). We identified individuals with asthma and CB using a specific questionnaire. In order to assess mental health, two indicators extracted from questionnaire SF-36 were used: psychological dysfunction and positive mental health status. RESULTS: Out of 19,598 subjects included in the study, 8.3% were classified as asthmatic and 7.4% as CB. Healthy individuals had significantly higher psychological dysfunction scores than those with asthma and CB. The same occurred with positive mental health. The variables independently associated with lower scores out of these variables were gender female, a greater number of chronic diseases and obesity. On the contrary, alcohol consumption and physical exercise were associated with a higher score in the aforementioned variables. CONCLUSIONS: Healthy individuals have significantly higher scores in psychological dysfunction and positive mental health than patients with asthma and CB. This suggests that their mental health is much better. The variables related with lower scores out of these variables, and therefore with worse mental health, are: being female, having a greater number of chronic diseases and obesity. On the contrary, alcohol consumption and the practicing of physical exercise are associated with a higher score in the aforementioned variables, thus indicating a greater degree of mental health. PMID- 22534039 TI - Multiple gamma-secretase product peptides are coordinately increased in concentration in the cerebrospinal fluid of a subpopulation of sporadic Alzheimer's disease subjects. AB - BACKGROUND: Alcadeinalpha (Alcalpha) is a neuronal membrane protein that colocalizes with the Alzheimer's amyloid-beta precursor protein (APP). Successive cleavage of APP by beta- and gamma-secretases generates the aggregatable amyloid beta peptide (Abeta), while cleavage of APP or Alcalpha by alpha- and gamma secretases generates non-aggregatable p3 or p3-Alcalpha peptides. Abeta and p3 Alcalpha can be recovered from human cerebrospinal fluid (CSF). We have previously reported alternative processing of APP and Alcalpha in the CSF of some patients with sporadic mild cognitive impairment (MCI) and AD (SAD). RESULTS: Using the sandwich enzyme-linked immunosorbent assay (ELISA) system that detects total p3-Alcalpha, we determined levels of total p3-Alcalpha in CSF from subjects in one of four diagnostic categories (elderly controls, MCI, SAD, or other neurological disease) derived from three independent cohorts. Levels of Abeta40 correlated with levels of total p3-Alcalpha in all cohorts. CONCLUSIONS: We confirm that Abeta40 is the most abundant Abeta species, and we propose a model in which CSF p3-Alcalpha can serve as a either (1) a nonaggregatable surrogate marker for gamma-secretase activity; (2) as a marker for clearance of transmembrane domain peptides derived from integral protein catabolism; or (3) both. We propose the specification of an MCI/SAD endophenotype characterized by co-elevation of levels of both CSF p3-Alcalpha and Abeta40, and we propose that subjects in this category might be especially responsive to therapeutics aimed at modulation of gamma-secretase function and/or transmembrane domain peptide clearance. These peptides may also be used to monitor the efficacy of therapeutics that target these steps in Abeta metabolism. PMID- 22534041 TI - Utility of fractional exhaled nitric oxide (F(E)NO) measurements in diagnosing asthma. AB - BACKGROUND: To facilitate the use of fractional exhaled nitric oxide (F(E)NO) as a clinical test, F(E)NO measurements need more clarification. AIM: We sought to evaluate the yield of F(E)NO measurement for the diagnosis of asthma and identify the determinants of F(E)NO in children. METHODS: Two hundred forty five consecutive steroid-naive patients aged 8-16 years with symptoms suggestive of asthma were included. Children were evaluated using F(E)NO measurements, questionnaires, skin prick tests, spirometries, and methacholine challenge tests. RESULTS: Asthma was diagnosed in 167 children. The sensitivity, specificity, and positive (PPV) and negative predictive values (NPV) of F(E)NO measurements for the diagnosis of asthma at the best cutoff value of 22 ppb were 56.9%, 87.2%, 90.5%, and 48.6%, respectively. At a cutoff value of 42 ppb, specificity and PPV were all 100% but at the cost of very low sensitivity (23.4%) and NPV (37.9%). Both atopy and asthma were identified as independent risk factors associated with high F(E)NO. The association of asthma with high F(E)NO was found only in atopic children because F(E)NO was low in non-atopic children regardless of asthma status. Although highest F(E)NO was observed in atopic asthmatic patients, 28% of these patients had F(E)NO values lower than 22 ppb. CONCLUSION: Atopic asthmatic patients with low F(E)NO values and non-atopic asthmatic patients were responsible for false-negative cases that might contribute to low sensitivity of F(E)NO measurements in diagnosing asthma. High specificity of F(E)NO measurements may help identify patients with atopic asthma among subjects with respiratory symptoms. PMID- 22534042 TI - Incidence and predictors of sudden death in patients having myocardial infarction -a population-based investigation in Taiwanese. PMID- 22534043 TI - Does left ventricular size impact on intrinsic right ventricular function in hypoplastic left heart syndrome? AB - BACKGROUND: The size of the remnant left ventricle (LV) may influence right ventricular function and thus long-term outcome in palliated hypoplastic left heart syndrome (HLHS). We therefore sought to assess the impact of the size of the hypoplastic LV on intrinsic RV function in HLHS patients after Fontan surgery. METHODS: Fifty-seven HLHS patients were studied 2.5 (range: 0.8-12.6) years after Fontan-type palliation with the pressure-volume conductance system. The patient cohort was divided into two groups according to the median LV area index (group 1: LV area index <= 1.33 cm(2)/m(2), n=29; group 2: LV area index>1.33 cm(2)/m(2), n=28). RESULTS: The slopes of the end systolic elastance (Ees) and the preload recruitable stroke work relation (Mw) were not different between group 1 and 2 (Ees: 2.70 +/- 1.92 vs. 3.68 +/- 2.68 mmHg/ml; Mw: 52.75 +/ 14.98 vs. 51.09 +/- 16.63 mmHg x ml; P=NS for all). Furthermore, the systolic responses to dobutamine were not statistically different between groups. However, the slope of the end diastolic stiffness (Eed) was higher in group 2 and catecholaminergic stimulation resulted in a decrease in Eed in group 2 (group 1: 0.40 +/- 0.26 vs. 0.52 +/- 0.45; group 2: 0.68 +/- 0.44 vs. 0.47 +/- 0.38 mmHg/ml, P<0.01). Furthermore Eed was lowest in patients with mitral atresia/aortic atresia, the anatomic subgroup with the smallest LV remnant. CONCLUSIONS: Intrinsic systolic RV function is not affected by the size of the hypoplastic LV in survivors of surgical palliation of HLHS. Diastolic stiffness, however, was higher in patients with a larger LV remnant. PMID- 22534044 TI - Increased dietary calcium intake is not associated with coronary artery calcification. PMID- 22534045 TI - Acute coronary syndrome and stable coronary artery disease: are they so different? Long-term outcomes in a contemporary PCI cohort. AB - BACKGROUND: Patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndromes (ACS) are known to have poorer short-term prognosis compared to stable coronary artery (CAD) patients undergoing elective PCI. Few studies have made direct comparison of long-term mortality between ACS and stable CAD patients undergoing PCI. The aim of our study was to compare the long-term mortality following PCI between patients with ACS and those with stable CAD. METHODS: We examined consecutive patients undergoing PCI with stenting at a tertiary referral hospital. Clinical, angiographic and biochemical data were collected and analysed. The primary outcome was all-cause mortality retrieved from the Statewide Death Registry database. RESULTS: Included were 1923 consecutive PCI patients (970 stable CAD and 953 ACS). The mean follow-up time was 4.1 years +/- 1.8 years. In-hospital mortality was 1.4% overall, seen exclusively in patients with ACS (n=28, 2.9%). Post-discharge mortality was 6.7% among patients with stable CAD and 10.5% for ACS (P<0.01). Multivariate predictors of post-discharge deaths for both groups included age (HR 1.08 per year, P<0.001) and impaired renal function (HR 2.49, P<0.001). Following adjustment for these factors, an ACS indication for PCI was not associated with greater post-discharge mortality (adjusted HR 1.18: 0.85-1.64, P=0.32). CONCLUSIONS: Patients undergoing PCI following an ACS have higher long-term mortality to those with stable CAD, which is potentially explained by a greater prevalence of comorbidities. This suggests that for the ACS population, contemporary interventional and medical management strategies may effectively and specifically counter the adverse prognostic impact of coronary instability and myocardial damage. PMID- 22534046 TI - Alternative ways to assess left atrial function in noncompaction cardiomyopathy by three-dimensional speckle-tracking echocardiography: (a case from the MAGYAR Path study). PMID- 22534047 TI - Implantable cardioverter defibrillator therapy activation for high risk patients with relatively well preserved left ventricular ejection fraction. Does it really work? AB - BACKGROUND: Current guidelines for the primary prevention of sudden cardiac death have used a left ventricular ejection fraction (LVEF) <= 35% as a critical point to justify implantable cardioverter defibrillator (ICD) implantation in post myocardial infarction patients and in those with nonischemic dilated cardiomyopathy. We compared mortality and ICD activation rates among different ICD group recipients using a cut-off value for LVEF <= 35%. METHODS: We followed up for a mean period of 41.1 months 495 ICD recipients (442 males, 65.6 years old, 68.9% post myocardial infarction patients, 422 with LVEF <= 35%). Prevention was considered primary in patients who fulfilled guidelines criteria or had inducible ventricular arrhythmia during programmed ventricular stimulation for patients with LVEF >35%. RESULTS: Over the course of the trial, 84 of 495 patients died; 69 experienced cardiac death (6 sudden) and 15 non cardiac death. ICD recipients with LVEF <= 35% compared to those with preserved LVEF (mean LVEF=43%) had a greater incidence of total mortality (18% vs. 11%, log rank p=0.028) and cardiac death (15.4% vs. 5.5%, log rank p=0.005). There was no difference in the incidence for appropriate device therapy between patients with LVEF <= 35% and those with LVEF >35% (56.9% vs. 65.8%, log rank p=0.93). In the multivariate analysis the presence of advanced New York Heart Association stage predicted both total mortality (HR=2.69, 95% CI 1.771-4.086) and cardiac death (HR=3.437, 95% CI 2.163-5.463). CONCLUSIONS: ICD therapy may protect heart failure patients at early stages from arrhythmic morbidity and mortality, based on an electrophysiology-guided risk stratification approach. PMID- 22534048 TI - Premenstrual syndrome (PMS): a peri-menopausal perspective. AB - PMS (premenstrual syndrome) affects 30-40% of the reproductive female population and hence creates significant impairment amongst women of working age [1]. Having such an economical and financial impact makes it an important disorder to know more about in terms of diagnosis and treatment. In this article, as well as addressing diagnosis and treatments, we focus mainly on peri-menopausal women who are equally (if not more) affected by this disorder and who are subjected to PMS via a host of widely used hormonal treatments. We describe the vicious cycle that exists between exogenous progestogen stimulating PMS-like symptoms and the progestogen that is required for endometrial protection and ways of avoiding this. The treatment should address all concerns of the individual, namely contraceptive requirements, control of PMS and menopausal symptoms. The main theory behind treatment of PMS is to suppress ovulation along the hypothalamo pituitary-ovarian axis, however neurotransmitters are also implicated in reducing sensitivity to progesterone via receptors, and therefore selective serotonin reuptake inhibitors are also useful. Surgical methods are strongly discouraged and are a last resort. With so many pitfalls, this article aims to tackle the issues commonly encountered with diagnosis and treatment of PMS in the peri menopause. PMID- 22534049 TI - Intra coronary freshly isolated bone marrow cells transplantation improve cardiac function in patients with ischemic heart disease. AB - BACKGROUND: Autologous bone marrow cell transplantation (BMCs-Tx) is a promising novel option for treatment of cardiovascular disease. In this study we analyzed whether intracoronary autologous freshly isolated BMCs-Tx have beneficial effects on cardiac function in patients with ischemic heart disease (IHD). RESULTS: In this prospective nonrandomized study we treated 12 patients with IHD by freshly isolated BMCs-Tx by use of point of care system and compared them with a representative 12 control group without cell therapy. Global ejection fraction (EF) and infarct size area were determined by left ventriculography.Intracoronary transplantation of autologous freshly isolated BMCs led to a significant reduction of infarct size (p < 0.001) and an increase of global EF (p = 0.003) as well as infarct wall movement velocity (p < 0.001) after 6 months follow-up compared to control group. In control group there were no significant differences of global EF, infarct size and infarct wall movement velocity between baseline and 6 months after coronary angiography. Furthermore, we found significant decrease in New York Heart Association (NYHA) as well as significant decrease of B-type natriuretic peptide (BNP) level 6 months after intracoronary cell therapy (p < 0.001), whereas there were no significant differences in control group 6 months after coronary angiography. CONCLUSIONS: These results demonstrate that intracoronary transplantation of autologous freshly isolated BMCs by use of point of care system is safe and may lead to improvement of cardiac function in patients with IHD. TRIAL REGISTRATION: REGISTRATION NUMBER: ISRCTN54510226. PMID- 22534050 TI - Ginsenoside Rg1 protection against beta-amyloid peptide-induced neuronal apoptosis via estrogen receptor alpha and glucocorticoid receptor-dependent anti protein nitration pathway. AB - Ginsenoside Rg1 (Rg1) acts as a neuroprotective agent against various insults, however, the underlying mechanism has not been fully elucidated yet. Here, we report that Rg1 protects primary rat cerebrocortical neurons against beta-amyloid peptide25-35 (Abeta25-35) injury via estrogen receptor alpha (ERalpha) and glucocorticoid receptor (GR)-dependent anti-protein nitration pathway. In primary rat cerebrocortical neuron cultures under basal conditions, Rg1 leads to nuclear translocation of ERalpha and GR, induces related responsive gene PR, pS2 and MKP 1, SGK transcription. Meantime, Rg1 also increases the basal level of ERK1/2 phosphorylation. In the presence of toxic level of Abeta25-35, Rg1 maintains ERK1/2 phosphorylation, attenuates iNOS expression, NO production, and inhibits NF-kappaB nuclear translocation, protein nitration and cell death. The antiapoptotic effects of Rg1 via both ERalpha and GR were abolished by small interfering RNAs (siRNA). ERK1/2 phosphorylation inhibitor U0126 can block downstream iNOS expression and NO generation. Interestingly, the anti-protein nitration effect of Rg1 is well matched with ERalpha and GR activation, although its anti-ROS production effect is in an ERalpha- and GR-independent manner. These results suggest that Rg1 ameliorates Abeta25-35-induced neuronal apoptosis at least in part by two complementary ERalpha- and GR-dependent downstream pathways: (1) upregulation of ERK1/2 phosphorylation followed by inhibiting iNOS expression, NO generation and protein tyrosine nitration. (2) reduction NF-kappaB nuclear translocation. These data provide new understanding into the mechanisms of Rg1 anti-apoptotic functions after Abeta25-35 exposure, suggesting that ERalpha and GR-dependent anti-protein tyrosine nitration pathway might take an important role in the neuroprotective effect of Rg1. PMID- 22534051 TI - Clopidogrel response up to six months after acute myocardial infarction. AB - High on-treatment platelet reactivity (HTPR) despite clopidogrel therapy is associated with adverse cardiac events after acute myocardial infarction (AMI). Most studies to date have assessed clopidogrel response at a single time point before or after percutaneous coronary intervention (PCI). It is unclear, however, whether the HTPR phenotype is stable over time. Therefore, we aimed to examine response to clopidogrel in patients with AMI treated with PCI over a 6-month period. Patients (n = 57) with AMI treated with PCI were assessed for response to clopidogrel at 3 time points: in hospital, 30 days, and 6 months after index hospitalization. Response to clopidogrel was determined by the VerifyNow P2Y12 assay (reported as P2Y12 response units) and multiple electrode aggregometry (MEA; reported as aggregation units). HTPR was defined as >=235 P2Y12 response units or >=47 aggregation units. Patients' mean age was 54.5 +/- 10.9 years, 91% were men, 19% had diabetes, and 74% were admitted with ST-segment elevation MI. HTPR based on MEA was observed in 22.8% of patients in hospital, 26.3% at 30 days, and 17.5% at 6 months (p = NS). HTPR based on the VerifyNow assay was observed in 38.6% of patients in hospital, 28.1% at 30 days, and 33.3% at 6 months (p = NS). Individual HTPR phenotypic assignment at baseline was stable in 73.7% (based on MEA) and 70.2% (based on VerifyNow) of patients at 6-month follow up. In conclusion, this is the first study evaluating the stability of clopidogrel response over time after AMI. Rates of HTPR to clopidogrel therapy appear to be relatively stable up to 6 months after AMI. PMID- 22534052 TI - Delaying primary percutaneous coronary intervention for computed tomographic scans in the emergency department. AB - Patients presenting with suspected ST-segment elevation myocardial infarction (STEMI) may have important alternative diagnoses (e.g., aortic dissection, pulmonary emboli) or safety concerns for STEMI management (e.g., head trauma). Computed tomographic (CT) scanning may help in identifying these alternative diagnoses but may also needlessly delay primary percutaneous coronary intervention (PCI). We analyzed the ACTIVATE-SF Registry, which consists of consecutive patients with a clinical diagnosis of STEMI admitted to the emergency departments of 2 urban hospitals. Of 410 patients with a suspected diagnosis of STEMI, 45 (11%) underwent CT scanning before primary PCI. Presenting electrocardiograms, baseline risk factors, and presence of an angiographic culprit vessel were similar in those with and without CT scanning before PCI. Only 2 (4%) of these CT scans changed clinical management by identifying a stroke. Patients who underwent CT scanning had far longer door-to-balloon times (median 166 vs 75 minutes, p <0.001) and higher in-hospital mortality (20% vs 7.8%, p = 0.006). After multivariate adjustment, CT scanning in the emergency department before primary PCI remained independently associated with longer door to-balloon times (100% longer, 95% confidence interval 60 to 160, p <0.001) but was no longer associated with mortality (odds ratio 1.4, p = 0.5). In conclusion, CT scanning before primary PCI rarely changed management and was associated with significant delays in door-to-balloon times. More judicious use of CT scanning should be considered. PMID- 22534053 TI - Cardiologist concordance with the American College of Cardiology appropriate use criteria for cardiac testing in patients with coronary artery disease. AB - The American College of Cardiology Appropriate Use Criteria (AUC) were developed to guide use of myocardial perfusion single-photon emission computed tomography (MPS), stress echocardiography, and cardiac computed tomographic angiography (CCTA). To date, cardiologist application of AUC from a patient-based multiprocedure perspective has not been evaluated. A Web-based survey of 15 clinical vignettes spanning a wide spectrum of indications for MPS, STE, and CCTA in coronary artery disease was administered to cardiologists who rated the ordered test as appropriate, inappropriate, or uncertain by AUC application and suggested a preferred alternative imaging procedure, if any. In total 129 cardiologists responded to the survey (mean age 49.5 years, board certification for MPS 65%, echocardiography 39%, CCTA 32%). Cardiologists agreed with published AUC ratings 65% of the time, with differences in all categories (appropriate, 50% vs 53%; inappropriate, 42% vs 20%; uncertain, 9% vs 27%, p <0.0001 for all comparisons). Physician age, practice type, or board certification in MPS or echocardiography had no effect on concordance with AUC ratings, with slightly higher agreement for those board certified in CCTA (68% vs 64%, p = 0.04). Cardiologist procedure preference was positively associated with active clinical interpretation of MPS and CCTA (p = 0.03 for the 2 comparisons) but not for ownership of the respective imaging equipment. In conclusion, cardiologist agreement with published AUC ratings is generally high, although physicians classify more uncertain indications as inappropriate. Active clinical interpretation of a procedure contributes most to increased procedure preference. PMID- 22534054 TI - Comparison of usefulness of Sokolow and Cornell criteria for left ventricular hypertrophy in subjects aged <20 years versus >30 years. AB - The use of electrocardiography in sports or military screening is considered an effective tool for diagnosing potentially fatal conditions. The present study was designed to compare the yield of electrocardiographic criteria for left ventricular hypertrophy (LVH) criteria for the diagnosis of LVH and hypertrophic obstructive cardiomyopathy in subjects aged <20 years and >30 years. The association between the electrocardiographic (ECG) criteria for LVH (ECG-LVH) and echocardiographic findings was compared in 4 groups of air force academy candidates: (1) young candidates undergoing echocardiography because of ECG-LVH findings (n = 666); (2) young candidates without ECG-LVH findings undergoing routine echocardiography (n = 4,043); (3) older designated aviators undergoing echocardiography because of ECG-LVH findings (n = 196); and (4) older designated aviators undergoing routine echocardiography without ECG-LVH findings (n = 1,098). The predictive value of ECG-LVH findings for echocardiographic LVH, left ventricular mass, posterior wall thickness, and interventricular septal thickness were compared among the 4 groups. The ECG criteria in young subjects correlated with the left ventricular mass and posterior wall thickness but not with the interventricular septal thickness. In older subjects, these criteria correlated with left ventricular mass, interventricular septal, and posterior wall thickness. The positive and negative predictive value of ECG-LVH findings for the echocardiographic diagnosis of LVH in young subjects was 6.0% and 99.0%, respectively. In older subjects the positive and negative predictive value of ECG LVH findings was 34% and 93%, respectively. In conclusion, ECG criteria are probably a useful tool for exclusion of LVH in young and older subjects; however, their low positive predictive value would probably lead to unnecessary echocardiographic tests, particularly in young subjects. PMID- 22534055 TI - Changes in left ventricular morphology and function after mitral valve surgery. AB - Degenerative mitral valve disease is the leading cause of mitral regurgitation in North America. Surgical intervention has hinged on the symptoms and ventricular changes that develop as compensatory ventricular remodeling occurs. In the present study, we sought to characterize the temporal response of left ventricular (LV) morphology and function to mitral valve surgery for degenerative disease and to identify the preoperative factors that influence reverse remodeling. From 1986 to 2007, 2,778 patients with isolated degenerative mitral valve disease underwent valve repair (n = 2,607 [94%]) or replacement (n = 171 [6%]) and had >=1 postoperative transthoracic echocardiogram; 5,336 transthoracic echocardiograms were available for analysis. Multivariate longitudinal repeated measures analysis was performed to identify the factors associated with reverse remodeling. The LV dimensions decreased in the first year after surgery (end diastolic from 5.7 +/- 0.80 to 4.9 +/- 1.4 cm; end-systolic from 3.4 +/- 0.71 to 3.1 +/- 1.4 cm). The LV mass index decreased from 139 +/- 44 to 112 +/- 73 g/m(2). The reduction in LV hypertrophy was less pronounced in patients with greater preoperative left heart enlargement (p <0.0001) and a greater preoperative LV mass (p <0.0001). The postoperative LV ejection fraction initially decreased from 58 +/- 7.0% to 53 +/- 20%, increased slightly during the first postoperative year, and was negatively influenced by preoperative heart failure symptoms (p <0.0001) and a lower preoperative LV ejection fraction (p <0.0001). The risk-adjusted response of LV morphology and function to valve repair and replacement was similar (p >0.2). In conclusion, a positive response toward normalization of LV morphology and function after mitral valve surgery is greatest in the first year. The best response occurs when surgery is performed before left heart dilation, LV hypertrophy, or LV dysfunction develop. PMID- 22534057 TI - Toward a better understanding of kidney stone disease: platinum priorities. PMID- 22534056 TI - Which fish should I eat? Perspectives influencing fish consumption choices. AB - BACKGROUND: Diverse perspectives have influenced fish consumption choices. OBJECTIVES: We summarized the issue of fish consumption choice from toxicological, nutritional, ecological, and economic points of view; identified areas of overlap and disagreement among these viewpoints; and reviewed effects of previous fish consumption advisories. METHODS: We reviewed published scientific literature, public health guidelines, and advisories related to fish consumption, focusing on advisories targeted at U.S. populations. However, our conclusions apply to groups having similar fish consumption patterns. DISCUSSION: There are many possible combinations of matters related to fish consumption, but few, if any, fish consumption patterns optimize all domains. Fish provides a rich source of protein and other nutrients, but because of contamination by methylmercury and other toxicants, higher fish intake often leads to greater toxicant exposure. Furthermore, stocks of wild fish are not adequate to meet the nutrient demands of the growing world population, and fish consumption choices also have a broad economic impact on the fishing industry. Most guidance does not account for ecological and economic impacts of different fish consumption choices. CONCLUSION: Despite the relative lack of information integrating the health, ecological, and economic impacts of different fish choices, clear and simple guidance is necessary to effect desired changes. Thus, more comprehensive advice can be developed to describe the multiple impacts of fish consumption. In addition, policy and fishery management interventions will be necessary to ensure long-term availability of fish as an important source of human nutrition. PMID- 22534058 TI - Prospective randomised controlled trial of transobturator tapes in management of urodynamic stress incontinence in women: 3-year outcomes from the Evaluation of Transobturator Tapes study. AB - BACKGROUND: There is a lack of information on the long-term outcomes of transobturator tension-free vaginal tape (TO-TVT) in the surgical treatment of female stress urinary incontinence (SUI). OBJECTIVES: To assess the 3-yr outcomes following TO-TVT and to compare the effectiveness of inside-out versus outside-in approaches. DESIGN, SETTING, AND PARTICIPANTS: A 3-yr follow-up study of the Evaluation of Transobturator Tapes (E-TOT) trial, a randomised controlled trial (RCT) conducted with women undergoing TO-TVT as a sole procedure between April 2005 and April 2007 in a tertiary urogynaecology centre in the United Kingdom. INTERVENTION: Patients (n=341) were randomised to undergo either TVT-O (Ethicon Inc., Somerville, NJ, USA) for the inside-out approach or TOT-Aris (Coloplast Corp., Minneapolis, MN, USA) for the outside-in approach. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was patient-reported success rate. Secondary outcomes included further treatment for SUI, improvement in quality of life, late complications, and risk factors for late failures. Categorical variables were compared using the chi-square or Fisher exact test. Within-group comparison was undertaken using Wilcoxon and Mann-Whitney tests. Risk factors for late failures were assessed in a multivariate regression model. All statistical analysis was performed using SPSS v.18.0 (IBM Corp., Armonk, NY, USA). RESULTS AND LIMITATIONS: The 3-yr follow-up was completed by 238 of the 341 women (70%). The overall success rate, based on Patient's Global Impression of Improvement response, was 73.1%, with no significant difference between the inside-out and the outside-in TO-TVT (73.18% vs 72.3%; odds ratio: 0.927; 95% confidence interval, 0.552-1.645; p=0.796). Compared with the 1-yr follow-up, there was a significant reduction in the patient-reported success rate (p=0.005); however, no independent risk factors were identified. A clinically significant improvement (>=10 points) was seen in 80% (n=191) of women, with no significant difference between both groups (p=0.113). Twenty-two women (6%) underwent further surgical treatment within 3 yr. The lack of an objective outcome assessment is a potential limitation of this RCT. CONCLUSIONS: The E-TOT RCT showed a 73% patient-reported success rate for TO-TVT at 3-yr follow-up, with no significant differences between inside-out and outside-in approaches. There was a significant drop in patient-reported success rates between 1 and 3 yr. PMID- 22534060 TI - Coating thickness affects surface stress measurement of brush electro-plating nickel coating using Rayleigh wave approach. AB - A surface ultrasonic wave approach was presented for measuring surface stress of brush electro-plating nickel coating specimen, and the influence of coating thickness on surface stress measurement was discussed. In this research, two Rayleigh wave transducers with 5MHz frequency were employed to collect Rayleigh wave signals of coating specimen with different static tensile stresses and different coating thickness. The difference in time of flight between two Rayleigh wave signals was determined based on normalized cross correlation function. The influence of stress on propagation velocity of Rayleigh wave and the relationship between the difference in time of flight and tensile stress that corresponded to different coating thickness were discussed. Results indicate that inhomogeneous deformation of coating affects the relationship between the difference in time of flight and tensile stress, velocity of Rayleigh wave propagating in coating specimen increases with coating thickness increasing, and the variation rate reduces of difference in time of flight with tensile stress increasing as coating thickness increases. PMID- 22534059 TI - Comorbidity and performance indices as predictors of cancer-independent mortality but not of cancer-specific mortality after radical cystectomy for urothelial carcinoma of the bladder. AB - BACKGROUND: Comorbidity and performance indices allow assessment of preoperative health status. However, the optimal tool for use in patients with urothelial carcinoma of the bladder (UCB) who are undergoing radical cystectomy (RC) has not yet been established. OBJECTIVE: To evaluate correlation of Adult Comorbidity Evaluation-27 (ACE27), Charlson Comorbidity Index, Age-Adjusted Charlson Comorbidity Index, Eastern Cooperative Oncology Group performance status, and American Society of Anesthesiologists (ASA) score with survival. DESIGN, SETTING, AND PARTICIPANTS: A retrospective multicenter study was carried out on 555 unselected consecutive patients who underwent RC for UCB from 2000 to 2010. INTERVENTION: RC with pelvic lymph node dissection in patients with UCB without neoadjuvant chemotherapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cox regression models were calculated with established variables to assess predictive capacity for cancer-specific mortality (CSM) and cancer-independent mortality (CIM). RESULTS AND LIMITATIONS: All indices were independent predictors for CIM but not for CSM. The ASA score was the only index that significantly increased the predictive accuracy of the predefined CIM model (+2.3%; p=0.045). To create a clinically valuable tool, we devised a weighted prognostic model including age and the best prognosticators within the performance and comorbidity scores (ASA/ACE27 0-1/2-3). A 3-yr CIM rate of 8%, 26%, and 47% was calculated for the low-, intermediate-, and high-risk groups, respectively. Patients >75 yr of age with ASA 3/4 and ACE27 >1 exhibited a CIM risk seven times greater than patients <=75 yr with ASA 1/2 and ACE27 0/1. This study is limited by the short follow-up and its retrospective nature. CONCLUSIONS: Comorbidity and performance assessment is mandatory in the preoperative prediction of CIM for patients undergoing RC for UCB. The present results indicate that the ASA score is the tool of choice. External and prospective validation is warranted. PMID- 22534061 TI - Rate effect on mechanical properties of hydraulic concrete flexural-tensile specimens under low loading rates using acoustic emission technique. AB - Acoustic emission (AE) waveform is generated by dislocation, microcracking and other irreversible changes in a concrete material. Based on the AE technique (AET), this paper focuses on strain rate effect on physical mechanisms of hydraulic concrete specimens during the entire fracture process of three point bending (TPB) flexural tests at quasi-static levels. More emphasis is placed on the influence of strain rate on AE hit rate and AE source location around peak stress. Under low strain rates, namely 0.77*10(-7)s(-1), 1*10(-7)s(-1) to 1*10( 6)s(-1) respectively, the results show that the tensile strength increases as the strain rate increases while the peak AE hit rate decreases. Meanwhile, the specimen under a relatively higher strain rate shows a relatively wider intrinsic process zone in a more diffuser manner, lots of distributed microcracks relatively decrease stress intensity, thus delay both microcracking localization and macrocrack propagation. These phenomena can be attributed to Stefan effect. In addition, further tests, namely the combination of AE monitoring and strain measuring systems was designed to understand the correlation between AE event activity and microfracture (i.e., microcracking and microcracking localization). The relative variation trend of cumulative AE events accords well with that of the load-deformation curve. PMID- 22534062 TI - Controlled cell aggregation in a pulsed acoustic field. AB - Cell aggregation in ultrasonic resonators can be obtained in a few seconds. Hundreds even thousands of cells can be levitated in suspension and generate 2D or 3D aggregates. Nevertheless, the aggregation rate and the 2D or 3D configurations of the resultant aggregates are very difficult to control. This work reports on a novel way of generating and controlling particle and cell aggregates using pulsed ultrasound. This technique specifically explores (in addition to the ultrasound wave, frequency and amplitude) the time of ultrasound application, i.e. the number of pulses as well as the pulse repetition frequency. We demonstrate that with pulsed ultrasound, particles and/or cells levitate in suspension, as with continuous ultrasound, and the aggregation rate can be modified in a controlled manner. By carefully tuning the number of pulses and the repetition frequency, the 3-D and 2-D configurations of the aggregates can be selectively generated. In addition, pulsed ultrasound limits transducer heating, thus allowing for higher acoustic energies than those currently employed with continuous ultrasound. PMID- 22534063 TI - Tissue specificity in nickel uptake and induction of oxidative stress in kidney and spleen of goldfish Carassius auratus, exposed to waterborne nickel. AB - Toxic and carcinogenic effects of nickel compounds are suggested to result from nickel-mediated oxidative damage to macromolecules and/or inhibition of cellular antioxidant defenses. We investigated the effects of waterborne Ni(2+) (10, 25 and 50 mg/L) on the blood and blood-producing tissues (kidney and spleen) of goldfish to identify relationships between Ni accumulation and oxidative stress. Whereas the main hematological parameters (total hemoglobin and hematocrit) were unaffected, Ni(2+) exposure had substantial influence on goldfish immune system, causing lymphopenia. Ni accumulation increased renal iron content (by 49-78%) and resulted in elevated lipid peroxide (by 29%) and protein carbonyl content (by 274 278%), accompanied by suppression of the activities of superoxide dismutase (by 50-53%), glutathione peroxidase (15-45%), glutathione reductase (31-37%) and glucose-6-phosphate dehydrogenase (20-44%), indicating development of oxidative stress in kidney. In contrast to kidney, in spleen the activation of glutathione peroxidase (by 34-118%), glutathione-S-transferase (by 41-216%) and glutathione reductase (by 47%), as well as constant levels of low molecular mass thiols and metals together with enhanced activity of glucose-6-phosphate dehydrogenase (by 41-94%) speaks for a powerful antioxidant potential that counteracts Ni-induced ROS production. Further, as Ni accumulation in this organ was negligible, Ni toxicity in spleen may be minimized by efficient exclusion of this otherwise toxic metal. PMID- 22534064 TI - Apoptosis-inducing factor downregulation increased neuronal progenitor, but not stem cell, survival in the neonatal hippocampus after cerebral hypoxia-ischemia. AB - BACKGROUND: A considerable proportion of all newly generated cells in the hippocampus will die before becoming fully differentiated, both under normal and pathological circumstances. The caspase-independent apoptosis-inducing factor (AIF) has not been investigated previously in this context. RESULTS: Postnatal day 8 (P8) harlequin (Hq) mutant mice, expressing lower levels of AIF, and wild type littermates were injected with BrdU once daily for two days to label newborn cells. On P10 mice were subjected to hypoxia-ischemia (HI) and their brains were analyzed 4 h, 24 h or 4 weeks later. Overall tissue loss was 63.5% lower in Hq mice 4 weeks after HI. Short-term survival (4 h and 24 h) of labeled cells in the subgranular zone was neither affected by AIF downregulation, nor by HI. Long-term (4 weeks) survival of undifferentiated, BLBP-positive stem cells was reduced by half after HI, but this was not changed by AIF downregulation. Neurogenesis, however, as judged by BrdU/NeuN double labeling, was reduced by half after HI in wild type mice but preserved in Hq mice, indicating that primarily neural progenitors and neurons were protected. A wave of cell death started early after HI in the innermost layers of the granule cell layer (GCL) and moved outward, such that 24 h after HI dying cells could be detected in the entire GCL. CONCLUSIONS: These findings demonstrate that AIF downregulation provides not only long-term overall neuroprotection after HI, but also protects neural progenitor cells, thereby rescuing hippocampal neurogenesis. PMID- 22534066 TI - Envelope solitons in acoustically dispersive vitreous silica. AB - Acoustic radiation-induced static strains, displacements, and stresses are manifested as rectified or 'dc' waveforms linked to the energy density of an acoustic wave or vibrational mode via the mode nonlinearity parameter of the material. An analytical model is developed for acoustically dispersive media that predicts the evolution of the energy density of an initial waveform into a series of energy solitons that generates a corresponding series of radiation-induced static strains (envelope solitons). The evolutionary characteristics of the envelope solitons are confirmed experimentally in Suprasil W1 vitreous silica. The value (- 11.9 +/- 1.43) for the nonlinearity parameter, determined from displacement measurements of the envelope solitons via a capacitive transducer, is in good agreement with the value (- 11.6 +/- 1.16) obtained independently from acoustic harmonic generation measurements. The agreement provides strong, quantitative evidence for the validity of the model. PMID- 22534065 TI - Control of Abeta release from human neurons by differentiation status and RET signaling. AB - Few studies have compared the processing of endogenous human amyloid precursor protein (APP) in younger and older neurons. Here, we characterized LUHMES cells as a human model to study Alzheimer's disease-related processes during neuronal maturation and aging. Differentiated LUHMES expressed and spontaneously processed APP via the secretase pathways, and they secreted amyloid beta (Abeta) peptide. This was inhibited by cholesterol depletion or secretase inhibition, but not by block of tau phosphorylation. In vitro aged cells increased Abeta secretion without upregulation of APP or secretases. We identified the medium constituent glial cell line-derived neurotrophic factor (GDNF) as responsible for this effect. GDNF-triggered Abeta release was associated with rapid upregulation of the GDNF coreceptor "rearranged during transfection" (RET). Other direct (neurturin) or indirect (nerve growth factor) RET activators also increased Abeta, whereas different neurotrophins were ineffective. Downstream of RET, we found activation of protein kinase B (AKT) to be involved. Accordingly, inhibitors of the AKT regulator phosphatidylinositol-3-kinase completely blocked GDNF-triggered AKT phosphorylation and Abeta increase. This suggests that RET signaling affects Abeta release from aging neurons. PMID- 22534067 TI - Mitigating 1,3-dichloropropene, chloropicrin, and methyl iodide emissions from fumigated soil with reactive film. AB - Implicated as a stratospheric ozone-depleting compound, methyl bromide (MeBr) is being phased out despite being considered to be the most effective soil fumigant. Its alternatives, i.e., 1,3-dichloropropene (1,3-D, which includes cis and trans isomers), chloropicrin (CP), and methyl iodide (MeI), have been widely used. High emissions of MeI from fumigated soil likely put farm workers and other bystanders at risk of adverse health effects. In this study, two types of constructed reactive film were tested for their ability to mitigate emissions of 1,3-D, CP, and MeI using laboratory permeability cells. Before activation, these films act as a physical barrier to trap fumigants leaving soil. After activation of the reactive layer containing ammonium thiosulfate solution, the films also act as a sink for the fumigants. Over 97% of trans-1,3-D and 99% of the cis-1,3-D, CP and MeI were depleted when they passed into the reactive film. Half-lives (t(1/2)) of cis-, trans-1,3-D, CP and MeI under activated reactive film were 1.2, 1.4, 1.6, and 2.0 h respectively at 40 degrees C. PMID- 22534068 TI - Tissue-wide overexpression of alpha-T-catenin results in aberrant trophoblast invasion but does not cause embryonic mortality in mice. AB - Transcriptional activation of CTNNA3, encoding alphaT-catenin, by the Y153H mutated form of the human STOX1 transcription factor was proposed to be responsible for altered fetal trophoblast invasion into the maternal endometrium during placentation in pre-eclampsia. Here we have generated a mouse model to investigate the in vivo effects of ectopic alphaT-catenin expression on trophoblast invasion. Histological analysis was used to determine the invasive capacities of trophoblasts from transgenic embryos, as well as proliferation rates of spongiotrophoblasts in the junctional zone. Augmented expression of alphaT-catenin reduced the number of invading trophoblasts but did not cause embryonic mortality. The, alphaT-catenin positive cells could still invade into the decidual layer and migrated as deeply as wild-type trophoblasts. Furthermore, the junctional zone is enlarged in placentas of mice overexpressing alphaT catenin due to hyperproliferation of the residing spongiotrophoblasts, suggesting a pivotal role of alphaT-catenin levels in the control of the proliferative versus invasive state of trophoblasts during placentation. Our study provides, for the first time, in vivo data on the effects of increased levels of alphaT catenin in the placenta. PMID- 22534069 TI - Surgical indications for arthroscopic management of femoroacetabular impingement. AB - PURPOSE: The clinical literature was systematically reviewed to determine the consistently reported indications for arthroscopic management of femoroacetabular impingement (FAI). METHODS: Two databases (Medline and EMBASE) were screened for clinical studies involving the arthroscopic surgical management of FAI. A full text review of eligible studies was conducted, and the references were searched. Articles published from 1980 until June 2011 were included, and the inclusion criteria were as follows: studies of human patients of all ages and genders with FAI, studies with a minimum of 6 months of patient follow-up, and studies reporting clinical outcome data. A quality assessment of the included articles was conducted. RESULTS: We included 20 articles in this review, involving a total of 1,368 patients. We identified a lack of consensus on clinical and radiographic indications for the arthroscopic management of FAI. The indications varied from a positive impingement sign (45%) and symptoms or pain for more than 6 months (35%) to a series of positive special tests (25%). Commonly reported radiographic indicators for arthroscopic FAI management included the following: results from a computed tomography scan or magnetic resonance imaging (60%), cam or pincer lesions evident on anteroposterior and/or lateral radiographs (50%), loss of sphericity of the femoral neck (30%), acetabular retroversion (30%), magnetic resonance arthrography (25%), reduction in head-neck offset (25%), an alpha angle greater than 50 degrees (25%), and coxa profunda (25%). CONCLUSIONS: We found that there was great inconsistency among the indications for arthroscopic management of FAI. Clinical and radiographic indices remain largely unvalidated. This review highlights the need for more consistent reporting of surgical indications for the arthroscopic management of FAI. Future research should explore what combination of clinical and radiographic indications should be best used to determine arthroscopic FAI management. LEVEL OF EVIDENCE: Level IV, systematic review of Level II to IV studies. PMID- 22534070 TI - Comparison of a 6.5, 10, and 15 mm cryoablation catheter-tip for the treatment of common atrial flutter. AB - AIM: Only a few studies have investigated the effect of large tip sizes for catheter-based cryoablation (cryo). This study evaluates the safety and efficacy of cryo of the cavotricuspid isthmus (CTI) using three cryocatheter-tip sizes. METHODS AND RESULTS: Forty-five consecutive patients with common atrial flutter (AFL) underwent cryo of the CTI using a 6.5, a 10, or a novel 15 mm catheter-tip. Single applications of 3 min were delivered at each site along the CTI. Baseline characteristics of the three groups were comparable. The overall acute success rate was 89% and there was no difference with respect to the tip electrode size (P > 0.05). Fewer applications were required for a 10 mm (6 +/- 2, range 3-7) and a 15 mm (6 +/- 1, range 4-8) compared with a 6.5 mm catheter-tip (8 +/- 3, range 4-14; P < 0.05). Procedure time was significantly shorter with the largest tip electrode (89 +/- 26 min vs. 132 +/- 28 min (6.5 mm tip), P < 0.05). No complications occurred. After a mean follow-up of 51 +/- 5 months, 43 patients (96%) were without recurrence of AFL. CONCLUSIONS: A large (10 or 15 mm) cryoablation catheter-tip requires significantly fewer applications to create bidirectional CTI block compared with a 6.5 mm tip. A significant decrease in procedure time with preservation of the overall safety and efficacy supports the preference of a 15 over a 6.5 mm catheter-tip for cryoablation of AFL. PMID- 22534072 TI - Organic oxalate as leachant and precipitant for the recovery of valuable metals from spent lithium-ion batteries. AB - Spent lithium-ion batteries containing lots of strategic resources such as cobalt and lithium are considered as an attractive secondary resource. In this work, an environmentally compatible process based on vacuum pyrolysis, oxalate leaching and precipitation is applied to recover cobalt and lithium from spent lithium-ion batteries. Oxalate is introduced as leaching reagent meanwhile as precipitant which leaches and precipitates cobalt from LiCoO(2) and CoO directly as CoC(2)O(4).2H(2)O with 1.0 M oxalate solution at 80 degrees C and solid/liquid ratio of 50 g L(-1) for 120 min. The reaction efficiency of more than 98% of LiCoO(2) can be achieved and cobalt and lithium can also be separated efficiently during the hydrometallurgical process. The combined process is simple and adequate for the recovery of valuable metals from spent lithium-ion batteries. PMID- 22534071 TI - Main risk factors for Salmonella-infections in pigs in north-western Germany. AB - Salmonellosis is one of the major zoonotic, food-borne diseases, among others, caused by pig derived food products. As infected pigs are one of the main sources of the introduction of the bacterium into the food chain, scientific research in the last years has focussed on identifying risk factors for infection as well as developing mitigation strategies on this level of production. In order to update the knowledge of the German situation by incorporating recent changes in the German pig industry, a case-control study was set up to identify the key contributing risk factors for farms located in the western part of Lower Saxony, the region with the highest pig density in Germany. Based on an extensive and systematic literature search, a comprehensive questionnaire with 302 questions concerning such topics as personnel hygiene, animal management, biosecurity, feeding management as well as cleaning and disinfection routines was utilized in a face-to-face interview on 104 case and 67 control farms. Within a stepwise forward selection process the preliminary identified factors were grouped contextually, associations between variables were calculated and multivariable logistic regression models were conducted. Identified risk factors were: the moving of individual animals during the fattening period (OR 5.3, CI 95% 1.35 20.35), not having a separate transporter for different age groups (OR 11.4, CI 95% 1.94-66.18) and pigs having contact to other animals (OR 4.3, CI 95% 1.39 12.96). The following factors were identified as being protective: not cleaning the transporter (OR 0.2, CI 95% 0.05-0.72) and not having clean boots available (OR 0.2, CI 95% 0.07-0.64). While this study was able to identify some factors which influence the Salmonella-infection of a herd, overall the process of analysis showed that the control of Salmonella on farm is due to a series of individual factors and therefore remains extremely complex. PMID- 22534073 TI - First report of (homo)anatoxin-a and dog neurotoxicosis after ingestion of benthic cyanobacteria in The Netherlands. AB - In April and May 2011, three dogs died and one dog became ill after swimming in Lake IJmeer (The Netherlands). At the time, the lake was infested with the benthic cyanobacterial species Phormidium. A Eurasian Coot (Fulica atra) and a Black-headed Gull (Chroicocephalus ridibundus) also died near Lake IJmeer in the same period. One of the dogs and both birds were subjected to a pathological investigation. Furthermore, the Phormidium mat; algal samples from the dikes; contents of the animals' digestive systems and organ tissues were analysed for the following cyanobacterial toxins: (homo)anatoxin-a; (7-deoxy )cylindrospermopsin; saxitoxins and gonyautoxins by LC-MS/MS. Samples were also analysed for the nontoxic (homo)anatoxin-a metabolites dihydro(homo)anatoxin-a and epoxy(homo)anatoxin-a. The dog necropsy results indicated neurotoxicosis and its stomach contained Phormidium filaments. Anatoxin-a was detected in the Phormidium mat (272 MUg g-1) dry weight, stdev 65, n=3) and in the dog's stomach contents (9.5 MUg g-1 dry weight, stdev 2.4, n=3). Both samples also contained the anatoxin-a metabolite dihydroanatoxin-a, and a trace of homoanatoxin-a was detected in the Phormidium mat. The birds were in bad nutritive condition at the time of necropsy and their stomachs and intestines did not contain any cyanobacterial material. Furthermore, no cyanobacterial toxins were detected in their stomachs, intestines and organs and they both had lesions that are not associated with cyanobacterial intoxication. This is the first report of anatoxin a and homoanatoxin-a occurrence in The Netherlands, these toxins have likely caused the deaths of three dogs. The birds probably died of other causes. Dutch recreational waters are at this moment only screened for pelagic cyanobacterial species, the current bathing water protocol therefore does not protect humans and animals from negative effects of blooms of benthic cyanobacteria. PMID- 22534074 TI - Jararhagin, a hemorrhagic snake venom metalloproteinase from Bothrops jararaca. AB - Jararhagin is a metalloproteinase isolated from Bothrops jararaca snake venom, which has been extensively studied. These studies showed its involvement on most of the systemic and local damaging effects of snakebite envenomings. In this review we comment on the major targets of jararhagin as the vascular endothelium, platelets and coagulation factors and also its action on other cell systems as inflammatory cells and their mediators, cancer and cell signaling. The mechanisms of jararhagin action are discussed together with structural features essential for the expression of its biological activities. The studies reviewed here denote jararhagin as a prototype for studies of snake venom metalloproteinases, bringing new insights into cellular-matrix interactions and adding for the improvement of snakebite treatment. PMID- 22534075 TI - Reliability of KRAS mutation testing in metastatic colorectal cancer patients across five laboratories. AB - BACKGROUND: Mutations in the KRAS gene are associated with poor response to epidermal growth factor receptor inhibitors used in the treatment of metastatic colorectal cancer. Factors influencing KRAS test results in tumor specimens include: tumor heterogeneity, sample handling, slide preparation, techniques for tumor enrichment, DNA preparation, assay design and sensitivity. We evaluated comparability and consistency of KRAS test results among five laboratories currently being used to determine KRAS mutation status of metastatic colorectal cancer specimens in a large, multi-center observational study. FINDINGS: Twenty formalin-fixed paraffin-embedded human colorectal cancer samples from colon resections previously tested for KRAS mutations were selected based on mutation status (6 wild type, 8 codon 12 mutations, and 6 codon 13 mutations). We found good agreement across laboratories despite differences in mutation detection methods. Eighteen of twenty samples (90%) were concordant across all five labs. Discordant results are likely not due to laboratory error, but instead to tumor heterogeneity, contamination of the tumor sample with normal tissue, or analytic factors affecting assay sensitivity. CONCLUSIONS: Our results indicate commercial and academic laboratories provide reliable results for the common KRAS gene mutations at codons 12 and 13 when an adequate percentage of tumor cells is present in the sample. PMID- 22534076 TI - Multi-specialty family planning training: collaborating to meet the needs of women. PMID- 22534077 TI - Post-ovulatory administration of levonorgestrel: interference with implantation is not excluded. PMID- 22534079 TI - Clustering of maternal-fetal clinical conditions and outcomes and placental lesions. AB - OBJECTIVE: To identify by an inductive statistical analysis mutually similar and clinically relevant clinicoplacental clusters. STUDY DESIGN: Twenty-nine maternofetal and 49 placental variables have been retrospectively analyzed in a 3382 case clinicoplacental database using a hierarchical agglomerative Ward dendrogram and multidimensional scaling. RESULTS: The exploratory cluster analysis identified 9 clinicoplacental (macerated stillbirth, fetal growth restriction, placenta creta, acute fetal distress, uterine hypoxia, severe ascending infection, placental abruption, and mixed etiology [2 clusters]), 5 purely placental (regressive placental changes, excessive extravillous trophoblasts, placental hydrops, fetal thrombotic vasculopathy, stem obliterative endarteritis), and 1 purely clinical (fetal congenital malformations) statistically significant clusters/subclusters. The clusters of such variables like clinical umbilical cord compromise, preuterine and postuterine hypoxia, gross umbilical cord or gross chorionic disk abnormalities did not reveal statistically significant stability. CONCLUSION: Although clinical usefulness of several well-established placental lesions has been confirmed, claims about high predictability of others have not. PMID- 22534080 TI - Stochastic model search with binary outcomes for genome-wide association studies. AB - OBJECTIVE: The spread of case-control genome-wide association studies (GWASs) has stimulated the development of new variable selection methods and predictive models. We introduce a novel Bayesian model search algorithm, Binary Outcome Stochastic Search (BOSS), which addresses the model selection problem when the number of predictors far exceeds the number of binary responses. MATERIALS AND METHODS: Our method is based on a latent variable model that links the observed outcomes to the underlying genetic variables. A Markov Chain Monte Carlo approach is used for model search and to evaluate the posterior probability of each predictor. RESULTS: BOSS is compared with three established methods (stepwise regression, logistic lasso, and elastic net) in a simulated benchmark. Two real case studies are also investigated: a GWAS on the genetic bases of longevity, and the type 2 diabetes study from the Wellcome Trust Case Control Consortium. Simulations show that BOSS achieves higher precisions than the reference methods while preserving good recall rates. In both experimental studies, BOSS successfully detects genetic polymorphisms previously reported to be associated with the analyzed phenotypes. DISCUSSION: BOSS outperforms the other methods in terms of F-measure on simulated data. In the two real studies, BOSS successfully detects biologically relevant features, some of which are missed by univariate analysis and the three reference techniques. CONCLUSION: The proposed algorithm is an advance in the methodology for model selection with a large number of features. Our simulated and experimental results showed that BOSS proves effective in detecting relevant markers while providing a parsimonious model. PMID- 22534081 TI - Evaluating alert fatigue over time to EHR-based clinical trial alerts: findings from a randomized controlled study. AB - OBJECTIVE: Inadequate participant recruitment is a major problem facing clinical research. Recent studies have demonstrated that electronic health record (EHR) based, point-of-care, clinical trial alerts (CTA) can improve participant recruitment to certain clinical research studies. Despite their promise, much remains to be learned about the use of CTAs. Our objective was to study whether repeated exposure to such alerts leads to declining user responsiveness and to characterize its extent if present to better inform future CTA deployments. METHODS: During a 36-week study period, we systematically documented the response patterns of 178 physician users randomized to receive CTAs for an ongoing clinical trial. Data were collected on: (1) response rates to the CTA; and (2) referral rates per physician, per time unit. Variables of interest were offset by the log of the total number of alerts received by that physician during that time period, in a Poisson regression. RESULTS: Response rates demonstrated a significant downward trend across time, with response rates decreasing by 2.7% for each advancing time period, significantly different from zero (flat) (p<0.0001). Even after 36 weeks, response rates remained in the 30%-40% range. Subgroup analyses revealed differences between community-based versus university based physicians (p=0.0489). DISCUSSION: CTA responsiveness declined gradually over prolonged exposure, although it remained reasonably high even after 36 weeks of exposure. There were also notable differences between community-based versus university-based users. CONCLUSIONS: These findings add to the limited literature on this form of EHR-based alert fatigue and should help inform future tailoring, deployment, and further study of CTAs. PMID- 22534082 TI - The effectiveness of interventions using electronic reminders to improve adherence to chronic medication: a systematic review of the literature. AB - BACKGROUND: Many patients experience difficulties in adhering to long-term treatment. Although patients' reasons for not being adherent are diverse, one of the most commonly reported barriers is forgetfulness. Reminding patients to take their medication may provide a solution. Electronic reminders (automatically sent reminders without personal contact between the healthcare provider and patient) are now increasingly being used in the effort to improve adherence. OBJECTIVE: To examine the effectiveness of interventions using electronic reminders in improving patients' adherence to chronic medication. METHODS: A comprehensive literature search was conducted in PubMed, Embase, PsycINFO, CINAHL and Cochrane Central Register of Controlled Trials. Electronic searches were supplemented by manual searching of reference lists and reviews. Two reviewers independently screened all citations. Full text was obtained from selected citations and screened for final inclusion. The methodological quality of studies was assessed. RESULTS: Thirteen studies met the inclusion criteria. Four studies evaluated short message service (SMS) reminders, seven audiovisual reminders from electronic reminder devices (ERD), and two pager messages. Best evidence synthesis revealed evidence for the effectiveness of electronic reminders, provided by eight (four high, four low quality) studies showing significant effects on patients' adherence, seven of which measured short-term effects (follow-up period <6 months). Improved adherence was found in all but one study using SMS reminders, four studies using ERD and one pager intervention. In addition, one high quality study using an ERD found subgroup effects. CONCLUSION: This review provides evidence for the short-term effectiveness of electronic reminders, especially SMS reminders. However, long-term effects remain unclear. PMID- 22534083 TI - Comparison of the efficacy and safety of single-agent and doublet chemotherapy in advanced non-small cell lung cancer in the elderly: a meta-analysis. AB - BACKGROUND: In patients with advanced non-small cell lung cancer (NSCLC) aged more than 70 years, the benefit-to-risk ratio of doublet chemotherapy vs single agent is not established. METHODS: We performed a meta-analysis (MA), with a PubMed query using keywords simultaneously (Randomized controlled trial, Aged, Anti-neoplastic combined chemotherapy protocols/therapeutic use, Carcinoma, Non small cell lung/drug therapy). Abstracts from ASCO, WCLC, and ESMO proceedings were reviewed. Articles were also obtained by cross-checking references. Third generation agents (gemcitabine, vinorelbine, paclitaxel, docetaxel) in combination with or without platinum were included. The efficacy outcomes were Overall Response Rate (ORR) and 1-Year Overall Survival (OS). We used EasyMA software and a random-effect model in case of heterogeneity. RESULTS: This MA comprised 10 studies including 2605 patients (mean age 74; 1866 men and 620 women; 654 stage IIIB and 1677 stage IV; 839 squamous cell cancers, 968 adenocarcinomas, 521 other pathological types). One-year OS (including the last trial by Abe) did not significantly improve for doublets compared with single agents (HR 0.92; 95% Confidence Interval or CI: 0.82-1.03) whereas it improved significantly before inclusion of this last study, when the study by Quoix et al., the most favorable to doublets, was included. However, doublet chemotherapy significantly improved ORR after inclusion of Abe study (HR 1.51; 1.22-1.86; p<0.001). OS was not significantly improved, neither by doublets including platinum (HR 0.90, 0.70-1.16), nor by those without platinum (HR 0.94, 0.84 1.07). ORR, but not OS, was improved by doublets including a taxane (docetaxel and paclitaxel) (HR 1.72; 1.28-2.33) except for paclitaxel with a significant OS and ORR benefit. All-grade neutropenia thrombocytopenia and anemia were significantly more frequent with doublets than with single-agents (HR 1.26, 1.15 1.39; 1.75, 1.11-2.77 and 1.33, 1.17-1.52 respectively). Grade 3/4 thrombocytopenia and anemia but not neutropenia were significantly more frequent with doublets (HRs 2.13, 1.01-4.49 and 1.84, 1.29-2.63 respectively). CONCLUSION: Compared with single-agents, doublets significantly improved ORR but not OS. They induced significantly more frequent thrombocytopenia and anemia. The benefit-to risk ratio of doublets in advanced NSCLC might be more favorable than that of single agents, based on ORR but not OS. PMID- 22534085 TI - Paraneoplastic symptoms: cachexia, polycythemia, and hypercalcemia are, respectively, related to vascular endothelial growth factor (VEGF) expression in renal clear cell carcinoma. AB - OBJECTIVES: To evaluate whether there is a relation between expression of vascular endothelial growth factor (VEGF) and any of the paraneoplastic syndromes (PNS) in clear cell renal cell carcinoma (ccRCC) patients. MATERIALS AND METHODS: A total of 667 patients with ccRCC and at least one PNS were included. Thorough history taking, physical examinations, and laboratory tests were used to diagnose PNS. Immunohistochemistry was performed for VEGF evaluation. RESULTS: There were 10 different PNS identified in the population. Sixty patients had a single paraneoplastic presentation. In all patients, presence of cachexia (n = 267, P < 0.0001), polycythemia (n = 40, P = 0.0014), and hypercalcemia (n = 48, P = 0.0006) was correlated to VEGF expression. Correlation was neither acquired in Stauffer's syndrome, pyrexia, elevated erythrocyte sedimentation rate (ESR), anemia, thrombocytosis, hypertension, neuromyopathy nor obtained within patients with single PNS. CONCLUSIONS: Relations between PNS and VEGF expression in renal cell carcinoma (RCC) has not been studied yet. The results we gained hereby can help us further understand the mechanistic of PNS in RCC. PMID- 22534084 TI - Tipping the balance of autism risk: potential mechanisms linking pesticides and autism. AB - BACKGROUND: Autism spectrum disorders (ASDs) have been increasing in many parts of the world and a portion of cases are attributable to environmental exposures. Conclusive replicated findings have yet to appear on any specific exposure; however, mounting evidence suggests gestational pesticides exposures are strong candidates. Because multiple developmental processes are implicated in ASDs during gestation and early life, biological plausibility is more likely if these agents can be shown to affect core pathophysiological features. OBJECTIVES: Our objectives were to examine shared mechanisms between autism pathophysiology and the effects of pesticide exposures, focusing on neuroexcitability, oxidative stress, and immune functions and to outline the biological correlates between pesticide exposure and autism risk. METHODS: We review and discuss previous research related to autism risk, developmental effects of early pesticide exposure, and basic biological mechanisms by which pesticides may induce or exacerbate pathophysiological features of autism. DISCUSSION: On the basis of experimental and observational research, certain pesticides may be capable of inducing core features of autism, but little is known about the timing or dose, or which of various mechanisms is sufficient to induce this condition. CONCLUSIONS: In animal studies, we encourage more research on gene * environment interactions, as well as experimental exposure to mixtures of compounds. Similarly, epidemiologic studies in humans with exceptionally high exposures can identify which pesticide classes are of greatest concern, and studies focused on gene * environment are needed to determine if there are susceptible subpopulations at greater risk from pesticide exposures. PMID- 22534086 TI - Risk factors for biochemical recurrence following radical perineal prostatectomy in a large contemporary series: a detailed assessment of margin extent and location. AB - OBJECTIVES: The implications of positive surgical margin (PSM) extent and location during radical perineal prostatectomy (RPP) have not been assessed in a contemporary series. We aimed to examine the incidence, location, and extent of PSM as well as their impact on biochemical recurrence (BCR) following RPP. MATERIALS AND METHODS: A total of 794 patients underwent RPP by a single surgeon between June 1993 and August 2010. Covariates included age, pathologic T stage, pathologic Gleason sum, preoperative PSA, prostate volume, PSM extent, and location. Life table, Kaplan-Meier, and Cox regression analyses assessed predictors of BCR following RPP. RESULTS: PSM were recorded in 162 patients (20.4%); of these, 83 (51.2%) were focal (<= 1 mm) whereas 79 (48.8%) were broad (>1 mm). Location of PSM was anterior 10.5%, posterior or lateral 14.8%, bladder neck 23.5%, apical 32.1%, and multifocal 19.1%. At a median follow-up of 54 months, the 5-year BCR-free probability was 90.8% in patients with negative margins, 77.5% in patients with focal PSM, and 47.5% in patients with broad PSM. On multivariable analyses adjusted for age, pathologic T stage, pathologic Gleason sum, preoperative PSA, and prostate volume, broad PSM, (HR = 3.49, P < 0.001) as well as anterior (HR = 3.77, P = 0.003), bladder neck (HR = 2.25, P = 0.01) and multifocal (HR = 3.55, P < 0.001) PSM were independent predictors of BCR. CONCLUSIONS: In this study, we present oncologic outcomes following RPP in a large contemporary cohort of patients undergoing RPP. In adjusted analyses, broad and anterior PSM carried the highest risk of recurrence after RPP. PMID- 22534088 TI - Oncologic outcomes for lymph node-positive urothelial carcinoma patients treated with robot assisted radical cystectomy: with mean follow-up of 3.5 years. AB - PURPOSE: Previous studies have shown robot assisted radical cystectomy (RARC) to have comparable perioperative outcomes to open radical cystectomy. There are few reports that have examined the oncologic results of RARC, specifically with respect to lymph node-positive patients. We report the outcomes of pathologic node-positive patients who have undergone RARC with medium-term follow-up. MATERIALS AND METHODS: A total of 275 patients underwent RARC at 2 institutions for invasive bladder cancer between April 2005 and June 2009. We examined the 50 patients with lymph node-positive disease. Oncologic outcomes, overall, and recurrence-free survival were analyzed and compared with the open literature. RESULTS: Mean (median) clinical follow-up in this cohort was 42 (39.5) months (range 16-75 months). The mean (median) number of lymph nodes (LN) removed was 18 (17.5) (range 5-35), and mean (median) number of positive LN was 3 (2) (range 1 12). Mean lymph node density was 18%. Seventeen (34%) patients had <= pT2 disease and 33 (66%) pT3/T4 disease. At this follow-up, 29 patients have recurred, and 22 patients have died of disease. Mean (median) time to recurrence was 10 (9) months. The estimated overall survival at 36 and 60 months was 55%, and 45%, respectively. The recurrence-free survival at 36 and 60 months was 43%, and 39%, respectively. Thirty-three (66%) patients had an LN density <20%. The estimated overall survival at 36 months of patients with a lymph node density of <20% was higher than those with a lymph node density >20%, though the difference was not statistically significant. A total of 58% of patients received chemotherapy in this cohort. The use of chemotherapy was associated with a statistically significant (P = 0.033) improvement in overall survival, with an overall survival of 68% at 36 months compared with 36% for the patients who did not receive any chemotherapy. CONCLUSIONS: The oncologic outcomes of patients with lymph node positive bladder cancer treated with robot assisted radical cystectomy (RARC) compare favorably to previous published studies of open radical cystectomy at medium-term (mean follow-up of 42 months). As our follow-up increases, we expect to continue to accurately define the long-term clinical suitability and oncologic success of this procedure in this high-risk population. PMID- 22534087 TI - Retrospective analysis of survival outcomes and the role of cisplatin-based chemotherapy in patients with urethral carcinomas referred to medical oncologists. AB - OBJECTIVES: Primary carcinomas of the urethra (PCU) are rare and often advanced when diagnosed. Treatment standards are lacking. We studied treatment response and survival in a cohort of patients with PCU, with emphasis on modern platinum containing chemotherapy regimens plus surgery for advanced disease. MATERIALS AND METHODS: This was a retrospective chart review of consecutive patients with PCU seen by medical oncologists at our institution over a recent 5-year period. Outcome was measured as best response to chemotherapy. Kaplan-Meier estimates were generated for survival and Cox proportional hazard was used for prognostic factors for survival. RESULTS: The 44 patients (64% women) included had a median age at diagnosis of 66.5 years. The most prevalent histologic subtypes of PCU were squamous cell carcinoma and adenocarcinoma. At diagnosis, 43% already had lymph node-positive [lymph node (LN)+] disease, and 16% had distant metastases. The entire cohort's overall survival (OS) was 31.7 months. The response rate to platinum-containing neoadjuvant chemotherapy was 72%. Twenty-one patients with locally advanced or LN+ PCU underwent chemotherapy plus surgery. Their median OS from chemotherapy initiation was 25.6 months. Four of 9 patients (44%) with LN+ PCU at diagnosis were alive at our review, with a minimum follow-up of more than 3 years. CONCLUSIONS: Modern platinum-containing regimens appear to be effective in advanced PCU. Preoperative chemotherapy is associated with prolonged disease free survival in a subgroup of LN+ cases. PMID- 22534089 TI - The alpha2 helix in the DNA ligase IV BRCT-1 domain is required for targeted degradation of ligase IV during adenovirus infection. AB - In adenovirus E4 mutant infections, viral DNAs form concatemers through a process that requires host Non-homologous End Joining (NHEJ) proteins including DNA Ligase IV (LigIV). Adenovirus proteins E4 34k and E1b 55k form the substrate selection component of an E3 ubiquitin ligase and prevent concatenation by targeting LigIV for proteasomal degradation. The mechanisms and sites involved in targeting this and other E3 ligase substrates generally are poorly-understood. Through genetic analysis, we identified the alpha2 helix of one LigIV BRCT domain (BRCT-1) as essential for adenovirus-mediated degradation. Replacement of the BRCT domain of DNA ligase III (LigIII), which is resistant to degradation, with LigIV BRCT-1 does not promote degradation. A humanized mouse LigIV that possesses a BRCT-1 alpha2 helix identical to the human protein, like its parent, is also resistant to adenovirus-mediated degradation. Thus, both the BRCT-1 alpha2 helix and an element outside BRCT-1 are required for adenovirus-mediated degradation of LigIV. PMID- 22534091 TI - Identification and characterization of Iflavirus 3C-like protease processing activities. AB - Viral replication and capsid assembly in the viruses in the order Picornavirales requires polyprotein proteolytic processing by 3C or 3C-like (3CL) proteases. We identified and characterized the 3CL protease of Ectropis obliqua virus (EoV) of the newly established family Iflaviridae (order Picornavirales). The bacterially expressed EoV 3CL protease domain autocatalytically released itself from larger precursors by proteolytic cleavage, and cleavage sites were determined via N terminal sequencing of the cleavage products. This protease also mediated trans proteolytic activity and cleaved the polyprotein at the same specific positions. Moreover, we determined the critical catalytic residues (H2261, D2299, C2383) for the protease activity, and characterized the biochemical properties of EoV 3CL and its responses to various protease inhibitors. Our work is the first study to identify an iflaviral 3CL protease and further characterize it in detail and should foster our understanding of EoV and other iflaviruses. PMID- 22534092 TI - Polycyclic aromatic hydrocarbon emissions from the combustion of alternative fuels in a gas turbine engine. AB - We report on the particulate-bound polycyclic aromatic hydrocarbons (PAH) in the exhaust of a test-bed gas turbine engine when powered by Jet A-1 aviation fuel and a number of alternative fuels: Sasol fully synthetic jet fuel (FSJF), Shell gas-to-liquid (GTL) kerosene, and Jet A-1/GTL 50:50 blended kerosene. The concentration of PAH compounds in the exhaust emissions vary greatly between fuels. Combustion of FSJF produces the greatest total concentration of PAH compounds while combustion of GTL produces the least. However, when PAHs in the exhaust sample are measured in terms of the regulatory marker compound benzo[a]pyrene, then all of the alternative fuels emit a lower concentration of PAH in comparison to Jet A-1. Emissions from the combustion of Jet A-1/GTL blended kerosene were found to have a disproportionately low concentration of PAHs and appear to inherit a greater proportion of the GTL emission characteristics than would be expected from volume fraction alone. The data imply the presence of a nonlinear relation between fuel blend composition and the emission of PAH compounds. For each of the fuels, the speciation of PAH compounds present in the exhaust emissions were found to be remarkably similar (R(2) = 0.94 0.62), and the results do provide evidence to support the premise that PAH speciation is to some extent indicative of the emission source. In contrast, no correlation was found between the PAH species present in the fuel with those subsequently emitted in the exhaust. The results strongly suggests that local air quality measured in terms of the particulate-bound PAH burden could be significantly improved by the use of GTL kerosene either blended with or in place of Jet A-1 kerosene. PMID- 22534093 TI - Advective-diffusive mass transfer in fractured porous media with variable rock matrix block size. AB - Traditional dual porosity models do not take into account the effect of matrix block size distribution on the mass transfer between matrix and fracture. In this study, we introduce the matrix block size distributions into an advective diffusive solute transport model of a divergent radial system to evaluate the mass transfer shape factor, which is considered as a first-order exchange coefficient between the fracture and matrix. The results obtained lead to a better understanding of the advective-diffusive mass transport in fractured porous media by identifying two early and late time periods of mass transfer. Results show that fractured rock matrix block size distribution has a great impact on mass transfer during early time period. In addition, two dimensionless shape factors are obtained for the late time, which depend on the injection flow rate and the distance of the rock matrix from the injection point. PMID- 22534090 TI - Production of prostaglandin E2 in response to infection with modified vaccinia Ankara virus. AB - Prostaglandin E2 (PGE2) is an arachidonic acid (AA)-derived signaling molecule that can influence host immune responses to infection or vaccination. In this study, we investigated PGE2 production in vitro by cells infected with the poxvirus vaccine strain, modified vaccinia Ankara virus (MVA). Human THP-1 cells, murine bone marrow-derived dendritic cells, and murine C3HA fibroblasts all accumulated PGE2 to high levels in culture supernatants upon infection with MVA. We also demonstrated that MVA induced the release of AA from infected cells, and this was, most unusually, independent of host cytosolic phospholipase A2 activity. The accumulation of AA and PGE2 was dependent on viral gene expression, but independent of canonical NF-kappaB signaling via p65/RelA. The production of PGE2 required host cyclooxygenase-2 (COX-2) activity, and COX-2 protein accumulated during MVA infection. The results of this study provide insight into a novel aspect of MVA biology that may affect the efficacy of MVA-based vaccines. PMID- 22534094 TI - CSF containing cystic lesion of the clivus-case report and review of the literature. PMID- 22534095 TI - Leptomeningeal carcinomatosis: prognostic value of clinical, cerebrospinal fluid, and neuroimaging features. AB - INTRODUCTION: Leptomeningeal carcinomatosis (LC) is a devastating complication occurring in 5% of all patients with cancer. To date there are no well established prognostic markers in patients with LC, except for the presence of cerebrospinal fluid (CSF) blocks and the Karnofsky performance status scale (KPS). We aimed to identify clinical, neuroradiologic and CSF prognostic factors related to LC survival and to develop an easy-to-use Prognostic Scoring Scale (PSS) to identify patients who are more likely to benefit from receiving treatment. METHODS: Single-center retrospective study evaluating patients who had a diagnosis of LC during a 10-year period. Diagnosis was made by malignant cytology or imaging; suspicious cases treated as LC were also included. RESULTS: Fifty patients with LC were analyzed (58% women). Median age was 54.4 years, and KPS was 60%. The most common types of tumor were breast (35%), lung (24%), and hematologic malignancies (16%). Thirty-two percent of patients were diagnosed by imaging, 22% by cytology, and 40% by both. Median overall survival (OS) was 10 weeks (95% confidence interval 5.1-14.9). Median OS for patients who received specific treatment was 21.2 weeks vs. 6.38 weeks for patients receiving supportive care only (p<0.001). In multivariate analysis, initial KPS, initial CSF protein level (<112 mg/dL) and time from diagnosis of primary tumor to diagnosis of LC (>67 weeks) were significant and independent predictors of increased survival. CONCLUSIONS: Prognosis remains poor in LC. The predictive factors for patients with LC here identified could help to improve the selection of patients who are more likely to benefit from receiving treatment. PMID- 22534096 TI - Prion subcellular fractionation reveals infectivity spectrum, with a high titre low PrPres level disparity. AB - BACKGROUND: Prion disease transmission and pathogenesis are linked to misfolded, typically protease resistant (PrPres) conformers of the normal cellular prion protein (PrPC), with the former posited to be the principal constituent of the infectious 'prion'. Unexplained discrepancies observed between detectable PrPres and infectivity levels exemplify the complexity in deciphering the exact biophysical nature of prions and those host cell factors, if any, which contribute to transmission efficiency. In order to improve our understanding of these important issues, this study utilized a bioassay validated cell culture model of prion infection to investigate discordance between PrPres levels and infectivity titres at a subcellular resolution. FINDINGS: Subcellular fractions enriched in lipid rafts or endoplasmic reticulum/mitochondrial marker proteins were equally highly efficient at prion transmission, despite lipid raft fractions containing up to eight times the levels of detectable PrPres. Brain homogenate infectivity was not differentially enhanced by subcellular fraction-specific co factors, and proteinase K pre-treatment of selected fractions modestly, but equally reduced infectivity. Only lipid raft associated infectivity was enhanced by sonication. CONCLUSIONS: This study authenticates a subcellular disparity in PrPres and infectivity levels, and eliminates simultaneous divergence of prion strains as the explanation for this phenomenon. On balance, the results align best with the concept that transmission efficiency is influenced more by intrinsic characteristics of the infectious prion, rather than cellular microenvironment conditions or absolute PrPres levels. PMID- 22534097 TI - [Coronary artery dissection complicated by myocardial infarction in a head trauma patient]. AB - Acute myocardial infarction, following coronary artery dissection, is a rare, but potentially fatal, syndrome after blunt chest trauma. The treatment is more complicated when intracerebral lesions are present, because of the need of anticoagulation. We report the case of a 37-year-old male patient, suffering from a polytraumatism with intracranial petechial haemorrhages who have a left coronary artery dissection with acute myocardial infarction. PMID- 22534098 TI - [Wernicke's encephalopathy complicating hyperemesis gravidarum]. PMID- 22534099 TI - Evaluation of an integrated graphical display to promote acute change detection in ICU patients. AB - OBJECTIVE: The purpose of this study was to evaluate ICU nurses' ability to detect patient change using an integrated graphical information display (IGID) versus a conventional tabular ICU patient information display (i.e. electronic chart). DESIGN: Using participants from two different sites, we conducted a repeated measures simulator-based experiment to assess ICU nurses' ability to detect abnormal patient variables using a novel IGID versus a conventional tabular information display. Patient scenarios and display presentations were fully counterbalanced. MEASUREMENTS: We measured percent correct detection of abnormal patient variables, nurses' perceived workload (NASA-TLX), and display usability ratings. RESULTS: 32 ICU nurses (87% female, median age of 29 years, and median ICU experience of 2.5 years) using the IGID detected more abnormal variables compared to the tabular display [F(1, 119)=13.0, p<0.05]. There was a significant main effect of site [F(1, 119)=14.2], with development site participants doing better. There were no significant differences in nurses' perceived workload. The IGID display was rated as more usable than the conventional display [F(1, 60)=31.7]. CONCLUSION: Overall, nurses reported more important physiological information with the novel IGID than tabular display. Moreover, the finding of site differences may reflect local influences in work practice and involvement in iterative display design methodology. Information displays developed using user-centered design should accommodate the full diversity of the intended user population across use sites. PMID- 22534100 TI - Combination therapy with arsenic trioxide, all-trans retinoic acid, and chemotherapy in acute promyelocytic leukemia patients with various relapse risks. AB - To improve the recovery rate of high-risk patients with acute promyelocytic leukemia (APL), we used all-trans retinoic acid (ATRA)/arsenic trioxide (ATO)/daunorubicin combination in remission induction, daunorubicin and cytarabine in consolidation, and ATRA/ATO/methotrexate +/- 6-mercaptopurine in maintenance treatment of APL patients with various risks for relapse. Our results showed a high complete remission rate of 95.3%. Excluding the cases of early death, no significant differences in event-free survival were observed between the intermediate-risk and high-risk group (p = 0.393) and the low-risk and high risk group (p = 0.162). In addition, there were no significant differences between the groups in cumulative incidence of central nervous system relapse. In conclusion, our results suggest that APL patients benefit from combination ATO/ATRA/chemotherapy, and that this regimen is especially beneficial for patients with high-risk prognostic factors. PMID- 22534101 TI - A role for caspase inhibitors in differentiation therapy of myeloid leukaemia. PMID- 22534102 TI - Novel snowflake-like Pt-Pd bimetallic clusters on screen-printed gold nanofilm electrode for H2O2 and glucose sensing. AB - Novel snowflake-like Pt-Pd bimetallic nanoclusters (Pt-PdBNC) were synthesized on a screen-printed gold nanofilm electrode (SPGFE) substrate by electrochemically reducing precursors with a new constant potential/multi-potential step deposition strategy. The electrocatalytic behavior of the modified electrode (SPGFE/Pt PdBNC) towards H(2)O(2) was investigated. The results indicate that the as prepared Pt-PdBNC significantly enhances the electrochemical reduction of H(2)O(2) in neutral media, exhibiting preferable electrocatalytic performance compared to Pt and Pd monometallic nanoclusters. Under optimum conditions, SPGFE/Pt-PdBNC offers linear responses for H(2)O(2) in the concentration range from 0.005 to 6 mM with an ultrahigh sensitivity of 804 mA M(-1) cm(-2) and excellent selectivity. Furthermore, glucose oxidase was immobilized on the Pt PdBNC structure, and the fabricated biosensor presents favorable properties for glucose sensing. PMID- 22534103 TI - Highly sensitive and selective colorimetric genotyping of single-nucleotide polymorphisms based on enzyme-amplified ligation on magnetic beads. AB - Herein we report a new strategy for highly sensitive and selective colorimatric assay for genotyping of single-nucleotide polymorphisms (SNPs). It is based on the use of a specific gap ligation reaction, horseradish peroxidase (HRP) for signal amplification, and magnetic beads for the easy separation of the ligated product. Briefly, oligonucleotide capture probe functionalized magnetic beads are first hybridized to a target DNA. Biotinylated oligonucleotide detection probes are then allowed to hybridize to the already captured target DNA. A subsequent ligation at the mutation point joins the two probes together. The introduction of streptavidin-conjugated HRP and a simple magnetic separation allow colorimetric genotyping of SNPs. The assay is able to discriminate one copy of mutant in 1000 copies of wild-type KRAS oncogene at 30 picomolar. The detection limit of the assay is further improved to 1 femtomolar by incorporating a ligation chain reaction amplification step, offering an excellent opportunity for the development of a simple and highly sensitive diagnostic tool. PMID- 22534104 TI - Surface plasmon resonance immunosensor for the detection of Salmonella typhi antibodies in buffer and patient serum. AB - Surface plasmon resonance (SPR) immunosensor using 4-mercaptobenzoic acid (4-MBA) modified gold SPR chip was developed first time for the detection of flagellin specific antibodies of Salmonella typhi (S. typhi). Flagellin protein of S. typhi was prepared by recombinant DNA technology. The modification of gold chip with 4 MBA was in-situ characterized by SPR and electrochemical impedance spectroscopy. By using kinetic evaluation software, K(D) and B(max) values were calculated and found to be 26.3 fM and 62.04 m degrees , respectively, for the immobilized monoclonal antibody (Moab) of recombinant flagellin (r-fla) protein of S. typhi (r-fla S. typhi). In addition, thermodynamic parameters such as DeltaG, DeltaH and DeltaS were determined first time for r-fla S. typhi and Moab of r-fla S. typhi interactions and the values revealed the interaction between r-fla S. typhi and Moab of r-fla S. typhi as spontaneous, endothermic and entropy driven one. Moreover, healthy human serum samples and patient sera (Widal positive and Widal negative) were subjected to SPR analysis. The present SPR based approach provides an alternative way for S. typhi detection in less than 10 min. PMID- 22534105 TI - Fabrication of hydrogen peroxide biosensor based on Ni doped SnO2 nanoparticles. AB - Ni doped SnO(2) nanoparticles (0-5 wt%) have been prepared by a simple microwave irradiation (2.45 GHz) method. Powder X-ray diffraction (XRD) and transmission electron microscopy (TEM) studies confirmed the formation of rutile structure with space group (P(42)/mnm) and nanocrystalline nature of the products with spherical morphology. Direct electrochemistry of horseradish peroxidase (HRP)/nano-SnO(2) composite has been studied. The immobilized enzyme retained its bioactivity, exhibited a surface confined, reversible one-proton and one-electron transfer reaction, and had good stability, activity and a fast heterogeneous electron transfer rate. A significant enzyme loading (3.374*10(-10) mol cm(-2)) has been obtained on nano-Ni doped SnO(2) as compared to the bare glassy carbon (GC) and nano-SnO(2) modified surfaces. This HRP/nano-Ni-SnO(2) film has been used for sensitive detection of H(2)O(2) by differential pulse voltammetry (DPV), which exhibited a wider linearity range from 1.0*10(-7) to 3.0*10(-4)M (R=0.9897) with a detection limit of 43 nM. The apparent Michaelis-Menten constant (K(M)(app)) of HRP on the nano-Ni-SnO(2) was estimated as 0.221 mM. This excellent performance of the fabricated biosensor is attributed to large surface to-volume ratio and Ni doping into SnO(2) which facilitate the direct electron transfer between the redox enzyme and the surface of electrode. PMID- 22534106 TI - Optical detection of organophosphorus compounds based on Mn-doped ZnSe d-dot enzymatic catalytic sensor. AB - In this paper, we report a sensitive and selective method for detection of organophosphorus compounds (OPs) based on Mn:ZnSe d-dots-enzyme-hydrogen peroxide (H(2)O(2)) fluorescence quenching system. Acetylcholine esterase (AChE) can hydrolyze acetylcholine (ACh) to choline. Subsequently, choline oxidase (ChOx) oxidizes choline to generate H(2)O(2). The enzyme-generated H(2)O(2) can quench the fluorescence of Mn:ZnSe d-dots. When paraoxon are introduced in solution, it can interact with the active centers of AChE and decrease the enzyme activity. This leads to the decrease of the H(2)O(2) production and then the fluorescence quenching rate of Mn:ZnSe d-dots. Experimental results showed that the enzyme inhibition percentage of Mn:ZnSe d-dots-ChOx-AChE-ACh system was proportional to the logarithm of paraoxon in the range 4.84*10(-11) to 4.84*10(-6) mol/L with the detection limit (S/N=3) of 1.31*10(-11) mol/L. The proposed biosensor has been employed for quick determination of paraoxon in tap water and milk samples with satisfactory reproducibility and accuracy. This nano-biosensor was proved to be sensitive, rapid, simple and tolerance of most interfering substances. PMID- 22534107 TI - Scalability and severity of keratoconus in children. AB - PURPOSE: To assess the severity of keratoconus at diagnosis and its scalability over a period of 2 years in children compared to adults. DESIGN: A retrospective monocentric study was conducted in the National Reference Center for Keratoconus, Bordeaux (France), between October 1997 and November 2010. METHODS: In total, 216 patients were studied, comprising 49 patients (22.7%) aged <= 15 and 167 patients (77.3%) aged >= 27 years at diagnosis, who were seen within 2 years of diagnosis. Severity at diagnosis was assessed using Krumeich's classification, and the scalability criteria of the US Food and Drug Administration (2010) were used. Student t tests and chi(2) tests were performed to compare the 2 groups. RESULTS: Keratoconus in children was significantly more severe at diagnosis, with 27.8% being stage 4 vs 7.8% of adults (P < .0001). In addition, ophthalmoscopic signs were more frequent in children (42.9% vs 29.5%, P = .05), while mean values of maximum, average, and minimum keratometry as well as simulated keratometric astigmatism were higher (P < .0001, P = .0002, P = .0005, and P = .001, respectively). After diagnosis, keratoconus did not evolve more frequently in children. However, in the case of progression, keratoconus evolved faster in children, with significant differences in the spherical equivalent and maximum and minimum keratometry (P = .03, P = .02, P = .04, respectively). CONCLUSION: At diagnosis, keratoconus is often more advanced in children than in adults, with faster disease progression. Early detection and close monitoring are therefore crucial in young patients. PMID- 22534108 TI - Photoreceptor damage and foveal sensitivity in surgically closed macular holes: an adaptive optics scanning laser ophthalmoscopy study. AB - PURPOSE: To assess photoreceptor structure using adaptive optics scanning laser ophthalmoscopy (AO SLO) and spectral-domain optical coherence tomography (SD OCT) and to evaluate the relationship between structural abnormalities and foveal sensitivity in eyes with surgically closed macular hole (MH). DESIGN: Prospective, interventional case series. METHODS: Twenty-one eyes of 19 patients with idiopathic MH underwent a full ophthalmologic examination, including SD OCT at baseline. Imaging with SD OCT, an original prototype AO SLO system, and microperimetry were performed at 6 months after surgery. RESULTS: All patients underwent anatomically successful MH closure. On AO SLO, dark areas (0.004 to 0.754 mm(2)) were seen in all eyes after MH repair. Lower cone density correlated with poorer postoperative visual acuity and lower mean foveal sensitivity (both P < .001). Larger dark areas on AO SLO correlated with poorer postoperative visual acuity (P = .003) and lower mean foveal sensitivity (P = .006). Cone density was significantly lower and dark areas were significantly larger in eyes that had defects of the outer segments in the fluid cuff before surgery (P = .018 and P = .001, respectively) and moderately reflective foveal lesions after surgery (P < .001 and P < .001, respectively). Larger dark areas correlated with longer symptom duration before surgery (P < .001). CONCLUSIONS: Structural damage to the photoreceptor layer correlated with greater decreases in visual function in eyes with surgically closed MH. AO SLO imaging is a useful and quantitative tool for detecting photoreceptor abnormalities and their association with visual acuity and retinal sensitivity in eyes with closed MH. PMID- 22534109 TI - Prevalence and correction of near vision impairment at seven sites in China, India, Nepal, Niger, South Africa, and the United States. AB - PURPOSE: To estimate the prevalence of near vision impairment and use of corrective spectacles among middle-aged and older adults in different settings and ethnic groups. DESIGN: Population-based, cross-sectional study. METHODS: People aged >= 35 years were randomly selected with cluster sampling in 4 rural settings in Shunyi (China), Kaski (Nepal), Madurai (India), and Dosso (Niger); 1 semi-urban area in Durban (South Africa); and 2 urban settings in Guangzhou (China) and Los Angeles (USA). Near visual acuity (VA), with and without presenting near correction, was measured at 40 cm using a logMAR near vision tumbling E chart. Subjects with uncorrected binocular near VA <= 20/40 were tested with plus spheres to obtain the best-corrected binocular VA. RESULTS: A total of 17 734 persons aged >= 35 years were enumerated and 14 805 (83.5%) were examined. The age- and sex-standardized prevalence of uncorrected near vision impairment (VA <= 20/40) ranged from 49% in Dosso to 60% in Shunyi and Guangzhou, 65% in Kaski and Los Angeles, and 83% in Madurai and Durban. The prevalence of near vision impairment based on best-corrected visual acuity was less than 10% in Guangzhou, Kaski, Durban, and Los Angeles, but as high as 23% in Madurai. In multiple logistic regression models, uncorrected near vision impairment was associated with older age (odds ratio [OR] = 1.14, P < .001) and female sex (OR = 1.12, P = .027), but not with educational level (OR = 1.01, P = .812). Over 90% of people in need of near refractive correction in rural settings did not have the necessary spectacles. These rates were 40% in urban settings. CONCLUSIONS: By 50 years of age, the majority of people suffer from near vision impairment, most of which can be corrected optically. Over 90% of those in need of near refractive correction in rural settings do not have the necessary spectacles. PMID- 22534111 TI - Effect of 3d doping on the electronic structure of BaFe2As2. AB - The electronic structure of BaFe(2)As(2) doped with Co, Ni and Cu has been studied by a variety of experimental and theoretical methods, but a clear picture of the dopant 3d states has not yet emerged. Herein we provide experimental evidence of the distribution of Co, Ni and Cu 3d states in the valence band. We conclude that the Co and Ni 3d states provide additional free carriers to the Fermi level, while the Cu 3d states are found at the bottom of the valence band in a localized 3d(10) shell. These findings help shed light on why superconductivity can occur in BaFe(2)As(2) doped with Co and Ni but not Cu. PMID- 22534110 TI - Maternal smoking during pregnancy and the prevalence of autism spectrum disorders, using data from the autism and developmental disabilities monitoring network. AB - BACKGROUND: Reported associations between gestational tobacco exposure and autism spectrum disorders (ASDs) have been inconsistent. OBJECTIVE: We estimated the association between maternal smoking during pregnancy and ASDs among children 8 years of age. METHODS: This population-based case-cohort study included 633,989 children, identified using publicly available birth certificate data, born in 1992, 1994, 1996, and 1998 from parts of 11 U.S. states subsequently under ASD surveillance. Of these children, 3,315 were identified as having an ASD by the active, records-based surveillance of the Autism and Developmental Disabilities Monitoring Network. We estimated prevalence ratios (PRs) of maternal smoking from birth certificate report and ASDs using logistic regression, adjusting for maternal education, race/ethnicity, marital status, and maternal age; separately examining higher- and lower-functioning case subgroups; and correcting for assumed under-ascertainment of autism by level of maternal education. RESULTS: About 13% of the source population and 11% of children with an ASD had a report of maternal smoking in pregnancy: adjusted PR (95% confidence interval) of 0.90 (0.80, 1.01). The association for the case subgroup autistic disorder (1,310 cases) was similar: 0.88 (0.72, 1.08), whereas that for ASD not otherwise specified (ASD-NOS) (375 cases) was positive, albeit including the null: 1.26 (0.91, 1.75). Unadjusted associations corrected for assumed under-ascertainment were 1.06 (0.98, 1.14) for all ASDs, 1.12 (0.97, 1.30) for autistic disorder, and 1.63 (1.30, 2.04) for ASD-NOS. CONCLUSIONS: After accounting for the potential of under-ascertainment bias, we found a null association between maternal smoking in pregnancy and ASDs, generally. The possibility of an association with a higher functioning ASD subgroup was suggested, and warrants further study. PMID- 22534112 TI - Cardiac dysfunction in StrepTSS: group A streptococcus disrupts the directional cardiomyocyte-to-macrophage crosstalk that maintains macrophage quiescence. AB - Myocardial dysfunction in group A streptococcal (GAS) toxic shock syndrome (StrepTSS) is characterized by severe biventricular dilatation and a striking reduction in ventricular performance; however, the mechanisms have not been fully elucidated. We have previously shown that pro-inflammatory cytokines are upregulated in the hearts of experimental animals with GAS bacteremia and that cardiomyocytes themselves as well as macrophages are the principal cytokine sources. Although macrophage-derived cytokines can clearly affect cardiac contractility, we questioned whether soluble cardiomyocyte-derived mediators might in turn affect macrophage function. Thus, we sought evidence of cardiomyocyte-to-macrophage directional cross-talk under resting versus GAS stimulated conditions, using production of matrix metalloproteinase-9 (MMP-9) as an indicator of such signaling. Our results demonstrate that unstimulated cardiomyocytes produce a soluble inhibitor/s that maintains macrophage functional quiescence. Further, viable GAS induced production of cardiomyocyte-derived stimulator/s that overcomes quiescence and boosts macrophages production of MMP-9 and expression of pro-inflammatory cytokines (IL-1beta, IL-6) and cardiodepressant factors (iNOS). Understanding the role of these cardiomyocyte derived effectors of macrophage function (herein termed "cardiokines") in sepsis associated cardiomyopathy may suggest new targets for therapeutic intervention. PMID- 22534113 TI - Opticin production is reduced by hypoxia and VEGF in human retinal pigment epithelium via MMP-2 activation. AB - Opticin, a small leucine rich repeat protein (SLRP) contributes to vitreoretinal adhesion. This study was conducted to investigate the effects of hypoxia and vascular endothelial growth factor (VEGF) on matrix metalloproteinase (MMP) mediated opticin production in retinal pigment epithelium (RPE) cells. Primary cultured human RPE cells were treated with hypoxia (low oxygen and cobalt chloride) or VEGF (0-100 ng/mL). The mRNA levels of opticin and the protein levels of intra and extracellular opticin in RPE cells were examined by RT-PCR and Western blot assay, respectively. Furthermore, the MMP activity was analyzed by zymography, and EDTA was used as an MMP inhibitor. Analysis of the effect of MMP-2 on opticin was performed by recombinant human (rh) MMP-2 stimulation in RPE cultures and by human vitreous sample digestion with activated rhMMP-2. Our results showed that opticin was expressed by primary cultured human RPE cells. Hypoxia and VEGF stimulation did not alter opticin mRNA and protein expression in RPE cells, but markedly decreased the protein levels of extracellular opticin following increased latent MMP-2 activity. The VEGF- and hypoxia induced opticin degradation in the culture medium was blocked by EDTA. Together, opticin levels in the culture medium were also reduced after rhMMP-2 treatment. In addition, opticin in human vitreous samples could be cleaved by rhMMP-2. These results reveal that VEGF and hypoxia could decrease opticin protein levels in the human RPE secretome, and that opticin may be an enzymatic substrate for MMP-2. PMID- 22534115 TI - [Stem cells and liver regeneration: looking toward the future]. PMID- 22534114 TI - Transitions from functionalization to fragmentation reactions of laboratory secondary organic aerosol (SOA) generated from the OH oxidation of alkane precursors. AB - Functionalization (oxygen addition) and fragmentation (carbon loss) reactions governing secondary organic aerosol (SOA) formation from the OH oxidation of alkane precursors were studied in a flow reactor in the absence of NO(x). SOA precursors were n-decane (n-C10), n-pentadecane (n-C15), n-heptadecane (n-C17), tricyclo[5.2.1.0(2,6)]decane (JP-10), and vapors of diesel fuel and Southern Louisiana crude oil. Aerosol mass spectra were measured with a high-resolution time-of-flight aerosol mass spectrometer, from which normalized SOA yields, hydrogen-to-carbon (H/C) and oxygen-to-carbon (O/C) ratios, and C(x)H(y)+, C(x)H(y)O+, and C(x)H(y)O(2)+ ion abundances were extracted as a function of OH exposure. Normalized SOA yield curves exhibited an increase followed by a decrease as a function of OH exposure, with maximum yields at O/C ratios ranging from 0.29 to 0.74. The decrease in SOA yield correlates with an increase in oxygen content and decrease in carbon content, consistent with transitions from functionalization to fragmentation. For a subset of alkane precursors (n-C10, n C15, and JP-10), maximum SOA yields were estimated to be 0.39, 0.69, and 1.1. In addition, maximum SOA yields correspond with a maximum in the C(x)H(y)O+ relative abundance. Measured correlations between OH exposure, O/C ratio, and H/C ratio may enable identification of alkane precursor contributions to ambient SOA. PMID- 22534116 TI - [Diagnosis and treatment of portal thrombosis in liver cirrhosis]. AB - Improved imaging techniques and the routine use of color Doppler ultrasound in the follow-up of patients with liver cirrhosis has increased diagnosis of portal vein thrombosis (PVT) in these patients. The extension of PVT should be evaluated with computed tomography angiography or magnetic resonance angiography. The natural history of PVT in cirrhosis and its impact on liver disease is unknown but it seems clear that PVT could increase the morbidity and mortality associated with liver transplantation and can even be a contraindication to this procedure when the thrombus extends to the superior mesenteric vein. Anticoagulation is a relatively safe and effective treatment in achieving recanalization of the splenoportal axis or in preventing progression of thrombosis and is therefore frequently used. The use of transjugular intrahepatic portosystemic shunts (TIPS) is reserved for patients unresponsive to anticoagulation or in those with severe complications of portal hypertension. PMID- 22534117 TI - Bacterial profile and drug susceptibility pattern of urinary tract infection in pregnant women at University of Gondar Teaching Hospital, Northwest Ethiopia. AB - BACKGROUND: Urinary tract infection (UTI) is a common health problem among pregnant women. Proper investigation and prompt treatment are needed to prevent serious life threatening condition and morbidity due to urinary tract infection that can occur in pregnant women. Recent report in Addis Ababa, Ethiopia indicated the prevalence of UTI in pregnant women was 11.6% and Gram negative bacteria was the predominant isolates and showed multi drug resistance. This study aimed to assess bacterial profile that causes urinary tract infection and their antimicrobial susceptibility pattern among pregnant women visiting antenatal clinic at University of Gondar Teaching Hospital, Northwest Ethiopia. METHODS: A cross-sectional study was conducted at University of Gondar Teaching Hospital from March 22 to April 30, 2011. Mid stream urine samples were collected and inoculated into Cystine Lactose Electrolyte Deficient medium (CLED). Colony counts yielding bacterial growth of 105/ml of urine or more of pure isolates were regarded as significant bacteriuria for infection. Colony from CLED was sub cultured onto MacConkey agar and blood agar plates. Identification was done using cultural characteristics and a series of biochemical tests. A standard method of agar disc diffusion susceptibility testing method was used to determine susceptibility patterns of the isolates. RESULTS: The overall prevalence of UTI in pregnant women was 10.4%. The predominant bacterial pathogens were Escherichia coli 47.5% followed by coagulase-negative staphylococci 22.5%, Staphylococcus aureus 10%, and Klebsiella pneumoniae 10%. Gram negative isolates were resulted low susceptibility to co-trimoxazole (51.9%) and tetracycline (40.7%) whereas Gram positive showed susceptibility to ceftriaxon (84.6%) and amoxicillin clavulanic acid (92.3%). Multiple drug resistance (resistance to two or more drugs) was observed in 95% of the isolates. CONCLUSION: Significant bacteriuria was observed in asymptomatic pregnant women. Periodic studies are recommended to check the outcome of asymptomatic bacteriuria and also monitor any changes in the susceptibility patterns of urinary tract pathogens in pregnant women. PMID- 22534118 TI - Nitrous oxide emissions from the oxidation tank of a pilot activated sludge plant. AB - This study discusses the results of the continuous monitoring of nitrous oxide emissions from the oxidation tank of a pilot conventional wastewater treatment plant. Nitrous oxide emissions from biological processes for nitrogen removal in wastewater treatment plants have drawn great attention over the last years, due to the high greenhouse effect. However, even if several studies have been carried out to quantify nitrous oxide emission rates from different types of treatment, quite wide ranges have been reported. Only grab samples or continuous measurements over limited periods were considered in previous studies, which can account for the wide variability of the obtained results. Through continuous monitoring over several months, our work tries to fill this gap of knowledge and get a deeper insight into nitrous oxide daily and weekly emission dynamics. Moreover, the influence of some operating conditions (sludge age, dissolved oxygen concentration in the oxidation tank, nitrogen load) was studied to determine good practices for wastewater treatment plant operation aiming at the reduction of nitrous oxide emissions. The dissolved oxygen set-point is shown to play a major role in nitrous oxide emissions. Low sludge ages and high nitrogen loads are responsible for higher emissions as well. An interesting pattern has been observed, with quite negligible emissions during most of the day and a peak with a bell-like shape in the morning in the hours of maximum nitrogen load in the plant, correlated to the ammonia and nitrite peaks in the tank. PMID- 22534119 TI - Bottled mineral water as a potential source of antibiotic resistant bacteria. AB - The antibiotic resistance phenotypes of the cultivable bacteria present in nine batches of two Portuguese and one French brands of commercially available mineral waters were examined. Most of the 238 isolates recovered on R2A, Pseudomonas Isolation agar or on these culture media supplemented with amoxicillin or ciprofloxacin, were identified (based on 16S rRNA gene sequence analysis) as Proteobacteria of the divisions Beta, Gamma and Alpha. Bacteria resistant to more than three distinct classes of antibiotics were detected in all the batches of the three water brands in counts up to 102 CFU/ml. In the whole set of isolates, it was observed resistance against all the 22 antimicrobials tested (ATB, bioMerieux and disc diffusion), with most of the bacteria showing resistance to three or more classes of antibiotics. Bacteria with the highest multi-resistance indices were members of the genera Variovorax, Bosea, Ralstonia, Curvibacter, Afipia and Pedobacter. Some of these bacteria are related with confirmed or suspected nosocomial agents. Presumable acquired resistance may be suggested by the observation of bacteria taxonomically related but isolated from different brands, exhibiting distinct antibiotic resistance profiles. Bottled mineral water was confirmed as a possible source of antibiotic resistant bacteria, with the potential to be transmitted to humans. PMID- 22534120 TI - Use of cork powder and granules for the adsorption of pollutants: a review. AB - Cork powder and granules are the major subproducts of the cork industry, one of the leading economic activities in Portugal and other Mediterranean countries. Many applications have been envisaged for this product, from cork stoppers passing through the incorporation in agglomerates and briquettes to the use as an adsorbent in the treatment of gaseous emissions, waters and wastewaters. This paper aims at reviewing the state of the art on the properties of cork and cork powder and their application in adsorption technologies. Cork biomass has been used on its original form as biosorbent for heavy metals and oils, and is also a precursor of activated carbons for the removal of emerging organic pollutants in water and VOCs in the gas phase. Through this literature review, different potential lines of research not yet explored can be more easily identified. PMID- 22534121 TI - Predation influences the structure of biofilm developed on ultrafiltration membranes. AB - This study investigates the impact of predation by eukaryotes on the development of specific biofilm structures in gravity-driven dead-end ultrafiltration systems. Filtration systems were operated under ultra-low pressure conditions (65 mbar) without the control of biofilm formation. Three different levels of predation were evaluated: (1) inhibition of eukaryotic organisms, (2) addition of cultured protozoa (Tetrahymena pyriformis), and (3) no modification of microbial community as a control. The system performance was evaluated based on permeate flux and structures of the biofilm. It was found that predation had a significant influence on both the total amount and also the structure of the biofilm. An open and heterogeneous structure developed in systems with predation whereas a flat, compact, and thick structure that homogeneously covered the membrane surface developed in absence of predation. Permeate flux was correlated with the structure of the biofilm with increased fluxes for smaller membrane coverage. Permeate fluxes in the presence or absence of the predators was 10 and 5 L m(-2) h(-1), respectively. It was concluded that eukaryotic predation is a key factor influencing the performance of gravity-driven ultrafiltration systems. PMID- 22534122 TI - New chlorinated amphetamine-type-stimulants disinfection-by-products formed during drinking water treatment. AB - Previous studies have demonstrated high removal rates of amphetamine-type stimulants (ATSs) through conventional drinking water treatments; however the behaviour of these compounds through disinfection steps and their transformation into disinfection-by-products (DBPs) is still unknown. In this work, for the first time, the reactivity of some ATSs such as amphetamine, methamphetamine, 3,4 methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA) and 3,4 methylenedioxyethylamphetamine (MDEA) with chlorine has been investigated under simulated and real drinking water treatment conditions in order to evaluate their ability to give rise to transformation products. Two new DBPs from these illicit drugs have been found. A common chlorinated-by-product (3-chlorobenzo)-1,3 dioxole, was identified for both MDA and MDEA while for MDMA, 3-chlorocatechol was found. The presence of these DBPs in water samples collected through drinking water treatment was studied in order to evaluate their formation under real conditions. Both compounds were generated through treatment from raw river water samples containing ATSs at concentration levels ranging from 1 to 15 ng/L for MDA and from 2.3 to 78 ng/L for MDMA. One of them, (3-chlorobenzo)-1,3-dioxole, found after the first chlorination step, was eliminated after ozone and GAC treatment while the MDMA DBP mainly generated after the postchlorination step, showed to be recalcitrant and it was found in final treated waters at concentrations ranging from 0.5 to 5.8 ng/L. PMID- 22534123 TI - Value of preoperative imaging in the diagnostics of isolated metopic suture synostosis: a risk-benefit analysis. AB - Radiographic evaluation including plain radiographies and computed tomographic (CT) scans are considered as a necessary tool for diagnosis of craniosynostosis. As recently concerns about harmful effects of ionising radiation in children have been raised, some authors have suggested the use of magnetic resonance imaging (MRI) as a helpful alternative in preoperative imaging of patients with isolated metopic synostosis. Besides confirming the diagnosis of trigonocephaly, MRI is the superior technique for the evaluation of underlying brain anomalies. However, if the benefit of preoperative imaging justifies possible side effects is still discussed controversially. Hence, this study investigated the value of preoperative imaging for the diagnosis of isolated synostosis of the metopic suture compared to a sole clinical examination. In a series of 63 cases with isolated metopic craniosynostosis operated at the Department of Oral and Maxillofacial Surgery, 48 (76.2%) patients received additional radiography or MRI investigation, while in 15 (23.8%) patients the diagnosis was based on clinical examinations only. In all patients, diagnosis was confirmed intra-operatively by a fused metopic suture. CT scans with three-dimensional reconstruction (12.5%) or plain radiographs (39.6%) did not provide any additional benefit for the diagnosis or the surgical treatment. In 23 patients (47.9%), MRI showed the typical soft-tissue alterations like triangular brain deformation in the frontal area. Besides these findings, no brain or other underlying anomalies were diagnosed which had required any additional treatment. The incidence of underlying brain abnormalities in isolated metopic synostosis seemed not to be different from that of the general population. As the characteristic clinical manifestations were sufficient for an accurate diagnosis of isolated metopic synostosis, and with respect to the biological effects of ionising radiation and risks of sedation especially in infants, preoperative imaging should be reduced to a minimum. PMID- 22534124 TI - The anatomy of the pectoral nerves and its significance in breast augmentation, axillary dissection and pectoral muscle flaps. AB - BACKGROUND: In many plastic surgeries, a detailed understanding of the pectoral nerve anatomy is often required. However, the information available on the anatomy of pectoral nerves is sparse and unclear. The purpose of this study is to provide detailed anatomical information on the pectoral nerves to allow for their easy intra-operative localisation and to improve the understanding of the pectoral muscle innervation. METHODS: We dissected 26 brachial plexuses from 15 fresh cadavers. The origins, locations, courses and branches of the pectoral nerves were recorded. RESULTS: We found three constant branches of the pectoral nerve. The superior branch travelled in a straight course to the pectoralis major to innervate the clavicular aspect. The middle branch coursed on the under surface of the pectoralis major near the pectoral branch of the thoraco-acromial artery to innervate the muscle's sternal aspect. The inferior branch passed beneath the pectoralis minor muscle to innervate the pectoralis minor muscle and the costal aspect of the pectoralis major muscle. CONCLUSIONS: Knowing the pectoral nerves' origins, courses and connections, in addition to understanding the functional consequences of iatrogenically severing these nerves, leads to a better understanding of the pectoral muscle's innervation. Precise anatomical data on the pectoral nerve allow for its easy localisation during axillary breast augmentation, axillary dissection, removal of the pectoralis minor muscle and harvesting the pectoralis major muscle island flap. PMID- 22534125 TI - Acute vasculitis resulting in free flap failure: the importance of early recognition and options for management. AB - Unusual or unexpected medical causes for free flap failure do occur but are uncommon. We present a rare case of a fibula free flap failure due to an acute vasculitis which was undiagnosed until after the flap had failed. In addition to two successful flap salvages and intravenous heparin, an epoprostenol infusion was commenced but a third salvage was not successful. The vasculitis resulted in marked blood vessel wall thickening, and cutaneous manifestations which presented as late signs. High peri-nuclear anti nuclear cytoplasmic antibody (pANCA) and myeloperoxidase (MOP) titres were subsequently found and histology from several blood vessels showed marked inflammation throughout the wall. A diagnosis of microscopic polyangiitis was made and high dose steroids were subsequently commenced. Interestingly, he had vasculitis several years previously treated with oral steroids but had been discharged from the rheumatology clinic. This rare case illustrates the potential hazards of free flap surgery in the vasculitides and discusses the warning signs and various management options to reduce the likelihood of flap failure in these patients. PMID- 22534127 TI - NAP1 family histone chaperones are required for somatic homologous recombination in Arabidopsis. AB - Homologous recombination (HR) is essential for maintaining genome integrity and variability. To orchestrate HR in the context of chromatin is a challenge, both in terms of DNA accessibility and restoration of chromatin organization after DNA repair. Histone chaperones function in nucleosome assembly/disassembly and could play a role in HR. Here, we show that the NUCLEOSOME ASSEMBLY PROTEIN1 (NAP1) family histone chaperones are required for somatic HR in Arabidopsis thaliana. Depletion of either the NAP1 group or NAP1-RELATED PROTEIN (NRP) group proteins caused a reduction in HR in plants under normal growth conditions as well as under a wide range of genotoxic or abiotic stresses. This contrasts with the hyperrecombinogenic phenotype caused by the depletion of the CHROMATIN ASSEMBLY FACTOR-1 (CAF-1) histone chaperone. Furthermore, we show that the hyperrecombinogenic phenotype caused by CAF-1 depletion relies on NRP1 and NRP2, but the telomere shortening phenotype does not. Our analysis of DNA lesions, H3K56 acetylation, and expression of DNA repair genes argues for a role of NAP1 family histone chaperones in nucleosome disassembly/reassembly during HR. Our study highlights distinct functions for different families of histone chaperones in the maintenance of genome stability and establishes a crucial function for NAP1 family histone chaperones in somatic HR. PMID- 22534126 TI - Alternative oxidases (AOX1a and AOX2) can functionally substitute for plastid terminal oxidase in Arabidopsis chloroplasts. AB - The immutans (im) variegation mutant of Arabidopsis thaliana is caused by an absence of PTOX, a plastid terminal oxidase bearing similarity to mitochondrial alternative oxidase (AOX). In an activation tagging screen for suppressors of im, we identified one suppression line caused by overexpression of AOX2. AOX2 rescued the im defect by replacing the activity of PTOX in the desaturation steps of carotenogenesis. Similar results were obtained when AOX1a was reengineered to target the plastid. Chloroplast-localized AOX2 formed monomers and dimers, reminiscent of AOX regulation in mitochondria. Both AOX2 and AOX1a were present in higher molecular weight complexes in plastid membranes. The presence of these proteins did not generally affect steady state photosynthesis, aside from causing enhanced nonphotochemical quenching in both lines. Because AOX2 was imported into chloroplasts using its own transpeptide, we propose that AOX2 is able to function in chloroplasts to supplement PTOX activity during early events in chloroplast biogenesis. We conclude that the ability of AOX1a and AOX2 to substitute for PTOX in the correct physiological and developmental contexts is a striking example of the capacity of a mitochondrial protein to replace the function of a chloroplast protein and illustrates the plasticity of the photosynthetic apparatus. PMID- 22534129 TI - The Gatsby Plant Science Summer School: inspiring the next generation of plant science researchers. AB - We provide evidence from a 5-year study to show that a single concerted effort at the start of undergraduate study can have a clear and lasting effect on the attitudes of students toward plant science. Attendance at a week-long residential plant science summer school in the first year of an undergraduate degree resulted in many students changing courses to include more plant science and increased numbers of graduates selecting plant-based PhDs. The evidence shows that the Gatsby Plant Science Summer School has increased the pool of high-quality plant science related PhD applicants in the UK and has had a positive impact on students' career aspirations. The results are discussed within the context of enhancing the pipeline of future plant scientists and reversing the decline of this vulnerable and strategically important subject relevant to addressing food security and other major global challenges. We have shown that a single well designed and timely intervention can influence future student behavior and as such offers a framework of potential use to other vulnerable disciplines. PMID- 22534128 TI - Lotus japonicus E3 ligase SEVEN IN ABSENTIA4 destabilizes the symbiosis receptor like kinase SYMRK and negatively regulates rhizobial infection. AB - The Lotus japonicus SYMBIOSIS RECEPTOR-LIKE KINASE (SYMRK) is required for symbiotic signal transduction upon stimulation of root cells by microbial signaling molecules. Here, we identified members of the SEVEN IN ABSENTIA (SINA) E3 ubiquitin-ligase family as SYMRK interactors and confirmed their predicted ubiquitin-ligase activity. In Nicotiana benthamiana leaves, SYMRK-yellow fluorescent protein was localized at the plasma membrane, and interaction with SINAs, as determined by bimolecular fluorescence complementation, was observed in small punctae at the cytosolic interface of the plasma membrane. Moreover, fluorescence-tagged SINA4 partially colocalized with SYMRK and caused SYMRK relocalization as well as disappearance of SYMRK from the plasma membrane. Neither the localization nor the abundance of Nod-factor receptor1 was altered by the presence of SINA4. SINA4 was transcriptionally upregulated during root symbiosis, and rhizobia inoculated roots ectopically expressing SINA4 showed reduced SYMRK protein levels. In accordance with a negative regulatory role in symbiosis, infection thread development was impaired upon ectopic expression of SINA4. Our results implicate SINA4 E3 ubiquitin ligase in the turnover of SYMRK and provide a conceptual mechanism for its symbiosis-appropriate spatio-temporal containment. PMID- 22534130 TI - The role of EHD proteins at the neuronal synapse. AB - Eps15 homology domain (EHD) proteins are conserved adenosine triphosphatases that are involved in membrane remodeling. EHD family members are structurally similar to the guanosine triphosphatase (GTPase) dynamin, and both are essential for the fission step of clathrin-mediated endocytosis. This Journal Club highlights a recent study by Jakobsson et al. that reports the unexpected finding that, rather than having a redundant function, EHD can regulate dynamin activity. Dynamin helices assemble around the neck of budding endocytic vesicles; as dynamin helices lengthen, the neck of the growing bud may become so long that GTP hydrolysis is no longer sufficient to promote fission. EHD increases the efficiency of dynamin-induced fission by restricting the length of dynamin helices. Furthermore, EHD is able to bind both dynamin and amphiphysin. Therefore, we propose a model whereby amphiphysin recruits both EHD and dynamin in neurons to regulate clathrin-dependent synaptic vesicle endocytosis. PMID- 22534131 TI - Linking NAADP to ion channel activity: a unifying hypothesis. AB - Nicotinic acid adenine dinucleotide phosphate (NAADP) is a potent Ca(2+) releasing second messenger that might regulate different ion channels, including the ryanodine receptor, two-pore channels, and TRP-ML1 (transient receptor potential channel, subtype mucolipin 1), a Ca(2+) channel localized to lysosomes. New evidence suggests that a 22- and 23-kilodalton pair of proteins could be the receptor for NAADP. Labeling of NAADP binding proteins was independent of overexpression or knockout of two-pore channels, indicating that two-pore channels, although regulated by NAADP, are not the NAADP receptors. I propose that NAADP binding proteins could bind to different ion channels and thus may explain how NAADP regulates diverse ion channels. PMID- 22534132 TI - Differential beta-arrestin-dependent conformational signaling and cellular responses revealed by angiotensin analogs. AB - The angiotensin type 1 receptor (AT1R) and its octapeptide ligand, angiotensin II (AngII), engage multiple downstream signaling pathways, including those mediated by heterotrimeric guanosine triphosphate-binding proteins (G proteins) and those mediated by beta-arrestin. Here, we examined AT1R-mediated Galpha(q) and beta arrestin signaling with multiple AngII analogs bearing substitutions at position 8, which is critical for binding to the AT1R and its activation of G proteins. Using assays that discriminated between ligand-promoted recruitment of beta arrestin to the AT1R and its resulting conformational rearrangement, we extend the concept of biased signaling to include the analog's propensity to differentially promote conformational changes in beta-arrestin, two responses that were differentially affected by distinct G protein-coupled receptor kinases. The efficacy of AngII analogs in activating extracellular signal-regulated kinases 1 and 2 correlated with the stability of the complexes between beta arrestin and AT1R in endosomes, rather than with the extent of beta-arrestin recruitment to the receptor. In vascular smooth muscle cells, the ligand-induced conformational changes in beta-arrestin correlated with whether the ligand promoted beta-arrestin-dependent migration or proliferation. Our data indicate that biased signaling not only occurs between G protein- and beta-arrestin mediated pathways but also occurred at the level of the AT1R and beta-arrestin, such that different AngII analogs selectively engaged distinct beta-arrestin conformations, which led to specific signaling events and cell responses. PMID- 22534133 TI - Studying the dynamics of SLP-76, Nck, and Vav1 multimolecular complex formation in live human cells with triple-color FRET. AB - Protein-protein interactions regulate and control many cellular functions. A multimolecular complex consisting of the adaptor proteins SLP-76 (Src homology 2 domain-containing leukocyte protein of 76 kD), Nck, and the guanine nucleotide exchange factor Vav1 is recruited to the T cell side of the interface with an antigen-presenting cell during initial T cell activation. This complex is crucial for regulation of the actin machinery, antigen recognition, and signaling in T cells. We studied the interactions between these proteins as well as the dynamics of their recruitment into a complex that governs cytoskeletal reorganization. We developed a triple-color Forster resonance energy transfer (3FRET) system to observe the dynamics of the formation of this trimolecular signaling complex in live human T cells and to follow the three molecular interactions in parallel. Using the 3FRET system, we demonstrated that dimers of Nck and Vav1 were constitutively formed independently of both T cell activation and the association between SLP-76 and Nck. After T cell receptor stimulation, SLP-76 was phosphorylated, which enabled the binding of Nck. A point mutation in the proline rich site of Vav1, which abolishes its binding to Nck, impaired actin rearrangement, suggesting that Nck-Vav1 dimers play a critical role in regulation of the actin machinery. We suggest that these findings revise the accepted model of the formation of a complex of SLP-76, Nck, and Vav1 and demonstrate the use of 3FRET as a tool to study signal transduction in live cells. PMID- 22534134 TI - [Anticoagulant therapeutics: In order not to jeopardize a potential therapeutical progress]. PMID- 22534135 TI - [Neurological manifestations of dengue]. AB - BACKGROUND: An epidemic of type 4 dengue was raging in the Pacific from 2008 to 2010. During this period, several patients were hospitalized at the Hospital Centre of Tahiti for neurological disorders occurring during a dengue fever. These events are not the typical picture, which is represented by a flu-like syndrome and sometimes, in severe cases, a haemorrhagic syndrome or shock. METHOD: We have established a review of the literature reporting the cases of dengue fever associated with neurological disorders with the terms "dengue" and "neurology". Despite the retrospective nature and incomplete data, we attempted to establish the epidemiological characteristics of these events, to give an order of frequency of these symptoms and the pathophysiological mechanisms involved. RESULTS: Among patients with neurological disorders occurring during a dengue fever, disorders of central nervous system are the most common. Among disorders of central nervous system, encephalopathy is by far the most encountered. CONCLUSION: None of observed neurologic disorders presenting with specific manifestation, discussion of dengue as etiology in endemic areas or in return from endemic area is well-founded. PMID- 22534136 TI - Implant breast reconstruction followed by radiotherapy: can helical tomotherapy become a standard irradiation treatment? AB - To evaluate the benefits and limitations of helical tomotherapy (HT) for loco regional irradiation of patients after a mastectomy and immediate implant-based reconstruction. Ten breast cancer patients with retropectoral implants were randomly selected for this comparative study. Planning target volumes (PTVs) 1 (the volume between the skin and the implant, plus margin) and 2 (supraclavicular, infraclavicular, and internal mammary nodes, plus margin) were 50 Gy in 25 fractions using a standard technique and HT. The extracted dosimetric data were compared using a 2-tailed Wilcoxon matched-pair signed-rank test. Doses for PTV1 and PTV2 were significantly higher with HT (V95 of 98.91 and 97.91%, respectively) compared with the standard technique (77.46 and 72.91%, respectively). Similarly, the indexes of homogeneity were significantly greater with HT (p = 0.002). HT reduced ipsilateral lung volume that received >=20 Gy (16.7 vs. 35%), and bilateral lungs (p = 0.01) and neighboring organs received doses that remained well below tolerance levels. The heart volume, which received 25 Gy, was negligible with both techniques. HT can achieve full target coverage while decreasing high doses to the heart and ipsilateral lung. However, the low doses to normal tissue volumes need to be reduced in future studies. PMID- 22534137 TI - Interfraction rotation of the prostate as evaluated by kilovoltage X-ray fiducial marker imaging in intensity-modulated radiotherapy of localized prostate cancer. AB - To quantify the daily rotation of the prostate during a radiotherapy course using stereoscopic kilovoltage (kV) x-ray imaging and intraprostatic fiducials for localization and positioning correction. From 2005 to 2009, radio-opaque fiducial markers were inserted into 38 patients via perineum into the prostate. The ExacTrac/Novalis Body X-ray 6-day image acquisition system (ET/NB; BrainLab AG, Feldkirchen, Germany) was used to determine and correct the target position. During the first period in 10 patients we recorded all rotation errors but used only Y (table) for correction. For the next 28 patients we used for correction all rotational coordinates, i.e., in addition Z (superior-inferior [SI] or roll) and X (left-right [LR] or tilt/pitch) according to the fiducial marker position by use of the Robotic Tilt Module and Varian Exact Couch. Rotation correction was applied above a threshold of 1 degrees displacement. The systematic and random errors were specified. Overall, 993 software-assisted rotational corrections were performed. The interfraction rotation errors of the prostate as assessed from the radiodense surrogate markers around the three axes Y, Z, and X were on average 0.09, -0.52, and -0.01 degrees with standard deviations of 2.01, 2.30, and 3.95 degrees , respectively. The systematic uncertainty per patient for prostate rotation was estimated with 2.30, 1.56, and 4.13 degrees and the mean random components with 1.81, 2.02, and 3.09 degrees . The largest rotational errors occurred around the X-axis (pitch), but without preferring a certain orientation. Although the error around Z (roll) can be compensated on average by a transformation with 4 coordinates, a significant error around X remains and advocates the full correction with 6 coordinates. Rotational errors as assessed via daily stereoscopic online imaging are significant and dominate around X. Rotation possibly degrades the dosimetric coverage of the target volume and may require suitable strategies for correction. PMID- 22534138 TI - The dosimetric impact of daily setup error on target volumes and surrounding normal tissue in the treatment of prostate cancer with intensity-modulated radiation therapy. AB - The purpose of this study was to evaluate the impact of daily setup error and interfraction organ motion on the overall dosimetric radiation treatment plans. Twelve patients undergoing definitive intensity-modulated radiation therapy (IMRT) treatments for prostate cancer were evaluated in this institutional review board-approved study. Each patient had fiducial markers placed into the prostate gland before treatment planning computed tomography scan. IMRT plans were generated using the Eclipse treatment planning system. Each patient was treated to a dose of 8100 cGy given in 45 fractions. In this study, we retrospectively created a plan for each treatment day that had a shift available. To calculate the dose, the patient would have received under this plan, we mathematically "negated" the shift by moving the isocenter in the exact opposite direction of the shift. The individualized daily plans were combined to generate an overall plan sum. The dose distributions from these plans were compared with the treatment plans that were used to treat the patients. Three-hundred ninety daily shifts were negated and their corresponding plans evaluated. The mean isocenter shift based on the location of the fiducial markers was 3.3 +/- 6.5 mm to the right, 1.6 +/- 5.1 mm posteriorly, and 1.0 +/- 5.0 mm along the caudal direction. The mean D95 doses for the prostate gland when setup error was corrected and uncorrected were 8228 and 7844 cGy (p < 0.002), respectively, and for the planning target volume (PTV8100) was 8089 and 7303 cGy (p < 0.001), respectively. The mean V95 values when patient setup was corrected and uncorrected were 99.9% and 87.3%, respectively, for the PTV8100 volume (p < 0.0001). At an individual patient level, the difference in the D95 value for the prostate volume could be >1200 cGy and for the PTV8100 could approach almost 2000 cGy when comparing corrected against uncorrected plans. There was no statistically significant difference in the D35 parameter for the surrounding normal tissue except for the dose received by the penile bulb and the right hip. Our dosimetric evaluation suggests significant underdosing with inaccurate target localization and emphasizes the importance of accurate patient setup and target localization. Further studies are needed to evaluate the impact of intrafraction organ motion, rotation, and deformation on doses delivered to target volumes. PMID- 22534139 TI - HybridArc: a novel radiation therapy technique combining optimized dynamic arcs and intensity modulation. AB - This investigation focuses on possible dosimetric and efficiency advantages of HybridArc-a novel treatment planning approach combining optimized dynamic arcs with intensity-modulated radiation therapy (IMRT) beams. Application of this technique to two disparate sites, complex cranial tumors, and prostate was examined. HybridArc plans were compared with either dynamic conformal arc (DCA) or IMRT plans to determine whether HybridArc offers a synergy through combination of these 2 techniques. Plans were compared with regard to target volume dose conformity, target volume dose homogeneity, sparing of proximal organs at risk, normal tissue sparing, and monitor unit (MU) efficiency. For cranial cases, HybridArc produced significantly improved dose conformity compared with both DCA and IMRT but did not improve sparing of the brainstem or optic chiasm. For prostate cases, conformity was improved compared with DCA but not IMRT. Compared with IMRT, the dose homogeneity in the planning target volume was improved, and the maximum doses received by the bladder and rectum were reduced. Both arc-based techniques distribute peripheral dose over larger volumes of normal tissue compared with IMRT, whereas HybridArc involved slightly greater volumes of normal tissues compared with DCA. Compared with IMRT, cranial cases required 38% more MUs, whereas for prostate cases, MUs were reduced by 7%. For cranial cases, HybridArc improves dose conformity to the target. For prostate cases, dose conformity and homogeneity are improved compared with DCA and IMRT, respectively. Compared with IMRT, whether required MUs increase or decrease with HybridArc was site-dependent. PMID- 22534140 TI - Can dead bacterial cells be defined and are genes expressed after cell death? AB - There is a paucity of knowledge on gene expression in dead bacterial cells. Why would this knowledge be useful? The cells are dead. However, the time duration of gene expression following cell death is often unknown, and possibly in the order of minutes. In addition, it is a challenge to determine if bacterial cells are dead, or viable but non-culturable (VBNC), and what is an agreed upon correct definition of dead bacteria. Cells in the bacterial population or community may die at different rates or times and this complicates both the viability and gene expression analysis. In this article, the definition of dead bacterial cells is discussed and its significance in continued gene expression in cells following death. The definition of living and dead has implications for possible, completely, synthetic bacterial cells that may be capable of growth and division. PMID- 22534142 TI - Full potential x-ray absorption calculations using time dependent density functional theory. AB - We report the implementation of a fully relativistic time dependent density functional theory (TDDFT) method for carrying out x-ray absorption spectroscopy calculations for extended systems. This is the first time that a TDDFT simulation of x-ray absorption in extended systems has featured a full potential ground state calculation. We prove that this unusual feature of the TDDFT implementation unequivocally yields improvement over the previous muffin-tin calculation methods. PMID- 22534141 TI - PCB-95 promotes dendritic growth via ryanodine receptor-dependent mechanisms. AB - BACKGROUND: Aroclor 1254 (A1254) interferes with normal dendritic growth and plasticity in the developing rodent brain, but the mechanism(s) mediating this effect have yet to be established. Non-dioxin-like (NDL) polychlorinated biphenyls (PCBs) enhance the activity of ryanodine receptor (RyR) calcium ion (Ca(2+)) channels, which play a central role in regulating the spatiotemporal dynamics of intracellular Ca(2+) signaling. Ca(2+) signaling is a predominant factor in shaping dendritic arbors, but whether PCB potentiation of RyR activity influences dendritic growth is not known. OBJECTIVE: We determined whether RyR activity is required for PCB effects on dendritic growth. METHODS AND RESULTS: Golgi analysis of hippocampi from weanling rats confirmed that developmental exposure via the maternal diet to NDL PCB-95 (2,2',3,5'6-pentachlorobiphenyl), a potent RyR potentiator, phenocopies the dendrite-promoting effects of A1254. Dendritic growth in dissociated cultures of primary hippocampal neurons and in hippocampal slice cultures is similarly enhanced by PCB-95 but not by PCB-66 (2,3,4',4-tetrachlorobiphenyl), a congener with negligible effects on RyR activity. The dendrite-promoting effects of PCB-95 are evident at concentrations as low as 2 pM and are inhibited by either pharmacologic blockade or siRNA knockdown of RyRs. CONCLUSIONS: Our findings demonstrate that environmentally relevant levels of NDL PCBs modulate neuronal connectivity via RyR-dependent effects on dendritic arborization. In addition, these findings identify RyR channel dysregulation as a novel mechanism contributing to dysmorphic dendritogenesis associated with heritable and environmentally triggered neurodevelopmental disorders. PMID- 22534143 TI - Chemical consequences of cutaneous photoageing. AB - Human skin, in common with other organs, ages as a consequence of the passage of time, but in areas exposed to solar ultraviolet radiation, the effects of this intrinsic ageing process are exacerbated. In particular, both the severity and speed of onset of age-related changes, such as wrinkle formation and loss of elasticity, are enhanced in photoaged (also termed extrinsically aged) as compared with aged, photoprotected, skin. The anatomy of skin is characterised by two major layers: an outer, avascular, yet highly cellular and dynamic epidermis and an underlying vascularised, comparatively static and cell-poor, dermis. The structural consequences of photoageing are mainly evident in the extracellular matrix-rich but cell-poor dermis where key extracellular matrix proteins are particularly susceptible to photodamage. Most investigations to date have concentrated on the cell as both a target for and mediator of, ultraviolet radiation-induced photoageing. As the main effectors of dermal remodelling produced by cells (extracellular proteases) generally have low substrate specificity, we recently suggested that the differential susceptibility of key extracellular matrix proteins to the processes of photoageing may be due to direct, as opposed to cell-mediated, photodamage.In this review, we discuss the experimental evidence for ultraviolet radiation (and related reactive oxygen species)-mediated differential degradation of normally long lived dermal proteins including the fibrillar collagens, elastic fibre components, glycoproteins and proteoglycans. Whilst these components exhibit highly diverse primary and hence macro- and supra-molecular structures, we present evidence that amino acid composition alone may be a useful predictor of age-related protein degradation in both photoexposed and, as a consequence of differential oxidation sensitivity, photoprotected, tissues. PMID- 22534145 TI - Awareness of methylmercury in fish and fish consumption among pregnant and postpartum women and women of childbearing age in the United States. AB - In 2004, the Food and Drug Administration (FDA) and the Environmental Protection Agency (EPA) reissued joint advice recommending that pregnant women, nursing mothers, young children, and women who may become pregnant not consume fish high in mercury such as shark, swordfish, king mackerel, and tilefish, and not consume more than 12 ounces (340.2g) of other lower mercury fish per week. These groups were encouraged to eat up to 12 ounces (340.2g) of low mercury fish per week to get the health benefits of fish. Using a survey of 1286 pregnant women, 522 postpartum women, and a control group of 1349 non-pregnant/non-postpartum women of childbearing age, this study evaluated awareness of mercury as a problem in food and examined fish consumption levels across groups using regression analysis. We also compared awareness of mercury as a problem in food to awareness of Listeria, dioxins and PCBs. We found that the majority of all 3 groups of women were aware of mercury and that nearly all women in all 3 groups limited consumption consistent with the advice; they ate less than 340.2g (12 oz) of fish per week and no high mercury fish. Compared with the control group, pregnant and postpartum women were more likely to be aware of mercury as a problem in food, and pregnant women ate less total fish and were less likely to eat fish, to eat more than 340.2g (12 oz) of fish, and to eat high mercury fish. However, all groups ate much less than the recommended 340.2g (12 oz) of low mercury fish per week for optimum health benefits. Among women who ate fish, the median intake of total fish was 51.6 g/wk (1.8 oz/wk), 71.4 g/wk (2.5 oz/wk), and 85.3 g/wk (3.0 oz/wk) for the pregnant, postpartum, and control groups, respectively. Thus, it appears that the targeted groups of women were more aware of mercury and were eating fish within the FDA/EPA guidelines, but these women may be missing the health benefits to themselves and their children of eating a sufficient amount of fish. PMID- 22534144 TI - Bioaccumulation, biotransformation and trophic transfer of arsenic in the aquatic food chain. AB - The occurrence, distribution, speciation, and biotransformation of arsenic in aquatic environment (marine and freshwater) have been studied extensively by several research groups during last couple of decades. However, most of those studies have been conducted in marine waters, and the results are available in a number of reviews. Speciation, bioaccumulation, and biotransformation of arsenic in freshwaters have been studied in recent years. Although inorganic arsenic (iAs) species dominates in both marine and freshwaters, it is biotransformed to methyl and organoarsenic species by aquatic organisms. Phytoplankton is considered as a major food source for the organisms of higher trophic levels in the aquatic food chain, and this autotrophic organism plays important role in biotransformation and distribution of arsenic species in the aquatic environment. Bioaccumulation and biotransformation of arsenic by phytoplankton, and trophic transfer of arsenic in marine and freshwater food chains have been important concerns because of possible human health effects of the toxic metalloid from dietary intake. To-date, most of the studies on arsenic biotransformation, speciation, and trophic transfer have focused on marine environments; little is known about these processes in freshwater systems. This article has been reviewed the bioaccumulation, biotransformation, and trophic transfer of arsenic in marine and freshwater food chain. PMID- 22534146 TI - A 3-year-old girl with vomiting and diarrhea. PMID- 22534147 TI - HIV status, burden of comorbid disease, and biomarkers of inflammation, altered coagulation, and monocyte activation. AB - BACKGROUND: Biomarkers of inflammation, altered coagulation, and monocyte activation are associated with mortality and cardiovascular disease (CVD) in the general population and among human immunodeficiency virus (HIV)-infected people. We compared biomarkers for inflammation, altered coagulation, and monocyte activation between HIV-infected and uninfected people in the Veterans Aging Cohort Study (VACS). METHODS: Biomarkers of inflammation (interleukin-6 [IL-6]), altered coagulation (d-dimer), and monocyte activation (soluble CD14 [sCD14]) were measured in blood samples from 1525 HIV-infected and 843 uninfected VACS participants. Logistic regression was used to determine the association between HIV infection and prevalence of elevated (>75th percentile) biomarkers, adjusting for confounding comorbidities. RESULTS: HIV-infected veterans had less prevalent CVD, hypertension, diabetes, obesity, hazardous drinking, and renal disease, but more dyslipidemia, hepatitis C, and current smoking than uninfected veterans. Compared to uninfected veterans, HIV-infected veterans with HIV-1 RNA >=500 copies/mL or CD4 count <200 cells/uL had a significantly higher prevalence of elevated IL-6 (odds ratio [OR], 1.54; 95% confidence interval [CI],1.14-2.09; OR, 2.25; 95% CI, 1.60-3.16, respectively) and d-dimer (OR, 1.97; 95% CI, 1.44-2.71, OR, 1.68; 95% CI, 1.22-2.32, respectively) after adjusting for comorbidities. HIV infected veterans with a CD4 cell count <200 cells/uL had significantly higher prevalence of elevated sCD14 compared to uninfected veterans (OR, 2.60; 95% CI, 1.64-4.14). These associations still persisted after restricting the analysis to veterans without known confounding comorbid conditions. CONCLUSIONS: These data suggest that ongoing HIV replication and immune depletion significantly contribute to increased prevalence of elevated biomarkers of inflammation, altered coagulation, and monocyte activation. This contribution is independent of and in addition to the substantial contribution from comorbid conditions. PMID- 22534148 TI - Evolving epidemiologic characteristics of invasive group a streptococcal disease in Utah, 2002-2010. AB - BACKGROUND: Invasive group A Streptococcus (GAS) infections are associated with substantial morbidity and mortality. Recent national surveillance data report stable rates of invasive GAS disease, although these may not capture geographic variation. METHODS: We performed a population-based, retrospective laboratory surveillance study of invasive GAS disease among Utah residents from 2002-2010. We used Intermountain Healthcare's electronic medical records and data warehouse to identify patients from whom GAS was isolated by culture. We defined clinical syndromes of invasive GAS disease on the basis of International Classification of Diseases, Ninth Revision codes. We abstracted demographic information, comorbidities, and microbiologic and laboratory findings. RESULTS: From 2002 2010, we identified 1514 cases of invasive GAS disease among Utah residents. The estimated mean annual incidence rate was 6.3 cases/100,000 persons, which was higher than the national rate of 3.6 cases/100,000 (P < .01). The incidence of invasive GAS disease in Utah rose from 3.5 cases/100,000 persons in 2002 to 9.8 cases/100,000 persons in 2010 (P = .01). Among children aged <18 years, the incidence of invasive GAS increased from 3.0 cases/100,000 children in 2002 to 14.1 cases/100,000 children in 2010 (P < .01). The increase in the pediatric population was due, in part, to an increase in GAS pneumonia (P = .047). The rate of invasive GAS disease in adults aged 18-64 years increased from 3.4 cases/100 000 persons in 2002 to 7.6 cases/100,000 persons in 2010 (P = .02). Rates among those aged >=65 years were stable. The incidence of acute rheumatic fever declined from 6.1 to 3.7 cases/100,000 (P = .04). CONCLUSIONS: The epidemiologic characteristics of invasive GAS disease in Utah has changed substantially over the past decade, including a significant increase in the overall incidence of invasive disease-driven primarily by increasing disease in younger persons-that coincided temporally with a decrease in the incidence of acute rheumatic fever. PMID- 22534150 TI - Editorial commentary: The epidemiology of group a streptococci: a need to understand the significance of the fertile fields. PMID- 22534149 TI - Mortality in hepatitis C virus-infected patients with a diagnosis of AIDS in the era of combination antiretroviral therapy. AB - BACKGROUND: Before the introduction of combination antiretroviral therapy (cART), patients infected with the human immunodeficiency virus (HIV) rarely died of liver disease. In resource-rich countries, cART dramatically increased longevity. As patients survived longer, hepatitis C virus (HCV) infection became a leading cause of death; however, because patients with AIDS continue to have 5-fold greater mortality than non-AIDS patients, it is unclear whether HCV infection increases mortality in them. METHODS: In this investigation, which is part of the Longitudinal Studies of the Ocular Complications of AIDS, plasma banked at enrollment from 2025 patients with AIDS as defined by the Centers for Disease Control and Prevention were tested for HCV RNA and antibodies. RESULTS: Three hundred thirty-seven patients had HCV RNA (chronic infection), 91 had HCV antibodies and no HCV RNA (cleared infection), and 1597 had no HCV markers. Median CD4(+) T-cell counts/uL were 200 (chronic), 193 (cleared), and 175 (no markers). There were 558 deaths. At a median follow-up of 6.1 years, patients with chronic HCV had a 50% increased risk of mortality compared with patients with no HCV markers (relative risk [RR], 1.5; 95% confidence interval [CI], 1.2 1.9; P = .001) in an adjusted model that included known risk factors. Mortality was not increased in patients with cleared infection (RR, 0.9; 95% CI, .6-1.5; P = .82). In patients with chronic HCV, 20.4% of deaths were liver related compared with 3.8% in patients without HCV. CONCLUSIONS: Chronic HCV infection is independently associated with a 50% increase in mortality among patients with a diagnosis of AIDS, despite competing risks. Effective HCV treatment may benefit HIV/HCV-coinfected patients with AIDS. PMID- 22534151 TI - Fluorescent zinc sensor with minimized proton-induced interferences: photophysical mechanism for fluorescence turn-on response and detection of endogenous free zinc ions. AB - A new fluorescent zinc sensor (HNBO-DPA) consisting of 2-(2'-hydroxy-3' naphthyl)benzoxazole (HNBO) chromophore and a di(2-picolyl)amine (DPA) metal chelator has been prepared and examined for zinc bioimaging. The probe exhibits zinc-induced fluorescence turn-on without any spectral shifts. Its crystal structure reveals that HNBO-DPA binds a zinc ion in a pentacoordinative fashion through the DPA and HNBO moieties. Steady-state photophysical studies establish zinc-induced deprotonation of the HNBO group. Nanosecond and femtosecond laser flash photolysis and electrochemical measurements provide evidence for zinc induced modulation of photoinduced electron transfer (PeT) from DPA to HNBO. Thus, the zinc-responsive fluorescence turn-on is attributed to suppression of PeT exerted by deprotonation of HNBO and occupation of the electron pair of DPA, a conclusion that is further supported by density functional theory and time dependent density functional theory (DFT/TD-DFT) calculations. Under physiological conditions (pH 7.0), the probe displays a 44-fold fluorescence turn on in response to zinc ions with a K(d) value of 12 pM. The fluorescent response of the probe to zinc ions is conserved over a broad pH range with its excellent selectivity for zinc ions among biologically relevant metal ions. In particular, its sensing ability is not altered by divalent transition metal ions such as Fe(II), Cu(II), Cd(II), and Hg(II). Cell experiments using HNBO-DPA show its suitability for monitoring intracellular zinc ions. We have also demonstrated applicability of the probe to visualize intact zinc ions released from cells that undergo apoptosis. More interestingly, zinc-rich pools in zebrafish embryos are traced with HNBO-DPA during early developmental stages. The results obtained from the in vitro and in vivo imaging studies demonstrate the practical usefulness of the probe to detect zinc ions. PMID- 22534152 TI - Hemodynamic effects of fluid restriction in preterm infants with significant patent ductus arteriosus. AB - OBJECTIVE: To determine the hemodynamic impact of fluid restriction in preterm newborns with significant patent ductus arteriosus. STUDY DESIGN: Newborns >=24 and <32 weeks' gestational age with significant patent ductus arteriosus were eligible for this prospective multicenter observational study. We recorded hemodynamic and Doppler echocardiographic variables before and 24 hours after fluid restriction. RESULTS: Eighteen newborns were included (gestational age 24.8 +/- 1.1 weeks, birth weight 850 +/- 180 g). Fluid intake was decreased from 145 +/- 15 to 108 +/- 10 mL/kg/d. Respiratory variables, fraction of inspired oxygen, blood gas values, ductus arteriosus diameter, blood flow-velocities in ductus arteriosus, in the left pulmonary artery and in the ascending aorta, and the left atrial/aortic root ratio were unchanged after fluid restriction. Although systemic blood pressure did not change, blood flow in the superior vena cava decreased from 105 +/- 40 to 61 +/- 25 mL/kg/min (P < .001). The mean blood flow velocity in the superior mesenteric artery was lower 24 hours after starting fluid restriction. CONCLUSIONS: Our results do not support the hypothesis that fluid restriction has beneficial effects on pulmonary or systemic hemodynamics in preterm newborns. PMID- 22534153 TI - Preterm infants of lower gestational age at birth have greater waist circumference-length ratio and ponderal index at term age than preterm infants of higher gestational ages. AB - OBJECTIVE: To assess anthropometric changes from birth to hospital discharge in infants born preterm and compare with a reference birth cohort of infants born full-term. STUDY DESIGN: Retrospective chart review was conducted of 501 preterm and 1423 full-term infants. We evaluated birth and hospital discharge weight, length, and waist circumference (WC). WC/length ratio (WLR), ponderal index, and body mass index (BMI) were calculated. Preterm infants were categorized into quartiles (Q1-4) based on birth weight (BW). RESULTS: At birth mean length, WC, WLR, BMI, and ponderal index were all significantly less for preterm infants in the lowest BW quartile (Q1) than preterm infants in higher BW quartiles or full term infants. Although their weight, length, and BMI remained significantly less at discharge, preterm infants in Q1 had a disproportionate increase in WLR and ponderal index such that at discharge their WLR and ponderal index were greater than infants in Q2-3 and comparable with infants in Q4 and full-term infants. Discharge WLR and ponderal index in Q1 were significantly higher with decreasing postmenstrual age at birth. CONCLUSIONS: Preterm infants of a lower birth postmenstrual age have disproportionate increases in WLR and ponderal index that are suggestive of increased visceral and total adiposity. PMID- 22534154 TI - [Article on SEIMC Procedure No.42: Environmental microbiological monitoring]. AB - The inanimate hospital environment is rarely implicated in infection transmission, except among vulnerable patients. Some authors argue against the use of environmental surveillance cultures because the tests can be expensive and time consuming, and because they should not be used instead of quality control and good practices in disinfection and maintenance procedures. Routine environmental sampling is not usually advised, except in situations where sampling is directed by epidemiologic principles, and results can be applied to adopt infection control measures. The incidence of health-care associated infections can be minimised by appropriate maintenance of medical equipment such as endoscope cleaning and disinfection, adherence to water-quality standards for haemodialysis, and to ventilation standards for specialised care environments such as isolation units, or operating rooms. This paper reviews the current knowledge on surveillance cultures in these settings in order to prevent iatrogenic infections in operating and isolation rooms, haemodialysis and endoscope reprocessing units, and cultures related to nosocomial infection outbreaks. PMID- 22534155 TI - [Outpatient antibiotic prescription in Aragon and the differences by gender and age]. AB - BACKGROUND: The objective of the study is to describe the use of antibiotics among outpatients, the pattern of sub-group prescribing, as well as to analyse age- and gender-specific patterns of use, and to identify high users. METHODS: A retrospective, observational study was designed, in which the rate of patients treated with antibiotics in Aragon (Spain) in 2008 was calculated. Data were extracted from the Aragon Pharmaceutical Consumption Database, a complete register of all dispensed prescriptions in Aragon in 2008. Defined Daily Dose (DDD) per 1000 inhabitants per day (DID) was calculated, and the number of patients who had received an antibacterial drug was analysed. RESULTS: The antibiotic prescription rate in 2008 in Aragon was 339.81 per 1000 inhabitants (303.54 and 375.34 per 1000 for men and women, respectively). The DID was 23.72. Population prevalence of antimicrobial use changed markedly between different age groups and between genders. Children (0-4 years) had the highest rate. Females, in general, used antibiotics more than males. Penicillins was the most used antibacterial group in all age groups, except for people of advanced age (>80 years), where quinolones were the most frequently used. Most of the individuals defined as high users (using more than 60 DDDs/year) were in the 60-80 years age group. CONCLUSION: We observed a high antibiotic prescription rate in Aragon, particularly in children. There are differences between men and women in the use of antibiotics. PMID- 22534156 TI - Removal of petroleum sulfonate from aqueous solutions using freshly generated magnesium hydroxide. AB - Freshly generated magnesium hydroxide (FGMH), produced by adding water-soluble magnesium salts to highly alkaline solutions, was used to remove anionic surfactant petroleum sulfonate (PS) from aqueous solutions. Adsorption experiments were carried out to investigate the effects of pH, adsorbent dosage, contact time, PS concentration, and temperature. The results showed that FGMH displayed excellent treatment efficiency for PS in the pH range 12.0-13.0. The maximum PS removal efficiency was reached within 60 s. The best dosage of magnesium chloride was 2.0 g/L. The adsorption capacity of FGMH for PS decreased as the temperature increased from 303 K to 333 K. The adsorption process was exothermic. The removal mechanism of PS by FGMH may be a coagulation-adsorption process involving a combination of flocculation, adsorption, charge neutralization, and netting catch affection. The results of this study showed that FGMH can be effectively used to treat surfactant wastewaters. PMID- 22534157 TI - Comparison of cytotoxic and inflammatory responses of pristine and functionalized multi-walled carbon nanotubes in RAW 264.7 mouse macrophages. AB - The increased application of carbon nanotubes (CNTs) has raised the level of public concern regarding possible toxicities. Using in vitro cellular assays, we were able to assess the immunotoxicity of pristine multi-wall carbon nanotubes (MWCNTs) and their derivatives, covalently functionalized with carboxyl (COOH) or polyethylene glycol (PEG), in rodent macrophage cells. Moreover, special focus was placed on the role of surface modification and nanotubes aggregation on toxicity. Results showed that pristine MWCNTs reduce cell viability compared with functionalized MWCNTs in RAW 264.7 macrophages when incubated at concentrations of 25, 50, 100, 200, 400, and 800 MUg/mL. However, in addition to causing cytotoxicity, functionalized MWCNTs induce serious inflammatory responses, as indicated by the production of inflammatory cytokines including TNF-alpha, IL 1beta and IL-6 at various MWCNTs concentrations (25, 50, 100, and 200 MUg/mL). Particle surface modification and dispersion status in biological medium were key factors in determining cytotoxicity. These findings imply that MWCNTs-induced inflammatory responses in macrophages may be associated with surface modification and aggregation of MWCNTs, which is reflected by alteration of inflammatory cytokine expression. PMID- 22534158 TI - How reliable are Hounsfield-unit measurements in forensic radiology? AB - OBJECTIVE: To assess the reliability of computed tomography (CT) numbers, also known as Hounsfield-units (HU) in the differentiation and identification of forensically relevant materials and to provide instructions to improve the reproducibility of HU measurements in daily forensic practice. MATERIALS AND METHODS: We scanned a phantom containing non-organic materials (glass, rocks and metals) on three different CT scanners with standardized parameters. The t-test was used to assess the influence of the scanner, the size and shape of different types of regions-of-interest (ROI), the composition and shape of the object, and the reader performance on HU measurements. Intra-class correlation coefficient was used to assess intra- and inter-reader reliability. RESULTS: HU values did not change significantly as a function of ROI-shape or -size (p>0.05). Intra reader reliability reached ICC values >0.929 (p<0.001). Inter-reader reliability was also excellent with an ICC of 0.994 (p<0.001). Four of seven objects yielded significantly different CT numbers at different levels within the object (p<0.05). In 6/7 objects the HU changed significantly from CT scanner to CT scanner (p<0.05). CONCLUSION: Reproducible CT number measurements can be achieved through correct ROI-placement and repeat measurements within the object of interest. However, HU may differ from CT-scanner to CT-scanner. In order to obtain comparable CT numbers we suggest that a dedicated Forensic Reference Phantom be developed. PMID- 22534159 TI - Large-Eddy Simulation of pollutant dispersion around a cubical building: analysis of the turbulent mass transport mechanism by unsteady concentration and velocity statistics. AB - Pollutant transport due to the turbulent wind flow around buildings is a complex phenomenon which is challenging to reproduce with Computational Fluid Dynamics (CFD). In the present study we use Large-Eddy Simulation (LES) to investigate the turbulent mass transport mechanism in the case of gas dispersion around an isolated cubical building. Close agreement is found between wind-tunnel measurements and the computed average and standard deviation of concentration in the wake of the building. Since the turbulent mass flux is equal to the covariance of velocity and concentration, we perform a detailed statistical analysis of these variables to gain insight into the dispersion process. In particular, the fact that turbulent mass flux in the streamwise direction is directed from the low to high levels of mean concentration (counter-gradient mechanism) is explained. The large vortical structures developing around the building are shown to play an essential role in turbulent mass transport. PMID- 22534160 TI - [The 2009 pandemic influenza A (H1N1) virus infection: experience of a paediatric service at a third-level hospital in Lisbon, Portugal]. AB - INTRODUCTION: The 2009 pandemic influenza A (H1N1) (i.e., Pandemic Influenza) is an acute, infectious illness caused by the influenza A (H1N1) 2009 virus. This disease involves respiratory, gastrointestinal and systemic symptoms along with a high incidence occurring at a paediatric age. OBJECTIVE: To study the epidemiology, approach and complications of Pandemic Influenza in the paediatric population of a third-level hospital in Lisbon, Portugal, between September and December 2009. MATERIALS AND METHODS: A retrospective study of children who had received the influenza A (H1N1) 2009 virus test by real time reverse transcriptase-polymerase chain reaction (RT-PCR) were included. The following parameters were analysed: number of tests, days of illness, sex, outcome, age, symptoms, hospitalisation and reason for testing. The distribution and test results were compared with the Pandemic Influenza activity in Portugal. Moreover, among the confirmed cases of infection, the need for hospitalisation, risk factors, severity, chest radiography, treatment and complications were also examined. RESULTS: A total of 351 tests were performed, on average, 2.6 days after initial symptoms, which included 71.8% outpatients and 30% children younger than three years of age. Overall, 54.4% of the tests were positive for the influenza A (H1N1) 2009 virus and the main comorbidities were respiratory and cardiovascular in nature. One hundred ninety-one cases were confirmed by laboratory studies, and 13.6% required hospitalisation, which lasted an average of 2.7 days. In 82.2% of the cases, the severity was mild, with fever and cough as the most frequent symptoms at 91.9% and 93.7%, respectively. Therapy with the antiviral drug, oseltamivir, was implemented in 35.6% of the cases. Additionally, oseltamivir was used in twelve infants younger than one year in age, including a one-month-old infant with no observed side effects. DISCUSSION: The epidemiological data obtained are consistent with the published national and international studies. The scientific information available and the recommendations of the irectorate-General for Health contributed to the uniformity of the approaches and the successful outcome. PMID- 22534161 TI - Oxidative stress biomarkers in patients with untreated obstructive sleep apnea syndrome. AB - BACKGROUND: The pathogenic role of oxidative stress in obstructive sleep apnea syndrome (OSAS) is still a matter of debate, with different studies obtaining contrasting results. METHODS: The aim of the present study was to evaluate three well-known markers of oxidative stress (advanced oxidation protein products [AOPP], ferric reducing antioxidant power [FRAP], and total glutathione [GSH]) in a cohort of 41 untreated patients with a new diagnosis of OSAS. RESULTS: We observed that OSAS patients showed increased protein oxidative damage and impaired antioxidant defenses. Patients with more severe OSAS had a lower total antioxidant capability. Preliminary data on a subgroup of patients (n=7) treated with CPAP show a significant increment of the FRAP values (P<0.005). CONCLUSIONS: Our findings indicate that such oxidative stress markers may be useful to detect and monitor redox imbalance in OSAS. Moreover, FRAP might be a new useful biomarker to monitor in vivo the oxidative response to CPAP therapy. PMID- 22534162 TI - Evidence against equimolarity of large repeat arrangements and a predominant master circle structure of the mitochondrial genome from a monkeyflower (Mimulus guttatus) lineage with cryptic CMS. AB - Despite intense investigation for over 25 years, the in vivo structure of plant mitochondrial genomes remains uncertain. Mapping studies and genome sequencing generally produce large circular chromosomes, whereas electrophoretic and microscopic studies typically reveal linear and multibranched molecules. To more fully assess the structure of plant mitochondrial genomes, the complete sequence of the monkeyflower (Mimulus guttatus DC. line IM62) mitochondrial DNA was constructed from a large (35 kb) paired-end shotgun sequencing library to a high depth of coverage (~30*). The complete genome maps as a 525,671 bp circular molecule and exhibits a fairly conventional set of features including 62 genes (encoding 35 proteins, 24 transfer RNAs, and 3 ribosomal RNAs), 22 introns, 3 large repeats (2.7, 9.6, and 29 kb), and 96 small repeats (40-293 bp). Most paired-end reads (71%) mapped to the consensus sequence at the expected distance and orientation across the entire genome, validating the accuracy of assembly. Another 10% of reads provided clear evidence of alternative genomic conformations due to apparent rearrangements across large repeats. Quantitative assessment of these repeat-spanning read pairs revealed that all large repeat arrangements are present at appreciable frequencies in vivo, although not always in equimolar amounts. The observed stoichiometric differences for some arrangements are inconsistent with a predominant master circular structure for the mitochondrial genome of M. guttatus IM62. Finally, because IM62 contains a cryptic cytoplasmic male sterility (CMS) system, an in silico search for potential CMS genes was undertaken. The three chimeric open reading frames (ORFs) identified in this study, in addition to the previously identified ORFs upstream of the nad6 gene, are the most likely CMS candidate genes in this line. PMID- 22534163 TI - Accumulation and rapid decay of non-LTR retrotransposons in the genome of the three-spine stickleback. AB - The diversity and abundance of non-long terminal repeat (LTR) retrotransposons (nLTR-RT) differ drastically among vertebrate genomes. At one extreme, the genome of placental mammals is littered with hundreds of thousands of copies resulting from the activity of a single clade of nLTR-RT, the L1 clade. In contrast, fish genomes contain a much more diverse repertoire of nLTR-RT, represented by numerous active clades and families. Yet, the number of nLTR-RT copies in teleostean fish is two orders of magnitude smaller than in mammals. The vast majority of insertions appear to be very recent, suggesting that nLTR-RT do not accumulate in fish genomes. This pattern had previously been explained by a high rate of turnover, in which the insertion of new elements is offset by the selective loss of deleterious inserts. The turnover model was proposed because of the similarity between fish and Drosophila genomes with regard to their nLTR-RT profile. However, it is unclear if this model applies to fish. In fact, a previous study performed on the puffer fish suggested that transposable element insertions behave as neutral alleles. Here we examined the dynamics of amplification of nLTR-RT in the three-spine stickleback (Gasterosteus aculeatus). In this species, the vast majority of nLTR-RT insertions are relatively young, as suggested by their low level of divergence. Contrary to expectations, a majority of these insertions are fixed in lake and oceanic populations; thus, nLTR-RT do indeed accumulate in the genome of their fish host. This is not to say that nLTR RTs are fully neutral, as the lack of fixed long elements in this genome suggests a deleterious effect related to their length. This analysis does not support the turnover model and strongly suggests that a much higher rate of DNA loss in fish than in mammals is responsible for the relatively small number of nLTR-RT copies and for the scarcity of ancient elements in fish genomes. We further demonstrate that nLTR-RT decay in fish occurs mostly through large deletions and not by the accumulation of small deletions. PMID- 22534164 TI - Genome-wide survey of mutual homologous recombination in a highly sexual bacterial species. AB - The nature of a species remains a fundamental and controversial question. The era of genome/metagenome sequencing has intensified the debate in prokaryotes because of extensive horizontal gene transfer. In this study, we conducted a genome-wide survey of outcrossing homologous recombination in the highly sexual bacterial species Helicobacter pylori. We conducted multiple genome alignment and analyzed the entire data set of one-to-one orthologous genes for its global strains. We detected mosaic structures due to repeated recombination events and discordant phylogenies throughout the genomes of this species. Most of these genes including the "core" set of genes and horizontally transferred genes showed at least one recombination event. Taking into account the relationship between the nucleotide diversity and the minimum number of recombination events per nucleotide, we evaluated the recombination rate in every gene. The rate appears constant across the genome, but genes with a particularly high or low recombination rate were detected. Interestingly, genes with high recombination included those for DNA transformation and for basic cellular functions, such as biosynthesis and metabolism. Several highly divergent genes with a high recombination rate included those for host interaction, such as outer membrane proteins and lipopolysaccharide synthesis. These results provide a global picture of genome wide distribution of outcrossing homologous recombination in a bacterial species for the first time, to our knowledge, and illustrate how a species can be shaped by mutual homologous recombination. PMID- 22534165 TI - Acentric magnetic and optical properties of chalcopyrite (CuFeS2). AB - The absence of spatial inversion symmetry at both local (point group 4) and global (crystal class (4)2m) levels greatly influences the electronic properties of chalcopyrite (CuFeS(2)). The predicted dichroic signals (natural circular, non reciprocal and magneto-chiral) and resonant, parity-odd Bragg diffraction patterns at space-group forbidden reflections portray the uncommon, acentric symmetry. Despite extensive experimental investigations over several decades, by mineralogists, chemists and physicists, there is no consensus view about the electrical and magnetic properties of chalcopyrite. New spectroscopic and diffraction data, gathered at various temperatures in the vicinity of the copper and iron L(2,3) edges, provide necessary confidence in the magnetic motif used in our analytic simulations of x-ray scattering. With the sample held at 10 and 65 K, our data establish beyond reasonable doubt that there is no valence transition, and ordering of the copper moments as the origin of the low temperature phase (T(c) ~ 53 K) is ruled out. PMID- 22534166 TI - Decarboxylation mechanisms in biological system. AB - This review examines the mechanisms propelling cofactor-independent, organic cofactor-dependent and metal-dependent decarboxylase chemistry. Decarboxylation, the removal of carbon dioxide from organic acids, is a fundamentally important reaction in biology. Numerous decarboxylase enzymes serve as key components of aerobic and anaerobic carbohydrate metabolism and amino acid conversion. In the past decade, our knowledge of the mechanisms enabling these crucial decarboxylase reactions has continued to expand and inspire. This review focuses on the organic cofactors biotin, flavin, NAD, pyridoxal 5'-phosphate, pyruvoyl, and thiamin pyrophosphate as catalytic centers. Significant attention is also placed on the metal-dependent decarboxylase mechanisms. PMID- 22534167 TI - [Renovascular hypertension secondary to pheochromocytoma]. PMID- 22534168 TI - [Are the CHADS(2) and CHA(2)DS(2)-VASc scales useful instruments to initiate anticoagulant medication?]. PMID- 22534169 TI - Design and immunological properties of Helicobacter pylori glycoconjugates based on a truncated lipopolysaccharide lacking Lewis antigen and comprising an alpha 1,6-glucan chain. AB - To investigate the vaccine potential of H. pylori lipopolysaccharide (LPS), truncated LPS of H. pylori strain 26695 HP0826::Kan lacking O-chain polysaccharide and comprising an extended alpha-1,6-linked glucan chain was conjugated to tetanus toxoid (TT) or bovine serum albumin (BSA). Two approaches were used for delipidation or partial delipidation of H. pylori LPS: (1) mild hydrolysis resulting in delipidated LPS (dLPS) and (2) treatment with anhydrous hydrazine resulting in removal of O-linked fatty acids (LPS-OH). Both LPS-OH and dLPS were covalently linked through a 2-keto-3-deoxy-octulosonic acid (Kdo) residue to a diamino group-containing spacer, followed by conjugation to thiolated TT or BSA to give conjugates LPS-OH-TT, dLPS-BSA and dLPS-TT, respectively. The LPS-OH-TT, dLPS-BSA and dLPS-TT conjugates were immunogenic in both rabbits and mice, inducing strong and specific IgG responses against homologous and heterologous strains of H. pylori. Moreover, the rabbit post immune sera showed cross-reactivity against clinical isolates of H. pylori in a whole-cell indirect ELISA, which was further confirmed by indirect immunofluorescent microscopy. A tenfold stronger IgG immune response to the immunizing antigen was generated in mice and rabbits that received dLPS containing conjugate. The post-immune sera of rabbits immunized with LPS-OH-TT, dLPS-BSA or dLPS-TT displayed significant bactericidal activity against mutant and wild-type alpha-1,6-glucan-expressing strains and selected clinical isolates of H. pylori. Finally, partial protection against H. pylori challenge was demonstrated in mice vaccinated with dLPS-TT conjugate adjuvanted with cholera toxin. In summary, this study shows that glycoconjugates based on delipidated or partially delipidated LPS from H. pylori 26695 HP0826::Kan mutant induce broadly cross-reactive functional antibodies in immunized animals and should be considered for further vaccine development and testing. PMID- 22534170 TI - Qualities of care managers in chronic disease management: patients and providers' expectations. AB - BACKGROUND: The collaborative care model has been shown in studies to be effective in achieving sustained treatment outcomes in chronic disease management. Its success is highly dependent on active patient engagement, provider endorsement and effective care management. This study sought to ask patients and providers what qualities they look for in a care manager. METHOD: A questionnaire with 3 open ended questions was mailed out randomly to 1000 patients residing in Olmsted County, MN identified through the registry to have type 2 diabetes mellitus. Forty-two primary care providers received similar questionnaire with 2 open ended questions. Answers were qualitatively analyzed using coding and identification of major themes. RESULT: One hundred seventy-five patients and 22 providers responded. Both groups listed being knowledgeable, having good communication skills and certain personality traits as common themes on what are desirable qualities in a care manager. Patients felt that a care manager would be most helpful by being accessible. Providers listed undesirable qualities to include not being a team player and not knowing practice limitations. CONCLUSION: Both patients and providers have clear expectations of a care manager which carry significant implications in recruiting and training care managers for chronic disease management. PMID- 22534171 TI - Opposite regulation by PI3K/Akt and MAPK/ERK pathways of tissue factor expression, cell-associated procoagulant activity and invasiveness in MDA-MB-231 cells. AB - BACKGROUND: Tissue factor (TF), an initiator of blood coagulation, participates in cancer progression and metastasis. We recently found that inhibition of MAPK/ERK upregulated both full length TF (flTF) and soluble isoform TF (asTF) gene expression and cell-associated TF activity in breast cancer MDA-MB-231 cells. We explored the possible mechanisms, especially the possible interaction with EGFR and PI3K/Akt pathways. METHODS: A plasmid containing TF promoter -2174 ~ +128 plus luciferase reporter gene was introduced into MDA-MB-231 cells to evaluate TF promoter activity. In order to study the interaction of these pathways, ERK inhibitor (PD98059), PI3K inhibitors (LY294002, wortmannin), Akt inhibitor (A6730), and EGFR inhibitor (erlotinib) as well as the corresponding siRNAs were used to treat MDA-MB-231 cells, and ovarian cancer OVCAR-3 and SKOV-3 cells. Quantitative PCR and western blot were used to determine TF expression. One stage clotting assays were used to measure pro-coagulation activity of the MDA-MB-231 cells. RESULTS: We show that PI3K inhibitors LY294002, wortmannin and A6730 significantly inhibited TF promoter activity, and reduced TF mRNA and protein levels due to the inhibition of Akt phosphorylation. In contrast, ERK inhibitor PD98059 and ERK siRNA enhanced TF promoter activity by 2.5 fold and induced an increase in TF mRNA and protein levels in a dose dependent manner in these cells. The PI3K/Akt pathway was shown to be involved in PD98059-induced TF expression because the induction was inhibited by PI3K/Akt inhibitors. Most interestingly, the EGFR inhibitor erlotinib and EGFR siRNA also significantly suppressed PD98059- or ERK siRNA-induced TF promoter activity and TF protein expression. Similar results were found with ovarian cancer cells SKOV-3 and OVCAR 3. Furthermore, in MDA-MB-231, mRNA levels of asTF were regulated in a similar way to that of TF in response to the cell treatment. CONCLUSIONS: This study showed a regulatory mechanism in which MAPK/ERK signals inhibit EGFR/PI3K/Akt mediated TF expression in breast cancer MDA-MB-231 cells. The same regulation was observed in ovarian cancer OVCAR-3 and SKOV-3 cells. Interestingly, we observed that both flTF and asTF could be regulated in a parallel manner in MDA-MB-231. As the PI3K/Akt pathway and EGFR regulate TF expression in cancer cells, targeting these signaling components is expected to potentially inhibit TF expression associated tumor progression. PMID- 22534172 TI - Effect of tumor shape and size on drug delivery to solid tumors. AB - : Tumor shape and size effect on drug delivery to solid tumors are studied, based on the application of the governing equations for fluid flow, i.e., the conservation laws for mass and momentum, to physiological systems containing solid tumors. The discretized form of the governing equations, with appropriate boundary conditions, is developed for predefined tumor geometries. The governing equations are solved using a numerical method, the element-based finite volume method. Interstitial fluid pressure and velocity are used to show the details of drug delivery in a solid tumor, under an assumption that drug particles flow with the interstitial fluid. Drug delivery problems have been most extensively researched in spherical tumors, which have been the simplest to examine with the analytical methods. With our numerical method, however, more complex shapes of the tumor can be studied. The numerical model of fluid flow in solid tumors previously introduced by our group is further developed to incorporate and investigate non-spherical tumors such as prolate and oblate ones. Also the effects of the surface area per unit volume of the tissue, vascular and interstitial hydraulic conductivity on drug delivery are investigated. PMID- 22534173 TI - Effects of lime and compost on earthworm (Eisenia fetida) reproduction in copper and arsenic contaminated soils from the Puchuncavi Valley, Chile. AB - The Puchuncavi Valley in central Chile has been exposed to atmospheric depositions from a copper smelter. Nowadays, soils in the surrounding area are acidic and contaminated with Cu and As. The objective of this study was to determine the effectiveness of lime and compost for in situ immobilization of trace elements in the soils of the Puchuncavi Valley by using earthworms as bioindicators of toxicity. The lime and compost treatments significantly increased soil pH and decreased the soluble and exchangeable Zn, exchangeable Cu, and free Cu(2+) activity. However, the compost treatment increased soluble Cu, and soluble and exchangeable As. Lime application had no effect on earthworm reproduction in comparison with the unamended control, whereas the application of compost increased cocoon and juvenile production. There was a spatial variability of soil properties within treatments in the field plots. This allowed the identification of which soil properties were actually having an impact on earthworm reproduction. For both cocoon and juvenile production, soil organic matter (SOM) was a positive factor, i.e., more SOM increased cocoon or juvenile production. The toxicity (negative) factor was total soil As. However, total Cu and total As were well correlated (R(2)=0.80, p<0.001), hence some of the trends could have been masked. In summary, compost treatment was effective in improving the quality of soils of Puchuncavi Valley, increasing earthworm reproduction. Future Chilean legislation on maximum permissible concentrations of trace elements in soils should consider SOM content due to its effect on trace element solubility and bioavailability. PMID- 22534174 TI - Role of Fe(IV)-oxo intermediates in stoichiometric and catalytic oxidations mediated by iron pyridine-azamacrocycles. AB - An iron(II) complex with a pyridine-containing 14-membered macrocyclic (PyMAC) ligand L1 (L1 = 2,7,12-trimethyl-3,7,11,17-tetra-azabicyclo[11.3.1]heptadeca 1(17),13,15-triene), 1, was prepared and characterized. Complex 1 contains low spin iron(II) in a pseudo-octahedral geometry as determined by X-ray crystallography. Magnetic susceptibility measurements (298 K, Evans method) and Mossbauer spectroscopy (90 K, delta = 0.50(2) mm/s, DeltaE(Q) = 0.78(2) mm/s) confirmed that the low-spin configuration of Fe(II) is retained in liquid and frozen acetonitrile solutions. Cyclic voltammetry revealed a reversible one electron oxidation/reduction of the iron center in 1, with E(1/2)(Fe(III)/Fe(II)) = 0.49 V vs Fc(+)/Fc, a value very similar to the half-wave potentials of related macrocyclic complexes. Complex 1 catalyzed the epoxidation of cyclooctene and other olefins with H(2)O(2). Low-temperature stopped-flow kinetic studies demonstrated the formation of an iron(IV)-oxo intermediate in the reaction of 1 with H(2)O(2) and concomitant partial ligand oxidation. A soluble iodine(V) oxidant, isopropyl 2-iodoxybenzoate, was found to be an excellent oxygen atom donor for generating Fe(IV)-oxo intermediates for additional spectroscopic (UV vis in CH(3)CN: lambda(max) = 705 nm, epsilon ~ 240 M(-1) cm(-1); Mossbauer: delta = 0.03(2) mm/s, DeltaE(Q) = 2.00(2) mm/s) and kinetic studies. The electrophilic character of the (L1)Fe(IV)?O intermediate was established in rapid (k(2) = 26.5 M(-1) s(-1) for oxidation of PPh(3) at 0 degrees C), associative (DeltaH(?) = 53 kJ/mol, DeltaS(?) = -25 J/K mol) oxidation of substituted triarylphosphines (electron-donating substituents increased the reaction rate, with a negative value of Hammet's parameter rho = -1.05). Similar double-mixing kinetic experiments demonstrated somewhat slower (k(2) = 0.17 M(-1) s(-1) at 0 degrees C), clean, second-order oxidation of cyclooctene into epoxide with preformed (L1)Fe(IV)?O that could be generated from (L1)Fe(II) and H(2)O(2) or isopropyl 2-iodoxybenzoate. Independently determined rates of ferryl(IV) formation and its subsequent reaction with cyclooctene confirmed that the Fe(IV) oxo species, (L1)Fe(IV)?O, is a kinetically competent intermediate for cyclooctene epoxidation with H(2)O(2) at room temperature. Partial ligand oxidation of (L1)Fe(IV)?O occurs over time in oxidative media, reducing the oxidizing ability of the ferryl species; the macrocyclic nature of the ligand is retained, resulting in ferryl(IV) complexes with Schiff base PyMACs. NH-groups of the PyMAC ligand assist the oxygen atom transfer from ferryl(IV) intermediates to olefin substrates. PMID- 22534175 TI - Dentin sialophosphoprotein and dentin matrix protein-1: Two highly phosphorylated proteins in mineralized tissues. AB - Dentin sialophosphoprotein (DSPP) and dentin matrix protein-1 (DMP-1) are highly phosphorylated proteins that belong to the family of small integrin-binding ligand N-linked glycoproteins (SIBLINGs), and are essential for proper development of hard tissues such as teeth and bones. In order to understand how they contribute to tissue organization, DSPP and DMP-1 have been analyzed for over a decade using both in vivo and in vitro techniques. Among the five SIBLINGs, the DSPP and DMP-1 genes are located next to each other and their gene and protein structures are most similar. In this review we examine the phenotypes of the genetically engineered mouse models of DSPP and DMP-1 and also introduce complementary in vitro studies into the molecular mechanisms underlying these phenotypes. DSPP affects the mineralization of dentin more profoundly than DMP-1. In contrast, DMP-1 significantly affects bone mineralization and importantly controls serum phosphate levels by regulating serum FGF-23 levels, whereas DSPP does not show any systemic effects. DMP-1 activates integrin signalling and is endocytosed into the cytoplasm whereupon it is translocated to the nucleus. In contrast, DSPP only activates integrin-dependent signalling. Thus it is now clear that both DSPP and DMP-1 contribute to hard tissue mineralization and the tissues affected by each are different presumably as a result of their different expression levels. In fact, in comparison with DMP-1, the functional analysis of cell signalling by DSPP remains relatively unexplored. PMID- 22534176 TI - PCB-95 modulates the calcium-dependent signaling pathway responsible for activity dependent dendritic growth. AB - BACKGROUND: Non-dioxin-like (NDL) polychlorinated biphenyls (PCBs) promote dendritic growth in hippocampal neurons via ryanodine receptor (RyR)-dependent mechanisms; however, downstream signaling events that link enhanced RyR activity to dendritic growth are unknown. Activity-dependent dendritic growth, which is a critical determinant of neuronal connectivity in the developing brain, is mediated by calcium ion (Ca(2+))-dependent activation of Ca(2+)/calmodulin kinase I (CaMKI), which triggers cAMP response element binding protein (CREB)-dependent Wnt2 transcription. RyRs regulate the spatiotemporal dynamics of intracellular Ca(2+) signals, but whether RyRs promote dendritic growth via modulation of this signaling pathway is not known. OBJECTIVE: We tested the hypothesis that the CaMKI-CREB-Wnt2 signaling pathway couples NDL PCB-enhanced RyR activity to dendritic arborization. METHODS AND RESULTS: Ca(2+) imaging of dissociated cultures of primary rat hippocampal neurons indicated that PCB-95 (2,2',3,5'6 pentachlorobiphenyl; a potent RyR potentiator), enhanced synchronized Ca(2+) oscillations in somata and dendrites that were blocked by ryanodine. As determined by Western blotting and quantitative polymerase chain reaction, PCB-95 also activated CREB and up-regulated Wnt2. Blocking CaMKK, CaMKIalpha/gamma, MEK/ERK, CREB, or Wnt2 prevented PCB-95-induced dendritic growth. Antagonism of gamma-aminobutyric acid (GABA) receptors with bicuculline (BIC) phenocopied the dendrite-promoting effects of PCB-95, and pharmacological antagonism or siRNA knockdown of RyR blocked BIC-induced dendritic growth in dissociated and slice cultures of hippocampal neurons. CONCLUSIONS: RyR activity contributes to dynamic remodeling of dendritic architecture in response to NDL PCBs via CaMKI-CREB-Wnt2 signaling in rats. Our findings identify PCBs as candidate environmental risk factors for neurodevelopmental disorders, especially in children with heritable deficits in calcium signaling associated with autism. PMID- 22534177 TI - Commentary on Harper S, Strumpf EC, Kaufman JS. Do medical marijuana laws increase marijuana use? Replication study and extension. PMID- 22534178 TI - Is intergenerational social mobility related to the type and amount of physical activity in mid-adulthood? Results from the 1946 British birth cohort study. AB - PURPOSE: Greater levels of leisure-time or moderate-vigorous physical activity have consistently been found in those with greater socioeconomic position (SEP). Less is known about the effects of intergenerational social mobility. METHODS: We examined the influence of SEP and social mobility on mid-adulthood physical activity in the Medical Research Council National Survey of Health and Development. Two sub-domains of SEP were used: occupational class and educational attainment. Latent classes for walking, cycling, and leisure-time physical activity (LTPA) were used, plus sedentary behavior at age 36. Associations between types of physical activity and SEP were examined with the use of logistic or multinomial logistic regression. RESULTS: Being a manual worker oneself or having a father who was a manual worker was, relative to nonmanual work, associated with lower levels of sedentary behavior and greater walking activity, but also with lower LTPA. Compared with those who remained in a manual occupational class, upward occupational mobility was associated with more sedentary behavior, less walking, and increased LTPA. Associations with downward mobility were in the opposite directions. Similar results were obtained for educational attainment. CONCLUSIONS: This study found clear evidence of social differences in physical activity. Persistently high SEP and upward social mobility were associated with greater levels of LTPA but also increased sedentary behavior and less walking. PMID- 22534179 TI - Vascular malformations of the head and neck. AB - OBJECTIVE: Vascular malformations may appear anywhere in the body; 14-65% are in the head and neck. There are several treatments (sclerotherapy, surgery, laser treatment, and embolization, etc.), but standardized guidelines for these treatments are lacking. We conducted a retrospective review of venous or capillary malformations of the head and neck, and analyzed the epidemiology, pathology and treatment. METHODS: We retrospectively reviewed 67 patients with pathologically diagnosed venous or capillary malformations of the head and neck; we analyzed the location, pathology and treatment, as well as recurrent/residual cases. RESULTS: The oral cavity (59%) and nasal cavity (35%) were the most common locations. The frequency of each pathological type depended upon location. Surgery was undertaken in 65 cases, and sclerotherapy done in one patient. Sixty one cases (92%) had resectable lesions. However polycystic masses (>=3 cysts) and large masses (diameter, >=5cm) were significantly difficult to cure by single treatment. CONCLUSIONS: Surgery is indicated for localized small vascular malformations. However if the lesions >=5cm or polycystic lesions were more likely to recur after surgery alone in our study population. PMID- 22534181 TI - Expression pattern of the cannabinoid receptor genes in the frontal cortex of mood disorder patients and mice selectively bred for high and low fear. AB - Although the endocannabinoid system (ECS) has been implicated in brain development and various psychiatric disorders, precise mechanisms of the ECS on mood and anxiety disorders remain unclear. Here, we have investigated developmental and disease-related expression pattern of the cannabinoid receptor 1 (CB1) and the cannabinoid receptor 2 (CB2) genes in the dorsolateral prefrontal cortex (PFC) of humans. Using mice selectively bred for high and low fear, we further investigated potential association between fear memory and the cannabinoid receptor expression in the brain. The CB1, not the CB2, mRNA levels in the PFC gradually decrease during postnatal development ranging in age from birth to 50 years (r2 > 0.6 & adj. p < 0.05). The CB1 levels in the PFC of major depression patients were higher when compared to the age-matched controls (adj. p < 0.05). In mice, the CB1, not the CB2, levels in the PFC were positively correlated with freezing behavior in classical fear conditioning (p < 0.05). These results suggest that the CB1 in the PFC may play a significant role in regulating mood and anxiety symptoms. Our study demonstrates the advantage of utilizing data from postmortem brain tissue and a mouse model of fear to enhance our understanding of the role of the cannabinoid receptors in mood and anxiety disorders. PMID- 22534182 TI - Comparison of medical expenditure according to types of hospice care in patients with terminal cancer. AB - BACKGROUND: Hospice care is perceived as enhancing life quality for patients with advanced, incurable illness, but cost comparisons to nonhospice patients are difficult to make. Several studies demonstrated that palliative hospice care reduced medical expenditure in terminally ill patients compared with that of nonhospice care. METHODS: Patients with terminal cancer who were registered in Hospice Care Program (HCP) by the written consent and died during same admission period in Seoul Veterans Hospital, Seoul, Korea, between January 2009 and December 2009 were included. We compared medical expenditure according to the ward type (hospice ward and general ward) in patients who received palliative hospice care in Seoul Veterans Hospital, Korea. RESULTS: The daily total average expenditure for each inpatient was 193 930 and 266 161 in the hospice and general ward, respectively (P = .001). Daily expenditure of parenteral nutrition and laboratory blood tests/X-ray was also significantly lower in hospice ward compared with general ward (P = .002 and P = .006), respectively; 12 (17%) of 72 patients had been admitted in the intensive care unit during hospice care period in general ward (P = .014); 1 (3%) of 32 patients received blood products in hospice ward, but 13 (18%) patients received blood products in general ward during palliative hospice care (P = .039). CONCLUSION: Hospice ward type in palliative hospice therapy may contribute to reduce economic medical costs as well as to more specific total care for terminally ill patients with cancer. PMID- 22534180 TI - Course of comorbid anxiety disorders among adults with bipolar disorder in the U.S. population. AB - OBJECTIVE: To examine the prevalence and correlates of comorbid anxiety disorders among individuals with bipolar disorders (BP) and their association with prospectively ascertained comorbidities, treatment, and psychosocial functioning. METHOD: As part of the National Epidemiologic Survey on Alcohol and Related Conditions, 1600 adults who met lifetime DSM-IV criteria for BP-I (n = 1172) and BP-II (n = 428) were included. Individuals were evaluated using the Alcohol Use Disorder and Associated Disabilities Interview Schedule-DMS-IV Version and data was analyzed from Waves 1 and 2, approximately 3 years apart. RESULTS: Sixty percent of individuals with BP had at least one lifetime comorbid anxiety disorder. Individuals with BP and anxiety disorders shared lifetime risk factors for major depressive disorder and had prospectively more depressive and manic/hypomanic episodes, suicidal ideation, suicide attempts, and more treatment seeking than those without anxiety. During the follow-up, higher incidence of panic disorder, drug use disorders, and lower psychosocial functioning were found in individuals with BP with versus without anxiety disorders. CONCLUSIONS: Anxiety disorders are prospectively associated with elevated BP severity and BP related mental health service use. Early identification and treatment of anxiety disorders are warranted to improve the course and outcome of individuals with BP. PMID- 22534184 TI - Discovery, design and synthesis of Y-shaped peroxisome proliferator-activated receptor delta agonists as potent anti-obesity agents in vivo. AB - We have discovered and demonstrated the in vitro and in vivo PPARdelta-selective activity of novel Y-shaped agonists. These compounds activated hPPARdelta with EC(50) values between 1 and 523 nM. Surprisingly, compounds 10a, 11d, 11e and 11f were the most potent and most selective hPPARdelta agonists with 10(4)-fold selectivity over the other two subtypes, namely, hPPARalpha and hPPARgamma. The PPARdelta ligands 10a, 11e and 11f showed good bioavailability and in vivo efficacy. PMID- 22534183 TI - Genome sequencing and cancer. AB - New technologies for DNA sequencing, coupled with advanced analytical approaches, are now providing unprecedented speed and precision in decoding human genomes. This combination of technology and analysis, when applied to the study of cancer genomes, is revealing specific and novel information about the fundamental genetic mechanisms that underlie cancer's development and progression. This review outlines the history of the past several years of development in this realm, and discusses the current and future applications that will further elucidate cancer's genomic causes. PMID- 22534185 TI - Synthesis, characterization and in vitro antitumour activity of a series of novel platinum(II) complexes bearing Schiff base ligands. AB - A series was neutral platinum(II) complexes bearing OCH(3)- or F-substituted 3,4 bis(4-fluorophenyl)-1,6-bis(2-hydroxyphenyl)-2,5-diazahexa-1,5-dienes (diarylsalenes) were synthesized and tested for in vitro antitumour activity. The growth inhibitory effects depended on the configuration and the substitution pattern of the salicylidene moiety. The lead compound [meso-3,4-bis(4 fluorophenyl)-1,6-bis(2-hydroxyphenyl)-2,5-diazahexa-1,5-diene]platinum(II) (1 Pt) reduced the cell growth of MCF-7 (IC(50) = 7.6 MUM) and MDA-MB 231 cells (IC(50) = 10.0 MUM), but was inactive against HT-29 cells at the used concentration range (IC(50) > 20 MUM). The change of the configuration (meso -> d,l) at the 1,2-diimino-1,2-diarylethane bridge and methoxy substitution led to completely inactive compounds, while fluorine substituents increased the antiproliferative effects depending on their position (3-F < 5-F < 4-F < 6-F). Complex 10-Pt (6-F: IC(50)(MCF-7) = 1.5 MUM, IC(50)(MDA-MB 231) = 1.3 MUM, IC(50) (HT-29) = 2.6 MUM) was as active as cisplatin (IC(50)(MCF-7) = 1.6 MUM, IC(50)(MDA-MB 231) = 1.5 MUM, IC(50)(HT-29) = 4.1 MUM). PMID- 22534186 TI - Quinazolino-benzothiazoles: fused pharmacophores as anticonvulsant agents. AB - A series of 6-bromo-2-ethyl-3-(substitutedbenzo[d]thiazol-2-yl)quinazolin-4(3H) one 3 (a-j) were synthesized using appropriate synthetic route and evaluated experimentally by the Maximal Electro Shock (MES) and the PTZ-induced seizure methods. Among the tested compounds, 3-(benzo[d]thiazol-2-yl)-6-bromo-2 ethylquinazolin-4(3H)-one (3a) has shown significant activity against tonic seizure by the MES model and 6-bromo-2-ethyl-3-(6-methoxybenzo[d]thiazol-2 yl)quinazolin-4(3H)-one (3h) against clonic seizure by PTZ-induced seizure model. Not one of the selected compounds demonstrated any sign of neurotoxicity and hepatotoxicity. PMID- 22534187 TI - The use of cortisol for the objective assessment of stress in animals: pros and cons. PMID- 22534188 TI - Acepromazine pharmacokinetics: a forensic perspective. AB - Acepromazine (ACP) is a useful therapeutic drug, but is a prohibited substance in competition horses. The illicit use of ACP is difficult to detect due to its rapid metabolism, so this study investigated the ACP metabolite 2-(1 hydroxyethyl)promazine sulphoxide (HEPS) as a potential forensic marker. Acepromazine maleate, equivalent to 30mg of ACP, was given IV to 12 racing-bred geldings. Blood and urine were collected for 7days post-administration and analysed for ACP and HEPS by liquid chromatography-mass spectrometry (LC-MS). Acepromazine was quantifiable in plasma for up to 3h with little reaching the urine unmodified. Similar to previous studies, there was wide variation in the distribution and metabolism of ACP. The metabolite HEPS was quantifiable for up to 24h in plasma and 144h in urine. The metabolism of ACP to HEPS was fast and erratic, so the early phase of the HEPS emergence could not be modelled directly, but was assumed to be similar to the rate of disappearance of ACP. However, the relationship between peak plasma HEPS and the y-intercept of the kinetic model was strong (P=0.001, r(2)=0.72), allowing accurate determination of the formation pharmacokinetics of HEPS. Due to its rapid metabolism, testing of forensic samples for the parent drug is redundant with IV administration. The relatively long half-life of HEPS and its stable behaviour beyond the initial phase make it a valuable indicator of ACP use, and by determining the urine-to-plasma concentration ratios for HEPS, the approximate dose of ACP administration may be estimated. PMID- 22534189 TI - Epidemiological factors associated with the exposure of cattle to Coxiella burnetii in the Madrid region of Spain. AB - Domestic ruminants are considered to be the major source of Coxiella burnetii, the causative agent of Q fever. Even though Q fever is considered to be present worldwide, its distribution in many areas and countries remains unknown. Here, a serological assay was used to estimate the seroprevalence of C. burnetii in cattle in the Madrid region of Spain, to assess its spatial distribution, and to identify risk factors associated with positive results. Ten animals from each of 110 herds (n=1100) were randomly selected and analyzed using an ELISA test. In addition, epidemiological information, at both the herd and individual level, was collected. Variables for which an association with test results was detected in a bivariate analysis were included as predictors (main effects) in a multivariable logistic regression model. Herd and individual seroprevalences were 30% (95% CI=22.2-39.1) and 6.76% (95% CI=5.42-8.41), respectively, and a strong spatial dependence was identified at the first neighbour level using the Cuzick-Edwards test. Production type (dairy >beef >bullfighting) and age of animals (old vs. young) were the only variables significantly associated (P<0.05) with positive serological results at the herd and individual levels, respectively. These results indicate that cattle are exposed to C. burnetii in the Madrid region The high herd seroprevalence found in dairy herds (75%) indicates a higher risk of infection (probably for management reasons) whereas no C. burnetii positive bullfighting herds were identified. PMID- 22534190 TI - The mglA gene and its flanking regions in Brucella: the role of mglA in tolerance to hostile environments, Fe-metabolism and in vivo persistence. AB - We previously demonstrated that a spontaneous smooth small-colony variant of Brucella abortus S19 is characterized by increased in vivo persistence and the differential expression of a gene predicted to encode a galactoside transport ATP binding protein (mglA). In order to further investigate the role of this gene in the context of its flanking regions, we analyzed the respective DNA sequences from the formerly described B. abortus S19 as well as from avirulent B. neotomae 5K33 and compared these with published data from other Brucella species. Deletion mutagenesis of mglA in the large-colony variant of B. abortus S19 resulted in increased tolerance of the deletion mutant to a hyperosmotic (toxic), galactose containing medium as well as to oxidative stress (H(2)O(2)). Whilst the deletion mutant is characterized by reduced growth on solid Fe(3+)-containing minimal medium (small-colony morphology), in vivo studies in mice demonstrated statistical significant differences in the bacterial load of spleens in the pre immune, but not in the late phase of the infection. PMID- 22534191 TI - Chemical usage in production agriculture: do crop insurance and off-farm work play a part? AB - In recent years a growing body of literature in the agricultural policy arena has examined the association between crop insurance and off-farm employment. However, little is known about the extent to which these two activities may be related to environmental quality, in particular their impacts on fertilizer/chemical use of the farm. To fill this gap, this paper examines the effect of crop insurance and off-farm work on fertilizer/chemical expenses within the farm household framework. Quantile regression results from a national representative farm-level data show that off-farm work by the farm operator tends to decrease fertilizer/chemical expenses, and the effect is more pronounced at the higher percentiles of the distribution of fertilizer/chemical expense. In contrast, a positive effect of crop insurance on fertilizer/chemical expenses is evident, and the effect is robust across the entire distribution. PMID- 22534192 TI - Life cycle assessment of central softening of very hard drinking water. AB - Many consumers prefer softened water due to convenience issues such as avoidance of removing limescale deposits from household appliances and surfaces, and to reduce consumption of cleaning agents and laundry detergents leading to lower household expenses. Even though central softening of drinking water entailed an increased use of energy, sand and chemicals at the waterworks, the distributed and softened drinking water supported a decrease in consumption of energy and chemical agents in the households along with a prolonged service life of household appliances which heat water. This study used Life Cycle Assessment (LCA) to quantify the environmental impacts of central softening of drinking water considering both the negative effects at the waterworks and the positive effects imposed by the changed water quality in the households. The LCA modeling considered central softening of drinking water from the initial hardness of the region of study (Copenhagen, Denmark) which is 362 mg/L as CaCO(3) to a final hardness as CaCO(3) of 254 (a softening depth of 108) mg/L or 145 (a softening depth of 217) mg/L. Our study showed that the consumer preference can be met together with reducing the impact on the environment and the resource consumption. Environmental impacts decreased by up to 3 mPET (milli Personal Equivalent Targeted) and the break-even point from where central softening becomes environmentally beneficial was reached at a softening depth of only 22 mg/L as CaCO(3). Both energy-related and chemically related environmental impacts were reduced as well as the consumption of resources. Based on scarcity criteria, nickel was identified as the most problematic non-renewable resource in the system, and savings of up to 8 mPR (milli Person Reserve) were found. PMID- 22534193 TI - Dissecting substrate specificity of two rice BADH isoforms: Enzyme kinetics, docking and molecular dynamics simulation studies. AB - Fragrance rice (Oryza sativa) contains two isoforms of BADH, named OsBADH1 and OsBADH2. OsBADH1 is implicated in acetaldehyde oxidation in rice plant peroxisomes, while the non-functional OsBADH2 is believed to be involved in the accumulation of 2-acetyl-1-pyrroline, the major compound of aroma in fragrance rice. In the present study, site-directed mutagenesis, molecular docking and molecular dynamics simulation studies were used to investigate the substrate specificity towards Bet-ald and GAB-ald. Consistent with our previous study, kinetics data indicated that the enzymes catalyze the oxidation of GAB-ald more efficiently than Bet-ald and the OsBADH1 W172F and OsBADH2 W170F mutants displayed a higher catalytic efficiency towards GAB-ald. Molecular docking analysis and molecular dynamics simulations for the first time provided models for aldehyde substrate-bound complexes of OsBADHs. The amino acid residues, E262, L263, C296 and W461 of OsBADH1 and E260, L261, C294 and W459 of OsBADH2 located within 5 A of the OsBADH active site mainly interacted with GAB-ald forming strong hydrogen bonds in both OsBADH isoforms. Residues W163, N164, Q294, C296 and F397 of OsBADH1-Bet-ald and Y163, M167, W170, E260, S295 and C453 of OsBADH2 Bet-ald formed the main interaction sites while E260 showed an interaction energy of -14.21 kcal/mol. Unconserved A290 in OsBADH1 and W288 in OsBADH2 appeared to be important for substrate recognition similar to that observed in PsAMADHs. Overall, the results here help to explain how two homologous rice BADHs recognize the aldehyde substrate differently, a key property to their biological role. PMID- 22534194 TI - (+)-Medioresinol leads to intracellular ROS accumulation and mitochondria mediated apoptotic cell death in Candida albicans. AB - The phytochemical (+)-Medioresinol, a furofuran type lignan identification and isolation on the stem bark of Sambucus williamsii, which is a folk medicinal plant used in traditional medicine. (+)-Medioresinol is known to possess a lesishmanicidal activity and cardiovascular disease risk reduction but its antifungal effects have not yet been identified. In this study, to confirm (+) Medioresinol's antifungal properties and mode of action, we observed morphological and physiological change in Candida albicans. In cells exposed to (+)-Medioresinol, arrested the cell cycle and intracellular reactive oxygen species (ROS) which is a major cause of apoptosis were increased. The increase of ROS induced oxidative stress and the mitochondria dysfunction which causes release of pro-apoptotic factors. We investigated a series of characteristic cellular changes of apoptosis by using various apoptosis detection methods. We report here for the first time that (+)-Medioresinol has effects on mitochondria and induced the accumulation of ROS in C. albicans cells. We demonstrated that one of the important features of apoptosis, mitochondrial membrane depolarization is caused by ROS. Substantially, we investigated the release of cytochrome c, which is one of the factors of metacaspase activity. We also show that the effects of (+)-Medioresinol are mediated at an early stage in apoptosis acting on the plasma membrane phosphatidylserine externalization. In addition, (+) Medioresinol induced apoptotic morphological changes, showing the reduced cell size (low FSC) and enhanced intracellular density (high SSC). In late stage of confirmation of diagnostic markers in yeast apoptosis include the effects of nucleus morphological change, DNA fragmentation and condensation by influence of oxidative stress. These apoptotic phenomena represent that oxidative stress and mitochondria dysfunctions by inducing the phytochemical (+)-Medioresinol must be an important factors of the apoptotic process in C. albicans. These results support the elucidation of the underlying antifungal mechanisms of (+) Medioresinol. PMID- 22534196 TI - The role of van der Waals interaction in the tilted binding of amine molecules to the Au(111) surface. AB - We present the results of ab initio electronic structure calculations for the adsorption characteristics of three amine molecules on Au(111), which show that the inclusion of van der Waals interactions between the isolated molecule and the surface leads in general to good agreement with experimental data on the binding energies. Each molecule, however, adsorbs with a small tilt angle (between -5 and 9 degrees ). For the specific case of 1,4-diaminobenzene (BDA) our calculations reproduce the larger tilt angle (close to 24 degrees ) measured by photoemission experiments, when intermolecular (van der Waals) interactions (for about 8% coverage) are included. These results point not only to the important contribution of van der Waals interactions to molecule-surface binding energy, but also that of intermolecular interactions, often considered secondary to that between the molecule and the surface, in determining the adsorption geometry and pattern formation. PMID- 22534195 TI - Understanding leptin-dependent regulation of skeletal homeostasis. AB - Despite growing evidence for adipose tissue regulation of bone mass, the role of the adipokine leptin in bone remodeling remains controversial. The majority of in vitro studies suggest leptin enhances osteoblastic proliferation and differentiation while inhibiting adipogenic differentiation from marrow stromal cells. Alternatively, some evidence demonstrates either no effect or a pro apoptotic action of leptin on stromal cells. Similarly, in vivo work has demonstrated both positive and negative effects of leptin on bone mass. Most of the literature supports the idea that leptin suppresses bone mass by acting in the brainstem to reduce serotonin-dependent sympathetic signaling from the ventromedial hypothalamus to bone. However, other studies have found partly or entirely contrasting actions of leptin. Recently one study found a significant effect of surgery alone with intracerebroventricular administration of leptin, a technique crucial for understanding centrally-mediated leptin regulation of bone. Thus, two mainstream hypotheses for the role of leptin on bone emerge: 1) direct regulation through increased osteoblast proliferation and differentiation and 2) indirect suppression of bone formation through a hypothalamic relay. At the present time, it remains unclear whether these effects are relevant in only extreme circumstances (i.e. models with complete deficiency) or play an important homeostatic role in the regulation of peak bone acquisition and skeletal remodeling. Ultimately, determining the actions of leptin on the skeleton will be critical for understanding how the obesity epidemic may be impacting the prevalence of osteoporosis. PMID- 22534197 TI - Mechanistic and kinetic study on the ozonolysis of n-butyl vinyl ether, i-butyl vinyl ether and t-butyl vinyl ether. AB - Density functional theory (DFT) and ab initio method are employed to elucidate the mechanisms for O(3)-initiated oxidation of n-butyl vinyl ether (n-BVE) and its isomers (i-BVE and t-BVE). For each BVE, the reactions proceed via O(3) cycloaddition resulting in the formation of primary ozonides (POZs) and then two self-decomposition pathways of POZs are followed. Major products are identified to be formaldehyde and butyl formates (CH(3)CH(2)CH(2)CH(2)OCHO for n-BVE, (CH(3))(2)CHCH(2)OCHO for i-BVE and (CH(3))(3)COCHO for t-BVE). The total and individual rate constants for main product channels have been calculated using the modified multichannel Rice-Ramsperger-Kassel-Marcus (RRKM) approach. At 298 K and 101 kPa, the calculated total rate constants are 2.50*10(-16), 3.41*10(-16) and 4.17*10(-16) cm(3) molecule(-1) s(-1) for n-BVE+O(3), i-BVE+O(3) and t BVE+O(3), respectively, which are in perfect agreement with experimental results. The total rate coefficients are almost pressure independent in the range of 0.001 101 kPa but obviously positive temperature dependent over the whole study temperature range (200-400 K). Also, the favorable reaction pathways have been determined through the estimation of branching ratios. Moreover, the influence of alkoxy group structure on the reactivity of vinyl ethers was examined. PMID- 22534198 TI - Zero valent iron mediated degradation of the pharmaceutical diazepam. AB - Parameters that influence the zero valent iron mediated degradation of the pharmaceutical diazepam (DZP) were evaluated including the iron concentration and its pre-treatment, the effect of complexation with EDTA and oxic versus anoxic condition. It was observed that acid pre-treatment of iron particles is important for degradation efficiency and that H(2)SO(4) is a better choice than HCl, resulting in higher degradation of DZP. Under oxic conditions, the degradation of DZP achieved 96% after 60 min using Fe(0) (25 g L(-1)) pre-treated with H(2)SO(4) in the presence of EDTA (119 mg L(-1)), while mineralization achieved around 60% after the same time. Under anoxic conditions, degradation occurred, however at lower extent, achieving 67% after 120 min. The addition of EDTA improved the treatment efficiency in 20% leading to 99% DZP degradation after 120 min. The first intermediates formed during DZP degradation were identified using LC/MS analysis and revealed the formation of mono- and di-hydroxylated products from DZP during Fe(0)/EDTA/O(2) degradation, which evidences that (.)OH was the main oxidizing species formed in this process. PMID- 22534199 TI - Captopril and its dimer captopril disulfide: photodegradation, aerobic biodegradation and identification of transformation products by HPLC-UV and LC ion trap-MS(n). AB - In some countries effluents from hospitals and households are directly emitted into open ditches without any further treatment and with very little dilution. Under such circumstances photo- and biodegradation in the environment can occur. However, these processes do not necessarily end up with the complete mineralization of a chemical. Therefore, the biodegradability of photoproduct(s) by environmental bacteria is of interest. Cardiovascular diseases are the number one cause of death globally. Captopril (CP) is used in this study as it is widely used in Egypt and stated as one of the essential drugs in Egypt for hypertension. Three tests from the OECD series were used for biodegradation testing: Closed Bottle test (CBT; OECD 301 D), Manometric Respirometry test (MRT; OECD 301 F) and the modified Zahn-Wellens test (ZWT; OECD 302 B). Photodegradation (150 W medium pressure Hg-lamp) of CP was studied. Also CBT was performed for captopril disulfide (CPDS) and samples received after 64 min and 512 min of photolysis. The primary elimination of CP and CPDS was monitored by LC-UV at 210 nm and structures of photoproducts were assessed by LC-UV-MS/MS (ion trap). Analysis of photodegradation samples by LC-MS/MS revealed CP sulfonic acid as the major photodegradation product of CP. No biodegradation was observed for CP, CPDS and of the mixture resulting from photo-treatment after 64 min in CBT. Partial biodegradation in the CBT and MRT was observed in samples taken after 512 min photolysis and for CP itself in MRT. Complete biodegradation and mineralization of CP occurred in the ZWT. PMID- 22534200 TI - Environmental release of dioxins from reservoir sources during beach nourishment programs. AB - In late 1990s, USEPA/FDA made an important connection regarding the presence of elevated levels of dioxins (e.g., 1500 ng kg(-1) TEQ) in ball clays mined in Mississippi (USA) from a geological deposit dated to ~40 million years (Mississippi Embayment) that stretches over several states (northern part of Mississippi to Kentucky) and levels of dioxins in selected animal food sources. Following a recent beach nourishment program along the mid-Atlantic coast of the US, a number of dark gray, blue tinted nuggets of varying sizes were found on beach strands and near the shoreline. Using the presence of these balls of clay (shape, color, and knowledge regarding their use in pottery) on the beach, together with our direct experience analyzing ball clays for dioxins, we made a possible association between these clays and elevated dioxins. Concerns regarding the potential of nourishment programs to cause severe damage to our beaches drove us to test the dioxin content of nourishment exposed clays. A number of the nuggets, along with freshly dredged and deposited sand (collected the morning after nourishment) with the same coloration, and others (sun-bleached), collected approximately 2 weeks after the completion of the nourishment efforts, were analyzed for the presence of PCDD/Fs, PCBs, and selected semi-volatile chlorinated organics. The clay PCDD/F WHO2005-TEQs (dry weight; ND=DL; EMPC=EMPC) ranged from 0.41 to 5.78 ng kg(-1) with an average of 2.64 ng kg(-1), whereas the sand sample's TEQs ranged from 0.18 to 0.31 ng kg(-1) PCDD/F WHO-2005, with an average of 0.22 ng kg(-1). The average total tetra- through octachlorinated dibenzo-p-dioxin concentration was 2700 ng kg(-1) (with a maximum of 5800 ng kg( 1)) for the clays and 8.5 ng kg(-1) (with a maximum of 16.8 ng kg(-1)) for the sand samples. The congener 2,3,7,8-TCDD (TEF=1) was detected in half of the clay samples (0.11-0.77 ng kg(-1)). All of the clay and sand samples displayed an unambiguous and dominating 1,4,6,9-chlorination pattern across homolog groups. No other chlorinated aromatics were detected above background levels. The observations, along with the absence or an extremely low level of polychlorinated dibenzofurans, together with the mineralogical analysis, supports the conclusion that off-shore dredging activities are reaching reservoir sources containing dioxin-tainted, smectic/kaolinite clay minerals. Subsequent beach erosion provides additional environmental releases over time, as buried balls of clay from previous nourishment efforts become exposed. PMID- 22534201 TI - Assessment of the interrelation between photooxidation and biodegradation of selected polyesters after artificial weathering. AB - Three commercially available biodegradable polymers, two different aromatic aliphatic copolyesters and polylactic acid, intended for the fabrication of agricultural mulching films, in addition to other applications, were subjected to a series of tests with the aim of studying the relationship between their photooxidation and biodegradation. Photooxidation resulted in the rearrangement of polymeric chains, in the case of both copolyesters the events led to polymeric chain crosslinking and the formation of insoluble polymeric gel. The tendency was significantly more pronounced for the copolyester with the higher content of the aromatic constituent. As regards polylactic acid photochemical reactions were not accompanied by crosslinking but instead provoked chain scissions. A biodegradation experiment showed that, despite marked structural changes, the extent of photooxidation was not the decisive factor, which significantly modified the rate of biodegradation in all three materials investigated. The specific surface area of the sample specimens was shown to be more important. PMID- 22534202 TI - Socioeconomic status, structural and functional measures of social support, and mortality: The British Whitehall II Cohort Study, 1985-2009. AB - The authors examined the associations of social support with socioeconomic status (SES) and with mortality, as well as how SES differences in social support might account for SES differences in mortality. Analyses were based on 9,333 participants from the British Whitehall II Study cohort, a longitudinal cohort established in 1985 among London-based civil servants who were 35-55 years of age at baseline. SES was assessed using participant's employment grades at baseline. Social support was assessed 3 times in the 24.4-year period during which participants were monitored for death. In men, marital status, and to a lesser extent network score (but not low perceived support or high negative aspects of close relationships), predicted both all-cause and cardiovascular mortality. Measures of social support were not associated with cancer mortality. Men in the lowest SES category had an increased risk of death compared with those in the highest category (for all-cause mortality, hazard ratio = 1.59, 95% confidence interval: 1.21, 2.08; for cardiovascular mortality, hazard ratio = 2.48, 95% confidence interval: 1.55, 3.92). Network score and marital status combined explained 27% (95% confidence interval: 14, 43) and 29% (95% confidence interval: 17, 52) of the associations between SES and all-cause and cardiovascular mortality, respectively. In women, there was no consistent association between social support indicators and mortality. The present study suggests that in men, social isolation is not only an important risk factor for mortality but is also likely to contribute to differences in mortality by SES. PMID- 22534203 TI - Are children with birth defects at higher risk of childhood cancers? AB - Birth defects may influence the risk of childhood cancer development through a variety of mechanisms. The rarity of both birth defects and childhood cancers makes it challenging to study these associations, particularly for the very rare instances of each. To address this limitation, the authors conducted a record linkage-based cohort study among Texas children born between 1996 and 2005. Birth defects in the cohort were identified through the Texas Birth Defects Registry, and children who developed cancer were identified by using record linkage with Texas Cancer Registry data. Over 3 million birth records were included; 115,686 subjects had birth defects, and there were 2,351 cancer cases. Overall, children with a birth defect had a 3-fold increased risk of developing cancer (incidence rate ratio (IRR) = 3.05, 95% confidence interval (CI): 2.65, 3.50), with germ cell tumors (IRR = 5.19, 95% CI: 2.67, 9.41), retinoblastomas (IRR = 2.34, 95% CI: 1.21, 4.16), soft-tissue sarcomas (IRR = 2.12, 95% CI: 1.09, 3.79), and leukemias (IRR = 1.39, 95% CI: 1.09, 1.75) having statistically significant elevated point estimates. All birth defect groups except for musculoskeletal had increased cancer incidence. Untangling the strong relation between birth defects and childhood cancers could lead to a better understanding of the genetic and environmental factors that affect both conditions. PMID- 22534205 TI - Association of environmental insecticide exposure and fetal growth with a Bayesian model including multiple exposure sources: the PELAGIE mother-child cohort. AB - It has been suggested that prenatal exposure to insecticides adversely affects fetal growth, but the overall results have been inconsistent, partly because of the different exposure sources and exposure assessments used. In the French PELAGIE (Perturbateurs Endocriniens: Etude Longitudinale sur les Anomalies de la Grossesse, l'Infertilite et l'Enfance) mother and child cohort (2002-2006), the authors investigated the association between fetal growth and insecticide exposure (n = 1,213) using an integrated Bayesian latent variable model to include multiple exposure sources: agricultural activities, nonorganic diet, household insecticide use on plants, and household insecticide use against insects. They used a questionnaire to collect information on household use and organic diet, and a national agricultural census provided data on agricultural activities in the women's municipalities of residence. A 0.10-cm decrease in head circumference at birth (95% credibility interval: -0.22, 0.01) was associated with fetal insecticide exposure from agricultural activities in the municipality of residence. Decreases in average birth weight (-27 g; 95% credibility interval: -59, 6) and head circumference (-0.12 cm; 95% credibility interval: -0.26, 0.01) were associated with household insecticide use to treat plants. The present results suggest an inverse association between fetal growth and prenatal insecticide exposure from nearby agricultural activity or household use. Bayesian modeling via latent variables is a natural framework for including multiple sources of exposure to environmental pollutants. PMID- 22534206 TI - Multicollinearity in associations between multiple environmental features and body weight and abdominal fat: using matching techniques to assess whether the associations are separable. AB - Because of the strong correlations among neighborhoods' characteristics, it is not clear whether the associations of specific environmental exposures (e.g., densities of physical features and services) with obesity can be disentangled. Using data from the RECORD (Residential Environment and Coronary Heart Disease) Cohort Study (Paris, France, 2007-2008), the authors investigated whether neighborhood characteristics related to the sociodemographic, physical, service related, and social-interactional environments were associated with body mass index and waist circumference. The authors developed an original neighborhood characteristic-matching technique (analyses within pairs of participants similarly exposed to an environmental variable) to assess whether or not these associations could be disentangled. After adjustment for individual/neighborhood socioeconomic variables, body mass index/waist circumference was negatively associated with characteristics of the physical/service environments reflecting higher densities (e.g., proportion of built surface, densities of shops selling fruits/vegetables, and restaurants). Multiple adjustment models and the neighborhood characteristic-matching technique were unable to identify which of these neighborhood variables were driving the associations because of high correlations between the environmental variables. Overall, beyond the socioeconomic environment, the physical and service environments may be associated with weight status, but it is difficult to disentangle the effects of strongly correlated environmental dimensions, even if they imply different causal mechanisms and interventions. PMID- 22534204 TI - Association between arsenic exposure from drinking water and plasma levels of cardiovascular markers. AB - The authors conducted a cross-sectional study to assess the relation between arsenic exposure from drinking water and plasma levels of markers of systemic inflammation and endothelial dysfunction (matrix metalloproteinase-9, myeloperoxidase, plasminogen activator inhibitor-1, soluble E-selectin, soluble intercellular adhesion molecule-1 (ICAM-1), and soluble vascular adhesion molecule-1 (VCAM-1)) using baseline data from 668 participants (age, >30 years) in the Health Effects of Arsenic Longitudinal Study in Bangladesh (2007-2008). Both well water arsenic and urinary arsenic were positively associated with plasma levels of soluble VCAM-1. For every 1-unit increase in log-transformed well water arsenic (ln MUg/L) and urinary arsenic (ln MUg/g creatinine), plasma soluble VCAM-1 was 1.02 (95% confidence interval: 1.01, 1.03) and 1.04 (95% confidence interval: 1.01, 1.07) times greater, respectively. There was a significant interaction between arsenic exposure and higher body mass index, such that the increased levels of plasminogen activator inhibitor-1 and soluble VCAM-1 associated with arsenic exposure were stronger among people with higher body mass index. The findings indicate an effect of chronic arsenic exposure from drinking water on vascular inflammation and endothelial dysfunction that could be modified by body mass index and also suggest a potential mechanism underlying the association between arsenic exposure and cardiovascular disease. PMID- 22534207 TI - Comparison of two ActiGraph accelerometer generations in the assessment of physical activity in free living conditions. AB - BACKGROUND: The aim of this study was to compare physical activity measured using GT1M ActiGraph and GT3X ActiGraph accelerometers in free living conditions. FINDINGS: Twenty-five adults wore GT1M and GT3X Actigraph accelerometers simultaneously during a typical weekday of activity. Data were uploaded from the monitor to a computer at the end of test (one day). Previously established thresholds were used for defining time spent at each level of physical activity, physical activity was assessed at varying intensities comparing data from the two accelerometers by ANOVA and Bland and Altman statistical analysis. The concordance correlation coefficient between accelerometers at each intensity level was 0.99. There were no significant differences between accelerometers at any of the activity levels. Differences between data obtained in minutes with the GT1M accelerometer and the GT3X monitor were to 0.56, 0.36, 0.52 and 0.44% for sedentary, light, moderate and vigorous, respectively. The Bland and Altman method showed good agreement between data obtained for the two accelerometers. CONCLUSIONS: Findings suggest that the two accelerometers provided similar results and therefore the GT3X may be used in clinical and epidemiological studies without additional calibration or validation studies. PMID- 22534208 TI - Rapid paracellular transmigration of Campylobacter jejuni across polarized epithelial cells without affecting TER: role of proteolytic-active HtrA cleaving E-cadherin but not fibronectin. AB - BACKGROUND: Campylobacter jejuni is one of the most important bacterial pathogens causing food-borne illness worldwide. Crossing the intestinal epithelial barrier and host cell entry by C. jejuni is considered the primary reason of damage to the intestinal tissue, but the molecular mechanisms as well as major bacterial and host cell factors involved in this process are still widely unclear. RESULTS: In the present study, we characterized the serine protease HtrA (high-temperature requirement A) of C. jejuni as a secreted virulence factor with important proteolytic functions. Infection studies and in vitro cleavage assays showed that C. jejuni's HtrA triggers shedding of the extracellular E-cadherin NTF domain (90 kDa) of non-polarised INT-407 and polarized MKN-28 epithelial cells, but fibronectin was not cleaved as seen for H. pylori's HtrA. Deletion of the htrA gene in C. jejuni or expression of a protease-deficient S197A point mutant did not lead to loss of flagella or reduced bacterial motility, but led to severe defects in E-cadherin cleavage and transmigration of the bacteria across polarized MKN-28 cell layers. Unlike other highly invasive pathogens, transmigration across polarized cells by wild-type C. jejuni is highly efficient and is achieved within a few minutes of infection. Interestingly, E-cadherin cleavage by C. jejuni occurs in a limited fashion and transmigration required the intact flagella as well as HtrA protease activity, but does not reduce transepithelial electrical resistance (TER) as seen with Salmonella, Shigella, Listeria or Neisseria. CONCLUSION: These results suggest that HtrA-mediated E cadherin cleavage is involved in rapid crossing of the epithelial barrier by C. jejuni via a very specific mechanism using the paracellular route to reach basolateral surfaces, but does not cleave the fibronectin receptor which is necessary for cell entry. PMID- 22534209 TI - Risk groups and predictors of short-term abstinence from smoking in patients with coronary heart disease. AB - OBJECTIVES: We sought to identify risk groups among smoking cardiac patients from their social cognitive profiles, and to assess predictors of smoking abstinence shortly after discharge. METHODS: Smoking cardiac patients (n = 133) completed questionnaires at hospital admission and 1 month after discharge. Hierarchical cluster analysis was used to detect risk groups of smokers, based on baseline scores for smoking-related social cognitions. Regression analyses were used to identify predictors of the intention to abstain from smoking and smoking abstinence 1 month after discharge. RESULTS: Three groups of smokers were distinguished that differed significantly on the pros of nonsmoking, self efficacy expectancies toward nonsmoking, social support, social modeling, and smoking behavior. Abstinence from smoking 1 month after discharge was predicted by group membership and a stronger intention to quit. A previous hospital admission because of a cardiac event significantly decreased the likelihood of abstinence. CONCLUSIONS: One third of cardiac patients are at high risk of continuing smoking after hospital discharge because of an unfavorable smoking and disease history and a poor social cognitive profile. Interventions for cardiac patients should address risk profiles to achieve long-term abstinence. The implications of nursing practices in smoking cessation treatments are discussed. PMID- 22534210 TI - Treatment of severe sepsis and septic shock in critically ill patients. PMID- 22534211 TI - The influence of the playing surface on the exercise intensity of small-sided recreational soccer games. AB - This study aimed to analyze the influence of the playing surface on movement pattern, physical loading, perceived exertion, and fatigue development during small-sided recreational soccer games. Time-motion, heart rate, blood lactate, and perceived exertion were measured for 16 recreational players aged 22 (range: 19-35) yrs. During 5-a-side soccer games on 3 different field surfaces: sand, artificial turf, and asphalt. Jump and sprint tests were performed prior to and after each game. Total distance covered was higher on asphalt and turf than on sand (3.89+/-0.04 and 3.73+/-0.12 vs. 2.59+/-0.21 km; p<.01), and the number of high-intensity runs was higher on asphalt than on turf (55+/-3 vs. 43+/-3; p<.05), but not sand (46+/-6). Mean heart rate (means+/-SEM, 160+/-3 vs. 171+/-1 b.p.m.) and time>90% HR(max) (20.8+/-5.1% vs. 44.1+/-5.0%) were lower (p<.05) on asphalt than on turf, with intermediate values for sand. Blood lactate was lower on asphalt than on sand (2.8+/-0.3 vs. 4.7+/-0.6 mmolL(-1); p<.05). Perceived exertion was lower on asphalt than on turf and sand (VAS 0-100: 52+/-3 vs. 72+/-3 and 72+/-3; p<.01). After the game, squat and countermovement jump performances were lower (4.9-8.1%, and 1.9-6.4%, respectively; p<.001) for all field surfaces, but no changes were observed in 5- and 30-m sprint performance. Small-sided recreational soccer games elicit high heart rates, multiple intense actions, and decreased jump performance for all the investigated playing surfaces, suggesting that multiple fitness and health benefits can be achieved through soccer on sand, artificial turf and asphalt. Nonetheless, locomotor activities, heart rate, blood lactate levels, and perceived exertion differ between surfaces. PMID- 22534212 TI - How timely can our hand movements be? AB - The temporal variability of our movements is reduced when we move fast. Here we study whether different sensory information (vision and proprioception) or prior knowledge of final position or travelled distance can affect the temporal precision of movements directed to static targets. We attempted to promote the use of either on-line feedback control (providing visual and proprioceptive information of the movement and maintaining the target position predictable trial to-trial) or forward control (removing visual feedback and maintaining a predictable target position). In a first experiment, the variability of movement times indicates that temporal precision is affected by the predictability of the target's position and by different feedback conditions. In a second experiment we disentangled the question regarding whether it is the target's position estimate, the travelled distance or the velocity that enhanced the temporal performance. In accordance with previous studies, results indicate that velocity is the main factor in controlling temporal precision across different conditions. PMID- 22534213 TI - Shoulder muscles recruitment during a power backward giant swing on high bar: a wavelet-EMG-analysis. AB - This study aimed at determining the upper limb muscles coordination during a power backward giant swing (PBGS) and the recruitment pattern of motor units (MU) of co-activated muscles. The wavelet transformation (WT) was applied to the surface electromyographic (EMG) signal of eight shoulder muscles. Total gymnast's body energy and wavelet synergies extracted from the WT-EMG by using a non negative matrix factorization were analyzed as a function of the body position angle of the gymnast. A cross-correlation analysis of the EMG patterns allowed determining two main groups of co-activated muscles. Two wavelet synergies representing the main spectral features (82% of the variance accounted for) discriminated the recruitment of MU. Although no task-group of MU was found among the muscles, it appeared that a higher proportion of fast MU was recruited within the muscles of the first group during the upper part of the PBGS. The last increase of total body energy before bar release was induced by the recruitment of the muscles of the second group but did not necessitate the recruitment of a higher proportion of fast MU. Such muscle coordination agreed with previous simulations of elements on high bar as well as the findings related to the recruitment of MU. PMID- 22534214 TI - Responses to article on benefits of slowing global warming. PMID- 22534215 TI - Responses to article on benefits of slowing global warming. PMID- 22534216 TI - Responses to article on benefits of slowing global warming. PMID- 22534217 TI - Responses to article on benefits of slowing global warming. PMID- 22534218 TI - Responses to article on benefits of slowing global warming. PMID- 22534220 TI - Interventions to increase cervical cancer screening rates. PMID- 22534221 TI - Antiretroviral therapy to prevent transmission in HIV-discordant couples. PMID- 22534222 TI - Labor analgesia. AB - Regional analgesia has become the most common method of pain relief used during labor in the United States. Epidural and spinal analgesia are two types of regional analgesia. With epidural analgesia, an indwelling catheter is directed into the epidural space, and the patient receives a continuous infusion or multiple injections of local anesthetic. Spinal injections are usually single injections into the intrathecal space. A combination of epidural and spinal analgesia, known as a walking epidural, also is available. This technique combines the rapid pain relief from the spinal regional block with the constant and consistent effects from the epidural block. It allows sufficient motor function for patients to ambulate. Complications with regional analgesia are uncommon, but may include postdural puncture headache. Rare serious complications include neurologic injury, epidural hematoma, or deep epidural infection. Regional analgesia increases the risk of instrument-assisted vaginal delivery, and family physicians should understand the contraindications and risks of complications. Continuous labor support (e.g., doula), systemic opioid analgesia, pudendal blocks, water immersion, sterile water injections into the lumbosacral spine, self-taught hypnosis, and acupuncture are other options for pain management during labor. PMID- 22534223 TI - Information from your family doctor. Options for managing pain during labor. PMID- 22534224 TI - Implementing advance directives in office practice. AB - Patients prepare advance directives in an effort to maintain autonomy during periods of incapacity or at the end of life. Advance directive documents are specific to the state in which the patient lives, but an effective strategy in the family physician's office involves more than filling out a form. Physician barriers to completing an advance directive include lack of time and discomfort with the topic. On the patient's part, lack of knowledge, fear of burdening family, and a desire to have the physician initiate the discussion are common barriers. Once the advance directive is complete, barriers to implementation include vague language, issues with the proxy decision maker, and accessibility of the advance directive. Overcoming these barriers depends on effective communication at multiple visits, including allowing the patient the opportunity to ask questions. Involving the family or a proxy early and over time can help the process. It may be helpful to integrate advance directive discussions at selected stages of the patient's life and as health status changes. PMID- 22534225 TI - Information from our family doctor. What you should know about advanced directives. PMID- 22534226 TI - Diagnosis and management of upper gastrointestinal bleeding. AB - Upper gastrointestinal bleeding causes significant morbidity and mortality in the United States, and has been associated with increasing nonsteroidal anti inflammatory drug use and the high prevalence of Helicobacter pylori infection in patients with peptic ulcer bleeding. Rapid assessment and resuscitation should precede the diagnostic evaluation in unstable patients with severe bleeding. Risk stratification is based on clinical assessment and endoscopic findings. Early upper endoscopy (within 24 hours of presentation) is recommended in most patients because it confirms the diagnosis and allows for targeted endoscopic treatment, including epinephrine injection, thermocoagulation, application of clips, and banding. Endoscopic therapy results in reduced morbidity, hospital stays, risk of recurrent bleeding, and need for surgery. Although administration of proton pump inhibitors does not decrease mortality, risk of rebleeding, or need for surgery, it reduces stigmata of recent hemorrhage and the need for endoscopic therapy. Despite successful endoscopic therapy, rebleeding can occur in 10 to 20 percent of patients; a second attempt at endoscopic therapy is recommended in these patients. Arteriography with embolization or surgery may be needed if there is persistent and severe bleeding. PMID- 22534227 TI - Bipolar disorders: a review. AB - Bipolar disorders are common, disabling, recurrent mental health conditions of variable severity. Onset is often in late childhood or early adolescence. Patients with bipolar disorders have higher rates of other mental health disorders and general medical conditions. Early recognition and treatment of bipolar disorders improve outcomes. Treatment of mood episodes depends on the presenting phase of illness: mania, hypomania, mixed state, depression, or maintenance. Psychotherapy and mood stabilizers, such as lithium, anticonvulsants, and antipsychotics, are first-line treatments that should be continued indefinitely because of the risk of relapse. Monotherapy with antidepressants is contraindicated in mixed states, manic episodes, and bipolar I disorder. Maintenance therapy for patients involves screening for suicidal ideation and substance abuse, evaluating adherence to treatment, and recognizing metabolic complications of pharmacotherapy. Active management of body weight reduces complications and improves lipid control. Patients and their support systems should be educated about mood relapse, suicidal ideation, and the effectiveness of early intervention to reduce complications. PMID- 22534228 TI - Information from your family doctor. Bipolar disorders. PMID- 22534229 TI - A case of medical uncertainty. PMID- 22534230 TI - Lateral knee pain in a male college student. PMID- 22534231 TI - ADA releases revisions to recommendations for standards of medical care in diabetes. PMID- 22534232 TI - AAP reports on the use of antipyretics for fever in children. PMID- 22534233 TI - Psychophysical and cerebral responses to heat stimulation in patients with central pain, painless central sensory loss, and in healthy controls. PMID- 22534235 TI - Expression and functional role of BK channels in chronically injured spinal cord white matter. AB - Spinal cord injury (SCI) causes neuronal death, demyelination of surviving axons, and altered ion channel functioning, resulting in impaired axonal conduction. The large-conductance, voltage and Ca(2+)-activated K(+) (BK or Maxi K(+)) channels contribute to the repolarization phase of action potentials. Therefore, they may play a significant role in regulating axonal conduction in SCI. In this paper, using combined electrophysiological and molecular approaches, we tested the hypothesis that the deficit in axonal conduction in chronic SCI is partially due to the activation of axonal BK channels. BK channels were found to be expressed in spinal cord white matter axons. These channels are not sensitive to BK channel blocker iberiotoxin in uninjured cords, likely reflecting their juxtaparanodal localization. After chronic injury, BK channels were exposed due to axonal demyelination at the injured site and their activation was found to depend on calcium influx, likely through N-type voltage-dependent calcium channels. Activation of BK channels introduced a reduction in the size of the compound action potentials (CAPs) and in axonal response to high frequency stimulation (HFS). Administration of BK channel blocker iberiotoxin significantly enhanced axonal conduction in the injured cords. Thus, pharmacological targeting of axonal BK channels may provide a therapeutic strategy for the treatment of chronic SCI, by restoring conduction to the remaining functional axons. PMID- 22534236 TI - Extrauterine environment influences spontaneous low-frequency oscillations in the preterm brain. AB - Low-frequency oscillations in cerebral blood flow that are suggestive of resting state brain activity have recently been reported, but no study on the development of resting-state brain activity in preterm infants has been performed. The objective of this study was to measure the cerebral blood flow oscillations, which are assumed to represent brain function in the resting state, in preterm and term infants of the same postconceptional age. The subjects were 9 preterm infants who had reached full term (gestational age (GA): 23-34 weeks, postconceptional age: 37-46 weeks) and 10 term infants (GA: 37-40 weeks, postconceptional age: 37-41 weeks). Their changes in concentration of oxyhemoglobin ([oxyHb]) and deoxyhemoglobin ([deoxyHb]) were measured in the parieto-temporal region during quiet sleep using multi-channel near-infrared spectroscopy, and the power spectral densities (PSD) of the oscillations in the concentrations of these molecules were analyzed and compared. The preterm infants displayed a higher proportion of 0.06-0.10 Hz low frequency oscillations of [oxyHb] and [deoxyHb] than the term infants, and the gestational age and the proportion of low frequency oscillations were inversely correlated. These findings suggest that resting-state cerebral blood flow oscillations differ between preterm and term infants, and that the development of circulatory regulation and nerve activity in preterm infants are influenced by the extrauterine environment. PMID- 22534237 TI - Non-protein-bound iron and 4-hydroxynonenal protein adducts in classic autism. AB - A link between oxidative stress and autism spectrum disorders (ASDs) remains controversial with opposing views on its role in the pathogenesis of the disease. We investigated for the first time the levels of non-protein-bound iron (NPBI), a pro-oxidant factor, and 4-hydroxynonenal protein adducts (4-HNE PAs), as a marker of lipid peroxidation-induced protein damage, in classic autism. Patients with classic autism (n=20, mean age 12.0+/-6.2years) and healthy controls (n=18, mean age 11.7+/-6.5years) were examined. Intraerythrocyte and plasma NPBI were measured by high performance liquid chromatography (HPLC), and 4-HNE PAs in erythrocyte membranes and plasma were detected by Western blotting. The antioxidant defences were evaluated as erythrocyte glutathione (GSH) levels using a spectrophotometric assay. Intraerythrocyte and plasma NPBI levels were significantly increased (1.98- and 3.56-folds) in autistic patients, as compared to controls (p=0.0019 and p<0.0001, respectively); likewise, 4-HNE PAs were significantly higher in erythrocyte membranes and in plasma (1.58- and 1.6-folds, respectively) from autistic patients than controls (p=0.0043 and p=0.0001, respectively). Erythrocyte GSH was slightly decreased (-10.34%) in patients compared to controls (p=0.0215). Our findings indicate an impairment of the redox status in classic autism patients, with a consequent imbalance between oxidative stress and antioxidant defences. Increased levels of NPBI could contribute to lipid peroxidation and, consequently, to increased plasma and erythrocyte membranes 4-HNE PAs thus amplifying the oxidative damage, potentially contributing to the autistic phenotype. PMID- 22534238 TI - Anchoring platinum on graphene using metallic adatoms: a first principles investigation. AB - First principles calculations based on spin-polarized density functional theory were used to identify metallic adatoms that would strengthen the Pt(111)/graphene interface (with a low work of separation of 0.009 J m(-2)), when the adatom was placed between the Pt(111) and the graphene. It was shown that the strength of the Pt-adatom bond, which had a metallic character, increased with the amount of charge transferred from the adatom to the Pt. The carbon-adatom bond, on the other hand, had a mixed ionic and covalent character and was weaker than the Pt adatom bond for each of the 25 elements considered. Consequently, the total Pt(111)/graphene interface strength and, hence, the anchoring effect of the adatom were controlled by the carbon-adatom bond strength. Metals with unfilled d orbitals increased the Pt/graphene interface strength to above 0.5 J m(-2). The carbon-adatom bond strength was proportional to the ratio between the charge transferred from the adatom to the graphene (DeltaZ(C)) and the charge transferred to the Pt surface (DeltaZ(Pt)); i.e., the DeltaZ(C)/DeltaZ(Pt) ratio defined the ability of an adatom to anchor Pt to graphene. For Ir, Os, Ru, Rh and Re, DeltaZ(C)/DeltaZ(Pt) > 1.0, making these elements the most effective adatoms for anchoring Pt to graphene. PMID- 22534239 TI - Visualisation of cerebrospinal fluid flow patterns in albino Xenopus larvae in vivo. AB - BACKGROUND: It has long been known that cerebrospinal fluid (CSF), its composition and flow, play an important part in normal brain development, and ependymal cell ciliary beating as a possible driver of CSF flow has previously been studied in mammalian fetuses in vitro. Lower vertebrate animals are potential models for analysis of CSF flow during development because they are oviparous. Albino Xenopus laevis larvae are nearly transparent and have a straight, translucent brain that facilitates the observation of fluid flow within the ventricles. The aim of these experiments was to study CSF flow and circulation in vivo in the developing brain of living embryos, larvae and tadpoles of Xenopus laevis using a microinjection technique. METHODS: The development of Xenopus larval brain ventricles and the patterns of CSF flow were visualised after injection of quantum dot nanocrystals and polystyrene beads (3.1 or 5.8 MUm in diameter) into the fourth cerebral ventricle at embryonic/larval stages 30-53. RESULTS: The fluorescent nanocrystals showed the normal development of the cerebral ventricles from embryonic/larval stages 38 to 53. The polystyrene beads injected into stage 47-49 larvae revealed three CSF flow patterns, left handed, right-handed and non-biased, in movement of the beads into the third ventricle from the cerebral aqueduct (aqueduct of Sylvius). In the lateral ventricles, anterior to the third ventricle, CSF flow moved anteriorly along the outer wall of the ventricle to the inner wall and then posteriorly, creating a semicircle. In the cerebral aqueduct, connecting the third and fourth cerebral ventricles, CSF flow moved rostrally in the dorsal region and caudally in the ventral region. Also in the fourth ventricle, clear dorso-ventral differences in fluid flow pattern were observed. CONCLUSIONS: This is the first visualisation of the orchestrated CSF flow pattern in developing vertebrates using a live animal imaging approach. CSF flow in Xenopus albino larvae showed a largely consistent pattern, with the exception of individual differences in left-right asymmetrical flow in the third ventricle. PMID- 22534242 TI - Ewing sarcoma/primitive neuroectodermal tumor of the kidney: clinicopathologic analysis of 34 cases. AB - The present study describes the clinicopathologic analysis of 34 cases of Ewing sarcoma/primitive neuroectodermal tumor occurring in the kidney. The patients were 21 males and 13 females with an age range of 6 to 44 years. Clinically, patients presented with multiple symptoms including hematuria, pain, and/or lump in the abdomen. Nephrectomy was performed in most of the cases. Grossly, whole of the renal parenchyma was involved by a variegated tumor. Histologically, the tumor was composed of monomorphic, small, and round cells arranged in a variety of patterns. Rosettes, geographical areas of necrosis, and arborizing vascular pattern were the prominent histologic features. The nucleus was monomorphic and round. Anisonucleosis was also noted in some cases. The nucleus was mostly hyperchromatic. A mixture of hyperchromatic and powdery chromatin was noted in few cases. Immunohistochemically, MIC2 (CD99) was positive in 32 of 34 cases followed by neuron-specific enolase (9/12 cases), vimentin (8/14 cases), synaptophysin (1/8 cases), and S-100 protein (1/4 cases). Molecular analysis by reverse transcriptase-polymerase chain reaction that was carried out in 26 cases revealed presence of EWS-FLI-1 type 1 translocation in 12 cases, EWS-FLI-1 type 2 translocation in 10 cases, and both type 1 and type 2 EWS-FLI-1 translocation in 2 cases. Two cases did not demonstrate any translocation. Follow-up data were available for 17 of 34 cases. Local recurrence of the tumor was seen in 4 patients, and 10 patients were recorded to have distant metastasis in various organs, such as lung, bone, and lymph node, during the course of the disease. PMID- 22534243 TI - Intraosseous spindle cell hemangioma of the calcaneus: a case report and review of the literature. AB - Spindle cell hemangioma, a rare benign tumor characterized by cavernous blood vessels and spindled areas, typically arises in the subcutis of the distal extremities, particularly the hand. The case of intraosseous spindle cell hemangioma is extremely rare, and only 1 case arises in the frontal bone has been reported previously. We describe herein a case of intraosseous spindle cell hemangioma occurring in the left calcaneus in a 65-year-old woman. The patient was successfully treated by the operation. The present case is instructive especially in the differential diagnosis of primary bone tumor structured by spindle cells, for which the possibility of spindle cell hemangioma should be considered. PMID- 22534244 TI - Renal angiomyoadenomatous tumor. AB - We report a case of a 40-year-old woman with renal angiomyoadenomatous tumor, a rare neoplasm with only 6 previous cases reported in the literature. Unlike our case, most tumors have been identified in middle-aged males; they present as well circumscribed, encapsulated tan-brown masses with variably prominent cystic areas. Microscopically, the tumors have a variably thick leiomyomatous capsule, which invaginates into the tumor and intermixes with tubules or solid nests of clear epithelial cells. The epithelial cells have low-grade basally oriented nuclei, and their basement membranes are intimately linked to a labyrinthine network of capillaries and pericytes. Microscopically, these tumors can be confused with clear cell carcinoma, papillary carcinoma, mixed epithelial and stromal tumors, and angiomyolipoma. This is also the first case report correlating the radiographic and morphological findings of this rare entity. The differentiating features of these neoplasms and a review of literature of are herein presented. PMID- 22534245 TI - Spectrum of neuroendocrine carcinomas of the uterine cervix, including histopathologic features, terminology, immunohistochemical profile, and clinical outcomes in a series of 50 cases from a single institution in India. AB - Neuroendocrine carcinomas of the cervix are uncommon, characterized by a histomorphological spectrum and, mostly, an aggressive clinical course. There are only few substantial studies on such cases documented from our country, where cervical cancer is the second most common cancer affecting women. Herein, we present a spectrum of 50 cervical neuroendocrine carcinomas, including histopathologic features, terminology, immunohistochemical (IHC) profile, and clinical outcomes, wherever available. Fifty tumors occurred in women, with their age ranging from 23 to 69 years (mean, 48.6 years; median, 46.5 years). Stagewise, among 25 cases, most cases (6, or 24%) presented with stage IB. Average tumor size was 4.7 cm. On histopathologic review, 26 tumors (52%) were classified as small cell carcinoma (SMCA); 14 (28%), as large cell neuroendocrine carcinomas (LCNECs); 4 (8%), as SMCA+LCNECs; and 6, as mixed carcinomas, including 3 tumors (6%) with SMCA and squamous cell carcinoma (SCC), 2 tumors (4%) with LCNEC and adenocarcinoma, and a single tumor (2%) with LCNEC and squamous cell carcinoma. On IHC performed in 41 tumors (82%), 36 tumors (87.8%) were positive for at least a single neuroendocrine marker, and 22 (53.6%) expressed 2 neuroendocrine markers. Synaptophysin was positive in 22 (59.4%) of 37 tumors; chromogranin, in 27 (72.9%) of 37; CD56, in 8 (100%) of 8; and neuron specific enolase in 7 (87.5%) of 8 tumors. Treatment wise, among 30 patients (60%), 6 (20%) underwent surgery, including Wertheim hysterectomy (5) and simple hysterectomy (1); 8 (26.6%) underwent surgery with adjuvant treatment, and 10 patients (33.3%) were offered chemotherapy and/or radiotherapy. On follow-up (27 patients, or 54%) over 1 to 144 months, 16 patients (59.2%) were alive with disease over median duration of 9 months, and 7 (25.9%) were free of disease over median duration of 26.5 months. There were 5 recorded deaths. Thirteen tumors (48.1%) metastasized, most commonly to liver. In cases with early stage disease and adjuvant treatment, including radiotherapy, LCNEC histology fared well. This study forms the largest documented series on cervical neuroendocrine carcinomas from our country, testifying the current histopathologic classification system. Although SMCAs can be recognized on morphology, LCNECs need to be correctly identified because these can be misdiagnosed in the absence of neuroendocrine markers. Synaptophysin, chromogranin, and CD56 are optimal IHC markers. Small cell carcinomas, pure or mixed, are relatively more aggressive. All these tumors are best treated with multimodal therapy. Early stage disease treated with radical surgery and adjuvant treatment seems to increase survival. Despite aggressive treatment, prognosis is dismal. PMID- 22534246 TI - Modulation of tight junction proteins in the perineurium to facilitate peripheral opioid analgesia. AB - BACKGROUND: Peripheral application of opioids reduces inflammatory pain but is less effective in noninflamed tissue of rats and human patients. Hypertonic solutions can facilitate the antinociceptive activity of hydrophilic opioids in noninflamed tissue in vivo. However, the underlying mechanisms are not well understood. We hypothesized that the enhanced efficacy of opioids may be because of opening of the perineurial barrier formed by tight junction-proteins like claudin-1. METHODS: Male Wistar rats were treated intraplantarly with 10% NaCl. Pain behavior (n = 6) and electrophysiological recordings (n = 9 or more) from skin-nerve preparations after local application of the opioid [d-Ala2,N-Me Phe4,Gly5-ol]enkephalin (DAMGO) were explored. Tight junction-proteins as well as permeability of the barrier were examined by immunohistochemistry and Western blot (n = 3 or more). RESULTS: Local administration of 10% NaCl facilitated increased mechanical nociceptive thresholds in response to DAMGO, penetration of horseradish peroxidase into the nerve, as well as a reduced response of C- but not Adelta-nociceptors to mechanical stimulation after application of DAMGO in the skin-nerve preparation. In noninflamed paw tissue, claudin-1 was expressed in the epidermis, blood vessels, and the perineurium, surrounding neurons immunoreactive for calcitonin gene-related peptide or protein gene product 9.5. Claudin-1 but not claudin-5 or occludin was significantly reduced after pretreatment with 10% NaCl. Intraplantar application of a metalloproteinase inhibitor (GM6001) completely reversed these effects. CONCLUSION: Hypertonic saline opens the perineurial barrier via metalloproteinase activation and claudin 1 regulation, thereby allowing access of hydrophilic drugs to peripheral opioid receptors. This principle may be used to specifically target hydrophilic drugs to peripheral neurons. PMID- 22534247 TI - High-volume hemofiltration in the intensive care unit: a blood purification therapy. AB - High-volume hemofiltration is an extracorporeal therapy that has been available in the intensive care unit for more than 10 yr. Recent improvements in technology have made its clinical application easier and safer. However, the definition, indications, and management of this technique are still unclear, and considerable controversy and confusion remain. The aim of this review is to analyze the available data while taking into account the distinction between two very different clinical situations: acute kidney injury requiring renal support, and severe inflammatory states where blood purification has been suggested as an adjuvant therapy. For patients with acute kidney injury requiring renal replacement therapy, the two largest multicenter studies performed to date established that high ultrafiltration flow rates are not necessary. Conversely, much experimental and some clinical evidence suggest that high-volume hemofiltration can be beneficial for the subset of critically ill patients with severe inflammatory states such as septic shock. PMID- 22534248 TI - In vitro kinetic evaluation of the free radical scavenging ability of propofol. AB - BACKGROUND: Propofol is a widely used, short-acting, and intravenously administered hypnotic agent with notable antioxidant and free radical scavenging activities. However, there are relatively few kinetic studies on the free radical scavenging ability of propofol. The goal of this study is to evaluate the kinetics of propofol scavenging 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical (ABTS(.+)). METHODS: The stock solution of ABTS(.+) was prepared by incubating 7 mM ABTS with 2.8 mM potassium persulfate in deionized water, and then diluted with 5 mM phosphate-buffered saline (pH 7.2) to get a working solution (36 MUM ABTS(.+) and 18 MUM ABTS). The reaction was monitored by measuring specific absorbance changes of ABTS and ABTS(.+) after adding 4 MUM propofol (final concentration) to the working solution. The propofol-ABTS(.+) reaction products were analyzed by high-performance liquid chromatography and liquid chromatography mass spectrometry/mass spectrometry. RESULTS: Wave scanning and kinetic evaluation demonstrated that the ABTS(.+) scavenging process of propofol is relatively fast. The ABTS(.+) consumption rate by propofol is greater than the rate of ABTS formation. The degradation products of reaction between propofol and ABTS(.+) were mainly ABTS-propofol, a part of the ABTS molecule, and a combination of propofol with a part of the ABTS molecule. CONCLUSIONS: Propofol scavenges ABTS(.+) with a fast and stable kinetic feature in vitro, which is useful and important for understanding propofol's antioxidant properties. The kinetic process of the free radical scavenging activity of propofol may also play a role in dynamic protection in the body. PMID- 22534249 TI - Meta-analysis of bleeding complications associated with cardiac rhythm device implantation. AB - BACKGROUND: Many patients receiving cardiac rhythm devices have conditions requiring antiplatelet (AP) and/or anticoagulant (AC) therapy. Current guidelines recommend a heparin-bridging strategy (HBS) for anticoagulated patients with moderate/high risk for thrombosis. Several studies reported lower bleeding risk with continued oral anticoagulation rather than HBS. The best strategy for perioperative management of patients on AP therapy is less clear. The present study was designed as a meta-analysis of device implantation-associated bleeding complications using different AC/AP therapies. METHODS AND RESULTS: PubMed and Cochrane Database searches identified articles based on design, outcomes, and available data. Device recipients were grouped as follows: no therapy, aspirin only, AC held, AC continued, dual AP, and HBS. The primary outcome was defined as a bleeding complication including hematoma, transfusion, or prolonged hospital stay. Thirteen articles were identified for analysis including 5978 patients. The combined incidence of bleeding complications was 274 of 5978 (4.6%), ranging from 2.2% (no therapy) to 14.6% (HBS). The estimated odds of bleeding were increased by 8.3 (95% CI, 5.5-12.9) times in the HBS group, 5.0 (95% CI, 3.0-8.3) for dual AP therapy, 1.7 (95% CI, 1.0-3.1) for AC held, 1.6 (95% CI, 0.9-2.6) for AC continued, and 1.5 (95% CI, 0.9-2.3) for aspirin only relative to the no therapy group. HBS significantly increased bleeding events compared with holding or continuing AC. Continuing AC did not increase bleeding events compared with no therapy. CONCLUSIONS: Continuing AC appears safer than HBS for device implantation. Dual AP therapy but not continuing AC carries a significant risk of bleeding. PMID- 22534250 TI - Early repolarization is an independent predictor of occurrences of ventricular fibrillation in the very early phase of acute myocardial infarction. AB - BACKGROUND: Recent evidence has linked early repolarization (ER) to idiopathic ventricular fibrillation (VF) in patients without structural heart disease. However, no studies have clarified whether or not there is an association between ER and the VF occurrences after the onset of an acute myocardial infarction (AMI). METHODS AND RESULTS: This study retrospectively included 220 consecutive patients with an AMI (57 female; mean age, 69+/-11 years) in whom the 12-lead ECGs before the AMI onset could be evaluated. The patients were classified on the basis of a VF occurrence within 48 hours after the AMI onset. Early repolarization was defined as an elevation of the QRS-ST junction of >0.1 mV from baseline in at least 2 inferior or lateral leads, manifested as QRS slurring or notching. Twenty-one (10%) patients had a VF occurrence within 48 hours of the AMI onset. A multivariate analysis revealed that ER (odds ratio [OR], 7.31; 95% confidence interval [CI], 2.21-24.14; P<0.01), a time from the onset to admission of <180 minutes (OR, 3.77; 95% CI, 1.13-12.59; P<0.05), and a Killip class greater than I (OR, 13.60; 95% CI, 3.43-53.99; P<0.001) were independent predictors of VF occurrences. As features of the ER pattern, a J-point elevation in the inferior leads, greater magnitude of the J-point elevation, notched morphology of the ER, and ER with a horizontal/descending ST segment, all were significantly associated with a VF occurrence. CONCLUSIONS: The presence of ER increased the risk of VF occurrences within 48 hours after the AMI onset. PMID- 22534251 TI - Vectorcardiography as a tool for easy optimization of cardiac resynchronization therapy in canine left bundle branch block hearts. AB - BACKGROUND: In cardiac resynchronization therapy (CRT), optimization of left ventricular (LV) stimulation timing is often time consuming. We hypothesized that the QRS vector in the vectorcardiogram (VCG) reflects electric interventricular dyssynchrony, and that the QRS vector amplitude (VAQRS), halfway between that during left bundle branch block (LBBB) and LV pacing, reflects optimal resynchronization, and can be used for easy optimization of CRT. METHODS AND RESULTS: In 24 canine hearts with LBBB (12 acute, 6 with heart failure, and 6 with myocardial infarction), the LV was paced over a wide range of atrioventricular (AV) delays. Surface ECGs were recorded from the limb leads, and VAQRS was calculated in the frontal plane. Mechanical interventricular dyssynchrony (MIVD) was determined as the time delay between upslopes of LV and right ventricular pressure curves, and systolic function was assessed as LV dP/dtmax. VAQRS and MIVD were highly correlated (r=0.94). The VAQRS halfway between that during LV pacing with short AV delay and intrinsic LBBB activation accurately predicted the optimal AV delay for LV pacing (1 ms; 95% CI, -5 to 8 ms). Increase in LV dP/dtmax at the VCG predicted AV delay was only slightly lower than the highest observed LV dP/dtmax (-2.7%; 95% CI, -3.6 to -1.8%). Inability to reach the halfway value of VAQRS during simultaneous biventricular pacing (53% of cases) was associated with suboptimal hemodynamic response, which could be corrected by sequential pacing. CONCLUSIONS: The VAQRS reflects electric interventricular dyssynchrony and accurately predicts optimal timing of LV stimulation in canine LBBB hearts. Therefore, VCG may be useful as a reliable and easy tool for individual optimization of CRT. PMID- 22534252 TI - Long-term effect of trauma splenectomy on blood glucose. AB - BACKGROUND: Increasing evidence suggests that the spleen harbors stem cells that act as precursors to insulin-producing pancreas cells. Additionally, small studies with short-term follow-up associate splenectomy with increased rates of diabetes mellitus. The purpose of this study was to analyze the long-term effect of trauma splenectomy on blood glucose. MATERIALS AND METHODS: Patients were included if a blood glucose level was measured more than 5 y after trauma splenectomy or laparotomy with bowel repair. Mean blood glucose level was then compared between the two groups. RESULTS: During the 10-y study period 61 patients underwent trauma splenectomy and 50 survived until discharge. In comparison, 229 patients underwent trauma laparotomy and bowel repair and 207 survived until discharge. Nine splenectomy patients compared with 12 control patients had, blood glucose measured at least 5 y after initial trauma. Mean follow-up period was not significantly different between groups (splenectomy 82.8 +/- 17.6 mo versus control 96.0 +/- 44.3 mo, P = 0.41). In the splenectomy cohort mean glucose level was significantly higher compared with the control (114 +/- 34 mg/dL versus 90 +/- 13 mg/dL, P = 0.04), as was the number of patients with recorded blood glucose level greater than 130 mg/dL (4 patient versus 0 patients P = 0.02). One new diagnosis of diabetes mellitus was noted only in the trauma splenectomy cohort. CONCLUSIONS: This small study suggests that trauma splenectomy may be associated with hyperglycemia at long-term follow-up. PMID- 22534253 TI - Surgical skills training restructured for the 21st century. AB - BACKGROUND: Few if any medical schools have a comprehensive surgical skills program taking medical students from learning basic knot tying and surgical skills to performing these skills at a level adequate for function during a primary care, surgical, or subspecialty residency. We have designed and continue to refine a program, which consists of five workshops focused on basic surgical skills, which are applicable to all medical and surgical disciplines. MATERIALS AND METHODS: During the first workshop students learn how to tie both one- and two-handed surgical knots. The second workshop involves teaching students differences in suture type and use, instrument handling, and suturing techniques. The third workshop is used to address problems and refine techniques previously learned in the first two sessions. The fourth workshop comprises a final examination to evaluate suture and knot tying skills. The fifth session is a voluntary knot tying and suturing competition with awards for speed, finesse, aesthetics, and the watertightness of a vascular surgical repair. Surgical faculty and house staff are present at each workshop to provide direction and constructive criticism. RESULTS: Fifty-seven third-year medical students have completed the surgical skills curriculum. Statistical analysis demonstrates significant improvement in both knot tying and suturing (P < 0.05) for these students. Forty-four percent of students have successfully sewn a watertight anastomosis. CONCLUSION: We hypothesize that this curriculum will produce medical students with basic surgical skills, appreciation of surgical technique, and the confidence to perform basic surgical skills at completion of the curriculum. PMID- 22534254 TI - New insight of ischemic postconditioning on stem cell therapy. PMID- 22534255 TI - Effects of ketoconazole and rifampicin on the pharmacokinetics of gemigliptin, a dipeptidyl peptidase-IV inhibitor: a crossover drug-drug interaction study in healthy male Korean volunteers. AB - BACKGROUND: Gemigliptin (LC15-0444) is a newly developed selective and competitive inhibitor of dipeptidyl peptidase (DPP)-4 and has potential for the treatment of type 2 diabetes mellitus. Gemigliptin is metabolized by the cytochrome P450 (CYP) 3A4 isozyme to yield the active major metabolite LC15-0636. OBJECTIVE: The effects of multiple oral doses of ketoconazole (a potent CYP3A4 inhibitor) and multiple oral doses of rifampicin (a potent CYP3A4 inducer) on the pharmacokinetic properties of a single oral dose of gemigliptin were evaluated in fasting healthy male Korean volunteers. METHODS: In this open-label, 2-part, 3 treatment, 1-sequence, 2-period crossover drug-drug interaction study, 1 group of subjects received a single 50-mg oral dose of gemigliptin on 2 separate occasions once as monotherapy and again after pretreatment with 400 mg of oral ketoconazole once daily for 7 days. The other group of subjects received a single 50-mg oral dose of gemigliptin on 2 separate occasions-once without pretreatment and again after pretreatment with 600 mg of oral rifampicin once daily for 10 days. Blood samples were obtained at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 48, and 72 hours after gemigliptin dosing. Plasma concentrations were determined using LC-MS/MS. Pharmacokinetic parameters were estimated via noncompartmental methods. Tolerability was assessed using measurements of vital signs, clinical chemistry tests, and interviews. RESULTS: Twenty-four subjects were enrolled (12 per group). Concurrent administration of ketoconazole was associated with increased total gemigliptin plasma exposure (AUC(0-infinity); 2.36-fold [90% CI, 2.19-2.54]) and decreased metabolism of gemigliptin until negligible concentrations of LC15-0636 were detected. Pretreatment with rifampicin was associated with decreased AUC(0-infinity) of gemigliptin (by 80% [90% CI, 78% 82%]) and a 2.9-fold increase (mean [SD], 0.18 [0.08] to 0.52 [0.10]) in the metabolic ratio of gemigliptin to LC15-0636. The treatments were well-tolerated, with no severe adverse events reported. Six of the 24 subjects (25%) experienced AEs during the first period of gemigliptin monotherapy administration. Six of 12 subjects (50%) each experienced AEs during concurrent administration with ketoconazole and rifampicin. CONCLUSIONS: In this select group of healthy male Korean volunteers, concurrent administration of gemigliptin with ketoconazole or rifampicin was associated with significantly increased or decreased systemic exposure to gemigliptin, respectively. These findings suggest that gemigliptin may require a dose adjustment when concurrently administered with drugs that alter CYP3A4 activity. Concurrent administration of gemigliptin with ketoconazole or rifampicin was well tolerated. ClinicalTrials.gov identifier: NCT01426906. PMID- 22534257 TI - Inference about the number of contributors to a DNA mixture: Comparative analyses of a Bayesian network approach and the maximum allele count method. AB - In the forensic examination of DNA mixtures, the question of how to set the total number of contributors (N) presents a topic of ongoing interest. Part of the discussion gravitates around issues of bias, in particular when assessments of the number of contributors are not made prior to considering the genotypic configuration of potential donors. Further complication may stem from the observation that, in some cases, there may be numbers of contributors that are incompatible with the set of alleles seen in the profile of a mixed crime stain, given the genotype of a potential contributor. In such situations, procedures that take a single and fixed number contributors as their output can lead to inferential impasses. Assessing the number of contributors within a probabilistic framework can help avoiding such complication. Using elements of decision theory, this paper analyses two strategies for inference on the number of contributors. One procedure is deterministic and focuses on the minimum number of contributors required to 'explain' an observed set of alleles. The other procedure is probabilistic using Bayes' theorem and provides a probability distribution for a set of numbers of contributors, based on the set of observed alleles as well as their respective rates of occurrence. The discussion concentrates on mixed stains of varying quality (i.e., different numbers of loci for which genotyping information is available). A so-called qualitative interpretation is pursued since quantitative information such as peak area and height data are not taken into account. The competing procedures are compared using a standard scoring rule that penalizes the degree of divergence between a given agreed value for N, that is the number of contributors, and the actual value taken by N. Using only modest assumptions and a discussion with reference to a casework example, this paper reports on analyses using simulation techniques and graphical models (i.e., Bayesian networks) to point out that setting the number of contributors to a mixed crime stain in probabilistic terms is, for the conditions assumed in this study, preferable to a decision policy that uses categoric assumptions about N. PMID- 22534256 TI - Gut-origin sepsis: evolution of a concept. AB - The concept of bacterial translocation and gut-origin sepsis as a cause of systemic infectious complications and the multiple organ dysfunction syndrome (MODS) in surgical and ICU patients has emerged over the last several decades, although the exact clinical relevance of these phenomena continues to be debated. Thus, the goal of this review is to trace the evolution of gut-origin sepsis and gut-induced MODS and put these disorders and observations into clinical perspective. Additionally, the mechanisms leading to gut-derived complications are explored as well as therapeutic options to limit or prevent these complications. From this work, several major conclusions emerge. First, that bacterial translocation occurs clinically and is responsible for increased infectious complications in patients undergoing major abdominal surgery. However, the phenomenon of bacterial translocation is not sufficient to explain the development of MODS in ICU patients. Instead, the development of MODS in these high-risk patients is likely due to gut injury and the systemic spread of non microbial, tissue-injurious factors that reach the systemic circulation via the intestinal lymphatics. These observations have resulted in the gut-lymph hypothesis of MODS. PMID- 22534258 TI - An exclusive human milk-based diet in extremely premature infants reduces the probability of remaining on total parenteral nutrition: a reanalysis of the data. AB - BACKGROUND: We have previously shown that an exclusively human milk-based diet is beneficial for extremely premature infants who are at risk for necrotizing enterocolitis (NEC). However, no significant difference in the other primary study endpoint, the length of time on total parenteral nutrition (TPN), was found. The current analysis re-evaluates these data from a different statistical perspective considering the probability or likelihood of needing TPN on any given day rather than the number of days on TPN. This study consisted of 207 premature infants randomized into three groups: one group receiving a control diet of human milk, formula and bovine-based fortifier ("control diet"), and the other two groups receiving only human milk and human milk-based fortifier starting at different times in the enteral feeding process (at feeding volumes of 40 or 100 mL/kg/day; "HM40" and "HM100", respectively). The counting process Cox proportional hazards survival model was used to determine the likelihood of needing TPN in each group. RESULTS: The two groups on the completely human-based diet had an 11-14 % reduction in the likelihood of needing nutrition via TPN when compared to infants on the control diet (p = 0.0001 and p = 0.001, respectively for the HM40 and HM100 groups, respectively). This was even more pronounced if the initial period of TPN was excluded (p < 0.0001 for both the HM40 and HM100 groups). CONCLUSIONS: A completely human milk-based diet significantly reduces the likelihood of TPN use for extremely premature infants when compared to a diet including cow-based products. This likelihood may be reduced even further when the human milk fortifier is initiated earlier in the feeding process. TRIAL REGISTRATION: This study was registered at http://www.clinicaltrials.gov reg. # NCT00506584. PMID- 22534259 TI - Solid pseudopapillary neoplasm, pancreas type, presenting as a primary ovarian neoplasm. AB - Solid pseudopapillary neoplasm has historically been associated with the pancreas, categorized as a tumor of low malignancy. Recently, solid pseudopapillary neoplasm was reported to arise as a primary ovarian tumor in 3 women. We report a fourth case identified in a 48 year-old woman with an 8-cm left ovarian mass. A left salpingo-oophorectomy was performed. Microscopic examination demonstrated a predominately cystic neoplasm comprised of solid nests of cells with an epithelioid to plasmacytoid appearance, associated with blood vessels, hemorrhage, and degenerative changes, that is, pseudopapillary structures. The tumor cells stained focally for pancytokeratin, progesterone receptor, and CD57 with diffuse nuclear expression of beta-catenin. Ki-67 was 5% to 10%. Synaptophysin, inhibin, and E-cadherin stains were negative. Clinical and radiologic follow-up of our patient demonstrated no pancreatic lesions. This is a rare report of a primary ovarian solid pseudopapillary neoplasm. Prolonged follow up is needed to determine how this case will fare clinically. PMID- 22534260 TI - The Kaiser Permanente experience with ultrasound-guided percutaneous endovascular abdominal aortic aneurysm repair. AB - BACKGROUND: This study was conducted to determine the effect of ultrasound (US) guided percutaneous access for percutaneous endovascular abdominal aortic aneurysm repair (PEVAR) on conversion to open repair by femoral cutdown. We also sought to identify other risk factors associated with failure of percutaneous access and conversion to femoral cutdowns. METHODS: This is a single-center, retrospective review of 101 patients who underwent PEVAR between January 1, 2005 and July 31, 2009 (56 months). Risk factors that were evaluated for unsuccessful PEVAR included gender, age (<=65 and >=66 years), US-guided percutaneous access, mechanical failure, abdominal aortic aneurysm size, and the following comorbidities: diabetes, hypertension, vessel calcification, and obesity (body mass index: >=30 kg/m(2)). RESULTS: There were 10 (9.9%) conversions from percutaneous to femoral cutdown, yielding a success rate of 90.1% for a total percutaneous approach. Each converted patient had one groin converted, resulting in a cutdown rate per groin of 10/202 (5%). There were no 30-day mortalities. Univariate analysis showed that hypertension (P = 0.261), age >=66 years (P = 0.741), current smoking history (P = 0.649), past smoking history (P = .093), diabetes (P = 0.908), vessel calcification (P = 0.8281), and body mass index >=30 kg/m(2) (P = 0.052) did not significantly predict conversion to endovascular aortic aneurysm repair (EVAR). Mechanical failure significantly predicted conversion to cutdown EVAR (P = 0.0002), whereas US-guided percutaneous access influenced successful PEVAR (P = 0.030). Multivariate analysis showed that mechanical failure significantly predicted conversion to cutdown EVAR (P = 0.003) and US-guided percutaneous access influenced successful PEVAR (P = 0.040) after adjusting for smoking history and obesity. CONCLUSION: PEVAR is a viable option for aortic aneurysm repair that may be improved with US-guided percutaneous access by reducing the rate of femoral cutdowns. PMID- 22534261 TI - Mycotic pseudoaneurysms due to injection drug use: a ten-year experience. AB - BACKGROUND: Arterial injury and infection due to repetitive injection drug use can result in mycotic pseudoaneurysm predisposing to hemorrhage, distal embolism, limb loss, and death. We hypothesized that debridement of the infected artery, followed by immediate vascular reconstruction, results in successful limb salvage in these patients. METHODS: The setting was a county hospital. A retrospective review of all patients diagnosed with lower extremity pseudoaneurysms by the Departments of Surgery and Radiology between 2000 and 2009 was conducted. Outcome measures were patient characteristics, site(s) of lesion, type and results of imaging, type of operation, length of hospital stay, and complications. RESULTS: Sixteen patients had 17 pseudoaneurysms. One of the patients had two mycotic pseudoaneurysms in the same region separated by a period of 10 months. Culture of the wall of the first pseudoaneurysm was not performed. The second pseudoaneurysm was culture positive. The 15 remaining mycotic pseudoaneurysms were all culture positive. Nine patients were men, and the median age of the patient group was 37 years. Common femoral pseudoaneurysms were the most frequent (76%). Symptoms included swelling (94%), pain (82%), and erythema (75.6%). A rapidly expanding pulsatile expansile mass was present in four of the patients. Computed tomography and percutaneous angiography were done in seven and four of the patients, respectively, and were diagnostic in all cases studied. Resection and reconstruction with autologous vein was the most common procedure (seven), followed by cadaveric grafting (four), synthetic grafting (two), ligation (two), and primary repair (two). Muscle flaps were used in 76.5% of the cases. Complications included anastomotic dehiscence (n = 3), acute thrombosis (n = 1), ischemia (n = 1), abscess (n = 1), and compartment syndrome (n = 1). Three of these patients required a second vascular reconstruction. One patient ultimately required an amputation. No postoperative deaths occurred. Methicillin-resistant Staphylococcus aureus was cultured from 13 of the 16 arterial walls. CONCLUSION: Methicillin-resistant Staphylococcus aureus is the predominant organism causing mycotic aneurysms of the common and superficial femoral arteries owing to injection drug use at San Francisco General Hospital. Wide debridement of the infected artery and reconstruction with an in-line reversed saphenous vein or cryopreserved vascular allograft is a safe and effective method of treatment. Long-term follow-up studies are needed to determine the durability of this method of treatment. PMID- 22534262 TI - Carotid artery surgery: high-risk patients or high-risk centers? AB - BACKGROUND: Carotid angioplasty and stenting has been proposed as an alternative to carotid endarterectomy (CEA) in patients deemed as at high risk for this surgical procedure. To date, definitely accepted criteria to identify "high-risk" patients for CEA do not exist. Our objective was to assess the relevance of numerous supposed high-risk factors in our experience, as well as their possible effect on our early postoperative results. METHODS: A retrospective review of 1,033 consecutive CEAs performed during a 5.6-year period at a single institution was conducted (Vascular Surgery Department, St. Etienne University Hospital, France). Early results in terms of mortality and neurologic events were recorded. Univariate and multivariate analyses for early risk of stroke, myocardial infarction, and death were performed, considering the influence of age, sex, comorbidities, clinical symptoms, and anatomic features. RESULTS: The cumulative 30-day stroke and death rate was 1.2%. A total of 10 strokes occurred and resulted in three deaths. The postoperative stroke risk was significantly higher in the subgroup of patients treated for symptomatic carotid artery disease: 2,6% (P = 0,004). Univariate analysis and logistic regression did not show statistical significance for 30-day results in any of the considered variables. CONCLUSION: Patients with significant medical comorbidities, contralateral carotid occlusion, and high carotid lesions can undergo surgery without increased complications. Those parameters should not be used as exclusion criteria for CEA. PMID- 22534263 TI - Complications of arteriovenous fistula for hemodialysis: an 8-year study. AB - BACKGROUND: To assess the frequency and characteristics of complications of arteriovenous fistula (AVF) and their effect on fistula outcome. METHODS: We retrospectively reviewed 628 AVFs constructed from November 2002 to October 2010 to record the complications and their management options. The association between age, sex, comorbidities (HIV, hypertension, and diabetes), fistula type, and complications was sought. RESULTS: Most patients were males (73.7%). The mean age was 45.3 years. Comorbidities seen included diabetes mellitus (22.12%), hypertension (83.12%), and HIV infection (9.87%). AVFs constructed were mainly radiocephalic (68%) and brachiocephalic (24.9%). The median follow-up period was 275 days. The cumulative patency rate was 76% and 51% at 1 year and 2 years, respectively. Altogether, 211 complications occurred in 16% of the AVFs. Among them, 36.96% were severe, 25.11% moderate, and 43.91% minor. With respect to the time of occurrence, 63.98% were late complications, 12.79% immediate, and 23.22% early. Aneurysms, failure to mature, and thrombosis were the most frequent complications occurring in 26.54%, 14.69%, and 12.79% of cases, respectively. The management options for the complications included the creation of a new access in 36.96%, a temporary catheter before a new AVF in 10.52%, and nonoperative management in 43.12%. We found no adverse effect of comorbid factors such as diabetes mellitus (chi(2) = 3.58, P > 0.05) or HIV-positive status (chi(2) = 0.64, P > 0.05) on the complication rate. CONCLUSION: This study shows an overall frequency of complications of 16%. These results show the potential for low complication rate of AVF in selected population. PMID- 22534264 TI - Best treatment approaches for carpal tunnel syndrome. PMID- 22534265 TI - Counseling women on options for management of early pregnancy loss. PMID- 22534266 TI - Conventional vs. liquid-based cytology Pap smears for diagnosing trichomoniasis. PMID- 22534268 TI - Providing confidential care for adolescents. PMID- 22534269 TI - Rivaroxaban vs. warfarin for stroke prevention in patients with nonvalvular atrial fibrillation. AB - Patients with nonvalvular atrial fibrillation and a CHADS2 score of 2 points or more should be placed on warfarin anticoagulation. If they do not meet the CHADS2 criteria for warfarin, then they should receive therapy with aspirin. If a patient's condition is well-controlled on warfarin, this study does not support transitioning him or her to rivaroxaban, the more expensive alternative. Home monitoring of INR should be considered for patients who are capable and motivated to perform self-monitoring. Rivaroxaban has no reversal agent and has significant drug interactions (P-glycoprotein inducers and CYP3A4 inhibitors increase the risk of bleeding; P-glycoprotein inducers reduce effectiveness). PMID- 22534270 TI - Promoting smoking cessation. AB - Cigarette smoking causes significant morbidity and mortality in the United States. Physicians can use the five A's framework (ask, advise, assess, assist, arrange) to promote smoking cessation. All patients should be asked about tobacco use and assessed for motivation to quit at every clinical encounter. Physicians should strongly advise patients to quit smoking, and use motivational interviewing techniques for patients who are not yet willing to stop smoking. Clinical contacts with unmotivated patients should emphasize the rewards and relevance of quitting, as well as the risks of smoking and anticipated barriers to abstinence. These messages should be repeated at every opportunity. Appropriate patients should be offered pharmacologic assistance in quitting, such as nicotine replacement therapies, bupropion, and varenicline. Use of pharmacologic support during smoking cessation can double the rate of successful abstinence. Using more than one type of nicotine replacement therapy ("patch plus" method) and combining these therapies with bupropion provide additional benefit. However, special populations pose unique challenges in pharmacotherapy for smoking cessation. Nicotine replacement therapies increase the risk of birth defects and should not be used during pregnancy. They are usually safe in patients with cardiovascular conditions, except for those with unstable angina or within two weeks of a coronary event. Varenicline may increase the risk of coronary events. Nicotine replacement therapies are safe for use in adolescents; however, they are less effective than in adults. Physicians also should arrange to have repeated contact with smokers around their quit date to reinforce cessation messages. PMID- 22534271 TI - Information from your family doctor. Smoking cigarettes: how do I quit? PMID- 22534272 TI - Evaluation and treatment of the suicidal patient. AB - Evaluation and treatment of a suicidal patient are challenging tasks for the physician. Because no validated predictive tools exist, clinical judgment guides the decision-making process. Although there is insufficient evidence to support routine screening, evidence shows that asking high-risk patients about suicidal intent leads to better outcomes and does not increase the risk of suicide. Important elements of the history that permit evaluation of the seriousness of suicidal ideation include the intent, plan, and means; the availability of social support; previous suicide attempts; and the presence of comorbid psychiatric illness or substance abuse. After intent has been established, inpatient and outpatient management should include ensuring patient safety and medical stabilization; activating support networks; and initiating therapy for psychiatric diseases. Care plans for patients with chronic suicidal ideation include these same steps, as well as referral for specialty care. In the event of a completed suicide, physicians should provide support for family members who may be experiencing grief complicated by guilt, while also activating their own support networks and risk management systems. PMID- 22534273 TI - Information from your family doctor. Help for people who are thinking about suicide. PMID- 22534274 TI - Thrombocytopenia. AB - Thrombocytopenia is defined as a platelet count of less than 150 * 10(3) per uL. It is often discovered incidentally when obtaining a complete blood count during an office visit. The etiology usually is not obvious, and additional investigation is required. Patients with platelet counts greater than 50 * 10(3) per uL rarely have symptoms. A platelet count from 30 to 50 * 10(3) per uL rarely manifests as purpura. A count from 10 to 30 * 10(3) per uL may cause bleeding with minimal trauma. A platelet count less than 5 * 10(3) per uL may cause spontaneous bleeding and constitutes a hematologic emergency. Patients who present with thrombocytopenia as part of a multisystem disorder usually are ill and require urgent evaluation and treatment. These patients most likely have an acute infection, heparin-induced thrombocytopenia, liver disease, thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, disseminated intravascular coagulation, or a hematologic disorder. During pregnancy, preeclampsia and the HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome are associated with thrombocytopenia. Patients with isolated thrombocytopenia commonly have drug-induced thrombocytopenia, immune thrombocytopenic purpura, pseudothrombocytopenia, or if pregnant, gestational thrombocytopenia. A history, physical examination, and laboratory studies can differentiate patients who require immediate intervention from those who can be treated in the outpatient setting. Treatment is based on the etiology and, in some cases, treating the secondary cause results in normalization of platelet counts. Consultation with a hematologist should be considered if patients require hospitalization, if there is evidence of systemic disease, or if thrombocytopenia worsens despite initial treatment. PMID- 22534275 TI - Information from your family doctor. Low platelet count: what does it mean? PMID- 22534276 TI - Evaluation and management of common anorectal conditions. AB - The prevalence of benign anorectal conditions in the primary care setting is high, although evidence of effective therapy is often lacking. In addition to recognizing common benign anorectal disorders, physicians must maintain a high index of suspicion for inflammatory and malignant disorders. Patients with red flags such as increased age, family history, persistent anorectal bleeding despite treatment, weight loss, or iron deficiency anemia should undergo colonoscopy. Pruritus ani, or perianal itching, is managed by treating the underlying cause, ensuring proper hygiene, and providing symptomatic relief with oral antihistamines, topical steroids, or topical capsaicin. Effective treatments for anal fissures include onabotulinumtoxinA, topical nitroglycerin, and topical calcium channel blockers. Symptomatic external hemorrhoids are managed with dietary modifications, topical steroids, and analgesics. Thrombosed hemorrhoids are best treated with hemorrhoidectomy if symptoms are present for less than 72 hours. Grades I through III internal hemorrhoids can be managed with rubber band ligation. For the treatment of grade III internal hemorrhoids, surgical hemorrhoidectomy has higher remission rates but increased pain and complication rates compared with rubber band ligation. Anorectal condylomas, or anogenital warts, are treated based on size and location, with office treatment consisting of topical trichloroacetic acid or podophyllin, cryotherapy, or laser treatment. Simple anorectal fistulas can be treated conservatively with sitz baths and analgesics, whereas complex or nonhealing fistulas may require surgery. Fecal impaction may be treated with polyethylene glycol, enemas, or manual disimpaction. Fecal incontinence is generally treated with loperamide and biofeedback. Surgical intervention is reserved for anal sphincter injury. PMID- 22534277 TI - FPIN's clinical inquiries. Medications for weight loss in patients with type 2 diabetes mellitus. PMID- 22534279 TI - Chronic anterior knee pain after mild trauma in a sedentary adolescent. Developmental dysplasia and dislocation of the patella. PMID- 22534281 TI - Survival comparison of allograft and autograft anterior cruciate ligament reconstruction at the United States Military Academy. AB - BACKGROUND: There is recent evidence that use of allograft tendons for anterior cruciate ligament (ACL) reconstruction in young patients may result in increased failure rates compared with autologous grafts. HYPOTHESIS: Allograft ACL reconstruction will result in higher failure rates in young athletes compared with autograft reconstruction. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A prospective cohort study of cadets at the United States Military Academy (USMA) was performed to assess performance of ACL reconstructions performed before entrance to service. Members of the classes of 2007 through 2013 who had undergone prior ACL reconstruction were identified through the Department of Defense Medical Evaluation Review Board reporting and waiver process and evaluated on the first day of matriculation. These participants were followed during their tenure at the academy with revision ACL reconstruction as the primary outcome measure of interest. Kaplan-Meier survival analysis was performed for all graft types using STATA with significance set as P < .05. RESULTS: A total of 120 cadets underwent 122 ACL reconstructions (2 bilateral) before matriculation and compose the prospective cohort. This cohort included 30 female and 90 male cadets. Of these 122 knees with prior ACL reconstructions, the grafts used were 61 bone-patellar tendon-bone (BTB), 45 hamstring, and 16 allograft. A total of 20 failures occurred among this cohort at an average of 545 days from matriculation. Of the failures requiring revision, 7 were BTB (11% of all BTB), 7 were allograft (44% of all allograft), and 6 were hamstring (13% of all hamstring). There was no significant difference in the graft failure between the BTB and hamstring autograft groups. In contrast, those who entered the USMA with an allograft were 7.7 times more likely to experience a subsequent graft failure during the follow-up period when compared with the BTB autograft group (hazard ratio = 7.74; 95% confidence interval [CI], 2.67-22.38; P < .001). When allografts were compared with all autografts combined, a similar increase failure was noted in the allograft group (hazard ratio = 6.71; 95% CI, 2.64-17.06; P < .001). CONCLUSION: In this young active cohort, individuals having undergone an allograft ACL reconstruction were significantly more likely to experience clinical failure requiring revision reconstruction compared with those who underwent autologous graft reconstruction. The authors recommend the use of autograft in ACL reconstruction in young athletes. PMID- 22534283 TI - Referral of elderly cancer patients to specialists: action proposals for general practitioners. AB - BACKGROUND: Many studies have identified advanced age as a barrier to accessing specialized oncological care. OBJECTIVES: To identify elements from the literature influencing general practitioners (GPs) in their decisions to refer elderly patients with cancer to oncology teams, and propose focused actions to improve referral processes. METHODS: Eligible articles published up to July 2010 identifying factors associated with referral decisions for elderly cancer patients were selected. A quality assessment of each article was performed. All factors identified were considered for possible interventions classified by the Effective Practice and Organisation of Care (EPOC) taxonomy and development of recommendations for referral of elderly patients. RESULTS: Thirty eligible articles were found with only 18 articles specifically exploring factors influencing physicians in the referral of their patients with cancer. Twelve focused on delay to treatment and only two uniquely on elderly patients. Patient age was the main factor associated with referral decisions, but this factor can influence GP's differently depending on the type of cancer. The small size of these studies, heterogeneity of study populations, and diversity of outcome measures used meant that compilation of guidelines based on high-quality evidence was not possible. However, organizational factors hindering decisions to refer are identified and highlighted as crucial for inclusion in intervention programs, specifically to reach GPs in smaller locations or with less experience in collaborating with specialists. For patient-related factors, professional and organizational interventions are necessary, aimed at both GPs and patients to update knowledge of the non-linear relationship between chronological age and a patient's ability to tolerate treatment. CONCLUSIONS: First and foremost, this article highlights the scarcity of literature specific to elderly patients with cancer. It also identifies the public health need for better knowledge of the factors for referral of elderly patients. Focussed action proposals are presented to improve knowledge and consequently, optimize the referral process. PMID- 22534282 TI - Genome sequencing reveals complex speciation in the Drosophila simulans clade. AB - The three species of the Drosophila simulans clade--the cosmopolitan species, D. simulans, and the two island endemic species, D. mauritiana and D. sechellia--are important models in speciation genetics, but some details of their phylogenetic and speciation history remain unresolved. The order and timing of speciation are disputed, and the existence, magnitude, and timing of gene flow among the three species remain unclear. Here we report on the analysis of a whole-genome four species sequence alignment that includes all three D. simulans clade species as well as the D. melanogaster reference sequence. The alignment comprises novel, paired short-read sequence data from a single highly inbred line each from D. simulans, D. mauritiana, and D. sechellia. We are unable to reject a species phylogeny with a basal polytomy; the estimated age of the polytomy is 242,000 yr before the present. However, we also find that up to 4.6% of autosomal and 2.2% of X-linked regions have evolutionary histories consistent with recent gene flow between the mainland species (D. simulans) and the two island endemic species (D. mauritiana and D. sechellia). Our findings thus show that gene flow has occurred throughout the genomes of the D. simulans clade species despite considerable geographic, ecological, and intrinsic reproductive isolation. Last, our analysis of lineage-specific changes confirms that the D. sechellia genome has experienced a significant excess of slightly deleterious changes and a dearth of presumed favorable changes. The relatively reduced efficacy of natural selection in D. sechellia is consistent with its derived, persistently reduced historical effective population size. PMID- 22534284 TI - Targeted radio-nuclide therapy of skeletal metastases. AB - In this review, we will focus on one particular class of stromal targeted therapy, i.e. the bone seeking radiopharmaceuticals (BSRs), but will also highlight selected issues related to the bone stroma as these concepts are new, rapidly evolving, and clearly linked to the underlying BSR mechanisms of targeting and action. Herein we review clinical BSR-trials of significance with randomized trials at center stage. Furthermore, we cover a new class of BSR in late clinical development based on bone-stromal targeted alpha-particle irradiation. Lastly, we discuss potential advances in combining BSR with bisphosphonates and/or chemotherapy and emphasize the feasibility of repeated dosing. PMID- 22534285 TI - Coexistence of benign phyllodes tumor and invasive ductal carcinoma in distinct breasts: case report. AB - This report describes a rare case of coexistence of benign phyllodes tumor, which measured 9 cm in the right breast, and invasive ductal carcinoma of 6 cm in the left breast, synchronous and independent, in a 66-year-old patient. The patient underwent a bilateral mastectomy due to the size of both lesions. Such situations are rare and usually refer to the occurrence of ductal or lobular carcinoma in situ when associated with malignant phyllodes tumors, and more often in ipsilateral breast or intra-lesional. PMID- 22534286 TI - Onecut factors control development of the Locus Coeruleus and of the mesencephalic trigeminal nucleus. AB - The Locus Coeruleus (LC), the main noradrenergic nucleus in the vertebrate CNS, contributes to the regulation of several processes including arousal, sleep, adaptative behaviors and stress. Regulators controlling the formation of the LC have been identified but factors involved in its maintenance remain unknown. Here, we show that members of the Onecut (OC) family of transcription factors, namely HNF-6, OC-2 and OC-3, are required for maintenance of the LC phenotype. Indeed, in embryos lacking any OC proteins, LC neurons properly differentiate but abnormally migrate and eventually lose their noradrenergic characteristics. Surprisingly, the expression of Oc genes in these neurons is restricted to the earliest differentiation stages, suggesting that OC factors may regulate maintenance of the LC in a non cell-autonomous manner. Accordingly, the OC factors are present throughout development in a population directly adjacent to the LC, the rhombencephalic portion of the mesencephalic trigeminal nucleus (MTN). In the absence of OC factors, rhombencephalic MTN neurons fail to be generated, suggesting that OC proteins cell-autonomously control their production. Hence, we propose that OC factors are required at early developmental stages for differentiation of the MTN neurons that are in turn necessary for maintenance of the LC. PMID- 22534287 TI - Dermoscopy in the diagnosis and management of non-melanoma skin cancers. AB - Over the past two decades, dermoscopy has remarkably enhanced the diagnostic accuracy of pigmented skin lesions and, more recently, of non-pigmented skin disorders, including skin cancers, inflammatory and infectious diseases. With respect to non-melanoma skin cancers (NMSC), dermoscopy is an effective diagnostic tool for the clinical assessment of basal cell carcinoma, Bowen's disease, actinic keratosis and squamous cell carcinoma. Besides its relevance for diagnostic purposes, further applications of dermoscopy in the management of NMSC have been suggested in the preoperative evaluation, in monitoring the outcome of topical, light-based or laser treatments and in the post-treatment follow-up. This article summarizes the dermoscopic diagnostic criteria of NMSC and provides a review of the published literature as well as of our own experience on the usefulness of dermoscopy in monitoring surgical and medical treatment of NMSC. PMID- 22534288 TI - Patient-centered outcomes of high-velocity, low-amplitude spinal manipulation for low back pain: a systematic review. AB - Low back pain (LBP) is a well-recognized public health problem with no clear gold standard medical approach to treatment. Thus, those with LBP frequently turn to treatments such as spinal manipulation (SM). Many clinical trials have been conducted to evaluate the efficacy or effectiveness of SM for LBP. The primary objective of this paper was to describe the current literature on patient centered outcomes following a specific type of commonly used SM, high-velocity low-amplitude (HVLA), in patients with LBP. A systematic search strategy was used to capture all LBP clinical trials of HVLA using our predefined patient-centered outcomes: visual analogue scale, numerical pain rating scale, Roland-Morris Disability Questionnaire, and the Oswestry Low Back Pain Disability Index. Of the 1294 articles identified by our search, 38 met our eligibility criteria. Like previous SM for LBP systematic reviews, this review shows a small but consistent treatment effect at least as large as that seen in other conservative methods of care. The heterogeneity and inconsistency in reporting within the studies reviewed makes it difficult to draw definitive conclusions. Future SM studies for LBP would benefit if some of these issues were addressed by the scientific community before further research in this area is conducted. PMID- 22534289 TI - Biochemical and molecular characterization of high population density bacteria isolated from sunflower. AB - Natural and beneficial associations between plants and bacteria have demonstrated potential commercial application for several agricultural crops. The sunflower has acquired increasing importance in Brazilian agribusiness owing to its agronomic characteristics such as the tolerance to edaphoclimatic variations, resistance to pests and diseases, and adaptation to the implements commonly used for maize and soybean, as well as the versatility of the products and by-products obtained from its cultivation. A study of the cultivable bacteria associated with two sunflower cultivars, using classical microbiological methods, successfully obtained isolates from different plant tissues (roots, stems, florets, and rhizosphere). Out of 57 plantgrowth- promoting isolates obtained, 45 were identified at the genus level and phylogenetically positioned based on 16S rRNA gene sequencing: 42 Bacillus (B. subtilis, B. cereus, B. thuringiensis, B. pumilus, B. megaterium, and Bacillus sp.) and 3 Methylobacterium komagatae. Random amplified polymorphic DNA (RAPD) analysis showed a broad diversity among the Bacillus isolates, which clustered into 2 groups with 75% similarity and 13 subgroups with 85% similarity, suggesting that the genetic distance correlated with the source of isolation. The isolates were also analyzed for certain growth promoting activities. Auxin synthesis was widely distributed among the isolates, with values ranging from 93.34 to 1653.37 microM auxin per microng of protein. The phosphate solubilization index ranged from 1.25 to 3.89, and siderophore index varied from 1.15 to 5.25. From a total of 57 isolates, 3 showed an ability to biologically fix atmospheric nitrogen, and 7 showed antagonism against the pathogen Sclerotinia sclerotiorum. The results of biochemical characterization allowed identification of potential candidates for the development of biofertilizers targeted to the sunflower crop. PMID- 22534290 TI - Genetic and phenotypic diversity of carbofuran-degrading bacteria isolated from agricultural soils. AB - Thirty-seven carbofuran-degrading bacteria were isolated from agricultural soils, and their genetic and phenotypic characteristics were investigated. The isolates were able to utilize carbofuran as a sole source of carbon and energy. Analysis of the 16S rRNA gene sequence indicated that the isolates were related to members of the genera Rhodococcus, Sphingomonas, and Sphingobium, including new types of carbofuran-degrading bacteria, Bosea and Microbacterium. Among the 37 isolates, 15 different chromosomal DNA patterns were obtained by polymerase chain reaction (PCR) amplification of repetitive extragenic palindromic (REP) sequences. Five of the 15 representative isolates were able to degrade carbofuran phenol, fenoxycarb, and carbaryl, in addition to carbofuran. Ten of the 15 representative isolates had 1 to 8 plasmids. Among the 10 plasmid-containing isolates, plasmid cured strains were obtained from 5 strains. The cured strains could not degrade carbofuran and other pesticides anymore, suggesting that the carbofuran degradative genes were on the plasmid DNAs in these strains. When analyzed with PCR amplification and dot-blot hybridization using the primers targeting for the previously reported carbofuran hydrolase gene (mcd), all of the isolates did not show any positive signals, suggesting that their carbofuran hydrolase genes had no significant sequence homology with the mcd gene. PMID- 22534292 TI - Metagenomic analysis of novel lignocellulose-degrading enzymes from higher termite guts inhabiting microbes. AB - A metagenomic fosmid library was constructed from genomic DNA isolated from the microbial community residing in hindguts of a wood-feeding higher termite (Microcerotermes sp.) collected in Thailand. The library was screened for clones expressing lignocellulolytic activities. Fourteen independent active clones (2 cellulases and 12 xylanases) were obtained by functional screening at pH 10.0. Analysis of shotgun-cloning and pyrosequencing data revealed six ORFs, which shared less than 59% identity and 73% similarity of their amino acid sequences with known cellulases and xylanases. Conserved domain analysis of these ORFs revealed a cellulase belonging to the glycoside hydrolase family 5, whereas the other five xylanases showed significant identity to diverse families including families 8, 10, and 11. Interestingly, one fosmid clone was isolated carrying three contiguous xylanase genes that may comprise a xylanosome operon. The enzymes with the highest activities at alkaline pH from the initial activity screening were characterized biochemically. These enzymes showed a broad range of enzyme activities from pH 5.0 to 10.0, with pH optimal of 8.0 retaining more than 70% of their respective activities at pH 9.0. The optimal temperatures of these enzymes ranged from 50 degrees C to 55 degrees C. This study provides evidence for the diversity and function of lignocellulose-degrading enzymes in the termite gut microbial community, which could be of potential use for industrial processes such as pulp biobleaching and denim biostoning. PMID- 22534291 TI - Visualization of candidate division OP3 cocci in limonene-degrading methanogenic cultures. AB - Members of candidate division OP3 were detected in 16S rRNA gene clone libraries from methanogenic enrichment cultures that utilized limonene as a carbon and energy source. We developed probes for the visualization of OP3 cells. In situ hybridization experiments with newly designed OP3-specific probes [OP3-565 and Eub-338(VI)] revealed abundant small OP3 cocci attached to larger cells. Syntrophic Deltaproteobacteria, OP3 cells, and methanogens affiliating with Methanoculleus and Methanosaeta formed the limonenedegrading community. PMID- 22534293 TI - Comparative analysis of envelope proteomes in Escherichia coli B and K-12 strains. AB - Recent genome comparisons of E. coli B and K-12 strains have indicated that the makeup of the cell envelopes in these two strains is quite different. Therefore, we analyzed and compared the envelope proteomes of E. coli BL21(DE3) and MG1655. A total of 165 protein spots, including 62 nonredundant proteins, were unambiguously identified by two-dimensional gel electrophoresis and mass spectrometry. Of these, 43 proteins were conserved between the two strains, whereas 4 and 16 strain-specific proteins were identified only in E. coli BL21(DE3) and MG1655, respectively. Additionally, 24 proteins showed more than 2 fold differences in intensities between the B and K-12 strains. The reference envelope proteome maps showed that E. coli envelope mainly contained channel proteins and lipoproteins. Interesting proteomic observations between the two strains were as follows: (i) B produced more OmpF porin with a larger pore size than K-12, indicating an increase in the membrane permeability; (ii) B produced higher amounts of lipoproteins, which facilitates the assembly of outer membrane beta-barrel proteins; and (iii) motility- (FliC) and chemotaxis-related proteins (CheA and CheW) were detected only in K-12, which showed that E. coli B is restricted with regard to migration under unfavorable conditions. These differences may influence the permeability and integrity of the cell envelope, showing that E. coli B may be more susceptible than K-12 to certain stress conditions. Thus, these findings suggest that E. coli K-12 and its derivatives will be more favorable strains in certain biotechnological applications, such as cell surface display or membrane engineering studies. PMID- 22534294 TI - Comparison of alpha-factor preprosequence and a classical mammalian signal peptide for secretion of recombinant xylanase xynB from yeast Pichia pastoris. AB - The secretory efficiency of recombinant xylanase xynB from yeast Pichia pastoris between the alpha-factor preprosequence and a classical mammalian signal peptide derived from bovine beta-casein was compared. The results showed that although the bovine beta-casein signal peptide could direct highlevel secretion of recombinant xylanase, it was relatively less efficient than the alpha-factor preprosequence. In contrast, the bovine beta-casein signal peptide caused remarkably more recombinant xylanase trapped intracellularly. Realtime RT-PCR analysis indicated that the difference in the secretory level between the two signal sequences was not due to the difference in the transcriptional efficiency. PMID- 22534295 TI - Characterization of the BolA homolog IbaG: a new gene involved in acid resistance. AB - BolA protein homologs are widely distributed in nature. In this report, we have studied for the first time YrbA, the only BolA homolog present in Escherichia coli, which we have renamed ibaG. We have constructed single and multiple ibaG mutants, and overexpressed ibaG in wildtype strains, in order to characterize this gene. The ibaG phenotypes are different from the bolA-associated round morphologies or growth profiles. Interestingly, ibaG and bolA single- and double deletion mutants grow faster and have higher viabilities in rich media, whereas the overexpressed strains are significantly growth impaired. However, the mutant strains have lower viabilities than the wild type in the late stationary phase, indicating that both bolA and ibaG are important for survival in difficult growth conditions. bolA, as a transcription factor, binds to some promoters, but ibaG does not interact with the same DNA regions. We have determined that ibaG is transcribed in an operon with the murA gene, involved in the synthesis of peptidoglycan precursors. ibaG was also seen to change its mRNA expression pattern in response to acidic stress. ibaG may thus represent a new gene involved in cell resistance against acid stress. PMID- 22534296 TI - Enhancement of anti-inflammatory activity of PEP-1-FK506 binding protein by silk fibroin peptide. AB - Silk fibroin (SF) peptide has been traditionally used as a treatment for flatulence, spasms, and phlegm. In this study, we examined whether SF peptide enhanced the antiinflammatory effect of PEP-1-FK506 binding protein (PEP-1 FK506BP) through comparing the anti-inflammatory activities of SF peptide and/or PEP-1-FK506BP. In the presence or absence of SF peptide, transduction levels of PEP-1-FK506BP into HaCaT cells and mice skin and anti-inflammatory activities of PEP-1-FK506BP were identified by Western blot and histological analyses. SF peptide alone effectively reduced both mice ear edema and the elevated levels of cyclooxygenase-2, interleukin-6 and -1beta, and tumor necrosis factor-alpha, showing similar anti-inflammatory effect to that of PEP-1-FK506BP. Furthermore, co-treatment with SF peptide and PEP-1- FK506BP exhibited more enhanced anti inflammatory effects than the samples treated with SF peptides or PEP- 1-FK506BP alone, suggesting the possibility that SF peptide and PEP-1-FK506BP might interact with each other. Moreover, the transduction data demonstrated that SF peptide did not affect the transduction of PEP-1- FK506BP into HaCaT cells and mice skin, indicating that the improvement of anti-inflammatory effect of PEP-1- FK506BP was not caused by enhanced transduction of PEP-1-FK506BP. Thus, these results suggest the possibility that co-treatment with SF peptide and PEP-1 FK506BP may be exploited as a useful therapy for various inflammationrelated diseases. PMID- 22534297 TI - Molecular and biochemical characterization of a novel intracellular low temperature-active xylanase. AB - A 990 bp full-length gene (xynAHJ2) encoding a 329- residue polypeptide (XynAHJ2) with a calculated mass of 38.4 kDa was cloned from Bacillus sp. HJ2 harbored in a saline soil. XynAHJ2 showed no signal peptide, distinct amino acid stretches of glycoside hydrolase (GH) family 10 intracellular endoxylanases, and the highest amino acid sequence identity of 65.3% with the identified GH 10 intracellular mesophilic endoxylanase iM-KRICT PX1-Ps from Paenibacillus sp. HPL-001 (ACJ06666). The recombinant enzyme (rXynAHJ2) was expressed in Escherichia coli and displayed the typical characteristics of low-temperatureactive enzyme (exhibiting optimum activity at 35 degrees C, 62% at 20 degrees C, and 38% at 10 degrees C; thermolability at > or =45 degrees C). Compared with the reported GH 10 low-temperature-active endoxylanases, which are all extracellular, rXynAHJ2 showed low amino acid sequence identities (<45%), low homology (different phylogenetic cluster), and difference of structure (decreased amount of total accessible surface area and exposed nonpolar accessible surface area). Compared with the reported GH 10 intracellular endoxylanases, which are all mesophilic and thermophilic, rXynAHJ2 has decreased numbers of arginine residues and salt bridges, and showed resistance to Ni2+, Ca2+, or EDTA at 10 mM final concentration. The above mechanism of structural adaptation for low-temperature activity of intracellular endoxylanase rXynAHJ2 is different from that of GH 10 extracellular low-temperature-active endoxylanases. This is the first report of the molecular and biochemical characterizations of a novel intracellular low temperatureactive xylanase. PMID- 22534298 TI - Large increase in Leuconostoc citreum KM20 dextransucrase activity achieved by changing the strain/inducer combination in an E. coli expression system. AB - A recombinant putative dextransucrase (DexT) was produced from Leuconostoc citreum KM20 as a 160 kDa protein, but its productivity was very low (264 U/l). For optimization, we examined enzyme activity in 7 Escherichia coli strains with inducer molecules such as lactose or IPTG. E. coli BL21-CodonPlus(DE3)-RIL exhibited the highest enzyme activity with lactose. Finally, DexT activity was remarkably increased by 12-fold under the optimized culture conditions of a cell density to start induction (OD600) of 0.95, a lactose concentration of 7.5 mM, and an induction temperature of 17 degrees C. These results may effectively apply to the heterologous expression of other large DexT genes. PMID- 22534299 TI - Proteomic analysis of proteins increased or reduced by ethanol of Lactobacillus plantarum ST4 isolated from Makgeolli, traditional Korean rice wine. AB - LAB were isolated from makgeolli locally produced around Jinju, Gyeongnam, S. Korea during spring of 2011. Randomly selected 11 isolates from MRS agar plates were identified first by API CHL 50 kits and then 16S rRNA gene sequencing. All 11 isolates were identified as Lactobacillus plantarum. Among them, ST4 grew in MRS broth with ethanol up to 10%, showing the highest alcohol resistance. L. plantarum ST4 was moderately resistant against acid and bile salts. When cellular proteins of L. plantarum ST4 under ethanol stress were analyzed by two dimensional gel electrophoresis (2DE), the intensities of 6 spots increased, whereas 22 spots decreased at least 2-fold. Those 28 spots were identified by peptide mass fingerprinting (PMF). FusA2 (elongation factor G) increased 18.8 fold (6% ethanol) compared with control. Other proteins were AtpD (ATP synthase subunit beta), DnaK, GroEL, Tuf (elongation factor Tu), and Npr2 (NADH peroxidase), respectively. Among the 22 proteins decreased in intensities, lactate dehydrogenases (LdhD and LdhL1) were included. PMID- 22534300 TI - Effect of a probiotic strain, Enterococcus faecium, on the immune responses of olive flounder (Paralichthys olivaceus). AB - The present study was aimed to investigate the effect of a probiotic, Enterococcus faecium, on the immune responses against infection with the marine fish pathogen Lactococcus garvieae in olive flounder (Paralichthys olivaceus). The immune responses were assessed by lysozyme activity, complement activity, protease activity, and expression of proinflammatory cytokines by RT-PCR. The lysozyme and complement activities were increased between 9 to 15 and 9 to 13 days, respectively, and antiprotease activity was slightly elevated after 5 days of probiotic treatment. The TNF-alpha and IL-1beta expressions were observed from kidney and spleen. The results of this study reveal that E. faecium induces immune-responsible materials and protects olive flounder from lactococcosis. PMID- 22534301 TI - Development of real-time PCR for the detection of Clostridium perfringens in meats and vegetables. AB - A real-time PCR assay was developed and validated inhouse specifically for the detection of Clostridium perfringens (Cl. perfringens) in meats and vegetables by comparing with the culture method. The detection limit of the real-time PCR assay in phosphate-buffered saline was 102 CFU/ml. When the two methods were compared in food samples inoculated with Cl. perfringens, the culture method detected 52 positives, whereas real-time PCR detected 51 positives out of 160 samples. The difference was without statistical significance (p>0.05). Real-time PCR assay is an option for quality assurance laboratories to perform standard diagnostic tests, considering its detection ability and time-saving efficiency. PMID- 22534302 TI - Cloning and characterization of ginsenoside Ra1-hydrolyzing beta-D-xylosidase from Bifidobacterium breve K-110. AB - beta-D-Xylosidase (E.C. 3.2.1.37) from Bifidobacterium breve K-110, which hydrolyzes ginsenoside Ra1 to ginsenoside Rb2, was cloned and expressed in Escherichia coli. The (His6)-tagged recombinant enzyme, designated as XlyBK- 110, was efficiently purified using Ni2+-affinity chromatography (109.9-fold, 84% yield). The molecular mass of XylBK- 100 was found to be 55.7 kDa by SDS-PAGE. Its sequence revealed a 1,347 bp open reading frame (ORF) encoding a protein containing 448 amino acids, which showed 82% identity (DNA) to the previously reported glycosyl hydrolase family 30 of Bifidobacterium adolescentis ATCC 15703. The Km and Vmax values toward p-nitrophenyl-beta-D-xylopyranoside (pNPX) were 1.45mM and 10.75 micromol/min/mg, respectively. This enzyme had pH and temperature optima at 6.0 and 45 degrees C, respectively. XylBK-110 acted to the greatest extent on xyloglucosyl kakkalide, followed by pNPX and ginsenoside Ra1, but did not act on p-nitrophenyl-alpha-Larabinofuranoside, p-nitrophenyl-beta-D glucopyranoside, or p-nitrophenyl-beta-D-fucopyranoside. In conclusion, this is the first report on the cloning and expression of beta-Dxylosidase- hydrolyzing ginsenoside Ra1 and kakkalide from human intestinal microflora. PMID- 22534303 TI - Growth response of Avena sativa in amino-acids-rich soils converted from phenol contaminated soils by Corynebacterium glutamicum. AB - The biodegradation of phenol in laboratory-contaminated soil was investigated using the Gram-positive soil bacterium Corynebacterium glutamicum. This study showed that the phenol degradation caused by C. glutamicum was greatly enhanced by the addition of 1% yeast extract. From the toxicity test using Daphnia magna, the soil did not exhibit any hazardous effects after the phenol was removed using C. glutamicum. Additionally, the treatment of the phenolcontaminated soils with C. glutamicum increased various soil amino acid compositions, such as glycine, threonine, isoleucine, alanine, valine, leucine, tyrosine, and phenylalanine. This phenomenon induced an increase in the seed germination rate and the root elongation of Avena sativa (oat). This probably reflects that increased soil amino acid composition due to C. glutamicum treatment strengthens the plant roots. Therefore, the phenol-contaminated soil was effectively converted through increased soil amino acid composition, and additionally, the phenol in the soil environment was biodegraded by C. glutamicum. PMID- 22534304 TI - Hexavalent chromium reduction by bacteria from tannery effluent. AB - Chromium is generated from several industrial processes. It occurs in different oxidation states, but Cr(III) and Cr(VI) are the most common ones. Cr(VI) is a toxic, soluble environmental contaminant. Some bacteria are able to reduce hexavalent chromium to the insoluble and less toxic Cr(III), and thus chromate bioremediation is of considerable interest. An indigenous chromium-reducing bacterial strain, Rb-2, isolated from a tannery water sample, was identified as Ochrobactrum intermedium, on the basis of 16S rRNA gene sequencing. The influence of factors like temperature of incubation, initial concentration of Cr, mobility of bacteria, and different carbon sources were studied to test the ability of the bacterium to reduce Cr(VI) under variable environmental conditions. The ability of the bacterial strain to reduce hexavalent chromium in artificial and industrial sewage water was evaluated. It was observed that the mechanism of resistance to metal was not due to the change in the permeability barrier of the cell membrane, and the enzyme activity was found to be inductive. Intracellular reduction of Cr(VI) was proven by reductase assay using cell-free extract. Scanning electron microscopy revealed chromium precipitates on bacterial cell surfaces, and transmission electron microscopy showed the outer as well as inner distribution of Cr(VI). This bacterial strain can be useful for Cr(VI) detoxification under a wide range of environmental conditions. PMID- 22534305 TI - Characterization of a new beta-lactamase gene from isolates of Vibrio spp. in Korea. AB - PCR was performed to analyze the beta-lactamase genes carried by ampicillin resistant Vibrio spp. strains isolated from marine environments in Korea between 2006 and 2009. All 36 strains tested showed negative results in PCR with the primers designed from the nucleotide sequences of various known beta-lactamase genes. This prompted us to screen new beta-lactamase genes. A novel beta lactamase gene was cloned from Vibrio alginolyticus KV3 isolated from the aquaculture water of Geoje Island of Korea. The determined nucleotide sequence (VAK-3 beta-lactamase) revealed an open reading frame (ORF) of 852 bp, encoding a protein of 283 amino acids (aa), which displayed low homology to any other beta lactamase genes reported in public databases. The deduced 283 aa sequence of VAK 3, consisting of a 19 aa signal peptide and a 264 aa mature protein, contained highly conserved peptide segments specific to class A beta-lactamases including the specific amino acid residues STFK (62-65), SDN (122-124), E (158), and RTG (226-228). Results from PCR performed with primers specific to the VAK-3 beta lactamase gene identified 3 of the 36 isolated strains as V. alginolyticus, Vibrio cholerae, and Photobacterium damselae subsp. damselae, indicating the utilization of various beta-lactamase genes including unidentified ones in ampicillin-resistant Vibrio spp. strains from the marine environment. In a mating experiment, none of the isolates transfered the VAK-3 beta-lactamase gene to the Escherichia coli recipient. This lack of mobility, and the presence of a chromosomal acyl-CoA flanking sequence upstream of the VAK-3 beta- lactamase gene, led to the assumption that the location of this new beta-lactamase gene was in the chromosome, rather than the mobile plasmid. Antibiotic susceptibility of VAK-3 beta-lactamase was indicated by elevated levels of resistance to penicillins, but not to cephalosporins in the wild type and E. coli harboring recombinant plasmid pKV-3, compared with those of the host strain alone. Phylogenetic analysis showed that VAK-3 beta-lactamase is a new and separate member of class A beta-lactamases. PMID- 22534306 TI - Monitoring of horizontal gene transfer from agricultural microorganisms to soil bacteria and analysis of microbial community in soils. AB - To investigate the possibility of horizontal gene transfer between agricultural microorganisms and soil microorganisms in the environment, Bacillus subtilis KB producing iturin and the PGPR recombinant strain Pseudomonas fluorescens MX1 were used as model microorganisms. The soil samples of cucumber or tomato plants cultivated in pots and the greenhouse for a six month period were investigated by PCR, real-time PCR, Southern hybridization, and terminal restriction fragment length polymorphism (T-RFLP) fingerprinting. Our data from Southern blotting and TRFLP patterns suggest that the model bacteria do not give significant impacts on the other bacteria in the pots and greenhouse during cultivation. PMID- 22534307 TI - In vitro activities of antimicrobials against Brucella abortus isolates from cattle in Korea during 1998-2006. AB - In vitro activities of 13 antibiotics were assessed against 85 Brucella abortus isolates from naturally infected cattle in the Republic of Korea during 1998 2006, using broth microdilution test. Tetracyclines showed the most excellent activity against B. abortus, displaying MIC values of 0.5 MUg/ml or below. In particular, minocycline showed the lowest MIC50/90 values (0.125/0.125 MUg/ml) in this study. Among four fluoroquinolones tested, ciprofloxacin (MIC50/90, 0.5/1 MUg/ml) and norfloxacin (MIC50/90, 8/8 MUg/ml) had the most and the least activities, respectively. Gentamicin (MIC50/90, 1/1 MUg/ml) was more effective than streptomycin, erythromycin, rifampin, and chloramphenicol (MIC50/90, 2/2 MUg/ml). PMID- 22534308 TI - Glyceraldehyde-3-phosphate, a glycolytic intermediate, prevents cells from apoptosis by lowering S-nitrosylation of glyceraldehyde-3-phosphate dehydrogenase. AB - Glyceraldehyde-3-phosphate (G-3-P), the substrate of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), is a key intermediate in several metabolic pathways. Recently, we reported that G-3-P directly inhibits caspase-3 activity in a reversible noncompetitive mode, suggesting the intracellular G-3-P level as a cell fate decision factor. It has been known that apoptotic stimuli induce the generation of NO, and NO S-nitrosylates GAPDH at the catalytic cysteine residue, which confers GAPDH the ability to bind to Siah-1, an E3 ubiquitin ligase. The GAPDH-Siah-1 complex is translocated into the nucleus and subsequently triggers the apoptotic process. Here, we clearly showed that intracellular G-3-P protects GAPDH from S-nitrosylation at above a certain level, and consequently maintains the cell survival. In case G-3-P drops below a certain level as a result of exposure to specific stimuli, G-3-P cannot inhibit S-nitrosylation of GAPDH anymore, and consequently GAPDH translocates with Siah-1 into the nucleus. Based on these results, we suggest that G-3-P functions as a molecule switch between cell survival and apoptosis by regulating S-nitrosylation of GAPDH. PMID- 22534309 TI - Nocturnal disturbances and restlessness in Parkinson's disease: using the Japanese version of the Parkinson's disease sleep scale-2. AB - OBJECTIVE: The aim of this study was to assess the validity and the reliability of the Japanese version of the Parkinson's disease sleep scale (PDSS)-2 and to use this scale to identify nocturnal symptoms and their impact on patient's quality of life. METHODS: A cross-sectional, case-controlled study was conducted consisting of 93 patients with Parkinson's disease (PD) and 93 age- and gender matched control subjects. The Japanese version of the PDSS-2 was used for the evaluation of nocturnal disturbances. The patient's quality of life was evaluated with the Parkinson's Disease Quality of Life questionnaire (PDQ-39) and their depressive symptoms were assessed with the Beck Depression Inventory-II (BDI-II), respectively. In addition, the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS) and Parkinson Fatigue Scale (PFS) were administered. RESULTS: As assessed using the PDSS-2, PD patients had significantly impaired scores compared with control subjects (15.0+/-9.7 vs. 9.1+/-6.6, p<0.001). The ESS, BDI-II and PFS scores were significantly impaired in PD patients compared with controls. A satisfactory internal consistency and test-retest reliability score were obtained for the PDSS-2 total score (Cronbach's alpha=0.86). The PDSS 2 was correlated with the PSQI, ESS, BDI-II, PFS, PDQ-39 summary index, all of the PDQ-39 domains and Unified Parkinson's Disease Rating Scale part III. The frequency of restless legs syndrome (RLS) was not significantly different between PD patients and controls (5.5% vs. 2.2%), but nocturnal restlessness was significantly more frequent in PD patients than controls. Stepwise linear regression analyses revealed the PDQ-39 summary index and the PSQI global score as significant predictors for the PDSS-2 total score. CONCLUSIONS: Our study confirmed the usefulness of the Japanese version of the PDSS-2 that enables the comprehensive assessment of nocturnal disturbances in PD. The association between RLS and nocturnal restlessness in PD requires further study. PMID- 22534310 TI - [Importance of searching for hypogonadism in patients with a longstanding history of leg ulcers?]. AB - Androgen replacement therapy has been reported to have a beneficial effect in patients with Klinefelter's syndrome or perforating plantar ulcers. We report the case of a 55-year-old man with a 35-year history of leg ulcers and venous insufficiency. His leg ulcers healed 4 months after a management scheme including vascular rehabilitation (intermittent pressure therapy, ankle mobilization, multiple layer compression bands on the lower limbs), skin grafts and foam sclerotherapy of the great saphenous vein. The ulcers recurred 1 month later. This recurrence and the unusually young age for development of venous leg ulcers led to a search for a rare cause. The diagnosis of anterior pituitary failure was established. Sclerotherapy and androgen replacement therapy led to complete healing without recurrence at the 1-year follow-up visit. A link between androgen deficiency and fibrinolysis, protein synthesis deficiency, inflammation and trophicity is well documented in the literature. A search for hypogonadism may be useful in young patients presenting a longstanding history of leg ulcers or in patients with suspected andropause irrespective of age. PMID- 22534311 TI - How does preoperative radiotherapy affect the rate of sphincter-sparing surgery in rectal cancer? AB - The use of preoperative radiotherapy has resulted in significant downstaging and downsizing of tumor, this in turn facilitated resections permitting sphincter preservation and coloanal anastomosis for patients who would otherwise have not been candidates for this type of surgery as concluded by some small studies. On the other hand, other clinical trials have shown that the effect of radiotherapy on the rate of sphincter preservation is still not clear. Moreover, different modes of radiotherapy have been tested on the rate of sphincter preservation such as pelvic irradiation with or without combination of chemotherapy, short or conventional course radiotherapy, and preoperative or postoperative radiotherapy with different timing intervals of surgery. Unfortunately, these trials didn't clearly answer the question of radiotherapy benefit for the sake of sphincter preserving of rectal cancer patients and the question remained hotly debated. PMID- 22534313 TI - Severe adalimumab-induced thrombocytopenia in a patient with Crohn's disease. AB - Crohn's disease is a chronic transmural inflammatory disorder characterized by inflammation of the intestine. Anti-TNF-alpha drugs are used for induction and maintenance of remission in patients with this condition. Thrombocytopenia is an uncommon side effect of treatment with anti-TNF-alpha drugs. We report the case of a 71-year-old woman diagnosed with Crohn's disease who developed severe adalimumab-induced thrombocytopenia and who did not respond to standard therapy for thrombocytopenia. PMID- 22534314 TI - Avian influenza rapidly induces antiviral genes in duck lung and intestine. AB - Ducks are the natural reservoir of influenza A and survive infection by most strains. To characterize the duck immune response to influenza, we sought to identify innate immune genes expressed early in an infection. We used suppressive subtractive hybridization (SSH) to construct 3 libraries enriched in differentially expressed genes from lung RNA of a duck infected with highly pathogenic avian influenza virus A/Vietnam/1203/04 (H5N1), or lung and intestine RNA of a duck infected with low pathogenic avian influenza A/mallard/BC/500/05 (H5N2) compared to a mock-infected duck. Sequencing of 1687 clones identified a transcription profile enriched in genes involved in antiviral defense and other cellular processes. Major histocompatibility complex class I (MHC I), interferon induced protein with tricopeptide repeats 5 (IFIT5), and 2'-5' oligoadenylate synthetase-like gene (OASL) were increased more than 1000-fold in relative transcript abundance in duck lung at 1dpi with highly pathogenic VN1203. These genes were induced much less in lung or intestine following infection with low pathogenic BC500. The expression of these genes following infection suggests that ducks initiate an immediate and robust response to a potentially lethal influenza strain, and a minimal response to a low pathogenic strain. PMID- 22534315 TI - Complex trait analysis of ventricular septal defects caused by Nkx2-5 mutation. AB - BACKGROUND: The occurrence of a congenital heart defect has long been thought to have a multifactorial basis, but the evidence is indirect. Complex trait analysis could provide a more nuanced understanding of congenital heart disease. METHODS AND RESULTS: We assessed the role of genetic and environmental factors on the incidence of ventricular septal defects (VSDs) caused by a heterozygous Nkx2-5 knockout mutation. We phenotyped >3100 hearts from a second-generation intercross of the inbred mouse strains C57BL/6 and FVB/N. Genetic linkage analysis mapped loci with lod scores of 5 to 7 on chromosomes 6, 8, and 10 that influence the susceptibility to membranous VSDs in Nkx2-5(+/-) animals. The chromosome 6 locus overlaps one for muscular VSD susceptibility. Multiple logistic regression analysis for environmental variables revealed that maternal age is correlated with the risk of membranous and muscular VSD in Nkx2-5(+/-) but not wild-type animals. The maternal age effect is unrelated to aneuploidy or a genetic polymorphism in the affected individuals. The risk of a VSD is not only complex but dynamic. Whereas the effect of genetic modifiers on risk remains constant, the effect of maternal aging increases over time. CONCLUSIONS: Enumerable factors contribute to the presentation of a congenital heart defect. The factors that modify rather than cause congenital heart disease substantially affect risk in predisposed individuals. Their characterization in a mouse model offers the potential to narrow the search space in human studies and to develop alternative strategies for prevention. PMID- 22534316 TI - Clinical, immunologic and genetic profiles of DOCK8-deficient patients in Kuwait. AB - Deficiency of dedicator of cytokinesis 8 (DOCK8) is a newly described combined primary immunodeficiency disease. It was found to account for 15% of combined immune deficiency cases in the National Primary Immunodeficiency Disorders Registry in Kuwait, a country with high prevalence of consanguinity. We present the clinical, immunologic and molecular characteristics of 9 Kuwaiti patients with DOCK8 deficiency and discuss differences that distinguish DOCK8 deficiency from atopic dermatitis. Clinical immunologists in areas with high incidence of consanguinity should have a high index of suspicion of DOCK8 deficiency in children with recalcitrant eczema, recurrent non-cutaneous infections and lymphopenia. PMID- 22534318 TI - IgE recognition of bullous pemphigoid (BP)180 and BP230 in BP patients and elderly individuals with pruritic dermatoses. AB - Bullous pemphigoid (BP) is the most common autoimmune bullous disease of the elderly and is associated with IgG and IgE autoantibodies against the hemidesmosomal proteins, BP180 and BP230. The purpose of this study was to characterize the epitope specificity of IgE against defined regions of BP180 and BP230 in 32 BP patients and 21 elderly patients with pruritic disorders who did not yet fulfill all the criteria of BP by immunoblot (IB), ELISA and indirect immunofluorescence microscopy. Our findings show that IgE from BP sera preferentially targets the COOH-terminus of BP230 (IB: 16/32, ELISA: 12/32) and, to a lesser extent, the BP180-NC16A domain (IB: 11/32, ELISA: 9/32). Noteworthy, a subgroup of elderly patients with pruritic dermatoses also showed IgE recognition of BP180-NC16A (IB: 1/21, ELISA: 4/21) and less frequently of BP230 (IB: 2/21, ELISA: 2/21). Thus, IgE recognition of the BP autoantigens is presumably an early pathogenetic event in BP. PMID- 22534319 TI - Acute and non-acute lower extremity pain in the pediatric population: part III. PMID- 22534321 TI - How do elliptical machines differ from walking: a study of torso motion and muscle activity. AB - BACKGROUND: The elliptical trainer is a popular exercise modality, yet its effect on the lumbar spine is poorly understood. The purpose of this study was to analyze the effect of different hand positions, speed and stride lengths on spine kinematics and corresponding muscle activity while using the elliptical trainer, and compare with those demonstrated in normal walking. METHODS: Electromyographic data was collected over 16 trunk and gluteal muscle sites on 40 healthy males (mean age (SD)=23(3)) while on the elliptical trainer. Two stride lengths (46, 66cm), 2 speeds (self-selected, 30% faster), and 3 hand positions (freehand, central bar, handles) were analyzed. Lumbar spine kinematics was calculated from data collected using a motion capture system. Results were compared to those found in walking using repeated measures ANOVA for each dependent variable with Bonferroni adjustments (P<0.004. Correlations were made between lumbar motion and various anthropometric measures. FINDINGS: All significance levels comparing walking to elliptical varied according to stride length, speed and hand position. Average lumbar flexion angles and lumbar rotation were generally greater on the elliptical trainer, whereas walking produced more frontal motion. Total lumbar flexion/extension was similar between the two activities. Muscle activation patterns of the gluteal muscles were consistently higher on the elliptical, whereas the back extensors, latissimi and internal obliques were greater in only selected conditions. INTERPRETATION: The various hand positions, speeds and stride lengths affect lumbar motion and muscle activity on the elliptical trainer, thus must be considered when incorporated into an exercise protocol. PMID- 22534320 TI - Evaluation of methods to relieve parental perceptions of vaccine-associated pain and anxiety in children: a pilot study. AB - INTRODUCTION: The pain and anxiety associated with vaccination is a significant reason why parents are reluctant to have their children vaccinated. Distraction methods and vapocoolant sprays may be use to modify the parent's perceptions of their child's pain and anxiety, thus encouraging parents to return for the child's next vaccination. METHODS: A convenience sample of 68 parents with children ranging in age from 2 to 12 years was selected. The parents and the child were randomly assigned to three groups: a control group, a DVD distraction group, or a vapocoolant spray group. After the child was vaccinated, parents evaluated the child's pain and anxiety. RESULTS: No significant difference in the parents' perception of their child's pain or anxiety was found between the two treatment groups compared with the control group. Some parents expressed the desire to be able to choose the type of distraction method their child received rather than having them randomly assigned to a group. DISCUSSION: Although quantitative results were not statistically significant in this pilot study, parents commented that the DVD distraction method seemed helpful before and/or after vaccination, but not during vaccination, and parents appreciated the distraction. Parents, however, would prefer to choose the intervention rather than being randomly assigned to a group. The effectiveness of interventions with regard to parental perceptions of pain or anxiety warrants further study. PMID- 22534317 TI - Dynamic role of epithelium-derived cytokines in asthma. AB - Asthma is an inflammatory disorder of the airways, characterized by infiltration of mast cells, eosinophils, and Th2-type CD4+ T cells in the airway wall. Airway epithelium constitutes the first line of interaction with our atmospheric environment. The protective barrier function of the airway epithelium is likely impaired in asthma. Furthermore, recent studies suggest critical immunogenic and immunomodulatory functions of airway epithelium. In particular, a triad of cytokines, including IL-25, IL-33 and TSLP, is produced and released by airway epithelial cells in response to various environmental and microbial stimuli or by cellular damage. These cytokines induce and promote Th2-type airway inflammation and cause remodeling and pathological changes in the airway walls, suggesting their pivotal roles in the pathophysiology of asthma. Thus, the airway epithelium can no longer be regarded as a mere structural barrier, but must be considered an active player in the pathogenesis of asthma and other allergic disorders. PMID- 22534322 TI - Does prior sustained compression make cartilage-on-bone more vulnerable to trauma? AB - BACKGROUND: This study investigated how varying levels of prior creep deformation in cartilage-on-bone samples influences their mechanical response and vulnerability to structural damage following a single traumatic impact. METHODS: Bovine patellae were subjected to varying intervals of prior creep loading at a constant stress of 4MPa. Immediately following removal of this stress the samples were impacted with a pendulum indenter system at a fixed energy of 2.2J. FINDINGS: With increasing prior creep, the peak force on impact rose, the duration of impact and time to reach peak force both decreased, and both the energy dissipated during impact and the magnitude of impulse were both unchanged by the level of prior creep. With increasing prior creep, the severity of impact induced osteochondral damage increased: articular cartilage cracks penetrated to a greater depth, extending to the calcified cartilage layer resulting in hairline fractures or articular cartilage delamination and associated secondary damage to the vascular channels in the subchondral bone. INTERPRETATION: The study shows that exposure of the cartilage-on-bone system to prior creep can significantly influence its response to subsequent impact, namely force attenuation and severity of damage to the articular cartilage, calcified cartilage and vascular channel network in the subchondral bone. PMID- 22534323 TI - Endometrial abnormality in women with polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is the most common endocrinopathy associated with infertility and metabolic disorder in women of reproductive age. Although the clinical and biochemical features are heterogeneous with individuals, the most widely accepted clinical characteristics of PCOS are oligo- or anovulation combined with hyperandrogenism. With the higher rate of implantation failure after induction of ovulation or higher risk of spontaneous miscarriage after pregnancy, the reduced fertility is apparently attributed not only to anovulation but also to endometrial dysfunction in patients with PCOS. Here we review the features of the endometrial abnormalities in women with PCOS. The ability to improve the endometrial functions is of potential therapeutic targets to increase reproductive outcome of women with PCOS. PMID- 22534325 TI - Increased expression of heat shock protein 27 correlates with peritoneal metastasis in epithelial ovarian cancer. AB - Ovarian cancer is the third most common gynecologic malignancy and the leading cause of death in gynecological cancer. Although the 5-year survival rate is increasing, peritoneal metastasis of ovarian cancer is still a problem because of no potential predictor. Heat shock proteins (HSPs) are a class of functionally related proteins that are highly expressed in many malignant cancers. Previous studies suggest high levels of HSP27 present in the serum of patients with ovarian cancer. In this study, we investigated whether the expression of HSP27 in epithelial ovarian cancer tissue was associated with peritoneal metastasis and whether HSP27 could be used as a potential predictor of peritoneal metastasis in epithelial ovarian cancer. Tissues from epithelial ovarian cancer with or without peritoneal metastasis were collected and the levels of HSP27 messenger RNA and protein determined by real-time polymerase chain reaction and Western blotting. Immunohistochemistry was used to determine the subcellular localization of HSP27. Immunohistochemistry images showed that HSP27 was highly expressed in the cytoplasm of epithelial cancer cells with peritoneal metastasis. Messenger RNA and protein levels of HSP27 were significantly increased in epithelial ovarian cancer with peritoneal metastasis compared with epithelial ovarian cancer without peritoneal metastasis. Higher expression of HSP27 correlated with poor clinical outcome. These data suggest that higher level of HSP27 was associated with peritoneal metastasis in epithelial ovarian cancer. Heat shock protein 27 may be a useful prognostic marker of poor survival and may provide a basis for the development of molecular therapeutics modulating this survival pathway. PMID- 22534324 TI - Reduction in embryonic malformations and alleviation of endoplasmic reticulum stress by nitric oxide synthase inhibition in diabetic embryopathy. AB - Maternal diabetes-induced neural tube defects (NTDs) are associated with increased programmed cell death (apoptosis) in the neuroepithelium, which is related to intracellular nitrosative stress. To alleviate nitrosative stress, diabetic pregnant mice were fed via gavage an inhibitor of nitric oxide (NO) synthase (NOS) 2, L-N6-(1-iminoethyl)-lysine (L-NIL; 80 mg/kg), once a day from embryonic (E) day 7.5 to 9.5 during early stages of neurulation. The treatment significantly reduced NTD rate in the embryos, compared with that in vehicle (normal saline)-treated diabetic group. In addition to alleviation of nitrosative stress, endoplasmic reticulum (ER) stress was also ameliorated, assessed by quantification of associated factors. Apoptosis was reduced, indicated by caspase 8 activation. These results show that nitrosative stress is important in diabetes induced NTDs via exacerbating ER stress, leading to increased apoptosis. Oral treatment with NOS-2 inhibitor alleviates nitrosative and ER stress, decreases apoptosis, and reduces NTDs in the embryos, providing information for further interventional studies to reduce diabetes-associated birth defects. PMID- 22534326 TI - Global profiling of TSEC proliferative potential by the use of a reporter mouse for proliferation. AB - INTRODUCTION: "Tissue-selective estrogen complex" or TSEC is a novel concept of estrogen replacement therapy for the postmenopause based on the combined use of estrogens and selective estrogen receptor modulators (SERMs). The aim of this study was to exploit the potential of a novel transgenic mouse where luciferase expression is associated with cell proliferation (the MITO-luc mouse) to investigate cell proliferation in reproductive and nonreproductive tissues in mice exposed to repetitive treatments with TSEC. MATERIAL AND METHODS: Ovariectomized MITO-Luc mice were subjected to a daily oral treatment with bazedoxifene, conjugated estrogen (CE), TSEC, or raloxifene for 21 days. During the treatment, the proliferative effects of treatments were monitored by bioluminescence-based in vivo imaging. At the end of the treatment, mice were euthanized and cell proliferation assessed in selected tissues by quantitative analysis of luciferase activity and by immunohistochemistry (IHC). RESULTS: In uterus treatment with CE, but not TSEC, induced a large increase in luciferase activity underlying the proliferative effect of the hormone. No accumulation of luciferase was observed in other organs and tissues target of estrogen action. We observed an increase of Ki67 immunoreactivity only in the uterus of mice treated with CE. CONCLUSION: Pairing of an SERM with estrogens results in a complete blockage of CE proliferative effects in uterus and the absence of any undesired proliferative effects in other organs; moreover, the MITO-Luc mouse is an efficacious tool for the global, rapid, and reliable analysis of drug-induced proliferation. PMID- 22534327 TI - Proteomic biomarkers in second trimester amniotic fluid that identify women who are destined to develop preeclampsia. AB - OBJECTIVES: This study investigated whether proteomic analysis of amniotic fluid (AF) in the early second trimester can be used to predict the development of preeclampsia. METHODS: Amniotic fluid samples were collected at the time of genetic amniocentesis (15-19 weeks of gestation) from women who subsequently developed preeclampsia and from gestational age-matched normotensive controls (n = 10 for each). Amniotic fluid samples were subjected to proteomic analysis using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry, sodium dodecyl sulfate polyacrylamide gel coupled with in-gel tryptic digestion, electrospray ionization tandem mass spectrometry (MS/MS), immunodepletion assays, and enzyme-linke immunosorbent assay. RESULTS: Five proteomic biomarkers were identified, which were differentially expressed in women who subsequently developed preeclampsia compared with those women who did not; four of these peaks were significantly upregulated (mass-to-charge ratio of 9080 [P = .006], 14 045 [P = .010], 14 345 [P = .049], and 28 087 [P = .006]) and one was significantly downregulated (mass-to-charge ratio of 4679 [P = .014]) in women who subsequently developed preeclampsia. Using electrospray ionization MS/MS and immunodepletion assays, two protein peaks were identified as albumin fragment and apolipoprotein A-I. CONCLUSIONS: Using proteomic technology, this study identified protein biomarkers that are differentially expressed in the early second trimester AF from women who subsequently develop preeclampsia compared with women who remained normotensive. Early identification of women at risk of developing preeclampsia will allow clinicians to better optimize maternal and perinatal outcomes. PMID- 22534328 TI - Cell cycle regulation of human endometrial stromal cells during decidualization. AB - OBJECTIVE: Differentiation of endometrial stromal cells into decidual cells is crucial for optimal endometrial receptivity. Data from our previous microarray study implied that expression of many cell cycle regulators are changed during decidualization and inhibition of DNA methylation in vitro. In this study, we hypothesized that both the classic progestin treatment and DNA methylation inhibition would inhibit stromal cell proliferation and cell cycle transition. METHODS: The human endometrial stromal cell line (HESC) was treated from 2 days to 18 days with the DNA methylation inhibitor, 5-aza-2'-deoxycytidine (AZA), a mixture of estradiol/progestin/cyclic adenosine monophosphate ([cAMP]; medroxy progesterone acetate [MPA mix]) or both. Cell growth was measured by cell counting, cell cycle transition and apoptosis were analyzed by flow cytometry, expression of cell cycle regulators were analyzed by quantitative polymerase chain reaction (qPCR) and Western blotting, and change in DNA methylation profiles were detected by methylation-specific PCR. RESULTS: Both AZA and MPA mix inhibited the proliferation of HESC for at least 7 days. Treatment with MPA mix resulted in an early G0/G1 inhibition followed by G2/M phase inhibition at 18 days. In contrast, AZA treatment inhibited cell cycle progression at the G2/M phase throughout. The protein levels of p21(Cip1)and 14-3-3sigma were increased with both AZA and MPA mix treatments without any change in the DNA methylation profiles of the genes. CONCLUSIONS: Our data imply that the decidualization of HESC is associated with cell cycle arrest at G0/G1 phase initially and G2/M phase at later stages. Our results also suggest that p53 pathway members play a role in the cell cycle regulation of endometrial stromal cells. PMID- 22534329 TI - A metabolomic approach identifies differences in maternal serum in third trimester pregnancies that end in poor perinatal outcome. AB - Metabolomics offers a powerful holistic approach to examine the metabolite composition of biofluids to identify disruptions present in disease. We used ultra performance liquid chromatography-mass spectroscopy on the maternal serum obtained in the third trimester to address the hypothesis that pregnancies ending in poor outcomes (small for gestational age infant, preterm birth, or neonatal intensive care admission, n = 40) would have a different maternal serum metabolic profiles to matched healthy pregnancies (n = 40). Ninety-eight identified metabolic features differed between normal and poor pregnancy outcomes. Classes of metabolites perturbed included free fatty acids, glycerolipids, progesterone metabolites, sterol lipids, vitamin D metabolites, and sphingolipids; these highlight potential molecular mechanisms associated with pregnancy complications in the third trimester linked by placental dysfunction. In this clinical setting, metabolomics has the potential to describe differences in fetoplacental and maternal metabolites in pregnancies with poor pregnancy outcomes compared with controls. PMID- 22534330 TI - Resveratrol prevents impairment in activation of retinoic acid receptors and MAP kinases in the embryos of a rodent model of diabetic embryopathy. AB - Diabetes induces impairments in gene expression during embryonic development that leads to premature and improper tissue specialization. Retinoic acid receptors (RARs and retinoid X receptor [RXRs]) and mitogen-activated protein kinases (MAPKs) play crucial roles during embryonic development, and their suppression or activation has been shown as a determinant of the fate of embryonic organogenesis. We studied the activation of RARs and MAPKs in embryonic day 12 (E12) in embryos of rats under normal, diabetic, and diabetic treated with resveratrol ([RSV]; 100 mg/kg body weight) conditions. We found downregulation of RARs and RXRs expressions as well as their DNA-binding activities in the embryos exhibiting developmental delays due to diabetes. Furthermore, the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 was decreased and phosphorylation of c-Jun N-terminal kinase (JNK) 1/2 and p38 was increased. Interestingly, embryos of diabetic rats treated with RSV showed normalized patterns of RARs, RXRs, neuronal markers, and ERK, JNK and p38 phosphorylation. PMID- 22534331 TI - Trichostatin A and ascorbic acid assist in the development of porcine handmade cloned embryos via different physiologic pathways. AB - The objective was to determine the effects of ascorbic acid (AA), trichostatin A (TSA), and their combined treatment (TA) on reprogramming and development of cloned porcine embryos. Embryos treated with AA (50 and 100 ug/mL) had a higher blastocyst rate than controls (49.6% and 44.0% vs 30.7%, P < .05). Blastocyst rates of handmade cloned (HMC) embryos were nearly 60% in both the 30 and 40 nmol/L TSA treatment groups, which were higher (P < .05) than the control (29.4%). The TA treatment groups had a higher blastocyst rate compared with the AA treatment alone (58.9% vs 43.5%, P < .05). Histone acetylation was much higher in the TSA and TA treatments (primarily in 2- and 4-celled embryos) but was not significantly different between AA-treated and untreated embryos. Both AA and TA treatments reduced apoptotic rates of blastocysts. In conclusion, AA supplementation improved blastocyst development in porcine HMC embryos mainly by a traditional antioxidant pathway rather than by cellular reprogramming. PMID- 22534332 TI - Immune response gene profiles in the term placenta depend upon maternal muscle mass. AB - Maternal thinness leads to metabolic challenges in the offspring, but it is unclear whether reduced maternal fat mass or muscle mass drives these metabolic changes. Recently, it has been shown that low maternal muscle mass--as measured by arm muscle area (AMA)--is associated with depressed nutrient transport to the fetus. To determine the role of maternal muscle mass on placental function, we analyzed the gene expression profiles of 30 human placentas over the range of AMA (25.2-90.8 cm(2)) from uncomplicated term pregnancies from the Southampton Women's Survey cohort. Eighteen percent of the ~60 genes that were highly expressed in less muscular women were related to immune system processes and the interferon-gamma (IFNG) signaling pathway in particular. Those transcripts related to the IFNG pathway included IRF1, IFI27, IFI30, and GBP6. Placentas from women with low muscularity are, perhaps, more sensitive to the effects of inflammatory cytokines than those from more muscular women. PMID- 22534334 TI - Male fertility, obesity, and bariatric surgery. AB - Obesity has become a new worldwide health problem with significant impact not only on cardiovascular diseases but also on many other related disorders, highlighting infertility. Obesity may adversely affect male reproduction by endocrinologic, thermal, genetic, and sexual mechanisms. There is good evidence that obesity can be associated with reduced sperm concentrations, but studies about sperm motility, morphology, and DNA fragmentation have been less numerous and more conflicting. Although weight loss is the cornerstone of the treatment of obesity-related infertility, with promising results in restoring fertility and normal hormonal profiles, bariatric surgery impact on male fertility is still unclear and until now there is not enough data to support the informed consent in this scenario. Physicians are encouraged to highlight possible positive and/or negative impacts concerning male capacity of fertilization when informing patients. A balanced judgment and a personalized case-by-case management with patient involvement in decisions are fundamental in this setting and indication of cryopreservation of semen samples should be considered in selected circumstances. Well-structured trials controlled for confounders including female factors and based on solid outcomes (ie, birth rates) must urgently come up to clarify this emerging scenario. PMID- 22534335 TI - Bariatric surgery does not interfere with sperm quality--a preliminary long-term study. AB - PURPOSE: Positive impact of weight loss on sexual function and hormones has been demonstrated, and male fertility in this scenario is to be better defined. We evaluated the impact of lifestyle modifications and gastric bypass on sperm quality. METHODS: We prospectively studied 20 morbidly obese men during 24 months, randomized for intervention: lifestyle modifications (exercise and diet) for 4 months and subsequently gastric bypass (n = 10); and control: follow-up (n = 10). All patients underwent International Index of Erectile Function (IIEF-5) questionnaire, serum estradiol, prolactin (PRL), luteinizing and follicle stimulating hormones (LH and FSH), free and total testosterones (FT and TT) and semen analysis at baseline (time 0), surgery 4 months later baseline (time 1) and final evaluation 24 months (time 2). RESULTS: Intervention group presented significant reduction in body mass index (BMI) at times 1 and 2, compared to control. There were no significant differences among sperm parameters between groups at times 0, 1, and 2 and among times 0, 1, and 2 in each group. Increases in IIEF-5 score (P = .0469), TT (P = .0349), and FSH (P = .0025) and reduction in PRL (P < .0001) were observed in the intervention group from times 0 to 2 and 1 to 2. Comparing groups at time 2, IIEF-5, TT, and FT increased significantly in the intervention group (P = .0224, P = .0043, and P = .0149, respectively). CONCLUSIONS: Surgery-induced massive weight loss does not interfere with sperm quality, while it increased the quality of sexual function, TT, FT and FSH and reduced PRL. Lifestyle modifications impacted merely the BMI. New studies are warranted, mostly considering birth rate as primary end point and including infertile men. PMID- 22534333 TI - Protective effect of N-acetylcysteine on liver damage during chronic intrauterine hypoxia in fetal guinea pig. AB - Chronic exposure to hypoxia during pregnancy generates a stressed intrauterine environment that may lead to fetal organ damage. The objectives of the study are (1) to quantify the effect of chronic hypoxia in the generation of oxidative stress in fetal guinea pig liver and (2) to test the protective effect of antioxidant treatment in hypoxic fetal liver injury. Pregnant guinea pigs were exposed to either normoxia (NMX) or 10.5% O(2) (HPX, 14 days) prior to term (65 days) and orally administered N-acetylcysteine ([NAC] 10 days). Near-term anesthetized fetuses were excised and livers examined by histology and assayed for malondialdehyde (MDA) and DNA fragmentation. Chronic HPX increased erythroid precursors, MDA (NMX vs HPX; 1.26 +/- 0.07 vs 1.78 +/- 0.07 nmol/mg protein; P < .001, mean +/- standard error of the mean [SEM]) and DNA fragmentation levels in fetal livers (0.069 +/- 0.01 vs 0.11 +/- 0.005 OD/mg protein; P < .01). N acetylcysteine inhibited erythroid aggregation and reduced (P < .05) both MDA and DNA fragmentation of fetal HPX livers. Thus, chronic intrauterine hypoxia generates cell and nuclear damage in the fetal guinea pig liver. Maternal NAC inhibited the adverse effects of fetal liver damage suggestive of oxidative stress. The suppressive effect of maternal NAC may implicate the protective role of antioxidants in the prevention of liver injury in the hypoxic fetus. PMID- 22534337 TI - The significance of endothelin in platelet-activating factor-induced fetal growth restriction. AB - The significance of endothelin-1 (ET-1) in platelet-activating factor (PAF) induced fetal growth restriction (FGR) was evaluated in timed-pregnant rats receiving intravenous carbamyl-PAF (c-PAF; 0.5, 1.0, or 2.5 ug/kg per h) or vehicle, with or without ET-1 receptor A (ET(A)) antagonist (10 or 20 mg/kg per d) for 7 days beginning on gestation day 14. Tissues were collected on day 21. Carbamyl-PAF reduced fetal weights dose dependently. Placental weights were significantly reduced but not dose dependently. ET(A) antagonism prevented FGR at the 0.5, but not the 1.0 and 2.5 ug/kg per h c-PAF doses. Correspondingly, placental, but not uterine, preproET-1 messenger RNA (mRNA) expression (determined by reverse transcription-polymerase chain reaction) was increased at 0.5 ug/kg per h but not at higher c-PAF doses. In summary, c-PAF infusion results in fetal and placental growth restriction in the rat. At low doses of c-PAF, ET-1 is central to the pathophysiology of PAF-induced FGR. At higher c-PAF doses, FGR is induced by mechanisms other than ET-1 action. PMID- 22534336 TI - Leptin alters adrenal responsiveness by decreasing expression of ACTH-R, StAR, and P450c21 in hypoxemic fetal sheep. AB - The late gestation increase in adrenal responsiveness to adrenocorticotropin (ACTH) is dependent upon the upregulation of the ACTH receptor (ACTH-R), steroidogenic acute regulatory protein (StAR), and steroidogenic enzymes in the fetal adrenal. Long-term hypoxia decreases the expression of these and adrenal responsiveness to ACTH in vivo. Leptin, an adipocyte-derived hormone which attenuates the peripartum increase in fetal plasma cortisol is elevated in hypoxic fetuses. Therefore, we hypothesized that increases in plasma leptin will inhibit the expression of the ACTH-R, StAR, and steroidogenic enzymes and attenuate adrenal responsiveness in hypoxic fetuses. Spontaneously hypoxemic fetal sheep (132 days of gestation, PO(2) ~ 15 mm Hg) were infused with recombinant human leptin (n = 8) or saline (n = 7) for 96 hours. An ACTH challenge was performed at 72 hours of infusion to assess adrenal responsiveness. Plasma cortisol and ACTH were measured daily and adrenals were collected after 96 hours infusion for messenger RNA (mRNA) and protein expression measurement. Plasma cortisol concentrations were lower in leptin- compared with saline-infused fetuses (14.8 +/- 3.2 vs 42.3 +/- 9.6 ng/mL, P < .05), as was the cortisol:ACTH ratio (0.9 +/- 0.074 vs 46 +/- 1.49, P < .05). Increases in cortisol concentrations were blunted in the leptin-treated group after ACTH(1-24) challenge (F = 12.2, P < .0001). Adrenal ACTH-R, StAR, and P450c21 expression levels were reduced in leptin-treated fetuses (P < .05), whereas the expression of Ob-Ra and Ob-Rb leptin receptor isoforms remained unchanged. Our results indicate that leptin blunts adrenal responsiveness in the late gestation hypoxemic fetus, and this effect appears mediated by decreased adrenal ACTH-R, StAR, and P450c21 expression. PMID- 22534338 TI - A small scale study on the effects of oral administration of the beta-glucan produced by Aureobasidium pullulans on milk quality and cytokine expressions of Holstein cows, and on bacterial flora in the intestines of Japanese black calves. AB - BACKGROUND: The beta-(1 -> 3),(1 -> 6)-D-glucan extracellularly produced by Aureobasidium pullulans exhibits immunomodulatory activity, and is used for health supplements. To examine the effects of oral administration of the beta-(1 > 3),(1 -> 6)-D-glucan to domestic animals, a small scale study was conducted using Holstein cows and newborn Japanese Black calves. FINDINGS: Holstein cows of which somatic cell count was less than 3 x 105/ml were orally administered with or without the beta-(1 -> 3),(1 -> 6)-D-glucan-enriched A. pullulans cultured fluid (AP-CF) for 3 months, and the properties of milk and serum cytokine expression were monitored. Somatic cell counts were not significantly changed by oral administration of AP-CF, whereas the concentration of solid non fat in the milk tended to increase in the AP-CF administered cows. The results of cytokine expression analysis in the serum using ELISA indicate that the expressions of tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6 in all cows which were orally administered with AP-CF became slightly lower than that of control cows after the two-month treatment. On the other hand, IL-8 expression tended to indicate a moderately higher level in all treated cows after the three-month administration of AP-CF in comparison with that of the control cows. Peripartum Japanese Black beef cows and their newborn calves were orally administered with AP-CF, and bacterial flora in the intestines of the calves were analyzed by T RFLP (terminal restriction fragment length polymorphism). The results suggest that bacterial flora are tendentiously changed by oral administration of AP-CF. CONCLUSIONS: Our data indicated the possibility that oral administration of the beta-(1 -> 3),(1 -> 6)-D- glucan produced by A. pullulans affects cytokine expressions in the serum of Holstein cows, and influences bacterial flora in the intestines of Japanese Black calves. The findings may be helpful for further study on the efficacies of oral administration of beta-(1 -> 3),(1 -> 6)-D glucans on domestic animals. PMID- 22534339 TI - Changes in T2 relaxation time after stroke reflect clearing processes. AB - BACKGROUND AND PURPOSE: CT and MR imaging techniques are frequently used for the diagnosis and progress monitoring of ischemic stroke in clinical practice and research. After stroke, both methods are characterized by a transient pseudo normalized imaging signal, the so-called fogging phenomenon. This study evaluates potential pathophysiological changes associated with fogging, as well as its influence on the correct determination of the ischemic lesion in a rat stroke model. METHODS: Male spontaneously hypertensive rats were subjected to permanent middle cerebral artery occlusion. Ischemic lesion volume, brain edema and gray scale value spread within the ischemic lesion were determined on T2-weighted MR sequences at days 1, 4, 8, 11 and 29 after stroke onset, and compared with immunohistochemistry for astrogliosis, microglia/macrophage infiltration and angiogenesis. RESULTS: All animals showed MR fogging at days 4, 8 and 11 after stroke. The transient normalization of T2 signals occurred independently from the development of infarct volumes, but coincided well with the spatio-temporal occurrence of necrosis, angiogenesis and microglia/macrophage infiltration. CONCLUSIONS: Our results suggest that the fogging effect reflects the clearance of necrotic tissue within the ischemic lesion and is thus not relevant for the determination of the lesion volume. PMID- 22534340 TI - Construction of a novel Pichia pastoris strain for production of xanthophylls. AB - In this study, we used the yeast carotenogenic producer Pichia pastoris Pp-EBIL strain, which has been metabolically engineered, by heterologously expressing beta-carotene-pathway enzymes to produce beta-carotene, as a vessel for recombinant astaxanthin expression. For this purpose, we designed new P. pastoris recombinant-strains harboring astaxanthin-encoding genes from carotenogenic microorganism, and thus capable of producing xanthophyllic compounds. We designed and constructed a plasmid (pGAPZA-WZ) containing both the beta-carotene ketolase (crtW) and beta-carotene hydroxylase (crtZ) genes from Agrobacterium aurantiacum, under the control of the GAP promoter and containing an AOX-1 terminator. The plasmid was then integrated into the P. pastoris Pp-EBIL strain genomic DNA, producing clone Pp-EBILWZ. The recombinant P. pastoris (Pp-EBILWZ) cells exhibited a strong reddish carotenoid coloration and were confirmed, by HPLC, to produce not only the previous described carotenoids lycopene and beta-carotene, but also de novo synthesized astaxanthin. PMID- 22534342 TI - Evaluation of chronic cough should consider cannabis use. PMID- 22534343 TI - Integrating cognitive behavioral therapy into management of depression. PMID- 22534344 TI - Financial incentives for improving the quality of primary care. PMID- 22534346 TI - Information from your family doctor. High blood pressure in children. PMID- 22534345 TI - High blood pressure in children and adolescents. AB - High blood pressure in children and adolescents is a growing health problem that is often overlooked by physicians. Normal blood pressure values for children and adolescents are based on age, sex, and height, and are available in standardized tables. Prehypertension is defined as a blood pressure in at least the 90th percentile, but less than the 95th percentile, for age, sex, and height, or a measurement of 120/80 mm Hg or greater. Hypertension is defined as blood pressure in the 95th percentile or greater. A secondary etiology of hypertension is much more likely in children than in adults, with renal parenchymal disease and renovascular disease being the most common. Overweight and obesity are strongly correlated with primary hypertension in children. A history and physical examination are needed for all children with newly diagnosed hypertension to help rule out underlying medical disorders. Children with hypertension should also be screened for other risk factors for cardiovascular disease, including diabetes mellitus and hyperlipidemia, and should be evaluated for target organ damage with a retinal examination and echocardiography. Hypertension in children is treated with lifestyle changes, including weight loss for those who are overweight or obese; a healthy, low-sodium diet; regular physical activity; and avoidance of tobacco and alcohol. Children with symptomatic hypertension, secondary hypertension, target organ damage, diabetes, or persistent hypertension despite nonpharmacologic measures should be treated with antihypertensive medications. Thiazide diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, beta blockers, and calcium channel blockers are safe, effective, and well tolerated in children. PMID- 22534348 TI - Information from your family doctor. Advanced kidney disease. PMID- 22534347 TI - End-stage renal disease: symptom management and advance care planning. AB - The prevalence of end-stage renal disease continues to increase, and dialysis is offered to older and more medically complex patients. Pain is problematic in up to one-half of patients receiving dialysis and may result from renal and nonrenal etiologies. Opioids can be prescribed safely, but the patient's renal function must be considered when selecting a drug and when determining the dosage. Fentanyl and methadone are considered the safest opioids for use in patients with end-stage renal disease. Nonpain symptoms are common and affect quality of life. Phosphate binders, ondansetron, and naltrexone can be helpful for pruritus. Fatigue can be managed with treatment of anemia and optimization of dialysis, but persistent fatigue should prompt screening for depression. Ondansetron, metoclopramide, and haloperidol are effective for uremia-associated nausea. Nondialytic management may be preferable to dialysis initiation in older patients and in those with additional life-limiting illnesses, and may not significantly decrease life expectancy. Delaying dialysis initiation is also an option. Patients with end-stage renal disease should have advance directives, including documentation of situations in which they would no longer want dialysis. PMID- 22534349 TI - Gynecomastia. AB - Gynecomastia is defined as benign proliferation of glandular breast tissue in men. Physiologic gynecomastia is common in newborns, adolescents, and older men. It is self-limited, but can be treated to minimize emotional distress and physical discomfort. Nonphysiologic gynecomastia may be caused by chronic conditions (e.g., cirrhosis, hypogonadism, renal insufficiency); use of medications, supplements, or illicit drugs; and, rarely, tumors. Discontinuing use of contributing medications and treating underlying disease are the mainstay of treatment. Medications, such as estrogen receptor modulators, and surgery have a role in treating gynecomastia in select patients. Treatment should be pursued early and should be directed by the patient. PMID- 22534350 TI - Flesh-colored penile lesion in an adolescent. PMID- 22534352 TI - Global impact of biotech crops: environmental effects, 1996-2010. AB - This paper updates the assessment of the impact commercialized agricultural biotechnology is having on global agriculture, from some important environmental perspectives. It focuses on the impact of changes in pesticide use and greenhouse gas emissions arising from the use of biotech crops. The technology has reduced pesticide spraying by 443 million kg (-9.1%) and, as a result, decreased the environmental impact associated with herbicide and insecticide use on these crops [as measured by the indicator the Environmental Impact Quotient (EIQ)] by 17.9%. The technology has also significantly reduced the release of greenhouse gas emissions from this cropping area, which, in 2010, was equivalent to removing 8.6 million cars from the roads. PMID- 22534353 TI - High pressure inactivation of Salmonella on Jalapeno and Serrano peppers destined for direct consumption or as ingredients in Mexican salsa and guacamole. AB - In summer of 2008, the United States witnessed one of the largest multi-state salmonellosis outbreak linked to the consumption of Jalapeno and Serrano peppers tainted with Salmonella enterica serovar Saintpaul. The first objective of this study was to assess the application of high hydrostatic pressure (HHP) to decontaminate Jalapeno and Serrano peppers from this pathogen. Jalapeno and Serrano peppers were inoculated with a five-strain cocktail of Salmonella to a final level of ca. ~6 log CFU/g and subsequently pressure-treated in the un wetted, wetted (briefly dipped in water) or soaked (immersed in water for 30 min) state at 300-500 MPa for 2 min at 20 degrees C. The extent of pressure inactivation increased as a function of the pressure level and in the order of soaked>wetted>un-wetted state achieving population reductions ranging from 1.1 to 6.6 log CFU/g. Overall, pressure treatment at 400-450 MPa (soaked) or 450-500 MPa (wetted) for 2 min at 20 degrees C rendered Salmonella undetectable. Since salsa and guacamole are two examples of widely consumed Mexican dishes that incorporate raw Jalapeno and Serrano peppers, we subsequently investigated the pressure inactivation of Salmonella in salsa and guacamole, originating from contaminated peppers used as ingredients. The storage time (0, 12 or 24 h) of the condiments prior to HHP as well as the pH (3.8-5.3) and the type of acidulants (vinegar and lemon juice) used all influenced the extent of Salmonella inactivation by HHP. This study demonstrates the dual efficacy of HHP to decontaminate fresh chile peppers destined for direct consumption and minimally process condiments possibly contaminated with raw peppers to enhance their microbiological safety. PMID- 22534354 TI - Experimental infection of Fusarium proliferatum in Oryza sativa plants; fumonisin B1 production and survival rate in grains. AB - Fusarium proliferatum is a plant pathogenic fungus associated with crops such as asparagus and corn, and it possesses the ability to produce a range of mycotoxins, including fumonisins. In Asia, rice (Oryza sativa) is a staple cereal and is occasionally colonized by this fungus without obvious physiological changes. F. proliferatum is closely related to Gibberella fujikuroi (anamorph F. fujikuroi) responsible for Bakanae disease in rice; however there are few reports of F. proliferatum as a rice pathogen. In this study, we examined the pathogenic potential of F. proliferatum in rice plants with respect to browning, fumonisin production, and survival rates in rice grains. Fungal inoculation was conducted by spraying a conidial suspension of F. proliferatum onto rice plants during the flowering period. Browning was found on the stalk, leaf, and ear of rice. Fumonisin B(1) was detected at levels from trace to 21 ng/g grains, using tandem mass spectrometry. Fungal recovery after 6 months indicated that F. proliferatum had high affinity to rice plants being still viable in grains. From this study, it can be concluded that F. proliferatum is a possible pathogen of rice and possesses a potential to produce fumonisin B(1) in rice grains in the field. PMID- 22534355 TI - Chitosan dipping or oregano oil treatments, singly or combined on modified atmosphere packaged chicken breast meat. AB - The present study examined the effect of natural antimicrobials: chitosan, oregano and their combination, on the shelf-life of modified atmosphere packaged chicken breast meat stored at 4 degrees C. Treatments examined in the present study were the following: M (control samples stored under modified atmosphere packaging), M-O (samples treated with oregano oil 0.25% v/w, stored under MAP), M CH (samples treated with chitosan 1.5% w/v, stored under MAP) and M-CH-O (treated with chitosan 1.5% w/v and oregano oil 0.25% v/w, stored under MAP). Treatment, M CH-O, significantly affected mesophilic Total Plate Counts (TPC), lactic acid bacteria (LAB), Brochothrix thermosphacta, Enterobacteriaceae, Pseudomonas spp., and yeasts-moulds during the storage period. Lipid oxidation (as determined by MDA values) of control and treated chicken samples was in general low and below 0.5 mg MDA/kg, showing no oxidative rancidity during the storage period. Addition of chitosan to the chicken samples produced higher (P<0.05) lightness (L*) values as compared to the control samples. The results of this study indicate that the shelf-life of chicken fillets can be extended using, either oregano oil singly, and/or chitosan, by approximately 6 (M-O) and >15 (M-CH and M-CH-O) days. Interestingly, chitosan (M-CH) or chitosan-oregano (M-CH-O) treated chicken samples were sensorially acceptable during the entire refrigerated storage period of 21 days. It is noteworthy that the presence of chitosan in M-CH and M-CH-O samples did not negatively influence the taste of chicken samples, with M-CH samples receiving a higher score (compared to M-CH-O), probably as a result of a distinct and "spicy" lemon taste of chitosan, that was well received by the panelists. Based primarily on sensory data (taste attribute) M-CH and M-O treatments extended the shelf-life of chicken fillets by 6 days, while M-CH-O treatment resulted in a product with a shelf-life of 14 days, maintaining acceptable sensory characteristics. PMID- 22534356 TI - Determinants of quality of life in patients with refractory focal epilepsy who were not eligible for surgery or who rejected surgery. AB - The aim of the study was to assess the determinants of quality of life (QOL) in adult patients with refractory focal epilepsy who were not eligible for surgery or who rejected surgery after presurgical evaluation. The QOLIE-31, the Hospital Anxiety and Depression Scale and PESOS questionnaire were mailed in 2009 to all adult patients who had been evaluated for suitability for epilepsy surgery between 2001 and 2007 in the Bethel Epilepsy Center and had been deemed not eligible for surgery or had decided against surgery. Questionnaires were sent by post to 359 patients: 172 (47.9%) replied, and of these, 125 patients were eligible for this study. The remaining 47 patients were excluded mainly because they did not fulfill the criteria of refractory epilepsy. Out of the included 125 patients, 106 were considered to be poor surgical candidates for medical reasons, and 19 had decided against surgery. The mean follow-up was 4.1+/-2.1 years. In the past 6 months, 13.9% of the patients were seizure free, 12 of them (9.6%) were seizure free for one year, 10.7% had 1-2 seizures, 11.5% had 3-5 seizures, 27.0% had one or more seizures a month, 23.0% had one or more seizures a week, and 13.9% had one or more seizures a day. Patient-perceived changes in their seizures since presurgical evaluation were rated by 15.6% of the patients as 'improved significantly', by 28.7% as 'improved', by 46.7% as 'no change', by 6.6% as 'deteriorated' and by 2.5% as 'significantly deteriorated'. Quality of life in patients with refractory epilepsy was much lower compared to operated patients from our center. Multivariate analysis of QOL showed that depression and anxiety are strong predictors but not exclusively. Furthermore, tolerability and efficacy of AEDs are significant predictors of most QOLIE-31 subscales. Employment, seizure frequency, patient-perceived change in their seizures, number of AEDs and the degree of comorbidity appeared as predictors for some aspects of QOL as well. When excluding anxiety and depression, the most important predictors of QOL were tolerability of AEDs and employment. For other aspects of QOL, efficacy of AEDs, gender, number of AEDs, degree of comorbidity and a certificate of disability were additional predictors. The results of the multivariate analysis did not essentially change when seizure-free patients were excluded. CONCLUSION: Quality of life in non-operated patients with refractory epilepsy is significantly lower than in operated patients from the same center. Besides depression and anxiety, patient-rated tolerability and efficacy of AEDs, seizure frequency and employment are the main determinants of QOL. PMID- 22534357 TI - Irreversible electroporation in eradication of rabbit VX2 liver tumor. AB - PURPOSE: To show the effectiveness and safety of irreversible electroporation (IRE) in treating large tumor models. MATERIALS AND METHODS: VX2 liver tumor implantation was performed in 35 New Zealand White Rabbits. The rabbits were divided into three groups 1 week after implantation. The control group included 15 rabbits; the remaining 20 rabbits were divided into two IRE treatment groups. For the treatment groups, 10 rabbits underwent ablation with a single IRE application (IRE-S group), and 10 rabbits underwent ablation with multiple IRE applications (IRE-M group). Treatments and outcomes were analyzed using ultrasound, contrast-enhanced computed tomography (CT), and immunohistologic staining (hematoxylin and eosin [H&E], P-53, Ki-67, CD30, and vascular endothelial growth factor receptor [VEGFR] staining, and terminal deoxynucleotidyl-transferase-mediated 2'-deoxyuridine 5'-triphosphate [dUTP] biotin nick-end labeling [TUNEL] assay). RESULTS: Multiple IRE ablations consistently produced complete cell death in all the animals in the IRE-M group (n = 10, IRE ablation time 2.45 minutes +/- 0.3). The results were validated with ultrasound, CT, H&E, Ki-67, P53, and TUNEL assay. A high level of CD30-positive cells were identified in the IRE groups. A sharply demarcated ablation zone with no damage to surrounding vital structures was observed in all IRE-treated tissues. No complications during or after ablation were observed in any of the animals. CONCLUSIONS: The effects of IRE were shown in a large tumor model with single and multiple IRE ablations (IRE-S and IRE-M treatment groups); complete ablation of the tumor was seen in the IRE-M group. These findings successfully show the beneficial effects and safety of IRE in the treatment of tumors and validate its potential as a clinically translatable treatment. PMID- 22534358 TI - Anatomic measurement of the depth and location of the sublingual fossa. AB - The purpose of this study was to measure the depth and location of the sublingual fossa, a potential site of sublingual bleeding/lingual cortical perforation during endosseous implant placement in the mandibular interforaminal region (MIR), to clarify anatomical variation. Using the mandibles of 37 Japanese cadavers, the lingual depth (LD) between the lingual surface and the line perpendicular to the inferior margin of the mandible (IMM), as well as the vertical distance (VD) between the lingual surface and the IMM or the mental foramen (MF) level, were measured at defined points and lines within the MIR. The definite sublingual fossa (SF) was identified by the LD (>= 1.0mm) and the VD, and the depth and location of the SF were determined. The depth ranged between 1.0mm and 5.8mm, and the vertical location ranged between 9.2mm and 15.7 mm from the IMM and between 2.2mm and 6.1mm from the MF level. These results revealed certain tendencies in the depth and location of the SF but the variation was substantial. The SF should be identified in each case as accurately as possible by CT before implant placement in the MIR to minimize the risk of the potential complications. PMID- 22534359 TI - Evaluation of neurosensory alterations via clinical neurosensory tests following anterior maxillary osteotomy (Bell technique). AB - Neurosensory deficits are the most common complication following orthognathic surgery. Le Fort I and sagittal split ramus osteotomies have been widely studied but there is a lack of data about the neurosensory alterations resulting from anterior maxillary osteotomy (AMO). This paper evaluates the neurosensory alterations in cutaneous regions including lower eyelid, cheek, nose, upper lip and vestibular and palatal mucosal areas using simple clinical tests following AMO performed with Bell's incision so patients can be properly informed about the extent of sensory loss and its rate of recovery following AMO. Twenty-four sides of 12 patients (eight females; four males) with a mean age of 14.20 +/- 1.86 years (range 12-17 years) were examined. Pin prick sensation, light touch sensation, static and dynamic two-point discrimination tests were used. Following AMO, vestibular mucosa, upper lip, nose and cheek were the most commonly affected sites. No alterations were detected in lower eyelid and palatal mucosa. The neurosensory deficits in cheek, nose and upper lip resolved 10 days after surgery. The vestibular mucosa showed normal sensation on day 30. In conclusion, following AMO, neurosensory alterations can occur, but it will resolve spontaneously in 30 days. PMID- 22534360 TI - Formation of diclofenac and sulfamethoxazole reversible transformation products in aquifer material under denitrifying conditions: batch experiments. AB - Soil-aquifer processes have proven to work as a natural treatment for the attenuation of numerous contaminants during artificial recharge of groundwater. Nowadays, significant scientific effort is being devoted to understanding the fate of pharmaceuticals in subsurface environments, and to verify if such semipersistent organic micropollutants could also be efficiently removed from water. In this context we carried out a series of batch experiments involving aquifer material, selected drugs (initial concentration of 1 MUg/L and 1 mg/L), and denitrifying conditions. Diclofenac and sulfamethoxazole exhibited an unreported and peculiar behavior. Their concentrations consistently dropped in the middle of the tests but recovered toward the end, which suggest a complex effect of denitrifying conditions on aromatic amines. The transformation products Nitro-Diclofenac and 4-Nitro-Sulfamethoxazole were detected in the biotic experiments, while nitrite was present in the water. Their concentrations developed almost opposite to those of their respective parent compounds. We conjecture that this temporal and reversible effect of denitrifying conditions on the studied aromatic amines could have significant environmental implications, and could explain at least partially the wide range of removals in subsurface environments reported in literature for DCF and SMX, as well as some apparent discrepancies on SMX behavior. PMID- 22534361 TI - Effect of current tobacco consumption on the male reproductive hormone profile. AB - The knowledge about the effect of cigarette smoking on the male reproductive function is still limited. The objective of this study was to evaluate the association between active exposure to tobacco smoke and the male reproductive hormone profile in a group of 136 Mexican flower growers. Serum levels of FSH, LH, prolactin, total testosterone, Inhibin B and estradiol were measured using enzyme-linked immunoabsorbent assay. Weight and height were also measured and a structured questionnaire was applied to get information on sociodemographic characteristics, clinical and work history and alcohol and tobacco consumption (current smoking habit and number of cigarettes smoked per day). Based on this information tobacco consumption was divided into four categories: never-smokers, ex-smokers, current smokers under five cigarettes/day and current smokers over or equal to five cigarettes/day. Using the group of never-smokers as reference and after adjusting for potential confounders, current smokers of five or more cigarettes/day showed significantly higher levels of LH (beta=0.33, p=0.01), prolactin (beta=0.18, p=0.03) and testosterone (beta=0.21, p=0.02). Current smokers of less than five cigarettes/day also showed higher levels of prolactin (beta=0.12, p=0.03) and testosterone (beta=0.18, p<0.01). Hormone levels of ex smokers were similar to those of never-smokers. Our results are compatible with the hypothesis that tobacco consumption may act as an endocrine disruptor on the male hormone profile. PMID- 22534362 TI - Concern that "EMF" magnetic fields from power lines cause cancer. AB - In 2002, the International Agency for Research on Cancer (IARC, 2002) categorized extremely low frequency (ELF) (including the power frequencies of 50 and 60 Hz) magnetic fields as "possibly carcinogenic to humans." That was based on pooled analyses of epidemiological research that reported an association between exposure to low-level magnetic fields and childhood leukemia. In 2007 a task group of scientific experts convened by the World Health Organization (WHO) acknowledged the IARC categorization but found that the laboratory studies and other research results did not support the association. Taking all evidence into account WHO reported that it could not confirm the existence of any health consequences from exposure to low-level magnetic fields. There remains continuing concern by some people that exposure to power frequency magnetic fields may cause adverse health effects, particularly childhood leukemia. Public health authorities need to fully understand the reasons for that ongoing concern and effective ways to address it. This paper describes what drives the concern, including how people perceive risks, how WHO and other public health authorities assess scientific research to determine whether health risks exist and the conclusions they have reached about power frequency magnetic fields. This paper also addresses the scientific basis of international exposure guidelines for power frequency magnetic fields and what precautionary measures are warranted to address the concern. PMID- 22534363 TI - Bioreceptivity of building stones: a review. AB - In 1995, Guillitte defined bioreceptivity, a new term in ecology, as the ability of a material to be colonized by living organisms. Information about the bioreceptivity of stone is of great importance since it will help us to understand the material properties which influence the development of biological colonization in the built environment, and will also provide useful information as regards selecting stones for the conservation of heritage monuments and construction of new buildings. Studies of the bioreceptivity of stone materials are reviewed here with the aim of providing a clear set of conclusions on the topic. Definitions of bioreceptivity are given, stone bioreceptivity experiments are described, and finally the stone properties related to bioreceptivity are discussed. We suggest that a standardized laboratory protocol for evaluating stone bioreceptivity and definition of a stone bioreceptivity index are required to enable creation of a database on the primary bioreceptivity of stone materials. PMID- 22534365 TI - Controlled ridge expansion using a two-stage split-crest technique with ultrasonic bone surgery. AB - PURPOSE: The aim of this study is to evaluate the two-stage split-crest technique with ultrasonic bone surgery for implant placement in patients with very narrow ridges, and to determine the status of soft and hard tissues and implant success rate. MATERIAL AND METHODS: Six patients received nine implants (BTI Biotechnology Institute, Vitoria, Spain) after a two-stage split-crest technique. Plasma rich in growth factors-Endoret was used during first and second stages to promote tissue regeneration. All implants were treated with plasma rich in growth factors-Endoret to promote osseointegration. Patients were recalled for clinical evaluation at least 6 months after implant loading. RESULTS: The status of soft tissues was very good showing adequate plaque index, bleeding index, and probing depth values. Success rate of implants at the end of follow-up (between 15 and 22 months after first surgery) was 100%. Bone ridge was measured and compared at final examination showing a mean ridge expansion of 5.60 mm (SD = 1.9) at apical and 7.33 mm (SD = 1.73) at occlusal. CONCLUSIONS: Two-stage split-crest with ultrasonic bone surgery can be considered a safe and predictable bone expansion technique for very narrow ridges. PMID- 22534364 TI - Prevalence and transmission of hepatitis E virus in domestic swine populations in different European countries. AB - BACKGROUND: Hepatitis E virus (HEV) genotype 3 and 4 can cause liver disease in human and has its main reservoir in pigs. HEV investigations in pigs worldwide have been performed but there is still a lack of information on the infection dynamics in pig populations. FINDINGS: The HEV transmission dynamics in commercial pig farms in six different European countries was studied. The data collected show prevalence in weaners ranging from 8% to 30%. The average HEV prevalence in growers was between 20% and 44%. The fatteners prevalence ranged between 8% and 73%. Sows prevalence was similar in all countries. Boar faeces were tested for HEV only in Spain and Czech Republic, and the prevalence was 4.3% and 3.5% respectively. The collected data sets were analyzed using a recently developed model to estimate the transmission dynamics of HEV in the different countries confirming that HEV is endemic in pig farms. CONCLUSIONS: This study has been performed using similar detection methods (real time RT-PCR) for all samples and the same model (SIR model) to analyse the data. Furthermore, it describes HEV prevalence and within-herd transmission dynamics in European Countries (EU): Czech Republic, Italy, Portugal, Spain, The Netherlands and United Kingdom, confirming that HEV is circulating in pig farms from weaners to fatteners and that the reproductive number mathematical defined as R0 is in the same range for all countries studied. PMID- 22534366 TI - Association between CDK5RAP1 polymorphisms and susceptibility to vitiligo in the Korean population. AB - The neuronal theory of the pathogenesis of vitiligo is supported by clinical, ultrastructural and biochemical findings. Cyclin-dependent kinase 5 regulatory subunit associated protein 1 (CDK5RAP1) is expressed in neuronal tissues, and cyclin-dependent kinase 5 (CDK5) seems to be critically involved in the migration of neuroblasts during early post-natal development. To evaluate whether CDK5RAP1 polymorphisms are associated with vitiligo patients in the Korean population, we conducted a case-control association study of 296 vitiligo patients and 426 healthy controls. A total of two single nucleotide polymorphisms (SNPs) of CDK5RAP1 were investigated. Genotypes were determined by polymerase chain reaction (PCR) and direct sequencing. A synonoymous SNP (rs291700, Thr54Thr) and intron SNP (rs158676) of CDK5RAP1 were associated with onset age of the vitiligo (rs291700, p=0.040 in co-dominant 1 and p=0.036 in overdominant; rs158676, p=0.034 in overdominant). Haplotype (AC) showed a difference between the vitiligo and control groups (p=0.036). These results suggest that CDK5RAP1 may be a risk factor of vitiligo in the Korean population. PMID- 22534367 TI - A three-stage culture process for improved exopolysaccharide production by Tremella fuciformis. AB - Tremella fuciformis produces several bioactive secondary metabolites including exopolysaccharides. Cultivation of the fungus was carried out in a three-stage process consisting of a 1.5-day cultivation with orbital shaking at 200 rpm, a 1.5-day cultivation with reciprocal shaking at 200 strokes, and a 1.5-day cultivation with orbital shaking at 200 rpm. Exopolysaccharide production and specific production rate reached 5.80 g L(-1) and 0.15 d(-1), respectively, which is an increase of 260% and 200% compared with the corresponding values for fermentations with orbital shaking only, and of 243% and 150% compared with the corresponding values for fermentations with reciprocal shaking only. The three stage culture method is time-saving and easy to operate. PMID- 22534368 TI - A review on dynamic membrane filtration: materials, applications and future perspectives. AB - This paper presents a comprehensive evaluation of the current status of dynamic membrane (DM) technology as an alternative to membrane bioreactor (MBR) systems. DM filtration makes use of a physical barrier (e.g. cloth or mesh) on which a cake layer is formed. It is already used in traditional filtration systems, but applications in biological wastewater treatment are still at its infancy. Dynamic filtration of sludge has lower risk of fouling and requires less energy and lower capital costs compared to MBR. A review of the state-of-art in both DM materials and configurations is presented. Factors affecting DM performance are discussed in order to determine the optimum and critical approaches for membrane operation. Future perspectives to enhance the applicability and functionality of the technology regarding the treatment and membrane performance are presented. PMID- 22534369 TI - Application of conductive polymers in biocathode of microbial fuel cells and microbial community. AB - Four kinds of conductive polymers, polyaniline (PANI) and its co-polymers poly (aniline-co-o-aminophenol) (PANOA), poly (aniline-co-2, 4-diaminophenol) (PANDAP) and poly (aniline-1, 8-diaminonaphthalene) (PANDAN) were applied to modify carbon felts as the aerobic abiotic cathodes and biocathodes in microbial fuel cells (MFC). Compare to unmodified, all the four polymers can significantly improve the power densities for both abiotic cathodes (increased by 300%) and biocathodes (increased by 180%). The co-polymers with different functional groups introduction had further special advantages in MFC performance: PANOA and PANDAP with -OH showed less sensitivity to DO and pH change in cathode; PANDAP and PANDAN with -NH(3) provided better attachment condition for biofilm which endowed them higher power output. With the help of conductive polymer coats, the cathode biofilm became thicker, and according to biodiversity analysis, the predominated phyla changed from beta-Proteobacteria (unmodified) to alpha, gamma Proteobacteria (modified), which may be responsible for the superiority of the modified MFCs. PMID- 22534370 TI - Membrane fouling mechanism in ultrafiltration of succinic acid fermentation broth. AB - The membrane fouling mechanism was studied in treating succinic acid fermentation broth during dead-end ultrafiltration. Different membranes were used and two models were applied to analyze the fouling mechanism. Resistance-in-series model was applied to determine the main factor that caused the operation resistance. Results indicated that most membranes tended to be fouled by cake layer or concentration polarization. Hermia's model, which is composed of four individual sub-models, was used to analyze the predominant fouling mechanism. Results showed that the fouling of RC 10 kDa and PES 30 kDa was controlled by the complete blocking mechanism, while PES 100 kDa was controlled by the intermediate blocking and PES 10 kDa was controlled by cake layer. This conclusion was also proved by SEM photos. Membrane characteristics were monitored before and after ultrafiltration by AFM and goniometer. Both contact angle and roughness of most membranes increased after ultrafiltration. PMID- 22534371 TI - Microbially-reduced graphene scaffolds to facilitate extracellular electron transfer in microbial fuel cells. AB - A one-pot method is exploited by adding graphene oxide (GO) and acetate into an microbial fuel cell (MFC) in which GO is microbially reduced, leading to in situ construction of a bacteria/graphene network in the anode. The obtained microbially reduced graphene (MRG) exhibits comparable conductivity and physical characteristics to the chemically reduced graphene. Electrochemical measurements reveal that the number of exoelectrogens involved in extracellular electron transfer (EET) to the solid electrode, increases due to the presence of graphene scaffolds, and the EET is facilitated in terms of electron transfer kinetics. As a result, the maximum power density of the MFC is enhanced by 32% (from 1440 to 1905 mW m(-2)) and the coulombic efficiency is improved by 80% (from 30 to 54%). The results demonstrate that the construction of the bacteria/graphene network is an effective alternative to improve the MFC performance. PMID- 22534372 TI - Efficient production of L-lactic acid with high optical purity by alkaliphilic Bacillus sp. WL-S20. AB - Highly efficient polymer-grade L-lactic acid production was achieved by an alkaliphilic strain Bacillus sp. WL-S20 using inexpensive peanut meal as nitrogen source and sodium hydroxide as neutralizing agent. In multi-pulse fed-batch fermentation of Bacillus sp. WL-S20, a L-lactic acid concentration of 225 g/l with a yield of 99.3% was obtained. In single-pulse fed-batch fermentation, a concentration of 180 g/l was obtained with a yield of 98.6%. No D-isomers of lactic acid were detected. The production of a high concentration of optically pure L-lactic acid by alkaliphilic Bacillus sp. WL-S20, combined with a low-cost nutrient and environment-friendly NaOH-based process, represent a potentially novel way for L-lactic acid production at an industrial scale. PMID- 22534373 TI - N2O and N2 production during heterotrophic nitrification by Alcaligenes faecalis strain NR. AB - A heterotrophic nitrifier, strain NR, was isolated from a membrane bioreactor. Strain NR was identified as Alcaligenes faecalis by Auto-Microbic system and 16S rRNA gene sequence analysis. A. faecalis strain NR shows a capability of heterotrophic nitrification and N(2)O and N(2) production as well under the aerobic condition. Further tests demonstrated that neither nitrite nor nitrate could be denitrified aerobically by strain NR. However, when hydroxylamine was used as the sole nitrogen source, nitrogenous gases were detected. With an enzyme assay, a 0.063 U activity of hydroxylamine oxidase was observed, while nitrate reductase and nitrite reductase were undetectable. Thus, nitrogenous gas was speculated to be produced via hydroxylamine. Therefore, two different metabolic pathways might exist in A. faecalis NR. One is heterotrophic nitrification by oxidizing ammonium to nitrite and nitrate. The other is oxidizing ammonium to nitrogenous gas directly via hydroxylamine. PMID- 22534374 TI - One-pot synthesis of 5-hydroxymethylfurfural directly from starch over SO(4)(2 )/ZrO2-Al2O3 solid catalyst. AB - The synthesis of 5-hydroxymethylfurfural (HMF) directly from starch was studied in dimethyl sulfoxide-water. The effects of catalyst variation, reaction time, water content, catalyst loading and temperature on the reaction were investigated. The SO(4)(2-)/ZrO(2)-Al(2)O(3) catalyst was found to act as a bifunctional catalyst with high activity for both hydrolysis and dehydration of starch. HMF yield of 55% was obtained after 6h at 423K for the reaction of starch (the molar ratio of water to glucose in starch is 44/1) over the SO(4)(2-)/ZrO(2) Al(2)O(3) catalyst, which bears high acidity and moderate basicity with Zr/Al molar ratio of 1:1. PMID- 22534376 TI - Representations of MDR and XDR-TB in South African newspapers. AB - The emergence of drug-resistant tuberculosis has brought with it diverse perspectives concerning the way in which the disease should be managed. The media is an important source of these perspectives, as they perform the dual role of reflecting and shaping public discourse. In this study, we are interested in how the media presents multi-drug resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) in South Africa, where both variants are a growing public health concern. We examined newspaper content from 310 South African newspaper articles from February 2004 to July 2009 that discussed MDR-TB and XDR-TB. Newspaper articles were collected from the Dow Jones Factiva database and imported into QDA Miner v3.2.1 for analysis. Using Attride-Stirling's thematic network analysis method, articles were analyzed according to themes, sub themes, and thematic networks. This analysis identified two main dimensions: causes of MDR/XDR-TB and treatment approaches/solutions. Causes of MDR/XDR-TB revolved around three main global themes: i) patient-centred causes (32.6%); ii) lack of infection control procedures (18.7%); and iii) health systems failures (19.4%). Treatment approaches or solutions to tackling MDR/XDR-TB focused on i) patient targeted solutions (38.4%); ii) improving infection control (12.3%); iii) systems restructuring (10.6%); and iv) new diagnostic and therapeutic options (10%). Our analysis identifies a trend in the South African media to identify a broad range of causes of MDR/XDR-TB, while emphasizing that treatment approaches should be directed primarily at the individual. Of particular importance is the fact that such a perspective runs contrary to the World Health Organization's (WHO) recommendations for approaching the TB epidemic, in particular by insufficiently addressing systemic and social drivers of the epidemic. Due to the media's potential influence on policy formation, how the media presents issues - especially issues pertaining to emerging public health concerns - should warrant more attention. PMID- 22534375 TI - The Sp1 transcription factor is essential for the expression of gliostatin/thymidine phosphorylase in rheumatoid fibroblast-like synoviocytes. AB - INTRODUCTION: Gliostatin/thymidine phosphorylase (GLS/TP) has angiogenic and arthritogenic activities, and aberrant GLS production has been observed in the active synovial membranes of rheumatoid arthritis (RA) patients. The human GLS gene promoter contains at least seven consensus binding sites for the DNA binding protein Sp1. Here we examined whether Sp1 is necessary for GLS production in RA. We also studied the effects of the Sp1 inhibitor mithramycin on GLS production in RA fibroblast-like synoviocytes (FLSs). METHODS: FLSs from RA patients were treated with specific inhibitors. The gene and protein expression of GLS were studied using the quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and an enzyme immunoassay. Intracellular signalling pathway activation was determined by western blotting analysis, a luciferase assay, a chromatin immunoprecipitation (ChIP) assay and a small interfering RNA (siRNA) transfection. RESULTS: The luciferase and ChIP assays showed that Sp1 binding sites in the GLS promoter were essential for GLS messenger RNA (mRNA) expression. GLS production was suppressed in FLSs by siRNA against Sp1 transfection. Mithramycin decreased GLS promoter activity, mRNA and protein expression in FLSs. Tumour necrosis factor-alpha (TNF-alpha) significantly increased GLS expression in RA FLSs; this effect was reduced by pre-treatment with cycloheximide and mithramycin. CONCLUSIONS: Pretreatment of mithramycin and Sp1 silencing resulted in a significant suppression of GLS production in TNF-alpha-stimulated FLSs compared to controls. GLS gene expression enhanced by TNF-alpha was partly mediated through Sp1. As physiological concentrations of mithramycin can regulate GLS production in RA, mithramycin is a promising candidate for anti-rheumatic therapy. PMID- 22534378 TI - The health care access and utilization of homeschooled children in the United States. AB - Although the population of homeschooled children in the United States is large and growing, little is known about their access to and utilization of preventive health care services. This paper compares the health care access and utilization of homeschooled children and public school children in the United States using data from the nationally-representative 2007 National Survey of Children's Health. Using logistic regression models, this study finds that homeschooled children were significantly less likely than public school children to have access to a medical home, to visit a health care professional annually, and to receive the Human Papillomavirus vaccine. They were not statistically less likely to have health insurance, to receive annual dental care, or to receive Tetanus or Meningitis vaccinations. This research suggests that public health practitioners, medical providers, researchers, and educators should be attentive to the health care needs of homeschooled children. PMID- 22534377 TI - Meta-analysis of marital dissolution and mortality: reevaluating the intersection of gender and age. AB - The study of marital dissolution (i.e. divorce and separation) and mortality has long been a major topic of interest for social scientists. We conducted meta analyses and meta-regressions on 625 mortality risk estimates from 104 studies, published between 1955 and 2011, covering 24 countries, and providing data on more than 600 million persons. The mean hazard ratio (HR) for mortality in our meta-analysis was 1.30 (95% confidence interval [CI], 1.23-1.37) among HRs adjusted for age and additional covariates. The mean HR was higher for men (HR, 1.37; 95% CI, 1.27-1.49) than for women (HR, 1.22; 95% CI: 1.13-1.32), but the difference between men and women decreases as the mean age increases. Other significant moderators of HR magnitude included sample size; being from Western Europe, Israel, the United Kingdom and former Commonwealth nations; and statistical adjustment for general health status. PMID- 22534380 TI - Paroxetine use should be avoided during pregnancy. PMID- 22534379 TI - Representations and uses of emergency contraception in West Africa. A social anthropological reading of a northern medicinal product. AB - Since the early 2000s a new form of progesterone based emergency contraception with no side effects has been on the African market, aimed at reducing contraceptive failure rates and the mortality associated with the practice of unsafe abortion. Studies of emergency contraception (EC) carried out in West Africa have only examined opinions and knowledge about EC. We hypothesized that representations and uses of this method takes place at the intersection of two dimensions: (i) a "Northern" pharmaceutical norm, and (ii) local understandings of the timing of conception. To test this hypothesis we used a discourse analysis of semi-structured interviews with 149 women and 77 with men aged between 18 and 40, of varying marital, social and professional status, resident in Dakar, Ouagadougou and Accra. The interviews were conducted in 2005-2007. EC is overwhelmingly perceived as a Northern medical treatment which encourages greater sexual freedom for women. Many respondents, both male and female, believe that EC is a "chemical" product that may cause sterility, and there is severe questioning of its supposed abortifacient character. EC is being used as recommended by the medical profession - in an occasional manner and in cases of urgent need; but it is also being used, like other post-coital methods which women have long employed, in a programmed and repeated manner. On the one hand the social issue raised by EC, namely the weakening of control by men of the sexuality and fertility of women, may be an obstacle to its diffusion. On the other hand, it may in the end be viewed as simply another post-coital method, whose use is framed by the prevailing systems of temporal representations in the three countries concerned in the study. PMID- 22534384 TI - Is spinal manipulation an effective treatment for low back pain? Yes: evidence shows benefit in most patients. PMID- 22534385 TI - Is spinal manipulation an effective treatment for low back pain? Yes: spinal manipulation is a useful adjunct therapy. PMID- 22534386 TI - Is spinal manipulation an effective treatment for low back pain? No: evidence shows no clinically significant benefit over watchful waiting. PMID- 22534387 TI - Evaluation of nail abnormalities. AB - Knowledge of the anatomy and function of the nail apparatus is essential when performing the physical examination. Inspection may reveal localized nail abnormalities that should be treated, or may provide clues to an underlying systemic disease that requires further workup. Excessive keratinaceous material under the nail bed in a distal and lateral distribution should prompt an evaluation for onychomycosis. Onychomycosis may be diagnosed through potassium hydroxide examination of scrapings. If potassium hydroxide testing is negative for the condition, a nail culture or nail plate biopsy should be performed. A proliferating, erythematous, disruptive mass in the nail bed should be carefully evaluated for underlying squamous cell carcinoma. Longitudinal melanonychia (vertical nail bands) must be differentiated from subungual melanomas, which account for 50 percent of melanomas in persons with dark skin. Dystrophic longitudinal ridges and subungual hematomas are local conditions caused by trauma. Edema and erythema of the proximal and lateral nail folds are hallmark features of acute and chronic paronychia. Clubbing may suggest an underlying disease such as cirrhosis, chronic obstructive pulmonary disease, or celiac sprue. Koilonychia (spoon nail) is commonly associated with iron deficiency anemia. Splinter hemorrhages may herald endocarditis, although other causes should be considered. Beau lines can mark the onset of a severe underlying illness, whereas Muehrcke lines are associated with hypoalbuminemia. A pincer nail deformity is inherited or acquired and can be associated with beta-blocker use, psoriasis, onychomycosis, tumors of the nail apparatus, systemic lupus erythematosus, Kawasaki disease, and malignancy. PMID- 22534388 TI - Pelvic inflammatory disease. AB - Pelvic inflammatory disease is a polymicrobial infection of the upper genital tract. It primarily affects young, sexually active women. The diagnosis is made clinically; no single test or study is sensitive or specific enough for a definitive diagnosis. Pelvic inflammatory disease should be suspected in at-risk patients who present with pelvic or lower abdominal pain with no identified etiology, and who have cervical motion, uterine, or adnexal tenderness. Chlamydia trachomatis and Neisseria gonorrhoeae are the most commonly implicated microorganisms; however, other microorganisms may be involved. The spectrum of disease ranges from asymptomatic to life-threatening tubo-ovarian abscess. Patients should be treated empirically, even if they present with few symptoms. Most women can be treated successfully as outpatients with a single dose of a parenteral cephalosporin plus oral doxycycline, with or without oral metronidazole. Delay in treatment may lead to major sequelae, including chronic pelvic pain, ectopic pregnancy, and infertility. Hospitalization and parenteral treatment are recommended if the patient is pregnant, has human immunodeficiency virus infection, does not respond to oral medication, or is severely ill. Strategies for preventing pelvic inflammatory disease include routine screening for chlamydia and patient education. PMID- 22534389 TI - Pelvic inflammatory disease. PMID- 22534390 TI - Common finger fractures and dislocations. AB - Finger fractures and dislocations are common injuries that are often managed by family physicians. A systematic physical examination is imperative to avoid complications and poor outcomes following these injuries. Radiography (commonly anteroposterior, true lateral, and oblique views) is required in the evaluation of finger fractures and dislocations. Dorsal dislocation of the proximal interphalangeal joint is the most common type of finger dislocation. Finger dislocations should be reduced as quickly as possible and concurrent soft tissue injuries treated appropriately. Referral to a hand specialist is needed if a dislocation cannot be reduced; is unstable following reduction; or involves significant ligament, tendon, or soft tissue injury. Some common finger fractures can be treated conservatively with appropriate reduction and immobilization. Referral to a hand specialist is required if a fracture is unstable, involves a large portion (greater than 30 percent) of the intra-articular surface, or has significant rotation. PMID- 22534391 TI - Symmetrical vesicular eruption on the palms. PMID- 22534392 TI - FPIN's Clinical Inquiries. Complementary and alternative therapies for atopic dermatitis. PMID- 22534395 TI - Is routine testing of vitamin B12 cost-effective in workup for cognitive impairment? PMID- 22534396 TI - Electrodesiccation and curettage for removal of nongenital warts. PMID- 22534398 TI - School achievement of children with intellectual disability: the role of socioeconomic status, placement, and parents' engagement. AB - The objective of this study was to describe the selected conditions for school achievement of students with mild intellectual disabilities from Polish elementary schools. Participants were 605 students with mild disabilities from integrative, regular, and special schools, and their parents (N=429). It was found that socioeconomic status (SES) was positively associated with child placement in integrative and regular schools rather than special schools, as well as with higher parental engagement in their children's studies. Parental engagement mediated the positive effects of SES and placement in regular and integrative schools on school achievement. The results are discussed in the context of inclusive education theory. PMID- 22534397 TI - Measuring the concept of impact of childhood disability on parents: validation of a multidimensional measurement in a cerebral palsy population. AB - Living with a child with a disability can affect family life in various domains. Impacts on time, expenses, work, relationships within the family, social relationships and physical and psychological health can be observed. The Family Impact of Childhood Disability (FICD) is a specific instrument designed to assess this situation. Used in a cross-sectional survey, this questionnaire was extended to consider two missing aspects: impact on work and health (FICD+4). This paper addresses the psychometric qualities of the FICD in Europe among parents living with an adolescent with cerebral palsy. Expecting the FICD+4 could assess detailed impact dimensions, an exploratory analysis was conducted. We interviewed 242 families of 13- to 17-year-old adolescents with cerebral palsy living in Europe. Good psychometric properties were found in negative and positive FICD scales and in six underlying factors extracted from exploratory factor analysis on FICD+4. These results support the psychometric validity of the FICD in the assessment of the impact of disability in European families who live with an adolescent with cerebral palsy. They also highlight the multifaceted aspects of the impact of childhood disability on the family and suggest that the FICD+4 is a good tool for assessing specific negative impacts on time, finances, work, social relationships and positive impacts on parental feeling and family attitude. This scale needs further validation and could be helpful for research and clinical interventions. PMID- 22534401 TI - Citalopram-induced subacute cutaneous lupus erythematosus -- first case and review concerning photosensitivity in selective serotonin reuptake inhibitors. AB - OBJECTIVE: This report describes a case of subacute cutaneous lupus erythematosus (SCLE) in a patient treated with citalopram and discusses evidence linking selective serotonin reuptake inhibitors (SSRIs) to the induction of photosensitivity. METHOD: Case report and review of published literature. RESULTS: A 71-year-old woman with major depression developed 2 days after intake of 20 mg citalopram a strongly itching and largely dimensioned confluencing erythema with infiltrations and blisters all over the trunk with fever and malaise. Histological and laboratory investigations were consistent with the diagnosis of SCLE. After stopping citalopram intake, dermatologic symptoms significantly improved within 2 weeks. SSRIs have been associated with 14 cases of adverse cutaneous events as a result of SSRI-induced photosensitivity. No case of SSRI-induced SCLE has been described. CONCLUSION: In clinical practice, indication and dosage of citalopram and other SSRIs should be carefully monitored. In the case of a SSRI-induced photosensitivity, medication can be switched to an antidepressant from another class. PMID- 22534399 TI - Global analysis reveals multiple pathways for unique regulation of mRNA decay in induced pluripotent stem cells. AB - Pluripotency is a unique state in which cells can self-renew indefinitely but also retain the ability to differentiate into other cell types upon receipt of extracellular cues. Although it is clear that stem cells have a distinct transcriptional program, little is known about how alterations in post transcriptional mechanisms, such as mRNA turnover, contribute to the achievement and maintenance of pluripotency. Here we have assessed the rates of decay for the majority of mRNAs expressed in induced pluripotent stem (iPS) cells and the fully differentiated human foreskin fibroblasts (HFFs) they were derived from. Comparison of decay rates in the two cell types led to the discovery of three independent regulatory mechanisms that allow coordinated turnover of specific groups of mRNAs. One mechanism results in increased stability of many histone mRNAs in iPS cells. A second pathway stabilizes a large set of zinc finger protein mRNAs, potentially through reduced levels of miRNAs that target them. Finally, a group of transcripts bearing 3' UTR C-rich sequence elements, many of which encode transcription factors, are significantly less stable in iPS cells. Intriguingly, two poly(C)-binding proteins that recognize this type of element are reciprocally expressed in iPS and HFF cells. Overall, our results highlight the importance of post-transcriptional control in pluripotent cells and identify miRNAs and RNA-binding proteins whose activity may coordinately control expression of a wide range of genes in iPS cells. PMID- 22534400 TI - Uncovering cis-regulatory sequence requirements for context-specific transcription factor binding. AB - The regulation of gene expression is mediated at the transcriptional level by enhancer regions that are bound by sequence-specific transcription factors (TFs). Recent studies have shown that the in vivo binding sites of single TFs differ between developmental or cellular contexts. How this context-specific binding is encoded in the cis-regulatory DNA sequence has, however, remained unclear. We computationally dissect context-specific TF binding sites in Drosophila, Caenorhabditis elegans, mouse, and human and find distinct combinations of sequence motifs for partner factors, which are predictive and reveal specific motif requirements of individual binding sites. We predict that TF binding in the early Drosophila embryo depends on motifs for the early zygotic TFs Vielfaltig (also known as Zelda) and Tramtrack. We validate experimentally that the activity of Twist-bound enhancers and Twist binding itself depend on Vielfaltig motifs, suggesting that Vielfaltig is more generally important for early transcription. Our finding that the motif content can predict context-specific binding and that the predictions work across different Drosophila species suggests that characteristic motif combinations are shared between sites, revealing context specific motif codes (cis-regulatory signatures), which appear to be conserved during evolution. Taken together, this study establishes a novel approach to derive predictive cis-regulatory motif requirements for individual TF binding sites and enhancers. Importantly, the method is generally applicable across different cell types and organisms to elucidate cis-regulatory sequence determinants and the corresponding trans-acting factors from the increasing number of tissue- and cell-type-specific TF binding studies. PMID- 22534402 TI - Antidepressants and menstruation disorders in women: a cross-sectional study in three centers. AB - OBJECTIVE: The relationship between menstruation disorders and antidepressant drugs usage in women remains unclear. In this study, we aimed to investigate the incidence rate of antidepressant-related menstruation disorders and to examine whether or not antidepressant use is associated with menstrual disorders in women. METHODS: The study sample was gathered from three centers and four hospitals. A total of 1432 women who met the criteria of inclusion were included in the study. The sample was divided into two groups: the antidepressant group (n=793) and the control group (n=639). The menstruation disorders were established with reports from the study participants on the basis of related gynecological descriptions. RESULTS: The prevalence of menstrual disorders was significantly higher in the antidepressant group (24.6%) than the control group (12.2%). The incidence of antidepressant-induced menstruation disorder was 14.5%. The antidepressants most associated with menstrual disorders were paroxetine, venlafaxine, sertraline and their combination with mirtazapine. Overall, the incidence rate was similar in women receiving selective serotonin reuptake inhibitors and serotonin noradrenaline reuptake inhibitors. CONCLUSIONS: The results of the present study suggest that menstruation disorders are frequently observed in women taking antidepressants and that it appears to be associated with antidepressant use at least in some women. PMID- 22534403 TI - The impact of progesterone on memory consolidation of threatening images in women. AB - Recent findings suggest that consolidation of emotional memories is influenced by menstrual phase in women. In contrast to other phases, in the mid-luteal phase when progesterone levels are elevated, cortisol levels are increased and correlated with emotional memory. This study examined the impact of progesterone on cortisol and memory consolidation of threatening stimuli under stressful conditions. Thirty women were recruited for the high progesterone group (in the mid-luteal phase) and 26 for the low progesterone group (in non-luteal phases of the menstrual cycle). Women were shown a series of 20 neutral or threatening images followed immediately by either a stressor (cold pressor task) or control condition. Participants returned two days later for a surprise free recall test of the images and salivary cortisol responses were monitored. High progesterone levels were associated with higher baseline and stress-evoked cortisol levels, and enhanced memory of negative images when stress was received. A positive correlation was found between stress-induced cortisol levels and memory recall of threatening images. These findings suggest that progesterone mediates cortisol responses to stress and subsequently predicts memory recall for emotionally arousing stimuli. PMID- 22534404 TI - Language lateralization and cognitive control across the menstrual cycle assessed with a dichotic-listening paradigm. AB - Lateralization has been shown to vary across the menstrual cycle, however, the underlying mechanisms are not fully understood, and results are inconsistent. Additionally, it has been suggested that estradiol enhances cognitive control. By modulating attention in a consonant-vowel dichotic listening test, the current study aims to investigate the effects of cycle-related changes on language lateralization (non-forced condition), as well as the effects of estradiol modulated cognitive control (forced left condition) on the ear advantage. Fifteen women and fifteen men tested three times on the dichotic listening test, women once in menstrual, follicular, and luteal phase (verified by hormone assays). Whereas the results from the non-forced and forced-right condition remained stable, results from the forced left condition changed across the cycle, where women in the follicular phase compared to both menstrual and luteal phases showed a stronger left ear advantage, i.e. better cognitive control performance. The increase in performance from menstrual to follicular phase correlated negatively with increase in estradiol levels, indicating a shift from a stimulus-driven right ear advantage (indicating a left hemispheric asymmetry for language) when estradiol levels were low toward a cognitively controlled left ear advantage when estradiol levels were high. This finding strongly suggests an active role of estradiol on cognitive control. The study further suggests that the degree of cognitive control demands of a given task is important to consider when investigating lateralization across the menstrual cycle. PMID- 22534405 TI - Development of psychophysiological motoric reactivity is influenced by peripubertal pharmacological inhibition of gonadotropin releasing hormone action- results of an ovine model. AB - This study reports the effects of peripubertal GnRH receptor inactivation on development of psychophysiological motoric reactivity (PMR; sometimes also called emotional reactivity), plasma cortisol concentrations and the relationship between plasma cortisol and PMR in male and female sheep. The study formed part of a larger trial and utilised 46 same sex twins. One twin remained untreated (control) while the other received a subcutaneous GnRH agonist (GnRHa Goserelin Acetate) implant every 4th week, beginning at 8 and 28 weeks of age, in males and females, respectively (different, due to sex specific age of puberty). PMR, a measure of an animals' response to social isolation, was measured over a two minute period at 8, 28 and 48 weeks of age, using a three axis accelerometer. During the test period vocalisation rate was recorded. Cortisol was assayed in blood samples collected on a single day when animals were 40 weeks of age. PMR and vocalisation rate were significantly higher in females than males at all ages tested. At 28 weeks of age (20 weeks treatment) PMR was increased in treated males to the level seen in control females, by 48 weeks of age treated males' PMR was significantly less than controls. In females, 20 weeks of GnRHa treatment (28 48 weeks of age) was not associated with differences in PMR. Cortisol concentrations were significantly higher in females than males but were not affected by treatment. Plasma cortisol concentrations were positively correlated with PMR; this relationship being driven by the treated animals in both sexes. The results demonstrate that PMR is sexually dimorphic and cortisol dependent in sheep from at least 8 weeks of age. Importantly, they also demonstrate that long term treatment of males with a GnRH agonist results in changes in age-dependent development of PMR. PMID- 22534406 TI - Added predictive ability of the CHA2DS2VASc risk score for stroke and death in patients with atrial fibrillation: the prospective Danish Diet, Cancer, and Health cohort study. AB - BACKGROUND: The objective of this study was to evaluate the added predictive ability of the CHA(2)DS(2)VASc prediction rule for stroke and death in a nonanticoagulated population of patients with atrial fibrillation. METHODS AND RESULTS: We included 1603 nonanticoagulated patients with incident atrial fibrillation from a Danish prospective cohort study of 57 053 middle-aged men and women. The Net Reclassification Improvement was calculated as a measure to estimate any overall improvement in reclassification with the CHA(2)DS(2)VASc sore as an alternative to the CHADS(2) score. After 1-year follow-up, crude incidence rates were 3.4 per 100 person-years for stroke and 13.6 for death. After a mean follow-up of 5.4 years (+/- 3.7 years), the crude incidence rates for stroke and death were 1.9 and 5.6, respectively. During the entire observation period, the c-statistics and negative predictive values were similar for both risk scores. The Net Reclassification Improvement analysis showed that 1 of 10 reclassified atrial fibrillation patients would have been upgraded correctly using the CHA(2)DS(2)VASc score. CONCLUSIONS: Both the CHADS(2) as well as the CHA(2)DS(2)VASc risk score can exclude a large proportion of patients from having high risk of stroke or death. However, using the CHA(2)DS(2)VASc risk score, fewer patients will fulfill the criterion for low risk (and are truly low risk for thromboembolism). For every 10 extra patients transferred to the treatment group at 5 years, using the CHA(2)DS(2)VASc risk score, 1 patient would have had a stroke that might have been avoided with effective treatment. PMID- 22534408 TI - Distributions and removal fluxes of trace metals in the water column of the Hung Tsai Trough off southwestern Taiwan. AB - Vertical profiles of dissolved and particulate Mn, Fe, Ni, Cu, Zn, Cd, Pb, and (234)Th were determined in the Hung-Tsai Trough off southwestern Taiwan during 19 23 November, 2004. Except in the case of Cd, the distribution coefficient (K(d)) of the trace elements showed a negative correlation with the suspended particle concentration. Based on the average K(d) values, the general sequence of particle affinities for the eight trace elements is, from highest to lowest, Fe>Mn~Pb>Zn~Th>Cd~Cu~Ni. The trace metal data was coupled with the particle removal flux estimated from (234)Th/(238)U disequilibrium to investigate metal removal by particle sinking from the euphotic layer. The residence time of trace elements with respect to particle removal from the euphotic layer was estimated. A negative correlation between the residence time and the distribution coefficient for the trace metals was found. PMID- 22534407 TI - Predictors of increased intravenous tissue plasminogen activator use among hospitals participating in the Massachusetts Primary Stroke Service Program. AB - BACKGROUND: We sought to determine if intravenous tissue plasminogen activator (IV tPA) use for acute ischemic stroke increased in Massachusetts in association with the Primary Stroke Service program, a statewide stroke center designation and quality improvement initiative. METHODS AND RESULTS: We analyzed prospectively acquired data from the Massachusetts Department of Public Health between October 2004 and June 2008, including 10 045 consecutive emergency department-based acute ischemic stroke encounters arriving <= 3 hours after stroke onset at 69 participating Massachusetts PSS hospitals. The overall rate of IV tPA use was 854 of 3866 (22.1%) of patients arriving <= 2 hours of symptom onset. IV tPA use increased steadily from 2005 (the first full year of the program) to 2008 (18.4%, 21.9%, 22.6%, 25.5%; P=0.001). Patients treated with IV tPA were more likely to be younger (72.3 +/- 14.1 versus 74.7 +/- 14.0 years, P<0.005) and to have presented after emergency medical services rerouting in July 2005 (96% versus 94%, P=0.009). Patients who arrived at hospitals with a performance achievement award from the Get With The Guidelines-Stroke program were more likely to receive IV tPA after versus before award recognition (28.1% versus 22.3%, P<0.001). CONCLUSIONS: In this nearly complete capture of statewide data, rates of IV tPA improved significantly in Massachusetts from 2005 to 2008 in association with a state Primary Stroke Service designation program. Further studies are needed to confirm that treatment disparities exist for older acute ischemic stroke patients and that the rates of thrombolysis have increased above and beyond secular trends. PMID- 22534409 TI - Impacts of human activities on coral reef ecosystems of southern Taiwan: a long term study. AB - In July 2001, the National Museum of Marine Biology and Aquarium, co-sponsored by the Kenting National Park Headquarters and Taiwan's National Science Council, launched a Long-Term Ecological Research (LTER) program to monitor anthropogenic impacts on the ecosystems of southern Taiwan, specifically the coral reefs of Kenting National Park (KNP), which are facing an increasing amount of anthropogenic pressure. We found that the seawater of the reef flats along Nanwan Bay, Taiwan's southernmost embayment, was polluted by sewage discharge at certain monitoring stations. Furthermore, the consequently higher nutrient and suspended sediment levels had led to algal blooms and sediment smothering of shallow water corals at some sampling sites. Finally, our results show that, in addition to this influx of anthropogenically-derived sewage, increasing tourist numbers are correlated with decreasing shallow water coral cover, highlighting the urgency of a more proactive management plan for KNP's coral reefs. PMID- 22534410 TI - An evaluation of factors affecting activated coagulation time. AB - OBJECTIVE: Although failure to achieve an adequate activated coagulation time (ACT) after full heparinization before cardiopulmonary bypass often is attributed to antithrombin (AT) deficiency, it remains unclear if this is a causative mechanism of decreased heparin responsiveness. Therefore, the authors determined the relationship between AT and other coagulation-related factors that affect the ACT measurement and heparin sensitivity index before the establishment of cardiopulmonary bypass. DESIGN: Observational study. SETTING: University medical center. PARTICIPANTS: Adult elective cardiac surgical patients. INTERVENTIONS: Preoperative data collection included demographics, type of preoperative medical therapy, hemoglobin, platelet count, and AT. Intraoperative measurements included ACT and anti-Xa activity. RESULTS: Of the 203 patients enrolled in this study, 10% (n = 21) did not achieve an adequate ACT (>=400 seconds) after full heparinization. Subnormal AT activity (55%-79%) was not related to a low ACT and a low heparin sensitivity index. Preoperative low-molecular-weight heparin therapy did not cause a decreased ACT response. However, preoperative low hemoglobin levels and high platelet counts were associated with a decreased ACT. CONCLUSIONS: All these observations suggest that failure to achieve an adequate ACT is, in general, not an indicator of AT deficiency but could be affected by high platelet counts and low hemoglobin levels. PMID- 22534411 TI - Transcutaneous ultrasound measurements of carotid flow to monitor for cerebral malperfusion during type-A aortic dissection repair. PMID- 22534412 TI - Perioperative management of antiplatelet agents in patients undergoing cardiac surgery. PMID- 22534413 TI - A case of an alveolar soft part sarcoma with secondary scapular involvement. PMID- 22534414 TI - Mortality attributable to tobacco by region based on the WHO Global Report. PMID- 22534415 TI - Diffuse reflectance spectroscopy: a new guidance tool for improvement of biopsy procedures in lung malignancies. AB - BACKGROUND: A significant number of percutaneous intrathoracic biopsy procedures result in indeterminate cytologic or histologic diagnosis in clinical practice. Diffuse reflectance spectroscopy (DRS) is an optical technique that can distinguish different tissue types on a microscopic level. DRS may improve needle localization accuracy during biopsy procedures. The objective of this study was to assess the ability of DRS to enhance diagnosis of malignant disease in human lung tissue. METHODS: Ex vivo analysis with a DRS system was performed on lung tissue from 10 patients after pulmonary resection for malignant disease. Tissue spectra measured from 500 to 1600 nm were analyzed using 2 analysis methods; a model-based analysis that derives clinical and optical properties from the measurements and a partial least-squares discriminant analysis (PLS-DA) that classifies measured spectra with respect to the histologic nature of the measured tissue. RESULTS: Sensitivity and specificity for discrimination of tumor from normal lung tissue were 89% and 79%, respectively, based on the model-based analysis. Overall accuracy was 84%. The PLS-DA analysis yielded a sensitivity of 78%, a specificity of 86%, and an overall accuracy of 81%. CONCLUSIONS: The presented results demonstrate that DRS has the potential to enhance diagnostic accuracy in minimally invasive biopsy procedures in the lungs in combination with conventional imaging techniques. PMID- 22534416 TI - Disrupted integrity of white matter in heroin-addicted subjects at different abstinent time. AB - PURPOSE: To investigate and compare the integrity of white matter in heroin addicted and healthy control subjects at different abstinent time using diffusion tensor imaging. MATERIALS AND METHODS: We performed voxelwise analysis of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) in 35 currently abstinent heroin abusers who were divided into long-term group (n = 17) and short-term group (n = 18) and 17 healthy volunteers. Measurements of FA and ADC of the identified regions (genu and splenium of corpus callosum, bilateral frontal lobe) were obtained from all subjects. RESULTS: The FA at callosal splenium was higher in the long-term group than in the short-term group (P < 0.05). The FA at left prefrontal cortex was higher in the short-term group than in the long-term group (P < 0.05). No significant difference in ADC was found among the 3 groups. The education history had a positive correlation with the FA value on the gena of corpus callosum (r = 0.402, P = 0.017). Months of abstinence had a negative correlation with left frontal FA (r = -0.366, P = 0.03) and a positive correlation with splenium FA (r = 0.348, P = 0.04). CONCLUSIONS: Heroin abuse seems to alter white matter microstructure differentially in long-term and short-term heroin addicts. This study will contribute to the current literature by examining the quality of white matter fiber structure in heroin abstinence. PMID- 22534417 TI - Evaluation of an experiential curriculum for addiction education among medical students. AB - OBJECTIVES: Undergraduate medical education about addictive disease can take many forms, but it is unclear which educational methods are most effective at shaping medical students into physicians who are interested in and competent at addressing addiction. The purpose of this study was to evaluate the efficacy of the Betty Ford Institute's Summer Institute for Medical Students (SIMS), a week long program aimed at educating medical students about addiction through a combination of traditional didactic and novel experiential sessions. METHODS: A written survey assessing beliefs, attitudes, and practices related to addictive disease was administered to physicians who previously participated in SIMS (n = 140) and to physicians matched for year of graduation from medical school who did not participate in SIMS (n = 105). RESULTS: Compared with their peers, and controlling for sex, age, year of graduation from medical school, specialty, personal experience with addiction, and training in talking to patients about substance use, physicians who participated in SIMS were more likely to believe that they could help addicted patients, find working with addicted patients satisfying, be confident in knowing available resources for addicted patients, believe that addiction is a disease, and be confident in speaking to patients about substance use. Physicians who participated in SIMS were not more likely to practice addiction medicine or to view talking to patients about substance use as clinically relevant. CONCLUSIONS: Undergraduate medical educational interventions combining traditional and experiential programming may render participants better equipped than peers receiving only traditional education to address addiction as physicians. PMID- 22534418 TI - Characterization of negatively charged phospholipids and cell origin of microparticles in women with gestational vascular complications. AB - INTRODUCTION: Gestational vascular complications (GVC) are a major cause of maternal and fetal morbidity which can be potentially reduced by LMWH. Microparticles (MPs) are involved in thrombosis and inflammation. However, characterization and role of MPs in GVC have not been elucidated. MATERIALS AND METHODS: MPs were isolated from non-pregnant women, healthy pregnant women, women with GVC (hypertension or preeclamptic toxemia (PET)) and women with a history of pregnancy complications who were treated with LMWH. MP count, cell origin and expression of negatively charged phospholipids were evaluated. RESULTS: Total numbers of MPs were similar in the study cohorts, with a non-significant trend toward an increase in the pregnant groups, while percentage of MPs bearing negatively charged phospholipids was significantly reduced in all the pregnancy groups. Endothelial CD144-MPs were elevated in the GVC groups compared to the healthy pregnant cohort. Endothelial CD31+/CD41-MPs were decreased in the LMWH group compared to women with PET. Percentage of placental trophoblast MPs was similar in all pregnancy groups and platelet MPs were reduced in healthy pregnant compared to non-pregnant women. Notably, percent of MPs bearing negatively charged phospholipids correlated only with platelet MPs, but not with endothelial, trophoblast or leukocyte MPs. CONCLUSION(S): Presence of negatively charged phospholipids cannot be considered universal characteristics of MPs in pregnancy. MPs may reflect the vascular injury characterizing GVC pathology. PMID- 22534419 TI - Symptom dimensions are associated with progressive brain volume changes in schizophrenia. AB - BACKGROUND: There is considerable variation in progressive brain volume changes in schizophrenia. Whether this is related to the clinical heterogeneity that characterizes the illness remains to be determined. This study examines the relationship between change in brain volume over time and individual variation in psychopathology, as measured by five continuous symptom dimensions (i.e. negative, positive, disorganization, mania and depression). METHODS: Global brain volume measurements from 105 schizophrenia patients and 100 healthy comparison subjects, obtained at inclusion and 5-year follow-up, were used in this study. Symptom dimension scores were calculated by factor analysis of clinical symptoms. Using linear regression analyses and independent-samples t-tests, the relationship between symptom dimensions and progressive brain volume changes, corrected for age, gender and intracranial volume, was examined. Antipsychotic medication, outcome and IQ were investigated as potential confounders. RESULTS: In patients, the disorganization dimension was associated with change in total brain (beta=-0.295, p=0.003) and cerebellar (beta=-0.349, p<0.001) volume. Furthermore, higher levels of disorganization were associated with lower IQ, irrespective of psychiatric status (i.e. patient or control). In healthy comparison subjects, disorganization score was not associated with progressive brain volume changes. CONCLUSION: Heterogeneity in progressive brain volume changes in schizophrenia is particularly associated with variation in disorganization. Schizophrenia patients with high levels of disorganization exhibit more progressive decrease of global brain volumes and have lower total IQ. We propose that these patients form a phenotypically and biologically homogenous subgroup that may be useful for etiological (e.g., genetic) studies. PMID- 22534421 TI - Weight loss and metabolic improvement in morbidly obese subjects implanted for 1 year with an endoscopic duodenal-jejunal bypass liner. AB - OBJECTIVE: To evaluate safety, weight loss, and cardiometabolic changes in obese subjects implanted with the duodenal-jejunal bypass liner (DJBL) for 1 year. BACKGROUND: The DJBL is an endoscopic implant that mimics the duodenal-jejunal bypass component of the Roux-en-Y gastric bypass. Previous reports have shown significant weight loss and improvement in type 2 diabetes for up to 6 months. METHODS: Morbidly obese subjects were enrolled in a single arm, open label, prospective trial and implanted with the DJBL. Primary endpoints included safety and weight change from baseline to week 52. Secondary endpoints included changes in waist circumference, blood pressure, lipids, glycemic control, and metabolic syndrome. RESULTS: The DJBL was implanted endoscopically in 39 of 42 subjects (age: 36 +/- 10 years; 80% female; weight: 109 +/- 18 kg; BMI: 43.7 +/- 5.9 kg/m); 24 completed 52 weeks of follow-up. Three subjects could not be implanted due to short duodenal bulb. Implantation time was 24 +/- 2 minutes. There were no procedure-related complications and there were 15 early endoscopic removals. In the 52-week completer population, total body weight change from baseline was 22.1 +/- 2.1 kg (P < 0.0001) corresponding to 19.9 +/- 1.8% of total body weight and 47.0 +/- 4.4% excess of weight loss. There were also significant improvements in waist circumference, blood pressure, total and low-density lipoprotein cholesterol, triglycerides, and fasting glucose. CONCLUSIONS: The DJBL is safe when implanted for 1 year, and results in significant weight loss and improvements in cardiometabolic risk factors. These results suggest that this device may be suitable for the treatment of morbid obesity and its related comorbidities. This study was registered at www.clinicaltrials.gov (NCT00985491). PMID- 22534423 TI - An important next step in the evolution of our understanding of the value and importance of trauma systems. PMID- 22534422 TI - Mesh reinforcement of pancreatic transection decreases incidence of pancreatic occlusion failure for left pancreatectomy: a single-blinded, randomized controlled trial. AB - INTRODUCTION: Pancreatic leak or fistula is the most frequent complication after left pancreatectomy. We performed a single-blinded, parallel-group, randomized controlled trial comparing stapled left pancreatectomy with stapled left pancreatectomy using mesh reinforcement of the staple line with either Seamguard or Peristrips Dry. METHODS: All patients undergoing left pancreatectomy at a large tertiary hospital were eligible for participation. Patients were randomized to either mesh reinforcement or no-mesh reinforcement intraoperatively after being determined a candidate for resection. Patients were blinded to the result of their randomization for 6 weeks. Primary outcome measure was clinically significant leak as defined by the ISGPF (International Study Group on Pancreatic Fistula) pancreatic leak grading system. RESULTS: One hundred patients were randomized to either mesh (54) or no-mesh (46) reinforcement of their pancreatic transection. There was 1 death in each group. ISGPF grade B and C leaks were seen in 1.9% (1/53) of patients undergoing resection with mesh reinforcement and 20% (11/45) of patients without mesh reinforcement (P = .0007). CONCLUSIONS: Mesh reinforcement of pancreatic transection line significantly reduces the incidence of significant pancreatic fistula in patients undergoing left pancreatectomy. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01359410. PMID- 22534420 TI - Prevalence and correlates of antipsychotic polypharmacy: a systematic review and meta-regression of global and regional trends from the 1970s to 2009. AB - OBJECTIVE: To assess the prevalence and correlates of antipsychotic polypharmacy (APP) across decades and regions. METHODS: Electronic PubMed/Google Scholar search for studies reporting on APP, published from 1970 to 05/2009. Median rates and interquartile ranges (IQR) were calculated and compared using non-parametric tests. Demographic and clinical variables were tested as correlates of APP in bivariate and meta-regression analyses. RESULTS: Across 147 studies (1,418,163 participants, 82.9% diagnosed with schizophrenia [IQR=42-100%]), the median APP rate was 19.6% (IQR=12.9-35.0%). Most common combinations included first generation antipsychotics (FGAs)+second-generation antipsychotics (SGAs) (42.4%, IQR=0.0-71.4%) followed by FGAs+FGAs (19.6%, IQR=0.0-100%) and SGAs+SGAs (1.8%, IQR=0.0-28%). APP rates were not different between decades (1970-1979:28.8%, IQR=7.5-44%; 1980-1989:17.6%, IQR=10.8-38.2; 1990-1999:22.0%, IQR=11-40; 2000 2009:19.2% IQR=14.4-29.9, p=0.78), but between regions, being higher in Asia and Europe than North America, and in Asia than Oceania (p<0.001). APP increased numerically by 34% in North America from the 1980s 12.7%) to 2000s (17.0%) (p=0.94) and decreased significantly by 65% from 1980 (55.5%) to 2000 (19.2%) in Asia (p=0.03), with non-significant changes in Europe. APP was associated with inpatient status (p<0.001), use of FGAs (p<0.0001) and anticholinergics (<0.001), schizophrenia (p=0.01), less antidepressant use (p=0.02), greater LAIs use (p=0.04), shorter follow-up (p=0.001) and cross-sectional vs. longitudinal study design (p=0.03). In a meta-regression, inpatient status (p<0.0001), FGA use (0.046), and schizophrenia diagnosis (p=0.004) independently predicted APP (N=66, R(2)=0.44, p<0.0001). CONCLUSIONS: APP is common with different rates and time trends by region over the last four decades. APP is associated with greater anticholinergic requirement, shorter observation time, greater illness severity and lower antidepressant use. PMID- 22534424 TI - A de novo 1.13 Mb microdeletion in 12q13.13 associated with congenital distal arthrogryposis, intellectual disability and mild dysmorphism. AB - A girl presented with congenital arthrogryposis, intellectual disability and mild bone-related dysmorphism. Molecular workup including the NimbleGen Human CGH 2.1M platform revealed a 1.13 Mb de novo microdeletion on chromosome 12q13.13 of paternal origin. The deletion contains 33 genes, including AAAS, AMRH2, and RARG genes as well as the HOXC gene cluster. At least one gene, CSAD, is expressed in fetal brain. The deletion partially overlaps number of reported benign CNVs and pathogenic duplications. This case appears to represent a previously unknown microdeletion syndrome and possibly the first description in humans of a disease phenotype associated with copy loss of HOXC genes. PMID- 22534425 TI - The use of diffusion tensor images of the corticospinal tract in intrinsic brain tumor surgery: a comparison with direct subcortical stimulation. AB - BACKGROUND: Diffusion tensor imaging (DTI) is now widely used in neurosurgery to preoperatively delineate the course of the pyramidal tract. OBJECTIVE: To evaluate the accuracy of the method by comparison with subcortical electrical stimulation and to evaluate the influence of the distance of the pyramidal tract from the tumor on the resection extent and postoperative clinical deficits. METHODS: A diffusion tensor imaging depiction of the pyramidal tract was used in preoperative planning and intraoperative navigation in 72 cases. In 36 cases, subcortical electrical stimulation was used during the resection. The preoperative tumor-to-tract distance was compared with the stimulation result, the extent of resection, and the short-term postoperative course. RESULTS: A significant nonlinear relationship between the tract-to-tumor distance and the probability of a motor response to subcortical stimulation was observed. The largest preoperatively measured tumor-to-tract distance with a positive stimulation result was 8 mm. Moreover, we observed a trend toward transient postoperative motor deterioration in patients with tumors close to the pyramidal tract. Resection extent was not significantly affected by the tumor-to-tract distance. CONCLUSION: Despite methodological obstacles, reasonable accuracy of the diffusion tensor imaging reconstructions of the pyramidal tracts was confirmed by our study. The occurrence of transient postoperative motor deterioration is higher in patients with tumors located close to the pyramidal tract. PMID- 22534426 TI - Efficacy and safety of endoscopic transventricular lamina terminalis fenestration for hydrocephalus. AB - BACKGROUND: Endoscopic third ventriculostomy (ETV) has become the procedure of choice in the treatment of obstructive hydrocephalus. In certain cases, standard ETV might not be technically possible or may engender significant risk. OBJECTIVE: To present an alternative through the lamina terminalis (LT) by a transventricular, transforaminal approach with flexible neuroendoscopy and to discuss the indications, technique, neuroendoscopic findings, and outcomes. METHODS: Between 1994 and 2010, all patients who underwent endoscopic LT fenestration as an alternative to ETV were analyzed and prospectively followed up. The decision to perform an LT fenestration was made intraoperatively. RESULTS: Twenty-five patients, ranging in age from 7 months to 76 years (mean, 28.1 years), underwent endoscopic LT fenestration. Patients had obstructive hydrocephalus secondary to neurocysticercosis (11 patients), neoplasms (6 patients), congenital aqueductal stenosis (3 patients), and other (5 patients). Thirteen patients (52%) had had at least 1 ventriculoperitoneal shunt that malfunctioned; 6 patients (24%) had undergone a previous endoscopic procedure. Intraoperative findings that led to an LT fenestration were the following: ETV not feasible to perform, basal subarachnoid space not sufficient, or adhesions in the third ventricle. No perioperative complications occurred. The mean follow-up period was 63.76 months. Overall, 19 patients (76%) had resolutions of symptoms, had no evidence of ventriculomegaly, and did not require another procedure. Six (24%) required a ventriculoperitoneal shunt. CONCLUSION: Endoscopic transventricular transforaminal LT fenestration with flexible neuroendoscopy is feasible with a low incidence of complications. It is a good alternative to standard ETV. Adequate intraoperative assessment of ETV success is necessary to identify patients who will benefit. PMID- 22534427 TI - Which individuals make dropout informative? AB - Markers are internal host factors that measure the current disease or recovery status of an individual. Individuals with more advanced disease progression are more likely to drop out, e.g. because they die. Marker data after dropout are missing. Such missingness is certainly not completely at random. A mixed effects model can be used if missingness of the marker data depends on measured marker values only (missing at random). If missingness is not at random, such models yield biased results. We describe various approaches that jointly model the marker development and dropout risk and may eliminate bias. One example of such a model is a random effects selection model. Based on a real data set with frequent follow-up, we compare results from a random effects model and a random effects selection model. Results are remarkably similar. In a simulation study, we investigate how the bias in the parameter estimates from a random effects model depends on the frequency of measurements and the time between the last measurement and the dropout or censoring time. Results from the simulation study confirm that the bias is small if follow-up is frequent. PMID- 22534428 TI - A Bayesian latent model with spatio-temporally varying coefficients in low birth weight incidence data. AB - In spatial epidemiology studies, the effects of covariates on adverse health outcomes could vary over space and time so examining the spatio-temporally varying effects is useful. In particular, the association between covariates and health outcomes could have locally different temporal patterns. In this article, we develop a Bayesian spatio-temporal latent model to identify spatial clusters in each of which covariate effects have homogeneous temporal patterns as well as estimate heterogeneous temporal effects of covariates depending on spatial groups. We compare the proposed model to several alternative models to assess the performance of the proposed model in terms of a range of model assessment measures. Low birth weight incidence data in Georgia for the years 1997-2006 are used. PMID- 22534429 TI - Prospective surveillance of multivariate spatial disease data. AB - Surveillance systems are often focused on more than one disease within a predefined area. On those occasions when outbreaks of disease are likely to be correlated, the use of multivariate surveillance techniques integrating information from multiple diseases allows us to improve the sensitivity and timeliness of outbreak detection. In this article, we present an extension of the surveillance conditional predictive ordinate to monitor multivariate spatial disease data. The proposed surveillance technique, which is defined for each small area and time period as the conditional predictive distribution of those counts of disease higher than expected given the data observed up to the previous time period, alerts us to both small areas of increased disease incidence and the diseases causing the alarm within each area. We investigate its performance within the framework of Bayesian hierarchical Poisson models using a simulation study. An application to diseases of the respiratory system in South Carolina is finally presented. PMID- 22534431 TI - It's time to get serious about ICD-10. PMID- 22534430 TI - Comparison of energy cost in transtibial amputees using "prosthesis" and "crutches without prosthesis" for walking activities. AB - BACKGROUND: In a survey of 100 transtibial amputees (TTA) in the study place, it was noticed that nearly 30% of total activities performed by crutches. It was recorded nearly 52% of the amputees were totally independent, 39% had to use a crutch or cane and only 9% need not used any devices simply because they are unaware of current technology or availability. Out of 39 TTA, nine used crutches only for performing daily activities while 30 used both prosthesis and crutch. Walking is a major activity in lower limb amputees and therefore it is imperative to know the energy cost in both the mobility devices (prosthesis and crutches without prosthesis) for walking activities. OBJECTIVES: The purpose of this study was to quantify and compare the difference in energy cost between the two most commonly used assistive devices (prosthesis and axillary crutches) in adults with Transtibial amputation by indirect calorimetric method at the self-selected speed in plane surface walking. METHODS: Thirty adults who had a unilateral transtibial amputation participated in this study. Oxygen consumption was measured with a Cosmed K4 b(2) oxygen analysis telemetry unit (Rome, Italy) as the participants walked over level ground for 30 meters at a self-selected speed. The variables that were analyzed were VO(2) rate (mL/min), VO(2) cost (mL/kg/m), heart rate (bpm), self-selected walking velocity (m/min) and energy expenditure per minute (Kcal/min). RESULTS: It was observed that VO(2) uptake rate and EE comparisons were highly significant for both prosthesis and crutches without prosthesis walking in adults with transtibial amputation (P<0.025). There was significant difference between prosthesis walking and crutches without prosthesis walking in terms of VO(2) uptake rate (P<0.005) and EE/min (P<0.00001). It was noticed the adults with transtibial amputation using prosthesis walked with 21% more efficient in terms of VO(2) uptake rate and 92% more efficient in terms of EE/min as compared to crutches without prosthesis. CONCLUSIONS: The data on energy cost indicates that all below knee amputee groups walk with less effort by using prosthesis. It may be concluded that crutches without prosthesis may not be used as a permanent rehabilitative measure in transtibial amputations. PMID- 22534432 TI - We are our own worst enemy. PMID- 22534433 TI - Community precepting: benefits for practices. PMID- 22534434 TI - Excision vs. removal of a skin lesion. PMID- 22534435 TI - Prescription refills: patient perspective is important too. PMID- 22534437 TI - Medicare annual wellness visits: don't forget the health risk assessment. PMID- 22534438 TI - ACOs are coming: should you sell your practice? PMID- 22534439 TI - A nursing home documentation tool for more efficient visits. PMID- 22534440 TI - Clinical decision support: using technology to identify patients' unmet needs. PMID- 22534441 TI - ICD-10: what you need to know now. PMID- 22534449 TI - Why I didn't get a paycheck last month. PMID- 22534450 TI - The discovery of potent and selective pyridopyrimidin-7-one based inhibitors of B RafV600E kinase. AB - Herein we describe the discovery of a novel series of ATP competitive B-Raf inhibitors via structure based drug design (SBDD). These pyridopyrimidin-7-one based inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 17, a potent, selective and orally available agent with excellent pharmacokinetic properties and robust tumor growth inhibition in xenograft studies. PMID- 22534452 TI - [Juridical report of lesions: use and abuse]. PMID- 22534451 TI - Mindfulness-based relapse prevention for substance craving. AB - Craving, defined as the subjective experience of an urge or desire to use substances, has been identified in clinical, laboratory, and preclinical studies as a significant predictor of substance use, substance use disorder, and relapse following treatment for a substance use disorder. Various models of craving have been proposed from biological, cognitive, and/or affective perspectives, and, collectively, these models of craving have informed the research and treatment of addictive behaviors. In this article we discuss craving from a mindfulness perspective, and specifically how mindfulness-based relapse prevention (MBRP) may be effective in reducing substance craving. We present secondary analyses of data from a randomized controlled trial that examined MBRP as an aftercare treatment for substance use disorders. In the primary analyses of the data from this trial, Bowen and colleagues (2009) found that individuals who received MBRP reported significantly lower levels of craving following treatment, in comparison to a treatment-as-usual control group, which mediated subsequent substance use outcomes. In the current study, we extend these findings to examine potential mechanisms by which MBRP might be associated with lower levels of craving. Results indicated that a latent factor representing scores on measures of acceptance, awareness, and nonjudgment significantly mediated the relation between receiving MBRP and self-reported levels of craving immediately following treatment. The mediation findings are consistent with the goals of MBRP and highlight the importance of interventions that increase acceptance and awareness, and help clients foster a nonjudgmental attitude toward their experience. Attending to these processes may target both the experience of and response to craving. PMID- 22534453 TI - [False-negative polymerase chain reaction test in cerebrospinal fluid in herpes simplex encephalitis]. PMID- 22534454 TI - [Non-invasive mechanical ventilation in emergencies]. PMID- 22534455 TI - [Arterial hypertension and peripheral artery disease. A dangerous relationship]. PMID- 22534456 TI - Ventral striatum reactivity to reward and recent life stress interact to predict positive affect. AB - BACKGROUND: Stressful life events are among the most reliable precipitants of major depressive disorder; yet, not everyone exposed to stress develops depression. It has been hypothesized that robust neural reactivity to reward and associated stable levels of positive affect (PA) may protect against major depressive disorder in the context of environmental adversity. However, little empirical data exist to confirm this postulation. Here, we test the hypothesis that individuals with relatively low ventral striatum (VS) reactivity to reward will show low PA levels in the context of recent life stress, while those with relatively high VS reactivity will be protected against these potentially depressogenic effects. METHODS: Differential VS reactivity to positive feedback was assessed using blood oxygen level-dependent functional magnetic resonance imaging in a sample of 200 nonpatient young adults. Recent life stress, current depressive symptoms, and PA were assessed via self-report. Linear regression models were used to investigate the moderating effects of VS reactivity on the relationship between recent stress and state PA across participants. RESULTS: Recent life stress interacted with VS reactivity to predict self-reported state PA, such that higher levels of life stress were associated with lower PA for participants with relatively low, but not for those with high, VS reactivity. These effects were independent of age, gender, race/ethnicity, trait PA, and early childhood trauma. CONCLUSIONS: The current results provide empirical evidence for the potentially protective role of robust reward-related neural responsiveness against reductions in PA that may occur in the wake of life stress and possibly vulnerability to depression precipitated by stressful life events. PMID- 22534457 TI - SCN1A affects brain structure and the neural activity of the aging brain. AB - BACKGROUND: The aging of the human brain is accompanied by changes in cortical structure as well as functional activity and variable degrees of cognitive decline. One-third of the observable inter-individual differences in cognitive decline are thought to be heritable. SCN1A encodes the sodium channel alpha subunit and is considered to be a susceptibility gene for several neurological disorders with prominent cognitive deficits. In a recent genome-wide association study the C allele of the SCN1A variant rs10930201 was observed to be significantly associated with poor short-term memory performance. rs10930201 was further observed to be related to differences in neural activity during a working memory task. METHODS: The aim of the present study was to explore whether SCN1A modifies the vulnerability to aging processes of the human brain. Therefore we assessed the interacting effects of the SCN1A vulnerability allele rs10930201 and age in terms of brain activity and brain morphology in 62 healthy volunteers between 21 and 82 years of age. RESULTS: In C allele carriers, activity in the right inferior frontal cortex and the posterior cingulate cortex increased with age. Moreover, exploratory analysis revealed regional effects of rs10930201 on brain structure, indicating reduced gray matter densities in the frontal and insular regions in the C allele carriers. CONCLUSIONS: Collectively, the present results suggest that the SCN1A polymorphism has modulatory effects on brain morphology and vulnerability to age-related alterations in brain activity of cortical regions that subserve working memory. PMID- 22534458 TI - The effect of beta-2 adrenoreceptor agonist inhalation on lungs donated after cardiac death in a canine lung transplantation model. AB - BACKGROUND: It is a matter of great importance in a donation after cardiac death to attenuate ischemia-reperfusion injury (IRI) related to the inevitable warm ischemic time. METHODS: Donor dogs were rendered cardiac-dead and left at room temperature. The dogs were allocated into 2 groups: the beta-2 group (n = 5) received an aerosolized beta-2 adrenoreceptor agonist (procaterol, 350 MUg) and ventilation with 100% oxygen for 60 minutes starting at 240 minutes after cardiac arrest, and the control group (n = 6) received an aerosolized control solvent with the ventilation. Lungs were recovered 300 minutes after cardiac arrest. Recipient dogs underwent left single-lung transplantation to evaluate the functions of the left transplanted lung for 240 minutes after the reperfusion. RESULTS: Oxygenation and dynamic compliance were significantly higher in the beta 2 group than in the control group. The beta-2 group revealed significantly higher levels of cyclic adenosine monophosphate and high-energy phosphates in the donor lung after the inhalation than before it. Histologic findings revealed that the beta-2 group had less edema and fewer inflammatory cells. CONCLUSION: Our results suggest that beta-2 adrenoreceptor agonist inhalation during the pre-procurement period may ameliorate IRI. PMID- 22534459 TI - Plexiform vasculopathy of severe pulmonary arterial hypertension and microRNA expression. AB - BACKGROUND: Recent studies have revealed that microRNAs (miRNAs) play a key role in the control of angiogenesis and vascular remodeling. Specific miRNAs in plexiform vasculopathy of severe pulmonary arterial hypertension (PAH) in humans have not yet been investigated. METHODS: We analyzed expression of miR-143/145 (vascular smooth muscle-specific), miR-126 (endothelial-specific) and related mRNAs in plexiform (PLs) and concentric lesions (CLs), which had been laser microdissected from specimens of formalin-fixed, paraffin-embedded, explanted lungs of PAH patients (n = 12) and unaffected controls (n = 8). Samples were analyzed by real-time polymerase chain reaction, and protein expression was determined by immunohistochemistry. RESULTS: Expression levels of miR-143/145 and its target proteins (e.g., myocardin, smooth muscle myosin heavy chain) were found to be significantly higher in CLs than in PLs, whereas miR-126 and VEGF-A were significantly up-regulated in PLs when compared with CLs, indicating a more prominent angiogenic phenotype of PL. This correlates with a down-regulation of miR-204 as well as an up-regulation of miR-21 in PLs, which in turn corresponds to enhanced cell proliferation. CONCLUSIONS: Our findings show that morphologic changes of plexiform vasculopathy in the end-stage PAH lung are reflected by alterations at the miRNA level. PMID- 22534460 TI - An alternative approach to needle thoracostomy for tension pneumothorax. PMID- 22534461 TI - Post-traumatic empyema: aetiology, surgery and outcome in 125 consecutive patients. AB - INTRODUCTION: Empyema remains a potentially serious condition with multiple etiologies including post-pneumonic, post-resection, and post-traumatic. There are few studies describing the latter. We reviewed our experience at a high volume trauma centre in injured patients with empyema, examining pre-operative status, surgical procedures, pathogens and outcome. METHODS: Retrospective trauma registry review, from 9/01 to 4/10. Empyema was defined as culture positive pleural fluid or purulence at operation. Data collected included demographics, injury mechanism, thoracic injuries, organ dysfunction, pathogens isolated, surgical procedures, outcomes and follow up. RESULTS: One hundred twenty-five consecutive patients with empyema were identified. Average injury severity score and age were 27.3 and 37.2 years respectively; 89.6% were male, 63.2% sustained blunt chest trauma. Time from injury to diagnosis averaged 12.1 days. All underwent decortication; 80% by thoracotomy, the remainder thoracoscopically. At operation over half were mechanically ventilated and 13.6% required vasoactive infusions. Monomicrobial cultures with Gram positive cocci predominating were obtained in 44%, 48% had polymicrobial cultures and 18.4% had a ruptured lung abscess. There were five deaths (4%); two occurring after a ruptured lung abscess. Recurrent empyema occurred in 6.4%, all successfully treated by re operation or catheter drainage. Intensive care and hospital stays were 18.1 and 30.6 days respectively. All survivors achieved resolution of empyema. CONCLUSIONS: Trauma patients with empyema represent a subset of severely injured critically ill patients with diverse pathogens and polymicrobial flora. Appropriate surgical management and specific antibiotic therapy yields excellent results with acceptable risk. A ruptured lung abscess may be the aetiology of the post-traumatic empyema in a subset of patients and may represent an increased operative risk. PMID- 22534462 TI - Retrograde nailing and compression bolts in the treatment of type C distal femoral fractures. AB - INTRODUCTION: This is a prospective study that verifies the usefulness of retrograde intramedullary nailing (IMN) combined with 'independent' compression bolts in the management of type C (AO/OTA classification) fractures of the distal femur. PATIENTS AND METHODS: Within a period of 4 years, 17 patients (mean age of 54 years) with intra-articular fractures of the distal femur (type C according to AO/OTA classification) were treated with retrograde IMN and compression condylar bolts. The patients followed an early mobilisation and weight-bearing protocol. RESULTS: All fractures healed in a mean time of 14.78 weeks with no incidences of malunion, nonunion or infections. No secondary failure of fixation occurred. Partial weight bearing was initiated in average 6.35 weeks postoperatively whilst full weight bearing in 14.6 weeks. The patients regained full extension and 117.22 degrees of mean flexion of the knee joint while the mean New Oxford knee score was 42.05. CONCLUSIONS: In the treatment of type C fractures of the distal femur, the combination of retrograde nailing and 'independent' compression condylar bolt (inserted prior to the nailing) provided a strong fixation that facilitated uncomplicated outcomes and uneventful early mobilisation. PMID- 22534463 TI - Emotive interference during cognitive processing in major depression: an investigation of lower alpha 1 activity. AB - BACKGROUND: Individuals with Major Depressive Disorder (MDD) tend to be more susceptible to distraction by negative emotional material than their non depressed counterparts. This extends to an enhanced vulnerability to interference from mood-congruent stimuli during cognitive processing. The current study investigated the electrophysiological correlates of competing cognitive and emotional processing demands in MDD. METHODS: Event-related alpha activity within the lower alpha 1 band was examined during the online information retention phase of a non-emotive WM task with extraneous emotional stimuli (positive, negative and neutral) presented as background images. EEG activity over posterior parietal cortex was compared between 15 acutely depressed and 16 never depressed right handed women. RESULTS: A valence specific dissociation in lower alpha 1 activity was observed between the two groups, consistent with greater attentional resource allocation to positive distracters in control participants and to negative distracters in MDD participants. No group differences were seen when neutral distracters were displayed. CONCLUSIONS: These results demonstrate that activity within the lower alpha 1 band is sensitive to competing emotional and cognitive processing demands and highlight the importance of posterior parietal regions in depression-related susceptibility to affective distractibility during cognitive processing. PMID- 22534464 TI - The Republic of Chile: an upper middle-income country at the crossroads of economic development and aging. AB - Chile is a developing country with a rapidly expanding economy and concomitant social and cultural changes. It is expected to become a developed country within 10 years. Chile is also characterized as being in an advanced demographic transition. Unique challenges are posed by the intersection of rapid economic development and an aging population, making Chile an intriguing case study for examining the impact of these societal-level trends on the aging experience. This paper highlights essential characteristics of this country for understanding its emerging aging society. It reveals that there is a fundamental lack of adequate and depthful epidemiologic and country-specific research from which to fully understand the aging experience and guide new policies in support of health and well-being. PMID- 22534465 TI - Low-dose non-enhanced CT versus full-dose contrast-enhanced CT in integrated PET/CT scans for diagnosing ovarian cancer recurrence. AB - OBJECTIVE: To evaluate low-dose non-enhanced CT (ldCT) and full-dose contrast enhanced CT (ceCT) in integrated 18F-fluorodeoxyglucose (FDG)-PET/CT studies for restaging of ovarian cancer. MATERIALS AND METHODS: One hundred and twenty women who had undergone treatment for ovarian cancer underwent a conventional PET/CT scans with ldCT, and then ceCT. Two observers interpreted and decided in consensus on the PET/ldCT and PET/ceCT images by a 3-point scale (N: negative, E: equivocal, P: positive) per patient and lesion site. Final diagnoses were obtained by histopathological examinations, or clinical follow-up for at least 6 months. RESULTS: Patient-based analysis showed that the sensitivity, specificity, and accuracy of PET/ceCT was 86.9% (40/46), 95.9% (71/74), and 92.5% (111/120), respectively, whereas those of PET/ldCT were 78.3% (36/46), 95.0% (70/74), and 88.3% (106/120), respectively. All sensitivity, specificity, and accuracy significantly differed between two methods (McNemar test, p<0.0005, p=0.023, and p<0.0001, respectively). The scales of detecting 104 recurrent lesion sites were N:14, E:6, P:84 for PET/ceCT, and N:15, E:17, P:72 for PET/ldCT, respectively. Eleven equivocal and one negative regions by PET/ldCT were correctly interpreted as positive by PET/ceCT. CONCLUSION: PET/ceCT is a more accurate imaging modality with higher confidence for assessing ovarian cancer recurrence than PET/ldCT. PMID- 22534466 TI - Congenital left ventricular wall abnormalities in adults detected by gated cardiac multidetector computed tomography: clefts, aneurysms, diverticula and terminology problems. AB - OBJECTIVES: Our aim was to evaluate congenital left ventricular wall abnormalities (clefts, aneurysms and diverticula), describe and illustrate imaging features, discuss terminology problems and determine their prevalence detected by cardiac CT in a single center. MATERIALS AND METHODS: Coronary CT angiography images of 2093 adult patients were evaluated retrospectively in order to determine congenital left ventricular wall abnormalities. RESULTS: The incidence of left ventricular clefts (LVC) was 6.7% (141 patients) and statistically significant difference was not detected between the sexes regarding LVC (P=0.5). LVCs were single in 65.2% and multiple in 34.8% of patients. They were located at the basal to mid inferoseptal segment of the left ventricle in 55.4%, the basal to mid anteroseptal segment in 24.1%, basal to mid inferior segment in 17% and septal-apical septal segment in 3.5% of cases. The cleft length ranged from 5 to 22 mm (mean 10.5 mm) and they had a narrow connection with the left ventricle (mean 2.5 mm). They were contractile with the left ventricle and obliterated during systole. Congenital left ventricular septal aneurysm that was located just under the aortic valve was detected in two patients (0.1%). No case of congenital left ventricular diverticulum was detected. CONCLUSION: Cardiac CT allows us to recognize congenital left ventricular wall abnormalities which have been previously overlooked in adults. LVC is a congenital structural variant of the myocardium, is seen more frequently than previously reported and should be differentiated from aneurysm and diverticulum for possible catastrophic complications of the latter two. PMID- 22534467 TI - Overexpression of Jumonji AT-rich interactive domain 1B and PHD finger protein 2 is involved in the progression of esophageal squamous cell carcinoma. AB - Jumonji AT-rich interactive domain 1B (JARID1B) and PHD finger protein 2 (PHF2), members of the histone demethylases, have been found to be involved in many types of tumors. However, the expression and prognostic significance of JARID1B and PHF2 in esophageal squamous cell carcinoma (ESCC) still remains unclear. In this study, JARID1B and PHF2 expression were detected on tissue microarrays of ESCC samples in 120 cases using immunohistochemical staining. Our results showed that JARID1B and PHF2 were overexpressed in ESCCs. In addition, a significant correlation was observed between JARID1B nuclear expression level and histological grade (P=0.003). Kaplan-Meier survival analysis showed a tendency that high cytoplasmic expression of JARID1B and PHF2 was associated with decreased overall survival of ESCC patients, whereas JARID1B high expression in the nucleus was associated with high overall survival, although there was no statistical significance. Overall, our data suggest that JARID1B and PHF2 are overexpressed in ESCC and that they may play crucial roles in the course of ESCC initiation and/or progression. PMID- 22534468 TI - Gene therapy for ventricular tachyarrhythmias. AB - Cardiac arrest is the leading cause of death in the United States and other developed countries. Ventricular tachyarrhythmias are the most prominent cause of cardiac arrest, and patients with structural heart disease are at increased risk for these abnormal heart rhythms. Drug and device therapies have important limitations that make them inadequate to meet this challenge. We and others have proposed development of arrhythmia gene therapy as an alternative to current treatment methods. In this review, I discuss the basic mechanisms of ventricular arrhythmias and summarize the literature on the use of gene therapy for ventricular tachyarrhythmias. PMID- 22534469 TI - Prospects for gene transfer for clinical heart failure. AB - Congestive heart failure is an inexorable disease associated with unacceptably high morbidity and mortality. Preclinical results indicate that gene transfer using various proteins is a safe and effective approach for increasing function of the failing heart. In the current review, we provide a summary of cardiac gene transfer in general and summarize findings using adenylyl cyclase 6 as therapeutic gene in the failing heart. We also discuss the potential usefulness of a new treatment for congestive heart failure, paracrine-based gene transfer. PMID- 22534471 TI - A controlled trial of a nurse follow-up dietary intervention on maintaining a heart-healthy dietary pattern among patients after myocardial infarction. AB - BACKGROUND AND RESEARCH OBJECTIVE: Post-myocardial infarction (MI) survivors are at a higher risk of coronary events. Therapeutic lifestyle changes, including dietary modification, have been emphasized as the cornerstone of secondary prevention. This study aimed to examine the effectiveness of a nurse follow-up dietary intervention (NFDI) on post-MI patients' dietary behavioral change (primary outcome) and blood lipid levels (secondary outcome). SUBJECTS AND METHODS: A total of 82 post-MI subjects with borderline dyslipidemia were recruited and randomly allocated to a control group or an intervention group (IG) (n = 41/group). The control group received conventional care and attended a heart health dietary class. The IG received, in addition, a structured 8-week NFDI (including a face-to-face consultation session, a take-home self-management workbook, and fortnightly telephone follow-ups). Data were collected at 3 time points: baseline (T0), 1-week posttest (T1), 3-month posttest (T2). The effect of the intervention was assessed by a self-report questionnaire and blood tests. T test and time-by-group analysis of variance with repeated-measures analysis of variance were used. An intention-to-treat analysis was conducted. RESULTS: Significant positive dietary changes were found among participants of the IG in reduced intake of saturated fat (F = 22.48, P < .001) and salted/preserved food (F = 13.58, P < .001) and increased intake of heart-healthy food (vegetables, fruit, nuts, and whole grains) (F = 40.88, P < .001). Although the results of secondary outcomes, triglyceride, and total cholesterol were not statistically significant, the high-density lipoprotein trend was in the expected direction for the IG (F = 8.982, P = .001). CONCLUSION: This study found positive changes in dietary behavior and an increase in high-density lipoprotein level from participants who undertook the NFDI for self-management in dietary modification. PMID- 22534470 TI - Suppression of endothelial cell activity by inhibition of TNFalpha. AB - INTRODUCTION: TNFalpha is a proinflammatory cytokine that plays a central role in the pathogenesis of rheumatoid arthritis (RA). We investigated the effects of certolizumab pegol, a TNFalpha blocker, on endothelial cell function and angiogenesis. METHODS: Human dermal microvascular endothelial cells (HMVECs) were stimulated with TNFalpha with or without certolizumab pegol. TNFalpha-induced adhesion molecule expression and angiogenic chemokine secretion were measured by cell surface ELISA and angiogenic chemokine ELISA, respectively. We also examined the effect of certolizumab pegol on TNFalpha-induced myeloid human promyelocytic leukemia (HL-60) cell adhesion to HMVECs, as well as blood vessels in RA synovial tissue using the Stamper-Woodruff assay. Lastly, we performed HMVEC chemotaxis, and tube formation. RESULTS: Certolizumab pegol significantly blocked TNFalpha induced HMVEC cell surface angiogenic E-selectin, vascular cell adhesion molecule 1 and intercellular adhesion molecule-1 expression and angiogenic chemokine secretion (P < 0.05). We found that certolizumab pegol significantly inhibited TNFalpha-induced HL-60 cell adhesion to HMVECs (P < 0.05), and blocked HL-60 cell adhesion to RA synovial tissue vasculature (P < 0.05). TNFalpha also enhanced HMVEC chemotaxis compared with the negative control group (P < 0.05) and this chemotactic response was significantly reduced by certolizumab pegol (P < 0.05). Certolizumab pegol inhibited TNFalpha-induced HMVEC tube formation on Matrigel (P < 0.05). CONCLUSION: Our data support the hypothesis that certolizumab pegol inhibits TNFalpha-dependent leukocyte adhesion and angiogenesis, probably via inhibition of angiogenic adhesion molecule expression and angiogenic chemokine secretion. PMID- 22534472 TI - The greater sensitivity of elderly APOE epsilon4 carriers to anticholinergic medications is independent of cerebrovascular disease risk. AB - BACKGROUND: Recent studies found use of anticholinergic medications to be associated with greater performance decrements in older persons who carry an epsilon4 allele of the apolipoprotein E (APOE) gene than in those carrying only epsilon2 or epsilon3 alleles. OBJECTIVES: The present study examined whether the apparently greater behavioral toxicity of anticholinergic drugs in epsilon4 carriers may result from an increased risk of cerebrovascular disease, which is more common in epsilon4 carriers. METHODS: Cross-sectional data were available from 240 elderly community volunteers who had participated in 2 different studies of the cognitive and motor effects of normal aging. As part of these studies, information was gathered on subjects' use of anticholinergic medications (based on an inventory of medications taken within 24 hours of testing), risk of cerebrovascular disease (Framingham Stroke Risk Profile), and APOE genotype. Performance data were also available from measures of general cognitive status (Mini-Mental State Examination), executive function (Trail Making Test), mood (Geriatric Depression Scale), sleep (Pittsburgh Sleep Quality Index), and walking speed. Logistic and linear regression models were used to examine how outcomes differed between genotypes and drug use, independent of the risk of cerebrovascular disease. RESULTS: In persons with a non-epsilon4 genotype, anticholinergic medication use did not significantly affect any of the behavioral measures. By contrast, among epsilon4 carriers, those taking anticholinergic drugs performed significantly worse than did those not taking such drugs on tests of general cognitive status, executive function, mood, and sleep. Adjusting for participants' stroke risk had a minimal effect on these results. CONCLUSIONS: Anticholinergic medication use was associated with poorer performance on measures of cognition, sleep, and mood only in older persons who carried 1 or more epsilon4 alleles of the APOE gene; this effect did not appear to be the result of an increased risk of cerebrovascular disease. PMID- 22534473 TI - A mixed methods approach to identifying factors related to voluntary HIV testing among injection drug users in Shanghai, China. AB - OBJECTIVES: Injection drug use is a major route of HIV transmission in China, yet relatively little is known about why so few injection drug users utilize free HIV testing services. This study aimed to examine barriers to HIV testing and voluntary counseling and testing (VCT) service utilization among injection drug users in Shanghai, China. METHODS: Utilizing mixed methods, we analyzed data from a survey of 540 compulsory drug abuse treatment patients and data from focus groups with 70 service providers and patients. RESULTS: Only 24.4% of patients expressed willingness to be tested for HIV. Willingness to be tested was associated with younger age and more positive attitudes towards condom use. Patients reported several barriers to utilization of voluntary HIV testing services, including lack of information about these services, perceptions of no risk or low-risk for HIV infection, fear of positive results, and the stigma or discrimination that may be experienced by the patient or their family. Having limited skills related to HIV counseling was reported by service providers as the primary barrier to encouraging patients to utilize HIV testing/VCT services. CONCLUSIONS: Special intervention programs targeting injection drug users, their family members, and service providers may increase HIV testing in China. PMID- 22534474 TI - Assessment of BRAF and KIT mutations in Japanese melanoma patients. PMID- 22534475 TI - Osseointegration: the slow delivery of BMP-2 enhances osteoinductivity. AB - Although the placement of dental and orthopedic implants is now generally a safe, reliable and successful undertaking, the functional outcome is less assured in patients whose bone-healing capacity is compromised. To enhance peri-implant osteogenesis in these individuals, BMP-2 could be locally administered. However, neither a free suspension nor an implant-adsorbed depot of the agent is capable of triggering sustained bone formation. We hypothesize that this end could be achieved by incorporating BMP-2 into the three-dimensional crystalline latticework of a bone-mineral like, calcium-phosphate implant coating, where from it would be liberated gradually - as the inorganic layer undergoes osteoclast mediated degradation - not rapidly, as from an implant-adsorbed (two-dimensional) depot. To test this postulate, we compared the osteoinductive efficacies of implant coatings bearing either an incorporated, an adorbed, or an incorporated and an adsorbed depot of BMP-2 at a maxillary site in miniature pigs. The implants were retrieved 1, 2 and 3 weeks after surgery for the histomorphometric analysis of bone formation within a defined 'osteoinductive' space. At each juncture, the volume of newly-formed bone within the osteoinductive space was greatest around implants that bore a coating-incorporated depot of BMP-2, peak osteogenic activity being attained during the first week and sustained thereafter. In the other groups, the temporal course of bone formation was variable, and the peak levels were not sustained. The findings of this study confirm our hypothesis: they demonstrate that we now have at our disposal a means of efficaciously augmenting and expediting peri-implant bone formation. Clinically, this possibility would render the process of implant placement a safer and a more reliable undertaking in patients whose bone-healing capacity is compromised, and would also permit a curtailment of the postoperative recovery period by a forestallment of the mechanical-loading phase. PMID- 22534476 TI - TLR-activated conventional DCs promote gamma-secretase-mediated conditioning of plasmacytoid DCs. AB - Cooperative events between DC subsets involve cell contact and soluble factors. Upon viral challenge, murine pDCs induce cDC cooperation through CD40-CD40L interactions and IL-15 secretion, whereas in humans, the same effect is mediated by IFN-alpha. Conversely, during bacterial infections, pDC maturation may be induced by activated cDCs, although no mechanisms had been described so far. Here, we investigate how human pDCs are "conditioned" by cDCs. Blood-borne DC subsets (cDCs and pDCs) were sorted from healthy donors. IL-3-maintained pDCs were cocultured with LPS-activated, poly (I:C)-activated, or control cDCs [cDC(LPS), cDC(P(I:C)), cDC(CTRL)]. Coculture experiments showed that cDC(LPS) conditioned pDCs up-regulated maturation markers, such as CD25 and CD86, whereas SNs contained higher amounts of IL-6 and CCL19 compared with control conditions. Gene-expression analyses on sorted cDC(LPS) or cDC(P(I:C)) conditioned pDCs confirmed the induction of several genes, including IL-6 and CCL19 and remarkably, several Notch target genes. Further studies using the gamma secretase/Notch inhibitor DAPT and soluble Notch ligands resulted in a significantly reduced expression of canonical Notch target genes in conditioned pDCs. DAPT treatment also hampered the secretion of CCL19 (but not of IL-6) by cDC(LPS) conditioned pDCs. These results reveal the involvement of gamma secretase-mediated mechanisms, including the Notch pathway, in the cell contact dependent communication between human DC subsets. The resulting partial activation of pDCs after encountering with mature cDCs endows pDCs with an accessory function that may contribute to T cell recruitment and activation. PMID- 22534477 TI - Single-incision laparoscopic surgery vs. multiport laparoscopic surgery for colectomy: a meta-analysis of eleven recent studies. AB - BACKGROUND/AIMS: Single-incision laparoscopic colectomy (SILC) is rapidly becoming the focal point of attraction for early adopters of minimally invasive surgery worldwide. The aim of this study was to compare SILC with multiport laparoscopic colectomy (MLC) when implemented by experienced laparoscopic surgeons. METHODOLOGY: Studies and relevant literature regarding the formation of SILC vs. MLC were searched though PubMed and Embase. The volume of bleeding, the rates of conversion /adding trocars and morbidities by using single-incision laparoscopic surgery or multiport laparoscopic surgery were pooled and compared using a meta-analysis. The risk ratios and mean different were calculated with 95% confidence intervals to evaluate the influence of SILC. RESULTS: Eleven recent studies including 800 patients in total were included in this meta analysis. These studies demonstrated that compared to MLC, SILC has the advantage of less bleeding, higher rates of conversion and has similar morbidities. Pooled mean difference of -29.9 (95% CI: -47.05-(-12.74); p<0.001), a pooled RR of 2.04 (95% CI: 1.24-3.36; p<0.01) and a pooled RR of 0.94 (0.72-1.21; p>0.05), respectively. CONCLUSIONS: SILC is a technically realistic and reliable approach with short-term results similar to those obtained with the MLC procedure. More large, prospective, randomized, controlled trials should be conducted to further compare the safety and efficacy of this approach. PMID- 22534478 TI - Prognostic value of expression of Kit67, p53, TopoIIa and GSTP1 for curatively resected advanced gastric cancer patients receiving adjuvant paclitaxel plus capecitabine chemotherapy. AB - BACKGROUND/AIMS: To investigate the role of Kit67, p53, topoisomerase II (TopoII) and glutathione S-transferase P1 (GSTP1) in predicting clinical outcome of advanced gastric cancer patients receiving capecitabine plus paclitaxel chemotherapy. METHODOLOGY: The clinical data and tissue samples from 136 curatively resected advanced gastric cancer patients receiving capecitabine plus paclitaxel in the third affiliated hospital of Kunming medical university from January 2005 to December 2007 were retrospectively collected and analyzed for Kit67, p53, TopoIIa and GSTP1 expressions by immunohistochemistry. The relationships between expressions of the biomarkers and survival were analyzed. RESULTS: p53 expression were associated with the significantly shorter disease free survival (DFS) (p<0.001) and overall survival (OS) (p=0.012) in the curatively resected advanced gastric cancer patients receiving capecitabine plus paclitaxel. Kit67, TopoIIa and GSTP1 expressions were not related to DFS and OS. CONCLUSIONS: p53 expression positive might predict prognosis in gastric cancer patients who underwent curative surgery followed by adjuvant capecitabine plus paclitaxel chemotherapy. A favorable effect of capecitabine plus paclitaxel might therefore be expected in patients that do not express p53. PMID- 22534479 TI - Randomized controlled study of plasma exchange combined with molecular adsorbent re-circulating system for the treatment of liver failure complicated with hepatic encephalopathy. AB - BACKGROUND/AIMS: To evaluate the use of plasma exchange (PE) combined with the molecular adsorbent re-circulating system (MARS) for the treatment of liver failure complicated with hepatic encephalopathy. METHODOLOGY: A prospective randomized controlled study was conducted to compare the therapeutic effect of MARS treatment (MARS group, n=60) with that of PE combined with MARS treatment (PE+MARS group, n=60) in patients with liver failure complicated with hepatic encephalopathy. RESULTS: The serum total bilirubin and blood ammonia levels were significantly decreased compared with pretreatment levels after 3 days of both the MARS treatment (p=0.0001, p<0.001) and PE+MARS treatment (both p<0.0001) and the Glasgow coma scale score was significantly increased (both p<0.0001). The 30 day mortality rate was 10.0% (6/60) in the MARS group and 11.7% (7/60) in the PE + MARS group. The per capita cost of treatment was significantly lower in the PE + MARS group than in the MARS group (p=0.0003). CONCLUSIONS: Both MARS and PE + MARS therapy can safely and effectively be used to treat liver failure complicated with hepatic encephalopathy, but PE + MARS therapy reduces serum total bilirubin level more effectively and is more cost-effective. PMID- 22534480 TI - Full-thickness cholecystectomy with limited lymphadenectomy for gallbladder cancer. AB - Aggressive radical resection is advocated for gallbladder cancer. However, this is a disease of the elderly and some patients have comorbid disease(s) and/or a debilitated condition that may preclude such an aggressive treatment strategy. Here, we describe a minimum radical procedure for gallbladder cancer, termed as "full-thickness cholecystectomy with limited lymphadenectomy". This procedure comprises full-thickness resection of the gallbladder (cholecystectomy combined with removal of the entire cystic plate) and removal of the first-echelon lymph nodes (the pericholedochal and cystic duct node groups). Since 1992, 12 consecutive patients underwent the described procedure for tumors confined to the gallbladder wall and with no gross evidence of distant metastases/nodal disease, resulting in no in-hospital mortality or recurrent disease. The median overall survival was 229 months with a cumulative 5-year survival of 100%. In conclusion, the minimal radical resection procedure is safe and effective for early-stage gallbladder cancer. This less invasive procedure can be applied to patients with advanced age and/or comorbid disease(s), provided that the tumor is apparently confined to the gallbladder wall and has no gross evidence of distant metastases/nodal disease. PMID- 22534481 TI - Structure-based 3D-QSAR models and dynamics analysis of novel N-benzyl pyridinone as p38alpha MAP kinase inhibitors for anticytokine activity. AB - A novel series of anticytokine N-benzyl pyridinone derivatives that targets p38alpha MAP kinase has been analyzed by utilizing a combination of molecular modeling techniques. Statistically significant structure-based 3D-QSAR models were generated for both CoMFA and CoMSIA, and validated through acceptable predictive ability to support both internal and external set of compounds. Structural changes within the protein key backbone residues (Met109 and Gly110), DFG loop position, and side chain movements (Lys53 and Asn114) as resulted by different substituents on these inhibitors were also examined by molecular dynamics simulation. The protocol applied in this study could be helpful to rationalize potent compounds with better inhibitory activity and selectivity profiles against p38alpha MAP kinase. PMID- 22534483 TI - Synchronization between the anterior and posterior cortex determines consciousness level in patients with traumatic brain injury (TBI). AB - Survivors of traumatic brain injury (TBI) often suffer disorders of consciousness as a result of a breakdown in cortical connectivity. However, little is known about the neural discharges and cortical areas working in synchrony to generate consciousness in these patients. In this study, we analyzed cortical connectivity in patients with severe neurocognitive disorder (SND) and in the minimally conscious state (MCS). We found two synchronized networks subserving consciousness; one retrolandic (cognitive network) and the other frontal (executive control network). The synchrony between these networks is severely disrupted in patients in the MCS as compared to those with better levels of consciousness and a preserved state of alertness (SND). The executive control network could facilitate the synchronization and coherence of large populations of distant cortical neurons using high frequency oscillations on a precise temporal scale. Consciousness is altered or disappears after losing synchrony and coherence. We suggest that the synchrony between anterior and retrolandic regions is essential to awareness, and that a functioning frontal lobe is a surrogate marker for preserved consciousness. This article is part of a Special Issue entitled: Brain Integration. PMID- 22534482 TI - Patterned expression of ion channel genes in mouse dorsal raphe nucleus determined with the Allen Mouse Brain Atlas. AB - The dorsal raphe nucleus (DR) is the major source of serotonin (5 hydroxytryptamine, 5-HT) in the forebrain and dysfunction of this midbrain structure is implicated in affective disorders. The DR is composed of several types of 5-HT and non-5-HT neurons and their excitable-membrane properties are heterogeneous and overlapping. In order to understand how these properties may be generated, we examined the mRNA expression patterns of voltage- and ligand-gated ion channels in the DR using the Allen Mouse Brain Atlas. Since DR cytoarchitecture is organized with respect to the midline, we sought to identify genes that were expressed in a pattern with respect to the midline, either enriched or depleted, rather than those that were homogenously expressed throughout the DR. Less than 10% of the screened genes for voltage-gated ion channels showed patterned expression within the DR. Identified genes included voltage-gated sodium channel beta subunits, potassium channels, P/Q-, N-type calcium channels, as well as the alpha2/delta-1 calcium channel. Several voltage gated chloride channels were also identified, although these may function within intracellular compartments. Of the ligand-gated ion channels examined, 20% showed patterned expression. These consisted primarily of glutamate and GABA-A receptor subunits. The identified genes likely contribute to unique excitable properties of different groups of neurons in the DR and may include novel pharmacologic targets for affective disorders. PMID- 22534484 TI - The influences of dark rearing on the transmission characteristics of layer II/III pyramidal cells during the critical period. AB - The characteristics of synaptic plasticity on layer II/III pyramidal cells in different ages of rats have been studied extensively, and dark rearing is one of the important impact factors. To systematically analyze the influence of dark rearing on synaptic plasticity during the critical period of visual development, we studied the characteristics of short-term and long-term synaptic plasticities of layer II/III pyramidal cells of rats in three rearing conditions during P14 to P37. The paired-pulse ratio (PPR) of inhibitory postsynaptic currents (IPSCs) of layer II/III pyramidal cells was effected by both ages and rearing conditions, but the PPR of excitatory postsynaptic currents (EPSCs) did not change obviously. Moreover, long-term synaptic plasticity of rats in the dark rearing condition did not significantly change with age, while it was elevated during P16 and P21 for rats in the normal rearing condition. These results suggest that visual experience can affect the characteristics of short-term and long-term synaptic plasticities. The IPSC/EPSC ratio increased gradually with aging for NR rats, but the ratio slightly decreased for DR rats, which indicates the relative increase of inhibitory components during the critical period of visual development. The characteristics during P35 and P37 of the 30-day dark-reared (30D*N) group had similar trends with the normal-reared rats during P16 and P21, which emphasizes that dark rearing can postpone the timing of the critical period. PMID- 22534485 TI - Can a school based programme in a natural environment reduce BMI in overweight adolescents? AB - Current levels of obesity amongst adolescents may be largely attributed to changes in environmental exposures that place vulnerable youth at risk, yet few studies have incorporated environmental approaches to normalising Body Mass Index (BMI). Our hypothesis is that a live-in school based programme in a natural environment can reduce the BMI of overweight children. The pilot study therefore explores the effects of such a programme on the BMI of adolescents in rural Victoria, Australia. Year 9 students (15 year olds, N = 1021) at a rural school with a physically demanding, 10-month, live-in outdoor programme had their BMIs measured at the beginning and end of the programme. Their observed BMI at the end of the programme was compared to expected BMI (based on adjustment of their initial BMI to account for normal growth using international standards). Participation in the programme reduced the BMI of boys who were in the normal to obese range (chi(2) = 8.57, p = 0.014), but not in girls. For the overweight and obese boys BMI decreased by up to 2.5 kg/m(2). These results suggests that school based environmental interventions may be effective in reducing obesity in adolescents, supporting our hypothesis. Our study is limited by its opportunistic observational nature, but it nevertheless suggests that such a live-in school programme in a natural environment may provide a valuable addition to the list of interventions available to combat the obesity epidemic. Although the programme reduced BMI in boys, the equivocal data for girls means that even an intensive programme such as this struggles to achieve a significant change in BMI across all obese adolescents. Our study nevertheless supports the need for further investigation of the possible contribution of school based programmes in natural environments to interventions to fight the obesity epidemic--because there is no magic bullet. PMID- 22534486 TI - Middle cerebral artery preponderance in ischemic stroke: a coincidence or fate? AB - Stroke is the leading cause of disability and the third leading cause of death in the United States. More than 700,000 persons per year suffer a first-time stroke in the United States, with 20% of these individuals dying within the first year after the stroke. Ischemic stroke accounts for majority of cases of stroke and within this subgroup also, anterior circulation stroke involving the middle cerebral artery (MCA) is the commonest one. There has been no speculation so far as to why this anatomical preponderance to middle cerebral artery exists in thrombotic stroke. While the role of nitric oxide (NO) as a vasculoprotective molecule has been well established, understanding the stimulus for its release and anatomical course of middle cerebral artery can provide a good justification for the clinical finding mentioned above. This bench to bedside correlation not only explains the predilection of ischemic thrombotic stroke to MCA but also highlights the significance of NO as a vasculoprotective molecule in cerebrovascular disease which has not been emphasized earlier. PMID- 22534487 TI - Incidence and survival for hepatic, pancreatic and biliary cancers in England between 1998 and 2007. AB - INTRODUCTION: Hepatic, pancreatic and biliary (HPB) cancers are a group of diverse malignancies managed ideally in specialist centres. This study describes recent patterns in the incidence and survival of HPB cancers in England over a ten year period (1998-2007). METHODS: Data on 99,379 English patients (50,656 males; 48,723 females) diagnosed with HPB cancers between 1998 and 2007 were extracted from the National Cancer Data Repository. Data were divided into six site-specific cancer groups; pancreas, ampulla of Vater, biliary tract, primary liver, gallbladder and duodenum. Age-standardised incidence rates (per 100,000 European standard population, (ASR(E))) were calculated for each of the six groups by year of diagnosis and by socioeconomic deprivation. Survival was estimated using the Kaplan-Meier method. RESULTS: The largest group was pancreatic cancers (63%), followed by primary liver (14%) and biliary cancers (13%). ASR(E) were highest for pancreatic and primary liver cancers whereas cancers of the gallbladder, duodenum and ampulla of Vater had a very low incidence. Over time the incidence of all six groups remained relatively stable, although primary liver cancer increased slightly in males. Incidence rates were higher in males than in females in all groups except gallbladder cancer, and all six groups had a higher incidence in the more deprived quintiles. Overall survival was poor in each of the HPB cancer groups. CONCLUSIONS: HPB tumours are uncommon and are associated with poor long term survival reflecting the late stage at presentation. Incidence patterns suggest variable rates linked to socioeconomic deprivation and highlight a male predominance in all sites except the gallbladder. Identification of high risk populations should be emphasised in initiatives to raise awareness and facilitate earlier diagnosis. PMID- 22534488 TI - Positive predictive value of the International Classification of Diseases, 10th revision, codes to identify osteonecrosis of the jaw in patients with cancer. AB - BACKGROUND: Osteonecrosis of the jaw (ONJ) is an important adverse event associated with therapies suppressing bone turnover, especially in patients with high-dose regimens of antiresorptive therapy, such as cancer patients. Danish health registries are an important resource for monitoring side effects of drugs. The International Classification of Diseases, 10th revision (ICD-10), currently used in Denmark, does not have a specific code for ONJ, making it difficult to monitor its occurrence. OBJECTIVES: To estimate the positive predictive value (PPV) for ONJ of currently used ICD-10 codes, suggested by Danish oral and maxillofacial surgeons, in order to assess feasibility of identification of ONJ cases among cancer patients in the Danish National Registry of Patients (DNRP). METHODS: This study was conducted in northern Denmark (1.8 million inhabitants) among patients with a history of cancer. In Denmark ONJ cases are referred to hospital-based departments of oral and maxillofacial surgery (DOMS). In the DNRP, we identified patients with potential ONJ diagnosed at DOMS (as suggested by a series of ICD-10 codes) from 1 January 2005 to 31 December 2009. To confirm or rule out ONJ, we reviewed hospital records of these patients originating from DOMS. A confirmed ONJ case was defined by the presence of exposed maxillofacial bone for 8 weeks or more, in the absence of previous craniofacial radiation therapy. The PPV was the proportion of confirmed cases among all potential cases. RESULTS: Among 85,910 eligible cancer patients, we identified 91 (0.11%) potential cases of ONJ, of which 18 were confirmed. The overall PPV was 20% (95% CI: 12-29%), ranging from 0% to50% for individual ICD-10 codes. CONCLUSIONS: A majority of cases identified by the suggested ICD-10 codes did not fulfill the criteria for ONJ, even though the potential cases were identified at DOMS. Therefore, reliance on ICD-10 codes, without hospital chart review, will lead to an overestimation of the occurrence of ONJ among cancer patients. PMID- 22534489 TI - Orai1 determines calcium selectivity of an endogenous TRPC heterotetramer channel. AB - RATIONALE: Canonical transient receptor potential 4 (TRPC4) contributes to the molecular composition of a channel encoding for a calcium selective store operated current, I(SOC), whereas Orai1 critically comprises a channel encoding for the highly selective calcium release activated calcium current, I(CRAC). However, Orai1 may interact with TRPC proteins and influence their activation and permeation characteristics. Endothelium expresses both TRPC4 and Orai1, and it remains unclear as to whether Orai1 interacts with TRPC4 and contributes to calcium permeation through the TPRC4 channel. OBJECTIVE: We tested the hypothesis that Orai1 interacts with TRPC4 and contributes to the channel's selective calcium permeation important for endothelial barrier function. METHODS AND RESULTS: A novel method to purify the endogenous TRPC4 channel and probe for functional interactions was developed, using TRPC4 binding to protein 4.1 as bait. Isolated channel complexes were conjugated to anti-TRPC protein antibodies labeled with cy3-cy5 pairs. Forster Resonance Energy Transfer among labeled subunits revealed the endogenous protein alignment. One TRPC1 and at least 2 TRPC4 subunits constituted the endogenous channel (TRPC1/4). Orai1 interacted with TRPC4. Conditional Orai1 knockdown reduced the probability for TRPC1/4 channel activation and converted it from a calcium-selective to a nonselective channel, an effect that was rescued on Orai1 reexpression. Loss of Orai1 improved endothelial cell barrier function. CONCLUSION: Orai1 interacts with TRPC4 in the endogenous channel complex, where it controls TRPC1/4 activation and channel permeation characteristics, including calcium selectivity, important for control of endothelial cell barrier function. PMID- 22534491 TI - Nurses' immediate response to the fall of a hospitalized patient: a comparison of actions and cognitions of experienced and novice nurses. AB - BACKGROUND: Falls represent a significant threat to patient safety for hospitalized patients throughout the world. Little is known, however, regarding nurses' immediate responses to the discovery of a fallen patient. OBJECTIVES: The objective of this study was to perform an experimental examination of experienced and novice nurses' reaction to the discovery of a fallen patient who has sustained a closed head injury. DESIGN: The study was based upon the expert performance approach, which utilizes a mixed methods approach to determining performance characteristics of individuals performing in a variety of domains. SETTING: The study was accomplished using a simulated task environment developed specifically for research concerning the performance of health professionals. PARTICIPANTS: The study included 12 experienced and 10 novice nurses, all of whom were currently employed in critical care settings. METHODS: The study used directly observed performance, which was quantified through the use of direct coding of clinical behaviors and the analysis of verbal reports of thought. RESULTS: The data indicate that experienced participants were not only more likely to call for help but that they were more likely to precede this action by checking for responsiveness, and then, after calling for help, establish the effectiveness of the patient's airway, breathing and circulation. These data confirmed that experienced participants were more likely to engage in the appropriate sequence of actions when faced with this unexpected and highly stressful situation. CONCLUSIONS: Novice nurses' superficial assessment of the situation and subsequent failure to react properly implied an overall pattern of superior performance by the experienced nurses. The results indicated that, compared with novice nurses, experienced nurses are more likely to initiate standard treatment protocols in situations such as the one reported in this study. PMID- 22534490 TI - A novel role for type 1 angiotensin receptors on T lymphocytes to limit target organ damage in hypertension. AB - RATIONALE: Human clinical trials using type 1 angiotensin (AT(1)) receptor antagonists indicate that angiotensin II is a critical mediator of cardiovascular and renal disease. However, recent studies have suggested that individual tissue pools of AT(1) receptors may have divergent effects on target organ damage in hypertension. OBJECTIVE: We examined the role of AT(1) receptors on T lymphocytes in the pathogenesis of hypertension and its complications. METHODS AND RESULTS: Deficiency of AT(1) receptors on T cells potentiated kidney injury during hypertension with exaggerated renal expression of chemokines and enhanced accumulation of T cells in the kidney. Kidneys and purified CD4(+) T cells from "T cell knockout" mice lacking AT(1) receptors on T lymphocytes had augmented expression of Th1-associated cytokines including interferon-gamma and tumor necrosis factor-alpha. Within T lymphocytes, the transcription factors T-bet and GATA-3 promote differentiation toward the Th1 and Th2 lineages, respectively, and AT(1) receptor-deficient CD4(+) T cells had enhanced T-bet/GATA-3 expression ratios favoring induction of the Th1 response. Inversely, mice that were unable to mount a Th1 response due to T-bet deficiency were protected from kidney injury in our hypertension model. CONCLUSIONS: The current studies identify an unexpected role for AT(1) receptors on T lymphocytes to protect the kidney in the setting of hypertension by favorably modulating CD4(+) T helper cell differentiation. PMID- 22534492 TI - Understanding coronary artery disease patients' decisions regarding the use of chelation therapy for coronary artery disease: descriptive decision modeling. AB - BACKGROUND: A considerable number of patients receive chelation therapy to treat their coronary artery disease. However, there is no current empirical evidence to support its use. AIM: To better understand patient's decision-making processes regarding the use of chelation therapy as a treatment for coronary artery disease. METHODS: Based on qualitative interviews with 32 coronary artery disease patients, a taxonomy of decision-related issues, hierarchical decision-model, and survey based on the model were developed. The model was then pilot tested with another group of 30 patients and revised accordingly. The final model was tested with another group of 167 patients (27 current users, 72 previous users, and 68 never users of chelation therapy). The primary examination of the model was to determine the degree to which it successfully identified people who fell within each behavioral group. This was done by dividing the total number of successes by the total number of cases on all paths (or questions in the questionnaire). RESULTS: The most important elements in the decision to use or not use chelation therapy were: previous experience with or learning about chelation therapy, openness to alternative treatments, satisfaction with current level of (traditional) care, physician opinion regarding chelation therapy, costs associated with chelation therapy, perceived access to chelation therapy provider, current state of health (good or bad), and wanting to do 'all one can' for heart health. When tested, the ability of the model to predict the appropriate outcome was nearly 93%. The most salient junctures in the model that led participants to different behavioral outcomes were: considering using non traditional treatments; perceptions regarding potential risks and benefits; cost; and believing that using chelation therapy was 'doing all that they can' to help their heart health. CONCLUSIONS: Descriptive decision-modeling is a useful method to depict cardiac patients' decision-making concerning the use of chelation therapy. It can also assist healthcare providers and policy makers in directing interventions and policy aimed at enhancing the use of evidence-based therapies for cardiac patients. PMID- 22534493 TI - A systematic review: the effects of orientation programs for cancer patients and their family/carers. AB - OBJECTIVES: To assess the effects of information interventions which orient patients and their carers/family to a cancer care facility and the services available within the facility. DESIGN: Systematic review of randomised controlled trials (RCTs), cluster RCTs and quasi-RCTs. DATA SOURCES: MEDLINE, CINAHL, PsycINFO, EMBASE and the Cochrane Central Register of Controlled Trials. METHODS: We included studies evaluating the effect of an orientation intervention, compared with a control group which received usual care, or with trials comparing one orientation intervention with another orientation intervention. RESULTS: Four RCTs of 610 participants met the criteria for inclusion. Findings from two RCTs demonstrated significant benefits of the orientation intervention in relation to reduced levels of distress (mean difference (MD): -8.96, 95% confidence interval (95%CI): -11.79 to -6.13), but non-significant benefits in relation to the levels state anxiety levels (MD -9.77) (95%CI: -24.96 to 5.41). There are insufficient data on the other outcomes of interest. CONCLUSIONS: This review has demonstrated the feasibility and some potential benefits of orientation interventions. There was a low level of evidence to suggest that orientation interventions can reduce distress in patients. However, other outcomes, including patient knowledge recall/satisfaction, remain inconclusive. The majority of trials were subjected to high risk of bias and were likely to be insufficiently powered. Further well conducted and powered RCTs are required to provide evidence for determining the most appropriate intensity, nature, mode and resources for such interventions. Patient and carer-focused outcomes should be included. PMID- 22534494 TI - Competence requirements in intensive and critical care nursing--still in need of definition? A Delphi study. AB - BACKGROUND: Empirical studies in competence are lacking in the field of intensive and critical care nursing. OBJECTIVE: To identify competence requirements, by soliciting the views of intensive care unit nurses and physicians. METHODS: Two rounds of the Delphi method were used in 2006 in Finland. Data were analysed by content analysis and with descriptive statistics. RESULTS: Competence requirements in intensive and critical care nursing can be divided into five main domains: knowledge base, skill base, attitude and value base, nursing experience base and personal base of the nurse. Four of these domains can be found in the existing requirements and one new domain - personal base of the nurse - was identified. CONCLUSIONS: Competence requirements are multidimensional. Earlier descriptions of competence are not sufficient; more comprehensive and cohesive descriptions are needed. The personal base of a nurse should also be included in the competence requirements in intensive and critical care nursing. PMID- 22534495 TI - One evidence based protocol doesn't fit all: brushing away ventilator associated pneumonia in trauma patients. AB - OBJECTIVES: Evaluate change in ventilator associated pneumonia (VAP) and nurse's attitudes, beliefs post implementation of an evidence based practice (EBP) oral hygiene protocol. METHODOLOGY/DESIGN/SETTING: Descriptive pre and post test design in two critical care units in a Level One Trauma Community Hospital. Oral hygiene protocol data was reanalysed to examine effects in medical surgical and trauma subgroups. OUTCOME MEASURES: Oral care practices, attitudes and beliefs among nurses, and VAP rates according to Centers for Disease Control and Prevention guidelines. RESULTS: Trauma rates increased from 6.4% to 10.0% (p=0.346), and medical/surgical rates decreased from 3.3% to 1.0% (p=0.042). Results revealed changes in nurses' beliefs regarding pre-admission colonisation (p=0.027) and having adequate training. Nurses' perception of facility support improved, by having suitable equipment and readily available supplies. Foam swabs with moisture agents at 4hours or less was 88.6% and toothbrush use at 12hours or less was 71%, with significant changes in frequency of oral care post intervention. CONCLUSIONS: Trauma patients present with unique characteristics which compromise oral care. Understanding risk and prognostic factors, mechanisms of transmission and systemic inflammatory response are important when implementing EBP protocols. Nurses' attitudes, beliefs are important, and staff adherence considered when initiating EBP changes. PMID- 22534496 TI - Determination of mercury, cadmium and lead in human milk in Iran. AB - Breast milk contains both essential and nonessential trace elements. Mercury, cadmium and lead are nonessential, potentially toxic heavy metals with hematotoxic, neurotoxic and nephrotoxic properties even at very low concentrations. The objectives of this study were to determine the concentrations of mercury, cadmium and lead in the breast milk of healthy lactating women who were living in Isfahan, Iran. Concentrations of mercury, cadmium and lead were determined by graphite furnace atomic absorption spectrometry in 37 milk samples from healthy lactating women collected on first to sixth postpartum week. Accuracy of the analysis was checked by various methods including the use of reference material. The mean +/- SD of the concentrations of mercury, cadmium and lead in human milk were 0.92 +/- 0.54 MUg/L (range 0.0-2.07 MUg/L), 1.92 +/- 1.04 MUg/L (range 0.45-5.87 MUg/L) and 7.11 +/- 3.96 MUg/L (range 3.06-19.47 MUg/L), respectively. The results of this study showed that the concentrations of mercury, lead and cadmium in the milk samples from lactating women in Isfahan were high, which makes a major public health hazard for the inhabitants, especially neonatal and children, of the industrial locations. The results of the present study indicate a need for establishing safe intake values of heavy metals in human milk. PMID- 22534497 TI - Spatio-temporal variation in the structure of a chromosomal polymorphism zone in the house mouse. AB - Several long-term temporal analyses of the structure of Robertsonian (Rb) hybrid zones in the western house mouse, Mus musculus domesticus, have been performed. Nevertheless, the detection of gradual or very rapid variations in a zone may be overlooked when the time elapsed between periods of study is too long. The Barcelona chromosomal polymorphism zone of the house mouse covers about 5000, km(2) around the city of Barcelona and is surrounded by 40 chromosome telocentric populations. Seven different metacentrics and mice with diploid numbers between 27 and 40 chromosomes and several fusions in heterozygous state (from one to seven) have been reported. We compare the present (period 2008-2010) and past (period 1996-2000) structure of this zone before examining its dynamics in more detail. Results indicate that there is not a Rb race in this area, which is consistent with the proposal that this zone was probably originated in situ, under a primary intergradation scenario. The lack of individuals with more than five metacentrics in heterozygous state in the current period suggests that selection acted against such mice. By contrast, this situation did not occur for mice with fewer than five fusions in heterozygous condition. Changes in human activity may affect the dynamics of gene flow between subpopulations, thus altering the chromosomal composition of certain sites. Although these local variations may have modified the clinal trend for certain metacentrics, the general staggered structure of the zone has not varied significantly in a decade. PMID- 22534498 TI - Pathological gambling severity and co-occurring psychiatric disorders in individuals with and without anxiety disorders in a nationally representative sample. AB - While anxiety disorders (ADs) and pathological gambling (PG) frequently co-occur with each other and other Axis I and Axis II disorders, previous studies have not examined the relative influence of ADs on the co-occurrences between PG severity and non-anxiety psychopathologies. The current study used data from the National Epidemiologic Survey on Alcohol and Related Conditions (N=43,093) to examine the influence of past-year ADs on the associations between past-year PG severity measures based on DSM-IV criteria for PG and non-anxiety psychiatric disorders. The findings revealed that increased PG severity was associated with Axes I and II psychopathology in both the groups with and without ADs. Significant anxiety by-gambling-group interactions were also observed, particularly with respect to mood and personality disorders. The interactions indicate a stronger relationship between PG severity and psychopathology in participants without ADs than in those with ADs. Future research should investigate specific factors contributing to the co-occurrence of anxiety, gambling, and other psychiatric disorders and how the co-occurrences might influence clinically relevant phenomena such as treatment selection or course. PMID- 22534499 TI - Pharmacogenetics of glutamate system genes and SSRI-associated sexual dysfunction. AB - We examined whether polymorphisms in the GRIK2, GRIA3 and GRIA1 genes were associated with selective serotonin reuptake inhibitor (SSRI)-associated sexual dysfunction in 114 participants treated for depression. One polymorphism in GRIA1 (rs1994862) was associated with arousal dysfunction, providing further evidence for the role of GRIA1 in mechanisms underlying SSRI-associated sexual side effects. PMID- 22534500 TI - Adherence styles of schizophrenia patients identified by a latent class analysis of the Medication Adherence Rating Scale (MARS): a six-month follow-up study. AB - The purpose of this study was to examine patients' response profiles to the Medication Adherence Rating Scale (MARS) and to evaluate the potential of response styles as predictors of the future course of psychotic disorders in terms of rehospitalisation and maintenance of medication. A total of 371 psychiatric in-patients with schizophrenia or schizoaffective disorder who were taking part in a naturalistic long-term study completed a German version of the MARS. A Latent Class Analysis (LCA) was performed. Five latent classes of response styles could be identified: "moderately adherent", "critical discontinuers", "good compliers", "careless and forgetful", and "compliant sceptics". Class membership was found to be related to the severity of symptoms, level of functioning, insight into illness, insight into necessity of treatment, treatment satisfaction and medication side effects. At a six-month follow-up appointment, significant differences between the classes persisted. Participants showing a "good compliers" response pattern had a significantly better prognosis in terms of rehospitalisation rate and maintenance of the original medication than "critical discontinuers". Evaluation of the MARS by studying response profiles provides informative results that reach beyond the results obtained by an evaluation by scores. Patients can be classified into adherence groups that are of predictive value for long-term patient outcome. PMID- 22534501 TI - The bidirectional interactions between addiction, behaviour approach and behaviour inhibition systems among adolescents in a prospective study. AB - Internet addiction is a worldwide mental health problem among adolescents. This study aimed to evaluate the prediction of the Behaviour Inhibition System (BIS) and the Behaviour Approach System (BAS) on the occurrence of Internet addiction, and determine whether Internet addiction would make any difference on the development of BIS/BAS among adolescents. Adolescents in grade 7 were recruited to complete assessment for Internet addiction and BIS/BAS. Then, a follow-up was performed 1 year later. The results demonstrated that higher BAS and BAS fun seeking predicted the occurrence of Internet addiction. Adolescents with Internet addiction decreased more on BAS and BIS 1 year later than the non-addiction group. These results suggest that higher BAS and fun seeking are risk factors for Internet addiction among adolescents. Besides, interventions for Internet addiction should pay attention to the disturbed development of BAS and BIS. PMID- 22534502 TI - Finasteride attenuates pathological gambling in patients with Parkinson disease. PMID- 22534503 TI - p53 and p73 expression in esophageal carcinoma correlate with clinicopathology of tumors. AB - BACKGROUND/AIMS: Inactivation of tumor suppressors like p53 and p73 plays an important role in cancer initiation. We explored the clinical significance of p53 and p73 expression in esophageal carcinoma, along with their correlation with clinicopathological parameters of tumors for potential use in clinical evaluation of this disease. METHODOLOGY: In the present study, tumor samples and adjacent normal tissue samples were collected from 37 patients with esophageal cancer and the expression of p53 and p73 was detected by immunohistochemistry and correlated with clinicopathological parameters of tumors. RESULTS: p53 and p73 were more frequently expressed in esophageal cancer than in adjacent normal tissue. Indeed, there was a positive correlation between p53 and p73 expression and esophageal cancer (p<0.05). Analysis of clinicopathological features revealed that p53 expression was correlated with differentiation, distant metastases, and TNM stage (p<0.05) of tumors, but not with gender; age, infiltration depth, tumor size, or lymph node metastasis. In contrast, p73 expression was correlated only with distant metastases (p<0.05). CONCLUSIONS: Increased expression of p53 and p73 in esophageal carcinoma may serve as an indicator of tumor severity. Detection of these proteins in future studies may help understand the mechanisms of development, invasion and metastasis in esophageal cancer. PMID- 22534504 TI - Genome-wide DNA methylation analysis reveals novel epigenetic changes in chronic lymphocytic leukemia. AB - We conducted a genome-wide DNA methylation analysis in CD19 (+) B-cells from chronic lymphocytic leukemia (CLL) patients and normal control samples using reduced representation bisulfite sequencing (RRBS). The methylation status of 1.8 2.3 million CpGs in the CLL genome was determined; about 45% of these CpGs were located in more than 23,000 CpG islands (CGIs). While global CpG methylation was similar between CLL and normal B-cells, 1764 gene promoters were identified as being differentially methylated in at least one CLL sample when compared with normal B-cell samples. Nineteen percent of the differentially methylated genes were involved in transcriptional regulation. Aberrant hypermethylation was found in all HOX gene clusters and a significant number of WNT signaling pathway genes. Hypomethylation occurred more frequently in the gene body including introns, exons, and 3'-UTRs in CLL. The NFATc1 P2 promoter and first intron was found to be hypomethylated and correlated with upregulation of both NFATc1 RNA and protein expression levels in CLL suggesting that an epigenetic mechanism is involved in the constitutive activation of NFAT activity in CLL cells. This comprehensive DNA methylation analysis will further our understanding of the epigenetic contribution to cellular dysfunction in CLL. PMID- 22534506 TI - Sequence type 101 (ST101) as the predominant carbapenem-non-susceptible Klebsiella pneumoniae clone in an acute general hospital in Italy. PMID- 22534505 TI - Antioxidant micronutrients in the critically ill: a systematic review and meta analysis. AB - INTRODUCTION: Critical illness is characterized by oxidative stress, which is a major promoter of systemic inflammation and organ failure due to excessive free radical production, depletion of antioxidant defenses, or both. We hypothesized that exogenous supplementation of trace elements and vitamins could restore antioxidant status, improving clinical outcomes. METHODS: We searched computerized databases, reference lists of pertinent articles and personal files from 1980 to 2011. We included randomized controlled trials (RCTs) conducted in critically ill adult patients that evaluated relevant clinical outcomes with antioxidant micronutrients (vitamins and trace elements) supplementation versus placebo. RESULTS: A total of 21 RCTs met inclusion criteria. When the results of these studies were statistically aggregated (n = 20), combined antioxidants were associated with a significant reduction in mortality (risk ratio (RR) = 0.82, 95% confidence interval (CI) 0.72 to 0.93, P = 0.002); a significant reduction in duration of mechanical ventilation (weighed mean difference in days = -0.67, 95% CI -1.22 to -0.13, P = 0.02); a trend towards a reduction in infections (RR= 0.88, 95% CI 0.76 to 1.02, P = 0.08); and no overall effect on ICU or hospital length of stay (LOS). Furthermore, antioxidants were associated with a significant reduction in overall mortality among patients with higher risk of death (>10% mortality in control group) (RR 0.79, 95% CI 0.68 to 0.92, P = 0.003) whereas there was no significant effect observed for trials of patients with a lower mortality in the control group (RR = 1.14, 95% 0.72 to 1.82, P = 0.57). Trials using more than 500 MUg per day of selenium showed a trend towards a lower mortality (RR = 0.80, 95% CI 0.63 to 1.02, P = 0.07) whereas trials using doses lower than 500 MUg had no effect on mortality (RR 0.94, 95% CI 0.67 to 1.33, P = 0.75). CONCLUSIONS: Supplementation with high dose trace elements and vitamins may improve outcomes of critically ill patients, particularly those at high risk of death. PMID- 22534507 TI - Trending 7 years of in vitro activity of tigecycline and comparators against Gram positive and Gram-negative pathogens from the Asia-Pacific region: Tigecycline Evaluation Surveillance Trial (TEST) 2004-2010. AB - A total of 10948 clinical isolates was collected throughout the Asia-Pacific region as part of the Tigecycline Evaluation Surveillance Trial (TEST) during 2004-2010, consisting of 7549 Gram-negative and 3399 Gram-positive pathogens. Susceptibility trends for all species demonstrated several significant species dependent susceptibility changes to multiple antibiotics. The most notable was minocycline, for which significant decreases in susceptibility (P<0.001) were observed for six of the ten species studied. In contrast, statistically significant susceptibility changes for tigecycline were observed in only two of the ten species, namely Klebsiella pneumoniae and Serratia marcescens. Seven years following the introduction of tigecycline into clinical use, this agent remains highly active against a wide range of pathogens from the Asia-Pacific region. PMID- 22534508 TI - Curing bacteria of antibiotic resistance: reverse antibiotics, a novel class of antibiotics in nature. AB - By screening cultures of soil bacteria, we re-discovered an old antibiotic (nybomycin) as an antibiotic with a novel feature. Nybomycin is active against quinolone-resistant Staphylococcus aureus strains with mutated gyrA genes but not against those with intact gyrA genes against which quinolone antibiotics are effective. Nybomycin-resistant mutant strains were generated from a quinolone resistant, nybomycin-susceptible, vancomycin-intermediate S. aureus (VISA) strain Mu 50. The mutants, occurring at an extremely low rate (<1 * 10(-11)/generation), were found to have their gyrA genes back-mutated and to have lost quinolone resistance. Here we describe nybomycin as the first member of a novel class of antibiotics designated 'reverse antibiotics'. PMID- 22534509 TI - Agarose-gel electrophoresis for the quality assurance and purity of heparin formulations. AB - The adulteration of raw heparin (Hep) with a synthetic oversulfated chondroitin sulfate (OSCS) not found in nature produced in 2007-2008 a global crisis giving rise to the development of additional, new and specific methods for its quality assurance and purity. In this study, a simple and sensitive agarose-gel electrophoresis method has been developed for the visualization of OSCS in Hep samples along with other natural glycosaminoglycans possibly present as "process related impurities", in particular dermatan sulfate (DS) and chondroitin sulfate (CS). Agarose-gel electrophoresis under non-conventional conditions is able to separate OSCS from Hep with its two components, the slow-moving and fast-moving species, DS and CS by performing separation for 15 h (overnight) and under high voltage (100 mA, ~200 V). Densitometric scanning enabled us to calculate a limit of detection of ~0.5 MUg OSCS with a linear behaviour from 0.1 to 5 MUg, comparable to CS/DS. Contaminated samples from Hep manufacturers were analyzed and quantitative data were found comparable to previous studies. Due to its capacity to process many samples in a single run and to the equipment commonly available in laboratories, this analytical method would be suitable for the identification and quantification of contamination by other polysaccharides, in particular OSCS and DS, within Hep preparations and formulations. PMID- 22534510 TI - The protective role of vitamin E on gill and liver tissue histopathology and micronucleus frequencies in peripheral erythrocytes of Oreochromis niloticus exposed to deltamethrin. AB - Deltamethrin, is a commonly used pyrethroid pesticide. Vitamin E is a antioxidant that plays an important role in protecting cells against toxicity by inactivating free radicals generated following pesticides exposure. Therefore, it was evaluated whether deltamethrin induced histopathological changes and nuclear abnormalities using micronucleus test in Oreochromis niloticus, and the possible protective effect of vitamin E against deltamethrin inducing adverse effects in O. niloticus were investigated. Fish was fed with no pesticide+control diet, no pesticide+vitamin E-supplemented diet, 1.45MUg/l deltamethrin+control diet, 1.45MUg/l deltamethrin+vitamin E-supplemented diet for 30 days. Pesticide and diet quality made an impact on histopathological lesions. In treatments of deltamethrin, group fed with control diet showed much greater damage in comparison with group fed with vitamin E supplemented diet. Vitamin E decreased some histopathological changes induced by deltamethrin, but did not confer complete protection. Deltamethrin treatment has been shown to results in a significant increase in the frequency of micronucleus. However, coadministration of deltamethrin and vitamin E showed decrease in the frequency of micronucleus as compared to deltamethrin treated fish. Our results indicate that, the MN assay and histopathology can be used as bioassays for monitoring pollution in aquatic medium. On the other hand, it was observed that vitamin E decreased the genotoxicity and histopathological changes induced by deltamethrin. PMID- 22534511 TI - [Histologic risk factors of basal cell carcinoma of the face, about 184 cases]. AB - BACKGROUND: Basal cell carcinoma is the most common type of skin cancer in humans. OBJECTIVES: The aim of our study was to determine the histologic risk factors involved in recurrence of basal cell carcinomas of the face. PATIENTS AND METHODS: We conducted a retrospective study of patients with primary basal cell carcinoma (BCC) of the face treated between March 2003 and December 2005. We analyzed the size of lateral and deep margins of tumor, histologic subtype, perineural invasion, and ulcerations. Clinical follow-up was observed until June 2011. RESULTS: We note that 184 cases of BCC were included. Eleven recurrences occurred during the follow-up, i.e. 6%. The population was divided into two groups according to histologic safety margins (1 mm for all basal cell carcinomas, 0.8 mm for nodular and 2 mm for aggressive-growth (AG-BCC) subtypes). There was a significant difference between groups in regards to cancer recurrence. Tumor size above 2 cm and presence of perineural invasion increased the risk of recurrence. DISCUSSION: Low histological safety margins appear to be critical on tumor recurrence. Depending on the tumor characteristics, and the patient, we advocate a re-excision in cases of histological safety margins inferior to 0.8 mm for the nodular subtypes and 2 mm for aggressive subtypes. Tumor size, and perineural invasion should be taken into consideration so as to make a well-informed decision between re-excision and a watching strategy in critical cases. PMID- 22534512 TI - [Two anomalous muscles of a forearm revealed by ulnar nerve compressions, a Double Crush syndrome]. AB - This article describes the concomitant presence of two anomalous muscles on a left forearm in a 40-year-old man. The anconeus epitrochlearis muscle was responsible for a cubital tunnel syndrome and the unusual origin of the flexor digiti minimi brevis muscle was responsible for a compartment syndrome with ulnar nerve compression at the level of Guyon's canal during effort diagnosed by MRI. Resection of these muscles relieved the symptoms and allowed the patient to return to work. PMID- 22534513 TI - Cardiovascular autonomic function and vibration perception threshold in type 2 diabetes mellitus. AB - OBJECTIVE: The aim of this study was to compare cardiovascular autonomic function tests (AFT) and vibration perception threshold (VPT) of patients with type 2 diabetes mellitus (T2DM) with controls. RESEARCH DESIGN/METHODS: The study was conducted on 60 diabetic patients comparing with 30 controls. The cardiovascular AFT and VPT were assessed in both groups. RESULTS: Among cardiovascular AFT, E:I ratio [1.24 (1.2-1.32) vs 1.3 (1.24-1.4), p=0.001], and Valsalva ratio [1.28 (1.22-1.4) vs 1.6 (1.5-1.73), p=0.001], the indicators of parasympathetic reactivity were reduced in T2DM. Rise in DBP during handgrip, an indicator of sympathetic reactivity was lower in T2DM [12 (10-14) vs 16 (14-18) mmHg, p=0.001] whereas, fall in SBP during head up tilt [4 (4-8) vs 5 (4-8) mmHg] was comparable. VPT (somatic sensation) was comparable between T2DM and control. CONCLUSION: Autonomic involvement is more marked than somatic, and parasympathetic involvement is more marked than the sympathetic, possibly reflecting severity and chronological pattern of their involvement. PMID- 22534514 TI - Urine alpha-Glutathione S-transferase, systemic inflammation and arterial function in juvenile type 1 diabetes. AB - BACKGROUND: Despite marked improvement in therapy and monitoring of patients with insulin-dependent (type 1) diabetes, diabetic nephropathy remains a serious complication, with subsequent end-stage renal disease in about 20% of cases. OBJECTIVE: To investigate in young patients with type 1 diabetes whether urine alpha-Glutathione S-transferase to creatinine ratio (alpha-GST:crea) relates to markers of systemic inflammation and subclinical vasculopathy. DESIGN: Children and adolescents (median age and diabetes duration 14 and 6 years, respectively) with type 1 diabetes screened in a previous study for proximal tubular (urine alpha-GST:crea ratio) and renal (plasma creatinine, cystatin C glomerular filtration rate (GFR), and timed urine albumin excretion rate (AER)) function were, within the same timeframe, also investigated for vascular (blood pressure, carotid artery intima-media thickness (IMT) and compliance (CAC), brachial artery flow-mediated dilatation (FMD) and plasma cyclic guanosine monophosphate (cGMP) and inflammatory (C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF alpha)) profiles. Exposure to environmental tobacco smoke (ETS) was assessed through questionnaire (n=67 respondents). RESULTS: None of the patients (n=69) had overt renal insufficiency. AER correlated with age (p=0.01, r=0.3), diabetes duration (p=0.02, r=0.3), FMD (p=0.04, r=-0.3, n=52), CAC (p=0.03, r=-0.3, n=62) and cGMP (p=0.01, r=-0.3, n=59). alpha-GST:crea was lower (p=0.03) in patients than in controls. alpha-GST:crea appeared to be particularly lower in older patients (p=0.004, r=-0.34 vs age), in those with worse diabetic control (p=0.03, r=-0.26 vs HbA1c), and in those with lower carotid artery elasticity (p=0.017, r=0.3 vs CAC). Although ETS had no direct significant impact on alpha-GST:crea, alpha-GST:crea correlated with FMD only in patients with ETS (r=0.5, p=0.009, n=13). alpha-GST:crea showed positive association with TNF-alpha (p=0.01, r=0.3). CONCLUSION: In children and adolescents with type 1 diabetes, lower levels of urine excretion of alpha-GST:crea appear to be associated with decreasing elasticity and endothelial vasomotor function of peripheral arteries, especially in patients with ETS. In contrast, higher levels of alpha-GST:crea are more common in patients with elevated markers of systemic inflammation. Large scale prospective studies are needed to clarify the meaning and mechanisms of this association. PMID- 22534515 TI - Sheep experimentally infected with a human isolate of Anaplasma phagocytophilum serve as a host for infection of Ixodes scapularis ticks. AB - Anaplasma phagocytophilum, first identified as a pathogen of ruminants in Europe, has more recently been recognized as an emerging tick-borne pathogen of humans in the U.S. and Europe. A. phagocytophilum is transmitted by Ixodes spp., but the tick developmental cycle and pathogen/vector interactions have not been fully described. In this research, we report on the experimental infection of sheep with the human NY-18 isolate of A. phagocytophilum which then served as a host for infection of I. scapularis nymphs and adults. A. phagocytophilum was propagated in the human promyelocytic cell line, HL-60, and the infected cell cultures were then used to infect sheep by intravenous inoculation. Infections in sheep were confirmed by PCR and an Anaplasma-competitive ELISA. Clinical signs were not apparent in any of the infected sheep, and only limited hematologic and mild serum biochemical abnormalities were identified. While A. phagocytophilum morulae were rarely seen in neutrophils, blood film evaluation revealed prominent large granular lymphocytes, occasional plasma cells, and rare macrophages. Upon necropsy, gross lesions were restricted to the lymphoid system. Mild splenomegaly and lymphadenomegaly with microscopic evidence of lymphoid hyperplasia was observed in all infected sheep. Female I. scapularis that were allowed to feed and acquire infection on each of the 3 experimentally infected sheep became infected with A. phagocytophilum as determined by PCR of guts (80-87%) and salivary glands (67-100%). Female I. scapularis that acquired infection as nymphs on an experimentally infected sheep transmitted A. phagocytophilum to a susceptible sheep, thus confirming transstadial transmission. Sheep proved to be a good host for the production of I. scapularis infected with this human isolate of A. phagocytophilum, which can be used as a model for future studies of the tick/pathogen interface. PMID- 22534516 TI - Another conversation with Stella. PMID- 22534518 TI - Impact of the combination of an angiotensin II receptor blocker and low-dose hydrochlorothiazide on patients with morning hypertension. PMID- 22534517 TI - Antihypertensive effect of gomisin A from Schisandra chinensis on angiotensin II induced hypertension via preservation of nitric oxide bioavailability. AB - Gomisin A (GA) is a small molecular weight lignan present in Schisandra chinensis, and has been demonstrated to have vasodilatory activity. In the present study, we investigated the effect of GA on blood pressure (BP) in angiotensin II (Ang II)-induced hypertensive mice. C57/BL6 mice infused subcutaneously with Ang II (1 and 2 MUg kg-1 per min for 2 weeks) showed an increase in BP with a decrease in nitric oxide (NO) metabolites in plasma, and a negative correlation between these two parameters was demonstrated. In the thoracic aorta from Ang II-induced hypertensive mice, a decrease in vascular NO that was accompanied by a diminution of phosphorylated endothelial nitric oxide synthase (eNOS), as well as by increased reactive oxygen species (ROS) production, was demonstrated. These alterations in BP, eNOS phosphorylation and ROS production in the vasculature of Ang II-treated mice were markedly and dose dependently reversed by simultaneous administration of GA (2 and 10 MUg kg-1 per min). In addition, Ang II-induced ROS production in cultured vascular cells such as endothelial cells and vascular smooth muscle cells was markedly attenuated by GA. These results suggested that GA attenuated the increase in BP via preservation of vascular NO bioavailability not only by inhibiting ROS production but also by preventing the impairment of eNOS function in the vasculature of Ang II-induced hypertensive mice. PMID- 22534519 TI - Association of early systolic blood pressure response to exercise with future cardiovascular events in patients with uncomplicated mild-to-moderate hypertension. AB - The relationship between blood pressure (BP) response during exercise and future cardiovascular events remains unclear. We assessed the association between an increase in early systolic BP (SBP) during exercise tests and future cardiovascular events in patients with sustained hypertension (sHT). Between 2002 and 2005, we enrolled 300 patients newly diagnosed with mild-to-moderate sHT without complications from the Asan Ambulatory Blood Pressure Monitoring registry. All the patients successfully performed treadmill tests, achieving target heart rate according to the Naughton/Balke protocol. The patients were divided into quartiles according to their SBP at 8 min (7.4 metabolic equivalent tasks). The primary outcome was the composite of all-cause death, new-onset ischemic heart disease and stroke. The 5-year survival rates did not differ significantly among quartiles 1-4 (100% vs. 96.6% vs. 94.4% vs. 98.3%, P=0.211). Relative to quartile 1, the 5-year event-free survival rates were significantly lower in patients in quartiles 3 (86.9% vs. 98.3%, P=0.023) and 4 (88.2% vs. 98.3%, P=0.023). After multivariable adjustment for covariates, the risk for the composite end point was higher for patients in quartiles 3 (Hazard ratio (HR) 4.69, 95% confidence interval (CI) 1.28-17.13, P=0.020) and 4 (HR 3.65, 95% CI 0.92-14.50, P=0.065) than in quartiles 1 and 2. Cardiovascular risk was significantly higher in patients with stage 4 SBP (>180 mm Hg) even after adjustment (HR 4.00, 95% CI 1.19-13.44, P=0.025). Increased submaximal SBP response to exercise may be a predictor of future cardiovascular events in patients with mild-to-moderate sHT. PMID- 22534521 TI - Does angiotensin II cross the blood-brain barrier? PMID- 22534520 TI - Prognostic significance of the brachial-ankle pulse wave velocity in patients with essential hypertension: final results of the J-TOPP study. AB - Brachial-ankle pulse wave velocity (baPWV) is a new tool for measuring arterial stiffness. The prognostic significance of this measure, however, is not fully established. We initiated a multicenter cohort study to examine the prognostic significance of baPWV in patients with essential hypertension in 2002. After baseline measurements were obtained, 662 previously untreated patients (mean age 60+/-12 years, mean blood pressure 156+/-19/94+/-12 mm Hg, 45% men) underwent long-term follow-up according to the current hypertension treatment guidelines. During the follow-up period (mean: 3 years, range: 3 months-8 years), 24 cardiovascular events were observed. The subjects were divided into high and low baPWV groups according to the median value (1750, cm s(-1)). Patients in the high baPWV group were older and had a lower body mass index, higher blood pressure, faster heart rate and higher fasting glucose and plasma creatinine concentrations compared with those in the low baPWV group. Cardiovascular morbidities per 1000 person-years for the high and low baPWV groups were 17.48 and 6.38, respectively (P<0.05), and the 8-year cardiovascular event-free survival rates were 78.2% and 93.5%, respectively (log-rank test, P=0.01). A multivariate Cox proportional hazard analysis showed that high baPWV compared with low baPWV was associated with a significantly poorer outcome (hazard ratio (HR) 2.97; 95% CI: 1.006 9.380). In conclusion, baPWV is an independent risk factor for future cardiovascular events in patients with essential hypertension. PMID- 22534522 TI - Comparison of hypertension management between cancer survivors and the general public. AB - Proper management of hypertension is important for better survival and quality of life of cancer survivors who have hypertension. We aimed to compare hypertension management between cancer survivors and the general population. A nationwide, multicenter, cross-sectional survey was administered to adult cancer patients, currently receiving treatment or follow-up, who had been diagnosed with hypertension. Comparison group was selected from among participants in the health behavior survey of the third Korean National Health and Nutrition Examination Survey. Self-reported hypertension management was surveyed, including antihypertensive medication adherence, frequency of blood pressure (BP) monitoring and perceived BP control. Multivariate logistic regression analysis was used to evaluate the relationship between cancer survivorship and each outcome measure. Compared with the general population, cancer survivors were more likely to report full adherence (92.7% vs. 73.0%; adjusted odds ratio (aOR)=3.45; 95% confidence interval (CI), 2.08-5.73), more frequent BP measurement (>= 24 per year: 50.1% vs. 24.7%; aOR=2.51; 95% CI, 1.83-3.46), and very good perceived BP control (60.8% vs. 26.2%; aOR=4.34; 95% CI, 3.13-6.02). Cancer survivors appear to be better with antihypertensive medication adherence and BP monitoring than those without cancer, and as a result, they appear to be under better BP control. However, several methodological limitations of our study prompt further research on this issue. PMID- 22534523 TI - Carotid extra-medial thickness in childhood: early life effects on the arterial adventitia. AB - OBJECTIVE: Structural modification of the arterial adventitia may be an early event in atherosclerosis. Carotid extra-medial thickness is a new measure of arterial adventitial thickness. We examined the association of cardiovascular risk factors with extra-medial thickness, in childhood. METHODS: Carotid extra medial thickness was assessed by high-resolution ultrasound in 389 non-diabetic children aged 8-years. A non-fasting blood sample was collected from 314 participants. Associations of gender, age, lipoproteins, blood pressure, BMI z score, waist:height ratio and parental history of early vascular disease, with extra-medial thickness were examined. RESULTS: Carotid extra-medial thickness was lower in girls (r=-.163, P=.001) and directly associated with systolic (r=.128, P=.009), diastolic blood pressure (r=.130, P=.009), and height (r=.170, P=.0006). These associations remained after adjustment for carotid intima-media thickness. In multivariable analysis including carotid intima-media thickness, only gender and height were significantly associated with carotid extra-medial thickness. In gender-stratified analysis, the strongest associations with extra-medial thickness were BMI z-score (r=.181, P=.01), height (r=.210, P=.003) and diastolic blood pressure (r=.167, P=.02) for boys; and systolic blood pressure (r=.153, P=.03) and parental history of premature cardiovascular disease (r=.139, P=.05) for girls. The association of BMI z-score with extra-medial thickness differed by gender (P-interaction=.04). CONCLUSIONS: Carotid extra-medial thickness is independently associated with gender and height in childhood. Extra-medial thickness may provide important information concerning early arterial health, particularly related to the arterial adventitia. PMID- 22534524 TI - Malaria. PMID- 22534525 TI - The numbers game. PMID- 22534526 TI - Drug development: Holding out for reinforcements. PMID- 22534527 TI - Public health: Death at the doorstep. PMID- 22534528 TI - Perspectives: The missing pieces. PMID- 22534529 TI - Vaccines: The take-home lesson. PMID- 22534530 TI - Vector control: The last bite. PMID- 22534531 TI - STAT6 and LRP1 polymorphisms are associated with food allergen sensitization in Mexican children. PMID- 22534532 TI - Promoter polymorphisms in CHI3L1 are associated with asthma. PMID- 22534533 TI - The effect of montelukast, budesonide alone, and in combination on exercise induced bronchoconstriction. PMID- 22534534 TI - Protection from childhood asthma and allergy in Alpine farm environments-the GABRIEL Advanced Studies. AB - BACKGROUND: Studies on the association of farm environments with asthma and atopy have repeatedly observed a protective effect of farming. However, no single specific farm-related exposure explaining this protective farm effect has consistently been identified. OBJECTIVE: We sought to determine distinct farm exposures that account for the protective effect of farming on asthma and atopy. METHODS: In rural regions of Austria, Germany, and Switzerland, 79,888 school aged children answered a recruiting questionnaire (phase I). In phase II a stratified random subsample of 8,419 children answered a detailed questionnaire on farming environment. Blood samples and specific IgE levels were available for 7,682 of these children. A broad asthma definition was used, comprising symptoms, diagnosis, or treatment ever. RESULTS: Children living on a farm were at significantly reduced risk of asthma (adjusted odds ratio [aOR], 0.68; 95% CI, 0.59-0.78; P< .001), hay fever (aOR, 0.43; 95% CI, 0.36-0.52; P< .001), atopic dermatitis (aOR, 0.80; 95% CI, 0.69-0.93; P= .004), and atopic sensitization (aOR, 0.54; 95% CI, 0.48-0.61; P< .001) compared with nonfarm children. Whereas this overall farm effect could be explained by specific exposures to cows, straw, and farm milk for asthma and exposure to fodder storage rooms and manure for atopic dermatitis, the farm effect on hay fever and atopic sensitization could not be completely explained by the questionnaire items themselves or their diversity. CONCLUSION: A specific type of farm typical for traditional farming (ie, with cows and cultivation) was protective against asthma, hay fever, and atopy. However, whereas the farm effect on asthma could be explained by specific farm characteristics, there is a link still missing for hay fever and atopy. PMID- 22534536 TI - Durability of long-term outcome of laparoscopic Nissen - comparison of the results at 5 and 10 years after surgery . AB - BACKGROUND/AIMS: It is not sufficiently clear whether the continued good outcomes obtained with laparoscopic Nissen operation after a short follow-up will continue after several years. The aim of our re-search was to make a comparative analysis of the quality of life and presence of symptoms 5 and 10 years after surgery. METHODOLOGY: 123 cases (69 men and 74 women) average age of 49.78 years (+12.13) were studied with average follow-up of 10.15 years. The quality of life was assessed based on a personal modified Gigli questionnaire with 32 items. RESULTS: The overall analysis revealed that the levels of quality of life decreased from 2006 (74.72) to 2011 (70.04) but remain significantly higher than those recorded prior to surgery (57.28). Of the 123 cases, 115 were satisfied with the surgery (93.5%) and 8 were not (6.5%);of the latter, six were undergoing antidepressant treatment. In 4 cases it was necessary to re-operate, 1 for dysphagia and 3 due to relapse. CONCLUSIONS: Al-though the results recorded in 2011 are slightly lower than those obtained in 2006, they remain well above those recorded before surgery. Therefore, the laparoscopic Nissen operation continues to be an excellent operation in the treatment of GERD PMID- 22534537 TI - Clinical significance of Smac and Ki-67 expression in pancreatic cancer. AB - BACKGROUND/AIMS: Tumors generally progress due to disruption in the balance between cellular proliferation and apoptosis. Thus, regulators of these processes tend to have altered expression in tumors, making them useful diagnostic and prognostic markers in the clinic. Here, we explored the potential usefulness of proteins involved in each of these processes, Smac (apoptosis) and Ki-67 (proliferation), in pancreatic cancer. METHODOLOGY: We collected 35 pancreatic cancer samples and 12 normal pancreas samples and applied immunohistochemistry and pathology to determine the expression of these two proteins and their correlation with clinicopathology of the tumors. RESULTS: Both Smac (35/35) and Ki-67 (33/35) were significantly more highly expressed in pancreatic tumors than in normal pancreas (1/12 and 2/12, respectively; p<0.05). However, no correlation was detected between Smac and Ki-67 expression in these tumors. Importantly, Smac expression was correlated only with pathological grade (p<0.05), while Ki-67 expression was correlated with pathological grade, lymph node metastasis, and clinical stage (p<0.05). CONCLUSIONS: The higher expression of Smac and Ki-67 appear to play a role in the pathogenesis of pancreatic cancer. Combined detection of these proteins may improve the prognostic evaluation of this disease. PMID- 22534535 TI - Glandular mast cells with distinct phenotype are highly elevated in chronic rhinosinusitis with nasal polyps. AB - BACKGROUND: Although chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) is characterized by T(H)2 inflammation, the role of mast cells is poorly understood. OBJECTIVE: The objective of this study was to investigate the presence, localization, and phenotype of mast cells in patients with CRS. METHODS: We collected nasal tissue and nasal lavage fluid from patients with CRS and control subjects. We analyzed mRNA for the mast cell proteases tryptase, chymase, and carboxypeptidase A3 by using real-time PCR and measured mast cell protease proteins by using ELISA, immunohistochemistry, and immunofluorescence. RESULTS: Tryptase mRNA was significantly increased in nasal polyps (NPs) from patients with CRSwNP (P< .001) compared with uncinate tissue from patients with CRS or control subjects. Tryptase protein was also elevated in NPs and in nasal lavage fluids from patients with CRSwNP. Immnohistochemistry showed increased numbers of mast cells in epithelium and glands but not within the lamina propria in NPs. The mast cells detected in the epithelium in NPs were characterized by the expression of tryptase and carboxypeptidase A3 but not chymase. Mast cells expressing all the 3 proteases were abundant within the glandular epithelium of NPs but were not found in normal glandular structures. CONCLUSIONS: Herein we demonstrated a unique localization of mast cells within the glandular epithelium of NPs and showed that mast cells in NPs have distinct phenotypes that vary by tissue location. Glandular mast cells and the diverse subsets of mast cells detected may contribute to the pathogenesis of CRSwNP. PMID- 22534538 TI - Importance of maintaining left gastric arterial flow at Appleby operation preserving whole stomach for central pancreatic cancer. AB - The safety of whole stomach-preserving Appleby operation with resection of the left gastric artery (LGA) for pancreatic cancer cannot be assured. The anatomy of the celiac axis (CA) with special regard to the position of the origin of the LGA was examined. Using 3D images of the vascular architecture reconstructed from volume data of helical CT, the length of the CA and the position of the origin of the LGA from the CA were measured in 53 patients. Among 53 patients, 47 patients (89%) had classical anatomy of the CA branches. The mean length(2 standard deviation) of the CA and the distance from the root of the LGA to the bifurcation of the CA were 25.2mm (-4.9) (range 14.6-36.5) and 10.3mm (+4.5)(range 2.4-21.9), respectively. In 23 (45%) cases, the LGA arose farther than 10mm away from the bifurcation of the CA. Among six patients with anatomical variation of the arteries, two (4%) had the LGA directly arising from the aorta. Conservation of the LGA at modified Appleby operation would give complete cancer removal by en bloc resection of the nerve plexus, without risk of ischemic complications of the stomach and liver. PMID- 22534539 TI - Strategies to prevent pancreatic fistula after pancreaticoduodenectomy. AB - BACKGROUND/AIMS: We evaluated the prevention of pancreatic fistula after pancreaticoduodenectomy in a retrospective clinical study. METHODOLOGY: Eighty patients undergoing pancreaticoduodenectomy between April 2007 and August 2011 were recruited.In all patients, the pancreas was reconstructed first,followed by reconstruction of the hepatic duct and the duodenum or stomach. RESULTS: Pancreatic fistulae were observed in 21 of 80 patients (26.3%; Grade A/B/C: 9/12/0). The incidence of pancreatic fistula in patients with soft pancreas was higher than that inpatients with hard pancreas (p<0.01). We investigated 54 patients with soft pancreas and pancreatic fistulae were diagnosed in 19 patients (35.2%; Grade A/B/C: 8/11/0). We evaluated pancreatic drainage methods (internal stent/external stent: 20/34) and in patients with soft pancreata, pancreatic fistulae were observed in 11 patients (55%) with internal stents vs. eight patients (23.5%) with external stents(p<0.05). CONCLUSIONS: We evaluated the management of pancreatic drainage methods and external stents were associated with a significantly lower incidence of pancreatic fistula compared with internal stents.We expect that external drainage of soft pancreas will decrease pancreatic juice leakage into the abdominal cavity. Many randomised control trials on pancreatic drainage have been reported recently; we plan to study them. PMID- 22534540 TI - The impact of obesity on perioperative outcomes of pancreaticoduodenectomy. AB - BACKGROUND/AIMS: The purpose of this study was to evaluate the impact of obesity on pancreaticoduodenectomy (PD) outcomes. METHODOLOGY: Subjects were 97 patients undergoing PD at our institution between April 2005 and April 2011. All patients had data including body mass index (BMI). Patients were divided into two groups based on BMI; normal group (BMI <25kg/m2) and overweight group (BMI >25kg/m'). Perioperative outcomes were collected prospectively. RESULTS: There were no significant differences between the two groups in terms of intraoperative data, surgical time, blood loss and blood transfusion rates. The over-all complication rate was 50.0% (53.6% in the over- weight group and 47.1% in the normal group; p=0.55).The most common complication overall was pancreatic fistula (34.7%). There was also a significant difference in the rate of intra-abdominal fluid collection (four patients in the overweight group (14.3%) vs. two patients in the normal group (2.9%), respectively; p<0.05).There was no significant difference in the mortality rate between the normal group and the overweight group(3.6% vs. 0%, p=0.11). CONCLUSIONS: Management of overweight patients in the perioperative period should therefore address any modifiable risk factors for operative complications. PMID- 22534541 TI - Surgical strategy for main pancreatic duct-type intraductal papillary mucinous neoplasm of the pancreas. AB - BACKGROUND/AIMS: Although surgical resection is recommended for all main duct type intraductal papillary mucinous neoplasms (IPMNs), controversies remain over the precise surgical strategy that should be adopted. This study thus aimed to investigate the appropriate surgical strategy for main duct IPMNs. METHODOLOGY: We retrospectively evaluated 46 patients with main duct-type IPMNs who underwent surgical resection at a single center between 1991 and 2010. RESULTS: Only 1 patient underwent total pancreatectomy (TP). Three patients underwent repeated pancreatectomy; TP was performed after distal pancreatectomy (DP) in 2 of these patients and after pylorus-preserving pancreaticoduodenectomy (PPPD) in the remaining patient. There current histology indicated minimally invasive carcinoma in all 3 of these patients. Among the 6 patients who died in the present study, no deaths occurred due to local recurrence of the remnant pancreas. CONCLUSIONS: Total pancreatectomy should be considered very selectively in the presence of a malignant lesion spreading to the whole pancreas. PMID- 22534542 TI - XELOX vs. FOLFOX4 as second line chemotherapy in advanced pancreatic cancer. AB - BACKGROUND/AIMS: The efficacy and tolerability of oxaliplatin in combination with either folinic acid, fluoro-uracil (5-FU) (FOLFOX4 regimen) or capecitabine (XE LOX regimen) was evaluated in advanced pancreatic cancer. METHODOLOGY: In this study, eighty-five patients with advanced pancreatic cancer were enrolled after failing to gemcitabine-based chemotherapy between November 2005 and August 2011. FOLFOX4 was repeated every two weeks and XELOX regimen was repeated every three weeks until either disease progression or unacceptable toxicity occurred. RESULTS: Eighty-five patients were evaluated for tumor response.Seven patients (18%) achieved a partial response with XELOX and stable disease was observed in 16 patients (41%). Eight patients (17%) achieved a partial response with FOLFOX4 and stable disease was observed in 12 patients (26%). Disease control rates were 59%in the XELOX arm and 43% in the FOLFOX4 arm. The median time to progression was 16 weeks in both arms.The median overall survival was 21 weeks with XELOX and 25 weeks with FOLFOX4. CONCLUSIONS: Oxaliplatin-based combination therapy showed moderate clinical activity with acceptable toxicity in patients who had progressive disease after receiving gemcitabine-based chemotherapy for advanced and/or metastatic pancreatic cancer. We conclude that XELOX is similar in terms of efficacy and toxicity profile to FOLFOX4 in the sec-ond-line treatment of metastatic pancreatic cancer. PMID- 22534544 TI - Modest alcohol consumption has an inverse association with liver fat content. AB - BACKGROUND/AIMS: Modest alcohol consumption has been suggested to be protective against alanine amino-transferase activities and ultrasonography-defined fat-ty liver. We aimed to explore the association between alcohol consumption and liver fat content as quantitative-ly determined by computed tomography (CT). METHODOLOGY: One-thousand two-hundred thirty-one Japanese males, aged over 40 years, voluntarily participated ina health check-up program including CT screening in 2009-2010. Exclusion criteria included positivity for the hepatitis B or C virus, abstinent alcoholics and potential hepatotoxic drug intake. Liver fat content, visceral adipose tissue (VAT) and subcutaneous adipose tis-sue were determined by CT. The association between alcohol consumption (g/week) and liver attenuation values (HU) was investigated by multivariate analysis with metabolic syndrome factors, liver enzyme activities and physical activities as covariates. RESULTS: One-thousand one-hundred thirty-eight subjects were eligible for this cross-sectional survey. VAT, triglyceride, glycated hemoglobin and alanine aminotransferase were significant and independent predictors for a decrease of liver attenuation. Alcohol consumption had a significant and independent association with an increase in liver attenuation (correlation coefficient=0.007, 95%CI=0.004-0.011, p<0.001) after adjusting for potential confounding variables. CONCLUSIONS: Alcohol consumption has an inverse association with CT-determined liv-er fat content independent of metabolic syndrome factors, liver enzyme activities and physical activities. PMID- 22534543 TI - FP3: a novel VEGF blocker with anti-angiogenic and anti-tumor effects. AB - BACKGROUND/AIMS: Vascular endothelial growth fac-tor (VEGF) serves as a logical target for antiangiogenic cancer therapy. This study is to investigate the inhibitory effects of FP3, a novel VEGF blocker, on angiogenesis in vitro and in vivo as well as anti-tumor effects ona liver cancer xenograft model in vivo. METHODOLOGY: The inhibitory effects of FP3 on angiogenesis were assessed by using human umbilical vein endothelial cells(HUVECs) in vitro and the chick embryo chorioallantoialc membrane (CAM) in viva. The inhibitory effect of FP3 on tumor growth in viva were evaluated in a human liver cancer cell line Hep-3B xenograft model in nude mice with the methods of tumor growth regression as-say. RESULTS: In experiments with HUVECs, FP3 inhibit-ed cell survival and tube formation. In CAM assay, FP3 suppressed MCF-7 human breast cancer cell-induced angiogenesis. In tumor growth regression assay, FP3 significantly blocked the growth of Hep-3B tumor cellin subcutaneous tumor xenograft model in nude mice. CONCLUSIONS: FP3 has excellent inhibitory effects on angiogenesis both in vitro and in viva and antitumor effect on liver cancer xenograft model; therefore, it might be used as an effective antiangiogenic agent in treatment of liver cancer. PMID- 22534545 TI - Local resection for rectal tumors: comparative study of transanal endoscopic microsurgery vs. conventional transanal excision - the experience in China. AB - BACKGROUND/AIMS: To compare the operative range,safety and therapeutic effect of local resection of rectal tumors by using transanal endoscopic microsurgery and conventional transanal excision. METHODOLOGY: We reviewed data from 76 patients treated using conventional TAE during the period from January 2003 to July 2006 and 53 patients treated using TEM during the period from September 2006 to February 2010 in the Ruijin Hospital affiliated with the Shanghai Jiaotong University School of Medicine. RESULTS: Age, gender, tumor size, blood loss and postoperative hospital stay were similar in the 2 groups. The median distance from the anal verge was significantly higher in the TEM group than in the TAE group. Operation time was significantly longer in the TEM group than in the TAE group.During the median follow-up of 40 months, the LRR in the TEM group was lower than that in the TAE group,especially for tumors that are larger (>3cm) and located higher (>8cm from the anal verge) and pT1 carcinomas. CONCLUSIONS: TEM is a safe, effective and minimally invasive surgical technique for the treatment of early rectal neoplasms. Compared to conventional TAE,TEM has a broader operative range and a better therapeutic effect. PMID- 22534546 TI - Prognostic factors of rectal cancer patients with lateral pelvic lymph node metastasis. AB - BACKGROUND/AIMS: We examined the clinicopathological characteristics of rectal cancer patients with lateral pelvic lymph node (LPLN) metastasis in order to clarify their associated prognostic factors. METHODOLOGY: A total of 91 rectal cancer patients with LPLN metastasis who underwent curative resection at the National Cancer Center Hospital between 1985 and 2004 were reviewed. RESULTS: The five-year overall survival rate and disease-free survival rate of the studied patient were 39% and 27%, respectively. Univariate analysis showed that tumor differentiation, lymphatic invasion, venous invasion, mesenteric lymph node status and LPLN status were significant prognostic factors. Multivariate analysis showed that tumor differentiation, mesenteric lymph node status and LPLN status were significant prognostic factors. Among 15 patients with LPLN metastasis and without mesenteric lymph node metastasis, 11 patients (73.3%) with one or two LPLN metastases survived more than five years. Among 12 patients with four or more LPLN metastases, two(16.7%) survived more than five years. CONCLUSIONS: Tumor differentiation, mesenteric lymph node status and LPLN status are significant prognostic factors of patients with LPLN metastasis. Because some patients with LPLN metastasis survive for a long period, LPLN dissection should be considered for them. PMID- 22534548 TI - An association between EGF and EGFR gene polymorphisms with gastric cancer in a Chinese Han population. AB - BACKGROUND/AIMS: The epidermal growth factor and its receptor play an important role in the development of gastric cancer. We investigate the potential association between epidermal growth factor and its receptor gene polymorphisms with gastric cancer in a Chinese Han population. METHODOLOGY: Polymerase chain reaction restriction fragment length polymorphism strategies were used to genotype EGF +61 G/A and EGFR+2073 A/T in 207 gastric cancer cases and 318 healthy controls. RESULTS: The A allele of EGF +61 G/A was less frequently in gastric cancer patients than in controls(OR=0.73, 95%CI=0.55-0.95, p=0.02). The A allele frequency was also associated with deeper tumor invasion(OR=1.74, 95%CI=1.05-2.89, p=0.03), increased lymph node metastasis (OR=1.74, 95%CI=1.08 2.82, p=0.02)and shorter survival time (95%CI=9.27-16.72, p=0.038).A T allele frequency in the EGFR +2073 A/T polymorphism was associated with increased lymph node metastasis in gastric cancer (OR=1.62, 95%CI=1.06-2.47,p=0.03). CONCLUSIONS: Our results suggest that the A allele of EGF +61 G/A polymorphism decreases the risk of gastric cancer. However, the presence of either the A allele of EGF +61 G/A or the EGFR +2073 T allele indicated a poor prognosis for gastric cancer patients. PMID- 22534547 TI - Trastuzumab combined with docetaxel-based regimens in previously treated metastatic gastric cancer patients with HER2 over-expression. AB - BACKGROUND/AIMS: This study evaluates the efficacy and safety of trastuzumab combined with docetaxel-based chemotherapy in previously treated metastatic gastric carcinoma of Chinese patients with HER2 over-expression. METHODOLOGY: Twenty-two meta-static gastric cancer patients with HER2 over-expression (3+ by immunohistochemistry or HER2 amplification by fluorescence in situ hybridization) previously treated with 5-fluorouracil-based chemotherapy were eligible. Trastuzumab was administrated at 8mg/kg as a loading dose followed by 6mg/kg ev ery 21 days. Docetaxel-based chemotherapy regimens were also given every 21 days. RESULTS: Median age was 56 years. ECOG performance status was 0-2. Thir-teen patients (59.1%) achieved partial response (PR)and 7 patients (31.8%) had stable disease (SD). Median progression free survival was 6.8 months and the median overall survival was 16.0 months. A patient with 3+ HER2 expression and HER2 gene amplification achieved PR after 6 cycles of combined treatment and received operation. Interestingly, his HER2 expression status in tumor tissue turned into negative after operation and he was still alive without progression until now. Trastuzumab combined with docetaxel-based chemotherapy was well tolerated. Grade 3-4 hematological toxicities were leucopenia (31.8%), neutropenia (18.2%) thrombocytopenia (9.1%) and ane-mia (4.5%). No unexpected toxicities, treatment related deaths and symptomatic congestive heart failure were observed. CONCLUSIONS: Combinations of trastuzumab plus docetaxel-based regimens were well tolerated and effective in previously treated metastatic gastric cancer of Chinese patients with HER2 over-expression or gene amplification. PMID- 22534549 TI - Prevalence and risk factors of otitis media with effusion in school children in Eastern Anatolia. AB - OBJECTIVE: To investigate the prevalence and demographic, environmental and child associated risk factors of OME in schoolchildren in Eastern Anatolia, Turkey, and analyze the results with reference to the review of the literature. METHODS: A total of 2355 children who were attending two different primary schools, one located in low, and the other located in a high socioeconomic district of city of Van were screened and 2320 children who met the inclusion criteria were enrolled to study. Standardized questionnaires that include nine questions for determination of risk factors were delivered to the parents to be filled before examination of each child. All of the children underwent both otoscopic examination and tympanometric evaluation to provide high accuracy on the diagnosis of OME. The association between children diagnosed as OME and the answers to the questionnaires were evaluated. Also, teachers of the children were asked to complete a questionnaire evaluating child's level of school success, and the success levels of children with or without OME were compared. RESULTS: The prevalence of OME was found to be 10.43%. Second-hand smoking (p<0.0001), low socioeconomic status (p<0.001), living in a crowded house (p<0.001), presence of atopy (p<0.01), lack of breast-feeding (p<0.05), presence of URTI (p<0.0001), young age (p<0.001) and snoring (p<0.0001) were found to be associated with prevalence of OME. No significance was found for duration of breast-feeding, gender, birth history and previous otolaryngological operations. Also, children with OME were tended to be less successful in terms of school success. CONCLUSIONS: The potential of OME to cause serious sequelae and complications that may affect children's life long-term, makes the disease an important health problem. Environmental, epidemiologic and familial factors play an important role in pathogenesis of OME. Caretakers must be informed about these highly modifiable risk factors, by this way the development or delayed diagnosis of the disease that may cause serious consequences can be prevented. PMID- 22534550 TI - Perinatal airway management of neonatal cervical teratomas. AB - Cervical teratomas are rare but life-threatening neonatal tumors and management of the fetus with a cervical teratoma that threatens the airway remains a clinical challenge. This has been revolutionized by advances in fetal imaging and management of the airway at delivery including the use of Ex-utero Intrapartum Treatments (EXIT procedures). We present a retrospective case series of three neonates managed over a 12-month period. Following pre-natal fetal MRI and a multi-disciplinary management approach, two newborns were managed by prompt post natal endotracheal intubation while an EXIT procedure was required in one. All three underwent surgical resection in the first few days of life. A decision regarding the best means by which to manage the airway in fetal cervical teratoma requires fetal MRI and a multi-disciplinary team approach to determine whether EXIT, or a safer approach from a maternal perspective can be employed. We also recommend routine endotracheal intubation at birth, due to the risk of spontaneous intra-tumoral hemorrhage. The need for surgery should be planned early, as rapid growth of the tumor can threaten the viability of the overlying skin and surrounding structures. PMID- 22534551 TI - Maternal personality traits and risk of preterm birth and fetal growth restriction. AB - BACKGROUND/AIMS: Maternal personality may increase vulnerability to stress, which could lead to an unfavourable intrauterine environment to the fetus. We sought to investigate the impact of maternal personality traits on adverse birth outcomes such as preterm birth, and fetal growth restriction in the mother-child cohort study (RHEA Study) in Crete, Greece 2007-2009. METHODS: Five hundred and eighty pregnant women participating in "Rhea" cohort study completed the Eysenck Personality Questionnaire-Revised (EPQ-R) at 28-32 weeks of gestation. Information on anthropometric measures at birth was obtained from the hospital delivery logs and medical records. Fetal growth restriction was based on a customized model, and multivariate logistic regression models were used adjusting for confounders. RESULTS: A per unit increase in the EPQ Neuroticism scale increased the risk for fetal weight growth restriction by 9% [odds ratio (OR)=1.09, 95 percent CI: 1.01, 1.19)], and for fetal head circumference growth restriction by 6% [OR=1.06, 95 percent CI: 1.01, 1.18] after adjusting for maternal age, education, origin, marital status, working status, pre-pregnancy BMI, delivery type, parity, smoking, and alcohol intake during pregnancy. CONCLUSIONS: Maternal neuroticism, which predisposes to negative mood, may be a risk factor for fetal growth restriction. PMID- 22534552 TI - The clinical implications of cognitive impairment and allostatic load in bipolar disorder. AB - BACKGROUND: Allostatic load (AL) relates to the neural and bodily "wear and tear" that emerge in the context of chronic stress. This paper aims to provide clinicians with a comprehensive overview of the role of AL in patophysiology of bipolar disorder (BD) and its practical implications. METHODS: PubMed searches were conducted on English-language articles published from 1970 to June 2011 using the search terms allostatic load, oxidative stress, staging, and bipolar disorder cross-referenced with cognitive impairment, comorbidity, mediators, prevention. RESULTS: Progressive neural and physical dysfunction consequent to mood episodes in BD can be construed as a cumulative state of AL. The concept of AL can help to reconcile cognitive impairment and increased rates of clinical comorbidities that occur over the course of cumulative BD episodes. CONCLUSIONS: Data on transduction of psychosocial stress into the neurobiology of mood episodes converges to the concept of AL. Mood episodes prevention would not only alleviate emotional suffering, but also arrest the cycle of AL, cognitive decline, physical morbidities and, eventually, related mortality. These objectives can be achieved by focusing on effective prophylaxis from the first stages of the disorder, providing mood-stabilizing agents and standardized psychoeducation and, potentially, addressing cognitive deficits by the means of specific medication and neuropsychological interventions. PMID- 22534553 TI - Prognostic factors for visual outcome after intravitreal anti-VEGF injection for naive myopic choroidal neovascularization. AB - PURPOSE: The aim of this study was to evaluate the prognostic factors of visual outcome after intravitreal anti-vascular endothelial growth factor injection in patients with myopic choroidal neovascularization (CNV). METHODS: Forty eyes of 40 consecutive patients with myopic CNV who had received intravitreal ranibizumab or bevacizumab injections were retrospectively reviewed. Baseline visual acuity, presence of lacquer crack, dark rim, peripapillary choroidal atrophy size, and location of myopic CNV were evaluated using fluorescein angiography and indocyanine green angiography. RESULTS: The logarithm of the minimum angle of resolution best-corrected visual acuity (BCVA) at 12 months after treatment was 0.23 +/- 0.28, and there was a significant improvement compared with the baseline BCVA (P = 0.001). After multiple linear regression analysis, baseline BCVA, presence of lacquer crack extending the fovea, and peripapillary choroidal atrophy size were the factors that significantly correlated with BCVA at 12 months (P = 0.001, P = 0.04, and P = 0.04). For mean change in BCVA over 12 months, there were also significant correlations with baseline BCVA, lacquer crack extension to the fovea, and peripapillary choroidal atrophy size (P = 0.001, P = 0.03, and P = 0.03). The mean number of anti-vascular endothelial growth factor injections was 2.8 +/- 2.0 over 12 months. Complete resolution of myopic CNV was noted in 22 eyes (55.0%) after initial first injection, and no additional treatment was required in 12 eyes (30%). CONCLUSION: Better baseline BCVA, lacquer crack extension to the fovea, and peripapillary atrophy were negative prognostic factors of visual acuity improvement, and there was quite a promising result of anti-vascular endothelial growth factor treatment in patients with myopic CNV. PMID- 22534555 TI - [The age of the patient over 70 is a contraindication to perform para-aortic lymphadenectomy for ovarian cancer]. PMID- 22534554 TI - Risk of contrast induced nephropathy in the critically ill: a prospective, case matched study. AB - INTRODUCTION: Computerized tomography is frequently employed in the critically ill, often using intravenous radiocontrast material. Many of these patients have clinical features that are considered risk factors for contrast induced nephropathy, but are simultaneously at risk for renal injury from other factors related to their acute illnesses. The attributable risk for renal dysfunction from radiocontrast exposure has not been well quantified in this population. METHODS: A prospective matched cohort study was conducted of patients scanned with or without radiocontrast enhancement while receiving intensive care in a Veterans Affairs Medical Center. Patients were matched for pre-scan measured creatinine clearance, diabetes, mechanical ventilation, and vasopressor use. Measured clearance was followed for three days after scanning. Evolution of nephropathy, as determined by change in measured clearance, was compared within matched pairs. RESULTS: Fifty-three pairs of patients satisfied matching criteria. Unmatched characteristics were similar among the pairs, including serum creatinine variability during the week preceding scanning (67 +/- 85% among contrast recipients, 63 +/- 62% among others) and clinical risk factors for renal failure. In 29 pairs, pre-scan measured clearances were less than 60 mL/minute/1.73 m2. Following scanning, measured clearance declined by at least 33% in 14 contrast and 19 non-contrast patients (95% confidence interval for contrast associated difference in nephropathy rates -27% to 9%), while a 50% reduction in clearance persisted three days after scanning in three contrast and nine non-contrast patients (95% confidence interval for difference in rates -25% to 2%). CONCLUSIONS: Among established intensive care unit patients declines in glomerular filtration following contrast-enhanced scanning are common, but these changes are far more likely to be attributable to factors other than the contrast exposure itself. The upper bound for the incidence of contrast induced renal injury lasting even three days was 2% in the population studied. PMID- 22534556 TI - Infrared and theoretical calculations in 2-halocycloheptanones conformational analysis. AB - 2-Halocycloheptanones (Halo=F, Cl, Br and I) were synthesized and their conformational analysis was performed through infrared spectroscopy data. The corresponding conformers geometries and energies were obtained by theoretical calculations at B3LYP/aug-cc-pVDZ level of theory in the isolated state and in solution. It was observed, by both approaches, that the conformational preferences were very sensitive to the solvent polarity, since its increase led to an increase in the population of the more polar conformer. An analysis of these conformational equilibria showed they suffer also the influence of stereoelectronic effects, like hyperconjugation and steric effects. These results were interpreted using natural bond orbital (NBO) analysis, which indicated that the electronic delocalization to the orbital pi*(C=O) is directly involved in the stability increase of conformers I and II. The relative effect of the period of the halogen can also be noted, with changes in the conformational preferences and in the energies involved in the interactions of NBO. PMID- 22534557 TI - Spectroscopic analysis (FT-IR/FT-Raman) and molecular structure investigation on m-fluoronitrobenzene using hybrid computational calculations. AB - In the present investigation, the FT-IR/FT-Raman spectra of the m fluoronitrobenzene (m-FNBZ) are recorded. The fundamental frequencies are assigned and the computational calculations are performed by DFT (B3LYP, B3PW91 and MPW1PW91) methods with 6-31++G(d,p) and 6-311++G(d,p) basis sets and the corresponding results are tabulated. The computed values of frequencies are scaled by using suitable factors. The distortion of the structure of the compound due to the substitutions of Fl and NO(2) is investigated. The alternation of the vibrational pattern of the pedestal molecule related to the substitutions is analyzed. A study on the electronic properties; absorption wavelengths, excitation energy, dipole moment and frontier molecular orbital energies, are performed by time dependent DFT (TD-DFT) approach. The electronic structure and the assignment of the absorption bands in the electronic spectra of steady compounds are discussed. The calculated HOMO and LUMO energies show that charge transfer occurs within the molecule. Besides frontier molecular orbitals (FMO), molecular electrostatic potential (MEP) was performed. Mulliken charges of the m FNBZ molecule was also calculated and interpreted. The thermodynamic properties (heat capacity, entropy, and enthalpy) of the title compound at different temperatures were calculated in gas phase. PMID- 22534558 TI - The investigation of the effect of thermal treatment on bentonites from Turkey with Fourier transform infrared and solid state nuclear magnetic resonance spectroscopic methods. AB - There is a great deal of interest in the building industry in burned clays for production of building materials. Therefore, the effect of heat treatment on natural bentonite from Turkey was investigated by Fourier transform infrared (FT IR) between the region of 4000-400cm(-1) and (29)Si, (27)Al magic angle spinning nuclear magnetic resonance (MAS NMR) measurement techniques at various temperatures between 200 and 700 degrees C for 2h. The structural changes were also investigated upon heat treatment. PMID- 22534559 TI - [Posterior tibial tendon dysfunction: what other structures are involved in the development of acquired adult flat foot?]. AB - OBJECTIVE: To evaluate the association of posterior tibial tendon dysfunction and lesions of diverse ankle structures diagnosed at MRI with radiologic signs of flat foot. MATERIAL AND METHODS: We retrospectively compared 29 patients that had posterior tibial tendon dysfunction (all 29 studied with MRI and 21 also studied with weight-bearing plain-film X-rays) with a control group of 28 patients randomly selected from among all patients who underwent MRI and weight-bearing plain-film X-rays for other ankle problems. In the MRI studies, we analyzed whether a calcaneal spur, talar beak, plantar fasciitis, calcaneal bone edema, Achilles' tendinopathy, spring ligament injury, tarsal sinus disease, and tarsal coalition were present. In the weight-bearing plain-film X-rays, we analyzed the angle of Costa-Bertani and radiologic signs of flat foot. To analyze the differences between groups, we used Fisher's exact test for the MRI findings and for the presence of flat foot and analysis of variance for the angle of Costa Bertani. RESULTS: Calcaneal spurs, talar beaks, tarsal sinus disease, and spring ligament injury were significantly more common in the group with posterior tibial tendon dysfunction (P<.05). Radiologic signs of flat foot and anomalous values for the angle of Costa-Bertani were also significantly more common in the group with posterior tibial tendon dysfunction (P<.001). CONCLUSION: We corroborate the association between posterior tibial tendon dysfunction and lesions to the structures analyzed and radiologic signs of flat foot. Knowledge of this association can be useful in reaching an accurate diagnosis. PMID- 22534560 TI - [Using magnetic resonance imaging for staging can change the therapeutic management in patients with breast cancer]. AB - OBJECTIVE: To compare two series of patients with breast cancer, one staged using preoperative MRI and the other staged using conventional techniques, analyzing the changes to treatment, the number of mastectomies, and the number of reinterventions due to involvement of the margins. MATERIAL AND METHODS: We reviewed 600 patients divided into 300 patients with preoperative MRI (series 1) and 300 without preoperative MRI (series 2). We recorded the following variables: age, menopausal status, tumor size on pathological examination, multiplicity and bilaterality, surgical treatment and type of treatment, the administration of neoadjuvant chemotherapy, and reintervention for involved margins. We used Student's t-test and the chi-square test to compare the variables between the two series. RESULTS: The mean age of patients in the two series was similar (51.5 and 51.8 years, P=0.71). The mean size of the tumor was smaller in series 1 (16.9 mm vs 22.3 mm) (P<.001). More multiple tumors were detected in series 1 (28.7 vs 15.7%) (P<.001). The rate of mastectomies was lower in series 1 (25 vs 48%) (P<.001). Oncoplastic and bilateral surgeries were performed only in series 1. Neoadjuvant chemotherapy was administered more often in series 1 (30.7 vs 9.3%) (P<.001). The difference in the number of reinterventions for involved margins did not reach significance (7.2% in series 1 vs 3.2% in series 2) (P=.095). CONCLUSION: When MRI was used for staging, neoadjuvant chemotherapy and oncoplastic surgery were used more often and the mastectomy rate decreased. Despite the increase in conservative surgery in patients staged with MRI, the number of reinterventions for involved margins did not increase, although there was a trend towards significance. PMID- 22534561 TI - Detection of type-specific antibodies to HSV-1 and HSV-2: comparative analysis of a chemiluminescence immunoassay with a conventional ELISA. AB - Type-specific serologic tests for human herpes simplex virus (HSV) are critically important for sexually transmitted disease evaluation. We compared the LIAISON(r) HSV-1 and HSV-2 Type Specific assays relative to an established commercial ELISA. The overall agreement of the chemiluminescence immunoassay versus the ELISA assay was 99.6% (HSV-1) and 100% (HSV-2). The LIAISON(r) methodology has several advantages. PMID- 22534562 TI - WiiFitTM Plus balance test scores for the assessment of balance and mobility in older adults. AB - The Nintendo WiiTM is becoming an increasingly popular technology for the training and assessment of balance in older adults. Recent studies have shown promising results for its use in fall prevention. However, it is not clear how scores on the WiiFitTM balance games relate to current standardized tests of balance and mobility. The purpose of this study was to evaluate the relationship between WiiFitTM Plus balance tests, and standardized tests of older adult fitness, balance, mobility, self-reported balance confidence, and visual attention and processing. Results from 34 older adult participants indicate that WiiFitTM balance tests do not correlate well with standardized functional balance, mobility and fitness tests. However, the Wii balance score, as measured by the Basic Balance Test of the WiiFitTM, does correlate with visual processing speed as measured by the Useful Field of View (UFOV((r))) test. These results indicate that WiiFitTM balance tests may provide advantageous information supplementary to information obtained through standard functional mobility and balance tests; however, caution should be used when using the WiiFitTM balance tests in isolation. Further research is necessary as these technologies become widely used in clinical and home settings for balance training and assessment. PMID- 22534563 TI - The impact of multiple biopsies on outcomes of nerve-sparing robotic-assisted radical prostatectomy. AB - Active surveillance of prostate cancer patients involves subjecting them to multiple prostate biopsies, and we sought to investigate the effects of this on functional outcomes after robotic-assisted radical prostatectomy (RARP). Between May 2009 and December 2009, 367 patients who consecutively underwent RARP by a single surgeon were divided into two groups, one that had single prostate biopsy and another multiple biopsies before RARP. The groups were matched for significant clinicopathologic preoperative variables, and only premorbidly potent low-risk cases that underwent nerve sparing were included. This left 50 and 23 patients for analysis in the single and multiple biopsy groups, respectively. The primary endpoint was potency and continence at 3 and 6 months after surgery. We found continence rates of 84% (83%) and 94% (96%) for single (multiple) biopsy groups at 3 and 6 months, respectively (P=0.88, P=0.77). Multiple biopsy patients had worse postoperative erectile function at 6 months (57% versus 80%, P=0.03). Men subject to multiple preoperative biopsies are more likely to become impotent postoperatively than those who undergo surgery after a single biopsy. This should be borne in mind when counseling men regarding repeat biopsy as part of an active surveillance strategy. PMID- 22534564 TI - Influence of pole plant time on the performance of a special jump and plant exercise in the pole vault. AB - The purpose of this study was to examine the effect of the timing of the pole plant during the stance phase of the jump on the energy level of the vaulter/pole system at take-off for a special pole vault take-off exercise (Jagodin). We hypothesised that an earlier pole plant would increase the pole energy at take off compared to the energy decrease of the vaulter during the jump and plant complex and so lead to a higher total energy of the vaulter/pole system at take off. Six male pole vaulters experienced three Jagodins each with different pole plant time building three groups of vaults (early, intermediate, late pole plant). Kinematic data of vaulter and pole were recorded, as were ground reaction forces measured at the end of the pole under the planting box and under the take off foot. These measurements allowed the energy exchange between the vaulter and pole to be determined. We found neither statistical significant differences in the mechanical energy level of the vaulter/pole system during take-off between the three groups nor a relationship between the timing of the pole plant and the energy level of the vaulter-pole system during take-off. We conclude that although the timing of the pole plant influences the interactions between the vaulter, the pole, and the ground, it does not affect the athlete's performance. Although a late pole plant decreases the loss of energy by the vaulter during the take-off, this is counterbalanced by a decrease in the energy stored in the pole at take-off. PMID- 22534565 TI - Anisotropic material behaviours of soft tissues in human trachea: an experimental study. AB - BACKGROUND: Human trachea is a multi-component structure composed of cartilage, trachealis muscle, mucosa and submucosa membrane and adventitial membrane. Its mechanical properties are essential for an accurate prediction of tracheal deformation, which has a significant clinic relevance. Efforts have been made in quantifying the material behaviour of tracheal cartilage and trachealis muscle. However, the material behaviours of other components have been least investigated. METHODS: Three human cadaveric trachea specimens were used in this study. Trachealis muscle, mucosa and submucosa membrane and adventitia membrane were excised to perform the uniaxial test in axial and circumferential directions. In total, 72 tissue strips were prepared and tested. Tangent modulus was used to quantified the stiffness of each tissue strip at various stretch levels. RESULTS: The obtained results indicated that all types of tracheal soft tissues were highly non-linear and anisotropic. Trachealis muscle in the circumferential direction had the most excellent extensibility; and the adventitial collagen membrane in the circumferential direction was the stiffest. CONCLUSION: This study is helpful in understanding the material behaviour of trachea. Obtained results can be used for computational and analytic modelling to quantify the tracheal deformation. PMID- 22534566 TI - A multi-centered epidemiological study evaluating the reliability of the treatment difficulty indices developed by the Japan Prosthodontic Society. AB - BACKGROUND: The diagnostic assessment of the level of difficulty in treating patients who need prosthodontic care is useful to establish a medico-economically efficient system with primary care dentists and prosthodontic specialists. MATERIALS AND METHODS: A multi-axis assessment protocol was established using the newly established treatment difficulty indices. The protocol contains Axis I: oral physiological conditions (e.g., teeth damage and/or missing teeth); Axis II: general health and sociological conditions (e.g., medical disorders); Axis III: oral health-related quality of life (OHRQOL; e.g., oral health impact profile: OHIP); and Axis IV: psychological health (e.g., mood, anxiety, somatoform disorders). A preliminary study on the test-retest consistency of the protocol was conducted to check the levels of reliability of the indices prior to a large scale, multi-center cohort study on the validity of the protocol. RESULTS: The test-retest consistency in terms of the oral physiological condition (Axis I) after data reduction was 0.82 [corrected] for patients with teeth problems, 0.73 [corrected] for partially edentulous patients, and 0.78 [corrected] for edentulous patients. The reliability for general health and sociological conditions (Axis II), OHRQOL (Axis III), and psychological health (Axis IV) were 0.88, 0.74, and 0.61, respectively. These values reflect either "sufficient agreement" or "excellent agreement" in accordance with the criteria established by Landis and Koch (1977) [1]. CONCLUSION: This protocol is the first multi-axis assessment scheme introduced for prosthodontic treatment with sufficient reliability. This new system is therefore expected to have a significant impact on future dental diagnostic nomenclature systems. PMID- 22534567 TI - Isolation of a distinct Mycobacterium tuberculosis mannose-capped lipoarabinomannan isoform responsible for recognition by CD1b-restricted T cells. AB - Mannose-capped lipoarabinomannan (ManLAM) is a complex lipoglycan abundantly present in the Mycobacterium tuberculosis cell envelope. Many biological properties have been ascribed to ManLAM, from directly interacting with the host and participating in the intracellular survival of M. tuberculosis, to triggering innate and adaptive immune responses, including the activation of CD1b-restricted T cells. Due to its structural complexity, ManLAM is considered a heterogeneous population of molecules which may explain its different biological properties. The presence of various modifications such as fatty acids, succinates, lactates, phosphoinositides and methylthioxylose in ManLAM have proven to correlate directly with its biological activity and may potentially be involved in the interactions between CD1b and the T cell population. To further delineate the specific ManLAM epitopes involved in CD1b-restricted T cell recognition, and their potential roles in mediating immune responses in M. tuberculosis infection, we established a method to resolve ManLAM into eight different isoforms based on their different isoelectric values. Our results show that a ManLAM isoform with an isoelectric value of 5.8 was the most potent in stimulating the production of interferon-gamma in different CD1b-restricted T-cell lines. Compositional analyses of these isoforms of ManLAM revealed a direct relationship between the overall charge of the ManLAM molecule and its capacity to be presented to T cells via the CD1 compartment. PMID- 22534568 TI - The human H3N2 influenza viruses A/Victoria/3/75 and A/Hiroshima/52/2005 preferentially bind to alpha2-3-sialylated monosialogangliosides with fucosylated poly-N-acetyllactosaminyl chains. AB - Among influenza A viruses, subtype H3N2 is the major cause of human influenza morbidity and is associated with seasonal epidemics causing annually half million deaths worldwide. Influenza A virus infection is initiated via hemagglutinin that binds to terminally sialylated glycoconjugates exposed on the surface of target cells. Gangliosides from human granulocytes were probed using thin-layer chromatography overlay assays for their binding potential to H3N2 virus strains A/Victoria/3/75 and A/Hiroshima/52/2005. Highly polar gangliosides with poly-N acetyllactosaminyl chains showing low chromatographic mobility exhibited strong virus adhesion which was entirely abolished by sialidase treatment. Auxiliary overlay assays using anti-sialyl Lewis(x) (sLe(x)) monoclonal antibodies showed identical binding patterns compared with those performed with the viruses. A comprehensive structural analysis of fractionated gangliosides by electrospray ionization quadrupole time-of-flight mass spectrometry revealed sLe(x) gangliosides with terminal Neu5Acalpha2-3Galbeta1-4(Fucalpha1-3)GlcNAc epitope and extended neolacto (nLc)-series core structures as the preferential virus binding gangliosides. More precisely, sLe(x) gangliosides with nLc8, nLc10 and nLc12Cer cores, carrying sphingosine (d18:1) and a fatty acid with variable chain length (mostly C24:0, C24:1 or C16:0) in the ceramide moiety and one or two additional internal fucose residues in the oligosaccharide portion, were identified as the preferred receptors recognized by H3N2 virus strains A/Victoria/3/75 and A/Hiroshima/52/2005. This study describes glycan-binding requirements of hemagglutinin beyond binding to glycans with a specific sialic acid linkage of as yet undefined neutrophil receptors acting as ligands for H3N2 viruses. In addition, our results pose new questions on the biological and clinical relevance of this unexpected specificity of a subtype of influenza A viruses. PMID- 22534569 TI - MUC1 in human and murine mammary carcinoma cells decreases the expression of core 2 beta1,6-N-acetylglucosaminyltransferase and beta-galactoside alpha2,3 sialyltransferase. AB - A good correlation between the expression of mucin1 (MUC1) and T antigen was found in breast cancer tumors and breast cancer cell lines, especially after treatment with neuraminidase. The association between the appearance of T antigen and the overexpression of MUC1 was further confirmed by transfecting MDA-MB-231 cells and murine 4T1 mammary carcinoma cells with cDNA for MUC1 and using an RNAi approach to inhibit the expression of MUC1 gene in T47D cells. Furthermore, we discovered that in 4T1 cells which express the sialyl Le(X) antigen, overexpression of MUC1 caused not only appearance of T antigen, but also loss of the sialyl Le(X) structure. As the observed changes in O-glycan synthesis can be associated with changes in the expression of specific glycosyltransferases, core 1 beta1,3-galactosyltransferase, core 2 beta1,6-N-acetylglucosaminyltransferase (C2GnT1) and beta-galactoside alpha2,3-sialyltransferase (ST3Gal I), we studied their expression in parental, vector-transfected and MUC1-transfected MDA-MB-231 and 4T1 cells as well as T47D cells transduced with small hairpin RNA targeted MUC1 mRNA. It was found that the expression of C2GnT1 and ST3Gal I is highly decreased in MUC1-expressing MDA-MB-231 and 4T1 cells and increased in T47D cells with suppressed expression of MUC1. Therefore, we found that changes in the structure of O-linked oligosaccharides, resulting in the occurrence of T antigen, are at least partially associated with MUC1 overexpression which down-regulates the expression of C2GnT1 and ST3Gal I. We showed also that the overexpression of MUC1 in 4T1 cells changes their adhesive properties, as MUC1-expressing cells do not adhere to E-selectin, but bind galectin-3. PMID- 22534570 TI - Does simile comprehension differ from metaphor comprehension? A functional MRI study. AB - Since Aristotle, people have believed that metaphors and similes express the same type of figurative meaning, despite the fact that they are expressed with different sentence patterns. In contrast, recent psycholinguistic models have suggested that metaphors and similes may promote different comprehension processes. In this study, we investigated the neural substrates involved in the comprehension of metaphor and simile using functional magnetic resonance imaging (fMRI) to evaluate whether simile comprehension differs from metaphor comprehension or not. In the metaphor and simile sentence conditions, higher activation was seen in the left inferior frontal gyrus. This result suggests that the activation in both metaphor and simile conditions indicates similar patterns in the left frontal region. The results also suggest that similes elicit higher levels of activation in the medial frontal region which might be related to inference processes, whereas metaphors elicit more right-sided prefrontal activation which might be related to figurative language comprehension. PMID- 22534571 TI - Assessing the double phonemic representation in bilingual speakers of Spanish and English: an electrophysiological study. AB - Event Related Potentials (ERPs) were recorded from Spanish-English bilinguals (N=10) to test pre-attentive speech discrimination in two language contexts. ERPs were recorded while participants silently read magazines in English or Spanish. Two speech contrast conditions were recorded in each language context. In the phonemic in English condition, the speech sounds represented two different phonemic categories in English, but represented the same phonemic category in Spanish. In the phonemic in Spanish condition, the speech sounds represented two different phonemic categories in Spanish, but represented the same phonemic categories in English. Results showed pre-attentive discrimination when the acoustics/phonetics of the speech sounds match the language context (e.g., phonemic in English condition during the English language context). The results suggest that language contexts can affect pre-attentive auditory change detection. Specifically, bilinguals' mental processing of stop consonants relies on contextual linguistic information. PMID- 22534572 TI - Distal sensory nerve transfers in lower-type injuries of the brachial plexus. AB - PURPOSE: To report the results of sensory nerve transfers to reconstruct sensation on the ulnar side of the hand in lower-type palsies of the brachial plexus. METHODS: From 2007 to 2009, we operated on 6 men and 2 women with a lower type injury of the brachial plexus and observed them for a minimum of 24 months. The mean interval between the injury and surgery was 8 months (SD +/- 8.6 mo). Before surgery, we documented anesthesia on the ulnar side of the hand in all patients. Donor nerves included cutaneous branches of the median nerve to the palm (n = 5) or the palmar cutaneous branch of the median nerve (n = 3). The ulnar proper digital nerve of the little finger was the recipient nerve. We evaluated sensory recovery by assessing static 2-point discrimination and sensation to Semmes-Weinstein monofilaments. RESULTS: According to the British Medical Council system of evaluation, 5 patients scored S3 and 3 scored S3+. CONCLUSIONS: In lower-type injuries of the brachial plexus, transfer of median nerve branches that innervate the palm of the hand to the ulnar proper digital nerve of the little finger predictably restored protective sensation on the ulnar side of the hand. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 22534573 TI - Focus on social neuroscience. PMID- 22534574 TI - Is the reward really worth it? PMID- 22534575 TI - Astrocytes join the plasticity party. PMID- 22534576 TI - Fat incites tanycytes to neurogenesis. PMID- 22534577 TI - On the scent of mitochondrial calcium. PMID- 22534578 TI - The roots of modern justice: cognitive and neural foundations of social norms and their enforcement. AB - Among animals, Homo sapiens is unique in its capacity for widespread cooperation and prosocial behavior among large and genetically heterogeneous groups of individuals. This ultra-sociality figures largely in our success as a species. It is also an enduring evolutionary mystery. There is considerable support for the hypothesis that this facility is a function of our ability to establish, and enforce through sanctions, social norms. Third-party punishment of norm violations ("I punish you because you harmed him") seems especially crucial for the evolutionary stability of cooperation and is the cornerstone of modern systems of criminal justice. In this commentary, we outline some potential cognitive and neural processes that may underlie the ability to learn norms, to follow norms and to enforce norms through third-party punishment. We propose that such processes depend on several domain-general cognitive functions that have been repurposed, through evolution's thrift, to perform these roles. PMID- 22534580 TI - Mental contamination: the effects of imagined physical dirt and immoral behaviour. AB - There is a growing body of empirical support for Rachman's (1994, 2004, 2006) conceptualization of mental contamination. The aim of this study was to tease apart manipulations of imagined physical descriptions (i.e., clean versus dirty), in the context of both morally sound and reprehensible acts (i.e., consensual versus non-consensual kiss) to expand our understanding of the experimental variables which may evoke mental contamination and address limitations of previous research. Female undergraduate student participants (n = 140) were randomly assigned to listen to one of four audio recordings and imagine receiving either a consensual or non-consensual kiss from a man described as either physically clean or physically dirty. Results indicated that participants who imagined a non-consensual kiss from a physically dirty man reported the greatest feelings of mental contamination; whereas, participants who imagined a consensual kiss from a physically clean man reported the lowest feelings of mental contamination. However, there were few significant differences in mental contamination feelings between those who imagined a consensual kiss from a physically dirty man and those who imagined a non-consensual kiss from a physically clean man. Results are discussed in terms of cognitive-behavioural conceptualizations of and treatments for contamination fears. PMID- 22534579 TI - Social influences on neuroplasticity: stress and interventions to promote well being. AB - Experiential factors shape the neural circuits underlying social and emotional behavior from the prenatal period to the end of life. These factors include both incidental influences, such as early adversity, and intentional influences that can be produced in humans through specific interventions designed to promote prosocial behavior and well-being. Here we review important extant evidence in animal models and humans. Although the precise mechanisms of plasticity are still not fully understood, moderate to severe stress appears to increase the growth of several sectors of the amygdala, whereas the effects in the hippocampus and prefrontal cortex tend to be opposite. Structural and functional changes in the brain have been observed with cognitive therapy and certain forms of meditation and lead to the suggestion that well-being and other prosocial characteristics might be enhanced through training. PMID- 22534581 TI - Retained subretinal perfluorocarbon liquid in microincision 23-gauge versus traditional 20-gauge vitrectomy for retinal detachment repair. AB - PURPOSE: To assess the rate of retained subretinal perfluorocarbon liquid (PFCL) in patients undergoing rhegmatogenous retinal detachment (RRD) repair with sutureless 23-gauge vitrectomy versus traditional 20-gauge vitrectomy. METHODS: A retrospective, consecutive, interventional comparative case series. All patients with a diagnosis of RRD who underwent pars plana vitrectomy with PFCL for RRD repair from November 1, 2005 through October 31, 2008 were included. RESULTS: A total of 234 RRD repairs were performed during the study period by one surgeon. Subretinal PFCL occurred in 4 of 176 eyes (2.3%) who underwent sutured 20-gauge pars plana vitrectomy and in 6 of 58 eyes (10.3%) who underwent sutureless 23 gauge pars plana vitrectomy for repair of retinal detachment (P = 0.0167, Fisher exact test, 2-tailed). CONCLUSION: There is a statistically significant 4.5-fold increased incidence of retained subretinal PFCL in patients undergoing RRD repair with sutureless 23-gauge vitrectomy versus traditional 20-gauge vitrectomy. This may be because of higher fluid flow through open 23-gauge cannulas, which causes disruption of the PFCL surface tension resulting in formation of small PFCL bubbles that can enter the subretinal space. Reduction of fluid flow may help prevent this complication. PMID- 22534582 TI - ELA-DRA polymorphisms are not associated with Equine Arteritis Virus infection in horses from Argentina. AB - Polymorphisms at Major Histocompatibility Complex (MHC) genes have been associated with resistance/susceptibility to infectious diseases in domestic animals. The aim of this investigation was to evaluate whether polymorphisms of the DRA gene the Equine Lymphocyte Antigen is associated with susceptibility to Equine Arteritis Virus (EAV) infection in horses in Argentina. The equine DRA gene was screened for polymorphisms using Pyrosequencing(r) Technology which allowed the detection of three ELA-DRA exon 2 alleles. Neither allele frequencies nor genotypic differentiation exhibited any statistically significant (P values=0.788 and 0.745) differences between the EAV-infected and no-infected horses. Fisher's exact test and OR calculations did not show any significant association. As a consequence, no association could be established between the serological condition and ELA-DRA. PMID- 22534583 TI - Ultrasonography of the reticulum, rumen, omasum and abomasum before, during and after ingestion of hay and grass silage in 10 calves. AB - The reticulum, rumen, omasum and abomasum were assessed via ultrasonography in 10 healthy female calves before, during and 2 h after feeding hay and grass silage. The evaluations were made using an ultrasound machine with a 5.0 MHz linear transducer. The reticulum could be visualized before feeding in all the calves. Its appearance and pattern of contractions were similar to those in adult cattle, although the amplitude (5.2+/-1.06 cm) and velocity (3.5+/-1.42 cm/s) of the first contraction were markedly less than in adult cattle. The position and size of the entire rumen including the dorsal and ventral sacs and the ruminal contents were assessed. Except for its smaller size, the ultrasonographic appearance of the omasum of calves was similar to that of adult cattle. The abomasum was seen to the left and right of the ventral midline before feeding in all calves; it occupied considerably more space on the left than the right. Compared with its appearance before feeding, the ultrasonographic appearance of the rumen, omasum and abomasum did not change during or after feeding. Ultrasonography is an ideal imaging tool for evaluating the reticulum, rumen, omasum and abomasum before, during and after feeding in calves. PMID- 22534584 TI - Enhancement of heating performance of carbon nanotube sheet with granular metal. AB - A strategy for enhancing the heating performance of freestanding carbon nanotube (CNT) sheet is presented that involves decorating the sheet with granular-type palladium (Pd) particles. When Pd is added to the sheet, the heating efficiency of CNT sheet is increased by a factor of 3.6 (99.9 degrees C cm(2)/W vs 27.3 degrees C cm(2)/W with no Pd). Suppression of convective heat transfer loss attributes to the enhanced heat generation efficiency. However, higher heating response of CNT/Pd sheet was observed compared to CNT sheet, hence suggesting that the electron-lattice energy exchange could be additional heating mechanism in the presence of granular-type particles of Pd having a diameter of 10 nm or less. CNT sheet/Pd is quite stable, retaining its initial characteristics even after 300 cycles of on-off voltage pulses and shows fast thermal responses of the heating and cooling rates being 154 and -248 degrees C/s, respectively. PMID- 22534586 TI - The impacts of DRG-based payments on health care provider behaviors under a universal coverage system: a population-based study. AB - OBJECTIVE: To examine the impacts of diagnosis-related group (DRG) payments on health care provider's behavior under a universal coverage system in Taiwan. METHODS: This study employed a population-based natural experiment study design. Patients who underwent coronary artery bypass graft surgery or percutaneous transluminal coronary angioplasty, which were incorporated in the Taiwan version of DRG payments in 2010, were defined as the intervention group. The comparison group consisted of patients who underwent cardiovascular procedures which were paid for by fee-for-services schemes and were selected by propensity score matching from patients treated by the same group of surgeons. The generalized estimating equations model and difference-in-difference analysis was used in this study. RESULTS: The introduction of DRG payment resulted in a 10% decrease (p<0.001) in patient's length of stay in the intervention group in relation to the comparison group. The intensity of care slightly declined with p<0.001. No significant changes were found concerning health care outcomes measured by emergency department visits, readmissions, and mortality after discharge. CONCLUSION: The DRG-based payment resulted in reduced intensity of care and shortened length of stay. The findings might be valuable to other countries that are developing or reforming their payment system under a universal coverage system. PMID- 22534585 TI - Economies of scale and scope in the Danish hospital sector prior to radical restructuring plans. AB - OBJECTIVE: The Danish hospital sector faces a significant rebuilding program driven by recent regional reform and guidelines for acute admission hospitals. Within the next 5-10 years, the number of public hospitals offering acute admission will be reduced from 35 to approximately 20 larger hospitals. As the administrative data may be biased during the middle of a restructuring process our objective was to analyze whether the configuration of Danish public hospitals was subject to economies of scale and scope prior to the restructuring plans. METHODS: We estimated a quadratic cost function using panel data on the total costs for somatic treatment, casemix adjusted DRG-production values, and other cost drivers for the three years before the 2007 reforms. A short-run cost function was used to derive estimates of a long-run cost function by applying the envelope condition. Next, we estimated economies of scale and scope. RESULTS: We identified moderate-to-significant economies of scale and scope. This indicates that the Danish hospital sector was characterized by unexploited gains from consolidation. CONCLUSIONS: Our results suggest that the proposed plans have the potential to result in hospitals that are more efficient. However, post restructuring studies elsewhere show that the strategy of horizontal integration has failed. PMID- 22534587 TI - Ensuring access to health care--Germany reforms supply structures to tackle inequalities. AB - Germany's ruling coalition has recently introduced a new bill to Parliament, the Care Structures Act (CSA), which aims to improve outpatient care supply structures, decentralize decision-making, facilitate cross-sectoral treatment, and strengthen innovation in the nation's health care sector. These objectives are to be achieved through a variety of measures, including changes in financial incentives for physicians, the transfer of decision-making to the regional level, and the creation of a new sector for highly specialized care. The opposition parties in Parliament and most health care stakeholders agree on the objectives of the reform package, but their evaluation of the bill is mixed. Physicians' representative organizations generally deem the law to be headed in the right direction, while the opposition parties, sickness funds, patients' rights groups and a majority of German federal states (Bundeslander) feel it does not adequately address the issues of supply inequity and sectoral division. This skepticism seems well founded. The reforms aimed at attracting physicians to high need regions have significant shortcomings, and the measures to overcome sectoral barriers between the outpatient care and hospital sectors remain weak. Furthermore, the new procedure for including innovative treatment methods in the SHI benefits catalogue falls short of internationally recognized standards. PMID- 22534588 TI - Contemporary performance of U.S. teaching and nonteaching hospitals. AB - PURPOSE: To compare the performance of U.S. teaching and nonteaching hospitals using a portfolio of contemporary, publicly reported metrics. METHOD: The authors classified acute care general hospitals filing a Medicare Institutional Cost Report according to teaching intensity: nonteaching, teaching, or Council of Teaching Hospitals member. They compared aggregate results across categories for Hospital Compare process compliance, mortality, and readmission rates (acute myocardial infarction [AMI], heart failure, pneumonia); Surgical Care Improvement Project (SCIP) performance; compliance with Leapfrog standards; patient experience; patient services and key technologies; safety (computerized physician order entry, intensive care unit staffing, National Quality Forum safe practices, hospital-acquired conditions); and cost/resource utilization (Medicare-adjusted expense per case; Leapfrog efficiency and resource use standards). RESULTS: Availability of patient services and advanced technologies were associated with teaching intensity (P < .0001), as were most hospital safety metrics. Teaching intensity was favorably associated with SCIP performance, AMI and heart failure process scores, and mortality (P < .0001). It was unfavorably associated with higher AMI and pneumonia readmission rates (P < .0001) and lower scores for individual patient satisfaction measures. Costs per case were similar (P = .4194) across hospital categories after correction for federally allowed adjustments (case mix, wages, and low-income patient care). CONCLUSIONS: Teaching hospitals offer advanced clinical capabilities, educate the next generation of providers, care for disadvantaged urban populations, and are leaders in health care research and innovation. However, many stakeholders may be unaware of an additional value relatively higher quality and safety in many areas, with similar adjusted costs. PMID- 22534589 TI - An educational intervention to improve cost-effective care among medicine housestaff: a randomized controlled trial. AB - PURPOSE: High medical costs create significant burdens. Research indicates that doctors have little awareness of costs. This study tested whether a brief educational intervention could increase residents' awareness of cost effectiveness and reduce costs without negatively affecting patient outcomes. METHOD: The authors conducted a clustered randomized controlled trial of 33 teams (96 residents) at an internal medicine residency program (2009-2010). The intervention was a 45-minute teaching session; residents reviewed the hospital bill of a patient for whom they had cared and discussed reducing unnecessary costs. Primary outcomes were laboratory, pharmacy, radiology, and total hospital costs per admission. Secondary measures were length of stay (LOS), intensive care unit (ICU) admission, 30-day readmission, and 30-day mortality. Multivariate adjustment controlled for patient demographics and health. A follow-up survey assessed resident attitudes three months later. RESULTS: Among 1,194 patients, there were no significant cost differences between intervention and control groups. In the intervention group, 30-day readmission was higher (adjusted odds ratio 1.51, P = .010). There was no effect on LOS or the composite outcome of readmission, mortality, and ICU transfer. In a subgroup analysis of 835 patients newly admitted during the study, the intervention group incurred $163 lower adjusted lab costs per admission (P = .046). The follow-up survey indicated persistent differences in residents' exposure to concepts of cost-effectiveness (P = .041). CONCLUSIONS: A brief intervention featuring a discussion of hospital bills can fill a gap in resident education and reduce laboratory costs for a subset of patients, but may increase readmission risk. PMID- 22534590 TI - Organizational culture in an academic health center: an exploratory study using a competing values framework. AB - PURPOSE: Implementing cultural change and aligning organizational cultures could enhance innovation, quality, safety, and job satisfaction. The authors conducted this mixed-methods study to assess academic physician-scientists' perceptions of the current and preferred future organizational culture at a university medical school and its partner health system. METHOD: In October 2010, the authors surveyed academic physicians and scientists jointly employed by the University of Oxford and its local, major partner health system. The survey included the U.S. Veterans Affairs Administration's 14-item Competing Values Framework instrument and two extra items prompting respondents to identify their substantive employer and to provide any additional open-ended comments. RESULTS: Of 436 academic physicians and scientists, 170 (39%) responded. Of these, 69 (41%) provided open ended comments. Dominant hierarchical culture, moderate rational and team cultures, and underdeveloped entrepreneurial culture characterized the health system culture profile. The university profile was more balanced, with strong rational and entrepreneurial cultures, and moderate-to-strong hierarchical and team cultures. The preferred future culture (within five years) would emphasize team and entrepreneurial cultures and-to a lesser degree-rational culture, and would deemphasize hierarchical culture. CONCLUSIONS: Whereas the university and the health system currently have distinct organizational cultures, academic physicians and scientists would prefer the same type of culture across the two organizations so that both could more successfully pursue the shared mission of academic medicine. Further research should explore strengthening the validity and reliability of the organizational culture instrument for academic medicine and building an evidence base of effective culture change strategies and interventions. PMID- 22534591 TI - Understanding the effects of short-term international service-learning trips on medical students. AB - PURPOSE: The purpose of this qualitative study was to understand what meaning(s) preclinical students attributed to participation in one-week international service-learning trips (ISLTs) and what specific experiences during the trips accounted for such perspectives. METHOD: Twenty-four first-year students who had participated in one-week ISLTs at the University of Michigan Medical School during February 2010 were invited to participate. Individual, semistructured interviews were conducted from March to August 2010 with 13 student participants. Using grounded theory analysis, several major themes were identified. RESULTS: Acquisition of clinical/language skills and knowledge of other health care systems were explicit benefits associated with student ISLT experiences. However, in-depth, reflective discussions revealed implicit insights and lessons, the most pervasive of which were student ambivalence concerning the value and effect of ISLTs on communities, issues of privilege and power, and ethical concerns when working with vulnerable populations. These implicit lessons stimulated new insights into future involvement in global health and emphasized the importance of reflection and discussion to enhance ISLT experiences. CONCLUSIONS: The current study suggests that one-week ISLTs may engender implicit insights and lessons regarding ethical and societal issues involved with global health and may stimulate the development of critical reflection on current and future professional roles for student participants. Furthermore, these activities should allow time and space for dialogue and reflection to ensure that this implicit understanding can be put to constructive educational and service-oriented uses. PMID- 22534592 TI - The relationship between response time and diagnostic accuracy. AB - PURPOSE: Psychologists theorize that cognitive reasoning involves two distinct processes: System 1, which is rapid, unconscious, and contextual, and System 2, which is slow, logical, and rational. According to the literature, diagnostic errors arise primarily from System 1 reasoning, and therefore they are associated with rapid diagnosis. This study tested whether accuracy is associated with shorter or longer times to diagnosis. METHOD: Immediately after the 2010 administration of the Medical Council of Canada Qualifying Examination (MCCQE) Part II at three test centers, the authors recruited participants, who read and diagnosed a series of 25 written cases of varying difficulty. The authors computed accuracy and response time (RT) for each case. RESULTS: Seventy-five Canadian medical graduates (of 95 potential participants) participated. The overall correlation between RT and accuracy was -0.54; accuracy, then, was strongly associated with more rapid RT. This negative relationship with RT held for 23 of 25 cases individually and overall when the authors controlled for participants' knowledge, as judged by their MCCQE Part I and II scores. For 19 of 25 cases, accuracy on each case was positively related to experience with that specific diagnosis. A participant's performance on the test overall was significantly correlated with his or her performance on both the MCCQE Part I and II. CONCLUSIONS: These results are inconsistent with clinical reasoning models that presume that System 1 reasoning is necessarily more error prone than System 2. These results suggest instead that rapid diagnosis is accurate and relates to other measures of competence. PMID- 22534593 TI - A study of national physician organizations' efforts to reduce racial and ethnic health disparities in the United States. AB - PURPOSE: To characterize national physician organizations' efforts to reduce health disparities and identify organizational characteristics associated with such efforts. METHOD: This cross-sectional study was conducted between September 2009 and June 2010. The authors used two-sample t tests and chi-square tests to compare the proportion of organizations with disparity-reducing activities between different organizational types (e.g., primary care versus subspecialty organizations, small [<1,000 members] versus large [>5,000 members]). Inclusion criteria required physician organizations to be (1) focused on physicians, (2) national in scope, and (3) membership based. RESULTS: The number of activities per organization ranged from 0 to 22. Approximately half (53%) of organizations had 0 or 1 disparity-reducing activities. Organizational characteristics associated with having at least 1 disparity-reducing effort included membership size (88% of large groups versus 58% of small groups had at least 1 activity; P = .004) and the presence of a health disparities committee (95% versus 59%; P < .001). Primary care (versus subspecialty) organizations and racial/ethnic minority physician organizations were more likely to have disparity-reducing efforts, although findings were not statistically significant. Common themes addressed by activities were health care access, health care disparities, workforce diversity, and language barriers. Common strategies included education of physicians/trainees and patients/general public, position statements, and advocacy. CONCLUSIONS: Despite the national priority to eliminate health disparities, more than half of national physician organizations are doing little to address this problem. Primary care and minority physician organizations, and those with disparities committees, may provide leadership to extend the scope of disparity-reduction efforts. PMID- 22534594 TI - Construct validity of the reporter-interpreter-manager-educator structure for assessing students' patient encounter skills. AB - PURPOSE: The aim of this study, done in Denmark, was to explore the construct validity of a Reporter-Interpreter-Manager-Educator (RIME)-structured scoring format for assessing patient encounter skills. METHOD: The authors developed a RIME-structured scoring form and explored its construct validity in a two-step procedure. The first step (implemented in 2009) was a randomized, controlled, experimental study in which the performance of three groups (16 fourth-year medical students, 16 sixth-year medical students, and 16 interns) was assessed in two simulated patient encounters. The second step (carried out during 2009-2010) was an observational study of patient encounter skills where clinician examiners used the scoring form in end-of-clerkship oral examinations of three consecutive cohorts of a total of 547 fourth-year medical students. RESULTS: In the experimental study, RIME scores showed significant difference between the three groups-fourth-year students, mean 41.7 (standard deviation [SD] 11.0); sixth-year students, mean 48.2 (SD 10.9); and interns, mean 61.9 (SD 8.5), one-way ANOVA, P < .0001-and showed a progression over the four RIME elements with participants' increasing competence.In the observational study, the mean RIME score was higher (83.8 [SD 15.5]), and advanced RIME levels were frequently missing or scored "not relevant" by the clinician examiners. CONCLUSION: In an experimental setup, the RIME structure demonstrated construct validity in terms of reflecting progress in competence in managing patient encounters when assessed according to an advanced criterion. However, clinician examiners may tacitly score the elements according to what can be expected at a certain level of student experience. PMID- 22534595 TI - Exploring error in team-based acute care scenarios: an observational study from the United kingdom. AB - PURPOSE: To investigate the errors made by junior doctors (first year after primary medical qualification) in simulated acute care settings, using (and, for some purposes, amplifying) a previously published generic error-modeling system (GEMS). Possible error types were skill-based slips and lapses, rule-based mistakes, knowledge-based mistakes, and violations. METHOD: In August 2010, 38 junior doctors participated in high-fidelity simulated acute care scenarios in NHS Lothian, Scotland. Each video-recorded scenario was immediately followed by an audio-recorded debrief that encouraged articulation of underlying cognitive processes. Two researchers used evidence from the scenario, debrief, and field notes to determine which errors were attributable to a single underlying cause. In such cases, the errors were coded by template analysis into the GEMS framework. Errors for which a single cause could be identified but which did not fit the framework were coded inductively. RESULTS: A total of 243 errors were identified, with sufficient evidence available to identify a single cause in 190. Skill-based slips and lapses, rule-based mistakes, and knowledge-based mistakes were all clearly identified within the data. Two error types not originally included in the GEMS framework were identified: compound errors and submission errors. CONCLUSIONS: Amplification of GEMS provides a valid framework for categorization of the errors made by junior doctors in simulated acute care contexts. In addition, the amplified framework may be transferable to other, team based contexts. An improved understanding of the knowledge and skills that are most vulnerable to each specific type of error will allow tailored educational strategies to be developed. PMID- 22534596 TI - Perspective: deconstructing integration: a framework for the rational application of integration as a guiding curricular strategy. AB - In response to historical criticism, evolving accreditation standards, and recent reports on curricula, medical educators and medical schools have been eagerly pursuing integration as a goal of curricular reform. The general education literature broadly considers integration to be the deliberate unification of separate areas of knowledge, and it provides support for the concept that integration better meets the needs of adult learners in professional education. The use of integration as a curricular goal is not without its critics, however, nor is it free of difficulties in implementation. In this perspective, the authors propose that most of these difficulties arise from a failure to recognize that integration is a strategy for curricular development rather than a goal in itself, and they argue that adopting a systematic approach to integration offers many potential benefits. They articulate the conceptual and practical issues that they believe are critical to consider in order to achieve successful curricular integration, and they suggest that integration should be approached as a subset of broader curriculum development decisions. They propose a three-level framework for applying integration as a guiding curricular strategy, in which decisions about integration must follow curricular decisions made at the program level, the course level, and then the individual session level. PMID- 22534597 TI - Have motivation theories guided the development and reform of medical education curricula? A review of the literature. AB - PURPOSE: Educational psychology indicates that learning processes can be mapped on three dimensions: cognitive (what to learn), affective or motivational (why learn), and metacognitive regulation (how to learn). In a truly student-centered medical curriculum, all three dimensions should guide curriculum developers in constructing learning environments. The authors explored whether student motivation has guided medical education curriculum developments. METHOD: The authors reviewed the literature on motivation theory related to education and on medical education curriculum development to identify major developments. Using the Learning-Oriented Teaching model as a framework, they evaluated the extent to which motivation theory has guided medical education curriculum developers. RESULTS: Major developments in the field of motivation theory indicate that motivation drives learning and influences students' academic performance, that gender differences exist in motivational mechanisms, and that the focus has shifted from quantity of motivation to quality of motivation and its determinants, and how they stimulate academic motivation. Major developments in medical curricula include the introduction of standardized and regulated medical education as well as problem-based, learner-centered, integrated teaching, outcome-based, and community-based approaches. These curricular changes have been based more on improving students' cognitive processing of content or metacognitive regulation than on stimulating motivation. CONCLUSIONS: Motivational processes may be a substantially undervalued factor in curriculum development. Building curricula to specifically stimulate motivation in students may powerfully influence the outcomes of curricula. The elements essential for stimulating intrinsic motivation in students, including autonomy support, adequate feedback, and emotional support, appear lacking as a primary aim in many curricular plans. PMID- 22534598 TI - Cultural competency 2.0: exploring the concept of "difference" in engagement with the other. AB - Cultural competency efforts have received much attention in medical education. Most efforts focus on the acquisition of knowledge and skills about various groups based on race and ethnic identity, national origins, religion, and the like. The authors propose an approach, "Cultural Competency 2.0," that does not reject such efforts but, rather, adds a more critical and expanded focus on learners' attitudes and beliefs toward people unlike themselves. Cultural Competency 2.0 includes learners' examination of the social position of most U.S. medical students, Bourdieu's concept of habitus, and the phenomenon of countertransference to come to new critical insights on learners' attitudes, beliefs, and, ultimately, interactions with all patients. Suggestions are offered for how and where Cultural Competency 2.0 can be used in the curriculum through narrative medicine, particularly through the development of reading practices that unmask illusions of "pure" objectivity often assumed in clinical settings, and that make visible how words and images constrain, manipulate, or empower individuals, groups, ideas, or practices.The authors argue that these educational approaches should be sustained throughout the students' clinical experiences, where they encounter patients of many kinds and see clinicians' varied approaches to these patients. Further, these educational approaches should include assisting students in developing strategies to exercise moral courage within the limitations of their hierarchical learning environments, to strengthen their voices, and, when possible, to develop a sense of fearlessness: to always be advocates for their patients and to do what is right, fair, and good in their care. PMID- 22534599 TI - The impact of a program in mindful communication on primary care physicians. AB - PURPOSE: In addition to structural transformations, deeper changes are needed to enhance physicians' sense of meaning and satisfaction with their work and their ability to respond creatively to a dynamically changing practice environment. The purpose of this research was to understand what aspects of a successful continuing education program in mindful communication contributed to physicians' well-being and the care they provide. METHOD: In 2008, the authors conducted in depth, semistructured interviews with primary care physicians who had recently completed a 52-hour mindful communication program demonstrated to reduce psychological distress and burnout while improving empathy. Interviews with a random sample of 20 of the 46 physicians in the Rochester, New York, area who attended at least four of eight weekly sessions and four of eight monthly sessions were audio-recorded, transcribed, and analyzed qualitatively. The authors identified salient themes from the interviews. RESULTS: Participants reported three main themes: (1) sharing personal experiences from medical practice with colleagues reduced professional isolation, (2) mindfulness skills improved the participants' ability to be attentive and listen deeply to patients' concerns, respond to patients more effectively, and develop adaptive reserve, and (3) developing greater self-awareness was positive and transformative, yet participants struggled to give themselves permission to attend to their own personal growth. CONCLUSIONS: Interventions to improve the quality of primary care practice and practitioner well-being should promote a sense of community, specific mindfulness skills, and permission and time devoted to personal growth. PMID- 22534600 TI - Cultural competence springs up in the desert: the story of the center for cultural competence in health care at Weill Cornell Medical College in Qatar. AB - The authors describe the factors that led Weill Cornell Medical College in Qatar (WCMC-Q) to establish the Center for Cultural Competence in Health Care from the ground up, and they explore challenges and successes in implementing cultural competence training.Qatar's capital, Doha, is an extremely high-density multicultural setting. When WCMC-Q's first class of medical students began their clinical clerkships at the affiliated teaching hospital Hamad Medical Corporation in 2006, the complicated nature of training in a multicultural and multilingual setting became apparent immediately. In response, initiatives to improve students' cultural competence were undertaken. Initiatives included launching a medical interpretation program in 2007; surveying the patients' spoken languages, examining the effect of an orientation program on interpretation requests, and surveying faculty using the Tool for Assessing Cultural Competence Training in 2008; implementing cultural competence training for students and securing research funding in 2009; and expanding awareness to the Qatar community in 2010. These types of initiatives, which are generally highly valued in U.S. and Canadian settings, are also apropos in the Arabian Gulf region.The authors report on their initial efforts, which can serve as a resource for other programs in the Arabian Gulf region. PMID- 22534601 TI - Developing a sustainable electronic portfolio (ePortfolio) program that fosters reflective practice and incorporates CanMEDS competencies into the undergraduate medical curriculum. AB - The University of Ottawa (uOttawa) Faculty of Medicine in 2008 launched a revised undergraduate medical education (UGME) curriculum that was based on the seven CanMEDS roles (medical expert, communicator, collaborator, health advocate, manager, scholar, and professional) and added an eighth role of person to incorporate the dimension of mindfulness and personal well-being. In this article, the authors describe the development of an electronic Portfolio (ePortfolio) program that enables uOttawa medical students to document their activities and to demonstrate their development of competence in each of the eight roles. The ePortfolio program supports reflective practice, an important component of professional competence, and provides a means for addressing the "hidden curriculum." It is bilingual, mandatory, and spans the four years of UGME. It includes both an online component for students to document their personal development and for student-coach dialogue, as well as twice-yearly, small-group meetings in which students engage in reflective discussions and learn to give and receive feedback.The authors reflect on the challenges they faced in the development and implementation of the ePortfolio program and share the lessons they have learned along the way to a successful and sustainable program. These lessons include switching from a complex information technology system to a user-friendly, Web-based blog platform; rethinking orientation sessions to ensure that faculty and students understand the value of the ePortfolio program; soliciting student input to improve the program and increase student buy-in; and providing faculty development opportunities and recognition. PMID- 22534602 TI - Medical student self-efficacy with family-centered care during bedside rounds. AB - PURPOSE: Factors that support self-efficacy in family-centered care (FCC) must be understood in order to foster FCC in trainees. Using social cognitive theory, the authors examined (1) how three supportive experiences (observing role models, practicing for mastery, and receiving feedback) influence self-efficacy with FCC during rounds and (2) whether the influence of these supportive experiences was mediated by self-efficacy with three key FCC tasks (relationship building, information exchange, and decision making). METHOD: Researchers surveyed third year students during pediatric clerkship rotations during the 2008-2011 academic years. Surveys assessed supportive experiences and students' self-efficacy both with FCC during rounds and with key FCC tasks. Researchers constructed measurement models via exploratory and confirmatory factor analyses. Composite indicator structural equation models evaluated whether supportive experiences influenced self-efficacy with FCC during rounds and whether self-efficacy with key FCC tasks mediated any such influences. RESULTS: Of 184 eligible students, 172 (93%) completed preclerkship surveys. Observing role models and practicing for mastery supported self-efficacy with FCC during rounds (each P < .01), whereas receiving feedback did not. Self-efficacy with two specific FCC tasks relationship building and decision making (each P < .05)-mediated the effects of these two supportive experiences on self-efficacy with FCC during rounds. CONCLUSIONS: Both observing role models and practicing for mastery foster students' self-efficacy with FCC during rounds, operating through self-efficacy with key FCC tasks. Results suggest the importance both of helping students gain self-efficacy in key FCC tasks before rounds and of helping educators implement supportive experiences during rounds. PMID- 22534603 TI - Revisiting cognitive and learning styles in computer-assisted instruction: not so useful after all. AB - In a previous systematic review, the author proposed that adaptation to learners' cognitive and learning styles (CLSs) could improve the efficiency of computer assisted instruction (CAI). In the present article, he questions that proposition, arguing that CLSs do not make a substantive difference in CAI. To support this argument, the author performed an updated systematic literature search, pooled new findings with those from the previous review, and reinterpreted this evidence with a focus on aptitude-treatment interactions. (An aptitude-treatment interaction occurs when a student with attribute 1 learns better with instructional approach A than with approach B, whereas a student with attribute 2 learns better with instructional approach B).Of 65 analyses reported in 48 studies, only 9 analyses (14%) showed significant interactions between CLS and instructional approach. It seems that aptitude-treatment interactions with CLSs are at best infrequent and small in magnitude. There are several possible explanations for this lack of effect. First, the influence of strong instructional methods likely dominates the impact of CLSs. Second, current methods for assessing CLSs lack validity evidence and are inadequate to accurately characterize the individual learner. Third, theories are vague, and empiric evidence is virtually nonexistent to guide the planning of style-targeted instructional designs. Adaptation to learners' CLSs thus seems unlikely to enhance CAI. The author recommends that educators focus on employing strong instructional methods. Educators might also consider assessing and adapting to learners' prior knowledge or allowing learners to select among alternate instructional approaches. PMID- 22534604 TI - Risk factors for acute respiratory failure in bariatric surgery: data from the Nationwide Inpatient Sample, 2006-2008. AB - BACKGROUND: Acute respiratory failure (ARF) can be a life-threatening postoperative complication after bariatric surgery and is defined as the presence of acute respiratory distress or pulmonary insufficiency. We sought to identify predictors of ARF in patients who underwent bariatric surgery. METHODS: Using the Nationwide Inpatient Sample database, from 2006 to 2008, the clinical data from morbidly obese patients who underwent bariatric surgery were examined. Multivariate regression analysis was performed to identify the independent factors predictive of ARF. The factors examined included patient characteristics, co-morbidities, payer type, teaching status of hospital, surgical techniques (laparoscopic versus open), and type of bariatric operation (gastric bypass versus nongastric bypass). RESULTS: A total of 304,515 patients underwent bariatric surgery during the 3-year period. The overall ARF rate was 1.35%. The greatest rate of ARF (4.10%) was observed after open gastric bypass surgery. The ARF rate was lower after laparoscopic than after the open surgical technique (.94% versus 3.87%, respectively; P < .01) and after nongastric bypass versus gastric bypass (.82% versus 1.54%, respectively; P < .01). Using multivariate regression analysis, congestive heart failure (adjusted odds ratio [AOR] 5.1), open surgery (AOR 3.3), chronic renal failure (AOR 2.9), gastric bypass (AOR 2.5), peripheral vascular disease (AOR 2.4), male gender (AOR 1.9), age >50 years (AOR 1.8), Medicare payer (AOR 1.8), alcohol abuse (AOR 1.8), chronic lung disease (AOR 1.6), diabetes mellitus (AOR 1.2), and smoking (AOR 1.1) were factors associated with greater rates of ARF. Compared with patients without ARF, patients with ARF had significantly greater in-hospital mortality (5.69% versus .04%, P < .01). CONCLUSION: We identified multiple risk factors that have an effect on the development of acute respiratory failure after bariatric surgery. Surgeons should consider these factors in surgical decision-making and inform patients of their risk of this potentially life-threatening complication. PMID- 22534605 TI - Pancreaticoduodenectomy for pancreatic carcinoma after complicated open Roux-en-Y gastric bypass surgery: an alternative approach to reconstruction. PMID- 22534606 TI - Leaf microbiota in an agroecosystem: spatiotemporal variation in bacterial community composition on field-grown lettuce. AB - The presence, size and importance of bacterial communities on plant leaf surfaces are widely appreciated. However, information is scarce regarding their composition and how it changes along geographical and seasonal scales. We collected 106 samples of field-grown Romaine lettuce from commercial production regions in California and Arizona during the 2009-2010 crop cycle. Total bacterial populations averaged between 10(5) and 10(6) per gram of tissue, whereas counts of culturable bacteria were on average one (summer season) or two (winter season) orders of magnitude lower. Pyrosequencing of 16S rRNA gene amplicons from 88 samples revealed that Proteobacteria, Firmicutes, Bacteroidetes and Actinobacteria were the most abundantly represented phyla. At the genus level, Pseudomonas, Bacillus, Massilia, Arthrobacter and Pantoea were the most consistently found across samples, suggesting that they form the bacterial 'core' phyllosphere microbiota on lettuce. The foliar presence of Xanthomonas campestris pv. vitians, which is the causal agent of bacterial leaf spot of lettuce, correlated positively with the relative representation of bacteria from the genus Alkanindiges, but negatively with Bacillus, Erwinia and Pantoea. Summer samples showed an overrepresentation of Enterobacteriaceae sequences and culturable coliforms compared with winter samples. The distance between fields or the timing of a dust storm, but not Romaine cultivar, explained differences in bacterial community composition between several of the fields sampled. As one of the largest surveys of leaf surface microbiology, this study offers new insights into the extent and underlying causes of variability in bacterial community composition on plant leaves as a function of time, space and environment. PMID- 22534607 TI - Functional metagenomics reveals novel salt tolerance loci from the human gut microbiome. AB - Metagenomics is a powerful tool that allows for the culture-independent analysis of complex microbial communities. One of the most complex and dense microbial ecosystems known is that of the human distal colon, with cell densities reaching up to 10(12) per gram of faeces. With the majority of species as yet uncultured, there are an enormous number of novel genes awaiting discovery. In the current study, we conducted a functional screen of a metagenomic library of the human gut microbiota for potential salt-tolerant clones. Using transposon mutagenesis, three genes were identified from a single clone exhibiting high levels of identity to a species from the genus Collinsella (closest relative being Collinsella aerofaciens) (COLAER_01955, COLAER_01957 and COLAER_01981), a high G+C, Gram-positive member of the Actinobacteria commonly found in the human gut. The encoded proteins exhibit a strong similarity to GalE, MurB and MazG. Furthermore, pyrosequencing and bioinformatic analysis of two additional fosmid clones revealed the presence of an additional galE and mazG gene, with the highest level of genetic identity to Akkermansia muciniphila and Eggerthella sp. YY7918, respectively. Cloning and heterologous expression of the genes in the osmosensitive strain, Escherichia coli MKH13, resulted in increased salt tolerance of the transformed cells. It is hoped that the identification of atypical salt tolerance genes will help to further elucidate novel salt tolerance mechanisms, and will assist our increased understanding how resident bacteria cope with the osmolarity of the gastrointestinal tract. PMID- 22534608 TI - Comparison of large-insert, small-insert and pyrosequencing libraries for metagenomic analysis. AB - The development of DNA sequencing methods for characterizing microbial communities has evolved rapidly over the past decades. To evaluate more traditional, as well as newer methodologies for DNA library preparation and sequencing, we compared fosmid, short-insert shotgun and 454 pyrosequencing libraries prepared from the same metagenomic DNA samples. GC content was elevated in all fosmid libraries, compared with shotgun and 454 libraries. Taxonomic composition of the different libraries suggested that this was caused by a relative underrepresentation of dominant taxonomic groups with low GC content, notably Prochlorales and the SAR11 cluster, in fosmid libraries. While these abundant taxa had a large impact on library representation, we also observed a positive correlation between taxon GC content and fosmid library representation in other low-GC taxa, suggesting a general trend. Analysis of gene category representation in different libraries indicated that the functional composition of a library was largely a reflection of its taxonomic composition, and no additional systematic biases against particular functional categories were detected at the level of sequencing depth in our samples. Another important but less predictable factor influencing the apparent taxonomic and functional library composition was the read length afforded by the different sequencing technologies. Our comparisons and analyses provide a detailed perspective on the influence of library type on the recovery of microbial taxa in metagenomic libraries and underscore the different uses and utilities of more traditional, as well as contemporary 'next-generation' DNA library construction and sequencing technologies for exploring the genomics of the natural microbial world. PMID- 22534609 TI - Diversity patterns and activity of uncultured marine heterotrophic flagellates unveiled with pyrosequencing. AB - Flagellated heterotrophic microeukaryotes have key roles for the functioning of marine ecosystems as they channel large amounts of organic carbon to the upper trophic levels and control the population sizes of bacteria and archaea. Still, we know very little on the diversity patterns of most groups constituting this evolutionary heterogeneous assemblage. Here, we investigate 11 groups of uncultured flagellates known as MArine STramenopiles (MASTs). MASTs are ecologically very important and branch at the base of stramenopiles. We explored the diversity patterns of MASTs using pyrosequencing (18S rDNA) in coastal European waters. We found that MAST groups range from highly to lowly diversified. Pyrosequencing (hereafter '454') allowed us to approach to the limits of taxonomic diversity for all MAST groups, which varied in one order of magnitude (tens to hundreds) in terms of operational taxonomic units (98% similarity). We did not evidence large differences in activity, as indicated by ratios of DNA:RNA-reads. Most groups were strictly planktonic, although we found some groups that were active in sediments and even in anoxic waters. The proportion of reads per size fraction indicated that most groups were composed of very small cells (~2-5 MUm). In addition, phylogenetically different assemblages appeared to be present in different size fractions, depths and geographic zones. Thus, MAST diversity seems to be highly partitioned in spatial scales. Altogether, our results shed light on these ecologically very important but poorly known groups of uncultured marine flagellates. PMID- 22534610 TI - A metaproteomic assessment of winter and summer bacterioplankton from Antarctic Peninsula coastal surface waters. AB - A metaproteomic survey of surface coastal waters near Palmer Station on the Antarctic Peninsula, West Antarctica, was performed, revealing marked differences in the functional capacity of summer and winter communities of bacterioplankton. Proteins from Flavobacteria were more abundant in the summer metaproteome, whereas winter was characterized by proteins from ammonia-oxidizing Marine Group I Crenarchaeota. Proteins prevalent in both seasons were from SAR11 and Rhodobacterales clades of Alphaproteobacteria, as well as many lineages of Gammaproteobacteria. The metaproteome data were used to elucidate the main metabolic and energy generation pathways and transport processes occurring at the microbial level in each season. In summer, autotrophic carbon assimilation appears to be driven by oxygenic photoautotrophy, consistent with high light availability and intensity. In contrast, during the dark polar winter, the metaproteome supported the occurrence of chemolithoautotrophy via the 3 hydroxypropionate/4-hydroxybutyrate cycle and the reverse tricarboxylic acid cycle of ammonia-oxidizing archaea and nitrite-oxidizing bacteria, respectively. Proteins involved in nitrification were also detected in the metaproteome. Taurine appears to be an important source of carbon and nitrogen for heterotrophs (especially SAR11), with transporters and enzymes for taurine uptake and degradation abundant in the metaproteome. Divergent heterotrophic strategies for Alphaproteobacteria and Flavobacteria were indicated by the metaproteome data, with Alphaproteobacteria capturing (by high-affinity transport) and processing labile solutes, and Flavobacteria expressing outer membrane receptors for particle adhesion to facilitate the exploitation of non-labile substrates. TonB dependent receptors from Gammaproteobacteria and Flavobacteria (particularly in summer) were abundant, indicating that scavenging of substrates was likely an important strategy for these clades of Southern Ocean bacteria. This study provides the first insight into differences in functional processes occurring between summer and winter microbial communities in coastal Antarctic waters, and particularly highlights the important role that 'dark' carbon fixation has in winter. PMID- 22534612 TI - Hybrid carotid stent for the management of a venous aneurysm of the sigmoid sinus treated by sole stenting. AB - We describe the case of a 59-year-old female presenting with a disabling pulsatile tinnitus caused by a venous aneurysm of the sigmoid sinus. This is the first successful case of sole stenting, using a closed-cell design in the central part of the stent, leading to the occlusion of the aneurysm and the cure of the tinnitus. Venous aneurysms of the dural sinuses are rare causes of pulsatile tinnitus and the sole stenting technique provides a simpler, safe, and effective approach. PMID- 22534611 TI - A metagenomic assessment of winter and summer bacterioplankton from Antarctica Peninsula coastal surface waters. AB - Antarctic surface oceans are well-studied during summer when irradiance levels are high, sea ice is melting and primary productivity is at a maximum. Coincident with this timing, the bacterioplankton respond with significant increases in secondary productivity. Little is known about bacterioplankton in winter when darkness and sea-ice cover inhibit photoautotrophic primary production. We report here an environmental genomic and small subunit ribosomal RNA (SSU rRNA) analysis of winter and summer Antarctic Peninsula coastal seawater bacterioplankton. Intense inter-seasonal differences were reflected through shifts in community composition and functional capacities encoded in winter and summer environmental genomes with significantly higher phylogenetic and functional diversity in winter. In general, inferred metabolisms of summer bacterioplankton were characterized by chemoheterotrophy, photoheterotrophy and aerobic anoxygenic photosynthesis while the winter community included the capacity for bacterial and archaeal chemolithoautotrophy. Chemolithoautotrophic pathways were dominant in winter and were similar to those recently reported in global 'dark ocean' mesopelagic waters. If chemolithoautotrophy is widespread in the Southern Ocean in winter, this process may be a previously unaccounted carbon sink and may help account for the unexplained anomalies in surface inorganic nitrogen content. PMID- 22534613 TI - Gene expression profiling in acute Stanford type B aortic dissection. AB - OBJECTIVE: To compare the gene expression profiles of the aorta specimens between patients with Stanford type B aortic dissection (AD) and controls. MATERIALS AND METHODS: Samples of descending aorta were collected from patients with type B AD (n = 12) and from multiorgan donors as controls (n = 12). Phalanx whole genome microarray was used to analyze differential gene expression. RESULTS: Of the 6375 probes validated, 623 genes were found to be differentially expressed between patients with type B AD and controls (fold change >=2). Gene ontology analysis identified significantly enriched gene groups pertaining to cell-cell adhesion, extracellular matrix, cell-matrix adhesion, cytoskeleton, immune and inflammatory response, and apoptosis. CONCLUSION: Genes encoding components related to integrity and strength of the aortic wall were downregulated, whereas those related to inflammatory response were upregulated in type B AD. The altered patterns of gene expression indicate preexisting structural defects that are probably a consequence of insufficient remodeling of the aortic wall. PMID- 22534614 TI - Those famous red pills-Deliberations and hesitations. Ethics of placebo use in therapeutic and research settings. AB - Placebo fascinates and mystifies. Even with today's medical science we still do not know how and if it works. The use of placebo both in therapy and in research evokes ethical problems that are not easily resolved either. Placebo is intrinsically linked to deception, while veracity is a basic tenet in today's thinking of a doctor-patient relationship. In research ethics placebo, though considered the golden control condition, leads to the question of the therapeutic obligation. This narrative review presents an overview of these ethical questions and offers considerations that are of relevance to daily medical and research practice both in psychiatry and elsewhere. PMID- 22534615 TI - New triggers and non-motor findings in a family with rapid-onset dystonia parkinsonism. AB - BACKGROUND: A woman from Italy presented with dystonic leg symptoms at the age of 59. Rapid-onset dystonia-parkinsonism (RDP) was not suspected until 3 affected children (2 male, 1 female) with presentations consistent with the disorder were recognized. METHODS: The mother and four of her children (3 with and 1 without dystonia) were evaluated with an extensive battery including standardized history questionnaire and rating scales. In addition, all four children had cognitive testing and three of the four children had psychiatric interviews. RESULTS: In this family, a T613M mutation in the ATP1A3 gene was confirmed, the most common mutation present in patients with RDP. The proband's limb dystonia was atypical of RDP, symptoms of the others affected included dysarthria, asymmetric limb dystonia, and dysphagia more consistent with RDP. The two sons developed dystonia parkinsonism in adolescence after consuming large amounts of alcohol. All 3 of those with psychiatric interviews reached diagnosable thresholds for mood disorder (bipolar or dysthymia) and some form of anxiety disorder. CONCLUSIONS: The phenotype and age of onset is broader than previously reported in RDP, suggesting that it could be under-reported. Prior to this study, neuropsychologic symptoms associated with RDP were under-appreciated. Those patients who are at risk or suspected of having RDP should be cautioned to avoid excessive alcohol intake. Further study is needed to assess if the cognitive and psychiatric features are part of a broader RDP phenotype and this may have implications for future research into genetic susceptibility for psychiatric disease. PMID- 22534616 TI - Twice-daily fludarabine and cytarabine combination with or without gentuzumab ozogamicin is effective in patients with relapsed/refractory acute myeloid leukemia, high-risk myelodysplastic syndrome, and blast- phase chronic myeloid leukemia. AB - We evaluated the efficacy and safety of the combination of twice-daily fludarabine and cytarabine (BIDFA) in patients with refractory/relapsed acute myeloid leukemia (AML), high-risk myelodysplastic syndromes (MDS), and chronic myeloid leukemia in myeloid blast phase (CML-BP). One hundred seven patients were enrolled. Overall, 27 (26%) patients responded with a complete remission (CR) rate of 21% and CR without platelet recovery (CRp) of 5%. The overall 4-week mortality rate was 9%. In conclusion, BIDFA is active and safe in heavily pretreated patients with myeloid malignancies. BACKGROUND: The purpose of this study was to evaluate the efficacy and safety of the combination of twice-daily fludarabine and cytarabine (BIDFA) in patients with refractory/relapsed acute myeloid leukemia (AML), high-risk myelodysplastic syndromes (MDS), and chronic myeloid leukemia in myeloid blast phase (CML-BP). PATIENTS AND METHODS: One hundred seven patients with refractory/relapsed AML, intermediate and high-risk MDS, and CML-BP, with a performance status of 3 or less and normal organ function were treated. Patients received fludarabine 15 mg/m(2) intravenously (IV) every 12 hours on days 1 to 5 and cytarabine 0.5 g/m(2) IV over 2 hours every 12 hours on days 1 to 5. Gemtuzumab ozogamicin (GO) was administered at 3 mg/m(2) IV on day 1 in the first 59 patients. Patients with CML-BP were allowed to receive concomitant tyrosine kinase inhibitors. RESULTS: Overall, 27 (26%) patients responded with a complete remission (CR) rate of 21% and CR without platelet recovery of 5%. The overall 4-week mortality rate was 9%. The CR rates for patients with relapsed AML with first CR duration greater than or equal to 12 months, relapsed AML with first CR duration less than 12 months, and refractory/relapsed AML beyond first salvage were 56%, 26%, and 11%, respectively. With a median follow-up of 7 months, the 6-month event-free survival, overall survival, and complete remission CR duration rates were 18%, 35%, and 70%, respectively. CONCLUSION: BIDFA is active with an overall response rate of 26% in a heavily pretreated population. This combination is safe with a low 4-week mortality rate of 9%. PMID- 22534617 TI - Rare frontal lobe intraparenchymal epidermoid cyst with atypical imaging. AB - Epidermoid cysts are slow-growing benign tumors derived from ectodermal tissue that are hypothesized to have been inwardly displaced from the ectodermal surfaces during embryologic development. These cysts represent 1% to 2% of all intracranial tumors, and occur most commonly in the cerebellopontine angle, parasellar region, and subarachnoid spaces of the basal cisterns. Epidermoid cysts that are exclusively intraparenchymal are very rare, and can be difficult to diagnose as they often do not have classic radiologic findings, and share many similar radiologic features to other tumors such as astrocytomas, arachnoid cysts, dermoid cysts, and cavernomas. The authors present a patient with a rare intraparenchymal epidermoid cyst of the frontal lobe with atypical imaging features. PMID- 22534618 TI - Cancer-testis and melanocyte-differentiation antigen expression in malignant glioma and meningioma. AB - Identification of well-defined glioma-specific antigens is a crucial and necessary step in developing immunotherapy for glioblastoma multiforme (GBM). In this study, we analyzed the composite expression of cancer-testis antigens (CTA) and melanocyte-differentiation antigens (MDA) in malignant glioma tissue and primary glioma cell lines and compared them with normal brain specimens and meningioma. CTA and MDA expression was assessed by the reverse transcription polymerase chain reaction. The following primers were analyzed for CTA: LAGE-1, NY-ESO-1, MAGE-1, MAGE-3, MAGE-4, MAGE-10, CT-7, CT-10, HOM-MEL 40, BAGE, and SCP 1; and for MDA: tyrosinase, gp100, MELAN-A/MART-1, and TRP-2. The expression level was determined by ethidium bromide-stained agarose gel. Among malignant glioma tissue, the highest CTA and MDA expression rates were found for MAGE-3 (22%), MAGE-1 (16%), CT-7 (11%), gp100 (40%), and TRP-2 (29%). Among primary glioma cell lines, the highest levels of expression were: CT-10 (38%), gp100 (100%), and TRP-2 (31%). NY-ESO-1 was the only CTA demonstrated and seen in 12% of meningioma tissue specimens. TRP-2 and gp100 were expressed in 65% and 38% of meningioma tissue, respectively; gp100 and TRP-2 were expressed in 100% and 50% of meningioma cell lines. Of the nine normal brain specimens, all samples tested positive for TRP-2. All other CTA and MDA tested negative in normal brain. We conclude that CTA and MDA demonstrate low-to-variable levels of expression within GBM. However, two CTA (MAGE-1 and MAGE-3) and one MDA (gp100) may be considered candidate antigens based on their restricted expression in GBM. These results will greatly accelerate the development of novel, specific immunotherapeutic strategies. PMID- 22534620 TI - Sphingosine 1-phosphate as a therapeutic target in heart failure: more questions than answers. PMID- 22534621 TI - Tumor necrosis factor-alpha-mediated downregulation of the cystic fibrosis transmembrane conductance regulator drives pathological sphingosine-1-phosphate signaling in a mouse model of heart failure. AB - BACKGROUND: Sphingosine-1-phosphate (S1P) signaling is a central regulator of resistance artery tone. Therefore, S1P levels need to be tightly controlled through the delicate interplay of its generating enzyme sphingosine kinase 1 and its functional antagonist S1P phosphohydrolase-1. The intracellular localization of S1P phosphohydrolase-1 necessitates the import of extracellular S1P into the intracellular compartment before its degradation. The present investigation proposes that the cystic fibrosis transmembrane conductance regulator transports extracellular S1P and hence modulates microvascular S1P signaling in health and disease. METHODS AND RESULTS: In cultured murine vascular smooth muscle cells in vitro and isolated murine mesenteric and posterior cerebral resistance arteries ex vivo, the cystic fibrosis transmembrane conductance regulator (1) is critical for S1P uptake; (2) modulates S1P-dependent responses; and (3) is downregulated in vitro and in vivo by tumor necrosis factor-alpha, with significant functional consequences for S1P signaling and vascular tone. In heart failure, tumor necrosis factor-alpha downregulates the cystic fibrosis transmembrane conductance regulator across several organs, including the heart, lung, and brain, suggesting that it is a fundamental mechanism with implications for systemic S1P effects. CONCLUSIONS: We identify the cystic fibrosis transmembrane conductance regulator as a critical regulatory site for S1P signaling; its tumor necrosis factor-alpha dependent downregulation in heart failure underlies an enhancement in microvascular tone. This molecular mechanism potentially represents a novel and highly strategic therapeutic target for cardiovascular conditions involving inflammation. PMID- 22534622 TI - Graphene oxide as an acid catalyst for the room temperature ring opening of epoxides. AB - The minute amount of hydrogen sulfate groups introduced into the graphene oxide (GO) obtained by Hummers oxidation of graphite renders this material as a highly efficient, recyclable acid catalyst for the ring opening of epoxides with methanol and other primary alcohols as nucleophile and solvent. PMID- 22534623 TI - A role for the insular cortex in long-term memory for context-evoked drug craving in rats. AB - Drug craving critically depends on the function of the interoceptive insular cortex, and may be triggered by contextual cues. However, the role of the insula in the long-term memory linking context with drug craving remains unknown. Such a memory trace probably resides in some neocortical region, much like other declarative memories. Studies in humans and rats suggest that the insula may include such a region. Rats chronically implanted with bilateral injection cannulae into the high-order rostral agranular insular cortex (RAIC) or the primary interoceptive posterior insula (pIC) were conditioned to prefer the initially aversive compartment of a 2-compartment place preference apparatus by repeatedly pairing it to amphetamine. We found a reversible but long-lasting loss (ca. 24 days) of amphetamine-conditioned place preference (CPP) and a decreased expression in the insula of zif268, a crucial protein in memory reconsolidation, when anisomycin (ANI) was microinjected into the RAIC immediately after the reactivation of the conditioned amphetamine/context memory. ANI infusion into the RAIC without reactivation did not change CPP, whereas ANI infusion into pIC plus caused a 15 days loss of CPP. We also found a 24 days loss of CPP when we reversibly inactivated pIC during extinction trials. We interpret these findings as evidence that the insular cortex, including the RAIC, is involved in a context/drug effect association. These results add a drug-related memory function to the insular cortex to the previously found role of the pIC in the perception of craving or malaise. PMID- 22534624 TI - Novel cues reinstate cocaine-seeking behavior and induce Fos protein expression as effectively as conditioned cues. AB - Cue reinstatement of extinguished cocaine-seeking behavior is a widely used model of cue-elicited craving in abstinent human addicts. This study examined Fos protein expression in response to cocaine cues or to novel cues as a control for activation produced by test novelty. Rats were trained to self-administer cocaine paired with either a light or a tone cue, or received yoked saline and cue presentations, and then underwent daily extinction training. They were then tested for reinstatement of extinguished cocaine-seeking behavior elicited by response-contingent presentations of either the cocaine-paired cue or a novel cue (that is, tone for those trained with a light or vice versa). Surprisingly, conditioned and novel cues both reinstated responding and increased Fos similarly in most brain regions. Exceptions included the anterior cingulate, which was sensitive to test cue modality in saline controls and the dorsomedial caudate putamen, where Fos was correlated with responding in the novel, but not conditioned, cue groups. In subsequent experiments, we observed a similar pattern of reinstatement in rats trained and tested for sucrose-seeking behavior, whereas rats trained and tested with the cues only reinstated to a novel, and not a familiar, light or tone. The results suggest that novel cues reinstate responding to a similar extent as conditioned cues regardless of whether animals have a reinforcement history with cocaine or sucrose, and that both types of cues activate similar brain circuits. Several explanations as to why converging processes may drive drug and novel cue reinforcement and seeking behavior are discussed. PMID- 22534628 TI - Basal glucagonlike peptide 1 levels and metabolic syndrome in obese patients. AB - OBJECTIVE: Glucagonlike peptide 1 (GLP-1) is the most potent stimulator of glucose-induced insulin secretion. The purpose of the present study was to investigate the relationships of basal circulating GLP-1 and metabolic syndrome in obese patients without cardiovascular disease. MATERIALS AND METHODS: A sample of 202 obese patients was enrolled. Dietary intake, weight, bioimpedance, blood pressure, fasting glucose, insulin, C-reactive protein, total cholesterol, low density lipoprotein cholesterol, high-density lipoprotein cholesterol, blood triglycerides, and GLP-1 levels were measured in all patients. To estimate the prevalence of metabolic syndrome, the definitions of the Adult Treatment Panel III was considered. RESULTS: Patients were divided at the median of GLP-1 value (8.02 ng/dL): group 1 (n = 101) and group 2 (n = 101). Metabolic syndrome (MS) prevalence was higher in patients with the lowest median group of GLP-1 (52.5% vs 38.6%; P < 0.05). Correlation analysis showed a significant correlation among serum GLP-1 levels and the independent variables; waist-to-hip ratio (r = -0.15; P < 0.05), glucose (r = -0.15; P < 0.05), total cholesterol (r = -0.22; P < 0.05), and low-density lipoprotein cholesterol (r = -0.27; P < 0.05). In the logistic analysis with MS presence/absence as an independent variable, only weight and GLP-1 levels remained in the model. Weight shows an odds ratio of 1.10 (95% confidence interval, 1.06-1.13) by each increase of 1 kg of weight, and GLP 1 levels shows an odds ratio of 0.89 (95% confidence interval, 0.80-0.99) by each increase of 1 ng/dL of GLP-1 levels. CONCLUSIONS: Obese patients with MS had lower mean GLP-1 levels than those without MS. Glucagonlike peptide 1 levels remained as a preventive factor to develop MS. PMID- 22534625 TI - Functional connectivity in brain networks underlying cognitive control in chronic cannabis users. AB - The long-term effect of regular cannabis use on brain function underlying cognitive control remains equivocal. Cognitive control abilities are thought to have a major role in everyday functioning, and their dysfunction has been implicated in the maintenance of maladaptive drug-taking patterns. In this study, the Multi-Source Interference Task was employed alongside functional magnetic resonance imaging and psychophysiological interaction methods to investigate functional interactions between brain regions underlying cognitive control. Current cannabis users with a history of greater than 10 years of daily or near daily cannabis smoking (n=21) were compared with age, gender, and IQ-matched non using controls (n=21). No differences in behavioral performance or magnitude of task-related brain activations were evident between the groups. However, greater connectivity between the prefrontal cortex and the occipitoparietal cortex was evident in cannabis users, as compared with controls, as cognitive control demands increased. The magnitude of this connectivity was positively associated with age of onset and lifetime exposure to cannabis. These findings suggest that brain regions responsible for coordinating behavioral control have an increased influence on the direction and switching of attention in cannabis users, and that these changes may have a compensatory role in mitigating cannabis-related impairments in cognitive control or perceptual processes. PMID- 22534626 TI - Behavioral, pharmacological, and immunological abnormalities after streptococcal exposure: a novel rat model of Sydenham chorea and related neuropsychiatric disorders. AB - Group A streptococcal (GAS) infections and autoimmunity are associated with the onset of a spectrum of neuropsychiatric disorders in children, with the prototypical disorder being Sydenham chorea (SC). Our aim was to develop an animal model that resembled the behavioral, pharmacological, and immunological abnormalities of SC and other streptococcal-related neuropsychiatric disorders. Male Lewis rats exposed to GAS antigen exhibited motor symptoms (impaired food manipulation and beam walking) and compulsive behavior (increased induced grooming). These symptoms were alleviated by the D2 blocker haloperidol and the selective serotonin reuptake inhibitor paroxetine, respectively, drugs that are used to treat motor symptoms and compulsions in streptococcal-related neuropsychiatric disorders. Streptococcal exposure resulted in antibody deposition in the striatum, thalamus, and frontal cortex, and concomitant alterations in dopamine and glutamate levels in cortex and basal ganglia, consistent with the known pathophysiology of SC and related neuropsychiatric disorders. Autoantibodies (IgG) of GAS rats reacted with tubulin and caused elevated calcium/calmodulin-dependent protein kinase II signaling in SK-N-SH neuronal cells, as previously found with sera from SC and related neuropsychiatric disorders. Our new animal model translates directly to human disease and led us to discover autoantibodies targeted against dopamine D1 and D2 receptors in the rat model as well as in SC and other streptococcal-related neuropsychiatric disorders. PMID- 22534627 TI - ACCF/AHA/AMA-PCPI 2011 performance measures for adults with heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Performance Measures and the American Medical Association-Physician Consortium for Performance Improvement. PMID- 22534629 TI - RANTES, TNF-alpha, oxidative stress, and hematological abnormalities in hepatitis C virus infection. AB - BACKGROUND: Chronic infection with hepatitis C virus (HCV) is associated with failures of T-cell-mediated immune clearance and with abnormal B-cell growth and activation. Hepatitis C virus infection is characterized by a systemic oxidative stress that is most likely caused by a combination of chronic inflammation, iron overload, liver damage, and proteins encoded by HCV. After a viral infection, multiple proinflammatory mediators contribute to recruitment of immune cells to the liver and to the generation of an antiviral immune response. Recent publications mark chemokines and their receptors as key players in leukocyte recirculation through the inflamed liver. MATERIALS AND METHODS: The present study involved 75 male subjects, divided into 2 groups: group 1 (n = 30), control group; group 2 (n = 45), patients with chronic HCV. For all subjects, the following investigations were performed: estimation of the levels of bilirubin, albumin, prothrombin concentration, glycosylated hemoglobin, creatinine, alpha fetoprotein, HCV RNA, and activities of alanine and aspartate transaminases as well as alkaline phosphatase. In addition, regulated on activation normal T cell expressed and secreted (RANTES), tumor necrosis factor alpha, malondialdehyde (MDA) and nitric oxide (NO) were assessed. Plasma HCV-RNA concentration (viral load) was determined by real-time polymerase chain reaction (PCR) StepOne system using Applied Biosystem. Complete blood picture was assayed using Abbott Cell-Dyn 3700 hematology analyzer. RESULTS: There were significant increases of the levels of RANTES, tumor necrosis factor alpha, MDA, and NO in HCV-infected patients compared with the control group (P <0.05); and in these patients, these levels showed significant positive correlation with the HCV RNA viral load. Also, mild leukopenia, thrombocytopenia, neutropenia, and lymphocytosis, with consequent significant increase in the lymphocytes/neutrophils ratio, were detected in these patients. CONCLUSION: The data support the concept of chemokines (RANTES) as mediators of liver cell injury in HCV infection. In addition, MDA and NO levels might be used as monitoring markers for oxidative stress in hepatitis C infection. PMID- 22534630 TI - Serum vitamin D levels are independently associated with severity of coronary artery disease. AB - BACKGROUND AND OBJECTIVES: Low-serum vitamin D levels have been associated with increased cardiovascular risk in the general population. We hypothesized that serum vitamin D levels would be inversely associated with inflammation and with severity of coronary atherosclerosis. We therefore investigated the link between serum vitamin D levels and (1) the extent of coronary artery disease (CAD) assessed by the Gensini score and (2) inflammatory parameters, including C reactive protein and fibrinogen. MATERIALS AND METHODS: We measured 25 hydroxyvitamin D (25[OH]D) and inflammatory markers in 239 patients who underwent coronary angiography. We analyzed the relation between serum levels of 25(OH)D and inflammatory markers and angiographic severity of CAD. The Gensini lesion severity score was used for assessing the severity of coronary atherosclerosis. RESULTS: Vitamin D insufficiency was very common among our study population: 83% of the study population had levels less than 30 ng/mL. The Gensini score was negatively associated with serum vitamin D levels (r = -0.416, P < 0.001), and positively correlated with age (r = 0.209, P = 0.001), blood pressure (r = 0.379, P < 0.001), diabetes (r = 0.335, P < 0.001), hyperlipidemia (r = 0.150, P = 0,021), and C-reactive protein levels (r = 0.214, P = 0,001). After adjustments for traditional and nontraditional cardiovascular risk factors, vitamin D (B = 0,345, P < 0,001) remained a significant predictor for the severity of CAD. CONCLUSIONS: Low-serum 25(OH)D levels are associated with the severity of coronary artery stenosis. Further studies are warranted to determine whether vitamin D supplementation could prevent progression of CAD. PMID- 22534631 TI - Association between resistin level and renal function in patients undergoing coronary artery bypass graft surgery. AB - AIM: The purpose of this study was to evaluate the association between resistin levels and renal function in patients undergoing coronary artery bypass graft (CABG) surgery. METHODS: Thirty-seven consecutive patients (mean +/- SD, age 60 +/- 10 years, 29 (78%) male) undergoing CABG surgery at our department were enrolled into our study. Blood samples were taken to examine quantities of resistin level and other blood parameters the day before surgery. The patients were categorized into 2 groups: lower resistin level (group 1) or higher resistin level (group 2) according to the median value of 9 ng/mL. RESULTS: Mean +/- SD resistin level, glomerular filtration rate (GFR), and urea and creatinine levels were 9.5 +/- 4.2 ng/mL, 78 +/- 25 mL/min per 1.73 m(2), 42 +/- 14 mg/dL, and 1.08 +/- 0.2 mg/dL, respectively. Resistin showed significant correlation with serum levels of urea (r = 0.448l P = 0.005), creatinine (r = 0.367; P = 0.026), inverse correlation with GFR (r = -0.398; P = 0.015), statin usage (r = -0.393; P = 0.016), and beta-blocker usage (r = -0.365; P = 0.026). In the multivariate logistic regression model, only GFR (odds ratio, 0.960; 95 confidence interval, 0.928-0.993; P = 0.018) remained independently associated with higher resistin levels after adjustment of other potential confounders in patients undergoing CABG surgery. According to the receiver operating characteristics curve analysis, the optimal cutoff value of GFR to predict higher resistin levels was found as 91 mL/min or less per 1.73 m(2), with 100% sensitivity and 61.1% specificity. CONCLUSION: The present study demonstrated that a lower glomerular filtration rate was associated with higher circulating resistin levels, independent of coronary heart disease risk factors in patients undergoing CABG surgery. PMID- 22534632 TI - A simple, fast, and easy assay for transition metal-catalyzed coupling reactions using a paper-based colorimetric iodide sensor. AB - A paper-based colorimetric iodide sensor (PBCIS) that consists of filter paper treated with starch and an oxidant is developed. It has been employed as a protocol to obtain the extent of conversion of aryl iodides in C-C, C-N, C-O and C-S bond formations, including polymer-supported Heck reactions, by transition metal catalysts such as palladium, nickel and copper. PMID- 22534633 TI - Cutaneous decidualized endometriosis in a nonpregnant female: a potential pseudomalignancy. AB - Endometriosis is a disease process characterized by ectopic endometrial tissue. Involvement most commonly occurs in the lower pelvis, outside the uterine cavity, but can occur elsewhere, including the skin. Cutaneous endometriosis is a rare manifestation of this disease, with decidualization occurring in a very small minority of cases, almost always seen in pregnant females. Cutaneous involvement of endometriosis may present a diagnostic problem for the pathologist, particularly in the event of decidualization. Decidualization may mimic a malignancy and as a result may result in unnecessary diagnostic studies for the patient. We present a case of a nonpregnant patient with decidualized cutaneous endometriosis, discuss the histopathologic and immunohistochemical features of this entity, and review the pertinent literature on this subject. To our knowledge, this is the second reported case of cutaneous decidualized endometriosis in a nonpregnant female. PMID- 22534634 TI - Expression of gelatinases (MMP-2, MMP-9) and gelatinase activator (MMP-14) in actinic keratosis and in in situ and invasive squamous cell carcinoma. AB - Given the established role of matrix metalloproteinases (MMPs) in physiological processes in the skin, we investigated the expression of MMP-2, MMP-9, and MMP-14 to evaluate their role in the grading and development of atypical epithelial lesions. Immunohistochemistry was performed using antibodies against these MMPs in actinic keratosis (AK; n = 24), squamous cell carcinoma (SCC) in situ (SCCIS; n = 27), SCC well differentiated (SCCWD; n = 28), and SCC moderately to poorly differentiated (SCCMPD; n = 20). Tumoral and stromal expression was assessed by intensity (SI) and percentage positivity (PC). The mean of the total score, calculated by adding intensity and percentage positivity, was used for statistical analyses. In AK, SCCIS, SCCWD, and SCCMPD, mean tumoral MMP-2 expression was 3.33, 4.07, 4.46, and 3.40, respectively (P = NS for all) and stromal expression was 1.42, 3.26, 3.07, and 1.55 respectively (P < 0.05 for AK vs. SCCIS/SCCWD and SCCMPD vs. SCCIS/SCCWD); mean tumoral MMP-9 expression was 4.33, 4.11, 4.46, and 3.35, respectively, and stromal expression was 4.29, 4.41, 4.75, and 4.60, respectively (P = NS for all) and, mean tumoral MMP-14 expression was 1.58, 2.41, 0.32, and 0.35, respectively (P < 0.05 AK vs. SCCWD and SCCIS vs. SCCWD/SCCMPD) and stromal expression was 3.04, 3.52, 0.46, and 0.60, respectively (P < 0.05 for AK vs. SCCWD/SCCMPD). Only MMP-14 showed a statistically significant linear trend with decreasing values for tumoral and stromal expression with invasion suggesting that it might be of use as a prognosticator. Enhanced stromal MMP-2 expression in SCCIS and SCCWD relative to AK suggests that it may be of relevance to disease progression. PMID- 22534635 TI - Lekti immunochemistry for the diagnosis of netherton syndrome. PMID- 22534636 TI - Equestrian perniosis: a report of 2 cases and a review of the literature. AB - Equestrian perniosis (EP) is a rare condition in which patients develop tender burning nodular plaques on their bilateral thighs after riding in the cold. These lesions tend to resolve rapidly with minimal exposure to cold, and wearing loose, layered warm clothing. Unlike acral perniosis, EP has no known systemic disease associations, although 2 reported cases did have elevated cold agglutinins. The histology of this disease is similar to perniosis; however, EP is distinct in that the perivascular lymphocytic infiltrate prominently involves the fat. In this case report, we discuss the clinical and histological findings in 2 cases of EP, including the first documented in a man. PMID- 22534637 TI - Atypical presentation of exophytic herpes simplex virus type 2 with concurrent cytomegalovirus infection: a significant pitfall in diagnosis. AB - We report 3 unusual cases of atypical exophytic cutaneous herpes simplex virus (HSV) type 2 with concurrent cytomegalovirus (CMV) infection in immunosuppressed patients and raise awareness to the significant clinical and pathologic challenges in establishing the correct diagnosis. In all the 3 cases, the lesions presented as fungating plaques and nodules with areas of superficial erosion. Initial clinical differential included genital warts, syphilis, versus cutaneous malignancy. All the 3 patients were referred to the dermatology clinic where a combination of cutaneous biopsies, viral cultures of the lesions, polymerase chain reaction, CMV antigenemia, and immunoperoxidase stains for CMV and HSV confirmed the diagnosis of HSV type 2 with concurrent CMV infection. All the 3 patients were treated with oral valganciclovir with significant improvement noted at the follow-up visit. In addition, we review the previously reported HSV/CMV cutaneous coinfection cases. PMID- 22534638 TI - Alpha-interferon secreting blastic plasmacytoid dendritic cells neoplasm: a case report with histological, molecular genetics and long-term tumor cells culture studies. AB - We report a new case of blastic plasmacytoid dendritic cell neoplasm (BPDCN) with extensive immunophenoptyping, genotyping (karyotype, array-comparative genomic hybridization, and fluorescent in situ hybridization), and long-term tumor cells culture. BPDCN is a very rare and aggressive disease clinically characterized by a skin revealing localization more or less rapidly disseminating to the bone marrow and other organs with or without and leukemia. The disease was initially phenotypically characterized by the expression of both CD4 and CD56 antigens, whereas lymphoid and myeloid lineage antigens were negative. A phenotypic link with alpha-interferon (IFN-I)-producing plasmacytoid dendritic cells was demonstrated. The data collected in this case report provide additional biological and genotypical data on tumor cells of BPDCN. This study confirms the capability of tumor cells to secrete IFN-I, demonstrated by biological IFN-I activity of cultured cells and immunohistochemical expression of Mx-1 protein. Although a common genetic profile involving chromosomes 5, 6, 9, 12, 13, and 15 has been identified, no specific genetic marker has been demonstrated that is specific to BPDCN. The demonstration of ETV6 gene deletion in this case deserves further investigations as a putative BPDCN marker. PMID- 22534639 TI - Signet ring cell primary cutaneous CD30+ lymphoproliferative disorder presenting as a monomorphic T-cell posttransplant lymphoproliferative disease. AB - T-cell posttransplant lymphoproliferative disorders are rare, with peripheral T cell lymphoma not otherwise specified being the most common type. Although cases of the signet ring cell variant of primary cutaneous CD30+ lymphoproliferative disorder have been reported, such cases have not been described in the posttransplant setting. We describe a case with emphasis on the special contextual differential diagnostic considerations. PMID- 22534640 TI - Adenolipoma-eccrine and apocrine variants with evidence for a hamartomatous process. PMID- 22534642 TI - Characterization of an arachidonic acid-deficient (Fads1 knockout) mouse model. AB - Arachidonic acid (20:4(Delta5,8,11,14), AA)-derived eicosanoids regulate inflammation and promote cancer development. Previous studies have targeted prostaglandin enzymes in an attempt to modulate AA metabolism. However, due to safety concerns surrounding the use of pharmaceutical agents designed to target Ptgs2 (cyclooxygenase 2) and its downstream targets, it is important to identify new targets upstream of Ptgs2. Therefore, we determined the utility of antagonizing tissue AA levels as a novel approach to suppressing AA-derived eicosanoids. Systemic disruption of the Fads1 (Delta5 desaturase) gene reciprocally altered the levels of dihomo-gamma-linolenic acid (20:3(Delta8,11,14), DGLA) and AA in mouse tissues, resulting in a profound increase in 1-series-derived and a concurrent decrease in 2-series-derived prostaglandins. The lack of AA-derived eicosanoids, e.g., PGE2 was associated with perturbed intestinal crypt proliferation, immune cell homeostasis, and a heightened sensitivity to acute inflammatory challenge. In addition, null mice failed to thrive, dying off by 12 weeks of age. Dietary supplementation with AA extended the longevity of null mice to levels comparable to wild-type mice. We propose that this new mouse model will expand our understanding of how AA and its metabolites mediate inflammation and promote malignant transformation, with the eventual goal of identifying new drug targets upstream of Ptgs2. PMID- 22534641 TI - The proteomics of lipid droplets: structure, dynamics, and functions of the organelle conserved from bacteria to humans. AB - Lipid droplets are cellular organelles that consists of a neutral lipid core covered by a monolayer of phospholipids and many proteins. They are thought to function in the storage, transport, and metabolism of lipids, in signaling, and as a specialized microenvironment for metabolism in most types of cells from prokaryotic to eukaryotic organisms. Lipid droplets have received a lot of attention in the last 10 years as they are linked to the progression of many metabolic diseases and hold great potential for the development of neutral lipid derived products, such as biofuels, food supplements, hormones, and medicines. Proteomic analysis of lipid droplets has yielded a comprehensive catalog of lipid droplet proteins, shedding light on the function of this organelle and providing evidence that its function is conserved from bacteria to man. This review summarizes many of the proteomic studies on lipid droplets from a wide range of organisms, providing an evolutionary perspective on this organelle. PMID- 22534643 TI - Peroxisomal L-bifunctional enzyme (Ehhadh) is essential for the production of medium-chain dicarboxylic acids. AB - L-bifunctional enzyme (Ehhadh) is part of the classical peroxisomal fatty acid beta-oxidation pathway. This pathway is highly inducible via peroxisome proliferator-activated receptor alpha (PPARalpha) activation. However, no specific substrates or functions for Ehhadh are known, and Ehhadh knockout (KO) mice display no appreciable changes in lipid metabolism. To investigate Ehhadh functions, we used a bioinformatics approach and found that Ehhadh expression covaries with genes involved in the tricarboxylic acid cycle and in mitochondrial and peroxisomal fatty acid oxidation. Based on these findings and the regulation of Ehhadh's expression by PPARalpha, we hypothesized that the phenotype of Ehhadh KO mice would become apparent after fasting. Ehhadh mice tolerated fasting well but displayed a marked deficiency in the fasting-induced production of the medium chain dicarboxylic acids adipic and suberic acid and of the carnitine esters thereof. The decreased levels of adipic and suberic acid were not due to a deficient induction of omega-oxidation upon fasting, as Cyp4a10 protein levels increased in wild-type and Ehhadh KO mice.We conclude that Ehhadh is indispensable for the production of medium-chain dicarboxylic acids, providing an explanation for the coordinated induction of mitochondrial and peroxisomal oxidative pathways during fasting. PMID- 22534645 TI - Tissue injury-induced initiation of the adaptive immune response. PMID- 22534646 TI - Human limb abnormalities caused by disruption of hedgehog signaling. AB - Human hands and feet contain bones of a particular size and shape arranged in a precise pattern. The secreted factor sonic hedgehog (SHH) acts through the conserved hedgehog (Hh) signaling pathway to regulate the digital pattern in the limbs of tetrapods (i.e. land-based vertebrates). Genetic analysis is now uncovering a remarkable set of pathogenetic mutations that alter the Hh pathway, thus compromising both digit number and identity. Several of these are regulatory mutations that have the surprising attribute of misdirecting expression of Hh ligands to ectopic sites in the developing limb buds. In addition, other mutations affect a fundamental structural property of the embryonic cell that is essential to Hh signaling. In this review, we focus on the role that the Hh pathway plays in limb development, and how the many human genetic defects in this pathway are providing clues to the mechanisms that regulate limb development. PMID- 22534644 TI - The farnesoid X receptor -1G>T polymorphism influences the lipid response to rosuvastatin. AB - The bile acid-activated nuclear receptor farnesoid X receptor (FXR) plays an important role in lipid and glucose metabolism, and in addition, it regulates multiple drug transporters involved in statin disposition. We examined whether a functional single nucleotide polymorphism (SNP) in FXR (-1G>T) influenced the lipid-lowering effect of rosuvastatin. In 385 Chinese patients with hyperlipidemia who had been treated with rosuvastatin 10 mg daily for at least 4 weeks, the association between the FXR -1G>T SNP and lipid response to rosuvastatin was analyzed. The FXR -1G>T SNP was not associated with baseline lipids but was significantly associated with the LDL cholesterol (LDL-C) and total cholesterol response to rosuvastatin. Carriers of the T-variant allele (GT+TT = 68+3) had 4.4% (95% CI: 1.2, 7.5%, P = 0.006) and 2.6% (95% CI: 0.3, 5.0%; P < 0.05) greater reductions in LDL-C and total cholesterol, respectively, compared with those with homozygous wild-type alleles. The association between the FXR polymorphism and the LDL-C response to rosuvastatin remained significant after adjusting for other covariants. This association of the variant allele of the FXR -1G>T polymorphism with a greater LDL-C response to rosuvastatin may suggest that this polymorphism influences the expression of the hepatic efflux transporters involved in biliary excretion of rosuvastatin. PMID- 22534647 TI - A giant intrathoracic osteolipoma: A case report and review of the literature. AB - INTRODUCTION: Lipomas are ubiquitous and can occur anywhere in the body. Intrathoracic lipomata are rare benign lesions. However, a complete removal giant intrathoracic osteolipoma is achieved with only 18 cases previous cases described in medical literature from 1960 to 2008. PRESENTATION OF CASE: A 66-year-old female presented to our hospital suffered from mild chest pain and mild shortness of breath for more than 10 days. A subsequent chest X-ray and CT scans revealed a large homogeneous, low-attenuation fat density mass containing an oval calcification area in the center of the mass. Following surgical resection was performed successfully to remove the entire mass, which weighed a total of 1568g and measured 26cm*19cm*12cm in size. The histological analysis confirmed a giant intrathoracic osteolipoma without evidence of malignancy. DISCUSSION: Intrathoracic lipomas are rare, slow-growing benign tumors without any symptom, which originate from the adipose tissue in submesothelial layers of the pleura parietalis, diaphragm, mediastinal and extrapericardial. They may extend into the chest cavity and fully encapsulate in most cases. Chest X-ray and CT and MRI scans are the most helpful tests in the diagnosis of intrathoracic lipomas. Complete enbloc removal of lipoma whenever possible, is the only definitive treatment option and the only way to prevent future recurrences. CONCLUSION: This case is the largest intrathoracic osteolipoma documented in the modern literature. Complete enbloc removal of lipoma whenever possible, is the only definitive treatment option. PMID- 22534648 TI - Tunneled modified lotus petal flap for surgical reconstruction of severe introital stenosis after radical vulvectomy. AB - INTRODUCTION: We presented the anatomical, functional and aesthetic results achieved with lotus petal flap in case of introital stenosis as a results of inadequate primary plastic reconstruction. We discussed the potential advantages of lotus petal flap compared to others vulvar reconstructive techniques. PRESENTATION OF CASE: We report a case of a 44-years old woman presenting a severe introital stenosis following radical surgery for vulvar cancer. She could not have a normal sexual activity life because the narrow scarred introitus resulting after primary closure of a large vulvar defect. The patient comes to our attention after three years from primary surgery. Once the scar was removed we performed a vulvoperineal reconstruction with bilateral tunneled lotus petal flaps. DISCUSSION: Lotus petal flap is a safe, easy and quick technique, has a good functional and cosmetic results in this young woman, and represents an optimal alternative solution for plastic reconstruction in case of severe introital stenosis after primary closure of large vulvoperineal defect. CONCLUSION: Tunneled lotus petal flaps represents a feasible, attractive and versatile surgical reconstructive technique that can be easily performed after surgical treatment of vulvoperineal neoplasms. PMID- 22534649 TI - Pharmaceutically active ionic liquids with solids handling, enhanced thermal stability, and fast release. AB - Pharmaceutically active compounds in ionic liquid form immobilized onto mesoporous silica are stable, easily handled solids, with fast and complete release from the carrier material when placed into an aqueous environment. Depending on specific ion-surface interactions, they may also exhibit improved thermal stability when compared to the non-adsorbed compounds. PMID- 22534651 TI - Nomimicin, a new spirotetronate-class polyketide from an actinomycete of the genus Actinomadura. AB - Nomimicin (1), a new spirotetronate-class polyketide, was isolated from the culture broth of an actinomycete of the genus Actinomadura. Its structure was established by spectroscopic methods, and the absolute configuration was determined by a combination of NOESY experiment, J-based configuration analysis and the modified Mosher method. Nomimicin (1) showed antimicrobial activity against Micrococcus luteus, Candida albicans and Kluyveromyces fragilis. PMID- 22534652 TI - JBIR-120: a new growth inhibitor of hormone-refractory prostate cancer cells. PMID- 22534653 TI - Dietary patterns and their association with cardiovascular risk factors in a population undergoing lifestyle changes: The Strong Heart Study. AB - BACKGROUND AND AIMS: Rates of cardiovascular disease (CVD) are disproportionately high in American Indians (AI), and changes in lifestyle may be responsible. It is not known whether diverse dietary patterns exist in this population and whether the patterns are associated with CVD risk factors. This article describes the relationships between dietary patterns and CVD risk factors in this high-risk population. METHODS AND RESULTS: Nutrition data were collected via food frequency questionnaire from 3438 Strong Heart Study (SHS) participants, >= age 15 y. All participants were members of 94 extended families. The final sample consisted of 3172 men and women. Diet patterns were ascertained using factor analysis with the principal component factoring method. We derived four predominant dietary patterns: Western, traditional AI/Mexican, healthy, and unhealthy. Participants following the Western pattern had higher LDL cholesterol (LDL-C) (p < 0.001), slightly higher systolic blood pressure (BP) (p < 0.001), lower HDL cholesterol (HDL-C) (p < 0.001), and slightly lower homeostasis model assessment estimates of insulin resistance (HOMA-IR) in the lowest vs. highest deciles of adherence to this pattern (p < 0.001). The traditional diet was associated with higher HDL-C (p < 0.001), but higher body mass index (BMI) (p < 0.001) and HOMA-IR (p < 0.001). Followers of the healthy pattern had lower systolic BP, LDL-C, BMI, and HOMA-IR in increasing deciles (p < 0.001). The unhealthy pattern was associated with higher LDL-C. CONCLUSIONS: Dietary patterns reflect the changing lifestyle of AI and several of the patterns are associated with CVD risk factors. Evolving methods of food preparation have made the traditional pattern less healthy. PMID- 22534654 TI - Mechanisms-based classifications of musculoskeletal pain: part 1 of 3: symptoms and signs of central sensitisation in patients with low back (+/- leg) pain. AB - As a mechanisms-based classification of pain 'central sensitisation pain' (CSP) refers to pain arising from a dominance of neurophysiological dysfunction within the central nervous system. Symptoms and signs associated with an assumed dominance of CSP in patients attending for physiotherapy have not been extensively studied. The purpose of this study was to identify symptoms and signs associated with a clinical classification of CSP in patients with low back (+/- leg) pain. Using a cross-sectional, between-subjects design; four hundred and sixty-four patients with low back (+/- leg) pain were assessed using a standardised assessment protocol. Patients' pain was assigned a mechanisms-based classification based on experienced clinical judgement. Clinicians then completed a clinical criteria checklist specifying the presence or absence of various clinical criteria. A binary logistic regression analysis with Bayesian model averaging identified a cluster of three symptoms and one sign predictive of CSP, including: 'Disproportionate, non-mechanical, unpredictable pattern of pain provocation in response to multiple/non-specific aggravating/easing factors', 'Pain disproportionate to the nature and extent of injury or pathology', 'Strong association with maladaptive psychosocial factors (e.g. negative emotions, poor self-efficacy, maladaptive beliefs and pain behaviours)' and 'Diffuse/non anatomic areas of pain/tenderness on palpation'. This cluster was found to have high levels of classification accuracy (sensitivity 91.8%, 95% confidence interval (CI): 84.5-96.4; specificity 97.7%, 95% CI: 95.6-99.0). Pattern recognition of this empirically-derived cluster of symptoms and signs may help clinicians identify an assumed dominance of CSP in patients with low back pain disorders in a way that might usefully inform their management. PMID- 22534655 TI - Determination of bullatacin in rat plasma by liquid chromatography-mass spectrometry. AB - A liquid chromatography-mass spectrometry method has been developed and validated for the quantification of bullatacin, a bistetrahydrofuran annonaceous acetogenin, in rat plasma. Squamostatin-A was selected as the internal standard. Analytes were extracted from rat plasma by liquid/liquid extraction using ethyl acetate with high efficiency. The chromatographical separation was performed on an Agilent Zorbax SB-C18 column (150 mm * 2.1 mm, 5 MUm). The mobile phase consisted of methanol and deionized water (95:5, v/v) containing 0.01% (v/v) formic acid. The chromatographic run time was 7 min per injection and flow rate was 0.2 mL/min. The retention time was 3.22 and 5.23 min for internal standard and bullatacin, respectively. The elutes were detected under positive electrospray ionization and the target analytes quantified by selected ion monitoring mode (645.9 m/z for bullatacin and 661.9 m/z for squamostatin-A). The method was sensitive with the limit of quantitation at 0.5 ng/mL in 100 MUL of rat plasma. Good linearity (r2=0.9998) was obtained covering the concentration of 0.5-2000 ng/mL. The intra- and inter-day assay precision ranged from 3.2 to 8.7% and 2.7 to 9.2%, respectively. In addition, the stability, extraction recovery and matrix effect involved in the method were also validated. This method was applied to measure the plasma bullatacin concentrations after a single tail vein intravenous administration of bullatacin in rats. PMID- 22534656 TI - Disulfiram metabolite S-methyl-N,N-diethylthiocarbamate quantitation in human plasma with reverse phase ultra performance liquid chromatography and mass spectrometry. AB - Disulfiram has been used extensively for alcohol abuse and may have a role in treatment for cocaine addiction. Recent data suggest that disulfiram may also reactivate latent HIV in reservoirs. Disulfiram has complex pharmacokinetics with rapid metabolism to active metabolites, including S-methyl-N,N diethylthiocarbamate (DET-Me) which is formed from cytochrome P450 (CYP450). Assessing disulfiram in HIV-infected individuals with a CYP450 inducing drug (e.g., efavirenz) or a CYP450 inhibiting drug (e.g., HIV-1 protease inhibitors) requires an assay that can measure a metabolite that is formed directly via CYP450 oxidation. Therefore, an assay to measure concentrations of DET-Me in human plasma was validated. DET-Me and the internal standard, S ethyldipropylthiocarbamate (EPTC) were separated by isocratic ultra performance liquid chromatography using a Waters Acquity HSS T3 column (2.1 mm * 100 mm, 1.8 MUm) and detection via electrospray coupled to a triple quadrupole mass spectrometer. Multiple reaction monitoring in positive mode was used with DET-Me at 148/100 and the internal standard at 190/128 with a linear range of 0.500-50.0 ng/mL with a 5 min run time. Human plasma (500 MUL) was extracted using a solid phase procedure. The interassay variation ranged from 1.86 to 7.74% while the intra assay variation ranged from 3.38 to 5.94% over three days. Representative results are provided from samples collected from subjects receiving daily doses of disulfiram 62.5mg or 250 mg. PMID- 22534657 TI - Determination of imidacloprid in rice by molecularly imprinted-matrix solid-phase dispersion with liquid chromatography tandem mass spectrometry. AB - A new method based on matrix solid-phase dispersion (MSPD) coupled with liquid chromatography tandem mass spectrometry has been developed for the determination of imidacloprid in rice. The molecularly imprinted polymers were synthesized and applied as the dispersant of MSPD for selective extraction of imidacloprid from rice, while interferences originated from sample matrices were eliminated simultaneously. The satisfactory recovery of imidacloprid was obtained by the optimized extraction conditions: 1:2 as the ratio of sample to MIPs; 8 min as the dispersion time; 20% aqueous methanol as washing solvent and methanol as elution solvent. Under the optimal conditions, the linearity of imidacloprid in rice sample was achieved in the range of 10-1000 ng/g, and limit of detection was 2.4 ng/g. The relative standard deviations of intra- and inter-day tests ranging from 4.5% to 5.9% and from 4.8% to 7.1% are obtained, respectively. The proposed method was applied to the determination of imidacloprid in eight rice samples with recoveries in the range of 83.8-92.5%. PMID- 22534658 TI - A retrospective analysis of two randomized trials of bupropion for methamphetamine dependence: suggested guidelines for treatment discontinuation/augmentation. AB - BACKGROUND: Two clinical trials have shown efficacy for bupropion in treating methamphetamine (MA) dependence among those with moderate baseline MA use. However, treatment response is highly variable and it is unclear what duration of treatment is necessary to determine if maintaining the treatment course is indicated or if discontinuation or augmentation is appropriate. The present study assessed the relationship among early bupropion treatment response for moderate MA users and end-of-treatment (EOT) abstinence. These data provide estimates of the duration of treatment and the degree of responsiveness required to persist in bupropion treatment. METHODS: Participants with moderate baseline MA use in the bupropion condition of two randomized double-blind placebo controlled trials were included. The relationship between early treatment response and EOT outcomes was assessed with Receiver Operating Characteristic (ROC) curves. RESULTS: With thrice weekly urine drug testing, excellent predictive power was established in the first two weeks of treatment. The inability to achieve at least three MA negative samples in the first two weeks is associated with greater than 90% likelihood of treatment failure. More closely approximating clinical settings, once-weekly testing featured reliable predictive power within three weeks, suggesting that the failure to produce at least two clean samples in the first three weekly visits confers high risk of treatment failure. DISCUSSION: The findings provide preliminary evidence to guide clinical decisions for moderate MA users receiving bupropion. The results are consistent with data from the smoking cessation literature and may highlight the importance of early response in addiction treatment. PMID- 22534659 TI - TDP-43: gumming up neurons through protein-protein and protein-RNA interactions. AB - Since the discovery that 43 kDa TAR DNA binding protein (TDP-43) is involved in neurodegeneration, studies of this protein have focused on the global effects of TDP-43 expression modulation on cell metabolism and survival. The major difficulty with these global searches, which can yield hundreds to thousands of variations in gene expression level and/or mRNA isoforms, is our limited ability to separate specific TDP-43 effects from secondary dysregulations occurring at the gene expression and various mRNA processing steps. In this review, we focus on two biochemical properties of TDP-43: its ability to bind RNA and its protein protein interactions. In particular, we overview how these two properties may affect potentially very important processes for the pathology, from the autoregulation of TDP-43 to aggregation in the cytoplasmic/nuclear compartments. PMID- 22534660 TI - A bi-ligand co-functionalized gold nanoparticles-based calcium ion probe and its application to the detection of calcium ions in serum. AB - In this study, the use of bi-ligand co-functionalized gold nanoparticles in a highly selective and sensitive colorimetric probe for Ca(2+) ions is demonstrated and this probe also determined the concentrations of Ca(2+) ions in serum samples. PMID- 22534661 TI - I will always be with you: traditional and complementary therapists' perspectives on patient-therapist-doctor communication regarding treatment of Arab patients with cancer in Israel. AB - OBJECTIVE: In 2008, an Integrative Oncology Program was implemented at the Clalit Oncology Service in Haifa, Israel, to promote patients' well-being during chemotherapy and advanced stages of disease. We hypothesized that studying the perceptions of Arab complementary and alternative medicine (CAM) therapists would facilitate development of a cross-culturally integrative oncology approach. METHODS: Semi-structured interviews were held with 27 Arab therapists who use medicinal herbs, the Quran and various CAM modalities, with the aim of characterizing their treatment practices and learning about their perspectives regarding conventional cancer care. RESULTS: Thematic analysis revealed that therapists act as go-betweens, mediating between patients and conventional physicians. Therapists translate diagnoses into Arabic and elucidate key concepts. They tend to perceive their role as gatekeepers accompanying patients through the conventional health system, referring them for further examinations, and providing CAM-based supportive care consultation. CONCLUSIONS: CAM therapists have an essential role in supportive care of Arab patients with cancer. Triangular patient-therapist-oncologist communication may have an impact on patients' experience and treatment quality. PRACTICE IMPLICATIONS: Recognition of CAM therapists as mediators between patients' health beliefs and conventional perceptions of care may improve doctor-patient dialogue and facilitate supportive care provision in a cross-cultural context. PMID- 22534662 TI - Synthesis of potent inhibitors of beta-ketoacyl-acyl carrier protein synthase III as potential antimicrobial agents. AB - Mycobacterium tuberculosis FabH, an essential enzyme in the mycolic acid biosynthetic pathway, is an attractive target for novel anti-tubercolosis agents. Structure-based design and synthesis of 1-(4-carboxybutyl)-4-(4-(substituted benzyloxy)phenyl)-1H-pyrrole-2-carboxylic acid derivatives 7a-h, a subset of eight potential FabH inhibitors, is described in this paper. The Vilsmeier-Haack reaction was employed as a key step. The structures of all the newly synthesized compounds were identified by IR, 1H-NMR, 13C-NMR, ESI-MS and HRMS. The alamarBlueTM microassay was employed to evaluate the compounds 7a-h against Mycobacterium tuberculosis H37Rv. The results demonstrate that the compound 7d possesses good in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (Minimum Inhibitory Concentration value [MIC], 12.5 ug/mL).These compounds may prove useful in the discovery and development of new anti-tuberculosis drugs. PMID- 22534663 TI - Preparation of SRN1-type coupling adducts from aliphatic gem-dinitro compounds in ionic liquids. AB - S(RN)1-type coupling adducts are readily prepared by the reaction between a sulfonylesters or a-cyanosulfones and gem-dinitro compounds in ionic liquids. The reactions progress smoothly and recovered ionic liquids can be used for several iterations, as long as they are washed with water to remove alkali metallic salts. The reaction rate is slower than the corresponding S(RN)1 reaction in DMSO, but no acceleration on irradiation or no inhibition in the presence of m DNB are observed. PMID- 22534664 TI - Comparison of different approaches to define the applicability domain of QSAR models. AB - One of the OECD principles for model validation requires defining the Applicability Domain (AD) for the QSAR models. This is important since the reliable predictions are generally limited to query chemicals structurally similar to the training compounds used to build the model. Therefore, characterization of interpolation space is significant in defining the AD and in this study some existing descriptor-based approaches performing this task are discussed and compared by implementing them on existing validated datasets from the literature. Algorithms adopted by different approaches allow defining the interpolation space in several ways, while defined thresholds contribute significantly to the extrapolations. For each dataset and approach implemented for this study, the comparison analysis was carried out by considering the model statistics and relative position of test set with respect to the training space. PMID- 22534665 TI - Synthesis of new indole derivatives structurally related to donepezil and their biological evaluation as acetylcholinesterase inhibitors. AB - New series of indole derivatives analogous to donepezil, a well known anti Alzheimer and acetylcholinesterase inhibitor drug, was synthesized. A full chemical characterization of the new compounds is provided. Biological evaluation of the new compounds as acetylcholinesterase inhibitors was performed. Most of the compounds were found to have potent acetylcholinesterase inhibitor activity compared to donepezil as standard. The compound 1-(2-(4-(2-fluorobenzyl) piperazin-1-yl)acetyl)indoline-2,3-dione (IIId) was found to be the most potent. PMID- 22534667 TI - Reduced expression of cyclin D2 is associated with poor recurrence-free survival independent of cyclin D1 in stage III non-small cell lung cancer. AB - BACKGROUND: Compared to well-known function of cyclin D1 in lung cancer, the role of cyclin D2 is not clear. This study was aimed at understanding the clinicopathological significance of cyclin D2 in primary non-small cell lung cancer (NSCLC). METHODS: We retrospectively analyzed expression statuses of cyclin D1, cyclin D2, p16, p21, p27, Ki-67, and phospho-pRb (Ser-807/811) using immunohistochemistry in 626 NSCLCs. RESULTS: Cyclin D2 was expressed in normal lung tissue, and its expression was reduced in 170 (27%) of 626 NSCLCs with a median duration of follow-up of 64 months. Mean phospho-pRb (Ser-807/811) levels were not associated with expression levels of cyclin D2 (P=0.15). The relationship between recurrence and the reduced expression of cyclin D2 was not homogenous by stage (Breslow-Day test for homogeneity, P=0.04). Reduced expression of cyclin D2 was not associated with patient's prognosis in 370 stage I, 112 stage II, and 18 stage IV NSCLCs. However, for 126 stage III NSCLCs, reduced expression of cyclin D2 was adversely associated with recurrence-free survival (RFS) (hazard ratio [HR]=3.71, 95% CI=1.54-13.17; P=0.01), independent of histology and expression of cyclin D1. The reduced expression of cyclin D2 was not associated with the overexpression of cyclin D1 (P=0.65). CONCLUSION: The present study suggests that reduced expression of cyclin D2 in stage III NSCLC may be associated with poor RFS. And, cyclin D2 may have a distinct role from cyclin D1 in NSCLC. PMID- 22534666 TI - Deconvoluting the context-dependent role for autophagy in cancer. AB - Autophagy (also known as macroautophagy) captures intracellular components in autophagosomes and delivers them to lysosomes, where they are degraded and recycled. Autophagy can have two functions in cancer. It can be tumour suppressive through the elimination of oncogenic protein substrates, toxic unfolded proteins and damaged organelles. Alternatively, it can be tumour promoting in established cancers through autophagy-mediated intracellular recycling that provides substrates for metabolism and that maintains the functional pool of mitochondria. Therefore, defining the context-specific role for autophagy in cancer and the mechanisms involved will be important to guide autophagy-based therapeutic intervention. PMID- 22534668 TI - Proteomics-based identification of secreted protein dihydrodiol dehydrogenase 2 as a potential biomarker for predicting cisplatin efficacy in advanced NSCLC patients. AB - BACKGROUND AND PURPOSE: Cisplatin is the major agent in the standard first-line chemotherapy for NSCLC. However, only a small portion of patients achieve a tumor response to cisplatin-based chemotherapy and eventually develop acquired resistance. The aim of this study was to identify potential biomarkers that could predict the efficacy of cisplatin. METHODS: Human lung adenocarcinoma cell line A549 was exposed to cisplatin for development of a resistant cell line, A549/DDP, and cisplatin-sensitivity was tested through the MTT assay. The global protein profiles from A549 and A549/DDP were compared using a proteomic approach. Western blot, real-time PCR and immunohistochemistry validated the expression of DDH2 in cell lines and tumor xenografts. Serum levels of DDH2 were measured by ELISA in 105 NSCLC patients treated with cisplatin-based chemotherapy. RESULT: The resistance of A549/DDP to cisplatin was 8.07-fold higher than that of A549 cells. Proteomic approach identified eight differentially (>5-fold) expressed proteins. Among them, secreted protein DDH2 was further investigated and it was found overexpressed through the method of Western blot, real-time PCR in cell lines, consistent with immunohistochemistry validation in xenograft. Clinical research showed that baseline serum DDH2 level in the patients with a progression disease was significantly higher than the patients of response or stable disease (9.036 vs. 3.529 and 3.982 ng/mL, P<0.001) and serum DDH2 levels were significantly increased after cisplatin-based doublet chemotherapy (5.515 vs. 12.935 vs. 18.406 ng/mL P<0.001, respectively). CONCLUSION: DDH2 expression might be a potential predictor and monitor of cisplatin efficacy in advanced NSCLC patients. PMID- 22534669 TI - Randomized phase II trial of first-line treatment with pemetrexed-cisplatin, followed sequentially by gefitinib or pemetrexed, in East Asian, never-smoker patients with advanced non-small cell lung cancer. AB - INTRODUCTION: Treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors or chemotherapy have shown improved survival outcomes in East Asian, never-smoker patients with non-small cell lung cancer (NSCLC). However, treatment sequence has not been optimized in patients with unknown EGFR mutation status. This trial compared first-line chemotherapy with pemetrexed (P)-cisplatin (C), followed by either gefitinib (G) or P maintenance. METHODS: East Asian, never-smoker, chemo-naive patients with stage IIIB/IV NSCLC, performance status <=1 and unknown EGFR mutation status were randomized 1:1 to receive 4 cycles of pemetrexed [500 mg/m(2)]+cisplatin [75 mg/m(2)] q3 weeks, followed by maintenance with either gefitinib [250 mg/d] (PC/G) or pemetrexed [500 mg/m(2)] q3 weeks and <=2 optional cycles of cisplatin (PC/P). The primary endpoint, progression-free survival (PFS), was calculated from randomization date. RESULTS: Between Feb and Nov 2007, 70 patients from China, Korea, and Taiwan were randomized and treated, among whom 59 patients (84.3%) had non-squamous NSCLC. Forty-nine patients (70.0%) completed the full sequential treatment (n=25 G; n=24 P). Median PFS was numerically longer for patients on PC/G (9.95 months) than those on PC/P (6.83 months; hazard ratio [HR]=0.53, 95% confidence interval [CI]=0.27, 1.04). In contrast, median overall survival was numerically higher for patients on PC/P (HR=2.15, 95% CI=0.83, 5.60), though there was a high censoring rate. Response rate was similar in both arms. Treatment arms were similar for grade 3/4/5 toxicities. CONCLUSIONS: East Asian never-smoker patients with advanced NSCLC and unknown EGFR mutation status had improved PFS following treatment with first-line PC and sequential G. Irrespective of subsequent maintenance treatment, induction PC was safe and efficacious, leading to prolonged OS in the Asian patient population. PMID- 22534670 TI - Use of erlotinib throughout pregnancy: a case-report of a patient with metastatic lung adenocarcinoma. AB - The use of erlotinib throughout pregnancy has not been previously reported. We present the case of a 40 year-old female patient with stage IV lung adenocarcinoma, mediastinal, bone and cerebral metastasis, a EGFR mutation and no smoking history, who had begun first line treatment with erlotinib 150 mg once daily. After two and a half months of treatment a fourteen-week pregnancy was documented, and after informing on fetal risks secondary to erlotinib use and maternal risks secondary to treatment withholding, she decided to continue with treatment under clinical surveillance by both the oncology and obstetrics clinics. At thirty-three weeks gestation a live born 1600 g female was born by caesarean section without evidence of congenital malformations. Imaging assessment after eight months of treatment showed complete bone and central nervous system response and partial lung and mediastinal response. The patient is currently undergoing the 11th month of treatment and is asymptomatic, the baby is 4 months old and is in good health. PMID- 22534671 TI - External ophthalmoplegia associated with Hashimoto's thyroiditis and recovered on corticosteroid treatment. AB - Five-year follow-up of a young male patient is presented. Total external ophthalmoplegia developed 1 week after an upper respiratory tract infection. After 3 years of the course, hyperthyreosis and clinical signs of thyroid associated ophthalmopathy occurred. Hashimoto's thyroiditis and ultrastructural signs of mitochondrial damage of striated muscle were found by histological investigations. The paresis of the external ocular muscles recovered after long term corticosteroid treatment. On the basis of clinical symptoms and histological results, the authors supposed that an immunological reaction had caused mitochondrial damage in the striated muscles, which also resulted in thyroiditis. This case history points that autoimmune mechanism more frequently might participate in the pathogenesis of chronic external ophthalmoplegia, and the symptoms might precede organ-specific or perhaps systemic autoimmune disorders. PMID- 22534673 TI - Pharmacologic reduction of angiographic vasospasm in experimental subarachnoid hemorrhage: systematic review and meta-analysis. PMID- 22534672 TI - Pharmacologic reduction of angiographic vasospasm in experimental subarachnoid hemorrhage: systematic review and meta-analysis. AB - Animal models have been developed to simulate angiographic vasospasm secondary to subarachnoid hemorrhage (SAH) and to test pharmacologic treatments. Our aim was to evaluate the effect of pharmacologic treatments that have been tested in humans and in preclinical studies to determine if animal models inform results reported in humans. A systematic review and meta-analysis of SAH studies was performed. We investigated predictors of translation from animals to humans with multivariate logistic regression. Pharmacologic reduction of vasospasm was effective in mice, rats, rabbits, dogs, nonhuman primates (standard mean difference of -1.74; 95% confidence interval -2.04 to -1.44) and humans. Animal studies were generally of poor methodologic quality and there was evidence of publication bias. Subgroup analysis by drug and species showed that statins, tissue plasminogen activator, erythropoietin, endothelin receptor antagonists, calcium channel antagonists, fasudil, and tirilazad were effective whereas magnesium was not. Only evaluation of vasospasm >3 days after SAH was independently associated with successful translation. We conclude that reduction of vasospasm is effective in animals and humans and that evaluation of vasospasm >3 days after SAH may be preferable for preclinical models. PMID- 22534674 TI - Assessing vascular function using dynamic retinal diameter measurements: a new insight on the endothelium. PMID- 22534675 TI - Complications of tibial plateau levelling osteotomy in dogs. AB - The tibial plateau levelling osteotomy (TPLO) is one of the most common surgical procedures used to treat cranial cruciate ligament disease in dogs. Complications occurring during or after TPLO can range in severity from swelling and bruising to fracture and osteomyelitis. Ten to 34% of TPLO surgical procedures are reported to experience a complication and approximately two to four percent require revision surgery to address a complication. Although the risk factors for many complications have not been fully assessed, the best available evidence suggests that complications of TPLO can be reduced with increased surgeon experience, careful surgical planning, and accurate execution of the surgical procedure. Identification of known or suspected risk factors and intra-operative technical errors allow subsequent action to be taken that is aimed at decreasing postoperative morbidity. There is a need for prospective studies with consistent data reporting in order to fully reveal the incidence risk factors for complications associated with TPLO. PMID- 22534676 TI - Monitoring of ozone effects on the vitality and increment of Norway spruce and European beech in the Central European forests. AB - The ozone effect on Norway spruce (Picea abies (L) Karst.) and European beech (Fagus sylvatica L.) was studied on 48 monitoring plots in 2005-2008. These plots represent two major forest tree species stands of different ages in eight regions of the Czech Republic. The forest conditions were represented by defoliation and the annual radial increment of individual trees. The ozone exposure was assessed by using modeled values of mean annual O(3) concentration and the AOT40 index. The malondialdehyde (MDA) content of the foliage was analysed and used as an indicator of oxidative stress. The correlation analysis showed a significant relation of Norway spruce defoliation to the AOT40 exposure index, and European beech defoliation to the MDA level. The radial increment response to ozone was significant only for the European beech: (a) the correlation analysis showed its decrease with increasing AOT40; (b) the regression model showed its decrease with increasing mean annual ozone concentration only at lower altitudes (<700 m a.s.l.). PMID- 22534677 TI - [Purulent lymphadenitis after peritonsillar abscess under immunosuppression. An often forgotten differential diagnosis]. AB - In the present case study, a 75-year-old, immunosuppressed man presented with recurrent cervical abscesses after a peritonsillar abscess. In the cervical region, an ulcer developed with persistent wound healing deficit. Subsequently, the patient's general condition deteriorated, showing symptoms of a Landouzy sepsis. In the course of the examination, Mycobacteria tuberculosis was detected in the cervical ulcer. He suffered from latent tuberculosis, which was reactivated by a combination of his disease, immunosuppressive therapy and the preceding peritonsillar abscess. Upon treatment with tuberculostatics, the patient fully recovered. PMID- 22534678 TI - [Botulinum toxin A after microvascular ALT flap in a patient with (corrected) squamous cell carcinoma of the tongue]. AB - We report the case of a 23-year-old man presenting with a cT4 cN1 M0squamous cell carcinoma of the right tongue. After tumor resection and covering of the defect with a microvascular anterolateral thigh (ALT) flap, the patient showed distinct drooling without any substantial regression after anticholinergic therapy. For this reason 75 units of Botox(r) were injected into the submandibular and parotid glands. After the intraglandular injections, good reduction of saliva secretion was achieved. The treatment improved flap healing, aspiration and patient satisfaction. Injection of botulinum toxin A into the salivary glands is a sufficient therapy for postoperative hypersalivation. PMID- 22534680 TI - [Castleman's disease : a rare differential diagnosis for Heerfordt's syndrome]. AB - A 50-year-old male patient demonstrated an existing left proptosis for several weeks. The patient was suffering from physical exhaustion and had lost considerable weight. Furthermore, we observed greatly enlarged parotid and submandibular glands on both sides. MRI of the neck showed multiple, sharply circumscribed lesions in the major salivary glands and both lacrimal glands as well as in the orbit. Initially we suspected Heerfordt's syndrome, a manifestation of sarcoidosis, but laboratory diagnosis could not reveal a pathological erythrocyte sedimentation rate or an increased ACE titer. After exploratory excision from the right submandibular gland, histological examination revealed Castleman's disease. Therefore, we initiated an immunomodulatory therapy with interleukin-6 receptor antagonists.Castleman's disease is one of the very rare, benign, lymphoproliferative processes that have a tendency to turn malignant. Isolated findings of Castleman's disease should be completely resected. There are no clear treatment strategies for multiple localizations of Castleman's disease. The approaches range from systemic glucocorticoid therapy with chemotherapy to immunomodulatory treatment. In contrast to isolated findings, the prognosis for multicentric occurrence is unfavorable. PMID- 22534679 TI - [Nonorganic (functional) hearing loss in children]. AB - Nonorganic (functional) hearing loss in children is characterized by hearing loss without a detectable corresponding pathology in the auditory system. It is not an uncommon disease in childhood. Typically, there is a discrepancy between elevated pure tone thresholds and normal speech discrimination in everyday life. We evaluated 85 original publications, 27 reviews and 4 textbook articles. Mean age at diagnosis was 11.3 years. Girls were affected twice as often as boys. Patient histories showed a high prevalence of emotional and school problems. Pre-existing organic hearing loss can be worsened by nonorganic causes. A brainstem audiometry should confirm the diagnosis. The differential diagnosis includes auditory processing disorder, elevated thresholds in mental retardation and auditory neuropathy. We recommend taking a personal history including biographical factors, a psychological assessment including intelligence testing and referral to a child psychiatrist. Prognosis seems to be dependent on the severity of the patient's school and/or personal problems. Categorization following the Austen Lynch model can be a valuable prognostic factor. PMID- 22534681 TI - ZmHSP16.9, a cytosolic class I small heat shock protein in maize (Zea mays), confers heat tolerance in transgenic tobacco. AB - Various organisms produce HSPs in response to high temperature and other stresses. The function of heat shock proteins, including small heat shock protein (sHSP), in stress tolerance is not fully explored. To improve our understanding of sHSPs, we isolated ZmHSP16.9 from maize. Sequence alignments and phylogenetic analysis reveal this to be a cytosolic class I sHSP. ZmHSP16.9 expressed in root, leaf and stem tissues under 40 degrees C treatment, and was up-regulated by heat stress and exogenous H2O2. Overexpression of ZmHSP16.9 in transgenic tobacco conferred tolerance to heat and oxidative stresses by increased seed germination rate, root length, and antioxidant enzyme activities compared with WT plants. These results support the positive role of ZmHSP16.9 in response to heat stress in plant. KEY MESSAGE: The overexpression of ZmHSP16.9 enhanced tolerance to heat and oxidative stress in transgenic tobacco. PMID- 22534682 TI - Pre-procambial cells are niches for pluripotent and totipotent stem-like cells for organogenesis and somatic embryogenesis in the peach palm: a histological study. AB - The direct induction of adventitious buds and somatic embryos from explants is a morphogenetic process that is under the influence of exogenous plant growth regulators and its interactions with endogenous phytohormones. We performed an in vitro histological analysis in peach palm (Bactris gasipaes Kunth) shoot apexes and determined that the positioning of competent cells and their interaction with neighboring cells, under the influence of combinations of exogenously applied growth regulators (NAA/BAP and NAA/TDZ), allows the pre-procambial cells (PPCs) to act in different morphogenic pathways to establish niche competent cells. It is likely that there has been a habituation phenomenon during the regeneration and development of the microplants. This includes promoting the tillering of primary or secondary buds due to culturing in the absence of NAA/BAP or NAA/TDZ after a period in the presence of these growth regulators. Histological analyses determined that the adventitious roots were derived from the dedifferentiation of the parenchymal cells located in the basal region of the adventitious buds, with the establishment of rooting pole, due to an auxin gradient. Furthermore, histological and histochemical analyses allowed us to characterize how the PPCs provide niches for multipotent, pluripotent and totipotent stem-like cells for vascular differentiation, organogenesis and somatic embryogenesis in the peach palm. The histological and histochemical analyses also allowed us to detect the unicellular or multicellular origin of somatic embryogenesis. Therefore, our results indicate that the use of growth regulators in microplants can lead to habituation and to different morphogenic pathways leading to potential niche establishment, depending on the positioning of the competent cells and their interaction with neighboring cells. KEY MESSAGE: Our results indicate that the use of growth regulators in microplants can lead to habituation and to different morphogenic pathways leading to potential niche establishment, depending on the positioning of the competent cells and their interaction with neighboring cells. PMID- 22534683 TI - Agroinfiltration of intact leaves as a method for the transient and stable transformation of saponin producing Maesa lanceolata. AB - A method has been developed to genetically transform the medicinal plant Maesa lanceolata. Initially, we tested conditions for transient expression of GFP bearing constructs in agroinfiltrated leaves. Leaf tissues of M. lanceolata were infiltrated with Agrobacterium tumefaciens carrying a nuclear-targeted GFP construct to allow the quantification of the transformation efficiency. The number of transfected cells was depended on the bacterial density, bacterial strains, the co-cultivation time, and presence of acetosyringone. The transient transformation assay generated the highest ratio of transfected cells over non transfected cells upon 5 days post-infiltration using A. tumefaciens strain LBA4404 at an OD600 = 1.0 in the presence of 100 MUM acetosyringone and in the absence of a viral suppressor construct. In a second series of experiments we set up a stable transformation protocol that resulted in the regeneration of kanamycin-resistant plants expressing nuclear GFP. This transformation protocol will be used to introduce overexpression and RNAi constructs into M. lanceolata plants that may interfere with triterpenoid saponin biosynthesis. KEY MESSAGE: We have developed a transformation protocol for saponin producing Maesa lanceolata. Using the protocol reported here, now we are able to generate the tools for the modification of saponin production. PMID- 22534684 TI - Prevalence of renal stones in an Italian urban population: a general practice based study. AB - Kidney stones represent a common condition characterized by significant morbidity and economic costs. The epidemiology of kidney stones is not completely understood and may vary substantially based on geographic, socioeconomic and clinical factors; the present study aims at defining the prevalence and diagnostic patterns of kidney stones in a cohort representative of the general population in Florence, Italy. A sample of 1,543 adult subjects, all Caucasians, was randomly selected from a population of over 25,000 subjects followed by 22 general practitioners (GPs). Subjects were administered a questionnaire requesting the patient's age and sex, any history of kidney stones and/or colics and the prescription of kidney ultrasound (US) examination. GPs data-bases were also interrogated. Crude and adjusted prevalence proportions and ratios (PRs) with corresponding 95% confidence intervals (CIs) were computed. Furthermore, the association between the practice pattern of each physician with respect to US prescription and the prevalence of kidney stones was investigated. The overall prevalence of kidney stones was 7.5% (95% confidence interval 6.2, 8.9%), increasing with age until 55-60 years and then decreasing. About 50% reported recurrent disease. There were no significant differences in prevalence among males and females. GPs who tended to prescribe more US examinations were more likely to have more patients with kidney stones (adjusted PR 1.80, 95% CI 1.11, 2.94; p = 0.020). The present study confirms both the high prevalence and the regional variability of kidney stones. Practice patterns may be involved in such variability. PMID- 22534685 TI - Arthroscopic treatment of Pipkin type I femoral head fractures: a report of 2 cases. AB - Pipkin type I fractures historically have required open treatment, with the potential-associated morbidity. Two cases of arthroscopic fracture fragment excision are described. These were completed using standard techniques and introducing the application of Steinman pins, through an accessory anterior portal, for capture of the fragment. Both the patients had satisfactory outcomes. We conclude that hip arthroscopy is a valuable option for the treatment of Pipkin I fractures. PMID- 22534686 TI - Short, locked humeral nailing via Neviaser portal: an anatomic study. AB - OBJECTIVE: Supraspinatus tendon trauma may contribute to residual shoulder pain after nail fixation for proximal humeral fractures. Some have proposed a more medial starting point for humeral nail insertion to avoid cuff tendon footprint damage. We hypothesized that percutaneous nail insertion via Neviaser portal would not only be possible, but would avoid tendon trauma, while sacrificing articular cartilage. MATERIALS AND METHODS: Under c-arm guidance and in percutaneous fashion, we nailed 16 consecutive complete (head and neck, etc, intact) specimen right proximal humeri with locked short humeral nails (Aequalis) via Neviaser portal. Each shoulder was dissected to study the damage to the rotator cuff and long head of the biceps tendons as well as to the articular surfaces. We measured the humeral-thoracic abduction arc before the damaged articular surface contacted the superior glenoid. There were 5 male specimens and 11 female specimens with a mean age of 83 years at the time of death. RESULTS: We successfully inserted 15 of 16 humeral nails through this percutaneous approach. No supraspinatus tendon or long head of the biceps tendon was damaged. All nails passed entirely through supraspinatus muscle belly. Thirteen of 15 starting points were entirely on articular surface. Mean arc of abduction before superior glenoid contact was 76 degrees (range, 50 degrees-130 degrees). Mean distance from the edge of the articular surface to the most lateral part of the nail insertion was 11 mm (0-25 mm). CONCLUSIONS: Short, locked humeral nail insertion is possible in percutaneous fashion via Neviaser portal without tendon injury. However, successful insertion comes at the cost of articular cartilage damage. PMID- 22534687 TI - A three-dimensional comparison of intramedullary nail constructs for osteopenic supracondylar femur fractures. AB - OBJECTIVES: This study developed a new 6 degree-of-freedom, unconstrained biomechanical model that replicated the in vivo loading environment of femoral fractures. The objective of this study was to determine whether various distal fixation strategies alter failure mechanisms and/or offer mechanical advantages when performing retrograde intramedullary nail (IMN) stabilization of supracondylar femur fractures in osteoporotic bone. METHODS: Forty fresh-frozen human femora were allocated into 2 groups of matched pairs: "locked" (fixed angle locking construct with both distal locking screws rigidly attached to the IMN) versus "unlocked" (conventional locking technique with 2 distal locking screws targeted through the distal locking screw holes of the IMN) and "locked" versus "washer" (fixed angle locking with the most distal screw exchanged for a bolt with condyle washers) distal fixation of a retrograde IM nails. A comminuted fracture (OTA 33-A3) was simulated with a wedge osteotomy. Bone density measurements were completed on all specimens before instrumentation. Instrumented femurs were loaded axially to failure, whereas 6 degree-of-freedom translations and angulations were measured using Roentgen stereophotogrammetric analysis. RESULTS: Mean (+/- SD) load born by "locked" specimens (1609 +/- 667 N) at clinical failure was 38.1% greater (P = 0.09) than the corresponding mean load born by "unlocked" specimens (1165 +/- 772 N). Clinical failure for the "washer" group (1738 +/- 772 N) was 29.9% greater (P = 0.07) than the corresponding mean of the "locked" counterparts (1338 +/- 822 N). Failure load was most clearly related to bone density in the "unlocked" fixation group. CONCLUSIONS: Predicting failure load based on bone density using a least squares estimate suggests that the washer construct provides superior fixation to other treatment techniques. The failure mechanism for a comminuted, supracondylar fracture cannot be analyzed accurately with a 1-dimensional measurement. The most common failure mechanism in this model was medial translation and varus angulation. PMID- 22534688 TI - A rat model of chondrocyte death after closed intra-articular fracture. AB - OBJECTIVE: The development of osteoarthritis after intra-articular fractures has been described for decades, although the exact mechanical and cellular changes that occur remain poorly understood. There are several animal models to study this phenomenon, but they are mechanistically different from physiologic fractures in several important ways. This article describes a novel model that recreates the kinematics present in high-energy trauma and intra-articular fractures. METHODS: We designed a "drop tower" for the creation of intercondylar femoral fractures in rats and tested it on cadaveric rats to determine the optimal kinetic parameters. Intra-articular fractures were then created in live rats and the animals were killed at 0, 24, and 72 hours after the fracture. Cartilage samples were obtained for live/dead staining, and the relationships among fracture time, cartilage depth, and cell viability were evaluated. RESULTS: The model reproduced intra-articular fractures very similar to those seen in high energy trauma, although we required significantly higher energies (3600 mJ) than those reported in other fracture models (40-200 mJ). Cartilage viability decreased with time (68% immediately after the fracture and 46% at 72 hours, P = 0.02) and increased with depth from the articular surface (47% at the surface vs. 66% in the deepest layer, P = 0.001). CONCLUSIONS: This model is a physiologically relevant reliable method for creating intra-articular fractures in rats and can produce meaningful data about the biologic changes occurring in cartilage after injury. Cell viability decreases with time postfracture and with proximity to the articular surface. PMID- 22534689 TI - The need to standardize functional outcome in randomized trials of hip fracture: a review using the ICF framework. AB - OBJECTIVES: The choice of ideal outcome assessment is complex with the ever growing number of possible instruments found in the orthopaedic literature. It is critical to reach a worldwide consensus approach in identifying the specific measures to be used in study designs for evaluating treatment of patients with hip fracture. In this article, we present results from a systematic review of the measures being used currently to assess functional outcome in randomized trials. We used the International Classification of Functioning Disability and Health (ICF) framework for conceptualizing outcome after hip fracture trauma from a body, individual, and societal perspective. DATA SOURCES: Relevant articles from 1980 to 2008 (week 52) were found using PubMed, Ovid MEDLINE, Cochrane, Ovid Healthstar, EMBASE, and CINAHL. STUDY SELECTION: Studies were included if (1) patients were older than 65 years and managed postoperatively after a hip fracture and (2) the studies were randomized and in the English language. DATA EXTRACTION: The intervention, sample size, follow-up, intention-to-treat analysis, mode of administration, and functional outcome domains and concepts using the ICF were recorded for each study. DATA SYNTHESIS: Ninety-seven studies containing 82 different instruments for assessing functional outcome were included. Those trials with a low risk of bias relied upon standardized patient reported outcomes when compared with those trials with a high risk of bias that adopted more investigator-developed instruments. Nineteen percent of the trials used the Harris hip score, 14% used the Katz activities of daily living index, and 10% used the new mobility score. CONCLUSIONS: We believe that standardized patient-reported outcomes should be used to assess functional outcome after hip fracture and more rigor is needed when conducting surgical trials in this area. Variation in outcome measures across trials leads to several problems. Clinicians may not be able to interpret their findings when different measures are used. Researchers will not be able to calculate summary treatment effects. Our findings are based on a process for delineating the categories from within the ICF framework that may serve, in the future, as a comprehensive foundation of content for outcomes in the area of hip fractures. PMID- 22534690 TI - Minimally invasive plate osteosynthesis of humeral shaft fractures: a technique to aid fracture reduction and minimize complications. AB - OBJECTIVES: To introduce a modified operative technique for minimally invasive plate osteosynthesis (MIPO) for acute displaced humeral shaft fractures and to evaluate the clinical and radiological outcomes. DESIGN: : Prospective clinical series study. SETTING: University hospital. PATIENTS: Twenty-one patients with acute displaced humeral shaft fractures were treated by MIPO with a modified fracture reduction technique. INTERVENTION: A narrow 4.5/5.0-mm locking compression plate was applied to the anterior aspect of the humerus. Fracture reduction and manipulation were performed using a plate and drill bits. MAIN OUTCOME MEASUREMENTS: The operating time, time to union, humeral alignment, and functional outcome of the shoulder and elbow joints were evaluated using the University of California Los Angeles shoulder score and Mayo elbow performance score. RESULTS: No patient experienced a neurological complication. Bony union was obtained in 20/21 patients at a mean 17.5 weeks postoperatively. Eighteen patients had excellent and 3 patients had good results in the University of California Los Angeles score. The average Mayo elbow performance score was 97.5. Two patients were converted to an open reduction during operation due to a failure of MIPO. There was 1 nonunion and 1 malunion in this series. CONCLUSIONS: Although the MIPO technique for humeral shaft fractures is technically demanding, satisfactory clinical outcomes in terms of bony union and shoulder and elbow function can be obtained using the modified fracture reduction method. Potential postoperative complications, such as malreduction and nonunion, must be considered. Appropriate surgical indications, a thorough understanding of the neurovascular anatomy and skillful surgical technique, are needed to reduce potential complications. PMID- 22534691 TI - Reduction of pullout strength caused by reinsertion of 3.5-mm cortical screws. AB - INTRODUCTION: Osteosynthesis of the tibia, tibial plafond, and calcaneus is commonly performed with plates and 3.5-mm self-tapping cortical screws. Screw insertion and reinsertion within the same hole in the bone may occur during surgery. Therefore, the purpose of this study was to evaluate the pullout strength of 3.5-mm self-tapping screws with up to 5 re-insertions in the diaphysis of the tibia, metaphysis of the distal tibia, calcaneus, and a polyurethane synthetic bone model. METHODS: Screws were inserted into a synthetic bone model and 5 pairs of human cadaveric diaphyseal tibiae, distal tibiae, and calcanei. The bone was predrilled, and then 3.5-mm cortical self-tapping 316 L stainless steel screws with a washer were inserted bicortically. Screws were inserted from 1 to 5 times at each location. The screws were grasped and subjected to 5-mm/min tensional force via the biaxial material testing systems machine. Statistical significance was determined using a paired 2-tailed t test. RESULTS: There was a significant difference in the pullout strength of the tibial diaphysis (1710 +/- 550 N), tibial metaphysis (471 +/- 266 N), and calcaneus (238 +/- 90 N; P < 0.01). The tibial diaphysis pullout strength was 1710 +/- 550 N for one insertion differing significantly relative to the groups with 4 (average 1030 +/- 543 N, P = 0.004) or 5 (average 364 +/- 209 N, P < 0.001) insertions. The tibial metaphyseal pullout strength for the single insertion group was 471 +/- 266 N and differed significantly relative to the 3 (P = 0.026), 4 (P = 0.044), and 5 (P = 0.042) insertion groups. The calcaneal pullout strength for the single insertion group was 238 +/- 90 N with a significant difference of the 1, 3, and 4, versus the 5 insertion group (P = 0.027, 0.040, and 0.033, respectively). The synthetic bone model pullout strength decreased significantly from the one insertion group relative to all other insertion groups (group 1, 1167 +/- 263 N; group 2, 768 +/- 199 N; group 3, 694 +/- 295 N; group 4, 662 +/- 356 N; and group 5, 154 +/- 183 N; P < 0.02). CONCLUSIONS: There is a significant decrease in relative pullout strength of 3.5-mm self-tapping cortical screws when comparing the tibial diaphysis, tibial metaphysis, and calcaneus. There is also a significant decrease in 3.5-mm self-tapping screw pullout strength after repeated reinsertions in the synthetic bone model, mid-shaft tibia, metaphyseal tibia, and calcaneus. We recommend that during osteosynthesis, careful screw insertion, and minimal reinsertion be performed. PMID- 22534692 TI - Electronic charging of non-metallic clusters: size-selected Mo(x)S(y) clusters supported on an ultrathin alumina film on NiAl(110). AB - Two photon photoemission was used to investigate the interfacial charge transfer for size-selected Mo(x)S(y) (x/y: 2/6, 4/6, 6/8, 7/10) clusters deposited on an ultrathin alumina film prepared on a NiAl(110) surface. The local work function of the surface increases with increasing cluster coverage, which is unexpected for charge transfer resulting from the formation of Mo-O bonds between the clusters and the alumina surface. By analogy with Au atoms and clusters on metal supported ultrathin oxide films, we invoke electron tunneling from the NiAl substrate to explain the charge transfer to the Mo(x)S(y) clusters. Electron tunneling is favored by the large electron affinities of the Mo(x)S(y) clusters and the relatively low work function induced by the presence of the alumina film. The interfacial dipole moments derived from coverage-dependent measurements are cluster dependent and reflect differences in Mo(x)S(y) cluster structure and surface bonding. These results extend previous observations of electronic charging to non-metallic clusters, specifically, metal sulfides, and suggest a novel way to modify the electronic structure and reactivity of nanocatalysts for heterogeneous chemistry. PMID- 22534693 TI - Time-dependent nanogel aggregation for naked-eye assays of alpha-amylase activity. AB - This work designs an enzyme-stimulated nanogel aggregation system for the naked eye assays of alpha-amylase activity. The visible aggregation of the starch stabilized CdTe nanogels may be accelerated by alpha-amylase through its efficient cleavage of glycosidic bonds in the starch network, which has been verified by the evidences from transmission electron microscopy and dynamic light scattering spectra. The required aggregation time, as validated by both the theoretical deduction and the experimental results, is inversely proportional to the enzymatic activity. Therefore a facile method has been proposed for the detection of enzyme activity, with an excellent linear range and a low detection limit. This nanogel-based protocol can be successfully applied in the fast and accurate assays of alpha-amylase activity in saliva samples with a satisfactory correlation with the standard protocol, suggesting its promising applications in the biomedical and clinical fields, especially in point-of-care testing. PMID- 22534694 TI - Primary assembly of soil communities: disentangling the effect of dispersal and local environment. AB - It has long been recognised that dispersal abilities and environmental factors are important in shaping invertebrate communities, but their relative importance for primary soil community assembly has not yet been disentangled. By studying soil communities along chronosequences on four recently emerged nunataks (ice free land in glacial areas) in Iceland, we replicated environmental conditions spatially at various geographical distances. This allowed us to determine the underlying factors of primary community assembly with the help of metacommunity theories that predict different levels of dispersal constraints and effects of the local environment. Comparing community assembly of the nunataks with that of non-isolated deglaciated areas indicated that isolation of a few kilometres did not affect the colonisation of the soil invertebrates. When accounting for effects of geographical distances, soil age and plant richness explained a significant part of the variance observed in the distribution of the oribatid mites and collembola communities, respectively. Furthermore, null model analyses revealed less co-occurrence than expected by chance and also convergence in the body size ratio of co-occurring oribatids, which is consistent with species sorting. Geographical distances influenced species composition, indicating that the community is also assembled by dispersal, e.g. mass effect. When all the results are linked together, they demonstrate that local environmental factors are important in structuring the soil community assembly, but are accompanied with effects of dispersal that may "override" the visible effect of the local environment. PMID- 22534695 TI - Localized pleural thickening: smoking and exposure to Libby vermiculite. AB - There is limited research on the combined effects of smoking and asbestos exposure on risk of localized pleural thickening (LPT). This analysis uses data from the Marysville cohort of workers occupationally exposed to Libby amphibole asbestos (LAA). Workers were interviewed to obtain work and health history, including ever/never smoking and chest X-rays. Cumulative exposure estimates were developed on the basis of fiber measurements from the plant and work history. Benchmark concentration (BMC) methodology was used to evaluate the exposure response relationship for exposure to LAA and a 10% increased risk of LPT, considering potential confounders and statistical model forms. There were 12 LPT cases among 118 workers in the selected study population. The mean exposure was 0.42 (SD=0.77) fibers/cc-year, and the prevalence of smoking history was 75.0% among cases and 51.9% among non-cases. When controlling for LAA exposure, smoking history was of borderline statistical significance (P-value=0.099), and its inclusion improved model fit, as measured by Akaike's Information Criterion. A comparison of BMC estimates was made to gauge the potential effect of smoking status. The BMC was 0.36 fibers/cc-year, overall. The BMC for non-smokers was approximately three times as high (1.02 fibers/cc-year) as that for the full cohort, whereas the BMC for smokers was about 1/2 that of the full cohort (0.17 fibers/cc-year). PMID- 22534696 TI - Exposure assessment for a cohort of workers at a former uranium processing facility. AB - Exposure was assessed for a cohort of 6409 workers at a former uranium processing facility as part of a mortality study. Workers at the facility had potential for exposure to a wide variety of radiological and chemical agents including uranium, thorium, radon, external ionizing radiation, acid mists, asbestos, and various solvents. Organ dose from internal exposure to uranium was assessed, along with dose from external ionizing radiation and exposure to radon. Qualitative assessment of exposure to thorium, acid mists, asbestos, coal dust, welding fumes, and other chemicals was also performed. Mean cumulative organ dose from internal uranium exposure ranged from 1.1 mGy (lung) to 6.7 MUGy (pancreas). Mean cumulative external ionizing radiation dose was 13.4 mGy. Mean cumulative radon exposure was 26 working level months (WLMs). The chemical agents to which the largest numbers of study subjects were exposed were acid mists, machining fluids, and a tributyl phosphate/kerosene mixture used in the refining process. PMID- 22534697 TI - Evaluating intra-abdominal pressures in a porcine model of acute lung injury by using a wireless motility capsule. AB - BACKGROUND: Intra-vesical pressure measurement as the reference standard for assessing intra-abdominal pressures is mainly indirect and discontinuous. We therefore evaluated a motility capsule for continuous intra-abdominal pressure measurement in an animal model with a high probability for capillary leakage and intestinal edema. MATERIAL/METHODS: Motility capsules were inserted into the stomachs of 8 anesthetized and ventilated pigs. Stomach pH, pressure, and temperature data were wirelessly transmitted to a recorder attached to each animal's abdomen. Intra-gastric pressures measured by the capsule were compared to intra-vesical pressures measured by a pressure transducer system. RESULTS: The intra-abdominal pressures ranged from 3 to 15 mmHg (7.8 +/- 2.4 mmHg [mean +/- SD]) measured via the bladder. The capsule pressure recordings ranged from 1 to 3 mmHg (1.7 +/- 0.5 mmHg [mean +/- SD]). Bland-Altman analysis revealed an unacceptable bias between the 2 methods. The test bias was 6.2 (+/- 1.4) mmHg and the limits of agreement were from 3.3 to 8.9 mmHg. CONCLUSIONS: Pressures in the stomach as measured by motility capsule underestimated the intra-vesical pressures. Discrepancies between gastric and intra-vesical pressures could be caused by gastric dilatation or different position of the 2 devices to the zero reference point. PMID- 22534698 TI - Establishment of a monoclonal antibody against a peptide of the novel zinc finger protein ZNF32 proved to be specific and sensitive for immunological measurements. AB - BACKGROUND: ZNF32 has been predicted to be a zinc finger protein and is involved in cell differentiation and tumor development, but its precise function is unknown. Specific monoclonal antibodies (mAbs) have been widely used in research and clinical diagnosis and treatments. Therefore, we established an anti-ZNF32 mAb to characterize this protein's function. MATERIAL/METHODS: Peptide49-63, a specific small peptide of ZNF32, was chosen and the synthetic keyhole limpet hemocyanin (KLH)-peptide49-63 was used as an antigen to immunize mice. A mAb against peptide49-63 was generated by hybridoma technology, and hybridoma cells were screened by limiting dilution. The isoform of mAb-pZNF32-8D9 was identified by double agar diffusion. The sensitivity and specificity of the mAb and expressed levels of ZNF32 in various cells and tissues were identified by enzyme linked immunosorbent assay (ELISA), immunocytochemistry, immunohistochemistry, and Western blotting. RESULTS: A stable anti-pZNF32-8D9 hybridoma secreting the anti-peptide49-63 mAb was established and the clone positive to the peptide49-63 in supernatant was 92% in ELISA. The mAb-pZNF32-8D9 is an immunoglobulin-1 that can be used for detecting the ZNF32 protein by immunocytochemistry, immunohistochemistry, and Western blotting and is highly sensitive and specific. We also found ZNF32 expressed at high levels in Jurkat and pulmonary squamous carcinoma cells, but it was not expressed in squamous epidermis cells. CONCLUSIONS: mAb-pZNF32-8D9 can be used for the identification and expression of ZNF32. It might also provide a new tool for diagnostics or therapy for ZNF32 related diseases. PMID- 22534699 TI - Intracerebellar application of P19-derived neuroprogenitor and naive stem cells to Lurcher mutant and wild type B6CBA mice. AB - BACKGROUND: Neurotransplantation has great potential for future treatments of various neurodegenerative disorders. Preclinically, the Lurcher mutant mouse represents an appropriate model of genetically-determined olivocerebellar degeneration. The aim of the present study was to assess survival of naive and neurally differentiated P19 carcinoma stem cells following transplantation into the cerebellum of Lurcher mice and wild type littermates. MATERIAL/METHODS: Adult normal wild type (n=51) and Lurcher mutant mice (n=87) of the B6CBA strain were used. The mean age of the animals at the time of transplantation was 261.5 days. Suspension of naive and neurally differentiated P19 carcinoma stem cells was injected into the cerebellum of the mice. In the Lurcher mutants, 2 depths of graft injection were used. Three weeks after implantation the brains of experimental animals were examined histologically. RESULTS: Survival of neuroprogenitor grafts at a depth of 1.6 mm was significantly higher in wild type vs. Lurcher mutant mice. In wild type mice, the typical graft localization was in the middle of the cerebellum, whereas in Lurcher mice the graft was never found inside the degenerated cerebellum and was primarily localized in the mesencephalon. CONCLUSIONS: We conclude that the appearance and low survival rate of cerebellar P19 carcinoma stem cell grafts in the Lurcher mutant mice weigh against the therapeutic value of this cell line in preclinical studies of neurodegeneration. PMID- 22534700 TI - Ghrelin accelerates the healing of cysteamine-induced duodenal ulcers in rats. AB - BACKGROUND: Previous studies have shown that administration of ghrelin exhibits protective and therapeutic effects in the gut. The aim of the present investigation was to examine the influence of ghrelin administration on the course of cysteamine-induced duodenal ulcers, as well as effects on mucosal production of oxygen free radicals and duodenal antioxidant defense. MATERIAL/METHODS: Duodenal ulcers were induced in male Wistar rats by cysteamine administered intragastrically at the dose of 200 mg/kg in 1 ml of saline, 3 times at 4-h intervals. Starting 24 h after the first dose of cysteamine, rats were treated intraperitoneally twice a day with saline or ghrelin given at the dose of 4, 8 or 16 nmol/kg/dose. Seven days after administration of the first dose of cysteamine, the study was terminated. RESULTS: Induction of ulcers by cysteamine was accompanied by a reduction in duodenal blood flow, mucosal DNA synthesis and mucosal activity of superoxide dismutase (SOD); whereas mucosal concentration of interleukin-1beta and malonyldialdehyde (MDA - an index of lipid peroxidation) were increased. Treatment with ghrelin increased healing rate of duodenal ulcers and enhanced duodenal blood flow, mucosal DNA synthesis and mucosal activity of SOD, and reduced mucosal concentration of interleukin-1beta and MDA. CONCLUSIONS: Treatment with ghrelin increases the healing rate of duodenal ulcers and this effect is related, at least in part, to improvement of duodenal mucosal blood flow, mucosal cell proliferation and antioxidant defense, as well as being related to reduction in mucosal oxidative stress and inflammatory response. PMID- 22534701 TI - Effect of different artificial tears against desiccation in cultured human epithelial cells. AB - BACKGROUND: A large number of artificial tears is widely used to treat dry eye symptoms. To test the efficacy of these drugs independent of individual parameters in vitro models are required. As described previously, we employed a reproducible in vitro cell culture system to evaluate the desiccation protection capability of some artificial tears. In THE PRESENT PAPER DATA IS PRESENTED OF ANOTHER SET OF PHARMACEUTICAL AGENTS. MATERIAL/METHODS: Conjunctival epithelial cell line Chang 1-5c-4 (series 1) and the corneal cell line 2.040 pRSV-T (series 2) were cultured under standard conditions. Confluent cells were wetted for 20 min with artificial tears (Arufil Uno, Arufil, Lacrimal, Lacophthal sine, Siccaprotect, Tears Again, Vidisept EDO, Vistil, Wet Comod) or PBS as a control. After exposure to a constant air flow for 0, 15, 30 and 45 minutes respectively, cells were incubated with the vital dye alamarBlue. Subsequently, absorption of the oxidised form of the dye was assessed using an ELISA-Reader. RESULTS: Cell best survival rates in series 1 after 15 min were found for Lacrimal (0.89), Wet Comod (0.84) compared to PBS (0.66) and in series 2 for Vidisept EDO (0.57) and Lacrimal (0.56) compared to PBS (0.01). After 45 min highest survival was seen in series 1 for Lacrimal (0.46) and Lacophthal sine (0.36) compared to PBS (0.33) and in series 2 for Lacrimal (-0.06) and Arufil (-0.16) compared to PBS (-0.23). CONCLUSIONS: Both cell lines tested showed different susceptibility towards desiccation and the artificial tears showed differences in preventing cells from desiccation. PMID- 22534702 TI - Laparoscopic simple enucleation and coagulation on tumor bed using argon beam coagulator for treating small renal cell carcinomas: an animal study followed by clinical application. AB - MATERIAL/METHODS: The animal experiments of coagulation therapy on the wound tissue bed during partial nephrectomy with an argon beam coagulator were performed on 16 rabbits, which were randomly divided into 4 groups. Groups A and B had renal artery occlusion; the treatment time of coagulation was 4 seconds and 6 seconds, respectively. Groups C and D did not have renal artery occlusion; the treatment time of coagulation was 2 seconds and 4 seconds, respectively. Then 30 clinical operations of laparoscopic simple enucleation and coagulation on tumor bed using an argon beam coagulator were performed. RESULTS: All 16 rabbits successfully underwent the operation. By the histological examination, the scab depth of the wound tissue bed in groups A, B, C, and D were 2.76 +/- 0.17 mm, 3.15 +/- 0.15 mm, 2.28 +/- 0.16 mm and 2.75 +/- 0.06 mm, respectively. Group A differed significantly from groups B and C (P=0.012, 0.007), and group D differed significantly from groups B and C (P=0.002, 0.002). In the clinical study, all 30 patients successfully underwent the operation. The mean operative time was 182 minutes, and the mean blood loss was 280 ml. With a median follow-up time of 37 months, neither local recurrence nor distant metastasis was found by computerized tomography scan. CONCLUSIONS: Laparoscopic simple enucleation and coagulation on tumor bed using an argon beam coagulator can be considered for treating small renal cell carcinomas. However, the indication of this procedure should be highly selected. PMID- 22534703 TI - Therapeutic challenges and management of heart failure during pregnancy (part I). AB - Therapeutic management in pregnant patients with heart failure still remains a challenge, even though in most pregnant women with cardiac diseases an outcome is good. A 32-year-old woman, 17 weeks pregnant, was admitted to hospital with heart failure (HF) NYHA class III/IV. Echocardiography revealed enlarged LV, LVEF 13%, significant mitral insufficiency and pulmonary hypertension. The patient wished to continue the pregnancy. In a life-threatening condition, metoprolol, enalapril, spironolactone (for 5 days), furosemide, and digitalis were administered. Enalapril was continued for 42 days. Then the patient was switched to a dihydralazine and isosorbide mononitrate regimen. The fetus was controlled ultrasonographically. In the 19th week of pregnancy, the patient's condition improved (NYHA class II, LVEF 23%). The patient experienced 2 more episodes of HF exacerbation. In the 26th week of pregnancy, in a primary prevention of sudden cardiac death and because of 2nd-degree AV block, an ICD was implanted. In the 32nd week of pregnancy a cesarean section was performed. A male infant was delivered. The patient made a good recovery and was discharged on the 7th postoperative day. The newborn was discharged after 4 weeks, in good general condition. At 1-year follow-up the patient presented NYHA class II.
PMID- 22534704 TI - Comparison of postoperative pain and satisfaction after dacryocystorhinostomy in patients operated on under local and general anesthesia. AB - BACKGROUND: There has been only 1 study on postoperative pain after external dacryocystorhinostomy (DCR) that compared pain between 2 groups of patients; 1 group received local anesthesia and the other received general anesthesia. To further characterize the relationship between these 2 types of anesthesia and postoperative pain, we designed a study in which a single patient received these 2 different anesthesia modalities for a short interval on 2 different sides. MATERIAL/METHODS: There were 50 participants in this study. External DCR was performed on the same participant on both sides using local anesthesia on 1 side and general anesthesia on the other. Postoperative pain was measured using the visual analogue scale (VAS), and localization and timing of pain were reported by the participants. Postoperative nausea and vomiting (PONV) were documented if present. RESULTS: Pain levels were significantly higher with general anesthesia 3 hours post-surgery, and 6 hours post-surgery the pain remains higher following general anesthesia but is borderline insignificant (p=0.051). However, 12 hours post-surgery, there is no significant difference in the pain level (p=0.240). There was no significant difference in the localization of pain with local and general anesthesia. Postoperative nausea is significantly more frequent after general anesthesia, and vomiting only occurs with general anesthesia. Local anesthesia was preferred by 94% of the participants (47 out of 50). CONCLUSIONS: The vast majority of patients in our study who have undergone both GA and LA DCR would choose LA again, providing a compelling case for use of the LA technique. PMID- 22534705 TI - Gastroesophageal reflux disease and pulmonary function: a potential role of the dead space extension. AB - BACKGROUND: To evaluate the differences in the existence and size of dead space in patients with and without Gastroesophageal Reflux Disease (GERD and non-GERD) expressed through the size of intrapulmonary shunt (QS/QT). MATERIAL/METHODS: The study enrolled 86 subjects - 43 patients referred for endoscopy because of symptoms of GERD (heartburn, acid regurgitation, dysfagia) and 43 healthy subjects with similar anthropometric characteristics without GERD symptoms. Based on endoscopy findings, patients were classified into the erosive reflux disease (ERD) group and non-erosive reflux disease (NERD) group. Spirometry values, single-breath diffusing capacity of the lung for carbon monoxide (DLCO) and intrapulmonary shunt (venous shunt - QS/QT) determined by the oxygen method were measured in all participants. RESULTS: Statistically significant differences between GERD and non-GERD groups in FVC (p=0.034), FEV1 (p=0.002), FEV1/FVC (p=0.001), and PEF (p=0.001) were observed. There were no statistically significant differences in FEF 25% (p=0.859), FEF 50% (p=0.850), and FEF 75% (p=0.058). Values of DLCO (p=0.006) and DLCO/VA (p=0.001) were significantly lower and QS/QT was significantly higher (p=0.001) in the GERD group than in the non-GERD group. However, in both groups the average values of DLCO and DLCO/VA expressed as a percentage of predictive values were within normal range, while the value of QS/QT in the GERD group showed pathological (6.0%) mean value (normal value <= 5.0%). There were no significant differences in respiratory function test results between patients with ERD and NERD. CONCLUSIONS: Our results suggest that microaspiration of stomach contents may cause surfactant damage, development of microatelectasis, and dead space expansion with consequent increase of intrapulmonary (venous) shunt. PMID- 22534706 TI - Prevalence and predictors of ventricular remodeling after anterior myocardial infarction in the era of modern medical therapy. AB - BACKGROUND: The consequences of aggressive therapy following a myocardial infarction (MI) on ventricular remodeling are not well established. Thus, the objective of this study was to analyze the prevalence, clinical characteristics, and predictors of left ventricular remodeling in the era of modern medical therapy. MATERIAL/METHODS: Clinical characteristics and echocardiographic data were analyzed in 66 consecutive patients with anterior infarction at admission and at 6-month follow-up. Ventricular remodeling was defined as an increase of 10% in ventricular end-systolic or end-diastolic diameter. RESULTS: In our study, 58% of patients presented with ventricular remodeling. Patients with remodeling possessed higher total plasma creatine kinase (CPK), MB-fraction (CPK-MB), heart rate, heart failure, shortness of breath, and reperfusion therapy than patients without remodeling. In contrast, patients with remodeling had a smaller ejection fraction, E-Wave deceleration time (EDT), and early (E' Wave) and late (A' Wave) diastolic mitral annulus velocity (average of septal and lateral walls), but a higher E/E' than patients without remodeling. Patients with remodeling used more diuretics, digoxin, oral anticoagulants and aldosterone antagonists than patients without remodeling. In the multivariate analyses, only E' Wave was an independent predictor of ventricular remodeling. Each 1 unit increase in the E' Wave was associated with a 59% increased odds of ventricular remodeling. CONCLUSIONS: In patients with anterior MI, despite contemporary treatment, ventricular remodeling is still a common event. In addition, diastolic function can have an important role as a predictor of remodeling in this scenario. PMID- 22534707 TI - Metabolic syndrome and left ventricular function: is the number of criteria actually important? AB - BACKGROUND: Metabolic syndrome (MS) is a clustering of cardiovascular risk factors responsible for the development of target organ damage. The aim of this study was to determine the effect of the increasing number of MS risk factors on left ventricular function assessed by noninvasive methods. MATERIAL/METHODS: The study included 204 subjects with MS and 76 controls with no MS risk factors. MS was defined by the presence of 3 or more of ATP-NCEP III criteria. MS subjects were grouped according to the number of criteria they fulfilled: 3 criteria (n=91), 4 criteria (n=65) and 5 criteria (n=48). All subjects underwent laboratory blood tests, complete 2-dimensional, pulse and tissue Doppler echocardiography. Echocardiography was used to assess systolic (LVEF, sseptal), diastolic function, by pulse-wave Doppler (E/A ratio) and tissue Doppler imaging (E/e'average), and global left ventricular function (Tei index). Appropriate time intervals for the estimation of the Tei index were obtained by tissue Doppler. RESULTS: Transmitral E/A ratio decreased significantly and progressively from the 3 criteria to the 5 criteria group (0.82 +/- 0.25 vs. 0.79 +/- 0.24 vs. 0.67 +/- 0.14, p<0.001). The transmitral E/E'average ratio was significantly and gradually increased from the 3 criteria to the 5 criteria group (7.76 +/- 1.81 vs. 9.44 +/- 2.35 vs. 10.82 +/- 2.56, p<0.001). The left ventricle Tei index progressively increased from the 3 criteria to the 5 criteria group (0.43 +/- 0.11 vs. 0.48 +/- 0.10 vs. 0.54 +/- 0.12, p<0.001). CONCLUSIONS: The increasing number of MS criteria is associated with cardiac diastolic dysfunction. PMID- 22534708 TI - The impact of aerobic exercise training on novel adipokines, apelin and ghrelin, in patients with type 2 diabetes. AB - BACKGROUND: Accumulating data support the atheroprotective role of the novel adipokines, apelin and ghrelin. The aim of the present randomized study was to investigate the effects of aerobic exercise training on these adipokines in patients with type 2 diabetes mellitus (T2DM). MATERIAL/METHODS: Fifty-four overweight (BMI >25 kg/m2) patients with T2DM, but without vascular complications, were randomized to either the aerobic exercise training group (EG, N=27), 4 times/week, 45-60 min/session; or to the control group (CG, N=27), orally instructed to increase physical activity. Clinical glycemic and lipid parameters, exercise capacity (VO2peak), insulin, HOMA-IR, and serum levels of apelin and ghrelin were assessed at baseline and after 12 weeks. RESULTS: Aerobic exercise significantly improved lipid and glycemic profile and insulin sensitivity compared to CG (p<0.05). Furthermore, between-groups comparison showed a considerable exercise-induced upregulation in apelin (p=0.007) and VO2peak (p<0.001) levels. Negligible changes in body-weight, waist-hip ratio and ghrelin concentrations were detected within and between groups after the completion of the study (p>0.05). However, subgroup analysis revealed a considerable increment in ghrelin levels only in the exercise-treated women compared to their control counterparts (p=0.038). LDL and HOMA-IR reduction were found to be independent predictors of apelin increment in multiple regression analysis (R2=0.391, p=0.011). CONCLUSIONS: In patients with T2DM, systemic, long term, aerobic exercise exerts positive effects on apelin and ghrelin (only in women), even in the absence of significant weight loss, suggesting its pleiotropic effects. PMID- 22534709 TI - Azithromycin versus Sulfadiazine and Pyrimethamine for non-vision-threatening toxoplasmic retinochoroiditis: a pilot study. AB - BACKGROUND: The purpose of this pilot study is to compare the efficacy and tolerance of azithromycin alone as opposed to standard treatment with sulfadiazine and pyrimethamine for active, non-vision-threatening toxoplasmic retinochoroiditis. MATERIAL/METHODS: We conducted a prospective, randomized, institutional clinical study comparing azithromycin to sulfadiazine and pyrimethamine for active, non-vision-threatening toxoplasmic retinochoroiditis. Nineteen out of 75 patients fulfilled inclusion criteria and were randomized into 2 treatment regimens. Nine patients were treated with sulfadiazine and pyrimethamine and 10 patients with azithromycin at a dose of 500 mg qd. Main outcome measures assessed were time to sharpening of lesion borders, time to lesion scarring, time to disease inactivity, and treatment tolerance. RESULTS: Azithromycin monotherapy achieved lesion scarring and disease inactivity in all but 1 patient. Although no statistically significant difference was found between the 2 patient groups as regards main outcome measures for treatment efficacy, all median times to endpoints (days) were longer for the azithromycin group - time to sharpening of lesion borders on clinical evaluation (25.5 vs. 24) and masked evaluation of photographs (30.5 vs. 24), time to lesion scarring on clinical evaluation (73 vs. 47) and masked evaluation of photographs (71.5 vs. 36) and time to disease inactivity (73 vs. 49). Treatment tolerance was significantly better for the azithromycin group (p=0.0005). CONCLUSIONS: Azithromycin monotherapy at a dose of 500 mg per day was shown to be effective and well tolerated for the treatment of active, non-vision-threatening toxoplasmic retinochoroiditis. Duration of treatment was clinically longer for the azithromycin group. PMID- 22534710 TI - Radiological and biomechanical analysis of humeral fractures occurring during arm wrestling. AB - BACKGROUND: Arm wrestling has recently become one of the most popular sports among young people, mainly due to its simplicity and spectacularity. Yet, unfortunately it is also injury prone. The aim of the study was to perform a biomechanical analysis of the forces which act during arm wrestling, as well as to explain the mechanism of the occurrence of humeral fractures of a similar topology as observed on X-rays. MATERIAL/METHODS: During the period 2001 to 2008 nine cases of humeral fractures resulting from arm wrestling were consulted and treated at the Clinic. The assessment of the limb condition included an interview and the examination of the fractured extremity. All the patients underwent surgical treatment, using the method of open reduction and internal fixation. The virtual dynamic model of the upper limb was established on the basis of a series of computer tomography scans of the bone, and literature data. The biomechanical analysis was carried out using the Finite Elements Method (FEM). RESULTS: There were five cases of the 12-B1 type in the AO Classification with butterfly fragments in five cases, and four of the 12-A1 type without the butterfly fragment. The maximum bone stress resulting from torsional loading which occurs during arm wrestling amounted to 60 MPa and was located 115 mm above the elbow on the medial - posterior side of the humeral. CONCLUSIONS: The strength analysis carried out during arm wrestling revealed that the forces of the acting muscles significantly exert stresses within the distal third of the humeral. PMID- 22534712 TI - The objective evaluation of effectiveness of manual treatment of spinal function disturbances. AB - BACKGROUND: The aim of this paper is the evaluation of effectiveness of manual therapy in the treatment of functional disturbances of the spine. MATERIAL/METHODS: The study subjects were 40 persons aged 45-60 years, in whom degenerative changes in intervertebral discs and physical limitations within the spine were found (NMR), which were manifested as pain. Subjects were randomly divided into 2 groups of 20 persons each. The first group went on a monthly rehabilitation tour, where the manual therapy methods were applied. The second group was treated by means of physical methods. In order to verify the results of effectiveness of the therapies, the examination of the sectional mobility and the evaluation of the spinal curvatures before and after the completion of the therapy were made by means of a tensiometric electrogoniometer. RESULTS: The percentage differences in significance result from the lower value of parameter t1 in the group of persons treated physically. The dynamics of changes in the parameters in the sectional mobility in both tested groups was highest in the cervical and lumbar spine. The manually treated group had greater dynamics of changes in functional parameters of the spine. CONCLUSIONS: Manual therapy is an effective method for treatment of functional changes and early structural changes within the spine, and may be used as supplementary therapy in relation to the standard model of treatment of spinal pain. PMID- 22534713 TI - The evaluation of esophageal stenting complications in palliative treatment of dysphagia related to esophageal cancer. AB - BACKGROUND: Esophageal cancer is the seventh-most frequent cause of cancer related deaths and it is usually diagnosed at an inoperable stage. In palliative treatment, endoscopic and non-endoscopic methods are applied to reduce dysphagia in patients with neoplastic esophageal obstruction. Because of severe complications, non-endoscopic treatment (surgery, radiotherapy, brachytherapy and chemotherapy) is applied rarely. Within the endoscopic methods, only the use of endoprostheses yields long-term effects. The aim of this study was to evaluate the safety and efficacy of implantation of self-expandable esophageal stents in palliative treatment of dysphagia related to esophageal cancer. MATERIAL/METHODS: A total number of 46 patients (41 males and 5 females) were qualified to palliative implantation of coated self-expandable stent. The mean age of the patients was 67 years (from 51 to 78 years). In all patients, Evolution-type coated self-expandable stents were used. In all cases, 24 hours after the implantation, radiological examination was performed to assess the stent location. RESULTS: Severe, possibly life-threatening, complications constituted 28% of all the complications and occurred in 9% of the patients. Less severe complications occurred in 17% of the observed patients and were not life threatening. CONCLUSIONS: In patients with neoplastic esophageal stenosis, stenting with coated, self-expandable nitinol prostheses is a safe, effective and fast method of palliative dysphagia treatment. PMID- 22534711 TI - Evaluation of prognostic value of selected biochemical markers in surgically treated patients with acute mediastinitis. AB - BACKGROUND: Monitoring of biochemical markers of inflammation in acute mediastinitis (AM) can be useful in the modification of treatment. This study was a retrospective evaluation of selected biochemical parameters with negative impact on the prognosis in surgically treated patients. MATERIAL/METHODS: There were 44 consecutive patients treated surgically due to AM of differentiated etiology. Selected biochemical markers (WBC, RBC, HGB, HCT, PLT, CRP, PCT, ionogram, protein and albumins) were assessed before surgery and on the 3rd day after surgery. ANOVA was applied to find factors influencing observations. Numerical data [laboratory parameters] were compared by means of medians. RESULTS: The overall hospital mortality rate was 31.82%. In the group of dead patients, there were observed statistically significant lower mean preoperative values of RBC [p=0.0090], HGB [p=0.0286], HCT [p=0.0354], protein [p= 0.0037], albumins [p=0.0003] and sodium [p<0.0001] and elevated values of CRP [P=0.0107] and PCT p<0.0001]. High level of inflammatory markers on day 3 after surgery was found to increase the risk of death - for WBC (by 67%), for CRP (by 88%) and for PCT (by 100%). CONCLUSIONS: Poor prognosis was more frequent in patients with preoperative high levels of CRP, PCT, anemia, hypoproteinemia and hyponatremia. The risk of death increases significantly if in the immediate postoperative period no distinct decrease in WBC count and of the CRP and PCT level is observed. In such a situation the patients should be qualified earlier for broadened diagnostic workup and for reoperation. PMID- 22534714 TI - Influence of hypertension, obesity and nicotine abuse on quantitative and qualitative changes in acute-phase proteins in patients with essential hypertension. AB - BACKGROUND: Hypertension is a powerful risk factor for cardiovascular disease and frequently occurs in conjunction with obesity. Accumulative evidence suggests a link between inflammation and hypertension. The aim of study was to evaluate whether blood pressure, obesity and smoking may influence acute-phase response. MATERIAL/METHODS: Ninety-two patients with essential hypertension and 75 healthy volunteers as a control group were studied. In all subjects assessment of hsCRP, alpha1-acid glycoprotein (AGP), alpha1-antichymotrypsin, transferrin, alpha1 antitrypsin, and C3 and C4 complement were performed. Evaluation of glycosylation profile and reactivity coefficient (RC) for AGP was done by means of affinity immunoelectrophoresis with concanavalin A as a ligand. RESULTS: When compared to the controls, hypertensive subjects presented significantly higher hsCRP concentrations and lower transferrin level. Hypertensive patients had elevated AGP-AC. The intensification of the inflammatory reaction was greater in the subgroup of hypertensive patients smoking cigarettes. In obese hypertensives, elevated serum C3 complement level was found. CONCLUSIONS: We conclude that arterial hypertension may evoke the acute-phase response in humans. Markers of acute-phase response are particularly strongly expressed in smokers. Serum C 3 complement, but not other APPs, is elevated in hypertension coexisting with obesity.
PMID- 22534715 TI - A novel TP53 somatic mutation involved in the pathogenesis of pediatric choroid plexus carcinoma. AB - BACKGROUND: Choroid plexus carcinoma (CPC) is an uncommon, aggressive, malignant, central nervous system neoplasm that typically occurs in children, presenting with the signs and symptoms of intracranial hypertension and cerebrospinal fluid obstruction. CASE REPORT: We report the case of a 2.5-year-old girl with CPC. The tumor was subtotally removed by microsurgery, followed by gamma knife radiosurgery for the residual lesion. H&E staining indicated that this was a rare case of CPC. Neuropathological studies, assayed by immunohistochemical staining, showed that the tumor sample was positive to antibodies against S-100, CgA, AE1/AE3 (cytokeratin), Ki-67, INI1 and TP53, and was negative to antibodies against Nestin, GFAP, CD133, EMA and AFP. Moreover, stainings for transthyretin and vimentin were focally positive. Interestingly, direct DNA sequencing of the paraffin-embedded tumor sample identified a novel R248Q mutation in the TP53 gene. In contrast to previous reports suggesting that TP53 germline mutations were associated with the pathogenesis of CPC, here we provide a rare case of CPC with TP53 somatic mutation, as evidence that the peritumoral tissue possesses the non-mutant TP53 allele. CONCLUSIONS: Our finding suggests that TP53 somatic mutations, in addition to its germline mutations, may also be involved in the pathogenesis of pediatric CPC. PMID- 22534716 TI - Guanylate cyclase inhibition by methylene blue as an option in the treatment of vasoplegia after a severe burn. A medical hypothesis. AB - Today it is known that severe burns can be accompanied by the phenomenon of vasoplegic syndrome (VS), which is manifested by persistent and diffuse vasodilation, hypotension and low vascular resistance, resulting in circulatory and respiratory failure. The decrease in systemic vascular resistance observed in VS is associated with excessive production of nitric oxide (NO). In the last 2 decades, studies have reported promising results from the administration of an NO competitor, methylene blue (MB), which is an inhibitor of the soluble guanylate cyclase (sGC), in the treatment of refractory cases of vasoplegia. This medical hypothesis rationale is focused on the tripod of burns/vasoplegia catecholamine resistant/methylene blue. This article has 3 main objectives: 1) to study the guanylate cyclase inhibition by MB in burns; 2) to suggest MB as a viable, safe and useful co-adjuvant therapeutic tool of fluid resuscitation, and; 3) to suggest MB as burns hypotensive vasoplegia amine-resistant treatment.
PMID- 22534717 TI - Myocardial bridging is a potential risk factor of very late stent thrombosis of drug eluting stent. AB - Drug eluting stents have been implanted worldwide and used in nearly 90% of percutaneous coronary interventions in China. Although many randomized trials have confirmed the efficacy and safety profile of drug eluting stents, they were not powered to detect or exclude the effect of drug eluting stents on rare events such as stent thrombosis. Several mechanisms of very late stent thrombosis have been postulated, but are not widely accepted. Virchow's triad describes the 3 main factors of thrombus formation - stasis of blood flow, endothelial injury and hypercoagulability. Myocardial bridging is a common congenital anomaly. Modern anatomy and angiography regard myocardial bridging as widespread, but its pathophysiological response is always ignored. According to Virchow's triad, myocardial bridging negatively affect endothelial function, and the turbulent shear stress and intimal trauma predispose the vessel toward thrombus formation. Therefore, we question whether a relationship between myocardial bridging and very late stent thrombosis of drug eluting stents exists. Also, we propose that myocardial bridging might be a potential risk factor of very late stent thrombosis of drug eluting stents; coronary artery bypass grafting might be a promising and novel choice in the treatment of myocardial bridging with severe stenosis in the coronary artery.
PMID- 22534718 TI - The clinical value of MRI using single-shot echoplanar DWI to identify liver involvement in patients with advanced gastroenteropancreatic-neuroendocrine tumors (GEP-NETs), compared to FSE T2 and FFE T1 weighted image after i.v. Gd-EOB DTPA contrast enhancement. AB - BACKGROUND: To assess the detection rate of liver lesions in patients with advanced gastroenteropancreatic neuroendocrine carcinomas (GEP-NETs) using echo planar (EP) DWI (diffusion weighted imaging) as compared to standard FSE T2 wi and FFE T1 wi with i.v. (Gd-EOB)-DTPA. MATERIAL/METHODS: This prospective single institution study included 55 patients with liver involvement confirmed by GEP NETs 1.5T MRI system, using FSE T2, EP DWI and FFE T1 with i.v. (Gd-EOB)-DTPA. The potential differences between detection rates of liver deposits using 3 different MR approaches and between groups of patients were compared. RESULTS: Mean number of liver deposits: FSE T2=20.7, FFE T1=25.7 and tested EP DWI=24.0. No significant difference was found in overall detection rate of liver deposits seen in 3 different techniques. A significant difference in detection rate of liver deposits was noted between male vs. female and secreting vs. non-secreting cancers. There was nearly perfect agreement between both observers, and each of the tested MRI approaches in regards to number of detected liver lesions (Cohen's kappa=0.848-1). CONCLUSIONS: There were no significant differences among the 3 different MRI approaches in detection rates of liver deposits. Perfect agreement with high detection rate of liver deposits provides a rationale for the use of EP DWI in follow-up studies in GEP-NET patients. PMID- 22534719 TI - The prevalence of metabolic risk factors among outpatients with diagnosed nonalcoholic fatty liver disease in Lithuania. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease; there is growing evidence that it is a hepatic manifestation of a metabolic syndrome. This study aimed to assess the prevalence of metabolic risk factors among patients with NAFLD. MATERIAL/METHODS: Outpatients with NAFLD were recruited into the study. Family physicians recorded patients' demographic and anthropometric data, leisure-time physical activity, concomitant diseases, and pharmacological treatment for NAFLD into standardized Case Report Forms. RESULTS: In total, data on 798 patients were analyzed. Most patients were women and they were older than the men (mean age, 60.2 +/- 9.6 vs. 54.5 +/- 11.4 years; p<0.05). Metabolic risk factors (obesity, arterial hypertension, dyslipidemia) were highly prevalent in the study patients, and these factors were more prevalent among women. There were no differences in the mean Body Mass Index (BMI), in the proportion of men or women with BMI >30 kg/m2 or central obesity in the 2 age groups (<= 60 years and >60 years). Hypertension and diabetes were more prevalent among older men and women. Dyslipidemia was more common among older women. The level of leisure-time physical activity was lower in women and in older patients. The most frequently prescribed pharmacological agents were cytoprotective agents, lipid-lowering drugs, and antioxidants. CONCLUSIONS: Metabolic risk factors were highly prevalent among patients with NAFLD. Obesity, hypertension, and dyslipidemia were more prevalent among women. The differences in the prevalence of hypertension seemed to be influenced by older age of women. PMID- 22534720 TI - A review of subclavian steal syndrome with clinical correlation. AB - Subclavian 'steal' phenomenon is a function of the proximal subclavian artery (SA) steno-occlusive disease, with subsequent retrograde blood flow in the ipsilateral vertebral artery (VA). The symptoms from the compromised vertebrobasilar and brachial blood flows constitute the subclavian steal syndrome (SSS), and include paroxysmal vertigo, drop attacks and/or arm claudication. Once thought to be rare, the emergence of new imaging techniques has drastically improved its diagnosis and prevalence. The syndrome, however, remains characteristically asymptomatic and solely poses no serious danger to the brain. Recent studies have shown a linear correlation between increasing arm blood pressure difference with the occurrence of symptoms. Atherosclerosis of the SA remains the most common cause. Doppler ultrasound is a useful screening tool, but the diagnosis must be confirmed by CT or MR angiography. Conservative treatment is the initial best therapy for this syndrome, with surgery reserved for refractory symptomatic cases. Percutaneous angioplasty and stenting, rather than bypass grafts of the subclavian artery, is the widely favored surgical approach. Nevertheless, large, prospective, randomized, controlled trials are needed to compare the long-term patency rates between the endovascular and open surgical techniques. PMID- 22534722 TI - Covalent decoration of graphene oxide with dendrimer-encapsulated nanoparticles for universal attachment of multiple nanoparticles on chemically converted graphene. AB - We report a method for universal assembly of multiple nanoparticles with different sizes and compositions on a single chemically converted graphene sheet with good control over particle sizes in the range of 1 to 2 nm through the covalent immobilization of dendrimer-encapsulated nanoparticles. PMID- 22534724 TI - Acupuncture and small needle scalpel therapy in the treatment of calcifying tendonitis of the gluteus medius: a case report. AB - The case is presented of a 68-year-old man with calcifying tendonitis involving the lateral part of the gluteus medius. The presenting symptoms were chronic pain in the posterolateral region of the right hip and limitation of movement of the right hip. The patient was treated with acupuncture and small needle scalpel therapy. Three months after the procedure the patient was completely pain-free and had full range of motion. Radiographic evaluation revealed complete disappearance of the calcific deposits with no recurrence after 6 months. The use of combined acupuncture and small needle scalpel therapy to treat calcifying tendonitis of the gluteus medius may lead to a good clinical outcome without surgery. PMID- 22534721 TI - Ophthalmic transplantology: anterior segment of the eye - part I. AB - BACKGROUND: Transplantology is a quickly developing field of ophthalmology. It currently is able to treat many inherited, degenerative, inflammatory, traumatic, and cancerous diseases. This review outlines recent concepts and methods of treating ocular diseases with tissue and cell grafts. Ocular transplants related to the anterior part of the eye, including the conjunctiva and the cornea, are reviewed in Part 1. MATERIAL/METHODS: The scientific literature dated from January 2005 to July 2011 was thoroughly searched using Medline and PubMed. Publications dated 2009, 2010, and 2011 were analyzed in detail. Search terms were as follows: auto-, homo-, heterologous transplantation, eyeball, ocular adnexa, anterior segment of the eye, cornea, lamellar keratoplasty, stem cells, cultured cells. Further data were found at the website of the Eye Bank Association of America. RESULTS: Nearly all tissues of the anterior segment of the eye (the conjunctiva, sclera, eye muscles, and cornea) are transplanted. Because of the recent significant progress in the field, cornea transplantation was analyzed in more detail, specifically procedures such as limbus grafts and anterior and posterior lamellar keratoplasty. Indications, advantages, and drawbacks of the transplant techniques were also reviewed. CONCLUSIONS: Recent progress in the field of cornea transplants allows treatment at the level of the endothelium and the use of cultured limbal epithelial stem cell grafts. However, compared with previous techniques, modern and multilayered transplant techniques of the cornea require much more expertise and longer training of the surgeon, as well as expensive and technologically advanced equipment. The availability of donor tissue is still the main limitation affecting all transplants. Therefore, cell culturing techniques such as stem cells, as well as artificial cornea projects, seem to be very promising. PMID- 22534723 TI - NUT midline carcinomas of the sinonasal tract. AB - NUT midline carcinoma (NMC) is a highly lethal tumor defined by translocations involving the NUT gene on chromosome 15q14. NMC involves midline structures including the sinonasal tract, but its overall incidence at this midline site and its full morphologic profile are largely unknown because sinonasal tumors are not routinely tested for the NUT gene translocation. The recent availability of an immunohistochemical probe for the NUT protein now permits a more complete characterization of sinonasal NMCs. The archival files of The Johns Hopkins Hospital Surgical Pathology were searched for all cases of primary sinonasal carcinomas diagnosed from 1995 to 2011. Tissue microarrays were constructed, and NUT immunohistochemical analysis was performed. All NUT-positive cases underwent a more detailed microscopic and immunohistochemical analysis. Among 151 primary sinonasal carcinomas, only 3 (2%) were NUT positive. NUT positivity was detected in 2 of 13 (15%) carcinomas diagnosed as sinonasal undifferentiated carcinoma and in 1 of 87 (1%) carcinomas diagnosed as squamous cell carcinoma. All occurred in men (26, 33, and 48 y of age). The NMCs grew as nests and sheets of cells with a high mitotic rate and extensive necrosis. Two were entirely undifferentiated, and 1 tumor showed abrupt areas of squamous differentiation. Each case had areas of cell spindling, and 2 were heavily infiltrated by neutrophils. Immunohistochemical staining was observed for cytokeratins (3 of 3), epithelial membrane antigen (3 of 3), p63 (2 of 3), CD34 (1 of 3), and synaptophysin (1 of 3). All patients died of the disease (survival time range, 8 to 16 mo; mean, 12 mo) despite combined surgery and chemoradiation. NMC represents a rare form of primary sinonasal carcinoma, but its incidence is significantly increased in those carcinomas that exhibit an undifferentiated component. Indiscriminant analysis for evidence of the NUT translocation is unwarranted. Instead, NUT analysis can be restricted to those carcinomas that demonstrate undifferentiated areas. The availability of an immunohistochemical probe has greatly facilitated this analysis and is helping to define the full demographic, morphologic, and immunohistochemical spectrum of sinonasal NMC. PMID- 22534725 TI - Spinal nerve root electroacupuncture for symptomatic treatment of lumbar spinal canal stenosis unresponsive to standard acupuncture: a prospective case series. AB - OBJECTIVE: To study the effectiveness of electroacupuncture of the spinal nerve root using a selective spinal nerve block technique for the treatment of lumbar and lower limb symptoms in patients with lumbar spinal canal stenosis. METHODS: Subjects were 17 patients with spinal canal stenosis who did not respond to 2 months of general conservative treatment and conventional acupuncture. Under x ray fluoroscopy, two acupuncture needles were inserted as close as possible to the relevant nerve root, as determined by subjective symptoms and x-ray and MRI findings, and low-frequency electroacupuncture stimulation was performed (10 Hz, 10 min). Patients received 3-5 once-weekly treatments, and were evaluated immediately before and after each treatment and 3 months after completion of treatment. RESULTS: After the first nerve root electroacupuncture stimulation, scores for lumbar and lower limb symptoms improved significantly (low back pain, p<0.05; lower limb pain, p<0.05; lower limb dysaesthesia, p<0.01) with some improvement in continuous walking distance. Symptom scores and continuous walking distance showed further improvement before the final treatment (p<0.01), and a significant sustained improvement was observed 3 months after completion of treatment (p<0.01). CONCLUSION: Lumbar and lower limb symptoms, for which conventional acupuncture and general conservative treatment had been ineffective, improved significantly during a course of electroacupuncture to the spinal nerve root, showing sustained improvement even 3 months after completion of treatment. The mechanisms of these effects may involve activation of the pain inhibition system and improvement of nerve blood flow. PMID- 22534726 TI - Cosmetic acupuncture to enhance facial skin appearance: a preliminary study. PMID- 22534727 TI - Two global haemostatic assays as additional tools to monitor treatment in cases of haemophilia A. AB - Haemophilia A patients with similar levels of factor VIII (FVIII) may have different bleeding phenotypes and responses to treatment with FVIII concentrate. Therefore, a test which determines overall haemostasis may be appropriate for treatment monitoring in some patients. We studied two global haemostatic methods:endogenous thrombin potential (ETP) and overall haemostatic potential(OHP) before and after injection of FVIII concentrate in patients with haemophilia A treated prophylactically and on-demand. A significant correlation between FVIII and both ETP and OHP was observed, while ETP and OHP differed between patients with severe and mild clinical phenotypes. Both ETP and OHP differed significantly between severe, moderate and mild haemophilia A and controls. ETP and OHP increased after intravenous injection of FVIII concentrate in both groups of patients, but in spite of higher pre-treatment values of both ETP and OHP in patients treated prophylactically, and much higher post-treatment FVIII levels in comparison with the values in patients treated on-demand, no difference after treatment was observed for either ETP or OHP. ETP and OHP may be additional alternatives for monitoring (and even for individual tailoring) treatment in patients with haemophilia A. PMID- 22534728 TI - Finite element analysis of the ovine hip: development, results and comparison with the human hip. AB - OBJECTIVES: The ovine hip is often used as an experimental research model to simulate the human hip. However, little is known about the contact pressures on the femoral and acetabular cartilage in the ovine hip, and if those are representative for the human hip. METHODS: A model of the ovine hip, including the pelvis, femur, acetabular cartilage, femoral cartilage and ligamentum transversum, was built using computed tomography and micro-computed tomography. Using the finite element method, the peak forces were analysed during simulated walking. RESULTS: The evaluation revealed that the contact pressure distribution on the femoral cartilage is horseshoe-shaped and reaches a maximum value of approximately 6 MPa. The maximum contact pressure is located on the dorsal acetabular side and is predominantly aligned in the cranial-to-caudal direction. The surface stresses acting on the pelvic bone reach an average value of approximately 2 MPa. CONCLUSIONS: The contact pressure distribution, magnitude, and the mean surface stress in the ovine hip are similar to those described in the current literature for the human hip. This suggests that in terms of load distribution, the ovine hip is well suited for the preclinical testing of medical devices designed for the human hip. PMID- 22534730 TI - How to assess liver function? AB - PURPOSE OF REVIEW: The liver comprises a multitude of parenchymal and nonparenchymal cells with diverse metabolic, hemodynamic and immune functions. Available monitoring options consist of 'static' laboratory parameters, quantitative tests of liver function based on clearance, elimination or metabolite formation and scores, most notably the 'model for end-stage liver disease'. This review aims at balancing conventional markers against 'dynamic' tests in the critically ill. RECENT FINDINGS: There is emerging evidence that conventional laboratory markers, most notably bilirubin, and the composite model for end-stage liver disease are superior to assess cirrhosis and their acute decompensation, while dynamic tests provide information in the absence of preexisting liver disease. Bilirubin and plasma disappearance rate of indocyanine green reflecting static and dynamic indicators of excretory dysfunction prognosticate unfavorable outcome, both, in the absence and presence of chronic liver disease better than other functions or indicators of injury. Although dye excretion is superior to conventional static parameters in the critically ill, it still underestimates impaired canalicular transport, an increasingly recognized facet of excretory dysfunction. SUMMARY: Progress has been made in the last year to weigh static and dynamic tests to monitor parenchymal liver functions, whereas biomarkers to assess nonparenchymal functions remain largely obscure. PMID- 22534729 TI - In vivo fluorescence imaging of atherosclerotic plaques with activatable cell penetrating peptides targeting thrombin activity. AB - Thrombin and other coagulation enzymes have been shown to be important during atherosclerotic disease development. Study of these proteases is currently limited because of lack of robust molecular imaging agents for imaging protease activity in vivo. Activatable cell penetrating peptides (ACPPs) have been used to monitor MMP activity in tumors and, in principle, can be modified to detect other proteases. We have developed a probe that incorporates the peptide sequence DPRSFL from the proteinase activated receptor 1 (PAR-1) into an ACPP and shown that it is preferentially cleaved by purified thrombin. Active thrombin in serum cleaves DPRSFL-ACPP with >90% inhibition by lepirudin or argatroban. The DPRSFL ACPP cleavage product accumulated in advanced atherosclerotic lesions in living mice, with 85% reduction in retention upon pre-injection of mice with hirudin. Uptake of the ACPP cleavage product was highest in plaques with histological features associated with more severe disease. Freshly resected human atheromas bathed in DPRSFL-ACPP retained 63% greater cleavage product compared to control ACPP. In conclusion, DPRSFL-ACPP can be used to study thrombin activity in coagulation and atherosclerosis with good spatial and temporal resolution. Thrombin-sensitive ACPPs may be developed into probes for early detection and intraoperative imaging of high risk atherosclerotic plaques. PMID- 22534731 TI - Triphenylamine-functionalized magnetic microparticles as a new adsorbent coupled with high performance liquid chromatography for the analysis of trace polycyclic aromatic hydrocarbons in aqueous samples. AB - Triphenylamine (TPA)-functionalized magnetic microspheres (Fe(3)O(4)/SiO(2)/TPA) were prepared and applied as solid phase extraction (SPE) adsorbents for the analysis of polycyclic aromatic hydrocarbons (PAHs) in environmental samples in combination with high-performance liquid chromatography (HPLC). The magnetic solid-phase extraction (MSPE) conditions affecting the extraction efficiency were optimized, including elution solvent, standing time, amount of sorbent, and salt concentration. Due to the strong pi-pi conjugate effect between the benzene rings of TPA and PAHs, high extraction efficiency was achieved with spiked recoveries of 80.21-108.33% and relative standard deviations (RSD) of less than 10%. Good linearities (R(2) > 0.997) for all calibration curves were obtained with low limits of detection (LOD) of 0.25, 0.5, 0.5, 3.75, 0.2 and 0.04 ng L(-1) for anthracene, fluoranthene, pyrene, chrysene, benzo[b]fluoranthene and benzo[k]fluoranthene, respectively. The achieved results indicate the applicability of Fe(3)O(4)/SiO(2)/TPA as MSPE adsorbents. PMID- 22534732 TI - Photochemical reactions in biological systems: probing the effect of the environment by means of hybrid quantum chemistry/molecular mechanics simulations. AB - Organisms have evolved a wide variety of mechanisms to utilize and respond to light. In many cases, the biological response is mediated by structural changes that follow photon absorption in a protein complex. The initial step in such cases is normally the photoisomerization of a highly conjugated prosthetic group. To understand better the factors controlling the isomerization, we perform atomistic molecular dynamics simulations. In this perspective article we briefly review the key theoretical concepts of photochemical reactions and present a practical simulation scheme for simulating photochemical reactions in biomolecular systems. In our scheme, a multi-configurational quantum mechanical description is used to model the electronic rearrangement for those parts of the system that are involved in the photon absorption. For the remainder, typically consisting of the apo-protein and the solvent, a simple force field model is used. The interactions in the systems are thus computed within a hybrid quantum/classical framework. Forces are calculated on-the-fly, and a diabatic surface hopping procedure is used to model the excited-state decay. To demonstrate how this method is used we review our studies on photoactivation of the photoactive yellow protein, a bacterial photoreceptor. We will show what information can be obtained from the simulations, and, by comparing to recent experimental findings, what the limitations of our simulations are. PMID- 22534733 TI - Efficacy of functional hemodynamic parameters in predicting fluid responsiveness with pulse power analysis in surgical patients. AB - BACKGROUND: In this study we quantify the ability of dynamic cardiovascular parameters measured by the PulseCOTM algorithm of the LiDCOTMplus monitor to predict the response to a fluid challenge in post-operative patients. METHODS: Surgical patients, admitted to the Intensive Care Unit from the operating theatre were monitored with the LiDCOTMplus system. A number of static and dynamic cardiovascular measurements were recorded before and after a fluid challenge. Receiver Operator Characteristic (ROC) curve analysis was used to identify the baseline values, with optimum sensitivity and specificity, to predict responsiveness to a fluid challenge. RESULTS: Thirty-one patients were enrolled, and received protocol-based fluid challenges. Twelve (38%) responded by demonstrating an increase in stroke volume of >15%. Heart rate (HR) and central venous pressure (CVP) were not statistically different between responders and non responders. Mean arterial pressure (mAP), systolic pressure variation (SPV), pulse pressure variation (PPV) and stroke volume variation (SVV) were statistically different between responders and non-responders. Parameters with a ROC area under the curve (AUC) significantly >0.5 included SPV 0.70 (0.52-0.88) P=0.046, PPV 0.87 (0.76-0.99) P<0.0002 and SVV 0.84 (0.71-0.96) P=0.0005. The best cut-off values (sensitivity and specificity) to predict fluid were SPV >9 mmHg (73%, 76%), PPV >13% (83%, 74%) and SVV >12.5% (75%, 83%). ROC analysis did not show the AUC to be significantly >0.5 for HR, mAP and CVP CONCLUSION: Dynamic indices measured by PulseCOTM (LiDCO) have a high sensitivity and specificity in predicting fluid responsiveness in sedated and mechanically ventilated patients. A cut-off value for PPV of 13% is the most sensitive and specific indicator of fluid responsiveness. PMID- 22534734 TI - Dialysis disequilibrium syndrome in a neurosurgical patient: the role of continuous veno-venous hemofiltration. PMID- 22534735 TI - Self-assembling DNA-peptide hybrids: morphological consequences of oligonucleotide grafting to a pathogenic amyloid fibrils forming dipeptide. AB - For the very first time, highly efficient synthesis of DNA-peptide hybrids to scaffold self-assembled nanostructures is described. Oligonucleotide conjugation to the diphenylalanine dipeptide triggers a morphological transition from fibrillar to vesicular structures which may potentially be used as delivery vehicles, since they exhibit pH triggered release. PMID- 22534736 TI - [A new evidence and consensus-based German guidelines for diagnosis and treatment of bipolar disorders]. PMID- 22534737 TI - [Pro and contra: a new rubric for Der Nervenarzt]. PMID- 22534738 TI - Robot-assisted transvaginal peritoneoscopy using confocal endomicroscopy: a feasibility study in a porcine model. AB - BACKGROUND: Optical biopsy methods such as probe-based confocal laser endomicroscopy (pCLE) provide useful intraoperative real-time information, especially during minimally invasive surgery with flexible endoscopic or robotic platforms. By translating the probe at constant pressure across the target tissue, undistorted "mosaics" can be produced. However, this poses ergonomic challenges with a conventional flexible endoscope. METHODS: A 100 MUm confocal depth pCLE probe was integrated into a previously described seven degrees-of freedom articulated endoscopic robot. After estimating the average workspace created by a female pneumoperitoneum, the accessibility of the peritoneal cavity by the device for robot-assisted pCLE peritoneoscopy was calculated. To demonstrate its in vivo feasibility, the robot was inserted transvaginally in a pig, under laparoscopic vision. Optical biopsy was performed of several targets within the peritoneal cavity. RESULTS: The workspace analysis calculated that 88 % of the surface of an estimated average female pneumoperitoneum could be contacted by the probe using the robot transvaginally. In vivo, the robot was manoeuvred to provide views of all abdominal and pelvic organs. At each target there was robotic acquisition of still pCLE images, and slowly translating images for the construction of increased field-of-view mosaics up to 2 mm in length. Optical biopsies took 1-2 min per target, and at 3.5 MUm lateral resolution, the mosaic images showed characteristic features of anterior abdominal wall, liver, and spleen. CONCLUSION: In the porcine model, the robotically actuated method of performing peritoneoscopy and pCLE mosaicked optical biopsy is safe and provides a consistent means of acquiring near-histological grade images of submesothelial tissue. Clinical translation is likely to provide sufficient accessibility of the peritoneal cavity. PMID- 22534739 TI - Prognostic significance of total disease length in esophageal cancer. AB - BACKGROUND: This study tested the hypothesis that endoluminal ultrasound (EUS) defined total length of disease (including both the primary tumor and the position and number of proximal and distal lymph nodes-ELoD) and the associated EUS lymph node metastasis count (ELNMC) are better predictors of outcome than endoscopic esophageal cancer (OC) length and radiological tumor node metastasis stage in patients who undergo potentially curative treatment with surgery or definitive chemoradiotherapy (dCRT). METHODS: A total of 645 consecutive patients diagnosed with OC and managed by a multidisciplinary team were staged by CT and EUS. The primary outcome measure was survival from date of diagnosis. RESULTS: A total of 323 patients received surgery (208 neoadjuvant chemotherapy), and 322 who were deemed unsuitable for surgery received dCRT. Univariable analysis revealed that survival was related to EUS T (p < 0.0001), N (p < 0.0001), EUS primary tumor length (p = 0.037), ELoD (p = 0.011), ELNMC (p < 0.0001), and treatment type (p = 0.001). Multivariable analysis revealed two factors: ELoD (hazard ratio (HR), 0.961; 95 % confidence interval (CI), 0.925-0.998; p = 0.041) and ELNMC (HR, 1.08; 95 % CI, 1.015-1.15; p = 0.016) were independently associated with survival. CONCLUSIONS: ELoD and ELNMC should become part of routine OC radiological staging to optimize stage-directed therapeutic outcomes. PMID- 22534740 TI - Is irrigation necessary during endoscopic necrosectomy of pancreatic necroses? PMID- 22534741 TI - Ablation efficiency and relative thermal confinement measurements using wavelengths 1,064, 1,320, and 1,444 nm for laser-assisted lipolysis. AB - Laser-assisted lipolysis is routinely used for contouring the body and the neck while modifications of the technique have recently been advocated for facial contouring. In this study, wavelength-dependence measurements of laser lipolysis effect were performed using different lasers at 1,064, 1,320, and 1,444 nm wavelengths that are currently used clinically. Fresh porcine skin with fatty tissue was used for the experiments with radiant exposure of 5-8 W with the same parameters (beam diameter = 600 MUm, peak power = 200 mJ, and pulse rate = 40 Hz) for 1,064, 1,320 and 1,444 nm laser wavelengths. After laser irradiation, ablation crater depth and width and tissue mass loss were measured using spectral optical coherence tomography and a micro-analytical balance, respectively. In addition, thermal temporal monitoring was performed with a thermal imaging camera placed over ex vivo porcine fat tissue; temperature changes were recorded for each wavelength. This study demonstrated greatest ablation crater depth and width and mass removal in fatty tissue at the 1,444 nm wavelength followed by, in order, 1,320 and 1,064 nm. In the evaluation of heat distribution at different wavelengths, reduced heat diffusion was observed at 1,444 nm. The ablation efficiency was found to be dependent upon wavelength, and the 1,444 nm wavelength was found to provide both the highest efficiency for fatty tissue ablation and the greatest thermal confinement. PMID- 22534742 TI - Patterns of urban mercury contamination detected by bioindication with terrestrial isopods. AB - Mercury (Hg) is a trace element with high toxicological impact on potential receptors, including human beings. Global Hg emissions are predicted to increase significantly during the next 40 years. After emission, the metal is transported by air currents and precipitations, leading to increasing depositions even in areas far from emission sources. In the terrestrial environment, Hg is subjected to redistribution and transformation into different inorganic and metal-organic species that are taken up by vegetation and soil organisms. In the present study, the woodlouse (Porcellio scaber) was used as a biological indicator of total Hg pollution in the city of Dornbirn (province of Vorarlberg), Austria. Woodlice were collected from 30 sampling points scattered over the city area, 25 of them situated within a rectangular transect crossing the city area from west-northwest to east-southeast, starting near the Rheintal motorway and ending at the slopes of the Bregenzer Wald hills. In addition to woodlice, soil substrate samples were collected at nine of the selected sampling points. Total Hg concentrations were measured in isopod tissues and soil substrate samples by means of an Hg analyzer. Total Hg concentrations in isopod tissues were significantly correlated with Hg soil contents (P < 0.05). Moreover, a gradient of increasing Hg concentrations was observed in isopod samples along the transect across Dornbirn, with the lowest concentrations detected in woodlouse samples near the Rheintal motorway and the highest levels toward the ascending slopes of the Bregenzer Wald hills. This gradient of increasing Hg concentrations across the city matches a concomitant increase in wet precipitations along the same direction, indicating that deposition by wet precipitation may be an important source for Hg contamination in the city of Dornbirn. Overall, the degree of Hg contamination across the study area can be regarded as rather low, i.e., comparable with concentrations observed in other, unpolluted terrestrial habitats. It is concluded that bioindication by total Hg analysis in woodlice can be applied to distinguish between different levels and sources of contamination in urban areas. PMID- 22534743 TI - Lead-induced cardiac and hematological alterations in aging Wistar male rats: alleviating effects of nutrient metal mixture. AB - Age related mitochondrial impairments are considered to be contributors of cardiovascular disease. This study was designed to examine whether early life exposure to lead (Pb) would lead to the Pb induced age related hematological and cardiac mitochondrial changes in rats, and to further examine the protective effect of nutrient metal mixture containing zinc, iron and calcium. Male albino rats were lactationally exposed to 0.2 % Pb-acetate or 0.2 % Pb-acetate together nutrient metal mixture (0.02 %) in drinking water of the mother from postnatal day 1 (PND1) to PND 21. The hemoglobin level, the activities of serum ceruloplasmin oxidase, cardiac mitochondrial enzymes catalase, manganese superoxide dismutase, copper zinc superoxide dismutase, glutathione peroxidase, succinate dehydrogenase, lipid peroxidation and Pb levels were analyzed at PND 45, 12 and 24 months age. The hematological parameters, and the cardiac TCA cycle and antioxidant enzyme markers and lipid peroxidation levels were significantly altered following Pb exposure in young rats (PND 45). These Pb induced changes persisted, though at much lower level in the aged rats. The Pb levels in blood and heart were also significantly higher in PND 45 and remained at detectable levels in older rats. The nutrient metal mixture containing iron, calcium and zinc significantly reversed these changes in all the chosen markers except lipid peroxidation in which the reversal effect was not significant. These data are supportive of age-related cardiac mitochondrial impairments and further provide evidence for the protective efficacy of nutrient metal mixture against Pb toxicity. PMID- 22534745 TI - [Result-related success rates of cataract operations. Results of a systematic literature review]. AB - This systematic literature review, including 7 publications released since 2000, provides references for outcome indicators of cataract surgery for quality management initiatives. The reported relative numbers of cases achieving visual rehabilitation and refractive accuracy were determined and compared. With one exception the success rates did not represent benchmarks defined as best possible outcome but describe the results of data collected in a population during routine clinical practice. A best corrected visual acuity (BCVA) of >= 0.5 was achieved in 84-93% of all patients and in 95-99% of patients without preoperative visually impairing comorbidities. A refractive accuracy (absolute deviation of target refraction from spherical equivalent) of <= 1 D was reported in 72-97% of the patients. The success rates of these well established outcome indicator levels were high. Differences between operators were more distinguishable and the clinical relevance higher with less liberal indicator levels. A BCVA >= 1 was realized in 30-47% of all patients and in 52-62% of patients without visually impairing comorbidities. A total of 45-80% of the patients showed a refractive accuracy of <= 0.5 D. Exogenous factors not influencable by the surgeon have a relevant impact on the success rates. The literature review confirms the strong association of visually impairing comorbidities and BCVA outcome. Based on literature methodological problems of quality management systems for cataract surgery are discussed. While voluntary initiatives have the ability to solve these difficulties appropriate concepts for mandatory procedures are currently lacking. PMID- 22534744 TI - Differences in transcriptional patterns of extracellular matrix, inflammatory, and myogenic regulatory genes in myofibroblasts, fibroblasts, and muscle precursor cells isolated from old male rat skeletal muscle using a novel cell isolation procedure. AB - Aged skeletal muscle displays increased fibrosis and impaired regeneration. While it is not well characterized how skeletal muscle fibroblasts contribute to these phenomena, transforming growth factor-beta1 (TGF-beta1) and Delta/Notch signaling have been implicated to influence muscle regeneration. In this study, a unique combination of aging phenotypes is identified in differentiating fibroblasts (myofibroblasts), proliferating fibroblasts, and muscle precursor cells (MPCs) that characterize an impaired regenerative potential observed in aged skeletal muscle. Using a novel dual-isolation technique, that isolates fibroblasts and MPCs from the same rat skeletal muscle sample, and cell culture conditions of 5 % O(2) and 5 % CO(2), we report for the first time that myofibroblasts from 32-mo old skeletal muscle, compared to 3-mo-old, display increased levels of mRNA for the essential extracellular matrix (ECM) genes, collagen 4alpha1 (83 % increase), collagen 4alpha2 (98 % increase), and laminin 2 (113 % increase), as well as increased levels of mRNA for the inflammatory markers, interleukin-6 (4.3-fold increase) and tumor necrosis factor alpha (3.2-fold increase), and TGF-beta1 (84 % increase), whose protein controls proliferation and differentiation. Additionally, we demonstrate that proliferating fibroblasts from 32-mo-old skeletal muscle display increased levels of mRNA for the Notch ligand, Delta 1 (>=2.0-fold increase). Together, these findings suggest that increased expression of ECM and inflammatory genes in myofibroblasts from 32-mo-old skeletal muscle may contribute to the fibrogenic phenotype that impairs regeneration in aged skeletal muscle. Furthermore, we believe the novel dual-isolation technique developed here may be useful in studies that investigate communications among MPCs, fibroblasts, and myofibroblasts in skeletal muscle. PMID- 22534747 TI - Radicular anatomy of twelve representatives of the Catasetinae subtribe (Orchidaceae: Cymbidieae). AB - Considering that the root structure of the Brazilian genera belonging to the Catasetinae subtribe is poorly known, we describe the roots of twelve representatives from this subtribe. For anatomical analysis, the roots were fixed in FAA 50, preserved in ethanol 70% and sectioned at its medium region using razor blades. The sections were stained with 0.05% astra blue and safranin and mounted in glycerin. For the identification of starch we used Lugol's solution; for lignin, floroglucin chloridric; for lipids, Sudan III, and for flavanoids, potassium hydroxide. The relevant aspects were registered using a digital camera joined with an Olympus microspope (BX51 model). The structural similarities of all roots support the placement of the subtribe Catasetinae into the monophyletic tribe Cymbidieae. Some root features are restricted to one or two taxa and can be useful in the systematics of the subtribe. For example, the occurrence of flavonoidic crystals characterizes the genera Catasetum and Cychnodes, and the number of the velamen layers and the shape of the epivelamen cells are useful to confirm the taxonomic position of Clowesia amazonica. The presence of velamen and flavonoidic crystals was interpreted as an adaptation to the epiphytic habit. PMID- 22534746 TI - The HAS-BLED score predicts bleedings during bridging of chronic oral anticoagulation. Results from the national multicentre BNK Online bRiDging REgistRy (BORDER). AB - Patients who receive long-term oral anticoagulant (OAC) therapy often require interruption of OAC for an elective invasive procedure. Current guidelines allow bridging therapy with either unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). Apart from the risk of embolism, bleeding is an important complication in this setting and the optimal perioperative management of such patients is still under discussion. The aims of this prospective, observational, multicentre registry of patients treated by cardiologists were: 1) to evaluate current practice of perioperative management of OAC in a large outpatient cohort, 2) to document embolic and haemorrhagic events, and 3) to identify risk factors predicting adverse events. In the years 2009 and 2010, 1,000 invasive procedures (cardiac catheterisation n=533, pacemaker implantation n = 128, surgery n = 194, other n = 145) were performed in patients with OAC. Sixty- one (6.1%) of those patients did not receive bridging therapy during interruption of OAC, 937 (93.7%) patients were treated with LMWH, two patients (0.2%) received UFH. In 22 patients (2.2%) LMWHs were given in prophylactic dose, 727 patients (72.7%) were treated with halved therapeutic (i.e. weight-adapted) LMWH doses and 188 (18.8%) received full therapeutic LMWH doses. Four thromboembolic complications were observed during 30 days of follow-up (two retinal embolisms, one stroke, one myocardial infarction; 0.4%). One major bleeding (0.1%) and 35 clinically relevant bleedings (3.5%) occurred. Rehospitalisation after bleedings was necessary in 20 patients. Independent predictors for bleedings were history of mechanical heart valve replacement (MVR) (p=0.0002) and the HAS-BLED score (<0.0001), with a cut off value >= 3 being the most predictive variable for haemorrhage (hazard ratio 11.8, 95% confidence interval 5.6-24.9, p<0.0001). A total of 527 patients with atrial fibrillation and a CHADS2 score <= 2 received halved therapeutic or full therapeutic dosages of LMWH despite a low embolic risk, whereas 49 of the patients with heart valve replacement (51%) did not receive dosages of bridging therapy as recommended in guidelines. In conclusion, in this registry of patients treated by cardiologists, 94% of patients who required interruption of OAC before invasive procedures received LMWH as a bridging therapy, of whom 73% were treated with halved therapeutic LMWH-dosages. Guideline recommendations were followed in only 31% of cases. Importantly, 69% of patients with AF were over-treated while 51% of patients with heart valve replacement were under-treated with LMWHs. A HASB-BLED score >= 3 was highly predictive of bleeding events. PMID- 22534749 TI - Innovative molecular approach to the identification of Colossoma macropomum and its hybrids. AB - Tambaqui (Colossoma macropomum) is the fish species most commonly raised in the Brazilian fish farms. The species is highly adaptable to captive conditions, and is both fast-growing and relatively fecund. In recent years, artificial breeding has produced hybrids with Characiform species, known as "Tambacu" and "Tambatinga". Identifying hybrids is a difficult process, given their morphological similarities with the parent species. This study presents an innovative molecular approach to the identification of hybrids based primarily on Multiplex PCR of a nuclear gene (alpha-Tropomyosin), which was tested on 93 specimens obtained from fish farms in northern Brazil. The sequencing of a 505-bp fragment of the Control Region (CR) permitted the identification of the maternal lineage of the specimen, all of which corresponded to C. macropomum. Unexpectedly, only two CR haplotype were found in 93 samples, a very low genetic diversity for the pisciculture of Tambaqui. Multiplex PCR identified 42 hybrids, in contrast with 23 identified by the supplier on the basis of external morphology. This innovative tool has considerable potential for the development of the Brazilian aquaculture, given the possibility of the systematic identification of the genetic traits of both fry-producing stocks, and the fry and juveniles raised in farms. PMID- 22534751 TI - Plankton diversity and limnological characterization in two shallow tropical urban reservoirs of Pernambuco State, Brazil. AB - Plankton diversity, physical and chemical variables and chlorophyll a were analyzed in two shallow urban reservoirs with different trophic degrees on Pernambuco State, northeastern Brazil. High eutrophication levels were observed in Apipucos reservoir, while Prata reservoir was considered oligotrophic. Values reported for physical and chemical variables and chlorophyll a differed among the studied ecosystems. Richness and plankton diversity were higher in Apipucos reservoir especially for phytoplankton. The presence of potential toxic Cyanophyceae in both reservoirs reflects a problem mainly to Prata reservoir, which is used for public water supply. Differences were observed for some variables among sites of study in Apipucos reservoir, while the differences among strata were negligible in both reservoirs, reflecting the water column mixing by wind action. Rainfall regulated the temporal dynamics for the analyzed variables, with significant seasonal differences, mainly for the major of limnological variables in Apipucos reservoir. Plankton diversity was higher in Apipucos reservoir, especially to phytoplankton, showing that eutrophication and pollution can favor plankton diversity in tropical urban shallow reservoirs. PMID- 22534756 TI - Nanostructure-based WO3 photoanodes for photoelectrochemical water splitting. AB - Nanostructured WO(3) has been developed as a promising water-splitting material due to its ability of capturing parts of the visible light and high stability in aqueous solutions under acidic conditions. In this review, the fabrication, photocatalytic performance and operating principles of photoelectrochemical cells (PECs) for water splitting based on WO(3) photoanodes, with an emphasis on the last decade, are discussed. The morphology, dimension, crystallinity, grain boundaries, defect and separation, transport of photogenerated charges will also be mentioned as the impact factors on photocatalytic performance. PMID- 22534757 TI - Quantitative information in decay curves obtained with a pulsed ion mobility spectrometer. AB - Ion mobility spectrometry (IMS) is well known for its very high sensitivity, and thus IMS spectra are commonly used in the identification of trace gases. Extracting quantitative information from IMS spectra is, in contrast, difficult, especially regarding the reproducibility due to the nature of the processes involved in the measurement of the spectra. Here we present data extracted from signal decay curves obtained with a pulsed IMS, which can support the determination of substance concentrations in the lower ppb range with good stability. PMID- 22534758 TI - Genotyping from saliva with a one-step microdevice. AB - This paper presents a disposable microfluidic device for on-chip lysing, PCR, and analysis in one continuous-flow process. Male-female sex determination was performed with human saliva in less than 20 min from spit to finish, and requiring only seconds of manual sample handling. This genetic analysis was based on the amplification and detection of the DYZ1 repeat region unique to the Y chromosome. The flow-through microfluidic chip consisted of a single serpentine channel designed to guide samples through 42 heating and cooling cycles. Cycling was performed by matching the local channel geometry to a steady-state temperature gradient established across the microfluidic chip. 38 channel segments were designed for rapid low volume PCR, and four were optimized for spatial DNA melting analysis. Fluorescence detection was used to monitor the amplification and to capture the melting signature of the amplicon was performed with a basic 8-bit CCD camera. The microfluidic device itself was fabricated from microscope slides and a double-sided tape. The simplicity of the system and its robust performance combine in an elegant solution for lab-on-a-chip genetic analysis. PMID- 22534759 TI - The precarious state of the liver after a Fontan operation: summary of a multidisciplinary symposium. AB - As the cohort of survivors with the single-ventricle type of congenital heart disease grows, it becomes increasingly evident that the state of chronically elevated venous pressure and decreased cardiac output inherent in the Fontan circulation provides the substrate for a progressive decline in functional status. One organ at great risk is the liver. Wedged between two capillary beds, with the pulmonary venous bed downstream, which typically has no pulsatile energy added in the absence of a functional right ventricle, and the splanchnic bed upstream, which may have compromised inflow due to inherent cardiac output restriction characteristic of the Fontan circulation, the liver exists in a precarious state. This review summarizes a consensus view achieved at a multidisciplinary symposium held at The Children's Hospital of Philadelphia in June 2011. The discussion includes current knowledge concerning the hemodynamic foundations of liver problems, the diagnostic tools available, the unique histopathology of the liver after the Fontan operation, and proposed mechanisms for hepatic fibrosis at the cellular level. At the completion of the symposium, a consensus recommendation was made by the authors' group to pursue a new prospective protocol for clinical evaluation of the liver for all patients in our practice 10 years after the Fontan operation. PMID- 22534760 TI - Short sleep duration among workers--United States, 2010. AB - Insufficient sleep can have serious and sometimes fatal consequences for fatigued workers and others around them. For example, an estimated 20% of vehicle crashes are linked to drowsy driving. The National Sleep Foundation recommends that healthy adults sleep 7-9 hours per day. To assess the prevalence of short sleep duration among workers, CDC analyzed data from the 2010 National Health Interview Survey (NHIS). The analysis compared sleep duration by age group, race/ethnicity, sex, marital status, education, and employment characteristics. Overall, 30.0% of civilian employed U.S. adults (approximately 40.6 million workers) reported an average sleep duration of <=6 hours per day. The prevalence of short sleep duration (<=6 hours per day) varied by industry of employment (range: 24.1% 41.6%), with a significantly higher rate of short sleep duration among workers in manufacturing (34.1%) compared with all workers combined. Among all workers, those who usually worked the night shift had a much higher prevalence of short sleep duration (44.0%, representing approximately 2.2 million night shift workers) than those who worked the day shift (28.8%, representing approximately 28.3 million day shift workers). An especially high prevalence of short sleep duration was reported by night shift workers in the transportation and warehousing (69.7%) and health-care and social assistance (52.3%) industries. Targeted interventions, such as evidence-based shift system designs that improve sleep opportunities and evidence-based training programs on sleep and working hours tailored for managers and employees, should be implemented to protect the health and safety of workers, their coworkers, and the public. PMID- 22534761 TI - Occupational phosphine gas poisoning at veterinary hospitals from dogs that ingested zinc phosphide--Michigan, Iowa, and Washington, 2006-2011. AB - Zinc phosphide (Zn3P2) is a readily available rodenticide that, on contact with stomach acid and water, produces phosphine (PH3), a highly toxic gas. Household pets that ingest Zn3P2 often will regurgitate, releasing PH3 into the air. Veterinary hospital staff members treating such animals can be poisoned from PH3 exposure. During 2006-2011, CDC's National Institute for Occupational Safety and Health (NIOSH) received reports of PH3 poisonings at four different veterinary hospitals: two in Michigan, one in Iowa, and one in Washington. Each of the four veterinary hospitals had treated a dog that ingested Zn3P2. Among hospital workers, eight poisoning victims were identified, all of whom experienced transient symptoms related to PH3 inhalation. All four dogs recovered fully. Exposure of veterinary staff members to PH3 can be minimized by following phosphine product precautions developed by the American Veterinary Medical Association (AVMA). Exposure of pets, pet owners, and veterinary staff members to PH3 can be minimized by proper storage, handling, and use of Zn3P2 and by using alternative methods for gopher and mole control, such as snap traps. PMID- 22534762 TI - Severe coinfection with seasonal influenza A (H3N2) virus and Staphylococcus aureus--Maryland, February-March 2012. AB - On March 5, 2012, the Maryland Department of Health and Mental Hygiene (DHMH) and the Calvert County Health Department were notified of three deaths following respiratory illness among members of a Maryland family. One family member (patient A) experienced upper-respiratory symptoms and died unexpectedly at home. Two others (patients B and C) sought medical care for fever, shortness of breath, and cough productive of bloody sputum and died during their hospitalizations. All three family members had confirmed infection with seasonal influenza A (H3N2) virus. Patients B and C had confirmed coinfection with methicillin-resistant Staphylococcus aureus (MRSA), which manifested in both patients as MRSA pneumonia and bacteremia. DHMH and the Calvert County Health Department, in collaboration with the District of Columbia Department of Health, local hospitals, and CDC, conducted an investigation to determine the cause of the illnesses and identify additional related cases. Three additional family members with influenza were identified, two of whom were confirmed to have influenza A (H3N2) and required hospitalization, but neither was coinfected with MRSA, and both recovered. Influenza vaccination remains the best method for preventing complications from influenza; when influenza infection is suspected, treatment with influenza antiviral agents is recommended in certain cases. In addition, when high clinical suspicion for serious S. aureus coinfection exists, empiric coverage with antibiotics, including those with activity against methicillin-resistant strains, should be instituted. PMID- 22534763 TI - [Laparoscopic vs. robotic operations in urology]. PMID- 22534764 TI - [Retroperitoneal lymphadenectomy - pro robotic]. AB - The indications to perform primary retroperitoneal lymph node dissection (RPLND) in patients with clinical stage I non-seminomatous germ cell tumors have changed. An initial surgical staging can be justified only for exceptional situations, such as a pure teratoma. Other indications can be the surgical staging and treatment of high risk patients in elective surgery. In this situation, however, only sparse data are available regarding the oncological and therapeutic effect of a minimally invasive approach compared to open surgery. Data are available on the feasibility of laparoscopically performed post-chemotherapy RPLND; however, patients for this approach must be highly selected. In general, robotic-assisted RPLND potentially offers major advantages in terms of safety and oncological efficiency compared to a classical laparoscopic approach. Especially in post chemotherapy RPLND, the division of lumbar vessels and the control of great vessel lesions may be facilitated. However, only surgeons who are capable of handling a major vessel lesion endoscopically should consider using a robotic assisted technique. Only patients with relatively small residual tumors without a major involvement of great vessels can be considered as candidates for robotic assisted post-chemotherapy RPLND. PMID- 22534765 TI - Synthesis and properties of caprolactone and ethylene glycol copolymers for neural regeneration. AB - Copolymer networks from poly(ethylene glycol) methacrylate (PEGMA) and caprolactone 2-(methacryloyloxy) ethyl ester were synthesized and the resulting structure of the copolymer network was characterized by differential scanning calorimetry, thermogravimetry, Fourier transform infrared spectroscopy, equilibrium water gain and dynamic mechanical analysis, results which were employed to conclude about the network structure of the resulting copolymers. The new material is a random copolymer with a good miscibility and increasing hydrophilicity as the PEGMA content increases in the composition. Physical data suggest an excess free volume and synergistic interactions between the lateral chains of both comonomers. Olfactory ensheathing cells were cultured on the different networks, and cell viability and proliferation were assessed by MTS assay. The copolymers with a 30 wt% of PEGMA showed the best results compared with the other compositions in this respect, indicating the relevance for biological performance of a balance of hydrophilic and hydrophobic functionalities in the polymer chain. PMID- 22534766 TI - A rare cause of hypertension in a healthy 2-year-old female: questions. PMID- 22534768 TI - Identification of novel members reveals the structural and functional divergence of lepidopteran-specific Lipoprotein_11 family. AB - 30K proteins (30KPs) are classified into the lepidopteran-specific Lipoprotein_11 family. They are involved in various physiological processes such as energy storage, embryonic development, and immune response in the silkworm. To date, 30KPs were only found in Bombyx mori and Manduca sexta. Moreover, the C-termini of ENF peptide binding proteins (ENF-BPs) show similarity to 30KPs. ENF peptides are multifunctional insect cytokines and involved in growth regulation and defense reaction, whereas ENF-BPs act as active regulators of ENF peptides. In order to get insights into this gene family in Lepidoptera, we performed an extensive survey of lepidopteran-derived genome and EST datasets. We identified 73 30KP homologous genes in 12 lepidopteran species, of which 56 are novel members. The structural and phylogenetic analyses revealed that these genes could be classified into three groups: ENF-BP genes, typical 30KP genes, and serine/threonine-rich 30KP (S/T-rich 30KP) genes. The C-terminal regions are common to all the three subfamilies, but the N-termini are highly variable. We found a novel subfamily of Lipoprotein_11 and named it S/T-rich 30KP according to its exclusive S/T-rich domain in the N terminus. ENF-BP was also found to contain a special domain in the N terminus, which is homologous to Pp-0912 of Pseudomonas putida. Microarray data and semi-quantitative RT-PCR showed that the three groups have their respective temporal-spatial expression patterns. S/T-rich 30KP genes have enriched expression in the mature testis and might be involved in spermiogenesis or fertilization. Typical 30KP genes are expressed mainly in the fat body and integument at the larvae and pupae stages. ENF-BP genes are expressed predominantly in the hemocyte. The differential spatial-temporal expression profiles revealed the functional divergence of three Lipoprotein_11 subfamilies. PMID- 22534769 TI - Climatic influence on the reproductive characteristics of Japanese males. AB - We previously performed a survey of the sperm characteristics of the partners of pregnant women in four cities in Japan. In the present study, we analyzed the sperm characteristics of these subjects and the correlations between these sperm characteristics and climatic changes or Y chromosome haplogroups. Our results showed that more haplogroup D2a1 males than O2b1 males were born in the first half of the year (January to June), whereas more O2b1 males were born in the last half of the year (July to December) (P<0.05). This was agreed and correlated with the seasonal variations in their mean sperm concentrations. The haplogroup C, D* and D2a1 males displayed lower sperm concentrations from March to May, followed by an increase in their sperm concentrations starting in June or July, while the O2b1 males displayed higher sperm concentrations in the first half of the year followed by a sudden decrease from July to August (P<0.05). We hypothesize that the Japanese climate has different effects on the sperm characteristics and reproductive seasonality of males from different lineages; and therefore, has influenced the modern population of Japan. PMID- 22534770 TI - Differences in allele frequencies of autosomal dominant hypercholesterolemia SNPs in the Malaysian population. AB - Hypercholesterolemia is caused by different interactions of lifestyle and genetic determinants. At the genetic level, it can be attributed to the interactions of multiple polymorphisms, or as in the example of familial hypercholesterolemia (FH), it can be the result of a single mutation. A large number of genetic markers, mostly single nucleotide polymorphisms (SNP) or mutations in three genes, implicated in autosomal dominant hypercholesterolemia (ADH), viz APOB (apolipoprotein B), LDLR (low density lipoprotein receptor) and PCSK9 (proprotein convertase subtilisin/kexin type-9), have been identified and characterized. However, such studies have been insufficiently undertaken specifically in Malaysia and Southeast Asia in general. The main objective of this study was to identify ADH variants, specifically ADH-causing mutations and hypercholesterolemia-associated polymorphisms in multiethnic Malaysian population. We aimed to evaluate published SNPs in ADH causing genes, in this population and to report any unusual trends. We examined a large number of selected SNPs from previous studies of APOB, LDLR, PCSK9 and other genes, in clinically diagnosed ADH patients (n=141) and healthy control subjects (n=111). Selection of SNPs was initiated by searching within genes reported to be associated with ADH from known databases. The important finding was 137 mono allelic markers (44.1%) and 173 polymorphic markers (55.8%) in both subject groups. By comparing to publicly available data, out of the 137 mono-allelic markers, 23 markers showed significant differences in allele frequency among Malaysians, European Whites, Han Chinese, Yoruba and Gujarati Indians. Our data can serve as reference for others in related fields of study during the planning of their experiments. PMID- 22534771 TI - Oxaliplatin-related thrombocytopenia. AB - Oxaliplatin is a third generation platinum compound that inhibits DNA synthesis, mainly through intrastrandal cross-links in DNA. Most of the experience with the clinical use of this drug is derived from colorectal cancer but it is also used in other tumor types such as ovary, breast, liver and non-Hodgkin's lymphoma. Thrombocytopenia is a frequent toxicity seen during oxaliplatin treatment, occurring at any grade in up to 70% of patients and leading to delays or even discontinuation of the chemotherapy. Although myelossupression is recognized as the main cause of oxaliplatin-related thrombocytopenia, new mechanisms for this side-effect have emerged, including splenic sequestration of platelets related to oxaliplatin-induced liver damage and immune thrombocytopenia. These new pathophysiology pathways have different clinical presentations and evolution and may need specific therapeutic maneuvers. This article attempts to review this topic and provides useful clinical information for the management of oxaliplatin related thrombocytopenia. PMID- 22534772 TI - Ultraviolet visual sensitivity in three avian lineages: paleognaths, parrots, and passerines. AB - Ultraviolet (UV) light-transmitted signals play a major role in avian foraging and communication, subserving functional roles in feeding, mate choice, egg recognition, and nestling discrimination. Sequencing functionally relevant regions of the short wavelength sensitive type 1 (SWS1) opsin gene that is responsible for modulating the extent of SWS1 UV sensitivity in birds allows predictions to be made about the visual system's UV sensitivity in species where direct physiological or behavioral measures would be impractical or unethical. Here, we present SWS1 segment sequence data from representative species of three avian lineages for which visually based cues for foraging and communication have been investigated to varying extents. We also present a preliminary phylogenetic analysis and ancestral character state reconstructions of key spectral tuning sites along the SWS1 opsin based on our sequence data. The results suggest ubiquitous ultraviolet SWS1 sensitivity (UVS) in both paleognaths, including extinct moa (Emeidae), and parrots, including the nocturnal and flightless kakapo (Strigops habroptilus), and in most, but not all, songbird (oscine) lineages, and confirmed violet sensitivity (VS) in two suboscine families. Passerine hosts of avian brood parasites were included both UVS and VS taxa, but sensitivity did not co-vary with egg rejection behaviors. The results should stimulate future research into the functional parallels between the roles of visual signals and the genetic basis of visual sensitivity in birds and other taxa. PMID- 22534774 TI - Behavioral response to antennal tactile stimulation in the field cricket Gryllus bimaculatus. AB - We examined behavioral responses of the field cricket Gryllus bimaculatus to tactile stimuli to the antennae. Three stimulants of similar shape and size but different textures were used: a tibia from the hunting spider Heteropoda venatoria (potential predator), a tibia from the orb-web spider Argiope bruennichi (less likely predator), and a glass rod. Each stimulus session comprised a first gentle contact and a second strong contact. The evoked behavioral responses were classified into four categories: aversion, aggression, antennal search, and no response. Regardless of the stimulants, the crickets exhibited antennal search and aversion most frequently in response to the first and second stimuli, respectively. The frequency of aversion was significantly higher to the tibia of H. venatoria than to other stimulants. The most striking observation was that aggressive responses were exclusive to the H. venatoria tibia. To specify the hair type that induced aggression, we manipulated two types of common hairs (bristle and fine) on the tibia of the predatory spider. When bristle hairs were removed from the H. venatoria tibia, aggression was significantly reduced. These results suggest that antennae can discriminate the tactile texture of external objects and elicit adaptive behavioral responses. PMID- 22534773 TI - Involvement of Na+/K+ pump in fine modulation of bursting activity of the snail Br neuron by 10 mT static magnetic field. AB - The spontaneously active Br neuron from the brain-subesophageal ganglion complex of the garden snail Helix pomatia rhythmically generates regular bursts of action potentials with quiescent intervals accompanied by slow oscillations of membrane potential. We examined the involvement of the Na(+)/K(+) pump in modulating its bursting activity by applying a static magnetic field. Whole snail brains and Br neuron were exposed to the 10-mT static magnetic field for 15 min. Biochemical data showed that Na(+)/K(+)-ATPase activity increased almost twofold after exposure of snail brains to the static magnetic field. Similarly, (31)P NMR data revealed a trend of increasing ATP consumption and increase in intracellular pH mediated by the Na(+)/H(+) exchanger in snail brains exposed to the static magnetic field. Importantly, current clamp recordings from the Br neuron confirmed the increase in activity of the Na(+)/K(+) pump after exposure to the static magnetic field, as the magnitude of ouabain's effect measured on the membrane resting potential, action potential, and interspike interval duration was higher in neurons exposed to the magnetic field. Metabolic pathways through which the magnetic field influenced the Na(+)/K(+) pump could involve phosphorylation and dephosphorylation, as blocking these processes abolished the effect of the static magnetic field. PMID- 22534775 TI - Accurate determination of rivaroxaban levels requires different calibrator sets but not addition of antithrombin. AB - Rivaroxaban is a direct factor Xa inhibitor, which can be monitored by anti factor Xa chromogenic assays. This ex vivo study evaluated different assays for accurate determination of rivaroxaban levels. Eighty plasma samples from patients receiving rivaroxaban (Xarelto) 10 mg once daily and 20 plasma samples from healthy volunteers were investigated using one anti-factor Xa assay with the addition of exogenous antithrombin and two assays without the addition of antithrombin. Two different lyophilised rivaroxaban calibration sets were used for each assay (low concentration set: 0, 14.5, 59.6 and 97.1 ng/ml; high concentration set: 0, 48.3, 101.3, 194.2 and 433.3 ng/ml). Using a blinded study design, the rivaroxaban concentrations determined by the assays were compared with concentrations measured by HPLC-MS/MS. All assays showed a linear relationship between the rivaroxaban concentrations measured by HPLC-MS/MS and the optical density of the anti-FXa assays. However, the assay with the addition of exogenous antithrombin detected falsely high concentrations of rivaroxaban even in plasma samples from controls who had not taken rivaroxaban (intercept values using the high calibrator set and the low calibrator set: +26.49 ng/ml and +13.71 ng/ml, respectively). Plasma samples, initially determined by the high calibrator setting and containing rivaroxaban concentrations <25 ng/ml, had to be re-run using the low calibrator setting for precise measurement. In conclusion, anti-factor Xa chromogenic assays that use rivaroxaban calibrators at different concentration levels can be used to measure accurately a wide range of rivaroxaban concentrations ex vivo. Assays including exogenous antithrombin are unsuitable for measurement of rivaroxaban. PMID- 22534776 TI - Study of echocardiographic alterations in the first six months after kidney transplantation. AB - BACKGROUND: Cardiac disorders are very common in individuals with chronic kidney disease and are associated with morbimortality. OBJECTIVE: To evaluate cardiac alterations after kidney transplantation. METHODS: We prospectively evaluated 40 patients with chronic kidney disease, immediately before and one month, three months and six months after kidney transplantation, using tissue Doppler echocardiographic study. The left ventricular mass, systolic and diastolic function parameters were analyzed. RESULTS: The mean age was 31.6 years and 40% of patients were female. We observed a reduction in left ventricular diastolic diameter (52.23 to 49.95 mm, p = 0.021) and LV mass index (131.48 to 113.039 g/m2, p = 0.002) after kidney transplantation. The mean E/e' decreased in the third and sixth months after kidney transplantation, when compared to basal values (8.13 and 7.85 vs. 9.79, p <0.05). The ejection fraction increased from the first month after kidney transplantation compared to basal assessment (69.72% vs. 65.68%, p <0.05). The prevalence of diastolic dysfunction decreased 43% during the evaluated period. The basal ejection fraction and mean E/e' were associated with reduced LV mass index after kidney transplantation. The LV mass index at baseline, female sex and decrease in serum phosphorus were associated with a reduction in the mean E/e ' ratio after kidney transplantation. CONCLUSION: Kidney transplantation resulted in significant alterations in Doppler echocardiographic parameters of LV mass, systolic and diastolic function in patients with chronic kidney disease. PMID- 22534777 TI - Analysis of the mortality trend due to cerebrovascular accident in Brazil in the XXI century. AB - BACKGROUND: Although it is the second leading cause of deaths worldwide, the cerebrovascular accident (CVA) has shown a significant reduction in mortality rates in recent decades. OBJECTIVE: To evaluate the trend of CVA mortality rate in Brazil, in both sexes, older than 30 years old, between 2000 and 2009. METHODS: Population data were obtained from the database of the Brazilian Institute of Geography and Statistics (IBGE) and deaths through the Mortality Information System of the Health Surveillance Secretariat of the Ministry of Health, and included codes I60 to I69 according to 10th International Classification of Diseases. We calculated the incidence of deaths/1,000 inhabitants, gross and standardized mortality rates /100,000 inhabitants. The modeling of the trend of rates was performed using regression models. RESULTS: There was an increase in mortality until 2006, followed by a decline until 2009, when the incidence was the lowest. Comparing the years 2000 and 2009, there is a downward trend in standardized mortality rate in both sexes (male = -14.69% and female = -17%) and total (-14.99%), with fluctuations during the period. Between 30 and 49 years in both sexes, there was a trend of continuous and linear decrease in mortality rate, while the other age groups showed a curvilinear function, leading to an effective decrease in values. CONCLUSION: There was a downward trend in mortality in all age groups and both sexes. The reduction in gross mortality rate was more pronounced in males, while the standardized mortality rate showed a greater reduction in females. PMID- 22534778 TI - Novel colorimetric assay of LSD1 activity using gold nanoparticles. AB - We have developed a simple and sensitive strategy for colorimetric LSD1 enzyme activity assay using avidin modified gold nanoparticles. The strategy is based on the vivid color change of a gold nanoparticle solution from red to violet upon addition of a test solution of peptide-antibody treated with LSD1. Thus, the presence of LSD1 in a sample can be determined by simple visual inspection with the naked eye. In addition, a wide range of LSD1 concentrations (13 pM to 0.13 MUM) were quantitatively determined by spectrophotometry, which shows the possibility of quantitative analysis of the over expression levels of LSD1 in cancer tissue samples. PMID- 22534779 TI - Theoretical study of HKrOX (X = F, Cl, Br and I): structure, anharmonic vibrational spectroscopy, stability and bonding. AB - The noble-gas molecules, HKrOX (with X = F, Cl, Br and I), have been investigated by ab initio calculation. Equilibrium geometry, harmonic and anharmonic vibrational frequencies, energies, partial charges are calculated. All HKrOX molecules studied here are bound equilibrium structures with Cs symmetry. The frequency calculation indicates that the H-Kr stretching mode is anharmonic and is very likely to be observed in the experiments. The two-body decomposition reaction is exothermic and lead to products of Kr as well as HOX, while the three body decomposition reaction is also exothermic with respect to the neutral decomposition products (H + Kr + OX). Moreover, HKrOX is kinetically stable with respect to the decomposition reactions due to the enough high energy barriers, which indicates the possibility to identify these HKrOX compounds in noble-gas matrices. The bonding in HKrOX is studied by QTAIM analysis and the localized molecular orbital energy decomposition analysis (LMO-EDA) method at the MP2 level of theory with a large basis set. The results show that HKrOX is a typical ionic bond, denoted as (HKr)(+)(OX)(-), and the electrostatic interaction between (HKr)(+) and (OX)(-) makes the main contribution to the ionic bond. PMID- 22534780 TI - Risk of non-melanoma cancers in first-degree relatives of CDKN2A mutation carriers. AB - The purpose of this study was to quantify the risk of cancers other than melanoma among family members of CDKN2A mutation carriers using data from the Genes, Environment and Melanoma study. Relative risks (RRs) of all non-melanoma cancers among first-degree relatives (FDRs) of melanoma patients with CDKN2A mutations (n = 65) and FDRs of melanoma patients without mutations (n = 3537) were calculated as the ratio of estimated event rates (number of cancers/total person-years) in FDRs of carriers vs noncarriers with exact Clopper-Pearson-type tests and 95% confidence intervals (CIs). All statistical tests were two-sided. There were 56 (13.1%) non-melanoma cancers reported among 429 FDRs of mutation carriers and 2199 (9.4%) non-melanoma cancers in 23 452 FDRs of noncarriers. The FDRs of carriers had an increased risk of any cancer other than melanoma (56 cancers among 429 FDRs of carrier probands vs 2199 cancers among 23 452 FDRs of noncarrier probands; RR = 1.5, 95% CI = 1.2 to 2.0, P = .005), gastrointestinal cancer (20 cancers among 429 FDRs of carrier probands vs 506 cancers among 23 452 FDRs of noncarrier probands; RR = 2.4, 95% CI = 1.4 to 3.7, P = .001), and pancreatic cancer (five cancers among 429 FDRs of carrier probands vs 41 cancers among 23 452 FDRs of noncarrier probands; RR = 7.4, 95% CI = 2.3 to 18.7, P = .002). Wilms tumor was reported in two FDRs of carrier probands and three FDRs of noncarrier probands (RR = 40.4, 95% CI = 3.4 to 352.7, P = .005). The lifetime risk of any cancer other than melanoma among CDKN2A mutation carriers was estimated as 59.0% by age 85 years (95% CI = 39.0% to 75.4%) by the kin-cohort method, under the standard assumptions of Mendelian genetics on the genotype distribution of FDRs conditional on proband genotype. PMID- 22534781 TI - Can a two-faced kinase be exploited for osteosarcoma? PMID- 22534783 TI - Cotinine conundrum--a step forward but questions remain. PMID- 22534782 TI - Glycogen synthase kinase-3beta, NF-kappaB signaling, and tumorigenesis of human osteosarcoma. AB - BACKGROUND: Glycogen synthase kinase-3beta (GSK-3beta), a serine/threonine protein kinase, may function as a tumor suppressor or an oncogene, depending on the tumor type. We sought to determine the biological function of GSK-3beta in osteosarcoma, a rare pediatric cancer for which the identification of new therapeutic targets is urgent. METHODS: We used cell viability assays, colony formation assays, and apoptosis assays to analyze the effects of altered GSK 3beta expression in U2OS, MG63, SAOS2, U2OS/MTX300, and ZOS osteosarcoma cell lines. Nude mice (n = 5-8 mice per group) were injected with U2OS/MTX300, and ZOS cells to assess the role of GSK-3beta in osteosarcoma growth in vivo and to evaluate the effects of inhibitors and/or anticancer drugs on tumor growth. We used an antibody array, polymerase chain reaction, western blotting, and a luciferase reporter assay to establish the effect of GSK-3beta inhibition on the nuclear factor-kappaB (NF-kappaB) pathway. Immunochemistry was performed on primary tumor specimens from osteosarcoma patients (n = 74) to determine the relationship of GSK-3beta activity with overall survival. RESULTS: Osteosarcoma cells with low levels of inactive p-Ser9-GSK-3beta formed colonies in vitro and tumors in vivo more readily than cells with higher levels and cells in which GSK 3beta had been silenced formed fewer colonies and smaller tumors than parental cells. Silencing or pharmacological inhibition of GSK-3beta resulted in apoptosis of osteosarcoma cells. Inhibition of GSK-3beta resulted in inhibition of the NF kappaB pathway and reduction of NF-kappaB-mediated transcription. Combination treatments with GSK-3beta inhibitors, NF-kappaB inhibitors, and chemotherapy drugs increased the effectiveness of chemotherapy drugs in vitro and in vivo. Patients whose osteosarcoma specimens had hyperactive GSK-3beta, and nuclear NF kappaB had a shorter median overall survival time (49.2 months) compared with patients whose tumors had inactive GSK-3beta and NF-kappaB (109.2 months). CONCLUSION: GSK-3beta activity may promote osteosarcoma tumor growth, and therapeutic targeting of the GSK-3beta and/or NF-kappaB pathways may be an effective way to enhance the therapeutic activity of anticancer drugs against osteosarcoma. PMID- 22534784 TI - Association between genetic variants on chromosome 15q25 locus and objective measures of tobacco exposure. AB - BACKGROUND: Two single-nucleotide polymorphisms, rs1051730 and rs16969968, located within the nicotinic acetylcholine receptor gene cluster on chromosome 15q25 locus, are associated with heaviness of smoking, risk for lung cancer, and other smoking-related health outcomes. Previous studies have typically relied on self-reported smoking behavior, which may not fully capture interindividual variation in tobacco exposure. METHODS: We investigated the association of rs1051730 and rs16969968 genotype (referred to as rs1051730-rs16969968, because these are in perfect linkage disequilibrium and interchangeable) with both self reported daily cigarette consumption and biochemically measured plasma or serum cotinine levels among cigarette smokers. Summary estimates and descriptive statistical data for 12 364 subjects were obtained from six independent studies, and 2932 smokers were included in the analyses. Linear regression was used to calculate the per-allele association of rs1051730-rs16969968 genotype with cigarette consumption and cotinine levels in current smokers for each study. Meta analysis of per-allele associations was conducted using a random effects method. The likely resulting association between genotype and lung cancer risk was assessed using published data on the association between cotinine levels and lung cancer risk. All statistical tests were two-sided. RESULTS: Pooled per-allele associations showed that current smokers with one or two copies of the rs1051730 rs16969968 risk allele had increased self-reported cigarette consumption (mean increase in unadjusted number of cigarettes per day per allele = 1.0 cigarette, 95% confidence interval [CI] = 0.57 to 1.43 cigarettes, P = 5.22 * 10(-6)) and cotinine levels (mean increase in unadjusted cotinine levels per allele = 138.72 nmol/L, 95% CI = 97.91 to 179.53 nmol/L, P = 2.71 * 10(-11)). The increase in cotinine levels indicated an increased risk of lung cancer with each additional copy of the rs1051730-rs16969968 risk allele (per-allele odds ratio = 1.31, 95% CI = 1.21 to 1.42). CONCLUSIONS: Our data show a stronger association of rs1051730-rs16969968 genotype with objective measures of tobacco exposure compared with self-reported cigarette consumption. The association of these variants with lung cancer risk is likely to be mediated largely, if not wholly, via tobacco exposure. PMID- 22534786 TI - Brain slice on a chip: opportunities and challenges of applying microfluidic technology to intact tissues. AB - Isolated brain tissue, especially brain slices, are valuable experimental tools for studying neuronal function at the network, cellular, synaptic, and single channel levels. Neuroscientists have refined the methods for preserving brain slice viability and function and converged on principles that strongly resemble the approach taken by engineers in developing microfluidic devices. With respect to brain slices, microfluidic technology may 1) overcome the traditional limitations of conventional interface and submerged slice chambers and improve oxygen/nutrient penetration into slices, 2) provide better spatiotemporal control over solution flow/drug delivery to specific slice regions, and 3) permit successful integration with modern optical and electrophysiological techniques. In this review, we highlight the unique advantages of microfluidic devices for in vitro brain slice research, describe recent advances in the integration of microfluidic devices with optical and electrophysiological instrumentation, and discuss clinical applications of microfluidic technology as applied to brain slices and other non-neuronal tissues. We hope that this review will serve as an interdisciplinary guide for both neuroscientists studying brain tissue in vitro and engineers as they further develop microfluidic chamber technology for neuroscience research. PMID- 22534787 TI - Increased precision for analysis of protein-ligand dissociation constants determined from chemical shift titrations. AB - NMR is ideally suited for the analysis of protein-protein and protein ligand interactions with dissociation constants ranging from ~2 MUM to ~1 mM, and with kinetics in the fast exchange regime on the NMR timescale. For the determination of dissociation constants (K ( D )) of 1:1 protein-protein or protein-ligand interactions using NMR, the protein and ligand concentrations must necessarily be similar in magnitude to the K ( D ), and nonlinear least squares analysis of chemical shift changes as a function of ligand concentration is employed to determine estimates for the parameters K ( D ) and the maximum chemical shift change (Deltadelta(max)). During a typical NMR titration, the initial protein concentration, [P (0)], is held nearly constant. For this condition, to determine the most accurate parameters for K ( D ) and Deltadelta(max) from nonlinear least squares analyses requires initial protein concentrations that are ~0.5 * K ( D ), and a maximum concentration for the ligand, or titrant, of ~10 * [P (0)]. From a practical standpoint, these requirements are often difficult to achieve. Using Monte Carlo simulations, we demonstrate that co-variation of the ligand and protein concentrations during a titration leads to an increase in the precision of the fitted K ( D ) and Deltadelta(max) values when [P (0)] > K ( D ). Importantly, judicious choice of protein and ligand concentrations for a given NMR titration, combined with nonlinear least squares analyses using two independent variables (ligand and protein concentrations) and two parameters (K ( D ) and Deltadelta(max)) is a straightforward approach to increasing the accuracy of measured dissociation constants for 1:1 protein-ligand interactions. PMID- 22534785 TI - Dietary supplements and cancer prevention: balancing potential benefits against proven harms. AB - Nutritional supplementation is now a multibillion-dollar industry, and about half of all US adults take supplements. Supplement use is fueled in part by the belief that nutritional supplements can ward off chronic disease, including cancer, although several expert committees and organizations have concluded that there is little to no scientific evidence that supplements reduce cancer risk. To the contrary, there is now evidence that high doses of some supplements increase cancer risk. Despite this evidence, marketing claims by the supplement industry continue to imply anticancer benefits. Insufficient government regulation of the marketing of dietary supplement products may continue to result in unsound advice to consumers. Both the scientific community and government regulators need to provide clear guidance to the public about the use of dietary supplements to lower cancer risk. PMID- 22534789 TI - Fine mapping, phenotypic characterization and validation of non-race-specific resistance to powdery mildew in a wheat-Triticum militinae introgression line. AB - Introgression of several genomic loci from tetraploid Triticum militinae into bread wheat cv. Tahti has increased resistance of introgression line 8.1 to powdery mildew in seedlings and adult plants. In our previous work, only a major quantitative trait locus (QTL) on chromosome 4AL of the line 8.1 contributed significantly to resistance, whereas QTL on chromosomes 1A, 1B, 2A, 5A and 5B were detected merely on a suggestive level. To verify and characterize all QTLs in the line 8.1, a mapping population of double haploid lines was established. Testing for seedling resistance to 16 different races/mixtures of Blumeria graminis f. sp. tritici revealed four highly significant non-race-specific resistance QTL including the main QTL on chromosome 4AL, and a race-specific QTL on chromosome 5B. The major QTL on chromosome 4AL (QPm.tut-4A) as well as QTL on chromosome 5AL and a newly detected QTL on 7AL were highly effective at the adult stage. The QPm.tut-4A QTL accounts on average for 33-49 % of the variation in resistance in the double haploid population. Interactions between the main QTL QPm.tut-4A and the minor QTL were evaluated and discussed. A population of 98 F(2) plants from a cross of susceptible cv. Chinese Spring and the line 8.1 was created that allowed mapping the QPm.tut-4A locus to the proximal 2.5-cM region of the introgressed segment on chromosome 4AL. The results obtained in this work make it feasible to use QPm.tut-4A in resistance breeding and provide a solid basis for positional cloning of the major QTL. PMID- 22534790 TI - Identification of FAD2 and FAD3 genes in Brassica napus genome and development of allele-specific markers for high oleic and low linolenic acid contents. AB - Modification of oleic acid (C18:1) and linolenic acid (C18:3) contents in seeds is one of the major goals for quality breeding after removal of erucic acid in oilseed rape (Brassica napus). The fatty acid desaturase genes FAD2 and FAD3 have been shown as the major genes for the control of C18:1 and C18:3 contents. However, the genome structure and locus distributions of the two gene families in amphidiploid B. napus are still not completely understood to date. In the present study, all copies of FAD2 and FAD3 genes in the A- and C-genome of B. napus and its two diploid progenitor species, Brassica rapa and Brassica oleracea, were identified through bioinformatic analysis and extensive molecular cloning. Two FAD2 genes exist in B. rapa and B. oleracea, and four copies of FAD2 genes exist in B. napus. Three and six copies of FAD3 genes were identified in diploid species and amphidiploid species, respectively. The genetic control of high C18:1 and low C18:3 contents in a double haploid population was investigated through mapping of the quantitative trait loci (QTL) for the traits and the molecular cloning of the underlying genes. One major QTL of BnaA.FAD2.a located on A5 chromosome was responsible for the high C18:1 content. A deleted mutation in the BnaA.FAD2.a locus was uncovered, which represented a previously unidentified allele for the high oleic variation in B. napus species. Two major QTLs on A4 and C4 chromosomes were found to be responsible for the low C18:3 content in the DH population as well as in SW Hickory. Furthermore, several single base pair changes in BnaA.FAD3.b and BnaC.FAD3.b were identified to cause the phenotype of low C18:3 content. Based on the results of genetic mapping and identified sequences, allele-specific markers were developed for FAD2 and FAD3 genes. Particularly, single-nucleotide amplified polymorphisms markers for FAD3 alleles were demonstrated to be a reliable type of SNP markers for unambiguous identification of genotypes with different content of C18:3 in amphidiploid B. napus. PMID- 22534791 TI - Identification of Ug99 stem rust resistance loci in winter wheat germplasm using genome-wide association analysis. AB - The evolution of a new race of stem rust, generally referred to as Ug99, threatens global wheat production because it can overcome widely deployed resistance genes that had been effective for many years. To identify loci conferring resistance to Ug99 in wheat, a genome-wide association study was conducted using 232 winter wheat breeding lines from the International Winter Wheat Improvement Program. Breeding lines were genotyped with diversity array technology, simple sequence repeat and sequence-tagged site markers, and phenotyped at the adult plant stage for resistance to stem rust in the stem rust resistance screening nursery at Njoro, Kenya during 2009-2011. A mixed linear model was used for detecting marker-trait associations. Twelve loci associated with Ug99 resistance were identified including markers linked to known genes Sr2 and Lr34. Other markers were located in the chromosome regions where no Sr genes have been previously reported, including one each on chromosomes 1A, 2B, 4A and 7B, two on chromosome 5B and four on chromosome 6B. The same data were used for investigating epistatic interactions between markers with or without main effects. The marker csSr2 linked to Sr2 interacted with wPt4930 on 6BS and wPt729773 in an unknown location. Another marker, csLV34 linked to Lr34, also interacted with wPt4930 on 6BS and wPt4916 on 2BS. The frequent involvement of wPt4916 on 2BS and wPt4930 on 6BS in interactions with other significant loci on the same or different chromosomes suggested complex genetic control for adult plant resistance to Ug99 in winter wheat germplasm. PMID- 22534793 TI - Arterial stiffness is associated with increased monocyte expression of adiponectin receptor mRNA and protein in patients with coronary artery disease. AB - BACKGROUND: Arterial stiffness and carotid intima-media thickness (IMT) constitute validated cardiovascular prognostic markers. Adiponectin and its receptors 1 (AdipoR1) and 2 (AdipoR2) are involved in coronary artery disease (CAD). We investigated whether AdipoR1 and R2 mRNA and protein expression are associated with arterial stiffness, IMT and extent of coronary atherosclerosis. METHODS: We studied 71 patients (61 men, 10 women) with angiographically proven CAD. We measured: (i) monocyte expression of AdipoR1 and AdipoR2 mRNA (quantitative real-time PCR) and protein expression (flow cytometry) (iii) adiponectin, metalloproteinase-9 (MMP-9) and C-reactive protein (CRP) blood levels, (iv) carotid-femoral artery pulse wave velocity (PWV) and carotid IMT. RESULTS: Patients with multi-vessel CAD had higher AdipoR1 and AdipoR2 mRNA than those with single-vessel (P < 0.05). PWV was associated with AdipoR1 mRNA (r = 0.474), AdipoR1 protein (r = 0.228), AdipoR2 mRNA (r = 0.716), AdipoR2-protein (r = 0.261), adiponectin (r = 0.236), and MMP-9 (r = 0.350) (P < 0.05, for all correlations). After adjustment for age, sex, waist-hip ratio, and mean blood pressure both AdipoR1 and AdipoR2 mRNA remained independent determinants of PWV (R(2) = 0.35 and R(2) = 0.57, P < 0.05). IMT was also associated with AdipoR2 mRNA, AdipoR2 protein, and MMP-9 (P < 0.05). Increased expression of ADR2 mRNA significantly related to MMP-9 (r = 0.210), and CRP (r = 0.531) (P < 0.05). CONCLUSION: Increased mRNA and protein expression of adiponectin receptors is related with increased aortic stiffness, coronary and peripheral atherosclerosis in patients with CAD. The interrelation of AdipoR2 with inflammatory markers, PWV and IMT suggests a compensatory increase of these receptors to counteract the excess inflammatory and atherogenic process in CAD. Thus, adiponectin receptors may provide a potential therapeutic target of agents activating their beneficial action.American Journal of Hypertension 2012; doi:10.1038/ajh.2012.42. PMID- 22534792 TI - Evolution of osmoregulatory patterns and gill ion transport mechanisms in the decapod Crustacea: a review. AB - Decapod crustaceans exhibit a wide range of osmoregulatory patterns and capabilities from marine osmoconformers to brackish and freshwater hyperregulators to terrestrial hyporegulators. The principal gill salt transport mechanisms proposed to underlie the ability of the better-known taxa to occupy these specific habitats are examined here. Traditional thinking suggests that a graduated series of successively stronger adaptive mechanisms may have driven the occupation of ever more dilute osmotic niches, culminating in the conquest of freshwater and dry land. However, when habitat and osmoregulatory parameters are analyzed quantitatively against the phylogenies of the taxa examined, as illustrated here using a palaemonid shrimp clade, their association becomes questionable and may hold true only in specific cases. We also propose a putative evolution for gill epithelial ion pump and transporter arrangement in a eubrachyuran crab clade whose lineages occupy distinct osmotic niches. By including the systematics of these selected groups, this review incorporates the notion of a protracted time scale, here termed 'phylophysiology', into decapod osmoregulation, allowing the examination of putative physiological transformations and their underlying evolutionary processes. This approach assumes that species are temporally linked, a factor that can impart phylogenetic structuring, which must be considered in comparative studies. Future experimental models in decapod osmoregulatory physiology should contemplate the phylogenetic relationships among the taxa chosen to better allow comprehension of the transformations arising during their evolution. PMID- 22534794 TI - A two-stage matched case-control study on multiple hypertensive candidate genes in Han Chinese. AB - BACKGROUND: Hypertension affects about 1/3 of adults worldwide, ~3.8 million in Taiwan, 160 million in China, and 1 billion worldwide. It is a major risk factor leading to stroke, cardiovascular disease, and end-stage renal disease. In each year, more than 13.5 million deaths are due to hypertension-related diseases worldwide. METHODS: We performed a two-stage association study of hypertension using genotype data of single-nucleotide polymorphisms (SNPs) from 992 young onset hypertensive cases and 992 matched controls of Han Chinese in Taiwan. A total of 238 SNPs of 36 highly replicated hypertension candidate genes with functional importance were investigated. Association analysis was carried out using conditional logistic regression. RESULTS: We identified two SNPs that were strongly associated with hypertension in both the first and the second stages. The first SNP (rs2301339) is located at guanine nucleotide-binding protein beta3 subunit (GNB3) and the other one (rs17254521) is located at insulin receptor (INSR). CONCLUSIONS: SNP rs2301339 is perfectly linked in linkage disequilibrium (LD) with C825T (rs5443) which has been associated with hypertension in Caucasian, but inconsistent in Asian populations. However, we found that in our sample this SNP has an opposite effect with the previous findings. In summary, this study identified one novel SNP in GNB3 and one novel SNP in INSR that are strongly associated with young-onset hypertension. Due to relatively small sample size, the results should still be interpreted with caution and need to be replicated in other studies. PMID- 22534795 TI - Docosahexaenoic acid monoacylglyceride decreases endothelin-1 induced Ca(2+) sensitivity and proliferation in human pulmonary arteries. AB - BACKGROUND: Pulmonary artery vasoconstriction and vascular remodeling contribute to a sustained elevation of pulmonary vascular resistance and pressure in patients with pulmonary arterial hypertension (PH), an often fatal hemodynamic disease. The effect of docosahexaenoic acid monoacylglyceride (MAG-DHA) and the role of the 17 kDa protein kinase C-potentiated inhibitor protein (CPI-17) were determined on vasoconstriction and smooth muscle cell proliferation of human pulmonary arteries (HPA). METHODS: HPA were obtained from 16 patients undergoing lung resection for carcinoma. The mechanical tension and Ca(2+) sensitivity were measured on arterial rings treated with endothelin-1 (ET-1) in the absence or presence of MAG-DHA. The effect of MAG-DHA on the level of proliferation of smooth muscle cells isolated from HPA was evaluated in order to determine the role of CPI-17 protein. RESULTS: MAG-DHA treatment decreased the reactivity and Ca(2+) sensitivity induced by ET-1 in HPA. MAG-DHA treatment also decreased the expression of vascular endothelial growth factor (VEGF) induced by ET-1. Moreover, both VEGF inhibitor and MAG-DHA treatments reduced Ca(2+) hypersensitivity induced by ET-1, which was associated to a reduction in CPI-17 and myosin-binding subunit of the myosin light chain phosphatase (MYPT-1) phosphorylation levels. Proliferation of ET-1-stimulated HPA smooth muscle cells (PASMc) was also decreased following CPI-17 small interfering RNA transfection and MAG-DHA treatments. Western blot analyses revealed that MAG-DHA treatment resulted in decreased phosphorylation levels of CPI-17 and extracellular signal regulated kinases (ERK) in PASMc treated with ET-1. CONCLUSIONS: We have demonstrated that VEGF interacts with CPI-17 signaling pathway resulting in an increase in Ca(2+) sensitivity and proliferation of PASMc, whereas MAG-DHA treatment reversed these effects. PMID- 22534796 TI - Lysine-specific demethylase 1: an epigenetic regulator of salt-sensitive hypertension. AB - BACKGROUND: Hypertension (HTN) represents a complex heritable disease in which environmental factors may directly affect gene function via epigenetic mechanisms. The aim of this study was to test the hypothesis that dietary salt influences the activity of a histone-modifying enzyme, lysine-specific demethylase 1 (LSD-1), which in turn is associated with salt-sensitivity of blood pressure (BP). METHODS: Animal and human studies were performed. Salt-sensitivity of LSD-1 expression was assessed in wild-type (WT) and LSD-1 heterozygote knockout (LSD-1(+/-)) mice. Clinical relevance was tested by multivariate associations between single-nuclear polymorphisms (SNPs) in the LSD-1 gene and salt-sensitivity of BP, with control of dietary sodium, in a primary African American hypertensive cohort and two replication hypertensive cohorts (Caucasian and Mexican-American). RESULTS: LSD-1 expression was modified by dietary salt in WT mice with lower levels associated with liberal salt intake. LSD-1(+/-) mice expressed lower LSD-1 protein levels than WT mice in kidney tissue. Similar to LSD-1(+/-) mice, African-American minor allele carriers of two LSD-1 SNPs displayed greater change in systolic BP (SBP) in response to change from low to liberal salt diet (rs671357, P = 0.01; rs587168, P = 0.005). This association was replicated in the Hispanic (rs587168, P = 0.04) but not the Caucasian cohort. Exploratory analyses demonstrated decreased serum aldosterone concentrations in African-American minor allele carriers similar to findings in the LSD-1(+/-) mice, decreased alpha-EnaC expression in LSD-1(+/-) mice, and impaired renovascular responsiveness to salt loading in minor allele carriers. CONCLUSION: The results of this translational research study support a role for LSD-1 in the pathogenesis of salt-sensitive HTN. PMID- 22534797 TI - Genetic surface-display of methyl parathion hydrolase on Yarrowia lipolytica for removal of methyl parathion in water. AB - In this study, the mph gene encoding methyl parathion hydrolase from Pseudomonas sp. WBC-3 was expressed in Yarrowia lipolytica and the expressed methyl parathion hydrolase was displayed on cell surface of Y. lipolytica. The activity of methyl parathion hydrolase displayed on the yeast cells of the transformant Z51 was 59.5 U mg-1 of cell dry cells (450.6 U per mL of the culture) in the presence of 5.0 mM of Co2+. The displayed methyl parathion hydrolase had the optimal pH of 9.5 and the optimal temperature of 40 degrees C, respectively and was stable in the pH range of 4.5-11 and up to 40 degrees C. The displayed methyl parathion hydrolase was also stimulated by Co2+, Cu2+, Ni2+ and Mn2+, and was not affected by Fe2+, Fe3+, Na+, K+, Ca2+ and Zn2+, but was inhibited by other cations tested. Under the optimal conditions (OD(600 nm) = 2.6, the substrate concentration = 100 mg L-1 and 40 degrees C), 90.8 % of methyl parathion was hydrolyzed within 30 min. Under the similar conditions, 98.7, 97.0, 96.5 and 94.4 % of methyl parathion in tap water (pH 9.5), tap water (pH 6.8), seawater (pH 9.5) and natural seawater (pH 8.2) were hydrolyzed, respectively, suggesting that the methyl parathion hydrolase displayed on the yeast cells can effectively remove methyl parathion in water. PMID- 22534799 TI - Platinum and anthracycline therapy for advanced cutaneous squamous cell carcinoma. AB - BACKGROUND: Because metastatic cutaneous squamous cell carcinoma (CSCC) is rare, standard chemotherapy has not been fully established. In Japan, combination platinum and anthracycline chemotherapy has been used for elderly patients with advanced CSCC because of its low toxicity. However, the clinical benefit of this therapy has not been fully examined. METHODS: We retrospectively examined the response rate of combination platinum and anthracycline chemotherapy for metastatic CSCC. RESULTS: Eight patients received combination chemotherapy for metastatic lesions; there were lymph node lesions in 6 patients and skin and lung lesions in one patient each. The combination regimens were as follows: cisplatin (CDDP) (60-90 mg/m(2)/day, day 1) and adriamycin (ADM) (20-40 mg/m(2)/day, day 1 or 2) was administered in 5 patients; CDDP (10-15 mg/m(2)/day, days 1-5) and epirubicin (epi-ADM) (10-15 mg/m(2)/day, days 1-5) was administered in 2 patients; and carboplatin (CBDCA) (200-400 mg/m(2)/day, day 1) and ADM (20-40 mg/m(2)/day, day 1 or 2) was administered in one patient. The responses were as follows: complete response in 2 patients (CDDP + ADM for lung metastasis, CDDP + epi-ADM for lymph node metastasis), partial response in 1 (CDDP + ADM for lymph node metastasis), stable disease in 2, and progressive disease in 3. A durable response was observed in 2 patients showing complete responses (58 and 112 months). CONCLUSIONS: The clinical effect of the combination of platinum and anthracycline for metastatic CSCC was limited despite the findings of two patients showing durable complete responses. PMID- 22534800 TI - Rational design of molecularly imprinted polymer: the choice of cross-linker. AB - The paper describes a rational approach for the selection of cross-linkers during the development of molecularly imprinted polymers (MIPs). As a model system for this research MIPs specific for the drug zidovudine (AZT) were designed and tested. Three cross-linkers trimethylolpropane trimethacrylate (TRIM), ethylene glycol dimethacrylate (EGDMA) and divinylbenzene (DVB) were studied. The analogue of zidovudine (AZT) ester (AZT-ES) was used as a dummy template. The imprinting factors for all of the polymers in the static adsorption experiments were calculated. The data on the AZT adsorption by control polymers (CP), which were prepared with different cross-linkers without a functional monomer, was also analyzed. DVB was found to be more inert towards zidovudine than EGDMA and TRIM, which was confirmed by both molecular modelling and adsorption experiments. It was demonstrated that DVB-based polymers had a higher imprinting factor (I = 1.85) compared with other tested cross-linked polymers. It was suggested that the selection of the cross-linker should be based on the strength of the interaction with the template: the cross-linker which displays lower binding of the template should be preferential because it generates MIPs with lower non-specific binding and a higher imprinting factor, and therefore specificity. Which cross-linker to use for the preparation of any particular MIP can be determined by analysis of the interactions between the cross-linker and template. This could be done either virtually using computational modelling or by template adsorption using a small library of polymers prepared using different cross-linkers. PMID- 22534798 TI - Comparison of pirarubicin-based versus gemcitabine-docetaxel chemotherapy for relapsed and refractory osteosarcoma: a single institution experience. AB - BACKGROUND: The prognoses for patients with relapsed and refractory osteosarcoma are poor and the optimal treatment strategy is still to be defined. We conducted this retrospective study to compare the feasibility and efficacy of pirarubicin based chemotherapy with gemcitabine-docetaxel combination regimens for the salvage of these patients. METHODS: The clinical data of 75 patients who received pirarubicin-based (n = 52) or gemcitabine-docetaxel (n = 23) chemotherapy as a second-line treatment for relapsed and refractory osteosarcoma between January 2005 and September 2011were reviewed retrospectively. Tumor response was evaluated every two chemotherapy cycles by computed tomography/magnetic resonance imaging (CT/MRI) scans using the Response Evaluation Criteria in Solid Tumors. Progression-free survival and overall survival (OS) were evaluated by Kaplan Meier analysis. Toxicity was examined according to the National Cancer Institute Toxicity Criteria grading system. RESULTS: Patient characteristics were well balanced in the two groups. The response rate was 25.0 % in patients who received pirarubicin-based chemotherapy, while it was 13.0 % in the gemcitabine-docetaxel group. Moreover, the median OS was longer in the pirarubicin-based chemotherapy group (14.0 vs. 9.0 months, P < 0.05), especially in the pirarubicin-ifosfamide (14.0 months) and pirarubicin-cisplatin (15.0 months) subgroups. The incidence of grade 3-4 neutropenia was higher in the gemcitabine-docetaxel group (5.8 vs. 43.5 %, P < 0.05); other grade 3-4 toxicities were comparable in the two groups. CONCLUSIONS: In our experience, pirarubicin-based chemotherapy was comparable with gemcitabine-docetaxel as a second-line treatment for relapsed and refractory osteosarcoma, and it even seemed to show greater efficacy, with milder toxicity. Further studies, especially prospective clinical trials, focusing on pirarubicin based treatments for relapsed and refractory osteosarcoma patients should be strongly considered. PMID- 22534801 TI - Engraftment of human adipose derived stem cells delivered in a hyaluronic acid preparation in mice. AB - PURPOSE: To evaluate the implant of human adipose derived stem cells (ADSC) delivered in hyaluronic acid gel (HA), injected in the subcutaneous of athymic mice. METHODS: Control implants -HA plus culture media was injected in the subcutaneous of the left sub scapular area of 12 athymic mice. ADSC implants: HA plus ADSC suspended in culture media was injected in the subcutaneous, at the contra lateral area, of the same animals. With eight weeks, animals were sacrificed and the recovered implants were processed for extraction of genomic DNA, and histological study by hematoxilin-eosin staining and immunufluorescence using anti human vimentin and anti von Willebrand factor antibodies. RESULTS: CONTROLS: Not visualized at the injection site. An amorphous substance was observed in hematoxilin-eosin stained sections. Human vimentin and anti von Willebrand factor were not detected. No human DNA was detected. ADSC implants - A plug was visible at the site of injection. Fusiform cells were observed in sections stained by hematoxilin- eosin and both human vimentin and anti von Willebrand factor were detected by immunofluorescence. The presence of human DNA was confirmed. CONCLUSION: The delivery of human adipose derived stem cells in preparations of hyaluronic acid assured cells engraftment at the site of injection. PMID- 22534802 TI - Closed head injury in rats: histopathological aspects in an experimental weight drop model. AB - PURPOSE: To study histopathological findings due to a model of closed head injury by weight loss in rats. METHODS: A platform was used to induce closed cranial lesion controlled by weight loss with a known and predefined energy. 25 male Wistar rats (Rattus novergicus albinus) were divided in five equal groups which received different cranial impact energy levels: G1, G2, G3 and G4 with 0.234J, 0.5J, 0.762J and 1J respectively and G5 (Sham). Under the effect of analgesia, the brain of each group was collected and prepared for histopathological analysis by conventional optic microscopy. RESULTS: It was observed greater number of injured neurons in animals of group 4, however neuronal death also could be noticed in animals of group 5. Intraparenchymal hemorrhages were more frequent in animals of group 4 and the cytotoxic brain swelling and vascular congestion were more intense in this group CONCLUSION: The histopathological analysis of these findings allowed to observe typical cranial trauma alterations and these keep close relation with impact energy. PMID- 22534803 TI - Influence of local or systemic corticosteroids on skin wound healing resistance. AB - PURPOSE: To compare the resistance of skin wound healing of mice submitted to local or systemic hydrocortisone administration, in different postoperative periods. METHODS: An incision and suture was performed on the thoracic skin of 130 male mice: Group 1 (n = 10) resistance of the integer skin; Group 2 (n = 30) submitted only to skin incision and suture; Group 3 (n = 30) skin incision and suture followed by administration of saline fluid; Group 4 (n = 30) skin incision and suture followed by administration of local hydrocortisone; Group 5 (n = 30) skin incision and suture followed by administration of systemic hydrocortisone. The resistance of the wound healing and the weight of the animals were studied on the seventh, 14(th) and 21(st) postoperative days. Histological examination was also performed. RESULTS: The mice that received corticoid (groups 4 and 5) presented significant decreasing on their weight (p = 0.02). The Groups 3, 4 and 5 showed lower scar resistance than Group 2 on the seventh postoperative day (p < 0.05). On the 14(th) and 21(st) days, there was no difference on the skin would healing resistance (p > 0.05). CONCLUSION: Administration of hydrocortisone in mice is responsible for weight decreasing and reduction of the skin wound healing resistance during the first postoperative week. PMID- 22534804 TI - Comparative study between polypropylene and polypropylene/poliglecaprone meshes used in the correction of abdominal wall defect in rats. AB - PURPOSE: To evaluate the healing process of a defect in the ventral abdominal wall of rats, comparing the polypropylene and polypropylene/poliglecaprone meshes on the 30(th) and 60(th) postoperative day. METHODS: Thirty two Wistar rats were submitted to a ventral abdominal wall defect, with integrity of the parietal peritoneum. In the repair, were used polypropylene (group A) and polypropylene/poliglecaprone (group B) meshes. The groups were subdivided into four subgroups of eight animals euthanized on the 30(th) (A30 and B30) and 60(th) postoperative day (A60 and B60). Fragments of the abdominal wall of the animals were submitted to macroscopic, tensiometric and histological evaluations. RESULTS: The tensiometry on subgroup A30 showed a mean average break point of 0.78 MPa and in A60, 0.66 Mpa. In subgroup B30 it was 0.84 MPa and in B60, 1.27 Mpa. The score of the inflammatory process showed subacute phase on A30 and B30 sub-groups and chronic inflammatory process in subgroups A30 and 60B. CONCLUSIONS: The tensile strength was higher on the wall repaired by polypropylene/poliglecaprone mesh in the 60(th) post-operative day. Histology showed higher concentration of fibrosis on the surface of the polypropylene mesh with a tendency to encapsulation. In polypropylene/poliglecaprone subgroups the histology showed higher concentration of fibrosis on the surface of mesh filaments. PMID- 22534805 TI - Evaluation of the donor site after liposuction with a syringe in rabbits. AB - PURPOSE: To evaluate the donor site of adipocytes as well as histopathological alterations secondary to liposuction. METHODS: All animals underwent liposuction with a syringe on the right side of the back. While the left side of the back was used as control and did not undergo intervention. The 10 rabbits were divided into two groups A and B according the postoperative day which were submitted to euthanasia: 90 and 120 days. All adipose tissue from the donor site was analyzed and compared with the control macroscopic and light microscopy. Tissues were weighed and analyzed searching for histological changes and late inflammatory response to trauma such as fibrosis, fat necrosis and inflammation and macrophage infiltration. RESULTS: There was wide variation in adipose tissue volume between the experimental and the control on macroscopic analysis. The presence of histopathological changes was found in two samples at 90 days. CONCLUSIONS: There was a relationship between the presence of fibrosis with the weight and number of days after liposuction surgery in rabbits. The study show macroscopic difference between control and experiment sides in all rabbits. PMID- 22534807 TI - Hemodynamic changes in lipid emulsion therapy (SMOFlipid) for bupivacaine toxicity in swines. AB - PURPOSE: To evaluate the hemodynamic changes following SMOFlipid emulsion therapy with after bupivacaine intoxication in swines. METHODS: Large White pigs were anesthetized with thiopental, tracheal intubation was performed and mechanical ventilation was instituted. Hemodynamic variables were recorded with invasive pressure monitoring and pulmonary artery catheterization (Swan-Ganz catheter). After a 30-minute resting period, 5 mg.kg(-1) of bupivacaine by intravenous injection was administered and new hemodynamic measures were performed 1 minute later; the animals were than randomly divided into two groups and received 4 ml.kg(-1) of saline solution or 4 ml.kg(-1) of SMOFlipid emulsion 20%. Hemodynamic changes were then re-evaluated at 5, 10, 15, 20 and 30 minutes. RESULTS: Bupivacaine intoxication caused fall in arterial blood pressure, cardiac index, ventricular systolic work index mainly and no important changes in vascular resistances. SMOFlipid emulsion therapy was able to improve blood pressure mainly by increasing vascular resistance since the cardiac index had no significant improvement in our study. Hemodynamic results of the use of lipid emulsion in bupivacaine intoxication were better than the control group. CONCLUSION: The SMOFlipid emulsion is a option for reversing hypotension in cases of intoxication by bupivacaine. PMID- 22534806 TI - A comparison of extradural tramadol and extradural morphine for postoperative analgesia in female dogs undergoing ovariohysterectomy. AB - PURPOSE: To compare the postoperative analgesic effects of the extradural tramadol or morphine in female dogs undergoing ovariohysterectomy. METHODS: Sixteen female dogs were randomly assigned to two groups of eight animals each and received morphine (0.1 mg kg(-1) M group) or tramadol (2 mg kg(-1) T group). The pre-anesthetic medication was intravenously (iv) acepromazine (0.05 mg kg( 1)). Anesthesia was induced with propofol (4 mg kg(-1)iv) and maintained with isoflurane. The degree of analgesia was evaluated using a numerical rating scale that included physiologic and behavior variables. Dogs were scored at one, three, six and 12 hours after surgery by one blinded observer. Dogs were treated with morphine (0.5 mg kg(-1)) if their scores were >6. Serum cortisol was measured before the pre-anesthetic medication was administered (basal), at the time of the ovarian pedicle clamping (T0), and at 1 (T1), 6 (T6) and 12 (T12) hours postoperative. RESULTS: The pain score did not differ between morphine and tramadol treatments. Rescue analgesia was administered to one dog in the T treatment group. Serum cortisol did not differ between treatments. CONCLUSION: The extradural administration of morphine or tramadol is a safe and effective method of inducing analgesia in female dogs undergoing ovariohyterectomy. PMID- 22534808 TI - Nerve growth factor with fibrin glue in end-to-side nerve repair in rats. AB - PURPOSE: To determine the effects of end-to-side nerve repair performed only with fibrin glue containing nerve growth in rats. METHODS: Seventy two Wistar rats were divided into six equal groups: group A was not submitted to nerve section; group B was submitted to nerve fibular section only. The others groups had the nerve fibular sectioned and then repaired in the lateral surface of an intact tibial nerve, with different procedures: group C: ETS with sutures; group D: ETS with sutures and NGF; group E: ETS with FG only; group F: ETS with FG containing NGF. The motor function was accompanied and the tibial muscle mass, the number and diameter of muscular fibers and regenerated axons were measured. RESULTS: All the analyzed variables did not show any differences among the four operated groups (p>0.05), which were statistically superior to group B (p<0.05), but inferior to group A (p>0.05). CONCLUSION: The end-to-side nerve repair presented the same recovery pattern, independent from the repair used, showing that the addition of nerve growth factor in fibrin glue was not enough for the results potentiating. PMID- 22534809 TI - Transplantation of mouse embryonic stem cell after middle cerebral artery occlusion. AB - PURPOSE: Stem cell transplantation has been extensively studied as individual therapies for ischemic stroke. The present investigation is an initial effort to combine these methods to achieve increased therapeutic effects after brain ischemia. Cell transplantation may recover massive neuronal loss by replacing damaged brain cells. METHODS: Undifferentiated mouse embryonic stem (mES) cells were used to induce differentiation in vitro into neuron-like cells with good cell viability for use a graft. In this study, middle cerebral artery occlusion (MCAO) was induced in rats using intra-luminal vascular occlusion, and infused mES cells after MCAO. The animals were examined behaviorally using motor and sensory test with neurological assessment. RESULTS: Motor function of the recipients was gradually improved, whereas little improvement was observed in control rats. This result may suggest that the grafted cells have synaptic connection in the recipient brain. Our study revealed that stem cell transplantation can have a positive effect on behavioral recovery and reduction of infarct size in focal ischemic rats. Consequently after euthanasia, rats were histochemically investigated to explore graft survival with green fluorescent protein (GFP). CONCLUSION: The mouse embryonic stem cells may have advantage for use as a donor source in various neurological disorders including motor dysfunction. PMID- 22534810 TI - Prevention of renal ischemia/reperfusion injury in rats using acetylcysteine after anesthesia with isoflurane. AB - PURPOSE: To evaluate the effect of N-acetylcysteine, as a renoprotective agent, when administered early after anesthesia induction, against ischemia/reperfusion injury in rats anesthetized with isoflurane. METHODS: Eighteen male Wistar rats weighing > 300 g were anesthetized with isoflurane. The internal jugular vein and the left carotid artery were dissected and cannulated. The animals were randomly divided into GAcetyl, receiving intravenous N-acetylcysteine, 300 mg/kg, and GIsot, isotonic saline. After 30 minutes, right nephrectomy was performed and the left renal artery was clamped during 45 minutes. The animals were sacrificed after 48 hours and blood samples were taken after anesthetic induction and upon sacrificing of the animals to evaluate blood creatinine. The kidneys were sent for histological analysis. RESULTS: The variation in serum creatinine was 2.33 mg/dL +/- 2.21 in GAcetyl and 4.38 mg/dL +/- 2.13 in GIsot (p=0.074). Two animals presented intense tubular necrosis in GAcetyl, compared to 5 in GIsot. Only GAcetyl presented animals free of tubular necrosis (two) and tubular degeneration (one). CONCLUSION: After renal ischemia/reperfusion, the rats which were given N acetylcysteine presented less variation in serum creatinine and milder kidney injuries than the control group. PMID- 22534811 TI - Effect of N-acetylcysteine in liver ischemia-reperfusion injury after 30% hepatectomy in mice. AB - PURPOSE: Evaluate the effect of N-acetylcysteine in liver remnant after hepatectomy associated to ischemia-reperfusion injury in mice. METHODS: Male adult BALB/c mice, weighing 20-22 g were used. Animals were anesthetized with ketamine (70 mg/kg) and xylazine (10 mg/kg); received N-acetylcysteine (150 mg/kg, H-IR-NAC group) or vehicle (H-IR group). Surgical procedures were performed under 10X magnification. Partial hepatectomy (30%) was followed by ischemia-reperfusion injury (30 minutes of ischemia and 60 minutes of reperfusion). Blood sample and liver tissue were removed before animal was euthanized. AST and ALT were evaluated in blood samples and histomorphological analyses were performed in remnant liver. Groups were compared by Mann-Whitney test, and it was considered significant when p<0.05. RESULTS: Biochemical evaluations showed reduced levels of ALT in NAC group (H-IR-NAC=376 +/- 127 U/l vs H-IR=636 +/- 39 U/l, p=0.023). AST was similar (p=0.456). H-IR group showed hepatic tissue with preserved architecture, large area of steatosis, vascular congestion and rare mitogenic activity. NAC group showed hepatic tissue with small area of steatosis, vascular congestion and elevated mitogenic activity, evidenced by increased binuclear cells (H-IR-NAC=15.88 +/- 0.52 vs H-IR=7.4 +/- 0.37, p<0.001). CONCLUSION: N-acetylcysteine promotes enzymatic and morphological protection against hepatectomy and ischemia-reperfusion injury. PMID- 22534812 TI - The influence of simvastatin in induced peritoneal fibrosis in rats by peritoneal dialysis solution with glucosis 4.25%. AB - PURPOSE: To investigate the influence of using simvastatin on the peritoneal fibrosis induced in rats using peritoneal dialysis solution with glucoses 4.25%. METHODS: Prospective controlled study in 20 non-uremic Wistar rats. The animals received a peritoneal infusion of 10 ml/100 g of peritoneal dialysis solution glucose 4.25% on a daily basis. The animals were divided in two groups: experimental and control. The experimental group received simvastatin 4 mg/kg/d, by a gastric tube. The control group did not receive any drug. The follow-up was 21 and 49 days. At the end, one surgical procedure was performed to get histological samples of visceral and parietal peritoneum. The samples were analyzed using Hematoxylin Eosin and Sirius Red, to evaluate the severity of the fibrosis. RESULTS: The analysis showed that the intensity of the fibrosis, the peritoneal thickness and the cell number in experimental and control groups were not statistically significant different in experimental and control groups. CONCLUSION: The simvastatin do not decrease the intensity of fibrosis on the peritoneal membrane that happens on rats on peritoneal dialysis. PMID- 22534813 TI - The application of percutaneous lysis of epidural adhesions in patients with failed back surgery syndrome. AB - PURPOSE: To investigate the efficacy and the feasibility of application of percutaneous lysis of epidural adhesions in failed back surgery syndrome (FBSS) using a stiff type guide wire and 4F vascular catheter. METHODS: Ninety two patients with FBSS were randomly divided into two groups, the control group (treated by injection dexamethasone only) and percutaneous lysis of epidural adhesions group. Visual analog scale scores (VAS) and therapeutic evaluation were observed in the preoperative, seven days postoperative, one month and six months postoperative. RESULTS: VAS scores for pain were significantly reduced in both groups at seven days. The VAS scores were in controlled group at one month, six months was significantly higher than that in epidural lysis group. However, there was no statistical difference in VAS scores of one month and six months when respectively compared to that of before operation in controlled group. Patients on epidural lysis reported clinical effectiveness rate was 50%. Patients on control was 5.26%, there was a statistical difference between two groups. CONCLUSION: Percutaneous lysis of epidural adhesions by using a stiff type guide wire and 4F vascular catheter is an effective method in the treatment of FBSS and it has a value in clinical application. PMID- 22534814 TI - Randomized phase 2b study of pralatrexate versus erlotinib in patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) after failure of prior platinum-based therapy. AB - INTRODUCTION: Pralatrexate, a folate analogue targeting dihydrofolate reductase, has antitumor activity in non-small-cell lung cancer (NSCLC). This randomized phase 2b trial was designed to further evaluate pralatrexate activity in NSCLC by estimating overall survival (OS) relative to erlotinib in patients with relapsed/refractory disease. METHODS: In 43 centers across 6 countries, patients were randomized 1:1 to receive intravenous pralatrexate 190 mg/m on days 1 and 15 of a 28-day cycle, or oral erlotinib 150 mg/day. The primary objective was to estimate OS in all patients and prespecified subgroups using relative comparisons of hazard ratios (HRs). Secondary endpoints included progression-free survival, response rate, and safety. Key eligibility criteria included: (1) >=1 prior platinum-based therapy, (2) Eastern Cooperative Oncology Group performance status of 0 to 1, and 3) a smoking history of 100 cigarettes or more. RESULTS: A total of 201 patients were randomized. A trend toward improvement in OS favoring pralatrexate was observed with an HR of 0.84 (95% confidence interval: 0.61-1.14) in the intent-to-treat population. This favorable survival result was seen in most prespecified subgroups for pralatrexate. The largest reduction in the risk of death was observed in patients with nonsquamous cell carcinoma (n = 107; HR = 0.65; 95% confidence interval: 0.42-1.0). The most common grade 3 to 4 adverse event in the pralatrexate arm was mucositis (23%). Discontinuation of pralatrexate for any grade of mucositis was 21%. CONCLUSIONS: Pralatrexate demonstrated a trend toward improved survival relative to erlotinib in patients with advanced NSCLC. Future studies should include a mucositis management plan to improve tolerability and maximize treatment benefit. PMID- 22534815 TI - Phase-I/II study of bortezomib in combination with carboplatin and bevacizumab as first-line therapy in patients with advanced non-small-cell lung cancer. AB - BACKGROUND: This study aimed to establish the maximum tolerated dose (MTD) of weekly bortezomib in combination with fixed standard doses of carboplatin and bevacizumab, and to estimate the efficacy (response rate and progression free survival [PFS]) and safety of combination therapy with carboplatin, bortezomib, and bevacizumab as first-line therapy in patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Patients were assigned to three dose levels of weekly bortezomib with the fixed standard doses of carboplatin AUC 6 and bevacizumab (15 mg/kg) every 3 weeks using a standard phase-I design. Bortezomib doses were 1.3 mg/m, 1.6 mg/m, and 1.8 mg/m weekly on day 1 and day 8 of every 3 week cycle. A maximum of six cycles was administered. Patients with complete, partial response or stable disease were continued on single-agent bevacizumab (15 mg/kg every 3 weeks) as maintenance therapy. In phase II, either level III or MTD was administered to evaluate the efficacy and safety of the combination in first line treatment of advanced NSCLC. RESULTS: Sixteen patients were enrolled (three, four, and nine patients in dose level I, II, and III, respectively). There was no predefined dose limiting toxicity in cycle 1 in all 16 patients. The recommended phase-II dose is bortezomib 1.8 mg/m weekly on day 1 and day 8 in combination with carboplatin AUC 6 and bevacizumab 15 mg/kg on every 21-day cycle. Totally 9 patients were treated at the recommended phase-II dose level. The most common treatment related grade-3/4 toxicities during the subsequent cycles were thrombocytopenia (58%), lymphopenia (25%), neutropenia (12%), and diarrhea (25%). The grade-1/2 neuropathy was seen in 7 out of 16 patients (44%). The response rate, PFS, and overall survival in all patients were 37.5% (95%CI 13.8%-61.2%), 5.0 months (95%CI: 3.1-8.4), 9.9 months (95% CI: 8.2-14.1), and among the 9 patients in phase-II portion are 44% (95%CI 15.3%-77.3%), 5.5 months (95%CI: 3.1 2.2) and 10.9 months (95%CI: 8.0-14.1). CONCLUSION: The recommended phase-II dose for this combination is: carboplatin AUC 6, bevacizumab 15 mg/kg on day 1 and bortezomib 1.8 mg/m on day 1 and day 8 on every 21-day cycle. The regimen was very well tolerated with interesting clinical activity in first-line treatment of NSCLC. PMID- 22534816 TI - The efficacy of PET staging for small-cell lung cancer: a systematic review and cost analysis in the Australian setting. AB - INTRODUCTION: This study aimed to establish from the published literature the efficacy of a positron emission tomography (PET)-based strategy for the staging of small-cell lung cancer compared to conventional methods, the potential impact on patient management and outcomes, and cost implications for the Australian health system. METHODS: EMBASE, Current Contents, PubMed, and OVID, databases were searched using relevant search terms. Reference lists of identified studies were examined for additional pertinent papers. Literature review identified 22 relevant studies containing data for 1663 patients. Studies were evaluated regarding the adequacy of pathological or clinical correlation of imaging findings. Efficacy of PET-staging was analyzed. The Medicare benefits schedule was used to compare costs of the two strategies. RESULTS: Published data confirm that PET staging has a sensitivity approaching 100% and specificity exceeding 90%. Data suggest that compared to conventional staging, PET can alter management (including radiotherapy portal changes) in at least 28% of patients, can result in the addition of life-prolonging radiotherapy in 6%, and avert unnecessary radiotherapy with associated toxicity in 9%. PET-based staging costs 1603 Australian dollars (AUD) and conventional staging 1610 AUD per patient. An additional 540,354 AUD may be saved annually through avoidance of unnecessary radiotherapy. CONCLUSIONS: PET-based staging seems superior to conventional staging, and can significantly alter patient management particularly with regard to the inclusion, omission, and portal design of radiotherapy. The initial costs of the two strategies do not seem significantly different. PET may ultimately reduce healthcare costs through avoidance of inappropriate thoracic radiotherapy. The major advantages of PET-staging may, however, lie in averting unnecessary toxicity and in the appropriate addition of thoracic radiotherapy with potential survival gains. PMID- 22534817 TI - Interleukin-17 and prostaglandin E2 are involved in formation of an M2 macrophage dominant microenvironment in lung cancer. AB - INTRODUCTION: Tumor-associated macrophages (TAMs) are divided into M1 and M2 macrophages. M1 macrophages inhibit tumor growth, whereas M2 macrophages promote tumor growth and metastasis. The aim of this study was to examine the possible causes leading to the formation of an M2-macrophage-dominant tumor microenvironment in non-small-cell lung cancer. METHODS: Forty-eight archived lung tumor samples were examined for the expression of interleukin-17 (IL-17) receptors, IL-17 receptor A (IL-17RA) and IL-17 receptor C (IL-17RC), and the number of TAMs using immunohistochemical staining. Twenty fresh lung tumors and matched normal lung tissues were examined for expression of IL-17, cyclooxygenase 2, and prostaglandin E2 (PGE2), using enzyme-linked immunosorbent assay and Western blot analysis. Macrophage-migration assays were performed using fresh lung tumor tissues and IL-17 as chemoattractants. Induction of M2-macrophage differentiation was analyzed using real-time quantitative polymerase chain reaction. RESULTS: TAMs expressed IL-17RA and IL-17RC. Lung tumors expressed higher levels of IL-17, cyclooxygenase-2, and PGE2, compared with normal lung tissues. Lung tumor tissues attracted migration of mouse RAW264.7 macrophages and primary peritoneal macrophages through IL-17, which was mediated by IL-17RA and IL-17RC. IL-17 did not induce either M1- or M2-macrophage differentiation. However, human lung cancer A549 cells strongly induced M2-macrophage differentiation of RAW264.7 macrophages when the two cell lines were cocultured. The inductive factor secreted by A549 cells was identified to be PGE2. CONCLUSIONS: IL-17 recruits macrophages, and PGE2 induces M2-macrophage differentiation, hence the increased levels of IL-17 and PGE2 in lung cancer contribute to the formation of an M2-macrophage-dominant tumor microenvironment. PMID- 22534818 TI - Suicide, negative interaction and emotional support among black Americans. AB - OBJECTIVES: This study is the first to investigate the relationship between perceived emotional support and negative interaction with family members and suicide ideation and attempts among African American and Caribbean black adults. METHOD: Cross-sectional epidemiologic data from the National Survey of American Life and multivariable logistic regression analyses were used to examine the association between perceived emotional support and negative interaction and suicide behaviors among 3,570 African Americans and 1,621 Caribbean blacks age 18 and older. RESULTS: Multivariate analyses found that perceived emotional support was associated with lower odds of suicide ideation and attempts for African Americans and Caribbean blacks. Negative interaction with family was associated with greater odds of suicide ideation among African Americans and Caribbean blacks. Ethnicity moderated the impact of emotional support and negative interaction on suicide attempts; among Caribbean blacks, those who reported more frequent emotional support from their family had a significantly greater reduced risk for suicide attempts than African Americans. The effect of negative interaction on suicide attempts was also more pronounced for Caribbean blacks compared to African Americans. DISCUSSION: Negative interaction was a risk factor for suicide ideation and emotional support was a protective factor for attempts and ideation. These associations were observed even after controlling for any mental disorder. The findings demonstrate the importance of social relationships as both risk and protective factors for suicide and ethnic differences in suicidal ideation and attempts among black Americans. PMID- 22534821 TI - The effect of ozone on the biodegradation of 17alpha-ethinylestradiol and sulfamethoxazole by mixed bacterial cultures. AB - The potential development of antibacterial resistance and endocrine disruption has led to increased research investigating the removal of contaminants from wastewater (WW) such as sulfamethoxazole (SMX) and 17alpha-ethinylestradiol (EE2). These compounds react quickly with ozone (O(3)), thus ozonation during WW treatment may result in their complete removal. Also, O(3) has demonstrated the ability to increase the biodegradability of WW and certain pharmaceuticals, suggesting its potential as a pretreatment to activated sludge (AS, biological treatment). The objective of this study was to determine whether ozonation, conducted at doses lower than commonly applied to treated WW, would lead to an increased biodegradability of SMX and EE2. The results show that after ozonation performed at lab-scale the bacterial mixtures removed 5 % to 40 % more SMX; however, 2 % to 23 % less EE2 was removed, which was attributed to the observed preferential degradation of a by-product of EE2 ozonation. These results suggest that although ozonation, used as a pretreatment, was shown in literature to increase the overall biodegradability of AS as well as some specific antibiotic compounds and a blood lipid regulator, the potential for increased removal of pharmaceuticals seems to be compound-dependent and cannot yet be extrapolated to this entire class of compounds. PMID- 22534820 TI - A single-center experience with eccentric syringomyelia found with pediatric Chiari I malformation. AB - INTRODUCTION: Eccentric syringes associated with Chiari I malformation have received scant attention in the medical literature. Herein, we describe our experience and long-term outcome in patients with this finding. MATERIALS AND METHODS: A retrospective analysis of a Chiari I database was performed. Patients known to have an associated syringomyelia were then further analyzed for the type of syrinx present. When an eccentric syrinx was noted, the symptoms and postoperative course of these patients were analyzed. RESULTS: Of well over 500 operative cases of Chiari I malformation, roughly 70 % (pre-syrinx and minimally dilated central canals were excluded) were found to have an associated syringomyelia. Of these, four patients were found to have an eccentrically positioned syrinx. Three of these cases presented with symptoms referable to the side of the eccentric syrinx. Postoperatively, cases with both a central and eccentrically located syrinx were found to have a greater decrease in the size of the central portion of their syrinx compared to the eccentrically located portion. Symptoms decreased in all patients. CONCLUSIONS: The minority of our patients with hindbrain-induced syringomyelia were found to have an eccentrically located syrinx. Of these, most will have symptoms localized to the abnormal fluid filled cavity, and these may not decrease in size as much as centrally located syringes following posterior fossa decompression. However, all symptoms decreased in those operated. Based on the literature, non-hindbrain-induced syringomyelia is more likely to result in an eccentrically placed syrinx. The mechanism for this is yet to be elucidated. PMID- 22534819 TI - Reduction of conditioned pain modulation in humans by naltrexone: an exploratory study of the effects of pain catastrophizing. AB - The current study tested the hypothesis that conditioned pain modulation is mediated by the release of endogenous opioids with a placebo-controlled (sugar pill) study of naltrexone (50 mg) in 33 healthy volunteers over two counter balanced sessions. Pain modulation consisted of rating of heat pain (palm) during concurrent cold water immersion (foot). Compared to baseline heat pain ratings, concurrent foot immersion lowered pain intensity ratings, which suggests an inhibitory effect, was reduced with naltrexone, suggesting at least partial dependence of inhibition on endogenous opioids. An exploratory analysis revealed that individual differences in catastrophizing moderated the effects of naltrexone; endogenous opioid blockade abolished modulation in subjects lower in catastrophizing while modulation was unaffected by naltrexone among high catastrophizers. The results suggest a role of endogenous opioids in endogenous analgesia, but hint that multiple systems might contribute to conditioned pain modulation, and that these systems might be differentially activated as a function of individual differences in responses to pain. PMID- 22534822 TI - Fluorescent protein vectors for promoter analysis in lactic acid bacteria and Escherichia coli. AB - Fluorescent reporter genes are valuable tools for real-time monitoring of gene expression in living cells. In this study we describe the construction of novel promoter-probe vectors containing a synthetic mCherry fluorescent protein gene, codon-optimized for lactic acid bacteria, divergently linked, or not, to a gene encoding the S65T and F64L variant of the green fluorescent protein. The utility of the transcriptional fusion vectors was demonstrated by the cloning of a single or two divergent promoter regions and by the quantitative evaluation of fluorescence during growth of Lactococcus lactis, Enterococcus faecalis, and Escherichia coli. PMID- 22534823 TI - Biochemical analysis of a highly specific, pH stable xylanase gene identified from a bovine rumen-derived metagenomic library. AB - A metagenomic library was generated using microbial DNA extracted from the rumen contents of a grass hay-fed dairy cow using a bacterial artificial chromosome based vector system. Functional screening of the library identified a gene encoding a potent glycoside hydrolase, xyn10N18, localised within a xylanolytic gene cluster consisting of four open-reading frames (ORFs). The ORF, xyn10N18, encodes an endo-beta-1,4-xylanase with a glycosyl hydrolase family 10 (GH10) catalytic domain, adopts a canonical alpha8/beta8-fold and possesses conserved catalytic glutamate residues typical of GH10 xylanases. Xyn10N18 exhibits optimal catalytic activity at 35 degrees C and pH 6.5 and was highly stable to pH changes retaining at least 85 % relative catalytic activity over a broad pH range (4.0-12.0). It retained 25 % of its relative activity at both low (4 degrees C) and high (55 degrees C) temperatures, however the stability of the enzyme rapidly decreased at temperatures of >40 degrees C. The specific activity of Xyn10N18 is enhanced by the divalent cations Mn(2+) and Co(2+) and is dramatically reduced by Hg(2+) and Cu(2+). Interestingly, EDTA had little effect on specific activity indicating that divalent cations do not function mechanistically. The enzyme was highly specific for xylan containing substrates and showed no catalytic activity against cellulose. Analysis of the hydrolysis products indicated that Xyn10N18 was an endoxylanase. Through a combination of structural modelling and in vitro enzyme characterisation this study provides an understanding of the mechanism and the substrate specificity of this enzyme serving as a starting point for directed evolution of Xyn10N18 and subsequent downstream use in industry. PMID- 22534827 TI - Exposure of Staphylococcus aureus to silver(I) induces a short term protective response. AB - The Ag(I) ion has well established anti-bacterial and antifungal properties. Exposure of Staphylococcus aureus to MIC(80) AgNO(3) (3 MUg/ml) lead to an increase in the activity of superoxide dismutase, glutathione reductase and catalase at 30 min but activity declined by 60 min. In addition, exposure of cells to this metal ion for 1 h lead to increased expression of a number of proteins such as elongation factors Ts, Tu and G, fructose-bisphosphate aldolase and triosephosphate isomerase but their expression declined following 4 h exposure. ATP binding cassette transporter protein and oligoendopeptidase F showed increased expression at 4 h. While Ag(I) is a potent antimicrobial agent this work demonstrates that S. aureus can mount a short-term protective response to exposure to the metal ion but that this is eventually overcome. PMID- 22534826 TI - A new algorithm to predict warfarin dose from polymorphisms of CYP4F2 , CYP2C9 and VKORC1 and clinical variables: derivation in Han Chinese patients with non valvular atrial fibrillation. AB - Few pharmacogenomic dosing regimens of warfarin have been developed for Chinese patients with non valvular atrial fibrillation (NVAF). The objective of this study was to develop a new algorithm by polymorphisms of CYP2C9, VKORC1 and CYP4F2 to predict the daily stable dose of warfarin in Chinese patients with NVAF. A total of 325 Chinese NVAF patients on stable dose of warfarin with a target international normalised ratio of 1.5 to 3.0 were recruited and divided randomly into two cohorts. CYP2C9*3, VKORC1-1639, VKORC1 1173 and CYP4F2 were detected by ligase detection reaction method. The new algorithm was developed with multivariate linear regression in cohort 1 (260 patients) and assessed with Pearson Correlation Analysis (PCA) in cohort 2 (65 patients). From 260 enrolled patients, the model (R2 = 51.7%) was developed as: Dose = 3.47 - 0.022 (AGE) + 0.017 (WT) + 0.189 (PTE) - 0.283 (beta-blocker) - 0.471 (AMIO) - 0.586 (CYP2C9 *1/*3) - 0.296 (VKORC1 CT) - 0.648 (VKORC1 TT) + 0.219 (CYP4F2 TT). PCA displayed that the algorithm was good (r = 0.658). The residual plots revealed that the predicted doses by the algorithm tend to be overestimated when lower doses were administered to patients and to be underestimated in higher doses. The algorithm developed by us might predict warfarin dose used by Chinese NVAF patients. PMID- 22534825 TI - Breaking the Law of Valgus: the surprising and unexplained prevalence of medial patellofemoral cartilage damage. AB - OBJECTIVES: To compare the prevalence of medial and lateral patellofemoral (PF) cartilage damage in three large osteoarthritis (OA) studies and determine the relationship of this damage to varus, neutral and valgus knee alignment. METHODS: In the Boston OA of the Knee, Framingham OA and Multicenter OA studies, MRIs were read for cartilage morphology at the medial and lateral patella and trochlea femoris using Whole-Organ MRI Scores (WORMS). WORMS scores >=2 (any cartilage defect), >=3 (areas of partial thickness loss), >=4 (diffuse partial thickness loss) and >=5 (extensive full thickness loss) were all variously considered as thresholds to identify damage that may indicate OA. Full-limb radiographs were measured for mechanical alignment, and varus (<-2 degrees ), neutral (-2 degrees to 2 degrees ) and valgus (>2 degrees ) knees were identified. RESULTS: The prevalence of medial PF cartilage damage exceeded that of lateral damage in all three studies and according to nearly every threshold. Only among severely involved knees (WORMS >=4 or >=5) did the prevalence of lateral PF cartilage damage approximate that of medial damage. The high prevalence of medial PF damage persisted in all strata of knee alignment. Even among knees with valgus alignment, the prevalence of lateral PF cartilage damage equalled or surpassed that of medial PF damage only when the threshold was specific to severely involved knees. CONCLUSIONS: Medial PF cartilage damage is at least as prevalent within these older adult populations as lateral PF cartilage damage. PMID- 22534828 TI - TIAF1 self-aggregation in peritumor capsule formation, spontaneous activation of SMAD-responsive promoter in p53-deficient environment, and cell death. AB - Self-aggregation of transforming growth factor beta (TGF-beta)1-induced antiapoptotic factor (TIAF1) is known in the nondemented human hippocampus, and the aggregating process may lead to generation of amyloid beta (Abeta) for causing neurodegeneration. Here, we determined that overexpressed TIAF1 exhibits as aggregates together with Smad4 and Abeta in the cancer stroma and peritumor capsules of solid tumors. Also, TIAF1/Abeta aggregates are shown on the interface between brain neural cells and the metastatic cancer cell mass. TIAF1 is upregulated in developing tumors, but may disappear in established metastatic cancer cells. Growing neuroblastoma cells on the extracellular matrices from other cancer cell types induced production of aggregated TIAF1 and Abeta. In vitro induction of TIAF1 self-association upregulated the expression of tumor suppressors Smad4 and WW domain-containing oxidoreductase (WOX1 or WWOX), and WOX1 in turn increased the TIAF1 expression. TIAF1/Smad4 interaction further enhanced Abeta formation. TIAF1 is known to suppress SMAD-regulated promoter activation. Intriguingly, without p53, self-aggregating TIAF1 spontaneously activated the SMAD-regulated promoter. TIAF1 was essential for p53-, WOX1- and dominant-negative JNK1-induced cell death. TIAF1, p53 and WOX1 acted synergistically in suppressing anchorage-independent growth, blocking cell migration and causing apoptosis. Together, TIAF1 shows an aggregation-dependent control of tumor progression and metastasis, and regulation of cell death. PMID- 22534829 TI - Passive control of cell locomotion using micropatterns: the effect of micropattern geometry on the migratory behavior of adherent cells. AB - Directed cell migration is critical to a variety of biological and physiological processes. Although simple topographical patterns such as parallel grooves and three-dimensional post arrays have been studied to guide cell migration, the effect of the dimensions and shape of micropatterns, which respectively represent the amount and gradient of physical spatial cues, on cell migration has not yet been fully explored. This motivates a quantitative characterization of cell migration in response to micropatterns having different widths and divergence angles. The changes in the migratory (and even locational) behavior of adherent cells, when the cells are exposed to physical spatial cues imposed by the micropatterns, are explored here using a microfabricated biological platform, nicknamed the "Rome platform". The Rome platform, made of a biocompatible, ultraviolet (UV) curable polymer (ORMOCOMP), consists of 3 MUm thick micropatterns with different widths of 3 to 75 MUm and different divergence angles of 0.5 to 5.0 degrees . The migration paths through which NIH 3T3 fibroblasts move on the micropatterns are analyzed with a persistent random walk model, thus quantifying the effect of the divergence angle of micropatterns on cell migratory characteristics such as cell migration speed, directional persistence time, and random motility coefficient. The effect of the width of micropatterns on cell migratory characteristics is also extensively investigated. Cell migration direction is manipulated by creating the gradient of physical spatial cues (that is, divergence angle of micropatterns), while cell migration speed is controlled by modulating the amount of them (namely, width of micropatterns). In short, the amount and gradient of physical spatial cues imposed by changing the width and divergence angle of micropatterns make it possible to control the rate and direction of cell migration in a passive way. These results offer a potential for reducing the healing time of open wounds with a smart wound dressing engraved with micropatterns (or microscaffolds). PMID- 22534830 TI - First clinical experience with integrated whole-body PET/MR: comparison to PET/CT in patients with oncologic diagnoses. AB - The recently introduced first integrated whole-body PET/MR scanner allows simultaneous acquisition of PET and MRI data in humans and, thus, may offer new opportunities, particularly regarding diagnostics in oncology. This scanner features major technologic differences from conventional PET/CT devices, including the replacement of photomultipliers with avalanche photodiodes and the need for MRI-based attenuation correction. The aim of this study was to evaluate the comparability of clinical performance between conventional PET/CT and PET/MR in patients with oncologic diseases. METHODS: Thirty-two patients with different oncologic diagnoses underwent a single-injection, dual-imaging protocol consisting of a PET/CT and subsequent PET/MR scan. PET/CT scans were performed according to standard clinical protocols (86 +/- 8 min after injection of 401 +/- 42 MBq of (18)F-FDG, 2 min/bed position). Subsequently (140 +/- 24 min after injection), PET/MR was performed (4 min/bed position). PET images of both modalities were reconstructed iteratively. Attenuation and scatter correction as well as regional allocation of PET findings were performed using low-dose CT data for PET/CT and Dixon MRI sequences for PET/MR. PET/MR and PET/CT were compared visually by 2 teams of observers by rating the number and location of lesions suspicious for malignancy, as well as image quality and alignment. For quantitative comparison, standardized uptake values (SUVs) of the detected lesions and of different tissue types were assessed. RESULTS: Simultaneous PET/MR acquisition was feasible with high quality in short acquisition time (<= 20 min). No significant difference was found between the numbers of suspicious lesions (n = 80) or lesion-positive patients (n = 20) detected with PET/MR or PET/CT. Anatomic allocation of PET/MR findings by means of the Dixon MRI sequence was comparable to allocation of PET/CT findings by means of low-dose CT. Quantitative evaluation revealed a high correlation between mean SUVs measured with PET/MR and PET/CT in lesions (rho = 0.93) and background tissue (rho = 0.92). CONCLUSION: This study demonstrates, for what is to our knowledge the first time, that integrated whole-body PET/MR is feasible in a clinical setting with high quality and in a short examination time. The reliability of PET/MR was comparable to that of PET/CT in allowing the detection of hypermetabolic lesions suspicious for malignancy in patients with oncologic diagnoses. Despite different attenuation correction approaches, tracer uptake in lesions and background correlated well between PET/MR and PET/CT. The Dixon MRI sequences acquired for attenuation correction were found useful for anatomic allocation of PET findings obtained by PET/MR in the entire body. These encouraging results may form the foundation for future studies aiming to define the added value of PET/MR over PET/CT. PMID- 22534831 TI - Differences in association between birth parameters and blood pressure in children from preschool to high school. AB - We aimed to investigate the association between birth parameters with blood pressure (BP) among preschool- and school-aged children. Two separate childhood datasets were used: (1) 1295 children aged 3-6 years were examined during 2007 2009; and (2) 1741 and 2353 children aged 6 and 12 years, respectively, were examined during 2004-2006. Birth parameter data were obtained from parental records. BP was measured using standard protocols. Among 6-year-old children, each 1 kg decrease in birth weight was associated with a 1.33- and 1.20-mm Hg higher systolic and diastolic BP, respectively, after multivariable adjustment. In 6-year-old children, a decrease of 1 week in gestational age was independently associated with a 0.33- and 0.37-mm Hg higher systolic and diastolic BP, respectively. Six-year-old children in the low birth weight category (<= 2499 g) versus those in the normal/high birth weight category (>= 2500 g) had significantly higher systolic BP (P<0.0001). Girls in the low birth weight category versus those in the normal/high weight category had higher systolic BP (P=0.02). Significant associations were not observed among preschool-aged children and preadolescents. Birth weight and gestational age were strongly associated with BP among 6-year-old children, particularly girls, but not among preschoolers or preadolescents. PMID- 22534833 TI - Production of novel polymer monolithic columns, with stationary phase gradients, using cyclic olefin co-polymer (COC) optical filters. AB - Polymer monolithic columns with controlled surface ligand density, providing stationary phase gradients within monolithic capillary columns, have been developed using photo-grafting through optical filters. Utilising commercially available cyclic olefin co-polymer (COC) films, the production of an optical filter capable of attenuating UV irradiation, in a tailored manner, was investigated. This novel optical filter was successfully applied to the surface modification of poly(BuMA-co-EDMA) monolithic columns in a multi-step grafting procedure. Fabricated columns were subjected to scanning capacitively coupled contactless conductivity (sC(4)D), to determine the distribution of the grafted functional groups, axially along the column. Further modification to produce a chelating stationary phase gradient of iminodiacetic acid (IDA) was demonstrated. To demonstrate the distribution of the IDA sites, a metal cation (Cu(2+)) was complexed to the IDA forming a chelate. Upon the formation of a complex of IDA with Cu(2+), an overall drop in conductive response was observed. The COC optical filter was also used in the fabrication of a grafted gradient of strong cation exchanger (SCX), sulphopropyl methacrylate (SPM) upon a polymer monolith, demonstrating the broader applicability of such a filter. PMID- 22534832 TI - Compression anastomoses in colorectal surgery: a review. AB - The main serious risks of anastomotic construction in the colon and rectum include dehiscence and stricture formation. There is a resurgence of interest in sutureless anastomoses formed by compression elements since the introduction of shape memory alloy (SMA) systems, which evoke minimal early inflammatory response whilst maintaining anastomotic integrity. Currently, the most commonly used SMA is the nickel-titanium (NiTi) alloy that is highly biocompatible, returning to its pre-deformed stable (austenite) shape under different mechanical and thermal loads for use in humans. Pre-clinical data for shape memory alloy systems in colorectal anastomoses are limited, but it appears to be safe in porcine and canine models with limited leakage and reduced stricture formation. There does not appear to be any difference in tissue biochemistry of inflammatory markers when compared with conventional stapled techniques, although the few studies available show a markedly reduced early inflammatory response at the anastomotic site with the NiTi device. The majority of the clinical data concerning compression anastomoses are derived from the biofragmentable anastomotic ring device. This device has fallen out of use because of reported leaks, instrumental failure and problems with device expulsion. A novel SMA device, the NiTi anastomotic ring, permits construction of a low rectal anastomosis construction during open or laparoscopic procedures. The preliminary data demonstrate a safety comparable to conventional staple technology. This device also provides the potential of benefit of reduced anastomotic inflammation, because the compression ring results in direct serosa-to-serosa (or alternatively serosa-to-muscularis propria) apposition without the persistence of residual foreign material. This type of construction could lead to a reduced incidence of early anastomotic leakage and/or the development of anastomotic stenosis. Randomized clinical trials employing a NiTi arm for elective, emergency and high-risk colorectal anastomoses are required to determine its indications and clinical profile as well as to assess whether such technology may selectively obviate the need for proximal diversion in low colorectal anastomoses. PMID- 22534834 TI - [The role of evaluation in decision-making in the management of health services]. AB - The management of health services is a complex administrative practice due to the breadth of the field of health and the need to reconcile individual, corporate and collective interests that are not always convergent. In this context, the evaluation needs to have specific characteristics in order to fulfill its role. The scope of this study was to establish the characteristics that the evaluation for the management of health services should have to contribute to decision making. Usefulness, opportunity, feasibility, reliability, objectivity and directionality represent the set of principles upon which the evaluation should be based. Evaluations should lead to decisions that guarantee not only their efficiency and effectiveness but also their implementation. The evaluation process should ensure that decisions involve all stakeholders in order to render the implementation of decisions feasible, and take into account the health needs of the population and the goals set for the services. The scope of this article is to elicit a debate among different stakeholders in the evaluation in the hope that it can contribute to the reflection on the real usefulness of evaluations in which the political component in management has been increasingly prevalent. PMID- 22534835 TI - [Intelligence in governance for support in decision-making]. PMID- 22534836 TI - [Meta-evaluation of health management: challenges for "new public health"]. PMID- 22534837 TI - [Regarding the impasses of the uses of evaluation for management: it is not necessary to invent, nor is it enough to simplify]. PMID- 22534838 TI - [The authors reply. The role of evaluation for decision-making in the management of health services]. PMID- 22534839 TI - [Methodology for construction of a panel of indicators for monitoring and evaluation of unified health system (SUS) management]. AB - This study sought to develop methodology for the construction of a Panel for the Monitoring and Evaluation of Management of the Unified Health System (SUS). The participative process used in addition to the systematization conducted made it possible to identify an effective strategy for building management tools in partnership with researchers, academic institutions and managers of the SUS. The final systematization of the Panel selected indicators for the management of the SUS in terms of Demand, Inputs, Processes, Outputs and Outcomes in order to provide a simple, versatile and useful tool for evaluation at any level of management and more transparent and easier communication with all stakeholders in decision-making. Taking the management of the SUS as the scope of these processes and practices in all normative aspects enabled dialog between systemic theories and those which consider the centrality of the social actor in the decision making process. PMID- 22534840 TI - [Evaluation of Management for Health Planning in municipalities in the State of Santa Catarina]. AB - This article presents the results of the evaluation of management for health planning in municipalities in the Southern Brazilian State of Santa Catarina. An evaluation model developed and validated from the theoretical framework for health planning was applied. It was complemented by guidelines for organization and operation of PlanejaSUS (national survey of 2007) and definitions of municipal responsibilities defined in the Management Pact. The evaluation matrix has two dimensions: the guarantee of resources and the guarantee of internal and external relations, with six sub-dimensions and twelve indicators. Data were collected via an electronic form developed by FormSUS, forwarded to and answered by 100% of the municipalities of Santa Catarina. The "good performance" classification was awarded in 113 municipalities in the overall evaluation, 96 in the dimension of guarantee of resources, and 43 in the dimension of guarantee of relations. The percentage classified as "poor" was high for some indicators, especially human resources and interaction with the population. The results suggest the need to reinforce actions linked to the dimension of guarantee of relations. PMID- 22534841 TI - [Municipal public health spending in the state of Pernambuco, Brazil, from 2000 to 2007]. AB - In order to assess the impact of macro-political measures implemented in the latter half of the 1990s on the increase in public spending on health and the possible reduction in allocation inequity, a descriptive, quantitative, cross sectional study was carried out involving 184 municipalities in the state of Pernambuco, Brazil. Data from the Public Health Budget Information System was used, with the selected indicator being spending on health per inhabitant under the responsibility of the municipality. The correlations of this variable with the municipal Human Development Index, population size and value of the municipal budget per capita were analyzed. It was seen that, although the mean increase in municipal spending on health is 190.76%, the value per capita has remained relatively low - at around R$183.79 - which is below the national and macro regional averages. Both spending on health per capita and growth percentages are distributed irregularly among health regions as well as among municipalities within a single region. In conclusion, there is marked allocation inequity among municipalities with regard to the distribution of public resources for health, despite the macro-political measures adopted to reduce this inequity. PMID- 22534842 TI - [Evaluation of the capability of decentralized management of epidemiological surveillance in the state of Bahia]. AB - Evaluative research into the capability of decentralized management of epidemiological vigilance (EV) was conducted in the operational, organizational and sustainable dimensions in the state of Bahia, Brazil. The quantitative approach was used in the construction of a baseline, with primary data obtained through an online questionnaire answered by thirty-eight municipal EV managers. In the qualitative approach to analyze the context and assess the management capability of municipalities in two case studies, techniques adapted to the analysis of discursive practices were used. This was done through semi-structured interviews with managers of regional and municipal government, health workers and representatives of the municipal health council. The case studies showed that the municipality with enhanced management capability is that in which the manager has the greatest potential of using the resources of his position, in addition to his ability to control, negotiate and coordinate with other actors. Due to decentralization of EV, considering the shared nature of management between the three spheres of government, there is a marked variation in the management capability of municipalities, determined by social, economic, political inequalities and management mechanisms adopted. PMID- 22534843 TI - [Identification and characterization of constituent elements of an intervention: pre-evaluation of the "ParticipaSUS" policy]. AB - This article presents the results of a pre-evaluation of the National Policy of Strategic and Participative Management of the Unified Health System (ParticipaSUS). It involved a feasibility study conducted between October 2010 and March 2011 with Federal Management and the Strategic and Participative Management Department/Ministry of Health as the unit of analysis. Document analysis was performed and consensus meetings were held with professionals of the SSPM/MH and academic area. A logical model and analysis and judgment matrix with criteria, indicators, standards, data sources and cut-off points was prepared. A description of the intervention elicited discussion on concepts, principles, guidelines and actions. The consensus was that the principles and guidelines prioritized the 'Support to Participative Management' component. The focal point for elaboration of the logical model was action at federal level on each component, as official documents failed to list them. The ParticipaSUS policy is an intervention open to evaluation, albeit its plausibility has been established. The pre-evaluation proved to be appropriate and better understood by professionals, with clearer definition of objectives and goals, while duly highlighting priority areas for future evaluation. PMID- 22534844 TI - [SUS management and monitoring and evaluation practices: possibilities and challenges for building a strategic agenda]. AB - This paper deals with the challenges involved in institutionalizing Monitoring and Evaluation practices within the scope of management of the Brazilian Unified Health System (SUS), based on the creation of a strategic agenda. This is structured around actions by the Federal Administration, from the perspective of defining the scope of the federative relationship. A summarized literature review is thus presented, placing into context the current SUS management process, which is based on the Pact for Health as well as theoretical and operational aspects inherent to monitoring and evaluation practices. The approach related to the strategic agenda highlights the creation of mechanisms that underpin the political and institutional decision, namely the creation of financial incentives and the development of technical mechanisms. These include organizational strategies for qualifying management teams and conducting studies and research and the dissemination of strategic information. These processes are based on the concept of providing for the management specificities in the different spheres of management based on a broad cooperation process involving teaching and research institutions and international organizations as well as the managers themselves. PMID- 22534845 TI - [Input on monitoring and evaluation practices of government management of Brazilian Municipal Health Departments]. AB - What do the leaders of the Municipal Health Service (SMS) report and say about the systematic monitoring and evaluation of their own government management? The purpose of this paper is to provide input for the formulation of plausible hypotheses about such institutional processes and practices based on information produced in an exploratory study. This is a multiple case study with quantitative and qualitative analysis of answers to a semi-structured questionnaire given to government officials of a systematic sample of 577 Municipal Health Services (10.4% of the total in Brazil). They were selected and stratified by proportional distribution among states and by the population size of municipalities. In general, it shows that approximately half of the respondents use information from Health Monitoring Evaluations to orient decision-making, planning and other management approaches. This proportion tends to decrease in cities with smaller populations. There are specific and significant gaps in financial, personnel and crisis management. The evidence from the hypotheses highlights the fact that these processes are still at an early stage. PMID- 22534846 TI - [Evaluation of performance of health systems: a model for analysis]. AB - This paper presents a review of the Dimension Matrix for Evaluation of the Brazilian Health System that was initially developed in 2003, as well as a conceptual update of some of the sub-dimensions for the evaluation of health service performance, namely effectiveness, access, efficiency and appropriateness of health care. It also describes the indicator selection process as well as the results obtained in each performance dimension. The behavior of the indicators used to assess the performance of health services in Brazil, with respect to each sub-dimension, was not uniform. Areas of marked improvement were found in indicators that are influenced by activities in the field of primary care. The most significant improvements were seen in the sub-dimensions of Effectiveness and Access. With respect to the Efficiency of health services, situations of high efficiency coexist with others with substandard performance. The performance of health services in the sub-dimension of Appropriateness of Health Care was the lowest of all indicators. PMID- 22534847 TI - [Scientific output on health systems management: a study carried out in Web space (1987-2009)]. AB - The objective of this study is to characterize Brazilian/Latin American scientific output in the "field" of health and on health systems management specifically, based on work registered on the Lilacs database in the period from 1987 to 2009. The terms "health management" and "health systems", identified in the BVS/Bireme "Health Science Descriptors" were used and 1,544 works were identified, of which 298 were selected (19.3%). The reading and analysis of these abstracts enabled the identification of a set of variables processed with the use of Epi-Info software, such as: year of publication of the work; type of document; object of the study; type of study; theoretical bases and methodological approach/nature. The results point to an irregular, albeit increasing trend, in the volume of the output in the area from the year 1988 onwards, with the emergence of studies and research in sub-areas that reveal the influence of the process of construction of the Brazilian Unified Health System in the 1990s and thereafter. The fact that very few abstracts made reference to the theoretical bases used is noticeable. From a methodological point of view it is seen that when they are declared in abstracts, descriptive studies with a qualitative approach are predominant. PMID- 22534848 TI - [Evaluation of the plenitude of epidemiological variables of the Information System on Mortality of women with deaths from breast cancer in the Southeast Region: Brazil (1998 - 2007)]. AB - The study evaluates the data from the Mortality Information System in Espirito Santo, southeastern Brazil in the period from 1998 to 2007. It is a descriptive analytic study based on secondary data. The variables of sex, age, race/color, level of education and marital status in women who died of breast cancer were evaluated. The scores used were excellent (variable shows less than 5% of incomplete coverage), good (5% to 10%), fair (10% to 20%), poor (20% to 50%) and very poor (50% or higher). The linear trend equations were calculated using SPSS, version 15.0 for non-plenitude over time. It is essential to include in the education of health professionals, especially in undergraduate and postgraduate studies in medicine, content that develops skills and competencies for systematic registration of epidemiological data, so they can be included in the health information systems. PMID- 22534849 TI - [Reliability of birth certificates as a source of information on congenital defects in the City of Sao Carlos, Sao Paulo, Brazil]. AB - The reliability of the information on congenital defects listed in birth certificates of the Live Birth Information System (SINASC) in the City of Sao Carlos, Sao Paulo, Brazil, was evaluated. A descriptive study that reviewed all 15,249 birth certificates from 2003 to 2007 compared the data with information from medical records and death certificates. Errors in accuracy and precision, mainly related to the description of the anomaly when it was transcribed from medical records to the birth certificates, in addition to coding and the input to SINASC, diminished the reliability of the birth certificates as a source of information on congenital defects. The results suggested that the involvement of the Municipal Health Department is essential to improve SINASC, because this is the location of the coding and input system, and training of the professionals who fill out the birth certificates. With guidance on the importance and function of the birth certificates, SINASC can become an excellent monitoring and surveillance system for congenital defects. PMID- 22534850 TI - [Analysis of information sources about breast self examination available on the Internet]. AB - OBJECTIVE: To analyze the information about breast self examination available on the Internet. METHODS: A descriptive documental study was performed via a search on the Google(r) and Yahoo(r) websites using the phrase "breast self examination" in Portuguese, and the first 50 results from each site were analyzed using the criteria of the American Medical Association and Health on the Net. RESULTS: 68 sites were selected and analyzed. Most of the sites were in the commercial domain, six were governmental sites and five were Portuguese sites. More than half had restrictions regarding criteria of authority and authorship; 61% did not have contact details and 52.94% considered breast self exam as part of a set of measures; 26.47% had correct and complete evidence-based content; 33.82% had context references. Government WebPages of health or professional institutions had restrictions regarding content or presentation. CONCLUSIONS: The information about breast self exam is heterogeneous. Only a small number of websites were concerned about quality criteria, both in terms of construction and content. The bulk of the information available is not evidence-based and there is potentially dangerous information for the patient. It is necessary to improve the quality of websites dealing with breast self exam. PMID- 22534851 TI - [The Impact of Prohibition on drinking and driving in Belo Horizonte in the State of Minas Gerais]. AB - The scope of this paper is to present comparative data on drinking and driving behavior among drivers in Belo Horizonte in the State of Minas Gerais, in the period from 2005 to 2009, evaluating the impact of Law No. 11.705 (Prohibition), dated June 6, 2008. Data regarding prevalence of this behavior, collected at Sobriety Checkpoints (internationally used methodology) were analyzed using representative samples obtained from drivers on different public roads with intensive traffic in Belo Horizonte (2005-2009), thus permitting analysis of the impact of the new law. In 2008, the data showed a reduction of approximately 50% in the prevalence of individuals driving with any level of alcohol in the blood, when compared to 2007, after the change in legislation. This study showed that the impact caused by Law No.11.705 was marked in the sense of modifying the behavior under scrutiny. However, other control measures need to be added to the current legislation, in order to obtain a continuous reduction of drinking and driving behavior, thereby fostering a culture of sobriety on the road. PMID- 22534852 TI - [Vocational Health Schools (ETSUS) in Brazil: regulation of the integration of teaching-service-administrative sustainability of ETSUS]. AB - The scope of this study was to discuss the administrative sustainability of Brazil's Vocational Health Schools (ETSUS) based on the principle of teaching and service integration, which brings a new dimension to healthcare work as yet unregulated by Brazilian public administration. It was a qualitative study using case study methodology. The research involved a semi-structured questionnaire given to ETSUS managers addressing institutional, administrative, and work management aspects. The sample was composed of 6 ETSUS that belong to the Network of Vocational Health Schools (RET-SUS). The ETSUS showed centralized planning and management, and decentralized implementation of their core activities. The majority did not have administrative autonomy and relied heavily on funding from the federal government. According to ETSUS managers, the lack of regulation of teaching activities by civil servants weakens the management of ETSUS. The ETSUS have managerial problems related to teaching-service integration, which has to be regulated in order to guarantee the sustainability of these schools and avoid conflicts with Brazilian legislation. PMID- 22534853 TI - ["The vein is missed": meanings of intravenous therapy practice in Neonatal Intensive Care Unit]. AB - Intravenous Therapy (IVT) is an important item among the necessary technologies for the survival of high-risk new-born babies. However, it is also a source of pain, stress and risk of serious complications. This article aims to assess the meanings of IVT as ascribed by care teams and to discuss the reflection of such meanings on the attention to new-born babies. The article, with a theoretical referential in Cultural Anthropology, presents an ethnographic case study carried out in a Neonatal Intensive Care Unit of municipal administration in Rio de Janeiro. Subjects were nine nurses, four doctors, and three nurse assistants. Data collection was carried out with a semi-structured interview and participative observation. The qualitative analysis was performed using the method of interpretation of the senses. Meanings, interweaved with the cultural network, showed that IVT practice is often reduced to peripheral puncture techniques, bringing on a series of complications for high risk new-born babies and intense emotional waste for the professional team and the family. Re signification of IVT practice will only be possible with a critical analysis of the cultural patterns it is now based on. PMID- 22534854 TI - [Critical epidemiology: for a theoretical praxis of knowing how and when to act]. AB - Some of the most significant questions related to the concept of health present in contemporary discursive practices, such as its relation with the normative capacity of the individuals when faced with the institution of new social and/or biological norms, are initially reexamined in this paper. Subsequently, the dialectical model of the social determination process of health-disease is examined in the context of the contradictory processes of the social reproduction system as in the scope of the bio-psychological nexuses on outcome and its historically specific ways of life. The contradictory dimensions of the capitalist social reproduction process and their techno-economic logic of production and consumption are then analyzed, considering their respective impacts on the living and health conditions of citizens and communities. Lastly, the importance of the emancipative praxis for epidemiology in the achievement of well-being and quality of life are considered and the need for commitment in the construction of a new paradigm for the public health field in its praxis of knowing how and when to act are emphasized. PMID- 22534855 TI - [Oral health and access to dental care services in relation to the Health Necessities Index: Sao Paulo, Brazil, 2008]. AB - The Health Department of Sao Paulo, Brazil, has developed a Health Necessities Index (HNI) to identify priority areas for providing health assistance. In 2008, a survey of the status of oral health was conducted. The objective of this ecological study was to analyze the status of oral health in relation to the HNI. The variables, stratified by the age of 5, 12 and 15 years old were: percentage of individuals with difficulty of access to dental care services; DMFT and DMFS; prevalence of the need for tooth extraction and treatment of dental caries. Data were analyzed for the 25 Health Technical Supervision Units (HTS). The Statistical Covariance Test was used as well as the Pearson correlation coefficient and linear regression model. A positive correlation was observed between high scores of the HNI and difficulty of access to services. In the HTS with high scores of HNI a higher incidence of dental caries was observed, a greater need for tooth extractions and low caries-free incidence. In order to improve health conditions of the population it is mandatory to prioritize actions in areas of social deprivation. PMID- 22534856 TI - [Narratives of intimate partner violence practiced against women]. AB - Research was conducted with women aged 15 to 49 living in an economically vulnerable area of the Brazilian state capital on the experience of victims of Intimate Partner Violence (IPV). The study adopted a qualitative technique called Collective Subject Discourse. During the interviews in their homes between February and July, 195 women reported incidents of violence throughout their lives. The discourses were grouped by similar violence using the CSD technique and organized into 7 major categories based on 395 key words; i) IPV Engineering (N = 114; 58.5%); ii) Rape of vulnerable sex (N = 77; 39.5%); iii) Silent or silenced violence (N = 43; 21%); iv) Years of Suffering (N = 43; 21%); v) New time despite the suffering (N = 39; 20%); vi) Talking about violence (N = 35; 18%); Violence is a language (N = 34; 17.4%). Three reports with the highest prevalence, entitled "IPV Engineering," are presented in full in this work. The narratives of violence revealed show the strength of vulnerability and abuse suffered by women and the existence of multiple dynamics of violence in intimate affective relationships. PMID- 22534857 TI - Intimate partner violence against women and healthcare in Australia: charting the scene. AB - Intimate partner violence against women is a common problem in all countries and generates a challenging agenda for the health sector. Exchanging experiences between different countries, specifically strategies to respond to this problem, can constitute a tool for stimulating debate and promoting reflection. The scope of this article is to present and reflect on aspects of the Australian health sector response to intimate partner violence, and chart the scenario that surrounds this issue. We draw on a range of methods, combining a literature review and a dialogue with different stakeholders and site visits. We describe historical, contemporary and conceptual aspects of healthcare responses to intimate partner violence in Australia. Further we present some of the strategies, public policies and innovative projects that have been developed in this field in Australia. Some of the strategies include: screening vs. case finding; primary care approaches for dealing with all family members; respect for diversity; and new randomized trials aiming for sustainable health system change for enhanced health professional care of people experiencing intimate partner violence. Despite the limitations of this approach to such a complex theme, we hope to stimulate thinking and discussion. PMID- 22534859 TI - [Perceptions of healthcare providers toward body art: adornment or stigma?]. AB - Nowadays, body art is widespread, especially among adolescents. This qualitative study seeks to assess whether the use of body art interferes with how nursing assistants care for hospitalized adolescents and to identify factors that influence the perceptions of these health care providers. Nursing assistants working in an adolescent-specific ward were interviewed. After the analysis, dominant themes emerged from the narratives, allowing for a better understanding of how nursing assistants perceive tattoos and piercing. Some themes were recurrent, especially the association of body art with deviant behavior, erotic appeal, consumerism, courage, health risks, and psychic disorders. Religion and family values prevail over professional knowledge in how body marks are perceived. It may thus be inferred that a negative attitude toward body art is directly related to quality of care. The number of marks, their location, their type, and the definite/temporary character of tattoos and piercing interfere with the providers' interpretation. However, piercing and tattoos are important semiological tools and must be included in the script for the evaluation of adolescents. PMID- 22534858 TI - [Bioethics and public health: epistemological convergences]. AB - This is a theoretical discussion about the epistemological statute of bioethics based on its convergences with public health, linked as scientific areas that came from the context of the second epistemological rupture, which questioned the critique to common sense inherent in modern science. The reapproximation with common sense in the second rupture means considering the determinants of environment and subjectivity in the methodology. Emerging from the second rupture, public health and bioethics include the social and subjective determinants in their analysis, with an enlarged and complex vision of human health and human actions involving environment, life and health. This requires a transdisciplinary focus in their approaches. What is the meaning of these premises for the epistemological statute of bioethics in its convergence with public health? As ethics, bioethics needs to be critical, but not aprioristic. The criticism of bioethics needs to come from the facticity of the social determinants expressed by the health iniquities. The only way to integrate criticism and facticity is hermeneutics, interpreting the significances constructed in the reality and become critical therefrom. This is the epistemological statute appropriate to bioethics in its convergence with public health. PMID- 22534860 TI - [Reasons and prevalence of body image dissatisfaction in adolescents]. AB - OBJECTIVE: To investigate the prevalence of body image (BI) dissatisfaction in adolescents. The study enrolled 641 adolescents aged 11 to 17 from the town of Saudades, Santa Catarina, Brazil. The prevalence of BI dissatisfaction was 60.4% (males = 54.5%, females = 65.7%; p < 0.05). Boys were more likely to wish to increase the size of their body silhouette (26.4%) while girls wished to reduce theirs (52.4%). Adolescents from urban areas manifested greater prevalence of BI dissatisfaction and were more likely to want to reduce their body silhouette. The reasons given by these adolescents for why they were dissatisfied with their body images were similar for both sexes (p = 0.156). When analyzed by neighborhood the urban adolescents said that their dissatisfaction was esthetic, whereas the rural adolescents said it was based on self-esteem. An association was detected between perceived BI and the reasons for dissatisfaction. CONCLUSIONS: Esthetics, self esteem and health were the most common reasons for BI dissatisfaction among these adolescents. More than half of them were dissatisfied with their body silhouettes. Therefore, there is a need for interventions by health services and professionals in this age range in order to avoid possible future problems with eating disorders (anorexia, bulimia and vigorexia). PMID- 22534861 TI - [Representations on patient illness and cure at the Chemical Dependency Center of the Central Navy Hospital]. AB - This article presents one of the segments of ethnographic research which was conducted over a two-year period, by means of participant observation, at the Chemical Dependency Center of the Brazilian Navy. Patients of 2 treatment groups were observed during 24 sessions of group therapy. Among the 22 existing patients of the two groups, 13 patients were randomly selected for individual interviews. Their illness and healing representations related to mental and behavioral disorders caused by drugs were examined, and also the influence of the work environment on patient involvement with drugs was investigated. Results show that patients believe that they are responsible for their illness and for their alcoholic sobriety and they also believe they will never be cured. Furthermore, they do not usually accept the on-going medical discourse or the Alcoholics Anonymous belief that they are recovering alcoholics; they build their own views about their diagnoses, prognoses, and treatments. There are cultural traits particular to the naval life that indicate that the categories analyzed are mainly social, and that certain work-related conditions lead to the emergence of alcoholism in many patients, despite the fact that drugs are commonly tackled from the administrative perspective. PMID- 22534863 TI - Accumulation of activated invariant natural killer T cells in the tumor microenvironment after alpha-galactosylceramide-pulsed antigen presenting cells. AB - PURPOSE: The intravenous administration of alpha-Galactosylceramide (alpha GalCer)-pulsed antigen presenting cells (APCs) is well tolerated and the increased IFN-gamma producing cells in the peripheral blood after the treatment appeared to be associated with prolonged survival. An exploratory study protocol was designed with the preoperative administration of alpha-GalCer-pulsed APCs to clarify the mechanisms of these findings, while especially focusing on the precise tumor site. METHODS: Patients with operable advanced lung cancer received an intravenous injection of alpha-GalCer-pulsed APCs before surgery. The resected lung and tumor infiltrating lymphocytes (TILs) as well as peripheral blood mononuclear cells were collected and the invariant NKT (iNKT) cell-specific immune responses were analyzed. RESULTS: Four patients completed the study protocol. We observed a significant increase in iNKT cell numbers in the TILs and augmented IFN-gamma production by the alpha-GalCer-stimulated TILs. CONCLUSION: The administration of alpha-GalCer-pulsed APCs successfully induced the dramatic infiltration and activation of iNKT cells in the tumor microenvironment. PMID- 22534865 TI - Tissue-engineered airway in the clinical setting: a call for information disclosure. PMID- 22534864 TI - Antiemetic efficacy of single-dose palonosetron and dexamethasone in patients receiving multiple cycles of multiple day-based chemotherapy. AB - INTRODUCTION: The goal of pharmacological prophylaxis of chemotherapy-induced nausea and vomiting (CINV) should be the elimination of both nausea and vomiting symptoms during all planned chemotherapy cycles. The aim of this study was to assess the efficacy of a single dose of palonosetron and dexamethasone to prevent CINV and to guarantee an adequate food intake (FI) in patients receiving several cycles of multiple day-based chemotherapy (MD-CT). METHODS: Patients with advanced cancer but without a compromised nutritional status (bone mass index >= 18.5) were treated with 0.25 mg palonosetron plus 20 mg dexamethasone before MD CT. The MD-CT regimen was either epirubicin plus ifosfamide or paclitaxel plus cisplatin and ifosfamide. Nausea, vomiting, and FI were monitored in a 7-day diary. Complete response (CR: no vomiting and no rescue therapy) was the primary endpoint, while complete control (CC: CR and no more than mild nausea) and the evaluation of FI were secondary endpoints. The endpoints were evaluated during the overall timescale (0-168 h) of the chemotherapy regimen. RESULTS: Fifty patients were enrolled, 80% of whom achieved CR and 78% achieved CC. During the six chemotherapy cycles, CR and CC ranged from 76% to 88% and from 62% to 88%, respectively. Moreover, patients with CR had a significantly (p < 0.0001) higher weekly food intake compared with patients not achieving CR. CONCLUSIONS: This trial was the first to assess the efficacy of palonosetron and dexamethasone for the prevention of both nausea and vomiting in patients receiving multiple cycles of MD-CT. In this trial, the ability of patients to intake an adequate amount of food each week was correlated with nausea, thus providing clinicians with an objective parameter for the measurement of the effects of nausea. A single dose of palonosetron and dexamethasone was able to prevent CINV in most patients receiving 3 days of chemotherapy during all planned chemotherapy cycles. PMID- 22534867 TI - The role of cannabinoids in chronic pain patients remains hazy. PMID- 22534868 TI - Transporter-mediated drug--drug interactions involving OATP substrates: predictions based on in vitro inhibition studies. AB - Transporter-mediated drug-drug interactions (DDIs) are among the most important of the clinically relevant pharmacokinetic DDIs. We investigated the validity of a static prediction of area under the plasma concentration-time curve (AUC) ratios (AUCRs; AUC(with inhibitor)/AUC(control) using in vitro inhibition profiles, and selected the types of assumptions that improved the prediction accuracy with minimizing false-negative predictions. We used data from 58 DDI studies involving 12 substrates of hepatic organic anion-transporting polypeptides (OATPs). With original assumptions regarding the maximal increase in intestinal availability, maximum unbound concentration at the inlet to the liver, and inhibition of only the hepatic uptake process, the predicted AUCRs were comparable to those reported within a two/threefold error margin in 44/52 studies, whereas in 16 studies, the predictions were judged to be falsenegatives. When the inhibitory effects on both hepatic uptake and efflux/metabolisms were considered, the overall prediction accuracy became worse, although the false negative prediction decreased to 11 studies. This illustrates that if appropriate assumptions are selected, unnecessary clinical DDI studies can be reasonably avoided. PMID- 22534869 TI - PhRMA survey of pharmacogenomic and pharmacodynamic evaluations: what next? AB - Interindividual variation in pharmacodynamic (PD) response to drugs is an ongoing area of research for drugs in clinical development, pre- and postapproval. To characterize how pharmacogenomic (PG ) variations can serves a predictor of differences in PD outcomes, the pharmaceutical industry has incorporated PG /PD analysis into clinical drug development. The Pharmaceutical Research and Manufacturers of America (PhRMA ) and the Industry Pharmacogenomics Working Group (I-PWG) conducted a survey of 16 pharmaceutical companies to ascertain to what extent PG/PD research is being incorporated into drug development. The survey results showed that, while the industry has made some attempt to incorporate PG/PD studies into drug development, application has been inconsistent. Nevertheless, several valid PG/PD markers have since emerged in drug labels. The I-PWG considers PG/PD research an important approach to improving success rates in drug development. This article reports the results of the survey and proposes steps toward increasing the use of PG/PD research by the industry. PMID- 22534870 TI - Electronic medical records as a tool in clinical pharmacology: opportunities and challenges. AB - The development and increasing sophistication of electronic medical record (EMR) systems hold the promise of not only improving patient care but also providing unprecedented opportunities for discovery in the fields of basic, translational, and implementation sciences. Clinical pharmacology research in the EMR environment has only recently started to become a reality, with EMRs becoming increasingly populated, methods to mine drug response and other phenotypes becoming more sophisticated, and links being established with DNA repositories. PMID- 22534871 TI - Associations between ABCC2 polymorphisms and cisplatin disposition and efficacy. AB - ABCC2 (MRP2, cMOAT) expression has been implicated in cisplatin resistance in vitro. In mice, cisplatin disposition and toxicity were unaffected by Abcc2 knockout (Abcc2-/-). Moreover, in cancer patients (n = 237), cisplatin pharmacokinetics (P > 0.12) and efficacy (P > 0.41) were not associated with seven of the single-nucleotide polymorphisms (SNPs) in ABCC2. These SNPs were also not correlated with ABCC2 expression in the NCI60 panel (P > 0.26) or with cisplatin-induced cytotoxicity (P = 0.21). These findings highlight the importance of verifying drug-transporter interactions with in vitro tests in humans. PMID- 22534872 TI - Incidentally detected cystic lesions of the pancreas on CT: review of literature and management suggestions. AB - PURPOSE: To facilitate a better understanding of incidentally noted cystic pancreatic lesions, since these lesions often pose a challenge regarding appropriate management. METHODS: This article reviews pathophysiology, prevalence, significance, and recommendations for management of the various pancreatic cystic lesions. Illustrative cases are demonstrated. RESULTS: Diagnostic benign lesions can be left alone. Cross-sectional imaging can be used to follow-up benign appearing lesions and to stage more aggressive ones. Endoscopic ultrasound with fine needle aspiration and cyst fluid analysis can be performed on certain indeterminate lesions. Lesions with high malignant potential should undergo resection. CONCLUSIONS: A better understanding of the variety of incidentally detected pancreatic cystic lesions can help direct appropriate management. PMID- 22534873 TI - Contaminations of metal in tissues of Siberian gull Larus heuglini: gender, age, and tissue differences. AB - The objective of the present study was to investigate the levels of metals, namely cadmium, lead, and zinc, in Siberian gull (Larus heuglini) (n = 15), in order to: (1) examine the sex and gender related variation in trace metal accumulation, and (2) to determine the significant between metal concentrations in the kidney, liver, and pectoral muscle. The concentrations were different between the tissues of bird as well as among the interaction (sex * age), but this difference (except cadmium in liver and zinc in kidney) between the gender (male and female) and age (adult and juvenile) didn't exist. Results showed that the metal concentrations in the Siberian gull were decreased in sequence of kidney > liver > muscle. The cadmium, lead, zinc concentration overall means they were measured as 2.2 +/- 0.7, 8.8 +/- 2.5, and 91.1 +/- 37. 1 MUg/g for kidney, 1.1 +/- 0.2, 5.1 +/- 0.8, and 68.3 +/- 27.8 MUg/g for liver, and 0.8 +/- 0.1, 3.4 +/- 0.6, and 34.4 +/- 23.2 MUg/g for pectoral muscle, respectively. PMID- 22534874 TI - Paraoxonase 2 acts as a quorum sensing-quenching factor in human keratinocytes. PMID- 22534875 TI - Kidney transplant recipients with cutaneous squamous cell carcinoma have an increased risk of internal malignancy. AB - This study aimed to investigate whether the occurrence of cutaneous squamous cell carcinomas (SCCs) is associated with an increased risk of internal malignancies (IMs) in kidney transplant recipients (KTRs). In a cohort study, all patients receiving kidney transplantation in Leiden, the Netherlands, between 1966 and 2006 were followed up. All malignancies that had developed between 1966 and 2007 were recorded. Time-dependent Cox regression analyses were used to calculate the association between the development of cutaneous SCCs and IMs. The incidence of IMs in the KTRs after transplantation was also compared with the general Dutch population by calculating standardized morbidity ratios (SMRs) and was matched for age, sex, and time period in which the malignancy had occurred. Among 1,800 KTRs, 176 (9.8%) developed cutaneous SCCs and 142 (7.9%) developed IMs after transplantation. In patients with prior cutaneous SCCs, the adjusted risk to develop IMs was 3.0 (1.9; 4.7). In KTRs without cutaneous SCCs, the risk of IM compared with the general population was hardly increased. KTRs with cutaneous SCCs have an increased risk to develop IMs, and this information can be used to identify KTRs who are at an increased risk for IMs. PMID- 22534876 TI - The human skin barrier is organized as stacked bilayers of fully extended ceramides with cholesterol molecules associated with the ceramide sphingoid moiety. AB - The skin barrier is fundamental to terrestrial life and its evolution; it upholds homeostasis and protects against the environment. Skin barrier capacity is controlled by lipids that fill the extracellular space of the skin's surface layer--the stratum corneum. Here we report on the determination of the molecular organization of the skin's lipid matrix in situ, in its near-native state, using a methodological approach combining very high magnification cryo-electron microscopy (EM) of vitreous skin section defocus series, molecular modeling, and EM simulation. The lipids are organized in an arrangement not previously described in a biological system-stacked bilayers of fully extended ceramides (CERs) with cholesterol molecules associated with the CER sphingoid moiety. This arrangement rationalizes the skin's low permeability toward water and toward hydrophilic and lipophilic substances, as well as the skin barrier's robustness toward hydration and dehydration, environmental temperature and pressure changes, stretching, compression, bending, and shearing. PMID- 22534877 TI - Follow-up study of the first genome-wide association scan in alopecia areata: IL13 and KIAA0350 as susceptibility loci supported with genome-wide significance. AB - Recently, the first genome-wide association study (GWAS) of alopecia areata (AA) was conducted in a North-American sample, and this identified eight susceptibility loci surpassing genome-wide significance. The aim of the present follow-up association analysis was to confirm five of these eight loci (single nucleotide polymorphisms (SNPs) from the CTLA4, IL-2RA, and HLA regions were not included due to previous own findings) and test 12 other loci from the GWAS, which did not surpass the threshold for genome-wide significance. Twenty-three SNPs from the 17 loci were investigated using a sample of 1,702 Central European AA patients and 1,723 controls. Of the five loci with previously reported genome wide significance, association was confirmed for all of these: ULBP3/ULBP6, PRDX5, IL-2/IL-21, STX17, and IKZF4/ERBB3 (P-value <0.05). To detect robust evidence for association among the 12 other loci, a meta-analysis of the present association data and the data of the recent GWAS was performed. Genome-wide significant association was found for rs20541 (P(comb)=7.52 * 10(-10); odds ratio (OR)=1.30 (1.23-1.38)) and rs998592 (P(comb)=1.11 * 10(-11); OR=1.28 (1.21 1.36)), thus establishing IL-13 and KIAA0350/CLEC16A as susceptibility loci for AA. Interestingly, IL-13 and KIAA0350/CLEC16A are susceptibility loci for other autoimmune diseases, supporting the hypothesis of shared pathways of autoimmune susceptibility. PMID- 22534878 TI - Array comparative genomic hybridization of keratoacanthomas and squamous cell carcinomas: different patterns of genetic aberrations suggest two distinct entities. AB - Keratoacanthoma (KA) is a benign keratinocytic neoplasm that spontaneously regresses after 3-6 months and shares features with squamous cell carcinomas (SCCs). Furthermore, there are reports of KAs that have metastasized, invoking the question of whether KA is a variant of SCC (Hodak et al., 1993). To date, no reported criteria are sensitive enough to discriminate reliably between KA and SCC, and consequently there is a clinical need for discriminating markers. Our previous study analyzed 132 KAs and 29 SCCs and revealed significantly different regions of genomic aberrations using chromosomal comparative genomic hybridization (CGH). In the present study, we applied array CGH to investigate 98 KAs and 22 SCCs from the above samples. The result shows that all KAs and SCCs have some degree of genetic aberrations. The distribution of numbers of aberrant clones per sample differed significantly between KAs and SCCs (P<0.02), which also demonstrated recurrent aberrations that differed significantly (P<0.001), as illustrated by unsupervised cluster analysis. Classifiers for clinicopathological parameters of KAs were established based on t-test statistics and permutation tests. Tumor size, fibrosis, and inflammation, which are related to the developmental stages of KAs, showed significant (t-test, permutation test) associations with aberrations of selected genomic regions. This suggests chromosomal instability during the whole life cycle of KAs. PMID- 22534879 TI - Incidence, mortality, and disease associations of pyoderma gangrenosum in the United Kingdom: a retrospective cohort study. AB - Pyoderma gangrenosum (PG) is an important disease with significant complications. The objectives of this study were to determine incidence and mortality of PG and strength of reported associations. A retrospective cohort study was completed using computerized medical records from the General Practice Research Database, a large representative UK database. Patients with PG and three groups of age-, sex , and practice-matched controls--general population, rheumatoid arthritis (RA), and inflammatory bowel disease (IBD) controls--were included in the study. Incidence and mortality were determined and validation undertaken to inform diagnostic accuracy. In all there were 313 people with the median age of 59 (interquartile range 41-72) years, and of them 185 (59%) were female. The adjusted incidence rate standardized to European standard population was 0.63 (95% confidence interval (CI) 0.57-0.71) per 100,000 person-years. The risk of death was three times higher than that for general controls (adjusted hazard ratio=3.03, 95% CI 1.84-4.73, P<0.001), 72% higher than that for IBD controls (adjusted hazard ratio=1.72, 95% CI 1.17-2.59, P=0.013), with a borderline increase compared with RA controls (adjusted hazard ratio=1.55, 95% CI 1.01-2.37, P=0.045). Disease associations were present in 110 (33%) participants: IBD, n=67 (20.2%); RA, n=39 (11.8%); and hematological disorders, n=13 (3.9%). To our knowledge, there are no previous population-based studies of the epidemiology of PG, an important disease with significantly increased mortality. PMID- 22534880 TI - A nation-wide analysis of venous thromboembolism in 497,180 cancer patients with the development and validation of a risk-stratification scoring system. AB - The Asian population is thought to have a low risk of venous thromboembolism (VTE), but the epidemiology of VTE in cancer patients remains unclear. The National Health Insurance Research Database of Taiwan was used to find hospitalised patients newly-diagnosed with cancer to determine the incidence of VTE in cancer patients and to identify the risk factors for VTE. Between 1997 and 2005, 497,180 cancer patients were identified. During a median follow-up of 21.3 months (range 0-119.9 months), 5,296 patients developed VTE. The estimated incidence was 185 events per 100,000 person-years. Patients with a prior history of VTE and female patients between the ages of 40 and 80 carried high risk of VTE. The rate of VTE was relatively high in patients with myeloma, prostate cancer, lung cancer, gynaecologic cancers, sarcoma, and metastasis of unknown origin. We developed a risk-stratification scoring system to divide the cancer patients into four discrete risk groups (very low risk, low risk, intermediate, and high risk). The incidence of VTE in each group was 0.5%, 0.9%, 1.5%, and 8.7%, respectively (p < 0.001). This scoring system was validated in a separate patient cohort. In conclusion, VTE is a distinct burden for cancer patients in Taiwan. The risk scoring system could prove helpful in decision-making concerning thromboprophylaxis in cancer patients. PMID- 22534881 TI - Does the radiographic transition zone correlate with the level of aganglionosis on the specimen in Hirschsprung's disease? AB - PURPOSE: The correlation between radiographic transition zone on contrast enema in Hirschsprung's disease and the total length of aganglionosis is known to be inaccurate. The aim of our study was to analyse this correlation more precisely to improve preoperative planning of the corrective surgery. METHODS: From 1998 to 2009, 79 patients were operated on for Hirschsprung's disease. All available preoperative contrast enemas (n = 61) had been single blind reviewed by the same radiologist who defined the radiographic transition zone when present in vertebral level. Four groups were determined (rectal, rectosigmoid, long segment, and absence of transition zone) and by Kappa coefficient of agreement correlated to the length of aganglionosis in the pathological report. RESULTS: Radiological findings were concordant with the specimen in pathology in 8 cases of 19 in rectal form (42 %), in 20 cases of 35 in rectosigmoid form (57 %), in all 6 cases of long-segment form (100 %), in the 2 cases of total colonic form (100 %) with a global agreement of 58.1 %, kappa = 0.39 CI [0.24; 0.57]. CONCLUSION: Correlation between level of radiographic transition zone on contrast enema and length of aganglionosis remains low. Systematic preoperative biopsy by coelioscopy or ombilical incision is mandatory. PMID- 22534882 TI - An electrochemical thermometer: voltammetric measurement of temperature and its application to amperometric gas sensing. AB - We report a temperature sensing system incorporated into an amperometric oxygen sensor. In the first part of this work, we introduce temperature sensing systems based upon voltammetric responses of both single molecule (1,2 diferrocenylethylene in 1-propyl-3-methylimidazolium bistrifluoromethylsulfonylimide) and two independent molecules (decamethylferrocene and N,N,N',N'-tetramethyl-p-phenylenediamine in 1-ethyl-3 methylimidazolium tetracyanoborate) respectively. In both systems, the difference in the formal potentials of two redox centres was measured as a function of temperature. The former was recorded as the peak difference in square wave voltammetry with the peak potential difference increases linearly with the increasing temperature. In order to show proof-of-concept in relation to a gas sensor, the latter system was investigated in the presence of oxygen, where the concentration and diffusion coefficient of oxygen varied with temperature, as well as the peak difference discussed previously, were studied in the presence of pure oxygen and dried air using chronoamperometry. A negligible variation of concentration of oxygen from both sources with temperature over the range 298 K to 318 K is demonstrated. These results obtained from pure oxygen and dried air were compared and a ca. 79% drop of cathodic signal from pure oxygen to dried air was found which is consistent with the percentage of oxygen in air. The diffusion coefficient of oxygen was related to temperature using an Arrhenius plot (natural log of diffusion coefficient as a function of reciprocal temperature), yielding a linear graph with high correlation. All experiments gave a high reproducibility. PMID- 22534884 TI - Coexistence of polymyositis and familial Mediterranean fever. AB - Familial Mediterranean fever (FMF) is an autosomal recessive disease affecting populations surrounding the Mediterranean area. In this case report, we report a Japanese female patient with polymyositis (PM) who presented with periodic fever. Genetic analysis revealed that she had compound heterozygous mutations in exon 2 of the MEFV gene (L110P/E148Q/R202Q). Treatment with colchicines (1.0 mg/day) successfully eliminated febrile attack and normalized the elevated levels of neutrophil CD64 expression, leading to the diagnosis of FMF. The association of FMF and PM has not previously been reported, so we discuss this rare association. PMID- 22534885 TI - Risk factors associated with elevated blood cytomegalovirus pp65 antigen levels in patients with autoimmune diseases. AB - OBJECTIVES: To further assess the relationship between elevated levels of cytomegalovirus (CMV) pp65 antigen in blood, as indicative of viral load, during treatment-free follow-up and CMV diseases in patients with autoimmune diseases and to identify any risk factors associated with elevated viral loads. METHODS: This was a retrospective review of the electronic medical charts of 148 patients with autoimmune diseases who tested positive for CMV pp65 antigen in the blood. RESULTS: A total of 106 patients were analyzed. During follow-up, elevated viral loads were detected in 35 patients who were not on antiviral therapy, of whom five developed CMV diseases. Elevated viral load was significantly associated with CMV diseases [5/35 vs. 0/71 (no elevated viral load); P = 0.001). Multivariate analysis revealed that lymphopenia [lymphocyte numbers <700/mm(3), odds ratio (OR) 34.44, 95 % confidence interval (CI), 7.82-151.66; P < 0.001], systemic lupus erythematosus (SLE) (OR 6.71, 95 % CI, 1.23-36.49; P = 0.028), and polymyositis/dermatomyositis (PM/DM) (OR 10.62, 95 % CI 1.41-79.77; P = 0.022) were significantly associated with elevated viral load. CONCLUSIONS: Elevated viral load was significantly associated with CMV diseases. Patients with SLE or PM/DM and lymphopenia would therefore benefit from a detailed viral load follow up and careful physical examination. PMID- 22534886 TI - Analysis on the saturation of refractive index modulation in fiber Bragg gratings (FBGs) written by partially coherent UV beams. AB - We present an analysis on the saturation of refractive index modulation of fiber Bragg gratings written in nonhydrogenated Ge-B co-doped single-mode photosensitive optical fiber by partially coherent pulsed UV beams. The UV beams of different spatial coherence properties were generated by second harmonic conversion of high repetition rate, high average power copper vapor laser (CVL) oscillators with different optical resonators. It is observed that for UV beams of higher spatial coherence, the fiber Bragg grating reflectivity growth was faster and saturation of refractive index modulation was higher. The experimental results are explained with the help of a physical model based on exponential decay of defect centers per unit volume on UV absorption in the fiber core. The subsequent increase in the refractive index was attributed to the structural modification and densification of the fiber core. PMID- 22534883 TI - Aluminium exposure disrupts elemental homeostasis in Caenorhabditis elegans. AB - Aluminium (Al) is highly abundant in the environment and can elicit a variety of toxic responses in biological systems. Here we characterize the effects of Al on Caenorhabditis elegans by identifying phenotypic abnormalities and disruption in whole-body metal homeostasis (metallostasis) following Al exposure in food. Widespread changes to the elemental content of adult nematodes were observed when chronically exposed to Al from the first larval stage (L1). Specifically, we saw increased barium, chromium, copper and iron content, and a reduction in calcium levels. Lifespan was decreased in worms exposed to low levels of Al, but unexpectedly increased when the Al concentration reached higher levels (4.8 mM). This bi-phasic phenotype was only observed when Al exposure occurred during development, as lifespan was unaffected by Al exposure during adulthood. Lower levels of Al slowed C. elegans developmental progression, and reduced hermaphrodite self-fertility and adult body size. Significant developmental delay was observed even when Al exposure was restricted to embryogenesis. Similar changes in Al have been noted in association with Al toxicity in humans and other mammals, suggesting that C. elegans may be of use as a model for understanding the mechanisms of Al toxicity in mammalian systems. PMID- 22534888 TI - Design and fabrication of a freeform microlens array for a compact large-field-of view compound-eye camera. AB - In this research, a unique freeform microlens array was designed and fabricated for a compact compound-eye camera to achieve a large field of view. This microlens array has a field of view of 48 degrees *48 degrees , with a thickness of only 1.6 mm. The freeform microlens array resides on a flat substrate, and thus can be directly mounted to a commercial 2D image sensor. Freeform surfaces were used to design the microlens profiles, thus allowing the microlenses to steer and focus incident rays simultaneously. The profiles of the freeform microlenses were represented using extended polynomials, the coefficients of which were optimized using ZEMAX. To reduce crosstalk among neighboring channels, a micro aperture array was machined using high-speed micromilling. The molded microlens array was assembled with the micro aperture array, an adjustable fixture, and a board-level image sensor to form a compact compound-eye camera system. The imaging tests using the compound-eye camera showed that the unique freeform microlens array was capable of forming proper images, as suggested by design. The measured field of view of +/-23.5 degrees also matches the initial design and is considerably larger compared with most similar camera designs using conventional microlens arrays. To achieve low manufacturing cost without sacrificing image quality, the freeform microlens array was fabricated using a combination of ultraprecision diamond broaching and a microinjection molding process. PMID- 22534887 TI - Backscatter signatures of biological aerosols in the infrared. AB - To develop a deeper understanding of the optical signatures of both biological aerosols and potential interferents, we made field measurements of optical cross sections and compared them to model-based predictions. We measured aerosol cross sections by conducting a hard-target calibration of a light detection and ranging system (LIDAR) based on the Frequency Agile Laser (FAL). The elastic backscatter cross sections are estimated at 19 long-wave infrared (LWIR) wavelengths spanning the range from 9.23 to 10.696 MUm. The theoretical modeling of the elastic backscatter cross sections is based on the measured refractive index and size distribution of the aerosols, which are used as inputs into Mie calculations. Both model calculations and experimental measurements show good agreement and also indicate the presence of spectral features based on single particle absorption in the backscatter cross sections that can be used as a basis for discrimination for both standoff and point sensors. PMID- 22534889 TI - Wind speed measurements of Doppler-shifted absorption lines using two-beam interferometry. AB - Wind speed can be measured remotely, with varying degrees of success, using interferometry of Doppler-shifted optical spectra. Under favorable conditions, active systems using laser pulse backscatter are capable of high resolution; passive systems, which measure Doppler shifts of atmospheric emission lines in the mesosphere, have also been shown. Two-beam interferometry of Doppler-shifted absorption lines has not been previously investigated; we describe such an effort here. Even in a well-defined environment, measuring absorption line Doppler shifts requires overcoming several technical hurdles in order to obtain sensitivity to wind speeds on the order of 10 m/s. These hurdles include precise knowledge of the shape of the absorption line, tight, stable filtering, and understanding precisely how an interferometer phase should respond to a change in the absorption profile. We discuss the instrument design, a Michelson interferometer and Fabry-Perot filter, and include an analysis of how to choose the optimal optical path difference of the two beams for a given spectrum and filter. We discuss two beam interferometric measurements of emission line and absorption line Doppler shifts, and include an illustration of the effects of filtering on LIDAR Doppler interferometry. Finally, we discuss the construction and implementation of a Michelson interferometer used to measure Doppler shifts of oxygen absorption lines and present results obtained with 5 m/s wind speed measurement precision. Although the theoretical shot noise limited Doppler wind speed measurement of the system described can be less than 1 m/s, the instrument's resolution limit is dominated by residual filter instability. Application of absorption line interferometry to determine atmospheric wind speeds remains problematic. PMID- 22534890 TI - Design of an LED-based sensor system to distinguish human skin from workpieces in safety applications. AB - Commercial light curtains use a technique known as muting to differentiate between work pieces and other objects (e.g., human limbs) based on precise model knowledge of the process. At manually fed machinery (e.g., bench saws), such precise models cannot be derived due to the way the machinery is used. This paper presents a multispectral scanning sensor to classify an object's surface material as a new approach for the problem. The system is meant to detect the presence of limbs and therefore optimized for human skin detection. Evaluation on a test set of skin and (wet) wood samples showed a sufficiently high reliability with respect to safety standards. PMID- 22534891 TI - Tailored complex 3D vortex lattice structures by perturbed multiples of three plane waves. AB - As three-plane waves are the minimum number required for the formation of vortex embedded lattice structures by plane wave interference, we present our experimental investigation on the formation of complex 3D photonic vortex lattice structures by a designed superposition of multiples of phase-engineered three plane waves. The unfolding of the generated complex photonic lattice structures with higher order helical phase is realized by perturbing the superposition of a relatively phase-encoded, axially equidistant multiple of three noncoplanar plane waves. Through a programmable spatial light modulator assisted single step fabrication approach, the unfolded 3D vortex lattice structures are experimentally realized, well matched to our computer simulations. The formation of higher order intertwined helices embedded in these 3D spiraling vortex lattice structures by the superposition of the multiples of phase-engineered three-plane waves interference is also studied. PMID- 22534892 TI - Plasmon-induced transparency by detuned magnetic atoms in trirod metamaterials. AB - We demonstrate theoretically an analog of electromagnetically induced transparency (EIT) in the plasmonic metamaterial with the unit cell consisting of three parallel metallic rods. The electromagnetic mechanism for the EIT-like transmission is discussed based on our investigation of the localized surface plasmon resonances in three trirod configurations. We find that the transmission minima surrounding the transparency window on both sides correspond to two detuned magnetic resonances, which arise respectively from the antiphase plasmon couplings between a long rod and a short rod and between two short rods. A decrease of more than 10 times in the group velocity can be achieved for the trirod structure at the transparency window in the optical regime, and the EIT like response can be well described by the theoretical model of two harmonic oscillators. This work not only reveals the EIT-like transmission in plasmonic metamaterial consisting of detuned magnetic "atoms," but also provides further insight into the plasmons' interactions, especially for metallic nanostructures comprising multiple metallic elements. PMID- 22534894 TI - Laser speckle reduction by multimode optical fiber bundle with combined temporal, spatial, and angular diversity. AB - We report significant speckle reduction in a laser illumination system using a vibrating multimode optical fiber bundle. The optical fiber bundle was illuminated by two independent lasers simultaneously. The beams from both lasers were first expanded and collimated and were further divided into multiple beams to illuminate the fiber optic bundle with normal and oblique incidence. Static diffusers were also placed at the input and output faces of the fiber bundle, thus introducing the spatial as well as angular diversity of illumination. Experiments were carried out both in free space and in imaging geometry configuration. Standard deviation, speckle contrast and signal-to-noise ratio of the images were computed, and the results were compared with those of white light illumination. Speckle contrast close to that of white light was obtained using a vibrating fiber bundle with combined temporal, spatial, and angular diversities of the illumination. PMID- 22534893 TI - Polymeric dual-slab waveguide interferometer for biochemical sensing applications. AB - A polymer based dual-slab waveguide Young's interferometer was demonstrated for biochemical sensing. Evanescent field is utilized for probing the binding events of biomolecules on the waveguide surface. Refractive index sensing in analyte and protein adsorption on the sensing surface were investigated with glucose de ionized water solution and bovine serum albumin, immunoglobulin G solutions in phosphate buffered saline buffer. A detection limit of 10(-5) RIU and 4 pg/mm(2) was achieved for homogeneous and surface sensing, respectively. Also, the influence of water absorption inside the polymeric device on the measurement stability was evaluated. The results indicate that the waveguide polymer sensor fabricated with the spin coating technique can achieve a satisfactory sensitivity for homogeneous refractive index sensing and, as well, for monitoring molecular binding events on the surface. PMID- 22534895 TI - Generation of deep ultraviolet narrow linewidth laser by mixing frequency Ti:sapphire laser at 5 kHz repetition rate. AB - We demonstrate a scheme to generate deep ultraviolet source by the single-stage high-power Ti:sapphire laser with linewidth of 0.05 nm cryogenically operating at repetition rate of 5 kHz. The fundamental laser was tuned by an intracavity birefringent filter and three etalons with an output power greater than 8 W, corresponding to about 17% optical efficiency. The pulse width was 112 ns and M2<1.1. By using the nonlinear crystals BiB3O6 and KBe2BO3F2, the output power of 2.2 W at second harmonic and 8.5 mW at fourth harmonic laser of about 195 nm were produced. This compact high-repetition rate laser with narrow linewidth would be a promising tunable source for spectroscopy. PMID- 22534896 TI - Fusion of infrared and visible images based on focus measure operators in the curvelet domain. AB - Aiming at the differences of physical characteristics between infrared sensors and visible ones, we introduce the focus measure operators into the curvelet domain in order to propose a novel image fusion method. First, the fast discrete curvelet transform is performed on the original images to obtain the coefficient subbands in different scales and various directions, and the focus measure values are calculated in each coefficient subband. Then, the local variance weighted strategy is employed to the low-frequency coefficient subbands for the purpose of maintaining the low-frequency information of the infrared image and adding the low-frequency features of the visible image to the fused image; meanwhile, the fourth-order correlation coefficient match strategy is performed to the high frequency coefficient subbands to select the suitable high-frequency information. Finally, the fused image can be obtained through the inverse curvelet transform. The practical experiments indicate that the presented method can integrate more useful information from the original images, and the fusion performance is proved to be much better than the traditional methods based on the wavelet, curvelet, and pyramids. PMID- 22534897 TI - Complete fringe order determination in scanning white-light interferometry using a Fourier-based technique. AB - White-light interferometry uses a white-light source with a short coherent length that provides a narrowly localized interferogram that is used to measure three dimensional surface profiles with possible large step heights without 2pi ambiguity. Combining coherence and phase information improves the vertical resolution. But, inconsistencies between phase and coherence occur at highly curved surfaces such as spherical and tilted surfaces, and these inconsistencies often cause what are termed ghost steps in the measurement result. In this paper, we describe a modified version of white-light interferometry for eliminating these ghost steps and improving the accuracy of white-light interferometry. Our proposed technique is verified by measuring several test samples. PMID- 22534898 TI - In-plane effects on segmented-mirror control. AB - Extremely large optical telescopes are being designed with primary mirrors composed of hundreds of segments. The "out-of-plane" piston, tip, and tilt degrees of freedom of each segment are actively controlled using feedback from relative height measurements between neighboring segments. The "in-plane" segment translations and clocking (rotation) are not actively controlled; however, in plane motions affect the active control problem in several important ways, and thus need to be considered. We extend earlier analyses by constructing the "full" interaction matrix that relates the height, gap, and shear motion at sensor locations to all six degrees of freedom of segment motion, and use this to consider three effects. First, in-plane segment clocking results in height discontinuities between neighboring segments that can lead to a global control system response. Second, knowledge of the in-plane motion is required both to compensate for this effect and to compensate for sensor installation errors, and thus, we next consider the estimation of in-plane motion and the associated noise propagation characteristics. In-plane motion can be accurately estimated using measurements of the gap between segments, but with one unobservable mode in which every segment clocks by an equal amount. Finally, we examine whether in-plane measurements (gap and/or shear) can be used to estimate out-of-plane segment motion; these measurements can improve the noise multiplier for the "focus-mode" of the segmented-mirror array, which involves pure dihedral angle changes between segments and is not observable with only height measurements. PMID- 22534899 TI - Sinusoidal phase-modulating interferometer insensitive to intensity modulation of a laser diode for displacement measurement. AB - In sinusoidal phase-modulating laser diode interferometers, an injection current of a laser diode is sinusoidally modulated to scan the laser wavelength. However, the modulation of the injection current also involves an intensity modulation of the light, which increases the measurement error if a conventional signal processing is used. A novel signal processing for displacement measurement is proposed to eliminate the influence of the intensity modulation. Numerical simulation results and experimental results make it clear that an optimal depth of the sinusoidal phase modulation exists that can reduce the measurement error to a few nanometers. PMID- 22534900 TI - Photoelastic lensing effect in Ti:sapphire crystal pumped by high-energy pulses. AB - We have built a setup with high temporal resolution to measure the very fast photoelastic lensing effect, which is on the scale of microseconds in a Ti:sapphire crystal pumped by very strong laser pulses (up to 5 J/cm2). The experimental results measured by this method and the real multimode beam profile taken by a CCD camera are applied to a three-dimensional crystal model to calculate one of the photoelastic constants of Ti:sapphire crystal, which is found to be p31=-0.03+/-0.01. This value is helpful to evaluate the photoelastic lensing effect in Ti:sapphire crystal for a laser beam polarized along the c axis, commonly used for laser amplification. PMID- 22534901 TI - Spectral calibration of radiometric detectors using tunable laser sources. AB - This paper describes the analysis of laser-based responsivity measurements using the Tunable Lasers in Photometry setup at the Physikalisch-Technische Bundesanstalt. An approach based on digital signal analysis is proposed to remove interference-caused oscillations in highly resolved spectral data from laser based measurements, yielding an improved reproducibility and comparability of results. Digital filters are used to selectively suppress the frequency components of interference fringes visible in the measurement data. We describe the algorithm used and discuss the associated uncertainty components of laser based measurements. Finally, we give examples of the calibration of different detectors with and without interference effects. PMID- 22534902 TI - Effect of intrapulse Raman scattering on broadband amplitude noise of supercontinuum generated in fiber normal dispersion region. AB - Based on the generalized stochastic nonlinear Schrodinger equation, the effect of intrapulse Raman scattering (IRS) on broadband amplitude noise of supercontinuum (SC) generated in the normal dispersion regime is investigated numerically. The results show that, in the normal dispersion regime, where the IRS contributes less to the bandwidth of the SC spectrum, the broadband amplitude noise of SC is amplified significantly in the process of SC generation because of the existence of IRS effect. Using fiber with an optimal negative dispersion slope, the IRS effect can be suppressed, and thus the SC amplitude noise is reduced without spectral bandwidth loss. PMID- 22534903 TI - Partially light-controlled imager based on liquid crystal plate and image intensifier for aurora and airglow measurement. AB - In order to obtain information both of aurora and airglow in one image by the same detector, a PLCI based on liquid crystal plate LCP and super second generation image intensifier SSGII is proposed in this research. The detection thresholds of the CCD for aurora and airglow are calculated. For the detectable illumination range of 10(4)-10(-2) lx, the corresponding electron count is 1.57*10(5) - 0.2 for every pixel of CCD. The structure and work principle of the PLCI are described. An LC is introduced in the front of CCD to decrease the intensities of aurora in overexposure areas by means of controlling transmittances pixel by pixel, while an image intensifier is set between the LC and CCD to increase the intensity of the weak airglow. The modulation transfer function MTF of this system is calculated as 0.391 at a Nyquist frequency of 15 lp/mm. The curve of transmittance with regard to gray level for the LC is obtained by calibration experiment. Based on the design principle, the prototype is made and used to take photos of objects under strong light greater than 2*10(5) lx. The clear details of [symbols: see text] presented in the image indicate that the PLCI can greatly improve the imaging quality. The theoretical calculations and experiment results prove that this device can extend the dynamic range and it provides a more effective method for upper atmospheric wind measurement. PMID- 22534904 TI - Achromatic quarter-wave plate using crystalline quartz. AB - Achromatic wave plates are ideal components for use with tunable and multiline laser systems, broadband sources, and in astronomical instrumentation. The present study deals with the design and characteristics of two different quarter wave achromatic retarders in the 500-700 nm range, using a cascaded system of two birefringent plates. The first of these shows a variation of less than +/-0.5 degrees , whereas the second system shows a variation of +/-4 degrees where the azimuth remains constant. Finally, a comparison between the two systems is made. The succinct and simple Jones matrix formalism has been used to derive the general expression for the equivalent retardation and azimuth of the combinations. It appears that the proposed arrangement has the promise of producing good achromatic combinations. PMID- 22534906 TI - Diffractive/refractive (hybrid) UV-imaging system for minimally invasive metrology: design, performance, and application experiments. AB - A hybrid imaging system was developed to enable the application of laser-based measurement techniques like UV laser-induced fluorescence in near-production engines with small access ports. For this task, wide-angle characteristics and high lens speed are required in combination with small engine-bound optics able to survive in harsh environmental conditions. Our approach combines a simple and robust access lens with refractive/diffractive (hybrid) imaging stages away from the engine that are customized for individual wavelength bands. We give a detailed insight into the design strategy, including the integration of diffractive optics and the performance of the system with analysis of the modulation transfer function (MTF), lens speed, and stray light. Finally, results from applications in an actual engine are shown. PMID- 22534907 TI - Fabrication and properties of ITO films treated by excited atomic oxygen. AB - We consider the crystallization of ITO films induced by excited atomic oxygen. Owing to it, transmittance of these films in visible ranges increased by ~20% and surface impedance dropped from 36 down to 4.6Omega/?. The treatment temperature (127 degrees C) was significantly below that of conventional crystallization (320 degrees C). Application of elastic light scattering diagnostics shows that rms surface roughness increased from 2.65 nm up to 4.07 nm after film treatment. ITO treatment does not change isotropic azimuthal structure of the surface. PMID- 22534908 TI - Comparison between elemental composition of human fingernails of healthy and opium-addicted subjects by laser-induced breakdown spectroscopy. AB - The objective of the present work is to identify differences in elemental fingernail composition between opium-addicted and healthy adult human subjects using laser-induced breakdown spectroscopy. Thirty nails from normal, healthy male subjects and 30 nails from opium-addicted male individuals were analyzed. Measurements on 60 nail samples were carried out, identifying 13 key species including 11 neutral elements and 2 ions. Discriminant Function Analysis (DFA) was used to classify the samples between the two groups. Spectral line intensities of elements including Fe, C, Ti, Mg, Si, Al, Ca, H, K, O, and Na were considered variables in DFA. This analysis demonstrates the efficient discrimination between the two groups. However, the number of samples in this work is not sufficient for a decisive conclusion and further research is needed to generalize this idea. PMID- 22534909 TI - Double-end-pumped Nd:YVO4 slab laser at 1064 nm. AB - We demonstrate a high-power laser diode stacks double-end-pumped Nd:YVO4 1064 nm slab laser with a folded stable-unstable hybrid resonator. An output power of 220 W was obtained at the pump power of 490 W with optical conversion efficiency of 44.9%. At the output power of 202 W, the M2 factors in the unstable direction and in the stable direction were 1.7 and 2.3, respectively. PMID- 22534910 TI - Tailoring fiber grating sensors for assessment of highly refractive fuels. AB - Three approaches that allow the tailoring of long period gratings based refractometric sensors for concentration measurement in fuel blends are employed to assess the fuel quality in biodiesel and biodiesel-petrodiesel blend. To allow the analysis of fuel samples with refractive index higher than fiber cladding one, the samples refractive indices were changed by thermo-optic effect and by dilution in a standard substance with low refractive index. The obtained results show the sensor can detect oil concentration in biodiesel samples with resolution as better as 0.07% and biodiesel concentration in biodiesel-petrodiesel samples with average resolution of 0.09%. PMID- 22534911 TI - Angular output of hollow, metal-lined, waveguide Raman sensors. AB - Hollow, metal-lined waveguides used as gas sensors based on spontaneous Raman scattering are capable of large angular collection. The collection of light from a large solid angle implies the collection of a large number of waveguide modes. An accurate estimation of the propagation losses for these modes is required to predict the total collected Raman power. We report a theory/experimental comparison of the Raman power collected as a function of the solid angle and waveguide length. New theoretical observations are compared with previous theory appropriate only for low-order modes. A cutback experiment is demonstrated to verify the validity of either theory. The angular distribution of Raman light is measured using aluminum and silver-lined waveguides of varying lengths. PMID- 22534912 TI - Two-dimensional wavelet transform for reliability-guided phase unwrapping in optical fringe pattern analysis. AB - This paper theoretically discusses modulus of two-dimensional (2D) wavelet transform (WT) coefficients, calculated by using two frequently used 2D daughter wavelet definitions, in an optical fringe pattern analysis. The discussion shows that neither is good enough to represent the reliability of the phase data. The differences between the two frequently used 2D daughter wavelet definitions in the performance of 2D WT also are discussed. We propose a new 2D daughter wavelet definition for reliability-guided phase unwrapping of optical fringe pattern. The modulus of the advanced 2D WT coefficients, obtained by using a daughter wavelet under this new daughter wavelet definition, includes not only modulation information but also local frequency information of the deformed fringe pattern. Therefore, it can be treated as a good parameter that represents the reliability of the retrieved phase data. Computer simulation and experimentation show the validity of the proposed method. PMID- 22534913 TI - Retrieval of aerosol extinction coefficient profiles from Raman lidar data by inversion method. AB - We regard the problem of differentiation occurring in the retrieval of aerosol extinction coefficient profiles from inelastic Raman lidar signals by searching for a stable solution of the resulting Volterra integral equation. An algorithm based on a projection method and iterative regularization together with the L curve method has been performed on synthetic and measured lidar signals. A strategy to choose a suitable range for the integration within the framework of the retrieval of optical properties is proposed here for the first time to our knowledge. The Monte Carlo procedure has been adapted to treat the uncertainty in the retrieval of extinction coefficients. PMID- 22534914 TI - Measurement of nonlinear refractive index coefficient using emission spectrum of filament induced by gigawatt-femtosecond pulse in BK7 glass. AB - A beam of 33 fs laser pulse with peak power of 15-40 GW was employed to explore a convenient method to determine the nonlinear refractive index coefficient of an optical glass. It is rare to investigate nonlinearities of optical glass with such an extreme ultrashort and powerful laser pulse. According to our method, only a single beam and a few experimental apparatuses are necessary to measure the nonlinear refractive index coefficient. The results from our method are in reasonable agreement with the others, which demonstrates that this new method works well, and the nonlinear refractive index coefficient is independent of measuring technology. Meanwhile, according to our results and those obtained by others in different laser power ranges, it seems that the nonlinear refractive index coefficient has a weak dependence on the laser peak power. PMID- 22534915 TI - Microoptics for efficient redirection of sunlight. AB - Ray-tracing calculations are employed to identify basic design rules for the configuration of microstructured daylighting systems. The results show the advantage of combinations of lenslike geometries in comparison to conventional microprism arrays regarding the overall light redirection efficiency as well as the producibility and cost efficiency. Measurements at silicone prototypes and large scale industrially produced acrylic panels confirmed the simulation results. Optimization leads to free-form geometries which can further be improved by selective roughening of specific microsurfaces. PMID- 22534916 TI - Double slit interferometry to measure the EUV refractive indices of solids using high harmonics. AB - Accurate values of the extreme ultraviolet (EUV) optical properties of materials are required to make EUV optics such as filters and multilayer mirrors. The optical properties of aluminum studied in this report are required, in particular, as aluminum is used as an EUV filter material. The complex refractive index of solid aluminum and the imaginary part of the refractive index of solid iron between 17 eV and 39 eV have been measured using EUV harmonics produced from an 800 nm laser focused to 10(14) Wcm(2) in an argon gas jet impinging on a double slit interferometer. PMID- 22534917 TI - Single-shot color fringe projection for three-dimensional shape measurement of objects with discontinuities. AB - A simple but effective fringe projection profilometry is proposed to measure 3D shape by using one snapshot color sinusoidal fringe pattern. One color fringe pattern encoded with a sinusoidal fringe (as red component) and one uniform intensity pattern (as blue component) is projected by a digital video projector, and the deformed fringe pattern is recorded by a color CCD camera. The captured color fringe pattern is separated into its RGB components and division operation is applied to red and blue channels to reduce the variable reflection intensity. Shape information of the tested object is decoded by applying an arcsine algorithm on the normalized fringe pattern with subpixel resolution. In the case of fringe discontinuities caused by height steps, or spatially isolated surfaces, the separated blue component is binarized and used for correcting the phase demodulation. A simple and robust method is also introduced to compensate for nonlinear intensity response of the digital video projector. The experimental results demonstrate the validity of the proposed method. PMID- 22534918 TI - Modulating and driving system for the application of microelectromechanical system infrared source array. AB - A problem demanding to be solved in the development of microelectromechanical system (MEMS) IR source array has been the driving circuit and system. A method that can achieve the requirements of high driving power, high output efficiency, high voltage precision, voltage compensation, and deep frequency modulation for driving and modulating a MEMS IR source array was proposed. A liner DC steady voltage integrated circuit ADP3336 is used to drive the source array directly with a programmable compensation module ensuring the precision of radiation peak wavelength. And a FPGA as the control core of the system modulates the frequency and width of the driving pulse to control the array coding pattern. The engineering value of the system would be increased with the application of the MEMS IR source. PMID- 22534919 TI - Robust and environmental insensitive fiber optic Sagnac interferometer for microwave photonic applications. AB - A technique that allows a fiber optic Sagnac interferometer based microwave photonic device to be implemented using non-polarization maintaining components inside the Sagnac loop while still obtaining an output that is insensitive to changes in environmental conditions is presented. It is based on inserting the non-polarization maintaining components in between a polarization beam combiner and a Faraday rotator mirror inside the loop. The technique also introduces a phase bias to the light propagating inside the loop. Experimental results demonstrate that the discretely and continuously tunable Sagnac loop based signal processors implemented using non-polarization maintaining components have an environmentally insensitive frequency response. PMID- 22534920 TI - Finite element modeling and testing of a deformable carbon fiber reinforced polymer mirror. AB - Thin-shelled composite mirrors have been recently proposed for use as deformable mirrors in optical systems. Large-diameter deformable composite mirrors can be used in the development of active optical zoom systems. We present the fabrication, testing, and modeling of a prototype 0.2 m diameter carbon fiber reinforced polymer mirror for use as a deformable mirror. In addition, three actuation techniques have been modeled and will be presented. PMID- 22534921 TI - Full-field digital gradient sensing method for evaluating stress gradients in transparent solids. AB - A full-field digital gradient sensing method is proposed for measuring small angular deflections of light rays due to local stresses in transparent planar solids. The working principle of the method is explained, and the governing equations are derived. The analysis shows that angular deflections of light rays can be linked to nonuniform changes in thickness and refractive index of the material. In mechanically loaded planar solids, the angular deflections can be further related to spatial gradients of first invariant of stresses under plane stress conditions. The proposed method is first demonstrated by capturing the angular deflection fields in two orthogonal directions for a thin plano-convex lens. The measured contours of constant angular deflection of light rays are in good agreement with the expected ones for a spherical wavefront. The method is also successfully implemented to study a stress concentration problem involving a line load acting on an edge of a large planar sheet. Again, the stress gradients, measured simultaneously along and perpendicular to the loading directions, are in good agreement with the analytical predictions. The measured stress gradients have also been used to estimate stresses in the load point vicinity where plane stress results hold. PMID- 22534922 TI - Reinforced direct bonding of optical materials by femtosecond laser welding. AB - A process for reinforcing a direct bond between optical materials using femtosecond laser welding is presented. As a side benefit, the optical transmission properties of the joined components are shown not to be altered by the joining process. The joints exhibits higher shear breakage loads, yielding a maximum measured joint strength of 5.25 MPa for an applied load of 75 kg in fused silica. The laser sealing of direct bonds between dissimilar materials improves their resistance to thermal shocks. Direct bonds sealed by a circular weld seam can withstand thermal shocks at temperatures at least twice as great as nonreinforced direct bonds. The combination of ultrashort laser welding and direct bonding provides an innovative joining method that benefits from the advantages of both contributing physical processes. PMID- 22534923 TI - Method to correct the distortion caused by amplified stimulated emission as motivated by LIF-based flow diagnostics. AB - Amplified stimulated emission (ASE) represents a significant issue in two-photon laser-induced fluorescence (TPLIF). The ASE effects are nonlinear and nonlocal, i.e., the ASE effects distort the LIF signal nonlinearly, and the distortion at one location depends on conditions at other locations. In this sense, the ASE effects pose a greater challenge to quantitative TPLIF than quenching and ionization. This work therefore seeks a method to correct such distortion. The method uses two LIF measurements, one with low signal-to-noise ratio (SNR) and negligible ASE distortion and another with high SNR but significant distortion, to generate a faithful measurement with high SNR. Extensive simulations were performed to evaluate the performance of this method for practical applications. PMID- 22534924 TI - Development and calibration of mirrors and gratings for the soft x-ray materials science beamline at the Linac Coherent Light Source free-electron laser. AB - This work discusses the development and calibration of the x-ray reflective and diffractive elements for the Soft X-ray Materials Science (SXR) beamline of the Linac Coherent Light Source (LCLS) free-electron laser (FEL), designed for operation in the 500 to 2000 eV region. The surface topography of three Si mirror substrates and two Si diffraction grating substrates was examined by atomic force microscopy (AFM) and optical profilometry. The figure of the mirror substrates was also verified via surface slope measurements with a long trace profiler. A boron carbide (B4C) coating especially optimized for the LCLS FEL conditions was deposited on all SXR mirrors and gratings. Coating thickness uniformity of 0.14 nm root mean square (rms) across clear apertures extending to 205 mm length was demonstrated for all elements, as required to preserve the coherent wavefront of the LCLS source. The reflective performance of the mirrors and the diffraction efficiency of the gratings were calibrated at beamline 6.3.2 at the Advanced Light Source synchrotron. To verify the integrity of the nanometer-scale grating structure, the grating topography was examined by AFM before and after coating. This is to our knowledge the first time B4C-coated diffraction gratings are demonstrated for operation in the soft x-ray region. PMID- 22534925 TI - ZrO2 thin-film-based sapphire fiber temperature sensor. AB - A submicrometer-thick zirconium dioxide film was deposited on the tip of a polished C-plane sapphire fiber to fabricate a temperature sensor that can work to an extended temperature range. Zirconium dioxide was selected as the thin film material to fabricate the temperature sensor because it has relatively close thermal expansion to that of sapphire, but more importantly it does not react appreciably with sapphire up to 1800 degrees C. In order to study the properties of the deposited thin film, ZrO2 was also deposited on C-plane sapphire substrates and characterized by x-ray diffraction for phase analysis as well as by atomic force microscopy for analysis of surface morphology. Using low coherence optical interferometry, the fabricated thin-film-based sapphire fiber sensor was tested in the lab up to 1200 degrees C and calibrated from 200 degrees to 1000 degrees C. The temperature resolution is determined to be 5.8 degrees C when using an Ocean Optics USB4000 spectrometer to detect the reflection spectra from the ZrO2 thin-film temperature sensor. PMID- 22534926 TI - Notes on Rayleigh scattering in lidar signals. AB - Classical and quantum formulations are used to estimate Rayleigh scattering within lidar signals. Within the classical approach, three scenarios are used to characterize atmospheric molecular composition: 2-component atmosphere (N2 and O2), 4-component atmosphere (N2, O2, Ar, and CO2), and 5-component atmosphere (N2, O2, Ar, CO2, and water vapor). First, analysis focuses on Rayleigh scattering, showing the relative difference between the three scenarios within classical approach. The relative difference in molecular scattering between 2(4) component atmosphere and 5-component atmosphere is below ~1%. The second analysis focuses on the lidar retrieval of aerosol backscatter and extinction coefficients showing the effect of different molecular formulations. A relative difference of +/-3% was found between the molecular formulation of 2-component atmosphere and the molecular formulation of 5-component atmosphere. Consideration of the Raman rotational lines blocked by the interference filter is important for the elastic channels, but of little significance in the N2 Raman channel. For lidar retrieval of aerosol profiles, the 5-component approximation is the best when the water vapor profile is known, but 2-component is still adequate and quite accurate when water vapor is only poorly known. PMID- 22534927 TI - Conceptual design of a 10 PW class laser with a hybrid amplification chain. AB - We design a 10 PW class laser system with a hybrid amplification chain. The hybrid amplification chain with a total gain of 10(4) composed of Ti:chrysoberyl amplifiers and Ti:sapphire amplifiers. The ability of this hybrid amplifier chain to control gain narrowing and gain saturation is demonstrated by numerical simulations. PMID- 22534928 TI - Characterization and closed-loop performance of a liquid mirror adaptive optical system. AB - A deformable mirror based on the principle of total internal reflection of light from an electrostatically deformed liquid-air interface was realized and used to perform closed-loop adaptive optical (AO) correction on a collimated laser beam aberrated by a rotating phase disk. Equations describing the resonant and oscillatory behavior of the liquid system were obtained and applied to the system under consideration. Characterization of the mirror included open- and closed loop frequency responses, determination of rise times, the damping times of the liquid, and the influence of liquid surface motion in the absence of external optical aberrations. The performance of the AO system was determined for static and dynamic aberrations for various sets of system parameters. The predictions of the general expressions were compared to the results of the experimental realization and were found to be in good agreement. PMID- 22534929 TI - Titanium dioxide nanoparticle based optical fiber humidity sensor with linear response and enhanced sensitivity. AB - An optical fiber humidity sensor employing an in-house scaled TiO2-nanoparticle doped nanostructured thin film as the fiber sensing cladding and evanescent wave absorption is reported. The main objective of the present work is to achieve a throughout-linear sensor response with high sensitivity, possibly over a wide dynamic range using the simplest possible sensor geometry. In order to realize this, first, the nanostructured sensing film is synthesized over a short length of a centrally decladded straight and uniform optical fiber and then a comprehensive experimental investigation is carried out to optimize the design configuration/parameters of the nanostructured sensing film and to achieve the best possible sensor response. Much improved sensitivity of 27.1 mV/%RH is observed for the optimized sensor along with a throughout-linear sensor response over a dynamic range as wide as 24% to 95%RH with an average response time of 0.01 s for humidification and 0.06 s for desiccation. In addition, the sensor exhibits a very good degree of reversibility and repeatability. PMID- 22534930 TI - Color separation of high-density dielectric rectangular grating in the Fresnel diffraction region. AB - A high-density dielectric rectangular grating is designed for color separation in a Fresnel diffraction field. The Fresnel field distribution is analyzed and the optimization conditions for color separation are given. The process of the modes propagating and energy exchanging with the diffraction orders are expressed by modal method. The color separation for different polarizations can be realized. The energy efficiency is 96.3% at the 633 nm wavelength and 86.9% at the 488 mm wavelength for both TE polarizations, while the energy efficiency is theoretically 96.3% at the 633 nm wavelength for TE polarization and 90.6% at the 488 nm wavelength for TM polarization. The field distributions are scanned by the near-field scanning optical microscopy, and the efficiency is 71.2% for the 633 nm wavelength and 67.3% for the 488 nm wavelength for both TE polarizations experimentally. PMID- 22534931 TI - Long memory retention time and high contrast ratio in a tristate liquid crystal display device. AB - We propose a method to obtain long memory retention time and high contrast ratio in a tristate liquid crystal display device. The proposed device has three unique liquid crystal (LC) states that are known as splay, pi twist, and bend, with different operating schemes for the two modes of operation, which are the memory (M) mode or dynamic (D) mode. A form of selective vertical or horizontal switching changes the optically compensated pi twist LC as a common black state in both the M and D modes into a bend LC state for the D mode or into the splay LC state for the M mode, respectively. PMID- 22534932 TI - Colors of transparent submicron suspensions on approaching the Rayleigh regime. AB - The features of scattered and transmitted light by dilute suspensions of transparent submicron particles are investigated both in the spectral and in the perceived colorimetric domains, as a function of effective particle diameter D, particle-host refractive-index mismatch m, and scattering angle theta. Our results show that the wavelength lambda-dependence of the scattering and extinction cross sections remains quite similar well beyond the Rayleigh regime up to particle sizes of a few hundreds nm, but only for specific scattering angles that depend on D and m, and tend to 90 degrees on approaching the Rayleigh regime. Close to this limit (D/lambda<<1), a simple criterion that relates the perceived scattering color at theta=90 degrees and the ratio of the sample extinction coefficients at two properly selected wavelengths is demonstrated. A comparison between computed and measured data is presented. PMID- 22534933 TI - Phase-function normalization for accurate analysis of ultrafast collimated radiative transfer. AB - The scattering of radiation from collimated irradiation is accurately treated via normalization of phase function. This approach is applicable to any numerical method with directional discretization. In this study it is applied to the transient discrete-ordinates method for ultrafast collimated radiative transfer analysis in turbid media. A technique recently developed by the authors, which conserves a phase-function asymmetry factor as well as scattered energy for the Henyey-Greenstein phase function in steady-state diffuse radiative transfer analysis, is applied to the general Legendre scattering phase function in ultrafast collimated radiative transfer. Heat flux profiles in a model tissue cylinder are generated for various phase functions and compared to those generated when normalization of the collimated phase function is neglected. Energy deposition in the medium is also investigated. Lack of conservation of scattered energy and the asymmetry factor for the collimated scattering phase function causes overpredictions in both heat flux and energy deposition for highly anisotropic scattering media. In addition, a discussion is presented to clarify the time-dependent formulation of divergence of radiative heat flux. PMID- 22534934 TI - Demonstration of spectral and spatial interferometry at THz frequencies. AB - A laboratory prototype spectral-spatial interferometer has been constructed to demonstrate the feasibility of the double-Fourier technique at far infrared (FIR) wavelengths (0.15-1 THz). It is planned to use this demonstrator to investigate and validate important design features and data-processing methods for future astronomical FIR interferometer instruments. In building this prototype, we have had to address several key technologies to provide an end-end system demonstration of this double-Fourier interferometer. We report on the first results taken when viewing single-slit and double-slit sources at the focus of a large collimator used to simulate real sources at infinity. The performance of the prototype instrument for these specific field geometries is analyzed to compare with the observed interferometric fringes and to demonstrate image reconstruction capabilities. PMID- 22534935 TI - Application of the fractional Fourier transform to the design of LCOS based optical interconnects and fiber switches. AB - It is shown that reflective liquid crystal on silicon (LCOS) spatial light modulator (SLM) based interconnects or fiber switches that use defocus to reduce crosstalk can be evaluated and optimized using a fractional Fourier transform if certain optical symmetry conditions are met. Theoretically the maximum allowable linear hologram phase error compared to a Fourier switch is increased by a factor of six before the target crosstalk for telecom applications of -40 dB is exceeded. A Gerchberg-Saxton algorithm incorporating a fractional Fourier transform modified for use with a reflective LCOS SLM is used to optimize multi casting holograms in a prototype telecom switch. Experiments are in close agreement to predicted performance. PMID- 22534936 TI - Emotions, arousal, and frontal alpha rhythm asymmetry during Beethoven's 5th symphony. AB - Music is capable of inducing emotional arousal. While previous studies used brief musical excerpts to induce one specific emotion, the current study aimed to identify the physiological correlates of continuous changes in subjective emotional states while listening to a complete music piece. A total of 19 participants listened to the first movement of Ludwig van Beethoven's 5th symphony (duration: ~7.4 min), during which a continuous 76-channel EEG was recorded. In a second session, the subjects evaluated their emotional arousal during the listening. A fast fourier transform was performed and covariance maps of spectral power were computed in association with the subjective arousal ratings. Subjective arousal ratings had good inter-individual correlations. Covariance maps showed a right-frontal suppression of lower alpha-band activity during high arousal. The results indicate that music is a powerful arousal modulating stimulus. The temporal dynamics of the piece are well suited for sequential analysis, and could be necessary in helping unfold the full emotional power of music. PMID- 22534937 TI - Acaricide resistance mechanisms in Rhipicephalus (Boophilus) microplus. AB - Acaricide resistance has become widespread in countries where cattle ticks, Rhipicephalus (Boophilus) microplus, are a problem. Resistance arises through genetic changes in a cattle tick population that causes modifications to the target site, increased metabolism or sequestration of the acaricide, or reduced ability of the acaricide to penetrate through the outer protective layers of the tick's body. We review the molecular and biochemical mechanisms of acaricide resistance that have been shown to be functional in R. (B.) microplus. From a mechanistic point of view, resistance to pyrethroids has been characterized to a greater degree than any other acaricide class. Although a great deal of research has gone into discovery of the mechanisms that cause organophosphate resistance, very little is defined at the molecular level and organophosphate resistance seems to be maintained through a complex and multifactorial process. The resistance mechanisms for other acaricides are less well understood. The target sites of fipronil and the macrocyclic lactones are known and resistance mechanism studies are in the early stages. The target site of amitraz has not been definitively identified and this is hampering mechanistic studies on this acaricide. PMID- 22534938 TI - Blood parasites in passerine birds from the Brazilian Atlantic Forest. AB - Parasites may lead bird species to extinction, affect host temporal and spatial population dynamics, alter community structure and alter individual' social status. We evaluated blood parasite prevalence and intensity according to bird families and species, among 925 birds that were caught in 2000 and 2001, in the Atlantic Forest in the State of Minas Gerais, Brazil. We applied Giemsa staining to thin blood smears, to detect blood parasites. The birds (n = 15.8%) in 11 families, were infected by at least one parasite genus, especially Muscicapidae (28.3%) and Conopophagidae (25%). Among the 146 infected birds, Plasmodium was detected in all bird families and had the highest prevalence (54.8%). Trypanosoma, Haemoproteus and microfilaria had lower prevalence rates (23.3, 23.3 and 2.1%, respectively). Birds caught during the rainy season were more infected than birds caught during the dry season. The overall low prevalence of blood parasites in birds is similar to the patterns found elsewhere in the Neotropical region. PMID- 22534939 TI - Use of coccidiostat in mineral salt and study on ovine eimeriosis. AB - Coccidiosis is a serious obstacle to sheep production, which is becoming a limiting factor, especially with regard to lamb production. However, there are few studies on this parasite in the State of Rio Grande do Norte. The aim of this study was to evaluate the action of decoquinate, added to mineral salt, for controlling Eimeria infection in lambs, and to identify which species are infecting sheep in the eastern region of the state. This study was carried out from August 2009 to January 2010, and used 76 animals. These were divided into two treatment groups: one with common mineral salt, and the other with mineral salt enriched with 6% micronized decoquinate. Fecal samples and body weight measurements were taken every 14 days for parasitological diagnosis, weight gain follow-up and quantitative analysis. The study showed that there was a significant difference in OPG only at the 7th collection, but no significant difference in weight gain. The Eimeria species found were E. ahsata. E. crandallis. E. granulosa. E. intrincata. E. ovina. E. faurei. E. ovinoidalis. E. pallida and E. parva. It was concluded that addition of decoquinate to mineral salt gave rise to lower oocyst elimination, thus favoring eimeriosis control in sheep. PMID- 22534940 TI - Biological parameters of cattle ticks fed on rabbits. AB - With the objective of encouraging the use of rabbits as alternative hosts for the cattle tick, four rabbits were infested on the ears and back. From the second day of infestation the developmental stages were observed. e duration of larval engorgement and changes were estimated between six and eight days in the region of the back and between 've and seven days in the pinna. e nymphal engorgement and changes occurred at approximately 10.80 +/- 2.65 days in the dorsal and 11.00 +/- 2.52 days in the ear, with the engorgement of adults and copulation occurring at 7.03 +/- 2.45 days, on the dorsal region and 8.55 +/- 1.82 days in the region of the pinna. e parasitic period ranged from 21 to 29 days (back) and from 23 to 30 days (pinna). e engorged females of the back and ear weighed on average 34.43 +/- 18.73 and 36.30 +/- 18.10 mg, respectively. e nutritional and reproductive efficiency indexes were 17.38 +/- 14.27 and 26.85 +/- 17.13% (back) and 17.42 +/- 12.22% and 30.70 +/- 19.80% (pinna). Although not appropriate to maintain successive generations of Rhipicephalus (Boophilus) microplus, rabbits can be used for different stages of engorgement of the ixodid, allowing experimental studies. PMID- 22534941 TI - Cyathostomin larvae: presence on Brachiaria humidicola grass during the rainy and dry seasons of Brazil. AB - The presence of cyathostomin larvae is directly associated to climatic conditions of each region. This study aimed to evaluate the ecology of infective larvae on Brachiaria humidicola during the dry and rainy seasons from October 2007 to September 2008 in a tropical region, Rio de Janeiro state, southeastern Brazil. Stools were collected from the rectum of horses naturally infected with cyathostomins at the beginning of the rainy season (October to March) and dry season (April to September). They were divided into four samples of 500 g and deposited on a grass patch of B. humidicola. Seven days later and every 15 days thereafter samples of feces and grass were collected and processed by the Baermann technique. The mean number of larvae recovered from the grass varied according to the season, with greater recovery of larvae during the peak of the dry season (14,700 L3.kg-1 DM). There was a statistically significant difference between L3 recovered from feces and grass, but not between L3 recovered from the grass base and apex. These results show that the region's climate favors the development and survival of infective cyathostomin larvae throughout the year, with a greater number of larvae during the dry season. PMID- 22534942 TI - Effectiveness of enrofloxacin for the treatment of experimentally-induced bovine anaplasmosis. AB - Four groups of six Holstein calves were inoculated with 3.6 * 10(7) erythrocytes parasitized with Anaplasma marginale. The criteria for treatment of calves were increasing A. marginale rickettsemia and 30% reduction of baseline packed cell volume (PCV) of each animal. Group 1 (G1) received 7.5 mg.kg(-1) of enrofloxacin in a single dose; Group 2 (G2) 7.5 mg.kg(-1) of enrofloxacin twice every three days; Group 3 (G3) 20 mg.kg(-1) of long-acting oxytetracycline in a single dose; and Group 4 (G4) a single dose of PBS. Physical examinations, blood smears and PCV were performed daily. On day treatment, G1, G2 and G3 animals had a mean rickettsemia of 17, 23 and 12%, respectively. At 2 days after treatment (DAT) G1 and G2 animals showed a significant reduction of rickettsemia (p < 0.05) compared to G3. G3 animals had high rates of rickettsemia in the first 2 DAT and a slow decrease until stabilization on 9 DAT. The mean PCV in G1 and G2 increased and stabilized after 7 and 8 DAT, respectively. PCV stabilization was achieved in G3 at 13 DAT. Both enrofloxacin and oxytetracycline were effective for the treatment of anaplasmosis, but enrofloxacin was faster reduction of rickettsemia and PCV recuperation (p < 0.05) compared to oxytetracycline. PMID- 22534943 TI - Molecular and serological detection of Ehrlichia spp. in cats on Sao Luis Island, Maranhao, Brazil. AB - Ehrlichiosis is a tick-borne disease that affects both humans and animals. The few existing reports on ehrlichiosis in Brazilian cats have been based on observation of morulae in leukocytes and, more recently, on molecular detection of Ehrlichia sp. In this study, we assessed occurrences of Ehrlichia sp. in the blood of 200 domestic cats in Sao Luis, Maranhao. Of the 200 animals tested, 11 (5.5%) were seropositive for Ehrlichia sp. and two (1%) were positive for Ehrlichia sp. in PCR. We also performed DNA sequence alignment to establish the identity of the parasite species infecting these animals, using the gene 16S rRNA. One cat presented infection with Ehrlichia sp. with 98% identity with E. canis, and another cat infected with Ehrlichia sp. showed 97% identity with E. chaffeensis. This is the first study on molecular detection of Ehrlichia sp. among domestic cats in Sao Luis, Maranhao. PMID- 22534944 TI - Toxoplasma gondii in goats from Curitiba, Parana, Brazil: risks factors and epidemiology. AB - Toxoplasmosis is a zoonosis caused by Toxoplasma gondii, a protozoan with wide geographical distribution and minimal parasitic specificity that affects many species of wild and domestic animals. In livestock, especially in small ruminants like goats, toxoplasmosis can cause abortion and the birth of weak animals, leading to economic losses to farmers, and is a major source of human infection. This is a seroepidemiological study of toxoplasmosis in goats in the state of Parana, Brazil. Sera from 405 goats from the metropolitan mesoregion of Curitiba, eastern state, were tested by the enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence antibody test (IFAT). Information on properties and goat characteristics was also collected using questionnaires. The prevalence of toxoplasmosis was 39.41 and 35.96% by ELISA and IFAT, respectively. T. gondii antibody prevalence increased with age. The risk factors for T. gondii infection in goats were: age over one year; exposure to cats, type of management and purpose of breeding. Other epidemiological factors and relevant control measures are discussed in the current study. PMID- 22534945 TI - Neospora caninum as causative agent of bovine encephalitis in Brazil. AB - For supporting the Brazilian bovine encephalitis surveillance program this study examined the differential diagnosis of Neospora caninum in central nervous system (CNS) by histological analysis (HE staining), immunohistochemistry (IHC), and nested-PCR using a set of primers from the Nc5 region of the genomic DNA and ITS1 region of the ribosomal DNA. A sample of 302 cattle presenting neurological syndrome and negative for rabies, aged 0 to 18 years, from herds in 10 Brazilian states was evaluated for N. caninum from January 2007 to April 2010. All specimens tested negative with IHC and nested-PCR using primers from the ITS1 region of ribosomal DNA, while two positive cases (0.66%) were found using primers from the Nc5 region of genomic DNA: a 20 month-old male and a 72 month old female, both from Sao Paulo State. Only the male presented severe multifocal necrotizing encephalitis associated with mononuclear cell infiltration, a pathognomonic lesion caused by parasites of the family Sarcocystidae, and only this case was associated with N. caninum thus representing 0.33% positivity. Future studies should explore the association of IHC and nested-PCR with real time PCR, a quantitative method that could be standardized for improving the detection of N. caninum in bovine CNS specimens. PMID- 22534946 TI - Trypanocidal activity of human plasma on Trypanosoma evansi in mice. AB - This study aimed to test an alternative protocol with human plasma to control Trypanosoma evansi infection in mice. Plasma from an apparently 27-year-old healthy male, blood type A+, was used in the study. A concentration of 100 mg.dL( 1) apolipoprotein L1 (APOL1) was detected in the plasma. Forty mice were divided into four groups with 10 animals each. Group A comprised uninfected animals. Mice from groups B, C and D were inoculated with a T. evansi isolate. Group B was used as a positive control. At three days post-infection (DPI), the mice were administered intraperitoneally with human plasma. A single dose of 0.2 mL plasma was given to those in group C. The mice from group D were administered five doses of 0.2 mL plasma with a 24 hours interval between the doses. Group B showed high increasing parasitemia that led to their death within 5 DPI. Both treatments eliminated parasites from the blood and increased the longevity of animals. An efficacy of 50 (group C) and 80% (group D) of human plasma trypanocidal activity was found using PCR. This therapeutic success was likely achieved in the group D due to their higher levels of APOL1 compared with group C. PMID- 22534947 TI - Effect of the granulometric characteristics of monensin sodium on controlling experimental coccidiosis in broiler chickens. AB - The aim of the present study was to investigate the efficacy of monensin sodium grain size on controlling coccidiosis in broiler chickens. Three hundred and fifty Cobb 700 chicks were infected experimentally with 8 * 10(4) sporulated oocysts of Eimeria spp. The birds were fed with diets supplemented with powdered (n = 150) or granulated (n = 150) monensin, with particle sizes of <= 100 um and 450-650 um, respectively. The remaining chicks (n = 50) were used as an unmedicated control group. The birds' weights and number of oocysts per gram of litter in each group were recorded weekly. A total of 96 birds were randomly selected and culled during the trial. Their intestinal oocyst counts and lesion scores were determined. No significant differences in body weights were found between the groups at the end of the study. The percentages of infected animals, oocyst counts and lesion scores were significantly higher in the control group than in the other two groups; the two treated groups did not show any appreciable differences to each other. Enteritis was observed in 14 birds, all in the group supplemented with granulated monensin. These results suggest that powdered and granulated monensin have comparable efficacy in controlling coccidiosis in broiler chickens. However, treatments with monensin sodium of high grain size may be subject to contraindications relating to enteritis. PMID- 22534948 TI - Occurrence of gastrointestinal parasites in goat kids. AB - Fecal samples from male and female goat kids, of different breeds and up to one year of age, were analyzed to determine egg and oocyst counts per gram of feces (EPG and OPG, respectively), and fecal culturing was performed to identify nematode genera. Helminth eggs and Eimeria spp. oocysts were found in 93.06% (188/202) and 77.22% (156/202) of the fecal samples, respectively. From fecal cultures, the following genera were identified: Cooperia in 11.88% (24/202), Haemonchus in 51.98% (105/202), Oesophagostomum in 9.4% (19/202), Strongyloides in 5.94 (12/202) and Trichostrongylus in 20.79% (42/202) of the samples. The Eimeria species found were E. alijevi in 25.24% (51/202), E. arloingi in 7.42% (15/202), E. caprina in 2.97% (6/202), E. caprovina in 10.39% (21/202), E. christenseni in 4.45% (9/202), E. joklchijevi in 11.38% (23/202), E. hirci in 9.4% (19/202) and E. ninakohlyakimovae in 28.71% (58/202) samples. Among the gastrointestinal parasites, the genus Haemonchus and two Eimeria species (E. ninakohlyakimovae and E. alijevi) were predominants. PMID- 22534949 TI - Detection of Neospora sp. antibodies in cart horses from urban areas of Curitiba, Southern Brazil. AB - Neospora caninum is a protozoan parasite which affects dogs as definitive hosts and several mammalian species as intermediate hosts mainly causing abortions and central nervous system disorders. The reemerging population of cart horses for carrying recycling material in urban areas of major cities in Brazil may have an impact on disease spreading, and these animals may be used as sentinels for environmental surveillance. Thus, the present study investigated the frequency of Neospora sp. antibodies in cart horses from Curitiba and surrounding areas, Parana State, Southern Brazil. IgG antibodies against Neospora sp. were detected using indirect fluorescence antibody test (IFAT), and titers equal to or higher than 1:50 were considered reactive. Of all samples, 14/97 (14.4%) were positive: 2/29 (6.9%) were younger than 5; 5/26 (19.2%) between 6 and 9; and 6/31 (19.4%) older than 10 years of age. One of the 11 animals with unknown age was positive (9.1%). Cart horses are likely to be more exposed to dog feces and to Neospora sp. oocyst contamination in urban settings and a lower frequency of disease in dogs may have a negative impact on horse infection risk in these areas. PMID- 22534950 TI - Gastrointestinal parasites of sheep, municipality of Lajes, Rio Grande do Norte, Brazil. AB - This study investigated the gastrointestinal parasitism by helminths and protozoa in sheep (Ovis aries) Santa Ines breed, municipality of Lajes, Rio Grande do Norte. Monthly, from April 2005 to August 2007, stool samples were collected from two tracer lambs in the first day of the experiment and performed a necropsy of these animals in 44th day. A total of 64 lambs were sampled, but only 62 lambs were slaughtered. The fecal samples were examined by sedimentation in water. The contents of the abomasum, small intestine and large intestine were examined for the recovery of helminths. The parasitological examination revealed eggs of the following groups of helminths: Strongyloidea, Strongyloides sp., Trichuris sp., and Moniezia sp. Also were found oocysts of Eimeria spp., cysts of Entamoeba ovis and Giardia duodenalis. The helminths identified from examining the contents were: Haemonchus contortus, Cooperia pectinata, Cooperia punctata, Trichostrongylus colubriformis, Moniezia expansa, Oesophagostomum sp. Skrjabinema ovis and Trichuris sp. PMID- 22534951 TI - Isolation and genotyping of Toxoplasma gondii from pregnant dairy cows (Bos taurus) slaughtered. AB - The current study aimed to evaluate serology, and isolate and genotype Toxoplasma gondii strains from pregnant dairy cows, slaughtered in an abattoir for human consumption, and their fetuses. Blood from 60 pregnant dairy cows and blood and tissue samples (brain, lung, heart, and liver) from their fetuses were collected and analyzed in a mouse bioassay. Antibodies against T. gondii were observed in 48.3% of cows and 3.7% of fetuses (IFAT, titers >= 50 for cows and 25 for fetuses were considered positive). Fourteen fetuses (23.3%) and six cows (10.0%) were identified as positive in the bioassay. T. gondii was isolated from a blood sample of a cow older than 4 years old in the 6th month of pregnancy, and from a blood sample of a fetus in the 6th month of gestation. These isolates were identified by polymerase chain reaction (PCR) as being of T. gondii and both strains showed type II alleles for all PCR-restriction fragment length polymorphism (PCR-RFLP) markers tested. T. gondii type II strain from cattle was isolated for the first time in Brazil. The current study also showed that transplacental transmission of T. gondii naturally occurs in dairy cows (23.3%) from Southern Brazil. PMID- 22534952 TI - Use of negative binomial distribution to describe the presence of Anisakis in Thyrsites atun. AB - Nematodes of the genus Anisakis have marine fishes as intermediate hosts. One of these hosts is Thyrsites atun, an important fishery resource in Chile between 38 and 41 degrees S. This paper describes the frequency and number of Anisakis nematodes in the internal organs of Thyrsites atun. An analysis based on spatial distribution models showed that the parasites tend to be clustered. The variation in the number of parasites per host could be described by the negative binomial distribution. The maximum observed number of parasites was nine parasites per host. The environmental and zoonotic aspects of the study are also discussed. PMID- 22534954 TI - SYBR Green I: fluorescence properties and interaction with DNA. AB - In this study, we have investigated the fluorescence properties of SYBR Green I (SG) dye and its interaction with double-stranded DNA (dsDNA). SG/dsDNA complexes were studied using various spectroscopic techniques, including fluorescence resonance energy transfer and time-resolved fluorescence techniques. It is shown that SG quenching in the free state has an intrinsic intramolecular origin; thus, the observed >1,000-fold SG fluorescence enhancement in complex with DNA can be explained by a dampening of its intra-molecular motions. Analysis of the obtained SG/DNA binding isotherms in solutions of different ionic strength and of SG/DNA association in the presence of a DNA minor groove binder, Hoechst 33258, revealed multiple modes of interaction of SG inner groups with DNA. In addition to interaction within the DNA minor groove, both intercalation between base pairs and stabilization of the electrostatic SG/DNA complex contributed to increased SG affinity to double-stranded DNA. We show that both fluorescence and the excited state lifetime of SG dramatically increase in viscous solvents, demonstrating an approximate 200-fold enhancement in 100 % glycerol, compared to water, which also makes SG a prospective fluorescent viscosity probe. A proposed structural model of the SG/DNA complex is compared and discussed with results recently reported for the closely related PicoGreen chromophore. PMID- 22534955 TI - Pulmonary function after anterior double thoracotomy approach versus posterior surgery with costectomies in idiopathic thoracic scoliosis. AB - INTRODUCTION: The surgical approach in the treatment of idiopathic thoracic scoliosis depends on the type of curve involved. In anterior correction, the rib hump is corrected by derotating the thoracic spine. In posterior scoliosis surgery, additional rib hump resection is sometimes necessary to achieve an optimal cosmetic result. The aim of this study was to compare pulmonary function in these two patient groups. MATERIALS AND METHODS: Forty patients in the anterior group (A) were treated with standard double thoracotomy, with an anterior derotation spondylodesis and a primary stable dual-rod system. The posterior group (P) included 29 patients who were treated with a pedicle screw based posterior instrumentation spondylodesis, with additional rib hump resection. Pulmonary function was evaluated preoperatively, on the 12th postoperative day, and at 3, 6, 12 and 24 months during the follow-up. RESULTS: The patients' mean age was 15 years in group A and 19 in group P with a standard deviation 8.7 years and a significant difference. With regard to body height or weight there were no significant differences between the two groups. In group A, the deterioration in pulmonary function immediately after the operation (from [Formula: see text] 75.3 %/71.3 % preoperatively to 38.5 %/36.1 % postoperatively) was clearer than in group P ([Formula: see text] 71.6 %/65.7 % preoperatively to 47.7 %/48.4 % postoperatively). During a follow-up period of 3 months, the values improved in both groups in comparison with the values immediately after the operation. Up to the 2 year follow-up, pulmonary function in the posterior and anterior groups corresponded to the preoperative values, with no significant differences. There was a trend toward moderately increased values in the posterior group and moderately decreased values in the anterior group at the 2-year follow-up examination, in comparison with the preoperative baseline, but without a statistically significant difference. Two major complications occurred in the anterior group, with reintubation and several bronchoscopy examinations due to atelectasis. CONCLUSION: The severe deterioration in group A is caused by the substantial trauma with double thoracotomy in contrast to rib hump resection. For patients with severe restrictive pulmonary distress, posterior instrumentation in combination with rib hump resection would be preferable to an anterior procedure involving double thoracotomy. Respiratory physiotherapy exercise should be administered in order to minimise postoperative pulmonary distress. In conclusion opening of the chest wall leads to deterioration of pulmonary function with improvement to the preoperative values after 6 months in the posterior and after 24 months in the anterior group. PMID- 22534956 TI - Myocardial infarction due to malposition of ECMO cannula. PMID- 22534957 TI - The clinical and radiographical results of reverse total shoulder arthroplasty with eccentric glenosphere. AB - BACKGROUND: Scapular notching is a common worrying finding after reverse total shoulder arthroplasty (RSA). Eccentric glenospheres have recently been developed in an attempt to prevent notching. The purpose of this study was to evaluate the clinical and radiological results of RSA with an eccentric glenosphere and compare the incidence and the severity of scapular notching using a concentric glenosphere. METHODS: A prospective evaluation was performed of 57 consecutive RSA performed over a two-year period. At a minimum of two years postoperatively, 47 RSAs with a mean 30.4 months follow-up were evaluated clinically and radiographically and compared to a historical control group of concentric glenospheres performed by the same surgeon. RESULTS: The mean Constant score significantly increased (from 32.4 to 71.8) postoperatively (p < 0.0001). Active forward flexion and external rotation also significantly increased (p < 0.0001). Overall, scapular notching was present in 19 shoulders (40.4 %). Grade 1 notching was observed in 13 shoulders (27.7 %), grade 2 in five shoulders (10.6 %), grade 3 in one shoulder (2.1 %), and grade 4 in no shoulders. There was no significant difference in the incidence (p = 0.289) of notching between the eccentric and concentric glenospheres. However, the severity of notching was significantly decreased (p = 0.011) with an eccentric glenosphere. The postoperative Constant score was not significantly different between patients with or without notching (p = 0.651). CONCLUSION: A Grammont type RSA with eccentric glenosphere can result in good clinical outcomes. An eccentric glenosphere does not prevent notching, but decreases the severity of scapular notching at early follow-up. PMID- 22534958 TI - Pain and activity levels before and after platelet-rich plasma injection treatment of patellar tendinopathy: a prospective cohort study and the influence of previous treatments. AB - PURPOSE: The aim of this study was to evaluate the outcome of patients with patellar tendinopathy treated with platelet-rich plasma injections (PRP). Additionally, this study examined whether certain characteristics, such as activity level or previous treatment affected the results. METHODS: Patients (n = 36) were asked to fill in the Victorian Institute of Sports Assessment - Patellar questionnaire (VISA-P) and visual analogue scales (VAS), assessing pain in activities of daily life (ADL), during work and sports, before and after treatment with PRP. Of these patients, 14 had been treated before with cortisone, ethoxysclerol, and/or surgical treatment (group 1), while the remaining patients had not been treated before (group 2). RESULTS: Overall, group 1 and group 2 improved significantly on the VAS scales (p < .0.05). However, group 2 also improved on VISA-P (p = .0.003), while group 1 showed less healing potential (p = 0.060). Although the difference between group 1 and group 2 at follow-up was not considered clinically meaningful, over time both groups showed a clinically significant improvement. CONCLUSION: After PRP treatment, patients with patellar tendinopathy showed a statistically significant improvement. In addition, these improvements can also be considered clinically meaningful. However, patients who were not treated before with ethoxysclerol, cortisone, and/or surgical treatment showed the improvement. PMID- 22534959 TI - The mechanism of the photochromic transformation of spirorhodamines. AB - We investigate the equilibrium, kinetics, and mechanism of the photochromic transformation of a series of amido spirorhodamine compounds-differing in the nature of the substituents of the amido group and in the rhodamine chromophore-in ethanol at room temperature in the presence of trifluoroacetic acid. A proton participates in the equilibrium between the spiro form and the open rhodamine form. The relaxation times in the dark or under continuous irradiation show a linear dependence on the proton concentration. The slopes of these plots show a linear free energy relation with the equilibrium constant of the transformation. A mechanism involving reversible reaction steps between four states: the two thermodynamically stable isomers, a protonated spiro form, and a deprotonated open form, can account for the kinetic observations in the dark and under irradiation. PMID- 22534960 TI - Starting dialysis is dangerous: how do we balance the risk? AB - Recent studies of timing of dialysis initiation have challenged the recent trend to earlier initiation of therapy. The observed outcomes though are a consequence of the balance between the risks of advanced uremia versus the inherent dangers relating to dialysis therapy itself. Many of these risks are inherent in how dialysis treatment is currently carried out, and may indeed be amenable to mitigation, through refinement of clinical practice (and potentially modality choice). This article aims to lay out a discussion relating to patient outcomes being the composite result of this balance, pivoting on the vulnerability of a particular patient to these attendant risks. PMID- 22534962 TI - Arterial stiffness and pulse pressure in CKD and ESRD. AB - We recognize that increased systolic pressure is the most challenging form of hypertension today and that pulse pressure as an independent cardiovascular risk factor has focused attention on arterial stiffness and wave reflections as the most important factors determining these pressures. In recent years, many studies emphasized the role of arterial rigidity in the development of cardiovascular diseases, and it was shown that stiffening of arteries is associated with increased cardiovascular mortality and morbidity. Moreover,arterial stiffening is linked to decreased glomerular filtration rate, and is predictive of kidney disease progression and the patient's cardiovascular outcome. Premature vascular aging and arterial stiffening are observed with progression of chronic kidney disease (CKD) and in end-stage renal disease(ESRD). This accelerated aging is associated with outward remodeling of large vessels, characterized by increased arterial radius not totally compensated for by artery wall hypertrophy. Arterial stiffening in CKD and ESRD patients is of multifactorial origin with extensive arterial calcifications representing a major covariate. With aging, the rigidity is more pronounced in the aorta than in peripheral conduit arteries, leading to the disappearance or inversion of the arterial stiffness gradient and less protection of the microcirculation from high-pressure transmission. Various non pharmacological or pharmacological interventions can modestly slow the progression of arterial stiffness,but arterial stiffness is, in part, pressure dependent and treatments able to stop the process mainly include antihypertensive drugs. PMID- 22534961 TI - Divergent roles of Smad3 and PI3-kinase in murine adriamycin nephropathy indicate distinct mechanisms of proteinuria and fibrogenesis. AB - Multiple transforming growth factor (TGF)-beta-induced fibrogenic signals have been described in vitro. To evaluate mechanisms in vivo, we used an adriamycin nephropathy model in 129x1/Svj mice that display massive proteinuria by days 5 to 7 and pathological findings similar to human focal segmental glomerulosclerosis by day 14. TGF-beta mRNA expression increased after day 7 along with nuclear translocation of the TGF-beta receptor-specific transcription factor Smad3. Inhibiting TGF-beta prevented both pathological changes and type-I collagen and fibronectin mRNA expression, but proteinuria persisted. Renal Akt was phosphorylated in adriamycin-treated mice, suggesting PI3-kinase activation. Expression of mRNA for the p110gamma isozyme of PI3-kinase was specifically increased and p110gamma colocalized with nephrin by immunohistochemistry early in disease. Nephrin levels subsequently decreased. Inhibition of p110gamma by AS605240 preserved nephrin expression and prevented proteinuria. In cultured podocytes, adriamycin stimulated p110gamma expression. AS605240, but not a TGF beta receptor kinase inhibitor, prevented adriamycin-induced cytoskeletal disorganization and apoptosis, supporting a role for p110gamma in podocyte injury. AS605240, at a dose that decreased proteinuria, prevented renal collagen mRNA expression in vivo but did not affect TGF-beta-stimulated collagen induction in vitro. Thus, PI3-kinase p110gamma mediates initial podocyte injury and proteinuria, both of which precede TGF-beta-mediated glomerular scarring. PMID- 22534963 TI - Changes to the end-stage renal disease quality incentive program. AB - Monitoring the quality of dialysis care has long been a component of the Medicare ESRD program. As part of the 2008 Medicare Improvements for Patients and Providers Act (MIPPA), Congress mandated the Quality Incentive Program (QIP), which linked measures of care quality to payments. The legislation embraced the idea that this linkage of federal money to performance would encourage the purchase of greater 'value.' The first 2 program years for the QIP use a simple scoring methodology and a limited scope of quality metrics. For payment year 2014 (performance period calendar year 2012), the program changes substantially, with an expanded number of quality measures and a more complex scoring methodology. In this article, we describe the program structure, quality measures, scoring system, and financial impact. PMID- 22534965 TI - A manager's priorities. PMID- 22534966 TI - Guidelines for conducting bulletproof workplace investigations: part I- preparation and interviewing issues. AB - Conducting proper and thorough investigations is one of the most important and most difficult responsibilities for today's health care manager in terms of avoiding or successfully defending lawsuits. This article provides guidance for managers on how to use proper interview and investigative techniques while avoiding a violation of employees' rights to privacy. Suggestions are provided on how to protect confidential information obtained by the investigation. Interview questions that may be asked during the investigation are provided. By asking appropriate questions and documenting all aspects of the investigative process, employers can provide useful information to their legal counsel and be on the winning side if the situation results in litigation. PMID- 22534964 TI - Sodium nitrite protects against kidney injury induced by brain death and improves post-transplant function. AB - Renal injury induced by brain death is characterized by ischemia and inflammation, and limiting it is a therapeutic goal that could improve outcomes in kidney transplantation. Brain death resulted in decreased circulating nitrite levels and increased infiltrating inflammatory cell infiltration into the kidney. Since nitrite stimulates nitric oxide signaling in ischemic tissues, we tested whether nitrite therapy was beneficial in a rat model of brain death followed by kidney transplantation. Nitrite, administered over 2 h of brain death, blunted the increased inflammation without affecting brain death-induced alterations in hemodynamics. Kidneys were transplanted after 2 h of brain death and renal function followed over 7 days. Allografts collected from nitrite-treated brain dead rats showed significant improvement in function over the first 2 to 4 days after transplantation compared with untreated brain-dead animals. Gene microarray analysis after 2 h of brain death without or with nitrite therapy showed that the latter significantly altered the expression of about 400 genes. Ingenuity Pathway Analysis indicated that multiple signaling pathways were affected by nitrite, including those related to hypoxia, transcription, and genes related to humoral immune responses. Thus, nitrite therapy attenuates brain death-induced renal injury by regulating responses to ischemia and inflammation, ultimately leading to better post-transplant kidney function. PMID- 22534967 TI - An employer's guide to controlling health care costs. AB - Employers are facing difficult times with respect to controlling costs associated with health care benefits provided to employees. Current trends in employer health care costs are unsustainable. Moreover, public policy changes in the form of the Patient Protection and Affordable Care Act are tied up in legal review, and the results are uncertain. This article provides a brief background on health care benefits and costs, discusses consumer-driven and traditional models of health care plans, and reviews cost-control tactics that employers should consider. It concludes with a review of the current situation with recommendations to employers for moderating future health care costs. PMID- 22534968 TI - Improving quality in long-term care facilities through increased regulations and enforcement. AB - This research addresses the origins and motivations that drive long-term-care regulations and enforcement. It outlines the historical development of the US long-term-care system and describes regulations that focus on improving quality of care. Current long-term-care regulations are inadequate and ineffective because of fragmentation and inconsistencies that have resulted in conflicts of interest, inequitable services, underfunded care, low reimbursement, cumbersome and duplicative processes, and inadequate training and compensation for providers. Reforms such as establishing higher standards and modifying enforcement procedures are necessary to bring about increased quality of care for long-term-care consumers. PMID- 22534969 TI - The effects of national health care reform on local businesses--part II: study methodology and primary research questions. AB - This is the second part of a 3-part examination of what may be potentially expected from the 2010 national health care reform legislation. Political researchers and pundits have speculated endlessly on the many changes mandated by the 2010 national health care reform legislation, styled the Patient Protection and Affordable Care Act. A review and assessment of this legislation at several levels (federal, state, state agency, local region, and individual business leaders) were undertaken. The results of this expanded analysis suggest strongly that, nationally, members of the business community and their employees will benefit from the legislation early on (years 1 through 3) and then likely will be impacted adversely as the payment mechanisms driving the legislation are tightened by new federal regulations (year 4 onward). As a result of this research, it is surmised that businesses will be immediately impacted by the legislation, with small business owners being the prime beneficiaries of the new legislation, owing to the availability of coverage to approximately 32 million individuals who previously had no access to coverage. In that regard, the soon-to be-newly insured population also will be a prime beneficiary of the legislation as the limitations on chronic illnesses and other preexisting conditions will be reduced or eliminated by the legislation. PMID- 22534971 TI - Project management office in health care: a key strategy to support evidence based practice change. AB - This article describes the contribution of a Transition Support Office (TSO) in a health care center in Canada to supporting changes in practice based on evidence and organizational performance in the early phase of a major organizational change. Semistructured individual interviews were conducted with 11 members of the TSO and 13 managers and clinicians from an ambulatory sector in the organization who received support from the TSO. The main themes addressed in the interviews were the description of the TSO, the context of implementation, and the impact. Using the Competing Value Framework by Quinn and Rohrbaugh [Public Product Rev. 1981;5(2):122-140], results revealed that the TSO is a source of expertise that facilitates innovation and implementation of change. It provides material support and human expertise for evidence-based projects. As a single organizational entity responsible for managing change, it gives a sense of cohesiveness. It also facilitates communication among human resources of the entire organization. The TSO is seen as an expertise provider that promotes competency development, training, and evidence-based practices. The impact of a TSO on change in practices and organizational performance in a health care system is discussed. PMID- 22534972 TI - Innovation spaces: six strategies to inform health care. AB - Innovation remains an understudied resource within health care. Furthermore, the goals of US health care reform make innovation vitally important, while the time and resource limitations characteristic of health care make new strategies for innovation both necessary and potentially highly meaningful. The purpose of this study was to examine strategies for innovation in various industries and draw lessons for improving innovation in health care. This qualitative study began with literature research that provided a framework for discussion and identified a recurrent challenge in innovation: balancing the freedom to be creative with the need for structured management of ideas. Researchers then identified leading innovative companies and conducted phone interviews with innovation officers and other experts about their strategies for addressing the major innovation challenge. This article breaks out innovation strategies into 6 categories (dedicated times, formal teams, outside ideas, idea-sharing platforms, company/job goals, and incentives) and evaluates them for levels of control, yield, and pervasiveness. Based on this analysis, recommendations are offered for improving innovation in health care, calling for employee time allocated to innovation, dedicated innovation teams, and the incorporation of outside ideas. PMID- 22534973 TI - Dysfunctional health service conflict: causes and accelerants. AB - This article examines the causes and accelerants of dysfunctional health service conflict and how it emerges from the health system's core hierarchical structures, specialized roles, participant psychodynamics, culture, and values. This article sets out to answer whether health care conflict is more widespread and intense than in other settings and if it is, why? To this end, health care power, gender, and educational status gaps are examined with an eye to how they undermine open communication, teamwork, and collaborative forms of conflict and spark a range of dysfunctions, including a pervasive culture of fear; the deny and-defend lawsuit response; widespread patterns of hierarchical, generational, and lateral bullying; overly avoidant conflict styles among non-elite groups; and a range of other behaviors that lead to numerous human resource problems, including burnout, higher staff turnover, increased errors, poor employee citizenship behavior, patient dissatisfaction, increased patient complaints, and lawsuits. Bad patient outcomes include decreased compliance and increased morbidity and mortality. Health care managers must understand the root causes of these problems to treat them at the source and implement solutions that avoid negative conflict spirals that undermine organizational morale and efficiency. PMID- 22534974 TI - Prolonged depletion of antioxidant capacity after ultraendurance exercise. AB - PURPOSE: The purpose of this study was to examine the short- and long-term (up to 1 month) effects of an ultraendurance running event on redox homeostasis. METHODS: Markers of oxidative stress and antioxidant capacity in peripheral blood were assessed after a single-stage 233-km (143 miles) running event. Samples were collected from nine men (mean+/-SD: age=46.1+/-5.3 yr, body mass index=24.9+/-2.3 kg.m-2, maximal oxygen uptake=56.3+/-3.3 mL.kg-1.min-1). Peripheral blood mononuclear cells were assayed for nonspecific DNA damage (frank strand breaks) and damage to DNA caused specifically by oxidative stress (formamidopyrimidine DNA glycosylase-dependent damage). Protein carbonylation and lipid peroxidation were assessed in plasma. Reduced glutathione (GSH) was measured in whole blood. RESULTS: Peripheral blood mononuclear cell frank strand breaks were elevated above baseline at 24 h after the race (P<0.001). Formamidopyrimidine DNA glycosylase-dependent oxidative DNA damage was increased immediately after the race (P<0.05). Protein carbonylation remained elevated for 7 d after the race (P<0.04), whereas lipid peroxidation was increased for 24 h (P<0.05) and fell below baseline 28 d later (P<0.05). GSH, a measure of antioxidant capacity, also showed a biphasic response, increasing by one-third after the race (P<0.01) and falling to two-thirds of baseline levels 24 h later (P<0.001). GSH remained depleted to approximately one-third of prerace values 28 d after the race (P<0.01). CONCLUSIONS: Ultraendurance exercise causes oxidative stress, which persists for one calendar month depending on the specific biomarker examined. These results suggest that ultraendurance events are associated with a prolonged period of reduced protection against oxidative stress. PMID- 22534977 TI - Increased platelet aggregation and serum thromboxane levels in aspirin-treated patients with prior myocardial infarction. AB - The antiplatelet effect of aspirin displays considerable inter-individual variability. We investigated the antiplatelet effect of aspirin in patients with coronary artery disease on aspirin mono-therapy with and without prior myocardial infarction (MI). Further, we investigated whether the effect of aspirin differed between patients with and without aspirin use at the time of MI onset. We performed a study on 231 patients, including 171 with prior MI. Among patients with only one prior MI (116 patients), 59 patients were on aspirin at the time of MI onset. All patients received 75 mg aspirin as mono-therapy. Platelet aggregation was assessed by multiple electrode aggregometry (Multiplate) and VerifyNow, and platelet activation was evaluated by soluble P-selectin. Furthermore, we measured serum thromboxane B2. MI patients had higher median platelet aggregation levels than patients without prior MI when evaluated by Multiplate (parachidonic acid<0.0001, pcollagen=0.20). This was not supported by VerifyNow. Furthermore, MI patients had higher median serum thromboxane B2 levels than patients without prior MI (p=0.01). Patients on aspirin before MI onset had significantly higher median aggregation levels compared with MI patients not on aspirin when evaluated by Multiplate (pcollagen=0.02) and VerifyNow (p<0.0001). In conclusion, patients with prior MI had higher platelet aggregation levels than patients without prior MI when evaluated by Multiplate, despite same aspirin dose and optimal compliance. Serum thromboxane B2 levels were higher in MI patients than in patients without prior MI. Finally, patients on aspirin before MI onset had higher aggregation levels compared with patients not on aspirin. PMID- 22534975 TI - Spontaneous osteonecrosis of the knee (SONK). AB - PURPOSE: Spontaneous osteonecrosis of the knee (SONK/Morbus Ahlback) mainly affects the medial condyle of elderly women. It is assumed that localized vascular insufficiency leads to necrosis of the subchondral bone with subsequent disruption of the nutrition supply to the cartilage above. The aetiology remains unclear in detail. Operative treatment procedures compete against non-operative strategies, whereas the outcome is unpredictable in many cases. METHOD: A consecutive case series of five patients suffering from SONK was analysed. All patients underwent a clinical examination, magnetic resonance imaging (MRI) and dual-energy X-ray absorptiometry scan, as well as laboratory analyses and visual analogue scale (VAS) evaluation. Our treatment regime is based on high-dose vitamin D administered orally and intravenous application of 3 mg ibandronate two times within 8 weeks. Another 8 weeks later, all patients were followed up including a follow-up MRI. RESULTS: Within 4 weeks, all patients were free of symptoms. The MRI follow-up showed remission of the bone marrow oedema in every case studied. VAS decreased significantly from 7.4 +/- 1.0 pre-interventional to 0.8 +/- 1.0 post-interventional. No allergic reactions or other side effects were documented. CONCLUSION: We showed that our treatment regime not only eliminated the pathological findings in the MRI of all cases studied, but also decreased the pain level and functional limitations within a short-time period. LEVEL OF EVIDENCE: IV. PMID- 22534976 TI - Associated factors of different nutrition indicators in German nursing home residents: comparative results of a multicenter cross-sectional study. AB - BACKGROUND: Malnutrition is one of the most important care problems in the nursing home care sector. The subject of this analysis is the investigation of associative factors for different indicators of malnutrition of residents in nursing homes in Germany. METHODS: A secondary data analysis was conducted using data from 4,478 nursing home residents. Unintended weight loss or reduced intake and BMI <= 20 were analysed as indicators for malnutrition. The influence of age, sex, co-morbidities and care dependency were investigated in logistic regression models. RESULTS: Residents with a high care dependency had a higher risk of suffering weight loss/reduced intake. With regard to BMI <= 20, residents aged > 85 years, female gender, cancer, musculoskeletal disease as well as high care dependency had a higher risk. CONCLUSION: In both models, care dependency plays a major role in explaining malnutrition. Associative factors for malnutrition must be interpreted according to the indicators used to define malnutrition. PMID- 22534978 TI - Roles of ZIP8, ZIP14, and DMT1 in transport of cadmium and manganese in mouse kidney proximal tubule cells. AB - Chronic exposure to cadmium causes preferential accumulation of cadmium in the kidney, leading to nephrotoxicity. In the process of renal cadmium accumulation, the cadmium bound to a low-molecular-weight metal-binding protein, metallothionein, has been considered to play an important role in reabsorption by epithelial cells of proximal tubules in the kidney. However, the role and mechanism of the transport of Cd(2+) ions in proximal tubule cells remain unclear. Zinc transporters such as Zrt, Irt-related protein 8 (ZIP8) and ZIP14, and divalent metal transporter 1 (DMT1) have been reported to have affinities for Cd(2+) and Mn(2+). To examine the roles of these metal transporters in the absorption of luminal Cd(2+) and Mn(2+) into proximal tubule cells, we utilized a cell culture system, in which apical and basolateral transport of metals can be separately examined. The uptake of Cd(2+) and Mn(2+) from the apical side of proximal tubule cells was inhibited by simultaneous addition of Mn(2+) and Cd(2+), respectively. The knockdown of ZIP8, ZIP14 or DMT1 by siRNA transfection significantly reduced the uptake of Cd(2+) and Mn(2+) from the apical membrane. The excretion of Cd(2+) and Mn(2+) was detected predominantly in the apical side of the proximal tubule cells. In situ hybridization of these transporters revealed that ZIP8 and ZIP14 are highly expressed in the proximal tubules of the outer stripe of the outer medulla. These results suggest that ZIP8 and ZIP14 expressed in the S3 segment of proximal tubules play significant roles in the absorption of Cd(2+) and Mn(2+) in the kidney. PMID- 22534979 TI - Formulation and mechanical properties of emulsion-based model polymer foams. AB - We produce cellular material based on the formulation of model emulsions whose drop size and composition may be continuously tuned. The obtained solid foams are characterized by narrow cell and pore size distributions in direct relation with the emulsion structure. The mechanical properties are examined, by varying independently the cell size and the foam density, and compared to theoretical predictions. Surprisingly, at constant density, Young's modulus depends on the cell size. We believe that this observation results from the heterogeneous nature of the solid material constituting the cell walls and propose a mean-field approach that allows describing the experimental data. We discuss the possible origin of the heterogeneity and suggest that the presence of an excess of surfactant close to the interface results in a softer polymer layer near the surface and a harder layer in the bulk. PMID- 22534980 TI - Conversion of carbohydrates into 5-hydroxymethylfurfural catalyzed by ZnCl2 in water. AB - The incompletely coordinated zinc ions in the concentrated aqueous ZnCl(2) solution catalyze the direct conversion of carbohydrates into 5 hydroxymethylfurfural, and a moderate HMF yield up to 50% can be achieved. PMID- 22534981 TI - Slow clinical improvement after treatment initiation in Leishmania/HIV coinfected patients. AB - INTRODUCTION: In Brazil there is a large area of overlap of visceral leishmaniasis (VL) and HIV infection, which favored a increased incidence of coinfection Leishmania/HIV. METHODS: This study evaluated 65 consecutive patients with VL and their clinical response to treatment in two health care settings in Belo Horizonte, Brazil. RESULTS: At baseline, the clinical picture was similar between both groups, although diarrhea and peripheral lymphadenomegaly were more frequent in HIV-infected subjects. HIV-positive patients had lower median blood lymphocyte counts (686/mm3 versus 948/mm3p = 0.004) and lower values of alanine aminotransferase (ALT) (48IU/L versus 75.6IU/L p = 0.016) than HIV-negative patients. HIV-positive status (hazard ratio = 0.423, p = 0.023) and anemia (HR = 0.205, p = 0.002) were independent negative predictors of complete clinical response following antileishmanial treatment initiation. CONCLUSIONS: This study reinforces that all patients with VL should be tested for HIV infection, regardless of their clinical picture. This practice would allow early recognition of coinfection with initiation of antiretroviral therapy and, possibly, reduction in treatment failure. PMID- 22534982 TI - Evaluation of inadequate anti-retroviral treatment in patients with HIV/AIDS. AB - INTRODUCTION: Since the emergence of antiretroviral therapy, the survival of patients infected with human immunodeficiency virus has increased. Non-adherence to this therapy is directly related to treatment failure, which allows the emergence of resistant viral strains. METHODS: A retrospective descriptive study of the antiretroviral dispensing records of 229 patients from the Center for Health Care, University Hospital, Federal University of Juiz de Fora, Brazil, was conducted between January and December 2009. RESULTS: The study aimed to evaluate patient compliance and determine if there was an association between non adherence and the therapy. Among these patients, 63.8% were men with an average age of 44.0 +/- 9.9 years. The most used treatment was a combination of 2 nucleoside reverse transcriptase inhibitors with 1 non-nucleoside reverse transcriptase inhibitor (55.5%) or with 2 protease inhibitors (28.8%). It was found that patients taking lopinavir/ritonavir with zidovudine and lamivudine had a greater frequency of inadequate treatment than those taking atazanavir with zidovudine and lamivudine (85% and 83.3%, respectively). Moreover, when the combination of zidovudine/ lamivudine was used, the patients were less compliant (chi2 = 4.468, 1 degree of freedom, p = 0.035). CONCLUSIONS: The majority of patients failed to correctly adhere to their treatment; therefore, it is necessary to implement strategies that lead to improved compliance, thus ensuring therapeutic efficacy and increased patient survival. PMID- 22534983 TI - Detection of Dientamoeba fragilis in patients with HIV/AIDS by using a simplified iron hematoxylin technique. AB - INTRODUCTION: Studies strongly indicate Dientamoeba fragilis as one of the causes of diarrhea in human immunodeficiency virus (HIV) patients. METHODS: The objective of the present study was to evaluate the prevalence of D. fragilis associated with the causes of diarrhea in 82 HIV/ AIDS patients hospitalized at the Instituto de Infectologia Emilio Ribas from September 2006 to November 2008. RESULTS: In total, 105 samples were collected from 82 patients. Unprotected sex was the most frequent cause of HIV infection (46.3%), followed by the use of injectable or non-injectable drugs (14.6%). Patients presented with viral loads of 49-750,000 copies/ mL (average: 73,849 +/- 124,850 copies/mL) and CD4 counts ranging of 2-1,306 cells/mm3 (average: 159 +/- 250 cells/mm3). On an average, the odds of obtaining a positive result by using the other techniques (Hoffman, Pons and Janer or Lutz; Ritchie) were 2.7 times higher than the chance of obtaining a positive result by using the simplified iron hematoxylin method. Significant differences were found between the methods (p = 0.003). CONCLUSIONS: The other techniques can detect a significantly greater amount of parasites than the simplified iron hematoxylin method, especially with respect to Isospora belli, Cryptosporidium sp., Schistosoma mansoni, and Strongyloides stercoralis, which were not detected using hematoxylin. Endolimax nana and D. fragilis were detected more frequently on using hematoxylin, and the only parasite not found by the other methods was D. fragilis. PMID- 22534984 TI - High prevalence of HTLV-1 and 2 viruses in pregnant women in Sao Luis, state of Maranhao, Brazil. AB - INTRODUCTION: Human T cell lymphotropic virus type 1 (HTLV-1) is endemic in the Caribbean, Japan, South America and regions of Africa. HTLV-2 is present in Native American populations and associated with IV drug use in Europe and North America. In Brazil, it is estimated that 1.5 million people are infected with HTLV-1/2. The study objective was to determine HTLV-1/2 prevalence in pregnant women in the prenatal care from three public services in Sao Luis, State of Maranhao, Brazil, and to counsel seropositive women to reduce viral transmission. METHODS: A cross-sectional study was conducted from February to December 2008; women with age of 18 to 45 years, with low risk for sexually transmitted disease (STD) were invited to participate. Blood samples were collected in filter paper, and HTLV-1/2 immunoenzymatic test (ELISA) was performed as a screening test. Women with reactive results were submitted to peripheral venous blood collection for ELISA repetition, followed by Western blot (WB) and real-time PCR to confirm and discriminate the infection between virus types 1 and 2. RESULTS: Of the 2,044 women tested, seven (0.3%) were ELISA reactive and confirmed positive (four were HTLV-1, and three were HTLV-2). All positive women were oriented not to breastfeed their newborns. CONCLUSIONS: This study showed that the virus is present in high prevalence in that population. Further studies covering other segments of the population are necessary to better characterize the presence of HTLV-1/2 in Maranhao and to elicit measures to prevent its spread. PMID- 22534985 TI - Interpretation of the presence of IgM and IgG antibodies in a rapid test for dengue: analysis of dengue antibody prevalence in Fortaleza City in the 20th year of the epidemic. AB - INTRODUCTION: The diagnosis of dengue and the differentiation between primary and secondary infections are important for monitoring the spread of the epidemic and identifying the risk of severe forms of the disease. The detection of immunoglobulin (Ig)M and IgG antibodies is the main technique for the laboratory diagnosis of dengue. The present study assessed the application of a rapid test for dengue concerning detection of new cases, reinfection recognition, and estimation of the epidemic attack rate. METHODS: This was a retrospective, cross sectional, descriptive study on dengue using the Fortaleza Health Municipal Department database. The results from 1,530 tested samples, from 2005-2006, were compared with data from epidemiological studies of dengue outbreaks in 1996, 2003, and 2010. RESULTS: The rapid test confirmed 52% recent infections in the tested patients with clinical suspicion of dengue: 40% detected using IgM and 12% of new cases using IgG in the non-reactive IgM results. The positive IgM plus negative IgG (IgM+ plus IgG-) results showed that 38% of those patients had a recent primary dengue infection, while the positive IgG plus either positive or negative IgM (IgG+ plus IgM+/-) results indicated that 62% had dengue for at least a second time (recent secondary infections). This proportion of reinfections permitted us to estimate the attack rate as >62% of the population sample. CONCLUSIONS: The rapid test for dengue has enhanced our ability to detect new infections and to characterize them into primary and secondary infections, permitting the estimation of the minimal attack rate for a population during an outbreak. PMID- 22534986 TI - Seroepidemiological monitoring in sentinel animals and vectors as part of arbovirus surveillance in the state of Mato Grosso do Sul, Brazil. AB - INTRODUCTION: From February-September 2010, seroepidemiological surveys were conducted on non-human primates and transmitter vector capture was used to investigate the possible circulation of arboviruses in the municipalities of Bonito, Campo Grande, and Jardim, State of Mato Grosso do Sul, Brazil. METHODS: A total of 65 primates from the wild and captivity were used, and potential vectors were captured using Castro and dip nets. Serum samples were tested at the Instituto Evandro Chagas, State of Para, using the hemagglutination inhibition test to detect total antibodies against 19 different arboviruses. Virus isolation was attempted from serum samples and arthropod suspensions using newborn mice and the C6/36 cell line clone. In addition, identification of the vector species was conducted. RESULTS: From the 19 serum samples from Campo Grande, 1 sample had a 1:20 titer for Flavivirus. From the 35 samples collected in Bonito, 17 samples had antibodies to arboviruses, 4 (11.4%) were positive for Alphavirus, and 5 (14.2%) were positive for Flavivirus. Monotypic reactions were observed for the Mayaro (n = 10) and Oropouche (n = 5) viruses, and 6 (17.1%) samples had titers for >1 virus. We captured 120 Culicidae individuals that were potential arbovirus transmitters in Jardim; however, all the samples were negative for the viruses. CONCLUSIONS: Mato Grosso do Sul has a variety of vertebrate hosts and transmission vectors, thereby providing ideal conditions for the emergence or reemergence of arboviruses, including some pathogenic to human beings. PMID- 22534987 TI - Variation in Aedes aegypti (Linnaeus) (Diptera, Culicidae) infestation in artificial containers in Caxias, state of Maranhao, Brazil. AB - INTRODUCTION: Dengue is a serious public health problem worldwide, with cases reported annually in tropical and subtropical regions. Aedes aegypti (Linnaeus, 1762), the main vector of dengue, is a domiciliary species with high dispersal and survival capacities and can use various artificial containers as breeding sites. We assessed potential container breeding sites of A. aegypti in the municipality of Caxias, Maranhao, Brazil. METHODS: In the initial phase, we analyzed 900 properties in 3 neighborhoods during the dry and rainy seasons (August-October 2005 and February-April 2006, respectively). During the second sampling period, September 2006-August 2007, we used 5 assessment cycles for 300 properties in a single neighborhood. RESULTS: During the dry and rainy seasons, water-storage containers comprised 55.7% (n = 1,970) and 48.5% (n = 1,836) of the total containers inspected, and showed the highest productivity of immature A. aegypti; we found 23.7 and 106.1 individuals/container, respectively, in peridomicile sites. In intradomicile sites, water-storage containers were also the most important breeding sites with 86.4% (n = 973) and 85.6% (n = 900) of all containers and a mean of 7.9 and 108.3 individuals/container in the dry and rainy seaso-October 2006 (1,342). The highest number of positives (70) was recorded in May, mostly (94%) in storage containers. CONCLUSIONS: Storage containers are the principal and most productive A. aegypti breeding sites and are a major contributing factor to the maintenance of this vector in Caxias. PMID- 22534988 TI - Circulation of the rabies virus in non-hematophagous bats in the city of Rio de Janeiro, Brazil, during 2001-2010. AB - INTRODUCTION: Rabies is one of the most known lethal zoonosis, responsible for 55,000 human deaths per year. It is transmitted to humans mainly by the bite of domestic or wild animals infected with the virus. This paper shows the circulation of this virus in non-hematophagous bats in the City of Rio de Janeiro, Brazil. METHODS: A survey was performed on the number of bats that had been sent for diagnosis by the Secao de Virologia of the Instituto Municipal de Medicina Veterinaria Jorge Vaitsman and were positive for rabies. The positive animals were identified, and the isolated viruses were sent for antigenic typification with indirect immunofluorescence. The results were compared with the antigenic panel of the Centers for Disease Control and Prevention. RESULTS: During 2001-2010, the laboratory received 555 non-hematophagous bats for rabies diagnosis, with 198 (35.7%) from Rio de Janeiro City. A total of 11 (5.5%) animals were positive for this disease. Antigenic typification revealed the predominance of variant 3 in 9 (81.8%) of the isolated viruses; 1 virus was classified as variant 4 and 1 variant was identified that segregated with the viruses in insectivorous bats. CONCLUSIONS: The data obtained in this study showed the presence of the rabies virus in synanthropic populations of non hematophagous bats in the City of Rio de Janeiro. The circulation of this agent in these animals represents a serious risk to human and animal health and requires attention and control measures by the authorities. PMID- 22534989 TI - Successful prevention of the transmission of vancomycin-resistant enterococci in a Brazilian public teaching hospital. AB - INTRODUCTION: Vancomycin-resistant enterococci (VRE) can colonize or cause infections in high-risk patients and contaminate the environment. Our objective was to describe the epidemiological investigation of an outbreak of VRE, the interventions made, and their impact on its control. METHODS: We conducted a retrospective, descriptive, non-comparative study by reviewing the charts of patients with a VRE-positive culture in the University Hospital of Campinas State University, comprising 380 beds, 40 of which were in intensive care units (ICUs), who were admitted from February 2008-January 2009. Interventions were divided into educational activity, reviewing the workflow processes, engineering measures, and administrative procedures. RESULTS: There were 150 patients, 139 (92.7%) colonized and 11 (7.3%) infected. Seventy-three percent were cared for in non-ICUs (p = 0.028). Infection was more frequent in patients with a central-line (p = 0.043), mechanical ventilation (p = 0.013), urinary catheter (p = 0.049), or surgical drain (p = 0.049). Vancomycin, metronidazole, ciprofloxacin, and third generation cephalosporin were previously used by 47 (31.3%), 31 (20.7%), 24 (16%), and 24 (16%) patients, respectively. Death was more frequent in infected (73%) than in colonized (17%) patients (p < 0.001). After the interventions, the attack rate fell from 1.49 to 0.33 (p < 0.001). CONCLUSIONS: Classical risk factors for VRE colonization or infection, e.g., being cared for in an ICU and previous use of vancomycin, were not found in this study. The conjunction of an educational program, strict adhesion to contact precautions, and reinforcement of environmental cleaning were able to prevent the dissemination of VRE. PMID- 22534990 TI - Methicillin-resistant Staphylococcus aureus bloodstream infection: risk factors and clinical outcome in non-intensive-care units. AB - INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) is spread out in hospitals across different regions of the world and is regarded as the major agent of nosocomial infections, causing infections such as skin and soft tissue pneumonia and sepsis. The aim of this study was to identify risk factors for methicillin-resistance in Staphylococcus aureus bloodstream infection (BSI) and the predictive factors for death. METHODS: A retrospective cohort of fifty-one patients presenting bacteraemia due to S. aureus between September 2006 and September 2008 was analysed. Staphylococcu aureus samples were obtained from blood cultures performed by clinical hospital microbiology laboratory from the Uberlandia Federal University. Methicillinresistance was determined by growth on oxacillin screen agar and antimicrobial susceptibility by means of the disk diffusion method. RESULTS: We found similar numbers of MRSA (56.8%) and methicillin-susceptible Staphylococcus aureus (MSSA) (43.2%) infections, and the overall hospital mortality ratio was 47%, predominantly in MRSA group (70.8% vs. 29.2%) (p=0.05). Age (p=0.02) was significantly higher in MRSA patients as also was the use of central venous catheter (p=0.02). The use of two or more antimicrobial agents (p=0.03) and the length of hospital stay prior to bacteraemia superior to seven days (p=0.006) were associated with mortality. High odds ratio value was observed in cardiopathy as comorbidity. CONCLUSIONS: Despite several risk factors associated with MRSA and MSSA infection, the use of two or more antimicrobial agents was the unique independent variable associated with mortality. PMID- 22534991 TI - Seroprevalence of Helicobacter pylori infection in chagasic and nonchagasic patients from the same geographical region of Brazil. AB - INTRODUCTION: In this study, we evaluated the seroprevalence of Helicobacter pylori infection among chagasic and non-chagasic subjects as well as among the subgroups of chagasic patients with the indeterminate, cardiac, digestive, and cardiodigestive clinical forms. METHODS: The evaluated subjects were from the Triangulo Mineiro region, Minas Gerais, Brazil. Chagasic patients showed positive reactions to the conventional serological tests used and were classified according to the clinical form of their disease. Immunoglobulin G antibodies specific to H. pylori were measured using a commercial enzyme-linked immunosorbent assay kit. RESULTS: The overall H. pylori prevalence was 77.1% (239/310) in chagasic and 69.1% (168/243) in non-chagasic patients. This difference was statistically significant even after adjustment for age and sex (odds ratio = 1.57; 95% confidence interval, 1.02-2.42; p = 0.04) in multivariate analysis. The prevalence of infection increased with age in the non-chagasic group (p = 0.007, chi2 for trend), but not in the chagasic group (p = 0.15, chi2 for trend). H. pylori infection was not associated with digestive or other clinical forms of Chagas disease (p = 0.27). CONCLUSIONS: Our findings demonstrate that chagasic patients have a higher prevalence of H. pylori compared to non-chagasic subjects; a similar prevalence was found among the diverse clinical forms of the disease. The factors contributing to the frequent co infection with H. pylori and Trypanosoma cruzi as well as its effects on the clinical outcome deserve further study. PMID- 22534992 TI - Leprosy in Buriticupu, state of Maranhao: active search in the general population. AB - INTRODUCTION: This study was developed to evaluate the situation of leprosy in the general population of the municipality of Buriticupu, State of Maranhao, Brazil. METHODS: We used the method of active search to identify new cases from 2008 to 2010. Bacilloscopy of intradermal scrapings was performed in all patients with skin lesions compatible with leprosy, and histopathological examination in those who had doubts on the definition of the clinical form. RESULTS: The study included 19,104 individuals, with 42 patients diagnosed with leprosy after clinical examination, representing a detection rate of 219.84 per 100,000 inhabitants. The predominant clinical presentation was tuberculoid with 24 (57.1%) cases, followed by borderline with 11, indeterminate with four, and lepromatous with three cases. The study also allowed the identification of 81 patients with a history of leprosy and other skin diseases, such as pityriasis versicolor, dermatophytosis, scabies, vitiligo, and skin carcinoma. The binomial test showed that the proportion of cases in the headquarters was significantly higher than that in the villages (p = 0.04), and the generalized exact test showed that there was no association between age and clinical form (p = 0.438) and between age and gender (p = 0.083). CONCLUSIONS: The elevated detection rate defines the city as hyperendemic for leprosy; the active search for cases, as well as the organization of health services, is an important method for disease control. PMID- 22534993 TI - Assessment of integration of the leprosy program into primary health care in Aracaju, state of Sergipe, Brazil. AB - INTRODUCTION: The aim of this study was to assess the epidemiological and operational characteristics of the Leprosy Program before and after its integration into the Primary healthcare Services of the municipality of Aracaju Sergipe, Brazil. METHODS: Data were drawn from the national database. The study periods were divided into preintegration (1996-2000) and postintegration (2001 2007). Annual rates of epidemiological detection were calculated. Frequency data on clinico-epidemiological variables of cases detected and treated for the two periods were compared using the Chi-squared (chi2) test adopting a 5% level of significance. RESULTS: Rates of detection overall, and in subjects younger than 15 years, were greater for the postintegration period and were higher than rates recorded for Brazil as a whole during the same periods. A total of 780 and 1,469 cases were registered during the preintegration and postintegration periods, respectively. Observations for the postintegration period were as follows: I) a higher proportion of cases with disability grade assessed at diagnosis, with increase of 60.9% to 78.8% (p < 0.001), and at end of treatment, from 41.4% to 44.4% (p < 0.023); II) an increase in proportion of cases detected by contact examination, from 2.1% to 4.1% (p < 0.001); and III) a lower level of treatment default with a decrease from 5.64 to 3.35 (p < 0.008). Only 34% of cases registered from 2001 to 2007 were examined. CONCLUSIONS: The shift observed in rates of detection overall, and in subjects younger than 15 years, during the postintegration period indicate an increased level of health care access. The fall in number of patients abandoning treatment indicates greater adherence to treatment. However, previous shortcomings in key actions, pivotal to attaining the outcomes and impact envisaged for the program, persisted in the postintegration period. PMID- 22534994 TI - Biological behavior of Trypanosoma cruzi stocks obtained from the State of Amazonas, Western Brazilian Amazon, in mice. AB - INTRODUCTION: The biological diversity of circulating Trypanosoma cruzi stocks in the Amazon region most likely plays an important role in the peculiar clinic epidemiological features of Chagas disease in this area. METHODS: Seven stocks of T. cruzi were recently isolated in the State of Amazonas, Brazil, from humans, wild mammals, and triatomines. They belonged to the TcI and Z3 genotypes and were biologically characterized in Swiss mice. Parasitological and histopathological parameters were determined. RESULTS: Four stocks did not promote patent parasitemia in mice. Three stocks produced low parasitemia, long pre-patent periods, and a patent period of 1 day or oscillating parasitemia. Maximum parasitemia ranged from 1,400 to 2,800 trypomastigotes/0.1 mL blood. Mice inoculated with the T. cruzi stocks studied showed low positivity during fresh blood examinations, ranging from 0% to 28.6%. In hemoculture, positivity ranged from 0% to 100%. Heart tissue parasitism was observed in mice inoculated with stocks AM49 and AM61. Stock AM49 triggered a moderate inflammatory process in heart tissue. A mild inflammatory process was observed in heart tissue for stocks AM28, AM38, AM61, and AM69. An inflammatory process was frequently observed in skeletal muscle. Examinations of brain tissue revealed inflammatory foci and gliosis in mice inoculated with stock AM49. CONCLUSIONS: Biological and histopathological characterization allowed us to demonstrate the low infectivity and virulence of T. cruzi stocks isolated from the State of Amazonas. PMID- 22534995 TI - Echocardiographic parameters associated with pulmonary congestion in outpatients with Chagas' cardiomyopathy and non-chagasic cardiomyopathy. AB - INTRODUCTION: Despite significant left ventricular (LV) systolic dysfunction and cardiomegaly, pulmonary congestion does not seem to be a major finding in Chagas' cardiomyopathy (CC). This study sought to identify echocardiographic parameters associated with pulmonary congestion in CC and in dilated cardiomyopathy of other etiologies, such as non-CC (NCC), and to compare pulmonary venous hypertension between the two entities. METHODS: A total of 130 consecutive patients with CC and NCC, with similar echocardiographic characteristics, were assessed using Doppler echocardiography and chest radiography. Pulmonary venous vessel abnormalities were graded using a previously described pulmonary congestion score, and this score was compared with Doppler echocardiographic parameters. RESULTS: NCC patients were older than CC patients (62.4 +/- 13.5 * 47.8 +/- 11.2, p = 0.00), and there were more male subjects in the CC group (66.2% * 58.5%, p = 0.4). Pulmonary venous hypertension was present in 41 patients in the CC group (63.1%) and in 63 (96.9%) in the NCC group (p = 0.0), the mean lung congestion score being 3.2 +/- 2.3 and 5.9 +/- 2.6 (p = 0.0), respectively. On linear regression multivariate analysis, the E/e' ratio (beta = 0.13; p = 0.0), LV diastolic diameter (beta = 0.06; p = 0.06), left atrial diameter (beta = 0.51; p = 0.08), and right ventricular (RV) end-diastolic diameter (beta = 0.02; p = 0.48) were the variables that correlated with pulmonary congestion in both groups. CONCLUSIONS: Pulmonary congestion was less significant in patients with CC. The degree of LV of systolic and diastolic dysfunction and the RV diameter correlated with pulmonary congestion in both groups. The E/e' ratio was the hallmark of pulmonary congestion in both groups. PMID- 22534996 TI - Effects of an exercise program on the functional capacity of patients with chronic Chagas' heart disease, evaluated by cardiopulmonary testing. AB - INTRODUCTION: Despite all efforts to restrict its transmission, Chagas' disease remains a severe public health problem in Latin America, affecting 8-12 million individuals. Chronic Chagas' heart disease, the chief factor in the high mortality rate associated with the illness, affects more than half a million Brazilians. Its evolution may result in severe heart failure associated with loss of functional capacity and quality of life, with important social and medical/labor consequences. Many studies have shown the beneficial effect of regular exercise on cardiac patients, but few of them have focused on chronic Chagas' heart disease. METHODS: This study evaluated the effects of an exercise program on the functional capacity of patients with chronic Chagas' disease who were treated in outpatient clinics at the Evandro Chagas Institute of Clinical Research and the National Institute of Cardiology, Rio de Janeiro, Brazil. The exercises were performed 3 times a week for 1 h (30 min of aerobic activity and 30 min of resistance exercises and extension) over 6 months in 2010. Functional capacity was evaluated by comparing the direct measurement of the O2 uptake volume (VO2) obtained by a cardiopulmonary exercise test before and after the program (p < 0.05). RESULTS: Eighteen patients (13 females) were followed, with minimum and maximum ages of 30 and 72 years, respectively. We observed an average increase of VO(2peak) > 10% (p = 0.01949). CONCLUSIONS: The results suggest a statistically significant improvement in functional capacity with regular exercise of the right intensity. PMID- 22534997 TI - Candida spp. isolated from inpatients, the environment, and health practitioners in the Pediatric Unit at the Universitary Hospital of the Jundiai Medical College, State of Sao Paulo, Brazil. AB - INTRODUCTION: This study aimed to isolate and identify Candida spp. from the environment, health practitioners, and patients with the presumptive diagnosis of candidiasis in the Pediatric Unit at the Universitary Hospital of the Jundiai Medical College, to verify the production of enzymes regarded as virulence factors, and to determine how susceptible the isolated samples from patients with candidiasis are to antifungal agents. METHODS: Between March and November of 2008 a total of 283 samples were taken randomly from the environment and from the hands of health staff, and samples of all the suspected cases of Candida spp. hospital-acquired infection were collected and selected by the Infection Control Committee. The material was processed and the yeast genus Candida was isolated and identified by physiological, microscopic, and macroscopic attributes. RESULTS: The incidence of Candida spp. in the environment and employees was 19.2%. The most frequent species were C. parapsilosis and C. tropicalis among the workers, C. guilliermondii and C. tropicalis in the air, C. lusitanae on the contact surfaces, and C. tropicalis and C. guilliermondii in the climate control equipment. The college hospital had 320 admissions, of which 13 (4%) presented Candida spp. infections; three of them died, two being victims of a C. tropicalis infection and the remaining one of C. albicans. All the Candida spp. in the isolates evidenced sensitivity to amphotericin B, nystatin, and fluconazole. CONCLUSIONS: The increase in the rate of hospital-acquired infections caused by Candida spp. indicates the need to take larger measures regarding recurrent control of the environment. PMID- 22534998 TI - Carbohydrate-rich high-molecular-mass antigens are strongly recognized during experimental Histoplasma capsulatum infection. AB - INTRODUCTION: During histoplasmosis, Histoplasma capsulatum soluble antigens (CFAg) can be naturally released by yeast cells. Because CFAg can be specifically targeted during infection, in the present study we investigated CFAg release in experimental murine histoplasmosis, and evaluated the host humoral immune response against high-molecular-mass antigens (hMMAg. >150 kDa), the more immunogenic CFAg fraction. METHODS: Mice were infected with 2.2 x 104 H. capsulatum IMT/HC128 yeast cells. The soluble CFAg, IgG anti-CFAg, IgG anti hMMAg, and IgG-hMMAg circulating immune complexes (CIC) levels were determined by enzymelinked immunosorbent assay, at days 0, 7, 14, and 28 post-infection. RESULTS: We observed a progressive increase in circulating levels of CFAg, IgG anti-CFAg, IgG anti-hMMAg, and IgG-hMMAg CIC after H. capsulatum infection. The hMMAg showed a high percentage of carbohydrates and at least two main immunogenic components. CONCLUSIONS: We verified for the first time that hMMAg from H. capsulatum IMT/HC128 strain induce humoral immune response and lead to CIC formation during experimental histoplasmosis. PMID- 22534999 TI - Trauma and envenoming caused by stingrays and other fish in a fishing community in Pontal do Paranapanema, state of Sao Paulo, Brazil: epidemiology, clinical aspects, and therapeutic and preventive measures. AB - INTRODUCTION: Accidents caused by fish are common in inland fishing communities in Brazil, being work-related injuries in the majority of cases. These populations have no information on the mechanisms of trauma or envenoming. METHODS: Through a questionnaire administered to fishermen, we obtained clinical and epidemiological data on accidents in Rosana, Pontal do Paranapanema, State of Sao Paulo, Brazil. These data were analyzed and converted into an easily understood prevention and treatment program for the colony. RESULTS: Thirty-nine fishermen replied to the survey. All of the patients had been hurt by fish. Of those mentioned, the yellow catfish (Pimelodus maculatus) was the main fish species associated with injuries, but others also caused trauma to the fishermen. Six fishermen had been envenomed by stingrays. Pain and ulcers were the main symptoms and were described as intolerable. Approximately half of those injured were treated using traditional folk remedies. CONCLUSIONS: The fishermen suffered multiple accidents with catfish, which are venomous and cause intense pain, as well as trauma due to other fish, such as surubins, trairas, freshwater croakers, and piranhas. Approximately 16% of those interviewed presented with envenomation from stingrays. Our data and previous experience in the area led to the creation of a pamphlet with clear language that can effectively help fishermen in the region, an area in need of health services and disease prevention. This initiative also applies to the whole La Plata River basin, which has similar fauna. PMID- 22535000 TI - Insights into the clinical and functional significance of cardiac autonomic dysfunction in Chagas disease. AB - INTRODUCTION: Exclusive or associated lesions in various structures of the autonomic nervous system occur in the chronic forms of Chagas disease. In the indeterminate form, the lesions are absent or mild, whereas in the exclusive or combined heart and digestive disease forms, they are often more pronounced. Depending on their severity these lesions can result mainly in cardiac parasympathetic dysfunction but also in sympathetic dysfunction of variable degrees. Despite the key autonomic effect on cardiovascular functioning, the pathophysiological and clinical significance of the cardiac autonomic dysfunction in Chagas disease remains unknown. METHODS: Review of data on the cardiac autonomic dysfunction in Chagas disease and their potential consequences, and considerations supporting the possible relationship between this disturbance and general or cardiovascular clinical and functional adverse outcomes. RESULTS: We hypothesise that possible consequences that cardiac dysautonomia might variably occasion or predispose in Chagas disease include: transient or sustained arrhythmias, sudden cardiac death, adverse overall and cardiovascular prognosis with enhanced morbidity and mortality, an inability of the cardiovascular system to adjust to functional demands and/or respond to internal or external stimuli by adjusting heart rate and other hemodynamic variables, and immunomodulatory and cognitive disturbances. CONCLUSIONS: Impaired cardiac autonomic modulation in Chagas disease might not be a mere epiphenomenon without significance. Indirect evidences point for a likely important role of this alteration as a primary predisposing or triggering cause or mediator favouring the development of subtle or evident secondary cardiovascular functional disturbances and clinical consequences, and influencing adverse outcomes. PMID- 22535001 TI - Evaluation of bacterial growth inhibition by mercaptopropionic acid in metallo beta-lactamase detection on multidrug-resistant Acinetobacter baumannii. AB - INTRODUCTION: Metallo-beta-lactamase (MBL) has been reported all over the world. METHODS: The inhibitory effect of mercaptopropionic acid (MPA) on bacterial growth was evaluated by comparison between disk diffusion and broth dilution methodology with determination of the minimum inhibitory concentration (MIC) for multidrug-resistant Acinetobacter baumanni strains. RESULTS: MPA significantly inhibited growth of the strains. CONCLUSIONS: The use of MPA can affect the results in phenotypic methods of MBL detection. PMID- 22535002 TI - Cat infected by a variant of bat rabies virus in a 29-year disease-free urban area of southern Brazil. AB - INTRODUCTION: After 29 years, rabies was detected in a cat in Curitiba, southern Brazil. METHODS: The fluorescent antibody test (FAT) and mouse inoculation test (MIT) were performed on central nervous system (CNS) samples. RESULTS: Direct immunofluorescence was negative, but the biological test was positive and rabies virus was characterized as variant 4 (from Tadarida brasiliensis). CONCLUSIONS: Reappearance of rabies in domestic animals warns of sylvatic-aerial risk of infection and the necessity of monitoring bats in historically rabies-free areas. PMID- 22535003 TI - Comparison among three polymerase chain reaction assays on detection of DNA from Leishmania in biological samples from patients with American cutaneous leishmaniasis. AB - INTRODUCTION: The study analyzed positivity of polymerase chain reaction (PCR) on detection of DNA from Leishmania in patients' samples. METHODS: Extracted DNA was submitted to L150/L152, 13Y/13Z, and seminested PCR (snPCR). RESULTS: Results were evidenced by bands of approximately 120, 720, and 670 bp for L150/L152, 13Y/13Z, and snPCR, respectively. L150/L152, 13Y/13Z, and snPCR positivity indexes were 76.9, 56.4, and 9.2 (p>0.05), respectively, for suspected and 93.7, 68.7, and 84.4 (p<0.05), respectively, for confirmed. CONCLUSIONS: Preliminary results showed that these assays, mainly L150/L152 and snPCR, can detect Leishmania DNA and carry potential on laboratory diagnosis of leishmaniasis. PMID- 22535004 TI - Antibody levels in children after 10 years of vaccination against hepatitis B: a Brazilian community-based study. AB - INTRODUCTION: It is known that the hepatitis B (HB) vaccine is effective, but it is alarming that sudden drops of antibody levels may coincide with the onset of adolescence. METHODS: Antibody levels against HB vaccine surface antigen (anti HBs) and HB vaccine core antigen (anti-HBc) were measured on the blood samples of children with a mean age of 11.4 years. RESULTS: About 54.8% had protective levels of anti-HBs. Of those who were anti-HBc-positive (4.4%), an average of 218.4 anti-HBs mIU/mL was found. CONCLUSIONS: Immunological protection was found in the majority of children. However, more studies are needed to elucidate the heritability of nonresponders and establish strategies against such events. PMID- 22535005 TI - [Patient with chronic Chagas heart disease, hepatosplenic schistosomiasis and acquired immunodeficency syndrome: possible spontaneous resolution of thrombus in the right ventricle]. AB - The presence of right-sided cardiac thrombi seems to increase the risk of death due to thromboembolic events. There is a discrepancy, however, between the prevalence of cardiac thrombus and clinical thromboembolic events. Besides, the individual characteristics associated with a high risk of mortality have not been established. We present here a case report of a patient with mansonic schistosomiasis and acquired immunodeficiency syndrome and chronic Chagas disease, who presents with a large thrombus in the right ventricle. The patient had uneventful evolution without any thromboembolic complications with resolution of right-ventricle thrombus. PMID- 22535006 TI - Advanced megaesophagus (Group III) secondary to vector-borne Chagas disease in a 20-month-old infant. AB - The authors report the case of a female infant with Group III (or Grade III) megaesophagus secondary to vector-borne Chagas disease, resulting in severe malnutrition that reversed after surgery (Heller technique). The infant was then treated with the antiparasitic drug benznidazole, and the infection was cured, as demonstrated serologically and parasitologically. After follow-up of several years without evidence of disease, with satisfactory weight and height development, the patient had her first child at age 23, in whom serological tests for Chagas disease yielded negative results. Thirty years after the initial examination, the patient's electrocardiogram, echocardiogram, and chest radiography remained normal. PMID- 22535007 TI - Bruns' syndrome and racemose neurocysticercosis: a case report. AB - Cysticercosis is an infection caused by the larval stage of the tapeworm Taenia solium. The parasite may infect the central nervous system, causing neurocysticercosis (NCC). The clinical manifestations depend on load, type, size, location, stage of development of the cysticerci, and the host's immune response against the parasite. The racemose variety occurs in the ventricles or basal cisterns and is a malignant form. Mobile ventricular mass can produce episodic hydrocephalus on changing head posture with attacks of headache, vomiting, and vertigo, triggered by abrupt movement of the head, a phenomenon called Bruns' syndrome (BS). We report a patient with racemose NCC and BS. PMID- 22535008 TI - Challenge in the management of infective endocarditis with multiple valvular involvement. AB - We describe the case of a 41-year-old man with congenital heart disease and infective endocarditis (IE), who presented multiple vegetations attached to the pulmonary, mitral, and aortic valves. Three valve replacements were performed, but the patient developed an abscess at the mitral-aortic intervalvular fibrosa and died due to sepsis. We briefly discuss the indications for surgery in IE, emphasizing its role in the treatment of uncontrolled infection. PMID- 22535009 TI - An AIDS patient asks for help. PMID- 22535010 TI - Atypical lymphocytosis in leptospirosis. PMID- 22535011 TI - Methicillin- and vancomycin-resistant Staphylococcus aureus colonization. PMID- 22535012 TI - Neurocysticercosis: a new trend in SUDEP research? PMID- 22535015 TI - Mastectomy without radiotherapy: outcome analysis after 10 years of follow-up in a single institution. AB - The aim of this study was to identify the prognostic factors associated with the risk of loco-regional recurrence (LRR) of women undergoing mastectomy and complete axillary dissection without radiotherapy. We analyzed data from 650 women operated between 1997 and 2001 in a single institution. Median follow-up was 10 years. Overall survival was 89.8 % at 5 years and 76.6 % at 10 years. The 10-year cumulative incidence of LRRs was 10.0 % (5.0, 10.5, 15.8, and 18.5 % in patients with 0, 1-3, 4-9, and >=10 positive lymph nodes (LNs), respectively). Sixty-two (9.5 %) LRRs were observed, 5 (0.8 %) of which occurred in the axillary LNs. Supraclavicular LNs recurrences (n = 16, 2.5 %) occurred more frequently in patients with four or more positive LNs, Ki-67 >= 20 % or extensive peritumoral vascular invasion (PVI). At multivariable analysis, nodal status was the only prognostic factor for local events, while nodal status, Ki-67 and PVI were significant prognostic factors for recurrences in the regional LNs. Moreover, within each category of positive LNs, high values of Ki-67 and extensive PVI were associated with the highest risk of LRR while low values of Ki-67 and absence of extensive PVI were associated with the lowest risk of LRR. Women with node negative tumors have the lowest risk of LRR and represent the group of patients that might benefit the least from radiotherapy. PVI and Ki-67 might help tailoring PMRT indications among patients with positive LNs. Finally, the very low incidence of recurrences in the axillary LNs raises questions about the inclusion of the axilla in the radiation field. PMID- 22535016 TI - Double heterozygosity for mutations in BRCA1 and BRCA2 in German breast cancer patients: implications on test strategies and clinical management. AB - Double heterozygosity for disease-causing BRCA1 and BRCA2 mutations is a very rare condition in most populations. Here we describe genetic and clinical data of eight female double heterozygotes (DH) for BRCA1 and BRCA2 mutations found in a cohort of 8162 German breast/ovarian cancer families and compare it with the data of their single heterozygous relatives and of the index patients of the German Consortium for Hereditary Breast and Ovarian Cancer. Furthermore, we analyze the phenotypic features of these patients with respect to age at onset of first cancer, first breast/ovarian cancer and the number of disease manifestations and compare them to that of published Caucasian female DHs and their single heterozygous female relatives. German DHs were not significantly younger at diagnosis of first breast cancer than the single heterozygous index patients of the German Consortium. However, if the data of our study were pooled with that of the literature, DHs were substantially younger at onset of first cancer (mean age 40.4 years, 95 % CI = 36.6-44.1) than their single heterozygous female relatives (mean age 51.9 years, 95 % CI = 46.8-57.0). The two groups also differed concerning the onset of first breast cancer (mean age 40.6 years, 95 % CI = 36.6 44.5 vs. 52.6, 95 % CI = 47.5-57.6). In addition, DHs had a more severe disease than their female relatives carrying a single BRCA mutation (1.4 vs. 0.6 manifestations per person). In contrast to Ashkenazi Jewish females, Caucasian DH females might develop breast cancer at an earlier age and have a more severe disease than single heterozygous BRCA mutation carriers. Therefore, DHs may benefit from more intensive surveillance programs/follow-up care and prophylactic surgery. PMID- 22535017 TI - Whole genome in vivo RNAi screening identifies the leukemia inhibitory factor receptor as a novel breast tumor suppressor. AB - Cancer is caused by mutations in oncogenes and tumor suppressor genes, resulting in the deregulation of processes fundamental to the normal behavior of cells. The identification and characterization of oncogenes and tumor suppressors has led to new treatment strategies that have significantly improved cancer outcome. The advent of next generation sequencing has allowed the elucidation of the fine structure of cancer genomes, however, the identification of pathogenic changes is complicated by the inherent genomic instability of cancer cells. Therefore, functional approaches for the identification of novel genes involved in the initiation and development of tumors are critical. Here we report the first whole human genome in vivo RNA interference screen to identify functionally important tumor suppressor genes. Using our novel approach, we identify previously validated tumor suppressor genes including TP53 and MNT, as well as several novel candidate tumor suppressor genes including leukemia inhibitory factor receptor (LIFR). We show that LIFR is a key novel tumor suppressor, whose deregulation may drive the transformation of a significant proportion of human breast cancers. These results demonstrate the power of genome wide in vivo RNAi screens as a method for identifying novel genes regulating tumorigenesis. PMID- 22535018 TI - Natural course of venous malformation after conservative treatment. AB - PURPOSE: To investigate the clinical course of patients with venous malformation (VM) treated conservatively. METHODS: We reviewed retrospectively the database of our Congenital Vascular Malformation clinic and interviewed 207 patients with VM, who had been managed only conservatively. The questionnaires asked about changes in size (no change, increase in proportion to growth, increase greater than in proportion to growth, decrease) and changes in symptoms (markedly worse, moderately worse, no change, moderately improved, markedly much improved). Progression of VMs was defined as an increase greater than in proportion to growth or worsening symptoms. RESULTS: Fifty patients (24 %) reported an increase in size greater than in proportion to growth and 25 patients (12 %) reported symptoms worsening from their initial symptoms. Overall, sixty-six (32 %) of the patients reported evidence of progression of their VM. A binary logistic regression model identified VM combined with capillary malformation (CM) or lymphatic malformation (LM) as an independent predictor of VM progression (OR 2.67, 95 % CI 1.29-5.53). CONCLUSIONS: Based on responses to the questionnaire, the size and symptoms of VM progressed in 32 % of patients over the course of their life. VMs combined with CM or LM were the only independent predictor of progression of a VM after conservative management. PMID- 22535019 TI - Occult papillary thyroid microcarcinoma manifesting only as a symptomatic lateral cervical mass: report of a case. AB - We report a case of occult papillary thyroid carcinoma (PTC) manifesting as a solitary lateral cervical mass. Few such cases have been reported and, to our knowledge, this is the first report of cervical lymph node involvement from thyroid cancer being so massive that it is the cause of the local symptoms. The patient, a 64-year-old man, presented with vocal cord paralysis and voice alteration and was found to have a 4 cm lateral cervical mass infiltrating the ipsilateral internal jugular vein and recurrent laryngeal nerve. The diagnosis of PTC was made preoperatively following an open-biopsy of the lesion. The patient underwent total thyroidectomy with modified radical neck dissection, followed by radioactive iodine therapy. His postoperative course was uneventful and he remains well without any signs of recurrence 7 years after the operation. PMID- 22535020 TI - Tuberculosis among Africans living in the United States, 2000-2009. AB - The incidence of tuberculosis (TB) has declined steadily in the United States; however, foreign-born persons are disproportionately affected. The aim of our study was to describe characteristics of TB patients diagnosed in the United States who originated from the African continent. Using data from the U.S. National Tuberculosis Surveillance System, we calculated TB case rates and analyzed differences between foreign-born patients from Africa compared with other foreign-born and U.S.-born patients. The 2009 TB case rate among Africans (48.1/100,000) was 3 times as high as among other foreign-born and 27 times as high as among U.S.-born patients. Africans living in the United States have high rates of TB disease; they are more likely to be HIV-positive and to have extrapulmonary TB. Identification and treatment of latent TB infection, HIV testing and treatment, and a high index of suspicion for extrapulmonary TB are needed to better address TB in this population. PMID- 22535021 TI - The effect modification of supplemental insurance on the relationship between race and bone mineral density screening in female Medicare beneficiaries. AB - To determine the effect modification of supplemental insurance on the relationship between race and bone mineral density (BMD) in female Medicare beneficiaries. Retrospectively analyzing hospital administrative claim and clinical data of female Medicare beneficiaries (n = 1,398), we performed multivariate logistic regressions of BMD testing including data from all study participants and the subsets of health insurance. Significantly fewer Black than White female Medicare beneficiaries received the BMD testing in the overall sample (odds ratio, OR = 0.63; p = 0.02) and those without supplementary health insurance (n = 709; OR = 0.38; p = 0.004). By contrast, the magnitude of this racial disparity in the BMD testing was diminished among those with supplementary private health insurance (n = 689). We found a significant racial disparity in BMD testing for Black and White female Medicare beneficiaries. This disparity became more pronounced among those without supplementary private health insurance. PMID- 22535022 TI - An accurate control of the surface wave using transformation optics. AB - In this paper, we study two surface wave control scenarios at microwave frequencies. The first is a surface wave traveling along an uneven interface with a triangular obstruction present on a grounded dielectric slab. The other is a surface wave that circumvents a metallic rhombus-shaped obstacle, which is partially buried in a flat grounded dielectric slab. With a consideration of the eigenmode properties of the surface wave, our proposed technique - based on transformation optics - offers an efficient and accurate way to perform the filed manipulation. On the one hand, we see that the surface wave is guided along the uneven interface with no scattering into the air, as the grounded dielectric slab is flat. On the other hand, we observe that the surface wave is capable of traversing the rhombus obstacle with no shadow left behind, as the obstacle is cloaked. This technique for surface wave control is also valid at higher frequency ranges, and can easily be extended to encompass other propagating modes. PMID- 22535023 TI - A 2.5 ns switching time MachZehnder modulator in as-deposited a-Si:H. AB - A very simple and fast Mach-Zehnder electro-optic modulator based on a p-i-n configuration, operating at lambda = 1.55 MUm, has been fabricated at 170 degrees C using the low cost technology of hydrogenated amorphous silicon (a Si:H). In spite of the device simplicity, refractive index modulation was achieved through the free carrier dispersion effect resulting in characteristic rise and fall times of ~2.5 ns. By reverse biasing the p-i-n device, the voltage length product was estimated to be V(pi)?L(pi) = 40 V?cm both from static and dynamic measurements. Such bandwidth performance in as-deposited a-Si:H demonstrates the potential of this material for the fabrication of fast active photonic devices integrated on standard microelectronic substrates. PMID- 22535024 TI - Full Poincare beams II: partial polarization. AB - Optical fields whose coherence and/or polarization properties appear to change under propagation have intrigued researchers for many years. We describe and experimentally demonstrate a class of optical fields whose polarization content at any transverse plane spans a disk-like region within the Poincare sphere. When examined through a paraxial focal region, the disk rotates under propagation, spanning all possible states of polarization. We map the change in Stokes parameters through focus for each case, comparing experiment with the theoretical predictions. PMID- 22535025 TI - A low-power high-speed InP microdisk modulator heterogeneously integrated on a SOI waveguide. AB - We report on the modulation characteristics of indium phosphide (InP) based microdisks heterogeneously integrated on a silicon-on-insulator (SOI) waveguide. We present static extinction ratios and dynamic operation up to 10 Gb/s. Operation with a bit-error rate below 1 * 10(-9) is demonstrated at 2.5, 5.0 and 10.0 Gb/s and the performance is compared with that of a commercial modulator. Power penalties are analyzed with respect to the pattern length. The power consumption is calculated and compared with state-of-the-art integrated modulator concepts. We demonstrate that InP microdisk modulators combine low-power and low voltage operation with low footprint and high-speed. Moreover, the devices can be fabricated using the same technology as for lasers, detectors and wavelength converters, making them very attractive for co-integration. PMID- 22535026 TI - Real-time concealed-object detection and recognition with passive millimeter wave imaging. AB - Millimeter wave (MMW) imaging is finding rapid adoption in security applications such as concealed object detection under clothing. A passive MMW imaging system can operate as a stand-off type sensor that scans people in both indoors and outdoors. However, the imaging system often suffers from the diffraction limit and the low signal level. Therefore, suitable intelligent image processing algorithms would be required for automatic detection and recognition of the concealed objects. This paper proposes real-time outdoor concealed-object detection and recognition with a radiometric imaging system. The concealed object region is extracted by the multi-level segmentation. A novel approach is proposed to measure similarity between two binary images. Principal component analysis (PCA) regularizes the shape in terms of translation and rotation. A geometric based feature vector is composed of shape descriptors, which can achieve scale and orientation-invariant and distortion-tolerant property. Class is decided by minimum Euclidean distance between normalized feature vectors. Experiments confirm that the proposed methods provide fast and reliable recognition of the concealed object carried by a moving human subject. PMID- 22535027 TI - Surpassing digital holography limits by lensless object scanning holography. AB - We present lensless object scanning holography (LOSH) as a fully lensless method, capable of improving image quality in reflective digital Fourier holography, by means of an extremely simplified experimental setup. LOSH is based on the recording and digital post-processing of a set of digital lensless holograms and results in a synthetic image with improved resolution, field of view (FOV), signal-to-noise ratio (SNR), and depth of field (DOF). The superresolution (SR) effect arises from the generation of a synthetic aperture (SA) based on the linear movement of the inspected object. The same scanning principle enlarges the object FOV. SNR enhancement is achieved by speckle suppression and coherent artifacts averaging due to the coherent addition of the multiple partially overlapping bandpass images. And DOF extension is performed by digital refocusing to different object's sections. Experimental results showing an impressive image quality improvement are reported for a one-dimensional reflective resolution test target. PMID- 22535028 TI - Demonstration of free space coherent optical communication using integrated silicon photonic orbital angular momentum devices. AB - We propose and demonstrate silicon photonic integrated circuits (PICs) for free space spatial-division-multiplexing (SDM) optical transmission with multiplexed orbital angular momentum (OAM) states over a topological charge range of -2 to +2. The silicon PIC fabricated using a CMOS-compatible process exploits tunable phase arrayed waveguides with vertical grating couplers to achieve space division multiplexing and demultiplexing. The experimental results utilizing two silicon PICs achieve SDM mux/demux bit-error-rate performance for 1-b/s/Hz, 10-Gb/s binary phase shifted keying (BPSK) data and 2-b/s/Hz, 20-Gb/s quadrature phase shifted keying (QPSK) data for individual and two simultaneous OAM states. PMID- 22535029 TI - Nonlinear couplers with tapered plasmonic waveguides. AB - We suggest and demonstrate numerically that, by employing tapered waveguides in the geometry of a directional coupler, we can enhance dramatically the performance for optical switching of nonlinear plasmonic couplers operating at the nanoscale, overcoming the detrimental losses but preserving the subwavelength confinement. We demonstrate that, by an appropriate choice of the taper angle of the coupled metal-dielectric slot waveguides, we can compensate for the amplitude decrease and enhance the sharpness of the response for the switching operation. PMID- 22535030 TI - Wideband slow-light modes for time delay of ultrashort pulses in symmetrical metal-cladding optical waveguide. AB - A widebandwidth optical delay line is a useful device for various fascinating applications, such as optical buffering and processing of ultrafast signal. Here, we experimentally demonstrated effective slow light of sub-picosecond signal over 10 THz frequency range by employing the wide slow light modes in thick symmetrical metal-cladding optical waveguide (SMCOW). Ultrahigh-order guided modes travelling as slow light in waveguide together with strong confinement provided by metal-cladding makes this scheme nearly material dispersion independent and compatible with wide bandwidth operation. PMID- 22535031 TI - Fabrication of three dimensional split ring resonators by stress-driven assembly method. AB - We demonstrate a self-assembly strategy for fabricating three dimensional (3D) metamaterials. This strategy represents the desired 3D curving prongs of the split ring resonators (SRRs) erected by metal stress force with appropriate thin film parameters. Transmittance spectra and field patterns corresponding to each resonance modes are calculated by finite element method (FEM). The eigen-modes of the SRRs can be excited by normal illumination with polarization state parallel to the erected SRRs, which are unlike for the cases of planar SRRs. This method opens a promising fabrication process for the application of tailored 3D SRRs. PMID- 22535032 TI - Enhanced photoluminescence of ordered macroporous germanium electrochemically prepared from ionic liquids. AB - Recently we reported our results on the successful synthesis of 3-D highly ordered macroporous (3DOM) structure of germanium via the template-assisted electrochemical deposition from air- and water stable ionic liquids. Herein we report our new results on the photoluminescence (PL) properties of the obtained ordered macroporous Ge and the Ge/polystyrene composite opal structure. The latter showed a strong green emission compared to a Ge film and a Ge inverse opal. The enhancement of PL intensity was ascribed to the disorder multiple scattering in polystyrene colloidal crystal structure which increased both the excitation light absorption efficiency and the light extraction efficiency. The X ray photoelectron spectroscopy (XPS) results suggested that the ordered macroporous Ge was capped with an oxide layer including a considerable amount of GeO(2). The observed green emission (539 nm) was related to GeO(2), likely resulting from the Ge-O bond related intrinsic defects. PMID- 22535033 TI - Surface wave sensors based on nanometric layers of strongly absorbing materials. AB - We demonstrate the excitation of guided modes in thin layers of strongly absorbing chalcogenide glasses. These modes are similar to surface plasmon polaritons in terms of resonance width and shift with changes in the permittivity of the surrounding medium. We exploit these characteristics to demonstrate a high sensitivity chalcogenide glass refractive index sensor that outperforms gold surface plasmon resonance sensors at short wavelengths in the visible. This demonstration opens a new range of possibilities for sensing using different materials. PMID- 22535034 TI - Kinoform microlenses for focusing into microfluidic channels. AB - Optical detection in microflow cytometry requires a tightly focused light beam within a microfluidic channel for effective microparticle analysis. Integrated planar lenses have demonstrated this function, but their design is usually derived from the conventional spherical lens. Compact, efficient, integrated planar kinoform microlenses are proposed for use in microflow cytometry. A detailed design procedure is given and several designs are simulated. A paraxial kinoform lens integrated with a microfluidic channel was then fabricated in a silicate glass material system and characterized for focal position and spotsize, in comparison with light emerging directly from a channel waveguide. Focal spotsizes of 5.6 MUm for kinoform lenses have been measured at foci as far as 56 MUm into the microfluidic channel. PMID- 22535035 TI - Triangular metallic gratings for large absorption enhancement in thin film Si solar cells. AB - We estimate high optical absorption in silicon thin film photovoltaic devices using triangular corrugations on the back metallic contact. We computationally show 21.9% overall absorptivity in a 100-nm-thick silicon layer, exceeding any reported absorptivity using single layer gratings placed on the top or the bottom, considering both transverse electric and transverse magnetic polarizations and a wide spectral range (280 - 1100 nm). We also show that the overall absorptivity of the proposed scheme is relatively insensitive to light polarization and the angle of incidence. We also discuss the implications of potential fabrication process variations on such a device. PMID- 22535036 TI - Pulse selection at 1 MHz with electrooptic fiber switch. AB - Two 78-cm long electrooptic fibers with nonlinear coefficient chi((2)) ~0.26 pm/V are used in a Sagnac loop for pulse selection at up to 1 MHz repetition rate. Laser pulses of 1.5 um wavelength arriving at every 140 ns are selected with an extinction ratio as high as -30 dB. The arrangement is entirely based on silica fiber. PMID- 22535037 TI - High-power high-repetition-rate single-mode Er-Yb-doped fiber laser system. AB - We demonstrate an all-fiber-integrated, high-power chirped-pulse-amplification system operating at 1550 nm. The seed source is a soliton fiber laser with 156 MHz repetition rate. Two-stage single mode amplifier provides an amplification of more than 40 dB without significant spontaneous amplified emission. The power amplifier is based on cladding-pumped 10 um-core Er-Yb co-doped fiber, the output of which was spliced into standard singlemode fiber. We obtain 10 W average power in a strictly singlemode operation. After dechirping with a grating compressor, near transform-limited, 450 fs-long pulses are obtained. The laser source exhibits excellent short and long-term intensity stability, with relative intensity noise measurements characterizing the short-term stability. PMID- 22535038 TI - Terahertz dynamic imaging of skin drug absorption. AB - Terahertz (THz) imaging is a nondestructive, label-free, rapid imaging technique which gives the possibility of a real-time tracing of drugs within the skin. We evaluated the feasibility of THz dynamic imaging for visualizing serial changes in the distribution and penetration of a topical agent, dimethyl sulfoxide (DMSO) containing ketoprofen, using excised mouse skins. THz imaging was performed for 6 h after drug application to the skin and was compared with the results obtained using the Franz cell diffusion test, a standard in vitro skin absorption test. THz dynamic reflection imaging showed that the reflection signals decreased rapidly during the early time period, and remained constant through the late time period. The area of drug permeation within the skin layer on THz imaging increased with time. The dynamic pattern of THz reflection signal decrease was similar to that of DMSO absorption analyzed by the Franz cell diffusion test, which indicates that THz imaging mainly reflects the DMSO component. This study demonstrates that THz imaging technique can be used for imaging the spatial distribution and penetration of drug-applied sites. PMID- 22535039 TI - Wall-induced Ramsey effects on electromagnetically induced absorption. AB - The effect of wall-induced Ramsey interference on the electromagnetically induced absorption (EIA) in an anti-relaxation coated vapor cell is studied in a four level closed N-type atomic system. We show that the atomic coherence spontaneously transferred from the excited states to the ground states may interfere via the Ramsey sequence of the moving atoms with decoherence-free wall collisions. The spectral narrowing of the EIA resonance lineshape is induced by the Ramsey effect because of the long lifetime of the spontaneously transferred atomic coherence between the ground states. This calculated Ramsey EIA spectrum is in good agreement with the narrow EIA spectrum obtained experimentally in the anti-relaxation coated vapor cell. PMID- 22535040 TI - Excitation control of long-range surface plasmons by two incident beams. AB - We demonstrate the excitation control of long-range surface plasmon polaritons (LRSPs) by experiments and simulations. We find that LRSPs and short-range surface plasmon polaritons can be selectively excited by two incident beams. This mechanism enables us to realize the excitation control of LRSPs using the phase difference or the intensity ratio between the two input signals. The excitation method analyzed here can be applied to active plasmonic devices based on LRSPs. PMID- 22535041 TI - Superradiance dynamics in semiconductor laser diode structures. AB - We analyze theoretically the superradiant emission (SR) in semiconductor edge emitting laser heterostructures using InGaN/GaN heterostructure quantum well (QW) as a model system. The generation of superradiant pulses as short as 500 fs at peak powers of over 200 W has been predicted for InGaN/GaN heterostructure QWs with the peak emission in the blue/violet wavelength range. Numerical simulations based on semiclassical traveling wave Maxwell-Bloch equations predict building up of macroscopic coherences in the ensemble of electrons and holes during SR pulse formation. We show that SR is covered by the Ginzburg-Landau equation for a phase transition to macroscopically coherent state of matter. The presented theory is applicable to other semiconductor materials. PMID- 22535042 TI - A novel optical readout infrared FPA imaging system with fiber reference channel. AB - A novel fiber reference optical readout method was proposed in the bi-material micro cantilever infrared imaging system, which consists of an infrared imaging channel, an optical readout channel and a fiber reference channel. The fiber reference channel is used to monitor the intensity fluctuation of the light source, and provide a signal to correct the distortion of the infrared images from the optical readout channel. Comparing with the typical optical readout method without any references, the noise equivalent temperature difference (NETD) of such an infrared imaging system with the fiber reference optical readout method can be reduced by about 33% and edges of the IR images become clearer. PMID- 22535043 TI - Mechanical active control of surface plasmon properties. AB - We present a multilayer device which allows the control of Surface Plasmon (SP) propagation properties (propagation length and extension). A simple modification on an inner air gap thickness strongly affects SP propagation mode due to coupling with Parallel-Plate (PP) mode. PMID- 22535044 TI - Flat-fields in DASH interferometry. AB - When analyzing the fringe pattern of an interferogram to determine atmospheric wind velocities, inhomogeneities in the optical components and illumination can introduce uncertainty into the results. These variations in the image, which are generally characteristics of the measurement device, are commonly referred to as the "flat-field" of the system. In this work we discuss the effect of this flat field on measurements made with a Doppler Asymmetric Spatial Heterodyne (DASH) spectrometer. It is found that the flat-field can have a significant effect on any single calculation of the fringe phase, but because the flat-field affects all measurements made with the same system, the uncertainty in the derived wind velocity, which is determined through a comparison of two interferogram fringe phases, typically remains small. Nonetheless, it is recommended to account for the flat-field when analyzing DASH data, if possible. To this end we discuss a method for determining the flat-field using only temperature variations of the system, which is particularly suitable for space-based instruments. PMID- 22535045 TI - Low-loss plasmonic metamaterial based on epitaxial gold monocrystal film. AB - We demonstrate high-finesse plasmonic metamaterial with strong resonant response in the near-IR spectral range fabricated using a thin low-loss film of gold monocrystal. The monocrystal was grown using specially formulated simplified crystal growth procedure based on epitaxial deposition, which makes it readily accessible to both plasmonics and metamaterials communities. PMID- 22535046 TI - Label-free tetra-modal molecular imaging of living cells with CARS, SHG, THG and TSFG (coherent anti-Stokes Raman scattering, second harmonic generation, third harmonic generation and third-order sum frequency generation). AB - We have developed a new multimodal molecular imaging system that combines CARS (coherent anti-Stokes Raman scattering), SHG (second harmonic generation), THG (third harmonic generation) and multiplex TSFG (third-order sum frequency generation) using a subnanosecond white-light laser source. Molecular composition and their distribution in living cells are clearly visualized with different contrast enhancements through different mechanisms of CARS, SHG, THG and TSFG. A correlation image of CARS and TSF reveals that the TSF signal is generated predominantly from lipid droplets inside a cell as well as the peripheral cell wall. PMID- 22535047 TI - Dynamics of femtosecond laser filamentation in argon with non-uniform density distribution. AB - We numerically investigated the femtosecond laser filamentation in a cell filled with argon of non-uniform density distribution. By comparison with the case of uniform density distribution, we demonstrated the crucial differences in the dynamics between the two cases. We found that the pulse-splitting appeared earlier due to the sensitivity of rear-part refocusing to the plasma density and a double Lambda shape appeared in the spatio-temporal intensity profile in the non-uniform density case. PMID- 22535048 TI - Characterization and modeling of Bragg gratings written in polymer fiber for use as filters in the THz region. AB - We demonstrate fiber Bragg gratings written in polymer fiber for use in the THz window for the first time. A KrF excimer laser operating at 248 nm was used to inscribe notch-type gratings in single component Topas subwavelength fiber. A transmission loss at the centre wavelength of the grating of 60 dB is observed in short gratings containing only 192 notches. Experimental results and modeling are presented. The gratings are expected to find use in THz signal filtering and chemical or biosensing applications. PMID- 22535049 TI - High efficiency and ultra broadband optical parametric four-wave mixing in chalcogenide-PMMA hybrid microwires. AB - We present polymer (PMMA) cladded chalcogenide (As(2)Se(3)) hybrid microwires that realize optical parametric four-wave mixing (FWM) with wavelength conversion bandwidth as broad as 190 nm and efficiency as high as 21 dB at peak input power levels as low as 70 mW. This represents 3-30 * increase in bandwidth and 30-50 dB improvement in conversion efficiency over previous demonstrations in tapered and microstructured chalcogenide fibers with the results agreeing well with the simulations. These properties, combined with small foot-print (10 cm length), low loss (<4 dB), ease of fabrication, and the transparency of As(2)Se(3) from near to-mid-infrared regions make this device a promising building block for lasers, optical instrumentation and optical communication devices. PMID- 22535050 TI - Back-scattered detection yields viable signals in many conditions. AB - Precision position-sensing is required for many microscopy techniques. One promising method, back-scattered detection (BSD), is incredibly sensitive, allowing for position measurements at the level of tens of picometers in three dimensions. In BSD the position of a micron-sized bead is measured by back scattering a focused laser beam off the bead and imaging the resulting interference pattern onto a detector. Since the detection system geometry is confined to one side of the objective, the technique is compatible with platforms that have restricted optical access (e.g. magnetic tweezers, atomic force microscopy, and microfluidics). However, general adoption of BSD may be limited according to a recent theory [Volpe et al., J. Appl. Phys. 102, 084701, 2007] that predicts diminished signals under certain conditions. We directly measured the BSD response while varying the experimental conditions, including bead radius, numerical aperture, and relative index. Contrary to the proposed theory, we find that all experimental conditions tested produced a viable signal for atomic-scale measurements. PMID- 22535051 TI - Plasmonic nanotweezers: strong influence of adhesion layer and nanostructure orientation on trapping performance. AB - Using Au bowtie nanoantennas arrays (BNAs), we demonstrate that the performance and capability of plasmonic nanotweezers is strongly influenced by both the material comprising the thin adhesion layer used to fix Au to a glass substrate and the nanostructure orientation with respect to incident illumination. We find that a Ti adhesion layer provides up to 30% larger trap stiffness and efficiency compared to a Cr layer of equal thickness. Orientation causes the BNAs to operate as either (1) a 2D optical trap capable of efficient trapping and manipulation of particles as small as 300 nm in diameter, or (2) a quasi-3D trap, with the additional capacity for size-dependent particle sorting utilizing axial Rayleigh Benard convection currents caused by heat generation. We show that heat generation is not necessarily deleterious to plasmonic nanotweezers and achieve dexterous manipulation of nanoparticles with non-resonant illumination of BNAs. PMID- 22535052 TI - Experimental and numerical analysis of ballistic and scattered light using femtosecond optical Kerr gating: a way for the characterization of strongly scattering media. AB - We have developed a new experimental setup based on optical Kerr gating in order to isolate either the transmitted or the scattered light going through an optically thick medium. This selectivity can be obtained by finely tuning the focusing of the different laser beams in the Kerr medium. We have developed an experimental setup. A Monte Carlo simulation scheme generates an accurate model of scattering processes taking into account the time of flight, the geometry of the Kerr gating and the polarization. We show that our experimental setup is capable of analyzing the transmitted light with optical densities up to OD = 9.7, and scattered light beyond OD = 347 in poly-disperse silica spheres in water (distribution centered on ~0.9 um radius) at lambda = 550 nm. Strongly positive correlations are obtained with simulations. PMID- 22535053 TI - Assembling of three-dimensional crystals by optical depletion force induced by a single focused laser beam. AB - We proposed a method to assemble microspheres into a three-dimensional crystal by utilizing the giant nonequilibrium depletion force produced by nanoparticles. Such assembling was demonstrated in a colloid formed by suitably mixing silica microspheres and magnetic nanoparticles. The giant nonequilibrium depletion force was generated by quickly driving magnetic nanoparticles out of the focusing region of a laser light through both optical force and thermophoresis. The thermophoretic binding of silica beads is so tight that a colloidal photonic crystal can be achieved after complete evaporation of solvent. This technique could be employed for fabrication of colloidal photonic crystals and molecular sieves. PMID- 22535054 TI - Giant Faraday rotation in Bi(x)Ce(3-x)Fe5O12 epitaxial garnet films. AB - Thin films of Bi(x)Ce(3-x)Fe(5)O(12) with x = 0.7 and 0.8 compositions were prepared by using pulsed laser deposition. We investigated the effects of processing parameters used to fabricate these films by measuring various physical properties such as X-ray diffraction, transmittance, magnetization and Faraday rotation. In this study, we propose a phase diagram which provides a suitable window for the deposition of Bi(x)Ce(3-x)Fe(5)O(12) epitaxial films. We have also observed a giant Faraday rotation of 1-1.10 degree/um in our optimized films. The measured Faraday rotation value is 1.6 and 50 times larger than that of CeYIG and YIG respectively. A theoretical model has been proposed for Faraday rotation based on density matrix method and an excellent agreement between experiment and theory is found. PMID- 22535055 TI - A high-brightness source of polarization-entangled photons optimized for applications in free space. AB - We present a simple but highly efficient source of polarization-entangled photons based on spontaneous parametric down-conversion (SPDC) in bulk periodically poled potassium titanyl phosphate crystals (PPKTP) pumped by a 405 nm laser diode. Utilizing one of the highest available nonlinear coefficients in a non degenerate, collinear type-0 phase-matching configuration, we generate polarization entanglement via the crossed-crystal scheme and detect 0.64 million photon pair events/s/mW, while maintaining an overlap fidelity with the ideal Bell state of 0.98 at a pump power of 0.025 mW. PMID- 22535056 TI - Self-referenceable frequency comb from an ultrafast thin disk laser. AB - We present the first measurement of the carrier envelope offset (CEO) frequency of an ultrafast thin disk laser (TDL). The TDL used for this proof-of-principle experiment was based on the gain material Yb:Lu(2)O(3) and delivered 7 W of average power in 142-fs pulses, which is more than two times shorter than previously realized with this material. Using only 65 mW of the output of the laser, we generated a coherent octave-spanning supercontinuum (SC) in a highly nonlinear photonic crystal fiber (PCF). We detected the CEO beat signal using a standard f-to-2f interferometer, achieving a signal-to-noise ratio of >25 dB (3 kHz resolution bandwidth). The CEO frequency was tunable with the pump current with a slope of 33 kHz/mA. This result opens the door towards high-power frequency combs from unamplified oscillators. Furthermore, it confirms the suitability of these sources for future intralaser extreme nonlinear optics experiments such as high harmonic generation and VUV frequency comb generation from compact sources. PMID- 22535057 TI - Linear semiconductor optical amplifiers for amplification of advanced modulation formats. AB - The capability of semiconductor optical amplifiers (SOA) to amplify advanced optical modulation format signals is investigated. The input power dynamic range is studied and especially the impact of the SOA alpha factor is addressed. Our results show that the advantage of a lower alpha-factor SOA decreases for higher order modulation formats. Experiments at 20 GBd BPSK, QPSK and 16QAM with two SOAs with different alpha factors are performed. Simulations for various modulation formats support the experimental findings. PMID- 22535058 TI - Dynamic spectroscopic phase microscopy for quantifying hemoglobin concentration and dynamic membrane fluctuation in red blood cells. AB - We report a technique for simultaneous label-free quantification of cytoplasmic hemoglobin Hb concentration and dynamic membrane fluctuation in individual red blood cells (RBCs). Spectroscopic phase microscopy equipped with three different coherent laser sources and a color detector records three wavelength-dependent quantitative phase images in a single shot of a color-coded hologram. Using molecular specific dispersion, we demonstrate the extraction of Hb concentration and the dynamic membrane fluctuation from individual RBCs. PMID- 22535059 TI - Hollow sinh-Gaussian beams and their paraxial properties. AB - A new mathematical model of dark-hollow beams, described as hollow sinh-Gaussian (HsG) beams, has been introduced. The intensity distributions of HsG beams are characterized by a single bright ring along the propagation whose size is determined by the order of beams; the shape of the ring can be controlled by beam width and this leads to the elliptical HsG beams. Propagation characteristics of HsG beams through an ABCD optical system have been researched, they can be regarded as superposition of a series of Hypergeometric-Gaussian (HyGG) beams. As a numerical example, the propagation characteristics of HsG beams in free space have been demonstrated graphically. PMID- 22535060 TI - Application and evaluation of quasi-Monte Carlo method in illumination optical systems. AB - In this article, we evaluate a quasi-Monte Carlo (QMC) method with various low discrepancy sequences (LDS) in illumination optical systems which are adopted in some commercial products, and clarify the method's effectiveness quantitatively. We assumed the evaluated systems were an illumination optical system with a perfectly diffusing surface, and we compared them against the theoretical irradiance distribution. The evaluation results indicate that the QMC method delivers higher asymptotic convergence rate than the MC method does, and there is little difference between each LDS. In evaluation of simple optical systems that can be boiled down to low-dimensional numerical integration problems, the QMC method was found to be extremely effective. PMID- 22535061 TI - Mode-locked Yb:YAG thin-disk oscillator with 41 uJ pulse energy at 145 W average infrared power and high power frequency conversion. AB - We demonstrate the generation of 1.1 ps pulses containing more than 41 uJ of energy directly out of an Yb:YAG thin-disk without any additional amplification stages. The laser oscillator operates in ambient atmosphere with a 3.5 MHz repetition rate and 145 W of average output power at a fundamental wavelength of 1030 nm. An average output power of 91.5 W at 515 nm was obtained by frequency doubling with a conversion efficiency exceeding 65%. Third harmonic generation resulted in 34 W at 343 nm at 34% efficiency. PMID- 22535062 TI - Matched-filtering generalized phase contrast using LCoS pico-projectors for beam forming. AB - We report on a new beam-forming system for generating high intensity programmable optical spikes using so-called matched-filtering Generalized Phase Contrast (mGPC) applying two consumer handheld pico-projectors. Such a system presents a low-cost alternative for optical trapping and manipulation, optical lattices and other beam-shaping applications usually implemented with high-end spatial light modulators. Portable pico-projectors based on liquid crystal on silicon (LCoS) devices are used as binary phase-only spatial light modulators by carefully setting the appropriate polarization of the laser illumination. The devices are subsequently placed into the object and Fourier plane of a standard 4f-setup according to the mGPC spatial filtering configuration. Having a reconfigurable spatial phase filter, instead of a fixed and fabricated one, allows the beam shaper to adapt to different input phase patterns suited for different requirements. Despite imperfections in these consumer pico-projectors, the mGPC approach tolerates phase aberrations that would have otherwise been hard to overcome by standard phase projection. PMID- 22535063 TI - Isolated attosecond pulse generation from pre-excited medium with a chirped and chirped-free two-color field. AB - We theoretically investigate the isolated attosecond pulse generation from pre excited medium with a chirped and chirped-free two-color field. It is found that the large initial population of the excited state can lead to the high density of the free electrons in the medium and the large distortion of the driving laser field after propagation, though it benefits large enhancement of harmonic intensity in single atom response. These effects can weaken the phase-match of the macroscopic supercontinuum. On the contrary, the small initial population of 4% can generate well phase-match intense supercontinuum. We also investigate an isolated attosecond pulse generation by using a filter centered on axis to select the harmonics in the far field. Our results reveal that the radius of the spatial filter should be chosen to be small enough to reduce the duration of the isolated attosecond pulse due to the curvature effect of spatiotemporal profiles of the generated attosecond pulses in the far field. PMID- 22535064 TI - SMS-based optimization strategy for ultra-compact SWIR telephoto lens design. AB - A new optical design strategy for rotational aspheres using very few parameters is presented. It consists of using the SMS method to design the aspheres embedded in a system with additional simpler surfaces (such as spheres, parabolas or other conics) and optimizing the free-parameters. Although the SMS surfaces are designed using only meridian rays, skew rays have proven to be well controlled within the optimization. In the end, the SMS surfaces are expanded using Forbes series and then a second optimization process is carried out with these SMS surfaces as a starting point. The method has been applied to a telephoto lens design in the SWIR band, achieving ultra-compact designs with an excellent performance. PMID- 22535065 TI - Highly integrated optical heterodyne phase-locked loop with phase/frequency detection. AB - A highly-integrated optical phase-locked loop with a phase/frequency detector and a single-sideband mixer (SSBM) has been proposed and demonstrated for the first time. A photonic integrated circuit (PIC) has been designed, fabricated and tested, together with an electronic IC (EIC). The PIC integrates a widely-tunable sampled-grating distributed-Bragg-reflector laser, an optical 90 degree hybrid and four high-speed photodetectors on the InGaAsP/InP platform. The EIC adds a single-sideband mixer, and a digital phase/frequency detector, to provide single sideband heterodyne locking from -9 GHz to 7.5 GHz. The loop bandwith is 400 MHz. PMID- 22535066 TI - Inserting a cyclic prefix using Arrayed-Waveguide Grating Routers in all-optical OFDM transmitters. AB - Arrayed-Waveguide Grating Routers (AWGR) can be used as multiplexers and demultiplexers in optical OFDM systems, as they provide both the serial-to parallel converter and the optical Fourier transform in one component. This paper shows how the design of the AWGR at the transmitter can be modified to insert a cyclic prefix or postfix (CP). We use simulations of a 4-subcarrier system to compare systems without the CP, with a guard-interval, and with a CP. We show that the CP greatly improves the orthogonality of the subcarriers and resilience to timing errors. Furthermore, the CP allows for uncompensated fiber dispersion, especially if the relative timing of the subcarriers upon transmission is adjusted. PMID- 22535067 TI - Color-dulling solid-state sources of light. AB - The spectral power distributions (SPDs) of solid-state sources were optimized for rendering the highest number of colors with a perceptually noticeable reduction in chroma (dulling) while maintaining the hue distortion below an acceptable threshold. Statistical color rendition indices derived from the analysis of color shift vectors of 1269 Munsell samples were used in the objective functions for the optimization of SPDs of the color-dulling sources. The starting optimization point was the SPD composed of narrow yellow and blue (YB) emissions, which both dulls colors and distorts hues. Two methods were applied to reduce the hue distorting effect of the narrow-band YB source. The first method, broadening the spectral bands, yields SPDs similar to that of a dichromatic white light-emitting diode (LED) with the partial conversion of narrow-band blue electroluminescence to wide-band yellow photoluminescence. The second method, multiplying the spectral bands, results in the SPDs similar to those of trichromatic clusters of red, yellow, and blue (RYB) and amber, green, and blue (AGB) LEDs. PMID- 22535068 TI - Ridge waveguide lasers in Nd:GGG crystals produced by swift carbon ion irradiation and femtosecond laser ablation. AB - We report on the fabrication of ridge waveguide in Nd:GGG crystal by using swift C(5+) ion irradiation and femtosecond laser ablation. At room temperature continuous wave laser oscillation at wavelength of ~1063 nm has been realized through the optical pump at 808 nm with a slope efficiency of 41.8% and the pump threshold is 71.6 mW. PMID- 22535069 TI - Magnetic imaging by Fourier transform holography using linearly polarized x-rays. AB - We present a method for imaging magnetic domains via x-ray Fourier transform holography at linearly polarized sources. Our approach is based on the separation of holographic mask and sample and on the Faraday rotation induced on the reference wave. We compare images of perpendicular magnetic domains obtained with either linearly or circularly polarized x-rays and discuss the relevance of this method to future experiments at free-electron laser and high-harmonic-generation sources. PMID- 22535070 TI - Real space soft x-ray imaging at 10 nm spatial resolution. AB - Using Fresnel zone plates made with our robust nanofabrication processes, we have successfully achieved 10 nm spatial resolution with soft x-ray microscopy. The result, obtained with both a conventional full-field and scanning soft x-ray microscope, marks a significant step forward in extending the microscopy to truly nanoscale studies. PMID- 22535071 TI - Thermal emission from a metamaterial wire medium slab. AB - We investigate thermal emission from a metamaterial wire medium embedded in a dielectric host and highlight two different regimes for efficient emission, respectively characterized by broadband emission near the effective plasma frequency of the metamaterial, and by narrow-band resonant emission at the band edge in the Bragg scattering regime. We discuss how to control the spectral position and relative strength of these two emission mechanisms by varying the geometrical parameters of the proposed metamaterial and its temperature. PMID- 22535072 TI - High wavevector temporal speckle correlations at the Linac Coherent Light Source. AB - We report on the feasibility of high wavevector temporal speckle correlation measurements at the world's first hard x-ray free electron laser, the Linac Coherent Light Source (LCLS). Due to the chaotic nature of LCLS, the spectral profile of the x-ray radiation fluctuates on a pulse-to-pulse basis. Its impact on the determination of the single shot speckle contrast in a wide angle x-ray scattering geometry is investigated by analyzing FEL power spectra that are simulated based on the nominal operational parameters of LCLS. Ultimately, a potential scheme to deliver a single-mode hard x-ray pulse is proposed by using a narrow bandpass crystal monochromator. PMID- 22535073 TI - Dramatic cutoff extension and broadband supercontinuum generation in multi-cycle two color pulses. AB - We propose a method to markedly increase the electron-recollision kinetic energy, using the combination of a 0.8 MUm/13 fs driving pulse with a much weaker multi cycle mid-infrared pulse at 10.4 MUm. The results show that the synthesized field effectively lengthens the accelerated distance of electron wave packet and the harmonic cutoff is significantly extended to IP+26UP, which is covered with the water-window spectral region. In addition, only one single quantum path contributes to harmonics, and those higher than IP+15UP become continuous. This supercontinuum can support the generation of an isolated sub-100 as pulse with tunable central wavelength and also the pulse with the duration below one atomic unit of time (24 as). Moreover, our scheme can further extend to more longer driving pulses, which provides a dramatic approach for cutoff extension and broadband supercontinuum generation with multi-cycle pump pulses. PMID- 22535074 TI - Measurement of thermal lensing in a CW BaWO4 intracavity Raman laser. AB - The thermal lens induced in an a-cut BaWO(4) crystal by stimulated Raman scattering is measured using lateral shearing interferometry. The strength of the lens is proportional to the Stokes output power. For light polarized parallel to the a-axis, and a Stokes mode radius of 120 MUm, the lens is negative and highly astigmatic: -0.8 D W(-1) in the plane parallel to the a-axis and -7.7 D W(-1) in the plane parallel to the c-axis. The implications of this thermal lens for Raman laser design are discussed. PMID- 22535075 TI - Chromatic polarization effects of swept waveforms in FDML lasers and fiber spools. AB - We present detailed investigations of chromatic polarization effects, caused by fiber spools used in FDML lasers and buffering spools for rapidly wavelength swept lasers. We introduce a novel wavelength swept FDML laser source, specially tailored for polarization sensitive optical coherence tomography (OCT) which switches between two different linear polarization states separated by 45 degrees , i.e. 90 degrees on the Poincare sphere. The polarization maintaining laser cavity itself generates a stable linear polarization state and uses an external buffering technique in order to provide alternating polarization states for successive wavelength sweeps. The design of the setup is based on a comprehensive analysis of the polarization output from FDML lasers, using a novel 150 MHz polarization analyzer. We investigate the fiber polarization properties related to swept source OCT for different fiber delay topologies and analyze the polarization state of different FDML laser sources. PMID- 22535076 TI - Pump-seed synchronization for MHz repetition rate, high-power optical parametric chirped pulse amplification. AB - We report on an active synchronization between two independent mode-locked lasers using a combined electronic-optical feedback. With this scheme, seed pulses at MHz repetition rate were amplified in a non-collinear optical parametric chirped pulse amplifier (OPCPA). The amplifier was seeded with stretched 1.5 nJ pulses from a femtosecond Ti:Sapphire oscillator, while pumped with the 1 ps, 2.9 uJ frequency-doubled output of an Yb:YAG thin-disk oscillator. The residual timing jitter between the two oscillators was suppressed to 120 fs (RMS), allowing for an efficient and broadband amplification at 11.5 MHz to a pulse energy of 700 nJ and an average power of 8 W. First compression experiment with 240 nJ amplified pulse energy resulted in a pulse duration of ~10 fs. PMID- 22535077 TI - Continuous-wave Watt-level Nd:YLF/KGW Raman laser operating at near-IR, yellow and lime-green wavelengths. AB - A Nd:YLF/KGW Raman laser has been investigated in this work. We have demonstrated CW output powers at six different wavelengths, 1147 nm (0.70 W), 1163 nm (0.95 W), 549 nm (0.65 W), 552 nm (1.90 W), 573 nm (0.60 W) and 581 nm (1.10 W), with higher peak powers achieved under quasi-CW operation. Raman conversion of the 1053 nm fundamental emission is reported for the first time, enabling two new wavelengths in crystalline Raman lasers, 549 nm and 552 nm. The weak thermal lensing associated with Nd:YLF has enabled to achieve good beam quality, M(2) <= 2.0, and stable operation in relatively long cavities. PMID- 22535078 TI - Optical performance monitoring using the novel parametric asynchronous eye diagram. AB - In this paper we present a novel technique, based in what we have called Parametric Asynchronous Eye Diagram (PAED). We have used a simulation scheme, which includes a differentiator and an Artificial Neural Network to monitor simultaneously several impairments such as Chromatic Dispersion, Polarization Mode Dispersion and Optical Signal to Noise Ratio. A number of modulation formats, including NRZ, RZ and QPSK is used in the computation of results. This paper also demonstrates the effectiveness of this technique in monitoring with one single device, mixed traffic, with different bit rates and On-Off Keying (OOK) modulation formats traveling through the network. PMID- 22535079 TI - 1.5-MUm band polarization entangled photon-pair source with variable Bell states. AB - In this paper we report a polarization-entangled photon-pair source in a 1.5-MUm band which can generate arbitrary entangled states including four maximum entangled states (Bell states) by using cascaded optical second nonlinearities (second-harmonic generation and the following spontaneous parametric down conversion) in a periodically poled LiNbO(3) (PPLN) ridge-waveguide device. Exchange among the Bell states was achieved by using an optical phase bias compensator (OPBC) in a Sagnac loop interferometer and a half-wave plate outside the loop for polarization conversion. Quantitative evaluation was made on the performance of the photon-pair source through the experiments of two-photon interferences, quantum state tomography, and test of violation of Bell inequality. We observed high visibilities of 96%, fidelities of 97%, and 2.71 of the S parameter in inequality of Clauser, Horne, Shimony, and Holt (CHSH). The experimental values, including peak coincidence counts in the two-photon interference (approximately 170 counts per second), remained almost unchanged in despite of the exchange among the Bell states. They were also in good agreement with the theoretical assumption from the mean number of the photon-pairs under the test (0.04 per pulse). More detailed experimental studies on the dependence of the mean number of the photon-pairs revealed that the quantum states were well understood as the Werner state. PMID- 22535080 TI - Characterizing the 3-D field distortions in low numerical aperture fluorescence zooming microscope. AB - In this article, we characterize the lateral field distortions in a low numerical aperture and large field-of-view (FOV) fluorescence imaging system. To this end, we study a commercial fluorescence MACROscope setup, which is a zooming microscope. The versatility of this system lies in its ability to image at different zoom ranges, so that sample preparations can be examined in three dimensions, at cellular, organ and whole body levels. Yet, we found that the imaging system's optics are optimized only for high magnifications where the observed FOV is small. When we studied the point-spread function (PSF) by using fluorescent polystyrene beads as "guide-stars", we noticed that the PSF is spatially varying due to field distortions. This variation was found to be laterally symmetrical and the distortions were found to increase with the distance from the center of the FOV. In this communication, we investigate the idea of using the field at the back focal plane of an optical system for characterizing distortions. As this field is unknown, we develop a theoretical framework to retrieve the amplitude and phase of the field at the back focal pupil plane, from the empirical bead images. By using the retrieved amplitude, we can understand and characterize the underlying cause of these distortions. We also propose a few approaches, before acquisition, to either avoid it or correct it at the optical design level. PMID- 22535081 TI - Simultaneous all-optical RZ-to-NRZ format conversion for two tributaries in PDM signal using a single section of highly nonlinear fiber. AB - Simultaneous all-optical RZ-OOK to NRZ-OOK format conversion for two tributaries in PDM signal is demonstrated utilizing a single section of highly nonlinear fiber through polarization nonlinear loop mirror configuration. Less than 1-dB power penalty is achieved in a 2 * 12.5-Gb/s PDM system, and only 1.4-dB SNR penalty is obtained in a 2 * 40-Gb/s PDM system. PMID- 22535082 TI - Propagation of a partially coherent hollow vortex Gaussian beam through a paraxial ABCD optical system in turbulent atmosphere. AB - The propagation of a partially coherent hollow vortex Gaussian beam through a paraxial ABCD optical system in turbulent atmosphere has been investigated. The analytical expressions for the average intensity and the degree of the polarization of a partially coherent hollow vortex Gaussian beam through a paraxial ABCD optical system are derived in turbulent atmosphere, respectively. The average intensity distribution and the degree of the polarization of a partially coherent hollow vortex Gaussian beam in turbulent atmosphere are numerically demonstrated. The influences of the beam parameters, the topological charge, the transverse coherent lengths, and the structure constant of the atmospheric turbulence on the propagation of a partially coherent hollow vortex Gaussian beam in turbulent atmosphere are also examined in detail. This research is beneficial to the practical applications in free-space optical communications and the remote sensing of the dark hollow beams. PMID- 22535083 TI - Quantitative phase contrast optimised cancerous cell differentiation via ptychography. AB - This paper shows that visible-light ptychography can be used to distinguish quantitatively between healthy and tumorous unstained cells. Advantages of ptychography in comparison to conventional phase-sensitive imaging techniques are highlighted. A novel procedure to automatically refocus ptychographic reconstructions is also presented, which improves quantitative analysis. PMID- 22535084 TI - 10m/500 Mbps WDM visible light communication systems. AB - A wavelength-division-multiplexing (WDM) visible light communiction (VLC) system employing red and green laser pointer lasers (LPLs) with directly modulating data signals is proposed and experimentally demonstrated. With the assistance of preamplifier and adaptive filter at the receiving sites, low bit error rate (BER) at 10 m/500 Mbps operation is obtained for each wavelength. The use of preamplifier and adaptive filter offer significant improvements for free-space transmission performance. Improved performance of BER of <10(-9), as well as better and clear eye diagram were achieved in our proposed WDM VLC systems. LPL features create a new category of good performance with high-speed data rate, long transmission length (>5m), as well as easy handling and installation. This proposed WDM VLC system reveals a prominent one to present its advancement in simplicity and convenience to be installed. PMID- 22535085 TI - Double Dirac cones in triangular-lattice metamaterials. AB - It is shown by tight-binding approximation and group theory that a double Dirac cone, or a pair of two identical Dirac cones, of the electromagnetic dispersion relation can be created in the Brillouin zone center by accidental degeneracy of E(1) and E(2) modes in triangular-lattice metamaterials of C(6v) symmetry. The Dirac point thus obtained is equivalent to a zero-index system, so we can expect unique optical propagation phenomena such as constant-phase waveguides and lenses of arbitrary shapes. Zitterbewegung is also expected without disturbance due to an auxiliary quadratic dispersion surface, which is present for other combinations of mode symmetries to materialize the Dirac cones. To the best of the author's knowledge, this is the first prediction of the presence of a double Dirac cone in metamaterials. PMID- 22535086 TI - Passively Q-switched 1.5-1.6 MUm Er:Yb:LuAl3(BO3)4 laser with Co2+:Mg(0.4)Al(2.4)O4 saturable absorber. AB - Using a Co(2+):Mg(0.4)Al(2.4)O(4) spinel crystal as saturable absorber, efficient passively Q-switched pulse laser operating at 1.5-1.6 MUm was realized in an Er:Yb:LuAl(3)(BO(3))(4) crystal end-pumped by a 970 nm diode laser. At absorbed pump power of 15.7 W, 1540 nm laser with 28.6 MUJ energy, 40 ns duration and 22 kHz repetition rate, and 1520 nm laser with 9.9 MUJ energy, 37 ns duration and 63 kHz repetition rate were obtained in a plano-concave cavity, respectively. For a plano-plano cavity, corresponding values of 1520 nm laser were 16.3 MUJ, 14 ns and 41 kHz, respectively, and the maximum output peak power was about 1.16 kW. PMID- 22535087 TI - Polarization holographic microscopy for extracting spatio-temporally resolved Jones matrix. AB - We present a high-speed holographic microscopic technique for quantitative measurement of polarization light-field, referred to as polarization holographic microscopy (PHM). Employing the principle of common-path interferometry, PHM quantitatively measures the spatially resolved Jones matrix components of anisotropic samples with only two consecutive measurements of spatially modulated holograms. We demonstrate the features of PHM with imaging the dynamics of liquid crystal droplets at a video-rate. PMID- 22535088 TI - Cavity ring-down spectroscopy of Doppler-broadened absorption line with sub-MHz absolute frequency accuracy. AB - A continuous-wave cavity ring-down spectrometer has been built for precise determination of absolute frequencies of Doppler-broadened absorption lines. Using a thermo-stabilized Fabry-Perot interferometer and Rb frequency references at the 780 nm and 795 nm, 0.1 - 0.6 MHz absolute frequency accuracy has been achieved in the 775-800 nm region. A water absorption line at 12579 cm(-1) is studied to test the performance of the spectrometer. The line position at zero pressure limit is determined with an uncertainty of 0.3 MHz (relative accuracy of 0.8 * 10(-9)). PMID- 22535089 TI - Spectroscopic polarization-sensitive full-field optical coherence tomography. AB - Full-field optical coherence tomography (FF-OCT) is a recent optical imaging technology based on low-coherence interference microscopy for imaging of semi transparent samples with ~1 um spatial resolution. FF-OCT produces en-face tomographic images obtained by arithmetic combination of interferometric images acquired by an array camera. In this paper, we demonstrate a unique multimodal FF OCT system, capable of measuring simultaneously the intensity, the power spectrum and the phase-retardation of light backscattered by the sample being imaged. Compared to conventional FF-OCT, this multimodal system provides enhanced imaging contrasts at the price of a moderate increase in experimental complexity and cost. PMID- 22535090 TI - Coordinate transformation formulation of electromagnetic scattering from imperfectly periodic surfaces. AB - This paper considers the electromagnetic scattering problem of periodically corrugated surface with local imperfection of structural periodicity, and presents a formulation based on the coordinate transformation method (C-method). The C-method is originally developed to analyze the plane-wave scattering from perfectly periodic structures, and uses the pseudo-periodic property of the fields. The fields in imperfectly periodic structures are not pseudo-periodic and the C-method cannot be directly applied. This paper introduces the pseudo periodic Fourier transform to convert the fields in imperfectly periodic structures to pseudo-periodic ones, and the C-method becomes then applicable. PMID- 22535091 TI - Intra-cavity gain shaping of mode-locked Ti:sapphire laser oscillations. AB - The gain properties of an oscillator strongly affect its behavior. When the gain is homogeneous, different modes compete for gain resources in a 'winner takes all' manner, whereas with inhomogeneous gain, modes can coexist if they utilize different gain resources. We demonstrate precise control over the mode competition in a mode locked Ti:sapphire oscillator by manipulation and spectral shaping of the gain properties, thus steering the competition towards a desired, otherwise inaccessible, oscillation. Specifically, by adding a small amount of spectrally shaped inhomogeneous gain to the standard homogeneous gain oscillator, we selectively enhance a desired two-color oscillation, which is inherently unstable to mode competition and could not exist in a purely homogeneous gain oscillator. By tuning the parameters of the additional inhomogeneous gain we flexibly control the center wavelengths, relative intensities and widths of the two colors. PMID- 22535092 TI - High performance of InGaN light-emitting diodes by air-gap/GaN distributed Bragg reflectors. AB - The effect of air-gap/GaN DBR structure, fabricated by selective lateral wet etching, on InGaN light-emitting diodes (LEDs) is investigated. The air-gap/GaN DBR structures in LED acts as a light reflector, and thereby improve the light output power due to the redirection of light into escape cones on both front and back sides of the LED. At an injection current of 20 mA, the enhancement in the radiometric power as high as 1.91 times as compared to a conventional LED having no DBR structure and a far-field angle as low as 128.2 degrees are realized with air-gap/GaN DBR structures. PMID- 22535093 TI - Probability theory for 3-layer remote sensing radiative transfer model: univariate case. AB - A probability model for a 3-layer radiative transfer model (foreground layer, cloud layer, background layer, and an external source at the end of line of sight) has been developed. The 3-layer model is fundamentally important as the primary physical model in passive infrared remote sensing. The probability model is described by the Johnson family of distributions that are used as a fit for theoretically computed moments of the radiative transfer model. From the Johnson family we use the SU distribution that can address a wide range of skewness and kurtosis values (in addition to addressing the first two moments, mean and variance). In the limit, SU can also describe lognormal and normal distributions. With the probability model one can evaluate the potential for detecting a target (vapor cloud layer), the probability of observing thermal contrast, and evaluate performance (receiver operating characteristics curves) in clutter-noise limited scenarios. This is (to our knowledge) the first probability model for the 3-layer remote sensing geometry that treats all parameters as random variables and includes higher-order statistics. PMID- 22535094 TI - Tunable color temperature of Ce3+/Eu2+, 3+ co-doped low silica aluminosilicate glasses for white lighting. AB - In this paper we report results of tunable lighting in Ce(3+)/Eu(2+,3+) doped low silica calcium aluminosilicate glass. Optical spectroscopy experiments indicate that there is a red color compensation from Eu(2+) and Eu(3+) to the green emission from Ce(3+), resulting in a broad and tunable emission spectra depending on the excitation wavelength. This result analysed in the CIE 1976 color diagram shows a close distance from the Plank emission and a correlated color temperature, varying from 5200 to 3500K. This indicates that our system can be easily excited by GaN based blue LEDs, being an interesting phosphor for white lighting devices. PMID- 22535096 TI - Processing of optical combs with fiber optic parametric amplifiers. AB - Low noise optical frequency combs consist of equally spaced narrow-linewidth optical tones. They are useful in many applications including, for example, line by-line pulse shaping, THz generation, and coherent communications. In such applications the comb spacing, extent of spectral coverage, degree of spectral flatness, optical tone power and tone-to-noise ratio represent key considerations. Simultaneously achieving the level of performance required in each of these parameters is often challenging using existing comb generation technologies. Herein we suggest and demonstrate how fiber optic parametric amplifiers can be used to enhance all of these key comb parameters, allowing frequency span multiplication, low noise amplification with simultaneous comb spectrum flattening, and improvement in optical tone-to-noise ratio through various phase insensitive as well as phase sensitive implementations. PMID- 22535095 TI - Optical properties of light absorbing carbon aggregates mixed with sulfate: assessment of different model geometries for climate forcing calculations. AB - Light scattering by light absorbing carbon (LAC) aggregates encapsulated into sulfate shells is computed by use of the discrete dipole method. Computations are performed for a UV, visible, and IR wavelength, different particle sizes, and volume fractions. Reference computations are compared to three classes of simplified model particles that have been proposed for climate modeling purposes. Neither model matches the reference results sufficiently well. Remarkably, more realistic core-shell geometries fall behind homogeneous mixture models. An extended model based on a core-shell-shell geometry is proposed and tested. Good agreement is found for total optical cross sections and the asymmetry parameter. PMID- 22535097 TI - Slowing down terahertz waves with tunable group velocities in a broad frequency range by surface magneto plasmons. AB - This paper proposes one broadly tunable terahertz (THz) slow-light system in a semiconductor-insulator-semiconductor structure. Subject to an external magnetic field, the structure supports in total two surface magneto plasmons (SMPs) bands above and below the surface plasma frequency, respectively. Both the SMPs bands can be tuned by the external magnetic field. Numerical studies show that leveraging on the two tunable bands, the frequency and the group velocity of the slowed-down THz wave can be widely tuned from 0.3 THz to 10 THz and from 1 c to 10(-6) c, respectively, when the external magnetic field increases up to 6 Tesla. The proposed method based on the two SMPs bands can be widely used for many other plasmonic devices. PMID- 22535098 TI - 40-fs Yb3+:CaGdAlO4 laser pumped by a single-mode 350-mW laser diode. AB - We report the results of the investigation on a passively mode-locked Yb(3+):CaGdAlO(4) laser, pumped by a single transverse mode laser diode emitting 350 mW at 980 nm. This particular pump source allows efficient pumping with a nearly TEM(00) beam and minimal thermal load, making the optimization of the mode locking performance more straightforward than with higher-power multimode beams. Indeed, using a semiconductor saturable absorber mirror and extra-cavity dispersion compensation, pulses as short as 40 fs (31-nm spectrum) have been measured, tunable across 20 nm with 15-mW output power. Slightly longer Fourier limited 46-fs pulses with 33 mW output power directly from the oscillator have been achieved, using a different saturable absorber mirror. Such overall performance, especially considering these are among the shortest pulses generated in diode-pumped ytterbium lasers, confirms the excellent qualities of Yb(3+):CaGdAlO(4). PMID- 22535099 TI - Coupling of spin and angular momentum of light in plasmonic vortex. AB - We present that two distinct optical properties of light, the spin angular momentum (SAM) and the orbital angular momentum (OAM), can be coupled in the plasmonic vortex. If a plasmonic vortex lens (PVL) is illuminated by the helical vector beam (HVB) with the SAM and OAM, then those distinct angular momenta contribute to the generation of the plasmonic vortex together. The analytical model reveals that the total topological charge of the generated plasmonic vortex is given by a linear summation of those of the SAM and OAM, as well as the geometric charge of the PVL. The generation of the plasmonic vortex and the manipulation of the fractional topological charge are also presented. PMID- 22535100 TI - Chalcogenide optical parametric oscillator. AB - We demonstrate the first optical parametric oscillator (OPO) based on chalcogenide glass. The parametric gain medium is an As(2)Se(3) chalcogenide microwire coated with a layer of polymer. The doubly-resonant OPO oscillates simultaneously at a Stokes and an anti Stokes wavelength shift of >50 nm from the pump wavelength that lies at lambda(P) = 1,552 nm. The oscillator has a peak power threshold of 21.6 dBm and a conversion efficiency of >19%. This OPO experiment provides an additional application of the chalcogenide microwire technology; and considering the transparency of As(2)Se(3) glass extending far in the mid-infrared (mid-IR) wavelengths, the device holds promise for realizing mid IR OPOs utilizing existing optical sources in the telecommunications wavelength region. PMID- 22535101 TI - 1000-km 7-core fiber transmission of 10 x 96-Gb/s PDM-16QAM using Raman amplification with 6.5 W per fiber. AB - We demonstrate 7-core fiber transmission of 10 x 96-Gb/s PDM-16QAM signals over 1000-km using distributed Raman amplification (DRA). DRA gain of 9-12 dB and equivalent noise figure of less than 1 dB are achieved in all cores. We also prove the feasibility of high power multi-core fiber transmission with per fiber power of 6.5 W. PMID- 22535102 TI - A scheme for detecting the atom-field coupling constant in the Dicke superradiation regime using hybrid cavity optomechanical system. AB - We proposed a scheme for detecting the atom-field coupling constant in the Dicke superradiation regime based on a hybrid cavity optomechanical system assisted by an atomic gas. The critical behavior of the Dicke model was obtained analytically using the spin-coherent-state representation. Without regard to the dynamics of cavity field an analytical formula of one-to-one correspondence between movable mirror's steady position and atom-field coupling constant for a given number of atoms is obtained. Thus the atom-field coupling constant can be probed by measuring the movable mirror's steady position, which is another effect of the cavity optomechanics. PMID- 22535103 TI - Tm3+ and Tm(3+)-Ho3+ co-doped tungsten tellurite glass single mode fiber laser. AB - We investigated the ~2 MUm spectroscopic and lasing performance of Tm(3+) and Tm(3+)-Ho(3+) co-doped tungsten tellurite glass single mode fibers with a commercial 800 nm laser diode. The double cladding single mode (SM) fibers were fabricated by using rod-in-tube method. The propagation loss of the fiber was ~2.5 dB/m at 1310 nm. The spectroscopic properties of the fibers were analyzed. A 494 mW laser operating at ~1.9 MUm was achieved in a Tm(3+) doped 20 cm long fiber, the slope efficiency was 26%, and the laser beam quality factor M(2) was 1.09. A 35 mW ~2.1 MUm laser output was also demonstrated in a 7 cm long of Tm(3+)-Ho(3+) co-doped tungsten tellurite SM fiber. PMID- 22535104 TI - Enhanced luminescence via energy transfer from Ag+ to RE ions (Dy3+, Sm3+, Tb3+) in glasses. AB - Oxyfluoride glasses containing Ag species and rare earth (RE) ions (Dy(3+), Sm(3+), Tb(3+)) were prepared by melt-quenching technique. The type of luminescent species of novel excitation band (230-300 nm peaked at 255 nm) and emission band (300-600 nm peaked at 350 nm) were investigated by absorption, excitation, emission spectra, as well as decay lifetime measurements and can be ascribed to isolated Ag(+) ions. Owing to energy transfer from Ag(+) to RE ions, significant enhancements of RE ions emission (76 times for Sm(3+), 41 times for Dy(3+)) were observed for non-resonant UV excitation (255 nm). Our research may extend the understanding of interactions between RE ions and Ag species. PMID- 22535105 TI - Low energy prepulse for 10 Hz operation of a soft-x-ray laser. AB - The influence on Nickel-like Molybdenum soft-x-ray laser performance and stability of a low energy laser prepulse arriving prior to the main laser pumping pulses is experimentally investigated. A promising regime for 10 Hz operation has been observed. A four times increase in soft-x-ray laser operation time with a same target surface is demonstrated. This soft-x-ray laser operation mode corresponds to an optimum delay between the prepulse and the main pulses and to a prepulse energy greater than 20 mJ. We also show that this regime is not associated with a weaker degradation of the target or any reduced ablation rate. Therefore the role of preplasma density gradient in this effect is discussed. PMID- 22535106 TI - Revisiting the Balazs thought experiment in the case of a left-handed material: electromagnetic-pulse-induced displacement of a dispersive, dissipative negative index slab. AB - We propose a set of postulates to describe the mechanical interaction between a plane-wave electromagnetic pulse and a dispersive, dissipative slab having a refractive index of arbitrary sign. The postulates include the Abraham electromagnetic momentum density, a generalized Lorentz force law, and a model for absorption-driven mass transfer from the pulse to the medium. These opto mechanical mechanisms are incorporated into a one-dimensional finite-difference time-domain algorithm that solves Maxwell's equations and calculates the instantaneous force densities exerted by the pulse onto the slab, the momentum per-unit-area of the pulse and slab, and the trajectories of the slab and system center-of-mass. We show that the postulates are consistent with conservation of global energy, momentum, and center-of-mass velocity at all times, even for cases in which the refractive index of the slab is negative or zero. Consistency between the set of postulates and well-established conservation laws reinforces the Abraham momentum density as the one true electromagnetic momentum density and enables, for the first time, identification of the correct form of the electromagnetic mass density distribution and development of an explicit model for mass transfer due to absorption, for the most general case of a ponderable medium that is both dispersive and dissipative. PMID- 22535107 TI - Mode-evolution-based polarization rotator-splitter design via simple fabrication process. AB - A mode-evolution-based polarization rotator-splitter built on InP substrate is proposed by combining a mode converter and an adiabatic asymmetric Y-coupler. The mode converter, consisting of a bi-level taper and a width taper, effectively converts the fundamental TM mode into the second order TE mode without changing the polarization of the fundamental TE mode. The following adiabatic asymmetric Y coupler splits the fundamental and the second order TE modes and also converts the second order TE mode into the fundamental TE mode. A shallow etched structure is proposed for the width taper to enhance the polarization conversion efficiency. The device has a total length of 1350 um, a polarization extinction ratio over 25 dB and an insertion loss below 0.5 dB both for TE and TM modes, over the wavelength range from 1528 to 1612 nm covering all C + L band. Because the device is designed based on mode evolution principle, it has a large fabrication tolerance. The insertion loss remains below 1 dB and the polarization extinction ratio remains over 17 dB with respect to a width variation of +/- 0.12 um at the wavelength of 1570 nm, or +/- 0.08 um over the entire C + L band. PMID- 22535108 TI - Enhancement of LED indoor communications using OPPM-PWM modulation and grouped bit-flipping decoding. AB - Combination of overlapping pulse position modulation and pulse width modulation at the transmitter and grouped bit-flipping algorithm for low-density parity check decoding at the receiver are proposed for visible Light Emitting Diode (LED) indoor communication system in this paper. The results demonstrate that, with the same Photodetector, the bit rate can be increased and the performance of the communication system can be improved by the scheme we proposed. Compared with the standard bit-flipping algorithm, the grouped bit-flipping algorithm can achieve more than 2.0 dB coding gain at bit error rate of 10-5. By optimizing the encoding of overlapping pulse position modulation and pulse width modulation symbol, the performance can be further improved. It is reasonably expected that the bit rate can be upgraded to 400 Mbit/s with a single available LED, thus transmission rate beyond 1 Gbit/s is foreseen by RGB LEDs. PMID- 22535109 TI - Miniature highly-birefringent microfiber loop with extremely-high refractive index sensitivity. AB - A miniature polarimetric interferometer with the twist of a highly-birefringent microfiber is demonstrated. Good transmission spectral characteristics, which are co-governed by the birefringence and the twist degree of the microfiber, are investigated. The structure exhibits extremely-high sensitivity of around 24,373 nm per refractive-index unit and excellent temperature stability of better than 0.005 nm/ degrees C. Featured with compactness, reconfigurability, stability, robustness, and compatibility with other fiberized components, our device has potential in tunable filtering, sensing, multi-wavelength lasing, and etc. PMID- 22535110 TI - Optimal lighting of RGB LEDs for oral cavity detection. AB - In this paper the optimal lighting for oral cavity detection is proposed. The illuminants consist of several LEDs with different intensity ratios and peak wavelengths, which can enhance the color difference between normal and abnormal regions in the oral cavity. An algorithm combined with multi-spectral imaging (MSI) and color reproduction technique is applied to find the best enhancement of this difference. The colored LEDs of the optimal lighting, the Color Rendering Index (CRI) of the illuminants, and comparison with traditional illuminants are discussed. The calculations show that color enhancement ability in the oral cavity is not entirely a function of the higher CRI of some illuminants, as the narrowband illuminants (LEDs) produce an image with greater contrast than the broadband spectra and higher CRI of traditional illuminants in the reddish oral environment. Accordingly, an illuminant with specific intensity ratio of red, green, and blue LEDs is proposed, which has optimal color enhancement for oral cavity detection. Compared with the fluorescent lighting commonly in the use now, the color difference between normal and inflamed tissues can be improved from 21.5732 to 30.5532, a 42% increase, thus making medical diagnosis more efficient, so helping patients receive early treatment. PMID- 22535111 TI - Homotopic, non-local sparse reconstruction of optical coherence tomography imagery. AB - The resolution in optical coherence tomography imaging is an important parameter which determines the size of the smallest features that can be visualized. Sparse sampling approaches have shown considerable promise in producing high resolution OCT images with fewer camera pixels, reducing both the cost and the complexity of an imaging system. In this paper, we propose a non-local approach to the reconstruction of high resolution OCT images from sparsely sampled measurements. An iterative strategy is introduced for minimizing a homotopic, non-local regularized functional in the spatial domain, subject to data fidelity constraints in the k-space domain. The novel algorithm was tested on human retinal, corneal, and limbus images, acquired in-vivo, demonstrating the effectiveness of the proposed approach in generating high resolution reconstructions from a limited number of camera pixels. PMID- 22535112 TI - On-chip three-dimensional high-Q microcavities fabricated by femtosecond laser direct writing. AB - We report on the fabrication of three-dimensional (3D) high-Q whispering gallery microcavities on a fused silica chip by femtosecond laser microfabriction, enabled by the 3D nature of femtosecond laser direct writing. The processing mainly consists of formation of freestanding microdisks by femtosecond laser direct writing and subsequent wet chemical etching. CO(2) laser annealing is followed to smooth the microcavity surface. Microcavities with arbitrary tilting angle, lateral and vertical positioning are demonstrated, and the quality (Q) factor of a typical microcavity is measured to be up to 1.07 * 10(6), which is currently limited by the low spatial resolution of the motion stage used during the laser patterning and can be improved with motion stages of higher resolutions. PMID- 22535113 TI - Toward scatter-free phosphors in white phosphor-converted light-emitting diodes. AB - Scatter-free phosphors promise to suppress the scattering loss of conventional micro-size powder phosphors in white phosphor-converted light-emitting diodes (pc LEDs). Large micro-size cube phosphors (~100 MUm) are newly designed and prepared as scatter-free phosphors, combining the two scatter-free conditions of particles based on Mie's scattering theory; the grain size or grain boundary was smaller than 50 nm and the particle size was larger than 30 MUm. A careful evaluation of the conversion efficiency and packaging efficiency of the large micro-size cube phosphor-based white pc-LED demonstrated that large micro-size cube phosphors are an outstanding potential candidate for scatter-free phosphors in white pc-LEDs. The luminous efficacy and packaging efficiency of the Y(3)Al(5)O(12):Ce(3+) large micro-size cube phosphor-based pc-LEDs were 123.0 lm/W and 0.87 at 4300 K under 300 mA, which are 17% and 34% higher than those of commercial powder phosphor based white LEDs (104.8 lm/W and 0.65), respectively. In addition, the introduction of large micro-size cube phosphors can reduce the wide variation in optical properties as a function of both the ambient temperature and applied current compared with those of conventional powder phosphor-based white LEDs. PMID- 22535115 TI - Enhancing angular sampling rate of integral floating display using dynamically variable apertures. AB - Two novel methods are proposed which enhance the angular sampling rate of the integral floating display by adopting dynamically variable apertures in front of the lenslet array or the floating lens. Adopted dynamically variable apertures are opened sequentially in synchronization with proper elemental images to subdivide the angular sampling step by time-multiplexing method. Our proposed method can enhance the angular sampling rate, which is related to an expressible longitudinal range, without sacrificing other visual quality factors in tradeoff relationship. Especially, our proposed method with apertures on the floating lens provides two-dimensional/three-dimensional convertible feature to integral floating display system. PMID- 22535114 TI - Swept source/Fourier domain polarization sensitive optical coherence tomography with a passive polarization delay unit. AB - Polarization sensitive optical coherence tomography (PS-OCT) is a functional imaging method that provides additional contrast using the light polarizing properties of a sample. This manuscript describes PS-OCT based on ultrahigh speed swept source / Fourier domain OCT operating at 1050 nm at 100 kHz axial scan rates using single mode fiber optics and a multiplexing approach. Unlike previously reported PS-OCT multiplexing schemes, the method uses a passive polarization delay unit and does not require active polarization modulating devices. This advance decreases system cost and avoids complex synchronization requirements. The polarization delay unit was implemented in the sample beam path in order to simultaneously illuminate the sample with two different polarization states. The orthogonal polarization components for the depth-multiplexed signals from the two input states were detected using dual balanced detection. PS-OCT images were computed using Jones calculus. 3D PS-OCT imaging was performed in the human and rat retina. In addition to standard OCT images, PS-OCT images were generated using contrast form birefringence and depolarization. Enhanced tissue discrimination as well as quantitative measurements of sample properties was demonstrated using the additional contrast and information contained in the PS OCT images. PMID- 22535116 TI - Stability of the nonlinear dynamics of an optically injected VCSEL. AB - Automated protocols have been developed to characterize time series data in terms of stability. These techniques are applied to the output power time series of an optically injected vertical cavity surface emitting laser (VCSEL) subject to varying injection strength and optical frequency detuning between master and slave lasers. Dynamic maps, generated from high resolution, computer controlled experiments, identify regions of dynamic instability in the parameter space. PMID- 22535117 TI - Building up low-complexity spectrally-efficient Terabit superchannels by receiver side duobinary shaping. AB - Recently, an increasing interest has been put on spectrally-efficient multi carrier superchannels for beyond 100G. Apart from orthogonal frequency-division multiplexing (OFDM) and Nyquist wavelength-division multiplexing (WDM), another low-complexity WDM approach based on transmitter-side pre-filtering and receiver side duobinary shaping is proposed to build up multi-carrier superchannels. This approach is referred to as receiver-side duobinary-shaped WDM (RS-DBS-WDM). Generation and transmission of a 1.232-Tbit/s 11-carrier superchannel is experimentally demonstrated. The superchannel signal can be well fit inside the passband of multiple 300-GHz reconfigurable optical add and drop multiplexers (ROADMs). In the superchannel scenario, the proposed RS-DBS-WDM is qualitatively compared with OFDM and Nyquist-WDM in terms of implementation complexity. In sum, the proposed RS-DBS-WDM approach features high transceiver analog-bandwidth efficiency, high spectral-efficiency, the absence of specific spectral manipulation, compatibility with conventional WDM technologies and coherent detection algorithms, and comparable implementation penalty. PMID- 22535118 TI - Ultra-small, self-holding, optical gate switch using Ge2Sb2Te5 with a multi-mode Si waveguide. AB - We report a multi-mode interference-based optical gate switch using a Ge(2)Sb(2)Te(5) thin film with a diameter of only 1 um. The switching operation was demonstrated by laser pulse irradiation. This switch had a very wide operating wavelength range of 100 nm at around 1575 nm, with an average extinction ratio of 12.6 dB. Repetitive switching over 2,000 irradiation cycles was also successfully demonstrated. In addition, self-holding characteristics were confirmed by observing the dynamic responses, and the rise and fall times were 130 ns and 400 ns, respectively. PMID- 22535119 TI - Automated statistical quantification of three-dimensional morphology and mean corpuscular hemoglobin of multiple red blood cells. AB - In this paper, we present an automated approach to quantify information about three-dimensional (3D) morphology, hemoglobin content and density of mature red blood cells (RBCs) using off-axis digital holographic microscopy (DHM) and statistical algorithms. The digital hologram of RBCs is recorded by a CCD camera using an off-axis interferometry setup and quantitative phase images of RBCs are obtained by a numerical reconstruction algorithm. In order to remove unnecessary parts and obtain clear targets in the reconstructed phase image with many RBCs, the marker-controlled watershed segmentation algorithm is applied to the phase image. Each RBC in the segmented phase image is three-dimensionally investigated. Characteristic properties such as projected cell surface, average phase, sphericity coefficient, mean corpuscular hemoglobin (MCH) and MCH surface density of each RBC is quantitatively measured. We experimentally demonstrate that joint statistical distributions of the characteristic parameters of RBCs can be obtained by our algorithm and efficiently used as a feature pattern to discriminate between RBC populations that differ in shape and hemoglobin content. Our study opens the possibility of automated RBC quantitative analysis suitable for the rapid classification of a large number of RBCs from an individual blood specimen, which is a fundamental step to develop a diagnostic approach based on DHM. PMID- 22535120 TI - Hard-X-ray imaging optics based on four aspherical mirrors with 50 nm resolution. AB - Ultraprecise imaging optics, which consists of two sets of elliptical mirrors and hyperbolic mirrors aligned perpendicular to each other (i.e., advanced Kirkpatrick-Baez mirrrors), is developed to realize high-resolution and achromatic full-field hard-X-ray microscopy. Experiments to form a demagnified image (with horizontal and vertical demagnification factors of 385 and 210, respectively) are conducted to evaluate the optical system at an X-ray energy of 11.5 keV at SPring-8. Results show that the imaging system can form a demagnified image with nearly diffraction-limited resolutions of ~50 nm in the horizontal and vertical directions. The field of view is also experimentally estimated to be ~12 * ~14 MUm(2) when used as a magnification imaging system. PMID- 22535121 TI - Noise suppression using optimum filtering of OCs generated by a multiport encoder/decoder. AB - We propose a novel receiver configuration using an extreme narrow band-optical band pass filter (ENB-OBPF) to reduce the multiple access interference (MAI) and beat noises in an optical code division multiplexing (OCDM) transmission. We numerically and experimentally demonstrate an enhancement of the code detectability, that allows us to increase the number of users in a passive optical network (PON) from 4 to 8 without any forward error correction (FEC). PMID- 22535122 TI - Ultrafast pump-probe microscopy with high temporal dynamic range. AB - Ultrafast pump-probe microscopy is a common method for time and space resolved imaging of short and ultra-short pulse laser ablation. The temporal delay between the ablating pump pulse and the illuminating probe pulse is tuned either by an optical delay, resulting in several hundred femtoseconds temporal resolution for delay times up to a few ns, or by an electronic delay, resulting in several nanoseconds resolution for longer delay times. In this work we combine both delay types for temporally high resolved observations of complete ablation processes ranging from femtoseconds to microseconds, while ablation is initiated by an ultrafast 660 fs laser pump pulse. For this purpose, we also demonstrate the calibration of the delay time zero point, the synchronization of both probe sources, as well as a method for image quality enhancing. In addition, we present for the first time to our knowledge pump-probe microscopy investigations of the complete substrate side selective ablation process of molybdenum films on glass. The initiation of mechanical film deformation is observed at about 400 ps, continues until approximately 15 ns, whereupon a Mo disk is sheared off free from thermal effects due to a directly induced laser lift-off ablation process. PMID- 22535123 TI - Towards full band colorless reception with coherent balanced receivers. AB - In addition to linear compensation of fiber channel impairments, coherent receivers also provide colorless selection of any desired data channel within multitude of incident wavelengths, without the need of a channel selecting filter. In this paper, we investigate the design requirements for colorless reception using a coherent balanced receiver, considering both the optical front end (OFE) and the transimpedance amplifier (TIA). We develop analytical models to predict the system performance as a function of receiver design parameters and show good agreement against numerical simulations. At low input signal power, an optimum local oscillator (LO) power is shown to exist where the thermal noise is balanced with the residual LO-RIN beat noise. At high input signal power, we show the dominant noise effect is the residual self-beat noise from the out of band (OOB) channels, which scales not only with the number of OOB channels and the common mode rejection ratio (CMRR) of the OFE, but also depends on the link residual chromatic dispersion (CD) and the orientation of the polarization tributaries relative to the receiver. This residual self-beat noise from OOB channels sets the lower bound for the LO power. We also investigate the limitations imposed by overload in the TIA, showing analytically that the DC current scales only with the number of OOB channels, while the differential AC current scales only with the link residual CD, which induces high peak-to-average power ratio (PAPR). Both DC and AC currents at the input to the TIA set the upper bounds for the LO power. Considering both the OFE noise limit and the TIA overload limit, we show that the receiver operating range is notably narrowed for dispersion unmanaged links, as compared to dispersion managed links. PMID- 22535124 TI - Ultra-long-haul 112 Gb/s PM-QPSK transmission systems using longer spans and Raman amplification. AB - Ultra-long-haul transmission at distances greater than 10,000 km is investigated for 112 Gb/s PM-QPSK signals using span lengths of 75 km and 100 km and all-Raman amplification. Two different ultra-low loss and large effective area optical fibers are studied. We demonstrate a reach length of 10,200 km for a 40 channel system using a fiber with effective area 112 MUm(2) with 100 km spans, and a reach length of 13,288 km for a system with 75 km spans using a fiber with effective area of 134 MUm(2). PMID- 22535125 TI - A single-scatter path loss model for non-line-of-sight ultraviolet channels. AB - In this paper, a novel single-scatter path loss model is presented for non-line of-sight (NLOS) ultraviolet (UV) channels. This model is developed based on the spherical coordinate system and extends the previous restricted models to handle the general noncoplanar case of arbitrarily pointing transmitter and receiver. Numerical examples on path loss are illustrated for various system geometries. These results are verified with a Monte Carlo (MC) model, demonstrating the validity of this model. PMID- 22535126 TI - Intracellular label-free gold nanorods imaging with photoacoustic microscopy. AB - Noninvasive photoacoustic microscopy was developed to image intracellular gold nanorods with high optical-absorption contrast. The endocytosed gold nanorods in MCF7 cells can be detected and imaged with the home-made photoacoustic microscope. Cell nucleus and gold nanorods in cytoplasm were clearly identified after hematoxylin and eosin (H&E) staining with dual-wavelength excitation. The intracellular gold nanorods were successfully monitored, and that the time dependent uptake and distribution of the gold nanorods in the cells were clearly shown. The result demonstrated an application of photoacoustic microscopy for complements to imaging of nonfluorescent nanoparticles, which will arm the in vivo microscopic imaging method to the nano-bio research. PMID- 22535127 TI - Wide-angle polarization independent infrared broadband absorbers based on metallic multi-sized disk arrays. AB - Two-dimensional metallic broadband absorbers on a SiO(2)/Ag/Si substrate were experimentally studied. The absorptivity of such structure can be increased by tailoring the ratio of disk size to the unit cell area. The metallic disk exhibits a localized surface plasmon polariton (LSPP) mode for both TE and TM polarizations. A broadband thermal emitter can be realized because the LSPP mode is independent of the periodicities. By manipulating the ratios and disk sizes, a high-performance, wide-angle, polarization-independent dual band absorber was experimentally achieved. The results demonstrated a substantial flexibility in absorber designs for applications in thermal photovoltaics, sensors, and camouflage. PMID- 22535128 TI - Optical interconnect transmitter based on guided-wave silicon optical bench. AB - An optical interconnect transmitter based on guided-wave silicon optical bench is demonstrated. The guided-wave silicon optical bench (GW-SiOB) is developed on a silicon-on-insulator (SOI) substrate. The three-dimensional guided-wave optical paths on the silicon optical bench are realized using trapezoidal waveguides monolithically integrated with 45 degrees micro-reflectors. Such three dimensional guided-w ave optical paths of SiOB would simplify and shrink the intra-chip optical interconnects located on a SOI substrate. The clearly open eye patterns operated at a data rate of 5 Gbps verifies the proposed GW-SiOB is suitable for intra-chip optical interconnects. PMID- 22535129 TI - Optical pressure and temperature sensor based on the luminescence properties of Nd3+ ion in a gadolinium scandium gallium garnet crystal. AB - Hypersensitivity to pressure and temperature is observed in the near-infrared emission lines of the Nd(3+) ion in a Cr(3+),Nd(3+):Gd(3)Sc(2)Ga(3)O(12) crystal, associated to the R(1,2)((4)F(3/2))->Z(5)((4)I(9/2)) and R(1,2)((4)F(3/2)) >Z(1)((4)I(9/2)) transitions. The former emissions show large linear pressure coefficients of -11.3 cm(-1)/GPa and -8.8 cm(-1)/GPa, while the latter show high thermal sensitivity in the low temperature range. Thus this garnet crystal can be considered a potential optical pressure and/or temperature sensor in high pressure and temperature experiments up to 12 GPa and below room temperature, used in diamond anvil cells and excited with different UV and visible commercial laser due to the multiple Cr(3+) and Nd(3+) absorption bands. PMID- 22535130 TI - Strong exciton-photon coupling in microcavities containing new fluorophenethylamine based perovskite compounds. AB - We synthetize some new perovskite thin layers: p-fluorophenethylamine tetraiodoplumbate pFC(6)H(4)C(2)H(4)NH(3))(2)PbI(4) perovskite molecules, included in a PMMA matrix. We report on the optical properties of the perovskite doped PMMA thin layers and we show that these layers are much more stable under laser illumination and present a smaller roughness than the spin-coated (C(6)H(5)C(2)H(4)NH(3))(2)PbI(4) layers. These new layers are used as the active material in vertical microcavities and the strong-coupling regime is evidenced by a clear anti-crossing appearing in the angular-resolved reflectivity experiments at room temperature. PMID- 22535131 TI - Statistical connection of binomial photon counting and photon averaging in high dynamic range beam-scanning microscopy. AB - Data from photomultiplier tubes are typically analyzed using either counting or averaging techniques, which are most accurate in the dim and bright signal limits, respectively. A statistical means of adjoining these two techniques is presented by recovering the Poisson parameter from averaged data and relating it to the statistics of binomial counting from Kissick et al. [Anal. Chem. 82, 10129 (2010)]. The point at which binomial photon counting and averaging have equal signal to noise ratios is derived. Adjoining these two techniques generates signal to noise ratios at 87% to approaching 100% of theoretical maximum across the full dynamic range of the photomultiplier tube used. The technique is demonstrated in a second harmonic generation microscope. PMID- 22535132 TI - Upstream capacity upgrade in TDM-PON using RSOA based tunable fiber ring laser. AB - An upstream multi-wavelength shared (UMWS) time division multiplexing passive optical network (TDM-PON) is presented by using a reflective semiconductor amplifier (RSOA) and tunable optical filter (TOF) based directly modulated fiber ring laser as upstream laser source. The stable laser operation is easily achieved no matter what the bandwidth and shape of the TOF is and it can be directly modulated when the RSOA is driven at its saturation region. In this UMWS TDM-PON system, an individual wavelength can be assigned to the user who has a high bandwidth demand by tuning the central wavelength of the TOF in its upgraded optical network unit (ONU), while others maintain their traditional ONU structure and share the bandwidth via time slots, which greatly and dynamically upgrades the upstream capacity. We experimentally demonstrated the bidirectional transmission of downstream data at 10-Gb/s and upstream data at 1.25-Gb/s per wavelength over 25-km single mode fiber (SMF) with almost no power penalty at both ends. A stable performance is observed for the upstream wavelength tuned from 1530 nm to 1595 nm. Moreover, due to the high extinction ratio (ER) of the upstream signal, the burst-mode transmitting is successfully presented and a better time-division multiplexing performance can be obtained by turning off the unused lasers thanks to the rapid formation of the laser in the fiber ring. PMID- 22535133 TI - Direct measurement of the near-field super resolved focused spot in InSb. AB - Under appropriate laser exposure, a thin film of InSb exhibits a sub-wavelength thermally modified area that can be used to focus light beyond the diffraction limit. This technique, called Super-Resolution Near-Field Structure, is a potential candidate for ultrahigh density optical data storage and many other high-resolution applications. We combined near field microscopy, confocal microscopy and time resolved pump-probe technique to directly measure the induced sub-diffraction limited spot in the near-field regime. The measured spot size was found to be dependent on the laser power and a decrease of 25% (100 nm) was observed. Experimental evidences that support a threshold-like simulation model to describe the effect are also provided. The experimental data are in excellent agreement with rigorous simulations obtained with a three dimensional Finite Element Method code. PMID- 22535134 TI - Metal-slotted hybrid optical waveguides for PCB-compatible optical interconnection. AB - For development of electro-optical printed circuit board (PCB) systems, PCB compatible metal-slotted hybrid optical waveguide was proposed and its optical characteristics are investigated at a wavelength of 1.31 MUm. To confine light in a metallic multilayered structure, a metal film with a wide trench is inserted at the center of a dielectric medium that is sandwiched between metal films of infinite width. A circularly symmetric spot of the guided mode was measured at the center of the metal-slotted optical waveguide, which is a good agreement with the theoretical prediction by using the finite-element method. The measured propagation loss is about 1.5 dB/cm. Successful transmission of 2.5 Gbps optical signal without any distortion of the eye diagram confirms that the proposed hybrid optical waveguide holds a potential transmission line for the PCB compatible optical interconnection. PMID- 22535135 TI - Trends in the inequality of fruit and vegetable consumption between education levels indicated by the Korea National Health and Nutrition Examination Surveys. AB - BACKGROUND/OBJECTIVES: The objective of this study was to investigate whether an inequality in fruit and/or vegetable (FV) consumption exists between adults of different educational levels in Korea and whether this has changed over the past decade. SUBJECTS/METHODS: This study included adults >= 20 years) who participated in the Korea National Health and Nutrition Examination Survey (1998 2009). The FV intakes were examined using 24-h dietary-recall surveys (n=35,725) and food frequency questionnaires (n=35,400). The relative index of inequality (RII) was used to examine the magnitude and trend of inequality in insufficient FV intake (<500 gram/day for total FV; <100 gram/day, less than once per day for fruits) between educational levels. RESULTS: The low-education group had lower intakes of total FV, vegetables excluding Kimchi and fruit (both by frequency and quantity), but higher intakes of Kimchi, in both sexes in most years in which surveys were conducted. This group also had a higher proportion of adults with insufficient total FV and fruit intakes. The inequality, as indicated by the RII, was apparent in both sexes and in each survey year. The inequality in insufficient total FV intake increased between 1998 and 2009 in both sexes (P<0.05). An increase in the inequality in fruit intake was only detected in women (P<0.0001 for frequency and P=0.0285 for quantity, from 2007 to 2009). CONCLUSION: There is a wide discrepancy in total FV and fruit consumption across education levels among Korean adults. This inequality has increased over time for total FV intake in both sexes and for fruit intake in women. PMID- 22535136 TI - The Benslimane's Artistic Model for Leg Beauty. AB - BACKGROUND: In 2000, the author started observing legs considered to be attractive. The goal was to have an ideal aesthetic model and compare the disparity between this model and a patient's reality. This could prove helpful during leg sculpturing to get closer to this ideal. Postoperatively, the result could then be compared to the ideal curves of the model legs and any remaining deviations from the ideal curves could be pointed out and eventually corrected in a second session. The lack of anthropometric studies of legs from the knee to the ankle led the author to select and study attractive legs to find out the common denominators of their beauty. METHOD: The study consisted in analyzing the features that make legs look attractive. The legs of models in magazines were scanned and inserted into a PowerPoint program. The legs of live models, Barbie dolls, and athletes were photographed. Artistic drawings by Leonardo da Vinci were reviewed and Greek sculptures studied. Sculptures from the National Archaeological Museum of Athens were photographed and included in the PowerPoint program. RESULTS AND CONCLUSION: This study shows that the first criterion for beautiful legs is the straightness of the leg column. Not a single attractive leg was found to deviate from the vertical, and each was in absolute continuity with the thigh. The second criterion is the similarity of curve distribution and progression from knee to ankle. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266. PMID- 22535137 TI - Three-dimensional evaluation of breast augmentation and the influence of anatomic and round implants on operative breast shape changes. AB - BACKGROUND: Currently, postoperative outcome analysis in breast augmentation is essentially subjective, and objective evaluation of treatment efficacy is lacking. This study evaluates the influence of anatomic and round implant parameters on breast contour changes after subpectoral breast augmentation using three-dimensional (3D) surface imaging. METHODS: 3D surface breast scans of 17 patients (34 breasts) undergoing subpectoral breast augmentation with round implants and of ten patients (20 breasts) receiving anatomic implants via an axillary approach under endoscopic assistance or a submammary fold incision were obtained before and 6 months postoperatively. 3D linear distance, breast volume, and surface measurement were correlated with the implanted round and anatomic implant parameters, and the resulting breast shape changes were evaluated. RESULTS: Total breast volume changed in correlation with the implant size (2.4% difference; r=0.894; p<0.001). Implant volume and type influence the nipple-to inframammary fold distance (N-IMF). Every inserted 100 ml implant volume enlarges the N-IMF distance by 0.8 cm (anatomic>round; p=0.01). Postoperatively, the IMF dropped by an average of 1.3 cm for round implants and by 1.1 cm for anatomic implants, without relevant differences between the applied surgical incision and the selected implants (p>0.05). Breast projection increased significantly more with anatomic implants (2.4 cm) than with round implants (1.7 cm) (p=0.01). The breast projection increase was 22% less than expected for round implants and 25% less than expected for anatomic implants based on the manufacturer implant parameters (p<0.01), without essential differences regarding the surgical incision. CONCLUSIONS: 3D breast shape changes induced by round and anatomic implants after subpectoral augmentation mammaplasty are objectively documented including breast projection, volume, and N-IMF distance changes. 3D surface imaging may have a potential clinical contribution to objective surgical outcome research. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266. PMID- 22535138 TI - The "Brazilian" bikini-shaped lip-reduction technique: new developments in cheiloplasty. AB - BACKGROUND: The lips, one of the most illustrious facial features, have a key role in forming facial expressions. In the past, hypertrophic lips were an aesthetic issue among certain ethnic groups. Although full lips are a desirable feature sought by many people, the current world of fashion tends emphasize equilibrium and significant matching of features, encouraging people to seek refinement through cosmetic surgery. The purpose is to reach the standard level of perceived attractiveness in current society. This article aims to present a novel lip reduction technique that restores an attractive labial contour by shifting the shape toward a more "Brazilian way" and resulting in more aesthetically appealing lips. METHODS: The technique described in this report was performed on more than 40 patients between 2008 and 2010. The major difference between this technique and others is that it transforms the shape of the bikini lines to a more "Brazilian" way. The upper resection is more conservative, whereas the lower resection is less triangular and more curved, displaying more of the bilateral "bands" on the lips. The reported patients did not present any infections or any other complications. CONCLUSION: The nature of human beings urges them to seek routes of assimilation into their society. This also applies to the rules of perceived attractiveness. The technique presented in this article has recaptured specific attention to the resultant lip contour, altering the shape of the marks on the lower lip. The new technique yields a harmonious relationship between the upper and lower lips. The aesthetic results and patient satisfaction attained through this novel technique of lip reduction have been very satisfactory. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266. PMID- 22535139 TI - Useful application of negative suction drainage on the umbilicus after transaxillary breast augmentation. AB - Simple application of negative suction drains through the umbilicus during transaxillary breast augmentation obtained a more natural drainage and an easier positioning of the drain at the dependant portions than placement of the drains at the transaxillary incision site. Moreover, the patient was more satisfied due to increased comfort while wearing clothes, which resulted in a quicker recovery to everyday activities. In addition, the scar of the drain site was hidden on the inner side of the umbilicus. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266. PMID- 22535140 TI - Another food-related disease affecting oral hard tissues is dental erosion. Foreword. PMID- 22535141 TI - Introduction: functional foods and oral health. PMID- 22535143 TI - Functional foods/ingredients and oral mucosal diseases. PMID- 22535144 TI - Functional foods/ingredients and periodontal diseases. PMID- 22535145 TI - Functional foods/ingredients on dental erosion. PMID- 22535142 TI - Functional foods/ingredients and dental caries. PMID- 22535146 TI - A dietary pattern that is associated with C-peptide and risk of colorectal cancer in women. AB - PURPOSE: Higher serum C-peptide concentrations have shown to be associated with an increased risk of colorectal cancer (CRC). Therefore, we used diet information to identify food groups that correlated with fasting serum concentrations of C peptide and assess the association of this dietary pattern and CRC risk. METHODS: Major food contributors to fasting C-peptide concentrations were identified with stepwise linear regression in a subsample (n = 833) of women from a large cohort. We then summed the consumption frequency of the major food contributors to form a C-peptide dietary pattern for the entire cohort (n = 66,714). Risk for CRC was computed using Cox proportional hazard model with the C-peptide dietary pattern score as the predictor. RESULTS: In up to 20 years of follow-up, we ascertained 985 cases of CRC and 758 colon cancer. After adjusting for confounders, the C peptide dietary pattern, characterized by higher meat, fish, and sweetened beverage intake, but lower coffee, high fat dairy, and whole grains intake, showed direct association with CRC risk (RR comparing extreme quintiles = 1.29, 95 % CI = 1.05-1.58, p trend = 0.048). The same comparison was slightly stronger for colon cancer (RR = 1.35, 95 % CI = 1.07-1.70, p trend = 0.009). In stratified analysis, there was no association between the C-peptide dietary pattern and colon cancer among lean and active women. However, for overweight or sedentary women, RR for the same comparison was 1.58 (95 % CI = 1.20-2.07, p trend = 0.002) (p for interaction = 0.007). CONCLUSION: We derived a dietary pattern that correlated with C-peptide concentrations. This pattern was associated with an increase in colon cancer, especially among women who were overweight or sedentary. PMID- 22535147 TI - Transcranial magnetic stimulation of visual cortex in migraine patients: a systematic review with meta-analysis. AB - We systematically reviewed the literature to evaluate the prevalence of phosphenes and the phosphene threshold (PT) values obtained during single-pulse transcranial magnetic stimulation (TMS) in adults with migraine. Controlled studies measuring PT by single-pulse TMS in adults with migraine with or without aura (MA, MwA) were systematically searched. Prevalence of phosphenes and PT values were assessed calculating mean difference (MD) and odds ratio (OR) with 95 % confidence intervals (CI). Ten trials (277 migraine patients and 193 controls) were included. Patients with MA had statistically significant lower PT compared with controls when a circular coil was used (MD -28.33; 95 % CI -36.09 to 20.58); a similar result was found in MwA patients (MD -17.12; 95 % CI -23.81 to 10.43); using a figure-of-eight coil the difference was not statistically significant. There was a significantly higher phosphene prevalence in MA patients compared with control subjects (OR 4.21; 95 % CI 1.18-15.01). No significant differences were found either in phosphene reporting between patients with MwA and controls, or in PT values obtained with a figure-of-eight coil in MA and MwA patients versus controls. Overall considered, these results support the hypothesis of a primary visual cortex hyper-excitability in MA, providing not enough evidence for MwA. A significant statistical heterogeneity reflects clinical and methodological differences across studies, and higher temporal variabilities among PT measurements over time, related to unstable excitability levels. Patients should therefore be evaluated in the true interictal period with an adequate headache-free interval. Furthermore, skull thickness and ovarian cycle should be assessed as possible confounding variables, and sham stimulation should be performed to reduce the rate of false positives. Phosphene prevalence alone cannot be considered a measure of cortical excitability, but should be integrated with PT evaluation. PMID- 22535148 TI - Migraine prevalence, alexithymia, and post-traumatic stress disorder among medical students in Turkey. AB - The aim of this study was to investigate the prevalence of migraine, alexithymia, and post-traumatic stress disorder among medical students at Cumhuriyet University of Sivas in Turkey. A total of 250 medical students participated in this study and answered the questionnaires. The study was conducted in three stages: the self-questionnaire, the neurological evaluation, and the psychiatric evaluation. In the first stage, the subjects completed a questionnaire to assess migraine symptoms and completed the three-item Identification of Migraine Questionnaire, the Toronto Alexithymia Scale, and the Post-Traumatic Stress Disorder Checklist-Civilian Version Scale. The subjects who reported having a migraine underwent a detailed neurological evaluation conducted by a neurologist to confirm the diagnosis. In the final stage, the subjects with a migraine completed a psychiatric examination using the structured clinical interview for DSM-IV-R Axis I. The actual prevalence of migraine among these medical students was 12.6 %. The students with a migraine were diagnosed with alexithymia and post traumatic stress disorder more frequently than those without migraine. The Migraine Disability Assessment Scale scores correlated with the post-traumatic stress disorder scores. The results of this study indicate that migraine was highly prevalent among medical students in Turkey and was associated with the alexithymic personality trait and comorbid psychiatric disorders including post traumatic stress disorder. Treatment strategies must be developed to manage these comorbidities. PMID- 22535149 TI - The effect of multiplex-PCR-assessed major pathogens causing subclinical mastitis on somatic cell profiles. AB - The major pathogens causing mastitis were evaluated by multiplex-polymerase chain reaction (M-PCR) with self-designed primers in four quarters of the first, third, and fifth parities in industrial, semi-industrial, and traditional dairy cattle farms in Iran. With the incidence of infection in the quarters by Staphylococcus aureus and Streptococcus agalactiae, the mean log somatic cell count (log SCC) increased from 5.06 to 5.77. The smallest changes occurred with Escherichia coli. Contagious pathogens, when compared with environmental pathogens, were more prevalent and common and created more profound quantitative and qualitative changes in SCC profiles. The second part of the study surveyed the diversity of contaminating pathogens and their effect on quantitative and qualitative profiles of somatic cells. M-PCR was used to determine the absence (M-PCR(-)) and presence of one (M-PCR(+1)), two (M-PCR(+2)), and three (M-PCR(+3)) major pathogens in raw milk samples. Quarter log SCC increased from 5.06 (for M-PCR(-1)) to 5.5 (for M PCR(+1)), 5.7 (for M-PCR(+2)), and 6 (for M-PCR(+3)). Percent changes in polymorphonuclears (PMNs) were not significant between different quarters and parities but were significant between different farms in terms of pathogen diversity (P < 0.05). Therefore, by increasing the number of types of major pathogens involved in subclinical mastitis, SCC of udder quarters and the proportion of PMNs significantly increased, whereas the proportion of lymphocytes significantly decreased. This subject is very important in increasing the shelf life of dairy products, because PMNs are introduced to the enzymatic pools. PMID- 22535150 TI - Population structure and genetic variability in the Murrah dairy breed of water buffalo in Brazil accessed via pedigree analysis. AB - The objective of this study was to use pedigree analysis to evaluate the population structure and genetic variability in the Murrah dairy breed of water buffalo (Bubalus bubalis) in Brazil. Pedigree analysis was performed on 5,061 animals born between 1972 and 2002. The effective number of founders (fe) was 60, representing 6.32 % of the potential number of founders. The effective number of ancestors (fa) was 36 and the genetic contribution of the 17 most influent ancestors explained 50 % of the genetic variability in the population. The ratio fe/fa (effective number of founders/effective number of ancestors), which expresses the effect of population bottlenecks, was 1.66. Completeness level for the whole pedigree was 76.8, 49.2, 27.7, and 12.8 % for, respectively, the first, second, third, and fourth known parental generations. The average inbreeding values for the whole analyzed pedigree and for inbreed animals were, respectively, 1.28 and 7.64 %. The average relatedness coefficient between individuals of the population was estimated to be 2.05 %-the highest individual coefficient was 10.31 %. The actual inbreeding and average relatedness coefficient are probably higher than estimated due to low levels of pedigree completeness. Moreover, the inbreeding coefficient increased with the addition of each generation to the pedigree, indicating that incomplete pedigrees tend to underestimate the level of inbreeding. Introduction of new sires with the lowest possible average relatedness coefficient and the use of appropriate mating strategies are recommended to keep inbreeding at acceptable levels and increase the genetic variability in this economically important species, which has relatively low numbers compared to other commercial cattle breeds. The inclusion of additional parameters, such as effective number of founders, effective number of ancestors, and fe/fa ratio, provides better resolution as compared to the inclusion of inbreeding coefficient and may help breeders and farmers adopt better precautionary measures against inbreeding depression and other deleterious genetic effects. PMID- 22535151 TI - Expression profile of HSP genes during different seasons in goats (Capra hircus). AB - The present study has demonstrated the expression of HSP60, HSP70, HSP90, and UBQ in peripheral blood mononuclear cells (PBMCs) during different seasons in three different age groups (Groups I, II, and III with age of 0-2, 2-5, and >5 years, respectively) of goats of tropical and temperate regions. Real-time polymerase chain reaction was applied to investigate mRNA expression of examined factors. Specificity of the desired products was documented using analysis of the melting temperature and high-resolution gel electrophoresis to verify that the transcripts are of the exact molecular size predicted. The mRNA expression of HSP60, HSP90, and UBQ was significantly higher (P < 0.05) in all age groups during peak summer season as compared with peak winter season in both tropical and temperate region goats. HSP70 mRNA expression was significantly higher (P < 0.05) during summer season as compared with winter season in tropical region goats. However, in the temperate region, in goats from all the three age groups studied, a non-significant difference of HSP70 expression between summer and winter seasons was noticed. In conclusion, results demonstrate that (1) HSP genes are expressed in caprine PBMCs and (2) higher expression of HSPs during thermal stress suggest possible involvement of them to ameliorate deleterious effect of thermal stress so as to maintain cellular integrity and homeostasis in goats. PMID- 22535152 TI - Some descriptive characteristics of a new goat breed called Honamli in Turkey. AB - This study has been carried out in the Western Mediterranean Region of Turkey on seven different Honamli goat flocks. The aim of this study was to determine the growth characters, survival rate (till weaning, 105th day), some reproductive characteristics and marketable milk yield. The data were collected from 516 does and 210 kids (125 buckling and 85 doelings). The results indicate that the numbers of multiple birth and litter size were 32.8 % and 1.35 respectively. Survival rates of kids at the 30th, 90th, and 105th days were 98.5, 97.2, and 97.2 %, respectively. The average birth weight for the buckling and doelings was 4.1 and 3.7 kg, respectively. The average weaning weights for buckling and doelings were 26.9 and 23.4 kg, respectively. The effects of dams' age, on sex and birth type on the growth of Honamli kids were statistically significant (p < 0.05, p < 0.01, and p < 0.001). While the diameters of erythrocytes of Honamli goats are smaller, the density of hemoglobin in the erythrocytes is more than Asian, Indian, and American caprine breeds. The average lactation length and marketable milk yield was assessed to be at 210.3 days and was 89 L, respectively. The growth characteristics of Honamli kids at weaning age were assessed to be higher than most of the other goat breeds in Turkey. The results further indicated that there is a significant variation in the production traits among the different Honamli goat flocks. Production traits of Honamli goats at different breeding conditions should further be investigated to come to a definite conclusion. PMID- 22535153 TI - Coadministration of epithelial junction opener JO-1 improves the efficacy and safety of chemotherapeutic drugs. AB - PURPOSE: Epithelial junctions between tumor cells inhibit the penetration of anticancer drugs into tumors. We previously reported on recombinant adenovirus serotype 3-derived protein (JO-1), which triggers transient opening of intercellular junctions in epithelial tumors through binding to desmoglein 2 (DSG2), and enhances the antitumor effects of several therapeutic monoclonal antibodies. The goal of this study was to evaluate whether JO-1 cotherapy can also improve the efficacy of chemotherapeutic drugs. EXPERIMENTAL DESIGN: The effect of intravenous application of JO-1 in combination with several chemotherapy drugs, including paclitaxel/Taxol, nanoparticle albumin-bound paclitaxel/Abraxane, liposomal doxorubicin/Doxil, and irinotecan/Camptosar, was tested in xenograft models for breast, colon, ovarian, gastric and lung cancer. Because JO-1 does not bind to mouse cells, for safety studies with JO-1, we also used human DSG2 (hDSG2) transgenic mice with tumors that overexpressed hDSG2. RESULTS: JO-1 increased the efficacy of chemotherapeutic drugs, and in several models overcame drug resistance. JO-1 treatment also allowed for the reduction of drug doses required to achieve antitumor effects. Importantly, JO-1 coadmininstration protected normal tissues, including bone marrow and intestinal epithelium, against toxic effects that are normally associated with chemotherapeutic agents. Using the hDSG2-transgenic mouse model, we showed that JO-1 predominantly accumulates in tumors. Except for a mild, transient diarrhea, intravenous injection of JO-1 (2 mg/kg) had no critical side effects on other tissues or hematologic parameters in hDSG2-transgenic mice. CONCLUSIONS: Our preliminary data suggest that JO-1 cotherapy has the potential to improve the therapeutic outcome of cancer chemotherapy. PMID- 22535154 TI - Distinguishing clinicopathologic features of patients with V600E and V600K BRAF mutant metastatic melanoma. AB - PURPOSE: Certain clinicopathologic features correlate with BRAF mutation status in melanoma including younger age and primary subtype. This study sought to determine the BRAF mutation status by age-decade and whether BRAF-mutant genotypes correlated with clinicopathologic features and outcome in patients with metastatic melanoma. METHODS: A prospectively assembled cohort of Australian patients were followed from diagnosis of metastatic melanoma (N = 308). Clinicopathologic variables were correlated with BRAF mutational status, genotype, and survival. RESULTS: Forty-six percent of patients had a BRAF mutation; 73% V600E, 19% V600K, and 8% other genotypes. An inverse relationship existed between BRAF mutation prevalence and age-decade (P < 0.001). All patients <30 years and only 25% >= 70 years had BRAF-mutant melanoma. Amongst BRAF-mutant melanoma, the frequency of non-V600E genotypes (including V600K) increased with increasing age. Non-V600E genotypes comprised <20% in patients <50 years and >40% in those >= 70 years. A higher degree of cumulative sun-induced damage correlated with V600K but not V600E melanoma (P = 0.002). The disease-free interval from diagnosis of primary melanoma to first distant metastasis was shorter for patients with V600K compared with V600E melanoma (17.4 vs. 39.2 months, P = 0.048), with no difference in survival thereafter. In patients BRAF tested at diagnosis of metastatic melanoma, one year survival from diagnosis of metastasis was significantly longer for patients with BRAF-mutant melanoma treated with an inhibitor (83%), than those not treated with an inhibitor (29%, P < 0.001), or patients with BRAF wild-type melanoma (37%, P < 0.001). CONCLUSION: Different genotypes exist within BRAF-mutant metastatic melanoma, representing biologically and clinically discrete subtypes, suggesting distinct etiology and behavior. PMID- 22535155 TI - Romidepsin for cutaneous T-cell lymphoma. AB - Cutaneous T-cell lymphomas (CTCL) are relatively rare lymphomas with an annual incidence of approximately 0.2 to 0.8/100,000 and comprise a variety of clinical entities; mycosis fungoides or its leukemic variant Sezary syndrome account for the majority of cases. Advanced-stage disease is typically treated with bexarotene (a retinoid), interferon, or conventional chemotherapeutic agents, but relapses are inevitable. Histone deacetylase inhibitors, which modify the epigenome, are an attractive addition to the armamentarium. On the basis of 2 large phase II studies, the U.S. Food and Drug Administration approved intravenous romidepsin for patients with relapsed and/or refractory CTCL. Romidepsin provides a subset of patients with an opportunity for prolonged clinical responses with a tolerable side effect profile. PMID- 22535156 TI - Darinaparsin: solid tumor hypoxic cytotoxin and radiosensitizer. AB - PURPOSE: Hypoxia is an important characteristic of the solid tumor microenvironment and constitutes a barrier for effective radiotherapy. Here, we studied the effects of darinaparsin (an arsenic cytotoxin) on survival and radiosensitivity of tumor cells in vitro under normoxia and hypoxia and in vivo using xenograft models, compared to effects on normal tissues. EXPERIMENTAL DESIGN: The cytotoxicity and radiosensitization of darinaparsin were first tested in vitro in a variety of solid tumor cell lines under both normoxia and hypoxia and compared with arsenic trioxide (ATO, an arsenical with reported cytotoxic and radiosensitizing activities on tumor cells). The effects were then tested in mouse models of xenograft tumors derived from tumor cell lines and clinical tumor specimens. The potential mechanisms of darinaparsin effects, including reactive oxygen species (ROS) generation, cellular damage, and changes in global gene expression, were also investigated. RESULTS: In comparison with ATO, darinaparsin had significantly higher in vitro cytotoxic and radiosensitizing activities against solid tumor cells under both normoxia and hypoxia. In vivo experiments confirmed these activities at doses that had no systemic toxicities. Importantly, darinaparsin did not radiosensitize normal bone marrow and actually radioprotected normal intestinal crypts. The darinaparsin-mediated antitumor effects under hypoxia were not dependent on ROS generation and oxidative damage, but were associated with inhibition of oncogene (RAS and MYC)-dependent gene expression. CONCLUSION: Darinaparsin has significant and preferential cytotoxic and radiosensitizing effects on solid tumors as compared with normal cells. Darinaparsin may therefore increase the therapeutic index of radiation therapy and has near term translational potential. PMID- 22535158 TI - Erythropoietin resistance and survival in non-dialysis patients with stage 4-5 chronic kidney disease and heart disease. AB - INTRODUCTION: Patients with chronic kidney disease (CKD) frequently suffer from heart disease as well. The combination of the two processes can exacerbate inflammation, resulting in increases in both resistance to erythropoietin (EPO) and mortality. OBJECTIVES: The aim of this study was to determine the prevalence of heart disease in a representative group of non-dialysis patients with stage 4 5 CKD, and the influence of that entity on EPO requirements and on mortality during a period of 36 months. METHODS: 134 patients (68% on EPO at the beginning, increasing to 72.3% during follow-up) were monitored for 36 months. To evaluate the dose-response effect of EPO therapy, we used the erythropoietin resistance index (ERI) calculated as the weekly weight-adjusted dose of EPO divided by the haemoglobin level. The ERI was determined both initially and during the last six months before the end of the study. RESULTS: 39 patients (29.1%) had history of heart disease; 22 (16.4%) had suffered from heart failure (HF). The ERI was higher in patients with a history of heart disease or HF and those treated with drugs acting on the renin-angiotensin system (ACE inhibitors or ARBs). Using ERI as the dependent variable in the multivariate analysis, the variables that composed the final model were ferritin, haemoglobin, glomerular filtration rate and history of HF. The 36 month mortality rate (n=39 patients) was higher in the group having ERI above the median (2.6IU/week/kg/gram of haemoglobin in 100ml) (P=.002), and in the groups with heart disease (P=.001) or HF (P=.001) according to the Kaplan-Meier survival analysis. CONCLUSIONS: Patients with history of heart disease or HF have a higher ERI, and all of these characteristics are associated with lower survival. ERI can be considered a marker for risk of death in the short to-medium term. PMID- 22535159 TI - Advances in immunosuppression for kidney transplantation: new strategies for preserving kidney function and reducing cardiovascular risk. AB - The development of new immunosuppressants for renal transplantation is aimed not only at improving short-term outcomes, but also at achieving better safety, cardiovascular, and metabolic profiles and at decreasing nephrotoxicity. Belatacept is a fusion protein that inhibits T cell activation by binding to CD80 and CD86 antigens. Clinical trials, particularly the BENEFIT and BENEFIT-EXT studies, have shown that belatacept preserves function and structure in renal grafts. The effects of belatacept provide long-term, sustained results, and the safety and efficacy of this drug have been demonstrated in cases of renal transplantation from expanded criteria donors. Compared to calcineurin inhibitors, belatacept is associated with a lower incidence of chronic allograft nephropathy and a more favourable cardiovascular and metabolic profile. PMID- 22535157 TI - A small-molecule inhibitor targeting the mitotic spindle checkpoint impairs the growth of uterine leiomyosarcoma. AB - PURPOSE: Uterine leiomyosarcoma (ULMS) is a poorly understood cancer with few effective treatments. This study explores the molecular events involved in ULMS with the goal of developing novel therapeutic strategies. EXPERIMENTAL DESIGN: Genome-wide transcriptional profiling, Western blotting, and real-time PCR were used to compare specimens of myometrium, leiomyoma, and leiomyosarcoma. Aurora A kinase was targeted in cell lines derived from metastatic ULMS using siRNA or MK 5108, a highly specific small-molecule inhibitor. An orthotopic model was used to evaluate the ability of MK-5108 to inhibit ULMS growth in vivo. RESULTS: We found that 26 of 50 gene products most overexpressed in ULMS regulate mitotic centrosome and spindle functions. These include UBE2C, Aurora A and B kinase, TPX2, and Polo-like kinase 1 (PLK1). Targeting Aurora A inhibited proliferation and induced apoptosis in LEIO285, LEIO505, and SK-LMS1, regardless of whether siRNA or MK-5108 was used. In vitro, MK-5108 did not consistently synergize with gemcitabine or docetaxel. Gavage of an orthotopic ULMS model with MK-5108 at 30 or 60 mg/kg decreased the number and size of tumor implants compared with sham fed controls. Oral MK-5108 also decreased the rate of proliferation, increased intratumoral apoptosis, and increased expression of phospho-histone H3 in ULMS xenografts. CONCLUSIONS: Our results show that dysregulated centrosome function and spindle assembly are a robust feature of ULMS that can be targeted to slow its growth both in vitro and in vivo. These observations identify novel directions that can be potentially used to improve clinical outcomes for this disease. PMID- 22535164 TI - [Micronutrient deficiencies in Mexico: an invisible public health problem]. PMID- 22535160 TI - Factors determining a low dose of haemodialysis as measured by ionic dialysance in critical patients with acute kidney injury. AB - BACKGROUND: Estimating the dialysis dose is a requirement commonly used to assess the quality of renal replacement therapy (RRT) in patients with chronic kidney disease (CKD). In patients with acute kidney injury (AKI), this value is not always evaluated and it has been estimated that the prescribed dose is seldom obtained. Reports addressing this issue in AKI individuals are scarce and most have not included an adequate number of patients or treatments, nor were patients treated with extended therapies. Kt values obtained by the ionic dialysance method have been validated for the evaluation of the dialysis dose and it has also been shown that, compared with Kt/V, this is the most sensitive strategy for revealing inadequate dialysis treatment in critically ill AKI individuals. The main aim of this study was to assess the difference between the prescribed and the administered dialysis dose in critically ill AKI patients, and to evaluate what factors determine this gap using Kt values assessed through ionic dialisance. MATERIAL AND METHOD: Data from 394 sessions of renal replacement therapy in 105 adult haemodialysis (HD) patients with oliguric acute kidney injury and admitted to ICU were included in this analysis. RRT was carried out with Fresenius 4008E dialysis machines equipped with on-line clearance monitoring (OCM(r) Fresenius), which use non-invasive techniques to monitor the effective ionic dialysance, equivalent to urea clearance. The baseline characteristics of the study population as well as the prescription and outcome of RRT were analysed. These variables were included in a multivariate model in which the dependent variable was the failure to obtain the threshold dose (TD). RESULTS: The main baseline characteristics of the study population/treatments were: age 66 +/- 15 years, 37% female, most frequent cause of AKI: sepsis (70%). Low BP and/or vasoactive drug requirement (71%), mechanical ventilation (70%) and average individual severity index: 0.7 +/- 0.26. Two hundred and one intermittent HD (IHD) and 193 extended HD (EHD) sessions were performed; the most frequently used temporary vascular access was the femoral vein catheter (79%). Prescribed Kt was 53.5 +/- 14L and 21% of prescriptions fell below the TD. Sixty-one percent of treatments did not fulfill the TD (31 +/- 8L) compared with 56 +/- 12L obtained in the subgroup that achieved the target. Compared to IHD, EHD provided a significantly larger Kt (46 +/- 16L vs 33L +/- 9L). Univariate analysis showed that inadequate compliance was associated with age (>65y), male gender, intra dialytic hypotension, low Qb, catheter line reversal, and IHD. The same variables with the exception of age and gender were independently associated in the multivariate analysis. CONCLUSIONS: The dialysis dose obtained was significantly lower than that prescribed. EHD achieved values closer to the prescribed KT and significantly higher than in IHD. Ionic Kt measurement facilitates monitoring and allows HD treatments to be extended based upon a previously established TD. Besides the chosen strategy to dispense the dose of dialysis, a well-functioning vascular access allowing for optimal blood flow and other approaches aimed at avoiding hemodynamic instability during RRT are the most important factors to achieve TD, mainly in elderly male patients. The dialysis dose should be prescribed and monitored for all critically ill AKI patients. PMID- 22535165 TI - [Current status of Menkes disease in Mexico]. PMID- 22535166 TI - [Impact of aging stereotypes on care given to older adults]. PMID- 22535167 TI - Incidence of positive DNA from cytomegalovirus, human parvovirus B19 and hepatitis B virus, at birth. PMID- 22535168 TI - [Widal reactions in a healthy population from Mexicali]. PMID- 22535170 TI - Prevalence of folate and vitamin B12 deficiency in Mexican children aged 1 to 6 years in a population-based survey. AB - OBJECTIVE: To describe the magnitude and distribution of folate and vitamin B12 deficiency in Mexican children. MATERIALS AND METHODS: Folate and vitamin B12 serum concentrations were measured in a probabilistic sample of 2 099 children. Adjusted prevalence, mean concentrations and relevant associations were calculated based on series of logistic and linear regression models. RESULTS: The overall prevalence of folate and vitamin B12 deficiency were 3.2% and 7.7%, respectively. The highest prevalence of folate was found in the 2-year-old (7.9%), and of vitamin B12 in the 1 year-old (9.1%) groups. Being a beneficiary of the fortified milk program Liconsa was protectively associated with serum folate (p=0.001) and daily Intake of milk with vitamin B12 (p=0.002) concentrations. CONCLUSIONS: We describe the magnitude of folate and vitamin B12 deficiencies in Mexican children. The deficiency of both vitamins in children under 2 years old is a moderate public health problem in Mexico. PMID- 22535169 TI - Nutritional causes of anemia in Mexican children under 5 years. Results from the 2006 National Health and Nutrition Survey. AB - OBJECTIVE: To describe the frequency and severity of anemia and the nutritional variables associated to hemoglobin levels (Hb) in children <5 years of age. MATERIALS AND METHODS: We studied 981 children measuring hemoglobin and serum concentrations of ferritin, soluble transferrin receptors (sTfR), C-reactive protein (CRP), zinc, iron, copper, magnesium, folate and vitamin B12. Ordinal logit or multiple regression models were constructed to assess the risk for anemia and the associations among nutritional variables. RESULTS: The overall prevalence of anemia was 20.6%, of which 14% were mild cases and 6.38% moderate. Anemia was associated with iron deficiency (ID) in 42.17% of the cases, whereas ID coexisted with either folate or vitamin B12 deficiency in 9%. Only 2% of cases of anemia were associated with either folate or vitamin B12 deficiencies. CRP (coef: 0.17 g/dl) and third tertile of s-copper (coef: -0.85 g/dl) were associated to unexplained anemia (p<0.05). CONCLUSIONS: ID is the main cause of anemia in children <5 y. Folate and vitamin B12 concentrations were associated with anemia. CRP was associated to unexplained anemia. However, vitamin A deficiency, which is associated with anemia, was not studied. PMID- 22535171 TI - Iron, zinc, copper and magnesium nutritional status in Mexican children aged 1 to 11 years. AB - OBJECTIVE: To describe the micronutrient nutritional status of a national sample of 1-11 year old Mexican children surveyed in 2006 in National Health and Nutrition Survey (ENSANUT 2006) and their association with dietary and sociodemographic factors. MATERIALS AND METHODS: Serum samples were used (n=5 060) to measure the concentrations of ferritin, transferrin receptor, zinc, copper and magnesium. RESULTS: Prevalence of deficiencies in 1-4 and 5-11y old children were for iron (using low ferritin) 26.0 and 13.0%; zinc, 28.1 and 25.8%, respectively; and copper, ~30% in both age groups. Magnesium low serum concentrations (MLSC), were found in 12.0% and 28.4% of the children, respectively. Being beneficiary of Liconsa (OR=0.32; C.I.95%, 0.17-0.61) or belonging to higher socioeconomic status (OR=0.63; C.I.95%, 0.41-0.97) were protective against iron deficiency. Increasing age (OR=0.59; C.I.95%, 1.19-1.32) and living in the Central Region (OR=0.59; C.I.95%, 0.36-0.97) were protective against MLSC. CONCLUSIONS: Deficiencies of iron and zinc are serious public health problems in Mexican children. PMID- 22535173 TI - Overview of the nutritional status of selected micronutrients in Mexican children in 2006. AB - OBJECTIVE: To present an overview of micronutrient status of Mexican children in 2006. MATERIALS AND METHODS: Data on iron, zinc, folate and vitamin B12 deficiencies and low serum copper and magnesium were gathered and critically analyzed from the 2006 National Health and Nutrition Survey. RESULTS: Iron deficiency is still the main nutritional deficiency in children (13%-26%). Zinc deficiency was high in all age groups (~25%) but reduced 5.6 PP in children <5 y from 1999 to 2006. Folate deficiency was 3.2% and vitamin B12 deficiency 7.7% in children. Low serum magnesium and copper were high (22.6% and 30.6%, respectively). CONCLUSIONS: The prevalence of iron deficiency seems to be lowering, and zinc deficiency has reduced in Mexican children. A high prevalence of copper and magnesium deficiencies warrants further research on their public health implications. PMID- 22535172 TI - Anemia and iron, zinc, copper and magnesium deficiency in Mexican adolescents: National Health and Nutrition Survey 2006. AB - OBJECTIVE: To describe the frequency of anemia and iron, zinc, copper and magnesium deficiencies among Mexican adolescents in the probabilistic survey ENSANUT 2006. MATERIALS AND METHODS: The sample included 2447 adolescents aged 12 to 19 y. Capillary hemoglobin and venous blood samples were collected to measure the concentrations of ferritin, sTFR, CRP, zinc, iron, copper and magnesium. Logistic regression models were constructed to assess the risk for mineral deficiencies. RESULTS: The overall prevalence of anemia was 11.8 and 4.6%, body iron deficiency 18.2 and 7.9% for females and males, respectively. Overall prevalence of tissue iron deficiency was 6.9%, low serum copper were 14.4 and 12.25%; zinc 28.4 and 24.5%, magnesium 40 and 35.3%; for females and males, respectively. CONCLUSIONS: There is a high prevalence of mineral deficiency in Mexican adolescents; females were more prone to have more mineral deficiencies. Nutritional interventions are necessaries in order to reduce and control them. PMID- 22535174 TI - Antibiotic knowledge and self-care for acute respiratory tract infections in Mexico. AB - OBJECTIVE: To examine knowledge of and self-treatment with antibiotics among medically-insured adults in Mexico. MATERIALS AND METHODS: We conducted a cross sectional, interviewer-administered survey among 101 adult patients seeking care for acute respiratory tract infections in a family medicine clinic in Mexico. Knowledge scores were calculated as a composite of correct, incorrect and don't know responses. Factors associated with antibiotic knowledge and antibiotic self treatment were explored with bivariate analyses. RESULTS: 47% of participants were taking antibiotics prior to the visit, 20% were self-treating. Antibiotic knowledge was highly variable. Many participants believed common non-antibiotic treatments for colds and coughs were antibiotics, such as ambroxol (45%), Desenfriol (45%) and paracetamol (44%). Older participants (>40 years) had better knowledge scores. DISCUSSION: Self-treatment with and misperceptions about antibiotics are common among medically insured adults seeking medical attention in Mexico. PMID- 22535175 TI - Use and understanding of the nutrition information panel of pre-packaged foods in a sample of Mexican consumers. AB - OBJECTIVE: To assess the use and understanding of the Nutritional information Panel (NIP) of pre-packaged foods by Mexican consumers. MATERIALS AND METHODS: A questionnaire and an understanding test for NIP were applied to adult consumers in supermarkets of six cities in the Northern, Central, and Southern regions of Mexico. Data were analyzed by frequencies and Poisson regression models. RESULTS: Interviewed 731 consumers; 71.5% were women, mean age 33 +/- 9.7 (range: 18-60), 70% completed high-school or a higher degree. In total, 17% of consumers use the NIP for making purchase decisions; 49% did not understand the NIP. Only 1.2% of consumers answered correctly the five questions of the NIP understanding test. CONCLUSIONS: The use and understanding of the NIP are low despite a high proportion self-reported reading and understanding. The lack of previous knowledge of the technical language prevents use and interpretation of NIP nutritional information for purchasing decisions. PMID- 22535176 TI - [DNA mutations associated to rifampicin or isoniazid resistance in M. tuberculosis clinical isolates from Sonora, Mexico]. AB - OBJECTIVE: To perform the analysis of specific regions of the major genes associated with resistance to isoniazid or rifampin. MATERIALS AND METHODS: Twenty two M. tuberculosis strains, isolated from human samples obtained in Sonora, Mexico. Specific primers for hotspots of the rpoB, katG, inhA genes and the ahpC-oxyR intergenic region were used. The purified PCR products were sequenced. RESULTS: Mutations in the promoter of inhA, the ahpC-oxyR region, and codon 315 of katG and in 451 or 456 codons of rpoB, were identified. CONCLUSIONS: Detection of mutations not previously reported requires further genotypic analysis of Mycobacterium tuberculosis isolates in Sonora. PMID- 22535177 TI - [The role of innate immunity in obesity]. AB - Obesity in Mexico is alarmingly increasing in prevalence in adults and children, and it is a risk factor for the development of insulin resistance, as well as, of other metabolic alterations. The discovery of the expression of the Toll-like receptors (TLRs) in adipocytes, suggests an important role in innate immunity. In different models of obesity, there has been observed an increase of TLRs expression in the fat tissue, therefore TLRs could be involved in systemic inflammation in this disease, and in the development of insulin resistance. TLR activation is mediated by fatty acids and their expression is regulated by leptin, adiponectin and PPARs. Knowledge of the role of TLRs in inflammation and adipocyte differentiation and their regulation, then it is important to try to develop new therapeutic anti-inflammatory targets that contribute in the treatment of obesity. PMID- 22535180 TI - Myeloid cell-specific expression of Ship1 regulates IL-12 production and immunity to helminth infection. AB - Helminth infection leads to the local proliferation and accumulation of macrophages in tissues. However, the function of macrophages during helminth infection remains unclear. SH2-containing inositol 5'-phosphatase 1 (Ship1, Inpp5d) is a lipid phosphatase that has been shown to play a critical role in macrophage function. Here, we identify a critical role for Ship1 in the negative regulation of interleukin (IL)-12/23p40 production by macrophages during infection with the intestinal helminth parasite Trichuris muris. Mice with myeloid cell-specific deletion of Ship1 (Ship1(DeltaLysM) mice) develop a non protective T-helper type 1 cell response and fail to expel parasites. Ship1 deficient macrophages produce heightened levels of IL-12/23p40 in vitro and in vivo and antibody blockade of IL-12/23p40 renders Ship1(DeltaLysM) mice resistant to Trichuris infection. Our results identify a critical role for the negative regulation of IL-12/23p40 production by macrophages in the development of a protective T(H)2 cell response. PMID- 22535181 TI - CRS-peptides: unique defense peptides of mouse Paneth cells. AB - The intestine is the most densely colonized site in both mice and man. Recent data suggest that the intestinal flora is, in part, controlled by antimicrobial substances secreted by the intestinal epithelium. The defense system of the small intestine includes a protective mucus layer, a high turnover of epithelial cells, and a regulated secretion of effector molecules, notably antimicrobial peptides. Human and mouse small intestines share many similarities in their intestinal defense micro-organization, including the secretion of the well-known alpha defensins. Mice, however, produce an additional unique antimicrobial peptide family, the CRS (cryptdin-related sequences)-peptides, not found in man. This review comprises a detailed presentation of the peptide-based defense of the gut, with specific emphasis on the CRS-peptide family. The first part presents the current knowledge of the CRS-peptide family's biochemical characteristics and nomenclature, and the second part is devoted to the possible role of this family in the homeostasis of the gut. PMID- 22535182 TI - Size controlled growth of germanium nanorods and nanowires by solution pyrolysis directly on a substrate. AB - Herein, we describe the controlled growth of 1 dimensional germanium nanostructures from high aspect ratio nanowires (>10 microns in length) to shorter aspect nanorods (100 nm in length) via a simple pyrolysis method. The synthetic route involves the thermal decomposition of selected germanium precursors by dropping a solution in a high boiling point solvent directly onto a pre-heated Si wafer in the presence of a copper source under inert conditions. PMID- 22535183 TI - Integrating climate change into habitat conservation plans under the U.S. endangered species act. AB - Habitat Conservation Plans (HCPs) under the Endangered Species Act (ESA) are an important mechanism for the acquisition of land and the management of terrestrial and aquatic ecosystems. HCPs have become a vital means of protecting endangered and threatened species and their habitats throughout the United States, particularly on private land. The scientific consensus that climate is changing and that these changes will impact the viability of species has not been incorporated into the conservation strategies of recent HCPs, rendering plans vulnerable biologically. In this paper we review the regulatory context for incorporating climate change into HCPs and analyze the extent to which climate change is linked to management actions in a subset of large HCPs. We conclude that most current plans do not incorporate climate change into conservation actions, and so we provide recommendations for integrating climate change into the process of HCP development and implementation. These recommendations are distilled from the published literature as well as the practice of conservation planning and are structured to the specific needs of HCP development and implementation. We offer nine recommendations for integrating climate change into the HCP process: (1) identify species at-risk from climate change, (2) explore new strategies for reserve design, (3) increase emphasis on corridors, linkages, and connectivity, (4) develop anticipatory adaptation measures, (5) manage for diversity, (6) consider assisted migration, (7) include climate change in scenarios of water management, (8) develop future-oriented management actions, and (9) increase linkages between the conservation strategy and adaptive management/monitoring programs. PMID- 22535184 TI - Mini-haplotypes as lineage informative SNPs and ancestry inference SNPs. AB - We propose that haplotyped loci with high heterozygosity can be useful in human identification, especially within families, if recombination is very low among the sites. Three or more SNPs extending over small molecular intervals (<10 KB) can be identified in the human genome to define miniature haplotypes with moderate levels of linkage disequilibrium. Properly selected, these mini haplotypes (or minihaps) consist of multiple haplotype lineages (alleles) that have evolved from the ancestral human haplotype but show no evidence of recurring recombination, allowing each distinct haplotype to be equated with an allele, all copies of which are essentially identical by descent. Historic recombinants, representing rare events that have drifted to common frequencies over many generations, can be identified in some cases, they do not equate to frequently recurring recombination. We have identified examples in our data collected on various projects and present eight such mini-haplotypes comprised of informative SNPs. We also discuss the ideal characteristics and advantages of minihaps for human familial identification and ancestry inference, and compare them to other types of forensic markers in use and/or that have been proposed. We expect that it is possible to carry out a systematic search and identify a useful panel of mini-haplotypes, with even better properties than the examples presented here. PMID- 22535185 TI - Genome-wide scan with nearly 700,000 SNPs in two Sardinian sub-populations suggests some regions as candidate targets for positive selection. AB - This paper explores the genetic structure and signatures of natural selection in different sub-populations from the Island of Sardinia, exploiting information from nearly 700,000 autosomal SNPs genotyped with the Affymetrix Genome-Wide Human SNP 6.0 Array. The genetic structure of the Sardinian population and its position within the context of other Mediterranean and European human groups were investigated in depth by comparing our data with publicly available data sets. Principal components and admixture analyses suggest a clustering of the examined samples in two significantly differentiated sub-populations (Ogliastra and Southern Sardinia), as confirmed by AMOVA (F(ST)=0.011; P<0.001). Differentiation of these sub-populations was still evident when they were pooled together with supplementary Sardinian samples from HGDP and compared with several other European, North-African and Near Eastern populations, confirming the uniqueness of the Sardinian genetic background. Moreover, by applying several statistical approaches aimed at assessing differences at the SNP level, the highest differentiated genomic regions between Ogliastra and Southern Sardinia were thus investigated via an extended haplotype homozygosity (EHH)-based test to point out potential selective sweeps. Using this approach, 40 genomic regions were detected, with significant differences between Ogliastra and Southern Sardinia. These regions were subsequently investigated using a long-range haplotype test, which found significant REHH values for SNPs rs11070188 and rs11070192 in the Ogliastra sub-population. In the light of these results and the overlap of the different computed statistics, the region encompassing these loci can be considered a strong candidate to have undergone selective pressure in Ogliastra. PMID- 22535186 TI - Autosomal dominant late-onset spinal motor neuronopathy is linked to a new locus on chromosome 22q11.2-q13.2. AB - Spinal muscular atrophies (SMAs) are hereditary disorders characterized by degeneration of lower motor neurons. Different SMA types are clinically and genetically heterogeneous and many of them show significant phenotypic overlap. We recently described the clinical phenotype of a new disease in two Finnish families with a unique autosomal dominant late-onset lower motor neuronopathy. The studied families did not show linkage to any known locus of hereditary motor neuron disease and thus seemed to represent a new disease entity. For this study, we recruited two more family members and performed a more thorough genome-wide scan. We obtained significant linkage on chromosome 22q, maximum LOD score being 3.43 at marker D22S315. The linked area is defined by flanking markers D22S686 and D22S276, comprising 18.9 Mb. The region harbours 402 genes, none of which is previously known to be associated with SMAs. This study confirms that the disease in these two families is a genetically distinct entity and also provides evidence for a founder mutation segregating in both pedigrees. PMID- 22535187 TI - Symptom dimensions as alternative phenotypes to address genetic heterogeneity in schizophrenia and bipolar disorder. AB - This study introduces a novel way to use the lifetime ratings of symptoms of psychosis, mania and depression in genetic linkage analysis of schizophrenia (SZ) and bipolar disorder (BP). It suggests using a latent class model developed for family data to define more homogeneous symptom subtypes that are influenced by a smaller number of genes that will thus be more easily detectable. In a two-step approach, we proposed: (i) to form homogeneous clusters of subjects based on the symptom dimensions and (ii) to use the information from these homogeneous clusters in linkage analysis. This framework was applied to a unique SZ and BP sample composed of 1278 subjects from 48 large kindreds from the Eastern Quebec population. The results suggest that our strategy has the power to increase linkage signals previously obtained using the diagnosis as phenotype and allows for a better characterization of the linkage signals. This is the case for a linkage signal, which we formerly obtained in chromosome 13q and enhanced using the dimension mania. The analysis also suggests that the methods may detect new linkage signals not previously uncovered by using diagnosis alone, as in chromosomes 2q (delusion), 15q (bizarre behavior), 7p (anhedonia) and 9q (delusion). In the case of the 15q and 2q region, the results coincide with linkage signals detected in other studies. Our results support the view that dissecting phenotypic heterogeneity by modeling symptom dimensions may provide new insights into the genetics of SZ and BP. PMID- 22535188 TI - Histopathological comparison of biodegradable polymer and permanent polymer based sirolimus eluting stents in a porcine model of coronary stent implantation. AB - Biodegradable stent coatings were recently introduced as a potential solution to overcome sustained inflammatory responses observed with permanent polymer-based drug-eluting stents. In a preliminary study, selected biodegradable or permanent polymer-based sirolimus-eluting stent (SES) formulations were screened for effectiveness in comparison to bare metal stents (BMS) at 28 days. Subsequently, the most favourable SES formulation was compared to commercially available SES (CypherTM) at 28, 90 and 180 days to investigate the histopathologic response as well as tissue, blood and organ pharmacokinetics. Overlapping SES implantation was conducted to evaluate vascular healing at 28 days in this particular setting. SES with biodegradable poly (L-lactide) polymer (PLLA) or poly(lactide-co glycolide) showed the most favourable outcome with regards to reductions in neointimal area in comparison to BMS at 28 days. The PLLA SES showed a similar reduction in neointimal area compared to CypherTM at 28 days, with significant greater reductions at 90 and 180 days (1.7 +/- 0.7 mm2 vs. 3.1 +/- 1.5 mm2, p=0.03 and 1.8 +/- 1.2 mm2 vs. 3.0 +/- 1.5 mm2, p=0.01, respectively). Sirolimus vascular tissue concentrations were detectable up to 90 days following implantation. Overlapping stented segments showed favourable histopathologic results with respect to fibrin deposition and endothelialisation at 28 days. In conclusion, the use of PLLA as drug-eluting matrix resulted in mild inflammatory responses in the presence of effective sirolimus tissue concentrations. The greater efficacy observed at long-term follow-up in PLLA SES compared to CypherTM may be a multifactorial result of stent design, polymer biocompatibility and improved release kinetics. PMID- 22535189 TI - 50 Years of metals in biology: the Gordon Research Conference. PMID- 22535190 TI - The beneficial effect of Radix Dipsaci total saponins on bone metabolism in vitro and in vivo and the possible mechanisms of action. AB - The purpose of this study is to investigate the anti-osteoporotic effects of Radix Dipsaci total saponins (RTS). We showed that RTS was able to improve bone properties by either an increase of osteoblastic activity or a decrease in osteoclastic activity. INTRODUCTION: Radix Dipsaci has long been used as an anti osteoporotic drug. The present study investigates the anti-osteoporotic effects of RTS. METHODS: Three-month-old female rats were randomly assigned into a sham operated group (sham) and five ovariectomy (OVX) subgroups, namely, OVX with vehicle (OVX), OVX with 17beta-ethinylestradiol (E(2)), and OVX with graded doses of RTS (50, 100, or 200 mg/kg/d). RTS and E(2) were administered orally, daily from 1 week after OVX treatment for 4 months. Bone mass, turnover, and strength were evaluated by dual-energy X-ray absorptiometry, biochemical markers, and the three-point bending test. The trabecular bone microarchitecture was assessed by microCT. In vitro experiments were performed to determine the potential molecular mechanisms of the anti-osteoporotic effect of RTS. RESULTS: RTS prevented the loss of bone mass induced by OVX. The preventive effect on bone loss was primarily indicated by decreasing levels of bone turnover markers and confirmed by the changes in urinary calcium and phosphorus excretion. The treatment also enhanced the biomechanical strength of bone and prevented the deterioration of trabecular bone microarchitecture. RTS induced MC3T3-E1 and primary osteoblastic cell maturation and differentiation and increased bone formation by increasing BMP-2 synthesis. In addition, RTS inhibited osteoclastogenesis through an increase in osteoprotegrin and a decrease in NF-kB ligand expression in vitro. CONCLUSIONS: RTS treatment can effectively suppress the loss of bone mass induced by OVX and in vitro evidence suggests this could be through actions on both osteoblasts and osteoclasts. PMID- 22535191 TI - Differential features of muscle fiber atrophy in osteoporosis and osteoarthritis. AB - We demonstrated that osteoporosis is associated with a preferential type II muscle fiber atrophy, which correlates with bone mineral density and reduced levels of Akt, a major regulator of muscle mass. In osteoarthritis, muscle atrophy is of lower extent and related to disease duration and severity. INTRODUCTION: Osteoarthritis (OA) and osteoporosis (OP) are associated with loss of muscle bulk and power. In these diseases, morphological studies on muscle tissue are lacking, and the underlying mechanisms of muscle atrophy are not known. The aim of our study was to evaluate the OP- or OA-related muscle atrophy and its correlation with severity of disease. Muscle levels of Akt protein, a component of IGF-1/PI3K/Akt pathway, the main regulator of muscle mass, have been determined. METHODS: We performed muscle biopsy in 15 women with OP and in 15 women with OA (age range, 60-85 years). Muscle fibers were counted, measured, and classified by ATPase reaction. By statistical analysis, fiber-type atrophy was correlated with bone mineral density (BMD) in the OP group and with Harris Hip Score (HHS) and disease duration in the OA group. Akt protein levels were evaluated by Western blot analysis. RESULTS: Our findings revealed in OP a preferential type II fiber atrophy that inversely correlated with patients' BMD. In OA, muscle atrophy was of lower extent, homogeneous among fiber types and related to disease duration and HHS. Moreover, in OP muscle, the Akt level was significantly reduced as compared to OA muscles. CONCLUSIONS: This study shows that in OP, there is a preferential and diffuse type II fiber atrophy, proportional to the degree of bone loss, whereas in OA, muscle atrophy is connected to the functional impairment caused by the disease. A reduction of Akt seems to be one of the mechanisms involved in OP-related muscle atrophy. PMID- 22535192 TI - Integration of the Image-Guided Surgery Toolkit (IGSTK) into the Medical Imaging Interaction Toolkit (MITK). AB - The development cycle of an image-guided surgery navigation system is too long to meet current clinical needs. This paper presents an integrated system developed by the integration of two open-source software (IGSTK and MITK) to shorten the development cycle of the image-guided surgery navigation system and save human resources simultaneously. An image-guided surgery navigation system was established by connecting the two aforementioned open-source software libraries. It used the Medical Imaging Interaction Toolkit (MITK) as a framework providing image processing tools for the image-guided surgery navigation system of medical imaging software with a high degree of interaction and used the Image-Guided Surgery Toolkit (IGSTK) as a library that provided the basic components of the system for location, tracking, and registration. The electromagnetic tracking device was used to measure the real-time position of surgical tools and fiducials attached to the patient's anatomy. IGSTK was integrated into MITK; at the same time, the compatibility and the stability of this system were emphasized. Experiments showed that an integrated system of the image-guided surgery navigation system could be developed in 2 months. The integration of IGSTK into MITK is feasible. Several techniques for 3D reconstruction, geometric analysis, mesh generation, and surface data analysis for medical image analysis of MITK can connect with the techniques for location, tracking, and registration of IGSTK. This integration of advanced modalities can decrease software development time and emphasize the precision, safety, and robustness of the image-guided surgery navigation system. PMID- 22535193 TI - Verification of DICOM GSDF in complex backgrounds. AB - While previous research has determined the contrast detection threshold in medical images, it has focused on uniform backgrounds, has not used calibrated monitors, or has involved a low number of readers. With complex clinical images, how the Grayscale Standard Display Function (GSDF) affects the detection threshold and whether the median background intensity shift has been minimized by GSDF remains unknown. We set out to determine if the median background affected the detection of a low-contrast object in a clustered lumpy background, which simulated a mammography image, and to define the contrast detection threshold for these complex images. Clustered lumpy background images were created of different median intensities and disks of varying contrasts were inserted. A reader study was performed with 17 readers of varying skill level who scored with a five-point confidence scale whether a disk was present. The results were analyzed using reader operating characteristic (ROC) methodology. Contingency tables were used to determine the contrast detection threshold. No statistically significant difference was seen in the area under the ROC curve across all of the backgrounds. Contrast detection fell below 50 % between +3 and +2 gray levels. Our work supports the conclusion that Digital Imaging and Communications in Medicine GSDF calibrated monitors do perceptually linearize detection performance across shifts in median background intensity. The contrast detection threshold was determined to be +3 gray levels above the background for an object of 1 degrees visual angle. PMID- 22535194 TI - Changes in endometrial receptivity in women with Asherman's syndrome undergoing hysteroscopic adhesiolysis. AB - OBJECTIVE: To determine whether there is any improvement in the endometrial receptivity in infertile women with Asherman's syndrome undergoing hysteroscopic adhesiolysis. MATERIALS AND METHODS: This was a prospective observational clinical analysis of 40 infertile patients who underwent hysteroscopic adhesiolysis for Asherman's syndrome in a tertiary level hospital. Endometrial thickness and blood flow impedance of the uterine spiral artery by transvaginal color pulsed Doppler ultrasound was measured post-menstrual on day 2/3 and post menstrual on day 21 pre- and post-hysteroscopic adhesiolysis or at a randomly chosen time in patients with amenorrhea. RESULTS: The age of the patients was 18 36 years (mean 29.2 years). The mean duration of infertility was 6.9 years. There were 27 (67.5 %) women with primary infertility and 13 (32.5 %) had secondary infertility. 22 (55 %) women had had genital tuberculosis in the past. A significant improvement in the endometrial thickness was observed on day 2 (p < 0.0001) and day 21 (p < 0.0001) 3 months post-adhesiolysis. The spiral artery RI was statistically significant (p < 0.04) on day 2 pre-adhesiolysis compared to post-adhesiolysis. CONCLUSIONS: A significant improvement in the endometrial thickness was observed post-adhesiolysis. A high blood flow impedance of spiral artery perhaps impairs growth of the endometrium making it unsuitable for successful implantation. PMID- 22535195 TI - Estimating the impact of pelvic immaturity and young maternal age on fetal malposition. AB - OBJECTIVE: Fetal malposition, specifically occiput posterior and transverse (OP/OT), is associated with higher intra-partum morbidity. We tested the hypothesis that young maternal age and pelvic immaturity are risk factors for fetal malposition. METHODS: In a cohort study of all nulliparous teen (<=18 years) deliveries over a 4-year period at one institution, fetal head position at time of delivery was collected and correlated with maternal characteristics and outcome data. Using Risser staging observations, pelvic maturity age was set at 16, and accordingly, the women were divided into two groups (younger vs. older teens). Analysis was performed using Fisher's exact, student t test, and logistic regression modeling. RESULTS: Older teen mothers (16-18 years, n = 609) had higher rates of malposition (22 vs. 12 %, p = 0.02) when compared with younger teens (<=15 years, n = 98). Among all women with a malpositioned fetus, older teens had a higher body mass index (BMI: 32.6 +/- 6.7 vs. 28.5 +/- 3.5, p = 0.04) and subsequent need for cesarean delivery (69 vs. 33 %, p = 0.02) when compared with their younger counterparts. Although younger teens were more successful in having a vaginal delivery (67 %) with an OP/OT position, it was at the expense of a 25 % rate of severe perineal laceration (third/fourth degree). CONCLUSION: Obesity, and not young maternal age or pelvic immaturity, is associated with fetal malposition. The direct association with increasing pre-pregnancy BMI and the long-term impacts of the high rates of cesarean delivery in this young population underscores the need for more public health focus. PMID- 22535196 TI - Occupational screening for sleep disorders in 12-h shift nurses using the Berlin Questionnaire. AB - BACKGROUND: The Berlin Questionnaire has been validated as a screening tool for sleep apnea in clinical samples, but no occupational studies have reported screening validity parameters for this instrument. The objectives of this pilot study were to describe the prevalence of sleep-disordered breathing symptoms in registered nurses and examine the validity of the Berlin Questionnaire to screen for sleep apnea in this chronically partially sleep-deprived group. Validity parameters for the Berlin Questionnaire are tabulated for published studies to 2012. METHODS: Twenty-one female nurses working full time 12-h shifts underwent overnight, in-laboratory polysomnography to identify sleep disorders and completed a Berlin Questionnaire. RESULTS: By polysomnogram, the prevalence of sleep-disordered breathing [Respiratory Disturbance Index (RDI) >= 5] was 43 %, although by the Berlin Questionnaire only 24 % were deemed high risk. The sensitivity of the Berlin Questionnaire to detect high-risk subjects (RDI > 5) was 0.33, with a specificity of 0.83, a positive predictive value of 0.60, and negative predictive value of 0.63. Berlin criterion 3 (obesity or hypertension) performed the best for predicting sleep apnea in 12-h shift nurses. CONCLUSIONS: Although the Berlin Questionnaire produced valuable data about symptoms of sleep apnea in this population, it had a high proportion of false negatives. To improve its sensitivity for screening health care workers for sleep apnea, it must better capture symptoms specific to this population. Increasing the weighting of Berlin criterion 3 items should be considered to improve its psychometric properties. PMID- 22535197 TI - Sleep-disordered breathing in children with craniosynostosis. AB - BACKGROUND: Syndromic craniosynostosis (SC) is associated with a high prevalence of sleep-disordered breathing (SDB). However, it remains unclear whether non syndromic craniosynostosis (NSC) is associated with an increased risk for SDB. SETTING: This study was conducted at a tertiary referral pediatric medical center. METHODS: A prospective polysomnographic (PSG) evaluation was conducted of all children diagnosed with craniosynostosis over a 3-year period and who had not undergone previous PSG for SDB-related symptoms. RESULTS: Among 14 children fulfilling inclusion criteria, 10 had NSC and 4 were diagnosed with SC (Crouzon syndrome). SDB was present in 50 % of the NSC and in 75 % of SC. No associations emerged between the number of sutures affected and the presence of SDB. CONCLUSIONS: SDB is highly prevalent not only in SC but also among asymptomatic children with NSC. The diagnosis of NSC should prompt a diagnostic PSG as a routine component of the clinical evaluation, and PSG findings may aid in the formulation of decisions regarding timing and need for surgical interventions. PMID- 22535198 TI - Functional neuroimaging of major depressive disorder: a meta-analysis and new integration of base line activation and neural response data. AB - OBJECTIVE: Functional neuroimaging investigations of major depressive disorder can advance both the neural theory and treatment of this debilitating illness. Inconsistency of neuroimaging findings and the use of region-of-interest approaches have hindered the development of a comprehensive, empirically informed neural model of major depression. In this context, the authors sought to identify reliable anomalies in baseline neural activity and neural response to affective stimuli in major depressive disorder. METHOD: The authors applied voxel-wise, whole-brain meta-analysis to neuroimaging investigations comparing depressed to healthy comparison groups with respect to baseline neural activity or neural response to positively and/or negatively valenced stimuli. RESULTS: Relative to healthy subjects, those with major depression had reliably higher baseline activity, bilaterally, in the pulvinar nucleus. The analysis of neural response studies using negative stimuli showed greater response in the amygdala, insula, and dorsal anterior cingulate cortex and lower response in the dorsal striatum and dorsolateral prefrontal cortex in individuals with major depressive disorder than in healthy subjects. CONCLUSIONS: The meta-analytic results support an elegant and neuroanatomically viable model of the salience of negative information in major depressive disorder. In this proposed model, high baseline pulvinar activity in depression first potentiates responding of the brain's salience network to negative information; next, and owing potentially to low striatal dopamine levels in depression, this viscerally charged information fails to propagate up the cortical-striatal-pallidalthalamic circuit to the dorsolateral prefrontal cortex for contextual processing and reappraisal. PMID- 22535199 TI - Risk factors and tumor response associated with hydrocephalus after gamma knife radiosurgery for vestibular schwannoma. AB - BACKGROUND: This study was designed to investigate the clinical characteristics and risk factors of hydrocephalus after gamma knife radiosurgery (GKRS) for vestibular schwannoma. METHODS: The authors retrospectively reviewed clinical and neuroimaging findings of 221 patients who underwent GKRS for newly diagnosed vestibular schwannoma. Mean patient age was 54.1 years (range 7-83 years), mean tumor volume was 3,010.4 mm(3) (range 34.7 to 14,300 mm(3)), mean marginal dose was 12.5 Gy (range 11 to 15 Gy), and mean follow-up duration was 31.9 months (range 1 to 107.6 months). RESULTS: Surgical intervention for cerebrospinal fluid (CSF) diversion after GKRS was necessary in 11 (5 %) of the patients. Median time between GKRS and ventriculoperitoneal (VP) shunt placement was 15.5 months (range 1.8-37.8 months). These 11 patients showed female predominance (11 females) and mean tumor volume was significantly larger than in the other without hydrocephalus (6,509 vs. 2,726 mm(3); p < 0.01). Decreases in tumor enhancement and swelling were observed in all 221 patients, and CSF protein was found to be elevated in five of nine patients with available data at the time of the shunt procedure. Hydrocephalic symptoms improved after VP shunt and tumor sizes further decreased at last follow-up in all patients. CONCLUSIONS: Hydrocephalus after radiosurgery may co-occur with a temporary change of tumor volume after radiation treatment. Therefore, hydrocephalus should be kept in mind during the time of tumor volume transition. Furthermore, the authors suggest that frequent patient monitoring for hydrocephalus be maintained for up to 3-4 years after GKRS. PMID- 22535201 TI - mBin1b transgenic mice show enhanced resistance to epididymal infection by bacteria challenge. AB - The mBin1b is a beta-defensin gene identified in the mouse epididymis. In the current report, its expression pattern and antibacterial activities were characterized, and a transgenic (TG) mouse model was developed in which mBin1b was exclusively overexpressed by up to 50-fold over normal levels in the caput epididymis. The experimental animals are healthy with normal reproductive activity, but are more resistant to epididymal infection from Escherichia coli than normal animals. The expression of IL1alpha and IL1beta in the epididymis was decreased in the TG mice, which suggests that mBin1b has a role in the regulation of inflammatory response in the epididymis. PMID- 22535202 TI - A highly efficient catalyst-free protocol for C-H bond activation: sulfamidation of alkyl aromatics and aldehydes. AB - A catalyst-free protocol has been developed for amidation of alkyl aromatics and aldehydes using TsNBr(2)via a nitrene transfer process in the presence of a base in excellent yield within a short time. The reaction was found to be selective for secondary and tertiary benzylic C-H bonds and C-H bonds of aldehydic groups. PMID- 22535200 TI - Unique contribution of IRF-5-Ikaros axis to the B-cell IgG2a response. AB - IRF-5 is a transcription factor activated by toll like receptor (TLR)7 and TLR9 during innate immune responses. IRF-5 activates not only Type I IFN, but also inflammatory cytokines. Most importantly, a genetic variation in the IRF-5 gene shows a strong association with autoimmune diseases such as Lupus. Here, we report that IRF5-deficient mice have attenuated IgG2a/c responses to T-cell dependent and -independent antigens and to polyoma virus infection. This defect is due to the intrinsic deletion of IRF-5 in B cells, as SCID mice reconstituted with Irf5-/- B cells show a decrease in IgG2a/c expression after viral infection compared with mice that received wild-type B cells. Irf5-/-B cells in vitro have diminished TLR and cytokine-induced class switching to IgG2a/c. Addressing the molecular mechanism, we show that IRF-5 regulates IgG2a/c expression by decreasing Ikaros expression; reconstitution of IRF-5 in Irf5-/- B cells downregulates Ikaros levels and increases switching to IgG2a/c. The IRF site in ikzf1 promoter binds IRF-5, IRF-4 and IRF-8. We show that IRF-8 but not IRF-4 activates the ikzf1 promoter, and IRF-5 inhibits the transcriptional activity of IRF-8. Collectively, these results identify the IRF-5-Ikaros axis as a critical modulator of IgG2a/c class switching. PMID- 22535203 TI - Study on bone density at various skeletal sites for the diagnosis of primary osteoporosis. AB - The objective of this study was to evaluate the diagnostic value of bone density changes in lumbar vertebrae and femoral necks in patients with primary osteoporosis (OP) at various ages. Dual-energy X-ray absorptiometry (DXA) scans were performed on patients who had their primary visits between March 2008 and February 2009. The bone mineral density (BMD) of the lumbar vertebrae 1-4 (L1-L4) in anteroposterior projection and the proximal femoral neck in lateral projection were measured. If the BMD values (T score) of any site is -2.5 or less (T <= 2.5), the patients were diagnosed as primary OP, and the T scores were statistically analyzed. The 81 patients who had lumbar vertebrae with a T <= -2.5 led to a positive rate of 80.1 % in the diagnosis of primary OP; the 47 patients who had femoral neck with a T <= -2.5 gave a positive rate of 47.0 %. The patients with type I or type II primary OP were divided into two age groups of <=70 and >=71 years old. The comparison of lumbar spine T score values did not show significant statistical difference (P > 0.05) between the age groups, while the result of the femoral necks revealed significant difference between the two groups (P < 0.001). In diagnosis of primary OP, anteroposterior lumbar spine offers a significantly higher detection rate than that of the femoral neck, but to the patients older than 70, the measurement of femoral neck may generate higher detection rate. It is more sensitive to measure lumbar trabecular bone, especially to the patients in early postmenopausal period. BMD in elderly patients may falsely increase with age, attention should be paid to the determination of the hip bone mass. PMID- 22535206 TI - Quantitative analysis of energy metabolic pathways in MCF-7 breast cancer cells by selected reaction monitoring assay. AB - To investigate the quantitative response of energy metabolic pathways in human MCF-7 breast cancer cells to hypoxia, glucose deprivation, and estradiol stimulation, we developed a targeted proteomics assay for accurate quantification of protein expression in glycolysis/gluconeogenesis, TCA cycle, and pentose phosphate pathways. Cell growth conditions were selected to roughly mimic the exposure of cells in the cancer tissue to the intermittent hypoxia, glucose deprivation, and hormonal stimulation. Targeted proteomics assay allowed for reproducible quantification of 76 proteins in four different growth conditions after 24 and 48 h of perturbation. Differential expression of a number of control and metabolic pathway proteins in response to the change of growth conditions was found. Elevated expression of the majority of glycolytic enzymes was observed in hypoxia. Cancer cells, as opposed to near-normal MCF-10A cells, exhibited significantly increased expression of key energy metabolic pathway enzymes (FBP1, IDH2, and G6PD) that are known to redirect cellular metabolism and increase carbon flux through the pentose phosphate pathway. Our quantitative proteomic protocol is based on a mass spectrometry-compatible acid-labile detergent and is described in detail. Optimized parameters of a multiplex selected reaction monitoring (SRM) assay for 76 proteins, 134 proteotypic peptides, and 401 transitions are included and can be downloaded and used with any SRM-compatible mass spectrometer. The presented workflow is an integrated tool for hypothesis driven studies of mammalian cells as well as functional studies of proteins, and can greatly complement experimental methods in systems biology, metabolic engineering, and metabolic transformation of cancer cells. PMID- 22535207 TI - A computational tool to detect and avoid redundancy in selected reaction monitoring. AB - Selected reaction monitoring (SRM), also called multiple reaction monitoring, has become an invaluable tool for targeted quantitative proteomic analyses, but its application can be compromised by nonoptimal selection of transitions. In particular, complex backgrounds may cause ambiguities in SRM measurement results because peptides with interfering transitions similar to those of the target peptide may be present in the sample. Here, we developed a computer program, the SRMCollider, that calculates nonredundant theoretical SRM assays, also known as unique ion signatures (UIS), for a given proteomic background. We show theoretically that UIS of three transitions suffice to conclusively identify 90% of all yeast peptides and 85% of all human peptides. Using predicted retention times, the SRMCollider also simulates time-scheduled SRM acquisition, which reduces the number of interferences to consider and leads to fewer transitions necessary to construct an assay. By integrating experimental fragment ion intensities from large scale proteome synthesis efforts (SRMAtlas) with the information content-based UIS, we combine two orthogonal approaches to create high quality SRM assays ready to be deployed. We provide a user friendly, open source implementation of an algorithm to calculate UIS of any order that can be accessed online at http://www.srmcollider.org to find interfering transitions. Finally, our tool can also simulate the specificity of novel data-independent MS acquisition methods in Q1-Q3 space. This allows us to predict parameters for these methods that deliver a specificity comparable with that of SRM. Using SRM interference information in addition to other sources of information can increase the confidence in an SRM measurement. We expect that the consideration of information content will become a standard step in SRM assay design and analysis, facilitated by the SRMCollider. PMID- 22535208 TI - PaxDb, a database of protein abundance averages across all three domains of life. AB - Although protein expression is regulated both temporally and spatially, most proteins have an intrinsic, "typical" range of functionally effective abundance levels. These extend from a few molecules per cell for signaling proteins, to millions of molecules for structural proteins. When addressing fundamental questions related to protein evolution, translation and folding, but also in routine laboratory work, a simple rough estimate of the average wild type abundance of each detectable protein in an organism is often desirable. Here, we introduce a meta-resource dedicated to integrating information on absolute protein abundance levels; we place particular emphasis on deep coverage, consistent post-processing and comparability across different organisms. Publicly available experimental data are mapped onto a common namespace and, in the case of tandem mass spectrometry data, re-processed using a standardized spectral counting pipeline. By aggregating and averaging over the various samples, conditions and cell-types, the resulting integrated data set achieves increased coverage and a high dynamic range. We score and rank each contributing, individual data set by assessing its consistency against externally provided protein-network information, and demonstrate that our weighted integration exhibits more consistency than the data sets individually. The current PaxDb release 2.1 (at http://pax-db.org/) presents whole-organism data as well as tissue-resolved data, and covers 85,000 proteins in 12 model organisms. All values can be seamlessly compared across organisms via pre-computed orthology relationships. PMID- 22535209 TI - DNA ends alter the molecular composition and localization of Ku multicomponent complexes. AB - The Ku heterodimer plays an essential role in non-homologous end-joining and other cellular processes including transcription, telomere maintenance and apoptosis. While the function of Ku is regulated through its association with other proteins and nucleic acids, the specific composition of these macromolecular complexes and their dynamic response to endogenous and exogenous cellular stimuli are not well understood. Here we use quantitative proteomics to define the composition of Ku multicomponent complexes and demonstrate that they are dramatically altered in response to UV radiation. Subsequent biochemical assays revealed that the presence of DNA ends leads to the substitution of RNA binding proteins with DNA and chromatin associated factors to create a macromolecular complex poised for DNA repair. We observed that dynamic remodeling of the Ku complex coincided with exit of Ku and other DNA repair proteins from the nucleolus. Microinjection of sheared DNA into live cells as a mimetic for double strand breaks confirmed these findings in vivo. PMID- 22535210 TI - Efficient inhibition of colorectal peritoneal carcinomatosis by drug loaded micelles in thermosensitive hydrogel composites. AB - In this work, we aim to develop a dual drug delivery system (DDDS) of self assembled micelles in thermosensitive hydrogel composite to deliver hydrophilic and hydrophobic drugs simultaneously for colorectal peritoneal carcinomatosis (CRPC) therapy. In our previous studies, we found that poly(epsilon-caprolactone) poly(ethylene glycol)-poly(epsilon-caprolactone) (PCEC) copolymers with different molecular weight and PEG/PCL ratio could be administered to form micelles or thermosensitive hydrogels, respectively. Therefore, the DDDS was constructed from paclitaxel (PTX) encapsulated PCEC micelles (PTX-micelles) and a fluorouracil (Fu) loaded thermosensitive PCEC hydrogel (Fu-hydrogel). PTX-micelles were prepared by self-assembly of biodegradable PCEC copolymer (M(n) = 3700) and PTX without using any surfactants or excipients. Meanwhile, biodegradable and injectable thermosensitive Fu-hydrogel (M(n) = 3000) with a lower sol-gel transition temperature at around physiological temperature was also prepared. The obtained PTX-micelles in thermosensitive Fu-hydrogel (PTX-micelles-Fu-hydrogel) composite is a free-flowing sol at ambient temperature and rapidly turned into a non-flowing gel at physiological temperature. In addition, the results of cytotoxicity, hemolytic study, and acute toxicity evaluation suggested that the PTX-micelles-Fu-hydrogel was non-toxic and biocompatible. In vitro release behaviors of PTX-micelles-Fu-hydrogel indicated that both PTX and Fu have a sustained release behavior. Furthermore, intraperitoneal application of PTX micelles-Fu-hydrogel effectively inhibited growth and metastasis of CT26 peritoneal carcinomatosis in vivo (p < 0.001), and induced a stronger antitumor effect than that of Taxol(r) plus Fu (p < 0.001). The pharmacokinetic study indicated that PTX-micelles-Fu-hydrogel significantly increased PTX and Fu concentration and residence time in peritoneal fluids compared with Taxol(r) plus Fu group. Thus, the results suggested the micelles-hydrogel DDDS may have great potential clinical applications. PMID- 22535211 TI - Evidence-based surgery: barriers, solutions, and the role of evidence synthesis. AB - BACKGROUND: Surgery is a rapidly evolving field, making the rigorous testing of emerging innovations vital. However, most surgical research fails to employ randomized controlled trials (RCTs) and has particularly been based on low quality study designs. Subsequently, the analysis of data through meta-analysis and evidence synthesis is particularly difficult. METHODS: Through a systematic review of the literature, this article explores the barriers to achieving a strong evidence base in surgery and offers potential solutions to overcome the barriers. RESULTS: Many barriers exist to evidence-based surgical research. They include enabling factors, such as funding, time, infrastructure, patient preference, ethical issues, and additionally barriers associated with specific attributes related to researchers, methodologies, or interventions. Novel evidence synthesis techniques in surgery are discussed, including graphics synthesis, treatment networks, and network meta-analyses that help overcome many of the limitations associated with existing techniques. They offer the opportunity to assess gaps and quantitatively present inconsistencies within the existing evidence of RCTs. CONCLUSIONS: Poorly or inadequately performed RCTs and meta-analyses can give rise to incorrect results and thus fail to inform clinical practice or revise policy. The above barriers can be overcome by providing academic leadership and good organizational support to ensure that adequate personnel, resources, and funding are allocated to the researcher. Training in research methodology and data interpretation can ensure that trials are conducted correctly and evidence is adequately synthesized and disseminated. The ultimate goal of overcoming the barriers to evidence-based surgery includes the improved quality of patient care in addition to enhanced patient outcomes. PMID- 22535213 TI - Interhospital transfers of acute care surgery patients: should care of nontraumatic surgical emergencies be regionalised? PMID- 22535212 TI - Postoperative adverse outcomes in surgical patients with dementia: a retrospective cohort study. AB - BACKGROUND: Dementia patients often present with coexisting medical conditions and potentially face higher risk of complications during hospitalization. Because the general features of postoperative adverse outcomes among surgical patients with dementia are unknown, we conducted a nationwide, retrospective cohort study to characterize surgical complications among dementia patients compared with sex- and age-matched nondementia controls. METHODS: Reimbursement claims from the Taiwan National Health Insurance Research Database were studied. A total of 18,923 surgical patients were enrolled with preoperative diagnosis of dementia for 207,693 persons aged 60 years or older who received inpatient major surgeries between 2004 and 2007. Their preoperative comorbidities were adjusted and risks for major surgical complications were analyzed. RESULTS: Dementia patients who underwent surgery had a significantly higher overall postoperative complication rate, adjusted odds ratio (OR) 1.79 (95 % confidence interval [CI] 1.72-1.86), with higher medical resources use, and in-hospital expenditures. Compared with controls, dementia patients had a higher incidence of certain postoperative complications that are less likely to be identified in their initial stage, such as: acute renal failure, OR = 1.32 (1.19-1.47); pneumonia, OR = 2.18 (2.06-2.31); septicemia, OR = 1.8 (1.69-1.92); stroke, OR = 1.51 (1.43-1.6); and urinary tract infection, OR = 1.62 (1.5-1.74). CONCLUSIONS: These findings have specific implications for postoperative care of dementia patients regarding complications that are difficult to diagnose in their initial stages. Acute renal failure, pneumonia, septicemia, stroke, and urinary tract infection are the top priorities for prevention, early recognition, and intervention of postoperative complications among surgical patients with dementia. Further efforts are needed to determine specific protocols for health care teams serving this population. PMID- 22535214 TI - Defining surgical role models and their influence on career choice. PMID- 22535216 TI - Adsorption of a water molecule on the MgO(100) surface as described by cluster and slab models. AB - The interaction of a water molecule with the (100) surface of MgO as described by cluster models is studied using MP2, coupled MP2 (MP2C) and symmetry-adapted perturbation theory (SAPT) methods. In addition, diffusion Monte Carlo (DMC) results are presented for several slab models as well as for the smallest, 2X2 cluster model. For the 2X2 model it is found that the MP2C, DMC, and CCSD(T) methods give nearly the same potential energy curve for the water-cluster interaction, whereas the potential energy curve from the SAPT calculations differs slightly from those of the other methods. The interaction of the water molecule with the cluster models of the MgO(100) surface is weakened upon expanding the number of layers from one to two and also upon expanding the description of the layers from 2X2 to 4X4 to 6X6. The SAPT calculations reveal that both these expansions of the cluster model are accompanied by reductions in the magnitudes of the induction and dispersion constributions. The best estimate of the energy for binding an isolated water molecule to the surface obtained from the cluster model calculations is in good agreement with that obtained from the DMC calculations using a 2-layer slab model with periodic boundary conditions. PMID- 22535217 TI - Do unmet needs differ geographically for children with special health care needs? AB - The purpose of this study was to identify geographic differences in health indicators for children with special health care needs (CSHCN). It was hypothesized that geographic differences in unmet health care needs exist among CSHCN by region in the United States. Data were obtained from the National Survey of Children with Special Health Care Needs, 2005-2006. Nine variables representing unmet needs were analyzed by geographic region. The region with the highest percent of unmet needs was identified for each service. Logistic regression was utilized to determine differences by region after controlling for age, gender, ethnicity, race, federal poverty level, relationship of responder to child, insurance status, severity of condition, and size of household. A total of 40,723 CSHCN were represented. Crude analysis demonstrated that the greatest unmet need for routine preventive care, specialist care, prescription medications, physical/occupational/speech therapy, mental health care, and genetic counseling occurred in the West. The greatest unmet need for preventive dental care, respite care, and vision care occurred in the South. Significant differences between regions remained for six of the nine services after controlling for potential confounders. Geographic differences in unmet health care needs exist for CSHCN. Further delving into these differences provides valuable information for program and policy planning and development. Meeting the needs of CSHCN is important to reduce cost burden and improve quality of life for the affected child and care providers. PMID- 22535218 TI - Maternal age and low birth weight: a reinterpretation of their association under a demographic transition in southern Brazil. AB - To evaluate the relationship between changes in fecundity rates and maternal age and the impact of maternal age on low birth weight (LBW) rates in a developed region in southern Brazil. A time series study evaluating birth weight and maternal ages through the born alive information system (SINASC) in Porto Alegre from 1996 to 2008. The Chi-square test for trends was used to evaluate the trend of LBW and fecundity rates at each maternal age. Population attributed risk (PAR) was used to calculate the impact of maternal age on LBW rates. The study included 271,100 newborns. There was a significant reduction in fecundity rates in all age groups younger than 34 years, but especially in the groups between 20 and 29 years. Overall LBW increased from 9.3 to 10.7 % (P < 0.001). The PAR for LBW showed a reduction in the group from 17 to 19 years (from 1.7 % in 1996-1999 to 0.1 % in 2004-2008), and an increase in the groups from 35 to 39 years (from 2.0 % in 1996-1999 to 2.3 % in 2004-2008) and above 40 (from 1.1 % in 1996-1999 to 1.5 % in 2004-2008). There was a significant change in fecundity pattern in the last 12 years in southern Brazil. Adolescent mothers were surpassed by mothers over 30 years of age in terms of vulnerability for LBW babies. The results show a change in the maternal age distribution towards older mothers, accompanied by an increasing incidence of LBW. This demographic transition also involved a paradoxical pattern with a remarkable reduction in fecundity rates in intermediate maternal age groups with concomitant increase in their risk for LBW. PMID- 22535220 TI - Decomposed liver has a significantly adverse affect on the development rate of the blowfly Calliphora vicina. AB - The development rate of immature Calliphora vicina reared on decomposed liver was significantly slower, by as much as 30 h (55.4 % of total development time) for mid-sized larvae, and 71 h (35.0 %) and 58 h (14.6 %) if using times to the onset of pupariation and eclosion, respectively, than those of immatures that developed on fresh whole pig's liver. Development rates of larvae reared on decomposed liver were also slower than those of larvae reared on minced pig's liver and frozen/thawed pig's liver. These results suggest that any estimate of minimum post-mortem interval may result in an over estimate if the blowflies used were developing on an already decomposed body. PMID- 22535219 TI - Coagulation activation and microparticle-associated coagulant activity in cancer patients. An exploratory prospective study. AB - Cancer increases the risk of venous thromboembolism (VTE). Here, we investigated the contribution of microparticle (MP)-dependent procoagulant activity to the prothrombotic state in these patients. In 43 cancer patients without VTE at study entry and 22 healthy volunteers, markers of in vivo and MP-dependent coagulation were measured and patients were prospectively followed for six months for the development of VTE. Procoagulant activity of MPs was measured in vitro using a tissue factor (TF)-independent phospholipid dependent test, a factor Xa generation assay with and without anti-TF, and a fibrin generation test (FGT) with and without anti-factor VII(a). Markers of in vivo coagulation activation and total number of MPs at baseline were significantly elevated in cancer patients compared to controls (F1+2 246 vs. 156 pM, thrombin-antithrombin complexes 4.1 vs. 3.0 mg/l, D-dimer 0.76 vs. 0.22 mg/l and 5.53 x 106 vs. 3.37 x 106 MPs/ml). Five patients (11.6%) developed VTE. Patients with VTE had comparable levels of coagulation activation markers and phospholipid-dependent MP procoagulant activity. However, median TF-mediated Xa-generation (0.82 vs. 0.21 pg/ml, p=0.016) and median VIIa-dependent FGT (13% vs. 0%, p=0.036) were higher in the VTE group compared with the non-VTE group. In this exploratory study the overall hypercoagulable state in cancer patients was not associated directly with the MP phospholipid-dependent procoagulant activity. However, in the patients who developed VTE within six months when compared to those who did not, an increased MP procoagulant activity was present already at baseline, suggesting this activity can be used to predict VTE. PMID- 22535221 TI - Fluorescent chemodosimeters using "mild" chemical events for the detection of small anions and cations in biological and environmental media. AB - Mild chemical processes of various analytes and detection methods involving revolutionary strategies in the fields of analytical chemistry, biology and environmental sciences have been extensively developed. This critical review focuses on representative examples of mild chemical processes that can be used in fluorescent chemodosimeters for ion sensing (anions and cations). A systematisation according to the type of reaction mechanism is established. Numerous examples including extensions combined with catalytic and material sciences applicable in fluorescence imaging and water treatment are also discussed (151 references). PMID- 22535222 TI - Putative type VI secretion systems of Vibrio parahaemolyticus contribute to adhesion to cultured cell monolayers. AB - Analysis of the genome sequence of Vibrio parahaemolyticus reveals two IcmF family genes in putative type VI secretion system (vpT6SS) clusters in chromosomes 1 (icmF1) and 2 (icmF2). The icmF1 gene is present in majority of clinical isolates (87.5 %), but has a low fraction (25.0 %) in environmental isolates. However, icmF2 is contained in all strains of both clinical and environmental sources. Deletion of either icmF1 or hcp1 significantly reduced bacterial adhesion to Caco-2 cells or HeLa monolayers. However, the DeltaicmF2 and Deltahcp2 mutants showed decreased adhesion only to HeLa monolayers. Western blot analysis showed that Hcp2 was present both in the supernatant and pellet samples in the wild-type strain, but only in the pellet of the DeltaicmF2 mutant, indicating that Hcp2 is a translocon of T6SS2. Although vpT6SS1 might be functional in cellular adhesion, the putative translocon Hcp1 was not detectable. Quantitative PCR revealed 10-fold and 17-fold less transcripts of hcp1 and icmF1 mRNA than those of hcp2 and icmF2 accordingly. Thus, we postulate that the putative vpT6SS systems contribute to adhesion of V. parahaemolyticus to host cells. PMID- 22535224 TI - Biodegradation of high molecular weight PAHs using isolated yeast mixtures: application of meta-genomic methods for community structure analyses. AB - Bioaugmentation for the removal of polyaromatic hydrocarbons (PAHs) from wastewater using bacteria and yeasts is considered environment-friendly and a cost-effective technique. The effectiveness of this biodegradation system depends on the stability of inoculated microorganisms and the availability of nutrients. This study is aimed to investigate the removal of high molecular weight (HMW) PAHs from biologically treated produced water using different biological systems. Three systems, inoculated with activated sludge (AS), the mixture of five yeast strains (MY), and the mixture of AS and the five yeast strains (SY), respectively, were constructed, and their performance for the removal of HMW-PAHs was compared over 10 weeks. The effluent of the biologically treated produced water from an oilfield was used as the influent after chrysene and benzo(a)pyrene were spiked as HMW-PAHs. Polymerase chain reaction-based denaturing gradient gel electrophoresis (PCR-DGGE) and fluorescent in situ hybridization (FISH) techniques were used to examine the changes in the structures and abundances of the bacterial and yeast communities in these three systems. Only SY and MY systems were capable to remove chrysene (90.7 % and 98.5 %, respectively) and benzo(a)pyrene (80.7 % and 95.2 %, respectively). PCR-DGGE analysis confirmed that all of the five yeast strains inoculated remained in the SY and MY systems, while FISH results showed that the relative abundance of yeast in the SY and MY systems (10.6 % to 21.9 %, respectively) were significantly higher than AS system (2.3 % to 7.8 %, respectively). The relative abundances of the catechol 2,3 dioxygenase (C23O) indicated that the copy number ratios of benzene ring cleavage gene C23O in the yeast amended systems were much higher than that in the AS system. In this study, all of the three systems were effective in removing the low molecular weight (LMW)-PAHs, while HMW-PAHs including chrysene and benzo(a)pyrene were efficiently removed by MY and SY systems, not by AS system. The high HMW-PAHs removal in the MY and SY bioaugmentation systems possibly attributed to the inoculation of the mixed yeast culture. By combining the PCR DGGE results with the FISH analyses, it was found that yeast probably consisting mainly of the five inoculated strains inhabited in the two bioaugmentation systems as a dominant population. The relatively higher performance of the SY system might be attributed to the suspended growth type which permitted a more efficient contact between microbial cells and contaminants. The bioaugmentation systems (SY and MY) were successfully established by inoculating with five nonindigenous yeast strains and demonstrated high performance in removal of HMW PAHs. PMID- 22535223 TI - Metal biosorption in lignocellulosic biofuel biorefinery effluent: an initial step towards sustainability of water resources. AB - Biosorption of metals by microorganisms is a promising technology to remove accumulated non-process elements in highly recycled biorefinery process water. Removal of these elements would enable greater water reuse and reduce the environmental impact of effluent discharge. A model lignocellulosic ethanol biorefinery wastewater was created based on pulp mill effluent. This generated a wastewater with an environmentally realistic high loading of dissolved natural organic matter (900 mg/l), a potentially important factor influencing metal biosorption. Analysis of feedstock and pulp mill effluent indicated that Mn and Zn are likely to be problematic in highly recycled lignocellulosic ethanol biorefinery process water. Therefore, the growth of several bacteria and fungi from existing collections, and some isolated from pulp mill effluent were tested in the model wastewater spiked with Mn and Zn (0.2 mM). Wastewater isolates grew the best in the wastewater. Metal uptake varied by species and was much greater for Zn than Mn. A bacterium, Novosphingobium nitrogenifigens Y88(T), removed the most metal per unit biomass, 35 and 17 mg Mn/g. No other organism tested decreased the Mn concentration. A yeast, Candida tropicalis, produced the most biomass and removed the most total metal (38 % of Zn), while uptake per unit biomass was 24 mg Zn/g. These results indicate that microorganisms can remove significant amounts of metals in wastewater with high concentrations of dissolved natural organic matter. Metal sorption by autochthonous microorganisms in an anaerobic bioreactor may be able to extend water reuse and therefore lower the water consumption of future biorefineries. PMID- 22535225 TI - Environmental and health challenges of the global growth of electronic waste. PMID- 22535226 TI - Evaluation of air quality by passive and active sampling in an urban city in Turkey: current status and spatial analysis of air pollution exposure. AB - Concentrations of air pollutants, nitrogen dioxide (NO(2)), sulfur dioxide (SO(2)), ozone (O(3)), particulate matter (PM(2.5) and PM(10)), trace metals, and polycyclic aromatic hydrocarbons (PAHs) were measured in 2008 and 2009 in the city of Eskisehir, central Turkey. Spatial distributions of NO(2), SO(2), and ozone were determined by passive sampling campaigns carried out during two different seasons with fairly large spatial coverage. A basic population exposure assessment was carried out employing Geographical Information System techniques by combining population density maps with pollutant distribution maps of NO(2) and SO(2). It was found that 95 % of the population is exposed to NO(2) levels close to the World Health Organization guideline value. Regarding SO(2), a large proportion of the population (83 %) is exposed to levels above the WHO second interim target value. Concentrations of all the pollutants showed a seasonal pattern increasing in winter period, except for ozone having higher concentrations in summer season. Daily PM(10) and PM(2.5) concentrations exceeded European Union limit values almost every sampling day. Toxic fractions of the measured PAHs were calculated and approximately fourfold increase was observed in winter period. Copper, Pb, Sn, As, Cd, Zn, Sb, and Se were found to be moderately to highly enriched in PM(10) fraction, indicating anthropogenic input to those elements measured. Exposure assessment results indicate the need for action to reduce pollutant emissions especially in the city center. Passive sampling turns out to be a practical and economical tool for air quality assessment with large spatial coverage. PMID- 22535227 TI - Maternal antibodies to dietary antigens and risk for nonaffective psychosis in offspring. AB - OBJECTIVE: The authors analyzed archival dried blood spots obtained from newborns to assess whether levels of immunoglobulin G (IgG) directed at dietary antigens were associated with a later diagnosis of a nonaffective psychotic disorder. METHOD: The study population consisted of individuals born in Sweden between 1975 and 1985 with verified register-based diagnoses of nonaffective psychoses made between 1987 and 2003 and comparison subjects matched on sex, date of birth, birth hospital, and municipality. A total of 211 case subjects and 553 comparison subjects consented to participate in the study. Data on factors associated with maternal status, pregnancy, and delivery were extracted from the Swedish Medical Birth Register. Levels of IgG directed at gliadin (a component of gluten) and casein (a milk protein) were analyzed in eluates from dried blood spots by enzyme linked immunosorbent assay. Odds ratios were calculated for levels of IgG directed at gliadin or casein for nonaffective psychosis. RESULTS: Levels of anti gliadin IgG (but not anti-casein IgG) above the 90th percentile of levels observed among comparison subjects were associated with nonaffective psychosis (odds ratio=1.7, 95% CI=1.1-2.8). This association was not confounded by differences in maternal age, immigrant status, or mode of delivery. Similarly, gestational age at birth, ponderal index, and birth weight were not related to maternal levels of anti-gliadin IgG. CONCLUSIONS: High levels of anti-gliadin IgG in the maternal circulation are associated with an elevated risk for the development of a nonaffective psychosis in offspring. Research is needed to identify the mechanisms underlying this association in order to develop preventive strategies. PMID- 22535228 TI - New insights into translational regulation in the endoplasmic reticulum unfolded protein response. AB - Homeostasis of the protein-folding environment in the endoplasmic reticulum (ER) is maintained by signal transduction pathways that collectively constitute an unfolded protein response (UPR). These affect bulk protein synthesis and thereby the levels of ER stress, but also culminate in regulated expression of specific mRNAs, such as that encoding the transcription factor ATF4. Mechanisms linking eukaryotic initiation factor 2 (eIF2) phosphorylation to control of unfolded protein load in the ER were elucidated more than 10 years ago, but recent work has highlighted the diversity of processes that impinge on eIF2 activity and revealed that there are multiple mechanisms by which changes in eIF2 activity can modulate the translation of individual mRNAs. In addition, the potential for affecting this step of translation initiation pharmacologically is becoming clearer. Furthermore, it is now clear that another strand of the UPR, controlled by the endoribonuclease inositol-requiring enzyme 1 (IRE1), also affects rates of protein synthesis in stressed cells and that its effector function, mediated by the transcription factor X-box-binding protein 1 (XBP1), is subject to important mRNA-specific translational regulation. These new insights into the convergence of translational control and the UPR will be reviewed here. PMID- 22535230 TI - Contemporary assessment of stent strut coverage by OCT. PMID- 22535232 TI - Neuraxial anesthesia and bladder dysfunction in the perioperative period: a systematic review. AB - PURPOSE: Urinary retention requiring catheterization carries the risk of infection. Neuraxial anesthesia causes transient impairment of bladder function ranging from delayed initiation of micturition to frank urinary retention. We undertook a review of the literature to determine the elements of neuraxial anesthesia and analgesia that prolong bladder dysfunction and increase the incidence of urinary retention. METHODS: We performed a systematic search of the PubMed, MEDLINE, and EMBASE databases (from January 1980 to January 2011) to identify studies where neuraxial anesthesia and/or analgesia were employed and at least one of the following outcomes was reported: urinary retention, time to micturition, or post void residual. We included randomized controlled trials and observational studies published in the English language and we excluded case reports. The randomized trials were graded according to the Jadad score. PRINCIPAL FINDINGS: Our search yielded 94 studies, and in 16 of these studies, the authors reported time to micturition after intrathecal anesthesia of varying local anesthetics and doses. Intrathecal injections were performed in 41 of these studies, epidural anesthesia/analgesia was used in 39 studies, and five studies involved both the intrathecal and epidural routes. Meta-analysis was not possible because of the heterogeneity of interventions and reported outcomes. The duration of detrusor dysfunction after intrathecal anesthesia is correlated with local anesthetic dose and potency. The incidence of urinary retention displays a similar trend and is further increased by the presence of neuraxial opioids, particularly long-acting variants. Urinary tract infection secondary to catheterization occurred rarely. CONCLUSIONS: Neuraxial anesthesia/analgesia results in transient detrusor dysfunction. The duration of dysfunction depends on the potency and dose of medication used; however, it does not appear to result in significant morbidity. PMID- 22535233 TI - Fatal laryngeal diphtheria in a UK child. AB - Over the last century, the infectious causes of acute upper airway obstruction have changed dramatically. Toxigenic Corynebacterium diphtheriae has become rare in the UK due to national immunisation programmes. Since 1986, eight sporadic cases of C diphtheriae were reported, all of whom had recently returned from endemic areas. We describe a case of fatal laryngeal diphtheria in an unimmunised child. Although appropriate antimicrobial cover was provided, antitoxin was not administered due to a low index of suspicion. This case represents the first UK death from C diphtheriae in 14 years and where travel to an endemic country or contact with a known case of diphtheria was not identified. We highlight the need to maintain a high index of suspicion in children for whom completion of the immunisation schedule is not confirmed regardless of travel history. Prompt recognition and timely administration of antitoxin may be life-saving. PMID- 22535229 TI - Wnt/Wingless signaling in Drosophila. AB - The Wingless (Wg) pathway represents one of the best-characterized intercellular signaling networks. Studies performed in Drosophila over the last 30 years have contributed to our understanding of the role of Wg signaling in the regulation of tissue growth, polarity, and patterning. These studies have revealed mechanisms conserved in the vertebrate Wnt pathways and illustrate the elegance of using the Drosophila model to understand evolutionarily conserved modes of gene regulation. In this article, we describe the function of Wg signaling in patterning the Drosophila embryonic epidermis and wing imaginal disc. As well, we present an overview of the establishment of the Wg morphogen gradient and discuss the differential modes of Wg-regulated gene expression. PMID- 22535234 TI - Two-week urgent referrals for suspected childhood cancer: experience within a large tertiary centre. PMID- 22535235 TI - Benign mesenchymoma presenting as a paraspinal mass. PMID- 22535236 TI - Teenage abortion and consent. PMID- 22535237 TI - Epidemiology of diagnosed childhood cancer in Western Kenya. AB - SETTING: Basic epidemiological information on childhood cancer in Western Kenya is lacking. This deficit obstructs efforts to improve the care and survival rates of children in this part of the world. OBJECTIVE: Our study provides an overview of childhood cancer patients presenting for treatment in Western Kenya. DESIGN: A retrospective analysis of childhood cancer patients presenting for treatment in Western Kenya was carried out using information from three separate databases at the Moi Teaching and Referral Hospital in Eldoret. All patients aged 0-19 years first presenting between January 2006 and January 2010 with a newly diagnosed malignancy were included. RESULTS: A total of 436 children with cancer were registered during the period. There were 256 (59%) boys and 180 (41%) girls with a male/female ratio of 1.4:1. The group aged 6-10 years contained most children (29%). Median age at admission was 8 years. Non-Hodgkin's lymphoma was the most common type of cancer (34%), followed by acute lymphoblastic leukaemia (15%), Hodgkin's lymphoma (8%), nephroblastoma (8%), rhabdomyosarcoma (7%), retinoblastoma (5%) and Kaposi's sarcoma (5%). Only four (1%) children with brain tumours were documented. Ewing's sarcoma was not diagnosed. CONCLUSIONS: Our study provides an overview of childhood cancer patients presenting for treatment in Western Kenya. The distribution of malignancies is similar to findings from other equatorial African countries but differs markedly from studies in high income countries. The new comprehensive cancer registration system will be continued and extended to serve as the basis for an evidence-based oncology program. Eventually this may lead to improved clinical outcomes. PMID- 22535238 TI - Hyperthyrotropinaemia in untreated subjects with Down's syndrome aged 6 months to 64 years: a comparative analysis. AB - OBJECTIVES: To determine whether an altered hypothalamic-pituitary-thyroid axis is inherent to Down's syndrome or if a high level of thyroid-stimulating hormone (TSH) is a feature in a subset of patients with Down's syndrome. DESIGN: Comparative analysis. SETTING: Major health maintenance organisation (3.8 million insured). PATIENTS: A data warehouse search identified all subjects with Down's syndrome who attended Clalit Health Services in 2006 and were tested for TSH and free thyroxine (T4) level on the day of diagnosis (intention-to-treat population). The study group consisted of patients who were not diagnosed with thyroid disease or did not receive thyroid-modulating medication (n=428). Their findings were compared with a control group of healthy age- and sex-matched subjects who were randomly selected from the general population. MAIN OUTCOME MEASURES: Distribution of free T4, TSH and total T3 levels. RESULTS: The distribution plot for TSH showed a significant shift of the curve to higher values in the study group compared with the controls (p<=0.0001). This finding held true on further analysis of the whole intention-to-treat population (p<0.006). The free T4 distribution curve also shifted significantly to higher levels in patients with Down's syndrome (p<=0.0001). CONCLUSIONS: Down's syndrome is associated with higher TSH levels. The results suggest that hyperthyrotropinaemia is an innate attribute of chromosome 21 trisomy. Therefore, T4 treatment should not be contemplated in Down's Syndrome unless the TSH is >95th centile in the presence of normal-range free T4 levels. PMID- 22535239 TI - Ethylene signaling in salt stress- and salicylic acid-induced programmed cell death in tomato suspension cells. AB - Salt stress- and salicylic acid (SA)-induced cell death can be activated by various signaling pathways including ethylene (ET) signaling in intact tomato plants. In tomato suspension cultures, a treatment with 250 mM NaCl increased the production of reactive oxygen species (ROS), nitric oxide (NO), and ET. The 10( 3) M SA-induced cell death was also accompanied by ROS and NO production, but ET emanation, the most characteristic difference between the two cell death programs, did not change. ET synthesis was enhanced by addition of ET precursor 1 aminocyclopropane-1-carboxylic acid, which, after 2 h, increased the ROS production in the case of both stressors and accelerated cell death under salt stress. However, it did not change the viability and NO levels in SA-treated samples. The effect of ET induced by salt stress could be blocked with silver thiosulfate (STS), an inhibitor of ET action. STS reduced the death of cells which is in accordance with the decrease in ROS production of cells exposed to high salinity. Unexpectedly, application of STS together with SA resulted in increasing ROS and reduced NO accumulation which led to a faster cell death. NaCl and SA-induced cell death was blocked by Ca(2+) chelator EGTA and calmodulin inhibitor W-7, or with the inhibitors of ROS. The inhibitor of MAPKs, PD98059, and the cysteine protease inhibitor E-64 reduced cell death in both cases. These results show that NaCl induces cell death mainly by ET-induced ROS production, but ROS generated by SA was not controlled by ET in tomato cell suspension. PMID- 22535241 TI - Myeloid-derived suppressor cells in transplantation and cancer. AB - Myeloid-derived suppressor cells (MDSC) are myeloid cells that suppress the immune response, a definition that reflects both their origin and their function. As negative regulators of the immune response, MDSC represent a novel therapeutic approach for manipulating the immune system toward tolerance or immunity. MDSC are present in cancer patients and tumor-bearing mice and are in part responsible for the inhibition of the cell-mediated immune response against the tumor. Our laboratories investigate the immunologic mechanisms of tumor acceptance mediated by MDSC, which can be exploited to prevent allograft rejection in transplantation. A better understanding of MDSC biology will open new avenues for therapeutic intervention, either by inhibiting their function (i.e. in cancer patients), or by enhancing their suppressive effects and promoting their expansion (i.e. in organ transplantation and alloimmune responses). In this review, we summarize some of the critical aspects of the immunoregulatory function of MDSC in cancer and transplantation and discuss their potential clinical applications. PMID- 22535242 TI - Peroxisome proliferator-activated receptor-alpha agonists repress expression of thrombin-activatable fibrinolysis inhibitor by decreasing transcript stability. AB - Thrombin-activatable fibrinolysis inhibitor (TAFI) (carboxypeptidase B2) is a plasma zymogen that is biosynthesised in the liver and released into the circulation. Activated TAFI is a prothrombotic factor which inhibits fibrin clot lysis. Cultured human hepatoma HepG2 cells were treated with peroxisome proliferator-activated receptor (PPAR)alpha, beta or gamma agonists, and the levels of TAFI antigen and mRNA (here, termed CPB2 mRNA) were measured. HepG2 cells treated with the PPARalpha agonist WY14643, but not agonists for PPARbeta or PPARgamma, decreased their release of TAFI antigen into the conditioned medium. In parallel, there were decreased levels of CPB2 mRNA and TAFI antigen in the cells. The WY14643-mediated decrease in CPB2 mRNA levels was accelerated by overexpression of PPARalpha and abolished by RNA interference of PPAR A mRNA. CPB2 gene promoter activity was not influenced by treatment of the cells with WY14643. The half-life of the CPB2 transcript was shortened by treatment with WY14643 as compared with that of the control, and the decreased half-life of mRNA returned to control levels by treatment with a PPARalpha antagonist MK886 or transfection of PPAR A-specific siRNA to WY14643-treated HepG2 cells. The present results suggest that PPARalpha agonists not only play a hypolipidaemic role, but also decrease the expression of TAFI, a prothrombotic factor, by decreasing stability of CPB2 transcripts. PMID- 22535244 TI - Intratumoral gene therapy injections with a multipronged, multi-side hole needle for rectal carcinoma. PMID- 22535243 TI - Margin size is an independent predictor of local tumor progression after ablation of colon cancer liver metastases. AB - PURPOSE: This study was designed to evaluate the relationship between the minimal margin size and local tumor progression (LTP) following CT-guided radiofrequency ablation (RFA) of colorectal cancer liver metastases (CLM). METHODS: An institutional review board-approved, HIPPA-compliant review identified 73 patients with 94 previously untreated CLM that underwent RFA between March 2003 and May 2010, resulting in an ablation zone completely covering the tumor 4-8 weeks after RFA dynamic CT. Comparing the pre- with the post-RFA CT, the minimal margin size was categorized to 0, 1-5, 6-10, and 11-15 mm. Follow-up included CT every 2-4 months. Kaplan-Meier methodology and Cox regression analysis were used to evaluate the effect of the minimal margin size, tumor location, size, and proximity to a vessel on LTP. RESULTS: Forty-five of 94 (47.9 %) CLM progressed locally. Median LTP-free survival (LPFS) was 16 months. Two-year LPFS rates for ablated CLM with minimal margin of 0, 1-5 mm, 6-10 mm, 11-15 mm were 26, 46, 74, and 80 % (p < 0.011). Minimal margin (p = 0.002) and tumor size (p = 0.028) were independent risk factors for LTP. The risk for LTP decreased by 46 % for each 5 mm increase in minimal margin size, whereas each additional 5-mm increase in tumor size increased the risk of LTP by 22 %. CONCLUSIONS: An ablation zone with a minimal margin uniformly larger than 5 mm 4-8 weeks postablation CT is associated with the best local tumor control. PMID- 22535245 TI - An Archaean heavy bombardment from a destabilized extension of the asteroid belt. AB - The barrage of comets and asteroids that produced many young lunar basins (craters over 300 kilometres in diameter) has frequently been called the Late Heavy Bombardment (LHB). Many assume the LHB ended about 3.7 to 3.8 billion years (Gyr) ago with the formation of Orientale basin. Evidence for LHB-sized blasts on Earth, however, extend into the Archaean and early Proterozoic eons, in the form of impact spherule beds: globally distributed ejecta layers created by Chicxulub sized or larger cratering events4. At least seven spherule beds have been found that formed between 3.23 and 3.47 Gyr ago, four between 2.49 and 2.63 Gyr ago, and one between 1.7 and 2.1 Gyr ago. Here we report that the LHB lasted much longer than previously thought, with most late impactors coming from the E belt, an extended and now largely extinct portion of the asteroid belt between 1.7 and 2.1 astronomical units from Earth. This region was destabilized by late giant planet migration. E-belt survivors now make up the high-inclination Hungaria asteroids. Scaling from the observed Hungaria asteroids, we find that E-belt projectiles made about ten lunar basins between 3.7 and 4.1 Gyr ago. They also produced about 15 terrestrial basins between 2.5 and 3.7 Gyr ago, as well as around 70 and four Chicxulub-sized or larger craters on the Earth and Moon, respectively, between 1.7 and 3.7 Gyr ago. These rates reproduce impact spherule bed and lunar crater constraints. PMID- 22535246 TI - Impact spherules as a record of an ancient heavy bombardment of Earth. AB - Impact craters are the most obvious indication of asteroid impacts, but craters on Earth are quickly obscured or destroyed by surface weathering and tectonic processes. Earth's impact history is inferred therefore either from estimates of the present-day impactor flux as determined by observations of near-Earth asteroids, or from the Moon's incomplete impact chronology. Asteroids hitting Earth typically vaporize a mass of target rock comparable to the projectile's mass. As this vapour expands in a large plume or fireball, it cools and condenses into molten droplets called spherules. For asteroids larger than about ten kilometres in diameter, these spherules are deposited in a global layer. Spherule layers preserved in the geologic record accordingly provide information about an impact even when the source crater cannot be found. Here we report estimates of the sizes and impact velocities of the asteroids that created global spherule layers. The impact chronology from these spherule layers reveals that the impactor flux was significantly higher 3.5 billion years ago than it is now. This conclusion is consistent with a gradual decline of the impactor flux after the Late Heavy Bombardment. PMID- 22535247 TI - Molecular mechanism of ATP binding and ion channel activation in P2X receptors. AB - P2X receptors are trimeric ATP-activated ion channels permeable to Na+, K+ and Ca2+. The seven P2X receptor subtypes are implicated in physiological processes that include modulation of synaptic transmission, contraction of smooth muscle, secretion of chemical transmitters and regulation of immune responses. Despite the importance of P2X receptors in cellular physiology, the three-dimensional composition of the ATP-binding site, the structural mechanism of ATP-dependent ion channel gating and the architecture of the open ion channel pore are unknown. Here we report the crystal structure of the zebrafish P2X4 receptor in complex with ATP and a new structure of the apo receptor. The agonist-bound structure reveals a previously unseen ATP-binding motif and an open ion channel pore. ATP binding induces cleft closure of the nucleotide-binding pocket, flexing of the lower body beta-sheet and a radial expansion of the extracellular vestibule. The structural widening of the extracellular vestibule is directly coupled to the opening of the ion channel pore by way of an iris-like expansion of the transmembrane helices. The structural delineation of the ATP-binding site and the ion channel pore, together with the conformational changes associated with ion channel gating, will stimulate development of new pharmacological agents. PMID- 22535249 TI - Extended leaf phenology and the autumn niche in deciduous forest invasions. AB - The phenology of growth in temperate deciduous forests, including the timing of leaf emergence and senescence, has strong control over ecosystem properties such as productivity and nutrient cycling, and has an important role in the carbon economy of understory plants. Extended leaf phenology, whereby understory species assimilate carbon in early spring before canopy closure or in late autumn after canopy fall, has been identified as a key feature of many forest species invasions, but it remains unclear whether there are systematic differences in the growth phenology of native and invasive forest species or whether invaders are more responsive to warming trends that have lengthened the duration of spring or autumn growth. Here, in a 3-year monitoring study of 43 native and 30 non-native shrub and liana species common to deciduous forests in the eastern United States, I show that extended autumn leaf phenology is a common attribute of eastern US forest invasions, where non-native species are extending the autumn growing season by an average of 4 weeks compared with natives. In contrast, there was no consistent evidence that non-natives as a group show earlier spring growth phenology, and non-natives were not better able to track interannual variation in spring temperatures. Seasonal leaf production and photosynthetic data suggest that most non-native species capture a significant proportion of their annual carbon assimilate after canopy leaf fall, a behaviour that was virtually absent in natives and consistent across five phylogenetic groups. Pronounced differences in how native and non-native understory species use pre- and post-canopy environments suggest eastern US invaders are driving a seasonal redistribution of forest productivity that may rival climate change in its impact on forest processes. PMID- 22535248 TI - Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. AB - Heart failure is a leading cause of morbidity and mortality in industrialized countries. Although infection with microorganisms is not involved in the development of heart failure in most cases, inflammation has been implicated in the pathogenesis of heart failure. However, the mechanisms responsible for initiating and integrating inflammatory responses within the heart remain poorly defined. Mitochondria are evolutionary endosymbionts derived from bacteria and contain DNA similar to bacterial DNA. Mitochondria damaged by external haemodynamic stress are degraded by the autophagy/lysosome system in cardiomyocytes. Here we show that mitochondrial DNA that escapes from autophagy cell-autonomously leads to Toll-like receptor (TLR) 9-mediated inflammatory responses in cardiomyocytes and is capable of inducing myocarditis and dilated cardiomyopathy. Cardiac-specific deletion of lysosomal deoxyribonuclease (DNase) II showed no cardiac phenotypes under baseline conditions, but increased mortality and caused severe myocarditis and dilated cardiomyopathy 10 days after treatment with pressure overload. Early in the pathogenesis, DNase II-deficient hearts showed infiltration of inflammatory cells and increased messenger RNA expression of inflammatory cytokines, with accumulation of mitochondrial DNA deposits in autolysosomes in the myocardium. Administration of inhibitory oligodeoxynucleotides against TLR9, which is known to be activated by bacterial DNA, or ablation of Tlr9 attenuated the development of cardiomyopathy in DNase II deficient mice. Furthermore, Tlr9 ablation improved pressure overload-induced cardiac dysfunction and inflammation even in mice with wild-type Dnase2a alleles. These data provide new perspectives on the mechanism of genesis of chronic inflammation in failing hearts. PMID- 22535250 TI - Comparing the yields of organic and conventional agriculture. AB - Numerous reports have emphasized the need for major changes in the global food system: agriculture must meet the twin challenge of feeding a growing population, with rising demand for meat and high-calorie diets, while simultaneously minimizing its global environmental impacts. Organic farming-a system aimed at producing food with minimal harm to ecosystems, animals or humans-is often proposed as a solution. However, critics argue that organic agriculture may have lower yields and would therefore need more land to produce the same amount of food as conventional farms, resulting in more widespread deforestation and biodiversity loss, and thus undermining the environmental benefits of organic practices. Here we use a comprehensive meta-analysis to examine the relative yield performance of organic and conventional farming systems globally. Our analysis of available data shows that, overall, organic yields are typically lower than conventional yields. But these yield differences are highly contextual, depending on system and site characteristics, and range from 5% lower organic yields (rain-fed legumes and perennials on weak-acidic to weak-alkaline soils), 13% lower yields (when best organic practices are used), to 34% lower yields (when the conventional and organic systems are most comparable). Under certain conditions-that is, with good management practices, particular crop types and growing conditions-organic systems can thus nearly match conventional yields, whereas under others it at present cannot. To establish organic agriculture as an important tool in sustainable food production, the factors limiting organic yields need to be more fully understood, alongside assessments of the many social, environmental and economic benefits of organic farming systems. PMID- 22535251 TI - Differential modulation of aryl hydrocarbon receptor regulated enzymes by arsenite in the kidney, lung, and heart of C57BL/6 mice. AB - During the last couple of decades, efforts have been made to study the toxic effects of individual aryl hydrocarbon receptors (AhR) ligands such as 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) or heavy metals typified by arsenic As(III). However, little is known about the combined toxic effects of TCDD and As(III) in vivo. Previous reports from our laboratory and others have demonstrated that As(III), by itself or in the presence of AhR ligands, such as TCDD, is capable of differentially altering the expression of various phase I and phase II AhR regulated genes in in vitro systems. Thus, the objective of the current study was to investigate whether or not similar effects would occur at the in vivo level. Therefore, we examined the effect of exposure to As(III) (12.5 mg/kg) in the absence and presence of TCDD (15 MUg/kg) on the AhR-regulated genes using C57Bl/6 mice. Our results demonstrated that As(III) alone inhibited Cyp1a1 and Cyp1a2 in the kidney, while it induced their levels in the lung and did not affect their mRNA levels in the heart. As(III) also induced Nqo1 and Gsta1 in all tested tissues. Upon co-exposure to As(III) and TCDD, As(III) inhibited the TCDD mediated induction of Cyp1a1 in the kidney and heart, Cyp1a2 in the kidney and heart, while it potentiated TCDD-mediated induction of Cyp1a1 in the lung, and Nqo1 and Gsta1 in the kidney and lung. In conclusion, the present study demonstrates for the first time that As(III) modulates constitutive and TCDD induced AhR-regulated genes in a time-, tissue-, and AhR-regulated enzyme specific manner. PMID- 22535252 TI - Clinical ethics ward rounds: building on the core curriculum. AB - The clinical years of medical student education are an ideal time for students to practise and refine ethical thinking and behaviour. We piloted a new clinical ethics teaching activity this year with undergraduate medical students within the Rural Clinical School at the University of New South Wales. We used a modified teaching ward round model, with students bringing deidentified cases of ethical interest for round-table discussion. We found that students were more engaged in the subject of clinical ethics after attending the teaching sessions and particularly appreciated having structured time to listen to and learn from their peers. Despite this, we found no change in student involvement in managing or planning action in situations that they find ethically challenging. A key challenge for educators in clinical ethics is to address the barriers that prevent students taking action. PMID- 22535253 TI - Variations in the protein level of Omi/HtrA2 in the heart of aged rats may contribute to the increased susceptibility of cardiomyocytes to ischemia/reperfusion injury and cell death : Omi/HtrA2 and aged heart injury. AB - Survival after acute myocardial infarction is decreased in elderly patients. The enhanced rates of apoptosis in the aging heart exacerbate myocardial ischemia/reperfusion (MI/R) injury. We have recently demonstrated that the X linked inhibitor of apoptosis protein (XIAP), the most potent endogenous inhibitor of apoptosis, was decreased in aging rats' hearts. XIAP was balanced by two mitochondria proteins, Omi/HtrA2 and Smac/DIABLO. However, the implicative role of XIAP, Omi/HtrA2, and Smac/DIABLO to aging-related MI/R injury has not been previously investigated. In our study, male aging rats (20-24 months) or young adult rats (4-6 months) were subjected to 30 min of myocardial ischemia followed by reperfusion. MI/R-induced cardiac injury was enhanced in aging rats, as evidenced by aggravated cardiac dysfunction, enlarged infarct size, and increased myocardial apoptosis (TUNEL and caspase-3 activity). Then, the XIAP, Omi/HtrA2, and Smac/DIABLO protein and mRNA expression was detected. XIAP protein and mRNA expression was decreased in both aging hearts and aging hearts subjected to MI/R. Meanwhile, myocardial XIAP protein expression was correlated to cardiac function after MI/R. However, Omi/HtrA2, but not Smac/DIABLO, expression was increased in aging hearts. Moreover, the translocation of Omi/HtrA2 from mitochondria to cytosol was increased in both aging hearts and aging hearts subjected to MI/R. Treatment with ucf-101 (a novel and specific Omi/HtrA2 inhibitor) attenuated XIAP degradation and caspase-3 activity and exerted cardioprotective effects. Taken together, these results demonstrated that increased expression and leakage of Omi/HtrA2 enhanced MI/R injury in aging hearts via degrading XIAP and promoting myocardial apoptosis. PMID- 22535254 TI - Lobar cerebral microbleeds associated with transient focal neurological symptoms followed by symptomatic intracerebral hemorrhage. PMID- 22535255 TI - Recognition and diagnosis of sleep disorders in Parkinson's disease. AB - Sleep disturbances are among the most frequent and incapacitating non-motor symptoms of Parkinson's disease (PD), and are increasingly recognized as an important determinant of impaired quality of life. Here we review several recent developments regarding the recognition and diagnosis of sleep disorders in PD. In addition, we provide a practical and easily applicable approach to the diagnostic process as a basis for tailored therapeutic interventions. This includes a stepwise scheme that guides the clinical interview and subsequent ancillary investigations. In this scheme, the various possible sleep disorders are arranged not in order of prevalence, but in a 'differential diagnostic' order. We also provide recommendations for the use of sleep registrations such as polysomnography. Furthermore, we point out when a sleep specialist could be consulted to provide additional diagnostic and therapeutic input. This structured approach facilitates early detection of sleep disturbances in PD, so treatment can be initiated promptly. PMID- 22535256 TI - Probing differences in binding of methylbenzylamine enantiomers to chiral cobalt(II) salen complexes. AB - In this work, we investigate the mode of chiral interactions between the asymmetric Co(II) salen complex, (S,S)-N,N'-bis(3,5-di-tert-butylsalicylidene) 1,2-cyclohexane-diamine-Co(II) ([Co(1)]), and single enantiomers of methylbenzylamine (MBA) using different continuous-wave and pulsed electron paramagnetic resonance techniques combined with density functional theory computations. While [Co(1)] displays a large affinity for binding a single MBA molecule, it has a much weaker affinity for binding a second MBA molecule. Subtle differences are detected in the EPR spectra of the homochiral (S,S-[Co(1)](S MBA)) and heterochiral (S,S-[Co(1)](R-MBA)) adducts using low [Co(1)] : MBA ratios. Moreover at high concentrations of racemic MBA, a strong preference (80%) is observed for the formation of the bis-ligated heterochiral adduct (S,S [Co(1)](R-MBA)(2)) compared to the homochiral analogue (20% of S,S-[Co(1)](S MBA)(2)). Differences in the (14)N hyperfine coupling from the diamine backbone in [Co(1)] were also evidenced by hyperfine sublevel correlation (HYSCORE), revealing magnetically equivalent N nuclei for the homochiral adducts and inequivalent N nuclei for the heterochiral adducts. Using DFT, these slight differences were reproduced, and explained based upon the different modes of alignment of the MBA molecule in the adduct. The current findings therefore reveal the appreciable enantiodiscrimination that occurs during the binding of MBA enantiomers to the chiral Co(II) salen complex. PMID- 22535258 TI - The effects of the pi-pi stacking interactions on the patterns of gold nanoparticles formed at the air-water interface. AB - Benzyl-n-hexadecyl dimethylammonium chloride (BHDC) monolayer-stabilized gold nanoparticles were synthesized in a two-phase liquid-liquid system and found to self-assemble into varied structures under the control of temperature at the air water interface. It has been demonstrated that the pi-pi stacking interactions between the capping agent molecules significantly affect the formation of the unique patterns. A possible mechanism based on Marangoni-Benard convection in the evaporating droplets and pi-pi stacking interactions was proposed. Four surfactants with similar structures: N-hexadecyl-N-methylpyrrolidinium bromide (C(16)MPB), 1-hexadecyl-3-methylimidazolium bromide (C(16)mimBr), 1-(2,4,6 trimethylphenyl)-3-hexadecylimidazolium bromide (C(16)pimBr) and hexadecyltrimethylammonium bromide (CTAB) were also used to further verify the formation mechanism mentioned above. PMID- 22535257 TI - Differing amygdala responses to facial expressions in children and adults with bipolar disorder. AB - OBJECTIVE: Child and adult bipolar patients show both behavioral deficits in face emotion processing and abnormal amygdala activation. However, amygdala function in pediatric relative to adult bipolar patients has not been compared directly. The authors used functional MRI to compare amygdala activity during a face processing task in children and adults with bipolar disorder and in healthy comparison subjects. METHOD: Amygdala responses to emotional facial expressions were examined in pediatric (N=18) and adult (N=17) bipolar patients and in healthy child (N=15) and adult (N=22) volunteers. Participants performed a gender identification task while viewing fearful, angry, and neutral faces. RESULTS: In response to fearful faces, bipolar patients across age groups exhibited right amygdala hyperactivity relative to healthy volunteers. However, when responses to all facial expressions were combined, pediatric patients exhibited greater right amygdala activation than bipolar adults and healthy children. CONCLUSIONS: Amygdala hyperactivity in response to fearful faces is present in both youths and adults with bipolar disorder. However, compared with bipolar adults and healthy child volunteers, pediatric bipolar patients showed amygdala hyperactivity in response to a broad array of emotional faces. Thus, abnormal amygdala activation during face processing appears to be more pervasive in children than in adults with bipolar disorder. Longitudinal studies are needed to elucidate the mechanisms of this developmental difference, thus facilitating developmentally sensitive diagnosis and treatment. PMID- 22535259 TI - Postoperative functional voice changes after conventional open or robotic thyroidectomy: a prospective trial. AB - PURPOSE: To use objective and subjective voice function analysis to compare outcomes in patients who had undergone conventional open thyroidectomy or robotic thyroidectomy. METHODS: The study involved 88 consecutive patients who underwent thyroid surgery between May 2009 and December 2009; 46 patients underwent a conventional open thyroidectomy, and 42 underwent a robotic thyroidectomy. Auditory perceptual evaluation was used to make subjective assessments of voice function, and videolaryngostroboscopy, acoustic voice analysis with aerodynamic study, electroglottography, and voice range profile were used to make objective assessments. Each assessment was made before surgery, and at 1 week and 3 months after surgery. RESULTS: The conventional open and robotic thyroidectomy groups were similar in terms of age, gender ratio, and disease profile. We found that 18 (20.5%) of the 88 patients showed some level of voice dysfunction at 1 week after surgery; that the dysfunction resolved by 3 months after surgery in all cases; and that it was not permanent according to postoperative videolaryngostroboscopy. The conventional open and robotic thyroidectomy groups were found to have similar levels of dysfunction at 1 week after surgery, except for jitter, which was greater in the robotic group. For both groups, any such dysfunction spontaneously resolved by 3 months after surgery, and there were no significant differences between the groups in terms of any voice function parameter. CONCLUSIONS: Voice dysfunction was present after both open and robotic thyroidectomy (without any evident laryngeal nerve injury). However, function subsequently normalized to preoperative levels at 3 months after surgery in both groups. Voice function outcomes after robotic thyroidectomy are similar to those after conventional open thyroidectomy. PMID- 22535260 TI - Abstracts of the American Society of Breast Surgeons 13th Annual Meeting. May 2 6, 2012. Phoenix, Arizona, USA. PMID- 22535261 TI - The real estate of gastric cancer induction therapy: location versus intrinsic molecular architecture. PMID- 22535262 TI - The role of gender in primary hyperparathyroidism: same disease, different presentation. AB - BACKGROUND: Hyperparathyroidism is much more common in women and therefore may represent different diseases in men and women. In order to understand the role of gender in hyperparathyroidism, we reviewed our experience. METHODS: We analyzed a prospective database of 1309 consecutive patients with primary hyperparathyroidism who underwent parathyroidectomy at our institution between March 2001 and August 2010. RESULTS: The female-to-male ratio was 3.3:1, and female patients were older at presentation (60 +/- 0 vs. 57 +/- 1 years, p < 0.005). Male patients were more commonly asymptomatic at presentation (25 % vs. 18 %, p = 0.005) and the most common symptom for men was kidney stones (23 % vs. 13 %, p < 0.0001). For patients with bone density scans, osteoporosis was more common in women (34 % vs. 17 %, p < 0.0001). Men had a slightly higher preoperative serum calcium level (11.1 +/- 0 vs. 11.0 +/- 0 mg/dl, p = 0.03), higher parathyroid hormone level (140 +/- 7 vs. 124 +/- 4 pg/ml, p = 0.04), higher urinary calcium level (376 +/- 10 vs. 314 +/- 5 mg/24 h, p < 0.005), and lower vitamin D level (28 +/- 1 vs. 32 +/- 0 ng/ml, p < 0.005). Men were more likely to have abnormally elevated creatinine values (15 % vs. 9 %, p = 0.004). The operative approach as well as the number of glands involved and their location did not significantly differ between the groups. The mean gland weight for a single adenomas was higher in male patients (1123 +/- 128 vs. 636 +/- 32 mg, p = 0.001). No significant difference was identified in the immediate and remote postoperative course. CONCLUSIONS: Hyperparathyroidism appears to present differently depending on gender. Male patients more often present without symptoms, present with vitamin D deficiency, and have larger parathyroid glands. Importantly, surgical outcomes were equivalent between men and women. PMID- 22535264 TI - Adverse effect of early epileptic seizures in patients receiving endovascular therapy for acute stroke. AB - BACKGROUND AND PURPOSE: The aim of this study was to analyze epileptic seizures and their impact on outcome in patients with stroke treated with endovascular therapy. METHODS: From December 1992 to December 2010 we managed 805 patients with stroke with endovascular therapy. Epileptic seizures, bleeding complications, and 3-month outcomes were recorded prospectively. Outcomes of patients with early seizures (within 24 hours of stroke onset) and patients with late seizures (>24 hours after stroke) were compared with outcomes of seizure free patients using uni- and multivariable statistics. RESULTS: Forty-four of 805 patients (5.5%) had seizures between stroke onset and 3-month follow-up, 26 patients early and 18 late. Outcome of patients with late seizures and seizure free patients was similar (P=0.144 and 0.807). Patients with early seizures had higher baseline National Institutes of Health Stroke Scale (P=0.023) and were younger (P=0.021) than seizure-free patients. Their mortality rate was 50% compared with 22.3% of the seizure free-patients (P=0.003), and less patients reached a favorable outcome (modified Rankin Scale 0-2): 15.4% and 46.8%, respectively (P=0.001). Early seizures independently predicted an unfavorable outcome (P=0.014; OR, 4.749; 95% CI, 0.376-3.914) and increased mortality (P=0.001; OR, 5.861; 95% CI, 0.770-2.947) in multiregression analysis. Patients with early seizures had a 1.6-fold higher risk for unfavorable outcome and a 2.2 fold higher risk for death compared with seizure-free patients. CONCLUSIONS: Seizures within 24 hours of stroke onset were associated with worse outcome in patients with stroke undergoing endovascular therapy. Our findings confirm a need for trials for prophylactic anticonvulsive treatment in patients receiving endovascular therapy for acute stroke. PMID- 22535263 TI - Delayed administration of a small molecule tropomyosin-related kinase B ligand promotes recovery after hypoxic-ischemic stroke. AB - BACKGROUND AND PURPOSE: Stroke is the leading cause of long-term disability in the United States, yet no drugs are available that are proven to improve recovery. Brain-derived neurotrophic factor stimulates neurogenesis and plasticity, processes that are implicated in stroke recovery. It binds to both the tropomyosin-related kinase B and p75 neurotrophin receptors. However, brain derived neurotrophic factor is not a feasible therapeutic agent, and no small molecule exists that can reproduce its binding to both receptors. We tested the hypothesis that a small molecule (LM22A-4) that selectively targets tropomyosin related kinase B would promote neurogenesis and functional recovery after stroke. METHODS: Four-month-old mice were trained on motor tasks before stroke. After stroke, functional test results were used to randomize mice into 2 equally, and severely, impaired groups. Beginning 3 days after stroke, mice received LM22A-4 or saline vehicle daily for 10 weeks. RESULTS: LM22A-4 treatment significantly improved limb swing speed and accelerated the return to normal gait accuracy after stroke. LM22A-4 treatment also doubled both the number of new mature neurons and immature neurons adjacent to the stroke. Drug-induced differences were not observed in angiogenesis, dendritic arborization, axonal sprouting, glial scar formation, or neuroinflammation. CONCLUSIONS: A small molecule agonist of tropomyosin-related kinase B improves functional recovery from stroke and increases neurogenesis when administered beginning 3 days after stroke. These findings provide proof-of-concept that targeting of tropomyosin-related kinase B alone is capable of promoting one or more mechanisms relevant to stroke recovery. LM22A-4 or its derivatives might therefore serve as "pro-recovery" therapeutic agents for stroke. PMID- 22535265 TI - Timing of intra-arterial neural stem cell transplantation after hypoxia-ischemia influences cell engraftment, survival, and differentiation. AB - BACKGROUND AND PURPOSE: Intra-arterial neural stem cell (NSC) transplantation shows promise as a minimally invasive therapeutic option for stroke. We assessed the effect of timing of transplantation on cell engraftment, survival, and differentiation. METHODS: Mouse NSCs transduced with a green fluorescent protein and renilla luciferase reporter gene were transplanted into animals 6 and 24 hours and 3, 7, and 14 days after hypoxia-ischemia (HI). Bioluminescent imaging was used to assess cell survival at 6 hours and 4 and 7 days after transplantation. Immunohistochemistry was used to assess NSC survival and phenotypic differentiation 1 month after transplantation. NSC receptor expression and brain gene expression were evaluated using real-time reverse transcription quantitative polymerase chain reaction to elucidate mechanisms of cell migration. Boyden chamber assays were used to assess cell migratory potential in vitro. RESULTS: NSC transplantation 3 days after HI resulted in significantly higher cell engraftment and survival at 7 and 30 days compared with all other groups (P<0.05). Early transplantation at 6 and 24 hours after HI resulted in significantly higher expression of glial fibrillary acidic protein (P=0.0140), whereas late transplantation at 7 and 14 days after HI resulted in higher expression of beta-tubulin (P<0.0001). Corroborating the high cell engraftment 3 days after HI was robust expression of vascular cell adhesion molecule-1, CCL2, and CXCL12 in brain homogenates 3 days after HI. CONCLUSIONS: Intra-arterial transplantation 3 days after HI results in the highest cell engraftment. Early transplantation of NSCs leads to greater differentiation into astrocytes, whereas transplantation at later time points leads to greater differentiation into neurons. PMID- 22535266 TI - Apolipoprotein E genotype predicts hematoma expansion in lobar intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: Hematoma volume is the most potent predictor of outcome in spontaneous intracerebral hemorrhage (ICH), and hematoma expansion after hospital presentation occurs in up to 40% of individuals. Among patients with lobar ICH, the apolipoprotein E (APOE) epsilon2 allele predicts larger hematoma volumes at presentation. We investigated whether the epsilon2 allele also identifies individuals at increased risk of hematoma expansion. METHODS: We analyzed 510 patients with primary ICH and genetic data available from an ongoing prospective cohort study. Baseline and follow-up CT scans were assessed for ICH location and volume using computer-assisted volumetric methods. RESULTS: Individuals with lobar ICH who possessed APOE epsilon2 were at increased risk for hematoma expansion (OR, 2.72; 95% CI, 1.19-6.23; P=0.009). The highest odds of expansion were in patients who qualified for the diagnosis of cerebral amyloid angiopathy-related ICH and carried the APOE epsilon2 allele (OR, 6.02; 95% CI, 1.60-22.58; P=0.008). There was no effect of epsilon2 on hematoma expansion in deep ICH and APOE epsilon4 had no effect on hematoma expansion in lobar or deep ICH. CONCLUSIONS: Possession of APOE epsilon2 predisposes individuals with lobar ICH to hematoma expansion. This effect is even more pronounced in patients with amyloid angiopathy-related ICH, consistent with the epsilon2 allele's role in vascular amyloid deposition and vessel fragility. PMID- 22535268 TI - Letter by Olie et al regarding article, "dietary flavonoids and risk of stroke in women". PMID- 22535267 TI - Age-related macular degeneration and long-term risk of stroke subtypes. AB - BACKGROUND AND PURPOSE: We examined the relationship of age-related macular degeneration (AMD) with incident stroke, including stroke subtypes of cerebral infarction and intracerebral hemorrhage. METHODS: We included 12 216 participants with retinal photographs taken at the third examination visit (1993-1995) from the Atherosclerosis Risk in Communities (ARIC) Study, a population-based cohort study in middle-aged persons. Images were evaluated for AMD signs according to a standardized protocol. Incident events of stroke and its subtypes were identified and validated through case record review over time. RESULTS: AMD was diagnosed in 591 participants, of whom 576 had early and 15 late AMD. After a mean follow-up of 13.0 years (SD, 3.3), 619 persons developed an incident stroke, including 548 cerebral infarction and 57 intracerebral hemorrhages. Participants with any AMD were at an increased risk of stroke (multivariable adjusted hazard ratio, 1.51; 95% CI, 1.11-2.06) with a stronger association for intracerebral hemorrhage (hazard ratio, 2.64; 95% CI, 1.18-5.87) than cerebral infarction (hazard ratio, 1.42; 95% CI, 1.01-1.99). CONCLUSIONS: Persons with AMD are at an increased risk of both cerebral infarction and intracerebral hemorrhage. These data provide further insight into common pathophysiological processes between AMD and stroke subtypes. PMID- 22535269 TI - Effects of blood pressure lowering on intracranial and extracranial bleeding in patients on antithrombotic therapy: the PROGRESS trial. AB - BACKGROUND AND PURPOSE: Observational studies demonstrate strong associations between blood pressure and bleeding complications of antithrombotic therapy. The objective was to determine whether blood pressure lowering reduces risks of bleeding in patients on antithrombotic therapy. METHODS: This is a subsidiary analysis of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial, a randomized, placebo-controlled trial. A total of 6105 patients with cerebrovascular disease were randomly assigned to either active treatment (perindopril +/- indapamide) or placebo(s). The outcomes were intracranial and extracranial bleeding. RESULTS: There were 4876 (80%) patients on antithrombotic therapy at baseline. Over a mean follow-up of 3.9 years, 119 intracranial and 123 extracranial bleeding events were observed. Among patients with and without antithrombotic therapy, active treatment lowered blood pressure by 8.9/4.0 and 9.3/3.8 mm Hg and reduced the risks of intracranial bleeding by 46% (95% CI, 7% 69%) and 70% (39%-85%), respectively. However, active treatment did not reduce the risks of extracranial bleeding significantly in either group. Among patients on antithrombotic therapy, the lowest risk of intracranial bleeding was observed in participants with the lowest follow-up systolic blood pressure levels (median, 113 mm Hg). CONCLUSIONS: Blood pressure lowering provides protection against intracranial bleeding among patients with cerebrovascular disease including those receiving antithrombotic therapy. PMID- 22535270 TI - Letter by Carin-Levy et al regarding article, "Delirium in acute stroke: a systematic review and meta-analysis". PMID- 22535271 TI - Cognitive and mood assessment in stroke research: focused review of contemporary studies. AB - BACKGROUND AND PURPOSE: International guidelines recommend cognitive and mood assessments for stroke survivors; these assessments also have use in clinical trials. However, there is no consensus on the optimal assessment tool(s). We aimed to describe use of cognitive and mood measures in contemporary published stroke trials. METHODS: Two independent, blinded assessors reviewed high-impact journals representing: general medicine (n=4), gerontology/rehabilitation (n=3), neurology (n=4), psychiatry (n=4), psychology (n=4), and stroke (n=3) January 2000 to October 2011 inclusive. Journals were hand-searched for relevant, original research articles that described cognitive/mood assessments in human stroke survivors. Data were checked for relevance by an independent clinician and clinical psychologist. RESULTS: Across 8826 stroke studies, 488 (6%) included a cognitive or mood measure. Of these 488 articles, total number with cognitive assessment was 408 (83%) and mood assessment tools 247 (51%). Total number of different assessments used was 367 (cognitive, 300; mood, 67). The most commonly used cognitive measure was Folstein's Mini-Mental State Examination (n=180 articles, 37% of all articles with cognitive/mood outcomes); the most commonly used mood assessment was the Hamilton Rating Scale of Depression(n=43 [9%]). CONCLUSIONS: Cognitive and mood assessments are infrequently used in stroke research. When used, there is substantial heterogeneity and certain prevalent assessment tools may not be suited to stroke cohorts. Research and guidance on the optimal cognitive/mood assessment strategies for clinical practice and trials is required. PMID- 22535272 TI - No increased risk of symptomatic intracerebral hemorrhage after thrombolysis in patients with European Cooperative Acute Stroke Study (ECASS) exclusion criteria. AB - BACKGROUND AND PURPOSE: The European Cooperative Acute Stroke Study (ECASS) III trial used additional exclusion criteria not present in current guidelines for thrombolytic therapy in the United States (age >80 years; National Institutes of Health Stroke Scale >25, combination of previous stroke and diabetes, aggressive measures required to control blood pressure [intravenous infusion], and oral anticoagulant treatment). We tested the hypothesis that thrombolysis is not safe in patients with 1 of the additional exclusion criteria. METHODS: All patients treated with intravenous tissue-type plasminogen activator for acute stroke at our center between June 2006 and June 2010 were identified (n=191), and stratified based on presence of each of the exclusion criteria. Primary outcomes were rate of symptomatic intracerebral hemorrhage and in-hospital mortality. Additionally, patients with and without symptomatic intracerebral hemorrhage were analyzed for differences in baseline characteristics. RESULTS: No exclusion criterion was associated with increased risk of symptomatic intracerebral hemorrhage. Symptomatic intracerebral hemorrhage was associated with atrial fibrillation (5 of 9 [55%], versus 35 of 182 [19.2%]; P=0.021), larger final infarct volume (mean 173 mL(3) versus 42 mL(3); P=0.0002), and elevated glucose (mean 166 mg/dL versus 127 mg/dL; P=0.038). There was higher mortality in patients >80 years (5 of 31 [16%] versus 6 of 160 [4%]; P=0.0186) and those with National Institutes of Health Stroke Scale >25 (2 of 5 [40%] versus 7 of 159 [4.4%]; P=0.025). CONCLUSIONS: In our cohort, none of the more stringent exclusion criteria from ECASS III were associated with increased risk of symptomatic intracerebral hemorrhage. Prospective randomized studies are needed clarify the safety and efficacy of tissue-type plasminogen activator in these patients through all treatment time windows. PMID- 22535273 TI - Risk of intracerebral hemorrhage in patients with cerebral microbleeds undergoing endovascular intervention. AB - BACKGROUND AND PURPOSE: Cerebral microbleeds (CMBs) on MRI gradient echo images are hemosiderin deposits, which may predict intracerebral hemorrhage (ICH). The risk of ICH in patients with CMBs could be exacerbated by the use of antithrombotics. The purpose of our study is to prospectively evaluate the risk of ICH in patients with ischemic stroke who receive dual antiplatelet therapy for endovascular intervention. METHODS: We analyzed MRI of 133 patients admitted consecutively for intra- and extracranial stenting for symptomatic large artery atherosclerosis who received aspirin and clopidogrel. Quantity and location of CMBs were recorded by neuroradiologists independent from the angioplasty team. The primary end point was symptomatic ICH as evident in CT of the brain within 12 weeks of procedure. RESULTS: CMBs were identified in 23 patients. Mean number of CMBs was 2.3 +/- 1.6. Four patients had >5 CMBs. Forty-seven patients had intracranial stents, 84 patients had extracranial stents, and 2 patients had both intracranial and extracranial stents. There was no difference in risk of symptomatic ICH between those with (4.3%) and without CMBs (5.5%) patient with CMBs (P=1.000). CONCLUSIONS: The presence of a small number of CMBs does not cause a large increase in the short-term risk of symptomatic ICH in patients with ischemic stroke who undergo endovascular intervention with dual antiplatelet therapy. The risk of ICH in patients with >= 5 CMBs, however, remains unclear. Further studies with a larger sample size of patients with multiple CMBs are needed. PMID- 22535274 TI - REPRINT: International, multicenter randomized preclinical trials in translational stroke research: it is time to act. PMID- 22535275 TI - Progress in sonothrombolysis for the treatment of stroke. PMID- 22535276 TI - Challenges in assessing hospital-level stroke mortality as a quality measure: comparison of ischemic, intracerebral hemorrhage, and total stroke mortality rates. AB - BACKGROUND AND PURPOSE: Public reporting efforts currently profile hospitals based on overall stroke mortality rates, yet the "mix" of hemorrhagic and ischemic stroke cases may impact this rate. METHODS: Using the 2005 to 2006 New York state data, we examined the degree to which hospital stroke mortality rankings varied regarding ischemic versus hemorrhagic versus total stroke. Observed/expected ratio was calculated using the Agency for Healthcare Research and Quality Inpatient Quality Indicator software. The observed/expected ratio and outlier status based on stroke types across hospitals were examined using Pearson correlation coefficients (r) and weighted kappa. RESULTS: Overall 30-day stroke mortality rates were 15.2% and varied from 11.3% for ischemic stroke and 37.3% for intracerebral hemorrhage. Hospital risk-adjusted ischemic stroke observed/expected ratio was weakly correlated with its own intracerebral hemorrhage observed/expected ratio (r=0.38). When examining hospital performance group (mortality better, worse, or no different than average), disagreement was observed in 35 of 81 hospitals (kappa=0.23). Total stroke mortality observed/expected ratio and rankings were correlated with intracerebral hemorrhage (r=0.61 and kappa=0.36) and ischemic stroke (r=0.94 and kappa=0.71), but many hospitals still switched classification depending on mortality metrics. However, hospitals treating a higher percent of hemorrhagic stroke did not have a statistically significant higher total stroke mortality rate relative to those treating fewer hemorrhagic strokes. CONCLUSIONS: Hospital stroke mortality ratings varied considerably depending on whether ischemic, hemorrhagic, or total stroke mortality rates were used. Public reporting of stroke mortality measures should consider providing risk-adjusted outcome on separate stroke types. PMID- 22535277 TI - The cost-effectiveness of primary stroke centers for acute stroke care. AB - BACKGROUND AND PURPOSE: Primary stroke centers (PSC) have demonstrated improved survival in patients with acute ischemic stroke (AIS). The objective of this study was to evaluate the cost-effectiveness of treating AIS patients in a PSC compared with a nonPSC hospital setting. METHODS: We developed a decision analytic model to project the lifetime outcomes and costs of 2 hypothetical cohorts of 75 AIS patients. Clinical data were derived from a recent observational study comparing PSC- and nonPSC-admitted patients, clinical trials, longitudinal cohort studies, and health state preference studies. Cost data were based on Medicare reimbursement and other published sources. We used a healthcare payer perspective, and the primary outcomes were incremental life expectancy, quality-adjusted life years, and healthcare costs. We performed sensitivity and scenario analyses to evaluate uncertainty in the results. RESULTS: Admission to a PSC resulted in a gain of 0.22 years of life (95% credible range [CR], 0.12-0.33) and 0.15 quality-adjusted life years (95% CR, 0.08-0.23) per patient, at a cost of $3600 (95% CR, $2400-$5000) per patient, compared with admission to a nonPSC hospital. The incremental cost/quality-adjusted life year gained was $24 000, and all probabilistic simulation results were below the $100 000/quality-adjusted life year threshold. In scenario analyses accounting for as few as 7 and as many as 500 AIS patients/year per PSC, cost-effectiveness improved as the number of AIS patients admitted per year increased. CONCLUSIONS: Our study indicates that care at a PSC for patients with AIS is cost-effective and improves outcomes across a wide range of possible scenarios. PMID- 22535278 TI - Regional brain injury on conventional and diffusion weighted MRI is associated with outcome after pediatric cardiac arrest. AB - BACKGROUND: To assess regional brain injury on magnetic resonance imaging (MRI) after pediatric cardiac arrest (CA) and to associate regional injury with patient outcome and effects of hypothermia therapy for neuroprotection. METHODS: We performed a retrospective chart review with prospective imaging analysis. Children between 1 week and 17 years of age who had a brain MRI in the first 2 weeks after CA without other acute brain injury between 2002 and 2008 were included. Brain MRI (1.5 T General Electric, Milwaukee, WI, USA) images were analyzed by 2 blinded neuroradiologists with adjudication; images were visually graded. Brain lobes, basal ganglia, thalamus, brain stem, and cerebellum were analyzed using T1, T2, and diffusion-weighted images (DWI). RESULTS: We examined 28 subjects with median age 1.9 years (IQR 0.4-13.0) and 19 (68 %) males. Increased intensity on T2 in the basal ganglia and restricted diffusion in the brain lobes were associated with unfavorable outcome (all P < 0.05). Therapeutic hypothermia had no effect on regional brain injury. Repeat brain MRI was infrequently performed but demonstrated evolution of lesions. CONCLUSION: Children with lesions in the basal ganglia on conventional MRI and brain lobes on DWI within the first 2 weeks after CA represent a group with increased risk of poor outcome. These findings may be important for developing neuroprotective strategies based on regional brain injury and for evaluating response to therapy in interventional clinical trials. PMID- 22535279 TI - Infliximab exerts no direct hepatotoxic effect on HepG2 cells in vitro. AB - BACKGROUND: Infliximab-induced hepatotoxicity is reported in several case studies involving patients with inflammatory bowel disease (IBD) and a direct hepatotoxic effect has been proposed. OBJECTIVE: The aim of this study was to determine the direct in vitro toxicity of infliximab. As a proof of principle the in vitro toxicity of thiopurines and methotrexate was also determined. METHODS: Cell survival curves and the half maximal inhibitory concentrations (IC(50)) were obtained after 24, 48 and 72 h of incubation in HepG2 cells with the IBD drugs azathioprine, 6-mercaptopurine, 6-thioguanine, methotrexate or infliximab by using the WST-1 cytotoxicity assay. RESULTS: No in vitro hepatotoxicity in HepG2 cells was seen with infliximab, while concentration-dependent cytotoxicity was observed when HepG2 cells were incubated with increasing concentrations of azathioprine, 6-mercaptopurine and 6-thioguanine. CONCLUSION: Infliximab alone or given in combination with azathioprine showed no direct hepatotoxic effect in vitro, indicating that the postulated direct hepatotoxicity of infliximab is unlikely. PMID- 22535280 TI - Gene polymorphisms involved in manifestation of leucopenia, digestive intolerance, and pancreatitis in azathioprine-treated patients. AB - BACKGROUND: Approximately 10-28 % of patients experience adverse drug reactions related to treatment with thiopurines. The most serious reaction is myelosuppression, typically manifested as leucopenia, which occurs in approximately 2-5 % of patients. Other adverse drug reactions that often accompany thiopurine therapy are pancreatitis, hepatotoxicity, allergic reactions, digestive intolerance, arthralgia, febrile conditions, and rash. OBJECTIVE: The objective of this study was to assess the relationship between variant alleles of thiopurine S-methyltransferase (SNPs 238G > C, 460G > A and 719A > G), inosine triphosphate diphosphatase (SNPs 94C > A and IVS2 + 21A > C), and xanthine dehydrogenase (837C > T) and the occurrence of adverse drug reactions to azathioprine therapy. METHODS: Genotype was determined for 188 Caucasians diagnosed with inflammatory bowel disease treated with a standard dose of azathioprine (1.4-2.0 mg/kg/day). Allelic variants were determined by PCR-REA and real-time PCR methods. Results were statistically evaluated by use of Fisher's test and by odds ratio calculation. RESULTS: Variant genotype thiopurine S-methyltransferase predisposes to development of leucopenia (P = 0.003, OR = 5, CI 95 %, 1.8058-13.8444). Although not statistically significant, we observed a trend that suggested correlation between the occurrence of digestive intolerance and the variant genotype inosine triphosphate diphosphatase (P = 0.1102; OR 15.63, CI 95 %, 1.162-210.1094), and between the occurrence of pancreatitis and the variant allele xanthine dehydrogenase 837T (P = 0.1124; OR 12,1, CI 95 %, 1.15-126.37). CONCLUSION: The variant genotype thiopurine S-methyltransferase has been associated with the occurrence of leucopenia. The involvement of polymorphisms in inosine triphosphate diphosphatase and xanthine dehydrogenase genes in the development of digestive intolerance and pancreatitis will require further verification. PMID- 22535281 TI - Elevated fecal short chain fatty acid and ammonia concentrations in children with autism spectrum disorder. AB - BACKGROUND AND AIM: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder where a high frequency of gastrointestinal disturbance (e.g., constipation and diarrhea) is reported. As large bowel fermentation products can have beneficial or detrimental effects on health, these were measured in feces of children with and without ASD to examine whether there is an underlying disturbance in fermentation processes in the disorder. METHODS: Fecal samples (48 h) were collected from children with ASD (n = 23), and without ASD (n = 31) of similar age. Concentrations of short chain fatty acids, phenols and ammonia were measured. RESULTS: Fecal total short chain fatty acid concentrations were significantly higher in children with ASD compared to controls (136.6 +/- 8.7 vs. 111.1 +/- 6.6 mmol/kg). Moreover, when concentrations of fecal acetic, butyric, isobutyric, valeric, isovaleric and caproic acids were measured, all were significantly higher in children with ASD compared with controls except for caproic acid. The concentration of fecal ammonia was also significantly greater in ASD participants than controls (42.7 +/- 3.3 vs. 32.3 +/ 1.9 mmol/kg). Fecal phenol levels and pH did not differ between groups. Macronutrient intake, as determined from dietary records kept by caregivers, also did not differ significantly between study groups. CONCLUSIONS: Our results suggest fermentation processes or utilization of fermentation products may be altered in children with ASD compared to children without ASD. PMID- 22535282 TI - Regulatory long non-coding RNA and its functions. AB - The discovery of large numbers of long non-coding RNAs (lncRNAs) has been driven by genome-wide transcriptional analyses. Compared to small ncRNAs, lncRNAs have been shown to harbor biological activities, but the functions of the great majority of lncRNAs are not known. There is growing evidence that lncRNAs can regulate gene expression at epigenetic, transcription, and post-transcription levels and widely take part in various physiological and pathological processes, such as participating in cell development, immunity, oncogenesis, clinical disease processes, etc. Here, the current research efforts on the function of lncRNA in recent years were summarized. PMID- 22535283 TI - Effects of curcumin and Ginkgo biloba on matrix metalloproteinases gene expression and other biomarkers of inflammatory bowel disease. AB - Treatment of inflammatory bowel disease (IBD) by synthetic active ingredients leads to many side effects. The objective of this study was to manage IBD using natural products as curcumin and Ginkgo biloba. Rats were divided into four groups (control, IBD, curcumin treated, and ginkgo treated). Inflammation was assessed by determination of myeloperoxidase, matrix metalloproteinases, metalloproteinase-1 inhibitor, nitric oxide, hydroxyproline, tumor necrosis factor-alpha, ceruloplasmin, and histopathological scoring. IBD induction significantly increased all measured parameters. Treated groups had significantly lower levels when compared with the IBD group. In conclusion, curcumin and ginkgo were effective in prevention and treatment of IBD. PMID- 22535284 TI - Effects of hyperoxia exposure on metabolic markers and gene expression in 3T3-L1 adipocytes. AB - Adipose tissue often becomes poorly oxygenated in obese subjects. This feature may provide cellular mechanisms involving chronic inflammation processes such as the release of pro-inflammatory cytokines and macrophage infiltration. In this context, the purpose of the present study was to determine whether a hyperoxia exposure on mature adipocytes may influence the expression of some adipokines and involve favorable changes in specific metabolic variables. Thus, 3T3-L1 adipocytes (14 days differentiated) were treated with 95 % oxygen for 24 h. Cell viability, intra and extracellular reactive oxygen species (ROS) content, glucose uptake, as well as lactate and glycerol concentrations were measured in the culture media. Also, mRNA levels of hypoxia-inducible factor (HIF)-1alpha, leptin, interleukin (IL)-6, monocyte chemotactic protein (MCP)-1, peroxisome proliferator-activated receptor (PPAR)-gamma, adiponectin, and angiopoietin related protein (ANGPTL)4 were analyzed. Hyperoxia treatment increased intra and extracellular ROS content, reduced glucose uptake and lactate release and increased glycerol release. Additionally, a higher oxygen tension led to an upregulation of the expression of IL-6, MCP-1, and PPAR-gamma, while ANGPTL4 was downregulated in the hyperoxia group with respect to control. The present data shows that hyperoxia treatment seems to produce an inflammatory response due to the release of ROS and the upregulation of pro-inflammatory adipokines, such as IL-6 and MCP-1. On the other hand, hyperoxia may have an indirect effect on insulin sensitivity due to the upregulation of PPAR-gamma signaling as well as a possible modulation of both glucose and lipid metabolic markers. To our knowledge, this is the first study analyzing the effect of hyperoxia in 3T3-L1 adipocytes. PMID- 22535286 TI - Erythropoietin, progenitor cells and restenosis. A critique of Stein et al. PMID- 22535288 TI - Public confusion caused by differing understandings of the term 'mental illness'. PMID- 22535285 TI - Impact of leucine on energy balance. AB - Body weight is determined by the balance between energy intake and energy expenditure. When energy intake exceeds energy expenditure, the surplus energy is stored as fat in the adipose tissue, which causes its expansion and may even lead to the development of obesity. Thus, there is a growing interest to develop dietary interventions that could reduce the current obesity epidemic. In this regard, data from a number of in vivo and in vitro studies suggest that the branched-chain amino acid leucine influences energy balance. However, this has not been consistently reported. Here, we review the literature related to the effects of leucine on energy intake, energy expenditure and lipid metabolism as well as its effects on the cellular activity in the brain (hypothalamus) and in peripheral tissues (gastro-intestinal tract, adipose tissue, liver and muscle) regulating the above physiological processes. Moreover, we discuss how obesity may influence the actions of this amino acid. PMID- 22535289 TI - The rise and fall of ADHD child prescribing in Western Australia: lessons and implications. PMID- 22535290 TI - Response to Whitely: a caution from the coalface. PMID- 22535291 TI - A systematic review of psychotropic drug prescribing for prisoners. AB - OBJECTIVE: To conduct a review of the literature on prescribing psychotropic drugs for prisoners. METHODS: Articles were retrieved from nine databases, reference lists, citations, governmental prison websites, and contact with authors. The articles included were written in English, focused on adults' time as prisoners, included at least one drug of interest, and discussed prescribing. Thirty-two articles met these inclusion criteria. RESULTS: Five main themes were identified from the reviewed studies: polypharmacy, high-dose therapy, duration of treatment, documentation and monitoring, and issues associated with the prisoners' environment. CONCLUSIONS: Consideration of these themes within the included studies identified areas for future research, particularly models of good practice, as numerous descriptions of poor practice exist. Policy-makers and prescribers should review current systems and practices, to ensure the care being offered to prisoners is optimal. PMID- 22535292 TI - Frontotemporal dementia as a frontostriatal disorder: neostriatal morphology as a biomarker and structural basis for an endophenotype. AB - OBJECTIVE: This article reviews the evidence for a re-conceptualisation of a subtype of frontotemporal lobar degeneration (FTLD), frontotemporal dementia (FTD), as a frontostriatal disorder, working towards an endophenotype. METHOD: We provide an overview of the role of frontostriatal circuits relevant to FTLD and FTD, as a subset of larger-scale distributed brain networks. We discuss the role of a strategic structure in these circuits, the neostriatum. Then we review the relationship of the clinical features of FTLD to frontostriatal circuits, correlating this with neuropsychological and neuropathological data. CONCLUSION: The unique structure and linkages of the neostriatum make it an ideal structure for in vivo neuroimaging to understand the neuroanatomical basis of FTD. We develop a frontostriatal endophenotypic model for FTD as a platform for further investigation. PMID- 22535293 TI - Changes in the prevalence of psychological distress and use of antidepressants or anti-anxiety medications associated with comorbid chronic diseases in the adult Australian population, 2001-2008. AB - OBJECTIVE: To investigate changes in the prevalence of psychological distress and use of antidepressants or anti-anxiety medications associated with comorbid chronic diseases in the adult Australian population from 2001 to 2008. METHODS: Participants were 48,359 adults aged >= 25 years from the 2001, 2004-05 or 2007 08 Australian National Health Surveys. Clinically significant psychological distress was determined with the 10-item Kessler Psychological Distress Scale (using scores >= 30). Contemporaneous use of antidepressants or anti-anxiety medications and the presence of chronic diseases including diabetes, cardiovascular disease, cancer, asthma and arthritis were by self-report. RESULTS: Overall, the prevalence of psychological distress was relatively stable (3.9 vs. 3.7%) between 2001 and 2008, but increased from 5.9 to 7.0% and 4.6 to 5.0% for people with diabetes and cardiovascular disease. In contrast, the use of antidepressants or anti-anxiety medications decreased from 7.3 to 4.8% across all disease categories. On average, the odds of psychological distress and use of antidepressants or anti-anxiety medications was 1.15 to 1.59-fold and 1.10 to 1.64-fold higher, respectively, for all chronic diseases after adjustments for socio-demographic and lifestyle variables. After further adjustment for all chronic disease predictors fitted jointly, these associations decreased in strength (percentage change in the log odds ratio) by 14 to 98%. Each additional chronic disease increased the odds of both psychological distress (1.34-fold higher) and use of antidepressants or anti-anxiety medications (1.40-fold higher) in a dose-response manner. CONCLUSIONS: Although the prevalence of psychological distress changed little for adult Australians between 2001 and 2008, it increased for people with diabetes and cardiovascular disease. Conversely, the reported use of antidepressants or anti-anxiety medications progressively decreased for people with, and without, chronic diseases. Overall, there was a persistently higher psychopathology burden associated with each and increasing number of comorbid chronic diseases. PMID- 22535294 TI - The prevalence and correlates of psychological distress in Australian tertiary students compared to their community peers. AB - OBJECTIVE: To examine differences between university students, vocational education and training (VET) students, tertiary students combined and non students in the prevalence of psychological distress and the socio-demographic and economic characteristics associated with psychological distress. METHOD: The Kessler Psychological Distress Scale was used to estimate the prevalence of moderate (16-21) and high (22-50) distress with data from three national surveys: the 2007 Household, Income and Labour Dynamics in Australia (HILDA) survey, the 2007-08 National Health Survey (NHS), and the 2007 National Survey of Mental Health and Wellbeing (NSMHWB). Multinomial logistic regression models were also estimated using the HILDA survey to examine any differences in the characteristics associated with moderate and high distress between the groups. RESULTS: There was evidence of a higher prevalence of moderate distress in tertiary students than non-students in the HILDA survey (27.1% vs. 21.2%, p < 0.05) and the NSMHWB (27.4% vs. 19.5%, p < 0.05), but not the NHS (26.1% vs. 22.5%, p > 0.05). However, standardized rates for age and gender attenuated the difference in moderate distress in the HILDA survey and the NSMHWB. The prevalence of high distress was similar between the groups in all three surveys. The multinomial regression analyses using the HILDA survey showed the following subgroups of students to be at a greater risk of high distress relative to those with low distress: younger university students, and university and VET students with financial problems. Compared to VET students and non-students, younger university students and those who worked 1-39 hours per week in paid employment were at a greater risk of high distress. CONCLUSIONS: There is evidence that tertiary students have a greater prevalence of moderate, but not high distress than non-students. Financial factors increase the risk of high distress and are likely to take on more importance as the participation rate of socio-economically disadvantaged students increases. PMID- 22535295 TI - Private health insurance, mental health and service use in Australia. AB - OBJECTIVE: To report on the private health insurance (PHI) status of individuals with and without a mental health problem, and examine whether PHI status is associated with access to psychological services. METHODS: This is a descriptive study of nationally representative population-based data collected in 2009 (HILDA) with participants aged 15-93 (n = 13,301). Key measures included: PHI status (categorised as 'hospital cover only', 'extras cover only', or 'both hospital and extras cover'); mental health status (categorised as 'have a mental health problem' or 'do not have a mental health problem' using the mental health index (MHI) of the medical outcomes study short form); mental health service use (access to a mental health professional (psychologist/psychiatrist) in the past 12 months categorised as 'yes' or 'no'). RESULTS: Individuals with a mental health problem were less likely to have PHI than those without a mental health problem. However, PHI was not associated with access to a mental health professional in the past 12 months. CONCLUSIONS: The findings suggest that while the discrepancy in PHI status is a marker of inequity between those with and without a mental health problem, it is not a key factor in facilitating access to mental health services. PMID- 22535296 TI - Are we mindful of psychosis? PMID- 22535297 TI - Behaviour and biomarkers in frontotemporal dementia: implications for general psychiatry. PMID- 22535298 TI - Access to mental health care in Australia: is there socioeconomic equality? PMID- 22535299 TI - More on narratives and conversations. PMID- 22535300 TI - Educating health care professionals about suicide prevention. PMID- 22535301 TI - Pellagra encephalopathy as a differential diagnosis for Creutzfeldt-Jakob disease. AB - In the present study we evaluated cases referred as suspected Creutzfeldt-Jakob disease (CJD). Five out of 59 without prion disease showed neuropathological features of pellagra encephalopathy with widespread chromatolytic neurons (age range 40-48 years at death; one woman). These patients presented with a progressive neuropsychiatric disorder lasting for 2 to 24 months. Common symptoms included gait disorder, para- or tetraspasticity, extrapyramidal symptoms, incontinence, and myoclonus. Protein 14-3-3 in the cerebrospinal fluid was examined in a single patient and was positive, allowing the clinical classification as probable sporadic CJD. Pellagra encephalopathy may be considered as a differential diagnosis of CJD including detection of protein 14-3 3. PMID- 22535303 TI - The three most common variations of the left renal vein: a review and meta analysis. AB - The authors describe three anatomic variations, circumaortic, retroaortic left renal vein, and retropelvic tributary of the renal vein, in Japanese cadavers. The incidences and the clinical significances of these variations are discussed with a detailed review of the literature. The median incidences of circumaortic left renal vein (CLRV) were 7.0% in cadavers examined and 1.8% in clinical subjects examined. The detection of CLRV in CT/MDCT or angiography was relatively difficult compared with that by cadaver dissection. The median incidences of retroaortic left renal vein (RLRV) were 1.7% in cadavers examined and 2.2% in clinical subjects examined. The detection of RLRV was lower in operations, and relatively easy by ultrasonography. The incidence of retropelvic tributary of the renal vein ranged from 30.0 to 46.4%, which is very frequent. Moreover, the incidences of communicating veins between the left renal vein and retroperitoneal veins ranged from 30.0 to 84.2% in cadaver dissections and from 34.0 to 75.8% in clinical reports. PMID- 22535305 TI - Multiple substance use and self-reported suicide attempts by adolescents in 16 European countries. AB - Substance use and suicide attempts are high-risk behaviors in adolescents, with serious impacts on health and well-being. Although multiple substance use among young people has become a common phenomenon, studies of its association with suicide attempts are scarce. The present study examines the association between multiple substance use and self-reported suicide attempts in a large multinational sample of adolescent students in Europe. Data on multiple substance use (tobacco, alcohol, tranquillizers/sedatives, cannabis, other illegal drugs) and self-reported suicide attempts were drawn from the 2007 European School Survey Project on Alcohol and Other Drugs (ESPAD). The ESPAD survey follows a standardized methodology in all participating countries. The present study is based on 45,086 16-year-old adolescents from 16 countries that had used the optional "psychosocial module" of the questionnaire, thereby including the question on suicide attempts. Logistic regression analyses were performed to examine the associations of any self-reported suicide attempt (dependent variable) with substance use controlling for country and gender. The strongest association with self-reported suicide attempts was for any lifetime tranquillizer or sedative use (odds ratio 3.34, 95 % confidence interval 3.00 3.71) followed by any lifetime use of illegal drugs other than cannabis (2.41, 2.14-2.70), 30-day regular tobacco use (2.02, 1.84-2.21), 30-day frequent alcohol use (1.47, 1.32-1.63) and any 30-day cannabis use (1.37, 1.18-1.58). The odds ratio of reporting a suicide attempt approximately doubled for every additional substance used. These findings on the association between multiple substance use, including legal drugs (tranquillizers or sedatives and tobacco), and the life threatening behavior of suicide attempts provide important cues for shaping prevention policies. PMID- 22535306 TI - A self-assembled polydopamine film on the surface of magnetic nanoparticles for specific capture of protein. AB - In this study, we report a facile method for the preparation of core-shell magnetic molecularly imprinted polymers (MIPs) for protein recognition. Uniform carboxyl group functionalized Fe(3)O(4) nanoparticles (NPs) were synthesized using a solvothermal method. Magnetic MIPs were synthesized by self polymerization of dopamine in the presence of template protein on the surface of the Fe(3)O(4) NPs. A thin layer of polydopamine can be coated on Fe(3)O(4) NPs via dopamine self-polymerization and the imprinted polydopamine shells can be controlled by the mass ratio of Fe(3)O(4) NPs and dopamine. More importantly, there is a critical value of polydopamine shell thickness for the maximum rebinding capacity. The as-prepared lysozyme-imprinted Fe(3)O(4)@polydopamine NPs show high binding capacity and acceptable specific recognition behavior towards template proteins. This method provides the possibility for the separation and enrichment of abundant proteins in proteomic analysis. PMID- 22535304 TI - beta-catenin/TCF-1 pathway in T cell development and differentiation. AB - T cells must undergo two critical differentiation processes before they become competent effectors that can mediate actual immune responses. Progenitor T cells undergo defined stages of differentiation in the thymus, which include positive and negative selection, to generate a repertoire of T cells that will respond to foreign but not self antigens. When these immunocompetent T cells first migrate out of thymus into peripheral lymphoid tissues, they are naive and are unable to mediate immune responses. However, upon antigen encounter, peripheral CD4+ naive T cells undergo another differentiation process to become armed effector T cells including Th1, Th2, Th17 or regulatory T cells, all of which are capable of regulating immune responses. A canonical Wnt/beta-catenin/T cell factor (TCF) pathway has been shown to regulate T cell differentiation in both the thymus and in peripheral lymphoid tissues. Dysfunction of this pathway at any stage of T cell differentiation could lead to severe autoimmunity including experimental autoimmune encephalomyelitis or immune deficiency. Understanding the role played by beta-catenin/TCF-1 in T cell differentiation will facilitate our understanding of the mechanisms that regulate T cell function and assist in identifying novel therapy targets for treating both autoimmune and immune diseases. Therefore, in this review, we will focus on the function of beta-catenin/TCF-1 pathway in the regulation of thymic and peripheral T cell differentiation processes. PMID- 22535308 TI - Cocaine self-administration behaviors in ClockDelta19 mice. AB - RATIONALE: A key role has been identified for the circadian locomotor output cycles kaput (Clock) gene in the regulation of drug reward. Mice bearing a dominant negative mutation in the Clock gene (ClockDelta19 mice) exhibit increased cocaine-induced conditioned place preference, reduced anxiety- and depression-like behavior, increased sensitivity to intracranial self-stimulation, and increased dopaminergic cell activity in the ventral tegmental area. OBJECTIVES: We sought to determine if this hyperhedonic phenotype extends to cocaine self-administration and measures of motivation. METHODS: Two separate serial testing procedures were carried out (n = 7-10/genotype/schedule). Testing began with acquisition of sucrose pellet self-administration, implantation of intravenous catheter, acquisition of cocaine self-administration, and dose response testing (fixed ratio or progressive ratio). To evaluate diurnal variations in acquisition behavior, these sessions occurred at Zeitgeber 2 (ZT2) or ZT14. RESULTS: WT and ClockDelta19 mice exhibited similar learning and readily acquired food self-administration at both ZT2 and ZT14. However, only ClockDelta19 mice acquired cocaine self-administration at ZT2. A greater percentage of ClockDelta19 mice reached acquisition criteria at ZT2 and ZT14. ClockDelta19 mice self-administered more cocaine than WT mice. Using fixed ratio and progressive ratio schedules of reinforcement dose-response paradigms, we found that cocaine is a more efficacious reinforcer in ClockDelta19 mice than in WT mice. CONCLUSION: Our results demonstrate that the Clock gene plays an important role in cocaine reinforcement and that decreased CLOCK function increases vulnerability for cocaine use. PMID- 22535309 TI - Aripiprazole in the treatment of challenging behaviour in adults with autism spectrum disorder. AB - BACKGROUND: Autism spectrum disorders (ASD) are associated with repetitive behaviours and often also with hyperactivity, aggression, self-injurious behaviour, irritability and lability of mood. There is emerging evidence that aripiprazole, an antipsychotic with partial agonist dopaminergic effect, may be effective in the treatment of these challenging behaviours. Nevertheless, there is little evidence for their efficacy in adults with ASD. OBJECTIVES: The aim of this article is to present preliminary data on the use of aripiprazole in the treatment of challenging behaviour in the setting of ASD. METHODS: We present a consecutive series of five inpatients of normal intelligence with challenging behaviour associated with ASD, diagnosed according to ICD-10 criteria, which was resistant to treatment with other medical and behavioural interventions and which was treated with aripiprazole. RESULTS: Four out of five patients were classified as "much improved" or "very much improved" according to the Clinical Global Impression-Improvement scale. Aripiprazole caused akathisia, at a dose of 30 mg in the one patient who was not classified as a responder but was otherwise well tolerated. CONCLUSIONS: This is the first case series of adults with ASD presenting with challenging behaviour who have been treated with aripiprazole. While the results are promising, controlled trials are required to confirm the findings. PMID- 22535310 TI - Intermittent explosive disorder as a disorder of impulsive aggression for DSM-5. AB - A disorder of impulsive aggression has been included in DSM since the first edition. In DSM-III, this disorder was codified as intermittent explosive disorder, and it was thought to be rare. However, the diagnostic criteria for the disorder were poorly operationalized, and empirical research was limited until research criteria were developed a decade ago. Subsequently, renewed interest in disorders of impulsive aggression led to a recent series of community-based studies that have documented intermittent explosive disorder to be as common as many other psychiatric disorders. Other recent research indicates that compared with DSM-IV criteria for intermittent explosive disorder, research criteria for the disorder better identify individuals with elevated levels of aggression, impulsivity, familial risk of aggression, and abnormalities in neurobiological markers of aggression. In addition, other data strongly suggest important delimitation from other disorders previously thought to obscure the diagnostic uniqueness of intermittent explosive disorder. Overall, these data suggest that the diagnostic validity for the integrated research criteria is substantial and is now sufficient for recognition and inclusion in DSM-5. PMID- 22535311 TI - Computational fluid dynamics of developing avian outflow tract heart valves. AB - Hemodynamic forces play an important role in sculpting the embryonic heart and its valves. Alteration of blood flow patterns through the hearts of embryonic animal models lead to malformations that resemble some clinical congenital heart defects, but the precise mechanisms are poorly understood. Quantitative understanding of the local fluid forces acting in the heart has been elusive because of the extremely small and rapidly changing anatomy. In this study, we combine multiple imaging modalities with computational simulation to rigorously quantify the hemodynamic environment within the developing outflow tract (OFT) and its eventual aortic and pulmonary valves. In vivo Doppler ultrasound generated velocity profiles were applied to Micro-Computed Tomography generated 3D OFT lumen geometries from Hamburger-Hamilton (HH) stage 16-30 chick embryos. Computational fluid dynamics simulation initial conditions were iterated until local flow profiles converged with in vivo Doppler flow measurements. Results suggested that flow in the early tubular OFT (HH16 and HH23) was best approximated by Poiseuille flow, while later embryonic OFT septation (HH27, HH30) was mimicked by plug flow conditions. Peak wall shear stress (WSS) values increased from 18.16 dynes/cm(2) at HH16 to 671.24 dynes/cm(2) at HH30. Spatiotemporally averaged WSS values also showed a monotonic increase from 3.03 dynes/cm(2) at HH16 to 136.50 dynes/cm(2) at HH30. Simulated velocity streamlines in the early heart suggest a lack of mixing, which differed from classical ink injections. Changes in local flow patterns preceded and correlated with key morphogenetic events such as OFT septation and valve formation. This novel method to quantify local dynamic hemodynamics parameters affords insight into sculpting role of blood flow in the embryonic heart and provides a quantitative baseline dataset for future research. PMID- 22535312 TI - Small molecule anticonvulsant agents with potent in vitro neuroprotection. AB - Severe seizure activity is associated with recurring cycles of excitotoxicity and oxidative stress that result in progressive neuronal damage and death. Intervention to halt these pathological processes is a compelling disease modifying strategy for the treatment of seizure disorders. In the present study, a core small molecule with anticonvulsant activity has been structurally optimized for neuroprotection. Phenotypic screening of rat hippocampal cultures with nutrient medium depleted of antioxidants was utilized as a disease model. Increased cell death and decreased neuronal viability produced by acute treatment with glutamate or hydrogen peroxide were prevented by our novel molecules. The neuroprotection associated with this chemical series has marked structure activity relationships that focus on modification of the benzylic position of a 2 phenyl-2-hydroxyethyl sulfamide core structure. Complete separation between anticonvulsant activity and neuroprotective action was dependent on substitution at the benzylic carbon. Chiral selectivity was evident in that the S-enantiomer of the benzylic hydroxy group had neither neuroprotective nor anticonvulsant activity, while the R-enantiomer of the lead compound had full neuroprotective action at <40 nM and antiseizure activity in three animal models. These studies indicate that potent, multifunctional neuroprotective anticonvulsants are feasible within a single molecular entity. PMID- 22535313 TI - The role of Munc18-1 and its orthologs in modulation of cortical F-actin in chromaffin cells. AB - Munc18-1 was originally described as an essential docking factor in chromaffin cells. Recent findings showed that Munc18-1 has an additional role in the regulation of the cortical F-actin network, which is thought to function as a physical barrier preventing secretory vesicles from access to their release sites under resting conditions. In our review, we discuss whether this function is evolutionarily conserved in all Sec1/Munc18-like (SM) proteins. In addition, we introduce a new quantification method that improves the analysis of cortical filamentous actin (F-actin) in comparison with existing methods. Since the docking process is highly evolutionarily conserved in the SM protein superfamily, we use our novel quantification method to investigate whether the F-actin regulating function is similarly conserved among SM proteins. Our preliminary data suggest that the regulation of cortical F-actin is a shared function of SM proteins, and we propose a way to gain more insight in the molecular mechanism underlying the Munc18-1-mediated cortical F-actin regulation. PMID- 22535314 TI - Development of polymeric sensing films based on a tridentate bis(phosphinic amide)-phosphine oxide for detecting europium(III) in water. AB - A novel europium(III) membrane luminescence sensor based on a tridentate bis(phosphinic amide)-phosphine oxide, PhPO(C(6)H(4)POPhN(CH(CH(3))(2))(2))(2) (1), is described. The new luminescent complex, [Eu(1)(2)]Cl(3)2, which is formed between europium(III) and ligand 1 and has a 1 : 2 stoichiometry, has been evaluated in solution. It has the excellent spectroscopic and chemical characteristics that make it appropriate for sensing film applications. All the parameters (polymer, plasticizer, ligand and ionic additive) that can affect the sensitivity and selectivity of the membrane sensor and instrumental conditions have been carefully optimized. The best sensing response (lambda(exc) = 229.04 nm, lambda(em) = 616.02 nm) was observed for 33.4 : 65.1 : 1.5 (%, w/w) PVC : DOS : 1. The sensing film shows a good response time (10 min) and a very good selectivity toward europium(III) with respect to other lanthanides(III) ions, such as La, Sm, Tb and Yb. The newly-developed sensing film has a linear range from 1.6 * 10(-7) to 5.0 * 10(-6) mol L(-1) for Eu ions with a very low detection limit (4.8 * 10(-8) mol L(-1)) and good sensitivity (9.41 * 10(-7) a.u. mol(-1) L(-1)) to europium. Complexes of [Eu(1)(2)]Cl(3) (2) and [Eu(1)]Cl(3) (4) were isolated by mixing ligand 1 with Eu(Cl(3)).6H(2)O in acetonitrile at room temperature in ligand : metal molar ratios of 1 : 2 and 1 : 1, respectively. The 1 : 1 derivative is the product of thermodynamic control when a molar ratio of ligand to europium salt of 1 : 1 is used. The new compounds have been characterized in both the solid form (IR, MS-TOF, elemental analysis, TGA and X ray diffraction) and in solution (multinuclear magnetic resonance). In both europium complexes, the ligand acts as a tridentate chelate. Thermogravimetric (TG) studies demonstrated that neither complex 2 or 4 possess any water molecules directly bound to the lanthanide metal, which corroborates the X-ray structure. The investigation of the solution behaviour of the Y(III) complexes with pulsed gradient spin-echo (PGSE) NMR diffusion measurements showed that average structures with 1 : 1 and 1 : 2 stoichiometries are retained in acetonitrile solutions. PMID- 22535315 TI - Biological efficacy of a 600 mg loading dose of clopidogrel in ST-elevation myocardial infarction. AB - Optimal platelet reactivity (PR) inhibition is critical to prevent thrombotic events in primary percutaneous coronary intervention (PCI). We aimed to determine the relationship between high on-treatment platelet reactivity (HTPR) and ST elevation myocardial infarction (STEMI) following a 600 mg loading dose (LD) of clopidogrel. We performed a prospective monocentre study enrolling patients on clopidogrel undergoing PCI. The VASP index was used to assess PR inhibition after clopidogrel LD. HTPR was defined according to the consensus as a VASP index >=50%. The present study included 833 patients undergoing PCI. Most patients had PCI for an acute coronary syndrome (58.7%). The mean VASP index was 50 +/- 23% with a large inter-individual variability (range: 1-94%). Patients with a VASP index >=50% were significantly older (p= 0.03), with a higher body mass index (BMI) (p<0.001), more often diabetic (p=0.03), taking omeprazole (p=0.03), admitted for an acute coronary syndrome (ACS) and with a high fibrinogen level compared to good responders (VASP <50%). In multivariate analysis BMI, omeprazole use, ACS and high fibrinogen level (p<0.001) remained significantly associated with HTPR. Of importance, in this analysis STEMI was independently associated with HTPR when compared with the other forms of ACS (NSTEMI and unstable angina) with an odd ratio of 2.14 (95% CI: 1.3 -3.5; p=0.003). In conclusion, STEMI is associated with high on-treatment platelet reactivity following 600 mg of clopidogrel. The present results suggest that 600 mg of clopidogrel may not be able to achieve an optimal PR inhibition in STEMI patients undergoing PCI and more potent drugs may be preferred. PMID- 22535316 TI - DNA damage and oxidative stress induced by endosulfan exposure in zebrafish (Danio rerio). AB - Endosulfan (6,7,8,9,10,10-hexachloro-1,5,5a,6,9,9a-hexahydro-6,9-methano-2,4,3 benzo-dioxathiepin-3-oxide), an organochlorine pesticide, is prevalently used all around the world. It is considered to be a new candidate for the persistent organic pollutants group. Endosulfan residues in the environment may cause serious damage to ecosystems, especially in aquatic environments. The present study was conducted to investigate the effect of endosulfan on antioxidant enzymes [catalase (CAT) and superoxide dismutase (SOD)], reactive oxygen species (ROS) generation and DNA damage in zebrafish. Male and female zebrafish were separated and exposed to a control solution and four concentrations of endosulfan (0.01, 0.1, 1, and 10 MUg L-1) and were sampled after 7, 14, 21, and 28 days. It is noteworthy that the present research explored the correlation among the three indicators induced by endosulfan. Low endosulfan concentrations (0.01 MUg L-1) induced a slight increase of SOD and CAT activity, which kept ROS in a stable level. High endosulfan concentration (10 MUg L-1) induced excessive ROS production which exceeded the capacity of the cellular antioxidants and exhausted the enzyme including CAT and SOD. The DNA damage of zebrafish was evaluated by single-cell gel electrophoresis and was enhanced with increasing endosulfan concentration. In conclusion, the present study showed that endosulfan (0.01-10 MUg L-1) has toxic effects on zebrafish. PMID- 22535317 TI - Antagonistic toxicity of arsenate and cadmium in a freshwater amphipod (Gammarus pulex). AB - Because toxicants rarely occur alone in the environment, a major challenge in risk assessment is to address the combined effects of chemicals on aquatic organisms. This work is aimed at investigating the joint toxicity action of binary mixtures of cadmium and arsenate on Gammarus pulex. Individuals were exposed during 240 h to four single arsenate or cadmium concentrations and binary mixtures of these metals according to a complete factorial plane. Observed mortality in binary mixtures was compared to observed mortality in single arsenate or cadmium exposures. In addition, interactive effects (antagonistic, additive or synergistic) were evaluated using a predictive model for the theoretically expected interactive effect of chemicals. For all the tested concentration combinations, we observed an antagonist 'between-metals' interaction on G. pulex mortality. This antagonistic effect was more marked for the lowest than for the highest (i.e. 1502.0 MUg(AsV) L(-1) and 28.5 MUg(Cd) L( 1)) tested concentrations of individual metals in binary mixtures. Metal concentrations in body tissues were evaluated and were significantly lower in binary mixtures than in single metal exposures at similar concentration, especially for combinations corresponding to the highest concentrations of both metals (1502.0 MUg(AsV) L(-1) and 28.5 MUg(Cd) L(-1)). Results were discussed in terms of (1) mechanisms of uptake and bioconcentration and (2) relationships between metal concentration in gammarid body and observed toxicity. PMID- 22535318 TI - Oncology clinicians' defenses and adherence to communication skills training with simulated patients: an exploratory study. AB - The aim of this exploratory study was to assess the impact of clinicians' defense mechanisms-defined as self-protective psychological mechanisms triggered by the affective load of the encounter with the patient-on adherence to a communication skills training (CST). The population consisted of oncology clinicians (N=31) who participated in a CST. An interview with simulated cancer patients was recorded prior and 6 months after CST. Defenses were measured before and after CST and correlated with a prototype of an ideally conducted interview based on the criteria of CST-teachers. Clinicians who used more adaptive defense mechanisms showed better adherence to communication skills after CST than clinicians with less adaptive defenses (F(1, 29) =5.26, p=0.03, d=0.42). Improvement in communication skills after CST seems to depend on the initial levels of defenses of the clinician prior to CST. Implications for practice and training are discussed. Communication has been recognized as a central element of cancer care [1]. Ineffective communication may contribute to patients' confusion, uncertainty, and increased difficulty in asking questions, expressing feelings, and understanding information [2, 3], and may also contribute to clinicians' lack of job satisfaction and emotional burnout [4]. Therefore, communication skills trainings (CST) for oncology clinicians have been widely developed over the last decade. These trainings should increase the skills of clinicians to respond to the patient's needs, and enhance an adequate encounter with the patient with efficient exchange of information [5]. While CSTs show a great diversity with regard to their pedagogic approaches [6, 7], the main elements of CST consist of (1) role play between participants, (2) analysis of videotaped interviews with simulated patients, and (3) interactive case discussion provided by participants. As recently stated in a consensus paper [8], CSTs need to be taught in small groups (up to 10-12 participants) and have a minimal duration of at least 3 days in order to be effective. Several systematic reviews evaluated the impact of CST on clinicians' communication skills [9-11]. Effectiveness of CST can be assessed by two main approaches: participant-based and patient-based outcomes. Measures can be self-reported, but, according to Gysels et al. [10], behavioral assessment of patient-physician interviews [12] is the most objective and reliable method for measuring change after training. Based on 22 studies on participants' outcomes, Merckaert et al. [9] reported an increase of communication skills and participants' satisfaction with training and changes in attitudes and beliefs. The evaluation of CST remains a challenging task and variables mediating skills improvement remain unidentified. We recently thus conducted a study evaluating the impact of CST on clinicians' defenses by comparing the evolution of defenses of clinicians participating in CST with defenses of a control group without training [13]. Defenses are unconscious psychological processes which protect from anxiety or distress. Therefore, they contribute to the individual's adaptation to stress [14]. Perry refers to the term "defensive functioning" to indicate the degree of adaptation linked to the use of a range of specific defenses by an individual, ranging from low defensive functioning when he or she tends to use generally less adaptive defenses (such as projection, denial, or acting out) to high defensive functioning when he or she tends to use generally more adaptive defenses (such as altruism, intellectualization, or introspection) [15, 16]. Although several authors have addressed the emotional difficulties of oncology clinicians when facing patients and their need to preserve themselves [7, 17, 18], no research has yet been conducted on the defenses of clinicians. For example, repeated use of less adaptive defenses, such as denial, may allow the clinician to avoid or reduce distress, but it also diminishes his ability to respond to the patient's emotions, to identify and to respond adequately to his needs, and to foster the therapeutic alliance. Results of the above-mentioned study [13] showed two groups of clinicians: one with a higher defensive functioning and one with a lower defensive functioning prior to CST. After the training, a difference in defensive functioning between clinicians who participated in CST and clinicians of the control group was only showed for clinicians with a higher defensive functioning. Some clinicians may therefore be more responsive to CST than others. To further address this issue, the present study aimed to evaluate the relationship between the level of adherence to an "ideally conducted interview", as defined by the teachers of the CST, and the level of the clinician' defensive functioning. We hypothesized that, after CST, clinicians with a higher defensive functioning show a greater adherence to the "ideally conducted interview" than clinicians with a lower defensive functioning. PMID- 22535319 TI - Cloning and characterization of SCIRR69: a novel transcriptional factor belonging to the CREB/ATF family. AB - The complete cDNA sequence of a novel gene, SCIRR69 (spinal cord injury and regeneration related no. 69 gene), was obtained by RACE technique. It codes for a protein of 521 amino acid residues homologous to human CREB3l2 (also known as BBF2H7) and mouse CREB3l2. The protein contains a basic DNA binding and leucine zipper dimerization (B-ZIP) motif and a hydrophobic region representing a putative transmembrane domain, similar to the structure of other CREB/ATF transcription factors. Monoclonal antibody against SCIRR69 was developed and could recognize the SCIRR69 protein in both native and denatured forms. Constructing of SCIRR69 fusion proteins with the GAL4 DNA-binding domain disclosed that SCIRR69 functioned as a transcriptional activator and its N terminal 60 amino acids accounted for the activation ability. SCIRR69 resides in the cytoplasm of primary neurons, whereas neuron damage by incision led to the cleavage and translocation from the cytoplasm to the nucleus. These results suggest that SCIRR69 is activated by proteolytic cleavage at the transmembrane domain in response to neuron damage and its amino-terminal cytoplasmic domain translocates into the nucleus to activate the transcription of target genes. PMID- 22535320 TI - Auxin-responsive grape Aux/IAA9 regulates transgenic Arabidopsis plant growth. AB - We report the characterization of VvIAA9, an auxin/indole-3-acetic acid (Aux/IAA) protein, in grapevine (Vitis vinifera L.). VvIAA9 was expressed abundantly in leaves and berries. VvIAA9 transcription was drastically upregulated from anthesis to onset of ripening (termed veraison), in which berry diameter rapidly increased. Treatment with exogenous IAA induced VvIAA9 expression in grape leaves, suggesting that VvIAA9 is an auxin-responsive Aux/IAA protein. The overexpression of VvIAA9 in Arabidopsis thaliana promoted plant growth, including rapid floral transition. However, no morphological differences were observed between the control plant and the VvIAA9-overexpressing plant. The overexpression of VvIAA9 in Arabidopsis plants rendered the plants hyposensitive to exogenous IAA. The exogenous IAA treatment did not induce VvIAA9-overexpressing Arabidopsis plant growth and expression of IAA-responsive HAT2. Taken together, we conclude that grape Aux/IAA9 protein is likely to play a crucial role as a plant growth regulator. PMID- 22535321 TI - Isolation of a CENTRORADIALIS/TERMINAL FLOWER1 homolog in saffron (Crocus sativus L.): characterization and expression analysis. AB - Genes in the phosphatidyl-ethanolamine-binding protein (PEBP) family are instrumental in regulating the fate of meristems and flowering time. To investigate the role of these genes in the monocotyledonous plant Crocus (Crocus sativus L), an industrially important crop cultivated for its nutritional and medicinal properties, we have cloned and characterized a CENTRORADIALIS/TERMINAL FLOWER1 (CEN/TFL1) like gene, named CsatCEN/TFL1-like, the first reported CEN/TFL1 gene characterized from such a perennial geophyte. Sequence analysis revealed that CsatCEN/TFL1 shows high similarity to its homologous PEBP family genes CEN/TFL1, FT and MFT from a variety of plant species and maintains the same exon/intron organization. Phylogenetic analysis of the CsatCEN/TFL1 amino acid sequence confirmed that the isolated sequences belong to the CEN/TFL1 clade of the PEBP family. CsatCEN/TFL1 transcripts could be detected in corms, flower and flower organs but not in leaves. An alternative spliced transcript was also detected in the flower. Comparison of expression levels of CsatCEN/TFL1 and its alternative spliced transcript in wild type flower and a double flower mutant showed no significant differences. Overexpression of CsatCEN/TFL1 transcript in Arabidopsis tfl1 plants reversed the phenotype of early flowering and terminal flowering of the tfl1 plants to a normal one. Computational analysis of the obtained promoter sequences revealed, next to common binding motifs in CEN/TFL1 like genes as well as other flowering gene promoters, the presence of two CArG binding sites indicative of control of CEN/TFL1 by MADS-box transcription factors involved in crocus flowering and flower organ formation. PMID- 22535322 TI - Characterization of grape C-repeat-binding factor 2 and B-box-type zinc finger protein in transgenic Arabidopsis plants under stress conditions. AB - Simultaneous induction of multiple stress tolerance by single-gene transfer is a powerful strategy to engineer crop plants to improve tolerance to environmental stress under field condition. The possibility of enhancement of multiple stress tolerance by four grape transcription factors that enhance low-temperature tolerance (VvCBF2, VvCBF4, VvCBFL, and VvZFPL) were analyzed using the Arabidopsis plants overexpressing these factors. Consequently, two of the four proteins, VvCBF2 and VvZFPL, were found to confer tolerance to cold, drought, and salinity stresses in Arabidopsis plants, but not to heat stress. Photosynthesis related genes were down-regulated in both CBF2- and ZFPL-overexpressing plants, resulting in plant growth retardation. On the other hand, the overexpression of VvCBF2 activated the transcription of CBL-interacting protein kinase 7, a serine/threonine kinase involved in cold response, in Arabidopsis plants. Our study provides that one of grape CBF family, VvCBF2, and one of B-box ZFP family, VvZFPL, confer multiple stress tolerance to plants. PMID- 22535323 TI - Transcriptional regulation of aquaporin-3 in human retinal pigment epithelial cells. AB - The expression of aquaporin (AQP) water channels may influence the development of retinal edema. We investigated the transcriptional regulation of AQP3 in cultured human retinal pigment epithelial (RPE) cells. As shown by RT-PCR and immunocytochemistry, cultured RPE cells express AQP3 mRNA and protein. The AQP3 mRNA level in RPE cells was elevated under the following conditions: chemical hypoxia induced by CoCl(2), hyperosmolarity induced by 100 mM NaCl, and upon stimulation of the cultures with PDGF, arachidonic acid, prostaglandin E(2), and blood serum, respectively. Chemical hypoxia increased AQP3 gene expression through MEK/ERK and JNK activation. The hyperosmolarity-, PDGF-, and serum induced upregulation of AQP3 was prevented by inhibition of the phospholipase A(2), but not by inhibition of the cyclooxygenase. Triamcinolone acetonide prevented the upregulation of AQP3 induced by arachidonic acid and prostaglandin E(2), but not by the other factors tested. It is concluded that AQP3 is transcriptionally activated in RPE cells by various pathogenic factors involved in the development of retinal edema in situ. Activation of phospholipase A(2) is a critical factor which induces AQP3 in RPE cells. PMID- 22535324 TI - CDH1 gene polymorphisms, plasma CDH1 levels and risk of gastric cancer in a Chinese population. AB - The genetic polymorphisms in E-cadherin gene (CDH1) may affect invasive/metastatic development of gastric cancer by altering gene transcriptional activity of epithelial cell. Our study aims to explore the associations among CDH1 gene polymorphisms, and predisposition of gastric cancer. We genotyped four potentially functional polymorphisms (rs13689, rs1801552, rs16260 and rs17690554) of the CDH1 gene in a case-control study of 387 incident gastric cancer cases and 392 healthy controls by polymerase chain reaction ligation detection reaction methods (PCR-LDR) and measured the plasma CDH1 levels using enzyme immunoassay among the subjects. The median and inter-quartile range were adopted for representing the mean level of non-normally distributed data, and we found the level of plasma CDH1 in gastric cancer patients (median: 171.00 pg/ml; inter-quartile range: 257.10 pg/ml) were significantly higher than that of controls (median: 137.40 pg/ml; inter-quartile range: 83.90 pg/ml, P = 0.003). However, none of the four polymorphisms or their haplotypes achieved significant differences in their distributions between gastric cancer cases and controls, and interestingly, in the subgroup analysis of gastric cancer, we found that CA genotype of rs26160 and CG genotype of rs17690554 were associated with the risk of diffuse gastric cancer, compared with their wild genotypes (OR = 2.98, 95 % CI: 1.60-5.53; OR = 2.10, 95 % CI: 1.14-3.85, respectively, P < 0.05). In conclusion, our results indicated that plasma CDH1 levels may serve as a risk marker against gastric cancer and variant genotypes of rs26160 and rs17690554 may contribute to the etiology of diffuse gastric cancer in this study. Further studies are warranted to verify these findings. PMID- 22535325 TI - A fluorescence turn-on H2O2 probe exhibits lysosome-localized fluorescence signals. AB - A new fluorescence turn-on probe that responds exclusively to H(2)O(2) exhibits subcellular localized fluorescence staining of lysosomes. PMID- 22535326 TI - Juridification, medicalisation, and the impact of EU Law: patient mobility and the allocation of scarce NHS resources. AB - This article explores the relationship between EU Law and the allocation of scarce NHS resources in the context of the EU's objective of facilitating access to health care for patients within the EU. Focusing on the Watts case and the recently adopted EU Patients' Rights Directive, the article addresses the political and economic aspects of the implications of EU Law for, inter alia, domestic law, medicine, and the NHS. It does so through developing an analytical framework comprising the notions of juridification and medicalisation. Those notions, which are drawn here from the work of Jurgen Habermas, Ivan Illich, and Sheila McLean, are not only helpful as means of thinking through the nature of the specific EU laws considered in the article; by virtue of their broader focus on, and critique of, the welfare state, they offer an opportunity to reflect more generally on the implications of these laws for the role of the welfare state and medical and legal professionals in the development of the EU's internal market in health care services. Having undertaken this analysis, the article argues that, in order to capture the developments and implications of EU Law on patient mobility, it is necessary to update and partially reformulate the notions of medicalisation and juridification. PMID- 22535327 TI - User interaction in smart ambient environment targeted for senior citizen. AB - Many countries are facing a problem when the age-structure of the society is changing. The numbers of senior citizen are rising rapidly, and caretaking personnel numbers cannot match the problems and needs of these citizens. Using smart, ubiquitous technologies can offer ways in coping with the need of more nursing staff and the rising costs of taking care of senior citizens for the society. Helping senior citizens with a novel, easy to use interface that guides and helps, could improve their quality of living and make them participate more in daily activities. This paper presents a projection-based display system for elderly people with memory impairments and the proposed user interface for the system. The user's process recognition based on a sensor network is also described. Elderly people wearing the system can interact the projected user interface by tapping physical surfaces (such as walls, tables, or doors) using them as a natural, haptic feedback input surface. PMID- 22535329 TI - How much of invasive clinical research is still ethically justified? PMID- 22535330 TI - Uncorrected refractive error in older British adults: the EPIC-Norfolk Eye Study. AB - AIM: To investigate the prevalence of, and demographic associations with, uncorrected refractive error (URE) in an older British population. METHODS: Data from 4428 participants, aged 48-89 years, who attended an eye examination in the third health check of the European Prospective Investigation into Cancer-Norfolk study and had also undergone an ophthalmic examination were assessed. URE was defined as >=1 line improvement of visual acuity with pinhole-correction in the better eye in participants with LogMar presenting visual acuity (PVA) <0.3 (PVA <6/12). Refractive error was measured using an autorefractor without cycloplegia. Myopia was defined as spherical equivalent <=-0.5 dioptre, and hypermetropia >=0.5 dioptre. RESULTS: Adjusted to the 2010 midyear British population, the prevalence of URE in this Norfolk population was 1.9% (95% CI 0.6% to 3.1%). Lower self-rated distance vision was correlated with higher prevalence of URE (p(trend)<0.001). In a multivariate logistic regression model adjusting for age, gender, retirement status, educational level and social class, independent significant associations with URE were increasing age (p(trend)<0.001) and having hypermetropic or myopic refractive error. Wearing distance spectacles was inversely associated with URE (OR 0.34, 95% CI 0.21 to 0.55, p<0.001). There were 3063 people (69.2%) who wore spectacles/contact lenses for distance vision. Spectacle wear differed according to type of refractive error (p<0.001), and use rose with increasing severity of refractive error (p(trend)<0.001). CONCLUSION: Although refractive error is common, the prevalence of URE was found to be low in this population reflecting a low prevalence of PVA<0.3. PMID- 22535331 TI - Patients' preferences in treatment for neovascular age-related macular degeneration in clinical routine. AB - PURPOSE: To assess the effect of ranibizumab treatment for neovascular age related macular degeneration (nvAMD) on patients' preferences and vision-related quality of life (VRQoL) in a routine clinical setting. METHODS: 55 treatment naive patients were examined before and after the initial upload of three monthly injections of 0.5 mg ranibizumab. VRQoL was assessed using a Rasch-adjusted NEI VFQ-25. Time trade-off (TTO), standard gamble, a visual analogue scale and the European Quality of Life Questionnaire (EQ-5D) were used to calculate utilities, and multiple logistic regression models were conducted to determine independent factors associated with utilities. RESULTS: Mean +/- SD age was 75 +/- 7 years, and 40 patients (73%) were female. Mean +/- SD best-corrected visual acuity of the treated eye increased from 20/80 at baseline (logMAR 0.60 +/- 0.35) to 20/63 (logMAR 0.52 +/- 0.36; p=0.020) at follow-up after three injections. Utility score increases ranged from 2 utils (standard gamble anchored for death) up to 6.6 utils (EQ-5D German TTO, p=0.023) and visual functioning improved (Rasch adjusted composite NEI-VFQ score 50 +/- 21 to 54 +/- 21, p=0.042). Whether the worse or better eye was treated was not significantly associated with improvements in utility or VRQoL, whereas VA improvement in the treated eye was associated with an increase in utility (TTO, p=0.020). CONCLUSIONS: TTO performed best in this sample of elderly nvAMD patients undergoing anti-VEGF therapy. Better or worse eye treatment was not associated with a change in reported utilities or visual functioning in patients with newly diagnosed nvAMD. Directly elicited, vision-specific utilities gained with TTO seem to be sensitive to a change in vision status. PMID- 22535333 TI - The value of genetic polymorphisms to predict toxicity in metastatic colorectal patients with irinotecan-based regimens. AB - PURPOSE: We are trying to identify predictive factors of high risk of toxicity by analyzing candidate genes in the irinotecan pathways in order to identify useful tools to improve mCRC patient management under real practice conditions. METHODS: Genomic DNA was genotyped for UGT1A1 (*28, *60 and *93) from all 101 patients, and irinotecan dose was 180 mg/m(2) every second week. Clinical data were obtained by retrospective chart review. The primary endpoint is to find out whether the pharmacogenetic test in the clinical practice may predict toxicity. RESULTS: Grade 3/4 diarrhea occurred in twelve patients and required dose reduction in six patients, and neutropenia reached grade 3/4 in 19 patients (only one patient with *28/*28 genotype). The UGT1A1*93 seemed to relate with grade 3/4 neutropenia but only in the heterozygote state (G/A), p = 0.071, and UGT1A*60 showed no association with neutropenia. Twenty-eight percentage of patients required the use of G-CSF; 64.3% of them harbored *1/*28 or *28/*28 genotypes, p = 0.003. Thirty-seven (36.6%) patients required dose reduction of irinotecan and/or 5-FU owing to toxicity, mainly neutropenia and diarrhea. No significant association was detected between *28, *60 and *93 UGT1A variants and severe irinotecan-associated hematologic or GI toxicity. CONCLUSION: The impact of increased risk of toxicity attributed to the UGT1A variants may be offset by irinotecan in clinical practice by dose reduction or the use of colony stimulating factor. PMID- 22535334 TI - Association of p73 G4C14-A4T14 polymorphisms with genetic susceptibilities to breast cancer: a case-control study. AB - The aim of this study was to evaluate the association of p73 G4C14-A4T14 polymorphisms with susceptibility to breast cancer in Chongqing women of Han Nationality in China. In a case-control study, single-nucleotide polymorphisms of p73 G4C14-A4T14 at exon 2 were genotyped by Sequenom MassArray((r)) iPLEX GOLD System in 170 patients with breast cancer and 178 healthy controls. Data were analyzed via t test, Chi-square test, and logistic regression analysis. The distribution of p73 genotypes and allelotypes had no significant difference between patients with breast cancer and healthy controls (chi(2) = 2.750, P = 0.253; chi(2) = 2.195, P = 0.138). More risk of developing triple negative breast cancer (TNBC) was found in the individuals who carried with GC/GC genotype than individuals carried with GC/AT and AT/AT genotypes (OR = 2.99; 95 % CI, 1.30 6.89; P = 0.010). p73 G4C14-A4T14 polymorphisms are closely associated with the increased risk for TNBC in Chongqing women of Han Nationality in China; GC/GC genotype is susceptible genotype for TNBC in Chongqing women of Han Nationality in China. The patients with breast cancer who carried with GC/GC genotype may have bad prognosis. Additional larger studies are required to confirm these findings. PMID- 22535336 TI - Heart rate regulation processed through wavelet analysis and change detection: some case studies. AB - Heart rate variability (HRV) is an indicator of the regulation of the heart, see Task Force (Circulation 93(5):1043-1065, 1996). This study compares the regulation of the heart in two cases of healthy subjects within real life situations: Marathon runners and shift workers. After an update on the state of the art on HRV processing, we specify our probabilistic model: We choose modeling heartbeat series by locally stationary Gaussian process (Dahlhaus in Ann Stat 25, 1997). HRV is then processed by the combination of two statistical methods: (1) Continuous wavelet transform for calculating the spectral density energy in the high frequency (HF) and low frequency (LF) bands and (2) Change point analysis to detect changes of heart regulation. Next, we plot the variations of the HF and LF energy in extreme conditions for both populations. This puts in light, that physical activities (rest, moderate sport, marathon race) can be ordered in a logical continuum. This allows to define a new index based on HF and LF energy that is log HF + log LF which appears relevant to measure HR regulation. The results obtained are pertinent but have to be completed by further studies. PMID- 22535335 TI - Fabrication of electric papers of graphene nanosheet shelled cellulose fibres by dispersion and infiltration as flexible electrodes for energy storage. AB - An electrically conductive and electrochemically active composite paper of graphene nanosheet (GNS) coated cellulose fibres was fabricated via a simple paper-making process of dispersing chemically synthesized GNS into a cellulose pulp, followed by infiltration. The GNS nanosheet was deposited onto the cellulose fibers, forming a coating, during infiltration. It forms a continuous network through a bridge of interconnected cellulose fibres at small GNS loadings (3.2 wt%). The GNS/cellulose paper is as flexible and mechanically tough as the pure cellulose paper. The electrical measurements show the composite paper has a sheet resistance of 1063 Omega?(-1) and a conductivity of 11.6 S m(-1). The application of the composite paper as a flexible double layer supercapacitor in an organic electrolyte (LiPF(6)) displays a high capacity of 252 F g(-1) at a current density of 1 A g(-1) with respect to GNS. Moreover, the paper can be used as the anode in a lithium battery, showing distinct charge and discharge performances. The simple process for synthesising the GNS functionalized cellulose papers is attractive for the development of high performance papers for electrical, electrochemical and multifunctional applications. PMID- 22535337 TI - Necrotic tumor growth: an analytic approach. AB - The present paper deals with a free boundary problem modeling the growth process of necrotic multi-layer tumors. We prove the existence of flat stationary solutions and determine the linearization of our model at such an equilibrium. Finally, we compute the solutions of the stationary linearized problem and comment on bifurcation. PMID- 22535338 TI - Room temperature asymmetric Pd-catalyzed methoxycarbonylation of norbornene: highly selective catalysis and HP-NMR studies. AB - Palladium complexes bearing monodentate and bidentate phosphine ligands (1-7) were synthesised and used as catalyst precursors in the methoxycarbonylation of norbornene. The catalytic systems bearing ligands 1, 3 and 4 afforded excellent conversions (>99%) and selectivity of the ester (>99%). NMR investigations showed that using complex 1a as the precursor resulted in the protonated phosphine, 1 H(+), being formed under catalytic conditions and thus the addition of acid is not required for the activation of this system since the reaction involving the precursor with methanol under CO pressure produces 2 equivalents of HCl and leads to the formation of the active species. The protonation of ligand 4 under methoxycarbonylation conditions was also observed and the diprotonated diphosphine was isolated and characterised. This compound was tested as a ligand and acid source in a catalysis and provided excellent conversion and high selectivity to the ester. PMID- 22535339 TI - [General rules of the management of diabetes with psychiatric disorders]. AB - BACKGROUND: Psychiatric disorders appear to be frequent in patients with diabetes mellitus. The presence of psychiatric co-morbidity may affect adherence to medication and self-care regimes. AIM: To establish rules of the management of diabetes among people with psychiatric disorders. METHODS: Literature review on the PUBMED database using the following keywords: diabetes, psychiatric disorders, anti-psychotics, complications. RESULTS: Psychiatric disorders appear to be frequent in patients with diabetes mellitus. Their presence is associated with poor glycemic control and more diabetes complications. This negative effect may be increased by taking atypical antipsychotics which expose to several metabolic effects such as overweight, insulin resistance, hyperglycemia, Type 2 diabetes and dyslipidemia. CONCLUSION: The management of diabetes among people with psychiatric disorders should be multidisciplinary including internist, diabetologist, psychiatrist, and paramedical staff. This treatment includes medical (anti-diabetics, anti-psychotics) and psychotherapeutic interventions through which we can have better glycemic control and decreased rates of diabetes complications. PMID- 22535340 TI - [Pathophysiology of complex regional pain syndrome (CRPS) type 1]. AB - BACKGROUND: If the pathophysiology of complex regional pain syndrome (CRPS) type 1 remains controversial, most authors agree on a combination in varying proportions, a sensitization of peripheral nerves. AIM: To describe the state of advances in the physiopathology of complex regional pain syndrome type 1. METHODS: Bibliographic research and literature review performed by referring to databases (Medline, Science Direct) RESULTS: The physiopathology of complex regional pain syndrome type 1 remains still poorly understood and controversial. Several arguments demonstrated both peripheral (inflammation, abnormal sympathetic ...) and central (neurological and cognitive) mechanisms. CONCLUSION: A better knowledge of the physiopathology of complex pain syndrome type 1 is necessary in order to adapt efficient curative therapy or to a better prevention of this syndrome. PMID- 22535332 TI - The brain renin-angiotensin system: a diversity of functions and implications for CNS diseases. AB - The classic renin-angiotensin system (RAS) was initially described as a hormone system designed to mediate cardiovascular and body water regulation, with angiotensin II as its major effector. The discovery of an independent local brain RAS composed of the necessary functional components (angiotensinogen, peptidases, angiotensins, and specific receptor proteins) significantly expanded the possible physiological and pharmacological functions of this system. This review first describes the enzymatic pathways resulting in active angiotensin ligands and their interaction with AT(1), AT(2), and AT(4) receptor subtypes. Next, we discuss the classic physiologies and behaviors controlled by the RAS including cardiovascular, thirst, and sodium appetite. A final section summarizes non classic functions and clinical conditions mediated by the brain RAS with focus on memory and Alzheimer's disease. There is no doubt that the brain RAS is an important component in the development of dementia. It also appears to play a role in normal memory consolidation and retrieval. The presently available anti dementia drugs are proving to be reasonably ineffective, thus alternative treatment approaches must be developed. At the same time, presently available drugs must be tested for their efficacy to treat newly identified syndromes and diseases connected with the RAS. The list of non-classic physiologies and behaviors is ever increasing in both number and scope, attesting to the multidimensional influences of the RAS. Such diversity in function presents a dilemma for both researchers and clinicians. Namely, the blunting of RAS subsystems in the hopes of combating one constellation of underlying causes and disease symptoms may be counter-balanced by unanticipated and unwanted consequences to another RAS subsystem. For example, the use of angiotensin converting enzyme inhibitors and AT(1) and/or AT(2) receptor blockers have shown great promise in the treatment of cardiovascular related pathologies; however, their use could negate the cerebroprotective benefits offered by this system. PMID- 22535341 TI - [Is APRI score a suitable tool for prediction of fibrosis in Tunisian patients with genotype 1 chronic viral hepatitis C?]. AB - BACKGROUND: Therapeutic indications in chronic genotype 1 hepatitis C are based on severity of fibrosis. APRI score is a simple, cheap and reproducible biochemical test. Performances of APRI score in Tunisian population with chronic hepatitis C were not previously prospectively studied. AIM: To evaluate the performances of APRI score in prediction of severity of fibrosis in chronic genotype 1 hepatitis C based on a prospective study. METHODS: We prospectively include patients with chronic genotype 1 hepatitis C and positive viral load. Hepatic biopsy was performed in all included patients and abnormalities were classified according to METAVIR classification. In all patients, APRI score was calculated based on biochemical data collected within the 15 days before hepatic biopsy. RESULTS: We studied 140 patients (46 men, mean age 48.4 years (20 - 65 years)). Mean APRI score was 0.89 (0.18 - 3.72). Statistically significant correlation was observed between APRI score and fibrosis severity (r = 0.31 p < 0.0001). APRI score was higher in patients with severe fibrosis (F2, F3 or F4) compared to patients with moderate fibrosis (F0 or F1) (0.97 + 0.68 vs 0.62 + 0.44; p 0.009). Threshold value of APRI score of 0.72 was associated with area under the curve of 0.65 + 0.05 (0.57 - 0.73), sensitivity of 56.3% and specificity of 75.8% in prediction of severe fibrosis. APRI score was also higher in patients with cirrhosis (1.24 + 0.79 vs 0.85 + 0.61; p = 0.01). Threshold value of 0.86 was associated with area under the curve of 0.69 + 0.07 (0.61 - 0.77), sensitivity of 76.4% and specificity of 65.8% in prediction of cirrhosis. CONCLUSION: APRI score is not a good alternative to hepatic biopsy although a strong correlation with fibrosis severity, because of relatively low area under the curve, sensitivity and specificity in prediction of severe fibrosis and cirrhosis. PMID- 22535342 TI - [Fibroids and pregnancy: complications]. AB - AIM: To study the maternal and fetal morbidity in the association fibroid and pregnancy and the management in this case. METHODS: A retrospective study of 80 cases of fibroids associated to pregnancy. These cases were taken from the department "C" of gynecology and obstetrics in the center of maternity and neonatology of Tunis. RESULTS: We studied 80 cases of fibroid associated to pregnancy in our study. The mean age of the patients was 32 years old. 45 % of the patients were primipares. The interstitial fibroids (68 %) are the most frequent. The average number of fibroid is 1, 7 in each pregnancy. The aseptic necrobiosis is the most frequent complication of the fibroid whereas for the mother the main complications are the premature delivery, the premature rupture of membranes and the placenta praevia during the third term of pregnancy. The dystocic presentations are more frequent than in the general population, responsible of a higher rate of caesarian sections. The delivery hemorrhage constitutes the most frequent complication of the post partum. The fetal prognosis is globally good with a morbidity dominated by growth restrictions but with no superior mortality rate. The myomectomy was practiced during the caesarian section in 3 cases, the abstention being the rule for the other patients. CONCLUSION: The association fibroid and pregnancy is not rare, the complications are frequent that is why it is considered as a high risk pregnancy. An early detection of the complications and a prevention of delivery hemorrhage would reduce the maternal and fetal morbidity. PMID- 22535343 TI - [Use of catecholamines for shock. A continuous debate!]. AB - BACKGROUND: Hypotension and shocks are frequently observed in patients requiring admission in ICU. However, the optimal adrenergic support in shock is controversial. AIM: To perform a descriptive approach of the current use of catecholamine in a medico-surgical ICU in patients with schoks. METHODS: Our study is prospective over 3 month period. Were included all patients admitted in our ICU during the study period's. We compared the populations with and without catecholamine, we analysed the catecholamine selected in various clinical settings and we studied the impact of the use of catecholamine on the patient outcomes. RESULTS: During the study's period, 226 patients were hospitalized in our service and were the subject of this study. The median age (+/- SD) was of 47+/- 24 years. During their hospitalization in the ICU, 132 patients (58.4%) presented a shock. The cardiogenic shock and the hypovolemic shock were the most observed (37.8% and 35.6% respectively). Hundred thirty patients (57.5%) received catecholamines during their stay in ICU. Eighty four patients (64.6% of the patients having received catecholamines) had received dopamine. Sixty two patients (47.7% of the patients having received catecholamines) had received dobutamine, 63 patients (48.5%) had received epinephrine and 22 patients (16.9%) had received norepinephrine. The mean's period of catecholamines use was 5 +/- 4 days. Among drugs proposed in order to manage patients with cardiogenic shock, dobutamine was chosen as the first choice agent in 62% of the cases. Among drugs proposed in order to manage patients with septic shock, Dopamine was chosen as the first choice agent in 85.7 % of the cases. In our study the patients of the class C or D in the Knauss classification are significantly predisposed to receive catecholamines during their ICU stay (OR: 5.3 ; IC 95% : 1.7 - 5.7).Moreover, the needing of catecholamine use is strongly associated with high mortality (OR: 16,8; IC 95% : 16.4 - 49.2). CONCLUSION: The choice of catecholamines is a matter of debate for critically ill patients. The use of catecholamines is a clinical marker of severity and provider of mortality. PMID- 22535344 TI - [Cervical incompetence: diagnosis, indications and cerclage outcome]. AB - BACKGROUND: Cervical incompetence, a major cause of late abortions and preterm delivery is a diagnosis increasingly easy to establish.Strapping is deemed effective to prevent recurrence of such accidents midwifery. AIM: To evaluate the relevance of the diagnosis of cervical incompetence, check the main indications of banding and study the outcome of rimmed pregnancies. METHODS: A retrospective study about 103 rimmed pregnancies collected in the service of Motherhood Hospital Mahmoud El Matri Ariana to the period of January 2001 until December 2008. RESULTS: The diagnosis of cervical incompetence is suspected in a body of evidence linking ATCD of late abortions or premature births found in respectively 46.2% and 31.1% of our patients in our series, 16.98% are carriers of known uterine defects. 8.49% are classified as high risk front of 3-ATCD of late abortions or preterm delivery and were circled systematically. 2.83% are rimmed after confirmation the incompetent cervix by calibration of the cervix and 55.99% because of clinically short cervix. The strapping has reduced the rate of late abortion which decreased from 46.6% before strapping to 7.6% after. As for preterm delivery, it is reduced from 31.1% before strapping to 18.5% after. This difference is statistically significant. The average term of confinement in our series is 36SA six days. 68 cases were delivered at term. Among patients in whom we have accepted the vaginal delivery, 74.2% had spontaneous labor. One case of rupture of the anterior lip of the cervix was noted. CONCLUSION: The indication of a cervical strapping needs a well established diagnosis involving data from history, clinical examination and possibly endo-vaginal ultrasound to confirm the high-risk of cervical incompetence. The strapping participates significantly to prolong the duration of pregnancy, to lower rates of early major premature and to improve the chance of viability and prognosis of fetuses without serious repercussions on the workflow. PMID- 22535345 TI - [Epidemiological profile, etiological diagnosis and prognosis of uterine synechias: report of 86 cases]. AB - BACKGROUND: Uterine synechias may pose real problems for fertility prognosis. It depends mainly on its etiology. AIM: To study the epidemiological profile of patients, describe the circumstances of discovery of uterine synechias, specify the diagnostic procedures for pelvic ultrasound, hysterography and hysteroscopy and estimate the benefits on fertility. METHODS: A retrospective study over a period of 10 years from 1 January 2000 to December 31, 2009 in the department of obstetrics gynecology B Charles Nicolle's Hospital in Tunis. RESULTS: We collected 86 patients. The age average was 35.42 years, gestit average of 1.36 with 37.2% of nulligeste and an average parity of 0.67. The uterine revision was the main etiology (55.8%). The main circumstance of discovery was the exploration of infertility (60%). Hysterosalpingography showed a luminal filling defect in 79% of patients mostly fundic location (37.3%). Faced with data from the hysteroscopy sensitivity of HSG was 78% and positive predictive value was 100%. For the seat of the synechia its sensitivity is only 40%. The surgical procedure took place in one time in 74 cases. Our complication rate is 8.14%: 2 uterine perforations, 2 falseroads and 3 cases of hemorrhage stopping surgery. CONCLUSION: The main etiology is a history of uterus revision. The main circumstance of discovery is the exploration of infertility. Anatomic results were generally good as testified hysteroscopy control. PMID- 22535346 TI - [Effects of tobacco on antipsychotic treatments and their symptoms in schizophrenia]. AB - BACKGROUND: The prevalence of cigarette smoking is significantly higher among patients with schizophrenia than in the general population. Several authors explained this excess of smoking by the self-medication hypothesis. It suggests that patients with schizophrenia smoke to reduce psychotic symptoms or antipsychotic side effects. AIM: In this study, we aimed to evaluate the prevalence of tobacco consumption in patients with schizophrenia and to test if smoking reduces psychotic and extra-pyramidal symptoms. METHODS: We included 115 patients with schizophrenia (DSM IV) treated with conventional antipsychotics. We assessed psychotic symptoms with the Positive and Negative Syndrome Scale (PANSS) and extrapyramidal symptoms with the Simpson-Angus scale. RESULTS: Prevalence of smoking was 60% (80% in men and 22.5% in women). The majority of them started their consumption before their illness. Smokers and non-smokers had similar rates of psychotic and extrapyramidal symptoms with comparable doses of antipsychotics and anticholinergic agents which were prescribed for similar durations. CONCLUSION: In this study, patients with schizophrenia smoke a lot for reasons other than reducing psychotic or extrapyramidal symptoms. PMID- 22535347 TI - [Protein S, C and antithrombin deficiency: association with myocardial infarction and thromboembolism in the young]. AB - BACKGROUND: The pathogenesis of myocardial infarction (MI) in young involves new factors including constitutional or acquired thrombophilia. AIM: To determine in patients 2 50 years, the association between coagulation factors deficiency, myocardial infarction and cardiovascular events during follow-up. METHODS: Protein C (PC), PS and antithrombin (AT) were screened in 50 patients admitted for acute MI and in a healthy control group. Univariate and multivariate analysis were performed using SPSS 11.5 version. RESULTS: PS and PC deficiency were associated to MI (respectively 24% vs 0%, p=0.001 and 14% vs 0%, p=0.016), independently for PC. No AT deficiency was detected in both groups. During followup, PS and C deficiency were predictive for venous thrombosis (p<0.05) and PS deficiency for pulmonary embolism. CONCLUSION: Protein C and S deficiency may play an important role in MI in young and also in thromboembolic complications during follow-up. Nevertheless, therapeutic implications remain controversial. PMID- 22535348 TI - [Contrast-induced nephropathy after cardiac catheterization: a prospective study of 180 patients]. AB - BACKGROUND: Contrast-induced nephropathy (CIN) is associated with an increased cardiovascular morbi-mortality. Little is known about the incidence and risk factors of CIN after cardiac catheterization in Tunisian patients. AIM: To determine the incidence of CIN and its predictors after coronary angiography as well as its prognostic and therapeutic repercussions in a Tunisian patients' cohort. METHODS: In this prospective single center study, 180 consecutive patients who underwent cardiac catheterization were enrolled; all patients were followed-up for 3 months. RESULTS: The incidence of CIN defined as an absolute increase in serum creatinine 3 5 mg/l (44MUmol/l) and/or a relative increase in serum creatinine 3 25%, was 17.2%. In multivariate logistic regression, independent predictors of CIN were: diabetes mellitus (Odds Ratio (OR)=2.26 ; 95% confidence interval (95%CI) : 1.29- 3.98, p=0.005), creatinine clearance < 80ml/mn (OR=2.87 ; 95%CI : 1.59-5.19, p<0.001), left ventricular ejection fraction (LVEF) < 45% (OR=2.03 ; 95%CI : 1.22-3.39, p=0.007) and use of a volume of contrast media > 90ml (1.72 ; 95%CI : 0.99-2.99, p=0.05). Perprocedural hypotension was the strongest independent predictor of CIN in our study (OR=3.99; 95% CI: 1.65-9.66, p=0.002). CIN was totally regressive within one month in 27 patients (86.7%) while 3 patients (10%) had a residual renal dysfunction at the end of the follow-up period (3 months). CONCLUSION: More than one angiocoronarography on 6 resulted in CIN in our population. CIN affects cardiovascular prognosis even if renal function normalization is usually obtained within one month after the investigation. Besides identifying risk factors of CIN in order to apply preventive measures in risky patients, we stress the necessity of insuring a good hemodynamic status while achieving the procedure. PMID- 22535350 TI - Pseudo-tumoral proliferative funiculitis of the spermatic cord. PMID- 22535349 TI - [Occupational low back pain in Tunisia]. AB - BACKGROUND: In Tunisia, eight researches works, dealing with low back trauma (LBT), have been achieved in some occupational sector activities and only 2 of them have been published. AIM: To synthesize data provided by these 8 works realized between 1998 and 2007, in order to estimate the disorder magnitude and to describe LBT victims profile in Tunisia. METHODS: The global population of study is made of 1357 LBT victims (977 belonging to the private sector and 380 to the public sector). The data collection was carried out according to an uniformed model for the 8 studies. RESULTS: In the public sector, Commission Medicale Centrale data show that LBT account for 4 to 5% of occupational accidents (OA) and that their annual incidence is from 32 to 36/100000. In the private sector, Caisse Nationale d'Assurance Maladie data reveal that LBT account for 7.7% to 9.5% of OA. LBT victim is a male (83%), with an age ranging between 36 and 43.5 years, married (84%), educated up to the secondary educational (91%) with a vertebral disorders history (34%). He belongs to the general-purpose workmen category in 1/2 of cases with an average seniority ranging between 7.8 and 16.2 years. LBT almost subjects, get at least of a sick leave. Work days lost is around 210 days for the private sector and 18 days for the public. The per annum amount versed for each LBT case, within the framework of the Total Temporary incapacity, is of 1449.319 DT and 45% of the subjects profit from a professional reclassification. CONCLUSION: Our results join those of international studies having dealt with LBD in professional environment. In spite of some limiting methodological issues, they allowed us to provide to professionals in occupational health useful data for this occupational risk management. PMID- 22535351 TI - [Pyroglutamic aciduria]. PMID- 22535352 TI - [Caudal regression syndrome]. PMID- 22535353 TI - Identification of a novel mutation in the MCFD2 gene in a Tunisian family with combined factor V and VIII deficiency. PMID- 22535354 TI - Association between scalp psoriasis and alopecia areata. PMID- 22535355 TI - [Disseminated peritoneal tuberculosis simulating ovarian cancer]. PMID- 22535356 TI - [Brucellosis endocarditis]. PMID- 22535357 TI - Idiopathic aeroportia and gastric pneumatosis. PMID- 22535358 TI - [Localized malignant mesothelioma of the pleura]. PMID- 22535359 TI - [Primary mediastinal melanoma]. PMID- 22535360 TI - Superficial acral fibromyxoma. PMID- 22535362 TI - Support for a tobacco endgame and increased regulation of the tobacco industry among New Zealand smokers: results from a National Survey. AB - AIM: To examine the prevalence of smoker support for a ban on cigarette sales in 10 years time and increased regulation of the tobacco industry and to investigate the independent associations of support for these measures. METHODS: The authors surveyed opinions among adult smokers in two survey waves (N=1376 and N=923) from the New Zealand arm of the International Tobacco Control Policy Evaluation Survey during 2007-2009. The authors report prevalence of support stratified by age, gender and ethnicity. The authors carried out multivariate analyses to identify significant associations among potential determinants (demographics, socioeconomic status, mental health and smoking-related beliefs and behaviours) of support. RESULTS: Most New Zealand smokers supported greater regulation of the tobacco industry (65%) and more government action on tobacco (59%). Around half (46%) supported banning sales of cigarettes in 10 years time, provided effective nicotine substitutes were available. In a fully adjusted model, significant associations with support for greater tobacco company regulation included Maori ethnicity, experience of financial stress and greater awareness about the harms of smoking. Significant associations with support for a ban on tobacco sales in 10 years time included increasing area-based deprivation level, increasing intention to quit and greater concern about the health effects of smoking. CONCLUSIONS: The findings suggest that most smokers will support stronger government action to control the tobacco industry and that many support radical 'endgame' approaches. Greater support among Maori, more deprived and possibly Pacific smokers, is an important finding, which could inform the design and implementation of new policies given the very high smoking prevalence among these groups and hence high priority for targeted tobacco control interventions. Perceived difficulties in gaining public support should not impede the introduction of rigorous tobacco control measures needed to achieve a tobacco free New Zealand. PMID- 22535361 TI - Antifungal effect of 4-arylthiosemicarbazides against Candida species. Search for molecular basis of antifungal activity of thiosemicarbazide derivatives. AB - The in vitro antifungal potency of six series of 4-arylthiosemicarbazides was evaluated. Two isoquinoline derivatives with an ortho-methoxy or ortho-methyl group at the phenyl ring were the most potent antifungal agents. Molecular modeling studies and docking of all 4-arylthiosemicarbazides into the active sites of sterol 14alpha-demethylase (CYP51), topoisomerase II (topo II), L: glutamine: D: -fructose-6-phosphate amidotransferase (GlcN-6-P), secreted aspartic proteinase (SAP), N-myristoyltransferase (NMT), and UDP-N-acetylmuramoyl L: -alanine:D: -glutamate ligase (MurD) indicated the importance of both structural and electronic factors in ligand recognition and thus for the antifungal effectiveness of 4-arylthiosemicarbazides. A possible antifungal target was identified (NMT) and isoquinoline-thiosemicarbazides showed more favorable affinity than the native ligand. PMID- 22535364 TI - The potential impact of smoking control policies on future global smoking trends. AB - BACKGROUND: The authors develop projections for global smoking prevalence for the years 2020 and 2030 with and without the implementation, starting in 2010, of the WHO's recommended multipronged approach to tobacco control known as the MPOWER policy package. METHODS: Using data from the WHO's Global InfoBase Database and the WHO's Global Adult Tobacco Survey, the authors construct adult cigarette smoking prevalence time series for 60 countries that account for 90% of the world's smokers and 85% of the world's population. The authors then use a stock/flow model to project those countries' smoking prevalence for the years 2020 and 2030, with and without the implementation of MPOWER. The authors aggregate the results and report regional and global figures. RESULTS: The authors estimate global adult cigarette smoking prevalence in 2010 to be 23.7%. If no additional policies are set in place and the initiation and cessation rates existing in 2010 persist, the authors estimate that global prevalence will be 22.7% by 2020 and 22.0% by 2030 (872 million smokers). If MPOWER had been implemented globally starting in 2010 with a 100% price increase for cigarettes, the authors estimate that global cigarette smoking prevalence would be 15.4% in 2020 and 13.2% in 2030 (523 million smokers). CONCLUSIONS: The estimates indicate the magnitude and trajectory of the global tobacco pandemic and of the impact the authors could expect if evidence-based tobacco control policies were applied immediately and universally throughout the world. As half of lifetime smokers die of tobacco-related diseases, if MPOWER were applied globally, within a few decades, many millions of premature tobacco-related deaths would be avoided. PMID- 22535363 TI - Cigarette packet warning labels can prevent relapse: findings from the International Tobacco Control 4-Country policy evaluation cohort study. AB - OBJECTIVES: To investigate the links between health warning labels (WLs) on cigarette packets and relapse among recently quit smokers. DESIGN: Prospective longitudinal cohort survey. SETTING: Australia, Canada, the UK and the USA. PARTICIPANTS: 1936 recent ex-smokers (44.4% male) from one of the first six waves (2002-2007) of the International Tobacco Control 4-Country policy evaluation survey, who were followed up in the next wave. MAIN OUTCOME MEASURES: Whether participants had relapsed at follow-up (approximately 1 year later). RESULTS: In multivariate analysis, very frequent noticing of WLs among ex-smokers was associated with greater relapse 1 year later (OR: 1.52, 95% CI 1.11 to 2.09, p<0.01), but this effect disappeared after controlling for urges to smoke and self-efficacy (OR: 1.29, 95% CI 0.92 to 1.80, p=0.135). In contrast, reporting that WLs make staying quit 'a lot' more likely (compared with 'not at all' likely) was associated with a lower likelihood of relapse 1 year later (OR: 0.65, 95% CI 0.49 to 0.86, p<0.01) and this effect remained robust across all models tested, increasing in some. CONCLUSIONS: This study provides the first longitudinal evidence that health warnings can help ex-smokers stay quit. Once the authors control for greater exposure to cigarettes, which is understandably predictive of relapse, WL effects are positive. However, it may be that ex smokers need to actively use the health consequences that WLs highlight to remind them of their reasons for quitting, rather than it being something that happens automatically. Ex-smokers should be encouraged to use pack warnings to counter urges to resume smoking. Novel warnings may be more likely to facilitate this. PMID- 22535365 TI - Denitrification potential of the Northern Arabian Gulf--an experimental study. AB - The study aims to establish denitrification potential of the Northern Arabian Gulf (NAG), as nitrogen critically affects the ocean productivity, obliterates acidity, oxidative capacity and radiative transfer capability of atmosphere. The experimental study was conducted by taking cores from intertidal zones from two different sites in North and South, referred as sites N and S; representing two distinct environmental milieu. The experiment was conducted in controlled laboratory conditions simulating the tidal cycles. Multiple cores were taken and loaded with seawater with different N concentrations, the redox potential was established for each condition. Redox potential was significantly lower at 10 cm depth compared to the surface in all cores (P < 0.001). The redox potential at surface and at 10 cm depth was significantly lower at site S compared to site N (P < 0.001; F = 714.2), suggesting anaerobic sediments at site S. Effects of nitrate spiked seawater on denitrification under nonflooded and flooded conditions at the two sites were also studied. Three-way ANOVA analysis indicated that site, nitrate concentration, and flooding had significant main and interactive effects on the rate of denitrification. The results suggest that under ambient nitrate concentrations (0.03 mg NO(3)-N l(-1)), 6.3 +/- 2.1 g NO(3) N ha day can be denitrified by inter-tidal zone sediments. At a nitrate concentration of 1 mg NO(3)-N l(-1), 92 +/- 16 g NO(3)-N ha day may be denitrified whilst at a very high nitrate load of 10 mg NO(3)-N l(-1), the sediments may attain a rate of denitrification close to 404 +/- 78 g NO(3)-N ha day. PMID- 22535366 TI - Seasonal variation of Sarpa salpa fish toxicity, as related to phytoplankton consumption, accumulation of heavy metals, lipids peroxidation level in fish tissues and toxicity upon mice. AB - The aim of this work was to investigate for Sarpa salpa the seasonal trend in the food sources, heavy metals bioaccumulation and the oxidative stress in the organs. In addition, the toxicity was assessed by mouse bioassay of extract of the fish's organs collected in autumn, the peak of occurrence of hallucinatory syndrome. The toxicity was further studied for compounds present in epiphyte collected from the sea at the end of spring and in summer that are digested by the S. salpa in these seasons. We observed a higher lipid peroxydation in different tissues of S. salpa compared to the control fish Diplodus annularis. Furthermore, heavy metals accumulation in organs of these fish showed a significant variation between the two species (P < 0.05). The lethal dose (LD50%) determined for crude ciguatoxin (neurotoxins) extracts of viscera, liver, brain and muscle of S. salpa were as follows: 1.217, 2.195, 14.395, 18.645 g/kg mouse, respectively. We noticed a significant correlation (P < 0.05) between the total amount of toxic dinoflagellates and the level of TBARS in the liver, the brain and the muscle, this for all seasons and all sizes. Moreover, the cytotoxic effect observed for epiphytes extract confirms the transfer of toxins originating from toxic dinoflagellates, which live as epiphytes on P. oceanica leaves, to the fish by grazing. Our work indicates that, toxic phytoplanktons and heavy metals accumulation are responsible for the increase of oxidative stress in the organs of S. salpa. Hence, the edible part of S. salpa, especially the viscera and liver, can cause a threat to human health, and consumption should, for this reason, be dissuaded. PMID- 22535367 TI - Relationships between watershed emergy flow and coastal New England salt marsh structure, function, and condition. AB - This study evaluated the link between watershed activities and salt marsh structure, function, and condition using spatial emergy flow density (areal empower density) in the watershed and field data from 10 tidal salt marshes in Narragansett Bay, RI, USA. The field-collected data were obtained during several years of vegetation, invertebrate, soil, and water quality sampling. The use of emergy as an accounting mechanism allowed disparate factors (e.g., the amount of building construction and the consumption of electricity) to be combined into a single landscape index while retaining a uniform quantitative definition of the intensity of landscape development. It expanded upon typical land use percentage studies by weighting each category for the intensity of development. At the RI salt marsh sites, an impact index (watershed emergy flow normalized for marsh area) showed significant correlations with mudflat infauna species richness, mussel density, plant species richness, the extent and density of dominant plant species, and denitrification potential within the high salt marsh. Over the 4 year period examined, a loading index (watershed emergy flow normalized for watershed area) showed significant correlations with nitrite and nitrate concentrations, as well as with the nitrogen to phosphorus ratios in stream discharge into the marshes. Both the emergy impact and loading indices were significantly correlated with a salt marsh condition index derived from intensive field-based assessments. Comparison of the emergy indices to calculated nitrogen loading estimates for each watershed also produced significant positive correlations. These results suggest that watershed emergy flow is a robust index of human disturbance and a potential tool for rapid assessment of coastal wetland condition. PMID- 22535370 TI - Thrombin activatable fibrinolysis inhibitor and thrombin-antithrombin-III-complex levels in patients with gastric cancer. AB - The relation between cancer and coagulation is the subject of investigation since a relation between tumor and thrombosis has been determined. Antithrombin III is an important thrombin inhibitor, and increased thrombin-antithrombin (TAT) complex levels activate coagulation. Activated thrombin activatable fibrinolysis inhibitor (TAFI) inhibits the conversion of plasminogen to plasmin. In addition, it directly inactivates plasmin. Defective fibrinolysis increases the risk of thrombosis. In this study, we evaluated homeostatic parameters, TAFI, and TAT levels in patients with gastric cancer applying to the medical oncology outpatient clinic. Fifty-two patients and 35 healthy controls were included. ELISA was used to measure TAFI and TAT complex levels. These were statistically higher in the patient group (p < 0.05 and p = 0.001, respectively). D-dimer levels were higher in stage IV (p = 0.05). Correlations between lymph nodes and TAFI and TAT levels were examined. Weak but positive correlation between lymph nodes and TAFI was detected (R = 0.452, p = 0.027). TAFI and TAT levels were evaluated using relative operating characteristic analysis to differentiate the disease. TAT was more specific than TAFI according to this analysis (TAFI area under curve (AUC), 0.676; TAT AUC, 0.874). Thrombotic events and bleeding disorders need to be borne in mind in gastric cancer. This situation is due to the impairment of the balance between coagulation and fibrinolysis. Further studies are now needed to evaluate the effects of TAFI and TAT on survey and prognosis as well as the potential of these parameters as tumor markers for gastric cancer. PMID- 22535371 TI - JDP2 inhibits the epithelial-to-mesenchymal transition in pancreatic cancer BxPC3 cells. AB - Pancreatic carcinoma is one of the most malignant and aggressive cancers. Increased motility and invasiveness of pancreatic cancer cells are believed to be associated with epithelial-to-mesenchymal transition (EMT). However, the molecular basis of EMT in pancreatic cancer cells is poorly understood. In this study, we examined the relationship between Jun dimerization protein 2 (JDP2), which is an AP-1 inhibitor, and EMT in human pancreatic carcinoma cells. We demonstrated that transforming growth factor-beta1 (TGF-beta1) promoted epidermal growth factor (EGF)-induced EMT in co-treated human pancreatic BxPC3 cells and that JDP2 overexpression reversed the EMT that was induced by co-treatment with TGF-beta1 and EGF. These results suggest that EGF plays a principal role in EMT through its association with TGF-beta1 in human pancreatic BxPC3 cells and that JDP2 may be a molecular target for pancreatic carcinoma intervention. PMID- 22535372 TI - mTNF reverse signalling induced by TNFalpha antagonists involves a GDF-1 dependent pathway: implications for Crohn's disease. AB - OBJECTIVE: Mechanisms of action (MoA) of anti-tumour necrosis factor alpha (TNFalpha) therapies in Crohn's disease (CD) may critically involve induction of immune cell apoptosis via membrane-bound TNFalpha (mTNFalpha) binding. Certolizumab pegol (CZP), which is effective in induction and maintenance of remission in CD lacks the ability to induce apoptosis. The aim of this study was to analyse transcriptomal responses of reverse signalling induced by the TNFalpha binding agents infliximab (IFX) and CZP in myelomonocytic cells. DESIGN: Induction of transcriptional patterns upon anti-TNFalpha stimulation was assessed using oligonucleotide microarrays. mRNA expression of GDF-1/ LASS1, which was identified as a shared target, was studied in inflammatory bowel disease by real time PCR, while signalling pathways induced by growth and differentiation factor 1 (GDF-1) were investigated using western blots and ELISA. RESULTS: IFX and CZP induced a common signature of 20 transcripts that could be categorised into control of cell cycle, transcription activation and pre-mRNA processing. We selected GDF-1/LASS1 for functional follow-up, which was found to be upregulated in inflamed CD tissues. We show that downregulation of GDF-1/LASS1 depends on autocrine release of transforming growth factor beta after mTNFalpha ligation. We demonstrate that GDF-1 itself acts as a novel proinflammatory factor via induction of interleukin 6 and signal transducer and activator of transcription 3 and is downregulated after IFX treatment. CONCLUSION: Commonalities in the MoA of IFX and CZP comprise modulation of non-apoptotic pathways through downregulation of proinflammatory GDF-1. Further characterisation of the molecular role of GDF-1 in complex inflammatory processes in vivo is warranted to decide whether this proinflammatory molecule is a promising therapeutic target in patients with CD. PMID- 22535373 TI - CHIP functions as a novel suppressor of tumour angiogenesis with prognostic significance in human gastric cancer. AB - OBJECTIVE: CHIP (carboxy terminus of Hsc70 interacting protein) is an E3 ubiquitin ligase that can induce ubiquitination and degradation of several tumour related proteins, and acts as a suppressor of tumour metastasis. This study explored the biological function and clinical significance of CHIP in gastric cancer (GC). METHODS: The prognostic value of CHIP expression was evaluated using tissue microarray and immunohistochemical staining in two independent human GC cohorts. The role of CHIP on tumorigenicity and angiogenesis was determined in vitro and in vivo. RESULTS: CHIP expression was significantly decreased in GC lesions compared with paired non-cancerous tissues. Low tumoral CHIP expression significantly correlated with clinicopathological characteristics in patients, as well as with shorter overall survival in both cohorts. Multivariate Cox regression analysis revealed that CHIP expression was an independent prognostic factor for human GC patients. Moreover, CHIP overexpression impeded the formation of anchorage independent colonies in soft agar, suppressed the growth of xenografts in nude mice and inhibited endothelial cell growth and tube formation by suppressing nuclear factor kappaB (NF-kappaB) mediated interleukin 8 (IL-8) expression in vitro. In vivo studies also confirmed that CHIP inhibited blood vessel formation and recruitment of CD31 positive cells in matrigel plugs. Also, CHIP interacted with NF-kappaB/p65 and promoted its ubiquitination and degradation by proteasome, terminating NF-kappaB activity and inhibiting IL-8 induced angiogenesis, which correlated with subsequent tumour metastasis. CONCLUSIONS: Decreased CHIP expression in GC resulted in increased angiogenesis and contributed to GC progression and poor prognosis. CHIP expression is a GC candidate clinical prognostic marker and a putative treatment target. PMID- 22535374 TI - Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression through paracrine neuregulin 1/HER3 signalling. AB - OBJECTIVE: Bone marrow-derived mesenchymal stem cells (BM-MSC) migrate to primary tumours and drive tumour progression. This study aimed to identify the molecular mechanisms associated with these heterotypic cellular interactions and analyse their relevance in colorectal cancer (CRC). DESIGN: Paracrine interactions of BM MSC with CRC cells were studied using collagen invasion assays, cell counts, flow cytometric cell-cycle analysis and tumour xenograft models. The role of neuregulin 1 (NRG1) and the human epidermal growth factor receptor (HER) family pathways were investigated using tyrosine kinase assays, mass spectrometry, pharmacological inhibition, antibody-mediated neutralisation and RNA interference. Transmembrane neuregulin 1 (tNRG1), HER2 and HER3 expression was analysed in primary CRC (n=54), adjacent normal colorectal tissues (n=4), liver metastases (n=3) and adjacent normal liver tissues (n=3) by immunohistochemistry. RESULTS: BM-MSC stimulate invasion, survival and tumorigenesis of CRC through the release of soluble NRG1, activating the HER2/HER3-dependent PI3K/AKT signalling cascade in CRC cells. Similarly, tumour-associated mesenchymal cells (T-MC) in CRC demonstrate high tNRG1 expression, which is significantly associated with advanced Union for International Cancer Control stage (p=0.005) and invasion depth (p=0.04) and decreased 5-year progression-free survival (p=0.01). HER2 and HER3 show membrane localisation in cancer cells of CRC tissue. CONCLUSION: Paracrine NRG1/HER3 signals initiated by BM-MSC and T-MC promote CRC cell progression, and high tNRG1 expression is associated with poor prognosis in CRC. PMID- 22535375 TI - Integrated epigenomics identifies BMP4 as a modulator of cisplatin sensitivity in gastric cancer. AB - OBJECTIVE: Cisplatin is a widely used gastric cancer (GC) chemotherapy; however, genetic factors regulating GC responses to cisplatin remain obscure. Identifying genes regulating cisplatin resistance could aid clinicians in tailoring treatments, by distinguishing cisplatin sensitive patients from those who might benefit from alternative platinum therapies, and highlight novel targeted strategies for overcoming cisplatin resistance. Here integrated epigenomics is applied to identify genes associated with GC cisplatin resistance. DESIGN: 20 GC cell lines were subjected to gene expression profiling, DNA methylation profiling and drug response assays. The molecular data were integrated to identify genes highly expressed and unmethylated specifically in cisplatin-resistant lines. Candidate genes were functionally tested by several in vitro and in vivo assays. Clinical impact of candidate genes was also assessed in a cohort of 197 GC patients. RESULTS: Epigenomic analysis identified bone morphogenetic protein 4 (BMP4) as an epigenetically regulated gene highly expressed in cisplatin resistant lines. Functional assays confirmed that BMP4 is necessary and sufficient for the expression of several prooncogenic traits, likely mediated through stimulation of the epithelial-mesenchymal transition. In primary tumours, BMP4 promoter methylation levels were inversely correlated with BMP4 expression, and patients with high BMP4-expressing tumours exhibited significantly worse prognosis. Therapeutically, targeted genetic inhibition of BMP4 caused significant sensitisation of GC cells to cisplatin. Notably, BMP4-expressing GCs also did not exhibit cross resistance to oxaliplatin. CONCLUSIONS: BMP4 epigenetic and expression status may represent promising biomarkers for GC cisplatin resistance. Targeting BMP4 may sensitise GC cells to cisplatin. Oxaliplatin, a clinically acceptable cisplatin alternative, may represent a potential therapeutic option for BMP4-positive GCs. PMID- 22535376 TI - Hepatocellular adenoma as a risk factor for hepatocellular carcinoma in a non cirrhotic liver: a plea against. PMID- 22535377 TI - Gut-derived lipopolysaccharide augments adipose macrophage accumulation but is not essential for impaired glucose or insulin tolerance in mice. AB - BACKGROUND: Obesity is associated with accumulation of macrophages in white adipose tissue (WAT), which contribute to the development of insulin resistance. Germ-free (GF) mice have reduced adiposity and are protected against diet-induced obesity, OBJECTIVE: To investigate whether the gut microbiota and, specifically, gut-derived lipopolysaccharide (LPS) promote WAT inflammation and contribute to impaired glucose metabolism. METHOD: Macrophage composition and expression of proinflammatory and anti-inflammatory markers were compared in WAT of GF, conventionally raised and Escherichia coli-monocolonised mice. Additionally, glucose and insulin tolerance in these mice was determined. RESULTS: The presence of a gut microbiota resulted in impaired glucose metabolism and increased macrophage accumulation and polarisation towards the proinflammatory M1 phenotype in WAT. Monocolonisation of GF mice for 4 weeks with E. coli W3110 or the isogenic strain MLK1067 (which expresses LPS with reduced immunogenicity) resulted in impaired glucose and insulin tolerance and promoted M1 polarisation of CD11b cells in WAT. However, colonisation with E. coli W3110 but not MLK1067 promoted macrophage accumulation and upregulation of proinflammatory and anti inflammatory gene expression as well as JNK phosphorylation. CONCLUSION: Gut microbiota induced LPS-dependent macrophage accumulation in WAT, whereas impairment of systemic glucose metabolism was not dependent on LPS. These results indicate that macrophage accumulation in WAT does not always correlate with impaired glucose metabolism. PMID- 22535378 TI - A microRNA panel to discriminate carcinomas from high-grade intraepithelial neoplasms in colonoscopy biopsy tissue. AB - OBJECTIVE: It is a challenge to differentiate invasive carcinomas from high-grade intraepithelial neoplasms in colonoscopy biopsy tissues. In this study, microRNA profiles were evaluated in the transformation of colorectal carcinogenesis to discover new molecular markers for identifying a carcinoma in colonoscopy biopsy tissues where the presence of stromal invasion cells is not detectable by microscopic analysis. METHODS: The expression of 723 human microRNAs was measured in laser capture microdissected epithelial tumours from 133 snap-frozen surgical colorectal specimens. Three well-known classification algorithms were used to derive candidate biomarkers for discriminating carcinomas from adenomas. Quantitative reverse-transcriptase PCR was then used to validate the candidates in an independent cohort of macrodissected formalin-fixed paraffin-embedded colorectal tissue samples from 91 surgical resections. The biomarkers were applied to differentiate carcinomas from high-grade intraepithelial neoplasms in 58 colonoscopy biopsy tissue samples with stromal invasion cells undetectable by microscopy. RESULTS: One classifier of 14 microRNAs was identified with a prediction accuracy of 94.1% for discriminating carcinomas from adenomas. In formalin-fixed paraffin-embedded surgical tissue samples, a combination of miR 375, miR-424 and miR-92a yielded an accuracy of 94% (AUC=0.968) in discriminating carcinomas from adenomas. This combination has been applied to differentiate carcinomas from high-grade intraepithelial neoplasms in colonoscopy biopsy tissues with an accuracy of 89% (AUC=0.918). CONCLUSIONS: This study has found a microRNA panel that accurately discriminates carcinomas from high-grade intraepithelial neoplasms in colonoscopy biopsy tissues. This microRNA panel has considerable clinical value in the early diagnosis and optimal surgical decision making of colorectal cancer. PMID- 22535380 TI - Ischemia hypothermia improved contractility under normothermia reperfusion in the model of cultured cardiomyocyte. AB - Though mild hypothermia displays an optimistic alleviation of contractive failure in the ischemia/reperfusion myocardium, we still lacked answers to many questions about its potential mechanisms. Our hypothesis is that hypothermia (32 degrees C) induced in ischemia can ease mitochondrial injury resulting in improvement of myocardial contractility even under the condition of a normothermic reperfusion. Fifty newly born 1-2 d Sprague-Dawley rats were executed and the primary cardiomyocytes were obtained and cultivated in vitro. Myocytes were randomized into three groups and then subjected to ischemia either at 32 degrees C or 37 degrees C, both prior to undergoing reperfusion at 37 degrees C. Contractility was presented as frequency and velocity. Ultrastructural alterations of cardiomyocytes and mitochondrion underwent semi-quantitative analysis with transmission electron microscopy and respiratory function of mitochondria was further assessed simultaneously. During cooling ischemia and following reperfusion, cardiomyocytes acquired a more immediate restoration to baseline level and had a significant difference as compared with those in normothermia (P < 0.05). Furthermore, hypothermia preserved the ultrastructure of myocytes and mitochondrion after ischemia. However, measurement on Heart Injury Score and form factor revealed no differences after 2-h reperfusion either in hypothermia or normothermia. On the contrary, the surface area and respiratory function of mitochondrion in reperfusion differed significantly in both groups (P < 0.05) which had an accordance with the variation on contractile performance. Hypothermia only induced in ischemia can bring contractility benefit even under a normothermia reperfusion in cultured cardiomyocytes. PMID- 22535379 TI - Transcriptional response of Medicago truncatula sulphate transporters to arbuscular mycorrhizal symbiosis with and without sulphur stress. AB - Sulphur is an essential macronutrient for plant growth, development and response to various abiotic and biotic stresses due to its key role in the biosynthesis of many S-containing compounds. Sulphate represents a very small portion of soil S pull and it is the only form that plant roots can uptake and mobilize through H(+)-dependent co-transport processes implying sulphate transporters. Unlike the other organically bound forms of S, sulphate is normally leached from soils due to its solubility in water, thus reducing its availability to plants. Although our knowledge of plant sulphate transporters has been growing significantly in the past decades, little is still known about the effect of the arbuscular mycorrhiza interaction on sulphur uptake. Carbon, nitrogen and sulphur measurements in plant parts and expression analysis of genes encoding putative Medicago sulphate transporters (MtSULTRs) were performed to better understand the beneficial effects of mycorrhizal interaction on Medicago truncatula plants colonized by Glomus intraradices at different sulphate concentrations. Mycorrhization significantly promoted plant growth and sulphur content, suggesting increased sulphate absorption. In silico analyses allowed identifying eight putative MtSULTRs phylogenetically distributed over the four sulphate transporter groups. Some putative MtSULTRs were transcribed differentially in roots and leaves and affected by sulphate concentration, while others were more constitutively transcribed. Mycorrhizal-inducible and -repressed MtSULTRs transcripts were identified allowing to shed light on the role of mycorrhizal interaction in sulphate uptake. PMID- 22535381 TI - Graphenes prepared by Staudenmaier, Hofmann and Hummers methods with consequent thermal exfoliation exhibit very different electrochemical properties. AB - Large-scale fabrication of graphene is highly important for industrial and academic applications of this material. The most common large-scale preparation method is the oxidation of graphite to graphite oxide using concentrated acids in the presence of strong oxidants and consequent thermal exfoliation and reduction by thermal shock to produce reduced graphene. These oxidation methods typically use concentrated sulfuric acid (a) in combination with fuming nitric acid and KClO(3) (Staudenmaier method), (b) in combination with concentrated nitric acid and KClO(3) (Hofmann method) or (c) in the absence of nitric acid but in the presence of NaNO(3) and KMnO(4) (Hummers method). The evaluation of quality and applicability of the graphenes produced by these various methods is of high importance and is attempted side-by-side for the first time in this paper. Full scale characterization of thermally reduced graphenes prepared by these standard methods was performed with techniques such as transmission and scanning electron microscopy, Raman spectroscopy and X-ray photoelectron spectroscopy. Their applicability for electrochemical devices was further evaluated by means of cyclic voltammetry techniques. We showed that while Staudenmaier and Hofmann methods (methods that do not use potassium permanganate as oxidant) generated thermally reduced graphenes with comparable electrochemical properties, the graphene prepared by the Hummers method which uses permanganate as oxidant showed higher heterogeneous electron transfer rates and lower overpotentials as compared to graphenes prepared by the Staudenmaier or Hofmann methods. This clearly shows that the methods of preparations have dramatic influences on the materials properties and, thus, such findings are of eminent importance for practical applications as well as for academic research. PMID- 22535382 TI - Hypoxia-inducible factors and their roles in energy metabolism. AB - Over the course of evolution, aerobic organisms have developed sophisticated systems for responding to alterations in oxygen concentration, as oxygen acts as a final electron acceptor in oxidative phosphorylation for energy production. Hypoxia-inducible factor (HIF) plays a central role in the adaptive regulation of energy metabolism, by triggering a switch from mitochondrial oxidative phosphorylation to anaerobic glycolysis in hypoxic conditions. HIF also reduces oxygen consumption in mitochondria by inhibiting conversion of pyruvate to acetyl CoA, suppressing mitochondrial biogenesis and activating autophagy of mitochondria concomitantly with reduction in reactive oxygen species production. In addition, metabolic reprogramming in response to hypoxia through HIF activation is not limited to the regulation of carbohydrate metabolism; it occurs in lipid metabolism as well. Recent studies using in vivo gene-targeting technique have revealed unexpected, but novel functions of HIF in energy metabolism in a context- and cell type-specific manner, and shed light on the possibility of pharmaceutical targeting HIF as a new therapy against many diseases, including cancer, diabetes, and fatty liver. PMID- 22535383 TI - Quantitative assessment of tumor angiogenesis using real-time motion-compensated contrast-enhanced ultrasound imaging. AB - PURPOSE: To develop and test a real-time motion compensation algorithm for contrast-enhanced ultrasound imaging of tumor angiogenesis on a clinical ultrasound system. MATERIALS AND METHODS: The Administrative Institutional Panel on Laboratory Animal Care approved all experiments. A new motion correction algorithm measuring the sum of absolute differences in pixel displacements within a designated tracking box was implemented in a clinical ultrasound machine. In vivo angiogenesis measurements (expressed as percent contrast area) with and without motion compensated maximum intensity persistence (MIP) ultrasound imaging were analyzed in human colon cancer xenografts (n = 64) in mice. Differences in MIP ultrasound imaging signal with and without motion compensation were compared and correlated with displacements in x- and y-directions. The algorithm was tested in an additional twelve colon cancer xenograft-bearing mice with (n = 6) and without (n = 6) anti-vascular therapy (ASA-404). In vivo MIP percent contrast area measurements were quantitatively correlated with ex vivo microvessel density (MVD) analysis. RESULTS: MIP percent contrast area was significantly different (P < 0.001) with and without motion compensation. Differences in percent contrast area correlated significantly (P < 0.001) with x- and y-displacements. MIP percent contrast area measurements were more reproducible with motion compensation (ICC = 0.69) than without (ICC = 0.51) on two consecutive ultrasound scans. Following anti-vascular therapy, motion-compensated MIP percent contrast area significantly (P = 0.03) decreased by 39.4 +/- 14.6 % compared to non treated mice and correlated well with ex vivo MVD analysis (Rho = 0.70; P = 0.05). CONCLUSION: Real-time motion-compensated MIP ultrasound imaging allows reliable and accurate quantification and monitoring of angiogenesis in tumors exposed to breathing-induced motion artifacts. PMID- 22535385 TI - Identification of differentially expressed genes involved in early bolting of Angelica sinensis (Apiaceae). AB - Angelica sinensis is a highly valued medicinal herb, known as female ginseng that is widely cultivated in China. Although A. sinensis is in great demand due to its multiple medicinal and food applications, its early bolting rate (almost 40%) seriously affects crop quality. To better understand its flowering mechanism, cDNA-amplified RFLP analysis was employed to look for gene expression differences between flower bud and shoot apical meristem tissues. Sixty-four primer sets were used, with each primer set amplified to 60 transcript-derived fragments. Some transcript-derived fragments were expressed only in the flower bud. After cloning, sequencing and a homology search, 46 distinct sequences were obtained; 26 of these were found to have homologous sequences in databases. These included trans-caffeoyl-CoA 3-O-methyltransferase, 1-deoxy-d-xylulose 5 phosphate reductoisomerase, 15-cis-zeta-carotene isomerase, isoamylase, and calmodulin-binding protein. These genes are closely related to pollen germination and pollen tube growth, terpenoid backbone biosynthesis, and other metabolic pathways. Confirmation of differential expression of 10 sequences was obtained by semi-quantitative RT-PCR, showing higher expression levels in flower buds. PMID- 22535384 TI - Molecular cloning and tissue distribution of the Toll receptor in the black tiger shrimp, Penaeus monodon. AB - The black tiger shrimp (Penaeus monodon) is economically important in many parts of the world, including Thailand. Shrimp immunity is similar to that of other invertebrate organisms; it consists of an innate immunity system. Toll or Toll-like receptors (TLRs) play an essential role in recognizing the cleaved form of the cytokine Spatzle, which is processed by a series of proteolytic cascades activated by secreted recognition molecules. We isolated a full-length Toll receptor from P. monodon. The cloned full-length sequence of the PmToll cDNA consists of 4144 nucleotides, containing a 5'-UTR with 366 nucleotides, a 3'-terminal UTR with 985 nucleotides, with a classical polyadenylation signal sequence AATAAA, a poly A-tail with 27 nucleotides, and an open reading frame coding for 931 amino acids. The deduced amino acid sequence of PmToll is a typical type I membrane domain protein, characteristic of TLR functional domains. It includes a putative signal peptide, an extracellular domain consisting of leucine-rich repeats, flanked by cysteine-rich motifs, a single pass transmembrane portion, and a cytoplasmic TLR domain. PmToll was expressed in all tissues tested, including gill, hemocytes, heart, hepatopancreas, lymphoid organs, muscle, nerve, pleopod, stomach, testis, and ovary. The deduced amino acid of PmToll is closely related to that of other shrimp Tolls, especially FcToll. Further studies elucidating the mechanism of action of Tolls will be of benefit for understanding the defense mechanisms of this economically important aquatic species. PMID- 22535386 TI - Genetic diversity and differentiation in Camellia reticulata (Theaceae) polyploid complex revealed by ISSR and ploidy. AB - Camellia reticulata is a well-known ornamental and oil plant that is endemic to southwest China. This species shows three cell ploidies, i.e., diploidy, tetraploidy and hexaploidy. We made the first investigation of genetic diversity and differentiation of natural populations of C. reticulata, and 114 individuals from 6 populations were sampled. Cytogeography results showed that ploidy is invariable within populations and evenly distributed. A relatively high level of genetic diversity was found in C. reticulata, both at the species level (PPB = 88.89%; H = 0.2809; I = 0.4278) and at the population level (mean PPB = 42.13%; mean H = 0.14; mean I = 0.21). We found a relatively low degree of differentiation among ploidies (G(ST) = 0.2384; AMOVA = 10.26%) and a relatively high degree of differentiation among populations (G(CS) = 0.3807; AMOVA = 48.75%). The high genetic diversity can be explained by its biological character, wide distribution and ploidies, and the special genetic structure can be ascribed to polyploid origin from hybridization with different Camellia spp. This information will be useful for the introduction, conservation and further studies of C. reticulata and related species. PMID- 22535387 TI - Establishment of an in vitro regeneration system for genetic transformation of selected sugarcane genotypes. AB - A good culture system provides considerable quantities of highly regenerable target tissues. Embryogenic callus cultures are ideal for micro-projectile mediated transformation, because regenerable cells are not very stable. Effective exploitation of genetic transformation requires good regeneration systems. We selected three sugarcane genotypes for the establishment and optimization of good in vitro regeneration systems, viz., S-2003-us-359, S-2006 sp-30, and S-2003-us-165. Three callus induction media were investigated. These media were composed of Murashige and Skoog (MS) medium salt plus 1, 2, and 3 mg/L 2,4-dichlorophenoxyacetic acid (2,4-D). Medium with 3 mg/L 2,4-D gave the greatest mass of embryogenic calli. The calli produced on the three callus induction media were transferred to 18 types of regeneration media (RM1-RM18). They varied with respect to plant growth regulators and sucrose levels but the basal medium was MS. Two levels of sucrose (30 and 40 g/L), three levels of 2,4 D (0.1, 0.25, 0.5 mg/L) and three levels of 6-benzylaminopurine (0, 0.25 and 0.5 mg/L) were studied in the regeneration media. The effects of callus age on regeneration were evaluated by transferring the calli to regeneration media after 15, 21, 28, and 35 days of culture. The 21-day-old callus of the genotype S-2003-us-359 on RM3 yielded the largest number of plants and was selected as the best for transformation. Six RAPD DNA primers were used to check genetic stability; this medium did not affect the sugarcane genomes. PMID- 22535388 TI - Genetic diversity in populations of Acrocomia aculeata (Arecaceae) in the northern region of Minas Gerais, Brazil. AB - Macauba (Acrocomia aculeata) is a palm of economic importance, widely distributed in natural forests from Mexico to Uruguay. We analyzed the genetic diversity of populations of macauba (A. aculeata) in the northern region of the State of Minas Gerais, Brazil. Young leaves from 10 macauba individuals encompassing 49 genotypes of macauba were collected from Montes Claros, Itacambira, Brasilia de Minas, Mirabela, and Grao Mogol. After extraction and amplification of samples, the amplified fragments were separated by electrophoresis. We found high levels of genetic diversity within the populations. Genetic diversity indices were high, except in the Itacambira and Mirabela populations. Results show that Mirabela and Itacambira populations can require conservation strategies because they present lower values of genetic diversity. PMID- 22535389 TI - DNA barcoding of Oryx leucoryx using the mitochondrial cytochrome C oxidase gene. AB - The massive destruction and deterioration of the habitat of Oryx leucoryx and illegal hunting have decimated Oryx populations significantly, and now these animals are almost extinct in the wild. Molecular analyses can significantly contribute to captive breeding and reintroduction strategies for the conservation of this endangered animal. A representative 32 identical sequences used for species identification through BOLD and GenBank/NCBI showed maximum homology 96.06% with O. dammah, which is a species of Oryx from Northern Africa, the next closest species 94.33% was O. gazella, the African antelope. DNA barcode sequences of the mitochondrial cytochrome C oxidase (COI) gene were determined for O. leucoryx; identification through BOLD could only recognize the genus correctly, whereas the species could not be identified. This was due to a lack of sequence data for O. leucoryx on BOLD. Similarly, BLAST analysis of the NCBI data base also revealed no COI sequence data for the genus Oryx. PMID- 22535390 TI - Fibroblast growth factor receptor 4 Gly388Arg polymorphism associated with severity of gallstone disease in a Chinese population. AB - The etiology of gallstone disease is multifactorial; supersaturation of bile with cholesterol is a primary cause for gallstone formation. In previous studies, we found that fibroblast growth factor receptor 4 (FGFR4) plays an important role in maintaining bile acid homeostasis by regulating the expression of cholesterol 7alpha-hydroxylase (CYP7A1), a rate-limiting enzyme for bile acid biosynthesis. The Gly388Arg (G-388R) polymorphism of FGFR4 affects stabilization and activation of FGFR4. Consequently, we studied the FGFR4 gene as a candidate gene for genetic susceptibility to gallstone disease. We found that overexpression of FGFR4, especially the G-388R mutant of FGFR4, inhibits luciferase activity of CYP7A1 reporter in HepG2 cells, indicating that the G 388R mutant of FGFR4 may have greater inhibitory activity against bile acid biosynthesis. To investigate the association of FGFR4 polymorphism with gallstone disease, 117 patients with gallstone disease and 457 controls were genotyped for FGFR4 polymorphism G-388R by PCR-RFLP. Although the incidence of gallstone disease was not greater in patients with the FGFR4 RR genotype, the ratio of gallstone patients with acute cholecystitis in the FGFR4 RR genotype (42%) was significantly higher than that in other genotypes of FGFR4 (P = 0.019). In conclusion, the FGFR4 polymorphism is a genetic risk factor contributing to aggravation of gallstone disease. PMID- 22535391 TI - Genetic diversity of Brazilian and introduced olive germplasms based on microsatellite markers. AB - Olive trees have been grown since the beginning of civilization, and the consumption of olives and olive products is increasing worldwide, due to their health benefits and organoleptic qualities. To meet the growing market for olives, commercial cultivation of this species is expanding from traditional areas to new regions. Although the Brazilian olive industry has just begun to be established, breeding programs are already developing cultivars that are more adapted to local conditions. We used 12 microsatellite markers to evaluate 60 olive accessions, including several cultivars that were developed in Brazil. The analyses identified 72 distinct alleles; the largest number of alleles per locus were at the markers GAPU 101 and GAPU 71B, which contained 10 and 9 alleles, respectively. The largest allelic diversity and polymorphic information contents were also found at the GAPU 101 and GAPU 71B markers, with values of 0.8399/0.8203 and 0.8117/0.7863, respectively. Additionally, the 12 microsatellite markers generated a cumulative identity probability of 1.51 x 10( 10), indicating a high level of accuracy of accession identification. The set of markers that we used allowed the identification of 52 of the 60 olive genotypes, in addition to the recognition of several varietal synonyms. The components of a two-dimensional principal coordinate analysis explained 48.6% of the total genetic variation. The results obtained from the microsatellite markers showed a substantial degree of genetic diversity in the olive tree accessions used in Brazil. PMID- 22535392 TI - Comparison of five DNA extraction methods for molecular analysis of Jerusalem artichoke (Helianthus tuberosus). AB - DNA extraction is an essential step for molecular analysis of an organism, but it is difficult to acquire a sufficient amount of pure DNA from plant tissue with high levels of phenolic compounds, carbohydrates, proteins, and secondary metabolites. Jerusalem artichoke (Helianthus tuberosus) has high levels of such substances. We compared five commonly used methods of extracting genomic DNA in tests made with leaves and seed of four Jerusalem artichoke genotypes: 1) modified method of Tai and Tanksley, 2) method of Doyle and Doyle, 3) method of Porebski, 4) modified method of Storchova, and 5) Plant DNA Kit of Omega Bio tek. The quality and quantity of extracted DNAs were assessed by photometric assay, electrophoresis on 1% agarose gel and a PCR-based technique. The modified method of Tai and Tanksley was found to be superior for both young leaves and seed. The quality of the extracted DNA was confirmed by sequence-related amplified polymorphism. This information will be useful for molecular analyses of Jerusalem artichoke and other related Helianthus species. PMID- 22535393 TI - RT-qPCR assay on the vitamin D receptor gene in type 2 diabetes and hypertension patients in Turkey. AB - RT-qPCR was used to analyze the vitamin D receptor (VDR) gene TaqI polymorphism in 100 Turkish patients with type 2 diabetes mellitus (T2DM) and hypertension compared with 100 healthy subjects, to determine whether VDR could be considered as one of the susceptibility genes for T2DM and hypertension. Genotyping was done with PCR, followed by melting curve analysis with specific fluorescent hybridization probes. The results showed that distributions for TT, Tt and tt genotypes were 51, 46 and 3% in the patient group, and 35, 49 and 16% in the control group, respectively. The frequency of the T allele in patients was also significantly higher than that in controls. Based on the results, the relationship between the VDR gene TaqI polymorphism and T2DM patients in the Turkish population was compared. In terms of the genotype distributions and allele frequencies of the VDR gene TaqI polymorphism, there was no statistically significant difference (P > 0.05) between the T2DM and hypertension patients and controls. Application of RT-qPCR method enabled us to assess the prevalence of the VDR gene TaqI polymorphism and its association with type 2 diabetes and hypertension. PMID- 22535394 TI - Comparison of efficiency of distance measurement methodologies in mango (Mangifera indica) progenies based on physicochemical descriptors. AB - We investigated seven distance measures in a set of observations of physicochemical variables of mango (Mangifera indica) submitted to multivariate analyses (distance, projection and grouping). To estimate the distance measurements, five mango progeny (total of 25 genotypes) were analyzed, using six fruit physicochemical descriptors (fruit weight, equatorial diameter, longitudinal diameter, total soluble solids in degrees Brix, total titratable acidity, and pH). The distance measurements were compared by the Spearman correlation test, projection in two-dimensional space and grouping efficiency. The Spearman correlation coefficients between the seven distance measurements were, except for the Mahalanobis' generalized distance (0.41 <= rs <= 0.63), high and significant (rs >= 0.91; P < 0.001). Regardless of the origin of the distance matrix, the unweighted pair group method with arithmetic mean grouping method proved to be the most adequate. The various distance measurements and grouping methods gave different values for distortion (-116.5 <= D <= 74.5), cophenetic correlation (0.26 <= rc <= 0.76) and stress (-1.9 <= S <= 58.9). Choice of distance measurement and analysis methods influence the. PMID- 22535395 TI - Genetic diversity analysis of Bt cotton genotypes in Pakistan using simple sequence repeat markers. AB - The popularity of genetically modified insect resistant (Bt) cotton has promoted large scale monocultures, which is thought to worsen the problem of crop genetic homogeneity. Information on genetic diversity among Bt cotton varieties is lacking. We evaluated genetic divergence among 19 Bt cotton genotypes using simple sequence repeat (SSR) markers. Thirty-seven of 104 surveyed primers were found informative. Fifty-two primers selected on the basis of reported intra hirsutum polymorphism in a cotton marker database showed a high degree of polymorphism, 56% compared to 13% for randomly selected primers. A total of 177 loci were amplified, with an average of 1.57 loci per primer, generating 38 markers. The amplicons ranged in size from 98 to 256 bp. The genetic similarities among the 19 genotypes ranged from 0.902 to 0.982, with an average of 0.947, revealing a lack of diversity. Similarities among genotypes from public sector organizations were higher than genotypes developed by private companies. Hybrids were found to be more distant compared to commercial cultivars and advanced breeding lines. Cluster analysis grouped the 19 Bt cotton genotypes into three major clusters and two independent entries. Cultivars IR 3701, Ali Akbar-802 and advanced breeding line VH-259 grouped in subcluster B2, with very narrow genetic distances despite dissimilar parentage. We found a very high level of similarity among Pakistani-bred Bt cotton varieties, which means that genetically diverse recurrent parents should be included to enhance genetic diversity. The intra-hirsutum polymorphic SSRs were found to be highly informative for molecular genetic diversity studies in these cotton varieties. PMID- 22535396 TI - Association of AFLP and SCAR markers with common leafspot resistance in autotetraploid alfalfa (Medicago sativa). AB - To identify amplified fragment length polymorphism (AFLP) markers associated with resistance or susceptibility of alfalfa to common leafspot (CLS) caused by the fungus Pseudopeziza medicaginis (Dermateaceae), bulked segregant analysis was conducted based on an F(1(M * M)) population of 93 plants and a BC(1)S population of 91 plants. Three AFLP markers, ACTCAA(R206), TAGCAC(R185), and GGACTA(S264), were found to be associated with CLS resistance or susceptibility. All three markers were found at significantly different frequencies (71.9, 80.3 and 91.8%) compared to resistant or susceptible plants in the original population. Subsequently, these three AFLP markers were converted into three SCAR markers, ACTCAA(R136), TAGCAC(R128) and GGACTA(S254), which are easier to employ in breeding programs. The three SCAR markers were used in a randomly selected population with 50% resistance; the probability of finding one resistant plant was increased to 67.3, 66.7 and 90.0% with markers ACTCAA(R136), TAGCAC(R128) and GGACTA(S254), independently. If two of the SCAR markers were used simultaneously, the probability would be higher than 89%. The three SCAR markers identified in this study would be applicable for selection for CLS resistance in alfalfa breeding programs. Moreover, the genetic analysis indicated that CLS resistance in alfalfa is conferred by a single dominant gene. PMID- 22535397 TI - Piperine inhibits cytokine production by human peripheral blood mononuclear cells. AB - Piperine, an amide isolated from Piper species (Piperaceae), has been reported to exhibit central nervous system depression, anti-pyretic and anti-inflammatory activity. Immunomodulatory and anti-tumor activity of piperine has been demonstrated in mouse carcinomas. However, there is little information available concerning the effect of piperine on humans. We evaluated the immunopharmacological activity of this compound in human immune cells. Human peripheral blood mononuclear cells (PBMCs) were exposed to piperine, and cell proliferation was determined by the MTS assay. Piperine significantly inhibited phytohemagglutinin-stimulated human PBMC proliferation after exposure for 72 h. This compound inhibited PBMC activity, with an IC(50) of 100.73 +/- 11.16 MUg/mL. Production of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) was measured using an ELISA assay and RT-PCR. Piperine inhibited IL-2 and IFN-gamma production in the PBMCs. RT-PCR data indicated that IL-2 and IFN-gamma mRNA expression in PBMCs is suppressed by piperine. This compound significantly inhibited the production of these two cytokines by activated PBMCs in a dose dependent manner. In conclusion, piperine appears to have potential as an immunomodulatory agent for immune system suppression. PMID- 22535398 TI - Phylogeny and evolution of Cervidae based on complete mitochondrial genomes. AB - Mitochondrial DNA sequences can be used to estimate phylogenetic relationships among animal taxa and for molecular phylogenetic evolution analysis. With the development of sequencing technology, more and more mitochondrial sequences have been made available in public databases, including whole mitochondrial DNA sequences. These data have been used for phylogenetic analysis of animal species, and for studies of evolutionary processes. We made phylogenetic analyses of 19 species of Cervidae, with Bos taurus as the outgroup. We used neighbor joining, maximum likelihood, maximum parsimony, and Bayesian inference methods on whole mitochondrial genome sequences. The consensus phylogenetic trees supported monophyly of the family Cervidae; it was divided into two subfamilies, Plesiometacarpalia and Telemetacarpalia, and four tribes, Cervinae, Muntiacinae, Hydropotinae, and Odocoileinae. The divergence times in these families were estimated by phylogenetic analysis using the Bayesian method with a relaxed molecular clock method; the results were consistent with those of previous studies. We concluded that the evolutionary structure of the family Cervidae can be reconstructed by phylogenetic analysis based on whole mitochondrial genomes; this method could be used broadly in phylogenetic evolutionary analysis of animal taxa. PMID- 22535399 TI - Hemagglutinin protein of Asian strains of human influenza virus A H1N1 binds to sialic acid--a major component of human airway receptors. AB - Hemagglutinin (HA) protein plays an important role in binding the influenza virus to infected cells and therefore mediates infection. Deposited HA sequences of 86 Asian strains of influenza A (H1N1) viruses during the first outbreak were obtained from the NCBI database and compared. Interaction of the HA protein of influenza A (H1N1) virus with the human sialic acid receptor was also studied using bioinformatics. Overall, not more than three single-point amino acid variants/changes were observed in the HA protein region of influenza A (H1N1) virus from Asian countries when a selected group sequence comparison was made. The bioinformatics study showed that the HA protein of influenza A (H1N1) binds to the sialic acid receptor in human airway receptors, possibly key to air-borne infection in humans. PMID- 22535400 TI - Genetic diversity analysis of barley landraces and cultivars in the Shanghai region of China. AB - We analyzed the genetic diversity of 115 barley germplasms, including 112 landraces and three new barley cultivars grown in the Shanghai region, using a set of 11 SSR markers. Sixty-six alleles were observed at the 11 SSR loci, ranged from three to ten, with a mean of six alleles per locus. The polymorphism information content ranged from 0.568 to 0.853, with a mean of 0.732, indicating considerable genetic variation in barley in the Shanghai area. Clustering analysis indicated that these barley accessions could be divided into two categories (A and B). Ninety-seven six-rowed barley cultivars were classified in the A category; sixteen two-rowed and two six-rowed barley cultivars were classified in the B category. This demonstrated genetic differences between two rowed and six-rowed barley varieties. In addition, we found that the three new barley cultivars are closely related. PMID- 22535401 TI - Polymorphisms of the ATP1A1 gene associated with mastitis in dairy cattle. AB - Mastitis affects the concentrations of potassium and sodium in milk. Since sodium-potassium adenosine triphosphatase (Na(+), K(+)-ATPase) is critical for maintaining the homeostasis of these two ions, and is involved in cell apoptosis and pathogenesis, we presumed that polymorphism of the ATP1A1 gene, which encodes the bovine Na(+), K(+)-ATPase alpha1 subunit could be associated with mastitis. The ATP1A1 gene was analyzed in 320 Holstein cows using PCR low ionic strength single-strand conformation polymorphism (PCR-LIS-SSCP) and DNA sequencing methods. A C/A SNP was identified at nucleotide position -15,739 in exon 17 of the ATP1A1 gene, but it did not induce any change in amino acids. We examined a possible association of polymorphism of the ATP1A1 gene with somatic cell score and 305-day milk yields. Individuals with genotype CC in ATP1A1 had significantly lower somatic cell scores and 305-day milk yields than those with genotype CA. We also examined changes in Na(+), K(+)-ATPase activity of red cell membranes. The Na(+), K(+)-ATPase activity was significantly higher in dairy cows with genotype CC compared to the other two genotypes, and the Na(+), K(+) ATPase activity of the resistant group was significantly higher than that of the susceptible group in dairy cows. We conclude that this polymorphism has potential as a marker for mastitis resistance in dairy cattle. PMID- 22535402 TI - Optimization of factors affecting Agrobacterium-mediated transformation of Micro Tom tomatoes. AB - Micro-Tom is the smallest known variety of tomatoes. An orthogonal experimental design L(16) (4(5)) was used to optimize Agrobacterium-mediated transformation of cotyledon explants of Lycopersicon esculentum cv. Micro-Tom. Four parameters were investigated to determine their effect on transformation frequency: the concentration of bacterial suspension, time of dip in bacterial suspension, co cultivation time, and concentration of carbenicillin. We also examined the effect of these parameters on contamination rate, necrosis rate, mortality, cut surface browning rate, and undamaged explant rate. Both the bacterial and carbenicillin concentrations had a significant influence on the rate of infected explants. The time of co-cultivation also had a significant influence on the transformation parameters. The optimal transformation protocol consisted of an Agrobacterium suspension of 0.5 * 10(8) cells/mL (OD(600) = 0.5) and an infection time of 5 min, one day of co-cultivation and 500 mg/L carbenicillin. Under these conditions, the transformation efficiency of the shoots reached 5.1%; the mean transformation frequency was 3.9% (N = 838). PMID- 22535403 TI - DNA extraction from skins of wild (Hydrochoerus hydrochaeris and Pecari tajacu) and domestic (Sus scrofa domestica) species using a novel protocol. AB - Sometimes, commercial products obtained from wild animals are sold as if they were from domestic animals and vice versa. At this point of the productive chain, legal control of possible wildlife products is difficult. Common in the commerce of northern Argentina, skins of two wild species, the carpincho and the collared peccary, look very similar to each other and to those of the domestic pig; it is extremely difficult to differentiate them after they have been tanned. Because there was no an adequate methodology to discriminate between leather of these three species, we developed a new methodology of DNA extraction from skin and leather. This new method involves digesting a leather sample using proteinase K, followed by precipitation of proteins with 5 M NaCl, cleaning with absolute isopropanol and DNA precipitation with 70% ethanol. DNA is hydrated in Tris-EDTA buffer. This protocol provided good-quality DNA suitable for analysis with molecular markers. This new protocol has potential for use in identifying leather products of these species using molecular markers based on RAPDs. PMID- 22535404 TI - Evaluation of wheat landrace genotypes for salinity tolerance at vegetative stage by using morphological and molecular markers. AB - Identification of new sources of salt tolerance is particularly important to develop crop varieties suitable for saline soils. We evaluated 129 Pakistani and 58 exotic wheat landraces/cultivars grown in Hoagland's hydroponic nutrient solution, under control (tap water equivalent to 10 mM salt) and salt stress (200 mM NaCl) conditions. Forty-four genotypes were also tested under 250 mM NaCl stress. High heritability and positive correlations suggested that number of tillers per plant, root length, root fresh and dry weights, and shoot fresh and dry weights are associated with salt tolerance and could be used as selection criteria. SSR markers revealed high genetic variation in the wheat genotypes. Twelve SSR markers (cfd 1, cfd 9, cfd 18, cfd 46, cfd 49, cfd 183, wmc 11, wmc 17, wmc 18, wmc 154, wmc 432, and wmc 503) were found to be associated with salt tolerance because they were amplified in tolerant genotypes only. Five markers, cfd 9, cfd 18, cfd 183, wmc 96, and wmc 405, were identified as most suitable to evaluate salt tolerance because they were associated with four or more salt tolerance traits studied. Cultivars Pasban 90, accessions 10790, 10828, 10823, and 4098805 from Pakistan and Sakha-92 from Egypt performed best at both stress levels. PMID- 22535405 TI - High segregation distortion in maize B73 x teosinte crosses. AB - Two genetic linkage maps of cultivated maize inbred lines and teosinte species were constructed. One population comprised 81 F(2) individuals derived from a cross between maize inbred line B73 and Zea mays ssp parviglumis, while the second consisted of 63 backcross individuals from a cross of maize inbred line B73 with Z. mays ssp diploperennis. In the B73 x Z. mays ssp parviglumis F(2) population, 172 simple sequence repeat (SSR) markers were mapped to 10 chromosomes, which covered 2210.8 cM. In the B73 x Z. mays ssp diploperennis backcross population, 258 SSR markers were mapped to 10 chromosomes, covering 1357.7 cM. Comparison of the two maps revealed that the total map length of Z. mays ssp diploperennis covers 1357.7 cM, which is about 61.4% of that of Z. mays ssp parviglumis (2210.8 cM). Extensive segregation distortion regions were found on chromosomes 1, 2, 3, 5, 6, 7, and 10 in the B73 x Z. mays ssp parviglumis F(2) population and on chromosomes 1-5 and 8-10 in the B73 x Z. mays ssp parviglumis backcross population. Segregation distortion analysis confirmed that the segregation distortion ratio in the interspecific population B73 x Z. mays ssp diploperennis was higher than in B73 x Z. mays ssp parviglumis. We found that the recombination distances are highly variable in these genetic crosses between cultivated and wild species of maize. PMID- 22535406 TI - Intra-specific genetic diversity in wild olives (Olea europaea ssp cuspidata) in Hormozgan Province, Iran. AB - Wild olive (O. europaea ssp cuspidata) plants grow in various regions of Iran and are expected to have considerable genetic diversity due to adaptation to the various environmental conditions. We examined the genetic diversity of four populations of wild olive growing in Hormozgan Province located in southern Iran by using 30 RAPDs and 10 ISSR markers. The mean value of polymorphism for RAPD loci was 73.71%, while the value for ISSR loci was 81.74%. The Keshar population had the highest value of intra-population polymorphism for both RAPD and ISSR loci (66.86 and 62.71%, respectively), while the Tudar population had the lowest values (20.35 and 28.81%, respectively). Similarly, the highest and lowest number of effective alleles, Shannon index and Nei's genetic diversity were also found for these two populations. The highest value of H(pop)/H(sp) within population genetic diversity for RAPD and ISSR loci was found for the Keshar population (H(pop) = 0.85 and H(sp) = 0.90). OPA04-750, OPA13-650 and OPA02-350 RAPD bands were specific for Tudar, Bondon and Keshar populations, respectively, while no specific ISSR bands were observed. Analysis of molecular variance as well as the pairwise F(ST) test showed significant differences for RAPD and ISSR markers among the populations. The NJ and UPGMA trees also separated the wild olive populations from each other, indicating their genetic distinctness. UPGMA clustering of the four wild olive populations placed the Tudar population far from the other populations; Keshar and Bokhoon population samples revealed more similarity and were grouped together. We conclude that there is high genetic diversity among O. europaea ssp cuspidata populations located in southern Iran. We also found RAPD and ISSR markers to be useful molecular tools to discriminate and evaluate genetic variations in wild olive trees. PMID- 22535407 TI - Vitellogenin genes in fish: differential expression on exposure to estradiol. AB - Three types of vitellogenins (Vgs) namely vitellogenin A (VgA), vitellogenin B (VgB) and vitellogenin C (VgC) have been identified in fishes. The existence of VgA and VgB is reported in the Indian freshwater murrel Channa punctatus. Gene specific primers were designed using available nucleotide sequences in National Centre for Biotechnology Information (NCBI), for amplification of VgA and VgB cDNA. Differential processing of Vgs is evident in many fishes. Adult male murrel expressed both the VgA and VgB genes when estradiol-17beta (E(2)) is injected in vivo and Vg levels in blood quantified by Enzyme linked immunosorbent assay (ELISA) showed a dose-related response in such treatments. Cultured hepatocytes on treatment with E(2), however, expressed only VgB as detected by RT-PCR, suggesting different regulatory mechanism for the VgA and VgB genes. PMID- 22535409 TI - Endosperm cellularization defines an important developmental transition for embryo development. AB - The endosperm is a terminal seed tissue that is destined to support embryo development. In most angiosperms, the endosperm develops initially as a syncytium to facilitate rapid seed growth. The transition from the syncytial to the cellularized state occurs at a defined time point during seed development. Manipulating the timing of endosperm cellularization through interploidy crosses negatively impacts on embryo growth, suggesting that endosperm cellularization is a critical step during seed development. In this study, we show that failure of endosperm cellularization in fertilization independent seed 2 (fis2) and endosperm defective 1 (ede1) Arabidopsis mutants correlates with impaired embryo development. Restoration of endosperm cellularization in fis2 seeds by reducing expression of the MADS-box gene AGAMOUS-LIKE 62 (AGL62) promotes embryo development, strongly supporting an essential role of endosperm cellularization for viable seed formation. Endosperm cellularization failure in fis2 seeds correlates with increased hexose levels, suggesting that arrest of embryo development is a consequence of failed nutrient translocation to the developing embryo. Finally, we demonstrate that AGL62 is a direct target gene of FIS Polycomb group repressive complex 2 (PRC2), establishing the molecular basis for FIS PRC2-mediated endosperm cellularization. PMID- 22535408 TI - Nf1 limits epicardial derivative expansion by regulating epithelial to mesenchymal transition and proliferation. AB - The epicardium is the primary source of coronary vascular smooth muscle cells (cVSMCs) and fibroblasts that reside in the compact myocardium. To form these epicardial-derived cells (EPDCs), the epicardium undergoes the process of epithelial to mesenchymal transition (EMT). Although several signaling pathways have been identified that disrupt EMT, no pathway has been reported that restricts this developmental process. Here, we identify neurofibromin 1 (Nf1) as a key mediator of epicardial EMT. To determine the function of Nf1 during epicardial EMT and the formation of epicardial derivatives, cardiac fibroblasts and cVSMCs, we generated mice with a tissue-specific deletion of Nf1 in the epicardium. We found that mutant epicardial cells transitioned more readily to mesenchymal cells in vitro and in vivo. The mesothelial epicardium lost epithelial gene expression and became more invasive. Using lineage tracing of EPDCs, we found that the process of EMT occurred earlier in Nf1 mutant hearts, with an increase in epicardial cells entering the compact myocardium. Moreover, loss of Nf1 caused increased EPDC proliferation and resulted in more cardiac fibroblasts and cVSMCs. Finally, we were able to partially reverse the excessive EMT caused by loss of Nf1 by disrupting Pdgfralpha expression in the epicardium. Conversely, Nf1 activation was able to inhibit PDGF-induced epicardial EMT. Our results demonstrate a regulatory role for Nf1 during epicardial EMT and provide insights into the susceptibility of patients with disrupted NF1 signaling to cardiovascular disease. PMID- 22535410 TI - Clathrin and AP-1 regulate apical polarity and lumen formation during C. elegans tubulogenesis. AB - Clathrin coats vesicles in all eukaryotic cells and has a well-defined role in endocytosis, moving molecules away from the plasma membrane. Its function on routes towards the plasma membrane was only recently appreciated and is thought to be limited to basolateral transport. Here, an unbiased RNAi-based tubulogenesis screen identifies a role of clathrin (CHC-1) and its AP-1 adaptor in apical polarity during de novo lumenal membrane biogenesis in the C. elegans intestine. We show that CHC-1/AP-1-mediated polarized transport intersects with a sphingolipid-dependent apical sorting process. Depleting each presumed trafficking component mislocalizes the same set of apical membrane molecules basolaterally, including the polarity regulator PAR-6, and generates ectopic lateral lumens. GFP::CHC-1 and BODIPY-ceramide vesicles associate perinuclearly and assemble asymmetrically at polarized plasma membrane domains in a co dependent and AP-1-dependent manner. Based on these findings, we propose a trafficking pathway for apical membrane polarity and lumen morphogenesis that implies: (1) a clathrin/AP-1 function on an apically directed transport route; and (2) the convergence of this route with a sphingolipid-dependent apical trafficking path. PMID- 22535411 TI - beta-Catenin 1 and beta-catenin 2 play similar and distinct roles in left-right asymmetric development of zebrafish embryos. AB - beta-Catenin-mediated canonical Wnt signaling has been found to be required for left-right (LR) asymmetric development. However, the implication of endogenous beta-catenin in LR development has not been demonstrated by loss-of-function studies. In zebrafish embryos, two beta-catenin genes, beta-catenin 1 (ctnnb1) and beta-catenin 2 (ctnnb2) are maternally expressed and their zygotic expression occurs in almost all types of tissues, including Kupffer's vesicle (KV), an essential organ that initiates LR development in teleost fish. We demonstrate here that morpholino-mediated knockdown of ctnnb1, ctnnb2, or both, in the whole embryo or specifically in dorsal forerunner cells (DFCs) interrupts normal asymmetry of the heart, liver and pancreas. Global knockdown of ctnnb2 destroys the midline physical and molecular barrier, while global knockdown of ctnnb1 impairs the formation of the midline molecular barrier. Depletion of either gene or both in DFCs/KV leads to poor KV cell proliferation, abnormal cilia formation and disordered KV fluid flow with downregulation of ntl and tbx16 expression. ctnnb1 and ctnnb2 in DFCs/KV differentially regulate the expression of charon, a Nodal antagonist, and spaw, a key Nodal gene for laterality development in zebrafish. Loss of ctnnb1 in DFCs/KV inhibits the expression of charon around KV and of spaw in the posterior lateral plate mesoderm, while ctnnb2 knockdown results in loss of spaw expression in the anterior lateral plate mesoderm with little alteration of charon expression. Taken together, our findings suggest that ctnnb1 and ctnnb2 regulate multiple processes of laterality development in zebrafish embryos through similar and distinct mechanisms. PMID- 22535412 TI - Laminin is required to orient epithelial polarity in the C. elegans pharynx. AB - The development of many animal organs involves a mesenchymal to epithelial transition, in which cells develop and coordinate polarity through largely unknown mechanisms. The C. elegans pharynx, which is an epithelial tube in which cells polarize around a central lumen, provides a simple system with which to understand the coordination of epithelial polarity. We show that cell fate regulators cause pharyngeal precursor cells to group into a bilaterally symmetric, rectangular array of cells called the double plate. The double plate cells polarize with apical localization of the PAR-3 protein complex, then undergo apical constriction to form a cylindrical cyst. We show that laminin, but not other basement membrane components, orients the polarity of the double plate cells. Our results provide in vivo evidence that laminin has an early role in cell polarity that can be distinguished from its later role in basement membrane integrity. PMID- 22535413 TI - BMP and Delta/Notch signaling control the development of amphioxus epidermal sensory neurons: insights into the evolution of the peripheral sensory system. AB - The evolution of the nervous system has been a topic of great interest. To gain more insight into the evolution of the peripheral sensory system, we used the cephalochordate amphioxus. Amphioxus is a basal chordate that has a dorsal central nervous system (CNS) and a peripheral nervous system (PNS) comprising several types of epidermal sensory neurons (ESNs). Here, we show that a proneural basic helix-loop-helix gene (Ash) is co-expressed with the Delta ligand in ESN progenitor cells. Using pharmacological treatments, we demonstrate that Delta/Notch signaling is likely to be involved in the specification of amphioxus ESNs from their neighboring epidermal cells. We also show that BMP signaling functions upstream of Delta/Notch signaling to induce a ventral neurogenic domain. This patterning mechanism is highly similar to that of the peripheral sensory neurons in the protostome and vertebrate model animals, suggesting that they might share the same ancestry. Interestingly, when BMP signaling is globally elevated in amphioxus embryos, the distribution of ESNs expands to the entire epidermal ectoderm. These results suggest that by manipulating BMP signaling levels, a conserved neurogenesis circuit can be initiated at various locations in the epidermal ectoderm to generate peripheral sensory neurons in amphioxus embryos. We hypothesize that during chordate evolution, PNS progenitors might have been polarized to different positions in various chordate lineages owing to differential regulation of BMP signaling in the ectoderm. PMID- 22535414 TI - AP-1 is required for the maintenance of apico-basal polarity in the C. elegans intestine. AB - Epithelial tubes perform functions that are essential for the survival of multicellular organisms. Understanding how their polarised features are maintained is therefore crucial. By analysing the function of the clathrin adaptor AP-1 in the C. elegans intestine, we found that AP-1 is required for epithelial polarity maintenance. Depletion of AP-1 subunits does not affect epithelial polarity establishment or the formation of the intestinal lumen. However, the loss of AP-1 affects the polarised distribution of both apical and basolateral transmembrane proteins. Moreover, it triggers de novo formation of ectopic apical lumens between intestinal cells along the lateral membranes later during embryogenesis. We also found that AP-1 is specifically required for the apical localisation of the small GTPase CDC-42 and the polarity determinant PAR 6. Our results demonstrate that AP-1 controls an apical trafficking pathway required for the maintenance of epithelial polarity in vivo in a tubular epithelium. PMID- 22535416 TI - Treatment of spinal fractures using Lubra plates. A retrospective clinical and radiological evaluation of 15 cases. AB - The purpose of this retrospective study was to review the clinical use along with the short- and long-term outcome in patients treated with Lubra plates to stabilize spinal fracture and dislocations that were considered unstable at time of surgery according to the 'three compartment theory'. The data that were collected included breed, age, gender, body weight of the patients, cause of injury, neurological grade (pre- and postoperative), radiographic findings, surgical treatment, and clinical and radiological outcome. Thirteen dogs and two cats were included with thoracic (1 case), thoracolumbar (3 cases), midlumbar (5 cases) and caudal lumbar (6 cases) vertebral fractures. For stabilization, the small-sized (3 cases), medium-sized (6 cases), and large-sized (6 cases) Lubra plates were used. The clinical outcome was excellent in 10/15 patients, functional in 2/15 and poor in 3/15 with a median follow-up period of nine years (range 2 months to 12 years). The fractures eventually stabilized by ventral spondylosis. No implant failure was seen, however demineralization of the spinous processes necessitated implant removal in one case. Our results suggest that Lubra plating is an appropriate technique for thoracolumbar and lumbar vertebral fractures as well as luxations in dogs and cats. The prognosis for neurological recovery was excellent when the animal had a neurological grade of 3 and was not paralyzed. PMID- 22535417 TI - Ni(II), Pd(II) and Pt(II) complexes of PNP and PSP tridentate amino-phosphine ligands. AB - The ligands D((CH(2))(2)NHPiPr(2))(2) (D = NH 1, S 2) react with (dme)NiCl(2) or (PhCN)(2)MCl(2) (M = Pd, Pt) to give complexes of the form [D((CH(2))(2)NHPiPr(2))(2)MX]X (X = Cl, I; M = Ni, Pd, Pt) which were converted to corresponding iodide derivatives by reaction with Me(3)SiI. Reaction of 1 or 2 with (COD)PdMeCl affords facile routes to [kappa(3)P,N,P NH((CH(2))(2)NHPiPr(2))(2)PdMe]Cl (8a) and [kappa(3)P,S,P S((CH(2))(2)NHPiPr(2))(2)PdMe]Cl (9a) in high yields. An alternative synthetic approach involves oxidative addition of MeI to a M(0) precursor yielding [kappa(3)P,N,P-HN(CH(2)CH(2)NHPiPr(2))(2)NiMe]I (10), [kappa(3)P,N,P HN(CH(2)CH(2)NHPiPr(2))(2)MMe]I (M = Pd 8b Pt 11) and [kappa(3)P,S,P S(CH(2)CH(2)NHPiPr(2))(2)MMe]I (M = Pd 9b, Pt 12). Alternatively, use of NEt(3)HCl in place of MeI produces the species [kappa(3)P,N,P HN(CH(2)CH(2)NHPiPr(2))(2)MH]X (X = Cl, M = Ni 13a, Pd 14a, Pt 16a). The analogs containing 2; [kappa(3)P,S,P-S((CH(2))(2)NHPiPr(2))(2)MH]X (M = Pd, X = PF(6)15: M = Pt, X = Br, 17a, PF(6)17b) were also prepared in yields ranging from 74-93%. In addition, aryl halide oxidative addition was also employed to prepare [kappa(3)P,N,P-HN(CH(2)CH(2)NHPiPr(2))(2)MC(6)H(4)F]Cl (M = Ni 18, Pd 19) and [kappa(3)P,S,P-S((CH(2))(2)NHPiPr(2))(2)Pd(C(6)H(4)F)]Cl (20). Crystal structures of 3a, 4a, 5a, 6a, 8a, 9a, 14b and 16b are reported. PMID- 22535415 TI - Genome-wide microRNA profiling of human temporal lobe epilepsy identifies modulators of the immune response. AB - Mesial temporal lobe epilepsy (mTLE) is a chronic neurological disorder characterized by recurrent seizures. The pathogenic mechanisms underlying mTLE may involve defects in the post-transcriptional regulation of gene expression. MicroRNAs (miRNAs) are non-coding RNAs that control the expression of genes at the post-transcriptional level. Here, we performed a genome-wide miRNA profiling study to examine whether miRNA-mediated mechanisms are affected in human mTLE. miRNA profiles of the hippocampus of autopsy control patients and two mTLE patient groups were compared. This revealed segregated miRNA signatures for the three different patient groups and 165 miRNAs with up- or down-regulated expression in mTLE. miRNA in situ hybridization detected cell type-specific changes in miRNA expression and an abnormal nuclear localization of select miRNAs in neurons and glial cells of mTLE patients. Of several cellular processes implicated in mTLE, the immune response was most prominently targeted by deregulated miRNAs. Enhanced expression of inflammatory mediators was paralleled by a reduction in miRNAs that were found to target the 3'-untranslated regions of these genes in reporter assays. miR-221 and miR-222 were shown to regulate endogenous ICAM1 expression and were selectively co-expressed with ICAM1 in astrocytes in mTLE patients. Our findings suggest that miRNA changes in mTLE affect the expression of immunomodulatory proteins thereby further facilitating the immune response. This mechanism may have broad implications given the central role of astrocytes and the immune system in human neurological disease. Overall, this work extends the current concepts of human mTLE pathogenesis to the level of miRNA-mediated gene regulation. PMID- 22535418 TI - Neural theory for the perception of causal actions. AB - The efficient prediction of the behavior of others requires the recognition of their actions and an understanding of their action goals. In humans, this process is fast and extremely robust, as demonstrated by classical experiments showing that human observers reliably judge causal relationships and attribute interactive social behavior to strongly simplified stimuli consisting of simple moving geometrical shapes. While psychophysical experiments have identified critical visual features that determine the perception of causality and agency from such stimuli, the underlying detailed neural mechanisms remain largely unclear, and it is an open question why humans developed this advanced visual capability at all. We created pairs of naturalistic and abstract stimuli of hand actions that were exactly matched in terms of their motion parameters. We show that varying critical stimulus parameters for both stimulus types leads to very similar modulations of the perception of causality. However, the additional form information about the hand shape and its relationship with the object supports more fine-grained distinctions for the naturalistic stimuli. Moreover, we show that a physiologically plausible model for the recognition of goal-directed hand actions reproduces the observed dependencies of causality perception on critical stimulus parameters. These results support the hypothesis that selectivity for abstract action stimuli might emerge from the same neural mechanisms that underlie the visual processing of natural goal-directed action stimuli. Furthermore, the model proposes specific detailed neural circuits underlying this visual function, which can be evaluated in future experiments. PMID- 22535419 TI - Effect of blood flow rate on internal filtration in a high-flux dialyzer with polysulfone membrane. AB - Internal filtration/backfiltration (IF/BF) of a dialyzer depends on several parameters. This study evaluated the effect of the blood flow rate (Q (B)) on the internal filtration flow rate (Q (IF)) measured using Doppler ultrasonography for a high-flux dialyzer with a polysulfone membrane, APS-15E. In an in vitro study, bovine blood was circulated through the dialyzer, at a Q (B) of 100-350 mL/min. The clearances (CL) of creatinine, beta(2)-microglobulin, and alpha(1) microglobulin were then investigated. Q (IF) increased with the Q (B) value. A good correlation was obtained between Q (IF) and the pressure difference between the pressures at the inlet of the blood compartment and the pressure at the outlet of the dialysate compartment. The creatinine CL values strongly depended on Q (B) because molecular diffusion was dominant. The beta(2)-microglobulin CL also depended on Q (B), because its removal rate seemed to be affected by both diffusive and convective transport caused by the IF/BF. An extremely low CL value was obtained for alpha(1)-microglobulin because of its low diffusivity and membrane fouling induced by proteins plugging the membrane. In conclusion, the IF/BF in the dialyzer strongly depends on Q (B). Furthermore, the dependence of the solute clearance on Q (B) decreased with increasing molecular size of the solute because of the decrease in diffusivity through the membrane. PMID- 22535420 TI - Plasma membrane calcium ATPases are important components of receptor-mediated signaling in plant immune responses and development. AB - Plasma membrane-resident receptor kinases (RKs) initiate signaling pathways important for plant immunity and development. In Arabidopsis (Arabidopsis thaliana), the receptor for the elicitor-active peptide epitope of bacterial flagellin, flg22, is encoded by FLAGELLIN SENSING2 (FLS2), which promotes plant immunity. Despite its relevance, the molecular components regulating FLS2 mediated signaling remain largely unknown. We show that plasma membrane ARABIDOPSIS-AUTOINHIBITED Ca(2+)-ATPase (ACA8) forms a complex with FLS2 in planta. ACA8 and its closest homolog ACA10 are required for limiting the growth of virulent bacteria. One of the earliest flg22 responses is the transient increase of cytosolic Ca(2+) ions, which is crucial for many of the well described downstream responses (e.g. generation of reactive oxygen species and the transcriptional activation of defense-associated genes). Mutant aca8 aca10 plants show decreased flg22-induced Ca(2+) and reactive oxygen species bursts and exhibit altered transcriptional reprogramming. In particular, mitogen-activated protein kinase-dependent flg22-induced gene expression is elevated, whereas calcium-dependent protein kinase-dependent flg22-induced gene expression is reduced. These results demonstrate that the fine regulation of Ca(2+) fluxes across the plasma membrane is critical for the coordination of the downstream microbe-associated molecular pattern responses and suggest a mechanistic link between the FLS2 receptor complex and signaling kinases via the secondary messenger Ca(2+). ACA8 also interacts with other RKs such as BRI1 and CLV1 known to regulate plant development, and both aca8 and aca10 mutants show morphological phenotypes, suggesting additional roles for ACA8 and ACA10 in developmental processes. Thus, Ca(2+) ATPases appear to represent general regulatory components of RK-mediated signaling pathways. PMID- 22535421 TI - DELLA signaling mediates stress-induced cell differentiation in Arabidopsis leaves through modulation of anaphase-promoting complex/cyclosome activity. AB - Drought is responsible for considerable yield losses in agriculture due to its detrimental effects on growth. Drought responses have been extensively studied, but mostly on the level of complete plants or mature tissues. However, stress responses were shown to be highly tissue and developmental stage specific, and dividing tissues have developed unique mechanisms to respond to stress. Previously, we studied the effects of osmotic stress on dividing leaf cells in Arabidopsis (Arabidopsis thaliana) and found that stress causes early mitotic exit, in which cells end their mitotic division and start endoreduplication earlier. In this study, we analyzed this phenomenon in more detail. Osmotic stress induces changes in gibberellin metabolism, resulting in the stabilization of DELLAs, which are responsible for mitotic exit and earlier onset of endoreduplication. Consequently, this response is absent in mutants with altered gibberellin levels or DELLA activity. Mitotic exit and onset of endoreduplication do not correlate with an up-regulation of known cell cycle inhibitors but are the result of reduced levels of DP-E2F-LIKE1/E2Fe and UV-B-INSENSITIVE4, both inhibitors of the developmental transition from mitosis to endoreduplication by modulating anaphase-promoting complex/cyclosome activity, which are down regulated rapidly after DELLA stabilization. This work fits into an emerging view of DELLAs as regulators of cell division by regulating the transition to endoreduplication and differentiation. PMID- 22535422 TI - Characterization of three O-methyltransferases involved in noscapine biosynthesis in opium poppy. AB - Noscapine is a benzylisoquinoline alkaloid produced in opium poppy (Papaver somniferum) and other members of the Papaveraceae. It has been used as a cough suppressant and more recently was shown to possess anticancer activity. However, the biosynthesis of noscapine in opium poppy has not been established. A proposed pathway leading from (S)-reticuline to noscapine includes (S)-scoulerine, (S) canadine, and (S)-N-methylcanadine as intermediates. Stem cDNA libraries and latex extracts of eight opium poppy cultivars displaying different alkaloid profiles were subjected to massively parallel pyrosequencing and liquid chromatography-tandem mass spectrometry, respectively. Comparative transcript and metabolite profiling revealed the occurrence of three cDNAs encoding O methyltransferases designated as SOMT1, SOMT2, and SOMT3 that correlated with the accumulation of noscapine in the eight cultivars. SOMT transcripts were detected in all opium poppy organs but were most abundant in aerial organs, where noscapine primarily accumulates. SOMT2 and SOMT3 showed strict substrate specificity and regiospecificity as 9-O-methyltransferases targeting (S) scoulerine. In contrast, SOMT1 was able to sequentially 9- and 2-O-methylate (S) scoulerine, yielding (S)-tetrahydropalmatine. SOMT1 also sequentially 3'- and 7-O methylated both (S)-norreticuline and (S)-reticuline with relatively high substrate affinity, yielding (S)-tetrahydropapaverine and (S)-laudanosine, respectively. The metabolic functions of SOMT1, SOMT2, and SOMT3 were investigated in planta using virus-induced gene silencing. Reduction of SOMT1 or SOMT2 transcript levels resulted in a significant decrease in noscapine accumulation. Reduced SOMT1 transcript levels also caused a decrease in papaverine accumulation, confirming the selective roles for these enzymes in the biosynthesis of both alkaloids in opium poppy. PMID- 22535423 TI - Structural and functional analysis of VQ motif-containing proteins in Arabidopsis as interacting proteins of WRKY transcription factors. AB - WRKY transcription factors are encoded by a large gene superfamily with a broad range of roles in plants. Recently, several groups have reported that proteins containing a short VQ (FxxxVQxLTG) motif interact with WRKY proteins. We have recently discovered that two VQ proteins from Arabidopsis (Arabidopsis thaliana), SIGMA FACTOR-INTERACTING PROTEIN1 and SIGMA FACTOR-INTERACTING PROTEIN2, act as coactivators of WRKY33 in plant defense by specifically recognizing the C terminal WRKY domain and stimulating the DNA-binding activity of WRKY33. In this study, we have analyzed the entire family of 34 structurally divergent VQ proteins from Arabidopsis. Yeast (Saccharomyces cerevisiae) two-hybrid assays showed that Arabidopsis VQ proteins interacted specifically with the C-terminal WRKY domains of group I and the sole WRKY domains of group IIc WRKY proteins. Using site-directed mutagenesis, we identified structural features of these two closely related groups of WRKY domains that are critical for interaction with VQ proteins. Quantitative reverse transcription polymerase chain reaction revealed that expression of a majority of Arabidopsis VQ genes was responsive to pathogen infection and salicylic acid treatment. Functional analysis using both knockout mutants and overexpression lines revealed strong phenotypes in growth, development, and susceptibility to pathogen infection. Altered phenotypes were substantially enhanced through cooverexpression of genes encoding interacting VQ and WRKY proteins. These findings indicate that VQ proteins play an important role in plant growth, development, and response to environmental conditions, most likely by acting as cofactors of group I and IIc WRKY transcription factors. PMID- 22535424 TI - The acyl-acyl carrier protein synthetase from Synechocystis sp. PCC 6803 mediates fatty acid import. AB - The transfer of fatty acids across biological membranes is a largely uncharacterized process, although it is essential at membranes of several higher plant organelles like chloroplasts, peroxisomes, or the endoplasmic reticulum. Here, we analyzed loss-of-function mutants of the unicellular cyanobacterium Synechocystis sp. PCC 6803 as a model system to circumvent redundancy problems encountered in eukaryotic organisms. Cells deficient in the only cytoplasmic Synechocystis acyl-acyl carrier protein synthetase (SynAas) were highly resistant to externally provided alpha-linolenic acid, whereas wild-type cells bleached upon this treatment. Bleaching of wild-type cells was accompanied by a continuous increase of alpha-linolenic acid in total lipids, whereas no such accumulation could be observed in SynAas-deficient cells (Deltasynaas). When SynAas was disrupted in the tocopherol-deficient, alpha-linolenic acid-hypersensitive Synechocystis mutant Deltaslr1736, double mutant cells displayed the same resistance phenotype as Deltasynaas. Moreover, heterologous expression of SynAas in yeast (Saccharomyces cerevisiae) mutants lacking the major yeast fatty acid import protein Fat1p (Deltafat1) led to the restoration of wild-type sensitivity against exogenous alpha-linolenic acid of the otherwise resistant Deltafat1 mutant, indicating that SynAas is functionally equivalent to Fat1p. In addition, liposome assays provided direct evidence for the ability of purified SynAas protein to mediate alpha-[(14)C]linolenic acid retrieval from preloaded liposome membranes via the synthesis of [(14)C]linolenoyl-acyl carrier protein. Taken together, our data show that an acyl-activating enzyme like SynAas is necessary and sufficient to mediate the transfer of fatty acids across a biological membrane. PMID- 22535425 TI - Bio-ethanol production from non-food parts of cassava (Manihot esculenta Crantz). AB - Global climate issues and a looming energy crisis put agriculture under pressure in Sub-Saharan Africa. Climate adaptation measures must entail sustainable development benefits, and growing crops for food as well as energy may be a solution, removing people from hunger and poverty without compromising the environment. The present study investigated the feasibility of using non-food parts of cassava for energy production and the promising results revealed that at least 28% of peels and stems comprise dry matter, and 10 g feedstock yields >8.5 g sugar, which in turn produced >60% ethanol, with pH ~ 2.85, 74-84% light transmittance and a conductivity of 368 mV, indicating a potential use of cassava feedstock for ethanol production. Thus, harnessing cassava for food as well as ethanol production is deemed feasible. Such a system would, however, require supportive policies to acquire a balance between food security and fuel. PMID- 22535426 TI - Cheaper fuel and higher health costs among the poor in rural Nepal. AB - Biomass fuels are used by the majority of resource poor households in low-income countries. Though biomass fuels, such as dung-briquette and firewood are apparently cheaper than the modern fuels indoor pollution from burning biomass fuels incurs high health costs. But, the health costs of these conventional fuels, mostly being indirect, are poorly understood. To address this gap, this study develops probit regression models using survey data generated through interviews from households using either dung-briquette or biogas as the primary source of fuel for cooking. The study investigates factors affecting the use of dung-briquette, assesses its impact on human health, and estimates the associated household health costs. Analysis suggests significant effects of dung-briquette on asthma and eye diseases. Despite of the perception of it being a cheap fuel, the annual health cost per household due to burning dung-briquette (US$ 16.94) is 61.3% higher than the annual cost of biogas (US$ 10.38), an alternative cleaner fuel for rural households. For reducing the use of dung-briquette and its indirect health costs, the study recommends three interventions: (1) educate women and aboriginal people, in particular, and make them aware of the benefits of switching to biogas; (2) facilitate tree planting in communal as well as private lands; and (3) create rural employment and income generation opportunities. PMID- 22535427 TI - Accounting carbon storage in decaying root systems of harvested forests. AB - Decaying root systems of harvested trees can be a significant component of belowground carbon storage, especially in intensively managed forests where harvest occurs repeatedly in relatively short rotations. Based on destructive sampling of root systems of harvested loblolly pine trees, we estimated that root systems contained about 32% (17.2 Mg ha(-1)) at the time of harvest, and about 13% (6.1 Mg ha(-1)) of the soil organic carbon 10 years later. Based on the published roundwood output data, we estimated belowground biomass at the time of harvest for loblolly-shortleaf pine forests harvested between 1995 and 2005 in South Carolina. We then calculated C that remained in the decomposing root systems in 2005 using the decay function developed for loblolly pine. Our calculations indicate that the amount of C stored in decaying roots of loblolly shortleaf pine forests harvested between 1995 and 2005 in South Carolina was 7.1 Tg. Using a simple extrapolation method, we estimated 331.8 Tg C stored in the decomposing roots due to timber harvest from 1995 to 2005 in the conterminous USA. To fully account for the C stored in the decomposing roots of the US forests, future studies need (1) to quantify decay rates of coarse roots for major tree species in different regions, and (2) to develop a methodology that can determine C stock in decomposing roots resulting from natural mortality. PMID- 22535428 TI - Impact of dust filter installation in ironworks and construction on brownfield area on the toxic metal concentration in street and house dust (Celje, Slovenia). AB - This article presents the impact of the ecological investment in ironworks (dust filter installation) and construction works at a highly contaminated brownfield site on the chemical composition of household dust (HD) and street sediment (SS) in Celje, Slovenia. The evaluation is based on two sampling campaigns: the first was undertaken 1 month before the ecological investment became operational and the second 3 years later. The results show that dust filter installations reduced the content of Co, Cr, Fe, Mn, Mo, W and Zn on average by 58% in HD and by 51% in SS. No reduction was observed at sampling points in the upwind direction from the ironworks. By contrast, the impact of the construction works on the highly contaminated brownfield site was detected by a significant increase (on average by 37%) of elements connected to the brownfield contamination in SS. Such increase was not detected in HD. PMID- 22535429 TI - A new framework for natural resource management in Amazonia. PMID- 22535430 TI - Brazilian Amazon: a significant five year drop in deforestation rates but figures are on the rise again. PMID- 22535431 TI - Estimating the size of tendu leaf and bidi trade using a simple back-of-the envelop method. PMID- 22535432 TI - Current antithrombotic treatment in East Asia: some perspectives on anticoagulation and antiplatelet therapy. PMID- 22535434 TI - Gamma knife radiosurgery for clinically persistent acromegaly. AB - Gamma knife radiosurgery (GKRS) is an important additional strategy for unresected clinically active pituitary adenomas. Radiosurgery for acromegaly aims to achieve tumor growth control and endocrine remission, potentially obviating the need for lifetime medication suppression therapy. Forty patients with clinically active acromegaly underwent GKRS between 1988 and 2009. Thirty-four patients had undergone prior surgical resection. The median follow-up interval was 72 months (range 24-145). Endocrine remission was defined as growth hormones (GH) level <2.5 ng/ml and a normal insulin-like growth factor 1 (IGF-1) level (age and sex adjusted) off growth hormone inhibiting drugs for at least 3 months. Endocrine control was defined as normal GH and IGF-1 levels on suppression medication. Endocrine remission was achieved in 19 (47.5 %) patients and endocrine control in four additional (10.0 %) patients. Patients with lower IGF-1 level and with tumors that were less invasive of the cavernous sinus before GKRS were associated with better GH remission rates. Imaging-defined local tumor control was achieved in 39 (97.5 %) patients (27 had tumor regression). One patient with delayed tumor progression underwent a second GKRS procedure. Three other patients had repeat GKRS because of persistently elevated and clinically symptomatic GH and IGF-1 levels. Sixteen (40.0 %) patients eventually developed a new pituitary axis deficiency at a median onset of 36 months after radiosurgery. No patient developed new visual dysfunction. Gamma knife radiosurgery, which is most often applied in clinically symptomatic acromegaly persistent after initial microsurgery, was most effective when the tumor was less invasive of the cavernous sinus and when patients had lower IGF-1 levels before GKRS. Almost one half of the patients no longer required long term medication suppression. PMID- 22535435 TI - Functional hybrid nickel nanostructures as recyclable SERS substrates: detection of explosives and biowarfare agents. AB - We present the synthesis of highly anisotropic nickel nanowires (NWs) and large area, free-standing carpets extending over cm(2) area by simple solution phase chemistry. The materials can be post-synthetically manipulated to produce hybrid tubes, wires, and carpets by galvanic exchange reactions with Au(3+), Ag(+), Pt(2+), and Pd(2+). All of these structures, especially the hybrid carpets and tubes, have been prepared in bulk and are surface enhanced Raman scattering (SERS) active substrates. Molecules of relevance such as dipicolinic acid (constituting 5-15% of the dry weight of bacterial spores of Bacillus anthracis), dinitrotoluene, hexahydro-1,3,5-triazine (RDX), and trinitrotoluene at nanomolar concentrations have been detected. An enhancement factor of ~10(10) was observed for the Ni-Au nanocarpet. The reusability of the Ni-Au nanocarpet for SERS applications was tested 5 times without affecting the sensitivity. The reusability and sensitivity over large area have been demonstrated by Raman microscopy. Our method provides an easy and cost effective way to produce recyclable, large area, SERS active substrates with high sensitivity and reproducibility which can overcome the limitation of one-time use of traditional SERS substrates. PMID- 22535433 TI - Bevacizumab therapy for adults with recurrent/progressive meningioma: a retrospective series. AB - Intracranial meningiomas are often indolent tumors which typically grow over years to decades. Nonetheless, meningiomas that progress after maximum safe resection and radiation therapy pose a significant therapeutic challenge and effective therapies have yet to be identified. Preclinical studies implicate angiogenesis in the pathophysiology of more aggressive meningiomas, suggesting that anti-angiogenic therapies may be of utility in this setting. We performed a retrospective review of fourteen patients with recurrent meningioma treated at Duke University Medical Center with bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, administered either alone or in combination with chemotherapy. Most patients were heavily pre-treated. Progression-free survival at 6 months was 86 % and was comparable regardless of meningioma grade and whether bevacizumab was administered as monotherapy or in combination with chemotherapy. Most toxicities were mild however single patients developed CNS hemorrhage (grade 1) and intestinal perforation (grade 4), respectively. Bevacizumab can be administered safely to patients with meningioma and appears to be associated with encouraging anti-tumor effect when administered as either a single agent or in combination with chemotherapy. Phase II trials investigating bevacizumab in patients with progressive/recurrent meningioma are warranted. PMID- 22535436 TI - Transcriptome analysis identifies genes involved in ethanol response of Saccharomyces cerevisiae in Agave tequilana juice. AB - During ethanol fermentation, yeast cells are exposed to stress due to the accumulation of ethanol, cell growth is altered and the output of the target product is reduced. For Agave beverages, like tequila, no reports have been published on the global gene expression under ethanol stress. In this work, we used microarray analysis to identify Saccharomyces cerevisiae genes involved in the ethanol response. Gene expression of a tequila yeast strain of S. cerevisiae (AR5) was explored by comparing global gene expression with that of laboratory strain S288C, both after ethanol exposure. Additionally, we used two different culture conditions, cells grown in Agave tequilana juice as a natural fermentation media or grown in yeast-extract peptone dextrose as artificial media. Of the 6368 S. cerevisiae genes in the microarray, 657 genes were identified that had different expression responses to ethanol stress due to strain and/or media. A cluster of 28 genes was found over-expressed specifically in the AR5 tequila strain that could be involved in the adaptation to tequila yeast fermentation, 14 of which are unknown such as yor343c, ylr162w, ygr182c, ymr265c, yer053c-a or ydr415c. These could be the most suitable genes for transforming tequila yeast to increase ethanol tolerance in the tequila fermentation process. Other genes involved in response to stress (RFC4, TSA1, MLH1, PAU3, RAD53) or transport (CYB2, TIP20, QCR9) were expressed in the same cluster. Unknown genes could be good candidates for the development of recombinant yeasts with ethanol tolerance for use in industrial tequila fermentation. PMID- 22535437 TI - Paenibacillus frigoriresistens sp. nov., a novel psychrotroph isolated from a peat bog in Heilongjiang, Northern China. AB - A novel cold-resistant bacterium, designated YIM 016(T), was isolated from a peat bog sample collected from Mohe County, Heilongjiang Province, Northern China and its taxonomic position was investigated using a polyphasic approach. The strain was Gram-positive, aerobic, endospore-forming, motile and rod-shaped. Phylogenetic analyses based on the 16S rRNA gene sequence clearly revealed that strain YIM 016(T) is a member of the genus Paenibacillus. The strain is closely related to Paenibacillus alginolyticus DSM 5050(T), Paenibacillus chondroitinus DSM 5051(T) and Paenibacillus pocheonensis Gsoil 1138(T) with similarities of 99.0 %, 97.0 % and 96.3 %, respectively. Meanwhile, the low DNA-DNA relatedness levels between strain YIM 016(T) and its closely related phylogenetic neighbours demonstrated that this isolate represents a new genomic species in the genus Paenibacillus. Phenotypic and chemotaxonomic tests showed that growth of strain YIM 016(T) occurred at 4-37 degrees C, pH 6.0-8.0 and with a NaCl tolerance up to 0.5 % (w/v). The peptidoglycan contained meso-diaminopimelic acid, alanine and glutamic acid. The whole-cell hydrolysates mainly contained glucose, galactose and ribose. The predominant menaquinone was MK-7 and the major fatty acids were anteiso-C(15:0) and iso-C(16:0). The DNA G+C content of strain YIM 016(T) was 51.7 mol %. On the basis of phylogenetic, phenotypic and chemotaxonomic characteristics, strain YIM 016(T) could be clearly distinguished from other species of the genus Paenibacillus. It is therefore concluded that strain YIM 016(T) represents a novel species in the genus Paenibacillus, for which the name Paenibacillus frigoriresistens sp. nov. is proposed. The type strain is YIM 016(T) (= CCTCC AB 2011150(T) = JCM 18141(T)). PMID- 22535438 TI - Challenges encountered in the analysis of phthalate esters in foodstuffs and other biological matrices. AB - Phthalate esters are ubiquitous environmental pollutants and are recognized as environmental endocrine disruptors because of their potential to elicit reproductive and developmental toxicity. Several phthalate esters have been listed by the US Environmental Protection Agency (EPA) as chemicals of concern. Determination of concentrations of phthalate esters in foodstuffs, typically present at sub to low nanogram-per-gram concentrations (between 0.1 and 100 ng g( 1)), is essential for assessment of human dietary exposure. However, phthalate esters are commonly present as contaminants in several laboratory products, including organic solvents, that are used in sample preparation and analysis. Therefore, accurate analysis of phthalates in food samples is a challenging task. In this review, we summarize the methods available for the determination of phthalate esters in foodstuffs and report on concentrations of phthalates in foodstuffs and potential sources of contamination by phthalates in the analysis of foodstuffs. We offer suggestions to eliminate and/or reduce background levels of contamination by phthalates in the analysis of food and other biological samples. We also introduce methods that are suitable for trace analysis of phthalates in a variety of liquid and solid food samples, in particular, a liquid liquid extraction method for removal of lipids from food samples, because these can substantially reduce background levels of phthalates in the analytical procedure. PMID- 22535439 TI - Colorimetric recognition and sensing of thiocyanate with a gold nanoparticle probe and its application to the determination of thiocyanate in human urine samples. AB - A colorimetric method for the determination of thiocyanate (SCN(-)) ion with a cystamine-modified gold nanoparticle (Au NP) probe is presented. In this method, recognition is based on electrostatic attraction and directional hydrogen bonding between thiocyanate and cystamine on the surface of an Au NP. In phosphate buffer solution (PBS, pH 5.2, 10 mM), the cystamine-modified Au NPs readily aggregated upon incubation with N,N-dimethyl-1-naphthylamine (denoted "2N"), and a visible change in the color of the solution from red to blue was observed. When present, thiocyanate interacted with the gold nanoparticle probe more prominently than 2N, thereby protecting the gold nanoparticles and attenuating the degree of aggregation. The solution was observed (by the naked eye) to change in color from blue to purple and then back to red as a function of thiocyanate concentration (<10 MUM). Iodide was noted to be a significant interferent; however, the optical absorption spectrum in the presence of iodide was fortunately easily distinguished from that for thiocyanate, thereby making it possible to discriminate iodide from thiocyanate. It was possible to determine thiocyanate in human urine samples using this method. This colorimetric method opens up a new avenue for assaying thiocyanate considering its rapid readout and simple implementation, which makes it convenient to determine thiocyanate in biological samples, especially at levels below 100 MUM. PMID- 22535440 TI - Improving the precision of quantitative bottom-up proteomics based on stable isotope-labeled proteins. AB - Stable isotope dilution-based quantitative proteomics with intact labeled proteins as internal standards in combination with a bottom-up approach, i.e., with quantification on the peptide level, is an established method. To explore the technical precision of this approach, calmodulin-like protein 3 was prepared in non-labeled (light) and SILAC-type labeled (heavy) form by cell-free synthesis, mixed, digested with trypsin, and analyzed by UPLC-ESI-MS. In total, 16 light/heavy peptide pair ratios were determined. Pair-wise comparison of ratios of 12 peptides selected according to S/N ratios >50 revealed that the majority exhibited ratios, which were different at a high level of statistical significance (p < 0.001). HPLC-MALDI-MS ratio data confirmed this observation, thus excluding the ionization method as a source of the observed ratio differences. Variation of the digestion time from 0.25 to 4 h showed that the light/heavy ratios of most peptides decrease with time, indicating a kinetic isotope effect leading to preferred cleavage of light calmodulin-like protein 3. The subset of peptides with statistically identical ratios resulted in an average ratio with a RSD of 1.0 %. The light/heavy ratio calculated on the basis of these peptides probably provides the most accurate molar protein ratio. PMID- 22535441 TI - Collaborative study for the detection of toxic compounds in shellfish extracts using cell-based assays. Part II: application to shellfish extracts spiked with lipophilic marine toxins. AB - Successive unexplained shellfish toxicity events have been observed in Arcachon Bay (Atlantic coast, France) since 2005. The positive mouse bioassay (MBA) revealing atypical toxicity did not match the phytoplankton observations or the liquid chromatography-tandem mass spectrometry (LC-MS/MS) investigations used to detect some known lipophilic toxins in shellfish. The use of the three cell lines (Caco2, HepG2, and Neuro2a) allows detection of azaspiracid-1 (AZA1), okadaic acid (OA), or pectenotoxin-2 (PTX2). In this study, we proposed the cell-based assays (CBA) as complementary tools for collecting toxicity data about atypical positive MBA shellfish extracts and tracking their chromatographic fractionation in order to identify toxic compound(s). The present study was intended to investigate the responses of these cell lines to shellfish extracts, which were either control or spiked with AZA1, OA, or PTX2 used as positive controls. Digestive glands of control shellfish were extracted using the procedure of the standard MBA for lipophilic toxins and then tested for their cytotoxic effects in CBA. The same screening strategy previously used with pure lipophilic toxins was conducted for determining the intra- and inter-laboratory variabilities of the responses. Cytotoxicity was induced by control shellfish extracts whatever the cell line used and regardless of the geographical origin of the extracts. Even though the control shellfish extracts demonstrated some toxic effects on the selected cell lines, the extracts spiked with the selected lipophilic toxins were significantly more toxic than the control ones. This study is a crucial step for supporting that cell-based assays can contribute to the detection of the toxic compound(s) responsible for the atypical toxicity observed in Arcachon Bay, and which could also occur at other coastal areas. PMID- 22535442 TI - Differential protein expression of hepatic cells associated with MeHg exposure: deepening into the molecular mechanisms of toxicity. AB - Understanding the molecular mechanisms underlying MeHg toxicity and the way in which this molecule interacts with living organisms is a critical point since MeHg represents a well-known risk to ecosystems and human health. We used a quantitative proteomic approach based on stable isotopic labeling by amino acids in cell culture in combination with SDS-PAGE and nanoflow LC-ESI-LTQ for analyzing the differential protein expression of hepatic cells associated to MeHg exposure. Seventy-eight proteins were found de-regulated by more than 1.5-fold. We identified a number of proteins involved in different essential biological processes including apoptosis, mitochondrial dysfunction, cellular trafficking and energy production. Among these proteins, we found several molecules whose de regulation has been already related to MeHg exposure, thus confirming the usefulness of our discovery approach, and new ones that helped to gain a deeper insight into the biomolecular mechanisms related to MeHg-induced toxicity. Overexpression of several HSPs and the proteasome 26S subunit itself showed the proteasome system as a molecular target of toxic MeHg. As for the interaction networks, the top ranked was the nucleic acid metabolism, where many of the identified de-regulated proteins are involved. PMID- 22535443 TI - Systematic review of obesity surgery mortality risk score--preoperative risk stratification in bariatric surgery. AB - Bariatric surgery is the best long term treatment for morbid obesity. However, it carries risks of considerable morbidity and potential mortality. There is no published review on pre-operative identification of high-risk patients in bariatric surgery. This systematic review analyses obesity surgery mortality risk score (OS-MRS) as a tool for pre-operative prediction of mortality risk in bariatric surgery. Medline and Embase was systematically searched using the medical subjects headings (MeSH) terms 'bariatric surgery' and 'mortality' with further free text search and cross references. Studies that described OS-MRS to predict mortality risk after bariatric surgery were included in this review. Six studies evaluated 9,382 patients to assess the validity of OS-MRS to predict the mortality risk after bariatric surgery. Patient's age ranged from 19 to 67 years, and the body mass index ranged from 30 to 84. There were 83 deaths among the 9,382 patients (0.88 %) with individual studies reporting a mortality range from 0 % to 1.49 %. There were 13 deaths among 4,912 (0.26 %) class A patients, 55 deaths among 4,124 (1.33 %) class B patients and 15 deaths among 346 (4.34 %) class C patients. Mortality in classes A, B and C was significantly different from each of the other two classes (P < 0.05, chi(2)). This systematic review confirms that OS-MRS stratifies the mortality risk in the three-risk classification subgroups of patients. The OS-MRS can be used for pre-operative identification of high-risk patients undergoing primary Roux-en-Y gastric bypass surgery. PMID- 22535445 TI - Experience-dependent recruitment of Arc expression in multiple systems during rest. AB - The patterns of ensemble activity in the hippocampal formation during wakeful, attentive behavior are recapitulated during subsequent resting states. This replay of activity has also been found in several brain regions across many species, indicating a very general biological phenomenon. Concomitantly, transcription of immediate-early genes (IEGs) such as Arc also reoccurs in the same hippocampal neurons, suggesting that IEGs contribute to "off-line" consolidation. If continued IEG expression during rest reflects a correlate of ensemble replay, then the same generality should be observed in IEG transcription patterns. This hypothesis was tested by examining Arc in F344 rats engaging in spatial exploration alongside a rest episode. The probability that an individual neuron participates in "constitutive" Arc expression during rest is increased by recent experience in multiple cortical regions as well as across the septal and temporal poles of the hippocampus, consistent with memory trace reactivation. That is, neurons that were recently active during spatial exploration are preferentially recruited into further Arc expression during subsequent rest. The continued Arc expression, however, occurs in only a small fraction of the cells that were engaged in transcription during previous behavior. This fraction is greatest in CA3 and progressively decreases in CA1, superficial, and deep cortical layers and is consistent with the idea that consolidation occurs rapidly in the hippocampus (centering on the CA3 recurrent network) while changes are much more gradual in neocortical synaptic networks. PMID- 22535444 TI - Chitinases in Pneumocystis carinii pneumonia. AB - Pneumocystis pneumonia remains an important complication of immune suppression. The cell wall of Pneumocystis has been demonstrated to potently stimulate host inflammatory responses, with most studies focusing on beta-glucan components of the Pneumocystis cell wall. In the current study, we have elaborated the potential role of chitins and chitinases in Pneumocystis pneumonia. We demonstrated differential host mammalian chitinase expression during Pneumocystis pneumonia. We further characterized a chitin synthase gene in Pneumocystis carinii termed Pcchs5, a gene with considerable homolog to the fungal chitin biosynthesis protein Chs5. We also observed the impact of chitinase digestion on Pneumocystis-induced host inflammatory responses by measuring TNFalpha release and mammalian chitinase expression by cultured lung epithelial and macrophage cells stimulated with Pneumocystis cell wall isolates in the presence and absence of exogenous chitinase digestion. These findings provide evidence supporting a chitin biosynthetic pathway in Pneumocystis organisms and that chitinases modulate inflammatory responses in lung cells. We further demonstrate lung expression of chitinase molecules during Pneumocystis pneumonia. PMID- 22535447 TI - A bisphosphonite calix[5]arene ligand that stabilizes eta6 arene coordination to palladium. AB - Treatment of a bis(phenylphosphonite)calix[5]arene ligand with either palladium(II) chloride or 1,5-cyclooctadieneplatinum(II) chloride yields square planar metal complexes in which the two phosphorus atoms bind cis to the MCl(2) moiety (M = Pd, Pt). Chloride was removed from the palladium complex to open a coordination site at the metal for catalysis. The chloride removal resulted in a rare and unexpected eta(6) coordination of an arene to the metal. The reaction is reversible upon addition of tetra-n-butyl ammonium chloride. PMID- 22535446 TI - The adaptive immune response in celiac disease. AB - Compared to other human leukocyte antigen (HLA)-associated diseases such as type 1 diabetes, multiple sclerosis, and rheumatoid arthritis, fundamental aspects of the pathogenesis in celiac disease are relatively well understood. This is mostly because the causative antigen in celiac disease-cereal gluten proteins-is known and the culprit HLA molecules are well defined. This has facilitated the dissection of the disease-relevant CD4+ T cells interacting with the disease associated HLA molecules. In addition, celiac disease has distinct antibody responses to gluten and the autoantigen transglutaminase 2, which give strong handles to understand all sides of the adaptive immune response leading to disease. Here we review recent developments in the understanding of the role of T cells, B cells, and antigen-presenting cells in the pathogenic immune response of this instructive disorder. PMID- 22535449 TI - [Characteristics of therapy of acute myocardial infarction in diabetes]. AB - Therapy of acute myocardial infarction (STEMI and NSTEMI) in diabetics does not principally differ from that of non-diabetic patients. Due to the higher mortality in diabetics reperfusion measures, such as direct percutaneous coronary intervention (PCI), should be rapidly performed. An intensive drug treatment with thrombocyte aggregation inhibitors, angiotensin-converting enzyme (ACE) inhibitors and beta-receptor blocking agents must be carried out according to the current guidelines. An important factor is the high risk of renal failure due to the contrast dye administered during PCI in the presence of pre-existing diabetic kidney damage which should be limited to 100 ml if possible. Direct PCI should be limited to the infarcted vessel. After stabilization a comprehensive strategy to cure coronary artery disease, whether with PCI or coronary artery bypass graft (CABG) should be finalized. If severe coronary 3-vessel disease is present, CABG should be favored in diabetic patients. After surviving an acute myocardial infarction differentiated metabolic monitoring is mandatory. PMID- 22535450 TI - [New drugs]. PMID- 22535448 TI - Microglia activation by SIV-infected macrophages: alterations in morphology and cytokine secretion. AB - HIV infection in the brain and the resultant encephalitis affect approximately one third of individuals infected with HIV, regardless of treatment with antiretroviral drugs. Microglia are the resident phagocytic cell type in the brain, serving as a "first responder" to neuroinvasion by pathogens. The early events of the microglial response to productively infected monocyte/macrophages entering the brain can best be investigated using in vitro techniques. We hypothesized that activation of microglia would be specific to the presence of simian immunodeficiency virus (SIV)-infected macrophages as opposed to responses to macrophages in general. Purified microglia were grown and stimulated with control or SIV-infected macrophages. After 6 h, aliquots of the supernatant were analyzed for 23 cytokines using Millipore nonhuman primate-specific kit. In parallel experiments, morphologic changes and cytokine expression by individual microglia were examined by immunofluorescence. Surprisingly, the presence of macrophages was more important to the microglial response rather than whether the macrophages were infected with SIV. None of the cytokines examined were unique to co-incubation with SIV-infected macrophages compared with control macrophages, or their supernatants. Media from SIV-infected macrophages, however, did induce secretion of higher levels of IL-6 and IL-8 than the other treatments. As resident macrophages in the brain, microglia would be expected to have a strong response to infiltrate innate immune cells such as monocyte/macrophages. This response is triggered by incubation with macrophages, irrespective of whether or not they are infected with SIV, indicating a rapid, generalized immune response when infiltrating macrophages entering the brain. PMID- 22535452 TI - [Antimicrobial resistance among E. coli in urinary specimens: prevalence data from three laboratories in Zurich between 1985 and 2010]. AB - Urinary tract infections in women are common. Drug resistance among Escherichia coli, the most frequent uropathogen, has increased worldwide. In a prevalence study we investigated the local antibiotic susceptibility of this microorganism in urinary specimens of three laboratories in Zurich. Resistance rates against trimethoprim-sulfamethoxazole 2010 were 28%, 16% against quinolones and 16% against amoxicillin/clavulanic acid. Resistance prevalence for nitrofurantoin and fosfomycin were low with 3,6%, resp. 0,7%. The rate of extended-spectrum beta lactamase-producing E. coli has rapidly increased to 4,3% in 2010. Based on this data and according to the international guidelines for the treatment of uncomplicated cystitis, therapy with trimethoprim-sulfamethoxazole and quinolones are no longer recommended. Nitrofurantoin and Fosfomycin are an appropriate choice. Microbiological testing is advised. PMID- 22535453 TI - [Polyps of the gallbladder]. AB - Gallbladder polyps are a common incidental finding in ultrasound. They may be clinically significant, because adenomas have a malignant potential, in contrast to the benign cholesterol polyps occuring more frequently. As non-neoplastic polyps and neoplastic polyps cannot be morphologically discriminated in ultrasound, maximal diameter of a polyp has proven to be the best predictor for malignancy. Cholecystectomy is widely accepted as the treatment of choice for patients with polyps >1 cm. Patients with polyps <1 cm should have a follow-up check for a longer period of time (with the exception of very small polyps). PMID- 22535454 TI - [Gynecology: urinary incontinence - mini-review and case reports]. AB - Although urinary incontinence affects one in three women, it is still a taboo topic. Today, effective conservative and surgical treatment options are available. When conservative therapies fail, minimally invasive surgical methods can be offered. The tension-free vaginal tape TVT is gold standard in the treatment of female stress urinary incontinence. In case of immobile urethra or in multi-morbid patients, the minimally invasive technique of periurethral injection of bulking agents may be useful. In patients with refractory overactive bladder, the intravesical injection of botulinum neurotoxin is available. PMID- 22535455 TI - [Adverse reactions of metal/metal hip prostheses - diagnosis and examination]. PMID- 22535456 TI - [Does zinc conquer the common cold?]. PMID- 22535457 TI - [An unexpected case of lower left-side abdominal pain. Acute reactivation of chronic osteomyelitis]. AB - Osteomyelitis caused by S. aureus can be reactivated after decades. Our patient presented with an acute episode of lower left-side abdominal pain and subfebrile temperature due to a reactivation of a S. aureus osteomyelitis in the iliac bone which was initially misinterpreted as a sigma diverticulitis. Diagnosis was established by conventional radiographs as well as CT and MR scans. Harvesting the responsible germ by a bone biopsy prior to therapy is mandatory. Therapy consists of a surgical debridement combined with a long-lasting antibiotic therapy. Relapse can be found after long latency. PMID- 22535458 TI - [Coumarin-induced necrotic purpura of the skin -- case report and review of the literature]. AB - We report the case of a 28-year old woman with extensive red-black colored lesions of the skin on the left thigh, which appeared without trauma. The disease arrived during longterm coumarin therapy because of a deep vein thrombosis and an antiphospholipid syndrome. After consideration of the differential diagnoses and due to the typical clinical picture we made the diagnosis of coumarin necrosis. We review the clinical and therapeutic features for this rare complication. PMID- 22535459 TI - [Vertebroplasty in patients with vertebral fracture not superior to placebo treatment]. PMID- 22535460 TI - [Intensive blood glucose control in type 2 diabetes: it is confirmed that the risk of severe hypoglycemias increases]. PMID- 22535461 TI - [CME ECG 37. Right bundle branch block]. PMID- 22535465 TI - Goniometric measurements of the forelimb and hindlimb joints in sheep. AB - OBJECTIVES: The aim of this study was to evaluate angle-of-motion values for the forelimb and hindlimb in clinically healthy adult Santa Ines sheep by means of a standard goniometer. METHODS: Twenty female Santa Ines sheep, ranging in age between three- to six-years-old, and weighing 32-45 kg (mean +/- standard deviation [SD]: 30.4 +/- 3.7) were used. A standard transparent plastic goniometer was used to measure passive maximum flexion, maximum extension, and range-of-motion (ROM) of the shoulder, elbow, carpal, hip, stifle, and tarsal joints in the right and left limbs. The goniometric measurements were done with the sheep awake and in a standing position. The measurements were made in triplicate by two independent investigators. RESULTS: In all evaluated joints, there was no significant difference either between the means of the two sides or between measurements performed by the two investigators. The mean +/- SD values of the measurements (degrees) were as follows: 20 +/- 1 (flexion), 170 +/- 2 (extension), and 150 +/- 2 (ROM) for the carpal joint; 34 +/- 4 (flexion), 145 +/ 6 (extension), and 110 +/- 4 (ROM) for the elbow joint; 88 +/- 2 (flexion), 144 +/- 6 (extension), and 56 +/- 5 (ROM) for shoulder joint; 35 +/- 4 (flexion), 163 +/- 3 (extension), and 129 +/- 4 (ROM) for tarsal joint; 46 +/- 4 (flexion), 146 +/- 6 (extension), and 100 +/- 4 (ROM) for the stifle joint; 54 +/- 3 (flexion), 143 +/- 7 (extension), and 89 +/- 5 (ROM) for the hip joint. CLINICAL SIGNIFICANCE: The data obtained provide useful and objective information on the joints. More studies are necessary using other sheep breeds. PMID- 22535466 TI - Phosphorylated modification and in vitro antioxidant activity of Radix Hedysari polysaccharide. AB - Phosphorylated modification of a polysaccharide obtained from Radix Hedysari (RHP) was studied. Three phosphorylated polysaccharides (RHPP) with variable degrees of substitution (DS(p)) were obtained with 4-dimethylaminopyridine (DMAP) and N, N' Dicyclocarbodiimide (DCC) as catalyst. The structures of RHPP were characterized by FT-IR spectra and (13)C NMR spectra. Depending on different reaction time, RHPP showed different DS(p) ranging from 0.30 to 0.66, and different Mw ranging from 86.6 to 89.7 KDa. Compared with RHP, RHPP exhibited superior antioxidant activities in vitro, which indicated that phosphorylated modification could enhance antioxidant activities of RHP. Furthermore, it was obvious that the DS(p) had a significant effect on the antioxidant activity. PMID- 22535467 TI - The class I alpha1,2-mannosidases of Caenorhabditis elegans. AB - During the biosynthesis of N-glycans in multicellular eukaryotes, glycans with the compositions Man(5)GlcNAc(2-3) are key intermediates. However, to reach this 'decision point', these N-glycans are first processed from Glc(3)Man(9)GlcNAc(2) through to Man(5)GlcNAc(2) by a number of glycosidases, whereby up to four alpha1 2-linked mannose residues are removed by class I mannosidases (glycohydrolase family 47). Whereas in the yeast Saccharomyces cerevisiae there are maximally three members of this protein family, in higher organisms there are multiple class I mannosidases residing in the endoplasmic reticulum and Golgi apparatus. The genome of the model nematode Caenorhabditis elegans encodes seven members of this protein family, whereby four are predicted to be classical processing mannosidases and three are related proteins with roles in quality control. In this study, cDNAs encoding the four predicted mannosidases were cloned and expressed in Pichia pastoris and the activity of these enzymes, designated MANS 1, MANS-2, MANS-3 and MANS-4, was verified. The first two can, dependent on the incubation time, remove three to four residues from Man(9)GlcNAc(2), whereas the action of the other two results in the appearance of the B isomer of Man(8)GlcNAc(2); together the complementary activities of these enzymes result in processing to Man(5)GlcNAc(2). With these data, another gap is closed in our understanding of the N-glycan biosynthesis pathway of the nematode worm. PMID- 22535468 TI - Predictors of thromboxane levels in patients with non-ST-elevation acute coronary syndromes on chronic aspirin therapy. AB - High levels of thromboxane A2 (TxA2), a key mediator of platelet activation and aggregation, are associated with an increased risk of cardiovascular events. We aimed at assessing the predictors of higher plasma levels of TxB2, the stable metabolite of TxA2, in consecutive patients presenting with non-ST-elevation acute coronary syndrome (NSTE-ACS) on previous aspirin (ASA) treatment undergoing coronary angiography. Ninety-eight consecutive patients (age 61 +/- 11, 75% males) with NSTE-ACS, on previous chronic ASA treatment, were prospectively enrolled in this study. Coronary disease extent was assessed by angiography according to the Bogaty score. In all patients, admission plasma levels of TxB2 (pg/ml) were measured by enzyme-linked immunosorbent assay, and patients showing TxB2 levels in the fourth quartile were compared to patients showing TxB2 levels in the lower quartiles. Multivariable logistic regression analysis showed that platelet count (odds ratio [OR] 1.18, 95% confidence interval [CI] 1.02-1.63, p=0.04), multivessel coronary disease (OR 1.37, 95% CI 1.13-3.67, p=0.03), and coronary atherosclerosis extent index (OR 1.91, 95% CI 1.45-6.79, p=0.001) were independent predictors of TxB2 level upper quartile. Of note, C-reactive protein serum levels were similar in patients with TxB2 levels in the upper quartile as compared to those in the lower quartiles (p=0.49). In conclusion, NSTE-ACS patients with severe coronary atherosclerosis may have incomplete suppression of TxA2 production despite chronic ASA therapy. This finding suggests that additional efforts should be made to lower TxA2 levels in patients with widespread coronary artery disease. PMID- 22535469 TI - Measuring use of evidence based psychotherapy for posttraumatic stress disorder. AB - To improve methods of estimating use of evidence-based psychotherapy for posttraumatic stress disorder in the Veteran's health administration, we evaluated administrative data and note text for patients newly enrolling in six VHA outpatient PTSD clinics in New England during the 2010 fiscal year (n = 1,924). Using natural language processing, we developed machine learning algorithms that mimic human raters in classifying note text. We met our targets for algorithm performance as measured by precision, recall, and F-measure. We found that 6.3 % of our study population received at least one session of evidence-based psychotherapy during the initial 6 months of treatment. Evidence based psychotherapies appear to be infrequently utilized in VHA outpatient PTSD clinics in New England. Our method could support efforts to improve use of these treatments. PMID- 22535470 TI - Substituent effects on axle binding in amide pseudorotaxanes: comparison of NMR titration and ITC data with DFT calculations. AB - The binding behaviour of differently substituted diamide axle molecules to Hunter/Vogtle tetralactam macrocycles was studied with a combination of NMR titration, isothermal titration calorimetry (ITC) experiments and calculations employing density functional theory (DFT), along with dispersion-corrected exchange-correlation functionals. Guests with alkyl or alkenyl chains attached to the diamide carbonyl groups have a significantly higher binding affinity to the macrocycle than guests with benzoyl amides and their substituted analogues. While the binding of the benzoyl and alkenyl substituted axles is enthalpically driven, the alkyl-substituted guest binds mainly because of a positive binding entropy. The electronic effects of para-substituents at the benzoyl moieties have an influence on the binding affinities. Electron donating substituents increase, while electron-withdrawing substituents decrease the binding energies. The binding affinities obtained from both NMR titration and ITC experiments correlate well with each other. The substituent effects observed in the experimental data are reflected in adiabatic interaction energies calculated with density functional methods. The calculated structures also agree well with pseudorotaxane crystal structures. PMID- 22535471 TI - The heat shock response in congeneric land snails (Sphincterochila) from different habitats. AB - Land snails are subject to daily and seasonal variations in temperature and in water availability, and use heat shock proteins (HSPs) as part of their survival strategy. We used experimental heat stress to test whether adaptation to different habitats affects HSP expression in two closely related Sphincterochila snail species, a desert species, Sphincterochila zonata, and a Mediterranean-type species, Sphincterochila cariosa. Our findings show that in S. cariosa, heat stress caused rapid induction of Hsp70 proteins and Hsp90 in the foot and kidney tissues, whereas the desert-inhabiting species S. zonata displayed delayed induction of Hsp70 proteins in the foot and upregulation of Hsp90 alone in the kidney. Our study suggests that Sphincterochila species use HSPs as part of their survival strategy following heat stress and that adaptation to different habitats results in the development of distinct strategies of HSP expression in response to heat, namely the reduced induction of HSPs in the desert-dwelling species. We suggest that the desert species S. zonata relies on mechanisms and adaptations other than HSP induction, thus avoiding the fitness consequences of continuous HSP upregulation. PMID- 22535472 TI - Improving care for patients after transient ischaemic attack (TIA). PMID- 22535473 TI - Which antiplatelet agent for whom? Which patient populations benefit most from novel antiplatelet agents (ticagrelor, prasugrel)? AB - Antiplatelet treatment is a cornerstone for patients with acute coronary syndromes treated invasively or conservatively to reduce the risk of early and late occurring ischemic complications and to improve survival. Compared to clopidogrel, the novel antiplatelet agents prasugrel and ticagrelor provide faster and more consistent inhibition of platelet aggregation and result in substantially improved clinical outcome in patients with acute coronary syndromes but also an increased bleeding risk. Therefore, balancing the rope between safety and efficacy of treatment is crucial for optimizing outcome. An understanding of the similarities but also differences in pharmacological effect, clinical trial design, and outcome is crucial for understanding which patient populations benefit the most from novel antiplatelet treatments. This review provides recommendations for their optimal use. PMID- 22535474 TI - Differential expression of the 5-HT(3A) and 5-HT(3B) receptor in differentiated NG108-15 cells. AB - Previous work from this laboratory has shown that the serotonin (5-HT) induced response is significantly augmented in differentiated NG108-15 (NG) cells treated with dibutyryl cAMP (Bt(2)cAMP) due to qualitative and quantitative changes in the expression of the 5-HT(3) receptor as demonstrated by specific [(3)H] LY 278584 (a selective 5HT(3) receptor antagonist) binding. In this study, we investigated whether there is any change in the relative expression of the 5 HT(3A) and 5-HT(3B) subunits in NG cells differentiated following Bt(2)cAMP treatment cells. The major findings of this study were that the relative amount of 5-HT(3B) subunit mRNA in Bt(2)cAMP-treated NG cells 5 days following Bt(2)cAMP treatment was greater than that in the untreated cells. In contrast, the relative expression of the 5-HT(3B) subunit protein in the Bt(2)cAMP-treated NG cells was much less than in the untreated cells, but the relative expression of the 5 HT(3A) subunit in the Bt(2)cAMP-treated NG cells was similar to the untreated cells. Therefore, no relationship between mRNA and protein expression for 5 HT(3A) and 5-HT(3B) subunits in Bt(2)cAMP treated and untreated NG cells were observed. It was also found that fluorescent intensity for the 5-HT(3B) subunit in the cell body of the Bt(2)cAMP treated and untreated NG cells gradually decreased from the day 1-5 after Bt(2)cAMP treatment. However, in specific areas such as the varicosity and nerve endings of the Bt(2)cAMP treated cells, staining intensity for the 5-HT(3B) subunits was stronger than in the untreated cells at the all time points, peaking at day 5 post-treatment. These results suggest that the augmented response induced by 5-HT acting via 5-HT(3) receptors in differentiated NG cells may be due to changes in the relative amount of the 5 HT(3B) subunit, particularly the ratio and distribution of the 5-HT(3A) to (3B) subunits. PMID- 22535477 TI - Therapeutic effects of human adipose stem cell-conditioned medium on stroke. AB - Stem cell therapy is a promising approach for stroke. However, low survival rates and potential tumorigenicity of implanted cells could undermine the efficacy of the cell-based treatment. The use of stem cell-conditioned medium (CM) may be a feasible approach to overcome these limitations. Especially, specific stem cell culture condition and continuous infusion of CM into ischemic brains would have better therapeutic results. The CM was prepared by culturing human adipose derived stem cells in a three-dimensional spheroid form to increase the secretion of angiogenic/neuroprotective factors. Ischemic stroke was induced by standard middle cerebral artery occlusion methods in the brain of 8-week-old Sprague Dawley rats. Continuous infusion of CM or alphaMEM media (0.5 MUl/hr) into the lateral ventricle was initiated 8 days after the surgery and maintained for 7 days. Alteration in the motor function was monitored by the rotarod test. Infarction volume and the number of microvessels or TUNEL-positive neural cells were analyzed 15 days after the surgery. Compared with alphaMEM, continuous CM infusion reduced the infarction volume and maintained motor function. The number of CD31-positive microvessels and TUNEL-positive neural cells significantly increased and decreased, respectively, in the penumbra regions. Although the apoptosis of all neural cell types decreased, reduction in the microglial apoptosis and astrogliosis was prominent and significant. In this study, the therapeutic effects of the CM against stroke were confirmed in an animal model. Increased endothelial cell proliferation, reduced neural cell apoptosis, and milder astrogliosis may play important roles in the treatment effects of CM. PMID- 22535475 TI - Effect of a novel podophage AB7-IBB2 on Acinetobacter baumannii biofilm. AB - Biofilm formation in Acinetobacter baumannii is a common cause of nosocomial infections in humans. Clinical devices and abiotic surfaces are important sites of colonization leading to formation of biofilms. Such infections are often resistant to multiple antibiotic therapies, and hence there is need for an effective mode of control. Herein, we describe the isolation, characterization of a new lytic bacteriophage of A. baumannii and its effect on biofilm. The phage AB7-IBB2, with a genome size of about 170 kb was identified to be of family Podoviridae as revealed by transmission electron microscopy. It had an isometric head (35 nm) and a short tail (7 nm). It lysed 19/39 (49 %) clinical isolates of A. baumannii. Rapid adsorption (>99 % adsorbed in 4 min), a latency period of 25 min and a burst size 22 PFU/infected cell was observed. The phage could inhibit A. baumannii biofilm formation and disrupt preformed biofilm as well. The phage has promising potential to be considered as a candidate biocontrol agent for A. baumannii infections. PMID- 22535478 TI - Repeatability of edited lactate and other metabolites in astrocytoma at 3T. AB - PURPOSE: To assess the repeatability of measurement of lactate and other metabolites in tumors using magnetic resonance spectroscopy (MRS). MATERIALS AND METHODS: MRS with spectral editing for lactate was performed on 10 patients with astrocytoma (two Grade III, eight Grade IV) using an 8-channel receive coil at 3T. Lactate, lipid, choline, creatine, and N-acetyl aspartate (NAA) signals were measured in regions of tumor and contralateral white matter. Metabolites were quantified relative to unsuppressed water using LCModel fitting software. RESULTS: The within-patient coefficients of variation were ~16% (tumor lactate), 6%-8% (tumor choline and contralateral choline, creatine, and NAA), and 22% (tumor lipid). As expected due to their low concentration in normal tissue, lactate and lipid were not reliably detected in white matter but were found at high levels in most tumors. NAA and creatine were lower in tumors than in normal white matter, and choline varied between above- and below-normal values. No consistent short-term variation in metabolite levels was observed, despite differences in the time elapsed since administration of contrast agent. CONCLUSION: MRS appears repeatable enough to provide longitudinal measures of metabolite content in tumors and contralateral tissue in the brain in vivo. PMID- 22535480 TI - Latero-distal transposition of the tibial crest in cases of medial patellar luxation with patella alta. AB - Medial patellar luxation is defined as medial displacement of the patella from the trochlear groove. In dogs, medial luxations account for 75% of all patellar luxation cases, and are frequently associated with patella alta. Common surgical treatments for medial luxation are trochleoplasty and lateral transposition of the crest to drive the patella into the correct anatomical alignment. Postoperative complications for this procedure are estimated to be between 18-29% of cases, with up to 48% of complications involving reluxation. It was previously hypothesized that in cases of medial luxation involving patella alta, the addition of a distal component to the lateral tibial crest transposition will result in repositioning of the patella into its proper position in the trochlear groove, thus reducing the recurrence of luxation. We performed this modified procedure on 14 dogs (17 limbs) that were suffering from medial luxation combined with patella alta, and our results led to favourable clinical outcomes. This modified surgical procedure places the patella into a more normal proximo-distal anatomical position, is simple to perform, and may become common practice for surgical treatment of medial patellar luxation with an alta component. PMID- 22535482 TI - Philosophy, medicine and healthcare: insights from the Italian experience. AB - To contribute to our understanding of the relationship between philosophical ideas and medical and healthcare models. A diachronic analysis is put in place in order to evaluate, from an innovative perspective, the influence over the centuries on medical and healthcare models of two philosophical concepts, particularly relevant for health: how Man perceives his identity and how he relates to Nature. Five epochs are identified--the Archaic Age, Classical Antiquity, the Middle Ages, the Modern Age, the 'Postmodern' Era--which can be seen, a la Foucault, as 'fragments between philosophical fractures'. From a historical background perspective, up to the early 1900s progress in medical and healthcare models has moved on a par with the evolution of philosophical debate. Following the Second World War, the Health Service started a series of reforms, provoked by anti-positivistic philosophical transformations. The three main reforms carried out however failed and the medical establishment remained anchored to a mechanical, reductionist approach, perfectly in line with the bureaucratic stance of the administrators. In this context, future scenarios are delineated and an anthropo-ecological model is proposed to re-align philosophy, medicine and health care. PMID- 22535481 TI - High HSP27 and HSP70 expression levels are independent adverse prognostic factors in primary resected colon cancer. AB - BACKGROUND: The expression of Heat Shock Proteins (HSPs) is increased in various cancers and has been shown to correlate with biological tumor behaviour. This study aimed to investigate the impact of HSP70, HSP60 and HSP27 expression in colon cancer. MATERIAL AND METHODS: HSP expression was determined by immunohistochemistry on a tissue microarray with 355 primary resected colon carcinomas of all stages. Expression patterns were correlated with pathologic features (UICC pTNM category, tumor grading) and survival. RESULTS: Expression of HSP27, HSP60 and HSP70 ranged from negative to high. There was no correlation between HSP27, HSP60 and HSP70 expression among each other and with UICC pT category, presence of lymph node or distant metastases or tumor grading. High HSP70 expression was associated with worse overall survival (p < 0.001) and was an independent prognostic factor (p = 0.004) in multivariate analysis including the pathological parameters mentioned above. For patients without lymph node or distant metastases (UICC stages I/II) and with complete tumor excision, HSP70 expression was the only independent prognostic factor for survival (p = 0.001) and superior to UICC pT category. In left sided UICC stage I/II carcinomas, high HSP27 expression also had adverse prognostic impact and was an independent prognostic factor (p = 0.016) besides HSP70 (p = 0.002). CONCLUSION: High HSP70 and HSP27 expression is associated with worse clinical outcome in colon cancer. Determination of tumoral HSP70 and HSP27 may be used as additional biomarker for risk stratification especially for UICC stage I/II patients. PMID- 22535485 TI - Diastereoselective synthesis of vicinal amino alcohols. AB - The vicinal amino alcohol is a common motif in natural products and pharmaceuticals. Amino acids constitute a natural, inexpensive, and enantiopure choice of starting material for the synthesis of such functionalities. However, the matters concerning diastereoselectivity are not obvious. This Perspective takes a look in the field of diastereoselective synthesis of vicinal amino alcohols starting from amino acids using various methods. PMID- 22535483 TI - Sequence polymorphisms of Der f 1, Der p 1, Der f 2 and Der p 2 from Korean house dust mite isolates. AB - Amino acid sequence variations have possible influences on the allergenicity of allergens and may be important factors in allergen standardization. This study was undertaken to investigate the sequence polymorphisms of group 1 and 2 allergens from Korean isolates of the house dust mites Dermatophagoides farinae and D. pteronyssinus. cDNA sequences encoding group 1 and 2 allergens were amplified by RT-PCR and compared the deduced amino acid sequences. Der f 1.0101, which appeared in 64.0 % of the 50 sequences analyzed, was found to be predominant. Among the Der p 1 sequences, Der p 1.0102 and 1.0105 were predominant (58 %). Among the Der f 2 sequences, Der f 2.0102 (40.7 %) and a new variant with Gly at position 42 (27.8 %) were predominant. The deduced amino acid sequences of 60 Der p 2 clones were examined, and 28 variants with 1-5 amino acid substitutions were found. Interestingly, all of the Der p 2 sequences had Thr instead of Lys at position 49. Two variants (Leu40, Thr49, and Asn114 (26.6 %); Val40, Thr49, and Asn114 (20.0 %)) were found to be the most predominant forms of Der p 2. Der p 1 has a high rate of sporadic substitutions and the group 2 allergens show a more regular pattern with orderly associations of amino acid substitutions. Der f 1 and Der p 2 from Korean mite isolates have unique amino acid sequence polymorphisms. These findings provide important data for house dust mite allergen standardization. PMID- 22535486 TI - Characterization and optimization of an online system for the simultaneous measurement of atmospheric water-soluble constituents in the gas and particle phases. AB - In this work we present the results of extensive characterization and optimization of the Ambient Ion Monitor-Ion Chromatograph (AIM-IC) system, an instrument developed by URG Corp. and Dionex Inc. for simultaneous hourly measurements of the water-soluble chemical composition of atmospheric fine particulate matter (PM(2.5)) and associated precursor gases. The sampling assembly of the AIM-IC consists of an inertial particle size-selection assembly, a parallel-plate wet denuder (PPWD) for the collection of soluble gases, and a particle supersaturation chamber (PSSC) for collection of particles, in series. The analytical assembly of the AIM-IC consists of anion and cation IC units. The system detection limits were determined to be 41 ppt, 5 ppt, and 65 ppt for gas phase NH(3(g)), SO(2(g)), and HNO(3(g)) and 29 ng m(-3), 3 ng m(-3), and 45 ng m( 3) for particle phase NH(4)(+), SO(4)(2-), and NO(3)(-) respectively. From external trace gas calibrations with permeation sources, we determined that the AIM-IC is biased low for NH(3(g)) (11%), SO(2(g)) (19%), and HNO(3(g)) (12%). The collection efficiency of SO(2(g)) was found to strongly depend on the composition of the denuder solution and was found to be the most quantitative with 5 mM H(2)O(2) solution for mixing ratios as high as 107 ppb. Using a cellulose membrane in the PPWD, the system responded to changes in SO(2(g)) and HNO(3(g)) within an hour, however for NH(3(g)), the timescale can be closer to 20 h. With a nylon membrane, the instrument response time for NH(3(g)) was significantly improved, becoming comparable to the responses for SO(2(g)) and HNO(3(g)). Performance of the AIM-IC for collection and analysis of PM(2.5) was evaluated by generating known number concentrations of ammonium sulfate and ammonium nitrate particles (with an aerodynamic diameter of 300 nm) under laboratory conditions and by comparing AIM-IC measurements to measurements from a collocated Aerosol Mass Spectrometer (AMS) during a field-sampling campaign. On average, the AIM-IC and AMS measurements agreed well and captured rapid ambient concentration changes at the same time. In this work we also present a novel inlet configuration and plumbing for the AIM-IC which minimizes sampling inlet losses, reduces peak smearing due to sample carryover, and allows for tower-height sampling from the base of a research tower. PMID- 22535488 TI - Interactions via intrinsically disordered regions: what kind of motifs? AB - Proteins containing intrinsically disordered (ID) regions are widespread in eukaryotic organisms and are mostly utilized in regulatory processes. ID regions can mediate binary interactions of proteins or promote organization of large assemblies. Post-translational modifications of ID regions often serve as decision points in signaling pathways. Why Nature distinguished ID proteins in molecular recognition functions? In a simple view, binding of ID regions is accompanied by a large entropic penalty as compared to folded proteins. Even in complexes however, ID regions can preserve their conformational freedom, thereby recruit further partners and perform various functions. What sort of benefits ID regions offer for molecular interactions and which properties are exploited in the corresponding complexes? Here, we review models explaining the recognition mechanisms of ID proteins. Motif-based interactions are central to all proposed scenarios, including prestructured elements, anchoring sites and linear motifs. We aim to extract consensus features of the models, which could be used to predict ID-binding sites for a variety of partners. PMID- 22535487 TI - Clinical development of novel therapeutics for castration-resistant prostate cancer: historic challenges and recent successes. AB - There have been more drugs approved by the US Food and Drug Administration for the treatment of castration-resistant prostate cancer in the past 3 years than in the prior 3 decades, with additional drugs on the verge of approval based on the results of recently reported randomized trials. While an improvement in the understanding of the pathogenesis of castration-resistant prostate cancer has undeniably accelerated the transition of novel approaches from "bench to bedside," the recent successes in the treatment of prostate cancer are also a result of the efforts of clinical investigators to redefine the framework in which drugs for castration-resistant disease are evaluated. This review will explore the shifting paradigm in drug development for castration-resistant prostate cancer over the past several decades, and highlight how new definitions, trial designs, and endpoints have facilitated the emergence of new therapies for this challenging disease. PMID- 22535490 TI - Changing within-trial array location and target object position enhances rats' (Rattus norvegicus) missing object recognition accuracy. AB - Six rats were trained to find a previously missing target or 'jackpot' object in a square array of four identical or different objects (the test segment of a trial) after first visiting and collecting sunflower seeds from under the other three objects (the study segment of a trial). During training, objects' local positions within the array and their global positions within the larger foraging array were varied over trials but were not changed between segments within a trial. Following this training, rats were tested on their accuracy for finding the target object when a trial's test array was sometimes moved to a different location in the foraging arena or when the position of the target object within the test array had been changed. Either of these manipulations initially slightly reduced rats' accuracy for finding the missing object but then enhanced it. Relocating test arrays of identical objects enhanced rats' performance only after 10-min inter-segment intervals (ISIs). Relocating test arrays of different objects enhanced rats' performance only after 2-min ISIs. Rats also improved their performance when they encountered the target object in a new position in test arrays of different objects. This enhancement effect occurred after either 2 or 30-min ISIs. These findings suggest that rats separately retrieved a missing (target) object's spatial and non-spatial information when they were relevant but not when they were irrelevant in a trial. The enhancement effects provide evidence for rats' limited retrieval capacity in their visuo-spatial working memory. PMID- 22535491 TI - Evaluation of drug-drug interaction screening software combined with pharmacist intervention. AB - BACKGROUND: Drug-drug interactions (DDI) in hospitalized patients are highly prevalent and an important source of adverse drug reactions. DI computerized screening system can prevent the occurrence of some of these events. OBJECTIVE: To evaluate the impact of drug-drug interaction (DDI) screening software combined with active intervention in preventing drug interactions. SETTING: The study was conducted at General Hospital of Vitoria da Conquista (HGVC), Brazil. METHOD: A quasi-experimental study was used to evaluate the impact of IM-Pharma, a locally developed drug-drug interaction screening system, coupled with pharmacist intervention on adverse drug events in the hospital setting. MAIN OUTCOME MEASURE: The proportion of patients co-prescribed two interacting drugs were measured in two phases, prior the implementation of IM-Pharma and during the intervention period. DDI rates per 100 patient days were calculated before and after implementation. Risk ratios were estimated by Poisson regression models. RESULTS: A total of 6,834 instances of drug-drug interactions were identified; there was an average of 3.3 DDIs per patient in phase one and 2.5 in phase two, a reduction of 24 % (P = 0.03). There was a 71 % reduction in high-severity drug drug interaction (P < 0.01). The risk for all DDIs decreased 50 % after the implementation of IM-Pharma (P < 0.01), and for those with high-severity, the reduction was 81 % (P < 0.01). CONCLUSION: The performance of IM-Pharma combined with pharmacist intervention was positive with an expressive reduction in the risk of DDIs. PMID- 22535493 TI - Peripheral nerve blocks of the pelvic limb in dogs: a retrospective clinical study. AB - OBJECTIVE: To evaluate the success rate and complications of lumbar plexus (LP) and femoral nerve (FN) blocks, each combined with a sciatic nerve (SN) block, in dogs undergoing pelvic limb orthopaedic surgery. DESIGN: Retrospective clinical study. PROCEDURE: The intra-operative and postoperative clinical records of dogs that underwent orthopaedic surgery of the pelvic limb were reviewed. Dogs were divided into two groups according to the analgesic technique used during surgery: dogs that received a peripheral nerve block (group PNB) and dogs in which opioid analgesia alone was used (group C). RESULTS: The PNB and C groups included 265 and 31 dogs, respectively. Complete statistical analysis was performed in 115/265 dogs of PNB group. The overall success rate of the PNB performed was 77% (89/115): 76% (72/95) and 85% (17/20) for LP-SN and FN-SN blocks, respectively. In group PNB, the prevalence of intra-operative hypotension was 7.8% (9/115). Only one (out of 95 [1.05%]) LP-SN block manifested transient postoperative bilateral pelvic limb paralysis. None of the 265 dogs in group PNB manifested neurological complications at six weeks postoperatively. CONCLUSION: The success rate and the absence of neurological complications obtained support the use of LP SN and FN-SN for loco-regional anaesthesia and analgesia in dogs undergoing orthopaedic surgery of the pelvic limb. PMID- 22535492 TI - Stromal factors SDF1alpha, sFRP1, and VEGFD induce dopaminergic neuron differentiation of human pluripotent stem cells. AB - Human embryonic stem cell (hESC)-derived dopaminergic (DA) neurons hold potential for treating Parkinson's disease (PD) through cell replacement therapy. Generation of DA neurons from hESCs has been achieved by coculture with the stromal cell line PA6, a source of stromal cell-derived inducing activity (SDIA). However, the factors produced by stromal cells that result in SDIA are largely undefined. We previously reported that medium conditioned by PA6 cells can generate functional DA neurons from NTera2 human embryonal carcinoma stem cells. Here we show that PA6-conditioned medium can induce DA neuronal differentiation in both NTera2 cells and the hESC I6 cell line. To identify the factor(s) responsible for SDIA, we used large-scale microarray analysis of gene expression combined with mass spectrometric analysis of PA6-conditioned medium (CM). The candidate factors, hepatocyte growth factor (HGF), stromal cell-derived factor-1 alpha (SDF1alpha), secreted frizzled-related protein 1 (sFRP1), and vascular endothelial growth factor D (VEGFD) were identified, and their concentrations in PA6 CM were established by immunoaffinity capillary electrophoresis. Upon addition of SDF1alpha, sFRP1, and VEGFD to the culture medium, we observed an increase in the number of cells expressing tyrosine hydroxylase (a marker for DA neurons) and betaIII-tubulin (a marker for immature neurons) in both the NTera2 and I6 cell lines. These results indicate that SDF1alpha, sFRP1, and VEGFD are major components of SDIA and suggest the potential use of these defined factors to elicit DA differentiation of pluripotent human stem cells for therapeutic intervention in PD. PMID- 22535495 TI - Comparison of quantiferon test with tuberculin skin test for the detection of tuberculosis infection in children. AB - The efficacy of Quantiferon-TB gold test (QFT-GIT) remains to be documented in pediatric population. Tuberculin skin test (TST) is a conventional test available for the diagnosis of latent tuberculosis infection (LTBI). We aimed to investigate the concordance between QFT-GIT and TST in children with and without tuberculosis infection. Ninety-seven patients, aged 3 months-14 years, admitted to pediatric outpatient clinics of Dr. Sadi Konuk Training Hospital Bakirkoy, Turkey between March 2008 and April 2009 were recruited. Demographic features, TST results, history of exposure to active tuberculosis (TB), chest X-ray findings, clinical history, presence of Bacillus Calmette Guerin (BCG) vaccination scar were recorded. Patients were categorized into four groups namely, active TB, LTBI, no TB and healthy. It was found that BCG scar positivity did not influence QFT-GIT results. There was a statistically significant agreement between QFT-GIT and TST results (kappa = 0.486; p < 0.01). In patients >= 5 years of age, TST positivity and QFT positivity had a significant relationship (p < 0.01). In all patient groups, sensitivity and specificity was 65.85 % and 82.14 %, respectively. In active TB group, TST and QFT-GIT results demonstrated significant agreement ratio of 40.8 % (kappa = 0.364; p < 0.01). Sensitivity and specificity was 100 % and 30 %, respectively. Utilization of QFT GIT in the diagnosis of LTBI reduces false-positive results and prevents unnecessary treatment with INH and its adverse effects. PMID- 22535494 TI - Retrogenes moved out of the z chromosome in the silkworm. AB - Previous studies on organisms with well-differentiated X and Y chromosomes, such as Drosophila and mammals, consistently detected an excess of genes moving out of the X chromosome and gaining testis-biased expression. Several selective evolutionary mechanisms were shown to be associated with this nonrandom gene traffic, which contributed to the evolution of the X chromosome and autosomes. If selection drives gene traffic, such traffic should also exist in species with Z and W chromosomes, where the females are the heterogametic sex. However, no previous studies on gene traffic in species with female heterogamety have found any nonrandom chromosomal gene movement. Here, we report an excess of retrogenes moving out of the Z chromosome in an organism with the ZW sex determination system, Bombyx mori. In addition, we showed that those "out of Z" retrogenes tended to have ovary-biased expression, which is consistent with the pattern of non-retrogene traffic recently reported in birds and symmetrical to the retrogene movement in mammals and fruit flies out of the X chromosome evolving testis functions. These properties of gene traffic in the ZW system suggest a general role for the heterogamety of sex chromosomes in determining the chromosomal locations and the evolution of sex-biased genes. PMID- 22535496 TI - Association of MicroRNA-146a with autoimmune diseases. AB - MicroRNAs (miRNAs) are a group of approximately 20-22-nucleotide-long non-coding RNAs that repress target gene expression through mRNA degradation and translation inhibition. MiRNA (miR)-146a, located in the second exon of the LOC285628 gene on human chromosome 5, is a negative regulator in immune and inflammatory responses. Studies have indicated that miR-146a is associated with the pathogenesis of several autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and Sjogren's syndrome. In this review, emphasis will be laid on the recent progress in the functional roles of miR-146a in these autoimmune diseases. PMID- 22535498 TI - The acceleration of the propagation phase of thrombin generation in patients with steady-state sickle cell disease is associated with circulating erythrocyte derived microparticles. AB - Sickle cell disease (SCD) is linked to hypercoagulability and is characterised by high concentrations of erythrocyte-derived microparticles (Ed-MPs). However, the impact of procoagulant cell-derived microparticles on the thrombin generation process remains unclear. We analysed the alterations of each phase of thrombin generation (TG) in relation to the concentration of erythrocyte- or platelet derived microparticles (Ed-MPs and Pd-MPs) in a cohort of patients with steady state SCD. We studied 92 steady-state SCD patients, 19 of which were under treatment with hydroxyurea, and 30 healthy age- and sex-matched individuals. TG was assessed by calibrated automated thrombogram. Ed-MP and Pd-MP expressing or not phosphatidylserine (PS) were determined by means of flow cytometry. Procoagulant phospholipid-dependent activity in the plasma was evaluated by the Procoag-PPL assay. Levels of thrombomodulin and haemoglobin in the plasma as well as red blood cell and reticulocyte counts were measured. SCD patients, independently of the administration of hydroxyurea, were marked by a significant acceleration in the propagation phase of TG which correlated with the Ed-MP/PS+ concentration. TG was significantly attenuated in hydroxyurea-treated patients. In conclusion, the acceleration of the propagation phase of TG, driven by Ed MP/PS+, is a major functional alteration in blood coagulation in patients with steady-state SCD. Treatment with hydroxyurea, in addition to the regulation of haemolysis, lowers Ed-MPs and attenuates thrombin generation. The thrombogram could be a useful tool for the diagnosis of hypercoagulability and optimisation of the treatment in patients with SCD. PMID- 22535497 TI - Allopurinol ameliorates thioacetamide-induced acute liver failure by regulating cellular redox-sensitive transcription factors in rats. AB - Oxidative stress plays important role in the development of acute liver failure. In this study, we investigated effects of allopurinol (AP) upon thioacetamide (TAA)-induced liver injury and the potential mechanisms leading to amelioration in inflammation with AP treatment. Acute liver failure was induced by intraperitoneal administration of TAA (300 mg/kg/day for 2 days). Thirty-five rats were divided into five groups as control (group 1), TAA (group 2), TAA + 25AP (group 3), TAA + 50 AP (group 4), and TAA + 100AP (group 5). The number of animals in each group was seven. At the end of the study, histopathological, biochemical, and western blot analysis were done. TAA treatment significantly increased serum levels of aminotransferases, liver malondialdehyde (MDA), nuclear factor-kappa B (NF-?B ), activator protein-1 (AP-1), tumor necrosis factor-alpha (TNF-alpha), cyclooxygenase-2 (COX-2) and interleukin-6 (IL-6) levels, and the necro-inflammation scores. Nevertheless, nuclear factor E2-related factor-2 and heme oxygenase-1 (HO-1) expressions in the liver were decreased by TAA. AP treatment significantly lowered the serum levels of aminotransferases (P < 0.01) and liver MDA, NF-kappaB, AP-1, TNF-alpha, COX-2, and IL-6 expressions (P < 0.05). Moreover, AP restored the liver Nrf2 and HO-1 expressions and improved the necro-inflammation scores significantly. AP improves oxidative stress-induced liver damage by regulating cellular redox-sensitive transcriptor factors and expression of pro-inflammatory and antioxidant defense mechanisms. AP probably exerts these beneficiary features by its free radical scavenging ability in a dose-dependent manner. PMID- 22535499 TI - Field-scale monitoring of the long-term impact and sustainability of drainage water reuse on the west side of California's San Joaquin Valley. AB - Diminishing freshwater resources have brought attention to the reuse of degraded water as a water resource rather than a disposal problem. Drainage water from tile-drained, irrigated agricultural land is degraded water that is often in large supply, but the long-term impact and sustainability of its reuse on soil is unknown. Similarly, nothing is known of the ramifications of terminating drainage water reuse. The objective of this study is (i) to monitor the long-term impact on soil chemical properties and thereby the sustainability of drainage water reuse on a marginally productive, saline-sodic, 32.4 ha field located on the west side of California's productive San Joaquin Valley and (ii) to assess spatially what happens to soil when drainage water reuse is terminated. The monitoring and assessment were based on spatial chemical data for soil collected during 10 years of irrigation with drainage water followed by 2 years of no applied irrigation water (only rainfall). Geo-referenced measurements of apparent soil electrical conductivity (EC(a)) were used to direct the soil sampling design to characterize spatial variability of impacted soil properties. Chemical analyses of soil samples were used (i) to characterize the spatial variability of salinity, Na, B, and Mo, which were previously identified as critical to the yield and quality of Bermuda grass (Cynodon dactylon (l.) Pers.) grown for livestock consumption and (ii) to monitor their change during the 12 year study. Soil samples were taken at 0.3 m increments to a depth of 1.2 m at each of 40 sample sites on five occasions: August 1999, April 2002, November 2004, August 2009, and May 2011. Drainage water varying in salinity (1.8-16.3 dS m(-1)), SAR (5.2-52.4), Mo (80 400 MUg L(-1)), and B (0.4-15.1 mg L(-1)) was applied from July 2000 to June 2009. Results indicate that salts, Na, Mo, and B were leached from the root zone causing a significant improvement in soil quality from 1999 to 2009. Salinity and SAR returned to original levels or higher in less than two years after termination of irrigation. Boron and Mo showed significant increases. Long-term sustainability of drainage water reuse was supported by the results, but once application of irrigation water was terminated, the field quickly returned to its original saline-sodic condition. PMID- 22535500 TI - Combination external beam radiation and brachytherapy boost with androgen deprivation for treatment of intermediate-risk prostate cancer: long-term results of CALGB 99809. AB - BACKGROUND: Combined transperineal prostate brachytherapy and external beam radiation therapy (EBRT) is widely used for treatment of prostate cancer. Long term efficacy and toxicity results of a multicenter phase 2 trial assessing combination of EBRT and transperineal prostate brachytherapy boost with androgen deprivation therapy (ADT) for intermediate-risk prostate cancer are presented. METHODS: Intermediate-risk patients per Memorial Sloan-Kettering Cancer Center/National Comprehensive Cancer Network criteria received 6 months of ADT, and 45 grays (Gy) EBRT to the prostate and seminal vesicles, followed by transperineal prostate brachytherapy with I125 (100 Gy) or Pd103 (90 Gy). Toxicity was graded using the National Cancer Institute Common Toxicity Criteria version 2 and Radiation Therapy Oncology Group late radiation morbidity scoring systems. Disease-free survival (DFS) was defined as time from enrollment to progression (biochemical, local, distant, or prostate cancer death). In addition to the protocol definition of biochemical failure (3 consecutive prostate specific antigen rises>1.0 ng/mL after 18 months from treatment start), the 1997 American Society for Therapeutic Radiology and Oncology (ASTRO) consensus and Phoenix definitions were also assessed in defining DFS. The Kaplan-Meier method was used to estimate DFS and overall survival. RESULTS: Sixty-one of 63 enrolled patients were eligible. Median follow-up was 73 months. Late grade 2 and 3 toxicity, excluding sexual dysfunction, occurred in 20% and 3% of patients. Six year DFS applying the protocol definition, 1997 ASTRO consensus, and Phoenix definitions was 87.1%, 75.1%, and 84.9%. Six deaths occurred; only 1 was attributed to prostate cancer. Six-year overall survival was 96.1%. CONCLUSIONS: In a cooperative setting, combination of EBRT and transperineal prostate brachytherapy boost plus ADT resulted in excellent DFS with acceptable late toxicity for patients with intermediate-risk prostate cancer. PMID- 22535501 TI - Most physicians were eligible for federal incentives in 2011, but few had EHR systems that met meaningful-use criteria. AB - As more physicians adopt electronic health record systems in their practices, policy interest is focusing on whether physicians are ready to meet the federal "meaningful use" criteria--a vital threshold to qualify for financial incentives. In our analysis of a 2011 nationally representative survey of office-based physicians, we found that 91 percent of physicians were eligible for Medicare or Medicaid meaningful-use incentives. About half of all physicians intended to apply. However, only 11 percent both intended to apply for the incentives and had electronic health record systems with the capabilities to support even two-thirds of the stage 1 core objectives required for meaningful use. Although the federal Medicare incentives will be available through 2016, and Medicaid incentives through 2021, widespread gaps in readiness throughout the states illustrate the challenges physicians face in meeting the federal schedule for the incentive programs. PMID- 22535502 TI - Physicians in nonprimary care and small practices and those age 55 and older lag in adopting electronic health record systems. AB - By 2011 more than half of all office-based physicians were using electronic health record systems, but only about one-third of those physicians had systems with basic features such as the abilities to record information on patient demographics, view laboratory and imaging results, maintain problem lists, compile clinical notes, or manage computerized prescription ordering. Basic features are considered important to realize the potential of these systems to improve health care. We found that although trends in adoption of electronic health record systems across geographic regions converged from 2002 through 2011, adoption continued to lag for non-primary care specialists, physicians age fifty five and older, and physicians in small (1-2 providers) and physician-owned practices. Federal policies are specifically aimed at encouraging primary care providers and small practices to achieve widespread use of electronic health records. To achieve their nationwide adoption, federal policies may also have to focus on encouraging adoption among non-primary care specialists, as well as addressing persistent gaps in the use of electronic record systems by practice size, physician age, and ownership status. PMID- 22535503 TI - Small, nonteaching, and rural hospitals continue to be slow in adopting electronic health record systems. AB - To achieve the goal of comprehensive health information record keeping and exchange among providers and patients, hospitals must have functioning electronic health record systems that contain patient demographics, care histories, lab results, and more. Using national survey data on US hospitals from 2011, the year federal incentives for the meaningful use of electronic health records began, we found that the share of hospitals with any electronic health record system increased from 15.1 percent in 2010 to 26.6 percent in 2011, and the share with a comprehensive system rose from 3.6 percent to 8.7 percent. The proportion able to meet our proxy criteria for meaningful use also rose; in 2011, 18.4 percent of hospitals had these functions in place in at least one unit and 11.2 percent had them across all clinical units. However, gaps in rates of adoption of at least a basic record system have increased substantially over the past four years based on hospital size, teaching status, and location. Small, nonteaching, and rural hospitals continue to adopt electronic health record systems more slowly than other types of hospitals. In sum, this is mixed news for policy makers, who should redouble their efforts among hospitals that appear to be moving slowly and ensure that policies do not further widen gaps in adoption. A more robust infrastructure for information exchange needs to be developed, and possibly a special program for the sizable minority of hospitals that have almost no health information technology at all. PMID- 22535504 TI - Renal cell carcinoma deep sequencing: recent developments. AB - Renal cell carcinoma (RCC) is the most common type of renal cancer in adults. RCC is notoriously resistant to current therapies suggesting the need to improve our knowledge and create more effective therapies. The molecular genetic defects that occur in RCC are extensive and complex ranging from single DNA changes, to large chromosomal defects, to signature disruptions in the transcription of hundreds of genes. These changes are often shared within each histological RCC subtype, illustrating their significance to the disease phenotype. This review presents an overview of the genetic abnormalities that occur within the most common subtypes of RCC. We discuss the recent molecular findings that have advanced our understanding of the somatic architecture of renal tumors and their impact on disease therapeutics. PMID- 22535505 TI - Management of non-small cell lung cancer with oligometastasis. AB - Patients with oligometastatic Non-Small Cell Lung Cancer (NSCLC) present a potential opportunity for curative therapy; however, the challenge remains the definitive treatment of their localized disease and ablation of their limited overt metastatic sites of disease. In selecting patients with oligometastatic NSCLC for definitive therapy, proper staging through radiographic studies, including PET and brain MRI, and the pathologic staging of the mediastinal lymph nodes and potential sites of metastatic disease, are critical. With that in mind, the available literature suggests that in highly selected patients with solitary metastases to the brain, adrenals and other organs, long term survival may be achieved with combined definitive therapy of both the primary lung tumor and the solitary metastatic site. PMID- 22535506 TI - Advances in adjuvant therapy of gastrointestinal stromal tumors. AB - The Gastrointestinal Stromal Tumor (GIST) is the most common sarcoma of the gastrointestinal tract. Major prognostic indices in the evaluation and management of GIST include the size, location and tumor mitotic rate. The discovery of the mutation in the tyrosine kinase receptor c-KIT (CD117) revolutionized the treatment of GIST in the early twenty-first century. Since the first case report of the success of the tyrosine kinase inhibitor (TKI) imatinib, in the treatment of a female patient with metastatic GIST, the paradigm of treatment of this tumor has evolved tremendously. The initial use in metastatic GISTs has progressed to use of the TKI in both the adjuvant and neoadjuvant settings. It is now standard of care for patients with complete resection of primary localized GIST, with high risk of recurrence, to have at least one year of adjuvant imatinib. Recent SSGVXIII study shows that patients benefit from extended duration of therapy. PMID- 22535507 TI - Current state-of-the-art systemic therapy for pediatric soft tissue sarcomas. AB - Pediatric soft tissue sarcomas (STS) are a heterogeneous group of tumors. Rhabdomyosarcomas (RMS) are the most common histologic subtype, while synovial sarcomas and undifferentiated sarcomas are among the more common non rhabdomyosarcomatous soft tissue sarcomas (NRSTS) encountered. While the survival outcome for certain groups of RMS patients is quite good, the prognosis for those with alveolar histology or those with metastatic or relapsed disease remains dismal. Also, the response rate for some NRSTS to conventional chemotherapy is suboptimal. Thus increased understanding of involved molecular pathways, such as the insulin growth factor and mammalian target of rapamycin pathways, may indicate potential targets for therapy. In addition, immunotherapy-based approaches that include both non-specific activation with interleukins as well as targeted tumor antigen specific T lymphocytes are emerging avenues in the treatment of children with soft tissue sarcomas. PMID- 22535508 TI - Effects of molecular weight and loading on matrix metalloproteinase-2 mediated release from poly(ethylene glycol) diacrylate hydrogels. AB - Herein, we report on continued efforts to understand an implantable poly(ethylene glycol) diacrylate (PEGDA) hydrogel drug delivery system that responds to extracellular enzymes, in particular matrix metalloproteinase-2 (MMP-2) to provide controlled drug delivery. By attaching peptide as pendant groups on the hydrogel backbone, drug release occurs at an accelerated rate in the presence of active protease. We investigated MMP-2 entry and optimized parameters of the drug delivery system. Mesh size for different PEGDA molecular weight macromers was measured with PEGDA 3,400 hydrogels having a mesh size smaller than the dimensions of MMP-2 and PEGDA 10,000 and PEGDA 20,000 hydrogels having mesh sizes larger than MMP-2. Purified MMP-2 increased release of peptide fragment compared to buffer at several loading concentrations. Cell-stimulated release was demonstrated using U-87 MG cells embedded in collagen. GM6001, an MMP inhibitor, diminished release and altered the identity of the released peptide fragment. The increase in ratio of release from PEGDA 10,000 and PEGDA 20,000 hydrogels compared to PEGDA 3,400 hydrogels suggests MMP-2 enters the hydrogel. PEGDA molecular weight of 10,000 and 15 % (w/V) were the optimal conditions for release and handling. The use of protease-triggered drug delivery has great advantage particularly with the control of protease penetration as a parameter for controlling rate of release. PMID- 22535509 TI - Reduction in retinal nerve fiber layer thickness in migraine patients. AB - Migraine is a common disorder and its pathogenesis remains still unclear. Several hypotheses about the mechanisms involved in the pathogenesis of migraine have been proposed, but the issue is still far from being fully clarified. Neurovascular system remains one of the most important mechanisms involved in the pathogenesis of migraine and it could be possible that hypoperfusion might involve other areas besides brain, including the retina. This is, for example, of particular interest in a form of migraine, the retinal migraine, which has been associated with hypoperfusion and vasoconstriction of the retinal vasculature. Although vasoconstriction of cerebral and retinal blood vessels is a transient phenomenon, the chronic nature of the migraine might cause permanent structural abnormalities of the brain and also of the retina. On this basis, a few studies have evaluated whether retina is involved in migraine patients: Tan et al. have not found differences in retinal nerve fiber layer (RNFL) thickness between migraine patients and healthy subjects, while Martinez et al. have shown that RNFL in the temporal retinic quadrant of migraineurs is thinner than in normal people. The aim of our study was to analyze if there are differences in retinal nerve fiber layer thickness between migraine patients and normal subjects by studying 24 consecutive migraine patients who presented at the Headache Center of our Neurological Department. Migraine diagnosis has been made according to the International Classification of Headache disorder (ICHD-II). Patients have been recruited according to strict inclusion criteria; then patients have undergone a complete ophthalmological examination at the Ophthalmological Department. All patients and controls who met the ophthalmological criteria have been examined with ocular coherence tomography spectral domain (OCT-SD) after pupillary dilation. OCT-SD is an optical system designed to acquire the retinal layer images simultaneously with fundus confocal images. The statistical analysis has been performed using the Statistical Package for Social Sciences program. The Student's t test has been used to compare numeric variables between migraine and control groups. p value >0.05 has been considered not significant. We have analyzed 40 female subjects, 24 included in the study group and 16 included in the control group. Two migraine patients have been excluded. No differences have been found in the visual acuity between the two groups. Comparing RNFLs of a single eye per person in the two groups, we have found that migraine patients showed significant reduction in the superior quadrants (p < 0.005). Also evaluating both eyes per person there was a significant difference in the same quadrant between the two groups (p < 0.05). The result of this present study show that migraine patients have RNFL thickness reduction in the superior retinal quadrant compared with normal subjects. It is important to underline that RNFL thickness measurement could be a new interesting technique to evaluate the evolution of migraine and perhaps to study if prophylactic treatment could reduce retinal abnormalities seen in migraine patients. OCT-SD is a simple exam that could be repeated and then used for evaluation of headache progression during the time. Our study shows that RNFLs thickness does not depend on illness duration and frequency. PMID- 22535510 TI - Predictors of endoscopic transsphenoidal surgery outcome in acromegaly: patient and tumor characteristics evaluated by magnetic resonance imaging. AB - The availability of various first-line treatment modalities for acromegaly and evolving surgical techniques emphasize the need for accurately defined predictors of surgical outcome. We retrospectively analysed the outcome of 30 patients with acromegaly after initial endoscopic transsphenoidal surgery in two university hospitals from 2001 until 2009, and reviewed comparable literature investigating predictive tumor characteristics. Medical records were monitored for patient characteristics. Each pituitary magnetic resonance imaging (MRI) scan was revised independently by two neuroradiologists using a standardised analysis form to record distinctive predefined tumor characteristics. All characteristics were independently analysed as predictors for persistent disease, and a multivariable predictive model was created. Literature from 2000 onwards was searched for studies describing tumor characteristics predictive for surgical outcome. The cohort consisted of 27 macroadenomas with 90 % demonstrating signs of parasellar extension. The surgical cure rate overall was 30 %. Independently, next to male sex and increasing tumor size, infrasellar and parasellar extension based on MRI staging tended to increase the risk of persistent disease. In a multivariable analysis, sex and parasellar extension of the tumor were demonstrated to be the variables allowing for the best fitted predictive model for persistent disease. Earlier studies on preoperative tumor characteristics showed comparable results, although these were based on several different tumor classification systems. This retrospective study demonstrates that accurately defined tumor characteristics based on imaging, especially for cavernous sinus invasion, can be helpful in predicting surgical outcome. Comparative studies on different treatment modalities are essential for clinical practice within the scope of re-evaluation of the role of surgery in GH-secreting adenomas. PMID- 22535511 TI - In vivo application of chitosan to facilitate intestinal acyclovir absorption in rats. AB - The effect of chitosan on the intestinal absorption of acyclovir (ACV) was evaluated in rats, and factors influencing its facilitative effect on the ACV absorption were examined. When ACV solution containing 1% chitosan with an average molecular weight of 150 kDa was administered into the upper jejunum, a significant increase in the plasma ACV concentration was observed, with the peak ACV concentration being eight times greater than that observed with the chitosan free solution. The chitosan-free ACV solution, whose viscosity was adjusted to remain unchanged with polyethylene glycol, did not cause an increase in the plasma concentration, and neither did the chitosan-free solutions substitutionally containing low molecular cationic compounds, triethanolamine and kanamycin. When chitosan was digested with chitosanase to shorten its polycationic polysaccharide structure, chitosan subjected to 150-min digestion retained its facilitative effect on ACV absorption, but that subjected to 420-min digestion no longer caused facilitation, in which its average molecular weight was reduced to around 10 kDa. It is therefore indicated that intestinal ACV absorption can be facilitated with chitosan, and that it is necessary for chitosan to have a certain length of polycationic polysaccharide structure to exert such facilitation. PMID- 22535512 TI - Hepatocyte growth factor overexpression in the nervous system enhances learning and memory performance in mice. AB - Hepatocyte growth factor (HGF) and its receptor, c-Met, play pivotal roles in the nervous system during development and in disease states. However, the physiological roles of HGF in the adult brain are not well understood. In the present study, to assess its role in learning and memory function, we used transgenic mice that overexpress HGF in a neuron-specific manner (HGF-Tg) to deliver HGF into the brain without injury. HGF-Tg mice displayed increased alternation rates in the Y-maze test compared with age-matched wild-type (WT) controls. In the Morris water maze (MWM) test, HGF-Tg mice took less time to find the platform on the first day, whereas the latency to escape to the hidden platform was decreased over training days compared with WT mice. A transfer test revealed that the incidence of arrival at the exact location of the platform was higher for HGF-Tg mice compared with WT mice. These results demonstrate that overexpression of HGF leads to an enhancement of both short- and long-term memory. Western blot analyses revealed that the levels of N-methyl-D-aspartate (NMDA) receptor subunits NR2A and NR2B, but not NR1, were increased in the hippocampus of HGF-Tg mice compared with WT controls, suggesting that an upregulation of NR2A and NR2B could represent one mechanism by which HGF enhances learning and memory performance. These results demonstrate that modulation of learning and memory performance is an important physiological function of HGF that contributes to normal CNS plasticity, and we propose HGF as a novel regulator of higher brain functions. PMID- 22535514 TI - Characterization of extrastriatal D2 in vivo specific binding of [18F](N methyl)benperidol using PET. AB - PET imaging studies of the role of the dopamine D2 receptor family in movement and neuropsychiatric disorders are limited by the use of radioligands that have near-equal affinities for D2 and D3 receptor subtypes and are susceptible to competition with endogenous dopamine. By contrast, the radioligand [18F]N methylbenperidol ([18F]NMB) has high selectivity and affinity for the D2 receptor subtype (D2R) and is not sensitive to endogenous dopamine. Although [18F]NMB has high binding levels in striatum, its utility for measuring D2R in extrastriatal regions is unknown. A composite MR-PET image was constructed across 14 healthy adult participants representing average NMB uptake 60 to 120 min after [18F]NMB injection. Regional peak radioactivity was identified using a peak-finding algorithm. FreeSurfer and manual tracing identified a priori regions of interest (ROI) on each individual's MR image and tissue activity curves were extracted from coregistered PET images. [18F]NMB binding potentials (BP(ND) s) were calculated using the Logan graphical method with cerebellum as reference region. In eight unique participants, extrastriatal BP(ND) estimates were compared between Logan graphical methods and a three-compartment kinetic tracer model. Radioactivity and BP(ND) levels were highest in striatum, lower in extrastriatal subcortical regions, and lowest in cortical regions relative to cerebellum. Age negatively correlated with striatal BP(ND) s. BP(ND) estimates for extrastriatal ROIs were highly correlated across kinetic and graphical methods. Our findings indicate that PET with [18F]NMB measures specific binding in extrastriatal regions, making it a viable radioligand to study extrastriatal D2R levels in healthy and diseased states. PMID- 22535513 TI - The role of inflammatory processes in Alzheimer's disease. AB - It has become increasingly clear that inflammatory processes play a significant role in the pathophysiology of Alzheimer's disease (AD). Neuroinflammation is characterized by the activation of astrocytes and microglia and the release of proinflammatory cytokines and chemokines. Vascular inflammation, mediated largely by the products of endothelial activation, is accompanied by the production and the release of a host of inflammatory factors which contribute to vascular, immune, and neuronal dysfunction. The complex interaction of these processes is still only imperfectly understood, yet as the mechanisms continue to be elucidated, targets for intervention are revealed. Although many of the studies to date on therapeutic or preventative strategies for AD have been narrowly focused on single target therapies, there is accumulating evidence to suggest that the most successful treatment strategy will likely incorporate a sequential, multifactorial approach, addressing direct neuronal support, general cardiovascular health, and interruption of deleterious inflammatory pathways. PMID- 22535515 TI - Effects of social context and predictive relevance on action outcome monitoring. AB - Outcome monitoring is crucial for subsequent adjustments in behavior and is associated with a specific electrophysiological response, the feedback-related negativity (FRN). Besides feedback generated by one's own action, the performance of others may also be relevant for oneself, and the observation of outcomes for others' actions elicits an observer FRN (oFRN). To test how these components are influenced by social setting and predictive value of feedback information, we compared event-related potentials, as well as their topographies and neural generators, for performance feedback generated by oneself and others in a cooperative versus competitive context. Our results show that (1) the predictive relevance of outcomes is crucial to elicit an FRN in both players and observers, (2) cooperation increases FRN and P300 amplitudes, especially in individuals with high traits of perspective taking, and (3) contrary to previous findings on gambling outcomes, oFRN components are generated for both cooperating and competing observers, but with smaller amplitudes in the latter. Neural source estimation revealed medial prefrontal activity for both FRN and oFRN, but with additional generators for the oFRN in the dorsolateral and ventral prefrontal cortex, as well as the temporoparietal junction. We conclude that the latter set of brain regions could mediate social influences on action monitoring by representing agency and social relevance of outcomes and are, therefore, recruited in addition to shared prediction error signals generated in medial frontal areas during action outcome observation. PMID- 22535516 TI - Impact of glomerular filtration estimate on bleeding risk in very old patients treated with vitamin K antagonists. Results of EPICA study on the behalf of FCSA (Italian Federation of Anticoagulation Clinics). AB - Vitamin K antagonists (VKA) therapy is increasingly used in elderly for prevention of venous thromboembolism (VTE) and of stroke in atrial fibrillation (AF). Glomerular filtration rate (GFR), usually estimated from different equations, decreases progressively with age and it is a risk factor for bleeding. In the frame of the EPICA study, a multicentre prospective observational study including 4,093 patients >=80 years naive to VKA treated for AF or after VTE, we performed this ancillary study to evaluate the prevalence of chronic kidney diseases (CKD) by estimated GFR (eGFR). Incidence of bleedings was recorded and bleeding risk was evaluated in relation to eGFR calculated by Cockroft-Gault (C G); Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas. In addition, the agreement among the three eGFR formulas was evaluated. We recorded 179 major bleedings (rate 1.87 x100 patient-years [py]), 26 fatal (rate 0.27 x100 py). Moderate CKD was detected in 69.3%, 59.3% and 47.0% and severe CKD in 5.8%, 7.4% and 10.0% of cases by C-G, MDRD and CKD-EPI, respectively. Bleeding risk was higher in patients with severe CKD irrespective of the applied equation. This study confirms that CKD represents an independent risk factor for bleeding and that a wide proportion of elderly on VKA had severe or moderate CKD, suggesting the need for frequent monitoring. Although the different available equations yield different eGFR, all appear to similarly predict the risk of major bleeding. PMID- 22535517 TI - Double-blind placebo-controlled trial of quetiapine in anorexia nervosa. AB - OBJECTIVE: Our objective is to determine whether quetiapine was superior to placebo in increasing weight or reducing core symptoms of anorexia nervosa as assessed by the Yale-Brown-Cornell Eating Disorder Scale and the Eating Disorder Inventory-2. METHOD: Participants were randomised to 8 weeks of quetiapine or placebo. RESULTS: There are 21 participants who signed informed consent, 15 were randomised, 14 returned for at least one visit after receiving drug and 10 completed the study. There were no differences between drug and placebo in questionnaire scores, weight or measures of anxiety or depression. DISCUSSION: There was no difference between quetiapine and placebo on weight gain or core symptoms. Small effect sizes suggest that a higher number of participants would not increase significant differences between groups. PMID- 22535519 TI - Evaluation of anticancer drug-loaded nanoparticle characteristics by nondestructive methodologies. AB - The purpose of this study was to utilize near-infrared (NIR) spectroscopy and near-infrared chemical imaging (NIR-CI) as non-invasive techniques to evaluate the drug loading in letrozole-loaded PLGA nanoparticle formulations prepared by the emulsification-solvent evaporation method. A Plackett-Burman design was applied to evaluate the main effects of amount of drug (X(1)), amount of polymer (X(2)), stirring rate (X(3)), emulsifier concentration (X(4)), organic to aqueous phase volume ratio (X(5)), type of organic solvent (X(6)), and homogenization time (X(7)) on drug entrapment efficiency. The influence of three different spectral pretreatment methods (multiplicative scatter correction, standard normal variate, and Savitzky-Golay second derivative transformation with third-order polynomial) and two different regression methods (PLS regression and principal component regression (PCR)) on model prediction ability were compared. PLS of spectra that were pretreated with Savitzky-Golay second derivative transformation provided better model prediction than PCR as it revealed better linear correlation (correlation coefficient of 0.991) for both calibration and prediction models. Relatively low values of root mean square errors of calibration (RMSEC = 0.748) and prediction (RMSEP = 0.786) and low standard errors of calibration (SEC = 0.758) and prediction (SEP = 0.589) suggested good predictability for estimation of the loading of letrozole in PLGA nanoparticles. NIR-CI analysis also revealed mutual homogenous distribution of both polymer and drug and was capable of clearly distinguishing the 12 formulations both quantitatively and qualitatively. In conclusion, NIR and NIR-CI could be potentially used to characterize anticancer drug-loaded nanoparticulate matrix. PMID- 22535518 TI - Single-injection HPLC method for rapid analysis of a combination drug delivery system. AB - Developing combination drug delivery systems (CDDS) is a challenging but necessary task to meet the needs of complex therapy regimes for patients. As the number of multi-drug regimens being administered increases, so does the difficulty of characterizing the CDDS as a whole. We present a single-step method for quantifying three model therapeutics released from a model hydrogel scaffold using high-performance liquid chromatography (HPLC). Poly(ethylene glycol) dimethacrylate (PEGDMA) hydrogel tablets were fabricated via photoinitiated crosslinking and subsequently loaded with model active pharmaceutical ingredients (APIs), namely, porcine insulin (PI), fluorescein isothiocyanate-labeled bovine serum albumin (FBSA), prednisone (PSE), or a combination of all three. The hydrogel tablets were placed into release chambers and sampled over 21 days, and APIs were quantified using the method described herein. Six compounds were isolated and quantified in total. Release kinetics based on chemical properties of the APIs did not give systematic relationships; however, PSE was found to have improved device loading versus PI and FBSA. Rapid analysis of three model APIs released from a PEGDMA CDDS was achieved with a direct, single-injection HPLC method. Development of CDDS platforms is posited to benefit from such analytical approaches, potentially affording innovative solutions to complex disease states. PMID- 22535520 TI - Improvement of aripiprazole solubility by complexation with (2-hydroxy)propyl beta-cyclodextrin using spray drying technique. AB - Due to the fact that the number of new poorly soluble active pharmaceutical ingredients is increasing, it is important to investigate the possibilities of improvement of their solubility in order to obtain a final pharmaceutical formulation with enhanced bioavailability. One of the strategies to increase drug solubility is the inclusion of the APIs in cyclodextrins. The aim of this study was to investigate the possibility of aripiprazole solubility improvement by inclusion in (2-hydroxy)propyl-beta-cyclodextrin (HPBCD) and simultaneous manipulation of pH of the medium and addition of polyvinylpyrrolidone. Aripiprazole-HPBCD complexes were prepared by spray drying aqueous drug-HPBCD solutions, and their properties were compared with those prepared by solvent-drop co-grinding and physical mixing. The obtained powders were characterized by thermoanalytical methods (TGA and DSC), FTIR spectroscopy, their dissolution properties were assessed, while the binding of aripiprazole into the cavity of HPBCD was studied by molecular docking simulations. The solubilization capacity was found to be dependent on pH as well as the buffer solution's ionic composition. The presence of PVP in the formulation could affect the solubilization capacity significantly, but further experimentation is required before its effect is fully understood. On the basis of solubility studies, the drug/HPBCD stoichiometry was found to be 1:3. The spray-dried products were free of crystalline aripiprazole, they possessed higher solubility and dissolution rate, and were stable enough over a prolonged period of storage. Spray drying of cyclodextrin solutions proved to be an appropriate and efficient technique for the preparation of highly soluble inclusion compounds of aripiprazole and HPBCD. PMID- 22535521 TI - The Ras-like protein R-Ras2/TC21 is important for proper mammary gland development. AB - R-Ras2/TC21 is a GTPase with high sequence and signaling similarity with Ras subfamily members. Although it has been extensively studied using overexpression studies in cell lines, its physiological role remains poorly characterized. Here we used RRas2-knockout mice expressing beta-galactosidase under the regulation of the endogenous RRas2 promoter to investigate the function of this GTPase in vivo. Despite its expression in tissues critical for organismal viability, RRas2(-/-) mice show no major alterations in viability, growth rates, cardiovascular parameters, or fertility. By contrast, they display a marked and specific defect in the development of the mammary gland during puberty. In the absence of R Ras2/TC21, this gland forms reduced numbers of terminal end buds (TEBs) and ductal branches, leading to a temporal delay in the extension and arborization of the gland tree in mammary fat pads. This phenotype is linked to cell-autonomous proliferative defects of epithelial cells present in TEBs. These cells also show reduced Erk activation but wild type-like levels of phosphorylated Akt. Using compound RRas2-, HRas-, and NRas-knockout mice, we demonstrate that these GTPases act in a nonsynergistic and nonadditive manner during this morphogenic process. PMID- 22535522 TI - Cell survival, DNA damage, and oncogenic transformation after a transient and reversible apoptotic response. AB - Apoptosis serves as a protective mechanism by eliminating damaged cells through programmed cell death. After apoptotic cells pass critical checkpoints, including mitochondrial fragmentation, executioner caspase activation, and DNA damage, it is assumed that cell death inevitably follows. However, this assumption has not been tested directly. Here we report an unexpected reversal of late-stage apoptosis in primary liver and heart cells, macrophages, NIH 3T3 fibroblasts, cervical cancer HeLa cells, and brain cells. After exposure to an inducer of apoptosis, cells exhibited multiple morphological and biochemical hallmarks of late-stage apoptosis, including mitochondrial fragmentation, caspase-3 activation, and DNA damage. Surprisingly, the vast majority of dying cells arrested the apoptotic process and recovered when the inducer was washed away. Of importance, some cells acquired permanent genetic changes and underwent oncogenic transformation at a higher frequency than controls. Global gene expression analysis identified a molecular signature of the reversal process. We propose that reversal of apoptosis is an unanticipated mechanism to rescue cells from crisis and propose to name this mechanism "anastasis" (Greek for "rising to life"). Whereas carcinogenesis represents a harmful side effect, potential benefits of anastasis could include preservation of cells that are difficult to replace and stress-induced genetic diversity. PMID- 22535523 TI - The ulnar-mammary syndrome gene, Tbx3, is a direct target of the retinoic acid signaling pathway, which regulates its expression during mouse limb development. AB - TBX3, a member of the T-box transcription factor gene family, is a transcriptional repressor that is required for the development of the heart, limbs, and mammary glands. Mutations in TBX3 that result in reduced functional protein lead to ulnar-mammary syndrome, a developmental disorder characterized by limb, mammary gland, tooth, and genital abnormalities. Increased levels of TBX3 have been shown to contribute to the oncogenic process, and TBX3 is overexpressed in several cancers, including breast cancer, liver cancer, and melanoma. Despite its important role in development and postnatal life, little is known about the signaling pathways that modulate TBX3 expression. Here we show, using in vitro and in vivo assays, that retinoic acid (RA) activates endogenous TBX3 expression, which is mediated by an RA-receptor complex directly binding and activating the TBX3 promoter, and we provide evidence that this regulation may be functionally relevant in mouse embryonic limb development. Our data identify TBX3 as a direct target of the RA signaling pathway and extend our understanding of the role and regulation of TBX3 in limb development. PMID- 22535524 TI - Plk1 regulates the kinesin-13 protein Kif2b to promote faithful chromosome segregation. AB - Solid tumors are frequently aneuploid, and many display high rates of ongoing chromosome missegregation in a phenomenon called chromosomal instability (CIN). The most common cause of CIN is the persistence of aberrant kinetochore microtubule (k-MT) attachments, which manifest as lagging chromosomes in anaphase. k-MT attachment errors form during prometaphase due to stochastic interactions between kinetochores and microtubules. The kinesin-13 protein Kif2b promotes the correction of k-MT attachment errors in prometaphase, but the mechanism restricting this activity to prometaphase remains unknown. Using mass spectrometry, we identified multiple phosphorylation sites on Kif2b, some of which are acutely sensitive to inhibition of Polo-like kinase 1 (Plk1). We show that Plk1 directly phosphorylates Kif2b at threonine 125 (T125) and serine 204 (S204), and that these two sites differentially regulate Kif2b function. Phosphorylation of S204 is required for the kinetochore localization and activity of Kif2b in prometaphase, and phosphorylation of T125 is required for Kif2b activity in the correction of k-MT attachment errors. These data demonstrate that Plk1 regulates both the localization and activity of Kif2b during mitosis to promote the correction of k-MT attachment errors to ensure mitotic fidelity. PMID- 22535525 TI - Orm protein phosphoregulation mediates transient sphingolipid biosynthesis response to heat stress via the Pkh-Ypk and Cdc55-PP2A pathways. AB - Sphingoid intermediates accumulate in response to a variety of stresses, including heat, and trigger cellular responses. However, the mechanism by which stress affects sphingolipid biosynthesis has yet to be identified. Recent studies in yeast suggest that sphingolipid biosynthesis is regulated through phosphorylation of the Orm proteins, which in humans are potential risk factors for childhood asthma. Here we demonstrate that Orm phosphorylation status is highly responsive to sphingoid bases. We also demonstrate, by monitoring temporal changes in Orm phosphorylation and sphingoid base production in cells inhibited for yeast protein kinase 1 (Ypk1) activity, that Ypk1 transmits heat stress signals to the sphingolipid biosynthesis pathway via Orm phosphorylation. Our data indicate that heat-induced sphingolipid biosynthesis in turn triggers Orm protein dephosphorylation, making the induction transient. We identified Cdc55 protein phosphatase 2A (PP2A) as a key phosphatase that counteracts Ypk1 activity in Orm-mediated sphingolipid biosynthesis regulation. In total, our study reveals a mechanism through which the conserved Pkh-Ypk kinase cascade and Cdc55-PP2A facilitate rapid, transient sphingolipid production in response to heat stress through Orm protein phosphoregulation. We propose that this mechanism serves as the basis for how Orm phosphoregulation controls sphingolipid biosynthesis in response to stress in a kinetically coupled manner. PMID- 22535526 TI - The PDZ-adaptor protein syntenin-1 regulates HIV-1 entry. AB - Syntenin-1 is a cytosolic adaptor protein involved in several cellular processes requiring polarization. Human immunodeficiency virus type 1 (HIV-1) attachment to target CD4(+) T-cells induces polarization of the viral receptor and coreceptor, CD4/CXCR4, and cellular structures toward the virus contact area, and triggers local actin polymerization and phosphatidylinositol 4,5-bisphosphate (PIP(2)) production, which are needed for successful HIV infection. We show that syntenin 1 is recruited to the plasma membrane during HIV-1 attachment and associates with CD4, the main HIV-1 receptor. Syntenin-1 overexpression inhibits HIV-1 production and HIV-mediated cell fusion, while syntenin depletion specifically increases HIV 1 entry. Down-regulation of syntenin-1 expression reduces F-actin polymerization in response to HIV-1. Moreover, HIV-induced PIP(2) accumulation is increased in syntenin-1-depleted cells. Once the virus has entered the target cell, syntenin-1 polarization toward the viral nucleocapsid is lost, suggesting a spatiotemporal regulatory role of syntenin-1 in actin remodeling, PIP(2) production, and the dynamics of HIV-1 entry. PMID- 22535527 TI - Constitutive dynein activity in She1 mutants reveals differences in microtubule attachment at the yeast spindle pole body. AB - The organization of microtubules is determined in most cells by a microtubule organizing center, which nucleates microtubule assembly and anchors their minus ends. In Saccharomyces cerevisiae cells lacking She1, cytoplasmic microtubules detach from the spindle pole body at high rates. Increased rates of detachment depend on dynein activity, supporting previous evidence that She1 inhibits dynein. Detachment rates are higher in G1 than in metaphase cells, and we show that this is primarily due to differences in the strengths of microtubule attachment to the spindle pole body during these stages of the cell cycle. The minus ends of detached microtubules are stabilized by the presence of gamma tubulin and Spc72, a protein that tethers the gamma-tubulin complex to the spindle pole body. A Spc72-Kar1 fusion protein suppresses detachment in G1 cells, indicating that the interaction between these two proteins is critical to microtubule anchoring. Overexpression of She1 inhibits the loading of dynactin components, but not dynein, onto microtubule plus ends. In addition, She1 binds directly to microtubules in vitro, so it may compete with dynactin for access to microtubules. Overall, these results indicate that inhibition of dynein activity by She1 is important to prevent excessive detachment of cytoplasmic microtubules, particularly in G1 cells. PMID- 22535529 TI - Three case reports of inherited antithrombin deficiency in China: double novel missense mutations, a nonsense mutation and a frameshift mutation. AB - Antithrombin is a plasma protein critical to the regulation of coagulation. It plays a pivotal anticoagulant role by preventing the activation of procoagulant proteinases. Inherited and (or) acquired deficiency of AT is an established risk factor for venous thromboembolism. Sequencing analysis of SERPINC1 gene of three families revealed that Family I had double novel missense mutations (c.134G > A&c.342T > G), Family II had a nonsense mutation (c.770G > A) while Family III had a frameshift mutation (c.800-803del). In addition, all of them had a large number of carriers in their families what was very rare in China. PMID- 22535528 TI - Effects of bone matrix proteins on fracture and fragility in osteoporosis. AB - Bone mineral density alone cannot reliably predict fracture risk in humans and laboratory animals. Therefore, other factors including the quality of organic bone matrix components and their interactions may be of crucial importance to understanding of fragility fractures. Emerging research evidence shows, that in addition to collagen, certain noncollagenous proteins (NCPs) play a significant role in the structural organization of bone and influence its mechanical properties. However, their contribution to bone strength still remains largely undefined. Collagen and NCPs undergo different post-translational modifications, which alter the quality of the extracellular matrix and the response of bone to mechanical load. The primary focus of this overview is on NCPs that, together with collagen, contribute to structural and mechanical properties of bone. Current information on several mechanisms through which some NCPs influence bone's resistance to fracture, including the role of nonenzymatic glycation, is also presented. PMID- 22535530 TI - Prothrombotic gene polymorphisms and plasma factors in young North Indian survivors of acute myocardial infarction. AB - The aim of this study was to evaluate the association of prothrombotic gene polymorphisms [factor V Leiden (FVL) 1691GA, factor VII (FVII) 10976GA, FVII HVR4, platelet membrane glycoproteins GP1BA 1018CT, GP1BA VNTR, integrin ITGB3 1565TC, integrin ITGA2 807CT and methylenetetrahydrofolate reductase (MTHFR) 677C/T], plasma factors (fibrinogen and homocysteine) and traditional risk factors with acute myocardial infarction (AMI) in 184 patients <= 40 years of age and 350 controls (<= 40 years) from north India. Multiple logistic-regression analysis showed that hypertension (OR 1.9, 95 % CI 1.1-3.8, p = 0.042), diabetes mellitus (OR 10.5, 95 % CI 2.0-56.7, p = 0.006), smoking (OR 7.1, 95 % CI 3.7 13.6, p < 0.001), low socio-economic status (OR 13.5, 95 % CI 2.3-78.4, p = 0.004), high waist-hip ratio (OR 35.6, 95 % CI 11.1-53.7, p < 0.001) and FVL 1691GA (OR 6.0, 95 % CI 1.2-13.4, p = 0.03) were independent risk predictors of AMI in young. Elevated plasma fibrinogen also showed association with increased AMI risk. ITGA2 807C/T polymorphism showed protection against AMI in univariate analysis only, while GP1BA VNTR-ac (OR 0.4, 95 % CI 0.2-0.9, p = 0.033) showed significant protection even after adjusting for age and sex. Multinominal logistic-regression analysis showed gene-gene (GP1BA 1018C/T with GP1BA VNTR and ITGA2 807C/T with ITGB3 1565T/C polymorphisms) and gene-environment interactions (gene polymorphisms with smoking) operating in the occurrence of AMI in young. In conclusion, the role of inherited predisposition to thrombosis in complex, polygenic and multifactorial disease like AMI is limited to certain genetic factors, in combination with environmental factor like smoking. PMID- 22535531 TI - Functional interaction between mesenchymal stem cells and spiral ligament fibrocytes. AB - Spiral ligament fibrocytes (SLFs) play an important role in normal hearing as well as in several types of sensorineural hearing loss attributable to inner ear homeostasis disorders. Our previous study showed that transplantation of mesenchymal stem cells (MSCs) into the inner ear of rats with damaged SLFs significantly accelerates hearing recovery compared with rats without MSC transplantation. To elucidate this mechanism of SLF repair and to determine the contribution of transplanted MSCs in this model, we investigated the mutual effects on differentiation and proliferation between MSCs and SLFs in a coculture system. Factors secreted by SLFs had the ability to promote the transdifferentiation of MSCs into SLF-like cells, and the factors secreted by MSCs had a stimulatory effect on the proliferation of SLFs. Cytokine antibody array analysis revealed the involvement of transforming growth factor-beta (TGF beta) in SLF proliferation induced by MSCs. In addition, a TGF-beta inhibitor reduced SLF proliferation induced by MSC stimulation. Our results suggest that there are two mechanisms of hearing recovery following transplantation of MSCs into the inner ear: 1) MSCs transdifferentiate into SLF-like cells that compensate for lost SLFs, and 2) transplanted MSCs stimulate the regeneration of host SLFs. Both mechanisms contribute to the functional recovery of the damaged SLF network. PMID- 22535532 TI - Application of membrane permeability evaluated in in vitro analyses to estimate blood-retinal barrier permeability. AB - The relationship between the in vitro membrane permeability and systemic blood retinal barrier (BRB) permeability of drugs was investigated. To determine membrane permeability trend lines in this relationship, the apparent permeability (P(app)) and initial uptake rate (V) of 23 compounds were evaluated in a parallel artificial membrane permeability assay and the uptake study with a rat retinal endothelial cell line (TR-iBRB2 cells) for comparison with their retinal uptake index (RUI). The RUI values of compounds undergoing passive diffusion across the BRB were correlated with a log of the P(app) [RUI = 7.93 * 10 * exp (0.994 * log P(app)), r(2) = 0.660] and a log of the V [RUI = 26.5 * exp (1.55 * log V), r(2) = 0.581]. The RUI values of compounds undergoing carrier-mediated transport across the BRB were correlated with a log of the V [RUI = 26.5 * exp (0.887 * log V), r(2) = 0.559]. These results showed that the membrane permeability trend lines derived from the RUI and V values reflect the transport of drugs at the BRB, suggesting that an in vitro analysis-based estimation of the BRB permeability can be obtained using TR-iBRB2 cells and membrane permeability trend lines. PMID- 22535533 TI - Abnormal expression of stathmin 1 in brain tissue of patients with intractable temporal lobe epilepsy and a rat model. AB - Microtubule dynamics have been shown to contribute to neurite outgrowth, branching, and guidance. Stathmin 1 is a potent microtubule-destabilizing factor that is involved in the regulation of microtubule dynamics and plays an essential role in neurite elongation and synaptic plasticity. Here, we investigate the expression of stathmin 1 in the brain tissues of patients with intractable temporal lobe epilepsy (TLE) and experimental animals using immunohistochemistry, immunofluorescence and western blotting. We obtained 32 temporal neocortex tissue samples from patients with intractable TLE and 12 histologically normal temporal lobe tissues as controls. In addition, 48 Sprague Dawley rats were randomly divided into six groups, including one control group and five groups with epilepsy induced by lithium chloride-pilocarpine. Hippocampal and temporal lobe tissues were obtained from control and epileptic rats on Days 1, 7, 14, 30, and 60 after kindling. Stathmin 1 was mainly expressed in the neuronal membrane and cytoplasm in the human controls, and its expression levels were significantly higher in patients with intractable TLE. Moreover, stathmin 1 was also expressed in the neurons of both the control and the experimental rats. Stathmin 1 expression was decreased in the experimental animals from 1 to 14 days postseizure and then significantly increased at Days 30 and 60 compared with the control group. Many protruding neuronal processes were observed in the TLE patients and in the chronic stage epileptic rats. These data suggest that stathmin 1 may participate in the abnormal network reorganization of synapses and contribute to the pathogenesis of TLE. PMID- 22535534 TI - Injury rates in team sport events: tackling challenges in assessing exposure time. PMID- 22535535 TI - Biomechanical insights into the aetiology of infraspinatus syndrome. AB - OBJECTIVE: Infraspinatus syndrome (IS) results from injury to the suprascapular nerve. For reasons that are poorly understood, volleyball players are at greater risk of developing IS than are athletes who compete in other overhead sports. Differences between the shoulder kinematics of volleyball-related overhead skills and those skills demanded by other overhead sports might explain the pronounced prevalence of IS among volleyball athletes. DESIGN: Observational, laboratory based, cross-sectional study. SETTING: The American Sports Medicine Institute. PARTICIPANTS: Fourteen healthy female Division 1 collegiate volleyball athletes. METHODS: Upper limb biomechanics of 14 healthy female Division 1 collegiate volleyball athletes while spiking and serving were quantified, then compared to the results from data previously obtained from female baseball pitchers and tennis players. RESULTS: Although the general movement pattern at the shoulder girdle is qualitatively similar for the upper limb skills required by a variety of overhead sports, volleyball spiking and serving result in greater shoulder abduction and horizontal adduction at the moment of ball contact/release than do baseball pitching or tennis serving. CONCLUSION: The authors suggest that the unique scapular mechanics which permit the extreme shoulder abduction and horizontal adduction that characterise volleyball spiking and serving place anatomically predisposed volleyball athletes at increased risk for developing cumulative traction-related injury to the suprascapular nerve at the level of the spinoglenoid notch. PMID- 22535536 TI - '23 and 1/2 h' goes viral: top 10 learnings about making a health message that people give to one another. PMID- 22535537 TI - What makes champions? A review of the relative contribution of genes and training to sporting success. AB - Elite sporting performance results from the combination of innumerable factors, which interact with one another in a poorly understood but complex manner to mould a talented athlete into a champion. Within the field of sports science, elite performance is understood to be the result of both training and genetic factors. However, the extent to which champions are born or made is a question that remains one of considerable interest, since it has implications for talent identification and management, as well as for how sporting federations allocate scarce resources towards the optimisation of high-performance programmes. The present review describes the contributions made by deliberate practice and genetic factors to the attainment of a high level of sporting performance. The authors conclude that although deliberate training and other environmental factors are critical for elite performance, they cannot by themselves produce an elite athlete. Rather, individual performance thresholds are determined by our genetic make-up, and training can be defined as the process by which genetic potential is realised. Although the specific details are currently unknown, the current scientific literature clearly indicates that both nurture and nature are involved in determining elite athletic performance. In conclusion, elite sporting performance is the result of the interaction between genetic and training factors, with the result that both talent identification and management systems to facilitate optimal training are crucial to sporting success. PMID- 22535538 TI - PSI's Pharmaceutical Statistics Journal Club. PMID- 22535539 TI - Activated platelets interact with lung cancer cells through P-selectin glycoprotein ligand-1. AB - Hematogenous metastasis always leads to the poor prognosis of non-small cell lung cancers (NSCLC). Activated platelets are involved in hematogenous metastasis and may be a potential therapeutic target. P-selectin is an important adhesion molecule and expressed on the surface of activated platelets. P-selectin glycoprotein ligand-1 (PSGL-1) as a transmembrane protein is expressed on the surface of various cell types. P-selectin can bind to PSGL-1, and thereby initiate the platelet-mediated cell adhesion. The aim of the study was to investigate the degree of platelet activation in NSCLC and the roles of PSGL-1 in the activation of platelets. Purified platelets were obtained from NSCLC patients (40 lung adenocarcinomas and 26 lung squamous cell carcinomas), and P-selectin expression was detected by fluorescence-activated cell sorter. The population of peripheral blood platelets with P-selectin expression in lung adenocarcinoma was 63.16 +/- 25.44 %, and significantly higher than that in lung squamous cell carcinoma (35.97 +/- 17.19 %) and the healthy population (9.12 +/- 7.66 %, n = 30). A specific small hairpin RNA (shRNA) for PSGL-1 was transfected into A549 human alveolar cell carcinoma cells. The expressions of PSGL-1 mRNA and protein were significantly reduced with the PSGL-1 shRNA (p < 0.01). Furthermore, the knockdown of PSGL-1 also resulted in the significantly reduced aggregate formation of activated platelets and A549 cells. Thus, activated platelets may interact with lung cancer cells through PSGL-1. Inhibiting platelet activation and/or down-regulating PSGL-1 expression may be useful for suppression of tumor metastasis. PMID- 22535540 TI - Quantitative sensory testing of neuropathic pain patients: potential mechanistic and therapeutic implications. AB - Quantitative sensory testing (QST) is a widely accepted tool to investigate somatosensory changes in pain patients. Many different protocols have been developed in clinical pain research within recent years. In this review, we provide an overview of QST and tested neuroanatomical pathways, including peripheral and central structures. Based on research studies using animal and human surrogate models of neuropathic pain, possible underlying mechanisms of chronic pain are discussed. Clinically, QST may be useful for 1) the identification of subgroups of patients with different underlying pain mechanisms; 2) prediction of therapeutic outcomes; and 3) quantification of therapeutic interventions in pain therapy. Combined with sensory mapping, QST may provide useful information on the site of neural damage and on mechanisms of positive and negative somatosensory abnormalities. The use of QST in individual patients for diagnostic purposes leading to individualized therapy is an interesting concept, but needs further validation. PMID- 22535541 TI - The effect of mannitol crystallization in mannitol-sucrose systems on LDH stability during freeze-drying. AB - The objective of this study was to investigate the influence of mannitol crystallization and the effect of annealing on the stability of lactate dehydrogenase (LDH) during freeze-drying. For this purpose, protein formulations with different weight ratios of mannitol to sucrose were freeze-dried with and without annealing. Product crystallinity was calculated based on differential scanning calorimetry data. Protein stability was evaluated both functionally by measuring the activity recovery of the model protein LDH after freeze-drying, and structurally by analyzing the protein secondary structure. LDH showed lower stability in annealed samples, and a correlation could be established between the extent of product crystallinity and the stability of the model protein. The destabilizing effect of mannitol crystallization on LDH during freeze-drying can likely be attributed to removal of mannitol from the amorphous phase containing the protein. In addition, the formation of mannitol crystals seemed to enhance the interfacial denaturation of protein during freeze-drying. The use of 0.01% of Tween 80 in the formulation greatly improved the structural and functional stability of LDH against stresses induced by mannitol crystallization. PMID- 22535542 TI - A supra-annular malposition of the Perceval S sutureless aortic valve: the 'chi movement' removal technique and subsequent reimplantation. AB - The Perceval S sutureless valve prosthesis has recently been introduced as a new biological aortic valve prosthesis, but a specific learning curve is required, as for every cardiac surgical centre dealing with a new technique. After the removal of the stenotic valve, the prosthetic valve is correctly positioned within the mildly decalcified aortic annulus. When a supra-annular malposition occurs, due to an excessively rapid release of the prosthesis in the aorta or incomplete annular visualization, the Perceval S valve can safely be removed even after balloon dilation. The procedure performed is a 'chi-movement' with the aid of anatomical forceps. If the prosthesis does not show any malformation after the procedure, it can be reimplanted in the correct intra-annular position. PMID- 22535543 TI - Local effects of high-powered neodymium-doped yttrium aluminium garnet laser systems on the pulmonary parenchyma: an experimental study on the isolated perfused pig lung lobe. AB - Neodymium-doped yttrium aluminium garnet (Nd:YAG) laser systems (with a power output up to 100 W, wavelength 1318 nm) have been introduced into clinical practice for resecting lung metastases. However, the extent of the local effect on the lung parenchyma and the role of the application time are unknown. All experiments were performed on normothermal, whole-blood-perfused paracardiac pig lung lobes (n = 6). Lobes were not ventilated during the laser application. The laser itself was clamped into a hydraulic feed system that moves horizontally at two different constant rates (10 and 20 mm/s). A 30-mm focus distance from the pulmonary parenchyma was maintained at all times. At each feed rate, the laser was applied thrice along a horizontal path using laser power outputs of 40, 60 and 100 W. After lasering, we recruited the lungs via a ventilation tube using pressures of up to 40 cm H(2)O and tested lung tightness. Both a gross inspection and a histological examination revealed larger coagulation zones for higher power outputs and lower laser feed rates. Exposure to higher outputs for shorter application times reduced the laser effect. When lungs were manually recruited, all lungs were airtight up to a pressure of 40 mmHg. Reducing the exposure time reduces local tissue coagulation even when the laser power output is increased. PMID- 22535544 TI - A rare disappearing right atrial mass. AB - Cardiac tuberculosis is rare and usually involves the pericardium. Myocardial tuberculoma is a very rare occurrence and only a few cases have been reported. We describe a rare case of cardiac tuberculoma involving the whole of the lateral right atrial wall, extending from the superior vena cava/right atrial junction up to a tricuspid valve. The initial diagnosis of right atrial myxoma was made based on the echocardiography report and surgical excision was planned. Intraoperatively, the excision of the mass was deferred due to the extensive nature of the disease and a high suspicion of malignancy. Cardiac tuberculoma was confirmed by histopathological examination. The patient made a remarkable recovery with the complete disappearance of the mass after anti-tuberculous treatment, as viewed by a postoperative echocardiography during the follow-up. PMID- 22535545 TI - Postinjury treatment with rolipram increases hemorrhage after traumatic brain injury. AB - The pathology caused by traumatic brain injury (TBI) is exacerbated by the inflammatory response of the injured brain. Two proinflammatory cytokines that contribute to inflammation after TBI are tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta). From previous studies using the parasagittal fluid-percussion brain injury model, we reported that the anti-inflammatory drug rolipram, a phosphodiesterase 4 inhibitor, reduced TNF-alpha and IL-1beta levels and improved histopathological outcome when administered 30 min prior to injury. We now report that treatment with (+/-)-rolipram given 30 min after injury significantly reduced TNF-alpha levels in the cortex and hippocampus. However, postinjury administration of (+/-)-rolipram significantly increased cortical contusion volume and increased atrophy of the cortex compared with vehicle treated animals at 10 days postinjury. Thus, despite the reduction in proinflammatory cytokine levels, histopathological outcome was worsened with post TBI (+/-)-rolipram treatment. Further histological analysis of (+/-)-rolipram treated TBI animals revealed significant hemorrhage in the contused brain. Given the well-known role of (+/-)-rolipram of increasing vasodilation, it is likely that (+/-)-rolipram worsened outcome after fluid-percussion brain injury by causing increased bleeding. PMID- 22535547 TI - Controlling morphology of peptide-based soft structures by covalent modifications. AB - Control of gross morphology of soft matter remains an area of continued interest. Towards this goal, this paper describes conjugation of mannose residues and introduction of thiol functionalities to diphenylalanine (FF) dipeptide, a fibrillating motif from amyloid-beta peptide, as covalent modifiers of its solution-phase self-assembly process. It was found that covalent attachment of a single mannose residue to FF leads to the retention of tubular structures, whereas the conjugation of two mannose units, linked through a Lys residue, resulted in a dramatic change from tubular morphology to spherical structures. However, a similar switch to spherical objects could be achieved by introducing a thiol residue in the mono-mannosylated FF dipeptide. Interestingly, these glycopeptides also exhibited interaction with concanavalin A, thereby providing an indirect evidence for the availability of mannose units for the process of lectin-carbohydrate interaction in the self-organized state. PMID- 22535546 TI - Redistribution of monocarboxylate transporter 2 on the surface of astrocytes in the human epileptogenic hippocampus. AB - Emerging evidence points to monocarboxylates as key players in the pathophysiology of temporal lobe epilepsy (TLE) with hippocampal sclerosis (mesial temporal lobe epilepsy, MTLE). Monocarboxylate transporters (MCTs) 1 and 2, which are abundantly present on brain endothelial cells and perivascular astrocyte endfeet, respectively, facilitate the transport of monocarboxylates and protons across cell membranes. Recently, we reported that the density of MCT1 protein is reduced on endothelial cells and increased on astrocyte plasma membranes in the hippocampal formation in patients with MTLE and in several animal models of the disorder. Because the perivascular astrocyte endfeet comprise an important part of the neurovascular unit, we now assessed the distribution of the MCT2 in hippocampal formations in TLE patients with (MTLE) or without hippocampal sclerosis (non-MTLE). Light microscopic immunohistochemistry revealed significantly less perivascular MCT2 immunoreactivity in the hippocampal formation in MTLE (n = 6) than in non-MTLE (n = 6) patients, and to a lesser degree in non-MTLE than in nonepilepsy patients (n = 4). Immunogold electron microscopy indicated that the loss of MCT2 protein occurred on perivascular astrocyte endfeet. Interestingly, the loss of MCT2 on astrocyte endfeet in MTLE (n = 3) was accompanied by an upregulation of the protein on astrocyte membranes facing synapses in the neuropil, when compared with non-MTLE (n = 3). We propose that the altered distribution of MCT1 and MCT2 in TLE (especially MTLE) limits the flux of monocarboxylates across the blood-brain barrier and enhances the exchange of monocarboxylates within the brain parenchyma. PMID- 22535548 TI - Evaluation of group visits for Chinese hypertensives based on primary health care center. AB - BACKGROUND: Hypertension is becoming a main health problem worldwide, but there is little evidence as to how care for hypertensive patients should be organized and delivered in the community to help improve blood pressure control. Group visit (GV) as a new care-delivering model has been shown to be less costly and have quality that is equal to or of better quality than usual care. The present study was conducted to evaluate the effectiveness of GVs for Chinese hypertensive patients compared with usual care. METHODS: A randomized, controlled trial was conducted, and a total of 1024 patients participated in the study. The patients in the GV groups received health care services in group format. The outcomes on blood pressure, treatment compliance, and self-efficacy were measured at baseline and at 6 months follow-up. RESULTS: The average diastolic blood pressure decrease in the GV groups (1.5 mm Hg) was more than that in the control groups (0.4 mm Hg) significantly. In the GV groups, compliance with medicine, physical activities, and diet increased to 14.7%, 9.7%, and 10.1%, respectively, which is more significant than that in the control groups (2.0%, 1.6%, and 8.0%); self-reported health and self-efficacy also improved significantly. CONCLUSION: The results suggest that the GV model is an acceptable and effective model for managing Chinese hypertensive patients in primary health care centers, and it could be a complement to the traditional individual office visit. PMID- 22535549 TI - Barriers to and facilitators of adherence to antiretroviral therapy among people living with HIV in Lao PDR: a qualitative study. AB - Adherence to antiretroviral therapy (ART) is essential to its effectiveness and avoidance of the development of drug-resistant HIV strains. Many studies have been undertaken on factors affecting adherence to ART; however, there is little information about Laos. Hence, this qualitative study examines barriers to and facilitators of adherence specific to this context. In-depth interviews and focus group discussions were undertaken with 43 people living with HIV (PLHIV) currently on ART across 2 hospitals in Laos: Setthathirath hospital in the capital Vientiane and Savannakhet Province hospital. Interviews were based on semistructured question guides and were undertaken in Lao, translated into English and audio-recorded for later analysis. Major barriers to adherence reported by participants included transport costs, distance to the hospital, and stigma and discrimination. Key facilitators discussed were the perceived benefits of medication, social support, and the acceptance of HIV status. PMID- 22535550 TI - Preventive behaviors and mental distress in response to H1N1 among university students in Guangzhou, China. AB - OBJECTIVE: To investigate the level of and factors involved in influenza virus subtype H1N1 (H1N1)-related preventive behaviors and mental distress among university students in Guangzhou. PARTICIPANTS: Self-administered questionnaires were used to collect data for 825 students from 2 universities. RESULTS: A total of 49.7% of the participants held misconception(s) concerning H1N1 transmission. Less than 30% washed their hands >10 times/d; 72.3% did not reduce the frequency of touching their mouths, noses, and eyes; only 9.3% would wear face masks if they had influenza-like symptoms. However, 45% worried that one/one's family would contract H1N1, 10.7% were panicking/feeling depressed/feeling emotionally disturbed as a result of H1N1, and 14.9% were fearful about the WHO's H1N1 pandemic announcement. Almost all cognitive variables of this study were significantly associated with mental distress caused by fear of H1N1 (odds ratio [OR] = 0.29-3.81), but very few were associated with adoption of preventive measures (OR = 0.65-1.90). CONCLUSIONS: Preventive measures are warranted to alleviate distress in the population studied via health education and promotion. PMID- 22535551 TI - Joint impact of physical activity and family history on the development of diabetes among urban adults in Mainland China: a pooled analysis of community based prospective cohort studies. AB - To examine the joint influences of physical activity (PA) and family history (FH) of diabetes on subsequent type 2 diabetes (T2D), the authors pooled and analyzed data from 2 community-based urban adult prospective cohort studies in 2011 in Nanjing, China. Among 4550 urban participants, the 3-year cumulative incidence of T2D was 5.1%. After adjustment for potential confounders, compared with those with FH+ and insufficient PA, the adjusted odds ratio (95% confidence interval) of developing T2D was 0.42 (0.18, 0.98) for participants with sufficient PA and FH+, 0.32 (0.22, 0.46) for participants with insufficient PA and FH-, and 0.15 (0.08, 0.28) for participants with sufficient PA and FH-. Such significant graduated associations between PA/FH and risk of developing T2D were also identified in either men or women, separately. Sufficient PA and FH- may jointly reduce the risk of developing T2D in urban Chinese adults. PMID- 22535552 TI - Does functional disability mediate the pain-depression relationship in older adults with osteoarthritis? A longitudinal study in China. AB - Older adults with osteoarthritis have been found to be impaired in physical functioning and report higher levels of depression. This study examined the relationships between pain, functional disability, and depression to test the activity restriction model in a cohort of 176 older adults in China. This model states that disability is a mediator for the relationship between pain and depression. Other investigators have found that pain and disability were two independent correlates of depression. In both cross-sectional and longitudinal analyses, the authors found that disability is a mediator, using commonly accepted methods (indirect effect 44%, Sobel Z = 4.07, P < .001; 41%, Sobel Z = 3.45, P < .001, respectively). However, this mediation effect was not seen when the outcome was residualized with the baseline value. When the baseline level of depression is residualized, the effect size of the relationship is reduced, requiring larger sample size to test its effect. PMID- 22535553 TI - The effects of cultural values on mental health among the Taiwanese people: mediating of attitudes toward emotional expression. AB - Empirical evidence has demonstrated that an individual's cultural values can influence his or her mental health. This study extends previous research by proposing and testing a model that examines mediating processes underlying the relationship between individuals' cultural values and their mental health. This 2 stage study used data collected from 208 (at time 1) and 159 (at time 2) full time staff employed by private enterprises in Taiwan. The author tested hypotheses through the use of hierarchical multiple regression. The results showed that under horizontal individualism and vertical collectivism, the predictors of negative mental health (ie, somatic symptoms, anxiety and insomnia, social dysfunction and/or severe depression) were partially and almost completely achieved through the mediating effect of the negative attitudes toward emotional expression. PMID- 22535554 TI - Comorbid visual and cognitive impairment: relationship with disability status and self-rated health among older Singaporeans. AB - The objective of this study was to examine the prevalence and consequences of coexisting vision and cognitive impairments in an Asian population. Data were collected from 4508 community-dwelling Singaporeans aged 60 years and older. Cognition was assessed by the Short Portable Mental Status Questionnaire whereas vision, disability, and self-rated health (SRH) were determined by self-report. Vision impairment was present in 902 (18.5%) participants and cognitive impairment in 835 (13.6%), with 232 (3.5%) participants experiencing both impairments. Persons with the comorbidity experienced higher odds of disability than persons with either single impairment. The association of vision impairment with SRH was stronger among women (odds ratio [OR] = 6.79, 95% confidence interval [CI] = 4.64-9.92) than among men (OR = 1.71, 95% CI = 1.21-2.41). Concurrent cognitive and vision impairment is prevalent in older Singaporeans and is associated with high rates of disability. Gender differences in vision dependent roles may affect the patient-perceived impact of this comorbidity. PMID- 22535556 TI - Distribution of body composition index and the relationship with blood pressure among children aged 7 to 12 years in Shandong, China. AB - Body mass index (BMI) is widely used to assess the prevalence of childhood obesity in populations, and the relationship of BMI with blood pressure has been observed. However, no study has reported on the distribution of body composition index and the relationship with blood pressure. The present study examined the distribution of body composition index and the relationship with blood pressure among children aged 7 to 12 years in Shandong, China. A total of 4326 students (2165 boys and 2161 girls) aged 7 to 12 years participated in this study. Height, weight, skinfold thickness, and blood pressure of all the subjects were measured. Body fat percentage (BF%) was calculated by regression equation, and fat mass index (FMI) and fat-free mass index (FFMI) were calculated according to following expressions: FMI = BF% * weight/height(2) and FFMI = (weight - BF% * weight)/height(2). The 50th percentile values of FMI and FFMI increased with age in both sexes. The mean values of FFMI were significantly higher in boys than in girls (P < .01), but no statistically significant differences in mean FMI between the 2 sexes were observed (P > .05). Both systolic blood pressure and diastolic blood pressure were significantly positively related to FMI and FFMI in both boys and girls (P < .05). FMI and FFMI are potentially useful in evaluating the body composition of individuals with different stature. There is a strong positive relationship between FMI and blood pressure in children; these findings emphasize the importance of the prevention of obesity in children and adolescents. PMID- 22535555 TI - Are diabetic physicians at a lower risk of hospitalization for coronary heart disease? A nationwide cohort study in Taiwan. AB - It is not uncommon for physicians to work through illness and to be reluctant to seek health care from their colleagues, which is detrimental for quality of care. This study sought to assess the risk of admission for coronary artery diseases (CADs) in diabetic physicians. A cohort of 995 diabetic physicians and 9950 age- and sex-matched controls with diabetes were identified in 2000 and were followed to the end of 2008. Over an 8-year period, 200 (20.1%) diabetic physicians and 2255 (22.7%) controls were admitted for CAD. After controlling for potential confounders, diabetic physicians experienced a reduced, but insignificantly, adjusted odds ratio (OR) of CAD admission (OR = 0.89; 95% confidence interval = 0.75-1.06). Diabetic physicians in Taiwan were not at a significantly reduced risk of CAD admission. Future studies are needed to further explore the barriers that impede diabetic physicians from appropriately managing their disease. PMID- 22535557 TI - Unequal geographic distribution of life expectancy in Seoul. AB - This study examined life expectancies in 25 gus, administrative districts of Seoul, the capital of Korea, by gender in 1995, 2002, and 2008 to explore trends in mortality inequality among areas. The authors constructed single-decrement life tables and employed between-group variance, the Theil index, and mean log deviation to measure absolute and relative disparities in life expectancy among areas during the periods 1995-2002 and 2002-2008. It was found that life expectancy gaps between gus have widened in absolute and relative terms in both genders over the decade, and that this pattern was particularly dramatic in females after 2002. This increasing gap could be attributable to the more negative health impact on females since the late 1990s stemming from the economic crisis, eventually reflected in their places of residence. Thus, a social buffer system to narrow the health gap between geographic areas and social classes must be established. PMID- 22535558 TI - Twelve weeks' sertraline and CBT in young people with anxiety disorders increases likelihood of no longer having the diagnosis compared with placebo or monotherapy, but residual symptoms remain. PMID- 22535559 TI - Non-receipt of psychiatric treatment among people in the USA reporting suicide thoughts or attempts is more common among men, younger people and non-white ethnic groups. PMID- 22535560 TI - Review: group-based behavioural and cognitive-behavioural parenting interventions are effective and cost-effective for reducing early-onset child conduct problems. PMID- 22535561 TI - Epidemiology of contrast material-induced nephropathy in the era of hydration. AB - PURPOSE: To evaluate the incidence of contrast material-induced nephropathy (CIN) in patients with an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m(2) who received intravenous contrast media and underwent treatment in accordance with current guidelines and to determine risk factors associated with CIN. MATERIALS AND METHODS: The research ethics committee waived the requirement for informed consent for this prospective cohort study. All nonhospitalized patients with an eGFR of less than 60 mL/min/1.73 m(2) were seen at a special outpatient clinic. Patients were stratified for the risk of CIN. They were classified as having high or low risk for CIN on the basis of absolute glomerular filtration rate (Modification of Diet in Renal Disease formula result multiplied by body surface area divided by 1.73 m(2)) and the presence of risk factors. Patients at high risk were hydrated with 1000 mL of isotonic saline before and after contrast material exposure. Serum creatinine level was measured 3-5 days later, and CIN was defined as an increase of 25% of more from the baseline level. Risk factors were recorded and compared between patients with CIN and those without CIN by using forward stepwise multiple logistic regression analysis. RESULTS: A total of 944 procedures in 747 patients were evaluated. Mean age was 71.3 years +/- 10 (standard deviation), and 42.9% of patients were female. In 511 procedures (54.1%), patients were hydrated. CIN developed after 23 procedures (2.4%). No patient needed hemodialysis treatment. Heart failure (odds ratio, 3.0), body mass index (BMI) (odds ratio, 0.9), and repeated contrast material administration (odds ratio, 2.8) were found to be independent predictors of CIN. CONCLUSION: Heart failure, low BMI, and repeated contrast material administration were identified as risk factors for CIN under the current treatment strategy. The low incidence of CIN supports the use of hydration as a preventive measure in patients at high risk for CIN. PMID- 22535562 TI - Malignant pleural disease: diagnosis by using diffusion-weighted and dynamic contrast-enhanced MR imaging--initial experience. AB - PURPOSE: To investigate the use of diffusion-weighted (DW) imaging for differentiating benign lesions from malignant pleural disease (MPD) and to retrospectively assess dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging acquisitions to find out whether combining these measurements with DW imaging could improve the diagnostic value of DW imaging. MATERIALS AND METHODS: This study was approved by the local ethics committee, and all patients provided written informed consent. Thirty-one consecutive patients with pleural abnormalities suspicious for MPD underwent whole-body positron emission tomography (PET)/computed tomography (CT) and thorax MR examinations. Diagnostic thoracoscopy with histopathologic analysis of pleural biopsies served as the reference standard. First-line evaluation of each suspicious lesion was performed by using the apparent diffusion coefficient (ADC) calculated from the DW image, and the optimal cutoff value was found by using receiver operating characteristic curve analysis. Afterward, DCE MR imaging data were used to improve the diagnosis in the range of ADCs where DW imaging results were equivocal. RESULTS: Sensitivity, specificity, and accuracy of PET/CT for diagnosis of MPD were 100%, 35.3%, and 64.5%. The optimal ADC threshold to differentiate benign lesions from MPD with DW MR imaging was 1.52 * 10(-3) mm(2)/sec, with sensitivity, specificity, and accuracy of 71.4%, 100%, and 87.1%, respectively. This result could be improved to 92.8%, 94.1%, and 93.5%, respectively, when DCE MR imaging data were included in those cases where ADC was between 1.52 and 2.00 * 10(-3) mm(2)/sec. A total of 20 patients had disease diagnosed correctly, nine had disease diagnosed incorrectly, and two cases were undetermined with PET/CT. DW imaging helped stage disease correctly in 27 patients and incorrectly in four. The undetermined cases at PET/CT were correctly diagnosed at MR imaging. CONCLUSION: DW imaging is a promising tool for differentiating MPD from benign lesions, with high accuracy, and supplementation with DCE MR imaging seems to further improve sensitivity. PMID- 22535564 TI - Deficit reduction act: effects on utilization of noninvasive musculoskeletal imaging. AB - PURPOSE: To ascertain the effects of the payment reductions in the Deficit Reduction Act (DRA), which affected only in-office imaging, on the utilization of noninvasive musculoskeletal imaging. MATERIALS AND METHODS: This study of nonidentifiable aggregate data did not require institutional review board approval. Medicare Part B Physician/Supplier Procedure Summary Files for 2004, 2006, and 2008 were used. By using descriptive statistics and weighted linear regression, all 111 relevant procedure codes were evaluated to measure the effect of the DRA's payment reductions on change in utilization growth rate between the pre-DRA (2004-2006) and post-DRA (2006-2008) periods. RESULTS: Overall, between the pre-DRA and post-DRA periods, the type of imaging studied demonstrated a 2% deceleration (reduction in per capita utilization growth rate) in the office and a 0.7% deceleration in the outpatient hospital setting. However, nonradiologist and radiologist utilization were both still growing, particularly for nonradiographic imaging. In the office, for both nonradiologists and radiologists, larger DRA payment reductions were associated with greater deceleration; deceleration was approximately 0.2% greater for each additional 1% of reimbursement reduction. There was no payment-reduction-size-related acceleration in the outpatient setting. CONCLUSION: The growth rate of in-office noninvasive musculoskeletal imaging performed by nonradiologists and the growth rate of this type of imaging being referred to radiologists decreased in the period following the implementation of the DRA. Nonetheless, after the DRA, in office nonradiographic noninvasive musculoskeletal imaging performed by nonradiologists was still growing much more rapidly than that performed by radiologists. PMID- 22535565 TI - Pediatric abdominal pain: use of imaging in the emergency department in the United States from 1999 to 2007. AB - PURPOSE: To evaluate use of imaging in children with acute abdominal pain who present to U.S. emergency departments (EDs). MATERIALS AND METHODS: This study received expedited review by the institutional review board. The National Hospital Ambulatory Medical Care Survey is a government-administered yearly survey of EDs that is used to estimate ED care throughout the United States. This retrospective cohort study interrogated the database for the period from 1999 to 2007. Univariate regression analysis was performed, and a multivariate regression model was developed. RESULTS: From 1999 to 2007, 16 900 000 pediatric ED visits were made for acute abdominal pain. Odds of undergoing computed tomography (CT) in this population increased during each year of the study period. No significant changes occurred in use of ultrasonography, number of patients admitted to the hospital, or number of patients with acute appendicitis. A multivariate model for CT use revealed increased odds of CT use in teens, white patients, the Midwest region, urban settings, patients with private insurance, and patients who were admitted or transferred. Odds of undergoing CT were significantly lower among patients who presented to a pediatric-focused emergency department (adjusted odds ratio, 0.72; 95% confidence interval: 0.58, 0.90). CONCLUSION: The main findings of this study are that the rate of CT use in the evaluation of abdominal pain in children increased every year between 1999 and 2007 and that the use of CT was greater among children seen in adult-focused EDs. Factors affecting CT use include sex, race, age, insurance status, and geographic region. PMID- 22535566 TI - Belimumab is approved by the FDA: what more do we need to know to optimize decision making? AB - The March 2011 approval of belimumab (Benlysta) by the US Food and Drug Administration has left rheumatologists in a bit of a quandary regarding its use. It is officially intended for adult patients with autoantibody-positive systemic lupus erythematosus whose disease remains active despite receipt of standard-of care therapy. The approved indication is broad and leaves interpretation to individual rheumatologists. Analyses of the phase 2 and 3 clinical trials of belimumab help answer some of the commonly asked questions, such as the following: 1) Who is the appropriate patient for belimumab? 2) How does one measure response? 3) When should results be expected in a patient newly treated with belimumab? 4) When should belimumab be discontinued? PMID- 22535567 TI - The rationale for BAFF inhibition in systemic lupus erythematosus. AB - BAFF (B-cell-activating factor) is a critical survival factor for transitional and mature B cells and is a promising therapeutic target for systemic lupus erythematosus (SLE). In 2010-2011, two phase 3 clinical trials showed that the addition of the anti-BAFF antibody belimumab to standard-of-care therapy in patients with moderately active SLE results in a better outcome at 52 weeks than standard-of-care therapy alone. Belimumab has been US Food and Drug Administration approved for the treatment of SLE, and other drugs that target BAFF are now in various stages of clinical testing. This review describes the function of BAFF and its homolog APRIL (a proliferation-inducing ligand) and addresses the rationale for the treatment of SLE with BAFF/APRIL inhibitors. PMID- 22535568 TI - Whole breast irradiation for small-sized breasts after conserving surgery: is the field-in-field technique optimal? AB - BACKGROUND: To determine the optimal whole breast irradiation technique in patients with small-sized breasts, tangential and field-in-field IMRT (FIF) techniques were compared. METHODS: Sixteen patients with <=3 cm breast height and <=350 cc volume were included. Seven patients had 4D CTs performed. The planning target volumes (PTV), editing 5 and 2 mm from the surface on the whole breast, were delineated and called PTV(5) and PTV(2), respectively. Dose-volume histograms of tangential techniques with open beam (OT) and wedge filter (WT), conventional FIF (cFIF), and modified FIF (mFIF) blocking out the lung were produced. Various dose-volume parameters, the dose heterogeneity index (DHtrI), dose homogeneity index (DHmI), and PTV dose improvement (PDI) were calculated. RESULTS: OT compared with WT showed a significantly favorable V 90 of the heart and lung, and PTV(5)-dose distribution. Comparing OT and cFIF, OT showed significant improvement in the V 95 of PTV(2), whereas cFIF showed significant improvement in the V 95, DHtrI, DHmI, and PDI of the PTV(5). In comparing cFIF and mFIF, mFIF showed improved dose distributions of the heart and lung, while cFIF presented the better V 95, DHtrI, DHmI, and PDI of the PTV(5). Respiratory influences on the absolute dose were mostly within 1 %. The ratio of free breathing and each respiratory phase was similar among OT, cFIF, and mFIF. CONCLUSIONS: cFIF has favorable dose conformity and is suggested to be an optimal method for small-sized breasts. However, OT for dose coverage close to the skin and mFIF for normal tissue may also be potential alternatives. Respiratory effects are minimal. PMID- 22535569 TI - Periodicity and time trends in the prevalence of total births and conceptions with congenital malformations among Jews and Muslims in Israel, 1999-2006: a time series study of 823,966 births. AB - BACKGROUND Congenital malformations (CMs) are a leading cause of infant disability. Geophysical patterns such as 2-year, yearly, half-year, 3-month, and lunar cycles regulate much of the temporal biology of all life on Earth and may affect birth and birth outcomes in humans. Therefore, the aim of this study was to evaluate and compare trends and periodicity in total births and CM conceptions in two Israeli populations. METHODS Poisson nonlinear models (polynomial) were applied to study and compare trends and geophysical periodicity cycles of weekly births and weekly prevalence rate of CM (CMPR), in a time-series design of conception date within and between Jews and Muslims. The population included all live births and stillbirths (n = 823,966) and CM (three anatomic systems, eight CM groups [n = 2193]) in Israel during 2000 to 2006. Data were obtained from the Ministry of Health. RESULTS We describe the trend and periodicity cycles for total birth conceptions. Of eight groups of CM, periodicity cycles were statistically significant in four CM groups for either Jews or Muslims. Lunar month and biennial periodicity cycles not previously investigated in the literature were found to be statistically significant. Biennial cycle was significant in total births (Jews and Muslims) and syndactyly (Muslims), whereas lunar month cycle was significant in total births (Muslims) and atresia of small intestine (Jews). CONCLUSION We encourage others to use the method we describe as an important tool to investigate the effects of different geophysical cycles on human health and pregnancy outcomes, especially CM, and to compare between populations. PMID- 22535571 TI - Management of complications following pancreatic resection: an evidence-based approach. AB - Despite significant improvements in operative mortality, morbidity remains a significant problem following pancreatectomy. Management of postpancreatectomy complications, namely pancreatic fistula, begins with a clear understanding of how these events are defined. There are now several unifying definitions for complications following pancreatectomy which have led to improved reporting of operative outcomes across institutions. Several randomized controlled trials have been performed in recent years that may lead to continued improvement in operative outcomes. PMID- 22535570 TI - Is there a genetic cause of appetite loss?-an explorative study in 1,853 cancer patients. AB - BACKGROUND: Appetite loss has a major impact on cancer patients. It is exceedingly prevalent, is a prognostic indicator and is associated with inferior quality of life. Cachexia is a multi-factorial syndrome defined by a negative protein and energy balance, driven by a variable combination of reduced food intake and abnormal metabolism. Not all cancer patients that experience weight loss have appetite loss, and the pathophysiology between cachexia and appetite loss may thus be different. Knowledge of pathophysiology of appetite loss in cancer patients is still limited. The primary object of this study was to explore the association with 93 predefined candidate single-nucleotide polymorphisms (SNPs) and appetite loss in cancer patients to possibly generate new theories of the pathophysiology of the condition. METHODS: A total of 1,853 cancer patients were phenotyped according to appetite loss and then genotyped. RESULTS: After allowing for multiple testing, there was no statistically significant association between any of the SNPs analysed and appetite loss. The ten most significant SNPs in the co-dominant model had observed odds ratios varying from 0.72 to 1.28. CONCLUSIONS: This large exploratory study could not find any associations with loss of appetite and 93 SNPs with a potential to be involved in appetite loss in cancer patients. This does not however rule out genes putative role in the development of the symptom, but the observed odds ratios are close to one which makes it unlikely that any of the individual SNPs explored in the present study have great importance. PMID- 22535572 TI - Cannabidiol-induced apoptosis in murine microglial cells through lipid raft. AB - Cannabidiol (CBD), the major nonpsychotropic phytocannabinoid, induces apoptosis in both immortalized and primary lymphocytes and monocytes. However, contrasting effects of CBD on the apoptosis between normal and immortalized glial cells have been reported. This study investigated the proapoptotic effect of CBD on primary microglial cells. Treatment of murine primary microglial cultures with CBD resulted in a time- and concentration-dependent induction of apoptosis, as shown by increase in hypodiploid cells and DNA strand breaks, and marked activation of both caspase-8 and -9. Mechanistic studies revealed that antioxidants, including N-acetyl-L-cysteine and glutathione, the G protein-coupled receptor 55 agonist abnormal-CBD and specific antagonists for vanilloid, and CB1 and CB2 cannabinoid receptors did not counteract the apoptosis induced by CBD. In contrast, methyl beta-cyclodextrin (MCD), a lipid raft disruptor, potently attenuated CBD-induced microglial apoptosis and caspase activation. Furthermore, CBD induced lipid raft coalescence and augmented the expression of GM1 ganglioside and caveolin-1, all of which were attenuated by MCD. Taken together, these results suggest that CBD induces a marked proapoptotic effect in primary microglia through lipid raft coalescence and elevated expression of GM1 ganglioside and caveolin-1. PMID- 22535573 TI - Increasing incidence of pediatric inflammatory bowel disease in Spain (1996 2009): the SPIRIT Registry. AB - BACKGROUND: Although pediatric inflammatory bowel disease (IBD) diagnosis has increased in the last decades in Spain, there are no consistent epidemiologic data. Our aim was to describe the changing pattern of pediatric IBD incidence in Spain in the last 14 years. METHODS: A retrospective survey of patients diagnosed below 18 years of age in the period 1996-2009 was performed. Patients' data were obtained from the hospitals' databases. To avoid reduced accrual of cases diagnosed by adult physicians, adult IBD units in referral centers were invited to participate. Seventy-eight centers participated in our survey. Rates of incidence were calculated using age-stratified population-based epidemiologic data. Incidence rates were compared for the last 14 years (1996-2009). RESULTS: In total, data from 2107 patients were obtained: 1,165 Crohn's disease (CD, 55.3%), 788 ulcerative colitis (UC, 37.4%), and 154 IBD unclassified. The sex distribution was 56.4% male, with higher predominance for CD (59.3%) as compared to UC (52.8%) and IBD unclassified (53.2%) (P = 0.012). The median age at diagnosis was 12.3 years (p25-75 9.7-14.6) with significant differences between diseases. IBD incidence increased from 0.97 to 2.8/100,000 inhabitants <18 years/year in the study period. Although this increase is more evident for CD (from 0.53 to 1.7), UC has also risen considerably (0.39 to 0.88). CONCLUSIONS: This is the first attempt to calculate the current incidence of pediatric IBD in Spain. A significant increase of incidence rates in the study period was observed. In the last 14 years pediatric IBD incidence has almost tripled, with a more important CD increase. PMID- 22535574 TI - A phase 1 dose escalation study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone for untreated follicular lymphoma and other low-grade B-cell lymphomas. AB - BACKGROUND: Bortezomib has demonstrated efficacy in patients with relapsed B-cell non-Hodgkin lymphoma (NHL) both alone and in combination with other agents; however, limited data exist regarding its toxicity in combination with common frontline therapies for indolent NHL. A phase 1 study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone (R CHOP) was conducted in patients with untreated follicular lymphoma (FL) and other indolent NHLs. METHODS: Nineteen patients, including 10 patients with FL, were enrolled. The median patient age was 59 years (range, 29-71 years). Seven patients had a FL International Prognostic Index score >=3. R-CHOP with the vincristine dose capped at 1.5 mg was administered on a 21-day cycle for 6 to 8 cycles, and 1 of 3 dose levels of bortezomib (1.0 mg/m(2) [n = 1], 1.3 mg/m(2) [n = 6], or 1.6 mg/m(2) [n = 12]) was administered on days 1 and 8 of each cycle using a Bayesian algorithm for dose escalation. RESULTS: The maximum tolerated dose (MTD) of bortezomib with modified R-CHOP was reached at 1.6 mg/m(2). Dose limiting toxicity was observed in 5 patients (1 patient at a bortezomib dose of 1.0 mg/m(2), 1 patient at a bortezomib dose of 1.3 mg/m(2), and 3 patients at a bortezomib dose of 1.6 mg/m(2)). Neuropathy occurred in 16 patients (84%), including 2 patients (11%) who experienced grade 3 sensory neuropathy. Grade 4 hematologic toxicity occurred in 4 patients. Of 19 evaluable patients, 100% responded, and the complete response rate was 68%. At a median follow-up of 32 months, the 3-year progression-free survival rate was 89.5%. CONCLUSIONS: Bortezomib combined with modified R-CHOP produced high response rates without substantial increases in toxicity. A phase 2 study of R-CHOP and bortezomib given at this established MTD is currently ongoing. PMID- 22535575 TI - m-Trifluoromethyl diphenyl diselenide attenuates glutaric acid-induced seizures and oxidative stress in rat pups: involvement of the gamma-aminobutyric acidergic system. AB - Glutaric acidemia type I (GA-I) is an inherited metabolic disease characterized by accumulation of glutaric acid (GA) and seizures. The intrastriatal GA administration in rats has been used as an animal model to mimic seizures presented by glutaric acidemic patients. m-Trifluoromethyl diphenyl diselenide, (m-CF(3) -C(6) H(4) Se)(2) , is an organoselenium compound that protects against seizures induced by pentylenetetrazole in mice. Thus, the aim of this study was to investigate whether (m-CF(3) -C(6) H(4) Se)(2) is effective against GA-induced seizures and oxidative stress in rat pups 21 days of age. Our findings demonstrate that (m-CF(3) -C(6) H(4) Se)(2) preadministration (50 mg/kg; p.o.) protected against the reduction in latency and the increased duration of GA (1.3 MUmol/right striatum)-induced seizures in rat pups. In addition, (m-CF(3) -C(6) H(4) Se)(2) protected against the increase in reactive species generation and the reduction in antioxidant defenses glutathione peroxidase and glutathione S transferase activities induced by GA. By contrast, no change in glutathione reductase or catalase activities was found. In addition, (m-CF(3) -C(6) H(4) Se)(2) was effective in protecting against inhibition of Na(+) ,K(+) -ATPase activity caused by GA in striatum of rat pups. This study showed for the first time that GA administration caused an increase in [(3) H]GABA uptake from striatum slices of rat pups and that (m-CF(3) -C(6) H(4) Se)(2) preadministration protected against this increase. A positive correlation between duration of seizures and [(3) H]GABA uptake levels was demonstrated. The results indicate that (m-CF(3) -C(6) H(4) Se)(2) protected against GA-induced seizures. Moreover, these findings suggest that the protection against oxidative stress, the inhibition of Na(+) ,K(+) -ATPase activity, and the increase in [(3) H]GABA uptake are possible mechanisms for the potential anticonvulsant action of (m CF(3) -C(6) H(4) Se)(2). PMID- 22535576 TI - Collegial ethics: supporting our colleagues. AB - The goal of collegial ethics is to actively support our colleagues and to develop the skills needed to do so. While collegial interactions are key for our careers, there is little or no training in this. Many of our actions and reactions with our colleagues are instinctive. Human nature has evolved to be self-protective, but many evolved and automatic responses to others are not always in the best interests of our society or of us. Developing courage and a style of supportive language, avoiding destructive acts, and adhering to the golden rule will improve our relationships and provide a more positive environment for all. PMID- 22535577 TI - Beyond patchwork precaution in the dual-use governance of synthetic biology. AB - The emergence of synthetic biology holds the potential of a major breakthrough in the life sciences by transforming biology into a predictive science. The dual-use characteristics of similar breakthroughs during the twentieth century have led to the application of benignly intended research in e.g. virology, bacteriology and aerobiology in offensive biological weapons programmes. Against this background the article raises the question whether the precautionary governance of synthetic biology can aid in preventing this techno-science witnessing the same fate? In order to address this question, this paper proceeds in four steps: it firstly introduces the emerging techno-science of synthetic biology and presents some of its potential beneficial applications. It secondly analyses contributions to the bioethical discourse on synthetic biology as well as precautionary reasoning and its application to life science research in general and synthetic biology more specifically. The paper then identifies manifestations of a moderate precautionary principle in the emerging synthetic biology dual-use governance discourse. Using a dual-use governance matrix as heuristic device to analyse some of the proposed measures, it concludes that the identified measures can best be described as "patchwork precaution" and that a more systematic approach to construct a web of dual-use precaution for synthetic biology is needed in order to guard more effectively against the field's future misuse for harmful applications. PMID- 22535578 TI - Text-based plagiarism in scientific publishing: issues, developments and education. AB - Text-based plagiarism, or copying language from sources, has recently become an issue of growing concern in scientific publishing. Use of CrossCheck (a computational text-matching tool) by journals has sometimes exposed an unexpected amount of textual similarity between submissions and databases of scholarly literature. In this paper I provide an overview of the relevant literature, to examine how journal gatekeepers perceive textual appropriation, and how automated plagiarism-screening tools have been developed to detect text matching, with the technique now available for self-check of manuscripts before submission; I also discuss issues around English as an additional language (EAL) authors and in particular EAL novices being the typical offenders of textual borrowing. The final section of the paper proposes a few educational directions to take in tackling text-based plagiarism, highlighting the roles of the publishing industry, senior authors and English for academic purposes professionals. PMID- 22535579 TI - Central venous catheter-associated bloodstream infections. AB - BACKGROUND: To investigate the epidemiologic and microbiological aspects of long term central vein catheter (CVC)-associated bloodstream infections (CABSI) in children <18 years old treated at the hemato-oncology unit during 1998-2008. PATIENTS AND METHODS: The two long-term access devices used were Hickman and Port A-Cath catheters. Information retrieved included demographic data, baseline pathologies, methods of insertion, anatomical insertion sites, duration of use, microbiological, and antibiotic susceptibility data and outcome. RESULTS: There were 178 CABSI episodes; average number of episodes/1,000 catheter days was 4.7. More CABSI episodes were recorded among patients with Hickman catheter than in patients with Port-A-Cath catheter (5.05 vs. 3.57/1,000 catheter days, P = 0.059). The CVC was removed due to BSI in 52/178 (29.2%) episodes. Overall, 243 pathogens were isolated (144 Gram-negative, 92 Gram-positive, and 7 Candida spp). More Enterobacteriaceae spp. were isolated in CABSI in patients with Hickman catheters than in patients with Port-A-Cath catheters (35/103, 34%, vs. 10/65, 15%, P = 0.008); more coagulase-negative staphylococci were isolated in patients with Port-A-Cath catheters than in patients with Hickman catheters (25/65, 38.5%, vs. 23/103, 22.3%, P = 0.02). No differences in pathogen distribution were found between CABSI recorded for jugular versus subclavian veins, open versus close inserted-CVC or for CVC requiring removal versus those treated conservatively. No fatalities directly related to CABSI were recorded. CONCLUSIONS: CABSI rates were higher in patients with Hickman catheters compared with those with Port-A-Cath catheters; Gram-negative organisms were the dominant etiologic agents of CABSI; CABSI in patients with Hickman catheters had different etiologies compared with patients with Port-A-Cath catheters. PMID- 22535580 TI - Tuberculous altantoaxial subluxation: a case report with review of literature. AB - Involvement of upper cervical and craniovertebral junction is rare but might lead to lethal consequences if the diagnosis is delayed. We present a case of atlantoaxial joint tuberculosis, resulting in gross instability of the joint. The patient was treated with antitubercular medication combined with posterior decompression and transarticular screw fixation. Patient improved neurologically, and clinical and radiological improvements were maintained at the latest follow up of 2 years. PMID- 22535581 TI - The association between prenatal alcohol exposure, fetal growth and preterm birth: evidence from a systematic review and meta-analyses. PMID- 22535582 TI - BZS1, a B-box protein, promotes photomorphogenesis downstream of both brassinosteroid and light signaling pathways. AB - Photomorphogenesis is controlled by multiple signaling pathways, including the light and brassinosteroid (BR) pathways. BR signaling activates the BZR1 transcription factor, which is required for suppressing photomorphogenesis in the dark. We identified a suppressor of the BR hypersensitive mutant bzr1-1D and named it bzr1-1D suppressor1-Dominant (bzs1-D). The bzs1-D mutation was caused by overexpression of a B-box zinc finger protein BZS1, which is transcriptionally repressed by BZR1. Overexpression of BZS1 causes de-etiolation in the dark, short hypocotyls in the light, reduced sensitivity to BR treatment, and repression of many BR-activated genes. Knockdown of BZS1 by co-suppression partly suppressed the short hypocotyl phenotypes of BR-deficient or insensitive mutants. These results support that BZS1 is a negative regulator of BR response. BZS1 overexpressors are hypersensitive to different wavelengths of light and loss of function of BZS1 reduces plant sensitivity to light and partly suppresses the constitutive photomorphogenesis 1 (cop1) mutant in the dark, suggesting a positive role in light response. BZS1 protein accumulates at an increased level after light treatment of dark-grown BZS1-OX plants and in the cop1 mutants, and BZS1 interacts with COP1 in vitro, suggesting that light regulates BZS1 through COP1-mediated ubiquitination and proteasomal degradation. These results demonstrate that BZS1 mediates the crosstalk between BR and light pathways. PMID- 22535583 TI - Tumor size predicts survival in mucinous gastric carcinoma. AB - BACKGROUND: Mucinous gastric carcinoma (MGC) is a distinct histologic subtype of gastric cancer. However, the prognostic significances of the current TNM staging system and histology in MGC have not been studied. METHODS: 206 patients who underwent R0 resection for MGC were classified by tumor size (<3 cm as T1; >= 3-5 cm as T2; >= 5-9 cm as T3; and >= 9 cm as T4). Immunohistochemistry for EGFR and HER2 was also performed. RESULTS: Tumor sizes ranged from 1.2 to 21.0 cm (median 6.2 cm). Large tumor size (>= 5 cm) was significantly associated with older patient age, deeper invasion depth, and more frequent lymph node metastasis (P < 0.05). Tumor size was a significant prognostic factor in both univariate (P < 0.001) and multivariate (P < 0.04) analyses. However, depth of invasion was not significant in multivariate analyses. A modified staging system based on tumor size predicted survival more accurately than did the conventional TNM staging system. We verified our results in an independent validation cohort of 123 MGC patients. Overexpression of either EGFR or HER2 was rare. CONCLUSIONS: In MGCs, tumor size is an independent prognostic factor and a modified TNM system based on tumor size predicted survival accurately. PMID- 22535584 TI - TNF Antagonists in IBD: Novel Antiinflammatory Mechanisms Beyond Cytokine Inhibition. PMID- 22535585 TI - Nilotinib versus imatinib: molecular mechanism(s) of its better efficacy. PMID- 22535586 TI - Predictors of and survival after incident stroke in type 1 diabetes. AB - Few studies have examined stroke risk in type 1 diabetes mellitus (T1DM). Stroke incidence, predictors, and survival were thus explored in this study. Pittsburgh Epidemiology of Diabetes Complications (EDC) Study participants (n = 658) with childhood-onset T1DM were followed biennially for 18 years. Baseline (1986-1988) mean age and diabetes duration were 28 and 19 years respectively. Stroke incidence and type was determined via survey or physician interview and, when possible, confirmed with medical or autopsy records. During follow-up, 31 (4.7%) strokes occurred (21 ischaemic, 8 haemorrhagic, 2 unclassified) in participants of mean age = 40.2 years (range 23-60). In exploratory multivariable Cox modelling, diabetes duration, systolic blood pressure (SBP), non-high density lipoprotein cholesterol (non-HDLc), white blood cells (WBC), and pulse significantly predicted ischaemic stroke. Adding overt nephropathy (ON) (hazard ratio = 4.4, 95% CI, 1.5-12.4) to the model replaced SBP. Participant survival after stroke was 80.6%, 45.2%, and 9.6% at 1, 5, and 10 years, respectively, and significantly worse after haemorrhagic stroke (p = 0.03). These risk factors merit careful evaluation and management to prevent stroke in T1DM, which occurs at least 20 years earlier than in the general population. PMID- 22535587 TI - Reduced arterial stiffness after weight loss in obese type 2 diabetes and impaired glucose tolerance: the role of immune cell activation and insulin resistance. AB - Weight loss after bariatric surgery reduces cardiac risk and morbidity. We examined weight loss effects on arterial stiffness in morbidly obese subjects, in relation to cytokines, circulating and subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT)-based immune cells and gene expression. Obese subjects with type 2 diabetes mellitus (T2D) or impaired glucose tolerance (n = 14, mean +/- SEM body mass index 42.9 kg/m(2)) underwent 24 weeks' caloric restriction, with gastric banding at 12 weeks. Measures were: arterial augmentation index (AIx), insulin resistance, circulating cytokines, immune cell activation markers, and SAT and VAT cytokine gene expression. Weight loss reduced AIx by 20% (p = 0.007), with falls in s-selectin (p = 0.001) and inter-cellular adhesion molecule (p = 0.04). Improved AIx related to reduced surface expression of the interleukin (IL)-2 receptor on T-lymphocytes (TL-IL2R) and granulocyte adhesion markers (r = 0.59, 0.64, respectively, p < 0.04). Higher VAT expression of interferon-gamma and monocyte chemoattractant protein-1 associated with a blunted AIx response. A model of TL-IL2R expression, waist, weight and insulin resistance explained 73% of the variance in AIx reduction (p = 0.005). In morbidly obese dysglycaemic subjects, modest weight loss reduces arterial stiffness, the magnitude of which relates to improved markers of inflammation. PMID- 22535588 TI - Does impact sport activity influence total hip arthroplasty durability? AB - BACKGROUND: Return to sport is a key patient demand after hip arthroplasty and some patients are even involved in high-impact sports. Although polyethylene wear is related to the number of cycles and the importance of the load, it is unclear whether high-impact sport per se influences THA durability. QUESTIONS/PURPOSES: Therefore, we compared (1) function between the patients involved in high-impact sports and the patients with lower activities as measured by the Harris hip score (HHS) and the Hip Osteoarthritis Outcome Score (HOOS); (2) linear wear rates; and (3) survivorships considering revision for mechanical failure with radiographic signs of aseptic loosening as the end point. METHODS: We retrospectively identified 70 patients who engaged in high-impact sports and 140 with low activity levels from among 843 THAs from a prospectively collected database performed between September 1, 1995, and December 31, 2000. Patients were evaluated at a minimum followup of 10 years (mean, 11 years; range, 10-15 years) by two independent observers. We obtained a HHS and HOOS at each followup. RESULTS: The mean HOOS was higher in the high-impact group for three of the five subscales of the HOOS. Mean linear wear was higher in the high-impact group than in the low-activities group. We also found a higher number of revisions in the high-activity group. CONCLUSIONS: Our observations confirm concern about the risk of THA mechanical failures related to high-impact sport, and patient and surgeons alike should be aware of these risks of mechanical failures. LEVEL OF EVIDENCE: Level III, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID- 22535589 TI - Prp2-mediated protein rearrangements at the catalytic core of the spliceosome as revealed by dcFCCS. AB - The compositional and conformational changes during catalytic activation of the spliceosome promoted by the DEAH box ATPase Prp2 are only poorly understood. Here, we show by dual-color fluorescence cross-correlation spectroscopy (dcFCCS) that the binding affinity of several proteins is significantly changed during the Prp2-mediated transition of precatalytic B(act) spliceosomes to catalytically activated B* spliceosomes from Saccharomyces cerevisiae. During this step, several proteins, including the zinc-finger protein Cwc24, are quantitatively displaced from the B* complex. Consistent with this, we show that Cwc24 is required for step 1 but not for catalysis per se. The U2-associated SF3a and SF3b proteins Prp11 and Cus1 remain bound to the B* spliceosome under near physiological conditions, but their binding is reduced at high salt. Conversely, high-affinity binding sites are created for Yju2 and Cwc25 during catalytic activation, consistent with their requirement for step 1 catalysis. Our results suggest high cooperativity of multiple Prp2-mediated structural rearrangements at the spliceosome's catalytic core. Moreover, dcFCCS represents a powerful tool ideally suited to study quantitatively spliceosomal protein dynamics in equilibrium. PMID- 22535590 TI - Properties of small rRNA methyltransferase RsmD: mutational and kinetic study. AB - Ribosomal RNA modification is accomplished by a variety of enzymes acting on all stages of ribosome assembly. Among rRNA methyltransferases of Escherichia coli, RsmD deserves special attention. Despite its minimalistic domain architecture, it is able to recognize a single target nucleotide G966 of the 16S rRNA. RsmD acts late in the assembly process and is able to modify a completely assembled 30S subunit. Here, we show that it possesses superior binding properties toward the unmodified 30S subunit but is unable to bind a 30S subunit modified at G966. RsmD is unusual in its ability to withstand multiple amino acid substitutions of the active site. Such efficiency of RsmD may be useful to complete the modification of a 30S subunit ahead of the 30S subunit's involvement in translation. PMID- 22535591 TI - Biomarkers for risk stratification of febrile neutropenia among children with malignancy: a pilot study. AB - BACKGROUND: Patients receiving myelosuppressive chemotherapy remain at increased risk for developing febrile neutropenia (FN). For this heterogeneous population, a biomarker based risk stratification of FN patients may be a useful clinical tool. We hypothesized that serum biomarkers during initial presentation of an FN event could be predictive of subsequent clinical outcome. PROCEDURE: Eighty-nine FN events from 36 non-consecutive subjects were analyzed. "High-risk" FN criteria included prolonged hospitalization (>= 7 days), admission to pediatric intensive care unit (PICU) or a microbiology confirmed bacteremia. Patients with "low risk" FN had none of the above. Biomarkers measured during the first 2 days of FN hospitalization were analyzed and correlated with respective clinical outcome. RESULTS: Of the 89 FN events, 44 (49%) fulfilled pre-defined high-risk criteria and 45 (51%) were low-risk. Procalcitonin level (>0.11 ng/ml) was found to be associated with the high-risk FN outcome with sensitivity of 97%. With an increase in log scale by 1, the odds of being high-risk FN increased twofold. Hs CRP >100 mg/L had sensitivity of 88% in predicting high-risk FN. The odds of a high-risk FN event increased by approximately 1.8-fold with an increase in the log scale of hs-CRP by 1 (10-fold). In univariate analysis, IL-6, IL-8, and IL-10 were statistically significant and associated with high-risk FN. However, no statistically significant difference was found for IL-1alpha, sIL-2Ra, IL-3, or TNF-alpha. CONCLUSIONS: Biomarkers with appropriate critical threshold values may be a useful clinical tool for appropriate risk stratification of children with FN. PMID- 22535592 TI - Acute myeloid leukemia with myelodysplasia-related changes are characterized by a specific molecular pattern with high frequency of ASXL1 mutations. AB - To determine whether the distinct and heterogeneous WHO category called "AML with myelodysplasia-related changes" (MRC-AML), presents specific molecular alterations we searched for mutations in genes known to be mutated in malignant myeloid diseases. In 48 MRC-AML patients analyzed, we found 17 mutations in ASXL1 (35%), eight in RUNX1 (17%), seven in TET2 (15%), 12 in IDH (n = 2) or IDH2 (n = 10) (25%), four in DNMT3A (8%), four in NPM1 (8%), and one in FLT3 (2%). Mutations were more frequent in the intermediate cytogenetic (IC) subgroup of 36 patients than in the unfavorable karyotype subgroup, with an average ratio mutations/patients of 1.36 [0-3] vs. 0.33 [0-2] (P < 0.001). Then, we compared these 36 patients with IC MRC-AML with a control panel of 37 no-MRC-AML patients, who had both IC and no dysplasia. IC MRC-AMLs were associated with higher incidence of ASXL1 mutations (47% vs. 0%, P < 0.001) and lower incidence of DNMT3A (6% vs. 38%, P = 0.001), NPM1 (11% vs. 62%, P < 0.001) and FLT3 (3% vs. 49%, P < 0.001) mutations. No difference was found in the incidence of IDH1/2 or TET2 mutations according to the presence of dysplasia. Complete remission rate after intensive treatment was lower in the MRC-AML group than in the no-MRC-AML group (48% vs. 78%, P = 0.023) and in wild type NPM1 patients (50% vs. 84%, P = 0.009). Our study showed that MRC-AML as defined in the WHO 2008 classification presents a specific mutation pattern characterized by a high frequency of ASXL1 mutations and a low rate of NPM1, FLT3, and DNMT3A mutations. PMID- 22535593 TI - Disorders of balance and gait in essential tremor are associated with midline tremor and age. AB - Disorders of balance and gait have been observed in patients with essential tremor (ET), but their association with tremor severity remains unclear. This study aimed to evaluate postural instability and gait changes in ET patients and to investigate their relationship to tremor characteristics with regard to cerebellar dysfunction as a possible common pathogenetic mechanism in ET. Thirty ET patients (8F, mean (SD) age 55.8 (17.8), range 19-81 years) and 25 normal controls (7F, 53.0 (17.7), 19-81) were tested with the scales of Activities specific Balance Confidence (ABC), Fullerton Advanced Balance (FAB), and International Cooperative Ataxia Rating Scale (ICARS). Posturography and gait were assessed using a Footscan(r) system. Tremor was evaluated by the Fahn-Tolosa Marin Tremor Rating Scale (TRS) and accelerometry in five upper limb positions. A mean (SD) TRS sum score of 27.0 (13.2) corresponded to mild to moderate tremor severity in most patients. In comparison with controls, ET subjects exhibited lower tandem gait velocity (0.21 vs. 0.26 m/s, P = 0.028), more missteps (0.57 vs. 0.12, P = 0.039), and increased postural sway in tandem stance (sway area 301.1 vs. 202.9 mm(2), P = 0.045). In normal gait, step width increased with the midline tremor subscore of TRS (Pearson r = 0.60, P = 0.046). Moreover, significant correlations were found between age and quantitative measures of normal and tandem gait in ET patients but not in controls. ABC, FAB, and ICARS scores did not significantly differ between patients and controls. In conclusion, gait and balance alterations in ET patients occur even without subjective complaints. Their relationship with midline tremor and dependence on age suggest a connection with cerebellar dysfunction. PMID- 22535594 TI - Subclinical Cushing's syndrome. AB - Subclinical Cushing's syndrome (SCS) refers to subtle autonomous cortisol hypersecretion that is insufficient to generate the typical, clinically recognizable overt syndrome. Diagnosis of SCS is challenging. The combination of 1 mg overnight dexamethasone suppression test, serum ACTH level, and urinary cortisol level are used to diagnose SCS. Laparoscopic adrenalectomy is the treatment of choice for SCS. Patients with adrenal incidentalomas and SCS should be treated with perioperative steroids to prevent post-operative hypocortisolism. PMID- 22535595 TI - Autonomous, hands-free shape memory in glassy, liquid crystalline polymer networks. AB - Repeatedly forming temporary shapes can be a limitation to the employment of shape memory polymers. This work utilizes glassy, liquid crystal polymer networks to spontaneously form 3D shapes that are independent of a user. These shapes are autonomously fixed with rapid temperature cycling. PMID- 22535597 TI - Heavy metal concentrations in surface sediments and Manila clams (Ruditapes philippinarum) from the Dalian coast, China after the Dalian port oil spill. AB - We conducted an investigation of heavy metal concentrations in Manila clams (Ruditapes philippinarum) and surface sediments after the Dalian Port oil spill. Samples were collected from three mariculture zones (Jinshitan, Dalijia, and Pikou) along the Dalian coast. Heavy metal concentrations in R. philippinarum were consistent and ranked in decreasing order of Zn > Cu > As > Cr > Pb > Cd > Hg, while concentrations in surface sediments were ranked as Zn > Cr > Cu > Pb > As > Cd > Hg, respectively. Bioaccumulation of Zn, Cd, and Hg had obviously occurred in R. philippinarum. Statistically significant correlations (p < 0.05) between concentrations of Pb, Cd, and Hg in R. philippinarum and in surface sediments were observed. Except for Cr and As, heavy metal concentrations in R. philippinarum were well within the legal limits for human consumption. PMID- 22535598 TI - Exogenous selenium pretreatment protects rapeseed seedlings from cadmium-induced oxidative stress by upregulating antioxidant defense and methylglyoxal detoxification systems. AB - The protective effect of selenium (Se) on antioxidant defense and methylglyoxal (MG) detoxification systems was investigated in leaves of rapeseed (Brassica napus cv. BINA sharisha 3) seedlings under cadmium (Cd)-induced oxidative stress. Two sets of 11-day-old seedlings were pretreated with both 50 and 100 MUM Se (Na(2)SeO(4), sodium selenate) for 24 h. Two concentrations of CdCl(2) (0.5 and 1.0 mM) were imposed separately or on the Se-pretreated seedlings, which were grown for another 48 h. Cadmium stress at any levels resulted in the substantial increase in malondialdehyde and H(2)O(2) levels. The ascorbate (AsA) content of the seedlings decreased significantly upon exposure to Cd stress. The amount of reduced glutathione (GSH) increased only at 0.5 mM CdCl(2), while glutathione disulfide (GSSG) increased at any level of Cd, with concomitant decrease in GSH/GSSG ratio. The activities of ascorbate peroxidase (APX) and glutathione S transferase (GST) increased significantly with increased concentration of Cd (both at 0.5 and 1.0 mM CdCl(2)), while the activities of glutathione reductase (GR) and glutathione peroxidase (GPX) increased only at moderate stress (0.5 mM CdCl(2)) and then decreased at 1.0 mM severe stress (1.0 mM CdCl(2)). Monodehydroascorbate reductase (MDHAR), dehydroascorbate reductase (DHAR), catalase (CAT), glyoxalase I (Gly I), and glyoxalase II (Gly II) activities decreased upon exposure to any levels of Cd. Selenium pretreatment had little effect on the nonenzymatic and enzymatic components of seedlings grown under normal conditions; i.e., they slightly increased the GSH content and the activities of APX, GR, GST, and GPX. On the other hand, Se pretreatment of seedlings under Cd-induced stress showed a synergistic effect; it increased the AsA and GSH contents, the GSH/GSSG ratio, and the activities of APX, MDHAR, DHAR, GR, GPX, CAT, Gly I, and Gly II which ultimately reduced the MDA and H(2)O(2) levels. However, in most cases, pretreatment with 50 MUM Se showed better results compared to pretreatment with 100 MUM Se. The results indicate that the exogenous application of Se at low concentrations increases the tolerance of plants to Cd induced oxidative damage by enhancing their antioxidant defense and MG detoxification systems. PMID- 22535599 TI - Infliximab-induced thrombocytopenia in an elderly patient with ileocolonic Crohn's disease. PMID- 22535600 TI - Malignant ectomesenchymoma in children and adolescents: report from the Cooperative Weichteilsarkom Studiengruppe (CWS). AB - BACKGROUND: Malignant ectomesenchymoma (MEM) is a soft tissue tumor with heterologous rhabdomyoblastic components believed to arise from pluripotent migratory neural crest cells. To date merely 50 cases have been published and the knowledge about the course of disease and optimal treatment is limited. METHODS: Six patients with MEM were registered 1996-2009. The diagnosis was confirmed according to current criteria. Their treatment and outcome was analyzed. RESULTS: The median age of the three females and three males was 0.6 years (range, 0.2 13.5). The mesenchymal component in all tumors was rhabdomyosarcoma (RMS), the neural component ganglioneuroblastoma/neuroblastoma (n = 5) and peripheral primitive neuroectodermal tumor in one case. Five patients presented with localized, one with metastatic disease. All but one patient received multiagent chemotherapy during their initial treatment. The tumors of 4/5 patients with localized MEM were at least grossly resected at best surgery; the patient without gross resection was additionally irradiated. Three of four evaluable tumors responded well to induction chemotherapy. All patients achieved a first complete remission (CR), but three recurrences (two local, one systemic) occurred. The individual with metastatic MEM did not survive, but all five patients with localized MEM are currently alive in CR with a median follow-up of 5 years (range: 2.1-13.7). CONCLUSIONS: Risk-factors and outcome of MEM appear to be comparable with other highly malignant pediatric soft tissue sarcoma when a multimodal treatment strategy including chemotherapy and adequate local treatment is pursued. We propose that treatment of patients with MEM be done according to pediatric protocols similar to other rhabdomyosarcoma-like soft tissue sarcoma. PMID- 22535601 TI - Acute promyelocytic leukemia: four distinct patterns by flow cytometry immunophenotyping. AB - A total of 97 acute promyelocytic leukemia (APL) patients with adequate flow cytometry (FC) data, bone marrow aspirates and presence of t(15;17)/PML-RARA by cytogenetics and/or FISH studies were analyzed for immunophenotypic pattern. Leukemic cells had the following phenotype: CD11b-, CD11c-, CD13+, CD33+, CD45+, CD64+/-, CD117+, and HLA-DR-. A subset of cases showed also an expression of CD2, CD4, CD34, and CD56. Based on the immunophenotype and side scatter properties (SSC), four FC patterns were recognized. The majority of cases represented classical (hypergranular) APL and were characterized by high SSC, positive CD117, lack of CD34, heterogeneous CD13, and bright CD33 (pattern 1). Second most common type, corresponding to the hypogranular (microgranular) variant of APL differed from classical APL by low SSC and frequent co-expression of CD2 and CD34 (pattern 2). Rare cases of APL (pattern 3) showed a mixture of neoplastic cells (low SSC/CD2+/CD13+/CD33+/CD34+/CD117+) and prominent population of benign granulocytes/maturing myeloid precursors (high SSC/CD10+/-/CD16+/-/ CD117-). One case showed two APL populations, one with hypogranular and one with hypergranular characteristics (pattern 4). Apart from a well-known FC pattern of hypergranular APL, we presented less common immunophenotypic variants of APL, which helps to identify an additional group of patients who would benefit from fast confirmatory FISH and/or PCR testing for t(15;17)/PML-RARA. PMID- 22535602 TI - Diagnostic, predictive and prognostic verification of DNA flow cytometric measurements performed at diagnosis for non-Hodgkin's lymphoma adult patients. AB - More than ten years ago we made first attempts at valuating a prognostic power of flow cytometric DNA measurement results for patients with non-Hodgkin's lymphoma. In multivariate overall survival analysis, S-phase fraction (SPF) showed to be the only independent prognostic factor within the group of patients with low grade lymphomas. In this paper, we have tried to check our previous results in a greater group of patients with longer follow-up, within the specific types of B cell and T/NK-cell lymphomas verified and classified according to criteria of the WHO 2008 classification. The study was performed on the material obtained from biopsies (85% of lymph nodes) of 484 NHL patients. Patients were diagnosed from 1991 to 2007. The medium follow-up time for living patients was 69 months (range: 25-202 months). All specimens were verified histologically and immunohistochemically. Ploidy and SPF were determined by flow cytometry on fresh tissue obtained during the diagnostic procedure. The diagnostic importance of ploidy and SPF has been confirmed. Ploidy had no predictive or prognostic impact in any of the NHL types, whereas SPF was found to be an independent predictive or prognostic factor in B-CLL/SLL, DLBCL and ALCL. PMID- 22535603 TI - The immunoexpression of Shh, Smo and Gli2 in Helicobacter pylori positive and negative gastric biopsies. AB - The Hedgehog signaling pathway plays a principal role during embryonic development, tissue regeneration and carcinogenesis in various adult tissues. Although hedgehog signaling is important in gastric carcinogenesis, its role in Helicobacter pylori-associated gastritis is unclear. The aim of our study was to examine Sonic Hedgehog (Shh) signaling pathway in response to H. pylori infection. Thirty-one formalin-fixed, paraffin-embedded tissue specimens of chronic gastritis were retrieved from archival material. The immunoexpression of Shh, Smoothened (Smo) and Glioblastoma transcription factor 2 (Gli2) were detected using the immunohistochemical method. Sonic Hedgehog protein was expressed in H. pylori-positive and H. pylori-negative groups of patients. The immunoexpression of Shh, Smo and Gli2 proteins was lower in H. pylori-positive group compared to H. pylori-negative group, however only the differences in Shh and Smo immunoexpression were statistically significant. The immunoexpression of Shh was significantly correlated with the immunoexpression of Smo in both tested groups (p < 0.001, p < 0.02, respectively). No statistically significant correlation was found between Shh and Gli2 among H. pylori-positive and H. pylori negative groups. The above findings support the hypothesis of the involvement of Shh signaling pathway in H. Pylori-associated gastritis. PMID- 22535604 TI - Expression of selected neuropeptides in pathogenesis of bullous pemphigoid and dermatitis herpetiformis. AB - Bullous pemphigoid (BP) and dermatitis herpetiformis (DH) are chronic subepidermal bullous diseases, which progress together with an itch and an inflammatory reaction. These symptoms may be the cause of a phenomenon described in the literature as a neurogenic skin inflammation. Neuropeptides are one of the mediators which take part in this process. The aim of our study was to indicate the expression of selected neuropeptides - CRF (corticotropin releasing factor), CGRP (calcitonin gene-related peptide), NKB (neurokinin B), SP (substance P) and the receptor for endothelin B (ETRB) - in the skin of patients suffering from BP or DH. A significantly increased expression of CRF was found in the specimen collected from the skin lesions of patients with BP and DH as well as a significantly increased expression of receptor for endothelin B in the patients with DH by the immunohistochemical method. The results obtained give evidence of a possible participation of CRF and receptor for endothelin B in the pathogenesis of the itch in the dermatitis herpetiformis as well as CRF in bullous pemphigoid. PMID- 22535605 TI - Prevalence of occult metastases in axillary sentinel lymph nodes of breast carcinoma. AB - Recently, sentinel lymph node biopsy (SLNB) has been accepted as a standard method of assessment of axillary lymph nodes in breast cancer patients with no clinical lymphadenopathy. There is no standard pathologic method to evaluate sentinel lymph nodes. The purpose of this study is to evaluate the frequency of occult lymph node metastasis in sentinel lymph nodes via serial sectioning and immunohistochemical study with cytokeratin and its relationship with other clinicopathologic factors. Paraffin-embedded blocks of axillary sentinel lymph nodes of breast cancer patients, biopsied in 2005-2009 and reported as negative, were reviewed with 3 um sections, H and E staining and immunohistochemical study with an epithelial cytokeratin marker. Clinicopathologic data and relapse, if occurred was recorded and its relationship with occult metastasis was statistically analyzed. Sixty-eight sentinel pathology blocks of 66 patients (65 women and one man, median age 49 years) were investigated. Four cases (5.8%) of occult metastases were found, one by HE staining, and three cases with IHC (1 micrometastasis, 2 isolated tumor cells). Accuracy of reported cases was 94.1% upon re-examination. Sixty-four patients were followed after surgery and adjuvant therapy (range: 6-38 months, median: 21 months). No relapse was reported. There was no significant statistical relationship between occult metastasis and disease free survival. Although 4 cases (5.8%) of sentinel lymph nodes were positive in the complementary study, with a median follow-up of 21 months, we found no difference in disease-free survival between these patients and others. To show a significant, however small, difference, one needs further research with a greater number of patients and longer follow-up. PMID- 22535606 TI - Adrenal myelolipomas composed with adrenal nodular hyperplasia in the same gland. AB - Adrenal myelolipoma is a benign neoplasm composed of an admixture of hemopoietic elements and mature adipose tissue. The incidence of adrenal myelolipoma is reported as between 4% and 5% of adrenal incidentaloma. The association of an adrenal myelolipoma and adrenal nodular hyperplasia or adrenal adenoma is rare. Four cases of adrenal myelolipomas in the material of 702 incidentally discovered adrenal lesions treated in our center are presented in this paper (in a group of 294 operated patients). Two myelolipomas have been reported as isolated adrenal masses and two - in association with adrenocortical nodular hyperplasia. PMID- 22535607 TI - Focal segmental glomerulosclerosis: a diagnostic problem. AB - Focal segmental glomerulosclerosis (FSGS) is an important clinical problem as it leads to end-stage renal disease. Clinicians have long been able to treat patients with FSGS. Therefore, the demands the clinicians make on pathomorphologists, which include the diagnosis of FSGS at a possibly early stage, are justifiable. However, early diagnosis of FSGS is difficult. The analysis involved 150 cases of FSGS diagnosed between 2003 and 2008. These constitute 14.53% of renal biopsy material of that period. The test material comes from 138 adults and 12 children. The adult group mostly included patients with albuminuria (58 patients) and nephrotic syndrome (36 patients). Smaller groups included patients with albuminuria and hypertension, erythrocyturia and albuminuria, isolated erythrocyturia. The children group mostly included patients with the nephrotic syndrome. Individual patients suffered from isolated albuminuria and erythrocyturia. In both groups, FSGS NOS lesions prevailed. However, FSGS hilar and FSGS tip lesions, as well as completely sclerotized glomeruli were also present. Diverse symptoms of diseases may pose specific difficulties in clinical diagnosis. Similarly, determination of FSGS lesion type may be difficult due to simultaneous presence of different subtypes in the same punctate. PMID- 22535608 TI - Expression of cytokeratin 19, HBME-1 and galectin-3 in neoplastic and nonneoplastic thyroid lesions. AB - In this study, 105 cases of thyroid lesions were evaluated to assess the role of HBME-1, cytokeratin-19 (CK-19), galectin-3 in distinguishing benign from malignant thyroid lesions. Thirty-seven papillary, 10 follicular, 6 medullary, 1 mixed medullary follicular cell carcinoma, 3 poorly differentiated carcinoma, 18 adenomatous nodular hyperplasia, 30 follicular adenoma cases were included in the study. Immunohistochemical staining was performed with HBME-1, CK-19, galectin-3 on cross-sections derived from selected paraffin blocks. Benign and malignant lesions were compared in terms of intensity, percentage and type of staining with CK-19, HBME-1 and galectin-3, and a statistically significant difference (p < 0.05) was found. The percentage and intensity of staining was higher in malignant lesions. Especially, strong and diffuse expressions of CK19, HBME-1 and galectin 3 were observed in papillary carcinomas. Membranous (luminal) staining was seen more frequently in malignant lesions; cytoplasmic staining in benign lesions. It was concluded that these markers could assist in the diagnosis of thyroid lesions with cellular properties suspicious for the diagnosis of papillary carcinoma and without capsule and vessel invasion. They may be used especially in cases where the follicular variant of papillary carcinoma, follicular adenoma and follicular carcinoma are confused with each other and follicular adenoma cannot be differentiated from follicular carcinoma. PMID- 22535609 TI - Origin and pathological characteristics of Klatskin tumor: a case report and literature review. AB - Hilar cholangiocarcinomas involving the bifurcation of the hepatic duct are called Klatskin tumors. A resected specimen of the hilar hepatic region with Klatskin tumor was analyzed. The lining epithelium of major biliary ducts was regular, while the majority of epithelial cells lining the excretory ducts of peribiliary glands (PBGs) exhibited malignant features. The connective tissue surrounding the PBGs was infiltrated by mucinous malignant epithelial cells, sometimes in a signet-ring cell form, with perineural invasion. The tumor epithelial cells showed distinct CK 7 and CA 19-9 positivity. The described cholangiocarcinoma was classified as the Bismuth-Corlette type IIIb and originated from the excretory ducts and acinar cells of PBGs. PMID- 22535610 TI - Pemphigoid gestationis in a female with progressive facial hemiatrophy: microchimerism as a speculative shared background is disputable. AB - The commonest source of naturally acquired microchimerism, i.e. small numbers of foreign cells within the organism, is two-way mother-fetus transplacental trafficking during pregnancy. Here, the first report on coexistence of pregnancy associated pemphigoid gestationis (PG) and progressive facial hemiatrophy, a form of "en coup de sabre" morphea, is presented. HE histopathology (eosinophil-rich subepidermal infiltration, inverted teardrop sign), direct immunofluorescence (linear IgG1, but not IgG4, deposits along the dermal-epidermal junction) and ELISA (elevated levels of serum and blister fluid IgG autoantibodies to BP180) corroborated the PG diagnosis. Microchimerism as a speculative shared background of those two rare autoimmune diseases is disputable. PMID- 22535611 TI - Enterocolic lymphocytic phlebitis: an unusual cause of abdominal complaints. AB - Enterocolic lymphocytic phlebitis (ELP) is a rare disease of unknown etiology involving most often the intramural and mesenteric small and medium-sized veins of the gastrointestinal tract. The diagnosis of the disorder is based on the histopathological examination of a surgical specimen as endoscopically obtained diagnostic material is usually too superficial. Clinical manifestation of ELP most frequently is characterized by acute symptoms, such as acute abdomen, signs suggesting acute appendicitis, gastrointestinal hemorrhage, sometimes it manifests as chronic gastrointestinal complaints. We report, to our knowledge for the first time in Poland, a case of ELP with clinical symptoms pointing to acute appendicitis, on laparoscopy manifesting as a tumorous mass in the colonic wall with an unchanged appendix. PMID- 22535612 TI - Quiz. Correct answer to the quiz. Check your diagnosis. Mesenchymal chondrosarcoma of the orbit: two cases and a brief review of the literature. AB - Mesenchymal chondrosarcoma (MChS) is a rare, high-grade malignant tumor which occurs both in the bone and soft tissue. The extraskeletal location comprises one third of all MChS and in review of the up-to-date literature, about 30 cases of the orbital involvement were found. The authors present clinical, radiological and pathological findings of two cases of MChS of the orbit occurring in young adult females: primary extraskeletal MChS of the orbit and skeletal MChS of the ethmomaxillary complex with secondary orbit involvement. The histopathological examination revealed a characteristic biphasic pattern composed of small round to spindle-shaped cells, mimicking Ewing sarcoma family of tumors, with areas of a haemangiopericytoma-like pattern and admixed cartilage foci. One of the patients had local recurrence 3 years after initial surgical removal. Subsequently, she underwent enucleation followed by chemotherapy. The other patient had a biopsy and debulking resection of the tumor and started chemotherapy. Ten months follow up of this patient show no evidence of metastasis. PMID- 22535614 TI - Mast cells and cancer: enemies or allies? AB - Mast cells are a component of cancer microenvironment the role of which is complex and poorly understood. Mast cells promote cancer growth by stimulation of neoangiogenesis, tissue remodeling and by modulation of the host immune response. The mediators of cancer promotion include protease-activated receptors, mitogen activated protein kinases, prostaglandins and histamine. Histamine may induce tumor proliferation and immunosuppression through H1 and H2 receptors, respectively. The mast cell-derived modulators of immune response include also interleukin 10 (IL-10), tumor necrosis factor alpha (TNF-alpha) and CD30L. Possibly stimulation of angiogenesis is the most important. Mast cells release potent proangiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), transforming growth factor beta (TGF beta), TNF- alpha and IL-8, and mast cells' enzymes, like metaloproteinases (MMPs), tryptase and chymase participate in vessels' formation. The anti-cancer actions of mast cells include direct growth inhibition, immunologic stimulation, inhibition of apoptosis and decreased cell mobility; the mediators of these processes include chymase, tryptase, TNF-alpha, IL-1 and IL-6. The very same mediators may exert both pro- or anti-cancer effects depending on concentration, presence of cofactors or location of secreting cells. In fact, peri- and intra tumoral mast cells may have dissimilar effects. Understanding of the role of mast cells in cancer could lead to improved prognostication and development of therapeutic methods targeting the mast cells. PMID- 22535615 TI - Novel highly conductive and transparent graphene-based conductors. AB - Transparent conductors based on few-layer graphene (FLG) intercalated with ferric chloride (FeCl(3)) have an outstandingly low sheet resistance and high optical transparency. FeCl(3)-FLGs outperform the current limit of transparent conductors such as indium tin oxide, carbon-nanotube films, and doped graphene materials. This makes FeCl(3)-FLG materials the best transparent conductor for optoelectronic devices. PMID- 22535617 TI - Metastases to retroperitoneal or lateral pelvic lymph nodes indicated unfavorable survival and high pelvic recurrence rates in a cohort of 102 patients with low rectal adenocarcinoma. AB - BACKGROUND AND OBJECTIVES: The Japanese protocol considers metastases to retroperitoneal or lateral pelvic lymph nodes (RLPNs) as regional lymphatic dissemination in rectal adenocarcinoma patients and recommends total mesorectal excision (TME) plus retroperitoneal and lateral pelvic lymphadenectomy (RLPL). Western protocols consider RLPN metastases to indicate advanced disease. METHODS: All outcomes were evaluated among a cohort of 102 rectal adenocarcinoma patients subjected to TME plus RLPL with a nerve-preserving technique. Chemoradiotherapy was delivered in patients with T3/T4 tumors or metastases to mesorectal nodes or RLPNs. RESULTS: Surgical mortality was 3.9%; surgical morbidity was 33.3%. Incidence of RLPN metastases was 17%. Pelvic recurrence was 14.5% in pT3/pT4 patients and 29.4% in patients with metastases to RLPNs. Survival at 50 months was 28.6% in patients with RLPN metastases versus 84.5% in patients without RLPN metastases (P < 0.0001). Survival at 50 months was 33.3% in TME stage II patients with RLPN metastases versus 97.1% in TME stage II patients without RLPN metastases (P < 0.0001), and 21.9% in TME stage III patients with RLPN metastases versus 68.9% in TME stage III patients without RLPN metastases (P = 0.0237). CONCLUSIONS: Patients who underwent RLPL had acceptable morbidity and mortality rates. Metastases to RLPNs indicated unfavorable survival and considerable pelvic recurrence rates. PMID- 22535616 TI - Dietary intakes of berries and flavonoids in relation to cognitive decline. AB - OBJECTIVE: Berries are high in flavonoids, especially anthocyanidins, and improve cognition in experimental studies. We prospectively evaluated whether greater long-term intakes of berries and flavonoids are associated with slower rates of cognitive decline in older women. METHODS: Beginning in 1980, a semiquantitative food frequency questionnaire was administered every 4 years to Nurses' Health Study participants. In 1995-2001, we began measuring cognitive function in 16,010 participants, aged >=70 years; follow-up assessments were conducted twice, at 2 year intervals. To ascertain long-term diet, we averaged dietary variables from 1980 through the initial cognitive interview. Using multivariate-adjusted, mixed linear regression, we estimated mean differences in slopes of cognitive decline by long-term berry and flavonoid intakes. RESULTS: Greater intakes of blueberries and strawberries were associated with slower rates of cognitive decline (eg, for a global score averaging all 6 cognitive tests, for blueberries: p-trend = 0.014 and mean difference = 0.04, 95% confidence interval [CI] = 0.01-0.07, comparing extreme categories of intake; for strawberries: p-trend = 0.022 and mean difference = 0.03, 95% CI = 0.00-0.06, comparing extreme categories of intake), after adjusting for multiple potential confounders. These effect estimates were equivalent to those we found for approximately 1.5 to 2.5 years of age in our cohort, indicating that berry intake appears to delay cognitive aging by up to 2.5 years. Additionally, in further supporting evidence, greater intakes of anthocyanidins and total flavonoids were associated with slower rates of cognitive decline (p-trends = 0.015 and 0.053, respectively, for the global score). INTERPRETATION: Higher intake of flavonoids, particularly from berries, appears to reduce rates of cognitive decline in older adults. PMID- 22535620 TI - A global perspective on sickle cell disease. AB - The global burden of sickle cell disease (SCD) is now being increasingly realized. SCD poses a significant public health problem in sub-Saharan Africa, the Middle East, some regions of India, the Caribbean, and Brazil. In many of these regions, progress in the management of SCD has been slow. Long-term North South and South-South partnerships between SCD professionals, funding agencies, governments, and industry are needed to help reduce the high disease burden in developing countries, through widespread SCD education, relevant research and implementation of evidence-based cost-effective interventions. A group of SCD professionals have responded with action by forming a global network. PMID- 22535619 TI - Increased suppressor of cytokine signaling-3 expression predicts mucosal relapse in ulcerative colitis. AB - BACKGROUND: Most biomarkers predicting mucosal relapse of ulcerative colitis (UC) patients in clinical remission represent low levels of mucosal inflammation. Since SOCS3 expression may increase the vulnerability of intestinal epithelial cells (IECs) to various insults, we investigated whether its expression predicts mucosal relapse in UC patients in clinical remission without any signs of mucosal inflammation. METHODS: UC patients (n = 32) in clinical, endoscopic, and histological remission were followed up for 9 years. IEC expression of SOCS3, p STAT3, and p-STAT1 were assessed with biopsies from the baseline colonoscopy, last colonoscopy before relapse, and colonoscopy at relapse. Clinical data, endoscopy, and histology reports were collected from patient charts. RESULTS: Twenty-six (81%) patients had histological relapse, 19 (59%) developed an endoscopic relapse, and 17 (53%) had a clinical relapse during follow-up. SOCS3 expression at first colonoscopy during remission correlated with shorter time to histological, endoscopic, and clinical relapse. SOCS3 expression was increased at the last colonoscopy before relapse, approaching relapse levels, whereas p-STAT3 expression was low during the entire remission. A positive correlation between IEC SOCS3 and its inducer p-STAT1 was shown. CONCLUSIONS: SOCS3 IEC expression during remission may be useful in predicting mucosal relapse in patients without any signs of mucosal inflammation. These data strengthen our hypothesis that SOCS3 contributes to enhanced vulnerability of IEC during remission. Thus, SOCS3 levels during remission may function as a therapeutic target for clinical monitoring and early induction of mucosal healing. PMID- 22535621 TI - Comparison of the clinical features, bacterial genotypes and outcomes of patients with bacteraemia due to heteroresistant vancomycin-intermediate Staphylococcus aureus and vancomycin-susceptible S. aureus. AB - OBJECTIVES: We compared the clinical characteristics and outcomes of, and the bacterial genotypes in, patients with bacteraemia due to heteroresistant vancomycin-intermediate Staphylococcus aureus (hVISA) and vancomycin-susceptible S. aureus (VSSA). METHODS: A total of 268 consecutive patients with methicillin resistant S. aureus (MRSA) bacteraemia were prospectively enrolled. All isolates were selected on the first day of bacteraemia and subjected to population analysis profiling for identification of hVISA phenotype and PCR analysis for 41 virulence factors. RESULTS: Of 268 MRSA isolates, 101 (37.7%) were identified as hVISA. Overall mortality was similar in hVISA- and VSSA-infected patients (45/101 versus 65/167; P = 0.36). The following factors were independently associated with the presence of hVISA: a vancomycin MIC >=2 mg/L by Etest [adjusted OR (aOR), 9.98; 95% CI, 4.22-23.59], rifampicin resistance (aOR, 5.74; 95% CI, 1.35 24.37), prior vancomycin therapy (aOR, 3.04; 95% CI, 1.49-6.17) and use of immunosuppressive therapy (aOR, 2.41; 95% CI, 1.12-5.17). Among patients with hVISA, bacteraemia was more likely to persist for >=7 days in patients with an initial vancomycin trough <15 mg/L than in those with an initial trough >=15 mg/L (13/34 versus 5/35; P = 0.02). The hVISA and VSSA isolates were genotypically similar. CONCLUSIONS: The hVISA phenotype was present in more than one-third of MRSA isolates and was independently associated with several baseline factors. Although this phenotype did not affect patient outcomes, our results indicate that targeting an initial vancomycin trough of 15-20 mg/L may be beneficial in patients with hVISA bacteraemia. PMID- 22535623 TI - The epithelium-produced growth factor midkine has fungicidal properties. AB - OBJECTIVES: The skin encounters many potential pathogens present in the environment, where Candida spp. are among the most common causes of fungal infestation. Midkine (MK) is a heparin-binding growth factor that is constitutively produced in the epidermis and this study looks at the antifungal activity of MK, potential co-localization and mode of action of MK. METHODS AND RESULTS: We show that MK is expressed in association with fungal infections of the skin. In vitro, MK showed strong fungicidal activity against Candida albicans and Candida parapsilosis. Scanning electron microscopy of fungi revealed blebbing and leakage of intracellular contents, indicating membrane interactions. Immunoelectron microscopy showed accumulation of MK in association with the membrane, but also a high degree of internalization, suggesting intracellular targets as well. Using liposome models mimicking fungal and human cell membranes (i.e. ergosterol- and cholesterol-containing membranes, respectively), MK was found to disrupt ergosterol-containing membranes to a higher degree than cholesterol-containing vesicles. Addition of increasing concentrations of salt caused a partial and dose-dependent decrease in the fungicidal activity exerted by MK in parallel with a decreased affinity for the yeast. However, at salt concentrations similar to those of an epithelial context (i.e. 50-100 mM), MK retained most of its fungicidal activity, in contrast to that of plasma (150 mM). CONCLUSIONS: The findings suggest that MK plays a role in host defence against fungal infections and could serve as a template for development of novel antifungal treatments. PMID- 22535622 TI - Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug. AB - OBJECTIVES: Infection with yellow fever virus (YFV), the prototypic mosquito borne flavivirus, causes severe febrile disease with haemorrhage, multi-organ failure and a high mortality. Moreover, in recent years the Flavivirus genus has gained further attention due to re-emergence and increasing incidence of West Nile, dengue and Japanese encephalitis viruses. Potent and safe antivirals are urgently needed. METHODS: Starting from the crystal structure of the NS3 helicase from Kunjin virus (an Australian variant of West Nile virus), we identified a novel, unexploited protein site that might be involved in the helicase catalytic cycle and could thus in principle be targeted for enzyme inhibition. In silico docking of a library of small molecules allowed us to identify a few selected compounds with high predicted affinity for the new site. Their activity against helicases from several flaviviruses was confirmed in in vitro helicase/enzymatic assays. The effect on the in vitro replication of flaviviruses was then evaluated. RESULTS: Ivermectin, a broadly used anti-helminthic drug, proved to be a highly potent inhibitor of YFV replication (EC50 values in the sub-nanomolar range). Moreover, ivermectin inhibited, although less efficiently, the replication of several other flaviviruses, i.e. dengue fever, Japanese encephalitis and tick-borne encephalitis viruses. Ivermectin exerts its effect at a timepoint that coincides with the onset of intracellular viral RNA synthesis, as expected for a molecule that specifically targets the viral helicase. CONCLUSIONS: The well-tolerated drug ivermectin may hold great potential for treatment of YFV infections. Furthermore, structure-based optimization may result in analogues exerting potent activity against flaviviruses other than YFV. PMID- 22535624 TI - In vitro antifungal susceptibility of filamentous fungi causing rare infections: synergy testing of amphotericin B, posaconazole and anidulafungin in pairs. AB - OBJECTIVES: Mucormycetes (formerly known as zygomycetes of the order Mucorales) and hyaline moulds such as those of the genus Fusarium or Paecilomyces are emerging as significant human pathogens. The aim of the study was to determine the in vitro antifungal susceptibility of these fungi to older and newer antifungals and to investigate the antifungal activity of amphotericin B, posaconazole and anidulafungin in dual combinations. METHODS: Twenty-one clinical isolates of mucormycetes and 16 of rare hyaline moulds were tested. MICs were determined by EUCAST methodology for conidia-forming moulds and Etesting. For antifungal combinations a chequerboard method based on EUCAST methodology was used. RESULTS: Against mucormycetes, amphotericin B exhibited the lowest MICs, followed by posaconazole. Ravuconazole was active against eight of the Rhizopus isolates (MIC 1 mg/L). Resistance to amphotericin B (MIC >= 2 mg/L) and posaconazole (MICs >= 4 mg/L) was observed in five and three Rhizopus isolates, respectively. Among Fusarium species variable susceptibility patterns were detected. Amphotericin B exhibited the lowest MICs, followed by voriconazole. Etesting for amphotericin B and posaconazole had excellent agreement with EUCAST methodology (78.6%-100%). Synergy between amphotericin B and anidulafungin was observed against two isolates (one Mucor circinelloides and one Fusarium proliferatum). Synergy or antagonism was not detected in any other combination. CONCLUSIONS: The study showed that mucormycetes and other rare hyaline moulds exhibit variable susceptibilities to antifungals, and hence antifungal testing is valuable. The fact that the combination of amphotericin B with anidulafungin was found synergistic in some cases merits further investigation. PMID- 22535625 TI - [Opioid replacement therapy--claims versus reality]. PMID- 22535626 TI - Bone cells from patients with quiescent Crohn's disease show a reduced growth potential and an impeded maturation. AB - Patients with Crohn's disease (CD) are at increased risk of developing osteoporosis. The mechanism underlying bone loss in CD patients is only partly understood. Inflammation is thought to contribute by causing a disturbed bone remodeling. In this study, we aimed to compare functional characteristics of osteoblasts from CD patients and controls, as osteoblasts are one of the effector cells in bone remodeling. The study included 18 patients with quiescent CD and 18 healthy controls. Bone cells obtained from iliac crest biopsies were cultured in the absence and presence of the inflammatory cytokines IL-1alpha, IL-1beta, IL-6, TNF-alpha, IL-10, and TGF-beta. At various time points, cell proliferation and differentiation were analyzed. Bone cells from CD patients showed a prolonged culture period to reach confluence and a decreased cell number at confluence. CD patient-derived bone cell cultures produced higher alkaline phosphatase levels, whereas osteocalcin levels were considerably reduced compared to control cultures. At the proliferation level, the responsiveness to inflammatory cytokines was similar in bone cells from CD patients and controls. At the differentiation level, CD cultures showed an increased responsiveness to IL-6 and a decreased responsiveness to TGF-beta. Responsiveness to the other cytokines tested was unaffected. In summary, we show a reduced growth potential and impeded maturation of bone cells from quiescent CD patients in vitro. These disease related alterations combined with an unchanged sensitivity of CD patient-derived bone cells to inflammatory cytokines, provide a new insight in the understanding of CD-associated bone loss. PMID- 22535627 TI - Fear no pain: uterine cavity and tubal patency assessment tests should be pain free. PMID- 22535628 TI - Intra- and interobserver variability in fetal ultrasound measurements. AB - OBJECTIVE: To assess intra- and interobserver variability of fetal biometry measurements throughout pregnancy. METHODS: A total of 175 scans (of 140 fetuses) were prospectively performed at 14-41 weeks of gestation ensuring an even distribution throughout gestation. From among three experienced sonographers, a pair of observers independently acquired a duplicate set of seven standard measurements for each fetus. Differences between and within observers were expressed in measurement units (mm), as a percentage of fetal dimensions and as gestational age-specific Z-scores. For all comparisons, Bland-Altman plots were used to quantify limits of agreement. RESULTS: When using measurement units (mm) to express differences, both intra- and interobserver variability increased with gestational age. However, when measurement of variability took into account the increasing fetal size and was expressed as a percentage or Z-score, it remained constant throughout gestation. When expressed as a percentage or Z-score, the 95% limits of agreement for intraobserver difference for head circumference (HC) were +/- 3.0% or 0.67; they were +/- 5.3% or 0.90 and +/- 6.6% or 0.94 for abdominal circumference (AC) and femur length (FL), respectively. The corresponding values for interobserver differences were +/- 4.9% or 0.99 for HC, +/- 8.8% or 1.35 for AC and +/- 11.1% or 1.43 for FL. CONCLUSIONS: Although intra- and interobserver variability increases with advancing gestation when expressed in millimeters, both are constant as a percentage of the fetal dimensions or when reported as a Z score. Thus, measurement variability should be considered when interpreting fetal growth rates. PMID- 22535629 TI - Re: limitations of current definitions of miscarriage using mean gestational sac diameter and crown-rump length measurements: a multicenter observational study. PMID- 22535631 TI - Re: limitations of current definitions of miscarriage using mean gestational sac diameter and crown-rump length measurements: a multicenter observational study. PMID- 22535633 TI - Impact of oral calcium on mortality of dialysis patients--an underestimated risk? PMID- 22535634 TI - Chronic kidney disease is not associated with a higher risk for mortality or acute kidney injury in transcatheter aortic valve implantation. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) has emerged as a new therapeutic option for surgical high-risk patients with severe aortic stenosis (AS). Many of these patients suffer from chronic kidney disease (CKD), which substantially increases the risk for acute kidney injury (AKI), need for renal replacement therapy (RRT) and mortality after surgical aortic valve repair. The impact of pre-existing CKD for the outcome of TAVI is still unclear. METHODS: We retrospectively evaluated 199 consecutive patients with symptomatic high-grade AS undergoing TAVI with the CoreValve prosthesis at our centre. We analysed incidence and predictive factors for AKI, RRT and mortality in patients with and without CKD (defined as an estimated glomerular filtration rate <60 mL/min). RESULTS: 26.8% of the patients suffered from AKI, 4.9% needed RRT and 5.5% died. All patients on chronic haemodialysis (n = 10) survived. There were no significant differences between patients with or without CKD concerning the incidence of AKI, RRT and mortality. Age, peripheral vascular disease and the need for blood transfusion were independently associated with AKI. AKI proved to be a predictive factor for mortality. CONCLUSIONS: Transcatheter aortic valve replacement with the CoreValve prosthesis does not seem to bear an increased risk for patients with CKD. For surgical high-risk patients with severe AS, a more liberal consideration for TAVI as an alternative to open surgery might be justified. PMID- 22535635 TI - Use of online blood volume and blood temperature monitoring during haemodialysis in critically ill patients with acute kidney injury: a single-centre randomized controlled trial. AB - BACKGROUND: Little is known about the clinical impact on cardiovascular stability during intermittent haemodialysis (IHD) for acute kidney injury (AKI) of online monitoring devices that control blood volume (BV) and blood temperature in the intensive care unit (ICU) setting. We compared different dialysis treatment modalities with or without these new systems among critically ill patients requiring IHD. METHODS: In a prospective single-centre three-arm randomized controlled trial, 600 dialysis sessions in 74 consecutive AKI critically ill patients were involved to assess intradialytic hypotension. Standard dialysis therapy with constant ultrafiltration (UF) rate, cool dialysate and high sodium conductivity (Treatment A) was compared to regimens with adjunctive interventions including BV control (Treatment B) and the combination of BV and active blood temperature control (Treatment C). Each dialysis session was randomly assigned to one of the three treatment arms and served as statistical unit. RESULTS: Five hundred and seventy-two dialysis sessions were analysed (188, 190 and 194 in Treatments A, B and C, respectively). Hypotension occurred in 16.6% treatments, with similar rates among the arms. Haemodynamic parameters and dialysis-related complications did not differ between therapies. Based on generalized estimating equation adjusted to dialysate sodium conductivity, higher Sequential Organ Failure Assessment the day of dialysis session, the need for vasopressors and lower systolic blood pressure at the onset of the session were identified as independent predictors of hypotensive episodes, whereas regimens containing the new online monitors were not. CONCLUSIONS: These results suggest that both actively controlled body temperature and UF profiled by online monitoring systems have no significant impact on the incidence of intradialytic hypotension in the ICU setting. Further research is needed before the use of these new sophisticated automatic methods can be applied routinely to the ICU setting. PMID- 22535636 TI - Cancer survival through lifestyle change (CASTLE): a pilot study of weight loss. AB - BACKGROUND: Excess weight is a strong predictor of incident breast cancer (BC) and survivorship. A limited number of studies comparing strategies for promoting successful weight loss in women with remitted BC exist. PURPOSE: CASTLE was a pilot study comparing the effectiveness/feasibility of in-person and telephonic behavioral-based lifestyle weight loss interventions in BC survivors. METHOD: Fifty-two overweight/obese women (BMI = 25-45 kg/m(2)) with remitted BC (stages I IIIa) who recently completed cancer treatment were assigned to either an in person group (n = 24) or an individual telephone-based condition (n = 11). Both interventions focused on increasing physical activity and reducing caloric intake. The phase I intervention lasted 6 months. The in-person condition received 16 group-based sessions, and the telephone condition received intervention calls approximately weekly. Phase II lasted 6 months (e.g., months 6 12), and all participants received monthly intervention calls via telephone. RESULTS: Participants were predominately Caucasian (80 %) with a mean age of 52.8 (8.0) years and BMI of 31.9 (5.4) kg/m(2). Mixed models ANOVAs showed significant within group weight loss after 6 months for both the in-person (-3.3 kg +/- 4.4, p = 0.002) and the telephonic (-4.0 kg +/- 6.0, p = 0.01) conditions with no between group differences. During phase II, the in-person group demonstrated significant weight regain (1.3 kg +/- 1.7, p = 0.009). CONCLUSION: Our pilot study findings demonstrated that telephone-based behavioral weight loss programs are effective and feasible in BC survivors and that telephonic programs may have advantages in promoting weight loss maintenance. PMID- 22535638 TI - Real-time three-dimensional echocardiographic evaluation of left ventricular systolic synchronicity in patients with chronic heart failure: comparison with tissue Doppler imaging. AB - BACKGROUND: To investigate the clinical value of real-time three-dimensional echocardiography (RT-3DE) for assessing of left ventricular systolic synchronicity. METHODS: Thirty healthy volunteers and 62 patients with congestive heart failure (CHF) were enrolled. The SD of time to peak systolic motion (TDI Ts12-SD) was measured with tissue Doppler imaging in 12 myocardial segments. The SD and maximal difference of the time to minimal systolic volume (Tmsv) between 16, 12, or 6 myocardial segments, expressed as a percentage of cardiac cycle duration, were measured with RT-3DE and labeled Tmsv16-SD%, Tmsv12-SD%, Tmsv6 SD%, Tmsv16-D%, Tmsv12-D%, and Tmsv6-D%, respectively. The Spearman coefficient and Kappa value were calculated, and Bland-Altman analysis was performed to investigate the correlation and agreement between the two methods. Tmsv values were compared with ejection fraction (EF). RESULTS: There was a moderately positive (p< 0.01) correlation between TDI-Ts12-SD and Tmsv16-SD%, Tmsv12-SD%, Tmsv16-D%, and Tmsv12-D% (r = 0.65, 0.64, and 0.65, respectively, with Kappa values of 0.66, 0.65, 0.72, and 0.74, respectively, p< 0.01). Tmsv16-SD%, Tmsv12 SD%, and Tmsv12-D% were significantly different between CHF patients with EF <= 35% and those with EF > 35%. CONCLUSIONS: RT-3DE can be used in patients with CHF to quantify left ventricular mechanical dyssynchrony. Tmsv12-SD% and Tmsv12-D% were the best indices of left ventricular systolic synchronicity in relation to the severity of CHF as evaluated from EF. PMID- 22535637 TI - Enhanced hepatocarcinogenesis in mouse models and human hepatocellular carcinoma by coordinate KLF6 depletion and increased messenger RNA splicing. AB - KLF6-SV1 (SV1), the major splice variant of KLF6, antagonizes the KLF6 tumor suppressor by an unknown mechanism. Decreased KLF6 expression in human hepatocellular carcinoma (HCC) correlates with increased mortality, but the contribution of increased SV1 is unknown. We sought to define the impact of SV1 on human outcomes and experimental murine hepatocarcinogenesis and to elucidate its mechanism of action. In hepatitis C virus (HCV)-related HCC, an increased ratio of SV1/KLF6 within the tumor was associated with features of more advanced disease. Six months after a single injection of diethylnitrosamine (DEN), SV1 hepatocyte transgenic mice developed more histologically advanced tumors, whereas Klf6-depleted mice developed bigger tumors compared to the Klf6fl(+/+) control mice. Nine months after DEN, SV1 transgenic mice with Klf6 depletion had the greatest tumor burden. Primary mouse hepatocytes from both the SV1 transgenic animals and those with hepatocyte-specific Klf6 depletion displayed increased DNA synthesis, with an additive effect in hepatocytes harboring both SV1 overexpression and Klf6 depletion. Parallel results were obtained by viral SV1 transduction and depletion of Klf6 through adenovirus-Cre infection of primary Klf6fl(+/+) hepatocytes. Increased DNA synthesis was due to both enhanced cell proliferation and increased ploidy. Coimmunoprecipitation studies in 293T cells uncovered a direct interaction of transfected SV1 with KLF6. Accelerated KLF6 degradation in the presence of SV1 was abrogated by the proteasome inhibitor MG132. CONCLUSION: An increased SV1/KLF6 ratio correlates with more aggressive HCC. In mice, an increased SV1/KLF6 ratio, generated either by increasing SV1, decreasing KLF6, or both, accelerates hepatic carcinogenesis. Moreover, SV1 binds directly to KLF6 and accelerates its degradation. These findings represent a novel mechanism underlying the antagonism of tumor suppressor gene function by a splice variant of the same gene. PMID- 22535639 TI - Enhanced FcalphaRI-mediated neutrophil migration towards tumour colonies in the presence of endothelial cells. AB - Neutrophils potently kill tumour cells in the presence of anti-tumour antibodies in vitro. However, for in vivo targeting, the neutrophils need to extravasate from the circulation by passing through endothelial barriers. To study neutrophil migration in the presence of endothelial cells in vitro, we established a three dimensional collagen culture in which SK-BR-3 tumour colonies were grown in the presence or absence of an endothelial barrier. We demonstrated that - in contrast to targeting FcgammaR on neutrophils with mAbs - targeting the immunoglobulin A Fc receptor (FcalphaRI) instead triggered neutrophil migration and degranulation leading to tumour destruction, which coincided with release of the pro inflammatory cytokines interleukin (IL)-1beta and tumour necrosis factor (TNF) alpha. Interestingly, neutrophil migration was enhanced in the presence of endothelial cells, which coincided with production of significant levels of the neutrophil chemokine IL-8. This supports the idea that stimulation of neutrophil FcalphaRI, but not FcgammaR, initiates cross-talk between neutrophils and endothelial cells, leading to enhanced neutrophil migration towards tumour colonies and subsequent tumour killing. PMID- 22535640 TI - Ctenophore population recruits entirely through larval reproduction in the central Baltic Sea. AB - The comb jelly Mertensia ovum, widely distributed in Arctic regions, has recently been discovered in the northern Baltic Sea. We show that M. ovum also exists in the central Baltic but that the population consists solely of small-sized larvae (less than 1.6 mm). Despite the absence of adults, eggs were abundant. Experiments revealed that the larvae were reproductively active. Egg production and anticipated mortality rates suggest a self-sustaining population. This is the first account of a ctenophore population entirely recruiting through larval reproduction (paedogenesis). We hypothesize that early reproduction is favoured over growth to compensate for high predation pressure. PMID- 22535641 TI - Long-term familiarity promotes joining in neighbour nest defence. AB - Familiarity plays an important role in the evolution of sociality and cooperation. Familiar individuals may gain a reputation for participating in, or defecting from, cooperative tasks. Previous research suggests that long-term familiarity with territorial neighbours benefits breeders. We tested the hypothesis that great tits (Parus major) are more likely to join in neighbours' nest defence if those neighbours are familiar from the previous year. We show that neighbours that shared a territory boundary the previous year are more likely to join their neighbours' nest defence than neighbours that did not share a boundary before. Closer neighbours did not differ from distant neighbours in their latency to join. For familiar neighbours that joined, there was no difference in call rate in relation to whether one or both members of the focal pair were familiar. First-time breeders (by definition unfamiliar) did not join each other's nest defence. This is the first evidence of a relationship between familiarity and joining in nest defence. Such direct benefits of familiarity may have important implications in the evolution of sociality. PMID- 22535642 TI - When it is costly to have a caring mother: food limitation erases the benefits of parental care in earwigs. AB - The aggregation of parents with offspring is generally associated with different forms of care that improve offspring survival at potential costs to parents. Under poor environments, the limited amount of resources available can increase the level of competition among family members and consequently lead to adaptive changes in parental investment. However, it remains unclear as to what extent such changes modify offspring fitness, particularly when offspring can survive without parents such as in the European earwig, Forficula auricularia. Here, we show that under food restriction, earwig maternal presence decreased offspring survival until adulthood by 43 per cent. This effect was independent of sibling competition and was expressed after separation from the female, indicating lasting detrimental effects. The reduced benefits of maternal presence on offspring survival were not associated with higher investment in future reproduction, suggesting a condition-dependent effect of food restriction on mothers and local mother-offspring competition for food. Overall, these findings demonstrate for the first time a long-term negative effect of maternal presence on offspring survival in a species with maternal care, and highlight the importance of food availability in the early evolution of family life. PMID- 22535643 TI - Dual specificity phosphatase 6 as a predictor of invasiveness in papillary thyroid cancer. AB - OBJECTIVE: The genetic mutations causing the constitutive activation of MEK/ERK have been regarded as an initiating factor in papillary thyroid carcinoma (PTC). The ERK-specific dual specificity phosphatase 6 (DUSP6) is part of the ERK dependent transcriptional output. Therefore, the coordinated regulation of the activities of ERK kinases and DUSP6 may need to be reestablished to make new balances in PTC. METHODS: To investigate the role of DUSP6 in the regulation of ERK1/2 (MAPK3/1)-dependent transcription, 42 benign neoplasms and 167 PTCs were retrospectively analyzed by immunohistochemistry with dideoxy sequencing to detect BRAF(V600E) mutation. RESULTS: The expressions of total ERK1/2, DUSP6, c Fos (FOS), c-Myc (MYC), cyclin D1, and PCNA were markedly increased in PTC compared with those in benign neoplasms. However, phospho-ERK1/2 was detected in only eight (4.8%) cases out of 167 PTC samples. Unexpectedly, the staining intensity and nuclear localization of ERK1/2 were not affected by the presence or absence of the BRAF(V600E) mutation. However, the expressions of c-Fos and PCNA were elevated in BRAF(V600E)-positive PTC compared with those in BRAF(V600E) negative PTC. Interestingly, the higher staining intensities of DUSP6 were associated with the level of total ERK1/2 expression (P=0.04) and with high-risk biological features such as age (P=0.05), tumor size (P=0.01), and extrathyroidal extension (linear by linear association, P=0.02). In addition, DUSP6 silencing significantly decreased the cell viability and migration rate of FRO cells. CONCLUSIONS: The coordinated upregulation of total ERK1/2 and its phosphatase, DUSP6, is related to bare detection of phospho-ERK1/2 in PTC regardless of BRAF(V)(600E) mutation status. A link between DUSP6 expression and high-risk features of PTC suggested that DUSP6 is an important independent factor affecting the signaling pathways in established PTC. PMID- 22535644 TI - Nonalcoholic fatty liver disease in adult hypopituitary patients with GH deficiency and the impact of GH replacement therapy. AB - BACKGROUND: Liver dysfunction in adult hypopituitary patients with GH deficiency (GHD) has been reported and an increased prevalence of nonalcoholic fatty liver disease (NAFLD) has been suggested. OBJECTIVE: The objective of the present study was to elucidate the pathophysiology of the liver in adult hypopituitary patients with GHD. PATIENTS AND METHODS: We recruited 69 consecutive Japanese adult hypopituitary patients with GHD and examined the prevalence of NAFLD by ultrasonography and nonalcoholic steatohepatitis (NASH) by liver biopsy. Patients had been given routine replacement therapy except for GH. We compared these patients with healthy age-, gender-, and BMI-matched controls. We further analyzed the effect of GH replacement therapy on liver function, inflammation and fibrotic markers, and histological changes. RESULTS: The prevalence of NAFLD in hypopituitary patients with GHD was significantly higher than in controls (77 vs 12%, P<0.001). Of 16 patients assessed by liver biopsy, 14 (21%) patients were diagnosed with NASH. GH replacement therapy significantly reduced serum liver enzyme concentrations in the patients and improved the histological changes in the liver concomitant with reduction in fibrotic marker concentrations in patients with NASH. CONCLUSIONS: Adult hypopituitary patients with GHD demonstrated a high NAFLD prevalence. The effect of GH replacement therapy suggests that the NAFLD is predominantly attributable to GHD. PMID- 22535645 TI - Subclinical hyperthyroidism and the risk of cardiovascular events and all-cause mortality: an updated meta-analysis of cohort studies. AB - OBJECTIVES: Whether subclinical hyperthyroidism (SCH) results in poor prognosis remains controversial. Our aim was to evaluate the association between SCH and the risk of cardiovascular disease (CVD), cardiovascular mortality, and all-cause mortality by conducting a meta-analysis of cohort studies. METHODS: The PubMed and Embase databases were searched through November 2011 to identify studies that met pre-stated inclusion criteria. Relevant information for analysis was extracted. Either a fixed or a random effects model was used to calculate the overall combined risk estimates. RESULTS: Seventeen cohort studies were included in this meta-analysis. The overall combined relative risks for individuals with SCH compared with the reference group were 1.19 (95% confidence interval (CI): 1.10 to 1.28) for CVD, 1.52 (95% CI: 1.08 to 2.13) for cardiovascular mortality, and 1.25 (95% CI: 1.00 to 1.55) for all-cause mortality. Subgroup analysis by sample source (community or convenience sample) showed that the significant association for cardiovascular and all-cause mortality only existed when pooling studies from convenience samples. Heterogeneity was observed when pooling studies on the association between SCH and cardiovascular and all-cause mortality. Sensitivity analysis showed omission of each individual study did not significantly change the pooled effects. No evidence of publication bias was observed. CONCLUSIONS: Our findings demonstrated that SCH significantly increased the risk of CVD for the general population and the risk of cardiovascular and all cause mortality for the individuals with other morbidities. PMID- 22535646 TI - Screening of LHX2 in patients presenting growth retardation with posterior pituitary and ocular abnormalities. AB - BACKGROUND: In humans, pituitary hormone deficiency may be part of a syndrome including extra-pituitary defects like ocular abnormalities. Very few genes have been linked to this particular phenotype. In the mouse, Lhx2, which encodes a member of the LIM (Lin-11, Isl-1, and Mec-3) class of homeodomain proteins, was shown to be expressed during early development in the posterior pituitary, eye, and liver, and its expression persists in adulthood in the central nervous system Lhx2(-/-) mice display absence of posterior pituitary and intermediate lobes, malformation of the anterior lobe, anophthalmia, and they die from anemia. METHODS: We tested the implication of the LHX2 gene in patients presenting pituitary hormone deficiency associated with ectopic or nonvisible posterior pituitary and developmental ocular defects. A cohort of 59 patients, including two familial cases, was studied. Direct sequencing of the LHX2 coding sequence and intron/exon boundaries was performed. LHX2 transcriptional activity on several pituitary promoters (AGSU, PRL, POU1F1, and TSHB) was tested in vitro. RESULTS: Six heterozygous sequence variations were identified, among which two are novel missense changes (p.Ala203Thr and p.Val333Met). In vitro, LHX2 activates transcription of TSHB, PRL, and POU1F1 promoters in the HEK293 cell line. A synergistic action of POU1F1 and LHX2 was also shown on these promoters. The two missense variations were tested and no significant difference was observed, leading to the conclusion that they are not deleterious. CONCLUSIONS: These results suggest that if LHX2 is involved in pituitary hormone deficiency associated with posterior pituitary and ocular defects, it would be a rare cause of this disease condition. PMID- 22535647 TI - Development of protein-labeling probes with a redesigned fluorogenic switch based on intramolecular association for no-wash live-cell imaging. PMID- 22535648 TI - Theoretical directions for an emancipatory concept of patient and public involvement. AB - Patient and public involvement (PPI) is now firmly embedded in the policies of the Department of Health in England. This article commences with a review of the changing structures of PPI in English health and social care, largely in terms of their own explicit rationales, using that as a spring board for the development of a general theoretical framework. Arguing that all democratic states face major dilemmas in seeking to meet conflicting demands and expectations for involvement, we identify the diverse and sometimes conflicting cultural and political features embedded in current models of involvement in England, in a context of rapid delegitimation of the wider political system. We identify some of the major inherent weaknesses of a monolithic, single-track model of patient and public involvement in the management and running of health and social care systems. Although the mechanisms and methods for delivering this may vary we suggest the model remains fundamentally the same. We also suggest why the current structures are unlikely to provide an effective response either to the pluralism of values, ideologies and social groups engaged in the sector or to the valuing of lay knowledge which could potentially sustain the social networks essential for effective participation and service improvement. The article proposes a four dimensional framework for analysing the nature of PPI. These dimensions, it is argued, provide the co-ordinates along which new 'knowledge spaces' for PPI could be constructed. These knowledge spaces could facilitate and support the emergence of social networks of knowledgeable actors capable of engaging with professionals on equal terms and influencing service provision. PMID- 22535649 TI - Credibility and the 'professionalized' lay expert: reflections on the dilemmas and opportunities of public involvement in health research. AB - Contemporary health policy in England places increasing emphasis on patient and public involvement (PPI) in health and health research. With regard to the latter, it has been suggested that PPI brings 'different' perspectives to research decision-making spaces, based on what has been referred to as 'experiential expertise'. This article presents findings from a qualitative study of PPI in cancer research settings in England. We argue that participants highlighted specific forms of expertise in their accounts about involvement, above and beyond experiential expertise, which they felt legitimated their claims to be credible participants within cancer research settings. We report here on the various strategies by which participants sought to accomplish this and highlight, in particular, a concomitant process of 'professionalization' of some within our group of participants. We discuss the significance of these findings in the context of recent debates around the status of experiential expertise. PMID- 22535650 TI - Plasma exchange for renal disease: evidence and use 2011. AB - Over the past 37 year the role of plasma exchange in the treatment of patients with renal disease has undergone several changes. The majority of the changes for the use of plasma exchange relied on randomized control trials and delineations of mechanisms that potentially would benefit from the use of plasma exchange. Over the past 11 years plasma exchange indications for renal disease, the absolute numbers have been relatively unchanged but the indications are quite different. The Canadian Apheresis Group indicated in 2010 that TTP/HUS is still the number 1 indication at 63% of the total plasma exchange activity for renal disease but P and C ANCA Vasculitis had risen to 14% followed by renal transplant at 10%, Goodpasture's Syndrome at 6% and transplant FSGS at 5% with Cryoglobulinemia 2% and Myeloma Nephropathy had dropped dramatically to less than 1% with no cases of SLE reported. This report describes the most common indications for plasma exchange in patient's with renal disease and the evidence that supports it's use in 2011. PMID- 22535651 TI - Accuracy of transvaginal sonography and contrast-enhanced magnetic resonance colonography for the presurgical staging of deep infiltrating endometriosis. AB - OBJECTIVE: To investigate the accuracy of transvaginal sonography (TVS) and contrast-enhanced magnetic resonance-colonography (CE-MR-C) for the presurgical assessment of deep infiltrating endometriosis (DIE). METHODS: Ninety women were enrolled prospectively for suspicion of DIE. All patients underwent TVS and CE-MR C, with each operator blinded to the results of the other exam, before laparoscopy. The sites of DIE examined by both imaging techniques were: rectovaginal septum, pouch of Douglas, uterosacral ligaments, vesicouterine pouch, bowel, bladder and vagina. The presence of adhesions and the involvement of adnexa and of a previous abdominal scar, when there was clinical suspicion, were also evaluated. TVS and CE-MR-C findings were compared with laparoscopic and histological results. RESULTS: Endometriosis was confirmed by laparoscopy in 95.6% (86/90) of cases. In 82.2% (74/90) of patients there was DIE. The global accuracy for TVS in the detection of DIE was 89.2%, sensitivity was 81.1%, specificity was 94.2%, positive predictive value was 89.6%, negative predictive value was 89.0%, the positive likelihood ratio was 13.9 and the negative likelihood ratio was 0.2. For CE-MR-C, these values were 87.2%, 71.1%, 97.1%, 93.7%, 84.6%, 24.4 and 0.3, respectively. CE-MR-C allowed diagnosis of all cases of bowel involvement; the accuracy for infiltration and stenosis was 100%. The accuracy of TVS for rectosigmoid nodules was 91.1% and that for infiltration was 88.9%. CONCLUSIONS: Both TVS and CE-MR-C showed satisfactory results for the presurgical assessment of DIE. TVS appears to be a powerful, simple, feasible, cost-effective tool for preoperative staging of DIE. CE-MR-C is an 'X-ray free' technique, which could be reserved for cases with deep infiltrating rectosigmoid lesions and for the prediction of stenosis and involvement of the upper part of the colon and small intestine. PMID- 22535652 TI - The effect of reactive atypia/inflammation on the laser-induced fluorescence diagnosis of non-dysplastic Barrett's esophagus. AB - BACKGROUND AND OBJECTIVES: Differential Normalized Fluorescence (DNF) technique has been used to distinguish high-grade dysplasia from non-dysplastic Barrett's esophagus. This technology may assist gastroenterologists in targeting biopsies, reducing the number of biopsies using the standard protocol. In the presence of reactive atypia/inflammation, it becomes difficult for the pathologist to differentiate non-dysplastic Barrett's esophagus from Barrett's esophagus with low-grade dysplasia. Before DNF technique may be used to guide target biopsies, it is critical to know whether reactive atypia/inflammation in non-dysplastic Barrett's may result in false positives. This study was conducted to determine whether DNF technique is adversely affected by the presence of reactive atypia/inflammation in non-dysplastic Barrett's esophagus resulting in false positives. STUDY DESIGN/MATERIALS AND METHODS: Four hundred ten-nanometer laser light was used to induce autofluorescence of Barrett's mucosa in 49 patients. The clinical study included 37 males and 12 females. This was a blinded retrospective data analysis study. A total of 303 spectra were collected and matched to non dysplastic Barrett's biopsy results. One hundred seventy-five spectra were collected from areas with a pathology of non-dysplastic Barrett's esophagus with reactive atypia/inflammation. One hundred twenty-eight spectra were collected from areas with non-dysplastic Barrett's esophagus without reactive changes/inflammation. The spectra were analyzed using the DNF Index at 480 nm and classified as positive or negative using the threshold of -0.75 * 10(-3). RESULTS: Using DNF technique, 92.6% of non-dysplastic samples with reactive atypia/inflammation were classified correctly (162/175). 92.2% of non-dysplastic samples without reactive atypia/inflammation were classified correctly (118/128). Comparing the ratios of false positives among the two sample groups, there was not a statistically significant difference between the two groups. CONCLUSION: Using DNF technique for classification of non-dysplastic Barrett's mucosa does not result in false-positive readings due to reactive atypia/inflammation. Target biopsies guided by DNF technique may drastically reduce the number of pinch biopsies using the standard biopsy protocol. PMID- 22535654 TI - The choice of vascular access for therapeutic apheresis. AB - Therapeutic apheresis (TA) is performed using either centrifugation-based or filter-based systems. The blood flow rate (BFR) used for TA using centrifugation based systems is less than 100 mL/min. Because of this low BFR requirement, even peripheral veins can be considered as an option for TA, especially for less frequent treatments and those performed for short periods. Other options for vascular access (VA) include central venous catheters (temporary or tunneled), totally implantable ports, and arteriovenous fistulae (AVF) or grafts (AVG). Nontunneled catheters should be considered as the choice of VA for relatively short-term treatments mainly in the inpatient settings. For long-term treatments, ports and tunneled catheters should be considered because of lower rates of infections compared to nontunneled catheters. However, studies in hemodialysis (HD) patients have demonstrated significantly higher morbidity and mortality rates associated with the use of tunneled catheters as compared to AVF. Therefore, if TA is being considered for several years, AVG and AVF would be the preferred options of VA. Studies in HD population indicate far better outcomes with the use of AVF as compared to AVG. This article, as presented at the Therapeutic Apheresis Academy in September 2011, is an overview of the available VA options for TA based on indication and duration of treatment. Pros and cons of each option are mentioned briefly. Finally, for those considered for AVF placement for chronic TA, specific recommendations are made for the care of AVF based on our own experience at University of Virginia. PMID- 22535653 TI - Lineage extrinsic and intrinsic control of immunoregulatory cell numbers by SHIP. AB - We previously showed that germline or induced SHIP deficiency expands immuno regulatory cell numbers in T lymphoid and myeloid lineages. We postulated these increases could be interrelated. Here, we show that myeloid-specific ablation of SHIP leads to the expansion of both myeloid-derived suppressor cell (MDSC) and regulatory T (Treg) cell numbers, indicating SHIP-dependent control of Treg-cell numbers by a myeloid cell type. Conversely, T-lineage specific ablation of SHIP leads to expansion of Treg-cell numbers, but not expansion of the MDSC compartment, indicating SHIP also has a lineage intrinsic role in limiting Treg cell numbers. However, the SHIP-deficient myeloid cell that promotes MDSC and Treg-cell expansion is not an MDSC as they lack SHIP protein expression. Thus, regulation of MDSC numbers in vivo must be controlled in a cell-extrinsic fashion by another myeloid cell type. We had previously shown that G-CSF levels are profoundly increased in SHIP(-/-) mice, suggesting this myelopoietic growth factor could promote MDSC expansion in a cell-extrinsic fashion. Consistent with this hypothesis, we find that G-CSF is required for expansion of the MDSC splenic compartment in mice rendered SHIP-deficient as adults. Thus, SHIP controls MDSC numbers, in part, by limiting production of the myelopoietic growth factor G-CSF. PMID- 22535655 TI - Imidazolidinone-derived enamines: nucleophiles with low reactivity. PMID- 22535656 TI - Dynamics of decision-related activity in hippocampus. AB - Place-selective activity in hippocampal neurons can be modulated by the trajectory that will be taken in the immediate future ("prospective coding"), information that could be useful in neural processes elaborating choices in route planning. To determine if and how hippocampal prospective neurons participate in decision making, we measured the time course of the evolution of prospective activity by recording place responses in rats performing a T-maze alternation task. After five or seven alternation trials, the routine was unpredictably interrupted by a photodetector-triggered visual cue as the rat crossed the middle of central arm, signaling it to suddenly change its intended choice. Comparison of the delays between light cue presentation and the onset of prospective activity for neurons with firing fields at various locations after the trigger point revealed a 420 ms processing delay. This surprisingly long delay indicates that prospective activity in the hippocampus appears much too late to generate planning or decision signals. This provides yet another example of a prominent brain activity that is unlikely to play a functional role in the cognitive function that it appears to represent (planning future trajectories). Nonetheless, the hippocampus may provide other contextual information to areas active at the earliest stages of selecting future paths, which would then return signals that help establish hippocampal prospective activity. PMID- 22535657 TI - Diagnostic accuracy of pocket-size handheld echocardiographs used by cardiologists in the acute care setting. AB - AIMS: Pocket-size echographs may be useful for bedside diagnosis in acute cardiac care, but their diagnostic accuracy in this setting has not been well tested. Our aim was to evaluate this tool in patients requiring an urgent echocardiogram. METHODS: Trained cardiologists performed echocardiograms with a pocket-size echograph (Vscan) in consecutive patients requiring urgent echocardiography. The exams were then compared in a blinded manner with echocardiograms performed with a high-end standard echocardiograph. RESULTS: A total of 104 patients were studied. There was an excellent agreement between the Vscan and the high-end echocardiograph for the left ventricular systolic function and pericardial effusion (Kappa: 0.89 and 0.81, respectively), and the agreement was good or moderate for evaluating the aortic, mitral, and tricuspid valve function and the left ventricular size (Kappa: 0.55-0.66). Visualization of the Vscan images in full-screen format on a PC did not in general confer added value. CONCLUSION: The Vscan used by a trained cardiologist has good diagnostic accuracy in the emergency setting compared with a high-end echocardiograph, despite small screen size and lack of pulse-wave and continuous Doppler. PMID- 22535659 TI - The superiority of haploidentical related stem cell transplantation over chemotherapy alone as postremission treatment for patients with intermediate- or high-risk acute myeloid leukemia in first complete remission. AB - We report the results of a prospective, patient self-selected study evaluating whether haploidentical related donor stem cell transplantation (HRD-HSCT) is superior to chemotherapy alone as postremission treatment for patients with intermediate- or high-risk acute myeloid leukemia (AML) in first complete remission (CR1). Among totally 419 newly diagnosed AML patients, 132 patients with intermediate- and high-risk cytogenetics achieved CR1 and received chemotherapy alone (n = 74) or HSCT (n = 58) as postremission treatment. The cumulative incidence of relapse at 4 years was 37.5% +/- 4.5%. Overall survival (OS) and disease-free survival (DFS) at 4 years were 64.5% +/- 5.1% and 55.6% +/- 5.0%, respectively. The cumulative incident of relapse for the HRD-HSCT group was significantly lower than that for the chemotherapy-alone group (12.0% +/- 4.6% vs 57.8% +/- 6.2%, respectively; P < .0001). HRD-HSCT resulted in superior survival compared with chemotherapy alone (4-year DFS, 73.1% +/- 7.1% vs 44.2% +/- 6.2%, respectively; P < .0001; 4-year OS, 77.5% +/- 7.1% vs 54.7% +/- 6.3%, respectively; P = .001). Multivariate analysis revealed postremission treatment (HRD-HSCT vs chemotherapy) and high WBC counts at diagnosis as independent risk factors affecting relapse, DFS, and OS. Our results suggest that HRD-HSCT is superior to chemotherapy alone as postremission treatment for AML. PMID- 22535658 TI - Myeloma as a model for the process of metastasis: implications for therapy. AB - Multiple myeloma (MM) is a plasma cell dyscrasia characterized by the presence of multiple myelomatous "omas" throughout the skeleton, indicating that there is continuous trafficking of tumor cells to multiple areas in the bone marrow niches. MM may therefore represent one of the best models to study cell trafficking or cell metastasis. The process of cell metastasis is described as a multistep process, the invasion-metastasis cascade. This involves cell invasion, intravasation into nearby blood vessels, passage into the circulation, followed by homing into predetermined distant tissues, the formation of new foci of micrometastases, and finally the growth of micrometastasis into macroscopic tumors. This review discusses the significant advances that have been discovered in the complex process of invasion-metastasis in epithelial carcinomas and cell trafficking in hematopoietic stem cells and how this process relates to progression in MM. This progression is mediated by clonal intrinsic factors that mediate tumor invasiveness as well as factors present in the tumor microenvironment that are permissive to oncogenic proliferation. Therapeutic agents that target the different steps of cell dissemination and progression are discussed. Despite the significant advances in the treatment of MM, better therapeutic agents that target this metastatic cascade are urgently needed. PMID- 22535660 TI - Exposure of R169 controls protein C activation and autoactivation. AB - Protein C is activated by thrombin with a value of k(cat)/K(m) = 0.11mM(-1)s(-1) that increases 1700-fold in the presence of the cofactor thrombomodulin. The molecular origin of this effect triggering an important feedback loop in the coagulation cascade remains elusive. Acidic residues in the activation domain of protein C are thought to electrostatically clash with the active site of thrombin. However, functional and structural data reported here support an alternative scenario. The thrombin precursor prethrombin-2 has R15 at the site of activation in ionic interaction with E14e, D14l, and E18, instead of being exposed to solvent for proteolytic attack. Residues E160, D167, and D172 around the site of activation at R169 of protein C occupy the same positions as E14e, D14l, and E18 in prethrombin-2. Caging of R169 by E160, D167, and D172 is responsible for much of the poor activity of thrombin toward protein C. The E160A/D167A/D172A mutant is activated by thrombin 63-fold faster than wild-type in the absence of thrombomodulin and, over a slower time scale, spontaneously converts to activated protein C. These findings establish a new paradigm for cofactor-assisted reactions in the coagulation cascade. PMID- 22535662 TI - Graft-versus-host disease disrupts intestinal microbial ecology by inhibiting Paneth cell production of alpha-defensins. AB - Allogeneic hematopoietic stem cell transplantation (SCT) is a curative therapy for various hematologic disorders. Graft-versus-host disease (GVHD) and infections are the major complications of SCT, and their close relationship has been suggested. In this study, we evaluated a link between 2 complications in mouse models. The intestinal microbial communities are actively regulated by Paneth cells through their secretion of antimicrobial peptides, alpha-defensins. We discovered that Paneth cells are targeted by GVHD, resulting in marked reduction in the expression of alpha-defensins, which selectively kill noncommensals, while preserving commensals. Molecular profiling of intestinal microbial communities showed loss of physiologic diversity among the microflora and the overwhelming expansion of otherwise rare bacteria Escherichia coli, which caused septicemia. These changes occurred only in mice with GVHD, independently on conditioning-induced intestinal injury, and there was a significant correlation between alteration in the intestinal microbiota and GVHD severity. Oral administration of polymyxin B inhibited outgrowth of E coli and ameliorated GVHD. These results reveal the novel mechanism responsible for shift in the gut flora from commensals toward the widespread prevalence of pathogens and the previously unrecognized association between GVHD and infection after allogeneic SCT. PMID- 22535661 TI - A foundation for universal T-cell based immunotherapy: T cells engineered to express a CD19-specific chimeric-antigen-receptor and eliminate expression of endogenous TCR. AB - Clinical-grade T cells are genetically modified ex vivo to express a chimeric antigen receptor (CAR) to redirect specificity to a tumor associated antigen (TAA) thereby conferring antitumor activity in vivo. T cells expressing a CD19 specific CAR recognize B-cell malignancies in multiple recipients independent of major histocompatibility complex (MHC) because the specificity domains are cloned from the variable chains of a CD19 monoclonal antibody. We now report a major step toward eliminating the need to generate patient-specific T cells by generating universal allogeneic TAA-specific T cells from one donor that might be administered to multiple recipients. This was achieved by genetically editing CD19-specific CAR(+) T cells to eliminate expression of the endogenous alphabeta T-cell receptor (TCR) to prevent a graft-versus-host response without compromising CAR-dependent effector functions. Genetically modified T cells were generated using the Sleeping Beauty system to stably introduce the CD19-specific CAR with subsequent permanent deletion of alpha or beta TCR chains with designer zinc finger nucleases. We show that these engineered T cells display the expected property of having redirected specificity for CD19 without responding to TCR stimulation. CAR(+)TCR(neg) T cells of this type may potentially have efficacy as an off-the-shelf therapy for investigational treatment of B-lineage malignancies. PMID- 22535663 TI - A critical role for endoglin in the emergence of blood during embryonic development. AB - Much remains unknown about the signals that induce early mesoderm to initiate hematopoietic differentiation. Here, we show that endoglin (Eng), a receptor for the TGFbeta superfamily, identifies all cells with hematopoietic fate in the early embryo. These arise in an Eng(+)Flk1(+) mesodermal precursor population at embryonic day 7.5 (E7.5), a cell fraction also endowed with endothelial potential. In Eng-knockout embryos, hematopoietic colony activity and numbers of CD71(+)Ter119(+) erythroid progenitors were severely reduced. This coincided with severely reduced expression of embryonic globin and key bone morphogenic protein (BMP) target genes, including the hematopoietic regulators Scl, Gata1, Gata2, and Msx-1. To interrogate molecular pathways active in the earliest hematopoietic progenitors, we applied transcriptional profiling to sorted cells from E7.5 embryos. Eng(+)Flk-1(+) progenitors coexpressed TGFbeta and BMP receptors and target genes. Furthermore, Eng(+)Flk-1(+) cells presented high levels of phospho SMAD1/5, indicating active TGFbeta and/or BMP signaling. Remarkably, under hematopoietic serum-free culture conditions, hematopoietic outgrowth of Eng expressing cells was dependent on the TGFbeta superfamily ligands BMP4, BMP2, or TGF-beta1. These data demonstrate that the E(+)F(+) fraction at E7.5 represents mesodermal cells competent to respond to TGFbeta1, BMP4, or BMP2, shaping their hematopoietic development, and that Eng acts as a critical regulator in this process by modulating TGF/BMP signaling. PMID- 22535664 TI - The differential production of cytokines by human Langerhans cells and dermal CD14(+) DCs controls CTL priming. AB - We recently reported that human epidermal Langerhans cells (LCs) are more efficient than dermal CD14(+) DCs at priming naive CD8(+) T cells into potent CTLs. We hypothesized that distinctive dendritic cell (DC) cytokine expression profiles (ie, IL-15 produced by LCs and IL-10 expressed by dermal CD14(+) DCs) might explain the observed functional difference. Blocking IL-15 during CD8(+) T cell priming reduced T-cell proliferation by ~ 50%. These IL-15-deprived CD8(+) T cells did not acquire the phenotype of effector memory cells. They secreted less IL-2 and IFN-gamma and expressed only low amounts of CD107a, granzymes and perforin, and reduced levels of the antiapoptotic protein Bcl-2. Confocal microscopy analysis showed that IL-15 is localized at the immunologic synapse of LCs and naive CD8(+) T cells. Conversely, blocking IL-10 during cocultures of dermal CD14(+) DCs and naive CD8(+) T cells enhanced the generation of effector CTLs, whereas addition of IL-10 to cultures of LCs and naive CD8(+) T cells inhibited their induction. TGF-beta1 that is transcribed by dermal CD14(+) DCs further enhanced the inhibitory effect of IL-10. Thus, the respective production of IL-15 and IL-10 explains the contrasting effects of LCs and dermal CD14(+) DCs on CD8(+) T-cell priming. PMID- 22535666 TI - Properties of mouse and human IgG receptors and their contribution to disease models. AB - Impressive advances in defining the properties of receptors for the Fc portion of immunoglobulins (FcR) have been made over the past several years. Ligand specificities were systematically analyzed for both human and mouse FcRs that revealed novel receptors for specific IgG subclasses. Expression patterns were redefined using novel specific anti-FcR mAbs that revealed major differences between human and mouse systems. The in vivo roles of IgG receptors have been addressed using specific FcR knockout mice or in mice expressing a single FcR, and have demonstrated a predominant contribution of mouse activating IgG receptors FcgammaRIII and FcgammaRIV to models of autoimmunity (eg, arthritis) and allergy (eg, anaphylaxis). Novel blocking mAbs specific for these activating IgG receptors have enabled, for the first time, the investigation of their roles in vivo in wild-type mice. In parallel, the in vivo properties of human FcRs have been reported using transgenic mice and models of inflammatory and allergic reactions, in particular those of human activating IgG receptor FcgammaRIIA (CD32A). Importantly, these studies led to the identification of specific cell populations responsible for the induction of various inflammatory diseases and have revealed, in particular, the unexpected contribution of neutrophils and monocytes to the induction of anaphylactic shock. PMID- 22535665 TI - CD1d expression on and regulation of murine hematopoietic stem and progenitor cells. AB - In the present study, surface CD1d, which is involved in immune cell interactions, was assessed for effects on hematopoiesis. Mouse BM hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) express CD1d. The numbers and cycling status of HPCs in the BM and spleen of different strains of cd1d(-/-) mice were enhanced significantly, suggesting that CD1d is a negative regulator of HPCs. In support of this, CD1d was required for the SCF and Flt3 ligand synergistic enhancement of CSF induction of HPC colony formation and for HPC response to myelosuppressive chemokines. Colony formation by immature subsets of HPCs was greatly enhanced when normal, but not cd1d(-/-), BM cells were pretreated with CD1d Abs in vitro. These effects required the full CD1d cytoplasmic tail. In contrast, long-term, but not short-term, repopulating HSC engraftment was impaired significantly, an effect that was minimally influenced by the presence of a truncated CD1d cytoplasmic tail. Pretreatment of normal BM cells with CD1d Abs greatly enhanced their engraftment of HSCs. The results of the present study implicate CD1d in a previously unrecognized regulatory role of normal and stressed hematopoiesis. PMID- 22535668 TI - Bile acids in nonalcoholic steatohepatitis: inserting nuclear receptors into the circle. PMID- 22535667 TI - Genome-wide identification of endothelial cell-enriched genes in the mouse embryo. AB - The early blood vessels of the embryo and yolk sac in mammals develop by aggregation of de novo-forming angioblasts into a primitive vascular plexus, which then undergoes a complex remodeling process. Angiogenesis is also important for disease progression in the adult. However, the precise molecular mechanism of vascular development remains unclear. It is therefore of great interest to determine which genes are specifically expressed in developing endothelial cells (ECs). Here, we used Flk1-deficient mouse embryos, which lack ECs, to perform a genome-wide survey for genes related to vascular development. We identified 184 genes that are highly enriched in developing ECs. The human orthologs of most of these genes were also expressed in HUVECs, and small interfering RNA knockdown experiments on 22 human orthologs showed that 6 of these genes play a role in tube formation by HUVECs. In addition, we created Arhgef15 knockout and RhoJ knockout mice by a gene-targeting method and found that Arhgef15 and RhoJ were important for neonatal retinal vascularization. Thus, the genes identified in our survey show high expression in ECs; further analysis of these genes should facilitate our understanding of the molecular mechanisms of vascular development in the mouse. PMID- 22535669 TI - Short-term exposure to 50 Hz ELF-EMF alters the cisplatin-induced oxidative response in AT478 murine squamous cell carcinoma cells. AB - The aim of this study was to assess the influence of cisplatin and an extremely low frequency electromagnetic field (ELF-EMF) on antioxidant enzyme activity and the lipid peroxidation ratio, as well as the level of DNA damage and reactive oxygen species (ROS) production in AT478 carcinoma cells. Cells were cultured for 24 and 72 h in culture medium with cisplatin. Additionally, the cells were irradiated with 50 Hz/1 mT ELF-EMF for 16 min using a solenoid as a source of the ELF-EMF. The amount of ROS, superoxide dismutase (SOD) isoenzyme activity, glutathione peroxidase (GSH-Px) activity, DNA damage, and malondialdehyde (MDA) levels were assessed. Cells that were exposed to cisplatin exhibited a significant increase in ROS and antioxidant enzyme activity. The addition of ELF EMF exposure to cisplatin treatment resulted in decreased ROS levels and antioxidant enzyme activity. A significant reduction in MDA concentrations was observed in all of the study groups, with the greatest decrease associated with treatment by both cisplatin and ELF-EMF. Cisplatin induced the most severe DNA damage; however, when cells were also irradiated with ELF-EMF, less DNA damage occurred. Exposure to ELF-EMF alone resulted in an increase in DNA damage compared to control cells. ELF-EMF lessened the effects of oxidative stress and DNA damage that were induced by cisplatin; however, ELF-EMF alone was a mild oxidative stressor and DNA damage inducer. We speculate that ELF-EMF exerts differential effects depending on the exogenous conditions. This information may be of value for appraising the pathophysiologic consequences of exposure to ELF EMF. PMID- 22535670 TI - Severity of chronic obstructive pulmonary disease and its relationship to lung cancer prognosis after surgical resection. AB - OBJECTIVE: The purpose was to determine the rates of postoperative pulmonary complications, and to clarify the impact of COPD on long-term survival in lung cancer patients after surgical resection. METHODS: A retrospective chart review was performed on 1,461 patients who had undergone pulmonary resection for lung cancer from 1990 to 2005. Classification of COPD severity was based on spirometric guidelines of the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Postoperative complication rates among the four COPD groups were compared and long-term overall and disease-specific survivals were analyzed. RESULTS: The frequencies of all pulmonary complications in three COPD groups were higher than in the non-COPD group (all p < 0.05). Overall and disease-specific survivals were significantly worse in relation to higher COPD grades (all p <= 0.05). Significant prognostic factors were age, body mass index, positive smoking history, tumor size, pneumonectomy, pathologic stage, and COPD grade (p < 0.05). CONCLUSION: Higher COPD grades had higher rates of postoperative pulmonary complications and poorer long-term survivals because of higher rates of cancer related deaths. PMID- 22535671 TI - Minimal invasive retrieval of dislodged Amplatzer occluder with subsequent impediments. AB - A 47-year-old female underwent interventional patent foramen ovale (PFO) closure with an Amplatzer septal occluder (AGA Medical Corporation, USA). After 48 hours of implantation, she experienced intermittent pulse synchronous retrosternal pain. Subsequently, device-associated compression of the aortic root was diagnosed. Occluder retrieval and surgical PFO-closure was accomplished successfully via minimal invasive, video-assisted anterolateral thoracotomy. PMID- 22535672 TI - Two cases of valve surgery through right anterior minithoracotomy in presence of severe postmastectomy irradiation sternal damage. AB - High dose postmastectomy radiation therapy for breast cancer can lead to severe postirradiation sternal damage. Under these circumstances, median sternotomy may be associated with a prohibitive risk of postoperative deep sternal wound infection and alternative approaches have to be evaluated. We report herein the use of a right anterior minithoracotomy through the third intercostal space for isolated aortic valve replacement in one and combined aortic and mitral valve replacement in combination with mitral ring decalcification and coronary artery bypass grafting to the proximal right coronary artery in another patient. PMID- 22535673 TI - Management of distal left main coronary artery aneurysm. AB - Aneurysms of the left main coronary artery are extremely rare. The cause of such aneurysms is uncertain. Although the treatment of distal left main aneurysms is very complicated, definitive treatment is necessary because the aneurysm may grow further and cause embolism or rupture. Herein, we report a case of acute myocardial infarction caused by aneurysm of the distal left main coronary artery, which was successfully treated by performing coronary artery bypass surgery, followed by implantation of a polytetrafluoroethylene-covered stent. PMID- 22535674 TI - Acute hemoptysis and pulmonary hemorrhage after judo as presentation of intralobar sequestration. AB - Intralobar sequestration (ILS) is a rare anomaly that is usually diagnosed with symptoms of cough, expectoration, or recurrent pneumonia in children. We experienced a case of an 11-year-old boy with massive hemoptysis after judo sports. He was admitted to hospital and intubated due to respiratory failure. His chest computed tomography (CT) scan which was performed without contrast agent revealed a large intrapulmonary hematoma or tumor, mimicking traumatic hemothorax. Due to blood loss and circulatory instability, emergency thoracotomy was performed and a massive intralobar hemorrhage due to a ruptured ILS artery was found. After lobectomy including resection of the ILS, the patient was stabilized and extubated. Aspergillus was detected in the resected lobe and postoperatively acute respiratory distress syndrome (ARDS) and invasive aspergillosis occurred and was treated specifically. However, the young patient was discharged home 3 weeks later. In young patients with hemoptysis and intrapulmonary hemorrhage after trauma, the possibility of ruptured ILS should be kept in mind. This report shows that ILS can have a dramatic course of disease, and for this reason a nonurgent resection should be considered in all patients when this diagnosis is made. PMID- 22535675 TI - Early and midterm results of single-port video-assisted thoracoscopic sympathectomy. AB - BACKGROUND: Video-assisted thoracoscopic sympathectomy (VATS) is the gold standard for patients with hyperhidrosis of the upper limbs. The primary aim of this retrospective study was to evaluate the midterm outcome and the degree of satisfaction of patients who underwent single-port VATS. METHODS: Forty three patients diagnosed with hyperhidrosis underwent T3, T4 VATS single-port approach, between January 2009 and May 2011. Early and midterm outcome with particular emphasis on patient satisfaction were collected by hospital chart and telephonic interview. RESULTS: The mean follow-up was 14 months. No major perioperative complication occurred except for chylothorax in a case. During the immediate postoperative period, all the patients reported palmar anhydrosis. Compensatory sweating (6.9%) and recurrence of hyperhidrosis (6.9%) are responsible mainly for dissatisfaction. No patients experienced moderate or severe chronic pain. CONCLUSIONS: Single-port VATS is a feasible and minimally invasive technique with a low incidence of chronic pain for the treatment of hyperhidrosis. A few patients may experience compensatory sweating and recurrence of hyperhidrosis. The degree of patient satisfaction with the midterm surgical results is high. PMID- 22535676 TI - Wilhelm Ebstein and the history of surgery for Ebstein's Disease. AB - In the mirror of the life-story of Wilhelm Ebstein, the discovery of "Ebstein's Disease" is presented. The readers are guided through the individual stages of the development of surgical treatment of the condition. PMID- 22535678 TI - Impact of a transfusion-related acute lung injury reduction strategy on apheresis platelet collections. AB - BACKGROUND: Most blood centers in the US have implemented transfusion-related acute lung injury (TRALI) mitigation strategies for apheresis platelet (AP) donations based on theoretical impact of donor loss. The aim of this study is to determine the actual impact of a TRALI mitigation strategy in a US blood center. STUDY DESIGN AND METHODS: Daily collection events and resulting products were retrospectively obtained before and after implementation of a TRALI reduction strategy (HLA antibody testing female AP donors four or more pregnancies) for comparison. The retention rate of reassigned donors was determined by reviewing whole blood (WB) and/or apheresis red blood cell (AR) donations post reassignment. Data were obtained to compare donor frequency and split rate from reassigned (historical data) and new AP donors. RESULTS: Mean daily collections (27.7 vs. 30.0) and total products (12,211 vs. 12,957) were significantly higher after implementation, but the number of products/collection event was lower (1.49 vs. 1.40). Mean collections/donor/year (4.0 vs. 1.8) and split rate (36% vs. 27%) were historically higher for reassigned (n = 45) versus new AP donors (n = 1,090). Seventy-three of 112 donors (65%) testing positive for HLA antibodies returned for WB or AR donations, 31 of 45 (69%) active AP donors returned. CONCLUSIONS: Donor loss may not be adequate to estimate impact on AP inventory, as donation characteristics may differ between new donors and those reassigned. We show successful implementation of a TRALI mitigation strategy by increasing collection goals and AP donor recruitment efforts beyond donor loss. Retaining the majority of reassigned donors is feasible. PMID- 22535677 TI - Complement regulates conventional DC-mediated NK-cell activation by inducing TGF beta1 in Gr-1+ myeloid cells. AB - Complement activation modulates DC-mediated T-cell activation, but whether complement affects DC-mediated priming of NK cells is unknown. Here, we demonstrated that conventional DCs (cDCs) from C3(-/-) and C5aR(-/-) mice are hyperresponsive to polyI:C, a TLR3 ligand, leading to enhanced NK-cell activation. We found that cDCs lack C5a receptor (C5aR) and do not respond to C5a directly. Depletion of Gr-1(+) myeloid cells augments polyI:C-induced cDC activation in WT but not in C3(-/-) or C5aR(-/-) mice, indicating that the effect of complement activation on cDCs is indirectly mediated through C5aR expressing Gr-1(+) myeloid cells. We further demonstrated that the mechanism by which Gr-1(+) myeloid cells regulate the activity of cDCs involves C5a-dependent TGF-beta1 production in Gr-1(+) myeloid cells. C5a enhances and blocking C5aR decreases TGF-beta1 production in cultured bone marrow Gr-1(+) CD11b(+) cells. C5aR deficiency is associated with reduced circulating TGF-beta1 levels, while depleting Gr-1(+) myeloid cells abrogates this difference between WT and C5aR(-/ ) mice. Lastly, we showed that enhanced cDC-NK-cell activity in C3(-/-) mice led to delayed melanoma tumor growth. Thus, complement activation indirectly regulates cDC-NK-cell activation in response to inflammatory stimuli such as TLR3 by promoting TGF-beta1 production in Gr-1(+) myeloid cells at steady state. PMID- 22535679 TI - Role of human TLR4 in respiratory syncytial virus-induced NF-kappaB activation, viral entry and replication. AB - TLRs play a key role in innate immune defenses. It was previously reported that purified respiratory syncytial virus (RSV) fusion protein elicits an inflammatory response in hematopoietic cells, which required expression of TLR4 and its co receptor CD14. However, a biological role of TLR4 in immunity to RSV, as initially proposed, has remained inconclusive and controversial. Here, we directly assess the role of human TLR4 and its co-receptors in NF-kappaB activation, viral entry and replication using intact virions rather than purified RSV components. We used HEK 293 reporter cells that are highly permissive for RSV and that either express or a lack a functional human TLR4/MD-2/CD14 complex. We demonstrate that RSV-mediated NF-kappaB activation, viral entry and replication are independent of the expression of a functional human TLR4/MD-2/CD14 complex and that, in turn, human TLR4 activation by LPS remains unaffected in RSV infected cells. Thus, although isolated viral compounds such as purified RSV F protein may bind TLR4 and/or CD14, a direct interaction between intact RSV particles and the human TLR4 receptor complex does not seem to play a biological role in RSV pathogenesis. PMID- 22535681 TI - A phosphorus/aluminum-based frustrated Lewis pair as an ion pair receptor: alkali metal hydride adducts and phase-transfer catalysis. PMID- 22535680 TI - Lipopolysaccharide binding protein inhibitory peptide alters hepatic inflammatory response post-hemorrhagic shock. AB - Translocation of microorganisms and endotoxin (LPS) across the gastrointestinal mucosa may exacerbate the inflammatory response and potentiate hepatic injury associated with hemorrhagic shock. Lipopolysaccharide binding protein (LBP) augments LPS signaling through TLR4. In addition, evidence suggests that TLR4 mediated injury in liver ischemia/reperfusion occurs through the IRF-3/MyD88 independent pathway. We hypothesized that administration of LBP inhibiting peptide, LBPK95A, given at the time of resuscitation would reduce liver inflammation and injury in a murine model of hemorrhagic shock by limiting LPS induced activation of the MyD88 independent pathway. Hemorrhagic shock was induced in male, C57BL/6 mice; a mean arterial blood pressure of 35 mmHg was maintained for 2.5 h. LBPK95A peptide or equal volume Lactated Ringer's solution was administered followed by fluid resuscitation. Mice were sacrificed at 2 and 6 h post-resuscitation. At 2 h, liver mRNA levels revealed a significant reduction in IFN-beta, a cytokine produced via the MyD88 independent pathway, with LBPK95A treatment. However, mRNA levels of TNF-alpha, a cytokine associated with the MyD88 dependent pathway, were unaffected by treatment. The LBP inhibitory peptide did selectively reduce activation of TLR4 signaling via the IRF-3/MyD88 independent pathway. These results suggest that LBP promotes cytokine production through the MyD88 independent pathway during hemorrhagic shock. PMID- 22535682 TI - 4D blood flow visualization fusing 3D and 4D MRA image sequences. AB - PURPOSE: To present and evaluate the feasibility of a novel automatic method for generating 4D blood flow visualizations fusing high spatial resolution 3D and time-resolved (4D) magnetic resonance angiography (MRA) datasets. MATERIALS AND METHODS: In a first step, the cerebrovascular system is segmented in the 3D MRA dataset and a surface model is computed. The hemodynamic information is extracted from the 4D MRA dataset and transferred to the surface model using rigid registration where it can be visualized color-coded or dynamically over time. The presented method was evaluated using software phantoms and 20 clinical datasets from patients with an arteriovenous malformation. Clinical evaluation was performed by comparison of Spetzler-Martin scores determined from the 4D blood flow visualizations and corresponding digital subtraction angiographies. RESULTS: The performed software phantom validation showed that the presented method is capable of producing reliable visualization results for vessels with a minimum diameter of 2 mm for which a mean temporal error of 0.27 seconds was achieved. The clinical evaluation based on 20 datasets comparing the 4D visualization to DSA images revealed an excellent interrater reliability. CONCLUSION: The presented method enables an improved combined representation of blood flow and anatomy while reducing the time needed for clinical rating. PMID- 22535683 TI - Elevated coffee consumption and reduced risk of insulin resistance in HIV-HCV coinfected patients (HEPAVIH ANRS CO-13). PMID- 22535684 TI - Extended acute toxicity study of (188) Re-liposome in rats. AB - Liposomes can selectively target cancer sites and carry payloads, thereby improving diagnostic and therapeutic effectiveness as well as reducing toxicity. To evaluate therapeutic strategies, it is essential to use animal models reflecting important safety aspects before clinical application. As our previous study found that a high dosage (185 of MBq) of (188) Re-N,N-bis (2-mercaptoethyl) N',N'-diethylethylenediamine-labeled pegylated liposomes ((188) Re-liposome) induced a decrease in white blood cell (WBC) count in Sprague-Dawley rats 7 days postinjection, the objective of the present study was to investigate extended acute radiotoxicity of (188) Re-liposome. Rats were administered via intravenous (i.v.) injection with (188) Re-liposome (185, 55.5 and 18.5 MBq), normal saline as a blank control or non-radioactive liposome as a vehicle control. Mortality, clinical signs, food consumption, body weights, urinary, biochemical and hematological analyzes were examined. In addition, gross necropsy and histopathological examinations were also performed at the end of the follow-up period. None of the rats died and no clinical sign was observed during the 28-day study period. Only male rats receiving (188) Re-liposome at a high dosage (185 MBq) displayed a slight weight loss compared with the control rats. In both male and female rats, the WBC counts of both high-dose and medium-dose (55.5 MBq) groups reduced significantly 7 days postinjection, but recovered to the normal range on Study Day 29. There was no significant difference in urinary analyzes, biochemical parameters and histopathological assessments between the (188) Re liposome-treated and control groups. The information generated from the present study on extended acute toxicity of (188) Re-liposome will serve as a safety reference for radiopharmaceuticals in early-phase clinical trials. PMID- 22535685 TI - Increment of hematopoietic progenitor cell count as an indicator of efficient autologs stem cell harvest in patients with multiple myeloma. AB - We previously showed that hematopoietic progenitor cell (HPC) count is a useful surrogate for the timing of autologs stem cell collection (ASCC). We investigated the role of HPC count increment in predicting the time for optimal ASCC in patients with multiple myeloma (MM). Between May 2002 and January 2011, 138 patients with MM who underwent ASCC after mobilization with cyclophosphamide (4 g/m(2)) and granulocyte-colony stimulating factor at Asan Medical Center. HPC monitoring was started on the 10th day of cyclophosphamide administration and ASCC was performed when HPC count reached at least 10/mm(3). Velocity of HPC increment (/mm(3) /day) was calculated as HPC count on the first day of ASCC/number of days from cyclophosphamide infusion to the first day of ASCC. A total of 422 leukapheresis were performed in 136 patients (median per patient: 3; range: 2-8). Of these patients, 131 (94.9%) successfully achieved optimal ASCC (>=5 * 106 CD34+ cells/kg). The median velocity of HPC increment was 2.17/mm(3) /day (range: 0.07-144.2/mm(3) /day). The mean +/- standard error numbers of apheresis procedures in patients with velocity of HPC increment <=2.0/mm(3) /day and >2.0/mm(3) /day were 3.43 +/- 0.17 and 2.70 +/- 0.11, respectively, and their median times to optimal ASCC were 15 and 13 days, respectively, with a hazard ratio of 0.47 (95% confidence interval, 0.32-0.68; P < 0.001) on multivariate analysis. Therefore, a slower increase of HPC of <=2.0/mm(3) /day is associated with larger number of apheresis procedures for optimal ASCC. PMID- 22535686 TI - Alberto Sols, teacher and mentor of spanish biochemists (1917-1989). AB - Biochemistry in Spain owes much to the figure of Alberto Sols. In words of Nobel Prize winner Severo Ochoa: "He has been the first scientist to establish successfully biochemistry in Spain." His intellectual rigour, care in experimental design, emphasis on quality, and attention to the presentation of results permeated far beyond his inner circle to the then fledging Spanish biochemical community. It would be difficult to find some Spanish biochemist of the generation that now starts to retire who has not been influenced in a way or another by the work of Sols. However, it is also likely that the new generations of biochemists and molecular biologists in the country ignore who was Sols and what their field owns to him. The following lines try to highlight some key points of his scientific biography, the circumstances in which they took place and the state of the corresponding research area at that moment. PMID- 22535687 TI - Radiological diagnosis of vesicouterine fistula: role of magnetic resonance imaging. AB - PURPOSE: To retrospectively assess the value of magnetic resonance imaging (MRI) in the diagnosis of vesicouterine fistula (VUF). MATERIALS AND METHODS: Between January 2003 and January 2011, 12 patients with a diagnosis of VUF were surgically managed at our center; among them, eight patients had MRI among their preoperative radiological investigations and those were included in our study. The clinical presentation, radiological investigations, and surgical findings of the patients were reviewed. RESULTS: The mean age of the patients was 31 years. Seven of the eight patients had complaints of cyclic hematuria and the remaining patient complained of urinary leakage through the vagina. The etiology of VUF was cesarean section in all patients. The preoperative radiological investigations included conventional cystography in five patients, intravenous urography in two, computed tomography (CT) urography in two, and MRI in eight. The sensitivities of diagnosis for these investigations were 40%, 0%, 50%, and 100%, respectively. CONCLUSION: In our small retrospective series, pelvic MRI was reliable and sensitive for diagnosis of VUF. It should be considered in the work-up of patients with suspected VUF. PMID- 22535688 TI - Potential repurposing of known drugs as potent bacterial beta-glucuronidase inhibitors. AB - The active metabolite of the chemotherapeutic irinotecan, SN-38, is detoxified through glucuronidation and then excreted into the gastrointestinal tract. Intestinal bacteria convert the glucuronidated metabolite back to the toxic SN-38 using beta-glucuronidase (GUS), resulting in debilitating diarrhea. Inhibiting GUS activity may relieve this side effect of irinotecan. In this study, we sought to determine whether any known drugs have GUS inhibitory activity. We screened a library of Food and Drug Administration-approved drugs with a cell-free biochemical enzyme assay using purified bacterial GUS. After triage, five drugs were confirmed to inhibit purified bacterial GUS. Three of these were the monoamine oxidase inhibitors nialamide, isocarboxazid, and phenelzine with average IC(50) values for inhibiting GUS of 71, 128, and 2300 nM, respectively. The tricyclic antidepressant amoxapine (IC(50) = 388 nM) and the antimalarial mefloquine (IC(50) = 1.2 uM) also had activity. Nialamide, isocarboxazid, and amoxapine had no significant activity against purified mammalian GUS but showed potent activity for inhibiting endogenous GUS activity in a cell-based assay using living intact Escherichia coli with average IC(50) values of 17, 336, and 119 nM, respectively. Thus, nialamide, isocarboxazid, and amoxapine have potential to be repurposed as therapeutics to reduce diarrhea associated with irinotecan chemotherapy and warrant further investigation for this use. PMID- 22535690 TI - Chemoprotective effects of carnosine against genotoxicity induced by cyclophosphamide in mice bone marrow cells. AB - The protective effects of carnosine as a natural dipeptide were investigated in mouse bone marrow cells against genotoxicity induced by cyclophosphamide. Mice were injected with solutions of carnosine at three different doses (10, 50 and 100 mg kg(-1) bw) for five consecutive days. On the fifth day of treatment, mice were injected cyclophosphamide and killed after 24 h. The frequency of micronuclei in polychromatic erythrocytes and the ratio of polychromatic erythrocyte/polychromatic erythrocyte + normochromatic erythrocyte [PCE/(PCE + NCE)] were evaluated by May-Grunwald/Giemsa staining. Histopathology of bone marrow was examined in mice treated with cyclophosphamide and carnosine. Carnosine significantly reduced micronucleated polychromatic erythrocytes (MnPCEs) induced by cyclophosphamide at all three doses. Carnosine at dose of 100 mg kg(-1) bw reduced MnPCEs 3.76-fold and completely normalized the PCE/(PCE + NCE) ratio. Administration of carnosine inhibited bone marrow toxicity induced by cyclophosphamide. It appeared that carnosine with protective activity reduced the oxidative stress and genotoxicity induced by cyclophosphamide in bone marrow cells of mice. PMID- 22535691 TI - The importance of thorough oral examination and the value of soft tissue radiography in the management of embedded tooth fragments. PMID- 22535689 TI - Alpha-fetoprotein has no prognostic role in small hepatocellular carcinoma identified during surveillance in compensated cirrhosis. AB - Alpha-fetoprotein is a tumor marker that has been used for surveillance and diagnosis of hepatocellular carcinoma (HCC) in patients with cirrhosis. The prognostic capability of this marker in patients with HCC has not been clearly defined. In this study our aim was to evaluate the prognostic usefulness of serum alpha-fetoprotein in patients with well-compensated cirrhosis, optimal performance status, and small HCC identified during periodic surveillance ultrasound who were treated with curative intent. Among the 3,027 patients included in the Italian Liver Cancer study group database, we selected 205 Child Pugh class A and Eastern Cooperative Group Performance Status 0 patients with cirrhosis with a single HCC <= 3 cm of diameter diagnosed during surveillance who were treated with curative intent (hepatic resection, liver transplantation, percutaneous ethanol injection, radiofrequency thermal ablation). Patients were subdivided according to alpha-fetoprotein serum levels (i.e., normal <= 20 ng/mL; mildly elevated 21-200 ng/mL; markedly elevated >200 ng/mL). Patient survival, as assessed by the Kaplan-Meier method, was not significantly different among the three alpha-fetoprotein classes (P = 0.493). The same result was obtained in the subgroup of patients with a single HCC <= 2 cm (P = 0.714). An alpha-fetoprotein serum level of 100 ng/mL identified by receiver operating characteristic curve had inadequate accuracy (area under the curve = 0.536, 95% confidence interval = 0.465-0.606) to discriminate between survivors and deceased patients. CONCLUSION: Alpha-fetoprotein serum levels have no prognostic meaning in well-compensated cirrhosis patients with single, small HCC treated with curative intent. PMID- 22535692 TI - Oral and maxillofacial surgery: the importance of undergraduate training for junior doctors in accident and emergency. PMID- 22535693 TI - Assessment of a reporting radiographer-led discharge system for minor injuries: a prospective audit over 2 years. AB - BACKGROUND AND PURPOSE: In the UK, there is a continuing effort within the National Health Service to reduce patient waiting times in emergency departments (EDs). This audit aimed to evaluate whether a reporting radiographer-led discharge system could reduce waiting times from x-ray to discharge with no detrimental effect on patient outcomes. METHODS: A prospective audit over 2 years was conducted. Patients were considered for discharge by a reporting radiographer led service if they were >5 years old, attended the hospital ED between 9:00 and 17:00, Monday to Friday, had an injury below the elbow in the upper limb or below the knee in the lower limb that required an x-ray, and were able to be discharged home without further medical intervention. Outcomes of interest were overall waiting times, accuracy of diagnosis and re-attendance at the ED within 28 days. RESULTS: Between July 2006 and June 2008, 497 patients met the inclusion criteria and were discharged home by the radiographer-led service, and 2632 were discharged home using standard practices. Overall waiting times were >20 min quicker for the radiographer-led service at 100.9 min. The false negative rate was reduced from 2.09% to 0.2%, and re-attendance at the ED within 28 days for the same injury was reduced from 3.27% to only 0.4% for radiographer-led discharge. CONCLUSIONS: The service reduced waiting times and re-attendance rates while improving the accuracy of diagnosis. The efficacy of such services should be further studied in relation to more complex patient groups. PMID- 22535694 TI - Female nile hippopotamus (Hippopotamus amphibius) space use in a naturalistic exhibit. AB - Zoological institutions provide naturalistic exhibits for their animals in order to offer a more appealing look for visitors and give the animal the opportunity to engage in more natural behaviors. Examining space use of the animals in the naturalistic exhibit may aid in the management of these animals and inform future naturalistic exhibit design. The hippopotamus is an amphibious ungulate that spends much of its days in the wild in the water but may be found along the banks of the rivers basking in the sun. Our objective was to determine how captive female hippos utilize their exhibit by examining whether hippos selected for certain areas of a naturalistic exhibit. Scan sample data were collected on a group of nine captive female hippos housed at Disney's Animal Kingdom(r). Using ArcView, the data were analyzed to determine distribution of hippos in the exhibit and their utilization of depth categories while in the water. Hippos were found to aggregate in preferred areas of the exhibit, mostly water, and selected most for water depths of 0.6-1.0 m. These results will aid in the understanding of hippopotamus space use and may aid zoological institutions in the design of naturalistic exhibits for hippos. PMID- 22535695 TI - Exposure to humans and activity pattern of European souslik (Spermophilus citellus) in zoo conditions. AB - European souslik (Spermophilus citellus) is an endangered species being the subject of reintroduction plan in some European countries, including Poland. It is important to obtain data about behavior of reintroduced species, especially a reaction to captivity of specimens prepared to release. The aim of this study was to evaluate influence of human exposure on sousliks behavior. Observed animals were kept in Poznan zoo in three enclosures. Two of them (called "high noise") were in part of the zoo available to the visitors, whereas one ("low noise") was in part closed for them. In "high noise" enclosures sousliks spent more time outside burrows and more specimens were present above ground. They also ate and ran more frequently in "high noise" enclosure, whereas emitted loud voices more often in the "low noise" one. In all enclosures more animals were present above grounds in absence of humans. Time spent by one souslik above ground was positively significantly correlated with the number of sousliks outside burrows. European sousliks observed in this study were used to humans and were less vigilant if they were exposed to permanent humans presence, but they did not become tamed and behave in a way similar to free living animals. PMID- 22535696 TI - Suitability of European climate for the Asian tiger mosquito Aedes albopictus: recent trends and future scenarios. AB - The Asian tiger mosquito (Aedes albopictus) is an invasive species that has the potential to transmit infectious diseases such as dengue and chikungunya fever. Using high-resolution observations and regional climate model scenarios for the future, we investigated the suitability of Europe for A. albopictus using both recent climate and future climate conditions. The results show that southern France, northern Italy, the northern coast of Spain, the eastern coast of the Adriatic Sea and western Turkey were climatically suitable areas for the establishment of the mosquito during the 1960-1980s. Over the last two decades, climate conditions have become more suitable for the mosquito over central northwestern Europe (Benelux, western Germany) and the Balkans, while they have become less suitable over southern Spain. Similar trends are likely in the future, with an increased risk simulated over northern Europe and slightly decreased risk over southern Europe. These distribution shifts are related to wetter and warmer conditions favouring the overwintering of A. albopictus in the north, and drier and warmer summers that might limit its southward expansion. PMID- 22535697 TI - Release profile and characteristics of electrosprayed particles for oral delivery of a practically insoluble drug. AB - Poly(lactic-co-glycolic acid) (PLGA) microspheres containing celecoxib were prepared via electrospraying, and the influence of three processing parameters namely flow rate, solute concentration and drug loading, on the physico-chemical properties of the particles and the drug-release profile was studied. Microspheres with diameters between 2 and 8 MUm were produced and a near monodisperse size distribution was achieved (polydispersivity indices of 6-12%). Further, the inner structure of the particles showed that the internal porosity of the particles increased with increasing solvent concentration. X-ray powder diffraction (XRPD) analysis indicated that the drug was amorphous and remained stable after eight months of storage. Drug release was studied in USP 2 (United States Pharmacopeia Dissolution Apparatus 2) dissolution chambers, and differences in release profiles were observed depending on the parametric values. Changes in release rate were found to be directly related to the influence of the studied parameters on particle size and porosity. The results indicate that electrospraying is an attractive technique for producing drug-loaded microspheres that can be tailored towards an intended drug-delivery application. Compared with the more conventional spray-drying process, it provides better control of particle characteristics and less aggregation during particle formation. In particular, this study demonstrated its suitability for preparing capsules in which the drug is molecularly dispersed and released in a sustained manner to facilitate improved bioavailability. PMID- 22535698 TI - Optimal homeostasis necessitates bistable control. AB - Bistability is a fundamental phenomenon in nature. In biology, a number of fine properties of bistability have been identified. However, these properties are only consequences of bistability at the physiological level, which do not explain why it had to emerge during evolution. Using optimal homeostasis as the first principle, I find that bistability emerges as an indispensable control mechanism. It is the only solution to a dilemma in glucose homeostasis: high insulin efficiency is required to confer rapidness in plasma glucose clearance, whereas an insulin sparing state is required to guarantee the brain's safety during fasting. The optimality consideration renders a clear correspondence between the molecular and physiological levels. This new perspective can illuminate studies on the twin epidemics of obesity and diabetes and the corresponding intervening strategies. For example, overnutrition and sedentary lifestyle may represent sudden environmental changes that cause the lose of optimality, which may contribute to the marked rise of obesity and diabetes in our generation. Because this bistability result is independent of the parameters of the mathematical model (for which the result is quite general), some other biological systems may also use bistability to control homeostasis. PMID- 22535699 TI - Common structure in the heterogeneity of plant-matter decay. AB - Carbon removed from the atmosphere by photosynthesis is released back by respiration. Although some organic carbon is degraded quickly, older carbon persists; consequently carbon stocks are much larger than predicted by initial decomposition rates. This disparity can be traced to a wide range of first-order decay-rate constants, but the rate distributions and the mechanisms that determine them are unknown. Here, we pose and solve an inverse problem to find the rate distributions corresponding to the decomposition of plant matter throughout North America. We find that rate distributions are lognormal, with a mean and variance that depend on climatic conditions and substrate. Changes in temperature and precipitation scale all rates similarly, whereas the initial substrate composition sets the time scale of faster rates. These findings probably result from the interplay of stochastic processes and biochemical kinetics, suggesting that the intrinsic variability of decomposers, substrate and environment results in a predictable distribution of rates. Within this framework, turnover times increase exponentially with the kinetic heterogeneity of rates, thereby providing a theoretical expression for the persistence of recalcitrant organic carbon in the natural environment. PMID- 22535700 TI - A model balancing cooperation and competition can explain our right-handed world and the dominance of left-handed athletes. AB - An overwhelming majority of humans are right-handed. Numerous explanations for individual handedness have been proposed, but this population-level handedness remains puzzling. Here, we present a novel mathematical model and use it to test the idea that population-level hand preference represents a balance between selective costs and benefits arising from cooperation and competition in human evolutionary history. We use the selection of elite athletes as a test-bed for our evolutionary model and find evidence for the validity of this idea. Our model gives the first quantitative explanation for the distribution of handedness both across and within many professional sports. It also predicts strong lateralization of hand use in social species with limited combative interaction, and elucidates the absence of consistent population-level 'pawedness' in some animal species. PMID- 22535701 TI - Analyzing the catalytic processes of immobilized redox enzymes by vibrational spectroscopies. AB - Analyzing the structure and function of redox enzymes attached to electrodes is a central challenge in many fields of fundamental and applied life science. Electrochemical techniques such as cyclic voltammetry which are routinely used do not provide insight into the molecular structure and reaction mechanisms of the immobilized proteins. Surface-enhanced infrared absorption (SEIRA) and surface enhanced resonance Raman (SERR) spectroscopy may fill this gap, if nanostructured Au or Ag are used as conductive support materials. In this account, we will first outline the principles of the methodology including a description of the most important strategies for biocompatible protein immobilization. Subsequently, we will critically review SERR and SEIRA spectroscopic approaches to characterize the protein and active site structure of the immobilized enzymes. Special emphasis is laid on the combination of surface-enhanced vibrational spectroscopies with electrochemical methods to analyze equilibria and dynamics of the interfacial redox processes. Finally, we will assess the potential of SERR and SEIRA spectroscopy for in situ investigations on the basis of the first promising studies on human sulfite oxidase and hydrogenases under turnover conditions. PMID- 22535702 TI - Test-retest stability analysis of resting brain activity revealed by blood oxygen level-dependent functional MRI. AB - PURPOSE: To assess test-retest stability of four functional magnetic resonance imaging (fMRI)-derived resting brain activity metrics: the seed-region-based functional connectivity (SRFC), independent component analysis (ICA)-derived network-based FC (NTFC), regional homogeneity (ReHo), and the amplitude of low frequency fluctuation (ALFF). METHODS: Simulations were used to assess the sensitivity of SRFC, ReHo, and ALFF to noise interference. Repeat resting blood oxygen level-dependent (BOLD) fMRI were acquired from 32 healthy subjects. The intraclass correlation coefficient (ICC) was used to assess the stability of the four metrics. RESULTS: Random noise yielded small random SRFC, small but consistent ReHo and ALFF. A neighborhood size greater than 20 voxels should be used for calculating ReHo in order to reduce the noise interference. Both the anterior cingulate cortex (ACC) and posterior cingulate cortex (PCC)-based SRFC were reproducible in more spatially extended regions than ICA NTFC. The two regional spontaneous brain activity (SBA) measures, ReHo and ALFF, showed test retest reproducibility in almost the whole gray matter. CONCLUSION: SRFC, ReHo, and ALFF are robust to random noise interference. The neighborhood size for calculating ReHo should be larger than 20 voxels. ICC > 0.5 and cluster size > 11 should be used to assess the ICC maps for ACC/PCC SRFC, ReHo, and ALFF. BOLD fMRI based SBA can be reliably measured using ACC/PCC SRFC, ReHo, and ALFF after 2 months. PMID- 22535704 TI - HSCs play a distinct role in different phases of oval cell-mediated liver regeneration. AB - Hepatic stem cell niche plays an important role in hepatic oval cell-mediated liver regeneration. As a component of hepatic stem cell niche, the role of hepatic stellate cells (HSCs) in oval cell proliferation needs further studies. In the present study, we isolated HSCs from rats at indicated time point after partial hepatectomy (PH) in 2-acetylaminofluorene/PH oval cell proliferation model. Conditional medium (CM) from HSCs were collected to detect their effects on proliferation and the mitogen-activated protein kinase pathway activation of two oval cell lines. We found that CM collected from HSCs at early phase of liver regeneration (4 and 9 days group) contained high levels of hepatocyte growth factor (HGF) and stimulated oval cell proliferation via extracellular signal regulated kinase and p38 pathway. CM collected from HSCs at terminal phase of liver regeneration (12 and 15 days group) contained high levels of transforming growth factor (TGF)-beta1, which suppressed DNA synthesis of oval cells. The shift between these two distinct effects depended on the balance between HGF and TGF-beta1 secreted by HSCs. Our study demonstrated that HSCs acted as a positive regulator at the early phase and a negative regulator at the terminal phase of the oval cell-mediated liver regeneration. PMID- 22535703 TI - LecT-Hepa, a glyco-marker derived from multiple lectins, as a predictor of liver fibrosis in chronic hepatitis C patients. AB - Assessment of liver fibrosis in patients with chronic hepatitis C (CHC) is critical for predicting disease progression and determining future antiviral therapy. LecT-Hepa, a new glyco-marker derived from fibrosis-related glyco alteration of serum alpha 1-acid glycoprotein, was used to differentiate cirrhosis from chronic hepatitis in a single-center study. Herein, we aimed to validate this new glyco-marker for estimating liver fibrosis in a multicenter study. Overall, 183 CHC patients were recruited from 5 liver centers. The parameters Aspergillus oryzae lectin (AOL) / Dature stramonium lectin (DSA) and Maackia amurensis lectin (MAL)/DSA were measured using a bedside clinical chemistry analyzer in order to calculate LecT-Hepa levels. The data were compared with those of seven other noninvasive biochemical markers and tests (hyaluronic acid, tissue inhibitor of metalloproteases-1, platelet count, aspartate aminotransferase-to-platelet ratio index [APRI], Forns index, Fib-4 index, and Zeng's score) for assessing liver fibrosis using the receiver-operating characteristic curve. LecT-Hepa correlated well with the fibrosis stage as determined by liver biopsy. The area under the curve (AUC), sensitivity, and specificity of LecT-Hepa were 0.802, 59.6%, and 89.9%, respectively, for significant fibrosis; 0.882, 83.3%, and 80.0%, respectively, for severe fibrosis; and 0.929, 84.6%, and 88.5%, respectively, for cirrhosis. AUC scores of LecT-Hepa at each fibrosis stage were greater than those of the seven aforementioned noninvasive tests and markers. CONCLUSION: The efficacy of LecT-Hepa, a glyco marker developed using glycoproteomics, for estimating liver fibrosis was demonstrated in a multicenter study. LecT-Hepa given by a combination of the two glyco-parameters is a reliable method for determining the fibrosis stage and is a potential substitute for liver biopsy. PMID- 22535705 TI - Reliability and validity of the kinematic dystonia measure for children with upper extremity dystonia. AB - This study was conducted to determine the test-retest reliability and construct validity of the Kinematic Dystonia Measure, a quantitative measure of upper extremity dystonia. To determine the effectiveness of various treatments, reliable and valid measures of dystonia are required. Test-retest reliability of the Kinematic Dystonia Measure using the intraclass correlation coefficient was excellent for the hand-tapping task (0.95) and substantial for the eye-blinking task (0.74). Construct validity testing for the hand-tapping task revealed that Kinematic Dystonia Measure scores correlated with total Barry-Albright Dystonia Scale scores (Pearson r = 0.79, P = .003), affected arm Barry-Albright Dystonia Scale subscores (Pearson r = 0.76, P = .0.007), and negatively correlated with Quality of Upper Extremity Skills Test scores (Pearson r = -0.60, P = .05). The Kinematic Dystonia Measure has excellent test-retest reliability and good construct validity using the hand-tapping task. When combined with functional outcome measures, the Kinematic Dystonia Measure can effectively measure dystonia in children. PMID- 22535706 TI - Implementation and assessment of diffusion-weighted partial Fourier readout segmented echo-planar imaging. AB - Single-shot echo-planar imaging has been used widely in diffusion magnetic resonance imaging due to the difficulties in correcting motion-induced phase corruption in multishot data. Readout-segmented EPI has addressed the multishot problem by introducing a two-dimensional nonlinear navigator correction with online reacquisition of uncorrectable data to enable acquisition of high resolution diffusion data with reduced susceptibility artifact and T*(2) blurring. The primary shortcoming of readout-segmented EPI in its current form is its long acquisition time (longer than similar resolution single-shot echo-planar imaging protocols by approximately the number of readout segments), which limits the number of diffusion directions. By omitting readout segments at one side of k space and using partial Fourier reconstruction, readout-segmented EPI imaging times could be reduced. In this study, the effects of homodyne and projection onto convex sets reconstructions on estimates of the fractional anisotropy, mean diffusivity, and diffusion orientation in fiber tracts and raw T(2)- and trace weighted signal are compared, along with signal-to-noise ratio results. It is found that projections onto convex sets reconstruction with 3/5 segments in a 2 mm isotropic diffusion tensor image acquisition and 9/13 segments in a 0.9 * 0.9 * 4.0 mm(3) diffusion-weighted image acquisition provide good fidelity relative to the full k-space parameters. This allows application of readout-segmented EPI to tractography studies, and clinical stroke and oncology protocols. PMID- 22535707 TI - Ectopic expression of murine CD47 minimizes macrophage rejection of human hepatocyte xenografts in immunodeficient mice. AB - Macrophages play an important role in the rejection of xenogeneic cells and therefore represent a major obstacle to generating chimeric mice with human xenografts that are useful tools for basic and preclinical medical research. The signal inhibitory regulatory protein alpha (SIRPalpha) receptor is a negative regulator of macrophage phagocytic activity and interacts in a species-specific fashion with its ligand CD47. Furthermore, SIRPalpha polymorphism in laboratory mouse strains significantly affects the extent of human CD47-mediated toleration of human xenotransplants. Aiming to minimize macrophage activity and thus optimize human cell engraftment in immunodeficient mice, we lentivirally transduced murine CD47 (Cd47) into human liver cells. Human HepG2 liver cells expressing Cd47 were less frequently contacted and phagocytosed by murine RAW264.7 macrophages in vitro than their Cd47-negative counterparts. For the generation of human-mouse chimeric livers in immunodeficient BALB DeltaRAG/gamma(c) -uPA (urokinase-type plasminogen activator) mice, freshly thawed cryopreserved human hepatocytes were transduced with a lentiviral expression vector for Cd47 using a refined in vitro transduction protocol immediately before transplantation. In vivo, Cd47-positive human primary hepatocytes were selectively retained following engraftment in immunodeficient mice, leading to at least a doubling of liver repopulation efficiencies. CONCLUSION: We conclude that ectopic expression of murine Cd47 in human hepatocytes selectively favors engraftment upon transplantation into mice, a finding that should have a profound impact on the generation of robust humanized small animal models. Moreover, dominance of ectopically expressed murine Cd47 over endogenous human CD47 should also widen the spectrum of immunodeficient mouse strains suitable for humanization. PMID- 22535709 TI - Severo Ochoa: biochemistry as a hobby. PMID- 22535708 TI - Multiparametric 3T endorectal mri after external beam radiation therapy for prostate cancer. AB - PURPOSE: To determine the best combination of magnetic resonance imaging (MRI) parameters for the detection of locally recurrent prostate cancer after external beam radiation therapy. MATERIALS AND METHODS: Our Institutional Review Board approved this study with a waiver of informed consent. Twenty-six patients with suspected recurrence due to biochemical failure were part of this research. The MR protocol included T2-weighted, MR spectroscopy, and diffusion-weighted MRI. Transrectal ultrasound-guided biopsy was the standard of reference. We used logistic regression to model the probability of a positive outcome and generalized estimating equations to account for clustering. The diagnostic performance of imaging was described using receiver operating characteristic (ROC) curves. RESULTS: The area under the ROC curve of MR spectroscopic imaging (MRSI) was 83.0% (95% confidence interval [CI] = 75.5-89.1). The combination of all MR techniques did not significantly improve the performance of imaging beyond the accuracy of MRSI alone, but a trend toward improved discrimination was noted (86.9%; 95% CI = 77.6-93.4; P = 0.09). CONCLUSION: Incorporation of MRSI to T2 weighted and/or diffusion-weighted MRI significantly improves the assessment of patients with suspected recurrence after radiotherapy and a combined approach with all three modalities may have the best diagnostic performance. PMID- 22535710 TI - Increased systemic inflammatory interleukin-1beta and interleukin-6 during agitation as predictors of Alzheimer's disease. AB - OBJECTS: Identification of biomarkers for Alzheimer's disease (AD) is important for its early diagnosis and prevention and a key in advancing our understanding of its pathophysiology. The aim of this study was to determine whether systemic inflammatory interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) as well as hypertension (HT), diabetes mellitus (DM), and body mass index (BMI) are predictors of AD. METHODS: We performed a 10-year follow-up study on 133 elderly who were institutionalized in a nursing home. The associations of IL-1beta and IL 6 at both rest and agitation, as well as HT, DM, and BMI at baseline, were analyzed with the incidences of vascular dementia (VD) and AD during a 10-year follow-up period. RESULTS: The Kaplan-Meier method with log-rank test and Cox regression analyses for the total of 133 subjects showed significantly higher incidences of both VD and AD in subjects with DM or HT at baseline. Resting IL 1beta or IL-6 value, or agitation score, was not significantly associated with the subsequent development of VD or AD. The analyses of 40 subjects who had shown agitation at least once in the previous 3 months demonstrated that IL-1beta and IL-6 values at the agitation stage were significantly associated with AD, but not with VD. CONCLUSION: Our results indicate that systemic inflammatory IL-1beta and IL-6 at the agitation stage are risk factors for the development of AD, but not VD. Inflammatory mechanisms for AD seem to be causal and specific to the development of AD. PMID- 22535711 TI - Nonparametric multistate representations of survival and longitudinal data with measurement error. AB - This paper proposes a nonparametric procedure to describe the progression of longitudinal cohorts over time from a population averaged perspective, leading to multistate probability curves with the states defined jointly by survival and longitudinal outcomes measured with error. To account for the challenges of informative dropout and nonlinear shapes of the longitudinal trajectories, we apply a bias corrected penalized spline regression to estimate the unobserved longitudinal trajectory for each subject. We then estimate the multistate probability curves on the basis of the survival data and the estimated longitudinal trajectories. We further use simulation-extrapolation method to reduce the estimation bias caused by the randomness of the estimated trajectories. We develop a bootstrap test to compare multistate probability curves between groups. We present theoretical justification of the estimation procedure along with a simulation study to demonstrate finite sample performance. We illustrate the procedure by data from the African American Study of Kidney Disease and Hypertension, and it can be widely applied in longitudinal studies. PMID- 22535712 TI - Reversible photoswitching in fluorescent proteins: a mechanistic view. AB - Phototransformable fluorescent proteins (FPs) have received considerable attention in recent years, because they enable many new exciting modalities in fluorescence microscopy and biotechnology. On illumination with proper actinic light, phototransformable FPs are amenable to long-lived transitions between various fluorescent or nonfluorescent states, resulting in processes known as photoactivation, photoconversion, or photoswitching. Here, we review the subclass of photoswitchable FPs with a mechanistic perspective. These proteins offer the widest range of practical applications, including reversible high-density data bio-storage, photochromic FRET, and super-resolution microscopy by either point scanning, structured illumination, or single molecule-based wide-field approaches. Photoswitching can be engineered to occur with high contrast in both Hydrozoan and Anthozoan FPs and typically results from a combination of chromophore cis-trans isomerization and protonation change. However, other switching schemes based on, for example, chromophore hydration/dehydration have been discovered, and it seems clear that ever more performant variants will be developed in the future. PMID- 22535713 TI - Reference intervals for fetal heart volume from 3-dimensional sonography using the extended imaging virtual organ computer-aided analysis method at gestational ages of 20 to 34 weeks. AB - OBJECTIVES: The purpose of this study was to establish the reference range for fetal heart volume from 3-dimensional (3D) sonography using the extended imaging virtual organ computer-aided analysis method. METHODS: The fetal heart volume was measured in 303 normal singleton pregnancies at gestational ages of 20 to 34 weeks using 3D sonography. The extended imaging virtual organ computer-aided analysis method was used to obtain a sequence of 10 parallel symmetric sections through the heart, according to examiner-determined limits (the apex at one extremity and the connection to the great vessels at the other). Heart contours were drawn manually in all sections to obtain the 3D volume measurement, which was provided automatically by the software. Normal z scores and percentile reference ranges for each gestational age were constructed. RESULTS: The fetal heart volume increased with gestational age. The mean values were 3.09 mL at 20 weeks, 9.18 mL at 26 weeks, and 24.89 mL at 34 weeks, according to the following formulas: fetal heart volume (mL) = 18.0076 - 2.1005 * gestational age + 0.0677 * gestational age2 (R(2) = 0.922); and SD (mL) = (4.5038 - 0.4281 * gestational age + 0.0114 * gestational age2) * ?1.495808 (R(2) = 0.922). CONCLUSIONS: A reference range for fetal heart volume using the 3D sonographic extended imaging virtual organ computer-aided analysis method at gestational ages of 20 to 34 weeks was established. PMID- 22535714 TI - Left versus right intra-abdominal umbilical arteries: comparison of their Doppler waveforms. AB - OBJECTIVES: The purpose of this study was to compare Doppler velocimetric indices between the left and right intra-abdominal umbilical arteries in normally grown and growth-restricted fetuses. METHODS: In this cross-sectional study, Doppler indices of the intra-abdominal segment of the left and right umbilical arteries were measured lateral to the fetal bladder. Measurements, including the systolic to diastolic ratio and pulsatility index, were obtained from both anatomic locations. The Student t test was used to make comparisons. RESULTS: Differences between left and right Doppler indices were noted in 98% of patients, and these differences were greater than 20% in at least one-third. Overall, the left umbilical artery had a higher systolic to diastolic ratio (P = .025) and pulsatility index (P = .007) than the right umbilical artery. CONCLUSIONS: The laterality of the umbilical artery, whether on the left or right side of the fetus, influences important Doppler blood flow parameters. PMID- 22535716 TI - Frequency of a persistent yolk sac and its relationship with the gestational outcome. AB - OBJECTIVES: This study aimed to determine the frequency of a persistent yolk sac in pregnancies at 12 to 13 weeks and to investigate whether a persistent yolk sac is associated with an adverse gestational outcome. METHODS: This study reviewed a total of 282 women who had normal singleton pregnancies with a gestational age of 12 weeks to 13 weeks 6 days and who were consecutively admitted to the study center for first-trimester screening (for chromosomal abnormalities) between April 2010 and February 2011. A persistent yolk sac has been defined as a yolk sac that has achieved a diameter of 5.6 mm or greater without losing its internal pressure at the 12th week of pregnancy or later. RESULTS: A persistent yolk sac was detected by sonography in 25 pregnancies. The average diameter of the persistent yolk sacs +/- SD was 6.3 +/- 0.2 mm (range, 5.6-8.0 mm). The frequency of a persistent yolk sac in pregnancies at 12 weeks was significantly higher than that at 13 weeks (P = .017). A persistent yolk sac was not associated with adverse perinatal outcomes, including abnormal sonographic findings, isolated structural defects, poor obstetric outcomes, and perinatal mortality. CONCLUSIONS: Although yolk sacs mostly disappear toward the end of the first gestational trimester, they may sometimes persist even to the 13th week of gestation. The persistence of the yolk sac seems to be unrelated to an adverse perinatal outcome. PMID- 22535715 TI - Role of fetal length in the prediction of fetal weight. AB - OBJECTIVES: The purpose of this study was to compare the accuracy of routine fetal biometric indices in the prediction of fetal length and to determine whether more accurate sonographic measures of fetal length can improve the accuracy of fetal weight estimation. METHODS: The accuracy of the common sonographic fetal biometric indices for predicting fetal length was determined using 3689 sonographic weight estimations performed within 3 days before delivery. The fetal length at the time of the sonographic examination was assumed to be equal to the neonatal length, which is routinely measured within 24 hours of delivery. Two new regression models for fetal weight estimation, one with and one without fetal length as an independent variable, were generated to determine the potential contribution of more accurate predictors of fetal length to the accuracy of fetal weight estimation. RESULTS: Abdominal circumference was a significantly more accurate predictor of fetal length (r = 0.732) compared with femur length (r = 0.712), biparietal diameter (r = 0.644), and head circumference (r = 0.661; P < .05), although each of these biometric indices explained only about 50% of the variance in fetal length (R(2) = 0.423-0.548). The addition of fetal length as an independent variable to a birth weight prediction model significantly improved the model's correlation with birth weight(r = 0.917 versus 0.903; P = .006), systematic error (0.2% versus 0.6%; P < .001), random error (6.7% versus 7.5%; P < .001), mean absolute percent error, and the proportion of estimations within 5% and 10% of birth weight. CONCLUSIONS: The correlation between routine biometric indices and fetal length is limited. Identification of new fetal sonographic biometric indices with greater predictive accuracy for fetal length may improve the accuracy of fetal weight estimation. PMID- 22535717 TI - Correlation between the duration of maternal rest in the left lateral decubitus position and the amniotic fluid volume increase. AB - OBJECTIVES: The purpose of this study was to show the relationship between amniotic fluid volume changes and the duration of maternal rest in the left lateral decubitus position. METHODS: Pregnant women (n = 34) with an amniotic fluid index between 6 and 24 cm and an uncomplicated singleton pregnancy at 35 to 40 weeks' gestation were included in the study. After the initial amniotic fluid index measurements, the women were instructed to rest in the left lateral position, and the measurements were repeated at 15, 30, 45, 60, 75, and 90 minutes. RESULTS: The amniotic fluid index increased at each sequential interval. Although each amniotic fluid index value was higher than the preceding one, only the 15- and 30-minute values were significantly higher than the preceding measurements (P < .001; P < .01, respectively). At the beginning of maternal rest in the left lateral position, 15 minutes of rest was sufficient to create significant changes (P < .001). However, after 30 minutes of rest, an additional 45 minutes was needed to create a significant amniotic fluid index increase (P < .01). The curve describing the amniotic fluid index increases caused by maternal rest resembled a saturation curve, and the maximum increase in the amniotic fluid volume was projected to be achieved approximately at the end of the second hour of the rest period. CONCLUSIONS: The correlation between the duration of maternal rest and amniotic fluid volume changes is not linear. However, maternal rest in the left lateral decubitus position significantly increases the amniotic fluid volume, particularly in the first 30 minutes (maximum increase in the first 15 minutes). PMID- 22535718 TI - Contrast ultrasound imaging of the aorta alters vascular morphology and circulating von Willebrand factor in hypercholesterolemic rabbits. AB - OBJECTIVES: Ultrasound contrast agents (UCAs) are intravenously infused microbubbles that add definition to ultrasonic images. Ultrasound contrast agents continue to show clinical promise in cardiovascular imaging, but their biological effects are not known with confidence. We used a cholesterol-fed rabbit model to evaluate these effects when used in conjunction with ultrasound (US) to image the descending aorta. METHODS: Male New Zealand White rabbits (n = 41) were weaned onto an atherogenic diet containing 1% cholesterol, 10% fat, and 0.11% magnesium. At 21 days, rabbits were exposed to contrast US at 1 of 4 pressure levels using either the UCA Definity (Lantheus Medical Imaging, Inc, North Billerica, MA) or a saline control (n = 5 per group). Blood samples were collected and analyzed for lipids and von Willebrand factor (vWF), a marker of endothelial function. Animals were euthanized at 42 days, and tissues were collected for histologic analysis. RESULTS: After adjustment for pre-exposure vWF, high-level US (in situ [at the aorta] peak rarefactional pressure of 1.4 or 2.1 MPa) resulted in significantly lower vWF 1 hour post exposure (P = .0127; P(adj) < .0762). This difference disappeared within 24 hours. Atheroma thickness in the descending aorta was lower in animals receiving the UCA compared to animals receiving saline. CONCLUSIONS: Contrast US affected the descending aorta, as evidenced by two separate outcome measures. These results may be a first step in elucidating a previously unknown biological effect of UCAs. Further research is warranted to characterize the effects of this procedure. PMID- 22535719 TI - Diagnostic value of real-time sonoelastography in congenital muscular torticollis. AB - OBJECTIVES: The purpose of this study was to evaluate the possible use of real time sonoelastography in infants with congenital muscular torticollis for predicting treatment outcomes. METHODS: The study included 20 infants with a sternocleidomastoid muscle thickness of greater than 10 mm, a sonoelastographic score of 4, and involvement of the entire length of the muscle (group 1) and 30 infants with a sternocleidomastoid muscle thickness of less than 10 mm, a sonoelastographic score of 3, and involvement of only part of the muscle (group 2). A physiatrist performed B-mode sonography and sonoelastography together, measured the thickness of the sternocleidomastoid muscle, and calculated the cross-sectional area of the involved muscle in both groups. On color scale sonoelastography, the sonoelastographic score of the sternocleidomastoid muscle was graded from 1 (purple to green: soft) to 4 (red: stiff), and the color histogram of the muscle was subsequently analyzed. RESULTS: The thickness and cross-sectional area of the sternocleidomastoid muscles in group 1 were significantly greater than those in group 2 (P = .001). On the color histograms, the median red pixel values in group 1 were significantly greater than those in group 2 (P = .001). In group 1, the mass in the affected muscle completely disappeared in 16 infants (80%), and a residual mass was detected in 4 (20%) on B mode sonography at the final outcome. However, in group 2, the mass in the affected sternocleidomastoid muscle completely disappeared in all of the infants. CONCLUSIONS: These findings suggest that real-time sonoelastography, although an ancillary technique to conventional sonography, may predict treatment outcomes of congenital muscular torticollis. PMID- 22535720 TI - Relationship between intraneural vascular flow measured with sonography and carpal tunnel syndrome diagnosis based on electrodiagnostic testing. AB - OBJECTIVES: The purpose of this study was to document and analyze intraneural vascular flow within the median nerve using power and spectral Doppler sonography and to determine the relationship of this vascular flow with diagnosis of carpal tunnel syndrome based on electrodiagnostic testing. METHODS: Power and spectral Doppler sonograms in the median nerve were prospectively collected in 47 symptomatic and 44 asymptomatic subjects. Doppler studies were conducted with a 12-MHz linear transducer. Strict inclusion criteria were established for postexamination assessment of waveforms; routine quality assurance was completed; electrodiagnostic tests were conducted on the same day as sonographic measurements; and the skin temperature was controlled. Included waveforms were categorized by location and averaged by individual for comparative analysis to electrodiagnostic testing. RESULTS: A total of 416 waveforms were collected, and 245 were retained for statistical analysis based on strict inclusion criteria. The mean spectral peak velocity among all waveforms was 4.42 (SD, 2.15) cm/s. At the level of the pisiform, the most consistent data point, mean peak systole, was 3.75 cm/s in symptomatic patients versus 4.26 cm/s in asymptomatic controls. Statistical trending showed an initial increase in the mean spectral peak velocity in symptomatic but diagnostically negative cases, with decreasing velocity as diagnostic categories progressed from mild to severe. CONCLUSIONS: An inverse relationship may exist between intraneural vascular flow in the median nerve and an increasing severity of carpal tunnel syndrome based on nerve conduction results. Randomized controlled trials are needed to determine whether spectral Doppler sonography can provide an additive benefit for diagnosing the severity of carpal tunnel syndrome. PMID- 22535721 TI - Application of contrast-enhanced sonography with time-intensity curve analysis to explore hypervascularity in Achilles tendinopathy by using a rabbit model. AB - OBJECTIVES: The purpose of this study was to investigate the ability of contrast enhanced sonography in staging and grading hypervascularity in tendinopathic tissues by using a rabbit model. METHODS: Fourteen rabbits were injected with 100 and 50 MUL of collagenase in their left and right Achilles tendons, respectively. The vascularity was assessed by non-contrast-enhanced and contrast-enhanced power Doppler sonography on day 0 (baseline) and days 1, 7, and 14 after collagenase injections. Color pixels within targeted areas were plotted according to time and analyzed by a curve-fitting method. RESULTS: Non-contrast-enhanced power Doppler sonography failed to differentiate vascularity at various stages or between bilateral tendons, whereas contrast-enhanced sonography showed that the peak color pixel amount reached its maximum on day 1 and declined over time in tendons treated with 100 MUL of collagenase. A similar trend was observed in tendons receiving 50 MUL of collagenase. For comparisons between bilateral tendons, higher vascularity was detected in those treated with more collagenase on day 1 or 7. Time-intensity curve analysis revealed rapid microbubble replenishment in both tendons during their initial phase after collagenase injections. CONCLUSIONS: Contrast-enhanced sonography discriminated the vascularity of various injury grades at different time points after collagenase injections. Time intensity curve analysis detailed the hemodynamics in tendinopathic tissues, which helped differentiate vascularity in acute inflammatory from later degenerative phases. PMID- 22535722 TI - Impact of atherosclerosis and age on Doppler sonographic parameters in the diagnosis of renal artery stenosis. AB - OBJECTIVES: The purpose of this study was to investigate the influence of atherosclerosis and age on 4 representative Doppler parameters in the diagnosis of renal artery stenosis. METHODS: The 4 parameters, renal peak systolic velocity (PSV), renal-aortic ratio, renal-interlobar ratio, and acceleration time, were measured in 208 patients before angiography. The 208 patients were divided into groups according to age and atherosclerosis stratification. The Student t test, 1 way analysis of variance, and the chi(2) test were used to compare all 4 parameters and clinical characteristics. The optimal cutoff values were determined by receiver operating characteristic curves. The diagnostic concordance between atherosclerosis and age strata was evaluated by the Cohen kappa coefficient. RESULTS: Of the 416 renal arteries shown on Doppler sonography, 204 had a diagnosis of renal artery stenosis and 19 as occlusion on angiography. The optimal cutoff values for the renal-aortic ratio and renal interlobar ratio in the groups aged 46 years or older and younger than 46 years were much different (2.3 versus 1.4 and 5.1 versus 6.5, respectively), whereas those for the renal PSV and acceleration time were close to each other or the same (170 versus 180 cm/s and 51 versus 51 milliseconds). The kappa coefficients for the renal PSV, renal-interlobar ratio, acceleration time, and renal-aortic ratio between the atherosclerosis and age strata were 0.93, 0.99, 1.00, and 0.71. CONCLUSIONS: Atherosclerosis and age show comparable influences on Doppler parameters in the diagnosis of renal artery stenosis. For clinical convenience, cutoff values may be separately established on the basis of a 46-year-old borderline for the renal-aortic ratio and renal-interlobar ratio, although this process is not necessary for the renal PSV and acceleration time. PMID- 22535723 TI - Effect of sonographically guided cerebral glioma surgery on survival time. AB - OBJECTIVES: We investigated the value of intraoperative sonography in improving the prevalence of total tumor resection and the survival time of patients who underwent resection of cerebral gliomas. METHODS: One hundred thirty-seven patients who underwent sonographically guided surgery were followed for 6 to 60 months. In addition, 60 randomly selected patients (30 with low-grade gliomas and 30 with high-grade gliomas) who had surgery in our hospital without sonographic guidance served as the control group. Follow-up included the survival time, and the difference in the survival time between the study and control groups was statistically analyzed. RESULTS: Total removal of the lesion was achieved in 77 cases (69%), and partial removal was achieved in 35 (31%). In the control low grade glioma group, 6-month survival was 96.7%; 1-year survival was 73.3%; and 2 year survival was 53.3%. In the study low-grade glioma group, survival rates at 6 months, 1 year, and 2 years were 98.0%, 96.1%, and 88.2%, respectively. In the control and study high-grade glioma groups, survival rates at 6 months, 1 year, and 2 years were 83.3% and 93.4%, 43.3% and 59.2%, and 13.3% and 32.8%. When comparing survival at 6 months, 1 year, and 2 years between the control and study groups, there was no significant difference at 6 months (P > .05), but survival at 1 and 2 years was significantly different (P < .05). CONCLUSIONS: Sonographically guided resection of cerebral gliomas helps the surgeon understand the relationship between the lesion and the surrounding structures. It is of value in improving the prevalence of total tumor resection and the patient's survival time. PMID- 22535724 TI - Preliminary study on the diagnostic value of acoustic radiation force impulse technology for differentiating between benign and malignant thyroid nodules. AB - OBJECTIVES: This study aimed to evaluate the diagnostic value of acoustic radiation force impulse (ARFI) elasticity imaging for differentiating between benign and malignant thyroid lesions. METHODS: Hospitalized patients needing thyroid surgery were evaluated. After routine thyroid sonography, the patients underwent ARFI elasticity imaging. Virtual Touch tissue imaging (VTI) and Virtual Touch tissue quantification (VTQ; Siemens Medical Solutions, Mountain View, CA) were used to qualitatively and quantitatively analyze the elasticity and hardness of nodules. For statistical analysis, the Student t test, analysis of variance, and the chi(2) test were used to compare the elastic parameters. RESULTS: Of the 98 thyroid nodules observed in 72 hospitalized patients, 56 were nodular goiters, 16 thyroid adenomas, 4 thyroiditis, and 22 thyroid malignancies, with mean VTQ values +/- SD of 2.034 +/- 0.484, 1.835 +/- 0.364, 2.293 +/- 0.787, and 3.941 +/- 1.393 m/s, respectively. The elastic parameters of malignant nodules were significantly higher than those of benign nodules (P < .001) and the surrounding thyroid parenchyma (P < .001). There was no significant difference between the VTQ value of benign nodules and that of the surrounding normal thyroid parenchyma (P > .05). For differentiating between benign and malignant nodules, the sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accordance rate were 86.36%, 93.42%, 79.17%, 95.95%, and 91.84% based on the standard VTQ value (2.555m/s). In total, 77.6% (59 of 76) of the benign nodules showed softer and equal images in the VTI mode, and 77.3% (17 of 22) of the malignant nodules showed stiffer images (P < .001). CONCLUSIONS: Acoustic radiation force impulse imaging has high sensitivity and specificity in evaluating benign and malignant thyroid nodules and therefore had good diagnostic value in clinical applications. PMID- 22535725 TI - Sonographic breast elastography: a primer. AB - Breast elastography is a new sonographic technique that provides additional characterization information on breast lesions over conventional sonography and mammography. This technique provides information on the strain or hardness of a lesion, similar to a clinical palpation examination. Two techniques are now available for clinical use: strain (compression-based elastography) and shear wave elastography. Initial evaluation of these techniques in clinical trials suggests that they may substantially improve the characterization of breast lesions as benign or malignant. This improvement may substantially reduce the number of benign biopsies performed. Elastography can be performed by several methods and is now available from several manufactures. This article reviews the basics of this technique, how to perform the examination, image interpretation, and artifacts. Although easy to perform, technique is critical to obtain adequate images for interpretation. This primer will highlight the technique and point out common pitfalls. PMID- 22535726 TI - Role of simulation-based education in ultrasound practice training. AB - The aim of this systematic review was to determine whether ultrasound (US)/US procedural simulation leads to improvement in US competence, particularly in the clinical setting. The electronic databases MEDLINE, EMBASE, CINAHL, ERIC, and OVID were searched for relevant published articles between 1950 and April 2011. Fourteen articles of an initial 371 articles met the inclusion criteria. The eligible studies differed in terms of the study population, sample size, study design, US simulator used, and measured outcomes. Most of the studies demonstrated acquisition of knowledge and skills with suggestions of correlation with simulation training and improved performance in the same simulated environment. There is little compelling evidence based on published studies at present to support the widespread adoption of simulation-based medical education to improve clinical US competence. PMID- 22535727 TI - Color Doppler twinkling artifacts in small-bowel bezoars. AB - Small-bowel bezoars usually form in the stomach and may subsequently cause small bowel obstruction. Bezoars associated with small-bowel obstruction have been accurately diagnosed by computed tomography, although some case reports have described the specific sonographic findings of small-bowel bezoars. Bezoars can be overlooked by sonographic examination if a dilated small-bowel loop contains a large amount of air. Twinkling artifacts on color Doppler images appear as rapidly fluctuating red and blue signals behind certain strongly reflecting structures. In this series, we hypothesize that twinkling artifacts might appear in small-bowel bezoars, and we describe the presence of twinkling artifacts in 3 cases of small-bowel bezoars presenting as small-bowel obstruction. PMID- 22535728 TI - Prenatal sonography in hydranencephaly: findings during the early stages of disease. AB - The purpose of this report is to describe the prenatal sonographic findings in fetuses with hydranencephaly diagnosed during the early stages of disease. Four cases with characteristics of hydranencephaly were retrospectively identified from 2 Latin American fetal medicine referral centers. Information on maternal demographics, sonographic findings, antenatal courses, and pregnancy outcomes was retrieved from the ultrasound reports and medical records. Cases were diagnosed between 21 and 23 weeks' gestation. The sonographic findings were similar in all cases and included absent cerebral hemispheres, which were replaced by homogeneous echogenic material filling the supratentorial space, and preservation of the thalami, brain stem, and cerebellum. The head circumference measurement was within the normal range, but the transverse cerebellar diameter was below the fifth percentile in 3 of the 4 cases. A follow-up scan in 1 of these cases demonstrated the classic anechoic fluid-filled appearance of hydranencephaly 2 weeks after diagnosis. Confirmation of the diagnosis was available in 2 cases, by postmortem examination in 1 and by fetal magnetic resonance imaging in the other. No further investigations were performed in the 2 women who opted for termination of pregnancy. In conclusion, during the early stages of disease, hydranencephaly is characterized by the presence of a large intracranial saclike structure containing homogeneous echogenic material, representing blood and necrotic debris secondary to massive liquefaction of the developing cerebral hemispheres. PMID- 22535729 TI - Sonography of adenomyosis. PMID- 22535730 TI - Incidental finding of decidualized vesical endometriosis in an asymptomatic obstetrical patient. PMID- 22535731 TI - Fetal true pancreatic cysts. PMID- 22535732 TI - Prenatal aberrant right subclavian artery: a hereditary malformation? PMID- 22535733 TI - Further evidence against the reliability of the human chorionic gonadotropin discriminatory level. PMID- 22535734 TI - Further evidence against the reliability of the human chorionic gonadotropin discriminatory level. PMID- 22535735 TI - Further evidence against the reliability of the human chorionic gonadotropin discriminatory level. PMID- 22535737 TI - Investigating asthma symptoms in primary care. PMID- 22535738 TI - Health campaigns that have changed public understanding. PMID- 22535740 TI - Springtime for open access in academia. PMID- 22535741 TI - Controversial allergy doctor is given formal warning by GMC. PMID- 22535742 TI - New centre sets out to better coordinate research into non-communicable diseases. PMID- 22535744 TI - Estrogen potentiates prostaglandin E2-stimulated duodenal mucosal HCO3- secretion in mice. AB - The cause of lower prevalence of duodenal ulcer in young women compared with men is largely unknown. We recently found that sex difference in duodenal mucosal HCO3- secretion existed in humans and mice, but the mechanisms are not clear. Prostaglandin E2 (PGE2) is an important endogenous mediator that plays an important role in the regulation of duodenal HCO3- secretion. Therefore, in the present study, we investigated the effect of estrogen on PGE2-stimulated duodenal HCO3- secretion and the underlying mechanisms. The results showed that 17beta estradiol at the physiological concentration (1 nM) had no significant effects on duodenal mucosal HCO3- secretion or short-circuit current (I(sc)) in mice. However, the pretreatment of 17beta-estradiol (1 nM) markedly potentiated PGE2 stimulated duodenal HCO3- secretion and I(sc) (P < 0.01 and P < 0.05). Global estrogen receptor (ER) antagonist ICI-182,780 and ERalpha-specific antagonist MPP, but not the ERbeta-specific antagonist PHTPP, abolished estrogen-potentiated PGE2-stimulated duodenal HCO3- secretion and I(sc). 17beta-Estradiol and PGE2 additively increased phosphatidylinositol 3-kinase (PI3K) activity and Akt phosphorylation. Wortmannin, a specific PI3K inhibitor, inhibited estrogen potentiated PGE2-stimulated duodenal HCO3- secretion and I(sc). In conclusion, estrogen at the physiological concentration potentiates PGE2-stimulated duodenal mucosal HCO3- secretion through the activation of ERalpha and the PI3K-dependent mechanism, which may contribute to the sex difference in duodenal mucosal HCO3- secretion and the lower prevalence of duodenal ulcer in young women. PMID- 22535743 TI - Cytokine-mediated beta-cell damage in PARP-1-deficient islets. AB - Poly(ADP)-ribose polymerase (PARP) is an abundant nuclear protein that is activated by DNA damage; once active, it modifies nuclear proteins through attachment of poly(ADP)-ribose units derived from beta-nicotinamide adenine dinucleotide (NAD(+)). In mice, the deletion of PARP-1 attenuates tissue injury in a number of animal models of human disease, including streptozotocin-induced diabetes. Also, inflammatory cell signaling and inflammatory gene expression are attenuated in macrophages isolated from endotoxin-treated PARP-1-deficient mice. In this study, the effects of PARP-1 deletion on cytokine-mediated beta-cell damage and macrophage activation were evaluated. There are no defects in inflammatory mediator signaling or inflammatory gene expression in macrophages and islets isolated from PARP-1-deficient mice. While PARP-1 deficiency protects islets against cytokine-induced islet cell death as measured by biochemical assays of membrane polarization, the genetic absence of PARP-1 does not effect cytokine-induced inhibition of insulin secretion or cytokine-induced DNA damage in islets. While PARP-1 deficiency appears to provide protection from cell death, it fails to provide protection against the inhibitory actions of cytokines on insulin secretion or the damaging actions on islet DNA integrity. PMID- 22535745 TI - Apolipoprotein A-I mimetic peptide inhibits atherosclerosis by altering plasma metabolites in hypercholesterolemia. AB - An apolipoprotein A-I mimetic peptide, D-4F, has been shown to improve vasodilation and inhibit atherosclerosis in hypercholesterolemic low-density lipoprotein receptor-null (LDLr(-/-)) mice. To study the metabolic variations of D-4F ininhibiting atherosclerosis, metabonomics, a novel system biological strategy to investigate the pathogenesis, was developed. Female LDLr(-/-) mice were fed a Western diet and injected with or without D-4F intraperitoneally. Atherosclerotic lesion formation was measured, whereas plasma metabolic profiling was obtained on the basis of ultra-high-performance liquid chromatography in tandem with time-of-flight mass spectrometry operating in both positive and negative ion modes. Data were processed by multivariate statistical analysis to graphically demonstrate metabolic changes. The partial least-squares discriminate analysis model was validated with cross-validation and permutation tests to ensure the model's reliability. D-4F significantly inhibited the formation of atherosclerosis in a time-dependent manner. The metabolic profiling was altered dramatically in hypercholesterolemic LDLr(-/-) mice, and a significant metabolic profiling change in response to D-4F treatment was observed in both positive and negative ion modes. Thirty-six significantly changed metabolites were identified as potential biomarkers. A series of phospholipid metabolites, including lysophosphatidylcholine (LysoPC), lysophosphatidylethanolamine (LysoPE), phosphatidylcholine (PC), phatidylethanolamine (PE), sphingomyelin (SM), and diacylglycerol (DG), particularly the long-chain LysoPC, was elevated dramatically in hypercholesterolemic LDLr(-/-) mice but reduced by D-4F in a time dependent manner. Quantitative analysis of LysoPC, LysoPE, PC, and DG using HPLC was chosen to validate the variation of these potential biomarkers, and the results were consistent with the metabonomics findings. Our findings demonstrated that D-4F may inhibit atherosclerosis by regulating phospholipid metabolites specifically by decreasing plasma long-chain LysoPC. PMID- 22535746 TI - Lack of Smad3 signaling leads to impaired skeletal muscle regeneration. AB - Smad3 is a key intracellular signaling mediator for both transforming growth factor-beta and myostatin, two major regulators of skeletal muscle growth. Previous published work has revealed pronounced muscle atrophy together with impaired satellite cell functionality in Smad3-null muscles. In the present study, we have further validated a role for Smad3 signaling in skeletal muscle regeneration. Here, we show that Smad3-null mice had incomplete recovery of muscle weight and myofiber size after muscle injury. Histological/immunohistochemical analysis suggested impaired inflammatory response and reduced number of activated myoblasts during the early stages of muscle regeneration in the tibialis anterior muscle of Smad3-null mice. Nascent myofibers formed after muscle injury were also reduced in number. Moreover, Smad3 null regenerated muscle had decreased oxidative enzyme activity and impaired mitochondrial biogenesis, evident by the downregulation of the gene encoding mitochondrial transcription factor A, a master regulator of mitochondrial biogenesis. Consistent with known Smad3 function, reduced fibrotic tissue formation was also seen in regenerated Smad3-null muscle. In conclusion, Smad3 deficiency leads to impaired muscle regeneration, which underscores an essential role of Smad3 in postnatal myogenesis. Given the negative role of myostatin during muscle regeneration, the increased expression of myostatin observed in Smad3-null muscle may contribute to the regeneration defects. PMID- 22535747 TI - Exercise tames the wild side of the Myc network: a hypothesis. AB - We propose that the well-documented therapeutic actions of repeated physical activities over human lifespan are mediated by the rapidly turning over proto oncogenic Myc (myelocytomatosis) network of transcription factors. This transcription factor network is unique in utilizing promoter and epigenomic (acetylation/deacetylation, methylation/demethylation) mechanisms for controlling genes that include those encoding intermediary metabolism (the primary source of acetyl groups), mitochondrial functions and biogenesis, and coupling their expression with regulation of cell growth and proliferation. We further propose that remote functioning of the network occurs because there are two arms of this network, which consists of driver cells (e.g., working myocytes) that metabolize carbohydrates, fats, proteins, and oxygen and produce redox-modulating metabolites such as H2O2, NAD+, and lactate. The exercise-induced products represent autocrine, paracrine, or endocrine signals for target recipient cells (e.g., aortic endothelium, hepatocytes, and pancreatic beta-cells) in which the metabolic signals are coupled with genomic networks and interorgan signaling is activated. And finally, we propose that lactate, the major metabolite released from working muscles and transported into recipient cells, links the two arms of the signaling pathway. Recently discovered contributions of the Myc network in stem cell development and maintenance further suggest that regular physical activity may prevent age-related diseases such as cardiovascular pathologies, cancers, diabetes, and neurological functions through prevention of stem cell dysfunctions and depletion with aging. Hence, regular physical activities may attenuate the various deleterious effects of the Myc network on health, the wild side of the Myc-network, through modulating transcription of genes associated with glucose and energy metabolism and maintain a healthy human status. PMID- 22535748 TI - Acute and long-term effects of Roux-en-Y gastric bypass on glucose metabolism in subjects with Type 2 diabetes and normal glucose tolerance. AB - Our aim was to study the potential mechanisms responsible for the improvement in glucose control in Type 2 diabetes (T2D) within days after Roux-en-Y gastric bypass (RYGB). Thirteen obese subjects with T2D and twelve matched subjects with normal glucose tolerance (NGT) were examined during a liquid meal before (Pre), 1 wk, 3 mo, and 1 yr after RYGB. Glucose, insulin, C-peptide, glucagon-like peptide 1 (GLP-1), glucose-dependent-insulinotropic polypeptide (GIP), and glucagon concentrations were measured. Insulin resistance (HOMA-IR), beta-cell glucose sensitivity (beta-GS), and disposition index (D(beta-GS): beta-GS * 1/HOMA-IR) were calculated. Within the first week after RYGB, fasting glucose [T2D Pre: 8.8 +/- 2.3, 1 wk: 7.0 +/- 1.2 (P < 0.001)], and insulin concentrations decreased significantly in both groups. At 129 min, glucose concentrations decreased in T2D [Pre: 11.4 +/- 3, 1 wk: 8.2 +/- 2 (P = 0.003)] but not in NGT. HOMA-IR decreased by 50% in both groups. beta-GS increased in T2D [Pre: 1.03 +/- 0.49, 1 wk: 1.70 +/- 1.2, (P = 0.012)] but did not change in NGT. The increase in DI(beta-GS) was 3-fold in T2D and 1.5-fold in NGT. After RYGB, glucagon secretion was increased in response to the meal. GIP secretion was unchanged, while GLP-1 secretion increased more than 10-fold in both groups. The changes induced by RYGB were sustained or further enhanced 3 mo and 1 yr after surgery. Improvement in glycemic control in T2D after RYGB occurs within days after surgery and is associated with increased insulin sensitivity and improved beta-cell function, the latter of which may be explained by dramatic increases in GLP-1 secretion. PMID- 22535750 TI - Interovulatory intervals in mares receiving deslorelin implants in Ireland (2009 to 2010). AB - Deslorelin acetate implants, recently licensed in Ireland and the UK for ovulation induction in mares, have been associated with prolonged interovulatory intervals in USA studies, leading to the practice of removing implants postovulation. Trial data in Australia indicate a less pronounced effect on interovulatory intervals, suggesting possible geographical variation. Objectives of the current study were to assess the effect of deslorelin implants, with and without removal on oestrous cycle length in Irish- and UK-based Thoroughbred broodmares. Data were collected retrospectively from 88 oestrous cycles. A statistically significant difference (P=0.02) was found between interovulatory intervals in mares in which the deslorelin implant was not removed, compared with administration and removal of the implant or the use of human chorionic gonadotrophin. The results suggest that implant removal when possible is advisable. The delay in subsequent ovulations was less marked than that reported in some studies from the USA. This information is useful in deciding when to schedule subsequent breeding for mares which received a deslorelin implant during the previous oestrous period and provides evidence to counter-concerns that mares treated with deslorelin implants may experience a long delay in return to oestrus if the implant is not removed. PMID- 22535751 TI - Evaluation of single reactor bovine tuberculosis breakdowns based on analysis of reactors slaughtered at an Irish export meat plant. AB - The 'Singleton Protocol' was adopted by the Irish Department of Agriculture Fisheries and Food (DAFF) in 1996 to address the incomplete specificity of the single intra-dermal comparative tuberculin test (SICTT) used in Ireland for the detection of animals infected with bovine tuberculosis (bTB). The protocol allows the early restoration of disease-free status to herds with a single reactor breakdown, where the herd was not confirmed as infected with Mycobacterium bovis by epidemiological investigation, by postmortem examination or by further test. The current study examines the ability of the Singleton Protocol to identify false-positive reactors. It investigates the subsequent herd-reactor rate following single reactor removal and analyses the factors leading to a positive postmortem lesion outcome and a positive reactor retest result. Postmortem lesion results were obtained for 371 reactor animals from single reactor breakdowns that were killed at an export meat plant over a 19-month period. Epidemiological and test data for these animals and their herds were obtained from DAFF databases and analysed by univariate and multivariate statistical analysis. Singleton candidates had an 18.7 per cent lower lesion rate than single animal breakdowns not meeting the singleton criteria. No significant difference was found between Singletons and non singletons in the subsequent reactor retest results. Skin thickness at the SICTT is the most significant determinant of a positive lesion result. The area bTB history was shown to be a significant variable in producing a positive reactor retest result. PMID- 22535749 TI - Effect of vertical sleeve gastrectomy in melanocortin receptor 4-deficient rats. AB - Bariatric surgery is currently the most effective treatment for obesity. Vertical sleeve gastrectomy (VSG), a commonly applied bariatric procedure, involves surgically incising most of the volume of the stomach. In humans, partial loss of melanocortin receptor-4 (MC4R) activity is the most common monogenic correlate of obesity regardless of lifestyle. At present it is unclear whether genetic alteration of MC4R signaling modulates the beneficial effects of VSG. Following VSG, we analyzed body weight, food intake, glucose sensitivity, and macronutrient preference of wild-type and MC4R-deficient (Mc4r(+/-) and Mc4r(-/-)) rats compared with sham-operated controls. VSG reduced body weight and fat mass and improved glucose metabolism and also shifted preference toward carbohydrates and away from fat. All of this occurred independently of MC4R activity. In addition, MC4R was resequenced in 46 human subjects who underwent VSG. We observed common genetic variations in the coding sequence of MC4R in five subjects. However, none of those variations appeared to affect the outcome of VSG. Taken together, these data suggest that the beneficial effect of VSG on body weight and glucose metabolism is not mediated by alterations in MC4R activity. PMID- 22535752 TI - A dynamic model using monitoring data and watershed characteristics to project fish tissue mercury concentrations in stream systems. AB - A complex interplay of factors determines the degree of bioaccumulation of Hg in fish in any particular basin. Although certain watershed characteristics have been associated with higher or lower bioaccumulation rates, the relationships between these characteristics are poorly understood. To add to this understanding, a dynamic model was built to examine these relationships in stream systems. The model follows Hg from the water column, through microbial conversion and subsequent concentration, through the food web to piscivorous fish. The model was calibrated to 7 basins in Kentucky and further evaluated by comparing output to 7 sites in, or proximal to, the Ohio River Valley, an underrepresented region in the bioaccumulation literature. Water quality and basin characteristics were inputs into the model, with tissue concentrations of Hg of generic trophic level 3, 3.5, and 4 fish the output. Regulatory and monitoring data were used to calibrate and evaluate the model. Mean average prediction error for Kentucky sites was 26%, whereas mean error for evaluation sites was 51%. Variability within natural systems can be substantial and was quantified for fish tissue by analysis of the US Geological Survey National Fish Database. This analysis pointed to the need for more systematic sampling of fish tissue. Analysis of model output indicated that parameters that had the greatest impact on bioaccumulation influenced the system at several points. These parameters included forested and wetlands coverage and nutrient levels. Factors that were less sensitive modified the system at only 1 point and included the unfiltered total Hg input and the portion of the basin that is developed. PMID- 22535753 TI - Sample size and repeated measures required in studies of foods in the homes of African-American families. AB - Measurement of the home food environment is of interest to researchers because it affects food intake and is a feasible target for nutrition interventions. The objective of this study was to provide estimates to aid the calculation of sample size and number of repeated measures needed in studies of nutrients and foods in the home. We inventoried all foods in the homes of 80 African-American first-time mothers and determined 6 nutrient-related attributes. Sixty-three households were measured 3 times, 11 were measured twice, and 6 were measured once, producing 217 inventories collected at ~2-mo intervals. Following log transformations, number of foods, total energy, dietary fiber, and fat required only one measurement per household to achieve a correlation of 0.8 between the observed and true values. For percent energy from fat and energy density, 3 and 2 repeated measurements, respectively, were needed to achieve a correlation of 0.8. A sample size of 252 was needed to detect a difference of 25% of an SD in total energy with one measurement compared with 213 with 3 repeated measurements. Macronutrient characteristics of household foods appeared relatively stable over a 6-mo period and only 1 or 2 repeated measures of households may be sufficient for an efficient study design. PMID- 22535754 TI - The Mediterranean diet pattern and its main components are associated with lower plasma concentrations of tumor necrosis factor receptor 60 in patients at high risk for cardiovascular disease. AB - Adherence to a Mediterranean diet (MD) is associated with a reduced risk of coronary heart disease. However, the molecular mechanisms involved are not fully understood. The aim of this study was to compare the effects of 2 MD with those of a low-fat-diet (LFD) on circulating inflammatory biomarkers related to atherogenesis. A total of 516 participants included in the Prevention with Mediterranean Diet Study were randomized into 3 intervention groups [MD supplemented with virgin olive oil (MD-VOO); MD supplemented with mixed nuts (MD Nuts); and LFD]. At baseline and after 1 y, participants completed FFQ and adherence to MD questionnaires, and plasma concentrations of inflammatory markers including intercellular adhesion molecule-1(ICAM-1), IL-6, and 2 TNF receptors (TNFR60 and TNFR80) were measured by ELISA. At 1 y, the MD groups had lower plasma concentrations of IL-6, TNFR60, and TNFR80 (P < 0.05), whereas ICAM-1, TNFR60, and TNFR80 concentrations increased in the LFD group (P < 0.002). Due to between-group differences, participants in the 2 MD groups had lower plasma concentrations of ICAM-1, IL-6, TNFR60, and TNFR80 compared to those in the LFD group (P <= 0.028). When participants were categorized in tertiles of 1-y changes in the consumption of selected foods, those in the highest tertile of virgin olive oil (VOO) and vegetable consumption had a lower plasma TNFR60 concentration compared with those in tertile 1 (P < 0.02). Moreover, the only changes in consumption that were associated with 1-y changes in the geometric mean TNFR60 concentrations were those of VOO and vegetables (P = 0.01). This study suggests that a MD reduces TNFR concentrations in patients at high cardiovascular risk. PMID- 22535755 TI - Quercetin ameliorates cardiovascular, hepatic, and metabolic changes in diet induced metabolic syndrome in rats. AB - Metabolic syndrome is a risk factor for cardiovascular disease and nonalcoholic fatty liver disease (NAFLD). We investigated the responses to the flavonol, quercetin, in male Wistar rats (8-9 wk old) divided into 4 groups. Two groups were given either a corn starch-rich (C) or high-carbohydrate, high-fat (H) diet for 16 wk; the remaining 2 groups were given either a C or H diet for 8 wk followed by supplementation with 0.8 g/kg quercetin in the food for the following 8 wk (CQ and HQ, respectively). The H diet contained ~68% carbohydrates, mainly as fructose and sucrose, and ~24% fat from beef tallow; the C diet contained ~68% carbohydrates as polysaccharides and ~0.7% fat. Compared with the C rats, the H rats had greater body weight and abdominal obesity, dyslipidemia, higher systolic blood pressure, impaired glucose tolerance, cardiovascular remodeling, and NAFLD. The H rats had lower protein expressions of nuclear factor (erythroid-derived 2) related factor-2 (Nrf2), heme oxygenase-1 (HO-1), and carnitine palmitoyltransferase 1 (CPT1) with greater expression of NF-kappaB in both the heart and the liver and less expression of caspase-3 in the liver than in C rats. HQ rats had higher expression of Nrf2, HO-1, and CPT1 and lower expression of NF kappaB than H rats in both the heart and the liver. HQ rats had less abdominal fat and lower systolic blood pressure along with attenuation of changes in structure and function of the heart and the liver compared with H rats, although body weight and dyslipidemia did not differ between the H and HQ rats. Thus, quercetin treatment attenuated most of the symptoms of metabolic syndrome, including abdominal obesity, cardiovascular remodeling, and NAFLD, with the most likely mechanisms being decreases in oxidative stress and inflammation. PMID- 22535756 TI - 100 years of vitamins: adequate intake in the elderly is still a matter of concern. AB - Demographic changes lead to an ever greater number of elderly people and mounting evidence suggests an association between vitamin status and the development of noncommunicable diseases. However, even in affluent Western countries, data from dietary intake surveys indicate that vitamin inadequacy is widespread even in healthy elderly. Changes inherent to the aging process lead to the need for increased nutrient density, which is difficult to achieve from diet alone. Where this is not sufficient to close the gap between actual vitamin intakes and recommendations, fortified foods and dietary supplements specifically targeted at the growing segment of healthy elderly can be a pragmatic solution. PMID- 22535757 TI - A summary index of feeding practices is positively associated with height-for age, but only marginally with linear growth, in rural Senegalese infants and toddlers. AB - Several studies have shown an association between an infant and young child feeding index (ICFI) and height-for-age Z-score (HAZ) in Latin America and Africa. A previous study was unable to reproduce these findings in 500 rural Senegalese 12-42-mo-old children. The relationship of ICFI, dietary diversity index (DDI), food variety index (FVI), meal frequency index (MFI), and breastfeeding (BF) to HAZ and growth in height/length over 6 mo was studied in 1060 6-36-mo-old Senegalese children during 2 visits. List-based food frequencies were recalled for the past 24 h, and height/length and weight measurements were taken. Indicators were transformed into tertiles in age-specific subgroups. DDI, FVI, MFI, and ICFI were poorly concordant across visits at all ages (weighted kappa: 0.02-0.25). In cross-sectional analyses that pooled children from the 2 visits, HAZ was positively associated with DDI and FVI at 6-12, 12-18, and 18-24 mo and with ICFI at 6-12 and 18-24 mo (P < 0.001 and P < 0.05, respectively) but was negatively associated with BF at 12-18, 18-24, and 24-30 mo. The length increment between visits was positively associated with MFI and ICFI, measured during the first visit in 18-24-mo-olds (P < 0.001 and P < 0.05, respectively) but not with DDI, FVI, or BF at any age. In conclusion, ICFI, DDI, and FVI were associated with HAZ, particularly during infancy, whereas no indicator was associated with linear growth in this age group. Therefore, the strong association between HAZ and ICFI during infancy may be partly due to maternal adaptation to infant clues, i.e., greater appetite for and interest in non-breast milk foods among taller infants. PMID- 22535758 TI - Phytosterols reduce cholesterol absorption by inhibition of 27-hydroxycholesterol generation, liver X receptor alpha activation, and expression of the basolateral sterol exporter ATP-binding cassette A1 in Caco-2 enterocytes. AB - Phytosterol-enriched foods are increasingly marketed to lower cholesterol levels and atherosclerosis in the general population. Phytosterols reduce cholesterol absorption, but the molecular mechanism is controversial. We therefore investigated the phytosterol effects on cholesterol metabolism in human enterocyte, hepatocyte, and macrophage models relevant for sterol absorption, reverse transport, and excretion. Isomolar sitosterol (50 MUmol/L) was less effectively taken up by enterocytes than cholesterol but suppressed apical cholesterol uptake by 50% (P < 0.01) and basolateral secretion by two-thirds (P < 0.01) whether added in micelles or ethanol or complexed to cyclodextrin. In contrast, enterocytes handled nanomolar (3)H-sitosterol similarly to cholesterol. Enterocytes selectively oxidized all sterols to 27-hydroxy- and 27-carboxy sterols. Conversion rates were much lower for sitosterol (0.05 +/- 0.02 nmol/mg protein) and campesterol (0.48 +/- 0.10) compared with cholesterol (3.73 +/- 0.60) (P < 0.001). 27-Hydroxycholesterol (27OH-C) activated liver-X-receptor alpha (LXRalpha) (P < 0.01) and stimulated ATP-binding cassette transporter (ABC) A1 expression (P < 0.001) and basolateral systemic cholesterol secretion from enterocytes (P < 0.05). In co-incubations, phytosterols inhibited 27OH-C generation by sterol 27-hydroxylase (P < 0.001) and reduced LXRalpha-mediated ABCA1 expression (P < 0.01) and basolateral systemic cholesterol secretion. In contrast, ABCG8 transcription and apical sterol resecretion was unchanged by LXRalpha activation in human enterocytes. Exogenous LXRalpha agonists reverted sterol selectivity and phytosterol cholesterol interaction. Due to constitutive apical expression of ABCG5/G8 and LXRalpha-enhanced basolateral expression of ABCA1 in enterocytes, interference of phytosterols with the generation of the dominating LXRalpha-agonist 27OH-C blocks the self-priming component of cholesterol absorption. This local LXRalpha antagonism of dietary phytosterols contributes to sterol selectivity and reduces fractional cholesterol absorption and preloading of nascent HDL with dietary cholesterol. PMID- 22535759 TI - Maternal nutritional status in early pregnancy is associated with body water and plasma volume changes in a pregnancy cohort in rural Bangladesh. AB - Plasma volume expansion has been associated with fetal growth. Our objective was to examine the associations between maternal nutritional status in early pregnancy and extracellular water (ECW), total body water (TBW), and percentage plasma volume change across pregnancy. In a subsample of 377 pregnant women participating in a cluster-randomized trial of micronutrient supplementation, hemoglobin, hematocrit, and multi-frequency bioelectrical impedance were measured at ~10, 20, and 32 wk of gestation. In early pregnancy, women were short (mean +/ SD, 148.9 +/- 5.3 cm) and thin (19.5 +/- 2.5 kg/m(2)). In mixed-effects multiple regression models, a 1-unit higher BMI at ~10 wk was associated with higher ECW and TBW (0.27 and 0.66 kg per kg/m(2), respectively; P < 0.01) at ~10, ~20, and ~32 wk. Height was also positively associated with ECW and TBW at each time point. Early pregnancy BMI was negatively associated with gains in ECW and TBW ( 0.06 and -0.14 kg per kg/m(2), respectively; P < 0.01) from 10 to 20 wk, but not with 20- to 32-wk gains after accounting for weight gain. BMI was positively associated with percentage changes in plasma volume from 20 to 32 wk (0.57% per kg/m(2); P < 0.05). Height was not associated with changes in body water or plasma volume. Women with low BMI and height in early pregnancy have lower ECW and TBW in early, mid, and late pregnancy and lower late pregnancy plasma volume expansion, potentially increasing risk of fetal growth restriction. PMID- 22535760 TI - Fish or long-chain (n-3) PUFA intake is not associated with pancreatic cancer risk in a meta-analysis and systematic review. AB - Long-chain (n-3) PUFA (LC-PUFA) have been hypothesized to be beneficial in preventing pancreatic carcinogenesis, but the associations of fish or LC-PUFA intake with pancreatic cancer found in epidemiologic studies have been controversial and inconclusive. To estimate the overall association of LC-PUFA or fish intake with pancreatic cancer, we performed a systematic literature search of English-language articles using PubMed and EMBASE through February 2012 and reviewed the reference lists from retrieved articles. Prospective cohort or case control studies that reported ratio estimates and corresponding 95% CI for the associations of fish or LC-PUFA intake and pancreatic cancer were selected. Independent data extraction was performed by 2 of the authors. The pooled associations were obtained by using a random-effects model. A database was derived from 9 independent cohorts that included 1,209,265 participants (3082 events) with a mean follow-up of 9 y and 10 independent case-control studies that included 2514 cases and 18,779 controls. Compared with those having the lowest fish consumption, the pooled RR of pancreatic cancer was 0.98 (95% CI: 0.86, 1.12) for those who had the highest fish intake from 8 cohort studies and was 0.96 (95% CI: 0.76, 1.21) from 9 case-control studies. We found similar results for LC-PUFA intake by combining data from 4 cohorts or 2 case-control studies. Our results do not support an overall inverse association of fish or LC-PUFA intake with risk of pancreatic cancer. Further studies that consider different species and preparation methods of fish, and additional adjustment for contaminants in fish, are warranted. PMID- 22535761 TI - Meat intake is not associated with risk of non-Hodgkin lymphoma in a large prospective cohort of U.S. men and women. AB - Meat intake has been inconsistently associated with risk of non-Hodgkin lymphoma (NHL), a heterogeneous group of malignancies of the lymphoid tissue etiologically linked to immunomodulatory factors. In a large U.S. cohort, we prospectively investigated several biologically plausible mechanisms related to meat intake, including meat-cooking and meat-processing compounds, in relation to NHL risk by histologic subtype. At baseline (1995-1996), participants of the NIH-AARP Diet and Health Study completed a diet and lifestyle questionnaire (n = 492,186), and a subcohort (n = 302,162) also completed a questionnaire on meat-cooking methods and doneness levels. Over a mean of 9 y of follow-up, we identified 3611 incident cases of NHL. In multivariable Cox proportional hazards regression models, we found no association between intake of red meat, processed meat, fish, poultry, heme iron, nitrite, nitrate, animal fat, or protein and NHL risk. MeIQx (2-amino 3,8-dimethylimidazo[4,5-f]quinoxaline) and DiMeIQx (2-amino-3,4,8 trimethylimidazo[4,5-f]quinoxaline), heterocyclic amines formed in meats cooked to well done at high temperatures, were inversely associated with chronic lymphocytic leukemia/small lymphocytic lymphoma [n = 979; HR (95% CI) for the highest vs. lowest quintile of intake: 0.73 (0.55, 0.96) and 0.77 (0.61, 0.98), respectively]. In this large U.S. cohort, meat intake was not associated with NHL or any histologic subtypes of NHL. Contrary to findings in animal models and other cancer sites, meat-cooking and -processing compounds did not increase NHL risk. PMID- 22535762 TI - Supplementation with cyanidin-3-O-beta-glucoside protects against hypercholesterolemia-mediated endothelial dysfunction and attenuates atherosclerosis in apolipoprotein E-deficient mice. AB - In this study, we investigated the protective effects of the anthocyanin cyanidin 3-O-beta-glucoside (C3G) on hypercholesterolemia-induced endothelial dysfunction in apoE-deficient (apoE(-/-)) mice. In the prevention study, twenty 8-wk-old male apoE(-/-) mice (n = 10/group) were fed a high-fat, cholesterol-rich diet (HCD) or the HCD supplemented with C3G (2 g/kg diet) for 8 wk. The endothelium-dependent relaxation response to acetylcholine in the aortas of the C3G-fed mice was greater compared with those fed the HCD (P < 0.05). The atherosclerotic plaque area in the aortic sinus of mice fed the C3G diet was lowered by 54% compared with those fed the HCD (P < 0.01). Mice fed C3G had greater expression of the ATP binding cassette transporter G1 (ABCG1) and lower cholesterol, mainly 7 ketocholesterol (7-KC), concentrations than those fed the HCD. Superoxide production and lipid hydroperoxides in aorta were lower in mice fed C3G compared with those fed the HCD. The phosphorylation levels at Ser1177 of endothelial NO synthase (eNOS) and the production of cyclic GMP (cGMP) in aorta were greater in C3G-fed mice than in HCD-fed mice. In the therapy study, apoE(-/-) mice were fed the HCD for 8 wk and then continued to receive the HCD or were switched to the HCD supplemented with C3G (2 g/kg diet) for another 8 wk. The established endothelial dysfunction and atherosclerosis were reversed, accompanied by greater ABCG1 expression in aorta, lower cholesterol and 7-KC concentrations, and greater generation of cGMP in mice fed C3G compared with those fed the HCD. Taken together, our results show that the anthocyanin C3G prevents or reverses hypercholesterolemia-induced endothelial dysfunction by inhibiting cholesterol and 7-oxysterol accumulation in the aorta and the subsequent decrease in superoxide production, thereby preserving eNOS activity and NO bioavailability. PMID- 22535763 TI - Proline supplementation to parenteral nutrition results in greater rates of protein synthesis in the muscle, skin, and small intestine in neonatal Yucatan miniature piglets. AB - Proline and arginine are each indispensable during parenteral feeding due to limited interconversion by an atrophied gut. Commercial amino acid parenteral products designed for neonates contain proline concentrations that differ by almost 4-fold. To assess the adequacy of the lowest concentration of proline provided in commercial total parenteral nutrition (TPN) products, we compared rates of tissue-specific protein synthesis and nitrogen balance in neonatal piglets provided TPN at 2 different proline concentrations. Yucatan miniature piglets (9-11 d old, n = 12) were randomized to complete isonitrogenous TPN diets with low proline (LP; L-proline as 3% of amino acids) or proline supplemented (PS; 9%). After 7 d of receiving TPN, rates of protein synthesis in liver, gastrocnemius muscle, jejunal mucosa, and skin were determined by the flooding dose technique and tissue free amino acids were measured. Nitrogen balance was assessed during the last 3 d. The LP TPN resulted in lower free proline concentrations in plasma, muscle, and skin (P < 0.05) and lower rates of protein synthesis in the jejunum (by 25%; P = 0.02), muscle (by 45%; P = 0.015), and skin (by 60%; P = 0.01); there was no difference in liver. Nitrogen retention was 20% lower in the LP group (P = 0.01). In conclusion, muscle and skin protein synthesis was profoundly sensitive to parenteral proline supply and the reduced protein synthesis in the intestine could affect intestinal integrity. Low-proline TPN solutions that are currently in wide use in neonatal care may result in impaired tissue growth. PMID- 22535764 TI - Pneumococcal carriage at age 2 months is associated with growth deficits at age 6 months among infants in South India. AB - Nasopharyngeal colonization is the first step in the pathway to Streptococcus pneumoniae (Spn) infection, a leading cause of childhood morbidity and mortality. We investigated the effect of Spn colonization at ages 2 and 4 mo on growth at age 6 mo among 389 infants living in rural South India by using data from an Spn carriage study nested within a randomized, double-blind, placebo-controlled community trial designed to evaluate the impact of newborn vitamin A supplementation on Spn carriage in the first 6 mo of life. Primary outcomes were weight, length, and anthropometric indices of nutritional status. Growth data at age 6 mo were available for 84% (389 of 464) of infants in the Spn carriage study. Carriage at age 2 mo was associated with increased odds of stunting [OR: 3.07 (95% CI: 1.29, 7.36) P = 0.012] and lower weight [beta: -266 g (95% CI: 527, -5) P = 0.045], length [beta: -1.31 cm (95% CI: -2.32, -0.31) P = 0.010], and length-for-age Z scores [beta: -0.59; (95% CI: -1.05, -0.13) P = 0.012] at age 6 mo. Spn carriage at age 4 mo did not affect growth. Carriage of invasive serotypes at age 2 mo was associated with decreases in mean weight [beta: -289 g; (95% CI: -491, -106) P = 0.002] and length [beta:-0.38 cm (95% CI: -1.49, -0.01) P = 0.047] at age 6 mo. Newborn vitamin A supplementation did not modify the association between Spn carriage and growth. Results suggest that pneumococcal carriage at age 2 mo is an independent risk factor for poor growth in young infants. Future studies need to clarify the role of Spn carriage on growth retardation in low-income countries. PMID- 22535765 TI - 17beta-Estradiol inhibits iron hormone hepcidin through an estrogen responsive element half-site. AB - Interaction of estrogen with iron at the systemic level is long suspected, but direct evidence linking the two is limited. In the present study, we examined the effects of 17beta-estradiol (E2) on hepcidin, a key negative regulator of iron absorption from the liver. We found that transcription of hepcidin was suppressed by E2 treatment in human liver HuH7 and HepG2 cells, and this down-regulation was blocked by E2 antagonist ICI 182780. Chromatin immunoprecipitation, deletion, and EMSA detected a functional estrogen responsive element half-site that is located between -2474 and -2462 upstream from the start of transcription of the hepcidin gene. After cloning the human hepcidin promoter into the pGL3Luc-Reporter vector, luciferase activity was also down-regulated by E2 treatment in HepG2 cells. E2 reduced hepcidin mRNA in wild-type mice as well as in hemochromatosis Fe gene knockout mice. In summary, our data suggest that hepcidin inhibition by E2 is to increase iron uptake, a mechanism to compensate iron loss during menstruation. This mechanism may also contribute to increased iron stores in oral contraceptive users. PMID- 22535766 TI - Ghrelin prevents incidence of malignant arrhythmia after acute myocardial infarction through vagal afferent nerves. AB - Ghrelin is a GH-releasing peptide mainly excreted from the stomach. Ghrelin administration has been shown to inhibit cardiac sympathetic nerve activity (CSNA), reduce malignant arrhythmia, and improve prognosis after acute myocardial infarction (MI). We therefore investigated the effects and potential mechanisms of the action of endogenous ghrelin on survival rate and CSNA after MI by using ghrelin-knockout (KO) mice. MI was induced by left coronary artery ligation in 46 KO mice and 41 wild-type mice. On the first day, malignant arrhythmia-induced mortality was observed within 30 min of the ligation and had an incidence of 2.4% in wild-type and 17.4% in KO mice (P < 0.05). We next evaluated CSNA by spectral analysis of heart rate variability. CSNA, represented by the low frequency/high frequency ratio, was higher in KO mice at baseline (2.18 +/- 0.43 vs. 0.98 +/- 0.09; P < 0.05), and especially after MI (25.5 +/- 11.8 vs. 1.4 +/- 0.3; P < 0.05), than in wild-type mice. Ghrelin (150 MUg/kg, s.c.) 15 min before ligation suppressed the activation of CSNA and reduced mortality in KO mice. Further, this effect of ghrelin was inhibited by methylatropine bromide (1 mg/kg, i.p.) or by perineural treatment of both cervical vagal trunks with capsaicin (a specific afferent neurotoxin). Our data demonstrated that both exogenous and endogenous ghrelin suppressed CSNA, prevented the incidence of malignant arrhythmia, and improved the prognosis after acute MI. These effects are likely to be via the vagal afferent nerves. PMID- 22535767 TI - PTTG-binding factor (PBF) is a novel regulator of the thyroid hormone transporter MCT8. AB - Within the basolateral membrane of thyroid follicular epithelial cells, two transporter proteins are central to thyroid hormone (TH) biosynthesis and secretion. The sodium iodide symporter (NIS) delivers iodide from the bloodstream into the thyroid, and after TH biosynthesis, monocarboxylate transporter 8 (MCT8) mediates TH secretion from the thyroid gland. Pituitary tumor-transforming gene binding factor (PBF; PTTG1IP) is a protooncogene that is up-regulated in thyroid cancer and that binds NIS and modulates its subcellular localization and function. We now show that PBF binds MCT8 in vitro, eliciting a marked shift in MCT8 subcellular localization and resulting in a significant reduction in the amount of MCT8 at the plasma membrane as determined by cell surface biotinylation assays. Colocalization and interaction between PBF and Mct8 was also observed in vivo in a mouse model of thyroid-specific PBF overexpression driven by a bovine thyroglobulin (Tg) promoter (PBF-Tg). Thyroidal Mct8 mRNA and protein expression levels were similar to wild-type mice. Critically, however, PBF-Tg mice demonstrated significantly enhanced thyroidal TH accumulation and reduced TH secretion upon TSH stimulation. Importantly, Mct8-knockout mice share this phenotype. These data show that PBF binds and alters the subcellular localization of MCT8 in vitro, with PBF overexpression leading to an accumulation of TH within the thyroid in vivo. Overall, these studies identify PBF as the first protein to interact with the critical TH transporter MCT8 and modulate its function in vivo. Furthermore, alongside NIS repression, PBF may thus represent a new regulator of TH biosynthesis and secretion. PMID- 22535768 TI - Notch1 is regulated by chorionic gonadotropin and progesterone in endometrial stromal cells and modulates decidualization in primates. AB - No other tissue in the body undergoes such a vast and extensive growth and remodeling in a relatively short period of time as the primate endometrium. Endometrial integrity is coordinated by ovarian hormones, namely, estrogens, progesterone, and the embryonic hormone chorionic gonadotropin (CG). These regulated events modulate the menstrual cycle and decidualization. The Notch family of transmembrane receptors regulate cellular proliferation, differentiation, and apoptosis, cellular processes required to maintain endometrial integrity. In two primate models, the human and the simulated pregnant baboon model, we demonstrated that Notch1 is increased during the window of uterine receptivity, concomitant with CG. Furthermore, CG combined with estrogens and progesterone up-regulate the level of Notch1, whereas progesterone increases the intracellular transcriptionally competent Notch1, which binds in a complex with progesterone receptor. Inhibition of Notch1 prevented decidualization, and alternatively, when decidualization is biochemically recapitulated in vitro, Notch1 is down-regulated. A focused microarray demonstrated that the Notch inhibitor, Numb, dramatically increased when Notch1 decreased during decidualization. We propose that in the endometrium, Notch has a dual role during the window of uterine receptivity. Initially, Notch1 mediates a survival signal in the uterine endometrium in response to CG from the implanting blastocyst and progesterone, so that menstrual sloughing is averted. Subsequently, Notch1 down-regulation may be critical for the transition of stromal fibroblast to decidual cells, which is essential for the establishment of a successful pregnancy. PMID- 22535769 TI - Ablation of vimentin results in defective steroidogenesis. AB - In steroidogenic tissues, cholesterol must be transported to the inner mitochondrial membrane to be converted to pregnenolone as the first step of steroidogenesis. Whereas steroidogenic acute regulatory protein has been shown to be responsible for the transport of cholesterol from the outer to the inner mitochondrial membrane, the process of how cholesterol moves to mitochondria from the cytoplasm is not clearly defined. The involvement of the cytoskeleton has been suggested; however, no specific mechanism has been confirmed. In this paper, using genetic ablation of an intermediate filament protein in mice, we present data demonstrating a marked defect in adrenal and ovarian steroidogenesis in the absence of vimentin. Cosyntropin-stimulated corticosterone production is decreased 35 and 50% in male and female Vimentin null (Vim(-/-)) mice, respectively, whereas progesterone production is decreased 70% in female Vim(-/-) mice after pregnant mare's serum gonadotropin and human chorionic gonadotropin stimulation, but no abnormalities in human chorionic gonadotropin-stimulated testosterone production is observed in male Vim(-/-) mice. These defects in steroid production are also seen in isolated adrenal and granulosa cells in vitro. Further studies show a defect in the movement of cholesterol from the cytosol to mitochondria in Vim(-/-) cells. Because the mobilization of cholesterol from lipid droplets and its transport to mitochondria is a preferred pathway for the initiation of steroid production in the adrenal and ovary but not the testis and vimentin is a droplet-associated protein, our results suggest that vimentin is involved in the movement of cholesterol from its storage in lipid droplets to mitochondria for steroidogenesis. PMID- 22535771 TI - In reply to the letter to the editor titled 'Is carpal tunnel syndrome overdiagnosed?'. PMID- 22535770 TI - Intestinotrophic glucagon-like peptide-2 (GLP-2) activates intestinal gene expression and growth factor-dependent pathways independent of the vasoactive intestinal peptide gene in mice. AB - The enteroendocrine and enteric nervous systems convey signals through an overlapping network of regulatory peptides that act either as circulating hormones or as localized neurotransmitters within the gastrointestinal tract. Because recent studies invoke an important role for vasoactive intestinal peptide (VIP) as a downstream mediator of glucagon-like peptide-2 (GLP-2) action in the gut, we examined the importance of the VIP-GLP-2 interaction through analysis of Vip(-/-) mice. Unexpectedly, we detected abnormal villous architecture, expansion of the crypt compartment, increased crypt cell proliferation, enhanced Igf1 and Kgf gene expression, and reduced expression of Paneth cell products in the Vip(-/ ) small bowel. These abnormalities were not reproduced by antagonizing VIP action in wild-type mice, and VIP administration did not reverse the intestinal phenotype of Vip(-/-) mice. Exogenous administration of GLP-2 induced the expression of ErbB ligands and immediate-early genes to similar levels in Vip(+/+) vs. Vip(-/-) mice. Moreover, GLP-2 significantly increased crypt cell proliferation and small bowel growth to comparable levels in Vip(+/+) vs. Vip(-/ ) mice. Unexpectedly, exogenous GLP-2 administration had no therapeutic effect in mice with dextran sulfate-induced colitis; the severity of colonic injury and weight loss was modestly reduced in female but not male Vip(-/-) mice. Taken together, these findings extend our understanding of the complex intestinal phenotype arising from loss of the Vip gene. Furthermore, although VIP action may be important for the antiinflammatory actions of GLP-2, the Vip gene is not required for induction of a gene expression program linked to small bowel growth after enhancement of GLP-2 receptor signaling. PMID- 22535772 TI - Argon-plasma-induced ultrathin thermal grafting of thermoresponsive pNIPAm coating for contractile patterned human SMC sheet engineering. AB - A new method for ultrathin grafting of pNIPAm on PDMS surfaces is introduced that employs plasma activation of the surface followed by thermal polymerization. This method is optimized for human primary SMC attachment and subsequent intact cell sheet detachment by lowering the temperature. The contractile gene expression of the cells showed that the contractile phenotype of the SMCs which is induced by aligning the cells through micropatterning is more preserved after thermoresponsive cell sheet detachment in contrast with enzymatic detachment. Given its simplicity and low cost, this thermoresponsive grafting method can be utilized for engineering patterned cell sheets for future bottom-up tissue engineering techniques. PMID- 22535773 TI - Membrane targeting of an alpha-like tetravirus replicase is directed by a region within the RNA-dependent RNA polymerase domain. AB - The members of the family Tetraviridae are small positive-sense insect RNA viruses that exhibit stringent host specificity and a high degree of tissue tropism, suggesting that complex virus-host interactions are likely to occur during infection and viral replication. The alpha-like replicase of Helicoverpa armigera stunt virus (HaSV) (genus Omegatetravirus) has been proposed to associate with membranes of the endocytic pathway, which is similar to Semliki Forest virus, Sindbis virus and rubella virus. Here, we have used replicase-EGFP fusion proteins and recombinant baculovirus expression to demonstrate that the HaSV replicase associates strongly with cellular membranes, including detergent resistant membranes, and that this association is maintained through a novel membrane targeting domain within the C-terminal region of the RNA-dependent RNA polymerase domain. We show a similar subcellular localization and strong association with detergent-resistant membranes for the carmo-like replicase of another tetravirus, Providence virus, in replicating cells, suggesting a common site of replication for these two tetraviruses. PMID- 22535774 TI - Use of influenza A viruses expressing reporter genes to assess the frequency of double infections in vitro. AB - Exchange of gene segments between mammalian and avian influenza A viruses may lead to the emergence of potential pandemic influenza viruses. Since co-infection of single cells with two viruses is a prerequisite for reassortment to take place, we assessed frequencies of double-infection in vitro using influenza A/H5N1 and A/H1N1 viruses expressing the reporter genes eGFP or mCherry. Double infected A549 and Madin-Darby canine kidney cells were detected by confocal microscopy and flow cytometry. PMID- 22535775 TI - Detection of host immune responses in acute phase sera of spontaneous resolution versus persistent hepatitis C virus infection. AB - Prior to the identification of hepatitis C virus (HCV), transfusion-transmission was common. Viral transmission in subjects with a known date of infection allows the study of the immune responses to acute HCV infection. We analysed 39 soluble immune factors in serum samples from subjects with transfusion-transmitted HCV. Dynamic expression kinetics of interferon gamma-induced protein 10 (IP-10), tumour necrosis factor-alpha and interleukin (IL)-10 were observed during acute HCV infection. Serum IP-10 was the only analyte that was significantly elevated in HCV resolvers compared with uninfected controls. In individuals who progressed to chronic HCV elevated levels of IP-10 and IL-10 coincided with first significant alanine aminotransferase elevation and remained elevated during the first year of acute HCV infection. In addition to monitoring lack of reduction in viral load, serum levels of IP-10 and IL-10 expression during acute HCV infection may be useful biomarkers to predict the progress to chronic HCV. PMID- 22535776 TI - Cross-species infection of pigs with a novel rabbit, but not rat, strain of hepatitis E virus isolated in the United States. AB - Hepatitis E virus (HEV) is an important human pathogen. In addition to humans, HEV has also been identified in pig, chicken, mongoose, deer, rat, rabbit and fish. There are four recognized and two putative genotypes of mammalian HEV. Genotypes 1 and 2 are restricted to humans, while genotypes 3 and 4 are zoonotic. The recently identified rabbit HEV is a distant member of genotype 3. Here, we first expressed and purified the recombinant capsid protein of rabbit HEV and showed that the capsid protein of rabbit HEV cross-reacted with antibodies raised against avian, rat, swine and human HEV. Conversely, we showed that antibodies against rabbit HEV cross-reacted with capsid proteins derived from chicken, rat, swine and human HEV. Since pigs are the natural host of genotype 3 HEV, we then determined if rabbit HEV infects pigs. Twenty pigs were divided into five groups of four each and intravenously inoculated with PBS, US rabbit HEV, Chinese rabbit HEV, US rat HEV and swine HEV, respectively. Results showed that only half of the pigs inoculated with rabbit HEV had low levels of viraemia and faecal virus shedding, indicative of active but not robust HEV infection. Infection of pigs by rabbit HEV was further verified by transmission of the virus recovered from pig faeces to naive rabbits. Pigs inoculated with rat HEV showed no evidence of infection. Preliminary results suggest that rabbit HEV is antigenically related to other HEV strains and infects pigs and that rat HEV failed to infect pigs. PMID- 22535778 TI - Anthropogenic noise's first reverberation into community ecology. PMID- 22535777 TI - Non-canonical translation in RNA viruses. AB - Viral protein synthesis is completely dependent upon the translational machinery of the host cell. However, many RNA virus transcripts have marked structural differences from cellular mRNAs that preclude canonical translation initiation, such as the absence of a 5' cap structure or the presence of highly structured 5'UTRs containing replication and/or packaging signals. Furthermore, whilst the great majority of cellular mRNAs are apparently monocistronic, RNA viruses must often express multiple proteins from their mRNAs. In addition, RNA viruses have very compact genomes and are under intense selective pressure to optimize usage of the available sequence space. Together, these features have driven the evolution of a plethora of non-canonical translational mechanisms in RNA viruses that help them to meet these challenges. Here, we review the mechanisms utilized by RNA viruses of eukaryotes, focusing on internal ribosome entry, leaky scanning, non-AUG initiation, ribosome shunting, reinitiation, ribosomal frameshifting and stop-codon readthrough. The review will highlight recently discovered examples of unusual translational strategies, besides revisiting some classical cases. PMID- 22535779 TI - Determinants of reproductive success across sequential episodes of sexual selection in a firefly. AB - Because females often mate with multiple males, it is critical to expand our view of sexual selection to encompass pre-, peri- and post-copulatory episodes to understand how selection drives trait evolution. In Photinus fireflies, females preferentially respond to males based on their bioluminescent courtship signals, but previous work has shown that male paternity success is negatively correlated with flash attractiveness. Here, we experimentally manipulated both the attractiveness of the courtship signal visible to female Photinus greeni fireflies before mating and male nuptial gift size to determine how these traits might each influence mate acceptance and paternity share. We also measured pericopulatory behaviours to examine their influence on male reproductive success. Firefly males with larger spermatophores experienced dual benefits in terms of both higher mate acceptance and increased paternity share. We found no effect of courtship signal attractiveness or pericopulatory behaviour on male reproductive success. Taken together with previous results, this suggests a possible trade-off for males between producing an attractive courtship signal and investing in nuptial gifts. By integrating multiple episodes of sexual selection, this study extends our understanding of sexual selection in Photinus fireflies and provides insight into the evolution of male traits in other polyandrous species. PMID- 22535780 TI - What conservationists need to know about farming. AB - Farming is the basis of our civilization yet is more damaging to wild nature than any other sector of human activity. Here, we propose that in order to limit its impact into the future, conservation researchers and practitioners need to address several big topics--about the scale of future demand, about which crops and livestock to study, about whether low-yield or high-yield farming has the potential to be least harmful to nature, about the environmental performance of new and existing farming methods, and about the measures needed to enable promising approaches and techniques to deliver on their potential. Tackling these issues requires conservationists to explore the many consequences that decisions about agriculture have beyond the farm, to think broadly and imaginatively about the scale and scope of what is required to halt biodiversity loss, and to be brave enough to test and when necessary support counterintuitive measures. PMID- 22535781 TI - Dermal bone in early tetrapods: a palaeophysiological hypothesis of adaptation for terrestrial acidosis. AB - The dermal bone sculpture of early, basal tetrapods of the Permo-Carboniferous is unlike the bone surface of any living vertebrate, and its function has long been obscure. Drawing from physiological studies of extant tetrapods, where dermal bone or other calcified tissues aid in regulating acid-base balance relating to hypercapnia (excess blood carbon dioxide) and/or lactate acidosis, we propose a similar function for these sculptured dermal bones in early tetrapods. Unlike the condition in modern reptiles, which experience hypercapnia when submerged in water, these animals would have experienced hypercapnia on land, owing to likely inefficient means of eliminating carbon dioxide. The different patterns of dermal bone sculpture in these tetrapods largely correlates with levels of terrestriality: sculpture is reduced or lost in stem amniotes that likely had the more efficient lung ventilation mode of costal aspiration, and in small-sized stem amphibians that would have been able to use the skin for gas exchange. PMID- 22535782 TI - Relationship between maternal transfer of immunity and mother fecundity in an insect. AB - Trans-generational immune priming (TGIP) corresponds to the plastic adjustment of offspring immunity as a result of maternal immune experience. TGIP is expected to improve mother's fitness by improving offspring individual performance in an environment where parasitism becomes more prevalent. However, it was recently demonstrated that maternal transfer of immunity to the offspring is costly for immune-challenged female insects. Thus, these females might not provide immune protection to all their offspring because of the inherent cost of other fitness related traits. Females are therefore expected to adjust their investment to individual offspring immune protection in ways that maximize their fitness. In this study, we investigated how bacterially immune-challenged females of the mealworm beetle, Tenebrio molitor, provision their eggs with immune protection according to egg production. We found that immune-challenged females provide a variable number of their eggs with internal antibacterial activity along egg laying bouts. Furthermore, within the first immune-protected egg-laying bout (2-4 days after the maternal immune challenge), the number of eggs protected was strongly dependent on the number of eggs produced. Immune-challenged females might therefore adjust their investment into TGIP and fecundity according of their individual perception of the risk of dying from the infection and the expected parasitic conditions for the offspring. PMID- 22535783 TI - Male reproductive fitness and queen polyandry are linked to variation in the supergene Gp-9 in the fire ant Solenopsis invicta. AB - Supergenes are clusters of tightly linked loci maintained in specific allelic combinations to facilitate co-segregation of genes governing adaptive phenotypes. In species where strong selection potentially operates at different levels (e.g. eusocial Hymenoptera), positive selection acting within a population to maintain specific allelic combinations in supergenes may have unexpected consequences for some individuals, including the preservation of disadvantageous traits. The nuclear gene Gp-9 in the invasive fire ant Solenopsis invicta is part of a non recombining, polymorphic supergene region associated with polymorphism in social organization as well as traits affecting physiology, fecundity and behaviour. We show that both male reproductive success and facultative polyandry in queens have a simple genetic basis and are dependent on male Gp-9 genotype. Gp-9(b) males are unable to maintain exclusive reproductive control over their mates such that queens mated to Gp-9(b) males remain highly receptive to remating. Queens mated to multiple Gp-9(B) males are rare. This difference appears to be independent of mating plug production in fertile males of each Gp-9 genotype. However, Gp-9(b) males have significantly lower sperm counts than Gp-9(B) males, which could be a cue to females to seek additional mates. Despite the reduced fitness of Gp-9(b) males, polygyne worker-induced selective mortality of sexuals lacking b-like alleles coupled with the overall success of the polygyne social form act to maintain the Gp-9(b) allele within nature. Our findings highlight how strong worker-induced selection acting to maintain the Gp-9(b) allele in the polygyne social form may simultaneously result in reduced reproductive fitness for individual sexual offspring. PMID- 22535784 TI - Evidence of correlated evolution of hypsodonty and exceptional longevity in endemic insular mammals. AB - Here, we test whether the increase in tooth height in insular endemics results from the expansion of the dietary niche under resource limitation, as widely considered, or whether it represents an investment in dental durability in response to the selection for extended longevity under low levels of extrinsic mortality. We tested these hypotheses in the extremely hypsodont fossil bovid Myotragus balearicus from the Balearic Islands, an ideal model to study the evolutionary trends on islands. Dental abrasion was significantly lower in the insular bovid than in highly hypsodont continental artiodactyls, suggesting that feeding habits are not the sole driving force behind increased crown height. However, the estimated longevity for M. balearicus based on dental durability was two times that predicted from body mass. Survivorship curves confirm that an extraordinarily large number of individuals approached the longevity of the species. Our results, hence, provide evidence that hypsodonty in insular endemics is the outcome of selection for increased durability of the permanent dentition in association with an extended lifespan. In the context of insularity, our results lend additional support to the disposable soma theory of ageing confirming the dependency of somatic maintenance and repair on lifespan, and its control by resource availability and extrinsic mortality. PMID- 22535785 TI - Spatiotopic perceptual maps in humans: evidence from motion adaptation. AB - How our perceptual experience of the world remains stable and continuous despite the frequent repositioning eye movements remains very much a mystery. One possibility is that our brain actively constructs a spatiotopic representation of the world, which is anchored in external--or at least head-centred--coordinates. In this study, we show that the positional motion aftereffect (the change in apparent position after adaptation to motion) is spatially selective in external rather than retinal coordinates, whereas the classic motion aftereffect (the illusion of motion after prolonged inspection of a moving source) is selective in retinotopic coordinates. The results provide clear evidence for a spatiotopic map in humans: one which can be influenced by image motion. PMID- 22535786 TI - The mechanisms of the residual force enhancement after stretch of skeletal muscle: non-uniformity in half-sarcomeres and stiffness of titin. AB - When activated skeletal muscles are stretched, the force increases significantly. After the stretch, the force decreases and reaches a steady-state level that is higher than the force produced at the corresponding length during purely isometric contractions. This phenomenon, referred to as residual force enhancement, has been observed for more than 50 years, but the mechanism remains elusive, generating considerable debate in the literature. This paper reviews studies performed with single muscle fibres, myofibrils and sarcomeres to investigate the mechanisms of the stretch-induced force enhancement. First, the paper summarizes the characteristics of force enhancement and early hypotheses associated with non-uniformity of sarcomere length. Then, it reviews new evidence suggesting that force enhancement can also be associated with sarcomeric structures. Finally, this paper proposes that force enhancement is caused by: (i) half-sarcomere non-uniformities that will affect the levels of passive forces and overlap between myosin and actin filaments, and (ii) a Ca(2+)-induced stiffness of titin molecules. These mechanisms are compatible with most observations in the literature, and can be tested directly with emerging technologies in the near future. PMID- 22535787 TI - In vivo NIRF imaging of tumor targetability of nanosized liposomes in tumor bearing mice. AB - To optimize tumor targetability of nanosized liposomes for application as drug carriers, various liposomes are prepared by incorporating different amounts (10, 30, and 50 wt%) of cationic, anionic, and PEGylated lipids into neutral lipid. In vivo near-infrared fluorescence images reveal that PEG-PE/PC liposomes display high tumor accumulation in tumor-bearing mice, while large amounts of DOTAP/PC liposomes are rapidly captured in the liver, resulting in poor tumor accumulation. These results demonstrate that optimization of the surface properties of liposomes is very important for their tumor targetability, and that in vivo imaging techniques are useful in developing and optimizing nanosized liposome-based drug carriers. PMID- 22535788 TI - Social and geographical factors affecting access to treatment of colorectal cancer: a cancer registry study. AB - OBJECTIVE: Cancer outcomes vary between and within countries with patients from deprived backgrounds known to have inferior survival. The authors set out to explore the effect of deprivation in relation to the accessibility of hospitals offering diagnostic and therapeutic services on stage at presentation and receipt of treatment. DESIGN: Analysis of a Cancer Registry Database. Data included stage and treatment details from the first 6 months. The socioeconomic status of the immediate area of residence and the travel time from home to hospital was derived from the postcode. SETTING: Population-based study of patients resident in a large area in the north of England. PARTICIPANTS: 39 619 patients with colorectal cancer diagnosed between 1994 and 2002. OUTCOMES MEASURED: Stage of diagnosis and receipt of treatment in relation to deprivation and distance from hospital. RESULTS: Patients in the most deprived quartile were significantly more likely to be diagnosed at stage 4 for rectal cancer (OR 1.516, p<0.05) but less so for colonic cancer. There was a trend for both sites for patients in the most deprived quartile to be less likely to receive chemotherapy for stage 4 disease. Patients with colonic cancer were very significantly less likely to receive any treatment if they came from any but the most affluent area (ORs 0.639, 0.603 and 0.544 in increasingly deprived quartiles), this may have been exacerbated if the hospital was distant from their residence (OR for forth quartile for both travel and deprivation 0.731, not significant). The effect was less for rectal cancer and no effect of distance was seen. CONCLUSIONS: Residing in a deprived area is associated with tendencies to higher stage at diagnosis and especially in the case of colonic cancer to reduced receipt of treatment. These observations are consistent with other findings and indicate that access to diagnosis requires further investigation. PMID- 22535789 TI - An exploratory analysis of gamma-synuclein expression in endometrioid endometrial cancer. AB - OBJECTIVE: This study aims to investigate the expression of gamma-synuclein in endometrioid endometrial carcinoma and assess if the gamma-synuclein expression correlates with the aggression of the tumour and its prognostic value in endometrioid endometrial carcinoma. DESIGN: This retrospective study evaluated (60) specimens of the primary untreated endometrioid endometrial carcinoma and (12) normal endometrium tissues, and the expression of gamma-synuclein was checked by immunohistochemistry. The correlation between gamma-synuclein expression and the clinicopathological features of patients with endometrioid endometrial carcinoma was analysed, and SPSS V.13.0 software was used for statistical analysis. RESULTS: The expression of gamma-synuclein was positive in 48.3% (29/60) endometrioid endometrial carcinomas compared with the control group, and the difference was significant (p=0.001). The expression level of gamma-synuclein in endometrioid endometrial carcinoma was closely associated with FIGO (International Federation of Gynecology and Obstetrics) stages, the depth of myometrial invasion and lymph nodes metastases (p<0.05), but not correlated with the histopathological grades, the patient's age and the expression of ER (estrogen receptor) and PR (progesterone receptor) (p>0.05). In univariate and multivariate analyses, the gamma-synuclein expression was significantly associated with a shorter overall survival (95% CI 1.429 to 101.892, p=0.020). CONCLUSIONS: This study suggests that the expression of gamma-synuclein is expected to be a useful marker for endometrioid endometrial carcinoma invasion, metastasis and prognosis in endometrioid endometrial carcinoma. PMID- 22535790 TI - The FEeding Support Team (FEST) randomised, controlled feasibility trial of proactive and reactive telephone support for breastfeeding women living in disadvantaged areas. AB - OBJECTIVE: To assess the feasibility of implementing a dedicated feeding support team on a postnatal ward and pilot the potential effectiveness and cost effectiveness of team (proactive) and woman-initiated (reactive) telephone support after discharge. DESIGN: Randomised controlled trial embedded within a before-and-after study. Participatory approach and mixed-method process evaluation. SETTING: A postnatal ward in Scotland. SAMPLE: Women living in disadvantaged areas initiating breast feeding. METHODS: Eligible women were recruited to a before-and-after intervention study, a proportion of whom were independently randomised after hospital discharge to intervention: daily proactive and reactive telephone calls for <=14 days or control: reactive telephone calls <= day 14. Intention-to-treat analysis compared the randomised groups on cases with complete outcomes at follow-up. MAIN OUTCOME MEASURES: PRIMARY OUTCOME: any breast feeding at 6-8 weeks assessed by a telephone call from a researcher blind to group allocation. SECONDARY OUTCOMES: exclusive breast feeding, satisfaction with care, NHS costs and cost per additional woman breast feeding. RESULTS: There was no difference in feeding outcomes for women initiating breast feeding before the intervention (n=413) and after (n=388). 69 women were randomised to telephone support: 35 intervention (32 complete cases) and 34 control (26 complete cases). 22 intervention women compared with 12 control women were giving their baby some breast milk (RR 1.49, 95% CI 0.92 to 2.40) and 17 intervention women compared with eight control women were exclusively breast feeding (RR 1.73, 95% CI 0.88 to 3.37) at 6-8 weeks after birth. The incremental cost of providing proactive calls was L87 per additional woman breast feeding and L91 per additional woman exclusively breast feeding at 6 8 weeks; costs were sensitive to service organisation. CONCLUSIONS: Proactive telephone care delivered by a dedicated feeding team shows promise as a cost effective intervention for improving breastfeeding outcomes. Integrating the FEeding Support Team (FEST) intervention into routine postnatal care was feasible. TRIAL REGISTRATION NUMBER: ISRCTN27207603. The study protocol and final report are available on request. PMID- 22535791 TI - Inclusion criteria provide heterogeneity in baseline profiles of patients with mild cognitive impairment: comparison of two prospective cohort studies. AB - BACKGROUND: Mild cognitive impairment (MCI) is considered to represent a transitional stage between ageing and Alzheimer's disease (AD). To aim at identifying neuroimaging measures associated with cognitive changes in healthy elderly and MCI patients, longitudinal multicentre studies are ongoing in several countries. The patient profiles of each study are based on unique inclusion criteria. OBJECTIVES: The purpose of the study is to clarify differences in baseline profiles of MCI patients between Studies on Diagnosis of Early Alzheimer's Disease-Japan (SEAD-J) and Alzheimer's Disease Neuroimaging Initiative (ADNI) and to examine the association between baseline profiles and risk of early conversion to AD. DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: SEAD-J recruited 114 patients from nine facilities in Japan. A total of 200 patients in ADNI with fluorodeoxyglucose-positron emission tomography (FDG-PET) were enrolled from the USA. METHODS: Baseline profiles were statistically analysed. For FDG-PET at a time of inclusion, associations between each profile and cerebral metabolic rate for glucose (CMRgl) were examined using SPM5 software. In each study, the ratio of conversion to AD within the 1-year and 2-year period after inclusion was investigated and differences in baseline profiles between AD converters and non-converters were analysed. RESULTS: SEAD-J included MCI patients with more severe verbal memory deficits and extracted patients with higher depressive tendencies. These differences were likely to be associated with criteria. SEAD-J exhibited a higher rate of conversion within 1 year compared with ADNI (24.5% vs 13.5%). In FDG-PET analyses of SEAD-J, AD converters within 1 year showed more severe decrease of FDG uptake in bilateral inferior parietal regions compared with non-converters. CONCLUSIONS: Different inclusion criteria provided differences in baseline profiles. The severity of memory deficit might cause increase of the AD conversion within 1 year. Clinical outcomes of multicentre studies for early diagnosis of AD should be interpreted carefully considering profiles of patients. PMID- 22535792 TI - How does comorbidity influence healthcare costs? A population-based cross sectional study of depression, back pain and osteoarthritis. AB - OBJECTIVES: To analyse how comorbidity among patients with back pain, depression and osteoarthritis influences healthcare costs per patient. A special focus was made on the distribution of costs for primary healthcare compared with specialist care, hospital care and drugs. DESIGN: Population-based cross-sectional study. SETTING: The County of Ostergotland, Sweden. PATIENTS: Data on diagnoses and healthcare costs for all 266 354 individuals between 20 and 75 years of age, who were residents of the County of Ostergotland, Sweden, in the year 2006, were extracted from the local healthcare register and the national register of drug prescriptions. MAIN OUTCOME MEASURES: The effects of comorbidity on healthcare costs were estimated as interactions in regression models that also included age, sex, number of other health conditions and education. RESULTS: The largest diagnosed group was back pain (11 178 patients) followed by depression (7412 patients) and osteoarthritis (5174 patients). The largest comorbidity subgroup was the combination of back pain and depression (772 patients), followed by the combination of back pain and osteoarthritis (527 patients) and the combination of depression and osteoarthritis (206 patients). For patients having both a depression diagnosis and a back pain diagnosis, there was a significant negative interaction effect on total healthcare costs. The average healthcare costs among patients with depression and back pain was SEK 11 806 lower for a patient with both diagnoses. In this comorbidity group, there were tendencies of a positive interaction for general practitioner visits and negative interactions for all other visits and hospital days. Small or no interactions at all were seen between depression diagnoses and osteoarthritis diagnoses. CONCLUSIONS: A small increase in primary healthcare visits in comorbid back pain and depression patients was accompanied with a substantial reduction in total healthcare costs and in hospital costs. Our results can be of value in analysing the cost effects of comorbidity and how the coordination of primary and secondary care may have an impact on healthcare costs. PMID- 22535793 TI - Grey and white matter abnormalities in chronic obstructive pulmonary disease: a case-control study. AB - OBJECTIVES: The irreversible airflow limitation characterised by chronic obstructive pulmonary disease (COPD) causes a decrease in the oxygen supply to the brain. The aim of the present study was to investigate brain structural damage in COPD. DESIGN: Retrospective case-control study. Patients with COPD and healthy volunteers were recruited. The two groups were matched in age, gender and educational background. SETTING: A hospital and a number of communities: they are all located in southern Fujian province, China. PARTICIPANTS: 25 stable patients and 25 controls were enrolled from December 2009 to May 2011. METHODS: Using voxel-based morphometry and tract-based spatial statistics based on MRI to analyse grey matter (GM) density and white matter fractional anisotropy (FA), respectively, and a battery of neuropsychological tests were performed. RESULTS: Patients with COPD (vs controls) showed decreased GM density in the limbic and paralimbic structures, including right gyrus rectus, left precentral gyrus, bilateral anterior and middle cingulate gyri, bilateral superior temporal gyri, bilateral anterior insula extending to Rolandic operculum, bilateral thalamus/pulvinars and left caudate nucleus. Patients with COPD (vs controls) had decreased FA values in the bilateral superior corona radiata, bilateral superior and inferior longitudinal fasciculus, bilateral optic radiation, bilateral lingual gyri, left parahippocampal gyrus and fornix. Lower FA values in these regions were associated with increased radial diffusivity and no changes of longitudinal diffusivity. Patients with COPD had poor performances in the Mini Mental State Examination, figure memory and visual reproduction. GM density in some decreased regions in COPD had positive correlations with arterial blood Po(2), negative correlations with disease duration and also positive correlations with visual tasks. CONCLUSION: The authors demonstrated that COPD exhibited loss of regional GM accompanied by impairment of white matter microstructural integrity, which was associated with disease severity and may underlie the pathophysiological and psychological changes of COPD. PMID- 22535794 TI - Process evaluation for the FEeding Support Team (FEST) randomised controlled feasibility trial of proactive and reactive telephone support for breastfeeding women living in disadvantaged areas. AB - OBJECTIVE: To assess the feasibility, acceptability and fidelity of a feeding team intervention with an embedded randomised controlled trial of team-initiated (proactive) and woman-initiated (reactive) telephone support after hospital discharge. DESIGN: Participatory approach to the design and implementation of a pilot trial embedded within a before-and-after study, with mixed-method process evaluation. SETTING: A postnatal ward in Scotland. SAMPLE: Women initiating breast feeding and living in disadvantaged areas. METHODS: Quantitative data: telephone call log and workload diaries. Qualitative data: interviews with women (n=40) with follow-up (n=11) and staff (n=17); ward observations 2 weeks before and after the intervention; recorded telephone calls (n=16) and steering group meetings (n=9); trial case notes (n=69); open question in a telephone interview (n=372). The Framework approach to analysis was applied to mixed-method data. MAIN OUTCOME MEASURES: Quantitative: telephone call characteristics (number, frequency, duration); workload activity. Qualitative: experiences and perspectives of women and staff. RESULTS: A median of eight proactive calls per woman (n=35) with a median duration of 5 min occurred in the 14 days following hospital discharge. Only one of 34 control women initiated a call to the feeding team, with women undervaluing their own needs compared to others, and breast feeding as a reason to call. Proactive calls providing continuity of care increased women's confidence and were highly valued. Data demonstrated intervention fidelity for woman-centred care; however, observing an entire breast feed was not well implemented due to short hospital stays, ward routines and staff-team-woman communication issues. Staff pragmatically recognised that dedicated feeding teams help meet women's breastfeeding support needs in the context of overstretched and variable postnatal services. CONCLUSIONS: Implementing and integrating the FEeding Support Team (FEST) trial within routine postnatal care was feasible and acceptable to women and staff from a research and practice perspective and shows promise for addressing health inequalities. TRIAL REGISTRATION: ISRCTN27207603. The study protocol and final report is available on request. PMID- 22535795 TI - The PROTECT in-hospital risk model: 7-day outcome in patients hospitalized with acute heart failure and renal dysfunction. AB - AIMS: In patients with acute heart failure (AHF), early worsening heart failure (WHF) predicts a significant proportion of post-discharge readmissions and mortality. We aimed to identify the predictors of 7-day heart failure events or death in patients hospitalized with AHF. METHODS AND RESULTS: A predictive model and risk score for the short-term primary composite endpoint of 7-day death, HF rehospitalization, or WHF was created using variables collected within 24 h of admission from patients with complete data (n = 2015) enrolled in the PROTECT trial of AHF patients. The 7-day composite was experienced by 294 patients (14.6%), with a mortality rate of 1.8% (n = 37), HF rehospitalization rate of 0.5% (n = 9), and WHF rate of 13.1% (n = 264). In multivariable analyses, the strongest predictor of short-term morbidity and mortality was higher blood urea nitrogen (BUN) concentration. Additional independent predictors of a worse outcome were lower serum albumin, cholesterol, and systolic blood pressure, as well as higher heart rate and respiratory rate. Model coefficients were converted to an additive risk score for predicting the 7-day composite endpoint with a total point range of 0-100. The risk score allowed discrimination of a wide spectrum of risk (4.8% risk with score <=35, to 28.7% risk with score >55). CONCLUSIONS: Using the PROTECT 7-day risk model and score, the main determinants of an adverse outcome for AHF patients included impaired metabolic status, neurohormonal activation, and reduced cardiac performance, gauged by BUN, serum albumin and cholesterol levels, systolic blood pressure, heart rate, and respiratory rate. PMID- 22535796 TI - NHERF-1 and the regulation of renal phosphate reabsoption: a tale of three hormones. AB - The renal excretion of inorganic phosphate is regulated in large measure by three hormones, namely, parathyroid hormone, dopamine, and fibroblast growth factor-23. Recent experiments have indicated that the major sodium-dependent phosphate transporter in the renal proximal tubule, Npt2a, binds to the adaptor protein sodium-hydrogen exchanger regulatory factor-1 (NHERF-1) and in the absence of NHERF-1, the inhibitory effect of these three hormones is absent. From these observations, a new model for the hormonal regulation of renal phosphate transport was developed. The downstream signaling pathways of these hormones results in the phosphorylation of the PDZ 1 domain of NHERF-1 and the dissociation of Npt2a/NHERF-1 complexes. In turn, this dissociation facilitates the endocytosis of Npt2a with a subsequent decrease in the apical membrane abundance of the transporter and a decrease in phosphate reabsorption. The current review outlines the experimental observations supporting the operation of this unique regulatory system. PMID- 22535798 TI - Protein kinase C-alpha comes to the rescue of aquaporin-2. PMID- 22535797 TI - Urinary bladder function in conscious rat pups: a developmental study. AB - Cystometric studies of bladder function in anesthetized neonatal rats have suggested specific changes in urodynamic parameters that coincide with the development of a mature bladder-to-bladder micturition reflex. Here, we used a conscious cystometry model that avoids the potentially confounding effects of anesthesia to characterize voiding patterns and urodynamic parameters during early postnatal development in healthy rat pups. Cystometry was performed on postnatal day (P)0, 3, 7, 14, and 21 rats with continuous intravesical instillation of NaCl via a bladder catheter. Micturition cycles were analyzed with respect to voiding pattern, nonvoiding contractions, infused volume, and basal, filling, threshold, and micturition pressures. Reproducible micturition patterns were obtained from all age groups. The time from stimulation to contraction was significantly longer (P <= 0.001) in <=1-wk-old rats (~10 s) than that in older rats (~3 s). An interrupted voiding pattern was observed in <=10 day-old subgroups. Micturition pressure progressively increased with age (from 21.77 +/- 1.92 cmH(2)O at P0 to 35.47 +/- 1.28 cmH(2)O at P21, P <= 0.001), as did bladder capacity. Nonvoiding contractions were prominent in the P3 age group (amplitude: 4.6 +/- 1.3 cmH(2)O, frequency: ~4.0 events/100 s). At P7, the pattern of spontaneous contractions became altered, acquiring a volume-related character that persisted in a less prominent manner through P21. Bladder compliance increased with age, i.e., maturation. In conclusion, conscious cystometry in rat pups resulted in reproducible micturition cycles that yielded consistent data. Our results revealed immature voiding and prolonged micturition contractions during the first 10 neonatal days and provide evidence for age related changes in urodynamic parameters. PMID- 22535799 TI - Fight-or-flight: murine unilateral ureteral obstruction causes extensive proximal tubular degeneration, collecting duct dilatation, and minimal fibrosis. AB - Unilateral ureteral obstruction (UUO) is the most widely used animal model of progressive renal disease. Although renal interstitial fibrosis is commonly used as an end point, recent studies reveal that obstructive injury to the glomerulotubular junction leads to the formation of atubular glomeruli. To quantitate the effects of UUO on the remainder of the nephron, renal tubular and interstitial responses were characterized in mice 7 and 14 days after UUO or sham operation under anesthesia. Fractional proximal tubular mass, cell proliferation, and cell death were measured by morphometry. Superoxide formation was identified by nitro blue tetrazolium, and oxidant injury was localized by 4-hydroxynonenol and 8-hydroxydeoxyguanosine. Fractional areas of renal vasculature, interstitial collagen, alpha-smooth muscle actin, and fibronectin were also measured. After 14 days of UUO, the obstructed kidney loses 19% of parenchymal mass, with a 65% reduction in proximal tubular mass. Superoxide formation is localized to proximal tubules, which undergo oxidant injury, apoptosis, necrosis, and autophagy, with widespread mitochondrial loss, resulting in tubular collapse. In contrast, mitosis and apoptosis increase in dilated collecting ducts, which remain patent through epithelial cell remodeling. Relative vascular volume fraction does not change, and interstitial matrix components do not exceed 15% of total volume fraction of the obstructed kidney. These unique proximal and distal nephron cellular responses reflect differential "fight-or-flight" responses to obstructive injury and provide earlier indexes of renal injury than do interstitial compartment responses. Therapies to prevent or retard progression of renal disease should include targeting proximal tubule injury as well as interstitial fibrosis. PMID- 22535800 TI - Receptor-mediated nonproteolytic activation of prorenin and induction of TGF beta1 and PAI-1 expression in renal mesangial cells. AB - While elevated plasma prorenin levels are commonly found in diabetic patients and correlate with diabetic nephropathy, the pathological role of prorenin, if any, remains unclear. Prorenin binding to the (pro)renin receptor [(p)RR] unmasks prorenin catalytic activity. We asked whether elevated prorenin could be activated at the site of renal mesangial cells (MCs) through receptor binding without being proteolytically converted to renin. Recombinant inactive rat prorenin and a mutant prorenin that is noncleavable, i.e., cannot be activated proteolytically, are produced in 293 cells. After MCs were incubated with 10(-7) M native or mutant prorenin for 6 h, cultured supernatant acquired the ability to generate angiotensin I (ANG I) from angiotensinogen, indicating both prorenins were activated. Small interfering RNA (siRNA) against the (p)RR blocked their activation. Furthermore, either native or mutant rat prorenin at 10(-7) M alone similarly and significantly induced transforming growth factor-beta(1), plasminogen activator inhibitor-1 (PAI-1), and fibronectin mRNA expression, and these effects were blocked by (p)RR siRNA, but not by the ANG II receptor antagonist, saralasin. When angiotensinogen was also added to cultured MCs with inactive native or mutant prorenin, PAI-1 and fibronectin were further increased significantly compared with prorenin or mutant prorenin alone. This effect was blocked partially by treatment with (p)RR siRNA or saralasin. We conclude that prorenin binds the (p)RR on renal MCs and is activated nonproteolytically. This activation leads to increased expression of PAI-1 and transforming growth factor beta(1) via ANG II-independent and ANG II-dependent mechanisms. These data provide a mechanism by which elevated prorenin levels in diabetes may play a role in the development of diabetic nephropathy. PMID- 22535801 TI - Glycoforms of UT-A3 urea transporter with poly-N-acetyllactosamine glycosylation have enhanced transport activity. AB - Urea transporters UT-A1 and UT-A3 are both expressed in the kidney inner medulla. However, the function of UT-A3 remains unclear. Here, we found that UT-A3, which comprises only the NH(2)-terminal half of UT-A1, has a higher urea transport activity than UT-A1 in the oocyte and that this difference was associated with differences in N-glycosylation. Heterologously expressed UT-A3 is fully glycosylated with two glycoforms of 65 and 45 kDa. By contrast, UT-A1 expressed in HEK293 cells and oocytes exhibits only a 97-kDa glycosylation form. We further found that N-glycans of UT-A3 contain a large amount of poly-N-acetyllactosamine. This highly glycosylated UT-A3 is more stable and is enriched in lipid raft domains on the cell membrane. Kifunensine, an inhibitor of alpha-mannosidase that inhibits N-glycan processing beyond high-mannose-type N-glycans, significantly reduced UT-A3 urea transport activity. We then examined the native UT-A1 and UT A3 glycosylation states from kidney inner medulla and found the ratio of 65 to 45 kDa in UT-A3 is higher than that of 117 to 97 kDa in UT-A1. The highly stable expression of highly glycosylated UT-A3 on the cell membrane in kidney inner medulla suggests that UT-A3 may have an important function in urea reabsorption. PMID- 22535802 TI - Posterior interbody grafting and instrumentation for spondylodiscitis. AB - PURPOSE: To report outcomes of 7 patients with bacterial spondylodiscitis treated through a posterior approach. METHODS: Five men and 2 women aged 40 to 80 years underwent one-stage posterior interbody debridement and instrumentation for single-segment bacterial spondylodiscitis of lumbar (n=5) or thoracic (n=2) vertebrae. The Oswestry Disability Score, the Frankel classification, the Cobb angle, and the visual analogue scale (VAS) for pain as well as bone union on radiographs were assessed. RESULTS: Patients were followed up for 19 to 36 months. None had relapses or complications. Postoperatively, 5 patients had no pain or used analgesics only occasionally; their VAS scores varied from 0 to 20. The remaining 2 patients had residual symptoms and received regular peripheral pain medication and opiates; their VAS scores ranged from 30 to 50. The mean Oswestry Disability Score improved to 21 (range, 12-38). The mean Cobb angle improved from 13.1 to 11.1 degrees. The segments were probably fused in 5 patients and questionable in 2. CONCLUSION: Posterior debridement and instrumentation was adequate for single-segment spondylodiscitis and achieved good outcomes. PMID- 22535803 TI - Discectomy for primary and recurrent prolapse of lumbar intervertebral discs. AB - PURPOSE: To reviewed 416 patients who underwent discectomy for primary or recurrent prolapse of lumbar intervertebral discs (PLID). METHODS: Records of 296 men and 102 women aged 19 to 60 (mean, 39) years who underwent discectomy for a primary PLID, and 14 men and 4 women aged 28 to 50 (mean, 40) years who underwent revision discectomy for a recurrent ipsilateral (n=14) or contralateral (n=4) PLID at L4-5 (n=14), L5-S1 (n=3), or L3-4 (n=1) were reviewed. The pain-free interval, side and degree of herniation, operating time, length of hospital stay, and pre- and post-operative visual analogue score (VAS) for pain were recorded. Clinical outcomes were evaluated using the modified Macnab criteria and the Oswestry Disability Index. RESULTS: Patients were followed up for one to 4 years. The mean operating time was significantly longer in revision discectomy (65 vs. 141 minutes, p<0.001, unpaired t-test). There was no significant difference between revision and primary discectomy in terms of length of hospital stay or clinical improvement rates. Age, gender, smoking, profession, level and extent of herniation, and pain-free interval did not affect clinical outcomes. In the 18 revision cases, the mean pain-free interval until recurrence was 31 (range, 1-42) months. At the one-year follow-up, results were excellent in 8, good in 6, fair in 3, and poor in one. Three of the patients had persistent pain despite taking analgesics. 14 of the patients had returned to their normal daily activities. Complications included foot drop (n=1), dural tear (n=3), and superficial wound infection (n=1). CONCLUSION: Discectomy achieved satisfactory results for both primary and recurrent PLIDs. PMID- 22535804 TI - Pyogenic discitis following discectomy. AB - PURPOSE: To assess the treatment outcome for disc infection in 35 patients. METHODS: Records of 23 men and 12 women aged 36 to 62 (mean, 43) years who underwent treatment for pyogenic discitis after open discectomy were reviewed. All patients had single-level disc herniation of L4-5 (n=28) or L5-S1 (n=6), except for one who had 2-level disc herniation of L4-S1. Single antibiotic was given one day prior to discectomy and continued for 2 days. All excised discs were found to be sterile. Discitis was classified into acute (n=26), subacute (n=7), and chronic (n=2). Antibiotic therapy was started immediately when the clinical diagnosis was made. 31 patients were treated with antibiotics alone; the remaining 4 underwent surgery entailing simple posterior superficial wound drainage (n=1), anterior radical surgery (n=2), or posterior instrumentation and posterolateral fusion for post-discectomy syndrome (n=1). Six of the 12 patients who had percutaneous disc space aspiration underwent disc space irrigation. RESULTS: The initial symptoms included mild-to-moderate fever (n=4), severe back pain (n=27), back muscle spasms (n=26), back pain radiating to the limb (n=2), Gower sign (n=11), and a draining wound (n=1). The wound aspirates of the 12 patients grew organisms, although blood cultures were negative in all. After antibiotic therapy, symptoms gradually subsided in parallel with normalisation of white blood cell count and inflammatory markers. Surgery was indicated only when symptoms worsened and the disease progressed. Spontaneous intercorporal fusion did not occur. CONCLUSION: Early diagnosis and treatment with appropriate antibiotics is important for post-discectomy discitis. PMID- 22535805 TI - Serum 25-hydroxy-calciferol level and failed back surgery syndrome. AB - PURPOSE: To assess the association of serum 25-hydroxy-calciferol levels with pain and low back function in patients with failed back surgery syndrome. METHODS: Records of 6 men and 3 women aged 25 to 54 (mean, 39.2) years who had failed back surgery syndrome after pedicular screw and rod instrumentation for lower lumbar degenerative diseases were reviewed. They had moderate-to-severe pain (visual analogue scale [VAS] score of >6) and low back function disability (Japanese Orthopaedic Association [JOA] back score of <10). In all patients, the serum 25-hydroxy-calciferol level was <30 ng/ ml, indicating vitamin D deficiency. Vitamin D2 (20 000 IU per day) was given for 10 days, and vitamin D3 (600 IU per day) was given for maintenance. Patients were followed up at months 3 and 6. Three men and 4 women aged 27 to 55 (mean, 41.3) years who were age- and disease-matched but achieved good outcomes (VAS score of 0-1 and mean JOA low back score of 14.7) were used as indirect referents. All 7 matched patients except one had a normal serum 25-hydroxy-calciferol level (mean, 40.6 ng/ml). RESULTS: In the 9 patients with failed back surgery syndrome, the mean duration of chronic pain was 2.6 years; the mean VAS score for pain was 7.7; the mean JOA low back score was 7.6; the mean number of reoperations was 2.2; and the mean serum 25-hydroxy-calciferol level was 17.0 ng/ml. Two male patients had grade-IV motor weakness and decreased sensory function based on the pin prick test. One patient had a history of prolonged (>3 months) antibiotic use after primary surgery, but had no evidence of infection. Six months after vitamin D2 and vitamin D3 supplementation, the mean serum 25-hydroxy-calciferol level improved significantly (17.0 vs. 42.5 ng/ml), as did the mean pain score (7.7 vs. 4.2) and mean JOA back score (7.6 vs. 11.1). Seven of the patients had a pain score of <6 and a JOA back score of >10, the remaining 2 patients had neurological deficits and only slight improvement. CONCLUSION: Vitamin D supplementation may be used as an adjuvant treatment for patients with failed back surgery syndrome. PMID- 22535806 TI - Continuous femoral nerve block versus patient-controlled analgesia following total knee arthroplasty. AB - PURPOSE: To compare total knee arthroplasty (TKA) patients who received continuous femoral nerve block (FNB) with local anaesthetics through a catheter versus patient-controlled analgesia (PCA) with intravenous morphine. METHODS: 50 women and 10 men aged 51 to 84 years with matched characteristics underwent TKA and received either continuous FNB with local anaesthetics through a catheter (n=30) or PCA with intravenous morphine (n=30). None of the patients had had previous knee surgery. All operations were performed according to the standard protocol. Daily mean pain numerical rating scale at rest (NRS-R) and during movement (NRS-M), requirement of extra pain control, complications related to pain control, and overall patient satisfaction in both groups were compared. RESULTS: Both groups were similar in terms of pain NRS-R and NRS-M, overall satisfaction, and length of hospital stay. Within each group, pain NRS-M score was significantly higher than pain NRS-R score. In the FNB group, 3 patients had dislodgement of the femoral catheter on day 1 and switched to PCA with intravenous morphine. Two of them had fair satisfaction. Patients in the PCA group had significantly more side-effects (nausea, vomiting, dizziness, and pruritis); 2 of the 5 patients with nausea and vomiting had fair satisfaction. No patients had any surgical complication. CONCLUSION: Both FNC and PCA provide reliable pain control. PMID- 22535807 TI - Serum intact-parathyroid hormone level following total knee arthroplasty. AB - PURPOSE: To evaluate short-term parathyroid hormone (PTH) secretion following total knee arthroplasty (TKA). METHODS: 119 Caucasian postmenopausal women aged 49 to 81 (mean, 69.8) years who underwent TKA for end-stage knee osteoarthritis were included. Serum levels of intact-PTH, calcium, phosphorus, and creatinine were evaluated pre- and post-operatively (on days -1 and 7). Creatinine clearance was also calculated. RESULTS: In 67 of the patients, serum intact-PTH levels decreased after TKA; this sample proportion was not significant (p=0.82). In 16 of the patients, such levels elevated abnormally (above normal range). In the remaining 36 patients, such levels elevated within the normal range. Therefore, the mean serum intact- PTH level of all patients increased slightly after TKA (45.4 vs. 45.3, p=0.162). The serum intact-PTH level did not correlate to body weight (r=-0.045, p=0.624), patient age (r=-0.061, p=0.508), serum creatinine level (r=0.084, p=0.366), and clearance of creatinine (r=-0.037, p=0.692). CONCLUSION: In most postmenopausal women, the serum intact-PTH level decreased moderately following TKA, but in some, the level was abnormally elevated. This may interfere the prosthesis incorporation process. PMID- 22535808 TI - Comparison of cross-sections of different femoral components for revision total knee replacement. AB - PURPOSE. To compare the inner contour of the femoral component of 10 total knee replacement (TKR) designs for possible exchange in use. METHODS: Inner contours of the femoral components of 10 cemented, cruciate-retaining TKR designs (e.motion, Genesis, Genia, Innex, LCS, Multigen Plus, NexGen, PFC, Scorpio, Vanguard) were scanned and reconstructed to 2-dimensional contours. Their cross sections were compared by superimposition and aligning at the distal and anterior cuts. The patellar notch and outer contour were not analysed. RESULTS: The maximum deviation was 5 mm in the posterior and posterior oblique cuts and 10 mm in the anterior oblique cut. Based on similarity of the inner contour, LCS and Innex was classified as group I, e.motion, Genesis, Scorpio, Vanguard, and Multigen Plus as group II, and Genia, NexGen, and PFC as group III. All 2 designs in group I were not compatible with the other 8 designs. Four of the 5 designs in group II showed good compatibility. All 3 designs in group III significantly differed in the posterior and oblique cuts. CONCLUSION: A standardised inner contour of the femoral component can increase compatibility of different TKR systems in revision surgery and reduces the extent of bone resection. PMID- 22535809 TI - Closed reduction and percutaneous screw fixation for tibial plateau fractures. AB - PURPOSE: To evaluate treatment outcomes of closed reduction and percutaneous screw fixation for tibial plateau fractures. METHODS: 48 men and 8 women aged 19 to 61 (mean, 36) years underwent closed reduction and percutaneous screw fixation for closed tibial plateau fractures with <5 mm depression. According to the Schatzker classification, patients were classified into type I (n=9), type II (n=22), type IV (n=5), and type V (n=20). Closed reduction was achieved using manual ligamentotaxis with traction in extension under image intensifier control. Reduction was fixed percutaneously with cancellous screws (6.5 mm) and washers. Functional outcome (pain, walking capacity, extension lag, range of motion, and stability) was evaluated using the Rasmussen score. A total score of 28 to 36 was considered as excellent, 20 to 27 as good, 10 to 20 as fair, and <10 as poor. RESULTS: Patients were followed up for a mean of 2.8 (range, 1-4) years. The mean length of hospital stay was 5 (range, 2-15) days. All the fracture united radiographically after a mean of 3 (range, 2.5-4.2) months. Respectively in Schatzker types-I, -II, -IV, and -V fractures, outcomes were excellent in 6, 10, 2, and 2 patients, good in 2, 9, 3, and 14 patients, fair in 1, 3, 0, and 2 patients, and poor in 0, 0, 0, and 2 patients. Outcome was satisfactory (good-to excellent) in 89%, 86%, 100%, and 80% of the respective fracture types of patients. The mean Rasmussen score was 25.7 for all patients; it was 27.7 for type I, 26.3 for type II, 28.6 for type IV, and 23.4 for type V fractures. The mean Rasmussen score was significantly lower in 12 patients with ligament injury than in 44 patients without ligament injury (19.8 vs. 27.3, p<0.001). No patient had any complication (infection, wound dehiscence or hardware problem). CONCLUSION: Closed reduction and percutaneous screw fixation for tibial plateau fractures is minimally invasive. It reduces the length of hospital stay and costs, enables early mobilisation with minimal instrumentation, and achieves satisfactory outcomes. PMID- 22535810 TI - Minimally invasive plate osteosynthesis for tibial plateau fractures. AB - PURPOSE: To evaluate radiological and clinical outcome of minimally invasive plate osteosynthesis (MIPO) for tibial plateau fractures. METHODS: 35 men and 6 women aged 19 to 75 (mean, 40; standard deviation [SD], 14) years underwent MIPO for displaced tibial plateau fractures. According to the Schatzker system, the tibial plateau fractures were classified as types I (n=3), II (n=9), III (n=11), IV (n=6), V (n=7), and VI (n=5). Six patients had open fractures; 2 of them underwent debridement before MIPO. 10 patients needed additional bone grafting. Radiological (at immediate postoperation) and clinical (at the 12-month follow up) assessments based on the Rasmussen anatomic and functional scoring system were recorded using a proforma. Patients with acceptable and unacceptable outcomes were compared in terms of age. RESULTS: The mean Rasmussen anatomic score was 15.1 (SD, 2.2; range, 10-18); the mean Rasmussen functional score was 25.3 (SD, 3.2; range, 14-29); and the mean range of knee motion was 118 (SD, 10; range, 90-140) degrees. Anatomic outcome was excellent in 10, good in 28, and unacceptable in 3 patients (one each had Schatzker type-I, -II, and -III fractures). 27 (71%) of the 38 patients with acceptable anatomic outcome were aged 45 years or younger, whereas 2 (67%) of the 3 patients with unacceptable anatomic outcome were aged 60 years or older (p=0.001). Functional outcome was excellent in 18, good in 19, and unacceptable in 4 patients (2 had Schatzker type III and another 2 had Schatzker type-I or -II fractures). 37 of the patients had a range of knee motion of 120 degrees or more; 27 (73%) of them were aged 45 years or younger, whereas 3 (75%) of the 4 patients with unacceptable functional outcome were aged 60 years or older (p=0.001). CONCLUSION: MIPO for tibial plateau fractures achieved good outcome with minimal soft-tissue complications. Older age was the predictor of unacceptable outcome. PMID- 22535812 TI - Questionnaire to assess treatment outcomes of acetabular fractures. AB - PURPOSE: To construct a questionnaire to assess outcomes in patients who underwent internal fixation for acetabular fractures. METHODS: 27 female and 100 male consecutive patients (mean age, 50 years) who underwent internal fixation for acetabular fractures were included. Patients were asked to report their outcomes at months 6, 12, and 24 using a questionnaire. The initial questionnaire was constructed by an expert group. There were 11 closed questions, each came with 6 responses from ?no discomfort? to ?very severe discomfort?. Three open questions were added to cover topics that were not included. The content validity and relevance of the 11 closed questions was determined using factor analysis to determine the number of factors involved. Factorability of the correlation matrix was measured via the Bartlett test of sphericity and Kaiser-Meyer- Olkin (KMO) measure of sampling sufficiency. Factor loadings of <0.50 were considered acceptable for factor representation. Reliability in terms of internal consistency was expressed as Cronbach alpha coefficients. The responses to the 3 open questions were analysed and categorised by a single assessor. RESULTS: 120 (94%) of the patients completed at least one questionnaire, and 92 (72%) completed all 3 questionnaires during the follow-up period. Based on responses to the 6-month questionnaire, responses to the 11 closed questions were significantly intercorrelated (Spearman 0.17-0.80). After factor analysis and analysis of responses to open questions, the number of questions was reduced to 6 and included questions related to pain, walking, hip motion, leg numbness, sexual life, and operation scar. Reliability of the questionnaire was estimated to alpha=0.89. Criterion validity was adequate with a high correlation with the Short Form 36 (r=0.56-0.80). CONCLUSION: Patients treated with acetabular fractures can be adequately assessed using the 6-item questionnaire and one global question concerning impact on activities of daily living. PMID- 22535811 TI - Antegrade interlocking nailing for distal femoral fractures. AB - PURPOSE: To assess outcomes of antegrade interlocking nailing for supracondylar or intercondylar fractures of the distal femur. METHODS: Records of 10 women and 20 men aged 20 to 70 (mean, 48.7) years who underwent antegrade interlocking nailing for distal femoral fractures were reviewed. 23 patients had closed fractures and 7 had open fractures; 6 had associated fractures of the forearm or tibia. According to the AO/ASIF system, fractures were classified as types A1 (n=13), A2 (n=6), A3 (n=3), and C1 (n=8). The affected leg was put in an extension shoe for traction, and reduction was achieved with the help of percutaneous lag screws. The nail was inserted from the tip of the greater trochanter and centred in both anteroposterior and lateral planes. The nail was modified to have 3 screw slots in the mediolateral plane and one screw slot in the anteroposterior plane distally for stability in multiple directions. Postoperatively early mobilisation and partial weight bearing were allowed. Patients were assessed using the modified knee-rating scale of the Hospital for Special Surgery. RESULTS: The mean time to bone union was 13.1 (range, 10-18) weeks. The mean follow-up period was 18.8 (range, 11-30) months. Three patients were lost to follow-up; outcomes in the remaining patients were excellent in 20 and good in 7. The mean range of knee flexion was 106 (range, 90-120) degrees. One patient developed a flexion deformity of 10 degrees. All patients attained full quadriceps strength. No patient had ligamentous instability, nerve injuries, superficial or deep infections, or implant failure. Three patients had malunion, which was located in the meta-diaphyseal segment and not in the intraarticular segment. Hence, there was no functional problem or shortening. The mechanical axis was not deviated. CONCLUSION: Antegrade interlocking nailing achieved good to-excellent outcomes for distal femoral fractures. PMID- 22535813 TI - Acutrak versus Herbert screw fixation for scaphoid non-union and delayed union. AB - PURPOSE: To compare the treatment outcome of Acutrak versus Herbert screw fixation for scaphoid non-union and delayed union. METHODS: Records of 132 patients who underwent Herbert screw fixation (n=61) or Acutrak screw fixation (n=71) with or without bone grafting for scaphoid non-union and delayed union by a single surgeon were reviewed. The most common fracture site was the waist of the scaphoid (n=95), followed by the proximal pole (n=31) and the distal pole (n=6). Screw placement was considered accurate (n=120) when the screw was placed in the central one-third (axially) of the scaphoid; otherwise it was eccentric (n=12). Bone union was assessed radiographically and clinically. Functional outcome was assessed using the modified Mayo wrist score. RESULTS: Respectively in the Herbert and Acutrak screw groups, the mean patient ages were 25.3 and 27.3 years (p=0.28), the mean intervals between injury and screw fixation were 12.2 and 17 months (p=0.38), the mean durations to bone union were 2.1 and 1.8 months (p=0.63), and the union rates were 77% and 93% (p=0.01). The union rate was significantly higher in fractures of the waist of the scaphoid than in the proximal and distal poles (94% vs. 71% vs. 33%, p=0.001). The union rate was significantly higher when the screw was placed accurately (axially) than eccentrically (Herbert screw: 84% vs. 40%, p=0.006; Acutrak screw: 96% vs. 0%, p=0.004). 84% of the Herbert screws were placed axially, compared to 97% for the Acutrak screws. Respectively, 67% and 85% of patients had satisfactory functional outcomes (p=0.03), whereas 23% and 7% of the patients had persistent non-union (p=0.05). CONCLUSION: The Acutrak screw enabled more accurate screw placement and achieved higher union rates and modified Mayo wrist scores than the Herbert screw did. PMID- 22535814 TI - Anterior deltopectoral approach for axillary nerve neurotisation. AB - PURPOSE: To report outcome of axillary nerve neurotisation for brachial plexus injury through the anterior deltopectoral approach. METHODS: Nine men aged 20 to 52 (mean, 27.8) years with brachial plexus injury underwent axillary nerve neurotisation through the anterior deltopectoral approach. Three of the patients had complete avulsion of C5-T1 nerve roots. The remaining 6 patients had brachial plexus injury of C5-C6 nerve roots, with associated subluxation of the glenohumeral joint, atrophy of the supraspinatus, deltoid and elbow flexors. They had no active shoulder abduction, external rotation, and elbow flexion. The pectoralis major and minor were cut and/or retracted to expose the underlying infraclavicular plexus. The axillary nerve was identified with respect to the available donor nerves (long head of triceps branch, thoracodorsal nerve, and medial pectoral nerve). In addition to the axillary nerve neurotisation, each patient had a spinal accessory nerve transferred to the suprascapular nerve for better shoulder animation. RESULTS: Patients were followed up for 24 to 30 (mean, 26) months. In the 3 patients with C5-T1 nerve root injuries, the mean active abduction and external rotation were 63 and 20 degrees, respectively, whereas the mean abduction strength was M3 (motion against gravity). In the 6 patients with C5-C6 nerve root injuries, the mean active abduction and external rotation were 133 and 65 degrees, respectively, whereas the strength of the deltoids and triceps was M5 (normal) in all. In 4 patients with the pectoralis major cut and repaired, the muscle regained normal strength. CONCLUSION: The anterior deltopectoral approach enabled easy access to all available donor nerves for axillary nerve neurotisation and achieved good outcomes. PMID- 22535815 TI - Ultrasonographic evaluation of Achilles tendons in clubfeet before and after percutaneous tenotomy. AB - PURPOSE: To measure the size of the Achilles tendons in congenital clubfeet using ultrasonography before and after percutaneous tenotomy. METHODS: 15 boys and 12 girls (39 feet) aged one to 11 (mean, 5) months with idiopathic clubfeet underwent percutaneous tenotomy (Ponseti method). The size of each Achilles tendon was measured ultrasonographically by a single radiologist before and after surgery. In patients with unilateral clubfoot, the normal foot was used as a referent. Longitudinal scans assessed the echotexture, echogenicity, and continuity of the tendon. Transverse scans assessed the shape, echotexture, echogenicity, thickness, and width of the tendon. The size of the Achilles tendon was estimated as an elliptical area using the formula: pi(thickness)x(width)/4. RESULTS: Before tenotomy, homogenous, hyperechoic, and linear continuous shadows were noted in longitudinal scans of both the normal and affected Achilles tendons. In transverse scans, the tendons were elliptical, homogenous, and echogenic in appearance. Four weeks after tenotomy, the tendons appeared as heterogeneous, linear continuous shadows with regular margins irrespective of patient age. There was decreased echogenicity in the treated foot. The transverse section of the tendons was elliptical with a heterogeneous echotexture that was predominantly hypoechoic. There was no significant difference in normal, unilateral, and bilateral tendons before and after tenotomy. CONCLUSION: The study reasserts functional continuity of the Achilles tendons 4 weeks after tenotomy using clinical and ultrasonographic methods. PMID- 22535816 TI - Infection risk from surgeons' eyeglasses. AB - PURPOSE: To assess bacterial contamination of 20 eyeglasses from surgeons. METHODS: 40 samples were taken from the nose pad (n=20) and earpiece (n=20) of 20 eyeglasses from orthopaedic surgeons using a sterile swab stick soaked in sterile distilled water. Swabs were incubated and inoculated onto 3 plates: Staphylococcus/Streptococcus agar plate, Mannitol salt plate, and Chromogenic agar plate. Organisms isolated were identified. RESULTS: Of 20 eyeglasses, 19 were contaminated with Staphylococcus epidermidis (3 of them additionally grew S haemolyticus or S xylosus) and the remaining one grew S aureus . CONCLUSION: Eyeglasses are a source of surgical infection. Contamination can be caused by direct contact of the eyeglasses to the wound and indirect contact by the surgeon's fingers, splashes from saline irrigation, and through air. Therefore, disinfection should be performed for eyeglasses of surgeons. The use of surgical visor masks or filtered exhaust helmets (space suits) are alternatives. PMID- 22535817 TI - Review article: Treatments for bone loss in revision total knee arthroplasty. AB - Bone deficiency hinders implant alignment and stabilisation of the bone-implant interface in revision total knee arthroplasty (TKA). Treatments for bone defects include bone cement, bone cement with screw reinforcement, metal augments, impaction bone grafts, structural allografts, and tantalum, depending on the location and size of the defects. Small defects are usually treated with cement, cement plus screws, or impaction allograft bone. Large defects are repaired with structural allografts or metal augments. Recent developments involve the use of highly porous osteoconductive tantalum. We reviewed the pros and cons of each method for bone defect management in revision TKA. PMID- 22535818 TI - Tarlov cysts: a report of two cases. AB - Perineural cysts are common and usually detected incidentally during magnetic resonance imaging of the lumbosacral spine. Treatment is indicated only when the cyst is symptomatic. We report one such patients presented with cauda equina syndrome and another with low back pain with claudication. They underwent excision and duraplasty; both motor and sensory fibres were carefully separated from the cyst wall using a nerve root retractor and penfield. There was no nerve root damage or neural deficit. Symptoms were relieved postoperatively. PMID- 22535819 TI - Intra-operative identification of conjoined lumbosacral nerve roots: a report of three cases. AB - We report 3 cases of conjoined nerve root anomalies identified during micro endoscopic discectomy (MED). Between 2009 and 2010, 61 men and 20 women aged 18 to 84 (mean, 42) years underwent MED for symptomatic lumbar disc herniation of L3 4 (n=1), L4-5 (n=44), and L5-S1 (n=36). Magnetic resonance imaging (MRI), myelogram, and postmyelo computed tomography did not identify the anomalies. All 3 patients were male and had type 2A S1 conjoined nerve roots, with a herniated disc at L5-S1. None of them had any preoperative pseudolocalising neurological signs, but all demonstrated stiffer positive straight leg raise sign and deterioration of the Achilles tendon reflex. Postoperatively, all 3 patients achieved excellent clinical outcomes. PMID- 22535820 TI - Massive psoas haematoma causing lumbar plexus palsy: a case report. AB - An 84-year-old man who was receiving oral anticoagulation therapy presented with complete lumbar plexus palsy caused by a massive psoas haematoma. Conservative treatment rather than drainage of the haematoma was undertaken, because of the risk of bleeding complications and mortality. At the one-year follow-up, the patient had no clinical signs of neurological recovery. The patient died 2 months later due to his concurrent medical problems. A high degree of suspicion is needed for the diagnosis because of the insidiously developing neurological deficit. PMID- 22535821 TI - Pedicle freezing with liquid nitrogen for malignant bone tumour in the radius: a new technique of osteotomy of the ulna. AB - We describe a new technique of pedicle freezing of the distal radius with malignant bone tumour and osteotomy of the normal ulna. The distal radius was sufficiently elevated to enable freezing without damaging adjacent tissues by releasing the distal radio-ulnar and radio-carpal joint and cutting the middle third of the ulna. The distal radius (including the tumour) was soaked in liquid nitrogen and the defect filled with iliac grafts. The ulna was repaired with plate and screws and was united at month 2. There was no local recurrence and the postoperative function score was 93%. This technique decreases the risk of non union of the osteotomy site of the tumorous bone. PMID- 22535822 TI - Fractures of the scaphoid, capitate and triquetrum in a child: a case report. AB - Carpal fractures in children are rare, especially with a combination of scaphoid, capitate, and triquetrum fractures. We report one such case in a 10-year-old boy who was successfully treated with Kirschner wires. PMID- 22535823 TI - Non-union of the triquetrum with pseudoarthrosis: a case report. AB - We report a case of symptomatic non-union of the triquetrum with pseudoarthrosis in a 34-year-old man. Motion of the pseudoarthrosis was noted from radial to ulnar deviation. The patient was treated with bone grafting and screw fixation. The non-union healed and the symptoms subsided. The Mayo wrist score had improved from 65 (fair) to 90 (excellent). PMID- 22535824 TI - Osteochondritis dissecans of the knee in identical twins: a report of two cases. AB - We report the second case of osteochondritis dissecans (OCD) of the knee in identical twins (bilaterally in one and unilaterally in the other). Fixations with bio-absorbable pins, cylindrical osteochondral graft, and osteochondral mosaicplasty were all successful and bone union was achieved. We considered that genetic factors remain essential even if other factors (particularly repetitive trauma) are mainly responsible for the occurrence of OCD. PMID- 22535825 TI - Patient-specific instrumentation for total knee replacement verified by computer navigation: a case report. AB - Patient-specific instrumentation (PSI) enables better restoration of the mechanical axis in total knee replacement (TKR) than conventional instrumentation (alignment guides) does. We verified the accuracy of the PSI by computer navigation. The PSI jigs were accurate only if they were pinned accurately onto the distal femur and proximal tibia. Any slight malposition of the jigs leads to malalignment of the bone cuts. In the absence of computer navigation, the accuracy of the jig alignments cannot be checked and may result in malalignment. PMID- 22535826 TI - Femoral canal obliteration secondary to prolonged alendronate use: a case report. AB - Insufficiency fractures secondary to prolonged alendronate use is due to inhibition of osteoclastic activity and suppressed bone turnover. Complications of fracture fixation include non-union, mal-union, and difficulty in intramedullary nail insertion. We report a technical challenge in intramedullary nailing of an obliterated femoral canal in a patient on long-term bisphosphonate treatment. The fracture site was explored. The medullary canal was re-created by drilling. Patience and caution during drilling and reaming are necessary to avoid iatrogenic fractures. PMID- 22535827 TI - Breakage of the radiopaque wire from the medullary tube during closed antegrade intramedullary nailing for femoral shaft fracture. AB - We report a complication of radiopaque wire breakage from the medullary tube during closed antegrade intramedullary nailing for a femoral shaft fracture. To avoid such complication, the medullary tube should be checked carefully for colour changes and surface defects, and tested for flexibility before each use. The medullary tube should also be replaced before 100 exposures to autoclaving. PMID- 22535828 TI - Recurrent shoulder dislocations secondary to coracoid process fracture: a case report. AB - Coracoid process fracture is easily missed in recurrent anterior shoulder dislocation. We report one such case in a 48-year-old man. Radiology revealed the Bankart lesion and the Hill-Sachs lesion only; the coracoid process fracture was discovered intra-operatively. The anatomy of the shoulder was restored by fixing the fragment to its scapular remnant with a 4-mm cannulated cancellous screw. The tip and the proximal fragment were reamed before inserting the screw. This fragment was routed with attached short head of biceps and coracobrachialis through the lower one third of the subscapularis, before homing it and fixing it to the proximal coracoid fragment. This extraarticular repair resulted in less stiffness than any intra-articular procedure. At the 2-year follow-up, the patient had had no further shoulder dislocation. PMID- 22535829 TI - Platelet-rich plasma for calcific tendinitis of the shoulder: a case report. AB - We report a 44-year-old woman with calcific tendinitis of the shoulder treated with platelet-rich plasma injection. Prior to this, she had no improvement of the symptoms after 6 weeks of ultrasound treatment, Codman exercises, and anti inflammatory treatment. Platelet-rich plasma was injected into the subacromial area 3 times at 2-week intervals. She had progressive improvement of pain after 2 weeks, and was asymptomatic at week 6. The patient then underwent the previous protocol of rehabilitation. At the one-year follow-up, the patient was pain-free and had complete resolution of calcific tendinitis. The patient had regained full range of movement and had resumed all her activities. PMID- 22535830 TI - Intra-osseous lipoma of the talus: a case report. AB - Intra-osseous lipomas are rare benign tumours. We report one such case in the talus of a 60-year-old man. The patient underwent curettage and bone grafting. At the 22-month follow-up, radiographs of the talus showed dense sclerosis with multiple cortical breaks in the anterior process and no evidence of local recurrence or avascular necrosis. The patient had a painless ankle joint with normal range of movement. PMID- 22535831 TI - Mycobacterium chelonae infection after total knee arthroplasty: a case report. AB - We present a case of Mycobacterium chelonae infection after total knee arthroplasty in a 70-year-old woman. The patient underwent implant removal, drainage, debridement, and insertion of a gentamycin-load cement spacer. After 4 months, the second-stage surgery was performed. Intravenous amikacin (6 weeks) and oral clarithromycin (12 weeks) were given. At the 12-month follow-up, the patient achieved 90 degrees of flexion and could walk with a stick for up to 15 minutes. She was not taking any analgesics. PMID- 22535833 TI - Natural radioactivity and external dose in the high background radiation area of Lambwe East,Southwestern Kenya. AB - Absorbed dose rates around the North and South Ruri hills in Lambwe east, southwestern Kenya were measured using survey meters. The area lies roughly between latitudes 0 degrees 30'S and 1 degrees 00'S. It is bounded on the east by longitude 34 degrees 30'E and on the west by the shores of Lake Victoria and Winnam Gulf. The measured absorbed dose varies from 0.7 to 6.0 uGy h(-1), and the mean is 2.3 uGy h(-1). Assuming an outdoor occupancy factor of 0.4, the corresponding range and mean annual effective doses are 1.7-14.7 and 5.7 mSv, respectively. The average activity concentrations (ACs) of (232)Th, (226)Ra and (40)K in samples of soils and rocks from the area are 1397, 179 and 509 Bq kg( 1), respectively. Values of absorbed dose rates calculated from the ACs are general lower than those obtained from in situ measurements. Possible causes of these discrepancies were discussed in the paper. PMID- 22535832 TI - Amino-functionalized cellulose nanoparticles: preparation, characterization, and interactions with living cells. AB - Spherical nanoparticles with sizes from 80 to 200 nm are obtained by self assembly of highly functionalized 6-deoxy-6-(omega aminoalkyl)aminocellulosecarbamates. The particles are very stable, nontoxic, and possess primary amino groups that are accessible to further modifications in aqueous suspension. The particles can be labeled with rhodamine B isothiocyanate without changing their size, stability, and shape. The nanoparticles obtained are investigated by means of photo correlation spectroscopy, zeta potential measurements, SEM and fluorescence spectroscopy. Incorporation of the nanoparticles in human foreskin fibroblasts BJ-1-htert and breast carcinoma MCF-7 cells without any transfection reagent is proved by means of confocal laser scanning microscopy. PMID- 22535834 TI - Single sevoflurane exposure decreases neuronal nitric oxide synthase levels in the hippocampus of developing rats. AB - BACKGROUND: The use of general anaesthetics in young children and infants has raised concerns regarding the adverse effects of these drugs on brain development. Sevoflurane might have harmful effects on the developing brain; however, these effects have not been well investigated. METHODS: Postnatal day 7 (P7) Sprague-Dawley rats were continuously exposed to 2.3% sevoflurane for 6 h. We used the Fox battery test and Morris water maze (MWM) to examine subsequent neurobehavioural performance. Cleaved caspase-3 and neuronal nitric oxide synthase (nNOS) were quantified by immunoblotting, and the Nissl staining was used to observe the histopathological changes in the hippocampus. RESULTS: A single 6 h sevoflurane exposure at P7 rats resulted in increased cleaved caspase 3 expression and decreased nNOS levels in the hippocampus, and induced the loss of pyramidal neurones in the CA1 and CA3 subfields of the hippocampus at P7-8. These changes were accompanied by temporal retardation of sensorimotor reflexes. However, neither the Fox battery test at P1-21 nor the MWM test at P28-32 showed differences between the air- and sevoflurane-treated groups. CONCLUSIONS: Although early exposure to sevoflurane increases activated caspase-3 expression and neuronal loss and decreases nNOS in the neonatal hippocampus, it does not affect subsequent neurobehavioural performances in juvenile rats. PMID- 22535835 TI - Effect of hydrocortisone on the production and glycosylation of an Fc-fusion protein in CHO cell cultures. AB - Glucocorticoids are known to modulate various cellular functions such as cell proliferation, metabolism, glycosylation, and secretion of many proteins. We tested the effect of hydrocortisone (HC) on cell growth, viability, metabolism, protein production, and glycosylation of an Fc-protein expressing Chinese hamster ovary (CHO) cell culture. HC extended cell viability but impaired cell growth. The inhibitory effect on cell growth was dose-dependent and decreased when the glucocorticoid addition was delayed. When HC was added after 2 or 3 days of culture, an increase in glutamate consumption was observed, which was reversed by the glucocorticoid receptor antagonist mifepristone (Mif). Titer and specific productivity increased in the presence of HC. The increase in titer was only slightly reversed by Mif. On the other hand, Mif by itself induced an increase in titer to a level comparable to or higher than HC. Protein glycosylation was altered by the glucocorticoid in a dose- and time-dependent manner, with a shift to more acidic bands, which correlated with an increase in sialic acid moieties. This increase, which was not linked to a decrease in extracellular sialidase activity in HC-treated cultures, was reversed by Mif. Predictive models based on design of experiments enabled the definition of optimal conditions for process performance in terms of viability and titer and for the quality of the Fc-fusion protein in terms of glycosylation. The data obtained suggest a use of glucocorticoids for commercial production of Fc-fusion proteins expressed in CHO cells. PMID- 22535836 TI - Social problem solving in children with fetal alcohol spectrum disorders. AB - BACKGROUND: Children with fetal alcohol spectrum disorders (FASD) show impairments in social functioning. However, the factors underlying these impairments are poorly understood. Recent evidence has shown that social problem solving is a critical component of effective social functioning. OBJECTIVES: The present study sought to examine social information processing as one potential factor contributing to social skills and behavior impairments observed in children with FASD. METHODS: Forty-three children, 20 with FASD (mean age 12.6 years) and 23 typically developing controls (TDC; mean age 12.5 years) were studied. Social information processing was investigated using the Children's Interpersonal Problem Solving task (ChIPS; Shure and Spivack, 1985), which assesses problem solving in response to social dilemmas. RESULTS: Children with FASD produced fewer relevant responses than TDC and their responses belonged to a fewer number of categories. CONCLUSION: Children with FASD show reduced ability in generating solutions for social dilemmas. By understanding this weakness, which may partially explain the social skill deficiencies in FASD, targeted therapies may be designed to improve social functioning following prenatal alcohol exposure. PMID- 22535839 TI - The pharmacists' role in the Patient-Centered Medical Home (PCMH): a white paper created by the Health Policy Committee of the Pennsylvania Pharmacists Association (PPA). PMID- 22535840 TI - Levofloxacin-induced tendinopathy of the hip. AB - OBJECTIVE: To describe what we believe to be the first reported possible case of tendinopathy of the hip in a patient receiving levofloxacin. CASE SUMMARY: A 58 year-old male with recurrent otitis media was admitted for left lateral hip pain of 10 on a scale of 10. He had started a 5-day course of levofloxacin 750 mg/day 10 days before he began experiencing pain. He also took simvastatin 20 mg/day and walked 90 minutes each day. He was treated with oxycodone with acetaminophen and physical therapy. His pain had improved significantly at a 10-day recheck. DISCUSSION: Fluoroquinolone-induced tendinopathy has been well-reported in the literature, but most cases involve pefloxacin and affect the Achilles tendon. Only 11 cases of tendinopathy have been reported with levofloxacin based on a MEDLINE search (1966-December 2011). This is the first known case reported that involved tendinopathy of the hip believed to be caused by fluoroquinolones. The Naranjo probability scale revealed a possible adverse reaction of levofloxacin induced tendinopathy of the hip. Contributing factors likely included the high dose of levofloxacin, concomitant use of a statin, and strenuous physical activity. CONCLUSIONS: Health care professionals should be aware of the possibility of tendinopathy of the hip in patients who receive fluoroquinolones. Thorough history for possible risk factors should be obtained. Patients on fluoroquinolones at risk for tendinopathy should be counseled to avoid strenuous physical activity. PMID- 22535841 TI - Efavirenz severe hypersensitivity reaction: case report and rapid desensitization protocol development. AB - OBJECTIVE: Long-term efavirenz desensitization protocols have been reported; however, publication of a rapid desensitization protocol has not been noted to date. We report a case of severe hypersensitivity reaction that was successfully managed using a rapid desensitization protocol. CASE SUMMARY: In a 52-year old HIV-positive woman, antiretroviral therapy was started with lamivudine 150 mg twice daily, zidovudine 300 mg twice daily, and efavirenz 600 mg daily. Nine days after starting antiretroviral therapy, she developed a generalized maculopapular rash. Despite concomitant chlorpheniramine administration, the rash did not improve. With suspicion of efavirenz hypersensitivity reaction, efavirenz was discontinued for 5 days and when the patient's rash resolved, the drug was restarted at 600 mg daily. The patient developed a severe generalized pruritic rash the next day and all antiretroviral agents were discontinued. One week later, lamivudine and zidovudine were restarted and were well tolerated. An OBJECTIVE: 20,000 solution of the target therapeutic dose, was successful. The patient was followed for 6 weeks and had no further signs or symptoms of a hypersensitivity reaction. DISCUSSION: Efavirenz hypersensitivity reactions typically include cutaneous reactions that are observed in the first 2 weeks of treatment, are often mild to moderate without systemic manifestation, and improve with continued therapy. Previously, successful desensitization protocols have been described in patients receiving efavirenz who developed rash without systemic symptoms, but these protocols were carried out over 7 or 14 days. This case report indicates a rapid desensitization protocol that may be an available option for some patients. CONCLUSIONS: Considering that efavirenz can be the cornerstone of many antiretroviral therapy regimens and hypersensitivity reactions can restrict regimen options, effective desensitization protocols are valuable, especially in the developing countries with limited available antiretroviral drugs. PMID- 22535843 TI - The cover. Willimantic thread factory. PMID- 22535842 TI - Aggressiveness of human melanoma xenograft models is promoted by aneuploidy driven gene expression deregulation. AB - Melanoma is a devastating skin cancer characterized by distinct biological subtypes. Besides frequent mutations in growth- and survival-promoting genes like BRAF and NRAS, melanomas additionally harbor complex non-random genomic alterations. Using an integrative approach, we have analysed genomic and gene expression changes in human melanoma cell lines (N=32) derived from primary tumors and various metastatic sites and investigated the relation to local growth aggressiveness as xenografts in immuno-compromised mice (N=22). Although the vast majority >90% of melanoma models harbored mutations in either BRAF or NRAS, significant differences in subcutaneous growth aggressiveness became obvious. Unsupervised clustering revealed that genomic alterations rather than gene expression data reflected this aggressive phenotype, while no association with histology, stage or metastatic site of the original melanoma was found. Genomic clustering allowed separation of melanoma models into two subgroups with differing local growth aggressiveness in vivo. Regarding genes expressed at significantly altered levels between these subgroups, a surprising correlation with the respective gene doses (>85% accordance) was found. Genes deregulated at the DNA and mRNA level included well-known cancer genes partly already linked to melanoma (RAS genes, PTEN, AURKA, MAPK inhibitors Sprouty/Spred), but also novel candidates like SIPA1 (a Rap1GAP). Pathway mining further supported deregulation of Rap1 signaling in the aggressive subgroup e.g. by additional repression of two Rap1GEFs. Accordingly, siRNA-mediated down-regulation of SIPA1 exerted significant effects on clonogenicity, adherence and migration in aggressive melanoma models. Together our data suggest that an aneuploidy-driven gene expression deregulation drives local aggressiveness in human melanoma. PMID- 22535844 TI - Media lab uses videos, comics, and more to help people understand health issues. PMID- 22535845 TI - Laws boost pediatric clinical trials, but report finds room for improvement. PMID- 22535846 TI - US reviews high-risk research portfolio. PMID- 22535847 TI - International variation in readmission after myocardial infarction. PMID- 22535848 TI - International variation in readmission after myocardial infarction. PMID- 22535849 TI - Dietary protein and weight gain. PMID- 22535850 TI - 2008 US Preventive Services Task Force recommendations and prostate cancer screening rates. PMID- 22535851 TI - Sharing clinical data electronically: a critical challenge for fixing the health care system. PMID- 22535852 TI - New physicians, the Affordable Care Act, and the changing practice of medicine. PMID- 22535853 TI - Specialty hospitalists: analyzing an emerging phenomenon. PMID- 22535854 TI - A piece of my mind. Keep that. PMID- 22535855 TI - Effect of a text messaging intervention on influenza vaccination in an urban, low income pediatric and adolescent population: a randomized controlled trial. AB - CONTEXT: Influenza infection results in substantial costs, morbidity, and mortality. Vaccination against influenza is particularly important in children and adolescents who are a significant source of transmission to other high-risk populations, yet pediatric and adolescent vaccine coverage remains low. Traditional vaccine reminders have had a limited effect on low-income populations; however, text messaging is a novel, scalable approach to promote influenza vaccination. OBJECTIVE: To evaluate targeted text message reminders for low-income, urban parents to promote receipt of influenza vaccination among children and adolescents. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial of 9213 children and adolescents aged 6 months to 18 years receiving care at 4 community-based clinics in the United States during the 2010 2011 influenza season. Of the 9213 children and adolescents, 7574 had not received influenza vaccine prior to the intervention start date and were included in the primary analysis. INTERVENTION: Parents of children assigned to the intervention received up to 5 weekly immunization registry-linked text messages providing educational information and instructions regarding Saturday clinics. Both the intervention and usual care groups received the usual care, an automated telephone reminder, and access to informational flyers posted at the study sites. MAIN OUTCOME MEASURES: Receipt of an influenza vaccine dose recorded in the immunization registry via an electronic health record by March 31, 2011. Receipt was secondarily assessed at an earlier fall review date prior to typical widespread influenza activity. RESULTS: Study children and adolescents were primarily minority, 88% were publicly insured, and 58% were from Spanish-speaking families. As of March 31, 2011, a higher proportion of children and adolescents in the intervention group (43.6%; n = 1653) compared with the usual care group (39.9%; n = 1509) had received influenza vaccine (difference, 3.7% [95% CI, 1.5% 5.9%]; relative rate ratio [RRR], 1.09 [95% CI, 1.04-1.15]; P = .001). At the fall review date, 27.1% (n = 1026) of the intervention group compared with 22.8% (n = 864) of the usual care group had received influenza vaccine (difference, 4.3% [95% CI, 2.3%-6.3%]; RRR, 1.19 [95% CI, 1.10-1.28]; P < .001). CONCLUSIONS: Among children and adolescents in a low-income, urban population, a text messaging intervention compared with usual care was associated with an increased rate of influenza vaccination. However, the overall influenza vaccination rate remained low. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01146912. PMID- 22535856 TI - Association between hospital recognition for nursing excellence and outcomes of very low-birth-weight infants. AB - CONTEXT: Infants born at very low birth weight (VLBW) require high levels of nursing intensity. The role of nursing in outcomes for these infants in the United States is not known. OBJECTIVE: To examine the relationships between hospital recognition for nursing excellence (RNE) and VLBW infant outcomes. DESIGN, SETTING, AND PATIENTS: Cohort study of 72,235 inborn VLBW infants weighing 501 to 1500 g born in 558 Vermont Oxford Network hospital neonatal intensive care units between January 1, 2007, and December 31, 2008. Hospital RNE was determined from the American Nurses Credentialing Center. The RNE designation is awarded when nursing care achieves exemplary practice or leadership in 5 areas. MAIN OUTCOME MEASURES: Seven-day, 28-day, and hospital stay mortality; nosocomial infection, defined as an infection in blood or cerebrospinal fluid culture occurring more than 3 days after birth; and severe (grade 3 or 4) intraventricular hemorrhage. RESULTS: Overall, the outcome rates were as follows: for 7-day mortality, 7.3% (5258/71,955); 28-day mortality, 10.4% (7450/71,953); hospital stay mortality, 12.9% (9278/71,936); severe intraventricular hemorrhage, 7.6% (4842/63,525); and infection, 17.9% (11,915/66,496). The 7-day mortality was 7.0% in RNE hospitals and 7.4% in non-RNE hospitals (adjusted odds ratio [OR], 0.87; 95% CI, 0.76-0.99; P = .04). The 28-day mortality was 10.0% in RNE hospitals and 10.5% in non-RNE hospitals (adjusted OR, 0.90; 95% CI, 0.80-1.01; P = .08). Hospital stay mortality was 12.4% in RNE hospitals and 13.1% in non-RNE hospitals (adjusted OR, 0.90; 95% CI, 0.81-1.01; P = .06). Severe intraventricular hemorrhage was 7.2% in RNE hospitals and 7.8% in non-RNE hospitals (adjusted OR, 0.88; 95% CI, 0.77-1.00; P = .045). Infection was 16.7% in RNE hospitals and 18.3% in non-RNE hospitals (adjusted OR, 0.86; 95% CI, 0.75 0.99; P = .04). Compared with RNE hospitals, the adjusted absolute decrease in risk of outcomes in RNE hospitals ranged from 0.9% to 2.1%. All 5 outcomes were jointly significant (P < .001). The mean effect across all 5 outcomes was OR, 0.88 (95% CI, 0.83-0.94; P < .001). In a subgroup of 68,253 infants with gestational age of 24 weeks or older, the ORs for RNE for all 3 mortality outcomes and infection were statistically significant. CONCLUSION: Among VLBW infants born in RNE hospitals compared with non-RNE hospitals, there was a significantly lower risk-adjusted rate of 7-day mortality, nosocomial infection, and severe intraventricular hemorrhage but not of 28-day mortality or hospital stay mortality. PMID- 22535858 TI - Botulinum toxin A for prophylactic treatment of migraine and tension headaches in adults: a meta-analysis. AB - CONTEXT: Botulinum toxin A is US Food and Drug Administration approved for prophylactic treatment for chronic migraines. OBJECTIVE: To assess botulinum toxin A for the prophylactic treatment of headaches in adults. DATA SOURCES: A search of MEDLINE, EMBASE, bibliographies of published systematic reviews, and the Cochrane trial registries between 1966 and March 15, 2012. Inclusion and exclusion criteria of each study were reviewed. Headaches were categorized as episodic (<15 headaches per month) or chronic (>=15 headaches per month) migraine and episodic or chronic daily or tension headaches. STUDY SELECTION: Randomized controlled trials comparing botulinum toxin A with placebo or other interventions for headaches among adults. DATA EXTRACTION: Data were abstracted and quality assessed independently by 2 reviewers. Outcomes were pooled using a random effects model. DATA SYNTHESIS: Pooled analyses suggested that botulinum toxin A was associated with fewer headaches per month among patients with chronic daily headaches (1115 patients, -2.06 headaches per month; 95% CI, -3.56 to -0.56; 3 studies) and among patients with chronic migraine headaches (n = 1508, -2.30 headaches per month; 95% CI, -3.66 to -0.94; 5 studies). There was no significant association between use of botulinum toxin A and reduction in the number of episodic migraine (n = 1838, 0.05 headaches per month; 95% CI, -0.26 to 0.36; 9 studies) or chronic tension-type headaches (n = 675, -1.43 headaches per month; 95% CI, -3.13 to 0.27; 7 studies). In single trials, botulinum toxin A was not associated with fewer migraine headaches per month vs valproate (standardized mean difference [SMD], -0.20; 95% CI, -0.91 to 0.31), topiramate (SMD, 0.20; 95% CI, -0.36 to 0.76), or amitriptyline (SMD, 0.29; 95% CI, -0.17 to 0.76). Botulinum toxin A was associated with fewer chronic tension-type headaches per month vs methylprednisolone injections (SMD, -2.5; 95% CI, -3.5 to -1.5). Compared with placebo, botulinum toxin A was associated with a greater frequency of blepharoptosis, skin tightness, paresthesias, neck stiffness, muscle weakness, and neck pain. CONCLUSION: Botulinum toxin A compared with placebo was associated with a small to modest benefit for chronic daily headaches and chronic migraines but was not associated with fewer episodic migraine or chronic tension-type headaches per month. PMID- 22535859 TI - Episodic abdominal and chest pain in a young adult. PMID- 22535860 TI - Text messaging: a new tool for improving preventive services. PMID- 22535861 TI - Improving systems in perinatal care: quality, not quantity. PMID- 22535862 TI - JAMA patient page. Sudden infant death syndrome. PMID- 22535863 TI - Pro-malignant properties of STAT3 during chronic inflammation. PMID- 22535857 TI - Clinical characteristics and outcome of infective endocarditis involving implantable cardiac devices. AB - CONTEXT: Infection of implantable cardiac devices is an emerging disease with significant morbidity, mortality, and health care costs. OBJECTIVES: To describe the clinical characteristics and outcome of cardiac device infective endocarditis (CDIE) with attention to its health care association and to evaluate the association between device removal during index hospitalization and outcome. DESIGN, SETTING, AND PATIENTS: Prospective cohort study using data from the International Collaboration on Endocarditis-Prospective Cohort Study (ICE-PCS), conducted June 2000 through August 2006 in 61 centers in 28 countries. Patients were hospitalized adults with definite endocarditis as defined by modified Duke endocarditis criteria. MAIN OUTCOME MEASURES: In-hospital and 1-year mortality. RESULTS: CDIE was diagnosed in 177 (6.4% [95% CI, 5.5%-7.4%]) of a total cohort of 2760 patients with definite infective endocarditis. The clinical profile of CDIE included advanced patient age (median, 71.2 years [interquartile range, 59.8 77.6]); causation by staphylococci (62 [35.0% {95% CI, 28.0%-42.5%}] Staphylococcus aureus and 56 [31.6% {95% CI, 24.9%-39.0%}] coagulase-negative staphylococci); and a high prevalence of health care-associated infection (81 [45.8% {95% CI, 38.3%-53.4%}]). There was coexisting valve involvement in 66 (37.3% [95% CI, 30.2%-44.9%]) patients, predominantly tricuspid valve infection (43/177 [24.3%]), with associated higher mortality. In-hospital and 1-year mortality rates were 14.7% (26/177 [95% CI, 9.8%-20.8%]) and 23.2% (41/177 [95% CI, 17.2%-30.1%]), respectively. Proportional hazards regression analysis showed a survival benefit at 1 year for device removal during the initial hospitalization (28/141 patients [19.9%] who underwent device removal during the index hospitalization had died at 1 year, vs 13/34 [38.2%] who did not undergo device removal; hazard ratio, 0.42 [95% CI, 0.22-0.82]). CONCLUSIONS: Among patients with CDIE, the rate of concomitant valve infection is high, as is mortality, particularly if there is valve involvement. Early device removal is associated with improved survival at 1 year. PMID- 22535864 TI - Two novel mutations in the L ferritin coding sequence associated with benign hyperferritinaemia unmasked by glycosylated ferritin assay. AB - Investigating persistent hyperferritinaemia without apparent iron overload is challenging. Even when inflammation, cirrhosis, Still's disease, fatty liver and malignancy are excluded, there remains a group of patients with unexplained hyperferritinaemia for whom rare forms of haemochromatosis (ferroportin disease) are a consideration. Preliminary results suggest that abnormal percentage glycosylation of serum ferritin is seen in some cases of genetically determined hyperferritinaemia. Serum ferritin is normally 50-81% glycosylated, but low glycosylation (20-42%) prevails in hereditary hyperferritinaemia cataract syndrome. This contrasts with hyperglycosylation (>90%) associated with the benign hyperferritinaemia related to missense L ferritin (p.Thr30Ile) mutation. Here, we describe two novel missense L ferritin variants also associated with hyperglycosylation, p.Gln26Ile and p.Ala27Val. Ferritin glycosylation, a comparatively simple measurement, can identify patients for DNA sequencing as hyperglycosylation (>90%) is associated with benign hyperferritinaemia and mutant L ferritin chain. PMID- 22535865 TI - Calcium adjustment equations in neonates and children. AB - BACKGROUND: Calcium exists in human blood in a free form and in a form bound to plasma proteins, principally albumin. Since it is the ionized form that is biologically active, it has long been common practice to present calcium adjusted on the basis of serum albumin concentration. The concept of adjusted calcium has only been evaluated in adults. In this study, we evaluated the use of the adult adjusted equation to report calcium in children. METHODS: We searched the laboratory information system over three teaching hospitals for young patients aged between newborn and 18 years old with a request for calcium and albumin analysis but with no evidence of disturbances of calcium homeostasis. These data were organized on the basis of age and was separated into four age groups (birth to 1 month old, 1 month to 1 year old, 1 to 5 years old and 5 to 18 years old). These data were subjected to regression analysis to derive the calcium-adjusted equation for each age group. RESULTS: There is an inverse relationship between the bias value and the age. The younger the age, the higher the difference between the adjusted calcium calculated by the adult equation and that calculated by the age-specific equation. This pattern was maintained on all sites. CONCLUSION: For all sites, the adult-adjusted calcium equation may be used to calculate the adjusted calcium for children aged one year old and above. PMID- 22535866 TI - Cost of haemolysis. PMID- 22535867 TI - Environmental persistence of amphibian and reptilian ranaviruses. AB - Ranaviruses infect fish, amphibians, and reptiles. The present study was conducted to compare the persistence of amphibian and reptilian ranaviruses in a pond habitat. The 4 viruses used in this study included 2 amphibian ranaviruses, Frog virus 3 (FV3, the type species of the genus Ranavirus) and an isolate from a frog, and 2 ranaviruses of reptilian origin (from a tortoise and from a gecko). A sandwich germ-carrier technique was used to study the persistence of these viruses in sterile and unsterile pond water (PW) and soil obtained from the bank of a pond. For each virus, virus-loaded carriers were placed in each of the 3 substrates, incubated at 4 and 20 degrees C, and titrated at regular intervals. Serial data were analyzed using a linear regression model to calculate T-90 values (time required for 90% reduction in the virus titer). Resistance of the viruses to drying was also studied. All 4 viruses were resistant to drying. At 20 degrees C, T-90 values of the viruses were 22 to 31 d in sterile PW and 22 to 34 d in unsterile PW. Inactivation of all 4 viruses in soil at this temperature appeared to be non-linear. T-90 values at 4 degrees C were 102 to 182 d in sterile PW, 58 to 72 d in unsterile PW, and 30 to 48 d in soil. Viral persistence was highest in the sterile PW, followed by the unsterile PW, and was lowest in soil. There were no significant differences in the survival times between the amphibian and reptilian viruses. The results of the present study suggest that ranaviruses can survive for long periods of time in pond habitats at low temperatures. PMID- 22535868 TI - Protection from yellow head virus (YHV) infection in Penaeus vannamei pre infected with Taura syndrome virus (TSV). AB - Pacific white shrimp Penaeus vannamei that were pre-exposed to Taura syndrome virus (TSV) and then challenged with yellow head virus (YHV) acquired partial protection from yellow head disease (YHD). Experimental infections were carried out using specific-pathogen-free (SPF) shrimp which were first exposed per os to TSV; at 27, 37 and 47 d post infection they were then challenged by injection with 1 * 104 copies of YHV per shrimp (designated the TSV-YHV group). Shrimp not infected with TSV were injected with YHV as a positive control. Survival analyses comparing the TSV-YHV and YHV (positive control) groups were conducted, and significant survival rates were found for all the time groups (p < 0.001). A higher final survival was found in the TSV-YHV group (mean 55%) than in the positive control (0%) (p < 0.05). Duplex reverse transcription quantitative PCR was used to quantify both TSV and YHV. Lower YHV copy numbers were found in the TSV-YHV group than in the positive control in pleopods (3.52 * 109 vs. 1.88 * 1010 copies ug RNA-1) (p < 0.001) and lymphoid organ (LO) samples (3.52 * 109 vs. 1.88 * 1010 copies ug RNA-1) (p < 0.01). In situ hybridization assays were conducted, and differences in the distribution of the 2 viruses in the target tissues were found. The foci of LO were infected with TSV but were not infected with YHV. This study suggests that a viral interference effect exists between TSV and YHV, which could, in part, explain the absence of YHD in the Americas, where P. vannamei are often raised in farms where TSV is present. PMID- 22535869 TI - Feeding hermit crabs to shrimp broodstock increases their risk of WSSV infection. AB - White spot syndrome virus (WSSV) is a serious shrimp pathogen that has spread globally to all major shrimp farming areas, causing enormous economic losses. Here we investigate the role of hermit crabs in transmitting WSSV to Penaeus monodon brooders used in hatcheries in Vietnam. WSSV-free brooders became PCR positive for WSSV within 2 to 14 d, and the source of infection was traced to hermit crabs being used as live feed. Challenging hermit crabs with WSSV confirmed their susceptibility to infection, but they remained tolerant to disease even at virus loads equivalent to those causing acute disease in shrimp. As PCR screening also suggests that WSSV infection occurs commonly in hermit crab populations in both Vietnam and Taiwan, their use as live feed for shrimp brooders is not recommended. PMID- 22535870 TI - Crassostrea gigas oysters as a shrimp farm bioindicator of white spot syndrome virus. AB - This study explored whether Crassostrea gigas oysters can be used as a bioindicator of white spot syndrome virus (WSSV) in shrimp farm water canals. Bioassays showed that C. gigas can accumulate WSSV in their gills and digestive glands but do not become infected, either by exposure to seawater containing WSSV or by cohabitation with infected shrimp. The use of a WSSV nested PCR to screen oysters placed in water canals at the entry of a shrimp farm allowed WSSV to be detected 16 d prior to the disease occurring. The finding that C. gigas can concentrate small amounts of WSSV present in seawater without being harmed makes it an ideal sentinel species at shrimp farms. PMID- 22535871 TI - First report of Perkinsus beihaiensis in Crassostrea madrasensis from the Indian subcontinent. AB - Protozoan parasites of the genus Perkinsus are considered important pathogens responsible for mass mortalities in many wild and farmed bivalve populations. The present study was initiated to screen populations of the Indian edible oyster Crassostrea madrasensis, a promising candidate for aquaculture along the Indian coasts, for the presence of Perkinsus spp. The study reports the presence of P. beihaiensis for the first time in C. madrasensis populations from the Indian subcontinent and south Asia. Samples collected from the east and west coasts of India were subjected to Ray's fluid thioglycollate medium (RFTM) culture and histology which indicated the presence of Perkinsus spp. PCR screening of the tissues using specific primers amplified the product specific to the genus Perkinsus. The taxonomic affinities of the parasites were determined by sequencing both internal transcribed spacer (ITS) and actin genes followed by basic local alignment search tool (BLAST) analysis. Analysis based on the ITS sequences showed 98 to 100% identity to Perkinsus spp. (P. beihaiensis and Brazilian Perkinsus sp.). The pairwise genetic distance values and phylogenetic analysis confirmed that 2 of the present samples belonged to the P. beihaiensis clade while the other 4 showed close affinities with the Brazilian Perkinsus sp. clade. The genetic divergence data, close affinity with the Brazilian Perkinsus sp., and co-existence with P. beihaiensis in the same host species in the same habitat show that the remaining 4 samples exhibit some degree of variation from P. beihaiensis. As expected, the sequencing of actin genes did not show any divergence among the samples studied. They probably could be intraspecific variants of P. beihaiensis having a separate lineage in the process of evolution. PMID- 22535872 TI - Lesion bacterial communities in American lobsters with diet-induced shell disease. AB - In southern New England, USA, shell disease affects the profitability of the American lobster Homarus americanus fishery. In laboratory trials using juvenile lobsters, exclusive feeding of herring Clupea harengus induces shell disease typified initially by small melanized spots that progress into distinct lesions. Amongst a cohabitated, but segregated, cohort of 11 juvenile lobsters fed exclusively herring, bacterial communities colonizing spots and lesions were investigated by denaturing gradient gel electrophoresis of 16S rDNA amplified using 1 group-specific and 2 universal primer sets. The Bacteroidetes and Proteobacteria predominated in both spots and lesions and included members of the orders Flavobacteriales (Bacteriodetes), Rhodobacterales, Rhodospirillales and Rhizobiales (Alphaproteobacteria), Xanthomonadales (Gammaproteobacteria) and unclassified Gammaproteobacteria. Bacterial communities in spot lesions displayed more diversity than communities with larger (older) lesions, indicating that the lesion communities stabilize over time. At least 8 bacterial types persisted as lesions developed from spots. Aquimarina 'homaria', a species commonly cultured from lesions present on wild lobsters with epizootic shell disease, was found ubiquitously in spots and lesions, as was the 'Candidatus Kopriimonas aquarianus', implicating putative roles of these species in diet-induced shell disease of captive lobsters. PMID- 22535873 TI - Inflammatory responses of Nile tilapia Oreochromis niloticus to Streptococcus agalactiae: effects of vaccination and yeast diet supplement. AB - This study evaluated the effects of dietary supplementation with 0.3% Saccharomyces cerevisiae yeast cell wall and of vaccination against Streptococcus agalactiae on the cellular component of acute inflammation induced in the coelomic cavity of Nile tilapia Oreochromis niloticus and on survival of the fish after challenge. A total of 84 tilapia of mean (+/-SD) weight 125.0 +/- 1.5 g were distributed among twelve 310 l fiberglass tanks according to a 2 * 2 * 3 factorial design in the following manner: with and without supplementation; 2 stimulations (oily solution without S. agalactiae vaccine and vaccination); 15 d later all fish were intracoelomically challenged with 108 CFU ml-1 of a homologous strain of S. agalactiae, and evaluated after 6, 24 and 48 h, with 7 replicates. The fish received the non-supplemented or supplemented diet for a total of 77 d. The vaccination was performed on the 60th day, intracoelomically, as a single injection of 0.5 ml of the vaccine containing 108 CFU ml-1. Fifteen days later, all the fish were challenged with S. agalactiae by means of an intracoelomic inoculation of 108 CFU ml-1. No mortality was observed among the supplemented fish. The fish that were fed the non-supplemented diet and immunized with the bacterium presented a mortality rate of 28.5%. Among the non supplemented and non-immunized fish, the mortality rate was 38.09%. Supplementation, in both vaccinated and non-vaccinated fish, induced larger accumulations of thrombocytes, lymphocytes and macrophages at the inflammatory focus. The results suggest that supplementation with 0.3% yeast cell wall, in both vaccinated and non-vaccinated fish, improved the inflammatory response of the fish and protected against the challenge. Vaccination increased the defense response, but the effect was stronger when associated with supplementation with S. cerevisiae. PMID- 22535874 TI - Eradication of the chytrid fungus Batrachochytrium dendrobatidis in the Japanese giant salamander Andrias japonicus. AB - The purpose of this study was to establish a method for eradicating a chytrid fungus (Batrachochytrium dendrobatidis; Bd) from the Japanese giant salamander Andrias japonicus. The emerging agent (Bd) has a high rate of detection in this endangered amphibian species, which is designated as a special natural monument in Japan. Four Japanese giant salamanders with Bd confirmed by PCR assay were bathed in 0.01% itraconazole for 5 min d-1 over 10 successive days. PCR assays were conducted prior to treatment, on Days 5 and 10 of treatment, and on Days 7 and 14 post-treatment. By treatment Day 5, all individuals tested negative for Bd and remained negative until the end of the experiment. No side effects associated with itraconazole were observed. The present method appears to be a safe and effective approach for Bd eradication and may contribute to reducing the threat and spread of Bd among endangered amphibians. Notably, this study represents the first reported Bd eradication experiment involving Japanese giant salamanders. PMID- 22535875 TI - Candidatus Renichlamydia lutjani, a Gram-negative bacterium in internal organs of blue-striped snapper Lutjanus kasmira from Hawaii. AB - The blue-striped snapper Lutjanus kasmira (Perciformes, Lutjanidae) are cosmopolitan in the Indo-Pacific but were introduced into Oahu, Hawaii, USA, in the 1950s and have since colonized most of the archipelago. Studies of microparasites in blue-striped snappers from Hawaii revealed chlamydia-like organisms (CLO) infecting the spleen and kidney, characterized by intracellular basophilic granular inclusions containing Gram-negative and Gimenez-positive bacteria similar in appearance to epitheliocysts when seen under light microscopy. We provide molecular evidence that CLO are a new member of Chlamydiae, i.e. Candidatus Renichlamydia lutjani, that represents the first reported case of chlamydial infection in organs other than the gill in fishes. PMID- 22535876 TI - PCR detection of the crayfish plague pathogen in narrow-clawed crayfish inhabiting Lake Egirdir in Turkey. AB - Many populations of the narrow-clawed crayfish Astacus leptodactylus in Turkey, including those inhabiting Lake Egirdir, declined drastically in the mid-1980s due to introduction of crayfish plague Aphanomyces astaci. However, unlike many other localities, there has been some recovery in the A. leptodactylus population inhabiting this lake even though crayfish plague has been suspected to have persisted since then. In support of this, DNA from 5 of 34 healthy-looking crayfish sampled recently from the lake tested positive by both conventional and real-time PCR using species-specific primers targeting the rDNA internal transcribed spacer region, and product sequence analysis confirmed the identification of A. astaci. This complies with other recent reports of coexistence of native European crayfish with this pathogen, and further research is now needed to identify the key mechanisms allowing it. PMID- 22535879 TI - A review of experimental techniques to produce a nacre-like structure. AB - The performance of man-made materials can be improved by exploring new structures inspired by the architecture of biological materials. Natural materials, such as nacre (mother-of-pearl), can have outstanding mechanical properties due to their complicated architecture and hierarchical structure at the nano-, micro- and meso levels which have evolved over millions of years. This review describes the numerous experimental methods explored to date to produce composites with structures and mechanical properties similar to those of natural nacre. The materials produced have sizes ranging from nanometres to centimetres, processing times varying from a few minutes to several months and a different range of mechanical properties that render them suitable for various applications. For the first time, these techniques have been divided into those producing bulk materials, coatings and free-standing films. This is due to the fact that the material's application strongly depends on its dimensions and different results have been reported by applying the same technique to produce materials with different sizes. The limitations and capabilities of these methodologies have been also described. PMID- 22535878 TI - Per-unit-living tissue normalization of real-time RT-PCR data in ischemic rat hearts. AB - In studies of gene expression in acute ischemic heart tissue, internal reference genes need to show stable expression per-unit-living tissue to hinder dead cells from biasing real-time RT-PCR data. Until now, this important issue has not been appropriately investigated. We hypothesized that the expression of seven internal reference genes would show stable per-unit-living tissue expression in Langendorff-perfused rat hearts subjected to ischemia-reperfusion. This was found for cyclophilin A, GAPDH, RPL-32, and PolR2A mRNA, with GAPDH showing the highest degree of stability (R = 0.11), suggesting unchanged rates of mRNA transcription in live cells and complete degradation of mRNA from dead cells. The infarct size dependent degradation of GAPDH was further supported by a close correlation between changes in GAPDH mRNA and changes in RNA quality measured as RNA integrity number (R = 0.90, P < 0.05). In contrast, beta-actin and 18S rRNA showed stable expression per-unit-weight tissue and a positive correlation with infarct size (R = 0.61 and R = 0.77, P < 0.05 for both analyses). The amount of total RNA extracted per-unit-weight tissue did not differ between groups despite wide variation in infarct size (7.1-50.1%). When beta-actin expression was assessed using four different normalization strategies, GAPDH and geNorm provided appropriate per-unit-living expression, while 18S and total RNA resulted in marked underestimations. In studies of ischemic tissues, we recommend using geometric averaging of carefully selected reference genes for normalization of real-time RT-PCR data. A marked shift in the mRNA/rRNA ratio renders rRNA as useless for normalization purposes. PMID- 22535877 TI - Multiplexed digital quantification of binge-like alcohol-mediated alterations in maternal uterine angiogenic mRNA transcriptome. AB - Genomic studies on fetal alcohol spectrum disorders (FASD) have utilized either genome-wide microarrays/bioinformatics or targeted real-time PCR (RT-PCR). We utilized herein for the first time a novel digital approach with high throughput as well as the capability to focus on one physiological system. The aim of the present study was to investigate alcohol-induced alterations in uterine angiogenesis-related mRNA abundance using digital mRNA technology. Four biological and three technical replicates of uterine arterial endothelial cells from third-trimester ewes were fluorescence-activated cell sorted, validated, and treated without or with binge-like alcohol. A capture probe covalently bound to an oligonucleotide containing biotin and a color-coded reporter probe were designed for 85 angiogenesis-related genes and analyzed with the Nanostring nCounter system. Twenty genes were downregulated (?) and two upregulated (?), including angiogenic growth factors/receptors (?placental growth factor), adhesion molecules (?angiopoietin-like-3; ?collagen-18A1; ?endoglin), proteases/matrix proteins/inhibitors (?alanyl aminopeptidase; ?collagen-4A3; ?heparanase; ?plasminogen, ?plasminogen activator urokinase; ?platelet factor-4; ?plexin domain containing-1; ?tissue inhibitor of metalloproteinases-3), transcription/signaling molecules (?heart and neural crest derivatives-2; ?DNA binding protein inhibitor; ?NOTCH-4; ?ribosomal protein-L13a1; ?ribosomal protein large-P1), cytokines/chemokines (?interleukin-1B), and miscellaneous growth factors (?leptin; ?platelet-derived growth factor-alpha); ?transforming growth factor (TGF-alpha; ?TGF-beta receptor-1). These novel data show significant detrimental alcohol effects on genes controlling angiogenesis supporting a mechanistic role for abnormal uteroplacental vascular development in FASD. The tripartite digital gene expression system is therefore a valuable tool to answer many additional questions about FASD from both mechanistic as well as ameliorative perspectives. PMID- 22535881 TI - Novel flavonoid didymin inhibits neuroblastomas--letter. PMID- 22535882 TI - Biomechanics of smart wings in a bat robot: morphing wings using SMA actuators. AB - This paper presents the design of a bat-like micro aerial vehicle with actuated morphing wings. NiTi shape memory alloys (SMAs) acting as artificial biceps and triceps muscles are used for mimicking the morphing wing mechanism of the bat flight apparatus. Our objective is twofold. Firstly, we have implemented a control architecture that allows an accurate and fast SMA actuation. This control makes use of the electrical resistance measurements of SMAs to adjust morphing wing motions. Secondly, the feasibility of using SMA actuation technology is evaluated for the application at hand. To this purpose, experiments are conducted to analyze the control performance in terms of nominal and overloaded operation modes of the SMAs. This analysis includes: (i) inertial forces regarding the stretchable wing membrane and aerodynamic loads, and (ii) uncertainties due to impact of airflow conditions over the resistance-motion relationship of SMAs. With the proposed control, morphing actuation speed can be increased up to 2.5 Hz, being sufficient to generate lift forces at a cruising speed of 5 m s(-1). PMID- 22535883 TI - Detection and characterization of small focal hepatic lesions (<=2.5 cm in diameter): a comparison of diffusion-weighted images before and after administration of gadoxetic acid disodium at 3.0T. AB - BACKGROUND: As diffusion-weighted imaging (DWI) is routinely incorporated into the standard clinical protocol, it is clinically relevant to determine whether DWI after gadoxetic acid is comparable to pre-contrast DWI, with regard to the detection and characterization of focal liver lesions. PURPOSE: To compare DWI before and after administration of gadoxetic acid in the detection and characterization of small (<=2.5 cm) focal hepatic lesions. MATERIAL AND METHODS: One hundred and fifty-eight patients with 237 focal hepatic lesions (<=2.5 cm) (124 HCCs, 50 metastases, 2 cholangiocarcinomas, 43 hemangiomas, and 18 cysts) were included. DWIs were obtained before and after administration of gadoxetic acid. Non-breath-hold DWI was performed with b values of 0, 100, and 800 s/mm(2). Signal-to-noise ratio (SNR), lesion-liver contrast-to-noise ratio (CNR), and apparent diffusion coefficients (ADCs) of the liver and lesion were calculated. Lesion detection with each DWI was evaluated with alternative free-response receiver-operating characteristic analysis by two observers. The sensitivity of the characterization of focal hepatic lesions as solid (malignancy) or non-solid (benignity) with each DWI was calculated using a five-point confidence scale. Inter-observer agreement regarding lesion detection and characterization was evaluated using kappa statistics. RESULTS: SNRs of the liver on post-contrast DWI were significantly lower than on unenhanced DWI at b = 800 s/mm(2) (P < 0.05). SNRs, CNRs, and ADCs of focal hepatic lesions were not significantly different between two DWIs (P > 0.05). The diagnostic accuracy (Az) for lesion detection and the sensitivity for lesion characterization did not show significant difference between two DWIs (P > 0.05). With regard to the detection and characterization of focal hepatic lesions, the kappa values for two DWIs indicated good and excellent inter-observer agreement, respectively. CONCLUSION: Gadoxetic acid-enhanced DWI showed comparable diagnostic capability to unenhanced DWI for the detection and characterization of small focal hepatic lesions. PMID- 22535884 TI - Accuracy of MRI with an endorectal coil for staging endometrial cancer. AB - BACKGROUND: The very good results of magnetic resonance imaging (MRI) using an endorectal coil in staging prostate cancer at 1.5T suggested that this imaging technique might be able to be used to stage endometrial cancer, the most common tumor in postmenopausal women. PURPOSE: To evaluate the accuracy of MRI with an endorectal surface coil for staging primary endometrial carcinoma. MATERIAL AND METHODS: A total of 33 consecutive patients with biopsy-proven endometrial cancer underwent 1.5T MRI with an endorectal surface coil (eMRI) using sagittal and axial T2-weighted (T2w) turbo spin echo (TSE), axial T1 gradient echo 2D fat saturated (fs), sagittal T1 gradient echo 3D with and without contrast enhancement (CE), and axial T1 TSE fs CE sequence. Evaluation of local tumor extension was based on the revised standard TNM classification for endometrial cancer. eMRI staging was compared with the histopathological results after surgery. RESULTS: A total of 33 consecutive patients underwent eMRI for staging endometrial cancer, and 21 of these underwent primary surgery. The histological stages were as follows: T1a (n = 8), T1b (n = 10), T2b (n = 2), and T3a (n = 1). Overall staging accuracy by eMRI was 71% (15 of 21). With regard to depth of myometrial invasion, eMRI correctly diagnosed stage T1a in 75% (6/8) and stage T1b in 80% (8/10). eMRI overstaged the tumor in four patients and understaged it in two. CONCLUSION: eMRI is highly accurate in staging myometrial invasion. However, eMRI at 1.5T does not seem to be significantly more accurate than pelvic MRI without an endorectal coil at 1.5T for staging primary endometrial cancer. eMRI for endometrial carcinoma therefore might not meet expectations compared with the results obtained using eMRI for staging prostate cancer at 1.5T. PMID- 22535885 TI - In-phase and out-of-phase gradient-echo imaging in abdominal studies: intra individual comparison of three different techniques. AB - BACKGROUND: T1-weighted gradient-echo in-phase and out-of-phase imaging is an essential component of comprehensive abdominal MR exams. It is useful for the study of fat-containing lesions and to identify various disease states related to the presence of fat in the liver. PURPOSE: To compare three T1-weighted in-phase and out-of-phase (IP/OP) gradient-echo imaging sequences in an intra-individual fashion, and to determine whether advantages exist for each of these sequences for various patient types. MATERIAL AND METHODS: One hundred and eighteen consecutive subjects (74 men, 44 women; mean age 53.9 +/- 13.8 years) who had MRI examinations containing all three different IP/OP sequences (two-dimensional spoiled gradient-echo [2D-GRE], three-dimensional gradient-echo [3D-GRE], and magnetization-prepared gradient-recall echo [MP-GRE]) were included. Two different reviewers independently and blindly qualitatively evaluated IP/OP sequences to determine image quality, extent of artifacts, lesion detectability and conspicuity, and subjective grading of liver steatosis for the various sequences. Quantitative analysis was also performed. Qualitative and quantitative data were subjected to statistical analysis. RESULTS: Respiratory ghosting, parallel imaging, and truncation artifacts as well as shading and blurring were more pronounced with 3D-GRE IP/OP imaging. Overall image quality was higher with 2D-GRE (P < 0.05). Detectability of low-fluid content lesions was lower with IP/OP MP-GRE sequences. MP-GRE sequences had the lowest SNRs (P < 0.001). Liver to-spleen and liver-to-lesion CNRs were significantly lower with 3D-GRE and MP GR, respectively (P < 0.001). Fat liver indexes showed strongly positive correlation between all sequences. CONCLUSION: Currently, 2D-GRE remains the best approach for clinical IP/OP imaging. The good image quality of MP-GRE sequences acquired in a free-breathing manner should recommend its use in patients unable to suspend breathing. PMID- 22535886 TI - A line-broadening analysis model for the microstructural characterization of nanocrystalline materials from asymmetric x-ray diffraction peaks. AB - Nanograin sizes and crystal lattice microstrains in nanocrystalline materials are typically evaluated from the broadening of their x-ray diffraction (XRD) peaks under the assumption of symmetrical diffraction profiles. Since this assumption is not entirely satisfactory, we formulate a line-broadening analysis model of a single peak that considers explicitly the XRD peak asymmetry. The model is a generalization of the variance method in which the shape of the XRD peaks is idealized through asymmetrical split pseudo-Voigt functions. The model is validated on two nanocrystalline powders. PMID- 22535888 TI - Orrin hatch and the dietary supplement health and education act: Pandora's Box revisited. AB - Products of unknown safety and efficacy were once referred to as "quackery," and the US Food and Drug Administration (FDA) was empowered to protect public health by preventing their sale and forcing them from the market. However, in 1994, the Dietary Supplement Health and Education Act legitimized their sale as "dietary supplements." Sales increased dramatically, and many Americans now use herbals, homeopathics, and other so-called supplements. The Food and Drug Administration cannot act against them until patients have already been harmed, a dangerous situation. Furthermore, no governmental agency has the authority to force the manufacturers to furnish proof of efficacy. It is vital for physicians to warn their patients that they should use these unproven products only with great caution, and must never discontinue legitimate medical therapy in lieu of unproven products. PMID- 22535887 TI - Androgen hormone action in prostatic carcinogenesis: stromal androgen receptors mediate prostate cancer progression, malignant transformation and metastasis. AB - It has been postulated that prostatic carcinogenesis is androgen dependent and that androgens mediate their effects primarily through epithelial cells; however, definitive proof of androgen hormone action in prostate cancer (PRCA) progression is lacking. Here we demonstrate through genetic loss of function experiments that PRCA progression is androgen dependent and that androgen dependency occurs via prostatic stromal androgen receptors (AR) but not epithelial AR. Utilizing tissue recombination models of prostatic carcinogenesis, loss of AR function was evaluated by surgical castration or genetic deletion. Loss of AR function prevented prostatic carcinogenesis, malignant transformation and metastasis. Tissue-specific evaluation of androgen hormone action demonstrated that epithelial AR was not necessary for PRCA progression, whereas stromal AR was essential for PRCA progression, malignant transformation and metastasis. Stromal AR was not necessary for prostatic maintenance, suggesting that the lack of cancer progression due to stromal AR deletion was not related to altered prostatic homeostasis. Gene expression analysis identified numerous androgen regulated stromal factors. Four candidate stromal AR-regulated genes were secreted growth factors: fibroblast growth factors-2, -7, -10 and hepatocyte growth factor which were significantly affected by androgens and anti-androgens in stromal cells grown in vitro. These data support the concept that androgens are necessary for PRCA progression and that the androgen-regulated stromal microenvironment is essential to carcinogenesis, malignant transformation and metastasis and may serve as a potential target in the prevention of PRCA. PMID- 22535890 TI - 100 years since Scott reached the pole: a century of learning about the physiological demands of Antarctica. AB - The 1910-1913 Terra Nova Expedition to the Antarctic, led by Captain Robert Falcon Scott, was a venture of science and discovery. It is also a well-known story of heroism and tragedy since his quest to reach the South Pole and conduct research en route, while successful was also fateful. Although Scott and his four companions hauled their sledges to the Pole, they died on their return journey either directly or indirectly from the extreme physiological stresses they experienced. One hundred years on, our understanding of such stresses caused by Antarctic extremes and how the body reacts to severe exercise, malnutrition, hypothermia, high altitude, and sleep deprivation has greatly advanced. On the centenary of Scott's expedition to the bottom of the Earth, there is still controversy surrounding whether the deaths of those five men could have, or should have, been avoided. This paper reviews present-day knowledge related to the physiology of sustained man-hauling in Antarctica and contrasts this with the comparative ignorance about these issues around the turn of the 20th century. It closes by considering whether, with modern understanding about the effects of such a scenario on the human condition, Scott could have prepared and managed his team differently and so survived the epic 1,600-mile journey. The conclusion is that by carrying rations with a different composition of macromolecules, enabling greater calorific intake at similar overall weight, Scott might have secured the lives of some of the party, and it is also possible that enhanced levels of vitamin C in his rations, albeit difficult to achieve in 1911, could have significantly improved their survival chances. Nevertheless, even with today's knowledge, a repeat attempt at his expedition would by no means be bound to succeed. PMID- 22535893 TI - Cadherins in brain morphogenesis and wiring. AB - Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. Various cadherin-related molecules have also been identified, which show diverse functions, not only for the regulation of cell adhesion but also for that of cell proliferation and planar cell polarity. During the past decade, understanding of the roles of these molecules in the nervous system has significantly progressed. They are important not only for the development of the nervous system but also for its functions and, in turn, for neural disorders. In this review, we discuss the roles of cadherins and related molecules in neural development and function in the vertebrate brain. PMID- 22535892 TI - The germline stem cell niche unit in mammalian testes. AB - This review addresses current understanding of the germline stem cell niche unit in mammalian testes. Spermatogenesis is a classic model of tissue-specific stem cell function relying on self-renewal and differentiation of spermatogonial stem cells (SSCs). These fate decisions are influenced by a niche microenvironment composed of a growth factor milieu that is provided by several testis somatic support cell populations. Investigations over the last two decades have identified key determinants of the SSC niche including cytokines that regulate SSC functions and support cells providing these factors, adhesion molecules that influence SSC homing, and developmental heterogeneity of the niche during postnatal aging. Emerging evidence suggests that Sertoli cells are a key support cell population influencing the formation and function of niches by secreting soluble factors and possibly orchestrating contributions of other support cells. Investigations with mice have shown that niche influence on SSC proliferation differs during early postnatal development and adulthood. Moreover, there is mounting evidence of an age-related decline in niche function, which is likely influenced by systemic factors. Defining the attributes of stem cell niches is key to developing methods to utilize these cells for regenerative medicine. The SSC population and associated niche comprise a valuable model system for study that provides fundamental knowledge about the biology of tissue-specific stem cells and their capacity to sustain homeostasis of regenerating tissue lineages. While the stem cell is essential for maintenance of all self-renewing tissues and has received considerable attention, the role of niche cells is at least as important and may prove to be more receptive to modification in regenerative medicine. PMID- 22535895 TI - Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update. AB - The mammalian stress-activated families of mitogen-activated protein kinases (MAPKs) were first elucidated in 1994, and by 2001, substantial progress had been made in identifying the architecture of the pathways upstream of these kinases as well as in cataloguing candidate substrates. This information remains largely sound. Nevertheless, an informed understanding of the physiological and pathophysiological roles of these kinases remained to be accomplished. In the past decade, there has been an explosion of new work using RNAi in cells, as well as transgenic, knockout and conditional knockout technology in mice that has provided valuable insight into the functions of stress-activated MAPK pathways. These findings have important implications in our understanding of organ development, innate and acquired immunity, and diseases such as atherosclerosis, tumorigenesis, and type 2 diabetes. These new developments bring us within striking distance of the development and validation of novel treatment strategies. Herein we first summarize the molecular components of the mammalian stress-regulated MAPK pathways and their regulation as described thus far. We then review some of the in vivo functions of these pathways. PMID- 22535896 TI - Nuclear hormone receptors enable macrophages and dendritic cells to sense their lipid environment and shape their immune response. AB - A key issue in the immune system is to generate specific cell types, often with opposing activities. The mechanisms of differentiation and subtype specification of immune cells such as macrophages and dendritic cells are critical to understand the regulatory principles and logic of the immune system. In addition to cytokines and pathogens, it is increasingly appreciated that lipid signaling also has a key role in differentiation and subtype specification. In this review we explore how intracellular lipid signaling via a set of transcription factors regulates cellular differentiation, subtype specification, and immune as well as metabolic homeostasis. We introduce macrophages and dendritic cells and then we focus on a group of transcription factors, nuclear receptors, which regulate gene expression upon receiving lipid signals. The receptors we cover are the ones with a recognized physiological function in these cell types and ones which heterodimerize with the retinoid X receptor. These are as follows: the receptor for a metabolite of vitamin A, retinoic acid: retinoic acid receptor (RAR), the vitamin D receptor (VDR), the fatty acid receptor: peroxisome proliferator activated receptor gamma (PPARgamma), the oxysterol receptor liver X receptor (LXR), and their obligate heterodimeric partner, the retinoid X receptor (RXR). We discuss how they can get activated and how ligand is generated and eliminated in these cell types. We also explore how activation of a particular target gene contributes to biological functions and how the regulation of individual target genes adds up to the coordination of gene networks. It appears that RXR heterodimeric nuclear receptors provide these cells with a coordinated and interrelated network of transcriptional regulators for interpreting the lipid milieu and the metabolic changes to bring about gene expression changes leading to subtype and functional specification. We also show that these networks are implicated in various immune diseases and are amenable to therapeutic exploitation. PMID- 22535897 TI - Physiological implications of hydrogen sulfide: a whiff exploration that blossomed. AB - The important life-supporting role of hydrogen sulfide (H(2)S) has evolved from bacteria to plants, invertebrates, vertebrates, and finally to mammals. Over the centuries, however, H(2)S had only been known for its toxicity and environmental hazard. Physiological importance of H(2)S has been appreciated for about a decade. It started by the discovery of endogenous H(2)S production in mammalian cells and gained momentum by typifying this gasotransmitter with a variety of physiological functions. The H(2)S-catalyzing enzymes are differentially expressed in cardiovascular, neuronal, immune, renal, respiratory, gastrointestinal, reproductive, liver, and endocrine systems and affect the functions of these systems through the production of H(2)S. The physiological functions of H(2)S are mediated by different molecular targets, such as different ion channels and signaling proteins. Alternations of H(2)S metabolism lead to an array of pathological disturbances in the form of hypertension, atherosclerosis, heart failure, diabetes, cirrhosis, inflammation, sepsis, neurodegenerative disease, erectile dysfunction, and asthma, to name a few. Many new technologies have been developed to detect endogenous H(2)S production, and novel H(2)S delivery compounds have been invented to aid therapeutic intervention of diseases related to abnormal H(2)S metabolism. While acknowledging the challenges ahead, research on H(2)S physiology and medicine is entering an exponential exploration era. PMID- 22535898 TI - A molecular imaging primer: modalities, imaging agents, and applications. AB - Molecular imaging is revolutionizing the way we study the inner workings of the human body, diagnose diseases, approach drug design, and assess therapies. The field as a whole is making possible the visualization of complex biochemical processes involved in normal physiology and disease states, in real time, in living cells, tissues, and intact subjects. In this review, we focus specifically on molecular imaging of intact living subjects. We provide a basic primer for those who are new to molecular imaging, and a resource for those involved in the field. We begin by describing classical molecular imaging techniques together with their key strengths and limitations, after which we introduce some of the latest emerging imaging modalities. We provide an overview of the main classes of molecular imaging agents (i.e., small molecules, peptides, aptamers, engineered proteins, and nanoparticles) and cite examples of how molecular imaging is being applied in oncology, neuroscience, cardiology, gene therapy, cell tracking, and theranostics (therapy combined with diagnostics). A step-by-step guide to answering biological and/or clinical questions using the tools of molecular imaging is also provided. We conclude by discussing the grand challenges of the field, its future directions, and enormous potential for further impacting how we approach research and medicine. PMID- 22535891 TI - The delicate balance between secreted protein folding and endoplasmic reticulum associated degradation in human physiology. AB - Protein folding is a complex, error-prone process that often results in an irreparable protein by-product. These by-products can be recognized by cellular quality control machineries and targeted for proteasome-dependent degradation. The folding of proteins in the secretory pathway adds another layer to the protein folding "problem," as the endoplasmic reticulum maintains a unique chemical environment within the cell. In fact, a growing number of diseases are attributed to defects in secretory protein folding, and many of these by-products are targeted for a process known as endoplasmic reticulum-associated degradation (ERAD). Since its discovery, research on the mechanisms underlying the ERAD pathway has provided new insights into how ERAD contributes to human health during both normal and diseases states. Links between ERAD and disease are evidenced from the loss of protein function as a result of degradation, chronic cellular stress when ERAD fails to keep up with misfolded protein production, and the ability of some pathogens to coopt the ERAD pathway. The growing number of ERAD substrates has also illuminated the differences in the machineries used to recognize and degrade a vast array of potential clients for this pathway. Despite all that is known about ERAD, many questions remain, and new paradigms will likely emerge. Clearly, the key to successful disease treatment lies within defining the molecular details of the ERAD pathway and in understanding how this conserved pathway selects and degrades an innumerable cast of substrates. PMID- 22535899 TI - Stronger incentives for quality improvement needed in NHS in England. PMID- 22535900 TI - Why listening to health care users really matters. PMID- 22535901 TI - How long should women persevere with IVF? AB - The Israeli public health insurance system covers an (almost) unlimited number of IVF cycles. In a global context, this is a policy which is looked upon as a northern star. However, many women may continue IVF treatment when the probability of a successful pregnancy is 'zero'. This paper argues that the implication of a policy of unlimited rounds of IVF from the perspective of the 'culture of perseverance' that develops in IVF clinics has not yet been fully assessed. A systematic long term assessment of the health and welfare of women after IVF in Israel--especially after prolonged treatment with IVF--is necessary. In a global context, an evidence-based policy on ART may improve both the allocation of resources and the duty of care, not only in Israel, but also in other countries. PMID- 22535902 TI - Response to 'Marginal costs of hospital-acquired conditions: information for priority-setting for patient safety programmes and research', Jackson et al., Journal of Health Services Research & Policy 2011;16:141-6. PMID- 22535904 TI - Automated drop-on-demand system with real-time gravimetric control for precise dosage formulation. AB - Many of the therapies for personalized medicine have few dosage options, and the successful translation of these therapies to the clinic is significantly dependent on the drug/formulation delivery platform. We have developed a lab scale integrated system for microdosing of drug formulations with high accuracy and precision that is capable of feedback control. The designed modular drug dispensing system includes a microdispensing valve unit and is fully automated with a LabVIEW-controlled computer interface. The designed system is capable of dispensing drug droplets with volumes ranging from nanoliters to microliters with high accuracy (relative standard deviation <1%). We have determined that the system is capable of accurate dosing and in-line real-time gravimetric control. PMID- 22535903 TI - Clinical and laboratory profile of enteric fever in children in northern India. AB - The diagnosis of enteric fever poses several problems due to the non-specific and wide array of clinical features. A five-year retrospective study enrolling 136 culture-proven cases of enteric fever was undertaken in order to estimate the clinical and laboratory characteristics, fever clearance time and outcome. The common symptoms and signs were: fever, vomiting, cough, anorexia, diarrhoea, abdominal pain, hepatomegaly, splenomegaly and coated tongue. Enteric fever should be considered in the differential diagnosis of febrile patients with abdominal symptoms. PMID- 22535905 TI - Scientific information repository assisting reflectance spectrometry in legal medicine. AB - Reflectance spectrometry is a fast and reliable method for the characterization of human skin if the spectra are analyzed with respect to a physical model describing the optical properties of human skin. For a field study performed at the Institute of Legal Medicine and the Freiburg Materials Research Center of the University of Freiburg, a scientific information repository has been developed, which is a variant of an electronic laboratory notebook and assists in the acquisition, management, and high-throughput analysis of reflectance spectra in heterogeneous research environments. At the core of the repository is a database management system hosting the master data. It is filled with primary data via a graphical user interface (GUI) programmed in Java, which also enables the user to browse the database and access the results of data analysis. The latter is carried out via Matlab, Python, and C programs, which retrieve the primary data from the scientific information repository, perform the analysis, and store the results in the database for further usage. PMID- 22535894 TI - Matricellular proteins in cardiac adaptation and disease. AB - The term matricellular proteins describes a family of structurally unrelated extracellular macromolecules that, unlike structural matrix proteins, do not play a primary role in tissue architecture, but are induced following injury and modulate cell-cell and cell-matrix interactions. When released to the matrix, matricellular proteins associate with growth factors, cytokines, and other bioactive effectors and bind to cell surface receptors transducing signaling cascades. Matricellular proteins are upregulated in the injured and remodeling heart and play an important role in regulation of inflammatory, reparative, fibrotic and angiogenic pathways. Thrombospondin (TSP)-1, -2, and -4 as well as tenascin-C and -X secreted protein acidic and rich in cysteine (SPARC), osteopontin, periostin, and members of the CCN family (including CCN1 and CCN2/connective tissue growth factor) are involved in a variety of cardiac pathophysiological conditions, including myocardial infarction, cardiac hypertrophy and fibrosis, aging-associated myocardial remodeling, myocarditis, diabetic cardiomyopathy, and valvular disease. This review discusses the properties and characteristics of the matricellular proteins and presents our current knowledge on their role in cardiac adaptation and disease. Understanding the role of matricellular proteins in myocardial pathophysiology and identification of the functional domains responsible for their actions may lead to design of peptides with therapeutic potential for patients with heart disease. PMID- 22535906 TI - Neuroimaging auditory hallucinations in schizophrenia: from neuroanatomy to neurochemistry and beyond. AB - Despite more than 2 decades of neuroimaging investigations, there is currently insufficient evidence to fully understand the neurobiological substrate of auditory hallucinations (AH). However, some progress has been made with imaging studies in patients with AH consistently reporting altered structure and function in speech and language, sensory, and nonsensory regions. This report provides an update of neuroimaging studies of AH with a particular emphasis on more recent anatomical, physiological, and neurochemical imaging studies. Specifically, we provide (1) a review of findings in schizophrenia and nonschizophrenia voice hearers, (2) a discussion regarding key issues that have interfered with progress, and (3) practical recommendations for future studies. PMID- 22535908 TI - The neurodynamic organization of modality-dependent hallucinations. AB - The pathophysiology of hallucinations remains mysterious. This research aims to specifically explore the interaction between hallucinations and spontaneous resting-state activity. We used multimodal magnetic resonance imaging during hallucinations occurrence in 20 drug-free adolescents with a "brief psychotic disorder." They were furthermore compared with 20 matched controls at rest or during exteroceptive stimuli. Anatomical and functional symptom-mapping demonstrated reduced cortical thickness and increased blood oxygen level dependent signal in modality-dependent association sensory cortices during auditory, visual, and multisensory hallucinations. On the contrary, primary sensory-cortex recruitment was not systematic and was shown to be associated with increased vividness of the hallucinatory experiences. Spatiotemporal activity patterns in the default-mode network (DMN) during hallucinations and symptom-free periods in patients were compared with patterns measured in healthy individuals. A disengagement of the DMN was concomitant to hallucinations, as for exogenous stimulations in healthy participants. Specifically, spatial and temporal instabilities of the DMN correlated with the severity of hallucinations but persisted during symptom-free periods. These results suggest that hallucinatory experiences emerge from a spontaneous DMN withdrawal, providing a convincing model for hallucinations beyond the auditory modality. PMID- 22535907 TI - What the human brain likes about facial motion. AB - Facial motion carries essential information about other people's emotions and intentions. Most previous studies have suggested that facial motion is mainly processed in the superior temporal sulcus (STS), but several recent studies have also shown involvement of ventral temporal face-sensitive regions. Up to now, it is not known whether the increased response to facial motion is due to an increased amount of static information in the stimulus, to the deformation of the face over time, or to increased attentional demands. We presented nonrigidly moving faces and control stimuli to participants performing a demanding task unrelated to the face stimuli. We manipulated the amount of static information by using movies with different frame rates. The fluidity of the motion was manipulated by presenting movies with frames either in the order in which they were recorded or in scrambled order. Results confirm higher activation for moving compared with static faces in STS and under certain conditions in ventral temporal face-sensitive regions. Activation was maximal at a frame rate of 12.5 Hz and smaller for scrambled movies. These results indicate that both the amount of static information and the fluid facial motion per se are important factors for the processing of dynamic faces. PMID- 22535909 TI - Chlamydia and gonorrhoea contamination of clinic surfaces. AB - INTRODUCTION: Nucleic acid amplification tests, with their ability to detect very small amounts of nucleic acid, have become the principle diagnostic tests for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) in many sexual health clinics. The aim of this study was to investigate the extent of surface contamination with CT and GC within a city centre sexual health clinic and to evaluate the potential for contamination of containers used for the collection of self-taken swabs. METHOD: Surface contamination with CT and GC was assessed by systematically sampling 154 different sites within one clinic using transcription mediated amplification (TMA), quantitative PCR and culture. The caps of containers used by patients to collect self-taken samples were also tested for CT and GC using TMA. RESULTS: Of the 154 sites sampled, 20 (13.0%) tested positive on TMA. Of these, five (3.2%) were positive for CT alone, 11 (7.1%) for GC alone and four (2.6%) for both CT and GC. The proportion of GC TMA-positive test results differed by gender, with 11 (18.3%) positive results from the male patient clinic area compared with one (1.6%) from the female area (p=0.002). Positive samples were obtained from a variety of locations in the clinic, but the patient toilets were more likely to be contaminated than examination rooms (p=0.015). Quantitative PCR and culture assays were negative for all samples. 46 caps of the containers used for self-taken swabs were negative for both CT and GC on TMA testing. CONCLUSIONS: Surface contamination with chlamydial and gonococcal rRNA can occur within sexual health clinics, but the quantity of nucleic acid detected is low and infection risk to patients and staff is small. There remains a potential risk of contamination of patient samples leading to false-positive results. PMID- 22535910 TI - Direct acetylation and determination of chlorophenols in aqueous samples by gas chromatography coupled with an electron-capture detector. AB - A method was developed that offers a rapid, simple and accurate technique for the determination of chlorophenols at trace levels in aqueous samples with very limited volumes of organic solvents. These compounds were acetylated, then preliminarily extracted with n-hexane. The enriched chlorophenols were directly analyzed using gas chromatography with an electron-capture detector. The detection limits were in the range of 0.001-0.005 mg/L, except for 2 chlorophenol, which was always above 0.013 mg/L. Relative standard deviation for the spiked water samples ranged from 2.2 to 6.1%, while relative recoveries were in the range of 67.1 to 101.3%. PMID- 22535911 TI - Differentiation of methylenedioxybenzylpiperazines and ethoxybenzylpiperazines by GC-IRD and GC-MS. AB - The substituted benzylpiperazines, 3,4-methylenedioxybenzylpiperazine, its regioisomer 2,3-methylenedioxybenzylpiperazine and three isobaric ring substituted ethoxybenzylpiperazines have equal mass and many common mass spectral fragment ions. The mass spectra of the three ethoxybenzylpiperazines yield a unique fragment at m/z 107 that allows the discrimination of the three ring substituted ethoxybenzylpiperazines from the two methylenedioxy isomers. Perfluoroacylation of the secondary amine nitrogen of these isomeric piperazines gave mass spectra with differences in relative abundance of some fragment ions, but acylation does not alter the fragmentation pathway and did not provide additional MS fragments of discrimination among these isomers. Gas chromatography coupled with infrared detection provides direct confirmatory data for the structural differentiation between the five isomers. The mass spectra in combination with the vapor phase infrared spectra provide for specific confirmation of each of the isomeric piperazines. The perfluoroacyl derivatives of the ring substituted benzylpiperazines were resolved on a stationary phase of 50% phenyl and 50% methylpolysiloxane. Gas chromatography coupled with time-of flight mass spectrometric detection provides an additional means of differentiating between the isobaric compounds 3,4-methylenedioxybenzylpiperazine and 4-ethoxybenzylpiperazine, which have similar nominal masses but are different in their calculated exact masses. PMID- 22535912 TI - Outpatient parathyroid surgery data from the University Health System Consortium. AB - OBJECTIVE: To determine demographics and cost for outpatients undergoing parathyroid surgery at hospitals belonging to the University Health System Consortium (UHC). STUDY DESIGN: UHC data were accessed in 2011 and reflected data collected from 2005 through 2010 (24 quarters). Searching strategy was based on diagnoses of parathyroid disease and patients undergoing parathyroidectomy across all UHC member facilities. Complications evaluated in this analysis included: hypocalcemia, hypoparathyroidism, aspiration pneumonia, hematoma, wound infection, stroke, myocardial infarction, deep venous thrombosis/pulmonary embolism (PE), and death. SETTING: The University Health System Consortium, Oak Brook, Illinois, was formed in 1984 and consists of 112 academic medical centers and 250 of their affiliated hospitals. This represents 90% of the nonprofit academic medical centers in the United States (www.uhc.edu). SUBJECTS AND METHODS: Patients enrolled in the UHC database were studied retrospectively. Data were compiled from discharge summaries into a secure, interactive, Web-based database. The outpatient data collection set has been a recent addition to the originally established UHC inpatient discharge database. RESULTS: There were 21,057 patients who had outpatient parathyroid surgery. The average age was 59.0 (0.8-96.2) yrs. Seventy-six percent of patients were female. Outpatient parathyroidectomy had lower charges than inpatient surgery ($12,738 and $14,657, respectively; P = 0.004, Wilcoxon signed-rank test). Complications were low but were likely underreported. CONCLUSION: Parathyroid surgery is increasingly being done in the outpatient setting in the United States. By virtue of omitting inpatient hospitalization, the outpatient approach becomes a more economical way to manage parathyroid disease. This is the largest known series reporting experience with outpatient parathyroid surgery. PMID- 22535913 TI - Long-term prognosis and significance of the sentinel lymph node in head and neck melanoma. AB - OBJECTIVE: To report the long-term significance of sentinel lymph node (SLN) biopsy on prognosis, determine false-negative SLN occurrences, and determine risk factors for death and recurrence in a large series of patients with head and neck melanoma. STUDY DESIGN: Case series with tumor registry review. SETTING: Academic tertiary care medical center. SUBJECTS AND METHODS: A database review was performed of all patients who underwent SLN biopsy for head and neck melanoma from 1994 to 2009. End points assessed were SLN status, recurrence, false negative SLN results, and survival comparing SLN-positive and SLN-negative patients and different locations. Survival curves and multivariate analyses were performed. RESULTS: SLN biopsy was performed in 365 patients. SLNs were identified in 98.6% of patients with a mean of 3.7 nodes removed from 1.6 nodal basins per patient. Median follow-up was 8 years. The SLN was positive in 40 (11%) patients. SLN-positive patients had significantly thicker melanomas, higher recurrence (P < .0001), and a significant decrease in overall survival compared with SLN-negative patients (P < .002). Scalp melanoma patients had significantly thicker melanomas and an elevated risk of SLN positivity, recurrence, and death compared with other sites. Seventeen of 365 SLN-negative patients developed regional nodal disease for a false-omission rate of 5.2% and a negative predictive value of a negative SLN to be 94.8%. Risks for false negative-SLN occurrences included thick melanomas and scalp melanomas. CONCLUSION: SLN biopsy is accurate in head and neck melanoma and provides significant prognostic data. Scalp melanoma patients present with thicker tumors with an increase in SLN positivity and false-negative SLN occurrences. PMID- 22535914 TI - Central presbycusis: an emerging view. AB - Age-related dysfunction of the central auditory system (central presbycusis) is common but rarely looked for by those who provide aural rehabilitation. Patients who complain of difficulty hearing in noise--the key symptom of central presbycusis--are generally disadvantaged with conventional rehabilitation. This symptom should be documented with commercially available speech-in-noise tests, which use materials that are uncomplicated to administer. Those patients who perform poorly on such tests should have a customized rehabilitation program aimed at optimizing their remaining communication abilities. Otolaryngologists who provide auditory rehabilitation may wish to consider expanding their practices to meet the communication needs of older patients with central presbycusis. Central presbycusis is an emerging area for basic and clinical research in auditory neurotology, particularly in the relation of cognitive dysfunction to impaired auditory processing. PMID- 22535915 TI - Diagnostic value of only 18F-fluorodeocyglucose positron emission tomography/computed tomography-positive lymph nodes in head and neck squamous cell carcinoma. AB - OBJECTIVE: The role of (18)F-fluorodeocyglucose positron emission tomography (PET)/computed tomography (CT) in only PET/CT-positive lymph nodes (LNs) is not well elucidated yet. This study was conducted to evaluate the diagnostic value of only PET/CT-positive LNs without correlating positive findings on conventional imaging modalities (CT, magnetic resonance imaging [MRI], and ultrasound [US]) in patients with head and neck squamous cell carcinoma (HNSCC). STUDY DESIGN: Case series with chart review. SETTING: Hallym University School of Medicine. SUBJECTS AND METHODS: From January 2006 to September 2009, 114 patients with HNSCC who underwent CT, MRI, US, and PET/CT before definitive surgery with neck dissection were reviewed. All imaging tests were interpreted on imaging-based nodal classification and were compared with histopathological findings. RESULTS: Only PET/CT-positive LNs were found at 48 nodal levels in 33 patients. Thirteen of 48 (27%) nodal levels were true-positive (TP), and 35 of 48 (73%) were false positive (FP). Fourteen nodal levels were included on N+ necks, and 34 were included on N0 necks. In N0 necks, the FP rate was significantly higher than the TP rate (28 vs 6, P = .034). Eleven only PET/CT-positive nodal levels in 10 patients were found on the contralateral neck side, and FP was significantly more prevalent than TP (8 vs 3, P = .041). No significant difference was observed for mean standardized uptake value and LN sizes between TP and FP. CONCLUSION: Only PET/CT-positive LNs can frequently be found and do not predict LN metastasis, because a high percentage of results were FP. Our results suggest that only PET/CT-positive LNs should be considered negative, especially in N0 and contralateral necks. PMID- 22535916 TI - Histopathological and postoperative behavioral comparison of rodent oral tongue resection: fiber-enabled CO2 laser versus electrocautery. AB - OBJECTIVE: To compare operative time and hemostasis of fiber-enabled CO(2) laser (FECL) energy to that of the electrocautery (EC) technique for oral tongue resection, to compare return to oral intake and preoperative weight after FECL and EC resection, and to compare histologic changes in adjacent tissue after FECL and EC resection. STUDY DESIGN: Prospective animal study. SETTING: Research laboratory. SUBJECTS AND METHODS: The CO(2) laser fiber and the Bovie cautery were each used to resect the anterior tongue in 15 adult rats. Fixative perfusion and killing were performed on postoperative day 0 (n = 10), 3 (n = 10), or 7 (n = 10). Body weight, food intake, and water intake were recorded daily for 3- and 7 day survival rats. After preparation for histologic analysis, the tongue tissue was graded with a mucosal wound-healing scale (MWHS). RESULTS: A higher incidence of intraoperative bleeding and shorter operative times were noted in the EC group. No statistically significant difference in postoperative food or water intake between the EC and FECL groups was noted. The FECL group returned to baseline weight by postoperative day 6. MWHS scores were lower in the EC group by postoperative day 3 and lower in the FECL group by postoperative day 7. CONCLUSIONS: Both EC and FECL are effective for resection of the tongue in rats. EC has the advantage of shorter operative time and lower MWHS scores by postoperative day 3; FECL has the advantages of less intraoperative bleeding, faster return to baseline body weight, and lower MWHS score by postoperative day 7. PMID- 22535917 TI - Spontaneous fracture of the larynx after coughing. PMID- 22535918 TI - Tinnitus and suicide: recent cases on the public record give cause for reconsideration. AB - Suicides among tinnitus sufferers are rare. Indeed, on examining the public record (newspapers and the Web), the authors identified only 4 cases in the past 10 years that had been examined by a coroner. Nevertheless, the deaths of Rick Tharp, Dietrich Hectors, William Morris, and Robert McIndoe prompt reconsideration of the association between tinnitus and suicide that appears to be weak. The article also draws attention to a subject that is receiving attention in the medical literature--namely, the role of "precipitants" (in this case, tinnitus) in completed suicide and the need to screen some cases of severe, disabling tinnitus for the presence or absence of coinciding psychopathology, which is very amenable to treatment. PMID- 22535919 TI - The effect of a computerized prescribing and calculating system on hypo- and hyperglycemias and on prescribing time efficiency in neonatal intensive care patients. AB - BACKGROUND: Prescribing glucose requires complex calculations because glucose is present in parenteral and enteral nutrition and drug vehicles, making it error prone and contributing to the burden of prescribing errors. OBJECTIVE: Evaluation of the impact of a computerized physician order entry (CPOE) system with clinical decision support (CDS) for glucose control in neonatal intensive care patients (NICU) focusing on hypo- and hyperglycemic episodes and prescribing time efficiency. METHODS: An interrupted time-series design to examine the effect of CPOE on hypo- and hyperglycemias and a crossover simulation study to examine the influence of CPOE on prescribing time efficiency. NICU patients at risk for glucose imbalance hospitalized at the University Medical Center Utrecht during 2001-2007 were selected. The risks of hypo- and hyperglycemias were expressed as incidences per 100 patient days in consecutive 3-month intervals during 3 years before and after CPOE implementation. To assess prescribing time efficiency, time needed to calculate glucose intake with and without CPOE was measured. RESULTS: No significant difference was found between pre- and post-CPOE mean incidences of hypo- and hyperglycemias per 100 hospital days of neonates at risk in every 3 month period (hypoglycemias, 4.0 [95% confidence interval, 3.2-4.8] pre-CPOE and 3.1 [2.7-3.5] post-CPOE, P = .88; hyperglycemias, 6.0 [4.3-7.7] pre-CPOE and 5.0 [3.7-6.3] post-CPOE, P = .75). CPOE led to a significant time reduction of 16% (1.3 [0.3-2.3] minutes) for simple and 60% (8.6 [5.1-12.1] minutes) for complex calculations. CONCLUSIONS: CPOE including a special CDS tool preserved accuracy for calculation and control of glucose intake and increased prescribing time efficiency. PMID- 22535920 TI - Evidence-based medicine should be evidence based! PMID- 22535921 TI - Review of supplements ignores evidence-based nutrition to promote tighter regulation. PMID- 22535923 TI - Consensus statement: Academy of Nutrition and Dietetics and American Society for Parenteral and Enteral Nutrition: characteristics recommended for the identification and documentation of adult malnutrition (undernutrition). AB - The Academy of Nutrition and Dietetics (Academy) and the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) recommend that a standardized set of diagnostic characteristics be used to identify and document adult malnutrition in routine clinical practice. An etiologically based diagnostic nomenclature that incorporates a current understanding of the role of the inflammatory response on malnutrition's incidence, progression, and resolution is proposed. Universal use of a single set of diagnostic characteristics will facilitate malnutrition's recognition, contribute to more valid estimates of its prevalence and incidence, guide interventions, and influence expected outcomes. This standardized approach will also help to more accurately predict the human and financial burdens and costs associated with malnutrition's prevention and treatment and further ensure the provision of high-quality, cost-effective nutrition care. PMID- 22535924 TI - Surviving relationship threats: the role of emotional capital. AB - In this article, a Theory of Emotional Capital is investigated, which stipulates that relationships are able to withstand threats when partners have built "emotional capital" within the relationship (by contributing to positive, shared experiences). Support for this idea was obtained in two studies using two samples (newlywed couples and more established married couples) and two methodologies (daily diary and observational methods). Both studies showed that individuals with high emotional capital were less reactive to relationship threats than those with low emotional capital. The importance of emotional capital for healthy and stable relationships is discussed. PMID- 22535925 TI - Culture, temporal focus, and values of the past and the future. AB - This article examines cultural differences in how people value future and past events. Throughout four studies, the authors found that European Canadians attached more monetary value to an event in the future than to an identical event in the past, whereas Chinese and Chinese Canadians placed more monetary value to a past event than to an identical future event. The authors also showed that temporal focus-thinking about the past or future-explained cultural influences on the temporal value asymmetry effect. Specifically, when induced to think about and focus on the future, Chinese valued the future more than the past, just like Euro-Canadians; when induced to think about and focus on the past, Euro-Canadians valued the past more than the future, just like Chinese. PMID- 22535926 TI - Complete genome sequence of the 2,3-butanediol-producing Klebsiella pneumoniae strain KCTC 2242. AB - Here we report the full genome sequence of Klebsiella pneumoniae KCTC 2242,consisting of a 5.26-Mb chromosome (57.6% GC%; 5,035 genes [4,923 encoding known proteins, 112 RNA genes]) and a 202-kb plasmid (50.2% GC%; 229 genes [229 encoding known proteins]). PMID- 22535927 TI - Draft genome sequence of Halomonas sp. strain KM-1, a moderately halophilic bacterium that produces the bioplastic poly(3-hydroxybutyrate). AB - We report the draft genome sequence of Halomonas sp. strain KM-1, which was isolated in Ikeda City, Osaka, Japan, and which produces the bioplastic poly(3 hydroxybutyrate). The total length of the assembled genome is 4,992,811 bp, and 4,220 coding sequences were predicted within the genome. Genes encoding proteins that are involved in the production and depolymerization of poly(3 hydroxybutyrate) were identified. The identification of these genes might be of use in the production of the bioplastic poly(3-hydroxybutyrate) and its monomer 3 hydroxybutyrate. PMID- 22535928 TI - Draft genome sequences of Staphylococcus aureus sequence type 34 (ST34) and ST42 hybrids. AB - Staphylococcus aureus is a major cause of antimicrobial-resistant infections of humans. Hybrids of S. aureus, which originate from large-scale chromosomal recombinations between parents of distinct genetic backgrounds, are of interest from clinical and evolutionary perspectives. We present draft genome sequences of two S. aureus hybrids of sequence type 34 (ST34) and ST42. PMID- 22535929 TI - Sequencing of K60, type strain of the major plant pathogen Ralstonia solanacearum. AB - Ralstonia solanacearum is a widespread and destructive plant pathogen. We present the genome of the type strain, K60 (phylotype IIA, sequevar 7). Sequevar 7 strains cause ongoing tomato bacterial wilt outbreaks in the southeastern United States. K60 generally resembles R. solanacearum CFBP2957, a Caribbean tomato isolate, but has almost 360 unique genes. PMID- 22535930 TI - High-quality draft genome sequence of the Opitutaceae bacterium strain TAV1, a symbiont of the wood-feeding termite Reticulitermes flavipes. AB - Microbial communities in the termite hindgut are essential for degrading plant material. We present the high-quality draft genome sequence of the Opitutaceae bacterium strain TAV1, the first member of the phylum Verrucomicrobia to be isolated from wood-feeding termites. The genomic analysis reveals genes coding for lignocellulosic degradation and nitrogen fixation. PMID- 22535931 TI - Genome sequences of type strains of seven species of the marine bacterium Pseudoalteromonas. AB - There are over 30 species in the marine bacterial genus Pseudoalteromonas. However, our knowledge about this genus is still limited. We sequenced the genomes of type strains of seven species in the genus, facilitating the study of the physiology, adaptation, and evolution of this genus. PMID- 22535932 TI - Genome sequence of Myroides injenensis M09-0166(T), isolated from clinical specimens. AB - A new Myroides species has been isolated from the urine of a patient with fever in spite of multiple antibiotic treatments who had undergone a radical hysterectomy for cervical cancer and percutaneous nephrostomies for hydronephrosis in the past. The isolate, Myroides injenensis M09-0166(T) (KCTC 23367(T)), showed a high level of resistance to multiple antibiotic agents. Here we provide the first report of the draft genome sequence of a novel species in the genus Myroides within the nonfermenting Gram-negative group. PMID- 22535933 TI - Complete genome sequence of Mycobacterium intracellulare strain ATCC 13950(T). AB - Here we report the first complete genome sequence of Mycobacterium intracellulare ATCC 13950(T), a Mycobacterium avium complex (MAC) strain. This genome sequence will serve as a valuable reference for understanding the epidemiologic, biological, and pathogenic aspects of the disparity between MAC members. PMID- 22535934 TI - Genomic comparison of Rickettsia helvetica and other Rickettsia species. AB - We report the complete and annotated genome sequence of Rickettsia helvetica strain C9P9, which was first isolated in 1979 from Ixodes ricinus ticks in Switzerland and is considered a human pathogen. PMID- 22535935 TI - Genome sequence of Blastococcus saxobsidens DD2, a stone-inhabiting bacterium. AB - Members of the genus Blastococcus have been isolated from sandstone monuments, as well as from sea, soil, plant, and snow samples. We report here the genome sequence of a member of this genus, Blastococcus saxobsidens strain DD2, isolated from below the surface of a Sardinian wall calcarenite stone sample. PMID- 22535936 TI - Complete genome sequence of the serotype k Streptococcus mutans strain LJ23. AB - Streptococcus mutans is the major pathogen of dental caries and occasionally causes infective endocarditis. Here we report the complete genome sequence of serotype k S. mutans strain LJ23, which was recently isolated from the oral cavity of a Japanese patient. PMID- 22535937 TI - Draft genome sequence of Mycobacterium abscessus subsp. bolletii BD(T). AB - Mycobacterium abscessus subsp. bolletii is an increasing cause of human pulmonary disease and infections of the skin and soft tissues. Consistent reports of human infections indicate that M. bolletii is a highly pathogenic, emerging species of rapidly growing mycobacteria (RGM). Here we report the first whole-genome sequence of M. abscessus subsp. bolletii BD(T). PMID- 22535938 TI - Genome sequence of the anaerobic bacterium Clostridium arbusti SL206(T). AB - A new Clostridium species has been isolated from pear orchard soil in Daejeon, Republic of Korea. The isolate, Clostridium arbusti SL206(T) (KCTC 5449(T)), showed a nitrogenase activity as well as an organic acid production. Here we first report the draft genome sequence of a novel species in the genus Clostridium within the largest Gram-positive group. PMID- 22535939 TI - Genome sequence of the bacterioplanktonic, mixotrophic Vibrio campbellii strain PEL22A, isolated in the Abrolhos Bank. AB - Vibrio campbellii PEL22A was isolated from open ocean water in the Abrolhos Bank. The genome of PEL22A consists of 6,788,038 bp (the GC content is 45%). The number of coding sequences (CDS) is 6,359, as determined according to the Rapid Annotation using Subsystem Technology (RAST) server. The number of ribosomal genes is 80, of which 68 are tRNAs and 12 are rRNAs. V. campbellii PEL22A contains genes related to virulence and fitness, including a complete proteorhodopsin cluster, complete type II and III secretion systems, incomplete type I, IV, and VI secretion systems, a hemolysin, and CTXPhi. PMID- 22535940 TI - Complete genome sequence of Nocardia brasiliensis HUJEG-1. AB - In Mexico, actinomycetoma is mainly caused by Nocardia brasiliensis, which is a soil inhabitant actinobacterium. Here, we report for the first time the draft genome of a strain isolated from a human case that has largely been found in in vitro and experimental models of actinomycetoma, N. brasiliensis HUJEG-1. PMID- 22535941 TI - Genome sequence of the fish pathogen Flavobacterium columnare ATCC 49512. AB - Flavobacterium columnare is a Gram-negative, rod-shaped, motile, and highly prevalent fish pathogen causing columnaris disease in freshwater fish worldwide. Here, we present the complete genome sequence of F. columnare strain ATCC 49512. PMID- 22535942 TI - Draft genome sequence of Pseudomonas fuscovaginae, a broad-host-range pathogen of plants. AB - Pseudomonas fuscovaginae was first reported as a pathogen of rice causing sheath rot in plants grown at high altitudes. P. fuscovaginae is now considered a broad host-range plant pathogen causing disease in several economically important plants. We report what is, to our knowledge, the first draft genome sequence of a P. fuscovaginae strain. PMID- 22535943 TI - Complete genome sequence of the anaerobic perchlorate-reducing bacterium Azospira suillum strain PS. AB - Azospira suillum strain PS (formally Dechlorosoma suillum strain PS) is a metabolically versatile betaproteobacterium first identified for its ability to grow by dissimilatory reduction of perchlorate and chlorate [denoted (per)chlorate]. Together with Dechloromonas species, these two genera represent the dominant (per)chlorate-reducing bacteria in mesophilic freshwater environments. In addition to (per)chlorate reduction, A. suillum is capable of the anaerobic oxidation of humic substances and is the first anaerobic nitrate dependent Fe(II) oxidizer outside the Diaphorobacter and Acidovorax genera for which there is a completed genome sequence. PMID- 22535944 TI - Draft genome sequence of the novel agarolytic bacterium Aquimarina agarilytica ZC1. AB - The marine bacterium ZC1 is the type strain of the recently identified novel species Aquimarina agarilytica. It can produce multiple agarases. Here we report the draft genome sequence of strain ZC1 (4,253,672 bp, with a GC content of 32.8%) and major findings from its annotation. It is the first reported genome in the genus Aquimarina. PMID- 22535945 TI - Complete annotated genome sequence of Mycobacterium tuberculosis Erdman. AB - We report the completely annotated genome sequence of Mycobacterium tuberculosis Erdman (TMC 107; ATCC 35801), which is a well-known laboratory strain of M. tuberculosis. PMID- 22535946 TI - Complete genome sequence of Mycobacterium intracellulare clinical strain MOTT-02. AB - Here, we report the first complete genome sequence of the Mycobacterium intracellulare clinical strain MOTT-02, which was previously grouped in the INT2 genotype of M. intracellulare. This genome sequence will serve as a valuable reference for improving the understanding of the disparity in the virulence and epidemiologic traits between M. intracellulare genotypes. PMID- 22535947 TI - Complete genome sequence of a sucrose-nonfermenting epidemic strain of Vibrio cholerae O1 from Brazil. AB - We report the genome sequence of Vibrio cholerae strain IEC224, which fails to ferment sucrose. It was isolated from a cholera outbreak in the Amazon. The defective sucrose phenotype was determined to be due to a frameshift mutation, and a molecular marker of the Latin American main epidemic lineage was identified. PMID- 22535948 TI - Genome sequence of Vibrio sp. strain EJY3, an agarolytic marine bacterium metabolizing 3,6-anhydro-L-galactose as a sole carbon source. AB - The metabolic fate of 3,6-anhydro-L-galactose (L-AHG) is unknown in the global marine carbon cycle. Vibrio sp. strain EJY3 is an agarolytic marine bacterium that can utilize L-AHG as a sole carbon source. To elucidate the metabolic pathways of L-AHG, we have sequenced the complete genome of Vibrio sp. strain EJY3. PMID- 22535949 TI - Genomic comparison between a virulent type A1 strain of Francisella tularensis and its attenuated O-antigen mutant. AB - We report the complete genome sequences of TI0902, a highly virulent type A1 strain, and TIGB03, a related, attenuated chemical mutant strain. Compared to the wild type, the mutant strain had 45 point mutations and a 75.9-kb duplicated region that had not been previously observed in Francisella species. PMID- 22535950 TI - Complete genome sequence of Paenibacillus mucilaginosus 3016, a bacterium functional as microbial fertilizer. AB - Paenibacillus mucilaginosus is a ubiquitous functional bacterium in microbial fertilizer. Here we report the complete sequence of P. mucilaginosus 3016. Multiple sets of functional genes have been found in the genome. To the best of our knowledge, this is the first announcement about the complete genome sequence of a P. mucilaginosus strain. PMID- 22535951 TI - Distinct properties of glycine receptor beta+/alpha- interface: unambiguously characterizing heteromeric interface reconstituted in homomeric protein. AB - The glycine receptor (GlyR) exists either in homomeric alpha or heteromeric alphabeta forms. Its agonists bind at extracellular subunit interfaces. Unlike subunit interfaces from the homomeric alpha GlyR, subunit interfaces from the heteromeric alphabeta GlyR have not been characterized unambiguously because of the existence of multiple types of interface within single receptors. Here, we report that, by reconstituting beta+/alpha- interfaces in a homomeric GlyR (alphaChb+a- GlyR), we were able to functionally characterize the alphabeta GlyR beta+/alpha- interfaces. We found that the beta+/alpha- interface had a higher agonist sensitivity than that of the alpha+/alpha- interface. This high sensitivity was contributed primarily by loop A. We also found that the beta+/alpha- interface differentially modulates the agonist properties of glycine and taurine. Using voltage clamp fluorometry, we found that the conformational changes induced by glycine binding to the beta+/alpha- interface were different from those induced by glycine binding to the alpha+/alpha- interface in the alpha GlyR. Moreover, the distinct conformational changes found at the beta+/alpha- interface in the alphaChb+a- GlyR were also found in the heteromeric alphabeta GlyR, which suggests that the alphaChb+a- GlyR reconstitutes structural components and recapitulates functional properties, of the beta+/alpha- interface in the heteromeric alphabeta GlyR. Our investigation not only provides structural and functional information about the GlyR beta+/alpha- interface, which could direct GlyR beta+/alpha- interface-specific drug design, but also provides a general methodology for unambiguously characterizing properties of specific protein interfaces from heteromeric proteins. PMID- 22535952 TI - Proteomic and metabolomic analyses of mitochondrial complex I-deficient mouse model generated by spontaneous B2 short interspersed nuclear element (SINE) insertion into NADH dehydrogenase (ubiquinone) Fe-S protein 4 (Ndufs4) gene. AB - Eukaryotic cells generate energy in the form of ATP, through a network of mitochondrial complexes and electron carriers known as the oxidative phosphorylation system. In mammals, mitochondrial complex I (CI) is the largest component of this system, comprising 45 different subunits encoded by mitochondrial and nuclear DNA. Humans diagnosed with mutations in the gene NDUFS4, encoding a nuclear DNA-encoded subunit of CI (NADH dehydrogenase ubiquinone Fe-S protein 4), typically suffer from Leigh syndrome, a neurodegenerative disease with onset in infancy or early childhood. Mitochondria from NDUFS4 patients usually lack detectable NDUFS4 protein and show a CI stability/assembly defect. Here, we describe a recessive mouse phenotype caused by the insertion of a transposable element into Ndufs4, identified by a novel combined linkage and expression analysis. Designated Ndufs4(fky), the mutation leads to aberrant transcript splicing and absence of NDUFS4 protein in all tissues tested of homozygous mice. Physical and behavioral symptoms displayed by Ndufs4(fky/fky) mice include temporary fur loss, growth retardation, unsteady gait, and abnormal body posture when suspended by the tail. Analysis of CI in Ndufs4(fky/fky) mice using blue native PAGE revealed the presence of a faster migrating crippled complex. This crippled CI was shown to lack subunits of the "N assembly module", which contains the NADH binding site, but contained two assembly factors not present in intact CI. Metabolomic analysis of the blood by tandem mass spectrometry showed increased hydroxyacylcarnitine species, implying that the CI defect leads to an imbalanced NADH/NAD(+) ratio that inhibits mitochondrial fatty acid beta-oxidation. PMID- 22535953 TI - Human high temperature requirement serine protease A1 (HTRA1) degrades tau protein aggregates. AB - Protective proteases are key elements of protein quality control pathways that are up-regulated, for example, under various protein folding stresses. These proteases are employed to prevent the accumulation and aggregation of misfolded proteins that can impose severe damage to cells. The high temperature requirement A (HtrA) family of serine proteases has evolved to perform important aspects of ATP-independent protein quality control. So far, however, no HtrA protease is known that degrades protein aggregates. We show here that human HTRA1 degrades aggregated and fibrillar tau, a protein that is critically involved in various neurological disorders. Neuronal cells and patient brains accumulate less tau, neurofibrillary tangles, and neuritic plaques, respectively, when HTRA1 is expressed at elevated levels. Furthermore, HTRA1 mRNA and HTRA1 activity are up regulated in response to elevated tau concentrations. These data suggest that HTRA1 is performing regulated proteolysis during protein quality control, the implications of which are discussed. PMID- 22535954 TI - Fas ligand enhances malignant behavior of tumor cells through interaction with Met, hepatocyte growth factor receptor, in lipid rafts. AB - Many late-stage cancer cells express Fas ligand (FasL) and show high malignancy with metastatic potential. We report here a novel signaling mechanism for FasL that hijacks the Met signal pathway to promote tumor metastasis. FasL-expressing human tumor cells express a significant amount of phosphorylated Met. The down regulation of FasL in these cells led to decreased Met activity and reduced cell motility. Ectopic expression of human FasL in NIH3T3 cells significantly stimulated their migration and invasion. The inhibition of Met and Stat3 activities reverted the FasL-associated phenotype. Notably, FasL variants activated the Met pathway, even though most of their intracellular domain or Fas binding sites were deleted. FasL interacted with Met through the FasL(105-130) extracellular region in lipid rafts, which consequently led to Met activation. Knocking down Met gene expression by RNAi technology reverted the FasL-associated motility to basal levels. Furthermore, treatment with synthetic peptides corresponding to FasL(117-126) significantly reduced the FasL/Met interaction, Met phosphorylation, and cell motility of FasL(+) transfectants and tumor cells. Finally, the transfectants of truncated FasL showed strong anchorage-independent growth and lung metastasis potential in null mice. Collectively, our results establish the FasL-Met-Stat3 signaling pathway and explains the metastatic phenotype of FasL-expressing tumors. PMID- 22535955 TI - Functional expression and extension of staphylococcal staphyloxanthin biosynthetic pathway in Escherichia coli. AB - The biosynthetic pathway for staphyloxanthin, a C(30) carotenoid biosynthesized by Staphylococcus aureus, has previously been proposed to consist of five enzymes (CrtO, CrtP, CrtQ, CrtM, and CrtN). Here, we report a missing sixth enzyme, 4,4' diaponeurosporen-aldehyde dehydrogenase (AldH), in the staphyloxanthin biosynthetic pathway and describe the functional expression of the complete staphyloxanthin biosynthetic pathway in Escherichia coli. When we expressed the five known pathway enzymes through artificial synthetic operons and the wild-type operon (crtOPQMN) in E. coli, carotenoid aldehyde intermediates such as 4,4' diaponeurosporen-4-al accumulated without being converted into staphyloxanthin or other intermediates. We identified an aldH gene located 670 kilobase pairs from the known staphyloxanthin gene cluster in the S. aureus genome and an aldH gene in the non-staphyloxanthin-producing Staphylococcus carnosus genome. These two putative enzymes catalyzed the missing oxidation reaction to convert 4,4' diaponeurosporen-4-al into 4,4'-diaponeurosporenoic acid in E. coli. Deletion of the aldH gene in S. aureus abolished staphyloxanthin biosynthesis and caused accumulation of 4,4'-diaponeurosporen-4-al, confirming the role of AldH in staphyloxanthin biosynthesis. When the complete staphyloxanthin biosynthetic pathway was expressed using an artificial synthetic operon in E. coli, staphyloxanthin-like compounds, which contained altered fatty acid acyl chains, and novel carotenoid compounds were produced, indicating functional expression and coordination of the six staphyloxanthin pathway enzymes. PMID- 22535956 TI - Novel AKT1-GLI3-VMP1 pathway mediates KRAS oncogene-induced autophagy in cancer cells. AB - Autophagy is an evolutionarily conserved degradation process of cytoplasmic cellular constituents. It has been suggested that autophagy plays a role in tumor promotion and progression downstream oncogenic pathways; however, the molecular mechanisms underlying this phenomenon have not been elucidated. Here, we provide both in vitro and in vivo evidence of a novel signaling pathway whereby the oncogene KRAS induces the expression of VMP1, a molecule needed for the formation of the authophagosome and capable of inducing autophagy, even under nutrient replete conditions. RNAi experiments demonstrated that KRAS requires VMP1 to induce autophagy. Analysis of the mechanisms identified GLI3, a transcription factor regulated by the Hedgehog pathway, as an effector of KRAS signaling. GLI3 regulates autophagy as well as the expression and promoter activity of VMP1 in a Hedgehog-independent manner. Chromatin immunoprecipitation assays demonstrated that GLI3 binds to the VMP1 promoter and complexes with the histone acetyltransferase p300 to regulate promoter activity. Knockdown of p300 impaired KRAS- and GLI3-induced activation of this promoter. Finally, we identified the PI3K-AKT1 pathway as the signaling pathway mediating the expression and promoter activity of VMP1 upstream of the GLI3-p300 complex. Together, these data provide evidence of a new regulatory mechanism involved in autophagy that integrates this cellular process into the molecular network of events regulating oncogene-induced autophagy. PMID- 22535957 TI - Intracellular trafficking of FXYD1 (phospholemman) and FXYD7 proteins in Xenopus oocytes and mammalian cells. AB - FXYD proteins are a group of short single-span transmembrane proteins that interact with the Na(+)/K(+) ATPase and modulate its kinetic properties. This study characterizes intracellular trafficking of two FXYD family members, FXYD1 (phospholemman (PLM)) and FXYD7. Surface expression of PLM in Xenopus oocytes requires coexpression with the Na(+)/K(+) ATPase. On the other hand, the Na(+)/Ca(2+) exchanger, another PLM-interacting protein could not drive it to the cell surface. The Na(+)/K(+) ATPase-dependent surface expression of PLM could be facilitated by either a phosphorylation-mimicking mutation at Thr-69 or a truncation of three terminal arginine residues. Unlike PLM, FXYD7 could translocate to the cell surface of Xenopus oocytes independently of the coexpression of alpha1beta1 Na(+)/K(+) ATPase. The Na(+)/K(+) ATPase-independent membrane translocation of FXYD7 requires O-glycosylation of at least two of three conserved threonines in its ectodomain. Subsequent experiments in mammalian cells confirmed the role of conserved extracellular threonine residues and demonstrated that FXYD7 protein, in which these have been mutated to alanine, is trapped in the endoplasmic reticulum and Golgi apparatus. PMID- 22535958 TI - beta-Subunit of the Ostalpha-Ostbeta organic solute transporter is required not only for heterodimerization and trafficking but also for function. AB - The organic solute transporter, Ost/Slc51, is composed of two distinct proteins that must heterodimerize to generate transport activity, but the role of the individual subunits in mediating transport activity is unknown. The present study identified regions in Ostbeta required for heterodimerization with Ostalpha, trafficking of the Ostalpha-Ostbeta complex to the plasma membrane, and bile acid transport activity in HEK293 cells. Bimolecular fluorescence complementation analysis revealed that a 25-amino acid peptide containing the Ostbeta transmembrane (TM) domain heterodimerized with Ostalpha, although the resulting complex failed to reach the plasma membrane and generate cellular [(3)H]taurocholate transport activity. Deletion of the single TM domain of Ostbeta abolished interaction with Ostalpha, demonstrating that the TM segment is necessary and sufficient for formation of a heteromeric complex with Ostalpha. Mutation of the highly conserved tryptophan-asparagine sequence within the TM domain of Ostbeta to alanines did not prevent cell surface trafficking, but abolished transport activity. Removal of the N-terminal 27 amino acids of Ostbeta resulted in a transporter complex that reached the plasma membrane and exhibited transport activity at 30 degrees C. Complete deletion of the C terminus of Ostbeta abolished [(3)H]taurocholate transport activity, but reinsertion of two native arginines immediately C-terminal to the TM domain rescued this defect. These positively charged residues establish the correct N(exo)/C(cyt) topology of the peptide, in accordance with the positive inside rule. Together, the results demonstrate that Ostbeta is required for both proper trafficking of Ostalpha and formation of the functional transport unit, and identify specific residues of Ostbeta critical for these processes. PMID- 22535959 TI - Apicomplexan parasite, Eimeria falciformis, co-opts host tryptophan catabolism for life cycle progression in mouse. AB - The obligate intracellular apicomplexan parasites, e.g. Toxoplasma gondii and Plasmodium species, induce an IFNgamma-driven induction of host indoleamine 2,3 dioxygenase (IDO), the first and rate-limiting enzyme of tryptophan catabolism in the kynurenine pathway. Induction of IDO1 supposedly depletes cellular levels of tryptophan in host cells, which is proposed to inhibit the in vitro growth of auxotrophic pathogens. In vivo function of IDO during infections, however, is not clear, let alone controversial. We show that Eimeria falciformis, an apicomplexan parasite infecting the mouse caecum, induces IDO1 in the epithelial cells of the organ, and the enzyme expression coincides with the parasite development. The absence or inhibition of IDO1/2 and of two downstream enzymes in infected animals is detrimental to the Eimeria growth. The reduced parasite yield is not due to a lack of an immunosuppressive effect of IDO1 in the parasitized IDO1(-/-) or inhibitor-treated mice because they did not show an accentuated Th1 and IFNgamma response. Noticeably, the parasite development is entirely rescued by xanthurenic acid, a by-product of tryptophan catabolism inducing exflagellation in male gametes of Plasmodium in the mosquito mid-gut. Our data demonstrate a conceptual subversion of the host defense (IFNgamma, IDO) by an intracellular pathogen for progression of its natural life cycle. Besides, we show utility of E. falciformis, a monoxenous parasite of a well appreciated host, i.e. mouse, to identify in vivo factors underlying the parasite-host interactions. PMID- 22535960 TI - Use of structural phylogenetic networks for classification of the ferritin-like superfamily. AB - In the postgenomic era, bioinformatic analysis of sequence similarity is an immensely powerful tool to gain insight into evolution and protein function. Over long evolutionary distances, however, sequence-based methods fail as the similarities become too low for phylogenetic analysis. Macromolecular structure generally appears better conserved than sequence, but clear models for how structure evolves over time are lacking. The exponential growth of three dimensional structural information may allow novel structure-based methods to drastically extend the evolutionary time scales amenable to phylogenetics and functional classification of proteins. To this end, we analyzed 80 structures from the functionally diverse ferritin-like superfamily. Using evolutionary networks, we demonstrate that structural comparisons can delineate and discover groups of proteins beyond the "twilight zone" where sequence similarity does not allow evolutionary analysis, suggesting that considerable and useful evolutionary signal is preserved in three-dimensional structures. PMID- 22535961 TI - The 1.8 A cholix toxin crystal structure in complex with NAD+ and evidence for a new kinetic model. AB - Certain Vibrio cholerae strains produce cholix, a potent protein toxin that has diphthamide-specific ADP-ribosyltransferase activity against eukaryotic elongation factor 2. Here we present a 1.8 A crystal structure of cholix in complex with its natural substrate, nicotinamide adenine dinucleotide (NAD(+)). We also substituted hallmark catalytic residues by site-directed mutagenesis and analyzed both NAD(+) binding and ADP-ribosyltransferase activity using a fluorescence-based assay. These data are the basis for a new kinetic model of cholix toxin activity. Further, the new structural data serve as a reference for continuing inhibitor development for this toxin class. PMID- 22535962 TI - New class of HIV-1 integrase (IN) inhibitors with a dual mode of action. AB - tert-Butoxy-(4-phenyl-quinolin-3-yl)-acetic acids (tBPQA) are a new class of HIV 1 integrase (IN) inhibitors that are structurally distinct from IN strand transfer inhibitors but analogous to LEDGINs. LEDGINs are a class of potent antiviral compounds that interacts with the lens epithelium-derived growth factor (LEDGF) binding pocket on IN and were identified through competition binding against LEDGF. LEDGF tethers IN to the host chromatin and enables targeted integration of viral DNA. The prevailing understanding of the antiviral mechanism of LEDGINs is that they inhibit LEDGF binding to IN, which prevents targeted integration of HIV-1. We showed that in addition to the properties already known for LEDGINs, the binding of tBPQAs to the IN dimer interface inhibits IN enzymatic activity in a LEDGF-independent manner. Using the analysis of two long terminal repeat junctions in HIV-infected cells, we showed that the inhibition by tBPQAs occurs at or prior to the viral DNA 3'-processing step. Biochemical studies revealed that this inhibition operates by compound-induced conformational changes in the IN dimer that prevent proper assembly of IN onto viral DNA. For the first time, tBPQAs were demonstrated to be allosteric inhibitors of HIV-1 IN displaying a dual mode of action: inhibition of IN-viral DNA assembly and inhibition of IN-LEDGF interaction. PMID- 22535963 TI - Catestatin (chromogranin A(352-372)) and novel effects on mobilization of fat from adipose tissue through regulation of adrenergic and leptin signaling. AB - Chromogranin A knock-out (Chga-KO) mice display increased adiposity despite high levels of circulating catecholamines and leptin. Consistent with diet-induced obese mice, desensitization of leptin receptors caused by hyperleptinemia is believed to contribute to the obese phenotype of these KO mice. In contrast, obesity in ob/ob mice is caused by leptin deficiency. To characterize the metabolic phenotype, Chga-KO mice were treated with the CHGA-derived peptide catestatin (CST) that is deficient in these mice. CST treatment reduced fat depot size and increased lipolysis and fatty acid oxidation. In liver, CST enhanced oxidation of fatty acids as well as their assimilation into lipids, effects that are attributable to the up-regulation of genes promoting fatty acid oxidation (Cpt1alpha, Pparalpha, Acox, and Ucp2) and incorporation into lipids (Gpat and CD36). CST did not affect basal or isoproterenol-stimulated cAMP production in adipocytes but inhibited phospholipase C activation by the alpha-adrenergic receptor (AR) agonist phenylephrine, suggesting inhibition of alpha-AR signaling by CST. Indeed, CST mimicked the lipolytic effect of the alpha-AR blocker phentolamine on adipocytes. Moreover, CST reversed the hyperleptinemia of Chga-KO mice and improved leptin signaling as determined by phosphorylation of AMPK and Stat3. CST also improved peripheral leptin sensitivity in diet-induced obese mice. In ob/ob mice, CST enhanced leptin-induced signaling in adipose tissue. In conclusion, our results implicate CST in a novel pathway that promotes lipolysis and fatty acid oxidation by blocking alpha-AR signaling as well as by enhancing leptin receptor signaling. PMID- 22535964 TI - X-ray structures of progesterone receptor ligand binding domain in its agonist state reveal differing mechanisms for mixed profiles of 11beta-substituted steroids. AB - We present here the x-ray structures of the progesterone receptor (PR) in complex with two mixed profile PR modulators whose functional activity results from two differing molecular mechanisms. The structure of Asoprisnil bound to the agonist state of PR demonstrates the contribution of the ligand to increasing stability of the agonist conformation of helix-12 via a specific hydrogen-bond network including Glu(723). This interaction is absent when the full antagonist, RU486, binds to PR. Combined with a previously reported structure of Asoprisnil bound to the antagonist state of the receptor, this structure extends our understanding of the complex molecular interactions underlying the mixed agonist/antagonist profile of the compound. In addition, we present the structure of PR in its agonist conformation bound to the mixed profile compound Org3H whose reduced antagonistic activity and increased agonistic activity compared with reference antagonists is due to an induced fit around Trp(755), resulting in a decreased steric clash with Met(909) but inducing a new internal clash with Val(912) in helix-12. This structure also explains the previously published observation that 16alpha attachments to RU486 analogs induce mixed profiles by altering the binding of 11beta substituents. Together these structures further our understanding of the steric and electrostatic factors that contribute to the function of steroid receptor modulators, providing valuable insight for future compound design. PMID- 22535965 TI - Interaction with caveolin-1 modulates G protein coupling of mouse beta3 adrenoceptor. AB - Caveolins act as scaffold proteins in multiprotein complexes and have been implicated in signaling by G protein-coupled receptors. Studies using knock-out mice suggest that beta(3)-adrenoceptor (beta(3)-AR) signaling is dependent on caveolin-1; however, it is not known whether caveolin-1 is associated with the beta(3)-AR or solely with downstream signaling proteins. We have addressed this question by examining the impact of membrane rafts and caveolin-1 on the differential signaling of mouse beta(3a)- and beta(3b)-AR isoforms that diverge at the distal C terminus. Only the beta(3b)-AR promotes pertussis toxin (PTX) sensitive cAMP accumulation. When cells expressing the beta(3a)-AR were treated with filipin III to disrupt membrane rafts or transfected with caveolin-1 siRNA, the cyclic AMP response to the beta(3)-AR agonist CL316243 became PTX-sensitive, suggesting Galpha(i/o) coupling. The beta(3a)-AR C terminus, SP(384)PLNRF(389)DGY(392)EGARPF(398)PT, resembles a caveolin interaction motif. Mutant beta(3a)-ARs (F389A/Y392A/F398A or P384S/F389A) promoted PTX-sensitive cAMP responses, and in situ proximity assays demonstrated an association between caveolin-1 and the wild type beta(3a)-AR but not the mutant receptors. In membrane preparations, the beta(3b)-AR activated Galpha(o) and mediated PTX sensitive cAMP responses, whereas the beta(3a)-AR did not activate Galpha(i/o) proteins. The endogenous beta(3a)-AR displayed Galpha(i/o) coupling in brown adipocytes from caveolin-1 knock-out mice or in wild type adipocytes treated with filipin III. Our studies indicate that interaction of the beta(3a)-AR with caveolin inhibits coupling to Galpha(i/o) proteins and suggest that signaling is modulated by a raft-enriched complex containing the beta(3a)-AR, caveolin-1, Galpha(s), and adenylyl cyclase. PMID- 22535966 TI - Phosphatidylinositol 4-kinase IIalpha is palmitoylated by Golgi-localized palmitoyltransferases in cholesterol-dependent manner. AB - Phosphatidylinositol 4-kinase IIalpha (PI4KIIalpha) is predominantly Golgi localized, and it generates >50% of the phosphatidylinositol 4-phosphate in the Golgi. The lipid kinase activity, Golgi localization, and "integral" membrane binding of PI4KIIalpha and its association with low buoyant density "raft" domains are critically dependent on palmitoylation of its cysteine-rich (173)CCPCC(177) motif and are also highly cholesterol-dependent. Here, we identified the palmitoyl acyltransferases (Asp-His-His-Cys (DHHC) PATs) that palmitoylate PI4KIIalpha and show for the first time that palmitoylation is cholesterol-dependent. DHHC3 and DHHC7 PATs, which robustly palmitoylated PI4KIIalpha and were colocalized with PI4KIIalpha in the trans-Golgi network (TGN), were characterized in detail. Overexpression of DHHC3 or DHHC7 increased PI4KIIalpha palmitoylation by >3-fold, whereas overexpression of the dominant negative PATs or PAT silencing by RNA interference decreased PI4KIIalpha palmitoylation, "integral" membrane association, and Golgi localization. Wild type and dominant-negative DHHC3 and DHHC7 co-immunoprecipitated with PI4KIIalpha, whereas non-candidate DHHC18 and DHHC23 did not. The PI4KIIalpha (173)CCPCC(177) palmitoylation motif is required for interaction because the palmitoylation-defective SSPSS mutant did not co-immunoprecipitate with DHHC3. Cholesterol depletion and repletion with methyl-beta-cyclodextrin reversibly altered PI4KIIalpha association with these DHHCs as well as PI4KIIalpha localization at the TGN and "integral" membrane association. Significantly, the Golgi phosphatidylinositol 4-phosphate level was altered in parallel with changes in PI4KIIalpha behavior. Our study uncovered a novel mechanism for the preferential recruitment and activation of PI4KIIalpha to the TGN by interaction with Golgi- and raft-localized DHHCs in a cholesterol-dependent manner. PMID- 22535967 TI - Redox regulation of carbonic anhydrases via thioredoxin in chloroplast of the marine diatom Phaeodactylum tricornutum. AB - Thioredoxins (Trxs) are important regulators of photosynthetic fixation of CO(2) and nitrogen in plant chloroplasts. To date, they have been considered to play a minor role in controlling the Calvin cycle in marine diatoms, aquatic primary producers, although diatoms possess a set of plastidic Trxs. In this study we examined the influences of the redox state and the involvement of Trxs in the enzymatic activities of pyrenoidal carbonic anhydrases, PtCA1 and PtCA2, in the marine diatom Phaeodactylum tricornutum. The recombinant mature PtCA1 and -2 (mPtCA1 and -2) were completely inactivated following oxidation by 50 MUm CuCl(2), whereas DTT activated CAs in a concentration-dependent manner. The maximum activity of mPtCAs in the presence of 6 mm reduced DTT increased significantly by addition of 10 MUm Trxs from Arabidopsis thaliana (AtTrx-f2 and m2) and 5 MUm Trxs from P. tricornutum (PtTrxF and -M). Analyses of mPtCA activation by Trxs in the presence of DTT revealed that the maximum mPtCA1 activity was enhanced ~3-fold in the presence of Trx, whereas mPtCA2 was only weakly activated by Trxs, and that PtTrxs activate PtCAs more efficiently compared with AtTrxs. Site-directed mutagenesis of potential disulfide-forming cysteines in mPtCA1 and mPtCA2 resulted in a lack of oxidative inactivation of both mPtCAs. These results reveal the first direct evidence of a target of plastidic Trxs in diatoms, indicating that Trxs may participate in the redox control of inorganic carbon flow in the pyrenoid, a focal point of the CO(2) concentrating mechanism. PMID- 22535968 TI - Current genetic data do not improve the prediction of type 2 diabetes mellitus: the CoLaus study. AB - CONTEXT: Several genetic risk scores to identify asymptomatic subjects at high risk of developing type 2 diabetes mellitus (T2DM) have been proposed, but it is unclear whether they add extra information to risk scores based on clinical and biological data. OBJECTIVE: The objective of the study was to assess the extra clinical value of genetic risk scores in predicting the occurrence of T2DM. DESIGN: This was a prospective study, with a mean follow-up time of 5 yr. SETTING AND SUBJECTS: The study included 2824 nondiabetic participants (1548 women, 52 +/ 10 yr). MAIN OUTCOME MEASURE: Six genetic risk scores for T2DM were tested. Four were derived from the literature and two were created combining all (n = 24) or shared (n = 9) single-nucleotide polymorphisms of the previous scores. A previously validated clinic + biological risk score for T2DM was used as reference. RESULTS: Two hundred seven participants (7.3%) developed T2DM during follow-up. On bivariate analysis, no differences were found for all but one genetic score between nondiabetic and diabetic participants. After adjusting for the validated clinic + biological risk score, none of the genetic scores improved discrimination, as assessed by changes in the area under the receiver-operating characteristic curve (range -0.4 to -0.1%), sensitivity (-2.9 to -1.0%), specificity (0.0-0.1%), and positive (-6.6 to +0.7%) and negative (-0.2 to 0.0%) predictive values. Similarly, no improvement in T2DM risk prediction was found: net reclassification index ranging from -5.3 to -1.6% and nonsignificant (P >= 0.49) integrated discrimination improvement. CONCLUSIONS: In this study, adding genetic information to a previously validated clinic + biological score does not seem to improve the prediction of T2DM. PMID- 22535969 TI - Metabolic slowing with massive weight loss despite preservation of fat-free mass. AB - CONTEXT: An important goal during weight loss is to maximize fat loss while preserving metabolically active fat-free mass (FFM). Massive weight loss typically results in substantial loss of FFM potentially slowing metabolic rate. OBJECTIVE: Our objective was to determine whether a weight loss program consisting of diet restriction and vigorous exercise helped to preserve FFM and maintain resting metabolic rate (RMR). PARTICIPANTS AND INTERVENTION: We measured body composition by dual-energy x-ray absorptiometry, RMR by indirect calorimetry, and total energy expenditure by doubly labeled water at baseline (n = 16), wk 6 (n = 11), and wk 30 (n = 16). RESULTS: At baseline, participants were severely obese (* +/- SD; body mass index 49.4 +/- 9.4 kg/m(2)) with 49 +/- 5% body fat. At wk 30, more than one third of initial body weight was lost (-38 +/- 9%) and consisted of 17 +/- 8% from FFM and 83 +/- 8% from fat. RMR declined out of proportion to the decrease in body mass, demonstrating a substantial metabolic adaptation (-244 +/- 231 and -504 +/- 171 kcal/d at wk 6 and 30, respectively, P < 0.01). Energy expenditure attributed to physical activity increased by 10.2 +/- 5.1 kcal/kg.d at wk 6 and 6.0 +/- 4.1 kcal/kg.d at wk 30 (P < 0.001 vs. zero). CONCLUSIONS: Despite relative preservation of FFM, exercise did not prevent dramatic slowing of resting metabolism out of proportion to weight loss. This metabolic adaptation may persist during weight maintenance and predispose to weight regain unless high levels of physical activity or caloric restriction are maintained. PMID- 22535970 TI - Increase in brown adipose tissue activity after weight loss in morbidly obese subjects. AB - CONTEXT: Stimulation of thermogenesis in brown adipose tissue (BAT) is a potential target to treat obesity. We earlier demonstrated that BAT activity is relatively low in obese subjects. It is unknown whether BAT can be recruited in adult humans. OBJECTIVE: To study the dynamics of BAT, we observed BAT activity in morbidly obese subjects before and after weight loss induced by bariatric surgery. DESIGN: This was an observational prospective cohort study. SETTING: The study was conducted at a referral center. PATIENTS: Ten morbidly obese subjects eligible for laparoscopic adjustable gastric banding surgery were studied before and 1 yr after bariatric surgery. MAIN OUTCOME MEASURE: The main outcome measure was BAT activity, as determined after acute cold stimulation using (18)F fluorodeoxyglucose positron emission tomography and computed tomography. RESULTS: Before surgery, only two of 10 subjects showed active BAT. One year after surgery, the number of subjects with active BAT was increased to five. After weight loss, BAT-positive subjects had significantly higher nonshivering thermogenesis compared with BAT-negative subjects (P < 0.05). CONCLUSIONS: The results show that in humans BAT can be recruited in the regions in which it was also reported in lean subjects before. These results for the first time show recruitment of BAT in humans and may open the door for BAT-targeted treatments of obesity. PMID- 22535971 TI - Androgens inhibit the stimulatory action of 17beta-estradiol on normal human breast tissue in explant cultures. AB - BACKGROUND: The data concerning the effects and safety of androgen in human breast tissue are conflicting. OBJECTIVE: Our aim was to analyze the effects of androgens on normal human breast tissue (HBT). APPROACH: We cultured explants of HBT (obtained from reduction mammoplasty operations of postmenopausal women) with or without testosterone (T) and 5alpha-dihydrotestosterone (DHT) or in combination with 17beta-estradiol (E(2)) for 7 and 14 d to study the effects of androgens on proliferation, apoptosis, target gene expression, and steroid receptors. The androgen receptor (AR) and estrogen receptor (ER) dependences of the effects were studied with the antihormones bicalutamide and fulvestrant, respectively. RESULTS: The hormone responsiveness of cultured breast tissue was assessed by assaying apolipoprotein-D and prostate-specific antigen expression increased by androgens and amphiregulin and trefoil factor-1 expression induced by E(2) treatment. T and DHT reduced proliferation and increased apoptosis in breast epithelium, the effects of which were reversed by bicalutamide. In combination with E(2), they suppressed E(2)-stimulated proliferation and cell survival. DHT also inhibited basal (P < 0.05) and E(2)-induced expression of cyclin-D1 mRNA (P < 0.05). Immunohistochemistry showed that T (P < 0.05) and DHT (P < 0.05) increased the relative number of AR-positive cells, whereas ERalpha positive (P < 0.001) cell numbers were strongly decreased. The percentage of ERbeta-positive cells remained unchanged. E(2) treatment increased ERalpha positive (P < 0.01) cells, whereas AR- (P < 0.05) and ERbeta-expressing (P < 0.001) cells diminished. These effects were repressed in combination cultures of E(2) with T and DHT. CONCLUSION: T and DHT inhibited proliferation and increased apoptosis in the epithelium of cultured normal HBT and opposed E(2)-stimulated proliferation and cell survival in an AR-dependent manner. These effects were associated with changes in the proportions of ERalpha- and AR-positive epithelial cells. PMID- 22535972 TI - Iodotyrosine deiodinase defect identified via genome-wide approach. AB - CONTEXT: Diagnosis of congenital hypothyroidism is hampered by the heterogeneity of inborn errors of thyroid metabolism and the possible delay in hypothyroidism development leading to missed cases by neonatal screen. OBJECTIVE: In the current study, we used a whole-genome approach to identify the mutation responsible for severe hypothyroidism and a huge goiter in the eldest child born to healthy first cousins. RESULTS: We identified a homozygous mutation of the iodotyrosine deiodinase gene (IYD). We delineated the phenotype of this defect in detail, including urinary monoiodotyrosine (MIT) and diiodotyrosine (DIT) excretion. Moreover, a 4.5-yr-old sister was found homozygous for the mutation. Her clinical and biological data were normal, except for elevated MIT and DIT excretion. The urinary loss of MIT and DIT iodine observed in most affected individuals was quite limited compared to the total iodine loss, except for the hypothyroid homozygote. Hypothyroidism could therefore be partially induced by a relative iodine deficiency caused by urinary iodine loss through MIT and DIT excretion, even in cases of normal iodine intake. The wide inter- and intrafamilial variability of the disease severity remains unclear. CONCLUSIONS: Besides refining the phenotype of the IYD defect, our observation shows that a global, genome-wide approach to the heterogeneous inborn thyroid defects was efficient in rapidly identifying the mutation in the proband and the disease recurrence in the still euthyroid sister. Although facilitated by consanguinity in this family, novel sequencing techniques will soon make whole-genome approaches readily amenable to more common cases. PMID- 22535973 TI - Adipose tissue secretion and expression of adipocyte-produced and stromavascular fraction-produced adipokines vary during multiple phases of weight-reducing dietary intervention in obese women. AB - CONTEXT: Obesity is associated with altered plasma levels of adipokines involved in the development of insulin resistance and obesity-related metabolic disturbances. OBJECTIVE: The aim was to investigate diet-induced changes in adipokine production in sc abdominal adipose tissue (SAT) during a 6-month, multiphase, weight-reducing dietary intervention. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS: Forty-eight obese women followed a dietary intervention consisting of a very low-calorie diet (VLCD) (1 month), followed by a weight stabilization (WS) period, which consisted of a low-calorie diet (2 months), and a weight-maintenance diet (3 months). MAIN OUTCOME MEASURES: Before and at the end of the VLCD and WS, samples of plasma and SAT were obtained. In a subgroup of 26 women, secretion of adipokines was determined in SAT explants, and in a subgroup of 22 women, SAT mRNA expression was measured. RESULTS: Body weight decreased and insulin sensitivity increased during the intervention. Plasma levels, SAT mRNA expression, and secretion rates of adipocyte-produced adipokines (leptin, serum amyloid A, and haptoglobin) decreased during the VLCD and increased during the WS period. Adipokines produced mainly from stroma-vascular cells (IL-6, IL-8, IL-10, IL-1Ra, TNFalpha, plasminogen activator inhibitor-1, and monocyte chemoattractant protein-1) increased or remained unchanged during VLCD and decreased to levels equal to or lower than prediet levels during the WS period. The diet-induced changes in homeostasis model assessment of insulin resistance correlated with changes in leptin plasma levels during VLCD, WS, and the entire dietary intervention period. CONCLUSIONS: Diet-induced regulation of adipokine production in SAT differs according to their cellular origin (adipocytes vs. stroma-vascular cells) and diet phase (VLCD vs. WS). Insulin sensitivity changes were associated only with those of plasma leptin. PMID- 22535974 TI - Role of ultrasonographic/clinical profile, cytology, and BRAF V600E mutation evaluation in thyroid nodule screening for malignancy: a prospective study. AB - CONTEXT: Ultrasound (US)-guided fine-needle aspiration biopsy (FNAB) is the most reliable nonsurgical test for distinguishing benign from malignant thyroid nodules. However, there is no consensus on which nodules should undergo FNAB. AIMS: The aims of this study were to evaluate the utility of US-guided FNAB in the diagnostic assessment of nodules with or without clinical/US features suggestive for malignancy and to investigate the additional contribution of BRAF V600E mutation analysis in the detection of differentiated thyroid cancer. DESIGN AND METHODS: Thyroid cytoaspirates from 2421 nodules at least 4 mm in diameter were performed in 1856 patients who underwent cytological evaluation and biomolecular analysis. RESULTS: Cytology showed high positive predictive value and specificity for the diagnosis of malignant lesions. BRAF V600E mutation was found in 115 samples, 80 of which were also cytologically diagnosed as papillary thyroid cancer. BRAF mutation analysis significantly enhanced the diagnostic value of cytology, increasing FNAB diagnostic sensitivity for malignant nodules by approximately 28%. Micro PTC (63% of diagnosed papillary thyroid carcinoma) showed a high prevalence of multifocality, extrathyroidal extension, and lymph node metastases, underlining the malignant potential of thyroid microcarcinomas. Each investigated US/clinical characteristic of suspected malignancy correlated with the presence of a thyroid cancer in thyroid nodules with diameter of at least 4 mm. CONCLUSIONS: These data indicate that nodules of at least 4 mm may underlie a thyroid cancer independently of US/clinical characteristics of suspected malignancy, suggesting the need to perform FNAB. The diagnostic sensitivity for thyroid cancer is significantly increased by BRAF V600E mutation analysis, indicating that the screening for BRAF mutation in FNAB samples has a relevant diagnostic potential. PMID- 22535975 TI - Decreased miR-181a expression in monocytes of obese patients is associated with the occurrence of metabolic syndrome and coronary artery disease. AB - CONTEXT: Inflammation during obesity is associated with higher risk of metabolic syndrome and coronary artery disease (CAD). Activation of the inflammatory toll like receptor (TLR)/nuclear factor kappaB (NFkappaB) signaling in monocytes contributes to inflammation. Weight loss after bariatric surgery leads to significant improvement of obesity-related comorbidities. MicroRNA (miR), a class of small noncoding RNA, have been implicated as negative regulators of inflammatory processes. OBJECTIVE: This study sought to identify dysregulated miR in monocytes of obese patients associated with TLR/NFkappaB signaling, metabolic syndrome, and CAD. DESIGN, SETTING, AND PATIENTS: This retrospective study included two independent cohorts of 21 morbidly obese and 125 high-risk obese and nonobese patients in a hospitalized care setting. INTERVENTION: INTERVENTION included bariatric surgery (n = 21) with a 3-month follow-up. MAIN OUTCOME MEASURES: miR expressions in CD14(+) monocytes were determined by microarray analysis. TLR/NFkappaB-related miR were identified by an in silico target prediction analysis. Their expression was validated by quantitative RT-PCR. Their association with metabolic syndrome and angiographically documented CAD was assessed. RESULTS: miR-181a, -181b, and -181d, identified as possible regulators of the TLR/NFkappaB signaling, were decreased in obese monocytes, and weight loss normalized their expression to levels observed in monocytes of lean persons. miR 181a but not miR-181b and miR-181d was associated with a higher number of metabolic syndrome components and with CAD even after adjustment for traditional risk factors, obesity and the metabolic syndrome. CONCLUSION: This study demonstrates that the TLR/NFkappaB-related miR-181a is down-regulated in monocytes of obese patients and suggests that it is a putative biomarker of metabolic syndrome and CAD. PMID- 22535976 TI - Allelic determinants of vitamin d insufficiency, bone mineral density, and bone fractures. AB - CONTEXT: Low 25-hydroxycholecalciferol [25(OH) vitamin D] status is known to play an important role in many diseases with focus on bone health. OBJECTIVE: Based on recently reported genetic determinants of vitamin D insufficiency, we aimed to analyze genetic variants of group-specific component (GC), 7-dehydrocholesterol reductase (DHCR7), and cytochrome P450IIR-1 (CYP2R1) for association with vitamin D levels, bone mineral density (BMD), and bone fractures. DESIGN: We conducted a cross-sectional BMD and fracture study and a prospective cohort study. SETTING: The cross-sectional study comprised participants of a BMD screening study, and the prospective cohort study comprised nursing home subjects. PATIENTS: The cross sectional study included 342 subjects (mean age, 55.3 +/- 12.0 yr), and the prospective study included 1093 subjects (mean age, 84.0 +/- 6.0 yr). INTERVENTIONS: Patients were stratified by GC, DHCR7, and CYP2R1 genotypes. For each gene, the allele associated with lower 25(OH) vitamin D levels was designated as "risk allele." The potential role of these risk alleles in fracture risk was analyzed by logistic regression analysis including age and sex as confounders. MAIN OUTCOME MEASURES: We measured BMD and fractures. RESULTS: GC genotypes were significantly associated with lower mean 25(OH) vitamin D levels in both cohorts (P = 0.001 and P = 0.048, respectively). There was no significant association of BMD with any of the genotypes. None of the alleles was associated with past fractures, whereas the DHCR7 G-allele was significantly associated with prospective fractures (odds ratio, 0.68; 95% confidence interval, 0.51-0.92; P = 0.011). CONCLUSIONS: The DHCR7 gene polymorphism may be a predictor for fracture risk. PMID- 22535977 TI - Reduced mRNA and protein expression of perilipin A and G0/G1 switch gene 2 (G0S2) in human adipose tissue in poorly controlled type 2 diabetes. AB - CONTEXT: Increased lipolysis and free fatty acid (FFA) levels contribute significantly to the pathogenesis of chronic and acute insulin resistance in type 2 diabetes, but the underlying mechanisms are uncertain. OBJECTIVE: Our objective was to test whether increased lipolysis and FFA levels induced by insulin withdrawal are accompanied by increased adipose tissue (AT) contents of adipose triglyceride lipase (ATGL) and/or altered intracellular ATGL regulation. DESIGN AND PARTICIPANTS: Nine patients with type 2 diabetes were examined twice in a randomized crossover design after 16 h of 1) hyperglycemia/insulin withdrawal and 2) euglycemia/insulin infusion. Blood samples were drawn and a sc abdominal AT biopsy was obtained. SETTING: The study was conducted at a university hospital research unit. RESULTS: Circulating glucose (7.2 +/- 0.3 vs. 11.2 +/- 0.8 mmol/liter) and FFA (0.51 +/- 0.05 vs. 0.65 +/- 0.04 mmol/liter) were increased and insulin levels decreased after insulin withdrawal. AT ATGL protein tended to be increased (P = 0.075) after insulin withdrawal; by contrast, AT protein and mRNA content of perilipin A (Plin) and G(0)/G(1) switch gene 2 (G0S2), known negative regulators of ATGL activity, were decreased by 20-30% (all P values <0.03). All measured parameters related to hormone-sensitive lipase remained unaffected. CONCLUSIONS: We found reduced mRNA and protein content of Plin and G0S2 and borderline increased ATGL protein in sc AT from poorly controlled type 2 diabetic subjects. This suggests that increased ATGL activity may contribute to the elevated lipolysis and circulating FFA levels in acute insulin withdrawal and metabolic dysregulation in type 2 diabetic patients and that this mechanism may be modifiable. PMID- 22535978 TI - In vitro interaction between cefixime and amoxicillin-clavulanate against extended-spectrum-beta-lactamase-producing Escherichia coli causing urinary tract infection. PMID- 22535979 TI - Biochemical, serological, and virulence characterization of clinical and oyster Vibrio parahaemolyticus isolates. AB - In this study, 77 clinical and 67 oyster Vibrio parahaemolyticus isolates from North America were examined for biochemical profiles, serotype, and the presence of potential virulence factors (tdh, trh, and type III secretion system [T3SS] genes). All isolates were positive for oxidase, indole, and glucose fermentation, consistent with previous reports. The isolates represented 35 different serotypes, 9 of which were shared by clinical and oyster isolates. Serotypes associated with pandemic strains (O1:KUT, O1:K25, O3:K6, and O4:K68) were observed for clinical isolates, and 7 (9%) oyster isolates belonged to serotype O1:KUT. Of the clinical isolates, 27% were negative for tdh and trh, while 45% contained both genes. Oyster isolates were preferentially selected for the presence of tdh and/or trh; 34% contained both genes, 42% had trh but not tdh, and 3% had tdh but not trh. All but 1 isolate (143/144) had at least three of the four T3SS1 genes examined. The isolates lacking both tdh and trh contained no T3SS2alpha or T3SS2beta genes. All clinical isolates positive for tdh and negative for trh possessed all T3SS2alpha genes, and all isolates negative for tdh and positive for trh possessed all T3SS2beta genes. The two oyster isolates containing tdh but not trh possessed all but the vopB2 gene of T3SS2alpha, as reported previously. In contrast to the findings of previous studies, all strains examined that were positive for both tdh and trh also carried T3SS2beta genes. This report identifies the serotype as the most distinguishing feature between clinical and oyster isolates. Our findings raise concerns about the reliability of the tdh, trh, and T3SS genes as virulence markers and highlight the need for more-detailed pathogenicity investigations of V. parahaemolyticus. PMID- 22535980 TI - The 2010 global proficiency study of human papillomavirus genotyping in vaccinology. AB - Accurate and internationally comparable human papillomavirus (HPV) DNA genotyping is essential both for evaluation of HPV vaccines and for effective monitoring and implementation of vaccination programs. The World Health Organization (WHO) HPV Laboratory Network (LabNet) regularly issues international proficiency studies. The 2010 HPV genotyping proficiency panel for HPV vaccinology contained 43 coded samples composed of purified plasmids of 16 HPV types (HPV types 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68a and 68b) and 3 coded extraction controls. Proficient typing was defined as detection in both single and multiple infections of 50 international units (IU) of HPV type 16 (HPV-16) and HPV-18 DNA and 500 genome equivalents (GE) for the other 14 HPV types. Ninety eight laboratories worldwide submitted a total of 132 data sets. Twenty-four different HPV genotyping assay methods were used, with Linear Array being the most commonly used. Other major assays used were a line blot assay (Inno-LiPa), CLART, type-specific real-time PCR, PCR Luminex, and different microarray assays. Altogether, 72 data sets were proficient for detection of more than 1 type, and only 26 data sets proficiently detected all 16 HPV types. The major oncogenic HPV types, 16 and 18, were proficiently detected in 95.0% (114/120) and 87.0% (94/108) of data sets, respectively. Forty-six data sets reported multiple false positive results and were considered nonproficient. A trend toward increased sensitivity of assays was seen for the 41 laboratories that participated in both 2008 and 2010. In conclusion, continued global proficiency studies will be required for establishing comparable and reliable HPV genotyping services for vaccinology worldwide. PMID- 22535981 TI - Successful identification of clinical dermatophyte and Neoscytalidium species by matrix-assisted laser desorption ionization-time of flight mass spectrometry. AB - Dermatophytes are keratinolytic fungi responsible for a wide variety of diseases of glabrous skin, nails, and hair. Their identification, currently based on morphological criteria, is hindered by intraspecies morphological variability and the atypical morphology of some clinical isolates. The aim of this study was to evaluate matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) as a routine tool for identifying dermatophyte and Neoscytalidium species, both of which cause dermatomycoses. We first developed a spectral database of 12 different species of common and unusual dermatophytes and two molds responsible for dermatomycoses (Neoscytalidium dimidiatum and N. dimidiatum var. hyalinum). We then prospectively tested the performance of the database on 381 clinical dermatophyte and Neoscytalidium isolates. Correct identification of the species was obtained for 331/360 dermatophytes (91.9%) and 18/21 Neoscytalidium isolates (85.7%). The results of MALDI-TOF MS and standard identification disagreed for only 2 isolates. These results suggest that MALDI TOF MS could be a useful tool for routine and fast identification of dermatophytes and Neoscytalidium spp. in clinical mycology laboratories. PMID- 22535982 TI - Development and validation of a semiquantitative, multitarget PCR assay for diagnosis of bacterial vaginosis. AB - Quantitative PCR assays were developed for 4 organisms reported previously to be useful positive indicators for the diagnosis of bacterial vaginosis (BV)- Atopobium vaginae, Bacterial Vaginosis-Associated Bacterium 2 (BVAB-2), Gardnerella vaginalis, and Megasphaera-1--and a single organism (Lactobacillus crispatus) that has been implicated as a negative indicator for BV. Vaginal samples (n = 169), classified as positive (n = 108) or negative (n = 61) for BV based on a combination of the Nugent Gram stain score and Amsel clinical criteria, were analyzed for the presence and quantity of each of the marker organisms, and the results were used to construct a semiquantitative, multiplex PCR assay for BV based on detection of 3 positive indicator organisms (A. vaginae, BVAB-2, and Megasphaera-1) and classification of samples using a combinatorial scoring system. The prototype BV PCR assay was then used to analyze the 169-member developmental sample set and, in a prospective, blinded manner, an additional 227 BV-classified vaginal samples (110 BV-positive samples and 117 BV negative samples). The BV PCR assay demonstrated a sensitivity of 96.7% (202/209), a specificity of 92.2% (153/166), a positive predictive value of 94.0%, and a negative predictive value of 95.6%, with 21 samples (5.3%) classified as indeterminate for BV. This assay provides a reproducible and objective means of evaluating critical components of the vaginal microflora in women with signs and symptoms of vaginitis and is comparable in diagnostic accuracy to the conventional gold standard for diagnosis of BV. PMID- 22535983 TI - Comparison of three Roche hepatitis B virus viral load assay formats. AB - Two FDA-approved (in vitro diagnostic [IVD]) hepatitis B virus (HBV) viral load assays, the manual Cobas TaqMan HBV Test for use with the High Pure System (HP) and the automated Cobas AmpliPrep/Cobas TaqMan HBV Test v2.0 (CAP/CTM), were compared to a modified (not FDA-approved) version of the HP assay by automating the DNA extraction using the Total Nucleic Acid Isolation (TNAI) kit on the Cobas AmpliPrep. On average, CAP/CTM measurements were 0.08 log IU/ml higher than HP results (n = 206), and TNAI results were 0.17 log IU/ml higher than HP results (n = 166). The limit of detection (LOD), as determined by probit analysis using dilutions of the 2nd HBV international standard, was 10.2 IU/ml for CAP/CTM. The data sets for HP and TNAI were insufficient for probit analysis; however, there was 100% detection at >= 5 or >= 10 IU/ml for TNAI and HP, respectively. Linearity was demonstrated between 60 and 2,000,000 IU/ml, with slopes between 0.95 and 0.99 and R(2) values of >0.99 for all assays. Total precision (log percent coefficient of variance [CV]) was between 0.8% and 2.1% at 4.3 log IU/ml and between 1.4% and 4.9% at 2.3 log IU/ml. Correlation of samples, reproducibility, linearity, and LOD were acceptable and similar in all assays. The CAP/CTM assay and, to a lesser extent, the TNAI assay reduced hands-on time due to automation. There were no instances of contamination detected in negative samples during the course of the study, despite testing several samples up to 9.6 log IU/ml. The incidence of false-positive negative controls in HP and CAP/CTM clinical testing was <0.5% over 6 to 7 months of testing. PMID- 22535984 TI - Use of matrix-assisted laser desorption ionization-time of flight mass spectrometry for caspofungin susceptibility testing of Candida and Aspergillus species. AB - Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) was evaluated for testing susceptibility to caspofungin of wild type and fks mutant isolates of Candida and Aspergillus. Complete essential agreement was observed with the CLSI reference method, with categorical agreement for 94.1% of the Candida isolates tested. Thus, MALDI-TOF MS is a reliable and accurate method to detect fungal isolates with reduced caspofungin susceptibility. PMID- 22535985 TI - Rapid and specific detection of Lassa virus by reverse transcription-PCR coupled with oligonucleotide array hybridization. AB - To facilitate sequence-specific detection of DNA amplified in a diagnostic reverse transcription (RT)-PCR for Lassa virus, we developed an array featuring 47 oligonucleotide probes for post-PCR hybridization of the amplicons. The array procedure may be performed with low-tech equipment and does not take longer than agarose gel detection. PMID- 22535986 TI - Accurate identification of Candida parapsilosis (sensu lato) by use of mitochondrial DNA and real-time PCR. AB - Candida parapsilosis is the Candida species isolated the second most frequently from blood cultures in South America and some European countries, such as Spain. Since 2005, this species has been considered a complex of 3 closely related species: C. parapsilosis, Candida metapsilosis, and Candida orthopsilosis. Here, we describe a real-time TaqMan-MGB PCR assay, using mitochondrial DNA (mtDNA) as the target, which readily distinguishes these 3 species. We first used comparative genomics to locate syntenic regions between these 3 mitochondrial genomes and then selected NADH5 as the target for the real-time PCR assay. Probes were designed to include a combination of different single-nucleotide polymorphisms that are able to differentiate each species within the C. parapsilosis complex. This new methodology was first tested using mtDNA and then genomic DNA from 4 reference and 5 clinical strains. For assay validation, a total of 96 clinical isolates and 4 American Type Culture Collection (ATCC) isolates previously identified by internal transcribed spacer (ITS) ribosomal DNA (rDNA) sequencing were tested. Real-time PCR using genomic DNA was able to differentiate the 3 species with 100% accuracy. No amplification was observed when DNA from other species was used as the template. We observed 100% congruence with ITS rDNA sequencing identification, including for 30 strains used in blind testing. This novel method allows a quick and accurate intracomplex identification of C. parapsilosis and saves time compared with sequencing, which so far has been considered the "gold standard" for Candida yeast identification. In addition, this assay provides a useful tool for epidemiological and clinical studies of these emergent species. PMID- 22535987 TI - Rapid, high-throughput detection of rifampin resistance and heteroresistance in Mycobacterium tuberculosis by use of sloppy molecular beacon melting temperature coding. AB - Rifampin resistance in Mycobacterium tuberculosis is largely determined by mutations in an 80-bp rifampin resistance determining region (RRDR) of the rpoB gene. We developed a rapid single-well PCR assay to identify RRDR mutations. The assay uses sloppy molecular beacons to probe an asymmetric PCR of the M. tuberculosis RRDR by melting temperature (T(m)) analysis. A three-point T(m) code is generated which distinguishes wild-type from mutant RRDR DNA sequences in approximately 2 h. The assay was validated on synthetic oligonucleotide targets containing the 44 most common RRDR mutations. It was then tested on a panel of DNA extracted from 589 geographically diverse clinical M. tuberculosis cultures, including isolates with wild-type RRDR sequences and 25 different RRDR mutations. The assay detected 236/236 RRDR mutant sequences as mutant (sensitivity, 100%; 95% confidence interval [CI], 98 to 100%) and 353/353 RRDR wild-type sequences as wild type (specificity, 100%; 95% CI, 98.7 to 100%). The assay identified 222/225 rifampin-resistant isolates as rifampin resistant (sensitivity, 98.7%; 95% CI, 95.8 to 99.6%) and 335/336 rifampin-susceptible isolates as rifampin susceptible (specificity, 99.7%; 95% CI, 95.8 to 99.6%). All mutations were either individually identified or clustered into small mutation groups using the triple T(m) code. The assay accurately identified mixed (heteroresistant) samples and was shown analytically to detect RRDR mutations when present in at least 40% of the total M. tuberculosis DNA. This was at least as accurate as Sanger DNA sequencing. The assay was easy to use and well suited for high-throughput applications. This new sloppy molecular beacon assay should greatly simplify rifampin resistance testing in clinical laboratories. PMID- 22535988 TI - Comparison of dimethyl sulfoxide and water as solvents for echinocandin susceptibility testing by the EUCAST methodology. AB - Ninety-six strains of Candida, including 29 resistant and 67 susceptible isolates with mutations in the FKS1 and FKS2 genes were tested by the European Committee on Antibiotic Susceptibility Testing EDef 7.1 and 7.2 methodologies to determine the impact on the MIC when water was replaced with dimethyl sulfoxide (DMSO) as the solvent for caspofungin and micafungin. The MICs were significantly lower and the MIC ranges were narrower when DMSO was used as the solvent. The use of DMSO may help to better discriminate between susceptible and resistant populations. PMID- 22535989 TI - Comparison of medium, temperature, and length of incubation for detection of vancomycin-resistant Enterococcus. AB - Campylobacter (Campy; BD Diagnostics, Sparks, MD), Spectra VRE (Remel, Lenexa, KS), and bile-esculin-azide-vancomycin (BEAV; Remel) agars were compared for their ability to detect vancomycin-resistant enterococci (VRE) in 750 stool specimens. The media were compared at 24 h and 48 h of incubation at 35 degrees C and 42 degrees C. When incubated for 24 h at 35 degrees C, Campy was the most sensitive (97.8%) and specific (99.9%) but was comparable to Spectra, which has a sensitivity of 95.6% and a specificity of 99.1%, whereas BEAV was significantly less sensitive (90%) and specific (96.1%). Incubation at 42 degrees C or extended incubation at 35 degrees C for 48 h yielded no advantage over incubation at 35 degrees C for 24 h. PMID- 22535991 TI - An unusual foreign body in the urinary bladder mimicking a parasitic worm. AB - We report an unusual case of a foreign body removed from the urinary bladder of a 63-year-old male which mimicked a parasitic worm. The foreign body was identified as an artificial fishing worm by morphological comparison to a similar commercially produced product and by infrared spectrum analysis. PMID- 22535990 TI - Seronegative hepatitis C virus infection in a child infected via mother-to-child transmission. AB - Hepatitis C virus (HCV) infection typically leads to antibody response within weeks after primary infection. Here, we describe the case of a child infected with HCV by mother-to-child transmission who remained persistently seronegative despite the presence of high levels of circulating HCV RNA. PMID- 22535992 TI - Recovery of influenza B virus with the H273Y point mutation in the neuraminidase active site from a human patient. AB - The H275Y oseltamivir resistance mutation confers high-level resistance to oseltamivir in isolates of human A(H1N1) influenza. We report the recovery and identification of an influenza B virus with the H273Y neuraminidase point mutation directly from a human patient. The H273Y influenza B isolate is resistant to oseltamivir and peramivir but sensitive to zanamivir. PMID- 22535993 TI - Survival of methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus spp. for an extended period of transport. AB - This study determined the survivability of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) for extended periods of time and temperatures using a standard swab for assessment. Our study showed that transportation in Liquid Amies medium could be performed at room temperature or 4 degrees C for up to 14 days without a decrease in recovery of MRSA or VRE. PMID- 22535994 TI - Immunoglobulin genes and immunity to herpes simplex virus type 1. PMID- 22535995 TI - Fertility fluctuations in times of war and pandemic influenza. PMID- 22535996 TI - The length of the Staphylococcus aureus protein A polymorphic region regulates inflammation: impact on acute and chronic infection. AB - Staphylococcus aureus protein A (SpA) plays a critical role in the induction of inflammation. This study was aimed to determine whether the number of short sequence repeats (SSRs) present in the polymorphic region modulates the inflammatory response induced by SpA. We demonstrated that there is a dose response effect in the activation of interferon (IFN)-beta signaling in airway epithelial and immune cells, depending on the number of SSRs, which leads to differences in neutrophil recruitment. We also determined that a significant proportion of isolates from patients with chronic infections such as osteomyelitis and cystic fibrosis carry fewer SSRs than do isolates from patients with acute infections or healthy carriers and that there was an inverse correlation between the number of SSRs and the length of disease course. Given the importance of IFN signaling in eradication of S. aureus, loss of SSRs may represent an advantageous mechanism to adapt to and persist in the host. PMID- 22535997 TI - Hepatitis C virus transmission in people who inject drugs: swabs may not be the main culprit. PMID- 22535999 TI - GB virus type C infection polarizes T-cell cytokine gene expression toward a Th1 cytokine profile via NS5A protein expression. AB - Human immunodeficiency virus (HIV) disease progression is associated with a helper T cell 1 (Th1) to helper T cell 2 (Th2) cytokine profile switch. Persistent GB virus type C (GBV-C) infection is associated with survival and a serum Th1 cytokine profile in HIV-infected individuals. We found that GBV-C infection increased gene expression of Th1 cytokines and decreased Th2 cytokine expression in peripheral blood mononuclear cells. Furthermore, expression of GBV C NS5A protein in a CD4(+) cell line resulted in upregulation of Th1 cytokines (tumor necrosis factor alpha) and downregulation of Th2 cytokines (interleukin 4, interleukin 5, interleukin 10, interleukin 13). GBV-C-induced modulation in T cell cytokines may contribute to the beneficial effect of GBV-C in HIV-infected individuals. PMID- 22536000 TI - Nontypeable pneumococcal isolates among navajo and white mountain apache communities: are these really a cause of invasive disease? AB - BACKGROUND: Pneumococci could evade pneumococcal conjugate vaccines (PCV) by modifying, mutating, or deleting vaccine-serotype capsule genes or by downregulating capsule production. We sought to assess whether pneumococci that are nontypeable (NT) by the Quellung reaction truly lack capsule genes or are failing to produce capsule in vitro. METHODS: We applied multilocus sequence typing and a microarray for detection of pneumococcal polysaccharide capsule biosynthesis genes to NT carriage (children aged <5 years; years 1997-2000, 2006 2008) and NT invasive disease (IPD) (all ages; years 1994-2007) isolates from Native American communities. RESULTS: Twenty-seven of 28 (96.4%) NT IPD isolates had sequence types (STs) typically found among typeable IPD isolates and contained whole or fragments of capsule genes that matched known serotypes; 1 NT IPD isolate had a profile resembling NT carriage isolates. Forty-nine of 76 (64.5%) NT carriage isolates had STs that typically lack capsule genes and were similar to NT carriage isolates found globally. CONCLUSIONS: This is the first documentation of IPD from an NT strain confirmed to lack all known capsule genes. Most NT IPD isolates have or had the capacity to produce capsule, whereas a majority of NT carriage isolates lack this capacity. We found no evidence of pneumococcal adaptation to PCV7 via downregulation or deletion of vaccine serotype capsule genes. PMID- 22536001 TI - Hematopoietic precursor cells isolated from patients on long-term suppressive HIV therapy did not contain HIV-1 DNA. AB - BACKGROUND: We address the key emerging question of whether Lin(-)/CD34(+) hematopoietic precursor cells (HPCs) represent an important latent reservoir of human immunodeficiency virus type 1 (HIV-1) during long-term suppressive therapy. METHODS: To estimate the frequency of HIV-1 infection in bone marrow, we sorted Lin(-)/CD34(+) HPCs and 3 other cell types (Lin(-)/CD34(-), Lin(-)/CD4(+), and Lin(+)/CD4(+)) from 8 patients who had undetectable viral loads for 3-12 years. Using a single-proviral sequencing method, we extracted, amplified, and sequenced multiple single HIV-1 DNA molecules from these cells and memory CD4(+) T cells from contemporaneous peripheral blood samples. RESULTS: We analyzed 100,000 870,000 bone marrow Lin(-)/CD34(+) HPCs from the 8 patients and found no HIV-1 DNA. We did isolate HIV-1 DNA from their bone marrow Lin(+)/CD4(+) cells that was genetically similar to HIV-1 DNA from lymphoid cells located in the peripheral blood, indicating an exchange of infected cells between these compartments. CONCLUSIONS: The absence of infected HPCs provides strong evidence that the HIV-1 infection frequency of Lin(-)/CD34(+) HPCs from bone marrow, if it occurred, was <.003% (highest upper 95% confidence interval) in all 8 patients. These results strongly suggest that Lin(-)/CD34(+) HPCs in bone marrow are not a source of persistent HIV-1 in patients on long-term suppressive therapy. PMID- 22536003 TI - Uncertainty and Fertility in a Generalized AIDS Epidemic. AB - Sociologists widely acknowledge that uncertainty matters for decision making, but they rarely measure it directly. In this article, we demonstrate the importance of theorizing about, measuring, and analyzing uncertainty as experienced by individuals. We adapt a novel probabilistic solicitation technique to measure personal uncertainty about HIV status in a high HIV prevalence area of southern Malawi. Using data from 2,000 young adults (ages 15 to 25 years), we demonstrate that uncertainty about HIV status is widespread and that it expands as young adults assess their proximate and distant futures. In conceptualizing HIV status as something more than sero-status itself, we gain insight into how what individuals know they don't know influences their lives. Young people who are uncertain about their HIV status express desires to accelerate their childbearing relative to their counterparts who are certain they are uninfected. Our approach and findings show that personal uncertainty is a measurable and meaningful phenomenon that can illuminate much about individuals' aspirations and behaviors. PMID- 22536004 TI - ? AB - Social competence is defined as the ability of an animal to optimize the expression of social behaviour as a function of the available social information. The social environment encountered early in life can affect the expression of various social behaviours later in life. We investigated whether early social experience can affect social competence. In the cooperatively breeding cichlid Neolamprologus pulcher, we tested whether individuals reared with older brood caring conspecifics persistently perform better in a series of tasks (1) simulating different social contexts, (2) assigning individuals different social roles and (3) exposing them to an unknown social situation. Fish that had been reared together with older conspecifics showed more appropriate behaviours both as winners (more aggressive displays) and as losers (more submissive displays) when aggressively competing with peers over a resource, and when trying to be accepted as subordinate group member and prospective brood care helper by an unfamiliar dominant pair (more submissive displays near shelters), a situation they had never encountered before. In both tasks fish that had grown up with older fish were tolerated better by conspecifics than fish reared with same-age siblings only. We detected effects of the early environment on social behaviour in the juvenile and adult stages of the test fish. Our results suggest that growing up in more complex social groups fosters a general social ability (i.e. social competence) in N. pulcher that improves their performance across different social roles and contexts, and which may provide fitness benefits. PMID- 22536005 TI - Modeling of electron conduction in contact resistive random access memory devices as random telegraph noise. AB - The intense development and study of resistive random access memory (RRAM) devices has opened a new era in semiconductor memory manufacturing. Resistive switching and carrier conduction inside RRAM films have become critical issues in recent years. Electron trapping/detrapping behavior is observed and investigated in the proposed contact resistive random access memory (CR-RAM) cell. Through the fitting of the space charge limiting current (SCLC) model, and analysis in terms of the random telegraph noise (RTN) model, the temperature-dependence of resistance levels and the high-temperature data retention behavior of the contact RRAM film are successfully and completely explained. Detail analyses of the electron capture and emission from the traps by forward and reverse read measurements provide further verifications for hopping conduction mechanism and current fluctuation discrepancies. PMID- 22536006 TI - Evaluation of defects generation in crystalline silicon ingot grown by cast technique with seed crystal for solar cells. AB - Although crystalline silicon is widely used as substrate material for solar cell, many defects occur during crystal growth. In this study, the generation of crystalline defects in silicon substrates was evaluated. The distributions of small-angle grain boundaries were observed in substrates sliced parallel to the growth direction. Many precipitates consisting of light elemental impurities and small-angle grain boundaries were confirmed to propagate. The precipitates mainly consisted of Si, C, and N atoms. The small-angle grain boundaries were distributed after the precipitation density increased. Then, precipitates appeared at the small-angle grain boundaries. We consider that the origin of the small-angle grain boundaries was lattice mismatch and/or strain caused by the high-density precipitation. PMID- 22536007 TI - About usefulness of kalemia monitoring after blunt liver trauma. AB - Background. The aim of this study is to investigate the evidence of hypokalemia as a suitable parameter for therapeutic decision making after severe blunt liver trauma. Methods. We reviewed the medical records of 11 patients (9 M, 2 F, mean age 32 years) admitted to San Matteo Hospital of Pavia between 2007-2009. All of them were victims of road accidents hospitalized for blunt liver injury and submitted to surgery. Results. Hypokalemia was observed in 7/11 (63.6%) patients during the preoperative period (mean value 2.91 mEq/L). Serum potassium concentration normalized in all patients at the 7th postoperative day only (P < 0.01). Conclusions. According to literature results, our study confirms that after blunt hepatic injury serum potassium levels may decrease significantly. Therefore, kalemia must be carefully monitored in order to establish appropriate treatment and avoid any complications. PMID- 22536008 TI - Are pyogenic liver abscesses still a surgical concern? A Western experience. AB - Backgrounds. Pyogenic liver abscess is a rare disease whose management has shifted toward greater use of percutaneous drainage. Surgery still plays a role in treatment, but its indications are not clear. Method. We conducted a retrospective study of pyogenic abscess cases admitted to our university hospital between 1999 and 2010 and assessed the factors potentially associated with surgical treatment versus medical treatment alone. Results. In total, 103 liver abscess patients were treated at our center. The mortality was 9%. The main symptoms were fever and abdominal pain. All of the patients had CRP > 6 g/dL. Sixty-nine patients had a unique abscess. Seventeen patients were treated with antibiotics alone and 57 with percutaneous drainage and antibiotics. Twenty-seven patients who were treated with percutaneous techniques required surgery, and 29 patients initially received it. Eventually, 43 patients underwent abscess surgery. The factors associated with failed medical treatment were gas-forming abscess (P = 0.006) and septic shock at the initial presentation (P = 0.008). Conclusion. Medical and percutaneous treatment constitute the standard management of liver abscess cases. Surgery remains necessary after failure of the initial treatment but should also be considered as an early intervention for cases presenting with gas-forming abscesses and septic shock and when treatment of the underlying cause is immediately required. PMID- 22536009 TI - Estimation of time-delayed mutual information and bias for irregularly and sparsely sampled time-series. AB - A method to estimate the time-dependent correlation via an empirical bias estimate of the time-delayed mutual information for a time-series is proposed. In particular, the bias of the time-delayed mutual information is shown to often be equivalent to the mutual information between two distributions of points from the same system separated by infinite time. Thus intuitively, estimation of the bias is reduced to estimation of the mutual information between distributions of data points separated by large time intervals. The proposed bias estimation techniques are shown to work for Lorenz equations data and glucose time series data of three patients from the Columbia University Medical Center database. PMID- 22536010 TI - Pharmacokinetic interactions between the hormonal emergency contraception, levonorgestrel (Plan B), and Efavirenz. AB - OBJECTIVES: Compare the Plan B levonorgestrel (LNG) area under the concentration- time curve (AUC(12)) prior to and with efavirenz (EFV). Design. Prospective, open label, single-arm, equivalence study. METHODS: Healthy HIV-negative subjects underwent 12 hr intensive pharmacokinetic (PK) sampling following single dose LNG alone and after 14 days of EFV. Geometric means, Geometric Mean Ratios, and 90% confidence intervals (CI) are reported for PK Parameters. T-tests were utilized. Clinical parameters and liver function tests (LFTs) were assessed. RESULTS: 24 women enrolled and 21 completed the study. With EFV, LNG AUC(12) was reduced 56% (95% CI: 49%, 62%) from 42.9 to 17.8 ng*hr/mL, and maximum concentration (C(max)) was reduced 41% (95% CI: 33%, 50%) from 8.4 to 4.6 ng/mL. LNG was well tolerated with no grade 3 or 4 treatment-related toxicities. CONCLUSIONS: EFV significantly reduced LNG exposures. Higher LNG doses may be required with EFV. These results reinforce the importance of effective contraception in women taking EFV. PMID- 22536011 TI - Dual protection use to prevent STIs and unintended pregnancy. PMID- 22536012 TI - Rapid, simultaneous detection of Clostridium sordellii and Clostridium perfringens in archived tissues by a novel PCR-based microsphere assay: diagnostic implications for pregnancy-associated toxic shock syndrome cases. AB - Clostridium sordellii and Clostridium perfringens are infrequent human pathogens; however, the case-fatality rates for the infections are very high, particularly in obstetric C. sordellii infections (>90%). Deaths from Clostridium sordellii and Clostridium perfringens toxic shock (CTS) are sudden, and diagnosis is often challenging. Formalin-fixed, paraffin-embedded (FFPE) tissues usually are the only specimens available for sudden fatal cases, and immunohistochemistry (IHC) for Clostridia is generally performed but it cannot identify species. A clear need exists for a rapid, species-specific diagnostic assay for FFPE tissues. We developed a duplex PCR-based microsphere assay for simultaneous detection of C. sordellii and C. perfringens and evaluated DNA extracted from 42 Clostridium isolates and FFPE tissues of 28 patients with toxic shock/endometritis (20 CTS, 8 non-CTS, as confirmed by PCR and sequencing). The microsphere assay correctly identified C. sordellii and C. perfringens in all known isolates and in all CTS patients (10 C. sordellii, 8 C. perfringens, 2 both) and showed 100% concordance with PCR and sequencing results. The microsphere assay is a rapid, specific, and cost-effective method for the diagnosis of CTS and offers the advantage of simultaneous testing for C. sordellii and C. perfringens in FFPE tissues using a limited amount of DNA. PMID- 22536013 TI - Canine liver transplantation model and the intermediate filaments of the cytoskeleton of the hepatocytes. AB - Liver transplantation has been a successful therapy for liver failure. However, a significant number of recipients suffer from graft dysfunction. Considerably, ischemia and reperfusion (I/R) injury is the most important factor leading to organ dysfunction, although the pathogenesis has not been fully described. I/R injury have several established features that are accompanied by and/or linked to bile duct loss or ductopenia, cholestasis, and biliary ductular proliferations in the posttransplant liver biopsy. However, biliary marker levels increase usually only 5-7 days after transplantation. Intermediate filaments are one of the three cytoskeletal proteins that have a major role in liver protection and maintaining both cellular structure and integrity of eukaryotic cells. We reviewed the canine liver transplantation model as I/R injury model to delineate the intermediate filaments of the cytoskeleton that are probably the determinants in changing the phenotype of hepatocytes to cholangiocytes. Remarkably, this interesting feature seems to occur earlier than frank cholestasis. We speculate that I/R liver injury through a phenotypical switch of the hepatocytes may contribute to the poor outcome of the liver graft. PMID- 22536014 TI - Toward personalized cell therapies by using stem cells. PMID- 22536015 TI - Biological applications of hybrid quantum mechanics/molecular mechanics calculation. AB - Since in most cases biological macromolecular systems including solvent water molecules are remarkably large, the computational costs of performing ab initio calculations for the entire structures are prohibitive. Accordingly, QM calculations that are jointed with MM calculations are crucial to evaluate the long-range electrostatic interactions, which significantly affect the electronic structures of biological macromolecules. A UNIX-shell-based interface program connecting the quantum mechanics (QMs) and molecular mechanics (MMs) calculation engines, GAMESS and AMBER, was developed in our lab. The system was applied to a metalloenzyme, azurin, and PU.1-DNA complex; thereby, the significance of the environmental effects on the electronic structures of the site of interest was elucidated. Subsequently, hybrid QM/MM molecular dynamics (MD) simulation using the calculation system was employed for investigation of mechanisms of hydrolysis (editing reaction) in leucyl-tRNA synthetase complexed with the misaminoacylated tRNA(Leu), and a novel mechanism of the enzymatic reaction was revealed. Thus, our interface program can play a critical role as a powerful tool for state-of the-art sophisticated hybrid ab initio QM/MM MD simulations of large systems, such as biological macromolecules. PMID- 22536016 TI - Comparative study of the effect of baicalin and its natural analogs on neurons with oxygen and glucose deprivation involving innate immune reaction of TLR2/TNFalpha. AB - This work is to study the baicalin and its three analogs, baicalin, wogonoside, and wogonin, on the protective effect of neuron from oxygen-glucose deprivation (OGD) and toll-like receptor 2 (TLR2) expression in OGD damage. The results showed that baicalin and its three analogs did protect neurons from OGD damage and downregulated protein level of TLR2. D-Glucopyranosiduronic acid on site 7 in the structure played a core of cytotoxicity of these flavonoid analogs. The methoxyl group on carbon 8 of the structure had the relation with TLR2 protein expression, as well as the anti-inflammation. In addition, we detected caspase3 and antioxidation capability, to investigate the effect of four analogs on cell apoptosis and total antioxidation competence in OGD model. PMID- 22536017 TI - Investigation of antimicrobial activity and statistical optimization of Bacillus subtilis SPB1 biosurfactant production in solid-state fermentation. AB - During the last years, several applications of biosurfactants with medical purposes have been reported. Biosurfactants are considered relevant molecules for applications in combating many diseases. However, their use is currently extremely limited due to their high cost in relation to that of chemical surfactants. Use of inexpensive substrates can drastically decrease its production cost. Here, twelve solid substrates were screened for the production of Bacillus subtilis SPB1 biosurfactant and the maximum yield was found with millet. A Plackett-Burman design was then used to evaluate the effects of five variables (temperature, moisture, initial pH, inoculum age, and inoculum size). Statistical analyses showed that temperature, inoculum age, and moisture content had significantly positive effect on SPB1 biosurfactant production. Their values were further optimized using a central composite design and a response surface methodology. The optimal conditions of temperature, inoculum age, and moisture content obtained under the conditions of study were 37 degrees C, 14 h, and 88%, respectively. The evaluation of the antimicrobial activity of this compound was carried out against 11 bacteria and 8 fungi. The results demonstrated that this biosurfactant exhibited an important antimicrobial activity against microorganisms with multidrug-resistant profiles. Its activity was very effective against Staphylococcus aureus, Staphylococcus xylosus, Enterococcus faecalis, Klebsiella pneumonia, and so forth. PMID- 22536018 TI - Antilisterial activity of nisin-like bacteriocin-producing Lactococcus lactis subsp. lactis isolated from traditional Sardinian dairy products. AB - With the aim of selecting LAB strains with antilisterial activity to be used as protective cultures to enhance the safety of dairy products, the antimicrobial properties of 117 Lactococcus lactis subsp. lactis isolated from artisanal Sardinian dairy products were evaluated, and six strains were found to produce bacteriocin-like substances. The capacity of these strains to antagonize Listeria monocytogenes during cocultivation in skimmed milk was evaluated, showing a reduction of L. monocytogenes counts of approximately 4 log units compared to the positive control after 24 h of incubation. In order for a strain to be used as bioprotective culture, it should be carefully evaluated for the presence of virulence factors, to determine what potential risks might be involved in its use. None of the strains tested was found to produce biogenic amines or to possess haemolytic activity. In addition, all strains were sensitive to clinically important antibiotics such as ampicillin, tetracycline, and vancomycin. Our results suggest that these bac+ strains could be potentially applied in cheese manufacturing to control the growth of L. monocytogenes. PMID- 22536019 TI - Lack of association between CLEC5A gene single-nucleotide polymorphisms and Kawasaki disease in Taiwanese children. AB - BACKGROUND: Kawasaki disease is characterized by systemic vasculitis of unknown etiology. Previous genetic studies have identified certain candidate genes associated with susceptibility to KD and coronary artery lesions. Host innate immune response factors are involved in modulating the disease outcome. The aim of this study was to investigate CLEC5A (C-type lectin domain family 5) genetic polymorphisms with regards to the susceptibility and outcome of KD. METHODS: A total of 1045 subjects (381 KD patients and 664 controls) were enrolled to identify 4 tagging single-nucleotide polymorphisms (tSNPs) of CLEC5A (rs1285968, rs11770855, rs1285935, rs1285933) by using the TaqMan Allelic Discrimination Assay. The Hardy-Weinberg equilibrium was assessed in cases and controls, and genetic effects were evaluated by the chi-square test. RESULTS: No significant associations were noted between the genotypes and allele frequency of the 4 CLEC5A tSNPs between controls and patients. In the patients, polymorphisms of CLEC5A showed no significant association with coronary artery lesion formation and intravenous immunoglobulin treatment response. CONCLUSIONS: This study showed for the first time that polymorphisms of CLEC5A are not associated with susceptibility to KD, coronary artery lesion formation, and intravenous immunoglobulin treatment response in a Taiwanese population. PMID- 22536020 TI - The bioethanol industry in sub-Saharan Africa: history, challenges, and prospects. AB - Recently, interest in using bioethanol as an alternative to petroleum fuel has been escalating due to decrease in the availability of crude oil. The application of bioethanol in the motor-fuel industry can contribute to reduction in the use of fossil fuels and in turn to decreased carbon emissions and stress of the rapid decline in crude oil availability. Bioethanol production methods are numerous and vary with the types of feedstock used. Feedstocks can be cereal grains (first generation feedstock), lignocellulose (second generation feedstock), or algae (third generation feedstock) feedstocks. To date, USA and Brazil are the leading contributors to global bioethanol production. In sub-Saharan Africa, bioethanol production is stagnant. During the 1980s, bioethanol production has been successful in several countries including Zimbabwe, Malawi, and Kenya. However, because of numerous challenges such as food security, land availability, and government policies, achieving sustainability was a major hurdle. This paper examines the history and challenges of bioethanol production in sub-Saharan Africa (SSA) and demonstrates the bioethanol production potential in SSA with a focus on using bitter sorghum and cashew apple juice as unconventional feedstocks for bioethanol production. PMID- 22536022 TI - A laccase with HIV-1 reverse transcriptase inhibitory activity from the broth of mycelial culture of the mushroom Lentinus tigrinus. AB - A 59 kDa laccase with inhibitory activity against HIV-1 reverse transcriptase (IC(50) = 2.4 MUM) was isolated from the broth of mycelial culture of the mushroom Lentinus tigrinus. The isolation procedure involved ion exchange chromatography on DEAE-cellulose and CM-cellulose, and gel filtration by fast protein liquid chromatography on Superdex 75. The laccase was adsorbed on both types of ion exchangers. About 95-fold purification was achieved with a 25.9% yield of the enzyme. The procedure resulted in a specific enzyme activity of 76.6 U/mg. Its N-terminal amino acid sequence was GIPDLHDLTV, which showed little similarity to other mushroom laccase and other Lentinus tigrinus strain laccase. Its characteristics were different from previously reported laccase of other Lentinus tigrinus strain. Maximal laccase activity was observed at a pH of 4 and at a temperature of 60 degrees C, respectively. This study yielded the information about the potentially exploitable activities of Lentinus tigrinus laccase. PMID- 22536021 TI - Efficiency of ferritin as an MRI reporter gene in NPC cells is enhanced by iron supplementation. AB - BACKGROUND: An emerging MRI reporter, ferritin heavy chain (FTH1), is recently applied to enhance the contrast and increase the sensitivity of MRI in the monitoring of solid tumors. However, FTH1-overexpression-related cytotoxicity is required to be explored. METHODS: By using the Tet-Off system, FTH1 overexpression was semi-quantitativiely and dynamicly regulated by doxycycline in a NPC cell line. Effects of FTH1 overexpression on the proliferation, cytotoxicity, apoptosis and migration of NPC cells were investigated in vitro, and MR relaxation rate was measured in vitro and in vivo. RESULTS: In vitro and in vivo overexpression of FTH1 significantly increased the transverse relaxivity (R(2)), which could be enhanced by iron supplementation. In vitro, overexpression of FTH1 reduced cell growth and migration, which were not reduced by iron supplementation. Furthermore, cells were subcutaneously inoculated into the nude mice. Results showed FTH1 overexpression decreased tumor growth in the absence of iron supplementation but not in the presence of iron supplementation. CONCLUSION: To maximize R(2) and minimize the potential adverse effects, supplementation of iron at appropriate dose is recommended during the application of FTH1 as a reporter gene in the monitoring of NPC by MRI. PMID- 22536023 TI - Self-organization of motor-propelled cytoskeletal filaments at topographically defined borders. AB - Self-organization phenomena are of critical importance in living organisms and of great interest to exploit in nanotechnology. Here we describe in vitro self organization of molecular motor-propelled actin filaments, manifested as a tendency of the filaments to accumulate in high density close to topographically defined edges on nano- and microstructured surfaces. We hypothesized that this "edge-tracing" effect either (1) results from increased motor density along the guiding edges or (2) is a direct consequence of the asymmetric constraints on stochastic changes in filament sliding direction imposed by the edges. The latter hypothesis is well captured by a model explicitly defining the constraints of motility on structured surfaces in combination with Monte-Carlo simulations [cf. Nitta et al. (2006)] of filament sliding. In support of hypothesis 2 we found that the model reproduced the edge tracing effect without the need to assume increased motor density at the edges. We then used model simulations to elucidate mechanistic details. The results are discussed in relation to nanotechnological applications and future experiments to test model predictions. PMID- 22536025 TI - Ustekinumab biotherapy and real-time psoriasis capacitance mapping: a pilot study. AB - In recent years, the treatment of moderate to severe psoriasis has benefited from the development of targeted biologicals. Assessing this new class of drugs calls for precise modalities of severity/improvement ratings of the disease. Bioengineering-driven dermometrology aims at improving objective and quantitative assessments of disease severity and treatment efficacy. Skin capacitance mapping/imaging is one of those emerging methods. Among its clinical applications, psoriasis capacitance mapping (PCM) was introduced in order to assess both skin scaliness and water trapping inside the stratum corneum (inflammatory serum deposits) on lesional skin. PCM was used for assessing the therapeutic effects of ustekinumab on target lesions of 5 psoriatic patients. The reduction in the inflammatory dampness of the stratum corneum was conveniently seen after a 1-month ustekinumab treatment. The present pilot study suggests that PCM could be used as a fast and convenient method for assessing the anti inflammatory efficacy of ustekinumab and other biotherapies. PMID- 22536024 TI - Classic and new animal models of Parkinson's disease. AB - Neurological disorders can be modeled in animals so as to recreate specific pathogenic events and behavioral outcomes. Parkinson's Disease (PD) is the second most common neurodegenerative disease of an aging population, and although there have been several significant findings about the PD disease process, much of this process still remains a mystery. Breakthroughs in the last two decades using animal models have offered insights into the understanding of the PD disease process, its etiology, pathology, and molecular mechanisms. Furthermore, while cellular models have helped to identify specific events, animal models, both toxic and genetic, have replicated almost all of the hallmarks of PD and are useful for testing new neuroprotective or neurorestorative strategies. Moreover, significant advances in the modeling of additional PD features have come to light in both classic and newer models. In this review, we try to provide an updated summary of the main characteristics of these models as well as the strengths and weaknesses of what we believe to be the most popular PD animal models. These models include those produced by 6-hydroxydopamine (6-OHDA), 1-methyl-1,2,3,6 tetrahydropiridine (MPTP), rotenone, and paraquat, as well as several genetic models like those related to alpha-synuclein, PINK1, Parkin and LRRK2 alterations. PMID- 22536026 TI - Cardiovascular activity of labdane diterpenes from Andrographis paniculata in isolated rat hearts. AB - The dichloromethane (DCM) extract of Andrographis paniculata Nees was tested for cardiovascular activity. The extract significantly reduced coronary perfusion pressure by up to 24.5 +/- 3.0 mm Hg at a 3 mg dose and also reduced heart rate by up to 49.5 +/- 11.4 beats/minute at this dose. Five labdane diterpenes, 14 deoxy-12-hydroxyandrographolide (1), 14-deoxy-11,12-didehydroandrographolide (2), 14-deoxyandrographolide (3), andrographolide (4), and neoandrographolide (5), were isolated from the aerial parts of this medicinal plant. Bioassay-guided studies using animal model showed that compounds, (2) and (3) were responsible for the coronary vasodilatation. This study also showed that andrographolide (4), the major labdane diterpene in this plant, has minimal effects on the heart. PMID- 22536028 TI - Evolution of visual performance in 70 eyes implanted with the Tecnis((r)) ZMB00 multifocal intraocular lens. AB - PURPOSE: To evaluate the development of visual acuity, dysphotopsia phenomena, and subjective sensations in patients implanted with the Tecnis((r)) ZMB00 (Advanced Medical Optics Inc, Santa Ana, CA) multifocal intraocular lens. METHODS: In a sample of 70 eyes, distance and near visual acuity, with and without correction, contrast sensitivity, and patient satisfaction, were analyzed at 15, 30, and 60 days post-surgery. RESULTS: Mean uncorrected distance visual acuity (logarithm of minimum angle of resolution) at 15, 30, and 60 days was 0.194 +/- 0.054, 0.119 +/- 0.026, and 0.076 +/- 0.014 (P < 0.0001), respectively, and with correction, 0.051 +/- 0.007 vs 0.041 +/- 0.004 vs 0.022 +/- 0.002 (P < 0.0001), respectively. At 60 days, 94.3% of eyes could read 1.00 close-up without correction. Patient satisfaction in terms of dysphotopsia effects and visual acuity was excellent. The mean contrast sensitivity was 1.64 +/- 0.10 (logarithmic units) measured with the Pelli-Robson test. CONCLUSION: This type of multifocal intraocular lens was very effective at the distances analyzed, producing excellent objective and subjective results. PMID- 22536027 TI - Mannose-binding lectin binds to amyloid beta protein and modulates inflammation. AB - Mannose-binding lectin (MBL), a soluble factor of the innate immune system, is a pattern recognition molecule with a number of known ligands, including viruses, bacteria, and molecules from abnormal self tissues. In addition to its role in immunity, MBL also functions in the maintenance of tissue homeostasis. We present evidence here that MBL binds to amyloid beta peptides. MBL binding to other known carbohydrate ligands is calcium-dependent and has been attributed to the carbohydrate-recognition domain, a common feature of other C-type lectins. In contrast, we find that the features of MBL binding to Abeta are more similar to the reported binding characteristics of the cysteine-rich domain of the unrelated mannose receptor and therefore may involve the MBL cysteine-rich domain. Differences in MBL ligand binding may contribute to modulation of inflammatory response and may correlate with the function of MBL in processes such as coagulation and tissue homeostasis. PMID- 22536029 TI - Pharmacological enhancement of treatment for amblyopia. AB - BACKGROUND: The purpose of this study was to compare a weight-adjusted dose of carbidopa- levodopa as treatment adjunctive to occlusion therapy with occlusion therapy alone in children and adults with different types of amblyopia. METHODS: This prospective study included 63 patients with amblyopia classified into two groups, ie, an occlusion group which included 35 patients who received occlusion therapy only and a pharmacological enhancement group which included 28 patients who received oral carbidopa-levodopa together with occlusion therapy for 6 weeks. RESULTS: The mean logarithm of the minimal angle of resolution (logMAR) of the eyes with amblyopia was not significantly different in the occlusion group (0.52, 0.52, and 0.51) than in the pharmacological enhancement group (0.58, 0.49, and 0.56) at three follow-up visits (at months 1, 3, and 12, respectively). There was a highly significant improvement in mean logMAR of amblyopic eyes compared with baseline in both occlusion groups (from 0.68 to 0.52, from 0.68 to 0.52, and from 0.68 to 0.51) and in the pharmacological enhancement group (from 0.81 to 0.58, from 0.81 to 0.49, and from 0.81 to 0.56) at the month 1, 3, and 12 visits (P = 0.01, P = 0.01, and P = 0.001, respectively). The improvement of mean logMAR in the subgroup of patients older than 12 years was greater in the pharmacological enhancement group (42.5%) than in the occlusion group (30%). The improvement of mean logMAR in the subgroup of patients with severe amblyopia was greater in the pharmacological enhancement group (34.3%) than in the occlusion group (22%). CONCLUSION: Significant improvement was reported in both groups at all follow-up visits over 1 year. Regardless of the etiology of amblyopia, levodopa-carbidopa may be added to part-time occlusion in older patients as a means of increasing the plasticity of the visual cortex. Levodopa may add to the effect of occlusion in severe amblyopia and bilateral amblyopia. PMID- 22536031 TI - Double-pass microkeratome technique for ultra-thin graft preparation in Descemet's stripping automated endothelial keratoplasty. AB - Endothelial keratoplasty is evolving with increased attention placed on the optical qualities of the posterior donor lenticule. In efforts to improve visual outcomes, the effects of the thickness, smoothness, and planar profile are being studied. This paper describes a double-pass microkeratome technique to create ultra-thin (less than 100 MUm) Descemet's stripping automated endothelial keratoplasty grafts. PMID- 22536030 TI - Conventional and emerging treatments in the management of acute primary angle closure. AB - The management of acute primary angle closure is directed at lowering the intraocular pressure and relieving pupil block. Conventional treatment involves the use of medical treatment and laser peripheral iridotomy, respectively, as a means for achieving these aims. Newer therapeutic strategies have been described that are potentially useful adjuncts or alternatives to conventional treatment. Emerging strategies that lower intraocular pressure include anterior chamber paracentesis, as well as laser procedures such as iridoplasty and pupilloplasty. A possible alternative to relieving pupil block is lens extraction, and may be combined with adjunctive measures such as goniosynechiolysis and viscogoniosynechiolysis. Trabeculectomy has a limited role in the acute setting. This review paper reviews the current evidence regarding conventional and newer treatment modalities for acute primary angle closure. PMID- 22536032 TI - Retinoschisis and macular detachment associated with acquired enlarged optic disc cup. AB - We describe a case of maculopathy consisting of macular retinoschisis and serous macular detachment occurring in a patient with an acquired enlarged optic disc cup, similar to the maculopathy observed in congenital optic nerve abnormalities, mainly optic nerve pits and colobomas, without vitreomacular traction nor angiographic leak. Pars plana vitrectomy with argon laser endophotocoagulation and gas tamponade was found to be useful. Traction from membranes covering deep optic disc cups may create small retinal dehiscences, as described in congenital optic nerve abnormalities, which will enable the liquefied vitreous to pass, leading to retinoschisis with or without associated neurosensory detachment. Vitrectomy, photocoagulation, and gas tamponade may be a useful therapy for this entity. PMID- 22536033 TI - Asymmetric severity of diabetic retinopathy in Waardenburg syndrome: response to authors. PMID- 22536034 TI - A multicenter evaluation of ocular surface disease prevalence in patients with glaucoma. AB - BACKGROUND: Glaucoma can be associated with an increase in the occurrence of ocular surface disease (OSD) symptoms. The objective of this study was to examine the prevalence of ocular surface complaints in patients with glaucoma who used topical intraocular pressure (IOP)-lowering therapies. METHODS: In this multicenter, international, noninterventional study, adults with glaucoma or ocular hypertension who were using 1 or more topical IOP-lowering medications completed the Ocular Surface Disease Index (OSDI) questionnaire during a regularly scheduled clinic visit. OSDI scores (ranging from 0 to 100) were calculated for each patient. An OSDI score >=13 indicated a clinically relevant presence of OSD. RESULTS: Of the 448 patients who were evaluated, 53.3% were women, 61.6% had a diagnosis of primary open-angle glaucoma, and the mean age was 63 years. The overall OSD prevalence rate in the evaluable population was 59.2%, with 25.7%, 13.2%, and 20.3% of the patients reporting mild, moderate, or severe OSD symptoms, respectively. Patients with glaucoma diagnoses of less than 6 years had a significantly lower mean OSDI score relative to patients with glaucoma diagnoses of 6 years or more (18 [mild OSD] versus 23 [moderate OSD], respectively; P = 0.03). As the number of IOP-lowering treatments increased from one or two medications to three or four medications, the mean OSDI score increased from mild to moderate, though the difference in scores was not statistically significant (P = 0.15). CONCLUSIONS: OSD was highly prevalent in this population of glaucoma patients who were using IOP-lowering medications. Longer duration since diagnosis was significantly correlated with worsening of OSD symptoms. Increases in the number of medications applied also showed a clinically relevant increase in OSD symptom severity. PMID- 22536035 TI - Evaluation of the surgical learning curve for I-125 episcleral plaque placement for the treatment of posterior uveal melanoma: a two decade review. AB - PURPOSE: To evaluate the surgical learning curve in episceral plaque brachytherapy placement in the management of posterior uveal melanoma. METHODS: A retrospective chart review of two cohorts of 250 consecutive patients undergoing plaque placement for posterior uveal melanoma from 2002 to 2004 and from 2008 to 2009 was conducted. The plaque-tumor apposition rates verified by intraoperative echography were evaluated and correlated with surgical volume over a 19-year period. RESULTS: In an initial study of 29 consecutive patients undergoing plaque placement from January 1992 to January 1995, a suboptimal plaque placement rate of 21% (n = 29) was identified. This percentage declined to 12% (n = 100) from January 2002 to January 2004, and further declined to 4% (n = 150) from June 2008 to August 2009. The tumor-plaque apposition rates for these three groups were 79% (1992-1995), 88% (2002-2004), and 96% (2008-2009). An estimated surgical volume of 1275 cases was performed to achieve a >90% precision rate for first application of primary plaque centration. CONCLUSION: There are challenges to mastering the precise placement of radioactive plaques for posterior uveal melanoma. We have demonstrated a significant learning curve for plaque placement techniques, and have emphasized the importance of intraoperative ultrasound in the verification of plaque placement, thus allowing for intraoperative repositioning. PMID- 22536036 TI - Management of endophthalmitis while preserving the uninvolved crystalline lens. AB - BACKGROUND: The purpose of this work is to report on the management of endophthalmitis in phakic eyes in which the crystalline lens was preserved. METHODS: The current study is a noncomparative consecutive case series of patients who developed culture-proven endophthalmitis and were treated between January 1995 and June 2009. The study included only phakic patients whose infection was managed without removal of the crystalline lens. Using a computerized search of Microbiology Department records, patients were identified with phakic lens status and clinically diagnosed endophthalmitis. RESULTS: A total of 12 phakic eyes from 11 patients met the study criteria. The etiology of infection was endogenous (n = 6), postoperative (n = 5), and post-traumatic (n = 1). Pars plana vitrectomy and injection of intravitreal antimicrobials was performed in seven eyes (58%), and vitreous tap and injection of antimicrobials was performed in five eyes (42%). All eyes showed progression of lens opacification after treatment. Overall, nine (75%) achieved visual acuity outcomes >=20/80, including five of seven (71%) eyes treated with vitrectomy and four of five eyes (80%) treated with injection of antibiotics alone. One of seven eyes (14%) treated with vitrectomy had a poor visual outcome (defined as <20/400) compared with one of five (20%) eyes treated with intravitreal antimicrobials alone. During follow-up, all 12 eyes had progression of lens opacification and five of 12 (42%) eyes underwent cataract surgery with posterior chamber intraocular lens placement. CONCLUSION: In phakic patients, successful treatment of endophthalmitis can be achieved while preserving the uninvolved crystalline lens. Future cataract surgery with posterior chamber intraocular lens placement can be accomplished in many of these patients. PMID- 22536037 TI - The effect of preoperative keratometry on visual outcomes after moderate myopic LASIK. AB - PURPOSE: To evaluate visual outcomes in moderately myopic eyes with flat and steep corneas (preoperatively) that have been treated with laser-assisted in situ keratomileusis (LASIK). PATIENTS AND METHODS: Records of ninety-six eyes with average preoperative keratometry (K) values between 39.9 and 42.0 diopters (D) (flat) were matched with 103 eyes with preoperative K values between 46.0 and 47.2 D (steep) that underwent LASIK between March 2007 and March 2010 for moderate myopia, and were retrospectively reviewed. The primary outcome measures used to determine the effect of preoperative keratometry on visual prognosis were refraction, visual acuity, change in keratometry (DeltaK), and change in spherical equivalent (DeltaSE), measured at 1, 3, 6, and 12 months postoperatively. RESULTS: Significant differences were found at 6 months postoperatively between the flat group and steep group in SE (P = 0.029), sphere (P = 0.018), DeltaK (P = 0.002), percentage of eyes achieving SE of -0.25 to + 0.25 D (P = 0.0125), -0.26 to -0.50 D (P = 0.003), -0.51 to -1.00 D (P = 0.044), and the percentage of eyes achieving uncorrected distance visual acuity of 20/15 or better (P = 0.0006). CONCLUSION: Moderately myopic eyes with flatter corneas preoperatively have better visual prognosis following LASIK compared with moderately myopic eyes with steeper corneas. PMID- 22536038 TI - Major single nucleotide polymorphisms in polypoidal choroidal vasculopathy: a comparative analysis between Thai and other Asian populations. AB - PURPOSE: To investigate the association in a Thai population between the major age-related macular degeneration (AMD) susceptibility loci, Y402H and I62V in the complement factor H (CFH) and A69S in the age-related maculopathy susceptibility 2 (ARMS2) genes, and polypoidal choroidal vasculopathy (PCV). METHODS: A case control study included 97 PCV cases and 102 age- and gender-matched controls without any retinopathy. The genotypic profiles of the three polymorphisms were obtained using a real-time polymerase chain reaction assay. The allelic and genotypic association between the polymorphisms and PCV were compared with those from the compiled data of other Asian populations reported previously. RESULTS: Strong associations between the Y402H, I62V, and A69S polymorphisms and PCV were observed in the present study (P = 0.002, 0.003, and 0.0008 respectively) and in the compiled data (P < 0.0001 for all three polymorphisms). The risk allele frequencies of the polymorphisms in PCVs and in controls from the present study (15.0% and 5.4% for Y402H, 71.7% and 57.4% for I62V, and 54.1% and 37.3% for A69S respectively) were also comparable with the frequencies from the compiled data (10.3% and 6.4% for Y402H, 75.2% and 58.3% for I62V, and 56.8% and 36.8% for A69S respectively). The genotype distribution for each polymorphism was also comparable in both datasets. CONCLUSION: The findings of this study support a significant genetic association between the major AMD susceptibility genes and PCV across Asian populations. This suggests that AMD and PCV, despite different phenotypic manifestation, may share common genetic risk factors. PMID- 22536039 TI - Cone dysfunctions in retinitis pigmentosa with retinal nerve fiber layer thickening. AB - PURPOSE: To investigate whether or not thicker retinal nerve fiber layer (RNFL) in retinitis pigmentosa (RP) patients relates to functional abnormalities of the photoreceptors. METHODS: Optical coherence tomography-based RNFL thickness was measured by Stratus-3TM (Zeiss, Basel, Switzerland) optical coherence tomography and electroretinogram (ERG) recordings made using the RETI-port((r)) system (Roland, Wiesbaden, Germany) in 27 patients with retinitis pigmentosa and in 30 healthy subjects. RESULTS: Photopic ERG b-wave amplitude, cone ERG b-wave latency, 30 Hz flicker amplitude, and 30 Hz flicker latency had significant correlations to the RNFL-temporal (r = -0.55, P = 0.004, r = 0.68, P = 0.001, r = -0.65, P = 0.001, and r = -0.52, P = 0.007, respectively). Eyes with thicker RNFL (ten eyes) differed significantly from those with thinner RNFL (eight eyes) regarding cone ERG b-wave latency values only (P = 0.001). CONCLUSION: Thicker RNFL in patients with retinitis pigmentosa may be associated with functional abnormality of the cone system. PMID- 22536040 TI - Intraoperative use of spectral-domain optical coherence tomography during Descemet's stripping automated endothelial keratoplasty. AB - PURPOSE: To evaluate the intraoperative changes in the donor lenticule, recipient cornea, and the reduction of interface fluid thickness during Descemet's stripping and automated endothelial keratoplasty with EndoGlideTM (Angiotech Pharmaceuticals Inc, Vancouver, Canada) donor insertion, using intraoperative spectral-domain optical coherence tomography. METHODS: Prospective observational case series of patients underwent Descemet's stripping and automated endothelial keratoplasty using the EndoGlide inserter. Spectral-domain optical coherence tomography (iVue; Optovue Inc, Fremont, CA) with a handheld probe was used to image the cornea and anterior chamber. Standardized software was used to measure interface fluid gap, host cornea, and donor lenticule thicknesses during the following surgical stages of Descemet's stripping and automated endothelial keratoplasty: (1) after donor insertion and immediately before full air tamponade; (2) after air tamponade and expression of fluid from venting incisions; (3) at 6 minutes of air tamponade; and (4) at 10 minutes of air tamponade. RESULTS: Ten patients with a mean age of 74.9 +/- 11.8 years were recruited. Spectral-domain optical coherence tomography measurements of the interface fluid gap after fluid was expressed through the venting incisions (P < 0.001), at 6 minutes of air tamponade (P < 0.001) and at 10 minutes of air tamponade (P < 0.001 and P = 0.001, respectively), were significantly decreased compared to the measurements immediately before air tamponade. Donor thickness increased significantly at 6 minutes of air tamponade (P = 0.004) but reduced by 10 minutes compared to immediately before air tamponade. CONCLUSION: Significant intraoperative changes in the donor, recipient cornea, and interface fluid thickness occurred following endothelial keratoplasty donor insertion. PMID- 22536041 TI - Diffuse unilateral subacute neuroretinitis in a young boy: a case report. AB - We report a case of diffuse unilateral subacute neuroretinitis in a young boy with no clinical visualization of nematode. The diagnosis was made based on clinical findings and detection of Toxocara immunoglobulin G by Western blot test. An 11-year-old Malay boy presented with progressive blurring of vision in the left eye for a duration of 1 year. It was associated with intermittent floaters. Visual acuity in the left eye was 6/45 and improved to 6/24 with pinhole. There was positive relative afferent pupillary defect, impaired color vision, and presence of red desaturation in the left eye. There were occasional cells in the anterior chamber with no conjunctiva injection. Posterior segment examination revealed mild-to-moderate vitritis and generalized pigmentary changes of the retina with attenuated vessels. The optic disk was slightly hyperemic with mild edema. There was presence of multiple, focal, gray-white subretinal lesions at the inferior part of the retina. Full blood picture results showed eosinophilia with detection of Toxocara immunoglobulin G by Western blot test. Investigations for other infective causes and connective tissue diseases were negative. The diagnosis of diffuse unilateral subacute neuroretinitis secondary to Toxocara was made based on clinical findings and laboratory results. He was treated with oral albendazole 400 mg daily for 5 days and oral prednisolone 1 mg/kg with tapering doses over 6 weeks. At 1 month follow-up, the inflammation had reduced, and multiple, focal, gray-white subretinal lesions were resolved; however there was no improvement of vision. PMID- 22536042 TI - Comparing the efficacy of the monocular trial treatment paradigm with multiple measurements of intraocular pressure before and after treatment initiation in primary open-angle glaucoma. AB - The monocular trial has been proposed as a test to help control for diurnal fluctuations in eye pressure when assessing medication effectiveness. We undertook a prospective study to determine the sensitivity and specificity of the monocular trial as a test for determining the effectiveness of a glaucoma medication. The efficacy of the monocular trial was compared to the diagnostic paradigm of repeated pre- and post-treatment measurements in determining whether an intraocular pressure (IOP)-lowering drug is effective. Forty-two patients with newly diagnosed open-angle glaucoma completed five visits: visit 1 for determining eligibility, obtaining consent, and measuring IOP, visit 2 for a second pressure measurement, and visit 3 for a third pressure reading. The new medication was then started in one eye. IOP measurements were made at weeks 4 and 6. The gold standard IOP change was defined as the difference in mean between the pre- and post-medication visits. A medication was deemed effective if this difference was at least 15%. The monocular trial pressure change was defined as the IOP change in the treated eye between the visit immediately before and immediately after the medication addition, corrected by subtracting the pressure change in the untreated eye. All 42 patients completed the full protocol with good compliance. Twenty-five of 42 (60%) medication additions were considered effective by the gold standard method, and 25/42 (60%) by the monocular trial method. However, the two methods agreed in only 26 patients (17 Yes/Yes, 9 No/No). The calculated sensitivity was low (0.68), with a specificity of 0.53. The monocular trial can give useful clues as to whether a medication is effective, but should not be the only information used in making this determination. To obtain the most valid results, multiple pressure checks should be done before and after starting a new medication. PMID- 22536043 TI - A clinically challenging diagnosis of adenoma of the retinal pigment epithelium presenting with clinical features of choroidal hemangioma. AB - BACKGROUND: Adenoma of the retinal pigment epithelium (RPE) is a rare intraocular tumor that can simulate other pigmented tumors such as choroidal melanoma. We report a case of non-pigmented adenoma of the RPE initially diagnosed as choroidal hemangioma. CASE REPORT: A 42-year-old woman presented to Kurume University Hospital in November 1992 with an orange-yellow tumor nasal to the optic disc in the left fundus. The tumor was 9.0 * 9.0 mm in diameter, 6.0 mm thick, and was characterized by high intensity on T1-weighted magnetic resonance imaging (MRI), low intensity on T2-weighted MRI, and enhancement on gadolinium MRI. Fluorescein angiography revealed early hypofluorescence and late hyperfluorescence of the tumor and retinal feeder vessels. By April 1996, exudate had developed around the tumor margins. The patient was treated with external beam radiation therapy (20 Gy) in July 1996, but the tumor did not diminish in size. Subsequently, she developed extensive loss of vision due to total retinal detachment. Accordingly, her left eye was enucleated in June 2005 because of severe ocular pain due to absolute glaucoma. Histopathological examination indicated that the tumor was contiguous with the normal surrounding RPE and was composed of cords and tubules of mostly non-pigmented spindle-shaped cells with round to oval nuclei and a small amount of cytoplasm containing melanin granules. The tumor cells were immunoreactive for vimentin, S-100 protein, and cytokeratin 18. The final diagnosis was adenoma of the RPE. CONCLUSION: Adenoma of the retinal pigment epithelium may be associated with incompetent vessels leading to serous retinal detachment and extensive visual loss, and may exhibit clinical characteristics similar to choroidal hemangioma. PMID- 22536044 TI - Relationship between endothelial cell loss and microcoaxial phacoemulsification parameters in noncomplicated cataract surgery. AB - PURPOSE: To assess the relationship between postoperative endothelial cell loss and microcoaxial phaco parameters using Ozil IP (Alcon Laboratories, Inc, Fort Worth, TX) in noncomplicated cataract surgery. METHODS: In this prospective observational study, 120 consecutive cases of cataract patients with different grades of nuclear hardness underwent microcoaxial phacoemulsification through a 2.2-mm clear corneal incision. An Alcon Infinity Vision System with Ozil IP (Alcon Laboratories) was used with an Ozil torsional handpiece and a Kelman-style 45 degrees phacoemulsification tip. Patients underwent preoperative and postoperative central endothelial cell counts. RESULTS: The study included 120 cases of age-related cataract whose mean age (standard deviation [SD]) was 59.68 years (9.47). There was a highly statistically significant endothelial cell loss (P < 0.001). The endothelial cell loss ranged 11-1149 cells/mm(2) with a median (interquartile range) of 386 cells/mm(2) (184.5-686 cells/mm(2)). The percentage of postoperative ECLoss% ranged from 0.48% to 47.8% with a median (interquartile range) of 15.4% (7.2% to 26.8%). A significant positive correlation was found between the ECLoss% and different phaco parameters. The Spearman's rank-order correlation coefficient values, rho, (rho) were as follows: CDE (rho = 0.425), aspiration time (rho = 0.176), and volume (rho = 0.278). Also, ECLoss% was significantly correlated with the grade of nuclear opalescence (Kendall's tau tau = 0.42). CONCLUSION: Microcoaxial phacoemulsification was efficient in removing noncomplicated cataracts; however a statistically significant endothelial cell loss was noted, especially with increased nuclear hardness. This endothelial cell loss was mostly related to the increased cumulative dissipated energy (CDE), aspiration time, and volume of balanced salt solution used. PMID- 22536045 TI - Dendritic immune cell densities in the central cornea associated with soft contact lens types and lens care solution types: a pilot study. AB - BACKGROUND: The purpose of this study was to assess whether differences in central corneal dendritic immune cell densities associated with combinations of soft contact lenses and lens care solutions could be detected by in vivo confocal microscopy. METHODS: Participants were adults naive to contact lens wear (n = 10) or who wore soft contact lenses habitually on a daily-wear schedule (n = 38) or on a study-assigned schedule for 30 days with daily disposable silicone hydrogel lenses (n = 15). Central corneas were scanned using an in vivo confocal microscope. Cell densities were compared among groups by demographic parameters, lens materials, and lens care solutions (polyhexamethylene biguanide [PHMB], polyquaternium-1 and myristamidopropyl dimethylamine [PQ/MAPD], peroxide, or blister pack solution [for daily disposable lenses]). RESULTS: Among lens wearers, no associations were observed between immune cell densities and age, gender, or years of lens-wearing experience. Mean cell density was significantly lower (P < 0.01) in nonwearers (29 +/- 23 cells/mm(2), n = 10) than in lens wearers (64 +/- 71 cells/mm(2), n = 53). Mean cell density was lower (P = 0.21) with traditional polymer lenses (47 +/- 44 cells/mm(2), n = 12) than with silicone hydrogel lenses (69 +/- 77 cells/mm(2), n = 41). Lowest to highest mean density of immune cells among lens wearers was as follows: PQ/MAPD solution (49 +/- 28 cells/mm(2)), blister pack solution (63 +/- 81 cells/mm(2)), PHMB solution (66 +/- 44 cells/mm(2)), and peroxide solution (85 +/- 112 cells/mm(2)). CONCLUSION: In this pilot study, in vivo confocal microscopy was useful for detecting an elevated immune response associated with soft contact lenses, and for identifying lens-related and solution-related immune responses that merit further research. PMID- 22536046 TI - Cytomegalovirus retinitis treated with valganciclovir in Wegener's granulomatosis. AB - A case of cytomegalovirus (CMV) retinitis in a patient with Wegener's granulomatosis treated with oral valganciclovir as maintenance therapy is reported. A 68-year-old male patient with anti-proteinase-3 ANCA-positive Wegener's granulomatosis who was receiving immunosuppressive therapy with methylprednisolone, cyclophosphamide, and azathioprine developed CMV retinitis. The patient received intravenous ganciclovir as induction therapy and oral valganciclovir as maintenance therapy. The patient responded to treatment and showed no recurrence for 8 months. There were no serious adverse effects associated with oral valganciclovir. Oral valganciclovir is convenient and effective for the management of CMV retinitis in the patient with Wegener's granulomatosis. PMID- 22536048 TI - Suprachoroidal gas injection as a complication of pars plana vitrectomy confirmed by computed tomography. AB - BACKGROUND: Suprachoroidal gas injection has been reported as a complication of pneumatic retinopexy, and the usefulness of B-scan ultrasonography has been reported. A case of suprachoroidal gas injection as a complication of pars plana vitrectomy confirmed by computed tomography (CT) is presented here. METHODS: A 64 year-old woman developed a vitreous hemorrhage due to a retinal tear secondary to an old branch retinal vein occlusion. A 23-gauge pars plana vitrectomy was performed. Sclerotomies were performed at a 30 degrees angle. After air-fluid exchange, sulfur hexafluoride gas was injected through a temporo-superior sutured sclerotomy with direct visualization of the entire needle tip. Postoperatively, a large choroidal elevation was identified temporo-superiorly with intravitreal gas, and the patient complained of a mild headache. RESULTS: On postoperative Day 7, a CT scan showed two low-density areas, confirming the presence of suprachoroidal gas; intravitreal gas blocked visualization of the suprachoroidal gas on B-scan ultrasonography. On postoperative Day 14, the intravitreal gas resolved and a CT scan showed a small amount of residual suprachoroidal gas. By this time, the headache had completely resolved. CONCLUSION: Suprachoroidal gas injection is a rare complication of pars plana vitrectomy that resolves spontaneously. In this case, CT scans confirmed the presence of suprachoroidal gas despite the presence of intravitreal gas. PMID- 22536047 TI - Sustained intraocular pressure reduction throughout the day with travoprost ophthalmic solution 0.004%. AB - BACKGROUND: The purpose of this study was to characterize intraocular pressure (IOP) reduction throughout the day with travoprost ophthalmic solution 0.004% dosed once daily in the evening. METHODS: The results of seven published, randomized clinical trials including at least one arm in which travoprost 0.004% was dosed once daily in the evening were integrated. Means (and standard deviations) of mean baseline and on-treatment IOP, as well as mean IOP reduction and mean percent IOP reduction at 0800, 1000, and 1600 hours at weeks 2 and 12 were calculated. RESULTS: From a mean baseline IOP ranging from 25.0 to 27.2 mmHg, mean IOP on treatment ranged from 17.4 to 18.8 mmHg across all visits and time points. Mean IOP reductions from baseline ranged from 7.6 to 8.4 mmHg across visits and time points, representing a mean IOP reduction of 30%. Results of the safety analysis were consistent with the results from the individual studies for travoprost ophthalmic solution 0.004%, with ocular hyperemia being the most common side effect. CONCLUSION: Travoprost 0.004% dosed once daily in the evening provides sustained IOP reduction throughout the 24-hour dosing interval in subjects with ocular hypertension or open-angle glaucoma. No reduction of IOP lowering efficacy was observed at the 1600-hour time point which approached the end of the dosing interval. PMID- 22536049 TI - Endothelial cell counts after Descemet's stripping automated endothelial keratoplasty versus penetrating keratoplasty in Asian eyes. AB - BACKGROUND: The purpose of this study was to compare endothelial cell counts after Descemet's stripping automated endothelial keratoplasty (DSAEK) and penetrating keratoplasty in Asian eyes. METHODS: This was a retrospective study of patients from our prospective Singapore Corneal Transplant Study cohort who received corneal transplantation in 2006-2008. We compared eyes that underwent DSAEK or penetrating keratoplasty for Fuchs' endothelial dystrophy or pseudophakic and aphakic bullous keratopathy. Clinical data, and donor and recipient characteristics were recorded. Of 241 patients who met our inclusion criteria, 68 underwent DSAEK and 173 underwent penetrating keratoplasty. The main outcome measure was endothelial cell loss at 1 year. Secondary outcome measures were graft survival and visual outcomes at 1-year follow-up. RESULTS: There were no significant differences in baseline characteristics of patients between the treatment groups. Percent endothelial cell loss at 1-year follow-up was greater in penetrating keratoplasty eyes (40.9% +/- 2.9%) compared with DSAEK eyes (22.4% +/- 2.3%; P < 0.001). DSAEK-treated eyes had significantly superior uncorrected visual acuity (mean difference = 0.42 +/- 0.0059; P < 0.001) and best spectacle corrected visual acuity (mean difference = 0.14 +/- 0.032; P < 0.001) as compared with penetrating keratoplasty-treated eyes. Penetrating keratoplasty-treated eyes had worse astigmatism as compared with DSAEK-treated eyes (-3.0 +/- 2.1 versus 1.7 +/- 0.8; P < 0.001). Graft survival at 1 year was comparable in both groups, ie, 66/68 (97.0%) DSAEK-treated eyes versus 158/173 (92.0%) of penetrating keratoplasty-treated eyes had clear grafts (P = 0.479). CONCLUSION: We report lower percent endothelial cell loss comparing DSAEK and penetrating keratoplasty at 1-year follow-up in Asian eyes, with comparable graft survival rates in both groups. PMID- 22536050 TI - Opaque intraocular lens implantation: a case series and lessons learnt. AB - PURPOSE: To report the use of opaque intraocular devices in three patients with complex neuro-ophthalmic symptoms. METHODS: A case series of three patients with neuro-ophthalmic symptoms requiring occlusion of one eye when alternative methods had failed to control symptoms. Morcher (Stuttgart, Germany) opaque intraocular implants were used in all patients. RESULTS: All three patients observed an improvement in symptoms following opaque intraocular device implantation. One patient (Case 2) required multiple devices for symptom relief. CONCLUSION: Opaque intraocular occlusive devices are an increasingly popular choice for clinicians in patients with intractable diplopia but we highlight their use in patients with other complex neuro-ophthalmic symptoms. We learned a number of useful lessons in these patients as summarized in this case series. PMID- 22536051 TI - Bilateral acute retinal necrosis after herpetic meningitis. AB - PURPOSE: The report of a case of bilateral acute retinal necrosis after herpetic meningitis. CASE REPORT: A 47-year-old man was admitted with the chief complaint of persistent high fever and transient loss of consciousness. Although his general condition improved after intravenous acyclovir administration, the patient presented with visual loss in both eyes 4 days after admission. Visual acuity in his right eye was 20/200 and his left eye had light perception alone. Both eyes showed panretinal arteritis diagnosed as acute retinal necrosis. Panretinal photocoagulation was performed for both eyes. Progression of retinal detachment was prevented in both eyes; however, visual acuity of the left eye was totally lost because of neovascular glaucoma. Visual acuity of the right eye recovered to 20/20. CONCLUSION: Although cases of bilateral acute retinal necrosis have been reported after herpetic encephalitis, this condition is rare after herpetic meningitis. Prophylactic acyclovir therapy and early panretinal photocoagulation may prevent retinal detachment and improve the prognosis. Neurologists and ophthalmologists should be aware that not only herpetic encephalitis but also herpetic meningitis can lead to acute retinal necrosis within a very short interval. PMID- 22536052 TI - Dynamic contour tonometry in asymmetric glaucoma patients. AB - BACKGROUND: The purpose of this study was to determine any difference in dynamic contour tonometry and ocular pulse amplitude in asymmetric glaucoma patients with the same applanation intraocular pressure. METHODS: This is a prospective, observational study of 30 glaucoma patients and 11 controls from June 2007 to February 2008. Most of the glaucoma patients were on prostaglandin analog treatment. RESULTS: Mean applanation intraocular pressure in the control group was 14.28 mmHg for the right eye and 14.10 mmHg for the left eye (P > 0.05). Corneal thickness was 519.10 MUm for the right eye and 511.07 MUm for the left eye (P > 0.05). Mean dynamic contour tonometry intraocular pressure was 17.28 mmHg for the right eye and 17.25 mmHg for the left eye (P > 0.05). Mean ocular pulse amplitude was 2.80 mmHg for the right eye and 2.92 mmHg for the left eye (P > 0.05). CONCLUSION: No differences in ocular pulse amplitude were found between the two groups and between the worst and the best eye. In spite of there being no difference in ocular pulse amplitude, dynamic contour tonometry intraocular pressure was 2.44 mmHg higher in the worst eye than in the best eye in the glaucoma patients, even with the same applanation intraocular pressure. Further studies are needed to confirm if this difference is related to glaucoma progression or a worst prognosis and whether it can be considered to be a new risk factor. PMID- 22536053 TI - Is age-related macular degeneration a problem in Ibadan, Sub-Saharan Africa? AB - BACKGROUND: Age-related macular degeneration (AMD) is considered uncommon in black populations including those of Sub-Saharan Africa. The aim of this review was to determine the pattern of presentation of AMD in our hospital located in Ibadan, the largest city in Sub-Saharan Africa. METHODS: A retrospective review of all cases with AMD presenting to the Eye and Retinal Clinic of the University College Hospital, Ibadan, West Africa was undertaken between October 2007 and September 2010. RESULTS: In the 3 years reviewed, 768 retinal cases were seen in the hospital, 101 (14%) of which were diagnosed with AMD. The peak age was 60-79 years. The male to female ratio was approximately 2:3. More males presented with the advanced form of dry AMD than females (odds ratio = 2.33). However, more females had advanced wet AMD than males (odds ratio = 1.85). Wet AMD was seen in 40 cases (40%). CONCLUSION: The review determined that, as AMD is not uncommon and wet AMD is relatively more common in our hospital than has been reported previously, this is probably true of Ibadan in general. PMID- 22536054 TI - It is not always about gains: utilities and disutilities associated with treatment features in patients with moderate-to-severe psoriasis. AB - BACKGROUND: Patient-centered care has been proposed as a strategy for improving treatment outcomes in the management of psoriasis and other chronic diseases. A more detailed understanding of patients' utilities and disutilities associated with treatment features may facilitate shared decision-making in the clinical encounter. The purpose of this study was to examine the features of psoriasis treatment that are most and least preferred by patients and to identify correlates of these preferences. METHODS: A cross-sectional survey of 163 patients with moderate-to-severe psoriasis was conducted in a German academic medical center. We assessed patients' characteristics, elicited their preferences for a range of potential treatment features, and quantified preference scores (utilities) associated with each treatment feature using hierarchical Bayes estimation. After identifying the most and least preferred treatment features, we explored correlates of these preferences using multivariate regression models. RESULTS: Mean preference scores (MPS) for the least preferred treatment features were consistently greater than those for the most preferred treatment features. Patients generally expressed strong preferences against prolonged treatments in the inpatient setting (MPS = -13.48) and those with a lower probability of benefit (MPS = -12.28), while treatments with a high probability of benefit (MPS = 10.51) were generally preferred. Younger patients and women were more concerned with treatment benefit as compared with older patients and men. CONCLUSION: Both negative and positive preferences appear important for shared decision-making. Recognition of characteristics associated with strong negative preferences may be particularly useful in promoting patient-centered environments. PMID- 22536055 TI - Neuropsychophysical optimization by REAC technology in the treatment of: sense of stress and confusion. Psychometric evaluation in a randomized, single blind, sham controlled naturalistic study. AB - PURPOSE: The aim of this study is to investigate the effects of neuropsychophysical optimization (NPPO) protocol treatment by radioelectric asymmetric conveyer (REAC) technology in the management of sense of stress and confusion (SSC); an analysis of a single cluster of the psychological stress measure (PSM) test. PATIENTS AND METHODS: The PSM, a self-administered questionnaire, was used to measure psychological stress and SSC for a group of 888 subjects. Data were collected immediately prior to and following the 4-week REAC-NPPO treatment cycle. RESULTS: This study demonstrates a significant reduction in scores measuring subjective perceptions of stress for subjects treated with one cycle of REAC-NPPO. At the end-point of the study, the number of treated subjects reporting symptoms of stress-related SSC on the PSM test was significantly reduced, whereas there was no difference in sham-treated subjects. CONCLUSION: One cycle of REAC-NPPO appears to reduce subjective perceptions of SSC measured by the PSM. TRIAL REGISTRATION: This trial has been registered in the Australian New Zealand Clinical Trials Registry as ACTRN12607000497404. PMID- 22536056 TI - A survey of patient preferences for a placebo orodispersible tablet. AB - AIM: To assess the attitudes and preferences of patients currently being treated for depression or anxiety disorders with traditional oral antidepressants relative to a placebo orodispersible (ODT) formulation of escitalopram. METHODS: This was an open study collecting patient-reported outcome data from patients with anxiety or depression that were treated with oral antidepressant medication on Day 0 before and after receiving a single placebo ODT, and on Day 3 or 4 after receiving two further daily doses of placebo ODT. Patients aged 18-80 years who were currently receiving treatment with oral antidepressants were recruited from general practice and by advertising. Patients with significant symptoms of anxiety or depression (scoring >=9 on either the depression or anxiety subscales of the Hospital Anxiety and Depression Scale) were included in the study. RESULTS: A total of 150 patients were enrolled in and completed the study. About 37% of the patients had had trouble with swallowing tablets, and patients with higher depression scores reported more general swallowing problems than those with lower scores (P = 0.002). Most patients (75.3%) believed that an ODT might work faster but that it would make no difference to the effectiveness of the medication (63.1%) or the number of side effects (81.3%). About 96% of the patients reported experiencing a pleasant taste following the placebo ODT, although seven patients did not like its taste or aftertaste. This study found that 80.7% of patients reported that the tablets were easy or very easy to get out of the packaging. CONCLUSION: Based on the results of the placebo version of escitalopram ODT, the escitalopram ODT is likely to be well accepted by patients suffering from anxiety or depressive symptoms. PMID- 22536057 TI - Secondary analysis of electronically monitored medication adherence data for a cohort of hypertensive African-Americans. AB - BACKGROUND: Electronic monitoring devices (EMDs) are regarded as the "gold standard" for assessing medication adherence in research. Although EMD data provide rich longitudinal information, they are typically not used to their maximum potential. Instead, EMD data are usually combined into summary measures, which lack sufficient detail for describing complex medication-taking patterns. This paper uses recently developed methods for analyzing EMD data that capitalize more fully on their richness. METHODS: Recently developed adaptive statistical modeling methods were used to analyze EMD data collected with medication event monitoring system (MEMSTM) caps in a clinical trial testing the effects of motivational interviewing on adherence to antihypertensive medications in a cohort of hypertensive African-Americans followed for 12 months in primary care practices. This was a secondary analysis of EMD data for 141 of the 190 patients from this study for whom MEMS data were available. RESULTS: Nonlinear adherence patterns for 141 patients were generated, clustered into seven adherence types, categorized into acceptable (for example, high or improving) versus unacceptable (for example, low or deteriorating) adherence, and related to adherence self efficacy and blood pressure. Mean adherence self-efficacy was higher across all time points for patients with acceptable adherence in the intervention group than for other patients. By 12 months, there was a greater drop in mean post-baseline blood pressure for patients in the intervention group, with higher baseline blood pressure values than those in the usual care group. CONCLUSION: Adaptive statistical modeling methods can provide novel insights into patients' medication taking behavior, which can inform development of innovative approaches for tailored interventions to improve medication adherence. PMID- 22536058 TI - Effect of adherence to self-monitoring of diet and physical activity on weight loss in a technology-supported behavioral intervention. AB - BACKGROUND: Examination of mediating behavioral factors could explain how an intervention works and thus provide guidance to optimize behavioral weight-loss programs. This study examined the mediating role of adherence to self-monitoring of diet and physical activity on weight loss in a behavioral weight-loss trial testing the use of personal digital assistants (PDA) for self-monitoring. METHODS: Mediation analysis was conducted to examine the possible mediating role of adherence to self-monitoring of diet and physical activity between treatments using varying self-monitoring methods (paper record, PDA, and PDA with daily tailored feedback messages) and weight loss. FINDINGS: The sample (N = 210) was predominantly white (78%) and female (85%). Compared to a paper record, using a PDA for self-monitoring diet (P = 0.027) and physical activity (P = 0.014) had significant direct effects on weight loss at 12 months, as well as a significant indirect effect on outcomes through improved adherence to self-monitoring (P(S) < 0.001). Receiving an automated daily feedback message via PDA only had a significant indirect effect on weight through self-monitoring adherence to diet (P = 0.004) and physical activity (P = 0.002). CONCLUSIONS: Adherence to self monitoring of diet and physical activity is important as the underlying mechanism in this technology-supported behavioral weight-loss intervention. PMID- 22536059 TI - Assessment of the impact of adherence and other predictors during HAART on various CD4 cell responses in resource-limited settings. AB - OBJECTIVE: The aim of this study was to quantify, by modeling, the impact of significant predictors on CD4 cell response during antiretroviral therapy in a resource-limited setting. METHODS: Modeling was used to determine which antiretroviral therapy response predictors (baseline CD4 cell count, clinical state, age, and adherence) significantly influence immunological response in terms of CD4 cell gain compared to a reference value at different periods of monitoring. RESULTS: At 6 months, CD4 cell response was significantly influenced by baseline CD4 count alone. The probability of no increase in CD4 cells was 2.6 higher in patients with a baseline CD4 cell count of >=200/mm(3). At 12 months, CD4 cell response was significantly influenced by both baseline CD4 cell count and adherence. The probability of no increase in CD4 cells was three times higher in patients with a baseline CD4 cell count of >=200/mm(3) and 0.15 times lower with adherent patients. At 18 months, CD4 cell response was also significantly influenced by both baseline CD4 cell count and adherence. The probability of no increase in CD4 cells was 5.1 times higher in patients with a baseline CD4 cell count of >=200/mm(3) and 0.28 times lower with adherent patients. At 24 months, optimal CD4 cell response was significantly influenced by adherence alone. Adherence increased the probability (by 5.8) of an optimal increase in CD4 cells. Age and baseline clinical state had no significant influence on immunological response. CONCLUSION: The relationship between adherence and CD4 cell response was the most significant compared to that of baseline CD4 cell count. Counseling before initiation of treatment and educational therapy during follow-up must always help to strengthen adherence and optimize the efficiency of antiretroviral therapy in a resource-limited setting. PMID- 22536061 TI - Experiences and perspectives on the GIST patient journey. AB - PURPOSE: The tyrosine kinase inhibitor (TKI) imatinib has improved outcomes for patients with unresectable or metastatic gastrointestinal stromal tumors (GIST), and for patients receiving adjuvant therapy following GIST resection. This qualitative study explored the experiences and emotions of patients through GIST diagnosis, treatment initiation, disease control, and in some patients, loss of response and therapy switch. PATIENTS AND METHODS: Ethnographic investigations were conducted, including semi- structured qualitative interviews of patients with resected or metastatic/unresectable GIST and their caregivers, from Canada (n = 15); the United States (n = 10); and Brazil, France, Germany, Russia, and Spain (n = 5 each). Some interviewees also kept 7-day photo journals. Responses were qualitatively analyzed to identify gaps and unmet needs where communication about disease, treatments, and adherence could be effective. RESULTS: Patients shared common experiences during each stage of disease management (crisis, hope, adaptation, new normal, and uncertainty). Patients felt a sense of crisis during diagnosis, followed by hope upon TKI therapy initiation. Over time, they came to adapt to their new lives (new normal) with cancer. With each follow-up, patients confronted the uncertainty of becoming TKI resistant and the possible need to switch therapy. During uncertainty many patients sought new information regarding GIST. Cases of disease progression and drug switching caused patients to revert to crisis and restart their emotional journey. Patients with primary or unresectable/metastatic GIST shared similar journeys, especially regarding uncertainty, although differences in the scope and timing of phases were observed. Strategies patients used to remain adherent included obtaining family support, setting reminder mechanisms, taking medicine at routine times, and storing medicine in prominent places. CONCLUSIONS: Physicians and support staff can manage patient expectations and encourage adherence to therapy, which may facilitate optimal patient outcomes. Patient education about current GIST developments and adherence across all phases of the patient journey are of benefit. PMID- 22536060 TI - Update on treatment of follicular non-Hodgkin's lymphoma: focus on potential of bortezomib. AB - Follicular lymphoma is predominantly managed as a chronic disease, with intermittent chemo/immunotherapy reserved for symptomatic progression. It is considered incurable with conventional treatments, and current therapeutic options are associated with significant toxicities that are especially limiting in older patients. Bortezomib (PS-341; Velcade((r))), a first-in-class drug targeting the proteolytic core subunit of the 26S proteasome, has emerged as a therapeutic alternative in follicular lymphoma, with promising preclinical data and efficacy in patients with other hematological malignancies. Several clinical trials were conducted with bortezomib for the treatment of non-Hodgkin's lymphoma. As a single agent, overall responses in follicular lymphoma varied greatly (16%-41%), with weekly bortezomib showing less neurotoxicity than twice weekly regimens, but with concern about decreased responses. Combination with rituximab was projected to improve the efficacy of bortezomib, but this resulted in increased toxicities and questionable added benefit. Although the largest Phase III study in follicular lymphoma of bortezomib plus rituximab versus rituximab alone demonstrated a significant progression-free survival difference, the absolute difference was small (12.8 months versus 11 months). Combining bortezomib with established regimens, such as rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP), or rituximab-bendamustine also did not show definite benefit, and many of these studies did not meet their primary endpoint when bortezomib failed to improve responses or survival to the degree anticipated. In a disease where the goal of treatment is palliative and affected patients often have other medical and treatment-related comorbidities, decisions regarding therapies which carry risks of additional toxicities must be considered carefully. Conclusive evidence of the ability of bortezomib to improve patient outcomes meaningfully and to justify the added toxicity is lacking, but limitations in cross-trial comparisons are recognized. Large randomized trials and investigations of combinations with promising novel targeted agents will aid in determining the role of bortezomib, if any, in the future treatment of follicular lymphoma. PMID- 22536062 TI - Patient perceptions of multiple sclerosis and its treatment. AB - BACKGROUND: In order to improve the treatment outcome in multiple sclerosis, it is important to document the factors that influence adherence to therapy. The purpose of this study was to determine patient perceptions and awareness of multiple sclerosis and its treatment, treatment adherence, and impact on quality of life and daily living. METHODS: This was a cross-sectional observational study performed in France. Each participating neurologist included the first three patients with relapsing-remitting multiple sclerosis who consulted after the start of the study. Data on clinical features were collected from a physician questionnaire and on disease and treatment perception and on quality of life from a patient autoquestionnaire. RESULTS: A total of 175 neurologists entered 202 patients in the study. The mean duration of disease was 8.0 +/- 7.0 years, and immunomodulatory treatment had been administered for a mean duration of 3.0 +/- 2.0 years. A total of 166 patients (82.2%) were treated with interferon-beta preparations and 36 patients (17.8%) with glatiramer acetate. Eighty-five patients (42.1%) reported missing their injections from time to time and 36 patients (17.8%) reported "drug holidays". The most frequently given reason for nonadherence was forgetfulness (38.7% of cases). Eighty-six patients (42.6%) and 70 patients (34.7%) claimed to be well informed about their disease and treatment, respectively. Adherence was significantly higher in well informed patients (P = 0.035). The majority of patients (176 patients, 87.1%) intended continuing their current treatment and 49.5% considered that their current treatment might reduce relapses. The most frequently reported side effect was muscle pain (124 patients, 61.4%). CONCLUSION: Patient understanding of treatment for disease enhances treatment adherence. Greater patient involvement in disease management requires better communication between physicians and their patients. PMID- 22536063 TI - Patterns and predictors of treatment initiation and completion in patients with chronic hepatitis C virus infection. AB - OBJECTIVES: Guidelines for hepatitis C (HCV) strongly recommend antiviral treatment for patients with more severe liver disease given their increased risk of developing cirrhosis and other liver-related complications. Despite the proven benefits of therapy, 70%-88% of patients chronically infected with HCV do not undergo treatment. The goal of this paper is to describe patterns of treatment initiation among patients with both mild and severe disease and to assess the factors that are associated with treatment initiation and completion. METHODS: Subjects completed previously validated questionnaires to ascertain sociodemographic characteristics, choice predisposition, and clinical characteristics prior to meeting with the hepatologist to discuss treatment initiation and were followed for 12 months. We examined the association between patient characteristics and treatment patterns controlling for liver disease severity. RESULTS: Of the 148 eligible subjects entered into our study, 55 (37%) initiated treatment during the 12-month follow-up period. Of the 86 subjects with severe liver disease, 43 (50%) initiated treatment. Financial barriers and geographic access to care were the most common reasons for treatment deferral. Of the 55 patients initiating treatment, 24 (44%) discontinued treatment, with intolerance of side effects being the most common reason for discontinuation. After adjusting for liver disease severity, patient choice predisposition (prior to discussion with their provider) was strongly associated with initiation of treatment, while sociodemographic characteristics were not. CONCLUSION: Treatment initiation did align with current recommendations (patients with severe disease were more likely to initiate treatment), however, rates of treatment initiation and completion were low. Patient choice predisposition is the strongest predictor of treatment initiation, independent of disease severity. Improving individualized treatment outcomes for patients with chronic HCV requires efforts at identifying patients' choice predisposition, and improving access for those wishing to initiate therapy. PMID- 22536064 TI - The impact of HIV clinical pharmacists on HIV treatment outcomes: a systematic review. AB - OBJECTIVE: Due to the rapid proliferation of human immunodeficiency virus (HIV) treatment options, there is a need for health care providers with knowledge of antiretroviral therapy intricacies. In a HIV multidisciplinary care team, the HIV pharmacist is well-equipped to provide this expertise. We conducted a systematic review to assess the impact of HIV pharmacists on HIV clinical outcomes. METHODS: We searched six electronic databases from January 1, 1980 to June 1, 2011 and included all quantitative studies that examined pharmacist's roles in the clinical care of HIV-positive adults. Primary outcomes were antiretroviral adherence, viral load, and CD(4) (+) cell count and secondary outcomes included health care utilization parameters, antiretroviral modifications, and other descriptive variables. RESULTS: Thirty-two publications were included. Despite methodological limitation, the involvement of HIV pharmacists was associated with statistically significant adherence improvements and positive impact on viral suppression in the majority of studies. CONCLUSION: This systematic review provides evidence of the beneficial impact of HIV pharmacists on HIV treatment outcomes and offers suggestions for future research. PMID- 22536065 TI - Hearing voices: does it give your patient a headache? A case of auditory hallucinations as acoustic aura in migraine. AB - OBJECTIVE: Auditory hallucinations are generally considered to be a psychotic symptom. However, they do occur without other psychotic symptoms in a substantive number of cases in the general population and can cause a lot of individual distress because of the supposed association with schizophrenia. We describe a case of nonpsychotic auditory hallucinations occurring in the context of migraine. METHOD: Case report and literature review. RESULTS: A 40-year-old man presented with imperative auditory hallucinations that caused depressive and anxiety symptoms. He reported migraine with visual aura as well which started at the same time as the auditory hallucinations. The auditory hallucinations occurred in the context of nocturnal migraine attacks, preceding them as aura. No psychotic disorder was present. After treatment of the migraine with propranolol 40 mg twice daily, explanation of the etiology of the hallucinations, and mirtazapine 45 mg daily, the migraine subsided and no further hallucinations occurred. The patient recovered. DISCUSSION: Visual auras have been described in migraine and occur quite often. Auditory hallucinations as aura in migraine have been described in children without psychosis, but this is the first case describing auditory hallucinations without psychosis as aura in migraine in an adult. For description of this kind of hallucination, DSM-IV lacks an appropriate category. CONCLUSION: Psychiatrists should consider migraine with acoustic aura as a possible etiological factor in patients without further psychotic symptoms presenting with auditory hallucinations, and they should ask for headache symptoms when they take the history. Prognosis may be favorable if the migraine is properly treated. Research is needed to explore the pathophysiological mechanism of auditory hallucinations as aura in migraine. PMID- 22536066 TI - Comparison of patients undergoing switching versus augmentation of antipsychotic medications during treatment for schizophrenia. AB - It is often difficult to determine whether a patient may best benefit by augmenting their current medication or switching them to another. This post-hoc analysis compares patients' clinical and functional profiles at the time their antipsychotic medications were either switched or augmented. Adult outpatients receiving oral antipsychotic treatment for schizophrenia were assessed during a 12-month international observational study. Clinical and functional measures were assessed at the time of first treatment switch/augmentation (0-14 days prior) and compared between Switched and Augmented patient groups. Due to low numbers of patients providing such data, interpretations are based on effect sizes. Data at the time of change were available for 87 patients: 53 Switched and 34 Augmented. Inadequate response was the primary reason for treatment change in both groups, whereas lack of adherence was more prevalent in the Switched group (26.4% vs 8.8%). Changes in clinical severity from study initiation to medication change were similar, as indicated by Clinical Global Impressions-Severity scores. However, physical and mental component scores of the 12-item Short-Form Health Survey improved in the Augmented group, but worsened in the Switched group. These findings suggest that the patient's worsening or lack of meaningful improvement prompts clinicians to switch antipsychotic medications, whereas when patients show some improvement, clinicians may be more likely to try bolstering the improvements through augmentation. Current findings are consistent with physicians' stated reasons for switching versus augmenting antipsychotics in the treatment of schizophrenia. Confirmation of these findings requires further research. PMID- 22536067 TI - Six-month treatment with atypical antipsychotic drugs decreased frontal-lobe levels of glutamate plus glutamine in early-stage first-episode schizophrenia. AB - OBJECTIVE: To study the effects of treatment with atypical antipsychotic drugs on brain levels of glutamate plus glutamine in early-stage first-episode schizophrenia. PARTICIPANTS: Sixteen patients (eight males, eight females; aged 30 +/- 11 years) completed the study. METHODS: We used administered 6 months of atypical antipsychotic drugs and used proton magnetic resonance spectroscopy to evaluate the results. RESULTS: We found that the administration of atypical antipsychotic drugs for 6 months decreased the glutamate plus glutamine/creatine ratio in the frontal lobe. These results suggest that the administration of atypical antipsychotic drugs for at least 6 months decreased glutamatergic neurotransmissions in the frontal lobe in early-stage first-episode schizophrenia, but there was no difference in frontal-lobe levels between patients and control subjects before administration. CONCLUSION: Taking these findings into account, the glutamatergic and GABAergic neurons are implicated in early-stage first-episode schizophrenia, but in complex ways. PMID- 22536068 TI - Clinical utility of vilazodone for the treatment of adults with major depressive disorder and theoretical implications for future clinical use. AB - BACKGROUND: Vilazodone is the latest approved antidepressant available in the United States. Its dual mechanism of action combines the inhibition of serotonin transporters while simultaneously partially agonizing serotonin-1a (5-HT1A) receptors. This combined activity results in serotonin facilitation across the brain's serotonergic pathways, which has been termed by the authors as that of a serotonin partial agonist and reuptake inhibitor, or SPARI. OBJECTIVE: The authors to review laboratory, animal model data, and human trial data to synthesize a working theory regarding the mechanism of antidepressant action of this agent and regarding its potential for additional indications. METHODS: A MEDLINE and Internet search was conducted and the resultant evidence reviewed. RESULTS: Vilazodone has randomized, controlled empirical data which has garnered it an approval for treating major depressive disorder. It combines two well-known pharmacodynamic mechanisms of serotonergic action into a novel agent. Although no head-to-head studies against other antidepressants are published, the efficacy data for vilazodone appears comparable to other known antidepressants, with associated gastrointestinal side effects similar to serotonin selective reuptake inhibitor and serotonin norepinephrine reuptake inhibitor antidepressants, but potentially with a lower incidence of sexual side effects and weight gain. DISCUSSION: As a new option for the treatment of major depressive disorder, vilazodone, due to its unique SPARI mechanism of action, may hold promise for patients who cannot tolerate or have not responded to previous antidepressant monotherapies. Additionally, its use may extend to the treatment of other mental health conditions similar to those treated by serotonin selective reuptake inhibitors. PMID- 22536069 TI - Higher FKBP5, COMT, CHRNA5, and CRHR1 allele burdens are associated with PTSD and interact with trauma exposure: implications for neuropsychiatric research and treatment. AB - OBJECTIVE: The study aim was to assess the cumulative burden of polymorphisms located within four genetic loci previously associated with posttraumatic stress disorder (PTSD) among outpatients at risk for PTSD. METHODS: Diagnostic interviews were completed and DNA samples collected among 412 pain patients to determine if FKBP5 (rs9470080), COMT (rs4680), CHRNA5 (rs16969968), and CRHR1 (rs110402) single nucleotide polymorphisms were cumulatively associated with increased risk for PTSD. RESULTS: In bivariate analyses, it was found that a count of specific PTSD risk alleles located within FKBP5, COMT, CHRNA5, and CRHR1 genetic loci (allele range = 0-6, mean count = 2.92, standard deviation = 1.36) was associated with lifetime (t [409] = 3.430, P = 0.001) and early onset PTSD (t [409] = 4.239, P = 0.000028). In logistic regression, controlling for demographic factors, personality traits, and trauma exposures, this risk allele count remained associated with both lifetime (odds ratio = 1.49, P = 0.00158) and early onset PTSD (odds ratio = 2.36, P = 0.000093). Interaction effects were also detected, whereby individuals with higher risk allele counts and higher trauma exposures had an increased risk of lifetime PTSD (allele count * high trauma, P = 0.026) and early onset PTSD (allele count * high trauma, P = 0.016) in these logistic regressions. Those with no or few risk alleles appeared resilient to PTSD, regardless of exposure history. CONCLUSION: A cumulative risk allele count involving four single nucleotide polymorphisms located within the FKBP5, COMT, CHRNA5, and CRHR1 genes are associated with PTSD. Level of trauma exposure interacts with risk allele count, such that PTSD is increased in those with higher risk allele counts and higher trauma exposures. Since the single nucleotide polymorphisms studied encompass stress circuitry and addiction biology, these findings may have implications for neuropsychiatric research and treatment. PMID- 22536070 TI - Effectiveness and tolerability of transdermal rivastigmine in the treatment of Alzheimer's disease in daily practice. AB - BACKGROUND: Oral cholinesterase inhibitors at doses efficacious for the treatment of Alzheimer's disease (AD) are often prematurely discontinued due to gastrointestinal side effects. In controlled clinical trials, transdermal rivastigmine demonstrated less such effects at similar efficacy. The current study aimed to verify the validity of this data in daily practice. METHODS: This was a prospective, multicenter, observational study on transdermal rivastigmine in Germany. Eligible patients were those with AD who had not yet been treated with rivastigmine. Outcome measures were changes in clock-drawing test, Mini Mental State Examination (MMSE), Caregiver Burden Scale, Clinical Global Impression (CGI), physicians' assessments of tolerability, and the incidence of adverse events (AEs) over 4 months of treatment. RESULTS: In 257 centers 1113 patients were enrolled; 614 women and 499 men, mean age 76.5 years. In 58% of patients AD was treated for the first time and in 42% therapy was switched to transdermal rivastigmine, mostly due to lack of tolerability (13.6%) or effectiveness (26.9%). After 4 months, 67.4% of patients were on the target dose of 9.5 mg/day and 21.8% were still on 4.6 mg/day. MMSE significantly improved in patients with and without pretreatment (DeltaMMSE, 0.9 +/- 3.4 and 0.8 +/- 3.4, respectively, both P < 0.001); the CGI score improved in 60.9% and 61.3% of patients, respectively. Overall 11.7% of patients had AEs, mainly affecting the skin or the gastrointestinal tract; in 1.1% of cases AEs were serious; 14.7% of patients discontinued therapy, 6.0% due to AEs. With rivastigmine treatment the percentage of patients taking psychotropic comedication decreased, particularly in first-time treated rivastigmine patients (from 27.1% to 22.6%; P < 0.001). CONCLUSION: Results were in line with data from controlled clinical trials. Switching from any other oral acetylcholinesterase inhibitor to transdermal rivastigmine may improve cognition. PMID- 22536071 TI - Preliminary pilot fMRI study of neuropostural optimization with a noninvasive asymmetric radioelectric brain stimulation protocol in functional dysmetria. AB - PURPOSE: This study assessed changes in functional dysmetria (FD) and in brain activation observable by functional magnetic resonance imaging (fMRI) during a leg flexion-extension motor task following brain stimulation with a single radioelectric asymmetric conveyer (REAC) pulse, according to the precisely defined neuropostural optimization (NPO) protocol. POPULATION AND METHODS: Ten healthy volunteers were assessed using fMRI conducted during a simple motor task before and immediately after delivery of a single REAC-NPO pulse. The motor task consisted of a flexion-extension movement of the legs with the knees bent. FD signs and brain activation patterns were compared before and after REAC-NPO. RESULTS: A single 250-millisecond REAC-NPO treatment alleviated FD, as evidenced by patellar asymmetry during a sit-up motion, and modulated activity patterns in the brain, particularly in the cerebellum, during the performance of the motor task. CONCLUSION: Activity in brain areas involved in motor control and coordination, including the cerebellum, is altered by administration of a REAC NPO treatment and this effect is accompanied by an alleviation of FD. PMID- 22536072 TI - Barriers to cardiovascular risk prevention and management in Germany--an analysis of the EURIKA study. AB - BACKGROUND AND PURPOSE: Despite the availability of risk engines to determine cardiovascular risk, risk factor control is suboptimal. Using EURIKA data we compared risk factor control in Germany with that of 11 other European countries (rest of Europe [ROE]) to identify differences and opportunities for improvement. METHODS: EURIKA was a multinational, cross-sectional study in 12 European countries including Germany from May 2009 to January 2010. Physicians' attitudes to risk factor control based on the 2007 European guidelines on cardiovascular disease (CVD) prevention in a representative cohort of 7641 primary care outpatients aged >= 50 years with no CV disease and at least one major CV risk factor were determined. RESULTS: Compared to the ROE, German physicians were more frequently male (72.7% vs 62.6%), had a higher mean age (51.7 +/- 8.4 vs 47.0 +/- 9.7 years), faced higher patient loads (37.9% vs 16.5% had >199 patients/week), and involved other health sector professionals (dieticians, psychologists) less (31.8% vs 41.0% in the ROE). The European Society of Cardiology (ESC) guidelines on CVD prevention were more important for German physicians (60.6% vs 55.9%), while those who didn't use them gave reasons for nonuse as too many (62.5% vs 46.2%), too confusing, unrealistic, or not applicable to their patients. Risk engines were used less (54.5% vs 70.7%), with perceived lack of time (65.5% vs 60.2%) a frequent reason for nonuse. Risk factor control in German patients was inadequate (control rates: hypertension 36.3%, dyslipidemia 30.4%, type 2 diabetes 40.6%, obesity 28.8%) but largely comparable to other ROE countries; however, physicians tended to overestimate control rates. CONCLUSION: EURIKA provides comprehensive data on the status of primary prevention of CVD in clinical practice in Germany and reveals considerable potential for improving the primary prevention of CVD. PMID- 22536073 TI - Effects of protein and omega-3 supplementation, provided during regular dialysis sessions, on nutritional and inflammatory indices in hemodialysis patients. AB - PURPOSE: Malnutrition and chronic inflammation in dialysis patients negatively impacts prognosis. However, intervening to correct this problem (through nutritional supplementation) is often hampered by poor compliance due to both medical and socioeconomic barriers. We have therefore performed a pilot study to investigate the technical feasibility of "directly observed treatment" of nutritional supplementation (protein and omega-3 fatty acids), administered during regular dialysis sessions. Secondary end points included observation of nutritional and inflammatory status of hypoalbuminemic patients undergoing hemodialysis. METHODS: Main inclusion criteria were serum albumin <= 3.9 g/dL (3 months prior to the study). Sixty-three eligible patients agreed to participate. Two intervention groups received 30 mL of a liquid protein supplement plus either 2.4 g omega-3 (1800 mg eicosapentaenoic acid + 600 mg docosahexaenoic acid) or a placebo, three times per week after their routine dialysis session for 6 months. Serum albumin, plasma lipids, and other indicators of nutritional and inflammatory status were measured. RESULTS: Directly observed nutritional supplementation resulted in a significant improvement in the low density lipoprotein cholesterol/high density lipoprotein cholesterol ratio in the omega-3 group as compared to the placebo group (P = 0.043). For the omega-3 group, serum albumin was also marginally higher after 6 months as compared to baseline (P = 0.07). The observed increase in C-reactive protein in the placebo group over 6 months was not apparent in the omega-3 group, although there was no significant difference between groups. Nuclear factor kappa B, malnutrition-inflammation score, normalized protein nitrogen appearance, body mass index, and hemoglobin were unaffected by the intervention. CONCLUSION: "Directly observed treatment" with an omega-3 based supplement (as opposed to a pure protein supplement) showed beneficial effects on the lipid profile, and C-reactive protein levels. Further studies using a combination of outpatient and inpatient "directly observed treatment" of omega-3 based supplementation is warranted. PMID- 22536074 TI - Hemocompatibility of stent materials: alterations in electrical parameters of erythrocyte membranes. AB - BACKGROUND: It is presently unknown if stents used in the correction of artery stenosis are fully hemocompatible or if their implantation causes alterations at the level of the plasma membrane in red blood cells. METHODS: We addressed this important issue by measuring the passive electrical properties of the erythrocyte membrane before and after stent insertion by means of dielectric relaxation spectroscopy in the radiowave frequency range in a series of patients who were undergoing standard surgical treatment of arterial disease. RESULTS: Our findings provide evidence that full hemocompatibility of stents has not yet been reached, and that there are some measurable alterations in the passive electrical behavior of the red blood cell membrane induced by the presence of the stent. CONCLUSION: It is possible that these changes do not have any physiological significance and simply reflect the intrinsic variability of biological samples. However, caution is urged, and the technique we describe here should be considered when investigating the hemocompatibility of a medical device at a cell membrane level. PMID- 22536075 TI - Outcomes of patients treated with the everolimus-eluting stent versus the zotarolimus eluting stent in a consecutive cohort of patients at a tertiary medical center. AB - BACKGROUND: In this study we compared the outcomes of the everolimus-eluting stent (EES) versus the zotarolimus-eluting stent (ZES) in patients treated at a tertiary medical center, with up to one year of follow-up. METHODS: Unselected consecutive patients were retrospectively recruited following stenting with the ZES (n = 197) or EES (n = 190). The first 100 consecutive patients in each cohort underwent syntax scoring. The primary endpoint of the study was target vessel failure, defined as the combined endpoint of cardiac death, non-fatal myocardial infarction, or target vessel revascularization. Secondary endpoints included target lesion revascularization, target lesion failure, acute stent thrombosis, total death, cardiac death, and non-fatal myocardial infarction. RESULTS: The two groups were similar, including for Syntax scores (19.6 +/- 12.8 versus 20.6 +/- 13.6), number of stents per patient (2.9 +/- 1.9 versus 2.9 +/- 2.1), and cardiovascular risk factors. By one year, the primary outcome occurred in 20.8% EES versus 26.7% ZES (P = 0.19) patients. The secondary endpoints were as follows: target lesion revascularization (8.9% versus 20.6%, P = 0.003), target vessel revascularization (18.9% versus 25.6%, P = 0.142), definite and probable stent thrombosis (0% versus 2.5%), non-fatal myocardial infarction (2.7% versus 3.6%), and mortality (3.2% versus 5.1%) for the EES versus the ZES, respectively. CONCLUSION: EES had similar target vessel failure to ZES, but superior target lesion revascularization and target lesion failure at one year of follow-up in an unselected cohort of patients. PMID- 22536076 TI - Correlation of natriuretic peptides and inferior vena cava size in patients with congestive heart failure. AB - BACKGROUND: The inferior vena cava (IVC) diameter and degree of inspiratory collapse are used as echocardiographic indices in the estimation of right atrial pressure. Brain-natriuretic peptides (BNPs) are established biomarkers of myocardial wall stress. There is no information available regarding the association between the IVC diameter and BNPs in patients with heart failure and various degrees of systolic performance. The purpose of this investigation is to quantify the degree to which natriuretic peptides (BNP and N-terminal pro-B natriuretic peptide [NT-ProBNP]) and echocardiographic-derived indices of right atrial pressure correlate in this patient population. METHODS: We examined 77 patients (mean age 61 +/- 17 years, 44% male) with decompensated heart failure who underwent transthoracic echocardiography and, within a timeframe of 24 hours, determination of BNP and NT-ProBNP levels in venous blood. BNP and NT-ProBNP were analyzed after log transformation. The degree of association was measured by the correlation coefficient using the Pearson's method. RESULTS: The mean ejection fraction was 50% +/- 20%, and 33% of the study cohort had a remote history of heart failure. The mean IVC diameter was 1.85 cm +/- 0.5, the mean BNP was 274 pg/mL, the confidence interval (CI) was 95% (95% CI: 197-382), and the mean NT ProBNP was 1994 pg/mL (95% CI: 1331-2989). There was a positive, albeit small, association between IVC diameter and BNP (r = 0.24, 95% CI: 0.01-0.44; P = 0.03) and NT-ProBNP (r = 0.27, 95% CI: 0.05-0.47; P = 0.01). Among patients with different degrees of IVC collapse in response to inspiration, values for BNP and NT-ProBNP did not differ substantially (P = 0.36 and 0.46 for BNP and NT-ProBNP, respectively). CONCLUSION: Natriuretic peptides correlate weakly with IVC size and do not predict changes in response to intrathoracic pressure. PMID- 22536078 TI - Evaluation of deficiencies in current discharge summaries for dialysis patients in Canada. AB - BACKGROUND: Deficits in the transfer of information between inpatient and outpatient physicians are common and pose a patient safety risk. This is particularly the case for vulnerable populations such as patients with end-stage renal disease requiring dialysis. These patients have unique and complex health care needs that may not be effectively communicated on standard discharge summaries, which may result in potential medical errors and adverse events. OBJECTIVE: To evaluate Canadian dialysis center directors' perceptions of deficiencies in the content and quality of hospital discharge summaries for dialysis patients. METHODS: A web-based, cross-sectional survey of Canadian dialysis center directors was performed between September and November 2010. The survey consisted of three parts. The first part was designed to assess dialysis center directors' attitudes on the quality of discharge summaries they receive. The second part was designed to elicit respondents' preferences for discharge summary content, and the third part consisted of questions regarding demographic and practice information. RESULTS: Of 79 dialysis center directors, 21 (27%) completed the survey. Sixty-two percent felt that current discharge summaries inadequately communicate dialysis-specific information. Receipt of antibiotics for line sepsis or peritonitis, modifications to vascular access, and changes in target weight/dialysis prescription were rated as essential dialysis-specific information to include in discharge summaries by respondents. CONCLUSION: Over three quarters of dialysis center directors find the current practice of transferring discharge information for hospitalized dialysis patients grossly inadequate. The inclusion of dialysis-specific information may improve the quality of discharge summaries for dialysis patients. PMID- 22536077 TI - Erythrocyte sedimentation rate as a marker for coronary heart disease. AB - BACKGROUND: Patients with angina pectoris or myocardial infarction frequently present without evidence of cardiac-specific heart enzymes by laboratory analysis or specific pathologic electro-cardiogram findings. The current study analyzed the efficacy of the erythrocyte sedimentation rate as an additional potential indicator for coronary heart disease, the aim being to enable quicker identification of patients with angina pectoris or myocardial infarction so that they can be more rapidly treated. METHODS: Patients with angina pectoris or myocardial infarction who had undergone a heart catheter examination were included in the study. The diagnosis of acute coronary heart disease was made by the physician who performed coronary angiography. Patients without coronary heart disease were used as a control group. The erythrocyte sedimentation rate was measured in all patients. Patients with angina pectoris or myocardial infarction and an inflammatory or tumor disease were excluded. RESULTS: The erythrocyte sedimentation rate was prolonged in 79 (58.09%) of 136 patients; 69 (50.74%) patients (95% confidence interval +/-8.4%, 42.34%-59.14%) had coronary heart disease and a prolonged erythrocyte sedimentation rate. The erythrocyte sedimentation rate was prolonged in ten (7.35%) patients (95% confidence interval +/-4.39%, 2.96%-11.74%) without coronary heart disease by coronary angiography. The specificity of the erythrocyte sedimentation rate for coronary heart disease was 70.59% and the sensitivity was 67.65%. CONCLUSION: Erythrocyte sedimentation rate may be a useful additional diagnostic criterion for coronary heart disease. PMID- 22536079 TI - Ability for self-care in urban living older people in southern Norway. AB - BACKGROUND: The number of older people living in urban environments throughout the world will increase in the coming years. There is a trend in most European countries towards improved health among older people, and increased life expectancy for both women and men. Norway has experienced less increase in life expectancy than some other European countries, and it is therefore important to investigate older urban Norwegian people's health and ways of living in a self care environment, with special regard to health promotion. AIM: The aim of this study was to describe self-care ability among home-dwelling older (65+ years) individuals living in urban areas in southern Norway in relation to general living conditions, sense of coherence (SOC), screened nutritional state, physical activity, perceived self-reported health, mental health, and perceived life situation. METHODS: In 2010, a randomized sample of 1044 men and women aged 65+ years who were living in urban areas in southern Norway answered a postal questionnaire consisting of five instruments, some background variables, and 17 health-related questions. Univariate and multivariate statistical methods were used in the analyses of the data. RESULTS: The mean age of the participants was 74.8 years (SD = 7.1). Eighty-three percent of the participants had higher abilities to care for themselves. Self-care agency, perceived good health, being active, being frequently active, good mental health, not being at risk of undernutrition, and satisfaction with life were all positively related to self care ability. Negative factors were perceived helplessness, receiving home nursing, being anxious, and being at a more advanced age. People aged 85+ years had worse mental health, were less physically active, and more at risk of undernutrition. CONCLUSION: Health professionals should focus on the health promoting factors that reinforce older people's ability to care for themselves, and be aware of important symptoms and signs associated with a reduction in a person's self-care ability. Politicians should assume responsibility for health care with a special regard to senior citizens. PMID- 22536080 TI - Validation of an HIV-related stigma scale among health care providers in a resource-poor Ethiopian setting. AB - BACKGROUND: Stigma and discrimination (SAD) against people living with human immunodeficiency virus (HIV) are barriers affecting effective responses to HIV. Understanding the causes and extent of SAD requires the use of a psychometrically reliable and valid scale. The objective of this study was to validate an HIV related stigma scale among health care providers in a resource-poor setting. METHODS: A cross-sectional validation study was conducted in 18 health care institutions in southwest Ethiopia, from March 14, 2011 to April 14, 2011. A total of 255 health care providers responded to questionnaires asking about sociodemographic characteristics, HIV knowledge, perceived institutional support (PIS) and HIV-related SAD. Exploratory factor analysis (EFA) with principal component extraction and varimax with Kaiser normalization rotation were employed to develop scales for SAD. Eigenvalues greater than 1 were used as a criterion of extraction. Items with item-factor loadings less than 0.4 and items loading onto more than one factor were dropped. The convergent validity of the scales was tested by assessing the association with HIV knowledge, PIS, training on topics related to SAD, educational status, HIV case load, presence of an antiretroviral therapy (ART) service in the health care facility, and perceived religiosity. RESULTS: Seven factors emerged from the four dimensions of SAD during the EFA. The factor loadings of the items ranged from 0.58 to 0.93. Cronbach's alphas of the scales ranged from 0.80 to 0.95. An in-depth knowledge of HIV, perceptions of institutional support, attendance of training on topics related to SAD, degree or higher education levels, high HIV case loads, the availability of ART in the health care facility and claiming oneself as nonreligious were all negatively associated with SAD as measured by the seven newly identified latent factors. CONCLUSION: The findings in this study demonstrate that the HIV-related stigma scale is valid and reliable when used in resource-poor settings. Considering the local situation, health care managers and researchers may use this scale to measure and characterize HIV-related SAD among health care providers. Tailoring for local regions may require further development of the tool. PMID- 22536081 TI - Long-term effects of aliskiren on blood pressure and the renin-angiotensin aldosterone system in hypertensive hemodialysis patients. AB - OBJECTIVE: The long-term effects of aliskiren in hypertensive hemodialysis patients remain to be elucidated. DESIGN: In this post hoc analysis, we followed up 25 hypertensive hemodialysis patients who completed 8-week aliskiren treatment in a previous study for 20 months to investigate the blood pressure-lowering effect and inhibitory effect on the renin-angiotensin-aldosterone system. RESULTS: Among the 25 patients, eleven patients continued with aliskiren treatment. Blood pressure (+/- standard deviation) decreased from 175 +/- 18/80 +/- 11 mmHg at baseline to 156 +/- 20/76 +/- 9 mmHg at month 20. Plasma renin activity, angiotensin I, and angiotensin II decreased from baseline to month 20 (plasma renin activity (ng/mL/h): 2.3 +/- 2.6 to 0.3 +/- 0.4 (P < 0.05), angiotensin I (pg/mL): 909.1 +/- 902.5 to 41.5 +/- 14.8 (P < 0.05), angiotensin II (pg/mL): 41.5 +/- 45.8 to 11.0 +/- 4.9 (P < 0.05)). CONCLUSION: Long-term treatment with aliskiren provides effective blood pressure lowering and inhibition of the renin-angiotensin-aldosterone system, which are sustained over 20 months in hypertensive hemodialysis patients. PMID- 22536082 TI - Methoxy polyethylene glycol-epoetin beta for anemia with chronic kidney disease. AB - Chronic kidney disease (CKD) is a risk factor for end-stage renal failure and cardiovascular events. In patients with CKD, anemia is often caused by decreased erythropoietin production relative to hemoglobin levels. As correction of anemia is associated with improved cardiac and renal function and quality of life, erythropoiesis-stimulating agents (ESAs) are standard therapy for anemia in CKD patients. However, traditional ESAs such as epoetin or darbepoetin have short half-lives and require frequent administration, dose changes, and close monitoring of hemoglobin concentration to maintain target hemoglobin levels. Methoxy polyethylene glycol-epoetin beta (MPG-EPO) is the only ESA that is generated by chemical modification of glycosylated erythropoietin through the integration of one specific, long, linear chain of polyethylene glycol. This ESA induces continuous erythropoietin receptor activation and has a long half-life (approximately 130 hours). Subcutaneous or intravenous administration of MPG-EPO once every 2 weeks or monthly achieved a high hemoglobin response rate in patients with anemia associated with CKD, regardless of whether the patient was undergoing dialysis. According to data from an observational time and motion study, MPG-EPO maintains hemoglobin levels when the same dose is administered, however infrequently. This suggests that compared with the use of traditional ESAs, administration of MPG-EPO reduces the overall time and cost associated with the management of anemia in CKD patients undergoing dialysis. MPG-EPO is generally well tolerated and most adverse events are of mild to moderate severity. The most commonly reported adverse effects are hypertension, nasopharyngitis, and diarrhea. Subcutaneous injection of MPG-EPO is significantly less painful than subcutaneous injection of darbepoetin. In conclusion, MPG-EPO is as effective and safe as traditional ESAs in managing renal anemia, irrespective of whether the patient is undergoing dialysis. PMID- 22536083 TI - The role of a parental history of Balkan endemic nephropathy in the occurrence of BEN: a prospective study. AB - Balkan endemic nephropathy (BEN) is a chronic kidney disease that affects persons living in the Balkans. Despite the unique geographical specificity of this disease, its etiology has remained unclear. Even if a positive family history of BEN has been identified, it is still uncertain how the disease develops in offspring. In this paper, we examine clinical mechanisms related to the onset of BEN in individuals who have a parental history of BEN to identify early detection of the disease and formulate interventions. We conducted a 5-year prospective study, using markers in years one and three to predict new cases of BEN in year five. New cases of BEN were defined based on three criteria: parental history of BEN, reduced kidney size, and reduced kidney function. Incident cases were divided into (1) probable, (2) definite, and (3) combined labeled total incidence. We evaluated parental history in relation to BEN and tested the potentially intervening effects of kidney length, kidney cortex width, beta(2) microglobulin, C-reactive protein, and creatinine clearance, using path analyses. The findings of the path analyses suggested that parental history of BEN had both direct and indirect effects. The direct effect was significant for all three modes of parental history (biparental, maternal, and paternal; odds ratios 71.5, 52.3, and 50.1, respectively). The indirect effects of maternal BEN acted via kidney length and creatinine clearance. Biparental BEN was mediated by (1) kidney length and creatinine clearance, and (2) creatinine clearance alone. Paternal BEN had three indirect effects: (1) through kidney length and creatinine clearance, (2) via kidney cortex width and creatinine clearance, and (3) via kidney cortex width only. In conclusion, a family history of BEN led to reduced kidney length and cortex width, and a decline in creatinine clearance, which in turn predicted the onset of BEN. PMID- 22536085 TI - A case of thrombotic thrombocytopenic purpura induced by acute pancreatitis. AB - Thrombotic thrombocytopenic purpura (TTP) is a multisystemic microvascular disorder that may be caused by an imbalance between unusually large von Willebrand factor multimers and the cleaving protease ADAMTS13. In acquired TTP, especially in secondary TTP with various underlying diseases, the diagnosis is difficult because there are many cases that do not exhibit severe deficiency of ADAMTS13 or raised levels of ADAMST13 inhibitors. It is well known that collagen disease, malignancy, and hematopoietic stem cell transplantation can be underlying conditions that induce TTP. However, TTP induced by acute pancreatitis, as experienced by our patient, has rarely been reported. Our patient completely recovered with treatments using steroids and plasma exchange (PE) only. In cases where patients develop acute pancreatitis with no apparent causes for hemolytic anemia and thrombocytopenia, the possibility of TTP should be considered. Treatments for TTP including PE should be evaluated as soon as a diagnosis is made. PMID- 22536084 TI - Emerging drug combinations to optimize renovascular protection and blood pressure goals. AB - Hypertension and renal disease are closely related. In fact, there is an inverse linear relationship between renal function and prevalence of hypertension. Hypertensive patients with renal dysfunction exhibit a poor clinical profile, which markedly increases their risk for cardiovascular outcomes. This review considers the available evidence on the best therapeutic approach for optimizing renovascular protection in the hypertensive population. To effectively reduce or at least slow the establishment and progression of renal disease in the hypertensive population it is critical to reach blood pressure targets. Many studies have shown that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers prevent or at least delay the development of microalbuminuria in patients with hypertension and type 2 diabetes, reduce the incidence of overt diabetic nephropathy, and are also beneficial in patients with nondiabetic renal disease. Therefore, renin-angiotensin system (RAS) inhibition plays a key role in the prevention of renal outcomes. As the majority of patients with hypertension will need at least two antihypertensive agents to achieve blood pressure goals, the use of RAS inhibitors is a mandatory part of antihypertensive therapy. The question of which antihypertensive agent is the best choice for combining with RAS blockers should be considered. Many studies have shown that diuretics and calcium channel blockers are the best choice. However, more studies are needed to clarify the subgroups of patients who will benefit more from a combination with a diuretic or from a combination with a calcium channel blocker. To date, RAS inhibitors recommended in this context are angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Aliskiren, the first oral direct renin inhibitor available, has shown promising results. PMID- 22536086 TI - Exercise on land or in water? PMID- 22536087 TI - Liraglutide therapy beyond glycemic control: an observational study in Indian patients with type 2 diabetes in real world setting. AB - BACKGROUND: Liraglutide is an analog of human glucagon-like peptide-1 (GLP-1) and acts as a GLP-1 receptor agonist. Liraglutide is presently used in the treatment of selected patients with type 2 diabetes mellitus (T2DM). OBJECTIVE: To assess efficacy and safety of liraglutide in, overweight and obese Indian patients with T2DM. METHODS: A single center, prospective, open-labeled, single-arm, observational study for 24 weeks in a real-world setting. Fourteen overweight and obese patients with T2DM who were clinically suitable for liraglutide therapy received liraglutide injections. The starting dose of liraglutide (Victoza) injection was 0.6 mg/day for 3 days followed by 1.2 mg for next 10 days and finally 1.8 mg/day for 22 weeks. Patients were evaluated at baseline and after 12 and 24 weeks of therapy. Adverse events (AE) noted during course of therapy were recorded. A repeated measure analysis of variance was performed to assess statistical significance. RESULTS: Fourteen patients were studied for 24 weeks. After 24 weeks of liraglutide therapy, mean fasting and postprandial plasma glucose decreased by 48.5 mg/dL and 66.71 mg/dL, respectively (P = 0.002 and P = 0004 over 24 weeks, respectively). A mean reduction of 2.26% of glycosylated hemoglobin was noted (P < 0.001 over 24 weeks). Mean decrease in body weight of 8.65 kg and mean decrease in body mass index of 3.26 kg/m(2) was noted (P < 0.001 over 24 weeks for each parameter). Systolic blood pressure was reduced by 15.15 mm of Hg (P = 0.004). Significant improvement in total cholesterol, low-density lipoprotein, triglycerides, and serum creatinine was noted. Nine patients reported AEs. The AEs noticed were nausea (n = 6), feeling of satiety (n = 3), and vomiting (n = 1). No serious AE or hypoglycemic episodes were observed. CONCLUSION: Liraglutide once a day improved overall glycemic control and was well tolerated. Clinically significant reduction in body weight, systolic blood pressure and improvement in lipid profile were noticed with liraglutide therapy in addition to glycemic control. PMID- 22536088 TI - Factors related to suicide attempts among individuals with major depressive disorder. AB - BACKGROUND: Major depressive disorder (MDD) is the leading cause of suicidal behaviors. Risk related to suicide attempts among individuals with MDD remains uninvestigated in upper northern Thailand, where the completed suicide rate is the highest in the nation. OBJECTIVE: To examine risk related to suicide attempts among individuals with MDD. METHODS: Individuals diagnosed with MDD using the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10), codes F32.x and F33.x, seeking care at Suanprung Psychiatric Hospital between October 2006 and May 2009 were eligible. All individuals with MDD admitted due to suicide attempts were defined as cases (n = 186), and four controls per case were selected from those who did not attempt suicide on the same day or within a week of case selection (n = 914). Their medical charts were reviewed for sociodemographic and clinical factors influencing suicide attempts using multivariable logistic regression analysis. RESULTS: Factors related to suicide attempts were stressful life events (adjusted odds ratio [OR], 2.32; 95% confidence interval [CI]: 1.27-4.24), alcohol use (adjusted OR, 2.08; 95% CI: 1.29-3.34), intermittent or poor psychiatric medications adherence (adjusted OR, 2.25; 95% CI: 1.44-3.51), up to two previous suicide attempts (adjusted OR, 3.64; 95% CI: 2.32-5.71), more than two previous suicide attempts (adjusted OR, 11.47; 95% CI: 5.73-22.95), and prescribed antipsychotics (adjusted OR, 3.84; 95% CI: 2.48-5.95). Risk factors that were inversely related to suicide attempts were increasing years of MDD treatment; one to five years (adjusted OR, 0.22; 95% CI: 0.11-0.44), over five years (adjusted OR, 0.44; 95% CI: 0.23-0.86), and antidepressant prescribed (norepinephrine [NE] and/or serotonin reuptake inhibitors [SRIs], adjusted OR, 0.28; 95% CI: 0.10 0.78). The final model explained 85.8% probability of suicide attempts. CONCLUSION: Seven key factors suggested from this study may facilitate clinicians to identify individuals with MDD at risk of suicide attempt and provide them close monitoring, timely assessment, and intensive treatments. PMID- 22536089 TI - Remission of progressive multifocal leukoencephalopathy following highly active antiretroviral therapy in a man with AIDS. AB - A 43-year-old Caucasian homosexual man with AIDS presented with blurring of vision, change of personality, and memory loss in March 1999. He had first been admitted 2 months previously for treatment of Pneumocystis jiroveci pneumonia. A magnetic resonance imaging scan on admission showed multiple white matter lesions involving both subcortical cerebral hemispheres and cerebellar regions, with no mass effect or surrounding edema. JC virus was detected by nested polymerase chain reaction in the cerebrospinal fluid. These findings were diagnostic of progressive multifocal leukoencephalopathy (PML). His CD4 count was 34 cells/mL, and his HIV ribonucleic acid level was 800,789 copies/mL. He was treated with a combination antiretroviral therapy. He was last reviewed in October 2011. He was fully independent socially and mentally, but he still had some residual neurologic signs with right-sided homonymous hemianopia and visual agnosia. His HIV ribonucleic acid level was undetectable, and his CD4 count was 574 cells/mm(3). Although the median survival of patients with PML was poor before the antiretroviral therapy era, our patient, who is now aged 55 years, is still alive 12 years after the diagnosis. The diagnosis of PML and differential diagnosis of focal neurologic signs in HIV-positive patients are discussed in this case report. PMID- 22536090 TI - Autonomic dysfunction and primary antiphospholipid syndrome: a frequent and frightening correlation? AB - INTRODUCTION: the correlation between primary antiphospholipid syndrome (APS) and cardiovascular events is well known, but the correlation between APS and sudden death is not clear; it probably correlates with sympathetic alterations of the autonomic system. AIM: To compare the autonomic nervous system (ANS) in a group of subjects suffering from APS against that of a control group with no cardiovascular risk factors, matched for age, sex, and body mass index. SUBJECTS AND METHODS: An equal number (n = 31) of subjects with APS, and healthy controls, underwent autonomic evaluation: tilt test, deep breath, Valsalva maneuver, hand grip, lying-to-standing, Stroop, and sweat tests. RESULTS: Cases in the APS group were positive for the tilt test, relating to changes in respiratory rate intervals, by comparison with controls. Results of other tests were also altered significantly in APS cases, by comparison with controls. (The sweat and Stroop tests were only performed in 14 cases). Autonomic disease did not correlate with age, sex, history of disease, arterial or venous thrombosis, or antibody positivity; only their coagulation parameters correlated with autonomic dysfunction. CONCLUSION: Autonomic dysfunction in APS seems to correlate with coagulation parameters. APS patients should receive autonomic evaluation, to minimize the risks of fatal arrhythmias and sudden death. PMID- 22536091 TI - Requested meals versus scheduled meals. AB - BACKGROUND: Scheduled meals are considered to be equivalent to those requested by the infant (null hypothesis). In adults, we have found high blood glucose before scheduled meals and low blood glucose after recognition of validated initial hunger. Low preprandial blood glucose is associated with a decrease in energy intake and body weight both in adults who are overtly overweight and in those who are of normal weight with insulin resistance (hidden overweight). In this study, we investigated the validity of the null hypothesis between scheduled and requested meals in 2-year-old infants with chronic nonspecific diarrhea. METHODS: We trained a "recognizing request" meal pattern in 70 mother-infant pairs. The trained meal pattern consisted of administering food after a first request that we validated by blood glucose measurement in the hospital laboratory. Using a 7 day food diary, mothers reported preprandial blood glucose measurements for their infants three times a day. We assessed mean preprandial blood glucose, daily energy intake, days with diarrhea, blood parameters, and anthropometry before training and 4 months after training, and compared the results with measurements in 73 randomly selected untrained controls. RESULTS: In the trained group, there was a decrease in mean blood glucose from 86.9 +/- 9.4 mg/dL to 76.4 +/- 6.7 mg/dL (P < 0.0001), as well as a decrease in energy intake and days with diarrhea in comparison with control infants who maintained scheduled meals. Only two of 21 infants who had a mean blood glucose lower than 81.2 mg/dL at recruitment showed a statistically significant decrease in mean blood glucose, whereas 36 of 49 infants above this cutoff level showed a statistically significant decrease after training (Chi-square test, P < 0.0001). CONCLUSION: Requested meals are associated with low preprandial blood glucose, significantly lower energy intake, and recovery from diarrhea, whereas scheduled meals are associated with high blood glucose, higher energy intake, and persistence of diarrhea. The disparities in blood glucose levels and energy intake disprove the null hypothesis, suggesting the need for a change from scheduled to requested meals early on in food administration, ie, during the neonatal period. PMID- 22536092 TI - Pharmacodynamic analysis of the analgesic effect of capsaicin 8% patch (QutenzaTM) in diabetic neuropathic pain patients: detection of distinct response groups. AB - Treatment of chronic pain is associated with high variability in the response to pharmacological interventions. A mathematical pharmacodynamic model was developed to quantify the magnitude and onset/offset times of effect of a single capsaicin 8% patch application in the treatment of painful diabetic peripheral neuropathy in 91 patients. In addition, a mixture model was applied to objectively match patterns in pain-associated behavior. The model identified four distinct subgroups that responded differently to treatment: 3.3% of patients (subgroup 1) showed worsening of pain; 31% (subgroup 2) showed no change; 32% (subgroup 3) showed a quick reduction in pain that reached a nadir in week 3, followed by a slow return towards baseline (16% +/- 6% pain reduction in week 12); 34% (subgroup 4) showed a quick reduction in pain that persisted (70% +/- 5% reduction in week 12). The estimate of the response-onset rate constant, obtained for subgroups 1, 3, and 4, was 0.76 +/- 0.12 week(-1) (median +/- SE), indicating that every 0.91 weeks the pain score reduces or increases by 50% relative to the score of the previous week (= t1/2). The response-offset rate constant could be determined for subgroup 3 only and was 0.09 +/- 0.04 week(-1) (t1/2 7.8 weeks). The analysis allowed separation of a heterogeneous neuropathic pain population into four homogenous subgroups with distinct behaviors in response to treatment with capsaicin. It is argued that this model-based approach may have added value in analyzing longitudinal chronic pain data and allows optimization of treatment algorithms for patients suffering from chronic pain conditions. PMID- 22536093 TI - A study of longitudinal data examining concomitance of pain and cognition in an elderly long-term care population. AB - PURPOSE: To examine if a concomitant relationship exists between cognition and pain in an elderly population residing in long-term care. BACKGROUND/SIGNIFICANCE: Prior research has found that cognitive load mediates interpretation of a stimulus. In the presence of decreased cognitive capacity as with dementia, the relationship between cognition and increasing pain is unknown in the elderly. PATIENTS AND METHODS: Longitudinal cohort design. Data collected from the Minimum Data Set-Resident Assessment Instrument (MDS-RAI) from the 2001 2003 annual assessments of nursing home residents. A covariance model was used to evaluate the relationship between cognition and pain at three intervals. RESULTS: The sample included 56,494 subjects from nursing homes across the United States, with an average age of 83 +/- 8.2 years. Analysis of variance scores (ANOVAs) indicated a significant effect (P < 0.01) for pain and cognition, with protected t test revealing scores decreasing significantly with these two measures. Relative stability was found for pain and cognition over time. Greater stability was found in the cognitive measure than the pain measure. Cross-legged effects observed between cognition and pain measures were inconsistent. A concomitant relationship was not found between cognition and pain. Even though the relationship was significant at the 0.01 level, the correlations were low (r <= 0.08), indicating a weak association between cognition and pain. CONCLUSION: Understanding the concomitance of pain and cognition aids in defining additional frameworks to extend models to include secondary needs, contextual factors, and resident outcomes. Cognitive decline, as with organic brain diseases, is progressive. Pain is a symptom that can be treated and reduced to improve resident quality of life. However, cognition can be used to determine the most appropriate method to assess pain in the elderly, thereby improving accuracy of pain detection in this population. PMID- 22536094 TI - Breathing-controlled electrical stimulation could modify the affective component of neuropathic pain after amputation: a case report. AB - In this case, a 31-year-old male suffered phantom neuropathic pain for more than 3 years after an above-the-knee amputation. His shooting phantom pain disappeared after the first session of breathing-controlled electrical stimulation, and reappeared or was triggered 28 days after an experimental error during which he received sustained electrical stimulation. In other words, painful shooting stimuli may not have been "cured" but forgotten and retriggered by a fearful event due to the experimental error. Therefore, this accidental finding provides a unique opportunity to understand sensory and affective components of neuropathic pain, and a novel intervention could modify the affective component of it. PMID- 22536095 TI - Cartographic analysis of woodlice fauna of the former USSR. AB - An inventory of the woodlice fauna of the former USSR yielded 190 species, 64 of them were recorded from the territory of Russia. According to the cartographic analysis, the limits of distribution of epigean terrestrial isopods over the area, excluding mountains, is explained by temperature. No woodlice records were found outside the isocline of 120 days a year with the mean daily air temperature >10 degrees C. The highest species diversity was found between the isoclines of 180 and 210 days. These areas correspond to forest-steppe and steppe zones. PMID- 22536096 TI - Discovery of Hemilepistus elongatus Budde-Lund, 1885 (Isopoda, Oniscidea) in Iran: redescription and intraspecific character variability. AB - In the present study, Hemilepistus elongatus Budde-Lund, 1885 is reported from Iran for the first time, redescribed and its diagnostic characters are figured. This species reveals a high variability in morphological characters. The division of the species at the subspecific level can not be supported anymore. This species differs from other species of the genus by the unique shape of male pleopod-endopodite I. PMID- 22536097 TI - Molting and cuticle deposition in the subterranean trichoniscid Titanethes albus (Crustacea, Isopoda). AB - Terrestrial isopods are a suitable group for the study of cuticle synthesis and calcium dynamics because they molt frequently and have evolved means to store calcium during molt. Little data is currently available on molting in Synocheta and subterranean isopods. We studied the molting dynamics in the subterranean trichoniscid Titanethes albus under laboratory conditions and performed a microscopic investigation of sternal CaCO(3) deposits and the tergal epithelium during molt in this species. In accordance with its lower metabolic rate, molting in the laboratory is roughly 2-3 times less frequent in Titanethes albus than would be expected for an epigean isopod under similar conditions. Animals assumed characteristic postures following the molt of each body half and did not consume the posterior exuviae after posterior molt. The structure of sternal calcium deposits and the ultrastructural characteristics of the epidermis during cuticle formation in Titanethes albus are similar to those described in representatives of Ligiidae. During the deposition of the exocuticle, the apical plasma membrane of epidermal cells forms finger-like extensions and numerous invaginations. In the ecdysial space of individuals in late premolt we observed cellular extensions surrounded by bundles of tubules. PMID- 22536098 TI - Exoskeleton anchoring to tendon cells and muscles in molting isopod crustaceans. AB - Specialized mechanical connection between exoskeleton and underlying muscles in arthropods is a complex network of interconnected matrix constituents, junctions and associated cytoskeletal elements, which provides prominent mechanical attachment of the epidermis to the cuticle and transmits muscle tensions to the exoskeleton. This linkage involves anchoring of the complex extracellular matrix composing the cuticle to the apical membrane of tendon cells and linking of tendon cells to muscles basally. The ultrastructural arhitecture of these attachment complexes during molting is an important issue in relation to integument integrity maintenance in the course of cuticle replacement and in relation to movement ability. The aim of this work was to determine the ultrastructural organization of exoskeleton - muscles attachment complexes in the molting terrestrial isopod crustaceans, in the stage when integumental epithelium is covered by both, the newly forming cuticle and the old detached cuticle. We show that the old exoskeleton is extensively mechanically connected to the underlying epithelium in the regions of muscle attachment sites by massive arrays of fibers in adult premolt Ligia italica and in prehatching embryos and premolt marsupial mancas of Porcellio scaber. Fibers expand from the tendon cells, traverse the new cuticle and ecdysal space and protrude into the distal layers of the detached cuticle. They likely serve as final anchoring sites before exuviation and may be involved in animal movements in this stage. Tendon cells in the prehatching embryo and in marsupial mancas display a substantial apicobasally oriented transcellular arrays of microtubules, evidently engaged in myotendinous junctions and in apical anchoring of the cuticular matrix. The structural framework of musculoskeletal linkage is basically established in described intramarsupial developmental stages, suggesting its involvement in animal motility within the marsupium. PMID- 22536099 TI - Egg envelopes and cuticle renewal in Porcellio embryos and marsupial mancas. AB - An important adaptation to land habitats in terrestrial isopod crustaceans is development of embryos in a fluid-filled female brood pouch, marsupium. The study brings insight into the structure and protective role of egg envelopes and cuticle renewal during ontogenetic development of Porcellio embryos and marsupial mancas. Egg envelopes cover embryos, the outer chorion until late-stage embryo and the inner vitelline membrane throughout the whole embryonic development. Egg envelopes of Porcellio have relatively simple ultrastuctural architecture compared to Drosophila egg envelopes. Exoskeletal cuticle is produced in late embryonic development by hypodermal cells of the embryo and is renewed in further development in relation to growth of developing embryos and mancas. Cuticle structure and renewal in prehatching late-stage embryos and marsupial mancas exhibit main features of cuticle in adults. Epicuticle is thin and homogenous. The characteristic arrangement of chitin-protein fibers and the dense distal layer in exocuticle are hardly discernible in prehatching embryo and distinct in marsupial mancas. Endocuticle consists of alternating electron dense and electron lucent sublayers and is perforated by pore canals in both stages. Differences from adult cuticle are evident in cuticle thickness, ultrastructure and mineralization. Signs of cuticle renewal in prehatching embryo and marsupial mancas such as detachment of cuticle from hypodermis, partial disintegration of endocuticle and assembly of new cuticle are described. PMID- 22536100 TI - Electron microscopic and preparative methods for the analysis of isopod cuticle. AB - The crustacean cuticle consists of a complex organic matrix and a mineral phase. The physical and chemical properties of the cuticle are corellated to the specific functions of cuticular elements, leading to a large variety in its structure and composition. Investigation of the structure-function relationship in crustacean cuticle requires sophisticated methodological tools for the analysis of different aspects of the cuticular architecture. In the present paper we report improved preparation methods that, in combination with various electron microscopic techniques, have led to new insights of cuticle structure and composition in the tergite cuticle of Porcellio scaber. We used thin sections of non-decalcified tergites and decalcified resin embedded material for transmission electron microscopy and scanning transmission electron microscopy. Etched sagittal planes of bulk tergite samples were analysed with field emission scanning electron microscopy. We have found a distinct distal region within the exocuticle that differs from the subjacent proximal exocuticle in the arrangement of fibres. Within this distal exocuticle chitin-protein fibrils assemble to fibres with diameters between 15 and 50 nm that are embedded in a mineral matrix. In the proximal exocuticle and the endocuticle fibrils do not assemble to fibres and are surrounded by mineral individually. Furthermore, we show that the pore canals are filled with mineral, and demonstrate that mild etching of polished sagittal cuticle surfaces reveals regions containing mineral of diverse solubility. PMID- 22536101 TI - The postmarsupial development of Porcellio siculoccidentalis, with some data on reproductive biology (Crustacea, Isopoda, Oniscidea). AB - In the broader context of research on the Sicilian Porcellio imbutus-complex, the postmarsupial development of Porcellio siculoccidentalis Viglianisi, Lombardo & Caruso, 1992 was studied in detail. This research was conducted in the laboratory under controlled conditions, allowing us to follow the stages of development, from the formation of the marsupium in ovigerous females until the larval stages and development of the seventh pair of legs. The timing of developmental stages and the morphological modifications of appendages in the postmarsupial manca stages (M I-M III) are described. The manca stage M I had a duration of about one hour. Ovigerous females were collected and reared separately, and the number of parturial molts in the absence of males was counted. The results showed a maximum of four successive parturial molts. Fecundity and fertility were evaluated as the number of eggs and embryos, respectively, inside the marsupium of the ovigerous females. Both parameters were positively correlated with the size of the females. The maximum numbers of eggs and embryos in the marsupium were 113 and 141, respectively. Data describing the total number of postmarsupial mancas released per month indicated that the highest release occurred in April. PMID- 22536102 TI - Biomineralizations: insights and prospects from crustaceans. AB - For growing, crustaceans have to molt cyclically because of the presence of a rigid exoskeleton. Most of the crustaceans harden their cuticle not only by sclerotization, like all the arthropods, but also by calcification. All the physiology of crustaceans, including the calcification process, is then linked to molting cycles. This means for these animals to find regularly a source of calcium ions quickly available just after ecdysis. The sources of calcium used are diverse, ranging from the environment where the animals live to endogenous calcium deposits cyclically elaborated by some of them. As a result, crustaceans are submitted to an important and energetically demanding calcium turnover throughout their life. The mineralization process occurs by precipitation of calcium carbonate within an organic matrix network of chitin-proteins fibers. Both crystalline and stabilized amorphous polymorphs of calcium carbonate are found in crustacean biominerals. Furthermore, Crustacea is the only phylum of animals able to elaborate and resorb periodically calcified structures. Notably for these two previous reasons, crustaceans are more and more extensively studied and considered as models of choice in the biomineralization research area. PMID- 22536103 TI - Widespread Wolbachia infection in terrestrial isopods and other crustaceans. AB - Wolbachia bacteria are obligate intracellular alpha-Proteobacteria of arthropods and nematodes. Although widespread among isopod crustaceans, they have seldom been found in non-isopod crustacean species. Here, we report Wolbachia infection in fourteen new crustacean species. Our results extend the range of Wolbachia infections in terrestrial isopods and amphipods (class Malacostraca). We report the occurrence of two different Wolbachia strains in two host species (a terrestrial isopod and an amphipod). Moreover, the discovery of Wolbachia in the goose barnacle Lepas anatifera (subclass Thecostraca) establishes Wolbachia infection in class Maxillopoda. The new bacterial strains are closely related to B-supergroup Wolbachia strains previously reported from crustacean hosts. Our results suggest that Wolbachia infection may be much more widespread in crustaceans than previously thought. The presence of related Wolbachia strains in highly divergent crustacean hosts suggests that Wolbachia endosymbionts can naturally adapt to a wide range of crustacean hosts. Given the ability of isopod Wolbachia strains to induce feminization of genetic males or cytoplasmic incompatibility, we speculate that manipulation of crustacean-borne Wolbachia bacteria might represent potential tools for controlling crustacean species of commercial interest and crustacean or insect disease vectors. PMID- 22536104 TI - Aggregation in woodlice: social interaction and density effects. AB - Terrestrial isopods are known to be sensitive to humidity, brightness or temperature. Until now, aggregation was assumed to depend on these sensitivities as a result of individual preferences. In this paper, we show that the social component is also important in the isopod aggregation phenomenon. In experimental arenas with two identical shelters up to nearly 90% of woodlice aggregated under shelters. This aggregation was quick as in 10 minutes most of the animals aggregated, irrespective of their density. Nonetheless, 10-15% of the animals walked around the arena, rarely forming very small and short-lasting aggregates outside shelters. Woodlice aggregated preferably under one of the shelters in 77% of experiments. Indeed, almost 80% of the animals out of 40, 60 or 80 animals in the arena aggregated under one shelter. In arenas with 100 individuals the aggregations were proportionally smaller (70%). Our results revealed that 70 animals was a maximum number of woodlice in an aggregate. We concluded that the location of aggregates is strongly governed by individual preferences but the dynamics of aggregation and collective choice are controlled by social interaction between congeners. The tested densities of the animals in the arena did not impact the aggregation patterns. PMID- 22536105 TI - The effect of external marking on the behaviour of the common pill woodlouse Armadillidium vulgare. AB - Zoologists distinguish individual animals using marking techniques. Generally they test the potential influence of marking on survival only; the influence on behaviour is usually neglected. We evaluated the influence of two external marking techniques (nail polish and queen-bee marker) on the behaviour of common pill woodlouse, Armadillidium vulgare. The behaviour was examined from two points of view: (1) activity during 24 hours and (2) specific expressions of behaviour (exploring, feeding, resting and hiding) over a 24 hour period. We compared behaviour among woodlice marked with nail polish and queen-bee marker with the unmarked control group during a nine-day experiment. Although we did not find any influence of marking on survival, there was an evident influence on behaviour in most cases. Generally, in the groups of marked individuals of Armadillidium vulgare there were large differences observed against the control group in the overall activity. Activity of marked individuals was significantly reduced and they preferred hiding. The influence of polish and marker on the overall frequencies of behavioural categories was evident, mainly in feeding, resting and hiding. The influence on the frequency of exploring was significant in the polish marked group only. PMID- 22536106 TI - Tonic immobility in terrestrial isopods: intraspecific and interspecific variability. AB - Many arthropods, including terrestrial isopods, are capable of entering a state of tonic immobility upon a mechanical disturbance. Here we compare the responses to mechanical stimulation in three terrestrial isopods Balloniscus glaber, Balloniscus sellowii and Porcellio dilatatus. We applied three stimuli in a random order and recorded whether each individual was responsive (i.e. showed tonic immobility) or not and the duration of the response. In another trial we related the time needed to elicit tonic immobility and the duration of response of each individual. Balloniscus sellowii was the least responsive species and Porcellio dilatatus was the most, with 23% and 89% of the tested individuals, respectively, being responsive. Smaller Balloniscus sellowii were more responsive than larger individuals. Porcellio dilatatus responded more promptly than the Balloniscus spp. but it showed the shortest response. Neither sex, size nor the type of stimulus explained the variability found in the duration of tonic immobility. These results reveal a large variability in tonic immobility behavior, even between closely related species, which seems to reflect a species specific response to predators with different foraging modes. PMID- 22536107 TI - Terrestrial isopod community as indicator of succession in a peat bog. AB - Terrestrial isopods were studied in the Dubravica peat bog and surrounding forest in the northwestern Croatia. Sampling was conducted using pitfall traps over a two year period. Studied peat bog has a history of drastically decrease in area during the last five decades mainly due to the process of natural succession and changes in the water level. A total of 389 isopod individuals belonging to 8 species were captured. Species richness did not significantly differ between bog, edge and surrounding forest. High species richness at the bog is most likely the result of progressive vegetation succession, small size of the bog and interspecific relationships, such as predation. With spreading of Molinia grass on the peat bog, upper layers of Sphagnum mosses become less humid and probably more suitable for forest species that slowly colonise bog area. The highest diversity was found at the edge mainly due to the edge effect and seasonal immigration, but also possibly due to high abundance and predator pressure of the Myrmica ants and lycosid spiders at the bog site. The most abundant species were Trachelipus rathkii and Protracheoniscus politus, in the bog area and in the forest, respectively. Bog specific species were not recorded and the majority of the species collected belong to the group of tyrphoneutral species. However, Hyloniscus adonis could be considered as a tyrphoxenous species regarding its habitat preferences. Most of collected isopod species are widespread eurytopic species that usually inhabit various habitats and therefore indicate negative successive changes or degradation processes in the peat bog. PMID- 22536108 TI - Assemblages of terrestrial isopods (Isopoda, Oniscidea) in a fragmented forest landscape in Central Europe. AB - Terrestrial isopods were collected in 13 forest fragments differing in area (within the range of 0.1 and 254.5 ha), shape and composition of forest vegetation (thermophilous oak, mesophilous oak-hornbeam, thermophilous oak hornbeam, acidophilous oak, basiphilous oak, beech oak-hornbeam, moist mixed deciduous forest, plantations of deciduous and coniferous trees), all situated in the Cesky kras Protected Landscape Area, Czech Republic, Central Europe. Number of sites sampled in each fragment of forest depended on its size and ranged from 1 to 7. Altogether 30 sites were sampled. Soil samples (5 per site collected twice a year) and pitfall trapping (5 traps per site in continuous operation throughout a year) during 2008-2009 yielded a total of 14 species of terrestrial isopods. The highest densities and highest epigeic activities of terrestrial isopods were recorded in the smallest fragments of woodland. Although a wider range of habitats were sampled in the larger fragments of woodland there was not a greater diversity of species there and the population densities and epigeic activities recorded there were lower. Porcellium collicola was most abundant in small fragments of woodland regardless the vegetation there. Armadillidium vulgare and Protracheoniscus politus were statistically more abundant in the larger fragments of woodland. The results indicate that forest fragmentation does not necessarily result in a decrease in the species richness of the isopod assemblages in such habitats. PMID- 22536109 TI - Occurrence and assemblage composition of millipedes (Myriapoda, Diplopoda) and terrestrial isopods (Crustacea, Isopoda, Oniscidea) in urban areas of Switzerland. AB - Terrestrial isopods and millipedes, members of the invertebrate macro-decomposer guild, were collected through pitfall traps in three Swiss cities (Zurich, Lucerne, Lugano). A total of 7,198 individuals of 17 isopod species (7093 ind.), and 10 millipede species (105 ind.) were captured. Besides the Alpine endemic isopod (Trichoniscus alemannicus) and millipede (Cylindroiulus verhoeffi), urban assemblages were mainly composed of widespread, native European and even cosmopolitan species, which are frequent in anthropogenic areas. Overall species richness (isopods and millipedes combined) was similar in Zurich (17 species) and Lucerne (16), while only 13 species were sampled in Lugano. According to the Sorensen index of similarity, species composition of Zurich and Lucerne were more alike, while the one of Lugano was more distinct from the other two cities. This result can be explained by the spatial proximity of Zurich and Lucerne in the north of the Alps compared to Lugano, which is located more distantly and in the south of the Alps. Dominant isopods and millipedes in Zurich and Lucerne were found to be widespread synanthropic species in temperate Europe(Porcellio scaber, Trachelipus rathkii and Ophyiulus pilosus) while the dominant isopod in Lugano (Trachelipus razzautii) is a species with a north-eastern Mediterranean distribution. Our study reveals that the urban millipede and isopod fauna in Swiss cities mainly consists of widespread species, but species of narrower distribution (e.g. Trichoniscus alemannicus, Cylindroiulus verhoeffi) may also find suitable habitats in cities. Despite some signs of biotic homogenization, our study also found compositional differences of millipede and isopod assemblages between northern and southern cities that suggest geographical effects of the regional species pool. PMID- 22536110 TI - The diversity of terrestrial isopods in the natural reserve "Saline di Trapani e Paceco" (Crustacea, Isopoda, Oniscidea) in northwestern Sicily. AB - Ecosystems comprising coastal lakes and ponds are important areas for preserving biodiversity. The natural reserve "Saline di Trapani e Paceco" is an interesting natural area in Sicily, formed by the remaining strips of land among salt pans near the coastline. From January 2008 to January 2010, pitfall trapping was conducted in five sampling sites inside the study area. The community of terrestrial isopods was assessed using the main diversity indices. Twenty-four species were collected, only one of them endemic to western Sicily: Porcellio siculoccidentalis Viglianisi, Lombardo & Caruso, 1992. Two species are new to Sicily: Armadilloniscus candidus Budde-Lund, 1885 and Armadilloniscus ellipticus (Harger, 1878). This is high species richness for a single reserve in Sicily. The extended sampling period also allowed us to study species phenology. Most of the species exhibited higher activity in spring than in autumn while some species also exhibited lower activity in the summer. The species richness revealed that the study area is in an acceptable conservation status; Shannon and Pielou indices also confirmed a more or less even distribution of individuals belonging to different species. PMID- 22536111 TI - Feeding rates of Balloniscus sellowii (Crustacea, Isopoda, Oniscidea): the effect of leaf litter decomposition and its relation to the phenolic and flavonoid content. AB - The goal of this study was to compare the feeding rates of Balloniscus sellowii on leaves of different decomposition stages according to their phenolic and flavonoid content. Leaves from the visually most abundant plants were offered to isopods collected from the same source site. Schinus terebinthifolius,the plant species consumed at the highest rate, was used to verify feeding rates at different decomposition stages. Green leaves were left to decompose for one, two, or three months, and then were offered to isopods. The total phenolic and flavonoid contents were determined for all decomposition stages. Consumption and egestion rates increased throughout decomposition, were highest for two-month-old leaves, and decreased again in the third month. The assimilation rate was highest for green leaves. The mode time of passage through the gut was two hours for all treatments. Ingestion of leaves occurred after two or three days for green leaves, and on the same day for one-, two- and three-month-old leaves. The speed of passage of leaves with different decomposition stages through the gut does not differ significantly when animals are fed continuously. However, it is possible that the amount retained in the gut during starvation differs depending on food quality. The digestibility value was corrected using a second food source to empty the gut of previously ingested food, so that all of the food from the experiment was egested. The digestibility value was highest for green leaves, whereas it was approximately 20% for all other stages. This was expected given that digestibility declines during decomposition as the metabolite content of the leaves decreases. The phenolic content was highest in the green leaves and lowest in three-month-old leaves. The flavonoid content was highest in green leaves and lowest after two months of decomposition. Animals ingested more phenolics when consumption was highest. The estimated amount of ingested flavonoids followed the same trend as assimilation rate. Flavonoids accounted for a large portion of total phenolics, and the estimated amount of flavonoids consumed was similar for one-, two- and three-month-old leaves. Our results suggest that the high phenolic and flavonoid concentrations in green leaves are feeding deterrents. Isopods may discriminate among concentrations of flavonoids and modify their consumption rates to maintain their intake of flavonoids when ingesting leaves with lower flavonoid content. PMID- 22536112 TI - Size dependent differences in litter consumption of isopods: preliminary results. AB - A series of experiments were applied to test how leaf orientation within microcosms affect consumption rates (Experiment 1), and to discover intra specific differences in leaf litter consumption (Experiment 2) of the common isopod species Porcellio scaber and Porcellionides pruinosus. A standardised microcosm setup was developed for feeding experiments to maintain standard conditions. A constant amount of freshly fallen black poplar litter was provided to three distinct size class (small, medium, large) of woodlice. We measured litter consumption after a fortnight. We maintained appr. constant isopod biomass for all treatments, and equal densities within each size class. We hypothesized that different size classes differ in their litter consumption, therefore such differences should occur even within populations of the species. We also hypothesized a marked difference in consumption rates for different leaf orientation within microcosms. Our results showed size-specific consumption patterns for Porcellio scaber: small adults showed the highest consumption rates (i.e. litter mass loss / isopod biomass) in high density microcosms, while medium sized adults of lower densities ate the most litter in containers. Leaf orientation posed no significant effect on litter consumption. PMID- 22536113 TI - Prolonged feeding of terrestrial isopod (Porcellio scaber, Isopoda, Crustacea) on TiO (2) nanoparicles. Absence of toxic effect. AB - Nanoparticles of titanium dioxide are one of most widely used nanomaterials in different products in everyday use and in industry, but very little is known about their effects on non- target cells and tissues. Terrestrial isopods were exposed to food dosed with nano-TiO(2) to give final nominal concentration 1000 and 2000 ug TiO(2)/g dry weight of food. The effects of ingested nano-TiO(2) on the model invertebrate Porcellio scaber (Isopoda, Crustacea) after short-term (3 and 7 days) and prolonged (14 and 28 days) dietary exposure was assessed by conventional toxicity measures such as feeding rate, weight change and mortality. Cell membrane destabilization was also investigated. No severe toxicity effects were observed after 3, 7, 14 or 28 days of dietary exposure to nano-TiO(2), but some animals, particularly those exposed to lower concentrations of nanoparticles, had severely destabilized digestive cell membranes. It was concluded that strong destabilization of the cell membrane was sporadic, and neither concentration- nor time-related. Further research is needed to confirm this sporadic toxic effect of nanoparticles. PMID- 22536114 TI - Soil ecotoxicology: state of the art and future directions. AB - Developments in soil ecotoxicology started with observations on pesticide effects on soil invertebrates in the 1960s. To support the risk assessment of chemicals, in the 1980s and 1990s development of toxicity tests was the main issue, including single species tests and also more realistic test systems like model ecosystems and field tests focusing on structural and functional endpoints. In the mean time, awareness grew about issues like bioavailability and routes of exposure, while biochemical endpoints (biomarkers) were proposed as sensitive and potential early-warning tools. In recent years, interactions between different chemicals (mixture toxicity) and between chemical and other stressors attracted scientific interest. With the development of molecular biology, omics tools are gaining increasing interest, while the ecological relevance of exposure and effects is translating into concepts like (chemical) stress ecology, ecological vulnerability and trait-based approaches. This contribution addresses historical developments and focuses on current issues in soil ecotoxicology. It is concluded that soil ecotoxicological risk assessment would benefit from extending the available battery of toxicity tests by including e.g. isopods, by paying more attention to exposure, bioavailability and toxicokinetics, and by developing more insight into the ecology of soil organisms to support better understanding of exposure and long-term consequences of chemical exposure at the individual, population and community level. Ecotoxicogenomics tools may also be helpful in this, but will require considerable further research before they can be applied in the practice of soil ecotoxicological risk assessment. PMID- 22536115 TI - Generation and Analysis of Expressed Sequence Tags from Chimonanthus praecox (Wintersweet) Flowers for Discovering Stress-Responsive and Floral Development Related Genes. AB - A complementary DNA library was constructed from the flowers of Chimonanthus praecox, an ornamental perennial shrub blossoming in winter in China. Eight hundred sixty-seven high-quality expressed sequence tag sequences with an average read length of 673.8 bp were acquired. A nonredundant set of 479 unigenes, including 94 contigs and 385 singletons, was identified after the expressed sequence tags were clustered and assembled. BLAST analysis against the nonredundant protein database and nonredundant nucleotide database revealed that 405 unigenes shared significant homology with known genes. The homologous unigenes were categorized according to Gene Ontology hierarchies (biological, cellular, and molecular). By BLAST analysis and Gene Ontology annotation, 95 unigenes involved in stress and defense and 19 unigenes related to floral development were identified based on existing knowledge. Twelve genes, of which 9 were annotated as "cold response," were examined by real-time RT-PCR to understand the changes in expression patterns under cold stress and to validate the findings. Fourteen genes, including 11 genes related to floral development, were also detected by real-time RT-PCR to validate the expression patterns in the blooming process and in different tissues. This study provides a useful basis for the genomic analysis of C. praecox. PMID- 22536117 TI - PASSIOMA: Exploring Expressed Sequence Tags during Flower Development in Passiflora spp. AB - The genus Passiflora provides a remarkable example of floral complexity and diversity. The extreme variation of Passiflora flower morphologies allowed a wide range of interactions with pollinators to evolve. We used the analysis of expressed sequence tags (ESTs) as an approach for the characterization of genes expressed during Passiflora reproductive development. Analyzing the Passiflora floral EST database (named PASSIOMA), we found sequences showing significant sequence similarity to genes known to be involved in reproductive development such as MADS-box genes. Some of these sequences were studied using RT-PCR and in situ hybridization confirming their expression during Passiflora flower development. The detection of these novel sequences can contribute to the development of EST-based markers for important agronomic traits as well as to the establishment of genomic tools to study the naturally occurring floral diversity among Passiflora species. PMID- 22536119 TI - Dolphinfish bycatch in Spanish Mediterranean large pelagic longline fisheries, 2000-2010. AB - The aim of this paper is to describe the dolphinfish bycatch rates in the longline fisheries of the Western Mediterranean and modelling the nominal bycatch abundance and distribution of dolphinfish from the Spanish Mediterranean as a function of technical, geographical, and seasonality factors. Our results indicate that the impact of the pelagic and semipelagic longline on the dolphinfish population is relatively low (1.083 fishes per 1000 hooks), in contrast with the greater effect on the target species population. We obtained a statistically significant logistic model, with the following factors: technical characteristics of the fishery, geographical location, and seasonality. Drifting surface longliners targeting albacore is the gear with the highest effect on Mediterranean dolphinfish population. The technical characteristics of the fishery and seasonality factors have an important role in explaining the absence or presence of dolphinfish bycatch in the different boat strata, gear types, and seasons. Moreover, sea surface temperature and lunar phases also present additional explanations. Lunar phase as SST has been frequently used as an explanatory variable affecting catch rates of dolphinfish. PMID- 22536118 TI - Expression, Purification, and Characterization of Ras Protein (BmRas1) from Bombyx mori. AB - The Ras subfamily is the member of small G proteins superfamily involved in cellular signal transduction. Activation of Ras signaling causes cell growth, differentiation, and survival. Bombyx mori Ras-like protein (BmRas1) may belong to the Ras subfamily. It contained an H-N-K-Ras-like domain. The BmRas1 mRNA consisted of 1459 bp. The open reading frame contained 579 bp, encoding 192 amino acids. The protein had such secondary structures as alpha-helices, extended strand, and random coil. BmRas1 was expressed successfully in E. coli BL21. The recombinant protein was purified with metal-chelating affinity chromatography. The GTPase activity of purified protein was determined by FeSO(4) (NH(4))(2)MoO(4) assay. The results showed that purified recombinant protein had intrinsic activity of GTPase. High titer polyclonal antibodies were generated by New Zealand rabbit immunized with purified protein. The gene expression features of BmRas1 at different stages and in different organs of the fifth instar larvae were analyzed by Western blot. The results showed that BmRas1 was expressed highly in three development stages including egg, pupae, and adult, but low expression in larva. BmRas1 was expressed in these tissues including head, malpighian tubule, genital gland, and silk gland. The purified recombinant protein would be utilized to further function studies of BmRas1. PMID- 22536116 TI - Alternative Mechanisms to Initiate Translation in Eukaryotic mRNAs. AB - The composition of the cellular proteome is under the control of multiple processes, one of the most important being translation initiation. The majority of eukaryotic cellular mRNAs initiates translation by the cap-dependent or scanning mode of translation initiation, a mechanism that depends on the recognition of the m(7)G(5')ppp(5')N, known as the cap. However, mRNAs encoding proteins required for cell survival under stress bypass conditions inhibitory to cap-dependent translation; these mRNAs often harbor internal ribosome entry site (IRES) elements in their 5'UTRs that mediate internal initiation of translation. This mechanism is also exploited by mRNAs expressed from the genome of viruses infecting eukaryotic cells. In this paper we discuss recent advances in understanding alternative ways to initiate translation across eukaryotic organisms. PMID- 22536120 TI - Influence of the flexible liposomes on the skin deposition of a hydrophilic model drug, carboxyfluorescein: dependency on their composition. AB - This study focuses on the effect of different flexible liposomes containing sodium cholate, Tween 80, or cineol on skin deposition of carboxyfluorescein (CF). Size distribution, morphology, zeta potential, and stability of the prepared vesicles were evaluated. The influence of these systems on the skin deposition of CF utilizing rat skin as membrane model was investigated. Results showed that all of the investigated liposomes had almost spherical shapes with low polydispersity (PDI < 0.3) and particles size range from 83 to 175 nm. All liposomal formulations exhibited negative zeta potential, good drug entrapment efficiency, and stability. In vitro skin deposition data showed that flexible liposomes gave significant deposition of CF on the skin compared to conventional liposomes and drug solutions. This study revealed that flexible liposomes, containing cineole, were able to deliver higher amount of CF suggesting that the hydrophilic drugs delivery to the skin was strictly correlated to the vesicle composition. PMID- 22536121 TI - Smoking behaviour before, during, and after pregnancy: the effect of breastfeeding. AB - Data for this study were obtained from a population-based follow-up study in 25 Italian Local Health Units (LHUs) to evaluate pregnancy, delivery, and postpartum care in Italy. A sample of 3534 women was recruited and interviewed within a few days of their giving birth and at 3, 6, and 12 months after delivery, by trained interviewers using questionnaires. The objective of the study was to evaluate changes in smoking behaviour from one interview to the next. Of 2546 women who completed the follow-up, smoking prevalences before and during pregnancy were 21.6% and 6.7%; smoking prevalences and smoking relapse at 3, 6, and 12 months were 8.1% and 18.5%, 10.3% and 30.3%, and 10.9% and 32.3%, respectively. Smoking during and after pregnancy was more likely among women who were less educated, single, not attending antenatal classes, employed, and not breastfeeding. The results show that women who are breastfeeding smoke less than not breastfeeding women, even after controlling for other predictors (i.e., smoking relapse at 12 months: OR = 0.43, 95% CI: 0.19, 0.94). A low maternal mood increases the risk of smoking relapse within 6 months of about 73%. This study also suggests that prolonged breastfeeding reduces the risk of smoking relapse and that this reduction may be persistent in time. Interventions targeting breastfeeding promotion may also indirectly support smoking cessation, even in absence of specific interventions. PMID- 22536122 TI - Obesity is a marker of reduction in QoL and disability. AB - The purpose of this paper is to verify the association between outcome measures of health-related quality of life (HRQoL) and disability, BMI, gender, and age. Adult obese patients were clustered using HRQoL (IWQoL-Lite) and disability (WHO DAS II) scores into three groups: mild, moderate, and high. One-way ANOVA with Bonferroni post hoc test was used to evaluate differences in age and BMI between subjects from different clusters, contingency coefficient to test the relationship between cluster groups and gender. In total, 117 patients were enrolled: subjects with higher disability and HRQoL decrement were older and had higher BMI. Women were more likely to present moderate disability and reduction in HRQoL, while men more likely presented mild disability and HRQoL reduction. Our data further confirm the connection between disability and HRQoL, high BMI and older age. These data obtained with outcomes measures might better address rehabilitation programs. PMID- 22536123 TI - An efficient protocol for the synthesis of quinoxaline derivatives at room temperature using recyclable alumina-supported heteropolyoxometalates. AB - We report a suitable quinoxaline synthesis using molybdophosphovanadates supported on commercial alumina cylinders as catalysts. These catalysts were prepared by incipient wetness impregnation. The catalytic test was performed under different reaction conditions in order to know the performance of the synthesized catalysts. The method shows high yields of quinoxaline derivatives under heterogeneous conditions. Quinoxaline formation was obtained using benzyl, o-phenylenediamine, and toluene as reaction solvent at room temperature. The CuH(2)PMo(11)VO(40) supported on alumina showed higher activity in the tested reaction. Finally, various quinoxalines were prepared under mild conditions and with excellent yields. PMID- 22536124 TI - Two new reference materials based on tobacco leaves: certification for over a dozen of toxic and essential elements. AB - The preparation, certification, and characterization of two new biological certified reference materials for inorganic trace analysis have been presented. They are based on two different varieties of tobacco leaves, namely, Oriental Basma Tobacco Leaves (INCT-OBTL-5), grown in Greece, and Polish Virginia Tobacco Leaves (INCT-PVTL-6), grown in Poland. Certification of the materials was based on the statistical evaluation of results obtained in a worldwide interlaboratory comparison, in which 87 laboratories from 18 countries participated, providing 2568 laboratory averages on nearly 80 elements. It was possible to establish the certified values of concentration for many elements in the new materials, that is, 37 in INCT-OBTL-5 and 36 in INCT-PVTL-6, including several toxic ones like As, Cd, Hg, Pb, and so forth. The share and the role of instrumental analytical techniques used in the process of certification of the new CRMs are discussed. PMID- 22536125 TI - Visualization of chronic myocardial infarction using the intravascular contrast agent MS-325 (gadofosveset) in patients. AB - AIMS: The aim of this study was to evaluate the potential of visualizing chronic myocardial infarction in patients using the intravascular CA MS-325 (gadofosveset, EPIX Pharmaceuticals, Mass, USA). METHODS: Nine patients were enrolled in a clinical phase II multicenter trial for MRCA and perfusion imaging using MS-325. They had objective evidence of chronic myocardial infarction as visualized by previously performed late gadolinium (Gd) enhancement imaging (LGE) with a conventional extracellular Gd-DTPA CA (Magnevist, Bayer Healthcare, Germany, 0.2 mmol/kg/body weight) serving as reference standard. A prepulse optimized LGE study was performed immediately and at several time points after injection of MS-325 (0.05 mmol/kg/body weight). The number and localization of segments demonstrating LGE with MS-325 as well as signal intensities were compared with the reference standard (Gd-DTPA). RESULTS: Using MS-325, LGE could be detected at every time point in all 9 patients. The accuracy of LGE with MS 325 as compared to LGE with Gd-DTPA was highest 54 +/- 4 minutes after contrast injection, resulting in a sensitivity of 84% with a specificity of 98%. CONCLUSION: The intravascular CA MS-325 has the potential to visualize chronic myocardial infarction. However, in comparison with Gd-DTPA, the transmural extent and the number of segments are smaller. PMID- 22536126 TI - Serial MRI features of canine GM1 gangliosidosis: a possible imaging biomarker for diagnosis and progression of the disease. AB - GM1 gangliosidosis is a fatal neurodegenerative lysosomal storage disease caused by an autosomal recessively inherited deficiency of beta-galactosidase activity. Effective therapies need to be developed to treat the disease. In Shiba Inu dogs, one of the canine GM1 gangliosidosis models, neurological signs of the disease, including ataxia, start at approximately 5 months of age and progress until the terminal stage at 12 to 15 months of age. In the present study, serial MR images were taken of an affected dog from a model colony of GM1 gangliosidosis and 4 sporadic clinical cases demonstrating the same mutation in order to characterize the MRI features of this canine GM1 gangliosidosis. By 2 months of age at the latest and persisting until the terminal stage of the disease, the MR findings consistently displayed diffuse hyperintensity in the white matter of the entire cerebrum on T2-weighted images. In addition, brain atrophy manifested at 9 months of age and progressed thereafter. Although a definitive diagnosis depends on biochemical and genetic analyses, these MR characteristics could serve as a diagnostic marker in suspect animals with or without neurological signs. Furthermore, serial changes in MR images could be used as a biomarker to noninvasively monitor the efficacy of newly developed therapeutic strategies. PMID- 22536127 TI - Photoassisted degradation of a herbicide derivative, dinoseb, in aqueous suspension of titania. AB - The titanium dioxide (TiO(2)) photoassisted degradation of herbicide dinoseb has been examined in aqueous suspensions under UV light irradiation. The degradation kinetics were studied under various conditions such as substrate concentration, type of catalyst, catalyst dosage, pH, and light intensity as well as in presence of electron acceptors such as hydrogen peroxide, potassium bromate, and potassium persulphate under continuous air purging, and the degradation rates were found to be strongly influenced by these parameters. The Degussa P25 was found to be more efficient photocatalyst as compared to other photocatalysts tested. Dinoseb was found to degrade efficiently in acidic pH and all the electron acceptors studied enhanced the degradation rate. The results manifested that the photocatalysis of dinoseb followed pseudo-first-order kinetics. A qualitative study of the degradation products generated during the process was performed by GC-MS, and a degradation mechanism was proposed. PMID- 22536128 TI - Endoparasite infections in pet and zoo birds in Italy. AB - Faecal samples were individually collected from pet (n = 63) and zoo (n = 83) birds representing 14 orders and 63 species. All the samples were examined by faecal flotation technique. In a subgroup of samples (n = 75), molecular assays were also used to detect Cryptosporidium oocysts and Giardia duodenalis cysts. Overall, 35.6% of the birds harboured parasites (42.2% of zoo birds and 27% of pet birds), including Strongyles-Capillarids (8.9%), Ascaridia (6.8%), Strongyles (5.5%), G. duodenalis Assemblage A (5.3%), Coccidia (4.1%), Cryptosporidium (4%), Porrocaecum (2.7%), Porrocaecum-Capillarids (2%), and Syngamus-Capillarids (0.7%). The zoonotic G. duodenalis Assemblage A and Cryptosporidium were exclusively found in Psittaciformes, with prevalences of 10.3% and 7.7% within this bird group. Zoo birds were more likely to harbor mixed infections (OR = 14.81) and symptomatic birds to be parasitized (OR = 4.72). Clinicians should be aware of the public health implications posed by zoonotic G. duodenalis Assemblages and Cryptosporidium species in captive birds. PMID- 22536129 TI - Biomedical evaluation of cortisol, cortisone, and corticosterone along with testosterone and epitestosterone applying micellar electrokinetic chromatography. AB - The validated micellar electrokinetic chromatography (MEKC) was proposed for the determination of five steroid hormones in human urine samples. That technique allowed for the separation and quantification of cortisol, cortisone, corticosterone, testosterone, and epitestosterone and was sensitive enough to detect low concentrations of these searched steroids in urine samples at the range of 2-300 ng/mL. The proposed MEKC technique with solid-phase extraction (SPE) procedure was simple, rapid, and has been successfully applied as a routine procedure to analyze steroids in human urine samples. The MEKC method offered a potential in clinical routine practice because of the short analysis time (8 min), low costs, and simultaneous analysis of five endogenous hormones. Due to its simplicity, speed, accuracy, and high recovery, the proposed method could offer a tool to determine steroid hormones as potential biomarkers in biomedical investigations, what was additionally revealed with healthy volunteers. PMID- 22536130 TI - Antinociceptive effect of rat D-serine racemase inhibitors, L-serine-O-sulfate, and L-erythro-3-hydroxyaspartate in an arthritic pain model. AB - N-methyl-D-aspartic acid receptor (NMDAr) activation requires the presence of D serine, synthesized from L-serine by a pyridoxal 5'-phosphate-dependent serine racemase (SR). D-serine levels can be lowered by inhibiting the racemization of L serine. L-serine-O-sulfate (LSOS) and L-erythro-3-hydroxyaspartate (LEHA), among others, have proven to be effective in reducing the D-serine levels in culture cells. It is tempting then to try these compounds in their effectiveness to decrease nociceptive levels in rat arthritic pain. We measured the C-reflex paradigm and wind-up potentiation in the presence of intrathecally injected LSOS (100 MUg/10 MUL) and LEHA (100 MUg/10 MUL) in normal and monoarthritic rats. Both compounds decreased the wind-up activity in normal and monoarthritic rats. Accordingly, all the antinociceptive effects were abolished when 300 MUg/10 MUL of D-serine were injected intrathecally. Since no in vivo results have been presented so far, this constitutes the first evidence that SR inhibitions lower the D-serine levels, thus decreasing the NMDAr activity and the consequent development and maintenance of chronic pain. PMID- 22536131 TI - Efficacy and safety of immunotherapy with interferon-gamma in the management of chronic sulfur mustard-induced cutaneous complications: comparison with topical betamethasone 1%. AB - The present trial investigated the efficacy of immunotherapy with interferon gamma (IFN-gamma) in the treatment of sulfur mustard (SM)-induced chronic skin complications. Forty subjects who were suffering from chronic skin complications of SM and were diagnosed to have severe atopic dermatitis, were assigned to IFN gamma (50 MUg/m(2)) subcutaneously three times per week (n = 20) or betamethasone valerate topical cream 0.1% (n = 20) every night for 30 days. Extent and intensity of cutaneous complications was evaluated using scoring atopic dermatitis (SCORAD) index, and quality of life using dermatology life quality index (DLQI) at baseline and at the end of trial. SCORAD-A and SCORAD-B scores were significantly decreased in both IFN-gamma and betamethasone. However, SCORAD C score was decreased only in the IFN-gamma group. There were significant reductions in overall as well as objective SCORAD scores in both groups. As for the magnitude of changes, treatment with IFN-gamma was associated with greater reductions in overall, objective and segmented SCORAD scores compared to betamethasone. DLQI reduction was found to be significantly greater in the IFN gamma group. Promising improvements in quality life and clinical symptoms that was observed in the present study suggest the application of IFN-gamma as an effective therapy for the management of SM-induced chronic skin complications. PMID- 22536132 TI - Socioeconomic differences in tobacco smoking in Italy: is there an interaction between variables? AB - OBJECTIVES: To assess the influence of sociodemographic factors on smoking habits in Italy and if an interaction exists between these variables. METHODS: Data from the national survey "Health Conditions and Healthcare Services Use" in 2005 were used. The independent association between tobacco smoking and sociodemographical variables was assessed using logistic regression analysis. Interactions between variables were investigated calculating the synergism index (SI). RESULTS: Sample population consists of 109.829 subjects (over 15 years). 21.9% are current and 21.8% are former smokers. Current smokers are mostly 45-54-years old males, from Central Italy, unemployed, divorced or separated but having a good health status without chronic medical conditions. Ever smokers are mostly 45-54 years old males, from Northeast Italy, unemployed, with chronic conditions. People with a university degree and with a good household income have the lowest OR for both conditions. A synergistic effect was found between marital status and educational level (for ever smokers SI = 1.96; for current smokers SI = 1.67). CONCLUSIONS: Smoking is prevalent in lower socioeconomic groups and there is the strong need to increase social, economic and cultural capital in order to reduce it. PMID- 22536133 TI - Prevalence of isolated atrial amyloidosis in young patients affected by congestive heart failure. AB - Atrial natriuretic peptide (ANP), whose amyloid is responsible of isolated atrial amyloidosis (IAA), is known to play an important role in the pathophysiology of congestive heart failure (CHF). We provide here the microscopic examination of atrial biopsies from 36 young (mean 40 years) CHF patients distinguished in idiopathic dilated cardiomyopathy (DC) affected and hypertrophic Cardiomyopathy (HC) affected, endorsing the presumptive association of early CHF with IAA. We utilized a multiple method, using Congo red (CR) staining, CR fluorescence (CRF), and immunohistochemistry to assess the presence of IAA in CHF. Immunostaining showed a moderate deposition of IAA in the atrium surrounding working myocardium with small intracellular deposits. Our findings suggest a monitoring of young CHF cases for the development of IAA. Our study also demonstrated how the concurrent use of immunohistochemistry, CR, and CRF may greatly enhance the detection of low grade amyloid deposits. PMID- 22536134 TI - The need for a specific risk prediction system in native valve infective endocarditis surgery. AB - The need for a specific risk score system for infective endocarditis (IE) surgery has been previously claimed. In a single-center pilot study, preliminary to future multicentric development and validation, bivariate and multivariate (logistic regression) analysis of early postoperative mortality predictors in 440 native valve IE patients were performed. Mathematical procedures assigned scores to the independent predictors emerged (AUC of the ROC curve: 0.88). Overall mortality was 9.1%. Six predictors were identified and assigned scores, including age (5-13 points), renal failure (5), NYHA class IV (9), critical preoperative state (11), lack of preoperative attainment of blood culture negativity (5), perivalvular involvement (5). Four risk classes were drawn ranging from "very low risk" (<=5 points, mean predicted mortality 1%), and to "very high risk" (>=20 points, 43% mortality). IE-specific risk stratification models are both needed, as disease-specific factors (e.g., cultures, abscess), beside the generic ones (e.g., age, renal impairment) affect mortality, and feasible. PMID- 22536135 TI - Use of spineless cactus (Opuntia ficus indica f. inermis) for dairy goats and growing kids: impacts on milk production, kid's growth, and meat quality. AB - The objective of this study was to determine the effect of spineless cactus incorporation in food of dairy goats and growing kids on milk production and composition and on kid's growth and meat characteristics. Two experiments were conducted on Tunisian local goats. In the first, 30 females were divided into two groups; goats of Control group were reared on grazing pasture receiving indoor 0.5 kg of hay and 0.4 kg of concentrate. Goats for the second group (Cac-FL) were kept in feedlot and fed cactus ad libitum more 0.5 kg of hay and 0.4 kg of concentrate. In the second experiment, 14 kids were divided into 2 groups receiving 600 g of hay. The Control group received ad libitum a concentrate containing 130 g crude protein (CP) per kg of dry matter. The second group received cactus ad-libitum plus the half concentrate quantity of control one with 260 g CP/kg DM (Cactus). The daily milk production averaged 485 ml for Control group and 407 ml for Cac-FL one. The milk fat content was significantly higher for Control than Cac-FL group. In the second experiment, animals in Control and Cactus groups had similar growth rate. Carcass fat was significantly lower in Cactus than in the Control group. Cactus in the diet was associated with more C18:2 and conjugated linoleic acid as well as a higher proportion of PUFA than Control ones. PMID- 22536136 TI - A novel HPLC method for the concurrent analysis and quantitation of seven water soluble vitamins in biological fluids (plasma and urine): a validation study and application. AB - An HPLC method was developed and validated for the concurrent detection and quantitation of seven water-soluble vitamins (C, B(1), B(2), B(5), B(6), B(9), B(12)) in biological matrices (plasma and urine). Separation was achieved at 30 degrees C on a reversed-phase C18-A column using combined isocratic and linear gradient elution with a mobile phase consisting of 0.01% TFA aqueous and 100% methanol. Total run time was 35 minutes. Detection was performed with diode array set at 280 nm. Each vitamin was quantitatively determined at its maximum wavelength. Spectral comparison was used for peak identification in real samples (24 plasma and urine samples from abstinent alcohol-dependent males). Interday and intraday precision were <4% and <7%, respectively, for all vitamins. Recovery percentages ranged from 93% to 100%. PMID- 22536137 TI - A refined methodology for defining plant communities using postagricultural data from the neotropics. AB - How best to define and quantify plant communities was investigated using long term plot data sampled from a recovering pasture in Puerto Rico and abandoned sugarcane and banana plantations in Ecuador. Significant positive associations between pairs of old field species were first computed and then clustered together into larger and larger species groups. I found that (1) no pasture or plantation had more than 5% of the possible significant positive associations, (2) clustering metrics showed groups of species participating in similar clusters among the five pasture/plantations over a gradient of decreasing association strength, and (3) there was evidence for repeatable communities-especially after banana cultivation-suggesting that past crops not only persist after abandonment but also form significant associations with invading plants. I then showed how the clustering hierarchy could be used to decide if any two pasture/plantation plots were in the same community, that is, to define old field communities. Finally, I suggested a similar procedure could be used for any plant community where the mechanisms and tolerances of species form the "cohesion" that produces clustering, making plant communities different than random assemblages of species. PMID- 22536138 TI - Possible therapeutic use of spermatogonial stem cells in the treatment of male infertility: a brief overview. AB - Development of germ cells is a process starting in fetus and completed only in puberty. Spermatogonial stem cells maintain spermatogenesis throughout the reproductive life of mammals. They are undifferentiated cells defined by their ability to both self-renew and differentiate into mature spermatozoa. This self renewal and differentiation in turn is tightly regulated by a combination of intrinsic gene expression as well as the extrinsic gene signals from the local tissue microenvironment. The human testis is prone to damage, either for therapeutic reasons or because of toxic agents from the environment. For preservation of fertility, patients who will undergo radiotherapy and/or chemotherapy have an attractive possibility to keep in store and afterwards make a transfer of spermatogonial stem cells. Germ cell transplantation is not yet ready for the human fertility clinic, but it may be reasonable for young cancer patients, with no other options to preserve their fertility. Whereas this technique has become an important research tool in rodents, a clinical application must still be regarded as experimental, and many aspects of the procedure need to be optimized prior to a clinical application in men. In future, a range of options for the preservation of male fertility will get a new significance. PMID- 22536139 TI - Variation of biophysical parameters of the skin with age, gender, and body region. AB - BACKGROUND: Understanding the physiological, chemical, and biophysical characteristics of the skin helps us to arrange a proper approach to the management of skin diseases. OBJECTIVE: The aim of this study was to measure 6 biophysical characteristics of normal skin (sebum content, hydration, transepidermal water loss (TEWL), erythema index, melanin index, and elasticity) in a normal population and assess the effect of sex, age, and body location on them. METHODS: Fifty healthy volunteers in 5 age groups (5 males and females in each) were enrolled in this study. A multifunctional skin physiology monitor (Courage & Khazaka electronic GmbH, Germany) was used to measure skin sebum content, hydration, TEWL, erythema index, melanin index, and elasticity in 8 different locations of the body. RESULTS: There were significant differences between the hydration, melanin index, and elasticity of different age groups. Regarding the locations, forehead had the highest melanin index, where as palm had the lowest value. The mean values of erythema index and melanin index and TEWL were significantly higher in males and anatomic location was a significant independent factor for all of 6 measured parameters. CONCLUSION: Several biophysical properties of the skin vary among different gender, age groups, and body locations. PMID- 22536141 TI - Postcraniotomy function of the temporal muscle in skull base surgery: technical note based on a preliminary study. AB - PURPOSE: Patients undergoing craniotomies necessitating preparation of the temporal muscle (TM) may experience postoperative functional impairment of the temporomandibular joint. This topic has not been thoroughly discussed in the literature so far. In the present study, the authors propose a questionnaire as an evaluation tool to assess to what degree different TM preparation techniques correlate with postoperative temporomandibular joint dysfunction. MATERIALS AND METHODS: Between 2004 and 2006, 286 patients underwent either pterional or temporal craniotomies in the department of craniotomies at the University of Munster in Germany. Intraoperatively the TM was prepared either interfascial, submuscular, or subfascial. A patient-based questionnaire was designed and validated (Kendalls-tau = +1) in order to evaluate the patients' postoperative temporomandibular functional outcome. Based on strict inclusion/exclusion criteria, 69 patients were eligible for the application of the questionnaire in this preliminary study. RESULTS: Seventeen percent of the patients complained of either temporomandibular joint pain (3%) or restricted mouth opening (13%) postoperatively in a follow-up period between 3 and 12 months. In 92% postoperative complaints were reported within the first 3 months and in 58% of the patients with complaints the pain eased off. In 34% a therapy was required for the pain to be controlled. In one patient (8%) a postoperative arthroscopy has been necessary. Of the patients who experienced postoperative complaints, 67% had undergone temporal and 33% pterional craniotomy. In the group where postoperatively there were issues of temporomandibular pain/dysfunction, 42% had had the TM dissected, in 25% incised, and in 8% transected. For 25% of the patients, the type of intraoperative manipulation remained unknown. CONCLUSION: For postoperative quality control, the questionnaire showed to be a suitable evaluation tool. Concerning the different preparation techniques, subfascial preparation of the TM tends to result in less postoperative complaints and is thus recommended. PMID- 22536140 TI - Technological progress in generation of induced pluripotent stem cells for clinical applications. AB - Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) is achieved by viral-mediated transduction of defined transcription factors. Generation of iPSCs is of great medical interest as they have the potential to be a source of patient-specific cells. For the eventual goal of clinical application, it is necessary to overcome the limitations of low reprogramming efficiency and chromosomal abnormalities due to viral DNA integration. In this paper, we summarize the current state of reprogramming technology for generation of iPSCs and also discuss potential approaches to the development of safe iPSCs for personalized cell-based replacement therapy. PMID- 22536142 TI - Bacterial infections, DNA virus infections, and RNA virus infections manifest differently in neutrophil receptor expression. AB - Treating viral illnesses or noninfective causes of inflammation with antibiotics is ineffective and contributes to the development of antibiotic resistance, toxicity, and allergic reactions, leading to increasing medical costs. A major factor behind unnecessary use of antibiotics is, of course, incorrect diagnosis. For this reason, timely and accurate information on whether the infection is bacterial in origin would be highly beneficial. In this paper we will present our recent studies on the expression of opsonin receptors on phagocytes. The analysis of the expression levels of FcgammaRI, CR1, and CR3, along with CRP and ESR data, provides a novel application to the diagnosis of infectious and inflammatory diseases. The best clinical benefit will be obtained when the individual variables are combined to generate the CIS point method for a bacterial infection marker, DNAVS point for differentiating between DNA and RNA virus infections, and CRP/CD11b ratio for a marker of Gram-positive sepsis. PMID- 22536143 TI - Psychoeducational characteristics of children with hypohidrotic ectodermal dysplasia. AB - OBJECTIVE: Hypohidrotic ectodermal dysplasia (HED) is an X-linked hereditary disorder characterized by hypohidrosis, hypotrichosis, and anomalous dentition. Estimates of up to 50% of affected children having intellectual disability are controversial. METHOD: In a cross-sectional study, 45 youth with HED (77% males, mean age 9.75 years) and 59 matched unaffected controls (70% males, mean age 9.79 years) were administered the Kaufman Brief Intelligence Test and the Kaufman Test of Educational Achievement, and their parents completed standardized neurodevelopmental and behavioral measures, educational, and health-related information regarding their child, as well as standardized and nonstandardized data regarding socioeconomic information for their family. RESULTS: There were no statistically significant differences between the two groups in intelligence quotient composite and educational achievement scores, suggesting absence of learning disability in either group. No gender differences within or between groups were found on any performance measures. Among affected youth, parental education level correlated positively with (1) cognitive vocabulary scores and cognitive composite scores; (2) educational achievement for mathematics, reading, and composite scores. CONCLUSION: Youth affected with HED and unaffected matched peers have similar profiles on standardized measures of cognition, educational achievement, and adaptive functioning although children with HED may be at increased risk for ADHD. PMID- 22536144 TI - Enhanced MRI and MRI-guided interventional procedures in women with asymptomatic silicone-injected breasts. AB - Asymptomatic women who have received silicone injection for breast augmentation have a risk of underestimating breast cancer by palpation, mammography, or breast sonography. Enhanced breast MRI is sensitive to display certain nonspecific enhanced lesions or suspicious lesions. Such nonspecific MRI-detected lesions could be managed by American College Radiology BI-RADS lexicon and selectively with MRI-guided techniques biopsy to prevent unnecessary surgery. PMID- 22536145 TI - Characterization of the antibiotic compound no. 70 produced by Streptomyces sp. IMV-70. AB - We describe the actinomycete strain IMV-70 isolated from the soils of Kazakhstan, which produces potent antibiotics with high levels of antibacterial activity. After the research of its morphological, chemotaxonomic, and cultural characteristics, the strain with potential to be developed further as a novel class of antibiotics with chemotherapeutics potential was identified as Streptomyces sp. IMV-70. In the process of fermentation, the strain Streptomyces spp. IMV-70 produces the antibiotic no. 70, which was isolated from the culture broth by extraction with organic solvents. Antibiotic compound no. 70 was purified and separated into individual components by HPLC, TLC, and column chromatography methods. The main component of the compound is the antibiotic 70 A, which was found to be identical to the peptolide etamycin A. Two other antibiotics 70-B and 70-C have never been described and therefore are new antibiotics. The physical-chemical and biological characteristics of these preparations were described and further researched. Determination of the optimal growth conditions to cultivate actinomycete-producer strain IMV-70 and development of methods to isolate, purify, and accumulate preparations of the new antibiotic no. 70 enable us to research further the potential of this new class of antibiotics. PMID- 22536146 TI - Ranging patterns of critically endangered colobine, Presbytis chrysomelas chrysomelas. AB - Presbytis chrysomelas chrysomelas endemic only in Sarawak and Kalimantan was categorized by IUCN as a critically endangered primate that require special attention from research and conservation perspectives. A qualitative study on ranging patterns of P. c. chrysomelas was conducted in the Samunsam Wildlife Sanctuary, Sarawak. The study was conducted over a period of 13 months from December 2004 to December 2005 with 213 days of observation. Behavioural observation covered 17 groups with special emphasis on two main groups and 1 subadult group. Scanning and focal sampling were employed as the observation methods. Results indicated that P. c. chrysomelas had vertical, straight horizontal, and cross-horizontal types of movement patterns. P. c. chrysomelas was recorded to have a short movement distance (31.8-54.3 m). Distribution, abundance types, and food resources might be the factors that shaped the patterns of movement and distance in P. c. chrysomelas. PMID- 22536147 TI - Effects of CO(2) enrichment on growth and development of Impatiens hawkeri. AB - The effects of CO(2) enrichment on growth and development of Impatiens hawkeri, an important greenhouse flower, were investigated for the purpose of providing scientific basis for CO(2) enrichment to this species in greenhouse. The plants were grown in CO(2)-controlled growth chambers with 380 (the control) and 760 (CO(2) enrichment) MUmol . mol(-1), respectively. The changes in morphology, physiology, biochemistry, and leaf ultrastructure of Impatiens were examined. Results showed that CO(2) enrichment increased flower number and relative leaf area compared with the control. In addition, CO(2) enrichment significantly enhanced photosynthetic rate, contents of soluble sugars and starch, activities of peroxidase (POD), superoxide dismutase (SOD), and ascorbate peroxidase (APX), but reduced chlorophyll content and malondialdehyde (MDA) content. Furthermore, significant changes in chloroplast ultrastructure were observed at CO(2) enrichment: an increased number of starch grains with an expanded size, and an increased ratio of stroma thylakoid to grana thylakoid. These results suggest that CO(2) enrichment had positive effects on Impatiens, that is, it can improve the visual value, promote growth and development, and enhance antioxidant capacity. PMID- 22536148 TI - Uranium in the surrounding of San Marcos-Sacramento River environment (Chihuahua, Mexico). AB - The main interest of this study is to assess whether uranium deposits located in the San Marcos outcrops (NW of Chihuahua City, Mexico) could be considered as a source of U-isotopes in its surrounding environment. Uranium activity concentrations were determined in biota, ground, and surface water by either alpha or liquid scintillation spectrometries. Major ions were analyzed by ICP-OES in surface water and its suspended matter. For determining uranium activity in biota, samples were divided in parts. The results have shown a possible lixiviation and infiltration of uranium from geological substrate into the ground and surface water, and consequently, a transfer to biota. Calculated annual effective doses by ingestion suggest that U-isotopes in biota could not negligibly contribute to the neighboring population dose. By all these considerations, it is concluded that in this zone there is natural enhancement of uranium in all environmental samples analyzed in the present work. PMID- 22536149 TI - Zinc oxide nanoparticles catalyzed condensation reaction of isocoumarins and 1,7 heptadiamine in the formation of bis-isoquinolinones. AB - The diversified bis-isoquinolinones were obtained in two steps, utilizing homophthalic acid and various acid chlorides providing 3-substituted isocoumarins in the first step which on further condensation with 1,7-heptadiamine involving C N bond formation from the lactone in the presence of 10 mol% zinc oxide nanoparticles (ZnO NPs) (<150 nm) afforded the desired bis-isoquinolinones in high yield and purity. The synthesized compounds were then characterized using FTIR, (1)H NMR, (13)C NMR, and HRMS techniques. PMID- 22536150 TI - The emergence and early evolution of biological carbon-fixation. AB - The fixation of CO2 into living matter sustains all life on Earth, and embeds the biosphere within geochemistry. The six known chemical pathways used by extant organisms for this function are recognized to have overlaps, but their evolution is incompletely understood. Here we reconstruct the complete early evolutionary history of biological carbon-fixation, relating all modern pathways to a single ancestral form. We find that innovations in carbon-fixation were the foundation for most major early divergences in the tree of life. These findings are based on a novel method that fully integrates metabolic and phylogenetic constraints. Comparing gene-profiles across the metabolic cores of deep-branching organisms and requiring that they are capable of synthesizing all their biomass components leads to the surprising conclusion that the most common form for deep-branching autotrophic carbon-fixation combines two disconnected sub-networks, each supplying carbon to distinct biomass components. One of these is a linear folate based pathway of CO2 reduction previously only recognized as a fixation route in the complete Wood-Ljungdahl pathway, but which more generally may exclude the final step of synthesizing acetyl-CoA. Using metabolic constraints we then reconstruct a "phylometabolic" tree with a high degree of parsimony that traces the evolution of complete carbon-fixation pathways, and has a clear structure down to the root. This tree requires few instances of lateral gene transfer or convergence, and instead suggests a simple evolutionary dynamic in which all divergences have primary environmental causes. Energy optimization and oxygen toxicity are the two strongest forces of selection. The root of this tree combines the reductive citric acid cycle and the Wood-Ljungdahl pathway into a single connected network. This linked network lacks the selective optimization of modern fixation pathways but its redundancy leads to a more robust topology, making it more plausible than any modern pathway as a primitive universal ancestral form. PMID- 22536151 TI - The effects of NMDA subunit composition on calcium influx and spike timing dependent plasticity in striatal medium spiny neurons. AB - Calcium through NMDA receptors (NMDARs) is necessary for the long-term potentiation (LTP) of synaptic strength; however, NMDARs differ in several properties that can influence the amount of calcium influx into the spine. These properties, such as sensitivity to magnesium block and conductance decay kinetics, change the receptor's response to spike timing dependent plasticity (STDP) protocols, and thereby shape synaptic integration and information processing. This study investigates the role of GluN2 subunit differences on spine calcium concentration during several STDP protocols in a model of a striatal medium spiny projection neuron (MSPN). The multi-compartment, multi channel model exhibits firing frequency, spike width, and latency to first spike similar to current clamp data from mouse dorsal striatum MSPN. We find that NMDAR mediated calcium is dependent on GluN2 subunit type, action potential timing, duration of somatic depolarization, and number of action potentials. Furthermore, the model demonstrates that in MSPNs, GluN2A and GluN2B control which STDP intervals allow for substantial calcium elevation in spines. The model predicts that blocking GluN2B subunits would modulate the range of intervals that cause long term potentiation. We confirmed this prediction experimentally, demonstrating that blocking GluN2B in the striatum, narrows the range of STDP intervals that cause long term potentiation. This ability of the GluN2 subunit to modulate the shape of the STDP curve could underlie the role that GluN2 subunits play in learning and development. PMID- 22536152 TI - Loss of anti-viral immunity by infection with a virus encoding a cross-reactive pathogenic epitope. AB - T cell cross-reactivity between different strains of the same virus, between different members of the same virus group, and even between unrelated viruses is a common occurrence. We questioned here how an intervening infection with a virus containing a sub-dominant cross-reactive T cell epitope would affect protective immunity to a previously encountered virus. Pichinde virus (PV) and lymphocytic choriomeningitis virus (LCMV) encode subdominant cross-reactive NP205-212 CD8 T cell epitopes sharing 6 of 8 amino acids, differing only in the MHC anchoring regions. These pMHC epitopes induce cross-reactive but non-identical T cell receptor (TCR) repertoires, and structural studies showed that the differing anchoring amino acids altered the conformation of the MHC landscape presented to the TCR. PV-immune mice receiving an intervening infection with wild type but not NP205-mutant LCMV developed severe immunopathology in the form of acute fatty necrosis on re-challenge with PV, and this pathology could be predicted by the ratio of NP205-specific to the normally immunodominant PV NP38-45-specific T cells. Thus, cross-reactive epitopes can exert pathogenic properties that compromise protective immunity by impairing more protective T cell responses. PMID- 22536153 TI - CLEC5A regulates Japanese encephalitis virus-induced neuroinflammation and lethality. AB - CLEC5A/MDL-1, a member of the myeloid C-type lectin family expressed on macrophages and neutrophils, is critical for dengue virus (DV)-induced hemorrhagic fever and shock syndrome in Stat1-/- mice and ConA-treated wild type mice. However, whether CLEC5A is involved in the pathogenesis of viral encephalitis has not yet been investigated. To investigate the role of CLEC5A to regulate JEV-induced neuroinflammation, antagonistic anti-CLEC5A mAb and CLEC5A deficient mice were generated. We find that Japanese encephalitis virus (JEV) directly interacts with CLEC5A and induces DAP12 phosphorylation in macrophages. In addition, JEV activates macrophages to secrete proinflammatory cytokines and chemokines, which are dramatically reduced in JEV-infected Clec5a-/- macrophages. Although blockade of CLEC5A cannot inhibit JEV infection of neurons and astrocytes, anti-CLEC5A mAb inhibits JEV-induced proinflammatory cytokine release from microglia and prevents bystander damage to neuronal cells. Moreover, JEV causes blood-brain barrier (BBB) disintegrity and lethality in STAT1-deficient (Stat1-/-) mice, whereas peripheral administration of anti-CLEC5A mAb reduces infiltration of virus-harboring leukocytes into the central nervous system (CNS), restores BBB integrity, attenuates neuroinflammation, and protects mice from JEV induced lethality. Moreover, all surviving mice develop protective humoral and cellular immunity against JEV infection. These observations demonstrate the critical role of CLEC5A in the pathogenesis of Japanese encephalitis, and identify CLEC5A as a target for the development of new treatments to reduce virus induced brain damage. PMID- 22536154 TI - Entry of human papillomavirus type 16 by actin-dependent, clathrin- and lipid raft-independent endocytosis. AB - Infectious endocytosis of incoming human papillomavirus type 16 (HPV-16), the main etiological agent of cervical cancer, is poorly characterized in terms of cellular requirements and pathways. Conflicting reports attribute HPV-16 entry to clathrin-dependent and -independent mechanisms. To comprehensively describe the cell biological features of HPV-16 entry into human epithelial cells, we compared HPV-16 pseudovirion (PsV) infection in the context of cell perturbations (drug inhibition, siRNA silencing, overexpression of dominant mutants) to five other viruses (influenza A virus, Semliki Forest virus, simian virus 40, vesicular stomatitis virus, and vaccinia virus) with defined endocytic requirements. Our analysis included infection data, i.e. GFP expression after plasmid delivery by HPV-16 PsV, and endocytosis assays in combination with electron, immunofluorescence, and video microscopy. The results indicated that HPV-16 entry into HeLa and HaCaT cells was clathrin-, caveolin-, cholesterol- and dynamin independent. The virus made use of a potentially novel ligand-induced endocytic pathway related to macropinocytosis. This pathway was distinct from classical macropinocytosis in regards to vesicle size, cholesterol-sensitivity, and GTPase requirements, but similar in respect to the need for tyrosine kinase signaling, actin dynamics, Na+/H+ exchangers, PAK-1 and PKC. After internalization the virus was transported to late endosomes and/or endolysosomes, and activated through exposure to low pH. PMID- 22536155 TI - Proteolytic processing of Nlrp1b is required for inflammasome activity. AB - Nlrp1b is a NOD-like receptor that detects the catalytic activity of anthrax lethal toxin and subsequently co-oligomerizes into a pro-caspase-1 activation platform known as an inflammasome. Nlrp1b has two domains that promote oligomerization: a NACHT domain, which is a member of the AAA+ ATPase family, and a poorly characterized Function to Find Domain (FIIND). Here we demonstrate that proteolytic processing within the FIIND generates N-terminal and C-terminal cleavage products of Nlrp1b that remain associated in both the auto-inhibited state and in the activated state after cells have been treated with lethal toxin. Functional significance of cleavage was suggested by the finding that mutations that block processing of Nlrp1b also prevent the ability of Nlrp1b to activate pro-caspase-1. By using an uncleaved mutant of Nlrp1b, we established the importance of cleavage by inserting a heterologous TEV protease site into the FIIND and demonstrating that TEV protease processed this site and induced inflammasome activity. Proteolysis of Nlrp1b was shown to be required for the assembly of a functional inflammasome: a mutation within the FIIND that abolished cleavage had no effect on self-association of a FIIND-CARD fragment, but did reduce the recruitment of pro-caspase-1. Our work indicates that a post translational modification enables Nlrp1b to function. PMID- 22536156 TI - Epstein-Barr virus LMP2A reduces hyperactivation induced by LMP1 to restore normal B cell phenotype in transgenic mice. AB - Epstein-Barr virus (EBV) latently infects most of the human population and is strongly associated with lymphoproliferative disorders. EBV encodes several latency proteins affecting B cell proliferation and survival, including latent membrane protein 2A (LMP2A) and the EBV oncoprotein LMP1. LMP1 and LMP2A signaling mimics CD40 and BCR signaling, respectively, and has been proposed to alter B cell functions including the ability of latently-infected B cells to access and transit the germinal center. In addition, several studies suggested a role for LMP2A modulation of LMP1 signaling in cell lines by alteration of TRAFs, signaling molecules used by LMP1. In this study, we investigated whether LMP1 and LMP2A co-expression in a transgenic mouse model alters B cell maturation and the response to antigen, and whether LMP2A modulates LMP1 function. Naive LMP1/2A mice had similar lymphocyte populations and antibody production by flow cytometry and ELISA compared to controls. In the response to antigen, LMP2A expression in LMP1/2A animals rescued the impairment in germinal center generation promoted by LMP1. LMP1/2A animals produced high-affinity, class-switched antibody and plasma cells at levels similar to controls. In vitro, LMP1 upregulated activation markers and promoted B cell hyperproliferation, and co-expression of LMP2A restored a wild-type phenotype. By RT-PCR and immunoblot, LMP1 B cells demonstrated TRAF2 levels four-fold higher than non-transgenic controls, and co expression of LMP2A restored TRAF2 levels to wild-type levels. No difference in TRAF3 levels was detected. While modulation of other TRAF family members remains to be assessed, normalization of the LMP1-induced B cell phenotype through LMP2A modulation of TRAF2 may be a pathway by which LMP2A controls B cell function. These findings identify an advance in the understanding of how Epstein-Barr virus can access the germinal center in vivo, a site critical for both the genesis of immunological memory and of virus-associated tumors. PMID- 22536157 TI - A GATA transcription factor recruits Hda1 in response to reduced Tor1 signaling to establish a hyphal chromatin state in Candida albicans. AB - Candida albicans is an important opportunistic fungal pathogen of immunocompromised individuals. One critical virulence attribute is its morphogenetic plasticity. Hyphal development requires two temporally linked changes in promoter chromatin, which is sequentially regulated by temporarily clearing the transcription inhibitor Nrg1 upon activation of the cAMP/PKA pathway and promoter recruitment of the histone deacetylase Hda1 under reduced Tor1 signaling. Molecular mechanisms for the temporal connection and the link to Tor1 signaling are not clear. Here, through a forward genetic screen, we report the identification of the GATA family transcription factor Brg1 as the factor that recruits Hda1 to promoters of hypha-specific genes during hyphal elongation. BRG1 expression requires both the removal of Nrg1 and a sub-growth inhibitory level of rapamycin; therefore, it is a sensitive readout of Tor1 signaling. Interestingly, promoters of hypha-specific genes are not accessible to Brg1 in yeast cells. Furthermore, ectopic expression of Brg1 cannot induce hyphae, but can sustain hyphal development. Nucleosome mapping of a hypha-specific promoter shows that Nrg1 binding sites are in nucleosome free regions in yeast cells, whereas Brg1 binding sites are occupied by nucleosomes. Nucleosome disassembly during hyphal initiation exposes the binding sites for both regulators. During hyphal elongation, Brg1-mediated Hda1 recruitment causes nucleosome repositioning and occlusion of Nrg1 binding sites. We suggest that nucleosome repositioning is the underlying mechanism for the yeast-hyphal transition. The hypha-specific regulator Ume6 is a key downstream target of Brg1 and functions after Brg1 as a built-in positive feedback regulator of the hyphal transcriptional program to sustain hyphal development. With the levels of Nrg1 and Brg1 dynamically and sensitively controlled by the two major cellular growth pathways, temporal changes in nucleosome positioning during the yeast-to-hypha transition provide a mechanism for signal integration and cell fate specification. This mechanism is likely used broadly in development. PMID- 22536158 TI - PIWI associated siRNAs and piRNAs specifically require the Caenorhabditis elegans HEN1 ortholog henn-1. AB - Small RNAs--including piRNAs, miRNAs, and endogenous siRNAs--bind Argonaute proteins to form RNA silencing complexes that target coding genes, transposons, and aberrant RNAs. To assess the requirements for endogenous siRNA formation and activity in Caenorhabditis elegans, we developed a GFP-based sensor for the endogenous siRNA 22G siR-1, one of a set of abundant siRNAs processed from a precursor RNA mapping to the X chromosome, the X-cluster. Silencing of the sensor is also dependent on the partially complementary, unlinked 26G siR-O7 siRNA. We show that 26G siR-O7 acts in trans to initiate 22G siRNA formation from the X cluster. The presence of several mispairs between 26G siR-O7 and the X-cluster mRNA, as well as mutagenesis of the siRNA sensor, indicates that siRNA target recognition is permissive to a degree of mispairing. From a candidate reverse genetic screen, we identified several factors required for 22G siR-1 activity, including the chromatin factors mes-4 and gfl-1, the Argonaute ergo-1, and the 3' methyltransferase henn-1. Quantitative RT-PCR of small RNAs in a henn-1 mutant and deep sequencing of methylated small RNAs indicate that siRNAs and piRNAs that associate with PIWI clade Argonautes are methylated by HENN-1, while siRNAs and miRNAs that associate with non-PIWI clade Argonautes are not. Thus, PIWI-class Argonaute proteins are specifically adapted to associate with methylated small RNAs in C. elegans. PMID- 22536159 TI - Polyglutamine toxicity is controlled by prion composition and gene dosage in yeast. AB - Polyglutamine expansion causes diseases in humans and other mammals. One example is Huntington's disease. Fragments of human huntingtin protein having an expanded polyglutamine stretch form aggregates and cause cytotoxicity in yeast cells bearing endogenous QN-rich proteins in the aggregated (prion) form. Attachment of the proline(P)-rich region targets polyglutamines to the large perinuclear deposit (aggresome). Aggresome formation ameliorates polyglutamine cytotoxicity in cells containing only the prion form of Rnq1 protein. Here we show that expanded polyglutamines both with (poly-QP) or without (poly-Q) a P-rich stretch remain toxic in the presence of the prion form of translation termination (release) factor Sup35 (eRF3). A Sup35 derivative that lacks the QN-rich domain and is unable to be incorporated into aggregates counteracts cytotoxicity, suggesting that toxicity is due to Sup35 sequestration. Increase in the levels of another release factor, Sup45 (eRF1), due to either disomy by chromosome II containing the SUP45 gene or to introduction of the SUP45-bearing plasmid counteracts poly-Q or poly-QP toxicity in the presence of the Sup35 prion. Protein analysis confirms that polyglutamines alter aggregation patterns of Sup35 and promote aggregation of Sup45, while excess Sup45 counteracts these effects. Our data show that one and the same mode of polyglutamine aggregation could be cytoprotective or cytotoxic, depending on the composition of other aggregates in a eukaryotic cell, and demonstrate that other aggregates expand the range of proteins that are susceptible to sequestration by polyglutamines. PMID- 22536160 TI - A new role for translation initiation factor 2 in maintaining genome integrity. AB - Escherichia coli translation initiation factor 2 (IF2) performs the unexpected function of promoting transition from recombination to replication during bacteriophage Mu transposition in vitro, leading to initiation by replication restart proteins. This function has suggested a role of IF2 in engaging cellular restart mechanisms and regulating the maintenance of genome integrity. To examine the potential effect of IF2 on restart mechanisms, we characterized its influence on cellular recovery following DNA damage by methyl methanesulfonate (MMS) and UV damage. Mutations that prevent expression of full-length IF2-1 or truncated IF2-2 and IF2-3 isoforms affected cellular growth or recovery following DNA damage differently, influencing different restart mechanisms. A deletion mutant (del1) expressing only IF2-2/3 was severely sensitive to growth in the presence of DNA damaging agent MMS. Proficient as wild type in repairing DNA lesions and promoting replication restart upon removal of MMS, this mutant was nevertheless unable to sustain cell growth in the presence of MMS; however, growth in MMS could be partly restored by disruption of sulA, which encodes a cell division inhibitor induced during replication fork arrest. Moreover, such characteristics of del1 MMS sensitivity were shared by restart mutant priA300, which encodes a helicase-deficient restart protein. Epistasis analysis indicated that del1 in combination with priA300 had no further effects on cellular recovery from MMS and UV treatment; however, the del2/3 mutation, which allows expression of only IF2 1, synergistically increased UV sensitivity in combination with priA300. The results indicate that full-length IF2, in a function distinct from truncated forms, influences the engagement or activity of restart functions dependent on PriA helicase, allowing cellular growth when a DNA-damaging agent is present. PMID- 22536161 TI - The probability of a gene tree topology within a phylogenetic network with applications to hybridization detection. AB - Gene tree topologies have proven a powerful data source for various tasks, including species tree inference and species delimitation. Consequently, methods for computing probabilities of gene trees within species trees have been developed and widely used in probabilistic inference frameworks. All these methods assume an underlying multispecies coalescent model. However, when reticulate evolutionary events such as hybridization occur, these methods are inadequate, as they do not account for such events. Methods that account for both hybridization and deep coalescence in computing the probability of a gene tree topology currently exist for very limited cases. However, no such methods exist for general cases, owing primarily to the fact that it is currently unknown how to compute the probability of a gene tree topology within the branches of a phylogenetic network. Here we present a novel method for computing the probability of gene tree topologies on phylogenetic networks and demonstrate its application to the inference of hybridization in the presence of incomplete lineage sorting. We reanalyze a Saccharomyces species data set for which multiple analyses had converged on a species tree candidate. Using our method, though, we show that an evolutionary hypothesis involving hybridization in this group has better support than one of strict divergence. A similar reanalysis on a group of three Drosophila species shows that the data is consistent with hybridization. Further, using extensive simulation studies, we demonstrate the power of gene tree topologies at obtaining accurate estimates of branch lengths and hybridization probabilities of a given phylogenetic network. Finally, we discuss identifiability issues with detecting hybridization, particularly in cases that involve extinction or incomplete sampling of taxa. PMID- 22536162 TI - A coordinated interdependent protein circuitry stabilizes the kinetochore ensemble to protect CENP-A in the human pathogenic yeast Candida albicans. AB - Unlike most eukaryotes, a kinetochore is fully assembled early in the cell cycle in budding yeasts Saccharomyces cerevisiae and Candida albicans. These kinetochores are clustered together throughout the cell cycle. Kinetochore assembly on point centromeres of S. cerevisiae is considered to be a step-wise process that initiates with binding of inner kinetochore proteins on specific centromere DNA sequence motifs. In contrast, kinetochore formation in C. albicans, that carries regional centromeres of 3-5 kb long, has been shown to be a sequence independent but an epigenetically regulated event. In this study, we investigated the process of kinetochore assembly/disassembly in C. albicans. Localization dependence of various kinetochore proteins studied by confocal microscopy and chromatin immunoprecipitation (ChIP) assays revealed that assembly of a kinetochore is a highly coordinated and interdependent event. Partial depletion of an essential kinetochore protein affects integrity of the kinetochore cluster. Further protein depletion results in complete collapse of the kinetochore architecture. In addition, GFP-tagged kinetochore proteins confirmed similar time-dependent disintegration upon gradual depletion of an outer kinetochore protein (Dam1). The loss of integrity of a kinetochore formed on centromeric chromatin was demonstrated by reduced binding of CENP-A and CENP-C at the centromeres. Most strikingly, Western blot analysis revealed that gradual depletion of any of these essential kinetochore proteins results in concomitant reduction in cellular protein levels of CENP-A. We further demonstrated that centromere bound CENP-A is protected from the proteosomal mediated degradation. Based on these results, we propose that a coordinated interdependent circuitry of several evolutionarily conserved essential kinetochore proteins ensures integrity of a kinetochore formed on the foundation of CENP-A containing centromeric chromatin. PMID- 22536163 TI - A companion cell-dominant and developmentally regulated H3K4 demethylase controls flowering time in Arabidopsis via the repression of FLC expression. AB - Flowering time relies on the integration of intrinsic developmental cues and environmental signals. FLC and its downstream target FT are key players in the floral transition in Arabidopsis. Here, we characterized the expression pattern and function of JMJ18, a novel JmjC domain-containing histone H3K4 demethylase gene in Arabidopsis. JMJ18 was dominantly expressed in companion cells; its temporal expression pattern was negatively and positively correlated with that of FLC and FT, respectively, during vegetative development. Mutations in JMJ18 resulted in a weak late-flowering phenotype, while JMJ18 overexpressors exhibited an obvious early-flowering phenotype. JMJ18 displayed demethylase activity toward H3K4me3 and H3K4me2, and bound FLC chromatin directly. The levels of H3K4me3 and H3K4me2 in chromatins of FLC clade genes and the expression of FLC clade genes were reduced, whereas FT expression was induced and the protein expression of FT increased in JMJ18 overexpressor lines. The early-flowering phenotype caused by the overexpression of JMJ18 was mainly dependent on the functional FT. Our findings suggest that the companion cell-dominant and developmentally regulated JMJ18 binds directly to the FLC locus, reducing the level of H3K4 methylation in FLC chromatin and repressing the expression of FLC, thereby promoting the expression of FT in companion cells to stimulate flowering. PMID- 22536164 TI - Molecular Mechanisms Governing IL-24 Gene Expression. AB - Interleukin-24 (IL-24) belongs to the IL-10 family of cytokines and is well known for its tumor suppressor activity. This cytokine is released by both immune and nonimmune cells and acts on non-hematopoietic tissues such as skin, lung and reproductive tissues. Apart from its ubiquitous tumor suppressor function, IL-24 is also known to be involved in the immunopathology of autoimmune diseases like psoriasis and rheumatoid arthritis. Although the cellular sources and functions of IL-24 are being increasingly investigated, the molecular mechanisms of IL-24 gene expression at the levels of signal transduction, epigenetics and transcription factor binding are still unclear. Understanding the specific molecular events that regulate the production of IL-24 will help to answer the remaining questions that are important for the design of new strategies of immune intervention involving IL-24. Herein, we briefly review the signaling pathways and transcription factors that facilitate, induce, or repress production of this cytokine along with the cellular sources and functions of IL-24. PMID- 22536165 TI - Baculovirus-based Vaccine Displaying Respiratory Syncytial Virus Glycoprotein Induces Protective Immunity against RSV Infection without Vaccine-Enhanced Disease. AB - BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract diseases in infancy and early childhood. Despite its importance as a pathogen, there is no licensed vaccine against RSV yet. The attachment glycoprotein (G) of RSV is a potentially important target for protective antiviral immune responses. Recombinant baculovirus has been recently emerged as a new vaccine vector, since it has intrinsic immunostimulatory properties and good bio-safety profile. METHODS: We have constructed a recombinant baculovirus based RSV vaccine, Bac-RSV/G, displaying G glycoprotein, and evaluated immunogenicity and protective efficacy by intranasal immunization of BALB/c mice with Bac-RSV/G. RESULTS: Bac-RSV/G efficiently provides protective immunity against RSV challenge. Strong serum IgG and mucosal IgA responses were induced by intranasal immunization with Bac-RSV/G. In addition to humoral immunity, G specific Th17- as well as Th1-type T-cell responses were detected in the lungs of Bac-RSV/G-immune mice upon RSV challenge. Neither lung eosinophilia nor vaccine induced weight loss was observed upon Bac-RSV/G immunization and subsequent RSV infection. CONCLUSION: Our data demonstrate that intranasal administration of baculovirus-based Bac-RSV/G vaccine is efficient for the induction of protection against RSV and represents a promising prophylactic vaccination regimen. PMID- 22536166 TI - The analysis of vitamin C concentration in organs of gulo(-/-) mice upon vitamin C withdrawal. AB - BACKGROUND: Vitamin C is an essential nutrient for maintaining human life. Vitamin C insufficiency in the plasma is closely related with the development of scurvy. However, in vivo kinetics of vitamin C regarding its storage and consumption is still largely unknown. METHODS: We used Gulo(-/-) mice, which cannot synthesize vitamin C like human. Vitamin C level in plasma and organs from Gulo(-/-) mice was examined, and it compared with the level of wild-type mice during 5 weeks. RESULTS: The significant weight loss of Gulo(-/-) mice was shown at 3 weeks after vitamin C withdrawal. However, there was no differences between wild-type and vitamin C-supplemented Gulo(-/-) mice (3.3 g/L in drinking water). The concentration of vitamin C in plasma and organs was significantly decreased at 1 week after vitamin C withdrawal. Vitamin C is preferentially deposited in adrenal gland, lymph node, lung, and brain. There were no significant changes in the numbers and CD4/CD8 ratio of splenocytes in Gulo(-/-) mice with vitamin C withdrawal for 4 weeks. And the architecture of spleen in Gulo(-/-) mice was disrupted at 5 weeks after vitamin C withdrawal. CONCLUSION: The vitamin C level of Gulo(-/-) mice was considerably decreased from 1 week after vitamin C withdrawal. Vitamin C is preferentially stored in some organs such as brain, adrenal gland and lung. PMID- 22536167 TI - Newly Identified TLR9 Stimulant, M6-395 Is a Potent Polyclonal Activator for Murine B Cells. AB - BACKGROUND: Toll-like receptors (TLRs) have been extensively studied in recent years. However, functions of these molecules in murine B cell biology are largely unknown. A TLR4 stimulant, LPS is well known as a powerful polyclonal activator for murine B cells. METHODS: In this study, we explored the effect of a murine TLR9 stimulant, M6-395 (a synthetic CpG ODNs) on B cell proliferation and Ig production. RESULTS: First, M6-395 was much more potent than LPS in augmenting B cell proliferation. As for Ig expression, M6-395 facilitated the expression of both TGF-beta1-induced germ line transcript alpha (GLTalpha) and IL-4-induced GLTgamma1 as levels as those by LPS and Pam3CSK4 (TLR1/2 agonist) : a certain Ig GLT expression is regarded as an indicative of the corresponding isotype switching recombination. However, IgA and IgG1 secretion patterns were quite different--these Ig isotype secretions by M6-395 were much less than those by LPS and Pam3CSK4. Moreover, the increase of IgA and IgG1 production by LPS and Pam3CSK4 was virtually abrogated by M6-395. The same was true for the secretion of IgG3. We found that this unexpected phenomena provoked by M6-395 is attributed, at least in part, to its excessive mitogenic nature. CONCLUSION: Taken together, these results suggest that M6-395 can act as a murine polyclonal activator but its strong mitogenic activity is unfavorable to Ig isotype switching. PMID- 22536168 TI - Generation of 1E8 Single Chain Fv-Fc Construct Against Human CD59. AB - BACKGROUND: Therapeutic approaches using monoclonal antibodies (mAbs) against complement regulatory proteins (CRPs:i.e.,CD46,CD55 and CD59) have been reported for adjuvant cancer therapy. In this study, we generated a recombinant 1E8 single chain anti-CD59 antibody (scFv-Fc) and tested anti-cancer effect.by using complement dependent cytotoxicity (CDC). METHODS: We isolated mRNA from 1E8 hybridoma cells and amplified the variable regions of the heavy chain (VH) and light chain (VL) genes using reverse-transcriptase polymerase chain reaction (RT PCR). Using a linker, the amplified sequences for the heavy and light chains were each connected to the sequence for a single polypeptide chain that was designed to be expressed. The VL and VH fragments were cloned into the pOptiVEC-TOPO vector that contained the human CH2-CH3 fragment. Then, 293T cells were transfected with the 1E8 single-chain Fv-Fc (scFv-Fc) constructs. CD59 expression was evaluated in the prostate cancer cell lines using flow cytometry. The enhancement of CDC effect by mouse 1E8 and 1E8 scFv-Fc were evaluated using a cytotoxicity assay. RESULTS: The scFv-Fc constructs were expressed by the transfected 293T cells and secreted into the culture medium. The immunoreactivity of the secreted scFv-Fc construct was similar to that of the mouse 1E8 for CCRF CEM cells. The molecular masses of 1E8 scFv-Fc were about 120 kDa and 55 kDa under reducing and non-reducing conditions, respectively. The DNA sequence of 1E8 scFv-Fc was obtained and presented. CD59 was highly expressed by the prostate cancer cell line. The recombinant 1E8 scFv-Fc mAb revealed significantly enhanced CDC effect similar with mouse 1E8 for prostate cancer cells. CONCLUSION: A 1E8 scFv-Fc construct for adjuvant cancer therapy was developed. PMID- 22536169 TI - Digital reconstructions of neuronal morphology: three decades of research trends. AB - The importance of neuronal morphology has been recognized from the early days of neuroscience. Elucidating the functional roles of axonal and dendritic arbors in synaptic integration, signal transmission, network connectivity, and circuit dynamics requires quantitative analyses of digital three-dimensional reconstructions. We extensively searched the scientific literature for all original reports describing reconstructions of neuronal morphology since the advent of this technique three decades ago. From almost 50,000 titles, 30,000 abstracts, and more than 10,000 full-text articles, we identified 902 publications describing ~44,000 digital reconstructions. Reviewing the growth of this field exposed general research trends on specific animal species, brain regions, neuron types, and experimental approaches. The entire bibliography, annotated with relevant metadata and (wherever available) direct links to the underlying digital data, is accessible at NeuroMorpho.Org. PMID- 22536170 TI - Habenula circuit development: past, present, and future. AB - The habenular neural circuit is attracting increasing attention from researchers in fields as diverse as neuroscience, medicine, behavior, development, and evolution. Recent studies have revealed that this part of the limbic system in the dorsal diencephalon is involved in reward, addiction, and other behaviors and its impairment is associated with various neurological conditions and diseases. Since the initial description of the dorsal diencephalic conduction system (DDC) with the habenulae in its center at the end of the nineteenth century, increasingly sophisticated techniques have resolved much of its anatomy and have shown that these pathways relay information from different parts of the forebrain to the tegmentum, midbrain, and hindbrain. The first part of this review gives a brief historical overview on how the improving experimental approaches have allowed the stepwise uncovering much of the architecture of the habenula circuit as we know it today. Our brain distributes tasks differentially between left and right and it has become a paradigm that this functional lateralization is a universal feature of vertebrates. Moreover, task dependent differential brain activities have been linked to anatomical differences across the left-right axis in humans. A good way to further explore this fundamental issue will be to study the functional consequences of subtle changes in neural network formation, which requires that we fully understand DDC system development. As the habenular circuit is evolutionarily highly conserved, researchers have the option to perform such difficult experiments in more experimentally amenable vertebrate systems. Indeed, research in the last decade has shown that the zebrafish is well suited for the study of DDC system development and the phenomenon of functional lateralization. We will critically discuss the advantages of the zebrafish model, available techniques, and others that are needed to fully understand habenular circuit development. PMID- 22536171 TI - The neurobiology of decision-making and responsibility: reconciling mechanism and mindedness. AB - This essay reviews recent developments in neurobiology which are beginning to expose the mechanisms that underlie some elements of decision-making that bear on attributions of responsibility. These "elements" have been mainly studied in simple perceptual decision tasks, which are performed similarly by humans and non human primates. Here we consider the role of neural noise, and suggest that thinking about the role of noise can shift the focus of discussions of randomness in decision-making away from its role in enabling alternate possibilities and toward a potential grounding role for responsibility. PMID- 22536172 TI - GSK-3beta and memory formation. AB - In Alzheimer's disease (AD), tau hyperphosphorylation and neurofibrillary tangle (NFT) formation are strongly associated with dementia, a characteristic and early feature of this disease. Glycogen synthase kinase 3beta (GSK-3beta) is a pivotal kinase in both the normal and pathological phosphorylation of tau. In the diseased state, hyperphosphorylated tau is deposited in NFTs, the formation of which, drive the disease process. GSK-3beta which is also involved in long-term depression induction, interacts with tau to inhibit synaptic long-term potentiation. Strong lines of evidence suggest that the activation of GSK-3beta is responsible for the memory deficits seen in both advanced age and AD. In this review, we will focus on the role of GSK-3beta in brain function, particularly in memory maintenance. We will examine human and mouse studies which suggest a role for GSK-3beta in memory maintenance and the eventual development of memory deficits. PMID- 22536173 TI - Structure of metabotropic glutamate receptor C-terminal domains in contact with interacting proteins. AB - Metabotropic glutamate receptors (mGluRs) regulate intracellular signal pathways that control several physiological tasks, including neuronal excitability, learning, and memory. This is achieved by the formation of synaptic signal complexes, in which mGluRs assemble with functionally related proteins such as enzymes, scaffolds, and cytoskeletal anchor proteins. Thus, mGluR associated proteins actively participate in the regulation of glutamatergic neurotransmission. Importantly, dysfunction of mGluRs and interacting proteins may lead to impaired signal transduction and finally result in neurological disorders, e.g., night blindness, addiction, epilepsy, schizophrenia, autism spectrum disorders and Parkinson's disease. In contrast to solved crystal structures of extracellular N-terminal domains of some mGluR types, only a few studies analyzed the conformation of intracellular receptor domains. Intracellular C-termini of most mGluR types are subject to alternative splicing and can be further modified by phosphorylation and SUMOylation. In this way, diverse interaction sites for intracellular proteins that bind to and regulate the glutamate receptors are generated. Indeed, most of the known mGluR binding partners interact with the receptors' C-terminal domains. Within the last years, different laboratories analyzed the structure of these domains and described the geometry of the contact surface between mGluR C-termini and interacting proteins. Here, I will review recent progress in the structure characterization of mGluR C termini and provide an up-to-date summary of the geometry of these domains in contact with binding partners. PMID- 22536174 TI - Absence of the calcium-binding protein calretinin, not of calbindin D-28k, causes a permanent impairment of murine adult hippocampal neurogenesis. AB - Calretinin (CR) and calbindin D-28k (CB) are cytosolic EF-hand Ca(2+)-binding proteins and function as Ca(2+) buffers affecting the spatiotemporal aspects of Ca(2+) transients and possibly also as Ca(2+) sensors modulating signaling cascades. In the adult hippocampal circuitry, CR and CB are expressed in specific principal neurons and subsets of interneurons. In addition, CR is transiently expressed within the neurogenic dentate gyrus (DG) niche. CR and CB expression during adult neurogenesis mark critical transition stages, onset of differentiation for CR, and the switch to adult-like connectivity for CB. Absence of either protein during these stages in null-mutant mice may have functional consequences and contribute to some aspects of the identified phenotypes. We report the impact of CR- and CB-deficiency on the proliferation and differentiation of progenitor cells within the subgranular zone (SGZ) neurogenic niche of the DG. Effects were evaluated (1) two and four weeks postnatally, during the transition period of the proliferative matrix to the adult state, and (2) in adult animals (3 months) to trace possible permanent changes in adult neurogenesis. The absence of CB from differentiated DG granule cells has no retrograde effect on the proliferative activity of progenitor cells, nor affects survival or migration/differentiation of newborn neurons in the adult DG including the SGZ. On the contrary, lack of CR from immature early postmitotic granule cells causes an early loss in proliferative capacity of the SGZ that is maintained into adult age, when it has a further impact on the migration/survival of newborn granule cells. The transient CR expression at the onset of adult neurogenesis differentiation may thus have two functions: (1) to serve as a self maintenance signal for the pool of cells at the same stage of neurogenesis contributing to their survival/differentiation, and (2) it may contribute to retrograde signaling required for maintenance of the progenitor pool. PMID- 22536176 TI - "Connectomic surgery": diffusion tensor imaging (DTI) tractography as a targeting modality for surgical modulation of neural networks. AB - Deep brain stimulation (DBS) is being used to treat a growing number of neurological disorders. Until recently, DBS has been thought to act mainly by suppressing local neuronal activity, essentially producing a functional lesion. Numerous studies are now demonstrating that DBS has widespread network effects mediated by white matter pathways. The new science of connectomics aims to map the connectivity between brain regions in health and disease. Targeting DBS specifically to pathways which exhibit pathological connectivity could greatly expand the possibilities for treating brain diseases. This brief review examines the current state of brain imaging for visualization of these networks and describes how DBS might be used to restore normal connectivity in pathological states. PMID- 22536175 TI - Intrinsic electrophysiological properties of entorhinal cortex stellate cells and their contribution to grid cell firing fields. AB - The medial entorhinal cortex (MEC) is an increasingly important focus for investigation of mechanisms for spatial representation. Grid cells found in layer II of the MEC are likely to be stellate cells, which form a major projection to the dentate gyrus. Entorhinal stellate cells are distinguished by distinct intrinsic electrophysiological properties, but how these properties contribute to representation of space is not yet clear. Here, we review the ionic conductances, synaptic, and excitable properties of stellate cells, and examine their implications for models of grid firing fields. We discuss why existing data are inconsistent with models of grid fields that require stellate cells to generate periodic oscillations. An alternative possibility is that the intrinsic electrophysiological properties of stellate cells are tuned specifically to control integration of synaptic input. We highlight recent evidence that the dorsal-ventral organization of synaptic integration by stellate cells, through differences in currents mediated by HCN and leak potassium channels, influences the corresponding organization of grid fields. Because accurate cellular data will be important for distinguishing mechanisms for generation of grid fields, we introduce new data comparing properties measured with whole-cell and perforated patch-clamp recordings. We find that clustered patterns of action potential firing and the action potential after-hyperpolarization (AHP) are particularly sensitive to recording condition. Nevertheless, with both methods, these properties, resting membrane properties and resonance follow a dorsal-ventral organization. Further investigation of the molecular basis for synaptic integration by stellate cells will be important for understanding mechanisms for generation of grid fields. PMID- 22536178 TI - Transformative art: art as means for long-term neurocognitive change. AB - Every artwork leads to a unique experience by the observer or participant, may it be sensory, emotional, cognitive, interactive, or spiritual experience. At the neurobiological level, such experiences are manifested as activation of the corresponding neural networks. Neuroscience has demonstrated that experience, in particular repeated experience, can cause a long-term change in the involved brain circuits (experience-dependent plasticity). This review will discuss the molding and transformative aspect of arts, examining how repeated and on-going experience of arts may alter cognitive, emotional, and behavioral patterns as well as their underlying neural circuits. The application of this approach to cognitive training and neuropsychological rehabilitation methods will be addressed as well. In addition, it will be suggested that this approach to art, as a long-term transformative medium, may lead to a novel viewpoint on art and a different approach to its creation. Artists can design artworks that aspire to form, in addition to one-shot influencing experience, on-going experiences which gradually create a lasting change, possibly improving audiences' neuropsychological functions. PMID- 22536177 TI - Automatic motor activation in the executive control of action. AB - Although executive control and automatic behavior have often been considered separate and distinct processes, there is strong emerging and convergent evidence that they may in fact be intricately interlinked. In this review, we draw together evidence showing that visual stimuli cause automatic and unconscious motor activation, and how this in turn has implications for executive control. We discuss object affordances, alien limb syndrome, the visual grasp reflex, subliminal priming, and subliminal triggering of attentional orienting. Consideration of these findings suggests automatic motor activation might form an intrinsic part of all behavior, rather than being categorically different from voluntary actions. PMID- 22536179 TI - Error-preceding brain activity reflects (mal-)adaptive adjustments of cognitive control: a modeling study. AB - Errors in choice tasks are preceded by gradual changes in brain activity presumably related to fluctuations in cognitive control that promote the occurrence of errors. In the present paper, we use connectionist modeling to explore the hypothesis that these fluctuations reflect (mal-)adaptive adjustments of cognitive control. We considered ERP data from a study in which the probability of conflict in an Eriksen-flanker task was manipulated in sub-blocks of trials. Errors in these data were preceded by a gradual decline of N2 amplitude. After fitting a connectionist model of conflict adaptation to the data, we analyzed simulated N2 amplitude, simulated response times (RTs), and stimulus history preceding errors in the model, and found that the model produced the same pattern as obtained in the empirical data. Moreover, this pattern is not found in alternative models in which cognitive control varies randomly or in an oscillating manner. Our simulations suggest that the decline of N2 amplitude preceding errors reflects an increasing adaptation of cognitive control to specific task demands, which leads to an error when these task demands change. Taken together, these results provide evidence that error-preceding brain activity can reflect adaptive adjustments rather than unsystematic fluctuations of cognitive control, and therefore, that these errors are actually a consequence of the adaptiveness of human cognition. PMID- 22536180 TI - Letting the daylight in: Reviewing the reviewers and other ways to maximize transparency in science. AB - With the emergence of online publishing, opportunities to maximize transparency of scientific research have grown considerably. However, these possibilities are still only marginally used. We argue for the implementation of (1) peer-reviewed peer review, (2) transparent editorial hierarchies, and (3) online data publication. First, peer-reviewed peer review entails a community-wide review system in which reviews are published online and rated by peers. This ensures accountability of reviewers, thereby increasing academic quality of reviews. Second, reviewers who write many highly regarded reviews may move to higher editorial positions. Third, online publication of data ensures the possibility of independent verification of inferential claims in published papers. This counters statistical errors and overly positive reporting of statistical results. We illustrate the benefits of these strategies by discussing an example in which the classical publication system has gone awry, namely controversial IQ research. We argue that this case would have likely been avoided using more transparent publication practices. We argue that the proposed system leads to better reviews, meritocratic editorial hierarchies, and a higher degree of replicability of statistical analyses. PMID- 22536181 TI - Visual systems for interactive exploration and mining of large-scale neuroimaging data archives. AB - While technological advancements in neuroimaging scanner engineering have improved the efficiency of data acquisition, electronic data capture methods will likewise significantly expedite the populating of large-scale neuroimaging databases. As they do and these archives grow in size, a particular challenge lies in examining and interacting with the information that these resources contain through the development of compelling, user-driven approaches for data exploration and mining. In this article, we introduce the informatics visualization for neuroimaging (INVIZIAN) framework for the graphical rendering of, and dynamic interaction with the contents of large-scale neuroimaging data sets. We describe the rationale behind INVIZIAN, detail its development, and demonstrate its usage in examining a collection of over 900 T1-anatomical magnetic resonance imaging (MRI) image volumes from across a diverse set of clinical neuroimaging studies drawn from a leading neuroimaging database. Using a collection of cortical surface metrics and means for examining brain similarity, INVIZIAN graphically displays brain surfaces as points in a coordinate space and enables classification of clusters of neuroanatomically similar MRI images and data mining. As an initial step toward addressing the need for such user-friendly tools, INVIZIAN provides a highly unique means to interact with large quantities of electronic brain imaging archives in ways suitable for hypothesis generation and data mining. PMID- 22536182 TI - The importance of combining MRI and large-scale digital histology in neuroimaging studies of brain connectivity and disease. AB - One of the major issues hindering a comprehensive connectivity model for the human brain is the difficulty in linking Magnetic Resonance Imaging (MRI) measurements to anatomical evidence produced by histological methods. In vivo and postmortem neuroimaging methodologies are still largely incompatible in terms of sample size, scale, and resolution. To help bridge the hiatus between different approaches we have established a program that characterizes the brain of individual subjects, combining MRI with postmortem neuroanatomy. The direct correlation of MRI and histological features is possible, because registered images from different modalities represent the same regions in the same brain. Comparisons are also facilitated by large-scale, digital microscopy techniques that afford images of the whole-brain sections at cellular resolution. The goal is to create a neuroimaging catalog representative of discrete age groups and specific neurological conditions. Individually, the datasets allow for investigating the relationship between different modalities; combined, they provide sufficient predictive power to inform analyzes and interpretations made in the context of non-invasive studies of brain connectivity and disease. PMID- 22536183 TI - Human Tuberculous Meningitis Caused by Mycobacterium caprae. AB - INTRODUCTION: Tuberculous meningitis (TM) causes substantial morbidity and mortality in humans. Human TM has been known to be induced by bacteria from the Mycobacterium tuberculosis complex (MTBC), such as M. tuberculosis and M. bovis. CASE PRESENTATION: We describe a case of meningitis treated with fosfomycin, which showed partial effectiveness in an 80-year-old patient. After a lethal myocardial infarction, M. caprae (MC) was identified in cerebrospinal fluid culture. This isolated acid-fast organism was first identified as MTBC by MTBC specific PCR (16S rDNA-PCR). Furthermore, species-specific identification of the isolate was done by gyrB PCR-restriction fragment length polymorphism analysis of a part of gyrB DNA. Colony morphology of the isolated MC strain showed dysgonic growth on Lowenstein-Jensen medium. The strain was susceptible to pyrazinamide (PZA). CONCLUSION: This isolated strain was convincingly identified as MC according to the phenotypic and genotypic characteristics and PZA sensitivity. This is the first report of MC causing TM. PMID- 22536184 TI - Differences between Old and Young Adults' Ability to Recognize Human Faces Underlie Processing of Horizontal Information. AB - Recent psychophysical research supports the notion that horizontal information of a face is primarily important for facial identity processes. Even though this has been demonstrated to be valid for young adults, the concept of horizontal information as primary informative source has not yet been applied to older adults' ability to correctly identify faces. In the current paper, the role different filtering methods might play in an identity processing task is examined for young and old adults, both taken from student populations. Contrary to most findings in the field of developmental face perception, only a near-significant age effect is apparent in upright and un-manipulated presentation of stimuli, whereas a bigger difference between age groups can be observed for a condition which removes all but horizontal information of a face. It is concluded that a critical feature of human face perception, the preferential processing of horizontal information, is less efficient past the age of 60 and is involved in recognition processes that undergo age-related decline usually found in the literature. PMID- 22536186 TI - Editorial on special topic: sirtuins in metabolism, aging, and disease. PMID- 22536185 TI - The effects of age on cerebral activations: internally versus externally driven processes. AB - Numerous studies using functional magnetic resonance imaging (fMRI) have described increased or decreased regional brain activations in older as compared to younger adults. This seeming inconsistency may reflect differences in the psychological constructs examined across studies. We hypothesized that behavioral tasks/contrasts engaging internally and externally driven processes are each associated with age-related decreases and increases, respectively, in cerebral activations. We examined the fMRI data of 103 healthy adults, 18-72 years of age, performing a stop signal task (SST), in which a frequent "go" signal triggered a prepotent response and a less frequent "stop" signal prompted inhibition of this response. Greater internally driven processes lead to stop successes (SS) as compared to stop errors (SE), and to speeding up instead of slowing down in go trials. Conversely, externally driven processes contribute to SE trials, which resulted from habitual, unmonitored responses triggered by the go signal (as compared to SS trials), and involved perceptual and cognitive processes elicited by the stop signal (as compared to go trials). Consistent with our hypothesis, the results showed age-related decreases and increases in cerebral activations each during these respective internally and externally driven processes. These findings further elucidate the influence of age on cognitive functioning and provide an additional perspective to understand the imaging literature of aging. PMID- 22536187 TI - Arsenate Impact on the Metabolite Profile, Production, and Arsenic Loading of Xylem Sap in Cucumbers (Cucumis sativus L.). AB - Arsenic uptake and translocation studies on xylem sap focus generally on the concentration and speciation of arsenic in the xylem. Arsenic impact on the xylem sap metabolite profile and its production during short term exposure has not been reported in detail. To investigate this, cucumbers were grown hydroponically and arsenate (As(V)) and DMA were used for plant treatment for 24 h. Total arsenic and arsenic speciation in xylem sap was analyzed including a metabolite profiling under As(V) stress. Produced xylem sap was quantified and absolute arsenic transported was determined. As(V) exposure had a significant impact on the metabolite profile of xylem sap. Four m/z values corresponding to four compounds were up-regulated, one compound down-regulated by As(V) exposure. The compound down-regulated was identified to be isoleucine. Furthermore, As(V) exposure had a significant influence on sap production, leading to a reduction of up to 96% sap production when plants were exposed to 1000 MUg kg(-1) As(V). No difference to control plants was observed when plants were exposed to 1000 MUg kg(-1) DMA. Absolute arsenic amount in xylem sap was the lowest at high As(V) exposure. These results show that As(V) has a significant impact on the production and metabolite profile of xylem sap. The physiological importance of isoleucine needs further attention. PMID- 22536188 TI - Evaluation of 15 Local Plant Species as Larvicidal Agents Against an Indian Strain of Dengue Fever Mosquito, Aedes aegypti L. (Diptera: Culicidae). AB - The adverse effects of chemical insecticides-based intervention measures for the control of mosquito vectors have received wide public apprehension because of several problems like insecticide resistance, resurgence of pest species, environmental pollution, toxic hazards to humans, and non-target organisms. These problems have necessitated the need to explore and develop alternative strategies using eco-friendly, environmentally safe, bio-degradable plant products which are non-toxic to non-target organisms too. In view of this, 15 plant species were collected from local areas in New Delhi, India. Different parts of these plants were separated, dried, mechanically grinded, and sieved to get fine powder. The 200 g of each part was soaked in 1000 mL of different solvents separately and the crude extracts, thus formed, were concentrated using a vacuum evaporator at 45 degrees C under low pressure. Each extract was screened to explore its potential as a mosquito larvicidal agent against early fourth instars of dengue vector, Aedes aegypti using WHO protocol. The preliminary screening showed that only 10 plants possessed larvicidal potential as they could result in 100% mortality at 1000 ppm. Further evaluation of the potential larvicidal extracts established the hexane leaf extract of Lantana camara to be most effective extract exhibiting a significant LC(50) value of 30.71 ppm while the Phyllanthus emblica fruit extract was found to be least effective with an LC(50) value of 298.93 ppm. The extracts made from different parts of other five plants; Achyranthes aspera, Zingiber officinalis, Ricinus communis, Trachyspermum ammi, and Cassia occidentalis also possessed significant larvicidal potential with LC(50) values ranging from 55.0 to 74.67 ppm. Other three extracts showed moderate toxicity against A. aegypti larvae. Further investigations would be needed to isolate and identify the primary component responsible for the larvicidal efficiency of the effective plants. PMID- 22536189 TI - Nitric oxide synthases and atrial fibrillation. AB - Oxidative stress has been implicated in the pathogenesis of atrial fibrillation. There are multiple systems in the myocardium which contribute to redox homeostasis, and loss of homeostasis can result in oxidative stress. Potential sources of oxidants include nitric oxide synthases (NOS), which normally produce nitric oxide in the heart. Two NOS isoforms (1 and 3) are normally expressed in the heart. During pathologies such as heart failure, there is induction of NOS 2 in multiple cell types in the myocardium. In certain conditions, the NOS enzymes may become uncoupled, shifting from production of nitric oxide to superoxide anion, a potent free radical and oxidant. Multiple lines of evidence suggest a role for NOS in the pathogenesis of atrial fibrillation. Therapeutic approaches to reduce atrial fibrillation by modulation of NOS activity may be beneficial, although further investigation of this strategy is needed. PMID- 22536190 TI - Effects of peroxisomal catalase inhibition on mitochondrial function. AB - Peroxisomes produce hydrogen peroxide as a metabolic by-product of their many oxidase enzymes, but contain catalase that breaks down hydrogen peroxide in order to maintain the organelle's oxidative balance. It has been previously demonstrated that, as cells age, catalase is increasingly absent from the peroxisome, and resides instead as an unimported tetrameric molecule in the cell cytosol; an alteration that is coincident with increased cellular hydrogen peroxide levels. As this process begins in middle-passage cells, we sought to determine whether peroxisomal hydrogen peroxide could contribute to the oxidative damage observed in mitochondria in late-passage cells. Early-passage human fibroblasts (Hs27) treated with aminotriazole (3-AT), an irreversible catalase inhibitor, demonstrated decreased catalase activity, increased levels of cellular hydrogen peroxide, protein carbonyls, and peroxisomal numbers. This treatment increased mitochondrial reactive oxygen species levels, and decreased the mitochondrial aconitase activity by ~85% within 24 h. In addition, mitochondria from 3-AT treated cells show a decrease in inner membrane potential. These results demonstrate that peroxisome-derived oxidative imbalance may rapidly impair mitochondrial function, and considering that peroxisomal oxidative imbalance begins to occur in middle-passage cells, supports the hypothesis that peroxisomal oxidant release occurs upstream of, and contributes to, the mitochondrial damage observed in aging cells. PMID- 22536192 TI - Event-Related Theta Power during Lexical-Semantic Retrieval and Decision Conflict is Modulated by Alcohol Intoxication: Anatomically Constrained MEG. AB - Language processing is commonly characterized by an event-related increase in theta power (4-7 Hz) in scalp EEG. Oscillatory brain dynamics underlying alcohol's effects on language are poorly understood despite impairments on verbal tasks. To investigate how moderate alcohol intoxication modulates event-related theta activity during visual word processing, healthy social drinkers (N = 22, 11 females) participated in both alcohol (0.6 g/kg ethanol for men, 0.55 g/kg for women) and placebo conditions in a counterbalanced design. They performed a double-duty lexical decision task as they detected real words among non-words. An additional requirement to respond to all real words that also referred to animals induced response conflict. High density whole-head MEG signals and midline scalp EEG data were decomposed for each trial with Morlet wavelets. Each person's reconstructed cortical surface was used to constrain noise-normalized distributed minimum norm inverse solutions for theta frequencies. Alcohol intoxication increased reaction time and marginally affected accuracy. The overall spatio temporal pattern is consistent with the left-lateralized fronto-temporal activation observed in language studies applying time-domain analysis. Event related theta power was sensitive to the two functions manipulated by the task. First, theta estimated to the left-lateralized fronto-temporal areas reflected lexical-semantic retrieval, indicating that this measure is well suited for investigating the neural basis of language functions. While alcohol attenuated theta power overall, it was particularly deleterious to semantic retrieval since it reduced theta to real words but not pseudowords. Second, a highly overlapping prefrontal network comprising lateral prefrontal and anterior cingulate cortex was sensitive to decision conflict and was also affected by intoxication, in agreement with previous studies indicating that executive functions are especially vulnerable to alcohol intoxication. PMID- 22536193 TI - Genetics of frontotemporal lobar degeneration. AB - Frontotemporal lobar degeneration (FTLD), the most frequent neurodegenerative disorder with a presenile onset, presents with a spectrum of clinical manifestations, ranging from behavioral and executive impairment to language disorders and motor dysfunction. Familial aggregation is frequently reported, and about 10% of cases have an autosomal dominant transmission. Microtubule associated protein tau (MAPT) gene mutations have been the first ones identified and are associated with early onset behavioral variant frontotemporal dementia phenotype. More recently, progranulin gene (GRN) mutations were recognized in association with familial form of FTLD. In addition, other genes are linked to rare cases of familial FTLD. Lastly, a number of genetic risk factors for sporadic forms have also been identified. In this review, current knowledge about mutations at the basis of familial FTLD will be described, together with genetic risk factors influencing the susceptibility to FTLD. PMID- 22536194 TI - The "brain-skin connection" in protein misfolding and amyloid deposits: embryological, pathophysiological, and therapeutic common grounds? PMID- 22536191 TI - Primum non nocere: an evolutionary analysis of whether antidepressants do more harm than good. AB - Antidepressant medications are the first-line treatment for people meeting current diagnostic criteria for major depressive disorder. Most antidepressants are designed to perturb the mechanisms that regulate the neurotransmitter serotonin - an evolutionarily ancient biochemical found in plants, animals, and fungi. Many adaptive processes evolved to be regulated by serotonin, including emotion, development, neuronal growth and death, platelet activation and the clotting process, attention, electrolyte balance, and reproduction. It is a principle of evolutionary medicine that the disruption of evolved adaptations will degrade biological functioning. Because serotonin regulates many adaptive processes, antidepressants could have many adverse health effects. For instance, while antidepressants are modestly effective in reducing depressive symptoms, they increase the brain's susceptibility to future episodes after they have been discontinued. Contrary to a widely held belief in psychiatry, studies that purport to show that antidepressants promote neurogenesis are flawed because they all use a method that cannot, by itself, distinguish between neurogenesis and neuronal death. In fact, antidepressants cause neuronal damage and mature neurons to revert to an immature state, both of which may explain why antidepressants also cause neurons to undergo apoptosis (programmed death). Antidepressants can also cause developmental problems, they have adverse effects on sexual and romantic life, and they increase the risk of hyponatremia (low sodium in the blood plasma), bleeding, stroke, and death in the elderly. Our review supports the conclusion that antidepressants generally do more harm than good by disrupting a number of adaptive processes regulated by serotonin. However, there may be specific conditions for which their use is warranted (e.g., cancer, recovery from stroke). We conclude that altered informed consent practices and greater caution in the prescription of antidepressants are warranted. PMID- 22536195 TI - Increased Corticomuscular Coherence in Idiopathic REM Sleep Behavior Disorder. AB - The authors hypothesized that if locomotor drive increases along with rapid eye movement (REM) sleep without atonia in idiopathic REM sleep behavior disorder (RBD), then RBD patients would have greater corticomuscular coherence (CMC) values during REM sleep than at other sleep stages and than in healthy control subjects during REM sleep. To explore this hypothesis, we analyzed beta frequency range CMC between sensorimotor cortex electroencephalography (EEG) and chin/limb muscle EMG in idiopathic RBD patients. Eleven drug naive idiopathic RBD patients and 11 age-matched healthy control subjects were included in the present study. All participants completed subjective sleep questionnaires and underwent polysomnography for one night. The CMC value between EEGs recorded at central electrodes and EMGs acquired at leg and chin muscles were computed and compared by repeated measures analysis of variance (ANOVA). Sleep stages and muscle (i.e., chin vs. leg) served as within-subject factors, and group served as the between subject factor. Repeated measures ANOVA revealed no significant main effect of group (F(1,20) = 0.571, p = 0.458) or muscle (F(1,20) = 1.283, p = 0.271). However, sleep stage was found to have a significant main effect (F(2.067,41.332) = 20.912, p < 0.001). The interaction between group and sleep stage was significant (F(2.067,41.332) = 3.438, p = 0.040). RBD patients had a significantly higher CMC value than controls during REM sleep (0.047 +/- 0.00 vs. 0.052 +/- 0.00, respectively, p = 0.007). This study reveals increased CMC during REM sleep in patients with RBD, which indicates increased cortical locomotor drive. Furthermore, this study supports the hypothesis that sufficient locomotor drive plays a role in the pathophysiology of RBD in addition to REM sleep without atonia. PMID- 22536196 TI - Cell receptors for influenza a viruses and the innate immune response. AB - The interaction of the hemagglutinin (HA) of the influenza A viruses (IAV) with the cell surface is a key factor for entry of the virus and productive infection of the cell. This glycoprotein has affinity for sialic acids (SA), and different strains present specificity for SA bound through alpha2,3 or alpha2,6 linkages to the underlying sugar chain, which is usually related with host and cell tropism. Nucleic acid recognizing receptors (mainly RIG-I and Toll-like receptors) are the most extensively studied pattern recognition receptors for IAV. However, due to the ability of the HA of avian, swine, or human influenza viruses to bind differently linked SA and also to the high levels and variability of glycosylations of their major virion glycoprotein components, HA and NA, IAV interacting proteins on the cell surface could also play an important role in initiating different signaling pathways to elicit the immune response in infected cells. But, at present, these processes are not well understood. In this mini review we discuss how the interactions of IAV with cell surface receptors on immune cells might be important for the induction of specific innate immune responses and as a result, for pathogenicity in humans. PMID- 22536198 TI - The Membrane QmoABC Complex Interacts Directly with the Dissimilatory Adenosine 5'-Phosphosulfate Reductase in Sulfate Reducing Bacteria. AB - The adenosine 5'-phosphosulfate reductase (AprAB) is the enzyme responsible for the reduction of adenosine 5'-phosphosulfate (APS) to sulfite in the biological process of dissimilatory sulfate reduction, which is carried out by a ubiquitous group of sulfate reducing prokaryotes. The electron donor for AprAB has not been clearly identified, but was proposed to be the QmoABC membrane complex, since an aprBA-qmoABC gene cluster is found in many sulfate reducing and sulfur-oxidizing bacteria. The QmoABC complex is essential for sulfate reduction, but electron transfer between QmoABC and AprAB has not been reported. In this work we provide the first direct evidence that QmoABC and AprAB interact in Desulfovibrio spp., using co-immunoprecipitation, cross-linking Far-Western blot, tag-affinity purification, and surface plasmon resonance studies. This showed that the QmoABC AprAB complex has a strong steady-state affinity (K(D) = 90 +/- 3 nM), but has a transient character due to a fast dissociation rate. Far-Western blot identified QmoA as the Qmo subunit most involved in the interaction. Nevertheless, electron transfer from menaquinol analogs to APS through anaerobically purified QmoABC and AprAB could not be detected. We propose that this reaction requires the involvement of a third partner to allow electron flow driven by a reverse electron bifurcation process, i.e., electron confurcation. This process is deemed essential to allow coupling of APS reduction to chemiosmotic energy conservation. PMID- 22536197 TI - Secondary Metabolites from Plants Inhibiting ABC Transporters and Reversing Resistance of Cancer Cells and Microbes to Cytotoxic and Antimicrobial Agents. AB - Fungal, bacterial, and cancer cells can develop resistance against antifungal, antibacterial, or anticancer agents. Mechanisms of resistance are complex and often multifactorial. Mechanisms include: (1) Activation of ATP-binding cassette (ABC) transporters, such as P-gp, which pump out lipophilic compounds that have entered a cell, (2) Activation of cytochrome p450 oxidases which can oxidize lipophilic agents to make them more hydrophilic and accessible for conjugation reaction with glucuronic acid, sulfate, or amino acids, and (3) Activation of glutathione transferase, which can conjugate xenobiotics. This review summarizes the evidence that secondary metabolites (SM) of plants, such as alkaloids, phenolics, and terpenoids can interfere with ABC transporters in cancer cells, parasites, bacteria, and fungi. Among the active natural products several lipophilic terpenoids [monoterpenes, diterpenes, triterpenes (including saponins), steroids (including cardiac glycosides), and tetraterpenes] but also some alkaloids (isoquinoline, protoberberine, quinoline, indole, monoterpene indole, and steroidal alkaloids) function probably as competitive inhibitors of P gp, multiple resistance-associated protein 1, and Breast cancer resistance protein in cancer cells, or efflux pumps in bacteria (NorA) and fungi. More polar phenolics (phenolic acids, flavonoids, catechins, chalcones, xanthones, stilbenes, anthocyanins, tannins, anthraquinones, and naphthoquinones) directly inhibit proteins forming several hydrogen and ionic bonds and thus disturbing the 3D structure of the transporters. The natural products may be interesting in medicine or agriculture as they can enhance the activity of active chemotherapeutics or pesticides or even reverse multidrug resistance, at least partially, of adapted and resistant cells. If these SM are applied in combination with a cytotoxic or antimicrobial agent, they may reverse resistance in a synergistic fashion. PMID- 22536200 TI - Productive Lifecycle of Human Papillomaviruses that Depends Upon Squamous Epithelial Differentiation. AB - Human papillomaviruses (HPVs) target the stratified epidermis, and can causes diseases ranging from benign condylomas to malignant tumors. Infections of HPVs in the genital tract are among the most common sexually transmitted diseases, and a major risk factor for cervical cancer. The virus targets epithelial cells in the basal layer of the epithelium, while progeny virions egress from terminally differentiated cells in the cornified layer, the surface layer of the epithelium. In infected basal cells, the virus maintains its genomic DNA at low-copy numbers, at which the viral productive lifecycle cannot proceed. Progression of the productive lifecycle requires differentiation of the host cell, indicating that there is tight crosstalk between viral replication and host differentiation programs. In this review, we discuss the regulation of the HPV lifecycle controlled by the differentiation program of the host cells. PMID- 22536201 TI - The Distribution of Ammonia-Oxidizing Betaproteobacteria in Stands of Black Mangroves (Avicennia germinans). AB - The distribution of species of aerobic chemolitho-autotrophic microorganisms such as ammonia-oxidizing bacteria are governed by pH, salinity, and temperature as well as the availability of oxygen, ammonium, carbon dioxide, and other inorganic elements required for growth. Impounded mangrove forests in the Indian River Lagoon, a coastal estuary on the east coast of Florida, are dominated by mangroves, especially stands of Black mangrove (Avicennia germinans) that differ in the size and density of individual plants. In March 2009, the management of one impoundment was changed to a regime of pumping estuarine water into the impoundment at critical times of the year to eliminate breeding sites for noxious insects. We collected soil samples in three different Black mangrove habitats before and after the change in management to determine the impacts of the altered hydrologic regimes on the distribution of 16s rRNA genes belonging to ammonia oxidizing betaproteobacteria (beta-AOB). We also sampled soils in an adjacent impoundment in which there had not been any hydrologic alteration. At the level of 97% mutual similarity in the 16s rRNA gene, 13 different operational taxonomic units were identified; the majority related to the lineages of Nitrosomonas marina (45% of the total clones), Nitrosomonas sp. Nm143 (23%), and Nitrosospira cluster 1 (19%). Long-term summer flooding of the impoundment in 2009, after initiation of the pumping regime, reduced the percentage of N. marina by half between 2008 and 2010 in favor of the two other major lineages and the potential ammonia-oxidizing activity decreased by an average of 73%. Higher interstitial salinities, probably due to a prolonged winter drought, had a significant effect on the composition of the beta-AOB in March 2009 compared to March 2008: Nitrosomonas sp. Nm143 was replaced by Nitrosospira cluster 1 as the second most important lineage. There were small, but significant differences in the bacterial communities between the flooded and non-flooded impoundments. There were also differences in the community composition of the bacteria in the three Black mangrove habitats. N. marina was most dominant in all three habitats, but was partly replaced by Nitrosospira cluster 1 in sites dominated by sparsely distributed trees and by Nitrosomonas sp. Nm143 in sites characterized by taller, more densely distributed Black mangrove trees. PMID- 22536202 TI - Effect of Metals on the Lytic Cycle of the Coccolithovirus, EhV86. AB - In this study we show that metals, and in particular copper (Cu), can disrupt the lytic cycle in the Emiliania huxleyi - EhV86 host-virus system. E. huxleyi lysis rates were reduced at high total Cu concentrations (> approximately 500 nM) in the presence and absence of EDTA (ethylenediaminetetraacetic acid) in acute short term exposure experiments. Zinc (Zn), cadmium (Cd), and cobalt (Co) were not observed to affect the lysis rate of EhV86 in these experiments. The cellular glutathione (GSH) content increased in virus infected cells, but not as a result of metal exposure. In contrast, the cellular content of phytochelatins (PCs) increased only in response to metal exposure. The increase in glutathione content is consistent with increases in the production of reactive oxygen species (ROS) on viral lysis, while increases in PC content are likely linked to metal homeostasis and indicate that metal toxicity to the host was not affected by viral infection. We propose that Cu prevents lytic production of EhV86 by interfering with virus DNA (deoxyribonucleic acid) synthesis through a transcriptional block, which ultimately suppresses the formation of ROS. PMID- 22536203 TI - Single-Cell Growth Probability of Listeria monocytogenes at Suboptimal Temperature, pH, and Water Activity. AB - The single-cell growth probability of Listeria monocytogenes was characterized in tryptone soy broth supplemented with 0.6% yeast extract at temperature ranging from 5 to 25 degrees C, pH ranging from 4.4 to 6.5, and water activity ranging from 0.919 to 0.989. Growth was monitored visually in 96-microwell plates and the growth probability was deduced from concentrations estimated with the MPN calculation. Models were proposed to describe the increase of the probability from 0 to 1 with increasing values of environmental factors. An exponential model was used for the temperature and the individual minimal temperature for growth ranged from -3.6 degrees C [-4.5 degrees C, -2.7 degrees C] to 17.3 degrees C [16.0 degrees C, 18.6 degrees C]. An inverse exponential model was convenient for the pH and the minimal pH for growth of individual cells ranged from 4.34 [3.93, 4.75] to 5.93 [4.85, 7.01]. A linear model was used for the water activity and the minimal value for growth of individual cells ranged from 0.917 [0.909, 0.925] to 0.988 [0.966, 1]. In spite of the great between-experiment variability, the minimal values estimated for the growth limits of individual cells were in accordance with values usually proposed for L. monocytogenes populations. This study provides models allowing the prediction of the growth probability of a few cells contaminating chilled foods with suboptimal pH and water activity improving thus the assessment of the behavior of L. monocytogenes cells naturally contaminating foods. PMID- 22536199 TI - The Acinetobacter baumannii Oxymoron: Commensal Hospital Dweller Turned Pan-Drug Resistant Menace. AB - During the past few decades Acinetobacter baumannii has evolved from being a commensal dweller of health-care facilities to constitute one of the most annoying pathogens responsible for hospitalary outbreaks and it is currently considered one of the most important nosocomial pathogens. In a prevalence study of infections in intensive care units conducted among 75 countries of the five continents, this microorganism was found to be the fifth most common pathogen. Two main features contribute to the success of A. baumannii: (i) A. baumannii exhibits an outstanding ability to accumulate a great variety of resistance mechanisms acquired by different mechanisms, either mutations or acquisition of genetic elements such as plasmids, integrons, transposons, or resistant islands, making this microorganism multi- or pan-drug-resistant and (ii) The ability to survive in the environment during prolonged periods of time which, combined with its innate resistance to desiccation and disinfectants, makes A. baumannii almost impossible to eradicate from the clinical setting. In addition, its ability to produce biofilm greatly contributes to both persistence and resistance. In this review, the pathogenesis of the infections caused by this microorganism as well as the molecular bases of antibacterial resistance and clinical aspects such as treatment and potential future therapeutic strategies are discussed in depth. PMID- 22536205 TI - Dark Matter RNA: Existence, Function, and Controversy. AB - The mysteries surrounding the ~97-98% of the human genome that does not encode proteins have long captivated imagination of scientists. Does the protein-coding, 2-3% of the genome carry the 97-98% as a mere passenger and neutral "cargo" on the evolutionary path, or does the latter have biological function? On one side of the debate, many commentaries have referred to the non-coding portion of the genome as "selfish" or "junk" DNA (Orgel and Crick, 1980), while on the other side, authors have argued that it contains the real blueprint for organismal development (Penman, 1995; Mattick, 2003), and the mechanisms of developmental complexity. Thus, this question could be referred to without much exaggeration as the most important issue in genetics today. PMID- 22536204 TI - The C1q family of proteins: insights into the emerging non-traditional functions. AB - Research conducted over the past 20 years have helped us unravel not only the hidden structural and functional subtleties of human C1q, but also has catapulted the molecule from a mere recognition unit of the classical pathway to a well recognized molecular sensor of damage-modified self or non-self antigens. Thus, C1q is involved in a rapidly expanding list of pathological disorders - including autoimmunity, trophoblast migration, preeclampsia, and cancer. The results of two recent reports are provided to underscore the critical role C1q plays in health and disease. First is the observation by Singh et al. (2011) showing that pregnant C1q-/- mice recapitulate the key features of human preeclampsia that correlate with increased fetal death. Treatment of the C1q-/- mice with pravastatin restored trophoblast invasiveness, placental blood flow, and angiogenic balance and, thus, prevented the onset of preeclampsia. Second is the report by Hong et al. (2009) which showed that C1q can induce apoptosis of prostate cancer cells by activating the tumor suppressor molecule WW-domain containing oxydoreductase (WWOX or WOX1) and destabilizing cell adhesion. Downregulation of C1q on the other hand, enhanced prostate hyperplasia and cancer formation due to failure of WOX1 activation. C1q belongs to a family of structurally and functionally related TNF-alpha-like family of proteins that may have arisen from a common ancestral gene. Therefore C1q not only shares the diverse functions with the tumor necrosis factor family of proteins, but also explains why C1q has retained some of its ancestral "cytokine-like" activities. This review is intended to highlight some of the structural and functional aspects of C1q by underscoring the growing list of its non-traditional functions. PMID- 22536206 TI - TFC6 (TFIIIC Subunit): A Bridge between Prokaryotic and Eukaryotic Gene Regulation. PMID- 22536207 TI - Assessing the accuracy and power of population genetic inference from low-pass next-generation sequencing data. AB - Next-generation sequencing (NGS) technologies have made it possible to address population genetic questions in almost any system, but high error rates associated with such data can introduce significant biases into downstream analyses, necessitating careful experimental design and interpretation in studies based on short-read sequencing. Exploration of population genetic analyses based on NGS has revealed some of the potential biases, but previous work has emphasized parameters relevant to human population genetics and further examination of parameters relevant to other systems is necessary, including situations where sample sizes are small and genetic variation is high. To assess experimental power to address several principal objectives of population genetic studies under these conditions, we simulated population samples under selective sweep, population growth, and population subdivision models and tested the power to accurately infer population genetic parameters from sequence polymorphism data obtained through simulated 4*, 8*, and 15* read depth sequence data. We found that estimates of population genetic differentiation and population growth parameters were systematically biased when inference was based on 4* sequencing, but biases were markedly reduced at even 8* read depth. We also found that the power to identify footprints of positive selection depends on an interaction between read depth and the strength of selection, with strong selection being recovered consistently at all read depths, but weak selection requiring deeper read depths for reliable detection. Although we have explored only a small subset of the many possible experimental designs and population genetic models, using only one SNP-calling approach, our results reveal some general patterns and provide some assessment of what biases could be expected under similar experimental structures. PMID- 22536208 TI - Using x-ray mammograms to assist in microwave breast image interpretation. AB - Current clinical breast imaging modalities include ultrasound, magnetic resonance (MR) imaging, and the ubiquitous X-ray mammography. Microwave imaging, which takes advantage of differing electromagnetic properties to obtain image contrast, shows potential as a complementary imaging technique. As an emerging modality, interpretation of 3D microwave images poses a significant challenge. MR images are often used to assist in this task, and X-ray mammograms are readily available. However, X-ray mammograms provide 2D images of a breast under compression, resulting in significant geometric distortion. This paper presents a method to estimate the 3D shape of the breast and locations of regions of interest from standard clinical mammograms. The technique was developed using MR images as the reference 3D shape with the future intention of using microwave images. Twelve breast shapes were estimated and compared to ground truth MR images, resulting in a skin surface estimation accurate to within an average Euclidean distance of 10 mm. The 3D locations of regions of interest were estimated to be within the same clinical area of the breast as corresponding regions seen on MR imaging. These results encourage investigation into the use of mammography as a source of information to assist with microwave image interpretation as well as validation of microwave imaging techniques. PMID- 22536209 TI - Mathematical methods for images and surfaces 2011. PMID- 22536210 TI - Fenofibrate enhances the in vitro differentiation of foxp3(+) regulatory T cells in mice. AB - Foxp3(+) regulatory T cells (Tregs) play a critical role in maintaining immune self-tolerance. Reduced number and activity of Tregs are usually found in autoimmune and inflammatory diseases, and enhancing the differentiation of Tregs may be a promising therapeutic strategy. Some reports suggested an anti inflammatory and anti-autoimmune potential for fenofibrate, a hypolipidemic drug used worldwide, whose lipid effects are mediated by the activation of peroxisome proliferator-activated receptor alpha (PPARalpha). In the present paper, we found that fenofibrate dose-dependently increased transforming growth factor-beta and interleukin-2-induced Treg differentiation in vitro, by 1.96-fold from 0 to 20 MUM (12.59 +/- 1.34% to 24.69 +/- 3.03%, P < 0.05). Other PPARalpha activators, WY14643 (100 MUM), gemfibrozil (50 MUM), and bezafibrate (30 MUM), could not enhance Treg differentiation. In addition, PPARalpha could not upregulate the promoter activity of the Treg-specific transcription factor Foxp3. Fenofibrate might exert its function by enhancing Smad3 phosphorylation, a critical signal in Treg differentiation, via Akt suppression. Our work reveals a new PPARalpha independent anti-inflammatory mechanism of fenofibrate in up-regulating mouse Treg differentiation. PMID- 22536211 TI - The Interplay of PPARs with Parasites and Related Intracellular Pathogens. PMID- 22536212 TI - Differential proteome profiling using iTRAQ in microalbuminuric and normoalbuminuric type 2 diabetic patients. AB - Diabetic nephropathy (DN) is a long-term complication of diabetes mellitus that leads to end-stage renal disease. Microalbuminuria is used for the early detection of diabetic renal damage, but such levels do not reflect the state of incipient DN precisely in type 2 diabetic patients because microalbuminuria develops in other diseases, necessitating more accurate biomarkers that detect incipient DN. Isobaric tags for relative and absolute quantification (iTRAQ) were used to identify urinary proteins that were differentially excreted in normoalbuminuric and microalbuminuric patients with type 2 diabetes where 710 and 196 proteins were identified and quantified, respectively. Some candidates were confirmed by 2-DE analysis, or validated by Western blot and multiple reaction monitoring (MRM). Specifically, some differentially expressed proteins were verified by MRM in urine from normoalbuminuric and microalbuminuric patients with type 2 diabetes, wherein alpha-1-antitrypsin, alpha-1-acid glycoprotein 1, and prostate stem cell antigen had excellent AUC values (0.849, 0.873, and 0.825, resp.). Moreover, we performed a multiplex assay using these biomarker candidates, resulting in a merged AUC value of 0.921. Although the differentially expressed proteins in this iTRAQ study require further validation in larger and categorized sample groups, they constitute baseline data on preliminary biomarker candidates that can be used to discover novel biomarkers for incipient DN. PMID- 22536213 TI - Rising intracellular zinc by membrane depolarization and glucose in insulin secreting clonal HIT-T15 beta cells. AB - Zinc (Zn(2+)) appears to be intimately involved in insulin metabolism since insulin secretion is correlated with zinc secretion in response to glucose stimulation, but little is known about the regulation of zinc homeostasis in pancreatic beta-cells. This study set out to identify the intracellular zinc transient by imaging free cytosolic zinc in HIT-T15 beta-cells with fluorescent zinc indicators. We observed that membrane depolarization by KCl (30-60 mM) was able to induce a rapid increase in cytosolic concentration of zinc. Multiple zinc transients of similar magnitude were elicited during repeated stimulations. The amplitude of zinc responses was not affected by the removal of extracellular calcium or zinc. However, the half-time of the rising slope was significantly slower after removing extracellular zinc with zinc chelator CaEDTA, suggesting that extracellular zinc affect the initial rising phase of zinc response. Glucose (10 mM) induced substantial and progressive increases in intracellular zinc concentration in a similar way as KCl, with variation in the onset and the duration of zinc mobilization. It is known that the depolarization of beta-cell membrane is coupled with the secretion of insulin. Rising intracellular zinc concentration may act as a critical signaling factor in insulin metabolism of pancreatic beta-cells. PMID- 22536214 TI - Comparison of oxidant/antioxidant, detoxification systems in various tissue homogenates and mitochondria of rats with diabetes induced by streptozocin. AB - OBJECTIVE: Oxidative stress is considered to be the main factor in the development of diabetic complications and tissue injury. our objective was to investigate and compare the oxidant/antioxidant conditions and detoxification mechanisms of the liver, lung, kidney, cardiac tissues, and mitochondria of rats with diabetes induced by streptozocin (STZ). METHODS: Rats with diabetes induced by streptozocin were anesthetized by administering 90 mg/kg ketamine hydrochloride and 3 mg/kg xylazine hydrochloride. Thoracic cavities were incised open; liver, lung, kidney, and cardiac tissues were removed and stored at -70 degrees C. All samples were homogenized and mitochondrial fractions were separated. Total Antioxidant Status (TAS), Total Oxidant Status (TOS), Oxidative Stress Index (OSI), Paraoxonase (PON), Arylesterase, Catalase (Cat), Malondialdehyde (MDA), and Glutathion-S-transferase were measured in each fraction. RESULTS: MDA and TOS levels were significantly increased in liver tissues, and T OS and OSI were increased in the mitochondrial fractions of diabetic rats. These increases were not statistically significant compared to the control group. No significant differences were determined in the antioxidant and GST activities. CONCLUSION: According to our results, oxidative stress has not developed in rats with diabetes induced by streptozocin. The detoxification system was induced; however, this induction did not differ significantly from the controls. PMID- 22536215 TI - Effects of restricted fructose access on body weight and blood pressure circadian rhythms. AB - High-fructose diet is known to produce cardiovascular and metabolic pathologies. The objective was to determine whether the timing of high fructose (10% liquid solution) intake affect the metabolic and cardiovascular outcomes. Male C57BL mice with radiotelemetric probes were divided into four groups: (1) 24 h water (control); (2) 24 h fructose (F24); (3) 12 h fructose during the light phase (F12L); (4) 12 h fructose during the dark phase (F12D). All fructose groups had higher fluid intake. Body weight was increased in mice on restricted access with no difference in total caloric intake. Fasting glycemia was higher in groups with restricted access. F24 mice showed a fructose-induced blood pressure increase during the dark period. Blood pressure circadian rhythms were absent in F12L mice. Results suggest that the timing of fructose intake is an important variable in the etiology of cardiovascular and metabolic pathologies produced by high fructose consumption. PMID- 22536217 TI - Upper gastrointestinal endoscopy detection of synchronous multiple primary cancers in esophagus and stomach: single center experience from china. AB - The present study was undertaken to clarify the prevalence and clinicopathological features of synchronous multiple primary cancers (SMPCs) under upper gastrointestinal endoscopic examination. We enrolled 45,032 consecutive patients who underwent upper gastrointestinal endoscopic examination for digestive disease from January 2006 to December 2007 in our hospital and analyzed the clinicopathological features of SMPCs in esophagus and stomach. SMPCs are defined as two or over two different cancerous lesions developing in the same or other organs within 6 months. SMPCs were identified in 46 patients (0.1%). The gender ratio was 5.6 : 1 (male/female) and the mean age was 59.4 years. Synchronous esophageal and gastric cancers were the most frequent, being seen in 32 patients (0.07%). The most common histological types of SMPCs were squamous cell carcinoma in esophagus and adenocarcinoma in stomach, respectively. There were 27 (59%) SMPCs patients who had the history of simultaneous exposure to tobacco smoking and alcohol drinking. Additionally, 32 (78%) esophageal squamous cell cancers were associated with tobacco use. And 23 adenocarcinomas of the stomach were associated with Helicobacter pylori infection. PMID- 22536218 TI - Association Analysis of ULK1 with Crohn's Disease in a New Zealand Population. AB - The gene ULK1 is an excellent candidate for Crohn's disease (CD) due to its role in autophagy. A recent study provided evidence for the involvement of ULK1 in the pathogenesis of CD (Henckaerts et al., 2011). We attempted to validate this association, using a candidate gene SNP study of ULK1 in CD. We identified tagging SNPs and genotyped these SNPs using the Sequenom platform in a Caucasian New Zealand dataset consisting of 406 CD patients and 638 controls. In this sample, we were able to demonstrate an association between CD and several different ULK1 SNPs and haplotypes. Phenotypic analysis showed an association with age of diagnosis 17-40 years and inflammatory behaviour. The findings of this study provide evidence to suggest that genetic variation in ULK1 may play a role in interindividual differences in CD susceptibility and clinical outcome. PMID- 22536216 TI - Regenerative therapies for diabetic microangiopathy. AB - Hyperglycaemia occurring in diabetes is responsible for accelerated arterial remodeling and atherosclerosis, affecting the macro- and the microcirculatory system. Vessel injury is mainly related to deregulation of glucose homeostasis and insulin/insulin-precursors production, generation of advanced glycation end products, reduction in nitric oxide synthesis, and oxidative and reductive stress. It occurs both at extracellular level with increased calcium and matrix proteins deposition and at intracellular level, with abnormalities of intracellular pathways and increased cell death. Peripheral arterial disease, coronary heart disease, and ischemic stroke are the main causes of morbidity/mortality in diabetic patients representing a major clinical and economic issue. Pharmacological therapies, administration of growth factors, and stem cellular strategies are the most effective approaches and will be discussed in depth in this comprehensive review covering the regenerative therapies of diabetic microangiopathy. PMID- 22536219 TI - Silicea gastrointestinal gel improves gastrointestinal disorders: a non controlled, pilot clinical study. AB - Aim. To investigate efficacy and tolerability of Silicea Gastrointestinal Gel in patients with gastrointestinal disorders. Methods. Open, prospective pivotal phase IV study with oral Silicea Gastrointestinal Gel over 6 weeks. Symptom score was part 1 of the Nepean Dyspepsia Index: 15 questions addressing intensity, frequency and impact of upper abdominal symptoms. 10 lower abdominal symptoms were asked analogously. A responder showed reduction of score of >50%. Results. 62 of 90 patients were evaluated per protocol. Upper and lower abdomen sum scores decreased already in the first three weeks (P < 0.001), which continued the following three weeks (P < 0.01). Mean symptom score for upper abdomen decreased from 52.2 +/- 31.0 to 33.7 +/- 28.7 (or by 35.4%; responder rate 37%); for lower from 39.6 +/- 24.7 to 22.6 +/- 21.7 (by 42.9%; responder rate 46%). Subgroups with diarrhea, IBS and GERD presented highest responder rates. 6% of patients reported adverse reactions with probable or possible relationship to the test product. Conclusions. Silicea Gastrointestinal Gel seems suitable beyond infectious acute gastrointestinal disorders. Responses are relevant for chronic functional disorders, but it remains unclear, how much of that might be placebo effect. Controlled studies are recommended in gastrointestinal syndromes like IBS or GERD. PMID- 22536220 TI - Clinical Significance of Peripheral Blood T Lymphocyte Subsets in Helicobacter pylori-Infected Patients. AB - Background. Helicobacter pylori chronically colonizes gastric/duodenal mucosa and induces gastroduodenal disease and vigorous humoral and cellular immune responses. Methods. In order to clarify the immunological changes induced by this infection, we determined the percentage and, as indicated, ratios of the following cells in peripheral blood of 45 H. pylori-infected patients and 21 control subjects: CD4(+) T cell, CD8(+) T cells, T helper 1 cells (Th1), T helper 2 cells (Th2), CD4(+)CD25(+) T cells, Foxp3(+) regulatory T cells (Tregs), CD4/CD8 ratio, and Th1/Th2 ratio. Results. The percentage of CD8(+) T cells was significantly lower in H. pylori-infected patients (mean +/- SD; 18.0 +/- 7.1%) compared to control subjects (mean +/- SD; 23.2 +/- 7.8%) (P < 0.05). The CD4/CD8 ratio was significantly higher in H. pylori-infected patients (mean +/- SD; 3.1 +/- 2.4) compared to control subjects (mean +/- SD; 2.1 +/- 1.0) (P < 0.05). The Th1/Th2 ratio was significantly lower in H. pylori-infected patients (mean +/- SD; 10.0 +/- 8.5) compared to control subjects (mean +/- SD; 14.5 +/- 9.0) (P < 0.05). The percentage of CD4(+)CD25(+) T cells in H. pylori-infected patients (mean +/- SD; 13.2 +/- 6.2%) was significantly higher than that in control subjects (mean +/- SD; 9.8 +/- 3.4%) (P < 0.05). However, there was no significant difference in Tregs. Conclusion. Tregs did not decrease, but the activation of humoral immunity and Th2 polarization were observed in the peripheral blood of H. pylori-infected patients. In some cases, these changes may induce systemic autoimmune diseases. PMID- 22536221 TI - Analysis of delayed bleeding after endoscopic submucosal dissection for gastric epithelial neoplasms. AB - Aim. Delayed bleeding after endoscopic submucosal dissection (ESD) for gastric epithelial neoplasms is a major complication. We investigated factors related to post-ESD bleeding to identify preventive measures. Methods. The study included 161 gastric epithelial neoplasms in 142 patients from June 2007 to September 2010. Post-ESD bleeding was defined as an ulcer with active bleeding or apparent exposed vessels diagnosed by an emergency endoscopy or a planned follow-up endoscopy. We analyzed associations between bleeding and the following factors: age, sex, morphology, pathology, tumor depth, ulcer presence/absence, location, size of the resected lesion, duration of the procedure, the number of times bleeding occurred during ESD, and the use of anticoagulants and/or antiplatelet drugs. Subsequently, we examined characteristics of bleeding cases. Results. Post ESD bleeding occurred in 21 lesions. Univariate analysis of these cases showed that ulcer presence/absence (P < 0.001), middle or lower third lesions (P = 0.036), circumference (P = 0.014), and a post-ESD ulcer with an extended lesser curve (P = 0.009) were significant predictors of bleeding. Multivariate analysis showed that ulcer presence/absence (OR 9.73, 95% CI 2.28-41.53) was the only significant predictor. Conclusion. Ulcer presence/absence was considered the most significant predictor of post-ESD bleeding. PMID- 22536222 TI - In situ absorption in rat intestinal tract of solid dispersion of annonaceous acetogenins. AB - Isolated from Annona squamosa L, Annonaceous acetogenins (ACGs) exhibit a broad range of biological properties yet absorbed badly due to the low solubility. Solid dispersion in polyethylene glycol 4000 (PEG 4000) has been developed to increase the solubility and oral absorption of ACGs. The formulation of ACGS solid dispersion was optimized by a simplex lattice experiment design and carried out by a solvent-fusion method. We studied the absorption property of ACGs in rat's intestine, which showed there was a good absorption and uptake percentages with solid dispersion. The study on uptake percentage in different regions of rat's intestine attested that the duodenum had the best permeability, followed by jejunum, ileum, and colon in order with no significant differences. So the paper drew the conclusion that solid dispersion could improve the solubility and oral absorption of annonaceous acetogenins. PMID- 22536223 TI - Endoscopic management of peri-pancreatic collections. AB - Endotherapy of peripancreatic fluid collections is an increasing utilized procedure in interventional endoscopy. The aim of this paper is to provide a general overview of the topic, highlighting the indications, technique, and important management issues relating to endoscopic management of the various forms of peri-pancreatic fluid collections. PMID- 22536224 TI - Improvement of sepsis by hepatocyte growth factor, an anti-inflammatory regulator: emerging insights and therapeutic potential. AB - Sepsis-induced multiple organ failure (MOF) is the most frequent lethal disease in intensive care units. Thus, it is important to elucidate the self-defensive mechanisms of sepsis-induced MOF. Hepatocyte growth factor (HGF) is now recognized as an organotrophic factor, which is essential for organogenesis during embryonic growth and regeneration in adulthood. HGF production is enhanced in response to infectious challenges, but the increase in endogenous HGF levels is transient and insufficient, with a time lag between tissue injuries and HGF upregulation, during progression of septic MOF. Thus, administration of active formed HGF might be a new candidate for therapeutic development of MOF. HGF has an ability to target endotoxin-challenged macrophages and inhibits the upregulation of inflammatory cytokines through nuclear factor-kappaB-inactivated mechanisms. HGF also targets the endothelium and epithelium of various organs to suppress local inflammation, coagulation, and apoptotic death. This paper summarizes the novel mechanisms of HGF for attenuating sepsis-related pathological conditions with a focus on sepsis-induced MOF. PMID- 22536225 TI - Rescue Therapy for Helicobacter pylori Infection 2012. AB - Helicobacter pylori infection is the main cause of gastritis, gastroduodenal ulcer disease, and gastric cancer. After 30 years of experience in H. pylori treatment, however, the ideal regimen to treat this infection has still to be found. Nowadays, apart from having to know well first-line eradication regimens, we must also be prepared to face treatment failures. In designing a treatment strategy, we should not only focus on the results of primary therapy alone but also on the final-overall-eradication rate. The choice of a "rescue" treatment depends on which treatment is used initially. If a first-line clarithromycin based regimen was used, a second-line metronidazole-based treatment (quadruple therapy) may be used afterwards, and then a levofloxacin-based combination would be a third-line "rescue" option. Alternatively, it has recently been suggested that levofloxacin-based "rescue" therapy constitutes an encouraging 2nd-line strategy, representing an alternative to quadruple therapy in patients with previous PPI-clarithromycin-amoxicillin failure, with the advantage of efficacy, simplicity and safety. In this case, quadruple regimen may be reserved as a 3rd line "rescue" option. Even after two consecutive failures, several studies have demonstrated that H. pylori eradication can finally be achieved in almost all patients if several "rescue" therapies are consecutively given. PMID- 22536227 TI - Artificial urinary sphincter: long-term results and patient satisfaction. AB - The published evidence concerning the safety, efficacy, and patient satisfaction for implantation of the current model of the artificial urinary sphincter (AS 800) in men with post prostatectomy urinary incontinence was the objective of this review. A Pub Med English language literature search from 1995 to 2011 was performed. A majority of men who undergo AUS implantation for post prostatectomy urinary incontinence achieve satisfactory results (0 to 1 pad per day). Infection rates range from 0.46 to 7%, cuff erosion rates range from 3.8 to 10%, and urethral atrophy ranges from 9.6 to 11.4%. Kaplan-Meier 5 year projections for freedom from any reoperation were 50% for a small series and 79.4% for a larger series. Kaplan-Meier projections for freedom from mechanical failure were 79% at 5 years and 72% at 10 years. In another series 10 year projections for freedom from mechanical failure were 64%. Although the artificial urinary sphincter (AUS) is the gold standard for the treatment of this disorder, most men will continue to need at least one pad per day for protection, and they are subject to a significant chance of future AUS revision or replacement. PMID- 22536228 TI - An Algorithm That Predicts CSI to Allocate Bandwidth for Healthcare Monitoring in Hospital's Waiting Rooms. AB - In wireless healthcare monitoring systems, bandwidth allocation is an efficient solution to the problem of scarce wireless bandwidth for the monitoring of patients. However, when the central unit cannot access the exact channel state information (CSI), the efficiency of bandwidth allocation decreases, and the system performance also decreases. In this paper, we propose an algorithm to reduce the negative effects of imperfect CSI on system performance. In this algorithm, the central unit can predict the current CSI by previous CSI when the current CSI is not available. We analyze the reliability of the proposed algorithm by deducing the standard error of estimated CSI with this algorithm. In addition, we analyze the efficiency of the proposed algorithm by discussing the system performance with this algorithm. PMID- 22536226 TI - Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABA(A) Receptor Modulators? AB - Despite decades of basic and clinical research, our understanding of how benzodiazepines tend to lose their efficacy over time (tolerance) is at least incomplete. In appears that tolerance develops relatively quickly for the sedative and anticonvulsant actions of benzodiazepines, whereas tolerance to anxiolytic and amnesic effects probably does not develop at all. In light of this evidence, we review the current evidence for the neuroadaptive mechanisms underlying benzodiazepine tolerance, including changes of (i) the GABA(A) receptor (subunit expression and receptor coupling), (ii) intracellular changes stemming from transcriptional and neurotrophic factors, (iii) ionotropic glutamate receptors, (iv) other neurotransmitters (serotonin, dopamine, and acetylcholine systems), and (v) the neurosteroid system. From the large variance in the studies, it appears that either different (simultaneous) tolerance mechanisms occur depending on the benzodiazepine effect, or that the tolerance inducing mechanism depends on the activated GABA(A) receptor subtypes. Importantly, there is no convincing evidence that tolerance occurs with alpha subunit subtype-selective compounds acting at the benzodiazepine site. PMID- 22536230 TI - Gerontechnology: providing a helping hand when caring for cognitively impaired older adults-intermediate results from a controlled study on the satisfaction and acceptance of informal caregivers. AB - The incidence of cognitive impairment in older age is increasing, as is the number of cognitively impaired older adults living in their own homes. Due to lack of social care resources for these adults and their desires to remain in their own homes and live as independently as possible, research shows that the current standard care provisions are inadequate. Promising opportunities exist in using home assistive technology services to foster healthy aging and to realize the unmet needs of these groups of citizens in a user-centered manner. ISISEMD project has designed, implemented, verified, and assessed an assistive technology platform of personalized home care (telecare) for the elderly with cognitive impairments and their caregivers by offering intelligent home support services. Regions from four European countries have carried out long-term pilot-controlled study in real-life conditions. This paper presents the outcomes from intermediate evaluations pertaining to user satisfaction with the system, acceptance of the technology and the services, and quality of life outcomes as a result of utilizing the services. PMID- 22536231 TI - Bacterial contamination of clothes and environmental items in a third-level hospital in Colombia. AB - Objective. This study evaluates the bacterial contamination rate of items in the hospital setting that are in frequent contact with patients and/or physicians. By determining the bacterial species and the associated antibiotic resistance that patients are exposed to. Methods. Hospital-based cross-sectional surveillance study of potential bacterial reservoirs. Cultures from 30 computer keyboards, 32 curtains, 40 cell phones, 35 white coats, and 22 ties were obtained. Setting. The study was conducted an urban academic 650-bed teaching hospital providing tertiary care to the city of Medellin, Colombia. Results. In total, 235 bacterial isolates were obtained from 159 surfaces sampled. 98.7% of the surfaces grew positive bacterial cultures with some interesting resistance profiles. Conclusion. There are significant opportunities to reduce patient exposure to frequently pathogenic bacteria in the hospital setting; patients are likely exposed to many bacteria through direct contact with white coats, curtains, and ties. They may be exposed to additional bacterial reservoirs indirectly through the hands of clinicians, using computer keyboards and cell phones. PMID- 22536232 TI - Hyperandrogenism Does Not Influence Metabolic Parameters in Adolescent Girls with PCOS. AB - Background. Underlying insulin resistance and/or obesity has clearly been implicated in the development of metabolic syndrome in adolescents and young adults with polycystic ovarian syndrome (PCOS). It is not clear however what role hyperandrogenism has on the development of metabolic syndrome or its role on those metabolic parameters associated with metabolic syndrome. Methods. We studied 107 adolescent girls; 54 had PCOS according to NIH criteria. Data was obtained for systolic and diastolic blood pressure (SBP and DBP), body mass index (BMI), total testosterone (T), luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin, fasting lipid profile, and glucose. The PCOS group was divided initially into subgroups according to BMI (kg/m(2)), then based on T (ng/dL) levels as follows: High Testosterone PCOS (HT), Intermediate Testosterone PCOS (IT), Obese and Normal Testosterone (ONT), and lean and normal T (Control, C). t-test analysis was performed in between all the groups. Results. There was no statistical difference between HT and IT, HT and ONT, or IT and ONT in SBP, DBP, fasting blood glucose, lipid panel, LH, FSH, and prolactin levels. The control group had lower SBP and BMI comparing with ONT, IT, and HT groups. There were no statistical differences found in DBP, fasting blood glucose, lipid panel, LH, FSH, or Prolactin. Conclusion. Metabolic profile in adolescent girls with PCOS is not affected by either the presence of hyperandrogenism or the degree of hyperandrogenism. PMID- 22536233 TI - How can we increase postpartum glucose screening in women at high risk for gestational diabetes mellitus? AB - Women with a history of gestational diabetes mellitus (GDM) are at increased risk for diabetes mellitus but postpartum followup is problematic for frequent nonattendance. Our aim was to increase coverage of postpartum oral glucose tolerance tests (ppOGTTs) and examine associated factors. This was a prospective observational study of altogether 266 high-risk women for GDM from 2005 to 2008 in four Finnish municipalities. The groups were as follows: women (n = 54) who had previously participated in early pregnancy lifestyle intervention study and high-risk women (n = 102) from the same municipalities studied within one-year after delivery. Furthermore, in two neighboring municipalities nurses were reminded to perform a ppOGTT on high-risk women (n = 110). The primary outcome was the prevalence of ppOGTT performed and associated factors. Overall the ppOGTT was performed in 35.7% of women. Only 14.7% of women returned for testing to health care centers, 30.9% after a reminder in municipalities, and 82.5% to the central hospital, respectively. The most important explaining factor was a special call or reminder from the central hospital (OR 13.4 (4.6-38.1), P < 0.001). Thus, additional reminders improved communication between primary care and secondary care and more attention to postpartum oral glucose testing in primary care are of great importance. PMID- 22536234 TI - Changes in maternal glucose metabolism after the administration of dexamethasone for fetal lung development. AB - Aims. Antenatal dexamethasone administration for fetal lung development may impair maternal glucose tolerance. In this study, we investigated whether glucose and insulin levels differed among singleton and twin pregnancies and pregnancies with impaired glucose tolerance (IGT) after treatment with dexamethasone. Methods. Singleton pregnancies, twin pregnancies, and pregnancies with IGT between 28 and 33 weeks of gestation whose mothers were treated with dexamethasone were enrolled in this study. Exclusion criteria included gestational hypertension, diabetes, renal disorders, and infectious diseases. The fasting plasma glucose and insulin levels were checked before administration and 24 h, 48 h, and 72 h after treatment was completed. Results. Mean glucose levels were significantly higher in the twin pregnancy and IGT groups at 24 h and 48 h after the administration of dexamethasone than those in the singleton pregnancy group (P < 0.05). Although there was no significant difference in glucose levels before administration and 72 h after dexamethasone administration among the three groups, insulin levels in the IGT group were significantly higher (P < 0.05). Insulin levels in the singleton pregnancy group at 24 h and 48 h after treatment were significantly lower than in the twin and IGT groups. Conclusion. The effects on maternal fasting blood glucose and insulin levels of dexamethasone administrated to promote fetal lung maturation correlated with embryo number and the presence of IGT. PMID- 22536235 TI - Checklist for the structural description of the deep phenotype in disorders of sexual development. AB - This paper addresses the question, how the variations of the deep phenotype in disorders of sex development (DSD) are appropriately described. This is a relevant question, because extensive phenotypic variability occurs in gonads and sex ducts. With the advance of video endoscopy and laparoscopy, fresh insight in gonadal and sex duct anatomy is emerging. So far, an attempt to standardize the diagnostic approach and, in particular, how to document these findings has not been published. We propose a standardized examination schedule for these procedures. It consists of 5 pictures of relevant anatomic features. For laparoscopy, it includes two pictures each of gonads and sex ducts on either side and an image of the retrovesical space. For endoscopy, the examination of the ureteric orifices, the posterior urethra, and the urogenital sinus derivates is recommended. Adherence of a standardized schedule and image storing enhances patient autonomy, because they can carry their examination for a second opinion without need for repeated examination. Physicians and scientists create a structured image library that facilitates the comparison of clinical outcomes, research on genotype phenotype associations and may lead to better classifications. PMID- 22536236 TI - Fetuin-A Characteristics during and after Pregnancy: Result from a Case Control Pilot Study. AB - Objective. Fetuin-A has been associated with gestational diabetes mellitus (GDM). We investigated fetuin-A levels during and after pregnancy in women with GDM. Fetuin-A measurements were performed in 10 women with GDM and 10 age and body mass index (BMI) matched healthy pregnant women. All women underwent an oral glucose tolerance test (OGTT) in and 3 months after gestation. Results. Fasting fetuin-A correlated with BMI in women with former GDM (r = 0.90, P < 0.0001) but showed no association with parameters of glucose tolerance in women with GDM or post-GDM. GDM featured significantly lower insulin sensitivity and higher insulin and C-peptide secretion profiles compared to NGT during pregnancy (P < 0.05). Fasting and postprandial fetuin-A did not differ between groups, neither during nor after pregnancy. Conclusion. Fetuin-A is not influenced by glucose tolerance during or after pregnancy or acute glucose elevations following glucose ingestion in young women, but closely relates to BMI early postpartum. PMID- 22536237 TI - Trastuzumab and Gemcitabine in Pretreated HER2 Overexpressing Metastatic Breast Cancer Patients: Retrospective Analysis of Our Series. AB - Trastuzumab-based regimes improved clinical outcome in women with overexpressing HER2 metastatic breast cancer, mainly due to the availability of different combination therapies, clinically active and well tolerated. In this study we retrospectively evaluated clinical activity and toxicity of trastuzuamb plus gemcitabine regimen in heavily pretreated HER2 positive metastatic breast cancer patients. Although the observed population was heavily pretreated, the evaluated regimen was notably effective in terms of response rate, time to progression and survival, with very mild toxicity. These data suggest that in over expressing HER2 metastatic breast cancer patients, sequential trastuzumab based chemotherapeutic regimens can achieve good response rate with prolonged TTP in responding patients, even after other target therapy such as lapatinib based combinations. PMID- 22536238 TI - Benign and Suspicious Ovarian Masses-MR Imaging Criteria for Characterization: Pictorial Review. AB - Ovarian masses present a special diagnostic challenge when imaging findings cannot be categorized into benign or malignant pathology. Ultrasonography (US), Computed Tomography (CT), and Magnetic Resonance Imaging (MRI) are currently used to evaluate ovarian tumors. US is the first-line imaging investigation for suspected adnexal masses. Color Doppler US helps the diagnosis identifying vascularized components within the mass. CT is commonly performed in preoperative evaluation of a suspected ovarian malignancy, but it exposes patients to radiation. When US findings are nondiagnostic or equivocal, MRI can be a valuable problem solving tool, useful to give also surgical planning information. MRI is well known to provide accurate information about hemorrhage, fat, and collagen. It is able to identify different types of tissue contained in pelvic masses, distinguishing benign from malignant ovarian tumors. The knowledge of clinical syndromes and MRI features of these conditions is crucial in establishing an accurate diagnosis and determining appropriate treatment. The purpose of this paper is to illustrate MRI findings in neoplastic and non-neoplastic ovarian masses, which were assessed into three groups: cystic, solid, and solid/cystic lesions. MRI criteria for the correct diagnosis and characteristics for differentiating benign from malignant conditions are shown in this paper. PMID- 22536239 TI - New perspectives on tooth wear. AB - Some of the efforts that have been made to document tooth wear are reviewed here with an emphasis on nonhuman mammals, literature with which dentists may not be very familiar. We project a change in research strategy from the description of wear at various scales of measurement towards investigation of the mechanical mechanisms that actually create the texture of a worn surface. These studies should reveal exactly how tooth tissue is lost and what aspects of the structure of dental tissues affect this. The most important aspects of the interaction between the tooth surface and wear particles would appear to be particle size, particle shape, their mechanical properties with respect to those of tooth tissues, and the influence of saliva. PMID- 22536229 TI - Nicotinamide, NAD(P)(H), and Methyl-Group Homeostasis Evolved and Became a Determinant of Ageing Diseases: Hypotheses and Lessons from Pellagra. AB - Compartmentalized redox faults are common to ageing diseases. Dietary constituents are catabolized to NAD(H) donating electrons producing proton-based bioenergy in coevolved, cross-species and cross-organ networks. Nicotinamide and NAD deficiency from poor diet or high expenditure causes pellagra, an ageing and dementing disorder with lost robustness to infection and stress. Nicotinamide and stress induce Nicotinamide-N-methyltransferase (NNMT) improving choline retention but consume methyl groups. High NNMT activity is linked to Parkinson's, cancers, and diseases of affluence. Optimising nicotinamide and choline/methyl group availability is important for brain development and increased during our evolution raising metabolic and methylome ceilings through dietary/metabolic symbiotic means but strict energy constraints remain and life-history tradeoffs are the rule. An optimal energy, NAD and methyl group supply, avoiding hypo and hyper-vitaminoses nicotinamide and choline, is important to healthy ageing and avoids utilising double-edged symbionts or uncontrolled autophagy or reversions to fermentation reactions in inflammatory and cancerous tissue that all redistribute NAD(P)(H), but incur high allostatic costs. PMID- 22536240 TI - Bone regeneration in artificial jaw cleft by use of carbonated hydroxyapatite particles and mesenchymal stem cells derived from iliac bone. AB - Objectives of the Study. Cleft lip and palate (CLP) is a prevalent congenital anomaly in the orofacial region. Autogenous iliac bone grafting has been frequently employed for the closure of bone defects at the jaw cleft site. Since the related surgical procedures are quite invasive for patients, it is of great importance to develop a new less invasive technique. The aim of this study was to examine bone regeneration with mesenchyme stem cells (MSCs) for the treatment of bone defect in artificially created jaw cleft in dogs. Materials and Methods. A bone defect was prepared bilaterally in the upper incisor regions of beagle dogs. MSCs derived from iliac bone marrow were cultured and transplanted with carbonated hydroxyapatite (CAP) particles into the bone defect area. The bone regeneration was evaluated by standardized occlusal X-ray examination and histological observation. Results. Six months after the transplantation, perfect closure of the jaw cleft was achieved on the experimental side. The X-ray and histological examination revealed that the regenerated bone on the experimental side was almost equivalent to the original bone adjoining the jaw cleft. Conclusion. It was suggested that the application of MSCs with CAP particles can become a new treatment modality for bone regeneration for CLP patients. PMID- 22536242 TI - Tooth wear. PMID- 22536241 TI - Quality-Shaping Factors and Endodontic Treatment amongst General Dental Practitioners with a Focus on Denmark. AB - There is a gap between the endodontic outcome that can be achieved and the outcome observed on the basis of worldwide general dental practitioner data. The quality of root canal treatment (RCT) is shaped by the dentist's knowledge, attitude, and skills, but it may also be influenced by the patient's demands and degree of satisfaction. The topic has only been sparsely investigated. Although dental health has increased over the years in Denmark, the number of performed root fillings has also increased, probably because the number of tooth extractions have declined and more molar teeth have been treated. Caries appears to be the main cause for performing RCT and a preventive approach by employing stepwise excavation may reduce RCT, but this strategy does not remove the gap. Factors influencing RCT quality could be the status on adoption of nickel titanium rotary technology, more focus on infection control (rubber dam use, knowledge of factors important for prognosis), as dentists often think that they are good at doing RCT, but often perform inadequately, an alteration of clinician's awareness of their performance in the context of dental practices, seems warranted. Finally, the development of new preventive modalities for pulp and apical inflammation are crucial. PMID- 22536243 TI - Supernumerary teeth in Indian children: a survey of 300 cases. AB - The aim of this investigation was to study children with supernumerary teeth who visited the Department of Pedodontics and Preventive Dentistry, Government Dental College and Hospital, Rohtak, Haryana, India. Only children with supernumerary teeth were included in the study while patients having supernumerary teeth with associated syndromes were excluded. Supernumeraries were detected by clinical and radiographic examination. The results indicated that males were affected more than females with a sex ratio of 2.9 : 1. Single supernumerary tooth was seen in 79% of the patients, 20% had double, and 1% had three or more supernumeraries. Premaxillary supernumeraries accounted for 93.8% of the cases. Conical shaped supernumerary teeth were the most common type (59.7%). Majority of supernumeraries remained unerupted (65%). Fusion of supernumerary tooth with a regular tooth was observed in 4% of the patients. Talon cusp, an associated dental anomaly, was seen in 5% of the cases. Simultaneous hypodontia occurred in 2.3% of patients with supernumeraries. PMID- 22536244 TI - Application of CZE Method in Routine Analysis for Determination of B-Complex Vitamins in Pharmaceutical and Veterinary Preparations. AB - A competitive CZE method for quality control analysis of multivitamin preparations and veterinary products containing B-group vitamins was developed. Vitamins of interest are thiamine hydrochloride (B(1)), thiamine monophosphate chloride (B(1a)), riboflavine (B(2)), riboflavine-5'monophosphate (B(2a)), nicotinamide (B(3)), d-pantothenic acid calcium salt (B(5)), pyridoxine hydrochloride (B(6)), folic acid (B(9)), and 4-aminobenzoic acid (B(10)). These analytes were separated optimizing the experimental conditions in 20 mM tetraborate buffer pH = 9.2 as a BGE (background electrolyte), on a Beckman P/ACE System MDQ instrument, using uncoated fused silica capillary. The effective capillary length was of 49.5 cm, I.D. = 50 MUm, the applied voltage 20 kV and the temperature 25 degrees C. Detection was performed by a diode array detector at 214 nm for all vitamins except B(5) (190 nm) and B(2a) (260 nm). Separation time was about 9 min. After experimental conditions optimization, the proposed method was validated. Precision of migration time and corrected peak area, linearity range, LOD and LOQ, accuracy (recovery), robustness, and ruggedness were evaluated for each analyte demonstrating the good reliability of the method. Analyses of the pharmaceutical real samples were performed and confirmed the versatility of this method. PMID- 22536245 TI - Antiproliferative factor-induced changes in phosphorylation and palmitoylation of cytoskeleton-associated protein-4 regulate its nuclear translocation and DNA binding. AB - Cytoskeleton-associated protein 4 (CKAP4) is a reversibly palmitoylated and phosphorylated transmembrane protein that functions as a high-affinity receptor for antiproliferative factor (APF)-a sialoglycopeptide secreted from bladder epithelial cells of patients with interstitial cystitis (IC). Palmitoylation of CKAP4 by the palmitoyl acyltransferase, DHHC2, is required for its cell surface localization and subsequent APF signal transduction; however, the mechanism for APF signal transduction by CKAP4 is unknown. In this paper, we demonstrate that APF treatment induces serine phosphorylation of residues S3, S17, and S19 of CKAP4 and nuclear translocation of CKAP4. Additionally, we demonstrate that CKAP4 binds gDNA in a phosphorylation-dependent manner in response to APF treatment, and that a phosphomimicking, constitutively nonpalmitoylated form of CKAP4 localizes to the nucleus, binds DNA, and mimics the inhibitory effects of APF on cellular proliferation. These results reveal a novel role for CKAP4 as a downstream effecter for APF signal transduction. PMID- 22536246 TI - Alternative macroautophagic pathways. AB - Macroautophagy is a bulk degradation process that mediates the clearance of long lived proteins, aggregates, or even whole organelles. This process includes the formation of autophagosomes, double-membrane structures responsible for delivering cargo to lysosomes for degradation. Currently, other alternative autophagy pathways have been described, which are independent of macroautophagic key players like Atg5 and Beclin 1 or the lipidation of LC3. In this review, we highlight recent insights in indentifying and understanding the molecular mechanism responsible for alternative autophagic pathways. PMID- 22536247 TI - Lipophagy: connecting autophagy and lipid metabolism. AB - Lipid droplets (LDs), initially considered "inert" lipid deposits, have gained during the last decade the classification of cytosolic organelles due to their defined composition and the multiplicity of specific cellular functions in which they are involved. The classification of LD as organelles brings along the need for their regulated turnover and recent findings support the direct contribution of autophagy to this turnover through a process now described as lipophagy. This paper focuses on the characteristics of this new type of selective autophagy and the cellular consequences of the mobilization of intracellular lipids through this process. Lipophagy impacts the cellular energetic balance directly, through lipid breakdown and, indirectly, by regulating food intake. Defective lipophagy has been already linked to important metabolic disorders such as fatty liver, obesity and atherosclerosis, and the age-dependent decrease in autophagy could underline the basis for the metabolic syndrome of aging. PMID- 22536248 TI - Nongenomic Mechanisms of PTEN Regulation. AB - A large amount of data supports the view that PTEN is a bona fide tumor suppressor gene. However, recent evidence suggests that derailment of cellular localization and expression levels of functional nonmutated PTEN is a determining force in inducing abnormal cellular and tissue outcomes. As the cellular mechanisms that regulate normal PTEN enzymatic activity resolve, it is evident that deregulation of these mechanisms can alter cellular processes and tissue architecture and ultimately lead to oncogenic transformation. Here we discuss PTEN ubiquitination, PTEN complex formation with components of the adherens junction, PTEN nuclear localization, and microRNA regulation of PTEN as essential regulatory mechanisms that determine PTEN function independent of gene mutations and epigenetic events. PMID- 22536249 TI - Pexophagy: the selective degradation of peroxisomes. AB - Peroxisomes are single-membrane-bounded organelles present in the majority of eukaryotic cells. Despite the existence of great diversity among different species, cell types, and under different environmental conditions, peroxisomes contain enzymes involved in beta-oxidation of fatty acids and the generation, as well as detoxification, of hydrogen peroxide. The exigency of all eukaryotic cells to quickly adapt to different environmental factors requires the ability to precisely and efficiently control peroxisome number and functionality. Peroxisome homeostasis is achieved by the counterbalance between organelle biogenesis and degradation. The selective degradation of superfluous or damaged peroxisomes is facilitated by several tightly regulated pathways. The most prominent peroxisome degradation system uses components of the general autophagy core machinery and is therefore referred to as "pexophagy." In this paper we focus on recent developments in pexophagy and provide an overview of current knowledge and future challenges in the field. We compare different modes of pexophagy and mention shared and distinct features of pexophagy in yeast model systems, mammalian cells, and other organisms. PMID- 22536250 TI - Receptor proteins in selective autophagy. AB - Autophagy has long been thought to be an essential but unselective bulk degradation pathway. However, increasing evidence suggests selective autophagosomal turnover of a broad range of substrates. Bifunctional autophagy receptors play a key role in selective autophagy by tethering cargo to the site of autophagosomal engulfment. While the identity of molecular components involved in selective autophagy has been revealed at least to some extent, we are only beginning to understand how selectivity is achieved in this process. Here, we summarize the mechanistic and structural basis of receptor-mediated selective autophagy. PMID- 22536252 TI - Cell adhesion in cancer. PMID- 22536251 TI - Mitochondrial dynamics: functional link with apoptosis. AB - Mitochondria participate in a variety of physiologic processes, such as ATP production, lipid metabolism, iron-sulfur cluster biogenesis, and calcium buffering. The morphology of mitochondria changes dynamically due to their frequent fusion and division in response to cellular conditions, and these dynamics are an important constituent of apoptosis. The discovery of large GTPase family proteins that regulate mitochondrial dynamics, together with novel insights into the role of mitochondrial fusion and fission in apoptosis, has provided important clues to understanding the molecular mechanisms of cellular apoptosis. In this paper, we briefly summarize current knowledge of the role of mitochondrial dynamics in apoptosis and cell pathophysiology in mammalian cells. PMID- 22536254 TI - Anxiety and depression in tinnitus patients: 5-year follow-up assessment after completion of habituation therapy. AB - Treatment programs based on a neurophysiological model have shown a positive effect on anxiety and depression in tinnitus patients. The aim of this paper was to assess the long-term effect of tinnitus habituation therapy. Sixty-eight individuals were treated with a comprehensive therapy program. The degree of anxiety and depression was assessed before, after, and five years after intervention using the Hospital Anxiety and Depression Scale. The positive and significant changes achieved after habituation therapy (pre = 1.10, post = 0.92 for anxiety and pre = 0.77, post = 0.62 for depression) were maintained five years after treatment ended (0.87 for anxiety and 0.52 for depression). A regression analysis revealed that individual evaluation of the treatment lectures, self-reported health condition, individual experiences of hyperacusis, and hearing loss could explain 44.3% of the variation in anxiety and 30.5% of the variation in depression posttreatment. Five years after, individual evaluation of the treatment lectures and self-reported health condition explained 22.2% of the variation in anxiety. These factors and individual experiences of hyperacusis could further explain 34.9% of the variation in depression. The effect of a neurophysiologic-based management treatment was maintained five years after treatment ended, indicating that the patients continued the improvement process without becoming dependent on professionals. PMID- 22536253 TI - Novel therapies for aggressive B-cell lymphoma. AB - Aggressive B-cell lymphoma (BCL) comprises a heterogeneous group of malignancies, including diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, and mantle cell lymphoma (MCL). DLBCL, with its 3 subtypes, is the most common type of lymphoma. Advances in chemoimmunotherapy have substantially improved disease control. However, depending on the subtype, patients with DLBCL still exhibit substantially different survival rates. In MCL, a mature B-cell lymphoma, the addition of rituximab to conventional chemotherapy regimens has increased response rates, but not survival. Burkitt lymphoma, the most aggressive BCL, is characterized by a high proliferative index and requires more intensive chemotherapy regimens than DLBCL. Hence, there is a need for more effective therapies for all three diseases. Increased understanding of the molecular features of aggressive BCL has led to the development of a range of novel therapies, many of which target the tumor in a tailored manner and are summarized in this paper. PMID- 22536255 TI - The importance of right otitis media in childhood language disorders. AB - Studies relating chronic otitis media and language disorders in children have not reported consistent findings. We carried out the first selective study aimed at discerning the role of chronic right otitis media in children less than 3 years of age in language development. A total of 35 children were studied using a full linguistic protocol, auditory brainstem responses, and middle latency responses. Twelve children had a history of chronic exclusive right otitis media. Seventeen age-matched children were selected as controls. Also, three children having a history of chronic left otitis media were compared with three age-matched controls. Linguistic tests showed significant differences between patients and controls in phonetic, phonological, and syntax scores but not semantics. Correlation studies between linguistic scores and auditory evoked responses in the whole cohort showed a significant coefficient in phonetic and phonological domains. These results emphasize the causative effect of right ear chronic otitis media and indicate that it mainly impairs phonetic and phonological coding of sounds, which may have implications for prophylactic treatment of at-risk children. PMID- 22536256 TI - The Utility of Serum IgG4 Concentrations as a Biomarker. AB - IgG4-related disease is a new disease entity involving IgG4 in its clinical presentation and having 6 characteristic features: (1) systemic involvement; (2) solitary or multiple lesions showing diffuse or localized swelling, masses, nodules, and/or wall thickening on imaging; (3) high serum IgG4 concentration >135 mg/dL; (4) abundant infiltration of lymphoplasmacytes and IgG4-bearing plasma cells; (5) a positive response to corticosteroid therapy; and (6) complications of other IgG4-related diseases. To date, most IgG4-related diseases have been recognized as extrapancreatic lesions of autoimmune pancreatitis. This paper will discuss the utility of IgG4 as a biomarker of IgG4-related diseases, including in the diagnosis of autoimmune pancreatitis and its differentiation from pancreatic cancer, in the prediction of relapse, in the long-term follow-up of patients with autoimmune pancreatitis and normal or elevated IgG4 concentrations, and in patients with autoimmune pancreatitis and extrapancreatic lesions, as well as the role of IgG4 in the pathogenesis of IgG4-related disease. PMID- 22536258 TI - Biologicals. PMID- 22536257 TI - Regulatory T cells in type 1 autoimmune pancreatitis. AB - Autoimmune pancreatitis (AIP) is a newly recognized pancreatic disorder. Recently, International Consensus Diagnostic Criteria for AIP (ICDC) was published. In this ICDC, AIP was classified into Type 1 and Type 2. Patients with Type 1 AIP have several immunologic and histologic abnormalities specific to the disease, including increased levels of serum IgG4 and storiform fibrosis with infiltration of lymphocytes and IgG4-positive plasmacytes in the involved organs. Among the involved organs showing extrapancreatic lesions, the bile duct is the most common, exhibiting sclerosing cholangitis (IgG4-SC). However, the role of IgG4 is unclear. Recently, it has been reported that regulatory T cells (Tregs) are involved in both the development of various autoimmune diseases and the shift of B cells toward IgG4, producing plasmacytes. Our study showed that Tregs were increased in the pancreas with Type 1 AIP and IgG4-SC compared with control. In the patients with Type 1 AIP and IgG4-SC, the numbers of infiltrated Tregs were significantly positively correlated with IgG4-positive plasma cells. In Type 1 AIP, inducible costimulatory molecule (ICOS)(+) and IL-10(+) Tregs significantly increased compared with control groups. Our data suggest that increased quantities of ICOS(+) Tregs may influence IgG4 production via IL-10 in Type 1 AIP. PMID- 22536259 TI - The Rare Coincidence: Nonrecurrent Laryngeal Nerve Pointed by a Zuckerkandl's Tubercle. AB - The safety of thyroid operations mainly depends on complete anatomical knowledge. Anatomical and embryological variations of the inferior laryngeal nerve (ILN), of the thyroid gland itself and unusual relations between ILN and the gland threaten operation security are discussed. The patient with toxic multinodular goiter is treated with total thyroidectomy. During dissection of the right lobe, the right ILN which has nonrecurrent course arising directly from cervical vagus nerve is identified and fully isolated until its laryngeal entry. At the operation, we observe bilateral Zuckerkandl's tubercles (ZTs) as posterior extension of both lateral lobes. The left ILN has usual recurrent course in the trachea-esophageal groove. The right ZT is placed between upper and middle third of the lobe points the nonrecurrent ILN. The coincidence of non-recurrent ILN pointed by a ZT is rare anatomical and embryological feature of this case. Based on anatomical and embryological variations, we suggest identification and full exposure of ILN before attempting excision of adjacent structures, like the ZT which has surgical importance for completeness of thyroidectomy. PMID- 22536260 TI - Unusual presentation of a colonic sarcoidosis. AB - Sarcoidosis is a multisystemic disorder of unknown cause that affects almost every tissue in the body. Colon is an extremely rare location of this disease. Clinical presentation, endoscopic appearances, and radiologic findings are not specific and may mimic much other affection. We report the case of a 64-year-old woman with inactive pulmonary sarcoidosis who presented alternating constipation and diarrhea. Colonoscopy revealed a stenotic tumor in the ascending colon. Histology failed to determine the nature of the lesion. Radiologic findings are those of a long stenotic tumor of the ascending colon associated with a multiple satellite lymphadenopathy. Endoscopic and radiologic descriptions are highly suggestive of a malignancy. The patient underwent a laparotomy, and a right hemicolectomy was performed. Examination of the resected specimen showed follicular structure with central epitheloid and giant cells and surrounding fibroblasts. These findings made the diagnosis of colonic sarcoidosis. The nonspecificity of the endoscopic and radiological signs of gastrointestinal sarcoidosis and the extreme rarity of colonic location make the preoperative diagnosis unlikely. The diagnosis will be then made only on histological examination of surgical specimens. We describe, through this observation, the results of paraclinical investigations that can suggest diagnosis and perhaps avoid surgery. PMID- 22536261 TI - Bilateral Insufficiency Fracture of the Pelvis Following THA: A Case Report. AB - Insufficiency fracture is of the stress fractures and is caused by repetitive stress on fragile bone. Insufficiency fractures of pubic rami are rare occurrences in association with total hip arthroplasty (THA). Postoperative stress fractures occur due to increase of patients activity following years of disability. The physician should consider the possibility of a pelvic insufficiency fracture in patients with RA after THA, if the patients present with groin pain. We demonstrate here the first case of bilateral insufficiency fracture of pubic rami and iliac bone following THA. PMID- 22536262 TI - Cerebral subdural hematoma following spinal anesthesia: report of two cases. AB - Postdural puncture headache and cerebral subdural hematoma are among complications of spinal anesthesia with some common characteristics; however misdiagnosis of these two could result in a catastrophic outcome or prevent unwanted results by urgent interventions. With the purpose of increasing awareness of such complications and a speedy diagnosis, we report two cases of postspinal anesthesia headache that was timely diagnosed as cerebral subdural hematoma and prevented the likelihood of a disastrous outcome. PMID- 22536263 TI - The Role of Partial Nephrectomy without Arterial Embolization in Giant Renal Angiomyolipoma. AB - Angiomyolipoma is a benign neoplasm composed of varying admixtures of blood vessels, smooth muscle cells, and adipose tissue. Because of an increased risk of spontaneous haemorrhage, surgical approach is needed greater than 4-8 cm size. We here report our partial nephrectomy experience in the 24 cm size giant angiomyolipoma. 26-year-old woman referred to our clinic with a 24 cm size angiomyolipoma in her lower pole of right kidney. The inferior vena cava was deviated to the left by the mass. All the blood tests were normal and we offered her the choices of partial nephrectomy or nephrectomy. Right subcostal approach was used. The patient underwent resection of the mass with a safety region of 1 cm. Frozen section evaluation was consistent with angiomyolipoma and free for surgical margin. Warm ischemia time was 35 min. and intraoperative bleeding volume was 200 cc. Postoperative 2nd day the drain was taken and hospital stay was 4 days. In literature we observed very rare angiomyolipoma cases with such a large dimension treated by partial nephrectomy without arterial embolization. If technically suitable partial nephrectomy is the main chioce in this kind of benign lesions in young patients. PMID- 22536264 TI - Pulmonary Rehabilitation Using Modified Threshold Inspiratory Muscle Trainer (IMT) in Patients with Tetraplegia. AB - It is aimed to present the usefulness of inspiratory muscle trainer (IMT) in treatment of a 20-year-old male patient with diaphragmatic paralysis and tetraplegia due to spinal cord injury (SCI), and supporting effect of IMT in recovering from respiratory failure by rendering his diaphragm functions. The treatment was applied through the tracheostomy cannula by a modified IMT device. After applying IMT for three weeks, it was observed that the diaphragm recovered its functions in electromyography (EMG) test. As a result, in this study, we present a case where a patient could live without any respiratory device for the rest of his life with the help of modified IMT. PMID- 22536265 TI - Juxta cortical tibia metastatic deposition in gastric cancer: a case report. AB - We report a 41 years old man with rapidly growing and tender lump on the anteromedial surface of tibia. The patient had the history of gastrectomy and gastrojejunostomy due to gastric carcinoma. On admission, the Simple X-ray of lower extremity disclosed a slight thinning of the anterior cortex of tibia without cortical destruction. The whole-body bone scan with (99m)TC MDP revealed activity of lesion in all 3 phases. The histopathological evaluation showed an infiltration of bone with tumor cells. Review No the literature revealed in previous cases of skeletal metastasis from gastric cancer in the tibia like this. PMID- 22536266 TI - Myocardial infarction in a young female with palindromic rheumatism: a consequence of negative remodeling. AB - Palindromic rheumatism is a rare disease associated with systemic inflammation. Negative or constrictive coronary artery remodeling is typically not seen until the 7th or 8th decade of life. We report a case of a young female with palindromic rheumatism who suffered a non-ST segment elevation myocardial infarction secondary to a flow-limiting lesion that demonstrated negative remodeling by intravascular ultrasound (IVUS). PMID- 22536267 TI - Recurrent acute pancreatitis probably induced by rosuvastatin therapy: a case report. AB - Context. Approximately 1.4-2% of all cases of acute pancreatitis are drug related in general population. The literature on statin-induced pancreatitis consists primarily of anecdotal case reports. We report a case of possible rosuvastatin induced pancreatitis. Case Report. A 67-year-old female presented with progressively worsening abdominal pain and vomiting for 7 days. Home medications included rosuvastatin and clonidine. CT scan of abdomen, with intravenous contrast, showed findings consistent with acute pancreatitis. She responded to conservative management. Rosuvastatin was resumed at the time of discharge from the hospital, and she presented two months later with recurrence of acute pancreatitis. Further workup ruled out all likely causes of acute pancreatitis. Rosuvastatin was stopped completely when she was discharged the second time, and she did not have any further episodes of acute pancreatitis. She was completely asymptomatic throughout the 18-month follow-up period. Conclusion. This paper reinforces the possible association of rosuvastatin, a novel statin, with acute pancreatitis, even though the exact underlying mechanism of statin-induced pancreatitis remains unknown. PMID- 22536268 TI - Lower extremity cutaneous lesions as the initial presentation of metastatic adenocarcinoma of the colon. AB - Cutaneous metastases from colorectal cancers are rare and are usually present on the abdominal wall or previous surgical incision sites. Remote cutaneous lesions have been reported, however, often occur in the setting of widespread metastatic disease including other visceral secondaries. We present a case of lower extremity cutaneous metastases as the first sign of metastatic disease in a patient with adenocarcinoma of the colon. This case illustrates that new skin lesions may be the initial presentation of metastatic disease in a patient with a history of cancer. PMID- 22536269 TI - Diffusion pattern and hotspot detection of dengue in belo horizonte, minas gerais, Brazil. AB - This study considers the dengue occurrence in the city of Belo Horizonte over the last fifteen years. Approximately 186,000 cases registered from 1996 to 2011 were analyzed. The home address of individuals whose dengue case was notified was used as a proxy for exposure location. For determining possible outbreaks of disease and the specific patterns of dengue cases, spatial statistics used included Kernel's estimation. The occurrence of waves of dengue outbreaks was correlated with climatic and vector presence data. Outbreaks had different durations and intensities: case clustering, thinned out both spatially and temporally. These findings may be useful for public health professionals responsible for fighting the disease providing some tools for improving evaluation of interventions such as vector control and patient care, minimizing the collective and individual burden of the disease. PMID- 22536271 TI - Identification of histoplasma-specific peptides in human urine. AB - Histoplasmosis is a severe dimorphic fungus infection, which is often difficult to diagnose due to similarity in symptoms to other diseases and lack of specific diagnostic tests. Urine samples from histoplasma-antigen-positive patients and appropriate controls were prepared using various sample preparation strategies including immunoenrichment, ultrafiltration, high-abundant protein depletion, deglycosylation, reverse-phase fractions, and digest using various enzymes. Samples were then analyzed by nanospray tandem mass spectrometry. Accurate mass TOF scans underwent molecular feature extraction and statistical analysis for unique disease makers, and acquired MS/MS data were searched against known human and histoplasma proteins. In human urine, some 52 peptides from 37 Histoplasma proteins were identified with high confidence. This is the first report of identification of a large number of Histoplasma-specific peptides from immunoassay-positive patient samples using tandem mass spectrometry and bioinformatics techniques. These findings may lead to novel diagnostic markers for histoplasmosis in human urine. PMID- 22536270 TI - Angiotensin-Converting Enzyme 2 (ACE2) Is a Key Modulator of the Renin Angiotensin System in Health and Disease. AB - Angiotensin-converting enzyme 2 (ACE2) shares some homology with angiotensin converting enzyme (ACE) but is not inhibited by ACE inhibitors. The main role of ACE2 is the degradation of Ang II resulting in the formation of angiotensin 1-7 (Ang 1-7) which opposes the actions of Ang II. Increased Ang II levels are thought to upregulate ACE2 activity, and in ACE2 deficient mice Ang II levels are approximately double that of wild-type mice, whilst Ang 1-7 levels are almost undetectable. Thus, ACE2 plays a crucial role in the RAS because it opposes the actions of Ang II. Consequently, it has a beneficial role in many diseases such as hypertension, diabetes, and cardiovascular disease where its expression is decreased. Not surprisingly, current therapeutic strategies for ACE2 involve augmenting its expression using ACE2 adenoviruses, recombinant ACE2 or compounds in these diseases thereby affording some organ protection. PMID- 22536272 TI - A randomised, double-blind pilot study of enzyme-potentiated desensitisation for prophylaxis of large local reactions to mosquito bites. AB - Primary Objective. To test the hypothesis that two injections of enzyme potentiated mosquito antigen significantly reduce the size of experimental mosquito bites in participants with LLR-MB. Design. Randomised, double-blind, placebo-controlled, parallel group comparison over 3 months. Setting. Hospital outpatient clinic. Participants. Fifty adult participants of both sexes. Interventions. Two injections of mosquito antigen or matching placebo, 6 weeks apart. Main Outcome Measures. Early (1 hour) and late (24 hours) mean square root of erythema area (SREA) following controlled mosquito bite with the second bite given at least 6 weeks following the final injection. Results. At 1 hour, mean SREA was slightly higher in the EPD group compared to placebo after adjusting for baseline values (0.46, 95% CI -6.11 to 7.03), but this was not statistically significant (P = 0.89, ANCOVA analysis); neither were the results at 24 hours ( 2.58, 95% CI -11.73 to 6.57) (P = 0.57). The proportion of participants experiencing a decrease in wheal size at 1 or 24 hours was similar between groups. Conclusions. EPD was not demonstrated to be effective for immediate or delayed LLR-MB. Methodological problems included a high variability in LLR-MB between subjects, suggesting that a crossover design should be used in future. PMID- 22536273 TI - Function of the airway epithelium in asthma. PMID- 22536274 TI - Can Serum-Specific IgE/Total IgE Ratio Predict Clinical Response to Allergen Specific Immunotherapy in Children Monosensitized to House Dust Mite? AB - Background. Allergen-specific immunotherapy (SIT) is one of the important regimens for the treatment of allergic diseases. Predictive tests for the clinical response to SIT are limited. In this study we aimed to evaluate whether specific IgE/total IgE levels can predict clinical improvement in monosensitized patients to house dust mite treated with immunotherapy. Patients and Methods. We analyzed 32 patients who had undergone 2 years of SIT. Serum t-IgE and s-IgE levels, and serum s-IgE/t-IgE ratios were calculated and tested for correlation with clinical response to SIT. Asthma symptom score (ASS), rhinitis symptom score (RSS), pulmonary functions and visual analogue scales (VAS) were evaluated at the beginning and after 2 years. Results. There were 17 boys and 15 girls with the mean age of 10.78 +/- 3.03 years. The mean serum house dust mite s-IgE level was 128.62 +/- 142.61 kU/L, t-IgE 608.90 +/- 529.98 IU/mL, and s-IgE/t-IgE ratio 33.83 +/- 53.18. Before immunotherapy, ASS was 6.23 +/- 1.63, RSS; 8.20 +/- 1.88, VAS; 7.38 +/- 2.01, FEV1 (%); 89.14 +/- 8.48, PEF (%); 88.93 +/- 13.57, and after 2 years, these values were determined as 1.90 +/- 1.10, 3.05 +/- 1.39, 1.35 +/- 1.24, 97.6 +/- 11.26, and 97.0 +/- 11.55, respectively. s-IgE/t-IgE ratio was correlated with change in RSS (r = -0.392, P = 0.08) and VAS (r = -0.367, P = 0.05). Conclusion. Although SIT is very effective treatment, all patients do not benefit from treatment. We assumed that s-IgE/t-IgE ratio would be useful to predict the clinical response to SIT. PMID- 22536275 TI - Increased mortality of respiratory diseases, including lung cancer, in the area with large amount of ashfall from Mount Sakurajima volcano. AB - OBJECTIVES: Mount Sakurajima in Japan is one of the most active volcanoes in the world. This work was conducted to examine the effect of volcanic ash on the chronic respiratory disease mortality in the vicinity of Mt. Sakurajima. METHODS: The present work examined the standardized mortality ratios (SMRs) of respiratory diseases during the period 1968-2002 in Sakurajima town and Tarumizu city, where ashfall from the volcano recorded more than 10.000 g/m2/yr on average in the 1980s. RESULTS: The SMR of lung cancer in the Sakurajima-Tarumizu area was 1.61 (95% CI=1.44-1.78) for men and 1.67 (95% CI=1.39-1.95) for women while it was nearly equal to one in Kanoya city, which neighbors Tarumizu city but located at the further position from Mt. Sakurajima, and therefore has much smaller amounts of ashfall. Sakurajima-Tarumizu area had elevated SMRs for COPDs and acute respiratory diseases while Kanoya did not. CONCLUSIONS: Cristobalite is the most likely cause of the increased deaths from those chronic respiratory diseases since smoking is unlikely to explain the increased mortality of respiratory diseases among women since the proportion of smokers in Japanese women is less than 20%, and SPM levels in the Sakurajima-Tarumizu area were not high. Further studies seem warranted. PMID- 22536276 TI - Study of heavy metal levels among farmers of Muda Agricultural Development Authority, Malaysia. AB - Heavy metals, particularly cadmium, lead, and arsenic, constitute a significant potential threat to human health. This study was conducted to determine the levels of cadmium, lead, and arsenic in nail samples from farmers at Muda Agricultural Development Authority (MADA), Kedah, Malaysia, and evaluate factors that can contribute to their accumulations. A total of 116 farmers participated in this study. Inductively coupled plasma mass spectrometry (ICP-MS) was used to analyze concentration of heavy metals in the nail samples and questionnaires were given to participants to get demographic, health status, and their agricultural activities data. In this paper, the level of heavy metals was within the normal range and varies according to demographic factors. We found that there were significant correlations between working period with level of lead and arsenic (r=0.315 and r=0.242, resp., P<0.01) and age with lead level (r=0.175, P<0.05). Our findings suggested that agricultural activities could contribute to the accumulation of heavy metals in farmers. Hence, the control of environmental levels of and human exposure to these metals to prevent adverse health effects is still an important public health issue. PMID- 22536277 TI - Mycoketide: a CD1c-presented antigen with important implications in mycobacterial infection. AB - Mycobacterium tuberculosis and related mycobacteria species are unique in that the acid-fast bacilli possess a highly lipid-rich cell wall that not simply confers resistance to treatment with acid alcohol, but also controls their survival and virulence. It has recently been established that a fraction of the cell wall lipid components of mycobacteria can function as antigens targeted by the acquired immunity of the host. Human group 1 CD1 molecules (CD1a, CD1b, and CD1c) bind a pool of lipid antigens expressed by mycobacteria and present them to specific T cells, thereby mediating an effective pathway for host defense against tuberculosis. The contrasting and mutually complementary functions of CD1a and CD1b molecules in terms of the repertoire of antigens they bind have been well appreciated, but it remains to be established how CD1c may play a unique role. Nevertheless, recent advances in our understanding of the CD1c structure as well as the biosynthetic pathway of a CD1c-presented antigen, mannose-1, beta phosphomycoketide, expressed by pathogenic mycobacteria now unravel a new aspect of the group 1 CD1 biology that has not been appreciated in previous studies of CD1a and CD1b molecules. PMID- 22536278 TI - Involvement of Heme Oxygenase-1 Induction in the Cytoprotective and Immunomodulatory Activities of Viola patrinii in Murine Hippocampal and Microglia Cells. AB - A number of diseases that lead to injury of the central nervous system are caused by oxidative stress and inflammation in the brain. In this study, NNMBS275, consisting of the ethanol extract of Viola patrinii, showed potent antioxidative and anti-inflammatory activity in murine hippocampal HT22 cells and BV2 microglia. NNMBS275 increased cellular resistance to oxidative injury caused by glutamate-induced neurotoxicity and reactive oxygen species generation in HT22 cells. In addition, the anti-inflammatory effects of NNMBS275 were demonstrated by the suppression of proinflammatory mediators, including proinflammatory enzymes (inducible nitric oxide synthase and cyclooxygenase-2) and cytokines (tumor necrosis factor-alpha and interleukin-1beta). Furthermore, we found that the neuroprotective and anti-inflammatory effects of NNMBS275 were linked to the upregulation of nuclear transcription factor-E2-related factor 2-dependent expression of heme oxygenase-1 in HT22 and BV2 cells. These results suggest that NNMBS275 possesses therapeutic potential against neurodegenerative diseases that are induced by oxidative stress and neuroinflammation. PMID- 22536279 TI - Qiliqiangxin affects L type ca(2+) current in the normal and hypertrophied rat heart. AB - Qiliqiangxin capsule is newly developed Chinese patent drug and proved to be effective and safe for the treatment of patients with chronic heart failure. We compared the effects of different dose Qiliqiangxin on L type Ca(2+) current (I(Ca-L)) between normal and hypertrophied myocytes. A total of 40 healthy Sprague-Dawley rats were used in the study. The rats were randomly divided into two groups (control group and hypertrophy group). Cardiac hypertrophy was induced by pressure overload produced by partial ligation of the abdominal aorta. The control group was the sham-operated group. After 1 month, cardiac ventricular myocytes were isolated from the hearts of rats. Ventricular myocytes were exposed to 10 and 50 MUmol/L Qiliqiangxin, and whole cell patch-clamp technique was used to study the effects of Qiliqiangxin on I(Ca-L). The current densities of I(Ca-L) were similar in control group (-12.70 +/- 0.53 pA/pF, n = 12) and in hypertrophy group (-12.39 +/- 0.62 pA/pF, n = 10). They were not statistically significant. 10 and 50 MUmol/L Qiliqiangxin can decrease I(Ca-L) peak current 48.6%+/-16.8% and 59.0%+/-4.4% in control group. However, the peak current was only reduced 16.73%+/-8.03% by 50 MUmol/L Qiliqiangxin in hypertrophied myocytes. The inhibited action of Qiliqiangxin on I(Ca-L) of hypertrophy group was lower than in control group. Qiliqiangxin affected L-type Ca(2+) channel and blocked I(Ca L), as well as affected cardiac function finally. Qiliqiangxin has diphasic action that is either class IV antiarrhythmic agent or the agent of effect cardiac function. PMID- 22536280 TI - Network-based gene expression biomarkers for cold and heat patterns of rheumatoid arthritis in traditional chinese medicine. AB - IN TRADITIONAL CHINESE MEDICINE (TCM), PATIENTS WITH RHEUMATOID ARTHRITIS (RA) CAN BE CLASSIFIED INTO TWO MAIN PATTERNS: cold-pattern and heat-pattern. This paper identified the network-based gene expression biomarkers for both cold- and heat-patterns of RA. Gene expression profilings of CD4+ T cells from cold-pattern RA patients, heat-pattern RA patients, and healthy volunteers were obtained using microarray. The differentially expressed genes and related networks were explored using DAVID, GeneSpring software, and the protein-protein interactions (PPI) method. EIF4A2, CCNT1, and IL7R, which were related to the up-regulation of cell proliferation and the Jak-STAT cascade, were significant gene biomarkers of the TCM cold pattern of RA. PRKAA1, HSPA8, and LSM6, which were related to fatty acid metabolism and the I-kappaB kinase/NF-kappaB cascade, were significant biomarkers of the TCM heat-pattern of RA. The network-based gene expression biomarkers for the TCM cold- and heat-patterns may be helpful for the further stratification of RA patients when deciding on interventions or clinical trials. PMID- 22536281 TI - Polysaccharides from the Medicinal Mushroom Cordyceps taii Show Antioxidant and Immunoenhancing Activities in a D-Galactose-Induced Aging Mouse Model. AB - Cordyceps taii, an edible medicinal mushroom native to south China, is recognized as an unparalleled resource of healthy foods and drug discovery. In the present study, the antioxidant pharmacological properties of C. taii were systematically investigated. In vitro assays revealed the scavenging activities of the aqueous extract and polysaccharides of C. taii against various free radicals, that is, 1,1-diphenyl-2-picrylhydrazyl radical, hydroxyl radical, and superoxide anion radical. The EC(50) values for superoxide anion-free radical ranged from 2.04 mg/mL to 2.49 mg/mL, which was at least 2.6-fold stronger than that of antioxidant thiourea. The polysaccharides also significantly enhanced the antioxidant enzyme activities (superoxide dismutase, catalase, and glutathione peroxidase) and markedly decreased the malondialdehyde production of lipid peroxidation in a D-galactose-induced aging mouse model. Interestingly, the immune function of the administration group was significantly boosted compared with the D-galactose-induced aging model group. Therefore, the C. taii polysaccharides possessed potent antioxidant activity closely associated with immune function enhancement and free radical scavenging. These findings suggest that the polysaccharides are a promising source of natural antioxidants and antiaging drugs. Consequently, a preliminary chemical investigation was performed using gas chromatography-mass spectroscopy and revealed that the polysaccharides studied were mainly composed of glucose, mannose, and galactose. Fourier transform infrared spectra also showed characteristic polysaccharide absorption bands. PMID- 22536282 TI - Traditional chinese herbal products for coronary heart disease: an overview of cochrane reviews. AB - Objective. The aim of this overview was to evaluate and summarize Cochrane reviews of traditional Chinese herbal products (TCHPs) as the treatment for coronary heart disease (CHD). Methods. We searched the Cochrane Database that was concerned with the effectiveness of TCHPs for CHD. We also searched the Cochrane Central Register of Controlled Trials. Reviews and primary studies of TCHP as the treatment of any type of CHD were included. Data were extracted according to predefined inclusion criteria by two independent reviewers. Results. Six Cochrane reviews were included. They related to a wide range of TCHPs for different types of CHD. Four reviews were concerned with angina pectoris (unstable or stable), one review was concerned with heart failure, and for acute myocardial infarction. No reviews concluded that TCHPs were definitely effective for CHD because of the weak evidence. Eight primary studies were TCHPs from CHD. These studies also maybe result in bias, but better than before. Conclusion. Several Cochrane reviews of TCHPs for the treatment of different types of CHD have recently been published. None of these reviews got definite conclusion favoring the effectiveness of TCHPs due to the weak evidence. With the improved quality of the new registered RCTs. The potential role of TCHPs in treating CHD is anticipated to be detected. PMID- 22536283 TI - Anti-Inflammatory Activities of Cinnamomum cassia Constituents In Vitro and In Vivo. AB - We have investigated the anti-inflammatory effects of Cinnamomum cassia constituents (cinnamic aldehyde, cinnamic alcohol, cinnamic acid, and coumarin) using lipopolysaccharide (LPS)-stimulated mouse macrophage (RAW264.7) and carrageenan (Carr)-induced mouse paw edema model. When RAW264.7 macrophages were treated with cinnamic aldehyde together with LPS, a significant concentration dependent inhibition of nitric oxide (NO), tumor necrosis factor (TNF-alpha), and prostaglandin E2 (PGE(2)) levels productions were detected. Western blotting revealed that cinnamic aldehyde blocked protein expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), nuclear transcription factor kappa B (NF-kappaB), and IkappaBalpha, significantly. In the anti-inflammatory test, cinnamic aldehyde decreased the paw edema after Carr administration, and increased the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in the paw tissue. We also demonstrated cinnamic aldehyde attenuated the malondialdehyde (MDA) level and myeloperoxidase (MPO) activity in the edema paw after Carr injection. Cinnamic aldehyde decreased the NO, TNF-alpha, and PGE(2) levels on the serum level after Carr injection. Western blotting revealed that cinnamic aldehyde decreased Carr-induced iNOS, COX-2, and NF-kappaB expressions in the edema paw. These findings demonstrated that cinnamic aldehyde has excellent anti-inflammatory activities and thus has great potential to be used as a source for natural health products. PMID- 22536284 TI - Ethanolic Extract of Vitis thunbergii Exhibits Lipid Lowering Properties via Modulation of the AMPK-ACC Pathway in Hypercholesterolemic Rabbits. AB - Vitis thunbergii (VT) is a wild grape that has been shown to provide various cardioprotective effects. The present study was designed to examine whether a VT extract could reduce serum lipid levels and prevent atherogenesis in a hypercholesterolemic rabbit model. At the end of an 8-week study, our results showed that a VT extract supplement markedly suppressed the serum levels of cholesterol and low-density lipoprotein, reduced lipid accumulation in liver tissues, and limited aortic fatty streaks. Our findings suggest that the VT extract activated AMPK (5'-adenosine monophosphate-activated protein kinase) with subsequent inhibition of the activation of ACC (acetyl-CoA carboxylase). Our results suggest that this VT extract could be further developed as a potential lipid-lowering agent and as a natural health food to prevent atherogenesis. PMID- 22536285 TI - A Study of the Wound Healing Mechanism of a Traditional Chinese Medicine, Angelica sinensis, Using a Proteomic Approach. AB - Angelica sinensis (AS) is a traditional Chinese herbal medicine that has been formulated clinically to treat various form of skin trauma and to help wound healing. However, the mechanism by which it works remains a mystery. In this study we have established a new platform to evaluate the pharmacological effects of total AS herbal extracts as well as its major active component, ferulic acid (FA), using proteomic and biochemical analysis. Cytotoxic and proliferation promoting concentrations of AS ethanol extracts (AS extract) and FA were tested, and then the cell extracts were subject to 2D PAGE analysis. We found 51 differentially expressed protein spots, and these were identified by mass spectrometry. Furthermore, biomolecular assays, involving collagen secretion, migration, and ROS measurements, gave results that are consistent with the proteomic analysis. In this work, we have demonstrated a whole range of pharmacological effects associated with Angelica sinensis that might be beneficial when developing a wound healing pharmaceutical formulation for the herbal medicine. PMID- 22536286 TI - Chemical Composition, Toxicity and Vasodilatation Effect of the Flowers Extract of Jasminum sambac (L.) Ait. "G. Duke of Tuscany". AB - Phytochemical analysis of the ethanolic Jasmine flower extract of Jasminum sambac (L.) Ait. "G. Duke of Tuscany" revealed the mixtures of coumarins, cardiac glycosides, essential oils, flavonoids, phenolics, saponins, and steroids. However, alkaloids, anthraquinones, and tannins were not detected. By intravenous injection at a single dose of 0.5 mL/mouse (15 mg) of the flower extract, no systemic biological toxicity demonstrated in ICR mice was observed. In Wistar rats, the LD(50) of the extract was higher than 5,000 mg/kg BW by oral administration. Vasodilatation effect of the 95% ethanolic extract on isolated aortic rats was also investigated. Compared with the control group, the Jasmine flowers extract in 0.05% DMSO clearly reduced tonus of isolated endothelium thoracic aortic rings preconstricted with phenylephrine (10(-6) M), as a dose dependent manner. Nevertheless, this pharmacological effect disappeared after the preincubation of the rings with atropine (10(-6) M) or with N(omega)-nitro-L arginine (10(-4) M). These are possibly due to the actions of the active components on the vessel muscarinic receptors or by causing the release of nitric oxide. PMID- 22536287 TI - Refined Qingkailing Protects MCAO Mice from Endoplasmic Reticulum Stress-Induced Apoptosis with a Broad Time Window. AB - In the current study, we are investigating effect of refined QKL on ischemia reperfusion-induced brain injury in mice. Methods. Mice were employed to induce ischemia-reperfusion injury of brain by middle cerebral artery occlusion (MCAO). RQKL solution was administered with different doses (0, 1.5, 3, and 6 mL/kg body weight) at the same time of onset of ischemia, and with the dose of 1.5 mL/kg at different time points (0, 1.5, 3, 6, and 9 h after MCAO). Neurological function and brain infarction were examined and cell apoptosis and ROS at prefrontal cortex were evaluated 24 h after MCAO, and western blot and intracellular calcium were also researched, respectively. Results. RQKL of all doses can improve neurological function and decrease brain infarction, and it performed significant effect in 0, 1.5, 3, and 6 h groups. Moreover, RQKL was able to reduce apoptotic process by reduction of caspase-3 expression, or restraint of eIF2a phosphorylation and caspase-12 activation. It was also able to reduce ROS and modulate intracellular calcium in the brain. Conclusion. RQKL can prevent ischemic-induced brain injury with a time window of 6 h, and its mechanism might be related to suppress ER stress-mediated apoptotic signaling. PMID- 22536288 TI - Acute and 28-Day Subchronic Oral Toxicity of an Ethanol Extract of Zingiber zerumbet (L.) Smith in Rodents. AB - The objective of this study was to evaluate the acute and subacute toxicity (28 days) of the ethanol extract of Z. zerumbet rhizomes (EEZZ) via the oral route in Wistar rats of both sexes. In the acute toxicity study, Wistar rats were administered a single dose of 15 g kg(-1) of body weight by gavage, and were monitored for 14 days. EEZZ did not produce any toxic signs or deaths; the 50% lethal dose must be higher than 15 g kg(-1). In the subchronic toxicity study, EEZZ was administered by gavage at doses of 1000, 2000 and 3000 mg/kg daily for 4 weeks to Wistar rats. The subacute treatment with EEZZ did not alter either the body weight gain or the food and water consumption. The hematological and biochemical analysis did not show significant differences in any of the parameters examined in female or male groups. Necropsy and histopathological examination, did not reveal any remarkable and treatment related changes. A no observed adverse-effect level for EEZZ is 3000 mg kg(-1) for rats under the conditions of this study. Hence, consumption of EEZZ for various medicinal purposes is safe. PMID- 22536290 TI - Clinical and Epidemiological Investigation of TCM Syndromes of Patients with Coronary Heart Disease in China. AB - To compare the regional differences in TCM syndromes of patients with coronary heart disease (CHD) between North and South China. A total of 624 patients with a diagnosis of CHD, confirmed by coronary angiography, were included in the comparative analysis to determine the occurrence pattern, characteristics of TCM syndrome distribution, and differences in syndrome combinations and major syndrome types (deficiency or excess) between North and South China. The incidence of CHD tended to be higher in North China (54.6%) compared with that in South China (45.4%). The proportions of patients with a qi-deficiency syndrome (83.7%), turbid phlegm syndrome (68.9%), or blood stasis syndrome (91.5%) were generally higher in the South group, while the proportion of patients with a cold congelation syndrome (7.9%) was identified to be obviously higher in the North group (P < 0.01). Moreover, compared with that in the South group, the overall frequency of syndrome combinations tended to be lower in the North group (P < 0.01); and the most common types of TCM syndrome were excess syndrome (193, 56.6%) and primary deficiency and secondary excess syndrome (244, 86.2%) in the North and South groups, respectively (P < 0.01). A regional difference does exist in the TCM syndromes of patients with CHD between North and South China, indicating that the prevention and treatment of CHD in South China should not only focus on promoting blood circulation and removing blood stasis, but also include supplementing qi and eliminating phlegm. PMID- 22536289 TI - Meditation-State Functional Connectivity (msFC): Strengthening of the Dorsal Attention Network and Beyond. AB - Meditation practice alters intrinsic resting-state functional connectivity (rsFC) in the default mode network (DMN). However, little is known regarding the effects of meditation on other resting-state networks. The aim of current study was to investigate the effects of meditation experience and meditation-state functional connectivity (msFC) on multiple resting-state networks (RSNs). Meditation practitioners (MPs) performed two 5-minute scans, one during rest, one while meditating. A meditation naive control group (CG) underwent one resting-state scan. Exploratory regression analyses of the relations between years of meditation practice and rsFC and msFC were conducted. During resting-state, MP as compared to CG exhibited greater rsFC within the Dorsal Attention Network (DAN). Among MP, meditation, as compared to rest, strengthened FC between the DAN and DMN and Salience network whereas it decreased FC between the DAN, dorsal medial PFC, and insula. Regression analyses revealed positive correlations between the number of years of meditation experience and msFC between DAN, thalamus, and anterior parietal sulcus, whereas negative correlations between DAN, lateral and superior parietal, and insula. These findings suggest that the practice of meditation strengthens FC within the DAN as well as strengthens the coupling between distributed networks that are involved in attention, self-referential processes, and affective response. PMID- 22536291 TI - The Effects of the KCNQ Openers Retigabine and Flupirtine on Myotonia in Mammalian Skeletal Muscle Induced by a Chloride Channel Blocker. AB - The purpose of this study was to investigate the effect of KCNQ (potassium channel, voltage-gated, KQT-like subfamily) openers in preventing myotonia caused by anthracene-9-carboxylic acid (9-AC, a chloride channel blocker). An animal model of myotonia can be elicited in murine skeletal muscle by 9-AC treatment. KCNQ openers, such as retigabine and flupirtine, can inhibit the increased twitch amplitude (0.1 Hz stimulation) and reduce the tetanic fade (20 Hz stimulations) observed in the presence of 9-AC. Furthermore, the prolonged twitch duration of skeletal muscle was also inhibited by retigabine or flupirtine. Lamotrigine (an anticonvulsant drug) has a lesser effect on the muscle twitch amplitude, tetanic fade, and prolonged twitch duration as compared with KCNQ openers. In experiments using intracellular recordings, retigabine and flupirtine clearly reduced the firing frequencies of repetitive action potentials induced by 9-AC. These data suggested that KCNQ openers prevent the myotonia induced by 9-AC, at least partly through enhancing potassium conductance in skeletal muscle. Taken together, these results indicate that KCNQ openers are potential alternative therapeutic agents for the treatment of myotonia. PMID- 22536292 TI - The Efficacy of Gelam Honey Dressing towards Excisional Wound Healing. AB - Honey is one of the oldest substances used in wound management. Efficacy of Gelam honey in wound healing was evaluated in this paper. Sprague-Dawley rats were randomly divided into four groups of 24 rats each (untreated group, saline group, Intrasite Gel group, and Gelam honey group) with 2 cm by 2 cm full thickness, excisional wound created on neck area. Wounds were dressed topically according to groups. Rats were sacrificed on days 1, 5, 10, and 15 of treatments. Wounds were then processed for macroscopic and histological observations. Gelam-honey-dressed wounds healed earlier (day 13) than untreated and saline treated groups, as did wounds treated with Intrasite Gel. Honey-treated wounds exhibited less scab and only thin scar formations. Histological features demonstrated positive effects of Gelam honey on the wounds. This paper showed that Gelam honey dressing on excisional wound accelerated the process of wound healing. PMID- 22536293 TI - A Study of Prognosis, Outcome, and Changing Tendency of Hospitalized AMI Patients in Beijing Third-Grade A-Level Traditional Chinese Medicine Hospitals from 1999 to 2008. AB - Objectives. To survey and analyse the prognosis, outcome, and changing tendency of the Acute Myocardial Infarction (AMI) patients in Beijing third-grade A-level Traditional Chinese Medicine (TCM) hospitals. Methods. We collected the clinical datum of hospitalized AMI patients in Beijing 6 TCM hospitals from January 1999 to December 2008 and then analysed the clinical datum. Results. (1) The mean age of patients had showed a slowly rising tendency during this ten years. The patients who had previous history of cerebrovascular diseasea and multiple comorbidities had increased year by year. (2) The rate of reperfusion therapy, revascularization and standardized using of drug, and usage of TCM of AMI patients presented a significant increasing tendency in these hospitals. (3) The proportion of AMI patients combined with cardiac arrhythmia and heart failure had decreased significantly. (4) The AMI mortality presented a decreasing tendency in 10 years. Conclusions. The AMI patients in Beijing TCM hospitals had their own unique clinical features, and it can improve their prognosis by combined therapy of Western Medicine and Traditional Chinese Medicine. PMID- 22536294 TI - Design and methods for a pilot study of a phone-delivered, mindfulness-based intervention in patients with implantable cardioverter defibrillators. AB - Background. Meditation practices are associated with a reduction in adrenergic activity that may benefit patients with severe cardiac arrhythmias. This paper describes the design and methods of a pilot study testing the feasibility of a phone-delivered mindfulness-based intervention (MBI) for treatment of anxiety in patients with implantable cardioverter defibrillators (ICDs). Design and Methods. Consecutive, clinically stable outpatients (n = 52) will be screened for study eligibility within a month of an ICD-related procedure or ICD shock and will be randomly assigned to MBI or to usual care. MBI patients will receive eight weekly individual phone sessions based on two mindfulness practices (awareness of breath and body scan) plus home practice with a CD for 20 minutes daily. Patients assigned to usual care will be offered the standard care planned by the hospital. Assessments will occur at baseline and at the completion of the intervention (between 9 and 12 weeks after randomization). The primary study outcome is feasibility; secondary outcomes include anxiety, mindfulness, and number of administered shocks during the intervention period. Conclusions. If proven feasible and effective, phone-delivered mindfulness-based interventions could improve psychological distress in ICD outpatients with serious cardiovascular conditions. PMID- 22536295 TI - Inference for ecological dynamical systems: a case study of two endemic diseases. AB - A Bayesian Markov chain Monte Carlo method is used to infer parameters for an open stochastic epidemiological modEL: the Markovian susceptible-infected recovered (SIR) model, which is suitable for modeling and simulating recurrent epidemics. This allows exploring two major problems of inference appearing in many mechanistic population models. First, trajectories of these processes are often only partly observed. For example, during an epidemic the transmission process is only partly observable: one cannot record infection times. Therefore, one only records cases (infections) as the observations. As a result some means of imputing or reconstructing individuals in the susceptible cases class must be accomplished. Second, the official reporting of observations (cases in epidemiology) is typically done not as they are actually recorded but at some temporal interval over which they have been aggregated. To address these issues, this paper investigates the following problems. Parameter inference for a perfectly sampled open Markovian SIR is first considered. Next inference for an imperfectly observed sample path of the system is studied. Although this second problem has been solved for the case of closed epidemics, it has proven quite difficult for the case of open recurrent epidemics. Lastly, application of the statistical theory is made to measles and pertussis epidemic time series data from 60 UK cities. PMID- 22536296 TI - Software tool for the prosthetic foot modeling and stiffness optimization. AB - We present the procedure for the optimization of the stiffness of the prosthetic foot. The procedure allows the selection of the elements of the foot and the materials used for the design. The procedure is based on the optimization where the cost function is the minimization of the difference between the knee joint torques of healthy walking and the walking with the transfemural prosthesis. We present a simulation environment that allows the user to interactively vary the foot geometry and track the changes in the knee torque that arise from these adjustments. The software allows the estimation of the optimal prosthetic foot elasticity and geometry. We show that altering model attributes such as the length of the elastic foot segment or its elasticity leads to significant changes in the estimated knee torque required for a given trajectory. PMID- 22536297 TI - The stochastic evolution of a protocell: the Gillespie algorithm in a dynamically varying volume. AB - We propose an improvement of the Gillespie algorithm allowing us to study the time evolution of an ensemble of chemical reactions occurring in a varying volume, whose growth is directly related to the amount of some specific molecules, belonging to the reactions set. This allows us to study the stochastic evolution of a protocell, whose volume increases because of the production of container molecules. Several protocell models are considered and compared with the deterministic models. PMID- 22536298 TI - Fuzzy modeling and control of HIV infection. AB - The present study proposes a fuzzy mathematical model of HIV infection consisting of a linear fuzzy differential equations (FDEs) system describing the ambiguous immune cells level and the viral load which are due to the intrinsic fuzziness of the immune system's strength in HIV-infected patients. The immune cells in question are considered CD4+ T-cells and cytotoxic T-lymphocytes (CTLs). The dynamic behavior of the immune cells level and the viral load within the three groups of patients with weak, moderate, and strong immune systems are analyzed and compared. Moreover, the approximate explicit solutions of the proposed model are derived using a fitting-based method. In particular, a fuzzy control function indicating the drug dosage is incorporated into the proposed model and a fuzzy optimal control problem (FOCP) minimizing both the viral load and the drug costs is constructed. An optimality condition is achieved as a fuzzy boundary value problem (FBVP). In addition, the optimal fuzzy control function is completely characterized and a numerical solution for the optimality system is computed. PMID- 22536299 TI - Falls prevention for the elderly. AB - BACKGROUND: An ageing population, a growing prevalence of chronic diseases and limited financial resources for health care underpin the importance of prevention of disabling health disorders and care dependency in the elderly. A wide variety of measures is generally available for the prevention of falls and fall-related injuries. The spectrum ranges from diagnostic procedures for identifying individuals at risk of falling to complex interventions for the removal or reduction of identified risk factors. However, the clinical and economic effectiveness of the majority of recommended strategies for fall prevention is unclear. Against this background, the literature analyses in this HTA report aim to support decision-making for effective and efficient fall prevention. RESEARCH QUESTIONS: The pivotal research question addresses the effectiveness of single interventions and complex programmes for the prevention of falls and fall-related injuries. The target population are the elderly (> 60 years), living in their own housing or in long term care facilities. Further research questions refer to the cost-effectiveness of fall prevention measures, and their ethical, social and legal implications. METHODS: Systematic literature searches were performed in 31 databases covering the publication period from January 2003 to January 2010. While the effectiveness of interventions is solely assessed on the basis of randomised controlled trials (RCT), the assessment of the effectiveness of diagnostic procedures also considers prospective accuracy studies. In order to clarify social, ethical and legal aspects all studies deemed relevant with regard to content were taken into consideration, irrespective of their study design. Study selection and critical appraisal were conducted by two independent assessors. Due to clinical heterogeneity of the studies no meta-analyses were performed. RESULTS: Out of 12,000 references retrieved by literature searches, 184 meet the inclusion criteria. However, to a variable degree the validity of their results must be rated as compromised due to different biasing factors. In summary, it appears that the performance of tests or the application of parameters to identify individuals at risk of falling yields little or no clinically relevant information. Positive effects of exercise interventions may be expected in relatively young and healthy seniors, while studies indicate opposite effects in the fragile elderly. For this specific vulnerable population the modification of the housing environment shows protective effects. A low number of studies, low quality of studies or inconsistent results lead to the conclusion that the effectiveness of the following interventions has to be rated unclear yet: correction of vision disorders, modification of psychotropic medication, vitamin D supplementation, nutritional supplements, psychological interventions, education of nursing personnel, multiple and multifactorial programs as well as the application of hip protectors. For the context of the German health care system the economic evaluations of fall prevention retrieved by the literature searches yield very few useful results. Cost-effectiveness calculations of fall prevention are mostly based on weak effectiveness data as well as on epidemiological and cost data from foreign health care systems. Ethical analysis demonstrates ambivalent views of the target population concerning fall risk and the necessity of fall prevention. The willingness to take up preventive measures depends on a variety of personal factors, the quality of information, guidance and decision-making, the prevention program itself and social support. THE ANALYSIS OF PAPERS REGARDING LEGAL ISSUES SHOWS THREE MAIN CHALLENGES: the uncertainty of which standard of care has to be expected with regard to fall prevention, the necessity to consider the specific conditions of every single case when measures for fall prevention are applied, and the difficulty to balance the rights to autonomous decision making and physical integrity. DISCUSSION AND CONCLUSIONS: The assessment of clinical effectiveness of interventions for fall prevention is complicated by inherent methodological problems (esp. absence of blinding) and meaningful clinical heterogeneity of available studies. Therefore meta-analyses are not appropriate, and single study results are difficult to interpret. Both problems also impair the informative value of economic analyses. With this background it has to be stated that current recommendations regarding fall prevention in the elderly are not fully supported by scientific evidence. In particular, for the generation of new recommendations the dependency of probable effects on specific characteristics of the target populations or care settings should be taken into consideration. This also applies to the variable factors influencing the willingness of the target population to take up and pursue preventive measures. In the planning of future studies equal weight should be placed on methodological rigour (freedom from biases) and transferability of results into routine care. Economic analyses require input of German data, either in form of a "piggy back study" or in form of a modelling study that reflects the structures of the German health care system and is based on German epidemiological and cost data. PMID- 22536300 TI - CT coronary angiography vs. invasive coronary angiography in CHD. AB - SCIENTIFIC BACKGROUND: Various diagnostic tests including conventional invasive coronary angiography and non-invasive computed tomography (CT) coronary angiography are used in the diagnosis of coronary heart disease (CHD). RESEARCH QUESTIONS: The present report aims to evaluate the clinical efficacy, diagnostic accuracy, prognostic value cost-effectiveness as well as the ethical, social and legal implications of CT coronary angiography versus invasive coronary angiography in the diagnosis of CHD. METHODS: A systematic literature search was conducted in electronic data bases (MEDLINE, EMBASE etc.) in October 2010 and was completed with a manual search. The literature search was restricted to articles published from 2006 in German or English. Two independent reviewers were involved in the selection of the relevant publications. The medical evaluation was based on systematic reviews of diagnostic studies with invasive coronary angiography as the reference standard and on diagnostic studies with intracoronary pressure measurement as the reference standard. Study results were combined in a meta analysis with 95 % confidence intervals (CI). Additionally, data on radiation doses from current non-systematic reviews were taken into account. A health economic evaluation was performed by modelling from the social perspective with clinical assumptions derived from the meta-analysis and economic assumptions derived from contemporary German sources. Data on special indications (bypass or in-stent-restenosis) were not included in the evaluation. Only data obtained using CT scanners with at least 64 slices were considered. RESULTS: No studies were found regarding the clinical efficacy or prognostic value of CT coronary angiography versus conventional invasive coronary angiography in the diagnosis of CHD. Overall, 15 systematic reviews with data from 44 diagnostic studies using invasive coronary angiography as the reference standard (identification of obstructive stenoses) and two diagnostic studies using intracoronary pressure measurement as the reference standard (identification of functionally relevant stenoses) were included in the medical evaluation. Meta-analysis of the nine studies of higher methodological quality showed that, CT coronary angiography with invasive coronary angiography as the reference standard, had a sensitivity of 96 % (95 % CI: 93 % to 98 %), specificity of 86 % (95 % CI: 83 % to 89 %), positive likelihood ratio of 6.38 (95 % CI: 5.18 to 7.87) and negative likelihood ratio of 0.06 (95 % CI: 0.03 to 0.10). However, due to non-diagnostic CT images approximately 3.6 % of the examined patients required a subsequent invasive coronary angiography. Using intracoronary pressure measurement as the reference standard, CT coronary angiography compared to invasive coronary angiography had a sensitivity of 80 % (95 % CI: 61 % to 92 %) versus 67 % (95 % CI: 51 % to 78 %), a specificity of 67 % (95 % CI: 47 % to 83 %) versus 75 % (95 % CI: 60 % to 86 %), an average positive likelihood ratio of 2.3 versus 2.6, and an average negative likelihood ratio 0.3 versus 0.4, respectively. Compared to invasive coronary angiography, the average effective radiation dose of CT coronary angiography was higher with retrospective electrocardiogram (ECG) gating and relatively similar with prospective ECG gating. The health economic model using invasive coronary angiography as the reference standard showed that at a pretest probability of CHD of 50 % or lower, CT coronary angiography resulted in lower cost per patient with true positive diagnosis. At a pretest probability of CHD of 70 % or higher, invasive coronary angiography was associated with lower cost per patient with true positive diagnosis. Using intracoronary pressure measurement as the reference standard, both types of coronary angiographies resulted in substantially higher cost per patient with true positive diagnosis. Two publications dealing explicitly with ethical aspects were identified. The first addressed ethical aspects regarding the principles of beneficence, autonomy and justice, and the second addressed those regarding radiation exposition, especially when used within studies. DISCUSSION: The discriminatory power of CT coronary angiography to identify patients with obstructive (above 50 %) coronary stenoses should be regarded as "high diagnostic evidence", to identify patients without coronary stenoses as "persuasive diagnostic evidence". The discriminatory power of both types of coronary angiography to identify patients with or without functionally relevant coronary stenoses should be regarded as "weak diagnostic evidence". It can be assumed that patients with a high pretest probability of CHD will need invasive coronary angiography and patients with a low pretest probability of CHD will not need subsequent revascularisation. Therefore, CT coronary angiography may be used before performing invasive coronary angiography in patients with an intermediate pretest probability of CHD. For identifying or excluding of obstructive coronary stenosis, CT coronary angiography was shown to be more cost-saving at a pretest probability of CHD of 50 % or lower, and invasive coronary angiography at a pretest probability of CHD of 70 % or higher. The use of both types of coronary angiography to identify or to exclude functionally relevant coronary stenoses should be regarded as highly cost consuming. WITH REGARD TO ETHICAL, SOCIAL OR LEGAL ASPECTS, THE FOLLOWING POSSIBLE IMPLICATIONS WERE IDENTIFIED: under-provision or over-provision of health care, unnecessary complications, anxiety, social stigmatisation, restriction of self-determination, unequal access to health care, unfair resource distribution and legal disputes. CONCLUSION: From a medical point of view, CT coronary angiography using scanners with at least 64 slices should be recommended as a test to rule out obstructive coronary stenoses in order to avoid inappropriate invasive coronary angiography in patients with an intermediate pretest probability of CHD. From a health economic point of view, this recommendation should be limited to patients with a pretest probability of CHD of 50 % or lower. From a medical and health economic point of view, neither CT coronary angiography using scanners with at least 64 slices nor invasive coronary angiography may be recommended as a single diagnostic test for identifying or ruling out functionally relevant coronary stenoses. To minimise any potential negative ethical, social and legal implications, the general ethical and moral principles of benefit, autonomy and justice should be considered. PMID- 22536301 TI - Acute mesenteric ischemia: a vascular emergency. AB - BACKGROUND: Acute mesenteric ischemia is still fatal in 50% to 70% of cases. This consensus paper was written with the participation of physicians from all of the involved specialties for the purpose of improving outcomes. Mesenteric ischemia must be recognized as a vascular emergency requiring rapid and efficient clinical evaluation and treatment. METHODS: We reviewed pertinent literature that was retrieved by a PubMed search on the terms "mesenteric ischemia" AND "arterial" OR "venous" OR "clinical presentation" OR "diagnosis" OR "therapy" OR "surgery" OR " interventional radiology." Our review also took account of the existing guidelines of the American College of Cardiology/American Heart Association. Intensive discussions among the participating physicians, representing all of the specialties involved in the management of mesenteric ischemia, led to the creation of this interdisciplinary paper. RESULTS: Biphasic contrast-enhanced computerized tomography is the diagnostic tool of choice for the detection of arterial or venous occlusion. If non-occlusive mesenteric ischemia is suspected, angiography should be performed, with the option of intraarterial pharmacotherapy to induce local vasodilation. Endovascular techniques have become increasingly important in the treatment of arterial occlusion. Embolic central mesenteric artery occlusion requires surgical treatment; surgery is also needed in case of peritonitis. Portal-vein thrombosis can be treated by local thrombolysis through a transhepatically placed catheter. This should be done within 3 to 4 weeks of the event to prevent later complications of portal hypertension. CONCLUSION: Rapid diagnosis (within 4 to 6 hours of symptom onset) and interdisciplinary cooperation in the provision of treatment are required if the poor outcome of this condition is to be improved. PMID- 22536303 TI - Scientific Advisory Board on Psychotherapy. PMID- 22536302 TI - Treatment algorithms for chronic osteomyelitis. AB - BACKGROUND: Osteomyelitis was described many years ago but is still incompletely understood. Its exogenously acquired form is likely to become more common as the population ages. We discuss biofilm formation as a clinically relevant pathophysiological model and present current recommendations for the treatment of osteomyelitis. METHODS: We selectively searched the PubMed and Cochrane databases for articles on the treatment of chronic osteomyelitis with local and systemic antibiotics and with surgery. The biofilm hypothesis is discussed in the light of the current literature. RESULTS: There is still no consensus on either the definition of osteomyelitis or the criteria for its diagnosis. Most of the published studies cannot be compared with one another, and there is a lack of scientific evidence to guide treatment. The therapeutic recommendations are, therefore, based on the findings of individual studies and on current textbooks. There are two approaches to treatment, with either curative or palliative intent; surgery is now the most important treatment modality in both. In addition to surgery, antibiotics must also be given, with the choice of agent determined by the sensitivity spectrum of the pathogen. CONCLUSION: Surgery combined with anti infective chemotherapy leads to long-lasting containment of infection in 70% to 90% of cases. Suitable drugs are not yet available for the eradication of biofilm producing bacteria. PMID- 22536305 TI - Experiences with other joints. PMID- 22536307 TI - Slow growth of the Rayleigh-Plateau instability in aqueous two phase systems. AB - This paper studies the Rayleigh-Plateau instability for co-flowing immiscible aqueous polymer solutions in a microfluidic channel. Careful vibration-free experiments with controlled actuation of the flow allowed direct measurement of the growth rate of this instability. Experiments for the well-known aqueous two phase system (ATPS, or aqueous biphasic systems) of dextran and polyethylene glycol solutions exhibited a growth rate of 1 s(-1), which was more than an order of magnitude slower than an analogous experiment with two immiscible Newtonian fluids with viscosities and interfacial tension that closely matched the ATPS experiment. Viscoelastic effects and adhesion to the walls were ruled out as explanations for the observed behavior. The results are remarkable because all current theory suggests that such dilute polymer solutions should break up faster, not slower, than the analogous Newtonian case. Microfluidic uses of aqueous two phase systems include separation of labile biomolecules but have hitherto be limited because of the difficulty in making droplets. The results of this work teach how to design devices for biological microfluidic ATPS platforms. PMID- 22536308 TI - Dielectrophoretic differentiation of mouse ovarian surface epithelial cells, macrophages, and fibroblasts using contactless dielectrophoresis. AB - Ovarian cancer is the leading cause of death from gynecological malignancies in women. The primary challenge is the detection of the cancer at an early stage, since this drastically increases the survival rate. In this study we investigated the dielectrophoretic responses of progressive stages of mouse ovarian surface epithelial (MOSE) cells, as well as mouse fibroblast and macrophage cell lines, utilizing contactless dielectrophoresis (cDEP). cDEP is a relatively new cell manipulation technique that has addressed some of the challenges of conventional dielectrophoretic methods. To evaluate our microfluidic device performance, we computationally studied the effects of altering various geometrical parameters, such as the size and arrangement of insulating structures, on dielectrophoretic and drag forces. We found that the trapping voltage of MOSE cells increases as the cells progress from a non-tumorigenic, benign cell to a tumorigenic, malignant phenotype. Additionally, all MOSE cells display unique behavior compared to fibroblasts and macrophages, representing normal and inflammatory cells found in the peritoneal fluid. Based on these findings, we predict that cDEP can be utilized for isolation of ovarian cancer cells from peritoneal fluid as an early cancer detection tool. PMID- 22536311 TI - Institutionalizing provider-initiated HIV testing and counselling for children: an observational case study from Zambia. AB - BACKGROUND: Provider-initiated testing and counselling (PITC) is a priority strategy for increasing access for HIV-exposed children to prevention measures, and infected children to treatment and care interventions. This article examines efforts to scale-up paediatric PITC at a second-level hospital located in Zambia's Southern Province, and serving a catchment area of 1.2 million people. METHODS AND PRINCIPAL FINDINGS: Our retrospective case study examined best practices and enabling factors for rapid institutionalization of PITC in Livingstone General Hospital. Methods included clinical observations, key informant interviews with programme management, and a desk review of hospital management information systems (HMIS) uptake data following the introduction of PITC. After PITC roll-out, the hospital experienced considerably higher testing uptake. In a 36-month period following PITC institutionalization, of total inpatient children eligible for PITC (n = 5074), 98.5% of children were counselled, and 98.2% were tested. Of children tested (n = 4983), 15.5% were determined HIV-infected; 77.6% of these results were determined by DNA polymerase chain reaction (PCR) testing in children under the age of 18 months. Of children identified as HIV-infected in the hospital's inpatient and outpatient departments (n = 1342), 99.3% were enrolled in HIV care, including initiation on co trimoxazole prophylaxis. A number of good operational practices and enabling factors in the Livingstone General Hospital experience can inform rapid PITC institutionalization for inpatient and outpatient children. These include the placement of full-time nurse counsellors at key areas of paediatric intake, who interface with patients immediately and conduct testing and counselling. They are reinforced through task-shifting to peer counsellors in the wards. Nurse counsellor capacity to draw specimen for DNA PCR for children under 18 months has significantly enhanced early infant diagnosis. The hospital's bolstered antiretroviral supply chain, package of on-site HIV services, and follow-up care for children and families improved the continuum of service uptake. CONCLUSIONS AND SIGNIFICANCE: The clinical impact and operational experience emphasizes that institutional PITC is a feasible strategy for increasing access to paediatric HIV care, particularly in generalized epidemic settings. PMID- 22536312 TI - Energetic plasticity underlies a variable response to ocean acidification in the pteropod, Limacina helicina antarctica. AB - Ocean acidification, caused by elevated seawater carbon dioxide levels, may have a deleterious impact on energetic processes in animals. Here we show that high PCO(2) can suppress metabolism, measured as oxygen consumption, in the pteropod, L. helicina forma antarctica, by ~20%. The rates measured at 180-380 uatm (MO(2) = 1.25 M(-0.25), p = 0.007) were significantly higher (ANCOVA, p = 0.004) than those measured at elevated target CO(2) levels in 2007 (789-1000 uatm, = 0.78 M(-0.32), p = 0.0008; Fig. 1). However, we further demonstrate metabolic plasticity in response to regional phytoplankton concentration and that the response to CO(2) is dependent on the baseline level of metabolism. We hypothesize that reduced regional Chl a levels in 2008 suppressed metabolism and masked the effect of ocean acidification. This effect of food limitation was not, we postulate, merely a result of gut clearance and specific dynamic action, but rather represents a sustained metabolic response to regional conditions. Thus, pteropod populations may be compromised by climate change, both directly via CO(2)-induced metabolic suppression, and indirectly via quantitative and qualitative changes to the phytoplankton community. Without the context provided by long-term observations (four seasons) and a multi-faceted laboratory analysis of the parameters affecting energetics, the complex response of polar pteropods to ocean acidification may be masked or misinterpreted. PMID- 22536313 TI - System dynamics to model the unintended consequences of denying payment for venous thromboembolism after total knee arthroplasty. AB - BACKGROUND: The Hospital Acquired Condition Strategy (HACS) denies payment for venous thromboembolism (VTE) after total knee arthroplasty (TKA). The intention is to reduce complications and associated costs, while improving the quality of care by mandating VTE prophylaxis. We applied a system dynamics model to estimate the impact of HACS on VTE rates, and potential unintended consequences such as increased rates of bleeding and infection and decreased access for patients who might benefit from TKA. METHODS AND FINDINGS: The system dynamics model uses a series of patient stocks including the number needing TKA, deemed ineligible, receiving TKA, and harmed due to surgical complication. The flow of patients between stocks is determined by a series of causal elements such as rates of exclusion, surgery and complications. The number of patients harmed due to VTE, bleeding or exclusion were modeled by year by comparing patient stocks that results in scenarios with and without HACS. The percentage of TKA patients experiencing VTE decreased approximately 3-fold with HACS. This decrease in VTE was offset by an increased rate of bleeding and infection. Moreover, results from the model suggest HACS could exclude 1.5% or half a million patients who might benefit from knee replacement through 2020. CONCLUSION: System dynamics modeling indicates HACS will have the intended consequence of reducing VTE rates. However, an unintended consequence of the policy might be increased potential harm resulting from over administration of prophylaxis, as well as exclusion of a large population of patients who might benefit from TKA. PMID- 22536314 TI - Can thermoclines be a cue to prey distribution for marine top predators? A case study with little penguins. AB - The use of top predators as bio-platforms is a modern approach to understanding how physical changes in the environment may influence their foraging success. This study examined if the presence of thermoclines could be a reliable signal of resource availability for a marine top predator, the little penguin (Eudyptula minor). We studied weekly foraging activity of 43 breeding individual penguins equipped with accelerometers. These loggers also recorded water temperature, which we used to detect changes in thermal characteristics of their foraging zone over 5 weeks during the penguin's guard phase. Data showed the thermocline was detected in the first 3 weeks of the study, which coincided with higher foraging efficiency. When a thermocline was not detected in the last two weeks, foraging efficiency decreased as well. We suggest that thermoclines can represent temporary markers of enhanced food availability for this top-predator to which they must optimally adjust their breeding cycle. PMID- 22536315 TI - Unrequested findings on cardiac computed tomography: looking beyond the heart. AB - OBJECTIVES: To determine the prevalence of clinically relevant unrequested extra cardiac imaging findings on cardiac Computed Tomography (CT) and explanatory factors thereof. METHODS: A systematic review of studies drawn from online electronic databases followed by meta-analysis with meta-regression was performed. The prevalence of clinically relevant unrequested findings and potentially explanatory variables were extracted (proportion of smokers, mean age of patients, use of full FOV, proportion of men, years since publication). RESULTS: Nineteen radiological studies comprising 12922 patients met the inclusion criteria. The pooled prevalence of clinically relevant unrequested findings was 13% (95% confidence interval 9-18, range: 3-39%). The large differences in prevalence observed were not explained by the predefined (potentially explanatory) variables. CONCLUSIONS: Clinically relevant extra cardiac findings are common in patients undergoing routine cardiac CT, and their prevalence differs substantially between studies. These differences may be due to unreported factors such as different definitions of clinical relevance and differences between populations. We present suggestions for basic reporting which may improve the interpretability and comparability of future research. PMID- 22536316 TI - Impact of carnivory on human development and evolution revealed by a new unifying model of weaning in mammals. AB - Our large brain, long life span and high fertility are key elements of human evolutionary success and are often thought to have evolved in interplay with tool use, carnivory and hunting. However, the specific impact of carnivory on human evolution, life history and development remains controversial. Here we show in quantitative terms that dietary profile is a key factor influencing time to weaning across a wide taxonomic range of mammals, including humans. In a model encompassing a total of 67 species and genera from 12 mammalian orders, adult brain mass and two dichotomous variables reflecting species differences regarding limb biomechanics and dietary profile, accounted for 75.5%, 10.3% and 3.4% of variance in time to weaning, respectively, together capturing 89.2% of total variance. Crucially, carnivory predicted the time point of early weaning in humans with remarkable precision, yielding a prediction error of less than 5% with a sample of forty-six human natural fertility societies as reference. Hence, carnivory appears to provide both a necessary and sufficient explanation as to why humans wean so much earlier than the great apes. While early weaning is regarded as essentially differentiating the genus Homo from the great apes, its timing seems to be determined by the same limited set of factors in humans as in mammals in general, despite some 90 million years of evolution. Our analysis emphasizes the high degree of similarity of relative time scales in mammalian development and life history across 67 genera from 12 mammalian orders and shows that the impact of carnivory on time to weaning in humans is quantifiable, and critical. Since early weaning yields shorter interbirth intervals and higher rates of reproduction, with profound effects on population dynamics, our findings highlight the emergence of carnivory as a process fundamentally determining human evolution. PMID- 22536317 TI - Performance of local light microscopy and the ParaScreen Pan/Pf rapid diagnostic test to detect malaria in health centers in Northwest Ethiopia. AB - BACKGROUND: Diagnostic tests are recommended for suspected malaria cases before treatment, but comparative performance of microscopy and rapid diagnostic tests (RDTs) at rural health centers has rarely been studied compared to independent expert microscopy. METHODS: Participants (N = 1997) with presumptive malaria were recruited from ten health centers with a range of transmission intensities in Amhara Regional State, Northwest Ethiopia during October to December 2007. Microscopy and ParaScreen Pan/Pf(r) RDT were done immediately by health center technicians. Blood slides were re-examined later at a central laboratory by independent expert microscopists. RESULTS: Of 1,997 febrile patients, 475 (23.8%) were positive by expert microscopists, with 57.7% P. falciparum, 24.6% P. vivax and 17.7% mixed infections. Sensitivity of health center microscopists for any malaria species was >90% in five health centers (four of which had the highest prevalence), >70% in nine centers and 44% in one site with lowest prevalence. Specificity for health center microscopy was very good (>95%) in all centers. For ParaScreen RDT, sensitivity was >=90% in three centers, >=70% in six and <60% in four centers. Specificity was >=90% in all centers except one where it was 85%. CONCLUSIONS: Health center microscopists performed well in nine of the ten health centers; while for ParaScreen RDT they performed well in only six centers. Overall the accuracy of local microscopy exceeded that of RDT for all outcomes. This study supports the introduction of RDTs only if accompanied by appropriate training, frequent supervision and quality control at all levels. Deficiencies in RDT use at some health centers must be rectified before universal replacement of good routine microscopy with RDTs. Maintenance and strengthening of good quality microscopy remains a priority at health center level. PMID- 22536318 TI - Functional variant in the autophagy-related 5 gene promotor is associated with childhood asthma. AB - RATIONALE AND OBJECTIVE: Autophagy is a cellular process directed at eliminating or recycling cellular proteins. Recently, the autophagy pathway has been implicated in immune dysfunction, the pathogenesis of inflammatory disorders, and response to viral infection. Associations between two genes in the autophagy pathway, ATG5 and ATG7, with childhood asthma were investigated. METHODS: Using genetic and experimental approaches, we examined the association of 13 HapMap derived tagging SNPs in ATG5 and ATG7 with childhood asthma in 312 asthmatic and 246 non-allergic control children. We confirmed our findings by using independent cohorts and imputation analysis. Finally, we evaluated the functional relevance of a disease associated SNP. MEASUREMENTS AND MAIN RESULTS: We demonstrated that ATG5 single nucleotide polymorphisms rs12201458 and rs510432 were associated with asthma (p = 0.00085 and 0.0025, respectively). In three independent cohorts, additional variants in ATG5 in the same LD block were associated with asthma (p<0.05). We found that rs510432 was functionally relevant and conferred significantly increased promotor activity. Furthermore, Atg5 expression was increased in nasal epithelium of acute asthmatics compared to stable asthmatics and non-asthmatic controls. CONCLUSION: Genetic variants in ATG5, including a functional promotor variant, are associated with childhood asthma. These results provide novel evidence for a role for ATG5 in childhood asthma. PMID- 22536319 TI - High-order SNP combinations associated with complex diseases: efficient discovery, statistical power and functional interactions. AB - There has been increased interest in discovering combinations of single nucleotide polymorphisms (SNPs) that are strongly associated with a phenotype even if each SNP has little individual effect. Efficient approaches have been proposed for searching two-locus combinations from genome-wide datasets. However, for high-order combinations, existing methods either adopt a brute-force search which only handles a small number of SNPs (up to few hundreds), or use heuristic search that may miss informative combinations. In addition, existing approaches lack statistical power because of the use of statistics with high degrees-of freedom and the huge number of hypotheses tested during combinatorial search. Due to these challenges, functional interactions in high-order combinations have not been systematically explored. We leverage discriminative-pattern-mining algorithms from the data-mining community to search for high-order combinations in case-control datasets. The substantially improved efficiency and scalability demonstrated on synthetic and real datasets with several thousands of SNPs allows the study of several important mathematical and statistical properties of SNP combinations with order as high as eleven. We further explore functional interactions in high-order combinations and reveal a general connection between the increase in discriminative power of a combination over its subsets and the functional coherence among the genes comprising the combination, supported by multiple datasets. Finally, we study several significant high-order combinations discovered from a lung-cancer dataset and a kidney-transplant-rejection dataset in detail to provide novel insights on the complex diseases. Interestingly, many of these associations involve combinations of common variations that occur in small fractions of population. Thus, our approach is an alternative methodology for exploring the genetics of rare diseases for which the current focus is on individually rare variations. PMID- 22536320 TI - Dynamic visuomotor transformation involved with remote flying of a plane utilizes the 'Mirror Neuron' system. AB - Brain regions involved with processing dynamic visuomotor representational transformation are investigated using fMRI. The perceptual-motor task involved flying (or observing) a plane through a simulated Red Bull Air Race course in first person and third person chase perspective. The third person perspective is akin to remote operation of a vehicle. The ability for humans to remotely operate vehicles likely has its roots in neural processes related to imitation in which visuomotor transformation is necessary to interpret the action goals in an egocentric manner suitable for execution. In this experiment for 3(rd) person perspective the visuomotor transformation is dynamically changing in accordance to the orientation of the plane. It was predicted that 3(rd) person remote flying, over 1(st), would utilize brain regions composing the 'Mirror Neuron' system that is thought to be intimately involved with imitation for both execution and observation tasks. Consistent with this prediction differential brain activity was present for 3(rd) person over 1(st) person perspectives for both execution and observation tasks in left ventral premotor cortex, right dorsal premotor cortex, and inferior parietal lobule bilaterally (Mirror Neuron System) (Behaviorally: 1(st)>3(rd)). These regions additionally showed greater activity for flying (execution) over watching (observation) conditions. Even though visual and motor aspects of the tasks were controlled for, differential activity was also found in brain regions involved with tool use, motion perception, and body perspective including left cerebellum, temporo-occipital regions, lateral occipital cortex, medial temporal region, and extrastriate body area. This experiment successfully demonstrates that a complex perceptual motor real-world task can be utilized to investigate visuomotor processing. This approach (Aviation Cerebral Experimental Sciences ACES) focusing on direct application to lab and field is in contrast to standard methodology in which tasks and conditions are reduced to their simplest forms that are remote from daily life experience. PMID- 22536321 TI - Modeling adaptive regulatory T-cell dynamics during early HIV infection. AB - Regulatory T-cells (Tregs) are a subset of CD4(+) T-cells that have been found to suppress the immune response. During HIV viral infection, Treg activity has been observed to have both beneficial and deleterious effects on patient recovery; however, the extent to which this is regulated is poorly understood. We hypothesize that this dichotomy in behavior is attributed to Treg dynamics changing over the course of infection through the proliferation of an 'adaptive' Treg population which targets HIV-specific immune responses. To investigate the role Tregs play in HIV infection, a delay differatial equation model was constructed to examine (1) the possible existence of two distinct Treg populations, normal (nTregs) and adaptive (aTregs), and (2) their respective effects in limiting viral load. Sensitivity analysis was performed to test parameter regimes that show the proportionality of viral load with adaptive regulatory populations and also gave insight into the importance of downregulation of CD4(+) cells by normal Tregs on viral loads. Through the inclusion of Treg populations in the model, a diverse array of viral dynamics was found. Specifically, oscillatory and steady state behaviors were both witnessed and it was seen that the model provided a more accurate depiction of the effector cell population as compared with previous models. Through further studies of adaptive and normal Tregs, improved treatments for HIV can be constructed for patients and the viral mechanisms of infection can be further elucidated. PMID- 22536323 TI - Evaluation of portable point-of-care CD4 counter with high sensitivity for detecting patients eligible for antiretroviral therapy. AB - BACKGROUND: Accurate, inexpensive point-of-care CD4+ T cell testing technologies are needed that can deliver CD4+ T cell results at lower level health centers or community outreach voluntary counseling and testing. We sought to evaluate a point-of-care CD4+ T cell counter, the Pima CD4 Test System, a portable, battery operated bench-top instrument that is designed to use finger stick blood samples suitable for field use in conjunction with rapid HIV testing. METHODS: Duplicate measurements were performed on both capillary and venous samples using Pima CD4 analyzers, compared to the BD FACSCalibur (reference method). The mean bias was estimated by paired Student's t-test. Bland Altman plots were used to assess agreement. RESULTS: 206 participants were enrolled with a median CD4 count of 396 (range; 18-1500). The finger stick PIMA had a mean bias of -66.3 cells/uL (95%CI 83.4-49.2, P<0.001) compared to the FACSCalibur; the bias was smaller at lower CD4 counts (0-250 cells/uL) with a mean bias of -10.8 (95%CI -27.3-+5.6, P = 0.198), and much greater at higher CD4 cell counts (>500 cells/uL) with a mean bias of -120.6 (95%CI -162.8, -78.4, P<0.001). The sensitivity (95%CI) of the Pima CD4 analyzer was 96.3% (79.1-99.8%) for a <250 cells/ul cut-off with a negative predictive value of 99.2% (95.1-99.9%). CONCLUSIONS: The Pima CD4 finger stick test is an easy-to-use, portable, relatively fast device to test CD4+ T cell counts in the field. Issues of negatively-biased CD4 cell counts especially at higher absolute numbers will limit its utility for longitudinal immunologic response to ART. The high sensitivity and negative predictive value of the test makes it an attractive option for field use to identify patients eligible for ART, thus potentially reducing delays in linkage to care and ART initiation. PMID- 22536322 TI - Cell cycle gene networks are associated with melanoma prognosis. AB - BACKGROUND: Our understanding of the molecular pathways that underlie melanoma remains incomplete. Although several published microarray studies of clinical melanomas have provided valuable information, we found only limited concordance between these studies. Therefore, we took an in vitro functional genomics approach to understand melanoma molecular pathways. METHODOLOGY/PRINCIPAL FINDINGS: Affymetrix microarray data were generated from A375 melanoma cells treated in vitro with siRNAs against 45 transcription factors and signaling molecules. Analysis of this data using unsupervised hierarchical clustering and Bayesian gene networks identified proliferation-association RNA clusters, which were co-ordinately expressed across the A375 cells and also across melanomas from patients. The abundance in metastatic melanomas of these cellular proliferation clusters and their putative upstream regulators was significantly associated with patient prognosis. An 8-gene classifier derived from gene network hub genes correctly classified the prognosis of 23/26 metastatic melanoma patients in a cross-validation study. Unlike the RNA clusters associated with cellular proliferation described above, co-ordinately expressed RNA clusters associated with immune response were clearly identified across melanoma tumours from patients but not across the siRNA-treated A375 cells, in which immune responses are not active. Three uncharacterised genes, which the gene networks predicted to be upstream of apoptosis- or cellular proliferation-associated RNAs, were found to significantly alter apoptosis and cell number when over-expressed in vitro. CONCLUSIONS/SIGNIFICANCE: This analysis identified co-expression of RNAs that encode functionally-related proteins, in particular, proliferation-associated RNA clusters that are linked to melanoma patient prognosis. Our analysis suggests that A375 cells in vitro may be valid models in which to study the gene expression modules that underlie some melanoma biological processes (e.g., proliferation) but not others (e.g., immune response). The gene expression modules identified here, and the RNAs predicted by Bayesian network inference to be upstream of these modules, are potential prognostic biomarkers and drug targets. PMID- 22536324 TI - TRF2 controls telomeric nucleosome organization in a cell cycle phase-dependent manner. AB - Mammalian telomeres stabilize chromosome ends as a result of their assembly into a peculiar form of chromatin comprising a complex of non-histone proteins named shelterin. TRF2, one of the shelterin components, binds to the duplex part of telomeric DNA and is essential to fold the telomeric chromatin into a protective cap. Although most of the human telomeric DNA is organized into tightly spaced nucleosomes, their role in telomere protection and how they interplay with telomere-specific factors in telomere organization is still unclear. In this study we investigated whether TRF2 can regulate nucleosome assembly at telomeres.By means of chromatin immunoprecipitation (ChIP) and Micrococcal Nuclease (MNase) mapping assay, we found that the density of telomeric nucleosomes in human cells was inversely proportional to the dosage of TRF2 at telomeres. This effect was not observed in the G1 phase of the cell cycle but appeared coincident of late or post-replicative events. Moreover, we showed that TRF2 overexpression altered nucleosome spacing at telomeres increasing internucleosomal distance. By means of an in vitro nucleosome assembly system containing purified histones and remodeling factors, we reproduced the short nucleosome spacing found in telomeric chromatin. Importantly, when in vitro assembly was performed in the presence of purified TRF2, nucleosome spacing on a telomeric DNA template increased, in agreement with in vivo MNase mapping.Our results demonstrate that TRF2 negatively regulates the number of nucleosomes at human telomeres by a cell cycle-dependent mechanism that alters internucleosomal distance. These findings raise the intriguing possibility that telomere protection is mediated, at least in part, by the TRF2-dependent regulation of nucleosome organization. PMID- 22536325 TI - Are we predicting the actual or apparent distribution of temperate marine fishes? AB - Planning for resilience is the focus of many marine conservation programs and initiatives. These efforts aim to inform conservation strategies for marine regions to ensure they have inbuilt capacity to retain biological diversity and ecological function in the face of global environmental change--particularly changes in climate and resource exploitation. In the absence of direct biological and ecological information for many marine species, scientists are increasingly using spatially-explicit, predictive-modeling approaches. Through the improved access to multibeam sonar and underwater video technology these models provide spatial predictions of the most suitable regions for an organism at resolutions previously not possible. However, sensible-looking, well-performing models can provide very different predictions of distribution depending on which occurrence dataset is used. To examine this, we construct species distribution models for nine temperate marine sedentary fishes for a 25.7 km(2) study region off the coast of southeastern Australia. We use generalized linear model (GLM), generalized additive model (GAM) and maximum entropy (MAXENT) to build models based on co-located occurrence datasets derived from two underwater video methods (i.e. baited and towed video) and fine-scale multibeam sonar based seafloor habitat variables. Overall, this study found that the choice of modeling approach did not considerably influence the prediction of distributions based on the same occurrence dataset. However, greater dissimilarity between model predictions was observed across the nine fish taxa when the two occurrence datasets were compared (relative to models based on the same dataset). Based on these results it is difficult to draw any general trends in regards to which video method provides more reliable occurrence datasets. Nonetheless, we suggest predictions reflecting the species apparent distribution (i.e. a combination of species distribution and the probability of detecting it). Consequently, we also encourage researchers and marine managers to carefully interpret model predictions. PMID- 22536326 TI - Accurate reconstruction of insertion-deletion histories by statistical phylogenetics. AB - The Multiple Sequence Alignment (MSA) is a computational abstraction that represents a partial summary either of indel history, or of structural similarity. Taking the former view (indel history), it is possible to use formal automata theory to generalize the phylogenetic likelihood framework for finite substitution models (Dayhoff's probability matrices and Felsenstein's pruning algorithm) to arbitrary-length sequences. In this paper, we report results of a simulation-based benchmark of several methods for reconstruction of indel history. The methods tested include a relatively new algorithm for statistical marginalization of MSAs that sums over a stochastically-sampled ensemble of the most probable evolutionary histories. For mammalian evolutionary parameters on several different trees, the single most likely history sampled by our algorithm appears less biased than histories reconstructed by other MSA methods. The algorithm can also be used for alignment-free inference, where the MSA is explicitly summed out of the analysis. As an illustration of our method, we discuss reconstruction of the evolutionary histories of human protein-coding genes. PMID- 22536328 TI - Comparison of newtonian and special-relativistic trajectories with the general relativistic trajectory for a low-speed weak-gravity system. AB - We show, contrary to expectation, that the trajectory predicted by general relativistic mechanics for a low-speed weak-gravity system is not always well approximated by the trajectories predicted by special-relativistic and newtonian mechanics for the same parameters and initial conditions. If the system is dissipative, the breakdown of agreement occurs for chaotic trajectories only. If the system is non-dissipative, the breakdown of agreement occurs for chaotic trajectories and non-chaotic trajectories. The agreement breaks down slowly for non-chaotic trajectories but rapidly for chaotic trajectories. When the predictions are different, general-relativistic mechanics must therefore be used, instead of special-relativistic mechanics (newtonian mechanics), to correctly study the dynamics of a weak-gravity system (a low-speed weak-gravity system). PMID- 22536327 TI - Prion protein is a key determinant of alcohol sensitivity through the modulation of N-methyl-D-aspartate receptor (NMDAR) activity. AB - The prion protein (PrP) is absolutely required for the development of prion diseases; nevertheless, its physiological functions in the central nervous system remain elusive. Using a combination of behavioral, electrophysiological and biochemical approaches in transgenic mouse models, we provide strong evidence for a crucial role of PrP in alcohol sensitivity. Indeed, PrP knock out (PrP(-/-)) mice presented a greater sensitivity to the sedative effects of EtOH compared to wild-type (wt) control mice. Conversely, compared to wt mice, those over expressing mouse, human or hamster PrP genes presented a relative insensitivity to ethanol-induced sedation. An acute tolerance (i.e. reversion) to ethanol inhibition of N-methyl-D-aspartate (NMDA) receptor-mediated excitatory post synaptic potentials in hippocampal slices developed slower in PrP(-/-) mice than in wt mice. We show that PrP is required to induce acute tolerance to ethanol by activating a Src-protein tyrosine kinase-dependent intracellular signaling pathway. In an attempt to decipher the molecular mechanisms underlying PrP dependent ethanol effect, we looked for changes in lipid raft features in hippocampus of ethanol-treated wt mice compared to PrP(-/-) mice. Ethanol induced rapid and transient changes of buoyancy of lipid raft-associated proteins in hippocampus of wt but not PrP(-/-) mice suggesting a possible mechanistic link for PrP-dependent signal transduction. Together, our results reveal a hitherto unknown physiological role of PrP on the regulation of NMDAR activity and highlight its crucial role in synaptic functions. PMID- 22536329 TI - Belief revision and delusions: how do patients with schizophrenia take advice? AB - The dominant cognitive model that accounts for the persistence of delusional beliefs in schizophrenia postulates that patients suffer from a general deficit in belief revision. It is generally assumed that this deficit is a consequence of impaired reasoning skills. However, the possibility that such inflexibility affects the entire system of a patient's beliefs has rarely been empirically tested. Using delusion-neutral material in a well-documented advice-taking task, the present study reports that patients with schizophrenia: 1) revise their beliefs, 2) take into account socially provided information to do so, 3) are not overconfident about their judgments, and 4) show less egocentric advice discounting than controls. This study thus shows that delusional patients' difficulty in revising beliefs is more selective than had been previously assumed. The specificities of the task and the implications for a theory of delusion formation are discussed. PMID- 22536330 TI - Antibody-directed lentiviral gene transduction for live-cell monitoring and selection of human iPS and hES cells. AB - The identification of stem cells within a mixed population of cells is a major hurdle for stem cell biology--in particular, in the identification of induced pluripotent stem (iPS) cells during the reprogramming process. Based on the selective expression of stem cell surface markers, a method to specifically infect stem cells through antibody-conjugated lentiviral particles has been developed that can deliver both visual markers for live-cell imaging as well as selectable markers to enrich for iPS cells. Antibodies recognizing SSEA4 and CD24 mediated the selective infection of the iPS cells over the parental human fibroblasts, allowing for rapid expansion of these cells by puromycin selection. Adaptation of the vector allows for the selective marking of human embryonic stem (hES) cells for their removal from a population of differentiated cells. This method has the benefit that it not only identifies stem cells, but that specific genes, including positive and negative selection markers, regulatory genes or miRNA can be delivered to the targeted stem cells. The ability to specifically target gene delivery to human pluripotent stem cells has broad applications in tissue engineering and stem cell therapies. PMID- 22536331 TI - Growth inhibition of human gynecologic and colon cancer cells by Phyllanthus watsonii through apoptosis induction. AB - Phyllanthus watsonii Airy Shaw is an endemic plant found in Peninsular Malaysia. Although there are numerous reports on the anti cancer properties of other Phyllanthus species, published information on the cytotoxicity of P. watsonii are very limited. The present study was carried out with bioassay-guided fractionation approach to evaluate the cytotoxicity and apoptosis induction capability of the P. watsonii extracts and fractions on human gynecologic (SKOV-3 and Ca Ski) and colon (HT-29) cancer cells. P. watsonii extracts exhibited strong cytotoxicity on all the cancer cells studied with IC(50) values of <= 20.0 ug/mL. Hexane extract of P. watsonii was further subjected to bioassay-guided fractionation and yielded 10 fractions (PW-1->PW-10). PW-4->PW-8 portrayed stronger cytotoxic activity and was further subjected to bioassay-guided fractionation and resulted with 8 sub-fractions (PPWH-1->PPWH-8). PPWH-7 possessed greatest cytotoxicity (IC(50) values ranged from 0.66-0.83 ug/mL) and was selective on the cancer cells studied. LC-MS/MS analysis of PPWH-7 revealed the presence of ellagic acid, geranic acid, glochidone, betulin, phyllanthin and sterol glucoside. Marked morphological changes, ladder-like appearance of DNA and increment in caspase-3 activity indicating apoptosis were clearly observed in both human gynecologic and colon cancer cells treated with P. watsonii especially with PPWH-7. The study also indicated that P. watsonii extracts arrested cell cycle at different growth phases in SKOV-3, Ca Ski and HT-29 cells. Cytotoxic and apoptotic potential of the endemic P. watsonii was investigated for the first time by bioassay-guided approach. These results demonstrated that P. watsonii selectively inhibits the growth of SKOV-3, Ca Ski and HT-29 cells through apoptosis induction and cell cycle modulation. Hence, P. watsonii has the potential to be further exploited for the discovery and development of new anti cancer drugs. PMID- 22536332 TI - Airflow dynamics of coughing in healthy human volunteers by shadowgraph imaging: an aid to aerosol infection control. AB - Cough airflow dynamics have been previously studied using a variety of experimental methods. In this study, real-time, non-invasive shadowgraph imaging was applied to obtain additional analyses of cough airflows produced by healthy volunteers. Twenty healthy volunteers (10 women, mean age 32.2+/-12.9 years; 10 men, mean age 25.3+/-2.5 years) were asked to cough freely, then into their sleeves (as per current US CDC recommendations) in this study to analyze cough airflow dynamics. For the 10 females (cases 1-10), their maximum detectable cough propagation distances ranged from 0.16-0.55 m, with maximum derived velocities of 2.2-5.0 m/s, and their maximum detectable 2-D projected areas ranged from 0.010 0.11 m(2), with maximum derived expansion rates of 0.15-0.55 m(2)/s. For the 10 males (cases 11-20), their maximum detectable cough propagation distances ranged from 0.31-0.64 m, with maximum derived velocities of 3.2-14 m/s, and their maximum detectable 2-D projected areas ranged from 0.04-0.14 m(2), with maximum derived expansion rates of 0.25-1.4 m(2)/s. These peak velocities were measured when the visibility of the exhaled airflows was optimal and compare favorably with those reported previously using other methods, and may be seen as a validation of these previous approaches in a more natural setting. However, the propagation distances can only represent a lower limit due to the inability of the shadowgraph method to visualize these cough airflows once their temperature cools to that of the ambient air, which is an important limitation of this methodology. The qualitative high-speed video footage of these volunteers coughing into their sleeves demonstrates that although this method rarely completely blocks the cough airflow, it decelerates, splits and redirects the airflow, eventually reducing its propagation. The effectiveness of this intervention depends on optimum positioning of the arm over the nose and mouth during coughing, though unsightly stains on sleeves may make it unacceptable to some. PMID- 22536333 TI - The OSCAR-IB consensus criteria for retinal OCT quality assessment. AB - BACKGROUND: Retinal optical coherence tomography (OCT) is an imaging biomarker for neurodegeneration in multiple sclerosis (MS). In order to become validated as an outcome measure in multicenter studies, reliable quality control (QC) criteria with high inter-rater agreement are required. METHODS/PRINCIPAL FINDINGS: A prospective multicentre study on developing consensus QC criteria for retinal OCT in MS: (1) a literature review on OCT QC criteria; (2) application of these QC criteria to a training set of 101 retinal OCT scans from patients with MS; (3) kappa statistics for inter-rater agreement; (4) identification reasons for inter rater disagreement; (5) development of new consensus QC criteria; (6) testing of the new QC criteria on the training set and (7) prospective validation on a new set of 159 OCT scans from patients with MS. The inter-rater agreement for acceptable scans among OCT readers (n = 3) was moderate (kappa 0.45) based on the non-validated QC criteria which were entirely based on the ophthalmological literature. A new set of QC criteria was developed based on recognition of: (O) obvious problems, (S) poor signal strength, (C) centration of scan, (A) algorithm failure, (R) retinal pathology other than MS related, (I) illumination and (B) beam placement. Adhering to these OSCAR-IB QC criteria increased the inter-rater agreement to kappa from moderate to substantial (0.61 training set and 0.61 prospective validation). CONCLUSIONS: This study presents the first validated consensus QC criteria for retinal OCT reading in MS. The high inter-rater agreement suggests the OSCAR-IB QC criteria to be considered in the context of multicentre studies and trials in MS. PMID- 22536335 TI - Visualization and curve-parameter estimation strategies for efficient exploration of phenotype microarray kinetics. AB - BACKGROUND: The Phenotype MicroArray (OmniLog(r) PM) system is able to simultaneously capture a large number of phenotypes by recording an organism's respiration over time on distinct substrates. This technique targets the object of natural selection itself, the phenotype, whereas previously addressed '-omics' techniques merely study components that finally contribute to it. The recording of respiration over time, however, adds a longitudinal dimension to the data. To optimally exploit this information, it must be extracted from the shapes of the recorded curves and displayed in analogy to conventional growth curves. METHODOLOGY: The free software environment R was explored for both visualizing and fitting of PM respiration curves. Approaches using either a model fit (and commonly applied growth models) or a smoothing spline were evaluated. Their reliability in inferring curve parameters and confidence intervals was compared to the native OmniLog(r) PM analysis software. We consider the post-processing of the estimated parameters, the optimal classification of curve shapes and the detection of significant differences between them, as well as practically relevant questions such as detecting the impact of cultivation times and the minimum required number of experimental repeats. CONCLUSIONS: We provide a comprehensive framework for data visualization and parameter estimation according to user choices. A flexible graphical representation strategy for displaying the results is proposed, including 95% confidence intervals for the estimated parameters. The spline approach is less prone to irregular curve shapes than fitting any of the considered models or using the native PM software for calculating both point estimates and confidence intervals. These can serve as a starting point for the automated post-processing of PM data, providing much more information than the strict dichotomization into positive and negative reactions. Our results form the basis for a freely available R package for the analysis of PM data. PMID- 22536334 TI - A genome-wide homozygosity association study identifies runs of homozygosity associated with rheumatoid arthritis in the human major histocompatibility complex. AB - Rheumatoid arthritis (RA) is a chronic inflammatory disorder with a polygenic mode of inheritance. This study examined the hypothesis that runs of homozygosity (ROHs) play a recessive-acting role in the underlying RA genetic mechanism and identified RA-associated ROHs. Ours is the first genome-wide homozygosity association study for RA and characterized the ROH patterns associated with RA in the genomes of 2,000 RA patients and 3,000 normal controls of the Wellcome Trust Case Control Consortium. Genome scans consistently pinpointed two regions within the human major histocompatibility complex region containing RA-associated ROHs. The first region is from 32,451,664 bp to 32,846,093 bp (-log10(p)>22.6591). RA susceptibility genes, such as HLA-DRB1, are contained in this region. The second region ranges from 32,933,485 bp to 33,585,118 bp (-log10(p)>8.3644) and contains other HLA-DPA1 and HLA-DPB1 genes. These two regions are physically close but are located in different blocks of linkage disequilibrium, and ~40% of the RA patients' genomes carry these ROHs in the two regions. By analyzing homozygote intensities, an ROH that is anchored by the single nucleotide polymorphism rs2027852 and flanked by HLA-DRB6 and HLA-DRB1 was found associated with increased risk for RA. The presence of this risky ROH provides a 62% accuracy to predict RA disease status. An independent genomic dataset from 868 RA patients and 1,194 control subjects of the North American Rheumatoid Arthritis Consortium successfully validated the results obtained using the Wellcome Trust Case Control Consortium data. In conclusion, this genome-wide homozygosity association study provides an alternative to allelic association mapping for the identification of recessive variants responsible for RA. The identified RA-associated ROHs uncover recessive components and missing heritability associated with RA and other autoimmune diseases. PMID- 22536336 TI - Unravelling soil fungal communities from different Mediterranean land-use backgrounds. AB - BACKGROUND: Fungi strongly influence ecosystem structure and functioning, playing a key role in many ecological services as decomposers, plant mutualists and pathogens. The Mediterranean area is a biodiversity hotspot that is increasingly threatened by intense land use. Therefore, to achieve a balance between conservation and human development, a better understanding of the impact of land use on the underlying fungal communities is needed. METHODOLOGY/PRINCIPAL FINDINGS: We used parallel pyrosequencing of the nuclear ribosomal its regions to characterize the fungal communities in five soils subjected to different anthropogenic impact in a typical mediterranean landscape: a natural cork-oak forest, a pasture, a managed meadow, and two vineyards. Marked differences in the distribution of taxon assemblages among the different sites and communities were found. Data analyses consistently indicated a sharp distinction of the fungal community of the cork oak forest soil from those described in the other soils. Each soil showed features of the fungal assemblages retrieved which can be easily related to the above-ground settings: ectomycorrhizal phylotypes were numerous in natural sites covered by trees, but were nearly completely missing from the anthropogenic and grass-covered sites; similarly, coprophilous fungi were common in grazed sites. CONCLUSIONS/SIGNIFICANCE: Data suggest that investigation on the below-ground fungal community may provide useful elements on the above-ground features such as vegetation coverage and agronomic procedures, allowing to assess the cost of anthropogenic land use to hidden diversity in soil. Datasets provided in this study may contribute to future searches for fungal bio-indicators as biodiversity markers of a specific site or a land-use degree. PMID- 22536337 TI - Neuroelectric evidence for cognitive association formation: an event-related potential investigation. AB - Although many types of learning require associations to be formed, little is known about the brain mechanisms engaged in association formation. In the present study, we measured event-related potentials (ERPs) while participants studied pairs of semantically related words, with each word of a pair presented sequentially. To narrow in on the associative component of the signal, the ERP difference between the first and second words of a pair (Word2-Word1) was derived separately for subsequently recalled and subsequently not-recalled pairs. When the resulting difference waveforms were contrasted, a parietal positivity was observed for subsequently recalled pairs around 460 ms after the word presentation onset, followed by a positive slow wave that lasted until around 845 ms. Together these results suggest that associations formed between semantically related words are correlated with a specific neural signature that is reflected in scalp recordings over the parietal region. PMID- 22536338 TI - Wording effects and the factor structure of the Hospital Anxiety & Depression Scale in HIV/AIDS patients on antiretroviral treatment in South Africa. AB - BACKGROUND: Given the immense burden of HIV/AIDS on health systems in sub-Saharan Africa and the intricate link between HIV/AIDS and mental health problems, health care providers need a valid and reliable instrument to assess mental health rapidly. The Hospital Anxiety and Depression Scale (HADS) may constitute such an instrument. The aims of this study were to: (1) examine the factor structure of the HADS in a population of South African HIV/AIDS patients on antiretroviral treatment (ART); and (2) identify and control the disturbing influence of systematic wording effects in vulnerable respondent groups. METHODOLOGY/PRINCIPAL FINDINGS: The translated scale was administered to 716 HIV/AIDS patients enrolled in the public sector ART program in South Africa. A combined confirmatory factor analysis and correlated-traits-correlated-methods framework was used to determine the preferred factor structure of the HADS, while controlling for the disturbing influence of systematic wording effects. When assessing the structure without a negative wording factor, all three factor structures displayed an acceptable fit to the data. The three-factor solution best fitted the data. Addition of a method factor significantly improved the fit of all three factor solutions. Using chi(2) difference testing, Razavi's one-factor solution displayed a superior fit compared to the other two factor solutions. CONCLUSIONS: The study outcomes support the use of the HADS as a valid and reliable means to screen for mental health problems in HIV/AIDS patients enrolled in a public-sector ART program in a resource-limited context. The results demonstrate the importance of evaluating and correcting for wording effects when examining the factor structure of the screening instrument in vulnerable patient groups. In light of the inter relationships between HIV/AIDS and mental health problems and the scarcity of adequate screening tools, additional studies on this topic are required. PMID- 22536339 TI - Changes in the diversity of soil arbuscular mycorrhizal fungi after cultivation for biofuel production in a Guantanamo (Cuba) tropical system. AB - The arbuscular mycorrhizal fungi (AMF) are a key, integral component of the stability, sustainability and functioning of ecosystems. In this study, we characterised the AMF biodiversity in a native vegetation soil and in a soil cultivated with Jatropha curcas or Ricinus communis, in a tropical system in Guantanamo (Cuba), in order to verify if a change of land use to biofuel plant production had any effect on the AMF communities. We also asses whether some soil properties related with the soil fertility (total N, Organic C, microbial biomass C, aggregate stability percentage, pH and electrical conductivity) were changed with the cultivation of both crop species. The AM fungal small sub-unit (SSU) rRNA genes were subjected to PCR, cloning, sequencing and phylogenetic analyses. Twenty AM fungal sequence types were identified: 19 belong to the Glomeraceae and one to the Paraglomeraceae. Two AMF sequence types related to cultured AMF species (Glo G3 for Glomus sinuosum and Glo G6 for Glomus intraradices-G. fasciculatum-G. irregulare) did not occur in the soil cultivated with J. curcas and R. communis. The soil properties (total N, Organic C and microbial biomass C) were higher in the soil cultivated with the two plant species. The diversity of the AMF community decreased in the soil of both crops, with respect to the native vegetation soil, and varied significantly depending on the crop species planted. Thus, R. communis soil showed higher AMF diversity than J. curcas soil. In conclusion, R. communis could be more suitable for the long-term conservation and sustainable management of these tropical ecosytems. PMID- 22536340 TI - First report of 13 species of Culicoides (Diptera: Ceratopogonidae) in mainland Portugal and Azores by morphological and molecular characterization. AB - The genus Culicoides (Diptera: Ceratopogonidae) contains important vectors of animal and human diseases, including bluetongue, African horse sickness and filariosis. A major outbreak of bluetongue occurred in mainland Portugal in 2004, forty eight years after the last recorded case. A national Entomological Surveillance Plan was initiated in mainland Portugal, Azores and the Madeira archipelagos in 2005 in order to better understand the disease and facilitate policy decisions. During the survey, the most prevalent Culicoides species in mainland Portugal was C. imicola (75.3%) and species belonging to the Obsoletus group (6.5%). The latter were the most prevalent in Azores archipelago, accounting for 96.7% of the total species identified. The Obsoletus group was further characterized by multiplex Polymerase Chain Reaction to species level showing that only two species of this group were present: C. obsoletus sensu strictu (69.6%) and C. scoticus (30.4%). Nine species of Culicoides were detected for the first time in mainland Portugal: C. alazanicus, C. bahrainensis, C. deltus, C. lupicaris, C. picturatus, C. santonicus, C. semimaculatus, C. simulator and C. subfagineus. In the Azores, C. newsteadi and C. circumscriptus were identified for the first time from some islands, and bluetongue vectors belonging to the Obsoletus group (C. obsoletus and C. scoticus) were found to be widespread. PMID- 22536341 TI - Replacement of retinyl esters by polyunsaturated triacylglycerol species in lipid droplets of hepatic stellate cells during activation. AB - Activation of hepatic stellate cells has been recognized as one of the first steps in liver injury and repair. During activation, hepatic stellate cells transform into myofibroblasts with concomitant loss of their lipid droplets (LDs) and production of excessive extracellular matrix. Here we aimed to obtain more insight in the dynamics and mechanism of LD loss. We have investigated the LD degradation processes in rat hepatic stellate cells in vitro with a combined approach of confocal Raman microspectroscopy and mass spectrometric analysis of lipids (lipidomics). Upon activation of the hepatic stellate cells, LDs reduce in size, but increase in number during the first 7 days, but the total volume of neutral lipids did not decrease. The LDs also migrate to cellular extensions in the first 7 days, before they disappear. In individual hepatic stellate cells. all LDs have a similar Raman spectrum, suggesting a similar lipid profile. However, Raman studies also showed that the retinyl esters are degraded more rapidly than the triacylglycerols upon activation. Lipidomic analyses confirmed that after 7 days in culture hepatic stellate cells have lost most of their retinyl esters, but not their triacylglycerols and cholesterol esters. Furthermore, we specifically observed a large increase in triacylglycerol-species containing polyunsaturated fatty acids, partly caused by an enhanced incorporation of exogenous arachidonic acid. These results reveal that lipid droplet degradation in activated hepatic stellate cells is a highly dynamic and regulated process. The rapid replacement of retinyl esters by polyunsaturated fatty acids in LDs suggests a role for both lipids or their derivatives like eicosanoids during hepatic stellate cell activation. PMID- 22536342 TI - Anti-HIV-1 activity of a new scorpion venom peptide derivative Kn2-7. AB - For over 30 years, HIV/AIDS has wreaked havoc in the world. In the absence of an effective vaccine for HIV, development of new anti-HIV agents is urgently needed. We previously identified the antiviral activities of the scorpion-venom-peptide derived mucroporin-M1 for three RNA viruses (measles viruses, SARS-CoV, and H5N1). In this investigation, a panel of scorpion venom peptides and their derivatives were designed and chosen for assessment of their anti-HIV activities. A new scorpion venom peptide derivative Kn2-7 was identified as the most potent anti-HIV-1 peptide by screening assays with an EC(50) value of 2.76 ug/ml (1.65 uM) and showed low cytotoxicity to host cells with a selective index (SI) of 13.93. Kn2-7 could inhibit all members of a standard reference panel of HIV-1 subtype B pseudotyped virus (PV) with CCR5-tropic and CXCR4-tropic NL4-3 PV strain. Furthermore, it also inhibited a CXCR4-tropic replication-competent strain of HIV-1 subtype B virus. Binding assay of Kn2-7 to HIV-1 PV by Octet Red system suggested the anti-HIV-1 activity was correlated with a direct interaction between Kn2-7 and HIV-1 envelope. These results demonstrated that peptide Kn2-7 could inhibit HIV-1 by direct interaction with viral particle and may become a promising candidate compound for further development of microbicide against HIV 1. PMID- 22536343 TI - Mitochondrial diabetes in children: seek and you will find it. AB - Maternally Inherited Diabetes and Deafness (MIDD) is a rare form of diabetes due to defects in mitochondrial DNA (mtDNA). 3243 A>G is the mutation most frequently associated with this condition, but other mtDNA variants have been linked with a diabetic phenotype suggestive of MIDD. From 1989 to 2009, we clinically diagnosed mitochondrial diabetes in 11 diabetic children. Diagnosis was based on the presence of one or more of the following criteria: 1) maculopathy; 2) hearing impairment; 3) maternal heritability of diabetes/impaired fasting glucose and/or hearing impairment and/or maculopathy in three consecutive generations (or in two generations if 2 or 3 members of a family were affected). We sequenced the mtDNA in the 11 probands, in their mothers and in 80 controls. We identified 33 diabetes-suspected mutations, 1/33 was 3243A>G. Most patients (91%) and their mothers had mutations in complex I and/or IV of the respiratory chain. We measured the activity of these two enzymes and found that they were less active in mutated patients and their mothers than in the healthy control pool. The prevalence of hearing loss (36% vs 75-98%) and macular dystrophy (54% vs 86%) was lower in our mitochondrial diabetic adolescents than reported in adults. Moreover, we found a hitherto unknown association between mitochondrial diabetes and celiac disease. In conclusion, mitochondrial diabetes should be considered a complex syndrome with several phenotypic variants. Moreover, deafness is not an essential component of the disease in children. The whole mtDNA should be screened because the 3243A>G variant is not as frequent in children as in adults. In fact, 91% of our patients were mutated in the complex I and/or IV genes. The enzymatic assay may be a useful tool with which to confirm the pathogenic significance of detected variants. PMID- 22536344 TI - Plant products affect growth and digestive efficiency of cultured Florida pompano (Trachinotus carolinus) fed compounded diets. AB - Costs of compounded diets containing fish meal as a primary protein source can be expected to rise as fish meal prices increase in response to static supply and growing demand. Alternatives to fish meal are needed to reduce production costs in many aquaculture enterprises. Some plant proteins are potential replacements for fish meal because of their amino acid composition, lower cost and wide availability. In this study, we measured utilization of soybean meal (SBM) and soy protein concentrate (SPC) by Florida pompano fed compounded diets, to determine the efficacy of these products as fish meal replacements. We also calculated apparent digestibility coefficients (ADCs) for canola meal (CM), corn gluten meal (CGM), and distillers dried grains with solubles (DDGS), following typical methods for digestibility trials. Juvenile Florida pompano were fed fish meal-free diets containing graded levels of SBM and SPC, and weight gain was compared to a control diet that contained SBM, SPC, and fish meal. Fish fed diets that contained 25-30 percent SBM in combination with 43-39 percent SPC had weight gain equivalent to fish fed the control diet with fish meal, while weight gain of fish fed other soy combinations was significantly less than that of the control group. Apparent crude protein digestibility of CGM was significantly higher than that of DDGS but not significantly different from CM. Apparent energy digestibility of DDGS was significantly lower than CGM but significantly higher than CM. Findings suggested that composition of the reference diet used in a digestibility trial affects the values of calculated ADCs, in addition to the chemical and physical attributes of the test ingredient. PMID- 22536345 TI - Tolfenamic acid induces apoptosis and growth inhibition in head and neck cancer: involvement of NAG-1 expression. AB - Nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) is induced by nonsteroidal anti-inflammatory drugs and possesses proapoptotic and antitumorigenic activities. Although tolfenamic acid (TA) induces apoptosis in head and neck cancer cells, the relationship between NAG-1 and TA has not been determined. This study investigated the induction of apoptosis in head and neck cancer cells treated by TA and the role of NAG-1 expression in this induction. TA reduced head and neck cancer cell viability in a dose-dependent manner and induced apoptosis. The induced apoptosis was coincident with the expression of NAG-1. Overexpression of NAG-1 enhanced the apoptotic effect of TA, whereas suppression of NAG-1 expression by small interfering RNA attenuated TA-induced apoptosis. TA significantly inhibited tumor formation as assessed by xenograft models, and this result accompanied the induction of apoptotic cells and NAG-1 expression in tumor tissue samples. Taken together, these results demonstrate that TA induces apoptosis via NAG-1 expression in head and neck squamous cell carcinoma, providing an additional mechanistic explanation for the apoptotic activity of TA. PMID- 22536346 TI - The origin of malarial parasites in orangutans. AB - BACKGROUND: Recent findings of Plasmodium in African apes have changed our perspectives on the evolution of malarial parasites in hominids. However, phylogenetic analyses of primate malarias are still missing information from Southeast Asian apes. In this study, we report molecular data for a malaria parasite lineage found in orangutans. METHODOLOGY/PRINCIPAL FINDINGS: We screened twenty-four blood samples from Pongo pygmaeus (Kalimantan, Indonesia) for Plasmodium parasites by PCR. For all the malaria positive orangutan samples, parasite mitochondrial genomes (mtDNA) and two antigens: merozoite surface protein 1 42 kDa (MSP-1(42)) and circumsporozoite protein gene (CSP) were amplified, cloned, and sequenced. Fifteen orangutans tested positive and yielded 5 distinct mitochondrial haplotypes not previously found. The haplotypes detected exhibited low genetic divergence among them, indicating that they belong to one species. We report phylogenetic analyses using mitochondrial genomes, MSP-1(42) and CSP. We found that the orangutan malaria parasite lineage was part of a monophyletic group that includes all the known non-human primate malaria parasites found in Southeast Asia; specifically, it shares a recent common ancestor with P. inui (a macaque parasite) and P. hylobati (a gibbon parasite) suggesting that this lineage originated as a result of a host switch. The genetic diversity of MSP-1(42) in orangutans seems to be under negative selection. This result is similar to previous findings in non-human primate malarias closely related to P. vivax. As has been previously observed in the other Plasmodium species found in non-human primates, the CSP shows high polymorphism in the number of repeats. However, it has clearly distinctive motifs from those previously found in other malarial parasites. CONCLUSION: The evidence available from Asian apes indicates that these parasites originated independently from those found in Africa, likely as the result of host switches from other non-human primates. PMID- 22536347 TI - Regulation of spike timing-dependent plasticity of olfactory inputs in mitral cells in the rat olfactory bulb. AB - The recent history of activity input onto granule cells (GCs) in the main olfactory bulb can affect the strength of lateral inhibition, which functions to generate contrast enhancement. However, at the plasticity level, it is unknown whether and how the prior modification of lateral inhibition modulates the subsequent induction of long-lasting changes of the excitatory olfactory nerve (ON) inputs to mitral cells (MCs). Here we found that the repetitive stimulation of two distinct excitatory inputs to the GCs induced a persistent modification of lateral inhibition in MCs in opposing directions. This bidirectional modification of inhibitory inputs differentially regulated the subsequent synaptic plasticity of the excitatory ON inputs to the MCs, which was induced by the repetitive pairing of excitatory postsynaptic potentials (EPSPs) with postsynaptic bursts. The regulation of spike timing-dependent plasticity (STDP) was achieved by the regulation of the inter-spike-interval (ISI) of the postsynaptic bursts. This novel form of inhibition-dependent regulation of plasticity may contribute to the encoding or processing of olfactory information in the olfactory bulb. PMID- 22536348 TI - Transcriptomics of in vitro immune-stimulated hemocytes from the Manila clam Ruditapes philippinarum using high-throughput sequencing. AB - BACKGROUND: The Manila clam (Ruditapes philippinarum) is a worldwide cultured bivalve species with important commercial value. Diseases affecting this species can result in large economic losses. Because knowledge of the molecular mechanisms of the immune response in bivalves, especially clams, is scarce and fragmentary, we sequenced RNA from immune-stimulated R. philippinarum hemocytes by 454-pyrosequencing to identify genes involved in their immune defense against infectious diseases. METHODOLOGY AND PRINCIPAL FINDINGS: High-throughput deep sequencing of R. philippinarum using 454 pyrosequencing technology yielded 974,976 high-quality reads with an average read length of 250 bp. The reads were assembled into 51,265 contigs and the 44.7% of the translated nucleotide sequences into protein were annotated successfully. The 35 most frequently found contigs included a large number of immune-related genes, and a more detailed analysis showed the presence of putative members of several immune pathways and processes like the apoptosis, the toll like signaling pathway and the complement cascade. We have found sequences from molecules never described in bivalves before, especially in the complement pathway where almost all the components are present. CONCLUSIONS: This study represents the first transcriptome analysis using 454-pyrosequencing conducted on R. philippinarum focused on its immune system. Our results will provide a rich source of data to discover and identify new genes, which will serve as a basis for microarray construction and the study of gene expression as well as for the identification of genetic markers. The discovery of new immune sequences was very productive and resulted in a large variety of contigs that may play a role in the defense mechanisms of Ruditapes philippinarum. PMID- 22536349 TI - Identification of thioredoxin glutathione reductase inhibitors that kill cestode and trematode parasites. AB - Parasitic flatworms are responsible for serious infectious diseases that affect humans as well as livestock animals in vast regions of the world. Yet, the drug armamentarium available for treatment of these infections is limited: praziquantel is the single drug currently available for 200 million people infected with Schistosoma spp. and there is justified concern about emergence of drug resistance. Thioredoxin glutathione reductase (TGR) is an essential core enzyme for redox homeostasis in flatworm parasites. In this work, we searched for flatworm TGR inhibitors testing compounds belonging to various families known to inhibit thioredoxin reductase or TGR and also additional electrophilic compounds. Several furoxans and one thiadiazole potently inhibited TGRs from both classes of parasitic flatworms: cestoda (tapeworms) and trematoda (flukes), while several benzofuroxans and a quinoxaline moderately inhibited TGRs. Remarkably, five active compounds from diverse families possessed a phenylsulfonyl group, strongly suggesting that this moiety is a new pharmacophore. The most active inhibitors were further characterized and displayed slow and nearly irreversible binding to TGR. These compounds efficiently killed Echinococcus granulosus larval worms and Fasciola hepatica newly excysted juveniles in vitro at a 20 uM concentration. Our results support the concept that the redox metabolism of flatworm parasites is precarious and particularly susceptible to destabilization, show that furoxans can be used to target both flukes and tapeworms, and identified phenylsulfonyl as a new drug-hit moiety for both classes of flatworm parasites. PMID- 22536350 TI - Laterally orienting C. elegans using geometry at microscale for high-throughput visual screens in neurodegeneration and neuronal development studies. AB - C. elegans is an excellent model system for studying neuroscience using genetics because of its relatively simple nervous system, sequenced genome, and the availability of a large number of transgenic and mutant strains. Recently, microfluidic devices have been used for high-throughput genetic screens, replacing traditional methods of manually handling C. elegans. However, the orientation of nematodes within microfluidic devices is random and often not conducive to inspection, hindering visual analysis and overall throughput. In addition, while previous studies have utilized methods to bias head and tail orientation, none of the existing techniques allow for orientation along the dorso-ventral body axis. Here, we present the design of a simple and robust method for passively orienting worms into lateral body positions in microfluidic devices to facilitate inspection of morphological features with specific dorso ventral alignments. Using this technique, we can position animals into lateral orientations with up to 84% efficiency, compared to 21% using existing methods. We isolated six mutants with neuronal development or neurodegenerative defects, showing that our technology can be used for on-chip analysis and high-throughput visual screens. PMID- 22536351 TI - Influence of cuticle nanostructuring on the wetting behaviour/states on cicada wings. AB - The nanoscale protrusions of different morphologies on wing surfaces of four cicada species were examined under an environmental scanning electron microscope (ESEM). The water contact angles (CAs) of the wing surfaces were measured along with droplet adhesion values using a high-sensitivity microelectromechanical balance system. The water CA and adhesive force measurements obtained were found to relate to the nanostructuring differences of the four species. The adhesive forces in combination with the Cassie-Baxter and Wenzel approximations were used to predict wetting states of the insect wing cuticles. The more disordered and inhomogeneous surface of the species Leptopsalta bifuscata demonstrated a Wenzel type wetting state or an intermediate state of spreading and imbibition with a CA of 81.3 degrees and high adhesive force of 149.5 uN. Three other species (Cryptotympana atrata, Meimuna opalifer and Aola bindusara) exhibited nanostructuring of the form of conically shaped protrusions, which were spherically capped. These surfaces presented a range of high adhesional values; however, the CAs were highly hydrophobic (C. atrata and A. bindusara) and in some cases close to superhydrophobic (M. opalifer). The wetting states of A. bindusara, C. atrata and M. opalifer (based on adhesion and CAs) are most likely represented by the transitional region between the Cassie-Baxter and Wenzel approximations to varying degrees. PMID- 22536352 TI - De novo transcriptomic analysis of an oleaginous microalga: pathway description and gene discovery for production of next-generation biofuels. AB - BACKGROUND: Eustigmatos cf. polyphem is a yellow-green unicellular soil microalga belonging to the eustimatophyte with high biomass and considerable production of triacylglycerols (TAGs) for biofuels, which is thus referred to as an oleaginous microalga. The paucity of microalgae genome sequences, however, limits development of gene-based biofuel feedstock optimization studies. Here we describe the sequencing and de novo transcriptome assembly for a non-model microalgae species, E. cf. polyphem, and identify pathways and genes of importance related to biofuel production. RESULTS: We performed the de novo assembly of E. cf. polyphem transcriptome using Illumina paired-end sequencing technology. In a single run, we produced 29,199,432 sequencing reads corresponding to 2.33 Gb total nucleotides. These reads were assembled into 75,632 unigenes with a mean size of 503 bp and an N50 of 663 bp, ranging from 100 bp to >3,000 bp. Assembled unigenes were subjected to BLAST similarity searches and annotated with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) orthology identifiers. These analyses identified the majority of carbohydrate, fatty acids, TAG and carotenoids biosynthesis and catabolism pathways in E. cf. polyphem. CONCLUSIONS: Our data provides the construction of metabolic pathways involved in the biosynthesis and catabolism of carbohydrate, fatty acids, TAG and carotenoids in E. cf. polyphem and provides a foundation for the molecular genetics and functional genomics required to direct metabolic engineering efforts that seek to enhance the quantity and character of microalgae based biofuel feedstock. PMID- 22536353 TI - MicroRNAs up-regulated by CagA of Helicobacter pylori induce intestinal metaplasia of gastric epithelial cells. AB - CagA of Helicobacter pylori is a bacterium-derived oncogenic protein closely associated with the development of gastric cancers. MicroRNAs (miRNAs) are a class of widespread non-coding RNAs, many of which are involved in cell growth, cell differentiation and tumorigenesis. The relationship between CagA protein and miRNAs is unclear. Using mammalian miRNA profile microarrays, we found that miRNA 584 and miRNA-1290 expression was up-regulated in CagA-transformed cells, miRNA 1290 was up-regulated in an Erk1/2-dependent manner, and miRNA-584 was activated by NF-kappaB. miRNA-584 sustained Erk1/2 activities through inhibition of PPP2a activities, and miRNA-1290 activated NF-kappaB by knockdown of NKRF. Foxa1 was revealed to be an important target of miRNA-584 and miRNA-1290. Knockdown of Foxa1 promoted the epithelial-mesenchymal transition significantly. Overexpression of miRNA-584 and miRNA-1290 induced intestinal metaplasia of gastric epithelial cells in knock-in mice. These results indicate that miRNA-584 and miRNA-1290 interfere with cell differentiation and remodel the tissues. Thus, the miRNA pathway is a new pathogenic mechanism of CagA. PMID- 22536354 TI - Heritability and genetic correlations of fear-related behaviour in Red Junglefowl -possible implications for early domestication. AB - Domesticated species differ from their wild ancestors in a number of traits, generally referred to as the domesticated phenotype. Reduced fear of humans is assumed to have been an early prerequisite for the successful domestication of virtually all species. We hypothesized that fear of humans is linked to other domestication related traits. For three generations, we selected Red Junglefowl (ancestors of domestic chickens) solely on the reaction in a standardized Fear of Human-test. In this, the birds were exposed for a gradually approaching human, and their behaviour was continuously scored. This generated three groups of animals, high (H), low (L) and intermediate (I) fearful birds. The birds in each generation were additionally tested in a battery of behaviour tests, measuring aspects of fearfulness, exploration, and sociality. The results demonstrate that the variation in fear response of Red Junglefowl towards humans has a significant genetic component and is genetically correlated to behavioural responses in other contexts, of which some are associated with fearfulness and others with exploration. Hence, selection of Red Junglefowl on low fear for humans can be expected to lead to a correlated change of other behavioural traits over generations. It is therefore likely that domestication may have caused an initial suite of behavioural modifications, even without selection on anything besides tameness. PMID- 22536355 TI - Habitat and scale shape the demographic fate of the keystone sea urchin Paracentrotus lividus in Mediterranean macrophyte communities. AB - Demographic processes exert different degrees of control as individuals grow, and in species that span several habitats and spatial scales, this can influence our ability to predict their population at a particular life-history stage given the previous life stage. In particular, when keystone species are involved, this relative coupling between demographic stages can have significant implications for the functioning of ecosystems. We examined benthic and pelagic abundances of the sea urchin Paracentrotus lividus in order to: 1) understand the main life history bottlenecks by observing the degree of coupling between demographic stages; and 2) explore the processes driving these linkages. P. lividus is the dominant invertebrate herbivore in the Mediterranean Sea, and has been repeatedly observed to overgraze shallow beds of the seagrass Posidonia oceanica and rocky macroalgal communities. We used a hierarchical sampling design at different spatial scales (100 s, 10 s and <1 km) and habitats (seagrass and rocky macroalgae) to describe the spatial patterns in the abundance of different demographic stages (larvae, settlers, recruits and adults). Our results indicate that large-scale factors (potentially currents, nutrients, temperature, etc.) determine larval availability and settlement in the pelagic stages of urchin life history. In rocky macroalgal habitats, benthic processes (like predation) acting at large or medium scales drive adult abundances. In contrast, adult numbers in seagrass meadows are most likely influenced by factors like local migration (from adjoining rocky habitats) functioning at much smaller scales. The complexity of spatial and habitat-dependent processes shaping urchin populations demands a multiplicity of approaches when addressing habitat conservation actions, yet such actions are currently mostly aimed at managing predation processes and fish numbers. We argue that a more holistic ecosystem management also needs to incorporate the landscape and habitat-quality level processes (eutrophication, fragmentation, etc.) that together regulate the populations of this keystone herbivore. PMID- 22536356 TI - Rhodolith beds are major CaCO3 bio-factories in the tropical South West Atlantic. AB - Rhodoliths are nodules of non-geniculate coralline algae that occur in shallow waters (<150 m depth) subjected to episodic disturbance. Rhodolith beds stand with kelp beds, seagrass meadows, and coralline algal reefs as one of the world's four largest macrophyte-dominated benthic communities. Geographic distribution of rhodolith beds is discontinuous, with large concentrations off Japan, Australia and the Gulf of California, as well as in the Mediterranean, North Atlantic, eastern Caribbean and Brazil. Although there are major gaps in terms of seabed habitat mapping, the largest rhodolith beds are purported to occur off Brazil, where these communities are recorded across a wide latitudinal range (2 degrees N 27 degrees S). To quantify their extent, we carried out an inter-reefal seabed habitat survey on the Abrolhos Shelf (16 degrees 50'-19 degrees 45'S) off eastern Brazil, and confirmed the most expansive and contiguous rhodolith bed in the world, covering about 20,900 km(2). Distribution, extent, composition and structure of this bed were assessed with side scan sonar, remotely operated vehicles, and SCUBA. The mean rate of CaCO(3) production was estimated from in situ growth assays at 1.07 kg m(-2) yr(-1), with a total production rate of 0.025 Gt yr(-1), comparable to those of the world's largest biogenic CaCO(3) deposits. These gigantic rhodolith beds, of areal extent equivalent to the Great Barrier Reef, Australia, are a critical, yet poorly understood component of the tropical South Atlantic Ocean. Based on the relatively high vulnerability of coralline algae to ocean acidification, these beds are likely to experience a profound restructuring in the coming decades. PMID- 22536357 TI - Development of a tetrameric streptavidin mutein with reversible biotin binding capability: engineering a mobile loop as an exit door for biotin. AB - A novel form of tetrameric streptavidin has been engineered to have reversible biotin binding capability. In wild-type streptavidin, loop(3-4) functions as a lid for the entry and exit of biotin. When biotin is bound, interactions between biotin and key residues in loop(3-4) keep this lid in the closed state. In the engineered mutein, a second biotin exit door is created by changing the amino acid sequence of loop(7-8). This door is mobile even in the presence of the bound biotin and can facilitate the release of biotin from the mutein. Since loop(7-8) is involved in subunit interactions, alteration of this loop in the engineered mutein results in an 11 degrees rotation between the two dimers in reference to wild-type streptavidin. The tetrameric state of the engineered mutein is stabilized by a H127C mutation, which leads to the formation of inter-subunit disulfide bonds. The biotin binding kinetic parameters (k(off) of 4.28*10(-4) s( 1) and K(d) of 1.9*10(-8) M) make this engineered mutein a superb affinity agent for the purification of biotinylated biomolecules. Affinity matrices can be regenerated using gentle procedures, and regenerated matrices can be reused at least ten times without any observable reduction in binding capacity. With the combination of both the engineered mutein and wild-type streptavidin, biotinylated biomolecules can easily be affinity purified to high purity and immobilized to desirable platforms without any leakage concerns. Other potential biotechnological applications, such as development of an automated high throughput protein purification system, are feasible. PMID- 22536358 TI - Optimal estimation of ion-channel kinetics from macroscopic currents. AB - Markov modeling provides an effective approach for modeling ion channel kinetics. There are several search algorithms for global fitting of macroscopic or single channel currents across different experimental conditions. Here we present a particle swarm optimization(PSO)-based approach which, when used in combination with golden section search (GSS), can fit macroscopic voltage responses with a high degree of accuracy (errors within 1%) and reasonable amount of calculation time (less than 10 hours for 20 free parameters) on a desktop computer. We also describe a method for initial value estimation of the model parameters, which appears to favor identification of global optimum and can further reduce the computational cost. The PSO-GSS algorithm is applicable for kinetic models of arbitrary topology and size and compatible with common stimulation protocols, which provides a convenient approach for establishing kinetic models at the macroscopic level. PMID- 22536359 TI - Impact of reporting bias in network meta-analysis of antidepressant placebo controlled trials. AB - BACKGROUND: Indirect comparisons of competing treatments by network meta-analysis (NMA) are increasingly in use. Reporting bias has received little attention in this context. We aimed to assess the impact of such bias in NMAs. METHODS: We used data from 74 FDA-registered placebo-controlled trials of 12 antidepressants and their 51 matching publications. For each dataset, NMA was used to estimate the effect sizes for 66 possible pair-wise comparisons of these drugs, the probabilities of being the best drug and ranking the drugs. To assess the impact of reporting bias, we compared the NMA results for the 51 published trials and those for the 74 FDA-registered trials. To assess how reporting bias affecting only one drug may affect the ranking of all drugs, we performed 12 different NMAs for hypothetical analysis. For each of these NMAs, we used published data for one drug and FDA data for the 11 other drugs. FINDINGS: Pair-wise effect sizes for drugs derived from the NMA of published data and those from the NMA of FDA data differed in absolute value by at least 100% in 30 of 66 pair-wise comparisons (45%). Depending on the dataset used, the top 3 agents differed, in composition and order. When reporting bias hypothetically affected only one drug, the affected drug ranked first in 5 of the 12 NMAs but second (n = 2), fourth (n = 1) or eighth (n = 2) in the NMA of the complete FDA network. CONCLUSIONS: In this particular network, reporting bias biased NMA-based estimates of treatments efficacy and modified ranking. The reporting bias effect in NMAs may differ from that in classical meta-analyses in that reporting bias affecting only one drug may affect the ranking of all drugs. PMID- 22536360 TI - Associations between XPD Asp312Asn polymorphism and risk of head and neck cancer: a meta-analysis based on 7,122 subjects. AB - BACKGROUND: To investigate the association between XPD Asp312Asn polymorphism and head and neck cancer risk through this meta-analysis. METHODS: We performed a meta-analysis of 9 published case-control studies including 2,670 patients with head and neck cancer and 4,452 controls. An odds ratio (OR) with a 95% confidence interval (CI) was applied to assess the association between XPD Asp312Asn polymorphism and head and neck cancer risk. RESULTS: Overall, no significant association between XPD Asp312Asn polymorphism and head and neck cancer risk was found in this meta-analysis (Asn/Asn vs. Asp/Asp: OR = 0.95, 95%CI = 0.80-1.13, P = 0.550, P(heterogeneity) = 0.126; Asp/Asn vs. Asp/Asp: OR = 1.11, 95%CI = 0.99 1.24, P = 0.065, P(heterogeneity) = 0.663; Asn/Asn+Asp/Asn vs. Asp/Asp: OR = 1.07, 95%CI = 0.97-1.19, P = 0.189, P(heterogeneity) = 0.627; Asn/Asn vs. Asp/Asp+Asp/Asn: OR = 0.87, 95%CI = 0.68-1.10, P = 0.243, P(heterogeneity) = 0.089). In the subgroup analysis by HWE, ethnicity, and study design, there was still no significant association detected in all genetic models. CONCLUSIONS: This meta-analysis demonstrates that XPD Asp312Asn polymorphism may not be a risk factor for developing head and neck cancer. PMID- 22536361 TI - The cotton centromere contains a Ty3-gypsy-like LTR retroelement. AB - The centromere is a repeat-rich structure essential for chromosome segregation; with the long-term aim of understanding centromere structure and function, we set out to identify cotton centromere sequences. To isolate centromere-associated sequences from cotton, (Gossypium hirsutum) we surveyed tandem and dispersed repetitive DNA in the genus. Centromere-associated elements in other plants include tandem repeats and, in some cases, centromere-specific retroelements. Examination of cotton genomic survey sequences for tandem repeats yielded sequences that did not localize to the centromere. However, among the repetitive sequences we also identified a gypsy-like LTR retrotransposon (Centromere Retroelement Gossypium, CRG) that localizes to the centromere region of all chromosomes in domestic upland cotton, Gossypium hirsutum, the major commercially grown cotton. The location of the functional centromere was confirmed by immunostaining with antiserum to the centromere-specific histone CENH3, which co localizes with CRG hybridization on metaphase mitotic chromosomes. G. hirsutum is an allotetraploid composed of A and D genomes and CRG is also present in the centromere regions of other AD cotton species. Furthermore, FISH and genomic dot blot hybridization revealed that CRG is found in D-genome diploid cotton species, but not in A-genome diploid species, indicating that this retroelement may have invaded the A-genome centromeres during allopolyploid formation and amplified during evolutionary history. CRG is also found in other diploid Gossypium species, including B and E2 genome species, but not in the C, E1, F, and G genome species tested. Isolation of this centromere-specific retrotransposon from Gossypium provides a probe for further understanding of centromere structure, and a tool for future engineering of centromere mini-chromosomes in this important crop species. PMID- 22536362 TI - Characterizing mutational heterogeneity in a glioblastoma patient with double recurrence. AB - Human cancers are driven by the acquisition of somatic mutations. Separating the driving mutations from those that are random consequences of general genomic instability remains a challenge. New sequencing technology makes it possible to detect mutations that are present in only a minority of cells in a heterogeneous tumor population. We sought to leverage the power of ultra-deep sequencing to study various levels of tumor heterogeneity in the serial recurrences of a single glioblastoma multiforme patient. Our goal was to gain insight into the temporal succession of DNA base-level lesions by querying intra- and inter-tumoral cell populations in the same patient over time. We performed targeted "next generation" sequencing on seven samples from the same patient: two foci within the primary tumor, two foci within an initial recurrence, two foci within a second recurrence, and normal blood. Our study reveals multiple levels of mutational heterogeneity. We found variable frequencies of specific EGFR, PIK3CA, PTEN, and TP53 base substitutions within individual tumor regions and across distinct regions within the same tumor. In addition, specific mutations emerge and disappear along the temporal spectrum from tumor at the time of diagnosis to second recurrence, demonstrating evolution during tumor progression. Our results shed light on the spatial and temporal complexity of brain tumors. As sequencing costs continue to decline and deep sequencing technology eventually moves into the clinic, this approach may provide guidance for treatment choices as we embark on the path to personalized cancer medicine. PMID- 22536363 TI - Differential effects of an O-GlcNAcase inhibitor on tau phosphorylation. AB - Abnormal hyperphosphorylation of microtubule-associated protein tau plays a crucial role in neurodegeneration in Alzheimer's disease (AD). The aggregation of hyperphosphorylated tau into neurofibrillary tangles is also a hallmark brain lesion of AD. Tau phosphorylation is regulated by tau kinases, tau phosphatases, and O-GlcNAcylation, a posttranslational modification of proteins on the serine or threonine residues with beta-N-acetylglucosamine (GlcNAc). O-GlcNAcylation is dynamically regulated by O-GlcNAc transferase, the enzyme catalyzing the transfer of GlcNAc to proteins, and N-acetylglucosaminidase (OGA), the enzyme catalyzing the removal of GlcNAc from proteins. Thiamet-G is a recently synthesized potent OGA inhibitor, and initial studies suggest it can influence O-GlcNAc levels in the brain, allowing OGA inhibition to be a potential route to altering disease progression in AD. In this study, we injected thiamet-G into the lateral ventricle of mice to increase O-GlcNAcylation of proteins and investigated the resulting effects on site-specific tau phosphorylation. We found that acute thiamet-G treatment led to a decrease in tau phosphorylation at Thr181, Thr212, Ser214, Ser262/Ser356, Ser404 and Ser409, and an increase in tau phosphorylation at Ser199, Ser202, Ser396 and Ser422 in the mouse brain. Investigation of the major tau kinases showed that acute delivery of a high dose of thiamet-G into the brain also led to a marked activation of glycogen synthase kinase-3beta (GSK 3beta), possibly as a consequence of down-regulation of its upstream regulating kinase, AKT. However, the elevation of tau phosphorylation at the sites above was not observed and GSK-3beta was not activated in cultured adult hippocampal progenitor cells or in PC12 cells after thiamet-G treatment. These results suggest that acute high-dose thiamet-G injection can not only directly antagonize tau phosphorylation, but also stimulate GSK-3beta activity, with the downstream consequence being site-specific, bi-directional regulation of tau phosphorylation in the mammalian brain. PMID- 22536364 TI - HIV incidence remains high in KwaZulu-Natal, South Africa: evidence from three districts. AB - BACKGROUND: HIV prevalence and incidence among sexually active women in peri urban areas of Ladysmith, Edendale, and Pinetown, KwaZulu-Natal, South Africa, were assessed between October 2007 and February 2010 in preparation for vaginal microbicide trials. METHODOLOGY/PRINCIPAL FINDINGS: Sexually active women 18-35 years, not known to be HIV-positive or pregnant were tested cross-sectionally to determine HIV and pregnancy prevalence (798 in Ladysmith, 1,084 in Edendale, and 891 in Pinetown). Out of these, approximately 300 confirmed non-pregnant, HIV negative women were subsequently enrolled at each clinical research center (CRC) in a 12-month cohort study with quarterly study visits. Women in the cohort studies were required to use a condom plus a hormonal contraceptive method. HIV prevalence rates in the baseline cross-sectional surveys were high: 42% in Ladysmith, 46% in Edendale and 41% in Pinetown. Around 90% of study participants at each CRC reported one sex partner in the last 3 months, but only 14-30% stated that they were sure that none of their sex partners were HIV-positive. HIV incidence rates based on seroconversions over 12 months were 14.8/100 person years (PY) (95% CI 9.7, 19.8) in Ladysmith, 6.3/100 PY (95% CI 3.2, 9.4) in Edendale, and 7.2/100 PY (95% CI 3.7, 10.7) in Pinetown. The 12-month pregnancy incidence rates (in the context of high reported contraceptive use) were: 5.7/100 PY (95% CI 2.6, 8.7) in Ladysmith, 3.1/100 PY (95% CI 0.9, 5.2) in Edendale and 6.3/100 PY (95% CI 3.0, 9.6) in Pinetown. CONCLUSIONS/SIGNIFICANCE: HIV prevalence and incidence remain high in peri-urban areas of KwaZulu-Natal. PMID- 22536365 TI - Targeted overexpression of osteoactivin in cells of osteoclastic lineage promotes osteoclastic resorption and bone loss in mice. AB - This study sought to test whether targeted overexpression of osteoactivin (OA) in cells of osteoclastic lineage, using the tartrate-resistant acid phosphase (TRAP) exon 1B/C promoter to drive OA expression, would increase bone resorption and bone loss in vivo. OA transgenic osteoclasts showed ~2-fold increases in OA mRNA and proteins compared wild-type (WT) osteoclasts. However, the OA expression in transgenic osteoblasts was not different. At 4, 8, and 15.3 week-old, transgenic mice showed significant bone loss determined by pQCT and confirmed by MU-CT. In vitro, transgenic osteoclasts were twice as large, had twice as much TRAP activity, resorbed twice as much bone matrix, and expressed twice as much osteoclastic genes (MMP9, calciton receptor, and ADAM12), as WT osteoclasts. The siRNA-mediated suppression of OA expression in RAW264.7-derived osteoclasts reduced cell size and osteoclastic gene expression. Bone histomorphometry revealed that transgenic mice had more osteoclasts and osteoclast surface. Plasma c-telopeptide (a resorption biomarker) measurements confirmed an increase in bone resorption in transgenic mice in vivo. In contrast, histomorphometric bone formation parameters and plasma levels of bone formation biomarkers (osteocalcin and pro-collagen type I N-terminal peptide) were not different between transgenic mice and WT littermates, indicating the lack of bone formation effects. In conclusion, this study provides compelling in vivo evidence that osteoclast derived OA is a novel stimulator of osteoclast activity and bone resorption. PMID- 22536366 TI - The influence of meteorology on the spread of influenza: survival analysis of an equine influenza (A/H3N8) outbreak. AB - The influences of relative humidity and ambient temperature on the transmission of influenza A viruses have recently been established under controlled laboratory conditions. The interplay of meteorological factors during an actual influenza epidemic is less clear, and research into the contribution of wind to epidemic spread is scarce. By applying geostatistics and survival analysis to data from a large outbreak of equine influenza (A/H3N8), we quantified the association between hazard of infection and air temperature, relative humidity, rainfall, and wind velocity, whilst controlling for premises-level covariates. The pattern of disease spread in space and time was described using extraction mapping and instantaneous hazard curves. Meteorological conditions at each premises location were estimated by kriging daily meteorological data and analysed as time-lagged time-varying predictors using generalised Cox regression. Meteorological covariates time-lagged by three days were strongly associated with hazard of influenza infection, corresponding closely with the incubation period of equine influenza. Hazard of equine influenza infection was higher when relative humidity was <60% and lowest on days when daily maximum air temperature was 20-25 degrees C. Wind speeds >30 km hour(-1) from the direction of nearby infected premises were associated with increased hazard of infection. Through combining detailed influenza outbreak and meteorological data, we provide empirical evidence for the underlying environmental mechanisms that influenced the local spread of an outbreak of influenza A. Our analysis supports, and extends, the findings of studies into influenza A transmission conducted under laboratory conditions. The relationships described are of direct importance for managing disease risk during influenza outbreaks in horses, and more generally, advance our understanding of the transmission of influenza A viruses under field conditions. PMID- 22536367 TI - Characterization of the single stranded DNA binding protein SsbB encoded in the Gonoccocal Genetic Island. AB - BACKGROUND: Most strains of Neisseria gonorrhoeae carry a Gonococcal Genetic Island which encodes a type IV secretion system involved in the secretion of ssDNA. We characterize the GGI-encoded ssDNA binding protein, SsbB. Close homologs of SsbB are located within a conserved genetic cluster found in genetic islands of different proteobacteria. This cluster encodes DNA-processing enzymes such as the ParA and ParB partitioning proteins, the TopB topoisomerase, and four conserved hypothetical proteins. The SsbB homologs found in these clusters form a family separated from other ssDNA binding proteins. METHODOLOGY/PRINCIPAL FINDINGS: In contrast to most other SSBs, SsbB did not complement the Escherichia coli ssb deletion mutant. Purified SsbB forms a stable tetramer. Electrophoretic mobility shift assays and fluorescence titration assays, as well as atomic force microscopy demonstrate that SsbB binds ssDNA specifically with high affinity. SsbB binds single-stranded DNA with minimal binding frames for one or two SsbB tetramers of 15 and 70 nucleotides. The binding mode was independent of increasing Mg(2+) or NaCl concentrations. No role of SsbB in ssDNA secretion or DNA uptake could be identified, but SsbB strongly stimulated Topoisomerase I activity. CONCLUSIONS/SIGNIFICANCE: We propose that these novel SsbBs play an unknown role in the maintenance of genetic islands. PMID- 22536368 TI - CD3Z genetic polymorphism in immune response to hepatitis B vaccination in two independent Chinese populations. AB - Vaccination against hepatitis B virus is an effective and routine practice that can prevent infection. However, vaccine-induced immunity to hepatitis B varies among individuals. CD4(+) T helper cells, which play an important role in both cellular and humoral immunity, are involved in the immune response elicited by vaccination. Polymorphisms in the genes involved in stimulating the activation and proliferation of CD4(+) T helper cells may influence the immune response to hepatitis B vaccination. In the first stage of the present study, a total of 111 single nucleotide polymorphisms (SNPs) in 17 genes were analyzed, using the iPLEX MassARRAY system, among 214 high responders and 107 low responders to hepatitis B vaccination. Three SNPs (rs12133337 and rs10918706 in CD3Z, rs10912564 in OX40L) were associated significantly with the immune response to hepatitis B vaccination (P = 0.008, 0.041, and 0.019, respectively). The three SNPs were analyzed further with the TaqMan-MGB or TaqMan-BHQ probe-based real-time polymerase chain reaction in another independent population, which included 1090 high responders and 636 low responders. The minor allele 'C' of rs12133337 continued to show an association with a lower response to hepatitis B vaccination (P = 0.033, odds radio = 1.28, 95% confidence interval = 1.01-1.61). Furthermore, in the stratified analysis for both the first and second populations, the association of the minor allele 'C' of rs12133337 with a lower response to hepatitis B vaccination was more prominent after individuals who were overweight or obese (body mass index >=25 kg/m(2)) were excluded (1(st) stage: P = 0.003, 2(nd) stage: P = 0.002, P-combined = 9.47e-5). These findings suggest that the rs12133337 polymorphism in the CD3Z gene might affect the immune response to hepatitis B vaccination, and that a lower BMI might increase the contribution of the polymorphism to immunity to hepatitis B vaccination. PMID- 22536369 TI - Proteomics characterization of cytoplasmic and lipid-associated membrane proteins of human pathogen Mycoplasma fermentans M64. AB - Mycoplasma fermentans is a potent human pathogen which has been implicated in several diseases. Notably, its lipid-associated membrane proteins (LAMPs) play a role in immunomodulation and development of infection-associated inflammatory diseases. However, the systematic protein identification of pathogenic M. fermentans has not been reported. From our recent sequencing results of M. fermentans M64 isolated from human respiratory tract, its genome is around 1.1 Mb and encodes 1050 predicted protein-coding genes. In the present study, soluble proteome of M. fermentans was resolved and analyzed using two-dimensional gel electrophoresis. In addition, Triton X-114 extraction was carried out to enrich amphiphilic proteins including putative lipoproteins and membrane proteins. Subsequent mass spectrometric analyses of these proteins had identified a total of 181 M. fermentans ORFs. Further bioinformatics analysis of these ORFs encoding proteins with known or so far unknown orthologues among bacteria revealed that a total of 131 proteins are homologous to known proteins, 11 proteins are conserved hypothetical proteins, and the remaining 39 proteins are likely M. fermentans specific proteins. Moreover, Triton X-114-enriched fraction was shown to activate NF-kB activity of raw264.7 macrophage and a total of 21 lipoproteins with predicted signal peptide were identified therefrom. Together, our work provides the first proteome reference map of M. fermentans as well as several putative virulence-associated proteins as diagnostic markers or vaccine candidates for further functional study of this human pathogen. PMID- 22536370 TI - Routine multiplex mutational profiling of melanomas enables enrollment in genotype-driven therapeutic trials. AB - PURPOSE: Knowledge of tumor mutation status is becoming increasingly important for the treatment of cancer, as mutation-specific inhibitors are being developed for clinical use that target only sub-populations of patients with particular tumor genotypes. Melanoma provides a recent example of this paradigm. We report here development, validation, and implementation of an assay designed to simultaneously detect 43 common somatic point mutations in 6 genes (BRAF, NRAS, KIT, GNAQ, GNA11, and CTNNB1) potentially relevant to existing and emerging targeted therapies specifically in melanoma. METHODS: The test utilizes the SNaPshot method (multiplex PCR, multiplex primer extension, and capillary electrophoresis) and can be performed rapidly with high sensitivity (requiring 5 10% mutant allele frequency) and minimal amounts of DNA (10-20 nanograms). The assay was validated using cell lines, fresh-frozen tissue, and formalin-fixed paraffin embedded tissue. Clinical characteristics and the impact on clinical trial enrollment were then assessed for the first 150 melanoma patients whose tumors were genotyped in the Vanderbilt molecular diagnostics lab. RESULTS: Directing this test to a single disease, 90 of 150 (60%) melanomas from sites throughout the body harbored a mutation tested, including 57, 23, 6, 3, and 2 mutations in BRAF, NRAS, GNAQ, KIT, and CTNNB1, respectively. Among BRAF V600 mutations, 79%, 12%, 5%, and 4% were V600E, V600K, V600R, and V600M, respectively. 23 of 54 (43%) patients with mutation harboring metastatic disease were subsequently enrolled in genotype-driven trials. CONCLUSION: We present development of a simple mutational profiling screen for clinically relevant mutations in melanoma. Adoption of this genetically-informed approach to the treatment of melanoma has already had an impact on clinical trial enrollment and prioritization of therapy for patients with the disease. PMID- 22536371 TI - Particular Candida albicans strains in the digestive tract of dyspeptic patients, identified by multilocus sequence typing. AB - BACKGROUND: Candida albicans is a human commensal that is also responsible for chronic gastritis and peptic ulcerous disease. Little is known about the genetic profiles of the C. albicans strains in the digestive tract of dyspeptic patients. The aim of this study was to evaluate the prevalence, diversity, and genetic profiles among C. albicans isolates recovered from natural colonization of the digestive tract in the dyspeptic patients. METHODS AND FINDINGS: Oral swab samples (n = 111) and gastric mucosa samples (n = 102) were obtained from a group of patients who presented dyspeptic symptoms or ulcer complaints. Oral swab samples (n = 162) were also obtained from healthy volunteers. C. albicans isolates were characterized and analyzed by multilocus sequence typing. The prevalence of Candida spp. in the oral samples was not significantly different between the dyspeptic group and the healthy group (36.0%, 40/111 vs. 29.6%, 48/162; P > 0.05). However, there were significant differences between the groups in the distribution of species isolated and the genotypes of the C. albicans isolates. C. albicans was isolated from 97.8% of the Candida-positive subjects in the dyspeptic group, but from only 56.3% in the healthy group (P < 0.001). DST1593 was the dominant C. albicans genotype from the digestive tract of the dyspeptic group (60%, 27/45), but not the healthy group (14.8%, 4/27) (P < 0.001). CONCLUSIONS: Our data suggest a possible link between particular C. albicans strain genotypes and the host microenvironment. Positivity for particular C. albicans genotypes could signify susceptibility to dyspepsia. PMID- 22536373 TI - Vitamin D receptor deficiency and low vitamin D diet stimulate aortic calcification and osteogenic key factor expression in mice. AB - Low levels of 25-hydroxy vitamin D (25(OH)D) are associated with cardiovascular diseases. Herein, we tested the hypothesis that vitamin D deficiency could be a causal factor in atherosclerotic vascular changes and vascular calcification. Aortic root sections of vitamin D receptor knockout (VDR(-/-)) mice that were stained for vascular calcification and immunostained for osteoblastic differentiation factors showed more calcified areas and a higher expression of the osteogenic key factors Msx2, Bmp2, and Runx2 than the wild-type mice (P<0.01). Data from LDL receptor knockout (LDLR(-/-)) mice that were fed western diet with either low (50 IU/kg), recommended (1,000 IU/kg), or high (10,000 IU/kg) amounts of vitamin D(3) over 16 weeks revealed increasing plasma concentrations of 25(OH)D (P<0.001) with increasing intake of vitamin D, whereas levels of calcium and phosphorus in plasma and femur were not influenced by the dietary treatment. Mice treated with the low vitamin D diet had more calcified lesions and a higher expression of Msx2, Bmp2, and Runx2 in aortic roots than mice fed recommended or high amounts of vitamin D (P<0.001). Taken together, these findings indicate vitamin D deficiency as a risk factor for aortic valve and aortic vessel calcification and a stimulator of osteogenic key factor expression in these vascular areas. PMID- 22536372 TI - Capturing single cell genomes of active polysaccharide degraders: an unexpected contribution of Verrucomicrobia. AB - Microbial hydrolysis of polysaccharides is critical to ecosystem functioning and is of great interest in diverse biotechnological applications, such as biofuel production and bioremediation. Here we demonstrate the use of a new, efficient approach to recover genomes of active polysaccharide degraders from natural, complex microbial assemblages, using a combination of fluorescently labeled substrates, fluorescence-activated cell sorting, and single cell genomics. We employed this approach to analyze freshwater and coastal bacterioplankton for degraders of laminarin and xylan, two of the most abundant storage and structural polysaccharides in nature. Our results suggest that a few phylotypes of Verrucomicrobia make a considerable contribution to polysaccharide degradation, although they constituted only a minor fraction of the total microbial community. Genomic sequencing of five cells, representing the most predominant, polysaccharide-active Verrucomicrobia phylotype, revealed significant enrichment in genes encoding a wide spectrum of glycoside hydrolases, sulfatases, peptidases, carbohydrate lyases and esterases, confirming that these organisms were well equipped for the hydrolysis of diverse polysaccharides. Remarkably, this enrichment was on average higher than in the sequenced representatives of Bacteroidetes, which are frequently regarded as highly efficient biopolymer degraders. These findings shed light on the ecological roles of uncultured Verrucomicrobia and suggest specific taxa as promising bioprospecting targets. The employed method offers a powerful tool to rapidly identify and recover discrete genomes of active players in polysaccharide degradation, without the need for cultivation. PMID- 22536374 TI - Production of transgenic pigs mediated by pseudotyped lentivirus and sperm. AB - Sperm-mediated gene transfer can be a very efficient method to produce transgenic pigs, however, the results from different laboratories had not been widely repeated. Genomic integration of transgene by injection of pseudotyped lentivirus to the perivitelline space has been proved to be a reliable route to generate transgenic animals. To test whether transgene in the lentivirus can be delivered by sperm, we studied incubation of pseudotyped lentiviruses and sperm before insemination. After incubation with pig spermatozoa, 62+/-3 lentiviral particles were detected per 100 sperm cells using quantitative real-time RT-PCR. The association of lentivirus with sperm was further confirmed by electron microscopy. The sperm incubated with lentiviral particles were artificially inseminated into pigs. Of the 59 piglets born from inseminated 5 sows, 6 piglets (10.17%) carried the transgene based on the PCR identification. Foreign gene and EGFP was successfully detected in ear tissue biopsies from two PCR-positive pigs, revealed via in situ hybridization and immunohistochemistry. Offspring of one PCR positive boar with normal sows showed PCR-positive. Two PCR-positive founders and offsprings of PCR-positive boar were further identified by Southern-blot analysis, out of which the two founders and two offsprings were positive in Southern blotting, strongly indicating integration of foreign gene into genome. The results indicate that incubation of sperm with pseudotyped lentiviruses can incorporated with sperm-mediated gene transfer to produce transgenic pigs with improved efficiency. PMID- 22536375 TI - Excreted thiocyanate detects live reef fishes illegally collected using cyanide- a non-invasive and non-destructive testing approach. AB - Cyanide fishing is a method employed to capture marine fish alive on coral reefs. They are shipped to markets for human consumption in Southeast Asia, as well as to supply the marine aquarium trade worldwide. Although several techniques can be used to detect cyanide in reef fish, there is still no testing method that can be used to survey the whole supply chain. Most methods for cyanide detection are time-consuming and require the sacrifice of the sampled fish. Thiocyanate anion (SCN(-)) is a metabolite produced by the main metabolic pathway for cyanide anion (CN(-)) detoxification. Our study employed an optical fiber (OF) methodology (analytical time <6 min) to detect SCN(-) in a non-invasive and non-destructive manner. Our OF methodology is able to detect trace levels (>3.16 ug L(-1)) of SCN(-) in seawater. Given that marine fish exposed to cyanide excrete SCN(-) in the urine, elevated levels of SCN(-) present in the seawater holding live reef fish indicate that the surveyed specimens were likely exposed to cyanide. In our study, captive-bred clownfish (Amphiprion clarkii) pulse exposed for 60 s to either 12.5 or 25 mg L(-1) of CN(-) excreted up to 6.96+/-0.03 and 9.84+/-0.03 ug L(-1) of SCN(-), respectively, during the 28 days following exposure. No detectable levels of SCN(-) were recorded in the water holding control organisms not exposed to CN(-), or in synthetic seawater lacking fish. While further research is necessary, our methodology can allow a rapid detection of SCN(-) in the holding water and can be used as a screening tool to indicate if live reef fish were collected with cyanide. PMID- 22536376 TI - Characterization of the modes of binding between human sweet taste receptor and low-molecular-weight sweet compounds. AB - One of the most distinctive features of human sweet taste perception is its broad tuning to chemically diverse compounds ranging from low-molecular-weight sweeteners to sweet-tasting proteins. Many reports suggest that the human sweet taste receptor (hT1R2-hT1R3), a heteromeric complex composed of T1R2 and T1R3 subunits belonging to the class C G protein-coupled receptor family, has multiple binding sites for these sweeteners. However, it remains unclear how the same receptor recognizes such diverse structures. Here we aim to characterize the modes of binding between hT1R2-hT1R3 and low-molecular-weight sweet compounds by functional analysis of a series of site-directed mutants and by molecular modeling-based docking simulation at the binding pocket formed on the large extracellular amino-terminal domain (ATD) of hT1R2. We successfully determined the amino acid residues responsible for binding to sweeteners in the cleft of hT1R2 ATD. Our results suggest that individual ligands have sets of specific residues for binding in correspondence with the chemical structures and other residues responsible for interacting with multiple ligands. PMID- 22536377 TI - Evaluation of the London Measure of Unplanned Pregnancy in a United States population of women. AB - OBJECTIVE: To evaluate the reliability and validity of the London Measure of Unplanned Pregnancy (a U.K.-developed measure of pregnancy intention), in English and Spanish translation, in a U.S. population of women. METHODS: A psychometric evaluation study of the London Measure of Unplanned Pregnancy (LMUP), a six-item, self-completion paper measure was conducted with 346 women aged 15-45 who presented to San Francisco General Hospital for termination of pregnancy or antenatal care. Analyses of the two language versions were carried out separately. Reliability (internal consistency) was assessed using Cronbach's alpha and item-total correlations. Test-retest reliability (stability) was assessed using weighted Kappa. Construct validity was assessed using principal components analysis and hypothesis testing. RESULTS: Psychometric testing demonstrated that the LMUP was reliable and valid in both U.S. English (alpha = 0.78, all item-total correlations >0.20, weighted Kappa = 0.72, unidimensionality confirmed, hypotheses met) and Spanish translation (alpha = 0.84, all item-total correlations >0.20, weighted Kappa = 0.77, unidimensionality confirmed, hypotheses met). CONCLUSION: The LMUP was reliable and valid in U.S. English and Spanish translation and therefore may now be used with U.S. women. PMID- 22536378 TI - Diversity in expression of phosphorus (P) responsive genes in Cucumis melo L. AB - BACKGROUND: Phosphorus (P) is a major limiting nutrient for plant growth in many soils. Studies in model species have identified genes involved in plant adaptations to low soil P availability. However, little information is available on the genetic bases of these adaptations in vegetable crops. In this respect, sequence data for melon now makes it possible to identify melon orthologues of candidate P responsive genes, and the expression of these genes can be used to explain the diversity in the root system adaptation to low P availability, recently observed in this species. METHODOLOGY AND FINDINGS: Transcriptional responses to P starvation were studied in nine diverse melon accessions by comparing the expression of eight candidate genes (Cm-PAP10.1, Cm-PAP10.2, Cm RNS1, Cm-PPCK1, Cm-transferase, Cm-SQD1, Cm-DGD1 and Cm-SPX2) under P replete and P starved conditions. Differences among melon accessions were observed in response to P starvation, including differences in plant morphology, P uptake, P use efficiency (PUE) and gene expression. All studied genes were up regulated under P starvation conditions. Differences in the expression of genes involved in P mobilization and remobilization (Cm-PAP10.1, Cm-PAP10.2 and Cm-RNS1) under P starvation conditions explained part of the differences in P uptake and PUE among melon accessions. The levels of expression of the other studied genes were diverse among melon accessions, but contributed less to the phenotypical response of the accessions. CONCLUSIONS: This is the first time that these genes have been described in the context of P starvation responses in melon. There exists significant diversity in gene expression levels and P use efficiency among melon accessions as well as significant correlations between gene expression levels and phenotypical measurements. PMID- 22536379 TI - Phocid seal leptin: tertiary structure and hydrophobic receptor binding site preservation during distinct leptin gene evolution. AB - The cytokine hormone leptin is a key signalling molecule in many pathways that control physiological functions. Although leptin demonstrates structural conservation in mammals, there is evidence of positive selection in primates, lagomorphs and chiropterans. We previously reported that the leptin genes of the grey and harbour seals (phocids) have significantly diverged from other mammals. Therefore we further investigated the diversification of leptin in phocids, other marine mammals and terrestrial taxa by sequencing the leptin genes of representative species. Phylogenetic reconstruction revealed that leptin diversification was pronounced within the phocid seals with a high dN/dS ratio of 2.8, indicating positive selection. We found significant evidence of positive selection along the branch leading to the phocids, within the phocid clade, but not over the dataset as a whole. Structural predictions indicate that the individual residues under selection are away from the leptin receptor (LEPR) binding site. Predictions of the surface electrostatic potential indicate that phocid seal leptin is notably different to other mammalian leptins, including the otariids. Cloning the grey seal leptin binding domain of LEPR confirmed that this was structurally conserved. These data, viewed in toto, support a hypothesis that phocid leptin divergence is unlikely to have arisen by random mutation. Based upon these phylogenetic and structural assessments, and considering the comparative physiology and varying life histories among species, we postulate that the unique phocid diving behaviour has produced this selection pressure. The Phocidae includes some of the deepest diving species, yet have the least modified lung structure to cope with pressure and volume changes experienced at depth. Therefore, greater surfactant production is required to facilitate rapid lung re inflation upon surfacing, while maintaining patent airways. We suggest that this additional surfactant requirement is met by the leptin pulmonary surfactant production pathway which normally appears only to function in the mammalian foetus. PMID- 22536380 TI - Processing of hand-related verbs specifically affects the planning and execution of arm reaching movements. AB - Even though a growing body of research has shown that the processing of action language affects the planning and execution of motor acts, several aspects of this interaction are still hotly debated. The directionality (i.e. does understanding action-related language induce a facilitation or an interference with the corresponding action?), the time course, and the nature of the interaction (i.e. under what conditions does the phenomenon occur?) are largely unclear. To further explore this topic we exploited a go/no-go paradigm in which healthy participants were required to perform arm reaching movements toward a target when verbs expressing either hand or foot actions were shown, and to refrain from moving when abstract verbs were presented. We found that reaction times (RT) and percentages of errors increased when the verb involved the same effector used to give the response. This interference occurred very early, when the interval between verb presentation and the delivery of the go signal was 50 ms, and could be elicited until this delay was about 600 ms. In addition, RTs were faster when subjects used the right arm than when they used the left arm, suggesting that action-verb understanding is left-lateralized. Furthermore, when the color of the printed verb and not its meaning was the cue for movement execution the differences between RTs and error percentages between verb categories disappeared, unequivocally indicating that the phenomenon occurs only when the semantic content of a verb has to be retrieved. These results are compatible with the theory of embodied language, which hypothesizes that comprehending verbal descriptions of actions relies on an internal simulation of the sensory-motor experience of the action, and provide a new and detailed view of the interplay between action language and motor acts. PMID- 22536381 TI - Tumor necrosis factor-alpha g308alpha gene polymorphism and essential hypertension: a meta-analysis involving 2244 participants. AB - BACKGROUND: The tumor necrosis factor-alpha (TNFalpha) G308A gene polymorphism has been implicated in susceptibility to essential hypertension (EH), but study results are still controversial. OBJECTIVE AND METHODS: The present meta-analysis is performed to investigate the relationship between the TNFalpha G308A gene polymorphism and EH. Electronic databases were searched and seven separate studies on the association of the TNF alpha G308A gene polymorphism with EH were analyzed. The meta-analysis involved 1092 EH patients and 1152 controls. The pooled odds ratios (ORs) and their corresponding 95% confidence interval (CI) were calculated by a fixed or random effect model. RESULTS: A significant relationship between the TNFalpha G308A gene polymorphism and EH was found in an allelic genetic model (OR: 1.45, 95% CI: 1.17 to 1.80, P = 0.0008), a recessive genetic model (OR: 3.181, 95% CI: 1.204 to 8.408, P = 0.02), and a homozygote model (OR: 3.454, 95% CI: 1.286 to 9.278, P = 0.014). No significant association between them was detected in both a dominant genetic model (OR: 1.55, 95% CI: 0.99 to 2.42, P = 0.06) or a heterozygote genetic model (OR: 1.45, 95% CI: 0.90 to 2.33, P = 0.13). CONCLUSION: The TNFalpha G308A gene polymorphism is associated with EH susceptibility. PMID- 22536382 TI - Immunization with SARS coronavirus vaccines leads to pulmonary immunopathology on challenge with the SARS virus. AB - BACKGROUND: Severe acute respiratory syndrome (SARS) emerged in China in 2002 and spread to other countries before brought under control. Because of a concern for reemergence or a deliberate release of the SARS coronavirus, vaccine development was initiated. Evaluations of an inactivated whole virus vaccine in ferrets and nonhuman primates and a virus-like-particle vaccine in mice induced protection against infection but challenged animals exhibited an immunopathologic-type lung disease. DESIGN: Four candidate vaccines for humans with or without alum adjuvant were evaluated in a mouse model of SARS, a VLP vaccine, the vaccine given to ferrets and NHP, another whole virus vaccine and an rDNA-produced S protein. Balb/c or C57BL/6 mice were vaccinated i.m. on day 0 and 28 and sacrificed for serum antibody measurements or challenged with live virus on day 56. On day 58, challenged mice were sacrificed and lungs obtained for virus and histopathology. RESULTS: All vaccines induced serum neutralizing antibody with increasing dosages and/or alum significantly increasing responses. Significant reductions of SARS CoV two days after challenge was seen for all vaccines and prior live SARS-CoV. All mice exhibited histopathologic changes in lungs two days after challenge including all animals vaccinated (Balb/C and C57BL/6) or given live virus, influenza vaccine, or PBS suggesting infection occurred in all. Histopathology seen in animals given one of the SARS-CoV vaccines was uniformly a Th2-type immunopathology with prominent eosinophil infiltration, confirmed with special eosinophil stains. The pathologic changes seen in all control groups lacked the eosinophil prominence. CONCLUSIONS: These SARS-CoV vaccines all induced antibody and protection against infection with SARS-CoV. However, challenge of mice given any of the vaccines led to occurrence of Th2-type immunopathology suggesting hypersensitivity to SARS-CoV components was induced. Caution in proceeding to application of a SARS-CoV vaccine in humans is indicated. PMID- 22536384 TI - Role of fractalkine/CX3CR1 interaction in light-induced photoreceptor degeneration through regulating retinal microglial activation and migration. AB - BACKGROUND: Excessive exposure to light enhances the progression and severity of some human retinal degenerative diseases. While retinal microglia are likely to be important in neuron damage associated with these diseases, the relationship between photoreceptor damage and microglial activation remains poorly understood. Some recent studies have indicated that the chemokine fractalkine is involved in the pathogenesis of many neurodegenerative diseases. The present study was performed to investigate the cross-talk between injured photoreceptors and activated retinal microglia, focusing on the role of fractalkine and its receptor CX3CR1 in light-induced photoreceptor degeneration. METHODOLOGY/PRINCIPAL FINDINGS: Both in vivo and in vitro experiments were involved in the research. In vivo, Sprague-Dawley rats were exposed to blue light for 24 hours. In vitro, the co-culture of primary retinal microglia and a photoreceptor cell line (661W cell) was exposed to blue light for five hours. Some cultures were pretreated by the addition of anti-CX3CR1 neutralizing antibody or recombinant fractalkine. Expression of fractalkine/CX3CR1 and inflammatory cytokines was detected by immunofluorescence, real-time PCR, Western immunoblot analysis, and ELISA assay. TUNEL method was used to detect cell apoptosis. In addition, chemotaxis assay was performed to evaluate the impact of soluble fractalkine on microglial migration. Our results showed that the expression of fractalkine that was significantly upregulated after exposure to light, located mainly at the photoreceptors. The extent of photoreceptor degeneration and microglial migration paralleled the increased level of fractalkine/CX3CR1. Compared with the control, the expression of inflammatory cytokines was significantly downregulated in the anti-CX3CR1 neutralizing antibody-treated group, and the number of photoreceptors was also well preserved. The addition of recombinant full-length fractalkine or soluble fractalkine resulted in fewer TUNEL-positive photoreceptors and an increased number of migratory microglia respectively. CONCLUSIONS/SIGNIFICANCE: These findings demonstrate that fractalkine/CX3CR1 interaction may play an important role in the photoreceptor-microglia cross-talk in light-induced photoreceptor degeneration. PMID- 22536383 TI - Mutagenesis and functional studies with succinate dehydrogenase inhibitors in the wheat pathogen Mycosphaerella graminicola. AB - A range of novel carboxamide fungicides, inhibitors of the succinate dehydrogenase enzyme (SDH, EC 1.3.5.1) is currently being introduced to the crop protection market. The aim of this study was to explore the impact of structurally distinct carboxamides on target site resistance development and to assess possible impact on fitness. We used a UV mutagenesis approach in Mycosphaerella graminicola, a key pathogen of wheat to compare the nature, frequencies and impact of target mutations towards five subclasses of carboxamides. From this screen we identified 27 amino acid substitutions occurring at 18 different positions on the 3 subunits constituting the ubiquinone binding (Qp) site of the enzyme. The nature of substitutions and cross resistance profiles indicated significant differences in the binding interaction to the enzyme across the different inhibitors. Pharmacophore elucidation followed by docking studies in a tridimensional SDH model allowed us to propose rational hypotheses explaining some of the differential behaviors for the first time. Interestingly all the characterized substitutions had a negative impact on enzyme efficiency, however very low levels of enzyme activity appeared to be sufficient for cell survival. In order to explore the impact of mutations on pathogen fitness in vivo and in planta, homologous recombinants were generated for a selection of mutation types. In vivo, in contrast to previous studies performed in yeast and other organisms, SDH mutations did not result in a major increase of reactive oxygen species levels and did not display any significant fitness penalty. However, a number of Qp site mutations affecting enzyme efficiency were shown to have a biological impact in planta.Using the combined approaches described here, we have significantly improved our understanding of possible resistance mechanisms to carboxamides and performed preliminary fitness penalty assessment in an economically important plant pathogen years ahead of possible resistance development in the field. PMID- 22536385 TI - Relationship between reproductive allocation and relative abundance among 32 species of a Tibetan alpine meadow: effects of fertilization and grazing. AB - BACKGROUND: Understanding the relationship between species traits and species abundance is an important goal in ecology and biodiversity science. Although theoretical studies predict that traits related to performance (e.g. reproductive allocation) are most directly linked to species abundance within a community, empirical investigations have rarely been done. It also remains unclear how environmental factors such as grazing or fertilizer application affect the predicted relationship. METHODOLOGY: We conducted a 3-year field experiment in a Tibetan alpine meadow to assess the relationship between plant reproductive allocation (RA) and species relative abundance (SRA) on control, grazed and fertilized plots. Overall, the studied plant community contained 32 common species. PRINCIPAL FINDINGS: At the treatment level, (i) RA was negatively correlated with SRA on control plots and during the first year on fertilized plots. (ii) No negative RA-SRA correlations were observed on grazed plots and during the second and third year on fertilized plots. (iii) Seed size was positively correlated with SRA on control plots. At the plot level, the correlation between SRA and RA were not affected by treatment, year or species composition. CONCLUSIONS/SIGNIFICANCE: Our study shows that the performance related trait RA can negatively affect SRA within communities, which is possibly due to the tradeoffs between clonal growth (for space occupancy) and sexual reproduction. We propose that if different species occupy different positions along these tradeoffs it will contribute to biodiversity maintenance in local communities or even at lager scale. PMID- 22536386 TI - Enhancing the antibiotic antibacterial effect by sub lethal tellurite concentrations: tellurite and cefotaxime act synergistically in Escherichia coli. AB - The emergence of antibiotic-resistant pathogenic bacteria during the last decades has become a public health concern worldwide. Aiming to explore new alternatives to treat antibiotic-resistant bacteria and given that the tellurium oxyanion tellurite is highly toxic for most microorganisms, we evaluated the ability of sub lethal tellurite concentrations to strengthen the effect of several antibiotics. Tellurite, at nM or uM concentrations, increased importantly the toxicity of defined antibacterials. This was observed with both gram negative and gram positive bacteria, irrespective of the antibiotic or tellurite tolerance of the particular microorganism. The tellurite-mediated antibiotic-potentiating effect occurs in laboratory and clinical, uropathogenic Escherichia coli, especially with antibiotics disturbing the cell wall (ampicillin, cefotaxime) or protein synthesis (tetracycline, chloramphenicol, gentamicin). In particular, the effect of tellurite on the activity of the clinically-relevant, third-generation cephalosporin (cefotaxime), was evaluated. Cell viability assays showed that tellurite and cefotaxime act synergistically against E. coli. In conclusion, using tellurite like an adjuvant could be of great help to cope with several multi-resistant pathogens. PMID- 22536387 TI - Antibody recognition of cancer-related gangliosides and their mimics investigated using in silico site mapping. AB - Modified gangliosides may be overexpressed in certain types of cancer, thus, they are considered a valuable target in cancer immunotherapy. Structural knowledge of their interaction with antibodies is currently limited, due to the large size and high flexibility of these ligands. In this study, we apply our previously developed site mapping technique to investigate the recognition of cancer-related gangliosides by anti-ganglioside antibodies. The results reveal a potential ganglioside-binding motif in the four antibodies studied, suggesting the possibility of structural convergence in the anti-ganglioside immune response. The structural basis of the recognition of ganglioside-mimetic peptides is also investigated using site mapping and compared to ganglioside recognition. The peptides are shown to act as structural mimics of gangliosides by interacting with many of the same binding site residues as the cognate carbohydrate epitopes. These studies provide important clues as to the structural basis of immunological mimicry of carbohydrates. PMID- 22536388 TI - Controlled in meso phase crystallization--a method for the structural investigation of membrane proteins. AB - We investigated in meso crystallization of membrane proteins to develop a fast screening technology which combines features of the well established classical vapor diffusion experiment with the batch meso phase crystallization, but without premixing of protein and monoolein. It inherits the advantages of both methods, namely (i) the stabilization of membrane proteins in the meso phase, (ii) the control of hydration level and additive concentration by vapor diffusion. The new technology (iii) significantly simplifies in meso crystallization experiments and allows the use of standard liquid handling robots suitable for 96 well formats. CIMP crystallization furthermore allows (iv) direct monitoring of phase transformation and crystallization events. Bacteriorhodopsin (BR) crystals of high quality and diffraction up to 1.3 A resolution have been obtained in this approach. CIMP and the developed consumables and protocols have been successfully applied to obtain crystals of sensory rhodopsin II (SRII) from Halobacterium salinarum for the first time. PMID- 22536389 TI - Habitat selection and temporal abundance fluctuations of demersal cartilaginous species in the Aegean Sea (eastern Mediterranean). AB - Predicting the occurrence of keystone top predators in a multispecies marine environment, such as the Mediterranean Sea, can be of considerable value to the long-term sustainable development of the fishing industry and to the protection of biodiversity. We analysed fisheries independent scientific bottom trawl survey data of two of the most abundant cartilaginous fish species (Scyliorhinus canicula, Raja clavata) in the Aegean Sea covering an 11-year sampling period. The current findings revealed a declining trend in R. clavata and S. canicula abundance from the late '90 s until 2004. Habitats with the higher probability of finding cartilaginous fish present were those located in intermediate waters (depth: 200-400 m). The present results also indicated a preferential species' clustering in specific geographic and bathymetric regions of the Aegean Sea. Depth appeared to be one of the key determining factors for the selection of habitats for all species examined. With cartilaginous fish species being among the more biologically sensitive fish species taken in European marine fisheries, our findings, which are based on a standardized scientific survey, can contribute to the rational exploitation and management of their stocks by providing important information on temporal abundance trends and habitat preferences. PMID- 22536390 TI - Microcolony imaging of Aspergillus fumigatus treated with echinocandins reveals both fungistatic and fungicidal activities. AB - BACKGROUND: The echinocandins are lipopeptides that can be employed as antifungal drugs that inhibit the synthesis of 1,3-beta-glucans within the fungal cell wall. Anidulafungin and caspofungin are echinocandins used in the treatment of Candida infections and have activity against other fungi including Aspergillus fumigatus. The echinocandins are generally considered fungistatic against Aspergillus species. METHODS: Culture of A. fumigatus from conidia to microcolonies on a support of porous aluminium oxide (PAO), combined with fluorescence microscopy and scanning electron microscopy, was used to investigate the effects of anidulafungin and caspofungin. The PAO was an effective matrix for conidial germination and microcolony growth. Additionally, PAO supports could be moved between agar plates containing different concentrations of echinocandins to change dosage and to investigate the recovery of fungal microcolonies from these drugs. Culture on PAO combined with microscopy and image analysis permits quantitative studies on microcolony growth with the flexibility of adding or removing antifungal agents, dyes, fixatives or osmotic stresses during growth with minimal disturbance of fungal microcolonies. SIGNIFICANCE: Anidulafungin and caspofungin reduced but did not halt growth at the microcony level; additionally both drugs killed individual cells, particularly at concentrations around the MIC. Intact but not lysed cells showed rapid recovery when the drugs were removed. The classification of these drugs as either fungistatic or fungicidal is simplistic. Microcolony analysis on PAO appears to be a valuable tool to investigate the action of antifungal agents. PMID- 22536391 TI - Systems analysis of MVA-C induced immune response reveals its significance as a vaccine candidate against HIV/AIDS of clade C. AB - Based on the partial efficacy of the HIV/AIDS Thai trial (RV144) with a canarypox vector prime and protein boost, attenuated poxvirus recombinants expressing HIV-1 antigens are increasingly sought as vaccine candidates against HIV/AIDS. Here we describe using systems analysis the biological and immunological characteristics of the attenuated vaccinia virus Ankara strain expressing the HIV-1 antigens Env/Gag-Pol-Nef of HIV-1 of clade C (referred as MVA-C). MVA-C infection of human monocyte derived dendritic cells (moDCs) induced the expression of HIV-1 antigens at high levels from 2 to 8 hpi and triggered moDCs maturation as revealed by enhanced expression of HLA-DR, CD86, CD40, HLA-A2, and CD80 molecules. Infection ex vivo of purified mDC and pDC with MVA-C induced the expression of immunoregulatory pathways associated with antiviral responses, antigen presentation, T cell and B cell responses. Similarly, human whole blood or primary macrophages infected with MVA-C express high levels of proinflammatory cytokines and chemokines involved with T cell activation. The vector MVA-C has the ability to cross-present antigens to HIV-specific CD8 T cells in vitro and to increase CD8 T cell proliferation in a dose-dependent manner. The immunogenic profiling in mice after DNA-C prime/MVA-C boost combination revealed activation of HIV-1-specific CD4 and CD8 T cell memory responses that are polyfunctional and with effector memory phenotype. Env-specific IgG binding antibodies were also produced in animals receiving DNA-C prime/MVA-C boost. Our systems analysis of profiling immune response to MVA-C infection highlights the potential benefit of MVA-C as vaccine candidate against HIV/AIDS for clade C, the prevalent subtype virus in the most affected areas of the world. PMID- 22536392 TI - De novo peroxisome biogenesis in Penicillium chrysogenum is not dependent on the Pex11 family members or Pex16. AB - We have analyzed the role of the three members of the Pex11 protein family in peroxisome formation in the filamentous fungus Penicillium chrysogenum. Two of these, Pex11 and Pex11C, are components of the peroxisomal membrane, while Pex11B is present at the endoplasmic reticulum. We show that Pex11 is a major factor involved in peroxisome proliferation. We also demonstrate that P. chrysogenum cells deleted for known peroxisome fission factors (all Pex11 family proteins and Vps1) still contain peroxisomes. Interestingly, we find that, unlike in mammals, Pex16 is not essential for peroxisome biogenesis in P. chrysogenum, as partially functional peroxisomes are present in a pex16 deletion strain. We also show that Pex16 is not involved in de novo biogenesis of peroxisomes, as peroxisomes were still present in quadruple Deltapex11 Deltapex11B Deltapex11C Deltapex16 mutant cells. By contrast, pex3 deletion in P. chrysogenum led to cells devoid of peroxisomes, suggesting that Pex3 may function independently of Pex16. Finally, we demonstrate that the presence of intact peroxisomes is important for the efficiency of beta-lactam antibiotics production by P. chrysogenum. Remarkably, distinct from earlier results with low penicillin producing laboratory strains, upregulation of peroxisome numbers in a high producing P. chrysogenum strain had no significant effect on penicillin production. PMID- 22536393 TI - Disruption of the autophagy-lysosome pathway is involved in neuropathology of the nclf mouse model of neuronal ceroid lipofuscinosis. AB - Variant late-infantile neuronal ceroid lipofuscinosis, a fatal lysosomal storage disorder accompanied by regional atrophy and pronounced neuron loss in the brain, is caused by mutations in the CLN6 gene. CLN6 is a non-glycosylated endoplasmic reticulum (ER)-resident membrane protein of unknown function. To investigate mechanisms contributing to neurodegeneration in CLN6 disease we examined the nclf mouse, a naturally occurring model of the human CLN6 disease. Prominent autofluorescent and electron-dense lysosomal storage material was found in cerebellar Purkinje cells, thalamus, hippocampus, olfactory bulb and in cortical layer II to V. Another prominent early feature of nclf pathogenesis was the localized astrocytosis that was evident in many brain regions and the more widespread microgliosis. Expression analysis of mutant Cln6 found in nclf mice demonstrated synthesis of a truncated protein with a reduced half-life. Whereas the rapid degradation of the mutant Cln6 protein can be inhibited by proteasomal inhibitors, there was no evidence for ER stress or activation of the unfolded protein response in various brain areas during postnatal development. Age dependent increases in LC3-II, ubiquitinated proteins, and neuronal p62-positive aggregates were observed, indicating a disruption of the autophagy-lysosome degradation pathway of proteins in brains of nclf mice, most likely due to defective fusion between autophagosomes and lysosomes. These data suggest that proteasomal degradation of mutant Cln6 is sufficient to prevent the accumulation of misfolded Cln6 protein, whereas lysosomal dysfunction impairs constitutive autophagy promoting neurodegeneration. PMID- 22536394 TI - Ethylene supports colonization of plant roots by the mutualistic fungus Piriformospora indica. AB - The mutualistic basidiomycete Piriformospora indica colonizes roots of mono- and dicotyledonous plants, and thereby improves plant health and yield. Given the capability of P. indica to colonize a broad range of hosts, it must be anticipated that the fungus has evolved efficient strategies to overcome plant immunity and to establish a proper environment for nutrient acquisition and reproduction. Global gene expression studies in barley identified various ethylene synthesis and signaling components that were differentially regulated in P. indica-colonized roots. Based on these findings we examined the impact of ethylene in the symbiotic association. The data presented here suggest that P. indica induces ethylene synthesis in barley and Arabidopsis roots during colonization. Moreover, impaired ethylene signaling resulted in reduced root colonization, Arabidopsis mutants exhibiting constitutive ethylene signaling, synthesis or ethylene-related defense were hyper-susceptible to P. indica. Our data suggest that ethylene signaling is required for symbiotic root colonization by P. indica. PMID- 22536395 TI - Protective immunity to Listeria monocytogenes infection mediated by recombinant Listeria innocua harboring the VGC locus. AB - In this study we propose a novel bacterial vaccine strategy where non-pathogenic bacteria are complemented with traits desirable for the induction of protective immunity. To illustrate the proof of principle of this novel vaccination strategy, we use the model organism of intracellular immunity Listeria. We introduced a, low copy number BAC-plasmid harbouring the virulence gene cluster (vgc) of L. monocytogenes (Lm) into the non-pathogenic L. innocua (L.inn) strain and examined for its ability to induce protective cellular immunity. The resulting strain (L.inn::vgc) was attenuated for virulence in vivo and showed a strongly reduced host detrimental inflammatory response compared to Lm. Like Lm, L.inn::vgc induced the production of Type I Interferon's and protection was mediated by Listeria-specific CD8(+) T cells. Rational vaccine design whereby avirulent strains are equipped with the capabilities to induce protection but lack detrimental inflammatory effects offer great promise towards future studies using non-pathogenic bacteria as vectors for vaccination. PMID- 22536396 TI - Magnetic resonance thermometry at 7T for real-time monitoring and correction of ultrasound induced mild hyperthermia. AB - While Magnetic Resonance Thermometry (MRT) has been extensively utilized for non invasive temperature measurement, there is limited data on the use of high field (>=7T) scanners for this purpose. MR-guided Focused Ultrasound (MRgFUS) is a promising non-invasive method for localized hyperthermia and drug delivery. MRT based on the temperature sensitivity of the proton resonance frequency (PRF) has been implemented in both a tissue phantom and in vivo in a mouse Met-1 tumor model, using partial parallel imaging (PPI) to speed acquisition. An MRgFUS system capable of delivering a controlled 3D acoustic dose during real time MRT with proportional, integral, and derivative (PID) feedback control was developed and validated. Real-time MRT was validated in a tofu phantom with fluoroptic temperature measurements, and acoustic heating simulations were in good agreement with MR temperature maps. In an in vivo Met-1 mouse tumor, the real-time PID feedback control is capable of maintaining the desired temperature with high accuracy. We found that real time MR control of hyperthermia is feasible at high field, and k-space based PPI techniques may be implemented for increasing temporal resolution while maintaining temperature accuracy on the order of 1 degrees C. PMID- 22536397 TI - Enhanced hippocampal long-term potentiation and fear memory in Btbd9 mutant mice. AB - Polymorphisms in BTBD9 have recently been associated with higher risk of restless legs syndrome (RLS), a neurological disorder characterized by uncomfortable sensations in the legs at rest that are relieved by movement. The BTBD9 protein contains a BTB/POZ domain and a BACK domain, but its function is unknown. To elucidate its function and potential role in the pathophysiology of RLS, we generated a line of mutant Btbd9 mice derived from a commercial gene-trap embryonic stem cell clone. Btbd9 is the mouse homolog of the human BTBD9. Proteins that contain a BTB/POZ domain have been reported to be associated with synaptic transmission and plasticity. We found that Btbd9 is naturally expressed in the hippocampus of our mutant mice, a region critical for learning and memory. As electrophysiological characteristics of CA3-CA1 synapses of the hippocampus are well characterized, we performed electrophysiological recordings in this region. The mutant mice showed normal input-output relationship, a significant impairment in pre-synaptic activity, and an enhanced long-term potentiation. We further performed an analysis of fear memory and found the mutant mice had an enhanced cued and contextual fear memory. To elucidate a possible molecular basis for these enhancements, we analyzed proteins that have been associated with synaptic plasticity. We found an elevated level of dynamin 1, an enzyme associated with endocytosis, in the mutant mice. These results suggest the first identified function of Btbd9 as being involved in regulating synaptic plasticity and memory. Recent studies have suggested that enhanced synaptic plasticity, analogous to what we have observed, in other regions of the brain could enhance sensory perception similar to what is seen in RLS patients. Further analyses of the mutant mice will help shine light on the function of BTBD9 and its role in RLS. PMID- 22536398 TI - Automatic design of synthetic gene circuits through mixed integer non-linear programming. AB - Automatic design of synthetic gene circuits poses a significant challenge to synthetic biology, primarily due to the complexity of biological systems, and the lack of rigorous optimization methods that can cope with the combinatorial explosion as the number of biological parts increases. Current optimization methods for synthetic gene design rely on heuristic algorithms that are usually not deterministic, deliver sub-optimal solutions, and provide no guaranties on convergence or error bounds. Here, we introduce an optimization framework for the problem of part selection in synthetic gene circuits that is based on mixed integer non-linear programming (MINLP), which is a deterministic method that finds the globally optimal solution and guarantees convergence in finite time. Given a synthetic gene circuit, a library of characterized parts, and user defined constraints, our method can find the optimal selection of parts that satisfy the constraints and best approximates the objective function given by the user. We evaluated the proposed method in the design of three synthetic circuits (a toggle switch, a transcriptional cascade, and a band detector), with both experimentally constructed and synthetic promoter libraries. Scalability and robustness analysis shows that the proposed framework scales well with the library size and the solution space. The work described here is a step towards a unifying, realistic framework for the automated design of biological circuits. PMID- 22536399 TI - Cross-dimensional mapping of number, length and brightness by preschool children. AB - Human adults in diverse cultures, children, infants, and non-human primates relate number to space, but it is not clear whether this ability reflects a specific and privileged number-space mapping. To investigate this possibility, we tested preschool children in matching tasks where the dimensions of number and length were mapped both to one another and to a third dimension, brightness. Children detected variation on all three dimensions, and they reliably performed mappings between number and length, and partially between brightness and length, but not between number and brightness. Moreover, children showed reliably better mapping of number onto the dimension of length than onto the dimension of brightness. These findings suggest that number establishes a privileged mapping with the dimension of length, and that other dimensions, including brightness, can be mapped onto length, although less efficiently. Children's adeptness at number-length mappings suggests that these two dimensions are intuitively related by the end of the preschool years. PMID- 22536400 TI - Asymmetric bidirectional transcription from the FSHD-causing D4Z4 array modulates DUX4 production. AB - Facioscapulohumeral Disease (FSHD) is a dominantly inherited progressive myopathy associated with aberrant production of the transcription factor, Double Homeobox Protein 4 (DUX4). The expression of DUX4 depends on an open chromatin conformation of the D4Z4 macrosatellite array and a specific haplotype on chromosome 4. Even when these requirements are met, DUX4 transcripts and protein are only detectable in a subset of cells indicating that additional constraints govern DUX4 production. Since the direction of transcription, along with the production of non-coding antisense transcripts is an important regulatory feature of other macrosatellite repeats, we developed constructs that contain the non coding region of a single D4Z4 unit flanked by genes that report transcriptional activity in the sense and antisense directions. We found that D4Z4 contains two promoters that initiate sense and antisense transcription within the array, and that antisense transcription predominates. Transcriptional start sites for the antisense transcripts, as well as D4Z4 regions that regulate the balance of sense and antisense transcripts were identified. We show that the choice of transcriptional direction is reversible but not mutually exclusive, since sense and antisense reporter activity was often present in the same cell and simultaneously upregulated during myotube formation. Similarly, levels of endogenous sense and antisense D4Z4 transcripts were upregulated in FSHD myotubes. These studies offer insight into the autonomous distribution of muscle weakness that is characteristic of FSHD. PMID- 22536401 TI - IL-6 and mouse oocyte spindle. AB - Interleukin 6 (IL-6) is considered a major indicator of the acute-phase inflammatory response. Endometriosis and pelvic inflammation, diseases that manifest elevated levels of IL-6, are commonly associated with higher infertility. However, the mechanistic link between elevated levels of IL-6 and poor oocyte quality is still unclear. In this work, we explored the direct role of this cytokine as a possible mediator for impaired oocyte spindle and chromosomal structure, which is a critical hurdle in the management of infertility. Metaphase-II mouse oocytes were exposed to recombinant mouse IL-6 (50, 100 and 200 ng/mL) for 30 minutes and subjected to indirect immunofluorescent staining to identify alterations in the microtubule and chromosomal alignment compared to untreated controls. The deterioration in microtubule and chromosomal alignment were evaluated utilizing both fluorescence and confocal microscopy, and were quantitated with a previously reported scoring system. Our results showed that IL-6 caused a dose-dependent deterioration in microtubule and chromosomal alignment in the treated oocytes as compared to the untreated group. Indeed, IL-6 at a concentration as low as 50 ng/mL caused deterioration in the spindle structure in 60% of the oocytes, which increased significantly (P<0.0001) as IL-6 concentration was increased. In conclusion, elevated levels of IL-6 associated with endometriosis and pelvic inflammation may reduce the fertilizing capacity of human oocyte through a mechanism that involves impairment of the microtubule and chromosomal structure. PMID- 22536402 TI - Cell cycle-dependent mobility of Cdc45 determined in vivo by fluorescence correlation spectroscopy. AB - Eukaryotic DNA replication is a dynamic process requiring the co-operation of specific replication proteins. We measured the mobility of eGFP-Cdc45 by Fluorescence Correlation Spectroscopy (FCS) in vivo in asynchronous cells and in cells synchronized at the G1/S transition and during S phase. Our data show that eGFP-Cdc45 mobility is faster in G1/S transition compared to S phase suggesting that Cdc45 is part of larger protein complex formed in S phase. Furthermore, the size of complexes containing Cdc45 was estimated in asynchronous, G1/S and S phase-synchronized cells using gel filtration chromatography; these findings complemented the in vivo FCS data. Analysis of the mobility of eGFP-Cdc45 and the size of complexes containing Cdc45 and eGFP-Cdc45 after UVC-mediated DNA damage revealed no significant changes in diffusion rates and complex sizes using FCS and gel filtration chromatography analyses. This suggests that after UV-damage, Cdc45 is still present in a large multi-protein complex and that its mobility within living cells is consistently similar following UVC-mediated DNA damage. PMID- 22536403 TI - Deficient signaling via Alk2 (Acvr1) leads to bicuspid aortic valve development. AB - Bicuspid aortic valve (BAV) is the most common congenital cardiac anomaly in humans. Despite recent advances, the molecular basis of BAV development is poorly understood. Previously it has been shown that mutations in the Notch1 gene lead to BAV and valve calcification both in human and mice, and mice deficient in Gata5 or its downstream target Nos3 have been shown to display BAVs. Here we show that tissue-specific deletion of the gene encoding Activin Receptor Type I (Alk2 or Acvr1) in the cushion mesenchyme results in formation of aortic valve defects including BAV. These defects are largely due to a failure of normal development of the embryonic aortic valve leaflet precursor cushions in the outflow tract resulting in either a fused right- and non-coronary leaflet, or the presence of only a very small, rudimentary non-coronary leaflet. The surviving adult mutant mice display aortic stenosis with high frequency and occasional aortic valve insufficiency. The thickened aortic valve leaflets in such animals do not show changes in Bmp signaling activity, while Map kinase pathways are activated. Although dysfunction correlated with some pro-osteogenic differences in gene expression, neither calcification nor inflammation were detected in aortic valves of Alk2 mutants with stenosis. We conclude that signaling via Alk2 is required for appropriate aortic valve development in utero, and that defects in this process lead to indirect secondary complications later in life. PMID- 22536404 TI - Turning the 'mustard oil bomb' into a 'cyanide bomb': aromatic glucosinolate metabolism in a specialist insect herbivore. AB - Plants have evolved a variety of mechanisms for dealing with insect herbivory among which chemical defense through secondary metabolites plays a prominent role. Physiological, behavioural and sensorical adaptations to these chemicals provide herbivores with selective advantages allowing them to diversify within the newly occupied ecological niche. In turn, this may influence the evolution of plant metabolism giving rise to e.g. new chemical defenses. The association of Pierid butterflies and plants of the Brassicales has been cited as an illustrative example of this adaptive process known as 'coevolutionary armsrace'. All plants of the Brassicales are defended by the glucosinolate-myrosinase system to which larvae of cabbage white butterflies and related species are biochemically adapted through a gut nitrile-specifier protein. Here, we provide evidence by metabolite profiling and enzyme assays that metabolism of benzylglucosinolate in Pieris rapae results in release of equimolar amounts of cyanide, a potent inhibitor of cellular respiration. We further demonstrate that P. rapae larvae develop on transgenic Arabidopsis plants with ectopic production of the cyanogenic glucoside dhurrin without ill effects. Metabolite analyses and fumigation experiments indicate that cyanide is detoxified by beta-cyanoalanine synthase and rhodanese in the larvae. Based on these results as well as on the facts that benzylglucosinolate was one of the predominant glucosinolates in ancient Brassicales and that ancient Brassicales lack nitrilases involved in alternative pathways, we propose that the ability of Pierid species to safely handle cyanide contributed to the primary host shift from Fabales to Brassicales that occured about 75 million years ago and was followed by Pierid species diversification. PMID- 22536405 TI - A unique combination of male germ cell miRNAs coordinates gonocyte differentiation. AB - The last 100 years have seen a concerning decline in male reproductive health associated with decreased sperm production, sperm function and male fertility. Concomitantly, the incidence of defects in reproductive development, such as undescended testes, hypospadias and testicular cancer has increased. Indeed testicular cancer is now recognised as the most common malignancy in young men. Such cancers develop from the pre-invasive lesion Carcinoma in Situ (CIS), a dysfunctional precursor germ cell or gonocyte which has failed to successfully differentiate into a spermatogonium. It is therefore essential to understand the cellular transition from gonocytes to spermatogonia, in order to gain a better understanding of the aetiology of testicular germ cell tumours. MicroRNA (miRNA) are important regulators of gene expression in differentiation and development and thus highly likely to play a role in the differentiation of gonocytes. In this study we have examined the miRNA profiles of highly enriched populations of gonocytes and spermatogonia, using microarray technology. We identified seven differentially expressed miRNAs between gonocytes and spermatogonia (down regulated: miR-293, 291a-5p, 290-5p and 294*, up-regulated: miR-136, 743a and 463*). Target prediction software identified many potential targets of several differentially expressed miRNA implicated in germ cell development, including members of the PTEN, and Wnt signalling pathways. These targets converge on the key downstream cell cycle regulator Cyclin D1, indicating that a unique combination of male germ cell miRNAs coordinate the differentiation and maintenance of pluripotency in germ cells. PMID- 22536406 TI - Effect of sub-lethal exposure to ultraviolet radiation on the escape performance of Atlantic cod larvae (Gadus morhua). AB - The amount of ultraviolet (UV) radiation reaching the earth's surface has increased due to depletion of the ozone layer. Several studies have reported that UV radiation reduces survival of fish larvae. However, indirect and sub-lethal impacts of UV radiation on fish behavior have been given little consideration. We observed the escape performance of larval cod (24 dph, SL: 7.6+/-0.2 mm; 29 dph, SL: 8.2+/-0.3 mm) that had been exposed to sub-lethal levels of UV radiation vs. unexposed controls. Two predators were used (in separate experiments): two spotted goby (Gobiusculus flavescens; a suction predator) and lion's mane jellyfish (Cyanea capillata; a "passive" ambush predator). Ten cod larvae were observed in the presence of a predator for 20 minutes using a digital video camera. Trials were replicated 4 times for goby and 5 times for jellyfish. Escape rate (total number of escapes/total number of attacks *100), escape distance and the number of larvae remaining at the end of the experiment were measured. In the experiment with gobies, in the UV-treated larvae, both escape rate and escape distance (36%, 38+/-7.5 mm respectively) were significantly lower than those of control larvae (75%, 69+/-4.7 mm respectively). There was a significant difference in survival as well (UV: 35%, CONTROL: 63%). No apparent escape response was observed, and survival rate was not significantly different, between treatments (UV: 66%, CONTROL: 74%) in the experiment with jellyfish. We conclude that the effect and impact of exposure to sub-lethal levels of UV radiation on the escape performance of cod larvae depends on the type of predator. Our results also suggest that prediction of UV impacts on fish larvae based only on direct effects are underestimations. PMID- 22536407 TI - Transcription factor binding site polymorphism in the motilin gene associated with left-sided displacement of the abomasum in German Holstein cattle. AB - Left-sided displacement of the abomasum (LDA) is a common disease in many dairy cattle breeds. A genome-wide screen for QTL for LDA in German Holstein (GH) cows indicated motilin (MLN) as a candidate gene on bovine chromosome 23. Genomic DNA sequence analysis of MLN revealed a total of 32 polymorphisms. All informative polymorphisms used for association analyses in a random sample of 1,136 GH cows confirmed MLN as a candidate for LDA. A single nucleotide polymorphism (FN298674:g.90T>C) located within the first non-coding exon of bovine MLN affects a NKX2-5 transcription factor binding site and showed significant associations (OR(allele) = 0.64; -log(10)P(allele) = 6.8, -log(10)P(genotype) = 7.0) with LDA. An expression study gave evidence of a significantly decreased MLN expression in cows carrying the mutant allele (C). In individuals heterozygous or homozygous for the mutation, MLN expression was decreased by 89% relative to the wildtype. FN298674:g.90T>C may therefore play a role in bovine LDA via the motility of the abomasum. This MLN SNP appears useful to reduce the incidence of LDA in German Holstein cattle and provides a first step towards a deeper understanding of the genetics of LDA. PMID- 22536408 TI - Climate change and the potential distribution of an invasive shrub, Lantana camara L. AB - The threat posed by invasive species, in particular weeds, to biodiversity may be exacerbated by climate change. Lantana camara L. (lantana) is a woody shrub that is highly invasive in many countries of the world. It has a profound economic and environmental impact worldwide, including Australia. Knowledge of the likely potential distribution of this invasive species under current and future climate will be useful in planning better strategies to manage the invasion. A process oriented niche model of L. camara was developed using CLIMEX to estimate its potential distribution under current and future climate scenarios. The model was calibrated using data from several knowledge domains, including phenological observations and geographic distribution records. The potential distribution of lantana under historical climate exceeded the current distribution in some areas of the world, notably Africa and Asia. Under future scenarios, the climatically suitable areas for L. camara globally were projected to contract. However, some areas were identified in North Africa, Europe and Australia that may become climatically suitable under future climates. In South Africa and China, its potential distribution could expand further inland. These results can inform strategic planning by biosecurity agencies, identifying areas to target for eradication or containment. Distribution maps of risk of potential invasion can be useful tools in public awareness campaigns, especially in countries that have been identified as becoming climatically suitable for L. camara under the future climate scenarios. PMID- 22536409 TI - Positive and negative regulation of prostate stem cell antigen expression by Yin Yang 1 in prostate epithelial cell lines. AB - Prostate cancer is influenced by epigenetic modification of genes involved in cancer development and progression. Increased expression of Prostate Stem Cell Antigen (PSCA) is correlated with development of malignant human prostate cancer, while studies in mouse models suggest that decreased PSCA levels promote prostate cancer metastasis. These studies suggest that PSCA has context-dependent functions, and could be differentially regulated during tumor progression. In the present study, we identified the multi-functional transcription factor Yin Yang 1 (YY1) as a modulator of PSCA expression in prostate epithelial cell lines. Increased YY1 levels are observed in prostatic intraepithelial neoplasia (PIN) and advanced disease. We show that androgen-mediated up-regulation of PSCA in prostate epithelial cell lines is dependent on YY1. We identified two direct YY1 binding sites within the PSCA promoter, and showed that the upstream site inhibited, while the downstream site, proximal to the androgen-responsive element, stimulated PSCA promoter activity. Thus, changes in PSCA expression levels in prostate cancer may at least partly be affected by cellular levels of YY1. Our results also suggest multiple roles for YY1 in prostate cancer which may contribute to disease progression by modulation of genes such as PSCA. PMID- 22536410 TI - A molecular phylogeny for the leaf-roller moths (Lepidoptera: Tortricidae) and its implications for classification and life history evolution. AB - BACKGROUND: Tortricidae, one of the largest families of microlepidopterans, comprise about 10,000 described species worldwide, including important pests, biological control agents and experimental models. Understanding of tortricid phylogeny, the basis for a predictive classification, is currently provisional. We present the first detailed molecular estimate of relationships across the tribes and subfamilies of Tortricidae, assess its concordance with previous morphological evidence, and re-examine postulated evolutionary trends in host plant use and biogeography. METHODOLOGY/PRINCIPAL FINDINGS: We sequenced up to five nuclear genes (6,633 bp) in each of 52 tortricids spanning all three subfamilies and 19 of the 22 tribes, plus up to 14 additional genes, for a total of 14,826 bp, in 29 of those taxa plus all 14 outgroup taxa. Maximum likelihood analyses yield trees that, within Tortricidae, differ little among data sets and character treatments and are nearly always strongly supported at all levels of divergence. Support for several nodes was greatly increased by the additional 14 genes sequenced in just 29 of 52 tortricids, with no evidence of phylogenetic artifacts from deliberately incomplete gene sampling. There is strong support for the monophyly of Tortricinae and of Olethreutinae, and for grouping of these to the exclusion of Chlidanotinae. Relationships among tribes are robustly resolved in Tortricinae and mostly so in Olethreutinae. Feeding habit (internal versus external) is strongly conserved on the phylogeny. Within Tortricinae, a clade characterized by eggs being deposited in large clusters, in contrast to singly or in small batches, has markedly elevated incidence of polyphagous species. The five earliest-branching tortricid lineages are all species-poor tribes with mainly southern/tropical distributions, consistent with a hypothesized Gondwanan origin for the family. CONCLUSIONS/SIGNIFICANCE: We present the first robustly supported phylogeny for Tortricidae, and a revised classification in which all of the sampled tribes are now monophyletic. PMID- 22536411 TI - Differentiation-dependent secretion of proangiogenic factors by mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) are a promising cell population for cell-based bone repair due to their proliferative potential, ability to differentiate into bone forming osteoblasts, and their secretion of potent trophic factors that stimulate angiogenesis and neovascularization. To promote bone healing, autogenous or allogeneic MSCs are transplanted into bone defects after differentiation to varying degrees down the osteogenic lineage. However, the contribution of the stage of osteogenic differentiation upon angiogenic factor secretion is unclear. We hypothesized that the proangiogenic potential of MSCs was dependent upon their stage of osteogenic differentiation. After 7 days of culture, we observed the greatest osteogenic differentiation of MSCs when cells were cultured with dexamethasone (OM+). Conversely, VEGF protein secretion and upregulation of angiogenic genes were greatest in MSCs cultured in growth media (GM). Using conditioned media from MSCs in each culture condition, GM-conditioned media maximized proliferation and enhanced chemotactic migration and tubule formation of endothelial colony forming cells (ECFCs). The addition of a neutralizing VEGF(165/121) antibody to conditioned media attenuated ECFC proliferation and chemotactic migration. ECFCs seeded on microcarrier beads and co-cultured with MSCs previously cultured in GM in a fibrin gel exhibited superior sprouting compared to MSCs previously cultured in OM+. These results confirm that MSCs induced farther down the osteogenic lineage possess reduced proangiogenic potential, thereby providing important findings for consideration when using MSCs for bone repair. PMID- 22536412 TI - Defects in the peripheral taste structure and function in the MRL/lpr mouse model of autoimmune disease. AB - While our understanding of the molecular and cellular aspects of taste reception and signaling continues to improve, the aberrations in these processes that lead to taste dysfunction remain largely unexplored. Abnormalities in taste can develop in a variety of diseases, including infections and autoimmune disorders. In this study, we used a mouse model of autoimmune disease to investigate the underlying mechanisms of taste disorders. MRL/MpJ-Fas(lpr)/J (MRL/lpr) mice develop a systemic autoimmunity with phenotypic similarities to human systemic lupus erythematosus and Sjogren's syndrome. Our results show that the taste tissues of MRL/lpr mice exhibit characteristics of inflammation, including infiltration of T lymphocytes and elevated levels of some inflammatory cytokines. Histological studies reveal that the taste buds of MRL/lpr mice are smaller than those of wild-type congenic control (MRL/+/+) mice. 5-Bromo-2'-deoxyuridine (BrdU) pulse-chase experiments show that fewer BrdU-labeled cells enter the taste buds of MRL/lpr mice, suggesting an inhibition of taste cell renewal. Real-time RT-PCR analyses show that mRNA levels of several type II taste cell markers are lower in MRL/lpr mice. Immunohistochemical analyses confirm a significant reduction in the number of gustducin-positive taste receptor cells in the taste buds of MRL/lpr mice. Furthermore, MRL/lpr mice exhibit reduced gustatory nerve responses to the bitter compound quinine and the sweet compound saccharin and reduced behavioral responses to bitter, sweet, and umami taste substances compared with controls. In contrast, their responses to salty and sour compounds are comparable to those of control mice in both nerve recording and behavioral experiments. Together, our results suggest that type II taste receptor cells, which are essential for bitter, sweet, and umami taste reception and signaling, are selectively affected in MRL/lpr mice, a model for autoimmune disease with chronic inflammation. PMID- 22536413 TI - Hemispheric asymmetry in white matter connectivity of the temporoparietal junction with the insula and prefrontal cortex. AB - The temporoparietal junction (TPJ) is a key node in the brain's ventral attention network (VAN) that is involved in spatial awareness and detection of salient sensory stimuli, including pain. The anatomical basis of this network's right lateralized organization is poorly understood. Here we used diffusion-weighted MRI and probabilistic tractography to compare the strength of white matter connections emanating from the right versus left TPJ to target regions in both hemispheres. Symmetry of structural connectivity was evaluated for connections between TPJ and target regions that are key cortical nodes in the right VAN (insula and inferior frontal gyrus) as well as target regions that are involved in salience and/or pain (putamen, cingulate cortex, thalamus). We found a rightward asymmetry in connectivity strength between the TPJ and insula in healthy human subjects who were scanned with two different sets of diffusion weighted MRI acquisition parameters. This rightward asymmetry in TPJ-insula connectivity was stronger in females than in males. There was also a leftward asymmetry in connectivity strength between the TPJ and inferior frontal gyrus, consistent with previously described lateralization of language pathways. The rightward lateralization of the pathway between the TPJ and insula supports previous findings on the roles of these regions in stimulus-driven attention, sensory awareness, interoception and pain. The findings also have implications for our understanding of acute and chronic pains and stroke-induced spatial hemineglect. PMID- 22536414 TI - Rare variants in ischemic stroke: an exome pilot study. AB - The genetic architecture of ischemic stroke is complex and is likely to include rare or low frequency variants with high penetrance and large effect sizes. Such variants are likely to provide important insights into disease pathogenesis compared to common variants with small effect sizes. Because a significant portion of human functional variation may derive from the protein-coding portion of genes we undertook a pilot study to identify variation across the human exome (i.e., the coding exons across the entire human genome) in 10 ischemic stroke cases. Our efforts focused on evaluating the feasibility and identifying the difficulties in this type of research as it applies to ischemic stroke. The cases included 8 African-Americans and 2 Caucasians selected on the basis of similar stroke subtypes and by implementing a case selection algorithm that emphasized the genetic contribution of stroke risk. Following construction of paired-end sequencing libraries, all predicted human exons in each sample were captured and sequenced. Sequencing generated an average of 25.5 million read pairs (75 bp*2) and 3.8 Gbp per sample. After passing quality filters, screening the exomes against dbSNP demonstrated an average of 2839 novel SNPs among African-Americans and 1105 among Caucasians. In an aggregate analysis, 48 genes were identified to have at least one rare variant across all stroke cases. One gene, CSN3, identified by screening our prior GWAS results in conjunction with our exome results, was found to contain an interesting coding polymorphism as well as containing excess rare variation as compared with the other genes evaluated. In conclusion, while rare coding variants may predispose to the risk of ischemic stroke, this fact has yet to be definitively proven. Our study demonstrates the complexities of such research and highlights that while exome data can be obtained, the optimal analytical methods have yet to be determined. PMID- 22536415 TI - Acute leptin treatment enhances functional recovery after spinal cord injury. AB - BACKGROUND: Spinal cord injury is a major cause of long-term disability and has no current clinically accepted treatment. Leptin, an adipocyte-derived hormone, is best known as a regulator of food intake and energy expenditure. Interestingly, several studies have demonstrated that leptin has significant effects on proliferation and cell survival in different neuropathologies. Here, we sought to evaluate the role of leptin after spinal cord injury. FINDINGS: Based on its proposed neuroprotective role, we have evaluated the effects of a single, acute intraparenchymal injection of leptin in a clinically relevant animal model of spinal cord injury. As determined by quantitative Real Time-PCR, endogenous leptin and the long isoform of the leptin receptor genes show time dependent variations in their expression in the healthy and injured adult spinal cord. Immunohistochemical analysis of post-injury tissue showed the long isoform of the leptin receptor expression in oligodendrocytes and, to a lesser extent, in astrocytes, microglia/macrophages and neurons. Moreover, leptin administered after spinal cord injury increased the expression of neuroprotective genes, reduced caspase-3 activity and decreased the expression of pro-inflammatory molecules. In addition, histological analysis performed at the completion of the study showed that leptin treatment reduced microglial reactivity and increased caudal myelin preservation, but it did not modulate astroglial reactivity. Consequently, leptin improved the recovery of sensory and locomotor functioning. CONCLUSIONS: Our data suggest that leptin has a prominent neuroprotective and anti-inflammatory role in spinal cord damage and highlights leptin as a promising therapeutic agent. PMID- 22536417 TI - Discrimination of juvenile yellowfin (Thunnus albacares) and bigeye (T. obesus) Tunas using mitochondrial DNA control region and liver morphology. AB - Yellowfin tuna, Thunnus albacares (Bonnaterre, 1788) and bigeye tuna, Thunnus obesus (Lowe, 1839) are two of the most economically important tuna species in the world. However, identification of their juveniles, especially at sizes less than 40 cm, is very difficult, often leading to misidentification and miscalculation of their catch estimates. Here, we applied the mitochondrial DNA control region D-loop, a recently validated genetic marker used for identifying tuna species (Genus Thunnus), to discriminate juvenile tunas caught by purse seine and ringnet sets around fish aggregating devices (FADs) off the Southern Iloilo Peninsula in Central Philippines. We checked individual identifications using the Neighbor-Joining Method and compared results with morphometric analyses and the liver phenotype. We tested 48 specimens ranging from 13 to 31 cm fork length. Morpho-meristic analyses suggested that 12 specimens (25%) were bigeye tuna and 36 specimens (75%) were yellowfin tuna. In contrast, the genetic and liver analyses both showed that 5 specimens (10%) were bigeye tuna and 43 (90%) yellowfin tuna. This suggests that misidentification can occur even with highly stringent morpho-meristic characters and that the mtDNA control region and liver phenotype are excellent markers to discriminate juveniles of yellowfin and bigeye tunas. PMID- 22536416 TI - High-throughput single-cell manipulation in brain tissue. AB - The complexity of neurons and neuronal circuits in brain tissue requires the genetic manipulation, labeling, and tracking of single cells. However, current methods for manipulating cells in brain tissue are limited to either bulk techniques, lacking single-cell accuracy, or manual methods that provide single cell accuracy but at significantly lower throughputs and repeatability. Here, we demonstrate high-throughput, efficient, reliable, and combinatorial delivery of multiple genetic vectors and reagents into targeted cells within the same tissue sample with single-cell accuracy. Our system automatically loads nanoliter-scale volumes of reagents into a micropipette from multiwell plates, targets and transfects single cells in brain tissues using a robust electroporation technique, and finally preps the micropipette by automated cleaning for repeating the transfection cycle. We demonstrate multi-colored labeling of adjacent cells, both in organotypic and acute slices, and transfection of plasmids encoding different protein isoforms into neurons within the same brain tissue for analysis of their effects on linear dendritic spine density. Our platform could also be used to rapidly deliver, both ex vivo and in vivo, a variety of genetic vectors, including optogenetic and cell-type specific agents, as well as fast-acting reagents such as labeling dyes, calcium sensors, and voltage sensors to manipulate and track neuronal circuit activity at single-cell resolution. PMID- 22536418 TI - Kinetics of PKCepsilon activating and inhibiting llama single chain antibodies and their effect on PKCepsilon translocation in HeLa cells. AB - Dysregulation of PKCepsilon is involved in several serious diseases such as cancer, type II diabetes and Alzheimer's disease. Therefore, specific activators and inhibitors of PKCepsilon hold promise as future therapeutics, in addition to being useful in research into PKCepsilon regulated pathways. We have previously described llama single chain antibodies (VHHs) that specifically activate (A10, C1 and D1) or inhibit (E6 and G8) human recombinant PKCepsilon. Here we report a thorough kinetic analysis of these VHHs. The inhibiting VHHs act as non competitive inhibitors of PKCepsilon activity, whereas the activating VHHs have several different modes of action, either increasing V(max) and/or decreasing K(m) values. We also show that the binding of the VHHs to PKCepsilon is conformation-dependent, rendering the determination of affinities difficult. Apparent affinities are in the micromolar range based on surface plasmon resonance studies. Furthermore, the VHHs have no effect on the activity of rat PKCepsilon nor can they bind the rat form of the protein in immunoprecipitation studies despite the 98% identity between the human and rat PKCepsilon proteins. Finally, we show for the first time that the VHHs can influence PKCepsilon function also in cells, since an activating VHH increases the rate of PKCepsilon translocation in response to PMA in HeLa cells, whereas an inhibiting VHH slows down the translocation. These results give insight into the mechanisms of PKCepsilon activity modulation and highlight the importance of protein conformation on VHH binding. PMID- 22536419 TI - Evidence that prefibrotic myelofibrosis is aligned along a clinical and biological continuum featuring primary myelofibrosis. AB - PURPOSE: In the WHO diagnostic classification, prefibrotic myelofibrosis (pre-MF) is included in the category of primary myelofibrosis (PMF). However, strong evidence for this position is lacking. PATIENTS AND METHODS: We investigated whether pre-MF may be aligned along a clinical and biological continuum in 683 consecutive patients who received a WHO diagnosis of PMF. RESULTS: As compared with PMF-fibrotic type, pre-MF (132 cases) showed female dominance, younger age, higher hemoglobin, higher platelet count, lower white blood cell count, smaller spleen index and higher incidence of splanchnic vein thrombosis. Female to male ratio and hemoglobin steadily decreased, while age increased from pre-MF to PMF- fibrotic type with early and to advanced bone marrow (BM) fibrosis. Likely, circulating CD34+ cells, LDH levels, and frequency of chromosomal abnormalities increased, while CXCR4 expression on CD34+ cells and serum cholesterol decreased along the continuum of BM fibrosis. Median survival of the entire cohort of PMF cases was 21 years. Ninety-eight, eighty-one and fifty-six percent of patients with pre-MF, PMF-fibrotic type with early and with advanced BM fibrosis, respectively, were alive at 10 years from diagnosis. CONCLUSION: Pre-MF is a presentation mode of PMF with a very indolent phenotype. The major consequences of this contention is a new clinical vision of PMF, and the need to improve prognosis prediction of the disease. PMID- 22536420 TI - Angiotensin II facilitates breast cancer cell migration and metastasis. AB - Breast cancer metastasis is a leading cause of death by malignancy in women worldwide. Efforts are being made to further characterize the rate-limiting steps of cancer metastasis, i.e. extravasation of circulating tumor cells and colonization of secondary organs. In this study, we investigated whether angiotensin II, a major vasoactive peptide both produced locally and released in the bloodstream, may trigger activating signals that contribute to cancer cell extravasation and metastasis. We used an experimental in vivo model of cancer metastasis in which bioluminescent breast tumor cells (D3H2LN) were injected intra-cardiacally into nude mice in order to recapitulate the late and essential steps of metastatic dissemination. Real-time intravital imaging studies revealed that angiotensin II accelerates the formation of metastatic foci at secondary sites. Pre-treatment of cancer cells with the peptide increases the number of mice with metastases, as well as the number and size of metastases per mouse. In vitro, angiotensin II contributes to each sequential step of cancer metastasis by promoting cancer cell adhesion to endothelial cells, trans-endothelial migration and tumor cell migration across extracellular matrix. At the molecular level, a total of 102 genes differentially expressed following angiotensin II pre treatment were identified by comparative DNA microarray. Angiotensin II regulates two groups of connected genes related to its precursor angiotensinogen. Among those, up-regulated MMP2/MMP9 and ICAM1 stand at the crossroad of a network of genes involved in cell adhesion, migration and invasion. Our data suggest that targeting angiotensin II production or action may represent a valuable therapeutic option to prevent metastatic progression of invasive breast tumors. PMID- 22536421 TI - Development and evaluation of a 9K SNP array for peach by internationally coordinated SNP detection and validation in breeding germplasm. AB - Although a large number of single nucleotide polymorphism (SNP) markers covering the entire genome are needed to enable molecular breeding efforts such as genome wide association studies, fine mapping, genomic selection and marker-assisted selection in peach [Prunus persica (L.) Batsch] and related Prunus species, only a limited number of genetic markers, including simple sequence repeats (SSRs), have been available to date. To address this need, an international consortium (The International Peach SNP Consortium; IPSC) has pursued a coordinated effort to perform genome-scale SNP discovery in peach using next generation sequencing platforms to develop and characterize a high-throughput Illumina Infinium(r) SNP genotyping array platform. We performed whole genome re-sequencing of 56 peach breeding accessions using the Illumina and Roche/454 sequencing technologies. Polymorphism detection algorithms identified a total of 1,022,354 SNPs. Validation with the Illumina GoldenGate(r) assay was performed on a subset of the predicted SNPs, verifying ~75% of genic (exonic and intronic) SNPs, whereas only about a third of intergenic SNPs were verified. Conservative filtering was applied to arrive at a set of 8,144 SNPs that were included on the IPSC peach SNP array v1, distributed over all eight peach chromosomes with an average spacing of 26.7 kb between SNPs. Use of this platform to screen a total of 709 accessions of peach in two separate evaluation panels identified a total of 6,869 (84.3%) polymorphic SNPs.The almost 7,000 SNPs verified as polymorphic through extensive empirical evaluation represent an excellent source of markers for future studies in genetic relatedness, genetic mapping, and dissecting the genetic architecture of complex agricultural traits. The IPSC peach SNP array v1 is commercially available and we expect that it will be used worldwide for genetic studies in peach and related stone fruit and nut species. PMID- 22536422 TI - Characterisation of innate fungal recognition in the lung. AB - The innate recognition of fungi by leukocytes is mediated by pattern recognition receptors (PRR), such as Dectin-1, and is thought to occur at the cell surface triggering intracellular signalling cascades which lead to the induction of protective host responses. In the lung, this recognition is aided by surfactant which also serves to maintain the balance between inflammation and pulmonary function, although the underlying mechanisms are unknown. Here we have explored pulmonary innate recognition of a variety of fungal particles, including zymosan, Candida albicans and Aspergillus fumigatus, and demonstrate that opsonisation with surfactant components can limit inflammation by reducing host-cell fungal interactions. However, we found that this opsonisation does not contribute directly to innate fungal recognition and that this process is mediated through non-opsonic PRRs, including Dectin-1. Moreover, we found that pulmonary inflammatory responses to resting Aspergillus conidia were initiated by these PRRs in acidified phagolysosomes, following the uptake of fungal particles by leukocytes. Our data therefore provides crucial new insights into the mechanisms by which surfactant can maintain pulmonary function in the face of microbial challenge, and defines the phagolysosome as a novel intracellular compartment involved in the innate sensing of extracellular pathogens in the lung. PMID- 22536423 TI - Restoration of contralateral representation in the mouse somatosensory cortex after crossing nerve transfer. AB - Avulsion of spinal nerve roots in the brachial plexus (BP) can be repaired by crossing nerve transfer via a nerve graft to connect injured nerve ends to the BP contralateral to the lesioned side. Sensory recovery in these patients suggests that the contralateral primary somatosensory cortex (S1) is activated by afferent inputs that bypassed to the contralateral BP. To confirm this hypothesis, the present study visualized cortical activity after crossing nerve transfer in mice through the use of transcranial flavoprotein fluorescence imaging. In naive mice, vibratory stimuli applied to the forepaw elicited localized fluorescence responses in the S1 contralateral to the stimulated side, with almost no activity in the ipsilateral S1. Four weeks after crossing nerve transfer, forepaw stimulation in the injured and repaired side resulted in cortical responses only in the S1 ipsilateral to the stimulated side. At eight weeks after crossing nerve transfer, forepaw stimulation resulted in S1 cortical responses of both hemispheres. These cortical responses were abolished by cutting the nerve graft used for repair. Exposure of the ipsilateral S1 to blue laser light suppressed cortical responses in the ipsilateral S1, as well as in the contralateral S1, suggesting that ipsilateral responses propagated to the contralateral S1 via cortico-cortical pathways. Direct high-frequency stimulation of the ipsilateral S1 in combination with forepaw stimulation acutely induced S1 bilateral cortical representation of the forepaw area in naive mice. Cortical responses in the contralateral S1 after crossing nerve transfer were reduced in cortex-restricted heterotypic GluN1 (NMDAR1) knockout mice. Functional bilateral cortical representation was not clearly observed in genetically manipulated mice with impaired cortico-cortical pathways between S1 of both hemispheres. Taken together, these findings strongly suggest that activity-dependent potentiation of cortico-cortical pathways has a critical role for sensory recovery in patients after crossing nerve transfer. PMID- 22536425 TI - A congeneric comparison shows that experimental warming enhances the growth of invasive Eupatorium adenophorum. AB - Rising air temperatures may change the risks of invasive plants; however, little is known about how different warming timings affect the growth and stress tolerance of invasive plants. We conducted an experiment with an invasive plant Eupatorium adenophorum and a native congener Eupatorium chinense, and contrasted their mortality, plant height, total biomass, and biomass allocation in ambient, day-, night-, and daily-warming treatments. The mortality of plants was significantly higher in E. chinense than E. adenophorum in four temperature regimes. Eupatorium adenophorum grew larger than E. chinense in the ambient climate, and this difference was amplified with warming. On the basis of the net effects of warming, daily-warming exhibited the strongest influence on E. adenophorum, followed by day-warming and night-warming. There was a positive correlation between total biomass and root weight ratio in E. adenophorum, but not in E. chinense. These findings suggest that climate warming may enhance E. adenophorum invasions through increasing its growth and stress-tolerance, and that day-, night- and daily-warming may play different roles in this facilitation. PMID- 22536424 TI - Disease dynamics and bird migration--linking mallards Anas platyrhynchos and subtype diversity of the influenza A virus in time and space. AB - The mallard Anas platyrhynchos is a reservoir species for influenza A virus in the northern hemisphere, with particularly high prevalence rates prior to as well as during its prolonged autumn migration. It has been proposed that the virus is brought from the breeding grounds and transmitted to conspecifics during subsequent staging during migration, and so a better understanding of the natal origin of staging ducks is vital to deciphering the dynamics of viral movement pathways. Ottenby is an important stopover site in southeast Sweden almost halfway downstream in the major Northwest European flyway, and is used by millions of waterfowl each year. Here, mallards were captured and sampled for influenza A virus infection, and positive samples were subtyped in order to study possible links to the natal area, which were determined by a novel approach combining banding recovery data and isotopic measurements (delta(2)H) of feathers grown on breeding grounds. Geographic assignments showed that the core natal areas of studied mallards were in Estonia, southern and central Finland, and northwestern Russia. This study demonstrates a clear temporal succession of latitudes of natal origin during the course of autumn migration. We also demonstrate a corresponding and concomitant shift in virus subtypes. Acknowledging that these two different patterns were based in part upon different data, a likely interpretation worth further testing is that the early arriving birds with more proximate origins have different influenza A subtypes than the more distantly originating late autumn birds. If true, this knowledge would allow novel insight into the origins and transmission of the influenza A virus among migratory hosts previously unavailable through conventional approaches. PMID- 22536426 TI - Glucose-dependent insulinotropic polypeptide prevents the progression of macrophage-driven atherosclerosis in diabetic apolipoprotein E-null mice. AB - AIM: We recently reported that glucose-dependent insulinotropic polypeptide (GIP) prevents the development of atherosclerosis in apolipoprotein E-null (Apoe(-/-)) mice. GIP receptors (GIPRs) are found to be severely down-regulated in diabetic animals. We examined whether GIP can exert anti-atherogenic effects in diabetes. METHODS: Nondiabetic Apoe(-/-) mice, streptozotocin-induced diabetic Apoe(-/-) mice, and db/db mice were administered GIP (25 nmol/kg/day) or saline (vehicle) through osmotic mini-pumps for 4 weeks. The animals were assessed for aortic atherosclerosis and for oxidized low-density lipoprotein-induced foam cell formation in exudate peritoneal macrophages. RESULTS: Diabetic Apoe(-/-) mice of 21 weeks of age exhibited more advanced atherosclerosis than nondiabetic Apoe(-/ ) mice of the same age. GIP infusion in diabetic Apoe(-/-) mice increased plasma total GIP levels by 4-fold without improving plasma insulin, glucose, or lipid profiles. GIP infusion significantly suppressed macrophage-driven atherosclerotic lesions, but this effect was abolished by co-infusions with [Pro(3)]GIP, a GIPR antagonist. Foam cell formation was stimulated by 3-fold in diabetic Apoe(-/-) mice compared with their nondiabetic counterparts, but this effect was halved by GIP infusion. GIP infusion also attenuated the foam cell formation in db/db mice. In vitro treatment with GIP (1 nM) reduced foam cell formation by 15% in macrophages from diabetic Apoe(-/-) mice, and this attenuating effect was weaker than that attained by the same treatment of macrophages from nondiabetic counterparts (35%). While GIPR expression was reduced by only about a half in macrophages from diabetic mice, it was reduced much more dramatically in pancreatic islets from the same animals. Incubation with high glucose (500 mg/dl) for 9-10 days markedly reduced GIPR expression in pancreatic islet cells, but not in macrophages. CONCLUSIONS: Long-term infusion of GIP conferred significant anti atherogenic effects in diabetic mice even though the GIPR expression in macrophages was mildly down-regulated in the diabetic state. PMID- 22536427 TI - Effects of MASP-1 of the complement system on activation of coagulation factors and plasma clot formation. AB - BACKGROUND: Numerous interactions between the coagulation and complement systems have been shown. Recently, links between coagulation and mannan-binding lectin associated serine protease-1 (MASP-1) of the complement lectin pathway have been proposed. Our aim was to investigate MASP-1 activation of factor XIII (FXIII), fibrinogen, prothrombin, and thrombin-activatable fibrinolysis inhibitor (TAFI) in plasma-based systems, and to analyse effects of MASP-1 on plasma clot formation, structure and lysis. METHODOLOGY/PRINCIPAL FINDINGS: We used a FXIII incorporation assay and specific assays to measure the activation products prothrombin fragment F1+2, fibrinopeptide A (FPA), and activated TAFI (TAFIa). Clot formation and lysis were assessed by turbidimetric assay. Clot structure was studied by scanning electron microscopy. MASP-1 activated FXIII and, contrary to thrombin, induced FXIII activity faster in the Val34 than the Leu34 variant. MASP 1-dependent generation of F1+2, FPA and TAFIa showed a dose-dependent response in normal citrated plasma (NCP), albeit MASP-1 was much less efficient than FXa or thrombin. MASP-1 activation of prothrombin and TAFI cleavage were confirmed in purified systems. No FPA generation was observed in prothrombin-depleted plasma. MASP-1 induced clot formation in NCP, affected clot structure, and prolonged clot lysis. CONCLUSIONS/SIGNIFICANCE: We show that MASP-1 interacts with plasma clot formation on different levels and influences fibrin structure. Although MASP-1 induced fibrin formation is thrombin-dependent, MASP-1 directly activates prothrombin, FXIII and TAFI. We suggest that MASP-1, in concerted action with other complement and coagulation proteins, may play a role in fibrin clot formation. PMID- 22536429 TI - Transcriptome analysis of the Chinese white wax scale Ericerus pela with focus on genes involved in wax biosynthesis. AB - BACKGROUND: The Chinese white wax scale, Ericerus pela Chavannes is economically significant for its role in wax production. This insect has been bred in China for over a thousand years. The wax secreted by the male scale insect during the second-instar larval stage has been widespread used in wax candle production, wax printing, engraving, Chinese medicine, and more recently in the chemical, pharmaceutical, food, and cosmetics industries. However, little is known about the mechanisms responsible for white wax biosynthesis. The characterization of its larval transcriptome may promote better understanding of wax biosynthesis. METHODOLOGY/PRINCIPAL FINDINGS: In this study, characterization of the transcriptome of E. pela during peak wax secretion was performed using Illumina sequencing technology. Illumina sequencing produced 41,839 unigenes. These unigenes were annotated by blastx alignment against the NCBI Non-Redundant (NR), Swiss-Prot, KEGG, and COG databases. A total of 104 unigenes related to white wax biosynthesis were identified, and 15 of them were selected for quantitative real time PCR analysis. We evaluated the variations in gene expression across different development stages, including egg, first/second instar larvae, male pupae, and male and female adults. Then we identified five genes involved in white wax biosynthesis. These genes were expressed most strongly during the second-instar larval stage of male E. pela. CONCLUSION/SIGNIFICANCE: The transcriptome analysis of E. pela during peak wax secretion provided an overview of gene expression information at the transcriptional level and a resource for gene mining. Five genes related to white wax biosynthesis were identified. PMID- 22536428 TI - Comparative genomics of Mycoplasma: analysis of conserved essential genes and diversity of the pan-genome. AB - Mycoplasma, the smallest self-replicating organism with a minimal metabolism and little genomic redundancy, is expected to be a close approximation to the minimal set of genes needed to sustain bacterial life. This study employs comparative evolutionary analysis of twenty Mycoplasma genomes to gain an improved understanding of essential genes. By analyzing the core genome of mycoplasmas, we finally revealed the conserved essential genes set for mycoplasma survival. Further analysis showed that the core genome set has many characteristics in common with experimentally identified essential genes. Several key genes, which are related to DNA replication and repair and can be disrupted in transposon mutagenesis studies, may be critical for bacteria survival especially over long period natural selection. Phylogenomic reconstructions based on 3,355 homologous groups allowed robust estimation of phylogenetic relatedness among mycoplasma strains. To obtain deeper insight into the relative roles of molecular evolution in pathogen adaptation to their hosts, we also analyzed the positive selection pressures on particular sites and lineages. There appears to be an approximate correlation between the divergence of species and the level of positive selection detected in corresponding lineages. PMID- 22536430 TI - Performance scores in general practice: a comparison between the clinical versus medication-based approach to identify target populations. AB - CONTEXT: From one country to another, the pay-for-performance mechanisms differ on one significant point: the identification of target populations, that is, populations which serve as a basis for calculating the indicators. The aim of this study was to compare clinical versus medication-based identification of populations of patients with diabetes and hypertension over the age of 50 (for men) or 60 (for women), and any consequences this may have on the calculation of P4P indicators. METHODS: A comparative, retrospective, observational study was carried out with clinical and prescription data from a panel of general practitioners (GPs), the Observatory of General Medicine (OMG) for the year 2007. Two indicators regarding the prescription for statins and aspirin in these populations were calculated. RESULTS: We analyzed data from 21.690 patients collected by 61 GPs via electronic medical files. Following the clinical-based approach, 2.278 patients were diabetic, 8,271 had hypertension and 1.539 had both against respectively 1.730, 8.511 and 1.304 following the medication-based approach (% agreement = 96%, kappa = 0.69). The main reasons for these differences were: forgetting to code the morbidities in the clinical approach, not taking into account the population of patients who were given life style and diet rules only or taking into account patients for whom morbidities other than hypertension could justify the use of antihypertensive drugs in the medication based approach. The mean (confidence interval) per doctor was 33.7% (31.5-35.9) for statin indicator and 38.4% (35.4-41.4) for aspirin indicator when the target populations were identified on the basis of clinical criteria whereas they were 37.9% (36.3-39.4) and 43.8% (41.4-46.3) on the basis of treatment criteria. CONCLUSION: The two approaches yield very "similar" scores but these scores cover different realities and offer food for thought on the possible usage of these indicators in the framework of P4P programmes. PMID- 22536431 TI - New insights into the evolution of metazoan tyrosinase gene family. AB - Tyrosinases, widely distributed among animals, plants and fungi, are involved in the biosynthesis of melanin, a pigment that has been exploited, in the course of evolution, to serve different functions. We conducted a deep evolutionary analysis of tyrosinase family amongst metazoa, thanks to the availability of new sequenced genomes, assessing that tyrosinases (tyr) represent a distinctive feature of all the organisms included in our study and, interestingly, they show an independent expansion in most of the analyzed phyla. Tyrosinase-related proteins (tyrp), which derive from tyr but show distinct key residues in the catalytic domain, constitute an invention of chordate lineage. In addition we here reported a detailed study of the expression territories of the ascidian Ciona intestinalis tyr and tyrps. Furthermore, we put efforts in the identification of the regulatory sequences responsible for their expression in pigment cell lineage. Collectively, the results reported here enlarge our knowledge about the tyrosinase gene family as valuable resource for understanding the genetic components involved in pigment cells evolution and development. PMID- 22536432 TI - Differential effects of short term feeding of a soy protein isolate diet and estrogen treatment on bone in the pre-pubertal rat. AB - BACKGROUND: Previous reports suggest that beneficial effects of soy on bone quality are due to the estrogenic actions of isoflavone phytochemicals associated with the protein. However, mechanistic studies comparing the effects of soy diet and estrogens on bone, particularly in rapidly growing animals are lacking. METHODOLOGY AND PRINCIPAL FINDINGS: We studied the effects of short term feeding of soy protein isolate (SPI) on bone in comparison to the effects of 17beta estradiol (E2) in pre-pubertal rats. Female rats were weaned to one of 4 treatments: 1) a control casein-based diet (CAS); 2) CAS with subcutaneous E2 (10 ug/kg/d) (CAS+E2); 3) a SPI-containing diet (SPI); or 4) SPI with subcutaneous E2 (SPI) or SPI with 10 ug/kg/d E2 (SPI+E2) for 14 days beginning on postnatal day 20. SPI increased while E2 decreased bone turnover compared to CAS. In contrast, both treatments decreased serum sclerostin levels. Microarray analysis of RNA isolated from bone revealed 652 genes regulated by SPI, 491 genes regulated by E2, and 266 genes regulated by both SPI diet and E2 compared to CAS. The expression of caveolin-1, a protein localized in the cell membrane, was down regulated (p<0.05) in rats fed SPI, but not by E2 compared to rats fed casein. Down-regulation of caveolin-1 by SPI was associated with increased BMP2, Smad and Runx2 expression in bone and osteoblasts (p<0.05). CONCLUSIONS/SIGNIFICANCE: These results suggest SPI and E2 have different effects on bone turnover prior to puberty. Approximately half of the genes are regulated in the same direction by E2 or SPI, but in combination, SPI blocks the estrogen effects and returns the profile towards control levels. In addition, there are E2 specific and SPI specific gene changes related to regulation of bone formation. PMID- 22536433 TI - Influence of primary care physician availability and socioeconomic deprivation on breast cancer from 1988 to 2008: a spatio-temporal analysis. AB - BACKGROUND: Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer death among women in the United States. It is unclear how county-level primary care physician (PCP) availability and socioeconomic deprivation affect the spatial and temporal variation of breast cancer incidence and mortality. METHODS: We used the 1988-2008 public-use county-based data from nine Surveillance, Epidemiology, and End Results (SEER) programs to analyze the temporal and spatial disparity of PCP availability and socioeconomic deprivation on early-stage incidence, advanced-stage incidence and breast cancer mortality. The spatio-temporal analysis was implemented by a novel structural additive modeling approach. RESULTS: Greater PCP availability was significantly associated with higher early-stage incidence, advanced-stage incidence and mortality during the entire study period while socioeconomic deprivation was significantly negatively associated with early-stage incidence, advanced-stage incidence, and mortality up to 1992. However, the observed influence of PCP availability and socioeconomic deprivation varied by county. CONCLUSIONS: We showed important associations of PCP availability and socioeconomic deprivation with the three breast cancer indicators. However, the effect of these associations varied over time and across counties. The association of PCP availability and socioeconomic deprivation was stronger in selected counties. PMID- 22536434 TI - Priority in selenium homeostasis involves regulation of SepSecS transcription in the chicken brain. AB - O-phosphoseryl-tRNA:selenocysteinyl-tRNA synthase (SepSecS) is critical for the biosynthesis and transformation of selenocysteine (Sec) and plays an important role in the biological function of Se through the regulation of selenoprotein synthesis. Selenium (Se) and Selenoprotein play a pivotal role in brain function. However, how intake of the micronutrient Se affects gene expression and how genetic factors influence Se metabolism in the brain is unknown. To investigate the regulation of SepSecS transcription induced by Se in the chicken brain, we determined the Se content of brain tissue, SepSecS gene expression levels and mRNA stability in the chicken brain and primary cultured chicken embryos neurons receiving Se supplements. These results showed that Se content in the brain remains remarkably stable during Se supplementation. A significant increase in SepSecS mRNA levels was observed in all of the brain tissues of chickens fed diets containing 1-5 mg/kg sodium selenite. Most strikingly, significant changes in SepSecS mRNA levels were not observed in neurons treated with Se. However, Se altered the SepSecS mRNA half-life in cells. These data suggest that Se could regulate SepSecS mRNA stability in the avian brain and that SepSecS plays an important role in Se homeostasis regulation. PMID- 22536435 TI - Differential brain development with low and high IQ in attention deficit/hyperactivity disorder. AB - Attention-Deficit/Hyperactivity Disorder (ADHD) and intelligence (IQ) are both heritable phenotypes. Overlapping genetic effects have been suggested to influence both, with neuroimaging work suggesting similar overlap in terms of morphometric properties of the brain. Together, this evidence suggests that the brain changes characteristic of ADHD may vary as a function of IQ. This study investigated this hypothesis in a sample of 108 children with ADHD and 106 typically developing controls, who participated in a cross-sectional anatomical MRI study. A subgroup of 64 children also participated in a diffusion tensor imaging scan. Brain volumes, local cortical thickness and average cerebral white matter microstructure were analyzed in relation to diagnostic group and IQ. Dimensional analyses investigated possible group differences in the relationship between anatomical measures and IQ. Second, the groups were split into above and below median IQ subgroups to investigate possible differences in the trajectories of cortical development. Dimensionally, cerebral gray matter volume and cerebral white matter microstructure were positively associated with IQ for controls, but not for ADHD. In the analyses of the below and above median IQ subgroups, we found no differences from controls in cerebral gray matter volume in ADHD with below-median IQ, but a delay of cortical development in a number of regions, including prefrontal areas. Conversely, in ADHD with above-median IQ, there were significant reductions from controls in cerebral gray matter volume, but no local differences in the trajectories of cortical development.In conclusion, the basic relationship between IQ and neuroanatomy appears to be altered in ADHD. Our results suggest that there may be multiple brain phenotypes associated with ADHD, where ADHD combined with above median IQ is characterized by small, more global reductions in brain volume that are stable over development, whereas ADHD with below median IQ is associated more with a delay of cortical development. PMID- 22536436 TI - Tau phosphorylation and MU-calpain activation mediate the dexamethasone-induced inhibition on the insulin-stimulated Akt phosphorylation. AB - Evidence has suggested that insulin resistance (IR) or high levels of glucocorticoids (GCs) may be linked with the pathogenesis and/or progression of Alzheimer's disease (AD). Although studies have shown that a high level of GCs results in IR, little is known about the molecular details that link GCs and IR in the context of AD. Abnormal phosphorylation of tau and activation of MU calpain are two key events in the pathology of AD. Importantly, these two events are also related with GCs and IR. We therefore speculate that tau phosphorylation and MU-calpain activation may mediate the GCs-induced IR. Akt phosphorylation at Ser-473 (pAkt) is commonly used as a marker for assessing IR. We employed two cell lines, wild-type HEK293 cells and HEK293 cells stably expressing the longest human tau isoform (tau-441; HEK293/tau441 cells). We examined whether DEX, a synthetic GCs, induces tau phosphorylation and MU-calpain activation. If so, we examined whether the DEX-induced tau phosphorylation and MU-calpain activation mediate the DEX-induced inhibition on the insulin-stimulated Akt phosphorylation. The results showed that DEX increased tau phosphorylation and induced tau mediated MU-calpain activation. Furthermore, pre-treatment with LiCl prevented the effects of DEX on tau phosphorylation and MU-calpain activation. Finally, both LiCl pre-treatment and calpain inhibition prevented the DEX-induced inhibition on the insulin-stimulated Akt phosphorylation. In conclusion, our study suggests that the tau phosphorylation and MU-calpain activation mediate the DEX-induced inhibition on the insulin-stimulated Akt phosphorylation. PMID- 22536437 TI - The effect of rosuvastatin in a murine model of influenza A infection. AB - RATIONALE: HMG-CoA reductase inhibitors such as rosuvastatin may have immunomodulatory and anti-inflammatory effects that may reduce the severity of influenza A infection. We hypothesized that rosuvastatin would decrease viral replication, attenuate lung injury, and improve mortality following influenza A infection in mice. METHODS: C57Bl/6 mice were treated daily with rosuvastatin (10 mg/kg/day) supplemented in chow (or control chow) beginning three days prior to infection with either A//Udorn/72 [H3N2] or A/WSN/33 [H1N1] influenza A virus (1*10(5) pfu/mouse). Plaque assays were used to examine the effect of rosuvastatin on viral replication in vitro and in the lungs of infected mice. We measured cell count with differential, protein and cytokines in the bronchoalveolar lavage (BAL) fluid, histologic evidence of lung injury, and wet to-dry ratio on Day 1, 2, 4, and 6. We also recorded daily weights and mortality. RESULTS: The administration of rosuvastatin had no effect on viral clearance of influenza A after infection. Weight loss, lung inflammation and lung injury severity were similar in the rosuvastatin and control treated mice. In the mice infected with influenza A (A/WSN/33), mortality was unaffected by treatment with rosuvastatin. CONCLUSIONS: Statins did not alter the replication of influenza A in vitro or enhance its clearance from the lung in vivo. Statins neither attenuated the severity of influenza A-induced lung injury nor had an effect on influenza A-related mortality. Our data suggest that the association between HMG CoA reductase inhibitors and improved outcomes in patients with sepsis and pneumonia are not attributable to their effects on influenza A infection. PMID- 22536438 TI - Impact of the location of CpG methylation within the GSTP1 gene on its specificity as a DNA marker for hepatocellular carcinoma. AB - Hypermethylation of the glutathione S-transferase pi 1 (GSTP1) gene promoter region has been reported to be a potential biomarker to distinguish hepatocellular carcinoma (HCC) from other liver diseases. However, reports regarding how specific a marker it is have ranged from 100% to 0%. We hypothesized that, to a large extent, the variation of specificity depends on the location of the CpG sites analyzed. To test this hypothesis, we compared the methylation status of the GSTP1 promoter region of the DNA isolated from HCC, cirrhosis, hepatitis, and normal liver tissues by bisulfite-PCR sequencing. We found that the 5' region of the position -48 nt from the transcription start site of the GSTP1 gene is selectively methylated in HCC, whereas the 3' region is methylated in all liver tissues examined, including normal liver and the HCC tissue. Interestingly, when DNA derived from fetal liver and 11 nonhepatic normal tissue was also examined by bisulfite-PCR sequencing, we found that methylation of the 3' region of the promoter appeared to be liver-specific. A methylation specific PCR assay targeting the 5' region of the promoter was developed and used to quantify the methylated GSTP1 gene in various diseased liver tissues including HCC. When we used an assay targeting the 3' region, we found that the methylation of the 5'-end of the GSTP1 promoter was significantly more specific than that of the 3'-end (97.1% vs. 60%, p<0.0001 by Fisher's exact test) for distinguishing HCC (n = 120) from hepatitis (n = 35) and cirrhosis (n = 35). Encouragingly, 33.8% of the AFP-negative HCC contained the methylated GSTP1 gene. This study clearly demonstrates the importance of the location of CpG site methylation for HCC specificity and how liver-specific DNA methylation should be considered when an epigenetic DNA marker is studied for detection of HCC. PMID- 22536439 TI - JC virus encephalopathy is associated with a novel agnoprotein-deletion JCV variant. AB - JC virus encephalopathy (JCVE) is a newly described gray matter disease of the brain caused by productive infection of cortical pyramidal neurons. We characterized the full length sequence of JCV isolated from the brain of a JCVE patient, analyzed its distribution in various compartments by PCR, and determined viral gene expression in the brain by immunohistochemistry(IHC). We identified a novel JCV variant, JCV(CPN1), with a unique 143 bp deletion in the Agno gene encoding a truncated 10 amino acid peptide, and harboring an archetype-like regulatory region. This variant lacked one of three nuclear protein binding regions in the Agno gene. It was predominant in the brain, where it coexisted with an Agno-intact wild-type strain. Double immunostaining with anti-Agno and anti- VP1 antibodies demonstrated that the truncated JCV(CPN1) Agno peptide was present in the majority of cortical cells productively infected with JCV. We then screened 68 DNA samples from 8 brain, 30 CSF and 30 PBMC samples of PML patients, HIV+ and HIV- control subjects. Another JCV(CPN) strain with a different pattern of Agno-deletion was found in the CSF of an HIV+/PML patient, where it also coexisted with wild-type, Agno-intact JCV. These findings suggest that the novel tropism for cortical pyramidal neurons of JCV(CPN1), may be associated with the Agno deletion. Productive and lytic infection of these cells, resulting in fulminant JCV encephalopathy and death may have been facilitated by the co infection with a wild-type strain of JCV. PMID- 22536440 TI - VCP/p97, down-regulated by microRNA-129-5p, could regulate the progression of hepatocellular carcinoma. AB - Valosin containing protein (VCP)/p97 plays various important roles in cells. Moreover, elevated expression of VCP in hepatocellular carcinoma (HCC) is correlated with increased incidence of recurrence. But the role of VCP in HCC progression in vitro and in vivo is unclear. And there are few reports about the regulation mechanism on the expression of VCP in HCC. In this study, it was identified that the level of VCP was frequently increased in human HCC tissues. In addition, down-regulation of VCP with siRNAs could dramatically suppress the genesis and progression of tumor in vivo. It was found that miR-129-5p directly inhibited the expression of VCP in several HCC cell lines. Meanwhile, the level of VCP in HCC tissues was negatively associated with the level of miR-129-5p. Our further investigation showed that the enhanced expression of miR-129-5p also suppressed tumor growth in vivo. Moreover, it was revealed that miR-129-5p could inhibit the degradation of IkappaBalpha and increase the apoptosis and reduce the migration of HCC cells by suppressing the expression of VCP. Our results revealed that the expression of VCP was directly regulated by miR-129-5p and this regulation played an important role in the progression of HCC. PMID- 22536441 TI - Comparison of handaxes from Bose Basin (China) and the western Acheulean indicates convergence of form, not cognitive differences. AB - Alleged differences between Palaeolithic assemblages from eastern Asia and the west have been the focus of controversial discussion for over half a century, most famously in terms of the so-called 'Movius Line'. Recent discussion has centered on issues of comparability between handaxes from eastern Asian and 'Acheulean' examples from western portions of the Old World. Here, we present a multivariate morphometric analysis in order to more fully document how Mid Pleistocene (i.e. ~803 Kyr) handaxes from Bose Basin, China compare to examples from the west, as well as with additional (Mode 1) cores from across the Old World. Results show that handaxes from both the western Old World and Bose are significantly different from the Mode 1 cores, suggesting a gross comparability with regard to functionally-related form. Results also demonstrate overlap between the ranges of shape variation in Acheulean handaxes and those from Bose, demonstrating that neither raw material nor cognitive factors were an absolute impediment to Bose hominins in making comparable handaxe forms to their hominin kin west of the Movius Line. However, the shapes of western handaxes are different from the Bose examples to a statistically significant degree. Moreover, the handaxe assemblages from the western Old World are all more similar to each other than any individual assemblage is to the Bose handaxes. Variation in handaxe form is also comparatively high for the Bose material, consistent with suggestions that they represent an emergent, convergent instance of handaxe technology authored by Pleistocene hominins with cognitive capacities directly comparable to those of 'Acheulean' hominins. PMID- 22536442 TI - MicroRNA genes and their target 3'-untranslated regions are infrequently somatically mutated in ovarian cancers. AB - MicroRNAs are key regulators of gene expression and have been shown to have altered expression in a variety of cancer types, including epithelial ovarian cancer. MiRNA function is most often achieved through binding to the 3' untranslated region of the target protein coding gene. Mutation screening using massively-parallel sequencing of 712 miRNA genes in 86 ovarian cancer cases identified only 5 mutated miRNA genes, each in a different case. One mutation was located in the mature miRNA, and three mutations were predicted to alter the secondary structure of the miRNA transcript. Screening of the 3'-untranslated region of 18 candidate cancer genes identified one mutation in each of AKT2, EGFR, ERRB2 and CTNNB1. The functional effect of these mutations is unclear, as expression data available for AKT2 and EGFR showed no increase in gene transcript. Mutations in miRNA genes and 3'-untranslated regions are thus uncommon in ovarian cancer. PMID- 22536443 TI - Analysis of the Nse3/MAGE-binding domain of the Nse4/EID family proteins. AB - BACKGROUND: The Nse1, Nse3 and Nse4 proteins form a tight sub-complex of the large SMC5-6 protein complex. hNSE3/MAGEG1, the mammalian ortholog of Nse3, is the founding member of the MAGE (melanoma-associated antigen) protein family and the Nse4 kleisin subunit is related to the EID (E1A-like inhibitor of differentiation) family of proteins. We have recently shown that human MAGE proteins can interact with NSE4/EID proteins through their characteristic conserved hydrophobic pocket. METHODOLOGY/PRINCIPAL FINDINGS: Using mutagenesis and protein-protein interaction analyses, we have identified a new Nse3/MAGE binding domain (NMBD) of the Nse4/EID proteins. This short domain is located next to the Nse4 N-terminal kleisin motif and is conserved in all NSE4/EID proteins. The central amino acid residues of the human NSE4b/EID3 domain were essential for its binding to hNSE3/MAGEG1 in yeast two-hybrid assays suggesting they form the core of the binding domain. PEPSCAN ELISA measurements of the MAGEC2 binding affinity to EID2 mutant peptides showed that similar core residues contribute to the EID2-MAGEC2 interaction. In addition, the N-terminal extension of the EID2 binding domain took part in the EID2-MAGEC2 interaction. Finally, docking and molecular dynamic simulations enabled us to generate a structure model for EID2 MAGEC2. Combination of our experimental data and the structure modeling showed how the core helical region of the NSE4/EID domain binds into the conserved pocket characteristic of the MAGE protein family. CONCLUSIONS/SIGNIFICANCE: We have identified a new Nse4/EID conserved domain and characterized its binding to Nse3/MAGE proteins. The conservation and binding of the interacting surfaces suggest tight co-evolution of both Nse4/EID and Nse3/MAGE protein families. PMID- 22536444 TI - PKCalpha binds G3BP2 and regulates stress granule formation following cellular stress. AB - Protein kinase C (PKC) isoforms regulate a number of processes crucial for the fate of a cell. In this study we identify previously unrecognized interaction partners of PKCalpha and a novel role for PKCalpha in the regulation of stress granule formation during cellular stress. Three RNA-binding proteins, cytoplasmic poly(A)(+) binding protein (PABPC1), IGF-II mRNA binding protein 3 (IGF2BP3), and RasGAP binding protein 2 (G3BP2) all co-precipitate with PKCalpha. RNase treatment abolished the association with IGF2BP3 and PABPC1 whereas the PKCalpha G3BP2 interaction was largely resistant to this. Furthermore, interactions between recombinant PKCalpha and G3BP2 indicated that the interaction is direct and PKCalpha can phosphorylate G3BP2 in vitro. The binding is mediated via the regulatory domain of PKCalpha and the C-terminal RNA-binding domain of G3BP2. Both proteins relocate to and co-localize in stress granules, but not to P bodies, when cells are subjected to stress. Heat shock-induced stress granule assembly and phosphorylation of eIF2alpha are suppressed following downregulation of PKCalpha by siRNA. In conclusion this study identifies novel interaction partners of PKCalpha and a novel role for PKCalpha in regulation of stress granules. PMID- 22536445 TI - Prospective validation of FibroTest in comparison with liver stiffness for predicting liver fibrosis in Asian subjects with chronic hepatitis B. AB - BACKGROUND AND AIMS: Diagnostic values of FibroTest (FT) for hepatic fibrosis have rarely been assessed in Asian chronic hepatitis B (CHB) patients. We aimed to validate its diagnostic performances in comparison with liver stiffness (LS). METHODS: From 2008 to 2010, 194 CHB patients who underwent liver biopsies along with FT and transient elastography were prospectively enrolled. Fibrosis stage was assessed according to the Batts and Ludwig system. RESULTS: To predict significant fibrosis (F>=2), advanced fibrosis (F>=3), and cirrhosis (F = 4), areas under receiver operating characteristic curves (AUROCs) of FT were 0.903, 0.907, and 0.866, comparable to those of LS (0.873, 0.897, and 0.910, respectively). Optimized cutoffs of FT to maximize sum of sensitivity and specificity were 0.32, 0.52, and 0.68 for F>=2, F>=3, and F = 4, while those of LS were 8.8, 10.2, and 14.1 kPa, respectively. According to FT and LS cutoffs, 123 (63.4%) and 124 (63.9%) patients were correctly classified consistent with histological fibrosis (F1, F2, F3, and F4), respectively. Overall concordance between each fibrosis stage estimated by FT and LS was observed in 111 patients, where 88 were correctly classified with histological results. A combination formula adding LS to FT (LS+FT) showed similar AUROC levels (0.885, 0.905, and 0.915), while another multiplying LS by FT (LS*FT) showed the best AUROCs (0.941, 0.931, and 0.929 for F>=2, F>=3, and F4, respectively). CONCLUSIONS: FT provides good fibrosis prediction, with comparable outcomes to LS in Asian CHB patients. FT substantially reduces need for liver biopsy, especially when used in combination with LS. PMID- 22536446 TI - DW-MRI as a biomarker to compare therapeutic outcomes in radiotherapy regimens incorporating temozolomide or gemcitabine in glioblastoma. AB - The effectiveness of the radiosensitizer gemcitabine (GEM) was evaluated in a mouse glioma along with the imaging biomarker diffusion-weighted magnetic resonance imaging (DW-MRI) for early detection of treatment effects. A genetically engineered murine GBM model [Ink4a-Arf(-/-) Pten(loxP/loxP)/Ntv-a RCAS/PDGF(+)/Cre(+)] was treated with gemcitabine (GEM), temozolomide (TMZ) +/- ionizing radiation (IR). Therapeutic efficacy was quantified by contrast-enhanced MRI and DW-MRI for growth rate and tumor cellularity, respectively. Mice treated with GEM, TMZ and radiation showed a significant reduction in growth rates as early as three days post-treatment initiation. Both combination treatments (GEM/IR and TMZ/IR) resulted in improved survival over single therapies. Tumor diffusion values increased prior to detectable changes in tumor volume growth rates following administration of therapies. Concomitant GEM/IR and TMZ/IR was active and well tolerated in this GBM model and similarly prolonged median survival of tumor bearing mice. DW-MRI provided early changes to radiosensitization treatment warranting evaluation of this imaging biomarker in clinical trials. PMID- 22536448 TI - Plastic traits of an exotic grass contribute to its abundance but are not always favourable. AB - In herbaceous ecosystems worldwide, biodiversity has been negatively impacted by changed grazing regimes and nutrient enrichment. Altered disturbance regimes are thought to favour invasive species that have a high phenotypic plasticity, although most studies measure plasticity under controlled conditions in the greenhouse and then assume plasticity is an advantage in the field. Here, we compare trait plasticity between three co-occurring, C(4) perennial grass species, an invader Eragrostis curvula, and natives Eragrostis sororia and Aristida personata to grazing and fertilizer in a three-year field trial. We measured abundances and several leaf traits known to correlate with strategies used by plants to fix carbon and acquire resources, i.e. specific leaf area (SLA), leaf dry matter content (LDMC), leaf nutrient concentrations (N, C:N, P), assimilation rates (Amax) and photosynthetic nitrogen use efficiency (PNUE). In the control treatment (grazed only), trait values for SLA, leaf C:N ratios, Amax and PNUE differed significantly between the three grass species. When trait values were compared across treatments, E. curvula showed higher trait plasticity than the native grasses, and this correlated with an increase in abundance across all but the grazed/fertilized treatment. The native grasses showed little trait plasticity in response to the treatments. Aristida personata decreased significantly in the treatments where E. curvula increased, and E. sororia abundance increased possibly due to increased rainfall and not in response to treatments or invader abundance. Overall, we found that plasticity did not favour an increase in abundance of E. curvula under the grazed/fertilized treatment likely because leaf nutrient contents increased and subsequently its' palatability to consumers. E. curvula also displayed a higher resource use efficiency than the native grasses. These findings suggest resource conditions and disturbance regimes can be manipulated to disadvantage the success of even plastic exotic species. PMID- 22536447 TI - Vimentin and PSF act in concert to regulate IbeA+ E. coli K1 induced activation and nuclear translocation of NF-kappaB in human brain endothelial cells. AB - BACKGROUND: IbeA-induced NF-kappaB signaling through its primary receptor vimentin as well as its co-receptor PSF is required for meningitic E. coli K1 penetration and leukocyte transmigration across the blood-brain barrier (BBB), which are the hallmarks of bacterial meningitis. However, it is unknown how vimentin and PSF cooperatively contribute to IbeA-induced cytoplasmic activation and nuclear translocation of NF-kappaB, which are required for bacteria-mediated pathogenicities. METHODOLOGY/PRINCIPAL FINDINGS: IbeA-induced E. coli K1 invasion, polymorphonuclear leukocyte (PMN) transmigration and IKK/NF-kappaB activation are blocked by Caffeic acid phenethyl ester (CAPE), an inhibitor of NF kappaB. IKKalpha/beta phosphorylation is blocked by ERK inhibitors. Co immunoprecipitation analysis shows that vimentin forms a complex with IkappaB, NF kappaB and tubulins in the resting cells. A dissociation of this complex and a simultaneous association of PSF with NF-kappaB could be induced by IbeA in a time dependent manner. The head domain of vimentin is required for the complex formation. Two cytoskeletal components, vimentin filaments and microtubules, contribute to the regulation of NF-kappaB. SiRNA-mediated knockdown studies demonstrate that IKKalpha/beta phosphorylation is completely abolished in HBMECs lacking vimentin and PSF. Phosphorylation of ERK and nuclear translocation of NF kappaB are entirely dependent on PSF. These findings suggest that vimentin and PSF cooperatively contribute to IbeA-induced cytoplasmic activation and nuclear translocation of NF-kappaB activation. PSF is essential for translocation of NF kappaB and ERK to the nucleus. CONCLUSION/SIGNIFICANCE: These findings reveal previously unappreciated facets of the IbeA-binding proteins. Cooperative contributions of vimentin and PSF to IbeA-induced cytoplasmic activation and nuclear translocation of NF-kappaB may represent a new paradigm in pathogen induced signal transduction and lead to the development of novel strategies for the prevention and treatment of bacterial meningitis. PMID- 22536449 TI - MyD88 associated ROS generation is crucial for Lactobacillus induced IL-12 production in macrophage. AB - It is well known that some strains of lactic acid bacteria (LAB) can induce IL-12 which plays an important role in modulating immune responses. However, the mechanisms by which LAB induce IL-12 production remain unclear. Here, we examine the role of toll-like receptors (TLR's) and reactive oxygen species (ROS) in IL 12 production by LAB stimulated peritoneal macrophages. Our results indicate that a TLR is not necessary for IL-12 induction by LAB, whilst the universal adaptor protein, MyD88, is essential. Specific strains of LAB induced ROS that correlated with both the frequency of phagocytosis and IL-12 production. Reduction in IL-12 production by NADPH oxidase inhibitors or ROS scavengers demonstrates the crucial role of ROS in IL-12 induction. Interestingly, deficiency of TLR2, 4, 9 or MyD88 did not affect the phagocytosis of LAB strain KW3110, a potent IL-12 inducer, and ROS production was significantly reduced only in MyD88 deficient macrophages. These results suggest the existence of TLR-MyD88 independent LAB recognition and MyD88 related ROS induction mechanisms. We show here the importance of ROS for IL 12 induction and provide new insights into IL-12 induction by LAB. PMID- 22536450 TI - PCR primers for metazoan mitochondrial 12S ribosomal DNA sequences. AB - BACKGROUND: Assessment of the biodiversity of communities of small organisms is most readily done using PCR-based analysis of environmental samples consisting of mixtures of individuals. Known as metagenetics, this approach has transformed understanding of microbial communities and is beginning to be applied to metazoans as well. Unlike microbial studies, where analysis of the 16S ribosomal DNA sequence is standard, the best gene for metazoan metagenetics is less clear. In this study we designed a set of PCR primers for the mitochondrial 12S ribosomal DNA sequence based on 64 complete mitochondrial genomes and then tested their efficacy. METHODOLOGY/PRINCIPAL FINDINGS: A total of the 64 complete mitochondrial genome sequences representing all metazoan classes available in GenBank were downloaded using the NCBI Taxonomy Browser. Alignment of sequences was performed for the excised mitochondrial 12S ribosomal DNA sequences, and conserved regions were identified for all 64 mitochondrial genomes. These regions were used to design a primer pair that flanks a more variable region in the gene. Then all of the complete metazoan mitochondrial genomes available in NCBI's Organelle Genome Resources database were used to determine the percentage of taxa that would likely be amplified using these primers. Results suggest that these primers will amplify target sequences for many metazoans. CONCLUSIONS/SIGNIFICANCE: Newly designed 12S ribosomal DNA primers have considerable potential for metazoan metagenetic analysis because of their ability to amplify sequences from many metazoans. PMID- 22536451 TI - Enhanced brain disposition and effects of Delta9-tetrahydrocannabinol in P glycoprotein and breast cancer resistance protein knockout mice. AB - The ABC transporters P-glycoprotein (P-gp, Abcb1) and breast cancer resistance protein (Bcrp, Abcg2) regulate the CNS disposition of many drugs. The main psychoactive constituent of cannabis Delta(9)-tetrahydrocannabinol (THC) has affinity for P-gp and Bcrp, however it is unknown whether these transporters modulate the brain accumulation of THC and its functional effects on the CNS. Here we aim to show that mice devoid of Abcb1 and Abcg2 retain higher brain THC levels and are more sensitive to cannabinoid-induced hypothermia than wild-type (WT) mice. Abcb1a/b (-/-), Abcg2 (-/-) and wild-type (WT) mice were injected with THC before brain and blood were collected and THC concentrations determined. Another cohort of mice was examined for THC-induced hypothermia by measuring rectal body temperature. Brain THC concentrations were higher in both Abcb1a/b ( /-) and Abcg2 (-/-) mice than WT mice. ABC transporter knockout mice exhibited delayed elimination of THC from the brain with the effect being more prominent in Abcg2 (-/-) mice. ABC transporter knockout mice were more sensitive to THC induced hypothermia compared to WT mice. These results show P-gp and Bcrp prolong the brain disposition and hypothermic effects of THC and offer a novel mechanism for both genetic vulnerability to the psychoactive effects of cannabis and drug interactions between CNS therapies and cannabis. PMID- 22536452 TI - Circular permutation in the Omega-loop of TEM-1 beta-lactamase results in improved activity and altered substrate specificity. AB - Generating diverse protein libraries that contain improved variants at a sufficiently high frequency is critical for improving the properties of proteins using directed evolution. Many studies have illustrated how random mutagenesis, cassette mutagenesis, DNA shuffling and similar approaches are effective diversity generating methods for directed evolution. Very few studies have explored random circular permutation, the intramolecular relocation of the N- and C-termini of a protein, as a diversity-generating step for directed evolution. We subjected a library of random circular permutations of TEM-1 beta-lactamase to selections on increasing concentrations of a variety of beta-lactam antibiotics including cefotaxime. We identified two circularly permuted variants that conferred elevated resistance to cefotaxime but decreased resistance to other antibiotics. These variants were circularly permuted in the Omega-loop proximal to the active site. Remarkably, one variant was circularly permuted such that the key catalytic residue Glu166 was located at the N-terminus of the mature protein. PMID- 22536453 TI - Lineages, sub-lineages and variants of enterovirus 68 in recent outbreaks. AB - Enterovirus 68 (EV68) was first isolated in 1962. Very few cases of EV68 infection were described over the ensuing 40 years. However, in the past few years, an increase in severe respiratory tract infections associated with EV68 has been reported. We identified two clusters of EV68 infection in South London, UK, one each in the autumn/winters of 2009 and 2010. Sequence comparison showed significant homology of the UK strains with those from other countries including the Netherlands, Japan and the Philippines, which reported EV68 outbreaks between 2008 and 2010. Phylogenetic analysis of all available VP1 sequences indicated the presence of two modern EV68 lineages. The 2010 UK strains belonged to lineage 2. Lineage 1 could be further divided into two sub-lineages: some Japanese and Dutch strains collected between 2004 and 2010 form a distinct sub-lineages (sub-lineage 1.1), whereas other strains from the UK, Japan, Netherlands and Philippines collected between 2008 and 2010 represent sub-lineage 1.2. The UK 2009 strains together with several Dutch and Japanese strains from 2009/2010 represents one variant (1.2.1), whereas those from the Philippines a second variant (1.2.2). Based on specific deletions and substitutions, we suggest rules for the assignment of lineages and sub-lineages. Molecular epidemiological analysis indicates rapid recent evolution of EV68 and this may explain the recent findings of a global resurgence of EV68. Continuous global monitoring of the clinical and molecular epidemiology of EV68 is recommended. PMID- 22536454 TI - Spermatogonial stem cells (SSCs) in buffalo (Bubalus bubalis) testis. AB - BACKGROUND: Water buffalo is an economically important livestock species and about half of its total world population exists in India. Development of stem cell technology in buffalo can find application in targeted genetic modification of this species. Testis has emerged as a source of pluripotent stem cells in mice and human; however, not much information is available in buffalo. OBJECTIVES AND METHODS: Pou5f1 (Oct 3/4) is a transcription factor expressed by pluripotent stem cells. Therefore, in the present study, expression of POU5F1 transcript and protein was examined in testes of both young and adult buffaloes by semi quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemical analysis. Further, using the testis transplantation assay, a functional assay for spermatogonial stem cells (SSCs), stem cell potential of gonocytes/spermatogonia isolated from prepubertal buffalo testis was also determined. RESULTS: Expression of POU5F1 transcript and protein was detected in prepubertal and adult buffalo testes. Western blot analysis revealed that the POU5F1 protein in the buffalo testis exists in two isoforms; large (~47 kDa) and small (~21 kDa). Immunohistochemical analysis revealed that POU5F1 expression in prepubertal buffalo testis was present in gonocytes/spermatogonia and absent from somatic cells. In the adult testis, POU5F1 expression was present primarily in post-meiotic germ cells such as round spermatids, weakly in spermatogonia and spermatocytes, and absent from elongated spermatids. POU5F1 protein expression was seen both in cytoplasm and nuclei of the stained germ cells. Stem cell potential of prepubertal buffalo gonocytes/spermatogonia was confirmed by the presence of colonized DBA-stained cells in the basal membrane of seminiferous tubules of xenotransplanted mice testis. CONCLUSION/SIGNIFICANCE: These findings strongly indicate that gonocytes/spermatogonia, isolated for prepubertal buffalo testis can be a potential target for establishing a germ stem cell line that would enable genetic modification of buffaloes. PMID- 22536455 TI - The DNA glycosylases Ogg1 and Nth1 do not contribute to Ig class switching in activated mouse splenic B cells. AB - During activation of B cells to undergo class switching, B cell metabolism is increased, and levels of reactive oxygen species (ROS) are increased. ROS can oxidize DNA bases resulting in substrates for the DNA glycosylases Ogg1 and Nth1. Ogg1 and Nth1 excise oxidized bases, and nick the resulting abasic sites, forming single-strand DNA breaks (SSBs) as intermediates during the repair process. In this study, we asked whether splenic B cells from mice deficient in these two enzymes would show altered class switching and decreased DNA breaks in comparison with wild-type mice. As the c-myc gene frequently recombines with the IgH S region in B cells induced to undergo class switching, we also analyzed the effect of deletion of these two glycosylases on DSBs in the c-myc gene. We did not detect a reduction in S region or c-myc DSBs or in class switching in splenic B cells from Ogg1- or Nth1-deficient mice or from mice deficient in both enzymes. PMID- 22536457 TI - Three-Dimensional Structure Determination from Common Lines in Cryo-EM by Eigenvectors and Semidefinite Programming(). AB - The cryo-electron microscopy reconstruction problem is to find the three dimensional (3D) structure of a macromolecule given noisy samples of its two dimensional projection images at unknown random directions. Present algorithms for finding an initial 3D structure model are based on the "angular reconstitution" method in which a coordinate system is established from three projections, and the orientation of the particle giving rise to each image is deduced from common lines among the images. However, a reliable detection of common lines is difficult due to the low signal-to-noise ratio of the images. In this paper we describe two algorithms for finding the unknown imaging directions of all projections by minimizing global self-consistency errors. In the first algorithm, the minimizer is obtained by computing the three largest eigenvectors of a specially designed symmetric matrix derived from the common lines, while the second algorithm is based on semidefinite programming (SDP). Compared with existing algorithms, the advantages of our algorithms are five-fold: first, they accurately estimate all orientations at very low common-line detection rates; second, they are extremely fast, as they involve only the computation of a few top eigenvectors or a sparse SDP; third, they are nonsequential and use the information in all common lines at once; fourth, they are amenable to a rigorous mathematical analysis using spectral analysis and random matrix theory; and finally, the algorithms are optimal in the sense that they reach the information theoretic Shannon bound up to a constant for an idealized probabilistic model. PMID- 22536458 TI - LETTER TO THE EDITOR Abnormal Responses of Keloid Tissue to Wounding Identified Using In Vitro Model System. PMID- 22536459 TI - Barbed screw through the hand. PMID- 22536456 TI - Use of cell-SELEX to generate DNA aptamers as molecular probes of HPV-associated cervical cancer cells. AB - BACKGROUND: Disease-specific biomarkers are an important tool for the timely and effective management of pathological conditions, including determination of susceptibility, diagnosis, and monitoring efficacy of preventive or therapeutic strategies. Aptamers, comprising single-stranded or double-stranded DNA or RNA, can serve as biomarkers of disease or biological states. Aptamers can bind to specific epitopes on macromolecules by virtue of their three dimensional structures and, much like antibodies, aptamers can be used to target specific epitopes on the basis of their molecular shape. The Systematic Evolution of Ligands by EXponential enrichment (SELEX) is the approach used to select high affinity aptamers for specific macromolecular targets from among the >10(13) oligomers comprising typical random oligomer libraries. In the present study, we used live cell-based SELEX to identify DNA aptamers which recognize cell surface differences between HPV-transformed cervical carcinoma cancer cells and isogenic, nontumorigenic, revertant cell lines. METHODOLOGY/PRINCIPAL FINDINGS: Whole-cell SELEX methodology was adapted for use with adherent cell lines (which we termed Adherent Cell-SELEX (AC-SELEX)). Using this approach, we identified high affinity aptamers (nanomolar range K(d)) to epitopes specific to the cell surface of two nontumorigenic, nontumorigenic revertants derived from the human cervical cancer HeLa cell line, and demonstrated the loss of these epitopes in another human papillomavirus transformed cervical cancer cell line (SiHa). We also performed preliminary investigation of the aptamer epitopes and their binding characteristics. CONCLUSIONS/SIGNIFICANCE: Using AC-SELEX we have generated several aptamers that have high affinity and specificity to the nontumorigenic, revertant of HPV-transformed cervical cancer cells. These aptamers can be used to identify new biomarkers that are related to carcinogenesis. Panels of aptamers, such as these may be useful in predicting the tumorigenic potential and properties of cancer biopsies and aid in the effective management of pathological conditions (diagnosis, predicted outcome, and treatment options). PMID- 22536460 TI - Lower lip necrosis. PMID- 22536461 TI - Accessory breast tissue. PMID- 22536462 TI - FAST WAVELET-BASED SINGLE-PARTICLE RECONSTRUCTION IN CRYO-EM. AB - This paper presents a novel algorithm for the 3D tomographic inversion problem that arises in single-particle electron cryo-microscopy (Cryo-EM). It is based on two key components: 1) a variational formulation that promotes sparsity in the wavelet domain and 2) the Toeplitz structure of the combined projection/back projection operator. The first idea has proven to be very effective for the recovery of piecewise-smooth signals, which is confirmed by our numerical experiments. The second idea allows for a computationally efficient implementation of the reconstruction procedure, using only one circulant convolution per iteration. PMID- 22536464 TI - Renal cell carcinoma in kidney transplant recipients and dialysis patients. AB - PURPOSE: In a group of surgery patients diagnosed with renal cell cancer, those who underwent dialysis were compared with those who received a kidney transplant. MATERIALS AND METHODS: The 43 subjects included in this study were patients who had been undergoing dialysis because of end-stage renal disease or had undergone kidney transplantation. The patients were diagnosed with renal cell carcinoma (RCC) during follow-up and underwent radical nephrectomy from May 1996 to December 2010. Their medical records were retrospectively analyzed as part of the study. RESULTS: In the transplantation group, the renal replacement therapy period averaged 54 months, and the period from transplantation to RCC averaged 119 months (range, 0 to 264 months). In the dialysis group, RCC was observed after an average of 124 months (range, 2 to 228 months) of dialysis, and nephrectomy was then conducted. Acquired cystic kidney disease (ACKD) was found more frequently in the dialysis group, and it had a statistically relevant effect on the occurrence of RCC by comparison with the transplantation group (p<0.01). CONCLUSIONS: Although the incidence rate of ACKD was significantly higher in the dialysis group among patients undergoing surgery for RCC, cancer was found even without ACKD development in some transplant recipients. Considering that the transplant recipients also underwent dialysis, an informative prospective study will be necessary to determine whether other immunosuppressive agents besides ACKD may function as a cancer risk factor. PMID- 22536463 TI - Current status of targeted therapy for advanced renal cell carcinoma. AB - The treatment of metastatic renal cell carcinoma (mRCC) has recently evolved from being predominantly cytokine-based treatment to the use of targeted agents, which include sorafenib, sunitinib, bevacizumab (plus interferon alpha [IFN-alpha]), temsirolimus, everolimus, pazopanib, and most recently, axitinib. Improved understanding of the molecular pathways implicated in the pathogenesis of RCC has led to the development of specific targeted therapies for treating the disease. In Korea, it has been 5 years since targeted therapy became available for mRCC. Thus, we now have broader and better therapeutic options at hand, leading to a significantly improved prognosis for patients with mRCC. However, the treatment of mRCC remains a challenge and a major health problem. Many questions remain on the efficacy of combination treatments and on the best methods for achieving complete remission. Additional studies are needed to optimize the use of these agents by identifying those patients who would most benefit and by elucidating the best means of delivering these agents, either in combination or as sequential single agents. Furthermore, numerous ongoing research activities aim at improving the benefits of the new compounds in the metastatic situation or their application in the early phase of the disease. This review introduces what is currently known regarding the fundamental biology that underlies clear cell RCC, summarizes the clinical evidence supporting the benefits of targeted agents in mRCC treatment, discusses survival endpoints used in pivotal clinical trials, and outlines future research directions. PMID- 22536465 TI - Discontinuation of anticoagulant or antiplatelet therapy for transrectal ultrasound-guided prostate biopsies: a single-center experience. AB - PURPOSE: Historically, it was thought that hemorrhagic complications were increased with transrectal ultrasound-guided prostate biopsies (TRUS biopsy) of patients receiving anticoagulation/antiplatelet therapy. However, the current literature supports the continuation of anticoagulation/antiplatelet therapy without additional morbidity. We assessed our experience regarding the continuation of anticoagulation/antiplatelet therapy during TRUS biopsy. MATERIALS AND METHODS: A total of 91 and 98 patients were included in the anticoagulation/antiplatelet (group I) and control (group II) groups, respectively. Group I subgroups consisted of patients on monotherapy or dual therapy of aspirin, warfarin, clopidogrel, or low molecular weight heparin. The TRUS biopsy technique was standardized to 12 cores from the peripheral zones. Patients completed a questionnaire over the 7 days following TRUS biopsy. The questionnaire was designed to assess the presence of hematuria, rectal bleeding, and hematospermia. Development of rectal pain, fever, and emergency hospital admissions following TRUS biopsy were also recorded. RESULTS: The patients' mean age was 65 years (range, 52 to 74 years) and 63.5 years (range, 54 to 74 years) in groups I and II, respectively. The overall incidence of hematuria was 46% in group I compared with 63% in group II (p=0.018). The incidence of hematospermia was 6% and 10% in groups I and II, respectively. The incidence of rectal bleeding was similar in group I (40%) and group II (39%). Statistical analysis was conducted by using Fisher exact test. CONCLUSIONS: There were fewer hematuria episodes in anticoagulation/antiplatelet patients. This study suggests that it is not necessary to discontinue anticoagulation/antiplatelet treatment before TRUS biopsy. PMID- 22536466 TI - Meta-analysis of studies analyzing the role of human papillomavirus in the development of bladder carcinoma. AB - PURPOSE: We aimed to ascertain the degree of association between bladder cancer and human papillomavirus (HPV) infection. MATERIALS AND METHODS: We performed a meta-analysis of observational studies with cases and controls with publication dates up to January 2011. The PubMed electronic database was searched by using the key words "bladder cancer and virus." Twenty-one articles were selected that met the required methodological criteria. We implemented an internal quality control system to verify the selected search method. We analyzed the pooled effect of all the studies and also analyzed the techniques used as follows: 1) studies with DNA-based techniques, among which we found studies with polymerase chain reaction (PCR)-based techniques and 2) studies with non-PCR-based techniques, and studies with non-DNA-based techniques. RESULTS: Taking into account the 21 studies that were included in the meta-analysis, we obtained a heterogeneity chi-squared value of Q(exp)=26.45 (p=0.383). The pooled odds ratio (OR) was 2.13 (95% confidence interval [CI], 1.54 to 2.95), which points to a significant effect between HPV and bladder cancer. Twenty studies assessed the presence of DNA. The overall effect showed a significant relationship between virus presence and bladder cancer, with a pooled OR of 2.19 (95% CI, 1.40 to 3.43). Of the other six studies, four examined the virus's capsid antigen and two detected antibodies in serum by Western blot. The estimated pooled OR in this group was 2.11 (95% CI, 1.27 to 3.51), which confirmed the relationship between the presence of virus and cancer. CONCLUSIONS: The pooled OR value showed a moderate relationship between viral infection and bladder tumors. PMID- 22536467 TI - alpha-blocker monotherapy and alpha-blocker plus 5-alpha-reductase inhibitor combination treatment in benign prostatic hyperplasia; 10 years' long-term results. AB - PURPOSE: We compared the effects of alpha-adrenergic receptor blocker (alpha blocker) monotherapy with those of combination therapy with alpha-blocker and 5 alpha-reductase inhibitor (5-ARI) on benign prostatic hyperplasia (BPH) progression for over 10 years. MATERIALS AND METHODS: A total of 620 patients with BPH who received alpha-blocker monotherapy (alpha-blocker group, n=368) or combination therapy (combination group, n=252) as their initial treatment were enrolled from January 1989 to June 2000. The incidences of acute urinary retention (AUR) and BPH-related surgery were compared between the two groups. Incidences stratified by follow-up period, prostate-specific antigen (PSA), and prostate volume (PV) were compared between the two groups. RESULTS: The incidence of AUR was 13.6% (50/368) in the alpha-blocker group and 2.8% (7/252) in the combination group (p<0.001). A total of 8.4% (31/368) and 3.2% (8/252) of patients underwent BPH-related surgery in the alpha-blocker and combination groups, respectively (p=0.008). According to the follow-up period, the incidence of AUR was significantly decreased in combination group. However, the incidence of BPH-related surgery was significantly reduced after 7 years of combination therapy. Cutoff levels of PSA and PV for reducing the incidences of AUR and BPH related surgery were 2.0 ng/ml and 35 g, respectively (p<0.001). CONCLUSIONS: Long-term combination therapy with alpha-blocker and 5-ARI can suppress the progression of BPH more efficiently than alpha-blocker monotherapy. For patients with BPH with PSA >2.0 ng/ml or PV >35 ml, combination therapy promises a better effect for reducing the risk of BPH progression. PMID- 22536468 TI - Transitional zone index and intravesical prostatic protrusion in benign prostatic hyperplasia patients: correlations according to treatment received and other clinical data. AB - PURPOSE: The aim of this research was to assess the value of the transitional zone index (TZI) and intravesical prostatic protrusion (IPP) from transrectal ultrasonography in evaluating the severity and progression of disease by analyzing the relationship between the 2 parameters and symptoms, clinical history, and urodynamics in benign prostatic hyperplasia (BPH) patients undergoing different treatment. MATERIALS AND METHODS: A total of 203 patients receiving medication and 162 patients who underwent transurethral resection of the prostate because of BPH were enrolled in this retrospective analysis. The clinical history and subjective and objective examination results of all patients were recorded and compared after being classified by TZI and IPP level. Linear regression was used to find correlations between IPP, TZI, and urodynamics. RESULTS: The 2 parameters were found to differ significantly between patients receiving medication and patients undergoing surgical therapy (p<0.05). PSA, maximum flow rate (Qmax), detrusor pressure at Qmax (PdetQmax), and the bladder outlet obstruction index (BOOI) differed according to various TZI levels (p<0.05). In addition, the voiding symptom score, Qmax, and BOOI of subgroups with various IPP levels were also significantly different (p<0.05). Both TZI and IPP had significant effects on Qmax, BOOI, and PdetQmax (p<0.05) and the incidence of acute urinary retention (p=0.000). CONCLUSIONS: The results demonstrated that both TZI and IPP had favorable value for assessing severity and progression in patients with BPH. Further studies are needed to confirm whether the two parameters have predictive value in the efficacy of BPH treatment and could be considered as factors in the selection of therapy. PMID- 22536469 TI - Randomized controlled study of MONARC(r) vs. tension-free vaginal tape obturator (TVT-O(r)) in the treatment of female urinary incontinence: comparison of 3-year cure rates. AB - PURPOSE: Transobturator approaches to midurethral sling surgery are one of the most commonly performed operations for female stress urinary incontinence throughout the world. However, very few results of randomized clinical trials of transobturator midurethral sling surgery (MONARC vs. TVT-O) for the treatment of female urinary incontinence have been reported. In this study, we compared the 3 year follow-up cure rates of these two procedures. MATERIALS AND METHODS: From July 2006 to June 2008, 74 patients who had undergone MONARC (35 patients) or TVT O (39 patients) were included in the study and were analyzed prospectively. The mean follow-up duration of both groups was 39.2 months. Preoperative and postoperative evaluations included physical examination, uroflowmetry and postvoid residual measurement, involuntary urine loss with physical activity, and urinary symptoms. Cure of female urinary incontinence was defined as patient report of no loss of urine upon physical activity. The patients' satisfaction after treatment was rated as very satisfied, satisfied, equivocal, and unsatisfied. Very satisfied and satisfied were considered as the satisfied rate. RESULTS: There were no significant differences in preoperative patient characteristics, postoperative complications, or success rate between the two groups. The cure rate of the MONARC and TVT-O groups was 85.7% and 84.6%, respectively. The patient satisfaction (very satisfied, satisfied) rate of the MONARC and TVT-O groups was 82.8% and 82.1%, respectively. CONCLUSIONS: The MONARC and TVT-O procedures were equally efficient for the treatment of female urinary incontinence, with maintenance of high cure rates for 3 years. Longer follow-up is needed to confirm these results. PMID- 22536470 TI - Prevalence and correlates of nocturia in community-dwelling older men: results from the korean longitudinal study on health and aging. AB - PURPOSE: To determine the prevalence and correlates of nocturia in Korean community-dwelling older men. MATERIALS AND METHODS: A study population of 439 Korean elderly men (>=65 years of age, including 299 men from a randomly sampled population) was sampled from residents of Seongnam, Korea. Standardized face-to face interviews and questionnaires were performed. In-person interviews solicited sociodemographic information, medical history, Mini-Mental State Examination (MMSE) score, and measurement of body mass index. Transrectal ultrasonography and laboratory tests including urinalysis and measurement of creatinine and prostate specific antigen were performed. For the analysis of prevalence, 299 randomly sampled men were included. Men who answered the International Prostate Symptom Score questionnaire (n=424) were included in the analysis of the correlates of nocturia. Nocturia was defined as having to get up to urinate two or more times per night (>=2). RESULTS: The overall prevalence of nocturia was 56.0% for community-dwelling older men. There was a significant correlation between age and the prevalence of nocturia (p<0.001). The univariate analysis revealed a significant association between nocturia and MMSE score (odds ratio [OR], 0.88; p<0.001), history of benign prostatic hyperplasia (BPH) (OR, 2.85; p=0.003), alpha-blocker usage (OR, 2.79; p=0.018), alcohol consumption (OR, 0.65; p=0.035), and smoking (OR, 0.58; p=0.025). Age, duration of education, MMSE score, and prostate volume were also significantly associated with nocturia. In the multivariate regression analysis using forward elimination, nocturia was significantly associated with a history of BPH and MMSE score. CONCLUSIONS: The prevalence of nocturia was 56.0% in Korean community-dwelling older men. Nocturia was associated with age and a history of BPH. MMSE score was protective. PMID- 22536471 TI - Influence of overweight on 24-hour urine chemistry studies and recurrent urolithiasis in children. AB - PURPOSE: We investigated the influence of overweight on 24-hour urine chemistry studies and recurrent urolithiasis (UL) in children. MATERIALS AND METHODS: A retrospective cohort study was designed to assess children who presented with UL at a pediatric institution between 1985 and 2010. We calculated body mass index percentile (BMIp) adjusted for gender and age according to the 2007 Korean Children and Adolescents Growth Chart and stratified the children into 3 BMI categories: lower body weight (LBW, BMIp<=10), normal BW (NBW, 10=85). Twenty-four hour urine chemistry studies (urine volume, creatinine, calcium, oxalate, citrate, and pH) were compared between the 3 BMIp groups. Univariate and multivariate analyses were performed to assess independent risk factors for stone recurrence. RESULTS: A total of 125 patients were included. The age of the patients in the NBW group was older than that of patients in the LBW group, but 24-hour urine chemistry studies did not differ significantly between the three groups. Mean urine citrate levels were lower (0.273+/-0.218 mg/mg/d vs. 0.429+/-0.299 mg/mg/d, p<0.05) and the incidence of hypocitraturia was higher (81.5% vs. 45.7%, p<0.05)) in the recurrent stone former group. In the univariate analysis, hypocitraturia and acidic urinary pH were risk factors, but in the multivariate analysis, only hypocitraturia was a risk factor for stone recurrence (hazard ratio, 3.647; 95% confidence interval, 1.047 to 12.703). In the Kaplan-Meier curve, the hypocitraturia group showed higher recurrence than did the normocitraturia group (p<0.05). CONCLUSIONS: Unlike in adults, in children, overweight adjusted for gender and age was not associated with 24-hour urine chemistry studies and was not a risk factor for recurrent UL. Hypocitraturia was the only risk factor for UL in children. PMID- 22536472 TI - Efficacy and safety of propiverine in children with overactive bladder. AB - PURPOSE: Antimuscarinic therapy remains one of the most common forms of therapy for overactive bladder (OAB) in children. However, few clinical studies on the outcomes of antimuscarinics in children with OAB have been published. Therefore, we evaluated the efficacy and safety of propiverine, which is frequently prescribed for the treatment of pediatric OAB. MATERIALS AND METHODS: We retrospectively reviewed children with OAB treated with propiverine within the past 5 years. The response rates were compared between the non-urge incontinence (non-UI) and urge incontinence (UI groups). The cumulative response rate by treatment duration was also compared between the two groups. RESULTS: Among a total of 68 children, 50 children (73.5%) experienced UI. The overall response rate was 86.8%. Functional bladder capacity after treatment was 150 ml, which represented an increase compared with the value (140 ml) before treatment. The voiding frequency per day decreased from 14.0 to 8.5 times. The overall response rate (88.0%) in the non-UI group was not significantly different from that seen in the UI group (83.3%; p>0.05). In non-UI children, the cumulative response rates were 36.0%, 54.0%, 68.0%, 74.0%, 76.0%, and 78.0% at 4, 8, 12, 16, 20, and 24 weeks, respectively. The cumulative response rates in the UI children were 11.1%, 33.3%, 44.4%, 50.0%, 50.0%, and 55.6%, respectively during the same respective time periods. Adverse effects were identified in only two (2.9%) patients, and neither case was severe. CONCLUSIONS: Propiverine is effective and well tolerated as a treatment for children suffering from OAB with or without UI. PMID- 22536473 TI - Fate of abstracts presented at the annual meeting of the korean urological association. AB - PURPOSE: The acceptance rate for journal publication of the abstracts presented at the annual Korean Urological Association (KUA) meeting, the time to publication, and the effect of abstract characteristics on the publication pattern were analyzed and compared with data for abstracts from other major urological meetings. MATERIALS AND METHODS: A total of 1,005 abstracts listed in the abstract books of the 2006 (58th) and 2007 (59th) annual KUA meetings were analyzed, and their subsequent publication as listed in PubMed or KoreaMed between August 2006 and August 2011 was evaluated. RESULTS: A total of 41.59% of abstracts were published as full-length reports. Abstracts on sexual dysfunction, neurourology, prostate cancer, basic research, and benign prostatic hyperplasia showed the highest publication rates (54%, 52.27%, 48%, 47.56%, and 45%, respectively). It took 19.01+/-12.83 months on average for abstracts to be published in a journal, whereas it took 25.24+/-14.64 months and 17.51+/-11.89 months for publication in foreign and Korean journals, respectively (p<0.001). CONCLUSIONS: Approximately 40% of studies presented as abstracts at the KUA meeting are subsequently published as full-length articles. The KJU is the most targeted journal. The mean time to publication is 1.5 years, and publication seems to be influenced by the study subject. PMID- 22536474 TI - Surgical treatment of inferior vena cava invasion in patients with renal pelvis transitional cell carcinoma by use of human cadaveric aorta. AB - We herein report a case of radical nephroureterectomy and replacement of the inferior vena cava (IVC) with ahuman cadaveric aortic graft for a patient with renal pelvis transitional cell carcinoma associated with IVC infiltration. In advanced disease, radical surgery is essential to achieve long-term survival. This case entails the use of another treatment option among the numerous options currently available for the management of patients with advanced renal cancer associated with IVC invasion. PMID- 22536475 TI - Wilms' Tumor with long-delayed recurrence: 25 years after initial treatment. AB - Wilms' tumor is one of the most frequent malignant neoplasms in childhood. Advances in treatment modalities such as the combination of chemoradiation therapy with surgery have enhanced overall survival. However, recurrence of Wilms' tumor is still a problem. In this case, a 28-year-old female had experienced intermittent abdominal pain, and the computed tomography scan showed a huge pelvic mass. The patient had a history of radical nephrectomy for Wilms' tumor with concurrent chemotherapy at the age of three. The pelvic mass was resected in February 2010 and was confirmed to be a recurrent Wilms' tumor. The recurrent tumor showed a classic triphasic Wilms' tumor growth pattern with frequent mitoses and tumor necrosis. Our case is an extraordinary case of a long delayed recurrent Wilms' tumor after 25 years, which is the longest disease-free interval ever reported. The possible effects of chemotherapy as well as some other mechanisms of this late relapse are discussed. PMID- 22536477 TI - Migration and malaria in europe. AB - The proportion of imported malaria cases due to immigrants in Europe has increased during the lasts decades, with higher rates associated with settled immigrants who travel to visit friends and relatives (VFRs) in their country of origin. Cases are mainly due to P. falciparum and Sub-Saharan Africa is the most common origin. Clinically, malaria in immigrants is characterised by a mild clinical presentation including asymptomatic or delayed malaria cases and low parasitic levels. These characteristics may be explained by a semi-immunity acquired after long periods of time exposed to stable malaria transmission. Malaria cases among immigrants, even asymptomatic patients with sub-microscopic parasitemia, could increase the risk of transmission and cause the reintroduction of malaria in certain areas that have adequate vectors and climate conditions. Moreover, imported malaria cases in immigrants can also play an important role in the non-vector transmission out of endemic areas, through blood transfusions, organ transplantation or congenital transmission or occupational exposures. Consequently, outside of endemic areas, malaria screening should be carried out among recently arrived immigrants coming from malaria endemic countries. The aim of screening is to reduce the risk of clinical malaria in the individual as well as to prevent autochthonous transmission of malaria in areas where it has been eradicated. PMID- 22536479 TI - Local antiferromagnetic exchange and collaborative Fermi surface as key ingredients of high temperature superconductors. AB - Cuprates, ferropnictides and ferrochalcogenides are three classes of unconventional high temperature superconductors, who share similar phase diagrams in which superconductivity develops after a magnetic order is suppressed, suggesting a strong interplay between superconductivity and magnetism, although the exact picture of this interplay remains elusive. Here we show that there is a direct bridge connecting antiferromagnetic exchange interactions determined in the parent compounds of these materials to the superconducting gap functions observed in the corresponding superconducting materials: in all high temperature superconductors, the Fermi surface topology matches the form factor of the pairing symmetry favored by local magnetic exchange interactions. We suggest that this match offers a principle guide to search for new high temperature superconductors. PMID- 22536478 TI - Successful Long Term Eradication of Factor VIII Inhibitor in Patients with Acquired Haemophilia A in Saudi Arabia. AB - Acquired haemophilia A is a serious and potentially fatal bleeding disorder. Diagnosis is difficult and maybe delayed due to its rarity. The high mortality rate and the complex nature of treatment necessitate patient management at a haemophilia centre, where the required expertise and resources are available. Prompt diagnosis is crucial and early initiation of therapy could be life saving. Management includes initial control of bleeding followed by an approach to eradicate the coagulation factor inhibitor. In this paper we describe our local experience with acquired haemophilia A, which resulted in the successful control of major bleeding at presentation and eradication of inhibitors. PMID- 22536480 TI - Controlling the quantum dynamics of a mesoscopic spin bath in diamond. AB - Understanding and mitigating decoherence is a key challenge for quantum science and technology. The main source of decoherence for solid-state spin systems is the uncontrolled spin bath environment. Here, we demonstrate quantum control of a mesoscopic spin bath in diamond at room temperature that is composed of electron spins of substitutional nitrogen impurities. The resulting spin bath dynamics are probed using a single nitrogen-vacancy (NV) centre electron spin as a magnetic field sensor. We exploit the spin bath control to dynamically suppress dephasing of the NV spin by the spin bath. Furthermore, by combining spin bath control with dynamical decoupling, we directly measure the coherence and temporal correlations of different groups of bath spins. These results uncover a new arena for fundamental studies on decoherence and enable novel avenues for spin-based magnetometry and quantum information processing. PMID- 22536483 TI - Hypertension: from epidemiology to therapeutics. PMID- 22536482 TI - Crystal structure of L-histidinium 2-nitrobenzoate. AB - A new nonlinear optical organic compound, namely, L-histidinium 2-nitrobenzoate (abbreviated as LH2NB (I); ([C(6)H(10)N(3)O(2)](+) [C(7)H(4)NO(4)](-))), was synthesized. The molecular structure of LH2NB (I) was elucidated using single crystal X-ray diffraction technique. The second harmonic generation (SHG) efficiency of this compound is about two times that of the standard potassium dihydrogen phosphate crystals. PMID- 22536481 TI - ETosis: A Microbicidal Mechanism beyond Cell Death. AB - Netosis is a recently described type of neutrophil death occurring with the release to the extracellular milieu of a lattice composed of DNA associated with histones and granular and cytoplasmic proteins. These webs, initially named neutrophil extracellular traps (NETs), ensnare and kill microorganisms. Similarly, other cell types, such as eosinophils, mast cells, and macrophages, can also dye by this mechanism; thus, it was renamed as ETosis, meaning death with release of extracellular traps (ETs). Here, we review the mechanism of NETosis/etosis, emphasizing its role in diseases caused by protozoan parasites, fungi, and viruses. PMID- 22536484 TI - Insights into the in vivo regulation of glutamate dehydrogenase from the foot muscle of an estivating land snail. AB - Land snails, Otala lactea, survive in seasonally hot and dry environments by entering a state of aerobic torpor called estivation. During estivation, snails must prevent excessive dehydration and reorganize metabolic fuel use so as to endure prolonged periods without food. Glutamate dehydrogenase (GDH) was hypothesized to play a key role during estivation as it shuttles amino acid carbon skeletons into the Krebs cycle for energy production and is very important to urea biosynthesis (a key molecule used for water retention). Analysis of purified foot muscle GDH from control and estivating conditions revealed that estivated GDH was approximately 3-fold more active in catalyzing glutamate deamination as compared to control. This kinetic difference appears to be regulated by reversible protein phosphorylation, as indicated by ProQ Diamond phosphoprotein staining and incubations that stimulate endogenous protein kinases and phosphatases. The increased activity of the high-phosphate form of GDH seen in the estivating land snail foot muscle correlates well with the increased use of amino acids for energy and increased synthesis of urea for water retention during prolonged estivation. PMID- 22536485 TI - Epigenetics and autoimmune diseases. AB - Epigenetics is defined as the study of all inheritable and potentially reversible changes in genome function that do not alter the nucleotide sequence within the DNA. Epigenetic mechanisms such as DNA methylation, histone modification, nucleosome positioning, and microRNAs (miRNAs) are essential to carry out key functions in the regulation of gene expression. Therefore, the epigenetic mechanisms are a window to understanding the possible mechanisms involved in the pathogenesis of complex diseases such as autoimmune diseases. It is noteworthy that autoimmune diseases do not have the same epidemiology, pathology, or symptoms but do have a common origin that can be explained by the sharing of immunogenetic mechanisms. Currently, epigenetic research is looking for disruption in one or more epigenetic mechanisms to provide new insights into autoimmune diseases. The identification of cell-specific targets of epigenetic deregulation will serve us as clinical markers for diagnosis, disease progression, and therapy approaches. PMID- 22536487 TI - (+)-z-bisdehydrodoisynolic Acid enhances Basal metabolism and Fatty Acid oxidation in female obese zucker rats. AB - We have previously reported that the synthetic estrogen, (+)-Z bisdehydrodoisynolic Acid [(+)-Z-BDDA], attenuated weight gain and cardiovascular risk in obese rodents. To determine if these antiobesity effects were attributed to changes in basal metabolism, we assessed indirect calorimetry and metabolic profile in female obese Zucker (OZR) rats provided (+)-Z-BDDA (0.0002% food admixture) for 11 weeks. Similar to our previous findings, (+)-Z-BDDA reduced weight gain and improved lipid and glucose homeostasis in OZR rats. Furthermore, resting energy expenditure was increased by (+)-Z-BDDA, as evident by heat production and oxygen consumption. We also observed a marked reduction in respiratory quotient (RQ) along with a corresponding induction of hepatic AMPK in rodents provided (+)-Z-BDDA. Collectively, these findings indicate that (+)-Z BDDA partially attenuated obesity and associated pathologies through increased resting energy expenditure and fatty acid utilization. Further investigation is required to fully elucidate the mechanisms involved as well as to determine the potential therapeutic implications for (+)-Z-BDDA on obesity and its related pathologies. PMID- 22536486 TI - Lupus nephritis: an overview of recent findings. AB - Lupus nephritis (LN) is one of the most serious complications of systemic lupus erythematosus (SLE) since it is the major predictor of poor prognosis. In susceptible individuals suffering of SLE, in situ formation and deposit of immune complexes (ICs) from apoptotic bodies occur in the kidneys as a result of an amplified epitope immunological response. IC glomerular deposits generate release of proinflammatory cytokines and cell adhesion molecules causing inflammation. This leads to monocytes and polymorphonuclear cells chemotaxis. Subsequent release of proteases generates endothelial injury and mesangial proliferation. Presence of ICs promotes adaptive immune response and causes dendritic cells to release type I interferon. This induces maturation and activation of infiltrating T cells, and amplification of Th2, Th1 and Th17 lymphocytes. Each of them, amplify B cells and activates macrophages to release more proinflammatory molecules, generating effector cells that cannot be modulated promoting kidney epithelial proliferation and fibrosis. Herein immunopathological findings of LN are reviewed. PMID- 22536488 TI - Diet, genetics, and disease: a focus on the middle East and north Africa region. AB - The Middle East and North Africa (MENA) region suffers a drastic change from a traditional diet to an industrialized diet. This has led to an unparalleled increase in the prevalence of chronic diseases. This review discusses the role of nutritional genomics, or the dietary signature, in these dietary and disease changes in the MENA. The diet-genetics-disease relation is discussed in detail. Selected disease categories in the MENA are discussed starting with a review of their epidemiology in the different MENA countries, followed by an examination of the known genetic factors that have been reported in the disease discussed, whether inside or outside the MENA. Several diet-genetics-disease relationships in the MENA may be contributing to the increased prevalence of civilization disorders of metabolism and micronutrient deficiencies. Future research in the field of nutritional genomics in the MENA is needed to better define these relationships. PMID- 22536490 TI - The Effects of Prenatal Protein Restriction on beta-Adrenergic Signalling of the Adult Rat Heart during Ischaemia Reperfusion. AB - A maternal low-protein diet (MLP) fed during pregnancy leads to hypertension in adult rat offspring. Hypertension is a major risk factor for ischaemic heart disease. This study examined the capacity of hearts from MLP-exposed offspring to recover from myocardial ischaemia-reperfusion (IR) and related this to cardiac expression of beta-adrenergic receptors (beta-AR) and their associated G proteins. Pregnant rats were fed control (CON) or MLP diets (n = 12 each group) throughout pregnancy. When aged 6 months, hearts from offspring underwent Langendorff cannulation to assess contractile function during baseline perfusion, 30 min ischemia and 60 min reperfusion. CON male hearts demonstrated impaired recovery in left ventricular pressure (LVP) and dP/dt(max) (P < 0.01) during reperfusion when compared to MLP male hearts. Maternal diet had no effect on female hearts to recover from IR. MLP males exhibited greater membrane expression of beta(2)-AR following reperfusion and urinary excretion of noradrenaline and dopamine was lower in MLP and CON female rats versus CON males. In conclusion, the improved cardiac recovery in MLP male offspring following IR was attributed to greater membrane expression of beta(2)-AR and reduced noradrenaline and dopamine levels. In contrast, females exhibiting both decreased membrane expression of beta(2)-AR and catecholamine levels were protected from IR injury. PMID- 22536491 TI - Parenteral nutrition in liver resection. AB - Albeit a very large number of experiments have assessed the impact of various substrates on liver regeneration after partial hepatectomy, a limited number of clinical studies have evaluated artificial nutrition in liver resection patients. This is a peculiar topic because many patients do not need artificial nutrition, while several patients need it because of malnutrition and/or prolonged inability to feeding caused by complications. The optimal nutritional regimen to support liver regeneration, within other postoperative problems or complications, is not yet exactly defined. This short review addresses relevant aspects and potential developments in the issue of postoperative parenteral nutrition after liver resection. PMID- 22536489 TI - Does Branched-Chain Amino Acids Supplementation Modulate Skeletal Muscle Remodeling through Inflammation Modulation? Possible Mechanisms of Action. AB - Skeletal muscle protein turnover is modulated by intracellular signaling pathways involved in protein synthesis, degradation, and inflammation. The proinflammatory status of muscle cells, observed in pathological conditions such as cancer, aging, and sepsis, can directly modulate protein translation initiation and muscle proteolysis, contributing to negative protein turnover. In this context, branched-chain amino acids (BCAAs), especially leucine, have been described as a strong nutritional stimulus able to enhance protein translation initiation and attenuate proteolysis. Furthermore, under inflammatory conditions, BCAA can be transaminated to glutamate in order to increase glutamine synthesis, which is a substrate highly consumed by inflammatory cells such as macrophages. The present paper describes the role of inflammation on muscle remodeling and the possible metabolic and cellular effects of BCAA supplementation in the modulation of inflammatory status of skeletal muscle and the consequences on protein synthesis and degradation. PMID- 22536493 TI - Whole grains, legumes, and health. PMID- 22536492 TI - The Interplay between Estrogen and Fetal Adrenal Cortex. AB - Estrogen is a steroid hormone that regulates embryogenesis, cell proliferation and differentiation, organogenesis, the timing of parturition, and fetal imprinting by carrying chemical messages from glands to cells within tissues or organs in the body. During development, placenta is the primary source of estrogen production but estrogen can only be produced if the fetus or the mother supplies dehydroepiandrosterone (DHEA), the estrogen prohormone. Studies show that the fetal zone of the fetal adrenal cortex supplies 60% of DHEA for placental estrogen production, and that placental estrogen in turn modulates the morphological and functional development of the fetal adrenal cortex. As such, in developed countries where humans are exposed daily to environmental estrogens, there is concern that the development of fetal adrenal cortex, and in turn, placental estrogen production may be disrupted. This paper discusses fetal adrenal gland development, how endogenous estrogen regulates the structure and function of the fetal adrenal cortex, and highlights the potential role that early life exposure to environmental estrogens may have on the development and endocrinology of the fetal adrenal cortex. PMID- 22536494 TI - Mitochondrial Respiration Is Decreased in Rat Kidney Following Fetal Exposure to a MaternalLow-ProteinDiet. AB - Maternal protein restriction in rat pregnancy is associated with impaired renal development and age-related loss of renal function in the resulting offspring. Pregnant rats were fed either control or low-protein (LP) diets, and kidneys from their male offspring were collected at 4, 13, or 16 weeks of age. Mitochondrial state 3 and state 4 respiratory rates were decreased by a third in the LP exposed adults. The reduction in mitochondrial function was not explained by complex IV deficiency or altered expression of the complex I subunits that are typically associated with mitochondrial dysfunction. Similarly, there was no evidence that LP-exposure resulted in greater oxidative damage to the kidney, differential expression of ATP synthetase beta-subunit, and ATP-ADP translocase 1. mRNA expression of uncoupling protein 2 was increased in adult rats exposed to LP in utero, but there was no evidence of differential expression at the protein level. Exposure to maternal undernutrition is associated with a decrease in mitochondrial respiration in kidneys of adult rats. In the absence of gross disturbances in respiratory chain protein expression, programming of coupling efficiency may explain the long-term impact of the maternal diet. PMID- 22536496 TI - Modeling Count Outcomes from HIV Risk Reduction Interventions: A Comparison of Competing Statistical Models for Count Responses. AB - Modeling count data from sexual behavioral outcomes involves many challenges, especially when the data exhibit a preponderance of zeros and overdispersion. In particular, the popular Poisson log-linear model is not appropriate for modeling such outcomes. Although alternatives exist for addressing both issues, they are not widely and effectively used in sex health research, especially in HIV prevention intervention and related studies. In this paper, we discuss how to analyze count outcomes distributed with excess of zeros and overdispersion and introduce appropriate model-fit indices for comparing the performance of competing models, using data from a real study on HIV prevention intervention. The in-depth look at these common issues arising from studies involving behavioral outcomes will promote sound statistical analyses and facilitate research in this and other related areas. PMID- 22536495 TI - Pharmacokinetics and Pharmacodynamics of Darunavir and Etravirine in HIV-1 Infected, Treatment-Experienced Patients in the Gender, Race, and Clinical Experience (GRACE) Trial. AB - Objectives. Evaluation of pharmacokinetics and pharmacodynamics of darunavir and etravirine among HIV-1-infected, treatment-experienced adults from GRACE, by sex and race. Methods. Patients received darunavir/ritonavir 600/100mg twice daily plus other antiretrovirals, which could include etravirine 200mg twice daily. Population pharmacokinetics for darunavir and etravirine were determined over 48 weeks and relationships assessed with virologic response and safety. Rich sampling for darunavir, etravirine, and ritonavir was collected in a substudy at weeks 4, 24, and 48. Results. Pharmacokinetics were estimated in 376 patients for darunavir and 190 patients for etravirine. Median darunavir AUC(12h) and C(0h) were 60,642ng.h/mL and 3624ng/mL, respectively; and for etravirine were 4183ng . h/mL and 280ng/mL, respectively. There were no differences in darunavir or etravirine AUC(12h) or C(0h) by sex or race. Age, body weight, or use of etravirine did not affect darunavir exposure. No relationships were seen between darunavir pharmacokinetics and efficacy or safety. Patients with etravirine exposure in the lowest quartile generally had lower response rates. Rich sampling showed no time-dependent relationship for darunavir, etravirine, or ritonavir exposure over 48 weeks. Conclusions. Population pharmacokinetics showed no relevant differences in darunavir or etravirine exposure by assessed covariates. Lower etravirine exposures were associated with lower response rates. PMID- 22536497 TI - Impact of Novel Resistance Profiles in HIV-1 Reverse Transcriptase on Phenotypic Resistance to NVP. AB - Objective. To clarify the impact of H221Y mutation on drug resistance to NVP. Methods. 646 bp HIV-1 pol gene fragments (from 592 to 1237 nucleotide) with different NNRTIs mutation profiles from AIDS patients receiving antiretroviral therapy containing NVP regimens were introduced into pNL4-3 backbone plasmid. H221Y and (or) Y181C mutations were reverted to wild type amino acids by site directed mutagenesis, then strains containing various mutation patterns were packaged. Phenotypic drug resistance was analyzed on TZM-bl cells. Results. 12 strains containing different drug-resistant mutation profiles were constructed, including the K101Q series (K101Q/Y181C/H221Y, K101Q/Y181C, K101Q/H221Y, and K101Q), the V179D series (V179D/Y181C/H221Y, V179D/Y181C, V179D/H221Y, and V179D), and the K103N series (K103N/Y181C/H221Y, K103N/Y181C, K103N/H221Y, K103N). For strains containing the mutation profiles (K101Q/Y181C, K101Q, V179D/Y181C, V179D, K103N/Y181C, and K103N), the presence of H221Y reduced NVP susceptibility by 2.1 +/- 0.5 to 3.6 +/- 0.5 fold. To the mutation profiles K101Q/H221Y, K101Q, V179D/H221Y, V179D, K103N/H221Y, and K103N, the presence of Y181C reduced NVP susceptibility by 41.9 +/- 8.4 to 1297.0 +/- 289.1 fold. For the strains containing K101Q, V179D, and K103N, the presence of Y181C/H221Y combination decreased NVP susceptibility by 100.6 +/- 32.5 to 3444.6 +/- 834.5 fold. Conclusion. On the bases of various NNRTIs mutation profiles, Y181C remarkably improved the IC(50) to NVP, although H221Ymutation alone just increases 2.1 ~ 3.6-fold resistance to NVP, the mutation could improve 100.6 ~ 3444.6-fold resistance to NVP when it copresent with Y181C, the phenotypic drug resistance fold was improved extremely. For strains containing the mutation profiles (K101Q/Y181C, K101Q, V179D/Y181C, V179D, K103N/Y181C, and K103N), the presence of H221Y reduced NVP susceptibility by 2.1 +/- 0.5 to 3.6 +/- 0.5 fold. PMID- 22536498 TI - Challenges in Providing Treatment and Care for Viral Hepatitis among Individuals Co-Infected with HIV in Resource-Limited Settings. AB - Hepatitis B and C infections are prevalent among HIV-infected individuals with different epidemiologic profiles, modes of transmission, natural histories, and treatments. Southeast Asian countries are classified as "highly prevalent zones," with a rate of hepatitis B and C coinfection in people living with HIV/AIDS of approximately 3.2-11%. Majority of hepatitis B coinfection is of genotype C. Most of the patients infected with hepatitis C in Thailand have genotype 3 which is significantly related to intravenous drug use whereas, in Vietnam, it is genotype 6. The options for antiretroviral drugs are limited and rely on global funds and research facilities. Only HBV treatment is available for free through the national health scheme. Screening tests for HBV and HCV prior to commencing antiretroviral treatment are low. Insufficient concern on hepatitis-virus-related liver malignancy and long-term hepatic morbidities is noted. Cost-effective HCV treatment can be incorporated into the national health program for those who need it by utilizing data obtained from clinical research studies. For example, patients infected with HCV genotype 2/3 with a certain IL-28B polymorphism can be treated with a shorter course of interferon and ribavirin which can also help reduce costs. PMID- 22536500 TI - Affective spectrum disorders in an urban Swedish adult psychiatric unit: a descriptive study. AB - Background. Several studies have found that patients with affective-/anxiety /stress-related syndromes present overlapping features such as cooccurrence within families and individuals and response to the same type of pharmacological treatment, suggesting that these syndromes share pathogenetic mechanisms. The term affective spectrum disorder (AfSD) has been suggested, emphasizing these commonalities. The expectancy rate, sociodemographic characteristics, and global level of functioning in AfSD has hitherto not been studied neglected. Material and Method. Out of 180 consecutive patients 94 were included after clinical investigations and ICD-10 diagnostics. Further investigations included well-known self-evaluation instruments assessing psychiatric symptoms, personality disorders, psychosocial stress, adaptation, quality of life, and global level of functioning. A neuropsychological screening was also included. Results. The patients were young, had many young children, were well educated, and had about expected (normal distribution of) intelligence. Sixty-one percent were identified as belonging to the group of AfSD. Conclusion. The study identifies a large group of patients that presents much suffering and failure of functioning. This group is shared between the levels of medical care, between primary care and psychiatry. The term AfSD facilitates identification of patient groups that share common traits and identifies individuals clinically, besides the referred patients, in need of psychiatric interventions. PMID- 22536501 TI - Role of talc modulation on cytokine activation in cancer patients undergoing pleurodesis. AB - We investigate the mechanism of talc pleurodesis (TP) in 20 patients with recurrent malignant pleural effusion and 10 patients with nonmalignant pleural effusions. We measured IL-8 levels before and 6 h after TP and find a significant threefold increase (2.26 ng/mL +/- 0.7 to 6.5 ng/mL 0.1), which explains the recruitment of inflammatory cells in these patients. We hypothesize that TP is enable by stimulating the mesothelial cells (MS) to secrete FGF. A significant tenfold increase in FGF-b (0.05 ng/mL +/- 0.02 to 0.44 ng/mL 0.6) was seen 24 h after talc instillation (P < 0.04). In order to examine whether FGF-b is secreted by MS cells, MS recovered from CHF patients with recurrent pleural effusions were cultured for 48 h in the presence or absence of increasing concentrations of talc (from 100 ng/mL to 1 mg/mL). They produced significant levels of FGF-b in a dose dependent manner (P < 0.005). We hypothesized that a successful pleurodesis involves an early enhanced recruitment of inflammatory cells through a rise of IL 8 followed by enrollment of fibroblasts from the submesothelial space through increased mesothelial FGF-b production. PMID- 22536499 TI - Low Tidal Volume Ventilation in Patients without Acute Respiratory Distress Syndrome: A Paradigm Shift in Mechanical Ventilation. AB - Protective ventilation with low tidal volume has been shown to reduce morbidity and mortality in patients suffering from acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Low tidal volume ventilation is associated with particular clinical challenges and is therefore often underutilized as a therapeutic option in clinical practice. Despite some potential difficulties, data have been published examining the application of protective ventilation in patients without lung injury. We will briefly review the physiologic rationale for low tidal volume ventilation and explore the current evidence for protective ventilation in patients without lung injury. In addition, we will explore some of the potential reasons for its underuse and provide strategies to overcome some of the associated clinical challenges. PMID- 22536502 TI - Management of infectious processes of the pleural space: a review. AB - Pleural effusions can present in 40% of patients with pneumonia. Presence of an effusion can complicate the diagnosis as well as the management of infection in lungs and pleural space. There has been an increase in the morbidity and mortality associated with parapneumonic effusions and empyema. This calls for employment of advanced treatment modalities and development of a standardized protocol to manage pleural sepsis early. There has been an increased understanding about the indications and appropriate usage of procedural options at clinicians' disposal. PMID- 22536503 TI - Prevalence and characteristics of lung involvement on high resolution computed tomography in patients with ankylosing spondylitis: a systematic review. AB - To determine the prevalence of lung involvement and the spectrum of abnormalities revealed on HRCT in patients with AS, a systematic literature review was conducted in the Medline database up to May 2009 and in the abstracts of rheumatology scientific meetings (2006-2008). A hand search of references was also performed. Among the 264 selected articles, 10 articles (303 patients) allowed a calculation of the prevalence of lung abnormalities on thoracic HRCT in AS. A total of 185 patients (61%) had an abnormal thoracic HRCT: upper lobe fibrosis in 21 (6.9%), emphysema in 55 (18.1%), bronchiectasis in 33 (10.8%), and ground glass attenuation in 34 (11.2%). Non specific interstitial abnormalities were observed in 101 (33%) patients. The most common observed abnormalities were pleural thickening (52%), parenchymal bands (45%) and interlobular septal thickening (30%). Only the prevalence of upper lobe fibrosis increased significantly with disease duration (3 studies). Mild and non-specific interstitial abnormalities on thoracic HRCT are common in patients with AS, even in patients with early disease and without respiratory symptoms. PMID- 22536504 TI - Pediatric nephrology. PMID- 22536505 TI - Sarcopenia: a major challenge in elderly patients with end-stage renal disease. AB - Sarcopenia is a condition of multifaceted etiology arising in many elderly people. In patients with chronic kidney, the loss of muscle mass is much more intensive and the first signs of sarcopenia are observed in younger patients than it is expected. It is associated with the whole-body protein-energy deficiency called protein-energy wasting (PEW). It seems to be one of the major factors limiting patient's autonomy as well as decreasing the quality of life. If it cannot be treated with the simple methods requiring some knowledge and devotion, we will fail to save patients who die due to cardiovascular disease and infection, despite proper conduction of renal replacement therapy. Many factors influencing the risk of sarcopenia development have been evaluated in number of studies. Many studies also were conducted to assess the efficacy of different therapeutic strategies (diet, physical activity, hormones). Nevertheless, there is still no consensus on treatment the patients with PEW. Therefore, in the paper we present the reasons and pathophysiology of sarcopenia as an important element of protein energy wasting (PEW) in elderly patients suffering from chronic kidney disease. We also analyze possible options for treatment according to up-to-date knowledge. PMID- 22536506 TI - The Myocardial Unfolded Protein Response during Ischemic Cardiovascular Disease. AB - Heart failure is a progressive and disabling disease. The incidence of heart failure is also on the rise, particularly in the elderly of industrialized societies. This is in part due to an increased ageing population, whom initially benefits from improved, and life-extending cardiovascular therapy, yet ultimately succumb to myocardial failure. A major cause of heart failure is ischemia secondary to the sequence of events that is dyslipidemia, atherosclerosis, and myocardial infarction. In the case of heart failure postmyocardial infarction, ischemia can lead to myocardial cell death by both necrosis and apoptosis. The extent of myocyte death postinfarction is associated with adverse cardiac remodeling that can contribute to progressive heart chamber dilation, ventricular wall thinning, and the onset of loss of cardiac function. In cardiomyocytes, recent studies indicate that myocardial ischemic injury activates the unfolded protein stress response (UPR) and this is associated with increased apoptosis. This paper focuses on the intersection of ischemia, the UPR, and cell death in cardiomyocytes. Targeting of the myocardial UPR may prove to be a viable target for the prevention of myocyte cell loss and the progression of heart failure due to ischemic injury. PMID- 22536507 TI - Carbon monoxide targeting mitochondria. AB - MITOCHONDRIA PRESENT TWO KEY ROLES ON CELLULAR FUNCTIONING: (i) cell metabolism, being the main cellular source of energy and (ii) modulation of cell death, by mitochondrial membrane permeabilization. Carbon monoxide (CO) is an endogenously produced gaseoustransmitter, which presents several biological functions and is involved in maintaining cell homeostasis and cytoprotection. Herein, mitochondrion is approached as the main cellular target of carbon monoxide (CO). In this paper, two main perspectives concerning CO modulation of mitochondrial functioning are evaluated. First, the role of CO on cellular metabolism, in particular oxidative phosphorylation, is discussed, namely, on: cytochrome c oxidase activity, mitochondrial respiration, oxygen consumption, mitochondrial biogenesis, and general cellular energetic status. Second, the mitochondrial pathways involved in cell death inhibition by CO are assessed, in particular the control of mitochondrial membrane permeabilization. PMID- 22536508 TI - Very Low Frequency of PAD in People with CHD in Six Middle Eastern Countries. PMID- 22536509 TI - Enhanced vascular endothelial growth factor gene expression in ischaemic skin of critical limb ischaemia patients. AB - Objectives. To perform a quantitative analysis of the vascular endothelial growth factor (VEGF) gene transcription in the skin of ischemic legs and provide information for VEGF in the pathogenesis in critical limb ischemia (CLI). Methods. Skin biopsies were obtained from 40 patients with CLI. Control samples came from 44 patients with chronic venous disease. VEGF gene expression was analysed using quantitative polymerase chain reaction. Results. Patients with CLI had higher skin VEGF expression than control group (RQ: 1.3 +/- 0.1 versus 1, P = 0.04). Conclusions. We found an association between ischemic skin and an elevated VEGF expression in legs from patients with CLI. These data support that the mechanism for VEGF upregulation in hypoxia conditions is intact and acts appropriately in the ischaemic limbs from patients with CLI. PMID- 22536511 TI - Paraoxonase-1 55 LL Genotype Is Associated with No ST-Elevation Myocardial Infarction and with High Levels of Myoglobin. AB - It is well known that serum paraoxonase (PON1) plays an important role in the protection of LDL from oxidation. PON1 55 polymorphism is currently investigated for its possible involvement in cardiovascular diseases. The objective of our study is to verify if PON1 55 polymorphism is associated with risk of acute coronary syndrome (ACS) and with biochemical myocardial ischemia markers, such as troponin I, creatine kinase (CK)-MB, myoglobin, and C-reactive protein. We analysed PON1 55 polymorphism in a total of 440 elderly patients who underwent an ACS episode: 98 patients affected by unstable angina (UA), 207 AMI (acute myocardial infarction) patients affected by STEMI (ST elevation), and 135 AMI patients affected by NSTEMI (no ST elevation). We found that individuals carrying PON1 55 LL genotype are significantly more represented among AMI patients affected by NSTEMI; moreover, the patients carrying LL genotype showed significantly higher levels of myoglobin in comparison to LM + MM carriers patients. Our study suggests that PON1 55 polymorphism could play a role in the pathogenesis of cardiac ischemic damage. In particular, the significant association between PON1 55 LL genotype and the occurrence of a NSTEMI may contribute to improve the stratification of the cardiovascular risk within a population. PMID- 22536510 TI - Lipid peroxidation and paraoxonase-1 activity in celiac disease. AB - Paraoxonase-1 (PON1) plays an antioxidant and anti-inflammatory role. Aim of the study was to investigate the alteration of paraoxonase-1 activity in celiac disease (CD), an intestinal disorder characterized by toxic injury exerted by gluten peptides. Activities of PON1, levels of biochemical markers of lipid peroxidation and total antioxidant capacity were evaluated in serum obtained from 27 celiac patients (11 at diagnosis, 16 treated with gluten free diet) and 25 healthy subjects. Moreover, the serum susceptibility of Cu(2+)-induced lipid peroxidation was investigated in controls and patients. The results showed a lower PON1 activity in serum of both groups of celiac patients with respect to control subjects. PON1 activity in CD was related with markers of disease severity and was negatively correlated with the levels of lipid hydroperoxide and with the susceptibility of serum to lipid peroxidation induced in vitro by metal ions. The alteration of PON1 activity and markers of lipid peroxidation realized at lower extent in patients who were on a gluten-free diet. PMID- 22536512 TI - Paraoxonase activity and expression is modulated by therapeutics in experimental rat nonalcoholic Fatty liver disease. AB - Objective. The objective of the present study is to investigate the effect of rosiglitazone, metformin, ezetimibe, and valsartan (alone or in combinations) on paraoxonase (PON) activity and PON-mRNA expression in nonalcoholic fatty liver disease (NAFLD). Methods. 54 Male Sprague-Dawley rats were divided to 9 groups: chow diet group (15 weeks); methionine-choline-deficient diet (MCDD) group (15 weeks); MCDD-treated groups for the last 6 weeks with either metformin (M), rosiglitazone (R), metformin plus rosiglitazone (M+R), ezetimibe (E), valsartan (V), or a combination of R+M+V or of R+M+V+E for a total period of 15 weeks. Results. PON activities in serum and liver were decreased in MCDD rats. PON activity in serum increased significantly in all treatment groups. PON activity in liver was also increased significantly, except only in groups R, E, V, R+M+V, and R+M+V+E. Liver PON3 mRNA expression increased significantly in groups R+M, E, V, R+M+V, and R+M+V+E whereas liver PON2 mRNA expression increased significantly in MCDD, R+M, E, V, R+M+V, and R+M+V+E. Conclusions. PON activities in serum and liver were decreased in NAFLD. Treatment with insulin sensitizers, ezetimibe, and valsartan increased PON activity and reduced oxidative stress both in serum and liver. PMID- 22536513 TI - "Human babesiosis": an emerging transfusion dilemma. AB - Babesiosis, a common disease of animals, can infect humans via vector "tick bite", particularly in endemic areas. The recent reports of fatal cases in Hepatitis C and postliver transplant patients resulting from transfusion of contaminated blood should alert the medical profession regarding this emerging dilemma in endemic as well as nonendemic areas and the need for accurate blood screening for transfusion. Here, we illustrate different stages of the parasite lifecycle, progression of babesiosis in animal model, some aspects of pathologic outcomes, ongoing therapeutic modalities, and a feasible Acridine Orange fluorescent methodology for the diagnostic evaluation of blood samples. PMID- 22536515 TI - Surgical treatment options for the young and active middle-aged patient with glenohumeral arthritis. AB - The diagnosis and treatment of symptomatic chondral lesions in young and active middle-aged patients continues to be a challenging issue. Surgeons must differentiate between incidental chondral lesions from symptomatic pathology that is responsible for the patient's pain. A thorough history, physical examination, and imaging work up is necessary and often results in a diagnosis of exclusion that is verified on arthroscopy. Treatment of symptomatic glenohumeral chondral lesions depends on several factors including the patient's age, occupation, comorbidities, activity level, degree of injury and concomitant shoulder pathology. Furthermore, the size, depth, and location of symptomatic cartilaginous injury should be carefully considered. Patients with lower functional demands may experience success with nonoperative measures such as injection or anti-inflammatory pharmacotherapy. When conservative management fails, surgical options are broadly classified into palliative, reparative, restorative, and reconstructive techniques. Patients with lower functional demands and smaller lesions are best suited for simpler, lower morbidity palliative procedures such as debridement (chondroplasty) and cartilage reparative techniques (microfracture). Those with higher functional demands and large glenohumeral defects will usually benefit more from restorative techniques including autograft or allograft osteochondral transfers and autologous chondrocyte implantation (ACI). Reconstructive surgical options are best suited for patients with bipolar lesions. PMID- 22536514 TI - Glenohumeral joint preservation: a review of management options for young, active patients with osteoarthritis. AB - The management of osteoarthritis of the shoulder in young, active patients is a challenge, and the optimal treatment has yet to be completely established. Many of these patients wish to maintain a high level of activity, and arthroplasty may not be a practical treatment option. It is these patients who may be excellent candidates for joint-preservation procedures in an effort to avoid or delay joint replacement. Several palliative and restorative techniques are currently optional. Joint debridement has shown good results and a combination of arthroscopic debridement with a capsular release, humeral osteoplasty, and transcapsular axillary nerve decompression seems promising when humeral osteophytes are present. Currently, microfracture seems the most studied reparative treatment modality available. Other techniques, such as autologous chondrocyte implantation and osteochondral transfers, have reportedly shown potential but are currently mainly still investigational procedures. This paper gives an overview of the currently available joint preserving surgical techniques for glenohumeral osteoarthritis. PMID- 22536516 TI - The need for continued development of ricin countermeasures. AB - Ricin toxin, an extremely potent and heat-stable toxin produced from the bean of the ubiquitous Ricinus communis (castor bean plant), has been categorized by the US Centers for Disease Control and Prevention (CDC) as a category B biothreat agent that is moderately easy to disseminate. Ricin has the potential to be used as an agent of biological warfare and bioterrorism. Therefore, there is a critical need for continued development of ricin countermeasures. A safe and effective prophylactic vaccine against ricin that was FDA approved for "at risk" individuals would be an important first step in assuring the availability of medical countermeasures against ricin. PMID- 22536517 TI - Programme costing of a physical activity programme in primary prevention: should the costs of health asset assessment and participatory programme development count? AB - This analysis aims to discuss the implications of the "health asset concept", introduced by the WHO, and the "investment for health model" requiring a "participatory approach" of cooperative programme development applied on a physical activity programme for socially disadvantaged women and to demonstrate the related costing issues as well as the relevant decision context. The costs of programme implementation amounted to ?48,700. Adding the costs for developing the programme design of ?48,800 results in total costs of ?97,500; adding on top of that the costs of asset assessment running to ?35,600 would total ?133,100. These four different cost figures match four different types of potentially relevant decisions contexts. Depending on the decision context the total costs, and hence the incremental cost-effectiveness ratio of a health promotion intervention, could differ considerably. Therefore, a detailed cost assessment and the identification of the decision context are of crucial importance. PMID- 22536518 TI - An Investigation about the Influence of Bleaching on Shear Bond Strength of Orthodontic Brackets and on Enamel Colour. AB - The aim of the study was to investigate the effect of bleaching on the colouration of tooth enamel and shear bond strength of orthodontic ceramic brackets based upon current whitening practice. The bleaching and bonding techniques were performed on extracted bovine teeth for the investigation of their colorimetric spectrum and the adhesive bond strength on surface enamel. One group was designated as the control group with no pre-treatment. Another group was treated with a 45% hydrogen peroxide solution prior to bonding. The difference in colour was expressed as the Euclidian distance DeltaE. The resulting shear bond strength was analyzed and evaluated by scores of Adhesion Remnant Index. Statistical analysis was performed using the Kruskall-Wallis and post-hoc test. The colorimetric analysis revealed statistically significant differences between original and bleached as well as bleached and debonded teeth setting off a blue colour shift. Furthermore, statistically there was no significant difference noted in bonding strength between non-treated surfaces and those treated with peroxide. It can be concluded that peroxide pre-treatment does result in colour differences of teeth. Bonding and debonding procedures seem to have no statistically significant influence on the enamel colour using current materials. PMID- 22536519 TI - Screening for Familial Colorectal Cancer Risk amongst Colonoscopy Patients New to an Open-Access Endoscopy Center. AB - Purpose. We evaluated a questionnaire to aid in the recognition of CRC risk, as well as patient interest in their risk status within an open-access endoscopy center. Methods. A questionnaire was administered to new patients presenting for colonoscopy from May 2007 to February 2008. 287 patients were enrolled. Family history was evaluated using Amsterdam 1, II, and Revised Bethesda criteria. Recognition of risk and referral for counseling was assessed. Patients' interest to be contacted by a genetic counselor was also assessed. Results. 13.2 % (38/287) of patients met Revised Bethesda criteria. Of these, 18 (47.4 %) were previously told about their increased risk for CRC. Only 1 patient who met Revised Bethesda criteria (2.6 %) was previously referred for genetics, whereas none of the 3 patients who met Amsterdam I or II criteria were referred. 23.7 % of high-risk patients did not want to be contacted if found to be at increased risk for cancer. Conclusion. In our open-access endoscopy system, a significant number of high-risk patients remain unidentified and underreferred for genetic counseling due to numerous barriers. Our findings lend support to taking a public health approach to identifying those at risk for Lynch syndrome by implementing universal screening of all CRC specimens. PMID- 22536520 TI - Anemia in heart failure patients. AB - Heart failure is a very common disease, with severe morbidity and mortality, and a frequent reason of hospitalization. Anemia and a concurrent renal impairment are two major risk factors contributing to the severity of the outcome and consist of the cardio renal anemia syndrome. Anemia in heart failure is complex and multifactorial. Hemodilution, absolute or functional iron deficiency, activation of the inflammatory cascade, and impaired erythropoietin production and activity are some pathophysiological mechanisms involved in anemia of the heart failure. Furthermore other concomitant causes of anemia, such as myelodysplastic syndrome and chemotherapy, may worsen the outcome. Based on the pathophysiology of cardiac anemia, there are several therapeutic options that may improve hemoglobin levels, tissues' oxygenation, and probably the outcome. These include administration of iron, erythropoiesis-stimulating agents, and blood transfusions but still the evidence provided for their use remains limited. PMID- 22536521 TI - Sexual dimorphism in hematocrit response following red blood cell transfusion of critically ill surgical patients. AB - The change in hematocrit (DeltaHct) following packed red blood cell (pRBCs) transfusion is a clinically relevant measurement of transfusion efficacy that is influenced by post-transfusion hemolysis. Sexual dimorphism has been observed in critical illness and may be related to gender-specific differences in immune response. We investigated the relationship between both donor and recipient gender and DeltaHct in an analysis of all pRBCs transfusions in our surgical intensive care unit (2006-2009). The relationship between both donor and recipient gender and DeltaHct (% points) was assessed using both univariate and multivariable analysis. A total of 575 units of pRBCs were given to 342 patients; 289 (49.9%) donors were male. By univariate analysis, DeltaHct was significantly greater for female as compared to male recipients (3.81% versus 2.82%, resp., P < 0.01). No association was observed between donor gender and DeltaHct, which was 3.02% following receipt of female blood versus 3.23% following receipt of male blood (P = 0.21). By multivariable analysis, recipient gender remained associated significantly with DeltaHct (P < 0.01). In conclusion, recipient gender is independently associated with DeltaHct following pRBCs transfusion. This association does not appear related to either demographic or anthropomorphic factors, raising the possibility of gender-related differences in recipient immune response to transfusion. PMID- 22536522 TI - Mechanism of protein-z-mediated inhibition of coagulation factor xa by z-protein dependent inhibitor: a molecular dynamic approach. AB - Protein Z is a plasma protein functioning as a carrier for ZPI. Protein Z also accelerates inhibitory effect of ZPI on factor Xa by 1000-fold. Inhibition of coagulation cascade via FXa by ZPI and other serpins is very important safety factor for normal homeostasis protecting human life against unwanted thrombosis. In the present work using native structure of PZ, ZPI, FXa and in a dynamic simulation, using NAMD software, the ternary complex was studied in an up to 10 nanoseconds protocol. Rely on trajectory analyses, we postulated that PZ binds ZPI by using its SP-like domain and through noncovalent forces. PZ then transfers ZPI through-out the blood, and by using its GLA domain and a bivalent cation of calcium, PZ binds to phospholipid bilayers (e.g., platelet) where the FXa is preallocated. In case of PZ-ZPI binding to plasma membrane, a series of complementary interactions take place between FXa, and PZ-ZPI complex including interactions between RCL loop of ZPI and catalytic site of FXa and some take place between long arm of PZ (composed of GLA, EGF1, and EGF2 domains) and GLA domain of FXa. In our claim these complementary interactions lead PZ to bind correctly to prelocated FXa. PMID- 22536523 TI - Clinical and electrocardiographic evaluation of sickle-cell anaemia patients with pulmonary hypertension. AB - Pulmonary hypertension is an emerging complication of sickle cell anaemia with associated increased risk of mortality. In order to evaluate the clinical and electrocardiographic findings in adult sickle-cell patients with pulmonary hypertension, a cross sectional study was conducted on sixty two sickle cell anaemia patients and sixty two age and sex matched normal controls. Elevated pulmonary artery pressures (PAP), defined by PAP >= 30 mm Hg on echocardiography, was demonstrated in 41.9% of patients with sickle cell anaemia and in 3.2% of the controls; chi(2) = 26.571, P < 0.001. Right ventricular hypertrophy, increased P wave duration, QTc interval, and QTc dispersion were significantly associated with pulmonary hypertension. Significant correlation was found between mean PAP and (1) Frequency of crisis (Spearman correlation = 0.320; P = 0.011), (2) body mass index (Pearson's correlation = -0.297; P = 0.019), and (3) QTc interval (Pearson's correlation 0.261; P = 0.040). Pulmonary hypertension in adult sickle anaemia patients is associated with electrocardiographic evidence of right ventricular hypertrophy, and correlates significantly with frequency of vaso occlusive crisis, and QTc interval. The observations by this study tend to suggest that these parameters could be useful for early detection and prevention of pulmonary hypertension in patients with sickle cell anaemia. PMID- 22536524 TI - Angiogenesis in Non-Hodgkin's Lymphoma: An Intercategory Comparison of Microvessel Density. AB - Background. This study was aimed at comparing angiogenesis, seen as microvessel density (MVD) in subtypes of non-Hodgkin's lymphoma (NHL). Methods. In this study, 64 cases of NHL diagnosed over a three-year period were included along with 15 lymph node biopsies of reactive hyperplasia. NHLs were classified using REAL classification, and immunohistochemistry was performed for CD34 in all cases. CD34-stained sections were evaluated for "hot spots," where MVD was assessed and expressed as per mm(2). Appropriate statistical methods were applied. Results. There were 6 cases of well-differentiated lymphocytic lymphoma (SLL), 21 diffuse large B-cell lymphoma (DLBCL), 15 follicular lymphoma, 10 lymphoblastic lymphoma, 7 MALToma, and 5 peripheral T-cell lymphoma (PTCL). Mean MVD was highest in reactive hyperplasia (191.92 +/- 12.16 per mm(2)) compared to all NHLs. Among NHLs, PTCL demonstrated the highest MVD (183.42 +/- 8.24) followed by DLBCL (149.91 +/- 13.68). A significant difference was found in MVD between reactive and individual lymphoma groups. SLL had significantly lower MVD than other lymphoma subtypes. Conclusion. Angiogenesis, assessed by MVD, showed significant differences among subtypes of NHL, especially the indolent types like SLL. The higher MVD in aggressive lymphomas like PTCL and DLBCL can potentially be utilized in targeted therapy with antiangiogenic drugs. PMID- 22536525 TI - The role of fine-needle aspiration cytology in the diagnosis of Basal cell carcinoma. AB - Background/Aims. Basal cell carcinoma (BCC) is the most common malignant tumor of the skin in humans. The diagnosis of BCC is made clinically, which can then be confirmed microscopically. Biopsy or surgical excision of the lesion provides the specimen for histopathological examination, which is the mainstay for diagnosis. Fine-needle aspiration cytology (FNAC) on the other hand is an even simpler procedure, which can provide accurate diagnosis to confirm or exclude the malignancy. Methods. Here, we present our experience on the role of FNAC in diagnosing BCC. We were able to recruit 37 patients, of which 35 had BCC. Both FNAC and biopsy were obtained and then interpreted independently of one another. Results. Cytology correlated with histopathology in all cases except for 2 in which the yield was deemed inadequate. The sensitivity and specificity of fine needle aspiration cytology for basal cell carcinoma were 94.3% and 100%, respectively. Conclusions. We, therefore, recommend this technique for the initial evaluation of a patient with suspected BCC or in cases of recurrence. The technique is cheap, quick, less invasive, and highly accurate for the diagnosis of BCC. The limitation of the technique is low yield in some of the cases. PMID- 22536526 TI - Effect of topical application of different substances on fibroplasia in cutaneous surgical wounds. AB - BACKGROUND: Fibroblasts on the edges of a surgical wound are induced to synthesize collagen during the healing process which is known as fibroplasia. OBJECTIVE: The aim of this study was to determine the effect of the application of different substances on fibroplasia of cutaneous surgical wounds on rats. MATERIALS AND METHODS: Forty-eight Wistar rats were divided into three groups. A surgical wound 1 cm in diameter and 1 mm in depth was created on the dorsum of each animal. The surgical wounds were submitted to the topical application of an alcoholic extract of 30% propolis, 70% alcohol, or 0.001% dexamethasone in a cream base every 12 hours. The animals were sacrificed three, seven, 14, and 28 days postoperatively. The specimens were histologically processed and stained with Masson's trichome. The assessment of fibroplasia was performed using a scoring system: (1) 5 to 25% collagen deposition; (2) 26 to 50% collagen deposition; (3) 51 to 75% collagen deposition; and (4) more than 75% collagen deposition. RESULTS: There were statistically significant differences in collagen deposition between the substances at all postoperative evaluation times. CONCLUSION: Propolis and alcohol promoted greater collagen deposition in surgical wounds than dexamethasone. PMID- 22536527 TI - Cassia tora Linn Cream Inhibits Ultraviolet-B-Induced Psoriasis in Rats. AB - The aim of present study was to determine the antipsoriatic activity of newly formulated O/W creams of methanolic extract of Cassia tora L. leaves by using ultraviolet-B-induced psoriasis in rat. The plant Cassia tora L. is traditionally claimed to be useful in the treatment of a number of skin diseases. However, there are no established scientific reports for its antipsoriatic activity. Methanolic Cassia tora L. leaves extract was used to prepare various concentrations of O/W creams and tested for acute dermal toxicity study. The different O/W creams showed good physical characteristics and passed the sensitivity, irritation, grittiness and bleeding test. The results of acute dermal toxicity showed that the creams were safe up to the dose of 2000 mg/kg. In case of psoriasis model, histopathological analysis revealed that there were absence of Munro's microabscess, elongation of rete ridges, and capillary loop dilation in the section in Test 2 (0.1%) and standard group. O/W creams and methanolic extract of Cassia tora L. leaves exhibited significant reduction in percentage of relative epidermal thickness and spleen index as compared to positive control. We concluded that topical O/W creams and crude extract containing methanolic extract of Cassia tora L. leaves have potent antipsoriatic activity in ultraviolet-B-induced psoriasis in rat. PMID- 22536528 TI - Predictors of metabolic syndrome in participants of a cardiac rehabilitation program. AB - Metabolic syndrome increases the risk of all-cause mortality, cardiovascular mortality and cardiovascular events in patients with cardiovascular disease (CVD). This study assessed the predictors of metabolic syndrome, both its incidence and resolution in a cohort of cardiac rehabilitation program graduates. Methods. A total of 154 and 80 participants without and with metabolic syndrome respectively were followed for 48 months. Anthropometric measurements, metabolic risk factors, and quality of life were assessed at baseline and at 48 months. Logistic regression models were used to assess the predictors of metabolic syndrome onset and resolution. Results. Increasing waist circumference (OR 1.175, P <= 0.001) was an independent predictor for incident metabolic syndrome (R(2) for model = 0.46). Increasing waist circumference (OR 1.234, P <= 0.001), decreasing HDL-C (OR 0.027, P = 0.005), and increasing triglycerides (OR 3.005, P = 0.003) were predictors of metabolic syndrome resolution. Conclusion. Patients with CVD that further develop metabolic syndrome are particularly susceptible for the cascade of cardiovascular events and mortality. Increasing waist circumference confers a higher risk for future onset of metabolic syndrome in this group of patients. They will require closer follow-up and should be targeted for further prevention strategies after cardiac rehabilitation program completion. PMID- 22536529 TI - Surgical therapy of atrial fibrillation. AB - Atrial fibrillation (AF) can be found in an increasing number of cardiac surgical patients due to a higher patient's age and comorbidities. Atrial fibrillation is known, however, to be a risk factor for a greater mortality, and one aim of intraoperative AF treatment is to approximate early and long-term survival of AF patients to survival of patients with preoperative sinus rhythm. Today, surgeons are more and more able to perform less complex, that is, minimally invasive cardiac surgical procedures. The evolution of alternative ablation technologies using different energy sources has revolutionized the surgical therapy of atrial fibrillation and allows adding the ablation therapy without adding significant risk. Thus, the surgical treatment of atrial fibrillation in combination with the cardiac surgery procedure allows to improve the postoperative long-term survival and to reduce permanent anticoagulation in these patients. This paper focuses on the variety of incisions, lesion sets, and surgical techniques, as well as energy modalities and results of AF ablation and also summarizes future trends and current devices in use. PMID- 22536530 TI - Connexins and diabetes. AB - Cell-to-cell interactions via gap junctional communication and connexon hemichannels are involved in the pathogenesis of diabetes. Gap junctions are highly specialized transmembrane structures that are formed by connexon hemichannels, which are further assembled from proteins called "connexins." In this paper, we discuss current knowledge about connexins in diabetes. We also discuss mechanisms of connexin influence and the role of individual connexins in various tissues and how these are affected in diabetes. Connexins may be a future target by both genetic and pharmacological approaches to develop treatments for the treatment of diabetes and its complications. PMID- 22536532 TI - Cardiac resynchronization therapy reduces metaboreflex contribution to the ventilatory response in heart failure population. AB - Background. Metaboreflex overactivation has been proprosed to explain exaggerated hyperventilation in heart failure population. We investigated the metaboreflex activation after cardiac resynchronization therapy (CRT). Methods. 10 heart failure patients (mean left ventricular ejection fraction (LVEF) 27 +/- 4%) schedulded for CRT implantation were prospectively studied. At baseline and after 6 month follow up two maximal cardiopulmonary exercise tests with and without regional circulatory occlusion (RCO) during recovery were performed. RCO was achieved by inflation of bilateral upper thigh tourniquets 30 mmHg above peak systolic blood pressure during 3 minutes after peak exercise. Metaboreflex contribution to the ventilatory response was assessed as the difference in ventilatory data at the third minute during recovery between the two tests (Delta). Results. Patients had enhanced VE/VCO(2) slope (40 +/- 9) and an evident metaboreflex contribution to the high ventilatory response (DeltaVE: 3 +/- 4 L/min; P = 0.05, DeltaRR: 4.5 +/- 4/min; P = 0.003 and DeltaVE/VCO(2): 5.5 +/- 4; P = 0.007). 6 months after CRT implantation, NYHA class, LVEF, peak VO(2) and VE/VCO(2) were significantly improved (1.4 +/- 0.5; P < 0.001, 42 +/- 7%; P < 0.001, 16.5 +/- 3 mL/kg/min; P = 0.003; 33 +/- 10; P = 0.01). Metaboreflex contribution to VE, RR, and VE/VCO(2) was reduced compared with baseline (P = 0.08, P = 0.01 and P = 0.4 resp.). Conclusion. 6 months after CRT metaboreflex contribution to the ventilatory response is reduced. PMID- 22536531 TI - Nitric oxide manipulation: a therapeutic target for peripheral arterial disease? AB - Peripheral Arterial Disease (PAD) is a cause of significant morbidity and mortality in the Western world. Risk factor modification and endovascular and surgical revascularisation are the main treatment options at present. However, a significant number of patients still require major amputation. There is evidence that nitric oxide (NO) and its endogenous inhibitor asymmetric dimethylarginine (ADMA) play significant roles in the pathophysiology of PAD. This paper reviews experimental work implicating the ADMA-DDAH-NO pathway in PAD, focussing on both the vascular dysfunction and effects within the ischaemic muscle, and examines the potential of manipulating this pathway as a novel adjunct therapy in PAD. PMID- 22536533 TI - Metabolic Syndrome Derived from Principal Component Analysis and Incident Cardiovascular Events: The Multi Ethnic Study of Atherosclerosis (MESA) and Health, Aging, and Body Composition (Health ABC). AB - Background. The NCEP metabolic syndrome (MetS) is a combination of dichotomized interrelated risk factors from predominantly Caucasian populations. We propose a continuous MetS score based on principal component analysis (PCA) of the same risk factors in a multiethnic cohort and compare prediction of incident CVD events with NCEP MetS definition. Additionally, we replicated these analyses in the Health, Aging, and Body composition (Health ABC) study cohort. Methods and Results. We performed PCA of the MetS elements (waist circumference, HDL, TG, fasting blood glucose, SBP, and DBP) in 2610 Caucasian Americans, 801 Chinese Americans, 1875 African Americans, and 1494 Hispanic Americans in the multiethnic study of atherosclerosis (MESA) cohort. We selected the first principal component as a continuous MetS score (MetS-PC). Cox proportional hazards models were used to examine the association between MetS-PC and 5.5 years of CVD events (n = 377) adjusting for age, gender, race, smoking and LDL-C, overall and by ethnicity. To facilitate comparison of MetS-PC with the binary NCEP definition, a MetS-PC cut point was chosen to yield the same 37% prevalence of MetS as the NCEP definition (37%) in the MESA cohort. Hazard ratio (HR) for CVD events were estimated using the NCEP and Mets-PC-derived binary definitions. In Cox proportional models, the HR (95% CI) for CVD events for 1-SD (standard deviation) of MetS-PC was 1.71 (1.54-1.90) (P < 0.0001) overall after adjusting for potential confounders, and for each ethnicity, HRs were: Caucasian, 1.64 (1.39-1.94), Chinese, 1.39 (1.06 1.83), African, 1.67 (1.37-2.02), and Hispanic, 2.10 (1.66-2.65). Finally, when binary definitions were compared, HR for CVD events was 2.34 (1.91-2.87) for MetS PC versus 1.79 (1.46-2.20) for NCEP MetS. In the Health ABC cohort, in a fully adjusted model, MetS-PC per 1-SD (Health ABC) remained associated with CVD events (HR = 1.21, 95%CI 1.12-1.32) overall, and for each ethnicity, Caucasian (HR = 1.24, 95%CI 1.12-1.39) and African Americans (HR = 1.16, 95%CI 1.01-1.32). Finally, when using a binary definition of MetS-PC (cut point 0.505) designed to match the NCEP definition in terms of prevalence in the Health ABC cohort (35%), the fully adjusted HR for CVD events was 1.39, 95%CI 1.17-1.64 compared with 1.46, 95%CI 1.23-1.72 using the NCEP definition. Conclusion. MetS-PC is a continuous measure of metabolic syndrome and was a better predictor of CVD events overall and in individual ethnicities. Additionally, a binary MetS-PC definition was better than the NCEP MetS definition in predicting incident CVD events in the MESA cohort, but this superiority was not evident in the Health ABC cohort. PMID- 22536534 TI - Novel therapeutics in Alzheimer's disease. PMID- 22536536 TI - History, present, and progress of frontotemporal dementia in china: a systematic review. AB - We aim to provide an overview of clinical and demographical features and neuropathological research on frontotemporal dementia (FTD) from China over the past decade. We reviewed the demographic features, clinical presentations, and neuropathology of the FTD-spectrum disorders from the 49 cases in China published since 1998. On the basis of these findings, we retrospect the history and speculate on future progress in terms of FTD in China. We found that most published papers comprise case reports with a few retrospective studies with small sample sizes. Behavior variant FTD (bvFTD) was the most common diagnostic subtype, of which 35% were associated with amyotrophic lateral sclerosis or Parkinsonian syndrome. More than 47% patients with FTD had age onset before 65. There were no differences in age of onset and sex distribution between diagnostic subtypes. The spectrum of neuropathological diagnosis of bvFTD was frontotemporal lobe degeneration (FTLD) with tau protein or ubiquitin-immunopositive inclusions, and FTLD without intracellular inclusions. Median survival in bvFTD was 14 years. This paper provides an overview of the current status and pointers for future research directions of FTD in China. PMID- 22536535 TI - Mild cognitive impairment: statistical models of transition using longitudinal clinical data. AB - Mild cognitive impairment (MCI) refers to the clinical state between normal cognition and probable Alzheimer's disease (AD), but persons diagnosed with MCI may progress to non-AD forms of dementia, remain MCI until death, or recover to normal cognition. Risk factors for these various clinical changes, which we term "transitions," may provide targets for therapeutic interventions. Therefore, it is useful to develop new approaches to assess risk factors for these transitions. Markov models have been used to investigate the transient nature of MCI represented by amnestic single-domain and mixed MCI states, where mixed MCI comprised all other MCI subtypes based on cognitive assessments. The purpose of this study is to expand this risk model by including a clinically determined MCI state as an outcome. Analyses show that several common risk factors play different roles in affecting transitions to MCI and dementia. Notably, APOE-4 increases the risk of transition to clinical MCI but does not affect the risk for a final transition to dementia, and baseline hypertension decreases the risk of transition to dementia from clinical MCI. PMID- 22536537 TI - Memory complaints associated with seeking clinical care. AB - Diagnosis of mild cognitive impairment relies on the presence of memory complaints. However, memory complaints are very frequent in healthy people. The objective of this study was to determine the severity and type of memory difficulties presented by elderly patients who seek for clinical help, as compared to the memory difficulties reported by subjects in the community. Assessment of subjective memory complaints was done with the subjective memory complaints scale (SMC). The mini-mental state examination was used for general cognitive evaluation and the geriatric depression scale for the assessment of depressive symptoms. Eight-hundred and seventy-one nondemented subjects older than 50 years were included. Participants in the clinical setting had a higher total SMC score (10.3 +/- 4.2) than those in the community (5.1 +/- 3.0). Item 3 of the SMC, Do you ever forget names of family members or friends? contributed significantly more to the variance of the total SMC score in the clinical sample (18%) as compared to the community sample (11%). Forgetting names of family members or friends plays an important role in subjective memory complaints in the clinical setting. This symptom is possibly perceived as particularly worrisome and likely drives people to seek for clinical help. PMID- 22536538 TI - Neuroprotective effects of meloxicam and selegiline in scopolamine-induced cognitive impairment and oxidative stress. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by a gradual decline in memory associated with shrinkage of brain tissue, with localized loss of neurons mainly in the hippocampus and basal forebrain, with diminished level of central cholinergic neurotransmitter acetylcholine and also reported to be associated with accumulation of ubiquitinated proteins in neuronal inclusions and also with signs of inflammation. In these disorders, the abnormal protein aggregates may themselves trigger the expression of inflammatory mediators, such as cyclooxygenase 2 (COX 2). In the present study, the effects of Meloxicam, Selegiline, and coadministration of these drugs on scopolamine-induced learning and memory impairments in mice were investigated. Rectangular maze test, Morris water maze test, Locomotor activity, and Pole climbing test were conducted to evaluate the learning and memory parameters. Various biochemical parameters such as acetylcholinesterase(AChE), TBARS assay, catalase activity, and DPPH assay were also assessed. The present study demonstrates that Meloxicam, Selegiline, and co administration of these test drugs had potential therapeutic effects on improving the antiamnesic activity in mice through inhibiting lipid peroxidation, augmenting endogenous antioxidant enzymes, and decreasing acetylcholinesterase activity in brain. The memory enhancing capacity of the drugs was very significant when compared to disease control (P < 0.001). PMID- 22536539 TI - Cuticular Hydrocarbon Content that Affects Male Mate Preference of Drosophila melanogaster from West Africa. AB - Intraspecific variation in mating signals and preferences can be a potential source of incipient speciation. Variable crossability between Drosophila melanogaster and D. simulans among different strains suggested the abundance of such variations. A particular focus on one combination of D. melanogaster strains, TW1(G23) and Mel6(G59), that showed different crossabilities to D. simulans, revealed that the mating between females from the former and males from the latter occurs at low frequency. The cuticular hydrocarbon transfer experiment indicated that cuticular hydrocarbons of TW1 females have an inhibitory effect on courtship by Mel6 males. A candidate component, a C25 diene, was inferred from the gas chromatography analyses. The intensity of male refusal of TW1 females was variable among different strains of D. melanogaster, which suggested the presence of variation in sensitivity to different chemicals on the cuticle. Such variation could be a potential factor for the establishment of premating isolation under some conditions. PMID- 22536540 TI - Comparative analyses of base compositions, DNA sizes, and dinucleotide frequency profiles in archaeal and bacterial chromosomes and plasmids. AB - In the present paper, I compared guanine-cytosine (GC) contents, DNA sizes, and dinucleotide frequency profiles in 109 archaeal chromosomes, 59 archaeal plasmids, 1379 bacterial chromosomes, and 854 bacterial plasmids. In more than 80% of archaeal and bacterial plasmids, the GC content was lower than that of the host chromosome. Furthermore, most of the differences in GC content found between a plasmid and its host chromosome were less than 10%, and the GC content in plasmids and host chromosomes was highly correlated (Pearson's correlation coefficient r = 0.965 in bacteria and 0.917 in archaea). These results support the hypothesis that horizontal gene transfers have occurred frequently via plasmid distribution during evolution. GC content and chromosome size were more highly correlated in bacteria (r = 0.460) than in archaea (r = 0.195). Interestingly, there was a tendency for archaea with plasmids to have higher GC content in the chromosome and plasmid than those without plasmids. Thus, the dinucleotide frequency profile of the archaeal plasmids has a bias toward high GC content. PMID- 22536542 TI - Inflammatory bowel disease. PMID- 22536541 TI - Ferritin in adult-onset still's disease: just a useful innocent bystander? AB - Background. Adult-Onset Still's Disease (AOSD) is an immune-mediated systemic disease with quotidian-spiking fever, rash, and inflammatory arthritis. Hyperferritinemia is a prominent feature, often used for screening. Methods. The key terms "ferritin" and "hyperferritinemia" were used to search PubMed and Medline and were cross-referenced with "Still's Disease." Results. Hyperferritinemia, although nonspecific, is particularly prevalent in AOSD. While most clinicians associate ferritin with iron metabolism, this is mostly true for the H isoform and not for the L isoform that tends to increase dramatically in hyperferritenemia. In these situations, hyperferritinemia is not associated with iron metabolism and may even mask an underlying iron deficiency. We review, in systematic fashion, the current basic science and clinical literature regarding the regulation of ferritin and its use in the diagnosis and management of AOSD. Conclusion. Serum hyperferritinemia in AOSD has been described for 2 decades, although its mechanism has not yet been completely elucidated. Regulation by proinflammatory cytokines such as interleukin (IL)-1b, IL-6, IL-18, MCSF, and INF alpha provides a link to the disease pathogenesis and may explain rapid resolution of hyperferritinemia after targeted treatment and inhibition of key cytokines. PMID- 22536543 TI - Pharmacological Evaluation of the SCID T Cell Transfer Model of Colitis: As a Model of Crohn's Disease. AB - Animal models are important tools in the development of new drug candidates against the inflammatory bowel diseases (IBDs) Crohn's disease and ulcerative colitis. In order to increase the translational value of these models, it is important to increase knowledge relating to standard drugs. Using the SCID adoptive transfer colitis model, we have evaluated the effect of currently used IBD drugs and IBD drug candidates, that is, anti-TNF-alpha, TNFR-Fc, anti-IL 12p40, anti-IL-6, CTLA4-Ig, anti-alpha4beta7 integrin, enrofloxacin/metronidazole, and cyclosporine. We found that anti-TNF-alpha, antibiotics, anti-IL-12p40, anti-alpha4beta7 integrin, CTLA4-Ig, and anti-IL-6 effectively prevented onset of colitis, whereas TNFR-Fc and cyclosporine did not. In intervention studies, antibiotics, anti-IL-12p40, and CTLA4-Ig induced remission, whereas the other compounds did not. The data suggest that the adoptive transfer model and the inflammatory bowel diseases have some main inflammatory pathways in common. The finding that some well-established IBD therapeutics do not have any effect in the model highlights important differences between the experimental model and the human disease. PMID- 22536544 TI - Interface Molecules of Angiostrongylus cantonensis: Their Role in Parasite Survival and Modulation of Host Defenses. AB - Angiostrongylus cantonensis is a nematode parasite that causes eosinophilic meningoencephalitis in humans. Disease presents following the ingestion of third stage larvae residing in the intermediate mollusk host and disease manifests as an acute inflammation of the meninges characterized by eosinophil infiltrates which release a battery of proinflammatory and cytotoxic agents in response to the pathogen. As a mechanism of neutralizing these host defenses, A. cantonensis expresses different molecules with immunomodulatory properties that are excreted or secreted (ES). In this paper we discuss the role of ES proteins on disease exacerbation and their potential use as therapeutic targets. PMID- 22536546 TI - Advances in corticosteroid therapy for ocular inflammation: loteprednol etabonate. AB - Topical corticosteroids are effective in reducing anterior segment inflammation but are associated with adverse drug reactions (ADRs) including elevation of intraocular pressure (IOP) and cataract formation. Retrometabolic drug design has advanced the development of new corticosteroids with improved therapeutic indices. Engineered from prednisolone, loteprednol etabonate (LE) has a 17alpha chloromethyl ester, in lieu of a ketone group, and a 17beta-etabonate group. LE is highly lipophilic and binds with high affinity to the glucocorticoid receptor; any unbound LE is metabolized to inactive metabolites. LE has been studied in several anterior segment inflammatory conditions (giant papillary conjunctivitis, allergic conjunctivitis, anterior uveitis, and keratoconjunctivitis sicca), and in postoperative ocular inflammation and pain. Combined with tobramycin, it is effective in blepharokeratoconjunctivitis. Elevations in IOP are infrequent with LE, and the absence of a C-20 ketone precludes formation of Schiff base intermediates with lens proteins, a common first step implicated in cataract formation with ketone steroids. PMID- 22536547 TI - A review on gastric leptin: the exocrine secretion of a gastric hormone. AB - A major advance in the understanding of the regulation of food intake has been the discovery of the adipokine leptin a hormone secreted by the adipose tissue. After crossing the blood-brain barrier, leptin reaches its main site of action at the level of the hypothalamic cells where it plays fundamental roles in the control of appetite and in the regulation of energy expenditure. At first considered as a hormone specific to the white adipose tissue, it was rapidly found to be expressed by other tissues. Among these, the gastric mucosa has been demonstrated to secrete large amounts of leptin. Secretion of leptin by the gastric chief cells was found to be an exocrine secretion. Leptin is secreted towards the gastric lumen into the gastric juice. We found that while secretion of leptin by the white adipose tissue is constitutive, secretion by the gastric cells is a regulated one responding very rapidly to secretory stimuli such as food intake. Exocrine-secreted leptin survives the hydrolytic conditions of the gastric juice by forming a complex with its soluble receptor. This soluble receptor is synthesized by the gastric cells and the leptin-leptin receptor complex gets formed at the level of the gastric chief cell secretory granules before being released into the gastric lumen. The leptin-leptin receptor upon resisting the hydrolytic conditions of the gastric juice is channelled, to the duodenum. Transmembrane leptin receptors expressed at the luminal membrane of the duodenal enterocytes interact with the luminal leptin. Leptin is actively transcytosed by the duodenal enterocytes. From the apical membrane it is transferred to the Golgi apparatus where it binds again its soluble receptor. The newly formed leptin-leptin receptor complex is then secreted baso-laterally into the intestinal mucosa to reach the blood capillaries and circulation thus reaching the hypothalamus where its action regulates food intake. Exocrine secreted gastric leptin participates in the short term regulation of food intake independently from that secreted by the adipose tissue. Adipose tissue leptin on the other hand, regulates in the long term energy storage. Both tissues work in tandem to ensure management of food intake and energy expenditure. PMID- 22536548 TI - Expression and roles of NUPR1 in cholangiocarcinoma cells. AB - Nuclear protein-1 (NUPR1) is a small nuclear protein that is responsive to various stress stimuli. Although NUPR1 has been associated with cancer development, its expression and roles in cholangiocarcinoma have not yet been described. In the present study, we found that NUPR1 was over-expressed in human cholangiocarcinoma tissues, using immunohistochemistry. The role of NUPR1 in cholangiocarcinoma was examined by its specific siRNA. NUPR1 siRNA decreased proliferation, migration and invasion of human cholangiocarcinoma cell lines (HuCCT1 and SNU1196 cells). From these results, we conclude that NUPR1 is over expressed in cholangiocarcinoma and regulates the proliferation and motility of cancer cells. PMID- 22536545 TI - Renin-Angiotensin system hyperactivation can induce inflammation and retinal neural dysfunction. AB - The renin-angiotensin system (RAS) is a hormone system that has been classically known as a blood pressure regulator but is becoming well recognized as a proinflammatory mediator. In many diverse tissues, RAS pathway elements are also produced intrinsically, making it possible for tissues to respond more dynamically to systemic or local cues. While RAS is important for controlling normal inflammatory responses, hyperactivation of the pathway can cause neural dysfunction by inducing accelerated degradation of some neuronal proteins such as synaptophysin and by activating pathological glial responses. Chronic inflammation and oxidative stress are risk factors for high incidence vision threatening diseases such as diabetic retinopathy (DR), age-related macular degeneration (AMD), and glaucoma. In fact, increasing evidence suggests that RAS inhibition may actually prevent progression of various ocular diseases including uveitis, DR, AMD, and glaucoma. Therefore, RAS inhibition may be a promising therapeutic approach to fine-tune inflammatory responses and to prevent or treat certain ocular and neurodegenerative diseases. PMID- 22536549 TI - Evidence of early involvement of apoptosis inducing factor-induced neuronal death in Alzheimer brain. AB - Apoptosis inducing factor (AIF) has been proposed to act as a putative reactive oxygen species scavenger in mitochondria. When apoptotic cell death is triggered, AIF translocates to the nucleus, where it leads to nuclear chromatin condensation and large-scale DNA fragmentation which result in caspase-independent neuronal death. We performed this study to investigate the possibility that, in addition to caspase-dependent neuronal death, AIF induced neuronal death could be a cause of neuronal death in Alzheimer's disease (AD). We have found that AIF immunoreactivity was increased in the hippocampal pyramidal neurons in the Alzheimer brains compared to those of healthy, age-matched control brains. Nuclear AIF immunoreactivity was detected in the apoptotic pyramidal CA1 neurons at the early stage of AD and CA2 at the advanced stage. Nuclear AIF positive neurons were also observed in the amygdala and cholinergic neurons of the basal forebrain (BFCN) from the early stages of AD. The results of this study imply that AIF-induced apoptosis may contribute to neuronal death within the hippocampus, amygdala, and BFCN in early of AD. PMID- 22536551 TI - Activated microglial cells synthesize and secrete AGE-albumin. AB - A holy grail of curing neurodegenerative diseases is to identify the main causes and mechanisms underlying neuronal death. Many studies have sought to identify these targets in a wide variety of ways, but a more important task is to identify critical molecular targets and their origins. Potential molecular targets include advanced glycation end products (AGEs) that can promote neuronal cell death, thereby contributing to neurodegenerative disorders such as Alzheimer disease or Parkinson disease. In this study, we showed that AGE-albumin (glycated albumin) is synthesized in microglial cells and secreted in the human brain. Our results provide new insight into which microglial cells can promote the receptor for AGE mediated neuronal cell death, eventually leading to neurodegenerative diseases. PMID- 22536550 TI - Nestin expressing progenitor cells during establishment of the neural retina and its vasculature. AB - In order to test if nestin is a useful marker for various types of progenitor cells, we explored nestin expression in the retina during development. Nestin expression was co-evaluated with bromodeoxyuridine (BrdU) labeling and Griffonia simplicifolia isolectin B4 (GSIB4) histochemistry. Nestin immunoreactivity appears in cell soma of dividing neural progenitor cells and their leading processes in retinas from embryonic day (E) 13 to E20, in accordance with a BrdU labeled pattern. At postnatal day (P) 5, it is restricted to the end feet of Muller cells. BrdU-labeled nuclei were mainly in the inner part of the inner nuclear layer in postnatal neonates. The retinal vessels demarcated with GSIB4 positive endothelial cells were first distributed in the nerve fiber layer from P3. Afterward the vascular branches sprouted and penetrated deeply into the retina. The endothelial cells positive for GSIB4 and the pericytes in the microvessels were additionally immunoreactive for nestin. Interestingly, the presumed migrating microglial cells showing only GSIB4 reactivity preceded the microvessels throughout the neuroblast layer during vascular sprouting and extension. These findings may suggest that nestin expression represents the proliferation and movement potential of the neural progenitor cells as well as the progenitor cells of the endothelial cell and the pericyte during retinal development. Thus, Muller glial cells might be potential neural progenitor cells of the retina, and the retinal microvasculature established by both the endothelial and the pericyte progenitor cells via vasculogenesis along microglia migrating routes sustains its angiogenic potential. PMID- 22536552 TI - Different frequency of the absence of the palmaris longus according to assessment methods in a Korean population. AB - The palmaris longus (PL) is a slender, spindle-shaped weak flexor of the wrist. Congenital absence of the PL is estimated to occur in 15% among individuals worldwide. However, the frequency of its absence varies considerably among different population groups and with different detection techniques. In the present study, the presence of the PL tendon was examined in a Korean population (n=269) using three clinical tests, namely the Traditional Test, Mishra's Test II, and the Gangata Test. We classified subjects into six types based on whether inspection or palpation was required to determine the presence of the PL and flexor carpi radialis. The most reliable test was determined using Kendall's coefficient of concordance. Our results showed that the PL tendon was absent in 4.1% of the subjects in our study, and bilateral and unilateral absences were 2.2% and 1.8%, respectively. Statistical analysis revealed that these tests had similar reliability for assessing the PL tendon, and the Traditional Test showed the highest effectiveness, at 93%. Therefore the Traditional Test was found to be the most effective for revealing the PL in this Korean population. PMID- 22536553 TI - Abnormal patterns of the renal veins. AB - Knowledge of the renal vascular anatomy may greatly contribute to the success of surgical, invasive and radiological procedures of the retroperitoneal region. Here, morphometric and histological studies of a human cadaveric specimen presented a complex, anomalous pattern of renal veins. The left renal vein had an oblique retro-aortic course and received two lumbar veins. It bifurcated near its drainage point into the inferior vena cava. The right renal vein received the right testicular vein. In addition, the left kidney was located at a low position. The spleen was enlarged. The present case is unique and provides information that may help surgeons or angiologists to apply safer interventions. PMID- 22536554 TI - Coexistence of multiple anomalies in the hepatobiliary system. AB - The co-occurrence of several anomalies in the hepatobiliary system is uncommon. In the present study, hepatic lobe anomalies occurring in combination with hepatic artery and biliary variations were observed in an adult male cadaver. There are no previous reports in the literature on the coexistence of such anatomical variations. Preoperative diagnosis of such coexisting anomalies is very difficult. Hence, a thorough knowledge of these variations will enable surgeons to select the most appropriate hepatobiliary surgical procedure and postoperative management. PMID- 22536555 TI - Bipartite clavicular attachment of the sternocleidomastoid muscle: a case report. AB - Morphological variations of the sternocleidomastoid (SCM) muscle assume relevance during attempted surgical interventions in the cervical region. The present study reports bipartite clavicular attachment of the SCM in the neck of an adult male cadaver during performance of a routine anatomy demonstration. The anomaly was unilaterally observed on the left side of the neck. The clavicular head of the muscle exhibited two bellies, one medial and one lateral. While the medial belly was fused with the sternal head, the lateral belly appeared to blend with the medial. Cranially, the SCM attached to the mastoid process and superior nuchal line. We have attempted to elucidate the embryological basis of the above muscular variant. Additionally, we discuss its clinical relevance, highlighting the utility of the SCM in various reconstructive procedures. We assert that detailed anatomical knowledge of such SCM variants is of utility not only to the gross anatomist, but also for neck and orthopaedic surgeons and anaesthetists. Moreover, radiologists require familiarity with such aberrations to decipher magnetic resonance imaging scans of the cervical region. PMID- 22536556 TI - Harold Ellis: a surgeon's contribution to anatomy education. PMID- 22536557 TI - Recombinant Factor VIIa in Post-partum Hemorrhage: A New Weapon in Obstetrician's Armamentarium. AB - Post-partum hemorrhage (PPH) is a life-threatening obstetric complication and the leading cause of maternal death. The usual manner for its management includes, first, noninvasive and nonsurgical methods, and, then invasive and surgical methods. However, mortality and morbidity related to PPH still remains unacceptably high, contributing to hysterectomy in at least 50% of cases. Early, effective, and preferably noninvasive treatments that can reduce maternal mortality and morbidity due to this entity are therefore essential. One of the most spectacular advancements in the control of PPH has been the use of recombinant activated factor (rFVIIa), both as initial and a life- and uterus saving therapy. rFVIIa also reduces costs of therapy and use of blood components in massive PPH. In cases of intractable bleeding with no other obvious indications for hysterectomy, administration of rFVIIa should be considered before surgery. A MEDLINE search was done to review relevant articles in English literature on use of rFVIIa in PPH. Data were constructed and issues were reviewed from there. Our experience in a series of three cases of PPH, two of atonic and one of traumatic, successfully managed using rFVIIa is also shared. PMID- 22536558 TI - Antibiotic susceptibility patterns of urinary pathogens in female outpatients. AB - BACKGROUND: Urinary tract Infection (UTI) is among the most common infections described in outpatient setting and hospital patients. In almost all cases empirical antimicrobial treatment initiates before the laboratory results of urine culture are available; thus antibiotic resistance may increase in uropathogens due to frequent use of antibiotics. AIMS: The study was designed to find the prevalence of UTI in females with urinary tract symptoms, to determine the causative organism (s) of UTI, and to determine the antibiotic susceptibility pattern of microbial agents isolated from urine culture (antibiogram). MATERIALS AND METHODS: The prospective, observational study involved 139 females, aged 15 years and above clinically suspected for UTI attending outpatient Departments of Vivekananda Polyclinic and Institute of Medical Sciences, Lucknow. A structured questionnaire was used to interview the study subjects. A chi-square test and Fisher Exact test were used to analyze data. RESULTS: The overall prevalence of UTI was found to be 45.32% (63/139). Escherichia coli (33.1%) and Klebsiella pneumoniae (7.9%) were the most common organisms isolated. The most effective antibiotic for both was Nitrofurantoin. CONCLUSIONS: Regular monitoring is required to establish reliable information about susceptibility pattern of urinary pathogens for optimal empirical therapy of patients with UTI. PMID- 22536559 TI - Frequency of human immunodeficiency virus infection among students of tertiary and secondary institutions in an endemic state. AB - BACKGROUND: Students are pivotal to manpower development and technological advancement of any nation. Nigerian nation was recently ranked third human immunodeficiency virus (HIV) most endemic nation in the world AIM: The study was designed to determine the frequency of HIV infection among Nigerian tertiary and secondary institution students. MATERIALS AND METHODS: A HIV screening test was conducted on 1,978 apparently healthy students composed of 981 males and 997 females aged 11-35 years, randomly selected from some Nigerian tertiary and secondary institutions RESULTS: Overall, the sero-prevalence rate of 13.7% was recorded consisting 9.9% in the tertiary and 3.8% in secondary institutions. The distribution of the infection showed no significant difference by age (chi(2)=1.07, P>0.05) and by gender (chi(2)=0.85, P>0.05). Also, the prevalence had no significant association with the settlement of students (chi(2)=0.96, P>0.05) and the status of educational institutions (chi(2)=1.42, P>0.05). CONCLUSION: The findings indicate a high HIV prevalence rate among students in this part of the globe. General behavioral changes about sex among the students are suggested. PMID- 22536560 TI - Procathepsin d involvement in chemoresistance of cancer cells. AB - BACKGROUND: The role of pCD in cancer has been studied for a long time. We have focused on the hypothesis that increased expression and/or secretion of pCD in cancer cells causes increased chemoresistance to apoptosis inducing molecules. AIM: The aim was to evaluate the effects of pCD expression/release on chemoresistance. MATERIALS AND METHODS: We tested the LC(50) values for various transfectants of breast cancer cell line MDA-MB-231 as well as effects of exogenous additions of pCD, its mutants, pepstatine, antibodies, and Brefeldin on the resistance. RESULTS: We found that pCD levels can be correlated with chemoresistance, the pro-resistant activity seems to be localized outside the cells, proteolytic activity is not involved, and PI3-Akt signaling has an important role in antiapoptotic effects of pCD. CONCLUSION: We can conclude that overexpression of pCD has strong influence on increased resistance of tumor cells. This could, in fact, be an important contribution in the possible use of pCD level determination for prognostic and/or therapeutic purposes. PMID- 22536561 TI - Evaluation of TNF-alpha and IL-6 Levels in Obese and Non-obese Diabetics: Pre- and Postinsulin Effects. AB - BACKGROUND: Type 2 diabetes (T2DM) mellitus is a serious implication of obesity. The effect of insulin therapy on levels of inflammatory markers among obese and non-obese diabetics has been inadequately studied. AIM: The study aimed to analyze the preinsulin and postinsulin levels of tumor necrosis factor alpha (TNF alpha) and IL-6 in nonobese and obese T2DM patients. MATERIALS AND METHODS: We assessed TNF-alpha and IL-6 levels in healthy controls (n=10) and diabetic patients (obese and nonobese; n=20 each) and analyzed the postinsulin effect on TNF-alpha and IL-6 levels after 24 and 48 weeks. TNF-alpha and IL-6 levels were also correlated with fasting plasma glucose of obese and nonobese diabetic patients after insulin therapy. RESULTS: There is augmentation of TNF-alpha and IL-6 levels in diabetic patients and augmentation is more in obese than in nonobese diabetics. The obese group showed a significant decrease (P value<0.05) after 24 weeks of insulin therapy and an extremely significant decrease (P<0.001) in TNF-alpha and IL-6 levels after 48 weeks of therapy. The nonobese group showed an extremely significant decrease (P<0.001) in TNF-alpha and IL-6levels after 24 and 48 weeks both. CONCLUSION: There is augmented inflammation in diabetes and it is more in obese diabetics. Insulin therapy tends to counter this inflammation, but the response is delayed in obese diabetics. PMID- 22536562 TI - Pattern of Angiotensin-converting enzyme inhibitors induced adverse drug reactions in South Indian teaching hospital. AB - BACKGROUND: Adverse drug reactions (ADRs) occur frequently with cardiovascular drugs leading to change in therapy, increasing morbidity, and mortality. AIM: The study was conducted to evaluate the incidence of ADRs due to angiotensin converting enzyme Inhibitors in cardiology department. MATERIALS AND METHODS: A cross-sectional observational study was carried out for a period of 6 months. The data were assessed for the pattern of the ADRs with respect to patient demographics, nature of the reaction, outcome of the reactions, causality, severity, and preventability. RESULTS: Among 692 patients, 51 (7.36%) had developed 60 ADRs, and majority of cases (56.66%) were in the age group of >61 years and most of them were developed in female (80%). The common ADRs observed were cough, hypotension, hyperkalemia, and acute renal failure. In 21.66% cases the dose of the suspected drug was altered and in 78.33% cases the drug was withdrawn. Considering the outcome, 93.33% of cases recovered from ADRs, whereas in 6.66% cases were continuing. Causality assessment showed that majority of ADRs was probable and were found to be moderately severe. CONCLUSION: Our study concludes geriatrics and female patients have higher incidence of ADRs. So early identification and management of ADRs are essential for this population. PMID- 22536563 TI - Ectopic pleomorphic adenoma. AB - We describe a case of pleomorphic adenoma of minor salivary glands occurring in the retromolar area. A 58-year-old male patient reported with complaint of a small mass in the left lower retromolar region of the mouth. It has grown slowly to the present size. Based on the history and clinical findings, differential diagnosis of fibroma, minor salivary gland tumor, and mucocele were considered. The microscopic findings revealed the presence of minor salivary gland tissue and the lesions showed the presence of myoepithelial and epithelial cell proliferation. The cells were arranged in ductal pattern. There were areas where the epithelial cells showed proliferation in sheets, cords, and strands. The patient was followed up for a period of 6 months and there was no evidence of recurrence. The retromolar area being affected as in the case presented is rare for this condition. Surgical excision along with surrounding normal tissue is the treatment of choice. PMID- 22536564 TI - Scimitar syndrome with renal agenesis. AB - Partial pulmonary venous connection anomaly is relatively uncommon form of congenital heart diseases. The quite rare combination of this anomaly with hypoplasia of the right lung and dextroposition of the heart is designated as scimitar syndrome. Most cases are presented in infantile period and adult presentation is exceedingly rare. Our patient, a 38-year-old man, was admitted to a doctor with flu-like complaint and because of abnormalities on chest X-ray he was sent to our clinic. He did not have any chronic complaints such as shortness of breath and fatigue. After investigation, scimitar syndrome was diagnosed. Left renal agenesis was determined with abdominal examination. Best of our knowledge in literature we did not detect any case both with Scimitar syndrome and renal agenesis, and we wanted to report the asymptomatic adult Scimitar syndrome case with left renal agenesis. PMID- 22536565 TI - Midgut malrotation with chronic abdominal pain. AB - Abnormalities in midgut rotation occur during the physiological herniation of midgut between the 5(th) and 10(th) week of gestation. The most significant abnormality is narrow small bowel mesentery which is prone to volvulus. This occurs most frequently in the neonatal period, less commonly midgut malrotation presents in adulthood with either acute volvulus or chronic abdominal symptoms. It is the latter group that represents a diagnostic challenge. We report a case of a 17-year-old male patient who presented with 10-year history of nonspecific gastro-intestinal symptoms. After extensive investigation the patient was diagnosed with midgut malrotation following computed tomography of abdomen. The patient was treated with a laparoscopic Ladd's procedure and at 3 months he was gaining weight and had stopped vomiting. A laparoscopic Ladd's procedure is an acceptable alternative to the open technique in treating symptomatic malrotation in adults. Midgut malrotation is a rare congenital anomaly which may present as chronic abdominal pain. Abdominal CT is helpful for diagnosis. PMID- 22536566 TI - Chondroblastoma of squamous part of the temporo-parietal region of skull vault: a case report and review of literature. AB - Chondroblastoma of squamous part of temporal bone is a very rare bone tumor. Although most of them are benign, the prognosis is not predictable. A 14-year-old girl presented with recurrent slowly growing mass over the right side of the temporo-parietal region of skull vault. Initial curettage material showed extensive chondroid areas and diagnosed histologically as "enchondroma." Histology of completely excised recurrent mass showed identifiable chondroblastic foci. She was followed up for 3 years and was free from recurrence. Chondroblastomas at very rare sites such as squamous part of temporal bone have variable histology, confusing with other giant cell lesions, variable prognosis, and require prompt diagnosis and complete excision. PMID- 22536567 TI - Practical use of apixaban in the prevention of venous thromboembolism after total knee or hip replacement. AB - Apixaban is an anticoagulant drug that acts by directly inhibiting coagulation factor Xa. Unlike low-molecular-weight heparins and fondaparinux, apixaban can be taken orally; in contrast to vitamin K antagonists, its clinical use does not require dose adjustments according to coagulation monitoring. Apixaban in a regimen of 2.5 mg twice daily has been approved in Europe for the prevention of venous thromboembolism in patients undergoing elective total hip or knee replacement. This approval was based on the results of two large phase III trials showing that, compared to the European approved regimen of enoxaparin for total hip and knee replacement (i.e., 40 mg once daily starting preoperatively), apixaban 2.5 mg twice daily initiated 12-24 hours after wound closure was more effective in preventing venous thromboembolism, without increasing the risk of bleeding. This apixaban regimen may therefore represent a convenient alternative to conventional anticoagulant drug regimens in the prevention of venous thromboembolism in this surgical setting. However, there are several precautions that prescribers should take into account before using this drug regimen. In this article, various points are considered, notably bleeding risk and the use of this novel oral anticoagulant in special populations or in the context of neuraxial anesthesia. PMID- 22536568 TI - Brentuximab vedotin: its role in the treatment of anaplastic large cell and Hodgkin's lymphoma. AB - Brentuximab vedotin is being developed in a joint collaboration between Seattle Genetics and Millennium: The Takeda Oncology Company. In August 2011, it was approved by the FDA for the treatment of patients with Hodgkin's lymphoma (HL) and anaplastic large cell lymphoma (ALCL). Brentuximab vedotin is an antibody drug conjugate that specifically targets the TNF receptor superfamily member 8 (CD30) antigen on the surface of cancer cells to induce cell death. Brentuximab vedotin has shown efficacy in inducing apoptosis in HL and ALCL cell lines that express CD30 and reducing tumor size in preclinical models. Brentuximab vedotin is under clinical evaluation for the treatment of relapsed or refractory HL and ALCL in both adults and children. It is being investigated for use as a combination agent with pre-existing frontline chemotherapies and as a stand-alone salvage therapy for use prior to autologous stem cell transplant. Treatment with brentuximab vedotin is generally well tolerated although it is associated with grade 1-2 adverse reactions such as neutropenia and there have been reports of grade 3-4 serious adverse events. In particular its use with chemotherapy regimens that include bleomycin is contraindicated because of adverse pulmonary effects. PMID- 22536569 TI - Crizotinib for the treatment of patients with advanced non-small cell lung cancer. AB - Crizotinib is a potent small-molecule inhibitor of ALK tyrosine kinase receptor (anaplastic lymphoma kinase; ALK) and hepatocyte growth factor receptor (HGF receptor, proto-oncogene c-Met). A range of tumors, including subsets of non small cell lung cancer (NSCLC), anaplastic large cell lymphoma and inflammatory myofibroblastic tumors harbor an ALK rearrangement that leads to oncogenic activation of ALK. Crizotinib has demonstrated preclinical and clinical activity against such malignancies through inhibition of ALK, and patients harboring ALK- rearranged NSCLC have demonstrated high response rates and prolonged progression free survival in phase I and II studies. In August 2011, crizotinib was approved for the treatment of advanced ALK-positive NSCLC. PMID- 22536570 TI - Utilizing pharmacodynamic properties of second-generation antipsychotics to guide treatment. AB - Second-generation antipsychotics (SGAs) are used for the treatment of multiple psychiatric disorders including schizophrenia, bipolar depression, bipolar mania, autism and major depressive disorder. Additionally, their off-label use has been expanding to include other disorders as well, including post-traumatic stress disorder, obsessive compulsive disorder, generalized anxiety disorder, eating disorders and personality disorders. All SGAs share common properties; however, each individual SGA has a unique pharmacodynamic profile that may be utilized to guide and individualize treatment. PMID- 22536571 TI - New thrombopoietin receptor agonists for platelet disorders. AB - Since thrombopoietin (TPO) was cloned in 1994, TPO receptor (TPO-R) agonists have been developed which have shown significant clinical activity in various conditions characterized by thrombocytopenia. First-generation TPO-R agonists were recombinant forms of human TPO. The clinical development of these molecules was discontinued after one of them, pegylated recombinant human megakaryocyte growth and development factor, was associated with the development of neutralizing autoantibodies cross-reacting with endogenous TPO. Second-generation TPO-R agonists are now available, which present no sequence homology to endogenous TPO. Two of these new agents, romiplostim and eltrombopag, have been granted marketing authorization for use in patients with primary immune thrombocytopenia unresponsive to conventional treatments. Clinical trials with TPO-R agonists are also ongoing in other thrombocytopenias, such as hepatitis C virus-related thrombocytopenia and the myelodysplastic syndromes. PMID- 22536572 TI - A report from the American Academy of Allergy, Asthma and Immunology 2012 annual meeting (March 2-6, 2012 - Orlando, Florida, U.S.A.). AB - Seeing children (and not so young people) crying is not an expected sight in Orlando, but during the pollen season this may not be so uncommon. Unfortunately, allergies are very frequent in the population, and although effective therapies are available, many have disadvantages, and research continues to develop novel medicines and immunotherapies that will more rapidly, effectively and safely help people with allergies to enjoy their lives without teary eyes, runny nose and, most particularly, dramatic fights for inhaling air. Orlando was the site of this year's American Academy of Allergy, Asthma and Immunology meeting, many of the findings reported during which in relation with treatments for allergic and immunological diseases are presented in the following report. PMID- 22536573 TI - Making a difference / Changer les choses. PMID- 22536574 TI - Unexpected positron emission tomography-positive actinomyces-related mass of the bronchial stump. AB - Pulmonary actinomycosis is a rare disease frequently misdiagnosed, even by experienced clinicians, as primary or metastatic lung cancer or as other more conventional lung infections. It is often an unexpected disease that is basically detected only on cytological/histological examination. A case involving a patient who presented with a mass in the bronchial stump (of a previous pulmonary lobectomy) is described. Despite a strong suspicion of recurrent lung cancer, positron emission tomography confirmed a diagnosis of a suture-related bronchial actinomycosis. PMID- 22536575 TI - Interferon-gamma release assays for screening of health care workers in low tuberculosis incidence settings: dynamic patterns and interpretational challenges. PMID- 22536576 TI - Use of interferon-gamma release assays in a health care worker screening program: experience from a tertiary care centre in the United States. AB - BACKGROUND: Interferon-gamma release assays including the QuantiFERON-TB Gold In Tube test (QFT-GIT [Cellestis Ltd, Australia]) may be used in place of the tuberculin skin test (TST) in surveillance programs for Mycobacterium tuberculosis infection control. However, data on performance and practicality of the QFT-GIT in such programs for health care workers (HCWs) are limited. OBJECTIVES: To assess the performance, practicality and reversion rate of the QFT GIT among HCWs at a tertiary health care institution in the United States. METHODS: Retrospective chart review of HCWs at Central Arkansas Veterans Healthcare System (Arkansas, USA) who underwent QFT-GIT testing as a part of their employee screening between November 1, 2008 and October 31, 2009. RESULTS: QFT-GIT was used to screen 3290 HCWs. The initial QFT-GIT was interpreted as positive for 129 (3.9%) HCWs, negative for 3155 (95.9%) and indeterminate for six (0.2%). Testing with QFT-GIT was repeated in 45 HCWs who had positive results on the initial test. The QFT-GIT reverted to negative in 18 (40.0%) HCWs, all of whom had negative TST status and initial interferon-gamma values of 0.35 IU/mL to 2.0 IU/mL. CONCLUSION: The QFT-GIT test is feasible in large health care setting as an alternative to TST for M tuberculosis infection screening in HCWs but is not free from challenges. The major concerns are the high number of positive test results and high reversion rates on repeat testing, illustrating poor short-term reproducibility of positive QFT-GIT test results. These results suggest adopting a borderline zone between interferon-gamma values of 0.35 IU/mL to 2.0 IU/mL, and cautious clinical interpretation of values in this range. PMID- 22536577 TI - Proximity to major roadways is a risk factor for airway hyper-responsiveness in adults. AB - BACKGROUND: Proximity to major roads is reported to be associated with asthma and airway hyper-responsiveness in children. Similar studies using objective measurements in adults are not available in Canada. OBJECTIVE: To test the hypothesis that adult asthmatic patients who live close to major roads and highways in an urban environment are at a risk of moderate to severe airway hyper responsiveness. METHODS: Airway responsiveness was determined using methacholine bronchial provocation (PC(20)) tests in a cohort of 2625 patients who attended an outpatient clinic in Hamilton, Ontario. Patient addresses were geocoded in a geographic information system to determine proximity to major roads and highways. Multivariate linear and multinomial regression analyses were used to assess whether proximity to roads was a risk factor for airway hyper-responsiveness as measured by PC(20) methacholine. RESULTS: Patients who lived within 200 m of a major road had increased odds (OR 1.38 [95% CI 1.04 to 1.85]) of having moderate airway hyperresponsiveness (0.25 mg/mL 16 mg/mL). Spatial analysis also revealed that the majority of patients with severe airway hyper-responsiveness lived within the urban core of the city while those with moderate to mild hyper-responsiveness were also dispersed in rural areas. CONCLUSIONS: In an adult population of patients attending an outpatient respiratory clinic in Hamilton, living close to major roadways was associated with an increased risk of moderate airway hyper responsiveness. This correlation suggests that exposure to traffic emissions may provoke the pathology of airway hyper-responsiveness leading to variable airflow obstruction. PMID- 22536578 TI - Active and uncontrolled asthma among children exposed to air stack emissions of sulphur dioxide from petroleum refineries in Montreal, Quebec: a cross-sectional study. AB - BACKGROUND: Little attention has been devoted to the effects on children's respiratory health of exposure to sulphur dioxide (SO2) in ambient air from local industrial emissions. Most studies on the effects of SO(2) have assessed its impact as part of the regional ambient air pollutant mix. OBJECTIVE: To examine the association between exposure to stack emissions of SO(2) from petroleum refineries located in Montreal's (Quebec) east-end industrial complex and the prevalence of active asthma and poor asthma control among children living nearby. METHODS: The present cross-sectional study used data from a respiratory health survey of Montreal children six months to 12 years of age conducted in 2006. Of 7964 eligible households that completed the survey, 842 children between six months and 12 years of age lived in an area impacted by refinery emissions. Ambient SO(2) exposure levels were estimated using dispersion modelling. Log binomial regression models were used to estimate crude and adjusted prevalence ratios (PRs) and 95% CIs for the association between yearly school and residential SO(2) exposure estimates and asthma outcomes. Adjustments were made for child's age, sex, parental history of atopy and tobacco smoke exposure at home. RESULTS: The adjusted PR for the association between active asthma and SO(2) levels was 1.14 (95% CI 0.94 to 1.39) per interquartile range increase in modelled annual SO(2). The effect on poor asthma control was greater (PR=1.39 per interquartile range increase in modelled SO(2) [95% CI 1.00 to 1.94]). CONCLUSIONS: Results of the present study suggest a relationship between exposure to refinery stack emissions of SO(2) and the prevalence of active and poor asthma control in children who live and attend school in proximity to refineries. PMID- 22536579 TI - Pleural mesothelioma surveillance: validity of cases from a tumour registry. AB - BACKGROUND: Pleural mesothelioma is a rare tumour associated with exposure to asbestos fibres. Fewer than than one-quarter of cases registered in the Quebec Tumour Registry (QTR) have been compensated as work-related. While establishing a surveillance system, this led to questioning as to whether there has been over registration of cases that are not authentic pleural mesotheliomas in the QTR. OBJECTIVE: To assess whether registered cases of pleural mesothelioma could be confirmed. METHODS: A medical chart review was designed to assess the proportion of mesothelioma cases newly registered in the QTR in 2001/2002 that could be confirmed. For each registered case, clinical, medical imaging and pathology information were sought and, occasionally, additional immunohistochemistry staining was obtained. Three specialists - a chest physician, a radiologist and a pathologist - reviewed the available information and material, coding each mesothelioma case as to degree of certainty of the mesothelioma diagnosis. RESULTS: The QTR reported 190 incident cases of mesothelioma (81% males) for the period. The specialists classified 81% of charts as 'certain/probable' or 'possible' mesotheliomas, 8% as 'unlikely to be a mesothelioma' and 11% as 'not a mesothelioma'. After excluding chart summaries of unsatisfactory quality, 87% to 88% of the charts were classified as 'certain/probable' or 'possible' mesotheliomas, and 9% to 11% were still considered 'not a mesothelioma'. CONCLUSION: Tumour registry data are a valid source of information for mesothelioma surveillance. While there is some over-registration of mesothelioma cases in the QTR, a significant majority of registered cases appeared to be authentic. Over-registration cannot explain the greater proportion of cases that were not compensated. PMID- 22536580 TI - Alpha-1 antitrypsin deficiency targeted testing and augmentation therapy: a Canadian Thoracic Society clinical practice guideline. AB - Alpha-1 antitrypsin (A1AT) functions primarily to inhibit neutrophil elastase, and deficiency predisposes individuals to the development of chronic obstructive pulmonary disease (COPD). Severe A1AT deficiency occurs in one in 5000 to one in 5500 of the North American population. While the exact prevalence of A1AT deficiency in patients with diagnosed COPD is not known, results from small studies provide estimates of 1% to 5%. The present document updates a previous Canadian Thoracic Society position statement from 2001, and was initiated because of lack of consensus and understanding of appropriate patients suitable for targeted testing for A1AT deficiency, and for the use of A1AT augmentation therapy. Using revised guideline development methodology, the present clinical practice guideline document systematically reviews the published literature and provides an evidence-based update. The evidence supports the practice that targeted testing for A1AT deficiency be considered in individuals with COPD diagnosed before 65 years of age or with a smoking history of <20 pack years. The evidence also supports consideration of A1AT augmentation therapy in nonsmoking or exsmoking patients with COPD (forced expiratory volume in 1 s of 25% to 80% predicted) attributable to emphysema and documented A1AT deficiency (level <=11 umol/L) who are receiving optimal pharmacological and nonpharmacological therapies (including comprehensive case management and pulmonary rehabilitation) because of benefits in computed tomography scan lung density and mortality. PMID- 22536581 TI - Pan-Canadian REspiratory STandards INitiative for Electronic Health Records (PRESTINE): 2011 national forum proceedings. AB - In a novel knowledge translation initiative, the Government of Ontario's Asthma Plan of Action funded the development of an Asthma Care Map to enable adherence with the Canadian Asthma Consensus Guidelines developed under the auspices of the Canadian Thoracic Society (CTS). Following its successful evaluation within the Primary Care Asthma Pilot Project, respiratory clinicians from the Asthma Research Unit, Queen's University (Kingston, Ontario) are leading an initiative to incorporate standardized Asthma Care Map data elements into electronic health records in primary care in Ontario. Acknowledging that the issue of data standards affects all respiratory conditions, and all provinces and territories, the Government of Ontario approached the CTS Respiratory Guidelines Committee. At its meeting in September 2010, the CTS Respiratory Guidelines Committee agreed that developing and standardizing respiratory data elements for electronic health records are strategically important. In follow-up to that commitment, representatives from the CTS, the Lung Association, the Government of Ontario, the National Lung Health Framework and Canada Health Infoway came together to form a planning committee. The planning committee proposed a phased approach to inform stakeholders about the issue, and engage them in the development, implementation and evaluation of a standardized dataset. An environmental scan was completed in July 2011, which identified data definitions and standards currently available for clinical variables that are likely to be included in electronic medical records in primary care for diagnosis, management and patient education related to asthma and COPD. The scan, sponsored by the Government of Ontario, includes compliance with clinical nomenclatures such as SNOMED-CT(r) and LOINC(r). To help launch and create momentum for this initiative, a national forum was convened on October 2 and 3, 2011, in Toronto, Ontario. The forum was designed to bring together key stakeholders across the spectrum of respiratory care, including clinicians, researchers, health informaticists and administrators to explore and recommend a potential scope, approach and governance structure for this important project. The Pan-Canadian REspiratory STandards INitiative for Electronic Health Records (PRESTINE) goal is to recommend respiratory data elements and standards for use in electronic medical records across Canada that meet the needs of providers, administrators, researchers and policy makers to facilitate evidence-based clinical care, monitoring, surveillance, benchmarking and policy development. The focus initially is expected to include asthma, chronic obstructive pulmonary disease and pulmonary function standards elements that are applicable to many respiratory conditions. The present article summarizes the process and findings of the forum deliberations. PMID- 22536582 TI - Canadian Thoracic Society 2012 guideline update: diagnosis and management of asthma in preschoolers, children and adults. AB - BACKGROUND: In 2010, the Canadian Thoracic Society (CTS) published a Consensus Summary for the diagnosis and management of asthma in children six years of age and older, and adults, including an updated Asthma Management Continuum. The CTS Asthma Clinical Assembly subsequently began a formal clinical practice guideline update process, focusing, in this first iteration, on topics of controversy and/or gaps in the previous guidelines. METHODS: Four clinical questions were identified as a focus for the updated guideline: the role of noninvasive measurements of airway inflammation for the adjustment of anti-inflammatory therapy; the initiation of adjunct therapy to inhaled corticosteroids (ICS) for uncontrolled asthma; the role of a single inhaler of an ICS/long-acting beta(2) agonist combination as a reliever, and as a reliever and a controller; and the escalation of controller medication for acute loss of asthma control as part of a self-management action plan. The expert panel followed an adaptation process to identify and appraise existing guidelines on the specified topics. In addition, literature searches were performed to identify relevant systematic reviews and randomized controlled trials. The panel formally assessed and graded the evidence, and made 34 recommendations. RESULTS: The updated guideline recommendations outline a role for inclusion of assessment of sputum eosinophils, in addition to standard measures of asthma control, to guide adjustment of controller therapy in adults with moderate to severe asthma. Appraisal of the evidence regarding which adjunct controller therapy to add to ICS and at what ICS dose to begin adjunct therapy in children and adults with poor asthma control supported the 2010 CTS Consensus Summary recommendations. New recommendations for the adjustment of controller medication within written action plans are provided. Finally, priority areas for future research were identified. CONCLUSIONS: The present clinical practice guideline is the first update of the CTS Asthma Guidelines following the Canadian Respiratory Guidelines Committee's new guideline development process. Tools and strategies to support guideline implementation will be developed and the CTS will continue to regularly provide updates reflecting new evidence. PMID- 22536585 TI - Ethics in the dental implant era. PMID- 22536583 TI - Prevalence of High Epworth Sleepiness Scale scores in a rural population. AB - BACKGROUND: Increased daytime sleepiness is an important symptom of obstructive sleep apnea (OSA). OSA is frequently underdiagnosed, and the Epworth Sleepiness Scale (ESS) can be a useful tool in alerting physicians to a potential problem involving OSA. OBJECTIVE: To measure the prevalence and determinants of daytime sleepiness measured using the ESS in a rural community population. METHODS: A community survey was conducted to examine the risk factors associated with ESS in a rural population in 154 households comprising 283 adults. Questionnaire information was obtained regarding physical factors, social factors, general medical history, family medical history, ESS score, and self-reported height and weight. Multivariable binary logistic regression analysis based on the generalized estimating equations approach to account for clustering within households was used to predict the relationship between a binary ESS score outcome (normal or abnormal) and a set of explanatory variables. RESULTS: The population included 140 men (49.5%) and 143 women (50.5%) with an age range of 18 to 97 years (mean [+/- SD] 52.0+/-14.9 years). The data showed that 79.2% of the study participants had an ESS score in the normal range (0 to 10) and 20.8% had an ESS score >10, which is considered to be abnormal or high sleepiness. Multivariable regression analysis revealed that obesity was significantly associated with an abnormal or high sleepiness score on the ESS (OR 3.40 [95% CI 1.31 to 8.80). CONCLUSION: High levels of sleepiness in this population were common. Obesity was an important risk factor for high ESS score. PMID- 22536584 TI - Validity of chronic obstructive pulmonary disease diagnoses in a large administrative database. AB - BACKGROUND: Administrative databases are often used for research purposes, with minimal attention devoted to the validity of the included diagnoses. AIMS: To determine whether the principal diagnoses of chronic obstructive pulmonary disease (COPD) made in hospitalized patients and recorded in a large administrative database are valid. METHODS: The medical charts of 1221 patients hospitalized in 40 acute care centres in Quebec and discharged between April 1, 2003 and March 31, 2004, with a principal discharge diagnosis of COPD (International Classification of Diseases, Ninth Revision codes 491, 492 or 496) were reviewed. The diagnosis of COPD was independently adjudicated by two pulmonologists using clinical history (including smoking status) and spirometry. The primary outcome measure was the positive predictive value (PPV) of the database for the diagnosis of COPD (ie, the proportion of patients with an accurate diagnosis of COPD corroborated by clinical history and spirometry). RESULTS: The diagnosis of COPD was validated in 616 patients (PPV 50.4% [95% CI 47.7% to 53.3%]), with 372 patients (30.5%) classified as 'indeterminate'. Older age and female sex were associated with a lower probability of an accurate diagnosis of COPD. Hospitalization in a teaching institution was associated with a twofold increase in the probability of a correct diagnosis. CONCLUSIONS: The results support the routine ascertainment of the validity of diagnoses before using administrative databases in clinical and health services research. PMID- 22536586 TI - An uncommon clinical feature of IAN injury after third molar removal: a delayed paresthesia case series and literature review. AB - After an inferior alveolar nerve (IAN) injury, the onset of altered sensation usually begins immediately after surgery. However, it sometimes begins after several days, which is referred to as delayed paresthesia. The authors considered three different etiologies that likely produce inflammation along the nerve trunk and cause delayed paresthesia: compression of the clot, fibrous reorganization of the clot, and nerve trauma caused by bone fragments during clot organization. The aim of this article was to evaluate the etiology of IAN delayed paresthesia, analyze the literature, present a case series related to three different causes of this pathology, and compare delayed paresthesia with the classic immediate symptomatic paresthesia. PMID- 22536587 TI - Degree of root resorption after root canal treatment with iodoform-containing filling material in primary molars. AB - OBJECTIVE: To compare the degree of root resorption in endodontically treated primary molars with that of homologous teeth without root canal treatment. METHOD AND MATERIALS: A retrospective study was carried out comprising 105 records of children who had received root canal treatment in a primary molar. Mean age at the time of treatment was 7.0 +/- 1.4 years. Inclusion criteria included one endodontically treated primary molar and a homologous primary molar with no root canal treatment on the other side of the mouth. All teeth were treated by the same operator in the same way using the same iodoform-containing root canal filling material. The degree of root resorption was compared by radiographic evaluation 12 or more months posttreatment. RESULTS: The degree of root resorption on the final follow-up radiograph in the endodontically treated primary molars was significantly higher (P < .05) than the degree of root resorption in the homologous teeth. The degree of root resorption was higher in boys than in girls. No statistical significance was found between the degree of root resorption and the age at the time of treatment in either the root canal treated teeth or the homologous teeth. Follow-up radiographs demonstrated a higher degree of root resorption in the root canal treated teeth than in the homologous teeth, regardless of the type of treatment performed on the homologous side. CONCLUSION: Root canal treatment performed with iodoform-containing root canal filling material accelerates root resorption in root canal-treated primary molars compared with homologous teeth without endodontic treatment. Clinicians should be aware that endodontically treated teeth will probably shed before homologous ones that are not root canal treated. PMID- 22536588 TI - Safety of increasing vertical dimension of occlusion: a systematic review. AB - OBJECTIVE: To review all the literature investigating the implications of increasing the vertical dimension of occlusion (VDO). METHOD AND MATERIALS: A comprehensive electronic search was conducted through PubMed with the aid of Boolean operators to combine the following key words: "occlusal vertical dimension," "increasing vertical dimension," "bite raising," "occlusal space," "resting vertical dimension," "rest position," "altered vertical dimension," "mandibular posture," "temporomandibular joint," and "masticatory muscles." The search was limited to peer-reviewed articles written in English and published through August 2011. Further, the literature search was endorsed by manual searching through peer-reviewed journals and reference lists of the selected articles. RESULTS: A total of 902 studies were initially retrieved, but only 9 met the specified inclusion criteria for the review. From the selected studies, four variables were identified to be relevant to the topic of VDO increase: magnitude of VDO increase, method of increasing VDO, occlusion scheme, and the adaptation period. CONCLUSION: Considering the limitations of this review, it could be concluded that whenever indicated, permanent increase of the VDO is a safe and predictable procedure. Intervention with a fixed restoration is more predictable and results in a higher adaptation level. Negative signs and symptoms were identified, but they were self-limiting. Due to the lack of a well-designed study, further controlled and randomized studies are needed to confirm the outcome of this review. PMID- 22536589 TI - Asymptomatic ossifying fibroma of the mandible: a case presentation. AB - Ossifying fibromas are rare benign bone-related lesions of the jaw. Early diagnosis based on clinical, radiologic, and pathohistologic findings is essential, since undetected lesions may expand and cause considerable functional and cosmetic problems. The treatment of choice is purely surgical. Periodic clinical and radiologic follow-up should be scheduled, since recurrence is possible. The present article describes the diagnostic procedures, surgical management, and follow-up of an asymptomatic ossifying fibroma in the mandible of a 21-year-old man. PMID- 22536590 TI - Potential surface alteration effects of laser-assisted periodontal surgery on existing dental restorations. AB - OBJECTIVE: Laser-assisted gingivectomies are performed in proximity to teeth, existing restorations, and implants. In case of accidental exposures, a detrimental surface defect may cause failure. Surface interactions should be evaluated for safety margin determination of certain laser-material combinations. The purpose of this in vitro study was to assess the microscopic and visible effects of CO2, Nd:YAG, and 810-nm diode laser irradiations on various dental materials and tooth tissue. METHOD AND MATERIALS: Study samples were fabricated (10 x 7.5 mm irradiation surface area, 1 mm thickness) from eight material groups (amalgam, base metal, gold, palladium-silver, composite, ceramic, titanium, and extracted tooth slices). Laser irradiations were performed with CO2, Nd:YAG, and 810-nm diode lasers using the manufacturer's recommended settings for gingivectomy at a 45-degree angle for 30 seconds. Irradiated surfaces were evaluated under SEM at 200x and 1,000x magnifications. Standardized photographs were obtained using a camera mount system (10x high-definition macro lens). The SEM images and photographs were correlated to determine surface interactions. RESULTS: Nd:YAG detrimentally affected all metallic materials and tooth structures. CO2 altered amalgam, gold, and palladium-silver slightly, whereas composite, ceramic, and tooth surfaces were detrimentally altered. The 810-nm diode altered amalgam, gold, titanium, palladium-silver, and composite but only gold and palladium-silver surfaces were barely traceable. CONCLUSION: Within the limitations of this in vitro study, surface effects were all instant; therefore, even a short accidental exposure may be destructive in some laser-material combinations. During gingivectomies, CO2 near tooth-colored restorations and Nd:YAG near metallic restorations and implants should be used carefully. The 810 nm diode was found to be safer due to its reversible alterations in only some materials. Further in vivo studies are necessary to clinically apply the outcomes of this study. PMID- 22536591 TI - Primary cheiloplasty on an elderly man: case report and review of the literature. AB - It is rare for surgeons in the United States to perform primary repair of a cleft lip on an adult. However, in developing nations with limited specialized health care, late presentation for primary cheiloplasty occurs due to limitations in access to care, lack of awareness of treatment availability, and inability to afford treatment. Oral and maxillofacial surgeons who participate in humanitarian surgical mission trips to the developing world may encounter this subpopulation of cleft patients. The following case report describes the repair of an incomplete bilateral cleft lip in a 68-year-old man performed during a mission trip to rural Bangladesh. Based on an extensive literature search, this is the oldest patient to have undergone primary cheiloplasty reported in the English language surgical literature. PMID- 22536593 TI - Modeling of S mutans and A naeslundii acid production in vitro with caries incidence of low- and high-risk children. AB - OBJECTIVES: Nowadays, the extended ecological plaque hypothesis equates dental health with the occurrence of acidogenic generalists in the plaque flora and explains disease?the irreversible demineralization of the dental hard tissue?by an ecologic shift in plaque composition, favoring acidogenic and aciduric specialists, following repeated conditions of high sugar. In the present study, aspects of the extended ecological plaque hypothesis were examined in retrospect. METHOD AND MATERIALS: Serving as a basis were data on (1) the caries incidence of children, classified according to their DMFT as having low or high caries risk; (2) the qualitative plaque composition of the children with the prevalence of mutans streptococci and actinomyces; (3) the amounts of acid and acid tolerance, determined by pH state titration (glucose), of representatively isolated strains of mutans streptococci and actinomyces; (4) the extrapolation of the acid amount to the occurrence of mutans streptococci and actinomyces in the plaque of children; and (5) the relationship between the extrapolated acid amount in plaque and caries incidence and the respective classification of the children into low and high caries risk. RESULTS: The synoptic consideration of the numbers of A naeslundii and S mutans in plaque of children, with their capacity for acid production in vitro, reflected the caries risk classification. CONCLUSION: The analysis of the clinical, microbiologic, and in vitro findings concerning the virulence of the plaque isolates supports the extended ecological plaque hypothesis. Children with low caries risk had developed one new decayed surface within 4 years; children with high caries risk developed four within the same time period. PMID- 22536592 TI - Efficacy of lycopene as a locally delivered gel in the treatment of chronic periodontitis: smokers vs nonsmokers. AB - OBJECTIVE: The present study was carried out as a multicenter, randomized controlled, split-mouth clinical trial to evaluate the efficacy of locally delivered lycopene on periodontal health and gingival crevicular fluid (GCF) levels of 8-hydroxydeoxyguanosine (8-OHdG) in smokers and nonsmokers compared with periodontally healthy control subjects. METHOD AND MATERIALS: One hundred ten subjects including 50 smokers, 50 nonsmokers, and 10 controls participated in this study. Subjects in the smoker and nonsmoker groups had contralateral sites treated with lycopene gel and a placebo. Clinical parameters included recording site-specific measures of plaque, gingivitis, probing depth, and clinical attachment level. GCF 8-OHdG values were analyzed using a commercially available ELISA kit. RESULTS: Compared with the placebo, lycopene-treated sites in smokers and nonsmokers showed significant reductions in probing depths and gain in the clinical attachment levels. However, there was no statistically significant difference in the clinical parameters when lycopene-treated sites in smokers and nonsmokers were compared, except for the reduction in the 8-OHdG levels. The 8 OHdG levels at 1 week and 3 months in sites treated with lycopene in the smoker and nonsmoker group were comparable with those in the periodontally healthy control group. CONCLUSION: The gel formulation was effective in increasing clinical attachment and reducing gingival inflammation, probing depth, and oxidative injury compared with the placebo in smoking and nonsmoking subjects. PMID- 22536594 TI - An in vitro radiographic analysis of the density of dental luting cements as measured by CCD-based digital radiography. AB - OBJECTIVE: According to the ISO, the radiopacity of luting cements should be equal to or greater than that of aluminum. The aim of this in vitro study was to determine the radiopacity of 13 commercially available dental luting cements and compare them with human enamel and dentin. METHOD AND MATERIALS: Five classes of luting cements were evaluated: zinc phosphate (Cegal N and Harvard Zinc Phosphate), zinc polycarboxylate (Harvard Polycarboxylate and Hoffmann's Carboxylate), glass ionomers (Ketac Cem Easymix, Ketac Cem Radiopaque, and Fuji I), resin-modified glass ionomer (Rely X Luting), and resin cements (Multilink Automix, Variolink II, Speed CEM, Rely X Unicem Automix, and three shades of Variolink Veneer). Tooth slices served as controls. Five specimens of each material measuring 8 mm in diameter and 1 mm thick were prepared and radiographed alongside tooth slices and an aluminum stepwedge using a Trophy RVG sensor. The radiopacity values were expressed in mm Al and analyzed by the ANOVA and Tukey tests (P < .05). RESULTS: All the cements examined except Variolink Veneer had significantly higher radiopacities than that of dentin. Rely X Unicem Automix, glass ionomer, and resin-modified glass-ionomer cements demonstrated radiopacities that were not significantly different with respect to enamel. Zinc phosphate, zinc polycarboxylate, and three of the resin cements presented radiopacity values that were significantly greater than that of enamel. CONCLUSION: Almost all the investigated materials presented an acceptable radiopacity. Radiopacity of dental cements seems to depend more on the presence of elements with high atomic numbers than on the type of the material. PMID- 22536596 TI - Regenerative wound healing in acute degree III mandibular defects in dogs. AB - OBJECTIVE: To evaluate the healing events in degree III furcation defects in dogs following the application of the combination of an enamel matrix derivative with a biphasic calcium phosphate (Emdogain Plus). METHOD AND MATERIALS: Seventeen degree III furcation defects, 5 mm high and 4 mm wide, were created in 9 dogs. In both groups, the defects were conditioned with EDTA. One defect was treated with Emdogain Plus (n = 9), while the contralateral defect serving as control remained empty (n = 8). The defects in both groups were fully covered by coronally repositioned flaps. After 5 months of healing, histologic and histometric analysis was preformed. RESULTS: A significant amount of new attachment and bone formation was observed in both control and test specimens. However, in a number of control specimens, ankylosis was also observed. In the control and test groups, respectively, the mean new cementum length was 10.8 +/- 2.1 mm and 8.6 +/ 3.2 mm; the mean periodontal ligament length was 7.6 +/- 3.8 mm and 8.1 +/- 4.0 mm. The mean new bone height was 4.4 +/- 1.3 mm and 4.3 +/- 1.6 mm in the control and test groups, respectively. No statistical differences were found between the two groups in terms of amount of cementum, periodontal ligament, and alveolar bone regeneration. CONCLUSION: The present study failed to show higher amounts of newly formed cementum and bone following treatment of acute degree III mandibular furcation defects following use of Emdogain Plus compared with a coronally advanced flap. Emdogain Plus seems to have a protective role against ankylosis in this type of defect. PMID- 22536595 TI - Hand-washing knowledge and practices among dentists and dental specialists. AB - OBJECTIVE: Hand washing is the most important way to prevent the spread of infection. However, studies have shown that there is a lack of knowledge among physicians about proper hand hygiene. The purpose of this study was to determine the knowledge of general dentists and dental specialists regarding the correct agents to use and the appropriate times to wash hands. METHOD AND MATERIALS: A questionnaire asking for demographic information and the answers to questions about proper hand hygiene practices and agents was sent via email to a list of general dentists and dental specialists. A total of 480 completed surveys were received (approximately 15% response). RESULTS: None of the respondents answered all the questions correctly. Six percent answered 4 questions correctly, 23% answered 3 questions correctly, and 47% answered only 2 questions correctly. There was no correlation between the number of correct answers and whether the respondent was a general dentist or a specialist. CONCLUSION: There is a lack of knowledge among dentists regarding proper hand hygiene. For the benefit of both the patient and the doctor, this situation must be remedied. PMID- 22536597 TI - Initial shear bond strength of orthodontic brackets bonded to bleached teeth with a self-etching adhesive system. AB - OBJECTIVES: To examine the initial shear bond strength of orthodontic brackets bonded to bleached teeth with a self-etching adhesive system, as well as the effect of the length of time after bleaching on the initial bond strength. METHOD AND MATERIALS: Ninety premolars were collected and divided equally among a control group (CG) of unbleached teeth with brackets bonded, an immediate group (IG) with teeth bonded soon after bleaching, and a delayed group (DG) consisting of teeth bleached and then immersed in artificial saliva for 7 days before bracket bonding. Subsequently, the teeth of each group were equally assigned to two different primer adhesive systems: the acid-etch-and-rinse adhesive system (35% phosphoric acid gel and Transbond XT primer) and the self-etching adhesive system (Transbond Plus self-etching primer). Initial bond strength was measured 24 hours after bracket bonding. RESULTS: IG registered the lowest mean initial bond strength when the self-etching adhesive system was in use, followed by DG and CG (in that order). As for the acid-etch-and-rinse adhesive system, the mean initial bond strength was significantly lower in IG than in CG and DG. Significant differences in mean initial bond strength were noted between the two adhesive systems in IG and DG. CONCLUSION: In trials using a self-etching adhesive system, the mean initial bond strength that declined immediately after bleaching returned to a clinically acceptable level of 6 MPa after the specimens were immersed in artificial saliva for 7 days but fell short of the level of unbleached teeth. PMID- 22536598 TI - [It is about more than the price of drugs!]. PMID- 22536599 TI - Retraction: Sphingosine kinase 1 regulates pro-inflammatory responses triggered by TNFa in primary human monocytes. L. Zhi, B. P. Leung, A. J. Melendez. PMID- 22536600 TI - In memoriam. PMID- 22536601 TI - We'll drink to that: the 200th anniversary of Australia's oldest hospital. PMID- 22536602 TI - Hospitalist activity by physician encounters: based on MGMA and SHM 2011 State of Hospital Medicine report. PMID- 22536603 TI - Studies highlight loss of empathy among dental students during training. PMID- 22536604 TI - It takes a team. PMID- 22536605 TI - Rough road ahead: Anti-IPAB bill faces Senate, Obama opposition. PMID- 22536606 TI - Noteworthy budget: Republican goals reflected in House bill. PMID- 22536607 TI - Showdown gets a head start: prior to ACA hearings, both sides take aim. PMID- 22536608 TI - 'SNFists' at work: nursing home docs patterned after hospitalists. PMID- 22536609 TI - Hospital utilization by state: ranked by total acute-care hospital discharges based on fiscal 2010 data. PMID- 22536610 TI - Largest CPOE systems: by percentage of the total number of M.D.s doing computerized physician order entry through 2010. PMID- 22536623 TI - "It Was Never Good World Sence Minister Must Have Wyves": clerical celibacy, clerical marriage, and anticlericalism in Reformation England. AB - The impact of the Reformation was felt strongly in the nature and character of the priesthood, and in the function and reputation of the priest. A shift in the understanding of the priesthood was one of the most tangible manifestations of doctrinal change, evident in the physical arrangement of the church, in the language of the liturgy, and in the relaxation of the discipline of celibacy, which had for centuries bound priests in the Latin tradition to a life of perpetual continence. Clerical celibacy, and accusations of clerical incontinence, featured prominently in evangelical criticisms of the Catholic church and priesthood, which made a good deal of polemical capital out of the perceived relationship of the priest and the efficacy of his sacred function. Citing St Paul, Protestant polemicists presented clerical marriage as the only, and appropriate remedy, for priestly immorality. But did the advent of a married priesthood create more problems than it solved? The polemical certainties that informed evangelical writing on sacerdotal celibacy did not guarantee the immediate acceptance of a married priesthood, and the vocabulary that had been used to denounce clergy who failed in their obligation to celibacy was all too readily turned against the married clergy. The anti-clerical lexicon, and its usage, remained remarkably static despite the substantial doctrinal and practical challenges posed to the traditional model of priesthood by the Protestant Reformation. PMID- 22536624 TI - The new "new racism" thesis: limited government values and race-conscious policy attitudes. AB - Some contend that Whites' application of values to form opinions about race conscious policy may constitute a subtle form of racism. Others challenge the new racism thesis, suggesting that racism and values are exclusive in their influence. Proponents of the thesis assert that many Whites' attitudes about such policy are structured by a mix of racism and American individualism. The author suggests that an even more subtle form of racism may exist. Racism may actually be expressed in opposition to big government. The test results presented here indicate that the effects of limited-government values on attitudes about race conscious policy are conditional on levels of racial prejudice for many Whites, whereas the effects on racially ambiguous social welfare policy attitudes are not. The author contends that these results provide support to the argument that racism still exists and has found a new subtle expression. PMID- 22536625 TI - Memories in photography and rebirth: toward a psychosocial therapy of the metaphysics of reincarnation among traditional Esan people of Southern Nigeria. AB - The aim of this article is to show that beyond the need for the justification of the belief in reincarnation, beyond the quest for evidences to prove its reality or otherwise, the idea of rebirth has a pragmatic role in the cultures where it is held. Using the theorization of rebirth among the Esan people of southern Nigeria as a pilot, it asserts that the idea of rebirth plays a psychosocial, therapeutic function of comfort and healing for those traumatized by the death of a loved one. This, it shall be seen, is similar to, even more reliable than, the role of photography in preserving cherished memories. The article does not, therefore, mean to join issues in the myth-reality or truth-falsehood debate on rebirth among scholars but attempts to establish the role of reincarnation, like photography, in bringing the past into the present. PMID- 22536626 TI - Young, black, and connected: Facebook usage among African American college students. AB - This article examines the extent and intensity of Facebook usage among African American college students and investigates their reasons for using Facebook. As expected, 98% of students in the survey had a Facebook account, and a large number of Facebook "friends." Younger users spent significantly more time on Facebook than older ones. Our findings underscore the importance of cultural influence for African American online users. Displaying photographs and personal interests on Facebook signals racial identity among African American college students. Personality traits, such as self-esteem, trust in people, satisfaction with university life, and racial identity, were not significant predictors on the time spent on Facebook. PMID- 22536627 TI - A change of the guard. PMID- 22536628 TI - Tracking progress towards global polio eradication, 2010-2011. PMID- 22536629 TI - Findings of research misconduct. PMID- 22536630 TI - "A monument to defective administration?" The London Commissions of Sewers in the early nineteenth century. PMID- 22536631 TI - Care coordination of the future and the nurse's role. PMID- 22536632 TI - [Centralization of gynecologic-obstetric care]. PMID- 22536633 TI - [Urinary tract infections in women--possibilities of differentiated approach in treatment and prevention]. AB - Urinary tract infections (UTIs) are among the most urgent health problems for which women in working age see their physician (whether the general practitioner, urologist or gynecologist). The most common manifestation of UTIs in women is acute uncomplicated cystitis the diagnosis and treatment of which is usually straightforward. When selecting an appropriate antimicrobial agent, it is advisable to consider its pharmacokinetics, expected spectrum of efficacy and effect on the vaginal flora. Short-term therapy of three to five days is preferred. In women with recurrent cystitides, it is necessary, in addition to performing comprehensive urological examination to rule out functional or anatomic abnormalities, to perform urine culture and targeted treatment according to sensitivity. The review article presents differentiated options of treatment and prevention of recurrent infections with both antimicrobial agents and regimen measures as well as preparations not included in the group of antimicrobial agents; however, when correctly indicated, their administration may bring long term relief to these women. The article also deals with complicated infections in women and asymptomatic bacteriuria in elderly women. PMID- 22536634 TI - [Phytoestrogenes in menopause: working mechanisms and clinical results in 28 patients]. AB - OBJECTIVE: Comparison of phytoestrogen treatment efficacy in menopausal women with and without ability to metabolise phytoestrogens. DESIGN: Clinical trial. SETTING: Department of Obstetrics and Gynaecology, Regional Hospital, Mlada Boleslav. METHODS: 28 menopausal women were treated with phytoestrogens in dose 80 mg daily. Before start and after finishing of treatment urinary concentrations of active metabolite S-equol were measured using ELISA method. Similarly before and after treatment Kupperman's index was measured. Patients with urinary concentrations of S-equol above 1 ng/ml were considered as S-equol producers, remaining patients formed control group. RESULTS: 16 out of 28 women were considered as S-equol producers, remainig 12 as a non-producers. Initial urinary concentrations of S-equol were 0.34 +/- 0.37 ng/ml in producers group and 0.29 +/ 0.30 ng/ml in non-producers. After finishing of therapy urinary concentration of S-equol increased to 10.67 +/- 11.57 ng/ml (p = 0.002) in producers group and 0.34 +/- 0.30 ng/ml (p = 0.701) in non-producers. Kupperman's index values were 23.44 +/- 11.57 in producers group and 17.25 +/- 7.78 in non-producers. After therapy value of Kupperman's index decreased to 14.44 +/- 9.97 (p = 0.003) in producers and to 12.00 +/- 7.18 (p = 0.100) in non-producers. No correlation between improvement in Kupperman's index and urinary concentration of S-equol after therapy was found similarly as between urinary concentration of S-equol before and after therapy in producents group. CONCLUSION: Significant phytoestrogen treatment effect in menopausal women producing S-equol was proven. Testing method for S-equol production introduced by our team togehter with suggested threshold urine concentration level of 1 ng/ml allows precise distinction of producers and non-producers of S-equol and subsequently to predict better treatment effect of phytoestrogens. PMID- 22536635 TI - [The psychosocial needs of newborn children in the context of perinatal care]. AB - OBJECTIVE: To outline the variety of the psychosocial needs of newborn children to be taken into account in maternal-child nursing and to present recommendations for good practice. DESIGN: Review article. SETTING: Department of Psychology, Faculty of Philosophy, Charles University, Prague. SUBJECT AND METHOD: This study is focused on psychological importance of birth experience for the newborn, early mother-child contact, initiation of breastfeeding as well as on the psychosocial needs of the preterm newborn and newborn children at health risk. Both conclusions of scientific literature and the results of our research demonstrate that respecting the psychosocial needs of the newborn in mother-child nursing is beneficial not only for psychological development of children, but also for their physical health in short-term as well as long-term perspective. CONCLUSION: Despite its rather high quality, the perinatal health care in the Czech republic still suffers from several shortcomings in the psychological field. More emphasis needs to be put on supporting the early mother-infant contact, individual needs of parturients and their infants and initiation of breastfeeding, especially as regards women after cesarean section delivery and mothers of preterm infants. PMID- 22536636 TI - [The new colposcopic signs--ridge sign and inner border]. AB - OBJECTIVE: To conclude knowledge about new colposcopic signs--ridge sign and inner border. DESIGN: Review article. SETTING: Oncogynecological center, Department of Gynecology and Obstetrics, General Faculty Hospital and 1st Medical School of Charles University, Prague. METHODS AND RESULTS: Recently updated colposcopic classification includes two new colposcopic signs--ridge sign and inner border. Both are mainly present in lesions associated with oncogenic human papillomaviruses infection. Ridge sign represents thick opaque acetowhite epithelium irregularly growing in the squamocolumnar junction as ledges. Inner border is a sharp acetowhite demarcation within a less opaque acetowhite area. The sensitivity and specificity for detection of underlying high-grade lesion is 33.1% and 93.1% in ridge sign and 20% and 97% in inner border sign respectively. CONCLUSIONS: Ridge sign and inner border are new colposcopic signs, which improve sensitivity and specificity of colposcopic examination. PMID- 22536637 TI - [Does the asymptomatic carriage of FV Leiden and FII prothrombin in heterozygous configuration represent the increased risk of thrombembolic complications during pregnancy, childbirth and postpartum?]. AB - OBJECTIVE: To evaluate the course of pregnancy and puerperium in asymptomatic carriers of FV Leiden and FII prothrombin mutation in heterozygous configuration in terms of risk of thrombembolic disease and late pregnancy complications. To evaluate whether global prophylactic LMWH administration already during pregnancy has brought some benefit to these women. TYPE OF STUDY: Prospective study. METHODS: From June 2007 to June 2011, we monitored the incidence of thrombembolic events (TED) and severe late pregnancy complications in 473 asymptomatic carriers of FV Leiden and FII prothrombin mutation in heterozygous configuration. We also compared the ongoing changes of commonly clinically available hemocoagulation tests. In selected women, we added to coagulation tests a thrombin generation test (TGA) and thrombin-antithrombin test (TAT). In 253 women (Group A), preventive LMWH application was introduced already during pregnancy. In 220 women (Group B), the application of LMWH was commenced as late as on the delivery day. In both groups application of LMWH continued during the puerperium. RESULTS: The incidence of TED in the whole group of carriers of thrombophylic mutations accounted for 0.19%. The incidence of severe late pregnancy complications was very low - 3%. Medians of the monitored parameters of the hemocoagulation in compared groups and 'healthy' controls did not show statistically significant differences at any stage of pregnancy, labor or end of puerperium, with the exception of the results of TAT test at the end of puerperium. CONCLUSIONS: No direct causal relationship has been established between asymptomatic carriage of Leiden and prothrombin mutation in heterozygous configuration and the occurrence of severe late pregnancy complications. These types of mutation represent only a slightly increased risk in terms of development of thrombophylic events. General LMWH prophylaxis during pregnancy is not indicated. However, individual careful monitoring of hemocoagulation changes and early detection of associated transient situations potentiating risk of thrombembolic events is desirable. Statistically significant differences in the TAT results between group A and B at the end of puerperium revealed that the recommended extended LMWH prophylaxis until the end of puerperium was not followed by a number of women who started the prophylaxis on the date of labor. PMID- 22536638 TI - [Risk factors for recurrent disease in borderline ovarian tumors]. AB - OBJECTIVE: To evaluate risk factors for development of recurrent disease in borderline ovarian tumors. DESIGN: Retrospective study of 10-years single institution population. SETTING: Dept. of Gynecology and Obstetrics, 3rd Medical Faculty of Charles University in Prague. METHOD: 59 consecutive cases of borderline ovarian tumors (BOT) were analyzed for age, histopathological type, DNA ploidy, stage, presence of invasive and non-invasive peritoneal implants, type of surgical procedure, residual disease, adjuvant therapy, recurrence and long-time prognosis of the patients. RESULTS: Median follow-up was 47 months (range 1-144). There were 5 (8.5%) patients with DNA aneuploid tumors in the study group; 4 of them were younger than 50 years, 4 of them were early stage serous BOT; no one recur so far. No death of disease was described in the whole study group; only 2 patients (3.4%) developed recurrent disease - both were young patients after conservative surgery for serous diploid stage I/II BOT. Conservative surgery was the only significant factor for recurrence in univariate analysis (p = 0.0159) in our setting. CONCLUSION: DNA ploidy was not proved to be prognostic factor in borderline ovarian tumors in our study group. The only significant risk factor for development of recurrent disease was conservative surgery, with no influence on overall survival. PMID- 22536639 TI - [Is the hysteroscopy the right choice for therapy of placental remnants?]. AB - OBJECTIVE: The evaluation of the effectiveness and safety of hysteroscopic management of residual trophoblastic tissue and to verify the miniinvasivity with the second-look hysteroscopy. DESIGN: Prospective study. SETTING: Department of Gynecology and Obstetrics, First Faculty od Medicine, Charles University and General Teaching Hospital, Prague. METHODOLOGY: From 11/2007 to 6/2011, 58 patiens with abnormal uterine bleeding longer than 6 weeks after delivery or abortion underwent ultrasound examination with fading of hyperechogenic content larger than 15mm in AP projection. There was the bipolar resectoscopic system used under general anestesia. Second-look office hysteroscopy was recommended to all patiens 4-6 weeks after a primary procedure. RESULTS: Median operative time was 15 (7-36) minutes, median time of hospitalisation was 7.1 hours. In four patients was necessary to divide the procedure into two phases (after 14 days). There was no serious uterine bleeding or inflamation in our study group. Only one serious surgical complication was registered: an uterine perforation in patient after 2 cesarean sections, there was the laparoscopic suture provided. The second look hysteroscopy was provided in 45 patients (77.6%). There was normal intrauterine finding in 16 (35.6%) patients, in 29 patients (64.4%) a small residual trophoblastic tissue was resected. There was no secondary intrauterine adhesive process described. CONCLUSION: Hysteroscopic resection is a safe and efficient operative technique, which is suitable for management of larger trophoblastic tissue left after delivery or abortion. PMID- 22536640 TI - Cost effectiveness, the economic considerations of prenatal screening strategies for trisomy 21 in the Czech Republic. AB - OBJECTIVES: To perform an incremental cost-effectiveness analysis for screening of trisomy 21 (Down syndrome) in the Czech Republic through a decision tree model designed to evaluate the costs and potential risks involved in using different strategies of screening. METHODS AND DATA ANALYSIS: Using decision-analysis modelling, we compared the cost-effectiveness of nine possible screening strategies for trisomy 21: 1. maternal age > or = 35 in first trimester, 2. maternal age > or = 35 in second trimester, 3. second trimester triple test (AFP, hCG, mu E3), 4. nuchal translucency measurement, 5. first trimester serum test (PAPP-A, fbeta-hCG), 6. first trimester combined (nuchal translucency, PAPP-A, fbeta-hCG) not in OSCAR manner, 7. first trimester combined (nuchal translucency, PAPP-A, fbeta-hCG) in OSCAR manner, 8. first trimester combined (nuchal translucency, nasal bone, PAPP-A, fbeta-hCG) not in OSCAR manner, 9. first trimester combined (nuchal translucency, nasal bone, PAPP-A, fbeta-hCG) in OSCAR manner. The analysis is performed from a health care payer perspective using relevant cost and outcomes related to each screening strategy in a cohort of 118,135 pregnant women presenting around 12 weeks of pregnancy in the Czech Republic. Using a computer spreadsheet Excel (Microsoft Corporation, Redmond, Wash) the following outcomes: overall cost-effectiveness, trisomy 21 cases detected, trisomy 21 live birth prevented and euploid losses from invasive procedures were obtained. The incremental cost-effectiveness ratios were also calculated by a comparison of strategy nine and strategy three (the current practice in the Czech Republic). RESULTS: Under the baseline assumptions, the model favors strategy nine as the most cost-effective trisomy 21 screening strategy. This strategy was the least expensive strategy per trisomy 21 cases averted. Although all the other strategies cost less, they all had lower trisomy 21 detection rates and higher numbers of procedure-related losses (except for strategies six and seven, which had same loss rate) compared with strategy nine. All strategies considered were cheaper compared with screening only by maternal age over 35 years. Adding the nasal bone and the OSCAR manner made strategy nine the most cost-effective one. The incremental cost-effectiveness (cost per additional trisomy 21 case prevented) comparing strategy nine and second trimester triple test (current practice in Czech Republic) yielded an additional baseline cost of 219,326 CZK. This would seem not to save money but due to the low false positive rate the test is less costly than might be expected and it is more cost-effective than the current practice in the Czech Republic (3,580,082 CZK for the current practice and 2,469,833 CZK for our strategy in terms of costs per DS case prevented). CONCLUSION: In our analysis the NT, NB, PAPP-A and fbeta hCG combined test carried out in the first trimester was the most cost-effective screening strategy for trisomy 21 in the Czech Republic. PMID- 22536641 TI - [Non-invasive monitoring of the timing of early embryo cleavages--objectively measurable predictor of human embryo viability]. AB - OBJECTIVE: The evaluation of the developmental abilities of human embryos according to the timing of their early mitotic cleavages. DESIGN: Retrospective study. SETTING: Prague Fertility Centre and Institute for Care of Mother and Child, CAR, Prague. METHODS: The embryos obtained in IVF program were used for further observations and subjected to automated time-lapse monitoring (PrimoVision, Cryo-Innovation, 1 picture/10 min, intermittent white-light illumination) under standard cultivation conditions (37.0 degrees C, 5% CO2 in humid air). Image sequences were digitally recorded for later use. For intravital spindle detection we used polaryzing microscopy (Oosight, Research Instruments) and Hoechst 33342 fluorescent dye for intravital chromatin visualization. A total number of 180 human embryos which gave a vital pregnancies (FHB, fetal heart beat) were analysed retrospectively for timing of early cleavages. In our study, the exact timing of the four interphases (IP) and synchrony of sister cell divisions (ID, interval division) occurring after fertilization were identified and manually recorded. Interphases: IP1 was defined as the period from fertilization till 2 cell stage. IP2 between 2 and 3 cells stages, IP3 between 3 and 5 and IP4 between 5 and 9 cells embryo. INTERVAL DIVISION: ID2 was recorded as a time interval between 3 and 4 cells, ID3 between 5 and 8 cells and ID4 between 9 and 16 cells stage embryos. RESULTS: In the embryos giving viable pregnancies, the durations of IP1 was 20-26 hrs. IP2 was 10-12 hrs, IP3 was 14-16 hrs and IP4 was 20-26 hrs. In these embryos, the sister blastomeres cleaved in a very synchronous manner. The duration of ID1 was recorded to varry from 120 to 210 min. ID2 from 20 to 60 min., ID3 from 120 to 240 min. and ID4 from 230 to 360 min. CONCLUSION: The viable embryos cleave in a very similar time pattern which can be defined and applied as referencial value. Non-invasive monitoring of the timing of early embryo cleavages can be used as an objectively measurable predictor of human embryo. PMID- 22536642 TI - [Genetic factors in etiology of uterine fibroids]. AB - Uterine fibroids are the most common pelvic tumors in women of reproductive age. The cause of development of uterine fibroids is still unknown, however recent cytogenetic and genetic studies led to advancement in understanding of etiology of these tumors. In accordance with the latest findings up to 40% of uterine fibroids bear some chromosomal abnormalities. The most common are aberration of chromosomes 6, 7, 12 and 14. Uterine fibroids have been linked to mutations of fumarate hydratase (FH) gene. Germline mutations in FH gene cause autosomal dominant syndromes MCUL1 (multiple cutaneous and uterine leiomyomata) and HLRCC (hereditary leiomyomatosis and renal cell cancer), characterized by multiple uterine and cutaneous leiomyomata and renal cancer. This paper reviews recent findings in the role of genetic in etiology of uterine fibroids. PMID- 22536643 TI - [Invasive cervical cancer incidence in the span from the preventive check-up to the national screening programing in the Czech Republic]. AB - OBJECTIVE: Former Czechoslovakia was the first European country in which the gynecological cytodiagnosticts was used for checking-up the cervix malignancy, in the years 1947-1957. The preventive measures in woman population together with building up the centres for gynekological oncological prevention result in the cervical cancer incidence lowering, as it is documented by national registry data. The cervical cancer incidence rate was 19.2/100 000 in the year 2008, that is the third endplace on the European scale. How to go positively forward? SETTING: 1st Faculty of medicine, Charles University Prague and General Teaching Hospital Prague. STUDY DESIGN: Analytical study od the incidence during the historical way up to now. Validity of the data should bring the strategy of solution. METHODS: The collected data od the cervical cancer incidence provided by national registry of the CR from the span 1960 to 2008 enabled to evaluate the effectivity od prevention measures used. RESULTS: The incidence rate od cervical cancer was 30/100 000 women before the prevention check-up started. the diagnosis was based cytology. The incidence of cervical cancer lowered to 22/100 000 in the year 1970. The establishment of the centres for oncological gynekological prevention ("COP") led up to the futher dropping up of cervical cancer incidence (20,7/100 000) the activity of the "COP" was based on the gynekologists having the II. degree certificate of the line, colposcopy skill, on cytolaboratory. The continuing education of cytotechnologists started in the year 1991 and it has influenced positively the cervical cancer incidence - its rate was below 20/100 000 -in the year 2008. the data analyses have shown, that the west regions of the CR (Karlovy Vary, Usti nad Labem) have high incidence steadely respectively. The graph of incidence of age groups of women has 3 peaks: In the age 35-39, 55-59 and 75-80. The whole Moravia region reached the lowest cervical cancer incidence 15,2/100 000, which is lower then the world incidence standard. The Czech part of the republic has shown 20,7/100 000 in the average in the year 2008. PMID- 22536645 TI - [The Czech and Slovak Pharmacy Journal at the beginning or 2012]. PMID- 22536646 TI - [Intended pharmacotherapeutical approaches of Alzheimer's disease therapy]. AB - Alzheimer's disease is a progressive neurodegenerative disorder mainly manifested by memory loss, personality changes, and cognitive dysfunction. Despite the fact that tireless research is being conducted, up-to-date pharmacotherapy of AD is presented only by two groups diverging in the mechanism of action. The larger one uses acetylcholinesterase inhibitors, and the second group is represented by the N-methyl-D-aspartate antagonist memantine. Even though the etiology of Alzheimer's disease is unknown, several different therapeutic approaches are being investigated. The aim of this paper is to provide an overview of the present state of intended therapeutics for AD, describing their mechanism of action if known, displaying chemical structures, and the state of clinical trials if any. PMID- 22536647 TI - [The possibilities of innovation of extemporaneous preparation in pharmacies in the Czech Republic]. AB - Extemporaneously prepared products still have an irreplaceable role in therapy. In order to boost the magistral preparation, the availability of appropriate substances for the pharmacies must be ensured. This is due to the fact that many commercial pharmaceutical products containing these active ingredients do not comply with the individual requirements of a particular patient. Based on the practice requirements, the most requested substances have been chosen and within two years 16 pure substances with quality certificates have been provided for magistral preparation in pharmacies, and there are other chemicals coming. The increased availability of these chemicals should in particular eliminate the inappropriate and sometimes unlawful use of commercial medicinal products in extemporaneously prepared products. The paper presents 16 substances and formulations created by the authors, some of which are based on foreign formulations; however, they have been adapted to meet the requirements of the domestic environment. These products should create the basis of standardized formulations for preparation in pharmacies in the Czech Republic. PMID- 22536648 TI - [Derivatives of phenylcarbamic acid as potential antituberculotics]. AB - Basic esters of phenylcarbamic acid were studied by the teams of Prof. Cizmarik and Prof. Waisser as potential antituberculotics. Their antimycobacterial activity increased with lipophilicity. The most active derivatives were substituted with an alkoxy group in position p- on the phenyl. The activity of some of them almost approached that of INH, but they exceeded it only in the evaluation against the INH-resistant strains M. avium and M. kansasii. The carbamates produced by Prof. Vinsova and co-workers published in the last year show that carbamates can be still topical. PMID- 22536649 TI - [Metabolomics in research of phytotherapeutics]. AB - Pharmaceutical and food industries are increasingly focused on the great potential of plant secondary metabolites or natural substances which can be used as therapeutics or model compounds for development of new drugs. The paper is devoted to the use of metabolomics, metabolic profiling and metabolic "fingerprint" for the identification of individual active phyto-substances in plant extracts, in profiling of unique groups of plant secondary metabolites that can be used to improve the classification of several species of medicinal plants as well as for a better characterization and quality control of medicinal extracts, tinctures and phytotherapeutic products prepared from these plants. Combined analytical methods and multivariate statistical analysis are used for metabolite identification. Using this approach, medicinal plants are evaluated not only on the basis of a limited number of pharmacologically important metabolites but also based on the fingerprints of minor metabolites and bioactive molecules. PMID- 22536650 TI - Stability testing of alginate-chitosan films. AB - Pellets containing rutin prepared by the extrusion/spheronization method were coated with sodium alginate-chitosan film. Important quality parameters in the pellets before coating were determined, and after coating the dissolution profiles of the drug were evaluated in dissolution media of the pH corresponding to the conditions in the gastrointestinal tract. Samples of coated pellets were located in the boxes for stability testing under different conditions, i.e. 25 degrees C and 60% of relative humidity (RH); 30 degrees C and 65% RH and 40 degrees C and 75% RH. After 1, 3, 6, 9 and 12 months (or 1, 3 and 6 months), the dissolution test was repeated and compared with the original profiles using similarity factors. All similarity factor values above 50 indicate excellent stability of alginate-chitosan films. PMID- 22536651 TI - [Compatibility of phosphates with calcium salts in parenteral nutrition]. AB - When making prescriptions for total parenteral nutrition (TPN) it is necessary to take into consideration also substitution with calcium and phosphorus. Under some clinical conditions, or in certain groups of patients, it is necessary to supply these substances in high doses with a reduced volume, which due to mutual interactions may be problematic. This experimental paper therefore examined the compatibility of commercially available or individual preparations containing the compounds of calcium and phosphorus. These preparations were examined in a mixture with clinically employed solutions of amino acids or with solutions of glucose. The evaluation was performed by titration until the development of a visible precipitate and also by means of the pharmacopoeial method of evaluation of particles below the level of visibility. Hydrogen phosphate was found to possess a lower compatibility and stability in mixtures containing calcium salts in comparison with dihydrogen phosphate or organic phosphate. Nevertheless, no significant differences were found between dihydrogen phosphate and organic phosphate. The experiment confirmed a better stability of organic calcium salt versus the inorganic one only in the samples containing solutions of amino acids. Of the solutions of amino acids under study, the best stabilizing properties were found in the solutions intended for use in neonatology and paediatrics. PMID- 22536652 TI - Monitoring of effectiveness of some preventive measures against influenza. AB - In our study we dealt with the frequently occurring influenza virus that infects humans regardless of age or sex. The flu is not of importance only in health problems but also in the economic ones, such as the treatment costs and patients' ability to work. We focused particularly on the most effective preventive measure against the virus, which is vaccination and the risk groups that are the most vulnerable ones to the virus. One of the objectives of this research was to identify the advantages and disadvantages of vaccination against influenza and available risks of vaccination within a group of 390 patients. We studied a group of 195 vaccinated patients and we tried to determine the effect of the vaccines used in these patients, and to compare this group with the same number of unvaccinated patients. The goal of the research was to identify the advantages and disadvantages of the vaccination against influenza, and the potential risks resulting from the vaccination. Based on our results, we found out that out of 195 vaccinated patients, only 4% returned to the doctor with the flu. Unvaccinated patients, however, visited the doctor four times more frequently, regardless of age. The resulting morbidity ratios clearly showed the importance, effectiveness and safety of the vaccination not only in high-risk groups, but also in people that are "out-of-danger", because the current flu virus spreads by droplet infection very quickly. Appropriate education and increased awareness among the population in Slovakia could improve the general attitude towards the vaccination against influenza and the vaccination rate (Slovakia 12%) could raise to a percentage comparable to that of the EU countries (France 30%, England 32%, the Netherlands 28% and Germany 26%). PMID- 22536653 TI - [Analytical profile of mono[{3-[4-(2-ethoxyethoxy)-benzoyloxy]-2-hydroxypropyl} tert-butylammonium] fumarate]. AB - The present paper aims at a complex spectral and physicochemical evaluation of mono[{3-[4-(2-eth-oxyethoxy)-benzoyloxy]-2-hydroxypropyl)-tert-butyl-ammonium] fumarate, the potential ultra-short acting blocker of beta1-adrenergic receptors. The identity of the evaluated compound (labelled as UPB-2) was confirmed by 1H-, 13C-NMR and IR spectral data as well. The estimated physicochemical parameters included melting point data, solubility in various media, purity checking (adsorption thin-layer chromatography), surface activity determination (non direct Traube stalagmometric method), acidobasic characteristics (pKa value determination by alkalimetric titration), log epsilon values estimation (spectrophotometrically in UV/VIS region) and a study of the influence of acidic and alkaline media towards the stability of UPB-2. Other experimentally estimated values were lipohydrophilic descriptors using RP-HPLC (log k') and the log PexpS in various lipohydrophilic media by the shake flask method. Based on the log Pexp readouts, the ability to permeate across the brain-blood barrier was predicted. For the content determination of UBP-2 the RP-HPLC (reversed-phase HPLC), the method of an internal standard and UV/VIS spectrophotometry at the wavelength of 260 nm (aqueous medium) and at 258 nm (methanolic medium) was applied. PMID- 22536654 TI - [Identification of lipoxygenase expressing omega-6 dioxygenase activity by means of liquid chromatography]. AB - Lipoxygenases (LOX) represent a family of lipid peroxidising enzymes which catalyse the reaction of achiral polyunsaturated fatty acids by oxygen forming chiral peroxide products possessing high positional stereospecific purity. The four double bonds of arachidonic acid, the main substrate of animal LOX, present the position for a wide range of enzymatic modifications enabling eicosanoid creation, unique molecules with biological significance. In this study, lipoxygenase from rat lung cytoplasma was isolated and purified to 40-fold by combining hydrophobic and gel chromatography. The forming positional specific fatty acid hydroxyl-isomers were separated on a nonpolar system (RP-HPLC) and identified on a polar adsorbent (SP-HPLC). In the purified enzyme, dual positional specificity was demonstrated by the production of 12- and 15-HETE in the ratio of 1,0:1,38, which responds to the product spectrum of mammalian 15-LOX 1. PMID- 22536655 TI - Study of local anaesthetics--Part 196 formulation of the local anaesthetic heptacaine into hydrogel on the basis of chitosan. AB - The study aimed to formulate the local anaesthetic heptacaine into hydrogels on the basis of chitosan. The gel-creating compounds used included natural polymers -three different types of chitosan, namely those of a medium molecular weight, from the shells of shrimp, and from the bumblebees species Bombus terrestris. The prepared hydrogels were evaluated on the basis of their rheological properties and drug liberation. From the point of drug liberation and flow properties, the optimal gel composition was as follows: 0.1% heptacaine + 2% chitosan (medium molecular weight) + 0.2% carbaethopendecinium bromide. PMID- 22536656 TI - UN summit: stepping up efforts to address oral diseases. PMID- 22536657 TI - Epidermolysis bullosa acquisita: a rare challenge in dental management. AB - Dentists often have the opportunity to detect and intercept serious patient medical conditions. Their role may even be central in helping patients overcome fears about their condition and motivating them to obtain an accurate diagnosis and proper treatment. This article features the case of an elderly woman who presented for treatment of painful intraoral mucosal blisters and erosions beneath her dentures and was diagnosed with potentially fatal epidermolysis bullosa acquisita (EBA). Given how quickly improper diagnosis and treatment could lead to morbidity and potential mortality-especially in a susceptible elderly patient-this case illustrates the importance of good communication between all health professionals involved in the multidisciplinary management of patients with challenges as complex and rare as EBA. The successful outcome of this case was directly dependent on the propitious initiative and intervention of the dentist. PMID- 22536658 TI - A modified ridge Expansion technique in the maxilla. AB - Localized ridge expansion of a deficient edentulous maxillary alveolar ridge segment is a useful technique when the goal of surgery is to provide an increase in ridge width as a means of establishing an adequate alveolar crest capable of receiving endosseous implants. The purpose of this article is to describe several modifications to the original ridge-splitting technique for deficient maxillary ridges. These modifications include full-thickness flap reflection, elimination of vertical intraosseous incisions, and simultaneous incorporation of guided bone regeneration. The modifications help to decrease complications associated with the original ridge-splitting technique while increasing the predictability of ridge augmentation in the buccal-palatal dimension. A case is presented that demonstrates the efficacy of the modified technique. PMID- 22536659 TI - Conservative restoration of a traumatically involved central incisor. AB - The use of a direct composite material known for excellent polishability, polish retention, and wear resistance is described in this case of a fractured central incisor restoration. The method used enabled the clinician to conserve tooth structure and maintain full control of the outcome while creating an esthetically imperceptible, reliable, and durable restoration for a young male patient. Emphasized in this case are the techniques of layering, contouring, and polishing of a nanocomposite used to maximize esthetics and meet patient expectations. To further ensure imperceptibility, the author recommends first facilitating color shade selection for both body and dentin-especially in two-shade or multiple shade restorations-by placing the composite in its planned area of the restoration and curing it in its proper thickness to allow a preview and recipe map. PMID- 22536660 TI - Improving quality of life using removable and fixed implant prostheses. AB - Removable and fixed implant-retained prostheses can greatly enhance patients' quality of life, improving their speech, appearance, and ability to eat and otherwise function normally. Yet patients may resist this type of treatment due to barriers, including cost, fear, and lengthy treatment times. It is, therefore, important that clinicians engage in discovering and understanding their patients' concerns and expectations in addition to making a thorough and complete diagnosis of their dental conditions. In the case presented, emphasis was placed on patient clinician communication to correctly facilitate the desired clinical result. The final restoration consisted of a maxillary removable, implant-assisted denture and a mandibular screw-retained, fixed, implant-supported prosthesis. PMID- 22536661 TI - Relevance of the water flosser: 50 years of data. AB - A review of the literature answers many questions related to the use of water flossers, the first of which was introduced in 1962. Numerous studies suggest that water flossers remove biofilm from tooth surfaces and bacteria from periodontal pockets better than string flossing and manual toothbrushing-together or alone. Clinicians should review these findings and consider recommending water flossers for appropriate patients to improve their oral health. As different irrigation or water-flossing devices now on the market offer different features, designs, and combinations of pulsation and pressure, clinicians must consider the needs of individual patients and supporting research in selecting a model that the patient will like and use, and that will provide improved oral health. PMID- 22536662 TI - A clinical evaluation comparing two H2O2 concentrations used with a light assisted chairside tooth whitening system. AB - The purpose of this study was to assess the efficacy of two different BriteSmile hydrogen peroxide (H2O2) gels in a split-arch protocol for whitening teeth in a clinical setting when used in conjunction with a BriteSmile BS4000 lamp. Fifteen subjects were enrolled into a single-center clinical trial. The efficacy of the BriteSmile BS4000 lamp using both 15% H2O2 and 25% H2O2 gel formulations was tested. Study subjects were concurrently exposed to the whitening lamp with the 15% H2O2 gel placed on half of their anterior teeth and the 25% H2O2 gel on the other half for a total light and gel exposure of 60 minutes. The clinical data collected were shade score, gingival health, and dentinal hypersensitivity self assessment. Changes in tooth shade were better for subjects exposed to the 25% gel and the dental whitening lamp (average 8.0 shade changes) compared to subjects exposed to the 15% gel and dental whitening lamp (average 7.6 shade changes) immediately after treatment. The same held true at the 7-day follow-up (25% gel average 7.4 shade changes versus 15% gel average 7.3 shade changes). However, these differences were not statistically significant. No reports of irritation of gingival soft tissues were documented. The relative changes in mean sensitivity scores were similar for both groups with no significant differences in mean sensitivity scores between the groups. Both concentrations of H2O2 gel and the whitening lamp combined gave study subjects an average of 8.0 (25% gel) and 7.6 (15% gel) shade changes immediately after treatment. The 7-day follow-up examination resulted in a regression of lightest to an average of 7.4 (25% gel) and 7.3 (15% gel). It was concluded that the use of the chairside whitening light and either 15% or 25% hydrogen peroxide gel is safe and effective for whitening teeth in 1 hour. PMID- 22536664 TI - 3M ESPE composites: making dentistry faster, easier, better. PMID- 22536663 TI - New posterior composite materials improving placement efficiency. PMID- 22536665 TI - DENTSPLY caulk: simplified composites with peak performance. PMID- 22536666 TI - Ivoclar Vivadent composites ensure patient benefits. PMID- 22536667 TI - Tokuyama: advancing composite restorations through R&D. PMID- 22536668 TI - Soft- and hard-tissue augmentation by orthodontic treatment in the esthetic zone. AB - A technique that may effectively create a greater volume of available hard and soft tissue in the vertical plane without surgical intervention is reported and explained. Limitations of the forced eruption are also discussed. Creating an esthetic implant-supported restoration is a challenge in patients who have alveolar resorption and/or attachment loss, especially when they present with a high smile line. Many methods to augment this loss of tissue have been proposed; most involve surgical procedures to add bone or bone substitutes to compensate for the loss of alveolar tissue. This case report presents an alternative to bone augmentation procedures with the use of orthodontic tooth movement in the esthetic zone of a 62-year-old woman. The tooth movement facilitated implant placement by increasing soft-tissue volume and facial bony contours. PMID- 22536669 TI - ICU helps in building healing environment. AB - In an article that first appeared in the The Australian Hospital Engineer, the monthly magazine of the Institute of Hospital Engineering Australia, Arup's Dr Gerard Healey examines the design and construction of a new intensive care unit (ICU) at Melbourne's Alfred Hospital in Victoria, Australia. Two of the project's key goals, and indeed major design drivers, were to reduce to the absolute minimum the risk of hospital-acquired infection, and to provide an environment that 'intentionally fosters staff and patient well-being, rather than just housing staff and patients'. PMID- 22536670 TI - Complex logistics for Trondheim facility. AB - Next year will see the completion of a 10-year new build and redevelopment project to create central Norway's largest regional hospital, in Trondheim, providing medical services for over 200,000 local people, and a further 450,000 inhabitants from the wider region. The new St Olavs Hospital will be Norway's first 100 per cent single-room healthcare facility, and is set to have close links with Trondheim's Norwegian University of Science and Technology. Designed to be as 'patient-centred' as possible from the outset, it incorporates a number of innovative technologies for enhancing and automating activities ranging from pill 'picking' and distribution, to logistics and waste disposal, as HEJ, and Bjorn Bakken, project manager, logistics, at hospital development company, Helsebygg Midt-Norge, explain. PMID- 22536671 TI - Making sense of the government's vision. AB - Making healthcare provision more sustainable against a backdrop where 'even the sceptics are admitting the Earth will face cataclysmic change if the economy and environment are not re-aligned', maintaining safe, sustainable care environments while experiencing 'a reform programme so big that you can see it from space', and the importance to a high quality future healthcare estate of construction frameworks, integrated supply chains, and new capital funding sources, were among the topics addressed in an interesting session involving speakers from the NHS Sustainable Development Unit, the NHS Confederation, and ProCure21 +, on the first morning of November's Healthcare Estates conference. HEJ editor Jonathan Baillie reports. PMID- 22536672 TI - Is the jury still out on PFI contracts? AB - Last September Andrew Lansley claimed that some NHS Trusts occupying PFI healthcare facilities had been 'landed with deals they could not afford', seemingly attributing much of the blame for a scenario where the Department of Health said 22 Trusts in England alone could be at significant financial risk to Labour, which, in the 1990s, greatly expanded a public/private funding partnership originally introduced by the Tories a decade earlier. Two key factors critics claim have put such Trusts 'at risk' are the 'inflexibility' of some PFI contracts, which makes varying terms difficult mid-contract, and the fact that many of the earlier deals were inexpertly negotiated by the 'public sector side'. HEJ editor Jonathan Baillie sought the views of Malcolm Austwick, a partner at top commercial law firm, DAC Beachcroft (see panel below), with extensive experience in the legal complexities of PFI, on whether or not the initiative's 'pros' do indeed outweigh the 'cons'. PMID- 22536673 TI - LED--panacea or marketing hype? AB - With energy efficiency and carbon reduction, and the importance of a relaxing, therapeutic patient environment, ever more in the spotlight, LED lighting's proponents claim the technology offers healthcare estates personnel many of the answers on both fronts. However some observers believe its benefits are being over-sold, often to the detriment of other high-performing types of more 'conventional lighting', and to a sometimes uninitiated audience too easily swayed by slick sales patter. HEJ editor Jonathan Baillie spoke to one highly experienced lighting professional, Nicholas Bukorovic, a former employee of Thorn, Cooper, and Thorlux Lighting, and the principal author of the last CIBSE/Society of Light and Lighting (SLL) Guide LG2 on healthcare lighting, to seek some expert illumination. PMID- 22536675 TI - Thinking ahead on diesel storage. AB - Hospital estates teams are no strangers to ensuring that they have a ready supply of diesel stored on site ready to fuel standby generators in the event of a power outage. However, new legislation now means that the formulation of red diesel is changing and, as Kenny Berrie, technical manager at generator specialist, Dieselec Thistle, explains, these changes will require a new approach to storing standby diesel supplies if hospitals are to avoid the costs and business continuity risks of stagnation. PMID- 22536674 TI - Markedly more than 'a breath of fresh air'. AB - Opened to the public last September, the Houghton-le-Spring Primary Care Centre in Sunderland, designed by P+HS Architects in conjunction with NHS South of Tyne & Wear for use by the Sunderland Teaching Primary Care Trust, was the UK's first ever large healthcare building to achieve a BREEAM 'Outstanding' rating at the final stage--for best practice in sustainable design and environmental performance for buildings. One of the key elements that enabled the centre to reach this environmental milestone--it also achieved a BREEAM 'Outstanding' at the design stage--was a low carbon natural ventilation system designed by Cambridge University spin-off, Breathing Buildings. HEJ editor Jonathan Baillie reports. PMID- 22536676 TI - A better dementia care environment. AB - Sarah Waller CBE, RGN, FRSA, programme director at The King's Fund's Enhancing the Healing Environment (EHE) programme, examines the work undertaken to date, and still ongoing, to improve the care environment for people living with dementia. At a time when estates and facilities budgets are tight, she argues that, as several successful King's Fund projects completed to date show, good schemes, that can have a significant impact on the lives of dementia patients being cared for in healthcare facilities, need by no means 'break the bank'. PMID- 22536677 TI - [Patient compliance with inhaled medication approach in community pharmacy]. AB - Non compliance with chronic administration of inhaled medication is a great pitfall. Pharmacists have an important task in optimizing patient compliance since they hold several advantages for that purpose: they possess an overview of the patient's medication, even prescription free medication such as cough medicines. Moreover, the pharmacist is capable of explaining the role of the medication in therapy and he enjoys the patient's confidence to do so. This article highlights some strategies to measure patient compliance and seeks to understand the underlying reasons for non-compliance. The appropriate pharmacist's action will depend on that reason. PMID- 22536678 TI - [Clinical studies, the interests and limits of using dabigatran in atrial fibrillation]. AB - Atrial fibrillation (AF) is the most frequent cardiac arrhythmia, especially in older people. This condition is associated with an increased risk of stroke, and long-term anticoagulation treatment is therefore needed. Vitamin K antagonists are effective in reducing the risk of stroke but optimal use of these drugs remains difficult. The development of new oral anticoagulant drugs is therefore highly relevant. Dabigatran is an oral direct thrombin inhibitor. Its prodrug, dabigatran etexilate, is marketed under the name of Pradaxa and was initially approved for the prevention of thromboembolic events in major orthopedic surgery. It has been recently approved for stroke prevention in patients with AF. The purpose of this paper is to review--in light of current knowledge--the interests and limits of using dabigatran etexilate in AF. Briefly, dabigatran etexilate is not inferior to warfarin in AF. However many questions remain unanswered, including questions related to the concomitant use of dabigatran etexilate and acetylsalicylic acid, the possible increased risk of myocardial infarction and the need for drug monitoring. PMID- 22536679 TI - [Genetic principles of food related problems--familial hypercholesterolaemia]. PMID- 22536680 TI - Ethinylestradiol and levonorgestrel preparations on the Belgian market: a comparative study. AB - Preparations formulated as coated or film-coated tablets, containing levonorgestrel and the combination ethinylestradiol/levonorgestrel, were evaluated in a comparative study. This study comprised in vitro dissolution, assay and content uniformity. The analytical methods were previously validated according to international guidelines. All examined products complied with the postulated requirements. PMID- 22536681 TI - [Medication errors on intensive care units: don't underestimate the risks due to transcription]. AB - INTRODUCTION; Medication errors [ME] can harm patients and increase costs. ME are frequent in the intensive care units (ICU], where patients are critically ill and therefore more vulnerable. Publications about ME in the critical care setting are rare. The differences between settings, the lack of standardized definitions and the use of different methods do not allow transposing published results to a specific ICU. The goal of this observational study is to analyse our local situation in relation to the literature findings and determine improvement opportunities. OUTCOMES: Rates of actual medication error [AME] and potential medication error [PME] per line of drug, and per patient-day. Distribution of errors among eight types considered clinically significant. CONTEXT: Intensive care unit, in a tertiary care hospital. METHOD: Error detection was based on the comparison between the prescriptions, the scheduling of the administrations [PME] and the actual medication administrations [AME). RESULTS: 229 lines with an AME were detected in 4636 lines of drugs administered to 144 patients during 373 patient-days. AME rate per line of drug was 5%. PME rate per line of drug was 17%. AME rate per patient-day was 61%. Dose omissions and not discontinued administrations accounted altogether for more than 50% of the total of AME. CONCLUSIONS: The literature does not consider the transcription stage as a priority target for error reduction, but this work shows that, depending on the context, transcriptions can significantly increase opportunities for errors. As transcription does not add any value, its suppression seems therefore to be an interesting target for medication safety improvement. PMID- 22536682 TI - [Pharmacological sheet. Dabigatran, oral administration (Pradaxa)]. PMID- 22536683 TI - [Pharmacological sheet. Febuxostat, oral (Adenuric)]. PMID- 22536684 TI - [Pharmaceutical sheet. Symphytum officinale L., dermal use (Flexagile cream)]. PMID- 22536685 TI - The facts ... about fluoride and your oral health. PMID- 22536686 TI - Pierce out! PMID- 22536687 TI - Women close the oral cancer gender gap. PMID- 22536688 TI - The 411 on health discount cards. PMID- 22536690 TI - "Corrosive competition and conflict will be Lansley's legacy". PMID- 22536691 TI - "There is no need for a warning label when it comes to education". PMID- 22536692 TI - "Staff and resident storytelling can help improve care homes". PMID- 22536693 TI - A new model of care for the older person. AB - This first in a three-part series explores the nature of the caring relationship between caregivers and older people in nursing and residential homes. It proposes a revision of the Caring For and Caring About model. Using this model, where appropriate, staff move their care approach from a protective focus of "caring for" residents to a remedial focus of "caring about" them; the latter aims to promote self-help and autonomy as much as possible. PMID- 22536689 TI - "Is it necessary for all nurses to be mentors"? PMID- 22536694 TI - Creating a protocol to reduce inpatient falls. AB - Falls in hospital are a widespread and challenging problem. They cause harm and distress to patients, and are a source of anxiety for nurses and relatives. This article describes how an acute trust in the North West of England improved its service through staff education and implementing a policy across the trust. The protocol included a falls risk assessment, bedrails risk/benefit assessment and preprinted falls risk assessment care plans. Nurses' knowledge and the quality and completeness of patient documentation improved and, over the three years, falls reduced by a statistically significant 17%. PMID- 22536695 TI - Developing standard data for handover. PMID- 22536696 TI - Best practice in colorectal cancer care. AB - Nurses need up-to-date knowledge of colorectal cancer. This article provides an overview of the aetiology and risk factors for this disease, diagnostic and staging investigations, treatment options and future care. Managing colorectal cancer is complex. Patients can have a range of healthcare needs. Nurses play an increasingly important role in informing, supporting and coordinating care to improve patients' quality of life. PMID- 22536697 TI - Sexual health that's holistic. PMID- 22536698 TI - Is any treatment better than no treatment at all? PMID- 22536699 TI - Organized dentistry saved my life and my practice. PMID- 22536701 TI - Passwords. PMID- 22536700 TI - Dental Groupons, incentives. Possible state, federal legal issues as well as ethical ones. PMID- 22536702 TI - Zinc. PMID- 22536703 TI - Emerging evidence base in third-molar management. PMID- 22536704 TI - Profile Dr. Nora Harmsen. PMID- 22536705 TI - "Scheme to boost nurse research will aid care". PMID- 22536706 TI - Lansley hits out at care failures. PMID- 22536707 TI - "Dignity is integral to nursing, not something you learn to 'deliver'". PMID- 22536708 TI - "Health promotion is swimming against a tide of greasy kebabs". PMID- 22536709 TI - "The tide of endless emails and sticky notes must be tackled". PMID- 22536710 TI - Nutrition screening in patients with COPD. AB - Nutrition and weight management are increasingly recognised as important factors in managing patients with chronic obstructive pulmonary disease (COPD). This article discusses the impact of COPD symptoms on nutrition, and gives advice on the importance of regular nutritional screening using a validated tool. PMID- 22536711 TI - Managing proximal femoral fractures. PMID- 22536712 TI - Benefits of digital thoracic drainage systems. AB - A number of risks and complications are associated with traditional chest drainage systems. A trust decided to trial digital drainage systems, and found the new systems improved treatment time and patient mobility. PMID- 22536713 TI - How nursing support staff contribute to care. AB - It has been suggested that low nurse to patient ratios adversely affect patient outcomes. This article critically assesses evidence on the impact of nursing workforce skill mix on health outcomes and suggests that some caution should be exercised when drawing conclusions. PMID- 22536715 TI - At home for the final days. PMID- 22536714 TI - Exploring the evidence for using TENS to relieve pain. AB - Transcutaneous electrical nerve stimulation (TENS) has several advantages as it is a non-addictive, non-invasive means of analgesia that is simple to use, portable and can give continuous analgesia for a variety of conditions. This article outlines how it works and examines the evidence on its efficacy and possible uses in clinical practice. PMID- 22536716 TI - Face up to doing the dreaded appraisals. PMID- 22536717 TI - Wage cuts likely for worst paid. PMID- 22536718 TI - England second in Europe burnout table. PMID- 22536719 TI - "Short-sighted cuts to training places will lead to a crisis in care". PMID- 22536720 TI - "The Lib Dems must show they do more than lay out the biscuits". PMID- 22536721 TI - "We can all do our bit so people with dementia feel included". PMID- 22536722 TI - Preventing, assessing and managing skin tears. AB - The ageing population means nurses in all care settings are increasingly likely to care for patients with skin tears. This article reviews the evidence on preventing, assessing and managing these. PMID- 22536723 TI - Multidimensional leg ulcer assessment. AB - Assessing patients presenting with a leg ulcer is like doing a multidimensional jigsaw puzzle, in which all the pieces need to fit together to make a whole picture that has depth and meaning. This enables rational clinical decisions to be made with patients, according to their capability and agreement to be involved. This article highlights some of the key features of leg ulcer assessment, drawing on recommendations in national guidelines. PMID- 22536724 TI - Implementing a care model for the older person. AB - This second in a three-part series shows how to use the Caring For and Caring About model in practice. Part 1, published last week, described the model; part 3, to be published online on 10 April, shows how to manage care using existing resources. PMID- 22536725 TI - Testing care pathways for prostate cancer survivors. AB - Although prostate cancer incidence rates have risen sharply over the last 30 years, the survival rate is also high. New pathways of care are needed to support patients, where appropriate, to self-manage. This article describes a project that is testing risk-stratified care pathways and nurses' role in this new model of care. PMID- 22536726 TI - 60 seconds with Ann Hemingway. PMID- 22536727 TI - Leading care with learning. PMID- 22536728 TI - Make tough talk plain sailing. PMID- 22536729 TI - [Detection of Aedes (Stegomyia) albopictus skus. Mosquitoes in the Russian Federation]. AB - Aedes (Stegomyia) albopictus Skus. mosquitoes were for the first time collected in the Bolshoi Sochi region in the Russian Federetion. 16 females and 1 male were morphologically and genetically identified as Ae. albopictus and Aedes aegypti, respectively. PMID- 22536730 TI - [The strategy of a parasite is to preserve and continue its species; some trends for achieving the goal]. AB - The authors show that the strategy of parasites, which is to preserve and continue its species is accomplished mainly by providing of a trophic substrate. Opisthorichiasis is used as an example to show that the nutriceutic biomass of cholangiocytes may be increased due to gene mutations, induced proliferation of liver stem cells, their differentiation to committed ones and cholangiocellular differon elements; moreover, the proliferative processes of mesenchymal components become active in other organs of a host. During their ontogenesis in the intermediate and final hosts, the parasites work out the mechanisms for prolonging their life span to complete a full development cycle (Margaritifera margaritifera glochidia); however, predominantly the parasite-host symbiosis is attended by the latter's lameness. Predation is one of the types of symbiotic relations. PMID- 22536731 TI - [Experience in predicting malaria epidemiological parameters in Russia in the 21st century]. AB - An attempt was made to create a model for the tertian malaria situation in European Russia and Western Siberia. Prediction was done on the basis of the data of climate modeling within the CMIP3 project by the IPCC A2 scenario, which revealed that there would be better conditions for malaria pathogen development in the mid-21st century, suggesting an increased epidemic danger. PMID- 22536732 TI - [The population-and-species-specific structure of malaria (Diptera, Culicidae) mosquitoes in the Caspian Lowland and Kuma-Manych Hollow]. AB - The authors studied the population-and-species-specific structure of malaria mosquitoes in the Caspian Lowland and Kuma-Manych Hollow (Republic of Kalmykia, Stavropol Territory). Five Anopheles mosquito species were identified. An. messeae and An. atroparvus were dominant; An. maculipennis, An. hyrcanus, and An. sacharovi were ecologically specialized and relatively rare. An. sacharovi was first found in Kalmykia, which is the most dangerous malaria vector in the south regions of the CIS. This allows the former known borders of its area to be expanded to the northwest Paleartics. An. messeae showed a high rate of inversions along both arms of chromosome 3 in homo- and heterozygous states, as well as a unique inversion in sex chromosome. The An. atroparvus population in the region was found to have a high rate of inversion on the 3L arm, which had been previously recognized as rare in Ukraine only. PMID- 22536733 TI - [Comparative insecticidal activity of agents based on cipermethrin and its isomers against some species of synanthropic insects]. PMID- 22536734 TI - [An immune response in HIV-infected people with cytomegalovirus infection]. PMID- 22536735 TI - [Irreversible sequels of leptospirosis]. AB - Leptospirosis is a zoonotic feral nidal disease (synonyms: Weil-Vasilyev disease, waterborne fever) running as an acute febrile disease with evident intoxication, renal, hepatic, and central nervous system involvements, evolving hemorrhagic syndrome mainly with its severe complicated course and high mortality rates. The clinical features of leptospirosis have been little studied in patients with comorbidities. Its poor outcomes are generally due to the development of serious complications, such as infection-toxic shock, acute renal and hepatic failure, massive hemorrhagic syndrome, infectious myocarditis, etc. This communication describes a case of the disease with developed irreversible complications: involvement of the kidney and heart in 1 case and that of the kidney with a fatal outcome. Leptospirosis mortality is frequently associated with delayed diagnosis due to the misunderstanding of the clinical picture of this disease (particularly in its similarity to hemorrhagic fever with renal syndrome). The severer acute course of the infectious process in leptospirosis is burdened with the activation of the infection foci existing in the body or the exacerbation of somatic comorbidity, which substantiates the necessity of goal-oriented early individual, background pathology-depended correction of diagnostic, etiotropic, and pathogenetic therapy, rehabilitative measures. Comorbidities in patients with leptospirosis exert a significant impact on the development of its clinical form and the course of the infectious process manifesting itself as its worsening, the more frequent and more prolonged signs ofendogenous intoxication and multiple organ dysfunction, and a larger number of nonspecific complications in the structure of causes of deaths. PMID- 22536736 TI - [Evaluation of the prevalence of helminthiasis among the population of the Republic of Tajikistan]. AB - Helminthological examinations of 2629 persons of different ages have shown that the prevalence rate of soil-transmitted helminths averages 54.24% of the examinees. There isa high rate of helminthiasis in the examined dwellers from two districts (Vanch and Faizobod) in the foothill and mountain zones (78.23% and 67.5%, respectively) and its low rate in the Murgab district in the high-altitude area. The non-observance of personal hygiene and sanitary standards and the use of water from open contamination-unprotected water sources contribute to intensive invasion of the population with helminthes. PMID- 22536737 TI - [Results of a sociological survey of the prevention of malaria in the Surkhandaryinsk Region, Republic of Uzbekistan]. AB - A sociological survey was made in the Sariasiysk and Uzun districts of the Surkhandaryinsk Region in October 2010 within the project UZB-809-G04-M "Consolidation of the achieved results and support of measures to eliminate malaria in Uzbekistan". These districts were selected due to the high susceptibility and vulnerability of the areas and to the results of surveys within the Global Fund project during 2005-2010. The results of the inquiry demonstrate progress in a number of indicators of awareness about malaria. In particular, 63% of the population knew the main symptoms of malaria, 65% could call main ways to prevent malaria; 97% was aware of that insecticide-impregnated canopies were the basic means of protection against mosquito bites, and 80% told all basic measures that could reduce the size of mosquitoes and to prevent their reproduction. Public population in the Sariasiysk district was much better than that in the Uzun district. Men were well aware than women; young people were less aware than adults. Awareness among persons with higher education exceeded that among those without professional education. Medical workers are the main source of information for the population. The role of mass media and local bodies was lower. Most of the population expressed their readiness to obtain expanded information on malaria. PMID- 22536738 TI - [The specific features of Diphyllobothrium latum circulation in the natural foci of the Kostroma region]. AB - Three hundred pikes in the Kostroma section of the Gorky Reservoir, in the Kostroma Overflow, and in the Galich and Chukloma Lakes were examined for infection with Diphyllobothrium latum larvae. In the Kostroma section of the Gorky Reservoir and in the Kostroma Overflow, diphyllobothriasis was recorded in 66.7% (12/18) and 14.7% (11/75) of the pikes, respectively. The high intensity of the epidemic process in diphyllobothriasis was confirmed in the Kostroma Region. The number of notified cases was noted to tend to increase: 35 and 173 cases in 1994 and 1999, respectively. PMID- 22536739 TI - [International collaboration of the E.I. Martsinovsky Institute of Medical Parasitology and Tropical Medicine: assistance for public health in the Republic of Guinea]. AB - Within the framework of international collaboration, the E.I. Martsinovsky Institute of Medical Parasitology and Tropical Medicine (IMPTM), I.M. Sechenov First Moscow State Medical University, assisted the Public Health System of the Republic of Guinea in detecting, diagnosing, studying, and preventing tropical infections of viral, bacterial, and parasitic etiologies, and in training national scientific manpower. The work was under way in the Soviet-Guinea Research Microbiology and Virology Laboratory, USSR Ministry of Health, in the Republic of Guinea (now the Pasteur Institute in Guinea (PIG)) in 1978-1991. The circulation of pathogens of a number of tropical infections, the fauna of vectors and carriers of transmissible infections, and their involvement of the circulation of pathogens of these diseases were found in this period. Consultative-and-methodological and medical assistance was given; national higher and middle-level brainpower trained. It is expedient to restore scientific ties between the IMPTM and the PIG. PMID- 22536740 TI - [MCT-26 and its antihymenolepidiasis activity]. PMID- 22536741 TI - [Serological diagnosis of ascariasis]. PMID- 22536742 TI - [A few types of helminthes in one patient]. PMID- 22536743 TI - [Treatment of children operated on for hepatic echinococcosis complicated by paecilomycotic myocarditis]. PMID- 22536744 TI - [Experience in using ecdisten in the treatment of hymenolepiasis]. AB - The paper presents the results of clinical and parasitological studies in 22 patients with hymenolepiasis after treatment with ecdisten. The drug was used in a dose of 5 ml thrice a day during two weeks. It normalized all clinical symptoms in 8 patients and improved most of them in other patients. The results of helminthoovoscopy were interpreted in terms of clinical data. The parasitological efficacy of ecdisten is 36.4%. Its good tolerance, no contraindications, and easiness-to-use permit the drug to be recommended as a supplementary health improving medication. PMID- 22536745 TI - [History of malaria: military epidemics]. PMID- 22536746 TI - [Resistance of the itch mites Sarcoptes scabiei De Geer, 1778 to scabicides]. AB - The paper gives the data available in the literature on cases of the resistance of human itch mites to acaricides from different groups of chemicals. It considers major mechanisms for S. scabiei resistance to the scabicides commonly used in the world. PMID- 22536747 TI - [Medical value of Blastocystis spp. infection]. PMID- 22536748 TI - Zinc adsorption on clays inferred from atomistic simulations and EXAFS spectroscopy. AB - Clay minerals are efficient sinks for heavy metals in the geosphere. Knowing the uptake mechanism of these elements on clays can help to protect the natural environment from industrial pollution. In this study ab initio molecular dynamics (MD) calculations were applied to simulate the uptake of Zn on the edge surfaces of montmorillonite, a dioctahedral clay, and to explain the measured K-edge extended X-ray absorption fine structure (EXAFS) spectra of adsorbed Zn. These experiments were carried out using a high ionic strength Na background electrolyte that enables one to block cation exchange processes and to restrict the Zn uptake to the sorption complexation at the edge sites of clay. The analysis of the experimental data and simulation results suggest that structurally incorporated Zn preferentially substitutes for Al(III) in the trans symmetric sites of the octahedral layer. At low loading, Zn is incorporated into the outermost trans-octahedra on (010) and (110) edges. At medium loading, Zn forms mono- and bidentate inner-sphere surface complexes attached to the octahedral layer of (010) and (110) edge sites. The maximal site density of inner sphere sorption sites inferred from molecular simulations agrees well with site capacities of surface complexation sites derived from macroscopic studies and modeling. PMID- 22536749 TI - Jailbreaking benzene dimers. AB - We suggest four new benzene dimers, (C(6)H(6))(2), all featuring one or more cyclohexadiene rings trans-fused to 4- or 6-membered rings. These hypothetical dimers are 50-99 kcal/mol less stable than two benzenes, but have computed activation energies to fragmentation >=27 kcal/mol. A thorough search of potential escape routes was undertaken, through cyclobutane ring cleavage to 12 annulenes, sigmatropic 1,5-H-shifts, electrocyclic ring-openings of the 6 membered rings, and Diels-Alder dimerizations. Some channels for reaction emerge, but there is a reasonable chance that some of these new benzene dimers can be made. PMID- 22536750 TI - Effects of analytical and experiential self-focus on rumination after a stress induction in patients with social anxiety disorder: a pilot study. AB - According to cognitive models, negative post-event processing rumination is a key maintaining factor in social anxiety disorder (SAD). Analogue research has supported the differentiation of self-focus into different modes of self-focused attention with distinct effects on rumination in depression and social anxiety. The purpose of this study was to replicate these effects with a sample of clients with SAD (N = 12) using (a) an experimental, cross-over design and (b) an evaluation situation (impromptu speech) prior to manipulation. Processing an identical list of symptoms, half of a sample was asked to successively adopt an analytic (abstract, evaluative) and an experiential (concrete, process-focused) self-focus; the other half employed the modes in the reversed order. Effects were assessed with a thought-listing (TL) procedure. As predicted, the two modes of self-focused attention affected cognitions differently; participants in the experiential condition showed a tendency for a decreased proportion of negative thoughts, whereas those in the analytical condition reported a decreased proportion of neutral thoughts. No difference was shown on positive cognitions. Furthermore, the participants' self-evaluation following the speech predicted their degree of subsequent negative thinking. After self-focus inductions, however, this effect was only seen in those participants who started by receiving the analytical self-focus induction. The results support previous findings that the analytical and the experiential self-focus modes affect cognitions differently, and that experiential processing may have beneficial effects on rumination in SAD. However, results need to be replicated in a larger sample. PMID- 22536751 TI - Multimode charge-transfer dynamics of 4-(dimethylamino)benzonitrile probed with ultraviolet femtosecond stimulated Raman spectroscopy. AB - 4-(Dimethylamino)benzonitrile (DMABN) has been one of the most studied photoinduced charge-transfer (CT) compounds for over 50 years, but due to the complexity of its excited electronic states and the importance of both intramolecular and solvent reorganization, the detailed microscopic mechanism of the CT is still debated. In this work, we have probed the ultrafast intramolecular CT process of DMABN in methanol using broad-band transient absorption spectroscopy from 280 to 620 nm and ultraviolet femtosecond stimulated Raman spectroscopy (FSRS) incorporating a 330 nm Raman pump pulse. Global analysis of the transient absorption kinetics revealed dynamics occurring with three distinct time constants: relaxation from the Franck-Condon L(a) state to the lower locally excited (LE) L(b) state in 0.3 ps, internal conversion in 2-2.4 ps that produces a vibrationally hot CT state, and vibrational relaxation within the CT state occurring in 6 ps. The 330 nm FSRS spectra established the dynamics along three vibrational coordinates: the ring-breathing stretch, nu(ph), at 764 cm(-1) in the CT state; the quinoidal C?C stretch, nu(CC), at 1582 cm(-1) in the CT state; and the nitrile stretch, nu(CN), at 2096 cm(-1) in the CT state. FSRS spectra collected with a 400 nm Raman pump probed the dynamics of the 1174 cm(-1) CH bending vibration, delta(CH). Spectral shifts of each of these modes occur on the 2-20 ps time scale and were analyzed in terms of the vibrational anharmonicity of the CT state, calculated using density functional theory. The frequencies of the delta(CH) and nu(CC) modes upshift with a 6-7 ps time constant, consistent with their off-diagonal anharmonic coupling to other modes that act as receiving modes during the CT process and then cool in 6-7 ps. It was found that the spectral down-shifts of the delta(CH) and nu(CN) modes are inconsistent with vibrational anharmonicity and are instead due to changes in molecular structure and hydrogen bonding that occur as the molecule relaxes within the CT state potential energy surface. PMID- 22536752 TI - Stature estimation from hand dimensions in a Han population of Southern China. AB - To analyze the relationship between stature and hand dimensions for forensic applications, the stature and hand dimensions of 400 healthy adults aged between 20 and 25 years were measured in a Han population of Southern China. The mean values of the stature are 170.49 and 159.72 cm in the men and the women, respectively. The statistically significant differences between the right- and the left-hand dimensions were not observed in the men, whereas the bilateral differences are statistically significant in female hand dimensions. The correlation coefficients were found to be statistically significant for the hand dimensions in both the sexes. The hand length showed higher correlation coefficients than the hand breadth in both sexes. Linear and multiple regressions were developed in this study; multiple regressions showed higher correlation coefficients than linear regressions. Two regression models could be used to estimate the stature from the hand dimensions in this population. PMID- 22536755 TI - Vitamin D was named in 1921. Foreword. PMID- 22536756 TI - "Vitamin D - why does it matter?" - defining vitamin D deficiency and its prevalence. AB - Vitamin D deficiency is prevalent in about 50 % of adults and limited data support a similar prevalence in children. This is of concern, as vitamin D deficiency is a risk factor for falls and fractures and several double-blind RCTs provide evidence that supplementation reduces the risk of fall and fractures among the senior population. Further, large epidemiologic studies consistently report that vitamin D deficiency confers an increased risk of mortality, cardiovascular disease and cancer, especially colo-rectal cancer. However, as large clinical trials for non-musculoskeletal endpoints are missing today, public health recommendations are based primarily on bone health to argue vitamin D repletion in the population. PMID- 22536757 TI - Metabolism and biomarkers of vitamin D. AB - The last decade has witnessed a renaissance in the interest in the metabolism and biological actions of vitamin D(3). Part of this new found interest stems from the discovery that its active form, 1,25-dihydroxyvitamin D3 [1,25(OH)(2)D3], through its nuclear vitamin D receptor [VDR], regulates hundreds of genes around the body including those coding for proteins involved in cell differentiation and cell proliferation as well as calcium and phosphate homeostasis. Furthermore, epidemiological association studies have suggested that levels of the main circulating form, 25-hydroxyvitamin D3 [25(OH)D3] correlate positively with various health outcomes connected to major diseases: cancer, immune function and infections and cardiovascular disease. Consequently, the biochemistry around the metabolism of vitamin D, its mechanism of its action in target cells and the clinical chemistry questions regarding its specific and sensitive assay remain relevant. This short article will review the current state of knowledge of the cytochrome P450-enzymes involved in activation and inactivation of vitamin D, as well as provide a synopsis of the biochemistry and physiology surrounding its roles in the body. The review will end by discussing the appropriate biomarkers to assess vitamin D metabolism and vitamin D status in various clinical disease settings. PMID- 22536753 TI - Evolution of transmitted HIV-1 drug resistance in HIV-1-infected patients in Italy from 2000 to 2010. AB - Prevalence and predictors of transmitted drug resistance (TDR), defined as the presence of at least one WHO surveillance drug resistance mutation (SDRM), were investigated in antiretroviral-naive HIV-1-infected patients, with a genotypic resistance test (GRT) performed <=6 months before starting cART between 2000 and 2010. 3163 HIV-1 sequences were selected (69% subtype B). Overall, the prevalence of TDR was 12% (13.2% subtype B, 9% non-B). TDR significantly declined overall and for the single drug classes. Older age independently predicted increased odds of TDR, whereas a more recent GRT, a higher HIV-RNA and C vs. B subtype predicted lower odds of TDR. PMID- 22536758 TI - Dietary strategies to maintain adequacy of circulating 25-hydroxyvitamin D concentrations. AB - The importance of vitamin D intake to nutritional status is a corollary of sunshine deficit. There is a dose-response of serum 25-hydroxyvitamin D (25(OH)D) concentrations to total vitamin D intake in persons who do not receive UVB exposure. This updated summary of vitamin D intakes and sources in adults and children focuses on data from North America and Europe. We explore the evidence that intakes of vitamin D are inadequate with reference to the Institute of Medicine (IOM) Dietary Reference Intakes. Due to mandatory fortification, usual vitamin D intakes are higher in the US and Canada than most of Europe, with the exception of the Nordic countries. Intakes of vitamin D in national surveys are typically below 5 MUg/d in most European countries and vary according to country specific fortification practices, sex and age. The main source of variation is the contribution from nutritional supplements. Usual vitamin D intake estimates need to capture data on the contributions from fortified and supplemental sources as well as the base diet. The current dietary supply of vitamin D makes it unfeasible for most adults to meet the IOM Estimated Average Requirement of 10 MUg/d. While supplements are an effective method for individuals to increase their intake, food fortification represents the best opportunity to increase the vitamin D supply to the population. Well-designed sustainable fortification strategies, which use a range of foods to accommodate diversity, have potential to increase vitamin D intakes across the population distribution and minimize the prevalence of low 25(OH)D concentrations. PMID- 22536759 TI - Vitamin D production after UVB: aspects of UV-related and personal factors. AB - During the last decade vitamin D has become a hot topic and our knowledge of its vital role in health and disease is constantly expanding. Solar ultraviolet-B (UVB, 280-320 nm) is both the initiator of vitamin D production in the skin and a risk factor for sunburn and skin carcinogenesis. At present, this dilemma is debated worldwide. In Northern Europe, it is possible to reach a sufficient vitamin D status through sun exposure in the summer months. However, in the winter, the ambient UVB radiation is too low to initiate any production of vitamin D and this has led to a widespread concern and focus on vitamin D status. This review focuses on aspects of UV-related and personal factors of importance for the cutaneous vitamin D production after UVB exposure. PMID- 22536760 TI - Vitamin D status as an international issue: national surveys and the problem of standardization. AB - Wide spread variation in measurement results of total 25-hydroxyvitamin D (25(OH)D) confounds international efforts to develop evidence-based clinical guidelines. Accordingly, NIH Office of Dietary Supplements (ODS) in collaboration with CDC National Center for Environmental Health (NCEH), National Institute of Standards and Technology (NIST) and Ghent University established the Vitamin D Standardization Program (VDSP) in November 2010. VDSP objectives include: (1) standardize 25(OH)D concentration measurements in national health surveys around the world, (2) evaluate survey differences, (3) extend standardization efforts to assay manufacturers, and to clinical, commercial, and research laboratories, (4) promote standardization of emerging metabolites of vitamin D status, and (5) enable the use of standardized data in patient care and public health. An interlaboratory comparison study is being conducted to assess measurement variability among current assays. Participants include national health surveys from Australia, Canada, Germany, Ireland, Mexico, South Korea, UK and USA, 15 assay manufacturers, and two external quality assurance programs. CDC will implement a formal laboratory certification program. Standardization activities will use single-donor, fresh-frozen serum collected using the CLSI C37 protocol. Initial assay performance criteria, based on biological variability data, are <= 10 % imprecision and <= 5 % bias in relation to the reference values. An ancillary study on commutability of NIST SRM 972a, external quality assurance testing materials is included. To increase the comparability of existing data from different national surveys, master equations will be developed to facilitate the conversion of already existing national survey data to the NIST-Ghent University reference measurement procedures. PMID- 22536761 TI - Standardization of measurements of 25-hydroxyvitamin D3 and D2. AB - The vitamin D status is increasingly assessed/monitored in different populations, research cohorts and individual patients. This is done by measuring the liver metabolites 25-hydroxyvitamin D3 and D2 as biomarkers. Recommendations for using specific serum concentrations of these biomarkers to assess a person's vitamin D status were done. This requires current vitamin D assays to be sufficiently accurate over time, location and laboratory procedures. In view of the fact that several studies demonstrated that current 25(OH)D measurement methods do not meet this prerequisite, standardization is needed. This paper rehearses the basic concept of standardization, in particular applied to measurements of 25 hydroxyvitamin D. Progress has been made by establishing a reference measurement system consisting of reference methods and reference materials. Coordinated efforts to improve the accuracy and standardize measurements are being performed by organizations such as the U.S. NIH, the CDC and Prevention, the NIST together with their national and international partners. Beyond describing the available reference measurement system and its use as calibration hierarchy to establish traceability of measurements with routine laboratory methods to the SI-unit, this report will also focus on other aspects considered essential for a successful and sustainable standardization, such as analytical issues related to the definition of the measurand and analytical performance goals. PMID- 22536762 TI - Approaches to measurement of vitamin D concentrations - immunoassays. AB - The clinical relevance of vitamin D calls for analytically reliable and cost effective testing methods. 25-hydroxyvitamin D (25(OH)D), the storage form of vitamin D in the blood circulation, is widely accepted as the best indicator of the individual vitamin D status. 25(OH)D immunoassays play a major role in routine testing in the clinical laboratory and many new automated immunoassays have been introduced to the market by the diagnostic industry in recent years. Detectability, precision, traceability and comparability to the reference method liquid chromatography - tandem mass spectroscopy (LCTMS) are essential quality requirements for 25(OH)D immunoassays. The hydrophobic nature of the analyte, the high concentration and affinity of vitamin D binding protein (VDBP) in serum and the cross-reactivity requirements due to the broad spectrum of metabolites of vitamin D are most demanding for assay development. It requires an adequate assay design including a thorough pretreatment process to inactivate the VDBP, careful selection of the specifier (antibody or binding protein) to meet the cross reactivity requirement, and standardization of the assay versus LCTMS to achieve comparability of results between methods. PMID- 22536763 TI - Approaches to measurement of vitamin D concentrations - mass spectrometry. AB - Mass spectrometry today is the only analytical technology which allows the specific determination of all known vitamin D metabolites. During the last few years the number of published methods rapidly increased and quantitative HPLC MS/MS procedures are described for all the major metabolites including 25(OH)D3, 3-epi25(OH)D3, 24,25(OH)(2)D3, 25(OH)D2 and 1,25(OH)(2)D3. For the first time these new methods have made the systematic study of the clinical relevance of vitamin D metabolites possible. In parallel to the development of methods for new metabolites, significant progress was made in improving the performance of HPLC MS/MS for quantifying 25(OH)D3 concentrations which has resulted in very short run times and thus enabling high throughput analysis for routine use and large sample sets. PMID- 22536764 TI - Interaction between vitamin D and calcium. AB - A low calcium intake aggravates the consequences of vitamin D deficiency. This suggests an interaction between vitamin D and calcium intake, which is the subject of this review. The active vitamin D metabolite, 1,25-dihydroxyvitamin D (1,25(OH)(2)D) binds to the vitamin D receptor (VDR) in the intestinal cell and stimulates the active calcium transport from the intestine to the circulation. Vitamin D is not needed for the paracellular transport of calcium, which depends on the calcium gradient. Active calcium absorption decreases when the serum 25 hydroxyvitamin D (25(OH)D) concentration is < 20 nmol/L. Studies in the VDR null mouse have demonstrated that bone mineralisation can be restored without vitamin D by a diet very high in calcium and lactose. Both calcium and vitamin D metabolites can decrease the secretion of parathyroid hormone (PTH) through the calcium sensing receptor and the VDR respectively. With an increasing serum 25(OH)D concentration up to 100 nmol/L or higher serum PTH is still decreasing. A high calcium intake increases the half life of 25(OH)D. In patients with primary or secondary hyperparathyroidism, the half life of 25(OH)D is shorter. Similar interactions between calcium intake and vitamin D status have been shown in rat experiments, generally indicating that a high calcium intake is good for the vitamin D economy. Clinical trials with vitamin D and/or calcium to decrease fracture incidence generally have shown that trials with vitamin D and calcium had better results than calcium or vitamin D alone. The effects of these trials also depend on baseline calcium intake, baseline vitamin D status, age and residence. Trials in institutionalized persons had better results than in independently living elderly. These results confirm that an interaction exists between calcium and vitamin D. PMID- 22536765 TI - Vitamin D and bone health. AB - Current data demonstrate that vitamin D deficiency contributes to the aetiology of at least two metabolic bone diseases, osteomalacia and osteoporosis. Osteomalacia, or rickets in children, results from a delay in mineralization and can be resolved by normalization of plasma calcium and phosphate homeostasis independently of vitamin D activity. The well characterized endocrine pathway of vitamin D metabolism and activities is solely responsible for vitamin D regulating plasma calcium and phosphate homeostasis and therefore for protecting against osteomalacia. In contrast a large body of clinical data indicate that an adequate vitamin D status as represented by the serum 25-hydroxyvitamin D concentration protects against osteoporosis by improving bone mineral density and reducing the risk of fracture. Interestingly adequate serum 1,25-dihydroxyvitamin D concentrations do not reduce the risk of fracture. In vitro human bone cell cultures and animal model studies indicate that 25-hydroxyvitamin D can be metabolised to 1,25-dihydroxyvitamin D by each of the major bone cells to activate VDR and modulate gene expression to reduce osteoblast proliferation and stimulate osteoblast and osteoclast maturation. These effects are associated with increased mineralization and decreased mineral resorption. Dietary calcium interacts with vitamin D metabolism at both the renal and bone tissue levels to direct either a catabolic action on bone through the endocrine system or an anabolic action through a bone tissue autocrine or paracrine system. PMID- 22536766 TI - The effect of Vitamin D on falls and fractures. AB - Vitamin D (cholecalciferol) is important for normal development and maintenance of the skeleton. The metabolites 25(OH)D and 1,25(OH)(2)D are not only important for treating rickets and osteomalacia but also for all types and clinical stages of osteoporosis. Patients with low calcium intake and a low vitamin D status are at risk to develop secondary hyperparathyroidism, increased bone resorbtion, osteopenia and fractures. This can be counteracted by a lifelong sufficient vitamin D supply plus dietary or supplementary calcium. The effects of vitamin D on muscle, balance and cognitive functions may be an added value in fracture prevention. Today it is generally accepted that a supplementation with vitamin D and calcium should be added to every specific medical treatment of osteoporosis. In contrast to this general recommendation the potency of vitamin D alone with or without calcium to reduce the incidence of falls and/or fractures is still a debated controversy. Studies and meta-analyses during the last two decades on the effect of vitamin D and calcium supplements have not resolved the controversy on the risk of falls and fractures in healthy or osteopenic elderly populations. A thorough analysis of these trials supports our clinical experience that the efficacy of vitamin D-calcium supplementation depends on factors related to patient selection, medical intervention and study design, e.g. age, mobility, preventing falls and fractures, co-morbidity, initial vitamin D status and renal function. We conclude that plain vitamin D (cholecalciferol) with sufficient calcium intake is able to reduce the risk of falls and fractures only when adopting optimal selection criteria for patients and study conditions. PMID- 22536767 TI - Vitamin D and cognitive function. AB - The role of vitamin D in skeletal health is well established, but more recent findings have also linked vitamin D deficiency to a range of non-skeletal conditions such as cardiovascular disease, cancer, stroke and metabolic disorders including diabetes. Cognitive impairment and dementia must now be added this list. Vitamin D receptors are widespread in brain tissue, and vitamin D's biologically active form [1,25(OH)(2)D3] has shown neuroprotective effects including the clearance of amyloid plaques, a hallmark of Alzheimer's Disease. Associations have been noted between low 25-hydroxyvitamin D [25(OH)D] and Alzheimer's disease and dementia in both Europe and the US. Similarly, the risk of cognitive impairment was up to four times greater in the severely deficient elders (25(OH)D < 25 nmol/L) in comparison with individuals with adequate levels (>= 75 nmol/L). Further studies have also shown associations between low 25(OH)D concentrations and cerebrovascular events such as large vessel infarcts, risk of cerebrovascular accident and fatal stroke. Cross-sectional studies cannot establish temporal relationships because cognitive decline and the onset of dementia itself may influence vitamin D concentrations through behavioural and dietary changes. However, two large prospective studies recently indicated that low vitamin D concentrations may increase the risk of cognitive decline. Large, well designed randomized controlled trials are now needed to determine whether vitamin D supplementation is effective at preventing or treating Alzheimer's disease and dementia. PMID- 22536768 TI - Vitamin D and cardiovascular disease: update and outlook. AB - Accumulating evidence suggests that vitamin D may play a role for cardiovascular health. Expression of the vitamin D receptor (VDR) and enzymes for vitamin D metabolism have been identified in the vasculature as well as in the heart. VDR knock-out mice suffer from cardiovascular disease (CVD) and even selective VDR deletion in cardiomyocytes causes myocardial hypertrophy. Many, but not all observational studies showed that vitamin D deficiency is associated with CVD and its risk factors. Low concentrations of 25-hydroxyvitamin D (25(OH)D) are an independent risk factor for cardiovascular events, in particular for strokes and sudden cardiac deaths. Only few randomized controlled trials (RCTs) are available on this topic. These RCTs are frequently limited by the additional supplementation of calcium which may increase the risk of CVD events. RCTs with pure vitamin D supplementation have partially but not consistently shown beneficial effects on cardiovascular risk factors such as arterial hypertension. A number of large RCTs on the impact of vitamin D supplementation on cardiovascular events and mortality have already started but limitations of the study designs such as inclusion of individuals with relatively high 25(OH)D concentrations have to be considered. At present, the evidence is not sufficient for general recommendations to supplement vitamin D in order to prevent and treat CVD. It should, however, be noted that justification for the prevention and treatment of vitamin D deficiency comes from evidence based benefits of vitamin D supplementation on musculoskeletal health. PMID- 22536769 TI - Vitamin D and immune function: autocrine, paracrine or endocrine? AB - Prominent amongst the non-classical effects of vitamin D is its interaction with the immune system. Although this has been recognized for many years, it is only through recent studies that we have been able to fully understand the impact of vitamin D on normal innate and adaptive immune function. In particular these studies have illustrated how impaired vitamin D status has important ramifications for dysregulated immune responses to infection and aberrant inflammatory responses associated with autoimmune disease. Indeed it seems likely that the effects of vitamin D will extend beyond these established immune diseases to include additional novel effects, such as interaction with the enteric gut microbiota. Central to this new perspective on vitamin D and immunity has been the elucidation of pivotal mechanisms that underpin the interface between vitamin D and target immune cells. In particular, it is now clear that effects of vitamin D on monocytes, macrophages, dendritic cells, and lymphocytes are not constrained by the metabolic pathways associated with classical endocrine actions of vitamin D. Instead, it is now important to also consider intracrine and paracrine pathways that are subject to a distinct set of modulatory signals, and which may also be influenced by disease-specific dysregulation. The current review will discuss this by comparing the intracrine, paracrine and endocrine metabolic systems that influence the interaction between vitamin D and the immune system. PMID- 22536770 TI - Vitamin D and cancer: integration of cellular biology, molecular mechanisms and animal models. AB - Epidemiologic data suggest that the incidence and severity of many types of cancer inversely correlates with indices of vitamin D status. The vitamin D receptor (VDR) is highly expressed in epithelial cells at risk for carcinogenesis including those resident in skin, breast, prostate and colon, providing a direct molecular link by which vitamin D status impacts on carcinogenesis. Consistent with this concept, activation of VDR by its ligand 1,25-dihydroxyvitamin D (1,25(OH)(2)D) triggers comprehensive genomic changes in epithelial cells that contribute to maintenance of the differentiated phenotype, resistance to cellular stresses and protection of the genome. Many epithelial cells also express the vitamin D metabolizing enzyme CYP27B1 which enables autocrine generation of 1,25(OH)(2)D from the circulating vitamin D metabolite 25-hydroxyvitamin D (25(OH)D), critically linking overall vitamin D status with cellular anti-tumor actions. Furthermore, pre-clinical studies in animal models have demonstrated that dietary supplementation with vitamin D or chronic treatment with VDR agonists decreases tumor development in skin, colon, prostate and breast. Conversely, deletion of the VDR gene in mice alters the balance between proliferation and apoptosis, increases oxidative DNA damage, and enhances susceptibility to carcinogenesis in these tissues. Because VDR expression is retained in many human tumors, vitamin D status may be an important modulator of cancer progression in persons living with cancer. Collectively, these observations reinforce the need to further define the molecular actions of the VDR and the human requirement for vitamin D in relation to cancer development and progression. PMID- 22536771 TI - Hope and challenge: the importance of ultraviolet (UV) radiation for cutaneous vitamin D synthesis and skin cancer. AB - Abstract Solar ultraviolet (UV)-radiation is the most important environmental risk factor for the development of non-melanoma skin cancer (most importantly basal and squamous cell carcinomas), that represent the most common malignancies in Caucasian populations. To prevent these malignancies, public health campaigns were developed to improve the awareness of the general population of the role of UV-radiation. The requirements of vitamin D is mainly achieved by UV-B-induced cutaneous photosynthesis, and the vitamin D-mediated positive effects of UV radiation were not always adequately considered in these campaigns; a strict "no sun policy" might lead to vitamin D-deficiency. This dilemma represents a serious problem in many populations, for an association of vitamin D-deficiency and multiple independent diseases has been convincingly demonstrated. It is crucial that guidelines for UV-exposure (e.g. in skin cancer prevention campaigns) consider these facts and give recommendations how to prevent vitamin D deficiency. In this review, we analyze the present literature to help developing well-balanced guidelines on UV-protection that ensure an adequate vitamin D status without increasing the risk to develop UV-induced skin cancer. PMID- 22536772 TI - Vitamin D supplementation in renal disease: is calcitriol all that is needed? AB - Vitamin D not only plays important roles in mineral metabolism, but also affects the risk of mortality and cardiovascular events. Since the kidney is the main organ that produces 1,25-dihydroxyvitamin D, active vitamin D sterols are widely used in patients with chronic kidney disease (CKD), especially those with secondary hyperparathyroidism. CKD patients also have higher risk of vitamin D deficiency, due to urinary loss associated with proteinuria and possible down regulation of megalin in the proximal tubular cells. Accordingly, it is reasonable to supplement nutritional vitamin D in CKD patients with vitamin D deficiency. Although still unclear, it has been suggested that local 1alpha hydroxylase activity plays more significant roles in CKD patients compared to those with normal kidney function. Future studies should examine whether correction of vitamin D deficiency, administration of active vitamin D, or both, provides survival benefits in patients with CKD. PMID- 22536773 TI - Vitamin D in children and adolescents. AB - Vitamin D is essential for bone growth and development in children and adolescents. Vitamin D deficiency leads to rickets, characterized by defective bone formation, in infants and children. Vitamin D prophylaxis during the first years of life has empirically shown to be effective in combating rickets in infants in some countries. Vitamin D insufficiency can have negative effects on bone health in older children and in adolescents. Vitamin D supplementation has been shown to have an effect on bone mineral density at least in vitamin D deprived older children and adolescents but not in those with a normal vitamin D status. A good vitamin D status during pregnancy seems to be important for bone health in the off-spring later in life, but randomized controlled studies are needed to establish an effect of vitamin D during pregnancy on bone and other health outcomes in the offspring. Vitamin D supplementation during childhood may offer protection against diabetes type 1, but randomized controlled trials are needed to ascertain causality. PMID- 22536774 TI - When should we measure vitamin D concentration in clinical practice? AB - The many recently published data on vitamin D have raised much interest in the medical community. One of the consequences has been a great increase in the prescription of vitamin D concentration measurements in clinical practice. It must be reminded that only the measurement of 25-hydroxyvitamin D (25(OH)D) concentration is indicated to evaluate vitamin D status. Furthermore, since vitamin D insufficiency is so common, since treatment is inexpensive and has a large safety margin, and since we already have much data suggesting that besides its classic effects on bone and mineral metabolism, vitamin D may potentially be helpful for the prevention/management of several diseases, perhaps should it be prescribed to everyone without prior testing? In our opinion, there are however groups of patients in whom estimation of vitamin D status is legitimate and may be recommended. This includes patients in whom a "reasonably" evidence-based target concentration (i.e., based on randomized clinical trials when possible) should be achieved and/or maintained such as patients with rickets/osteomalacia, osteoporosis, chronic kidney disease and kidney transplant recipients, malabsorption, primary hyperparathyroidism, granulomatous disease, and those receiving treatments potentially inducing bone loss. Other patients in whom vitamin D concentration may be measured are those with symptoms compatible with a severe vitamin D deficiency or excess persisting without explanation such as those with diffuse pain, or elderly individuals who fall, or those receiving treatments which modify vitamin D metabolism such as some anti-convulsants. Measurement of Vitamin D concentrations should also be part of any exploration of calcium/phosphorus metabolism which includes measurement of serum calcium, phosphate and PTH. PMID- 22536775 TI - Dietary reference intervals for vitamin D. AB - Dietary reference intervals relate to the distribution of dietary requirement for a particular nutrient as defined by the distribution of physiological requirement for that nutrient. These have more commonly been called Dietary Reference Values (DRV) or Dietary Reference Intakes (DRI), amongst other names. The North American DRI for vitamin D are the most current dietary reference intervals and arguably arising from the most comprehensive evaluation and report on vitamin D nutrition to date. These are a family of nutrient reference values, including the Estimated Average Requirement (EAR), the Recommended Dietary Allowance (RDA), the Adequate Intake, and Tolerable Upper Intake Level. In particular, the EAR is used for planning and assessing diets of populations; it also serves as the basis for calculating the RDA, a value intended to meet the needs of nearly all people. The DRVs for vitamin D in the UK and the European Community have been in existence for almost two decades, and both are currently under review. The present paper briefly overviews these three sets of dietary reference intervals as case studies to highlight both the similarities as well as possible differences that may exist between reference intervals for vitamin D in different countries/regions. In addition, it highlights the scientific basis upon which these are based, which may explain some of the differences. Finally, it also overviews how the dietary reference intervals for vitamin D may be applied, and especially in terms of assessing the adequacy of vitamin D intake in populations. PMID- 22536776 TI - Implications for 25-hydroxyvitamin D testing of public health policies about the benefits and risks of vitamin D fortification and supplementation. AB - Vitamin D status is of interest to physicians caring for patients in poor general health. The tool for assessing vitamin D status is the serum 25-hydroxyvitamin D (25(OH)D) concentration. Based on clinical trials and epidemiology the low end of the desirable concentration of this analyte generally ranges from 50 nmol/L to 75 nmol/L. Based on clinical trials, the high end of the safe concentration for 25(OH)D is at about 225 nmol/L, with an unspecified margin of safety beyond that. In the absence of sunlight, 225 nmol/L is achieved with prolonged consumption of about 10,000 IU/day (250 MUg/day) of vitamin D3. Hence that intake should be regarded as safe, and in the absence of sunshine, comparable vitamin D-wise to abundant sun exposure. Government policy is very conservative, and consequently, the latest advice from the Institute of Medicine for Canada and the USA specifies that in the absence of sunshine, a recommended dietary allowance (RDA) of 600 IU/day (15 MUg/day) of vitamin D will provide a serum 25(OH)D concentration of at least 50 nmol/L. Dietary-vitamin D-intake statistics for adult populations show that average intakes from food and supplements are 200-400 IU/day (5-10 MUg/day), respectively. Therefore, adult populations are consuming vitamin D in amounts far below the RDA. Even if adults were to consume the RDA for vitamin D, it would still not be enough to ensure 25(OH)D > 50 nmol/L. The implication of all these things for the clinical laboratory is that there will continue to be a demand for 25(OH)D measurements for many years to come. PMID- 22536777 TI - Key questions in vitamin D research. AB - Despite interest and expanding research on non-bone health outcomes, the evidence remains inconclusive concerning the causal role of vitamin D in the non-bone health outcomes. To improve our understanding of its role, research needs to address five key areas related to vitamin D: 1) its physiology and molecular pathways. 2) its relationship to health outcomes. 3) its exposure-response relationships, 4) its interactions with genotype and other nutrients and 5) its adverse effects. Its metabolism needs to be elucidated including extra-renal activation and catabolism, distribution and mobilization from body pools, kinetics of this distribution, and their regulation during pregnancy and lactation. Rigorous, well-designed randomized clinical trials need to evaluate the causal role of vitamin D in a diverse array of non-bone health and chronic disease outcomes across the life cycle and reproductive states. Critically needed is the determination of the exposure-response, inflection and threshold of serum 25(OH)D concentrations relative to functional and health outcomes. The dose response relationships of standardized measures of serum 25(OH)D need to be understood in response to low and high doses of total vitamin D with careful consideration of confounding factors including catabolic rates. How do relevant genetic polymorphisms, dietary calcium and phosphate and potentially dietary cholesterol interact with vitamin D exposure on its bioavailability, transport, distribution in body pools, metabolism and action as well as on bone and non-bone health outcomes? The nature and mechanisms of U-shaped risk relationships with adverse health outcomes at higher exposure to vitamin D needs elucidated across the life cycle and reproductive stages. PMID- 22536778 TI - Nicotinic acid hydroxamate downregulated the melanin synthesis and tyrosinase activity through activating the MEK/ERK and AKT/GSK3beta signaling pathways. AB - In this study, nicotinic acid hydroxamate (NAH), a nicotinic acid derivative, was found to show dose-dependent inhibition of melanin content and tyrosinase activity of murine melanoma B16F10 cells with or without being cotreated with cAMP stimulators. In the studies on signaling pathways for skin whitening, NAH treated B16F10 cells resulted in a decrease in the expression of tyrosinase, tyrosinase-related protein-1, and microphthalmia-associated transcription factor (MITF). PD98059 and LY294002 additions were obviously to increase melanin contents in B16F10 cells; however, they were reversed by NAH cotreatments. NAH mediated increases in the phosphorylation of mitogen-activated protein kinase kinase (MEK)/ERK and AKT/glycogen synthase kinase-3beta (GSK3beta) were also found, which in turn led to the inhibition of MITF expression and then downregulated tyrosinase and tyrosinase-related protein (TRP)-1 expressions. These results suggest that NAH may be an active component in the inhibition of melanogenesis, which will have potential uses as cosmetics for whitening and need further investigation. PMID- 22536779 TI - Ankylosing spondylitis in three Sub-Saharan populations: HLA-B*27 and HLA-B*14 contribution. PMID- 22536780 TI - Mineralocorticoid receptor activation in myocardial infarction and failure: recent advances. AB - The classical view of aldosterone actions via the mineralocorticoid receptor (MR) limited to control of fluid balance and blood pressure homoeostasis has been progressively overcome by clinical and experimental evidence emphasizing the pleiotropic role of MR activation in the pathogenesis of cardiovascular disease. Clinical studies have shown the benefit of MR blockade in patients with left ventricular dysfunction and heart failure after myocardial infarction (MI), hypertension or diabetic nephropathy. Deleterious effects of MR activation include cardiac structural and electrical remodelling, cardiovascular fibrosis, inflammation and oxidative stress. Complexity of pathophysiological role of MR derives from the presence of circulating glucocorticoids at higher concentrations than aldosterone and the equal affinity of the MR for aldosterone, cortisol and corticosterone. Recent experimental studies using different animal models and genetic tools have deeply explored the cell-specific functional role of MR in cardiovascular pathology. This review addresses emerging preclinical studies as well as ongoing clinical trials regarding MR activation in MI and failure. PMID- 22536781 TI - The impact of MMX mesalazine on disease-specific health-related quality of life in ulcerative colitis patients. AB - BACKGROUND: Past studies with ulcerative colitis (UC) patients indicate that disease activity strongly predicts health-related quality of life (HRQL). AIM: To examine the degree to which daily treatment with MMX mesalazine predicts improved HRQL for patients with active UC and with stable HRQL for patients with quiescent UC. METHODS: Data from two phases of a multicentre open-label trial were examined. In the acute phase, 132 patients with mild-to-moderate active UC received MMX mesalazine 2.4-4.8 g/day for 8 weeks, while 206 patients with quiescent UC received MMX mesalazine 2.4 g/day for a 12-month maintenance phase. Disease-specific HRQL was measured at baseline and endpoint of each phase using the Short Inflammatory Bowel Disease Questionnaire (SIBDQ). Repeated-measures anova models examined baseline-endpoint changes in SIBDQ, stool frequency (SF), and rectal bleeding severity (RBS). Correlations assessed the associations between SIBDQ and SF/RBS scores, while ancova techniques tested the sensitivity of SIBDQ to disease recurrence. RESULTS: SIBDQ scores significantly increased for active mild-to-moderate UC patients following 8 weeks of treatment, while SIBDQ scores remained stable for quiescent UC patients following 12 months of treatment. Changes in SIBDQ scores correlated significantly with changes in SF and RBS scores. Patients with recurrent UC at maintenance phase endpoint had significantly lower SIBDQ scores than nonrecurrent patients. CONCLUSIONS: Daily MMX mesalazine therapy was associated with significant improvement in disease specific HRQL for patients with mild-to-moderate active UC and with the maintenance of HRQL for patients with quiescent UC. In both patient groups, HRQL was significantly associated with disease activity. PMID- 22536782 TI - Bivalent binding drives the formation of the Grb2-Gab1 signaling complex in a noncooperative manner. AB - Although the growth factor receptor binder 2 (Grb2)-Grb2-associated binder (Gab)1 macromolecular complex mediates a multitude of cellular signaling cascades, the molecular basis of its assembly has hitherto remained largely elusive. Herein, using an array of biophysical techniques, we show that, whereas Grb2 exists in a monomer-dimer equilibrium, the proline-rich (PR) domain of Gab1 is a monomer in solution. Of particular interest is the observation that although the PR domain appears to be structurally disordered, it nonetheless adopts a more or less compact conformation reminiscent of natively folded globular proteins. Importantly, the structurally flexible conformation of the PR domain appears to facilitate the binding of Gab1 to Grb2 with a 1:2 stoichiometry. More specifically, the formation of the Grb2-Gab1 signaling complex is driven via a bivalent interaction through the binding of the C-terminal homology 3 (cSH3) domain within each monomer of Grb2 homodimer to two distinct RXXK motifs, herein designated G1 and G2, located within the PR domain of Gab1. Strikingly, in spite of the key role of bivalency in driving this macromolecular assembly, the cSH3 domains bind to the G1 and G2 motifs in an independent manner with zero cooperativity. Taken together, our findings shed new light on the physicochemical forces driving the assembly of a key macromolecular signaling complex that is relevant to cellular health and disease. PMID- 22536783 TI - Clinically identified postpartum depression in Asian American mothers. AB - OBJECTIVE: To identify the clinical diagnosis rate of postpartum depression (PPD) in Asian American subgroups (Asian Indian, Chinese, Filipino, Japanese, Korean, Vietnamese) compared to non-Hispanic Whites. DESIGN: Cross-sectional study using electronic health records (EHR). SETTING: A large, outpatient, multiservice clinic in Northern California. PARTICIPANTS: A diverse clinical population of non Hispanic White (N = 4582), Asian Indian (N = 1264), Chinese (N = 1160), Filipino (N = 347), Japanese (N = 124), Korean (N = 183), and Vietnamese (N = 147) mothers. METHODS: Cases of PPD were identified from EHRs using physician diagnosis codes, medication usage, and age standardized for comparison. The relationship between PPD and other demographic variables (race/ethnicity, maternal age, delivery type, marital status, and infant gender) were examined in a multivariate logistic regression model. RESULTS: The PPD diagnosis rate for all Asian American mothers in aggregate was significantly lower than the diagnosis rate in non-Hispanic White mothers. Moreover, of the six Asian American subgroups, PPD diagnosis rates for Asian Indian, Chinese, and Filipino mothers were significantly lower than non-Hispanic White mothers. In multivariate analyses, race/ethnicity, age, and cesarean were significant predictors of PPD. CONCLUSION: In this insured population, PPD diagnosis rates were lower among Asian Americans, with variability in rates across the individual Asian American subgroups. It is unclear whether these lower rates are due to underreporting, underdiagnosis, or underutilization of mental health care in this setting. PMID- 22536785 TI - Melatonin suppresses doxorubicin-induced premature senescence of A549 lung cancer cells by ameliorating mitochondrial dysfunction. AB - Melatonin is an indolamine that is synthesized in the pineal gland and shows a wide range of physiological functions. Although the anti-aging properties of melatonin have been reported in a senescence-accelerated mouse model, whether melatonin modulates cellular senescence has not been determined. In this study, we examined the effect of melatonin on anticancer drug-induced cellular premature senescence. We found that the doxorubicin (DOX)-induced senescence of A549 human lung cancer cells and IMR90 normal lung cells was substantially inhibited by cotreatment with melatonin in a dose-dependent manner. Mechanistically, the DOX induced G2/M phase cell cycle arrest and the decrease in cyclinB and cdc2 expression were not affected by melatonin. However, the DOX-induced increase in intracellular levels of ROS, which is necessary for premature senescence, was completely abolished upon melatonin cotreatment. In addition, the reduction in mitochondrial membrane potential that occurs upon DOX treatment was inhibited by melatonin. An aberrant increase in mitochondrial respiration was also significantly suppressed by melatonin, indicating that melatonin ameliorates the mitochondrial dysfunction induced by DOX treatment. The treatment of A549 cells with luzindole, a potent inhibitor of melatonin receptors, failed to prevent the effects of melatonin treatment on mitochondrial functions and premature senescence in cells also treated with DOX; this suggests that melatonin suppresses DOX-induced senescence in a melatonin receptor-independent manner. Together, these results reveal that melatonin has an inhibitory effect of melatonin on premature senescence at the cellular level and that melatonin protects A549 cells from DOX-induced senescence. Thus, melatonin might have the therapeutic potential to prevent the side effects of anticancer drug therapy. PMID- 22536784 TI - Predictors of the long-term course of comorbid PTSD: a naturalistic prospective study. AB - OBJECTIVES: The study examined the long-term course of posttraumatic stress disorder (PTSD) by analyzing rates of recurrence and the predictive value of comorbid psychiatric disorders and psychosocial functioning. METHODS: This study is based on diagnostic assessments administered at intake and subsequent follow up interviews over a period of 15 years in a sample of 90 anxiety-disordered patients with comorbid PTSD who participated in the Harvard Brown Anxiety Research project (HARP). Kaplan-Meier life table analysis revealed a 0.20 probability of full remission during the 15 years of follow-up. RESULTS: Latent growth model (LGM) analysis revealed that the number of trauma exposures was a predictor of a worse course of PTSD but only during some intervals of the 15-year follow-up. Subjects with full social phobia were more likely to experience worsening of PTSD over time in comparison with subjects with less severe social phobia. Role functioning in the areas of household and employment was a significant predictor of a declining course of PTSD. CONCLUSIONS: These findings revealed the dynamic nature of the predictive value of traumatic experiences, the deleterious effect of social phobia and the long term effect of psychosocial functioning on the course of PTSD. Implications for treatment planning and development of interventions for PTSD are discussed. PMID- 22536787 TI - A sperm nuclear basic protein from the sperm of the marine worm Chaetopterus variopedatus with sequence similarity to the arginine-rich C-termini of chordate protamine-likes. AB - The sperm nuclear basic proteins (SNBPs) of the marine annelid worm Chaetopterus variopedatus have been shown previously to consist of a mixture of two SNBPs: histone H1-like (CvH1) and C.variopedatus protamine-like (CvPL). Here, we report the structural characterization of CvPL. The protein has a molecular weight of 8370.5 Da, a K/R ratio of 0.34, and a secondary structure, which are intermediate between those of protamine (P) and protamine-like (PL) SNBPs. The N-terminal sequence of CvPL shows a high extent of similarity with the arginine-rich C terminal domain of chordate PL-type SNBPs. Furthermore, the protein binds to DNA in a similar fashion as vertebrate PLs and their own CvH1, but in a way that is different from that of the lysine-rich somatic H1 histones. We have experimentally determined the molar ratio CvH1:CvPL to be ~1:6 in C. variopedatus sperm. Based on all of these, a model is proposed for the organization of the sperm chromatin by CvH1 and CvPL. PMID- 22536786 TI - In vitro study of uptake and synthesis of creatine and its precursors by cerebellar granule cells and astrocytes suggests some hypotheses on the physiopathology of the inherited disorders of creatine metabolism. AB - BACKGROUND: The discovery of the inherited disorders of creatine (Cr) synthesis and transport in the last few years disclosed the importance of blood Cr supply for the normal functioning of the brain. These putatively rare diseases share a common pathogenetic mechanism (the depletion of brain Cr) and similar phenotypes characterized by mental retardation, language disturbances, seizures and movement disorders. In the effort to improve our knowledge on the mechanisms regulating Cr pool inside the nervous tissue, Cr transport and synthesis and related gene transcripts were explored in primary cultures of rat cerebellar granule cells and astrocytes. METHODS: Cr uptake and synthesis were explored in vitro by incubating monotypic primary cultures of rat type I astrocytes and cerebellar granule cells with: a) D3-Creatine (D3Cr) and D3Cr plus beta-guanidinopropionate (GPA, an inhibitor of Cr transporter), and b) labelled precursors of Guanidinoacetate (GAA) and Cr (Arginine, Arg; Glycine, Gly). Intracellular D3Cr and labelled GAA and Cr were assessed by ESI-MS/MS. Creatine transporter (CT1), L-arginine:glycine amidinotransferase (AGAT), and S-adenosylmethionine:guanidinoacetate N methyltransferase (GAMT) gene expression was assessed in the same cells by real time PCR. RESULTS: D3Cr signal was extremely high in cells incubated with this isotope (labelled/unlabelled Cr ratio reached about 10 and 122, respectively in cerebellar granule cells and astrocytes) and was reduced by GPA. Labelled Arg and Gly were taken up by the cells and incorporated in GAA, whose concentration paralleled that of these precursors both in the extracellular medium and inside the cells (astrocytes). In contrast, the increase of labelled Cr was relatively much more limited since labelled Cr after precursors' supplementation did not exceed 2,7% (cerebellar granule cells) and 21% (astrocytes) of unlabelled Cr. Finally, AGAT, GAMT and SLC6A8 were expressed in both kind of cells. CONCLUSIONS: Our results confirm that both neurons and astrocytes have the capability to synthesize and uptake Cr, and suggest that at least in vitro intracellular Cr can increase to a much greater extent through uptake than through de novo synthesis. Our results are compatible with the clinical observations that when the Cr transporter is defective, intracellular Cr is absent despite the brain should be able to synthesize it. Further research is needed to fully understand to what extent our results reflect the in vivo situation. PMID- 22536788 TI - Catching up on printing-accepted articles and more stringent scientific criteria going forward. PMID- 22536789 TI - Superior patient and technique survival with very high standard Kt/V in quotidian home hemodialysis. AB - We studied the association of patient and dialysis factors with patient and technique survival in a cohort of all of our 191 of patients surviving >3 months on quotidian home hemodialysis (QHHD). Eighty-one patients were on nocturnal QHHD and 110 on short -daily QHHD. Weekly dialysis time was 7.5-48 hours, single pool Kt/V was 0.38-4.5 per treatment, and weekly standardKt/V was 2.1-7.5. The association of 18 patient and dialysis variables with patient and technique survival was analyzed by Kaplan-Meier and Cox analyses. Ninety-nine patients (52%) remained on QHHD, 34 (18%) were transplanted, 31 (16%) returned to 3/week HD, and 27 (14%) died. The 5-year patient survival was 71% +/- 6% (night: 79% +/- 7%, day: 69% +/- 9%, P = 0.002). The 5-year technique survival was 80% +/- 4% (night: 93% +/- 3%, day: 46% +/- 17%, P = 0.001). In Cox analyses, patient survival was independently associated with standard Kt/V (hazard ratio [HR] = 0.29, P < 0.0001), graduating from high school (HS) (HR = 0.11, P = 0.0002), and use of graft/fistula (HR = 0.22, P = 0.007). Technique survival was independently associated with standard Kt/V (HR = 0.50, P = 0.0003) and start of QHHD after 2003 (HR = 0.18, P = 0.007). Every increase in standard Kt/V was associated with improved survival. The highest survival occurred when standard Kt/V exceeded 5.1, only possible when weekly dialysis hours exceed 35 hours. In QHHD, higher standard Kt/V, education, and subcutaneous access are associated with better patient survival and higher standard Kt/V and longer experience of center with better technique survival. There was no upper limit of standard Kt/V, where survival plateaus. The amount of minimally "adequate" dialysis should be much increased. PMID- 22536790 TI - In vivo biodistribution of prion- and GM1-targeted polymersomes following intravenous administration in mice. AB - Due to the aging of the population, the incidence of neurodegenerative diseases, such as Parkinson's and Alzheimer's, is expected to grow and, hence, the demand for adequate treatment modalities. However, the delivery of medicines into the brain for the treatment of brain-related diseases is hampered by the presence of a tight layer of endothelial cells that forms the blood-brain barrier (BBB). Furthermore, most conventional drugs lack stability and/or bioavailability. These obstacles can be overcome by the application of nanocarriers, in which the therapeutic entity has been incorporated, provided that they are effectively targeted to the brain endothelial cell layer. Drug nanocarriers decorated with targeting ligands that bind BBB receptors may accumulate efficiently at/in brain microvascular endothelium and hence represent a promising tool for brain drug delivery. Following the accumulation of drug nanocarriers at the brain vasculature, the drug needs to be transported across the brain endothelial cells into the brain. Transport across brain endothelial cells can occur via passive diffusion, transport proteins, and the vesicular transport pathways of receptor mediated and adsorptive-mediated transcytosis. When a small lipophilic drug is released from its carrier at the brain vasculature, it may enter the brain via passive diffusion. On the other hand, the passage of intact nanocarriers, which is necessary for the delivery of larger and more hydrophilic drugs into brain, may occur via active transport by means of transcytosis. In previous work we identified GM1 ganglioside and prion protein as potential transcytotic receptors at the BBB. GM1 is a glycosphingolipid that is ubiquitously present on the endothelial surface and capable of acting as the transcytotic receptor for cholera toxin B. Likewise, prion protein has been shown to have transcytotic capacity at brain endothelial cells. Here we determine the transcytotic potential of polymersome nanocarriers functionalized with GM1- and prion-targeting peptides (G23, P50 and P9), that were identified by phage display, in an in vitro BBB model. In addition, the biodistribution of polymersomes functionalized with either the prion-targeting peptide P50 or the GM1-targeting peptide G23 is determined following intravenous injection in mice. We show that the prion targeting peptides do not induce efficient transcytosis of polymersomes across the BBB in vitro nor induce accumulation of polymersomes in the brain in vivo. In contrast, the G23 peptide is shown to have transcytotic capacity in brain endothelial cells in vitro, as well as a brain-targeting potential in vivo, as reflected by the accumulation of G23-polymersomes in the brain in vivo at a level comparable to that of RI7217-polymersomes, which are targeted toward the transferrin receptor. Thus the G23 peptide seems to serve both of the requirements that are needed for efficient brain drug delivery of nanocarriers. An unexpected finding was the efficient accumulation of G23-polymersomes in lung. In conclusion, because of its combined brain-targeting and transcytotic capacity, the G23 peptide could be useful in the development of targeted nanocarriers for drug delivery into the brain, but appears especially attractive for specific drug delivery to the lung. PMID- 22536791 TI - The extracellular matrix and diffusion barriers in focal cortical dysplasias. AB - Focal cortical dysplasias (FCDs) of the brain are recognized as a frequent cause of intractable epilepsy. To contribute to the current understanding of the mechanisms of epileptogenesis in FCD, our study provides evidence that not only cellular alterations and synaptic transmission, but also changed diffusion properties of the extracellular space (ECS), induced by modified extracellular matrix (ECM) composition and astrogliosis, might be involved in the generation or spread of seizures in FCD. The composition of the ECM in FCD and non-malformed cortex (in 163 samples from 62 patients) was analyzed immunohistochemically and correlated with the corresponding ECS diffusion parameter values determined with the real-time iontophoretic method in freshly resected cortex (i.e. the ECS volume fraction and the geometrical factor tortuosity, describing the hindrances to diffusion in the ECS). The ECS in FCD was shown to differ from that in non malformed cortex, mainly by the increased accumulation of certain ECM molecules (tenascin R, tenascin C, and versican) or by their reduced expression (brevican), and by the presence of an increased number of astrocytic processes. The consequent increase of ECS diffusion barriers observed in both FCD type I and II (and, at the same time, the enlargement of the ECS volume in FCD type II) may alter the diffusion of neuroactive substances through the ECS, which mediates one of the important modes of intercellular communication in the brain - extrasynaptic volume transmission. Thus, the changed ECM composition and altered ECS diffusion properties might represent additional factors contributing to epileptogenicity in FCD. PMID- 22536792 TI - A complex case of infected total knee arthroplasty in a haemophilic patient with inhibitor. PMID- 22536793 TI - Comparing the effectiveness of infertility treatments by numbers needed to treat (NNT). AB - To compare the clinical efficiency of different modes of treatment of infertile couples and to estimate the possible benefit of nutraceutical food supplementation (NFS), the numbers needed to treat (NNT) was calculated in 4143 infertile couples based on controlled trials in recent literature and personal data. The NNT expresses the number of individuals who need to be treated to obtain one complementary pregnancy. In female infertility, the NNT of mild or moderate endometriosis was 8.4, and in anti-estrogens treatment of anovulation, it was 5.9. In tamoxifen treatment of idiopathic oligozoospermia, NNT was 3.9, and in antioxidant supplementation, it was 7.8. Treatment of varicocele yielded NNT of 6.3 and 6.8 after 1 year in multi- or single-centre trials, respectively, and NFS lowered the NNT after 3 months to 2.6. Adding NFS to the male partner increased the ongoing pregnancy rate by IVF with NNT of 8.3, and adding NFS to both partners reduced the NNT to 4.0. Although these results were obtained in heterogeneous trials and populations, it is suggested that the NNT should be useful for comparing the effectiveness of different modes of treatment of the infertile couple, and that complementary nutraceutical food supplementation may be beneficial. PMID- 22536794 TI - The hereditary angioedema burden of illness study in Europe (HAE-BOIS-Europe): background and methodology. AB - BACKGROUND: Hereditary angioedema (HAE) is a rare but serious disease marked by swelling attacks in the extremities, face, trunk, airway, or abdominal areas that can be spontaneous or the result of trauma and other triggers. It can be life threatening due to the risk of asphyxiation. While there have been major advancements in our understanding of the immunogenetics of HAE, there are significant gaps in the literature regarding understanding of the humanistic and economic impact of the disease, particularly in Europe. The purpose of the HAE Burden of Illness Study-Europe (HAE-BOIS-Europe), the development and methodology of which is described here, is to better understand the management and impact of HAE from the patient perspective in Europe. METHODS/DESIGN: This is a cross sectional study in which retrospective data were also collected being conducted in Denmark, Germany and Spain. The study is open to patients ages 12 and older with a diagnosis of HAE-I or HAE-II. Data collection includes: (i) a survey on individuals' health care resource use, direct and indirect medical costs, impact on work and school, treatment satisfaction, and emotional functioning (via the Hospital Anxiety and Depression Scale); and (ii) one-on-one interviews to collect detailed descriptive data and patient testimonials on the impact of HAE on patients' health-related quality of life. DISCUSSION: The present manuscript describes the development and plans for implementing a multi-country European study with the aim of characterizing the humanistic and economic burden of HAE from the patient perspective. This study will help raise awareness of HAE as a rare but debilitating condition with wide-ranging impacts. PMID- 22536796 TI - Fear of falling and changed functional ability following hip fracture among community-dwelling elderly people: an explanatory sequential mixed method study. AB - PURPOSE: The aims of the study were to assess self-reported fear of falling (FOF) and functional ability among community-dwelling elderly people 3-6 months post hospital discharge after a hip fracture, to investigate the association between FOF and functional ability, and to explore the lived experience of FOF and disability when recovering from a hip fracture. METHOD: A sequential explanatory mixed method design was used in a "face-to-face" survey assessing FOF (Falls Efficacy Scale-International, FES-I), avoidance of activities (Modified survey of Activities and Fear of Falling, mSAFFE), functional ability (Functional Recovery Score, FRS), and mobility (New Mobility Score, NMS) followed by in-depth interviews of four participants. Interviews were analyzed using systematic text condensation. RESULTS: Among the 33 participants 58% had a high degree of FOF and avoided more activities, needed more assistance in activities of daily living, and were less mobile than participants who had a low degree of FOF (p < 0.0001). According to the informants FOF reduced their functional ability and seriously altered their lives. CONCLUSIONS: FOF was common and significantly associated with activity avoidance, disability, and affected the lives of elderly recovering from a hip fracture. Some patients were physically incapacitated by FOF. PMID- 22536795 TI - Maternal and foetal immune responses of cattle following an experimental challenge with Neospora caninum at day 70 of gestation. AB - The immune responses of pregnant cattle and their foetuses were examined following inoculation on day 70 of gestation either intravenously (iv) (group 1) or subcutaneously (sc) (group 2) with live NC1 strain tachyzoites or with Vero cells (control) (group 3). Peripheral blood mononuclear cell (PBMC) responses to Neospora antigen and foetal viability were assessed throughout the experiment. Two animals from each group were sacrificed at 14, 28, 42 and 56 days post inoculation (pi). At post mortem, maternal lymph nodes, spleen and PBMC and when possible foetal spleen, thymus and PBMC samples were collected for analysis. Inoculation with NC1 (iv and sc) lead to foetal deaths in all group 1 dams (6/6) and in 3/6 group 2 dams from day 28pi; statistically significant (p <= 0.05) increases in cell-mediated immune (CMI) responses including antigen-specific cell proliferation and IFN-gamma production as well as increased levels of IL-4, IL-10 and IL-12 were observed in challenged dams compared to the group 3 animals. Lymph node samples from the group 2 animals carrying live foetuses showed greater levels of cellular proliferation as well as significantly (p <= 0.05) higher levels of IFN-gamma compared to the dams in group 2 carrying dead foetuses. Foetal spleen, thymus and PBMC samples demonstrated cellular proliferation as well as IFN-gamma, IL-4, IL-10 and IL-12 production following mitogenic stimulation with Con A from day 14pi (day 84 gestation) onwards. This study shows that the generation of robust peripheral and local maternal CMI responses (lymphoproliferation, IFN-gamma) may inhibit the vertical transmission of the parasite. PMID- 22536797 TI - Ligand-controlled regioselectivity in the hydrothiolation of alkynes by rhodium N heterocyclic carbene catalysts. AB - Rh-N-heterocyclic carbene compounds [Rh(MU-Cl)(IPr)(eta(2)-olefin)](2) and RhCl(IPr)(py)(eta(2)-olefin) (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2 carbene, py = pyridine, olefin = cyclooctene or ethylene) are highly active catalysts for alkyne hydrothiolation under mild conditions. A regioselectivity switch from linear to 1-substituted vinyl sulfides was observed when mononuclear RhCl(IPr)(py)(eta(2)-olefin) catalysts were used instead of dinuclear precursors. A complex interplay between electronic and steric effects exerted by IPr, pyridine, and hydride ligands accounts for the observed regioselectivity. Both IPr and pyridine ligands stabilize formation of square-pyramidal thiolate hydride active species in which the encumbered and powerful electron-donor IPr ligand directs coordination of pyridine trans to it, consequently blocking access of the incoming alkyne in this position. Simultaneously, the higher trans director hydride ligand paves the way to a cis thiolate-alkyne disposition, favoring formation of 2,2-disubstituted metal-alkenyl species and subsequently the Markovnikov vinyl sulfides via alkenyl-hydride reductive elimination. DFT calculations support a plausible reaction pathway where migratory insertion of the alkyne into the rhodium-thiolate bond is the rate-determining step. PMID- 22536798 TI - Estimation of the major source and sink of methylmercury in the Florida Everglades. AB - Mercury methylation and/or demethylation have been observed in several compartments [soil (saturated soils covered by standing water), floc, periphyton, and water] of the Everglades, a wetland with mercury as one of the major water quality concerns. However, it is still unclear which compartment is the major source or sink due to the lack of estimation and comparison of the net methylmercury (MeHg) production or degradation in these compartments. The lack of this information has limited our understanding of Hg cycling in this ecosystem. This study adopted a double stable isotope ((199)Hg(2+) and Me(201)Hg) addition technique to determine the methylation/demethylation rate constants and the net MeHg production rates in each compartment. This study improved the previous models for estimating these parameters by (1) taking into account the difference between newly input and ambient mercury in methylation/demethylation efficiency and (2) correcting the contribution of photodemethylation to Me(199)Hg concentration when calculating methylation rates in water. The net MeHg production rate in each compartment was then estimated to identify the major sources and sinks of MeHg. The results indicate that these improvements in modeling are necessary, as a significant error would occur otherwise. Soil was identified to be the largest source of MeHg in the Everglades, while the floc and water column were identified as the major sinks. The role of periphyton varies, appearing to be a source in the northern Everglades and a sink in the southern Everglades. Soil could be the largest source for MeHg in the water column, while methylation in periphyton could also contribute significantly in the northern Everglades. PMID- 22536801 TI - What challenges hamper Kenyan family physicians in pursuing their family medicine mandate? A qualitative study among family physicians and their colleagues. AB - BACKGROUND: Since 2005, Kenyan medical universities have been training general practitioners, providing them with clinical, management, teaching and research skills, in order to enhance access to and quality of health care services for the Kenyan population. This study assesses what expectations family physicians, colleagues of family physicians and policy makers have of family medicine, what expectations family physicians live up to and which challenges they face. METHODS: Family physicians were observed and interviewed about their expectations and challenges concerning family medicine. Expectations among their colleagues were assessed through focus group discussions. Policy makers' expectations were assessed by analysing the governmental policy on family medicine and a university's curriculum. RESULTS: Roles perceived for and performed by family physicians included providing comprehensive care, health care management, teaching, and to a lesser extent community outreach and performing research. Challenges faced by family physicians were being posted in situations where they are regarded as just another type of specialist, lack of awareness of the roles of family physicians among colleagues, lack of time, lack of funds and inadequate training. CONCLUSIONS: The ministry's posting policy has to be improved to ensure that family physicians have a chance to perform their intended roles. Creating an environment in which family physicians can function best requires more effort to enlighten other players in the health care system, like colleagues and policy makers, about the roles of family physicians. PMID- 22536799 TI - Race, ABO blood group, and venous thromboembolism risk: not black and white. AB - BACKGROUND: The rate of venous thromboembolism (VTE) has been reported to be higher in blacks compared to whites. Non-O blood groups have also been associated with a significantly higher VTE risk. Given that a higher proportion of blacks have O blood group, one might have expected that black individuals would have fewer VTEs. STUDY DESIGN AND METHODS: In this study, we analyzed race, sex, age, ABO or Rh blood group, and VTE risk in 60,982 black and white patients admitted over a span of 10 years. RESULTS: The overall occurrence of VTEs was 7.6%, higher in males (8.7% males vs. 7.2% females), higher in non-O blood groups (8.5% non-O vs. 6.9% O blood group), and increased with age (5.8% <65 years, 11.3% >=65 years). No difference in VTE rate was noted with Rh antigen positivity. When stratified by age, VTE rate was consistently higher in blacks and non-O blood groups. No difference was detected among the various non-O blood groups. To assess the potential confounder of comorbidities, we stratified patients according to Charlson comorbidity score. In a subgroup of healthy patients with age-independent Charlson comorbidity scores of 0 (n = 28,387), blacks still had an increased VTE risk and this risk was still higher with increasing age and in those with non-O blood groups. CONCLUSION: We conclude that black race and non-O blood groups have increased VTE risk when stratified for age and that associated comorbidities do not explain these differences. PMID- 22536802 TI - Exploring the relationship between the severity of oligozoospermia and the frequencies of sperm chromosome aneuploidies. AB - The study was aimed to investigate the association between the degree of oligozoospermia and sperm chromosome aneuploidy frequencies in male infertility and to determine whether chromosomal profiles of sperm nuclei would be used for a supportive test before additive reproduction technics. The meiotic segregation profiles of chromosomes X, Y, 13, 18 and 21 were compared by fluorescent in-situ hybridisation (FISH) on the spermatozoa of 30 normally karyotyped oligozoospermic (10 mild, 11 moderate, nine severe) cases without Y-microdeletions, and 10 normozoospermic cases. The results showed significantly higher frequencies of chromosomes 13, 18, 21 disomies (P < 0.001) in the group of patients with moderate and severe oligozoospermia compared with the disomy frequencies of normozoospermic group. The statistically significant differences were also determined in disomy frequencies of sex chromosomes (XY, XX and YY) in between oligozoospermic and normozoospermic groups (P < 0.001, P < 0.001, P < 0.040, respectively). Because oligozoospermic patients are the ones consulted the most for assisted reproductive techniques, identification of sperm aneuploidy rates in men could be considered as an appropriate supportive test before the reproductive implementations. Furthermore, the patients should be counselled with respect to genetic screening results for the potential risk of aneuploid embryo and pre implantation genetic diagnosis or prenatal diagnosis. PMID- 22536808 TI - Idiopathic noncirrhotic portal hypertension is associated with poor survival: results of a long-term cohort study. AB - BACKGROUND: Idiopathic noncirrhotic portal hypertension (INCPH) is a rare disease in the Western world. As a result, little is known about the clinical characteristics and outcome of these patients. Survival in these patients is considered to be similar to that of the general population. AIM: To investigate the clinical manifestations, pathophysiology, outcome and determinants of survival in Western INCPH patients. METHODS: Multicentre cohort study of INCPH patients. RESULTS: A total of 62 patients were followed for a median time of 90 months (range 24-310). Initial manifestations leading to the diagnosis of INCPH were related to portal hypertension in 82% of the patients. Histological signs of portal blood supply disturbances were present in nearly all patients. During follow-up, 12 of 62 patients developed liver decompensation, of which four were considered for liver transplantation. One patient died in the context of variceal bleeding. Hepatocellular carcinoma was not observed during follow-up. A total of 23 patients died during follow-up, only four of them due to liver related mortality. The Kaplan-Meier estimates for overall survival were 100% (95% CI 95 100%), 78% (95% CI 67-89%) and 56% (95% CI 40-72%) at 1, 5 and 10 years respectively. Survival for INCPH was significantly decreased (P < 0.001) compared to survival of the general population. Ascites was an independent predictor of poor outcome. CONCLUSIONS: In comparison to the general population, survival in INCPH patients is poor. Mortality is related to associated disorders and medical conditions occurring at older age. Patients rarely die due to liver related complications. Patients with ascites have a poor prognosis. PMID- 22536809 TI - Laser-flash photolysis indicates that internal electron transfer is triggered by proton uptake by Alcaligenes xylosoxidans copper-dependent nitrite reductase. AB - Enzyme-catalysed electron transfer reactions are often controlled by protein motions and coupled to chemical change such as proton transfer. We have investigated the nature of this control in the blue copper-dependent nitrite reductase from Alcaligenes xylosoxidans (AxNiR). Inter-Cu electron transfer from the T1Cu site to the T2Cu catalytic site in AxNiR occurs via a proton-coupled electron transfer mechanism. Here we have studied the kinetics of both electron and proton transfer independently using laser-flash photolysis for native AxNiR and its proton-channel mutant N90S. In native AxNiR, both inter-Cu electron transfer and proton transfer exhibit similar rates, and show an unusual dependence on the nitrite concentration. An initial decrease in the observed rates at low nitrite concentrations is followed by an increase in the observed rates at high nitrite concentrations (> 5 mm). In N90S, in which the T1Cu reduction potential is elevated by 60 mV, no inter-Cu electron transfer or proton transfer was observed in the absence of nitrite. Only in the presence of nitrite were both processes detected, with similar [nitrite] dependence, but the nitrite dependence was different compared with native enzyme. The substrate dependence in N90S was similar to that observed in steady-state assays, suggesting that this substitution resulted in proton-coupled electron transfer becoming rate-limiting. A pH perturbation experiment with native AxNiR revealed that protonation triggers inter-Cu electron transfer and generation of NO. Our results show a strong coupling of inter-Cu electron transfer and proton transfer for both native AxNiR and N90S, and provide novel insights into the controlled delivery of electrons and protons to the substrate-utilization T2Cu active site of AxNiR. PMID- 22536810 TI - Setting up a platform for plant-based influenza virus vaccine production in South Africa. AB - BACKGROUND: During a global influenza pandemic, the vaccine requirements of developing countries can surpass their supply capabilities, if these exist at all, compelling them to rely on developed countries for stocks that may not be available in time. There is thus a need for developing countries in general to produce their own pandemic and possibly seasonal influenza vaccines. Here we describe the development of a plant-based platform for producing influenza vaccines locally, in South Africa. Plant-produced influenza vaccine candidates are quicker to develop and potentially cheaper than egg-produced influenza vaccines, and their production can be rapidly upscaled. In this study, we investigated the feasibility of producing a vaccine to the highly pathogenic avian influenza A subtype H5N1 virus, the most generally virulent influenza virus identified to date. Two variants of the haemagglutinin (HA) surface glycoprotein gene were synthesised for optimum expression in plants: these were the full length HA gene (H5) and a truncated form lacking the transmembrane domain (H5tr). The genes were cloned into a panel of Agrobacterium tumefaciens binary plant expression vectors in order to test HA accumulation in different cell compartments. The constructs were transiently expressed in tobacco by means of agroinfiltration. Stable transgenic tobacco plants were also generated to provide seed for stable storage of the material as a pre-pandemic strategy. RESULTS: For both transient and transgenic expression systems the highest accumulation of full length H5 protein occurred in the apoplastic spaces, while the highest accumulation of H5tr was in the endoplasmic reticulum. The H5 proteins were produced at relatively high concentrations in both systems. Following partial purification, haemagglutination and haemagglutination inhibition tests indicated that the conformation of the plant-produced HA variants was correct and the proteins were functional. The immunisation of chickens and mice with the candidate vaccines elicited HA-specific antibody responses. CONCLUSIONS: We managed, after synthesis of two versions of a single gene, to produce by transient and transgenic expression in plants, two variants of a highly pathogenic avian influenza virus HA protein which could have vaccine potential. This is a proof of principle of the potential of plant-produced influenza vaccines as a feasible pandemic response strategy for South Africa and other developing countries. PMID- 22536811 TI - Difference in mother-child interaction between preterm- and term-born preschoolers with and without disabilities. AB - AIM: To investigate differences in the quality of mother-child interaction between preterm- and term-born children at age 5, and to study the association of mother-child interaction with sociodemographic characteristics and child disability. METHODS: Preterm children (n = 94), born at <30 weeks' gestation and/or birth weight <1000 g, and term children (n = 84) were assessed at corrected age of 5 using a mother-child interaction observation. Disabilities were assessed using an intelligence test, behaviour questionnaires for parents and teachers, and motor and neurological examinations. RESULTS: Mothers of preterm-born children were less supportive of and more interfering with their children's autonomy than mothers of term-born children. This difference was only partly explained by sociodemographic factors. Dyads showed a lower quality of mother-child interaction if children had a severe disability, especially when mothers had a lower level of education. CONCLUSION: Five years after birth, mother-child interaction of very premature children and their mothers compared unfavourably with term children and their mothers. Mothers with sociodemographic disadvantages, raising a preterm child with severe disabilities, struggle most with giving adequate sensitive support for the autonomy development of their child. Focused specialized support for these at risk groups is warranted. PMID- 22536812 TI - End of life, death and dying in neonatal intensive care units in Latin America. AB - AIM: Most analyses of end of life decisions in Neonatal Intensive Care Units (NICUs) have come from Europe/English-speaking countries. Would decisions be different in Latin American NICUs? Therefore, we aim to evaluate the approach to dying infants/families in NICUs in Latin America. METHODS: Multinational descriptive study of all deaths in babies born at >22 weeks in eight NICUs in five Latin American countries. Deaths were categorized as: (i) no Cardiopulmonary Resuscitation (CPR) or life support offered; (ii) life support initiated but do not resuscitate (DNR) orders written or no CPR provided; (iii) full life support and CPR; and (iv) unclassifiable. RESULTS: There were 100 deaths, 81% in >27 weeks. Seventeen infants received no CPR/life support at birth, 10 died in DR and seven in NICU. There were 27 infants in group 2, 54 in group three and two in group 4. No baby had care withdrawn or care withdrawn/CPR withheld. Thirty-two infants had 'do not resuscitate' order. Decisions without parents' involvement in 15%, both parents present at death 24% and sedatives/narcotics documented 14%. CONCLUSIONS: Latin American NICUs differ from those in Northern Europe/English speaking countries. More deaths are accompanied by full life support and CPR. DNR orders are rare. Withdrawal of life support is virtually non-existent. Latin American's doctors are more likely to make decisions without the objections of family about withholding life-sustaining treatment. PMID- 22536813 TI - Sleep problems in children with cerebral palsy and their relationship with maternal sleep and depression. AB - AIM: To compare sleep problems in children with cerebral palsy to typically developing children. To study the relationship between sleep problems in children with cerebral palsy and maternal sleep quality and depression. METHODS: Fifty seven children with cerebral palsy aged 4-12 years were identified from a UK disability database. Maternal sleep disturbance and mood were assessed using the Pittsburgh Sleep Quality Index and the Major Depression Inventory. Child sleep problems, assessed with the Children's Sleep Habits Questionnaire, but not maternal variables, were compared to 102 typically developing children. RESULTS: Forty children (70%) were recruited with a mean age of 7.8 (SD 2.4). Sleep anxiety, night wakings, parasomnias and sleep-disordered breathing sub-scales indicated significantly more difficulties than in typically developing children. 40% of mothers of children with cerebral palsy had poor sleep quality of whom 44% had depressed mood. Child and maternal sleep disturbance were significantly correlated. Maternal sleep quality predicted 50% of the variance in maternal depression. CONCLUSIONS: Children with cerebral palsy have more sleep problems than typically developing peers. Their mothers also have disturbed sleep that correlates with maternal depression. Childhood sleep problems can be treated and should be identified in routine clinical practice. PMID- 22536814 TI - Comparative study of spring dextrin impact on amylose retrogradation. AB - The effects of spring dextrin on amylose recrystallization were investigated by wide-angle X-ray diffraction (WXRD) and differential scanning calorimetry (DSC). Recrystallinity of amylose was reduced in terms of adding SD(7), SD(9), or SD(11). Alternatively, SD(3) or SD(5) accelerated the degree of crystallinity. DSC data were analyzed using the Avrami equation and confirmed the results of WXRD. Finally, molecular dynamic simulation was adapted to predict the behavior of polymers in water, and the results showed that the small spring dextrins disturbed amylose retrogradation by inhibiting or altering amylose-amylose interaction. PMID- 22536815 TI - Oestrogen-dependent suppression of pulsatile luteinising hormone secretion and kiss1 mRNA expression in the arcuate nucleus during late lactation in rats. AB - Follicular development and ovulation are strongly suppressed during lactation in mammals via a profound suppression of gonadotrophin secretion. The present study aimed to examine the role of oestrogen feedback action in suppressing luteinising hormone (LH) secretion and hypothalamic kisspeptin expression during the latter half of lactation. Plasma LH concentrations kept at low levels throughout the lactating period in intact and oestrogen-replaced ovariectomised (OVX) lactating rats, whereas plasma LH concentrations gradually elevated from day 10 postpartum in lactating OVX rats. OVX lactating rats showed frequent LH pulses at late lactation, although the LH pulses were significantly inhibited by an oestrogen replacement, which is much less effective on LH release in nonlactating rats. Oestrogen replacement in lactating OVX rats significantly reduced the number of Kiss1 mRNA-expressing cells in the arcuate nucleus (ARC) at late lactation, although the same oestrogen treatment did not affect the number of Kiss1 expressing cells in nonlactating controls. Exogenous kisspeptin challenge (0.2 nmol) into the third cerebroventricle significantly increased LH secretion in lactating OVX, lactating OVX + subcutaneous 17beta-oestradiol and intact lactating rats at day 16 postpartum. These results suggest that LH pulse suppression during late lactation could be a result of the enhanced oestrogen dependent suppression of ARC kisspeptin expression. PMID- 22536817 TI - Retrograde spinal cord stimulator lead placement for right L5 radiculopathy. PMID- 22536816 TI - Clostridium difficile infection in the community: a zoonotic disease? AB - Clostridium difficile infections (CDIs) are traditionally seen in elderly and hospitalized patients who have used antibiotic therapy. In the community, CDIs requiring a visit to a general practitioner are increasingly occurring among young and relatively healthy individuals without known predisposing factors. C. difficile is also found as a commensal or pathogen in the intestinal tracts of most mammals, and various birds and reptiles. In the environment, including soil and water, C. difficile may be ubiquitous; however, this is based on limited evidence. Food products such as (processed) meat, fish and vegetables can also contain C. difficile, but studies conducted in Europe report lower prevalence rates than in North America. Absolute counts of toxigenic C. difficile in the environment and food are low, however the exact infectious dose is unknown. To date, direct transmission of C. difficile from animals, food or the environment to humans has not been proven, although similar PCR ribotypes are found. We therefore believe that the overall epidemiology of human CDI is not driven by amplification in animals or other sources. As no outbreaks of CDI have been reported among humans in the community, host factors that increase vulnerability to CDI might be of more importance than increased exposure to C. difficile. Conversely, emerging C. difficile ribotype 078 is found in high numbers in piglets, calves, and their immediate environment. Although there is no direct evidence proving transmission to humans, circumstantial evidence points towards a zoonotic potential of this type. In future emerging PCR ribotypes, zoonotic potential needs to be considered. PMID- 22536818 TI - Contemporary management of complicated monochorionic twins. AB - Monochorionic twins are at increased risk for unique complications including twin twin transfusion syndrome (TTTS), selective intrauterine growth restriction (sIUGR), and twin-reversed arterial perfusion (TRAP) sequence. Twin-twin transfusion syndrome is treated with laser photocoagulation whereas selective reduction is an option in previable sIUGR or TRAP sequence. The nurse is integral in the management, education, care and support of women with complicated pregnancies. PMID- 22536819 TI - The impact of treatment transitions between dialysis and transplantation on illness cognitions and quality of life - a prospective study. AB - OBJECTIVES: Treatment transitions are frequent in end-stage renal disease (ESRD) but little is known about cognitive responses pre- to post-transplantation or after transplant failure. The purpose of this study was to examine changes in illness cognitions across treatment transitions between dialysis and transplantation and their impact on quality of life (QOL). METHODS: In this longitudinal study, ESRD patients (N= 262) patients were followed up across treatment transitions over a 7-year observation window using the Illness Perceptions Questionnaire, the Illness Effects Questionnaire, and measures of QOL. Study sample comprised the patients from this cohort who switched treatment modality (N= 60 post-transplantation; N= 28 transplant failure). Data were collected while on dialysis or transplantation and at 6 months post-treatment change. RESULTS: Significant changes in QOL and illness perceptions were found in treatment transitions with opposite patterns of either improvement or deterioration following transplantation or transplantation failure. Pre- to post transplantation, QOL improves and patients report less symptoms, lower consequences, and illness intrusiveness, more acute timeline and stronger control beliefs (ps < .01). QOL is diminished following transplant failure and patients report more symptoms, consequences, illness disruptiveness, more chronic timeline, and lower control. Changes in cognitions are associated with changes in QOL (R(2) = .469-.789). CONCLUSIONS: Treatment transitions marked significant changes in illness perceptions that were associated with changes in QOL. Interventions to prepare patients for treatment transitions and prevent increasingly negative patterns of illness perceptions with transplant failure may serve towards maintaining or improving adjustment outcomes. PMID- 22536820 TI - The shadow map: a general contact definition for capturing the dynamics of biomolecular folding and function. AB - Structure-based models (SBMs) are simplified models of the biomolecular dynamics that arise from funneled energy landscapes. We recently introduced an all-atom SBM that explicitly represents the atomic geometry of a biomolecule. While this initial study showed the robustness of the all-atom SBM Hamiltonian to changes in many of the energetic parameters, an important aspect, which has not been explored previously, is the definition of native interactions. In this study, we propose a general definition for generating atomically grained contact maps called "Shadow". The Shadow algorithm initially considers all atoms within a cutoff distance and then, controlled by a screening parameter, discards the occluded contacts. We show that this choice of contact map is not only well behaved for protein folding, since it produces consistently cooperative folding behavior in SBMs but also desirable for exploring the dynamics of macromolecular assemblies since, it distributes energy similarly between RNAs and proteins despite their disparate internal packing. All-atom structure-based models employing Shadow contact maps provide a general framework for exploring the geometrical features of biomolecules, especially the connections between folding and function. PMID- 22536821 TI - Backbone modification of retinal induces protein-like excited state dynamics in solution. AB - The drastically different reactivity of the retinal chromophore in solution compared to the protein environment is poorly understood. Here, we show that the addition of a methyl group to the C?C backbone of all-trans retinal protonated Schiff base accelerates the electronic decay in solution making it comparable to the proton pump bacteriorhodopsin. Contrary to the notion that reaction speed and efficiency are linked, we observe a concomitant 50% reduction in the isomerization yield. Our results demonstrate that minimal synthetic engineering of potential energy surfaces based on theoretical predictions can induce drastic changes in electronic dynamics toward those observed in an evolution-optimized protein pocket. PMID- 22536822 TI - Simulation of chemical metabolism for fate and hazard assessment. V. Mammalian hazard assessment. AB - Animals and humans are exposed to a wide array of xenobiotics and have developed complex enzymatic mechanisms to detoxify these chemicals. Detoxification pathways involve a number of biotransformations, such as oxidation, reduction, hydrolysis and conjugation reactions. The intermediate substances created during the detoxification process can be extremely toxic compared with the original toxins, hence metabolism should be accounted for when hazard effects of chemicals are assessed. Alternatively, metabolic transformations could detoxify chemicals that are toxic as parents. The aim of the present paper is to describe specificity of eukaryotic metabolism and its simulation and incorporation in models for predicting skin sensitization, mutagenicity, chromosomal aberration, micronuclei formation and estrogen receptor binding affinity implemented in the TIMES software platform. The current progress in model refinement, data used to parameterize models, logic of simulating metabolism, applicability domain and interpretation of predictions are discussed. Examples illustrating the model predictions are also provided. PMID- 22536823 TI - Design and application of a direct-push vadose zone gravel permeameter. PMID- 22536824 TI - Gamete donors' motivation in a Swedish national sample: is there any ambivalence? A descriptive study. AB - OBJECTIVE: To study donors' motivation and ambivalence before donation of gametes. DESIGN: Cross-sectional study. SETTING: Seven Swedish university hospital clinics. Sample. Of the 220 eligible oocyte donors and 156 eligible sperm donors who were approached, 181 (82%) oocyte donors and 119 (76%) sperm donors agreed to participate. METHODS: Gamete donors completed a questionnaire in the clinic prior to the donation. MAIN OUTCOME MEASURES: Motives and ambivalence towards donation. RESULTS: In general, gamete donors donated for altruistic reasons (95%). A greater percentage of oocyte than sperm donors had a personal experience of biological children, which motivated them to donate (65 vs. 32%). A greater percentage of sperm donors compared with oocyte donors were curious about their own fertility (24 vs. 9%), and they also believed that they were contributing what they regarded as their own good genes to other couples (45 vs. 20%). Prior to donation, potential sperm donors were more ambivalent towards donating than were oocyte donors (39 and 21%, p < 0.001). CONCLUSIONS: The motives to donate gametes are mainly altruistic. We conclude that men and women differ in their view towards donating gametes. Sperm donors had a higher degree of ambivalent feelings towards donation than oocyte donors. PMID- 22536825 TI - Vapor trapping growth of single-crystalline graphene flowers: synthesis, morphology, and electronic properties. AB - We report a vapor trapping method for the growth of large-grain, single crystalline graphene flowers with grain size up to 100 MUm. Controlled growth of graphene flowers with four lobes and six lobes has been achieved by varying the growth pressure and the methane to hydrogen ratio. Surprisingly, electron backscatter diffraction study revealed that the graphene morphology had little correlation with the crystalline orientation of underlying copper substrate. Field effect transistors were fabricated based on graphene flowers and the fitted device mobility could achieve ~4200 cm(2) V(-1) s(-1) on Si/SiO(2) and ~20 000 cm(2) V(-1 )s(-1) on hexagonal boron nitride (h-BN). Our vapor trapping method provides a viable way for large-grain single-crystalline graphene synthesis for potential high-performance graphene-based electronics. PMID- 22536826 TI - Neuromodulation mediated by the tachykinin NK3-receptor agonist [MePhe7] neurokinin B in the isolated perfused lung of nonsensitized nonchallenged and ovalbumin-sensitized and -challenged guinea pig. AB - The neuromodulatory action of the tachykinin NK(3)-receptor agonist [MePhe(7)] neurokinin B ([MePhe(7)]-NKB) was evaluated on vagal stimulation-induced bronchoconstriction in nonsensitized nonchallenged and ovalbumin (OVA)-sensitized and -challenged guinea pig using the isolated perfused lung preparation. Lungs were placed inside a warmed (37 degrees C) glass chamber and suspended from a force displacement transducer (Grass FT-03) with both vagi connected to a stimulating electrode. Isolated lungs were stimulated at a constant voltage (20 V) and pulse duration (5 ms) with electrical stimulation frequencies ranging from 1 to 128 Hz. The authors demonstrated that vagal stimulation produced frequency dependent bronchoconstriction and [MePhe(7)]-NKB, at a dose (0.1 MUM) that does not produce bronchoconstriction by itself, potentiated the vagally induced bronchoconstriction at all frequencies in nonsensitized nonchallenged animals and to a greater extent in OVA-sensitized and -challenged guinea pigs; the potentiations were totally inhibited by the tachykinin NK(3)-receptor antagonist SR 142801 (1 MUM). In a second set of experiments, [MePhe(7)]-NKB produced bronchoconstriction in a dose-dependent (1 to 300 MUg/mL) manner with similar potencies and maximum responses in nonsensitized nonchallenged (EC(50) = 8.6 +/- 1.1 MUM; E(Max) = 61.1 +/- 3.5 mm Hg) and OVA-sensitized and -challenged (EC(50) = 8.5 +/- 1.3 MUM; E(Max) = 63.5 +/- 3.7 mm Hg) animals. In conclusion, these results demonstrated that [MePhe(7)]-NKB potentiated vagal stimulation-induced bronchoconstriction via the tachykinin NK(3)-receptors and OVA sensitization caused development of airway hyperresponsiveness in these potentiations. However, OVA sensitization had no effect on airway responsiveness of vagal stimulation-and [MePhe(7)]-NKB-induced bronchoconstrictions. PMID- 22536827 TI - Do reactions after whole blood donation predict syncope on return donation? AB - BACKGROUND: Adverse reactions after whole blood donation reduce the likelihood of a subsequent donation. Still, many donors return to give blood even after experiencing a reaction. Consequently, we evaluated the risk of recurrent syncope among returning donors. STUDY DESIGN AND METHODS: Allogeneic whole blood donors in 2009 who had vasovagal-type reactions including syncope were evaluated for return donation within 12 months and subsequent reactions, based on donation status (novice [first-time] or active [repeat]) or age at index donation. RESULTS: Syncope after a first whole blood donation significantly reduced the frequency of return donation (18%), compared to either presyncopal symptoms (27%; p < 0.0001) or no reaction (35%; p < 0.0001). Among novice donors who returned to donate, syncope was more likely among donors who had any reaction (0.8%) or syncope (3.5%) at their first donation, compared to donors who had no reaction (0.3%; p < 0.0001). Syncope at a first donation identified only 2% (19 of 1062) of syncopal reactions among returning donors. For active, repeat donors who experienced syncope in 2009, a history of prior reactions had no effect on the likelihood of return donation or recurrent syncope. CONCLUSION: Donation experience strongly influences the likelihood of return donation and the risk of subsequent reactions, but a prior reaction after whole blood donation does not reliably predict recurrent syncope among returning donors. PMID- 22536828 TI - Dental care utilization among North Carolina rural older adults. AB - OBJECTIVES: This analysis delineates the predisposing, need, and enabling factors that are associated with regular and recent dental care in a multiethnic sample of rural older adults. METHODS: A cross-sectional, comprehensive, oral-health survey conducted with a random, multiethnic (African American, American Indian, white) sample of 635 community-dwelling adults aged 60 years and older was completed in two rural southern counties. Logistic regression models assessed the simultaneous associations of dental care with predisposing, enabling, and need factors. RESULTS: Almost no edentulous rural older adults received dental care; 27.1 percent of dentate rural older adults had received regular dental care, and 36.7 percent had received recent dental care. Predisposing (less than high-school education, dental anxiety), enabling (no regular place for dental care), and need factors (no filled teeth) reduced the odds of regular dental, while predisposing (dental anxiety), enabling (no regular place for dental care), and need factors (no filled teeth) reduced the odds of recent dental care. Having excellent, very good, or good self-rated oral health increased the odds of receiving regular and recent dental care. CONCLUSIONS: Regular and recent dental care are infrequent among rural older adults. Contrary to expectations, those not receiving dental care are those who most need care; this has been referred to as the Paradox of Dental Need. Community access to dental care and the ability of older adults to pay for dental care must be addressed by public-health policy to improve the health and quality of life of older adults in rural communities. PMID- 22536829 TI - Phytochrome interacting factors 4 and 5 control seedling growth in changing light conditions by directly controlling auxin signaling. AB - Plant growth is strongly influenced by the presence of neighbors that compete for light resources. In response to vegetational shading shade-intolerant plants such as Arabidopsis display a suite of developmental responses known as the shade avoidance syndrome (SAS). The phytochrome B (phyB) photoreceptor is the major light sensor to mediate this adaptive response. Control of the SAS occurs in part with phyB, which controls protein abundance of phytochrome-interacting factors 4 and 5 (PIF4 and PIF5) directly. The shade-avoidance response also requires rapid biosynthesis of auxin and its transport to promote elongation growth. The identification of genome-wide PIF5-binding sites during shade avoidance revealed that this bHLH transcription factor regulates the expression of a subset of previously identified SAS genes. Moreover our study suggests that PIF4 and PIF5 regulate elongation growth by controlling directly the expression of genes that code for auxin biosynthesis and auxin signaling components. PMID- 22536830 TI - Developmental pharmacokinetics of propylene glycol in preterm and term neonates. AB - AIM: Propylene glycol (PG) is often applied as an excipient in drug formulations. As these formulations may also be used in neonates, the aim of this study was to characterize the pharmacokinetics of propylene glycol, co-administered intravenously with paracetamol (800 mg PG/1000 mg paracetamol) or phenobarbital (700 mg PG/200 mg phenobarbital) in preterm and term neonates. METHODS: A population pharmacokinetic analysis was performed based on 372 PG plasma concentrations from 62 (pre)term neonates (birth weight (bBW) 630-3980 g, postnatal age (PNA) 1-30 days) using NONMEM 6.2. The model was subsequently used to simulate PG exposure upon administration of paracetamol or phenobarbital in neonates (gestational age 24-40 weeks). RESULTS: In a one compartment model, birth weight and PNA were both identified as covariates for PG clearance using an allometric function (CL(i) = 0.0849 * {(bBW/2720)(1.69) * (PNA/3)(0.201)}). Volume of distribution scaled allometrically with current bodyweight (V(i) = 0.967 * {(BW/2720)(1.45)}) and was estimated 1.77 times higher when co administered with phenobarbital compared with paracetamol. By introducing these covariates a large part of the interindividual variability on clearance (65%) as well as on volume of distribution (53%) was explained. The final model shows that for commonly used dosing regimens, the population mean PG peak and trough concentrations range between 33-144 and 28-218 mg l(-1) (peak) and 19-109 and 6 112 mg l(-1) (trough) for paracetamol and phenobarbital formulations, respectively, depending on birth weight and age of the neonates. CONCLUSION: A pharmacokinetic model was developed for PG co-administered with paracetamol or phenobarbital in neonates. As such, large variability in PG exposure may be expected in neonates which is dependent on birth weight and PNA. PMID- 22536831 TI - CBDB: the codon bias database. AB - BACKGROUND: In many genomes, a clear preference in the usage of particular codons exists. The mechanisms that induce codon biases remain an open question; studies have attributed codon usage to translational selection, mutational bias and drift. Furthermore, correlations between codon usage within host genomes and their viral pathogens have been observed for a myriad of host-virus systems. As such, numerous studies have investigated codon usage and codon bias in an effort to better understand how species evolve. Numerous metrics have been developed to identify biases in codon usage. In addition, a few data repositories of codon bias data are available, differing in the metrics reported as well as the number and taxonomy of strains examined. DESCRIPTION: We have created a new web resource called the Codon Bias Database (CBDB) which provides information regarding the codon bias within the set of highly expressed genes for 300+ bacterial genomes. CBDB was developed to provide a resource for researchers investigating codon bias in bacteria, facilitating comparisons between strains and species. Furthermore, the site was created to serve those studying adaptation in phage; the genera selected for this first release of CBDB all have sequenced, annotated bacteriophages. The annotations and sequences for the highly expressed gene set are available for each strain in addition to the strain's codon bias measurements. CONCLUSIONS: Comparing species and strains provides a comprehensive look at how codon usage has been shaped over evolutionary time and can elucidate the putative mechanisms behind it. The Codon Bias Database provides a centralized repository of look-up tables and codon usage bias measures for a wide variety of genera, species and strains. Through our analysis of the variation in codon usage within the strains presently available, we find that most members of a genus have a codon composition most similar to other members of its genus, although not necessarily other members of its species. PMID- 22536832 TI - High toxicity and specificity of the saponin 3-GlcA-28-AraRhaxyl-medicagenate, from Medicago truncatula seeds, for Sitophilus oryzae. AB - BACKGROUND: Because of the increasingly concern of consumers and public policy about problems for environment and for public health due to chemical pesticides, the search for molecules more safe is currently of great importance. Particularly, plants are able to fight the pathogens as insects, bacteria or fungi; so that plants could represent a valuable source of new molecules. RESULTS: It was observed that Medicago truncatula seed flour displayed a strong toxic activity towards the adults of the rice weevil Sitophilus oryzae (Coleoptera), a major pest of stored cereals. The molecule responsible for toxicity was purified, by solvent extraction and HPLC, and identified as a saponin, namely 3-GlcA-28-AraRhaxyl-medicagenate. Saponins are detergents, and the CMC of this molecule was found to be 0.65 mg per mL. Neither the worm Caenorhabditis elegans nor the bacteria E. coli were found to be sensitive to this saponin, but growth of the yeast Saccharomyces cerevisiae was inhibited at concentrations higher than 100 MUg per mL. The purified molecule is toxic for the adults of the rice weevils at concentrations down to 100 MUg per g of food, but this does not apply to the others insects tested, including the coleopteran Tribolium castaneum and the Sf9 insect cultured cells. CONCLUSIONS: This specificity for the weevil led us to investigate this saponin potential for pest control and to propose the hypothesis that this saponin has a specific mode of action, rather than acting via its non-specific detergent properties. PMID- 22536833 TI - The relationship between literacy and multimorbidity in a primary care setting. AB - BACKGROUND: Multimorbidity is now acknowledged as a research priority in primary care. The identification of risk factors and people most at risk is an important step in guiding prevention and intervention strategies. The aim of this study was to examine the relationship between literacy and multimorbidity while controlling for potential confounders. METHODS: Participants were adult patients attending the family medicine clinic of a regional health centre in Saguenay (Quebec), Canada. Literacy was measured with the Newest Vital Sign (NVS). Multimorbidity was measured with the Disease Burden Morbidity Assessment (DBMA) by self-report. Information on potential confounders (age, sex, education and family income) was also collected. The association between literacy (independent variable) and multimorbidity was examined in bivariate and multivariate analyses. Two operational definitions of multimorbidity were used successively as the dependent variable; confounding variables were introduced into the model as potential predictors. RESULTS: One hundred three patients (36 men) 19-83 years old were recruited; 41.8% had completed 12 years of school or less. Forty-seven percent of patients provided fewer than four correct answers on the NVS (possible low literacy) whereas 53% had four correct responses or more. Literacy and multimorbidity were associated in bivariate analyses (p < 0.01) but not in multivariate analyses, including age and family income. CONCLUSION: This study suggests that there is no relationship between literacy and multimorbidity when controlling for age and family income. PMID- 22536834 TI - Polyelectrolyte-promoted forward osmosis-membrane distillation (FO-MD) hybrid process for dye wastewater treatment. AB - Polyelectrolytes have proven their advantages as draw solutes in forward osmosis process in terms of high water flux, minimum reverse flux, and ease of recovery. In this work, the concept of a polyelectrolyte-promoted forward osmosis-membrane distillation (FO-MD) hybrid system was demonstrated and applied to recycle the wastewater containing an acid dye. A poly(acrylic acid) sodium (PAA-Na) salt was used as the draw solute of the FO to dehydrate the wastewater, while the MD was employed to reconcentrate the PAA-Na draw solution. With the integration of these two processes, a continuous wastewater treatment process was established. To optimize the FO-MD hybrid process, the effects of PAA-Na concentration, experimental duration, and temperature were investigated. Almost a complete rejection of PAA-Na solute was observed by both FO and MD membranes. Under the conditions of 0.48 g mL(-1) PAA-Na and 66 degrees C, the wastewater was most efficiently dehydrated yet with a stabilized PAA-Na concentration around 0.48 g mL(-1). The practicality of PAA-Na-promoted FO-MD hybrid technology demonstrates not only its suitability in wastewater reclamation, but also its potential in other membrane-based separations, such as protein or pharmaceutical product enrichment. This study may provide the insights of exploring novel draw solutes and their applications in FO related processes. PMID- 22536835 TI - Supporting a caring fatherhood in cyberspace - an analysis of communication about caring within an online forum for fathers. AB - BACKGROUND: Today's parents seek out social support on the Internet. A key motivation behind the choice to go online is the need for more experience based information. In recent years, new fathers have increasingly taken on an active parental role. Men's support for their caring activities for infants on the Internet needs attention. AIM: The aim was to describe communication about caring activities for infants among men who visited an Internet-based forum for fathers and elaborate on the dimensions of support available in the forum. METHOD: An archival and cross-sectional observational forum study was undertaken using principles for conducting ethnographic research online: "nethnography". A total of 1203 pages of data from an Internet forum for fathers were gathered and analysed. RESULT: Support for a caring fatherhood in cyberspace can be understood as fathers' communicating encouragement, confirmation and advice. The findings show that important ways of providing support through the forum included a reciprocal sharing of concerns - how to be a better father - in relation to caring for an infant. Concerns for their child's well-being and shared feelings of joy and distress in everyday life were recurrent supportive themes in the communication. Information gained from contacting others in similar situations is one important reason for the fathers' use of the Internet. DISCUSSION: Support offered in this kind of forum can be considered as a complement to formal support. Professionals can use it to provide choices for fathers who are developing themselves as caregivers without downplaying the parental support offered by formal health care regimes. FURTHER RESEARCH: Online support will probably be one of the main supporting strategies for fathers in Scandinavia. Caring and nursing researchers need to closely monitor support activities that develop, and over time, as these ill likely become an important source of support for people. PMID- 22536836 TI - Is there clinical benefit from early electroencephalography monitoring in very preterm infants? PMID- 22536837 TI - Testosterone replacement therapy outcomes among opioid users: the Testim Registry in the United States (TRiUS). AB - OBJECTIVE: Among patients with hypogonadism-associated comorbidities, opioid users have the highest incidence of hypogonadism. Data from the Testim Registry in the United States were analyzed to determine the efficacy of testosterone replacement therapy in opioid users vs nonusers. DESIGN: Prospective, 12-month observational cohort registry. SUBJECTS: Hypogonadal men (N = 849) prescribed Testim (but not necessarily testosterone replacement) for the first time. INTERVENTIONS: Testim 1% testosterone gel (5-10 g/day). OUTCOME MEASURES: Total and free testosterone, sex hormone-binding globulin, prostate-specific antigen, sexual function, mood/depression, and anthropometric data were assessed. Changes from baseline were analyzed using repeated measures mixed-effects analysis of variance; multiple linear regressions of changes in testosterone levels with sexual function, mood, and opioid use were computed. RESULTS: 90/849 patients (10.6%) reported opioid use at baseline; 75/90 (83%) used opioids for >= 30 days prior to baseline. Baseline total testosterone and prostate-specific antigen were not statistically different between opioid users and nonusers; there was a trend for higher sex hormone-binding globulin (P = 0.08) and lower free testosterone (P = 0.05) in opioid users. After 1 month, both opioid users and nonusers had significant (P < 0.001) increases in total and free testosterone, which continued through 12 months. Sexual function and mood improved significantly in both opioid users and nonusers over 12 months, and significantly correlated with change in total testosterone. CONCLUSIONS: Testosterone replacement therapy increased serum testosterone in hypogonadal opioid users and nonusers alike. The data suggest that with testosterone replacement, hypogonadal opioid users might be expected to have similar improvements in sexual function and mood as opioid nonusers. PMID- 22536839 TI - Adsorption and diffusion of Li on pristine and defective graphene. AB - With first-principles DFT calculations, the interaction between Li and carbon in graphene-based nanostructures is investigated as Li is adsorbed on graphene. It is found that the Li/C ratio of less than 1/6 for the single-layer graphene is favorable energetically, which can explain what has been observed in Raman spectrum reported recently. In addition, it is also found that the pristine graphene cannot enhance the diffusion energetics of Li ion. However, the presence of vacancy defects can increase the ratio of Li/C largely. With double-vacancy and higher-order defects, Li ion can diffuse freely in the direction perpendicular to the graphene sheets and hence boost the diffusion energetics to some extent. PMID- 22536838 TI - Characterization of the protein ubiquitination response induced by Doxorubicin. AB - Doxorubicin is commonly considered to exert its anti-tumor activity by triggering apoptosis of cancer cells through DNA damage. Recent reports have shown that Doxorubicin elicits a marked heat shock response, and that either inhibition or silencing of heat shock proteins enhance the Doxorubicin apoptotic effect in neuroblastoma cells. In order to investigate whether Doxorubicin may also act through protein modification, we performed a proteomic analysis of ubiquitinated proteins. Here we show that nanomolar Doxorubicin treatment of neuroblastoma cells caused: (a) dose-dependent over-ubiquitination of a specific set of proteins in the absence of measurable inhibition of proteasome, (b) protein ubiquination patterns similar to those with Bortezomib, a proteasome inhibitor, (c) depletion and loss of activity of ubiquitinated enzymes such as lactate dehydrogenase and alpha-enolase, and (d) a decrease in HSP27 solubility, probably a consequence of its binding to denatured proteins. These data strongly reinforce the hypothesis that Doxorubicin may also exert its effect by damaging proteins. PMID- 22536840 TI - The model of pathways to treatment: conceptualization and integration with existing theory. AB - BACKGROUND: Studying and understanding pathways to diagnosis and treatment is vital for the development of successful interventions to encourage early detection, presentation, and diagnosis. An existing framework posited to describe the decisional and behavioural processes that occur prior to treatment (Andersen et al.'s General Model of Total Patient Delay) does not appear to match the complex and dynamic nature of the pathways into and through the health care system or provide a clear framework for research. Therefore a revised descriptive framework, the Model of Pathways to Treatment, has been proposed. PURPOSE: This paper presents the concepts and definitions of the Model of Pathways to Treatment and specifies how the model can encompass existing psychological theory, with particular focus on the Appraisal and Help-seeking intervals. The potential and direction for future work is also discussed. STATEMENT OF CONTRIBUTION: WHAT IS ALREADY KNOWN ON THIS SUBJECT?: * The use of theory is often lacking in existing research into delays in presentation, diagnosis and treatment of illness. WHAT DOES THIS STUDY ADD?: * A detailed account of the concepts and definitions of a revised framework: the Model of Pathways to Treatment. * Specification of how the Model of Pathways to Treatment can encompass existing psychological theory such as the Common Sense Model of Illness Self-regulation and Social Cognitive Theory. PMID- 22536841 TI - Single samarium atoms in large fullerene cages. Characterization of two isomers of Sm@C92 and four isomers of Sm@C94 with the X-ray crystallographic identification of Sm@C1(42)-C92, Sm@C(s)(24)-C92, and Sm@C3v(134)-C94. AB - Two isomers of Sm@C(92) and four isomers of Sm@C(94) were isolated from carbon soot obtained by electric arc vaporization of carbon rods doped with Sm(2)O(3). Analysis of the structures by single-crystal X-ray diffraction on cocrystals formed with Ni(II)(octaethylporphyrin) reveals the identities of two of the Sm@C(92) isomers: Sm@C(92)(I), which is the more abundant isomer, is Sm@C(1)(42) C(92), and Sm@C(92)(II) is Sm@C(s)(24)-C(92). The structure of the most abundant form of the four isomers of Sm@C(94), Sm@C(94)(I), is Sm@C(3v)(134)-C(94), which utilizes the same cage isomer as the previously known Ca@C(3v)(134)-C(94) and Tm@C(3v)(134)-C(94). All of the structurally characterized isomers obey the isolated pentagon rule. While the four Sm@C(90) and five isomers of Sm@C(84) belong to common isomerization maps that allow these isomers to be interconverted through Stone-Wales transformations, Sm@C(1)(42)-C(92) and Sm@C(s)(24)-C(92) are not related to each other by any set of Stone-Wales transformations. UV-vis-NIR spectroscopy and computational studies indicate that Sm@C(1)(42)-C(92) is more stable than Sm@C(s)(24)-C(92) but possesses a smaller HOMO-LUMO gap. While the electronic structures of these endohedrals can be formally described as Sm(2+)@C(2n)(2-), the net charge transferred to the cage is less than two due to some back-donation of electrons from pi orbitals of the cage to the metal ion. PMID- 22536842 TI - Re-creating missing population baselines for Pacific reef sharks. AB - Sharks and other large predators are scarce on most coral reefs, but studies of their historical ecology provide qualitative evidence that predators were once numerous in these ecosystems. Quantifying density of sharks in the absence of humans (baseline) is, however, hindered by a paucity of pertinent time-series data. Recently researchers have used underwater visual surveys, primarily of limited spatial extent or nonstandard design, to infer negative associations between reef shark abundance and human populations. We analyzed data from 1607 towed-diver surveys (>1 ha transects surveyed by observers towed behind a boat) conducted at 46 reefs in the central-western Pacific Ocean, reefs that included some of the world's most pristine coral reefs. Estimates of shark density from towed-diver surveys were substantially lower (<10%) than published estimates from surveys along small transects (<0.02 ha), which is not consistent with inverted biomass pyramids (predator biomass greater than prey biomass) reported by other researchers for pristine reefs. We examined the relation between the density of reef sharks observed in towed-diver surveys and human population in models that accounted for the influence of oceanic primary productivity, sea surface temperature, reef area, and reef physical complexity. We used these models to estimate the density of sharks in the absence of humans. Densities of gray reef sharks (Carcharhinus amblyrhynchos), whitetip reef sharks (Triaenodon obesus), and the group "all reef sharks" increased substantially as human population decreased and as primary productivity and minimum sea surface temperature (or reef area, which was highly correlated with temperature) increased. Simulated baseline densities of reef sharks under the absence of humans were 1.1-2.4/ha for the main Hawaiian Islands, 1.2-2.4/ha for inhabited islands of American Samoa, and 0.9-2.1/ha for inhabited islands in the Mariana Archipelago, which suggests that density of reef sharks has declined to 3-10% of baseline levels in these areas. PMID- 22536843 TI - Identification of cases with adverse neonatal outcome monitored by cardiotocography versus ST analysis: secondary analysis of a randomized trial. AB - OBJECTIVE: To evaluate whether correct adherence to clinical guidelines might have led to prevention of cases with adverse neonatal outcome. DESIGN: Secondary analysis of cases with adverse outcome in a multicenter randomized clinical trial. SETTING: Nine Dutch hospitals. POPULATION: Pregnant women with a term singleton fetus in cephalic position. METHODS: Data were obtained from a randomized trial that compared monitoring by STAN(r) (index group) with cardiotocography (control group). In both trial arms, three observers independently assessed the fetal surveillance results in all cases with adverse neonatal outcome, to determine whether an indication for intervention was present, based on current clinical guidelines. MAIN OUTCOME MEASURES: Adverse neonatal outcome cases fulfilled one or more of the following criteria: (i) metabolic acidosis in umbilical cord artery (pH < 7.05 and base deficit in extracellular fluid >12 mmol/L); (ii) umbilical cord artery pH < 7.00; (iii) perinatal death; and/or (iv) signs of moderate or severe hypoxic ischemic encephalopathy. RESULTS: We studied 5681 women, of whom 61 (1.1%) had an adverse outcome (26 index; 35 control). In these women, the number of performed operative deliveries for fetal distress was 18 (69.2%) and 16 (45.7%), respectively. Reassessment of all 61 cases showed that there was a fetal indication to intervene in 23 (88.5%) and 19 (57.6%) cases, respectively. In 13 (50.0%) vs. 11 (33.3%) cases, respectively, this indication occurred more than 20 min before the time of delivery, meaning that these adverse outcomes could possibly have been prevented. CONCLUSIONS: In our trial, more strict adherence to clinical guidelines could have led to additional identification and prevention of adverse outcome. PMID- 22536844 TI - Thermodynamic analysis of the molecular interactions between amyloid beta-protein fragments and (-)-epigallocatechin-3-gallate. AB - (-)-Epigallocatechin-3-gallate (EGCG) has been proven effective in preventing the aggregation of amyloid beta-protein 42 (Abeta42), and the thermodynamic interactions between Abeta42 and EGCG have been studied in our previous work ( J. Phys. Chem. B 2010, 114, 11576). Herein, to further probe the interactions between different regions of Abeta42 and EGCG, three Abeta42 fragments (i.e., Abeta1-16, Abeta1-30, and Abeta31-42) were synthesized, and the thermodynamic interactions between each of the fragments and EGCG at different EGCG and salt concentrations were investigated by isothermal titration calorimetry. The results indicate that, although hydrogen bonding and hydrophobic interaction are both involved in the interactions between Abeta42 and EGCG, hydrogen bonding mainly happens in Abeta1-16 while hydrophobic interaction mainly happens in Abeta17-42. It is found that when Abeta42 and its fragments are saturated by EGCG, their thermodynamic parameters have linear relationships. The saturated binding stoichiometry (N(s)) for Abeta42 is the sum of the N(s) values for Abeta1-30 and Abeta31-42, while DeltaH(s), DeltaS(s), and DeltaG(s) for Abeta42 are half the sum of the values for Abeta1-30 and Abeta31-42. The result suggests that there are no specific interactions and binding sites in the Abeta42 and EGCG binding. The orders of DeltaH(s) and TDeltaS(s) values for the Abeta fragments are determined as Abeta17-42 > Abeta31-42 > Abeta1-30 > Abeta1-16. Moreover, there is significant enthalpy-entropy compensation in the binding of EGCG to Abeta42 and its fragments, resulting in insignificant change of DeltaG with the change of the solution environment. The research has shed new light on the molecular mechanisms of the interactions between EGCG and Abeta42. PMID- 22536846 TI - Police witness identification images: a geometric morphometric analysis. AB - Research into witness identification images typically occurs within the laboratory and involves subjective likeness and recognizability judgments. This study analyzed whether actual witness identification images systematically alter the facial shapes of the suspects described. The shape analysis tool, geometric morphometrics, was applied to 46 homologous facial landmarks displayed on 50 witness identification images and their corresponding arrest photographs, using principal component analysis and multivariate regressions. The results indicate that compared with arrest photographs, witness identification images systematically depict suspects with lowered and medially located eyebrows (p = <0.000001). This was found to occur independently of the Police Artist, and did not occur with composites produced under laboratory conditions. There are several possible explanations for this finding, including any, or all, of the following: The suspect was frowning at the time of the incident, the witness had negative feelings toward the suspect, this is an effect of unfamiliar face processing, the suspect displayed fear at the time of their arrest photograph. PMID- 22536847 TI - Thawing of cryopreserved hematopoietic progenitor cells from apheresis with a new dry-warming device. AB - BACKGROUND: Current thawing techniques of cryopreserved progenitor cells are based on the use of a water bath. The aim of this study has been to assess the progenitor cell viability and the time of hematopoietic engraftment after transplantation of cell products thawed with a new dry-thawing device. STUDY DESIGN AND METHODS: In the preclinical phase, two cryobags from the same patient were thawed with the standard technique and with the dry system method in parallel (n=5, Protocol A and Protocol B, respectively). In the clinical phase, cryobags were thawed with the dry system and the time to hematopoietic engraftment after autologous transplantation (n=52) was compared with those of a control group of patients whose progenitor cell products were thawed with the standard technique (n=52). RESULTS: There were no statistical differences in nuclear and CD34+ cell viability, total colony-forming cells, and cloning efficiency after thawing with Protocols A and B. Days to neutrophil (>0.5*10(9) and >1*10(9) /L) and platelet engraftment (>20*10(9) and >50*10(9) /L) were not different between patients transplanted with products thawed with Protocols A and B. CONCLUSION: Progenitor cell viability and function are preserved with this dry thawing system. The time to hematopoietic engraftment of patients after transplantation is comparable to those infused with progenitor cells thawed with the water bath technique. Thawing cell products without the use of water and in a dry environment might favor the use of this dry method. PMID- 22536848 TI - Stabilizing vortices in interacting nano-objects: a chemical approach. AB - We report a chemical method to prepare metallic Fe porous nanocubes. The presence of pores embedded inside the cubes was attested by electron tomography. Thanks to electronic holography and micromagnetic simulations, we show that the presence of these defects stabilizes the vortices in assembly of interacting cubes. These results open new perspectives toward magnetic vortex stabilization at relatively low cost for various applications (microelectronics, magnetic recording, or biological applications). PMID- 22536849 TI - Discrepancy between initial high expression of interest in clinical cancer genetic testing and actual low uptake in an Asian population. AB - AIMS: Little is known about the acceptance of clinical cancer genetic testing in Asians. We surveyed the attitudes and perceived motivators and barriers to genetic testing immediately after genetic counseling in at-risk patients for hereditary cancer in a cancer genetics clinic in Singapore, and compared the responses of actual test acceptors and decliners. RESULTS: Three hundred seventeen patients participated, including 199 cancer-affected and 118 cancer free probands or family members. Overall, 70% of patients expressed an initial willingness to be tested, and most did not perceive major barriers. However, only 69/199 (35%) of cancer-affected probands were actually tested. There was no significant difference in age, education, marital status, or initial expression of negative feelings toward genetic information between the test acceptors and decliners, although the decliners were more likely to have indicated a wish not to be tested (22% vs. 4%, p<0.001) and cited cost as a barrier (32% vs. 12%, p=0.002). The most common actual reasons against testing were cost (60%), not wanting to bear the emotional burden of genetic information (16%), and the perception that the medical management will not change (16%). CONCLUSION: A significant discrepancy exists between an initial high interest in testing and actual low uptake. Health programs that address cost issues and education to correct misperceptions may improve genetic information utilization. PMID- 22536850 TI - CROES global PCNL project: completing the puzzle of quality. PMID- 22536851 TI - Metaphors used by in-service training nurses for in-service training nurses in Turkey. AB - AIM: To report a study conducted using a qualitative and quantitative study pattern with an aim to reveal the perceptions of in-service training nurses about in-service training nurses via metaphors. BACKGROUND: The in-service training nurse assumes great responsibility in the effective and efficient implementation of the educational activities in healthcare. In line with this, determining the perceptions of the in-service training nurses about in-service training nurses via metaphors and taking this into consideration in professional activities are important in terms of developing, changing, or questioning the perspectives of the in-service training nurses about their roles and developing their own training nurse identity. DESIGN: This article was designed as qualitative and quantitative study pattern. METHODS: The population of the study included 93 in service training nurses. Data were collected between June-September 2009. To collect data, each in-service training nurse was asked to complete the blanks in the sentence, 'The in-service training nurse is like a/an.....................because..................' The data were analysed using qualitative (content analysis) and quantitative (chi-square) data analysis methods. FINDINGS: According to the findings of the study, the in-service training nurses identified 59 metaphors in total. The metaphors were grouped under nine conceptual categories depending on the characteristics they had in common. In cognitive image of the in-service training nurses relating to the concept of in-service training nurse, the outstanding conceptual category was the in-service training nurse as a knowledge provider. CONCLUSION: The metaphors can be used as a strong research tool in understanding, revealing and explaining the cognitive images of the in-service training nurses. PMID- 22536852 TI - Isostructural dinuclear phenoxo-/acetato-bridged manganese(II), cobalt(II), and zinc(II) complexes with labile sites: kinetics of transesterification of 2 hydroxypropyl-p-nitrophenylphosphate. AB - Using the dinucleating phenol-based ligand 2,6-bis[3-(pyridin-2-yl)pyrazol-1 ylmethyl]-4-methylphenol] (HL(2)), in its deprotonated form, the six new dinuclear complexes [M(II)(2)(L(2))(MU-O(2)CMe)(2)(MeCN)(2)][PF(6)] (M = Mn (2a), Co (3a), Zn (4a)) and [M(II)(2)(L(2))(MU-O(2)CMe)(2)(MeCN)(2)][BPh(4)] (M = Mn (2b), Co (3b), Zn (4b)) have been synthesized. Crystallographic analyses on 2b.2MeCN, 3b.2MeCN, and 4b.2MeCN reveal that these complexes have closely similar MU-phenoxo bis(MU-carboxylato) structures. The physicochemical properties (absorption and ESI-MS spectral data, 2a,b, 3a,b, and 4a,b; (1)H NMR, 4a,b) of the cations of 2a-4a are identical with those of 2b-4b. Each metal ion is terminally coordinated by a pyrazole nitrogen and a pyridyl nitrogen from a 3 (pyridin-2-yl)pyrazole unit and a solvent molecule (MeCN). Thus, each metal center assumes distorted-octahedral M(II)N(3)O(3) coordination. Temperature dependent magnetic studies on Mn(II) and Co(II) dimers reveal the presence of intramolecular antiferromagnetic (J = -8.5 cm(-1)) for 2b and ferromagnetic exchange coupling (J = +2.51 cm(-1)) for 3b, on the basis of the Hamiltonian H = JS(1).S(2). The exchange mechanism is discussed on the basis of magneto structural parameters (M...M distance). Spectroscopic properties of the complexes have also been investigated. The pH titration and kinetics of phosphatase (transesterification) activity on 2-hydroxypropyl-p-nirophenylphosphate (HPNP) were studied in MeOH/H(2)O (33%, v/v) with 2a-4a, due to solubility reasons. This comparative kinetic study revealed the effect of the metal ion on the rate of hydrolysis of HPNP, which has been compared with what we recently reported for [Ni(II)(2)(L(2))(MU-O(2)CMe)(2)(MeOH)(H(2)O)][ClO(4)] (1a). The efficacy in the order of conversion of substrate to product (p-nitrophenolate ion) follows the order 4a > 3a > 2a > 1a, under identical experimental conditions. Notably, this trend follows the decrease of pK(a) values of M(II)-coordinated water (7.95 +/- 0.04 and 8.78 +/- 0.03 for 1a, 7.67 +/- 0.08 and 8.69 +/- 0.06 for 2a, 7.09 +/- 0.05 and 8.05 +/- 0.06 for 3a, and 6.20 +/- 0.04 and 6.80 +/- 0.03 for 4a). In this work we demonstrate that the stronger the Lewis acidity (Z(eff)/r) of the metal ion, the more acidic is the M(II)-coordinated water and the greater is the propensity of the metal ion to catalyze hydrolysis of the activated phosphate ester HPNP. Notably, the observed k(2) values (M(-1) s(-1)) for Mn(II) (2a, 0.152), Co(II) (3a, 0.208), and Zn(II) (4a, 0.230) complexes (1a, 0.058; already reported) linearly correlate with Z(eff)/r values of the metal ion. In each case a pseudo-first-order kinetic treatment has been done. Kinetic data analysis of complexes 2a-4a were also done following Michaelis-Menten treatment (catalytic efficiency k(cat)/K(M) values 0.170 M(-1) s(-1) for 2a, 0.194 M(-1) s(-1) for 3a and 0.161 M(-1) s(-1) for 4a; for 1a the value is 0.089 M(-1) s(-1)). Temperature dependent measurements were done to evaluate kinetic/thermodynamic parameters for the hydrolysis/transesterification of HPNP and yielded comparable activation parameters (E(a) (kJ mol(-1)): 71.00 +/- 4.60 (1a; reported), 67.95 +/- 5.71 (2a), 62.60 +/- 4.46 (3a), 67.80 +/- 3.25 (4a)) and enthalpy/entropy of activation values (DeltaH(?) (kJ mol(-1)) = 68.00 +/- 4.65 (1a; reported), 65.40 +/- 5.72 (2a), 60.00 +/- 4.47 (3a), 65.29 +/- 3.26 (4a); DeltaS(?) (J mol(-1) K( 1)) = -109.00 +/- 13 (1a; reported), -107.30 +/- 16 (2a), -122.54 +/- 14 (3a), 104.67 +/- 10 (4a)). The E(a) values for all the complexes are comparable, suggesting a closely similar reaction barrier, meaning thereby similar course of reaction. The DeltaS(?) values are consistent with an associative process. Positive DeltaH(?) values correspond to bond breaking of the activated complex as a result of nucleophilic attack at the phosphorus atom, releasing cyclic phosphate and p-nitrophenolate ion. These data have helped us to propose a common mechanistic pathway: deprotonation of a metal-bound species to form the effective nucleophile, binding of the substrate to the metal center(s), intramolecular nucleophilic attack on the electrophilic phosphorus atom with the release of the leaving group, and possibly regeneration of the catalyst. PMID- 22536853 TI - Lack of adherence to hypertension treatment guidelines among GPs in southern Sweden-a case report-based survey. AB - BACKGROUND: General practitioners (GPs) often fail to correctly adhere to guidelines for the treatment of hypertension. The reasons for this are unclear, but could be related to lack of knowledge in assessing individual patients' cardiovascular disease risk. Our aim was to investigate how GPs in southern Sweden adhere to clinical guidelines for the treatment of hypertension when major cardiovascular risk factors are taken into consideration. METHOD: A questionnaire with five genuine cases of hypertension with different cardiovascular risk profiles was sent to a random sample of GPs in southern Sweden (n=109) in order to investigate the attitude towards blood pressure (BP) treatment when major cardiovascular risk factors were present. RESULTS: In general, GPs who responded tended to focus on the absolute target BP rather than assessing the entire cardiovascular risk factor profile. Thus, cases with the highest risk of cardiovascular disease were not treated accordingly. However, there was also a tendency to overtreat the lowest risk individuals. Furthermore, the BP levels for initiating pharmacological treatment varied widely (systolic BP 140-210 mmHg). ACE inhibitors (70%) were the most common first choice of pharmacological treatment. CONCLUSION: In this study, GPs in Southern Sweden were suggesting, for different cases, either under- or overtreatment in relation to current guidelines for treatment of hypertension. On reason may be that they failed to correctly assess individual cardiovascular risk factor profiles. PMID- 22536855 TI - PROSO II--a new method for protein solubility prediction. AB - Many fields of science and industry depend on efficient production of active protein using heterologous expression in Escherichia coli. The solubility of proteins upon expression is dependent on their amino acid sequence. Prediction of solubility from sequence is therefore highly valuable. We present a novel machine learning-based model called PROSO II which makes use of new classification methods and growth in experimental data to improve coverage and accuracy of solubility predictions. The classification algorithm is organized as a two layered structure in which the output of a primary Parzen window model for sequence similarity and a logistic regression classifier of amino acid k-mer composition serve as input for a second-level logistic regression classifier. Compared with previously published research our model is trained on five times more data than used by any other method before (82 000 proteins). When tested on a separate holdout set not used at any point of method development our server attained the best results in comparison with other currently available methods: accuracy 75.4%, Matthew's correlation coefficient 0.39, sensitivity 0.731, specificity 0.759, gain (soluble) 2.263. In summary, due to utilization of cutting edge machine learning technologies combined with the largest currently available experimental data set the PROSO II server constitutes a substantial improvement in protein solubility predictions. PROSO II is available at http://mips.helmholtz-muenchen.de/prosoII. PMID- 22536854 TI - Exploring functionally related enzymes using radially distributed properties of active sites around the reacting points of bound ligands. AB - BACKGROUND: Structural genomics approaches, particularly those solving the 3D structures of many proteins with unknown functions, have increased the desire for structure-based function predictions. However, prediction of enzyme function is difficult because one member of a superfamily may catalyze a different reaction than other members, whereas members of different superfamilies can catalyze the same reaction. In addition, conformational changes, mutations or the absence of a particular catalytic residue can prevent inference of the mechanism by which catalytic residues stabilize and promote the elementary reaction. A major hurdle for alignment-based methods for prediction of function is the absence (despite its importance) of a measure of similarity of the physicochemical properties of catalytic sites. To solve this problem, the physicochemical features radially distributed around catalytic sites should be considered in addition to structural and sequence similarities. RESULTS: We showed that radial distribution functions (RDFs), which are associated with the local structural and physicochemical properties of catalytic active sites, are capable of clustering oxidoreductases and transferases by function. The catalytic sites of these enzymes were also characterized using the RDFs. The RDFs provided a measure of the similarity among the catalytic sites, detecting conformational changes caused by mutation of catalytic residues. Furthermore, the RDFs reinforced the classification of enzyme functions based on conventional sequence and structural alignments. CONCLUSIONS: Our results demonstrate that the application of RDFs provides advantages in the functional classification of enzymes by providing information about catalytic sites. PMID- 22536856 TI - Guilt and shame--a semantic concept analysis of two concepts related to palliative care. AB - BACKGROUND: The theoretical viewpoint of the study was based on the fundamental motive in caring science, the suffering person and his/her health and life situation, which according to the philosophy of palliative care also includes the next of kin. The latter often wish to participate in the care of their loved ones and it is thus important for them to be able to make decisions that can generate a meaningful participation. Unfulfilled obligations or wrong decisions, concerning their dying relative, can result in experiences of guilt and shame in relation to the care of the loved one. A semantic concept analysis can provide a deeper understanding of these concepts and create a deeper insight into what the concepts mean for the individual. AIM: The aim of the study was to elucidate the meaning of and the distinction between the concepts of guilt and shame. METHODS: Semantic concept analysis based on Koort and Eriksson. FINDINGS: The findings show that guilt and shame are two separate concepts. Guilt contains meaning dimensions of being the cause of and sin. Shame contains meaning dimensions of something that gives rise to shame and ability to experience shame. The synonyms for each concept do not overlap each other. CONCLUSION: The semantic analysis creates an understanding of the concepts ontologically and provides a basis for theoretical, contextual and clinical understanding and development. PMID- 22536857 TI - Effect of tolfenamic acid on canine cancer cell proliferation, specificity protein (sp) transcription factors, and sp-regulated proteins in canine osteosarcoma, mammary carcinoma, and melanoma cells. AB - BACKGROUND: Tolfenamic acid (TA) is an NSAID currently under investigation as an anticancer agent in humans. TA induces proteosome-dependent degradation of transcription factors Sp 1, 3, and 4. These proteins are known to be overexpressed in many human cancers. HYPOTHESIS: To evaluate the protein expression of Sps in canine tissue, and efficacy of TA against several canine tumor cell lines. METHODS: Six canine cell lines (2 osteosarcoma, 2 mammary carcinoma, 2 melanoma) were evaluated. Protein levels of Sp 1-4 and their downstream targets were evaluated using Western Blots. Cell survival and TUNEL assays were performed on cell lines, and Sp1 expression was evaluated on histologic samples from archived canine cases. ANIMALS: Six immortalized canine cancer cell lines derived from dogs were used. Archived tissue samples were also used. RESULTS: Sps were highly expressed in all 6 cell lines and variably expressed in histologic tissues. TA decreased expression of Sps 1-4 in all cell lines. All of the downstream targets of Sps were inhibited in the cell lines. Variable Sp1 expression was identified in all histologic samples examined. TA significantly inhibited cell survival in all cell lines in a dose dependant fashion. The number of cells undergoing apoptosis was significantly increased (P < .05) in all cell lines after exposure to TA in a dose-dependent fashion. CONCLUSIONS, AND CLINICAL IMPORTANCE: Tolfenamic acid is a potential anticancer NSAID and further investigation is needed to determine its usefulness in a clinical setting. PMID- 22536859 TI - Proceedings from the Great Lakes Bioinformatics Conference 2011. Preface. PMID- 22536858 TI - Pain ratings by patients and their providers of radionucleotide injection for breast cancer lymphatic mapping. AB - BACKGROUND: Disparity between patient report and physician perception of pain from radiotracer injection for sentinel node biopsy is thought to center on the severity of the intervention, ethnic composition of population queried, and socioeconomic factors. OBJECTIVE: The objectives of this study were, first, to explore agreement between physicians' and their breast cancer patients' pain assessment during subareolar radionucleotide injection; and second, to evaluate potential ethnic differences in ratings. METHODS: A trial was conducted, from January 2006 to April 2009, where 140 breast cancer patients were randomly assigned to standard topical lidocaine-4% cream and 99mTc-sulfur colloid injection, or to one of three other groups: placebo cream and 99mTc-sulfur colloid injection containing NaHCO3, 1% lidocaine, or NaHCO3 + 1% lidocaine. Providers and patients completed numeric pain scales (0-10) immediately after injection. RESULTS: Patients and providers rated pain similarly over the entire cohort (median, 3 vs 2, P = 0.15). Patients rated pain statistically significantly higher than physicians in the standard (6 vs 5, P = 0.045) and placebo + NaHCO3 (5 vs 4, P = 0.032) groups. No significant difference in scores existed between all African Americans and their physicians (3 vs 4, P = 0.27). CONCLUSION: Patient-physician pain assessment congruence over the less painful injections and their statistically similar scores with the more painful methods suggests the importance of utilizing the least painful method possible. Providers tended to underestimate patients with the highest pain ratings-those in the greatest analgesic need. Lack of statistical difference between African American and physician scores may reflect the equal-access-to-care over the entire patient cohort, supporting the conclusion that socioeconomic factors may lie at the heart of previously reported discrepancies. PMID- 22536860 TI - Reordering based integrative expression profiling for microarray classification. AB - BACKGROUND: Current network-based microarray analysis uses the information of interactions among concerned genes/gene products, but still considers each gene expression individually. We propose an organized knowledge-supervised approach - Integrative eXpression Profiling (IXP), to improve microarray classification accuracy, and help discover groups of genes that have been too weak to detect individually by traditional ways. To implement IXP, ant colony optimization reordering (ACOR) algorithm is used to group functionally related genes in an ordered way. RESULTS: Using Alzheimer's disease (AD) as an example, we demonstrate how to apply ACOR-based IXP approach into microarray classifications. Using a microarray dataset - GSE1297 with 31 samples as training set, the result for the blinded classification on another microarray dataset - GSE5281 with 151 samples, shows that our approach can improve accuracy from 74.83% to 82.78%. A recently-published 1372-probe signature for AD can only achieve 61.59% accuracy in the same condition. The ACOR-based IXP approach also has better performance than the IXP approach based on classic network ranking, graph clustering, and random-ordering methods in an overall classification performance comparison. CONCLUSIONS: The ACOR-based IXP approach can serve as a knowledge-supervised feature transformation approach to increase classification accuracy dramatically, by transforming each gene expression profile to an integrated expression files as features inputting into standard classifiers. The IXP approach integrates both gene expression information and organized knowledge - disease gene/protein network topology information, which is represented as both network node weights (local topological properties) and network node orders (global topological characteristics). PMID- 22536861 TI - Matching phosphorylation response patterns of antigen-receptor-stimulated T cells via flow cytometry. AB - BACKGROUND: When flow cytometric data on mixtures of cell populations are collected from samples under different experimental conditions, computational methods are needed (a) to classify the samples into similar groups, and (b) to characterize the changes within the corresponding populations due to the different conditions. Manual inspection has been used in the past to study such changes, but high-dimensional experiments necessitate developing new computational approaches to this problem. A robust solution to this problem is to construct distinct templates to summarize all samples from a class, and then to compare these templates to study the changes across classes or conditions. RESULTS: We designed a hierarchical algorithm, flowMatch, to first match the corresponding clusters across samples for producing robust meta-clusters, and to then construct a high-dimensional template as a collection of meta-clusters for each class of samples. We applied the algorithm on flow cytometry data obtained from human blood cells before and after stimulation with anti-CD3 monoclonal antibody, which is reported to change phosphorylation responses of memory and naive T cells. The flowMatch algorithm is able to construct representative templates from the samples before and after stimulation, and to match corresponding meta-clusters across templates. The templates of the pre stimulation and post-stimulation data corresponding to memory and naive T cell populations clearly show, at the level of the meta-clusters, the overall phosphorylation shift due to the stimulation. CONCLUSIONS: We concisely represent each class of samples by a template consisting of a collection of meta-clusters (representative abstract populations). Using flowMatch, the meta-clusters across samples can be matched to assess overall differences among the samples of various phenotypes or time-points. PMID- 22536862 TI - Fold change and p-value cutoffs significantly alter microarray interpretations. AB - BACKGROUND: As context is important to gene expression, so is the preprocessing of microarray to transcriptomics. Microarray data suffers from several normalization and significance problems. Arbitrary fold change (FC) cut-offs of >2 and significance p-values of <0.02 lead data collection to look only at genes which vary wildly amongst other genes. Therefore, questions arise as to whether the biology or the statistical cutoff are more important within the interpretation. In this paper, we reanalyzed a zebrafish (D. rerio) microarray data set using GeneSpring and different differential gene expression cut-offs and found the data interpretation was drastically different. Furthermore, despite the advances in microarray technology, the array captures a large portion of genes known but yet still leaving large voids in the number of genes assayed, such as leptin a pleiotropic hormone directly related to hypoxia-induced angiogenesis. RESULTS: The data strongly suggests that the number of differentially expressed genes is more up-regulated than down-regulated, with many genes indicating conserved signalling to previously known functions. Recapitulated data from Marques et al. (2008) was similar but surprisingly different with some genes showing unexpected signalling which may be a product of tissue (heart) or that the intended response was transient. CONCLUSIONS: Our analyses suggest that based on the chosen statistical or fold change cut-off; microarray analysis can provide essentially more than one answer, implying data interpretation as more of an art than a science, with follow up gene expression studies a must. Furthermore, gene chip annotation and development needs to maintain pace with not only new genomes being sequenced but also novel genes that are crucial to the overall gene chips interpretation. PMID- 22536863 TI - Predicting glioblastoma prognosis networks using weighted gene co-expression network analysis on TCGA data. AB - BACKGROUND: Using gene co-expression analysis, researchers were able to predict clusters of genes with consistent functions that are relevant to cancer development and prognosis. We applied a weighted gene co-expression network (WGCN) analysis algorithm on glioblastoma multiforme (GBM) data obtained from the TCGA project and predicted a set of gene co-expression networks which are related to GBM prognosis. METHODS: We modified the Quasi-Clique Merger algorithm (QCM algorithm) into edge-covering Quasi-Clique Merger algorithm (eQCM) for mining weighted sub-network in WGCN. Each sub-network is considered a set of features to separate patients into two groups using K-means algorithm. Survival times of the two groups are compared using log-rank test and Kaplan-Meier curves. Simulations using random sets of genes are carried out to determine the thresholds for log rank test p-values for network selection. Sub-networks with p-values less than their corresponding thresholds were further merged into clusters based on overlap ratios (>50%). The functions for each cluster are analyzed using gene ontology enrichment analysis. RESULTS: Using the eQCM algorithm, we identified 8,124 sub networks in the WGCN, out of which 170 sub-networks show p-values less than their corresponding thresholds. They were then merged into 16 clusters. CONCLUSIONS: We identified 16 gene clusters associated with GBM prognosis using the eQCM algorithm. Our results not only confirmed previous findings including the importance of cell cycle and immune response in GBM, but also suggested important epigenetic events in GBM development and prognosis. PMID- 22536864 TI - Computational and experimental analyses of retrotransposon-associated minisatellite DNAs in the soybean genome. AB - BACKGROUND: Retrotransposons are mobile DNA elements that spread through genomes via the action of element-encoded reverse transcriptases. They are ubiquitous constituents of most eukaryotic genomes, especially those of higher plants. The pericentromeric regions of soybean (Glycine max) chromosomes contain >3,200 intact copies of the Gmr9/GmOgre retrotransposon. Between the 3' end of the coding region and the long terminal repeat, this retrotransposon family contains a polymorphic minisatellite region composed of five distinct, interleaved minisatellite families. To better understand the possible role and origin of retrotransposon-associated minisatellites, a computational project to map and physically characterize all members of these families in the G. max genome, irrespective of their association with Gmr9, was undertaken. METHODS: A computational pipeline was developed to map and analyze the organization and distribution of five Gmr9-associated minisatellites throughout the soybean genome. Polymerase chain reaction amplifications were used to experimentally assess the computational outputs. RESULTS: A total of 63,841 copies of Gmr9 associated minisatellites were recovered from the assembled G. max genome. Ninety percent were associated with Gmr9, an additional 9% with other annotated retrotransposons, and 1% with uncharacterized repetitive DNAs. Monomers were tandemly interleaved and repeated up to 149 times per locus. CONCLUSIONS: The computational pipeline enabled a fast, accurate, and detailed characterization of known minisatellites in a large, downloaded DNA database, and PCR amplification supported the general organization of these arrays. PMID- 22536865 TI - A signal processing approach for enriched region detection in RNA polymerase II ChIP-seq data. AB - BACKGROUND: RNA polymerase II (PolII) is essential in gene transcription and ChIP seq experiments have been used to study PolII binding patterns over the entire genome. However, since PolII enriched regions in the genome can be very long, existing peak finding algorithms for ChIP-seq data are not adequate for identifying such long regions. METHODS: Here we propose an enriched region detection method for ChIP-seq data to identify long enriched regions by combining a signal denoising algorithm with a false discovery rate (FDR) approach. The binned ChIP-seq data for PolII are first processed using a non-local means (NL means) algorithm for purposes of denoising. Then, a FDR approach is developed to determine the threshold for marking enriched regions in the binned histogram. RESULTS: We first test our method using a public PolII ChIP-seq dataset and compare our results with published results obtained using the published algorithm HPeak. Our results show a high consistency with the published results (80-100%). Then, we apply our proposed method on PolII ChIP-seq data generated in our own study on the effects of hormone on the breast cancer cell line MCF7. The results demonstrate that our method can effectively identify long enriched regions in ChIP-seq datasets. Specifically, pertaining to MCF7 control samples we identified 5,911 segments with length of at least 4 Kbp (maximum 233,000 bp); and in MCF7 treated with E2 samples, we identified 6,200 such segments (maximum 325,000 bp). CONCLUSIONS: We demonstrated the effectiveness of this method in studying binding patterns of PolII in cancer cells which enables further deep analysis in transcription regulation and epigenetics. Our method complements existing peak detection algorithms for ChIP-seq experiments. PMID- 22536866 TI - Amino acid function and docking site prediction through combining disease variants, structure alignments, sequence alignments, and molecular dynamics: a study of the HMG domain. AB - BACKGROUND: The DNA binding domain of HMG proteins is known to be important in many diseases, with the Sox sub-family of HMG proteins of particular significance. Numerous natural variants in HMG proteins are associated with disease phenotypes. Integrating these natural variants, molecular dynamic simulations of DNA interaction and sequence and structure alignments give detailed molecular knowledge of potential amino acid function such as DNA or protein interaction. RESULTS: A total of 33 amino acids in HMG proteins are known to have natural variants in diseases. Eight of these amino acids are normally conserved in human HMG proteins and 27 are conserved in the human Sox sub-family. Among the six non-Sox conserved amino acids, amino acids 16 and 45 are likely targets for interaction with other proteins. Docking studies between the androgen receptor and Sry/Sox9 reveals a stable amino acid specific interaction involving several Sox conserved residues. CONCLUSION: The HMG box has structural conservation between the first two of the three helixes in the domain as well as some DNA contact points. Individual sub-groups of the HMG family have specificity in the location of the third helix, DNA specific contact points (such as amino acids 4 and 29), and conserved amino acids interacting with other proteins such as androgen receptor. Studies such as this help to distinguish individual members of a much larger family of proteins and can be applied to any protein family of interest. PMID- 22536868 TI - Interfacing medicinal chemistry with structural bioinformatics: implications for T box riboswitch RNA drug discovery. AB - BACKGROUND: The T box riboswitch controls bacterial transcription by structurally responding to tRNA aminoacylation charging ratios. Knowledge of the thermodynamic stability difference between two competing structural elements within the riboswitch, the terminator and the antiterminator, is critical for effective T box-targeted drug discovery. METHODS: The DeltaG of aminoacyl tRNA synthetase (aaRS) T box riboswitch terminators and antiterminators was predicted using DINAMelt and the resulting DeltaDeltaG (DeltaG Terminator - DeltaG Antiterminator) values were compared. RESULTS: Average DeltaDeltaG values did not differ significantly between the bacterial species analyzed, but there were significant differences based on the type of aaRS. CONCLUSIONS: The data indicate that, of the bacteria studied, there is little potential for drug targeting based on overall bacteria-specific thermodynamic differences of the T box antiterminator vs. terminator stability, but that aaRS-specific thermodynamic differences could possibly be exploited for designing drug specificity. PMID- 22536869 TI - Evaluation of multiple protein docking structures using correctly predicted pairwise subunits. AB - BACKGROUND: Many functionally important proteins in a cell form complexes with multiple chains. Therefore, computational prediction of multiple protein complexes is an important task in bioinformatics. In the development of multiple protein docking methods, it is important to establish a metric for evaluating prediction results in a reasonable and practical fashion. However, since there are only few works done in developing methods for multiple protein docking, there is no study that investigates how accurate structural models of multiple protein complexes should be to allow scientists to gain biological insights. METHODS: We generated a series of predicted models (decoys) of various accuracies by our multiple protein docking pipeline, Multi-LZerD, for three multi-chain complexes with 3, 4, and 6 chains. We analyzed the decoys in terms of the number of correctly predicted pair conformations in the decoys. RESULTS AND CONCLUSION: We found that pairs of chains with the correct mutual orientation exist even in the decoys with a large overall root mean square deviation (RMSD) to the native. Therefore, in addition to a global structure similarity measure, such as the global RMSD, the quality of models for multiple chain complexes can be better evaluated by using the local measurement, the number of chain pairs with correct mutual orientation. We termed the fraction of correctly predicted pairs (RMSD at the interface of less than 4.0A) as fpair and propose to use it for evaluation of the accuracy of multiple protein docking. PMID- 22536867 TI - THINK Back: KNowledge-based Interpretation of High Throughput data. AB - Results of high throughput experiments can be challenging to interpret. Current approaches have relied on bulk processing the set of expression levels, in conjunction with easily obtained external evidence, such as co-occurrence. While such techniques can be used to reason probabilistically, they are not designed to shed light on what any individual gene, or a network of genes acting together, may be doing. Our belief is that today we have the information extraction ability and the computational power to perform more sophisticated analyses that consider the individual situation of each gene. The use of such techniques should lead to qualitatively superior results. The specific aim of this project is to develop computational techniques to generate a small number of biologically meaningful hypotheses based on observed results from high throughput microarray experiments, gene sequences, and next-generation sequences. Through the use of relevant known biomedical knowledge, as represented in published literature and public databases, we can generate meaningful hypotheses that will aide biologists to interpret their experimental data. We are currently developing novel approaches that exploit the rich information encapsulated in biological pathway graphs. Our methods perform a thorough and rigorous analysis of biological pathways, using complex factors such as the topology of the pathway graph and the frequency in which genes appear on different pathways, to provide more meaningful hypotheses to describe the biological phenomena captured by high throughput experiments, when compared to other existing methods that only consider partial information captured by biological pathways. PMID- 22536870 TI - Constructing patch-based ligand-binding pocket database for predicting function of proteins. AB - BACKGROUND: Many of solved tertiary structures of unknown functions do not have global sequence and structural similarities to proteins of known function. Often functional clues of unknown proteins can be obtained by predicting small ligand molecules that bind to the proteins. METHODS: In our previous work, we have developed an alignment free local surface-based pocket comparison method, named Patch-Surfer, which predicts ligand molecules that are likely to bind to a protein of interest. Given a query pocket in a protein, Patch-Surfer searches a database of known pockets and finds similar ones to the query. Here, we have extended the database of ligand binding pockets for Patch-Surfer to cover diverse types of binding ligands. RESULTS AND CONCLUSION: We selected 9393 representative pockets with 2707 different ligand types from the Protein Data Bank. We tested Patch-Surfer on the extended pocket database to predict binding ligand of 75 non homologous proteins that bind one of seven different ligands. Patch-Surfer achieved the average enrichment factor at 0.1 percent of over 20.0. The results did not depend on the sequence similarity of the query protein to proteins in the database, indicating that Patch-Surfer can identify correct pockets even in the absence of known homologous structures in the database. PMID- 22536871 TI - Convergence of genetic influences in comorbidity. AB - BACKGROUND: Predisposition to complex diseases is explained in part by genetic variation, and complex diseases are frequently comorbid, consistent with pleiotropic genetic variation influencing comorbidity. Genome Wide Association (GWA) studies typically assess association between SNPs and a single-disease phenotype. Fisher meta-analysis combines evidence of association from single disease GWA studies, assuming that each study is an independent test of the same hypothesis. The Rank Product (RP) method overcomes limitations posed by Fisher assumptions, though RP was not designed for GWA data. METHODS: We modified RP to accommodate GWA data, and we call it modRP. Using p-values output from GWA studies, we aggregate evidence for association between SNPs and related phenotypes. To assess significance, RP randomly samples the observed ranks to develop the null distribution of the RP statistic, and then places the observed RPs into the null distribution. ModRP eliminates the effect of linkage disequilibrium and controls for differences in power at tested SNPs, to meet RP assumptions in application to GWA data. RESULTS: After validating modRP based on both positive and negative control studies, we searched for pleiotropic influences on comorbid substance use disorders in a novel study, and found two SNPs to be significantly associated with comorbid cocaine, opium, and nicotine dependence. Placing these SNPs into biological context, we developed a protein network modeling the interaction of cocaine, nicotine, and opium with these variants. CONCLUSIONS: ModRP is a novel approach to identifying pleiotropic genetic influences on comorbid complex diseases. It can be used to assess association for related phenotypes where raw data is unavailable or inappropriate for analysis using other approaches. The method is conceptually simple and produces statistically significant, biologically relevant results. PMID- 22536872 TI - Interpolative multidimensional scaling techniques for the identification of clusters in very large sequence sets. AB - BACKGROUND: Modern pyrosequencing techniques make it possible to study complex bacterial populations, such as 16S rRNA, directly from environmental or clinical samples without the need for laboratory purification. Alignment of sequences across the resultant large data sets (100,000+ sequences) is of particular interest for the purpose of identifying potential gene clusters and families, but such analysis represents a daunting computational task. The aim of this work is the development of an efficient pipeline for the clustering of large sequence read sets. METHODS: Pairwise alignment techniques are used here to calculate genetic distances between sequence pairs. These methods are pleasingly parallel and have been shown to more accurately reflect accurate genetic distances in highly variable regions of rRNA genes than do traditional multiple sequence alignment (MSA) approaches. By utilizing Needleman-Wunsch (NW) pairwise alignment in conjunction with novel implementations of interpolative multidimensional scaling (MDS), we have developed an effective method for visualizing massive biosequence data sets and quickly identifying potential gene clusters. RESULTS: This study demonstrates the use of interpolative MDS to obtain clustering results that are qualitatively similar to those obtained through full MDS, but with substantial cost savings. In particular, the wall clock time required to cluster a set of 100,000 sequences has been reduced from seven hours to less than one hour through the use of interpolative MDS. CONCLUSIONS: Although work remains to be done in selecting the optimal training set size for interpolative MDS, substantial computational cost savings will allow us to cluster much larger sequence sets in the future. PMID- 22536873 TI - Reliability and validity testing for the Child Oral Health Impact Profile-Reduced (COHIP-SF 19). AB - OBJECTIVES: This study assessed the reliability and validity of the Child Oral Health Impact Profile-Short Form 19 (COHIP-SF 19) from the validated 34-item COHIP. METHODS: Participants included 205 pediatric, 107 orthodontic, and 863 patients with craniofacial anomalies (CFAs). Item level evaluations included examining content overlap, distributional properties, and use of the response set. Confirmatory factor analysis identified potential items for deletion. Scale reliability was assessed with Cronbach's alpha. Discriminant validity of the COHIP-SF 19 was evaluated as follows: among pediatric participants, scores were compared with varying amounts of decayed and filled surfaces (DFS) and presence of caries on permanent teeth; for orthodontic patients, scores were correlated with anterior tooth spacing/crowding; and for those with CFA, scores were compared with clinicians' ratings of extent of defect (EOD) for nose and lip and/or speech hypernasality. Convergent validity was assessed by examining the partial Spearman correlation between the COHIP scores and a standard Global Health self-rating. Comparisons between the COHIP and the COHIP-SF 19 were completed across samples. RESULTS: The reduced questionnaire consists of 19 items: Oral Health (five items), Functional Well-Being (four items), and a combined subscale named Socio-Emotional Well-Being (10 items). Internal reliability is >= 0.82 for the three samples. Results demonstrate that the COHIP SF 19 discriminates within and across treatment groups by EOD and within a community-based pediatric sample. The measure is associated with the Global Health rating (P < 0.05), thereby indicating convergent validity. CONCLUSIONS: Reliability and validity testing demonstrate that the COHIP-SF 19 is a psychometrically sound instrument to measure oral health-related quality of life across school-aged pediatric populations. PMID- 22536875 TI - Factors responsible for the discrepancy between IL28B polymorphism prediction and the viral response to peginterferon plus ribavirin therapy in Japanese chronic hepatitis C patients. AB - AIM: IL28B polymorphisms serve to predict response to pegylated interferon plus ribavirin therapy (PEG IFN/RBV) in Japanese patients with chronic hepatitis C (CHC) very reliably. However, the prediction by the IL28B polymorphism contradicted the virological response to PEG IFN/RBV in some patients. Here, we aimed to investigate the factors responsible for the discrepancy between the IL28B polymorphism prediction and virological responses. METHODS: CHC patients with genotype 1b and high viral load were enrolled in this study. In a case control study, clinical and virological factors were analyzed for 130 patients with rs8099917 TT genotype and 96 patients with rs8099917 TG or GG genotype who were matched according to sex, age, hemoglobin level and platelet count. RESULTS: Higher low-density lipoprotein (LDL) cholesterol, lower gamma glutamyltransferase and the percentage of wild-type phenotype at amino acids 70 and 91 were significantly associated with the rs8099917 TT genotype. Multivariate analysis showed that rs8099917 TG or GG genotype, older age and lower LDL cholesterol were independently associated with the non-virological responder (NVR) phenotype. In patients with rs8099917 TT genotype (predicted as virological responder [VR]), multivariate analysis showed that older age was independently associated with NVR. In patients with rs8099917 TG or GG genotype (predicted as NVR), multivariate analysis showed that younger age was independently associated with VR. CONCLUSION: Patient age gave rise to the discrepancy between the prediction by IL28B polymorphism and the virological responses, suggesting that patients should be treated at a younger age. PMID- 22536876 TI - Optimization of the double pump-probe technique: decoupling the triplet yield and cross section. AB - The double pump-probe technique (DPP), first introduced by Swatton et al. [Appl. Phys. Lett. 1997, 71, 10], is a variant of the standard pump-probe method but uses two pumps instead of one to create two sets of initial conditions for solving the rate equations, allowing a unique determination of singlet- and triplet-state absorption parameters and transition rates. We investigate the advantages and limitations of the DPP theoretically and experimentally and determine the influence of several experimental parameters on its accuracy. The accuracy with which the DPP determines the triplet-state parameters improves when the fraction of the population in the triplet state relative to the ground state is increased. To simplify the analysis of the DPP, an analytical model is presented, which is applicable to both the reverse saturable and the saturable absorption regimes. We show that the DPP is optimized by working in the saturable absorption regime. Although increased accuracy is in principle achievable by increasing the pump fluence in the reverse saturable absorption range, this can cause photoinduced decomposition in photochemically unstable molecules. Alternatively, we can tune the excitation wavelength to the spectral region of larger ground-state absorption, to achieve similar accuracy. This results in an accurate separation of triplet yield and excited-state absorption cross section. If the cross section at another wavelength is then desired, a second pump-probe experiment at that wavelength can be utilized given the previously measured triplet yield under the usually valid assumption that the triplet yield is independent of excitation wavelength. PMID- 22536877 TI - Differences in loosely bound fluoride formation and anticaries effect of resin based fluoride varnishes. AB - OBJECTIVE. Our in vitro study evaluated calcium fluoride formation in enamel and the anticaries effect of seven resin-based varnishes under cariogenic challenge. METHODS. Enamel blocks were subjected to pH cycling. The experimental groups received fluoride varnish application, the positive control received topical fluoride gel treatment, and the negative control did not receive any treatment. The pH cycling surface hardness (SH1 ) and integrated loss of subsurface hardness (DeltaKHN) were then determined. We measured the amount of fluoride released into the demineralizing and remineralizing (DE-RE) solutions used in pH cycling. The fluoride concentration in the enamel was determined 24 h after application of the products as loosely bound fluoride and firmly bound fluoride. RESULTS. Higher deposits of loosely bound fluoride were observed for Duofluorid, followed by Biophat. For Duraphat, Bifluorid, Duraflur, and Duofluorid, no difference was observed in the SH1 and DeltaKHN values, with the lowest mineral loss compared to the other groups. The Bifluorid and Duofluorid groups released high fluoride amounts into the DE-RE, and statistically significant difference was noted between them. CONCLUSIONS. The anticaries effect showed no correlation with higher deposited fluoride amounts, resin type, or fluoride source. PMID- 22536874 TI - Unexpected extra-renal effects of loop diuretics in the preterm neonate. AB - The loop diuretics furosemide and bumetanide are commonly used in neonatal intensive care units (NICUs). Furosemide, because of its actions on the ubiquitous Na(+) -K(+) -2Cl(-) isoform cotransporter and its promotion of prostanoid production and release, also has non-diuretic effects on vascular smooth muscle, airways, the ductus arteriosus and theoretically the gastrointestinal tract. Loop diuretics also affect the central nervous system through modulation of the GABA-A chloride channel. CONCLUSION: The loop diuretics have a variety of biological effects that are potentially harmful as well as beneficial. Care should be taken with the use of these agents because the range of their effects may be broader than the single action sought by the prescribing physician. PMID- 22536878 TI - Restoration of wadi aquifers by artificial recharge with treated waste water. AB - Fresh water resources within the Kingdom of Saudi Arabia are a rare and precious commodity that must be managed within a context of integrated water management. Wadi aquifers contain a high percentage of the naturally occurring fresh groundwater in the Kingdom. This resource is currently overused and has become depleted or contaminated at many locations. One resource that could be used to restore or enhance the fresh water resources within wadi aquifers is treated municipal waste water (reclaimed water). Each year about 80 percent of the country's treated municipal waste water is discharged to waste without any beneficial use. These discharges not only represent a lost water resource, but also create a number of adverse environmental impacts, such as damage to sensitive nearshore marine environments and creation of high-salinity interior surface water areas. An investigation of the hydrogeology of wadi aquifers in Saudi Arabia revealed that these aquifers can be used to develop aquifer recharge and recovery (ARR) systems that will be able to treat the impaired-quality water, store it until needed, and allow recovery of the water for transmittal to areas in demand. Full-engineered ARR systems can be designed at high capacities within wadi aquifer systems that can operate in concert with the natural role of wadis, while providing the required functions of additional treatment, storage and recovery of reclaimed water, while reducing the need to develop additional, energy-intensive desalination to meet new water supply demands. PMID- 22536880 TI - Increased T-allele frequency of 677 C>T polymorphism in the methylenetetrahydrofolate reductase gene in differentiated thyroid carcinoma. AB - BACKGROUND: Epigenetic alterations in the global DNA methylation status may be associated with an increased risk of some cancer types in humans. The methylenetetrahydrofolate reductase (MTHFR) gene is involved in folic acid metabolism and plays an essential role in inherited DNA methylation profiles. The common 677 C>T and 1298 A>C polymorphisms in the MTHFR gene cause the production of a thermolabile enzyme with reduced function and, eventually, genomic DNA hypomethylation. The current preliminary study was designed to determine the association between germ-line polymorphism in the MTHFR gene and differentiated thyroid carcinoma (DTC). METHODS: In the current case-control study of 60 thyroid carcinomas (TC); 45 papillary TC, 9 follicular TC, and 6 DTC of an uncertain malignant potential were examined. Genomic DNA was extracted from peripheral blood with EDTA, genotyped by a multiplex real-time polymerase chain reaction. RESULTS: An elevated 2.33-fold risk was observed for DTC in individuals with the 677TT genotype when compared with the control group (odds ratio [OR]: 1.92, 95% confidence interval [CI]: 1.03-3.58). Current DTC patients showed similar results as a control group for the 1298 A>C allele. No significant risk was detected for the homozygous 1298CC genotype (CC vs. AA or AC) (OR: 1.30, 95% CI: 0.73-2.29). CONCLUSION: The current results are supportive of the hypothesis that the homozygous MTHFR 677TT genotype increases the risk factor of developing thyroid cancer, and further large-scale studies are needed to validate this association. PMID- 22536881 TI - Gold(III) diazonium complexes for electrochemical reductive grafting. AB - Gold(III) diazonium complexes were synthesized for the first time and studied for electrochemical reductive grafting. The diazonium complex [CN-4 C(6)H(4)N=N]AuCl(4) was synthesized by protonating CN-4-C(6)H(4)NH(2) with chloroauric acid H[AuCl(4)].3H(2)O to form the ammonium salt [CN-4 C(6)H(4)NH(3)]AuCl(4), which was then oxidized by the one-electron oxidizing agent [NO]PF(6) in CH(3)CN. The highly irreversible reduction potential of 0.1 mM [CN-4-C(6)H(4)N=N]AuCl(4) observed at -0.06 V versus Ag/AgCl in CH(3)CN/0.1 M [Bu(4)N]PF(6) encompasses both gold(0) deposition and diazonium reduction. Repeated scans showed the absence of the reduction peak on the second run, which indicates that surface modification with a blocking gold aryl film has occurred and is largely complete. PMID- 22536879 TI - Aggressive intervention of previable preterm premature rupture of membranes. AB - OBJECTIVE: To assess the neonatal and maternal outcomes of pregnancy complicated by previable preterm premature rupture of membranes (PPROM). DESIGN: Retrospective study. SETTING: Tertiary referral hospital. Sample. Forty-five women having aggressive intervention with antibiotics, amnioinfusion, cerclage and tocolysis. METHODS: The hospital database between July 2001 and December 2009 was reviewed for women with singleton fetuses and PPROM before 23(+0) weeks of gestation. We analysed maternal and neonatal characteristics. MAIN OUTCOME MEASURES: Neonatal survival without major morbidity. RESULTS: Thirty-eight infants were delivered alive and seven were stillborn. Ten infants died in the neonatal intensive care unit and one in the labor ward. Twenty-seven live-born infants survived to discharge from hospital. The survival rate of pregnancies with aggressive management was 60% (27 of 45); that of live-born infants was 71.1% (27 of 38). The median gestational age at PPROM and at delivery were significantly lower in the non-surviving group than the surviving group. Thirty seven women (82.2%) had an amniotic neutrophil elastase level >0.15 MUg/mL. Only four women (8.9%) developed clinical chorioamnionitis. Overall, 90.7% of the women showed histological evidence of chorioamnionitis. Eighty-three per cent of the surviving children had bronchopulmonary dysplasia. Nine infants had serious sequelae at a corrected age of one and a half years. Maternal complications were uncommon. CONCLUSIONS: An aggressive treatment protocol for women with previable PPROM resulted in a high neonatal survival rate. Neonatal survival was associated with higher gestational age at delivery and with more frequent use of antenatal corticosteroids. The prognosis is still bad in PPROM before 22(+0) weeks of gestation. PMID- 22536882 TI - Analysis of dopamine D2 receptor (DRD2) gene polymorphisms in cannabinoid addicts. AB - The gene encoding the dopamine D2 receptor (DRD2) has been suggested as a candidate gene for substance dependence. In this study, the possible association between Taq1A and Taq1B DRD2 polymorphisms and cannabinoid dependence was investigated. One hundred and twelve cannabinoid addicted and 130 healthy control subjects were included in this study. The Taq1A and Taq1B genotypes were determined in all subjects by polymerase chain reaction. For each polymorphism (A or B), the subjects were categorized into three groups according to their genotype, that is, the subjects with alleles A1/A1, A1/A2, A2/A2; B1/B1, B1/B2, and B2/B2. A significant association was found between Taq1A gene polymorphism and cannabinoid addicts compared to the control subjects. This finding suggests that polymorphism of the Taq1A, but not the Taq1B, may be associated with the susceptibility to cannabinoid dependence. Further clinical studies are required to be carried out for confirmation and evaluation of these findings. PMID- 22536883 TI - Point-of-care detection of lipoarabinomannan (LAM) in urine for diagnosis of HIV associated tuberculosis: a state of the art review. AB - Detection of Mycobacterium tuberculosis antigens in urine is attractive as a potential means of diagnosing tuberculosis (TB) regardless of the anatomical site of disease. The most promising candidate antigen is the cell wall lipopolysaccharide antigen lipoarabinomannan (LAM), which has been used to develop commercially available enzyme-linked immunosorbent assays. Although highly variable diagnostic accuracy has been observed in different clinical populations, it is now clear that this assay has useful sensitivity for diagnosis of HIV-associated TB in patients with advanced immunodeficiency and low CD4 cell counts. Thus, this assay is particularly useful when selectively used among patients enrolling in antiretroviral treatment services or in HIV-infected patients requiring admission to hospital medical wards. These are the very patients who have the highest mortality risk and who stand to gain the most from rapid diagnosis, permitting immediate initiation of TB treatment. A recently developed low-cost, lateral-flow (urine 'dip-stick') format of the assay provides a result within 30 minutes and is potentially a major step forward as it can be used at the point-of-care, making the possibility of immediate diagnosis and treatment a reality. This paper discusses the likely utility of this point-of care assay and how it might best be used in combination with other diagnostic assays for TB. The many further research studies that are needed on this assay are described. Consideration is particularly given to potential reasons for the variable specificity observed in existing field evaluations of LAM ELISAs. Whether this might be related to the assay itself or to the challenges associated with study design is discussed. PMID- 22536885 TI - Evaluation of the clinical benefit of long-term (beyond 2 years) treatment of skeletal-related events in advanced cancers with zoledronic acid. AB - BACKGROUND: Skeletal complications of malignant bone disease are common among patients with both solid tumors and multiple myeloma (MM). Zoledronic acid (ZOL; Zometa*) is an intravenous bisphosphonate with proven efficacy in reducing the incidence of skeletal complications and delaying the time to a first skeletal complication. This study was designed to assess the continued benefit of ZOL treatment over a prolonged period. METHODS: This was a retrospective claims analysis study using information gathered from two national US managed-care plan databases. Patients >=18 years of age with a single type of solid tumor or MM who were diagnosed with bone lesions and experienced at least one skeletal complication (before or after receiving ZOL) were included. RESULTS: Of the 28,385 patients, those with lung and breast cancer composed the largest group. Greater percentages of MM and breast cancer patients were treated with ZOL. On average, those with renal cell carcinoma and lung cancer had a longer time between bone metastasis diagnosis and start of therapy with ZOL. Compared with an untreated cohort, patients treated with ZOL had a 24% reduction in incidence of fracture, a 45% reduction in incidence of spinal cord compression, and a 56% reduction in risk of mortality. Patients with persistence with ZOL over 180 days had a reduced incidence of fracture before controlling for other factors. CONCLUSIONS: Patients treated with ZOL had reduced risks of fracture, spinal cord compression, and mortality compared with patients in the no-treatment cohort. Longer persistence with ZOL was associated with better outcomes. Greatest benefits were observed for patients treated on a regular basis with ZOL for a period beyond 18 months. PMID- 22536884 TI - Biologically implausible carotid intima-media thickness measurement values: effects on rate of change over time. AB - OBJECTIVE: Carotid intima-media thickness (CIMT) is a marker of atherosclerosis that is commonly used to assess the effect of therapeutic interventions. It is currently unclear to what extent biologically implausible values affect treatment effects. We evaluated the impact of biologically implausible CIMT values on the estimated rate of change in CIMT. METHODS: Data were used from the METEOR (Measuring Effects on Intima-media Thickness: an Evaluation of Rosuvastatin) trial. METEOR was a randomized, placebo-controlled trial showing that rosuvastatin reduced the 2-year change in CIMT among low-risk individuals with subclinical atherosclerosis. In the main METEOR analysis, the data were analyzed without exclusion of biologically implausible data. In this post-hoc analysis, we constructed twelve definitions to define mildly or extremely biologically implausible values using distance from the interquartile range, median or mean. We evaluated the effect of removing implausible values on the estimated rate of change in CIMT. RESULTS: The percentage of biologically implausible CIMT values ranged from 0.6% to 9.7%, depending on the definition used. Across all definitions, removal of biologically implausible CIMT values marginally reduced standard errors and did not change the primary outcome (i.e., a nonsignificant change in the rosuvastatin group, significant progression in the placebo group, and a statistically significant difference between treatment groups). LIMITATION: This study was focussed on the impact of implausible values in the analytical part of a CIMT study. Ultrasound images were not re-examined to determine whether an implausible measurement was due to measurement error or temporal morphological thickening, CONCLUSION: Removal of biologically implausible CIMT values marginally decreased the variability of the estimated rate of change in CIMT without having a large impact on the estimated rate of change. PMID- 22536887 TI - Clinical decision-making process for early nonspecific signs of infection in institutionalised elderly persons: experience of nursing assistants. AB - AIM: To illuminate nursing assistant's experiences of the clinical decision making process when they suspect that a resident has an infection and how their process relates to other professions. BACKGROUND: The assessment of possible infection in elderly individuals is difficult and contributes to a delayed diagnosis and treatment, worsening the goal of good care. Recently we explored that nursing assistants have a keen observational ability to detect early signs and symptoms that might help to confirm suspected infections early on. To our knowledge there are no published papers exploring how nursing assistants take part in the clinical decision-making process. DESIGN: Explorative, qualitative study. SETTING: Community care for elderly people. PARTICIPANTS: Twenty-one nursing assistants, 22-61 years. METHODS: Focus groups with verbatim transcription. The interviews were subjected to qualitative content analysis for manifest and latent content with no preconceived categories. FINDINGS: The findings are described as a decision-making model consisting of assessing why a resident feels unwell, divided into recognition and formulation and strategies for gathering and evaluating information, influenced by personal experiences and preconceptions and external support system and, secondly, as taking action, consisting of reason for choice of action and action, influenced by feedback from the nurse and physician. CONCLUSION: Nursing assistant's assessment is based on knowing the resident, personal experiences and ideas about ageing. Nurses and physician's response to the nursing assistant's observations had a great impact on the latter's further action. A true inter-professional partnership in the clinical decision-making process would enhance the possibility to detect suspected infection early on, and thereby minimize the risk of delayed diagnosis and treatment and hence unnecessary suffering for the individual. RELEVANCE TO CLINICAL PRACTICE: In order to improve the clinical evaluation of the individual, and thereby optimise patient safety, it is important to involve nursing assistants in the decision-making process. PMID- 22536886 TI - Anti-atherosclerotic function of Astragali Radix extract: downregulation of adhesion molecules in vitro and in vivo. AB - BACKGROUND: Atherosclerosis is considered to be a chronic inflammatory disease. Astragali Radix extract (ARE) is one of the major active ingredients extracted from the root of Astragalus membranaceus Bge. Although ARE has an anti inflammatory function, its anti-atherosclerotic effects and mechanisms have not yet been elucidated. METHODS: Murine endothelial SVEC4-10 cells were pretreated with different doses of ARE at different times prior to induction with tumor necrosis factor (TNF)-alpha. Cell adhesion assays were performed using THP-1 cells and assessed by enzyme-linked immunosorbent assay, western blotting and immunofluorescence analyses to detect the expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), phosphorylated inhibitor of kappaB (p-ikappaB) and nuclear factor (NF)-kappaB. We also examined the effect of ARE on atherosclerosis in the aortic endothelium of apolipoprotein E-deficient (apoE(-/-)) mice. RESULTS: TNF-alpha strongly increased the expression of VCAM-1 and ICAM-1 accompanied by increased expression of p-ikappaB and NF-kappaB proteins. However, the expression levels of VCAM-1 and ICAM-1 were reduced by ARE in dose- and time-dependent manners, with the strongest effect at a dose of 120 MUg/ml incubated for 4 h. This was accompanied by significantly decreased expression of p-ikappaB and inhibited activation of NF-kappaB. Immunofluorescence analysis also revealed that oral administration of ARE resulted in downregulation of adhesion molecules and decreased expression of macrophages in the aortic endothelium of apoE(-/-) mice. ARE could suppress the inflammatory reaction and inhibit the progression of atherosclerotic lesions in apoE(-/-) mice. CONCLUSION: This study demonstrated that ARE might be an effective anti-inflammatory agent for the treatment of atherosclerosis, possibly acting via the decreased expression of adhesion molecules. PMID- 22536888 TI - Vitamin D, parathyroid hormone, serum calcium and phosphorus in patients with schizophrenia and major depression. AB - OBJECTIVE: Vitamin D deficiency has been associated with an increased risk of depression and schizophrenia. The aim was to compare serum levels of vitamin D, calcium, phosphorus and parathyroid hormone in schizophrenics, depressed patients and healthy subjects in an Iranian population. METHODS: In a cross-sectional study, 100 patients with schizophrenia and 100 with major depression were enrolled. A questionnaire was filled by using medical records of patients. After that a serum sample was taken and levels of vitamin D, calcium, phosphorus and parathyroid hormone were assessed and then compared between the three groups. RESULTS: Post-hoc analysis of Tukey showed that vitamin D level in healthy participants was significantly higher than depressed patients and schizophrenics while there was no significant difference between vitamin D level in depressed and schizophrenic patients. CONCLUSION: The findings suggest that vitamin D affects the brain independent of hormonal pathways which regulate serum level of calcium. Non-significant difference in the serum level of vitamin D between the schizophrenics and the depressed patients suggests that the independent effect of vitamin D in brain is a general effect and is not specialized to a specific region or pathway in the brain; however, differences between psychiatric and non psychiatric patients might be resulted from differences in psychosocial backgrounds. PMID- 22536889 TI - Efficacy of acupuncture for acute migraine attack: a multicenter single blinded, randomized controlled trial. AB - OBJECTIVE: We aim to investigate the efficacy of acupuncture for acute migraine attacks comparing with sham acupuncture. DESIGN: The study was designed as a multicenter, single-blinded, randomized controlled clinical trial. SETTING AND PATIENTS: From March 2007 to February 2009, 150 patients were randomly allocated to verum or sham acupuncture group in a ratio of 1:1. INTERVENTIONS: Every patient received a verum or sham acupuncture treatment when having a migraine attack and, medications were allowed if the pain failed to be relieved two hours after the acupuncture. OUTCOME MEASURES: The primary outcome was visual analog scale (VAS) scores for pain, ranging from 0 (no pain) to 10 (worst pain ever). RESULTS: The mean VAS scores 24 hours after treatment decreased from 5.7 +/- 1.4 to 3.3 +/- 2.5 in the verum acupuncture group, and from 5.4 +/- 1.3 to 4.7 +/- 2.4 in the sham acupuncture group. Significant differences existed between the two groups (P = 0.001). CONCLUSIONS: This trial suggested that verum acupuncture group was superior to sham acupuncture group on relieving pain and reducing the usage of acute medication. PMID- 22536890 TI - The influence of clay zones on land subsidence from groundwater pumping. AB - The objective of this article is to analyze the influence of clay zones on subsidence from groundwater pumping. Finite element analyses were conducted on a sand-only aquifer and a sand aquifer with two clay zones located at different distances from the well face. A model that accounts for recoverable and nonrecoverable strains was used to simulate the sand and clay. This model couples the groundwater flow with the stress-deformation response of the aquifer materials. Each aquifer was pumped from a single well for a period of 6 months, and then the groundwater level was lowered gradually to an elevation below the elevation of the clay zones and kept there for 10 years. The groundwater level was then raised gradually back to the original elevation over a period of 10 years. The results of the analyses show that the ground surface subsidence profile is strongly influenced by the presence of the clays zones. The ground surface sags where these clay zones are present resulting in a wavy ground surface profile. Subsidence continued when pumping is stopped, albeit at a much slower rate than during pumping, and when the groundwater level is below the elevation of the clay zones. Clay zones further away from the well face lag the subsidence of clay zones nearer the well face because of lower changes in hydrostatic head. Sags in ground surface subsidence profile from groundwater pumping are indicators of the presence of low hydraulic conductive geological materials. PMID- 22536891 TI - Spatially resolved protein hydrogen exchange measured by subzero-cooled chip based nanoelectrospray ionization tandem mass spectrometry. AB - Mass spectrometry has become a valuable method for studying structural dynamics of proteins in solution by measuring their backbone amide hydrogen/deuterium exchange (HDX) kinetics. In a typical exchange experiment one or more proteins are incubated in deuterated buffer at physiological conditions. After a given period of deuteration, the exchange reaction is quenched by acidification (pH 2.5) and cooling (0 degrees C) and the deuterated protein (or a digest thereof) is analyzed by mass spectrometry. The unavoidable loss of deuterium (back exchange) that occurs under quench conditions is undesired as it leads to loss of information. Here we describe the successful application of a chip-based nanoelectrospray ionization mass spectrometry top-down fragmentation approach based on cooling to subzero temperature (-15 degrees C) which reduces the back exchange at quench conditions to very low levels. For example, only 4% and 6% deuterium loss for fully deuterated ubiquitin and beta(2)-microglobulin were observed after 10 min of back-exchange. The practical value of our subzero-cooled setup for top-down fragmentation HDX analyses is demonstrated by electron transfer dissociation of ubiquitin ions under carefully optimized mass spectrometric conditions where gas-phase hydrogen scrambling is negligible. Our results show that the known dynamic behavior of ubiquitin in solution is accurately reflected in the deuterium contents of the fragment ions. PMID- 22536892 TI - Recent trends in dental emergency department visits in the United States:1997/1998 to 2007/2008. AB - OBJECTIVE: The author focused on recent national trends in dental emergency department (ED) visits. Patients who presented at an ED for a dental condition are described and the author look at the extent to which these patients have changed over time. METHODS: This study was based on the National Ambulatory Medical Care Survey, a national probability survey of hospital ED visits. A dental ED visit was defined using International Classification of Diseases, Ninth Edition, Clinical Modification diagnostic codes. RESULTS: Between 1997/1998 and 2007/2008, dental ED visits increased from 1.15 to 1.87 percent of total ED visits. The largest increase in the number of dental ED visits per 1,000 persons was found for young adults 20-34 years old. Primary payer, a measure of insurance status, suggests that patients from all income levels participated in the increase. CONCLUSIONS: Although dental-related ED visits account for a relatively small percentage of total ED visits, both the number and the percentage of such visits grew from 1997/1998 to 2007/2008. Young adults 20-34 years old were most likely to present at an ED with a dental problem. PMID- 22536893 TI - Learning pair-wise gene functional similarity by multiplex gene expression maps. AB - BACKGROUND: The relationships between the gene functional similarity and gene expression profile, and between gene function annotation and gene sequence have been studied extensively. However, not much work has considered the connection between gene functions and location of a gene's expression in the mammalian tissues. On the other hand, although unsupervised learning methods have been commonly used in functional genomics, supervised learning cannot be directly applied to a set of normal genes without having a target (class) attribute. RESULTS: Here, we propose a supervised learning methodology to predict pair-wise gene functional similarity from multiplex gene expression maps that provide information about the location of gene expression. The features are extracted from expression maps and the labels denote the functional similarities of pairs of genes. We make use of wavelet features, original expression values, difference and average values of neighboring voxels and other features to perform boosting analysis. The experimental results show that with increasing similarities of gene expression maps, the functional similarities are increased too. The model predicts the functional similarities between genes to a certain degree. The weights of the features in the model indicate the features that are more significant for this prediction. CONCLUSIONS: By considering pairs of genes, we propose a supervised learning methodology to predict pair-wise gene functional similarity from multiplex gene expression maps. We also explore the relationship between similarities of gene maps and gene functions. By using AdaBoost coupled with our proposed weak classifier we analyze a large-scale gene expression dataset and predict gene functional similarities. We also detect the most significant single voxels and pairs of neighboring voxels and visualize them in the expression map image of a mouse brain. This work is very important for predicting functions of unknown genes. It also has broader applicability since the methodology can be applied to analyze any large-scale dataset without a target attribute and is not restricted to gene expressions. PMID- 22536894 TI - FUSE: a profit maximization approach for functional summarization of biological networks. AB - BACKGROUND: The availability of large-scale curated protein interaction datasets has given rise to the opportunity to investigate higher level organization and modularity within the protein interaction network (PPI) using graph theoretic analysis. Despite the recent progress, systems level analysis of PPIS remains a daunting task as it is challenging to make sense out of the deluge of high dimensional interaction data. Specifically, techniques that automatically abstract and summarize PPIS at multiple resolutions to provide high level views of its functional landscape are still lacking. We present a novel data-driven and generic algorithm called FUSE (Functional Summary Generator) that generates functional maps of a PPI at different levels of organization, from broad process process level interactions to in-depth complex-complex level interactions, through a pro t maximization approach that exploits Minimum Description Length (MDL) principle to maximize information gain of the summary graph while satisfying the level of detail constraint. RESULTS: We evaluate the performance of FUSE on several real-world PPIS. We also compare FUSE to state-of-the-art graph clustering methods with GO term enrichment by constructing the biological process landscape of the PPIS. Using AD network as our case study, we further demonstrate the ability of FUSE to quickly summarize the network and identify many different processes and complexes that regulate it. Finally, we study the higher-order connectivity of the human PPI. CONCLUSION: By simultaneously evaluating interaction and annotation data, FUSE abstracts higher-order interaction maps by reducing the details of the underlying PPI to form a functional summary graph of interconnected functional clusters. Our results demonstrate its effectiveness and superiority over state-of-the-art graph clustering methods with GO term enrichment. PMID- 22536895 TI - Scalable global alignment for multiple biological networks. AB - BACKGROUND: Advances in high-throughput technology has led to an increased amount of available data on protein-protein interaction (PPI) data. Detecting and extracting functional modules that are common across multiple networks is an important step towards understanding the role of functional modules and how they have evolved across species. A global protein-protein interaction network alignment algorithm attempts to find such functional orthologs across multiple networks. RESULTS: In this article, we propose a scalable global network alignment algorithm based on clustering methods and graph matching techniques in order to detect conserved interactions while simultaneously attempting to maximize the sequence similarity of nodes involved in the alignment. We present an algorithm for multiple alignments, in which several PPI networks are aligned. We empirically evaluated our algorithm on three real biological datasets with 6 different species and found that our approach offers a significant benefit both in terms of quality as well as speed over the current state-of-the-art algorithms. CONCLUSION: Computational experiments on the real datasets demonstrate that our multiple network alignment algorithm is a more efficient and effective algorithm than the state-of-the-art algorithm, IsoRankN. From a qualitative standpoint, our approach also offers a significant advantage over IsoRankN for the multiple network alignment problem. PMID- 22536896 TI - Genome-scale NCRNA homology search using a Hamming distance-based filtration strategy. AB - BACKGROUND: NCRNAs (noncoding RNAs) play important roles in many biological processes. Existing genome-scale ncRNA search tools identify ncRNAs in local sequence alignments generated by conventional sequence comparison methods. However, some types of ncRNA lack strong sequence conservation and tend to be missed or mis-aligned by conventional sequence comparison. RESULTS: In this paper, we propose an ncRNA identification framework that is complementary to existing sequence comparison tools. By integrating a filtration step based on Hamming distance and ncRNA alignment programs such as FOLDALIGN or PLAST-ncRNA, the proposed ncRNA search framework can identify ncRNAs that lack strong sequence conservation. In addition, as the ratio of transition and transversion mutation is often used as a discriminative feature for functional ncRNA identification, we incorporate this feature into the filtration step using a coding strategy. We apply Hamming distance seeds to ncRNA search in the intergenic regions of human and mouse genomes and between the Burkholderia cenocepacia J2315 genome and the Ralstonia solanacearum genome. The experimental results demonstrate that a carefully designed Hamming distance seed can achieve better sensitivity in searching for poorly conserved ncRNAs than conventional sequence comparison tools. CONCLUSIONS: Hamming distance seeds provide better sensitivity as a filtration strategy for genome-wide ncRNA homology search than the existing seeding strategies used in BLAST-like tools. By combining Hamming distance seeds matching and ncRNA alignment, we are able to find ncRNAs with sequence similarities below 60%. PMID- 22536897 TI - Comparative analysis and visualization of multiple collinear genomes. AB - BACKGROUND: Genome browsers are a common tool used by biologists to visualize genomic features including genes, polymorphisms, and many others. However, existing genome browsers and visualization tools are not well-suited to perform meaningful comparative analysis among a large number of genomes. With the increasing quantity and availability of genomic data, there is an increased burden to provide useful visualization and analysis tools for comparison of multiple collinear genomes such as the large panels of model organisms which are the basis for much of the current genetic research. RESULTS: We have developed a novel web-based tool for visualizing and analyzing multiple collinear genomes. Our tool illustrates genome-sequence similarity through a mosaic of intervals representing local phylogeny, subspecific origin, and haplotype identity. Comparative analysis is facilitated through reordering and clustering of tracks, which can vary throughout the genome. In addition, we provide local phylogenetic trees as an alternate visualization to assess local variations. CONCLUSIONS: Unlike previous genome browsers and viewers, ours allows for simultaneous and comparative analysis. Our browser provides intuitive selection and interactive navigation about features of interest. Dynamic visualizations adjust to scale and data content making analysis at variable resolutions and of multiple data sets more informative. We demonstrate our genome browser for an extensive set of genomic data sets composed of almost 200 distinct mouse laboratory strains. PMID- 22536898 TI - Efficient path-based computations on pedigree graphs with compact encodings. AB - A pedigree is a diagram of family relationships, and it is often used to determine the mode of inheritance (dominant, recessive, etc.) of genetic diseases. Along with rapidly growing knowledge of genetics and accumulation of genealogy information, pedigree data is becoming increasingly important. In large pedigree graphs, path-based methods for efficiently computing genealogical measurements, such as inbreeding and kinship coefficients of individuals, depend on efficient identification and processing of paths. In this paper, we propose a new compact path encoding scheme on large pedigrees, accompanied by an efficient algorithm for identifying paths. We demonstrate the utilization of our proposed method by applying it to the inbreeding coefficient computation. We present time and space complexity analysis, and also manifest the efficiency of our method for evaluating inbreeding coefficients as compared to previous methods by experimental results using pedigree graphs with real and synthetic data. Both theoretical and experimental results demonstrate that our method is more scalable and efficient than previous methods in terms of time and space requirements. PMID- 22536899 TI - A novel k-mer mixture logistic regression for methylation susceptibility modeling of CpG dinucleotides in human gene promoters. AB - BACKGROUND: DNA methylation is essential for normal development and differentiation and plays a crucial role in the development of nearly all types of cancer. Aberrant DNA methylation patterns, including genome-wide hypomethylation and region-specific hypermethylation, are frequently observed and contribute to the malignant phenotype. A number of studies have recently identified distinct features of genomic sequences that can be used for modeling specific DNA sequences that may be susceptible to aberrant CpG methylation in both cancer and normal cells. Although it is now possible, using next generation sequencing technologies, to assess human methylomes at base resolution, no reports currently exist on modeling cell type-specific DNA methylation susceptibility. Thus, we conducted a comprehensive modeling study of cell type specific DNA methylation susceptibility at three different resolutions: CpG dinucleotides, CpG segments, and individual gene promoter regions. RESULTS: Using a k-mer mixture logistic regression model, we effectively modeled DNA methylation susceptibility across five different cell types. Further, at the segment level, we achieved up to 0.75 in AUC prediction accuracy in a 10-fold cross validation study using a mixture of k-mers. CONCLUSIONS: The significance of these results is three fold: 1) this is the first report to indicate that CpG methylation susceptible "segments" exist; 2) our model demonstrates the significance of certain k-mers for the mixture model, potentially highlighting DNA sequence features (k-mers) of differentially methylated, promoter CpG island sequences across different tissue types; 3) as only 3 or 4 bp patterns had previously been used for modeling DNA methylation susceptibility, ours is the first demonstration that 6-mer modeling can be performed without loss of accuracy. PMID- 22536900 TI - Metabolic network alignment in large scale by network compression. AB - Metabolic network alignment is a system scale comparative analysis that discovers important similarities and differences across different metabolisms and organisms. Although the problem of aligning metabolic networks has been considered in the past, the computational complexity of the existing solutions has so far limited their use to moderately sized networks. In this paper, we address the problem of aligning two metabolic networks, particularly when both of them are too large to be dealt with using existing methods. We develop a generic framework that can significantly improve the scale of the networks that can be aligned in practical time. Our framework has three major phases, namely the compression phase, the alignment phase and the refinement phase. For the first phase, we develop an algorithm which transforms the given networks to a compressed domain where they are summarized using fewer nodes, termed supernodes, and interactions. In the second phase, we carry out the alignment in the compressed domain using an existing network alignment method as our base algorithm. This alignment results in supernode mappings in the compressed domain, each of which are smaller instances of network alignment problem. In the third phase, we solve each of the instances using the base alignment algorithm to refine the alignment results. We provide a user defined parameter to control the number of compression levels which generally determines the tradeoff between the quality of the alignment versus how fast the algorithm runs. Our experiments on the networks from KEGG pathway database demonstrate that the compression method we propose reduces the sizes of metabolic networks by almost half at each compression level which provides an expected speedup of more than an order of magnitude. We also observe that the alignments obtained by only one level of compression capture the original alignment results with high accuracy. Together, these suggest that our framework results in alignments that are comparable to existing algorithms and can do this with practical resource utilization for large scale networks that existing algorithms could not handle. As an example of our method's performance in practice, the alignment of organism-wide metabolic networks of human (1615 reactions) and mouse (1600 reactions) was performed under three minutes by only using a single level of compression. PMID- 22536901 TI - Algorithms for optimizing cross-overs in DNA shuffling. AB - BACKGROUND: DNA shuffling generates combinatorial libraries of chimeric genes by stochastically recombining parent genes. The resulting libraries are subjected to large-scale genetic selection or screening to identify those chimeras with favorable properties (e.g., enhanced stability or enzymatic activity). While DNA shuffling has been applied quite successfully, it is limited by its homology dependent, stochastic nature. Consequently, it is used only with parents of sufficient overall sequence identity, and provides no control over the resulting chimeric library. RESULTS: This paper presents efficient methods to extend the scope of DNA shuffling to handle significantly more diverse parents and to generate more predictable, optimized libraries. Our CODNS (cross-over optimization for DNA shuffling) approach employs polynomial-time dynamic programming algorithms to select codons for the parental amino acids, allowing for zero or a fixed number of conservative substitutions. We first present efficient algorithms to optimize the local sequence identity or the nearest neighbor approximation of the change in free energy upon annealing, objectives that were previously optimized by computationally-expensive integer programming methods. We then present efficient algorithms for more powerful objectives that seek to localize and enhance the frequency of recombination by producing "runs" of common nucleotides either overall or according to the sequence diversity of the resulting chimeras. We demonstrate the effectiveness of CODNS in choosing codons and allocating substitutions to promote recombination between parents targeted in earlier studies: two GAR transformylases (41% amino acid sequence identity), two very distantly related DNA polymerases, Pol X and beta (15%), and beta-lactamases of varying identity (26-47%). CONCLUSIONS: Our methods provide the protein engineer with a new approach to DNA shuffling that supports substantially more diverse parents, is more deterministic, and generates more predictable and more diverse chimeric libraries. PMID- 22536902 TI - Combining automated peak tracking in SAR by NMR with structure-based backbone assignment from 15N-NOESY. AB - BACKGROUND: Chemical shift mapping is an important technique in NMR-based drug screening for identifying the atoms of a target protein that potentially bind to a drug molecule upon the molecule's introduction in increasing concentrations. The goal is to obtain a mapping of peaks with known residue assignment from the reference spectrum of the unbound protein to peaks with unknown assignment in the target spectrum of the bound protein. Although a series of perturbed spectra help to trace a path from reference peaks to target peaks, a one-to-one mapping generally is not possible, especially for large proteins, due to errors, such as noise peaks, missing peaks, missing but then reappearing, overlapped, and new peaks not associated with any peaks in the reference. Due to these difficulties, the mapping is typically done manually or semi-automatically, which is not efficient for high-throughput drug screening. RESULTS: We present PeakWalker, a novel peak walking algorithm for fast-exchange systems that models the errors explicitly and performs many-to-one mapping. On the proteins: hBclXL, UbcH5B, and histone H1, it achieves an average accuracy of over 95% with less than 1.5 residues predicted per target peak. Given these mappings as input, we present PeakAssigner, a novel combined structure-based backbone resonance and NOE assignment algorithm that uses just 15N-NOESY, while avoiding TOCSY experiments and 13C-labeling, to resolve the ambiguities for a one-to-one mapping. On the three proteins, it achieves an average accuracy of 94% or better. CONCLUSIONS: Our mathematical programming approach for modeling chemical shift mapping as a graph problem, while modeling the errors directly, is potentially a time- and cost-effective first step for high-throughput drug screening based on limited NMR data and homologous 3D structures. PMID- 22536903 TI - Predicting folding pathways between RNA conformational structures guided by RNA stacks. AB - BACKGROUND: Accurately predicting low energy barrier folding pathways between conformational secondary structures of an RNA molecule can provide valuable information for understanding its catalytic and regulatory functions. Most existing heuristic algorithms guide the construction of folding pathways by free energies of intermediate structures in the next move during the folding. However due to the size and ruggedness of RNA energy landscape, energy-guided search can become trapped in local optima. RESULTS: In this paper, we propose an algorithm that guides the construction of folding pathways through the formation and destruction of RNA stacks. Guiding the construction of folding pathways by coarse grained movements of RNA stacks can help reduce the search space and make it easier to jump out of local optima. RNAEAPath is able to find lower energy barrier folding pathways between secondary structures of conformational switches and outperforms the existing heuristic algorithms in most test cases. CONCLUSIONS: RNAEAPath provides an alternate approach for predicting low-barrier folding pathways between RNA conformational secondary structures. The source code of RNAEAPath and the test data sets are available at http://genome.ucf.edu/RNAEAPath. PMID- 22536904 TI - Detection of gene expression changes at chromosomal rearrangement breakpoints in evolution. AB - BACKGROUND: We study the relation between genome rearrangements, breakpoints and gene expression. Genome rearrangement research has been concerned with the creation of breakpoints and their position in the chromosome, but the functional consequences of individual breakpoints remain virtually unknown, and there are no direct genome-wide studies of breakpoints from this point of view. A question arises of what the biological consequences of breakpoint creation are, rather than just their structural aspects. The question is whether proximity to the site of a breakpoint event changes the activity of a gene. RESULTS: We investigate this by comparing the distribution of distances to the nearest breakpoint of genes that are differentially expressed with the distribution of the same distances for the entire gene complement. We study this in data on whole blood tissue in human versus macaque, and in cerebral cortex tissue in human versus chimpanzee. We find in both data sets that the distribution of distances to the nearest breakpoint of "changed expression genes" differs little from this distance calculated for the rest of the gene complement. In focusing on the changed expression genes closest to the breakpoints, however, we discover that several of these have previously been implicated in the literature as being connected to the evolutionary divergence of humans from other primates. CONCLUSIONS: We conjecture that chromosomal rearrangements occasionally interrupt the regulatory configurations of genes close to the breakpoint, leading to changes in expression. PMID- 22536905 TI - Win percentage: a novel measure for assessing the suitability of machine classifiers for biological problems. AB - BACKGROUND: Selecting an appropriate classifier for a particular biological application poses a difficult problem for researchers and practitioners alike. In particular, choosing a classifier depends heavily on the features selected. For high-throughput biomedical datasets, feature selection is often a preprocessing step that gives an unfair advantage to the classifiers built with the same modeling assumptions. In this paper, we seek classifiers that are suitable to a particular problem independent of feature selection. We propose a novel measure, called "win percentage", for assessing the suitability of machine classifiers to a particular problem. We define win percentage as the probability a classifier will perform better than its peers on a finite random sample of feature sets, giving each classifier equal opportunity to find suitable features. RESULTS: First, we illustrate the difficulty in evaluating classifiers after feature selection. We show that several classifiers can each perform statistically significantly better than their peers given the right feature set among the top 0.001% of all feature sets. We illustrate the utility of win percentage using synthetic data, and evaluate six classifiers in analyzing eight microarray datasets representing three diseases: breast cancer, multiple myeloma, and neuroblastoma. After initially using all Gaussian gene-pairs, we show that precise estimates of win percentage (within 1%) can be achieved using a smaller random sample of all feature pairs. We show that for these data no single classifier can be considered the best without knowing the feature set. Instead, win percentage captures the non-zero probability that each classifier will outperform its peers based on an empirical estimate of performance. CONCLUSIONS: Fundamentally, we illustrate that the selection of the most suitable classifier (i.e., one that is more likely to perform better than its peers) not only depends on the dataset and application but also on the thoroughness of feature selection. In particular, win percentage provides a single measurement that could assist users in eliminating or selecting classifiers for their particular application. PMID- 22536906 TI - Ab initio detection of fuzzy amino acid tandem repeats in protein sequences. AB - BACKGROUND: Tandem repetitions within protein amino acid sequences often correspond to regular secondary structures and form multi-repeat 3D assemblies of varied size and function. Developing internal repetitions is one of the evolutionary mechanisms that proteins employ to adapt their structure and function under evolutionary pressure. While there is keen interest in understanding such phenomena, detection of repeating structures based only on sequence analysis is considered an arduous task, since structure and function is often preserved even under considerable sequence divergence (fuzzy tandem repeats). RESULTS: In this paper we present PTRStalker, a new algorithm for ab initio detection of fuzzy tandem repeats in protein amino acid sequences. In the reported results we show that by feeding PTRStalker with amino acid sequences from the UniProtKB/Swiss-Prot database we detect novel tandemly repeated structures not captured by other state-of-the-art tools. Experiments with membrane proteins indicate that PTRStalker can detect global symmetries in the primary structure which are then reflected in the tertiary structure. CONCLUSIONS: PTRStalker is able to detect fuzzy tandem repeating structures in protein sequences, with performance beyond the current state-of-the art. Such a tool may be a valuable support to investigating protein structural properties when tertiary X-ray data is not available. PMID- 22536907 TI - Sensitive detection of pathway perturbations in cancers. AB - BACKGROUND: The normal functioning of a living cell is characterized by complex interaction networks involving many different types of molecules. Associations detected between diseases and perturbations in well-defined pathways within such interaction networks have the potential to illuminate the molecular mechanisms underlying disease progression and response to treatment. RESULTS: In this paper, we present a computational method that compares expression profiles of genes in cancer samples to samples from normal tissues in order to detect perturbations of pre-defined pathways in the cancer. In contrast to many previous methods, our scoring function approach explicitly takes into account the interactions between the gene products in a pathway. Moreover, we compute the sub-pathway that has the highest score, as opposed to merely computing the score for the entire pathway. We use a permutation test to assess the statistical significance of the most perturbed sub-pathway. We apply our method to 20 pathways in the Netpath database and to the Global Cancer Map of gene expression in 18 cancers. We demonstrate that our method yields more sensitive results than alternatives that do not consider interactions or measure the perturbation of a pathway as a whole. We perform a sensitivity analysis to show that our approach is robust to modest changes in the input data. Our method confirms numerous well-known connections between pathways and cancers. CONCLUSIONS: Our results indicate that integrating differential gene expression with the interaction structure in a pathway is a powerful approach for detecting links between a cancer and the pathways perturbed in it. Our results also suggest that even well-studied pathways may be perturbed only partially in any given cancer. Further analysis of cancer-specific sub pathways may shed new light on the similarities and differences between cancers. PMID- 22536908 TI - Methylation of gamma-carboxylated Glu (Gla) allows detection by liquid chromatography-mass spectrometry and the identification of Gla residues in the gamma-glutamyl carboxylase. AB - gamma-Carboxylated Glu (Gla) is a post-translational modification required for the activity of vitamin K-dependent (VKD) proteins that has been difficult to study by mass spectrometry due to the properties of this negatively charged residue. Gla is generated by a single enzyme, the gamma-glutamyl carboxylase, which has broad biological impact because VKD proteins have diverse functions that include hemostasis, apoptosis, and growth control. The carboxylase also contains Glas, of unknown function, and is an integral membrane protein with poor sequence coverage. To locate these Glas, we first established methods that resulted in high coverage (92%) of uncarboxylated carboxylase. Subsequent analysis of carboxylated carboxylase identified a Gla peptide (729-758) and a missing region (625-647) that was detected in uncarboxylated carboxylase. We therefore developed an approach to methylate Gla, which efficiently neutralized Gla and improved mass spectrometric analysis. Methylation eliminated CO2 loss from Gla, increased the ionization of Gla-containing peptide, and appeared to facilitate trypsin digestion. Methylation of a carboxylated carboxylase tryptic digest identified Glas in the 625-647 peptide. These studies provide valuable information for testing the function of carboxylase carboxylation. The methylation approach for studying Gla by mass spectrometry is an important advance that will be broadly applicable to analyzing other VKD proteins. PMID- 22536909 TI - Motion perception in children with foetal alcohol syndrome. AB - AIM: To evaluate the visual magnocellular pathway by a coherent motion perception test in children with foetal alcohol syndrome (FAS). METHODS: Eighty-nine children (49 with verified FAS and 40 without FAS) aged from 10 to 16 years were included into the study. Both the study and the control group were children living in orphanages. A coherent motion perception test was used. The test consisted of 150 white moving dots on a black background presented in different signal-to-noise ratio conditions. The task was direction detection of the coherently moving dots whose percentage decreased at each step. RESULTS: A significant difference between the two groups was found (p = 0.018). Children with FAS had lower coherent motion perception ability in all the signal-to-noise ratio conditions. A significant difference between difficulty levels (p < 0.001) was found for all subjects in both groups - decreasing the stimulus signal-to noise level decreased the motion perception score. In both groups, the motion perception score differed for vertical and horizontal stimuli (p = 0.003) with better performance with vertical stimuli. CONCLUSION: Impaired motion perception in FAS children could be indicative of a dorsal stream developmental dysfunction resulting from alcohol brain damage. PMID- 22536911 TI - Girls and violence: a review of the literature. AB - Violence and its prevention are key issues in community health nursing. Significant concern and controversy surrounds the current involvement of girls as witnesses, offenders, and victims of violence. This article provides a review of the literature about girls and violence, including the girls' roles as offenders, victims, and witnesses, predictors of violence, consequences associated with violence, and potential ideas for violence prevention. This information paves the way for a subsequent manuscript presenting a review of the literature about girls' perceptions of violence and its prevention and the results of a focus group study designed to determine girls' thoughts about community violence and prevention. PMID- 22536912 TI - Girls' perceptions of violence and prevention. AB - This research examines girls' perceptions of violence and its prevention. A purposive sample of 32 young women ages 12-18 who were incarcerated, affiliated with the juvenile justice system, or self-identified as living in disadvantaged neighborhoods participated in 1 of 4 focus groups. Recursive, iterative analysis yielded seven themes, including: violence is learned, violence is contagious, violence is unstoppable, violence is necessary to manage stress and conflict, violence is belonging, violence is connected to other crime, and maybe it can be stopped. These themes provide important insights into young women's thoughts on violence and may inform policies and programs as prevention strategies. PMID- 22536910 TI - Effects of perfusion and dynamic loading on human neocartilage formation in alginate hydrogels. AB - Dynamic loading and perfusion culture environments alone are known to enhance cartilage extracellular matrix (ECM) production in dedifferentiated articular chondrocytes. In this study, we explored whether a combination of these factors would enhance these processes over a free-swelling (FS) condition using adult human articular chondrocytes embedded in 2% alginate. The alginate constructs were placed into a bioreactor for perfusion (P) only (100 MUL/per minute) or perfusion and dynamic compressive loading (PL) culture (20% for 1 h, at 0.5 Hz), each day. Control FS alginate gels were maintained in six-well static culture. Gene expression analysis was conducted on days 7 and 14, while cell viability, immunostaining, and mechanical property testing were performed on day 14 only. Total glycosaminoglycan (GAG) content and GAG synthesis were assessed after 14 days. Col2a1 mRNA expression levels were significantly higher (at least threefold; p<0.05) in both bioreactor conditions compared with FS by days 7 and 14. For all gene studies, no significant differences were seen between P and PL treatments. Aggrecan mRNA levels were not significantly altered in any condition although both GAG/DNA and (35)S GAG incorporation studies indicated higher GAG retention and synthesis in the FS treatment. Collagen type II protein deposition was low in all samples, link protein distribution was more diffuse in FS condition, and aggrecan deposition was located in the outer regions of the alginate constructs in both bioreactor conditions, yet more uniformly in the FS condition. Catabolic gene expression (matrix metalloproteinase 3 [MMP3] and inducible nitric oxide synthase [iNOS]) was higher in bioreactor conditions compared with FS, although iNOS expression levels decreased to approximately fourfold less than the FS condition by day 14. Our data indicate that conditions created in the bioreactor enhanced both anabolic and catabolic responses, similar to other loading studies. Perfusion was sufficient alone to promote this dual response. PL increased the deposition of aggrecan surrounding cells compared with the other conditions; however, overall low GAG retention in the bioreactor system was likely due to both perfusion and catabolic conditions created. Optimal conditions, which permit appropriate anabolic and catabolic processes for accumulation of ECM and tissue remodeling for neocartilage development, specifically for humans, are needed. PMID- 22536913 TI - Choosing fatherhood: how teens in the justice system embrace or reject a father identity. AB - The purpose of this qualitative study was to further the understanding of father identity and role development among adolescents involved in the justice system. Youth who were expecting a child or parenting an infant and who were incarcerated, arrested, or had admitted to criminal behavior participated in interviews and observations in a juvenile detention center and in the community. Data analysis revealed 4 patterns of fathering intentions: (a) embracing fatherhood, (b) being barred from fatherhood, (c) being ambivalent about fatherhood, or (d) rejecting fatherhood. Community health nurses can use this information to assess father identity status and address factors that interfere with father engagement. PMID- 22536914 TI - The potential influence of a social media intervention on risky sexual behavior and Chlamydia incidence. AB - The purpose of this descriptive pilot study was to evaluate an evidence-based social-networking intervention aimed at reducing the incidence of Chlamydia among 15- to 24-year-olds. The intervention consists of a Facebook site that addresses signs, symptoms, treatment, screening, and prevention of Chlamydia infection. Findings included a 23% self-reported increase in condom utilization, and a 54% reduction in positive Chlamydia cases among 15- to 17-year-olds. Study results support that social media may be an effective mechanism for information dissemination and the promotion of positive behavioral changes among this population. PMID- 22536917 TI - Teamwork, pleasure and bargaining in animal social behaviour. AB - Intimate behaviour between animals is hypothesized to enable teamwork. The pleasure experienced in grooming, preening, dancing, mating and singing in synchrony is hypothesized to motivate participants to coordinate actions directed towards a shared goal that enhances each individual's fitness. This cooperative behaviour evolves as a mutual direct benefit, not as altruism. Teamwork leads to an equilibrium set of returns to the participants that may be modelled as a Nash bargaining solution instead of as the more familiar Nash equilibrium. The dynamics leading to that equilibrium may be modelled based on joint action instead of the more familiar individualistic action. Confusions by Binmore (J. Evol. Biol. 2010; 23: 1351) about this hypothesis are corrected. PMID- 22536915 TI - Detecting delirium in older adults living at home. AB - The aim of this study was to determine whether in-home care nurses had the necessary knowledge to detect delirium in older adults. To this end, 87 home care nurses from 2 sites in the greater Quebec City region in Canada answered a questionnaire. The results showed nurses had limited level of knowledge about the diagnostic criteria for delirium, the main signs and symptoms of delirium, and the tools for its detection. Moreover, 54.4% of the in-home care nurses were able to recognize delirium, from structured clinical vignettes. PMID- 22536918 TI - Effects of sheath injury and trimetazidine on endothelial dysfunction of radial artery after transradial catheterization. AB - OBJECTIVE: We evaluated the effects of sheath injury and trimetazidine (TMZ) on endothelial dysfunction of the radial artery (RA) after transradial coronary artery angiography (TRCAG) or transradial percutaneous coronary intervention (TRPCI) with flow-mediated dilation (FMD). METHODS: One hundred twenty patients who underwent TRCAG or TRPCI with either a long 5Fr or 6Fr sheath were randomly assigned to the TMZ group or the control group. Baseline, postsheath injury (<24 hours after sheath injury), and 10-week FMDs were performed. RESULTS: In all cannulated RAs, the postsheath injury FMDs were significantly lower than the baseline FMDs (P < 0.01). In the control group, the 10-week FMD was significantly lower than the baseline FMD, but no difference was found in the TMZ group (10.4 +/- 3.4% vs. 6.3 +/- 2.9%, P < 0.01 and 10.1 +/- 3.6% vs. 9.2 +/- 3.6%, P = 0.09, respectively). Repeated measures ANOVA revealed significant differences in FMD between the TMZ group and the control group (F = 9.87, P < 0.01). Including coronary artery disease, heparin dose during procedure, sheath size, sheath-RA size ratio, sheath indwelling time in RA, RA spasm, repeated RA sheath injury (upsizing from 5Fr to 6Fr), and TMZ use, the multivariate analysis showed that repeated RA sheath injury and TMZ use (OR 7.40, 95% CI 1.42-38.53, P < 0.05, and OR 0.08, 95% CI 0.02-0.30, P < 0.01, respectively) were independent predictors of the decrement of FMD > 50% (DeltaFMDbaseline - 10 week > 50%). CONCLUSION: Repeated sheath injury negatively influences endothelial recovery after long 6Fr sheath injury to the RA, and TMZ lessens endothelial dysfunction of the RA after radial catheterization. PMID- 22536920 TI - Exploration of the pi-electronic structure of singlet, triplet, and quintet states of fulvenes and fulvalenes using the electron localization function. AB - The singlet ground states and lowest triplet states of penta- and heptafulvene, their benzannulated derivatives, as well as the lowest quintet states of pentaheptafulvalenes, either the parent compound or compounds in which the two rings are intercepted by either an alkynyl or a phenyl segment, were investigated at the (U)OLYP/6-311G(d,p) density functional theory level. The influence of (anti)aromaticity was analyzed by the structure-based aromaticity index HOMA, the harmonic oscillator model of aromaticity. The extent of (anti)aromatic character was also evaluated in terms of the pi-electron (de)localization as measured by the pi component of the electron localization function (ELF(pi)). The natural atomic orbital (NAO) occupancies were calculated in order to evaluate the degree of pi-electron shift caused by the opposing electron-counting rules for aromaticity in the electronic ground state (S(0); Huckel's rule) and the first pipi* excited triplet state (T(1); Baird's rule). Pentaheptafulvalene (5) shows a shift of 0.5 pi electrons from the 5-ring to the 7-ring when going from the S(0) state to the lowest quintet state (Qu(1)). The pentaheptafulvalene 5 and [5.6.7]quinarene 7 were also investigated in their 90 degrees twisted conformations. From our study it is apparent that excitation localization in fulvalenes, but not in fulvenes, to a substantial degree is determined by aromaticity localization to triplet biradical 4n pi-electron cycles. Isolated benzene rings in these compounds tend to remain as closed-shell 6pi-electron cycles. PMID- 22536919 TI - A comparison of the potency of a novel bispyridinium oxime K203 and currently available oximes (obidoxime, HI-6) to counteract the acute neurotoxicity of sarin in rats. AB - The neuroprotective effects of a newly developed oxime K203 and currently available oximes (obidoxime, HI-6) in combination with atropine in rats poisoned with sarin were studied. The sarin-induced neurotoxicity was monitored using a functional observatory battery at 2 hr after sarin challenge. The results indicate that the potency of a novel bispyridinium oxime K203 to counteract sarin induced neurotoxicity is relatively low and roughly corresponds to the neuroprotective efficacy of obidoxime. Among tested oximes, the oxime HI-6 seems to be significanlty more efficacious to counteract acute neurotoxicity of sarin than commonly used obidoxime and a newly developed oxime K203. Thus, the oxime K203 does not provide any beneficial effect for the antidotal treatment of acute poisoning with sarin in comparison with the oxime HI-6 that should be considered to be the best oxime for antidotal treatment of acute sarin poisonings. PMID- 22536921 TI - Fish to meat intake ratio and cooking oils are associated with hepatitis C virus carriers with persistently normal alanine aminotransferase levels. AB - AIM: Dietary habits are involved in the development of chronic inflammation; however, the impact of dietary profiles of hepatitis C virus carriers with persistently normal alanine transaminase levels (HCV-PNALT) remains unclear. The decision-tree algorithm is a data-mining statistical technique, which uncovers meaningful profiles of factors from a data collection. We aimed to investigate dietary profiles associated with HCV-PNALT using a decision-tree algorithm. METHODS: Twenty-seven HCV-PNALT and 41 patients with chronic hepatitis C were enrolled in this study. Dietary habit was assessed using a validated semiquantitative food frequency questionnaire. A decision-tree algorithm was created by dietary variables, and was evaluated by area under the receiver operating characteristic curve analysis (AUROC). RESULTS: In multivariate analysis, fish to meat ratio, dairy product and cooking oils were identified as independent variables associated with HCV-PNALT. The decision-tree algorithm was created with two variables: a fish to meat ratio and cooking oils/ideal bodyweight. When subjects showed a fish to meat ratio of 1.24 or more, 68.8% of the subjects were HCV-PNALT. On the other hand, 11.5% of the subjects were HCV PNALT when subjects showed a fish to meat ratio of less than 1.24 and cooking oil/ideal bodyweight of less than 0.23 g/kg. The difference in the proportion of HCV-PNALT between these groups are significant (odds ratio 16.87, 95% CI 3.40 83.67, P = 0.0005). Fivefold cross-validation of the decision-tree algorithm showed an AUROC of 0.6947 (95% CI 0.5656-0.8238, P = 0.0067). CONCLUSION: The decision-tree algorithm disclosed that fish to meat ratio and cooking oil/ideal bodyweight were associated with HCV-PNALT. PMID- 22536922 TI - Blood ordering from the operating room: turnaround time as a quality indicator. AB - BACKGROUND: Quality indicators in transfusion medicine are necessary for patient safety and customer satisfaction. The turnaround time (TAT) of issuing red blood cells (RBCs) has emerged as a quality indicator but is not an established benchmark. We examined the TAT for issuing RBCs from the blood bank to the operating rooms (ORs) at Vanderbilt University Medical Center (VUMC) and Stanford University Medical Center (SUMC). STUDY DESIGN AND METHODS: TAT was defined from time of request to when RBCs exited the blood bank. Cases eligible for analysis had completed type-and-screen results with requests for four or fewer RBC units. Patients with a positive antibody screen had serologically crossmatched units prepared and reserved for intraoperative use. We also e-mailed surveys to academic institutions to establish the current state of TAT monitoring and to anesthesiologists at VUMC to gauge the TAT expectations of the OR. RESULTS: The mean TATs at the two institutions were comparable (VUMC, 10 +/- 3.8 min; SUMC, 14 +/- 7.2 min) for orders of RBCs. The most common reasons for delayed TAT were overlapping orders, medical technologists occupied by phone calls, and oversaturation of pneumatic tube stations. Only 3 of 24 surveyed institutions actively monitored RBC TAT. Surveyed anesthesiologists (n = 7) reported an expectation for RBC TAT of 5 to 15 minutes for urgent cases. Established internal TAT policies were 15 and 20 minutes at VUMC and SUMC, respectively, for crossmatched RBC requests for patients with complete diagnostic testing. CONCLUSION: Many of the surveyed institutions do not monitor stat RBC issue TAT as a quality indicator. This study serves as a starting point for establishing a benchmark for TAT for issuing RBCs from the blood bank to ORs. PMID- 22536924 TI - Mechanism and fluorescence application of electrochromism in photochromic dithienylcyclopentene. AB - The kinetic process of key intermediates involved in the electrochemical ring opening of photochromic dithienylcyclopentenes (DTEs) has been observed for the first time, where the electronic nature of the DTEs is an important factor that determines the rate-determining step in the electrochromism. The dual chromic property has been implemented to a single molecular fluorescence memory. PMID- 22536925 TI - Computation of induced dipoles in molecular mechanics simulations using graphics processors. AB - In this work, we present a tentative step toward the efficient implementation of polarizable molecular mechanics force fields with GPU acceleration. The computational bottleneck of such applications is found in the treatment of electrostatics, where higher-order multipoles and a self-consistent treatment of polarization effects are needed. We have implemented a GPU accelerated code, based on the Tinker program suite, for the computation of induced dipoles. The largest test system used shows a speedup factor of over 20 for a single precision GPU implementation, when comparing to the serial CPU version. A discussion of the optimization and parametrization steps is included. Comparison between different graphic cards and CPU-GPU embedding is also given. The current work demonstrates the potential usefulness of GPU programming in accelerating this field of applications. PMID- 22536929 TI - Prediction of projectile ricochet behavior after water impact. AB - Although not very common, forensic investigation related to projectile ricochet on water can be required when undesirable collateral damage occurs. Predicting the ricochet behavior of a projectile is challenging owing to numerous parameters involved: impact velocity, incident angle, projectile stability, angular velocity, etc. Ricochet characteristics of different projectiles (K50 BMG, 0.5 cal Ball M2, 0.5-cal AP-T C44, 7.62-mm Ball C21, and 5.56-mm Ball C77) were studied in a pool. The results are presented to assess projectile velocity after ricochet, ricochet angle, and projectile azimuth angle based on impact velocity or incident angle for each projectile type. The azimuth ranges show the highest variability at low postricochet velocity. The critical ricochet angles were ranging from 15 to 30 degrees . The average ricochet angles for all projectiles were pretty close for all projectiles at 2.5 and 10 degrees incident angles for the range of velocities studied. PMID- 22536930 TI - Correlates of antiretroviral and antidepressant adherence among depressed HIV infected patients. AB - Although crucial for efficacy of pharmacotherapy, adherence to prescribed medication regimens for both antiretrovirals and antidepressants is often suboptimal. As many depressed HIV-infected individuals are prescribed both antiretrovirals and antidepressants, it is important to know whether correlates of nonadherence are similar or different across type of regimen. The HIV Translating Initiatives for Depression into Effective Solutions (HI-TIDES) study was a single-blinded, longitudinal, randomized controlled effectiveness trial comparing collaborative care to usual depression care at three Veterans Affairs HIV clinics. The current investigation utilized self-report baseline interview and chart-abstracted data. Participants were 225 depressed HIV-infected patients who were prescribed an antidepressant (n=146), an antiretroviral (n=192), or both (n=113). Treatment adherence over the last 4 days was dichotomized as "less than 90% adherence" or "90% or greater adherence." After identifying potential correlates of nonadherence, we used a seemingly unrelated regression (SUR) bivariate probit model, in which the probability of adherence to HIV medications and the probability of adherence to antidepressant medications are modeled jointly. Results indicated that 75.5% (n=146) of those prescribed antiretrovirals reported 90%-plus adherence to their antiretroviral prescription and 76.7% (n=112) of those prescribed antidepressants reported 90%-plus adherence to their antidepressant prescription, while 67% of those prescribed both (n=113) reported more than 90% adherence to both regimens. SUR results indicated that education, age, and HIV symptom severity were significant correlates of antiretroviral medication adherence while gender and generalized anxiety disorder diagnosis were significant correlates of adherence to antidepressant medications. In addition, antiretroviral adherence did not predict antidepressant adherence (beta=1.62, p=0.17), however, antidepressant adherence did predict antiretroviral adherence (beta=2.30, p<0.05). PMID- 22536923 TI - Epigenetic mechanisms in anti-cancer actions of bioactive food components--the implications in cancer prevention. AB - The hallmarks of carcinogenesis are aberrations in gene expression and protein function caused by both genetic and epigenetic modifications. Epigenetics refers to the changes in gene expression programming that alter the phenotype in the absence of a change in DNA sequence. Epigenetic modifications, which include amongst others DNA methylation, covalent modifications of histone tails and regulation by non-coding RNAs, play a significant role in normal development and genome stability. The changes are dynamic and serve as an adaptation mechanism to a wide variety of environmental and social factors including diet. A number of studies have provided evidence that some natural bioactive compounds found in food and herbs can modulate gene expression by targeting different elements of the epigenetic machinery. Nutrients that are components of one-carbon metabolism, such as folate, riboflavin, pyridoxine, cobalamin, choline, betaine and methionine, affect DNA methylation by regulating the levels of S-adenosyl-L methionine, a methyl group donor, and S-adenosyl-L-homocysteine, which is an inhibitor of enzymes catalyzing the DNA methylation reaction. Other natural compounds target histone modifications and levels of non-coding RNAs such as vitamin D, which recruits histone acetylases, or resveratrol, which activates the deacetylase sirtuin and regulates oncogenic and tumour suppressor micro-RNAs. As epigenetic abnormalities have been shown to be both causative and contributing factors in different health conditions including cancer, natural compounds that are direct or indirect regulators of the epigenome constitute an excellent approach in cancer prevention and potentially in anti-cancer therapy. PMID- 22536933 TI - Phase 1 results from a study of romidepsin in combination with gemcitabine in patients with advanced solid tumors. AB - Romidepsin is a potent histone deacetylase inhibitor; preclinical studies showed potential synergy with the nucleoside analog gemcitabine. This phase 1 trial was conducted to determine the maximum tolerated dose for two schedules of romidepsin plus gemcitabine in patients with advanced solid tumors in which gemcitabine had previously demonstrated clinical activity. The recommended phase 2 dose was 12 mg/m(2) romidepsin plus 800 mg/m(2) gemcitabine on days 1 and 15 every 28 days. Results suggest additive hematologic toxicities of romidepsin plus gemcitabine, but the level of antitumor activity observed warrants more formal trials of this combination to further assess safety and efficacy. PMID- 22536931 TI - Stressors and sources of support: the perceptions and experiences of newly diagnosed Latino youth living with HIV. AB - Little is known of the experience of Latino youth with HIV infection in the United States, especially with respect to stressors and how these youth cope with said stressors. This study reports on a subset (Latino/Hispanic self-identified youth, n=14) of qualitatively interviewed youth (n=30), both in individual interviews and in focus group discussion settings, aware of their HIV diagnosis for 12-24 months (mean: 16.7 months; standard deviation [SD], 4.89) Youth were 16 24 years old (M=21.5 years), female (43%) and males (57%). Youth were recruited from three cities: Chicago, New York, and San Juan (Puerto Rico). Interviews of Latinos (n=14) were reviewed for sources of stressors and support. Seven themes emerged in analyzing stated sources of stressors: (1) initial psychosocial responses to HIV diagnosis, (2) disclosure to family and friends, (3) stigma related to receiving an HIV diagnosis, (4) body image and concerns of the physical changes associated with HIV and antiretroviral medications, (5) taking antiretroviral medications and side effects, (6) the disruption of their future life goals, and (7) reproductive health concerns. Identified sources of support and coping were described including; gaining appreciation for what matters in life, adapting and developing achievable goals, reordering priorities and relying on religion and spiritual beliefs for health outcomes. The information gathered is from individual interviews and from focus group discussions can be used to increase the understanding of this understudied population while improving services to engage and retain these youth in care. PMID- 22536934 TI - TNF-alpha expression in the UCB-MSCs as stable source inhibits gastric cancers growth in nude mice. AB - Mesenchymal stem cells (MSCs) are potentially vehicles for therapy of malignant diseases. In our study, we investigated whether UCB-MSCs are capable to carry TNF alpha to target tumor cells in vivo. The human gastric cancer cells SGC-7901 were subcutaneously injected into the abdomen near groins of 15 nude mice to establish experiment tumor models. MSC-TNF-alpha demonstrated a strong suppressive effect on the tumor growth compared with MSC and NaCl. Thus, MSC-TNF-alpha can obviously inhibit Gastric cancers growth in nude mice, indicating that UCB-MSCs may have the potential to become a prevention approach against gastric cancer. PMID- 22536935 TI - Polymorphisms of MTHFR C677T and A1298C association with oral carcinoma risk: a meta-analysis. AB - Investigations regarding association of MTHFR polymorphisms with oral carcinoma risk have yielded inconclusive results. Thus, meta-analyses were performed. Results showed that no associations of C677T polymorphisms with oral carcinoma were observed for the overall data. In subgroup analyses by drinking status, homozygous TT alleles exhibited elevated oral cancer susceptibility in heavy drinkers. For A1298C polymorphism, CC alleles presented a possible preventive role for oral cancer. Collectively, results suggest that MTHFR 677TT polymorphism might be a low-penetrant risk factor for oral carcinoma only in heavy drinkers. Conversely, 1298CC alleles might play a preventive role for oral cancer. PMID- 22536936 TI - Exercise training improves heart rate variability in older patients with heart failure: a randomized, controlled, single-blinded trial. AB - Reduced heart rate variability (HRV) in older patients with heart failure (HF) is common and indicates poor prognosis. Exercise training (ET) has been shown to improve HRV in younger patients with HF. However, the effect of ET on HRV in older patients with HF is not known. Sixty-six participants (36% men), aged 69+/ 5 years, with HF and both preserved ejection fraction (HFPEF) and reduced ejection fraction (HFREF), were randomly assigned to 16 weeks of supervised ET (ET group) vs attention-control (AC group). Two HRV parameters (the standard deviation of all normal RR intervals [SDNN] and the root mean square of successive differences in normal RR intervals [RMSSD]) were measured at baseline and after completion of the study. When compared with the AC group, the ET group had a significantly greater increase in both SDNN (15.46+/-5.02 ms in ET vs 2.37+/-2.13 ms in AC, P=.016) and RMSSD (17.53+/-7.83 ms in ET vs 1.69+/-2.63 ms in AC, P=.003). This increase was seen in both sexes and HF categories. ET improved HRV in older patients with both HFREF and HFPEF. PMID- 22536937 TI - Reliability and validity of the Korean Standard Pattern Identification for Stroke (K-SPI-Stroke) questionnaire. AB - BACKGROUND: The present study was conducted to examine the reliability and validity of the 'Korean Standard Pattern Identification for Stroke (K-SPI Stroke)', which was developed and evaluated within the context of traditional Korean medicine (TKM). METHODS: Between September 2006 and December 2010, 2,905 patients from 11 Korean medical hospitals were asked to complete the K-SPI-Stroke questionnaire as a part of project ' Fundamental study for the standardization and objectification of pattern identification in traditional Korean medicine for stroke (SOPI-Stroke). Each patient was independently diagnosed by two TKM physicians from the same site according to one of four patterns, as suggested by the Korea Institute of Oriental Medicine: 1) a Qi deficiency pattern, 2) a Dampness-phlegm pattern, 3) a Yin deficiency pattern, or 4) a Fire-heat pattern. We estimated the internal consistency using Cronbach's alpha coefficient, the discriminant validity using the means score of patterns, and the predictive validity using the classification accuracy of the K-SPI-Stroke questionnaire. RESULTS: The K-SPI-Stroke questionnaire had satisfactory internal consistency (alpha = 0.700) and validity, with significant differences in the mean of scores among the four patterns. The overall classification accuracy of this questionnaire was 65.2 %. CONCLUSION: These results suggest that the K-SPI-Stroke questionnaire is a reliable and valid instrument for estimating the severity of the four patterns. PMID- 22536938 TI - Do-not-resuscitate orders in the last days of life. AB - BACKGROUND: The purpose of this analysis was to describe the presence and timing of do-not-resuscitate (DNR) orders for imminently dying patients in VA Medical Centers, and to examine factors associated with these processes. METHODS: Data on DNR orders in the last 7 days of life were abstracted from the medical records of 1,069 veterans who had died in one of six VA hospitals in 2005. RESULTS: Of the 1069 records, 681 (63.7%) had an active DNR order at time of death. Among these, records indicated that the order was written within the last 24 hours for 219 (32.2%), 1-2 days prior to death for 54 (7.9%), 3-7 days prior to death for 256 (37.6%), and > 7 days prior to death for 152 (22.3%). Veterans with a family member present at time of death and those who received pastoral care visits were more likely to have DNR orders. African American veterans and veterans who died unexpectedly were less likely to have DNR orders. Compared with those dying on a general medicine unit, veterans dying in the emergency department or an intensive care unit (ICU) and veterans dying during a procedure or in transit were less likely to have DNR orders. Mental health diagnoses were not associated with presence of a DNR order. CONCLUSION: Results suggest that the DNR process might be improved by interventions that target ICU settings, facilitate transitions to less intensive locations of care, ensure the involvement and availability of pastoral care staff, and create environments that support the presence of family members. PMID- 22536939 TI - Microarray-to-microarray transfer of reagents by snapping of two chips for cross reactivity-free multiplex immunoassays. AB - Whereas microarray and microfluidic technologies have progressed on many fronts, servicing microchips with minute amounts of reagents still constitutes an important challenge for many applications. Recently, chip-to-chip reagent transfer methods were introduced that simplify the delivery of reagents but required manual, visual alignment, custom-built microwells, and only showed the reaction of a single sample with multiple chemicals. Here, we present the snap chip, which uses common glass slides for transfer, back-side alignment for achieving precise alignment in spite of mirroring, and a snap-apparatus for facile transfer of arrays of chemicals at once by snapping the two slides together. We recently established that cross-reactivity was a significant problem in multiplex assays both theoretically and experimentally and found that it can be eliminated by avoiding mixing, but which necessitates delivering each detection antibody to a single spot with the cognate capture antibody. Using the snap chip, multiplexed sandwich immunoassays without mixing were performed: a slide with multiple arrays of 10 different capture antibodies was incubated with a sample, and then all detection antibodies transferred at once by snapping, each to the single cognate spot. All binding curves were established and limits of detection in the pg/mL range were obtained. Snap chips were stored up to 3 months prior to usage. The snap chip, by dissociating microarray production, which requires expensive equipment, from assay execution, which can be achieved using a hand-held alignment apparatus, will allow for multiplex reactions to be performed using a user-friendly kit. This new liquid handling format can be easily adapted to other applications that require transfer of minute amounts of different reagents in parallel. PMID- 22536940 TI - HLA-A*11:53 is shown to be identical to the corrected A*11:02:01 allele sequence. AB - According to the IMGT/HLA Database, the DNA sequence of A*11:53 is identical to A*11:02:01 in exons 2, 3, 4 and 5 except at codon 276. A*11:53 was reported as a rare variant of A*11, while A*11:02:01 was understood to be the second most frequently observed variant of A*11 after A*11:01:01 in Taiwanese. We sequenced HLA-A locus exons 2, 3, 4 and 5 of Taiwanese blood donors (n = 50) previously typed to carry A*11:02:01. We found out all of their sequences are identical to A*11:53 in exons 2, 3, 4 and 5' part of exon 5 including codon 276. PMID- 22536941 TI - Peripheral blood stem cell transplant-related Plasmodium falciparum infection in a patient with sickle cell disease. AB - BACKGROUND: Although transmission of Plasmodium falciparum (Pf) infection during red blood cell (RBC) transfusion from an infected donor has been well documented, malaria parasites are not known to infect hematopoietic stem cells. We report a case of Pf infection in a patient 11 days after peripheral blood stem cell transplant for sickle cell disease. STUDY DESIGN AND METHODS: Malaria parasites were detected in thick blood smears by Giemsa staining. Pf HRP2 antigen was measured by enzyme-linked immunosorbent assay on whole blood and plasma. Pf DNA was detected in whole blood and stem cell retention samples by real-time polymerase chain reaction using Pf species-specific primers and probes. Genotyping of eight Pf microsatellites was performed on genomic DNA extracted from whole blood. RESULTS: Pf was not detected by molecular, serologic, or parasitologic means in samples from the recipient until Day 11 posttransplant, coincident with the onset of symptoms. In contrast, Pf antigen was retrospectively detected in stored plasma collected 3 months before transplant from the asymptomatic donor. Pf DNA was detected in whole blood from both the donor and the recipient after transplant, and genotyping confirmed shared markers between donor and recipient Pf strains. Lookback analysis of RBC donors was negative for Pf infection. CONCLUSIONS: These findings are consistent with transmission by the stem cell product and have profound implications with respect to the screening of potential stem cell donors and recipients from malaria endemic regions. PMID- 22536943 TI - Photodissociation of N2O: excitation of 1A" states. AB - We investigate the contributions of the lowest two (1)A" states in the UV photodissociation of N(2)O employing three-dimensional potential energy surfaces and transition dipole moment functions. Because the transition dipole moments are much smaller than for the 2 (1)A' state, we conclude that excitation of the (1)A" states has a marginal effect. The dense vibrational spectrum of the quasi-bound 2(1)A" state possibly explains some of the tiny, noise-like structures of the measured absorption spectrum. PMID- 22536942 TI - Inhibitory effect of Bifidobacterium infantis-mediated sKDR prokaryotic expression system on angiogenesis and growth of Lewis lung cancer in mice. AB - BACKGROUND: To construct the Bifidobacterium infantis-mediated soluble kinase insert domain receptor (sKDR) prokaryotic expression system and to observe its inhibitory effect on growth of human umbilicus vessel endothelial cells (HUVECs) in vitro and Lewis lung cancer (LLC) on mice in vivo. METHODS: The Bifidobacterium infantis-mediated sKDR prokaryotic expression system was constructed through electroporation and subsequently identified through PCR and Western blot analysis. HUVECs were added to the products of this system to evaluate the anti-angiogenesis effect through MTT assay in vitro. The LLC mice models were divided into three groups: one group treated with saline (group a); one group treated with recombinant Bifidobacterium infantis containing pTRKH2-PsT plasmid group (group b); and one group treated with recombinant Bifidobacterium infantis containing pTRKH2-PsT/sKDR plasmid group (group c). The quality of life and survival of mice were recorded. Tumor volume, tumor weight, inhibitive rate, and necrosis rate of tumor were also evaluated. Necrosis of tumor and signals of blood flow in tumors were detected through color Doppler ultrasound. In addition, microvessel density (MVD) of the tumor tissues was assessed through CD31 immunohistochemical analysis. RESULTS: The positively transformed Bifidobacterium infantis with recombinant pTRKH2-PsT/sKDR plasmid was established, and was able to express sKDR at gene and protein levels. The proliferation of HUVECs cultivated with the extract of positively transformed bacteria was inhibited significantly compared with other groups (P < 0. 05). The quality of life of mice in group c was better than in group a and b. The recombinant Bifidobacterium infantis containing pTRKH2-PsT/sKDR plasmid enhanced the efficacy of tumor growth suppression and prolongation of survival, increased the necrosis rate of tumor significantly, and could obviously decrease MVD and the signals of blood flow in tumors. CONCLUSION: The Bifidobacterium infantis-mediated sKDR prokaryotic expression system was constructed successfully. This system could express sKDR at gene and protein levels and significantly inhibit the growth of HUVECs induced by VEGF in vitro. Moreover, it could inhibit tumor growth and safely prolong the survival time of LLC C57BL/6 mice. PMID- 22536945 TI - Infection intensity and infectivity of the tick-borne pathogen Borrelia afzelii. AB - The 'trade-off' hypothesis for virulence evolution assumes that between-host transmission rate is a positive and saturating function of pathogen exploitation and virulence, but there are as yet few tests of this assumption, in particular for vector-borne pathogens. Here, I show that the infectivity (probability of transmission) of the tick-borne bacterium Borrelia afzelii from two of its natural rodent hosts (bank vole and yellow-necked mouse) to its main tick vector increases asymptotically with increasing exploitation (measured as bacterial load in skin biopsies). Hence, this result provides support for one of the basic assumptions of the 'trade-off hypothesis'. Moreover, there was no difference in infectivity between bank voles and yellow-necked mice despite bacterial loads being on average an order of magnitude higher in bank voles, most likely because ticks took larger blood meals from mice. This shows that interspecific variation in host resistance does not necessarily translate into a difference in infectivity. PMID- 22536946 TI - Development of a PCR assay to detect the potential production of nivalenol in Fusarium poae. AB - Fusarium species can produce mycotoxins, which can contaminate cereal-based food producing adverse effects for human and animal health. In recent years, the importance of Fusarium poae has increased within the Fusarium head blight complex. Fusarium poae is known to produce trichothecenes, especially nivalenol, a potent mycotoxin able to cause a variety of toxic effects. In this study, a specific primer pair was designed based on the tri7 gene to detect potential nivalenol-producing F. poae isolates. A total of 125 F. poae, four F. cerealis, two F. culmorum, one F. langsethiae, one F. sporotrichioides and seven F. graminearum, plus F. austroamericanum, F. meridionale, F. graminearum sensu stricto and F. cortaderiae from the NRRL collection were analysed, and only F. poae isolates gave a positive result for the presence of a 296-bp partial tri7 DNA fragment. Moreover, the primer set was tested from cereal seed samples where F. poae and other Fusarium species with a negative result for the specific reaction ( F. graminearum, F. oxysporum, F. chlamydosporum, F. sporotrichioides, F. equiseti and F. acuminatum) were isolated, and the expected fragment was amplified. We developed a rapid and reliable PCR assay to detect potential nivalenol-producing F. poae isolates. PMID- 22536947 TI - Developmental haemostasis for factor V and factor VIII levels in neonates: a case report of spontaneous cephalhaematoma. AB - Combined factor V and VIII deficiency is a rare bleeding disorder. Diagnosis of congenital coagulation factor deficiency in a neonate is challenging due to "immaturity" of the hemostatic system. A 2-day-old baby girl presented with spontaneous cephalhematoma. She was found to have persistent abnormal coagulation tests and finally diagnosed as combined factor V and VIII deficiency. Interestingly, factor V and factor VIII in developmental hemostasis are quite similar with adult levels in newborn, and hence early diagnosis is possible. An investigation to detect underlying hemostatic defects is recommended in newborns with spontaneous cephalhematoma. PMID- 22536944 TI - Synthesis and biological evaluation of the first dual tyrosyl-DNA phosphodiesterase I (Tdp1)-topoisomerase I (Top1) inhibitors. AB - Substances with dual tyrosyl-DNA phosphodiesterase I-topoisomerase I inhibitory activity in one low molecular weight compound would constitute a unique class of anticancer agents that could potentially have significant advantages over drugs that work against the individual enzymes. The present study demonstrates the successful synthesis and evaluation of the first dual Top1-Tdp1 inhibitors, which are based on the indenoisoquinoline chemotype. One bis(indenoisoquinoline) had significant activity against human Tdp1 (IC(50) = 1.52 +/- 0.05 MUM), and it was also equipotent to camptothecin as a Top1 inhibitor. Significant insights into enzyme-drug interactions were gained via structure-activity relationship studies of the series. The present results also document the failure of the previously reported sulfonyl ester pharmacophore to confer Tdp1 inhibition in this indenoisoquinoline class of inhibitors even though it was demonstrated to work well for the steroid NSC 88915 (7). The current study will facilitate future efforts to optimize dual Top1-Tdp1 inhibitors. PMID- 22536948 TI - Topiramate for migraine prevention: an update. PMID- 22536949 TI - Blood graft composition after plerixafor injection in patients with NHL. AB - BACKGROUND: Plerixafor is used to mobilize CD34(+) hematopoietic stem cells from bone marrow to circulation. Limited data are available in regard to graft cellular content collected after plerixafor. OBJECTIVES: The aim of this study was to assess effects of plerixafor added to chemomobilization on graft CD34(+) cell subclasses, lymphocyte subsets, engraftment, and post-transplant course in non-Hodgkin lymphoma (NHL) patients. METHODS: Thirty-four patients with NHL were included. All patients received chemotherapy plus G-CSF to mobilize stem cells. Nineteen patients received plerixafor pre-emptively owing to poor mobilization or poor collection yields. The rest of the patients constituted the control group. Flow cytometric analyzes were performed from cryopreserved graft samples. Also, data on post-transplant engraftment and outcome were collected. RESULTS: The proportion of primitive stem cells (CD34(+) CD133(+) CD38(-) ) was significantly higher after the plerixafor injection when compared to the first collection in the control group. The amount of T cells (CD3(+) ), helper (CD3(+) CD4(+) ) T subsets, and suppressor (CD3(+) CD8(+) ) T subsets in the graft was all significantly higher in the plerixafor group. Also, the amount of NK cells (CD3(-) CD16/56(+) ) was higher. Engraftment after high-dose therapy was comparable between the groups, but leukocyte and platelet count at 6 months were higher in patients receiving plerixafor-mobilized grafts. CONCLUSION: Plerixafor, when used pre-emptively in addition to chemomobilization, seems to mobilize more primitive CD34(+) stem cells, T lymphocytes, and NK cells. Whether these differences are associated with immune reconstitution, long-term engraftment, or patient outcomes needs to be evaluated in larger patient groups with longer follow-up. PMID- 22536950 TI - A small-molecule probe of the histone methyltransferase G9a induces cellular senescence in pancreatic adenocarcinoma. AB - Post-translational modifications of histones alter chromatin structure and play key roles in gene expression and specification of cell states. Small molecules that target chromatin-modifying enzymes selectively are useful as probes and have promise as therapeutics, although very few are currently available. G9a (also named euchromatin histone methyltransferase 2 (EHMT2)) catalyzes methylation of lysine 9 on histone H3 (H3K9), a modification linked to aberrant silencing of tumor-suppressor genes, among others. Here, we report the discovery of a novel histone methyltransferase inhibitor, BRD4770. This compound reduced cellular levels of di- and trimethylated H3K9 without inducing apoptosis, induced senescence, and inhibited both anchorage-dependent and -independent proliferation in the pancreatic cancer cell line PANC-1. ATM-pathway activation, caused by either genetic or small-molecule inhibition of G9a, may mediate BRD4770-induced cell senescence. BRD4770 may be a useful tool to study G9a and its role in senescence and cancer cell biology. PMID- 22536951 TI - Adapted bikes: what children and young people with cerebral palsy told us about their participation in adapted dynamic cycling. AB - PURPOSE: Children and young people with Cerebral Palsy have limited opportunities for participation and there has been limited research to explore this concept. Adapted dynamic cycling (ADC) is one activity that can enable them to participate in the community. The aim of this paper is to report the views and experiences of children and young people with CP and their families regarding their participation in ADC. METHODS: This was part of a mixed methods study of which the qualitative findings are reported here. Iterative creative methods were developed which involved semi-structured interviews and diaries about the ADC experience. RESULTS: The themes that emerged were the staff and the environment at the cycling hire project, the facilitators and barriers to ADC, the technical set up of the bike and the impact on the child and family in terms of developments over time, future aspirations, learning cycling skills, social participation and health benefits. CONCLUSIONS: The data showed that children's experiences of ADC were fun and enjoyable. This fun exercise should be incorporated into a physiotherapy programme as part of the child or young person with CP's rehabilitation. Policy makers and parents may find the information useful to increase the child's participation. PMID- 22536952 TI - Systematic comparison of fractionation methods for in-depth analysis of plasma proteomes. AB - Discovery and validation of plasma biomarkers are quite challenging because of the high complexity and wide dynamic range of the plasma proteome. Current plasma protein profiling strategies usually use major protein immunodepletion and nanoLC MS/MS as the first and final analytical steps, respectively, but additional fractionation is needed to detect and quantify low-abundance disease biomarkers. In this study, the performances of 1-D SDS-PAGE, peptide isoelectrofocusing, and peptide high pH reverse-phase chromatography for fractionation of immunodepleted human plasma were systematically compared by evaluating protein coverage, peptide resolution, and capacity to detect known low-abundance proteins. Trade-offs between increasing the number of fractions to improve proteome coverage and resulting decreases in throughput also were assessed. High pH reverse-phase HPLC exhibited the highest peptide resolution and yielded the best depth of analysis with detection of the largest number of known low-abundance proteins for a given level of fractionation. Another advantage of using high pH reverse-phase fractionation rather than 1-D SDS gels is that all fractionation steps except for abundant protein depletion occur at the peptide level, making this strategy more compatible with quantitative biomarker validation methods such as stable isotope dilution multiple reaction monitoring. PMID- 22536954 TI - Bioinformatics in Italy: BITS2011, the Eighth Annual Meeting of the Italian Society of Bioinformatics. AB - The BITS2011 meeting, held in Pisa on June 20-22, 2011, brought together more than 120 Italian researchers working in the field of Bioinformatics, as well as students in Bioinformatics, Computational Biology, Biology, Computer Sciences, and Engineering, representing a landscape of Italian bioinformatics research.This preface provides a brief overview of the meeting and introduces the peer-reviewed manuscripts that were accepted for publication in this Supplement. PMID- 22536953 TI - The alpha7 nicotinic ACh receptor agonist compound B and positive allosteric modulator PNU-120596 both alleviate inflammatory hyperalgesia and cytokine release in the rat. AB - BACKGROUND AND PURPOSE: Agonists selective for the alpha7 nicotinic acetylcholine (nACh) receptor produce anti-hyperalgesic effects in rodent models of inflammatory pain, via direct actions on spinal pain circuits and possibly via attenuated release of peripheral pro-inflammatory mediators. Increasingly, allosteric modulation of ligand-gated receptors is recognized as a potential strategy to obtain desired efficacy in the absence of the putative adverse effects associated with agonist activation. EXPERIMENTAL APPROACH: We compared the anti-hyperalgesic and anti-inflammatory effects of the alpha7 nACh receptor agonist compound B with the positive allosteric modulator (PAM) PNU-120596 and the standard non-steroidal anti-inflammatory drug (NSAID), diclofenac, in rats with hind paw inflammation induced by either formalin, carrageenan or complete Freund's adjuvant (CFA). KEY RESULTS: When administered before carrageenan, both diclofenac (30 mg.kg(-1) ) and PNU-120596 (30 mg.kg(-1) ) significantly reduced mechanical hyperalgesia and weight-bearing deficits for up to 4 h. Compound B (30 mg.kg(-1) ) also attenuated both measures of pain-like behaviour, albeit less robustly. Whereas compound B and PNU-120596 attenuated the carrageenan-induced increase in levels of TNF-alpha and IL-6 within the hind paw oedema, diclofenac only attenuated IL-6 levels. Established mechanical hyperalgesia induced by carrageenan or CFA was also partially reversed by compound B and PNU-120596. However, diclofenac was considerably more efficacious. Formalin-induced nocifensive behaviours were only reversed by compound B, albeit at doses which disrupted motor performance. CONCLUSIONS AND IMPLICATIONS: alpha7 nACh receptor PAMs could prove to be useful in the treatment of inflammatory pain conditions, which respond poorly to NSAIDs or in situations where NSAIDs are contra indicated. PMID- 22536955 TI - Accurate multiple sequence alignment of transmembrane proteins with PSI-Coffee. AB - BACKGROUND: Transmembrane proteins (TMPs) constitute about 20~30% of all protein coding genes. The relative lack of experimental structure has so far made it hard to develop specific alignment methods and the current state of the art (PRALINETM) only manages to recapitulate 50% of the positions in the reference alignments available from the BAliBASE2-ref7. METHODS: We show how homology extension can be adapted and combined with a consistency based approach in order to significantly improve the multiple sequence alignment of alpha-helical TMPs. TM-Coffee is a special mode of PSI-Coffee able to efficiently align TMPs, while using a reduced reference database for homology extension. RESULTS: Our benchmarking on BAliBASE2-ref7 alpha-helical TMPs shows a significant improvement over the most accurate methods such as MSAProbs, Kalign, PROMALS, MAFFT, ProbCons and PRALINETM. We also estimated the influence of the database used for homology extension and show that highly non-redundant UniRef databases can be used to obtain similar results at a significantly reduced computational cost over full protein databases. TM-Coffee is part of the T-Coffee package, a web server is also available from http://tcoffee.crg.cat/tmcoffee and a freeware open source code can be downloaded from http://www.tcoffee.org/Packages/Stable/Latest. PMID- 22536956 TI - Stochastic simulations of minimal cells: the Ribocell model. AB - BACKGROUND: Over the last two decades, lipid compartments (liposomes, lipid coated droplets) have been extensively used as in vitro "minimal" cell models. In particular, simple and complex biomolecular reactions have been carried out inside these self-assembled micro- and nano-sized compartments, leading to the synthesis of RNA and functional proteins inside liposomes. Despite this experimental progress, a detailed physical understanding of the underlying dynamics is missing. In particular, the combination of solute compartmentalization, reactivity and stochastic effects has not yet been clarified. A combination of experimental and computational approaches can reveal interesting mechanisms governing the behavior of micro compartmentalized systems, in particular by highlighting the intrinsic stochastic diversity within a population of "synthetic cells". METHODS: In this context, we have developed a computational platform called ENVIRONMENT suitable for studying the stochastic time evolution of reacting lipid compartments. This software - which implements a Gillespie Algorithm - is an improvement over a previous program that simulated the stochastic time evolution of homogeneous, fixed-volume, chemically reacting systems, extending it to more general conditions in which a collection of similar such systems interact and change over the course of time. In particular, our approach is focused on elucidating the role of randomness in the time behavior of chemically reacting lipid compartments, such as micelles, vesicles or micro emulsions, in regimes where random fluctuations due to the stochastic nature of reacting events can lead an open system towards unexpected time evolutions. RESULTS: This paper analyses the so-called Ribocell (RNA-based cell) model. It consists in a hypothetical minimal cell based on a self-replicating minimum RNA genome coupled with a self-reproducing lipid vesicle compartment. This model assumes the existence of two ribozymes, one able to catalyze the conversion of molecular precursors into lipids and the second able to replicate RNA strands. The aim of this contribution is to explore the feasibility of this hypothetical minimal cell. By deterministic kinetic analysis, the best external conditions to observe synchronization between genome self-replication and vesicle membrane reproduction are determined, while its robustness to random fluctuations is investigated using stochastic simulations, and then discussed. PMID- 22536957 TI - Characterization of an inducible promoter in different DNA copy number conditions. AB - BACKGROUND: The bottom-up programming of living organisms to implement novel user defined biological capabilities is one of the main goals of synthetic biology. Currently, a predominant problem connected with the construction of even simple synthetic biological systems is the unpredictability of the genetic circuitry when assembled and incorporated in living cells. Copy number, transcriptional/translational demand and toxicity of the DNA-encoded functions are some of the major factors which may lead to cell overburdening and thus to nonlinear effects on system output. It is important to disclose the linearity working boundaries of engineered biological systems when dealing with such phenomena. RESULTS: The output of an N-3-oxohexanoyl-L-homoserine lactone (HSL) inducible RFP-expressing device was studied in Escherichia coli in different copy number contexts, ranging from 1 copy per cell (integrated in the genome) to hundreds (via multicopy plasmids). The system is composed by a luxR constitutive expression cassette and a RFP gene regulated by the luxI promoter, which is activated by the HSL-LuxR complex. System output, in terms of promoter activity as a function of HSL concentration, was assessed relative to the one of a reference promoter in identical conditions by using the Relative Promoter Units (RPU) approach. Nonlinear effects were observed in the maximum activity, which is identical in single and low copy conditions, while it decreases for higher copy number conditions. In order to properly compare the luxI promoter strength among all the conditions, a mathematical modeling approach was used to relate the promoter activity to the estimated HSL-LuxR complex concentration, which is the actual activator of transcription. During model fitting, a correlation between the copy number and the dissociation constant of HSL-LuxR complex and luxI promoter was observed. CONCLUSIONS: Even in a simple inducible system, nonlinear effects are observed and non-trivial data processing is necessary to fully characterize its operation. The in-depth analysis of model systems like this can contribute to the advances in the synthetic biology field, since increasing the knowledge about linearity and working boundaries of biological phenomena could lead to a more rational design of artificial systems, also through mathematical models, which, for example, have been used here to study hard-to-predict interactions. PMID- 22536958 TI - In-silico and in-vivo analyses of EST databases unveil conserved miRNAs from Carthamus tinctorius and Cynara cardunculus. AB - BACKGROUND: MicroRNAs (miRNAs) are small RNAs (21-24 bp) providing an RNA-based system of gene regulation highly conserved in plants and animals. In plants, miRNAs control mRNA degradation or restrain translation, affecting development and responses to stresses. Plant miRNAs show imperfect but extensive complementarity to mRNA targets, making their computational prediction possible, useful when data mining is applied on different species. In this study we used a comparative approach to identify both miRNAs and their targets, in artichoke and safflower. RESULTS: Two complete expressed sequence tags (ESTs) datasets from artichoke (3.6 . 10(4) entries) and safflower (4.2 . 10(4)), were analysed with a bioinformatic pipeline and in vitro experiments, identifying 17 potential miRNAs. For each EST, using RNAhybrid program and 953 non redundant miRNA mature sequences, available in mirBase as reference, we searched matching putative targets. 8730 out of 42011 ESTs from safflower and 7145 of 36323 ESTs from artichoke showed at least one predicted miRNA target. BLAST analysis showed that 75% of all ESTs shared at least a common homologous region (E-value < 10(-4)) and about 50% of these displayed 400 bp or longer aligned sequences as conserved homologous/orthologous (COS) regions. 960 and 890 ESTs of safflower and artichoke organized in COS shared 79 different miRNA targets, considered functionally conserved, and statistically significant when compared with random sequences (signal to noise ratio > 2 and specificity >= 0.85). Four highly significant miRNAs selected from in silico data were experimentally validated in globe artichoke leaves. CONCLUSIONS: Mature miRNAs and targets were predicted within EST sequences of safflower and artichoke. Most of the miRNA targets appeared highly/moderately conserved, highlighting an important and conserved function. In this study we introduce a stringent parameter for the comparative sequence analysis, represented by the identification of the same target in the COS region. After statistical analysis 79 targets, found on the COS regions and belonging to 60 miRNA families, have a signal to noise ratio > 2, with >= 0.85 specificity. The putative miRNAs identified belong to 55 dicotyledon plants and to 24 families only in monocotyledon. PMID- 22536959 TI - Design of a multi-signature ensemble classifier predicting neuroblastoma patients' outcome. AB - BACKGROUND: Neuroblastoma is the most common pediatric solid tumor of the sympathetic nervous system. Development of improved predictive tools for patients stratification is a crucial requirement for neuroblastoma therapy. Several studies utilized gene expression-based signatures to stratify neuroblastoma patients and demonstrated a clear advantage of adding genomic analysis to risk assessment. There is little overlapping among signatures and merging their prognostic potential would be advantageous. Here, we describe a new strategy to merge published neuroblastoma related gene signatures into a single, highly accurate, Multi-Signature Ensemble (MuSE)-classifier of neuroblastoma (NB) patients outcome. METHODS: Gene expression profiles of 182 neuroblastoma tumors, subdivided into three independent datasets, were used in the various phases of development and validation of neuroblastoma NB-MuSE-classifier. Thirty three signatures were evaluated for patients' outcome prediction using 22 classification algorithms each and generating 726 classifiers and prediction results. The best-performing algorithm for each signature was selected, validated on an independent dataset and the 20 signatures performing with an accuracy > = 80% were retained. RESULTS: We combined the 20 predictions associated to the corresponding signatures through the selection of the best performing algorithm into a single outcome predictor. The best performance was obtained by the Decision Table algorithm that produced the NB-MuSE-classifier characterized by an external validation accuracy of 94%. Kaplan-Meier curves and log-rank test demonstrated that patients with good and poor outcome prediction by the NB-MuSE classifier have a significantly different survival (p < 0.0001). Survival curves constructed on subgroups of patients divided on the bases of known prognostic marker suggested an excellent stratification of localized and stage 4s tumors but more data are needed to prove this point. CONCLUSIONS: The NB-MuSE-classifier is based on an ensemble approach that merges twenty heterogeneous, neuroblastoma related gene signatures to blend their discriminating power, rather than numeric values, into a single, highly accurate patients' outcome predictor. The novelty of our approach derives from the way to integrate the gene expression signatures, by optimally associating them with a single paradigm ultimately integrated into a single classifier. This model can be exported to other types of cancer and to diseases for which dedicated databases exist. PMID- 22536960 TI - Argot2: a large scale function prediction tool relying on semantic similarity of weighted Gene Ontology terms. AB - BACKGROUND: Predicting protein function has become increasingly demanding in the era of next generation sequencing technology. The task to assign a curator reviewed function to every single sequence is impracticable. Bioinformatics tools, easy to use and able to provide automatic and reliable annotations at a genomic scale, are necessary and urgent. In this scenario, the Gene Ontology has provided the means to standardize the annotation classification with a structured vocabulary which can be easily exploited by computational methods. RESULTS: Argot2 is a web-based function prediction tool able to annotate nucleic or protein sequences from small datasets up to entire genomes. It accepts as input a list of sequences in FASTA format, which are processed using BLAST and HMMER searches vs UniProKB and Pfam databases respectively; these sequences are then annotated with GO terms retrieved from the UniProtKB-GOA database and the terms are weighted using the e-values from BLAST and HMMER. The weighted GO terms are processed according to both their semantic similarity relations described by the Gene Ontology and their associated score. The algorithm is based on the original idea developed in a previous tool called Argot. The entire engine has been completely rewritten to improve both accuracy and computational efficiency, thus allowing for the annotation of complete genomes. CONCLUSIONS: The revised algorithm has been already employed and successfully tested during in-house genome projects of grape and apple, and has proven to have a high precision and recall in all our benchmark conditions. It has also been successfully compared with Blast2GO, one of the methods most commonly employed for sequence annotation. The server is freely accessible at http://www.medcomp.medicina.unipd.it/Argot2. PMID- 22536961 TI - Primates and mouse NumtS in the UCSC Genome Browser. AB - BACKGROUND: NumtS (Nuclear MiTochondrial Sequences) are mitochondrial DNA sequences that, after stress events involving the mitochondrion, colonized the nuclear genome. Accurate mapping of NumtS avoids contamination during mtDNA PCR amplification, thus supplying reliable bases for detecting false heteroplasmies. In addition, since they commonly populate mammalian genomes (especially primates) and are polymorphic, in terms of presence/absence and content of SNPs, they may be used as evolutionary markers in intra- and inter-species population analyses. RESULTS: The need for an exhaustive NumtS annotation led us to produce the Reference Human NumtS compilation, followed, as reported in this paper, by those for chimpanzee, rhesus macaque and mouse ones. Identification of NumtS inside the UCSC Genome Browser and their inter-species comparison required the design and the implementation of NumtS tracks, starting from the compilation data. NumtS retrieval through the UCSC Genome Browser, in the species examined, is now feasible at a glance. CONCLUSIONS: Analyses involving NumtS tracks, together with other genome element tracks publicly available at the UCSC Genome Browser, can provide deep insight into genome evolution and comparative genomics, thus improving studies dealing with the mechanisms that drove the generation of NumtS. In addition, the NumtS tracks constitute a useful tool in the design of mitochondrial DNA primers. PMID- 22536962 TI - Intuitive representation of surface properties of biomolecules using BioBlender. AB - BACKGROUND: In living cells, proteins are in continuous motion and interaction with the surrounding medium and/or other proteins and ligands. These interactions are mediated by protein features such as electrostatic and lipophilic potentials. The availability of protein structures enables the study of their surfaces and surface characteristics, based on atomic contribution. Traditionally, these properties are calculated by physico-chemical programs and visualized as range of colors that vary according to the tool used and imposes the necessity of a legend to decrypt it. The use of color to encode both characteristics makes the simultaneous visualization almost impossible, requiring these features to be visualized in different images. In this work, we describe a novel and intuitive code for the simultaneous visualization of these properties. METHODS: Recent advances in 3D animation and rendering software have not yet been exploited for the representation of biomolecules in an intuitive, animated form. For our purpose we use Blender, an open-source, free, cross-platform application used professionally for 3D work. On the basis Blender, we developed BioBlender, dedicated to biological work: elaboration of protein motion with simultaneous visualization of their chemical and physical features. Electrostatic and lipophilic potentials are calculated using physico-chemical software and scripts, organized and accessed through BioBlender interface. RESULTS: A new visual code is introduced for molecular lipophilic potential: a range of optical features going from smooth-shiny for hydrophobic regions to rough-dull for hydrophilic ones. Electrostatic potential is represented as animated line particles that flow along field lines, proportional to the total charge of the protein. CONCLUSIONS: Our system permits visualization of molecular features and, in the case of moving proteins, their continuous perception, calculated for each conformation during motion. Using real world tactile/sight feelings, the nanoscale world of proteins becomes more understandable, familiar to our everyday life, making it easier to introduce "un-seen" phenomena (concepts) such as hydropathy or charges. Moreover, this representation contributes to gain insight into molecular functions by drawing viewer's attention to the most active regions of the protein. The program, available for Windows, Linux and MacOS, can be downloaded freely from the dedicated website http://www.bioblender.eu. PMID- 22536963 TI - Identification of binding pockets in protein structures using a knowledge-based potential derived from local structural similarities. AB - BACKGROUND: The identification of ligand binding sites is a key task in the annotation of proteins with known structure but uncharacterized function. Here we describe a knowledge-based method exploiting the observation that unrelated binding sites share small structural motifs that bind the same chemical fragments irrespective of the nature of the ligand as a whole. RESULTS: PDBinder compares a query protein against a library of binding and non-binding protein surface regions derived from the PDB. The results of the comparison are used to derive a propensity value for each residue which is correlated with the likelihood that the residue is part of a ligand binding site. The method was applied to two different problems: i) the prediction of ligand binding residues and ii) the identification of which surface cleft harbours the binding site. In both cases PDBinder performed consistently better than existing methods. PDBinder has been trained on a non-redundant set of 1356 high-quality protein-ligand complexes and tested on a set of 239 holo and apo complex pairs. We obtained an MCC of 0.313 on the holo set with a PPV of 0.413 while on the apo set we achieved an MCC of 0.271 and a PPV of 0.372. CONCLUSIONS: We show that PDBinder performs better than existing methods. The good performance on the unbound proteins is extremely important for real-world applications where the location of the binding site is unknown. Moreover, since our approach is orthogonal to those used in other programs, the PDBinder propensity value can be integrated in other algorithms further increasing the final performance. PMID- 22536964 TI - Bluues: a program for the analysis of the electrostatic properties of proteins based on generalized Born radii. AB - BACKGROUND: The Poisson-Boltzmann (PB) equation and its linear approximation have been widely used to describe biomolecular electrostatics. Generalized Born (GB) models offer a convenient computational approximation for the more fundamental approach based on the Poisson-Boltzmann equation, and allows estimation of pairwise contributions to electrostatic effects in the molecular context. RESULTS: We have implemented in a single program most common analyses of the electrostatic properties of proteins. The program first computes generalized Born radii, via a surface integral and then it uses generalized Born radii (using a finite radius test particle) to perform electrostaic analyses. In particular the ouput of the program entails, depending on user's requirement: 1) the generalized Born radius of each atom; 2) the electrostatic solvation free energy; 3) the electrostatic forces on each atom (currently in a developmental stage); 4) the pH dependent properties (total charge and pH-dependent free energy of folding in the pH range -2 to 18; 5) the pKa of all ionizable groups; 6) the electrostatic potential at the surface of the molecule; 7) the electrostatic potential in a volume surrounding the molecule; CONCLUSIONS: Although at the expense of limited flexibility the program provides most common analyses with requirement of a single input file in PQR format. The results obtained are comparable to those obtained using state-of-the-art Poisson-Boltzmann solvers. A Linux executable with example input and output files is provided as supplementary material. PMID- 22536965 TI - CONS-COCOMAPS: a novel tool to measure and visualize the conservation of inter residue contacts in multiple docking solutions. AB - BACKGROUND: The development of accurate protein-protein docking programs is making this kind of simulations an effective tool to predict the 3D structure and the surface of interaction between the molecular partners in macromolecular complexes. However, correctly scoring multiple docking solutions is still an open problem. As a consequence, the accurate and tedious screening of many docking models is usually required in the analysis step. METHODS: All the programs under CONS-COCOMAPS have been written in python, taking advantage of python libraries such as SciPy and Matplotlib. CONS-COCOMAPS is freely available as a web tool at the URL:http://www.molnac.unisa.it/BioTools/conscocomaps/. RESULTS: Here we presented CONS-COCOMAPS, a novel tool to easily measure and visualize the consensus in multiple docking solutions. CONS-COCOMAPS uses the conservation of inter-residue contacts as an estimate of the similarity between different docking solutions. To visualize the conservation, CONS-COCOMAPS uses intermolecular contact maps. CONCLUSIONS: The application of CONS-COCOMAPS to test-cases taken from recent CAPRI rounds has shown that it is very efficient in highlighting even a very weak consensus that often is biologically meaningful. PMID- 22536966 TI - PyMod: sequence similarity searches, multiple sequence-structure alignments, and homology modeling within PyMOL. AB - BACKGROUND: In recent years, an exponential growing number of tools for protein sequence analysis, editing and modeling tasks have been put at the disposal of the scientific community. Despite the vast majority of these tools have been released as open source software, their deep learning curves often discourages even the most experienced users. RESULTS: A simple and intuitive interface, PyMod, between the popular molecular graphics system PyMOL and several other tools (i.e., [PSI-]BLAST, ClustalW, MUSCLE, CEalign and MODELLER) has been developed, to show how the integration of the individual steps required for homology modeling and sequence/structure analysis within the PyMOL framework can hugely simplify these tasks. Sequence similarity searches, multiple sequence and structural alignments generation and editing, and even the possibility to merge sequence and structure alignments have been implemented in PyMod, with the aim of creating a simple, yet powerful tool for sequence and structure analysis and building of homology models. CONCLUSIONS: PyMod represents a new tool for the analysis and the manipulation of protein sequences and structures. The ease of use, integration with many sequence retrieving and alignment tools and PyMOL, one of the most used molecular visualization system, are the key features of this tool.Source code, installation instructions, video tutorials and a user's guide are freely available at the URL http://schubert.bio.uniroma1.it/pymod/index.html. PMID- 22536967 TI - Modeling gene regulatory network motifs using Statecharts. AB - BACKGROUND: Gene regulatory networks are widely used by biologists to describe the interactions among genes, proteins and other components at the intra-cellular level. Recently, a great effort has been devoted to give gene regulatory networks a formal semantics based on existing computational frameworks.For this purpose, we consider Statecharts, which are a modular, hierarchical and executable formal model widely used to represent software systems. We use Statecharts for modeling small and recurring patterns of interactions in gene regulatory networks, called motifs. RESULTS: We present an improved method for modeling gene regulatory network motifs using Statecharts and we describe the successful modeling of several motifs, including those which could not be modeled or whose models could not be distinguished using the method of a previous proposal.We model motifs in an easy and intuitive way by taking advantage of the visual features of Statecharts. Our modeling approach is able to simulate some interesting temporal properties of gene regulatory network motifs: the delay in the activation and the deactivation of the "output" gene in the coherent type-1 feedforward loop, the pulse in the incoherent type-1 feedforward loop, the bistability nature of double positive and double negative feedback loops, the oscillatory behavior of the negative feedback loop, and the "lock-in" effect of positive autoregulation. CONCLUSIONS: We present a Statecharts-based approach for the modeling of gene regulatory network motifs in biological systems. The basic motifs used to build more complex networks (that is, simple regulation, reciprocal regulation, feedback loop, feedforward loop, and autoregulation) can be faithfully described and their temporal dynamics can be analyzed. PMID- 22536968 TI - BEAT: Bioinformatics Exon Array Tool to store, analyze and visualize Affymetrix GeneChip Human Exon Array data from disease experiments. AB - BACKGROUND: It is known from recent studies that more than 90% of human multi exon genes are subject to Alternative Splicing (AS), a key molecular mechanism in which multiple transcripts may be generated from a single gene. It is widely recognized that a breakdown in AS mechanisms plays an important role in cellular differentiation and pathologies. Polymerase Chain Reactions, microarrays and sequencing technologies have been applied to the study of transcript diversity arising from alternative expression. Last generation Affymetrix GeneChip Human Exon 1.0 ST Arrays offer a more detailed view of the gene expression profile providing information on the AS patterns. The exon array technology, with more than five million data points, can detect approximately one million exons, and it allows performing analyses at both gene and exon level. In this paper we describe BEAT, an integrated user-friendly bioinformatics framework to store, analyze and visualize exon arrays datasets. It combines a data warehouse approach with some rigorous statistical methods for assessing the AS of genes involved in diseases. Meta statistics are proposed as a novel approach to explore the analysis results. BEAT is available at http://beat.ba.itb.cnr.it. RESULTS: BEAT is a web tool which allows uploading and analyzing exon array datasets using standard statistical methods and an easy-to-use graphical web front-end. BEAT has been tested on a dataset with 173 samples and tuned using new datasets of exon array experiments from 28 colorectal cancer and 26 renal cell cancer samples produced at the Medical Genetics Unit of IRCCS Casa Sollievo della Sofferenza.To highlight all possible AS events, alternative names, accession Ids, Gene Ontology terms and biochemical pathways annotations are integrated with exon and gene level expression plots. The user can customize the results choosing custom thresholds for the statistical parameters and exploiting the available clinical data of the samples for a multivariate AS analysis. CONCLUSIONS: Despite exon array chips being widely used for transcriptomics studies, there is a lack of analysis tools offering advanced statistical features and requiring no programming knowledge. BEAT provides a user-friendly platform for a comprehensive study of AS events in human diseases, displaying the analysis results with easily interpretable and interactive tables and graphics. PMID- 22536969 TI - Improving biomarker list stability by integration of biological knowledge in the learning process. AB - BACKGROUND: The identification of robust lists of molecular biomarkers related to a disease is a fundamental step for early diagnosis and treatment. However, methodologies for biomarker discovery using microarray data often provide results with limited overlap. It has been suggested that one reason for these inconsistencies may be that in complex diseases, such as cancer, multiple genes belonging to one or more physiological pathways are associated with the outcomes. Thus, a possible approach to improve list stability is to integrate biological information from genomic databases in the learning process; however, a comprehensive assessment based on different types of biological information is still lacking in the literature. In this work we have compared the effect of using different biological information in the learning process like functional annotations, protein-protein interactions and expression correlation among genes. RESULTS: Biological knowledge has been codified by means of gene similarity matrices and expression data linearly transformed in such a way that the more similar two features are, the more closely they are mapped. Two semantic similarity matrices, based on Biological Process and Molecular Function Gene Ontology annotation, and geodesic distance applied on protein-protein interaction networks, are the best performers in improving list stability maintaining almost equal prediction accuracy. CONCLUSIONS: The performed analysis supports the idea that when some features are strongly correlated to each other, for example because are close in the protein-protein interaction network, then they might have similar importance and are equally relevant for the task at hand. Obtained results can be a starting point for additional experiments on combining similarity matrices in order to obtain even more stable lists of biomarkers. The implementation of the classification algorithm is available at the link: http://www.math.unipd.it/~dasan/biomarkers.html. PMID- 22536970 TI - Tandem repeats discovery service (TReaDS) applied to finding novel cis-acting factors in repeat expansion diseases. AB - BACKGROUND: Tandem repeats are multiple duplications of substrings in the DNA that occur contiguously, or at a short distance, and may involve some mutations (such as substitutions, insertions, and deletions). Tandem repeats have been extensively studied also for their association with the class of repeat expansion diseases (mostly affecting the nervous system). Comparative studies on the output of different tools for finding tandem repeats highlighted significant differences among the sets of detected tandem repeats, while many authors pointed up how critical it is the right choice of parameters. RESULTS: In this paper we present TReaDS - Tandem Repeats Discovery Service, a tandem repeat meta search engine. TReaDS forwards user requests to several state of the art tools for finding tandem repeats and merges their outcome into a single report, providing a global, synthetic, and comparative view of the results. In particular, TReaDS allows the user to (i) simultaneously run different algorithms on the same data set, (ii) choose for each algorithm a different setting of parameters, and (iii) obtain a report that can be downloaded for further, off-line, investigations. We used TReaDS to investigate sequences associated with repeat expansion diseases. CONCLUSIONS: By using the tool TReaDS we discover that, for 27 repeat expansion diseases out of a currently known set of 29, long fuzzy tandem repeats are covering the expansion loci. Tests with control sets confirm the specificity of this association. This finding suggests that long fuzzy tandem repeats can be a new class of cis-acting elements involved in the mechanisms leading to the expansion instability.We strongly believe that biologists can be interested in a tool that, not only gives them the possibility of using multiple search algorithm at the same time, with the same effort exerted in using just one of the systems, but also simplifies the burden of comparing and merging the results, thus expanding our capabilities in detecting important phenomena related to tandem repeats. PMID- 22536971 TI - GIDL: a rule based expert system for GenBank Intelligent Data Loading into the Molecular Biodiversity Database. AB - BACKGROUND: In the scientific biodiversity community, it is increasingly perceived the need to build a bridge between molecular and traditional biodiversity studies. We believe that the information technology could have a preeminent role in integrating the information generated by these studies with the large amount of molecular data we can find in bioinformatics public databases. This work is primarily aimed at building a bioinformatic infrastructure for the integration of public and private biodiversity data through the development of GIDL, an Intelligent Data Loader coupled with the Molecular Biodiversity Database. The system presented here organizes in an ontological way and locally stores the sequence and annotation data contained in the GenBank primary database. METHODS: The GIDL architecture consists of a relational database and of an intelligent data loader software. The relational database schema is designed to manage biodiversity information (Molecular Biodiversity Database) and it is organized in four areas: MolecularData, Experiment, Collection and Taxonomy. The MolecularData area is inspired to an established standard in Generic Model Organism Databases, the Chado relational schema. The peculiarity of Chado, and also its strength, is the adoption of an ontological schema which makes use of the Sequence Ontology. The Intelligent Data Loader (IDL) component of GIDL is an Extract, Transform and Load software able to parse data, to discover hidden information in the GenBank entries and to populate the Molecular Biodiversity Database. The IDL is composed by three main modules: the Parser, able to parse GenBank flat files; the Reasoner, which automatically builds CLIPS facts mapping the biological knowledge expressed by the Sequence Ontology; the DBFiller, which translates the CLIPS facts into ordered SQL statements used to populate the database. In GIDL Semantic Web technologies have been adopted due to their advantages in data representation, integration and processing. RESULTS AND CONCLUSIONS: Entries coming from Virus (814,122), Plant (1,365,360) and Invertebrate (959,065) divisions of GenBank rel.180 have been loaded in the Molecular Biodiversity Database by GIDL. Our system, combining the Sequence Ontology and the Chado schema, allows a more powerful query expressiveness compared with the most commonly used sequence retrieval systems like Entrez or SRS. PMID- 22536972 TI - An ICT infrastructure to integrate clinical and molecular data in oncology research. AB - BACKGROUND: The ONCO-i2b2 platform is a bioinformatics tool designed to integrate clinical and research data and support translational research in oncology. It is implemented by the University of Pavia and the IRCCS Fondazione Maugeri hospital (FSM), and grounded on the software developed by the Informatics for Integrating Biology and the Bedside (i2b2) research center. I2b2 has delivered an open source suite based on a data warehouse, which is efficiently interrogated to find sets of interesting patients through a query tool interface. METHODS: Onco-i2b2 integrates data coming from multiple sources and allows the users to jointly query them. I2b2 data are then stored in a data warehouse, where facts are hierarchically structured as ontologies. Onco-i2b2 gathers data from the FSM pathology unit (PU) database and from the hospital biobank and merges them with the clinical information from the hospital information system. Our main effort was to provide a robust integrated research environment, giving a particular emphasis to the integration process and facing different challenges, consecutively listed: biospecimen samples privacy and anonymization; synchronization of the biobank database with the i2b2 data warehouse through a series of Extract, Transform, Load (ETL) operations; development and integration of a Natural Language Processing (NLP) module, to retrieve coded information, such as SNOMED terms and malignant tumors (TNM) classifications, and clinical tests results from unstructured medical records. Furthermore, we have developed an internal SNOMED ontology rested on the NCBO BioPortal web services. RESULTS: Onco-i2b2 manages data of more than 6,500 patients with breast cancer diagnosis collected between 2001 and 2011 (over 390 of them have at least one biological sample in the cancer biobank), more than 47,000 visits and 96,000 observations over 960 medical concepts. CONCLUSIONS: Onco-i2b2 is a concrete example of how integrated Information and Communication Technology architecture can be implemented to support translational research. The next steps of our project will involve the extension of its capabilities by implementing new plug-in devoted to bioinformatics data analysis as well as a temporal query module. PMID- 22536973 TI - OREMPdb: a semantic dictionary of computational pathway models. AB - BACKGROUND: The information coming from biomedical ontologies and computational pathway models is expanding continuously: research communities keep this process up and their advances are generally shared by means of dedicated resources published on the web. In fact, such models are shared to provide the characterization of molecular processes, while biomedical ontologies detail a semantic context to the majority of those pathways. Recent advances in both fields pave the way for a scalable information integration based on aggregate knowledge repositories, but the lack of overall standard formats impedes this progress. Indeed, having different objectives and different abstraction levels, most of these resources "speak" different languages. Semantic web technologies are here explored as a means to address some of these problems. METHODS: Employing an extensible collection of interpreters, we developed OREMP (Ontology Reasoning Engine for Molecular Pathways), a system that abstracts the information from different resources and combines them together into a coherent ontology. Continuing this effort we present OREMPdb; once different pathways are fed into OREMP, species are linked to the external ontologies referred and to reactions in which they participate. Exploiting these links, the system builds species-sets, which encapsulate species that operate together. Composing all of the reactions together, the system computes all of the reaction paths from-and-to all of the species-sets. RESULTS: OREMP has been applied to the curated branch of BioModels (2011/04/15 release) which overall contains 326 models, 9244 reactions, and 5636 species. OREMPdb is the semantic dictionary created as a result, which is made of 7360 species-sets. For each one of these sets, OREMPdb links the original pathway and the link to the original paper where this information first appeared. PMID- 22536974 TI - Towards linked open gene mutations data. AB - BACKGROUND: With the advent of high-throughput technologies, a great wealth of variation data is being produced. Such information may constitute the basis for correlation analyses between genotypes and phenotypes and, in the future, for personalized medicine. Several databases on gene variation exist, but this kind of information is still scarce in the Semantic Web framework. In this paper, we discuss issues related to the integration of mutation data in the Linked Open Data infrastructure, part of the Semantic Web framework. We present the development of a mapping from the IARC TP53 Mutation database to RDF and the implementation of servers publishing this data. METHODS: A version of the IARC TP53 Mutation database implemented in a relational database was used as first test set. Automatic mappings to RDF were first created by using D2RQ and later manually refined by introducing concepts and properties from domain vocabularies and ontologies, as well as links to Linked Open Data implementations of various systems of biomedical interest. Since D2RQ query performances are lower than those that can be achieved by using an RDF archive, generated data was also loaded into a dedicated system based on tools from the Jena software suite. RESULTS: We have implemented a D2RQ Server for TP53 mutation data, providing data on a subset of the IARC database, including gene variations, somatic mutations, and bibliographic references. The server allows to browse the RDF graph by using links both between classes and to external systems. An alternative interface offers improved performances for SPARQL queries. The resulting data can be explored by using any Semantic Web browser or application. CONCLUSIONS: This has been the first case of a mutation database exposed as Linked Data. A revised version of our prototype, including further concepts and IARC TP53 Mutation database data sets, is under development.The publication of variation information as Linked Data opens new perspectives: the exploitation of SPARQL searches on mutation data and other biological databases may support data retrieval which is presently not possible. Moreover, reasoning on integrated variation data may support discoveries towards personalized medicine. PMID- 22536975 TI - Fine-tuning anti-tumor immunotherapies via stochastic simulations. AB - BACKGROUND: Anti-tumor therapies aim at reducing to zero the number of tumor cells in a host within their end or, at least, aim at leaving the patient with a sufficiently small number of tumor cells so that the residual tumor can be eradicated by the immune system. Besides severe side-effects, a key problem of such therapies is finding a suitable scheduling of their administration to the patients. In this paper we study the effect of varying therapy-related parameters on the final outcome of the interplay between a tumor and the immune system. RESULTS: This work generalizes our previous study on hybrid models of such an interplay where interleukins are modeled as a continuous variable, and the tumor and the immune system as a discrete-state continuous-time stochastic process. The hybrid model we use is obtained by modifying the corresponding deterministic model, originally proposed by Kirschner and Panetta. We consider Adoptive Cellular Immunotherapies and Interleukin-based therapies, as well as their combination. By asymptotic and transitory analyses of the corresponding deterministic model we find conditions guaranteeing tumor eradication, and we tune the parameters of the hybrid model accordingly. We then perform stochastic simulations of the hybrid model under various therapeutic settings: constant, piece-wise constant or impulsive infusion and daily or weekly delivery schedules. CONCLUSIONS: Results suggest that, in some cases, the delivery schedule may deeply impact on the therapy-induced tumor eradication time. Indeed, our model suggests that Interleukin-based therapies may not be effective for every patient, and that the piece-wise constant is the most effective delivery to stimulate the immune-response. For Adoptive Cellular Immunotherapies a metronomic delivery seems more effective, as it happens for other anti-angiogenesis therapies and chemotherapies, and the impulsive delivery seems more effective than the piece wise constant. The expected synergistic effects have been observed when the therapies are combined. PMID- 22536976 TI - Characterization of the emergent properties of a synthetic quasi-cellular system. AB - BACKGROUND: The process of solutes entrapment during liposomes formation is interesting for the investigation of the relationship between the formation of compartments and the distribution of molecules inside them; a relevant issue in the studies of the origin of life. Theoretically, when no interactions are supposed among the chemical species to be entrapped, the entrapment is described by a standard Poisson process. But very recent experimental findings show that, for small liposomes (100 nm diameter), the distribution of entrapped molecules is best described by a power-law function. This is of a great importance, as the two random processes give rise to two completely different scenarios. Here we present an in silico stochastic simulation of the encapsulation of a cell-free molecular translation system (the PURE system), obtained following two different entrapment models: a pure Poisson process, and a power-law. The protein synthesis inside the liposomes has been studied in both cases, with the aim to highlight experimental observables that could be measured to assess which model gives a better representation of the real process. RESULTS: Firstly, a minimal model for in vitro protein synthesis, based on the PURE system molecular composition, has been formalized. Then, we have designed a reliable experimental simulation where stochastic factors affect the reaction course inside the compartment. To this end, 24 solutes, which represent the PURE system components, have been stochastically distributed among vesicles by following either a Poisson or a power-law distribution. The course of the protein synthesis within each vesicle has been consequently calculated, as a function of vesicle size. Our study can predict translation yield in a population of small liposomes down to the attoliter (10(-18) L) range. Our results show that the efficiency of protein synthesis peaks at approximately 3 . 10(-16) L (840 nm diam.) with a Poisson distribution of solutes, while a relative optimum is found at around 10(-17) L (275 nm diam.) for the power-law statistics. CONCLUSIONS: Our simulation clearly shows that the wet-lab measurement of an effective protein synthesis at smaller volumes than 10(-17) L would rule out, according to our models, a Poisson distribution of solutes. PMID- 22536978 TI - Algorithm for early diagnosis in nontuberculous mycobacterial lymphadenitis. PMID- 22536979 TI - Breast imaging for interventional pathologists. AB - CONTEXT: Pathologist-performed, ultrasound-guided fine-needle aspiration biopsy is one of the frontiers of pathology. The College of American Pathologists, American Society for Clinical Pathology, and American Society of Cytopathology offer courses and certificate programs for pathologists in this area. The courses emphasize the biopsy of masses in the thyroid and head and neck. There is little training in ultrasound-guided biopsy of breast masses. To successfully perform an imaging-guided biopsy of the breast, pathologists should understand the basics of mammography and breast ultrasound. OBJECTIVE: To review the basics of mammography and breast ultrasound to help interventional pathologists add ultrasound-guided, fine-needle aspiration and core-needle biopsies of the breast to their list of core competencies. DATA SOURCES: Classic and recent literature and textbooks on mammography and breast ultrasound. CONCLUSIONS: The heart of early breast cancer detection is the screening mammogram. Abnormalities detected on screening, such as masses, densities, architectural distortions, nipple retraction, skin thickening, abnormal lymph nodes, and microcalcifications, will lead to a diagnostic mammogram and/or breast ultrasound. Lesions classified as Breast Imaging Reporting and Data System 4 or 5, and a few classified as 3 lesions, require biopsy. If the lesion is visible on ultrasound, ultrasound-guided fine needle aspiration biopsy and/or core-needle biopsy is the procedure of choice. Suspicious lesions visible only on mammogram require stereotactic x-ray-guided biopsy. Interventional pathologists who understand the values and limitations of mammography and breast ultrasound are ready for the challenges of pathologist performed, ultrasound-guided, fine-needle aspiration and core-needle biopsies of the breast. PMID- 22536980 TI - The association of individual characteristics and neighborhood poverty on the dental care of American adolescents. AB - OBJECTIVE: The purpose of this study was to explore the extent to which neighborhood poverty was associated with the utilization of dental care by American adolescents. METHODS: To accomplish the study goals we conducted multilevel modeling analyses of two nationally representative data sets: National Longitudinal Study of Adolescent Health (Add Health) and the Early Childhood Longitudinal Study, Kindergarten Class of 1998-1999 (ECLS-K). RESULTS: As hypothesized, neighborhood poverty predicted frequency of dental care in both studies (t = 6.06; P < 0.001; t = 2.44; P < 0.05). Even after accounting for individual level predictors such as household income, health insurance, and parental education, adolescents living in poor neighborhoods are less likely than their counterparts in non-poor neighborhoods to utilize dental care. CONCLUSIONS: The findings from this study indicate that neighborhoods influence dental care utilization patterns in adolescents. PMID- 22536977 TI - Decoupling polymer properties to elucidate mechanisms governing cell behavior. AB - Determining how a biomaterial interacts with cells ("structure-function relationship") reflects its eventual clinical applicability. Therefore, a fundamental understanding of how individual material properties modulate cell biomaterial interactions is pivotal to improving the efficacy and safety of clinically translatable biomaterial systems. However, due to the coupled nature of material properties, their individual effects on cellular responses are difficult to understand. Structure-function relationships can be more clearly understood by the effective decoupling of each individual parameter. In this article, we discuss three basic decoupling strategies: (1) surface modification, (2) cross-linking, and (3) combinatorial approaches (i.e., copolymerization and polymer blending). Relevant examples of coupled material properties are briefly reviewed in each section to highlight the need for improved decoupling methods. This follows with examples of more effective decoupling techniques, mainly from the perspective of three primary classes of synthetic materials: polyesters, polyethylene glycol, and polyacrylamide. Recent strides in decoupling methodologies, especially surface-patterning and combinatorial techniques, offer much promise in further understanding the structure-function relationships that largely govern the success of future advancements in biomaterials, tissue engineering, and drug delivery. PMID- 22536981 TI - Mn-promoted aerobic oxidative C-C bond cleavage of aldehydes with dioxygen activation: a simple synthetic approach to formamides. AB - A novel Mn-promoted aerobic oxidative C-C bond cleavage of aldehydes with dioxygen activation has been developed. The usage of molecular oxygen (1 atm) as oxidant, reactant, and an initiator to trigger this transformation makes this transformation very green and practical. A plausible radical process is proposed on the basis of mechanistic studies. Furthermore, this method provides a practical, neutral, and mild synthetic approach to formamides, which are important units in biologically active molecules. PMID- 22536982 TI - Bacterial lipopolysaccharide protects the retina from light-induced damage. AB - Light-induced damage is a widely used model to study retinal degeneration. We examined whether bacterial lipopolysaccharide (LPS) protects the retina against light-induced injury. One day before intense light exposure for 24 h, rats were intravitreally injected with LPS in one eye and vehicle in the contralateral eye. At several time points after light exposure, rats were subjected to electroretinography and histological analysis. Bax, Bcl-xL, p-Akt, and p-Stat3 levels were assessed by Western blotting, and retinal thiobarbituric acid reactive substances levels were measured as an index of lipid peroxidation. One group of animals received injections of dexamethasone, aminoguanidine (an inducible NOS inhibitor), 5-hydroxydecanoic acid (a mitochondrial K(+) /ATP channel blocker), or wortmannin [a phosphoinositide-3-kinase (PI3K) inhibitor] in order to analyze their effect on the protection induced by LPS. LPS afforded significant morphologic and functional protection in eyes exposed to intense light. Light damage induced an increase in mitochondrial Bax/cytoplasmic Bax ratio, and lipid peroxidation which were prevented by LPS. Dexamethasone and wortmannin (but not aminoguanidine or 5-hydroxydecanoic acid) prevented the effect of LPS. Moreover, wortmannin prevented the effect of LPS on p-Akt levels. These results indicate that LPS provides retinal protection against light-induced stress, probably through a PI3K/Akt-dependent mechanism. PMID- 22536983 TI - Exercise training in heart failure with preserved systolic function: a randomized controlled trial of the effects on cardiac function and functional capacity. AB - Exercise training improves functional capacity in patients with exercise limitation attributed to systolic dysfunction (SD), but exercise training effects in patients with diastolic dysfunction is unclear. The authors determined the functional capacity, quality of life, and echocardiography responses of heart failure with preserved ejection fraction (HFpEF) patients to 16 weeks exercise training. Thirty patients with HFpEF were randomized to an exercise training or non-exercising control group. The patients had a baseline mean age of 64 +/- 8 years, left ventricular ejection fraction 57% +/- 10%, and peak oxygen consumption (peak VO(2) ) of 13.3 +/- 3.8 mL O(2) /kg/min. Minnesota Living With Heart Failure and Hare-Davis scores and echocardiographic measures (ejection fraction, systolic and diastolic tissue velocity and filling pressure [E/E']) were performed at baseline and after 16 weeks of exercise training. The exercise training and non-exercising control groups showed similar baseline VO(2) (12.2 +/ 3.6 mL/kg/min vs 14.1 +/- 4.1 mL/kg/min), ejection fraction (58% +/- 13% vs 57% +/- 8%), and systolic and diastolic function. After exercise training the increment in peak VO(2) in the exercise training group was (24.6%, P=.02), and the non-exercising control group (5.1%, P=.19). V(E) /VCO(2) slope was reduced by 12.7% in the exercise training group (P=.02) but was unchanged in the non exercising control group (P=.03). No significant changes in diastolic or systolic function were noted in either group. Quality-of-life and depression scores were unchanged with exercise training. Changes in peak VO(2) and V(E) /VCO(2) slope were unrelated to measures of diastolic and systolic function. In patients with exercise limitation attributed to HFpEF, the improvement in peak VO(2) with exercise training was not clearly related to changes in cardiac function. PMID- 22536987 TI - Surface-catalyzed chlorine and nitrogen activation: mechanisms for the heterogeneous formation of ClNO, NO, NO2, HONO, and N2O from HNO3 and HCl on aluminum oxide particle surfaces. AB - It is well-known that chlorine active species (e.g., Cl(2), ClONO(2), ClONO) can form from heterogeneous reactions between nitrogen oxides and hydrogen chloride on aerosol particle surfaces in the stratosphere. However, less is known about these reactions in the troposphere. In this study, a potential new heterogeneous pathway involving reaction of gaseous HCl and HNO(3) on aluminum oxide particle surfaces, a proxy for mineral dust in the troposphere, is proposed. We combine transmission Fourier transform infrared spectroscopy with X-ray photoelectron spectroscopy to investigate changes in the composition of both gas-phase and surface-bound species during the reaction under different environmental conditions of relative humidity and simulated solar radiation. Exposure of surface nitrate-coated aluminum oxide particles, from prereaction with nitric acid, to gaseous HCl yields several gas-phase products, including ClNO, NO(2), and HNO(3), under dry (RH < 1%) conditions. Under humid more conditions (RH > 20%), NO and N(2)O are the only gas products observed. The experimental data suggest that, in the presence of adsorbed water, ClNO is hydrolyzed on the particle surface to yield NO and NO(2), potentially via a HONO intermediate. NO(2) undergoes further hydrolysis via a surface-mediated process, resulting in N(2)O as an additional nitrogen-containing product. In the presence of broad-band irradiation (lambda > 300 nm) gas-phase products can undergo photochemistry, e.g., ClNO photodissociates to NO and chlorine atoms. The gas-phase product distribution also depends on particle mineralogy (Al(2)O(3) vs CaCO(3)) and the presence of other coadsorbed gases (e.g., NH(3)). These newly identified reaction pathways discussed here involve continuous production of active ozone-depleting chlorine and nitrogen species from stable sinks such as gas-phase HCl and HNO(3) as a result of heterogeneous surface reactions. Given that aluminosilicates represent a major fraction of mineral dust aerosol, aluminum oxide can be used as a model system to begin to understand various aspects of possible reactions on mineral dust aerosol surfaces. PMID- 22536985 TI - Thai ethnomedicinal plants as resistant modifying agents for combating Acinetobacter baumannii infections. AB - BACKGROUND: Acinetobacter baumannii is well-recognized as an important nosocomial pathogen, however, due to their intrinsic resistance to several antibiotics, treatment options are limited. Synergistic effects between antibiotics and medicinal plants, particularly their active components, have intensively been studied as alternative approaches. METHODS: Fifty-one ethanol extracts obtained from 44 different selected medicinal plant species were tested for resistance modifying agents (RMAs) of novobiocin against A. baumannii using growth inhibition assay. RESULTS: At 250 MUg/ml, Holarrhena antidysenterica, Punica granatum, Quisqualis indica, Terminalia bellirica, Terminalia chebula, and Terminalia sp. that possessed low intrinsic antibacterial activity significantly enhanced the activity of novobiocin at 1 MUg/ml (1/8xminimum inhibitory concentration) against this pathogen. Holarrhena antidysenterica at 7.8 MUg/ml demonstrated remarkable resistant modifying ability against A. baumannii in combination with novobiocin. The phytochemical study revealed that constituents of this medicinal plant contain alkaloids, condensed tannins, and triterpenoids. CONCLUSION: The use of Holarrhena antidysenterica in combination with novobiocin provides an effective alternative treatment for multidrug resistant A. baumannii infections. PMID- 22536986 TI - Analogues of fenarimol are potent inhibitors of Trypanosoma cruzi and are efficacious in a murine model of Chagas disease. AB - We report the discovery of nontoxic fungicide fenarimol (1) as an inhibitor of Trypanosoma cruzi ( T. cruzi ), the causative agent of Chagas disease, and the results of structure-activity investigations leading to potent analogues with low nM IC(50)s in a T. cruzi whole cell in vitro assay. Lead compounds suppressed blood parasitemia to virtually undetectable levels after once daily oral dosing in mouse models of T. cruzi infection. Compounds are chemically tractable, allowing rapid optimization of target biological activity and drug characteristics. Chemical and biological studies undertaken in the development of the fenarimol series toward the goal of delivering a new drug candidate for Chagas disease are reported. PMID- 22536988 TI - ACR Appropriateness Criteria(r) non-spine bone metastases. AB - Bone is one of the most common sites of metastatic spread of malignancy, with possible deleterious effects including pain, hypercalcemia, and pathologic fracture. External beam radiotherapy (EBRT) remains the mainstay for treatment of painful bone metastases. EBRT may be combined with other local therapies like surgery or with systemic treatments like chemotherapy, hormonal therapy, osteoclast inhibitors, or radiopharmaceuticals. EBRT is not commonly recommended for patients with asymptomatic bone metastases unless they are associated with a risk of pathologic fracture. For those who do receive EBRT, appropriate fractionation schemes include 30 Gy in 10 fractions, 24 Gy in 6 fractions, 20 Gy in 5 fractions, or a single 8 Gy fraction. Single fraction treatment maximizes convenience, while fractionated treatment courses are associated with a lower incidence of retreatment. The appropriate postoperative dose fractionation following surgical stabilization is uncertain. Reirradiation with EBRT may be safe and provide pain relief, though retreatment might create side effect risks which warrant its use as part of a clinical trial. All patients with bone metastases should be considered for concurrent management by a palliative care team, with patients whose life expectancy is less than six months appropriate for hospice evaluation. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every two years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. PMID- 22536989 TI - A noninferiority trial of a problem-solving intervention for hospice caregivers: in person versus videophone. AB - PURPOSE OF THE STUDY: Problem-solving therapy (PST) has been found effective when delivered to informal caregivers of patients with various conditions. In hospice, however, its translation to practice is impeded by the increased resources needed for its delivery. The study purpose was to compare the effectiveness of a PST intervention delivered face-to-face with one delivered via videophone to hospice primary caregivers. DESIGN AND METHODS: The study design was a randomized noninferiority trial with two groups, Group 1 in which caregivers received PST face-to-face, and Group 2 in which caregivers received PST via videophone. Family hospice caregivers were recruited from two urban hospice agencies and received the PST intervention (in three visits for Group 1 or three video-calls in Group 2) in an approximate period of 20 days after hospice admission. Standard caregiver demographic data were collected. Psychometric instruments administered to caregivers at baseline and at study completion included the CQLI-R (Caregiver Quality of Life Index-Revised), the STAI (State-Trait Anxiety Inventory), and the PSI (Problem-Solving Inventory). RESULTS: One hundred twenty-six caregivers were recruited in the study; 77 were randomly assigned to Group 1 and 49 to Group 2. PST delivered via video was not inferior to face-to-face delivery. The observed changes in scores were similar for each group. Caregiver quality of life improved and state anxiety decreased under both conditions. CONCLUSIONS: The delivery of PST via videophone was not inferior to face-to-face. Audiovisual feedback captured by technology may be sufficient, providing a solution to the geographic barriers that often inhibit the delivery of these types of interventions to older adults in hospice. PMID- 22536990 TI - End of life and women aging with a disability. AB - Approximately 21 million noninstitutionalized Americans with physical disabilities will ultimately face end-of-life [EOL] issues. Studies have documented disparate care and poorer outcomes for persons with preexisting disabilities who have life-limiting illnesses, which raises the question of how EOL experiences may differ for these individuals. The aim of this qualitative, descriptive study was to explore how EOL issues might emerge within the life stories of women aging with functional disabilities. Interview data were obtained from a larger, ongoing ethnographic study focused on the creation of an explanatory model of health disparities of disablement in women with mobility impairment. Each participant was interviewed three to four times using a life course perspective that captures life trajectories and transitions experienced over time. For this analysis, 41 interviews were selected from 20 participants who discussed issues related to death and dying. Content analysis of the data revealed five analytic categories: death as a signpost, impact of others' deaths, deaths that affected personal insights and choice, EOL possibilities, and a personal brush with death. EOL issues were manifested in a variety of ways that revealed both determination to remain as independent as possible within the context of declining functional ability and uncertainty regarding the future. PMID- 22536991 TI - The use of complementary and alternative medicine by people with cardiovascular disease: a systematic review. AB - BACKGROUND: Complementary and alternative medicine (CAM) may offer benefits as well as risks to people with cardiovascular disease. Understanding the prevalence and the nature of CAM use will encourage beneficial CAM therapies, prevent potential herb-drug interactions and foster communication between patients and physicians. METHODS: A systematic search of eight bibliographic databases was conducted for studies that investigated CAM use in patients with cardiovascular diseases. Two independent reviewers selected relevant abstracts and evaluated the quality of included studies. RESULTS: Twenty-seven studies were included. Prevalence of CAM use in cardiac patients ranged from 4% - 61%. Biologically based therapies usage ranged from 22% to 68%. Herbal medicines were used by between 2% and 46%. A large proportion of patients did not inform medical practitioners about their CAM use and up to 90% of treating physicians did not discuss CAM use with their patients. CONCLUSIONS: CAM use in patients with cardiovascular disease appears common. The findings suggest that the effects of CAM on medical management of cardiovascular disease may be overlooked and that patient-physician communication need to be strengthened. PMID- 22536992 TI - Reaction-based fluorescent probe for selective discrimination of thiophenols over aliphaticthiols and its application in water samples. AB - The development of highly sensitive and selective detection techniques for the discrimination of relevant toxic benzenethiols and biologically active aliphatic thiols is of considerable importance in the fields of chemical, biological, and environmental sciences. In this article, we describe a new design of reaction based fluorescent probe for discrimination of thiophenols over aliphaticthiols through intramolecular charge transfer pathways using N-butyl-4-amino-1,8 naphthalimide as a fluorophore, the strongly electron-withdrawing 2,4 dinitrobenzenesulfonamide group as a recognition unit, and 2,3-dihydroimidazo [1,2-a] pyridine moiety as a linker. This rational design not only affords finely tunable spectroscopic properties by adding 2,3-dihydroimidazo-[1,2-a] pyridine moiety but also provides the chance to regulate the selectivity and sensitivity of the probe due to the formation of a new type of potentially reversible sulfonamide bond through 4-dimethylaminopyridine-like resonance. The developed probe displayed high off/on signal ratios, good selectivity, and sensitivity with a detection limit of 20 nM and a relative standard deviation of 1.7% for 11 replicate detections of 0.33 MUM thiophenol and was successfully applied to the determination of thiophenols in water samples with quantitative recovery (from 94% to 97%) demonstrating its application prospect for thiophenols sensing in environmental and biological sciences. PMID- 22536993 TI - Electrophysiology procedures in adults with congenital heart disease. AB - BACKGROUND: In adult congenital heart disease (CHD), arrhythmias contribute significantly to morbidity and mortality. Often, these adult patients are treated at a freestanding pediatric facility. Limited data exist looking at this cohort. METHODS: A retrospective review was performed of all electrophysiology (EP) procedures performed in adults at our institution during a 5-year period from January 1, 2006 through December 31, 2010. RESULTS: There were 99 cases performed in a total of 87 adults with CHD during this time period. The mean patient age was 27.1 years (18-51 years). The most common congenital cardiac diagnoses were: 27% with D-transposition of the great arteries (n = 27)-of which 85% (n = 23) have had a previous atrial switch procedure, 20% with tetralogy of Fallot (n = 20), and 16% with previous Rastelli repair (n = 16). Overall, 37 EP studies were performed, with the majority done in patients with complex CHD. There were 74 additional cases. These procedures consisted of: 38 pacemakers (51%), 26 implantable cardiac defibrillators (36%), six laser lead extractions (8%), two loop recorders (3%), and two pocket revisions (3%). During this 5-year period, there was one major complication (1%) and seven minor complications (7%). CONCLUSIONS: The complex care of adults with CHD requiring EP procedures can be safely and effectively accomplished in a freestanding pediatric hospital with low complications, provided institutional support of an adult CHD program. PMID- 22536994 TI - Identification of a novel UTY-encoded minor histocompatibility antigen. AB - Minor histocompatibility antigens (mHags) encoded by the Y-chromosome (H-Y-mHags) are known to play a pivotal role in allogeneic haematopoietic cell transplantation (HCT) involving female donors and male recipients. We present a new H-Y-mHag, YYNAFHWAI (UTY(139-147)), encoded by the UTY gene and presented by HLA-A*24:02. Briefly, short peptide stretches encompassing multiple putative H-Y mHags were designed using a bioinformatics predictor of peptide-HLA binding, NetMHCpan. These peptides were used to screen for peptide-specific HLA-restricted T cell responses in peripheral blood mononuclear cells obtained post-HCT from male recipients of female donor grafts. In one of these recipients, a CD8+ T cell response was observed against a peptide stretch encoded by the UTY gene. Another bioinformatics tool, HLArestrictor, was used to identify the optimal peptide and HLA-restriction element. Using peptide/HLA tetramers, the specificity of the CD8+ T cell response was successfully validated as being HLA-A*24:02-restricted and directed against the male UTY(139-147) peptide. Functional analysis of these T cells demonstrated male UTY(139-147) peptide-specific cytokine secretion (IFNgamma, TNFalpha and MIP-1beta) and cytotoxic degranulation (CD107a). In contrast, no responses were seen when the T cells were stimulated with patient tumour cells alone. CD8+ T cells specific for this new H-Y-mHag were found in three of five HLA-A*24:02-positive male recipients of female donor HCT grafts available for this study. PMID- 22536995 TI - A summary of a year as a Kenneth M. Viste Jr. Neurology Public Policy Fellow. PMID- 22536996 TI - Intra-specific variation in the morphology and the benefit of large genital sclerites of males in the adzuki bean beetle (Callosobruchus chinensis). AB - Rapid evolution has led to a large diversity in the sizes and morphology of male genitals across taxa, but the mechanisms driving this evolution remain controversial. In this study, we investigated the function of male genital sclerites in the adzuki bean beetle (Callosobruchus chinensis) and compared the length and morphology of genital sclerites between two populations that vary in their degree of polyandry. We found that the length of male genital sclerites was negatively correlated with copulation duration but positively correlated with the speed of matings with multiple females. Additionally, we found that the average length and number of genital sclerite spines of males from the more polyandrous population were larger than those from the less polyandrous population. We suggest that the genital sclerite of male adzuki bean beetles evolved by sexual selection, and a larger genital sclerite has a selective advantage because it allows for rapid copulations with multiple females. PMID- 22536998 TI - Collective identity and wellbeing of Roma minority adolescents in Bulgaria. AB - In Europe and particularly in Bulgaria, Roma represent the largest low-status minority group that is subjected to marked public intolerance and discrimination. This study examined links among Roma (N = 207) and Bulgarian (N = 399) adolescents' ethnic, familial, and religious identities as salient identity aspects for their psychological wellbeing. Results indicated that, as expected, Roma youth reported lower levels of wellbeing than Bulgarian youth. The latter revealed a weaker religious identity than Roma youth, whereas no ethnic group differences emerged regarding Bulgarian or familial identity. Furthermore, we observed that collective identity was higher in older participants of both groups. Finally, a multigroup analysis using structural equation modeling showed that collective identity was a positive predictor of wellbeing for both Roma and Bulgarian adolescents. Findings demonstrated differences in salience as well as structural communalities regarding ways in which collective identity affects wellbeing of youth from two ethnically diverse communities. PMID- 22536997 TI - Genomic sequence-based discovery of novel angucyclinone antibiotics from marine Streptomyces sp. W007. AB - A large number of novel bioactive compounds were discovered from microbial secondary metabolites based on the traditional bioactivity screenings. Recent fermentation studies indicated that the crude extract of marine Streptomyces sp. W007 possessed great potential in agricultural fungal disease control against Phomopsis asparagi, Polystigma deformans, Cladosporium cucumerinum, Monilinia fructicola, and Colletotrichum lagenarium. To further evaluate the biosynthetic potential of secondary metabolites, we sequenced the genome of Streptomyces sp. W007 and analyzed the identifiable secondary metabolite gene clusters. Moreover, one gene cluster with type II PKS implied the possibility of Streptomyces sp. W007 to produce aromatic polyketide of angucyclinone antibiotics. Therefore, two novel compounds, 3-hydroxy-1-keto-3-methyl-8-methoxy-1,2,3,4-tetrahydro benz[alpha]anthracene and kiamycin with potent cytotoxicities against human cancer cell lines, were isolated from the culture broth of Streptomyces sp. W007. In addition, other four known angucyclinone antibiotics were obtained. The gene cluster for these angucyclinone antibiotics could be assigned to 20 genes. This work provides powerful evidence for the interplay between genomic analysis and traditional natural product isolation research. PMID- 22536999 TI - A novel genotyping technique for distinguishing between Flavobacterium psychrophilum isolates virulent and avirulent to ayu, Plecoglossus altivelis altivelis (Temminck & Schlegel). AB - We developed a simple genotyping method for Flavobacterium psychrophilum for analysing two single nucleotide polymorphisms (SNPs) in the gyrA gene and to distinguish between isolates that are virulent and avirulent to ayu, Plecoglossus altivelis altivelis (Temminck & Schlegel). The genotyping method is an on/off switch assay and is based on the polymerase chain reaction technique with phosphorothioated primers. We classified 232 isolates from four families of fish (i.e. Plecoglossidae, Osmeridae, Cyprinidae and Salmonidae) into four genotypes (G-C, A-T, A-C and G-T). The G-C type isolates exhibited strong pathogenicity to ayu, whereas the A-T and G-T types did not show any pathogenicity to this species. The A-C type exhibited no or weak pathogenicity to ayu. These results indicate that genotyping F. psychrophilum isolates with two SNPs from gyrA can clearly distinguish between isolates potentially harmful to ayu (G-C type) and those that are potentially not harmful or less harmful (A-C, A-T and G-T type). The on/off switch assay provides a quick, simple, and very powerful DNA genotyping technique for F. psychrophilum isolates. PMID- 22537000 TI - Effect of overreaching on cognitive performance and related cardiac autonomic control. AB - The purpose of this study was to characterize the effect of a 2-week overload period immediately followed by a 1-week taper period on different cognitive processes including executive and nonexecutive functions, and related heart rate variability. Eleven male endurance athletes increased their usual training volume by 100% for 2 weeks, and decreased it by 50% for 1 week. A maximal graded test, a constant speed test at 85% of peak treadmill speed, and a Stroop task with the measurement of heart rate variability were performed at each period. All participants were considered as overreached. We found a moderate increase in the overall reaction time to the three conditions of the Stroop task after the overload period (816 +/- 83 vs 892 +/- 117 ms, P = 0.03) followed by a return to baseline after the taper period (820 +/- 119 ms, P = 0.013). We found no association between cognitive performance and cardiac parasympathetic control at baseline, and no association between changes in these measures. Our findings clearly underscore the relevance of cognitive performance in the monitoring of overreaching in endurance athletes. However, contrary to our hypothesis, we did not find any relationship between executive performance and cardiac parasympathetic control. PMID- 22537001 TI - Cognitive coping and goal adjustment are associated with symptoms of depression and anxiety in people with acquired hearing loss. AB - OBJECTIVE: The present study examined the joint influence of cognitive coping strategies and goal adjustment on symptoms of depression and anxiety in people with acquired hearing loss (AHL). DESIGN: The study had a cross-sectional design in which participants were asked to fill in written questionnaires. STUDY SAMPLE: The sample consisted of 119 individuals with moderate to profound AHL, acquired in adulthood. Symptoms of depression and anxiety, cognitive coping strategies, and goal-related coping processes were assessed. RESULTS: Relationships between these variables were statistically tested by Pearson correlations and multiple regression analyses. The results showed that ruminative and catastrophizing ways of coping were related to the reporting of more symptoms of depression and/or anxiety. In contrast, refocusing attention to more pleasant issues, disengaging from unattainable goals, and re-engaging in alternative, meaningful goals were related to the reporting of less symptomatology. CONCLUSIONS: These results provide us with important targets for prevention and intervention of mental health problems in people with AHL. PMID- 22537002 TI - Steady-state analysis of auditory evoked potentials over a wide range of stimulus repetition rates: profile in children vs. adults. AB - OBJECTIVE: Auditory steady-state responses (ASSR) evoked by recurrent brief tones were assessed over a wide range of stimulus repetition rates apropos the traditionally measured obligatory, transient, auditory evoked potentials. Repetition rates of <= 10 Hz have received little attention in the context of the ASSR stimulus-response analysis approach, speculated to provide technical advantages/additional information over more traditional transient stimulus response paradigms. DESIGN: Magnitudes were measured at repetition rates from 0.75 to 80 Hz, using trains of repeated tone-burst stimuli. STUDY SAMPLE: Twelve normal-hearing children and a reference sample of 25 young adults. RESULTS: Results show that response magnitudes were significantly larger in children than adults at repetition rates of <= 5 Hz. Magnitudes were largest at the two lowest repetition rates, following the trends expected from the transient auditory evoked potential (AEP) literature. The harmonic sum is proposed as a more appropriate measure of response magnitude than amplitude of the fundamental alone. CONCLUSIONS: The analysis methods used in this paper may give information that will have applications for clinical testing. Of pragmatic importance is that the stimulus rate profile could be determined without subjective wave identification and/or interpretation, and thus by a method that is inherently more objective than conventional AEP analysis. PMID- 22537003 TI - Robust two-dimensional separation of intact proteins for bottom-up tandem mass spectrometry of the human CSF proteome. AB - Cerebrospinal fluid (CSF) is produced in the brain by cells in the choroid plexus at a rate of 500 mL/day. It is the only body fluid in direct contact with the brain. Thus, any changes in the CSF composition will reflect pathological processes and make CSF a potential source of biomarkers for different disease states. Proteomics offers a comprehensive view of the proteins found in CSF. In this study, we use a recently developed nongel based method of sample preparation of CSF followed by liquid chromatography-high accuracy mass spectrometry (LC-MS) for MS and MS/MS analyses, allowing unambiguous identification of peptides/proteins. Gel-eluted liquid fraction entrapment electrophoresis (Gelfree) is used to separate a CSF complex protein mixture in 12 user-selectable liquid-phase molecular weight fractions. Using this high throughput workflow, we have been able to separate CSF intact proteins over a broad mass range (3.5-100 kDa) with high resolution (between 15 and 100 kDa) in 2 h and 40 min. We have completely eliminated albumin and were able to interrogate the low abundance CSF proteins in a highly reproducible manner from different CSF samples at the same time. Using LC-MS as a downstream analysis, we identified 368 proteins using MidiTrap G-10 desalting columns and 166 proteins (including 57 unique proteins) using Zeba spin columns with a 5% false discovery rate (FDR). Prostaglandin D2 synthase, Chromogranin A, Apolipoprotein E, Chromogranin B, Secretogranin III, Cystatin C, VGF nerve growth factor, and Cadherin 2 are a few of the proteins that were characterized. Gelfree-LC-MS is a robust method for the analysis of the human proteome that we will use to develop biomarkers for several neurodegenerative diseases and to quantitate these markers using multiple reaction monitoring. PMID- 22537004 TI - Mechanism and molecular basis for the sodium channel subtype specificity of u conopeptide CnIIIC. AB - BACKGROUND AND PURPOSE: Voltage-gated sodium channels (Na(V) channels) are key players in the generation and propagation of action potentials, and selective blockade of these channels is a promising strategy for clinically useful suppression of electrical activity. The conotoxin u-CnIIIC from the cone snail Conus consors exhibits myorelaxing activity in rodents through specific blockade of skeletal muscle (Na(V) 1.4) Na(V) channels. EXPERIMENTAL APPROACH: We investigated the activity of u-CnIIIC on human Na(V) channels and characterized its inhibitory mechanism, as well as the molecular basis, for its channel specificity. KEY RESULTS: Similar to rat paralogs, human Na(V) 1.4 and Na(V) 1.2 were potently blocked by u-CnIIIC, the sensitivity of Na(V) 1.7 was intermediate, and Na(V) 1.5 and Na(V) 1.8 were insensitive. Half-channel chimeras revealed that determinants for the insensitivity of Na(V) 1.8 must reside in both the first and second halves of the channel, while those for Na(V) 1.5 are restricted to domains I and II. Furthermore, domain I pore loop affected the total block and therefore harbours the major determinants for the subtype specificity. Domain II pore loop only affected the kinetics of toxin binding and dissociation. Blockade by u CnIIIC of Na(V) 1.4 was virtually irreversible but left a residual current of about 5%, reflecting a 'leaky' block; therefore, Na(+) ions still passed through u-CnIIIC-occupied Na(V) 1.4 to some extent. TTX was excluded from this binding site but was trapped inside the pore by u-CnIIIC. CONCLUSION AND IMPLICATIONS: Of clinical significance, u-CnIIIC is a potent and persistent blocker of human skeletal muscle Na(V) 1.4 that does not affect activity of cardiac Na(V) 1.5. PMID- 22537005 TI - Stable stem enabled Shannon entropies distinguish non-coding RNAs from random backgrounds. AB - BACKGROUND: The computational identification of RNAs in genomic sequences requires the identification of signals of RNA sequences. Shannon base pairing entropy is an indicator for RNA secondary structure fold certainty in detection of structural, non-coding RNAs (ncRNAs). Under the Boltzmann ensemble of secondary structures, the probability of a base pair is estimated from its frequency across all the alternative equilibrium structures. However, such an entropy has yet to deliver the desired performance for distinguishing ncRNAs from random sequences. Developing novel methods to improve the entropy measure performance may result in more effective ncRNA gene finding based on structure detection. RESULTS: This paper shows that the measuring performance of base pairing entropy can be significantly improved with a constrained secondary structure ensemble in which only canonical base pairs are assumed to occur in energetically stable stems in a fold. This constraint actually reduces the space of the secondary structure and may lower the probabilities of base pairs unfavorable to the native fold. Indeed, base pairing entropies computed with this constrained model demonstrate substantially narrowed gaps of Z-scores between ncRNAs, as well as drastic increases in the Z-score for all 13 tested ncRNA sets, compared to shuffled sequences. CONCLUSIONS: These results suggest the viability of developing effective structure-based ncRNA gene finding methods by investigating secondary structure ensembles of ncRNAs. PMID- 22537006 TI - PIntron: a fast method for detecting the gene structure due to alternative splicing via maximal pairings of a pattern and a text. AB - BACKGROUND: A challenging issue in designing computational methods for predicting the gene structure into exons and introns from a cluster of transcript (EST, mRNA) sequences, is guaranteeing accuracy as well as efficiency in time and space, when large clusters of more than 20,000 ESTs and genes longer than 1 Mb are processed. Traditionally, the problem has been faced by combining different tools, not specifically designed for this task. RESULTS: We propose a fast method based on ad hoc procedures for solving the problem. Our method combines two ideas: a novel algorithm of proved small time complexity for computing spliced alignments of a transcript against a genome, and an efficient algorithm that exploits the inherent redundancy of information in a cluster of transcripts to select, among all possible factorizations of EST sequences, those allowing to infer splice site junctions that are largely confirmed by the input data. The EST alignment procedure is based on the construction of maximal embeddings, that are sequences obtained from paths of a graph structure, called embedding graph, whose vertices are the maximal pairings of a genomic sequence T and an EST P. The procedure runs in time linear in the length of P and T and in the size of the output.The method was implemented into the PIntron package. PIntron requires as input a genomic sequence or region and a set of EST and/or mRNA sequences. Besides the prediction of the full-length transcript isoforms potentially expressed by the gene, the PIntron package includes a module for the CDS annotation of the predicted transcripts. CONCLUSIONS: PIntron, the software tool implementing our methodology, is available at http://www.algolab.eu/PIntron under GNU AGPL. PIntron has been shown to outperform state-of-the-art methods, and to quickly process some critical genes. At the same time, PIntron exhibits high accuracy (sensitivity and specificity) when benchmarked with ENCODE annotations. PMID- 22537007 TI - Accelerating pairwise statistical significance estimation for local alignment by harvesting GPU's power. AB - BACKGROUND: Pairwise statistical significance has been recognized to be able to accurately identify related sequences, which is a very important cornerstone procedure in numerous bioinformatics applications. However, it is both computationally and data intensive, which poses a big challenge in terms of performance and scalability. RESULTS: We present a GPU implementation to accelerate pairwise statistical significance estimation of local sequence alignment using standard substitution matrices. By carefully studying the algorithm's data access characteristics, we developed a tile-based scheme that can produce a contiguous data access in the GPU global memory and sustain a large number of threads to achieve a high GPU occupancy. We further extend the parallelization technique to estimate pairwise statistical significance using position-specific substitution matrices, which has earlier demonstrated significantly better sequence comparison accuracy than using standard substitution matrices. The implementation is also extended to take advantage of dual-GPUs. We observe end-to-end speedups of nearly 250 (370) * using single-GPU Tesla C2050 GPU (dual-Tesla C2050) over the CPU implementation using Intel Corei7 CPU 920 processor. CONCLUSIONS: Harvesting the high performance of modern GPUs is a promising approach to accelerate pairwise statistical significance estimation for local sequence alignment. PMID- 22537008 TI - Multi-dimensional characterization of electrostatic surface potential computation on graphics processors. AB - BACKGROUND: Calculating the electrostatic surface potential (ESP) of a biomolecule is critical towards understanding biomolecular function. Because of its quadratic computational complexity (as a function of the number of atoms in a molecule), there have been continual efforts to reduce its complexity either by improving the algorithm or the underlying hardware on which the calculations are performed. RESULTS: We present the combined effect of (i) a multi-scale approximation algorithm, known as hierarchical charge partitioning (HCP), when applied to the calculation of ESP and (ii) its mapping onto a graphics processing unit (GPU). To date, most molecular modeling algorithms perform an artificial partitioning of biomolecules into a grid/lattice on the GPU. In contrast, HCP takes advantage of the natural partitioning in biomolecules, which in turn, better facilitates its mapping onto the GPU. Specifically, we characterize the effect of known GPU optimization techniques like use of shared memory. In addition, we demonstrate how the cost of divergent branching on a GPU can be amortized across algorithms like HCP in order to deliver a massive performance boon. CONCLUSIONS: We accelerated the calculation of ESP by 25-fold solely by parallelization on the GPU. Combining GPU and HCP, resulted in a speedup of at most 1,860-fold for our largest molecular structure. The baseline for these speedups is an implementation that has been hand-tuned SSE-optimized and parallelized across 16 cores on the CPU. The use of GPU does not deteriorate the accuracy of our results. PMID- 22537009 TI - Parametric modeling of cellular state transitions as measured with flow cytometry. AB - BACKGROUND: Gradual or sudden transitions among different states as exhibited by cell populations in a biological sample under particular conditions or stimuli can be detected and profiled by flow cytometric time course data. Often such temporal profiles contain features due to transient states that present unique modeling challenges. These could range from asymmetric non-Gaussian distributions to outliers and tail subpopulations, which need to be modeled with precision and rigor. RESULTS: To ensure precision and rigor, we propose a parametric modeling framework StateProfiler based on finite mixtures of skew t-Normal distributions that are robust against non-Gaussian features caused by asymmetry and outliers in data. Further, we present in StateProfiler a new greedy EM algorithm for fast and optimal model selection. The parsimonious approach of our greedy algorithm allows us to detect the genuine dynamic variation in the key features as and when they appear in time course data. We also present a procedure to construct a well fitted profile by merging any redundant model components in a way that minimizes change in entropy of the resulting model. This allows precise profiling of unusually shaped distributions and less well-separated features that may appear due to cellular heterogeneity even within clonal populations. CONCLUSIONS: By modeling flow cytometric data measured over time course and marker space with StateProfiler, specific parametric characteristics of cellular states can be identified. The parameters are then tested statistically for learning global and local patterns of spatio-temporal change. We applied StateProfiler to identify the temporal features of yeast cell cycle progression based on knockout of S phase triggering cyclins Clb5 and Clb6, and then compared the S-phase delay phenotypes due to differential regulation of the two cyclins. We also used StateProfiler to construct the temporal profile of clonal divergence underlying lineage selection in mammalian hematopoietic progenitor cells. PMID- 22537010 TI - Maximum expected accuracy structural neighbors of an RNA secondary structure. AB - BACKGROUND: Since RNA molecules regulate genes and control alternative splicing by allostery, it is important to develop algorithms to predict RNA conformational switches. Some tools, such as paRNAss, RNAshapes and RNAbor, can be used to predict potential conformational switches; nevertheless, no existent tool can detect general (i.e., not family specific) entire riboswitches (both aptamer and expression platform) with accuracy. Thus, the development of additional algorithms to detect conformational switches seems important, especially since the difference in free energy between the two metastable secondary structures may be as large as 15-20 kcal/mol. It has recently emerged that RNA secondary structure can be more accurately predicted by computing the maximum expected accuracy (MEA) structure, rather than the minimum free energy (MFE) structure. RESULTS: Given an arbitrary RNA secondary structure S0 for an RNA nucleotide sequence a = a1,..., a(n), we say that another secondary structure S of a is a k neighbor of S0, if the base pair distance between S0 and S is k. In this paper, we prove that the Boltzmann probability of all k-neighbors of the minimum free energy structure S0 can be approximated with accuracy epsilon and confidence 1 - p, simultaneously for all 0 <= k < K, by a relative frequency count over N sampled structures, provided that N>N(epsilon,p,K)=Phi-1(p/2K)2/4epsilon2, where Phi(z) is the cumulative distribution function (CDF) for the standard normal distribution. We go on to describe the algorithm RNAborMEA, which for an arbitrary initial structure S0 and for all values 0 <= k < K, computes the secondary structure MEA(k), having maximum expected accuracy over all k-neighbors of S0. Computation time is O(n3 . K2), and memory requirements are O(n2 . K). We analyze a sample TPP riboswitch, and apply our algorithm to the class of purine riboswitches. CONCLUSIONS: The approximation of RNAbor by sampling, with rigorous bound on accuracy, together with the computation of maximum expected accuracy k neighbors by RNAborMEA, provide additional tools toward conformational switch detection. Results from RNAborMEA are quite distinct from other tools, such as RNAbor, RNAshapes and paRNAss, hence may provide orthogonal information when looking for suboptimal structures or conformational switches. Source code for RNAborMEA can be downloaded from http://sourceforge.net/projects/rnabormea/ or http://bioinformatics.bc.edu/clotelab/RNAborMEA/. PMID- 22537012 TI - Exploring behaviors of stochastic differential equation models of biological systems using change of measures. AB - Stochastic Differential Equations (SDE) are often used to model the stochastic dynamics of biological systems. Unfortunately, rare but biologically interesting behaviors (e.g., oncogenesis) can be difficult to observe in stochastic models. Consequently, the analysis of behaviors of SDE models using numerical simulations can be challenging. We introduce a method for solving the following problem: given a SDE model and a high-level behavioral specification about the dynamics of the model, algorithmically decide whether the model satisfies the specification. While there are a number of techniques for addressing this problem for discrete state stochastic models, the analysis of SDE and other continuous-state models has received less attention. Our proposed solution uses a combination of Bayesian sequential hypothesis testing, non-identically distributed samples, and Girsanov's theorem for change of measures to examine rare behaviors. We use our algorithm to analyze two SDE models of tumor dynamics. Our use of non-identically distributed samples sampling contributes to the state of the art in statistical verification and model checking of stochastic models by providing an effective means for exposing rare events in SDEs, while retaining the ability to compute bounds on the probability that those events occur. PMID- 22537011 TI - Inferring serum proteolytic activity from LC-MS/MS data. AB - BACKGROUND: In this paper we deal with modeling serum proteolysis process from tandem mass spectrometry data. The parameters of peptide degradation process inferred from LC-MS/MS data correspond directly to the activity of specific enzymes present in the serum samples of patients and healthy donors. Our approach integrate the existing knowledge about peptidases' activity stored in MEROPS database with the efficient procedure for estimation the model parameters. RESULTS: Taking into account the inherent stochasticity of the process, the proteolytic activity is modeled with the use of Chemical Master Equation (CME). Assuming the stationarity of the Markov process we calculate the expected values of digested peptides in the model. The parameters are fitted to minimize the discrepancy between those expected values and the peptide activities observed in the MS data. Constrained optimization problem is solved by Levenberg-Marquadt algorithm. CONCLUSIONS: Our results demonstrates the feasibility and potential of high-level analysis for LC-MS proteomic data. The estimated enzyme activities give insights into the molecular pathology of colorectal cancer. Moreover the developed framework is general and can be applied to study proteolytic activity in different systems. PMID- 22537013 TI - A newborn pustular eruption. PMID- 22537014 TI - EuFishBioMed (COST Action BM0804): a European network to promote the use of small fishes in biomedical research. AB - Small fresh water fishes such as the zebrafish (Danio rerio) have become important model organisms for biomedical research. They currently represent the best vertebrate embryo models in which it is possible to derive quantitative data on gene expression, signaling events, and cell behavior in real time in the living animal. Relevant phenotypes in fish mutants are similar to those of other vertebrate models and human diseases. They can be analyzed in great detail and much faster than in mammals. In recent years, approximately 2500 genetically distinct fish lines have been generated by European research groups alone. Their potential, including their possible use by industry, is far from being exploited. To promote zebrafish research in Europe, EuFishBioMed was founded and won support by the EU COST programme ( http://www.cost.esf.org/ ). The main objective of EuFishBioMed is to establish a platform of knowledge exchange for research on small fish models with a strong focus on widening its biomedical applications and an integration of European research efforts and resources. EuFishBioMed currently lists more than 300 member laboratories in Europe, offers funding for short-term laboratory visits, organizes and co-sponsors meetings and workshops, and has successfully lobbied for the establishment of a European Zebrafish Resource Centre. To maintain this network in the future, beyond the funding period of the COST Action, we are currently establishing the European Society for Fish Models in Biology and Medicine. PMID- 22537015 TI - Understanding the reactivity of strained sandwich compounds with aluminum or gallium in bridging positions: experiments and DFT calculations. AB - The aluminum and gallium dichlorides (Mamx)ECl(2)1a (E = Al; 82%) and 1b (E = Ga; 79%) (Mamx = 2,4-di-tert-butyl-6-[(dimethylamino)methyl]phenyl) reacted with dilithioferrocene or dilithioruthenocene to give [1]ferrocenophanes (2a, 2b) and [1]ruthenocenophanes (3a, 3b), respectively. The galla[1]ruthenocenophane 3b could be isolated from the reaction mixture through precipitation into hexane (50%), while 2a, 2b, and 3a underwent ring-opening polymerization under the reaction conditions of their formation reactions to give metallopolymers (M(w) (DLS) between 8.07 and 106 kDa). Monomer 3b was polymerized using Karstedt's catalyst resulting in an M(w) of 28.6(+/-6.3) kDa. In order to get an indication of the structure of polymers, bis(ferrocenyl) compounds (Mamx)EFc(2) (E = Al (4a), 51%; E = Ga (4b), 49%) were prepared and characterized by single crystal X ray analysis. DFT calculations shed some light on the unexpected high reactivity of these new strained sandwich species. Optimized geometries of known aluminum and gallium-bridged [1]ferrocenophanes (Al(Pytsi) (6a), Ga(Pytsi) (6b); Pytsi = [dimethyl(2-pyridyl)silyl]bis(trimethylsilyl)methyl) and [1]ruthenocenophanes (Al(Me(2)Ntsi) (7a), Ga(Me(2)Ntsi) (7b); Me(2)Ntsi = [(dimethylamino)dimethylsilyl]bis(trimethylsilyl)methyl) matched very well with experimental molecular structures. Geometries of species 2a, 2b, 3a, and 3b were optimized (BP86/TZ2P) and the structural influence of the tBu group of the Mamx ligand in ortho position was evaluated by optimizing molecular structures of the four unknown species where the ortho-tBu group was replaced by an H atom (2a(H), 2b(H), 3a(H), and 3b(H)). The most pronounced structural effect was seen as a change of the orientation of the bridging moiety with respect to the sandwich unit. As the tBu group was removed, the aromatic ligand moved toward the freed-up space. The energetics (DeltaE, DeltaH(298K), and DeltaG(298K)) accompanied by the structural changes were evaluated by a hydrogenolysis reaction of strained species resulting in Cp(2)M (M = Fe, Ru) and respective aluminum and gallium dihydrides. This nonisodesmic reaction showed that [1]metallocenophanes equipped with the ortho-tBu group were on average 5.5 kcal/mol higher strained (DeltaH(298K)) than species where the tBu group was lacking. The investigation of the isodesmic reaction between strained species and Cp(2)M yielding bis(metallocenyl) compounds revealed that the ortho-tBu group sterically interacts with one of the metallocenyl units. The bis(metallocenyl) compounds are model compounds for the respective metallopolymers and one can conclude that even though the ortho-tBu group imposes additional strain on the starting metallocenophanes, this effect cancels out in ROPs because the ortho-tBu group imposes a similar strain on the resulting polymers. The uncovered steric repulsion between the ortho-tBu group and the sandwich moieties probably causes the ortho-tBu to act as an unusually sensitive NMR probe of the tacticity of the polymers. PMID- 22537016 TI - Comparative transcriptome analysis of transporters, phytohormone and lipid metabolism pathways in response to arsenic stress in rice (Oryza sativa). AB - * Arsenic (As) contamination of rice (Oryza sativa) is a worldwide concern and elucidating the molecular mechanisms of As accumulation in rice may provide promising solutions to the problem. Previous studies using microarray techniques to investigate transcriptional regulation of plant responses to As stress have identified numerous differentially expressed genes. However, little is known about the metabolic and regulatory network remodelings, or their interactions with microRNA (miRNA) in plants upon As(III) exposure. * We used Illumina sequencing to acquire global transcriptome alterations and miRNA regulation in rice under As(III) treatments of varying lengths of time and dosages. * We found that the response of roots was more distinct when the dosage was varied, whereas that of shoots was more distinct when the treatment time was varied. In particular, the genes involved in heavy metal transportation, jasmonate (JA) biosynthesis and signaling, and lipid metabolism were closely related to responses of rice under As(III) stress. Furthermore, we discovered 36 new As(III) responsive miRNAs, 14 of which were likely involved in regulating gene expression in transportation, signaling, and metabolism. * Our findings highlight the significance of JA signaling and lipid metabolism in response to As(III) stress and their regulation by miRNA, which provides a foundation for subsequent functional research. PMID- 22537017 TI - Copper(I)-mediated cascade reactions: an efficient approach to the synthesis of functionalized benzofuro[3,2-d]pyrimidines. AB - A novel cascade reaction was developed for the synthesis of diverse members of a series of benzofuro[3,2-d]pyrimidine derivatives. The process utilizes readily prepared 3-chlorochromenones and various commercially available amidines and their analogues as starting materials. This tandem reaction is promoted by using a simple copper(I) reagent and involves a chemoselective Michael addition heterocyclization-intramolecular cyclization sequence. PMID- 22537018 TI - Fibroblast growth factor 2 regulates dopaminergic neuron development in vivo. AB - Fibroblast growth factor 2 (FGF-2) is a neurotrophic factor participating in regulation of proliferation, differentiation, apoptosis and neuroprotection in the central nervous system. With regard to dopaminergic (DA) neurons of substantia nigra pars compacta (SNpc), which degenerate in Parkinson's disease, FGF-2 improves survival of mature DA neurons in vivo and regulates expansion of DA progenitors in vitro. To address the physiological role of FGF-2 in SNpc development, embryonic (E14.5), newborn (P0) and juvenile (P28) FGF-2-deficient mice were investigated. Stereological quantification of DA neurons identified normal numbers in the ventral tegmental area, whereas the SNpc of FGF-2-deficient mice displayed a 35% increase of DA neurons at P0 and P28, but not at earlier stage E14.5. Examination of DA marker gene expression by quantitative RT-PCR and in situ hybridization revealed a normal patterning of embryonic ventral mesencephalon. However, an increase of proliferating Lmx1a DA progenitors in the subventricular zone of the ventral mesencephalon of FGF-2-deficient embryos indicated altered cell cycle progression of neuronal progenitors. Increased levels of nuclear FgfR1 in E14.5 FGF-2-deficient mice suggest alterations of integrative nuclear FgfR1 signaling (INFS). In summary, FGF-2 restricts SNpc DA neurogenesis in vivo during late stages of embryonic development. PMID- 22537019 TI - Using routine data to monitor inequalities in an acute trust: a retrospective study. AB - BACKGROUND: Reducing inequalities is one of the priorities of the National Health Service. However, there is no standard system for monitoring inequalities in the care provided by acute trusts. We explore the feasibility of monitoring inequalities within an acute trust using routine data. METHODS: A retrospective study of hospital episode statistics from one acute trust in London over three years (2007 to 2010). Waiting times, length of stay and readmission rates were described for seven common surgical procedures. Inequalities by age, sex, ethnicity and social deprivation were examined using multiple logistic regression, adjusting for the other socio-demographic variables and comorbidities. Sample size calculations were computed to estimate how many years of data would be ideal for this analysis. RESULTS: This study found that even in a large acute trust, there was not enough power to detect differences between subgroups. There was little evidence of inequalities for the outcome and process measures examined, statistically significant differences by age, sex, ethnicity or deprivation were only found in 11 out of 80 analyses. Bariatric surgery patients who were black African or Caribbean were more likely than white patients to experience a prolonged wait (longer than 64 days, aOR = 2.47, 95% CI: 1.36 4.49). Following a coronary angioplasty, patients from more deprived areas were more likely to have had a prolonged length of stay (aOR = 1.66, 95% CI: 1.25 2.20). CONCLUSIONS: This study found difficulties in using routine data to identify inequalities on a trust level. Little evidence of inequalities in waiting time, length of stay or readmission rates by sex, ethnicity or social deprivation were identified although some differences were identified which warrant further investigation. Even with three years of data from a large trust there was little power to detect inequalities by procedure. Data will therefore need to be pooled from multiple trusts to detect inequalities. PMID- 22537020 TI - Physical activity during pregnancy and risk of hyperglycemia. AB - OBJECTIVE: To determine the association between moderate and vigorous physical activities (MVPA) during midpregnancy and the risk of hyperglycemia. METHODS: Data were from 1437 pregnant women. Frequency, duration, and intensity of MVPA during the previous 7 days were collected via questionnaire at 17-22 weeks' gestation. Modes of MVPA included work, recreation, transportation, caregiving, and indoor and outdoor household activities. Hyperglycemia was defined as a glucose concentration >=130 mg/dL on a 1-hour, 50-g glucose challenge test or gestational diabetes mellitus (GDM) assessed at ~27 weeks' gestation. Multivariable Poisson regression estimated risks of hyperglycemia associated with total and mode-specific MVPA. RESULTS: There were 269 women (18.7%) with hyperglycemia. Any metabolic equivalent (MET) hours/week of recreational MVPA was associated with a 27% lower risk of hyperglycemia (adjusted relative risk, [aRR] 0.73, 95% confidence interval [95%CI] 0.54-0.99). Multiplicative interaction terms were significant for prepregnancy body mass index (BMI) and recreational MVPA (p=0.01). Among women with prepregnancy BMI <25 kg/m(2), recreational MVPA was associated with a 48% lower risk of hyperglycemia (aRR 0.52, 95%CI 0.33-0.83) compared to women who reported none. There was no association of hyperglycemia and recreational MVPA among women with prepregnancy BMI <25 kg/m(2). CONCLUSIONS: Recreational MVPA during pregnancy is associated with a lower risk of hyperglycemia, specifically among women with prepregnancy BMI <25 kg/m(2). Further research is warranted to determine recommended amounts and intensities of physical activity and to discern whether there are differences in the effects of physical activity between specific modes of physical activity or among subgroups of women in relation to hyperglycemia. PMID- 22537022 TI - A Yersinia pestis YscN ATPase mutant functions as a live attenuated vaccine against bubonic plague in mice. AB - Yersinia pestis is the causative agent responsible for bubonic and pneumonic plague. The bacterium uses the pLcr plasmid-encoded type III secretion system to deliver virulence factors into host cells. Delivery requires ATP hydrolysis by the YscN ATPase encoded by the yscN gene also on pLcr. A yscN mutant was constructed in the fully virulent CO92 strain containing a nonpolar, in-frame internal deletion within the gene. We demonstrate that CO92 with a yscN mutation was not able to secrete the LcrV protein (V-Antigen) and attenuated in a subcutaneous model of plague demonstrating that the YscN ATPase was essential for virulence. However, if the yscN mutant was complemented with a functional yscN gene in trans, virulence was restored. To evaluate the mutant as a live vaccine, Swiss-Webster mice were vaccinated twice with the DeltayscN mutant at varying doses and were protected against bubonic plague in a dose-dependent manner. Antibodies to F1 capsule but not to LcrV were detected in sera from the vaccinated mice. These preliminary results suggest a proof-of-concept for an attenuated, genetically engineered, live vaccine effective against bubonic plague. PMID- 22537021 TI - Development and embryonic staging in non-model organisms: the case of an afrotherian mammal. AB - Studies of evolutionary developmental biology commonly use 'model organisms' such as fruit flies or mice, and questions are often functional or epigenetic. Phylogenetic investigations, in contrast, typically use species that are less common and mostly deal with broad scale analyses in the tree of life. However, important evolutionary transformations have taken place at all taxonomic levels, resulting in such diverse forms as elephants and shrews. To understand the mechanisms underlying morphological diversification, broader sampling and comparative approaches are paramount. Using a simple, standardized protocol, we describe for the first time the development of soft tissues and some parts of the skeleton, using MUCT-imaging of developmental series of Echinops telfairi and Tenrec ecaudatus, two tenrecid afrotherian mammals. The developmental timing of soft tissue and skeletal characters described for the tenrecids is briefly compared with that of other mammals, including mouse, echidna, and the opossum. We found relatively few heterochronic differences in development in the armadillo vs. tenrec, consistent with a close relationship of Xenarthra and Afrotheria. Ossification in T. ecaudatus continues well into the second half of overall gestation, resembling the pattern seen in other small mammals and differing markedly from the advanced state of ossification evident early in the gestation of elephants, sheep, and humans. PMID- 22537023 TI - Novel hybrid comprehensive 2D-multidimensional gas chromatography for precise, high-resolution characterization of multicomponent samples. AB - A novel hybrid (sequential) comprehensive 2D-multidimensional gas chromatography (GC * GC-MDGC) method for complex sample manipulation and separation is described. It incorporates a separation step that approximates slow modulation GC * GC, prior to microfluidic Deans switch heart-cutting of a targeted region(s) into a third analytical column. It allows discrete single or multiple components, bands or regions, or any combination of these to be selected and excised from within the 2D GC * GC separation space. The excised individual components can be further collected and studied. Alternatively, any unresolved or poorly resolved components, or regions that require further separation, can be transferred to an additional (third) column separation step. The method is applied to separation and quantitative analysis of oxygenates in a thermally stressed algae-derived biofuel oil by using flame ionization detection (FID), without any prefractionation. This permits oxygenated compounds to be fully resolved from saturated (matrix) compounds, which are completely excluded from the third column. Improved separation was obtained between target classes (aldehydes, 2 ketones, alcohols, acids). Excellent calibration linearity, and retention time and peak area reproducibility were obtained for 14 oxy-compounds present in trace amount in the complex biofuel matrix. Accuracy of microfluidic transfer to the third column, and the profile reproducibility before and after heart-cut operations, was demonstrated by extracting single components from a complex coffee volatile sample. PMID- 22537024 TI - An outer membrane vesicle vaccine for prevention of serogroup A and W-135 meningococcal disease in the African meningitis belt. AB - The bacterium Neisseria meningitidis of serogroups A and W-135 has in the recent decade caused most of the cases of meningococcal meningitis in the African meningitis belt, and there is currently no efficient and affordable vaccine available demonstrated to protect against both these serogroups. Previously, deoxycholate-extracted outer membrane vesicle (OMV) vaccines against serogroup B meningococci have been shown to be safe and induce protection in humans in clonal outbreaks. The serogroup A and W-135 strains isolated from meningitis belt epidemics demonstrate strikingly limited variation in major surface-exposed protein structures. We have here investigated whether the OMV vaccine strategy also can be applied to prevent both serogroups A and W-135 meningococcal disease. A novel vaccine combining OMV extracted from recent African serogroup A and W-135 strains and adsorbed to aluminium hydroxide was developed and its antigenic characteristics and immunogenicity were studied in mice. The specificity of the antibody responses was analysed by immunoblotting and serum bactericidal activity (SBA) assays. Moreover, the bivalent A+W-135 vaccine was compared with monovalent A and W-135 OMV vaccines. The bivalent OMV vaccine was able to induce similar SBA titres as the monovalent A or W-135 OMV towards both serogroups. High SBA titres were also observed against a meningococcal serogroup C strain. These results show that subcapsular antigens may be of importance when developing broadly protective and affordable vaccines for the meningitis belt. PMID- 22537025 TI - Prognostic value of capnography during rest and exercise in patients with heart failure. AB - New variables obtained from cardiopulmonary exercise testing (CPX) have received attention in recent years, in particular the partial pressure of end-tidal carbon dioxide (P(ET) CO(2) ). The purpose of this study was to therefore comprehensively assess the ability of resting and exercise P(ET) CO(2) to predict major cardiac events in a heart failure (HF) cohort referred for CPX. A total of 963 patients with systolic HF undergoing symptom-limited CPX were included in the analysis. Resting and exercise P(ET) CO(2) along with other CPX variables were determined, and patients were followed for major adverse events. With regard to resting measures, multivariate analysis revealed that left ventricular ejection fraction was the most robust prognostic marker (P<.001) while resting P(ET) CO(2) added significant predictive value and was retained in the regression (P<.001). When exercise data were considered, the multivariate analysis revealed that the P(ET) CO(2) apex during exercise added predictive value and was retained (P<.05). In what is the largest evaluation of P(ET) CO(2) in the assessment of systolic HF patients to date, the authors substantiate prior (smaller) studies showing prognostic utility of P(ET) CO(2) , both as a resting measure (an important potential screening tool) and during exercise. These data add to the rationale to incorporate P(ET) CO(2) as a routine monitoring component in HF management. PMID- 22537026 TI - A low prevalence of mycobacteria in freshwater fish from water reservoirs, ponds and farms. AB - A survey of the occurrence of mycobacteria was conducted from 717 freshwater fish (25 species) in two water reservoirs, five ponds and two farms in the Czech Republic. A total of 2182 tissue samples from these fish were examined using the conventional culture method. Thirteen mycobacterial isolates were obtained from 12 (1.7%) fish belonging to nine species. Isolates were identified using sequence analysis of the 16SrRNA gene as: Mycobacterium algericum, M. fortuitum, M. gordonae, M. insubricum, M. kumamotonense, M. nonchromogenicum, two isolates of M. peregrinum, M. terrae and M. triplex. Mycobacteria were isolated more frequently from fish skin and gills than from internal organs or muscles. PMID- 22537027 TI - The potential to avoid heart transplantation in children: outpatient bridge to recovery with an intracorporeal continuous-flow left ventricular assist device in a 14-year-old. AB - Pediatric mechanical circulatory support has evolved considerably in the past decade. Improvements in device design and availability have led to increased short-, medium-, and long-term support options for pediatric patients with heart failure. Most pediatric mechanical circulatory support is utilized as a bridge to transplant and as a bridge to recovery in patients with temporary etiologies of heart failure (i.e., myocarditis). Described herein is our recovery program, and we report our experience as an independent pediatric ventricular assist device program with an intracorporeal continuous-flow device employed as an out-of hospital bridge to recovery for a child with end-stage chronic heart failure. PMID- 22537028 TI - The effect of an unstructured, moderate to vigorous, before-school physical activity program in elementary school children on academics, behavior, and health. AB - BACKGROUND: Physical inactivity has been deemed a significant, contributing factor to childhood overweight and obesity. In recent years, many school systems removed recess and/or physical education from their curriculum due to growing pressure to increase academic scores. With the vast majority of children's time spent in school, alternative strategies to re-introduce physical activity back into schools are necessary. A creative yet underutilized solution to engage children in physical activity may be in before-school programs. The objective of the proposed study is to examine the effect of an unstructured, moderate to vigorous, before-school physical activity program on academic performance, classroom behavior, emotions, and other health related measures. METHODS/DESIGN: Children in 3rd-5th grade will participate in a before-school (7:30-8:15 a.m.), physical activity program for 12 weeks, 3 days a week. Children will be able to choose their preferred activity and asked to sustain physical activity of moderate to vigorous intensity with individual heart rate monitored during each session. DISCUSSION: The proposed study explores an innovative method of engaging and increasing physical activity in children. The results of this study will provide evidence to support the feasibility of an unstructured, moderate to vigorous, before-school physical activity program in children and provide insight regarding the ideal physical activity intensity and duration necessary to achieve a positive increase in academic performance. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01505244. PMID- 22537029 TI - Credible suggestions affect false autobiographical beliefs. AB - False memory implantation studies are characterised by suggestions indicating that specific unremembered events occurred, attributing suggested events to a knowledgeable source (e.g., parents), and including true events that provide evidence that this source was consulted. These characteristics create a particular retrieval context that influences how individuals come to believe that false events occurred. Two studies used a variant of implantation methods to vary the proportion of events attributed to parents and the presence of true events within the suggestion. In Study 1 participants received six false events, and were told that all or some events came from parents. Participants told that all of the events came from parents formed more and stronger false beliefs. In Study 2 participants also received two true events, and a third group was told that half of the events came from their parents. Participants given the specific ratio ("half") endorsed more false beliefs, and beliefs between the other groups no longer differed. Across both studies participants told that some events came from parents reported stronger memory phenomenology. The effect of suggestions on false beliefs in implantation studies depends partly on the credibility of suggestions derived from providing information about the source of suggested events. PMID- 22537030 TI - Experimental evidence of early costs of reproduction in conspecific viviparous and oviparous lizards. AB - Reproduction entails costs, and disentangling the relative importance of each stage of the reproductive cycle may be important to assess the costs and benefits of different reproductive strategies. We studied the early costs of reproduction in oviparous and viviparous lizard females of the bimodal reproductive species Zootoca vivipara. Egg retention time in oviparous females is approximately one third of the time in viviparous females. We compared the vitellogenesis and egg retention stages that are common to both reproductive modes. Precisely, we monitored the thermoregulatory behaviour, the weight gain and the immunocompetence of the females. Moreover, we injected an antigen in half of the females (immune challenge) to study the trade-offs between reproductive mode and immune performance and between different components of the immune system. Finally, we experimentally induced parturition in viviparous females at the time of egg laying in oviparous females. Oviparous and viviparous females did not show strong differences in response to the immune challenge. However, viviparous females spent more time thermoregulating while partially hidden and gained more weight than oviparous females. The greater weight gain indicates that the initial period of egg retention is less costly for viviparous than for oviparous females or that viviparous females are able to save and accumulate energy at this period. This energy may be used by viviparous females to cope with the subsequent costs of the last two-third of the gestation. Such an ability to compensate the higher costs of a longer egg retention period may account for the frequent evolution of viviparity in squamate reptiles. PMID- 22537031 TI - miRNA and protein expression profiles of visceral adipose tissue reveal miR 141/YWHAG and miR-520e/RAB11A as two potential miRNA/protein target pairs associated with severe obesity. AB - Adipose tissues show selective gene expression patterns, to whom microRNAs (miRNAs) may contribute. We evaluated in visceral adipose tissue (VAT) from obese and nonobese females, both miRNA and protein expression profiles, to identify miRNA/protein target pairs associated with obesity (metabolic pathways miRNA deregulated during obesity). Obese and nonobese females [BMI 42.2 +/- 1.6 and 23.7 +/- 1.2 kg/m(2) (mean +/- SEM), respectively] were enrolled in this study. Notably, most miRNAs were down-expressed in obese tissues, whereas most of the proteins from the investigated spots were up-expressed. Bioinformatics integration of miRNA expression and proteomic data highlighted two potential miRNA/protein target pairs: miR-141/YWHAG (tyrosine 3-monooxygenase/tryptophan 5 monooxygenase activation protein, gamma polypeptide) and miR-520e/RAB11A (Ras related protein RAB-11A); the functional interaction between these miRNAs and their target sequences on the corresponding mRNAs was confirmed by luciferase assays. Both RAB11A and YWHAG proteins are involved in glucose homeostasis; YWHAG is also involved in lipid metabolism. Hence, the identified miRNA/protein target pairs are potential players in the obese phenotype. PMID- 22537032 TI - Acceptable noise level: repeatability with Danish and non-semantic speech materials for adults with normal hearing. AB - OBJECTIVE: The acceptable noise level (ANL) is used to quantify the amount of background noise that subjects can accept while listening to speech, and is suggested for prediction of individual hearing-aid use. The aim of this study was to assess the repeatability of the ANL measured in normal-hearing subjects using running Danish and non-semantic speech materials as stimuli and modulated speech spectrum and multi-talker babble noises as competing stimuli. DESIGN: ANL was measured in both ears at two test sessions separated by a period ranging from 12 to 77 days. At each session the measurements at the first and the second ear were separated in time by 15-30 minutes. Bland-Altman plots and calculation of the coefficient of repeatability (CR) were used to estimate the repeatability. STUDY SAMPLE: Thirty nine normal-hearing subjects. RESULTS: The ANL CR was 6.0-8.9 dB for repeated tests separated by about 15-30 minutes and 7.2-10.2 dB for repeated tests separated by 12 days or more. CONCLUSIONS: The ANL test has poor repeatability when assessed with Danish and non-semantic speech materials on normal-hearing subjects. The same CR among hearing-impaired subjects would imply too poor repeatability to predict individual patterns of future hearing-aid use. PMID- 22537033 TI - A Spanish matrix sentence test for assessing speech reception thresholds in noise. AB - OBJECTIVE: To develop, optimize, and evaluate a new Spanish sentence test in noise. DESIGN: The test comprises a basic matrix of ten names, verbs, numerals, nouns, and adjectives. From this matrix, test lists of ten sentences with an equal syntactical structure can be formed at random, with each list containing the whole speech material. The speech material represents the phoneme distribution of the Spanish language. The test was optimized for measuring speech reception thresholds (SRTs) in noise by adjusting the presentation levels of the individual words. Subsequently, the test was evaluated by independent measurements investigating the training effects, the comparability of test lists, open-set vs. closed-set test format, and performance of listeners of different Spanish varieties. STUDY SAMPLE: In total, 68 normal-hearing native Spanish speaking listeners. RESULTS: SRTs measured using an adaptive procedure were 6.2 +/- 0.8 dB SNR for the open-set and 7.2 +/- 0.7 dB SNR for the closed-set test format. The residual training effect was less than 1 dB after using two double lists before data collection. CONCLUSIONS: No significant differences were found for listeners of different Spanish varieties indicating that the test is applicable to Spanish as well as Latin American listeners. Test lists can be used interchangeably. PMID- 22537034 TI - Hearing-aid outcomes in Chinese adults: clinical application and psychometric properties of the Chinese version of the Satisfaction with Amplification in Daily Life questionnaire. AB - OBJECTIVE: To adapt the Satisfaction with Amplification in Daily Life questionnaire into Chinese (the SADL-CH questionnaire) and investigate hearing aid satisfaction in a group of adult Hong Kong Chinese fitted with free hearing aids. DESIGN: Cross-sectional survey. STUDY SAMPLE: One hundred and twenty-five experienced hearing-aid users. METHODS: The subjects completed a history form seeking demographic data and a questionnaire combining the SADL-CH instrument with questions seeking subjects' subjective ratings of satisfaction with some hearing-aid features and overall satisfaction with their hearing aid. RESULTS: The SADL-CH questionnaire had a good internal consistency reliability estimate (alpha = 0.79) comparable to that of the original version. SADL-CH scores were observed to have significant correlations with other satisfaction ratings on some hearing-aid features and the overall satisfaction measure. A high degree of test retest reliability (intraclass correlation coefficient = 0.79) was observed. Confirmatory factor analysis revealed that the SADL-CH questionnaire had a four factor structure. Interim norms were derived for the SADL-CH questionnaire. The level of hearing-aid satisfaction in Chinese adults was generally lower than that reported in studies conducted among Western populations. CONCLUSION: The SADL-CH questionnaire is a reliable and valid instrument for measuring hearing-aid satisfaction. PMID- 22537035 TI - Influence of head acceleration on ocular vestibular-evoked myogenic potentials via skull vibration at Fz versus Fpz sites. AB - OBJECTIVE: This study applied bone vibration (BV) stimulation to the Fz and Fpz sites to investigate the influence of head acceleration on the ocular vestibular evoked myogenic potentials (oVEMPs). DESIGN: Prospective study. STUDY SAMPLE: Fourteen healthy subjects underwent oVEMP tests combined with real-time triaxial accelerometry. RESULTS: Under BV stimulation from a vibrator to the Fz and Fpz sites, acceleration magnitudes along x-, y- or z-axis did not significantly differ between the two sites. The mean nI and pI latencies of the oVEMPs stimulated at Fz were significantly earlier than those at Fpz. However, no statistical differences existed in the nI-pI interval and amplitude between the two sites. A blunt or double peak nI configuration was noted in three subjects (22%) when tapping at Fpz, but not at Fz, likely because different muscles contributing to the oVEMPs. CONCLUSION: While both Fz and Fpz are effective sites for generating an oVEMP, the variation in human skull shapes and properties will lead to different acceleration profiles being transmitted to the vestibular apparatus. These differing stimuli may lead to different oVEMP profiles, so if one site does not produce the expected response, the clinician should try the other site. PMID- 22537036 TI - Equivalent hearing threshold levels for the Etymotic Research ER-10C otoacoustic emission probe. AB - OBJECTIVE: To determine the equivalent threshold sound pressure levels (ETSPL) for a commercially available distortion product otoacoustic emission (DPOAE) probe, and to study the impact of probe fitting and eartip size on the calibration. DESIGN: Twenty-eight otologically normal test subjects participated in the ETSPL determination for the Etymotic Research ER-10C probe. STUDY SAMPLE: ETSPLs were determined up to 16 kHz and were compared to the reference hearing thresholds associated with the ER-3A insert earphone. Both 'regular' and 'baby' foam eartips were used. RESULTS: At most frequencies, no significant threshold differences were observed between the insert earphone and the DPOAE probe. However, at 1 kHz and 4 kHz, the mean thresholds for the insert earphone were generally lower than those for the DPOAE probe, suggesting systematic differences at those frequencies. Repeated calibration runs resulted in deviations of about 0.6 dB. Similar deviations were noticed when using foam eartips of different sizes up to 10 kHz. CONCLUSIONS: Knowing the reference thresholds for DPOAE probes enables measurements of (subjective) hearing thresholds and (objective) otoacoustic emissions using the same probe. Probe fitting and eartip size had negligible effect on the determination of ETSPLs. The obtained data may be proposed for inclusion in future audiometry standards. PMID- 22537037 TI - Why adductor magnus muscle is large: the function based on muscle morphology in cadavers. AB - The aim of this study was to examine anatomical properties of the adductor magnus through a detailed classification, and to hypothesize its function and size to gather enough information about morphology. Ten cadaveric specimens of the adductor magnus were used. The muscle was separated into four portios (AM1-AM4) based on the courses of the corresponding perforating arteries, and its volume, muscle length, muscle fiber length and physiological cross-sectional area were assessed. The architectural characteristics of these four portions of the adductor magnus were then classified with the aid of principal component analysis. The results led us into demarcating the most proximal part of the adductor magnus (AM1) from the remaining parts (AM2, AM3, and AM4). Classification of the adductor magnus in terms of architectural characteristics differed from the more traditional anatomical distinction. The AM2, AM3, and AM4, having longer muscle fiber lengths than the AM1, appear to be designed as displacers for moving the thigh through a large range of motion. The AM1 appears instead to be oriented principally toward stabilizing the hip joint. The large mass of the adductor magnus should thus be regarded as a complex of functionally differentiable muscle portions. PMID- 22537038 TI - Exploiting sparseness in de novo genome assembly. AB - BACKGROUND: The very large memory requirements for the construction of assembly graphs for de novo genome assembly limit current algorithms to super-computing environments. METHODS: In this paper, we demonstrate that constructing a sparse assembly graph which stores only a small fraction of the observed k-mers as nodes and the links between these nodes allows the de novo assembly of even moderately sized genomes (~500 M) on a typical laptop computer. RESULTS: We implement this sparse graph concept in a proof-of-principle software package, SparseAssembler, utilizing a new sparse k-mer graph structure evolved from the de Bruijn graph. We test our SparseAssembler with both simulated and real data, achieving ~90% memory savings and retaining high assembly accuracy, without sacrificing speed in comparison to existing de novo assemblers. PMID- 22537040 TI - Challenges in estimating percent inclusion of alternatively spliced junctions from RNA-seq data. AB - Transcript quantification is a long-standing problem in genomics and estimating the relative abundance of alternatively-spliced isoforms from the same transcript is an important special case. Both problems have recently been illuminated by high-throughput RNA sequencing experiments which are quickly generating large amounts of data. However, much of the signal present in this data is corrupted or obscured by biases resulting in non-uniform and non-proportional representation of sequences from different transcripts. Many existing analyses attempt to deal with these and other biases with various task-specific approaches, which makes direct comparison between them difficult. However, two popular tools for isoform quantification, MISO and Cufflinks, have adopted a general probabilistic framework to model and mitigate these biases in a more general fashion. These advances motivate the need to investigate the effects of RNA-seq biases on the accuracy of different approaches for isoform quantification. We conduct the investigation by building models of increasing sophistication to account for noise introduced by the biases and compare their accuracy to the established approaches. We focus on methods that estimate the expression of alternatively spliced isoforms with the percent-spliced-in (PSI) metric for each exon skipping event. To improve their estimates, many methods use evidence from RNA-seq reads that align to exon bodies. However, the methods we propose focus on reads that span only exon-exon junctions. As a result, our approaches are simpler and less sensitive to exon definitions than existing methods, which enables us to distinguish their strengths and weaknesses more easily. We present several probabilistic models of of position-specific read counts with increasing complexity and compare them to each other and to the current state-of-the-art methods in isoform quantification, MISO and Cufflinks. On a validation set with RT-PCR measurements for 26 cassette events, some of our methods are more accurate and some are significantly more consistent than these two popular tools. This comparison demonstrates the challenges in estimating the percent inclusion of alternatively spliced junctions and illuminates the tradeoffs between different approaches. PMID- 22537039 TI - Reconstructing cancer genomes from paired-end sequencing data. AB - BACKGROUND: A cancer genome is derived from the germline genome through a series of somatic mutations. Somatic structural variants - including duplications, deletions, inversions, translocations, and other rearrangements - result in a cancer genome that is a scrambling of intervals, or "blocks" of the germline genome sequence. We present an efficient algorithm for reconstructing the block organization of a cancer genome from paired-end DNA sequencing data. RESULTS: By aligning paired reads from a cancer genome - and a matched germline genome, if available - to the human reference genome, we derive: (i) a partition of the reference genome into intervals; (ii) adjacencies between these intervals in the cancer genome; (iii) an estimated copy number for each interval. We formulate the Copy Number and Adjacency Genome Reconstruction Problem of determining the cancer genome as a sequence of the derived intervals that is consistent with the measured adjacencies and copy numbers. We design an efficient algorithm, called Paired-end Reconstruction of Genome Organization (PREGO), to solve this problem by reducing it to an optimization problem on an interval-adjacency graph constructed from the data. The solution to the optimization problem results in an Eulerian graph, containing an alternating Eulerian tour that corresponds to a cancer genome that is consistent with the sequencing data. We apply our algorithm to five ovarian cancer genomes that were sequenced as part of The Cancer Genome Atlas. We identify numerous rearrangements, or structural variants, in these genomes, analyze reciprocal vs. non-reciprocal rearrangements, and identify rearrangements consistent with known mechanisms of duplication such as tandem duplications and breakage/fusion/bridge (B/F/B) cycles. CONCLUSIONS: We demonstrate that PREGO efficiently identifies complex and biologically relevant rearrangements in cancer genome sequencing data. An implementation of the PREGO algorithm is available at http://compbio.cs.brown.edu/software/. PMID- 22537041 TI - MGMR: leveraging RNA-Seq population data to optimize expression estimation. AB - BACKGROUND: RNA-Seq is a technique that uses Next Generation Sequencing to identify transcripts and estimate transcription levels. When applying this technique for quantification, one must contend with reads that align to multiple positions in the genome (multireads). Previous efforts to resolve multireads have shown that RNA-Seq expression estimation can be improved using probabilistic allocation of reads to genes. These methods use a probabilistic generative model for data generation and resolve ambiguity using likelihood-based approaches. In many instances, RNA-seq experiments are performed in the context of a population. The generative models of current methods do not take into account such population information, and it is an open question whether this information can improve quantification of the individual samples RESULTS: In order to explore the contribution of population level information in RNA-seq quantification, we apply a hierarchical probabilistic generative model, which assumes that expression levels of different individuals are sampled from a Dirichlet distribution with parameters specific to the population, and reads are sampled from the distribution of expression levels. We introduce an optimization procedure for the estimation of the model parameters, and use HapMap data and simulated data to demonstrate that the model yields a significant improvement in the accuracy of expression levels of paralogous genes. CONCLUSIONS: We provide a proof of principal of the benefit of drawing on population commonalities to estimate expression. The results of our experiments demonstrate this approach can be beneficial, primarily for estimation at the gene level. PMID- 22537042 TI - Haplotype reconstruction using perfect phylogeny and sequence data. AB - Haplotype phasing is a well studied problem in the context of genotype data. With the recent developments in high-throughput sequencing, new algorithms are needed for haplotype phasing, when the number of samples sequenced is low and when the sequencing coverage is blow. High-throughput sequencing technologies enables new possibilities for the inference of haplotypes. Since each read is originated from a single chromosome, all the variant sites it covers must derive from the same haplotype. Moreover, the sequencing process yields much higher SNP density than previous methods, resulting in a higher correlation between neighboring SNPs. We offer a new approach for haplotype phasing, which leverages on these two properties. Our suggested algorithm, called Perfect Phlogeny Haplotypes from Sequencing (PPHS) uses a perfect phylogeny model and it models the sequencing errors explicitly. We evaluated our method on real and simulated data, and we demonstrate that the algorithm outperforms previous methods when the sequencing error rate is high or when coverage is low. PMID- 22537043 TI - Biases in read coverage demonstrated by interlaboratory and interplatform comparison of 117 mRNA and genome sequencing experiments. AB - High-throughput sequencing of whole genomes and transcriptomes allows one to generate large amounts of sequence data very rapidly and at a low cost. The goal of most mRNA sequencing studies is to perform the comparison of the expression level between different samples. However, given a broad variety of modern sequencing protocols, platforms and versions thereof, it is not clear to what extent the obtained results are consistent across platforms and laboratories. The comparison of 117 human mRNA and genome high-throughput sequencing experiments performed on the Illumina and SOLiD platforms at 26 institutions all over the world demonstrated high dependency of the gene coverage profiles on the producing laboratory. Gene coverage profiles showed laboratory-specific non-uniformity that survived the 3'-bias correction and mappability normalization, suggesting that there are other yet unknown mRNA-associated biases. PMID- 22537044 TI - KISSPLICE: de-novo calling alternative splicing events from RNA-seq data. AB - BACKGROUND: In this paper, we address the problem of identifying and quantifying polymorphisms in RNA-seq data when no reference genome is available, without assembling the full transcripts. Based on the fundamental idea that each polymorphism corresponds to a recognisable pattern in a De Bruijn graph constructed from the RNA-seq reads, we propose a general model for all polymorphisms in such graphs. We then introduce an exact algorithm, called KISSPLICE, to extract alternative splicing events. RESULTS: We show that KISSPLICE enables to identify more correct events than general purpose transcriptome assemblers. Additionally, on a 71 M reads dataset from human brain and liver tissues, KISSPLICE identified 3497 alternative splicing events, out of which 56% are not present in the annotations, which confirms recent estimates showing that the complexity of alternative splicing has been largely underestimated so far. CONCLUSIONS: We propose new models and algorithms for the detection of polymorphism in RNA-seq data. This opens the way to a new kind of studies on large HTS RNA-seq datasets, where the focus is not the global reconstruction of full-length transcripts, but local assembly of polymorphic regions. KISSPLICE is available for download at http://alcovna.genouest.org/kissplice/. PMID- 22537045 TI - An improved approach for accurate and efficient calling of structural variations with low-coverage sequence data. AB - BACKGROUND: Recent advances in sequencing technologies make it possible to comprehensively study structural variations (SVs) using sequence data of large scale populations. Currently, more efforts have been taken to develop methods that call SVs with exact breakpoints. Among these approaches, split-read mapping methods can be applied on low-coverage sequence data. With increasing amount of data generated, more efficient split-read mapping methods are still needed. Also, since sequence errors can not be avoided for the current sequencing technologies, more accurate split-read mapping methods are still needed to better handle sequence errors. RESULTS: In this paper, we present a split-read mapping method implemented in the program SVseq2 which improves our previous work SVseq1. Similar to SVseq1, SVseq2 calls deletions (and insertions) with exact breakpoints. SVseq2 achieves more accurate calling through split-read mapping within focal regions. SVseq2 also has a much desired feature: there is no need to specify the maximum deletion size, while some existing split-read mapping methods need more memory and longer running time when larger maximum deletion size is chosen. SVseq2 is also much faster because it only needs to examine a small number of ways of splitting the reads. Moreover, SVseq2 supports insertion calling from low-coverage sequence data, while SVseq1 only supports deletion finding. The program SVseq2 can be downloaded at http://www.engr.uconn.edu/~jiz08001/. CONCLUSIONS: SVseq2 enables accurate and efficient SV calling through split-read mapping within focal regions using paired end reads. For many simulated data and real sequence data, SVseq2 outperforms some other existing approaches in accuracy and efficiency, especially when sequence coverage is low. PMID- 22537046 TI - PAIR: polymorphic Alu insertion recognition. AB - BACKGROUND: Alu polymorphisms are some of the most common polymorphisms in the genome, yet few methods have been developed for their detection. METHODS: We present algorithms to discover Alu polymorphisms using paired-end high throughput sequencing data from multiple individuals. We consider the problem of identifying sites containing polymorphic Alu insertions. RESULTS: We give efficient and practical algorithms that detect polymorphic Alus, both those that are inserted with respect to the reference genome and those that are deleted. The algorithms have a linear time complexity and can be run on a standard desktop machine in a very short amount of time on top of the output of tools standard for sequencing analysis. CONCLUSIONS: In our simulated dataset we are able to locate 98.1% of Alus inserted with respect to the reference and 97.7% of Alus deleted, our simulations also show an excellent correlations between the deletions detected in parents and children. We further run our algorithms on publicly available data from the 1000 genomes project and find several thousand Alu polymorphisms in each individual. PMID- 22537047 TI - High-resolution genetic mapping with pooled sequencing. AB - BACKGROUND: Modern genetics has been transformed by high-throughput sequencing. New experimental designs in model organisms involve analyzing many individuals, pooled and sequenced in groups for increased efficiency. However, the uncertainty from pooling and the challenge of noisy sequencing data demand advanced computational methods. RESULTS: We present MULTIPOOL, a computational method for genetic mapping in model organism crosses that are analyzed by pooled genotyping. Unlike other methods for the analysis of pooled sequence data, we simultaneously consider information from all linked chromosomal markers when estimating the location of a causal variant. Our use of informative sequencing reads is formulated as a discrete dynamic Bayesian network, which we extend with a continuous approximation that allows for rapid inference without a dependence on the pool size. MULTIPOOL generalizes to include biological replicates and case only or case-control designs for binary and quantitative traits. CONCLUSIONS: Our increased information sharing and principled inclusion of relevant error sources improve resolution and accuracy when compared to existing methods, localizing associations to single genes in several cases. MULTIPOOL is freely available at http://cgs.csail.mit.edu/multipool/. PMID- 22537048 TI - A context-based approach to identify the most likely mapping for RNA-seq experiments. AB - BACKGROUND: Sequencing of mRNA (RNA-seq) by next generation sequencing technologies is widely used for analyzing the transcriptomic state of a cell. Here, one of the main challenges is the mapping of a sequenced read to its transcriptomic origin. As a simple alignment to the genome will fail to identify reads crossing splice junctions and a transcriptome alignment will miss novel splice sites, several approaches have been developed for this purpose. Most of these approaches have two drawbacks. First, each read is assigned to a location independent on whether the corresponding gene is expressed or not, i.e. information from other reads is not taken into account. Second, in case of multiple possible mappings, the mapping with the fewest mismatches is usually chosen which may lead to wrong assignments due to sequencing errors. RESULTS: To address these problems, we developed ContextMap which efficiently uses information on the context of a read, i.e. reads mapping to the same expressed region. The context information is used to resolve possible ambiguities and, thus, a much larger degree of ambiguities can be allowed in the initial stage in order to detect all possible candidate positions. Although ContextMap can be used as a stand-alone version using either a genome or transcriptome as input, the version presented in this article is focused on refining initial mappings provided by other mapping algorithms. Evaluation results on simulated sequencing reads showed that the application of ContextMap to either TopHat or MapSplice mappings improved the mapping accuracy of both initial mappings considerably. CONCLUSIONS: In this article, we show that the context of reads mapping to nearby locations provides valuable information for identifying the best unique mapping for a read. Using our method, mappings provided by other state-of-the-art methods can be refined and alignment accuracy can be further improved. AVAILABILITY: http://www.bio.ifi.lmu.de/ContextMap. PMID- 22537049 TI - Subjective pubertal timing and health-compromising behaviours among Swiss adolescent girls reporting an on-time objective pubertal timing. AB - AIM: The aim of this research is to assess the associations between subjective pubertal timing (SPT) and onset of health-compromising behaviours among girls reporting an on-time objective pubertal timing (OPT). METHODS: Data were drawn from the Swiss SMASH 2002 survey, a self-administered questionnaire study conducted among a nationally representative sample of 7548 adolescents aged 16-20 years. From the 3658 girls in the initial sample, we selected only those (n = 1003) who provided information about SPT and who reported the average age at menarche, namely 13, considering this as an on-time OPT. Bivariate and logistic analyses were conducted to compare the early, on-time and late SPT groups in terms of onset of health-compromising behaviours. RESULTS: A perception of pubertal precocity was associated with sexual intercourse before age 16 [adjusted odds ratio (AOR): 2.10 (1.30-3.37)] and early use of illegal drugs other than cannabis [AOR: 2.55 (1.30-5.02)]. Conversely, girls perceiving their puberty as late were less likely to report intercourse before age 16 [AOR: 0.30 (0.12 0.75)]. CONCLUSION: Faced with an adolescent girl perceiving her puberty as early, the practitioner should investigate the existence of health-compromising behaviours even if her puberty is or was objectively on-time. PMID- 22537050 TI - Growth hormone secretagogue receptor antagonists. AB - The patent claims peptidic/nonpeptidic inhibitors of the ghrelin receptor, the growth hormone secretagogue receptor (GHSR) 1A. Among these compounds, it was disclosed that the addition in some compounds of a GlyMetAla tripeptide at the N terminus of the ghrelin peptide agonists converts them into ghrelin receptor antagonists. One of these peptides, among the few that have been studied in vivo, was shown to be able to reduce food intake and body weight gain in rats. PMID- 22537051 TI - Giant molecular shape amphiphiles based on polystyrene-hydrophilic [60]fullerene conjugates: click synthesis, solution self-assembly, and phase behavior. AB - This paper reports a comprehensive study on the synthesis and self-assembly of two model series of molecular shape amphiphiles, namely, hydrophilic [60]fullerene (AC(60)) tethered with one or two polystyrene (PS) chain(s) at one junction point (PS(n)-AC(60) and 2PS(n)-AC(60)). The synthesis highlighted the regiospecific multiaddition reaction for C(60) surface functionalization and the Huisgen 1,3-dipolar cycloaddition between alkyne functionalized C(60) and azide functionalized polymer to give rise to shape amphiphiles with precisely defined surface chemistry and molecular topology. When 1,4-dioxane/DMF mixture was used as the common solvent and water as the selective solvent, these shape amphiphiles exhibited versatile self-assembled micellar morphologies which can be tuned by changing various parameters, such as molecular topology, polymer tail length, and initial molecular concentration, as revealed by transmission electron microscopy and light scattering experiments. In the low molecular concentration range of equal or less than 0.25 (wt) %, micellar morphology of the series of PS(n)-AC(60) studied was always spheres, while the series of 2PS(n)-AC(60) formed vesicles. Particularly, PS(44)-AC(60) and 2PS(23)-AC(60) are synthesized as a topological isomer pair of these shape amphiphiles. PS(44)-AC(60) formed spherical micelles while 2PS(23)-AC(60) generated bilayer vesicles under identical conditions. The difference in the self-assembly of PS(n)-AC(60) and 2PS(n)-AC(60) was understood by the molecular shape aspect ratio. The stretching ratio of PS tails decreased with increasing PS tail length in the spherical micelles of PS(n)-AC(60), indicating a micellar behavior that changes from small molecular surfactant-like to amphiphilic block copolymer-like. For the series of PS(n)-AC(60) in the high molecular concentration range [>0.25 (wt) %], their micellar morphological formation of spheres, cylinders, and vesicles was critically dependent upon both the initial molecular concentration and the PS tail length. On the other hand, the series of 2PS(n)-AC(60) remained in the state of bilayer vesicles in the same concentration range. Combining both of the experimental results obtained in the low and high molecular concentrations, a systematic morphological phase diagram was constructed for the series of PS(n)-AC(60) with different PS tail lengths. The versatile and concentration-sensitive phase behaviors of these molecular shape amphiphiles are unique and have not been systematically explored in the traditional surfactants and block copolymers systems. PMID- 22537052 TI - Glasshouse vs field experiments: do they yield ecologically similar results for assessing N impacts on peat mosses? AB - * Peat bogs have accumulated more atmospheric carbon (C) than any other terrestrial ecosystem today. Most of this C is associated with peat moss (Sphagnum) litter. Atmospheric nitrogen (N) deposition can decrease Sphagnum production, compromising the C sequestration capacity of peat bogs. The mechanisms underlying the reduced production are uncertain, necessitating multifactorial experiments. * We investigated whether glasshouse experiments are reliable proxies for field experiments for assessing interactions between N deposition and environment as controls on Sphagnum N concentration and production. We performed a meta-analysis over 115 glasshouse experiments and 107 field experiments. * We found that glasshouse and field experiments gave similar qualitative and quantitative estimates of changes in Sphagnum N concentration in response to N application. However, glasshouse-based estimates of changes in production--even qualitative assessments-- diverged from field experiments owing to a stronger N effect on production response in absence of vascular plants in the glasshouse, and a weaker N effect on production response in presence of vascular plants compared to field experiments. * Thus, although we need glasshouse experiments to study how interacting environmental factors affect the response of Sphagnum to increased N deposition, we need field experiments to properly quantify these effects. PMID- 22537053 TI - Access to cyclic or branched peptides using bis(2-sulfanylethyl)amido side-chain derivatives of Asp and Glu. AB - Bis(2-sulfanylethyl)amido (SEA) side-chain derivatives of aspartic and glutamic acids enable the synthesis of tail-to-side chain cyclic or branched peptides using standard Fmoc-SPPS followed by SEA native peptide ligation. PMID- 22537055 TI - Carnobacterium divergens - a dominating bacterium of pork meat juice. AB - Nonspoiled food that nevertheless contains bacterial pathogens constitutes a much more serious health problem than spoiled food, as the consumer is not warned beforehand. However, data on the diversity of bacterial species in meat juice are rare. To study the bacterial load of fresh pork from ten different distributors, we applied a combination of the conventional culture-based and molecular methods for detecting and quantifying the microbial spectrum of fresh pork meat juice samples. Altogether, we identified 23 bacterial species of ten different families analyzed by 16S rRNA gene sequencing. The majority of isolates were belonging to the typical spoilage bacterial population of lactic acid bacteria (LAB), Enterococcaceae, and Pseudomonadaceae. Several additional isolates were identified as Staphylococcus spp. and Bacillus spp. originating from human and animal skin and other environmental niches including plants, soil, and water. Carnobacterium divergens, a LAB contributing to the spoilage of raw meat even at refrigeration temperature, was the most frequently isolated species in our study (5/10) with a bacterial load of 10(3) - 10(7) CFU mL(-1). In several of the analyzed pork meat juice samples, two bacterial faecal indicators, Serratia grimesii and Serratia proteamaculans, were identified together with another opportunistic food-borne pathogen, Staphylococcus equorum. Our data reveal a high bacterial load of fresh pork meat supporting the potential health risk of meat juice for the end consumer even under refrigerated conditions. PMID- 22537054 TI - Central obesity is important but not essential component of the metabolic syndrome for predicting diabetes mellitus in a hypertensive family-based cohort. Results from the Stanford Asia-pacific program for hypertension and insulin resistance (SAPPHIRe) Taiwan follow-up study. AB - BACKGROUND: Metabolic abnormalities have a cumulative effect on development of diabetes, but only central obesity has been defined as the essential criterion of metabolic syndrome (MetS) by the International Diabetes Federation. We hypothesized that central obesity contributes to a higher risk of new-onset diabetes than other metabolic abnormalities in the hypertensive families. METHODS: Non-diabetic Chinese were enrolled and MetS components were assessed to establish baseline data in a hypertensive family-based cohort study. Based on medical records and glucose tolerance test (OGTT), the cumulative incidence of diabetes was analyzed in this five-year study by Cox regression models. Contribution of central obesity to development of new-onset diabetes was assessed in subjects with the same number of positive MetS components. RESULTS: Among the total of 595 subjects who completed the assessment, 125 (21.0%) developed diabetes. Incidence of diabetes increased in direct proportion to the number of positive MetS components (P ? 0.001). Although subjects with central obesity had a higher incidence of diabetes than those without (55.7 vs. 30.0 events/1000 person-years, P ? 0.001), the difference became non-significant after adjusting of the number of positive MetS components (hazard ratio = 0.72, 95%CI: 0.45 1.13). Furthermore, in all participants with three positive MetS components, there was no difference in the incidence of diabetes between subjects with and without central obesity (hazard ratio = 1.04, 95%CI: 0.50-2.16). CONCLUSION: In Chinese hypertensive families, the incidence of diabetes in subjects without central obesity was similar to that in subjects with central obesity when they also had the same number of positive MetS components. We suggest that central obesity is very important, but not the essential component of the metabolic syndrome for predicting of new-onset diabetes. ( TRIAL REGISTRATION: NCT00260910, ClinicalTrials.gov). PMID- 22537057 TI - Heterologous expression and characterization of Indian Sahiwal cattle (Bos indicus) alpha inhibin. AB - Inhibin is a non-steroidal glycoprotein hormone of gonadal origin with major action as negative feedback control of the production of FSH by the anterior pituitary gland. The physiological role of inhibin has led to the development of inhibin immunogens for fertility enhancement in farm animals. It is envisaged that a reduction of endogenous inhibin secretion would increase FSH concentrations and thus offers a potential for increasing the number of ovulatory follicles in the ovary. The present work was carried out to produce recombinant bovine (Indian Sahiwal Cattle; Bos indicus) alpha inhibin (bINH-alpha) in E. coli by optimizing its expression and purification in biologically active form and to study its immunological characterization. A bacterial protein expression vector system based on the phage T(5) promoter was used. The bINH-alpha encoding gene was successfully cloned and expressed in E. coli and the purified recombinant bINH-alpha was characterized. Recombinant bINH-alpha (25 ug mL(-1)) immunized guinea pigs had a significant increase in litter size compared to the control group. These results indicate a role for recombinant bINH-alpha as a fecundity vaccine to enhance the ovulation rate and litter size in animals. PMID- 22537056 TI - Blockade of adipocyte differentiation by cordycepin. AB - BACKGROUND AND PURPOSE: Cordyceps militaris has the potential to suppress differentiation of pre-adipocytes. However, the active entities in the extract and the underlying mechanisms of its action are not known. Hence, we investigated whether and how cordycepin (3'-deoxyadenosine), a constituent of C. militaris, inhibits adipogenesis. EXPERIMENTAL APPROACH: Differentiation of 3T3-L1 pre adipocytes and pre-adipocytes in primary cultures was induced by Insulin, dexamethasone and IBMX, and these were used as in vitro models of adipogenesis. The effects of cordycepin on adipogenesis were examined with particular focus on the regulation of CCAAT/enhancer-binding protein beta (C/EBPbeta) and PPARgamma. KEY RESULTS: Cordycepin suppressed the lipid accumulation and induction of adipogenic markers that occurred on differentiation of pre-adipocytes and also blocked the down-regulation of a pre-adipocyte marker. This anti-adipogenic effect was reversible and mediated by an adenosine transporter, but not A1, A2 or A3 adenosine receptors. This effect of cordycepin was not reproduced by other adenosine-related substances, including ATP, ADP and adenosine. Early induction of the adipogenic C/EBPbeta-PPARgamma pathway was suppressed by cordycepin. Blockade of mTORC1 via inhibition of PKB (Akt) and activation of AMP kinase was identified as the crucial upstream event targeted by cordycepin. In addition to its negative effect on adipogenesis, cordycepin suppressed lipid accumulation in mature adipocytes. CONCLUSIONS AND IMPLICATIONS: These results suggest that the anti-adipogenic effects of cordycepin occur through its intervention in the mTORC1-C/EBPbeta-PPARgamma pathway. Cordycepin, by blocking both adipogenesis and lipid accumulation, may have potential as a therapeutic agent for effective treatment of obesity and obesity-related disorders. PMID- 22537058 TI - High level expression of recombinant human antithrombin in the mammary gland of rabbits by adenoviral vectors infection. AB - Expression of recombinant pharmaceutical proteins in the mammalian mammary gland is of great interest for the medical industry. This study was designed to express recombinant human antithrombin (rhAT) in the mammary gland of rabbits by adenovirus vectors infection. Replication-defective adenovirus encoding human antithrombin complementary DNA (cDNA) was constructed and directly infused into the mammary gland of rabbits via the teat canal. The milk serum was collected from the infected mammary gland 48 h post-infection and subjected to Western blot analysis, Enzyme-linked immunosorbent assay (ELISA), and antithrombotic activity assay. In this way, the target protein was verified, and a high expression level of rhAT up to 4.8 g/L was obtained, and antithrombotic activity of the rhAT was not different than that of a standard human antithrombin protein (p > 0.05). Compared to previous attempts to produce human antithrombin in the mammary gland of transgenic animals or fractionation the plasma of blood donors, the method for rhAT expression we established would reduce production cost and further increase production efficacy. PMID- 22537059 TI - Associations between bovine IGFBP2 polymorphisms with fertility, milk production, and metabolic status in UK dairy cows. AB - Insulin-like growth factor binding protein-2 (IGFBP2) is a key regulator of IGF activity that has been associated with insulin resistance and obesity. In cows, IGFBP2 mRNA expression is differentially regulated according to nutritional status in different tissues including the liver, reproductive tract, and mammary gland. This study investigated associations between single nucleotide polymorphisms (SNPs) in bovine IGFBP2 with fertility, milk production, and metabolic traits in Holstein-Friesian dairy cows. Fertility was assessed in heifers by measuring age at first service, age at first conception, and age at first calving. During the first and second lactation, the number of postpartum days for commencement of luteal activity (based on milk progesterone profiles), days to first service, days to conception, average milk production per day, 305 day milk yield, total milk yield, and total days in milk were recorded. Blood samples were taken at -1, +1, and +8 weeks relative to first and second calving for assessment of metabolic status (IGF1, insulin, beta-hydroxybutyrate, and glucose). Five novel SNPs were identified in IGFBP2, two of which had significant associations with fertility (age at conception in heifers and commencement of luteal activity) and 305-day milk yield in lactation 1. Trends of association were also observed with the peripartum metabolic status, in particular the glucose, insulin, and beta-hydroxybutyrate concentrations around second calving. These results indicate that IGFBP2 SNPs may influence tissue mobilization in dairy cows and may thus be of interest for marker assisted selection. PMID- 22537060 TI - Alternative splicing of testis-specific lactate dehydrogenase C gene in mammals and pigeon. AB - The objective of the present study was to confirm the widespread existence of alternative splicing of lactate dehydrogenase c (ldhc) gene in mammals. RT-PCR was employed to amplify cDNAs of ldhc from testes of mammals including pig, dog, rabbit, cat, rat, and mouse, as well as pigeon. Two to six kinds of splice variants of ldhc were observed in the seven species as a result of deletion of one or more exons or insertion of partial sequence of an intron in the mature mRNA. The deleted exons occur mostly in exons 5, 4, 6, and 3. The insertion of a partial sequence of introns, which resulted in an abnormal stop codon in the inserted intron sequence, was observed only in dog and rat. The deletion of exons also resulted in a reading frame shift and formation of a stop codon in some variants. No alternative splicing was observed for ldha and ldhb genes in testis of yak. Native polyacrylamide gel electrophoresis and Western blot analysis revealed no obvious LDH-C4 activity derived from expressed ldhc variants. Our results demonstrated the widespread and unique existence of alternative splicing of ldhc genes in mammals. PMID- 22537061 TI - Molecular cloning, tissue distribution, and functional analysis of porcine Akirin2. AB - Akirin2 is a recently discovered gene that is involved in innate immune response. In this study, the porcine Akirin2 gene was cloned. The full-length coding sequence (CDS) of porcine Akirin2 consists of 612 bp and encodes 203 amino acids with a molecular mass of 22493 kD. The homology tree analysis showed that the pig Akirin2 has closer genetic relationships and distance with the known mammalian Akirin2. Real time quantitative PCR analysis showed that the porcine Akirin2 transcript was most abundant in the lung, followed by the skeletal muscle, heart, liver, fat, thymus, lymph node, small intestine, kidney, and spleen. Overexpression of porcine Akirin2 increased expression of IL-6 in porcine jejunal epithelial cell line IPEC-J2 cells. Our data suggest that porcine Akirin2 could play an important role in intestinal immune regulation. PMID- 22537062 TI - Polymorphism and haplotype structure in River Buffalo (Bubalus bubalis) toll-like receptor 5 (TLR5) coding sequence. AB - Most of the 160 million river buffalo in the world are in Asia where they are used extensively, both as a food source and for draught power. Only recently have investigations begun exploring the buffalo genome for variation that might influence health and productivity of these economically important animals. This paper describes the sequence variability of the toll-like receptor 5 (TLR5) gene, which recognizes bacterial flagellin and is a key player in the immune system. TLR5 is comprised of a single exon that is 2577 bp and codes 858 amino acids. We examined single-nucleotide polymorphisms (SNPs) located within the coding region. Overall, 17 SNPs were discovered, seven of which are non-synonymous. Our study population yielded four different haplotypes. We examined predicted protein domain structure and found that river buffalo, swamp buffalo, and African Forest buffalo shared the same protein domain structure and are more similar to each other than they are to cattle and American bison, which are similar to each other. PolyPhen 2 analysis revealed one amino acid substitution in the river buffalo population with potential functional significance. PMID- 22537063 TI - HSF is the most important transcriptional factor for porcine MC4R promoter. AB - The melanocortin-4 receptor (MC4R) is involved in feed intake regulation. It is significantly associated with growth and fatness traits in most breeds and crosses. To understand the essential transcriptional regions of the porcine MC4R promoter, eleven primer pairs were designed to amplify different segment lengths of the MC4R promoter. The PCR products were then ligated along with the Firefly luciferase reporter gene into the PGL3-basic vector. The results showed that a 90 bp fragment could contain the essential regions for control of transcription. Further research found that a short sequence "AGAAAGAAG" (the recognition site of transcription factor HSF) was the most important sequence for supporting activity of the pig MC4R promoter. PMID- 22537064 TI - Vitamin D receptor genotype in pancreas allograft: a pilot study. AB - OBJECTIVES: Transplanting of pancreatic grafts is an established treatment for diabetes mellitus. Polymorphisms in genes, coding for proteins involved in an immune response, may influence immunologic and nonimmunologic mechanisms that lead to allograft loss. Vitamin D receptor agonists have been shown to increase long-term allograft survival in humans. MATERIALS AND METHODS: Twenty-one pancreatic recipients transplanted in the Transplantation center of Shiraz University of Medical Sciences were selected and genotyped for the polymorphism of the vitamin D receptor genes (FokI), and the association of each genotype with acute rejection was evaluated. A control group of 100 unrelated otherwise healthy individuals, from the Iranian Blood Transfusion Organization were enrolled. The individuals were selected from Shiraz (a city located in Southern Iran), and the genotype frequency was compared with control group. RESULTS: The overall prevalence acute rejection was 28% (6/21). In the genotype study, homozygous FF presented in 15 patients (71%), heterozygous Ff presented in 6 patients (29%), and no homozygous ff was identified. In the control group, there were 50% with FF, 48% with Ff, and 2% with the ff genotype identified. The only genotype that was detected in rejection group was FF, while the frequency of FF in the nonrejection group was 60%. CONCLUSIONS: This study examined several patients to determine whether the vitamin D receptor (FokI) genotype is involved in acute allograft rejection and requires deeper investigation. PMID- 22537065 TI - Text messaging as a new method for injury registration in sports: a methodological study in elite female football. AB - Methodological differences in epidemiologic studies have led to significant discrepancies in injury incidences reported. The aim of this study was to evaluate text messaging as a new method for injury registration in elite female football players and to compare this method with routine medical staff registration. Twelve teams comprising 228 players prospectively recorded injuries and exposure through one competitive football season. Players reported individually by answering three text messages once a week. A designated member of the medical staff conducted concurrent registrations of injuries and exposure. Injuries and exposure were compared between medical staff registrations from nine teams and their 159 affiliated players. During the football season, a total of 232 time-loss injuries were recorded. Of these, 62% were captured through individual registration only, 10% by the medical staff only, and 28% were reported through both methods. The incidence of training injuries was 3.7 per 1000 player hours when calculated from individual registration vs 2.2 from medical staff registration [rate ratio (RR): 1.7, 1.2-2.4]. For match injuries, the corresponding incidences were 18.6 vs 5.4 (RR: 3.4, 2.4-4.9), respectively. There was moderate agreement for severity classifications in injury cases reported by both methods (kappa correlation coefficient: 0.48, confidence interval: 0.30-0.66). PMID- 22537066 TI - Enhancing peptide ligand binding to vascular endothelial growth factor by covalent bond formation. AB - Formation of a stable covalent bond between a synthetic probe molecule and a specific site on a target protein has many potential applications in biomedical science. For example, the properties of probes used as receptor-imaging ligands may be improved by increasing their residence time on the targeted receptor. Among the more interesting cases are peptide ligands, the strongest of which typically bind to receptors with micromolar dissociation constants, and which may depend on processes other than simple binding to provide images. The side chains of cysteine, histidine, or lysine are attractive for chemical attachment to improve binding to a receptor protein, and a system based on acryloyl probes attaching to engineered cysteine provides excellent positron emission tomographic images in animal models (Wei et al. (2008) J. Nucl. Med. 49, 1828-1835). In nature, lysine is a more common but less reactive residue than cysteine, making it an interesting challenge to modify. To seek practically useful cross-linking yields with naturally occurring lysine side chains, we have explored not only acryloyl but also other reactive linkers with different chemical properties. We employed a peptide-VEGF model system to discover that a 19mer peptide ligand, which carried a lysine-tagged dinitrofluorobenzene group, became attached stably and with good yield to a unique lysine residue on human vascular endothelial growth factor (VEGF), even in the presence of 70% fetal bovine serum. The same peptide carrying acryloyl and related Michael acceptors gave low yields of attachment to VEGF, as did the chloroacetyl peptide. PMID- 22537067 TI - Serial examination of serum IL-8, IL-10 and IL-1Ra levels is significant in neonatal seizures induced by hypoxic-ischaemic encephalopathy. AB - We investigated changes in the levels of significant cytokines in relation to neonatal seizures, a pattern of cytokine concentrations serially and the severity of brain insult. The hypoxic-ischaemic encephalopathy-induced seizure group consisted of 13 patients, and another 15 normal newborns were enrolled as a control group. All of the initial samples were obtained within the first 24 h of admission, and the second samples were obtained between 48 and 72 h in both groups. Only the third samples were taken in the seizure group on the 5th day. During neonatal seizures, the levels of most cytokines increased within 24 h, and, in particular, the levels of interleukin (IL)-8 significantly increased (P < 0.05). After 48-72 h of seizure onset, the levels of most cytokines decreased, especially, IL-1Ra; however, IL-8 and IL-10 remained increased (P < 0.05). During the prognosis, one patient who was diagnosed with quadriplegic cerebral palsy at 6 months of age presented extreme elevation of IL-1beta, IL-1Ra, IL-6, IL-8, IL 10 and tumor necrosis factor-alpha in the initial sample, reflecting the severity of brain damage. A significant increase in IL-8 may serve as a biomarker for earlier detection of brain damage in neonatal seizure, if detected within 24 and 48-72 h of the seizure. PMID- 22537068 TI - Alpha-synuclein impairs normal dynamics of mitochondria in cell and animal models of Parkinson's disease. AB - Alpha-synuclein (alpha-syn) is a synaptic protein that mutations have been linked to Parkinson's disease (PD), a common neurodegenerative disorder that is caused by the degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNc). How alpha-syn can contribute to neurodegeneration in PD is not conclusive but it is agreed that mutations or excessive accumulation of alpha-syn can lead to the formation of alpha-syn oligomers or aggregates that interfere with normal cellular function and contribute to the degeneration of dopaminergic neurons. In this study, we found that alpha-syn can impair the normal dynamics of mitochondria and this effect is particular prominent in A53T alpha-syn mutant. In mice expressing A53T alpha-syn, age-dependent changes in both mitochondrial morphology and proteins that regulate mitochondrial fission and fusion were observed. In the cellular model of PD, we found that alpha-syn reduces the movement of mitochondria in both SH-SY5Y neuroblastoma and hippocampal neurons. Taken together, our study provides a new mechanism of how alpha-syn can contribute to PD through the impairment of normal dynamics of mitochondria. PMID- 22537069 TI - Paediatric speech-language pathology service delivery: an exploratory survey of Australian parents. AB - Consideration of client values and preferences for service delivery is integral to engaging with the evidence-based practice triangle (E(3)BP), but as yet such preferences are under-researched. This exploratory study canvassed paediatric speech-language pathology services around Australia through an online survey of parents and compared reported service delivery to preferences, satisfaction, and external research evidence on recommended service delivery. Respondents were 154 parents with 192 children, living across a range of Australian locations and socio-economic status areas. Children had a range of speech and language disorders. A quarter of children waited over 6 months to receive initial assessment. Reported session type, frequency, and length were incongruent with both research recommendations and parents' wishes. Sixty per cent of parents were happy or very happy with their experiences, while 27% were unhappy. Qualitative responses revealed concerns such as; a lack of available, frequent, or local services, long waiting times, cut-off ages for eligibility, discharge processes, and an inability to afford private services. These findings challenge the profession to actively engage with E(3)BP including; being cognisant of evidence based service delivery literature, keeping clients informed of service delivery policies, individualizing services, and exploring alternative service delivery methods. PMID- 22537070 TI - Effect of broccoli sprouts on insulin resistance in type 2 diabetic patients: a randomized double-blind clinical trial. AB - Use of antioxidant components is a new approach for improvement of insulin resistance (IR) as a main feature of type 2 diabetes and its complications. The aim of this study was to investigate the effects of broccoli sprouts powder (BSP) containing high concentration of sulphoraphane on IR in type 2 diabetic patients. Eighty-one patients were randomly assigned to receive 10 g/d BSP (A, n = 27), 5 g/d BSP (B, n = 29) and placebo (C, n = 25) for 4 weeks. Fasting serum glucose and insulin concentration, glucose to insulin ratio and homoeostasis model assessment of IR (HOMA-IR) index were measured at baseline and again 4 weeks after treatment. Seventy-two patients completed the study and 63 were included in the analysis. After 4 weeks, consumption of 10 g/d BSP resulted in a significant decrease in serum insulin concentration and HOMA-IR (p = 0.05 for treatment effect). Therefore, broccoli sprouts may improve IR in type 2 diabetic patients. PMID- 22537072 TI - Clinical picture and social characteristics of super-elderly patients with heart failure in Japan. AB - The number of super-elderly patients older than 80 years with chronic heart failure (HF) is dramatically increased in Japan; however, therapeutic strategies for patients 80 years or older remains to be established. The present investigation was undertaken to clarify the clinical picture and socioeconomic characteristics of super-elderly HF patients. A total of 380 consecutive patients with acute HF or acutely worsening chronic HF were divided into three groups according to age: patients younger than 60 years, those 60 to 80 years, and those 80 years or older (super-elderly group). HF patients in the super-elderly group initially presented with more atypical symptoms at admission compared with those in the younger age group. The prevalence of HF with preserved ejection fraction was more pronounced compared with the patients in the younger age group. Furthermore, the social background was quite different for the 3 groups in several respects: recurrent hospitalization, the prevalence of dementia, and the number of patients living alone all increased with age. The lack of social support in patients with HF is a problem that needs to be resolved in the "super graying" societies such as Japan. PMID- 22537071 TI - Osteoporosis-related fracture case definitions for population-based administrative data. AB - BACKGROUND: Population-based administrative data have been used to study osteoporosis-related fracture risk factors and outcomes, but there has been limited research about the validity of these data for ascertaining fracture cases. The objectives of this study were to: (a) compare fracture incidence estimates from administrative data with estimates from population-based clinically-validated data, and (b) test for differences in incidence estimates from multiple administrative data case definitions. METHODS: Thirty-five case definitions for incident fractures of the hip, wrist, humerus, and clinical vertebrae were constructed using diagnosis codes in hospital data and diagnosis and service codes in physician billing data from Manitoba, Canada. Clinically validated fractures were identified from the Canadian Multicentre Osteoporosis Study (CaMos). Generalized linear models were used to test for differences in incidence estimates. RESULTS: For hip fracture, sex-specific differences were observed in the magnitude of under- and over-ascertainment of administrative data case definitions when compared with CaMos data. The length of the fracture-free period to ascertain incident cases had a variable effect on over-ascertainment across fracture sites, as did the use of imaging, fixation, or repair service codes. Case definitions based on hospital data resulted in under-ascertainment of incident clinical vertebral fractures. There were no significant differences in trend estimates for wrist, humerus, and clinical vertebral case definitions. CONCLUSIONS: The validity of administrative data for estimating fracture incidence depends on the site and features of the case definition. PMID- 22537073 TI - Time-course of eye movement-related decrease in vividness and emotionality of unpleasant autobiographical memories. AB - The time-course of changes in vividness and emotionality of unpleasant autobiographical memories associated with making eye movements (eye movement desensitisation and reprocessing, EMDR) was investigated. Participants retrieved unpleasant autobiographical memories and rated their vividness and emotionality prior to and following 96 seconds of making eye movements (EM) or keeping eyes stationary (ES); at 2, 4, 6, and 10 seconds into the intervention; then followed by regular larger intervals throughout the 96-second intervention. Results revealed a significant drop compared to the ES group in emotionality after 74 seconds compared to a significant drop in vividness at only 2 seconds into the intervention. These results support that emotionality becomes reduced only after vividness has dropped. The results are discussed in light of working memory theory and visual imagery theory, following which the regular refreshment of the visual memory needed to maintain it in working memory is interfered with by eye movements that also tax working memory, which affects vividness first. PMID- 22537074 TI - Asymmetric reproductive interference between specialist and generalist predatory ladybirds. AB - 1. Closely related species often differ greatly in the quality and breadth of resources exploited, but the actual mechanisms causing these differences are poorly understood. Because in the laboratory specialized species often survive and perform as well or better on host species that are never utilized in nature, negative ecological interactions restricting host range must exist. Here, we focused on reproductive interference, which has been theoretically predicted to drive niche separation between closely related species with overlapping mating signals. 2. We examined the interspecific sexual interactions in relation to ecological specialization and generalization in two sibling ladybird species, Harmonia yedoensis and Harmonia axyridis. Harmonia yedoensis is a specialist predator that preys only on pine aphids, which are highly elusive prey for ladybird hatchlings, whereas H. axyridis is a generalist predator with a broad prey and habitat range. 3. We experimentally showed that conspecific sperm fertilized the vast majority of eggs regardless of mating order (i.e. conspecific sperm precedence) when a female of H. yedoensis or H. axyridis mated with both a conspecific and a heterospecific male. Moreover, we demonstrated that mating opportunities of H. yedoensis females strongly decreased as heterospecific density increased relative to conspecific density. In contrast, in H. axyridis, female mating success was high regardless of conspecific or heterospecific density. 4. Our results suggest that the generalist H. axyridis should be dominant to the specialist H. yedoensis in terms of reproductive interference. Our results support the hypothesis that asymmetric reproductive interference from the dominant species may force the non-dominant species to become a specialist predator that exclusively utilizes less preferred prey in nature. PMID- 22537075 TI - Immune response in the skin of zebrafish, Danio rerio (Hamilton), against Staphylococcus chromogenes. PMID- 22537076 TI - Neonatal myocardial infarction: case report and review of the literature. AB - Myocardial infarction in a neonate is rare. We describe the case of a full-term male who presented with respiratory distress. A chest radiograph demonstrated cardiomegaly. An electrocardiogram revealed ST segment changes suggestive of ischemia. Cardiac enzymes were elevated and an echocardiogram revealed a regional wall motion abnormality. Cardiac catheterization was performed demonstrating occlusion of the ramus intermedius branch of the left main coronary artery. The patient decompensated, requiring extracorporeal membrane oxygenation (ECMO). The infant was able to be decannulated from ECMO support in 5 days and was ultimately discharged on hospital day 25. We review this case as well as the literature on neonatal myocardial infarction. PMID- 22537078 TI - Determinants for Arabidopsis peptide transporter targeting to the tonoplast or plasma membrane. AB - Di- and tripeptide transporters of the PTR/NRT1 (peptide transporter/nitrate transporter1)-family are localized either at the tonoplast (TP) or plasma membrane (PM). As limited information is available on structural determinants required for targeting of plant membrane proteins, we performed gene shuffling and domain swapping experiments of Arabidopsis PTRs. A 7 amino acid fragment of the hydrophilic N-terminal region of PTR2, PTR4 and PTR6 was required for TP localization and sufficient to redirect not only PM-localized PTR1 or PTR5, but also sucrose transporter SUC2 to the TP. Alanine scanning mutagenesis identified L(11) and I(12) of PTR2 to be essential for TP targeting, while only one acidic amino acid at position 5, 6 or 7 was required, revealing a dileucine (LL or LI) motif with at least one upstream acidic residue. Similar dileucine motifs could be identified in other plant TP transporters, indicating a broader role of this targeting motif in plants. Targeting to the PM required the loop between transmembrane domain 6 and 7 of PTR1 or PTR5. Deletion of either PM or TP targeting signals resulted in retention in internal membranes, indicating that PTR trafficking to these destination membranes requires distinct signals and is in both cases not by default. PMID- 22537077 TI - Gene expression analysis of mammary tissue during fetal bud formation and growth in two pig breeds--indications of prenatal initiation of postnatal phenotypic differences. AB - BACKGROUND: The mammary gland is key to all mammal species; in particular in multiparous species like pigs the number and the shape of functional mammary gland complexes are major determinants of fitness. Accordingly, we aimed to catalog the genes relevant to mammogenesis in pigs. Moreover, we aimed to address the hypothesis that the extent and timing of proliferation, differentiation, and maturation processes during prenatal development contribute to postnatal numerical, morphological and functional properties of the mammary gland. Thus we focused on differentially expressed genes and networks relevant to mammary complex development in two breeds that are subject to different selection pressure on number, shape and function of teats and show largely different prevalence of non-functional inverted teats. The expression patterns of fetal mammary complexes obtained at 63 and 91 days post conception (dpc) from German Landrace (GL) and Pietrain (PI) were analyzed by Affymetrix GeneChip Porcine Genome Arrays. RESULTS: The expression of 11,731 probe sets was analysed between the two stages within and among breeds. The analysis showed the largest distinction of samples of the breed GL at 63 dpc from all other samples. According to Ingenuity Pathways Analysis transcripts with abundance at the four comparisons made (GL63-GL91, PI63-PI93, GL63-PI63 and GL91-PI91) were predominantly assigned to biofunctions relevant to 'cell maintenance, proliferation, differentiation and replacement', 'organismal, organ and tissue development' and 'genetic information and nucleic acid processing'. Moreover, these transcripts almost exclusively belong to canonical pathways related to signaling rather than metabolic pathways. The accumulation of transcripts that are up-regulated in GL compared to PI indicate a higher proliferating activity in GL, whereas processes related to differentiation, maturation and maintenance of cells are more prominent in PI. Differential expression was validated by quantitative RT-PCR of five genes (GAB1, MAPK9, PIK3C2B, PIK3C3 and PRKCH) that are involved in several relevant signaling pathways. CONCLUSIONS: The results indicate that mammary complex development in PI precedes GL. The differential expression between the two breeds at fetal stages likely reflects the prenatal initiation of postnatal phenotypes concerning the number and shape as well as functionality of teats. PMID- 22537079 TI - Selective cannabinoid receptor 2 modulators: a patent review 2009--present. AB - INTRODUCTION: The activation of the cannabinoid receptor 2 (CB2) affects a myriad of immune responses from inflammation to neuroprotection, demonstrates analgesic effects and suppresses responses in many animal models of pain. Questions around the involvement of CB1 activation in these effects remain, but efforts have been directed toward the discovery of highly selective CB2 modulators lacking the psychotropic effects of cannabinoids, which are mediated by the CB1 receptor. AREAS COVERED: This review covers the patent literature which was published since April 2009 on CB2 selective modulators. It provides a general summary of the CB2 biology supporting the interest in CB2 as a drug target, new potential therapeutic indications and the development status of selective CB2 agonists. EXPERT OPINION: There is a continuous interest in the CB2 receptor as a drug target. Many highly selective compounds of various chemotypes have been identified and their analgesic effects in animal models further support the potential of this mechanism in pain therapy. Several companies have initiated clinical trials. While some of these have been terminated for various reasons, one can anticipate the emergence of new drugs from CB2 modulation once a better understanding around the cannabinoid receptors is gained. PMID- 22537081 TI - Palladium-catalyzed cyclization reactions of 2,3-allenyl amines with propargylic carbonates. AB - A highly efficient and atom-economic route to synthesize 5-(1,3,4-alkatrien-2 yl)oxazolidin-2-ones via palladium-catalyzed cyclization reactions of 2,3-allenyl amines with propargylic carbonates was reported. The CO(2) generated in situ from propargylic carbonates is incorporated into the oxazolidin-2-one unit with high efficiency, affording the products in 70-92% yields. PMID- 22537080 TI - Correcting for the influence of sampling conditions on biomarkers of exposure to phenols and phthalates: a 2-step standardization method based on regression residuals. AB - BACKGROUND: Environmental epidemiology and biomonitoring studies typically rely on biological samples to assay the concentration of non-persistent exposure biomarkers. Between-participant variations in sampling conditions of these biological samples constitute a potential source of exposure misclassification. Few studies attempted to correct biomarker levels for this error. We aimed to assess the influence of sampling conditions on concentrations of urinary biomarkers of select phenols and phthalates, two widely-produced families of chemicals, and to standardize biomarker concentrations on sampling conditions. METHODS: Urine samples were collected between 2002 and 2006 among 287 pregnant women from Eden and Pelagie cohorts, from which phthalates and phenols metabolites levels were assayed. We applied a 2-step standardization method based on regression residuals. First, the influence of sampling conditions (including sampling hour, duration of storage before freezing) and of creatinine levels on biomarker concentrations were characterized using adjusted linear regression models. In the second step, the model estimates were used to remove the variability in biomarker concentrations due to sampling conditions and to standardize concentrations as if all samples had been collected under the same conditions (e.g., same hour of urine collection). RESULTS: Sampling hour was associated with concentrations of several exposure biomarkers. After standardization for sampling conditions, median concentrations differed by--38% for 2,5-dichlorophenol to +80 % for a metabolite of diisodecyl phthalate. However, at the individual level, standardized biomarker levels were strongly correlated (correlation coefficients above 0.80) with unstandardized measures. CONCLUSIONS: Sampling conditions, such as sampling hour, should be systematically collected in biomarker-based studies, in particular when the biomarker half-life is short. The 2-step standardization method based on regression residuals that we proposed in order to limit the impact of heterogeneity in sampling conditions could be further tested in studies describing levels of biomarkers or their influence on health. PMID- 22537082 TI - Contamination rates of different urine collection methods for the diagnosis of urinary tract infections in young children: an observational cohort study. AB - AIMS: The optimal method for diagnostic collection of urine in children is unclear. National Institute of Health and Clinical Excellence recommend specimens taken by clean catch urine (CCU) for identification of urinary tract infection (UTI). We investigated contamination rates for CCU, suprapubic aspiration (SPA), catheter specimen urine (CSU) and bag specimen urine (BSU) collections. METHOD: Retrospective observational cohort study with review of microbiology data and medical records at a large tertiary children's hospital. We reviewed urine culture growth from consecutive first urine specimens of children aged <2 years, over a 3-month period in 2008. Patient demographics, collection method, location (emergency department, inpatient ward), culture growth, history of UTI, urogenital tract abnormality and antibiotic use were assessed. Contamination rates for collection methods were compared using logistic regression. RESULTS: Urine culture specimens of 599 children (mean age 7.0 months, 54% male) were included. There were 34% CCU, 16% CSU, 14% SPA, 2% BSU and 34% with unknown sample method. Contamination rates were 26% in CCU, 12% in CSU (odds ratio (OR) 0.4, 95% confidence interval (CI) 0.2-0.8) and 1% in SPA (OR 0.03 95% CI 0.0 0.3). Concurrent antibiotics use was associated with a lower contamination rate. Contamination rates were not associated with age, sex, location, history of UTI or urogenital abnormalities. CONCLUSION: Contamination rates in CCU are much higher than in CSU and SPA samples. Ideally, SPA should be used for microbiological assessment of urine in young children. Collection procedures need to be optimised if CCU is used. PMID- 22537083 TI - The rapidly emerging ESBL-producing Escherichia coli O25-ST131 clone carries LPS core synthesis genes of the K-12 type. AB - The clone Escherichia coli O25 ST131, typically producing extended-spectrum beta lactamases (ESBLs), has spread globally and became the dominant type among extraintestinal isolates at many parts of the world. However, the reasons behind the emergence and success of this clone are only partially understood. We compared the core type genes by PCR of ESBL-producing and ESBL-nonproducing strains isolated from urinary tract infections in the United Arab Emirates and found a surprisingly high frequency of the K-12 core type (44.6%) among members of the former group, while in the latter one, it was as low (3.7%), as reported earlier. The high figure was almost entirely attributable to the presence of members of the clone O25 ST131 among ESBL producers. Strains from the same clone isolated in Europe also carried the K-12 core type genes. Sequencing the entire core operon of an O25 ST131 isolate revealed a high level of similarity to known K-12 core gene sequences and an almost complete identity with a recently sequenced non-O25 ST131 fecal isolate. The exact chemical structure and whether and how this unusual core type contributed to the sudden emergence of ST131 require further investigations. PMID- 22537084 TI - The immunosuppressive molecule HLA-G and its clinical implications. AB - Human leukocyte antigen G (HLA-G) is a non-classical major histocompatibility complex (MHC) class I molecule that, through interaction with its receptors, exerts important tolerogenic functions. Its main physiological expression occurs in placenta where it seems to participate in the maternal tolerance toward the fetus. HLA-G has been studied as a marker of pregnancy complications such as abortion or pre-eclapmsia. Although HLA-G is not expressed in most adult tissues, its ectopic expression has been observed in some diseases such as viral infections, autoimmune disorders, and especially cancer. HLA-G neo-expression in cancer is associated with the capability of tumor cells to evade the immune control. In this review, we will summarize HLA-G biology and how it participates in these physiopathological processes. Special attention will be paid to its role as a diagnostic tool and also as a therapeutic target. PMID- 22537085 TI - Dose-dependent mesothelioma induction by intraperitoneal administration of multi wall carbon nanotubes in p53 heterozygous mice. AB - Among various types of multi-wall carbon nanotubes (MWCNT) are those containing fibrous particles longer than 5 MUm with an aspect ratio of more than three (i.e. dimensions similar to mesotheliomagenic asbestos). A previous study showed that micrometer-sized MWCNT (MUm-MWCNT) administered intraperitoneally at a dose of 3000 MUg/mouse corresponding to 1 * 10(9) fibers per mouse induced mesotheliomas in p53 heterozygous mice. Here, we report a dose-response study; three groups of p53 heterozygous mice (n = 20) were given a single intraperitoneal injection of 300 MUg/mouse of MUm-MWCNT (corresponding to 1 * 10(8) fibers), 30 MUg/mouse (1 * 10(7)) or 3 MUg/mouse (1 * 10(6)), respectively, and observed for up to 1 year. The cumulative incidence of mesotheliomas was 19/20, 17/20 and 5/20, respectively. The severity of peritoneal adhesion and granuloma formation were dose-dependent and minimal in the lowest dose group. However, the time of tumor onset was apparently independent of the dose. All mice in the lowest dose group that survived until the terminal kill had microscopic atypical mesothelial hyperplasia considered as a precursor lesion of mesothelioma. Right beneath was a mononuclear cell accumulation consisting of CD45- or CD3-positive lymphocytes and CD45/CD3-negative F4/80 faintly positive macrophages; some of the macrophages contained singular MWCNT in their cytoplasm. The lesions were devoid of epithelioid cell granuloma and fibrosis. These findings were in favor of the widely proposed mode of action of fiber carcinogenesis, that is, frustrated phagocytosis where the mesotheliomagenic microenvironment on the peritoneal surface is neither qualitatively altered by the density of the fibers per area nor by the formation of granulomas against agglomerates. PMID- 22537087 TI - The effect of sex on outcome of preterm infants - a population-based survey. AB - AIM: To provide comprehensive data on potential sex differences in maternal and neonatal characteristics, short-term morbidity and neurodevelopmental outcome within an entire geographically determined collective of infants born at a gestational age <32 weeks. METHODS: Between 2003 and 2008, we prospectively enrolled all infants born in Tyrol at <32 weeks of gestation; the association between sex, and a wide set of pre- and postnatal factors, post-discharge morbidity and neurodevelopmental outcome was analysed. RESULTS: Girls less frequently suffered from early-onset sepsis than boys (p = 0.030). After adjustment for multiple corrections (Bonferroni's p = 0.003), no sex differences were seen within any maternal or neonatal parameter. Analysis of morbidity revealed a higher readmission rate in boys (p < 0.0001), which was primarily caused by a greater incidence of respiratory problems (p = 0.003). Boys did not show a greater adverse neurodevelopmental outcome at the age of 12 or 24 months. CONCLUSION: Parents of boys should be prepared for a potentially higher frequency of readmission after initial discharge, but our data currently give no reason for parents of boys to be disproportionately anxious about their neurodevelopmental outcome. Whether boys also enjoy a rosy prognosis for developmental outcome at school age remains to be elucidated. PMID- 22537086 TI - Dominance of flow-mediated constriction over flow-mediated dilatation in the rat carotid artery. AB - BACKGROUND AND PURPOSE: The shearing forces generated by flow generally evoke dilatation in systemic vessels but constriction in the cerebral circulation. The aim of this study was to determine the effects of flow on the conduit artery delivering blood to the brain in the rat, that is, the carotid artery. EXPERIMENTAL APPROACH: Carotid artery segments were mounted in a pressure myograph and pressurized to 100 mmHg. Changes in vessel diameter to flow (0.5-10 mL.min-1 for 2-10 min) at constant pressure were then measured using a video dimension analyser. KEY RESULTS: Following the induction of tone, the onset of flow evoked a transient dilatation followed by a powerful constriction that was sustained until the termination of flow. Endothelial denudation or treatment with indomethacin, N(G)-nitro-L-arginine methyl ester, or the combination of apamin and TRAM-34 showed that the initial flow-mediated dilatation arose from the combined actions of endothelium-derived NO and endothelium-derived hyperpolarizing factor (EDHF). The flow-mediated constriction, which increased in magnitude with increasing flow rate and duration of flow, was also endothelium dependent, but was unaffected by treatment with superoxide dismutase, BQ-123, indomethacin, HET0016 or carbenoxolone. Flow-mediated constriction therefore appeared not to involve superoxide anion, endothelin-1, a COX product, 20-HETE or gap-junctional communication. CONCLUSIONS AND IMPLICATIONS: Although a weak, transient flow-mediated dilatation is observed in the rat carotid artery, the dominant response to flow is a powerful and sustained constriction. Whether this flow-mediated constriction in the carotid artery serves as an extracranial mechanism to regulate cerebral blood flow remains to be determined. PMID- 22537088 TI - Detection of prion protein oligomers by single molecule fluorescence imaging. AB - The degree of polymerization of PrP has a close relationship with the pathological mechanisms of prion diseases. We examined, at the molecular level, the polymerization state of PrP in lysates of prion-infected cells using total internal reflection fluorescence microscopy (TIRFM). The crude lysates were fractionated by gel-filtration spin columns according to their molecular size. Both the oligomer-rich and the monomer-rich fractions were probed with fluorescein-labeled anti-PrP antibodies (mAb SAF70 and mAb 8G8). Fluorescent spots of varying intensity were detected, with the ratio of intense fluorescent spots being greater in the oligomer fraction samples with mAb SAF70 than those with 8G8, the specific epitope of which is thought to be buried in abnormal PrP molecules. The results indicated that PrP oligomers could be specifically detected and conformational changes of abnormal PrP molecules observed. Imaging by TIRFM may aid in determining the polymerization state and properties of PrP oligomers in pathological processes. PMID- 22537089 TI - Genesis of creativity. AB - As advances in nanoscience and nanotechnology are sought, what will be the source of the inspiration to open the doors for new developments? In my opinion, it most often resides in the ingenuity of students, and among those ingenious students, was there a formative spark or a progressive set of stimuli in their childhoods that gave rise to the most precious asset in scientific advance, namely, creativity? Here, I outline the work of three of my students who have propelled the field of nanotechnology, and then I glimpse into their childhood years to see if there lays the key. PMID- 22537090 TI - Optimized fast and sensitive acquisition methods for shotgun proteomics on a quadrupole orbitrap mass spectrometer. AB - Advances in proteomics are continually driven by the introduction of new mass spectrometric instrumentation with improved performances. The recently introduced quadrupole Orbitrap (Q Exactive) tandem mass spectrometer allows fast acquisition of high-resolution higher-energy collisional dissociation (HCD) tandem mass spectra due to the parallel mode of operation, where the generation, filling, and storage of fragment ions can be performed while simultaneously measuring another ion packet in the Orbitrap mass analyzer. In this study, data-dependent acquisition methods for "fast" or "sensitive" scanning were optimized and assessed by comparing stable isotope labeled yeast proteome coverage. We discovered that speed was the most important parameter for sample loads above 125 ng, where a 95 ms HCD scanning method allowed for identification and quantification of more than 2000 yeast proteins from 1 h of analysis time. At sample loads below 125 ng, a 156 ms HCD acquisition method improved the sensitivity, mass accuracy, and quality of data and enabled us to identify 30% more proteins and peptides than the faster scanning method. A similar effect was observed when the LC gradient was extended to 2 or 3 h for the analysis of complex mammalian whole cell lysates. Using a 3 h LC gradient, the sensitive method enabled identification of more than 4000 proteins from 1 MUg of tryptic HeLa digest, which was almost 200 more identifications compared to the faster scanning method. Our results demonstrate that peptide identification on a quadrupole Orbitrap is dependent on sample amounts, acquisition speed, and data quality, which emphasizes the need for acquisition methods tailored for different sample loads and analytical preferences. PMID- 22537091 TI - Chimerism but not neonatal antigen exposure induces transplant tolerance. AB - Acquired transplant tolerance could be readily induced during foetal or neonatal period through donor cell infusion, but it is not the case in adults. This phenomenon has been attributed to the variation of immune system development in neonatal and adult periods. To investigate the role of immature immune system and chimerism in neonatal transplant tolerance, irradiated spleen cells or cell fraction from F1 (BALB/c * C57BL/6) or GFP-F1 mice were injected intravenously into neonatal C57BL/6 mice to induce tolerance. Irradiated cells or cell fraction could not induce chimerism and transplant tolerance in neonatal mice, even increasing the dose of donor cells to 5 * 10(7). Living donor cells induced tolerance in neonatal mice, and the quantity of living cells was correlated with the degree of chimerism and tolerance. At the amount of 3 * 10(7) F1 spleen cells, skin grafts were survived permanently in more than 80% of treated mice. However, the amount of 0.7 * 10(7) F1 spleen cells could only slightly prolong allografts' survival. The more donor cells were infused, the higher level of chimerism was achieved, and the higher frequency of alloreactive T cells was deleted. Chimerism is prerequisite for the induction and maintenance of tolerance. Chimerism in long-term tolerant mice was significantly higher than that in chronic graft rejected mice, with 6.48 +/- 4.02% versus 1.41 +/- 0.77%. It implies that transplant tolerance depends on the establishment of chimerism, but not on antigen exposure to immature immune system in foetus or neonates. PMID- 22537092 TI - The neuroprotective and neurogenic effects of neuropeptide Y administration in an animal model of hippocampal neurodegeneration and temporal lobe epilepsy induced by trimethyltin. AB - The effects of intracerebroventricular administration of neuropeptide Y (NPY), which is believed to play an important role in neuroprotection against excitotoxicity and in the modulation of adult neurogenesis, were evaluated in an animal model of hippocampal neurodegeneration and temporal lobe epilepsy represented by trimethyltin (TMT) intoxication. A single TMT injection (8 mg/kg) causes, in the rat brain, massive neuronal death, selectively involving pyramidal neurons, accompanied by glial activation and enhanced hippocampal neurogenesis. Our data indicate that intracerebroventricular administration of exogenous NPY (at the dose of 2 MUg/2 MUL, 4 days after TMT-administration), in adult rats, exerts a protective role in regard to TMT-induced hippocampal damage and a proliferative effect on the hippocampal neurogenic niche through the up regulation of Bcl-2, Bcl2l1, Bdnf, Sox-2, NeuroD1, Noggin and Doublecortin genes, contributing to delineate more clearly the role of NPY in in vivo neurodegenerative processes. PMID- 22537093 TI - Association between occupational exposure and the clinical characteristics of COPD. AB - BACKGROUND: The contribution of occupational exposures to COPD and their interaction with cigarette smoking on clinical pattern of COPD remain underappreciated. The aim of this study was to explore the contribution of occupational exposures on clinical pattern of COPD. METHODS: Cross-sectional data from a multicenter tertiary care cohort of 591 smokers or ex-smokers with COPD (median FEV1 49%) were analyzed. Self-reported exposure to vapor, dust, gas or fumes (VDGF) at any time during the entire career was recorded. RESULTS: VDGF exposure was reported in 209 (35%) subjects aged 31 to 88 years. Several features were significantly associated with VDGF exposure: age (median 68 versus 64 years, p < 0.001), male gender (90% vs 76%; p < 0.0001), reported work-related respiratory disability (86% vs 7%, p < 0.001), current wheezing (71% vs 61%, p = 0.03) and hay fever (15.5% vs 8.5%, p < 0.01). In contrast, current and cumulative smoking was less (p = 0.01) despite similar severity of airflow obstruction. CONCLUSION: In this patient series of COPD patients, subjects exposed to VDGF were older male patients who reported more work-related respiratory disability, more asthma-like symptoms and atopy, suggesting that, even in smokers or ex-smokers with COPD, occupational exposures are associated with distinct patients characteristics. PMID- 22537094 TI - 11-Oxoaerothionin isolated from the marine sponge Aplysina fistularis shows anti inflammatory activity in LPS-stimulated macrophages. AB - Marine sponges of the order Verongida are a rich source of biologically active bromotyrosine-derived secondary metabolites. However, none of these compounds are known to display anti-inflammatory activity. In the present investigation, we report the anti-inflammatory effects of 11-oxoaerothionin isolated from the Verongida sponge Aplysina fistularis. When RAW264.7 cells and primary macrophages were preincubated with 11-oxoaerothionin and stimulated with LPS (lipopolysaccharide), a concentration-dependent inhibition of iNOS(inducible nitric oxide synthase) protein and NO(2)(-) (Nitrite) production were observed. The same effect was observed when proinflammatory cytokines and PGE(2) (Prostaglandin E2) production was evaluated. In summary, we demonstrated that in the presence of LPS, 11-oxoaerothionin suppresses NO(2) and iNOS expression as well as inflammatory cytokines and PGE(2). PMID- 22537095 TI - The Working Memory Questionnaire: a scale to assess everyday life problems related to deficits of working memory in brain injured patients. AB - The objective of the present study was to develop a scale designed to assess the consequences of working memory deficits in everyday life. The Working Memory Questionnaire (WMQ) is a self-administered scale, addressing three dimensions of working memory: short-term storage, attention, and executive control. The normative sample included 313 healthy participants. The patient group included 69 brain injured patients, who were compared to a subsample of 69 matched healthy controls. The questionnaire was found to have a good internal consistency, both in healthy participants and in patients with brain injury (Cronbach's alpha = .89 and .94, respectively). In healthy participants, significant effects of age (p < .0001) and education (p < .01) were found, due to more complaints in participants aged 60 or more and (unexpectedly) in those aged below 30, and for less educated participants, below high school level. The WMQ was found to have the sensitivity to discriminate patients from matched controls, in the three domains (p < .0001). A good concurrent validity was found with the Cognitive Failure Questionnaire and the Rating Scale of Attentional Behaviour (Spearman's Rho = .90 and .81, respectively, both ps < .0001). In addition, the total complaint score significantly correlated with neuropsychological measures of working memory (visual spans and short-term memory with interference) and with global intellectual efficiency (Raven's Matrices) but not with digit spans. Further studies are needed to measure the internal structure of the scale, and to compare self- and proxy-ratings. PMID- 22537096 TI - Comparative study of imidazolium- and pyrrolidinium-based ionic liquids: thermodynamic properties. AB - Heat capacities of liquid, crystal(s) and liquid-quenched glass (LQG) of room temperature ionic liquid 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)amide ([bmim][Tf(2)N]) and N-butyl-N methylpyrrolidinium bis(trifluoromethylsulfonyl)amide ([bmp][Tf(2)N]) were measured by adiabatic calorimetry. The melting points of [bmim][Tf(2)N] and [bmp][Tf(2)N] were 270.42 and 265.82 K, respectively. Heat capacity anomalies depending on thermal history after crystallization were observed above 200 K in both compounds. Two thermal anomalies due to glass transitions in crystalline [bmim][Tf(2)N] were observed at 59 and 73 K. One thermal anomaly independent of thermal history was observed in a metastable crystalline [bmp][Tf(2)N]. Thermal properties related to LQG of [bmim][Tf(2)N] and [bmp][Tf(2)N] are similar to those of other glass formers, and they are classified as fragile liquids. Heat capacities of [bmim](+) and [bmp](+) due to normal modes of the intramolecular vibration were evaluated through DFT calculations. The comparison between experimental and calculated heat capacity differences shows that the trends in the liquid phase are consistent with each other, while those in the crystal phase deviate further as the temperature is increased. This result supports the authors' previous conclusion that the origin of the low melting point is not a curious property of the liquid but primarily related to properties of the crystal. PMID- 22537097 TI - Nur77: a potential therapeutic target in cancer. AB - INTRODUCTION: The orphan nuclear receptor Nur77 (also known as NR4A1, NGFIB, TR3, TIS1, NAK-1, or N10) is a unique transcription factor encoded by an immediate early gene. Nur77 signaling is deregulated in many cancers and constitutes an important molecule for drug targeting. AREAS COVERED: Nur77 as a versatile transcription factor that displays distinct dual roles in cell proliferation and apoptosis. In addition, several recent insights into Nur77's non-genomic signaling through its physical interactions with various signaling proteins and its phosphorylation-dependent regulation will be highlighted. The possible mechanisms by which Nur77 supports carcinogenesis and specific examples in different human cancers will be summarized. Different approaches to target Nur77 using mimetics, natural products, and synthetic compounds are also described. EXPERT OPINION: These latest findings shed light on the novel roles of Nur77 as an exploitable target for new cancer therapeutics. Further work which focuses on a more complete understanding of the Nur77 interactome as well as how the different networks of Nur77 functional interactions are orchestrated in a stimulus or context-specific way will aid the development of more selective, non toxic approaches for targeting Nur77 in future. PMID- 22537098 TI - Congenital quadricuspid pulmonary valve in an adult patient with double valvular lesions and poststenotic dilatation of the trunk and the left branch of the pulmonary artery: a case presentation and review of the literature. AB - The quadricuspid pulmonary valve (QPV) is a rare congenital anomaly reported in the general population. There are less than 300 reported cases in the literature to date. It has been found in one in 400 to one in 2000 autopsies. We describe here the case of a 47-year-old patient who presents with a QPV with double valvular lesions (stenosis and insufficiency), causing a poststenotic dilatation of the trunk and the left branch of the pulmonary artery (PA). The diagnosis was made by transesophageal echocardiography (TEE) and confirmed by tomographic angiography (computed tomography). The English as well as the Spanish literature were reviewed. To the best of our knowledge, this is the first case of: (1) congenital QPV with double valvular lesions (stenosis and insufficiency), complicated with (2) aneurysmatic dilatation of the PA trunk as well as left branch, and (3) diagnosed by a TEE. PMID- 22537099 TI - Long-term results of renal transplant from living donors aged over 60 years. AB - OBJECTIVES: This study sought to determine whether recipients of grafts from donors aged 60 years or older achieve the same benefit as those from younger donors in the long term. MATERIALS AND METHODS: Between January 2004 and July 2008, one hundred seventeen living renal transplants were performed. The patients were divided into an older donor group (aged >= 60 y, n=23) and a younger donor group (aged < 60 y, n=94). Characteristics and evolution of the donors and recipients were compared between the groups. RESULTS: There was no statistically significant difference between the groups respecting sex, body mass index, duration on dialysis, ischemia time, human leukocyte antigen matches and incidence of primary nonfunction, delayed graft function, acute rejection, and infection (P > .05). The 1-, 3-, and 5-year graft survival for the older group versus the younger group was 95.7% versus 97.9% (P > .05), 91.3% versus 93.6% (P > .05), and 81.8% versus 83.3% (P > .05). Patient survival at 1, 3, and 5 years was 100% versus 100% (P > .05), 95.7% versus 96.8% (P > .05), and 90.9% versus 88.9% (P > .05) with no significant difference in the log-rank test for Kaplan Meier. CONCLUSIONS: Our studies suggest that in the long term, renal transplant from live donors older than 60 years it is an acceptable alternative. PMID- 22537100 TI - Results of a double-blind, placebo-controlled, fixed-dose assessment of once daily OROS(r) hydromorphone ER in patients with moderate to severe pain associated with chronic osteoarthritis. AB - OBJECTIVE: Opioids are recommended for patients with moderate to severe pain due to osteoarthritis (OA), who do not receive adequate analgesia from nonopioid treatment. The objective of this study was to evaluate the efficacy and safety of OROS hydromorphone extended-release (ER) compared with placebo in patients with moderate to severe pain associated with OA. METHODS: This was a randomized, placebo-controlled, double-blind, fixed-dose study. Patients received placebo or fixed-dose OROS hydromorphone ER (8 or 16 mg). The primary efficacy measure was pain intensity score (11-point Numeric Rating Scale) at Maintenance Week 12, analyzed with baseline observation carried forward (BOCF) imputation for missing data. RESULTS: This study did not meet the primary efficacy measure using the BOCF imputation. Study discontinuation was high (52%). When analyzed using last observation carried forward (LOCF) imputation, the prespecified alternate method, OROS hydromorphone ER 16 mg provided significantly better analgesia than placebo (P = 0.0009). Treatment was associated with significant improvements in patient global assessment (P = 0.01), the overall Western Ontario and McMaster Osteoarthritis Index (WOMAC) (P = 0.0003), and its subscales: pain (P = 0.0001), stiffness (P = 0.0023), and physical function (P = 0.0006). Gastrointestinal adverse events, such as constipation and nausea, were common among patients receiving OROS hydromorphone ER. CONCLUSIONS: OROS hydromorphone ER failed to achieve statistical significance for the primary endpoint using the prespecified imputation method (BOCF), likely due to the high discontinuation rate associated with the fixed-dose design. When data were analyzed according to an alternate method of imputation (LOCF), OROS hydromorphone ER demonstrated statistically significant improvements in pain, stiffness, and physical function. PMID- 22537102 TI - Lewis base promoted intramolecular acylcyanation of alpha-substituted activated alkenes: construction of ketones bearing beta-quaternary carbon centers. AB - A novel phosphine-promoted intramolecular acylcyanation of alpha-substituted activated alkenes has been developed, which provides a unique access to densely functionalized acyclic ketones bearing beta-quaternary carbon centers with a remarkable feature that both alpha- and beta-positions of activated alkene are functionalized. PMID- 22537101 TI - Effects of milnacipran, a 5-HT and noradrenaline reuptake inhibitor, on C-fibre evoked field potentials in spinal long-term potentiation and neuropathic pain. AB - BACKGROUND AND PURPOSE: The analgesic action of 5-HT and noradrenaline reuptake inhibitors (SNRIs) on nociceptive synaptic transmission in the spinal cord is poorly understood. We investigated the effects of milnacipran, an SNRI, on C fibre-evoked field potentials (FPs) in spinal long-term potentiation (LTP), a proposed synaptic mechanism of hypersensitivity, and on the FPs in a neuropathic pain model. EXPERIMENTAL APPROACH: C-fibre-evoked FPs by electrical stimulation of the sciatic nerve fibres were recorded in the spinal dorsal horn of anaesthetized adult rats, and LTP was induced by high-frequency stimulation of the sciatic nerve fibres. A rat model of neuropathic pain was produced by L5 spinal nerve ligation and transection. KEY RESULTS: Milnacipran produced prolonged inhibition of C-fibre-evoked FPs when applied spinally after the establishment of LTP of C-fibre-evoked FPs in naive animals. In the neuropathic pain model, spinal administration of milnacipran clearly reduced the basal C fibre-evoked FPs. These inhibitory effects of milnacipran were blocked by spinal administration of methysergide, a 5-HT1/2 receptor antagonist, and yohimbine or idazoxan, alpha2-adrenoceptor antagonists. However, spinal administration of milnacipran in naive animals did not affect the basal C-fibre-evoked FPs and the induction of spinal LTP. CONCLUSION AND IMPLICATIONS: Milnacipran inhibited C fibre-mediated nociceptive synaptic transmission in the spinal dorsal horn after the establishment of spinal LTP and in the neuropathic pain model, by activating both spinal 5-hydroxytryptaminergic and noradrenergic systems. The condition dependent inhibition of the C-fibre-mediated transmission by milnacipran could provide novel evidence regarding the analgesic mechanisms of SNRIs in chronic pain. PMID- 22537103 TI - The co-occurrence of autism spectrum disorder and attention-deficit/hyperactivity disorder symptoms in parents of children with ASD or ASD with ADHD. AB - BACKGROUND: Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) share about 50-72% of their genetic factors, which is the most likely explanation for their frequent co-occurrence within the same patient or family. An additional or alternative explanation for the co-occurrence may be (cross-)assortative mating, e.g., the tendency to choose a partner that is similar or dissimilar to oneself. Another issue is that of parent-of-origin effect which refers to the possibility of parents differing in the relative quantity of risk factors they transmit to the offspring. The current study sets out to examine (cross-)assortative mating and (cross-)parent-of-origin effects of ASD and ADHD in parents of children with either ASD or ASD with ADHD diagnosis. METHODS: In total, 121 families were recruited in an ongoing autism-ADHD family genetics project. Participating families consisted of parents and at least one child aged between 2 and 20 years, with either autistic disorder, Asperger disorder or PDD-NOS, and one or more biological siblings. All children and parents were carefully screened for the presence of ASD and ADHD. RESULTS: No correlations were found between maternal and paternal ASD and ADHD symptoms. Parental ASD and ADHD symptoms were predictive for similar symptoms in the offspring, but with maternal hyperactive-impulsive symptoms, but not paternal symptoms, predicting similar symptoms in daughters. ASD pathology in the parents was not predictive for ADHD pathology in the offspring, but mother's ADHD pathology was predictive for offspring ASD pathology even when corrected for maternal ASD pathology. CONCLUSIONS: Cross-assortative mating for ASD and ADHD does not form an explanation for the frequent co-occurrence of these disorders within families. Given that parental ADHD is predictive of offspring' ASD but not vice versa, risk factors underlying ASD may overlap to a larger degree with risk factors underlying ADHD than vice versa. However, future research is needed to clarify this issue. PMID- 22537104 TI - A critical histidine residue within LIMP-2 mediates pH sensitive binding to its ligand beta-glucocerebrosidase. AB - The lysosomal membrane protein type 2 is a novel identified lysosomal sorting receptor for beta-glucocerebrosidase (GC). Mutations in both genes underlie human pathologies causing action myoclonus-renal failure syndrome (AMRF) and Gaucher disease (GD), respectively. We now demonstrate that the lumenal acidification mediated by the vacuolar (H(+) )-ATPase triggers the dissociation of LIMP-2 and GC in late endosomal/lysosomal compartments. Moreover, we identified a single histidine residue in LIMP-2 that is necessary for LIMP-2 and GC binding. This residue is in close proximity to a proposed coiled-coil domain, which determines the binding to GC and may function as a critical pH sensor. PMID- 22537105 TI - On the application of network theory to arbuscular mycorrhizal fungi-plant interactions: the importance of basic assumptions. PMID- 22537107 TI - Molecular phylogeny of grunts (Teleostei, Haemulidae), with an emphasis on the ecology, evolution, and speciation history of new world species. AB - BACKGROUND: The fish family Haemulidae is divided in two subfamilies, Haemulinae and Plectorhynchinae (sweetlips), including approximately 17 genera and 145 species. The family has a broad geographic distribution that encompasses contrasting ecological habitats resulting in a unique potential for evolutionary hypotheses testing. In the present work we have examined the phylogenetic relationships of the family using selected representatives of additional Percomorpha based on Bayesian and Maximum likelihood methods by means of three mitochondrial genes. We also developed a phylogenetic hypothesis of the New World species based on five molecular markers (three mitochondrial and two nuclear) as a framework to evaluate the evolutionary history, the ecological diversification and speciation patterns of this group. RESULTS: Mitochondrial genes and different reconstruction methods consistently recovered a monophyletic Haemulidae with the Sillaginidae as its sister clade (although with low support values). Previous studies proposed different relationships that were not recovered in this analysis. We also present a robust molecular phylogeny of Haemulinae based on the combined data of two nuclear and three mitochondrial genes. All topologies support the monophyly of both sub-families (Haemulinae, Plectorhinchinae). The genus Pomadasys was shown to be polyphyletic and Haemulon, Anisotremus, and Plectorhinchus were found to be paraphyletic. Four of seven presumed geminate pairs were indeed found to be sister species, however our data did not support a contemporaneous divergence. Analyses also revealed that differential use of habitat might have played an important role in the speciation dynamics of this group of fishes, in particular among New World species where extensive sample coverage was available. CONCLUSIONS: This study provides a new hypothesis for the sister clade of Hamulidae and a robust phylogeny of the latter. The presence of para- and polyphyletic genera underscores the need for a taxonomic reassessment within the family. A scarce sampling of the Old World Pomadasys species prevents us to definitively point to a New World origin of the sub-familiy Hamulinae, however our data suggest that this is likely to be the case. This study also illustrates how life history habitat influences speciation and evolutionary trajectories. PMID- 22537106 TI - Clinical mapping approach to diagnose electrical rotors and focal impulse sources for human atrial fibrillation. AB - INTRODUCTION: The perpetuating mechanisms for human atrial fibrillation (AF) remain undefined. Localized rotors and focal beat sources may sustain AF in elegant animal models, but there has been no direct evidence for localized sources in human AF using traditional methods. We developed a clinical computational mapping approach, guided by human atrial tissue physiology, to reveal sources of human AF. METHODS AND RESULTS: In 49 AF patients referred for ablation (62 +/- 9 years; 30 persistent), we defined repolarization dynamics using monophasic action potentials (MAPs) and recorded AF activation from 64-pole basket catheters in left atrium and, in n = 20 patients, in both atria. Careful positioning of basket catheters was required for optimal mapping. AF electrograms at 64-128 electrodes were combined with repolarization and conduction dynamics to construct spatiotemporal AF maps. We observed sustained sources in 47/49 patients, in the form of electrical rotors (n = 57) and focal beats (n = 11) that controlled local atrial activation with peripheral wavebreak (fibrillatory conduction). Patients with persistent AF had more sources than those with paroxysmal AF (2.1 +/- 1.0 vs 1.5 +/- 0.8, P = 0.02), related to shorter cycle length (163 +/- 19 milliseconds vs 187 +/- 25 milliseconds, P < 0.001). Approximately one-quarter of sources lay in the right atrium. CONCLUSIONS: Physiologically guided computational mapping revealed sustained electrical rotors and repetitive focal beats during human AF for the first time. These localized sources were present in 96% of AF patients, and controlled AF activity. These results provide novel mechanistic insights into human AF and lay the foundation for mechanistically tailored approaches to AF ablation. PMID- 22537108 TI - Concurrent blockade of free radical and microsomal prostaglandin E synthase-1 mediated PGE2 production improves safety and efficacy in a mouse model of amyotrophic lateral sclerosis. AB - While free radicals and inflammation constitute major routes of neuronal injury occurring in amyotrophic lateral sclerosis (ALS), neither antioxidants nor non steroidal anti-inflammatory drugs have shown significant efficacy in human clinical trials. We examined the possibility that concurrent blockade of free radicals and prostaglandin E(2) (PGE(2))-mediated inflammation might constitute a safe and effective therapeutic approach to ALS. We have developed 2-hydroxy-5-[2 (4-trifluoromethylphenyl)-ethylaminobenzoic acid] (AAD-2004) as a derivative of aspirin. AAD-2004 completely removed free radicals at 50 nM as a potent spin trapping molecule and inhibited microsomal PGE(2) synthase-1 (mPGES-1) activity in response to both lipopolysaccharide-treated BV2 cell with IC(50) of 230 nM and recombinant human mPGES-1 protein with IC(50) of 249 nM in vitro. In superoxide dismutase 1(G93A) transgenic mouse model of ALS, AAD-2004 blocked free radical production, PGE(2) formation, and microglial activation in the spinal cords. As a consequence, AAD-2004 reduced autophagosome formation, axonopathy, and motor neuron degeneration, improving motor function and increasing life span. In these assays, AAD-2004 was superior to riluzole or ibuprofen. Gastric bleeding was not induced by AAD-2004 even at a dose 400-fold higher than that required to obtain maximal therapeutic efficacy in superoxide dismutase 1(G93A). Targeting both mPGES-1-mediated PGE(2) and free radicals may be a promising approach to reduce neurodegeneration in ALS and possibly other neurodegenerative diseases. PMID- 22537110 TI - Characterization of surface properties and cytocompatibility of ion-etched chitosan films. AB - Surface modification of biomaterials has been highlighted by biomedical engineers as a facile method for improving cell-biomaterial interactions without the expense and time required to develop new materials. In the present study, we investigated the influence of ion-etching on the surface characteristics of chitosan films using XPS and ATR FT-IR. The physiological behavior of human dermal fibroblasts (hDFs) grown on such surfaces was studied by evaluating adhesive and proliferative properties, and by examining surface morphologies of hDFs using AFM. hDFs displayed different shapes depending on the ion-etching time. hDFs grown on chitosan films ion-etched for 5 min displayed better development of lamellipodia and filopodia around the hDF periphery than did cells grown on nonmodified chitosan film, whereas hDFs did not spread well on films ion etched for 20 min. Films ion-etched for 5 min or less had higher NH(2) and COOH contents, leading to enhanced hDF adhesion and proliferation. PMID- 22537109 TI - Identification of a novel family of BRAF(V600E) inhibitors. AB - The BRAF oncoprotein is mutated in about half of malignant melanomas and other cancers, and a kinase activating single valine to glutamate substitution at residue 600 (BRAF(V600E)) accounts for over 90% of BRAF-mediated cancers. Several BRAF(V600E) inhibitors have been developed, although they harbor some liabilities, thus motivating the development of other BRAF(V600E) inhibitor options. We report here the use of an ELISA based high-throughput screen to identify a family of related quinolol/naphthol compounds that preferentially inhibit BRAF(V600E) over BRAF(WT) and other kinases. We also report the X-ray crystal structure of a BRAF/quinolol complex revealing the mode of inhibition, employ structure-based medicinal chemistry efforts to prepare naphthol analogues that inhibit BRAF(V600E) in vitro with IC(50) values in the 80-200 nM range under saturating ATP concentrations, and demonstrate that these compounds inhibit MAPK signaling in melanoma cells. Prospects for improving the potency and selectivity of these inhibitors are discussed. PMID- 22537111 TI - Breastmilk hepatitis A virus RNA in nursing mothers with acute hepatitis A virus infection. AB - Breastmilk specimens from three women with acute hepatitis A virus (HAV) infection were studied. Anti-HAV immunoglobulin M and immunoglobulin G antibodies were detected in serum and breastmilk specimens of the three women. The three women also had serum HAV RNA. However, HAV RNA was detected only in two of the three breastmilk specimens. It is interesting that none of the three infants contracted clinical HAV infection. Furthermore, mothers with HAV infection should not be encouraged to discontinue breastfeeding. PMID- 22537112 TI - Predominant characteristics of CTX-M-producing Klebsiella pneumoniae isolates from patients with lower respiratory tract infection in multiple medical centers in China. AB - From February 2010 to July 2011, 183 of 416 presumptive Klebsiella pneumoniae isolates with reduced susceptibility to third-generation cephalosporins from patients with lower respiratory tract infection were collected from seven tertiary hospitals in China. Phenotypic and genotypic methods were employed to characterize 158 extended-spectrum beta-lactamase (ESBL)-producers. Among the 158 isolates analyzed, 134 (84.8%) harbored bla(CTX-M) , within which the most predominant ESBL gene was CTX-M-14 (49.4%), followed by CTX-M-15 (12.0%) and CTX M-27 (10.8%). Also, 120 (75.9%) harbored bla(SHV) . One novel SHV variant, bla(SHV -142) with T18A and L35Q substitutions, was identified. Ninety-one isolates carried bla(TEM-1). An isolate containing bla(TEM-135) was first identified in Klebsiella spp. bla(KPC)-2) was detected in 5 isolates. More than one ESBL combination was detected in 18 isolates (11.4%). Fifty-four (34.2%) isolates demonstrated the multidrug resistant (MDR) phenotype. Seventy-four sequence types (STs) were identified, which showed large genetic background diversity in ESBL-producing K. pneumoniae isolates from the six areas. This is the first report on the high prevalence of CTX-M-27 in China with the possible transmission of a single clone (ST48). The correlated surveillance of organisms with MDR phenotype should be investigated in future. PMID- 22537113 TI - Association between arachidonate 5-lipoxygenase-activating protein (ALOX5AP) and lung function in a Korean population. AB - Arachidonate 5-lipoxygenase-activating protein (ALOX5AP) plays a role in the 5 lipoxygenase (LO) pathway, which includes the LTC(4), LTD(4), LTE(4) and LTB(4). These leukotrienes are known causative factors of asthma, allergy, atopy and cardiovascular diseases. ALOX5AP lacks enzyme activity and acts by helping 5-LO function. In this study, healthy and general subjects who live in rural and urban areas of Korea were tested for the association of ALOX5AP polymorphisms with lung function. Lung function was also estimated by calculating the predicted values for forced expiratory volume in one second (FEV(1) _%PRED) and the proportion of the forced vital capacity exhaled in the first second (FEV(1) /FVC_PRED). The linear regression was adjusted for residence area, gender, age, height and smoking status. The analysis revealed associations between FEV(1) and the single nucleotide polymorphism (SNP) rs9506352 and the haplotype TCAC (permuted P-value < 0.05). The linkage disequilibrium block that included the significant SNPs overlapped with SNPs that were revealed previously to associate with myocardial infarction and asthma and to affect lung function. This study is the first to demonstrate the association between lung function and ALOX5AP polymorphisms in a healthy and general population. PMID- 22537114 TI - Immunohistochemical Ki67 labeling index has similar proliferation predictive power to various gene signatures in breast cancer. AB - The objective of this study was to examine the association between the immunohistochemical Ki67 labeling index (IHC Ki67), Ki67 mRNA expression level, and first-generation gene signatures in a cohort of breast cancer patients. We assessed associations between IHC Ki67 and first-generation gene signatures in a panel of 39 tumor samples, using an oligonucleotide microarray. Gene expression analyses included Ki67 alone (MKi67), 21-gene signature, mitosis kinome score signature, and genomic grade index. Correlation coefficients were calculated by Spearman's rank correlation test. In all cases, IHC Ki67, MKi67, and three genetic markers were highly correlated (rho, 0.71-0.97). Estrogen receptor (ER) positive cases showed strong correlations between IHC Ki67 and other signatures (rho, 0.79-0.83). The ER-negative cases showed slightly lower correlations (rho, 0.58-0.73). In ER-positive cases, the low IHC Ki67 group showed significantly longer relapse-free survival than the high IHC Ki67 group (P = 0.007). This difference was confirmed by multivariate analysis. Our data indicate that IHC Ki67 shows similar predictive power for proliferation in ER-positive cancers as genomic markers. Further study of IHC Ki67 is needed to define prognostic factors and predictive factors for chemotherapy using central laboratory assessment. PMID- 22537115 TI - Usefulness of tissue transglutaminase type 2 antibodies in early pregnancy. AB - Celiac disease (CD), an autoimmune disease triggered by dietary gluten, is a multi-systemic disorder that primarily results in mucosal damage of the small intestine. Reproductive disorders and pregnancy complications have been associated with CD. Conflicting results have been published concerning CD and the risk of impaired fetal growth with reduced birthweight. The aim of our multicentric, perspective, case-control study was to determine the prevalence of undiagnosed CD in mothers of small for gestational age (SGA) newborns in two regions of Italy. The study included 480 mothers: group A consisted of 284 SGA newborns' mothers and group B consisted of 196 appropriate for gestational age (AGA) newborns' mothers. Tissue transglutaminase type 2 antibodies (TG2) IgA and IgG were measured in blood samples. We diagnosed two new cases of CD in asymptomatic mothers. It may be appropriate to include the TG2 to the panel of prenatal blood test. PMID- 22537117 TI - Evidence-based cognitive rehabilitation after acquired brain injury: a systematic review of content of treatment. AB - We reviewed all randomised trials on cognitive rehabilitation in order to determine the effective elements in terms of patients' and treatment characteristics, treatment goals and outcome. A total of 95 random controlled trials were included from January 1980 until August 2010 studying 4068 patients in total. Most studies had been conducted on language (n = 25), visuospatial functioning (n = 24), and memory (n = 14). Stroke patients were the commonest subjects (57%; overall mean age = 52.2, SD = 15.0 years). Of the interventions 39% were offered more than 12 months after onset and 23% were offered within two months of onset. The mean (SD) number of hours of treatment actually delivered was 4.1 (3.6) per week; treatment was mostly offered individually. No papers gave specific information on the expertise or competences of the staff involved. With 95 RCTs there is a large body of evidence to support the efficacy of cognitive rehabilitation, and the current study can serve as a database for clinicians and researchers. But most studies have given little information about the actual content of the treatment which makes it difficult to use the studies when making treatment decisions in daily clinical practice. We suggest developing an international checklist to make standardised description of non-pharmacological complex interventions possible. PMID- 22537116 TI - Racial differences in the built environment--body mass index relationship? A geospatial analysis of adolescents in urban neighborhoods. AB - BACKGROUND: Built environment features of neighborhoods may be related to obesity among adolescents and potentially related to obesity-related health disparities. The purpose of this study was to investigate spatial relationships between various built environment features and body mass index (BMI) z-score among adolescents, and to investigate if race/ethnicity modifies these relationships. A secondary objective was to evaluate the sensitivity of findings to the spatial scale of analysis (i.e. 400- and 800-meter street network buffers). METHODS: Data come from the 2008 Boston Youth Survey, a school-based sample of public high school students in Boston, MA. Analyses include data collected from students who had georeferenced residential information and complete and valid data to compute BMI z-score (n = 1,034). We built a spatial database using GIS with various features related to access to walking destinations and to community design. Spatial autocorrelation in key study variables was calculated with the Global Moran's I statistic. We fit conventional ordinary least squares (OLS) regression and spatial simultaneous autoregressive error models that control for the spatial autocorrelation in the data as appropriate. Models were conducted using the total sample of adolescents as well as including an interaction term for race/ethnicity, adjusting for several potential individual- and neighborhood level confounders and clustering of students within schools. RESULTS: We found significant positive spatial autocorrelation in the built environment features examined (Global Moran's I most >= 0.60; all p = 0.001) but not in BMI z-score (Global Moran's I = 0.07, p = 0.28). Because we found significant spatial autocorrelation in our OLS regression residuals, we fit spatial autoregressive models. Most built environment features were not associated with BMI z-score. Density of bus stops was associated with a higher BMI z-score among Whites (Coefficient: 0.029, p < 0.05). The interaction term for Asians in the association between retail destinations and BMI z-score was statistically significant and indicated an inverse association. Sidewalk completeness was significantly associated with a higher BMI z-score for the total sample (Coefficient: 0.010, p < 0.05). These significant associations were found for the 800-meter buffer. CONCLUSION: Some relationships between the built environment and adolescent BMI z-score were in the unexpected direction. Our findings overall suggest that the built environment does not explain a large proportion of the variation in adolescent BMI z-score or racial disparities in adolescent obesity. However, there are some differences by race/ethnicity that require further research among adolescents. PMID- 22537118 TI - Iatrogenic dural arteriovenous fistula and aneurysmal subarachnoid hemorrhage. AB - The authors present the case of a patient who presented acutely with aneurysmal subarachnoid hemorrhage (SAH) and a contralateral iatrogenic dural arteriovenous fistula (DAVF). Diagnostic angiography was performed, revealing a right-sided middle cerebral artery (MCA) aneurysm and a left-sided DAVF immediately adjacent to the entry of the ventriculostomy and bur hole site. A craniotomy was performed for clipping of the ruptured MCA aneurysm, and the patient subsequently underwent endovascular obliteration of the DAVF 3 days later. The authors present their treatment of an iatrogenic DAVF in a patient with an aneurysmal SAH, considerations in management options, and a literature review on the development of iatrogenic DAVFs. PMID- 22537119 TI - Dural arteriovenous fistulas presenting with brainstem dysfunction: diagnosis and surgical treatment. AB - A cerebral dural arteriovenous fistula (DAVF) is an acquired abnormal arterial-to venous connection within the leaves of the intracranial dura with a wide range of clinical presentations and natural history. The Cognard classification correlates venous drainage patterns with neurological course, identifying 5 DAVF types with increasing rates of symptomatic presentation. A spinal DAVF occurs when a radicular artery makes a direct anomalous shunt with a radicular vein within the dural leaflets of the nerve root sleeve. A cervical DAVF is a rare entity, as most spinal DAVFs present as thoracolumbar lesions with myelopathy. In this paper the authors present 2 patients presenting initially with brainstem dysfunction rather than myelopathy secondary to craniocervical DAVF. The literature is then reviewed for similar rare aggressive DAVFs at the craniocervical junction presenting with brainstem symptomatology. PMID- 22537120 TI - Spinal dural arteriovenous fistulas: outcome and prognostic factors. AB - The aim of this study is to review the clinical outcome of patients treated for spinal dural arteriovenous malformations and investigate the presence of pretreatment indicators of outcome after short- and midterm follow-up. The authors retrospectively reviewed the records of 65 consecutive patients treated either surgically or endovascularly in 3 neurosurgery departments between 1989 and 2009. After treatment, 80% of patients reported improvement of at least 1 symptom. Motor symptoms improved more than sensory disorders, pain, or sphincter impairment. Spinal dural arteriovenous fistulas at the thoracic level, and in particular at the lower level, responded better than those in other spinal areas. Spinal dural arteriovenous fistula is a rare pathology with a malignant course that should be treated aggressively. This study appears to confirm that neurological status before treatment, anatomical location of the fistula, and symptoms at presentation are all factors that can predict outcome. Early diagnosis of spinal dural arteriovenous malformations in the lower thoracic area in patients with an Aminoff scale score < 3 was associated with the most favorable outcome. PMID- 22537121 TI - Recurrence of "cured" dural arteriovenous fistulas after Onyx embolization. AB - Endovascular embolization with Onyx has been increasingly used to treat intracranial and spinal dural arteriovenous fistulas (DAVFs). Several case series have been published in recent years reporting high DAVF cure rates with this technique. Although it is seldom reported, DAVF recurrence may occur despite initial "cure." The authors present 3 separate cases of a recurrent DAVF after successful transarterial Onyx embolization. Despite adequate Onyx penetration into the fistula and draining vein, these cases demonstrate that DAVF recanalization may reappear with filling from previous or newly recruited arterial feeders. Other published reports of DAVF recurrence are examined, and potential contributory factors are discussed. These cases highlight the need for awareness of this possible phenomenon and suggest that follow-up angiography should be considered in patients treated with catheter embolization. PMID- 22537122 TI - The superior ophthalmic vein approach for the treatment of carotid-cavernous fistulas: a novel technique using Onyx. AB - OBJECT: Endovascular therapy is the primary treatment option for carotid cavernous fistulas (CCFs). Operative cannulation of the superior ophthalmic vein (SOV) provides a reasonable alternative route to the cavernous sinus when all transvenous and transarterial approaches have been unsuccessful. The role of the liquid embolic agent Onyx in the management of CCFs has not been well documented, especially when using an SOV approach. The purpose of this study is to assess the safety and efficacy of Onyx embolization of CCFs through a surgical cannulation of the SOV. METHODS: The authors retrospectively reviewed all patients with CCFs who were treated with Onyx through an SOV approach between April 2009 and April 2011. Traditional endovascular approaches had failed in all patients. RESULTS: A total of 10 patients were identified, 1 with a Type A CCF, 5 with a Type B CCF, and 4 with a Type D CCF. All fistulas were embolized in 1 session. Onyx was the sole embolic agent used in 7 cases and was combined with coils in 3 other cases. Complete obliteration was achieved in 8 patients and a significant reduction in fistulous flow was achieved in 2 patients, which later progressed to near complete occlusion on angiographic follow-up. All patients experienced a complete clinical recovery with excellent cosmetic results and were free from recurrence at their latest clinical follow-up evaluations. CONCLUSIONS: Onyx embolization is an excellent therapy for CCFs in general, and through an SOV approach in particular. Direct operative cannulation of the SOV followed by Onyx embolization may be the best treatment option in patients with CCFs when all other endovascular approaches have been exhausted. PMID- 22537123 TI - Treatment of carotid-cavernous fistulas using intraarterial balloon assistance: case series and technical note. AB - OBJECT: Multiple approaches have been used to treat carotid-cavernous fistulas (CCFs). The transvenous approach has become a popular and effective route. Onyx is a valuable tool in today's endovascular armamentarium. The authors describe the use of a balloon-assisted technique in the treatment of CCFs with Onyx and assess its feasibility, utility, and safety. METHODS: The authors searched their prospectively maintained database for CCFs embolized using Onyx with the assistance of a compliant balloon placed in the internal carotid artery (ICA). RESULTS: Five patients were treated between July 2009 and July 2011 at the authors' institution. A balloon helped to identify the fistulous point, served as a buttress for coils, protected from inadvertent arterial embolizations, and prevented Onyx and coils from obscuring the ICA during the course of embolization. No balloon-related complications were noted in any of the 5 cases. All 5 fistulas were completely obliterated at the end of the procedure. Four patients had available clinical follow-ups, and all 4 showed reversal of nerve palsies. CONCLUSIONS: Balloon-assisted Onyx embolization of CCFs offers a powerful combination that prevents inadvertent migration of the embolic material into the arterial system, facilitates visualization of the ICA, and serves as a buttress for coils deployed in the cavernous sinus through the fistulous point. Despite adding another layer of technical complexity, an intraarterial balloon can provide valuable assistance in the treatment of CCFs. PMID- 22537124 TI - Absence of abnormal vessels in the subarachnoid space on conventional magnetic resonance imaging in patients with spinal dural arteriovenous fistulas. AB - Spinal dural arteriovenous fistula (DAVF) is an uncommon condition that can be difficult to diagnose. This often results in misdiagnosis and treatment delay. Although conventional MRI plays an important role in the initial screening for the disease, the typical MRI findings may be absent. In this article, the authors present a series of 4 cases involving patients with angiographically proven spinal DAVFs who demonstrated cord T2 prolongation on conventional MRI but without abnormal subarachnoid flow voids or enhancement. These cases suggest that spinal DAVF cannot be excluded in symptomatic patients with cord edema based on conventional MRI findings alone. Dynamic Gd-enhanced MR angiography (MRA) was successful in demonstrating abnormal spinal vasculature in all 4 cases. This limited experience provides support for the role of spinal MRA in patients with abnormal cord signal and symptoms suggestive of DAVF even when typical MRI findings of a DAVF are absent. PMID- 22537125 TI - Management of tandem occlusion stroke with endovascular therapy. AB - OBJECT: Approximately 25% of patients with middle cerebral artery (MCA) occlusion will have a concomitant internal carotid artery (ICA) occlusion, and 50% of patients with an ICA occlusion will have a proximal MCA occlusion. Cervical ICA occlusion with MCA embolic occlusion is associated with a low rate of recanalization and poor outcome after intravenous thrombolysis. The authors report their experience with acute ischemic stroke patients who suffered tandem ICA/MCA (TIM) occlusions and underwent intravenous thrombolysis followed by extracranial ICA angioplasty and intracranial MCA mechanical thrombectomy. METHODS: In a retrospective analysis of their stroke database (2008-2011), the authors identified 2 patients with TIM occlusion treated with intravenous thrombolysis followed by extracranial ICA angioplasty and intracranial mechanical thrombectomy. They examined early neurological improvement defined by a greater than 10-point reduction of National Institutes of Health Stroke Scale (NIHSS) score and an improved modified Rankin Scale (mRS) score at 60 days. Successful recanalization based on thrombolysis in cerebral infarction (TICI) score of 2 or 3 was also evaluated. RESULTS: In both patients a TICI score of 2b or 3 was achieved, signifying successful recanalization. In addition, both patients had a reduction in the NIHSS score by greater than 10 points and an mRS score of 0 at 60 days. CONCLUSIONS: Tandem occlusions of the cervical ICA and MCA may be successfully treated using the multimodality approach of intravenous thrombolysis followed by extracranial ICA angioplasty and intracranial mechanical thrombectomy. PMID- 22537126 TI - Clinical presentation and prognostic factors of spinal dural arteriovenous fistulas: an overview. AB - Spinal dural arteriovenous fistulas (AVFs), the most common type of spinal cord vascular malformation, can be a challenge to diagnose and treat promptly. The disorder is rare, and the presenting clinical symptoms and signs are nonspecific and insidious at onset. Spinal dural AVFs preferentially affect middle-aged men, and patients most commonly present with gait abnormality or lower-extremity weakness and sensory disturbances. Symptoms gradually progress or decline in a stepwise manner and are commonly associated with pain and sphincter disturbances. Surgical or endovascular disconnection of the fistula has a high success rate with a low rate of morbidity. Motor symptoms are most likely to improve after treatment, followed by sensory disturbances, and lastly sphincter disturbances. Patients with severe neurological deficits at presentation tend to have worse posttreatment functional outcomes than those with mild or moderate pretreatment disability. However, improvement or stabilization of symptoms is seen in the vast majority of treated patients, and thus treatment is justified even in patients with substantial neurological deficits. The extent of intramedullary spinal cord T2 signal abnormality does not correlate with outcomes and should not be used as a prognostic factor. PMID- 22537127 TI - Stereotactic radiosurgery for cerebral dural arteriovenous fistulas. AB - OBJECT: Given the feasibility of curative surgical and endovascular therapy for cerebral dural arteriovenous fistulas (DAVFs), there is a relative paucity of radiosurgical series for these lesions as compared with their arteriovenous malformation counterparts. METHODS: The authors reviewed records of 56 patients with 70 cerebral DAVFs treated at their institution over the past 6 years. Ten DAVFs (14%) in 9 patients were treated with stereotactic radiosurgery (SRS), with follow-up obtained for 8 patients with 9 DAVFs. They combined their results with those obtained from a comprehensive review of the literature, focusing on obliteration rates, post-SRS hemorrhage rates, and other complications. RESULTS: In the authors' group of 9 DAVFs, angiographic obliteration was seen in 8 cases (89%), and no post-SRS hemorrhage or complications were observed after a mean follow-up of 2.9 years. Combining the results in these cases with data obtained from their review of the literature, they found 558 DAVFs treated with SRS across 14 series. The overall obliteration rate was 71%; transient worsening occurred in 9.1% of patients, permanent worsening in 2.4% (including 1 death, 0.2% of cases), and post-SRS hemorrhage occurred in 1.6% of cases (4.8% of those with cortical venous drainage [CVD]). The obliteration rate for cavernous DAVFs was 84%, whereas the rates for transversesigmoid and for tentorial DAVFs were 58% and 59%, respectively (adjusted p values, p(cav,TS) = 1.98 * 10(-4), p(cav,tent) = 0.032). Obliteration rates were greater for DAVFs without CVD (80%, compared with 60% for those with CVD, p = 7.59 * 10(-4)). Both transient worsening and permanent worsening were less common in patients without CVD than in those with CVD (3.4% vs 7.3% for transient worsening and 0.9% vs 2.4% for permanent worsening). CONCLUSIONS: Stereotactic radiosurgery with or without adjunctive embolization is an effective therapy for DAVFs that are not amenable to surgical or endovascular monotherapy. It is best suited for lesions without CVD and for cavernous DAVFs. PMID- 22537128 TI - Cerebral dural arteriovenous fistulas and aneurysms. AB - OBJECT: The association of aneurysms and cerebral arteriovenous malformations is well established in the literature. Aside from a small number of case reports and small patient series, this association has not been well explored with cerebral dural arteriovenous fistulas (DAVFs). This study was designed to elucidate this relationship in the authors' own patient cohort with DAVFs. METHODS: Cerebral angiograms of 56 patients with 70 DAVFs were reviewed for the presence of cerebral aneurysms. Background patient demographics, mode of presentation, and DAVF and aneurysm angiographic characteristics were noted. RESULTS: Twelve patients (21%) had aneurysms in addition to their DAVF. Three patients had multiple aneurysms. Of a total of 15 aneurysms, 5 (33%) occurred on DAVF feeding arteries and 10 (67%) were in remote locations. These patients more commonly presented with hemorrhage (58% vs 20% for those without aneurysms). Aneurysms were associated with DAVFs in any location (feeding artery or remote), but flow related feeding artery aneurysms were more likely to be associated with Borden Type III DAVFs. CONCLUSIONS: Twenty-one percent of patients with cerebral DAVFs also had aneurysms in this patient cohort. It is thus prudent to perform 6-vessel digital subtraction angiography on patients with DAVFs to rule out potential feeding artery and remote aneurysms. This association may be explained by flow related phenomena, the initial inciting event leading to DAVF formation, as well as a potential genetic component or predisposition to develop these lesions. PMID- 22537129 TI - Surgical treatment of Type I spinal dural arteriovenous fistulas. AB - OBJECT: Type I spinal dural arteriovenous fistulas (SDAVFs) are low-flow vascular shunts fed by radicular arteries in patients who most often present with myelopathy. Although some fistulas are amenable to endovascular embolization, nearly all can be treated with direct microsurgical obliteration. METHODS: The authors reviewed their experience in treating 214 craniospinal arteriovenous malformations and/or fistulas over the last 8 years. Of these, 19 were spinal (9%), of which 15 (79%) were Type I SDAVFs. The authors reviewed the patients' epidemiological characteristics, presenting symptoms, and SDAVF angioarchitecture in all cases. They subsequently analyzed surgical obliteration rates and outcomes of all 11 patients who underwent fistula microsurgical obliteration. RESULTS: In all patients who underwent microsurgical treatment, complete angiographic obliteration of the fistula was achieved. At follow-up, 10 (91%) of 11 patients exhibited improvement, 1 patient (9%) was the same, and no patients were worse. Specifically, 8 (73%) of 11 patients had improvement in strength and sensation, 5 (71%) of 7 had improvement of bowel/bladder function, and 3 (60%) of 5 had improvement of preoperative paresthesias. There were no wound infections, CSF leaks, or permanent neurological deficits. CONCLUSIONS: Microsurgical treatment of SDAVF provides direct access to the fistula point, allowing for high obliteration rates with excellent long-term improvement of preoperative deficits and limited periprocedural complications. PMID- 22537130 TI - Curative Onyx embolization of tentorial dural arteriovenous fistulas. AB - OBJECT: The authors conducted a study to review their experience with tentorial dural arteriovenous fistulas (DAVFs) treated with transarterial endovascular embolization in which Onyx was used. METHODS: The authors reviewed prospectively collected data in 9 patients with tentorial DAVFs treated with Onyx embolization between 2008 and 2011. Information reviewed included clinical presentation, angiographic features, treatment, and clinical and radiologically documented outcome. Clinical follow-up was available in every patient. Radiological follow up studies were available in 8 of 9 patients (mean follow-up 4.6 months). RESULTS: Six of 9 patients had complete angiographic obliteration (in 5 this was confirmed by a follow-up angiogram obtained 3-6 months later), and 2 patients had near-complete obliteration (faint filling of the venous drainage in the late venous phase). One patient had partial obliteration and required surgical disconnection. In all patients with complete obliteration, transarterial embolization was performed through the posterior branch of the middle meningeal artery. There were no procedural complications, and no morbidity or mortality resulted from Onyx embolization. CONCLUSIONS: Transarterial Onyx embolization is a valid, effective, and safe alternative to surgical disconnection in many patients with tentorial DAVFs. The presence of an adequate posterior branch of the middle meningeal artery is critical to achieve a microcatheter position distal enough to increase the likelihood of complete obliteration. PMID- 22537131 TI - Effects of topically administered FK506 on sciatic nerve regeneration and reinnervation after vein graft repair of short nerve gaps. AB - OBJECT: Despite the development of various nerve coaptation materials and techniques, achievement of desired functional peripheral nerve regeneration is still inadequate, and repair of peripheral nerve injuries is still one of the most challenging tasks and concerns in neurosurgery. The effect of an FK506 loaded vein graft as an in situ delivery system for FK506 in bridging the defects was studied using a rat sciatic nerve regeneration model. METHODS: A 10-mm sciatic nerve defect was bridged using an inside-out vein graft (IOVG) filled with 10 MUl of a carrier-drug dilution (10 ng/ml FK506) in the IOVG/FK506 group. In the IOVG control group, the vein was filled with the same volume of carrier dilution alone. The regenerated fibers were studied 4, 8, and 12 weeks after surgery. RESULTS: Functional study confirmed faster recovery of the regenerated axons in the IOVG/FK506 group than in the IOVG group (p < 0.05). There was a statistically significant difference between the mean gastrocnemius muscle weight ratios of the IOVG/FK506 and IOVG control groups (p < 0.05). Morphometric indices of regenerated fibers showed that the number and diameter of the myelinated fibers were significantly higher in the IOVG/FK506 group than in the IOVG control group. Immunohistochemical analysis showed more positive immunoreactivity to S100 protein in the IOVG/FK506 group than in the IOVG control group. CONCLUSIONS: When loaded in a vein graft, FK506 resulted in improvement of functional recovery and quantitative morphometric indices of sciatic nerve. Topical application of this readily available agent offers the benefit of cost savings as well as avoiding the complications associated with systemic administration. PMID- 22537132 TI - Rotational angiography for diagnosis and surgical planning in the management of spinal vascular lesions. AB - OBJECT: The management of spinal vascular malformations has undergone significant evolution with the advent of advanced endovascular and angiographic technology. Three-dimensional rotational spinal angiography is an advanced tool that allows the surgeon to gain a better appreciation of the anatomy of these spinal vascular lesions and their relation to surrounding structures. This article describes the use of rotational angiography and 3D reconstructions in the diagnosis and management of spinal vascular malformations. METHODS: The authors present representative cases involving surgical treatment planning for spinal vascular malformations with focus on the utility and technique of rotational spinal angiography. They report the use of rotational spinal angiography for a heterogeneous collection of vascular pathological conditions. RESULTS: Eight patients underwent rotational spinal angiography in addition to digital subtraction angiography (DSA) for the diagnosis and characterization of various spinal vascular lesions. Postprocessed images were used to characterize the lesion in relation to surrounding bone and to enhance the surgeon's ability to precisely localize and obliterate the abnormality. The reconstructions provided superior anatomical detail compared with traditional DSA. No associated complications from the rotational angiography were noted, and there was no statistically significant difference in the amount of radiation exposure to patients undergoing rotational angiography relative to traditional angiography. CONCLUSIONS: The use of rotational spinal angiography provides a rapid and powerful diagnostic tool, superior to conventional DSA in the diagnosis and preoperative planning of a variety of spinal vascular pathology. A more detailed understanding of the anatomy of such lesions provided by this technique may improve the safety of the surgical approach. PMID- 22537133 TI - Magnetic resonance imaging/magnetic resonance angiography fusion technique for intraoperative navigation during microsurgical resection of cerebral arteriovenous malformations. AB - OBJECT: Microsurgical resection of arteriovenous malformations (AVMs) is facilitated by real-time image guidance that demonstrates the precise size and location of the AVM nidus. Magnetic resonance images have routinely been used for intraoperative navigation, but there is no single MRI sequence that can provide all the details needed for characterization of the AVM. Additional information detailing the specific location of the feeding arteries and draining veins would be valuable during surgery, and this detail may be provided by fusing MR images and MR angiography (MRA) sequences. The current study describes the use of a technique that fuses contrast-enhanced MR images and 3D time-of-flight MR angiograms for intraoperative navigation in AVM resection. METHODS: All patients undergoing microsurgical resection of AVMs at the Dartmouth Cerebrovascular Surgery Program were evaluated from the surgical database. Between 2009 and 2011, 15 patients underwent surgery in which this contrast-enhanced MRI and MRA fusion technique was used, and these patient form the population of the present study. RESULTS: Image fusion was successful in all 15 cases. The additional data manipulation required to fuse the image sets was performed on the morning of surgery with minimal added setup time. The navigation system accurately identified feeding arteries and draining veins during resection in all cases. There was minimal imaging-related artifact produced by embolic materials in AVMs that had been preoperatively embolized. Complete AVM obliteration was demonstrated on intraoperative angiography in all cases. CONCLUSIONS: Precise anatomical localization, as well as the ability to differentiate between arteries and veins during AVM microsurgery, is feasible with the aforementioned MRI/MRA fusion technique. The technique provides important information that is beneficial to preoperative planning, intraoperative navigation, and successful AVM resection. PMID- 22537134 TI - Comparative analysis of spinal extradural arteriovenous fistulas with or without intradural venous drainage: a systematic literature review. AB - OBJECT: Spinal arteriovenous malformations (AVMs) are classified into types according to anatomical characteristics: dural arteriovenous fistulas (AVFs), intramedullary AVMs, perimedullary AVFs, and extradural AVFs. Spinal extradural AVFs are much rarer than other types of spinal AVMs, and the available literature on this clinical entity has been based only on case reports or small case series. To investigate the clinical characteristics of patients with spinal extradural AVFs, the authors systematically reviewed the associated literature in the MRI era. METHODS: The PubMed database was searched for all relevant English-language case reports and case series published from 1990 to 2011. The clinical differences between Type A with and Type B without intradural venous drainage were statistically compared, especially regarding clinical features and angiographic and MRI findings. RESULTS: Forty-five cases of spinal extradural AVFs were found. Type A spinal extradural AVFs were diagnosed in patients with a significantly older age (mean 63.5 years) as compared with Type B AVFs (mean 34.3 years, p < 0.0001). Most cases of Type A spinal extradural AVFs exhibited a diffuse high signal intensity of the spinal cord on T2-weighted MR images and no mass effect (p < 0.0001), and they commonly occurred in the thoracolumbar and lumbar regions (p < 0.0001). On the other hand, cases of Type B lesions exhibited a normal signal intensity of the cord with severe mass effect due to an enlarged extradural venous plexus, and they commonly occurred in the cervical and upper thoracic regions (p < 0.0001), frequently in patients with neurofibromatosis Type 1 (p = 0.049). Because Type B AVFs consisted of high-flow, multiple complex anastomoses between arteries and the epidural venous plexus, patients with these lesions tended to undergo multisession treatments, and the rate of partial AVF occlusion was significantly higher than for Type A AVFs (p = 0.018), although there was no difference in symptom outcomes between the 2 groups. CONCLUSIONS: To the best of the authors' knowledge, a comparative analysis of the clinical differences in patients with extradural AVFs with or without intradural venous drainage has yet to be described in the literature. They concluded that in the diagnosis of spinal extradural AVF, evaluation of intradural venous drainage is important because the cause of myelopathy determines the treatment goals. PMID- 22537135 TI - Carotid-cavernous fistulas. AB - Carotid-cavernous fistulas (CCFs) are vascular shunts allowing blood to flow from the carotid artery into the cavernous sinus. The characteristic clinical features seen in patients with CCFs are the sequelae of hemodynamic dysfunction within the cavernous sinus. Once routinely treated with open surgical procedures, including carotid ligation or trapping and cavernous sinus exploration, endovascular therapy is now the treatment modality of choice in many cases. The authors provide a review of CCFs, detailing the current classification and clinical management of these lesions. Therapeutic options including conservative management, open surgery, endovascular intervention, and radiosurgical therapy are presented. The complications and treatment results as reported in the contemporary literature are also reviewed. PMID- 22537136 TI - Vascular fistulas of the brain and spinal cord. PMID- 22537137 TI - Immunity after (re)vaccination of paediatric patients following haematopoietic stem cell transplantation. AB - AIMS: Loss of specific immunity follows allogeneic haematopoietic stem cell transplantation (HSCT) in the majority of cases. Responses to (re)vaccinations can be used as indicators of a functional immunological recovery. METHODS: Twenty three paediatric recipients of HSCT were enrolled in a single centre setting and responses to scheduled immunizations analysed. RESULTS: Immunity to vaccine preventable diseases was impaired post HSCT, but (re)vaccinations induced protective responses in 59-100%, depending on the vaccine, regardless of prior graft-versus-host disease (GVHD) history. CONCLUSION: Despite the marked impact of moderate to severe chronic prior GVHD on both the qualitative and quantitative T-cell recovery post allogenic HSCT, most paediatric recipients of allogeneic stem cell grafts appear to attain protective antibody levels after immunization. PMID- 22537139 TI - Trends in socioeconomic inequalities in smoking prevalence, consumption, initiation, and cessation between 2001 and 2008 in the Netherlands. Findings from a national population survey. AB - BACKGROUND: Widening of socioeconomic status (SES) inequalities in smoking prevalence has occurred in several Western countries from the mid 1970's onwards. However, little is known about a widening of SES inequalities in smoking consumption, initiation and cessation. METHODS: Repeated cross-sectional population surveys from 2001 to 2008 (n ~ 18,000 per year) were used to examine changes in smoking prevalence, smoking consumption (number of cigarettes per day), initiation ratios (ratio of ever smokers to all respondents), and quit ratios (ratio of former smokers to ever smokers) in the Netherlands. Education level and income level were used as indicators of SES and results were reported separately for men and women. RESULTS: Lower educated respondents were significantly more likely to be smokers, smoked more cigarettes per day, had higher initiation ratios, and had lower quit ratios than higher educated respondents. Income inequalities were smaller than educational inequalities and were not all significant, but were in the same direction as educational inequalities. Among women, educational inequalities widened significantly between 2001 and 2008 for smoking prevalence, smoking initiation, and smoking cessation. Among low educated women, smoking prevalence remained stable between 2001 and 2008 because both the initiation and quit ratio increased significantly. Among moderate and high educated women, smoking prevalence decreased significantly because initiation ratios remained constant, while quit ratios increased significantly. Among men, educational inequalities widened significantly between 2001 and 2008 for smoking consumption only. CONCLUSIONS: While inequalities in smoking prevalence were stable among Dutch men, they increased among women, due to widening inequalities in both smoking cessation and initiation. Both components should be addressed in equity-oriented tobacco control policies. PMID- 22537138 TI - Urinary interleukin-18 and urinary neutrophil gelatinase-associated lipocalin predict acute kidney injury following pulmonary valve replacement prior to serum creatinine. AB - BACKGROUND: It is becoming increasingly recognized that manifestations of congenital heart disease (CHD) extend beyond the cardiovascular system. The factors contributing to renal dysfunction in patients with CHD are multifactorial, with acute kidney injury (AKI) at time of cardiac surgery playing a major role. AKI is often diagnosed based on changes in serum creatinine and estimated glomerular filtration rate (eGFR). Such measurements are often late and imprecise. Recent data indicate that urinary biomarkers interleukin-18 (IL-18) and neutrophil gelatinase-associated lipocalin (NGAL) are earlier markers of AKI. We sought to determine the efficacy of urinary IL-18 and NGAL for detecting early AKI in patients undergoing surgical pulmonary valve replacement (PVR). METHODS: Twenty patients presenting for surgical PVR with a history of previous repair of a conotruncal anomaly were enrolled. Preoperative clinical data were measured and urine samples and serum creatinine were collected at 6, 12, 24, and 72 hours post bypass. Urine was evaluated for NGAL and IL-18. AKI was determined using the Risk, Injury, Failure, Loss and End Stage Renal Disease (RIFLE) classification system. RESULTS: Using the RIFLE classification system, seven patients (35%) were found to have AKI defined as a drop in the eGFR or an increase in serum creatinine. All seven patients with AKI had marked increase from preoperative baseline in urine IL-18 (sixfold) and NGAL (26-fold). Using NGAL and IL-18, AKI was detected at 6 hours postoperatively, resulting in AKI being identified 12-36 hours prior to detection by conventional methods. No preoperative predictors for AKI were identified. CONCLUSION: Both NGAL and IL-18 are early predictive biomarkers of AKI, and both increase in tandem after surgical PVR. Importantly, both rise before an increase in creatinine or a decrease in eGFR is present. Monitoring both biomarkers may allow for earlier detection and subsequent interventions to prevent AKI at time of surgery for CHD. PMID- 22537140 TI - Design of patchy particles using quaternary self-assembled monolayers. AB - Binary and ternary self-assembled monolayers (SAMs) adsorbed on gold nanoparticles (NPs) have been previously studied for their propensity to form novel and unexpected patterns. The patterns found were shown to arise from a competition between immiscibilty of unlike surfactants and entropic gains due to length or other architectural differences between them. We investigate patterns self-assembled from quaternary monolayers on spherical nanoparticles. We perform simulations to study the effect of NP radius, degree of immiscibility between surfactants, length differences, and stoichiometry of the SAM on the formation of patterns. We report patterns analogous to binary and ternary cases, as well as some novel patterns specific to quaternary SAMs. PMID- 22537141 TI - Two-hour postdose level of cyclosporine monitoring of solid-organ transplant patients. PMID- 22537143 TI - Synthesis of 3,5-disubstituted isoxazoles via Cope-type hydroamination of 1,3 dialkynes. AB - An efficient method for the synthesis of 3,5-disubstituted isoxazoles is described. The reactions of 1,3-dialkynes with hydroxylamine proceeded smoothly in DMSO under mild reaction conditions to produce 3,5-disubstituted isoxazoles in satisfactory to excellent yields. PMID- 22537142 TI - Discovery of purinergic signalling, the initial resistance and current explosion of interest. AB - There has been a remarkable growth of papers published about purinergic signalling via ATP since 1972. I am most grateful to the wonderful PhD students and postdoctoral fellows who have worked with me over the years to pursue the purinergic hypothesis despite early opposition and to the many outstanding scientists around the world who are currently extending the story. Recently, therapeutic approaches to pathological disorders include the development of selective P1 and P2 receptor subtype agonists and antagonists, as well as of inhibitors of extracellular ATP breakdown and of ATP transport enhancers and inhibitors. Medicinal chemists are starting to develop small molecule purinergic drugs that are orally bioavailable and stable in vivo. PMID- 22537145 TI - Validation of a dental image-analyzer tool to measure the radiographic defect angle of the intrabony defect in periodontitis patients. AB - BACKGROUND AND OBJECTIVE: A report describing the software Dental Image Analyzer (DIA) was published in this journal in 2009. A new function - measurement of the periodontal intrabony defect angle - was added to the software in 2010. The purpose of this study was to investigate whether measurements of the radiographic intrabony defect angle using digital radiographs and the newly developed DIA tool were comparable with measurements obtained using the conventional protractor method. MATERIAL AND METHODS: The baseline radiographic defect angle of intrabony defects was measured conventionally, using a protractor, in 60 selected teeth from 47 patients and then digitally using the newly developed DIA tool. The measurements were made independently by four experienced dentists. The radiographic defect angle of intrabony defects was measured after the three anatomical landmarks were identified, namely the cemento enamel junction, the top of the crest and the bottom of the defect. RESULTS: Both methods showed a high interexaminer reliability for measurements of the radiographic defect angle of intrabony defects (intraclass correlation coefficient > 0.97). Moreover, both methods showed high reliability (intraclass correlation coefficient > 0.96). On the other hand, the new DIA tool, compared with the conventional method, exhibited high sensitivity (0.92) and high specificity (0.91) in selecting defects of >= 37 degrees or < 37 degrees . Analysis of the time taken for measurements revealed significant differences between the two methods, with the protractor method being more time consuming. CONCLUSIONS: This study provided evidence for the lack of a significant difference between the conventional method and the DIA tool for radiographic measurement of intrabony defects. However, digital analysis was significantly faster. PMID- 22537146 TI - Changes in the maternal cytokine profile in pregnancies complicated by fetal growth restriction. AB - Fetal growth restriction (FGR) is an important and poorly understood condition of pregnancy, which results in significant fetal, neonatal and long-term morbidity and mortality. The aetiology of FGR is unknown and is likely to result from sub optimal placental implantation and feto-maternal immunological interaction. The diagnostic criteria for FGR vary between studies, and the condition often occurs with preeclampsia (PET). We present a review of studies of maternal cytokines in FGR and compare these with studies of Small for Gestational Age and PET pregnancies. PMID- 22537144 TI - Enhancer identification in mouse embryonic stem cells using integrative modeling of chromatin and genomic features. AB - BACKGROUND: Epigenetic modifications, transcription factor (TF) availability and differences in chromatin folding influence how the genome is interpreted by the transcriptional machinery responsible for gene expression. Enhancers buried in non-coding regions are found to be associated with significant differences in histone marks between different cell types. In contrast, gene promoters show more uniform modifications across cell types. Here we used histone modification and chromatin-associated protein ChIP-Seq data sets in mouse embryonic stem (ES) cells as well as genomic features to identify functional enhancer regions. Using co-bound sites of OCT4, SOX2 and NANOG (co-OSN, validated enhancers) and co-bound sites of MYC and MYCN (limited enhancer activity) as enhancer positive and negative training sets, we performed multinomial logistic regression with LASSO regularization to identify key features. RESULTS: Cross validations reveal that a combination of p300, H3K4me1, MED12 and NIPBL features to be top signatures of co OSN regions. Using a model from 10 signatures, 83% of top 1277 putative 1 kb enhancer regions (probability greater than or equal to 0.8) overlapped with at least one TF peak from 7 mouse ES cell ChIP-Seq data sets. These putative enhancers are associated with increased gene expression of neighbouring genes and significantly enriched in multiple TF bound loci in agreement with combinatorial models of TF binding. Furthermore, we identified several motifs of known TFs significantly enriched in putative enhancer regions compared to random promoter regions and background. Comparison with an active H3K27ac mark in various cell types confirmed cell type-specificity of these enhancers. CONCLUSIONS: The top enhancer signatures we identified (p300, H3K4me1, MED12 and NIPBL) will allow for the identification of cell type-specific enhancer regions in diverse cell types. PMID- 22537147 TI - Colorectal cancer surgery 2000-2008: evaluation of a prospective database. AB - BACKGROUND: Colorectal cancer is a common cause of cancer death in Australia and is primarily managed operatively. Surgical databases are valuable in monitoring performance in cancer treatment and detecting problems and trends. METHODS: Diagnostic and treatment variables and short-term outcomes were gathered prospectively for patients undergoing resection for colorectal cancer over a 9-year period. Survival data were obtained by linkage to state and interstate death indices. RESULTS: Eight hundred and five patients underwent resection for colorectal cancer during the study period. Overall 5-year survival was 61%. Five-year cancer-specific survival was 73%. Five-year cancer-specific survival for Australian Clinico-Pathological Staging (ACPS) stages A, B, C and D was 96, 80, 61 and 19%, respectively (P < 0.0001). Emergency presentations showed diminished survival (59% versus 75%, P < 0.0001) after controlling for age and stage (hazard ratio (HR) 1.78, P= 0.005), as did transfusion recipients (63% versus 74%, P= 0.0014; HR 1.78, P= 0.004). Anastomotic leak did not affect survival in multivariable analysis. Non-cancer causes accounted for 26% deaths, primarily comprising cardiovascular deaths in the elderly. DISCUSSION: High case ascertainment, data completeness and accuracy can be obtained with prospective, independently gathered data linked electronically to national death records. Survival for colorectal cancer in South Australia continues to improve. Close follow-up for disease recurrence is warranted for transfusion recipients, emergencies and advanced disease. Locally managed databases with linkage to state registries and other institutions are powerful methods to improve data quality and surgical care at a national level. PMID- 22537148 TI - NCPP treatment alleviates ConA-induced hepatitis via reducing CD4+T activation and NO production. AB - Corynebacterium parvum (CP), a kind of immunomodulator, has been well documented in many diseases. Non-cell C. parvum product (NCPP) is a newly-found nano preparation. To investigate the effect of NCPP on Con A-induced murine severe hepatitis, we pretreated mice with NCPP intraperitoneally. After 12 h, ConA (25 MUg/g body wt) was injected intravenously to provoke severe hepatitis and the degree of liver injury was evaluated by serum transaminase analysis and heptatic tissue pathology. Results have shown that levels of serum transaminase and degree of liver injury in ConA/NCPP groups had significantly declined than those in ConA/PBS groups. Notably, results of flow cytometry have demonstrated that activation of CD4+T cells in ConA/NCPP groups has been down-regulated, compared with ConA/PBS groups. Further, levels of serum and KC-related nitric oxide (NO) was displayed significantly lower in ConA/NCPP groups than those in ConA/PBS groups. The results indicate that NCPP may alleviate ConA-induced hepatitis by reducing CD4+T activation and NO production. PMID- 22537149 TI - Development of new IL28B genotyping method using Invader Plus assay. AB - IL28B polymorphism is associated with the response to pegylated interferon-alpha with ribavirin (PEG-IFN-alpha/RBV) treatment in chronic hepatitis C patients. As a genotyping assay for IL28B single nucleotide polymorphisms (SNPs) in clinical practice, the Invader Plus assay was developed. The accuracy, intra-assay, inter assay precision, and the limit of detection of the Invader Plus assay were evaluated. Two SNPs (rs8099917 and rs12979860) associated with IL28B were genotyped by the Invader Plus and TaqMan assay in 512 Japanese patients. In comparison with direct sequencing, the Invader Plus assay showed 99% accuracy in rs8099917 and 100% accuracy in rs12979860. Intra-assay and inter-assay precision were sufficient to use in clinical practice and the detection limit was 1ngDNA/assay. Genotyping by rs8099917 showed that 361 (71%), 144 (28%) and seven (1%) of the patients were major homozygous, heterozygous and minor homozygous types, respectively. Five of the 512 cases (1%) had haplotype differences, but none showed differences between the two genotyping methods. For patients with HCV genotype 1, the prevalence of responders in the major homozygous type was 83.3%, and that of non-responders in the minor heterozygous/homozygous type was 72.5%. A convenient IL28B genotyping method using the Invader Plus assay could be useful to predict the treatment outcome in clinical practice. PMID- 22537150 TI - Conversion of viable but nonculturable enteric bacteria to culturable by co culture with eukaryotic cells. AB - Viable but nonculturable (VBNC) Vibrio cholerae non-O1/non-O139, V. parahaemolyticus, enterohemorrhagic Escherichia coli, enterotoxigenic E. coli, enteropathogenic E. coli, Shigella flexneri, and Salmonella enterica were converted to the culturable state by co-culture with selected eukaryotic cells, e.g., HT-29, Caco-2, T84, HeLa, Intestine 407, and CHO cells. PMID- 22537151 TI - Early muscle and brain ultrastructural changes in polymerase gamma 1-related encephalomyopathy. AB - Mutations affecting the mitochondrial DNA-polymerase gamma 1 (POLG1) gene have been shown to cause Alpers-Huttenlocher disease. Ultrastructural data on brain and muscle tissue are rare. We report on ultrastructural changes in brain and muscle tissue of two sisters who were compound heterozygous for the c.2243G>C and c.1879C>T POLG1 mutations. Patient 1 (16 years) presented with epilepsia partialis continua that did not respond to antiepileptic treatment. Neuroimaging showed right occipital and bithalamic changes. Light microscopy from a brain biopsy performed after 3 weeks suggested chronic encephalitis showing astro- and microgliosis as well as perivascular CD8-positive T-cells. However, immunosuppressive therapy failed to improve her condition. When her 17-year-old sister (patient 2) also developed epilepsy, an intensified search for metabolic diseases led to the diagnosis. On electron microscopy mitochondrial abnormalities mainly affecting neurons were detected in the brain biopsy of patient 1, including an increase in number and size, structural changes and globoid inclusions. In patient 2, light and electron microscopy on a muscle biopsy confirmed a mitochondrial myopathy, also revealing an increase in mitochondrial size and number, as well as globoid inclusions. Neurons may be the primary target of mitochondrial dysfunction in brains of patients with Alpers disease related to POLG1 mutations. During early disease stages, brain histopathology may be misleading, showing reactive inflammatory changes. PMID- 22537152 TI - Expression and prognostic significance of CIP2A mRNA in hepatocellular carcinoma and nontumoral liver tissues. AB - OBJECTIVE: This study was undertaken to determine the role of cancerous inhibitor of protein phosphatase 2A (CIP2A) in predicting prognosis of hepatocellular carcinoma (HCC). METHODS: CIP2A mRNA level of 136 pairs of tumor and nontumoral liver tissues of HCC patients after hepatectomy were investigated by quantitative real-time reverse transcription polymerase chain reaction. RESULTS: Intratumoral CIP2A mRNA was not associated with patients' prognosis. However, nontumoral CIP2A mRNA, which was correlated with lack of tumor encapsulation, poor tumor differentiation, intrahepatic metastasis, and high tumor-node-metastasis stage was an independent risk factor for overall survival and recurrence-free survival. CONCLUSIONS: Nontumoral CIP2A mRNA expression might serve as a novel biomarker for HCC patients undergoing resection. PMID- 22537154 TI - Contrast effects in typicality judgements: a hierarchical Bayesian approach. AB - We examine the influence of contrast categories on the internal graded membership structure of everyday concepts using computational models proposed in the artificial category learning tradition. In particular, the generalized context model (Nosofsky, 1986), which assumes that only members of a given category contribute to the typicality of a category member, is contrasted to the similarity-dissimilarity generalized context model (SD-GCM; Stewart & Brown, 2005), which assumes that members of other categories are also influential in determining typicality. The models are compared in a hierarchical Bayesian framework in their account of the typicality gradient of five animal categories and six artefact categories. For each target category, we consider all possible relevant contrast categories. Three separate issue are examined: (a) whether contrast effects can be found, (b) which categories are responsible for these effects, and (c) whether more than one category influences the typicality. Results indicate that the internal category structure is codetermined by dissimilarity towards potential contrast categories. In most cases, only a single contrast category contributed to the typicality. The present findings suggest that contrast effects might be more widespread than has previously been assumed. Further, they stress the importance of characteristics particular of everyday concepts, which require careful consideration when applying computational models of representation of the artificial category learning tradition to everyday concepts. PMID- 22537153 TI - Chemocentric informatics approach to drug discovery: identification and experimental validation of selective estrogen receptor modulators as ligands of 5 hydroxytryptamine-6 receptors and as potential cognition enhancers. AB - We have devised a chemocentric informatics methodology for drug discovery integrating independent approaches to mining biomolecular databases. As a proof of concept, we have searched for novel putative cognition enhancers. First, we generated Quantitative Structure-Activity Relationship (QSAR) models of compounds binding to 5-hydroxytryptamine-6 receptor (5-HT(6)R), a known target for cognition enhancers, and employed these models for virtual screening to identify putative 5-HT(6)R actives. Second, we queried chemogenomics data from the Connectivity Map ( http://www.broad.mit.edu/cmap/ ) with the gene expression profile signatures of Alzheimer's disease patients to identify compounds putatively linked to the disease. Thirteen common hits were tested in 5-HT(6)R radioligand binding assays and ten were confirmed as actives. Four of them were known selective estrogen receptor modulators that were never reported as 5-HT(6)R ligands. Furthermore, nine of the confirmed actives were reported elsewhere to have memory-enhancing effects. The approaches discussed herein can be used broadly to identify novel drug-target-disease associations. PMID- 22537156 TI - Human pathogens utilize host extracellular matrix proteins laminin and collagen for adhesion and invasion of the host. AB - Laminin (Ln) and collagen are multifunctional glycoproteins that play an important role in cellular morphogenesis, cell signalling, tissue repair and cell migration. These proteins are ubiquitously present in tissues as a part of the basement membrane (BM), constitute a protective layer around blood capillaries and are included in the extracellular matrix (ECM). As a component of BMs, both Lns and collagen(s), thus function as major mechanical containment molecules that protect tissues from pathogens. Invasive pathogens breach the basal lamina and degrade ECM proteins of interstitial spaces and connective tissues using various ECM-degrading proteases or surface-bound plasminogen and matrix metalloproteinases recruited from the host. Most pathogens associated with the respiratory, gastrointestinal, or urogenital tracts, as well as with the central nervous system or the skin, have the capacity to bind and degrade Lns and collagen(s) in order to adhere to and invade host tissues. In this review, we focus on the adaptability of various pathogens to utilize these ECM proteins as enhancers for adhesion to host tissues or as a targets for degradation in order to breach the cellular barriers. The major pathogens discussed are Streptococcus, Staphylococcus, Pseudomonas, Salmonella, Yersinia, Treponema, Mycobacterium, Clostridium, Listeria, Porphyromonas and Haemophilus; Candida, Aspergillus, Pneumocystis, Cryptococcus and Coccidioides; Acanthamoeba, Trypanosoma and Trichomonas; retrovirus and papilloma virus. PMID- 22537157 TI - American tegumentary leishmaniasis: cytokines and nitric oxide in active disease and after clinical cure, with or without chemotherapy. AB - The influence of immune response on the treatment of American tegumentary leishmaniasis is pointed by several authors, and the existence of protective immunity in self-healed patients (SH) is also suggested. Thus, interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha), interleukin (IL-) 10, IL 17, IL-22 and nitric oxide (NO) production was determined in PBMC culture supernatants from patients with active disease (AD) and after therapy, SH patients and healthy subjects, in response to the soluble antigen of Leishmania (Viannia) braziliensis. It was demonstrated that, during the active disease, there is a predominance of IFN-gamma and TNF-alpha, indicating a proinflammatory phase of the response; IL-17 is also highlighted at this clinical state. Also, TNF-alpha was slightly increased in patients after therapy. NO secretion was noticed in SH individuals, while IL-17 appeared in low levels in these patients and seems to be regulated by NO. The presence of IL-10 was observed in all groups of patients. From this study, we can suggest that in the active disease and after clinical cure, with or without chemotherapy, specific cellular immunity takes part against Leishmania, but with some similarities between the clinical states. Thus, it indicates that the mediators herein described are necessary for the cure to occur. PMID- 22537155 TI - Decreased plasma cytokines are associated with low platelet counts in aplastic anemia and immune thrombocytopenic purpura. AB - BACKGROUND: We previously found plasma levels of CD40 ligand (CD40L), chemokine (C-X-C motif) ligand 5 (CXCL5), chemokine (C-C motif) ligand 5 (CCL5) and epidermal growth factor (EGF) to be low in aplastic anemia (AA) patients and to be correlated with platelet count. OBJECTIVES: To study the association of CD40L, CXCL5, CCL5 and EGF with platelets. METHODS: We measured cytokines in the plasma of immune thrombocytopenic purpura (ITP) and AA patients using the Luminex assay and confirmed the results in a mouse model and in vitro experiments. RESULTS: Both ITP and AA showed similarly low levels of CD40L, CXCL5, CCL5 and EGF, compared with healthy controls. In ITP, levels of these proteins were significantly greater in patients with higher platelet counts than in those with lower platelet counts. In a murine thrombocytopenia model, levels of CD40L, CXCL5, CCL5 and EGF decreased with platelet count after immune-mediated destruction, while the cytokine levels increased when the platelet count recovered. In vitro, concentrations of these cytokines in the supernatants of platelet suspensions were proportional to platelet numbers, and levels in sera prepared by simple blood coagulation were equivalent to those in platelet-rich plasma-converted sera. mRNA expression for CXCL5, CCL5 and EGF was higher in platelets than in megakaryocytes, peripheral blood mononuclear cells, granulocytes and non-megakaryocytic bone marrow cells. CONCLUSIONS: Plasma CD40L, CXCL5, CCL5 and EGF are mainly platelet-derived, suggesting a role of platelets in immune responses and inflammation. Measurement of CD40L, CXCL5, CCL5 and EGF in human blood allowed testable inferences concerning physiology and pathophysiology in quantitative platelet disorders. PMID- 22537159 TI - Peripheral blood NK cell cytotoxicities are negatively correlated with CD8(+) T cells in fertile women but not in women with a history of recurrent pregnancy loss. AB - PROBLEM: We aim to investigate NK cell cytolytic activities and its relationship to other lymphocyte subsets in peripheral blood of women with a history of recurrent pregnancy loss (RPL). METHODS OF STUDY: Women with a history of RPL (n = 48) comprised RPL group, and 15 fertile women served as controls. Lymphocyte subsets such as T (CD3(+)), T helper (CD3(+)/4(+)), cytotoxic T (CD3(+)/8(+)), NK (CD3(-)/56(+)), and peripheral blood NK cell cytolytic activities at three different effector to target cell ratios (E/T ratio, 50:1, 25:1 and 12.5:1) are measured by flow cytometric analysis. RESULTS: Peripheral blood NK cell levels are significantly increased in women with RPL as compared to controls (P = 0.001). NK cell cytolytic activities in RPL group are significantly increased as compared to those of controls at E/T ratio of 50:1 (42.5 +/- 16.3 versus 29.9 +/- 13.8, P = 0.009), 25:1 (31.6 +/- 15.0 versus 19.4 +/- 10.1, P = 0.004), and 12.5:1 (20.1 +/- 10.9 versus 12.3 +/- 7.5, P = 0.011). In RPL group, peripheral blood NK cell levels (%) showed a significant positive correlation with NK cell cytolytic activities at E/T ratio of 50:1 (r = 0.522, P < 0.001), 25:1 (r = 0.588, P < 0.001), and 12.5:1 (r = 0.604, P < 0.001). In controls, CD3(+)/8(+) cells (%) show a negative correlation with NK cell cytolytic activities at E/T ratio of 50:1 (r = -0.566, P = 0.028), 25:1 (r = -0.60., P = 0.017), and 12.5:1 (r = -0.602, P = 0.018). Ratios of T-helper cell to T-cytotoxic cell are positively correlated with NK cell cytolytic activities at E/T ratio of 50:1 (r = 0.601, P = 0.018), 25:1 (r = 0.632, P = 0.012), and 12.5:1 (r = 0.637, P = 0.011). CONCLUSION: NK cell-mediated immunopathology plays a role in RPL. Women with RPL have a disrupted immune regulation between cytotoxic T and NK cells. Failure of immune modulation by CD8(+) T cells may exert NK cell activation and reproductive failures in women with RPL. PMID- 22537158 TI - Regional- and agonist-dependent facilitation of human neurogastrointestinal functions by motilin receptor agonists. AB - BACKGROUND AND PURPOSE: Delayed gastric emptying is poorly managed. Motilin agonists are potential treatments but inadequate understanding into how enteric nerve functions are stimulated compromises drug/dose selection. Resolution is hampered by extreme species dependency so methods were developed to study human gastrointestinal neuromuscular activities and the neurobiology of motilin. EXPERIMENTAL APPROACH: Protocols to study neuromuscular activities were developed for different regions of human stomach and intestine (71 patients) using circular muscle preparations and electrical field stimulation (EFS) of intrinsic nerves. Other tissues were fixed for immunohistochemistry. KEY RESULTS: EFS evoked contractions and/or relaxations via cholinergic and nitrergic neurons, with additional tachykinergic activity in colon; these were consistent after 154 min (longer if stored overnight). Motilin 1-300 nM and the selective motilin agonist GSK962040 0.1-30 uM acted pre-junctionally to strongly facilitate cholinergic contractions of the antrum (E(max) ~ 1000% for motilin), with smaller increases in fundus, duodenum and ileum; high concentrations increased baseline muscle tension in fundus and small intestine. There were minimal effects in the colon. In the antrum, cholinergic facilitation by motilin faded irregularly, even with peptidase inhibitors, whereas facilitation by GSK962040 was long lasting. Motilin receptor immunoreactivity was identified in muscle and myenteric plexus predominantly in the upper gut, co-expressed with choline acetyltransferase in neurons. CONCLUSIONS AND IMPLICATIONS: Motilin and GSK962040 strongly facilitated cholinergic activity in the antrum, with lower activity in fundus and small intestine only. Facilitation by motilin was short lived, consistent with participation in migrating motor complexes. Long-lasting facilitation by GSK962040 suggests different receptor interactions and potential for clinical evaluation. PMID- 22537160 TI - Strain-gated piezotronic transistors based on vertical zinc oxide nanowires. AB - Strain-gated piezotronic transistors have been fabricated using vertically aligned ZnO nanowires (NWs), which were grown on GaN/sapphire substrates using a vapor-liquid-solid process. The gate electrode of the transistor is replaced by the internal crystal potential generated by strain, and the control over the transported current is at the interface between the nanowire and the top or bottom electrode. The current-voltage characteristics of the devices were studied using conductive atomic force microscopy, and the results show that the current flowing through the ZnO NWs can be tuned/gated by the mechanical force applied to the NWs. This phenomenon was attributed to the piezoelectric tuning of the Schottky barrier at the Au-ZnO junction, known as the piezotronic effect. Our study demonstrates the possibility of using Au droplet capped ZnO NWs as a transistor array for mapping local strain. More importantly, our design gives the possibility of fabricating an array of transistors using individual vertical nanowires that can be controlled independently by applying mechanical force/pressure over the top. Such a structure is likely to have important applications in high-resolution mapping of strain/force/pressure. PMID- 22537161 TI - Nicotine, IFN-gamma and retinoic acid mediated induction of MUC4 in pancreatic cancer requires E2F1 and STAT-1 transcription factors and utilize different signaling cascades. AB - BACKGROUND: The membrane-bound mucins are thought to play an important biological role in cell-cell and cell-matrix interactions, in cell signaling and in modulating biological properties of cancer cell. MUC4, a transmembrane mucin is overexpressed in pancreatic tumors, while remaining undetectable in the normal pancreas, thus indicating a potential role in pancreatic cancer pathogenesis. The molecular mechanisms involved in the regulation of MUC4 gene are not yet fully understood. Smoking is strongly correlated with pancreatic cancer and in the present study; we elucidate the molecular mechanisms by which nicotine as well as agents like retinoic acid (RA) and interferon-gamma (IFN-gamma) induce the expression of MUC4 in pancreatic cancer cell lines CD18, CAPAN2, AsPC1 and BxPC3. RESULTS: Chromatin immunoprecipitation assays and real-time PCR showed that transcription factors E2F1 and STAT1 can positively regulate MUC4 expression at the transcriptional level. IFN-gamma and RA could collaborate with nicotine in elevating the expression of MUC4, utilizing E2F1 and STAT1 transcription factors. Depletion of STAT1 or E2F1 abrogated the induction of MUC4; nicotine-mediated induction of MUC4 appeared to require alpha7-nicotinic acetylcholine receptor subunit. Further, Src and ERK family kinases also mediated the induction of MUC4, since inhibiting these signaling molecules prevented the induction of MUC4. MUC4 was also found to be necessary for the nicotine-mediated invasion of pancreatic cancer cells, suggesting that induction of MUC4 by nicotine and other agents might contribute to the genesis and progression of pancreatic cancer. CONCLUSIONS: Our studies show that agents that can promote the growth and invasion of pancreatic cancer cells induce the MUC4 gene through multiple pathways and this induction requires the transcriptional activity of E2F1 and STAT1. Further, the Src as well as ERK signaling pathways appear to be involved in the induction of this gene. It appears that targeting these signaling pathways might inhibit the expression of MUC4 and prevent the proliferation and invasion of pancreatic cancer cells. PMID- 22537162 TI - First-line sunitinib plus FOLFIRI in Japanese patients with unresectable/metastatic colorectal cancer: a phase II study. AB - This phase II, open-label, single-arm study investigated sunitinib + FOLFIRI in Japanese patients with treatment-naive unresectable/metastatic colorectal cancer. Patients received i.v. FOLFIRI (levo-leucovorin 200 mg/m(2) + irinotecan 180 mg/m(2), followed by 5-fluorouracil 400 mg/m(2) bolus then 2400 mg/m(2) 46-h infusion) every 2 weeks, and oral sunitinib 37.5 mg/day on Schedule 4/2 (4 weeks on, 2 weeks off), until disease progression or treatment withdrawal. Progression free survival (PFS) was the primary endpoint, with a target median of 10.8 months (35% improvement over FOLFIRI alone). Seventy-one patients started a median of 3 (range 1-11) sunitinib cycles (median relative dose intensity, <60%). The median PFS was 6.7 months (95% confidence interval, 4.7-9.2) by independent review, 7.2 months (95% confidence interval, 5.4-9.5) by investigator assessment. Objective response rate (complete responses + partial responses) was 36.6% (independent review) and 42.3% (investigator assessment). Clinical benefit rate (complete responses + partial responses + stable disease) was 83.1% (independent review) and 88.7% (investigator assessment). Common all-causality, any-grade, adverse events were: neutropenia and leukopenia (both 97.2%); thrombocytopenia (84.5%); diarrhea and nausea (both 78.9%); decreased appetite (74.6%); and fatigue (66.2%). Neutropenia (96%) was the most frequent grade 3/4 adverse event. This study was closed early due to findings from a concurrent phase III study of sunitinib + FOLFIRI in non-Japanese patients with metastatic colorectal cancer. In conclusion, the median PFS for sunitinib + FOLFIRI in Japanese patients was shorter than the 10.8 month target, indicating that sunitinib did not add to the antitumor activity of FOLFIRI. This study was registered with www.ClinicalTrials.gov (NCT00668863). PMID- 22537170 TI - LMWH - action-monitoring for all patients. PMID- 22537169 TI - The n-Hexane, ethylacetate, and butanol fractions from Hydnocarpi Semen enhanced wound healing in a mice ulcer model. AB - Our previous report showed that Hydnocarpi Semen (HS) extract has wound repair activity at ulcer lesion in diabetic mice. In this study, fractions of n-Hexane, ethylacetate (EtOAc), and butanol (BuOH) from HS crude extract were evaluated for their wound healing activity by using in vivo diabetic ulcer models and in vitro acute inflammation model. Although n-Hexane and EtOAc fractions promote wound healing in mice with ulcer, the BuOH fraction exhibited the most potent wound healing activity and the wound area score significantly decreased after treatment of BuOH fraction even at dose of 2 mg/kg. BuOH fraction stimulated macrophages to increase the production of nitric oxide (NO) and TNF-alpha. The BuOH fraction also enhanced the production of TGF-beta and VEGF, which were involved in fibroblast activation and angiogenesis. The mRNA expression and activation of MMP 9 were increased by three fractions and the activity was higher in BuOH fraction treated group compared to the other groups. The mechanism that the HS helps to promote healing of diabetic ulcer is possibly associated with the production of TNF-alpha, a proinflammatory cytokine, as well as the secretion of VEGF, TGF beta, and MMP-9, which were involved in proliferation of capillaries and fibroblasts. These results suggest that HS can be a new candidate material for the treatment of wound in skin ulcer. PMID- 22537171 TI - Donor-acceptor-type polymers based on dithieno[2,3-b;7,6-b]carbazole unit for photovoltaic applications. AB - Dithieno[2,3-b;7,6-b]carbazole (TCZT), a type of heteropentacene with nitrogen and sulfur atoms, was synthesized with a focus on the unique reactivity of carbazole via double intramolecular Friedel-Crafts acylation. A donor-acceptor type polymer (PTCZTBT) was also synthesized, and its physicochemical properties are reported. PMID- 22537173 TI - In vitro and in vivo identification of a novel cytotoxic T lymphocyte epitope from Rv3425 of Mycobacterium tuberculosis. AB - The identification of novel cytotoxic T lymphocyte (CTL) epitopes is important to analysis of the involvement of CD8(+) T cells in Mycobacterium tuberculosis infection as well as to the development of peptide vaccines. In this study, a novel CTL epitope from region of difference 11 encoded antigen Rv3425 was identified. Epitopes were predicted by the reversal immunology approach. Rv3425 p118 (LIASNVAGV) was identified as having relatively strong binding affinity and stability towards the HLA-A*0201 molecule. Peripheral blood mononuclear cells pulsed by this peptide were able to release interferon-gamma in healthy donors (HLA-A*02(+) purified protein derivative(+)). In cytotoxicity assays in vitro and in vivo, Rv3425-p118 induced CTLs to specifically lyse the target cells. Therefore, this epitope could provide a subunit component for designing vaccines against Mycobacterium tuberculosis. PMID- 22537174 TI - Surgical management of cystic lesions in the liver. AB - BACKGROUND: Liver cysts are common, occurring in up to 5% of the population. For many types of cysts, a variety of different treatment options exist and the preferred management is unclear. METHODS: A Pubmed and Medline literature review using key words non-parasitic hepatic cysts, polycystic liver disease, echinococcus, hydatid cysts parasitic cysts, Caroli's disease, cystadenoma; liver abscess, surgery, aspiration and treatment was undertaken and papers pertaining to the diagnosis and management of cystic lesions within the liver were retrieved. RESULTS: Asymptomatic simple cysts in the liver require no treatment. Therapy for symptomatic cysts may incorporate aspiration with sclerotherapy or de roofing. At present, insufficient evidence exists to recommend one over the other. Polycystic liver disease presents a unique management problem because of high morbidity and mortality rates from intervention and high rates of recurrence. Careful patient counselling and assessment of symptom index is essential before embarking on any treatment. New medical treatments may ameliorate symptoms. Acquired cystic lesions in the liver require a thorough work up to fully characterize the abnormality and direct appropriate treatment. Hydatid cysts are best treated by chemotherapy followed by some form of surgical intervention (either aspiration and sclerotherapy or surgery). Liver abscesses can effectively be treated by aspiration or drainage. With improved antimicrobial efficacy, prolonged treatment with antibiotics may also be considered. CONCLUSION: All patients with cystic lesions in the liver require discussion at multi-disciplinary meetings to confirm and the diagnosis and determine the most appropriate method of treatment. PMID- 22537175 TI - Expression patterns and potential roles of SIRT1 in human medulloblastoma cells in vivo and in vitro. AB - Medulloblastoma is a primitive neuroectodermal tumor, which originates in the cerebellum, presumably due to the alterations of some neurogenetic elements. Sirtuin 1 (SIRT1), a class III histone deacetylase (HDAC), regulates differentiation of neuronal stem cells but its status in medulloblastomas remains largely unknown. The current study aimed to address this issue by checking SIRT1 expression in noncancerous cerebellar tissues, medulloblastoma tissues and established cell lines. The roles of SIRT1 in proliferation and survival of UW228 3 medulloblastoma cells were analyzed by SIRT1 small interfering RNA (siRNA) transfection and SIRT1 inhibitor nicotinamide treatment. The results revealed that the frequency of SIRT1 expression in medulloblastoma tissues was 64.17% (77/120), while only one out of seven tumor-surrounding noncancerous cerebellar tissues showed restricted SIRT1 expression in the cells within the granule layer. Of the three morphological subtypes, the rates of SIRT1 detection in the large cell/anaplastic cell (79.07%; 34/43) and the classic medulloblastomas (60.29%; 41/68) are higher than that (22.22%; 2/9) in nodular/desmoplastic medulloblastomas (P<0.01 and P<0.05, respectively). Heterogeneous SIRT1 expression was commonly observed in classic medulloblastoma. Inhibition of SIRT1 expression by siRNA arrested 64.96% of UW228-3 medulloblastoma cells in the gap 1 (G1) phase and induced 14.53% of cells to apoptosis at the 48-h time point. Similarly, inhibition of SIRT1 enzymatic activity with nicotinamide brought about G1 arrest and apoptosis in a dose-related fashion. Our data thus indicate: (i) that SIRT1 may act as a G1-phase promoter and a survival factor in medulloblastoma cells; and (ii) that SIRT1 expression is correlated with the formation and prognosis of human medulloblastomas. In this context, SIRT1 would be a potential therapeutic target of medulloblastomas. PMID- 22537176 TI - Spontaneous termination of ventricular fibrillation in a patient with congenital coronary anomaly. AB - Sudden death is common in patients with congenital coronary artery anomalies mainly when the left main coronary artery originates from the right coronary sinus. Ventricular fibrillation in these patients is irreversible unless defibrillation can be rapidly performed. We describe a 57-year-old male with an anomalous origin of circumflex and the left anterior descending coronary arteries from the right coronary sinus. He developed two episodes of ventricular fibrillation that terminated spontaneously, 10 hours after percutaneous revascularization of the circumflex coronary artery. Computed tomography angiography, in addition to confirming the anomalous origin of the coronary arteries, showed a muscle bridge over the midportion of the left anterior descending coronary artery. This is the first report of spontaneous termination of ventricular fibrillation in a patient with congenital anomaly of the coronary arteries. PMID- 22537177 TI - Alternative oxidase modulates leaf mitochondrial concentrations of superoxide and nitric oxide. AB - * The nonenergy-conserving alternative oxidase (AOX) has been hypothesized to modulate the amount of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in plant mitochondria but there is sparse direct in planta evidence to support this. * Laser scanning fluorescent confocal microscopy and biochemical methods were used to directly estimate in planta leaf concentrations of superoxide (O2(-)), nitric oxide (NO), peroxynitrite (ONOO(-)) and hydrogen peroxide (H(2)O(2)) in wildtype (Wt) tobacco (Nicotiana tabacum) and transgenic tobacco with altered amounts of AOX. * We found that plants lacking AOX have increased concentrations of leaf mitochondrial-localized O2(-) and leaf NO in comparison to the Wt, while leaf concentrations of H(2)O(2) were similar or lower in the AOX-suppressed plants. * Based on our results, we suggest that AOX respiration acts to reduce the generation of ROS and RNS in plant mitochondria by dampening the leak of single electrons from the electron transport chain to O(2) or nitrite. This may represent a universal role for AOX in plants. More work is now needed to establish the functional implications of this role, such as during abiotic and biotic stress. PMID- 22537178 TI - Charting, navigating, and populating natural product chemical space for drug discovery. AB - Natural products are a heterogeneous group of compounds with diverse, yet particular molecular properties compared to synthetic compounds and drugs. All relevant analyses show that natural products indeed occupy parts of chemical space not explored by available screening collections while at the same time largely adhering to the rule-of-five. This renders them a valuable, unique, and necessary component of screening libraries used in drug discovery. With ChemGPS NP on the Web and Scaffold Hunter two tools are available to the scientific community to guide exploration of biologically relevant NP chemical space in a focused and targeted fashion with a view to guide novel synthesis approaches. Several of the examples given illustrate the possibility of bridging the gap between computational methods and compound library synthesis and the possibility of integrating cheminformatics and chemical space analyses with synthetic chemistry and biochemistry to successfully explore chemical space for the identification of novel small molecule modulators of protein function.The examples also illustrate the synergistic potential of the chemical space concept and modern chemical synthesis for biomedical research and drug discovery. Chemical space analysis can map under explored biologically relevant parts of chemical space and identify the structure types occupying these parts. Modern synthetic methodology can then be applied to efficiently fill this "virtual space" with real compounds.From a cheminformatics perspective, there is a clear demand for open-source and easy to use tools that can be readily applied by educated nonspecialist chemists and biologists in their daily research. This will include further development of Scaffold Hunter, ChemGPS-NP, and related approaches on the Web. Such a "cheminformatics toolbox" would enable chemists and biologists to mine their own data in an intuitive and highly interactive process and without the need for specialized computer science and cheminformatics expertise. We anticipate that it may be a viable, if not necessary, step for research initiatives based on large high-throughput screening campaigns,in particular in the pharmaceutical industry, to make the most out of the recent advances in computational tools in order to leverage and take full advantage of the large data sets generated and available in house. There are "holes" in these data sets that can and should be identified and explored by chemistry and biology. PMID- 22537179 TI - Study protocol: can a school gardening intervention improve children's diets? AB - BACKGROUND: The current academic literature suggests there is a potential for using gardening as a tool to improve children's fruit and vegetable intake. This study is two parallel randomised controlled trials (RCT) devised to evaluate the school gardening programme of the Royal Horticultural Society (RHS) Campaign for School Gardening, to determine if it has an effect on children's fruit and vegetable intake. METHOD/DESIGN: Trial One will consist of 26 schools; these schools will be randomised into two groups, one to receive the intensive intervention as "Partner Schools" and the other to receive the less intensive intervention as "Associate Schools". Trial Two will consist of 32 schools; these schools will be randomised into either the less intensive intervention "Associate Schools" or a comparison group with delayed intervention. Baseline data collection will be collected using a 24-hour food diary (CADET) to collect data on dietary intake and a questionnaire exploring children's knowledge and attitudes towards fruit and vegetables. A process measures questionnaire will be used to assess each school's gardening activities. DISCUSSION: The results from these trials will provide information on the impact of the RHS Campaign for School Gardening on children's fruit and vegetable intake. The evaluation will provide valuable information for designing future research in primary school children's diets and school based interventions. TRIAL REGISTRATION: ISRCTN11396528. PMID- 22537181 TI - Repetition of self-harm and suicide following self-harm in children and adolescents: findings from the Multicentre Study of Self-harm in England. AB - BACKGROUND: Self-harm (intentional self-poisoning and self-injury) in children and adolescents is often repeated and is associated with increased risk of future suicide. We have investigated factors associated with these outcomes. METHOD: We used data collected in the Multicentre Study of Self-harm in England on all self harm hospital presentations by individuals aged 10-18 years between 2000 and 2007, and national death information on these individuals to the end of 2010. Cox hazard proportional models were used to identify independent and multivariable predictors of repetition of self-harm and of suicide. RESULTS: Repetition of self harm occurred in 27.3% of individuals (N = 3920) who presented between 2000 and 2005 and were followed up until 2007. Multivariate analysis showed that repetition was associated with age, self-cutting, and previous self-harm and psychiatric treatment. Of 51 deaths in individuals who presented between 2000 and 2007 and were followed up to 2010 (N = 5133) half (49.0%) were suicides. The method used was usually different to that used for self-harm. Multivariate analysis showed that suicide was associated with male gender [Hazard ratio (HR) = 2.4, 95% CI 1.2-4.8], self-cutting (HR = 2.1, 95% CI 1.1-3.7) and prior psychiatric treatment at initial presentation (HR = 4.2, 95% CI 1.7-10.5). It was also associated with self-cutting and history of psychiatric treatment at the last episode before death, and history of previous self harm. CONCLUSIONS: Self cutting as a method of self-harm in children and adolescents conveys greater risk of suicide (and repetition) than self-poisoning although different methods are usually used for suicide. The findings underline the need for psychosocial assessment in all cases. PMID- 22537183 TI - Fundamental role of microRNAs in androgen-dependent male reproductive biology and prostate cancerogenesis. AB - Male reproductive failure has been linked to successive development of various urologic diseases including prostate cancer. There is strong epidemiologic data in support of this association, it is important therefore to identify the fundamental grounds that lay beneath such a connection. Male reproductive biology, as sex determined, is significantly dependent upon the hormonal regulation of androgens. With the advancement of knowledge on androgen receptivity and epigenetic regulation, the role of new regulatory factors such as microRNAs becomes essential. This review focuses on unraveling the role of microRNA tight incorporation in androgen-dependent male reproductive biology in the context of recent prostate cancer data. PMID- 22537184 TI - Preliminary examination of the reliability and concurrent validity of the attention-deficit/hyperactivity disorder self-report scale v1.1 symptom checklist to rate symptoms of attention-deficit/hyperactivity disorder in adolescents. AB - OBJECTIVE: To validate the attention-deficit/hyperactivity disorder (ADHD) Self Report Scale (ASRS) v1.1 Symptom Checklist versus the clinician-administered ADHD Rating Scale (ADHD-RS) in adolescents with ADHD. METHOD: A total of 88 adolescents with ADHD aged 13-17 years participated in the study. The study was completed in one or two visits, 1-9 weeks apart. At each visit, participants completed the ASRS v1.1 Symptom Checklist, after which raters administered the ADHD-RS. Internal consistency of the ASRS v1.1 Symptom Checklist was assessed by Cronbach's alpha (Cronbach's alpha). Concurrent validity between the scales was assessed using Pearson's correlation coefficients. Item-by-item reliability between the scales was assessed by the Kappa coefficient of agreement. RESULTS: The mean age of participants was 14.9+/-1.5 SD years. 76.1% (n=67) were male. 73.9% (n=65) were currently receiving medication for ADHD. Internal consistency of ASRS v1.1 Symptom Checklist items was high, with Cronbach's alpha coefficients of 0.93 at Visit 1 and 0.94 at Visit 2. Pearson's correlation coefficients between the ASRS v1.1 Symptom Checklist and ADHD-RS were highly significant at Visit 1 (r=0.72, p<0.0001) and Visit 2 (r=0.73, p<0.0001). There was moderate item-by-item agreement between individual items on the scales (% agreement: 35.2% 63.4%) with statistically significant kappa coefficients for 17 of the 18 items. CONCLUSION: The ASRS v1.1 Symptoms Checklist showed high internal consistency and high concurrent validity with the clinician-administered ADHD-RS in adolescents with ADHD. Results of this study suggest that the ASRS v1.1 Symptom Checklist is an internally consistent self-report scale for the assessment of adolescent ADHD and is moderately associated with a concurrently administered clinician measure of ADHD symptoms. PMID- 22537186 TI - Diphenhydramine use in the treatment of risperidone-induced sialorrhea. PMID- 22537182 TI - Characterization of the transcriptome profiles related to globin gene switching during in vitro erythroid maturation. AB - BACKGROUND: The fetal and adult globin genes in the human beta-globin cluster on chromosome 11 are sequentially expressed to achieve normal hemoglobin switching during human development. The pharmacological induction of fetal gamma-globin (HBG) to replace abnormal adult sickle betaS-globin is a successful strategy to treat sickle cell disease; however the molecular mechanism of gamma-gene silencing after birth is not fully understood. Therefore, we performed global gene expression profiling using primary erythroid progenitors grown from human peripheral blood mononuclear cells to characterize gene expression patterns during the gamma-globin to beta-globin (gamma/beta) switch observed throughout in vitro erythroid differentiation. RESULTS: We confirmed erythroid maturation in our culture system using cell morphologic features defined by Giemsa staining and the gamma/beta-globin switch by reverse transcription-quantitative PCR (RT-qPCR) analysis. We observed maximal gamma-globin expression at day 7 with a switch to a predominance of beta-globin expression by day 28 and the gamma/beta-globin switch occurred around day 21. Expression patterns for transcription factors including GATA1, GATA2, KLF1 and NFE2 confirmed our system produced the expected pattern of expression based on the known function of these factors in globin gene regulation. Subsequent gene expression profiling was performed with RNA isolated from progenitors harvested at day 7, 14, 21, and 28 in culture. Three major gene profiles were generated by Principal Component Analysis (PCA). For profile-1 genes, where expression decreased from day 7 to day 28, we identified 2,102 genes down-regulated > 1.5-fold. Ingenuity pathway analysis (IPA) for profile-1 genes demonstrated involvement of the Cdc42, phospholipase C, NF-Kbeta, Interleukin-4, and p38 mitogen activated protein kinase (MAPK) signaling pathways. Transcription factors known to be involved in gamma-and beta-globin regulation were identified.The same approach was used to generate profile-2 genes where expression was up-regulated over 28 days in culture. IPA for the 2,437 genes with > 1.5-fold induction identified the mitotic roles of polo-like kinase, aryl hydrocarbon receptor, cell cycle control, and ATM (Ataxia Telangiectasia Mutated Protein) signaling pathways; transcription factors identified included KLF1, GATA1 and NFE2 among others. Finally, profile-3 was generated from 1,579 genes with maximal expression at day 21, around the time of the gamma/beta-globin switch. IPA identified associations with cell cycle control, ATM, and aryl hydrocarbon receptor signaling pathways. CONCLUSIONS: The transcriptome analysis completed with erythroid progenitors grown in vitro identified groups of genes with distinct expression profiles, which function in metabolic pathways associated with cell survival, hematopoiesis, blood cells activation, and inflammatory responses. This study represents the first report of a transcriptome analysis in human primary erythroid progenitors to identify transcription factors involved in hemoglobin switching. Our results also demonstrate that the in vitro liquid culture system is an excellent model to define mechanisms of global gene expression and the DNA-binding protein and signaling pathways involved in globin gene regulation. PMID- 22537185 TI - Parent perspectives on the decision to initiate medication treatment of attention deficit/hyperactivity disorder. AB - OBJECTIVES: Despite substantial evidence supporting the efficacy of stimulant medication for children with attention-deficit/hyperactivity disorder (ADHD), adherence to stimulant treatment is often suboptimal. Applying social/cognitive theories to understanding and assessing parent attitudes toward initiating medication may provide insight into factors influencing parent decisions to follow ADHD treatment recommendations. This report describes results from formative research that used focus groups to obtain parent input to guide development of a provider-delivered intervention to improve adherence to stimulants. METHODS: Participants were caregivers of children with ADHD who were given a stimulant treatment recommendation. Focus groups were recorded and transcribed verbatim. Data were analyzed by inductive, grounded theory methods as well as a deductive analytic strategy using an adapted version of the Unified Theory of Behavior Change to organize and understand parent accounts. RESULTS: Five groups were conducted with 27 parents (mean child age=9.35 years; standard deviation [SD]=2.00), mean time since diagnosis=3.33 years (SD=2.47). Most parents (81.5%) had pursued stimulant treatment. Inductive analysis revealed 17 attitudes facilitating adherence and 25 barriers. Facilitators included parent beliefs that medication treatment resulted in multiple functional gains and that treatment was imperative for their children's safety. Barriers included fears of personality changes and medication side effects. Complex patterns of parent adherence to medication regimens were also identified, as well as preferences for psychiatrists who were diagnostically expert, gave psychoeducation using multiple modalities, and used a chronic illness metaphor to explain ADHD. Theory-based analyses revealed conflicting expectancies about treatment risks and benefits, significant family pressures to avoid medication, guilt and concern that their children required medication, and distorted ideas about treatment risks. Parents, however, took pride in successfully pursuing efforts to manage their child behaviorally and to avoid medication when possible. CONCLUSIONS: Focus group data identified social, cognitive, and affective influences on treatment decision making. Results support prior research comparing family/social functioning, physician characteristics, and adherence. Findings suggest that parent attitudes to psychiatric care need to be assessed comprehensively at initial evaluation to aid the development of psychoeducational messages, and a more careful consideration about how parents interpret and respond to adherence-related questioning. PMID- 22537187 TI - A case of excessive weight gain with guanfacine extended release: 9.53 kg in 4 weeks. PMID- 22537188 TI - Platelet- and erythrocyte-derived microparticles trigger thrombin generation via factor XIIa. AB - BACKGROUND: The procoagulant properties of microparticles (MPs) are due to the of the presence of phosphatidylserine (PS) and tissue factor (TF) on their surface. The latter has been demonstrated especially on MPs derived from monocytes. OBJECTIVES: To investigate the relative contribution of TF and factor (F)XII in initiating coagulation on MPs derived from monocytes, platelets and erythrocytes. METHODS: Microparticles were isolated from calcium ionophore-stimulated platelets, erythrocytes and monocytic THP-1 cells. MPs were quantified, characterized for cell-specific antigens and analyzed for TF, PS exposure and their thrombin-generating potential. RESULTS: The MP number was not proportional to PS exposure and the majority of the MPs exposed PS. TF activity was undetectable on platelet- and erythrocyte-derived MPs (< 1 fM nM(-1) PS), whereas monocyte-derived MPs exposed TF (32 fM nM(-1) PS). Platelet-, erythrocyte- and monocyte-derived MPs, but not purified phospholipids, initiated thrombin generation in normal plasma in the absence of an external trigger (lag time < 11 min). Deficiency or inhibition of FVII had no effect on thrombin generation induced by platelet- and erythrocyte-derived MPs, but interfered with monocyte MP triggered coagulation. Platelet- and erythrocyte-derived MPs completely failed to induce thrombin generation in FXII-deficient plasma. In contrast, monocyte derived MPs induced similar thrombin generation in normal vs. FXII-deficient plasma. CONCLUSION: MPs from platelets and erythrocytes not only propagate coagulation by exposing PS but also initiate thrombin generation independently of TF in a FXII-dependent manner. In contrast, monocyte-derived MPs trigger coagulation predominantly via TF. PMID- 22537190 TI - Glucose-responsive vehicles containing phenylborate ester for controlled insulin release at neutral pH. AB - This study is devoted to developing amphiphilic block polymers based on phenylborate ester, which can self-assemble to form nanoparticles, as a glucose sensitive drug carrier. Poly(ethylene glycol)-block-poly[(2-phenylboronic esters 1,3-dioxane-5-ethyl) methylacrylate] (MPEG5000-block-PBDEMA) was fabricated with MPEG5000-Br as a macroinitiator via atom transfer radical polymerization (ATRP). Using the solvent evaporation method, these block polymers can disperse in aqueous milieu to self-assemble into micellar aggregates with a spherical core shell structure. Zeta potential and fluorescence techniques analysis showed a good purification effect, high encapsulation efficiency, and loading capacity of fluorescein isothiocyanate (FITC)-insulin-loaded polymeric micelles under optimal conditions. The in vitro insulin release profiles revealed definite glucose responsive behavior of the polymeric micelles at pH 7.4 and 37 degrees C, depending on the environmental glucose concentration and the chemical composition of the block polymers. Further, circular dichroism spectroscopy demonstrated that the overall tertiary structure of the released insulin was in great agreement with standard insulin. (1)H NMR results of the polymeric micelles during glucose responsive process supposed one possible insulin release mechanism via the polymer polarity transition from amphiphilic to double hydrophilic. The analysis of L929 mouse fibroblast cells viability suggested that the polymeric micelles from MPEG5000-block-PPBDEMA had low cell toxicity. The block polymers containing phenylborate ester that responded to changes in the glucose concentration at neutral pH are being aimed for use in self-regulated insulin delivery. PMID- 22537189 TI - A CARD-FISH protocol for the identification and enumeration of cyanobacterial akinetes in lake sediments. AB - Akinetes are the dormant cells of Nostocales (cyanobacteria) that enable the organisms to survive harsh environmental conditions while resting in bottom sediments. The germination of akinetes assists the dispersal and persistence of the species. The assessment of the akinete pool in lake sediments is essential to predict the bloom formation of the Nostocales population. We present here the implementation of an improved catalysed reporter deposition (CARD)-fluorescence in situ hybridization (FISH) protocol to assist the identification and quantification of akinetes in sediment samples. Several 16S rRNA gene oligonucleotide probes were evaluated for labelling akinetes of various species of Anabaena, Aphanizomenon and Cylindrospermopsis. Akinetes of all the taxa studied were successfully labelled and could be easily detected by their bright fluorescence signal. The probes' specificity was tested with 32 strains of different taxa. All six Cylindrospermopsis raciborskii strains were labelled with a specific probe for its 16S rRNA gene. A more general probe labelled 73% of the Anabaena and Aphanizomenon strains. The counting data of field samples obtained with CARD-FISH and the regular light microscopy approach did not differ significantly, confirming the suitability of both methods. The CARD-FISH approach was found to be less time-consuming because of better visibility of akinetes. PMID- 22537191 TI - Impact of membrane fluidity on steric stabilization by lipopolymers. AB - In this work, the impact of lipid lateral mobility on the steric interaction between membranes containing poly(ethylene glycol) (PEG) functionalized lipids was investigated using the surface force apparatus. The force-distance profiles show the presence of electrostatic and steric repulsion that arise from the presence of negatively charged PEG functionalized lipids. Fluid-phase bilayers have high lateral diffusion relative to gel-phase bilayers; however, a quantitative comparison of the interaction forces between membranes in these two different phase states demonstrates a reduced rate of diffusion in the fluid phase for the PEG-lipids under constrained geometries. Thus, the amount of polymer in the contact zone can be modulated and is reduced with fluid membranes; however, complete exclusion was not achieved. As a result, the steric repulsion afforded by PEG chains or binding affinity of ligated PEG chains can only be modestly tailored by the phase state of the liposome. PMID- 22537193 TI - Improving open circuit potential in hybrid P3HT:CdSe bulk heterojunction solar cells via colloidal tert-butylthiol ligand exchange. AB - Organic ligands have the potential to contribute to the reduction potential, or lowest unoccupied molecular orbital (LUMO) energy, of semiconductor nanocrystals. Rationally introducing small, strongly binding, electron-donating ligands should enable improvement in the open circuit potential of hybrid organic/inorganic solar cells by raising the LUMO energy level of the nanocrystal acceptor phase and thereby increasing the energy offset from the polymer highest occupied molecular orbital (HOMO). Hybrid organic/inorganic solar cells fabricated from blends of tert-butylthiol-treated CdSe nanocrystals and poly(3-hexylthiophene) (P3HT) achieved power conversion efficiencies of 1.9%. Compared to devices made from pyridine-treated and nonligand exchanged CdSe, the thiol-treated CdSe nanocrystals are found to consistently exhibit the highest open circuit potentials with V(OC) = 0.80 V. Electrochemical determination of LUMO levels using cyclic voltammetry and spectroelectrochemistry suggest that the thiol treated CdSe nanocrystals possess the highest lying LUMO of the three, which translates to the highest open circuit potential. Steady-state and time-resolved photoluminescence quenching experiments on P3HT:CdSe films provide insight into how the thiol-treated CdSe nanocrystals also achieve greater current densities in devices relative to pyridine-treated nanocrystals, which are thought to contain a higher density of surface traps. PMID- 22537192 TI - Honokiol promotes non-rapid eye movement sleep via the benzodiazepine site of the GABA(A) receptor in mice. AB - BACKGROUND AND PURPOSE: Decoctions of the Chinese herb houpu contain honokiol and are used to treat a variety of mental disorders, including depression. Depression commonly presents alongside sleep disorders and sleep disturbances, which appear to be a major risk factor for depression. Here, we have evaluated the somnogenic effect of honokiol and the mechanisms involved. EXPERIMENTAL APPROACH: Honokiol was administered i.p. at 20:00 h in mice. Flumazenil, an antagonist at the benzodiazepine site of the GABA(A) receptor, was administered i.p. 15 min before honokiol. The effects of honokiol were measured by EEG and electromyogram (EMG), c-Fos expression and in vitro electrophysiology. KEY RESULTS: Honokiol (10 and 20 mg.kg-1) significantly shortened the sleep latency to non-rapid eye movement (non REM, NREM) sleep and increased the amount of NREM sleep. Honokiol increased the number of state transitions from wakefulness to NREM sleep and, subsequently, from NREM sleep to wakefulness. However, honokiol had no effect on either the amount of REM sleep or EEG power density of both NREM and REM sleep. Honokiol increased c-Fos expression in ventrolateral preoptic area (VLPO) neurons, as examined by immunostaining, and excited sleep-promoting neurons in the VLPO by whole-cell patch clamping in the brain slice. Pretreatment with flumazenil abolished the somnogenic effects and activation of the VLPO neurons by honokiol. CONCLUSION AND IMPLICATIONS: Honokiol promoted NREM sleep by modulating the benzodiazepine site of the GABA(A) receptor, suggesting potential applications in the treatment of insomnia, especially for patients who experience difficulty in falling and staying asleep. PMID- 22537194 TI - Molecular mechanism implicated in Pemetrexed-induced apoptosis in human melanoma cells. AB - BACKGROUND: Metastatic melanoma is a lethal skin cancer and its incidence is rising every year. It represents a challenge for oncologist, as the current treatment options are non-curative in the majority of cases; therefore, the effort to find and/or develop novel compounds is mandatory. Pemetrexed (Alimta(r), MTA) is a multitarget antifolate that inhibits folate-dependent enzymes: thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase, required for de novo synthesis of nucleotides for DNA replication. It is currently used in the treatment of mesothelioma and non-small cell lung cancer (NSCLC), and has shown clinical activity in other tumors such as breast, colorectal, bladder, cervical, gastric and pancreatic cancer. However, its effect in human melanoma has not been studied yet. RESULTS: In the current work we studied the effect of MTA on four human melanoma cell lines A375, Hs294T, HT144 and MeWo and in two NSCLC cell lines H1299 and Calu-3. We have found that MTA induces DNA damage, S-phase cell cycle arrest, and caspase dependent and -independent apoptosis. We show that an increment of the intracellular reactive oxygen species (ROS) and p53 is required for MTA-induced cytotoxicity by utilizing N-Acetyl-L-Cysteine (NAC) to blockage of ROS and p53 defective H1299 NSCLC cell line. Pretreatment of melanoma cells with NAC significantly decreased the DNA damage, p53 up-regulation and cytotoxic effect of MTA. MTA was able to induce p53 expression leading to up-regulation of p53 dependent genes Mcl-1 and PIDD, followed by a postranscriptional regulation of Mcl-1 improving apoptosis. CONCLUSIONS: We found that MTA induced DNA damage and mitochondrial-mediated apoptosis in human melanoma cells in vitro and that the associated apoptosis was both caspase-dependent and -independent and p53 mediated. Our data suggest that MTA may be of therapeutic relevance for the future treatment of human malignant melanoma. PMID- 22537195 TI - Targeting matrix metalloproteinases in acute inflammatory shock syndromes. AB - The integrity of the vascular wall and its intrinsic basement membrane structures ensure that plasma and the corpuscular elements of the blood remain confined to the intravascular milieu and can enter into the extravascular compartment in a well controlled fashion in cases of tissue infection or inflammation. However, sometimes inflammatory stimuli act on blood leukocytes and on endothelial cells from within the blood vessels and in an overwhelming way, leading to inflammatory shock syndromes. These severe conditions with high mortality rates are characterized by intravascular neutrophil degranulation, permeability changes of endothelia and disintegration of basement membranes and lead to almost uncontrollable edema, coagulation changes and multi-organ failure. Matrix metalloproteinases (MMPs) have been functionally linked with septic and endotoxin shock, with cytokine release syndromes and with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Here we review a number of association studies, compare inflammatory shock data from gene knockout studies in mice and provide some insights from recent investigations with inhibitors of MMPs. This evaluation strengthens the expectation that MMP inhibitors, in particular those blocking neutrophil proteases, may become useful in the early phase of acute inflammatory shock syndromes. PMID- 22537207 TI - Patient-reported convenience of once-daily versus three-times-daily dosing during long-term studies of pramipexole in early and advanced Parkinson's disease. AB - BACKGROUND AND PURPOSE: In chronic diseases including Parkinson's disease (PD), complex pharmacotherapy dosing schedules are reported to reduce adherence, perhaps leading to less-effective symptom control and, in PD, more erratic stimulation of dopamine receptors. However, blinded clinical-trial designs preclude direct comparisons of adherence to various schedules. METHODS: In two double-blind (DB) studies of early PD and one of advanced PD, subjects received three-times-daily (t.i.d.) pramipexole or placebo. In open-label (OL) extensions, subjects took extended-release, once-daily (q.d.) pramipexole. At 24 or 32 OL weeks, q.d. versus t.i.d. dosing preference was surveyed by questionnaire. RESULTS: Of 590 DB-trial completers with early PD, 511 entered the OL extension. Of 374 survey respondents, 94.4% preferred q.d. dosing (72.2% of them found it 'very much more convenient' and 27.8%'more convenient'), 2.7% preferred t.i.d., and 2.9% chose 'no difference'. Of 465 DB-trial completers with advanced PD, 391 entered its OL extension. Of 334 survey respondents, 88.9% preferred q.d. dosing (59.9% of them found it 'very much more convenient' and 40.1%'more convenient'), 5.7% preferred t.i.d., and 5.4% chose 'no difference'. Results excluding DB-placebo recipients were highly similar. CONCLUSIONS: In this first direct comparison of patient preference for q.d. versus t.i.d. dopamine-agonist dosing, patients with early or advanced PD had a strong preference for q.d. rather than t.i.d. pramipexole. The high proportion of advanced-PD patients declaring this preference indicates that it does not depend on whether a patient is taking concomitant PD medications dosed more frequently than q.d. PMID- 22537208 TI - Poisoning mortality in Danish children and adolescents, 1970-2006 - a registry based study. AB - AIM: To study poisoning mortality from birth to the end of teenage. METHODS: Registry study within the Danish population including all deaths from poisoning in the 0-19-year age groups for the years 1970-2006. RESULTS: Poisoning mortality was age dependent with a modest peak in preschool children because of accidents and a very steep increase from 0.1/10(5) person years (p.y.) at 12 years to 6.1/10(5) p.y. at 19 years. Accidents, suicide and undetermined manner of death all contributed to the increase. A significant proportion of accidental and undetermined manner of death was caused by opioides and probably abuse related. During the study period, mortality decreased by more than 50% with all manners of death contributing significantly to the decline. Carbon monoxide poisoning was the overall dominating cause of death and contributed most to reduction in mortality. Poisoning death caused by opioides and unspecified drugs was unchanged over time. CONCLUSION: Poisoning mortality among the youngest Danish children was dominated by accidental poisonings. During teenage, the level and pattern of adults was approached with respect to suicidal and abuse related deaths. A fall in mortality since mid-eighties was explained by fewer deaths from carbon monoxide poisoning. PMID- 22537209 TI - Order parameters , , and of aligned nematic liquid-crystalline polymer as determined by numerical simulation of electron paramagnetic resonance spectra. AB - High rank order parameters may comprise substantial information about molecular orientational distribution of liquid-crystalline materials. There are few experimental procedures targeted at the determination of high rank order parameters. We suggest a procedure for the determination of order parameters of a spin probe by numerical simulation of electron paramagnetic resonance (EPR) spectra. The procedure is based on revealing the molecular orientation axis of a spin probe. Order parameters , , and of the spin probe in aligned liquid-crystalline polymer have been measured by the suggested procedure. It was shown that the procedure gives more reliable and complete characteristics of molecular order than does polarized UV-visible spectroscopy. PMID- 22537210 TI - Insulinemia and the risk of breast cancer and its relapse. AB - A fairly large body of evidence has shown that insulin is a tumour-promoting agent, especially for breast cancer. High circulating and microenvironmental levels of insulin may directly increase the risk of breast cancer via the activation of cognate receptors expressed on normal and cancer cells and indirectly be associated with other known metabolic risk factors of cancer that usually are present in conjunction with the hyperinsulinic state. The focus of this review is to analyse and discuss available data in the literature on the possible causative/prognostic role of insulin resistance/hyperinsulinemia in breast cancer development and progression. PMID- 22537211 TI - Phenotypic characterization of Aspergillus niger and Candida albicans grown under simulated microgravity using a three-dimensional clinostat. AB - The living and working environments of spacecraft become progressively contaminated by a number of microorganisms. A large number of microorganisms, including pathogenic microorganisms, some of which are fungi, have been found in the cabins of space stations. However, it is not known how the characteristics of microorganisms change in the space environment. To predict how a microgravity environment might affect fungi, and thus how their characteristics could change on board spacecraft, strains of the pathogenic fungi Aspergillus niger and Candida albicans were subjected to on-ground tests in a simulated microgravity environment produced by a three-dimensional (3D) clinostat. These fungi were incubated and cultured in a 3D clinostat in a simulated microgravity environment. No positive or negative differences in morphology, asexual reproductive capability, or susceptibility to antifungal agents were observed in cultures grown under simulated microgravity compared to those grown in normal earth gravity (1 G). These results strongly suggest that a microgravity environment, such as that on board spacecraft, allows growth of potentially pathogenic fungi that can contaminate the living environment for astronauts in spacecraft in the same way as they contaminate residential areas on earth. They also suggest that these organisms pose a similar risk of opportunistic infections or allergies in astronauts as they do in people with compromised immunity on the ground and that treatment of fungal infections in space could be the same as on earth. PMID- 22537212 TI - Free radicals and antioxidants: updating a personal view. AB - This article looks back to the antioxidant/free radical field in 1994 and discusses how it has progressed in the past 18 years. In some areas, there has been little change: the role of oxygen radicals and other reactive oxygen species (ROS) in the origin or progression of most human diseases remains uncertain, with cancer and neurodegenerative disease being likely exceptions. Even in diseases in which ROS are involved there has been little progress in developing effective antioxidant treatments. Mega-doses of dietary antioxidants have also generally failed to prevent human disease, in part because they do not decrease oxidative damage in vivo (as revealed by robust biomarkers). However, some strategies that are known to delay disease onset may act, at least in part, by decreasing oxidative damage levels. Nevertheless, far more is known today about endogenous antioxidant defenses and how they are regulated, which has led to a deeper understanding of how some ROS can act as signaling molecules. Increasing endogenous antioxidant levels (e.g., by supplying "pro-oxidants") may be a better approach to therapeutics and disease prevention than consuming large doses of "dietary antioxidants." PMID- 22537213 TI - Bioactive compounds and nutritional significance of virgin argan oil--an edible oil with potential as a functional food. AB - This review compiles recently published scientific reports on the bioactive compounds present in virgin argan oil along with their possible beneficial effects on human health, which could justify consideration of this oil as a new functional food. Virgin argan oil is characterized by high levels of linoleic and oleic acids, tocopherols (especially gamma-tocopherol), and minor compounds such as sterols, carotenoids, and squalene. The total antioxidant capacity of virgin argan oil is higher than that of other vegetable oils. Recent studies suggest that this edible oil, as a functional food, may play a role in disease prevention. For example, some authors have found it to have hypolipidemic, hypocholesterolemic, hypoglycemic, and antihypertensive effects as well as a possible role in cancer prevention. This review demonstrates the need for further studies in order to fully characterize argan oil from bromatological, nutritional, culinary, and technological perspectives. In particular, the scarcity of clinical data hampers relevant conclusions from being drawn regarding the therapeutic effects of virgin argan oil. PMID- 22537214 TI - Vitamin D bioavailability in cystic fibrosis: a cause for concern? AB - Despite the inclusion of extra vitamin D in their regimen of fat-soluble vitamin supplementation, cystic fibrosis patients remain chronically depleted of vitamin D. The persistence of suboptimal vitamin D status is often blamed on the maldigestion and malabsorption of fat. However, the mitigated success of recent clinical trials with high-dose vitamin D supplementation suggests that vitamin D bioavailability might be impaired in these patients. Given the growing understanding of the importance of this vitamin in the regulation of multiple biological functions beyond skeletal health, the present review analyzes the current literature by addressing each step of vitamin D metabolism and action in the context of this life-limiting pathology. In addition, it highlights the importance of vitamin D in relation to organs and or conditions affected by cystic fibrosis. PMID- 22537215 TI - Evaluating the links between intake of milk/dairy products and cancer. AB - Milk and dairy products are widely recommended as part of a healthy diet. These products, however, can contain hormones such as insulin-like growth factor 1, and some studies have suggested that a high intake of milk and dairy products may increase the risk of cancer. This review examines recent studies on this topic, with the evidence suggesting that the recommended intake of milk and dairy products (3 servings/day) is safe and, importantly, does not seem to increase the risk of cancer. On the basis of the studies included in this review, cultured milk, yogurt, and low-fat dairy products should be preferred as the milk and dairy products of choice. PMID- 22537216 TI - Communication strategies to help reduce the prevalence of non-communicable diseases: proceedings from the inaugural IFIC Foundation Global Diet and Physical Activity Communications Summit. AB - Non-communicable diseases (NCDs), which include cardiovascular disease, cancer, and diabetes, all of which are associated with the common risk factors of poor diet and insufficient physical activity, caused 63% of all deaths globally in 2008. The increasing discussion of global NCDs, including at the 2011 United Nations General Assembly High-level Meeting on the Prevention and Control of Non communicable Diseases, and a request for multi-stakeholder engagement, prompted the International Food Information Council Foundation to sponsor the Global Diet and Physical Activity Communications Summit: "Insights to Motivate Healthful, Active Lifestyles" on September 19, 2011, in New York City. The Summit brought together a diverse group of stakeholders, representing 34 nations from governments; communication, health, nutrition, and fitness professions; civil society; nonprofits; academia; and the private sector. The Summit provided expert insights and best practices for the use of science-based, behavior-focused communications to motivate individuals to achieve healthful, active lifestyles, with the goal of reducing the prevalence of NCDs. Presented here are some of the highlights and key findings from the Summit. PMID- 22537218 TI - Imbalance in cytokines from interleukin-1 family - role in pathogenesis of endometriosis. AB - PROBLEM: To assess whether interleukin (IL)-1beta, IL-18 and interleukin-1 converting enzyme (ICE) are involved in the pathogenesis of endometriosis. METHOD OF STUDY: Peritoneal fluid (PF) was obtained from 85 women with and without endometriosis. Peritoneal macrophages were cultured and the culture media collected. IL-1beta, IL-18 and ICE levels were measured by the enzyme-linked immunosorbent assay (ELISA). RESULTS: Levels of IL-1beta and ICE in PF of women with endometriosis were higher than those in the control group. However, PF level of IL-18 was significantly lower in the study group than in the controls. Higher secretion of IL-1beta by peritoneal macrophages and lower IL-18 and ICE in endometriosis patients than in control were observed. Following lipopolysaccharide (LPS) stimulation, the macrophages secreted more IL-1beta, IL 18 and ICE in all groups. CONCLUSIONS: The results pointed to impairment of the secretion of the IL-1 cytokine family in endometriosis. Invalid IL-1beta and IL 18 maturation by ICE may be an important pathogenic factor in endometriosis. PMID- 22537219 TI - Vascular and autonomic function in preschool-aged children with congenital heart disease. AB - OBJECTIVE: To compare indices of vascular health and heart rate variability in preschool-aged children with repaired congenital heart disease (CHD) including tetralogy of Fallot (n = 6) and coarctation of the aorta (n = 6). DESIGN: A cross-sectional study design was used. All measures were noninvasive and collected over a single testing session under the supervision of a parent/guardian. SETTING: Data collection took place in a quiet, temperature controlled room (23 degrees +/- 1 degrees C) with the participant in a supine position. PATIENTS: Twelve (six females, six males) preschool-aged children with repaired CHD (CHD: 4 +/- 1 years) and 12 age- and gender-matched healthy controls (CON: 5 +/- 1 years) participated in the study. OUTCOME MEASURES: Supine, resting measures of heart rate variability (time, frequency, and nonlinear domains), whole-body pulse wave velocity (ventricular depolarization to dorsalis pedis artery), brachial blood pressures, and carotid artery distensibility, lumen diameter, intima-media thickness, and wall/lumen ratio were collected in both groups. RESULTS: The groups were similar in age, height, and weight; however, CON had significantly higher body mass index values (CON: 16.9 +/- 2.2, CHD: 15.1 +/- 1.0, P < .05) and body mass index percentiles (CON: 69 +/- 27%tile, CHD: 36 +/- 24%tile, P < .01) compared to CHD. No group differences were found for resting brachial blood pressures, whole-body pulse wave velocity, heart rate variability, and carotid artery distensibility, lumen diameter, and intima media thickness (P > .05). Carotid artery pulse pressures (CHD: 38 +/- 6 mm Hg, CON: 31 +/- 6 mm Hg, P < .05) and wall/lumen ratios (CHD: 0.091 +/- 0.007, CON: 0.085 +/- 0.006, P < .01) were significantly higher in the CHD group. CONCLUSIONS: These results may indicate that preschool-aged children with repaired CHD display early signs of vascular remodeling, but not autonomic or vascular dysfunction. The effects of larger wall/lumen ratios on cardiovascular disease risk require further investigation. PMID- 22537221 TI - Concentric necklace nanolenses for optical near-field focusing and enhancement. AB - In this paper, we design and analyze concentric necklace nanolenses (CNNLs) which consist of metal nanoparticle dimers placed in the center of one or more concentric rings of plasmonic necklaces. We use three-dimensional finite difference time-domain simulations, electron-beam lithography fabrication, dark field scattering analysis, and surface-enhanced Raman scattering (SERS) measurements to investigate the far-field scattering and near-field light localization properties of CNNLs. Using these methods, we show that CNNLs display far-field scattering properties that arise from coupling between the dimer and surrounding necklace(s), leading to two pronounced peaks in single-necklace CNNLs and three pronounced peaks in double-necklace CNNLs. In our near-field analysis, we find that the number of particles in the surrounding necklace is an important degree of freedom in the optimization of near-field intensity within the dimer hot-spot region. By using CNNLs where the necklace diameters have a diameter equal to an integer multiple of the resonance wavelength of the isolated dimer times a constant scaling factor, the intensity of near-fields can be optimized for all geometries over a broad-band wavelength range. Using optimized geometries, we perform SERS experiments on CNNLs coated with a pMA monolayer and demonstrate 7* Raman enhancement in the single-necklace CNNL and 18* enhancement in the double-necklace CNNL over the reference dimer antenna geometry, with an average Raman enhancement value of approximately 7 * 10(5). PMID- 22537220 TI - MicroRNA modulate alveolar epithelial response to cyclic stretch. AB - BACKGROUND: MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression implicated in multiple cellular processes. Cyclic stretch of alveoli is characteristic of mechanical ventilation, and is postulated to be partly responsible for the lung injury and inflammation in ventilator-induced lung injury. We propose that miRNAs may regulate some of the stretch response, and therefore hypothesized that miRNAs would be differentially expressed between cyclically stretched and unstretched rat alveolar epithelial cells (RAECs). RESULTS: RAECs were isolated and cultured to express type I epithelial characteristics. They were then equibiaxially stretched to 25% change in surface area at 15 cycles/minute for 1 hour or 6 hours, or served as unstretched controls, and miRNAs were extracted. Expression profiling of the miRNAs with at least 1.5-fold change over controls revealed 42 miRNAs were regulated (34 up and 8 down) with stretch. We validated 6 of the miRNAs using real-time PCR. Using a parallel mRNA array under identical conditions and publicly available databases, target genes for these 42 differentially regulated miRNAs were identified. Many of these genes had significant up- or down-regulation under the same stretch conditions. There were 362 down-regulated genes associated with up-regulated miRNAs, and 101 up-regulated genes associated with down-regulated miRNAs. Specific inhibition of two selected miRNAs demonstrated a reduction of the increased epithelial permeability seen with cyclic stretch. CONCLUSIONS: We conclude that miRNA expression is differentially expressed between cyclically stretched and unstretched alveolar epithelial cells, and may offer opportunities for therapeutic intervention to ameliorate stretch-associated alveolar epithelial cell dysfunction. PMID- 22537223 TI - Reconciling slip measurements in symmetric and asymmetric systems. AB - In the past decade, the slip of simple liquids on solid surfaces has been demonstrated by many groups. However, the slip of liquids on wettable surfaces is heavily debated. Using colloid probe atomic force microscopy (AFM), we found the slip length of di-n-octylphthalate in a symmetric wettable system (silica) to be around 11 nm, which raises the question of what the measured slip length in an asymmetric hydrophilic-hydrophobic system would be. To answer this question, we investigated liquid slip in one symmetric nonwettable system (hydrophobic DCDMS or OTS) and in one asymmetric hydrophilic (silica)-hydrophobic (DCDMS) system by the same method at driving velocities of between 10 and 80 MUm/s. The slip results obtained from the three systems are in agreement with each other, and this comparison provides a means to self-assess the accuracy and reproducibility of the measured force curves and the fitted slip length in our systems. Furthermore, this method provides access to reliable values of the actual slip length on any investigated flat surface in an asymmetric system, avoiding the difficulty of preparing a symmetric probe/flat surface system in a colloid probe AFM force measurement. PMID- 22537222 TI - Weight gain prevention among black women in the rural community health center setting: the Shape Program. AB - BACKGROUND: Nearly 60% of black women are obese. Despite their increased risk of obesity and associated chronic diseases, black women have been underrepresented in clinical trials of weight loss interventions, particularly those conducted in the primary care setting. Further, existing obesity treatments are less effective for this population. The promotion of weight maintenance can be achieved at lower treatment intensity than can weight loss and holds promise in reducing obesity associated chronic disease risk. Weight gain prevention may also be more consistent with the obesity-related sociocultural perspectives of black women than are traditional weight loss approaches. METHODS/DESIGN: We conducted an 18 month randomized controlled trial (the Shape Program) of a weight gain prevention intervention for overweight black female patients in the primary care setting. Participants include 194 premenopausal black women aged 25 to 44 years with a BMI of 25-34.9 kg/m2. Participants were randomized either to usual care or to a 12 month intervention that consisted of: tailored obesogenic behavior change goals, self-monitoring via interactive voice response phone calls, tailored skills training materials, 12 counseling calls with a registered dietitian and a 12 month YMCA membership.Participants are followed over 18 months, with study visits at baseline, 6-, 12- and 18-months. Anthropometric data, blood pressure, fasting lipids, fasting glucose, and self-administered surveys are collected at each visit. Accelerometer data is collected at baseline and 12-months.At baseline, participants were an average of 35.4 years old with a mean body mass index of 30.2 kg/m2. Participants were mostly employed and low-income. Almost half of the sample reported a diagnosis of hypertension or prehypertension and 12% reported a diagnosis of diabetes or prediabetes. Almost one-third of participants smoked and over 20% scored above the clinical threshold for depression. DISCUSSION: The Shape Program utilizes an innovative intervention approach to lower the risk of obesity and obesity-associated chronic disease among black women in the primary care setting. The intervention was informed by behavior change theory and aims to prevent weight gain using inexpensive mobile technologies and existing health center resources. Baseline characteristics reflect a socioeconomically disadvantaged, high-risk population sample in need of evidence-based treatment strategies. TRIAL REGISTRATION: The trial is registered with clinicaltrials.gov NCT00938535. PMID- 22537225 TI - Controlled thermoresponsive hydrogels by stereocomplexed PLA-PEG-PLA prepared via hybrid micelles of pre-mixed copolymers with different PEG lengths. AB - The stereocomplexed hydrogels derived from the micelle mixture of two enantiomeric triblock copolymers, PLLA-PEG-PLLA and PDLA-PEG-PDLA, reported in 2001 exhibited sol-to-gel transition at approximately body temperature upon heating. However, the showed poor storage modulus (ca. 1000 Pa) determined their insufficiency as injectable implant biomaterials for many applications. In this study, the mechanical property of these hydrogels was significantly improved by the modifications of molecular weights and micelle structure. Co-micelles composed of block copolymers with two sizes of PEG block length were shown to possess unique and dissimilar properties from the micelles composed of single sized block copolymers. The stereomixture of PLA-PEG-PLA comicelles showed a controllable sol-to-gel transition at a wide temperature range of 4 and 80 degrees C. The sol-gel phase diagram displays a linear relationship of temperature versus copolymer composition; hence, a transition at body temperature can be readily achieved by adjusting the mixed copolymer ratio. The resulting thermoresponsive hydrogels exhibit a storage modulus notably higher (ca. 6000 Pa) than that of previously reported hydrogels. As a physical network solely governed by self-reorganization of micelles, followed by stereocomplexation, this unique system offers practical, safe, and simple implantable biomaterials. PMID- 22537224 TI - Non-specific chemical inhibition of the Fanconi anemia pathway sensitizes cancer cells to cisplatin. AB - BACKGROUND: Platinum compounds such as cisplatin and carboplatin are DNA crosslinking agents widely used for cancer chemotherapy. However, the effectiveness of platinum compounds is often tempered by the acquisition of cellular drug resistance. Until now, no pharmacological approach has successfully overcome cisplatin resistance in cancer treatment. Since the Fanconi anemia (FA) pathway is a DNA damage response pathway required for cellular resistance to DNA interstrand crosslinking agents, identification of small molecules that inhibit the FA pathway may reveal classes of chemicals that sensitize cancer cells to cisplatin. RESULTS: Through a cell-based screening assay of over 16,000 chemicals, we identified 26 small molecules that inhibit ionizing radiation and cisplatin-induced FANCD2 foci formation, a marker of FA pathway activity, in multiple human cell lines. Most of these small molecules also compromised ionizing radiation-induced RAD51 foci formation and homologous recombination repair, indicating that they are not selective toward the regulation of FANCD2. These compounds include known inhibitors of the proteasome, cathepsin B, lysosome, CHK1, HSP90, CDK and PKC, and several uncharacterized chemicals including a novel proteasome inhibitor (Chembridge compound 5929407).Isobologram analyses demonstrated that half of the identified molecules sensitized ovarian cancer cells to cisplatin. Among them, 9 demonstrated increased efficiency toward FA pathway-proficient, cisplatin-resistant ovarian cancer cells. Six small molecules, including bortezomib (proteasome inhibitor), CA-074-Me (cathepsin B inhibitor) and 17-AAG (HSP90 inhibitor), synergized with cisplatin specifically in FA-proficient ovarian cancer cells (2008 + FANCF), but not in FA-deficient isogenic cells (2008). In addition, geldanamycin (HSP90 inhibitor) and two CHK1 inhibitors (UCN-01 and SB218078) exhibited a significantly stronger synergism with cisplatin in FA-proficient cells when compared to FA-deficient cells, suggesting a contribution of their FA pathway inhibitory activity to cisplatin sensitization. CONCLUSION: Our findings suggest that, despite their lack of specificity, pharmaceutical inhibition of the FA pathway by bortezomib, CA-074 Me, CHK1 inhibitors or HSP90 inhibitors may be a promising strategy to sensitize cisplatin-resistant, FA pathway-proficient tumor cells to cisplatin. In addition, we identified four new small molecules which synergize with cisplatin. Further development of their analogs and evaluation of their combination with cisplatin may lead to the development of efficient cancer treatments. PMID- 22537226 TI - Identifying patient subgroups who benefit most from a treatment: using administrative claims data to uncover treatment heterogeneity. AB - OBJECTIVES: To illustrate how claims data can be used to (1) develop outcome scores that predict response to a traditional treatment and (2) estimate the economic impact of individualized assignment to a newer treatment based on the outcome score. An example application is based on two treatments for attention deficit hyperactivity disorder (ADHD): osmotic-release oral system methylphenidate (OROS-MPH) and lisdexamfetamine dimesylate (LDX). METHODS: Adolescents with ADHD initiating OROS-MPH (n=6320) or LDX (n=6394) were selected from the MarketScan claims database. A model was developed for predicting risk of switching/augmentation with OROS-MPH using multiple baseline characteristics. The model was applied to an independent sample to stratify patients by their predicted risk and, within each stratum, risk of switching/augmentation and ADHD related total costs were compared between OROS-MPH and LDX patients using inverse probability of treatment weighting. RESULTS: The prediction model resulted in substantial stratification, showing risk of switching/augmentation with OROS-MPH ranging from 11.3-42.1%. In the two strata where OROS-MPH had highest risk of switching/augmentation, LDX had significantly lower risk of switching/augmentation than OROS-MPH (by 7.0-8.2%) and lower ADHD-related annual total costs (by $264-$625 per patient). LIMITATIONS: The current study has used the risk of switching/augmentation as a proxy measure for treatment efficacy to establish the prediction model. Future research using a clinical measure for ADHD symptoms is warranted to verify the findings. CONCLUSIONS: Combining multiple patient characteristics into a predicted score for treatment outcomes with a traditional treatment can help identify subgroups of patients who benefit most from a new treatment. In this analysis, ADHD patients with a high predicted score for switching/augmentation with OROS-MPH had a lower rate of switching/augmentation with LDX. Assigning OROS-MPH and LDX treatments based on the predicted scores that are heterogeneous in a patient population may help improve clinical outcomes and the cost-effectiveness of care. PMID- 22537227 TI - A prospective study measuring the development of antibodies against platelet factor 4-heparin in healthy males after exposure to heparins. PMID- 22537228 TI - Simultaneous occurrence of foetal and neonatal alloimmune thrombocytopenia and neonatal neutropenia due to maternal neutrophilic autoantibodies: a case study and review of the literature. AB - Foetal and neonatal alloimmune thrombocytopenia (FNAIT) and neonatal neutropenia caused by maternal autoantibodies against neutrophils are rare disorders. We describe a newborn with severe thrombocytopenia and intracerebral bleeding caused by maternal anti-HPA-3a alloantibodies and mild neutropenia caused by maternal autoantibodies against HNA-1b. This appears to be the first case of simultaneous occurrence of these two conditions. CONCLUSION: This case report and review of the literature demonstrate that anti-HPA-3a antibodies can be overlooked by standard assays. PMID- 22537229 TI - Determination of carbon dioxide transport coefficients in liquids and polymers by NMR spectroscopy. AB - In liquids and in polymeric membranes, a precise determination of their transport properties is of paramount importance. In this work, an NMR method to measure sequentially the solubility and diffusion coefficients of carbon dioxide in liquids (n-alkanes and 1-alkanols) and in polymer membranes (polyethylene, polybutadiene, and polycarbonate) is described. The results show that NMR measurements are very reproducible and in good agreement with those determined by other methods. Considering that the gas permeability is defined as the product of the solubility and diffusion coefficients, the method allows the determination of all transport parameters in an accurate manner. The influence of chain length, viscosity, and solubility parameters on the transport coefficients of [(13)C]O(2) in alkanes and 1-alkanols was also analyzed and compared to those measured in polyethylene. PMID- 22537230 TI - Identification of new Potato virus Y (PVY) molecular determinants for the induction of vein necrosis in tobacco. AB - Two tobacco vein necrosis (TVN) determinants, the residues K(400) and E(419) , have been identified previously in the helper component-protease (HC-Pro) protein sequence of Potato virus Y (PVY). However, since their description, non-necrotic PVY isolates with both K(400) and E(419) necrotic determinants have been reported in the literature. This suggests the presence in the viral genome of other, as yet uncharacterized, TVN determinant(s). The identification of PVY(N) pathogenicity determinants was approached through the replacement of genomic regions of the necrotic PVY(N) -605 infectious clone by corresponding sequences from the non-necrotic PVY(O) -139 isolate. Series of PVY(N/O) chimeras and site directed PVY mutants were constructed to test the involvement of different parts of the PVY genome (from nucleotide 421 to nucleotide 9629) in the induction of TVN symptoms. The analysis of both the genomic characteristics and biological properties of these mutants made it possible to highlight the involvement, in addition to residues K(400) and E(419), of the residue N(339) of the HC-Pro protein and two regions in the cytoplasmic inclusion (CI) protein to nuclear inclusion protein a-protease (NIa-Pro) sequence (nucleotides 5496-5932 and 6233 6444) in the induction of vein necrosis in tobacco infected by PVY isolates. PMID- 22537231 TI - Extracranial metastasizing solitary fibrous tumors (SFT) of meninges: histopathological features of a case with long-term follow-up. AB - Extrapleural solitary fibrous tumors are uncommon mesenchymal neoplasms frequently observed in middle-aged adults and are classified, according to the WHO classification of soft tissue tumors, as part of the hemangiopericytoma tumor group. However, these two entities remain separated in the WHO classification of tumors of the central nervous system. In fact, meningeal solitary fibrous tumors are believed to be benign lesion and only in a minority of cases local relapses have been described, although detailed survival clinical studies on solitary fibrous tumors of meninges are rare. In contrast to hemangiopericytoma, which frequently shows distant extracranial metastases, such an event is exceptional in patients with meningeal solitary fibrous tumors and has been clinically reported in a handful of cases only and their histopathological features have not been investigated in detail. In this report, we describe the detailed clinico pathological features of a meningeal solitary fibrous tumor presenting during a 17-year follow-up period, multiple intra-, extracranial relapses and lung metastases. PMID- 22537232 TI - Secretory leukocyte protease inhibitor binds to Neisseria gonorrhoeae outer membrane opacity protein and is bactericidal. AB - PROBLEM: Secretory leukocyte protease inhibitor (SLPI) is an innate immune peptide present on the genitourinary tract mucosa that has antimicrobial activity. In this study, we investigated the interaction of SLPI with Neisseria gonorrhoeae. METHOD OF STUDY: ELISA and far-Western blots were used to analyze binding of SLPI to gonococci. The binding site for SLPI was identified by tryptic digests and mass spectrometry. Antimicrobial activity of SLPI for gonococci was determined using bactericidal assays. SLPI protein levels in cell supernatants were measured by ELISA, and SLPI mRNA levels were assessed by quantitative RT PCR. RESULTS: SLPI bound directly to the gonococcal Opa protein and was bactericidal. Epithelial cells from the reproductive tract constitutively expressed SLPI at different levels. Gonococcal infection of cells did not affect SLPI expression. CONCLUSION: We conclude that SLPI is bactericidal for gonococci and is expressed by reproductive tract epithelial cells and thus is likely to play a role in the pathogenesis of gonococcal infection. PMID- 22537233 TI - Evolution of vertebrate interferon inducible transmembrane proteins. AB - BACKGROUND: Interferon inducible transmembrane proteins (IFITMs) have diverse roles, including the control of cell proliferation, promotion of homotypic cell adhesion, protection against viral infection, promotion of bone matrix maturation and mineralisation, and mediating germ cell development. Most IFITMs have been well characterised in human and mouse but little published data exists for other animals. This study characterised IFITMs in two distantly related marsupial species, the Australian tammar wallaby and the South American grey short-tailed opossum, and analysed the phylogeny of the IFITM family in vertebrates. RESULTS: Five IFITM paralogues were identified in both the tammar and opossum. As in eutherians, most marsupial IFITM genes exist within a cluster, contain two exons and encode proteins with two transmembrane domains. Only two IFITM genes, IFITM5 and IFITM10, have orthologues in both marsupials and eutherians. IFITM5 arose in bony fish and IFITM10 in tetrapods. The bone-specific expression of IFITM5 appears to be restricted to therian mammals, suggesting that its specialised role in bone production is a recent adaptation specific to mammals. IFITM10 is the most highly conserved IFITM, sharing at least 85% amino acid identity between birds, reptiles and mammals and suggesting an important role for this presently uncharacterised protein. CONCLUSIONS: Like eutherians, marsupials also have multiple IFITM genes that exist in a gene cluster. The differing expression patterns for many of the paralogues, together with poor sequence conservation between species, suggests that IFITM genes have acquired many different roles during vertebrate evolution. PMID- 22537235 TI - Speckle tracking-derived mitral annular velocities predict mortality in patients with acute coronary syndrome. AB - BACKGROUND: Myocardial ischemia can impair myocardial relaxation and result in increased left ventricular (LV) diastolic pressure. Noninvasive measurements of mitral annular velocities have been used to evaluate LV diastolic pressure. We sought to determine whether mitral annular velocities, derived from novel speckle tracking echocardiography (STE), could predict mortality in patients with acute coronary syndrome (ACS). METHODS: A total of 246 patients with ACS were retrospectively studied. STE was analyzed offline with the sample volume placed on septal, lateral, inferior, and anterior mitral annulus. Peak early (E') and late (A') diastolic velocities of the mitral annulus were measured and averaged from the four regions. Peak early diastolic mitral inflow velocity (E) was obtained using pulsed-wave Doppler. RESULTS: Lower E' (P = 0.03), lower A' (P = 0.001), higher E'/A' ratio (P = 0.007), and higher E/E' ratio (P = 0.003) were independently associated with increased risk of death with adjustment for clinical and echocardiographic variables over the follow-up period of 21 months. The optimal cutoff value of E/E' ratio derived from the receiver operating characteristic analysis for predicting death was 30 (area under the curve = 0.65). E/E' ratio greater than 30 was predictive of death in univariate (HR, 2.40; CI, 1.42-4.06; P = 0.001) and multivariate (adjusted HR, 1.91; CI, 1.09 3.32; P = 0.02) models. CONCLUSION: The measurements of mitral annular velocities by STE are predictive of mortality in patients with ACS. PMID- 22537236 TI - Incremental value of live/real time three-dimensional transesophageal echocardiography over the two-dimensional technique in the assessment of aortic aneurysm and dissection. AB - We compared findings from intraoperative live/real time three-dimensional transesophageal echocardiography (3DTEE) and two-dimensional transesophageal echocardiography (2DTEE) with surgery in 67 patients having aortic aneurysm and/or aortic dissection. Of these, 20 patients had aortic aneurysm without dissection, 21 aortic aneurysm and dissection, and 26 aortic dissection without aneurysm. 3DTEE diagnosed the type and location of aneurysm correctly in all patients unlike 2DTEE, which missed an aneurysm in one case. There were four cases of aortic aneurysm rupture. Three of them were diagnosed by 3DTEE but only one by 2DTEE, and one missed by both techniques. The mouth of saccular aneurysm, site of aortic aneurysm rupture, and communication sites between perfusing and nonperfusing lumens of aortic dissection could be viewed en face only with 3DTEE, enabling comprehensive measurements of their area and dimensions as well as increasing the confidence level of their diagnosis. In all patients with aortic dissection, 3DTEE enabled a more confident diagnosis of dissection because the dissection flap when viewed en face presented as a sheet of tissue rather than a linear echo seen on 2DTEE which can be confused with an artifact. 2DTEE missed dissection in one patient. In six cases the dissection flap involved the right coronary artery orifice by 3DTEE and surgery. These were missed by 2DTEE. Aortic regurgitation severity was more comprehensively assessed by 3DTEE than 2DTEE. Aneurysm size by 3DTEE correlated well with 2DTEE and surgery/computed tomography scan. In conclusion, 3DTEE provides incremental information over 2DTEE in patients with aortic aneurysm and dissection. PMID- 22537238 TI - Intracranial hemorrhage as a complication of dobutamine stress echocardiography: case report and review of the literature. AB - Dobutamine stress echocardiography is a generally well-tolerated study to evaluate patients with suspected coronary artery disease. Rare but life threatening complications of this study have been well described. Severe hypertensive responses are a known but uncommon adverse reaction to dobutamine infusion. The authors report a case of intracranial hemorrhage in the setting of severe hypertension as a complication of dobutamine stress echocardiography. The patient was on systemic anticoagulation with warfarin for a prosthetic mitral valve and had an international normalized ratio (INR) of 3.8 that was slightly over the therapeutic goal INR of 2.5-3.5. He had no predisposing intracranial lesions such as tumor, vascular malformation, or aneurysm. He suffered an intraparenchymal hemorrhage in three distinct areas of his brain. Intracranial hemorrhage related to dobutamine infusion has not been reported previously, but given the known risk of hypertension, life-threatening sequelae including intracranial hemorrhage are possible. PMID- 22537241 TI - Effect of salts on the phase behavior and the stability of nanoemulsions with rapeseed oil and an extended surfactant. AB - For many decades, the solubilization of long-chain triglycerides in water has been a challenge. A new class of amphiphiles has been created to overcome this solubilization problem. The so-called "extended" surfactants contain a hydrophilic-lipophilic linker to reduce the contrast between the surfactant-water and surfactant-oil interfaces. In the present contribution, the effects of different anions and cations on the phase behavior of a mixture containing an extended surfactant (X-AES), a hydrotrope (sodium xylene sulfonate, SXS), water, and rapeseed oil were determined as a function of temperature. Nanoemulsions were obtained and characterized by conductivity measurements, light scattering, and optical microscopy. All salting-out salts show a transition from a clear region (O/W nanoemulsion), to a lamellar liquid crystalline phase region, a clear phase (bicontinuous L(3)), and again to a lamellar liquid crystalline phase region with increasing temperature. For the phase diagrams with NaSCN and Na(2)SO(4), only one clear region (O/W nanoemulsion) was observed, which turns into a lamellar phase region at elevated temperatures. Furthermore, the stability of the nanoemulsions was investigated by time-dependent measurements: the visual observation of phase separation, droplet size by dynamic light scattering (DLS), and optical microscopy. The mechanism of the different phase transitions is also discussed. PMID- 22537240 TI - Pathways to catastrophic health expenditure for acute coronary syndrome in Kerala: 'Good health at low cost'? AB - BACKGROUND: Universal health coverage through the removal of financial and other barriers to access, particularly for people who are poor, is a global priority. This viewpoint describes the many pathways to catastrophic health expenditure (CHE) for patients with Acute Coronary Syndrome (ACS) based on two case studies and the thematic analysis of field notes regarding 210 patients and their households from a study based in Kerala, India. DISCUSSION: There is evidence of the severe financial impact of non-communicable diseases (NCDs), which is in contradiction to the widely acclaimed Kerala model: Good health at low cost. However, it is important to look beyond the out-of-pocket expenditure (OOPE) and CHE to the possible pathways and identify the triggers that make families vulnerable to CHE. The identified pathways include a primary and secondary loop. The primary pathway describes the direct path by which families experience CHE. These include: 1) factors related to the pre-event period that increase the likelihood of experiencing CHE, such as being from the lower socio-economic strata (SES), past financial losses or loans that leave families with no financial shock absorber at the time of illness; 2) factors related to the acute event, diagnosis, treatment and hospitalization and expenditures incurred for the same and; 3) factors related to the post-event period such as loss of gainful employment and means of financing both the acute period and the long-term management particularly through distress financing. The secondary pathway arises from the primary and includes: 1) the impact of distress financing and; 2) the long- and short- term consequences of CHE. These factors ultimately result in a vicious cycle of debt and poverty through non-compliance and repeat acute events. SUMMARY: This paper outlines the direct and indirect pathways by which patients with ACS and their families are trapped in a vicious cycle of debt and poverty. It also contradicts the prevailing impression that only low-income families are susceptible to CHE, distress financing and their aftermaths and underscores the need for a deeper understanding at the micro-level, if Kerala and India as a whole are to undertake the difficult exercise of achieving universal health coverage to successfully tackle its growing NCD burden. PMID- 22537243 TI - Characterisation of von Willebrand factor A1 domain mutants I1416N and I1416T: correlation of clinical phenotype with flow-based platelet adhesion. AB - BACKGROUND: Type 2M von Willebrand disease (VWD) results from mutations in the A1 domain of von Willebrand factor (VWF) that reduce its platelet-binding function. However, currently employed VWF functional static assays may not distinguish between clinical phenotype. METHODS: Fifteen individuals from five kindreds with VWF-A1 domain mutations I1416T or I1416N, correlated with mild and moderate clinical phenotypes, respectively, were investigated. The mutations were reproduced by site-directed mutagenesis and expressed in HEK293T cells; functional studies of the recombinant mutants, including GPIbalpha binding using a flow-based assay, were performed. RESULTS: Plasma from all individuals demonstrated discordant reductions in VWF antigen and platelet-binding function in the presence of high-molecular-weight VWF multimers consistent with VWD type 2M. There was lowered expression and secretion of both mutants compared with wild type (WT) recombinant (r)VWF as well as a significant reduction in GPIbalpha binding. Binding to collagen was normal and electrophoretic analysis demonstrated a similar multimer distribution between the mutant proteins and wt-rVWF. GPIbalpha binding under flow was also significantly reduced for I1416N and I1416T rVWF. Impairment of GPIbalpha binding was more marked for I1416N rVWF than I1416T under both static and flow conditions: this was in spite of similar VWF:Ristocetin cofactor (RCo) activities in patient plasma and is consistent with a respective clinical phenotype. CONCLUSIONS: Our findings have established for the first time that I1416N and I1416T are responsible for a type 2M VWD phenotype and demonstrate that quantification of VWF function under shear stress may provide a more accurate measure of clinical severity than the static functional measurements in current diagnostic use. PMID- 22537242 TI - Runx2 mediates epigenetic silencing of the bone morphogenetic protein-3B (BMP 3B/GDF10) in lung cancer cells. AB - BACKGROUND: The Runt-related transcription factor Runx2 is essential for bone development but is also implicated in progression of several cancers of breast, prostate and bone, where it activates cancer-related genes and promotes invasive properties. The transforming growth factor beta (TGF-beta) family member bone morphogenetic protein-3B (BMP-3B/GDF10) is regarded as a tumor growth inhibitor and a gene silenced in lung cancers; however the regulatory mechanisms leading to its silencing have not been identified. RESULTS: Here we show that Runx2 is highly expressed in lung cancer cells and downregulates BMP-3B. This inverse relationship between Runx2 and BMP-3B expression is further supported by increased expression of BMP-3B in mesenchymal cells from Runx2 deficient mice. The ectopic expression of Runx2, but not DNA binding mutant Runx2, in normal lung fibroblast cells and lung cancer cells resulted in suppression of BMP-3B levels. The chromatin immunoprecipitation studies identified that the mechanism of Runx2 mediated suppression of BMP-3B is due to the recruitment of Runx2 and histone H3K9-specific methyltransferase Suv39h1 to BMP-3B proximal promoter and a concomitant increase in histone methylation (H3K9) status. The knockdown of Runx2 in H1299 cells resulted in decreased histone H3K9 methylation on BMP-3B promoter and increased BMP-3B expression levels. Furthermore, co-immunoprecipitation studies showed a direct interaction of Runx2 and Suv39h1 proteins. Phenotypically, Runx2 overexpression in H1299 cells increased wound healing response to TGFbeta treatment. CONCLUSIONS: Our studies identified BMP-3B as a new Runx2 target gene and revealed a novel function of Runx2 in silencing of BMP 3B in lung cancers. Our results suggest that Runx2 is a potential therapeutic target to block tumor suppressor gene silencing in lung cancer cells. PMID- 22537244 TI - Potential effects of chocolate on human pregnancy: a randomized controlled trial. AB - OBJECTIVE: This trial was undertaken to evaluate the effects of high-cocoa content chocolate supplementation in pregnancy on several haematochemical and clinical parameters. The study had as reference population the pregnant women requesting an obstetric control at Outpatient Clinic of Obstetrics and Gynaecology of the S. Maria della Misericordia University Hospital, Perugia, Italy. Candidates who participated in this study were all Caucasian women aged 18 40 years, who had a single gestation pregnancy between 11th + 0 and 13th + 0 week gestational age. METHODS: We conducted a single-center randomized controlled trial. The pregnant women selected were randomized into Group A, which received daily doses of 30 g of chocolate (70% cocoa), and Group B, which was free to increase their diet with other foods. RESULTS: Ninety women were randomized. Significant difference was found between the two groups for diastolic blood pressure (p = 0.05), systolic (p < 0.0001) and levels of liver enzymes, with values lower in Group A than in Group B. Total cholesterol levels and weight gain in Group A did not increase more than in Group B. CONCLUSIONS: A modest daily intake of high-cocoa-content chocolate contributes to reduce blood pressure, glycemic and liver pattern during pregnancy without affecting the weight gain. PMID- 22537245 TI - Are ellipsoids feasible micelle shapes? An answer based on a molecular thermodynamic model of nonionic surfactant micelles. AB - The existence of ellipsoidal micelles in aqueous solution has been debated in the literature. Although a number of experimental studies suggest that certain surfactants form ellipsoidal micelles, many theoretical studies have claimed that micelles with an ellipsoidal shape cannot exist. To shed light on this topic, in this paper, we develop a curvature-corrected, molecular-thermodynamic model for the free energy of micellization of nonionic surfactant biaxial ellipsoidal micelles. We subsequently use this model to evaluate the feasibility of forming ellipsoidal micelles, compared to forming spherical, spherocylindrical, and discoidal micelles, and conclude that ellipsoidal micelles can exist in solution. Utilizing the model developed here, we also establish theoretical limits on the size of the ellipsoidal micelles. These limits depend solely on the chemical structure of the surfactant molecule. PMID- 22537246 TI - 12-month-olds' phonotactic knowledge guides their word-object mappings. AB - This study examined whether 12-month-olds will accept words that differ phonologically and phonetically from their native language as object labels in an associative learning task. Sixty infants were presented with sets of English word object (N = 30), Japanese word-object (N = 15), or Czech word-object (N = 15) pairings until they habituated. Infants associated CVCV English, CCVC English, and CVCV Japanese words, but not CCVC Czech words, with novel objects. These results demonstrate that by 12 months of age, infants are beginning to apply their language-specific knowledge to their acceptance of word forms. That is, they will not map words that violate the phonotactics of their native language to objects. PMID- 22537247 TI - Estimating the current and future costs of Type 1 and Type 2 diabetes in the UK, including direct health costs and indirect societal and productivity costs. AB - AIMS: To estimate the current and future economic burdens of Type 1 and Type 2 diabetes in the UK. METHODS: A top-down approach was used to estimate costs for 2010/2011 from aggregated data sets and literature. Prevalence and population data were used to project costs for 2035/2036. Direct health costs were estimated from data on diagnosis, lifestyle interventions, ongoing treatment and management, and complications. Indirect costs were estimated from data on mortality, sickness, presenteeism (potential loss of productivity among people who remain in work) and informal care. RESULTS: Diabetes cost approximately L 23.7bn in the UK in 2010/2011: L 9.8bn in direct costs (L1bn for Type 1 diabetes and L 8.8bn for Type 2 diabetes) and L 13.9bn in indirect costs (L 0.9bn and L 13bn). In real terms, the 2035/2036 cost is estimated at L 39.8bn: L 16.9bn in direct costs (L 1.8bn for Type 1 diabetes and L 15.1bn for Type 2 diabetes) and L 22.9bn in indirect costs (L 2.4bn and L 20.5bn). Sensitivity analysis applied to the direct costs produced a range of costs: between L 7.9bn and L 11.7bn in 2010/2011 and between L 13.8bn and L20bn in 2035/2036. Diabetes currently accounts for approximately 10% of the total health resource expenditure and is projected to account for around 17% in 2035/2036. CONCLUSIONS: Type 1 and Type 2 diabetes are prominent diseases in the UK and are a significant economic burden. Data differentiating between the costs of Type 1 and Type 2 diabetes are sparse. Complications related to the diseases account for a substantial proportion of the direct health costs. As prevalence increases, the cost of treating complications will grow if current care regimes are maintained. PMID- 22537249 TI - Diabetes and contact lens wear. AB - The literature suggests that diabetic patients may have altered tear chemistry and tear secretion as well as structural and functional changes to the corneal epithelium, endothelium and nerves. These factors, together with a reported increased incidence of corneal infection, suggest that diabetic patients may be particularly susceptible to developing ocular complications during contact lens wear. Reports of contact lens-induced complications in diabetic patients do exist, although a number of these reports concern patients with advanced diabetic eye disease using lenses on an extended wear basis. Over the past decade or so, there have been published studies documenting the response of the diabetic eye to more modern contact lens modalities. The results of these studies suggest that contact lenses can be a viable mode of refractive correction for diabetic patients. Furthermore, new research suggests that the measurement of tear glucose concentration could, in future, be used to monitor metabolic control non invasively in diabetic patients. This could be carried out using contact lenses manufactured from hydrogel polymers embedded with glucose-sensing agents or nanoscale digital electronic technology. The purpose of this paper is to review the literature on the anterior ocular manifestations of diabetes, particularly that pertaining to contact lens wear. PMID- 22537250 TI - Doped biomolecules in miniaturized electric junctions. AB - Control over molecular scale electrical properties within nano junctions is demonstrated, utilizing site-directed C(60) targeting into protein macromolecules as a doping means. The protein molecules, self-assembled in a miniaturized transistor device, yield robust and reproducible operation. Their device signal is dominated by an active center that inverts affinity upon guest incorporation and thus controls the properties of the entire macromolecule. We show how the leading routes of electron transport can be drawn, spatially and energetically, on the molecular level and, in particular, how the dopant effect is dictated by its "strategic" binding site. Our findings propose the extension of microelectronic methodologies to the nanometer scale and further present a promising platform for ex situ studies of biochemical processes. PMID- 22537248 TI - The stable traits of melanoma genetics: an alternate approach to target discovery. AB - BACKGROUND: The weight that gene copy number plays in transcription remains controversial; although in specific cases gene expression correlates with copy number, the relationship cannot be inferred at the global level. We hypothesized that genes steadily expressed by 15 melanoma cell lines (CMs) and their parental tissues (TMs) should be critical for oncogenesis and their expression most frequently influenced by their respective copy number. RESULTS: Functional interpretation of 3,030 transcripts concordantly expressed (Pearson's correlation coefficient p-value < 0.05) by CMs and TMs confirmed an enrichment of functions crucial to oncogenesis. Among them, 968 were expressed according to the transcriptional efficiency predicted by copy number analysis (Pearson's correlation coefficient p-value < 0.05). We named these genes, "genomic delegates" as they represent at the transcriptional level the genetic footprint of individual cancers. We then tested whether the genes could categorize 112 melanoma metastases. Two divergent phenotypes were observed: one with prevalent expression of cancer testis antigens, enhanced cyclin activity, WNT signaling, and a Th17 immune phenotype (Class A). This phenotype expressed, therefore, transcripts previously associated to more aggressive cancer. The second class (B) prevalently expressed genes associated with melanoma signaling including MITF, melanoma differentiation antigens, and displayed a Th1 immune phenotype associated with better prognosis and likelihood to respond to immunotherapy. An intermediate third class (C) was further identified. The three phenotypes were confirmed by unsupervised principal component analysis. CONCLUSIONS: This study suggests that clinically relevant phenotypes of melanoma can be retraced to stable oncogenic properties of cancer cells linked to their genetic back bone, and offers a roadmap for uncovering novel targets for tailored anti-cancer therapy. PMID- 22537251 TI - Concurrent medical conditions and long-term outcome in dogs with nontraumatic intracranial hemorrhage. AB - Nontraumatic intracranial hemorrhage is bleeding originating from the brain or surrounding structures. It results from blood vessel rupture and may be primary or secondary in origin. The magnetic resonance imaging (MRI) characteristics of 75 dogs with nontraumatic intracranial hemorrhage were reviewed to determine signalment; intracranial compartment involved, size and number of lesions; type and prevalence of concurrent medical conditions; and long-term outcome. Hemorrhagic lesions were intraparenchymal (n = 72), subdural (n = 2) or intraventricular (n = 1). Thirty-three of 75 dogs had a concurrent medical condition. A concurrent condition was detected in 13 of 43 dogs with a single lesion >=5 mm and included Angiostrongylus vasorum infection, intracranial lymphoma and meningioma. Of the 20 dogs with multiple lesions >=5 mm, 7 had A. vasorum infection, 2 had hemangiosarcoma metastasis, 5 had suspected brain metastasis, and 1 was septicemic. Of the 12 dogs with multiple lesions, 2 had hyperadrenocorticism, 2 had chronic kidney disease, and 1 had hypothyroidism. Of these five dogs, all were hypertensive and four died within 12 months. No dog had a single lesion <5 mm. Long-term outcome was favorable in 26 of 43 dogs with single lesions >=5 mm, 6 of 20 dogs with multiple lesions >=5 mm, and 8 of 12 dogs with multiple lesions <5 mm. A. vasorum infection was the most common concurrent condition in dogs with nontraumatic intracranial hemorrhage (16/75), with an excellent outcome in 14 of 16 dogs. Prognosis in nontraumatic intracranial hemorrhage is reported in terms of concurrent medical conditions and the number and size of lesions. PMID- 22537252 TI - Examining the knowledge, attitudes and practices of domestic and international university students towards seasonal and pandemic influenza. AB - BACKGROUND: Prior to the availability of the specific pandemic vaccine, strategies to mitigate the impact of the disease typically involved antiviral treatment and "non-pharmaceutical" community interventions. However, compliance with these strategies is linked to risk perceptions, perceived severity and perceived effectiveness of the strategies. In 2010, we undertook a study to examine the knowledge, attitudes, risk perceptions, practices and barriers towards influenza and infection control strategies amongst domestic and international university students. METHODS: A study using qualitative methods that incorporated 20 semi-structured interviews was undertaken with domestic and international undergraduate and postgraduate university students based at one university in Sydney, Australia. Participants were invited to discuss their perceptions of influenza (seasonal vs. pandemic) in terms of perceived severity and impact, and attitudes towards infection control measures including hand washing and the use of social distancing, isolation or cough etiquette. RESULTS: While participants were generally knowledgeable about influenza transmission, they were unable to accurately define what 'pandemic influenza' meant. While avian flu or SARS were mistaken as examples of past pandemics, almost all participants were able to associate the recent "swine flu" situation as an example of a pandemic event. Not surprisingly, it was uncommon for participants to identify university students as being at risk of catching pandemic influenza. Amongst those interviewed, it was felt that 'students' were capable of fighting off any illness. The participant's nominated hand washing as the most feasible and acceptable compared with social distancing and mask use. CONCLUSIONS: Given the high levels of interaction that occurs in a university setting, it is really important that students are informed about disease transmission and about risk of infection. It may be necessary to emphasize that pandemic influenza could pose a real threat to them, that it is important to protect oneself from infection and that infection control measures can be effective. PMID- 22537253 TI - Unusual primary intracranial dural-based poorly differentiated synovial sarcoma with t(X; 18)(p11; q11). AB - Synovial sarcoma is a rare aggressive neoplasm occurring at any site of the body, mainly in young adults. It may also arise in the CNS but has seldom been reported. We report a case of unusual intracranial synovial sarcoma in a young male patient. Neuroimaging revealed a large gadolinium-enhancing mass was located at the right anterior cranial fossa and was associated with multiple cyst formation. The mass was dural-based and was observed to invade the right orbital apex and ethmoidal bulla. Histologically, the tumor was composed of uniform oval and round cells with scant cytoplasm and indistinct borders. The tumor cells were observed to form densely cellular sheets, but in some areas, the tumor showed hemangiopericytomatous vascular pattern consisting of tumor cells arranged around dilated, thin-walled blood vessels. By immunohistochemistry, vimentin, CD99 and Bcl-2 were diffusely positive in most cells, and a focally weak reactivity for S 100 protein was also observed. However, the tumor cells were negative for cytokeratin (AE1/AE3), CK7, CK8/18, CK19, epithelial membrane antigen, CD34, synaptophysin, GFAP, desmin, myogenin, and smooth muscle actin. Cytogenetic analysis using fluorescence in situ hybridization (FISH) demonstrated a translocation t(X;18)(p11;q11), an aberration specific for synovial sarcoma. A diagnosis of primary dural-based poorly differentiated synovial sarcoma was made. To our knowledge, this is the first report of a poorly differentiated variant of synovial sarcoma occurring in dura mater and confirmed by cytogenetic analysis. The present case indicates that appropriate immunohistochemical analysis, and in particular molecular analysis, are essential for accurately diagnosing small, round-cell neoplasms in unusual locations. PMID- 22537254 TI - Stepwise ordering of imidazolium-based cationic surfactants during cooling induced crystallization. AB - Surfactants bearing imidazolium cations represent a new class of building blocks in molecular self-assembly. These imidazolium-based cationic surfactants can exhibit various morphologies during phase transformations. In this work, we studied the self-assembly and phase behavior of 1-hexadecyl-3-methylimidazolium chloride (C(16)mimCl) aqueous dispersions (0.5-10 wt %) by using isothermal titration calorimetry, differential scanning calorimetry, synchrotron small- and wide-angle X-ray scattering, freeze-fracture electron microscopy, optical microscopy, electrical conductance, and Fourier transform infrared spectroscopy. It was found that C(16)mimCl in aqueous solutions can form two different crystalline phases. At higher C(16)mimCl concentrations (>6 wt %), the initial spherical micelles convert directly to the stable crystalline phase upon cooling. At lower concentrations (0.5 or 1 wt %), the micelles first convert to a metastable crystalline phase upon cooling and then transform to the stable crystalline phase upon further incubation at low temperature. The electrical conductance measurement reveals that the two crystalline phases have similar surface charge densities and surface curvatures. Besides, the microscopic and spectroscopic investigations of the two crystalline phases suggest that the metastable crystalline phase has preassembled morphology and a preordered submolecular packing state that contribute to the final stable crystalline structure. The formation of a preordered structure prior to the final crystalline state deepens our understanding of the crystallization mechanisms of common surfactants and amphiphilic ionic liquids and should thus be widely recognized and explored. PMID- 22537255 TI - Correction: visualization of the intracavitary blood flow in systemic ventricles of Fontan patients by contrast echocardiography using particle image velocimetry. PMID- 22537256 TI - Semantic knowledge fractionations: verbal propositions vs. perceptual input? Evidence from a child with Klinefelter syndrome. AB - This paper addresses the relative independence of different types of lexical- and factually-based semantic knowledge in JM, a 9-year-old boy with Klinefelter syndrome (KS). JM was matched to typically developing (TD) controls on the basis of chronological age. Lexical-semantic knowledge was investigated for common noun (CN) and mathematical vocabulary items (MV). Factually-based semantic knowledge was investigated for general and number facts. For CN items, JM's lexical stores were of a normal size but the volume of correct 'sensory feature' semantic knowledge he generated within verbal item descriptions was significantly reduced. He was also significantly impaired at naming item descriptions and pictures, particularly for fruit and vegetables. There was also weak object decision for fruit and vegetables. In contrast, for MV items, JM's lexical stores were elevated, with no significant difference in the amount and type of correct semantic knowledge generated within verbal item descriptions and normal naming. JM's fact retrieval accuracy was normal for all types of factual knowledge. JM's performance indicated a dissociation between the representation of CN and MV vocabulary items during development. JM's preserved semantic knowledge of facts in the face of impaired semantic knowledge of vocabulary also suggests that factually-based semantic knowledge representation is not dependent on normal lexical-semantic knowledge during development. These findings are discussed in relation to the emergence of distinct semantic knowledge representations during development, due to differing degrees of dependency upon the acquisition and representation of semantic knowledge from verbal propositions and perceptual input. PMID- 22537257 TI - Postpartum maternal codeine therapy and the risk of adverse neonatal outcomes: a retrospective cohort study. AB - OBJECTIVES: To examine whether postpartum maternal prescription of codeine was associated with an increased risk of harm to newborns. DESIGN: Population-based retrospective cohort study. SETTING: Ontario, Canada, from April 1, 1998 to March 1, 2008. PARTICIPANTS: A total of 7804 mothers with publically-funded prescription drug coverage. Women who received a prescription for a codeine containing product within 7 days following hospital discharge and their neonates were matched to 7804 mothers who did not receive codeine following delivery. MAIN OUTCOME MEASURES: The primary outcome was readmission of the neonate to hospital for any reason within 30 days. Secondary outcomes included arrival to hospital by ambulance, hospitalization for dehydration, for injury, any hospitalization involving resuscitation or assisted ventilation, and all-cause mortality. RESULTS: We studied 7804 infants whose mothers filled a prescription for codeine shortly after delivery and 7804 whose mothers did not. In the primary analysis, infants whose mothers received codeine were no more likely to be readmitted to hospital in the subsequent 30 days than children whose mothers did not (hazard ratio 0.95, 95% confidence interval (CI) 0.81-1.11). Moreover, we found no association between maternal codeine use and the other adverse neonatal outcomes studied. A stratified analysis revealed no differential risk among infants born by Caesarean section (hazard ratio 0.86; 95% CI 0.69-1.08). CONCLUSIONS: In this large population-based study, maternal prescription of codeine following delivery was not associated with death or hospitalization in the early neonatal period. PMID- 22537258 TI - Budget scalpel hovers over medical research. PMID- 22537259 TI - Transmissible fatty liver disease. PMID- 22537260 TI - Induction of transplant tolerance through mixed hematopoietic chimerism. PMID- 22537261 TI - mTOR inhibitors: a myth, a cure for cancer or something in between? PMID- 22537262 TI - Below the waterline -- the danger of de novo donor-specific HLA antibodies. PMID- 22537265 TI - A renal transplant recipient with weakness and dyspnea. PMID- 22537268 TI - Genetic modification; the development of transgenic ornamental plant varieties. AB - Plant transformation technology (hereafter abbreviated to GM, or genetic modification) has been used to develop many varieties of crop plants, but only a few varieties of ornamental plants. This disparity in the rate and extent of commercialisation, which has been noted for more than a decade, is not because there are no useful traits that can be engineered into ornamentals, is not due to market potential and is not due to a lack of research and development activity. The GM ornamental varieties which have been released commercially have been accepted in the marketplace. In this article, progress in the development of transgenic ornamentals is reviewed and traits useful to both consumers and producers are identified. In considering possible factors limiting the release of genetically modified ornamental products it is concluded that the most significant barrier to market is the difficulty of managing, and the high cost of obtaining, regulatory approval. PMID- 22537270 TI - Stacking of hexagonal nanocrystal layers during Langmuir-Blodgett deposition. AB - Hexagonally ordered close-packed monolayers of sterically stabilized FePt nanocrystals were deposited on substrates using the Langmuir-Blodgett technique. Monolayers of nanocrystals were also stacked by sequential Langmuir-Blodgett transfer. The structures of the nanocrystal monolayers and multilayer stacks were examined with scanning electron microscopy (SEM) and grazing-incidence small angle scattering (GISAXS). An analytical model derived from the quasikinematic approximation provides a convenient description of the GISAXS data of the stacked layers. The transferred monolayers showed good in-plane hexagonal order, even for trilayers. Bilayers exhibited spatial registry with the top layer positioned above the 3-fold coordinated sites of the bottom layer. Trilayers, on the other hand, exhibited significant disorder. PMID- 22537269 TI - Evolution of vitreomacular traction following the use of the dexamethasone intravitreal implant (Ozurdex) in the treatment of macular edema secondary to central retinal vein occlusion. AB - PURPOSE: To report a case of worsening of vitreomacular traction (VMT) after the dexamethasone intravitreal implant (Ozurdex; Allergan, Inc., Irvine, CA) for the treatment of macular edema secondary to central retinal vein occlusion (CRVO). CASE: A 71-year-old man who presented with macular edema secondary to CRVO was treated by intravitreal injections of bevacizumab followed by Ozurdex. RESULTS: VMT developed during the course of treatment and became more evident when macular edema resolved after treatment with Ozurdex. CONCLUSION: VMT may become apparent and worsen after resolution of macular edema treated with intravitreal Ozurdex. PMID- 22537272 TI - Decreased level of melatonin in serum predicts left ventricular remodelling after acute myocardial infarction. AB - As experimental studies suggest that melatonin is cardioprotective after myocardial infarction (MI), this study sought to investigate the relationships between circulating levels of melatonin and left ventricular (LV) remodelling in patients after acute MI. This prospective study included 161 patients (age 61+/ 3yr; 78% men) undergoing primary percutaneous coronary intervention who were assessed echocardiographically at hospital discharge (day 3-7) and at 12 months. LV remodelling was defined as >20% increase in LV end-diastolic volume at 12 month follow-up compared with baseline. Serum melatonin concentrations were measured at admission, during the light period. Twenty-four patients showed LV remodelling, and 137 had no evidence of LV remodelling. Patients with LV remodelling had lower levels of melatonin at study entry [9.96 (8.28-11.03) versus 16.74 (13.77-19.59) pg/mL, respectively; P <0.0001]. Multivariate analysis showed that melatonin levels (OR=2.10, CI 95% 1.547-2.870, P<0.001) were an independent predictor of LV remodelling at 12-month follow-up. Receiver operating characteristic (ROC) analysis showed an area under the curve of 0.959 (CI 95% 0.93-0.98; P<0.0001). To our knowledge, this is the first study to show the relationship between melatonin and LV remodelling during the chronic phase post MI. PMID- 22537271 TI - Monitoring microcirculation changes in port wine stains during vascular targeted photodynamic therapy by laser speckle imaging. AB - This study was conducted to test laser speckle perfusion imaging (LSPI) for imaging microcirculation and monitoring microcirculatory changes of port wine stains (PWS) during vascular targeted photodynamic therapy (V-PDT). Before and 5 min after V-PDT, PWS lesions and the corresponding contralateral healthy skins of 24 PWS patients were scanned, whereas seven PWS patients were scanned throughout V-PDT. V-PDT was conducted immediately after intravenous injection of photocarcinorin (4-5 mg kg(-1)). A 532 nm laser was used for irradiation (power density: 80-100 mW cm(-2), exposure time: 20-50 min). Before V-PDT, all 24 PWS patients demonstrated a significant difference in perfusion between the PWS lesion and the contralateral healthy control skin (1132 +/- 724 and 619 +/- 478 PU, respectively, P < 0.01). Five minutes after V-PDT, the mean perfusion value of the 24 PWS lesions was 1246 +/- 754 PU. There was no significant difference compared to the perfusion before V-PDT (P > 0.05). During V-PDT, the perfusion of seven PWS patients increased rapidly after initiation of V-PDT, reached a maximum within 10 min, lasted for several minutes, and slowly returned to a relatively lower level at the end of V-PDT. On the basis of these results, LSPI is capable of imaging PWS microvasculature and monitoring microvascular reactivity to V-PDT. PMID- 22537274 TI - Metabolic classification of microbial genomes using functional probes. AB - BACKGROUND: Microorganisms able to grow under artificial culture conditions comprise only a small proportion of the biosphere's total microbial community. Until recently, scientists have been unable to perform thorough analyses of difficult-to-culture microorganisms due to limitations in sequencing technology. As modern techniques have dramatically increased sequencing rates and rapidly expanded the number of sequenced genomes, in addition to traditional taxonomic classifications which focus on the evolutionary relationships of organisms, classifications of the genomes based on alternative points of view may help advance our understanding of the delicate relationships of organisms. RESULTS: We have developed a proteome-based method for classifying microbial species. This classification method uses a set of probes comprising short, highly conserved amino acid sequences. For each genome, in silico translation is performed to obtained its proteome, based on which a probe-set frequency pattern is generated. Then, the probe-set frequency patterns are used to cluster the proteomes/genomes. CONCLUSIONS: Features of the proposed method include a high running speed in challenge of a large number of genomes, and high applicability for classifying organisms with incomplete genome sequences. Moreover, the probe-set clustering method is sensitive to the metabolic phenotypic similarities/differences among species and is thus supposed potential for the classification or differentiation of closely-related organisms. PMID- 22537275 TI - Assessing disutility associated with diabetic retinopathy, diabetic macular oedema and associated visual impairment using the Vision and Quality of Life Index. AB - BACKGROUND: Use of generic multi-attribute utility instruments (MAUI) to assess the impact of diabetic retinopathy (DR) on health-related quality of life (HRQoL) has produced inconsistent findings. Therefore, we assessed the impact of DR, diabetic macular oedema (DME) and associated visual impairment on vision-related QoL (VRQoL) using a vision-specific MAUI. METHODS: In this cross-sectional study, 203 diabetic patients were recruited from specialised eye clinics in a Melbourne tertiary eye hospital. Severity of combined DR/DME was categorised as: no DR/no DME, mild non-proliferative DR (NPDR) and/or mild DME; moderate NPDR and/or moderate DME and vision-threatening DR (severe NPDR or proliferative DR (PDR) and/or severe DME) in the worse eye. Visual impairment was categorised as: none (up to 0.18 logMAR); mild (from 0.18 to 0.3 logMAR); moderate (from 0.3 to 0.48 logMAR); severe (from 0.48 to 0.78 logMAR); and profound (worse than 0.78 logMAR). The Vision and Quality of Life Index (VisQoL) vision-specific MAUI was the main outcome measure. As the distribution of the utilities was skewed, independent associations with covariates were explored using multivariable quantile regression models (five groups: 15(th) , 30(th) , 45(th) , 60(th) and 75(th) percentiles) ranging from poorest to highest VRQoL. RESULTS: Participants' median age was 65 years (range: 27 to 90 years). Of the 203 participants, 50 (24.6 per cent) had no DR/DME, 24 (11.8 per cent) had mild NPDR/DME, 47 (23.2 per cent) had moderate NPDR/DME and 82 (40.4 per cent) had vision-threatening DR. After adjusting for relevant covariables, only profound visual impairment was independently associated with VisQoL utilities (beta= -0.297 +/- 0.098 p < 0.01). Severity of DR/DME was not significantly associated with any group of VisQoL utilities. CONCLUSION: The variation in VisQoL utilities was attributed to profound visual impairment but not mild, moderate or severe visual impairment or DR/DME severity. These findings support the use of vision-specific MAUI to capture the impact of profound visual impairment associated with DR and DME. A DR specific MAUI might be required to assess the specific utility deficits associated with DR/DME across the spectrum of the condition. PMID- 22537278 TI - Metal-catalyzed transesterification for healing and assembling of thermosets. AB - Catalytic control of bond exchange reactions enables healing of cross-linked polymer materials under a wide range of conditions. The healing capability at high temperatures is demonstrated for epoxy-acid and epoxy-anhydride thermoset networks in the presence of transesterification catalysts. At lower temperatures, the exchange reactions are very sluggish, and the materials have properties of classical epoxy thermosets. Studies of model molecules confirmed that the healing kinetics is controlled by the transesterification reaction rate. The possibility of varying the catalyst concentration brings control and flexibility of welding and assembling of epoxy thermosets that do not exist for thermoplastics. PMID- 22537277 TI - Effect of breed, age, weight and gender on radiographic renal size in the dog. AB - In the adult dog, kidney length has been reported as 2.98 +/- 0.44 times the length of L2 on ventrodorsal views and 2.79 +/- 0.46 times the length of L2 on lateral radiographs. Our aim was to test the hypothesis that the suggested maximum normal left kidney size is too high, and to evaluate the effect of breed type, gender, weight and age of the dog on kidney size. Abdominal radiographs of 200 dogs with no evidence of concurrent disease that might have an effect on renal size were included in the study. The mean ratio of kidney length to the second lumbar vertebra length was similar to previous reports. For the right lateral view it measured 2.98 +/- 0.60 and for the ventrodorsal view 3.02 +/- 0.66. Significant differences of this ratio between skull type were present, especially between brachycephalic and dolichocephalic dogs. On the right lateral view brachycephalic dogs had the highest median LK/L2 ratio of 3.1 (3.20 +/- 0.40), whereas for dolichocephalic dogs it was 2.8 (2.82 +/- 0.50), and for mesaticephalic dogs it was 2.97 (3.01 +/- 0.6). A ratio >3.5 was found only in mesaticephalic dogs on the ventrodorsal view. There was a significant difference in the LK/L2 ratio between small (<=10kg) and large breed dogs (>30kg) where small dogs had a significantly higher LK/L2 ratio. There was no statistically significant relation between this ratio and age or gender. The previously reported ratios for kidney size seem valid, but because skull type has an impact on the LK/L2 ratio, a single normal ratio should not be used for all dogs. PMID- 22537276 TI - Fine motor skills and executive function both contribute to kindergarten achievement. AB - This study examined the contribution of executive function (EF) and multiple aspects of fine motor skills to achievement on 6 standardized assessments in a sample of middle-socioeconomic status kindergarteners. Three- and 4-year-olds' (n=213) fine and gross motor skills were assessed in a home visit before kindergarten, EF was measured at fall of kindergarten, and Woodcock-Johnson III Tests of Academic Achievement were administered at fall and spring. Correlations indicated that EF and fine motor skills appeared distinct. Further, controlling for background variables, higher levels of both EF and fine motor skills, specifically design copy, predicted higher achievement on multiple subtests at kindergarten entry, as well as improvement from fall to spring. Implications for research on school readiness are discussed. PMID- 22537273 TI - Evaluation of six candidate DNA barcoding loci in Ficus (Moraceae) of China. AB - Ficus, with about 755 species, diverse habits and complicated co-evolutionary history with fig wasps, is a notoriously difficult group in taxonomy. DNA barcoding is expected to bring light to the identification of Ficus but needs evaluation of candidate loci. Based on five plastid loci (rbcL, matK, trnH-psbA, psbK-psbI, atpF-atpH) and a nuclear locus [internal transcribed spacer (ITS)], we calculated genetic distances and DNA barcoding gaps individually and in combination and constructed phylogenetic trees to test their ability to distinguish the species of the genus. A total of 228 samples representing 63 putative species in Ficus (Moraceae) of China were included in this study. The results demonstrated that ITS has the most variable sites, greater intra- and inter-specific divergences, the highest species discrimination rate (72%) and higher primer universality among the single loci. It is followed by psbK-psbI and trnH-psbA with moderate variation and considerably lower species discrimination rates (about 19%), whereas matK, rbcL and atpF-atpH could not effectively separate the species. Among the possible combinations of loci, ITS + trnH-psbA performed best but only marginally improved species resolution over ITS alone (75% vs. 72%). Therefore, we recommend using ITS as a single DNA barcoding locus in Ficus. PMID- 22537279 TI - Molecular characterization of circumventricular organs and third ventricle ependyma in the rat: potential markers for periventricular tumors. AB - Circumventricular organs (CVOs) are specialized ventricular structures around the third and fourth ventricles of the brain. In humans, these structures are present during the fetal period and some become vestigial after birth. Some of these organs, such as the pineal gland (PG), subcommissural organ (SCO), and organum vasculosum of the lamina terminalis, might be the sites of origin of periventricular tumors, notably pineal parenchymal tumors, papillary tumor of the pineal region and chordoid glioma. In contrast to the situation in humans, CVOs are present in the adult rat and can be dissected by laser capture microdissection (LCM). In this study, we used LCM and microarrays to analyze the transcriptomes of three CVOs, the SCO, the subfornical organ (SFO), and the PG and the third ventricle ependyma in the adult rat, in order to better characterize these organs at the molecular level. Several genes were expressed only, or mainly, in one of these structures, for example, Erbb2 and Col11a1 in the ependyma, Epcam and Claudin-3 (CLDN3) in the SCO, Ren1 and Slc22a3 in the SFO and Tph, Aanat and Asmt in the PG. The expression of these genes in periventricular tumors should be examined as evidence for a possible origin from the CVOs. Furthermore, we performed an immunohistochemical study of CLDN3, a membrane protein involved in forming cellular tight junctions and found that CLDN3 expression was restricted to the apical pole of ependymocytes in the SCO. This microarray study provides new evidence regarding the possible origin of some rare periventricular tumors. PMID- 22537281 TI - Physical activity levels six months after a randomised controlled physical activity intervention for Pakistani immigrant men living in Norway. AB - BACKGROUND: To our knowledge, no studies have aimed at improving the PA level in south Asian immigrant men residing in Western countries, and few studies have considered the relevance of SCT constructs to the PA behaviour of this group in the long term. The observed low physical activity (PA) level among south Asian immigrants in Western countries may partly explain the high prevalence of cardiovascular diseases (CVD) and type 2 diabetes (T2D) in this group. We have shown previously in a randomised controlled trial, the Physical Activity and Minority Health study (PAMH) that a social cognitive based intervention can beneficially influence PA level and subsequently reduce waist circumference and insulin resistance in the short-term. In an extended follow-up of the PAMH study: we aimed 1) to determine if the intervention produced long-term positive effects on PA level six months after intervention (follow-up 2 (FU2)), and 2) to identify the social cognitive mediators of any intervention effects. METHODS: Physically inactive Pakistani immigrant men (n = 150) who were free of CVD and T2D were randomly assigned to a five months PA intervention or a control group. Six months after the intervention ended, we telephoned all those who attended FU1 and invited them for a second follow-up test (FU2) (n = 133). PA was measured using ActiGraph accelerometers. Statistical differences between groups were determined by use of ANCOVA. RESULTS: Significant differences (baseline to FU2) between the groups were found for all PA variables (e.g., total PA level, sedentary time, PA intensity). Support from family and outcome expectancies increased more in the intervention group compared with the control group. Self-efficacy did not differ significantly between groups. CONCLUSIONS: Our results show that a multi component PA programme can increase PA over the short and long term in a group of immigrant Pakistani men. However, we could not identify the factors that mediated these changes in PA. PROTOCOL ID: 07112001326, NCT ID: NCT00539903. PMID- 22537280 TI - Patterns of condom use and associated factors among adult HIV positive clients in North Western Ethiopia: a comparative cross sectional study. AB - BACKGROUND: The introduction of antiretroviral therapy (ART) has sharply decreased morbidity and mortality rates among HIV infected patients. Due to this, more and more people with HIV live longer and healthier lives. Yet if they practice sex without condom, those with high viral load have the potential to infect their sero-negative sexual partner or at risk of acquiring drug resistant viral strains from their sexual partner who are already infected. Hence, we aimed to assess practice of condom use and associated factors among HIV positive clients at Felege Hiwot Referral Hospital in North Western Ethiopia. METHODS: Hospital based comparative cross sectional study was conducted at Felege Hiwot Referral Hospital in northwest Ethiopia. Systematic random sampling technique was used to select 466 study participants from the ART and pre ART clinic of the Hospital. A structured interview administered questionnaire first prepared in English then translated into Amharic was used to collect data. Nurses who were working in the hospital but not in the HIV clinic were recruited and trained as data collectors. RESULTS: A total of 454 (224 respondents from ART naive and 230 ART experienced groups) were included in the study. Females constitute 151 (67.4%) and 133 (57.8%) of pre ART and ART group respectively. The ages of the participants ranged from 18 to 72 years. The average age was 31.7 years for women and 36.6 years for the men. About half of the participants (47.4% of ART group and 50.4% of the pre ART group) were sexually active. Inconsistent condom use was reported by 61(56%) ART and 50 (44.2%) of the pre ART sexually active study participants. CONCLUSIONS: The study found that those who are on ART were at lower risk of using condom inconsistently as compared to the ART naive patients living with HIV. Therefore, these results are of high importance in order to design tailored interventions. PMID- 22537282 TI - Current approaches in tamper-resistant and abuse-deterrent formulations. AB - CONTEXT: The escalating abuse of prescription drugs has recently spawned the development of novel drug formulations resistant to various methods of tampering and misuse. OBJECTIVE: The intent of this paper is to provide an overview and classification system of formulation approaches, developed to produce what most refer to as abuse-deterrent or tamper-resistant dosage forms. METHODS: A comprehensive literature search was conducted within EmbaseTM and Medline using key words "abuse deterrenta and "tamper resistanta to identify relevant technologies. Only issued patents were examined using the phrase "abuse deterrent compositiona searched through PatFT from the United States Patent and Trademark Office. Current information from press releases and product innovator websites was obtained for additional data. RESULTS: Identified formulation approaches were organized into two categories, physical approaches and chemical approaches. Physical approaches were subcategorized into solids, gels or non-intentionals, while chemical approaches were further broken down into agonists/antagonists, aversives, or metabolics. Among issued patents specifying an abuse-deterrent method, nine diverse approaches were found. Most formulations under development combined approaches, and utilized proprietary technologies from pharmaceutical manufacturers. CONCLUSIONS: Prodrug and agonist/antagonist formulations are popular in marketed products, while solid and gel approaches are more recent additions. However, the inclusion of aversive agents or enzyme inhibitors in a product is proving to be more difficult to develop. Overall, detailed formulation and manufacturing methods still remain rather elusive to protect public health. Moreover, these innovative formulations are mostly untried in the general population and their abuse deterring effects has yet to be proven. PMID- 22537283 TI - Integration of gold nanoparticles in optical resonators. AB - The optical absorption of one-dimensional photonic crystal based resonators containing different types of gold nanoparticles is controllably modified by means of the interplay between planar optical cavity modes and localized surface plasmons. Spin-casting of metal oxide nanoparticle suspensions was used to build multilayered photonic structures that host (silica-coated) gold nanorods and spheres. Strong reinforcement and depletion of the absorptance was observed at designed wavelength ranges, thus proving that our method provides a reliable means to modify the optical absorption originated at plasmonic resonances of particles of arbitrary shape and within a wide range of sizes. These observations are discussed on the basis of calculations of the spatial and spectral dependence of the optical field intensity within the multilayers. PMID- 22537287 TI - H1N1-associated acute retinitis. AB - PURPOSE: To present the first reported case of bilateral H(1)N(1)-associated acute retinitis and its successful treatment. DESIGN: Interventional case report. METHODS: A 41-year-old HIV-positive male presented with acute vision loss, panuveitis, and retinitis. A diagnostic and therapeutic vitrectomy with intravitreal injection of vancomycin and ganciclovir and endolaser was performed. One month later, the patient returned with similar symptoms in the fellow eye and underwent the same procedure. RESULTS: ELISA immunoassay revealed H(1)N(1) antibodies in both the vitreous and serum. PCR for herpes viruses included HSV, CMV, and VZV. Bacterial and fungal cultures were negative. On 1-year follow-up, the vision remained 20/20 in both eyes without evidence of recurrent inflammation. CONCLUSIONS: H(1)N(1) should be included in the differential diagnosis of any patient with a history of recent influenza A (H(1)N(1)) infection and acute retinitis. H(1)N(1) may carry a better prognosis than other viruses causing acute retinitis. PMID- 22537286 TI - Infectious keratitis in severe limbal stem cell deficiency: characteristics and risk factors. AB - PURPOSE: To evaluate the incidence, clinical and microbiological characteristics and risk factors of infectious keratitis in patients with limbal stem cell deficiency (LSCD). METHODS: Retrospective comparative case series of 35 patients with severe LSCD. RESULTS: The mean follow-up time was 46 months. Infectious keratitis were mainly caused by Gram positive bacteria (94%). Only 7 infections (37%) healed under fortified adapted antibiotics. In 8 cases (42%), amniotic membrane transplantation was required and in 4 cases (21%) "a chaud" keratoplasty was performed. Significant risk factors associated with infectious keratitis were: soft contact lens extended wear, history of persistent epithelial defects, number of quadrants of corneal vascularization, re-epithelialization time after amniotic membrane or corneal transplantation, and use of corticosteroid or cyclosporin eye drops. CONCLUSION: Infectious keratitis in LSCD is frequent and severe. The restoration of the epithelial barrier integrity and a careful use of therapeutic contact lenses may help to prevent infection. PMID- 22537288 TI - Multiphasic DNA adsorption to silica surfaces under varying buffer, pH, and ionic strength conditions. AB - Reversible interactions between DNA and silica are utilized in the solid phase extraction and purification of DNA from complex samples. Chaotropic salts commonly drive DNA binding to silica but inhibit DNA polymerase amplification. We studied DNA adsorption to silica using conditions with or without chaotropic salts through bulk depletion and quartz crystal microbalance (QCM) experiments. While more DNA adsorbed to silica using chaotropic salts, certain buffer conditions without chaotropic salts yielded a similar amount of eluted DNA. QCM results indicate that under stronger adsorbing conditions the adsorbed DNA layer is initially rigid but becomes viscoelastic within minutes. These results qualitatively agreed with a mathematical model for a multiphasic adsorption process. Buffer conditions that do not require chaotropic salts can simplify protocols for nucleic acid sample preparation. Understanding how DNA adsorbs to silica can help optimize nucleic acid sample preparation for clinical diagnostic and research applications. PMID- 22537291 TI - Preparation, characterization, and in vivo evaluation of triamcinolone acetonide microspheres after intravitreal administration. AB - PURPOSE: The aim of this study was to evaluate the intraocular pressure (IOP) increasing effect and bioavailability of triamcinolone acetonide (TA) microspheres, as a novel drug delivery system, after intravitreal administration. METHODS: Microspheres loaded by TA were prepared by the solvent evaporation method. After encapsulation, the final microspherical formulation was tested in an animal model. The left eyes of rabbits received microspherical TA and the right eyes were injected with conventional TA suspension. The drug concentration in the vitreous samples at days 7, 14, 28, and 56 after the injection was determined by high-performance liquid chromatography. The IOP was also checked at the same days with the Schiotz tonometer. RESULTS: There was no statistically significant (P>0.05) difference between mean concentration of TA in the vitreous of right and left eyes at the different sampling times except day 56. Mean IOP of eyes that received microspherical TA was increased less than that of the eyes injected with TA suspension, and the difference was statistically significant (P<0.05) for each measurement day. TA was detectable in both eyes after 8 weeks. Both TA microsphere and suspension showed the sustained release profile. CONCLUSION: The results of this study showed less IOP increasing effect of triamcinolone microspheres in comparison with suspension form. PMID- 22537289 TI - Melatonin modulates TLR4-mediated inflammatory genes through MyD88- and TRIF dependent signaling pathways in lipopolysaccharide-stimulated RAW264.7 cells. AB - Increasing evidence demonstrates that melatonin has an anti-inflammatory effect. Nevertheless, the molecular mechanisms remain obscure. In this study, we investigated the effect of melatonin on toll-like receptor 4 (TLR4)-mediated molecule myeloid differentiation factor 88 (MyD88)-dependent and TRIF-dependent signaling pathways in lipopolysaccharide (LPS)-stimulated macrophages. RAW264.7 cells were incubated with LPS (2.0 MUg/mL) in the absence or presence of melatonin (10, 100, 1000 MUm). As expected, melatonin inhibited TLR4-mediated tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, IL-8, and IL-10 in LPS-stimulated macrophages. In addition, melatonin significantly attenuated LPS-induced upregulation of cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) in macrophages. Further analysis showed that melatonin inhibited the expression of MyD88 in LPS-stimulated macrophages. Although it had no effect on TLR4-mediated phosphorylation of c-Jun N-terminal kinase (JNK), p38, and extracellular regulated protein kinase (ERK), melatonin significantly attenuated the activation of nuclear factor kappa B (NF-kappaB) in LPS-stimulated macrophages. In addition, melatonin inhibited TLR4-mediated Akt phosphorylation in LPS-stimulated macrophages. Moreover, melatonin significantly attenuated the elevation of interferon (IFN)-regulated factor-3 (IRF3), which was involved in TLR4-mediated TRIF-dependent signaling pathway, in LPS-stimulated macrophages. Correspondingly, melatonin significantly alleviated LPS-induced IFN beta in macrophages. In conclusion, melatonin modulates TLR4-mediated inflammatory genes through MyD88-dependent and TRIF-dependent signaling pathways. PMID- 22537292 TI - Posology, efficacy, and safety of epidermal growth factor eye drops in 305 patients: logistic regression and group-wise odds of published data. AB - The aim of this article is to investigate clinical research on indications, posology, efficacy, and safety of epidermal growth factor (EGF) eye drops in the treatment of some human corneal disorders. Methods used include systematic search and selection of series of cases and clinical trials in Medline database up to January 2012, kappa index (K) to validate retrieval information, cumulative Mantel-Haenszel-stratified meta-analysis, 2*2 contingency table of randomized EGF vehicle-controlled treated groups, and statistical program SPSSv12. Our results indicate that EGF eye drops appear to be a very effective treatment of acute heterogeneous corneal diseases, without significant adverse effects, with a 86.8% clinical efficacy reported by authors, a 98% (P<0.05) probabilistic expected efficacy, and 51.3 (17.4-148.7 confidence interval 95%; P<0.05) odds ratio EGF/vehicle. However, clinical trials are scarce, with low sample sizes and serious inconsistencies in EGF posology. EGF eye drops (50-1,000 ng, 2-3 times/day) could be a useful treatment for promoting postoperative refractive surgery, reversing cases of keratopathy secondary to systematic EGF receptor inhibitors, diabetic keratopathy, and other corneal and conjunctival disorders. PMID- 22537293 TI - Total syntheses of anominine and tubingensin A. AB - A divergent strategy for the total syntheses of the indole terpenoid anominine (1) and its natural congener tubingensin A (2) has been developed. The common intermediate 11 bearing all of the required stereogenic centers for both natural products was first assembled by employing a Ueno-Stork radical cyclization and a Sc(OTf)(3)-mediated Mukaiyama aldol reaction to form the key C-C bonds in a stereocontrolled manner. The route to anominine features a radical deoxygenation followed by an efficient side-chain installation, while the path to tubingensin A exploits a CuOTf-promoted 6pi-electrocyclization/aromatization sequence to forge the central region of the pentacyclic scaffold. PMID- 22537294 TI - Findings from focus groups indicating what Chinese American immigrant women think about breast cancer and breast cancer screening. AB - OBJECTIVES: To explore beliefs of Chinese American, immigrant women related to breast cancer and mammography. DESIGN: Qualitative description with semistructured focus groups. SETTING: Metropolitan Portland, Oregon. PARTICIPANTS: Thirty eight foreign-born Chinese women, age 40 and older, in five focus groups. METHODS: Focus group discussions in Chinese were audiotaped, transcribed, and translated into English. Using a process of directed content analysis, group transcripts were coded for themes based on the discussion guide. RESULTS: Three main themes emerged from the analysis: knowledge and beliefs; support, communication, and educational needs; and access to care. Subthemes included beliefs such as barriers and facilitators to screening and perceptions about personal breast cancer risk. Several women were profoundly affected by the negative breast cancer-related experiences of relatives and friends. Some common myths remain about causes and treatment of breast cancer. CONCLUSIONS: Although Chinese American immigrant women share beliefs with other minority women in the United States, some culturally related barriers such as alienation due to cultural reasons for not sharing diagnosis with anyone and beliefs about the efficacy of Eastern versus Western medicine may affect adherence to screening and treatment. Facilitators included being told to get the test and getting screened for the sake of the family, whereas erroneous information about the cause of breast cancer such as diet and stress remained. Primary care providers such as advanced practice nurses should take into account culturally driven motivations and barriers to mammography adherence among Chinese American immigrant women. Provider/client interactions should involve more discussion about women's breast cancer risks and screening harms and benefits. Such awareness could open a dialogue around breast cancer that is culturally sensitive and nonthreatening to the patient. Information may need to be tailored to women individually or targeted to subethnic groups rather than using generic messages for all Asian immigrant women. PMID- 22537296 TI - Identification of conserved splicing motifs in mutually exclusive exons of 15 insect species. AB - BACKGROUND: During alternative splicing, the inclusion of an exon in the final mRNA molecule is determined by nuclear proteins that bind cis-regulatory sequences in a target pre-mRNA molecule. A recent study suggested that the regulatory codes of individual RNA-binding proteins may be nearly immutable between very diverse species such as mammals and insects. The model system Drosophila melanogaster therefore presents an excellent opportunity for the study of alternative splicing due to the availability of quality EST annotations in FlyBase. METHODS: In this paper, we describe an in silico analysis pipeline to extract putative exonic splicing regulatory sequences from a multiple alignment of 15 species of insects. Our method, ESTs-to-ESRs (E2E), uses graph analysis of EST splicing graphs to identify mutually exclusive (ME) exons and combines phylogenetic measures, a sliding window approach along the multiple alignment and the Welch's t statistic to extract conserved ESR motifs. RESULTS: The most frequent 100% conserved word of length 5 bp in different insect exons was "ATGGA". We identified 799 statistically significant "spike" hexamers, 218 motifs with either a left or right FDR corrected spike magnitude p-value < 0.05 and 83 with both left and right uncorrected p < 0.01. 11 genes were identified with highly significant motifs in one ME exon but not in the other, suggesting regulation of ME exon splicing through these highly conserved hexamers. The majority of these genes have been shown to have regulated spatiotemporal expression. 10 elements were found to match three mammalian splicing regulator databases. A putative ESR motif, GATGCAG, was identified in the ME-13b but not in the ME-13a of Drosophila N-Cadherin, a gene that has been shown to have a distinct spatiotemporal expression pattern of spliced isoforms in a recent study. CONCLUSIONS: Analysis of phylogenetic relationships and variability of sequence conservation as implemented in the E2E spikes method may lead to improved identification of ESRs. We found that approximately half of the putative ESRs in common between insects and mammals have a high statistical support (p < 0.01). Several Drosophila genes with spatiotemporal expression patterns were identified to contain putative ESRs located in one exon of the ME exon pairs but not in the other. PMID- 22537295 TI - A 95 kDa protein of Plasmodium vivax and P. cynomolgi visualized by three dimensional tomography in the caveola-vesicle complexes (Schuffner's dots) of infected erythrocytes is a member of the PHIST family. AB - Plasmodium vivax and P. cynomolgi produce numerous caveola-vesicle complex (CVC) structures within the surface of the infected erythrocyte membrane. These contrast with the electron-dense knob protrusions expressed at the surface of Plasmodium falciparum-infected erythrocytes. Here we investigate the three dimensional (3-D) structure of the CVCs and the identity of a predominantly expressed 95 kDa CVC protein. Liquid chromatography - tandem mass spectrometry analysis of immunoprecipitates by monoclonal antibodies from P. cynomolgi extracts identified this protein as a member of the Plasmodium helical interspersed subtelomeric (PHIST) superfamily with a calculated mass of 81 kDa. We named the orthologous proteins PvPHIST/CVC-81(95) and PcyPHIST/CVC-81(95) , analysed their structural features, including a PEXEL motif, repeated sequences and a C-terminal PHIST domain, and show that PHIST/CVC-81(95) is most highly expressed in trophozoites. We generated images of CVCs in 3-D using electron tomography (ET), and used immuno-ET to show PHIST/CVC-81(95) localizes to the cytoplasmic side of the CVC tubular extensions. Targeted gene disruptions were attempted in vivo. The pcyphist/cvc-81(95) gene was not disrupted, but parasites containing episomes with the tgdhfr selection cassette were retrieved by selection with pyrimethamine. This suggests that PHIST/CVC-81(95) is essential for survival of these malaria parasites. PMID- 22537297 TI - CMRF: analyzing differential gene regulation in two group perturbation experiments. AB - BACKGROUND: Microarray experiments often measure expressions of genes taken from sample tissues in the presence of external perturbations such as medication, radiation, or disease. The external perturbation can change the expressions of some genes directly or indirectly through gene interaction network. In this paper, we focus on an important class of such microarray experiments that inherently have two groups of tissue samples. When such different groups exist, the changes in expressions for some of the genes after the perturbation can be different between the two groups. It is not only important to identify the genes that respond differently across the two groups, but also to mine the reason behind this differential response. In this paper, we aim to identify the cause of this differential behavior of genes, whether because of the perturbation or due to interactions with other genes. RESULTS: We propose a new probabilistic Bayesian method CMRF based on Markov Random Field to identify such genes. CMRF leverages the information about gene interactions as the prior of the model. We compare the accuracy of CMRF with SSEM and Student's t test and our old method SMRF on semi-synthetic dataset generated from microarray data. CMRF obtains high accuracy and outperforms all the other three methods. We also conduct a statistical significance test using a parametric noise based experiment to evaluate the accuracy of our method. In this experiment, CMRF generates significant regions of confidence for various parameter settings. CONCLUSIONS: In this paper, we solved the problem of finding primarily differentially regulated genes in the presence of external perturbations when the data is sampled from two groups. The probabilistic Bayesian method CMRF based on Markov Random Field incorporates dependency structure of the gene networks as the prior to the model. Experimental results on synthetic and real datasets demonstrated the superiority of CMRF compared to other simple techniques. PMID- 22537298 TI - High-performance biocomputing for simulating the spread of contagion over large contact networks. AB - BACKGROUND: Many important biological problems can be modeled as contagion diffusion processes over interaction networks. This article shows how the EpiSimdemics interaction-based simulation system can be applied to the general contagion diffusion problem. Two specific problems, computational epidemiology and human immune system modeling, are given as examples. We then show how the graphics processing unit (GPU) within each compute node of a cluster can effectively be used to speed-up the execution of these types of problems. RESULTS: We show that a single GPU can accelerate the EpiSimdemics computation kernel by a factor of 6 and the entire application by a factor of 3.3, compared to the execution time on a single core. When 8 CPU cores and 2 GPU devices are utilized, the speed-up of the computational kernel increases to 9.5. When combined with effective techniques for inter-node communication, excellent scalability can be achieved without significant loss of accuracy in the results. CONCLUSIONS: We show that interaction-based simulation systems can be used to model disparate and highly relevant problems in biology. We also show that offloading some of the work to GPUs in distributed interaction-based simulations can be an effective way to achieve increased intra-node efficiency. PMID- 22537299 TI - Haplotype and minimum-chimerism consensus determination using short sequence data. AB - BACKGROUND: Assembling haplotypes given sequence data derived from a single individual is a well studied problem, but only recently has haplotype assembly been considered for population-sampled data. We discuss a software tool called Hapler, which is designed specifically for low-diversity, low-coverage data such as ecological samples derived from natural populations. Because such data may contain error as well as ambiguous haplotype information, we developed methods that increase confidence in these assemblies. Hapler also reconstructs full consensus sequences while minimizing and identifying possible chimeric points. RESULTS: Experiments on simulated data indicate that Hapler is effective at assembling haplotypes from gene-sized alignments of short reads. Further, in our tests Hapler-generated consensus sequences are less chimeric than the alternative consensus approaches of majority vote and viral quasispecies estimation regardless of error rate, read length, or population haplotype bias. CONCLUSIONS: The analysis of genetically diverse sequence data is increasingly common, particularly in the field of ecoinformatics where transcriptome sequencing of natural populations is a cost effective alternative to genome sequencing. For such studies, it is important to consider and identify haplotype diversity. Hapler provides robust haplotype information and identifies possible phasing errors in consensus sequences, providing valuable information for population studies and downstream usage of resulting assemblies. PMID- 22537300 TI - A graph-theoretic approach for classification and structure prediction of transmembrane beta-barrel proteins. AB - BACKGROUND: Transmembrane beta-barrel proteins are a special class of transmembrane proteins which play several key roles in human body and diseases. Due to experimental difficulties, the number of transmembrane beta-barrel proteins with known structures is very small. Over the years, a number of learning-based methods have been introduced for recognition and structure prediction of transmembrane beta-barrel proteins. Most of these methods emphasize on homology search rather than any biological or chemical basis. RESULTS: We present a novel graph-theoretic model for classification and structure prediction of transmembrane beta-barrel proteins. This model folds proteins based on energy minimization rather than a homology search, avoiding any assumption on availability of training dataset. The ab initio model presented in this paper is the first method to allow for permutations in the structure of transmembrane proteins and provides more structural information than any known algorithm. The model is also able to recognize beta-barrels by assessing the pseudo free energy. We assess the structure prediction on 41 proteins gathered from existing databases on experimentally validated transmembrane beta-barrel proteins. We show that our approach is quite accurate with over 90% F-score on strands and over 74% F-score on residues. The results are comparable to other algorithms suggesting that our pseudo-energy model is close to the actual physical model. We test our classification approach and show that it is able to reject alpha-helical bundles with 100% accuracy and beta-barrel lipocalins with 97% accuracy. CONCLUSIONS: We show that it is possible to design models for classification and structure prediction for transmembrane beta-barrel proteins which do not depend essentially on training sets but on combinatorial properties of the structures to be proved. These models are fairly accurate, robust and can be run very efficiently on PC like computers. Such models are useful for the genome screening. PMID- 22537301 TI - Towards accurate detection and genotyping of expressed variants from whole transcriptome sequencing data. AB - BACKGROUND: Massively parallel transcriptome sequencing (RNA-Seq) is becoming the method of choice for studying functional effects of genetic variability and establishing causal relationships between genetic variants and disease. However, RNA-Seq poses new technical and computational challenges compared to genome sequencing. In particular, mapping transcriptome reads onto the genome is more challenging than mapping genomic reads due to splicing. Furthermore, detection and genotyping of single nucleotide variants (SNVs) requires statistical models that are robust to variability in read coverage due to unequal transcript expression levels. RESULTS: In this paper we present a strategy to more reliably map transcriptome reads by taking advantage of the availability of both the genome reference sequence and transcript databases such as CCDS. We also present a novel Bayesian model for SNV discovery and genotyping based on quality scores. CONCLUSIONS: Experimental results on RNA-Seq data generated from blood cell tissue of three Hapmap individuals show that our methods yield increased accuracy compared to several widely used methods. The open source code implementing our methods, released under the GNU General Public License, is available at http://dna.engr.uconn.edu/software/NGSTools/. PMID- 22537302 TI - Working conditions as risk factors for disability retirement: a longitudinal register linkage study. AB - BACKGROUND: Early retirement due to disability is a public health and work environment problem that shortens working careers. Transition to disability retirement is based on ill-health, but working conditions are also of relevance. We examined the contributions of work arrangements, physical working conditions and psychosocial working conditions to subsequent disability retirement. METHODS: The data were derived from the Helsinki Health Study cohort on employees of the City of Helsinki, Finland. Information on working conditions was obtained from the baseline surveys conducted in 2000, 2001 and 2002. These data were linked with register data on disability retirement and their main diagnoses obtained from the Finnish Centre for Pensions. Follow up by the end of 2008 yielded 525 disability retirement events. The analysed data included 6525 participants and 525 disability retirement events. Hazard ratios (HR) and 95% confidence intervals (95% CI) were calculated from Cox regression analysis. RESULTS: Several working conditions showed own associations with disability retirement before adjustment. After adjustment for all working conditions, the primary risk factors for all cause disability retirement were physical workload among women (HR 2.02, 95% CI 1.57-2.59) and men (HR 2.00, 95% CI 1.18-3.38), and low job control among women (HR 1.60, 95% CI 1.29-1.99). In addition, for disability retirement due to musculoskeletal causes, the risk factors were physical workload and low job control. For disability retirement due to mental causes the risk factors were computer work and low job control. Furthermore, occupational class was a risk factor for disability retirement due to all causes and musculoskeletal diseases. CONCLUSIONS: Among various working conditions, those that are physically demanding and those that imply low job control are potential risk factors for disability retirement. Improving the physical working environment and enhancing control over one's job is likely to help prevent early retirement due to disability. PMID- 22537307 TI - Speciation of copper-peptide complexes in water solution using DFTB and DFT approaches: case of the [Cu(HGGG)(Py)] complex. AB - The DFTB and DFT methods are applied to the study of different forms of the [Cu(HGGG)(Py)] complex in water, with the aim of identifying the most stable isomer. The DFTB calculations were possible thanks to a careful parametrization of the atom-atom repulsive energy terms for Cu-H, Cu-C, Cu-N, and Cu-O. The speciation process is carried out by computing different DFTB-steered molecular dynamics (SMD) trajectories, each of which ends in a well-defined different form. The last frame of each trajectory is subjected to geometry optimization at both DFTB and DFT levels, leading to a different isomer. From the corresponding energy values, a rank of relative stability of the isomers can be established. The computational protocol developed here is of general applicability to other metal peptide systems and represents a new powerful tool for the study of speciation of metal-containing systems in water solution, particularly useful when the full characterization of the compound cannot be carried out on the basis of experimental results only. PMID- 22537306 TI - Nuclear overexpression of metastasis-associated protein 1 correlates significantly with poor survival in nasopharyngeal carcinoma. AB - BACKGROUND: Metastasis-associated protein 1 (MTA1) has been associated with poor prognosis in several malignant carcinomas. The purpose of this study was to investigate the expression and prognostic value of MTA1 in nasopharyngeal carcinoma (NPC). METHODS: MTA1 expression was assessed using immunohistochemistry in paraffin-embedded tumor specimens from 208 untreated NPC patients. Cox regression analysis was used to calculate the hazard ratio (HR), 95% confidence interval (CI) and identify independent prognostic factors, and recursive partitioning analysis was used to create a decision tree. RESULTS: Nuclear overexpression of MTA1 was observed in 48.6% (101/208) of the NPC tissues. Nuclear overexpression of MTA1 correlated positively with N classification (P = 0.02), clinical stage (P = 0.04), distant metastasis (P < 0.01) and death (P = 0.01). Additionally, nuclear overexpression of MTA1 correlated significantly with poorer distant metastasis-free survival (DMFS; P <0.01) and poorer overall survival (OS; P < 0.01). MTA1 had prognostic significance in NPC patients with stage II disease, but not stage III or IV disease. Multivariate analysis demonstrated that nuclear overexpression of MTA1 was independently associated with poorer DMFS (HR, 2.05; 95% CI, 1.13-3.72; P = 0.02) and poorer OS (HR, 1.98; 95% CI, 1.09-3.59; P = 0.03). Using recursive partitioning analysis, the NPC patients could be classified with a low, intermediate or high risk of distant metastasis and death, on the basis of clinical stage, age and MTA1 expression. CONCLUSION: The results of this study suggest that nuclear overexpression of MTA1 correlates significantly with poorer DMFS and poorer OS in NPC. MTA1 has potential as a novel prognostic biomarker in NPC. PMID- 22537308 TI - Natural mentors, racial identity, and educational attainment among african american adolescents: exploring pathways to success. AB - The present study explored how relationships with natural mentors may contribute to African American adolescents' long-term educational attainment by influencing adolescents' racial identity and academic beliefs. This study included 541 academically at-risk African American adolescents transitioning into adulthood. The mean age of participants at Time 1 was 17.8 (SD = .64) and slightly over half (54%) of study participants were female. Results of the current study indicated that relationships with natural mentors promoted more positive long-term educational attainment among participants through increased private regard (a dimension of racial identity) and stronger beliefs in the importance of doing well in school for future success. Implications of these findings and directions for future research are discussed. PMID- 22537309 TI - Effect of polymer molecular weight and of polymer blends on the properties of rapidly gelling nasal inserts. AB - The objective was to investigate the potential of polymer molecular weight (MW) and polymer blends for the control of drug release from in situ gelling nasal inserts prepared by lyophilization of solutions of model drugs (oxymetazoline HCl, diprophyllin) and polymers. Drug release, polymer solution viscosity, water uptake and mass loss, mechanical properties, and bioadhesion potential were measured. Sonication was effective to reduce the viscosity/polymer MW of carrageenan solutions. Nasal inserts prepared from sonicated carrageenan showed an insignificant reduction in water uptake with sonication time and no disintegration of the gel matrix. In contrast, inserts of different MW Na alginates revealed a reduced water uptake and an increased mass loss with lower MW. Inserts prepared from carrageenan/low MW Na-alginate blends took up more water at a higher low MW Na-alginate content. Sonicated carrageenan inserts released oxymetazoline HCl independent of the sonication time and diprophyllin with only a slight reduction in the release rate. Release of both drugs from Na alginate inserts was slow from high MW inserts because no insert dissolution occurred. Increasing the Na-alginate content of inserts prepared from polymer blends accelerated the drug release enabling release rates over a broad range. The bioadhesion potential of Na-alginate inserts was strongly reduced for the low MW grades because of dissolution of the inserts. Xanthan gum and Carbopol 971 blended with Na-alginate formed inserts with poor bioadhesion. The use of polymer blends to control the drug release from nasal inserts was superior to the use of polymers of different MW. PMID- 22537310 TI - Volume specific response criteria for brain metastases following salvage stereotactic radiosurgery and associated predictors of response. AB - BACKGROUND: We aimed to derive three-dimensional volume-based (V(3D)) response criteria that approximate those based on Response Evaluation Criteria in Solid Tumours (RECIST) in patients with brain metastases (BM) treated with salvage stereotactic radiosurgery (SRS). MATERIAL AND METHODS: Seventy patients with 178 BM were treated with SRS. Each BM was characterised at baseline and at each follow-up MRI according to its widest diameter and V(3D) using ITK-SNAP image segmentation software. RESULTS: The median tumour diameter was 1.2 cm (range, 0.2 4.5 cm) and V(3D) was 0.73 cm(3) (range, 0.01-22.7 cm(3)). The V(3D) percent changes that best matched RECIST response criteria were: an increase of >=71.5% for progressive disease, a >=58.5% decrease for partial response and a <58.5% decrease or increase of <71.5% for stable disease (k =0.85). A baseline diameter >3.0 cm (p =0.006) and a V(3D) >6.0 cm(3) (p =0.043) predicted for local failure, and a baseline cumulative V(3D) of >3.0 cm(3) (p =0.02) was adversely prognostic for survival. CONCLUSIONS: We define 3D volume specific criteria to base response upon for brain metastases treated with salvage SRS. Tumours with a V(3D) of greater than 6 cm(3) are at a higher risk of local failure. PMID- 22537311 TI - Existential aspects are neglected in the evaluation of support-intervention in breast cancer patients. PMID- 22537312 TI - Detection of BK virus in urine from renal transplant subjects by mass spectrometry. AB - BACKGROUND: The diagnosis and management of BK virus (BKV) reactivation following renal transplantation continues to be a significant clinical problem. Following reactivation of latent virus, impaired cellular immunity enables sustained viral replication to occur in urothelial cells, which potentially leads to the development of BKV-associated nephropathy (BKVAN). Current guidelines recommend regular surveillance for BKV reactivation through the detection of infected urothelial cells in urine (decoy cells) or viral nucleic acid in urine or blood. However, these methods have variable sensitivity and cannot routinely distinguish between different viral subtypes. We therefore asked whether mass spectrometry might be able to overcome these limitations and provide an additional non invasive technique for the surveillance of BKV and identification of recipients at increased risk of BKVAN. RESULTS: Here we describe a mass spectrometry (MS) based method for the detection of BKV derived proteins directly isolated from clinical urine samples. Peptides detected by MS derived from Viral Protein 1 (VP1) allowed differentiation between subtypes I and IV. Using this approach, we observed an association between higher decoy cell numbers and the presence of the VP1 subtype Ib-2 in urine samples derived from a cohort of 20 renal transplant recipients, consistent with the hypothesis that certain viral subtypes may be associated with more severe BKVAN. CONCLUSIONS: This is the first study to identify BK virus proteins in clinical samples by MS and that this approach makes it possible to distinguish between different viral subtypes. Further studies are required to establish whether this information could lead to stratification of patients at risk of BKVAN, facilitate distinction between BKVAN and acute rejection (AR), and ultimately improve patient treatment and outcomes. PMID- 22537313 TI - Two-dimensional paper network format that enables simple multistep assays for use in low-resource settings in the context of malaria antigen detection. AB - The lateral flow test has become the standard bioassay format in low-resource settings because it is rapid, easy to use, and low in cost, uses reagents stored in dry form, and is equipment-free. However, lateral flow tests are often limited to a single chemical delivery step and not capable of the multistep processing characteristic of high performance laboratory-based assays. To address this limitation, we are developing a paper network platform that extends the conventional lateral flow test to two dimensions; this allows incorporation of multistep chemical processing, while still retaining the advantages of conventional lateral flow tests. Here, we demonstrate this format for an easy-to use, signal-amplified sandwich format immunoassay for the malaria protein PfHRP2. The card contains reagents stored in dry form such that the user need only add sample and water. The multiple flows in the device are activated in a single user step of folding the card closed; the configuration of the paper network automatically delivers the appropriate volumes of (i) sample plus antibody conjugated to a gold particle label, (ii) a rinse buffer, and (iii) a signal amplification reagent to the capture region. These results highlight the potential of the paper network platform to enhance access to high-quality diagnostic capabilities in low-resource settings in the developed and developing worlds. PMID- 22537314 TI - Quality of hemodialysis water in a resource-poor country: the Nigerian example. AB - Hemodialysis (HD) patients are exposed to large volumes of water, separated from patients' blood by semipermeable membrane of dialyzers. Chemical contaminants in poorly treated water impact negatively on quality of life of these patients. This survey was carried out to assess the HD water quality in Lagos, Nigeria. Ten milliliters of feed and treated water from all six HD centers in Lagos were tested for aluminum, copper, zinc, magnesium, calcium using atomic absorption spectrometry; sodium and potassium were tested using flame photometry, fluoride with molecular photoluminescence method; sulfate using turbidimetry, nitrates measured by cadmium column reduction method, chloramines and free chlorine were measured using N, N-diethyl-1-P-phenylenediamine colorimetric method. Information on sources of feed water, frequency of testing of HD water, methods of water treatment, type of water purification system and maintenance was also obtained. All centers used borehole as main source of water supply. None of the centers met Association for the Advancement of Medical Instrumentation (AAMI) guidelines for most chemical contaminants. Only chlorine (0.48 +/- 0.07 mg/L) and potassium (3.9 +/- 0.95 mg/L) levels met AAMI standards after treatment. Mean levels of chemical contaminants in treated water were as follows: aluminum 0.04 +/- 0.01 mg/L, zinc 0.27 +/- 0.08 mg/L, chloramines 0.16 +/- 0.03 mg/L, fluoride 1.83 +/- 0.40 mg/L, sulfate 117 +/- 86.1 mg/L which were mildly elevated; calcium 126.00 +/- 22.7 mg/L, sodium 179 +/- 25.6 mg/L, and nitrate 70.5 +/- 50.8 mg/L, which were markedly elevated; and magnesium 8.3 +/- 3.38 mg/L, which was moderately elevated above AAMI recommended levels. HD water quality is poor in our environment. Concerted efforts are required to ensure good quality water for HD. PMID- 22537315 TI - Determination of cytokine protein levels in oral secretions in patients undergoing radiotherapy for head and neck malignancies. AB - BACKGROUND: Cytokines may be elevated in tumor and normal tissues following irradiation. Cytokine expression in these tissues may predict for toxicity or tumor control. The purpose of this pilot study was to determine the feasibility of measuring local salivary cytokine levels using buccal sponges in patients receiving chemo-radiation for head and neck malignancies. PATIENTS AND METHODS: 11 patients with epithelial malignancies of the head and neck were recruiting to this study. All patients received radiotherapy to the head and neck region with doses ranging between 60 - 67.5 Gy. Chemotherapy was delivered concurrently with radiation in all patients. Salivary samples were obtained from high dose and low dose regions prior to treatment and at three intervals during treatment for assessment of cytokine levels (IL-4, IL-6, IL-8, IL-10, EGF, MCP-1, TNF-alpha, and VEGF). RESULTS: Cytokine levels were detectable in the salivary samples. Salivary cytokine levels of IL-4, IL-6, IL-8, EGF, MCP-1, TNF- alpha , and VEGF were higher in the high dose region compared to the low dose region at all time points (p < 0.05). A trend toward an increase in cytokine levels as radiation dose increased was observed for IL-6, IL-8, MCP-1, and TNF-alpha. CONCLUSION: Assessment of salivary cytokine levels may provide a novel method to follow local cytokine levels during radiotherapy and may provide a mechanism to study cytokine levels in a regional manner. PMID- 22537316 TI - Phantom digit somatotopy: a functional magnetic resonance imaging study in forearm amputees. AB - Forearm amputees often experience non-painful sensations in their phantom when the amputation stump is touched. Cutaneous stimulation of specific stump areas may be perceived as stimulation of specific phantom fingers (stump hand map). The neuronal basis of referred phantom limb sensations is unknown. We used functional magnetic resonance imaging to demonstrate a somatotopic map of the phantom fingers in the hand region of the primary somatosensory cortex after tactile stump stimulation. The location and extent of phantom finger activation in the primary somatosensory cortex corresponded well to the location of normal fingers in a reference population. Stimulation of the stump hand map resulted in an increased bilateral activation of the primary somatosensory cortex compared with stimulation of forearm regions outside the stump hand map. Increased activation was also seen in contralateral posterior parietal cortex and premotor cortex. Ipsilateral primary somatosensory cortex activation might represent a compensatory mechanism and activation of the non-primary fronto-parietal areas might correspond to awareness of the phantom limb, which is enhanced when experiencing the referred sensations. It is concluded that phantom sensation elicited by stimulation of stump hand map areas is associated with activation of finger-specific somatotopical representations in the primary somatosensory cortex. This suggests that the primary somatosensory cortex could be a neural substrate of non-painful phantom sensations. The stump hand map phenomenon might be useful in the development of prosthetic hand devices. PMID- 22537318 TI - Hippocampal commissure defects in crosses of four inbred mouse strains with absent corpus callosum. AB - It is known that four common inbred mouse strains show defects of the forebrain commissures. The BALB/cJ strain has a low frequency of abnormally small corpus callosum, whereas the 129 strains have many animals with deficient corpus callosum. The I/LnJ and BTBR T+ tf/J strains never have a corpus callosum, whereas half of I/LnJ and almost all BTBR show severely reduced size of the hippocampal commissure. Certain F1 hybrid crosses among these strains are known to be less severely abnormal than the inbred parents, suggesting that the parent strains have different genetic causes of commissure defects. In this study, all hybrid crosses among the four strains were investigated. The BTBR * I/Ln hybrid expressed almost no defects of the hippocampal commissure, unlike its inbred parent strains. Numerous three-way crosses among the four strains yielded many mice with no corpus callosum and severely reduced hippocampal commissure, which shows that the phenotypic defect can result from several different combinations of genetic alleles. The F2 and F3 hybrid crosses of BTBR and I/LnJ had almost 100% absence of the corpus callosum but about 50% frequency of deficient hippocampal commissure. The four-way hybrid cross among all four abnormal strains involved highly fertile parents and yielded a very wide phenotypic range of defects from almost no hippocampal commissure to totally normal forebrain commissures. The F2 and F3 crosses as well as the four-way cross provide excellent material for studies of genetic linkage and behavioral consequences of commissure defects. PMID- 22537317 TI - Role of CD40 ligation in dendritic cell semimaturation. AB - BACKGROUND: DC are among the first antigen presenting cells encountering bacteria at mucosal surfaces, and play an important role in maintenance of regular homeostasis in the intestine. Upon stimulation DC undergo activation and maturation and as initiators of T cell responses they have the capacity to stimulate naive T cells. However, stimulation of naive murine DC with B. vulgatus or LPS at low concentration drives DC to a semimature (sm) state with low surface expression of activation-markers and a reduced capacity to activate T-cells. Additionally, semimature DC are nonresponsive to subsequent TLR stimulation in terms of maturation, TNF-alpha but not IL-6 production. Ligation of CD40 is an important mechanism in enhancing DC maturation, function and capacity to activate T-cells. We investigated whether the DC semimaturation can be overcome by CD40 ligation. RESULTS: Upon CD40 ligation smDC secreted IL-12p40 but not the bioactive heterodimer IL-12p70. Additionally, CD40 ligation of smDC resulted in an increased production of IL-6 but not in an increased expression of CD40. Analysis of the phosphorylation pattern of MAP kinases showed that in smDC the p38 phosphorylation induced by CD40 ligation is inhibited. In contrast, phosphorylation of ERK upon CD40 ligation was independent of the DC maturation state. CONCLUSION: Our data show that the semimature differentiation state of DC can not be overcome by CD40 ligation. We suggest that the inability of CD40 ligation in overcoming DC semimaturation might contribute to the tolerogenic phenotype of semimature DC and at least partially account for maintenance of intestinal immune homeostasis. PMID- 22537319 TI - Pharmacological and biochemical analysis of interactions between N-acetylcysteine and some antiepileptic drugs on experimental seizures in mice. AB - PURPOSE: In view of a putative role of oxidative stress in the pathophysiology of seizures, this study addressed the interactions between N-acetylcysteine (NAC), a potent antioxidant and two antiepileptic drugs sodium valproate (SVP) and phenytoin (PHT) on experimental seizures in mice. METHODS: The interaction was studied at three fixed ratio combinations (i.e., 1:1, 1:3, and 3:1) in the mouse maximal electroshock (MES) test using isobolographic analysis. Markers of oxidative stress (reduced glutathione [GSH] and malondialdehyde [MDA]) were estimated in the cortex of mice pretreated with either of these drugs alone or their 3:1 ratio combinations at the experimentally determined ED(50) values (ED(50 exp) values). The grip strength and spontaneous alternation behavior (SAB) were also assessed. In addition, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and calcium levels were estimated. RESULTS: We found an anticonvulsant action of NAC in the MES test. Further, the ED(50 exp) values for the combinations of PHT and NAC did not differ from the theoretically calculated ED(50) values indicating additive effects. In case of SVP and NAC, however, the ED(50 exp) values were lower than the theoretically calculated ED(50) values. The interaction of SVP with NAC at the fixed ratios of 1:3 and 3:1 was found to be synergistic. No significant changes were observed in the grip strength, SAB, cortical GSH and MDA levels, serum AST, ALT, ALP, or calcium levels. CONCLUSION: Our results thus hold promise for the use of NAC as an adjunct to PHT and SVP therapy. PMID- 22537323 TI - Direct His bundle and paraHisian cardiac pacing. AB - The success rate of direct His bundle pacing (DHBP) and paraHisian pacing has improved remarkably in the last 3-5 years with the advent of dedicated fixation systems that have reduced procedural duration, dislodgement rate, and fluoroscopy time. The methodology of DBHP remains still more complex than paraHisian pacing and is associated with high-pacing thresholds. Thus, DHBP entails greater battery current drain and reduced device longevity. A shift toward paraHisian pacing (which is fusion pacing of myocardium and His bundle) has occurred because its implementation is easier and the electrical parameters are superior to those of DBHP. Currently, an additional safety lead is inserted at the RV apex or outflow tract to prevent asystole, especially in patients with pure DHBP. It is often possible to avoid a safety lead with paraHisian pacing because ventricular pacing is virtually assured on a long-term basis via myocardial capture. DBHP and paraHisian pacing can be achieved in a substantial proportion of patients with varying grades of narrow QRS AV block or after AV junctional ablation and in some patients with the ECG manifestation of bundle branch block caused by an intraHisian lesion. Preliminary observations suggest that DHBP may be useful in some patients requiring cardiac resynchronization if it produces a narrow QRS complex because the site of an intraHisian lesion responsible for left bundle branch block is above the site of DHBP. PMID- 22537320 TI - The epidemiology of travel-related Salmonella Enteritidis in Ontario, Canada, 2010-2011. AB - BACKGROUND: Increases in the number of salmonellosis cases due to Salmonella Enteritidis (SE) in 2010 and 2011 prompted a public health investigation in Ontario, Canada. In this report, we describe the current epidemiology of travel related (TR) SE, compare demographics, symptoms and phage types (PTs) of TR and domestically-acquired (DA) cases, and estimate the odds of acquiring SE by region of the world visited. METHODS: All incident cases of culture confirmed SE in Ontario obtained from isolates and specimens submitted to public health laboratories were included in this study. Demographic and illness characteristics of TR and DA cases were compared. A national travel survey was used to provide estimates for the number of travellers to various destinations to approximate rates of SE in travellers. Multivariate logistic regression was used to estimate the odds of acquiring SE when travelling to various world regions. RESULTS: Overall, 51.9% of SE cases were TR during the study period. This ranged from 35.7% TR cases in the summer travel period to 65.1% TR cases in the winter travel period. Compared to DA cases, TR cases were older and were less likely to seek hospital care. For Ontario travellers, the adjusted odds of acquiring SE was the highest for the Caribbean (OR 37.29, 95% CI 17.87-77.82) when compared to Europe. Certain PTs were more commonly associated with travel (e.g., 1, 4, 5b, 7a, Atypical) than with domestic infection. Of the TR cases, 88.9% were associated with travel to the Caribbean and Mexico region, of whom 90.1% reported staying on a resort. Within this region, there were distinct associations between PTs and countries. CONCLUSIONS: There is a large burden of TR illness from SE in Ontario. Accurate classification of cases by travel history is important to better understand the source of infections. The findings emphasize the need to make travellers, especially to the Caribbean, and health professionals who provide advice to travellers, aware of this risk. The findings may be generalized to other jurisdictions with travel behaviours in their residents similar to Ontario residents. PMID- 22537324 TI - The year of 2010 in electrocardiology. PMID- 22537325 TI - The terminal part of the QT interval (T peak to T end): a predictor of mortality after acute myocardial infarction. AB - BACKGROUND: The terminal part of the QT interval (T peak to T end; Tp-e)-an index for dispersion of cardiac repolarization-is often prolonged in patients experiencing malignant ventricular arrhythmias after acute myocardial infarction (AMI). We wanted to explore whether high Tp-e might predict mortality or fatal arrhythmia post-AMI. METHODS: Tp-e was measured prospectively in 1359/1384 (98.2%) consecutive patients with ST elevation (n = 525) or non-ST elevation (n = 859) myocardial infarction (STEMI or NSTEMI) admitted for coronary angiography. RESULTS: Tp-e was significantly correlated with age, heart rate (HR), heart failure, LVEF, creatinine, three-vessel disease, previous AMI and QRS and QT duration. During a mean follow-up of 1.3 years (range 0.4-2.3),109 patients (7.9%) died; 25, 45, and 39 from cardiac arrhythmia, nonarrhythmic cardiac causes and other causes, respectively. Long Tp-e was strongly associated with increased risk of death, and Tp-e remained a significant predictor of death in multivariable Cox analyses (RR 1.5, 95% CI[1.3-1.7]). HR-corrected Tp-e (cTp-e) was the strongest predictor of death (RR 1.6 [1.4-1.9]). Tp-e and cTp-e were particularly strong predictors of fatal cardiac arrhythmia (RR 1.6 [1.2-2.1] and RR 1.8 [1.4-2.4]). Findings were similar in STEMI and NSTEMI. When comparing two methods for measuring Tp-e, one including the tail of the T wave and one not, the former had markedly higher predictive power (P < 0.001). CONCLUSION: Tp-e, and in particular cTp-e, were strong predictors of mortality during the first year post AMI, and should be further evaluated as prognostic factors additional to established post-AMI risk factors. PMID- 22537326 TI - Behavior of repolarization variables during exercise test in the athlete's heart. AB - BACKGROUND: T peak-T end, QT peak/QT ratio and T peak-T end/QT ratio are markers able to test myocardial repolarization homogeneity, their increase has been related to a higher risk of ventricular tachyarrhythmias. These parameters have not yet been studied in left ventricular hypertrophy due to training. Aim of the research was to test the behavior of these variables in the athlete's heart during exercise. METHODS: We examined 70 athletes, all males, divided into two groups according to the absence or the presence of a left ventricular mass index over 49 g/m(2.7) and a control group composed of 35 healthy, untrained males. All study participants underwent electrocardiogram at rest, transthoracic echocardiogram, and ergometric test. Repolarization markers (QT, corrected QT, QT dispersion, T peak-T end, QT peak/QT, T peak-T end/QT) were calculated at rest, at peak exercise and during recovery. RESULTS: There was no statistically significant difference among the groups regarding all the parameters studied, except for corrected QT at rest between athletes with left ventricular hypertrophy and control group. The behavior of repolarization markers during exercise was not dissimilar in the three groups. CONCLUSIONS: Athlete's heart is not associated to any alteration in ventricular repolarization homogeneity, neither at rest nor during physical activity nor during recovery. Training induced left ventricular hypertrophy does not affect relationship QT parameters/RR interval. PMID- 22537327 TI - Dynamicity of early and late phases of repolarization in patients with remote anterior myocardial infarction: the interlead differences. AB - BACKGROUND: Repolarization dynamicity (QT/RR) is supposed to be a prognostic marker in post-MI patients. However, data on the relationships between early and late phases of QT and RR intervals (QT peak/RR and T peak-T end/RR) are insufficient, and which ECG lead should be used for the analysis is unclear. We analyzed repolarization dynamicity in patients after anterior MI with and without VT/VF history using two leads of Holter recordings- modified V(5) and V(3) . The daytime and nighttime periods were also analyzed. METHODS: Cohort of 88 patients after anterior MI (>6 months) consisted of 43 patients without VT/VF (33 males; 59 +/- 12 years; LVEF: 41 +/- 7%; NoVT/VF), and 45 patients with VT/VF history- ICD implanted as secondary prevention (40 males; 64 +/- 10 years; LVEF: 32 +/- 8%; VT/VF). QT/RR, QT peak/RR and T peak-T end/RR were calculated from 24-hour ECG for the entire recording, daytime and nighttime periods, from V(5) and V(3) leads, respectively. RESULTS: VT/VF patients had lower LVEF (P = 0.001). There were no differences in age and gender. VT/VF group had steeper QT/RR, QT peak/RR, and T peak-T end/RR in V(5) : 0.233 +/- 0.04 versus 0.150 +/- 0.05, P = 0.0001, 0.181 +/- 0.04 versus 0.120 +/- 0.04, P = 0.0001, 0.052 +/- 0.02 versus 0.030 +/- 0.02, P = 0.0001, and in V(3) : 0.201 +/- 0.04 versus 0.149 +/- 0.05, P = 0.0001, 0.159 +/- 0.03 versus 0.118 +/- 0.04, P = 0.0001, and 0.042 +/- 0.02 versus 0.031 +/- 0.02, P = 0.004; respectively. VT/VF patients had higher indices in V(5) than in V(3) lead (P = 0.001). QT/RR and QT peak/RR were steeper at daytime period in both leads. It was not found for T peak-T end/RR. CONCLUSIONS: Patients with VT/VF history are characterized by steeper relationships between repolarization duration and RR intervals. These findings are more evident in modified V(5) lead. PMID- 22537328 TI - Specificity of elevated intercostal space ECG recording for the type 1 Brugada ECG pattern. AB - BACKGROUND: Right precordial (V1-3) elevated electrode placement ECG (EEP-ECG) is often used in the diagnosis of Brugada syndrome (BrS). However, the specificity of this has only been studied in smaller studies in Asian populations. We aimed to study this in a larger European population. METHODS: Two different populations consisting of healthy subjects were used. A total of 340 subjects were included, 80% were men, the median age was 43 year (interquartile range: 31-51) and all were of European ethnicity. RESULTS: No type 1 ECG patterns were identified but 16 (4.7%) subjects with a type 2 ECG and 32 (9.4%) subjects with a type 3 ECG were identified in any lead placement. In total 43 (13%) subjects had any BrS ECG pattern in any lead placement. The specificity was 100% (one-sided 97.5% CI: 99%) for the use of EEP-ECG to uncover type 1 pattern. For type 2 pattern the specificity was 95% (95% CI: 92-97%) and for type 3 pattern 91% (95% CI: 88-94%). CONCLUSIONS: Elevated electrode placement ECG in the diagnosis of BrS seems to have a very high specificity with regards to the finding of a type 1 ECG pattern in a European population; conversely a finding of a type 2 or 3 pattern is of a significantly lower specificity and should perhaps be disregarded. PMID- 22537329 TI - Prevalence of conduction abnormalities in a systolic heart failure population by race, ethnicity, and gender. AB - BACKGROUND: There is paucity of data regarding conduction abnormalities in the Hispanic population with systolic heart failure (HF). We aimed to evaluate the prevalence of electrocardiogram (ECG) abnormalities in a systolic HF population, with attention to the Hispanic population. METHODS: A cross sectional study of 926 patients enrolled in a systolic HF disease management program. ECGS were obtained in patients with an ejection fraction (EF) <= 40% by echocardiography at enrollment. Univariate and multivariate analysis adjusted by ethnicities was performed. RESULTS: White patients exhibited higher prevalence of atrial fibrillation (14.7%) than black patients (8.0%, P = 0.01) whereas Hispanics presented higher prevalence of paced rhythm (14.3% in Hispanics vs. 6.5% in whites and 5.2% in blacks, P<0.01 for both comparisons), higher prevalence of left bundle branch block (LBBB, 14.5% in Hispanics vs. 8.8% in whites and 5.8% in blacks, P = 0.002) and increased frequency of abnormal QT intervals (76.7% in Hispanics) than whites (59.6%) and blacks (69%) patients (P< 0.01 for both comparisons). A QRS interval greater than 120 ms was less prevalent among blacks (15.8% vs. 26.0% in whites and 25.3% in Hispanics, P = 0.01 for both comparisons). Univariate and multivariate analysis disclosed no influence of other characteristics (age, sex, coronary artery disease, hypertension, ejection fraction, medications) in the ECG findings. CONCLUSIONS: Hispanics with Systolic HF presented with increased prevalence of paced rhythm, LBBB, and abnormal QT intervals. Attention should be addressed to these ECG variations to recommend additional guidance for therapeutic interventions and provide important prognostic information. PMID- 22537330 TI - Global and regional ventricular repolarization study by body surface potential mapping in patients with left bundle-branch block and heart failure undergoing cardiac resynchronization therapy. AB - BACKGROUND: The controversial effects promoted by cardiac resynchronization therapy (CRT) on the ventricular repolarization (VR) have motivated VR evaluation by body surface potential mapping (BSPM) in CRT patients. METHODS: Fifty-two CRT patients, mean age 58.8 +/- 12.3 years, 31 male, LVEF 27.5 +/- 9.2, NYHA III-IV heart failure with QRS181.5 +/- 14.2 ms, underwent 87-lead BSPM in sinus rhythm (BASELINE) and biventricular pacing (BIV). Measurements of mean and corrected QT intervals and dispersion, mean and corrected T peak end intervals and their dispersion, and JT intervals characterized global and regional (RV, Intermediate, and LV regions) ventricular repolarization response. RESULTS: Global QTm (P < 0.001) and QTc(m) (P < 0.05) were decreased in BIV; QTm was similar across regions in both modes (P = ns); QTc(m) values were lower in RV/LV than in Intermediate region in BASELINE and BIV (P < 0.001); only RV/Septum showed a significant difference (P < 0.01) in the BIV mode. QTD values both of BASELINE (P < 0.01) and BIV (P < 0.001) were greater in the Intermediate than in the LV region. CRT effect significantly reduced global/regional QTm and QTc(m) values. QTD was globally decreased in RV/LV (Intermediate: P = ns). BIV mode significantly reduced global T peak end mean and corrected intervals and their dispersion. JT values were not significant. CONCLUSIONS: Ventricular repolarization parameters QTm, QTc(m), and QTD global/regional values, as assessed by BSPM, were reduced in patients under CRT with severe HF and LBBB. Greater recovery impairment in the Intermediate region was detected by the smaller variation of its dispersion. PMID- 22537331 TI - Comparison of standard versus orthogonal ECG leads for T-wave alternans identification. AB - T-wave alternans (TWA), an electrophysiologic phenomenon associated with ventricular arrhythmias, is usually detected from selected ECG leads. TWA amplitude measured in the 12-standard and the 3-orthogonal (vectorcardiographic) leads were compared here to identify which lead system yields a more adequate detection of TWA as a noninvasive marker for cardiac vulnerability to ventricular arrhythmias. Our adaptive match filter (AMF) was applied to exercise ECG tracings from 58 patients with an implanted cardiac defibrillator, 29 of which had ventricular tachycardia or fibrillation during follow-up (cases), while the remaining 29 were used as controls. Two kinds of TWA indexes were considered, the single-lead indexes, defined as the mean TWA amplitude over each lead (MTWAA), and lead-system indexes, defined as the mean and the maximum MTWAA values over the standard leads and over the orthogonal leads. Significantly (P < 0.05) higher TWA in the cases versus controls was identified only occasionally by the single lead indexes (odds ratio: 1.0-9.9, sensitivity: 24-76%, specificity: 76-86%), and consistently by the lead-system indexes (odds ratio: 4.5-8.3, sensitivity: 57 72%, specificity: 76%). The latter indexes also showed a significant correlation (0.65-0.83) between standard and orthogonal leads. Hence, when using the AMF, TWA should be detected in all leads of a system to compute the lead-system indexes, which provide a more reliable TWA identification than single-lead indexes, and a better discrimination of patients at increased risk of cardiac instability. The standard and the orthogonal leads can be considered equivalent for TWA identification, so that TWA analysis can be limited to one-lead system. PMID- 22537332 TI - PR depression is useful in the differential diagnosis of myopericarditis and ST elevation myocardial infarction. AB - BACKGROUND: Deviation of the PR segment is a common but often ignored ECG finding in acute myopericarditis, but seems to be rare in the acute phase of ST elevation myocardial infarction (STEMI). Since rapid bedside differential diagnosis of acute myopericarditis and STEMI is essential, we decided to assess the diagnostic power of PR depressions in patients presenting with ST elevations in the emergency room. METHODS: Thirty-four consecutive patients with acute myopericarditis and 46 STEMI patients presenting with ST elevations fulfilling the criteria for STEMI were included. The first ECG recorded in the emergency room was analyzed with a focus on the PR segment. The diagnoses of myopericarditis and STEMI were ascertained with clinical follow-up together with rise in troponin levels, and in the STEMI patients also with coronary angiography. RESULTS: In myopericarditis, the most common location for PR depression was lead II (55.9%), while this ECG finding least likely appeared in lead aVL (2.9%). PR depression in any lead had a high sensitivity (88.2%), but fairly low specificity (78.3%) for myopericarditis. The combination of PR depressions in both precordial and limb leads had the most favorable predictive power to differentiate myopericarditis from STEMI (positive 96.7% and negative power 90%). CONCLUSIONS: Our present observations show that PR segment analysis is a powerful tool in the differential diagnosis of myopericarditis and STEMI. This simple information should be added to the diagnostic workup of patients presenting with ST elevations. PMID- 22537333 TI - Syncope and exercise-related ventricular tachycardia. PMID- 22537334 TI - ST segment elevation in one lead: a case report. AB - BACKGROUND: We describe an unusual finding in an electrocardiogram showing ST segment elevation not related to coronary artery stenosis, pericarditis, bundle branch block, or other well known disorders. CASE PRESENTATION: A 60-year-old African American woman admitted for elective coronary artery bypass graft surgery. A temporary pacemaker with pacing wires was placed intraoperatively for prevention and treatment of postoperative bradyarrhythmia. One day following uneventful surgery, her electrocardiogram demonstrated marked ST segment elevation confined to lead V(6). These changes were comparable to tracings obtained from direct epicardial electrocardiogram, due to contact between the V(6) electrode and the temporary pacemaker ventricular lead wire. CONCLUSION: Current-of-injury patterns are represented on surface electrocardiogram by deviations of the ST segment from the isoelectric baseline. The pacing wire causes direct localized epicardial current-of-injury, affecting the action potential and the resting membrane potentials of cardiomyocytes. Our case report demonstrates epicardial current-of-injury pattern obtained via surface rather than epicardial electrocardiogram, with surface leads as surrogates of epicardial tracing. Measurement of ST-segment shifts from the epicardial electrocardiogram has been shown to provide a more sensitive measurement of ischemia when compared to surface precordial ECG. PMID- 22537335 TI - Variations of left atrial activation patterns in congestive heart failure. AB - We report about a case of a patient admitted to the Intensive Cardiac Care Unit for severe congestive heart failure which showed modification of P-wave morphology and duration, correlated with the clinical evolution. In the case here described, we show that ECG analysis, specifically P wave, allow us to assess the hemodynamic evolution of the acute decompensated heart failure patient. Electrocardiographic examination is the first and the most simple and available diagnostic tool in the evaluation of patients with cardiac diseases. Usually, P wave evaluation is not carefully assessed, in spite of very useful informations we can draw from its interpretation. We report about a patient admitted to our Intensive Cardiac Care Unit (ICCU) for severe congestive heart failure which showed peculiar modification of P-wave morphology and duration, well correlated with the clinical course. PMID- 22537336 TI - Importance of tachogram length and period of recording during noninvasive investigation of the autonomic nervous system. PMID- 22537337 TI - Electrovectorcardiographic diagnosis of left septal fascicular block. PMID- 22537339 TI - Role of environment for catalysis of the DNA repair enzyme MutY. AB - Control of the N-glycosylase reaction by the DNA repair enzyme, MutY, entails the organization of solvent molecules. Classical molecular dynamics and QM/MM simulations were used to investigate the solvent and environment effects contributing to catalysis. Our findings suggest that the entire reaction is an energetically neutral process, in which the first step is rate determining, requiring protonation of adenine (N(7)) to initiate cleavage, and the second step is strongly exothermic, involving hydrolysis of an oxacarbenium ion intermediate. Although water molecules are catalytically active in both steps, the first step requires an entirely different level of solvent organization compared to the second. Needed to secure protonation at N(7), a long-term solvation pattern is established which facilitates the involvement of three out of the five structured water molecules in the active site. This persistent arrangement coordinates the catalytically active water molecules into prime positions to assist the proton transfer: (i) a water molecule frequently bridges the catalytic residues and (ii) the bridging water molecule is assisted by 1-2 other 'supporting' water molecules. To maintain this configuration, MutY, surprisingly, uses hydrophobic residues in combination with hydrophilic residues to tune the microenvironment into a 'water trap'. Hydrophilic residues prolong solvent residence times by maintaining hydrogen-bonding networks, whereas the hydrophobic residues constrain the positioning of the catalytic water molecules that assist the proton-transfer event. In this way, the enzyme uses both entropic and enthalpic considerations to guide the water-assisted reaction. PMID- 22537338 TI - A pilot study using an implantable device to characterize cardiac arrhythmias in hemodialysis patients: implications for future research. PMID- 22537340 TI - EFFICACY OF GBR USING COMPOSITE BONE GRAFT AND RESORBABLE COLLAGEN MEMBRANE IN SEIBERT'S CLASS I RIDGE DEFECTS- RADIOLOGICAL EVALUATION. AB - Abstract The purpose of the study was to radiologically evaluate the efficacy of Guided Bone Regeneration (GBR) using Composite Bone Graft (Autogenous Bone graft & Anorganic Bovine Bone graft (Bio-Oss)) along with Resorbable Collagen Membrane (BioMend Extend) in the augmentation of Seibert's class I ridge defects in maxilla. Bone width was evaluated using computed tomography at 0 day and at 180th day at 2mm, 4mm, and 6mm from the crest.There was a statistically significant increase in bone width between 0 day and 180th day at 2mm, 4mm and 6mm from the crest. The results of the study demonstrated an increase in bone width of Seibert's class I ridge defects in maxilla in the study patients. PMID- 22537341 TI - Carbon-modified TiO2 for photocatalysis. AB - Here we present a method to produce TiO2 nanocrystals coated by thin layer of graphitic carbon. The coating process was prepared via chemical vapor deposition (CVD) with acetylene used as a carbon feedstock with TiO2 used as a substrate. Different temperatures (400 degrees C and 500 degrees C) and times (10, 20, and 60 s) of reaction were explored. The prepared nanocomposites were investigated by means of transmission electron microscopy, Raman spectroscopy, thermogravimetric analysis, Fourier transform infrared spectroscopy/diffuse reflectance spectroscopy and ultraviolet-vis (UV-vis)/diffuse reflectance spectroscopy. Furthermore, photocatalytic activity of the materials was investigated under visible and UV-vis light irradiation in the process of phenol decomposition. It was found that TiO2 modification with carbon resulted in a significant increase of photoactivity under visible irradiation and decrease under UV-vis light irradiation. Interestingly, a shorter CVD time and higher process temperature resulted in the preparation of the samples exhibiting higher activity in the photocatalytic process under visible light irradiation. PMID- 22537342 TI - Hydrolytic and oxidative stability of L-(+)-ascorbic acid supported in pectin films: influence of the macromolecular structure and calcium presence. AB - The hydrolytic and oxidative stability of L-(+)-ascorbic acid (AA) into plasticized pectin films were separately studied in view of preserving vitamin C activity and/or to achieve localized antioxidant activity at pharmaceutical and food interfaces. Films were made with each one of the enzymatically tailored pectins (50%, 70%, and 80% DM; Cameron et al. Carbohydr. Polym.2008, 71, 287-299) or commercial high methoxyl pectin (HMP; 72% DM). Since AA stability was dependent on water availability in the network, pectin nanostructure affected the AA kinetics. Higher AA retention and lower browning rates were achieved in HMP films, and calcium presence in them stabilized AA because of higher water immobilization. Air storage did not change AA decay and browning rates in HMP films, but they significantly increased in Ca-HMP films. It was concluded that the ability of the polymeric network to immobilize water seems to be the main factor to consider in order to succeed in retaining AA into film materials. PMID- 22537343 TI - Management of anaphylaxis in schools: Evaluation of an epinephrine auto-injector (EpiPen(r)) use by school personnel and comparison of two approaches of soliciting participation. AB - BACKGROUND: There has been no large study characterizing selection bias in allergy and evaluating school personnel's ability to use an epinephrine auto injector (EpiPen(r)). Our objective was to determine if the consent process introduces selection bias by comparing 2 methods of soliciting participation of school personnel in a study evaluating their ability to demonstrate the EpiPen(r). METHODS: School personnel from randomly selected schools in Quebec were approached using a 1) partial or 2) full disclosure approach and were assessed on their ability to use the EpiPen(r) and identify anaphylaxis. RESULTS: 343 school personnel participated. In the full disclosure group, the participation rate was lower: 21.9% (95%CI, 19.0%-25.2%) versus 40.7% (95%CI, 36.1%-45.3%), but more participants achieved a perfect score: 26.3% (95%CI, 19.6% 33.9%) versus 15.8% (95%CI, 10.8%-21.8%), and identified 3 signs of anaphylaxis: 71.8% (95%CI, 64.0%-78.7%) versus 55.6% (95%CI, 48.2%-62.9%). CONCLUSIONS: Selection bias is suspected as school personnel who were fully informed of the purpose of the assessment were less likely to participate; those who participated among the fully informed were more likely to earn perfect scores and identify anaphylaxis. As the process of consent can influence participation and bias outcomes, researchers and Ethics Boards need to consider conditions under which studies can proceed without full consent. Despite training, school personnel perform poorly when asked to demonstrate the EpiPen(r). PMID- 22537344 TI - Synthesis, properties, and OFET characteristics of 5,5'-di(2-azulenyl)-2,2' bithiophene (DAzBT) and 2,5-di(2-azulenyl)-thieno[3,2-b]thiophene (DAzTT). AB - Two azulene-based pi-conjugated systems, 5,5'-di(2-azulenyl)-2,2'-bithiophene and 2,5-di(2-azulenyl)-thieno[3,2-b]thiophene, were constructed via Suzuki-Miyaura cross-coupling reactions. The crystal structures of both revealed an edge-to-face orientation in a well-defined herringbone packing. The molecules stood nearly perpendicular to the substrate in the film form, with features of an organic field-effect transistor at hole mobilities of up to 5.0 * 10(-2) cm(2) V(-1) s( 1). PMID- 22537346 TI - 3rd congress of the international foot and ankle biomechanics community sydney, australia. 11-13 march 2012. Abstracts. PMID- 22537345 TI - The association of serum neutrophil markers and acute coronary syndrome. AB - An association exists between chronic infection-induced inflammation, such as periodontitis, and acute coronary syndrome (ACS). We studied the association of serum neutrophil markers, myeloperoxidase (MPO), matrix metalloproteinase (MMP) 8, tissue inhibitor of metalloproteinase (TIMP)-1 concentrations and MMP-8/TIMP-1 ratio, with the risk of recurrent ACS. Radiographic periodontal status was recorded from 141 patients with acute non-Q-wave infarction or unstable angina pectoris, who participated in a double-blind, placebo-controlled study with clarithromycin for 3 months. Serum samples were collected within arrival to the hospital, at 1 week, 3 months and 1 year. Recurrent ACS events were registered during the 1-year follow-up. In the whole population, high serum MPO concentrations at 1 week (fourth quartile versus quartiles 1-3) were associated with the risk of recurrent ACS with a relative risk (RR) of 2.52 (95% CI, 1.277 4.980; P = 0.008). In patients without periodontal disease, high MPO concentration at 1 week and 1 year predicted recurrent ACS with RRs of 3.54 (1.600-7.831; P = 0.002) and 2.87 (1.171-7.038; P = 0.021), respectively. In the placebo group, but not in the clarithromycin group, high serum MMP-8/TIMP-1 ratio at 1 week predicted recurrent ACS with an RR of 3.23 (1.295-8.063; P = 0.012). Our results suggest that high serum neutrophil markers reflect increased risk of recurrent ACS, especially in patients without periodontal disease and not receiving antimicrobial medication. PMID- 22537347 TI - Relations between colorblind socialization and children's racial bias: evidence from European American mothers and their preschool children. AB - To examine European American parents' racial socialization, mothers (n = 84) were videotaped while reading 2 race-themed books to their 4- to 5-year-old children and completed surveys concerning their racial attitudes and behaviors. Children completed measures of their racial attitudes and both groups (mothers and preschoolers) predicted the others' racial attitudes. Results indicated that nearly all mothers adopted "colormute" and "colorblind" approaches to socialization. Furthermore, neither children nor mothers accurately predicted the others' views. Children's racial attitudes were unrelated to their mothers' attitudes but were predicted by their mothers' cross-race friendships; those children whose mothers had a higher percentage of non-European American friends showed lower levels of racial biases than those children whose mothers had a lower percentage of non-European American friends. PMID- 22537348 TI - Brown tumors in dialyzed patients with secondary hyperparathyroidism: report of 16 cases. AB - Brown tumors (BTs) are relatively uncommon but they are serious complications of renal osteodystrophy. The objective of this study was to analyze the clinical, biological, and radiological characteristics of 16 patients with BTs provoked by secondary hyperparathyroidism (sHPT) and its response to the decrease in parathyroid hormone levels after parathyroidectomy (PTX). The management of that uncommon condition was also reviewed. We conducted a retrospective study including 16 end-stage renal disease patients who underwent subtotal PTX between 1997 and 2007 for severe sHPT with BTs. Our study included 10 men and 6 women, whose average age was 34 years. All patients were on dialysis. Ten of them were on dialysis for more than 5 years. The median duration on dialysis was 84 months. Patients included suffered from swellings associated with functional limitations. BTs had multiple locations in 7 patients. Jaw was the most frequent location (62%). Radiography and tomodensitometry demonstrated a mixed radio lucent and radio-opaque lesions with an expansion of the cortical bone. Bone scan demonstrated an increased uptake of lesions. Chirurgical treatment was indicated in all cases because of severe refractory sHPT with functional limitations and/or disfiguring deformities. In all cases, BTs stopped its progression and even decreased in size. However, it was insufficient in four cases, which required a surgical resection. PTX remains an efficacious approach in resistant cases of sHPT with persistent BTs. PMID- 22537349 TI - Women's experience of hospitalized bed rest during high-risk pregnancy. AB - OBJECTIVE: To describe the lived experience of the hospitalized pregnant woman on bed rest. DESIGN: A qualitative, phenomenological design. SETTING: Three high risk antepartum units in the midwestern United States. PARTICIPANTS: A self selected, convenience sample of 11 high-risk pregnant women. METHOD: Phenomenological study using thematic analysis of completed handwritten journals and/or online blogs. RESULTS: Women described the battles that they fought each day for the lives of their unborn children. Using an imagery of war, three categories emerged: (a) the war within, (b) fighting each battle, and (c) bringing in reinforcements. CONCLUSIONS: Women experience many different emotions and stressors during restricted bed rest. A nurse's understanding of this experience is essential to provide adequate care and coping strategies for women at this time. PMID- 22537350 TI - Functional requirements for inhibitory signal transmission by the immunomodulatory receptor CD300a. AB - BACKGROUND: Activation signals can be negatively regulated by cell surface receptors bearing immunoreceptor tyrosine-based inhibitory motifs (ITIMs). CD300a, an ITIM bearing type I transmembrane protein, is expressed on many hematopoietic cells, including subsets of lymphocytes. RESULTS: We have taken two approaches to further define the mechanism by which CD300a acts as an inhibitor of immune cell receptor signaling. First, we have expressed in Jurkat T cells a chimeric receptor consisting of the extracellular domains of killer-cell immunoglobulin-like receptor (KIR)2DL2 fused to the transmembrane and cytoplasmic segments of CD300a (KIR-CD300a) to explore surrogate ligand-stimulated inhibition of superantigen stimulated T cell receptor (TCR) mediated cell signaling. We found that intact CD300a ITIMs were essential for inhibition and that the tyrosine phosphorylation of these ITIMs required the src tyrosine kinase Lck. Tyrosine phosphorylation of the CD300a ITIMs created docking sites for both src homology 2 domain containing protein tyrosine phosphatase (SHP)-1 and SHP-2. Suppression of SHP-1 and SHP-2 expression in KIR-CD300a Jurkat T cells with siRNA and the use of DT40 chicken B cell lines expressing CD300a and deficient in several phosphatases revealed that SHP-1, but not SHP-2 or the src homology 2 domain containing inositol 5' phosphatase SHIP, was utilized by CD300a for its inhibitory activity. CONCLUSION: These studies provide new insights into the function of CD300a in tuning T and B cell responses. PMID- 22537352 TI - Low bone mineral density is associated with the onset of spontaneous osteonecrosis of the knee. AB - BACKGROUND AND PURPOSE: The primary event preceding the onset of symptoms in spontaneous osteonecrosis in the medial femoral condyle (SONK) may be a subchondral insufficiency fracture, which may be associated with underlying low bone mineral density (BMD). However, the pathogenesis of SONK is considered to be multifactorial. Women over 60 years of age tend to have higher incidence of SONK and low BMD. We investigated whether there may be an association between low BMD and SONK in women who are more than 60 years old. METHODS: We compared the BMD of 26 women with SONK within 3 months after the onset of symptoms to that of 26 control women with medial knee osteoarthritis (OA). All the SONK patients had typical clinical presentations and met specified criteria on MRI. The BMDs measured at the lumbar spine, ipsilateral femoral neck, and knee condyles and the ratios of medial condyle BMD to lateral condyle BMD (medial-lateral ratios) in the femur and tibia were compared between the two groups. The medial-lateral ratios were used as parameters for comparisons of the BMDs at both condyles. RESULTS: The mean femoral neck, lateral femoral condyle, and lateral tibial condyle BMDs were between x% and y% lower in the SONK patients than in the OA patients (p < 0.001). The mean femoral and tibial medial-lateral ratios were statistically significantly higher in the SONK patients than in the OA patients. INTERPRETATION: A proportion of women over 60 years of age have low BMD that progresses rapidly after menopause and can precipitate a microfracture. These findings support the subchondral insufficiency fracture theory for the onset of SONK based on low BMD. PMID- 22537353 TI - Trace detection of meglumine and diatrizoate from Bacillus spore samples using liquid chromatography/mass spectrometry. AB - Following the September 11, 2001 terrorist attacks, letters containing Bacillus anthracis were distributed through the United States postal system killing five people. A complex forensic investigation commenced to identify the perpetrator of these mailings. A novel liquid chromatography/mass spectrometry protocol for the qualitative detection of trace levels of meglumine and diatrizoate in dried spore preparations of B. anthracis was developed. Meglumine and diatrizoate are components of radiographic imaging products that have been used to purify bacterial spores. Two separate chromatographic assays using multiple mass spectrometric analyses were developed for the detection of meglumine and diatrizoate. The assays achieved limits of detection for meglumine and diatrizoate of 1.00 and 10.0 ng/mL, respectively. Bacillus cereus T strain spores were effectively used as a surrogate for B. anthracis spores during method development and validation. This protocol was successfully applied to limited evidentiary B. anthracis spore material, providing probative information to the investigators. PMID- 22537351 TI - Association of single nucleotide polymorphisms in the genes ATM, GSTP1, SOD2, TGFB1, XPD and XRCC1 with risk of severe erythema after breast conserving radiotherapy. AB - PURPOSE: To examine the association of polymorphisms in ATM (codon 158), GSTP1 (codon 105), SOD2 (codon 16), TGFB1 (position -509), XPD (codon 751), and XRCC1 (codon 399) with the risk of severe erythema after breast conserving radiotherapy. METHODS AND MATERIALS: Retrospective analysis of 83 breast cancer patients treated with breast conserving radiotherapy. A total dose of 50.4 Gy was administered, applying 1.8 Gy/fraction within 42 days. Erythema was evaluated according to the Radiation Therapy Oncology Group (RTOG) score. DNA was extracted from blood samples and polymorphisms were determined using either the Polymerase Chain Reaction based Restriction-Fragment-Length-Polymorphism (PCR-RFL) technique or Matrix-Assisted-Laser-Desorption/Ionization -Time-Of-Flight-Mass-Spectrometry (MALDI-TOF). Relative excess heterozygosity (REH) was investigated to check compatibility of genotype frequencies with Hardy-Weinberg equilibrium (HWE). In addition, p-values from the standard exact HWE lack of fit test were calculated using 100,000 permutations. HWE analyses were performed using R. RESULTS: Fifty six percent (46/83) of all patients developed erythema of grade 2 or 3, with this risk being higher for patients with large breast volume (odds ratio, OR = 2.55, 95% confidence interval, CI: 1.03-6.31, p = 0.041). No significant association between SNPs and risk of erythema was found when all patients were considered. However, in patients with small breast volume the TGFB1 SNP was associated with erythema (p = 0.028), whereas the SNP in XPD showed an association in patients with large breast volume (p = 0.046). A risk score based on all risk alleles was neither significant in all patients nor in patients with small or large breast volume. Risk alleles of most SNPs were different compared to a previously identified risk profile for fibrosis. CONCLUSIONS: The genetic risk profile for erythema appears to be different for patients with small and larger breast volume. This risk profile seems to be specific for erythema as compared to a risk profile for fibrosis. PMID- 22537355 TI - Use and misuse of serum troponin assays in pediatric practice. AB - Cardiac troponin (cTn) is instrumental in screening and diagnosing myocardial ischemia in adults. However, the role of cTn screening in the pediatric population is less clear. The purpose of this study was to evaluate the current clinical practice, diagnostic and prognostic value, and resource utilization associated with cTn assays in the pediatric population. A multicenter, retrospective review of all cTn assays performed on patients aged <=18 years from January 2003 to December 2010 in the Intermountain Healthcare system was conducted. Data collected included patient demographics, location, presenting symptoms, provisional and discharge diagnoses, additional tests, clinical outcomes (hospitalization days, ventilation, and death), and patient charges. During the study period, cTn assays were performed on 3,497 pediatric patients. The most common presenting diagnoses were chest pain (40%), trauma (11%), and poisoning or drug overdose (9%). Irrespective of diagnosis, elevated cTn was associated with an increased rate of hospitalization, ventilation, and death. Overall, 12% of patients had elevated cTn. Of the patients with chest pain, 4% had elevated cTn, 53% of whom were diagnosed with myopericarditis. In the myopericarditis group, 66% presented with fever, and 98% had abnormal electrocardiographic findings. For patients presenting with chest pain, approximately $162,000 was spent per positive result. In conclusion, cTn screening has strong prognostic value in pediatric patients, even in noncardiac diagnoses such as trauma or drug overdose. However, cTn screening in pediatric patients with chest pain provides minimal benefits and is associated with increased resource utilization, unless patients have constitutional symptoms, such as fever and/or electrocardiographic abnormalities. PMID- 22537354 TI - Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. AB - New oral anticoagulants, including apixaban, dabigatran, and rivaroxaban, have been developed as alternatives to warfarin, the standard oral anticoagulation therapy for patients with atrial fibrillation (AF). A systematic review and meta analysis of randomized controlled trials was performed to compare the efficacy and safety of new oral anticoagulants to those of warfarin in patients with AF. The published research was systematically searched for randomized controlled trials of >1 year in duration that compared new oral anticoagulants to warfarin in patients with AF. Random-effects models were used to pool efficacy and safety data across randomized controlled trials. Three studies, including 44,563 patients, were identified. Patients randomized to new oral anticoagulants had a decreased risk for all-cause stroke and systemic embolism (relative risk [RR] 0.78, 95% confidence interval [CI] 0.67 to 0.92), ischemic and unidentified stroke (RR 0.87, 95% CI 0.77 to 0.99), hemorrhagic stroke (RR 0.45, 95% CI 0.31 to 0.68), all-cause mortality (RR 0.88, 95% CI 0.82 to 0.95), and vascular mortality (RR 0.87, 95% CI 0.77 to 0.98). Randomization to a new oral anticoagulant was associated with a lower risk for intracranial bleeding (RR 0.49, 95% CI 0.36 to 0.66). Data regarding the risks for major bleeding (RR 0.88, 95% CI 0.71 to 1.09) and gastrointestinal bleeding (RR 1.25, 95% CI 0.91 to 1.72) were inconclusive. In conclusion, the new oral anticoagulants are more efficacious than warfarin for the prevention of stroke and systemic embolism in patients with AF. With a decreased risk for intracranial bleeding, they appear to have a favorable safety profile, making them promising alternatives to warfarin. PMID- 22537356 TI - Effect of weight loss after bariatric surgery on left ventricular mass and ventricular repolarization in normotensive morbidly obese patients. AB - To assess the effect of weight loss on ventricular repolarization in morbidly obese patients, 39 normotensive subjects whose baseline body mass indexes were >=40 kg/m(2) before weight loss from bariatric surgery were studied. All patients were free of underlying organic heart disease, heart failure, and conditions that might affect ventricular repolarization. Twelve-lead electrocardiography and transthoracic echocardiography were performed just before surgery and at the nadir of postoperative weight loss. The corrected QT interval (QTc) was derived using Bazett's formula. QTc dispersion was calculated by subtracting the minimum from the maximum QTc on the 12-lead electrocardiogram. Echocardiographic left ventricular (LV) mass was indexed to height(2.7). The mean body mass index decreased from 42.8 +/- 2.1 to 31.9 +/- 2.2 kg/m(2) (p <0.0005). For the entire group, weight loss was associated with significant reductions in mean QTc (from 428.7 +/- 18.5 to 410.5 +/- 11.9 ms, p <0.0001) and mean QTc dispersion (from 44.1 +/- 11.2 to 33.2 +/- 3.3 ms, p <0.0005). Mean QTc and QTc dispersion decreased significantly with weight loss in patients with LV hypertrophy but not in subjects without LV hypertrophy. Multivariate analysis identified pre-weight loss LV mass/height(2.7) as the most important predictor of pre-weight loss QTc and QTc dispersion and also identified weight loss-induced change in LV mass/height(2.7) as the most important predictor of weight loss-induced changes in QTc and QTc dispersion. In conclusion, LV hypertrophy is a key determinant of QTc and QTc dispersion in normotensive morbidly obese patients. Regression of LV hypertrophy associated with weight loss decreases QTc and QTc dispersion. PMID- 22537358 TI - Remission in children and adolescents diagnosed with attention deficit/hyperactivity disorder via an effective and tolerable titration scheme for osmotic release oral system methylphenidate. AB - OBJECTIVES: The purpose of this study was to identify the optimal dose of osmotic release oral system methylphenidate (OROS-MPH) using a dosage forced-titration scheme to achieve symptomatic remission in children with attention- deficit/hyperactivity disorder (ADHD). We also evaluated the efficacy and safety of, and patient and parent satisfaction with, the change in therapy from immediate-release methylphenidate (IR-MPH) to OROS-MPH over 10 weeks. METHOD: We recruited 521 children and adolescents aged 6-18 years with an American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) diagnosis of ADHD, who had received IR-MPH treatments (<70 mg/day) for at least 1 month. The treatment, switched from IR-MPH to OROS-MPH according to a conversion scheme, started with a 6-week forced-titration phase of OROS-MPH to achieve symptomatic remission (defined as a score of 0 or 1 for each of the first 18 ADHD items in the Chinese version of the Swanson, Nolan, and Pelham, Version IV [SNAP-IV]), followed by a 4-week maintenance phase. The global ADHD severity and drug side effects of the participants were evaluated. Parents completed the ratings scales for the ADHD-related symptoms. Patient and parent satisfaction for the OROS-MPH treatment was also assessed. RESULTS: Among the 439 participants with ADHD who completed the trial, 290 participants (66.1%) achieved symptomatic remission. The mean dose of OROS-MPH among participants in remission was 36.7 mg (1.08 mg/kg) per day. Increased efficacy, superior satisfaction, and safety equivalent to that of IR-MPH were demonstrated in intra-individual comparisons from the baseline to the end of study. Determinants for remission included less severe ADHD symptoms (SNAP-IV score < 40), no family history of ADHD, and an appropriate dosage of medication according to the patient's weight. CONCLUSIONS: The findings suggest remission as a treatment goal for ADHD therapy by providing an optimal dosage of medication for children and adolescents with ADHD through using an effective and tolerable forced-titration scheme. PMID- 22537357 TI - Gray matter differences between healthy and depressed adolescents: a voxel-based morphometry study. AB - BACKGROUND: Major depressive disorder (MDD) frequently begins during adolescence and is associated with significant morbidity and mortality. However, little is known about the neurobiology of adolescent depression. A better understanding of the neurobiology will be helpful in developing more effective preventive and treatment interventions for this highly disabling illness. METHODS: Using a voxel based morphometric method, the study compared gray matter and white matter volumes in 22 adolescents with MDD and 22 age- and gender-matched normal controls. RESULTS: Compared with controls, depressed adolescents had smaller gray matter volume in the frontal lobe and caudate nucleus bilaterally and right superior and middle temporal gyri. However, the groups did not differ significantly on white matter volume. CONCLUSIONS: These findings in depressed adolescents are consistent with the previous findings of gray matter abnormalities in frontolimbic areas and the striatum in depressed adults and suggest the presence of these structural changes at the onset of depressive illness. PMID- 22537360 TI - A retrospective review of the effectiveness of aripiprazole in the treatment of sensory abnormalities in autism. AB - Although sensory deficits are frequently observed in autistic individuals, pharmacologic interventions targeting these abnormalities are lacking. The goal of this investigation was to assess the effectiveness of aripiprazole in targeting sensory deficits in children and adolescents with autism. Using an outpatient clinic registry for pervasive developmental disorder, 13 individuals who had received aripiprazole for treating disruptive behaviors and had completed behavioral rating scales (aberrant behavior checklist [ABC] and sensory profile questionnaire [SPQ]) were identified. Mean treatment duration was 24.4 weeks with a mean final aripiprazole dosage of 10.8 mg. Aripiprazole yielded improvements in the total ABC and in several items of the SPQ including registration, inattention/distractibility, auditory processing, and modulation of visual input affecting emotional responses and activity level, suggesting that aripiprazole might be beneficial in targeting sensory abnormalities in autism. PMID- 22537359 TI - Placebo-controlled pilot trial of mecamylamine for treatment of autism spectrum disorders. AB - OBJECTIVE: To explore possible benefits of a nicotinic acetylcholine receptor (nAChR) agent for autistic symptoms based on postmortem observation of nAChR abnormalities (deficient alpha4beta2 nAChRs, excess alpha7 nAChRs) in brains of patients with autism. METHOD: Mecamylamine, because of its safety record in children with other disorders, was chosen for this first exploration. Twenty children with autism spectrum disorder age 4-12 years were randomly assigned for 14 weeks to placebo (n=8) or mecamylamine (n=12) in ascending fixed doses: 0.5 mg/day for 6 weeks, 2.5 mg for 2 weeks, then 5 mg/day for 6 weeks. Improvement was rated by a blinded independent evaluator. Because of small sample, data analysis was descriptive. RESULTS: Eighteen participants (10 mecamylamine, 8 placebo) completed the study. All doses were well tolerated; the only side effect of note was constipation (50% compared with 25% of placebo group). Three children had clinically nonsignificant electrocardiographic QT prolongation. Both groups showed modest to moderate improvement, but differences between groups were negligible. On the primary outcome measure, the Ohio Autism Clinical Impressions Scale, 90% of the active treatment group showed improvement at some point (but only 40% sustained it), compared with 62% on placebo. Of the four in active treatment that sustained improvement, three had a maximum dose of 0.13-0.15 mg/kg/day, while those who regressed had doses >=0.18 mg/kg/day. Graphed means suggested better outcome with lower mg/kg and longer medication duration. Four parents spontaneously reported reduced hyperactivity and irritability and better verbalization and continued mecamylamine at their own expense. CONCLUSION: Mecamylamine appeared to be safe, but not very effective in autism. The suggestion of better results at lower doses and longer exposure warrants consideration for future trials. The next step would be exploration of a more specific alpha4beta2 nAChR agonist, such as varenicline. PMID- 22537361 TI - Medicaid expenditures on psychotropic medications for children in the child welfare system. AB - OBJECTIVE: Children in the child welfare system are the most expensive child population to insure for their mental health needs. The objective of this article is to estimate the amount of Medicaid expenditures incurred from the purchase of psychotropic drugs - the primary drivers of mental health expenditures - for these children. METHODS: We linked a subsample of children interviewed in the first nationally representative survey of children coming into contact with U.S. child welfare agencies, the National Survey of Child and Adolescent Well-Being (NSCAW), to their Medicaid claims files obtained from the Medicaid Analytic Extract. Our data consist of children living in 14 states, and Medicaid claims for 4 years, adjusted to 2010 dollars. We compared expenditures on psychotropic medications in the NSCAW sample to a propensity score-matched comparison sample obtained from Medicaid files. RESULTS: Children surveyed in NSCAW had over thrice the odds of any psychotropic drug use than the comparison sample. Each maltreated child increased Medicaid expenditures by between $237 and $840 per year, relative to comparison children also receiving medications. Increased expenditures on antidepressants and amphetamine-like stimulants were the primary drivers of these increased expenditures. On average, an African American child in NSCAW received $399 less expenditure than a white child, controlling for behavioral problems and other child and regional characteristics. Children scoring in the clinical range of the Child Behavior Checklist received, on average, $853 increased expenditure on psychotropic drugs. CONCLUSION: Each child with child welfare involvement is likely to incur upwards of $1482 in psychotropic medication expenditures throughout his or her enrollment in Medicaid. Medicaid agencies should focus their cost-containment strategies on antidepressants and amphetamine-type stimulants, and expand use of instruments such as the Child Behavior Checklist to identify high-cost children. Both of these strategies can assist Medicaid agencies to better predict and plan for these expenditures. PMID- 22537362 TI - Cytotoxic and anti-inflammatory triterpenoids from Toona ciliata. AB - Toonaciliatavarins A-H (1-8), including three new protolimonoids (1-3), two new tirucallane-type triterpenoids (4 and 5), and three new tetranortriterpenoids (6 8), and 10 known compounds were isolated from the stem barks of Toona ciliata Roem. var. henryi. Their structures were identified on the basis of spectroscopic analysis. The absolute configurations of 2 and 8 were determined by ECD calculation. The new isolates were evaluated for their cytotoxicities using six human cancer cell lines and also for their inhibitory effects on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells. Compounds 4 and 5 showed moderate cytotoxicities, and the protolimonoids (1-3) exhibited marked inhibitory effects on LPS-stimulated NO production. PMID- 22537363 TI - Phenanthrene derivatives from Cymbidium Great Flower Marie Laurencin and their biological activities. AB - A new phenanthrendione, ephemeranthoquinone B (1), two phenanthrenes, marylaurencinols A (2) and B (3), and a phenanthrene glucoside, marylaurencinoside A (4), were isolated from the roots of Cymbidium Great Flower Marie Laurencin, along with six known phenanthrenes, 5-10. The structures of these compounds were established by a combination of extensive NMR spectroscopy and/or X-ray crystallographic analysis and chemical degradation. The compounds were tested for antibacterial activities against Bacillus subtilis and Klebsiella pneumoniae and for cytotoxic activity against the human promyelocytic leukemia (HL-60) cell line. Compounds 1, 3, and 6 showed antibacterial activities with minimum inhibitory concentration (MIC) values in the range of 4.88 to 65.10 MUM. Notably, ephemeranthoquinone B (1) had a strong antibacterial effect on B. subtilis. Furthermore, 1 exhibited moderate cytotoxic activity (IC(50) 2.8 MUM) against HL-60 cells. Compounds 4-9 also showed weak cytotoxic activity against the HL-60 cell line with IC(50) values of 19.3-52.4 MUM. PMID- 22537364 TI - Drugs prescription in patients with chronic liver disease: rules for adjusting doses and beyond. PMID- 22537365 TI - Drug dosage recommendations in patients with chronic liver disease. AB - Chronic liver diseases (CLD) alter the kinetics of drugs. Despite dosage adjustment is based on Child-Pugh scores, there are no available recommendations and/or algorithms of reference to facilitate dosage regimens. A literature review about dose adjustment of the drugs from the hospital guide -which are included in the list of the WHO recommended drugs to be avoided or used with caution in patients with liver disease- was carried out. The therapeutic novelties from the last few years were also included. In order to do so, the summary of product characteristics (SPC), the database DrugDex-Micromedex, the WHO recommendations and the review articles from the last 10 years in Medline were reviewed. Moreover, the kinetic parameters of each drug were calculated with the aim of establishing a theoretical recommendation based on the proposal of Delco and Huet. Recommendations for 186 drugs are presented according to the SPC (49.5%), DrugDex-Micromedex (26.3%) and WHO (18.8%) indications; six recommendations were based on specific publications; the theoretical recommendation based on pharmacokinetic parameters was proposed in four drugs. The final recommendations for clinical management were: dosage modification (26.9%), hepatic/analytical monitoring of the patient (8.6%), contraindication (18.8%), use with caution (19.3%) and no adjustment required (26.3%). In this review, specific recommendations for the practical management of patients with chronic liver disease are presented. It has been elaborated through a synthesis of the published bibliography and completed by following a theoretical methodology. PMID- 22537366 TI - Self-expanding metal stents versus antrectomy for the palliative treatment of obstructive adenocarcinoma of the gastric antrum. AB - BACKGROUND: gastric cancer patients are first diagnosed with an unresectable tumor in up to 40% of cases. Gastric outlet obstruction causes nausea, vomiting, dehydration and malnutrition. The aim of the study was to compare self-expanding metal stents to antrectomy and Roux-en Y gastrojejunostomy for palliation of obstructive adenocarcinoma of the gastric antrum. METHODS: retrospective study in patients with obstructing cancer of the gastric antrum. Patients were divided into two groups: group A, underwent endoscopic placement of self-expanding metal stents and group B underwent surgical treatment with antrectomy and Roux-en Y gastrojejunostomy. Collected data included: age, gender, performance status (Karnofsky's score), body mass index, histopathology, clinical stage (TNM classification), technical and clinical success of the procedure, time to oral intake, in-hospital stay, reintervention rate, and complications related to the treatment and survival. RESULTS: a total of 39 patients with gastric adenocarcinoma were included, 21 male and 18 female. Nineteen patients were assigned to group A and 20 patients to group B. There were no statistically significant differences between groups in regards to age, body mass index, Karnofsky's score and clinical stage. The technical and clinical success was similar for both groups. There was a statistically significant difference between groups favoring self-expanding metal stent in time to oral intake (1 +/- 0 vs. 4.9 +/- 0.6 days, p = 0.0001) and in-hospital stay (0.94 +/- 1.18 vs. 7.8 +/- 7.7 days, p = 0.0005). We did not find statistically significant differences with regards to long-term survival. CONCLUSIONS: in patients with malignant gastric outlet obstruction due to gastric cancer, endoscopic palliation with self expanding metal stents provide a shorter interval to oral intake, shorter in hospital stay and lower rate of complications. PMID- 22537367 TI - Is there still a role for intraoperative enteroscopy in patients with obscure gastrointestinal bleeding? AB - BACKGROUND: in 21st century, endoscopic study of the small intestine has undergone a revolution with capsule endoscopy and balloon-assisted enteroscopy. The difficulties and morbidity associated with intraoperative enteroscopy, the gold-standard in the 20th century, made this technique to be relegated to a second level. AIMS: evaluate the actual role and assess the diagnostic and therapeutic value of intraoperative enteroscopy in patients with obscure gastrointestinal bleeding. PATIENTS AND METHODS: we conducted a retrospective study of 19 patients (11 males; mean age: 66.5 +/- 15.3 years) submitted to 21 IOE procedures for obscure GI bleeding. Capsule endoscopy and double balloon enteroscopy had been performed in 10 and 5 patients, respectively. RESULTS: with intraoperative enteroscopy a small bowel bleeding lesion was identified in 79% of patients and a gastrointestinal bleeding lesion in 94%. Small bowel findings included: angiodysplasia (n = 6), ulcers (n = 4), small bowel Dieulafoy's lesion (n = 2), bleeding from anastomotic vessels (n = 1), multiple cavernous hemangiomas (n = 1) and bleeding ectopic jejunal varices (n = 1). Agreement between capsule endoscopy and intraoperative enteroscopy was 70%. Endoscopic and/or surgical treatment was used in 77.8% of the patients with a positive finding on intraoperative enteroscopy, with a rebleeding rate of 21.4% in a mean 21-month follow-up period. Procedure-related mortality and postoperative complications have been 5 and 21%, respectively. CONCLUSIONS: intraoperative enteroscopy remains a valuable tool in selected patients with obscure GI bleeding, achieving a high diagnostic yield and allowing an endoscopic and/or surgical treatment in most of them. However, as an invasive procedure with relevant mortality and morbidity, a precise indication for its use is indispensable. PMID- 22537368 TI - Laparoscopic versus open transhiatal esophagectomy for distal and junction cancer. AB - BACKGROUND: the only curative treatment for esophageal cancer is surgical resection. This treatment is associated with a high morbidity rate and long in hospital recovery period. Both transthoracic and transhiatal esophagectomies are performed worldwide. The transhiatal approach may reduce the respiratory infection rate in compromised patients with distal esophageal and gastro esophageal (GE) cancers. Minimally invasive esophagectomy could further improve post-operative outcome. Two cohorts of laparoscopic and open transhiatal esophagectomy for cancer were compared for short- and long-term outcome. METHODS: from January 2001 through December 2004, 50 patients who underwent laparoscopic transhiatal esophagectomy were compared to a historical group of 50 patients who had undergone open transhiatal esophagectomy between January 1998 and December 2000. Post-operative management was identical in both groups. RESULTS: no significant differences were seen between the two groups with regard to baseline characteristics and oncological parameters including resection margin (R0 82 vs. 74%, p = 0.334) and 5-year survival. Operation time did not differ significantly between the groups. (300 vs. 280 min, p = 0.110). Median hospital stay and intensive care unit stay were significantly shorter in the laparoscopic group (13 vs. 16 days, p = 0.001 and 1 vs. 3 days, p = 0.000 respectively). CONCLUSION: minimally invasive transhiatal esophagectomy is feasible and has the same oncological outcome as open transhiatal esophagectomy. Faster recovery without a significant longer operation time could be the major benefit of the laparoscopic transhiatal approach. To our knowledge, this is the largest comparative study in literature comparing laparoscopic transhiatal with open transhiatal esophagectomy for cancers of distal and GE junction. Randomized trials are needed to further clarify the role of laparoscopic transhiatal approach for esophageal cancer. PMID- 22537369 TI - Chronic hepatitis in man and in dog: a comparative update. AB - Chronic hepatitis is a frequent pathologic condition encountered in both dogs and humans; however, in the latter etiologic factors are usually searched and found that allow targeted therapeutic approaches, whereas in dogs this is less frequent. This review will take into consideration chronic hepatitis in dogs, and discuss differences and similarities between the two species with respect to this disease. PMID- 22537370 TI - Bronchobiliary fistula. PMID- 22537371 TI - Radiation enteritidis diagnosed by wireless capsule endoscopy. PMID- 22537372 TI - Herpetic esophagitis: a case report on an immunocompetent adolescent. AB - Herpetic esophagitis in immunocompetent individuals is a rare entity that should be suspected clinically by an acute onset of symptoms, and without apparent cause of a symptomatic triad consisting on odynophagia, heartburn and fever. Its occurrence may be due to reactivation of a previous infection or less often a primary infection. Herpes simplex type 1 is the most common cause. Upper endoscopy establishes the diagnosis of suspicion of herpetic esophagitis. It also allows to take multiple biopsy samples and viral culture, leading to a definitive diagnosis. The severity of symptoms is related to the degree of oesophageal involvement. In immunocompromised patients treatment is indicated with acyclovir, but the indication in immunocompetent patients is controversial because the process is time, limited with a low probability of complications. We present a case of acute herpetic esophagitis in an immunocompetent host that debuted acutely with severe upper gastrointestinal tract symptoms, associated with an insidious and nonspecific onset of flu-like symptoms. Endoscopic findings showed a severe involvement in the lower third of the oesophageal mucosa. PMID- 22537373 TI - [Patient information. Endoscopy in antiaggregated patients]. PMID- 22537374 TI - Splenic rupture following diagnostic colonoscopy. PMID- 22537375 TI - Relationship between H. pylori and hepatitis A virus infection. PMID- 22537376 TI - The mathematics behind the twin-stoma gastrostomy. PMID- 22537377 TI - Doubts and similarities between Crohn's disease and Henoch-Schonlein purpura. PMID- 22537378 TI - Collagenous sprue with associated features of refractory celiac disease. PMID- 22537379 TI - Contribution of contrast enhanced sonography in the etiological diagnosis of focal splenic lesions. PMID- 22537380 TI - Melatonin effects on Plasmodium life cycle: new avenues for therapeutic approach. AB - Malaria remains a global health problem affecting more than 515 million people all over the world including Malaysia. It is on the rise, even within unknown regions that previous to this were free of malaria. Although malaria eradication programs carried out by vector control programs are still effective, anti malarial drugs are also used extensively for curtailing this disease. But resistance to the use of anti-malarial drugs is also increasing on a daily basis. With an increased understanding of mechanisms that cause growth, differentiation and development of malarial parasites in rodents and humans, new avenues of therapeutic approaches for controlling the growth, synchronization and development of malarial parasites are essential. Within this context, the recent discoveries related to IP3 interconnected signalling pathways, the release of Ca2+ from intracellular stores of Plasmodium, ubiquitin protease systems as a signalling pathway, and melatonin influencing the growth and differentiation of malarial parasites by its effects on these signalling pathways have opened new therapeutic avenues for arresting the growth and differentiation of malarial parasites. Indeed, the use of melatonin antagonist, luzindole, has inhibited the melatonin's effect on these signalling pathways and thereby has effectively reduced the growth and differentiation of malarial parasites. As Plasmodium has effective sensors which detect the nocturnal plasma melatonin concentrations, suppression of plasma melatonin levels with the use of bright light during the night or by anti-melatonergic drugs and by using anti-kinase drugs will help in eradicating malaria on a global level. A number of patients have been admitted with regards to the control and management of malarial growth. Patents related to the discovery of serpentine receptors on Plasmodium, essential for modulating intra parasitic melatonin levels, procedures for effective delivery of bright light to suppress plasma melatonin levels and thereby arresting the growth and elimination of malarial parasites from the blood of the host are all cited in the paper. The purpose of the paper is to highlight the importance of melatonin acting as a cue for Plasmodium faciparum growth and to discuss the ways of curbing the effects of melatonin on Plasmodium growth and for arresting its life cycle, as a method of eliminating the parasite from the host. PMID- 22537381 TI - Position on donors and smallpox vaccine: a committee opinion. AB - Although there is presently no definitive evidence linking vaccinia virus transmission through reproductive cells, SART/ASRM accordingly recommends that ART practitioners consider deferring donors who have recently received smallpox vaccine or contracted symptomatic vaccinia virus infection through close contact with a vaccine recipient (until after the vaccine or infectious scab has spontaneously separated). Good donor practice further suggests that donors who are not in good health, including those with recent complications from smallpox vaccine, should be similarly deferred. (This document was reviewed by the ASRM Practice Committee in 2011). PMID- 22537382 TI - Fertility treatment when the prognosis is very poor or futile: a committee opinion. AB - The Ethics Committee recommends development of evidence-based policies that are patient-centered for each in vitro fertilization (IVF) center. In most cases, the provision of futile therapies is not ethically justifiable. For those treatments with very poor success rates, clinicians must be vigilant in their presentation of risks, benefits, and alternatives. This document was reviewed in January 2012. This version replaces the previous version of this document, published in 2009. PMID- 22537383 TI - Recommendations for development of an emergency plan for in vitro fertilization programs: a committee opinion. AB - All in vitro fertilization (IVF) programs and clinics should have a plan to protect fresh and cryopreserved human tissue (embryos, oocytes, sperm) and to provide for continuation of patient care in the event of an emergency or natural disaster. This document was reviewed and affirmed by the Practice Committee in 2011. PMID- 22537384 TI - Adverse perinatal outcome and in vitro fertilization singleton pregnancies: what lies beneath? Further evidence to support an underlying role of the modifiable hormonal milieu in in vitro fertilization stimulation. PMID- 22537385 TI - Screening for partial AZFa microdeletions in the Y chromosome of infertile men: is it of clinical relevance? AB - OBJECTIVE: To evaluate the frequency of complete and partial AZFa Y-chromosome microdeletions among infertile Israeli men. To review the published frequencies and histologic findings of AZFa deletions. DESIGN: Retrospective study. SETTING: Academic medical center. PATIENT(S): A total of 1,260 infertile Israeli men. Literature review (2000-2010) of reports on men with AZFa deletions and their testicular findings. INTERVENTION(S): The DNA of 1,260 infertile men was evaluated for AZF microdeletions. The DNA of 657 of them with undetected microdeletions was analyzed for partial AZFa deletion in the USP9Y and DDX3Y genes using sequence-tagged sites beyond EAA/EMQN recommendations. MAIN OUTCOME MEASURE(S): The frequency of complete and partial AZFa microdeletions. Availability of sperm cells for intracytoplasmic sperm injection in men with complete/partial microdeletions. RESULT(S): Two men had complete AZFa deletion (a frequency of 0.28% among nonobstructive azoospermic men). None had partial AZFa deletions. CONCLUSION(S): The likelihood of finding sperm cells in men with complete AZFa deletions is negligible. Complete AZFa deletion is rare and usually associated with azoospermia and absence of sperm cells in testicular tissue. The low frequency of partial AZFa deletions and the inconsistent prospects for spermatogenesis reported in the literature question the need for routine assessment of microdeletions in genes, such as USP9Y or DDX3Y. PMID- 22537386 TI - UBXN7 docks on neddylated cullin complexes using its UIM motif and causes HIF1alpha accumulation. AB - BACKGROUND: The proteins from the UBA-UBX family interact with ubiquitylated proteins via their UBA domain and with p97 via their UBX domain, thereby acting as substrate-binding adaptors for the p97 ATPase. In particular, human UBXN7 (also known as UBXD7) mediates p97 interaction with the transcription factor HIF1alpha that is actively ubiquitylated in normoxic cells by a CUL2-based E3 ligase, CRL2. Mass spectrometry analysis of UBA-UBX protein immunoprecipitates showed that they interact with a multitude of E3 ubiquitin-ligases. Conspicuously, UBXN7 was most proficient in interacting with cullin-RING ligase subunits. We therefore set out to determine whether UBXN7 interaction with cullins was direct or mediated by its ubiquitylated targets bound to the UBA domain. RESULTS: We show that UBXN7 interaction with cullins is independent of ubiquitin- and substrate-binding. Instead, it relies on the UIM motif in UBXN7 that directly engages the NEDD8 modification on cullins. To understand the functional consequences of UBXN7 interaction with neddylated cullins, we focused on HIF1alpha, a CUL2 substrate that uses UBXD7/p97 as a ubiquitin-receptor on its way to proteasome-mediated degradation. We find that UBXN7 over-expression converts CUL2 to its neddylated form and causes the accumulation of non ubiquitylated HIF1alpha. Both of these effects are strictly UIM-dependent and occur only when UBXN7 contains an intact UIM motif. We also show that HIF1alpha carrying long ubiquitin-chains can recruit alternative ubiquitin-receptors, lacking p97's ATP-dependent segregase activity. CONCLUSIONS: Our study shows that independently of its function as a ubiquitin-binding adaptor for p97, UBXN7 directly interacts with neddylated cullins and causes the accumulation of the CUL2 substrate HIF1alpha. We propose that by sequestering CUL2 in its neddylated form, UBXN7 negatively regulates the ubiquitin-ligase activity of CRL2 and this might prevent recruitment of ubiquitin-receptors other than p97 to nuclear HIF1alpha. PMID- 22537387 TI - The powerful pre-treatment effect: placebo responses in restless legs syndrome trials. AB - OBJECTIVE: To investigate whether dopaminergic pre-treatment alters placebo and dopamine agonist responses in restless legs syndrome (RLS). METHODS: Two large, multi-centre trials (SP790 and SP792; registration numbers NCT00136045 and NCT00135993) on the efficacy of rotigotine in RLS reported supplemental International RLS (IRLS) sum score data for pre-treated and drug-naive patients, allowing for the estimation of the regression slope of the clinical response (change in the IRLS sum score) on baseline IRLS sum score. RESULTS: In both trials, patients pre-treated with dopaminergic medications tended to have blunted responses after placebo administration compared with drug-naive patients. In the SP790 study, the pre-treated group had a negative slope (i.e. the response observed after placebo administration decreased as the baseline IRLS sum score increased), whereas the slope was positive in drug-naive patients (slope, -0.43 vs. 0.28; P = 0.027). In the SP792 study, the two slopes were parallel (P = 0.84), but the magnitude of the response after placebo administration was smaller in the pre-treated group (6.31 vs. 10.49; P = 0.0089). Pre-treatment had no significant effect on rotigotine-group responses in either of the two studies. CONCLUSIONS: In RLS trials, dopaminergic pre-treatment tends to increase the apparent effect of new dopaminergic drugs by decreasing the placebo effect in the placebo arm without substantially modifying the placebo effect in the active treatment arm. This observation highlights that placebo-controlled trials are not necessarily placebo-effect controlled trials. PMID- 22537389 TI - Perceived challenges to public health in Central and Eastern Europe: a qualitative analysis. AB - BACKGROUND: There is a major gradient in burden of disease between Central and Eastern Europe compared to Western Europe. Many of the underlying causes and risk factors are amenable to public health interventions. The purpose of the study was to explore perceptions of public health experts from Central and Eastern European countries on public health challenges in their countries. METHODS: We invited 179 public health experts from Central and Eastern European countries to a 2-day workshop in Berlin, Germany. A total of 25 public health experts from 14 countries participated in May 2008. The workshop was structured into 8 sessions of 1.5 hours each, with the topic areas covering coronary heart disease, stroke, prevention, obesity, alcohol, tobacco, tuberculosis, and HIV/AIDS. The workshop was recorded and the proceedings transcribed verbatim. The transcripts were entered into atlas.ti for content analysis and coded according to the session headings. After analysis of the content of each session discussion, a re-coding of the discussions took place based on the themes that emerged from the analysis. RESULTS: Themes discussed recurred across disease entities and sessions. Major themes were the relationship between clinical medicine and public health, the need for public health funding, and the problems of proving the effectiveness of disease prevention. Areas for action identified included the need to engage with the public, to create a better scientific basis for public health interventions, to identify "best practices" of disease prevention, and to implement registries/surveillance instruments. The need for improved data collection was seen throughout all areas discussed, as was the need to harmonize data across countries. CONCLUSIONS: To reduce the burden of disease across Europe, closer collaboration of countries across Europe seems important in order to learn from each other. A more credible scientific basis for effective public health interventions is urgently needed. The monitoring of health trends is crucial to evaluate the impact of public health programmes. PMID- 22537390 TI - Effect of mother/infant skin-to-skin contact on postpartum depressive symptoms and maternal physiological stress. AB - OBJECTIVE: To investigate the effect of mother/infant skin-to-skin contact (SSC) on mothers' postpartum depressive symptoms during the first 3 postpartum months and their physiological stress during the first postpartum month. DESIGN: Longitudinal quasi-experiment. SETTING: Data were collected during home visits. PARTICIPANTS: Mothers in the SSC group (n = 30) provided approximately 5 hours per day of SSC with their infants in the infants' first week and then more than 2 hours per day until the infants were age one month. Mothers in the control group (n = 60) provided little or no SSC. All mothers had full-term infants. METHODS: Mothers completed self-report depression scales when infants were 1 week, 1 month, 2 months, and 3 months of age. RESULTS: Compared to mothers in the control group, mothers in the SSC group had lower scores on the depression scales when the infants were one week and marginally lower scores when the infants were one month; when the infants were age 2 and 3 months, there were no differences between groups in the mothers' depression scores. Over their infants' first month, mothers in the SSC group had a greater reduction in their salivary cortisol than mothers in the control group. CONCLUSION: Mother/infant SSC benefits mothers by reducing their depressive symptoms and physiological stress in the postpartum period. PMID- 22537392 TI - Children's use of dental services: influence of maternal dental anxiety, attendance pattern, and perception of children's quality of life. AB - OBJECTIVES: The purpose of the study was to investigate the influence of a child's clinical condition; maternal characteristics such as dental anxiety and dental visit pattern; socioeconomic conditions; and maternal perception of the child's oral health-related quality of life (OHRQoL) on a child's use of dental care services. METHODS: A cross-sectional study of 608 mother-child dyads was conducted during the Children's Immunization Campaign in Pelotas, Brazil. Mothers answered a questionnaire regarding their use of dental services, dental anxiety (Dental Anxiety Scale), socioeconomic status, and perception of their children's OHRQoL (the Early Childhood Oral Health Impact Scale). Clinical examination of the children was performed to assess dental caries (dmf-t). Associations between the above-mentioned factors and child use of dental services were assessed using Poisson regression models (prevalence ratio [PR]; 95% CI; P <= 0.05). RESULTS: The majority of children (79.3%) had never had a dental appointment and of the children who had visited a dentist, 55 (43.65%) presented with untreated dental caries at the time of examination. More than half the mothers (60.2%) did not visit a dentist regularly. In the final model, low schooling level of mothers (PR, 0.64) and irregular visits to a dentist by the mother (PR, 0.48) were factors because of which a child did not have a dental appointment. Children who had experienced pain (PR, 1.56), those who had poor OHRQoL (PR, 1.49), and older children (PR, 2.14) visited a dentist with higher frequency. CONCLUSIONS: Use of dental care services by preschool children was low, and treatment was neglected even among children who had visited a dentist. Children of mothers with low schooling level who do not visit a dentist regularly were at greater risk of not receiving dental care. Maternal perception of their child's oral health motivated visits to the dentist. PMID- 22537388 TI - The microbial diversity of a storm cloud as assessed by hailstones. AB - Being an extreme environment, the atmosphere may act as a selective barrier for bacterial dispersal, where only most robust organisms survive. By remaining viable during atmospheric transport, these cells affect the patterns of microbial distribution and modify the chemical composition of the atmosphere. The species evenness and richness, and the community composition of a storm cloud were studied applying cultivation-dependent and cultivation-independent techniques to a collection of hailstones. In toto 231 OTUs were identified, and the total species richness was estimated to be about 1800 OTUs. The diversity indices - species richness and evenness - suggest a functionally stable community, capable of resisting environmental stress. A broad substrate spectrum of the isolates with epiphytic origin (genus Methylobacterium) implied opportunistic ecologic strategy with high growth rates and fast growth responses. These may grow in situ despite their short residence times in cloud droplets. In addition, epiphytic isolates utilized many atmospheric organic compounds, including a variety of carboxylic acids. In summary, the highly diverse bacterial community, within which the opportunistic bacteria may be particularly important in terms of atmospheric chemistry, is likely to remain functional under stressful conditions. Overall our study adds important details to the growing evidence of active microbial life in clouds. PMID- 22537391 TI - Spinal cord regeneration in Xenopus tadpoles proceeds through activation of Sox2 positive cells. AB - BACKGROUND: In contrast to mammals, amphibians, such as adult urodeles (for example, newts) and anuran larvae (for example, Xenopus) can regenerate their spinal cord after injury. However, the cellular and molecular mechanisms involved in this process are still poorly understood. RESULTS: Here, we report that tail amputation results in a global increase of Sox2 levels and proliferation of Sox2(+) cells. Overexpression of a dominant negative form of Sox2 diminished proliferation of spinal cord resident cells affecting tail regeneration after amputation, suggesting that spinal cord regeneration is crucial for the whole process. After spinal cord transection, Sox2(+) cells are found in the ablation gap forming aggregates. Furthermore, Sox2 levels correlated with regenerative capabilities during metamorphosis, observing a decrease in Sox2 levels at non regenerative stages. CONCLUSIONS: Sox2(+) cells contribute to the regeneration of spinal cord after tail amputation and transection. Sox2 levels decreases during metamorphosis concomitantly with the lost of regenerative capabilities. Our results lead to a working hypothesis in which spinal cord damage activates proliferation and/or migration of Sox2(+) cells, thus allowing regeneration of the spinal cord after tail amputation or reconstitution of the ependymal epithelium after spinal cord transection. PMID- 22537393 TI - A minimally invasive system for glucose area under the curve measurement using interstitial fluid extraction technology: evaluation of the accuracy and usefulness with oral glucose tolerance tests in subjects with and without diabetes. AB - BACKGROUND: Recent studies have highlighted the importance of managing postprandial hyperglycemia, but adequate monitoring of postprandial glucose remains difficult because of wide variations in levels. We have therefore developed a minimally invasive system to monitor postprandial glucose area under the curve (AUC). This system involves no blood sampling and uses interstitial fluid glucose (IG) AUC (IG-AUC) as a surrogate marker of postprandial glucose. This study aimed to evaluate the usefulness of this system by comparing data with the findings of oral glucose tolerance tests (OGTTs) in subjects with and without diabetes. SUBJECTS AND METHODS: The glucose AUC monitoring system was validated by OGTTs in 37 subjects with and 10 subjects without diabetes. A plastic microneedle array was stamped on the forearm to extract IG. A hydrogel patch was then placed on the pretreated area to accumulate IG. Glucose and sodium ion concentrations in the hydrogel were measured to calculate IG-AUC at 2-h postload glucose. Plasma glucose (PG) levels were measured every 30 min to calculate reference PG-AUC. RESULTS: IG-AUC correlated strongly with reference PG-AUC (r=0.93) over a wide range. The level of correlation between IG-AUC and maximum PG level was also high (r=0.86). The painless nature of the technique was confirmed by the response of patients to questionnaires. CONCLUSIONS: The glucose AUC monitoring system using IG provided good estimates of reference PG-AUC and maximum PG level during OGTTs in subjects with and without diabetes. This system provides easy-to-use monitoring of glucose AUC, which is a good indicator of postprandial glucose. PMID- 22537394 TI - Will a peripheral blood (PB) sample yield the same diagnostic and prognostic cytogenetic data as the concomitant bone marrow (BM) in myelodysplasia? AB - In patients with myelodysplastic syndromes (MDS), chromosome anomalies are detected by conventional cytogenetic studies (CCS) and/or interphase fluorescence in situ hybridization (FISH) of bone marrow (BM) samples and provide prognostic and diagnostic information, which can direct therapy. Whether peripheral blood (PB) can be substituted for bone marrow in these cases and can provide the same information remains unknown. Concurrent BM and PB specimens collected from 100 patients with recently diagnosed MDS were studied using both CCS and FISH. While 68% of BM samples showed an abnormal karyotype by CCS, only 31% of PB samples were abnormal by CCS. In 12% of patients, FISH and CCS were discordant due to the inability of the FISH panel to detect all possible abnormalities. However, only one case (1%) had a cryptic abnormality detected by FISH. BM and PB FISH were discordant in 3% of cases, most likely due to the smaller clone size in PB vs. BM. While PB should not be substituted for BM at diagnosis, it is a viable alternative for monitoring patients using the appropriate FISH probe(s). PMID- 22537395 TI - Subclinical myocardial dysfunction in patients with reverse-remodeled dilated cardiomyopathy. AB - BACKGROUND: The aim of this study was to test the hypothesis that patients with reverse-remodeled dilated cardiomyopathy (DCM), whose ejection fractions (EFs) were normalized after optimal pharmacologic therapy, had subclinical myocardial dysfunction. METHODS: Thirty-two patients with reverse-remodeled DCM, defined as having an initial EF <= 35%, which then recovered to >=50% after optimal pharmacologic therapy, and 11 normal controls with preserved EFs were retrospectively studied. Averaged peak systolic and early diastolic radial, circumferential, and longitudinal speckle-tracking strain rates were assessed from an 18-segment left ventricular model. Similarly, averaged peak systolic radial, circumferential, and longitudinal speckle-tracking strain was obtained. RESULTS: Peak systolic and early diastolic longitudinal strain rates, peak systolic and early diastolic circumferential strain rates, and peak circumferential and longitudinal strain in patients with reverse-remodeled DCM were significantly lower than those in normal controls, but peak systolic and early diastolic radial strain rates and peak radial strain in patients with reverse-remodeled DCM were similar to those in normal controls. Isometric handgrip stress testing showed a significant decrease in EF from 56 +/- 5% to 51 +/- 5% (P < .001). Of note, the increase of afterload resulting from isometric handgrip stress testing was associated with a decrease in peak systolic circumferential and longitudinal strain rates and peak circumferential strain in patients with reverse-remodeled DCM. CONCLUSIONS: The circumferential and longitudinal myocardial function of patients with reverse-remodeled DCM is lower compared with that of normal controls with preserved EFs. Furthermore, the increase in afterload was associated with the decrease in circumferential and longitudinal myocardial systolic function. These findings suggest that in treated patients with DCM with reverse remodeling, left ventricular mechanics may not be normal, even when EFs are normal. PMID- 22537397 TI - What do I need to know about immunoglobulin light chain (AL) amyloidosis? AB - Immunoglobulin light chain (AL) amyloidosis is the most common acquired systemic amyloidoses. Its presentation is often insidious and progressive, which may delay diagnosis. The interval between first symptoms and actual diagnosis along the intrinsic heterogeneity of tissue tropism create a wide spectrum of presentations, both in terms of scope and depth of symptoms and signs and functional status of patients. In this review, the authors review the pathogenesis, diagnosis and differential diagnosis of AL amyloidosis along with the prognosis and state-of-the-art management for patients with this affliction. PMID- 22537396 TI - Quantification of mitral valve anatomy by three-dimensional transesophageal echocardiography in mitral valve prolapse predicts surgical anatomy and the complexity of mitral valve repair. AB - BACKGROUND: Three-dimensional (3D) transesophageal echocardiography (TEE) is more accurate than two-dimensional (2D) TEE in the qualitative assessment of mitral valve (MV) prolapse (MVP). However, the accuracy of 3D TEE in quantifying MV anatomy is less well studied, and its clinical relevance for MV repair is unknown. METHODS: The number of prolapsed segments, leaflet heights, and annular dimensions were assessed using 2D and 3D TEE and compared with surgical measurements in 50 patients (mean age, 61 +/- 11 years) who underwent MV repair for mainly advanced MVP. RESULTS: Three-dimensional TEE was more accurate (92% 100%) than 2D TEE (80%-96%) in identifying prolapsed segments. Three-dimensional TEE and intraoperative measurements of leaflet height did not differ significantly, while 2D TEE significantly overestimated the height of the posterior segment P1 and the anterior segment A2. Three-dimensional TEE quantitative MV measurements were related to surgical technique: patients with more complex MVP (one vs two to four vs five or more prolapsed segments) showed progressive enlargement of annular anteroposterior (31 +/- 5 vs 34 +/- 4 vs 37 +/ 6 mm, respectively, P = .02) and commissural diameters (40 +/- 6 vs 44 +/- 5 vs 50 +/- 10 mm, respectively, P = .04) and needed increasingly complex MV repair with larger annuloplasty bands (60 +/- 13 vs 67 +/- 9 vs 72 +/- 10 mm, P = .02) and more neochordae (7 +/- 3 vs 12 +/- 5 vs 26 +/- 6, P < .01). CONCLUSIONS: Measurements of MV anatomy on 3D TEE are accurate compared with surgical measurements. Quantitative MV characteristics, as assessed by 3D TEE, determined the complexity of MV repair. PMID- 22537398 TI - Whole genomes in the clinic: uncovering de novo mutations in sporadic infantile epilepsy. PMID- 22537399 TI - Gasification of pelletized biomass in a pilot scale downdraft gasifier. AB - This work presents a pilot-scale investigation aimed at assessing the feasibility and reliability of biomass pellet gasification. Wood sawdust and sunflower seeds pellets were tested in a 200 kW downdraft gasifier operating with air as gasifying agent. The gasification of pelletized biomass led to rather high and unstable pressure drops, reducing the gasifier productivity and stability. Furthermore the generation of fine residues compromised the operation of wet ash removal systems. On the other hand, good syngas compositions (H(2) 17.2%, N(2) 46.0%, CH(4) 2.5%, CO 21.2%, CO(2) 12.6%, and C(2)H(4) 0.4%), specific gas production (2.2-2.4 N m(3) kg(-1)) and cold gas efficiency (67.7-70.0%) were achieved. For these reasons pelletized biomass should be considered only as complementary fuel in co-gasification with other feedstock. PMID- 22537400 TI - Chemical and enzymatic sequential pretreatment of oat straw for methane production. AB - Oat straw was subjected to sequential pretreatment: acid/alkaline/enzymatic, to convert the lignocellulosic material in soluble sugars. The hydrolysates from acid pretreatment (2% HCl, 90 degrees C) and enzymatic pretreatment (cellulase, pH 4.5, 45 degrees C) were used as substrates in two lab-scale UASB reactors for methane production. The acid and enzymatic hydrolysates contained 25.6 and 35.3g/L of total sugars, respectively, which corresponded to a COD of 23.6 and 30.5 g/L, respectively. The UASB reactor fed with acid hydrolysate achieved a maximum methane yield of 0.34 L CH(4)/g COD at an organic loading rate (OLR) of 2.5 g COD/L-d. In the reactor fed with enzymatic hydrolysate the methane yield was 0.36 LCH(4)/g COD at OLR higher than 8.8 g COD/L-d. The anaerobic digestion of both hydrolysates was feasible without the need of a detoxification step. The sequential pretreatment of oat straw allowed to solubilize 96.8% of hemicellulose, 77.2% of cellulose and 42.2% of lignin. PMID- 22537401 TI - Optimization of struvite crystallization protocol for pretreating the swine wastewater and its impact on subsequent anaerobic biodegradation of pollutants. AB - Higher contents of NH(4)(+) and SS in wastewater hamper the anaerobic digestion; necessitating its pretreatment to reduce them. This study reveals optimization of struvite/MAP precipitation protocol followed by anaerobic digestion of pretreated swine wastewater for pollutants removal. Levels of different treatments: stirring speeds, 400 and 160 rpm; pH values, 9.0, 9.5, 10.0, 10.5, 11.0 and 11.5; and P:Mg:N ratios, 1:1:1.2, 1:1:1.7, 1:1:2.2, 1:1:2.7, 1:1:4.0 and 1:1:5.0 were evaluated for MAP crystallization. Among various combinations, protocol comprising of initial 10 min stirring at 400 rpm followed by 160 rpm for 30 min, pH 10.0, and P:Mg:N ratio 1:1:1.2 rendered the best removal efficiency for NH(4)(+), PO(4)(3-), COD, TC and TOC. Subsequent anaerobic biodegradation revealed superiority of MAP supernatant over raw swine wastewater for methane yield and NH(4)(+)-N, PO(4)(3-)-P, COD, TC and TOC removals. It suggests that struvite precipitation as pretreatment to anaerobic digestion is highly effective and advantageous in wastewater treatment. PMID- 22537402 TI - Pilot-scale ethanol production from rice straw hydrolysates using xylose fermenting Pichia stipitis. AB - Ethanol was produced at pilot scale from rice straw hydrolysates using a Pichia stipitis strain previously adapted to NaOH-neutralized hydrolysates. The highest ethanol yield was 0.44 +/- 0.02 g(p)/g(s) at an aeration rate of 0.05 vvm using overliming-detoxified hydrolysates. The yield with hydrolysates conditioned by ammonia and NaOH was 0.39 +/- 0.01 and 0.34 +/- 0.01 g(p)/g(s), respectively, were achieved at the same aeration rate. The actual ethanol yield from hydrolysate fermentation with ammonia neutralization was similar to that with overliming hydrolysate after taking into account the xylose loss resulting from these conditioning processes. Moreover, the ethanol yield from ammonia neutralized hydrolysates could be further enhanced by increasing the initial cell density by two-fold or reducing the combined concentration of furfural and 5 hydroxymethyl furfural to 0.6g/L by reducing the severity of operational conditions in pretreatment. This study demonstrated the potential for commercial ethanol production from rice straw via xylose fermentation. PMID- 22537403 TI - Fate of tetracycline, sulfonamide and fluoroquinolone resistance genes and the changes in bacterial diversity during composting of swine manure. AB - This study monitored the abundance of antibiotic resistant genes (ARGs) and the bacterial diversity during composting of swine manure spiked with chlortetracycline, sulfadiazine and ciprofloxacin at two different levels and a control without antibiotics. Resistance genes of tetracycline (tetQ, tetW, tetC, tetG, tetZ and tetY), sulfonamide (sul1, sul2, dfrA1 and dfrA7) and fluoroquinolone (gyrA and parC) represented 0.02-1.91%, 0.67-10.28% and 0.00005 0.0002%, respectively, of the total 16S rDNA copies in the initial composting mass. After 28-42 days of composting, these ARGs, except parC, were undetectable in the composting mass indicating that composting is a potential method of manure management. Polymerase chain reaction-denaturing gradient gel electrophoresis analysis of bacterial 16S rDNA of the composting mass indicated that the addition of antibiotics up to 100, 20 and 20mg/kg of chlortetracycline, sulfadiazine and ciprofloxacin, respectively, elicited only a transient perturbation and the bacterial diversity was restored in due course of composting. PMID- 22537404 TI - Recombinant hepatitis B virus surface antigen formulated with B-type CpG oligodeoxynucleotide induces therapeutic immunity against hepatitis B virus surface antigen-expressing liver cancer cells in mice. AB - To develop a therapeutic vaccine against hepatitis B virus surface antigen (HBsAg)-expressing liver cancer, we tried to prepare a vaccine by formulating recombinant HBsAg with BW006, a B type CpG oligodeoxynucleotide (ODN) with Th1 biasing activity, and examined its potency of inducing therapeutic immunity against HBsAg-expressing liver cancer cells in mice. When applied therapeutically, BW006 could assist HBsAg to induce vigorous immune responses capable of inhibiting the growth of HBsAg-expressing liver cancer cells and prolonging the survival of mice bearing HBsAg-expressing liver cancer cells. In vivo and in vitro experiments showed that the BW006-adjuvanted HBsAg enhanced the production of IgG2a antibodies, interferon-gamma, and interleukin-12 and facilitated the generation of specific cytotoxic T lymphocyte that killed the HBsAg-expressing liver cancer cells. These results suggest that the BW006 adjuvanted HBsAg might be developed into a candidate tumor vaccine for the treatment of HBsAg-expressing liver cancer. PMID- 22537405 TI - Serum response factor modulates neuron survival during peripheral axon injury. AB - BACKGROUND: The transcription factor SRF (serum response factor) mediates neuronal survival in vitro. However, data available so far suggest that SRF is largely dispensable for neuron survival during physiological brain function. FINDINGS: Here, we demonstrate that upon neuronal injury, that is facial nerve transection, constitutively-active SRF-VP16 enhances motorneuron survival. SRF VP16 suppressed active caspase 3 abundance in vitro and enhanced neuron survival upon camptothecin induced apoptosis. Following nerve fiber injury in vitro, SRF VP16 improved survival of neurons and re-growth of severed neurites. Further, SRF VP16 enhanced immune responses (that is microglia and T cell activation) associated with neuronal injury in vivo. Genome-wide transcriptomics identified target genes associated with axonal injury and modulated by SRF-VP16. CONCLUSION: In sum, this is a first report describing a neuronal injury-related survival function for SRF. PMID- 22537406 TI - Structures of xyloglucans in primary cell walls of gymnosperms, monilophytes (ferns sensu lato) and lycophytes. AB - Little is known about the structures of the xyloglucans in the primary cell walls of vascular plants (tracheophytes) other than angiosperms. Xyloglucan structures were examined in 13 species of gymnosperms, 13 species of monilophytes (ferns sensu lato), and two species of lycophytes. Wall preparations were obtained, extracted with 6 M sodium hydroxide, and the extracts treated with a xyloglucan specific endo-(1->4)-beta-glucanase preparation. The oligosaccharides released were analysed by matrix-assisted laser-desorption ionisation time-of-flight mass spectrometry and by high-performance anion-exchange chromatography. The xyloglucan oligosaccharide profiles from the gymnosperm walls were similar to those from the walls of most eudicotyledons and non-commelinid monocotyledons, indicating that the xyloglucans were fucogalactoxyloglucans, containing the fucosylated units XXFG and XLFG. The xyloglucan oligosaccharide profiles for six of the monilophyte species were similar to those of the gymnosperms, indicating they were also fucogalactoxyloglucans. Phylogenetically, these monilophyte species were from both basal and more derived orders. However, the profiles for the other monilophyte species showed various significant differences, including additional oligosaccharides. In three of the species, these additional oligosaccharides contained arabinosyl residues which were most abundant in the profile of Equisetum hyemale. The two species of lycophytes examined, Selaginella kraussiana and Lycopodium cernuum, had quite different xyloglucan oligosaccharide profiles, but neither were fucogalactoxyloglucans. The S. kraussiana profile had abundant oligosaccharides containing arabinosyl residues. The L. cernuum profile indicated the xyloglucan had a very complex structure. PMID- 22537407 TI - Potential of calcium to scaffold an endodontic biofilm, thus protecting the micro organisms from disinfection. AB - Biofilms in the root canal of a tooth (endodontic biofilm) can induce and sustain apical periodontitis which is an oral inflammatory disease. Still, little is known about the composition of the endodontic biofilm. Studies on biofilms in root canals focus on the identification of the microbial species, but the majority of the biofilm consists of matrix material. Environmental aspects determine the structure of the biofilm and extracellular matrix. Calcium is involved in biofilm formation and activity at three levels. Firstly in cell environment; calcium may 'condition' the surfaces of support and bacterial cells. Secondly, in cell-cell interaction; calcium plays a role in build up of biofilm structures. Typically, calcium ions act as 'cation bridges' between polysaccharides originating from different cells. Thirdly, within cells, calcium is required for certain biochemical reactions in bacteria and some bacterial physiological activities. Because calcium is present in the root canal, it could play a significant role in the organization of the biofilm. Chelators, already used in endodontics to remove the smear layer by disintegration of the structural cohesion calcium bonds, could weaken the biofilm matrix by removing calcium from the extracellular matrix thus disturbing its coherence. Subsequently, this disruption could increase the efficacy of disinfecting agents. PMID- 22537408 TI - Vascularized the greater trochanter grafting treatment cysts of the femoral neck. AB - Bone cyst is a common benign bone tumor lesion, it is characterized by a clear boundary appearing round or oval osteolytic area, cortical bone thinning, and sometimes it can be visible sclerotic margin. Limb long bone cysts occur more common shares, the current jaw bone cysts are also relatively common, and most patients are asymptomatic. Femoral neck bone cyst can lead to pain and pathologic fractures, which is one of the main reasons why patients are in treatment. Due to the lesion site and patients age specificity of femoral proximal bone cysts especially femoral neck bone cysts in young adults, treatment is necessary to completely remove the lesion to prevent cyst recurrence, but also as far as possible to restore function in patients with hip joint. PMID- 22537409 TI - The cardiorenal link in advanced cirrhosis. AB - A considerable number of patients with advanced cirrhosis develop a hepatorenal syndrome. The pathogenesis involves liver dysfunction, splanchnic vasodilatation, and activation of vasoconstrictive systems. There are now several observations that indicate a relation between the renal failure and impaired cardiac function in patients with advanced cirrhosis. Cirrhotic cardiomyopathy has been described as a condition with impaired contractile responsiveness to stress and altered diastolic relaxation. We propose a cardiorenal interaction in patients with advanced cirrhosis and renal dysfunction that refers to a condition where cardiac dysfunction in cirrhosis is a major determinant of kidney function and survival. Thus, the relation between cardiac dysfunction and renal insufficiency should be target for future studies and development of new treatments should focus on ameliorating the cardiac dysfunction. PMID- 22537410 TI - A muscle spindle abnormity in one laryngeal muscle would be sufficient to cause stuttering. AB - Muscle spindles are increasingly recognized as playing a pivotal role in the cause of dystonia. This development and own laryngeal observations that support the idea of causally "well-intentioned" stuttering motivated us to present the following hypothesis: stuttering events compensate for a sensory problem that arises when the abductor/adductor ratio of afferent impulse rates from the posterior cricoarytenoid and lateral cricoarytenoid muscle spindles is abnormally reduced and processed for the occasional determination of the vocal fold position. This hypothesis implies that functional and structural brain abnormalities might be interpreted as secondary compensatory reactions. Verification of this hypothesis (using technologies such as microneurography, dissection and muscle afferent block) is important because its confirmation could relink dystonia and stuttering research, change the direction of stuttering therapy and destigmatize stuttering radically. PMID- 22537411 TI - Health care provider challenges for reaching Hispanic immigrants with HPV vaccination in rural Georgia. AB - INTRODUCTION: The objective of this pilot study was to understand, from the Vaccines for Children (VFC) program provider's perspective, issues relating to vaccine access and compliance for Hispanic adolescents in a rural setting. RESULTS: Researchers conducted individual structured interviews with VFC providers and focus groups with Hispanic immigrant parents in rural southern Georgia. RESULTS: Overall, the VFC providers said that their Hispanic patients were very positive toward vaccines in general, but there were cost issues related to stocking the vaccine and reaching the Hispanic population. The focus group discussions revealed that most Hispanic parents were not aware of the existence of the human papilloma virus (HPV) vaccine, nor had they heard about the VFC program. CONCLUSION: Numerous vaccination barriers continue to impact HPV vaccine uptake in the Hispanic immigrant population in the US South. PMID- 22537413 TI - Genetic diversity of symbiotic cyanobacteria in Cycas revoluta (Cycadaceae). AB - The diversity of cyanobacterial species within the coralloid roots of an individual and populations of Cycas revoluta was investigated based on 16S rRNA gene sequences. Sixty-six coralloid roots were collected from nine natural populations of cycads on Kyushu and the Ryukyu Islands, covering the entire distribution range of the species. Approximately 400 bp of the 5'-end of 16S rRNA genes was amplified, and each was identified by denaturing gradient gel electrophoresis. Most coralloid roots harbored only one cyanobiont, Nostoc, whereas some contained two or three, representing cyanobiont diversity within a single coralloid root isolated from a natural habitat. Genotypes of Nostoc within a natural population were occasionally highly diverged and lacked DNA sequence similarity, implying genetic divergence of Nostoc. On the other hand, Nostoc genotypes showed no phylogeographic structure across the distribution range, while host cycads exhibited distinct north-south differentiation. Cycads may exist in symbiosis with either single or multiple Nostoc strains in natural soil habitats. PMID- 22537412 TI - Trauma and amyotrophic lateral sclerosis: a case-control study from a population based registry. AB - BACKGROUND AND PURPOSE: Published reports on the association between amyotrophic lateral sclerosis (ALS) and trauma are controversial suggesting the need for a new case-control study done in a large population. METHODS: A case-control study was undertaken in Italy to assess this association. Cases were patients with newly diagnosed ALS from four population-based registries. For each case, two hospital controls were selected, matched for age, sex, and province of residence, one with a neurological (non-degenerative) disease and one with a non neurological disease (other than orthopedic or surgical). Traumatic events (defined as accidental events causing injuries requiring medical care) were recorded with details on type, site, timing, severity, and complications. The risks were assessed as odds ratios (ORs) with 95% confidence intervals (CI), crude and adjusted for age, sex, education, interviewee (patient or surrogate), physical activity, smoking, alcohol, and coffee. RESULTS: The study population comprised 377 patients in each of the three groups. One or more traumatic events were reported by 225 cases (59.7%), 191 neurological controls (50.7%), and 179 non-neurological controls (47.5%) (P < 0.01) (OR 1.63; 95% CI 1.25-2.14) (P < 0.01). The ORs were 3.07 (95% CI 1.86-5.05) for patients reporting 3+ traumatic events and 2.44 (95% CI 1.36-4.40) for severe traumatic events. The ORs remained significant when the analysis was limited to events that occurred 5+ and 10+ years before ALS onset, to incident ALS, and direct informant. CONCLUSION: Antecedent trauma, repeated trauma, and severe trauma may be risk factors for ALS. PMID- 22537414 TI - Inhibition of gamma-secretase worsens memory deficits in a genetically congruous mouse model of Danish dementia. AB - BACKGROUND: A mutation in the BRI2/ITM2b gene causes familial Danish dementia (FDD). BRI2 is an inhibitor of amyloid-beta precursor protein (APP) processing, which is genetically linked to Alzheimer's disease (AD) pathogenesis. The FDD mutation leads to a loss of BRI2 protein and to increased APP processing. APP haplodeficiency and inhibition of APP cleavage by beta-secretase rescue synaptic/memory deficits of a genetically congruous mouse model of FDD (FDDKI). beta-cleavage of APP yields the beta-carboxyl-terminal (beta-CTF) and the amino terminal-soluble APPbeta (sAPPbeta) fragments. gamma-secretase processing of beta CTF generates Abeta, which is considered the main cause of AD. However, inhibiting Abeta production did not rescue the deficits of FDDKI mice, suggesting that sAPPbeta/beta-CTF, and not Abeta, are the toxic species causing memory loss. RESULTS: Here, we have further analyzed the effect of gamma-secretase inhibition. We show that treatment with a gamma-secretase inhibitor (GSI) results in a worsening of the memory deficits of FDDKI mice. This deleterious effect on memory correlates with increased levels of the beta/alpha-CTFs APP fragments in synaptic fractions isolated from hippocampi of FDDKI mice, which is consistent with inhibition of gamma-secretase activity. CONCLUSION: This harmful effect of the GSI is in sharp contrast with a pathogenic role for Abeta, and suggests that the worsening of memory deficits may be due to accumulation of synaptic-toxic beta/alpha-CTFs caused by GSI treatment. However, gamma-secretase cleaves more than 40 proteins; thus, the noxious effect of GSI on memory may be dependent on inhibition of cleavage of one or more of these other gamma-secretase substrates. These two possibilities do not need to be mutually exclusive. Our results are consistent with the outcome of a clinical trial with the GSI Semagacestat, which caused a worsening of cognition, and advise against targeting gamma-secretase in the therapy of AD. Overall, the data also indicate that FDDKI is a valuable mouse model to study AD pathogenesis and predict the clinical outcome of therapeutic agents for AD. PMID- 22537415 TI - Circadian profiles of focal epileptic seizures: a need for reappraisal. AB - Circadian rhythm of seizure is underestimated in the study of focal epilepsies. A review of the current literature revealed a clear correlation between cortical epileptogenic focus and the circadian phase of seizure peak occurrence in adult patients. A single diurnal peak at 19:00 was found in seizures originating from the occipital lobe, between 5:00 and 7:00 in frontal lobe seizures, and between 16:00 and 17:00 h in temporal lobe seizures. Two diurnal peaks, between 5:00 and 7:00, and at 23:00 are reported in seizures from the parietal lobe, and between 7:00 to 8:00 and 16:00 to 17:00 in mesial temporal onset seizures. This circadian character of seizure occurrence in focal epilepsies may not be unique to partial seizures since recent clinical and experimental data indicate that generalized seizures also demonstrate circadian effects. The clinical evidence on generalized seizures and epilepsies is not recent, but a formal integration of circadian rhythmicity in our understanding and clinical management of epilepsies may be warranted. PMID- 22537416 TI - Branchi-oculo-facial syndrome: a case report to highlight recent genetic considerations. AB - Branchio-oculo-facial syndrome (BOFS) is a rare entity described during the last century which has been recently linked to mutations of the gene encoding for the transcription factor named 'TFAPA2'. We report here a sporadic case of BOFS with a partial phenotype caused by a de novo mutation of this gene and discuss recent genetic findings. PMID- 22537417 TI - Re: Surgical tips: areolar tattoo prior to nipple reconstruction. PMID- 22537418 TI - The role of comfort and discomfort in insulin therapy. AB - Despite the recognized importance of optimal insulin therapy, patient adherence to insulin therapy is an ongoing clinical care challenge. Insulin omission continues to be frequent and underestimated and has been correlated with poorer glycemic control and increased rates of diabetes-related complications. Insulin users consistently identify multiple factors that contribute to insulin injection related anxiety and to non-adherence. Injection-related discomfort continues to bear a significant contribution. Over the last decade, with advances in needle manufacturing technology, shorter and narrower needles have been associated with progressively improving patient self-rating of injection discomfort. Consequently, patient surveys of insulin users show discomfort to rank in the bottom third of significant contributors by prevalence. However, healthcare providers (HCP) and family member care providers continue to demonstrate a high level of anticipated and perceived pain for the patient. HCP anxiety and pain anticipation are each associated with patient anxiety and may therefore play a significant contributing role in patient non-adherence. PMID- 22537419 TI - Reproductive outcomes in women with classic bladder exstrophy: an observational cross-sectional study. AB - OBJECTIVE: We sought to examine the reproductive outcomes of 52 women with classical bladder exstrophy. STUDY DESIGN: This was an observational study with cross-sectional and retrospective arms. RESULTS: The average age of the sample was 33 years (range, 17-63). Of those who had tried, 19/38 (66%) had conceived. A total of 57 pregnancies (3 sets of twins) were reported for the 19 patients and resulted in 34/57 live births (56%), 21/57 miscarriages (35%), 1/57 (2%) termination, and 4/57 (7%) stillbirths or neonatal deaths. Four deliveries resulted in major complications including 1 transection of the ureter (4%), 1 fistula formation (4%), and 2 postpartum hemorrhages (8%). There were 2 admissions to intensive care, one for urinary sepsis and another for massive obstetric hemorrhage. CONCLUSION: Fertility is impaired in women with bladder exstrophy. Pregnancy is high risk both for the mother and baby. Delivery should be at a tertiary referral obstetric unit with urology cover. In the majority of cases planned cesarean section is the most appropriate mode of delivery. PMID- 22537420 TI - Temporal alterations in vascular angiotensin receptors and vasomotor responses in offspring of protein-restricted rat dams. AB - OBJECTIVE: Examine temporal alterations in vascular angiotensin II receptors (AT(1)R and AT(2)R) and determine vascular response to angiotensin II in growth restricted offspring. STUDY DESIGN: Offspring of pregnant rats fed low-protein (6%) and control (20%) diet were compared. RESULTS: Prenatal protein restriction reprogrammed AT(1a)R messenger RNA expression in male rats' mesenteric arteries to cause 1.7- and 2.3-fold increases at 3 and 6 months of age associated with arterial pressure increases of 10 and 33 mm Hg, respectively; however, in female rats, increased AT(1a)R expression (2-fold) and arterial pressure (15 mm Hg) occurred only at 6 months. Prenatal protein restriction did not affect AT(2)R expression. Losartan abolished hypertension, suggesting that AT(1a)R plays a primary role in arterial pressure elevation. Vasoconstriction to angiotensin II was exaggerated in all protein-restricted offspring, with greater potency and efficacy in male rats. CONCLUSION: Prenatal protein restriction increased vascular AT(1)R expression and vasoconstriction to angiotensin II, possibly contributing to programmed hypertension. PMID- 22537421 TI - Effect of hemoglobin target on progression of kidney disease: a secondary analysis of the CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) trial. AB - BACKGROUND: Conflicting relationships have been described between anemia correction using erythropoiesis-stimulating agents and progression of chronic kidney disease (CKD). This study was undertaken to examine the impact of target hemoglobin level on progression of kidney disease in the CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) trial. STUDY DESIGN: Secondary analysis of a randomized controlled trial. SETTING & PARTICIPANTS: 1,432 participants with CKD and anemia. INTERVENTION: Participants were randomly assigned to target hemoglobin levels of 13.5 versus 11.3 g/dL with the use of epoetin alfa. OUTCOMES & MEASUREMENTS: Cox regression was used to estimate HRs for progression of CKD (a composite of doubling of creatinine level, initiation of renal replacement therapy, or death). Interactions between hemoglobin target and select baseline variables (estimated glomerular filtration rate, proteinuria, diabetes, heart failure, and smoking history) also were examined. RESULTS: Participants randomly assigned to higher hemoglobin targets experienced shorter time to progression of kidney disease in both univariate (HR, 1.25; 95% CI, 1.03 1.52; P = 0.02) and multivariable models (HR, 1.22; 95% CI, 1.00-1.48; P = 0.05). These differences were attributable to higher rates of renal replacement therapy and death for participants in the high hemoglobin arm. Hemoglobin target did not interact with estimated glomerular filtration rate, proteinuria, diabetes, or heart failure (P > 0.05 for all). In the multivariable model, hemoglobin target interacted with tobacco use (P = 0.04) such that the higher target had a greater risk of CKD progression for participants who currently smoked (HR, 2.50; 95% CI, 1.23-5.09; P = 0.01), which was not present for those who did not currently smoke (HR, 1.15; 95% CI, 0.93-1.41; P = 0.2). LIMITATIONS: A post hoc analysis; thus, cause and effect cannot be determined. CONCLUSIONS: These results suggest that a high hemoglobin target is associated with a greater risk of progression of CKD. This risk may be augmented by concurrent smoking. Further defining the mechanism of injury may provide insight into methods to optimize outcomes in anemia management. PMID- 22537423 TI - Bleeding complications of native kidney biopsy: a systematic review and meta analysis. AB - BACKGROUND: Kidney biopsy provides important information for nephrologists, but the risk of complications has not been systematically described. STUDY DESIGN: Meta-analysis of randomized controlled trials and prospective or retrospective observational studies. SETTING & POPULATION: Adults undergoing native kidney biopsy in an inpatient or outpatient setting. SELECTION CRITERIA FOR STUDIES: MEDLINE indexed studies from January 1980 through June 2011; sample size of 50 or more. INTERVENTION: Native kidney biopsy with automated biopsy device and real time ultrasonographic guidance. OUTCOMES: Macroscopic hematuria and erythrocyte transfusion rates and factors associated with these outcomes. RESULTS: 34 studies of 9,474 biopsies met inclusion criteria. The rate of macroscopic hematuria was 3.5% (95% CI, 2.2%-5.1%), and erythrocyte transfusion was 0.9% (95% CI, 0.4% 1.5%). Significantly higher rates of transfusion were seen with the following: 14 gauge compared with smaller needles (2.1% vs 0.5%; P = 0.009), studies with mean serum creatinine level >=2.0 mg/dL (2.1% vs 0.4%; P = 0.02), >=50% women (1.9% vs 0.6%; P = 0.03), and >=10% of biopsies for acute kidney injury (1.1% vs 0.04%; P < 0.001). Higher transfusion rates also were observed in studies with a mean age of 40 years or older (1.0% vs 0.2%; P = 0.2) and mean systolic blood pressure >=130 mm Hg (1.4% vs 0.1%; P = 0.09). Similar relationships were noted for the macroscopic hematuria rate with the same predictors, but none was statistically significant. LIMITATIONS: Publication bias, few randomized controlled trials, and missing data. CONCLUSIONS: Native kidney biopsy using automated biopsy devices and real-time ultrasonography is associated with a relatively small risk of macroscopic hematuria and erythrocyte transfusion requirement. Using smaller gauge needles may lower complication rates. Patient selection may affect outcome because studies with higher serum creatinine levels, more women, and higher rates of acute kidney injury had higher complication rates. Future studies should further evaluate risk factors for complications. PMID- 22537422 TI - Combined association of albuminuria and cystatin C-based estimated GFR with mortality, coronary heart disease, and heart failure outcomes: the Atherosclerosis Risk in Communities (ARIC) Study. AB - BACKGROUND: Serum cystatin C level has been shown to have a stronger association with clinical outcomes than serum creatinine level. However, little is known about the combined association of cystatin C-based estimated glomerular filtration rate (eGFR(cys)) and albuminuria with clinical outcomes, particularly at levels lower than current chronic kidney disease (CKD) cutoffs. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: 10,403 ARIC (Atherosclerosis Risk in Communities) Study participants followed up for a median of 10.2 years. PREDICTOR: eGFR(cys), albuminuria. OUTCOMES: Mortality, coronary heart disease (CHD), and heart failure, as well as a composite of any of these separate outcomes. RESULTS: Both decreased eGFR(cys) and albuminuria were associated independently with the composite outcome, as well as mortality, CHD, and heart failure. Although eGFR(cys) of 75-89 mL/min/1.73 m(2) in the absence of albuminuria (albumin-creatinine ratio [ACR] <10 mg/g) or albuminuria with ACR of 10-29 mg/g with normal eGFR(cys) (90-104 mL/min/1.73 m(2)) was not associated significantly with any outcome compared with eGFR(cys) of 90-104 mL/min/1.73 m(2) and ACR <10 mg/g, the risk of each outcome was significantly higher in those with both eGFR(cys) of 75-89 mL/min/1.73 m(2) and ACR of 10-29 mg/g (for mortality, HR of 1.4 [95% CI, 1.1-2.0]; for CHD, HR of 1.9 [95% CI, 1.4-2.6]; for heart failure, HR of 1.8 [95% CI, 1.2-2.7]). Combining the 2 markers improved risk classification for all outcomes (P < 0.001), even in those without overt CKD. LIMITATIONS: Only one measurement of cystatin C. CONCLUSIONS: Mildly decreased eGFR(cys) and mild albuminuria independently contributed to the risk of mortality, CHD, and heart failure. Even minimally decreased eGFR(cys) (75-89 mL/min/1.73 m(2)) is associated with increased risk in the presence of mild albuminuria. Combining the 2 markers is useful for improved risk stratification even in those without clinical CKD. PMID- 22537424 TI - A framework for effective collaboration between specialist and broad-spectrum groups for delivering priority Cochrane reviews. AB - OBJECTIVES: We aimed to develop and pilot a process for joint working between Cochrane Review Groups (specialist-area groups responsible for producing Cochrane reviews) and Cochrane Fields (broad-spectrum interest groups), for identifying high priority review topics and enhancing quality and dissemination of priority reviews. STUDY DESIGN AND SETTING: We developed and piloted a framework for collaboration between a Cochrane Review Group (specializing in musculoskeletal injuries) and a Cochrane Field (focusing on health care of older people) for identifying, delivering, and disseminating priority Cochrane intervention reviews using hip fracture rehabilitation as an exemplar. The processes adopted included consultation of members of both the entities, mapping of trials from the Review Group's Specialized Register, jointly establishing criteria for topic prioritization, identification of researchers, and facilitating provision of expert peer review from the field. RESULTS: A framework for effective collaboration between a Cochrane Review Group and Cochrane Field for identifying and delivering priority Cochrane Reviews was devised and piloted. Additionally, two new Cochrane reviews, preceded by protocols, were published. CONCLUSION: The project demonstrated the feasibility and potential benefits of a structured collaboration between a Cochrane Review Group and a Cochrane Field for the identification and production of Cochrane reviews on priority topics. PMID- 22537425 TI - Rebutal of Kahan's critique of rank minimization. PMID- 22537427 TI - Rank minimization with a two-step analysis should not replace randomization in clinical trials. PMID- 22537426 TI - Primary study authors of significant studies are more likely to believe that a strong association exists in a heterogeneous meta-analysis compared with methodologists. AB - OBJECTIVE: To assess the interpretation of a highly heterogeneous meta-analysis by authors of primary studies and by methodologists. STUDY DESIGN AND SETTING: We surveyed the authors of studies on the association between insulin-like growth factor 1 (IGF-1) and prostate cancer, and 20 meta-analysis methodologists. Authors and methodologists presented with the respective meta-analysis results were queried about the effect size and potential causality of the association. We evaluated whether author responses correlated with the number of IGF-related articles they had published and their study results included in the meta analysis. We also compared authors' and methodologists' responses. RESULTS: Authors who had published more IGF-related papers offered more generous effect size estimates for the association (rho(s)=0.61, P=0.01) and higher likelihood that the odds ratio (OR) was greater than 1.20 (rho(s)=0.63, P=0.01). Authors who had published themselves studies with statistically significant effects for a positive association were more likely to believe that the true OR is greater than 1.20 compared with methodologists (median likelihood 50% versus 2.5%, P=0.01). CONCLUSION: Researchers are influenced by their own investment in the field, when interpreting a meta-analysis that includes their own study. Authors who published significant results are more likely to believe that a strong association exists compared with methodologists. PMID- 22537428 TI - Informed consent documents do not encourage good-quality decision making. AB - OBJECTIVE: Informed consent for research has emphasized information provision over support to people making a difficult decision. We assessed the extent to which existing informed consent documents (ICDs) conform to the International Patient Decision Aid Standards for supporting decision making. STUDY DESIGN AND SETTING: One hundred thirty-nine ICDs for trials registered with ClinicalTrials.gov were obtained from study investigators. Using a four-point scale, two raters assessed each ICD on 32 items. RESULTS: Overall agreement between raters was 95.1% (linear weighted kappa-0.745). For 12 items focused on providing enough information, conformity was above 50% for three, and 0% for another four. For all eight items focused on how to present outcome probabilities, conformity was below 20%. For two items focused on clarifying and expressing values, conformity was below 10%. For two items focused on improving structured guidance, conformity was below 5%. For four items focused on using evidence, one item showed conformity of 74%; all others showed conformity below 5%. For four items focused on transparency, conformity was high (above 60% for two, above 80% for the others). CONCLUSIONS: Existing ICDs do not meet most validated standards for encouraging good decision making. These standards make clear predictions about how one might improve ICDs ensure that research participants are fully informed. PMID- 22537429 TI - The fatty acid amide hydrolase inhibitor URB597 exerts anti-inflammatory effects in hippocampus of aged rats and restores an age-related deficit in long-term potentiation. AB - BACKGROUND: Several factors contribute to the deterioration in synaptic plasticity which accompanies age and one of these is neuroinflammation. This is characterized by increased microglial activation associated with increased production of proinflammatory cytokines like interleukin-1beta (IL-1beta). In aged rats these neuroinflammatory changes are associated with a decreased ability of animals to sustain long-term potentiation (LTP) in the dentate gyrus. Importantly, treatment of aged rats with agents which possess anti-inflammatory properties to decrease microglial activation, improves LTP. It is known that endocannabinoids, such as anandamide (AEA), have anti-inflammatory properties and therefore have the potential to decrease the age-related microglial activation. However, endocannabinoids are extremely labile and are hydrolyzed quickly after production. Here we investigated the possibility that inhibiting the degradation of endocannabinoids with the fatty acid amide hydrolase (FAAH) inhibitor, URB597, could ameliorate age-related increases in microglial activation and the associated decrease in LTP. METHODS: Young and aged rats received subcutaneous injections of the FAAH inhibitor URB597 every second day and controls which received subcutaneous injections of 30% DMSO-saline every second day for 28 days. Long-term potentiation was recorded on day 28 and the animals were sacrificed. Brain tissue was analyzed for markers of microglial activation by PCR and for levels of endocannabinoids by liquid chromatography coupled to tandem mass spectrometry. RESULTS: The data indicate that expression of markers of microglial activation, MHCII, and CD68 mRNA, were increased in the hippocampus of aged, compared with young, rats and that these changes were associated with increased expression of the proinflammatory cytokines interleukin (IL)-1beta and tumor necrosis factor-alpha (TNFalpha) which were attenuated by treatment with URB597. Coupled with these changes, we observed an age-related decrease in LTP in the dentate gyrus which was partially restored in URB597-treated aged rats. The data suggest that enhancement of levels of endocannabinoids in the brain by URB597 has beneficial effects on synaptic function, perhaps by modulating microglial activation. PMID- 22537430 TI - Dextromethorphan abuse leading to assault, suicide, or homicide. AB - Dextromethorphan is a commonly encountered antitussive medication which has found additional therapeutic use in the treatment of pseudobulbar disorder and as an adjunct to opiate use in pain management. Dextromethorphan at high doses has phencyclidine-like effects on the NMDA receptor system; recreational use of high doses has been found to cause mania and hallucinations. The toxicology and pharmacology of the drug in abuse are reviewed, and the historical literature of adverse psychiatric outcomes is assessed. Five new cases of dextromethorphan intoxication that resulted in assault, suicide, and homicide are reported, together with the corresponding toxicology results. Blood concentrations ranged from 300 to 19,000 MUg/L. These results are compared with typical concentrations reported in therapeutic use and impaired driving cases. Based on these findings, dextromethorphan should be considered as a potential causative agent in subjects presenting with mania, psychosis, or hallucinations, and abusers are at risk for violent and self-destructive acts. PMID- 22537431 TI - Viral hepatitis at a crossroad. PMID- 22537432 TI - Epidemiology of viral hepatitis and hepatocellular carcinoma. AB - Most cases of hepatocellular carcinoma (HCC) are associated with cirrhosis related to chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Changes in the time trends of HCC and most variations in its age-, sex-, and race specific rates among different regions are likely to be related to differences in hepatitis viruses that are most prevalent in a population, the timing of their spread, and the ages of the individuals the viruses infect. Environmental, host genetic, and viral factors can affect the risk of HCC in individuals with HBV or HCV infection. This review summarizes the risk factors for HCC among HBV- or HCV infected individuals, based on findings from epidemiologic studies and meta analyses, as well as determinants of patient outcome and the HCC disease burden, globally and in the United States. PMID- 22537433 TI - Is hepatitis C virus carcinogenic? PMID- 22537434 TI - Animal models for the study of hepatitis C virus infection and related liver disease. AB - Hepatitis C virus (HCV) causes liver-related death in more than 300,000 people annually. Treatments for patients with chronic HCV are suboptimal, despite the introduction of directly acting antiviral agents. There is no vaccine that prevents HCV infection. Relevant animal models are important for HCV research and development of drugs and vaccines. Chimpanzees are the best model for studies of HCV infection and related innate and adaptive host immune responses. They can be used in immunogenicity and efficacy studies of HCV vaccines. The only small animal models of robust HCV infection are T- and B- cell deficient mice with human chimeric livers. Although these mice cannot be used in studies of adaptive immunity, they have provided new insights into HCV neutralization, interactions between virus and receptors, innate host responses, and therapeutic approaches. Recent progress in developing genetically humanized mice is exciting, but these models only permit studies of specific steps in the HCV life cycle and have limited or no viral replication. PMID- 22537435 TI - HCV infection and metabolic syndrome: which is the chicken and which is the egg? PMID- 22537436 TI - Noninvasive methods to assess liver disease in patients with hepatitis B or C. AB - The prognosis and management of patients with chronic viral hepatitis B and C depend on the amount and progression of liver fibrosis and the risk for cirrhosis. Liver biopsy, traditionally considered to be the reference standard for staging of fibrosis, has been challenged over the past decade by the development of noninvasive methodologies. These methods rely on distinct but complementary approaches: a biologic approach, which quantifies serum levels of biomarkers of fibrosis, and a physical approach, which measures liver stiffness by ultrasound or magnetic resonance elastography. Noninvasive methods were initially studied and validated in patients with chronic hepatitis C but are now used increasingly for patients with hepatitis B, reducing the need for liver biopsy analysis. We review the advantages and limitations of the noninvasive methods used to manage patients with chronic viral hepatitis B or C infection. PMID- 22537440 TI - Genetic factors and hepatitis C virus infection. PMID- 22537438 TI - Maximizing opportunities and avoiding mistakes in triple therapy for hepatitis C virus. AB - Recently developed drugs and innovative strategies for the treatment of chronic infection with genotype 1 hepatitis C virus (HCV) have become the standard of care. The protease inhibitors telaprevir (Incivek) and boceprevir (Victrelis) are the first direct-acting antiviral (DAA) agents approved, and many more are being developed. These drugs substantially increased rates of sustained virologic response in treatment-naive and -experienced patients, in conjunction with peginterferon and ribavirin (triple therapy), in phase 3 trials. The efficacy of triple therapy depends on appropriate selection of patients, although the population of patients that receive triple therapy could be expanded as the risk/benefit ratio improves. Attention to details that reflect the standard of care, such as appropriate dosing, anticipation of adverse effects, and strict adherence to stopping rules, will insure the success of these drugs and lead the way for new combination therapies. PMID- 22537437 TI - New virologic tools for management of chronic hepatitis B and C. AB - Molecular biology techniques are routinely used to diagnose and monitor treatment of patients with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. These tools can detect and quantify viral genomes and analyze their sequence to determine their genotype or subtype and to identify nucleotide or amino acid substitutions associated with resistance to antiviral drugs. They include real-time target amplification methods, which have been standardized and are widely used in clinical practice to diagnose and monitor HBV and HCV infections, and next-generation sequencing techniques, which are still restricted to research laboratories. In addition, new enzyme immunoassays can quantify hepatitis B surface and hepatitis C core antigens, and point-of-care tests and alternatives to biologic tests that require whole-blood samples obtained by venipuncture have been developed. We review these new virologic methods and their clinical and research applications to HBV and HCV infections. PMID- 22537441 TI - Anti-hepatitis C virus drugs in development. AB - Development of robust cell culture models for hepatitis C viral infection has greatly increased our understanding of this virus and its life cycle. This knowledge has led to the development of many drugs that target specific elements of viral replication, including viral proteins and host factors required for replication. The NS3/4A serine protease inhibitors were the first of these to be used in the clinic, and reagents that target other elements of the viral lifecycle are in advanced stages of clinical development. These include new NS3/4A protease inhibitors, NS5B RNA-dependent RNA polymerase inhibitors, NS5A inhibitors, and host-directed antivirals, such as cyclophilin inhibitors. Alternative interferons with possibly improved tolerability, specifically interferon-lambda1 (interleukin-29), are also under development. These new reagents against hepatitis C virus should lead to highly effective, well tolerated, and likely interferon-sparing therapies in the next several years. PMID- 22537442 TI - Will interferon-free regimens prevail? PMID- 22537439 TI - Management of patients coinfected with HCV and HIV: a close look at the role for direct-acting antivirals. AB - With the development of effective therapies against human immunodeficiency virus (HIV), hepatitis C virus (HCV) infection has become a major cause of morbidity and mortality among patients with both infections (coinfection). In addition to the high prevalence of chronic HCV, particularly among HIV-infected injection drug users, the rate of incident HIV infections is increasing among HIV-infected men who have sex with men, leading to recommendations for education and screening for HCV in this population. Liver disease is the second leading and, in some cases, a preventable cause of death among coinfected patients. Those at risk for liver disease progression are usually treated with a combination of interferon (IFN) and ribavirin (RBV), which is not highly effective; it has low rates of sustained virologic response (SVR), especially for coinfected patients with HCV genotype 1 and those of African descent. Direct-acting antivirals might overcome factors such as immunodeficiency that can reduce the efficacy of IFN. However, for now it remains challenging to treat coinfected patients due to interactions among drugs, additive drug toxicities, and the continued need for combination therapies that include pegylated IFN. Recently developed HCV protease inhibitors such as telaprevir and boceprevir, given in combination with pegylated IFN and RBV, could increase the rate of SVR with manageable toxicity and drug interactions. We review the latest developments and obstacles to treating coinfected patients. PMID- 22537443 TI - Is there a role for ribavirin in the era of hepatitis C virus direct-acting antivirals? PMID- 22537444 TI - Effectiveness of hepatitis B treatment in clinical practice. AB - It is important to examine the effectiveness of current therapies for chronic hepatitis B in clinical practice, given the therapeutic advances over the past 15 years. A 2010 Institute of Medicine report on hepatitis and liver cancer stated that the public and health care providers have a lack of knowledge and awareness about viral hepatitis, and that there is a gap between medical innovation and community care. We review the efficacy of hepatitis B treatment, based on results from clinical trials, and discuss the effectiveness of these treatments in clinical practice. We also discuss why having efficacious treatments alone would have a small impact on the global health burden of hepatitis B, and highlight the importance of educating the public and the medical community and coordination of care. PMID- 22537445 TI - Is hepatitis virus resistance to antiviral drugs a threat? PMID- 22537446 TI - Viral hepatitis in liver transplantation. AB - Liver transplantation is the only alternative for patients with end-stage liver disease. Viral hepatitis B and C are among the most common causes of cirrhosis and hepatocellular carcinoma and a frequent indication for liver transplantation. Hepatitis B virus immunoglobulin and nucleot(s)ide analogues have facilitated the management of patients with hepatitis B who have received liver transplants and resulted in excellent long-term outcomes. On the contrary, recurrence of hepatitis C is the main cause of graft loss in most transplant programs. Current therapeutic approaches are far from optimal, because sustained virologic responses are only achieved in one-third of treated patients, and adverse effects are common and severe. However, the rapid development of direct-acting antivirals against hepatitis C virus will change the management of this disease and in a few years prevent graft infection with this virus. PMID- 22537448 TI - Pathogenesis and treatment of hepatitis e virus infection. AB - Hepatitis E has been considered to be a travel-associated, acute, self-limiting liver disease that causes fulminant hepatic failure in specific high-risk groups only. However, hepatitis E virus (HEV) infection can also be acquired in industrialized countries-HEV genotype 3 infection is a zoonosis, with pigs and rodents serving as animal reservoirs. In recent years, cases of chronic HEV infection that were associated with progressive liver disease have been described in several cohorts of immunocompromised individuals, including recipients of organ transplants. The topic of hepatitis E is therefore re-emerging and has raised the following important questions: what is the risk for HEV infection in Western countries (eg, from eating uncooked meat)? How frequently does chronic hepatitis E develop among human immunodeficiency virus-infected patients and recipients of organ transplants? What are the treatment options? What is the current status of vaccine development? What do we know about the pathogenesis of HEV infection, and why does it have a more severe course in pregnant women? This review summarizes the current knowledge on the pathogenesis and treatment of HEV infection. PMID- 22537447 TI - Will there be a vaccine to protect against the hepatitis C virus? PMID- 22537449 TI - Synthesis of indolizidinone analogues of cytotoxic alkaloids: monocyclic precursors are also active. AB - Readily available proline derivatives can be transformed in just two steps into analogues of cytotoxic phenanthroindolizidine alkaloids. The key step uses a sequential radical scission-oxidation-alkylation process, which yields 2 substituted pyrrolidine amides. A second process effects the cyclization to give the desired alkaloid analogues, which possess an indolizidine core. The major and minor isomers (dr 3:2 to 3:1) can be easily separated, allowing their use to study structure-activity relationships (SAR). The process is versatile and allows the introduction of aryl and heteroaryl groups (including biphenyl, halogenated phenyl, and pyrrole rings). Some of these alkaloid analogues displayed a selective cytotoxic activity against tumorogenic human neuronal and mammary cancer cells, and one derivative caused around 80% cell death in both tumor lines at micromolar doses. The cytotoxicity of some monocyclic precursors was also studied, being comparable or superior to the bicyclic derivatives. PMID- 22537450 TI - Discovery of cariprazine (RGH-188): a novel antipsychotic acting on dopamine D3/D2 receptors. AB - Medicinal chemistry optimization of an impurity isolated during the scale-up synthesis of a pyridylsulfonamide type dopamine D(3)/D(2) compound (1) led to a series of new piperazine derivatives having affinity to both dopamine D(3) and D(2) receptors. Several members of this group showed excellent pharmacokinetic and pharmacodynamic properties as demonstrated by outstanding activities in different antipsychotic tests. The most promising representative, 2m (cariprazine) had good absorption, excellent brain penetration and advantageous safety profile. Based on its successful clinical development we are looking forward to the NDA filing of cariprazine in 2012. PMID- 22537451 TI - Occurrence of risk factors for dental erosion in the population of young adults in Norway. AB - OBJECTIVES: The aim of this study was to describe the occurrence of risk factors for dental erosion for a group of young adults who are particularly susceptible to erosion. Another aim was to describe the awareness of erosion and distribution of risk factors according to the educational background of the parents. METHODS: The sample (n = 2004 individuals) was randomly drawn from the population of 19-20 year-old Norwegians. The data were collected using telephone interviews. We measured awareness about erosion using the following question: 'Have you ever heard about dental erosion?' We obtained information about the frequency of intake of the following risk factors: soft drinks with and without sugar, and juice. Soft drinks with sugar included lemonade (Coca-Cola, Solo, Pepsi, Mozell and ice tea) and sport drinks (XL1, Maxim). Soft drinks without sugar included Cola light, Zero, PepsiMax, Solo light and ice tea light. Juice included orange, grapefruit, apple and kiwi juice. The parents' level of education was based on the Norwegian school system, which has three levels: compulsory schooling (10 years), upper secondary school education (up to 13 years) and university/college education. The data were analysed using logistic regressions analyses. RESULTS: Awareness of erosion was high - 93.5% of respondents were aware of the problem. The majority of respondents believed that erosion can be prevented - altogether 84.9%. They also believed that soft drinks with and without sugar are equally important for the development of erosion. 17.5% of respondents drank soft drinks with sugar daily or several times a day. The corresponding figures for soft drinks without sugar and juice were 4.9% and 34.1%, respectively. Young adults with mothers with high education drank soft drinks both with and without sugar less frequently than those who had mothers with low education. This pattern was the opposite for juice. CONCLUSION: Consumption of soft drinks and juice is high, even though awareness and knowledge about the causes of erosion are widespread. This indicates the need for effective intervention strategies to reduce the level of consumption. These strategies should take into account the fact that the distribution of risk factors is skewed with respect to parents' level of education. PMID- 22537452 TI - Environmental contaminants and animal health. Abstracts of the 26th Symposium of the Nordic Committee for Veterinary Scientific Cooperation (NKVet). Helsinki, Finland. October 6-7, 2011. PMID- 22537453 TI - Genotype-dependent sulphite tolerance of Australian Dekkera (Brettanomyces) bruxellensis wine isolates. AB - AIMS: The aim of this study was to determine sulphite tolerance for a large number of Dekkera bruxellensis isolates and evaluate the relationship between this phenotype and previously assigned genotype markers. METHODS AND RESULTS: A published microplate-based method for evaluation of yeast growth in the presence of sulphite was benchmarked against culturability following sulphite treatment, for the D. bruxellensis type strain (CBS 74) and a reference wine isolate (AWRI 1499). This method was used to estimate maximal sulphite tolerance for 41 D. bruxellensis isolates, which was found to vary over a fivefold range. Significant differences in sulphite tolerance were observed when isolates were grouped according to previously assigned genotypes and ribotypes. CONCLUSIONS: Variable sulphite tolerance for the wine spoilage yeast D. bruxellensis can be linked to genotype markers. SIGNIFICANCE AND IMPACT OF THE STUDY: Strategies to minimize risk of wine spoilage by D. bruxellensis must take into account at least a threefold range in effective sulphite concentration that is dependent upon the genotype group(s) present. The isolates characterized in this study will be a useful resource for establishing the mechanisms conferring sulphite tolerance for this industrially important yeast species. PMID- 22537454 TI - Carotid artery plaque progression and cognitive decline: the Tromso Study 1994 2008. AB - BACKGROUND: Carotid atherosclerosis is a risk factor for stroke and cognitive decline, but knowledge on how progression of carotid atherosclerosis affects cognitive function in stroke-free individuals is scarce. METHODS: In the population-based Tromso study, we calculated the change in ultrasound-assessed carotid plaque number and total plaque area from baseline (survey 4) to follow-up 7 years later (survey 5) in 4274 middle-aged stroke-free subjects. Cognitive function was assessed at follow-up by the verbal memory test, the digit-symbol coding test, and the tapping test and repeated after an additional 6 years in a subgroup of 2042 subjects (survey 6). Associations between the average of survey 4 and survey 5 plaque scores and the progression of plaque scores and cognitive test scores were assessed in regression analyses adjusted for baseline age, sex, education, depression, and cardiovascular risk factors. RESULTS: Progression of total plaque area was associated with lower scores in the digit-symbol coding test (multivariable adjusted standardized beta, -0.03; 95% CI, -0.05 to -0.00; P = 0.04) and the tapping test (beta, -0.03; 95% CI, -0.06 to -0.00; P = 0.03). Similar results were seen for progression of plaque number. The average plaque scores were associated with lower scores in all cognitive tests (P-values <= 0.01). No association was found between plaque scores and cognitive decline. CONCLUSIONS: The average plaque scores were associated with lower scores in all cognitive tests. Progression of plaque scores was associated with lower scores in the digit-symbol coding test and the tapping test, but not with the verbal memory test or with cognitive decline. PMID- 22537455 TI - A multiplex immunoassay gives different results than singleplex immunoassays which may bias epidemiologic associations. AB - OBJECTIVES: Multiplex immunoassays are increasingly used in epidemiologic studies to measure inflammatory factors, however there are few published evaluations of this technology. Our objective was to compare a common multiplex immunoassay to singleplex immunoassays for measuring inflammatory factors, and to examine how combining data from each affects an epidemiologic association. DESIGN AND METHODS: Plasma IL-1 beta, IFN-gamma, IL-6, and TNF-alpha were measured in 100 samples using a multiplex kit from Mesoscale Discovery (MSD) and singleplex ELISAs from R&D Systems. Separate samples (n=80) were collected to compare multiplex and singleplex assays from MSD. We simulated the effect of combining MSD multiplex and R&D singleplex data on the association between sugar sweetened beverage (SSB) intake and IL-6 in the Health Professionals Follow-up Study (HPFS; n=1314). RESULTS: Compared to R&D ELISAs, the MSD multiplex proportionally and significantly overestimated IL-1 beta (slope=1.2), and IFN-gamma (slope=2.9) but underestimated IL-6 (slope=0.5). Correlations were >= 0.81 except for TNF-alpha (r=0.31). Compared to MSD singleplex, the MSD multiplex proportionally underestimated IFN-gamma (slope=0.7) and TNF-alpha (slope=0.5). Correlations were >= 0.96. The association between sugar sweetened beverage intake and IL-6 in the HPFS (+0.16 pg/mL per serving/day, p=0.02, all singleplex) was gradually attenuated as multiplex data made an increasing contribution to the data-set. (+0.09 pg/mL [-45%], p=0.02, all multiplex) CONCLUSIONS: A multiplex immunoassay for inflammatory factors yielded significantly different results than singleplex immunoassays-including those from the same company. Correlations were not consistently high, except among assays from the same company. Such differences may distort epidemiologic relationships if data from both methods are merged. PMID- 22537456 TI - Serum soluble death receptor 5 concentration in patients with chronic hepatitis B is associated with liver damage and viral antigen level. AB - OBJECTIVES: To measure the levels of serum soluble death receptor 5 (sDR5) in patients with hepatitis B. DESIGN AND METHODS: sDR5 concentration in 60 HBV infected patients and 30 healthy volunteers were measured by ELISA. RESULTS: sDR5 concentration in the HBV infected patients was decreased and correlated with serum ALT, Tbil level, albumin/globulin ratio and HBV antigen level. CONCLUSIONS: Decreased serum sDR5 is associated with high level of liver damage and inhibited HBV antigen expression. PMID- 22537458 TI - Change in nickel levels in the saliva of patients with fixed orthodontic appliances. AB - Nickel-titanium (NiTi) alloys are used frequently in orthodontics. Nickel release thus poses a problem on account of the biological effects it may have. The aim of our paper is to evaluate levels of nickel released into saliva by fixed orthodontic appliances. To this end, we performed an in vivo study on 16 patients (eight boys, eight girls). Nickel levels in saliva were evaluated by mass spectrometry before appliance placement, just after placement, and 8 weeks after placement. Results showed a significant increase in nickel levels just after NiTi archwire insertion. However, the difference was non-significant 8 weeks later. Certain studies concur with ours, showing appreciable changes in concentration, but with no significant difference. Others, though, have shown a statistically significant difference. In conclusion, orthodontic appliances release nickel ions mainly at the start of orthodontic treatment. PMID- 22537459 TI - Surgical and orthodontic treatment of skeletal Class III featuring severe transversal and sagittal discrepancy. AB - AIMS: Anterior cross-bite is a difficult malocclusion to treat in adult patients, especially if compounded by skeletal discrepancy. The present study describes a dentoskeletal Class III case and aims to provide the clinician with rational guidelines for presurgical orthodontic preparation and postsurgical finishing. PATIENT AND METHODS: In this case, a 20-year-old male patient, R.M, was treated for severe dental and skeletal Class III malocclusion on both the transversal and anteroposterior planes via combined orthodontics and surgery. Initially, the treatment involved surgically-assisted expansion of the upper jaw (total 1 month), followed by a fixed-orthodontics phase to decompensate for the malocclusion in preparation for movement of the osseous bases with the aim of achieving maximum coordination of the dental arches. After 19 months of orthodontic preparation, the patient underwent combined orthognathic surgery (upper and lower jaws). In the subsequent 4 months, orthodontic stabilization and finishing were performed, and debonding was carried out 24 months after the start of active treatment. RESULTS: The combined orthodontic and surgical treatment adequately corrected the severe Class III over a period of 2 years, leading to a satisfactory occlusal, functional and aesthetic result. CONCLUSIONS: Thorough diagnosis and close communication between the orthodontist and maxillofacial surgeon, operating as an interdisciplinary team, ensures good outcomes, even in complex orthodontic and surgical cases. PMID- 22537461 TI - Resting and dobutamine stress test induced serum concentrations of brain natriuretic peptide in German Shepherd dogs. AB - Studies of clinical uses of brain natriuretic peptide (BNP) represent one of the most important advances in cardiology since the introduction of echocardiography as a clinical diagnostic procedure. Defining the clinical potential of BNP in canine cardiology has not been completed yet. The aim of this study is to measure BNP concentrations in healthy German Shepherd dogs of different ages as a baseline in resting and when conventional protocol of the dobutamine stress test (DST) is applied to dogs. Concentrations of BNP were measured in blood serum by the radioimmunoassay method. The values of BNP concentrations were compared to cardiac parameters obtained by standard cardiac diagnostic procedures (radiology, electrocardiography and echocardiography). No significant differences in serum BNP concentrations existed in dogs of different ages. A statistically significant increase in BNP concentrations was registered after DST. These changes in BNP concentrations were related to ST/T electrocardiographic changes, and correlated to changes in the left ventricular internal diameter in systole (LVESD). These data suggest that BNP is not increased in aged dogs with normal cardiac systolic function and renal function, and that myocardial ischemia leads to a significant increase in BNP concentrations even in dogs with normal left ventricular function. PMID- 22537462 TI - A simple and rapid immunocytochemical technique for detection of cytokeratin, vimentin, and S-100 protein in veterinary diagnostic cytology. AB - The objective of this study was to establish a simple and rapid immunocytochemical technique that can be used in veterinary diagnostic cytology. Air-dried impression smears were collected from canine tumors. Samples of epithelial tumors, mesenchymal tumors, and malignant peripheral nerve sheath tumors and melanomas were used for detection of cytokeratin, vimentin, and S-100 protein, respectively. The labeled streptavidin-biotin system was used in the present study. Optimal fixation was determined using standard immunocytochemical procedures, and acetone fixation was found to be the most effective. Optimal concentrations of primary and secondary antibodies were determined at a preset 5 min incubation. Omission of H2O2 treatment, shortening the time for blocking and labeled-streptavidin incubation, and simplifying washing did not decrease immunopositive intensities or enhance false-positive reactions. The described rapid protocol requires approximately 45 min without the use of any special equipment. PMID- 22537463 TI - Pediatric urology fellowship training: are we teaching what they need to learn? AB - OBJECTIVE: Pediatric urology training has traditionally been based on an apprenticeship model. As part of our curriculum re-development, we surveyed recent graduates (2007-2009) regarding the teaching of clinical/surgical skills and medical knowledge during their training. METHODS: 44 pediatric urologists who completed 2 years of ACGME (Accreditation Council for Graduate Medical Education) accredited programs and had been practicing for at least 18 months were anonymously surveyed. An IRB-approved survey was developed by a team of educators at the Johns Hopkins School of Medicine and Bloomberg School of Public Health. RESULTS: 31 of 44 responded to 100% of the questions; 90% of the respondents felt their fellowship successfully prepared them for discussing surgical options and performing the procedures that they are now doing; 74% felt well trained to manage perioperative complications and 65% felt well trained to manage non surgical problems. Faculty feedback/supervision, independent reading, and conferences were rated as a very effective method of teaching (87%). Top three procedures they wished they had learned: laparoscopic/robotic surgery, hypospadias repair, and augmentation/Mitrofanoff. Top three non-surgical topics: urinary tract infection, voiding dysfunction, and billing/coding. CONCLUSION: It is reassuring that ACGME fellowship-trained pediatric urologists feel prepared in commonly performed procedures and perioperative care. Faculty supervision/feedback is highly valued. PMID- 22537464 TI - Attenuation of phosphoinositide 3-kinase delta signaling restrains autoimmune disease. AB - Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by the production of autoantibodies against nuclear components. Lyn deficient mice are an excellent animal model of SLE manifesting clinical, pathological and biochemical features seen in the human disease. They develop autoreactive antibodies, glomerulonephritis and show generalized inflammation, and their B cells have a hyperactive phenotype. Since loss of Lyn confers hyper activation of phosphoinositide 3-kinase (PI3K) signaling, we studied the effect of down-modulating PI3K in Lyn-deficient mice. We found that heterozygous inactivation of the p110delta isoform of PI3K was sufficient to restrain disease in Lyn-deficient mice, leading to significantly decreased autoantibody development and autoimmune-mediated kidney pathology, and improved survival. Intriguingly, haploinsufficiency of p110delta did not dampen signaling in Lyn deficient B cells. However, plasma cell numbers, serum immunoglobulin titers, inflammation and T cell signaling and activation were significantly moderated in Lyn(-/-)p110delta(+/KD) mice. Importantly, we have shown that haploinsufficiency of p110delta has minor effects on the B cell compartment per se but leads to significant defects in T cell activation and B cell class-switching. These studies suggest that agents targeting p110delta PI3K need not achieve full blockade of the enzyme to be of great benefit in the treatment of SLE. PMID- 22537465 TI - Molecular hydrogen and radiation protection. AB - Molecular hydrogen (dihydrogen, H(2)) acts as a therapeutic antioxidant by selectively reducing hydroxyl radicals (*OH) and peroxynitrite (ONOO-). It has been well-known that ionising radiation (IR) causes oxidative damage and consequent apoptosis mainly due to the production of *OH that follows radiolysis of H(2)O. Our department reported the protective effect of H(2) in irradiated cells and mice for the first time, and this effect is well repeated by us and another laboratory in different experimental animal models. A randomised, placebo controlled investigation also showed consumption of H(2) can improve the quality of life of patients treated with radiotherapy for liver tumours. These encouraging results suggested that H(2) has a potential as a radioprotective agent with efficacy and non-toxicity. PMID- 22537466 TI - The effect of Qigong on menopausal symptoms and quality of sleep for perimenopausal women: a preliminary observational study. AB - OBJECTIVES: The study objectives were to examine the effect of a 12-week 30 minute-a-day Ping Shuai Qigong exercise program on climacteric symptoms and sleep quality in perimenopausal women. DESIGN: This was a prospective observational study. SETTINGS/LOCATION: The subjects (N=70) from two communities were women aged 45 years and above who were experiencing menopausal symptoms. SUBJECTS: Thirty-five (35) women from one community were assigned to a Ping Shuai Qigong intervention group, while 35 women from the other community were assigned to the control group. INTERVENTIONS: This was a 12-week, 30-minute-a-day Ping Shuai Qigong program. OUTCOME MEASURES: The Greene Climacteric Symptom scale and the Pittsburgh Sleep Quality Index were the outcome measures. METHODS: Descriptive analysis and repeated-measures analysis of variance were used. RESULTS: Pretest scores at baseline found no significant group differences in climacteric symptoms or sleep quality. Significant improvements in climacteric symptoms were found at 6 weeks and 12 weeks (t=4.07, p<0.001 and t=11.83, p<0.001) in the intervention group. They were also found to have significant improvements in sleep quality in those times (t=5.93, p<0.001 and t=10.58, p<0.001, respectively). CONCLUSIONS: Ping Shuai Qigong improved climacteric symptoms and sleep quality in perimenopausal women at 6 weeks and 12 weeks. The longer a person practiced this form of meditative exercise, the greater the improvement in sleeping quality and climacteric symptoms. PMID- 22537467 TI - The patients' perspective is key, also in research. PMID- 22537468 TI - The standardized and mini versions of the PAQLQ are valid, reliable, and responsive measurement tools. AB - OBJECTIVE: The Paediatric Asthma Quality of Life Questionnaire (PAQLQ) is a validated tool developed to assess the impact of symptoms on quality of life. Here we assess the validity, reliability and responsiveness of two new simpler versions of this questionnaire: the Standardised PAQLQ and the MiniPAQLQ. STUDY DESIGN AND SETTING: Participants included 42 children with asthma, who completed the PAQLQ, PAQLQ(S), MiniPAQLQ, Asthma Control Questionnaire, and Health Utilities Index at baseline, one, five and nine weeks. Concordance between questionnaires was examined using intraclass correlation coefficients (ICC), bias by paired Student's t-tests and closeness of association by Pearson correlation coefficients. RESULTS: Correlation coefficients for each of the corresponding domains of the PAQLQ with the PAQLQ(S) were strong (r>0.97), and moderate to strong (r=0.50-0.94) with the MiniPAQLQ. Reliability was strong for both the PAQLQ(S) (ICC>0.89) and MiniPAQLQ (ICC>0.91). The responsiveness index values for the PAQLQ(S) (0.96) and the MiniPAQLQ (1.05) were both higher than that of the original PAQLQ (0.90). Cross sectional and longitudinal correlation coefficients were similar for all three instruments. CONCLUSION: The PAQLQ(S) and the MiniPAQLQ are valid, reliable and responsive to change. They can be used with confidence for long-term monitoring in clinical trials. PMID- 22537469 TI - SmartStretchTM technology: V. the impact of SmartStretchTM technology on beef topsides (m. semimembranosus) meat quality traits under commercial processing conditions. AB - This study evaluated the effect of SmartStretchTM technology and ageing on meat quality traits of hot-boned beef m. semimembranosus from cull cows. The technology uses a flexible rubber sleeve surrounded by inflatable bladders that are housed within an airtight chamber. The sleeve is expanded allowing the meat to be inserted. Air is then pumped into the inflatable bladders causing the meat to be compressed by force and ejected into packaging. No significant treatment effect (P>0.05) on shear force was found although ageing did significantly reduce shear force (P<0.001). There was a significantly greater (P<0.05) cook loss at 14 days, but less (P<0.05) thaw loss and purge with 0 day cook loss unaffected (P>0.05). Sarcomere length examined by both laser diffraction and a filar micrometre method was significantly increased (P<0.05) following the treatment although a proportion of individual myofibrils appeared to have short and long sarcomeres. PMID- 22537470 TI - Massive systemic fat embolism detected by postmortem imaging and biopsy. AB - Postmortem computed tomography (pmCT) and pmCT angiography (pmCTA) provide a minimally invasive method to determine the cause of death. Postmortem image guided biopsy allows for precise sampling of histological specimens. This case study describes the findings of lethal systemic fat embolism (FE) on whole-body unenhanced pmCT, pmCTA, and image-guided biopsy, with autopsy and histopathologic correlation. Unenhanced pmCT revealed a distinct fat level on top of sedimented layers of corpuscular blood particles and serum in the arterial system and pulmonary trunk. Subsequent pmCTA showed reproducible results, and image-guided biopsy confirmed fatal FE. pm CT/pmCTA combined with image-guided biopsy established the cause of death as right heart failure as a result of systemic fatal FE prior to autopsy. All imaging findings were consistent with traditional autopsy and histological specimens. This unique case demonstrates new imaging findings in massive, fatal FE and highlights that postmortem imaging, supplemented by image-guided biopsy, may detect the cause of death prior to traditional autopsy. PMID- 22537471 TI - Prevention of early-onset pneumonia in surgical patients by chemoprophylaxis. AB - BACKGROUND: The purpose of this study was to explore the impact of surgical antimicrobial chemoprophylaxis on the prevention of early-onset postsurgical pneumonia (EOPP) using a logistic regression model that included the principal risk or confusion factors associated with incidence of early-onset postsurgical pneumonia. MATERIALS AND METHODS: The sample chosen corresponded to 13 years during which the epidemiological surveillance system was in place in the general and digestive surgery department (N = 13,024 patients) and was designed as a prospective cohort study. Risk factors associated with EOPP development were analyzed using a cohort-nested case-control study. RESULTS: Cumulative incidence of EOPP in this series of patients was .6%, accounting for 24.7% of total nosocomial pneumonias. The multivariate model showed the following risks or confusion factors for EOPP: age, emergency admission, type of surgery, duration of surgical intervention, infection on admission, and antimicrobial chemoprophylaxis (administered, odds ratio = .18; 95% confidence interval, .09 .33). CONCLUSIONS: Surgical antimicrobial chemoprophylaxis was associated as an independent factor with incidence reduction of early-onset postsurgical pneumonia, and, aside from its known effect on surgical site infection, its administration, where indicated, is useful for the prevention of early-onset postsurgical pneumonia. PMID- 22537472 TI - Educational feedback in the operating room: a gap between resident and faculty perceptions. AB - BACKGROUND: Immediate feedback regarding performance in the operating room remains a key component of resident education. The aim of this study was to assess resident and faculty perceptions regarding postoperative feedback. METHODS: Anonymous surveys were distributed to residents and faculty members. Questions addressed the timing, amount, and specificity of feedback; satisfaction; and the definition and importance of feedback. Additional questions regarded the importance and frequency of feedback in 7 specific areas of surgical competency. RESULTS: Resident satisfaction with timing, amount, and specificity of feedback was significantly lower than faculty satisfaction. Perceptions of the importance of feedback for each of the 7 specific areas did not differ. Faculty members' perceptions on the frequency of feedback were higher than residents' perception in all competencies of feedback (5-point scale, all P values = .001). CONCLUSIONS: There are significant differences between resident and faculty perceptions regarding postoperative feedback. Although faculty members believed they delivered appropriate amounts of timely, quality feedback, this perception was not shared by residents. PMID- 22537473 TI - Systematic review and meta-analysis of electrocautery versus scalpel for surgical skin incisions. AB - BACKGROUND: The creation of surgical skin incisions has historically been performed using a cold scalpel. The use of electrocautery for this purpose has been controversial with respect to patient safety and surgical efficacy. A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to compare skin incisions made by electrocautery and a scalpel. DATA SOURCES: A systematic electronic literature search was performed using 2 electronic databases (MEDLINE and PubMed), and the methodological quality of included publications was evaluated. Six RCTs were identified comparing electrocautery (n = 606) and a scalpel (n = 628) for skin incisions. CONCLUSIONS: No significant difference in wound infection rates or scar cosmesis was identified between the treatment groups. Electrocautery significantly reduced the incision time and postoperative wound pain. A trend toward less incisional blood loss from skin incisions made with electrocautery was noted. Electrocautery is a safe and effective method for performing surgical skin incisions. PMID- 22537474 TI - Immobilization and characterization of hemoglobin on modified sporopollenin surfaces. AB - Hemoglobin was covalently immobilized onto modified sporopollenin surface with different functional groups by chemical reactions to enhance binding ability of protein. In this study, the influence of various silane linker molecules on the capacity of protein binding was studied. For this purpose, activated sporopollenin was modified by 3-aminopropyltriethoxysilane (APTS), 3 chloropropyltrimethoxysilane (CPTS) and (3-glycidyloxypropyl)trimethoxysilane (GPTS). Hemoglobin (Hb) was immobilized on modified sporopollenin surfaces in phosphate buffer saline solution (PBS, pH 7.4) at 4 degrees C. Results showed that GPTS modified sporopollenin surfaces resulted in the highest binding capacity for Hb. Micro porosity of samples was observed through scanning electron microscopy (SEM) and thermal behavior of the samples were studied with thermogravimetric analysis (TGA) within a temperature range: 25-900 degrees C. TGA studies demonstrated the advantages of silane modification for high temperature applications and illustrated differences of the structures due to the different tail groups. PMID- 22537475 TI - Investigation into the mechanism of (-)-epigallocatechin-3-gallate-induced precipitation of insulin. AB - The molecular interactions between EGCG and insulin were investigated to probe the mechanism of EGCG-induced insulin precipitation. The results indicated that 1 5mM EGCG induced insulin into reversible globular precipitates of 185-365 nm. The formation of precipitates was facilitated at high salt concentration and pH values close to insulin's isoelectric point, indicating that hydrophobic interaction was the main driving force. The precipitation was positively related to insulin concentration, but for EGCG, there was a suitable concentration (2 mM at 2 mg/mL of insulin) at which the precipitate content reached maximum. Mass spectroscopy analysis indicated that EGCG formed clusters in the aqueous solution and the clusters correlate with the insulin precipitation. Based on extensive investigation, a physical model was proposed to explain the molecular interactions between EGCG and insulin. Namely, EGCG monomers and clusters first bound to insulin dimers via hydrophobic interaction, leading to the reduction of the thickness of the hydration layer and the partial denaturation of insulin. Then, EGCG clusters acted as bridges to induce the aggregation and precipitation of insulin. PMID- 22537476 TI - Time to effective antibiotic administration in adult patients with septic shock: a descriptive analysis. AB - OBJECTIVE: To determine the median time to antibiotic administration following the onset of septic shock at our institution as well as the appropriateness of empiric therapy, sources of delay in antibiotic administration and the effect of delays on survival. RESEARCH METHODOLOGY: Retrospective health record review of 55 patients with septic shock admitted to the intensive care unit (ICU) between July 1, 2008 and December 31, 2009. SETTING: Nine-bed adult medical-surgical ICU within a 300-bed community acute care hospital. MAIN OUTCOME MEASURES: Median time to antibiotic administration, appropriateness of empiric therapy, sources of delay in antibiotic administration. RESULTS: The median (min,max) time to the initiation of antibiotics was determined to be 1.7 (0,31) hours. Only 34% (19/55) of patients received antibiotics within the recommended one hour. Empiric antibiotic therapy was determined to be appropriate in 91% (50/55) of patients. The median (min,max) time to administration of effective antibiotic therapy tended to be faster in the emergency room [1.1 (0,16) hours] compared to the ICU [2.3 (0,13)]. CONCLUSION: The median time to antibiotic administration at our institution following the onset of septic shock was longer than the evidence based guideline recommendations of within one hour. PMID- 22537477 TI - A review of the utility of EEG depth of anaesthesia monitors in the paediatric intensive care environment. AB - OBJECTIVES: This paper aims to bring together current evidence regarding the use of depth of anaesthesia monitors (DoAM) as objective measures of sedation for paediatric intensive care (PIC) patients. BACKGROUND: Delivering appropriate dosages of sedative agents, to individual PIC patients, is important to reduce the many risks of over- or under-sedation. Although based on adult anaesthesia, DoAMs could offer increased objectivity to the titration of sedative agents for children in PIC. This article synthesises the current available evidence from studies investigating DoAM use in the PIC environment. METHOD: Literature regarding DoAM use in PIC was reviewed, from 1996 and August 2011, after EMBASE, PubMed, CINAHL and ProQuest Dissertation & Theses Database were searched using key search terms. FINDINGS: Fourteen original research articles addressing sedation assessment using DoAMs in PIC were identified. The main findings were that DoAMs generally have a moderate or poor correlation with sedation scores and their performance varies in varying clinical settings. DoAMs do not make reliable conclusions about depth of sedation of individual PIC children, and can be influenced by children's age. CONCLUSION: Evidence to support DoAMs in the PIC setting is currently not sufficient to advocate their routine use in clinical practice. PMID- 22537478 TI - The sound environment in an ICU patient room--a content analysis of sound levels and patient experiences. AB - This study had two aims: first to describe, using both descriptive statistics and quantitative content analysis, the noise environment in an ICU patient room over one day, a patient's physical status during the same day and early signs of ICU delirium; second, to describe, using qualitative content analysis, patients' recall of the noise environment in the ICU patient room. The final study group comprised 13 patients. General patient health status data, ICU delirium observations and sound-level data were collected for each patient over a 24-hour period. Finally, interviews were conducted following discharge from the ICU. The sound levels in the patient room were higher than desirable and the LAF max levels exceed 55dB 70-90% of the time. Most patients remembered some sounds from their stay in the ICU and whilst many were aware of the sounds they were not disturbing to them. However, some also experienced feelings of fear related to sounds emanating from treatments and investigations of the patient beside them. In this small sample, no statistical connection between early signs of ICU delirium and high sound levels was seen, but more research will be needed to clarify whether or not a correlation does exist between these two factors. PMID- 22537479 TI - Comparative spatiotemporal analysis of the intrathecal immune response in natural listeric rhombencephalitis of cattle and small ruminants. AB - This study examined the spatiotemporal immune response in listeric rhombencephalitis of ruminants in situ. Our data support the view that astrocytes facilitate the containment of infectious lesions. Results on the natural disease recapitulate observations in experimental rodent models and suggest that the mounted adaptive lymphocytic response of ruminants is effective in eliminating Listeria monocytogenes (LM). However, our data indicate earlier participation of the adaptive immune response, a stronger B lymphocyte contribution and a more protracted macrophage infiltration in the natural disease than it has been deduced from experimental models. Therefore, such models should be complemented by studies in natural host systems. Various macrophage and microglia subsets are involved in listeric rhombencephalitis and their differential contribution may account for species differences in clinical course and outcome of infection as might species differences in the B-cell response. Future functional ex vivo and in vitro studies are necessary to further investigate the findings obtained in the present study. PMID- 22537480 TI - Genetic diversity and frequency of bovine viral diarrhea virus (BVDV) detected in cattle in Turkey. AB - The aim of this study was to investigate the frequency and diversity of bovine viral diarrhea viruses (BVDV) infecting cattle in Turkey. A total of 1124 bovine blood samples from 19 farms in 4 different Turkish regions were tested by antigen capture ELISA (ACE). BVDV antigen was found in 26 samples from 13 farms. Only 20 of the 26 initial test positive cattle were available for retesting. Of these, 6 of 20 tested positive for BVDV, by ACE and real-time RT-PCR, one month after initial testing. Phylogenetic analysis, based on comparison of the E2 or the 5'UTR coding regions, from 19 of the 26 initial positive samples, indicated that 17 belonged to the BVDV-1 genotype and 2 to the BVDV-2 genotype. Comparison of 5'UTR sequences segregated 8 BVDV-1 strains (strains 5, 6, 10, 11, 12, 13, 17, and 19) to the BVDV1f, 1 strain (strain 8) to the BVDV1i and 1 strain (strain 14) to the BVDV1d subgenotypes. One strain (strain 4) did not group with other subgenotypes but was closer to the BVDV1f. The remaining 6 BVDV-1 strains (strains 1, 2, 3, 7, 9, and 18) segregated to a novel subgenotype. The E2 sequence comparison results were similar, with the exception that strain 5 grouped with the novel subgenotype rather than BVDV1f subgenotype. It appears that among the diverse BVDV strains in circulation there may be a subgenotype that is unique to Turkey. This should be considered in the design of diagnostics and vaccines to be used in Turkey. PMID- 22537481 TI - Immunoadsorption therapy in patients with multiple sclerosis with steroid refractory optical neuritis. AB - BACKGROUND: In multiple sclerosis relapses refractory to intravenous corticosteroid therapy, plasma exchange is recommended. Immunoadsorption (IA) is regarded as an alternative therapy, but its efficacy and putative mechanism of action still needs to be established. METHODS: We prospectively treated 11 patients with multiple sclerosis who had optical neuritis and fulfilled the indications for apheresis therapy (Trial registration DE/CA25/00007080-00). In total, five IA treatments were performed using tryptophan-IA. Clinical activity (visual acuity, Expanded Disability Status Scale, Incapacity Status Scale), laboratory values and visual evoked potentials were measured before, during and after IA, with a follow-up of six months. Moreover, proteomic analyses were performed to analyze column-bound proteins as well as corresponding changes in patients' sera. RESULTS: After the third IA, we detected an improvement of vision in eight of eleven patients, whom we termed responders. Amongst these, the mean visual acuity improved from 0.15 +/- 0.12 at baseline to 0.47 +/- 0.32 after the third IA (P = 0.0252) up to 0.89 +/- 0.15 (P < 0.0001) at day 180 +/- 10 after IA. Soluble interleukin-2 receptor decreased in responders (P = 0.03), whereas in non-responders it did not. Proteomic analyses of proteins adsorbed to IA columns revealed that several significant immunological proteins as well as central nervous system protein fragments, including myelin basic protein, had been removed by IA. CONCLUSIONS: IA was effective in the treatment of corticosteroid refractory optic neuritis. IA influenced the humoral immune response. Strikingly, however, we found strong evidence that demyelination products and immunological mediators were also cleared from plasma by IA. PMID- 22537482 TI - Factors affecting sick leave prescribing by dentists. AB - OBJECTIVES: The aim was to examine the prescribing of sick leave by dentists and factors affecting prescribing practices. METHODS: A questionnaire study covering sick leave-prescribing practice during the preceding year and in response to 16 hypothetical patient cases was conducted among 1132 Finnish dentists. The effects of both dentist-related and local structural background variables on sick leave prescribing were studied. RESULTS: During the preceding year, dentists who were young, male, or practicing in small municipalities prescribed more days of sick leave than comparator groups. In response to the 16 hypothetical cases, dentists prescribed a mean of 31.6 days of sick leave (range, 0-98 days). The dentists with a specialty degree in oral and maxillofacial surgery prescribed longer sick leave than other dentists. Dentists working only in public dental services (PDS) and older dentists prescribed significantly less sick leave than others. CONCLUSIONS: There is considerable variation among dentists in sick leave prescribing practices. The most significant factors affecting this variation are having a specialty in oral and maxillofacial surgery and working only in PDS. Further education and guidelines on dental sick leave prescribing are needed. PMID- 22537483 TI - Social capital and self-rated health--a study of temporal (causal) relationships. AB - Despite the vast amount of research over the past fifteen years, there is still lively debate surrounding the role of social capital on individual health outcomes. This seems to stem from a lack of consistency regarding the definition, measurement and plausible theories linking this contextual phenomenon to health. We have further identified a knowledge gap within this field - a distinct lack of research investigating temporal relationships between social capital and health outcomes. To remedy this shortfall, we use four waves of the British Household Panel Survey to follow the same individuals (N = 8114) between years 2000 and 2007. We investigate temporal relationships and association between our outcome variable self-rated health (SRH) and time-lagged explanatory variables, including three individual-level social capital proxies and other well-known health determinants. Our results suggest that levels of the social capital proxy 'generalised trust' at time point (t - 1) are positively associated with SRH at subsequent time point (t), even after taking into consideration levels of other well-known health determinants (such as smoking status) at time point (t - 1). That we investigate temporal relationships at four separate occasions over the seven-year period lends considerable weight to our results and the argument that generalised trust is an independent predictor of individual health. However, lack of consensus across a variety of disciplines as to what generalised trust is believed to measure creates ambiguity when attempting to identify possible pathways from higher trust to better health. PMID- 22537485 TI - Protective effect of urantide against ischemia-reperfusion injury via protein kinase C and phosphtidylinositol 3'-kinase - Akt pathway. AB - Urantide is the most potent UT receptor antagonist compound found to date. Our previous studies have shown that it has cardioprotective effect against ischemia reperfusion injury. However, it is unclear which signal transduction pathways are involved in the urantide-induced cardioprotective effect. This study was designed to investigate whether the effect of urantide on myocardial ischemia-reperfusion injury in rats via the protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway. The results showed that urantide at 10 and 30 ug/kg markedly inhibited the increases in serum creatine kinase fraction and lactate dehydrogenase activities and the level of cardiac troponin I, reduced the ratio of myocardial infarct size to area at risk. Urantide significantly decreased the histological damage to the myocardium and modified the ultrastructural damage in cardiac myocytes. In the presence of chelerythrine (an inhibitor of PKC, 1 mg/kg) or LY294002 (an inhibitor of PI3K-Akt, 0.3 mg/kg), the protective effect of urantide was almost completely abolished. Urantide (30 ug/kg) markedly enhanced the expression of p-Akt protein during myocardial ischemia-reperfusion injury, and this enhancement was significantly attenuated by LY294002. Therefore, our results demonstrate that urantide has a potent protective effect against myocardial ischemia-reperfusion injury in rats that may be involved with the PKC and PI3K-Akt signaling pathways. PMID- 22537484 TI - Regional differences in HIV prevalence and individual attitudes among service providers in China. AB - We examined the relationships between a region's HIV prevalence and HIV-related knowledge, perceived risk of HIV infection, perceived institutional support for HIV care, and avoidance attitude toward persons living with HIV (PLH) among service providers in China. Data were collected from 40 county-level hospitals in two provinces, including 1760 service providers. Multi-sample standardization and decomposition analysis was performed for HIV knowledge, perceived risk, institutional support, and avoidance attitude toward PLH. After adjusting for potential confounders, service providers from the province with higher HIV prevalence perceived a higher risk of contracting HIV at work, recognized more institutional support for HIV care, and reported a lower level of avoidance attitude toward PLH compared to those from the province with lower HIV prevalence. After confounding factors were standardized across provinces, occupational exposure experience was determined to be the strongest influence on the discrepancy of avoidance attitudes in the two provinces. Regional contextual factors could shape individual providers' attitudes and beliefs and impact the quality of care. Stigma reduction interventions need to be culturally tailored and region-specific. PMID- 22537487 TI - Intravenous thrombolysis in ischaemic stroke secondary to cervical artery dissection: safe but not effective? PMID- 22537486 TI - Anti-proliferative effects of Salacia reticulata leaves hot-water extract on interleukin-1beta-activated cells derived from the synovium of rheumatoid arthritis model mice. AB - BACKGROUND: Salacia reticulata (SR) is a plant native to Sri Lanka. In ayurvedic medicine, SR bark preparations, taken orally, are considered effective in the treatment of rheumatism and diabetes. We investigated the ability of SR leaves (SRL) to inhibit in vitro the interleukin-1beta (IL-1beta)-activated proliferation of synoviocyte-like cells derived from rheumatoid arthritis model mice. FINDINGS: Inflammatory synovial tissues were harvested from type II collagen antibody-induced arthritic mice. From these tissues, a synoviocyte-like cell line was established and named MTS-C H7. To determine whether SRL can suppress cell proliferation and gene expression in MTS-C H7 cells, fractionation of the SRL hot-water extract was performed by high-performance liquid chromatography (HPLC), liquid-liquid extraction, sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE), and protease digestion.The 50% inhibitory concentration of the SRL hot-water extract against MTS-C H7 cells proliferation was ~850 MUg/mL. Treatment with a low dose (25 MUg dry matter per millilitre) of the extract inhibited IL-1beta-induced cell proliferation and suppressed the expression of the matrix metalloproteinase (MMP) genes in MTS-C H7 cells. Various polyphenolic fractions obtained from HPLC and the fractions from liquid-liquid extraction did not affect cell proliferation. Only the residual water sample from liquid-liquid extraction significantly affected cell proliferation and the expression of MMP genes. The results of SDS-PAGE and protease digestion experiment showed that low molecular weight proteins present in SRL inhibited the IL-1beta-activated cell proliferation. CONCLUSIONS: We surmised that the residual water fraction of the SRL extract was involved in the inhibition of IL-1beta-activated cell proliferation and regulation of mRNA expression in MTS-C H7 cells. In addition, we believe that the active ingredients in the extract are low molecular weight proteins. PMID- 22537488 TI - Zebrafish sox9b is crucial for hepatopancreatic duct development and pancreatic endocrine cell regeneration. AB - Recent zebrafish studies have shown that the late appearing pancreatic endocrine cells are derived from pancreatic ducts but the regulatory factors involved are still largely unknown. Here, we show that the zebrafish sox9b gene is expressed in pancreatic ducts where it labels the pancreatic Notch-responsive cells previously shown to be progenitors. Inactivation of sox9b disturbs duct formation and impairs regeneration of beta cells from these ducts in larvae. sox9b expression in the midtrunk endoderm appears at the junction of the hepatic and ventral pancreatic buds and, by the end of embryogenesis, labels the hepatopancreatic ductal system as well as the intrapancreatic and intrahepatic ducts. Ductal morphogenesis and differentiation are specifically disrupted in sox9b mutants, with the dysmorphic hepatopancreatic ducts containing misdifferentiated hepatocyte-like and pancreatic-like cells. We also show that maintenance of sox9b expression in the extrapancreatic and intrapancreatic ducts requires FGF and Notch activity, respectively, both pathways known to prevent excessive endocrine differentiation in these ducts. Furthermore, beta cell recovery after specific ablation is severely compromised in sox9b mutant larvae. Our data position sox9b as a key player in the generation of secondary endocrine cells deriving from pancreatic ducts in zebrafish. PMID- 22537489 TI - Polyclonal origin and hair induction ability of dermal papillae in neonatal and adult mouse back skin. AB - Hair follicle development and growth are regulated by Wnt signalling and depend on interactions between epidermal cells and a population of fibroblasts at the base of the follicle, known as the dermal papilla (DP). DP cells have a distinct gene expression signature from non-DP dermal fibroblasts. However, their origins are largely unknown. By generating chimeric mice and performing skin reconstitution assays we show that, irrespective of whether DP form during development, are induced by epidermal Wnt activation in adult skin or assemble from disaggregated cells, they are polyclonal in origin. While fibroblast proliferation is necessary for hair follicle formation in skin reconstitution assays, mitotically inhibited cells readily contribute to DP. Although new hair follicles do not usually develop in adult skin, adult dermal fibroblasts are competent to contribute to DP during hair follicle neogenesis, irrespective of whether they originate from skin in the resting or growth phase of the hair cycle or skin with beta-catenin-induced ectopic follicles. We propose that during skin reconstitution fibroblasts may be induced to become DP cells by interactions with hair follicle epidermal cells, rather than being derived from a distinct subpopulation of cells. PMID- 22537491 TI - Zebrafish bcl2l is a survival factor in thyroid development. AB - Regulated cell death, defined in morphological terms as apoptosis, is crucial for organ morphogenesis. While differentiation of the thyroid gland has been extensively studied, nothing is yet known about the survival mechanisms involved in the development of this endocrine gland. Using the zebrafish model system, we aim to understand whether genes belonging to the Bcl-2 family that control apoptosis are implicated in regulation of cell survival during thyroid development. Evidence of strong Bcl-2 gene expression in mouse thyroid precursors prompted us to investigate the functions played by its zebrafish homologs during thyroid development. We show that the bcl2-like (bcl2l) gene is expressed in the zebrafish thyroid primordium. Morpholino-mediated knockdown and mutant analyses revealed that bcl2l is crucial for thyroid cell survival and that this function is tightly modulated by the transcription factors pax2a, nk2.1a and hhex. Also, the bcl2l gene appears to control a caspase-3-dependent apoptotic mechanism during thyroid development. Thyroid precursor cells require an actively maintained survival mechanism to properly proceed through development. The bcl2l gene operates in the inhibition of cell death under direct regulation of a thyroid specific set of transcription factors. This is the first demonstration of an active mechanism to ensure survival of the thyroid primordium during morphogenesis. PMID- 22537490 TI - E-cadherin regulates the behavior and fate of epithelial stem cells and their progeny in the mouse incisor. AB - Stem cells are essential for the regeneration and homeostasis of many organs, such as tooth, hair, skin, and intestine. Although human tooth regeneration is limited, a number of animals have evolved continuously growing teeth that provide models of stem cell-based organ renewal. A well-studied model is the mouse incisor, which contains dental epithelial stem cells in structures known as cervical loops. These stem cells produce progeny that proliferate and migrate along the proximo-distal axis of the incisor and differentiate into enamel forming ameloblasts. Here, we studied the role of E-cadherin in behavior of the stem cells and their progeny. Levels of E-cadherin are highly dynamic in the incisor, such that E-cadherin is expressed in the stem cells, downregulated in the transit-amplifying cells, re-expressed in the pre-ameloblasts and then downregulated again in the ameloblasts. Conditional inactivation of E-cadherin in the cervical loop led to decreased numbers of label-retaining stem cells, increased proliferation, and decreased cell migration in the mouse incisor. Using both genetic and pharmacological approaches, we showed that Fibroblast Growth Factors regulate E-cadherin expression, cell proliferation and migration in the incisor. Together, our data indicate that E-cadherin is an important regulator of stem cells and their progeny during growth of the mouse incisor. PMID- 22537492 TI - Defining structural homology between the mammalian and avian hippocampus through conserved gene expression patterns observed in the chick embryo. AB - The mammalian hippocampus, a center of neurogenesis in the adult brain, is involved in critical functions such as learning and memory processing. Although there is an overall functional conservation between birds and mammals in the hippocampal region of the brain, there are several morphological differences. A few different models have been proposed for identifying regional and structural homology between the avian and mammalian hippocampus however a consensus is yet to be reached. In this study we have systematically and comprehensively characterized the developing chicken hippocampus at the molecular level. We have identified the time window of neurogenesis and apoptosis during hippocampal development as well as the likely origin and migration path of neurons of the ventral v-shaped region of chick hippocampus. In addition to this we have identified several genes with expression patterns that are conserved between the hippocampus of chicken and mice. Our study provides molecular data that partially supports one of the models reported in literature for structural homology between the avian and mammalian hippocampus. Functional characterization of the genes found in this study to be specifically expressed in the developing chicken hippocampus is likely to provide valuable information on the mechanisms regulating hippocampus development of birds and perhaps could be extrapolated to mammalian hippocampus development as well. PMID- 22537493 TI - Cadherin-6B stimulates an epithelial mesenchymal transition and the delamination of cells from the neural ectoderm via LIMK/cofilin mediated non-canonical BMP receptor signaling. AB - We previously provided evidence that cadherin-6B induces de-epithelialization of the neural crest prior to delamination and is required for the overall epithelial mesenchymal transition (EMT). Furthermore, de-epithelialization induced by cadherin-6B was found to be mediated by BMP receptor signaling independent of BMP. We now find that de-epithelialization is mediated by non-canonical BMP signaling through the BMP type II receptor (BMPRII) and not by canonical Smad dependent signaling through BMP Type I receptor. The LIM kinase/cofilin pathway mediates non-canonical BMPRII induced de-epithelialization, in response to either cadherin-6B or BMP. LIMK1 induces de-epithelialization in the neural tube and dominant negative LIMK1 decreases de-epithelialization induced by either cadherin 6B or BMP. Cofilin is the major known LIMK1 target and a S3A phosphorylation deficient mutated cofilin inhibits de-epithelialization induced by cadherin-6B as well as LIMK1. Importantly, LIMK1 as well as cadherin-6B can trigger ectopic delamination when co-expressed with the competence factor SOX9, showing that this cadherin-6B stimulated signaling pathway can mediate the full EMT in the appropriate context. These findings suggest that the de-epithelialization step of the neural crest EMT by cadherin-6B/BMPRII involves regulation of actin dynamics via LIMK/cofilin. PMID- 22537494 TI - Zebrafish globin switching occurs in two developmental stages and is controlled by the LCR. AB - Globin gene switching is a complex, highly regulated process allowing expression of distinct globin genes at specific developmental stages. Here, for the first time, we have characterized all of the zebrafish globins based on the completed genomic sequence. Two distinct chromosomal loci, termed major (chromosome 3) and minor (chromosome 12), harbor the globin genes containing alpha/beta pairs in a 5'-3' to 3'-5' orientation. Both these loci share synteny with the mammalian alpha-globin locus. Zebrafish globin expression was assayed during development and demonstrated two globin switches, similar to human development. A conserved regulatory element, the locus control region (LCR), was revealed by analyzing DNase I hypersensitive sites, H3K4 trimethylation marks and GATA1 binding sites. Surprisingly, the position of these sites with relation to the globin genes is evolutionarily conserved, despite a lack of overall sequence conservation. Motifs within the zebrafish LCR include CACCC, GATA, and NFE2 sites, suggesting functional interactions with known transcription factors but not the same LCR architecture. Functional homology to the mammalian alpha-LCR MCS-R2 region was confirmed by robust and specific reporter expression in erythrocytes of transgenic zebrafish. Our studies provide a comprehensive characterization of the zebrafish globin loci and clarify the regulation of globin switching. PMID- 22537495 TI - Engrailed cooperates directly with Extradenticle and Homothorax on a distinct class of homeodomain binding sites to repress sloppy paired. AB - Even skipped (Eve) and Engrailed (En) are homeodomain-containing transcriptional repressors with similar DNA binding specificities that are sequentially expressed in Drosophila embryos. The sloppy-paired (slp) locus is a target of repression by both Eve and En. At blastoderm, Eve is expressed in 7 stripes that restrict the posterior border of slp stripes, allowing engrailed (en) gene expression to be initiated in odd-numbered parasegments. En, in turn, prevents expansion of slp stripes after Eve is turned off. Prior studies showed that the two tandem slp transcription units are regulated by cis-regulatory modules (CRMs) with activities that overlap in space and time. An array of CRMs that generate 7 stripes at blastoderm, and later 14 stripes, surround slp1 (Fujioka and Jaynes, 2012). Surprisingly given their similarity in DNA binding specificity and function, responsiveness to ectopic Eve and En indicates that most of their direct target sites are either in distinct CRMs, or in different parts of coregulated CRMs. We localized cooperative binding sites for En, with the homeodomain-containing Hox cofactors Extradenticle (Exd) and Homothorax (Hth), within two CRMs that drive similar expression patterns. Functional analysis revealed two distinct, redundant sites within one CRM. The other CRM contains a single cooperative site that is both necessary and sufficient for repression in the en domain. Correlating in vivo and in vitro analysis suggests that cooperativity with Exd and Hth is a key ingredient in the mechanism of En dependent repression, and that apparent affinity in vitro is an unreliable predictor of in vivo function. PMID- 22537496 TI - Hh-induced Smoothened conformational switch is mediated by differential phosphorylation at its C-terminal tail in a dose- and position-dependent manner. AB - The activation of Smoothened (Smo) requires phosphorylation at three clusters of Serine residues in Drosophila Hedgehog (Hh) signaling. However, the mechanism by which phosphorylation promotes Smo conformational change and subsequently activates Smo in response to Hh gradient remains unclear. Here, we show that the conformational states of Smo are determined by not only the amount but also the position of the negative charges provided by phosphorylation. By using a Smo phospho-specific antibody, we demonstrate that Smo is differentially phosphorylated at three clusters of serine residues in response to levels of Hh activity. Mutating the first cluster, compared to mutating the other clusters, impairs Smo activity more severely, whereas mutating the last cluster prohibits C terminus dimerization. In addition, phosphorylation of the membrane proximal cluster promotes phosphorylation of the distal cluster. We propose a zipper-lock model in which the gradual phosphorylation at these clusters induces a gradual conformational change in the Smo cytoplasmic tail, which promotes the interaction between Smo and Costal2 (Cos2). Moreover, we show that Hh regulates both PKA and CK1 phosphorylation of Smo. Thus, the differential phosphorylation of Smo mediates the thresholds of Hh activity. PMID- 22537497 TI - Drosophila melanogaster Zelda and Single-minded collaborate to regulate an evolutionarily dynamic CNS midline cell enhancer. AB - The Drosophila Zelda transcription factor plays an important role in regulating transcription at the embryonic maternal-to-zygotic transition. However, expression of zelda continues throughout embryogenesis in cells including the developing CNS and trachea, but little is known about its post-blastoderm functions. In this paper, it is shown that zelda directly controls CNS midline and tracheal expression of the link (CG13333) gene, as well as link blastoderm expression. The link gene contains a 5' enhancer with multiple Zelda TAGteam binding sites that in vivo mutational studies show are required for link transcription. The link enhancer also has a binding site for the Single minded:Tango and Trachealess:Tango bHLH-PAS proteins that also influences link midline and tracheal expression. These results provide an example of how a transcription factor (Single-minded or Trachealess) can interact with distinct co regulatory proteins (Zelda or Sox/POU-homeodomain proteins) to control a similar pattern of expression of different target genes in a mechanistically different manner. While zelda and single-minded midline expression is well-conserved in Drosophila, midline expression of link is not well-conserved. Phylogenetic analysis of link expression suggests that ~60 million years ago, midline expression was nearly or completely absent, and first appeared in the melanogaster group (including D. melanogaster, D. yakuba, and D. erecta) >13 million years ago. The differences in expression are due, in part, to sequence polymorphisms in the link enhancer and likely due to altered binding of multiple transcription factors. Less than 6 million years ago, a second change occurred that resulted in high levels of expression in D. melanogaster. This change may be due to alterations in a putative Zelda binding site. Within the CNS, the zelda gene is alternatively spliced beginning at mid-embryogenesis into transcripts that encode a Zelda isoform missing three zinc fingers from the DNA binding domain. This may result in a protein with altered, possibly non-functional, DNA binding properties. In summary, Zelda collaborates with bHLH-PAS proteins to directly regulate midline and tracheal expression of an evolutionary dynamic enhancer in the post-blastoderm embryo. PMID- 22537498 TI - The Nkx5/HMX homeodomain protein MLS-2 is required for proper tube cell shape in the C. elegans excretory system. AB - Cells perform wide varieties of functions that are facilitated, in part, by adopting unique shapes. Many of the genes and pathways that promote cell fate specification have been elucidated. However, relatively few transcription factors have been identified that promote shape acquisition after fate specification. Here we show that the Nkx5/HMX homeodomain protein MLS-2 is required for cellular elongation and shape maintenance of two tubular epithelial cells in the C. elegans excretory system, the duct and pore cells. The Nkx5/HMX family is highly conserved from sea urchins to humans, with known roles in neuronal and glial development. MLS-2 is expressed in the duct and pore, and defects in mls-2 mutants first arise when the duct and pore normally adopt unique shapes. MLS-2 cooperates with the EGF-Ras-ERK pathway to turn on the LIN-48/Ovo transcription factor in the duct cell during morphogenesis. These results reveal a novel interaction between the Nkx5/HMX family and the EGF-Ras pathway and implicate a transcription factor, MLS-2, as a regulator of cell shape. PMID- 22537500 TI - Nerve signaling regulates basal keratinocyte proliferation in the blastema apical epithelial cap in the axolotl (Ambystoma mexicanum). AB - The ability of adult vertebrates to repair tissue damage is widespread and impressive; however, the ability to regenerate structurally complex organs such as the limb is limited largely to the salamanders. The fact that most of the tissues of the limb can regenerate has led investigators to question and identify the barriers to organ regeneration. From studies in the salamander, it is known that one of the earliest steps required for successful regeneration involves signaling between nerves and the wound epithelium/apical epithelial cap (AEC). In this study we confirm an earlier report that the keratinocytes of the AEC acquire their function coincident with exiting the cell cycle. We have discovered that this unique, coordinated behavior is regulated by nerve signaling and is associated with the presence of gap junctions between the basal keratinocytes of the AEC. Disruption of nerve signaling results in a loss of gap junction protein, the reentry of the cells into the cell cycle, and regenerative failure. Finally, coordinated exit from the cell cycle appears to be a conserved behavior of populations of cells that function as signaling centers during both development and regeneration. PMID- 22537501 TI - Evaluation of the analytical performance of a fuel cell breath alcohol testing instrument: a seven-year comprehensive study. AB - Between 2003 and 2009, 54,255 breath test sequences were performed on 129 AlcoSensor IV-XL evidential instruments in Orange County, CA. The overall mean breath alcohol concentration and standard deviation from these tests was 0.141 +/ 0.051 g/210 L. Of these test sequences, 38,580 successfully resulted in two valid breath alcohol results, with 97.5% of these results agreeing within +/ 0.020 g/210 L of each other and 86.3% within +/-0.010 g/210 L. The mean absolute difference between duplicate tests was 0.006 g/210 L with a median of 0.004 g/210 L. Of the 2.5% of duplicate test results that did not agree within +/-0.020 g/210 L, 95% of these had a breath alcohol concentration of 0.10 g/210 L or greater and 77% had an alcohol concentration of 0.15 g/210 L or greater. The data indicate that the AlcoSensor IV-XL can measure a breath sample for alcohol concentration with adequate precision even amid the effects of biological variations. PMID- 22537499 TI - beta-Catenin stabilization in skeletal muscles, but not in motor neurons, leads to aberrant motor innervation of the muscle during neuromuscular development in mice. AB - beta-Catenin, a key component of the Wnt signaling pathway, has been implicated in the development of the neuromuscular junction (NMJ) in mice, but its precise role in this process remains unclear. Here we use a beta-catenin gain-of-function mouse model to stabilize beta-catenin selectively in either skeletal muscles or motor neurons. We found that beta-catenin stabilization in skeletal muscles resulted in increased motor axon number and excessive intramuscular nerve defasciculation and branching. In contrast, beta-catenin stabilization in motor neurons had no adverse effect on motor innervation pattern. Furthermore, stabilization of beta-catenin, either in skeletal muscles or in motor neurons, had no adverse effect on the formation and function of the NMJ. Our findings demonstrate that beta-catenin levels in developing muscles in mice are crucial for proper muscle innervation, rather than specifically affecting synapse formation at the NMJ, and that the regulation of muscle innervation by beta catenin is mediated by a non-cell autonomous mechanism. PMID- 22537502 TI - CAD-associated reader error in CT colonography. AB - RATIONALE AND OBJECTIVES: Computed tomographic colonographic interpretation with computer-aided detection (CAD) may be superior to unaided viewing, although polyp characteristics may influence accuracy. Reader error due to polyp characteristics was evaluated in a multiple-case, multiple-reader trial of computed tomographic colonography with CAD. MATERIALS AND METHODS: Two experts retrospectively reviewed 52 positive cases (74 polyps) and categorized them as hard, moderate, or easy to detect. Each case was evaluated without and with CAD. Features that may influence a reader's ability to detect a polyp or to accept or reject a CAD mark were tabulated. The association between polyp characteristics and detection rates in the trial was assessed. The difference in detection rates (CAD vs unassisted) was calculated, and regression analysis was performed. RESULTS: Of 64 polyps found by CAD, experts categorized 20 as hard, 28 as moderate, and 16 as easy to detect. Reader characterization errors predominated (47.3%) over other errors. Factors associated with lower detection rates included small size, flat morphology, and resemblance to a thickened fold. CAD was superior for polyps resembling lipomas compared to those that did not resemble lipomas (average increase in detection rate with CAD, 12.8% vs 5.5%; P < .05). CONCLUSIONS: Polyp characteristic may impair computed tomographic colonographic interpretation augmented by CAD. Readers can avoid errors of measurement by evaluating diminutive polyp candidates with sample measurements. Caution should be taken when evaluating focally thick folds and when using visual impression to dismiss a polyp candidate as a lipoma when it is submerged in densely tagged fluid. PMID- 22537503 TI - Comparison of radiologist performance with photon-counting full-field digital mammography to conventional full-field digital mammography. AB - RATIONALE AND OBJECTIVES: The purpose of this study was to assess the performance of a MicroDose photon-counting full-field digital mammography (PCM) system in comparison to full-field digital mammography (FFDM) for area under the receiver operating characteristic (ROC) curve (AUC), sensitivity, specificity, and feature analysis of standard-view mammography for women presenting for screening mammography, diagnostic mammography, or breast biopsy. MATERIALS AND METHODS: A total of 133 women were enrolled in this study at two European medical centers, with 67 women who had a pre-existing 10-36 months FFDM enrolled prospectively into the study and 66 women who underwent breast biopsy and had screening PCM and diagnostic FFDM, including standard craniocaudal and mediolateral oblique views of the breast with the lesion, enrolled retrospectively. The case mix consisted of 49 cancers, 17 biopsy-benign cases, and 67 normal cases. Sixteen radiologists participated in the reader study and interpreted all 133 cases in both conditions, separated by washout period of >=4 weeks. ROC curve and free-response ROC curve analyses were performed for noninferiority of PCM compared to FFDM using a noninferiority margin Delta value of 0.10. Feature analysis of the 66 cases with lesions was conducted with all 16 readers at the conclusion of the blinded reads. Mean glandular dose was recorded for all cases. RESULTS: The AUC for PCM was 0.947 (95% confidence interval [CI], 0.920-0.974) and for FFDM was 0.931 (95% CI, 0.898-0.964). Sensitivity per case for PCM was 0.936 (95% CI, 0.897-0.976) and for FFDM was 0.908 (95% CI, 0.856-0.960). Specificity per case for PCM was 0.764 (95% CI, 0.688-0.841) and for FFDM was 0.749 (95% CI, 0.668 0.830). Free-response ROC curve figures of merit were 0.920 (95% CI, 0.881-0.959) and 0.903 (95% CI, 0.858-0.948) for PCM and FFDM, respectively. Sensitivity per lesion was 0.903 (95% CI, 0.846-0.960) and 0.883 (95% CI, 0.823-0.944) for PCM and FFDM, respectively. The average false-positive marks per image of noncancer cases were 0.265 (95% CI, 0.171-0.359) and 0.281 (95% CI, 0.188-0.374) for PCM and FFDM, respectively. Noninferiority P values for AUC, sensitivity (per case and per lesion), specificity, and average false-positive marks per image were all statistically significant (P < .001). The noninferiority P value for free response ROC was <.025, from the 95% CI for the difference. Feature analysis resulted in PCM being preferred to FFDM by the readers for >=70% of the cases. The average mean glandular dose for PCM was 0.74 mGy (95% CI, 0.722-0.759 mGy) and for FFDM was 1.23 mGy (95% CI, 1.199-1.262 mGy). CONCLUSIONS: In this study, radiologist performance with PCM was not inferior to that with conventional FFDM at an average 40% lower mean glandular dose. PMID- 22537504 TI - Improved understanding of human anatomy through self-guided radiological anatomy modules. AB - RATIONALE AND OBJECTIVE: To quantifiably measure the impact of self-instructed radiological anatomy modules on anatomy comprehension, demonstrated by radiology, gross, and written exams. MATERIALS AND METHODS: Study guides for independent use that emphasized structural relationships were created for use with two online radiology atlases. A guide was created for each module of the first year medical anatomy course and incorporated as an optional course component. A total of 93 of 96 eligible students participated. All exams were normalized to control for variances in exam difficulty and body region tested. An independent t-test was used to compare overall exam scores with respect to guide completion or incompletion. To account for aptitude differences between students, a paired t test of each student's exam scores with and without completion of the associated guide was performed, thus allowing students to serve as their own controls. RESULTS: Twenty-one students completed no study guides; 22 completed all six guides; and 50 students completed between one and five guides. Aggregate comparisons of all students' exam scores showed significantly improved mean performance when guides were used (radiology, 57.8% [percentile] vs. 45.1%, P < .001; gross, 56.9% vs. 46.5%, P = .001; written, 57.8% vs. 50.2%, P = .011). Paired comparisons among students who completed between one and five guides demonstrated significantly higher mean practical exam scores when guides were used (radiology, 49.3% [percentile] vs. 36.0%, P = .001; gross, 51.5% vs. 40.4%, P = .005), but not higher written scores. CONCLUSIONS: Radiological anatomy study guides significantly improved anatomy comprehension on radiology, gross, and written exams. PMID- 22537505 TI - Bromelain, a cysteine protease from pineapple (Ananas comosus) stem, is an inhibitor of fungal plant pathogens. AB - AIM: This study aimed to evaluate the effect of bromelain, a cysteine protease isolated from pineapple (Ananas comosus), on growth of several agronomically important fungal pathogens. METHODS AND RESULTS: Purification of bromelain from pineapple stems was carried out by chromatography techniques, and its antimicrobial activity was tested against the fungal pathogens Fusarium verticillioides, Fusarium oxysporum and Fusarium proliferatum by broth microdilution assay. A concentration of 0.3 MUmol l(-1) of bromelain was sufficient for 90% growth inhibition of F. verticillioides. The capability of bromelain to inhibit fungal growth is related to its proteolytic activity. CONCLUSIONS: The study demonstrates that stem bromelain exhibits a potent antifungal activity against phytopathogens and suggests its potential use as an effective agent for crop protection. SIGNIFICANCE AND IMPACT OF THE STUDY: The results support the use of a natural protease that accumulates at high levels in pineapple stems as alternative to the use of chemical fungicides for crop protection. PMID- 22537507 TI - Abstracts of the London Trauma and Pre-Hospital Care Conference. London, United Kingdom. June 22-24, 2011. PMID- 22537506 TI - Urinary trypsin inhibitor reduced inflammatory response after stent injury in minipig. AB - This study investigated whether urinary trypsin inhibitor (UTI) inhibits neointimal formation by reducing inflammatory response after stent injury. Twenty minipigs having undergone oversized bare material stent implantation in the left anterior descending artery were randomly subdivided into two groups: a UTI group (n=10) and a control group (n=10). Two systemic markers of inflammation (serum macrophage chemoattractant protein-1 and interleukin-6 levels measured by ELISA) were increased after stent implantation, and two days after stem implantation, their levels were positively correlated with the maximal percentage of area stenosis on day 28 (r(2)=0.889 and 0.743, respectively). This effect was abolished by UTI administration. Twenty-eight days after implantation, morphometric analysis of the stented arteries revealed significantly reduced luminal stenosis (38+/-6% vs. 64+/-12%, P<0.05), a neointimal area (3.22+/-0.57 mm(2) vs. 5.21+/-1.04 mm(2), P<0.05), neointimal thickness (0.31+/-0.13 mm vs. 0.46+/-0.16 mm, P<0.05), and an inflammatory score of 1.02+/-0.05 vs. 1.30+/-0.08 in UTI-treated animals as compared with controls. Twenty-eight days after stenting, arterial nuclear factor-kappaB expression was 36.93+/-7.16% in all of the cells in controls and 23.32+/-4.54% in UTI-treated minipigs. UTI could reduce neointimal formation after stenting by inhibiting the local and the systemic inflammatory response. Percutaneous coronary intervention could benefit from precocious anti-inflammatory treatment. PMID- 22537508 TI - Effects of an integrated approach of hatha yoga therapy on functional disability, pain, and flexibility in osteoarthritis of the knee joint: a randomized controlled study. AB - OBJECTIVES: The study objectives were to evaluate the efficacy of integrating hatha yoga therapy with therapeutic exercises for osteoarthritis (OA) of the knee joints. DESIGN: This was a prospective, randomized, active controlled trial. Two hundred and fifty (250) participants who had OA knees and who were between 35 and 80 years (yoga 59.56+/-9.54) and (control 59.42+/-10.66) from the outpatient department of Ebnezar Orthopedic Center, Bengaluru, were randomly assigned to receive hatha yoga therapy or therapeutic exercises after transcutaneous electrical stimulation and ultrasound treatment (20 minutes per day). Both of the groups practiced supervised interventions (40 minutes per day) for 3 months. One hundred and eighteen (118) (yoga) and 117 (control) subjects were available for the final analysis. RESULTS: There were significant differences within (Wilcoxon's, p<0.001) and between the groups (Mann-Whitney U, p<0.001) on all the variables, with better improvements in the yoga than the control groups. Walking pain in the yoga (37.3%, 64.9%) and control (24.9%, 42%), knee disability in the yoga (59.7%, 83%) and control (32.7%, 53.6%), range of knee flexion in yoga (12.7%, 26.5% right, 13.5%, 28% left) and control (6.9%, 13.3% right, 5.6%, 11.5% left), joint tenderness in yoga (52.3%, 86.1%) and control (28%, 57.1%), swelling in yoga (55.4%, 85.9%) and control (32.1%, 60%), crepitus in yoga (44.0%, 79.9%) and control (27.0%, 47.8%) and walking time in yoga (26.6%, 52.8%) and control (9.3%, 21.6%), all improved more in the yoga than the control groups on the 15th and 90th day, respectively. CONCLUSIONS: An integrated approach of hatha yoga therapy is better than therapeutic exercises as an adjunct to transcutaneous electrical stimulation and ultrasound treatment in improving walking pain, range of knee flexion, walking time, tenderness, swelling, crepitus, and knee disability in patients with OA knees. PMID- 22537509 TI - Gemcitabine and paclitaxel combination as second-line chemotherapy in patients with small-cell lung cancer: a phase II study. AB - BACKGROUND: Although small-cell lung cancer is a chemosensitive malignancy, most patients rapidly relapse. Results of second-line treatment are generally poor. We conducted a phase II study to evaluate the activity and toxicity of a combination of gemcitabine and paclitaxel as second-line chemotherapy. PATIENTS AND METHODS: Eligible patients were refractory or relapsed small-cell lung cancer, with an Eastern Cooperative Oncology Group performance status of 0-2 and measurable disease. Paclitaxel was administered at 135 mg/m(2) days 1 and 8 immediately followed by gemcitabine at 1000 mg/m(2) every 3 weeks up to 6 courses. Restaging of disease was scheduled every 3 courses. RESULTS: Forty-one patients were enrolled. The median age was 65 years. Nineteen patients were considered refractory (progressive disease during or within 90 days from completion of first line treatment), whereas 22 patients were chemotherapy sensitive. A total of 135 courses was administered (range, 1-6; median, 3). Nine patients achieved a partial remission (partial response, 22%), and 10 patients had stable disease (24%), with a disease control rate (partial response + stable disease) of 46%: in 12 (55%) of 22 patients who were sensitive and in 7 (37%) of 19 patients with refractory disease, respectively. All partial responses but one were observed in the sensitive group. The median duration of response was 5 months. The most frequent severe toxicities were neutropenia grade 3-4 and neurologic grade 3 in 24% and 7% of delivered courses, respectively. CONCLUSIONS: The combination of gemcitabine and paclitaxel investigated in our study achieved a high disease control rate, but the schedule we adopted appeared to be quite toxic. PMID- 22537510 TI - [SIADH and vaptans]. AB - The vaptans are non-peptide arginine-vasopressin-receptor antagonists, that are orally and intravenously active. A few vaptans have undergone sufficient clinical development to be on the market. In the EU only tolvaptan is accepted to treat hyponatremia related to SIADH. The place of this new treatment is compared with water restriction, demeclocyclin, furosemide and urea. PMID- 22537511 TI - [Recent progress in the treatment of Cushing's disease]. AB - Transsphenoidal surgery, possibly through the endoscopic approach, remains the first line treatment. Opposing cortisol action with mifepristone proved efficacious in some individual cases but but with major monitoring difficulties. Combined treatment with three anticortisolic drugs (metyrapone, ketokonazole, O,p'DDD) is particularly attractive in severe cases. The Nelson's syndrome has been revisited, and the corticotroph tumor progression should rather be cautiously assessed after bilateral adrenalectomy. Two molecules potentially act directly to suppress the ACTH secretion by the corticotroph adenoma: agonists of the D2 Dopamine receptor and of the somatostatin receptor type 5. Their efficacy remains modest (20 to 30% of the patients actually normalize urinary cortisol). Pituitary radiotherapy can be efficiently performed by stereotaxic approach. PMID- 22537512 TI - Autoimmune hypophysitis: autoantigens and association with CTLA-4 blockade. PMID- 22537513 TI - Synthesis and properties of methoxyphenyl-substituted derivatives of indolo[3,2 b]carbazole. AB - The synthesis and full characterization of new derivatives of indolo[3,2 b]carbazole with differently substituted phenyl groups at nitrogen atoms is reported. Comparative study on their thermal, optical electrochemical, and photoelectrical properties is presented. The synthesized compounds are electrochemically stable. Their highest occupied molecular orbital energy values range from -5.14 to -5.07 eV. The electron photoemission spectra of the films of synthesized materials revealed the ionization potentials of 5.31-5.47 eV. Hole drift mobility of the amorphous film of 5,11-bis(3-methoxyphenyl)-6-pentyl-5,11 dihydroindolo[3,2-b]carbazole exceed 10(-3) cm(2)/V.s at high electric fields, as it was established by xerographic time-of-flight technique. In contrast to diphenylamino substituted derivatives of carbazole, no effect of the position of methoxy groups on the photoelectrical properties was observed for the synthesized methoxyphenyl-substituted derivatives of indolo[3,2-b]carbazole. The indolo[3,2 b]carbazole core has a larger resonance structure that includes 3 phenyl rings, and thus the energy gap of the HOMO and LUMO pi orbitals is lower as compared to that of carbazoles. With a larger energy difference between the phenyl substituents and the core moiety, the indolo[3,2-b]carbazole derivatives studied all have a weaker coupling between the phenyl group and a much weaker dependence of the molecular properties on the position of substituents on the phenyl groups as compared to those observed in substituted carbazoles. PMID- 22537514 TI - [Stimulated sweating in order to improve the water-and-salt balance in hemodialysis patients. A case report]. AB - Obtaining the desired dry weight in dialysis patients is challenging once residual diuresis has disappeared, considering the trend of increasing dietary salt intake and shortening dialysis time over the last 40 years. We describe the case of a 55-year-old patient of Sudanese origin, who presented excessive interdialytic weight gain and hypertension on maintenance hemodialysis. After failure of conservative measures, a therapy of daily hot water baths of 30 minutes each on non-dialysis days was introduced. All clinical parameters improved, including potassium profile. In this article, we review the history, pathophysiological mechanisms, efficacy and possible side effects of this interesting, somewhat forgotten technique. PMID- 22537515 TI - [Local haemostasis with an adhesive cyanoacrylate-coated membrane following tooth extraction in patients under anticoagulant or anti-platelet therapy]. AB - OBJECTIVE: Assessment of a local hemostasis with a compressive, extemporaneous gutter glued to the alveolar crest after tooth avulsion in patients under anticoagulant and/or platelet aggregation inhibitors, and economical impact of this technique. MATERIAL AND METHOD: Ninety-seven tooth extractions were performed in patients under AVK and/or anti-platelet drugs. The interventions were consecutive and concerned 251 teeth (138 different alveolar sites). The extraction alveolus was protected by an absorbable oxycellulose membrane coated with sterilized cyanoacrylate adhesive for medical use. This procedure was used with all patients, whatever the hemorrhagic risk (the only inclusion criterion was INR less than 4 for patients under AVK). All procedures were performed under local anesthesia. RESULTS: There was one hemorrhagic complication (0.72%) due to mechanical gutter destruction by an antagonist tooth. The adhesive did not run, there was no tissue necrosis, and no wound infection requiring gutter removal. DISCUSSION: This local hemostasis procedure is reliable. It may be an alternative to substitution of heparin, without or with hospitalization. This procedure, requiring modification of treatment, greatly decreases healthcare costs. Contra indications include the presence of an antagonist tooth harmful for the gutter, and patients with impaired consciousness or tongue dyspraxia. PMID- 22537516 TI - An accurate maxillary superior repositioning technique without intraoperative measurement in bimaxillary orthognathic surgery. AB - This article describes a simple and accurate technique for maxillary superior repositioning without any intraoperative measurement using reference points that can be the source of error in bimaxillary orthognathic surgery. A bilateral straight locking miniplates (SLMs)/screw system secured to the maxilla and mandible maintains the three-dimensional relationship between the mandible and the skull base precisely like the incisor pin of an articulator in model surgery. The maxilla can then be accurately moved into the planned position identical to that in model surgery by the SLMs technique. PMID- 22537518 TI - A mass spectrometric line for tritium analysis of water and noble gas measurements from different water amounts in the range of microlitres and millilitres. AB - This paper describes the procedure followed for noble gas measurements for litres, millilitres and microlitres of water samples in our laboratory, including sample preparation, mass spectrometric measurement procedure, and the complete calibrations. The preparation line extracts dissolved gases from water samples of volumes of 0.2 MU l to 3 l and it separates them as noble and other chemically active gases. Our compact system handles the following measurements: (i) determination of tritium concentration of environmental water samples by the (3)He ingrowth method; (ii) noble gas measurements from surface water and groundwater; and (iii) noble gas measurements from fluid inclusions of solid geological archives (e.g. speleothems). As a result, the tritium measurements have a detection limit of 0.012 TU, and the expectation value (between 1 and 20 TU) is within 0.2 % of the real concentrations with a standard deviation of 2.4 %. The reproducibility of noble gas measurements for water samples of 20-40 ml allows us to determine solubility temperatures by an uncertainty better than 0.5 degrees C. Moreover, noble gas measurements for tiny water amounts (in the microlitre range) show that the results of the performed calibration measurements for most noble gas isotopes occur with a deviation of less than 2 %. Theoretically, these precisions for noble gas concentrations obtained from measurements of waters samples of a few microlitres allow us to determine noble gas temperatures by an uncertainty of less than 1 degrees C. Here, we present the first noble gas measurements of tiny amounts of artificial water samples prepared under laboratory conditions. PMID- 22537517 TI - Maxillary stability after Le Fort I osteotomy using three different plate systems. AB - The purpose of this study was to compare postoperative changes in maxillary stability after Le Fort I osteotomy in three groups: with an unsintered hydroxyapatite (u-HA)/poly-L-lactic acid (PLLA) plate; a PLLA plate; and a titanium plate. Subjects comprised 60 Japanese patients diagnosed with mandibular prognathism. All patients underwent Le Fort I osteotomy and bilateral sagittal split ramus osteotomy. All patients were randomized in groups of 20 to a u HA/PLLA group, a PLLA plate group and a titanium plate group. Changes in postoperative time intervals between the plate groups were compared using lateral and posteroanterior cephalography. The uHA/PLLA group had significantly larger values than the PLLA group regarding change of mx1-S perpendicular to SN between 3 and 12 months (T3) (P=0.0269). The uHA/PLLA group had a significantly larger value than the PLLA group regarding change of S-A perpendicular to SN between baseline and 1 month (T1) (P=0.0257). There was no significant difference in the other measurements. This study suggests that maxillary stability with satisfactory results could be obtained in the u-HA/PLLA, PLLA plate and titanium plate groups, although there was a slight difference between the u-HA/PLLA and PLLA plate systems in Le Fort I osteotomy. PMID- 22537519 TI - A prospective evaluation of neonatal hypoglycaemia in infants of women with gestational diabetes mellitus. AB - OBJECTIVE: To analyse first-day-of-life glucose levels in infants of women with gestational diabetes (GDM) and the influence of maternal, gestational and peripartum factors on the development of neonatal hypoglycaemia. STUDY DESIGN: Prospective cohort study including newborns of GDM mothers. Capillary blood glucose (CBG) was measured serially on the first day of life. CBG values were defined as normal (>= 2.5 mmol/l), mild hypoglycaemia (2.2-2.4 mmol/l), moderate hypoglycaemia (1.6-2.1 mmol/l) and severe hypoglycaemia (<1.6 mmol/l). RESULTS: One hundred and ninety infants were included: 23 (12.1%) presented mild, 20 (10.5%) moderate and only 5 (2.6%) severe hypoglycaemia. Hypoglycaemic infants were more frequently large-for-gestational-age (29.3% vs 11.3%, p=0.003), had lower umbilical cord pH (7.28 vs 7.31, p=0.03) and their mothers had more frequently been hyperglycaemic during labour (18.8% vs 8.5%, p=0.04). In multivariate analysis Pakistani origin (OR: 2.94; 95% CI: 1.14-7.55) and umbilical cord venous pH (OR: 0.04, 95% CI: 0.261-0.99) were significantly and independently associated with hypoglycaemia. CONCLUSIONS: Mild and moderate neonatal hypoglycaemias were common although severe episodes were unusual in infants of women with GDM. Hypoglycaemia is mainly influenced by ethnicity and cord blood pH, although maternal peripartum glycaemic control and large-for gestational-age condition may also play a role. PMID- 22537520 TI - Teacher-child relationships from an attachment perspective. AB - This special issue aims to prompt reflection on the mutual contribution of attachment theory, on the one hand, and teacher-child relationship research, on the other, by bringing together conceptual and empirical contributions taking an attachment perspective on teacher-child relationships. In this introductory article, we contend that the teacher can be regarded as an ad hoc attachment figure with a safe haven and secure base function, although for most children the relationship with the teacher is probably not an attachment bond. Furthermore, we explain how attachment theory and research: (1) shape the way in which "high quality" teacher-child relationships are conceptualized and operationalized; (2) highlight the importance of teacher sensitivity to children's needs, as a central proximal determinant of relationship quality; (3) guide research hypotheses regarding the consequences of teacher-child relationship quality and the intervening mechanisms; and (4) inspire the development of interventions to improve teacher-child relationships. PMID- 22537521 TI - Recent trends in research on teacher-child relationships. AB - Theoretical and empirical work on relationships between teachers and children relies on developmental systems theory as the foundational conceptual model, drawing heavily from basic work in attachment as well as research on social development. Recently, the focus on relational processes in effort to support children's development in the classroom has proliferated, with multiple disciplines and fields engaging in research on teacher-child relationship quality to understand and improve the experiences and learning of students. This paper updates the conceptual framework and continues the necessary integration between disciplines by exploring three areas of research: (1) concordance between children's relationships with teachers and parents; (2) the moderating role of teacher-child relationships for the development of at-risk children; and (3) training teachers from a relational perspective. Each of the three areas of research on teacher-child relationships is examined in light of recent findings and considers implications for understanding the nature and impact of relationships between teachers and children. PMID- 22537522 TI - Relationships with mother, teacher, and peers: unique and joint effects on young children's self-concept. AB - This study tested the unique and joint effects of three significant relationships in young children's social lives, namely their relationships with mother, teacher, and peers, on three dimensions of self-concept (general, academic, and social). A sample of 113 children participated. Mother-child attachment quality was observed in preschool. In first grade, teacher ratings of teacher-child relationship quality, peer ratings of peer acceptance, and child reports of self concept were administered. The results revealed domain-specific links between social relationships and self-concept dimensions. Specifically, academic self concept related to teacher-child relationship quality, social self-concept to peer acceptance, and general self-concept to the quality of attachment to mother. Moreover, an indirect effect was revealed of earlier mother-child attachment quality on the academic dimension of self through its effect on current adult child relationships in school. This way, the study uncovered the pathways through which significant social relationships shape the formation of young children's self-concept. PMID- 22537523 TI - Student-teacher relationships and classroom climate in first grade: how do they relate to students' stress regulation? AB - The present study involved 105 German students at the end of their first semester in elementary school in order to explore the stress that students may experience within the school environment, and how the relationship with the teacher buffers or exacerbates the stress. Student-teacher relationships were explored on both classroom and individual interaction levels. Classrooms were described by external observers in terms of teachers' support and classroom organization. Teachers reported on the relationships with their students regarding closeness, conflict, and dependency, which determined four specific patterns of student teacher relationships. Furthermore, saliva samples were taken on a Monday and a Friday of the same week (four times each day) to display diurnal cortisol profiles. These profiles were later evaluated by means of slopes and intercepts, reflecting students' daily stress regulation. Comparisons between Monday and Friday profiles of the same student served as an estimate for the stress regulation throughout the week. Finally, associations between the profiles and the specific relationship patterns provided information on significant environmental conditions for students' stress. Students in non-supportive, as compared to supportive, classrooms had flatter cortisol profiles, suggesting that classrooms of low quality hindered sufficient down-regulation of cortisol levels at both the beginning and the end of the week. Moreover, students with conflict loaded relationships with their teachers were less able to appropriately down regulate stress (especially on Fridays) than students with proximal-balanced relationships, showing the most optimal cortisol profiles. PMID- 22537524 TI - Behavior problems in late childhood: the roles of early maternal attachment and teacher-child relationship trajectories. AB - The purposes of the current study were: (1) to examine the roles of early maternal attachment relationships and teacher-child relationships during childhood for externalizing and internalizing behaviors in late childhood, and (2) to investigate teacher-child relationships, as well as externalizing and internalizing behaviors in early childhood as possible mechanisms linking early maternal attachment relationships to behavior problems in late childhood. Longitudinal data from the National Institute of Child Health and Human Development Early Child Care Research Network Study of Early Child Care and Youth Development (N = 1140 mothers and children) were used in this investigation. There were three main findings. First, insecure/other maternal attachment relationships in early childhood (i.e., 36 months) were associated with externalizing and internalizing behaviors in late childhood (Grade 5). Second, elevated levels of teacher-child conflict during childhood were associated with externalizing behaviors in late childhood whereas low levels of teacher-child closeness were associated with internalizing behaviors. Third, the effects of insecure/other attachment on externalizing and internalizing behaviors in late childhood were mediated through teacher-child relationships during childhood and early externalizing and internalizing behaviors. Implications for attachment theory are discussed. PMID- 22537525 TI - Teacher-student interactions and attachment states of mind as predictors of early romantic involvement and risky sexual behaviors. AB - Adolescents' capacities to negotiate sexual behavior in romantic relationships have important implications for their reproductive and health outcomes. This study examined adolescents' interactions with teachers and attachment states of mind as predictors of their romantic involvement and risky sexual behavior in an economically disadvantaged sample. Negative interactions with teachers predicted increased sexual risk-taking behaviors and females' early romantic involvement. Preoccupied states of mind increased risk for early romantic involvement and the likelihood that females would engage in risky sexual behavior. The findings demonstrate how adolescents' school experiences contribute to adaptation in romantic relationships in mid to late adolescence above and beyond representations of parent-child attachment. PMID- 22537526 TI - Supporting teachers' relationships with disruptive children: the potential of relationship-focused reflection. AB - A relationship-focused reflection program (RFRP) was developed that targeted teachers' mental representations of relationships with specific children. Relative effectiveness was examined in a randomized comparative trial with repeated measures. Thirty-two teachers were assigned to the RFRP or the comparison intervention directly aimed at teacher behavior. Per teacher, two children (N = 64) were selected with above-median levels of externalizing behavior. Multilevel growth modeling was used to explore intervention effects on teacher-reported Closeness and Conflict, and observed Teacher Sensitivity and Behavior Management Quality. Teaching Efficacy was included as a moderator. The RFRP yielded changes over time in closeness for about half of the teacher-child dyads. In addition, teachers with high efficacy beliefs were more likely to report declines in conflict than low-efficacy teachers. Lastly, significant increases were found in observed sensitivity. These effects were different from those found in the comparison condition and provided preliminary evidence for the potential of in-depth reflection on specific relationships to promote teacher child relationships. PMID- 22537527 TI - Teacher-student relationships and school adjustment: progress and remaining challenges. AB - This commentary highlights the ways in which the articles in this special issue contribute to the second generation of research on teacher-student relationships. Second generation research aims to increase our understanding of the development of these relationships, and the processes responsible for their effects, as well as to evaluate theoretically-informed interventions designed to enhance teacher student interactions. Despite unanswered questions and challenges that confront this field of inquiry, the current state of knowledge is adequate to apply the knowledge gained to the task of increasing teachers' abilities to provide positive social and emotional learning environments, thereby improving students' learning and behavioral adjustment. PMID- 22537528 TI - Teacher-child relationships as a developmental issue. AB - Teacher-child relationships may be a developmental issue in its own right, instead of an aspect of wider developmental issues such as attachment or adaptation to school. This paper discusses research findings on teacher-child relationships to argue that teacher-child relationships are important for carrying forward the experiences represented in the attachment behavioral system, although it is not clear whether teacher-child relationships themselves add to the attachment behavioral system or to the sociability behavioral system. The research demonstrates that attachment theory offers a useful template for understanding the role of teacher-child relationships in development. Listing teacher-child relationships among main developmental issues for today's children puts the spotlight on avenues for improving teacher-child relationships. PMID- 22537530 TI - Fraud or flawed ? At the end of the day it may be the patient who pays the bill ! PMID- 22537531 TI - Aortic stiffness and calcification in men in a population-based international study. AB - OBJECTIVES: Aortic stiffness, a hallmark of vascular aging, is an independent risk factor of cardiovascular disease and all-cause mortality. The association of aortic stiffness with aortic calcification in middle-aged general population remains unknown although studies in patients with end-stage renal disease or elderly subjects suggest that aortic calcification is an important determinant of aortic stiffness. The goal of this study was to examine the association of aortic calcification and stiffness in multi-ethnic population-based samples of relatively young men. METHODS: We examined the association in 906 men aged 40-49 (81 Black Americans, 276 Japanese Americans, 258 White Americans and 291 Koreans). Aortic stiffness was measured as carotid-femoral pulse wave velocity (cfPWV) using an automated waveform analyzer. Aortic calcification from aortic arch to iliac bifurcation was evaluated using electron-beam computed tomography. RESULTS: Aortic calcium score was calculated and was categorized into four groups: zero (n=303), 1-100 (n=411), 101-300 (n=110), and 401+ (n=82). Aortic calcification category had a significant positive association with cfPWV after adjusting for age, race, and mean arterial pressure (mean (standard error) of cfPWV (cm/s) from the lowest to highest categories: 836 (10), 850 (9), 877 (17) and 941 (19), P for trend <0.001). The significant positive association remained after further adjusting for other cardiovascular risk factors. The significant positive association was also observed in each race group. CONCLUSIONS: The results suggest that aortic calcification can be one mechanism for aortic stiffness and that the association of aortic calcification with stiffness starts as early as the 40s. PMID- 22537533 TI - Contemporary surgical management of cardiac paragangliomas. AB - BACKGROUND: Cardiac paragangliomas are an extremely rare subset of chromaffin cell tumors that develop from neural crest cells. METHODS: Between March 2004 and October 2010, 7 male patients from our two institutions who underwent surgical resection of cardiac paraganglioma were retrospectively reviewed. RESULTS: In 5 patients, paragangliomas originated from the roof of the left atrium, and in 2 patients, they originated from the aortic root. Hospital mortality was 14%. CONCLUSIONS: Complete surgical resection remains the mainstay of therapy and can be curative, but carries a significant risk of intraoperative bleeding and usually requires cardiopulmonary bypass and often complex resection techniques, including cardiac autotransplantation. PMID- 22537532 TI - Anti-inflammatory effect of simvastatin in an experimental model of spinal cord trauma: involvement of PPAR-alpha. AB - BACKGROUND: Statins such as simvastatin are inhibitors of 3-hydroxy-3 methylglutaryl-coenzyme A (HMG-CoA) reductase used in the prevention of cardiovascular disease. In addition to their cholesterol-lowering activities, statins exert pleiotropic anti-inflammatory effects, which might contribute to their beneficial effects on lipid-unrelated inflammatory diseases. Recently it has been demonstrated that the peroxisome proliferator-activated receptor (PPAR) alpha mediates anti-inflammatory effects of simvastatin in vivo models of acute inflammation. Moreover, previous results suggest that PPAR-alpha plays a role in control of secondary inflammatory process associated with spinal cord injury (SCI). METHODS: With the aim to characterize the role of PPAR-alpha in simvastatin activity, we tested the efficacy of simvastatin (10 mg/kg dissolved in saline i.p. 1 h and 6 h after the trauma) in an experimental model of SCI induced in mice by extradural compression of the spinal cord (T6-T7 level) using an aneurysm clip with a closing force of 24 g via a four-level T5-T8 laminectomy, and comparing mice lacking PPAR-alpha (PPAR-alpha KO) with wild type (WT) mice. In order to elucidate whether the effects of simvastatin are due to activation of the PPAR-alpha, we also investigated the effect of a PPAR-alpha antagonist, GW6471 (1 mg/kg administered i.p. 30 min prior treatment with simvastatin) on the protective effects of on simvastatin. RESULTS: Results indicate that simvastatin activity is weakened in PPAR-alpha KO mice, as compared to WT controls. In particular, simvastatin was less effective in PPAR-alpha KO, compared to WT mice, as evaluated by inhibition of the degree of spinal cord inflammation, neutrophil infiltration, nitrotyrosine formation, pro-inflammmatory cytokine expression, nuclear factor (NF)-kappaB activation, inducible nitric-oxide synthase (iNOS) expression, and apoptosis. In addition we demonstrated that GW6471 significantly antagonized the effect of the statin and thus abolished the protective effect. CONCLUSIONS: This study indicates that PPAR-alpha can contribute to the anti inflammatory activity of simvastatin in SCI. PMID- 22537534 TI - Association of heart rhythm with exercise capacity after operation for chronic mitral regurgitation. AB - BACKGROUND: Although atrial fibrillation (AF) and decreased exercise capacity are common in chronic mitral regurgitation patients, the relationship between rhythm status and exercise capacity after corrective surgery is largely unknown. METHODS: Seventy-one patients undergoing repair or replacement of mitral valve for chronic severe mitral regurgitation were examined with preoperative and 6 months' postoperative cardiopulmonary exercise test and two-dimensional echocardiography. Patients were divided into three groups according to preoperative versus postoperative rhythm (sinus/sinus, SS [n=42]; AF/sinus, AS [n=17]; AF/AF, AA group [n=12]). RESULTS: Preoperative maximal oxygen consumption was lower and ventilatory efficiency was higher in the AS and AA groups compared with the SS group. However, maximal oxygen consumption improved only in the AS group at 6 months' postoperative cardiopulmonary exercise test (24.0+/-6.9 versus 24.6+/-6.1 mL.kg(-1).min(-1) in the SS group, 19.3+/-5.9 versus 23.2+/-6.4 mL.kg( 1).min(-1) in the AS group, 19.8+/-5.4 versus 18.8+/-5.1 mL.kg(-1).min(-1) in the AA group; p=0.016 for maximal oxygen consumption by analysis of covariance) as well as ventilatory efficiency. Echocardiography verified more significant reduction of left atrial volume in the SS and AS groups than in the AA group (172.2+/-68.0 versus 96.7+/-31.0 mL in the SS group, 247.5+/-77.8 versus 129.2+/ 25.7 mL in the AS group, 316.7+/-210.0 versus 192.0+/-95.0 mL in the AA group; p=0.001 for left atrial volume by analysis of covariance) as well as pulmonary artery systolic pressure. When analyzed for significant predictors of postoperative maximal oxygen consumption, being in the AS group but not the SS group was a significant positive predictor when compared with the AA group (beta=5.475; p=0.006). CONCLUSIONS: Successful sinus conversion of AF, preferably by maze operation, in patients undergoing surgical correction of chronic severe mitral regurgitation confers improved exercise capacity. Reduction of left atrial volume and pulmonary artery pressure may contribute to this improvement. PMID- 22537535 TI - Surgical valvuloplasty versus balloon aortic dilation for congenital aortic stenosis: are evidence-based outcomes relevant? AB - BACKGROUND: For children with congenital aortic stenosis (AS) who are selected for biventricular repair, valvuloplasty can be achieved by surgical aortic valvuloplasty (SAV) or by transcatheter balloon aortic dilation (BAD). A retrospective study was undertaken to compare the effectiveness of BAD versus SAV, evaluating the long-term survival, incidence of aortic valve restenosis or aortic insufficiency (AI) or both, and freedom from reoperation for repeated valve repair or replacement. Neonates less than 2 months of age were excluded from this comparison. METHODS: We reviewed the outcomes of children undergoing repair by SAV (n = 89) and BAD (n = 69) at our institution during a recent 20 year period. Clinical and echocardiographic follow-up were analyzed. The patient groups were compared with regard to the persistence or recurrence of postoperative aortic gradients and valve insufficiency and valve-related reintervention, including aortic valve replacement (AVR). RESULTS: There was no significant difference between the groups with respect to mean age, body surface area, valve anatomy, sex, and preoperative gradients. Our data demonstrate that gradient reduction, AI, and the need for reintervention were worse for BAD. Aortic gradients at last follow-up were similar in both cohorts, but return of a significant gradient occurred sooner for patients who had BAD. Aortic gradient at discharge was significantly better for the patients who underwent SAV. Kaplan Meier analysis showed that at 10 years, comparison of SAV and BAD was as follows: freedom from reintervention, 72% versus 53% (p = 0.02) and freedom from AVR, 80% versus 75% (p = 0.32). CONCLUSIONS: BAD yields less gradient reduction, more postprocedural AI, and a shorter interval between initial and subsequent reintervention than does SAV. Our results demonstrate that SAV is safe and effective and that residual gradients and degree of AI are low. After SAV, the need for AVR can usually be delayed until the child is significantly older. The long-term functional stability after SAV is excellent. BAD in comparison is associated with an increased frequency and severity of AI and the need for earlier reintervention and valve replacement. SAV should be offered to all patients beyond the newborn period because it gives superior and longer lasting palliation. PMID- 22537536 TI - Effects of a dolphin interaction program on children with autism spectrum disorders: an exploratory research. AB - BACKGROUND: Interaction programs involving dolphins and patients with various pathologies or developmental disorders (e.g., cerebral palsy, intellectual impairment, autism, atopic dermatitis, post-traumatic stress disorder, depression) have stimulated interest in their beneficial effects and therapeutic potential. However, the true effects observed in different clinical and psycho educational setups are still controversial. RESULTS: An evaluation protocol consisting of the Childhood Autism Rating Scale (CARS), Psychoeducational Profile Revised (PEP-R), Autism Treatment Evaluation Checklist (ATEC), Theory of Mind Tasks (ToM Tasks) and a custom-made Interaction Evaluation Grid (IEG) to evaluate behavioural complexity during in-pool interactions was applied to 10 children diagnosed with Autism Spectrum Disorders. The ATEC, ToM Tasks and CARS results show no benefits of the dolphin interaction program. Interestingly, the PEP-R suggests some statistically significant effects on 'Overall development score', as well as on their 'Fine motor development', 'Cognitive performance' and 'Cognitive verbal development'. Also, a significant evolution in behavioural complexity was shown by the IEG. CONCLUSIONS: This study does not support significant developmental progress resulting from the dolphin interaction program. PMID- 22537537 TI - Forensic identification using a multiplex assay of 47 SNPs. AB - As a powerful alternative to short tandem repeat (STR) profiling, we have developed a novel panel of 47 single nucleotide polymorphisms (SNPs) for DNA profiling and ABO genotyping. We selected 42 of the 47 SNPs from a panel of 86 markers that were previously validated as universal individual identification markers and identified five additional SNPs including one gender marker and four ABO loci. Match probability of the 42 validated SNPs was found to be 9.5 * 10( 18) in Han Chinese. SNP analysis correctly assessed a panel of historical cases, including both paternity identifications in trios and individual identifications. In addition, while STR profiling of degraded DNA provided information for 11 loci of 16 potential markers with low peak intensities, SNPstream((r)) genotyping was sufficient to identify all 47 SNPs. In summary, SNP analysis is equally effective as STR profiling, but appears more suited for individual identification than STR profiling in cases where DNA may be degraded. PMID- 22537538 TI - Long-term outcomes of radiotherapy for stage II testicular seminoma--the Mayo Clinic experience. AB - OBJECTIVES: To report long-term outcomes of patients with stage II testicular seminoma treated with radiotherapy (RT). MATERIALS AND METHODS: A retrospective review was performed of 52 patients who received megavoltage RT for stage II testicular seminoma at Mayo Clinic between 1974 and 2007. Forty-eight patients (92%) had computed tomography staging. Overall survival (OS), relapse-free survival (RFS), and cause-specific survival (CSS) were determined using the Kaplan-Meier method. Major cardiac event (MCE) was defined as myocardial infarction, coronary artery bypass grafting or stenting, or valve replacement. Second malignancy (SM) was defined as biopsy-confirmed malignancy occurring in the RT field. RESULTS: The median patient age at diagnosis was 36 years. Stage was IIA (n = 24), IIB (n = 7), IIC (n = 17), and II not otherwise specified (NOS, n = 4). The median infradiaphragmatic RT dose was 30.7 Gy. Twenty-six patients (50%) received prophylactic mediastinal/supraclavicular (MSCV) RT. The median follow-up was 19 years. Estimates of OS, RFS, and CSS were 94%, 80%, and 96% at 10 years, and 83%, 72%, and 96% at 20 years, respectively. RFS at 10 years for stage IIA, IIB, IIC, and II NOS were 83%, 54%, 81%, and 100%, respectively (log rank P = 0.21). Ten patients (19%) experienced disease relapse in the MSCV region (n = 7), para-aortic lymph nodes (n = 1), lung (n = 1), or peritoneal cavity (n = 1). Eight patients were successfully salvaged with chemotherapy and/or surgery, while 2 died of seminoma. Risk of MSCV relapse was significantly lower in patients who received MSCV RT vs. those who did not (10-year estimates: 4% vs. 21%, respectively, log-rank P = 0.01). MCE occurred in 10 patients (19%) at a median of 18 years (range 7-30) after RT. SM occurred in 5 patients (10%) at a median of 27 years (range 20-34) after RT. CONCLUSIONS: In patients with stage II testicular seminoma treated with RT, relapse in the irradiated site was uncommon. Infradiaphragmatic RT alone was associated with a significant risk of MSCV failure. Most MCE and SM events occurred more than 20 years after RT, highlighting the importance of vigilant long-term follow-up. PMID- 22537539 TI - The role of hypoxia-inducible factor-1alpha and -2alpha in androgen insensitive prostate cancer cells. AB - OBJECTIVES: The aim of this study was to investigate the effects of induction and knocking down of hypoxia-inducible factor (HIF)-1alpha and/or -2alpha on tumor biology in androgen insensitive prostate cancer cell lines. MATERIALS AND METHODS: The induction patterns of HIF-1alpha and -2alpha after treatment with ZnSO4 were evaluated in PC3 and DU145 cells. Both cell lines were transfected with siRNA targeted against HIF-1alpha and/or -2alpha, and the expression patterns of these 2 HIF isoforms were examined. We next performed cell counting Kit-8 (CCK-8) assays and matrigel invasion assays. Potential additive effects of HIF blockade to chemotherapy (docetaxel) or target agents (sunitinib and sorafenib) were examined. In addition, gene expression changes were determined in ZnSO4-treated DU145 cells using Western blotting. RESULTS: ZnSO4 affected the expression of HIF in a dose-dependent manner. HIF expression was increased within the first 3 hours but then decreased. Cells in which HIF-1alpha and/or -2alpha had been knocked down using siRNA showed decreased cell viability. Invasion abilities were increased by ZnSO4 treatment in both cell lines overexpressing HIF. However, invasion potencies were decreased in response to treatment with HIF siRNAs. Blocking HIF prominently augmented the antitumor effects of target agents. The underlying mechanism could be associated with p21, cMET, IGF-1, and GLUT-1. CONCLUSIONS: Our results demonstrate that HIF-1alpha and -2alpha are important for cell proliferation and invasion ability in prostate cancer. Together, our results indicate that combinations of target agents with HIF knockdown may represent a promising strategy for the treatment of prostate cancer. PMID- 22537540 TI - Long-term follow-up of preoperative pelvic radiation therapy and concomitant boost irradiation in locally advanced rectal cancer patients: a multi institutional phase II study (KROG 04-01). AB - PURPOSE: To perform a prospective phase II study to investigate the efficacy and safety of preoperative pelvic radiation therapy and concomitant small-field boost irradiation with 5-fluorouracil and leucovorin for 5 weeks in locally advanced rectal cancer patients. METHODS AND MATERIALS: Sixty-nine patients with locally advanced, nonmetastatic, mid-to-lower rectal cancer were prospectively enrolled. They had received preoperative chemoradiation therapy and total mesorectal excision. Pelvic radiation therapy of 43.2 Gy in 24 fractions plus concomitant boost radiation therapy of 7.2 Gy in 12 fractions was delivered to the pelvis and tumor bed for 5 weeks. Two cycles of 5-fluorouracil and leucovorin were administered for 3 days in the first and fifth week of radiation therapy. The pathologic response, survival outcome, and treatment toxicity were evaluated for the study endpoints. RESULTS: Of 69 patients, 8 (11.6%) had a pathologically complete response. Downstaging rates were 40.5% for T classification and 68.1% for N classification. At the median follow-up of 69 months, 36 patients have been followed up for more than 5 years. The 5-year disease-free survival (DFS) and overall survival rates were 66.0% and 75.3%, respectively. Higher pathologic T (P=.045) and N (P=.032) classification were significant adverse prognostic factors for DFS, and high-grade histology was an adverse prognostic factor for both DFS (P=.025) and overall survival (P=.031) on the multivariate analysis. Fifteen patients (21.7%) experienced grade 3 or 4 acute toxicity, and 7 patients (10.1%) had long-term toxicity. CONCLUSION: Preoperative pelvic radiation therapy with concomitant boost irradiation with 5-fluorouracil and leucovorin for 5 weeks showed acceptable acute and long-term toxicities. However, the benefit of concomitant small-field boost irradiation for 5 weeks in rectal cancer patients was not demonstrated beyond conventional irradiation for 6 weeks in terms of tumor response and survival. PMID- 22537541 TI - Updated results and patterns of failure in a randomized hypofractionation trial for high-risk prostate cancer. AB - PURPOSE: To report long-term results and patterns of failure after conventional and hypofractionated radiation therapy in high-risk prostate cancer. METHODS AND MATERIALS: This randomized phase III trial compared conventional fractionation (80 Gy at 2 Gy per fraction in 8 weeks) vs hypofractionation (62 Gy at 3.1 Gy per fraction in 5 weeks) in combination with 9-month androgen deprivation therapy in 168 patients with high-risk prostate cancer. Freedom from biochemical failure (FFBF), freedom from local failure (FFLF), and freedom from distant failure (FFDF) were analyzed. RESULTS: In a median follow-up of 70 months, biochemical failure (BF) occurred in 35 of the 168 patients (21%) in the study. Among these 35 patients, local failure (LF) only was detected in 11 (31%), distant failure (DF) only in 16 (46%), and both LF and DF in 6 (17%). In 2 patients (6%) BF has not yet been clinically detected. The risk reduction by hypofractionation was significant in BF (10.3%) but not in LF and DF. We found that hypofractionation, with respect to conventional fractionation, determined only an insignificant increase in the actuarial FFBF but no difference in FFLF and FFDF, when considering the entire group of patients. However, an increase in the 5-year rates in all 3 endpoints-FFBF, FFLF, and FFDF-was observed in the subgroup of patients with a pretreatment prostate-specific antigen (iPSA) level of 20 ng/mL or less. On multivariate analysis, the type of fractionation, iPSA level, Gleason score of 4+3 or higher, and T stage of 2c or higher have been confirmed as independent prognostic factors for BF. High iPSA levels and Gleason score of 4+3 or higher were also significantly associated with an increased risk of DF, whereas T stage of 2c or higher was the only independent variable for LF. CONCLUSION: Our results confirm the isoeffectiveness of the 2 fractionation schedules used in this study, although a benefit in favor of hypofractionation cannot be excluded in the subgroup of patients with an iPSA level of 20 ng/mL or less. The alpha/beta ratio might be more appropriately evaluated by FFLF than FFBF results, at least in high-risk disease. PMID- 22537542 TI - Differential bystander signaling between radioresistant chondrosarcoma cells and fibroblasts after x-ray, proton, iron ion and carbon ion exposures. AB - PURPOSE: Chondrosarcoma is well known as a radioresistant tumor, but the mechanisms underlying that resistance are still unclear. The bystander effect is well documented in the field of radiation biology. We investigated the bystander response induced by X-rays, protons, carbon ions, and iron ions in chondrosarcoma cells using a transwell insert co-culture system that precludes physical contact between targeted and bystander cells. METHODS AND MATERIALS: Human chondrosarcoma cells were irradiated with 0.1-, 0.5-, 1-, and 2-Gy X-rays, protons, carbon ions or iron ions using a transwell insert co-culture system. Formation of micronuclei and p53 binding protein 1 staining in bystander and irradiated cells were analyzed and bystander signaling between mixed cultures of chondrosarcoma cells, and normal human skin fibroblasts was investigated. RESULTS: In this study, we show that the fraction of cells with DNA damages in irradiated chondrosarcoma cells showed dose-dependent increases with all beams. However, the fraction of cells with DNA damages in all bystander chondrosarcoma cells did not show any change from the levels in control cells. In the bystander signaling between mixed cultures of chondrosarcoma cells and fibroblasts, the amount of micronucleus formation in all bystander chondrosarcoma cells co-cultured with irradiated fibroblasts were the same as the levels for control cells. However, all bystander fibroblasts co-cultured with irradiated chondrosarcoma cells showed significant increases in the fraction of micronucleated cells compared to the rate of control cells. CONCLUSIONS: We conclude that chondrosarcoma cells in the transwell insert co-culture system could release bystander stimulations but could not develop bystander responses. PMID- 22537544 TI - Apamin inhibits THP-1-derived macrophage apoptosis via mitochondria-related apoptotic pathway. AB - The development of atherosclerotic lesions is mainly due to macrophage death. The oxidative stresses of monocytes/macrophages play a vital role in the initiation and amplification of atherosclerosis. Apamin, a component of bee venom, exerts an anti-inflammatory effect, and selectively inhibits the Ca(2+)-activated K(+) channels. The mechanisms involved in the inhibition of macrophage apoptosis have been fully elucidated. We induced oxidized low-density lipoprotein (oxLDL) in THP 1-derived macrophage and studied the effect of apamin on intercellular lipid levels, mitochondria-related apoptotic pathway and numbers of apoptotic cells. Oil-red O staining indicates that the inhibition of apamin in the condition significantly prevents intracellular lipid deposition. Treatment with apamin significantly decreased the apoptotic macrophages by decreasing the expression of pro-apoptotic genes Bax, caspase-3 and PARP protein levels, as well as through increasing expression of anti-apoptotic genes Bcl-2 and Bcl-xL protein levels in the absence and presence of oxLDL. In vivo, with apamin treatment reduced apoptotic cells death by TUNEL staining. These results indicate that apamin plays an important role in monocyte/macrophage apoptotic processing, which may provide a potential drug for preventing atherosclerosis. PMID- 22537543 TI - Merkel cell polyomavirus in non-small cell lung carcinomas from Chile. AB - Lung cancer is a leading pathology strongly associated with the smoking habit. However, a viral etiology for a subset of patients developing lung cancer has been suggested. Polyomaviruses (PyVs) are small double stranded DNA viruses associated with the development of some human diseases. However, a causal role of these viruses in human cancer has been difficult to demonstrate. In this study, eighty-six non-small cell lung carcinomas (NSCLCs), including adenocarcinomas (AdCs) and squamous cell lung carcinomas (SQCs) from Chile were analyzed for the presence of PyVs using polymerase chain reaction (PCR). All of the specimens were positive for a fragment of the betaglobin gene. We found that 4/86 (4.7%) of lung carcinomas were positive for PyVs. After sequencing and BlastN alignment, all four cases were identified as Merkel cell polyomaviruses (MCV) that corresponded to two AdCs and two SQCs. A non-significant statistical association was found between the presence of MCV and clinic-pathological features of the patients and tumors. In addition, 1/4 (25%) of the carcinomas were actively expressing large T antigen (LT) transcripts, as demonstrated by reverse-transcriptase PCR (RT-PCR). Thus a possible role of MCV in a very small subset of patients with lung cancer cannot be ruled out and warrants more investigation. PMID- 22537545 TI - Immunohistochemical analysis of bone morphological protein signaling pathway in human myometrium. AB - We assessed by immunohistochemistry the expression of the phosphorylated (activated) form of Smad1 and 5 (P-SMAD1/5), of Noggin and of two smooth muscle cell markers (alpha-SMA and SM22) in a series of human myometrium samples and in a smooth muscle cell line derived from human myometrium (HUt-SMC, PromoCell, USA). Myometrium samples were removed from two cadavers (a fetus at 26 weeks of gestation and a neonate) and from ten non-menopausal women who underwent hysterectomy for adenomyosis and leiomyoma. P-SMAD1/5 expression was never detected in myometrium (both normal and pathological specimens), but only as a nuclear positive staining in glandular and luminal epithelial cells in sections in which also the endometrial mucosa was present. Noggin was strongly expressed especially in myometrium and adenomyosis samples from non-menopausal patients in comparison to the neonatal and fetal myometrium specimens in which muscle cells were less positive. In more than 95% of HUt-SMCs, alpha-SMA and Desmin were co expressed, indicating a pure smooth muscle phenotype. When progesterone was added to the culture medium, no P-SMAD1/5 expression was detected, whereas the expression Noggin and SM22, a marker of differentiated smooth muscle cells, increased by 3 fold (p=0.002) and 4.3 fold (p=0.001), respectively (p=0.002). Our results suggest that, in non-menopausal normal human myometrium, the BMP pathway might be inhibited and that this inhibition might be enhanced by progesterone, which increases the differentiation of smooth muscle cells (SM22 levels). These findings could help in the identification of new mechanisms that regulate uterine motility. PMID- 22537547 TI - Vitamin D deficiency decreases the expression of VDR and prohibitin in the lungs of mice with allergic airway inflammation. AB - AIMS: Asthma is one of the most common chronic inflammatory diseases of the airways. Calcitriol exerts its action through Vitamin D receptor (VDR), which is a high affinity nuclear receptor. VDR is a transcription factor that alters the transcription of target genes which are involved in a wide spectrum of biological responses. Lower serum vitamin D levels are associated with airway hyperresponsiveness and increased asthma severity. Prohibitin is a ubiquitously expressed protein localized to the cell and mitochondrial membranes and the nucleus. METHODS AND RESULTS: HBSMCs were cultured and treated with calcitriol and/or TNF-alpha. The mRNA and protein expression of prohibitin and VDR were analyzed using qPCR and immunoblotting, respectively. In the in vivo studies, female BALB/c mice were fed with special vitamin D-deficient or 2000IU/kg of vitamin D-supplemented diet for 13weeks. Mouse model of allergic airway inflammation was developed by OVA-sensitization and challenge. The expression pattern of TNF-alpha, prohibitin and VDR in the lung of OVA-sensitized mice was analyzed using immunofluorescence. Calcitriol significantly increased and TNF alpha decreased the protein and mRNA expression of prohibitin and VDR in HBSMCs. There was significantly increased expression of TNF-alpha and decreased expression of VDR and prohibitin in the lung of vitamin D-deficient mouse model of allergic airway inflammation. CONCLUSION: These results suggest that under inflammatory conditions there is decreased expression of VDR resulting in decreased expression of prohibitin, which is a vitamin D target gene. Vitamin D deficiency causes increase in the expression of TNF-alpha, thereby increasing inflammation and decreases the expression of VDR and prohibitin. Supplementation with vitamin D might reduce the levels of TNF-alpha, thereby increasing the expression of VDR and prohibitin that could be responsible for reducing allergic airway inflammation. PMID- 22537546 TI - Vitamin D deficiency induces cardiac hypertrophy and inflammation in epicardial adipose tissue in hypercholesterolemic swine. AB - INTRODUCTION: Vitamin D is a sectosteroid that functions through Vitamin D receptor (VDR), a transcription factor, which controls the transcription of many targets genes. Vitamin D deficiency has been linked with cardiovascular diseases, including heart failure and coronary artery disease. Suppressor of cytokine signaling (SOCS)3 regulates different biological processes such as inflammation and cellular differentiation and is an endogenous negative regulator of cardiac hypertrophy. OBJECTIVE: The purpose of this study was to test the hypothesis that vitamin D deficiency causes cardiomyocyte hypertrophy and increased proinflammatory profile in epicardial adipose tissue (EAT), and this correlates with decreased expression of SOCS3 in cardiomyocytes and EAT. METHODS: Eight female Yucatan miniswine were fed vitamin D-sufficient (900 IU/d) or vitamin D deficient hypercholesterolemic diet. Lipid profile, metabolic panel, and serum 25(OH)D levels were regularly measured. After 12 months animals were euthanized and histological, immunohistochemical and qPCR studies were performed on myocardium and epicardial fat. RESULTS: Histological studies showed cardiac hypertrophy, as judged by cardiac myocyte cross sectional area, in the vitamin D deficient group. Immunohistochemical and qPCR analyses showed significantly decreased mRNA and protein expression of VDR and SOCS3 in cardiomyocytes of vitamin D-deficient animals. EAT from vitamin D-deficient group had significantly higher expression of TNF-alpha, IL-6, MCP-1, and decreased adiponectin in association with increased inflammatory cellular infiltrate. Interestingly, EAT from vitamin D-deficient group had significantly decreased expression of SOCS3. CONCLUSION: These data suggest that vitamin D deficiency induces hypertrophy in cardiomyocytes which is associated with decreased expression of VDR and SOCS3. Vitamin D deficiency is also associated with increased inflammatory markers in EAT. Activity of VDR in the body is controlled through regulation of vitamin D metabolites. Therefore, restoration of VDR function by supplementation of VDR ligands in vitamin D-deficient population might be helpful in reducing inflammation and cardiovascular risk. PMID- 22537548 TI - Overexpression of Shp-2 attenuates apoptosis in neonatal rat cardiac myocytes through the ERK pathway. AB - During cardiac ischemia and end-stage heart disease, a large number of cardiac cells are apoptotic, and therefore, heart function is impaired. Although the role of Shp-2 in cell survival has been reported, its regulation of cardiac apoptosis is still undetermined. To better understand the potential role of Shp-2 in apoptosis, cell death was determined in serum-depleted cardiomyocytes. Shp-2 was inhibited by NSC87877, and apoptosis, Cyt C release and caspase 3 activation were determined. To evaluate the notion that Shp-2 plays a role in survival stimulation, wild-type and gain-of-function mutant Shp-2 adenoviruses were infected into neonatal cardiomyocytes, and ERK activation was examined. Finally, the MEK inhibitor U0126 was utilized to block the ERK pathway and determine the role of Shp-2 in this pathway. We found that Shp-2 inhibition enhanced apoptosis via regulation of mitochondrial Cyt C release and activation of caspase 3. Overexpression of Shp-2 inhibited apoptosis through activation of ERK. The MEK inhibitor U0126 abolished Shp-2's effect on apoptosis in cardiomyocytes. Our results have revealed that Shp-2 functions as an intracellular inhibitor of apoptosis. These data provide insight into the pathogenesis and the therapeutic strategies of heart diseases. PMID- 22537549 TI - Cardiac fibroblast death by ischemia/reperfusion is partially inhibited by IGF-1 through both PI3K/Akt and MEK-ERK pathways. AB - Cardiac fibroblast (CF) death by ischemia/reperfusion (I/R) has major implications for cardiac wound healing. Although IGF-1 has well-known cytoprotective effects, no study has been done on CF subjected to simulated I/R. Simulated ischemia of neonate rat CF was performed in a free oxygen chamber in an ischemic medium; reperfusion was done in normal culture conditions. Cell viability was evaluated by trypan blue assay, and apoptosis by a FACS flow cytometer; p-ERK-1/2 and p-Akt levels were determined by western blot. We showed that simulated I/R triggers CF death by necrosis and apoptosis. IGF-1 partially inhibits I/R-induced apoptosis. PD98059 and LY294002 neutralize the preventive effects of IGF-1. CONCLUSION: IGF-1 partially inhibits CF apoptosis induced by simulated I/R by PI3K/Akt- and MEK/ERK1/2-dependent signaling pathways. PMID- 22537550 TI - The role of N-acetylglucosaminyltransferases V in the malignancy of human hepatocellular carcinoma. AB - To investigate the role of N-acetylglucosaminyltransferases V (GnT-V) in the malignancy of human hepatocellular carcinoma (HCC), the GnT-V stably suppressed cell line HepG2 GnT-V/1564 was constructed from HepG2. The proliferation, migration, invasion, metastasis of HepG2 GnT-V/1564 was investigated both in vitro and in vivo. The clinical pathological significance of GnT-V expression was also studied in 140 cases of HCC tissues. This study showed that down-regulation of GnT-V inhibited the proliferation, migration and invasion of the HepG2 cells. In addition, GnT-V expression was shown in 138 cases of 140 (98.6%) HCC samples, in 3 cases of 31 (9.7%) in liver cirrhosis cases and in 1 cases of 20 (5.0%) in normal liver tissues. Besides, a higher level of GnT-V was observed more frequently in the advanced tumors with higher T stage and histological grade. These data suggested that GnT-V expression was positively related with malignancy in HCC and GnT-V may be both a differentiation marker and a potential target for the treatment of HCC. PMID- 22537551 TI - Fabry disease in unselected patients with TIA or stroke: population-based study. AB - BACKGROUND: Fabry disease (FD) is an X-linked lysosomal storage disorder frequently associated with cerebrovascular disease. In recent years, the prevalence of FD has been reported to be up to 4% in cryptogenic young stroke patients. However, there have been no population-based studies in unselected patients with transient ischaemic attack (TIA) or stroke across the full range of ages. METHODS: We determined the prevalence of FD mutations in consecutive patients from a population-based study of acute TIA or ischaemic stroke (Oxford Vascular Study). Analysis included amplifying of the alpha-galactosidase A gene by polymerase chain reaction, denaturing high-performance liquid chromatography (dHPLC) analysis and sequencing using standard automated sequencing protocols [Mutation Surveyor software (Softgenetics)] where the dHPLC indicated a possible mutation. RESULTS: Samples of 1046 consecutive patients (52% women; mean age 73.2 years; 15% age <60 years; 572 stroke; 474 TIA) were tested. No patient had a known gene mutation causing FD, giving an upper 95% confidence interval around the estimated frequency of 0.35% overall and 2.37% in the 154 patients aged under 60 years. However, in 5 (0.48%) samples, a known polymorphism or sequence variation in the gene was identified that can be associated with lower than normal enzyme activity in plasma without causing the full clinical manifestation of FD. CONCLUSIONS: Fabry disease is rare in an unselected group of UK patients with TIA or stroke. Larger studies in unselected younger patients with cryptogenic stroke are required to determine whether routine screening is justified in this group. PMID- 22537552 TI - A new approach to isolating siderophore-producing actinobacteria. AB - AIMS: This study was conducted to investigate the application of 2,2'-dipyridyl as a new approach to isolating siderophore-producing actinobacteria. METHODS AND RESULTS: Isolation of actinobacteria from soil was conducted by a soil dilution plate technique using starch-casein agar. Iron starvation was fostered by the incorporation of the iron chelator 2,2'-dipyridyl in the isolation medium. Pretreatment of the samples at an elevated temperature (40 degrees C) ensured that the majority of nonsporulating bacteria were excluded. The survivors of this treatment were largely actinobacteria. Of the viable cultures grown in the presence of 2,2'-dipyridyl, more than 78-88% (average of three separate studies) were reported to produce siderophore-like compounds compared to 13-18% (average of three separate studies) when grown on the basic media in the absence of the chelating agent. The most prolific producers as assessed by the chrome azurol sulphate (CAS) assay were further characterized and found to belong to the genus Streptomyces. CONCLUSIONS: Selective pressure using 2,2'-dipyridyl as an iron chelating agent in starch-casein media increased the isolation of siderophore producing actinobacteria compared to the unamended medium. SIGNIFICANCE AND IMPACT OF THE STUDY: The study described represents a new approach to the isolation of siderophore-producing actinobacteria using a novel procedure that places a selection on cell population based upon the incorporation of a chelating agent in the medium. PMID- 22537553 TI - Association between education level and dentition status in Japanese adults: Japan public health center-based oral health study. AB - OBJECTIVES: The aim of this study was to examine whether there is an educational gradient in dentition status among Japanese adults who are under the universal public health insurance system. METHODS: Subjects were 1201 community residents aged 55-75 years as of May 2005 who completed a self-administered questionnaire and had a standard clinical oral examination. Analysis focused on the association of three education levels (junior high school, senior high school, and any college or higher education) with dentition status. RESULTS: The proportion of subjects with 20 or more teeth (P < 0.001), number of teeth present (P = 0.037), number of filled teeth (P = 0.016), and two types of functional tooth units (FTUs): FTUs with natural teeth (n-FTUs) (P < 0.001) and FTUs with natural teeth and artificial teeth on implant-supported and fixed prostheses (nif-FTUs) (P < 0.001) were significantly associated with education level after adjusting for confounders. The significant trend of these values in dental indexes indicated a poorer dentition status with a lower education level. CONCLUSIONS: The results suggest that the level of education has an independent impact on dentition status in a group of Japanese adults, even after taking into account oral health-related factors. Therefore, providing appropriate oral health information from an early age within a compulsory school education program appears necessary to enhance health literacy and lessen the inequalities in dental health by educational level. PMID- 22537554 TI - Characterization of the replication origin of the myxobacterial self-replicative plasmid pMF1. AB - Thus far, pMF1 is the only endogenous myxobacterial plasmid whose replication mechanism is unclear. In this study, we determined that the plasmid replicates via the theta-mode. The pMF1.14 gene, located in the pMF1.13-pMF1.15 operon (repABC), encodes an essential replication initiation protein that was predicted to have no typical DNA/protein binding motifs but contains rich disordered regions. The pMF1 replication-related essential cis-acting DNA region, approximate 370bp, was located within pMF1.14, and was found to contain several directly and inverted atypical repeats. The unique characteristics of the pMF1 replicon are suggested to be the reason for its strict narrow host range in Myxococcus cells. PMID- 22537555 TI - Andrographolide exerted its antimicrobial effects by upregulation of human beta defensin-2 induced through p38 MAPK and NF-kappaB pathway in human lung epithelial cells. AB - Andrographis paniculata (Burm. f) Nees is a traditional herbal medicine for the treatment of infection and inflammation in China. Andrographolide (andro) is one of the major components. Human beta-defensin-2 (hBD-2) is an inducible antimicrobial peptide that plays an important role in innate immunity. The present study aimed to investigate the effect of andro on upregulation of hBD-2 and the key signaling pathways involved in andro-induced hBD-2 expression. Real time reverse transcription - PCR and Western blot assays showed that andro (1.0 10 umol/L) can upregulate the expression of hBD-2 in a dose-dependent manner. Further studies suggested that hBD-2 mRNA and protein expression in responsive to andro were attenuated by pretreatment with SB203580 (an inhibitor of p38 mitogen activated protein kinase (p38 MAPK)), MG-132 (an inhibitor of nuclear factor kappaB (NF-kappaB)), and an NF-kappaB activator inhibitor, but not by an inhibitor of ERK (PD98059) or by an inhibitor of JNK(SP600125). Moreover, we found that a second p38 MAPK inhibitor (SB202190) significantly blocked andro mediated hBD-2 induction in SPC-A-1 lung epithelial cells. Finally, the p-c-Jun transcription factor activity assay also showed that AP-1 activity was induced by andro compared with the untreated group. We conclude that andro may exert its antimicrobial effects by upregulating the expression of hBD-2 through the p38 MAPK and NF-kappaB pathway. PMID- 22537556 TI - Autogenous osteochondral graft transplantation for steroid-induced osteonecrosis of the femoral condyle: A report of three young patients. AB - Steroid-induced osteonecrosis of the femoral condyle is a relatively uncommon condition and is often difficult to select appropriate treatment especially in young patients. Three young men (aged 25, 18, and 24) presented with severe pain and dysfunction of the knee diagnosed as steroid-induced osteonecrosis of the femoral condyle by magnetic resonance imaging (MRIs). Full-thickness cartilage defects sized 20 * 10, 15 * 10, and 30 * 20 mm respectively were classified as International Cartilage Repair Society Grade IV lesions and treated with osteochondral autograft transplantation. They were treated successfully with osteochondral autograft transplantation certificated by post-operative MRI and second look arthroscopy. PMID- 22537557 TI - A theoretical study of cyclohexyne addition to carbonyl-Calpha bonds: allowed and forbidden electrocyclic and nonpericyclic ring-openings of strained cyclobutenes. AB - The mechanism of cyclohexyne insertion into a C(O)-C(alpha) bond of cyclic ketones, explored experimentally by the Carreira group, has been investigated using density functional theory. B3LYP and M06-2X calculations were performed in both gas phase and THF (CPCM, UAKS radii). The reaction proceeds through a stepwise [2 + 2] cycloaddition of cyclohexyne to the enolate, followed by three disparate ring-opening possibilities of the cyclobutene alkoxide to give the product: (1) thermally allowed conrotatory electrocyclic ring-opening, (2) thermally forbidden disrotatory electrocyclic ring-opening, or (3) nonpericyclic C-C bond cleavage. Our computational results for the model alkoxide and potassium alkoxide systems show that the thermally allowed electrocyclic ring-opening pathway is favored by less than 1 kcal/mol. In more complex systems containing a potassium alkoxide (e-f), the barrier of the allowed conrotatory ring-opening is disfavored by 4-8 kcal/mol. This suggests that the thermodynamically more stable disrotatory product can be formed directly through a "forbidden" pathway. Analysis of geometrical parameters and atomic charges throughout the ring-opening pathways provides evidence for a nonpericyclic C-C bond cleavage, rather than a thermally forbidden disrotatory ring-opening. A true forbidden disrotatory ring opening transition structure was computed for the cyclobutene alcohol; however, it was 19 kcal/mol higher in energy than the allowed conrotatory transition structure. An alternate mechanism in which the disrotatory product forms via isomerization of the conrotatory product was also explored for the alkoxide and potassium alkoxide systems. PMID- 22537558 TI - "There's more to this pain than just pain": how patients' understanding of pain evolved during a randomized controlled trial for chronic pain. AB - Chronic pain is prevalent, is costly, and exerts an emotional toll on patients and providers. Little is known about chronic pain in veterans of the recent military conflicts in Afghanistan and Iraq (OEF/OIF/OND [Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn] veterans). This study's objective was to ascertain veterans' perceptions of a multicomponent intervention tested in a randomized controlled trial for OEF/OIF/OND veterans with chronic musculoskeletal pain (ESCAPE: Evaluation of Stepped Care for Chronic Pain). Qualitative interviews were conducted with patients in the intervention arm of ESCAPE. Questions related to veterans' experiences with trial components, overall perceptions of the intervention, strengths, and suggestions for improvement. Twenty-six veterans (21% of total intervention patients) participated. Patients were purposefully sampled to include treatment responders (defined as >=30% reduction in pain-related disability or pain severity) and non-responders. Non completers (completed <50% of the trial) were also sampled. Qualitative analysis was guided by grounded theory, using constant comparative methodology. Both responders and non-responders spoke about their evolving understanding of their pain experience during the trial, and how this new understanding helped them to manage their pain more effectively. This evolution is reported under 2 themes: 1) learning to recognize physical and psychosocial factors related to pain; and 2) learning to manage pain through actions and thoughts. PERSPECTIVE: Responders and non-responders both described making connections between their pain and other factors in their lives, and how these connections positively influenced how they managed their pain. Traditional quantitative measures of response to pain interventions may not capture the full benefits that patients report experiencing. PMID- 22537559 TI - Descriptors of pain sensation: a dual hierarchical model of latent structure. AB - Recently, the lexicon of pain was refined into a parsimonious set of words making up the Pain Descriptor System (PDS). The present study investigated the latent structure of the sensory category of the PDS with its 24 descriptors distributed equally across 8 subcategories. A sample of 629 chronic pain patients rated the degree to which each of these words described their pain. It was found that coldness-related words were rarely used and shared high covariance with other descriptors, thus warranting their removal as a subcategory. Confirmatory factor analysis of a previously theorized single higher-order model of 7 latent factors (each with 3 observed variables) resulted in poor fit, x(2)(181) = 377.72, P < .05; comparative fit index (CFI) = .915; root mean square error of approximation (RMSEA) = .04. This model was replaced with a dual higher-order model retaining the same 7 latent factors plus 2 higher-order factors corresponding to deep pain versus superficial pain. This model provided a good representation of the data, x(2)(181) = 301.07, P < .05; CFI = .948; RMSEA = .032. Therefore, descriptors of pain sensation differentiate sensory quality while also reflecting a fundamental dichotomy supported by neurophysiological research. Thus, the lexicon can illuminate pathophysiology, thereby clarifying pain diagnoses. PERSPECTIVE: Confirmatory factor analysis was performed on pain sensation descriptors used by 629 patients. This supported a hierarchical model with 7 lower-order factors plus 2 higher-order factors corresponding to deep pain versus superficial pain. By reflecting neurophysiology, this lexicon of pain can offer diagnostic clues. PMID- 22537561 TI - Spatial pain propagation over time following painful glutamate activation of latent myofascial trigger points in humans. AB - The aim of this present study was to test the hypothesis that tonic nociceptive stimulation of latent myofascial trigger points (MTPs) may induce a spatially enlarged area of pressure pain hyperalgesia. Painful glutamate (.2 mL, 1M) stimulation of latent MTPs and non-MTPs in the forearm was achieved by an electromyography-guided procedure. Pain intensity (as rated on the visual analog scale [VAS]) and referred pain area following glutamate injections were recorded. Pressure pain threshold (PPT) was measured over 12 points in the forearm muscles and at the mid-point of tibialis anterior muscle before and at .5 hour, 1 hour, and 24 hours after glutamate injections. The results showed that maximal pain intensity, the area under the VAS curve, and referred pain area were significantly higher and larger following glutamate injection into latent MTPs than non-MTPs (all, P < .05). A significantly lower PPT level was detected over time after glutamate injection into latent MTPs at .5 hour (at 4 points), 1 hour (at 7 points), and 24 hours (at 6 points) in the forearm muscles. However, a significantly lower PPT was observed only at 24 hours after glutamate injection into non-MTPs in the forearm muscles (at 4 points, P < .05) when compared to the pre-injection PPT. PPT at the mid-point of the tibialis anterior was significantly decreased at 1 hour only as compared to the pre-injection PPT in both groups (< .05). The results of the present study indicate that nociceptive stimulation of latent MTPs is associated with an early onset of locally enlarged area of mechanical hyperalgesia. PERSPECTIVE: This study shows that MTPs are associated with an early occurrence of a locally enlarged area of pressure hyperalgesia associated with spreading central sensitization. Inactivation of MTPs may prevent spatial pain propagation. PMID- 22537560 TI - Modulation of spinal GABAergic analgesia by inhibition of chloride extrusion capacity in mice. AB - Spinal gamma-aminobutyric acid receptor type A (GABA(A)) receptor modulation with agonists and allosteric modulators evokes analgesia and antinociception. Changes in K(+)-Cl(-) cotransporter isoform 2 (KCC2) expression or function that occur after peripheral nerve injury can result in an impairment in the Cl(-) extrusion capacity of spinal dorsal horn neurons. This, in turn, alters Cl(-)-mediated hyperpolarization via GABA(A) receptor activation, contributing to allodynia or hypersensitivity associated with nerve injury or inflammation. A gap in knowledge exists concerning how this loss of spinal KCC2 activity differentially impacts the analgesic efficacy or potency of GABA(A) agonists and allosteric modulators. We utilized intrathecal drug administration in the tail flick assay to measure the analgesic effects of general GABA(A) agonists muscimol and Z-3 [(aminoiminomethyl)thio]prop-2-enoic acid (ZAPA), the ?-subunit-preferring agonist 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP), and allosteric modulators of the benzodiazepine (midazolam) and neurosteroid (ganaxolone) class, alone or in the presence of K(+)-Cl(-) cotransporter isoform (KCC) blockade. Intrathecal muscimol, ZAPA, THIP midazolam, and ganaxolone all evoked significant analgesia in the tail flick test. Coadministration of either agonists or allosteric modulators with [(dihydroindenyl)oxy] alkanoic acid (DIOA) (a drug that blocks KCC2) had no effect on agonist or allosteric modulator potency. On the other hand, the analgesic efficacy of muscimol and ZAPA and the allosteric modulator ganaxolone were markedly reduced whereas THIP and midazolam were unaffected. Finally, in the spared nerve injury model, midazolam significantly reversed tactile hypersensitivity while ganaxolone had no effect. These results indicate that the KCC2-dependent Cl(-) extrusion capacity differentially regulates the analgesic efficacy of agonists and allosteric modulators at the GABA(A) receptor complex. PERSPECTIVE: Our work suggests that drug discovery efforts for the treatment of chronic pain disorders should target benzodiazepine or ?-subunit-containing sites at the GABA(A) complex. PMID- 22537562 TI - Effects of transcutaneous electrical nerve stimulation on motion sickness induced by rotary chair: a crossover study. AB - OBJECTIVES: Motion sickness (MS) is evoked by the conflict among somatosensory, visual, and vestibular input. Some of the MS symptoms and signs are mediated by activation of the autonomic nervous system (ANS). Transcutaneous electrical nerve stimulation (TENS), a maneuver used for pain control, was found to influence cardiovascular responses through ANS reflex, and to enhance motor function, visuospatial abilities, postural control, and cognitive function. The purpose of the present study is to investigate the effects of TENS on MS. SUBJECTS AND DESIGN: Fifteen (15) healthy young men participated in a within-subjects crossover study. Each completed four test sessions (control, rotation, TENS, TENS+rotation) in randomized order. Rotary chair (120 degrees /s) combined with pitch movement of the subject's head was used as a model to provoke MS. Whole rotation protocol consisted of 5 1-minute rotations, each separated by a 1-minute rest period. TENS protocol involved simultaneous electrical stimulation of posterior neck and Zusanli acupoint. OUTCOME MEASURES: Motion sickness susceptibility was rated on a standardized questionnaire (Motion Sickness Susceptibility Questionnaire). Motion sickness symptoms, blood pressure (BP), skin temperature, heart rate (HR), and heart rate variability (HRV) were measured. Saliva samples were collected to analyze the level of stress markers. Cognitive function was evaluated with d2 test prior to and after MS provocation. RESULTS: Spinning by itself significantly decreased task response speed and contraction. MS symptom scores, BP, as well as the sympathetic parameter of HRV increased progressively with MS provocation (p<0.05), but skin temperature decreased (p=0.023). Severity of MS symptoms significantly decreased with TENS intervention (p<0.05). After TENS treatment, subjects were able to concentrate better and showed fewer errors in a cognitive test. Salivary cortisol concentration significant decreased after TENS treatment. CONCLUSIONS: Sympathetic activity increased but parasympathetic activity decreased during MS. TENS was effective in reducing MS symptoms as well as alleviating cognitive impairment. PMID- 22537563 TI - A case of unilateral pleural effusion secondary to congestive heart failure successfully treated with traditional Chinese herbal formulas. AB - OBJECTIVES: A case is presented that illustrates the potential effect of traditional Chinese medicine (TCM) herbal formulas on treatment for unilateral pleural effusion secondary to congestive heart failure (CHF). SUBJECT: A 79-year old woman experienced episodic dyspnea with unilateral pleural effusion for 2 years. Thoracocentesis with pleural fluid analysis revealed no infection, tuberculosis, or malignancy. She had received conventional treatment for CHF but the symptoms persisted. Therefore, she visited the authors' TCM clinic for help. INTERVENTIONS AND OUTCOME: This patient was treated with TCM herbal granules including Shengmaisan, Xiebaisan, and Tinglizi, 3 times a day for 4 weeks. The daily dosage was adjusted on the basis of the patient's clinical response and her follow-up chest x-ray studies. After 8 months of treatment, her symptoms improved and the pleural effusion showed significant regression. CONCLUSIONS: It is suggested that TCM herbal formulas could play an important role in preventing the progression of unilateral pleural effusion secondary to CHF, in case of poor response to conservative treatment. Additional studies about the mechanism of action of the medication involved are warranted. PMID- 22537564 TI - A comparative pilot study of litholytic properties of Celosia argental (Sitivaraka) versus potassium citrate in renal calculus disease. PMID- 22537565 TI - Application and expression of Toxoplasma gondii surface antigen 2 (SAG2) and rhoptry protein 2 (ROP2) from recombinant Escherichia coli strain. AB - The gene encoding surface antigen 2 (SAG2) or rhoptry protein 2 (ROP2) of Toxoplasma gondii was cloned into the plasmid pGEX-4T-1 and subsequently expressed in Escherichia coli as a glutathione-s-transferase (GST) fusion protein. The characteristics of purified GST-SAG2 or GST-ROP2 were analysed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblot analysis. The specific IgG of a panel of serum samples provided by the National Institute for the Control of Pharmaceutical and Biological Products were tested with commercial ELISA and the lateral flow immunoassay (LFIA) based on GST SAG2, GST-ROP2 or GST-SAG2+ROP2. A total of 1096 sera and saliva samples from pregnant women were tested by GST-SAG2+ROP2-LFIA. In total, 20 T. gondii IgM positive sera (1.82%), 81 T. gondii IgG positive sera (7.4%) and 23 T. gondii IgA positive saliva (2.1%) were finally confirmed. The SAG2+ROP2 specific IgG and IFN gamma producing CD8+ T cells were induced in mice immunised with GST-SAG2+ROP2. The results indicate that GST-SAG2+ROP2 protein can be used as an antigen for diagnosing T. gondii infection and provide a strategy for development of subunit vaccines for protection against T. gondii infection. PMID- 22537566 TI - Murine typhus in Cyprus: a 9-year survey. AB - Epidemiological and clinical data of 193 human cases of murine typhus in Cyprus were recorded and analysed during a 9-year period (2000-2008). The incidence rate was estimated at 24.5 cases/100,000 population/year. The incidence rate varied considerably between rural, urban and semi-urban areas, with residents in rural areas accounting for 79.3% of the total cases. Most (72.5%) of the cases occurred in late summer (July and August) and early autumn (September to October) with a peak in September. Well-established persistent endemic foci with clusters of cases were identified and characterised as 'high risk' areas. Presence of or contact with rats and fleas, presence of domestic/peridomestic animals and residence in rural areas, especially locations near the 'green line' (a narrow zone patrolled by UN forces that separates the northern and southern parts of the island), increased the possibility of murine typhus infection. The results of the current study enhance the belief that murine typhus is a serious public health problem in Cyprus. PMID- 22537568 TI - Can martial arts techniques reduce fall severity? An in vivo study of femoral loading configurations in sideways falls. AB - Sideways falls onto the hip are a major cause of femoral fractures in the elderly. Martial arts (MA) fall techniques decrease hip impact forces in sideways falls. The femoral fracture risk, however, also depends on the femoral loading configuration (direction and point of application of the force). The purpose of this study was to determine the effect of fall techniques, landing surface and fall height on the impact force and the loading configuration in sideways falls. Twelve experienced judokas performed sideways MA and Block ('natural') falls on a force plate, both with and without a judo mat on top. Kinematic and force data were analysed to determine the hip impact force and the loading configuration. In falls from a kneeling position, the MA technique reduced the impact force by 27%, but did not change the loading configuration. The use of the mat did not change the loading configuration. Falling from a standing changed the force direction. In all conditions, the point of application was distal and posterior to the greater trochanter, but it was less distal and more posterior in falls from standing than from kneeling position. The present decrease in hip impact force with an unchanged loading configuration indicates the potential protective effect of the MA technique on the femoral fracture risk. The change in loading configuration with an increased fall height warrant further studies to examine the effect of MA techniques on fall severity under more natural fall circumstances. PMID- 22537567 TI - An odor-specific threshold deficit implicates abnormal cAMP signaling in youths at clinical risk for psychosis. AB - BACKGROUND: While olfactory deficits have been reported in schizophrenia and youths at-risk for psychosis, few studies have linked these deficits to current pathophysiological models of the illness. There is evidence that disrupted cyclic adenosine 3',5'-monophosphate (cAMP) signaling may contribute to schizophrenia pathology. As cAMP mediates olfactory signal transduction, the degree to which this disruption could manifest in olfactory impairment was ascertained. Odor detection thresholds to two odorants that differ in the degree to which they activate intracellular cAMP were assessed in clinical risk and low-risk participants. METHOD: Birhinal assessments of odor-detection threshold sensitivity to lyral and citralva were acquired in youths experiencing prodromal symptoms (n=17) and controls at low risk for developing psychosis (n=15). Citralva and lyral are odorants that differ in cAMP activation; citralva is a strong cAMP activator and lyral is a weak cAMP activator. RESULTS: The overall group-by-odor interaction was statistically significant. At-risk youths showed significantly reduced odor detection thresholds for lyral, but showed intact detection thresholds for citralva. This odor-specific threshold deficit was uncorrelated with deficits in odor identification or discrimination, which were also present. ROC curve analysis revealed that olfactory performance correctly classified at-risk and low-risk youths with greater than 97% accuracy. CONCLUSIONS: This study extends prior findings of an odor-specific hyposmia implicating cAMP-mediated signal transduction in schizophrenia and unaffected first-degree relatives to include youths at clinical risk for developing the disorder. These results suggest that dysregulation of cAMP signaling may be present during the psychosis prodrome. PMID- 22537569 TI - Influence of hydration on nanoindentation induced energy expenditure of dentin. AB - Improved understanding of the effects of hydration and drying in mineralized tissues is highly desirable, particularly for physiologically hydrated biological materials such as dentin. We investigated the influence of hydration on the nanomechanical properties of healthy dentin and hypothesized that drying leads to an increase in indentation induced energy expenditure and hardness. Hydrated and dry dentin were tested with a UMIS set up with a Berkovich indenter at a maximum load of 50 mN. Values representative of the energy expenditure behavior were presented as dissipated energy, U(d), recovered energy, U(e), normalized energy expenditure index, psi, and hardness, H. Energy expenditure index results, which normalize the energy expenditure for each test and describe the relative energy dissipation-recovery behavior of a material, suggested that, for the relatively severe contact strains about a sharp Berkovich indenter, dissipation dominates the mechanical response of both the hydrated and dry dentin. In support of our initial hypothesis, dry dentin presented a significantly higher energy expenditure index than hydrated dentin (p<0.0001). These results were primarily associated with a lower U(e) that was found upon drying. Hydration also decreased H significantly (p<0.0001). In summary, this study presents the first direct measurements of the energy expenditure behavior of hydrated and dry dentin using instrumented nanoindentation. PMID- 22537570 TI - Does screw-bone interface modelling matter in finite element analyses? AB - The effect of screw-bone interface modelling strategies was evaluated in the setting of a tibial mid-shaft fracture stabilised using locking plates. Three interface models were examined: fully bonded interface; screw with sliding contact with bone; and screw with sliding contact with bone in an undersized pilot hole. For the simulation of the last interface condition we used a novel thermal expansion approach to generate the pre-stress that the bone would be exposed to during screw insertion. The study finds that the global load deformation response is not influenced by the interface modelling approach employed; the deformation varied by less than 1% between different interaction models. However, interface modelling is found to have a considerable impact on the local stress-strain environment within the bone in the vicinity of the screws. Frictional and tied representations did not have significantly different peak strain values (<5% difference); the frictional interface had higher peak compressive strains while the tied interface had higher tensile strains. The undersized pilot hole simulation produced the largest strains. The peak minimum principal strains for the frictional interface were 26% of those for the undersized pilot hole simulation at a load of 770 N. It is concluded that the commonly used tie constraint can be used effectively when the only interest is the global load-deformation behaviour. Different contact interface models, however, alter the mechanical response around screw holes leading to different predictions for screw loosening, bone damage and stress shielding. PMID- 22537571 TI - A fibreoptic endoscopic study of upper gastrointestinal bleeding at Bugando Medical Centre in northwestern Tanzania: a retrospective review of 240 cases. AB - BACKGROUND: Upper gastrointestinal (GI) bleeding is recognized as a common and potentially life-threatening abdominal emergency that needs a prompt assessment and aggressive emergency treatment. A retrospective study was undertaken at Bugando Medical Centre in northwestern Tanzania between March 2010 and September 2011 to describe our own experiences with fibreoptic upper GI endoscopy in the management of patients with upper gastrointestinal bleeding in our setting and compare our results with those from other centers in the world. FINDINGS: A total of 240 patients representing 18.7% of all patients (i.e. 1292) who had fibreoptic upper GI endoscopy during the study period were studied. Males outnumbered female by a ratio of 2.1:1. Their median age was 37 years and most of patients (60.0%) were aged 40 years and below. The vast majority of the patients (80.4%) presented with haematemesis alone followed by malaena alone in 9.2% of cases. The use of non-steroidal anti-inflammatory drugs, alcohol and smoking prior to the onset of bleeding was recorded in 7.9%, 51.7% and 38.3% of cases respectively. Previous history of peptic ulcer disease was reported in 22(9.2%) patients. Nine (3.8%) patients were HIV positive. The source of bleeding was accurately identified in 97.7% of patients. Diagnostic accuracy was greater within the first 24 h of the bleeding onset, and in the presence of haematemesis. Oesophageal varices were the most frequent cause of upper GI bleeding (51.3%) followed by peptic ulcers in 25.0% of cases. The majority of patients (60.8%) were treated conservatively. Endoscopic and surgical treatments were performed in 30.8% and 5.8% of cases respectively. 140 (58.3%) patients received blood transfusion. The median length of hospitalization was 8 days and it was significantly longer in patients who underwent surgical treatment and those with higher Rockall scores (P < 0.001). Rebleeding was reported in 3.3% of the patients. The overall mortality rate of 11.7% was significantly higher in patients with variceal bleeding, shock, hepatic decompensation, HIV infection, comorbidities, malignancy, age > 60 years and in patients with higher Rockall scores and those who underwent surgery (P < 0.001). CONCLUSION: Oesophageal varices are the commonest cause of upper gastrointestinal bleeding in our environment and it is associated with high morbidity and mortality. The diagnostic accuracy of fibreoptic endoscopy was related to the time interval between the onset of bleeding and endoscopy. Therefore, it is recommended that early endoscopy should be performed within 24 h of the onset of bleeding. PMID- 22537573 TI - The evolution and current use of invasive hemodynamic monitoring for predicting volume responsiveness during resuscitation, perioperative, and critical care. AB - Traditional hemodynamic monitors such as pulmonary artery and central venous catheters provide continuous data and secure intravenous access, but their diagnostic efficacy has been criticized. Dynamic arterial waveform monitoring is promising, but studies suggest it is reliable only within narrow ventilation and rhythm parameters. Newer algorithm-based hemodynamic monitors have emerged; they, too, are limited in their accuracy and applicability. Intravascular monitors are used to predict fluid responsiveness and need for alternative therapies, such as vasomotor or inotropic support. Recent efficacy data, along with other important clinical findings, are reviewed with regard to invasive monitors. We caution against over-generalizing from existing studies, and provide guidance for clinicians wishing to target monitoring techniques for appropriate patients. PMID- 22537572 TI - Hypotension from spinal anesthesia in patients aged greater than 80 years is due to a decrease in systemic vascular resistance. AB - STUDY OBJECTIVES: To determine the exact mechanism underlying spinal anesthesia induced hypotension in the elderly patient. DESIGN: Retrospective case-control study. SETTING: Operating room (OR) in a general hospital. MEASUREMENTS: Records from 60 consecutive patients over 80 years of age, who underwent hip fracture repair (intramedullary nail or compression hip screw) during spinal anesthesia were studied. After injection of isobaric 0.5% bupivacaine in the L(3)-L(4) intervertebral space in the lateral decubitus position, patients were turned supine. Acetate Ringer's solution (300 mL) was infused over 30 minutes after subarachnoid puncture. A decrease in systolic arterial pressure to less than 100 mmHg was treated with an intravenous injection of 5 mg ephedrine. The hypotension group (n=18) comprised patients who required ephedrine during the 30 minutes after the puncture, and the nonhypotension group (n=42) consisted of patients who maintained stable arterial pressure with crystalloid infusion only. MEASUREMENTS: Cardiac output (CO) and stroke volume variation (SVV) every 20 seconds using the Vigileo-FloTrac system continuously from arrival in the operating room (OR) to 30 minutes after the subarachnoid puncture were recorded. Serial changes in systemic vascular resistance (SVR), CO, and SVV from baseline after puncture were compared between the two groups. MAIN RESULTS: The decrease in SVR over 20 minutes after the puncture was significantly greater in the hypotension group than the nonhypotension group (P = 0.047). Cardiac output was stable in the two groups. Stroke volume variation in the first 10 minutes after the puncture increased to similar levels in the two groups, then decreased gradually to baseline. No significant differences were noted in circulatory parameters on arrival at the OR. CONCLUSIONS: A decrease in SVR, not CO, is the main mechanism of hypotension seen during spinal anesthesia in elderly patients. PMID- 22537574 TI - A case of serotonin syndrome precipitated by fentanyl and ondansetron in a patient receiving paroxetine, duloxetine, and bupropion. PMID- 22537575 TI - Superior vena cava stent as an unusual cause of difficult Swan-Ganz catheter placement. PMID- 22537576 TI - A case of paradoxical presentation of postural postdural puncture headache. PMID- 22537577 TI - Preoperative continuous sciatic nerve block for perioperative analgesia and for phantom limb prevention. PMID- 22537578 TI - Use of the TruView EVO2 laryngoscope in Treacher Collins syndrome after unplanned extubation. PMID- 22537579 TI - Oxygen line leakage originated from the inside of an anesthetic machine. PMID- 22537580 TI - Two new C-15 enolic acyl phragmalin-type limonoids from Chukrasia tabularis var. velutina. AB - Two new C-15 enolic acyl phragmalin-type limonoid orthoesters, chukvelutilide G (1) and chukrasine F (2), were isolated from the stem barks of Chukrasia tabularis var. velutina. Their structures were elucidated by their extensive high resolution-electrospray ionization mass spectrometry (HR-ESI-MS), one- and two dimensional spectroscopic analysis, including heteronuclear single quantum coherence (HSQC), HMBC and NOESY experiments. PMID- 22537581 TI - Reforming the Greek health system: a role for non-medical, clinical bioscientists. AB - Within the context of the recent debt crisis and the subsequently adopted austerity measures, the Greek health system faces important challenges including the necessity to rationalize public spending. One domain where there is scope for reducing expenses is laboratory medicine services, that are provided by both public and private facilities. Specialized non-medical, clinical bioscientists (such as molecular biologists, biochemists and geneticists) massively participate in the provision of laboratory medicine services in both sectors; however, they are excluded from key positions, such as the direction of laboratories and sitting in regulatory bodies. This is in breach with European standards of practice and also constitutes an impediment to the much anticipated rationalization of spending; therefore has to be addressed by the Greek health services authorities. PMID- 22537582 TI - Supine hypotensive syndrome as the probable cause of both maternal and fetal death. AB - Supine hypotensive syndrome is characterized by severe supine hypotension in late pregnancy, whose clinical presentation ranges from minimal cardiovascular alterations to severe shock, resulting from inferior vena cava compression by gravid uterus. We report a case of a 41-year-old 39-week-pregnant woman found dead supine. Autopsy revealed the following: cyanosis of the limbs; congestion of the jugular and subclavian veins; abundant abdominal subcutaneous fatty tissue; uterus displacing intestine and diaphragm; collapsed inferior vena cava; both femoral veins dilated and filled with blood; edematous and congested lungs; and placenta 790 g, fetus 3475 g, amniotic fluid 800 cm(3). The diagnosis of supine hypotensive syndrome as the probable cause of death is supported by the position of the body and autopsy findings. This syndrome can be considered as the first stage of the physio-pathological mechanism that led to death in the case presented herein and should be considered by pathologists as a cause of sudden death. PMID- 22537583 TI - Application of enteric viruses for fecal pollution source tracking in environmental waters. AB - Microbial source tracking (MST) tools are used to identify sources of fecal pollution for accurately assessing public health risk and implementing best management practices (BMPs). This review focuses on the potential of enteric viruses for MST applications. Following host infection, enteric viruses replicate and are excreted in high numbers in the hosts' feces and urine. Due to the specificity in host infection, enteric viruses have been considered one of the most accurate library-independent culture-independent MST tools. In an assessment of molecular viral assays based on sensitivity, specificity and the density of the target virus in fecal-impacted samples, human adenovirus and human polyomavirus were found to be the most promising human-specific viral markers. However, more research is needed to identify promising viral markers for livestock because of cross-reactions that were observed among livestock species or the limited number of samples tested for specificity. Other viral indicators of fecal origin, F+ RNA coliphage and pepper mild mottle virus, have also been proposed as potential targets for developing MST markers. Enhancing the utility of enteric viruses for MST applications through next generation sequencing (NGS) and virus concentration technology is discussed in the latter part of this review. The massive sequence databases generated by shotgun and gene-targeted metagenomics enable more efficient and reliable design of MST assays. Finally, recent studies revealed that alternative virus concentration methodologies may be more cost-effective than standard technologies such as 1MDS; however, improvements in the recovery efficiency and consistency are still needed. Overall, developments in metagenomic information combined with efficient concentration methodologies, as well as high host-specificity, make enteric viruses a promising tool in MST applications. PMID- 22537584 TI - Distal interphalangeal joint arthrodesis for degenerative osteoarthritis with compression screw: results in 102 digits. AB - PURPOSE: To assess objective and subjective outcomes of distal interphalangeal joint arthrodesis with a headless compression screw for degenerative osteoarthritis. METHODS: We retrospectively analyzed 102 cases of distal interphalangeal joint arthrodesis performed with headless compression screws on 59 patients. We included only primary cases of degenerative osteoarthritis with a minimum follow-up of 7 months. We identified appropriate bone coaptation and hardware positioning on postoperative radiographs in all digits. The mean follow up period was 26 months (range, 7-67 mo). RESULTS: In 89 of 102 cases, patients were fully satisfied; in 9 cases, they were satisfied. Four complications occurred: 2 cases of prominent hardware, 1 complex regional pain syndrome type 1, and 1 symptomatic bony callus on the fused joint. Secondary surgery was required in each of these 4 cases. No nonunion, malunion, nail dystrophy, pseudarthrosis, or infection occurred. All arthrodeses healed. CONCLUSIONS: Distal interphalangeal joint arthrodesis with headless compression screws was shown to be safe and effective in cases of degenerative osteoarthritis, with a low complication rate. PMID- 22537585 TI - Biomechanical differences of the proximal interphalangeal joint volar plate during active and passive motion: a dynamic ultrasonographic study. AB - PURPOSE: To define the biomechanical differences of the volar plate (VP) of the proximal interphalangeal joint during active and passive motion, which may provide clues to understanding the functional importance of the volar elevation of the VP. METHODS: We imaged the volar aspect of the proximal interphalangeal joint in 10 healthy middle fingers using ultrasonography. Cine videos recorded the movements of the VP during joint motion from full extension to more than 60 degrees of flexion both actively and passively. We plotted 5 points on the volar surface of the VP and traced them for motion analysis. We statistically analyzed the volar distances and volar angulation of the VP in full extension, 30 degrees , 45 degrees , and 60 degrees of flexion to determine the differences between active and passive flexion. RESULTS: In active flexion, the VP showed significantly higher volar distances in 45 degrees and 60 degrees and changed its configuration from the original flattened figure to an inverted U shape, with a significant higher angulation at 45 degrees compared with passive flexion. Conversely, in passive flexion, we did not observe the volar elevation of the VP and the flattened configuration was maintained throughout the motion arc. CONCLUSIONS: From an anatomical viewpoint, volar elevation of the VP seen in active flexion could provide dynamic stresses on the adjacent ligaments and contribute to the stability and smooth gliding of the joint. PMID- 22537586 TI - Trapezial metastasis as the first indication of primary non-small cell carcinoma of the lung. AB - Metastasis to the bones of the hand and wrist is not common, and its discovery may reveal an advanced primary tumor located centrally. Clinically, hand metastasis is hard to differentiate from other more common hand pathologies. Its rarity, coupled with a lack of unique clinical manifestations, makes hand and wrist metastasis difficult to diagnose. However, its diagnosis is critical to initiate an appropriate course of treatment. We present a patient in whom lung carcinoma metastasis to the trapezium was definitively diagnosed upon surgical management of symptoms that were consistent with thumb carpometacarpal arthritis. PMID- 22537587 TI - Domestic bird bites. PMID- 22537588 TI - Preface. Report 2012: Intracranial aneurysms: Clips or coils. PMID- 22537590 TI - Foreword. Report 2012: Intracranial aneurysms: Clips or coils. PMID- 22537592 TI - Structured cognition and neural systems: from rats to language. AB - Much of animal and human cognition is compositional in nature: higher order, complex representations are formed by (rule-governed) combination of more primitive representations. We review here some of the evidence for compositionality in perception and memory, motivating an approach that takes ideas and techniques from computational linguistics to model aspects of structural representation in cognition. We summarize some recent developments in our work that, on the one hand, use algorithms from computational linguistics to model memory consolidation and the formation of semantic memory, and on the other hand use insights from the neurobiology of memory to develop a neurally inspired model of syntactic parsing that improves over existing (not cognitively motivated) models in computational linguistics. These two theoretical studies highlight interesting analogies between language acquisition, semantic memory and memory consolidation, and suggest possible neural mechanisms, implemented in computational algorithms that may underlie memory consolidation. PMID- 22537593 TI - The GOLD initiative 2011: a change of paradigm? AB - Ten years after the publication of the first GOLD strategy (Global Strategy for the Diagnosis, Management, and Prevention of COPD) for chronic obstructive pulmonary disease (COPD), the new revision published on the GOLD website at the end of 2011 represents a significant change in the diagnostic approach, clinical evaluation and therapeutic treatment of the disease. This revision debates not only the most significant aspects, which remain relatively intact, but also, and in particular, those that have been substantially modified compared with the GOLD revision from 2006. PMID- 22537594 TI - The future is now in community-acquired pneumonia: cardiovascular complications and conjugate vaccines. PMID- 22537595 TI - Learning, memory, and glial cell changes following recovery from chronic unpredictable stress. AB - Previous research has indicated that chronic stress induces inflammatory responses, cognitive impairments, and changes in microglia and astrocytes. However, whether stress-induced changes following recovery are reversible is unclear. The present study examined the effects of chronic unpredictable stress (CUS) following recovery on spatial learning and memory impairments, changes in microglia and astrocytes, and interleukine-1beta (IL-1beta) and glial-derived neurotrophic factor (GDNF) levels. Mice were randomly divided into control, stress, and recovery groups, and CUS was applied to mice in the stress and recovery groups for 40 days. Following the application of CUS, the recovery group was allowed 40 days without stress. The results of the Morris water maze illustrated that CUS-induced spatial learning and memory impairments could be reversed or even improved by a period of recovery. Immunohistochemical tests revealed that CUS-induced alterations in microglia could dissipate with time in the CA3 region of the hippocampus and prelimbic areas. However, CUS-induced activation of astrocytes was sustained in the CA3 area following recovery. Western blot analyses revealed that CUS induced a significant increase of GDNF and a significant decrease in IL-1beta. Additionally, increased GDNF levels were sustained in the hippocampus during recovery. In conclusion, this study provides evidence that CUS-induced learning and memory impairments could be reversible following recovery. However, activated astrocytes and increased GDNF levels in the hippocampus remained elevated after recovery, suggesting that activated astrocytes and increased GDNF play important roles in the adaptation of the brain to CUS and in repairing CUS-induced impairments during recovery. PMID- 22537596 TI - Identification of a highly conserved valine-glycine-phenylalanine amino acid triplet required for HIV-1 Nef function. AB - BACKGROUND: The Nef protein of HIV facilitates virus replication and disease progression in infected patients. This role as pathogenesis factor depends on several genetically separable Nef functions that are mediated by interactions of highly conserved protein-protein interaction motifs with different host cell proteins. By studying the functionality of a series of nef alleles from clinical isolates, we identified a dysfunctional HIV group O Nef in which a highly conserved valine-glycine-phenylalanine (VGF) region, which links a preceding acidic cluster with the following proline-rich motif into an amphipathic surface was deleted. In this study, we aimed to study the functional importance of this VGF region. RESULTS: The dysfunctional HIV group O8 nef allele was restored to the consensus sequence, and mutants of canonical (NL4.3, NA-7, SF2) and non canonical (B2 and C1422) HIV-1 group M nef alleles were generated in which the amino acids of the VGF region were changed into alanines (VGF->AAA) and tested for their capacity to interfere with surface receptor trafficking, signal transduction and enhancement of viral replication and infectivity. We found the VGF motif, and each individual amino acid of this motif, to be critical for downregulation of MHC-I and CXCR4. Moreover, Nef's association with the cellular p21-activated kinase 2 (PAK2), the resulting deregulation of cofilin and inhibition of host cell actin remodeling, and targeting of Lck kinase to the trans-golgi-network (TGN) were affected as well. Of particular interest, VGF integrity was essential for Nef-mediated enhancement of HIV virion infectivity and HIV replication in peripheral blood lymphocytes. For targeting of Lck kinase to the TGN and viral infectivity, especially the phenylalanine of the triplet was essential. At the molecular level, the VGF motif was required for the physical interaction of the adjacent proline-rich motif with Hck. CONCLUSION: Based on these findings, we propose that this highly conserved three amino acid VGF motif together with the acidic cluster and the proline-rich motif form a previously unrecognized amphipathic surface on Nef. This surface appears to be essential for the majority of Nef functions and thus represents a prime target for the pharmacological inhibition of Nef. PMID- 22537597 TI - Resveratrol protects H9c2 embryonic rat heart derived cells from oxidative stress by inducing autophagy: role of p38 mitogen-activated protein kinase. AB - Recently, many studies have attempted to illustrate the mechanism of autophagy in protection against oxidative stress to the heart induced by H(2)O(2). However, whether resveratrol-induced autophagy involves the p38 mitogen-activated protein kinase (MAPK) pathway is still unknown. This study aimed to investigate whether treating H9c2 cells with resveratrol increases autophagy and attenuates the cell death and apoptosis induced by oxidative stress via the p38 MAPK pathway. Resveratrol with or without SB202190, an inhibitor of the p38 MAPK pathway, was added 30 min before H(2)O(2). After H(2)O(2) treatment, the cells were incubated under 5% CO(2) at 37 degrees C for 24 h to assess cell survival and death or incubated for 20 min for Western blot and transmission electron microscopy. Flow cytometry was used to detect apoptosis after 6 h of H(2)O(2) treatment. Resveratrol at 20 umol/L protected H9c2 cells treated with 100 umol/L H(2)O(2) from oxidative damage. It increased cell survival and markedly decrease lactate dehydrogenase release. In addition, resveratrol increased autophagy and decreased H(2)O(2)-induced apoptosis. Furthermore, the protective effects of resveratrol were inhibited by 10 umol/L SB202190. Thus, resveratrol protected H(2)O(2) treated H9c2 cells by upregulating autophagy via the p38 MAPK pathway. PMID- 22537598 TI - Improved decoding of neural activity from fMRI signals using non-separable spatiotemporal deconvolutions. AB - The goal of most functional Magnetic Resonance Imaging (fMRI) analyses is to investigate neural activity. Many fMRI analysis methods assume that the temporal dynamics of the hemodynamic response function (HRF) to neural activation is separable from its spatial dynamics. Although there is empirical evidence that the HRF is more complex than suggested by space-time separable canonical HRF models, it is difficult to assess how much information about neural activity is lost when assuming space-time separability. In this study we directly test whether spatiotemporal variability in the HRF that is not captured by separable models contains information about neural signals. We predict intracranially measured neural activity from simultaneously recorded fMRI data using separable and non-separable spatiotemporal deconvolutions of voxel time series around the recording electrode. Our results show that abandoning the spatiotemporal separability assumption consistently improves the decoding accuracy of neural signals from fMRI data. We compare our findings with results from optical imaging and fMRI studies and discuss potential implications for classical fMRI analyses without invasive electrophysiological recordings. PMID- 22537599 TI - Hierarchical Bayesian inference for the EEG inverse problem using realistic FE head models: depth localization and source separation for focal primary currents. AB - The estimation of the activity-related ion currents by measuring the induced electromagnetic fields at the head surface is a challenging and severely ill posed inverse problem. This is especially true in the recovery of brain networks involving deep-lying sources by means of EEG/MEG recordings which is still a challenging task for any inverse method. Recently, hierarchical Bayesian modeling (HBM) emerged as a unifying framework for current density reconstruction (CDR) approaches comprising most established methods as well as offering promising new methods. Our work examines the performance of fully-Bayesian inference methods for HBM for source configurations consisting of few, focal sources when used with realistic, high-resolution finite element (FE) head models. The main foci of interest are the correct depth localization, a well-known source of systematic error of many CDR methods, and the separation of single sources in multiple source scenarios. Both aspects are very important in the analysis of neurophysiological data and in clinical applications. For these tasks, HBM provides a promising framework and is able to improve upon established CDR methods such as minimum norm estimation (MNE) or sLORETA in many aspects. For challenging multiple-source scenarios where the established methods show crucial errors, promising results are attained. Additionally, we introduce Wasserstein distances as performance measures for the validation of inverse methods in complex source scenarios. PMID- 22537600 TI - Dynamics of electrocorticographic (ECoG) activity in human temporal and frontal cortical areas during music listening. AB - Previous studies demonstrated that brain signals encode information about specific features of simple auditory stimuli or of general aspects of natural auditory stimuli. How brain signals represent the time course of specific features in natural auditory stimuli is not well understood. In this study, we show in eight human subjects that signals recorded from the surface of the brain (electrocorticography (ECoG)) encode information about the sound intensity of music. ECoG activity in the high gamma band recorded from the posterior part of the superior temporal gyrus as well as from an isolated area in the precentral gyrus was observed to be highly correlated with the sound intensity of music. These results not only confirm the role of auditory cortices in auditory processing but also point to an important role of premotor and motor cortices. They also encourage the use of ECoG activity to study more complex acoustic features of simple or natural auditory stimuli. PMID- 22537601 TI - Is on-demand treatment effective in patients with severe haemophilia? AB - On-demand therapy enables stopping haemorrhages rapidly, reducing joint pain and restoring joint mobility, but does not prevent the beginning and subsequent development of haemophilic arthropathy. The main objective of this study was to identify the clinical and orthopaedic status of severe haemophilic patients with bleeding phenotype receiving on-demand treatment in Spain. We conducted an epidemiological, observational, retrospective study, recruiting 167 patients from 36 centres (92% of them with haemophilia A), median age at enrolment of 35 years. Forty per cent of the patients received a combination of on-demand and short-term prophylaxis regimen; the rest was under on-demand treatment. One hundred and forty-five patients (87%) reported at least one bleeding episode and 22 (13%) of the biologically severe patients had no bleeding phenotype. Seventy-one per cent of the studied population presented established haemophilic arthropathy, reaching 80% if we exclude patients without bleeding phenotype. Forty-three per cent of these patients had one or two joints affected, 28% of them had three or four affected joints, 20% reported five or six affected joints and 9% more than six injured joints. An increase in established haemophilic arthropathy with age was observed. Forty-six patients underwent orthopaedic surgery at least once. These data show that on-demand therapy is not effective in preventing the development of haemophilic arthropathy in severe haemophilic population with bleeding phenotype. Therefore, we suggest that the optimal treatment in these patients should be based on prophylaxis. We recommend analysing the reasons for ending prophylaxis, in case its reinstatement should be necessary. PMID- 22537602 TI - Leucocyte subpopulations in the seminal plasma and their effects on fertilisation rates in an IVF cycle. AB - Controversy exists on the role of leucocytospermia on fertilisation rates and IVF outcomes. The aim of our study was to identify the effect of leucocytes and leucocyte subpopulations on fertilisation rates in an IVF cycle. A prospective comparative study of the leucocyte subpopulations of seminal fluid of partners of women attending an IVF cycle was conducted. The samples underwent immunocytochemical staining. The monoclonal antibodies used in this study include CD3, CD4, CD8 (T Cells), CD14 (monocytes/macrophages), CD16 (granulocytes), CD20 (B Cells), CD45 (Pan Leucocytes), CD56 (natural killer cells) and CD69 (activated T and B Cells). Of 21 patients who were recruited into the study, seven were identified as poor fertilisers (<35%) and 14 were identified as good fertilisers (>60%). Data were analysed with SPSS version 14. The total leucocyte counts (CD45) between the poor and good fertilisers were not statistically significant. The macrophages and the monocytes (CD14) were significantly elevated in the good fertilisers group in comparison with the poor fertilisers (P < 0.05). We also found that T cells (CD2, CD4, CD8) and CD14 (macrophages) correlated significantly (r = 0.47, P value < 0.01) with the fertilisation rate. Our study confirms that the presence of leucocytes does not adversely affect the fertilisation rates and the outcome of an IVF cycle. However, macrophages and the monocytes (CD14) were significantly elevated in the good fertilisers group. The increased phagocytic activity in these individuals might increase their fertilising potential by removing spermatozoa with abnormal morphology. PMID- 22537604 TI - Extension of the liquid chromatography/quantitative structure-property relationship method to assess the lipophilicity of neutral, acidic, basic and amphotheric drugs. AB - A reported chromatographic method to determine the 1-octanol/water partition coefficient (logP(o/w)) has been used to estimate the lipophilicity of 33 drugs with diverse structures and functionalities, including neutral, acid, basic, and amphoteric compounds. The applicability of the chromatographic method has been extended to the UHPLC technique, and the results obtained were compared to those obtained from conventional HPLC. No significant difference between the results obtained by both techniques is noticed. Thus, the suitability of UHPLC, which involves shorter run times, for lipophilicity assessment is demonstrated. In order to show the consistency of this chromatographic method, the logP(o/w) values of those drugs which have acid-base properties have been also determined by potentiometry, and the final results have been compared with both values derived from the chromatographic method and the ones from the literature. PMID- 22537603 TI - Short and long terms healing of the experimentally transverse sectioned tendon in rabbits. AB - BACKGROUND: The incidences of tendon injuries in certain sections of human or animal populations such as athletes are high, but every human or animal, regardless of age or level of activity experiences some degree of tendon injury. In spite of the various investigations of injuries and treatment, comprehensive studies dealing with the histological, ultrastructural and biomechanical aspects of healing of load-bearing tendons are rare. This study was designed to compare the outcome of healing of the transverse sectioned superficial digital flexor tendon (SDFT) after 28 and 84 days post injury (DPI) in rabbits. METHODS: Forty white New Zealand mature female rabbits were randomly divided into two equal groups of 28 and 84 DPI After tenotomy and surgical repair of the left SDFT, the injured legs were casted for 14 days. The weight of the animals, tendon diameter, and clinical, radiographic and ultrasonographic evaluations were conducted at weekly intervals. The animals were euthanized on 28 and 84 DPI and the tendons were evaluated for histopathological, ultrastructural, biomechanical and percentage dry weight parameters. RESULTS: Although the clinical, ultrastructural, morphological and biomechanical properties of the injured tendons on day 84 showed a significant improvement compared to those of the 28 DPI, these parameters were still significantly inferior to their normal contra lateral tendons. CONCLUSIONS: This study showed that tendon healing is very slow and at 84 days post-injury the morphological and biomechanical parameters were still inferior to the normal tendons and many collagen fibrils still had the same diameter as those seen at 28 DPI. PMID- 22537605 TI - Untargeted screening of urinary peptides with liquid chromatography coupled to hybrid linear-ion trap tandem mass spectrometry. AB - We formerly developed and applied a liquid chromatography coupled with hybrid triple quadrupole-linear ion trap mass spectrometry technique for the detection and identification of exogenous compounds in clinical and forensic toxicology. In this study, we aimed to adapt this technique to the detection and identification of the constituents of the urinary peptidome. After solid-phase extraction, separation was performed using gradient reversed-phase liquid chromatography. The mass spectrometer was operated in the information-dependent acquisition mode, switching between: a survey scan acquired in the enhanced multi-charged scan mode with dynamic subtraction of background noise; and two dependent scans obtained in the enhanced product ion scan mode. The results obtained show that: (i) the present procedure is able to detect and identify peptides which, together with their inferred parent proteins, are similar to those referenced in the related literature; (ii) the structure of some peptides can generally be resolved from their enhanced product ion spectra; and (iii) confirmation of the sequences proposed through library search by in silico verification of the fragments observed in the enhanced product ion spectra seems to be indispensable to avoid misinterpretations. PMID- 22537606 TI - Selective extraction of genotoxic impurities and structurally alerting compounds using polymeric ionic liquid sorbent coatings in solid-phase microextraction: Alkyl halides and aromatics. AB - A series of polymeric ionic liquids (PILs) possessing varied chemical makeup and composition were applied as selective solid-phase microextraction (SPME) sorbent coatings for the analysis of genotoxic impurities (GTIs) and related structurally alerting compounds, namely, alkyl halides and aromatics. In addition to exploiting two previously synthesized PILs as selective coatings, two new PILs, namely, N,N-didecyl-N-methyl-D-glucaminium poly(2-methyl-acrylic acid 2-[1-(3-{2 [2-(3-trifluoromethanesulfonylamino-propoxy)-ethoxy]-ethoxy}-propylamino) vinylamino]-ethyl ester) (poly([DDMGlu][MTFSI])), and poly(1-vinyl-3 propylphenylimidazolium) chloride (poly([VPPIM][Cl])), were designed, synthesized, and their selectivity examined in the extraction of the selected analytes. The glucaminium-based coating was developed to exploit the hydrogen bond-acidic hydroxyl groups within the carbohydrate moiety of the PIL in addition to dispersive capabilities resulting from the cation and anion. The poly([VPPIM][Cl]) coating was tailored to possess pi-pi interaction capabilities through the phenyl functionality while also containing the hydrogen bond-basic chloride anion. Calibration studies were performed via headspace extraction to determine the sensitivity and limit of detection (LOD) for all analytes with respect to each PIL-based sorbent coating and compared to the polyacrylate (PA) and polydimethylsiloxane (PDMS) sorbent coatings. PILs containing the chloride anion exhibited high selectivity for aniline-based compounds. The glucaminium based PIL exhibited good sensitivity for larger aliphatic alkyl halides. The poly(1-4-vinylbenzyl-3-hexadecylimidazolium) bis[(trifluoromethyl)sulfonyl] imide (poly([VBHDIM][NTf2])) PIL coating demonstrated superior selectivity for larger aliphatic/aromatic analytes. The LODs of both commercial and PIL-based coatings for the two classes of GTIs ranged from low part-per-billion (ppb) to mid part per-trillion (ppt) levels. Recovery studies were performed at two concentration levels within the linear range in order to validate the accuracy of the technique. Scanning electron micrographs were obtained for three PIL-based coatings following approximately 70 extraction/desorption steps, wherein the fiber coatings were observed to be largely smooth and intact. PMID- 22537607 TI - Outcomes in 144 patients with colorectal cancer treated in a phase I clinic: the MD Anderson Cancer Center experience. AB - BACKGROUND: Patients with advanced colorectal cancer have a poor prognosis once standard therapies fail. This retrospective study presents the characteristics and outcomes in 144 patients treated in phase I clinical trials. METHODS: We retrospectively reviewed the clinical outcomes in 144 consecutive patients with colorectal cancer referred to the phase I clinic at MD Anderson. RESULTS: Median age was 60 years (range, 35-86 years). The median number of previous systemic therapies was 4 (range, 1-7). The median PFS with the last line of conventional systemic treatment was 12.3 weeks (95% confidence interval [CI], 11.0-14.4); the median PFS of the best phase I treatment was shorter at 8.1 weeks (95% CI, 7.9 8.7 weeks; log-rank test, P < .0001). In the multivariate analysis that included the RMH score, sex (male vs. female, P = .02; hazard ratio [HR], 1.57), hemoglobin (< 10.5 vs. >= 10.5 g/dL; P = .03; HR 1.79), and the RMH score (2-3 vs. 0-1; P < .003; HR, 1.85) were significant predictors of poor survival. CONCLUSION: The PFS of patients with colorectal cancer in phase I treatment was shorter than it was on their last line of conventional systemic treatment. Multivariate analysis confirmed the value of the RMH score for predicting overall survival in patients with colorectal cancer enrolled in phase I studies. PMID- 22537608 TI - Influence of KRAS p.G13D mutation in patients with metastatic colorectal cancer treated with cetuximab. AB - BACKGROUND: Patients with metastatic colorectal cancer (mCRC) with activating mutations at codon 12 or 13 of the KRAS gene are currently excluded from treatment with monoclonal antibodies against the epidermal growth factor receptor (EGFR), for example, cetuximab. Occasionally, some of these patients benefit from treatment with cetuximab, especially patients with a mutation at codon 13. We conducted an analysis to study the influence of the KRAS p.G13D mutation in patients with mCRC who were treated with cetuximab. MATERIALS AND METHODS: We analyzed the KRAS mutation status of 110 patients who were treated with cetuximab between September 2003 and October 2008 at Hospital Clinico, San Carlos. We compared progression-free survival, overall survival, and response rate according to KRAS mutation status. RESULTS: Patients with mutations at codon 13 compared with those with other KRAS mutations showed no statistically significant differences in progression-free survival (4.96 months [95% CI, 3.04-6.89 months] vs. 3.10 months [95% CI, 1.58-4.61 months]; hazard ratio [HR] 0.88 [95% CI, 44 1.75]; P = .72) and overall survival (8.2 months [95% CI, 4.2-12.1 months] vs. 14.6 months [95% CI, 8.0-21.2 months]; HR 0.50 [95% CI, 0.23-1.09]; P = .084). Patients with KRAS wild-type tumors have a longer progression-free survival (7.30 months [95% CI, 4.48-10.12 months]; HR 0.46 [95% CI, 0.23-0.91]; P = .025) and overall survival (19.0 months [95% CI, 10.2-27.8 months]; HR 0.32 [95% CI, 0.15 0.69]; P = .004) than patients with p.G13D-mutated tumors. Differences in the response rate were not observed between groups. CONCLUSION: Patients with mCRC and mutation at codon 13 of the KRAS gene do not appear to benefit from treatment with cetuximab. These results support the current clinical practice. PMID- 22537609 TI - Oxaliplatin-induced hepatoportal sclerosis, portal hypertension, and variceal bleeding successfully treated with transjugular intrahepatic portosystemic shunt. PMID- 22537610 TI - Regional plantar pressure during walking, stair ascent and descent. AB - Regional plantar pressures during stair walking may be injurious in at risk populations. However, limited data are available examining the reliability of plantar pressure data collected during stair walking. The aims of this study were three fold; to assess the reliability of the plantar pressure data recorded during stair walking, to assess the effects of level ground and stair walking on plantar loading, and to develop regression equations to predict regional plantar pressures in stair walking from those collected on level ground. Fifteen subjects without conditions affecting their ability to walk on level surfaces or stairs were recruited. Each participant performed at least 10 steps in level ground and stair walking while plantar pressure data were recorded in six foot regions. Reliability was assessed using Intraclass Correlation Coefficient. A repeated measures ANOVA was used to assess the effect of activity on plantar pressure, and a linear regression was used to predict forefoot loading during stair walking. A reliability of 0.9 was achieved within 10 steps in all foot regions, with the forefoot requiring fewer steps. Plantar pressures were influenced by both, foot region and activity, with the heel and forefoot regions generally experiencing lower peak pressures and maximal forces during stair walking than level ground walking. The regression equations predicting peak pressure during stair walking accounted for between 37% and 70% of the variance of the stair walking data. These findings establish the reliability of plantar pressure data collected during stair walking. Future studies should investigate these parameters in clinical populations. PMID- 22537611 TI - Cellular origin of Barrett's esophagus: controversy and therapeutic implications. PMID- 22537612 TI - Circulating microparticles as disease-specific biomarkers of severity of inflammation in patients with hepatitis C or nonalcoholic steatohepatitis. AB - BACKGROUND & AIMS: Microparticles released into the bloodstream upon activation or apoptosis of CD4(+) and CD8(+) T cells correlate with inflammation as determined by histologic analysis in patients with chronic hepatitis C (CHC). Patients with nonalcoholic fatty liver (NAFL) or nonalcoholic steatohepatitis (NASH) can be differentiated from those with CHC based on activation of distinct sets of immune cells in the liver. METHODS: We compared profiles of circulating microparticles from patients with NAFL and NASH (n = 67) to those of CHC (n = 42), with healthy individuals (controls) using flow cytometry; the profiles were correlated with inflammation grade and fibrosis stage based on histologic analyses. We assessed the ability of the profiles to determine the severity of inflammation and fibrosis based on serologic and histologic analyses. RESULTS: Patients with CHC had increased levels of microparticles from CD4(+) and CD8(+) T cells; the levels correlated with disease severity based on histologic analysis and levels of alanine aminotransferase. Patients with NAFL or NASH had significant increases in numbers of microparticles from invariant natural killer T cells and macrophages/monocytes (CD14(+)), which mediate pathogenesis of NASH. Microparticles from CD14(+) and invariant natural killer T cells correlated with levels of alanine aminotransferase and severity of NASH (based on histology). Levels of microparticles could differentiate between patients with NAFL or NASH and those with CHC, or either group of patients and controls (area under the receiver operating characteristic curves ranging from 0.56 to 0.99). CONCLUSIONS: Quantification of immune cell microparticles from serum samples can be used to assess the extent and characteristics of hepatic inflammation in patients with chronic liver disease. PMID- 22537614 TI - Changes in photoinduced cutaneous erythema with topical application of a combination of vitamins C and E before and after UV exposure. AB - BACKGROUND: Ultraviolet radiation is harmful for human skin, and photodamaging pathologies such as actinic erythema, are formerly described as a consequence of UV direct effect on DNA and indirectly by local immune reactions. However, the degree of participation of oxidative stress in actinic erythema and the role of antioxidants in photoprotection are still not fully understood. OBJECTIVE: To evaluate the possible palliative role of a combination of the antioxidants vitamins C and E in human cutaneous erythema when applied topically before and after UV exposure. MATERIALS AND METHODS: The study included 20 volunteers of phototypes II, II-III and III with no solar exposure for two months prior to the study. The volunteers were submitted to a phototest consisting on the analysis of the minimal erythemal dose (MED) under different treatments: 1. Untreated irradiated skin; 2. Irradiated skin previously treated with vehicle; 3. Irradiated skin previously treated with a combination of vitamins (2.5% vit E-5% vit C); and 4. Skin treated with the antioxidant combination after irradiation. Cutaneous erythema was evaluated 24h after exposure and the MED was calculated for each treatment. RESULTS: The application of vehicle did not significantly affect the MED compared to untreated irradiated skin. Application of the antioxidant combination, prior to irradiation, increased the MED in all phototypes compared with untreated irradiated skin with an average increase of 36.9%. Antioxidants applied after exposure promoted an average increase of the MED by 19.8%. CONCLUSIONS: Combination of topical antioxidants (vitamins C and E) shows photoprotection activity against erythema, mainly owing to their high absorption properties. Moreover, their antioxidant activity could be considered as additive, and independent of their optical properties. PMID- 22537613 TI - Consensus statements for management of Barrett's dysplasia and early-stage esophageal adenocarcinoma, based on a Delphi process. AB - BACKGROUND & AIMS: Esophageal adenocarcinoma (EA) is increasingly common among patients with Barrett's esophagus (BE). We aimed to provide consensus recommendations based on the medical literature that clinicians could use to manage patients with BE and low-grade dysplasia, high-grade dysplasia (HGD), or early-stage EA. METHODS: We performed an international, multidisciplinary, systematic, evidence-based review of different management strategies for patients with BE and dysplasia or early-stage EA. We used a Delphi process to develop consensus statements. The results of literature searches were screened using a unique, interactive, Web-based data-sifting platform; we used 11,904 papers to inform the choice of statements selected. An a priori threshold of 80% agreement was used to establish consensus for each statement. RESULTS: Eighty-one of the 91 statements achieved consensus despite generally low quality of evidence, including 8 clinical statements: (1) specimens from endoscopic resection are better than biopsies for staging lesions, (2) it is important to carefully map the size of the dysplastic areas, (3) patients that receive ablative or surgical therapy require endoscopic follow-up, (4) high-resolution endoscopy is necessary for accurate diagnosis, (5) endoscopic therapy for HGD is preferred to surveillance, (6) endoscopic therapy for HGD is preferred to surgery, (7) the combination of endoscopic resection and radiofrequency ablation is the most effective therapy, and (8) after endoscopic removal of lesions from patients with HGD, all areas of BE should be ablated. CONCLUSIONS: We developed a data-sifting platform and used the Delphi process to create evidence-based consensus statements for the management of patients with BE and early-stage EA. This approach identified important clinical features of the diseases and areas for future studies. PMID- 22537616 TI - The development of a decision analytic model of changes in mean deviation in people with glaucoma: the COA model. AB - PURPOSE: To create and validate a statistical model predicting progression of primary open-angle glaucoma (POAG) assessed by loss of visual field as measured in mean deviation (MD) using 3 landmark studies of glaucoma progression and treatment. DESIGN: A Markov decision analytic model using patient level data described longitudinal MD changes over 7 years. PARTICIPANTS: Patient-level data from the Collaborative Initial Glaucoma Treatment Study (n = 607), the Ocular Hypertension Treatment Study (OHTS; n = 148; only those who developed POAG in the first 5 years of OHTS) and Advanced Glaucoma Intervention Study (n = 591), the COA model. METHODS: We developed a Markov model with transition matrices stratified by current MD, age, race, and intraocular pressure categories and used a microsimulation approach to estimate change in MD over 7 years. Internal validation compared model prediction for 7 years to actual MD for COA participants. External validation used a cohort of glaucoma patients drawn from university clinical practices. MAIN OUTCOME MEASURES: Change in visual field as measured in MD in decibels (dB). RESULTS: Regressing the actual MD against the predicted produced an R(2) of 0.68 for the right eye and 0.63 for the left. The model predicted ending MD for right eyes of 65% of participants and for 63% of left eyes within 3 dB of actual results at 7 years. In external validation the model had an R(2) of 0.79 in the right eye and 0.77 in the left at 5 years. CONCLUSIONS: The COA model is a validated tool for clinicians, patients, and health policy makers seeking to understand longitudinal changes in MD in people with glaucoma. PMID- 22537615 TI - Validity of self-reported eye disease and treatment in a population-based study: the Los Angeles Latino Eye Study. AB - PURPOSE: To examine the validity of self-reported eye disease, including cataract, age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy (DR), and self-reported surgical treatment for cataract and DR in the Los Angeles Latino Eye Study (LALES). DESIGN: Population-based, cross-sectional study. PARTICIPANTS: A total of 6357 Latinos aged 40+ years from the LALES. METHODS: Participants underwent a detailed interview, including survey questions about ocular health, diagnoses, and timing of last eye examination, and a standardized clinical examination. Self-report was compared with examination to determine sensitivity and specificity by length of time since last eye examination. Stepwise logistic regression was used to determine factors associated with inaccurate self-report. MAIN OUTCOME MEASURES: Sensitivity and specificity were calculated for 4 self-reported eye diseases (cataract, AMD, glaucoma, and DR) and for surgical treatment of cataract and DR. Odds ratios (ORs) were determined for factors associated with inaccurate self-report underestimating eye disease and treatment. RESULTS: For each disease, sensitivity and specificity in those who reported their last eye examination as <1 year ago were 36.8% and 92.5% for cataract, 37.7% and 96.3% for glaucoma, 5.1% and 98.9% for AMD, and 25.7% and 94.2% for DR, respectively. Self-report was less accurate with increasing time since last eye examination. Inaccurate self-report was independently associated with better visual acuity (OR, 2.4), <2 comorbidities (OR, 1.7), last eye examination/visit 1 to 5 years ago and >= 5 years ago (OR, 2.3 and 4.9, respectively), and less education (OR, 1.3 for 7-12 years and 1.7 for <7 years). Of 88 participants surgically treated for cataract who reported an eye examination <1 year ago, sensitivity and specificity of self-reported surgical history were 90.9% and 99.9%, respectively. Of the 31 participants treated for DR (laser/surgery) and reporting an eye examination <1 year ago, sensitivity and specificity of self-reported surgical history were 19.4% and 99.6%, respectively. CONCLUSIONS: Among Latinos, self-reporting of eye disease and surgical history provides a significant underestimate of the disease burden. This may lead to significant misclassification in vision research if self-report alone is used to identify persons with eye disease. PMID- 22537617 TI - One-year outcomes of the da Vinci Study of VEGF Trap-Eye in eyes with diabetic macular edema. AB - PURPOSE: To compare different doses and dosing regimens of Vascular Endothelial Growth Factor (VEGF) Trap-Eye with laser photocoagulation in eyes with diabetic macular edema (DME). DESIGN: Randomized, double-masked, multicenter, phase 2 clinical trial. PARTICIPANTS: Diabetic patients (n = 221) with center-involved DME. METHODS: Participants were assigned randomly to 1 of 5 treatment regimens: VEGF Trap-Eye 0.5 mg every 4 weeks (0.5q4); 2 mg every 4 weeks (2q4); 2 mg every 8 weeks after 3 initial monthly doses (2q8); or 2 mg dosing as needed after 3 initial monthly doses (2PRN), or macular laser photocoagulation. MAIN OUTCOME MEASURES: The change in best-corrected visual acuity (BCVA) at 24 weeks (the primary end point) and at 52 weeks, proportion of eyes that gained 15 letters or more in Early Treatment of Diabetic Retinopathy Study (ETDRS) BCVA, and mean changes in central retinal thickness (CRT) from baseline. RESULTS: As previously reported, mean improvements in BCVA in the VEGF Trap-Eye groups at week 24 were 8.6, 11.4, 8.5, and 10.3 letters for 0.5q4, 2q4, 2q8, and 2PRN regimens, respectively, versus 2.5 letters for the laser group (P <= 0.0085 versus laser). Mean improvements in BCVA in the VEGF Trap-Eye groups at week 52 were 11.0, 13.1, 9.7, and 12.0 letters for 0.5q4, 2q4, 2q8, and 2PRN regimens, respectively, versus -1.3 letters for the laser group (P <= 0.0001 versus laser). Proportions of eyes with gains in BCVA of 15 or more ETDRS letters at week 52 in the VEGF Trap-Eye groups were 40.9%, 45.5%, 23.8%, and 42.2% versus 11.4% for laser (P = 0.0031, P = 0.0007, P = 0.1608, and P = 0.0016, respectively, versus laser). Mean reductions in CRT in the VEGF Trap-Eye groups at week 52 were -165.4 MUm, -227.4 MUm, -187.8 MUm, and -180.3 MUm versus -58.4 MUm for laser (P < 0.0001 versus laser). Vascular Endothelial Growth Factor Trap-Eye generally was well tolerated. The most frequent ocular adverse events with VEGF Trap-Eye were conjunctival hemorrhage, eye pain, ocular hyperemia, and increased intraocular pressure, whereas common systemic adverse events included hypertension, nausea, and congestive heart failure. CONCLUSIONS: Significant gains in BCVA from baseline achieved at week 24 were maintained or improved at week 52 in all VEGF Trap-Eye groups. Vascular Endothelial Growth Factor Trap-Eye warrants further investigation for the treatment of DME. PMID- 22537618 TI - Modelling the transfer of 14C from the atmosphere to grass: a case study in a grass field near AREVA-NC La Hague. AB - Radioactive (14)C is formed as a by-product of nuclear power generation and from operation of nuclear fuel reprocessing plants like AREVA-NC La Hague (North France), which releases about 15 TBq per year of (14)C into the atmosphere. Since the autumn of 2006, (14)C activity concentrations in samples from the terrestrial environment (air, grass and soil) have been monitored monthly on grassland 2 km downwind of the reprocessing plant. The monitoring data provides an opportunity to validate radioecology models used to assess (14)C transfer to grassland ecosystems. This article compares and discusses the ability of two different models to reproduce the observed temporal variability in grass (14)C activity in the vicinity of AREVA-NC La Hague. These two models are the TOCATTA model which is specifically designed for modelling transfer of (14)C and tritium in the terrestrial environment, and PaSim, a pasture model for simulating grassland carbon and nitrogen cycling. Both TOCATTA and PaSim tend to under-estimate the magnitude of observed peaks in grass (14)C activity, although they reproduce the general trends. PaSim simulates (14)C activities in substrate and structural pools of the plant. We define a mean turn-over time for (14)C within the plant, which is based on both experimental data and the frequency of cuts. An adapted PaSim result is presented using the 15 and 20 day moving average results for the (14)C activity in the substrate pool, which shows a good match to the observations. This model reduces the Root Mean Square Error (RMSE) by nearly 40% in comparison to TOCATTA. PMID- 22537620 TI - Prospective study of transarterial infusion of docetaxel and cisplatin to treat non-small-cell lung cancer in patients contraindicated for standard chemotherapy. AB - Our previous retrospective study indicated a good response rate of non-small-cell lung carcinoma (NSCLC) to transarterial infusion chemotherapy, but the precise effect remains unresolved. This prospective study enrolled 25 patients with stage III or IV or recurrent NSCLC without distant metastasis (M1b) who were not candidates for either standard chemotherapy or chemoradiotherapy. The feeding arteries of each tumor detected by angiography were recorded and tumor staining was visually graded on a scale of I-IV. Docetaxel and cisplatin (25 and 25 mg/m(2), respectively) were administered by arterial infusion. The total dose of each was divided among feeding arteries according to the degree of tumor staining. The end points included response rate, progression-free survival (PFS), overall survival (OS) and toxicity. Correlations between effects and some clinical aspects were investigated. Of 25 patients enrolled between May 2007 and April 2011, 24 of them were evaluable. One complete response and 12 partial responses were achieved for an overall response rate of 52% (95% confidence interval [CI]: 35-69%). The median progression-free survival and overall survival periods were 6.5 (95% CI: 5.4-7.6) and 17.4 (95% CI: 14.2-20.6) months, respectively. The 1- and 2-year survival rates were 81% and 32%, respectively. Grade 3-4 hematological toxicity was not evident. Grade 3 general fatigue or appetite loss developed in patients with performance status (PS) >=3. Neither grade 4 non-hematological toxicity nor treatment-related death occurred. Among various clinical aspects, ECOG PS significantly correlated with PFS and OS, whereas tumor staining significantly correlated with response. Survival was significantly better for patients with good PS (0 or 1) than poor PS (>=2) and those with, than without grade IV tumor staining. If a sufficient number of feeding arteries are detected and the tumor is appropriately stained, then arterial infusion chemotherapy has favorable response rates with less toxicity for patients with stage III or IV or recurrent NSCLC without distant metastasis (M1b) who cannot tolerate standard chemotherapy. PMID- 22537619 TI - Differential expression of the angiogenesis growth factors in psoriasis vulgaris. AB - BACKGROUND: Angiogenesis has been reported to be one of the contributory factors to the pathogenesis of psoriasis vulgaris. This study aims to compare the expression of different angiogenesis growth factors namely (1) the vascular endothelial growth factor (VEGF) subfamily: A, B, C, D and placenta growth factor (PlGF); (2) nerve growth factor (NGF) and (3) von Willebrand factor (vWFr) in the skins of patients with psoriasis vulgaris and non-psoriatic volunteers. RESULTS: Comparative immunohistochemistry study was performed on the paraffin-sectioned psoriatic and healthy skins with the abovementioned markers. VEGF-C (p = 0.016) and NGF (p = 0.027) were expressed intensely in the cases when compared with the controls. The NGF was the only marker that was solely expressed in the cases and absent in all the controls. CONCLUSION: The NGF (angiogenesis) and VEGF-C (lymphangiogenesis) might play a crucial role in the pathogenesis of psoriasis vulgaris and could be researched further as potential new targeted therapies for psoriasis vulgaris. PMID- 22537622 TI - Periodontal diseases at the transition from the late antique to the early mediaeval period in Croatia. AB - OBJECTIVE: We tested the hypothesis that the transition from the late antique to the early mediaeval period in Croatia had a negative impact on the periodontal health. METHODS: 1118 skulls were examined for dental calculus, alveolar bone resorption, fenestrations, dehiscences and root furcation involvement. RESULTS: The prevalence of teeth with calculus varied from 40.7% in the LA sample of continental parts of Croatia to 50.3% in the LA sample of Adriatic Croatia. The prevalence of alveolar bone resorption ranged between 21.2% in the EM sample from continental Croatia and 32.3% in the LA sample from Adriatic Croatia. The prevalence of individuals with alveolar bone dehiscences varied from 8.6% in the LA sample from continental Croatia up to 15.0% in the EM sample from Adriatic Croatia. The prevalence of individuals with alveolar bone fenestrations varied from 21.5% in the LA sample from Adriatic Croatia up to 36.2% in the LA sample from continental Croatia. The prevalence of individuals with exposed root bifurcations or trifurcations varied from 9.0% in the EM sample from Adriatic Croatia up to 20.7% in the EM sample from continental Croatia. Statistically significant differences were found between samples. CONCLUSION: The transition from the late antique to the early mediaeval period in Croatia did not have a negative impact on periodontal health. Studies of periodontal health of ancient populations should be performed to provide a better and more reliable reconstruction of living conditions in the past. PMID- 22537621 TI - Peroxiredoxins and tropomyosins as plasma biomarkers for lung cancer and asbestos exposure. AB - The prognosis of lung cancer is poor due to late diagnosis, the lack of established screening programs, and the paucity of early biomarkers for high-risk populations. Plasma proteome analysis was used to identify novel biomarkers for diagnosing lung cancer, and to unravel the mechanisms of underlying pathogenesis. Plasma proteins obtained from asbestos-exposed lung cancer cases detected by CT screening, asbestos-exposed subjects, clinical lung cancer patients, and healthy tobacco smokers, 5-6 cases in each group, were separated by two-dimensional gel electrophoresis, and identified with tandem mass spectrometry (LC-MS/MS). Nine proteins were selected for immunological confirmation in a test or validation set of plasma samples from an additional 49 clinical lung cancer cases, 66 asbestos exposed patients, and 107 healthy tobacco smokers. Twenty-eight unique proteins were differentially expressed between the four study groups (p<0.05). Peroxiredoxin 1 (PRX1) was detected as a novel plasma marker for lung cancer (p=0.001). We also confirmed the previously found association of serum amyloid A with lung cancer (p<0.001). High plasma levels of tropomyosin 4 (TPM4: p<0.001) and peroxiredoxins 1 and 2 (PRX2: p<0.001) correlated with asbestos exposure or a diagnosis of asbestosis. PRX1 and PRX2 exhibited an inverse correlation with tobacco smoking (p<0.001). Plasma peroxiredoxins 1 and 2, and tropomyosin 4 were shown to associate with asbestos-exposure, and peroxiredoxin 1 with lung cancer. High plasma levels of peroxiredoxin 1 may result from genetic damage caused by reactive oxygen species. This study has identified several biomarkers worthy of further investigation in lung cancer and asbestos-related diseases. PMID- 22537623 TI - Antiparasite behavior. PMID- 22537624 TI - Sex determination. PMID- 22537625 TI - Screening mammal biodiversity using DNA from leeches. PMID- 22537626 TI - Male spotted bowerbirds propagate fruit for use in their sexual display. PMID- 22537627 TI - Colour patterns: channelling Turing. AB - Very little is known about how animal colour patterns develop. The stripes of the zebrafish provide a tractable a model for colour pattern formation, which now suggests an unconventional patterning mechanism. PMID- 22537628 TI - Sensory ecology: giant eyes for giant predators? AB - Mathematical models suggest the enormous eyes of giant and colossal squid evolved to see the bioluminescence induced by the approach of predatory whales. PMID- 22537629 TI - Replication: DNA building block synthesis on demand. AB - Correct regulation of DNA nucleotide biosynthesis is emerging as a key issue of importance for genome integrity. The fission yeast Spd1 protein can modulate the activity of ribonucleotide reductase (RNR) by at least three different mechanisms. Now a paper reports that Spd1 turnover is linked to ongoing DNA synthesis. PMID- 22537631 TI - Homologous recombination: how RecA finds the perfect partner. AB - How do two identical DNA sequences find each other during homologous recombination, amidst a 'sea' of unrelated DNA? New studies reveal how RecA promotes the search for homology by sampling DNA in three dimensions. PMID- 22537630 TI - Mushroom-body memories: an obituary prematurely written? AB - Studies on insect olfactory learning have established the mushroom bodies as key brain structures for the formation of long-term memory (LTM). Two new neurons in the fly brain are reported now as essential sites for LTM formation, while mushroom bodies are claimed to be unnecessary to this end. PMID- 22537632 TI - Palaeontology: the 165-million-year itch. AB - New flea-like fossils from China provide a rare, tantalizing glimpse of bizarre insects in the Cretaceous and Jurassic. Possibly the oldest flea-like animals known, they provide a challenge to the functional morphologist to infer which animals they may have targeted. PMID- 22537633 TI - Animal behavior: the orphan rebellion. AB - After their queen has left with a swarm, orphaned larvae exhibiting rebel traits emerge in honeybee colonies. As adults, these orphans have reduced food glands to feed the colony's larvae and more developed ovaries to selfishly reproduce their own offspring. PMID- 22537634 TI - Cell polarity: centrosomes release signals for polarization. AB - New findings reveal that, in Caenorhabditis elegans embryos, the centrosome provides signals that induce cell polarization, independently of its function as the microtubule-organizing center. PMID- 22537635 TI - Speciation: don't fly and diversify? AB - Loss of flight in Japanese carrion beetles is correlated with greater population subdivision and higher speciation rate. This reveals the complex relationship of trait evolution with dispersal power, range size and diversification. PMID- 22537636 TI - Probable diffuse retinopathy caused by adalimumab in a patient with Crohn's disease. AB - Adalimumab is a tumor necrosis factor-alpha (TNF-alpha) antagonist used to treat several immunologic diseases. It is believed that unexpected adverse events related to anti-TNF drugs will occur as administration of this drug becomes more widespread. We report the case of a 37-year-old woman who complained of nonspecific abnormalities of vision in both eyes one month after beginning treatment with adalimumab for Crohn's disease. The results of the initial ophthalmologic examination were normal. The visual fields showed diffuse and severe depression in both eyes. Other diseases that could have caused the visual field defects were ruled out. The results of electrophysiological tests were compatible with diffuse bilateral retinopathy. Treatment with adalimumab was discontinued. Six months later, visual field loss persists, although it has improved slightly. To our knowledge, this is the first report of diffuse retinopathy probable caused by systemic administration of adalimumab. This form of retinal toxicity should be considered in patients with disorders of vision treated with this drug. PMID- 22537638 TI - Immunohistochemical search for viral and bacterial antigens in Crohn's disease. AB - BACKGROUND: Recent studies show that diseased intestinal tissues of patients with Crohn's disease (CD) contain obstructed lymphatics, granulomas, and tertiary lymphoid organs, representing responses to persistent antigen. METHODS: Forty seven tissue sections from 28 CD patients and 20 tissue sections from 17 control patients were studied. Tissues were immunostained with antibody directed against adenovirus, Epstein-Barr virus, herpes simplex virus I, parvovirus B19, Listeria monocytogenes, Escherichia coli, Clostridium perfringens, and Mycobacterium avium subspecies paratuberculosis. RESULTS: There was no evidence of adenovirus, Epstein-Barr virus, parvovirus B19, or M. avium subsp. paratuberculosis in the tissues. Clostridia were positively stained in the mucus of 18.5% of CD patients versus 35.3% of controls and in the tissue of 11.1% of CD patients but in no controls. Immunoreactivity to listeria antibody occurred in the mucus of 3.7% of CD patients and in 5.9% of controls while it occurred in the tissue of 37.0% of CD patients and 29.4% of controls. E. coli occurred in the mucus of 48.1% CD and 64.7% controls and in the tissue of 18.5% and 5.9% respectively. CONCLUSIONS: Of the agents demonstrated in this search, none was located in granulomas or inflamed lymphatics. Finding the common gut microbes, E. coli and clostridia, in the mucus of patients and controls was not unexpected. The minor focal staining of E. coli and clostridia does not suggest a primary role for these pathogens in CD. Positive staining for listeria in patients and controls may very well represent cross reactivity rather than specific identification. PMID- 22537639 TI - Does active smoking really influence the course of Crohn's disease? A retrospective observational study. AB - BACKGROUND: Active smoking has been associated with a higher risk of developing Crohn's disease (CD). However, its impact on clinical outcomes has been controversial among studies. AIMS: To evaluate the influence of active smoking on initial manifestations of CD, the development of disease-related complications, and therapeutic requirements. METHODS: Patients diagnosed with CD within a ten year period (1994-2003) were identified. Clinical and therapeutic features until October 2008 or loss of follow-up were recorded. Smoking status was assessed at each major disease-related event (e.g. penetrating and stricturing complications, perianal disease, intestinal resection, introduction of immunomodulators or biological agents). RESULTS: A total of 259 patients were included in the study with a median follow-up period of 91 months. At diagnosis, 50.5% were active smokers and only 12% of them quit smoking during follow-up, mostly after a major disease-related event occurred. Smoking at diagnosis was not associated with a particular CD presentation. Active smoking did not influence the development of strictures, intraabdominal and perianal penetrating complications, or increased resectional surgery, biological therapy or immunomodulators requirements. CONCLUSIONS: Patients who develop CD while smoking seem to have a similar disease course to those who never smoked. PMID- 22537637 TI - Adalimumab dose escalation and dose de-escalation success rate and predictors in a large national cohort of Crohn's patients. AB - BACKGROUND AND AIMS: Adalimumab is efficacious in inducing and maintaining remission in Crohn's disease but dose escalation is needed in 30-40% after 1 year. Attempts for dose de-escalation have not been studied. This study aimed to assess the need for, predictors, and outcome of dose escalation and de-escalation in a large cohort of adalimumab treated Crohn's patients. METHODS: All consecutive patients treated with open label adalimumab for active Crohn's disease from the participating centres were included in this cohort study. A detailed retrospective chart review was performed to look for possible factors predicting outcome. RESULTS: Eighty four percent of 720 patients had a primary response and were followed up for a median of 14 months. Thirty four percent needed escalation after a median of 7 months (0-55 months). Multivariate predictors for dose escalation were the following: prior anti-TNF use (p<0.0001), no concomitant azathioprine or <3 m (p<0.02) and abnormal CRP at start (p<0.05). Dose escalation re-induced response for at least 6 months in 67%. Only abnormal CRP at start correlated with failure of dose escalation (p=0.02). Dose de escalation was attempted in 54% and was successful in 63%. After a median follow up of 14 m adalimumab was discontinued in 29% of patients. CONCLUSION: In this study real life nationwide cohort of Crohn's patients treated with adalimumab dose escalation was needed in 34% and was successful in 67%. Dose de-escalation was attempted in 54% and was successful in 63%. Overall 71% of patients maintained long term response on adalimumab. PMID- 22537640 TI - Ginsenoside rich fraction of Panax ginseng C.A. Meyer improve feeding behavior following radiation-induced pica in rats. AB - Panax ginseng is an indigenous medicinal herb and has traditionally been used among Asian population for relief of many human ailments. We investigated the prophylactic role of Korean P. ginseng extract (KG) against X-ray irradiation induced emesis in an acute rat pica model. Rats were treated with KG (12.5, 25, 50 mg/kg orally at -48, -24 and 0 h) prior to X-ray irradiation (6 Gy), and intake of kaolin and normal food and body weight changes examined as an index of the acute emetic stimulus. Levels of serotonin in small intestine tissue were assessed and histopathology of gastric tissue, small intestine and colon examined specific staining. Pre-treatment with KG (12.5 and 25 mg/kg) reduced X-ray irradiation-induced kaolin intake at 24h. Normal food intake was improved in rats treated with 25 mg/kg KG. The anti-emetic effect of KG was further confirmed on the basis of serotonin release, histopathological findings. Our findings collectively indicate that KG protects against X-ray irradiation-induced acute pica to a moderate extent, leading to improved feeding behavior in rats. PMID- 22537641 TI - Ginkgolide B produced endophytic fungus (Fusarium oxysporum) isolated from Ginkgo biloba. AB - To screen the presence of ginkgolide B-producing endophytic fungi from the root bark of Ginkgo biloba, a total of 27 fungal isolates, belonging to 6 different genus, were isolated from the internal root bark of the plant Ginkgo biloba. The fungal isolates were fermented on solid media and their metabolites were analyzed by TLC. The obtained potential ginkgolides-producing fungus, the isolate SYP0056 which was identified as Fusarium oxysporum, was successively cultured in the liquid fermentation media, and its metabolite was analyzed by HPLC. The ginkgolide B was successfully isolated from the metabolite and identified by HPLC/ESI-MS and (13)C-NMR. The current research provides a new method to produce ginkgolide B by fungal fermentation, which could overcome the natural resource limitation of isolating from the leaves and barks of the plant Ginkgo biloba. PMID- 22537643 TI - Bioactivity-guided isolation of antiproliferative compounds from Centaurea jacea L. AB - Bioassay-guided fractionation of the chloroform extract of Centaurea jacea L. afforded the isolation of cirsiliol, apigenin, hispidulin, eupatorin, isokaempferide, axillarin, centaureidin, 6-methoxykaempferol 3-methyl ether, trachelogenin, cnicin, 4'-acetylcnicin and three aliphatic glucose diesters, including the new natural product 1beta-isobutanoyl-2-angeloyl-glucose. The structures of the compounds were established on the basis of spectroscopic analyses (UV, MS and NMR). All compounds were isolated for the first time from this species. The compounds were evaluated for their tumour cell growth inhibitory activities on HeLa, MCF-7 and A431 cells. Different types of secondary metabolites (flavonoids, sesquiterpenes) were found to be responsible for the antitumour effects of the extracts; the highest activity was exerted by centaureidin, in addition to moderately active compounds (cirsiliol, isokaempferide, apigenin, hispidulin, cnicin and 4'-acetylcnicin). PMID- 22537642 TI - Cycloartane triterpenoids from the stems of Schisandra glaucescens and their bioactivity. AB - Five new cycloartane triterpenoids, schiglausins K-O (1-5), including one hexanortriterpenoid (1) and one octanortriterpenoid (2), as well as two known compounds (6-7), were isolated from the stems of Schisandra glaucescens Diels. Their structures were elucidated on the basis of spectroscopic methods, including extensive NMR spectra. Compounds 2-7 were tested for their FXR agonistic and antagonistic effects. Compound 7 exhibited significant antagonistic effect against FXR with IC(50) of 1.50 MUM. PMID- 22537644 TI - Targeting neuronal nicotinic receptors in cancer: new ligands and potential side effects. AB - In the nervous system, the neuronal nicotinic acetylcholine receptors (nAChRs) mediate fast excitatory postsynaptic potentials as well as slower paracrine actions of ACh. They are also widely expressed in non-nervous tissue, including the neoplastic, which is intriguing as smoking is an established risk factor for cancer. Moreover, recent evidence attributes to the gene cluster coding for the alpha3/alpha5/beta4 nAChR subunits a role in both development of lung cancer and nicotine addiction. Many cellular effects of nicotine and the tobacco-derived carcinogenic N-nitrosamines are probably caused by nAChR activation, which regulates cell proliferation, migration, apoptosis and neoangiogenesis. Nonetheless, the precise nAChR roles in tumors are difficult to determine because cancer cells express a wide variety of nicotinic subunits, whose function is unclear. Patented compounds which selectively target nAChRs subtypes are increasingly available and will hopefully allow better understanding of the physiology of these channels in specific cell types, as well as suggest novel diagnostic and therapeutic approaches. At the present state, however, thorough functional studies of these compounds are still limited and whether they act as agonists, antagonists or partial agonists is often unclear. Such a blurred distinction between activators and inhibitors makes detailed studies in expression systems sorely needed for both physiological understanding and outlining the possible side-effects. PMID- 22537645 TI - Quantitative real-time PCR for detection of the neurotoxin gene of Clostridium botulinum type B in equine and bovine samples. AB - Clostridium botulinum type B is estimated to cause more than 85% of cases of equine botulism in the United States, as well as many outbreaks in cattle. In this study, a quantitative real-time polymerase chain reaction for detection of the neurotoxin gene of C. botulinum type B was compared to the mouse bioassay using 45 positive and 43 negative samples of equine, bovine or associated environmental origin. The sensitivity of the qPCR assay was 96%, whereas the sensitivity of the mouse bioassay was 84%. The specificity of the qPCR assay was 95% and the specificity of the mouse bioassay was 100%. PMID- 22537646 TI - Overutilization of endoscopic surveillance in nondysplastic Barrett's: too much of a good thing? PMID- 22537647 TI - Within you, without you: is gastroenterology ready to embrace the "exposome"? PMID- 22537648 TI - Eradicating Helicobacter pylori in functional dyspepsia. PMID- 22537649 TI - Gender-specific differences in colorectal neoplasia and potential implications for screening policy: is it time to discriminate based on gender? PMID- 22537650 TI - A novel approach to surface electromyography: an exploratory study of electrode pair selection based on signal characteristics. AB - A 3*4 electrode array was placed over each of seven muscles and surface electromyography (sEMG) data were collected during isometric contractions. For each array, nine bipolar electrode pairs were formed off-line and sEMG parameters were calculated and evaluated based on repeatability across trials and comparison to an anatomically placed electrode pair. The use of time-domain parameters for the selection of an electrode pair from within a grid-like array may improve upon existing electrode placement methodologies. PMID- 22537651 TI - Iatrogenic fracture of the proximal tibia as a complication of knee manipulation under anaesthesia in a haemophilia patient with an ipsilateral stiff knee secondary to a supracondylar non-union of the femur. PMID- 22537652 TI - Molecular phylogeny of Aphyocharacinae (Characiformes, Characidae) with morphological diagnoses for the subfamily and recognized genera. AB - The subfamily Aphyocharacinae was recently redefined to comprise eight genera: Aphyocharax, Prionobrama, Paragoniates, Phenagoniates, Leptagoniates, Xenagoniates, Rachoviscus and Inpaichthys. This new composition, however, is partially incongruent with published results of molecular studies especially concerning the positions of Rachoviscus and Inpaichthys. Our goal was to investigate the monophyly of Aphyocharacinae and its interrelationships using three distinct phylogenetic methodologies: Maximum-likelihood and Bayesian analyses of molecular data, and also Parsimony analysis of a concatenated molecular and morphological dataset. All tree topologies recovered herein suggest that Rachoviscus, Inpaichthys and Leptagoniates pi do not belong to the Aphyocharacinae. The remaining aphyocharacin taxa analyzed do form a monophyletic group, which is itself composed of two subgroups being one comprised of Paragoniates, Phenagoniates, Leptagoniates and Xenagoniates, and the other comprised of Aphyocharax and Prionobrama. Internal relationships among these genera are statistically well supported and morphological synapomorphies are presented at the generic level. All tree topologies also indicate that Aphyocharacidium is closely related to Aphyocharacinae suggesting that it should be included in this subfamily. As recognized in the present study, the Aphyocharacinae is diagnosed by a single morphological synapomorphy: two dorsal fin rays articulating with the first dorsal pterygiophore. PMID- 22537653 TI - Transthyretin amyloidosis and the kidney. AB - The amyloidoses are protein-misfolding disorders associated with progressive organ dysfunction. Immunoglobulin light chain is the most common, amyloid A the longest recognized, and transthyretin-associated amyloidosis (ATTR) the most frequent inherited systemic form. Although ATTR, an autosomal-dominant disease, is associated with at least 100 different transthyretin (TTR) mutations, the single amino-acid substitution of methionine for valine at position 30 is the most common mutation. Each variant has a different organ involvement, although clinical differences attributed to environmental and genetic factors exist within the same mutation. Peripheral neuropathy and cardiomyopathy are broadly described, and insights into disease reveal that kidney impairment and proteinuria are also clinical features. This review combines clinical and laboratory findings of renal involvement from the main geographic regions of disease occurrence and for different mutations of TTR. Fifteen nephropathic variants have been described, but the TTR V30M mutation is the best documented. Nephropathy affects patients with late-onset neuropathy, low penetrance in the family, and cardiac dysrhythmias. Microalbuminuria can be the disorder's first presentation, even before the onset of neuropathy. Amyloid renal deposits commonly occur, even in the absence of urinary abnormalities. The experience with renal replacement therapy is based on hemodialysis, which is associated with poor survival. Because TTR is synthesized mainly in the liver, liver transplantation has been considered an acceptable treatment; simultaneous liver-kidney transplantation is recommended to avoid recurrence of nephropathy. In addition, the kidney-safety profile of new drugs in development may soon be available. PMID- 22537655 TI - Photodegradation of Rhodamine B over unexcited semiconductor compounds of BiOCl and BiOBr. AB - This study reported, for the first time systematically, photodegradation of Rhodamine B (RhB) in aqueous solution over BiOCl and BiOBr semiconductors. Under visible light irradiation (lambda>400 nm, lambda>420 nm and lambda=550+/-15 nm), RhB adsorbed on the surface of BiOCl and BiOBr was photosensitized and decomposed effectively over unexcited BiOCl and BiOBr. The degradation of Methyl Orange (MO) and Methylene Blue (MB) over BiOCl and BiOBr was investigated as well, and the results were compared with RhB photodegradation. It was found that MB molecules having the lowest LUMO could not be degraded by this process. Utilizing the quantum chemical calculation (Gaussian 03 program), the relationship between frontier orbital energy of selected dye molecules and photodegradation rate was established for the first time in this study. PMID- 22537654 TI - Use of postoperative creatinine to predict sustained kidney injury in patients undergoing mesothelioma surgery. AB - BACKGROUND AND OBJECTIVES: AKI leads to increased morbidity and mortality and progression to chronic kidney injury is a frequent consequence of AKI. Surgical treatment of mesothelioma is associated with increased risk for kidney injury. However, sustained kidney injury may limit therapeutic options for treating residual cancer. This study hypothesized that patients with significant serum creatinine (sCr) elevation within 48 hours of surgery would be at risk for sustained kidney injury. The goal was to determine the best acute sCr measure predictive of sustained kidney injury defined as a 50% increase in sCr from baseline measured 2-4 weeks after surgery. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a prospective, observational cohort of surgical patients with mesothelioma, receiver operator characteristic curves were generated for the 24- and 48-hour absolute difference and relative sCr change over baseline in the derivation cohort (n=279). The prediction was tested in a validation cohort (n=207). The ability of various other AKI definitions to predict sustained kidney injury was evaluated. RESULTS: Sustained kidney injury occurred in 9.8% of patients in the derivation cohort. A >=59% increase in sCr 48 hours after surgery was most predictive of sustained kidney injury (c statistic=0.78). Among other AKI definitions, a sCr increase of 0.3 mg/dl in 24 hours or 0.5 mg/dl increase in 48 hours (Waikar and Bonventre criteria) also reliably predicted sustained kidney injury. CONCLUSIONS: Development of clinically significant sustained kidney injury can be predicted by acute postoperative sCr elevation in patients treated for mesothelioma. PMID- 22537656 TI - Delay in pathological tissue processing time vs. mortality in oral cancer: short communication. AB - Several factors have been identified to affect morbidity and mortality in oral cancer patients. The time taken to process a resected cancer specimen in a patient presenting with primary or recurrent disease can be of interest as delay can affect earlier interventions post-surgery. We looked at this variable in a group of 168 consecutive oral cancer patients and assessed its relationship to mortality from the disease at 3 and 5 years. It is expected that delay in pathological processing time of surgical specimens acquired from patients with recurrent disease may increase or contribute to the increased rate of mortality. Further high evidence-based studies are required to confirm this. PMID- 22537657 TI - Central neurocytoma. AB - Central neurocytomas (CN) are rare intraventricular tumors with prominent neuronal differentiation. CN commonly arise in the lateral ventricles of young adults who predominantly present with raised intracranial pressure. Few studies have described the clinical, pathological, and radiological features of these tumors, and those that have are typically single case reports. Herein, we report ten patients with CN with variable clinical and pathological features and discuss the management of these tumors. Nine tumors occupied the lateral ventricle and only one was located in the sellar region. On MRI, all 10 tumors showed heterogeneous hypo-or iso-intensity on T1-weighted and hyperintensity on T2 weighted MRI. Contrast enhancement varied greatly from very slight to intense. All patients were surgically treated by macroscopic total or subtotal removal. Postoperative radiotherapy was given to six patients (four of whom had undergone subtotal resection and two of whom had undergone total resection). The surgical and histopathological data of these patients were reviewed and analyzed. No recurrences were noted although we were unable to contact two patients for follow up. A brief review of the literature concerning differential diagnosis and therapeutic aspects of these tumors is also presented. PMID- 22537658 TI - Diagnostic value of Hoover sign and motor-evoked potentials in acute somatoform unilateral weakness and sensory impairment mimicking vascular stroke. AB - Acute unilateral weakness along with sensory impairment is commonly caused by obstruction of major cortical arteries in either adults or children. A somatoform presentation mimicking acute vascular stroke is very rare, especially in the pediatric age group. Here we report three adolescents presenting with acute unilateral weakness and sensory impairment along with diminished tendon reflexes who were suspected to have an acute stroke but who had developed a somatoform psychogenic disorder. Two adolescents had complete hemiplegia and one had weakness of the left leg - two had moved the alleged paralytic limbs during sleep. A normal Hoover sign was suggestive of a somatoform psychogenic etiology rather than true vascular stroke. Cortical and spinal MRI, motor-evoked potentials (MEP) and somatosensory-evoked potentials were normal. All adolescents recovered completely. Therefore, a somatoform conversion reaction should be considered in children presenting with acute unilateral weakness and sensory alterations, which is corroborated by a normal Hoover sign and intact MEP. PMID- 22537659 TI - Chronic Q fever: expert opinion versus literature analysis and consensus. AB - Q fever has long been considered a rare disease. The extensive outbreak in the Netherlands generated a body of literature based solely on the consensus in the Netherlands. As a long-standing expert on Q fever, I offer my experience and recommendations to the E-CDC and the Dutch Q fever Consensus Group. My (biased) opinion is that experts deeply involved in the field continue to be useful in the management of outbreaks and can avoid decisions that produce an unfavorable progression in patients. Here, I propose that the definition of "chronic Q fever" be avoided and suggest a new score-based diagnosis for Q fever endocarditis and vascular infection. PMID- 22537660 TI - Physiological status and intersex in the endobenthic bivalve Scrobicularia plana from thirteen estuaries in northwest France. AB - The bivalve Scrobicularia plana, an important species for the structure and functioning of estuarine and coastal mudflats, was studied in thirteen sites from NW France differing by their degree of contamination to document the presence of reproduction impairments (intersex, sex ratio, gonadosomatic indices) in relation to the condition revealed by using hepatosomatic and condition indices. In agreement with recent studies in other European estuaries, intersex was revealed in all the studied estuaries, including sites the chemical and ecological status of which is considered "good" according to the criteria of the European Water Framework Directive. The presence of endocrine disrupting chemicals (EDCs) could result in such disturbances. Our results re-inforce the concern linked to the subtle effects of EDCs, which are active at very low doses, often in the absence of any major sign of toxicity. However at this stage, no clear link may be established between intersex and population effects. PMID- 22537661 TI - Prevalence and some psychosocial characteristics of social anxiety disorder in an urban population of Turkish children and adolescents. AB - PURPOSE: To define the prevalence and some of the psychosocial characteristics of social anxiety disorder (SAD) in an urban population of Turkish children and adolescents. SUBJECTS AND METHODS: This was a two-stage cross-sectional urban based study conducted in Fatih, Istanbul, Turkey. The initial sample included 1,482 students between the 4th and 8th grades. The first stage involved screening using the Social Anxiety Scale for Children-Revised (SASC-R) and the Capa Social Phobia Scale for Children and Adolescents (CSPSCA). According to the test results, 324 children were interviewed using the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS PL) in the second stage. RESULTS: The SAD prevalence rate was 3.9%. According to the multiple regression analysis, low paternal education and trait anxiety were associated with SASC-R scores, whereas female gender and trait anxiety were associated with CSPSCA scores. According to logistic regression analysis, the anxiety subscale of the self-concept scale and trait anxiety were associated with SAD. CONCLUSION: SAD is a relatively common disorder that is associated with lower self-concept in children and adolescents. Low paternal education, trait anxiety, and low self-concept may be the intervention targets for SAD prevention and treatment. PMID- 22537662 TI - Anaemia among adults in Kassala, Eastern Sudan. AB - BACKGROUND: The increased heterogeneity in the distribution of social and biological risk factors makes the epidemiology of anaemia a real challenge. A cross-sectional study was conducted at Kassala, Eastern Sudan during the period of January-March 2011 to investigate the prevalence and predictors of anaemia among adults (> 15 years old). FINDINGS: Out of 646, 234 (36.2%) adults had anaemia; 68 (10.5%); 129 (20.0%) and 37 (5.7%) had mild, moderate and severe anaemia, respectively. In logistic regression analyses, age (OR = 1.0, CI = 0.9 1, P = 0.7), rural vs. urban residency (OR = 0.9, CI = 0.7-1.3, P = 0.9), female vs. male gender (OR = 0.8, CI = 0.6-1.1, P = 0.3), educational level >= secondary level vs. < secondary level (OR = 1.0, CI = 0.6-1.6, P = 0.8) and Hudandawa vs. non-Hudandawa ethnicity (OR = 0.8, CI = 0.6-1, P = 0.1) were not associated with anaemia. CONCLUSION: There was a high prevalence of anaemia in this setting, anaemia affected adults regardless to their age, sex and educational level. Therefore, anaemia is needed to be screened for routinely and supplements have to be employed in this setting. PMID- 22537663 TI - Di-(2-ethylhexyl) phthalate and autism spectrum disorders. AB - ASDs (autism spectrum disorders) are a complex group of neurodevelopment disorders, still poorly understood, steadily rising in frequency and treatment refractory. Extensive research has been so far unable to explain the aetiology of this condition, whereas a growing body of evidence suggests the involvement of environmental factors. Phthalates, given their extensive use and their persistence, are ubiquitous environmental contaminants. They are EDs (endocrine disruptors) suspected to interfere with neurodevelopment. Therefore they represent interesting candidate risk factors for ASD pathogenesis. The aim of this study was to evaluate the levels of the primary and secondary metabolites of DEHP [di-(2-ethylhexyl) phthalate] in children with ASD. A total of 48 children with ASD (male: 36, female: 12; mean age: 11 +/- 5 years) and age- and sex comparable 45 HCs (healthy controls; male: 25, female: 20; mean age: 12 +/- 5 years) were enrolled. A diagnostic methodology, based on the determination of urinary concentrations of DEHP metabolites by HPLC-ESI-MS (HPLC electrospray ionization MS), was applied to urine spot samples. MEHP [mono-(2-ethylhexenyl) 1,2-benzenedicarboxylate], 6-OH-MEHP [mono-(2-ethyl-6-hydroxyhexyl) 1,2 benzenedicarboxylate], 5-OH-MEHP [mono-(2-ethyl-5-hydroxyhexyl) 1,2 benzenedicarboxylate] and 5-oxo-MEHP [mono-(2-ethyl-5-oxohexyl) 1,2 benzenedicarboxylate] were measured and compared with unequivocally characterized, pure synthetic compounds (>98%) taken as standard. In ASD patients, significant increase in 5-OH-MEHP (52.1%, median 0.18) and 5-oxo-MEHP (46.0%, median 0.096) urinary concentrations were detected, with a significant positive correlation between 5-OH-MEHP and 5-oxo-MEHP (rs = 0.668, P<0.0001). The fully oxidized form 5-oxo-MEHP showed 91.1% specificity in identifying patients with ASDs. Our findings demonstrate for the first time an association between phthalates exposure and ASDs, thus suggesting a previously unrecognized role for these ubiquitous environmental contaminants in the pathogenesis of autism. PMID- 22537664 TI - Impact of kinins in the treatment of cardiovascular diseases. AB - In recent years, ACE Inhibitors (ACEIs) and Angiotensin II receptor antagonists (also known as AT1 receptor antagonists (AT1-RAs), angiotensin receptor blockers (ARBs), or Sartans), have become the drugs of choice for the treatment of hypertension, heart and renal failure, coronary artery diseases, myocardial infarction and diabetes. By suppressing angiotensin and potentiating bradykinin effects, ACEIs and ARBs activate hemodynamic, metabolic and cellular mechanisms that not only reduce high blood pressure, but also protect the endothelium, the heart, the kidney and the brain, namely the target organs which are at risk in cardiovascular diseases. Major therapeutic benefits of these drugs are the reduction of cardiovascular events and the amelioration of the quality of life and of the patient survival. Results from large clinical trials have established that ACEIs and ARBs are efficient and safe drugs, suitable for the chronic treatments of cardiovascular diseases. Side effects are rare and easily manageable in most cases. The following is a brief review of the basic actions and mechanisms by which two opposing systems, the renin-angiotensin (RAS) and the kallikrein-kinin (KKS), interact in the regulation of cardiovascular and fluid homeostasis to keep the balance in healthy life and correct the imbalance in pathological conditions. Here we discuss how and why imbalances created by overactive RAS are best corrected by treatments with ACEI or AT1-RAs. PMID- 22537665 TI - P16INK4a immunocytochemistry/immunohistochemistry: need for scoring uniformization to be clinically useful in gynecological pathology. AB - High-risk (HR) human papillomaviruses (HPVs) are the main agents involved in the pathogenesis of cervical preinvasive and invasive lesions. Their regression or persistence is paramount in the progression or regression of preinvasive lesions. Therefore, the diagnosis of the presence or absence of HR-HPV is essential in the prognosis and follow-up of low-grade and high-grade squamous intraepithelial lesions. Human papillomavirus DNA and messenger RNA can be identified by a variety of molecular methods; however, their clinical use has limitations. The fact that p16(INK4a) is a surrogate marker for the presence of HR-HPV is well established. However, the clinical usefulness of p16(INK4a) is currently limited by the lack of immunohistologic and cytologic standardization of a scoring system. This article presents an overview illustrating this shortcoming based on relevant literature data. PMID- 22537666 TI - Evolution and mortality risk factors in children with continuous renal replacement therapy after cardiac surgery. AB - INTRODUCTION AND OBJECTIVES: To study the clinical course of children requiring continuous renal replacement therapy after cardiac surgery and to analyze factors associated with mortality. METHODS: A prospective observational study was performed that included children requiring continuous renal replacement therapy after cardiac surgery. Univariate and multivariate analyses were performed to determine the influence of each factor on mortality. We compared these patients with other critically ill children requiring continuous renal replacement therapy. RESULTS: Of 1650 children undergoing cardiac surgery, 81 (4.9%) required continuous renal replacement therapy, 65 of whom (80.2%) presented multiple organ failure. The children who started continuous renal replacement therapy after cardiac surgery had lower mean arterial pressure, lower urea and creatinine levels, and higher mortality (43%) than the other children on continuous renal replacement therapy (29%) (P=.05). Factors associated with mortality in the univariate analysis were age less than 12 months, weight under 10 kg, higher pediatric risk of mortality score, hypotension, lower urea and creatinine levels when starting continuous renal replacement therapy, and the use of hemofiltration. In the multivariate analysis, hypotension when starting continuous renal replacement therapy, pediatric risk of mortality scores equal to or greater than 21, and hemofiltration were associated with mortality. CONCLUSIONS: Although only a small percentage of children undergoing cardiac surgery required continuous renal replacement therapy, mortality among these patients was high. Hypotension and severity of illness when starting the technique and hemofiltration were factors associated with higher mortality. PMID- 22537667 TI - The emerging medical ecology of the human gut microbiome. AB - It is increasingly clear that the human gut microbiome has great medical importance, and researchers are beginning to investigate its basic biology and to appreciate the challenges that it presents to medical science. Several striking new empirical results in this area are perplexing within the standard conceptual framework of biomedicine, and this highlights the need for new perspectives from ecology and from dynamical systems theory. Here, we discuss recent results concerning sources of individual variation, temporal variation within individuals, long-term changes after transient perturbations and individualized responses to perturbation within the human gut microbiome. PMID- 22537668 TI - In defense of 'niche modeling'. AB - There is a growing awareness of problems with the estimation of the ecological tolerances of species through correlative modeling approaches. These problems have led some investigators to argue for abandoning terms such as 'ecological niche model' and 'environmental niche model' in favor of the ostensibly more value-neutral 'species distribution model', as the models are thought to frequently be poor estimators of the niche. Here, I argue that most applications to which these models are put require the assumption that they do estimate the niche, however imperfectly, and that obscuring this inescapable and potentially flawed assumption in the terminology may only serve to hinder the development of the field. PMID- 22537669 TI - 'Ecosystomics': ecology by sequencer. PMID- 22537671 TI - Characterizing adrenocortical activity in zoo-housed southern three-banded armadillos (Tolypeutes matacus). AB - Improving the husbandry in the southern three-banded armadillo (Tolypeutes matacus) through gaining knowledge of its stress physiology is imperative to maintaining a healthy, zoo-housed population. Our objectives were to: 1) validate the use of fecal hormone analysis for monitoring adrenocortical activity using both an adrenocorticotropic hormone (ACTH) challenge and biological events; and 2) characterize longitudinal adrenocortical activity in male and female southern three-banded armadillos. An ACTH injection was given intra-muscularly to one male (4IU/kg; 5.6IU total) and one female (5.5IU/kg; 8IU total) southern three-banded armadillo. Fecal samples were collected 1 day pre- and continued 5 days post-ACTH to capture the physiological response measured by elevated fecal glucocorticoid metabolites (FGM) to validate these techniques. Additionally, natural and routine events, including pairing individuals for breeding and veterinary procedures/handling, were used to biologically validate these techniques. To characterize adrenocortical activity, fecal samples (~3025 total; n=275/animal/yr) were collected from 11 (5 males; 6 females) southern three banded armadillos 5-7 times a week for 1 year at Lincoln Park Zoo (Chicago, IL). A cortisol enzyme immunoassay was used for FGM analysis. The ACTH challenge in the male resulted in a twofold increase of FGM (1123.2+/-36.2 ng/g dry feces) above baseline (675.7+/-10.0 ng/g dry feces) at approximately 54-94h post- injection. The female exhibited a twofold increase (1635.4 ng/g dry feces) over baseline FGMs (608.5+/-12.3 ng/g dry feces) approximately 30h post-injection. Reproductive behaviors and veterinary procedures resulted in elevated FGM concentrations from all individuals except for one male. The longitudinal characterization demonstrated that sex and season did not influence (P<0.05) FGM concentrations. Individuals were highly variable with mean FGM concentration of 2010.1+/-862.4 ng/g dry feces (range, 816.3-7889.1 ng/g dry feces). Mean FGM baseline concentration was 878.5+/-201.8ng/g dry feces (range, 475.2-1955.5 ng/g dry feces) with a mean elevated FGM concentrations of 2694.3+/-1111.4 ng/g dry feces (range, 1110.3-10,683.3 ng/g dry feces). This study provides the foundation for future research on how the environment directly affects the adrenocortical activity in this species of armadillo. PMID- 22537670 TI - Exploring metabolic dysfunction in chronic kidney disease. AB - Impaired kidney function and chronic kidney disease (CKD) leading to kidney failure and end-stage renal disease (ESRD) is a serious medical condition associated with increased morbidity, mortality, and in particular cardiovascular disease (CVD) risk. CKD is associated with multiple physiological and metabolic disturbances, including hypertension, dyslipidemia and the anorexia-cachexia syndrome which are linked to poor outcomes. Specific hormonal, inflammatory, and nutritional-metabolic factors may play key roles in CKD development and pathogenesis. These include raised proinflammatory cytokines, such as interleukin 1 and -6, tumor necrosis factor, altered hepatic acute phase proteins, including reduced albumin, increased C-reactive protein, and perturbations in normal anabolic hormone responses with reduced growth hormone-insulin-like growth factor 1 axis activity. Others include hyperactivation of the renin-angiotensin aldosterone system (RAAS), with angiotensin II and aldosterone implicated in hypertension and the promotion of insulin resistance, and subsequent pharmacological blockade shown to improve blood pressure, metabolic control and offer reno-protective effects. Abnormal adipocytokine levels including leptin and adiponectin may further promote the insulin resistant, and proinflammatory state in CKD. Ghrelin may be also implicated and controversial studies suggest activities may be reduced in human CKD, and may provide a rationale for administration of acyl-ghrelin. Poor vitamin D status has also been associated with patient outcome and CVD risk and may indicate a role for supplementation. Glucocorticoid activities traditionally known for their involvement in the pathogenesis of a number of disease states are increased and may be implicated in CKD-associated hypertension, insulin resistance, diabetes risk and cachexia, both directly and indirectly through effects on other systems including activation of the mineralcorticoid receptor. Insight into the multiple factors altered in CKD may provide useful information on disease pathogenesis, clinical assessment and treatment rationale such as potential pharmacological, nutritional and exercise therapies. PMID- 22537672 TI - Caste differences in dopamine-related substances and dopamine supply in the brains of honeybees (Apis mellifera L.). AB - We determined the mechanisms underlying caste differences in the brain levels of dopamine-related substances in adult honeybees (Apis mellifera L.). Brain levels of dopamine, DOPA (a dopamine precursor), and N-acetyldopamine (a dopamine metabolite, NADA) were significantly higher in three-day-old virgin queens than same-aged workers. Caste differences in dopamine and NADA levels were also found in the hemolymph. The in vitro enzymatic activities of DOPA decarboxylase (DDC) during dopamine synthesis in brains were not significantly different between castes. The DDC activity in adult queens was mainly found in the brain, but with lower levels of activity detected in the mandibular glands, salivary glands and ovaries. Oral application of DOPA to workers led to DOPA uptake in the brain and significantly higher dopamine and NADA levels in the brain, suggesting that dopamine synthesis could be controlled by the amount of DDC substrate. Royal jelly samples taken from queen cells had a >25-fold higher concentration of dopamine compared with honey samples collected from honey cells. However, oral application of the same concentration of dopamine did not significantly enhance the brain levels of dopamine and NADA. These results suggest that the higher levels of brain dopamine in queens compared with workers can be explained by the higher level of DDC substrate, rather than DDC activity in the brain and other tissues of queens as well as exogenous dopamine in the royal jelly. PMID- 22537673 TI - Lytic bone disease as the presenting feature of Philadelphia-positive monosomy 7 myelodysplasia progressing to acute myeloid leukaemia. AB - We describe an unusual case of Philadelphia-positive, monosomy 7 myelodysplasia progressing to acute myeloid leukaemia in a 53 year old male who presented with bone-pain and B-symptoms and was found to have diffuse osteolytic lesions. Molecular genetic analysis revealed both b3a2 and e1a2 t(9;22) transcripts. Cytogenetic analysis was an additional useful test in determining the course and management of an atypical BCR-ABL positive myelodysplasia. PMID- 22537674 TI - Lack of association between TLR4 Asp299Gly and Thr399Ile polymorphisms and sepsis susceptibility: a meta-analysis. AB - Sepsis, a condition of systemic inappropriate inflammation response to the invasion of microorganisms, results in considerable morbidity and mortality in patients. Some, but not all, epidemiological studies have suggested that Toll like receptor 4 (TLR4) polymorphisms, Asp299Gly and Thr399Ile, may influence the risk of at-risk patients for sepsis. Our work tried to further study the association of the two common polymorphisms with sepsis susceptibility by performing a meta-analysis of previous data. Electronic searches of MEDLINE, EMBASE and Web of Science databases were performed. Original observational studies dealing with the association between polymorphisms Asp299Gly and/or Thr399Ile and sepsis risk were selected. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with random-effects model or fixed effects model based on the heterogeneity analysis. Seventeen studies including 2212 cases and 3880 controls were included with most subjects of Caucasian ethnicity. The odds ratio for the association of Asp299Gly polymorphism with sepsis risk was 1.22 (95% CI: 0.90-1.65, P=0.21), and the association of Thr399Ile polymorphism was 1.16 (95%CI: 0.70-1.91, P=0.57). Subgroup analysis and sensitivity analysis did not change the results. Our meta-analysis revealed that the two common TLR4 polymorphisms, Asp299Gly and Thr399Ile, have no strong association with the likelihood of sepsis in Caucasian populations. Further studies are needed to investigate the effect of genetic networks and their mutual interactions in TLR4 signaling pathway on sepsis susceptibility. PMID- 22537675 TI - Complex rearrangement involving 9p deletion and duplication in a syndromic patient: genotype/phenotype correlation and review of the literature. AB - We describe a 7-year-old boy with a complex rearrangement involving the whole short arm of chromosome 9 defined by means of molecular cytogenetic techniques. The rearrangement is characterized by a 18.3 Mb terminal deletion associated with the inverted duplication of the adjacent 21,5 Mb region. The patient shows developmental delay, psychomotor retardation, hypotonia. Other typical features of 9p deletion (genital disorders, midface hypoplasia, long philtrum) and of the 9p duplication (brachycephaly, down slanting palpebral fissures and bulbous nasal tip) are present. Interestingly, he does not show trigonocephaly that is the most prominent dysmorphism associated with the deletion of the short arm of chromosome 9. Patient's phenotype and the underlying flanking opposite 9p imbalances are compared with that of reported patients and the proposed critical regions for 9p deletion and 9p duplication syndromes. PMID- 22537676 TI - Genetic structure and polymorphisms of the N16 gene in Pinctada fucata. AB - The molluscan shell is a composite of inorganic crystals comprising calcium carbonate and a minute amount of organic matrix. The organic matrix (OM) is intimately involved in every step of shell formation and has consequently received much attention in recent years. However, most of the deposited information has resulted from cDNA analysis, with little analysis of the genome, including the presence and effects of polymorphic genes encoding OM proteins. The current study aimed to clarify the genome structure of the N16 gene from the Japanese pearl oyster, Pinctada fucata, with particular reference to polymorphisms. The N16 gene was analyzed using PCR and DNA sequencing. 23 polymorphic variants were identified from 28 individuals. The variants were analyzed for their relationship to shell formation. All the variations detected by genomic PCR appeared in the cDNAs, implying that all the polymorphisms were transcribed and translated into N16 proteins. Additional genome analysis revealed at least two N16 genes, which were sequentially positioned, each of them comprising four exons and three introns. Further analyses of the transcriptional regulation and function of the N16 genes may provide new insights into their role in molluscan biomineralization. PMID- 22537677 TI - Functional coupling of transcription and splicing. AB - The tightly regulated process of precursor messenger RNA (pre-mRNA) alternative splicing is a key mechanism to increase the number and complexity of proteins encoded by the genome. Evidence gathered in recent years has established that transcription and splicing are physically and functionally coupled and that this coupling may be an essential aspect of the regulation of splicing and alternative splicing. Recent advances in our understanding of transcription and of splicing regulation have uncovered the multiple interactions between components from both types of machinery. These interactions help to explain the functional coupling of RNAPII transcription and pre-mRNA alternative splicing for efficient and regulated gene expression at the molecular level. Recent technological advances, in addition to novel cell and molecular biology approaches, have led to the development of new tools for addressing mechanistic questions to achieve an integrated and global understanding of the functional coupling of RNAPII transcription and pre-mRNA alternative splicing. Here, we review major milestones and insights into RNA polymerase II transcription and pre-mRNA alternative splicing as well as new concepts and challenges that have arisen from multiple genome-wide approaches and analyses at the single-cell resolution. PMID- 22537678 TI - 3-Deoxy-3,4-dehydro analogs of XM462. Preparation and activity on sphingolipid metabolism and cell fate. AB - Three analogs of the dihydroceramide desaturase inhibitor XM462 are reported. The compounds inhibit both dihydroceramide desaturase and acid ceramidase, but with different potencies depending on the N-acyl moiety. Other enzymes of sphingolipid metabolism, such as neutral ceramidase, acid sphingomyelinase, acid glucosylceramide hydrolase, sphingomyelin synthase and glucosylceramide synthase, are not affected. The effect on the sphingolipidome of the two best inhibitors, namely (R,E)-N-(1-hydroxy-4-(tridecylthio)but-3-en-2-yl)octanamide (RBM2-1B) and (R,E)-N-(1-hydroxy-4-(tridecylthio)but-3-en-2-yl)pivalamide (RBM2-1D), is in accordance with the results obtained in the enzyme assays. These two compounds reduce cell viability in A549 and HCT116 cell lines with similar potencies and both induced apoptotic cell death to similar levels than C8-Cer in HCT116 cells. The possible therapeutic implications of the activities of these compounds are discussed. PMID- 22537679 TI - Synthesis and biological evaluation of a new class of glycoconjugated disulfides that exhibit potential anticancer properties. AB - A synthetic strategy, based on the in situ generation of sulfenic acids and their thermolysis in the presence of thiols, was developed for obtaining a collection of polyvalent disulfides in which a benzene scaffold accommodates two or three flexible arms connecting saccharide moieties. Targeting carbohydrate metabolism or carbohydrate-binding proteins may constitute important approaches in the discovery process of new therapeutic anticancer agents. Therefore, a preliminary screening to ascertain the cytostatic/cytotoxic potential of this new class of enantiopure glycoconjugated disulfides has been conducted. Among them, products with two disulfide arms, harbouring galactose rings, induced high levels of apoptosis on U937 histiocytic lymphoma cells, but lower levels of cell death on peripheral blood mononuclear cells from healthy donors. Further experiments indicated that apoptosis induced by these glycoconjugated bis(disulfides) in U937 cells corresponds to the Bcl-2-sensitive, intrinsic form of apoptotic cell death. The bioinvestigation was extended to a panel of human cancer cell lines with different levels of malignancy and resistance to chemotherapeutic agents. Compounds under study proved to induce detectable levels of cell death towards all the tested cancer cell lines. PMID- 22537680 TI - Synthesis of methoxylated goniothalamin, aza-goniothalamin and gamma-pyrones and their in vitro evaluation against human cancer cells. AB - The present work describes the preparation of three novel series of compounds based on the structure of goniothalamin, a natural styryl lactone which has been found to display cytotoxic and antiproliferative activities against a variety of cancer cell lines. A focused library of 29 novel goniothalamin analogues was prepared and evaluated against seven human cancer cell lines. While the gamma pyrones and the aza-goniothalamin analogues were less potent than the lead compound, 2,4-dimethoxy analogue 88 has shown to be more potent in vitro than goniothalamin against all cancer cell lines evaluated. Furthermore, it was more potent than doxorubicin against NCI-ADR/RES, OVCAR-03 and HT-29 while being less toxic to human keratinocytes (HaCat). The 3,5-dimethoxy analogue 90 and 2,4,5 trimethoxy analogue 92 also displayed promising antiproliferative activity when compared to goniothalamin (1). These results provide new elements for the design and synthesis of novel representatives of this family of natural compounds. PMID- 22537681 TI - A novel tetrahydrobenzoangelicin with dark and photo biological activity. AB - The synthesis of 8,9,10,11-tetrahydro-5-(3-dimethylaminopropoxy)-4 methylbenzofuro[2,3-h]coumarin (5) is described. The new compound showed the ability to inhibit cell growth both upon UVA irradiation and in the dark. The investigation on the mechanism of action highlighted the capacity of 5 to covalently photoadd to thymine, as demonstrated by the isolation and characterization of the 4',5'-monoadduct. Furthermore, in the ground state 5 interferes with the topoisomerase II relaxation activity, suggesting that this enzyme could constitute a molecular target responsible for the dark antiproliferative effect. PMID- 22537682 TI - Inverse Virtual Screening allows the discovery of the biological activity of natural compounds. AB - A small library of phenolic natural compounds belonging to different chemical classes was screened on a panel of targets involved in the genesis and progression of cancer. The re-investigation of their potential activity was achieved through the Inverse Virtual Screening approach. The normalization of the predicted binding energies permitted the selection of promising compounds on definite targets, avoiding the selection of false positive results. In vitro biological tests revealed the inhibitory activity of xanthohumol and isoxanthohumol on PDK1 and PKC protein kinases. This study validates the robustness of the Inverse Virtual Screening in silico approach as a useful tool for the identification of the specific biological activity of a given set of compounds. PMID- 22537683 TI - An efficient and convenient microwave-assisted chemical synthesis of (thio)xanthones with additional in vitro and in silico characterization. AB - Xanthones and their thio-derivatives are a class of pleiotropic compounds with various reported pharmacological and biological activities. Although these activities are mainly determined in laboratory conditions, the class itself has a great potential to be utilized as promising chemical scaffold for the synthesis of new drug candidates. One of the main obstacles in utilization of these compounds was related to the difficulties in their chemical synthesis. Most of the known methods require two steps, and are limited to specific reagents not applicable to a large number of starting materials. In this paper a new and improved method for chemical synthesis of xanthones is presented. By applying a new procedure, we have successfully obtained these compounds with the desired regioselectivity in a shorter reaction time (50s) and with better yield (>80%). Finally, the preliminary in vitro screenings on different bacterial species and cytotoxicity assessment, as well as in silico activity evaluation were performed. The obtained results confirm potential pharmacological use of this class of molecules. PMID- 22537684 TI - The use of hormonal contraceptive agents and mood disorders in women. AB - BACKGROUND: Mood disorders are a major cause of disability in developed countries, and contraceptive agents among the most widely used medications. The relationship between contraceptive agents and mood is unclear. The aim of this study was therefore to investigate the association between current contraception use and mood disorders in a random population-based sample of women. METHODS: This study examined epidemiological data obtained from 498 women aged 20-50year participating in the Geelong Osteoporosis Study (GOS). Mood disorders were diagnosed using a clinical interview (SCID-I/NP) and information on medication use and other lifestyle factors were documented. RESULTS: After adjusting for age and socioeconomic status (SES), women taking progestin-only contraceptive agents had an increased likelihood of a current mood disorder (OR 3.0 95%CI: 1.1-7.8, p=0.03). In contrast, women taking combined contraceptive agents had a decreased likelihood of a current mood disorder, adjusting this for age and SES (OR 0.3 95%CI: 0.1, 0.9 p=0.03). These findings were not explained by weight, physical activity level, past depression, number of medical conditions or cigarette smoking. LIMITATIONS: This study is cross-sectional, which precludes any determination regarding the direction of the relationships. CONCLUSIONS: These data suggest a protective effect of the combined contraceptive pill, and a deleterious effect of progestin only agents in regards to mood disorders. PMID- 22537685 TI - Depression in elderly persons subject to childhood maltreatment is not modulated by corpus callosum and hippocampal loss. AB - Childhood adversity has been observed to engender structural changes in the hippocampus and corpus callosum associated with increased risk for depression in childhood and early adulthood. This study investigated this association in the elderly. Corpus callosum area and hippocampal volume were measured from structural MRI in 427 community dwelling elderly. Information on childhood adversity was obtained in the course of a clinical examination using a questionnaire covering multiple aspects of abuse. Multivariate analyses found a significant increase in corpus callosum area and hippocampal volume in subjects exposed to mental disorder in parents and poverty, respectively. No association was found with childhood sexual and physical abuse. PMID- 22537686 TI - Neuroendocrine system of the digestive tract in Rhamdia quelen juvenile: an immunohistochemical study. AB - In this work, an immunohistochemical study was performed to determine the distribution and relative frequencies of some neuromodulators of the digestive tract of silver catfish (Rhamdia quelen). The digestive tract of silver catfish was divided into six portions; the oesophagus, stomach, intestine (ascendant, descendant and convoluted segments), and rectum. Immunohistochemical method using a pool of specific antisera against-gastrin, -cholecystokinin-8, -leu-enkephalin, -neuropeptide Y, -calcitonin gene-related peptide (CGRP), and -vasoactive intestinal peptide (VIP) was employed. Immunoreactivity to all antisera was identified in neuroendocrine cells (NECs) localized in the gut epithelium, although no reaction was observed in the oesophagus or stomach. The morphology of NECs immunopositive to each antibody was similar. They were slender in shape, with basally located nucleus, and their main axis perpendicular to the basement membrane. The number of NECs immunoreactive to all antisera was higher in the ascendant and descendant intestine, exhibiting a decreasing trend toward distal segments of the gut. In addition, immunoreactivity to CGRP and VIP was observed in the myenteric plexus and nerve fibers distributed in the mucosal, submucosal and muscular layers. The higher number of immunopositive NECs in the ascendant and descendant intestine may indicate the primary role of these segments in the control of food intake by means of orexigenic and anorexigenic peripheral signals. PMID- 22537687 TI - Progenitor cells and TNF-alpha involvement during morphological changes in pancreatic islets of obese mice. AB - Overnutrition during pregnancy and lactation lend increasing support to the development of obesity and several chronic diseases in adulthood such as type 2 diabetes mellitus, which leads to beta-cell dysfunction and insulin resistance. In this work, we aimed to study the effects of early life overnutrition on the development of obesity, analyzing the morphological changes, expression of TNF alpha, and also the stem cell marker CD133 in the pancreatic islets of young and adult mice. Overnutrition during lactation phase was used as an experimental model to induce obesity. The animals were analyzed at 28 and 150 days of age, when pancreata were collected for histological, ultrastructural and western blotting analysis. The results showed that islet hypertrophy is established in obese groups at day 28 and remained until adulthood. CD133+ cells were observed as small cells within pancreatic islets in both control and obese young mice. However, at day 150, these cells were observed only in the islet peripheries and near ducts of the obese group. Furthermore, TNF-alpha expression in pancreatic islets was increased in both young and adult obese groups when compared to control groups. This work shows interesting data about CD133 receptor and TNF alpha roles in the pancreas during obesity development. PMID- 22537688 TI - IBD is associated with an increase in carcinoma in PSC irrespective of the presence of dominant bile duct stenosis. PMID- 22537689 TI - Patient safety and quality improvement in rehabilitation medicine. AB - Patient safety in medical settings has become a major concern. As more and more individuals seek rehabilitative care for their medical conditions or are referred to rehabilitation specialists with increasingly complex medical conditions, the issue of patient safety in the rehabilitation setting takes on added importance. This article introduces the concepts of patient safety, cognitive biases, systems thinking, and quality improvement as they apply to the rehabilitation medicine. PMID- 22537690 TI - Safety precautions in the rehabilitation medicine prescription. AB - The rehabilitation medicine prescription is a communication tool between the referring physician and the rehabilitation team in both the inpatient and outpatient settings. This instrument is critical in both directing a course of treatment as well as minimizing risk to the patient during the treatment sessions. The goal of this article is to provide an overview of the rehabilitation prescription with an emphasis on safety. PMID- 22537691 TI - Patient safety at handoff in rehabilitation medicine. AB - The Joint Commission Center for Transforming Healthcare has cited communication as the most frequent root cause in sentinel events, with failed patient handoffs playing a "role in an estimated 80% of serious preventable adverse events." Handoff, or transfer of patient care information, occurs formally and informally many times each day, within and between care teams, across all levels of care providers and between institutions. Handoff at rehabilitation admission is at a particularly high risk for communication failure, potentially affecting patient safety. This review of the patient handoff literature discusses the importance of safe handoff, the information to be included, barriers to handoff, and improvement methodologies. PMID- 22537692 TI - Safety in the rehabilitation setting: a nursing perspective. AB - Patient safety, including keeping patients safe from harm or unintentional injury, is key to shortening the length of hospital stays, encouraging positive patient outcomes, and contributing to the hospital's financial state. Freedom from pressure ulcers, falls, and medication errors is an important component of patient safety. The parallel concept of nurse safety cannot be ignored. Keeping nurses safe from injury helps decrease their feelings of stress and minimizes sick time. Maintaining a safe environment for patients and staff is a win-win situation for all involved. PMID- 22537693 TI - Medication safety in rehabilitation medicine. AB - Rehabilitation medicine is practiced in a variety of settings. Physiatrists are an integral part of the care provided in many of these settings and are often consulted to provide diagnostic and therapeutic services and expertise to individuals with a variety of diagnoses. In this role, it is imperative that physiatrists have a working knowledge of various medications as well as the principles of medication safety. This article provides a foundation in the general and specific aspects of medication safety as they apply to the practice of rehabilitation medicine. PMID- 22537694 TI - Falls in the inpatient rehabilitation facility. AB - Older adults are rehabilitated for a variety of conditions in an inpatient rehabilitation facility (IRF), and they are often at an increased risk for falling during their stay. This article (1) provides an overview of the incidence, prevalence, and impact of falls in facilities that provide inpatient rehabilitation; (2) provides some key factors to be considered in the assessment of the patient admitted to the IRF for risk factors associated with falling; and (3) identifies strategies that can help reduce the risk of falling in patients admitted to an IRF. PMID- 22537695 TI - Patient safety considerations in the rehabilitation of the individual with cognitive impairment. AB - Deficits in cognitive functioning are associated with many safety concerns, including difficulties performing activities of daily living, medication errors, motor vehicle accidents, impaired awareness of deficits, decision-making capacity, falls, and travel away from home. Preventing adverse safety outcomes is particularly relevant in rehabilitation patients. Integration of information and recommendations stemming from allied disciplines, such as rehabilitation medicine, physical therapy, occupational therapy, speech therapy, and neuropsychology, is the most effective way to limit poor outcomes. Education and prevention counseling by health care professionals is an important approach in limiting adverse safety outcomes in patients with cognitive impairment. PMID- 22537696 TI - Safety concerns and multidisciplinary management of the dysphagic patient. AB - The interdisciplinary health care team is responsible for providing medical care based on a patient-centered model while maintaining professional and ethical standards. However, an emerging body of research suggests that ineffective and inappropriate care, or fatal errors, arise from the lack of productive communication between patients, families, and medical caregivers. This has prompted the evolution of a new health care discipline, patient safety, which became increasingly prominent in the 1990s. The purpose of this article is to bridge the gap between the discipline of patient safety and its relationship to the diagnosis of dysphagia. PMID- 22537697 TI - Safety considerations for patients with communication disorders in rehabilitation medicine settings. AB - Communication barriers can pose a significant safety risk for patients. Individuals in a communication-vulnerable state are commonly seen in rehabilitation settings. These patients cannot adequately communicate their symptoms, wants, and needs to providers. Causes of communication barriers include neurologic impairments, such as stroke, cerebral palsy, and Parkinson disease, and language barriers. The ability of clinicians to adequately diagnose, treat, and monitor these patients is also hindered. This article identifies key communication barriers and strategies that clinicians can use to effectively communicate with these patients. PMID- 22537698 TI - Patient safety in rehabilitation medicine: traumatic brain injury. AB - This article describes patient safety after traumatic brain injury (TBI). Patient safety in rehabilitation after TBI is important. Thorough assessment on initial evaluation, vigilance for medical and procedural errors, appropriate communication between medical professionals, and evaluation of systems-based practices increases patient safety. It is the responsibility of the rehabilitation treatment team to ensure that appropriate measures are taken to reduce risk of adverse events. This article is intended to promote discussion of patient safety after TBI within rehabilitation teams and to help improve outcomes throughout the spectrum of recovery. PMID- 22537699 TI - Patient safety in the rehabilitation of the adult with a spinal cord injury. AB - There are approximately 12,000 new cases of traumatic spinal cord injury (SCI) annually. In 2010, there were approximately 265,000 individuals living with SCI. Over time, the average age of people with SCI has steadily risen, and it is now 40.7 years. There are multiple medical complications that are commonly seen in individuals with SCI. These include, but are not exclusively limited to, pneumonia, decubiti ulcers, undiagnosed fractures, urinary tract infections, autonomic dysreflexia, deep venous thrombosis, and pulmonary embolism. This article addresses the issue of patient safety in the care of adults living with an SCI. PMID- 22537700 TI - Patient safety in the rehabilitation of the adult with an amputation. AB - This article reviews and summarizes the literature on patient safety issues in the rehabilitation of adults with an amputation. Safety issues in the following areas are discussed; the prosthesis, falls, wound care, pain, and treatment of complex patients. Specific recommendations for further research and implementation strategies to prevent injury and improve safety are also provided. Communication between interdisciplinary team members and patient and caregiver education are crucial to executing a safe treatment plan. The multidisciplinary rehabilitation team members should feel comfortable discussing safety issues with patients and be able to recommend preventive approaches to patients as appropriate. PMID- 22537701 TI - Patient safety in the rehabilitation of children with traumatic brain injury and cerebral palsy. AB - With the advent of newer and better therapies available, patient safety is emerging as a new topic. Pediatric patient safety is relatively new, in that there are few guidelines available. Safety in children with traumatic brain injury (TBI) given the incidence of TBI is very vital. This is an attempt to identify the key points in TBI. PMID- 22537702 TI - Patient safety in the rehabilitation of children with spinal cord injuries, spina bifida, neuromuscular disorders, and amputations. AB - Pediatric patient safety continues to challenge both pediatricians and pediatric physiatrists. While there is a trend toward developing general patient safety initiatives, there is little research on pediatric patient safety. This article identifies major areas of general safety risk, with a focus on timely diagnosis and care coordination to prevent secondary complications that compromise health, function, and quality of life in pediatric neuromuscular disease, spinal cord disorders, and amputation. PMID- 22537703 TI - Patient safety in interventional pain procedures. AB - The objective of this article was to present a systematic review of the safety issues encountered in interventional pain management. Patient safety is an important consideration in the practice of interventional pain management. Although there is a paucity of scientific articles addressing this topic, the authors have reviewed the literature and present a review of the topic, as well as strategies to minimize the risk to patients undergoing interventional spine procedures. PMID- 22537704 TI - Safety considerations during cardiac and pulmonary rehabilitation program. AB - As more and more patients with cardiac and pulmonary diseases are living longer lives, the need for cardio-pulmonary rehabilitation continues to grow. The goal of this article is to provide clinicians of rehabilitation medicine with an overview of the safety concerns and strategies to implement in the rehabilitation of patients with cardiac and/or pulmonary disorder. PMID- 22537705 TI - Patient safety in cancer rehabilitation. AB - Cancer patients receive rehabilitation services in acute hospitalizations, rehabilitation wards, outpatient rehabilitation facilities, and home settings. Given the complexity and acuity of their medical care coupled with the long-term effects of the cancer and its treatments, patient safety is a significant concern in the delivery of rehabilitation services for this population. Cancer survivorship is growing in importance as a significant number of adults and children diagnosed with cancer are surviving beyond the 5-year mark. The goal of this article is to provide an overview to rehabilitation clinicians on the topic of patient safety in the rehabilitation of cancer patients. PMID- 22537706 TI - Patient safety in rehabilitation medicine. Preface. PMID- 22537707 TI - ORF3 of duck circovirus: a novel protein with apoptotic activity. AB - Duck circovirus (DuCV) is classified in the genus Circovirus of the Circoviridae family. Two major open reading frames (ORFs), encoding the replicase (ORF1/rep) and the capsid protein (ORF2/cap), have been recognized for DuCV. Sequence analysis show that another major conserved ORF (named ORF3) is located in the complementary strand of ORF1/rep of DuCV, and its function remains to be investigated. In this study, the ORF3 of DuCV was expressed in recombinant baculovirus-infected Sf9 cells. By IFA and Western blot analysis, the ORF3 protein was positive for the sera from ducks infected with DuCV. The percentages of apoptotic cells of the Sf9 cells infected with the recombinant baculovirus encoding ORF3 of DuCV were significantly higher than (P<0.05) that of the Sf9 cells infected with wild-type baculovirus at 24, 48 and 72 h postinfection. Based on our knowledge, we deduced that the ORF3 protein of DuCV might play an important role in viral pathogenesis via its apoptotic activity. PMID- 22537708 TI - Human as a source of tuberculosis for cattle. First evidence of transmission in Poland. PMID- 22537709 TI - Improving the performance of power plant cooling ponds. AB - A study was conducted on the effectiveness of using vertical baffles to improve the thermal performance of power plant cooling ponds. A small scale physical model of a rectangular cooling pond was used. A base case was established using traditional horizontal baffles to create a serpentine flow pattern through the pond. The horizontal baffles were then replaced by a series of underflow weirs that spanned the pond. An improvement in cooling of over 30% was realized. PMID- 22537710 TI - The effects of fuel reduction treatments on runoff, infiltration and erosion in two shrubland areas in the north of Spain. AB - The immediate effects of prescribed burning, shrub clearing and shrub mastication on runoff, infiltration and erosion were evaluated in two contrasting shrubland areas in northern Spain. Rainfall simulations (67 mm h(-1) for 30 min) were conducted immediately after fuel reduction treatments in each runoff plot. Compared to shrub mastication and shrub clearing, prescribed burning generated the lowest infiltration rate and highest runoff and erosion rates at both study sites. However, sediment yields measured immediately after treatments were low in all cases, from 0.31 to 2.22 g m(-2) after shrub clearing, 0.40-1.63 g m(-2) after shrub mastication and 2.30-8.11 g m(-2) after prescribed burning. Slope, type of fuel reduction treatment and the depth and cover of the soil organic layer remaining after treatment were the most important variables determining runoff and erosion during the first rainfall event following treatment. In the rainfall simulation plots subjected to prescribed burning, the maximum temperatures reached at the organic layer/mineral soil interface during burning also had a significant effect on soil loss. The findings show that good fuel management prescriptions make fire hazard reduction and soil conservation compatible in cases where the remaining soil cover is about 70%. PMID- 22537711 TI - Interactions of extracts from selected chewing stick sources with Aggregatibacter actinomycetemcomitans. AB - BACKGROUND: Aggregatibacter actinomycetemcomitans produces a leukotoxin that activates a pro-inflammatory death of human monocytes/macrophages. A specific clone of this bacterium (JP2) has a 530-base pair deletion in the leukotoxin promoter gene and significantly enhanced expression of leukotoxin. This specific clone of A. actinomycetemcomitans is common in some African populations and has a strong association with periodontal attachment loss in adolescents in these populations. Chewing sticks of plant origin are commonly used as oral hygiene tool in Africa, but their role as a therapeutic agent in periodontal disease is poorly investigated. RESULTS: Ethanol extracts were made from 7 common plants used as chewing sticks in West-Africa. None of the tested extracts inhibited growth of A. actinomycetemcomitans. However, extracts from Psidium guajava (Guava) completely neutralized the cell death and pro-inflammatory response of human leukocytes induced by the leukotoxin. None of the six other tested chewing stick extracts showed this effect. CONCLUSIONS: The discovery that extracts from Guava efficiently neutralizes A. actinomycetemcomitans leukotoxicity might lead to novel therapeutic agents and strategies for prevention and treatment of aggressive forms of periodontitis induced by infections with the highly leukotoxic JP2 clone of this bacterium. PMID- 22537712 TI - The cost burden of oral, oral pharyngeal, and salivary gland cancers in three groups: commercial insurance, Medicare, and Medicaid. AB - BACKGROUND: Head and neck cancers are of particular interest to health care providers, their patients, and those paying for health care services, because they have a high morbidity, they are extremely expensive to treat, and of the survivors only 48% return to work. Consequently the economic burden of oral cavity, oral pharyngeal, and salivary gland cancer (OC/OP/SG) must be understood. The cost of these cancers in the U.S. has not been investigated. METHODS: A retrospective analysis of administrative claims data for 6,812 OC/OP/SG cancer patients was undertaken. Total annual health care spending for OC/OP/SG cancer patients was compared to similar patients without OC/OP/SG cancer using propensity score matching for enrollees in commercial insurance, Medicare, and Medicaid. Indirect costs, as measured by short term disability days were compared for employed patients. RESULTS: Total annual health care spending for OC/OP/SG patients during the year after the index diagnosis was $79,151 for the Commercial population. Health care costs were higher for OC/OP/SG cancer patients with Commercial Insurance ($71,732, n = 3,918), Medicare ($35,890, n = 2,303) and Medicaid ($44,541, n = 585) than the comparison group (all p < 0.01). Commercially-insured employees with cancer (n = 281) had 44.9 more short-term disability days than comparison employees (p < 0.01). Multimodality treatment was twice the cost of single modality therapy. Those patients receiving all three treatments (surgery, radiation, and chemotherapy) had the highest costs of cost of care, from $96,520 in the Medicare population to $153,892 in the Commercial population. CONCLUSIONS: In the U.S., the cost of OC/OP/SG cancer is significant and may be the most costly cancer to treat in the U.S. The results of this analysis provide useful information to health care providers and decision makers in understanding the economic burden of head and neck cancer. Additionally, this cost information will greatly assist in determining the cost-effectiveness of new technologies and early detection systems. Earlier identification of cancers by patients and providers may potentially decrease health care costs, morbidity and mortality. PMID- 22537713 TI - Drought stress has contrasting effects on antioxidant enzymes activity and phenylpropanoid biosynthesis in Fraxinus ornus leaves: an excess light stress affair? AB - The experiment was conducted using Fraxinus ornus plants grown outside under full sunlight irradiance, and supplied with 100% (well-watered, WW), 40% (mild drought, MD), or 20% (severe drought, SD) of the daily evapotranspiration demand, with the main objective of exploring the effect of excess light stress on the activity of antioxidant enzymes and phenylpropanoid biosynthesis. Net CO2 assimilation rate at saturating light and daily assimilated CO2 were significantly smaller in SD than in WW and MD plants. Xanthophyll-cycle pigments supported nonphotochemical quenching to a significantly greater extent in SD than in MD and WW leaves. As a consequence, the actual efficiency of PSII (Phi(PSII)) was smaller, while the excess excitation-energy in the photosynthetic apparatus was greater in SD than in WW or MD plants. The concentrations of violaxanthin cycle pigments relative to total chlorophyll (Chl(tot)) exceeded 200 mmol mol-1 Chl(tot) in SD leaves at the end of the experiment. This leads to hypothesize for zeaxanthin a role not only as nonphotochemical quencher, but also as chloroplast antioxidant. Reductions in ascorbate peroxidase and catalase activities, as drought-stress progressed, were paralleled by greater accumulations of esculetin and quercetin 3-O-glycosides, both phenylpropanoids having effective capacity to scavenge H2O2. The drought-induced accumulation of esculetin and quercetin 3-O glycosides in the vacuoles of mesophyll cells is consistent with their putative functions as reducing agents for H2O2 in excess light-stressed leaves. Nonetheless, the concentration of H2O2 and the lipid peroxidation were significantly greater in SD than in MD and WW leaves. It is speculated that vacuolar phenylpropanoids may constitute a secondary antioxidant system, even on a temporal basis, activated upon the depletion of primary antioxidant defences, and aimed at keeping whole-cell H2O2 within a sub-lethal concentration range. PMID- 22537714 TI - Predicting chronicity in acute back pain: validation of a French translation of the Orebro Musculoskeletal Pain Screening Questionnaire. AB - OBJECTIVE: To establish the predictive validity of a French translation of the Orebro Musculoskeletal Pain Screening Questionnaire (OMPSQ), a screening tool assessing the risk of chronicity in patients with back pain. METHODS: Prospective follow-up study. Assessment was performed at inclusion and 6 months later with the OMPSQ and the Oswestry Disability Index (ODI). Four outcome variables (pain index, two functional variables and work absence) were defined. RESULTS: Ninety one patients were included, of whom 80% completed the study. Depending on the outcome variable considered, 42 to 82% of the patients recovered within 6 months. ROC AUC, a global measure of the performance of the questionnaire integrating sensitivity and specificity data, ranged from 0.73 to 0.83. When considering the functional outcome variable derived from the ODI, a low cut-off score of 71 (corresponding to 80% sensitivity) and a high cut-off score of 106 (corresponding to 80% specificity) can be used to distinguish three groups of patients: low, intermediate and high risk of chronicity. CONCLUSION: The predictive value of the French version of the OMPSQ is reasonably good, in line with the studies in other languages. This questionnaire may be particularly valuable in secondary care settings. PMID- 22537716 TI - Structure and function in native and pathological erythrocytes: a quantitative view from the nanoscale. AB - The red blood cells (RBCs) are among the most simple and less expensive cells to purify; for this reason and for their physiological relevance, they have been extensively studied with a variety of techniques. The picture that results is that these cells have several peculiarities including extreme mechanical performances, relatively simple architecture, biological relevance and predictable behavior that make them a perfect laboratory of testing for novel techniques, methodologies and ideas. These include the re-evaluation of old concepts, such as the relationship between structure and function (which is one of the guideline of this report) but considered at the cellular level. The studies reported on this paper, indeed, exploit the full potential of an high resolution quantitative microscopy such as the atomic force microscopy (AFM) to investigate different aspect of the erythrocytes' life, death and interaction with the environment. Indeed, the erythrocytes have a special relationship with the environment that is able to deeply influence their morphology as consequence of alteration of their biochemical or biophysical status. In this context the conditions under which the erythrocytes can be considered as biochemically programmable systems have been investigated by analyzing different environmentally induced alteration of the cell's morphology and comparing the results with naturally occurring pathological morphologies. This class of studies takes great advantage by the additional consideration of the nanomechanical properties of the cells. These latter are particularly important for the cell functionality and are shown to be of practical usefulness to discriminate and partition environmental effects charging different cellular structure (e.g. membrane or membrane-skeleton). Moreover, the development of novel morphological parameter can be important to push the level of investigation on the RBCs' status towards the molecular level. In particular, we describe the introduction and use of the plasma membrane roughness as a morphometric parameter of simple derivation from the AFM images and that results sensitive to the structural integrity of the cells' membrane-skeleton. This offer a remarkable opportunity to investigate the relationship between structure and function in normal and pathological cells by using a morphometric parameter that probes the cell surface at the nanoscale level. At last, a complex but physio-pathologically important phenomenon such as the erythrocytes aging was considered. To properly analyze the many variation that the cells experience during the whole aging path we used all the parameters that the AFM can provides: quantitative imaging, analysis of the membrane roughness and local measure of the nanomechanical properties analyzed together with biochemical parameter such as the ATP content. The picture that emerged is that the aging path is triggered by the ATP intracellular concentration that influence the membrane-skeleton structure and the support exerted on the plasma membrane. The consequences of the membrane-skeleton involvement can be monitored by AFM and showed the occurrence of peculiar morphologies and morphological defects that appear in the very place where the membrane-skeleton contact with the membrane became loose. As a whole, the collected data enable to describe the entire phenomenon as a sequence of morphological intermediates following one another along the aging path. PMID- 22537717 TI - Analysis of p53 binding to DNA by fluorescence imaging microscopy. AB - Transcription factors play a central role in cell biology through binding to target DNA elements and regulating gene expression. In this study, we used the p53 tumour suppressor as a model transcription factor to develop an imaging based assay to measure DNA binding. The assay utilizes fluorescence imaging microscopy to detect labelled p53 bound to DNA coated on microbeads. We demonstrate the ability to multiplex the assay by interrogating simultaneous binding to variant DNA sequences present on tractable beads. Additionally, the assay measures activation of p53 for increased DNA binding by a known peptide in addition to reactivation of mutant p53 by a small molecule. It may therefore be adaptable to a high-content imaging screen for compounds capable of restoring the function of mutant p53 associated with cancer. PMID- 22537715 TI - Distinct degree of radiculopathy at different levels of peripheral nerve injury. AB - BACKGROUND: Lumbar radiculopathy is a common clinical problem, characterized by dorsal root ganglion (DRG) injury and neural hyperactivity causing intense pain. However, the mechanisms involved in DRG injury have not been fully elucidated. Furthermore, little is known about the degree of radiculopathy at the various levels of nerve injury. The purpose of this study is to compare the degree of radiculopathy injury at the DRG and radiculopathy injury proximal or distal to the DRG. RESULTS: The lumbar radiculopathy rat model was created by ligating the L5 nerve root 2 mm proximal to the DRG or 2 mm distal to the DRG with 6.0 silk. We examined the degree of the radiculopathy using different points of mechanical sensitivity, immunohistochemistry and in vivo patch-clamp recordings, 7 days after surgery. The rats injured distal to the DRG were more sensitive than those rats injured proximal to the DRG in the behavioral study. The number of activated microglia in laminas I-II of the L5 segmental level was significantly increased in rats injured distal to the DRG when compared with rats injured proximal to the DRG. The amplitudes and frequencies of EPSC in the rats injured distal to the DRG were higher than those injured proximal to the DRG. The results indicated that there is a different degree of radiculopathy at the distal level of nerve injury. CONCLUSIONS: Our study examined the degree of radiculopathy at different levels of nerve injury. Severe radiculopathy occurred in rats injured distal to the DRG when compared with rats injured proximal to the DRG. This finding helps to correctly diagnose a radiculopathy. PMID- 22537718 TI - In situ ultra-high vacuum transmission electron microscopy studies of the transient oxidation stage of Cu and Cu alloy thin films. AB - Because environmental stability is an essential property of most engineered materials, many theories exist to explain oxidation mechanisms. Yet, nearly all classical oxidation theories assume a uniform growing film, where structural changes were not considered because of the previous lack of experimental procedure to visualize this non-uniform growth in conditions that allowed for highly controlled surfaces and impurities. With the advent of vacuum technologies and advances in microcopy techniques, especially in situ, one can now see structural changes under controlled surface conditions. Here, we present a review of our systematic studies on the transient oxidation stages of a model metal system, Cu, and its alloys, Cu-Au and Cu-Ni, by in situ ultra-high vacuum transmission electron microscopy (UHV-TEM). The dependence of the oxidation behavior on the crystal orientation, oxygen pressure, temperature and alloying is attributed to the structures of the oxygen-chemisorbed layer, oxygen surface diffusion, surface energy and the interfacial strain energy. Heteroepitaxial concepts, developed to explain thin film formation on a dissimilar substrate material (e.g., Ge on Si), described well these initial oxidation stages. PMID- 22537719 TI - Antimicrobial effect of linalool and alpha-terpineol against periodontopathic and cariogenic bacteria. AB - Linalool and alpha-terpineol exhibited strong antimicrobial activity against periodontopathic and cariogenic bacteria. However, their concentration should be kept below 0.4 mg/ml if they are to be used as components of toothpaste or gargling solution. Moreover, other compounds with antimicrobial activity against periodontopathic and cariogenic bacteria should be used in combination. PMID- 22537720 TI - A sunlight-induced rapid synthesis of silver nanoparticles using sodium salt of N cholyl amino acids and its antimicrobial applications. AB - Aqueous solution containing two additives, silver nitrate (AgNO(3)) and sodium salt of N-cholyl amino acid were irradiated by sunlight for the synthesis of spherical shaped AgNPs without the need for an additional stabilizer or capping agent. Variations of N-cholyl amino acid concentration provided good control over the morphology of the AgNPs, while the carboxylate group of bile salt reduced the Ag(+) ions and the amide group binds strongly to the surface of the NPs. The optical properties, morphology of the AgNPs were characterized by UV-visible, transmission electron microscopy (TEM) and dynamic light scattering (DLS) studies. The interaction of N-cholyl amino acid on the AgNPs surface was studied using cyclic voltammetry and FT-IR techniques. The reduction process was completed within 5 min and the synthesized AgNPs were stable for more than 6 months. The possible mechanism of N-cholyl amino acid on the reduction and stabilization of AgNPs is also discussed. The antimicrobial activity of N-cholyl amino acid capped AgNPs against Escherichia coli, Staphylococcus aureus and Pseudomonas aeroginosa using Mueller Hinton broth and the antifungal activity against Candida albicans, Candida krusei and Candida tropicalis using RPMI broth were determined by MIC studies as per CLSI guidelines. PMID- 22537721 TI - Irritability in Huntington's disease. AB - Irritability is a frequent neuropsychiatric symptom in patients with Huntington's disease (HD). The Irritability Scale (IS) and the irritability factor of the Problem Behaviours Assessment (PBA) was used to assess irritability among 130 HD mutation carriers and 43 verified non-carriers. The IS was tested using receiver operating characteristic analysis against different cut-offs of the PBA irritability factor. A robust IS cut-off score of >=14 points was found indicating that 45 (35%) of the 130 mutation carriers were irritable vs. 4 (9%) of the 43 non-carriers (P=0.001). The level of agreement between self-report and informant-report IS was of moderate strength (intraclass correlation=0.61). Using univariate and multivariate regression analyses, independent correlates of irritability were being married/living together (P=0.02), CAG repeat length (P=0.01), and use of benzodiazepines (P=0.008). Using the same model with the informant's irritability score, use of benzodiazepines was the only significant independent correlate of irritability (P=0.005). Irritability is a prominent symptom of HD and can be reliably assessed with the IS using a cut-off score >=14 points. Although it is unclear whether benzodiazepine use causes irritability, or irritability leads to the prescription of benzodiazepines, clinical evaluation with respect to the use of benzodiazepines in HD warrants attention. PMID- 22537722 TI - Hair pulling disorder (trichotillomania): genes, neurobiology, and a model for understanding impulsivity and compulsivity. AB - Hair pulling disorder (trichotillomania) affects at least 3.7 million people in the United States and results in marked functional impairment. This article reviews empirical research investigating the genetics and neurobiology of hair pulling disorder (HPD). We also discuss recent advances in the characterization of this phenotype which have led to evidence supporting the existence of at least two disparate pulling styles-automatic and focused pulling. These pulling styles exhibit facets of behavioral processes, impulsivity and compulsivity, characteristic of several classes of disorders (e.g., obsessive-compulsive spectrum disorders, impulse control disorders). Available genetic, neurobiological, and clinical data support the importance of impulsivity for conceptualizing HPD. Impulsivity alone is insufficient to fully understand this complex phenotype. Characterizations of both automatic and focused pulling as well as preliminary findings from affective neuroscience across species highlight the importance of compulsivity for understanding HPD. Opposing and complementary aspects to impulsivity-compulsivity provide a more comprehensive conceptualization of HPD and supports HPD's potential importance for advancing scientific inquiry in relation to the pathogenesis and treatment of related phenotypes. This review concludes with a description of areas-phenotype, neurobiology, and genes-in need of further study. PMID- 22537723 TI - A cross-validation study of clustering of schizotypy using a non-clinical Chinese sample. AB - This study aimed to examine whether the same clusters of individuals with schizotypy as reported in Western samples are present in a Chinese sample. Cluster analysis was conducted on the responses of 418 individuals to the Chapman Psychosis-Proneness Scales. Results revealed that similar clusters of schizotypy exist in Chinese and Western samples, and that the emotional and neuropsychological symptoms they manifest are consistent with their cluster type. PMID- 22537724 TI - Developmental epidemiology of depressive disorders. AB - Definitions, understanding, and treatment of childhood depressive disorders are changing. The last 40 years have seen a move from questioning whether depression even existed in younger children to evidence-based descriptive models. The field is now moving toward developmentally informed multifactorial models that more accurately reflect the complexity, heterogeneity, and dimensionality of depressive disorders. Knowledge about genetic, temperamental, and developmental risks has increased. Inability to self-regulate seems to be common in depressive and related disorders. Positive modulation can be promoted through experiences, psychotherapies, and, possibly, medications. The authors provide an overview of childhood depressive disorders with emphasis on the developmental/etiologic underpinnings. PMID- 22537726 TI - Developmental risk of depression: experience matters. AB - This article focuses on discussing risks for depression onset and the role of environmental factors in promoting resilience in children and adolescents. The authors review the current literature on specific (eg, family history of depression) and nonspecific (eg, poverty, stressful life events) risk factors for youth depression to underscore the need for prevention efforts promoting resiliency in this population. PMID- 22537727 TI - Developmentally informed evaluation of depression: evidence-based instruments. AB - This article has two primary aims: (1) to describe how to incorporate evidence based assessment procedures into diagnostic practice and (2) to present a review of the more commonly used interview methods and clinical measures of depression among preschoolers, school-age children, and adolescents. PMID- 22537728 TI - Child and adolescent depression intervention overview: what works, for whom and how well? AB - The authors review the currently available evidence-based treatments of child and adolescent major depressive disorder. Medication monotherapy, namely with selective serotonin reuptake inhibitors, is supported by large clinical trials in adolescents. For mild to moderate depression, cognitive behavior therapy (CBT) and interpersonal therapy are reasonable options as monotherapies. There is also evidence that the combination of medication and CBT is superior to medication alone for accelerating the pace of treatment response and remission, despite some negative studies. Response, remission, and recurrence rates after acute treatment and during long-term follow-ups are also presented and discussed. PMID- 22537725 TI - Developmental risk I: depression and the developing brain. AB - This article discusses recent findings on the neurobiology of pediatric depression as well as the interplay between genetic and environmental factors in determining the risk for the disorder. Utilizing data from both animal and human studies, the authors focus on the evolving understanding of the developmental neurobiology of emotional regulation, cognitive function and social behavior as it applies to the risk and clinical course of depression. Treatment implications and directions for future research are also discussed. PMID- 22537729 TI - Developmentally informed pharmacotherapy for child and adolescent depressive disorders. AB - This article reviews evidence-based pharmacotherapy for children and adolescents with depression. Several randomized controlled trials (RCTs) support the use of fluoxetine for the treatment of childhood and adolescent depression as well as escitalopram in the treatment of adolescent depression. To date, one RCT has demonstrated the effectiveness of sertraline or citalopram for the treatment of major depressive disorder in youth. Only a small number of RCTs for depression have included children, and none of these trials were adequately powered to detect differences in the efficacy of medication between children and adolescents. PMID- 22537730 TI - Contextual emotion regulation therapy: a developmentally based intervention for pediatric depression. AB - For this special issue about child and adolescent depression, the authors were asked to describe contextual emotion regulation therapy as an example of a developmentally informed psychosocial intervention. The article begins with the authors' definition of the elements that should comprise such an intervention. A succinct summary of this contextual emotion regulation therapy is then provided, including its explanatory paradigm of depression, followed by an exposition of how it addresses the various definitional criteria of a developmentally informed intervention. The article concludes with a brief overview of the challenges of implementing a developmentally sensitive psychotherapy for depressed children and adolescents. PMID- 22537731 TI - Enhancing the developmental appropriateness of treatment for depression in youth: integrating the family in treatment. AB - Treatment models for youth depression that emphasize interpersonal functioning, particularly family relationships, may be particularly promising. This article first reviews the current state of knowledge on the efficacy of psychosocial treatments for depression in youth, with an emphasis on family involvement in treatment. It then discusses developmental factors that may impact the applicability and structure of family-focused treatment models for preadolescent and adolescent youth. Finally, two family-based treatment models that are currently being evaluated in randomized clinical trials are described: one focusing on preadolescent depressed youth and the other on adolescents who have made a recent suicide attempt. PMID- 22537733 TI - Primary care management of child & adolescent depressive disorders. AB - This article outlines the importance of primary health care in addressing the public health challenge presented by pediatric depressive disorders. The current realities of depression management in primary care are discussed. The models emerging from intervention research and the barriers to their implementation in practice are then reviewed. Drawing on this background, recent new standards for primary care management of pediatric depressive disorders are discussed, along with resources that have been developed to support their achievement. PMID- 22537734 TI - Education and depression. AB - This article is intended to assist educators in the medical field in promoting competency among medical students and trainees on the key issues in child and adolescent depression, including approach, understanding, and management. Using clinical vignettes, up-to-date research, and expert opinion and referencing accessible guidelines, resources, and tools, the authors' goal is to create information that is engaging and useful. It is designed to reach a broad audience with emphasis on trainees who are early in their career path (eg, medical students or interns) and/or who are going into primary care. PMID- 22537732 TI - The complex role of sleep in adolescent depression. AB - Psychological and pharmacologic treatments for youth depression yield post-acute response and remission rates that are modest at best. Improving these outcomes is an important long-term goal. The authors examine the possibility that a youth cognitive behavioral therapy insomnia intervention may be an adjunct to traditional depression-focused treatment with the aim of improving depression outcomes. This "indirect route" to improving youth depression treatment outcomes is based on research indicating that the risk of depression is increased by primary insomnia and that sleep problems interfere with depression treatment success and on emerging adult depression randomized controlled trial results. The authors describe the protocol they developed. PMID- 22537735 TI - Child and adolescent depression. Preface. PMID- 22537737 TI - Risk factors associated with nicotine dependence in a sample of Romanian pregnant smokers. AB - OBJECTIVES: To fill the gap in assessing nicotine dependence during pregnancy in an unexplored population in Central and Eastern Europe and to analyze the associations of maternal characteristics and prenatal risk factors with moderate heavy nicotine dependence among pregnant smokers. STUDY DESIGN: A questionnaire was applied to pregnant smokers in Romania to assess nicotine dependence and other related risks poorly documented in Central and Eastern Europe. The response rate was >80% and the valid sample included 137 pregnant smokers. Descriptive statistics and logistic regressions were used to assess nicotine dependence and to analyze the associations of maternal characteristic and prenatal risk factors with moderate-heavy nicotine dependence. RESULTS: Approximately 43% of the pregnant smokers in our sample (59 of 137) had moderate to heavy nicotine dependence. Depressive symptoms were associated with moderate-heavy nicotine dependence among pregnant smokers (OR=3.07, p<0.05). Women carrying an unwanted pregnancy had higher odds of moderate-heavy nicotine dependence (OR=2.59, p<0.05) compared to other pregnant women. High stress, lack of social support, and socioeconomic status were not associated with nicotine dependence. CONCLUSIONS: A large proportion of women had moderate-heavy nicotine dependence in a sample of Romanian pregnant smokers. The more dependent pregnant smokers were more likely to have depressive symptoms. Prenatal care should include brief nicotine dependence assessments and mental health screening and referrals for pregnant women who smoke. Special and intensive efforts, including psychosocial components, may be needed for the nicotine dependent pregnant smokers. PMID- 22537736 TI - Effects of vitamin D supplementation on the bone specific biomarkers in HIV infected individuals under treatment with efavirenz. AB - BACKGROUND: It was reported that antiretroviral drugs such as efavirenz can increase the catabolism of vitamin D in HIV infected individuals. We have not found any study that evaluated effects of vitamin D supplementation on the bone specific biomarkers in HIV positive patients under treatment with antiretroviral regimen containing efavirenz. FINDINGS: Vitamin D deficiency was detected in 88.4 % of included patients. Baseline osteocalcin, but not collagen telopeptidase, serum levels were lower than normal range in all of these individuals. Both bone biomarkers' concentrations increased significantly (p < 0.001 for both of them) after supplementation of vitamin D and it was more predominant for osteocalcin. CONCLUSION: In the HIV-infected patients under treatment with efavirenz, vitamin D deficiency is prevalent. After supplementation with single dose of 300,000 IU vitamin D in this population, the activation of osteoblasts and osteoclasts stimulates bone formation and resorption respectively with favorable bone formation without any adverse event. Significant percent of HIV infected individuals are vitamin d deficient that could benefit from vitamin D supplementation. PMID- 22537738 TI - Phylogenetic relationships of trypanosomatids parasitising true bugs (Insecta: Heteroptera) in sub-Saharan Africa. AB - Three hundred and eighty-six heteropteran specimens belonging to more than 90 species captured in Ghana, Kenya and Ethiopia were examined for the presence of trypanosomatid flagellates. Of those, 100 (26%) specimens were positive for trypanosomatids and the spliced leader RNA gene sequence was obtained from 81 (80%) of the infected bugs. Its sequence-based analysis placed all examined flagellates in 28 typing units. Among 19 newly described typing units, 16 are restricted to sub-Saharan Africa, three belong to previously described species and six to typing units found on other continents. This result was corroborated by the analysis of the ssrRNA gene, sequenced for at least one representative of each major spliced leader RNA-based clade. In all trees obtained, flagellates originating from sub-Saharan Africa were intermingled with those isolated from American, Asian and European hosts, revealing a lack of geographic correlation. They are dispersed throughout most of the known diversity of monoxenous trypanosomatids. However, a complex picture emerged when co-evolution with their heteropteran hosts was taken into account, since some clades are specific for a single host clade, family or even species, whereas other flagellates display a very low host specificity, with a capacity to parasitise heteropteran bugs belonging to different genera/families. The family Reduviidae contains the widest spectrum of trypanosomatids, most likely a consequence of their predatory feeding behaviour, leading to an accumulation of a variety of flagellates from their prey. The plant pathogenic genus Phytomonas is reported here from Africa, to our knowledge for the first time. Finding the same typing units in hosts belonging to different heteropteran families and coming from different continents strongly indicates that the global diversity of the insect trypanosomatids is most likely lower than was predicted on the basis of the "one host-one parasite" paradigm. The analysis presented significantly extends the known diversity of monoxenous insect trypanosomatids and will be instrumental in building a new taxonomy that reflects their true phylogenetic relationships. PMID- 22537739 TI - Ultrafine carbon black disturbs heart rate variability in mice. AB - Previous epidemiological and toxicological studies have reported the associations between ambient particulate matter (PM) exposure and changes in heart rate variability (HRV), a marker of cardiac autonomic nervous system (ANS) function. However, both the responsible components in PM and their mechanisms affecting HRV remain uncertain. We propose that carbon black (CB), one of the main components in PM, may affect HRV through mechanisms independent of cardio-pulmonary and systemic inflammation and/or injury. Male C57BL/6 mice were exposed by intra tracheal instillation to ultrafine CB (once every two days for three times) at doses of 0, 0.05, 0.15 and 0.6 mg/kg. HRV indices, standard deviation of all normal R-R intervals (SDNN) and the square root of mean of sum of squares of differences between adjacent normal R-R intervals (RMSSD), showed significant decreases in 0.15 and 0.6 mg/kg CB exposed groups. Slight pulmonary inflammation and myocardial injury were only observed in 0.6 mg/kg CB exposed group. We conclude that CB can disturb cardiac ANS function in mice, indicated by the withdrawal of parasympathetic modulation, through mechanisms independent of apparent myocardial and pulmonary injury. PMID- 22537743 TI - Infrared microspectroscopy combined with conventional atomic force microscopy. AB - This paper reports nanotopography and mid infrared (IR) microspectroscopic imaging coupled within the same atomic force microscope (AFM). The reported advances are enabled by using a bimaterial microcantilever, conventionally used for standard AFM imaging, as a detector of monochromatic IR light. IR light intensity is recorded as thermomechanical bending of the cantilever measured upon illumination with intensity-modulated, narrowband radiation. The cantilever bending is then correlated with the sample's IR absorption. Spatial resolution was characterized by imaging a USAF 1951 optical resolution target made of SU-8 photoresist. The spatial resolution of the AFM topography measurement was a few nanometers as expected, while the spatial resolution of the IR measurement was 24.4 MUm using relatively coarse spectral resolution (25-125 cm(-1)). In addition to well-controlled samples demonstrating the spatial and spectral properties of the setup, we used the method to map engineered skin and three-dimensional cell culture samples. This research combines modest IR imaging capabilities with the exceptional topographical imaging of conventional AFM to provide advantages of both in a facile manner. PMID- 22537744 TI - Practical aspects of Boersch phase contrast electron microscopy of biological specimens. AB - Implementation of physical phase plates into transmission electron microscopes to achieve in-focus contrast for ice-embedded biological specimens poses several technological challenges. During the last decade several phase plates designs have been introduced and tested for electron cryo-microscopy (cryoEM), including thin film (Zernike) phase plates and electrostatic devices. Boersch phase plates (BPPs) are electrostatic einzel lenses shifting the phase of the unscattered beam by an arbitrary angle. Adjusting the phase shift to 90 degrees achieves the maximum contrast transfer for phase objects such as biomolecules. Recently, we reported the implementation of a BPP into a dedicated phase contrast aberration corrected electron microscope (PACEM) and demonstrated its use to generate in focus contrast of frozen-hydrated specimens. However, a number of obstacles need to be overcome before BPPs can be used routinely, mostly related to the phase plate devices themselves. CryoEM with a physical phase plate is affected by electrostatic charging, obliteration of low spatial frequencies, and mechanical drift. Furthermore, BPPs introduce single sideband contrast (SSB), due to the obstruction of Friedel mates in the diffraction pattern. In this study we address the technical obstacles in detail and show how they may be overcome. We use X-ray photoelectron spectroscopy (XPS) and Auger electron spectroscopy (AES) to identify contaminants responsible for electrostatic charging, which occurs with most phase plates. We demonstrate that obstruction of low-resolution features is significantly reduced by lowering the acceleration voltage of the microscope. Finally, we present computational approaches to correct BPP images for SSB contrast and to compensate for mechanical drift of the BPP. PMID- 22537745 TI - Genetic variants in the chemokines and chemokine receptors in Chagas disease. AB - Clinical symptoms of Chagas' disease occur in 30% of the individuals infected with Trypanosoma cruzi and are characterised by heart inflammation and dysfunction. Chemokines and chemokine receptors control the migration of leukocytes during the inflammatory process and are involved in the modulation of Th1 or Th2 responses. To determine their influence, we investigated the possible role of CCL5/RANTES and CXCL8/IL8 chemokines, and CCR2 and CCR5 chemokines receptors cluster gene polymorphisms with the development of chagasic cardiomyopathy. Our study included 260 Chagas seropositive individuals (asymptomatic, n=130; cardiomyopathic, n=130) from an endemic area of Colombia. Genotyping was performed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and TaqMan SNP genotyping assay. We found statistically significant differences in the distribution of the CCR5 human haplogroup (HH)-A (p=0.027; OR=3.78, 95% CI=1.04-13.72). Moreover, we found that the CCR5-2733 G and CCR5-2554 T alleles are associated, respectively, with a reduced risk of susceptibility and severity to develop chagasic cardiomyopathy. No other associations were found to be significant for the other polymorphisms analysed in the CCR5, CCR2, CCL5/RANTES and CXCL8/IL8 genes. Our data suggest that the analysed chemokines and chemokine receptor genetic variants have a weak but important association with the development of chagasic cardiomyopathy in the population under study. PMID- 22537746 TI - NKRP1A+ gammadelta and alphabeta T cells are preferentially induced in patients with Salmonella infection. AB - NKRP1A(+) gammadelta and alphabeta T cells play an important role at the early phase of Salmonella infection in mice. Meanwhile, association between NKRP1A(+) T cells and human Salmonella infection has not been reported. The objective of this study was to investigate the role of the peripheral NKRP1A(+) T cells in immune response to Salmonella infection. Expression of NKRP1A in peripheral gammadelta and alphabeta T cells and production of interferon (IFN) gamma and interleukin (IL)-4 in NKRP1A(+) gammadelta and alphabeta T cells were analyzed in 28 patients with acute phase Salmonella infection, 23 patients with acute bacterial enterocolitis other than Salmonella infection (disease controls) and 44 normal controls by flow cytometry. The proportion of gammadelta T cells expressing NKRP1A and that of IFNgamma-producing cells in NKRP1A(+) gammadelta cells were significantly higher in Salmonella group than those in other two groups. Compared with normal controls, the proportion of alphabeta T cells expressing NKRP1A and that of IL-4-producing cells in NKRP1A(+) alphabeta cells were significantly higher in Salmonella group. These data suggested that NKRP1A(+) T cells might play an important role in the early defense mechanism against Salmonella infection. PMID- 22537747 TI - Diagnostic accuracy of solid phase HLA antibody assays for prediction of crossmatch strength. AB - Solid phase antibody assays are increasingly used to provide quantitative measures of donor-specific HLA antibodies for assessment of pretransplant risk, although cell-based crossmatches continue to serve as gold standards for determination of donor HLA antibody strength. This study determined the ability of HLA antibody solid phase assays to predict the strength of cell-based flow cytometric (FC) and complement-dependent cytotoxicity (CDC) crossmatches. Eighty two recipient/donors pairs were analyzed using receiver operating characteristic (ROC) curve analyses to determine the accuracy of donor-specific median fluorescence intensity values (Sigma MFI) from single antigen bead assays for predicting strong FC and CDC crossmatches. Diagnostic sensitivity and specificity of optimal Sigma MFI values were highest for predicting strong T cell FCs. Sigma MFI values showed good sensitivity for predicting positive direct and AHG augmented CDC crossmatches (91% and 94%, respectively), but with lower specificity (67% each). Specificity and sensitivity for predicting positive B cell CDC crossmatches were 73% and 84%. Sigma MFI values derived from single antigen bead assays can predict strong flow and positive CDC crossmatches, but with tradeoffs between sensitivity and specificity. The results support the use of solid phase assays for quantitative virtual crossmatching and as a replacement for cell-based crossmatching. PMID- 22537748 TI - Genetic polymorphisms of IL17A and pri-microRNA-938, targeting IL17A 3'-UTR, influence susceptibility to gastric cancer. AB - We report an association between gastric cancer (GC) and polymorphisms in IL17A, rs2275913 (-197 G > A), rs3748067 (*1249 C > T), and pri-miR-938, rs2505901 (T > C). We employed the multiplex PCR-SSCP method to detect gene polymorphisms in 337 GC cases and 587 controls. The minor allele frequency of rs2275913 was significantly higher, and those of rs3748067 and rs2505901 significantly lower, in GC cases than controls. The rs2275913 AA homozygote was associated with an increased risk (OR, 2.38; 95%CI, 1.63-3.46; p < 0.0001) for the development of both intestinal and diffuse types of GC. The rs3748067 T polymorphism was associated with a decreased risk for intestinal GC (OR, 0.511; 95%CI, 0.272 0.962; p = 0.037), whereas rs2505901 C locus carried a decreased risk overall for GC (OR, 0.733; 95%CI, 0.545-0.985; p = 0.039). In addition, rs3748067 T allele was inversely correlated with lymph node metastasis. Our results suggest that polymorphisms in both IL17A and pri-miR-938 contribute to cancer risk susceptibility and therefore can affect the development of gastric cancer. PMID- 22537749 TI - CRYAB-650 C>G (rs2234702) affects susceptibility to Type 1 diabetes and IAA positivity in Swedish population. AB - BACKGROUND: Single nucleotide polymorphisms (SNPs) in the promoter region of CRYAB gene have been associated with in multiple sclerosis. CRYAB gene, which encodes alpha B-crystallin (a member of small heat shock protein), was reported as a potential autoimmune target. In this study we investigated whether SNPs in the promoter region of CRYAB gene were also important in the etiology of Type 1 diabetes (T1D). METHODS: Genotyping of SNPs in the promoter region of CRYAB gene was performed in a Swedish cohort containing 444 T1D patients and 350 healthy controls. Three SNPs were included in this study: CRYAB-652 A>G (rs762550), -650 C>G (rs2234702) and -249 C > G (rs14133). Two SNPs (CRYAB-652 and -650) were not included in previous genome wide association studies. RESULTS: CRYAB-650 (rs2234702)*C allele was significantly more frequent in patients than in controls (OR = 1.48, Pc = 0.03). CRYAB-650*C allele was associated with IAA positivity (OR = 8.17, Pc < 0.0001) and IA-2A positivity (OR = 2.14, Pc = 0.005) in T1D patients. This association with IAA was amplified by high-risk HLA carrier state (OR = 10.6, P < 0.0001). No association was found between CRYAB-650 and other autoantibody positivity (GADA and ICA). CRYAB haplotypes were also associated with IAA and IA-2A positivity (highest OR = 2.07 and 2.11, respectively), these associations remain in high HLA-risk T1D patients. CONCLUSIONS: CRYAB-650 was associated with T1D in the Swedish cohort we studied. CRYAB-650*C allele might confers susceptibility to the development of T1D. CRYAB-650 was also associated with the development of IAA-positivity in T1D patients, especially in those carrying T1D high-risk HLA haplotypes. PMID- 22537750 TI - Ancestry markers from the human chromosome 6: Alu repeats from the MHC in autochthonous Basques. AB - Polymorphic Alu insertions from the MHC class I region were analyzed in 215 autochthonous Basques from Guipuzcoa and Navarre provinces, with the aim of contributing new MHC Alu data in European ancestry populations. We also seek to assess both the genetic position of native Basques among worldwide samples and the efficiency of the MHC Alu elements as ancestry informative markers (AIMs). According to the MDS and AMOVA results, worldwide populations included in the comparative analyses were grouped in three major clusters defined by genetic ancestry (Africans, Asians and Europeans). The delta values (differences in weighted allele frequencies) among ancestry groups indicated that Alu elements within the alpha-block (AluHF, AluHJ and AluHG) showed an adequate resolving power to discriminate appropriately between some of the major ancestry groups. Alpha block Alu were also revealing of the exceptionality of Basques, as they allowed for the detection of genetic heterogeneity even between Basques and the other Iberian collection considered in the analysis (Valencia). Thus, analysis of the Alu loci within the alpha-block may represent a reliable, informative and cost-effective method to explore the ancestry, geographic origins and demographic history of human populations, which can be very helpful for studies into epidemiological, forensic or evolutionary perspectives. PMID- 22537751 TI - IL10 -1082, IL10 -819 and IL10 -592 polymorphisms are associated with chronic periodontitis in a Macedonian population. AB - Genetic polymorphisms in the interleukin 10 (IL10) gene have been reported to influence the host response to microbial challenge by altering levels of cytokine expression. We analyzed nucleotide polymorphisms in the promoter region of the IL10 gene and its relation with periodontal disease in a Macedonian population. The study population consisted of 111 unrelated subjects with chronic periodontitis and 299 healthy controls. DNA was isolated and IL10 genotyping performed by PCR-SSP (Heidelberg kit) for the alleles and genotypes of IL10 1082, IL10 -819 and IL10 -592. Frequencies of IL10 haplotypes and the haplotype zygotes were also examined. Comparisons between groups were tested using the Pearson's p-value. After Bonferroni adjustment, significant associations were detected between subjects with chronic periodontitis and IL10 genotypes (IL10 1082/A:G was negative or protective and IL10 -1082/G:G was positive or susceptible). Cytokine polymorphism on the IL10 gene appears to be associated with susceptibility to chronic periodontitis in Macedonians. PMID- 22537752 TI - Association of TLR3-hyporesponsiveness and functional TLR3 L412F polymorphism with recurrent herpes labialis. AB - HSV-1 persistently infects almost 90% of our population; however, only 30% of the infected subjects suffer from recurrent herpes lesions, most frequently herpes labialis (HL). We hypothesized that variations in toll-like receptor (TLR) functions might contribute to HL susceptibility. In our study, the TLR-2/1,-3, and -7/8 responses of immune cell subsets derived from asymptomatic HSV-1 carriers were compared with responses of subjects with HL history. Remarkably, natural killer (NK) cells isolated from HL subjects showed significantly lower IFN-gamma responses selectively to the TLR3 agonist poly(I:C). Furthermore, the TLR3 L412F genetic polymorphism was found to reduce NK cell TLR3-responsiveness and is associated with susceptibility to recurrent HL. The TLR3 response detected in HL total peripheral blood mononuclear cells (PBMCs), however, was not impaired, indicating restoration of NK cell TLR3-deficiency through co stimulatory functions. In conclusion, our results suggest that decreased TLR3 response of NK cells is associated with HL susceptibility; and potentially explain why symptomatic outbreak of HL usually occurs after stress or prolonged UV light exposure, when host co-stimulatory functions are disturbed. PMID- 22537753 TI - Non-HLA autoimmunity genetic factors contributing to Autoimmune Polyglandular Syndrome type II in Tunisian patients. AB - Autoimmune Polyglandular Syndrome Type II (APSII) is characterized by the co occurrence of clinical insufficiency of at least two endocrine glands. Although, HLA determinants of APSII predisposition have been identified, little attention has been paid to non-HLA genes. Here, we used SNP genotyping in a Sequenom platform and genetic association tests to study a cohort of 60 APSII Tunisian patients presenting highly frequent co-occurrence of Autoimmune Thyroid Disease (AITD) and Type 1 Diabetes (T1D) and lower frequency of Addison's disease (AD). We tested the high a priori possibility that well-established non-HLA autoimmunity loci were involved in APSII and confirmed five association signals to APSII, namely: (1) two T1D-associated SNPs, in CTLA4 and IL2RA, suggest their involvement in T1D pathogenesis in this cohort; (2) two SNPs in STAT4 and IL15 not previously associated to endocrinopathies, are possibly involved in co occurrence of organ autoimmunity in APSII, and; (3) one SNP in TNF alpha showed association to APSII irrespective of AD. While this work was performed in a relatively small cohort, these results support the notion that the non-HLA genetic component of APSII include genetic factors specific of particular autoimmune manifestations as well as genetic factors that promote the co occurrence of multiple autoimmune endocrinopathies. PMID- 22537754 TI - Maternal homozygocity for a 14 base pair insertion in exon 8 of the HLA-G gene and carriage of HLA class II alleles restricting HY immunity predispose to unexplained secondary recurrent miscarriage and low birth weight in children born to these patients. AB - Homozygous carriage of a 14 base pair (bp) insertion in exon 8 of the HLA-G gene may be associated with low levels of soluble HLA-G and recurrent miscarriage (RM). We investigated the G14bp insertion(ins)/deletion(del) polymorphism in 339 women with unexplained RM and 125 control women. In all patients and patients with secondary RM after a firstborn boy, 19.2% and 23.9%, respectively, were G14bp ins/ins compared with 11.2% of controls (p<0.05 and p<0.01). Among secondary RM patients with a firstborn boy, G14bp del/del and no carriage of an HLA class II (HYrHLA) allele restricting immunity against male-specific minor HY antigens was found less often than in controls (p<0.05) whereas G14bp ins/ins and carriage of HYrHLA predisposed (p<0.08) to this clinical entity. The mean birth weight of firstborn boys born to G14bp ins positive secondary RM patients was significantly lower than expected (p<0.001) but only in carriers of HYrHLA alleles (p<0.01). In conclusion, homozygosity for G14bp ins predisposes to RM. The combination of G14 ins homozygosity and carriage of HYrHLA predisposes to secondary RM in women with a firstborn boy and negatively affects birth weight in these boys. PMID- 22537755 TI - Elevated profiles of Th22 cells and correlations with Th17 cells in patients with immune thrombocytopenia. AB - T-helper (Th) 22 and Th17 cells are implicated in the pathogenesis of autoimmune diseases. However, the role of Th22 cells in the pathophysiology of immune thrombocytopenia (ITP) remains unclear. Th22, Th17 and Th1 cells in both ITP patients and healthy controls were examined by flow cytometry. Plasma interleukin 22 (IL-22) level was measured by enzyme linked immunosorbent assay (ELISA). Signal transducers and activators of transcription 3 (STAT-3) and transcription factor RAR-related organ receptor C (RORC) messenger RNA (mRNA) expressions were examined by quantitative reverse transcription polymerase chain reaction (RT PCR). Th22 cells, Th17 cells, Th1 cells and plasma IL-22 were significantly higher in ITP patients than in healthy controls. Moreover, Th22 cells showed a positive correlation with the levels of plasma IL-22 as well as Th17 and Th1 cells in ITP patients. Significant up-regulations of both STAT-3 and RORC transcription factors were also observed. Additionally, the percentage of Th22 cells was higher in autoantibody-negative ITP patients than in autoantibody positive patients. Our results demonstrate a possible role of Th22 cells in ITP, and thus, the blockade of IL-22 may be a reasonable therapeutic strategy for ITP. PMID- 22537756 TI - Cutoff values and data handling for solid-phase testing for antibodies to HLA: effects on listing unacceptable antigens for thoracic organ transplantation. AB - Application of single-antigen solid-phase immunoassay (SPI) in virtual crossmatch based organ allocation has been hindered by continued debate over the biologic relevance of detected antibodies and the relationship between cutoff mean fluorescence intensity (MFI) values with crossmatch testing results. To define SPI parameters accurately predicting crossmatch testing, we analyzed a series of anti-HLA antibodies from highly-sensitized patients awaiting lung or heart transplantation. Serial dilution of serum for SPI and cytotoxic crossmatch (CXM) enabled comparison over a wide spectrum of antibody "strengths". Receiver operating characteristic (ROC) analysis identified predictive cutoff values for HLA Class I and DR-specific antibodies. However, antibodies to HLA-DQ antigens demonstrated a significantly different characteristic, highlighting difficulties in interpretation of clinical significance. We also quantitatively characterized two data handling methods, MFI ratio (MR) and relative ratio (RR), to examine their potential impact on identifying unacceptable antigens. In combination with user defined cutoff values, MFI, MR and RR lead to discordant identification of antibodies. Establishment of cutoff values for MR and RR that are comparable to MFI demonstrated increased consistency in antibody identification. This single laboratory experience is an example of establishing statistically robust cutoff values and validation across different data handling methods for use of SPI in virtual crossmatch. PMID- 22537757 TI - Characterization of mutations in barley fch2 encoding chlorophyllide a oxygenase. AB - The barley (Hordeum vulgare L.) mutants fch2 and clo-f2 comprise an allelic group of 14 Chl b-deficient lines. The genetic map position of fch2 corresponds to the physical map position of the gene encoding chlorophyllide a oxygenase. This enzyme converts chlorophyllide a to chlorophyllide b and it is essential for Chl b biosynthesis. The fch2 and clo-f2 barley lines were shown to be mutated in the gene for chlorophyllide a oxygenase. A five-base insertion was found in fch2 and base deletions in clo-f2.101, clo-f2.105, clo-f2.2800 and clo-f2.3613. In clo f2.105 and clo-f2.108, nonsense base exchanges were discovered. All of these mutations led to a premature stop of translation and none of the mutants formed Chl b. The mutant clo-f2.2807 was transcript deficient and formed no Chl b. Missense mutations in clo-f2.102 (leading to the amino acid exchange D495N) and clo-f2.103 (G280D) resulted in a total lack of Chl b, whereas in the missense mutants clo-f2.107 (P419L), clo-f2.109 (A94T), clo-f2.122 (C320Y), clo-f2.123 (A94T), clo-f2.133 (A376V) and clo-f2.181 (L373F) intermediate contents of Chl b were determined. The missense mutations affect conserved residues, and their effect on chlorophyllide a oxygenase is discussed. The mutations in clo-f2.102, clo-f2.103, clo-f2.133 and clo-f2.181 may influence electron transfer as illustrated in the active site of a structural model protein. The changes in clo f2.107, clo-f2.109, clo-f2.122 and clo-f2.123 may lead to Chlb deficiency by interfering with the regulation of chlorophyllide a oxygenase. The correlation of mutations and phenotypes strongly supports that the barley locus fch2 encodes chlorophyllide a oxygenase. PMID- 22537759 TI - Arabidopsis GUX proteins are glucuronyltransferases responsible for the addition of glucuronic acid side chains onto xylan. AB - Xylan, the second most abundant cell wall polysaccharide, is composed of a linear backbone of beta-(1,4)-linked xylosyl residues that are often substituted with sugar side chains, such as glucuronic acid (GlcA) and methylglucuronic acid (MeGlcA). It has recently been shown that mutations of two Arabidopsis family GT8 genes, GUX1 and GUX2, affect the addition of GlcA and MeGlcA to xylan, but it is not known whether they encode glucuronyltransferases (GlcATs) or indirectly regulate the GlcAT activity. In this study, we performed biochemical and genetic analyses of three Arabidopsis GUX genes to determine their roles in the GlcA substitution of xylan and secondary wall deposition. The GUX1/2/3 genes were found to be expressed in interfascicular fibers and xylem cells, the two major types of secondary wall-containing cells that have abundant xylan. When expressed in tobacco BY2 cells, the GUX1/2/3 proteins exhibited an activity capable of transferring GlcA residues from the UDP-GlcA donor onto xylooligomer acceptors, demonstrating that these GUX proteins possess xylan GlcAT activity. Analyses of the single, double and triple gux mutants revealed that simultaneous mutations of all three GUX genes led to a complete loss of GlcA and MeGlcA side chains on xylan, indicating that all three GUX proteins are involved in the GlcA substitution of xylan. Furthermore, a complete loss of GlcA and MeGlcA side chains in the gux1/2/3 triple mutant resulted in reduced secondary wall thickening, collapsed vessel morphology and reduced plant growth. Together, our results provide biochemical and genetic evidence that GUX1/2/3 are GlcATs responsible for the GlcA substitution of xylan, which is essential for normal secondary wall deposition and plant development. PMID- 22537758 TI - Molecular and functional characterization of broccoli EMBRYONIC FLOWER 2 genes. AB - Polycomb group (PcG) proteins regulate major developmental processes in Arabidopsis. EMBRYONIC FLOWER 2 (EMF2), the VEFS domain-containing PcG gene, regulates diverse genetic pathways and is required for vegetative development and plant survival. Despite widespread EMF2-like sequences in plants, little is known about their function other than in Arabidopsis and rice. To study the role of EMF2 in broccoli (Brassica oleracea var. italica cv. Elegance) development, we identified two broccoli EMF2 (BoEMF2) genes with sequence homology to and a similar gene expression pattern to that in Arabidopsis (AtEMF2). Reducing their expression in broccoli resulted in aberrant phenotypes and gene expression patterns. BoEMF2 regulates genes involved in diverse developmental and stress programs similar to AtEMF2 in Arabidopsis. However, BoEMF2 differs from AtEMF2 in the regulation of flower organ identity, cell proliferation and elongation, and death-related genes, which may explain the distinct phenotypes. The expression of BoEMF2.1 in the Arabidopsis emf2 mutant (Rescued emf2) partially rescued the mutant phenotype and restored the gene expression pattern to that of the wild type. Many EMF2-mediated molecular and developmental functions are conserved in broccoli and Arabidopsis. Furthermore, the restored gene expression pattern in Rescued emf2 provides insights into the molecular basis of PcG-mediated growth and development. PMID- 22537760 TI - Hemoptysis due to breath-hold diving following chemotherapy and lung irradiation. AB - Breath-hold diving, also known as free-diving, describes the practice of intentional immersion under water without an external supply of oxygen. Pulmonary hemorrhage with hemoptysis has been reported as a complication of immersion and breath-hold diving in young healthy athletes. We report the case of a 60-year-old man with a history of radiation and chemotherapy for breast carcinoma, who developed the abrupt onset of hemoptysis in the setting of swimming and breath hold diving. A computed tomography (CT) scan of the chest demonstrated an area of ground glass opacification, suggestive of pulmonary hemorrhage, superimposed on a background of reticular opacities within the prior radiation field. A follow-up CT scan of the chest, obtained 2 months after presentation, demonstrated resolution of the ground glass opacification, but persistence of fibrotic features attributable to prior radiation therapy. We postulate that prior irradiation of the chest resulted in lung injury and fibrosis which, in turn, rendered the affected region of the lung susceptible to "stress failure," due to an increase in the transcapillary pressure gradient arising from immersion and breath-hold diving. Patients with a history of lung injury resulting from chest irradiation should be cautioned about pulmonary hemorrhage and hemoptysis as a potential complication of swimming and breath-hold diving. PMID- 22537761 TI - Historical prostate cancer screening and treatment outcomes from a single institution. AB - OBJECTIVE: To quantify outcomes of individuals diagnosed and treated for prostate cancer in a single institution. DESIGN: Retrospective electronic chart abstraction. SETTING: Marshfield Clinic, the largest private multispecialty group practice in Wisconsin, and one of the largest in the United States, provides health care services annually to approximately 385,000 unique patients through 1.8 million annual patient encounters. PARTICIPANTS: Individuals within the Marshfield Clinic cancer registry who had been diagnosed with prostate cancer between 1960 and 2009. METHODS: Electronic chart abstraction from the cancer registry and the electronic medical record was conducted (N=6,181). Data abstracted included age at diagnosis; stage and grade of tumor; prostate specific antigen (PSA) values before, at, and after diagnosis; initial cancer treatment; follow-up time; subsequent cancer treatments; evidence of metastasis; age of death; and cause of death, if known. RESULTS: The average age of prostate cancer diagnosis has decreased from 70-71 years in the 1960's and 1970's to an average age at diagnosis of 67 years in the 2000's (P<0.001). This decrease in age occurred within the decades of implementation of PSA screening. Approximately 74% of men diagnosed with prostate cancer within the PSA screening era had at least one PSA test, and the presence of a PSA test did not appear to change treatment outcome. Age, grade, and stage were the biggest predictors of prostate cancer outcome. There was no difference in event-free survival between current treatment types (radical prostatectomy, brachytherapy, photon treatment, or intensity modulated radiation therapy) (2003 or later) when stratified by age (greater than 85%, 5-year event-free survival P=0.85); however, more events occurred with older external beam radiation treatment regimens (1993-2003) (70% to 75%, 5-year event free survival P=0.001). CONCLUSION: Individuals diagnosed and treated for prostate cancer within the Marshfield Clinic comprehensive care setting follow national trends with a decreased age of diagnosis since the advent of PSA screening. Outcomes for individuals treated within the Clinic system are also comparable to national trends. PMID- 22537762 TI - Bilateral enlarged vestibular aqueduct with associated bilateral Mondini's dysplasia. AB - Enlarged Vestibular Aqueduct (EVA) and Mondini's dysplasia (incomplete partitioning type II) are entitites that have been fairly well described in the literature as potential causes of hearing loss in the young. However, it is uncommon for this condition to be detected bilaterally, especially so for both conditions to coexist bilaterally in the same patient. This is a brief description of a patient with the above bilateral condition with attached high resolution CT scan images of the temporal bone to illustrate the case. PMID- 22537763 TI - The relation of urinary estrogen metabolites with mammographic densities in premenopausal women. AB - BACKGROUND: Mammographic density is a strong predictor of breast cancer risk. The total amount and the metabolism of endogenous estrogens, e.g., the ratio of 2 hydroxyestrone (2-OHE(1)) and 16alpha-OHE(1) may influence breast cancer risk. This study examined the association of urinary estrogen metabolites with breast density in premenopausal women. METHODS: Urine samples were collected at baseline and after 2 years, analyzed for 11 estrogen metabolites plus progesterone and testosterone by liquid chromatography mass spectrometry, and adjusted for creatinine levels. Mixed-effects regression was applied to examine the association of estrogens with breast density. RESULTS: Total estrogen metabolites (181 +/- 113 vs. 247 +/- 165 pmol/mg creatinine, p=0.01) and the 2/16alpha-OH ratio (8.4 +/- 10.4 vs. 13.0 +/- 17.1, p=0.02) were lower in the 74 Asian than in the 114 non-Asian women. In adjusted models, positive associations of total estrogen metabolites (p=0.002) and the 2/16alpha-OHE(1) ratio (p=0.08) with percent density were detected in Asians only. In all women, mammographic density was positively associated with the 2-OH pathway (p=0.01), inversely related to the 16alpha-OH pathway (p=0.01), and not associated with the 4-OH pathway, testosterone, and progesterone. Results for the size of the dense area weakly reflected the findings for percent density, while associations with the non-dense area were in the opposite direction. CONCLUSIONS: The findings that the 2-OH pathway is associated with higher and the 16alpha-OH pathway with lower breast density contradicts the hypothesized risk profile of these metabolites, but, if a relation between estrogen metabolites and breast cancer risk exists, it may be mediated through pathways other than mammographic density. PMID- 22537764 TI - High serum levels of soluble interleukin-2 receptor in acute myeloid leukemia: correlation with poor prognosis and CD4 expression on blast cells. AB - BACKGORUND: Although increased serum levels of soluble interleukin-2 receptor (sIL-2R) and their clinical importance are well known in mature type lymphoproliferative disorders (LD), little data is available about such information in acute type hematological malignancies. METHODS: We examined the serum levels of sIL-2R in 57 adult patients with acute type leukemias: 32 with acute myeloid leukemia (AML), 14 acute lymphoblastic leukemia (ALL) and 11 chronic myelocytic leukemia in blast crisis (CMLBC), and in 29 adult patients with mature type LD, and assessed their cellular and clinical relevance in acute type leukemias. RESULTS: No significant differences were seen in the sIL-2R levels between acute type leukemias and mature type LD. In AML, serum sIL-2R levels were related to the cell surface CD4 expression on blast cells, and patients with higher levels ?2000U/ml had a poorer prognosis (lower response to chemotherapy and shorter overall survival). CONCLUSIONS: These results suggest that serum sIL-2R level elevates in acute type leukemias like mature type LD, and increased sIL-2R levels in adult AML are correlated with certain biological and clinical characteristics. PMID- 22537766 TI - Women's experiences of Group Cognitive Behaviour Therapy for hot flushes and night sweats following breast cancer treatment: an interpretative phenomenological analysis. AB - OBJECTIVES: Many women with breast cancer experience problematic treatment related menopausal symptoms (HF/NS). This study explores how these women experienced a Group Cognitive Behaviour Therapy (CBT) intervention to help them manage their treatment-related HF/NS. The study was conducted as part of a randomised control trial/RCT (MENOS 1) evaluating the intervention among this target group. METHODS: In-depth semi-structured interviews were conducted with twenty trial participants to explore how they experienced the intervention and its effects. The interviews were analysed using interpretative phenomenological analysis. RESULTS: The analysis revealed four superordinate themes: Making sense of symptom change; new ways of coping and regaining control; tailoring the treatment to meet individual needs and resources; and valuing the group context, social support and social comparisons. All the women found Group CBT improved their ability to cope with their HF/NS, while also developing an appreciation of the role of psychological factors in their symptom experience. Through the knowledge and understanding acquired women developed a more accepting stance to their symptoms, as well as gaining a 'sense of control'. CONCLUSIONS: The results are consistent with the main RCT outcomes which showed that Group CBT led to a clinically significant reduction in 'HF/NS problem rating' relative to 'treatment as usual', as well as improvements in mood and physical and social functioning. The results complement the trial outcomes by illuminating women's experience of different components of the intervention and highlighting possible mechanisms of change. PMID- 22537765 TI - The skin function: a factor of anti-metabolic syndrome. AB - The body's total antioxidant capacity represents a sum of the antioxidant capacity of various tissues/organs. A decrease in the body's antioxidant capacity may induce oxidative stress and subsequent metabolic syndrome, a clustering of risk factors for type 2 diabetes and cardiovascular disease. The skin, the largest organ of the body, is one of the major components of the body's total antioxidant defense system, primarily through its xenobiotic/drug biotransformation system, reactive oxygen species-scavenging system, and sweat glands- and sebaceous glands-mediated excretion system. Notably, unlike other contributors, the skin contribution is variable, depending on lifestyles and ambient temperature or seasonal variations. Emerging evidence suggests that decreased skin's antioxidant and excretory functions (e.g., due to sedentary lifestyles and low ambient temperature) may increase the risk for metabolic syndrome. This review focuses on the relationship between the variability of skin mediated detoxification and elimination of exogenous and endogenous toxic substances and the development of metabolic syndrome. The potential role of sebum secretion in lipid and cholesterol homeostasis and its impact on metabolic syndrome, and the association between skin disorders (acanthosis nigricans, acne, and burn) and metabolic syndrome are also discussed. PMID- 22537767 TI - Effect of hot flushes on cardiovascular autonomic responsiveness: a randomized controlled trial on hormone therapy. AB - OBJECTIVES: To compare the responses of heart rate and blood pressure to various autonomic tests in women with and without pre-treatment hot flushes during estradiol and estradiol+medroxyprogesterone acetate (MPA) use. STUDY DESIGN AND MAIN OUTCOME MEASURES: Hundred and fifty recently postmenopausal women (72 with and 78 without hot flushes) were randomized to receive transdermal estradiol (1mg/day), oral estradiol (2 mg/day) alone or in combination with MPA (5mg/day), or placebo for six months. Cardiovascular responsiveness was comprehensively assessed with controlled and deep breathing, active orthostatic test, Valsalva maneuver and handgrip test. RESULTS: Hot flushes were accompanied with a significant reduction (-2.2+/-0.7 vs. 1.3+/-1.1 beats/min, p=0.03) in resting heart rate during estradiol-only treatment; the route of estradiol administration was no factor in this regard. This effect was attenuated by the addition of MPA to oral estradiol. Hot flushes were also associated with reduced maximal heart rate in response to handgrip during the use of estradiol-only therapy (-2.2+/-1.3 vs. 2.8+/-1.5 beats/min, p=0.038); again, the MPA addition eliminated this effect. Hot flushes were accompanied with lowered resting but augmented blood pressure responses to handgrip test during all hormone regimens, whereas in women without hot flushes estradiol-only regimen tended to elevate diastolic resting blood pressure. CONCLUSIONS: Hot flushes appear as determinants for cardiovascular responses to hormone therapy. Estradiol-only therapy causes beneficial changes in cardiovascular regulation in flushing women, and these are blunted, in part, by the addition of MPA. PMID- 22537768 TI - Patients with fibromyalgia display less functional connectivity in the brain's pain inhibitory network. AB - BACKGROUND: There is evidence for augmented processing of pain and impaired endogenous pain inhibition in Fibromyalgia syndrome (FM). In order to fully understand the mechanisms involved in FM pathology, there is a need for closer investigation of endogenous pain modulation. In the present study, we compared the functional connectivity of the descending pain inhibitory network in age matched FM patients and healthy controls (HC).We performed functional magnetic resonance imaging (fMRI) in 42 subjects; 14 healthy and 28 age-matched FM patients (2 patients per HC), during randomly presented, subjectively calibrated pressure pain stimuli. A seed-based functional connectivity analysis of brain activity was performed. The seed coordinates were based on the findings from our previous study, comparing the fMRI signal during calibrated pressure pain in FM and HC: the rostral anterior cingulate cortex (rACC) and thalamus. RESULTS: FM patients required significantly less pressure (kPa) to reach calibrated pain at 50 mm on a 0-100 visual analogue scale (p < .001, two-tailed). During fMRI scanning, the rACC displayed significantly higher connectivity to the amygdala, hippocampus, and brainstem in healthy controls, compared to FM patients. There were no regions where FM patients showed higher rACC connectivity. Thalamus showed significantly higher connectivity to the orbitofrontal cortex in healthy controls but no regions showed higher thalamic connectivity in FM patients. CONCLUSION: Patients with FM displayed less connectivity within the brain's pain inhibitory network during calibrated pressure pain, compared to healthy controls. The present study provides brain-imaging evidence on how brain regions involved in homeostatic control of pain are less connected in FM patients. It is possible that the dysfunction of the descending pain modulatory network plays an important role in maintenance of FM pain and our results may translate into clinical implications by using the functional connectivity of the pain modulatory network as an objective measure of pain dysregulation. PMID- 22537769 TI - KGA-2727, a novel selective inhibitor of a high-affinity sodium glucose cotransporter (SGLT1), exhibits antidiabetic efficacy in rodent models. AB - The high-affinity sodium glucose cotransporter (SGLT1) plays a critical role in glucose absorption from the gastrointestinal tract. We have developed 3-(3-{4-[3 (beta-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazol-4-ylmethyl]-3 methylphenoxy}propylamino)propionamide (KGA-2727), which has a pyrazole-O glucoside structure, as the first selective SGLT1 inhibitor. KGA-2727 inhibited SGLT1 potently and highly selectively in an in vitro assay using cells transiently expressing recombinant SGLTs. In a small intestine closed loop absorption test with normal rats, KGA-2727 inhibited the absorption of glucose but not that of fructose. After oral intake of starch along with KGA-2727 in normal rats, the residual content of glucose in the gastrointestinal tract increased. In the oral glucose tolerance test with streptozotocin-induced diabetic rats, KGA-2727 attenuated the elevation of plasma glucose after glucose loading, indicating that KGA-2727 improved postprandial hyperglycemia. In Zucker diabetic fatty (ZDF) rats, chronic treatments with KGA-2727 reduced the levels of plasma glucose and glycated hemoglobin. Furthermore, KGA-2727 preserved glucose stimulated insulin secretion and reduced urinary glucose excretion with improved morphological changes of pancreatic islets and renal distal tubules in ZDF rats. In addition, the chronic treatment with KGA-2727 increased the level of glucagon like peptide-1 in the portal vein. Taken together, our data indicate that the selective SGLT1 inhibitor KGA-2727 had antidiabetic efficacy and allow us to propose KGA-2727 as a candidate for a novel and useful antidiabetic agent. PMID- 22537770 TI - Naltrindole inhibits human multiple myeloma cell proliferation in vitro and in a murine xenograft model in vivo. AB - It has been demonstrated previously that immune cell activation and proliferation were sensitive to the effects of naltrindole, a nonpeptidic delta-opioid receptor selective antagonist; therefore, we hypothesized that human multiple myeloma (MM) would be a valuable model for studying potential antineoplastic properties of naltrindole. [(3)H]naltrindole exhibited saturable, low-affinity binding to intact human MM cells; however, the pharmacological profile of the binding site differed considerably from the properties of delta-, kappa-, and MU-opioid receptors, and opioid receptor mRNA was not detected in MM cells by reverse transcriptase-polymerase chain reaction. Naltrindole inhibited the proliferation of cultured human U266 MM cells in a time- and dose-dependent manner with an EC(50) of 16 MUM. The naltrindole-induced inhibition of U266 cell proliferation was not blocked by a 10-fold molar excess of naltrexone, a nonselective opioid antagonist. Additive inhibition of MM cell proliferation was observed when using a combination of naltrindole with the histone deacetylase inhibitor sodium valproate, the proteasome inhibitor bortezomib, the glucocorticoid receptor agonist dexamethasone, and the HMG CoA reductase inhibitor simvastatin. Treatment of U266 cells with naltrindole significantly decreased the level of the active, phosphorylated form of the kinases, extracellular signal-regulated kinase and Akt, which may be related to its antiproliferative activity. The antiproliferative activity of naltrindole toward MM cells was maintained in cocultures of MM and bone marrow-derived stromal cells, mimicking the bone marrow microenvironment. In vivo, naltrindole significantly decreased tumor cell volumes in human MM cell xenografts in severe combined immunodeficient mice. We hypothesize that naltrindole inhibits the proliferation of MM cells through a nonopioid receptor-dependent mechanism. PMID- 22537772 TI - Selectivity of action of pregabalin on Ca(2+) channels but not on fusion pore, exocytotic machinery, or mitochondria in chromaffin cells of the adrenal gland. AB - The present study was planned to investigate the action of pregabalin on voltage dependent Ca(2+) channels (VDCCs) and novel targets (fusion pore formed between the secretory vesicle and the plasma membrane, exocytotic machinery, and mitochondria) that would further explain its inhibitory action on neurotransmitter release. Electrophysiological recordings in the perforated-patch configuration of the patch-clamp technique revealed that pregabalin inhibits by 33.4 +/- 2.4 and 39 +/- 4%, respectively, the Ca(2+) current charge density and exocytosis evoked by depolarizing pulses in mouse chromaffin cells. Approximately half of the inhibitory action of pregabalin was rescued by l-isoleucine, showing the involvement of alpha2delta-dependent and -independent mechanisms. Ca(2+) channel blockers were used to inhibit Cav1, Cav2.1, and Cav2.2 channels in mouse chromaffin cells, which were unselectively blocked by the drug. Similar values of Ca(2+) current charge blockade were obtained when pregabalin was tested in human or bovine chromaffin cells, which express very different percentages of VDCC types with respect to mouse chromaffin cells. These results demonstrate that the inhibitory action of pregabalin on VDCCs and exocytosis does not depend on alpha1 Ca(2+) channel subunit types. Carbon fiber amperometric recordings of digitonin permeabilized cells showed that neither the fusion pore nor the exocytotic machinery were targeted by pregabalin. Mitochondrial Ca(2+) measurements performed with mitochondrial ratiometric pericam demonstrated that Ca(2+) uptake or release from mitochondria were not affected by the drug. The selectivity of action of pregabalin might explain its safety, good tolerability, and reduced adverse effects. In addition, the inhibition of the exocytotic process in chromaffin cells might have relevant clinical consequences. PMID- 22537771 TI - Apolipoprotein A-I mimetic peptides inhibit expression and activity of hypoxia inducible factor-1alpha in human ovarian cancer cell lines and a mouse ovarian cancer model. AB - Our previous results demonstrated that the apolipoprotein A-I (apoA-I) mimetic peptides L-4F and L-5F inhibit vascular endothelial growth factor production and tumor angiogenesis. The present study was designed to test whether apoA-I mimetic peptides inhibit the expression and activity of hypoxia-inducible factor-1alpha (HIF-1alpha), which plays a critical role in the production of angiogenic factors and angiogenesis. Immunohistochemistry staining was used to examine the expression of HIF-1alpha in tumor tissues. Immunoblotting, real-time polymerase chain reaction, immunofluorescence, and luciferase activity assays were used to determine the expression and activity of HIF-1alpha in human ovarian cancer cell lines. Immunohistochemistry staining demonstrated that L-4F treatment dramatically decreased HIF-1alpha expression in mouse ovarian tumor tissues. L-4F inhibited the expression and activity of HIF-1alpha induced by low oxygen concentration, cobalt chloride (CoCl(2), a hypoxia-mimic compound), lysophosphatidic acid, and insulin in two human ovarian cancer cell lines, OV2008 and CAOV-3. L-4F had no effect on the insulin-induced phosphorylation of Akt, but inhibited the activation of extracellular signal-regulated kinase and p70s6 kinase, leading to the inhibition of HIF-1alpha synthesis. Pretreatment with L-4F dramatically accelerated the proteasome-dependent protein degradation of HIF 1alpha in both insulin- and CoCl(2)-treated cells. The inhibitory effect of L-4F on HIF-1alpha expression is in part mediated by the reactive oxygen species scavenging effect of L-4F. ApoA-I mimetic peptides inhibit the expression and activity of HIF-1alpha in both in vivo and in vitro models, suggesting the inhibition of HIF-1alpha may be a critical mechanism responsible for the suppression of tumor progression by apoA-I mimetic peptides. PMID- 22537773 TI - Long term behavioral effects of functional dopaminergic neurons generated from human neural stem cells in the rat 6-OH-DA Parkinson's disease model. Effects of the forced expression of BCL-X(L). AB - Parkinson's disease (PD) motor symptoms are caused by the progressive degeneration of ventral mesencephalic (VM) dopaminergic neurons (DAn) in the Substantia Nigra pars compacta (SNpc). Cell replacement therapy for PD is based on the concept that the implantation of DAn in the striatum can functionally restore the dopamine levels lost in the disease. In the current study we have used an immortalized human VM neural stem cell line (hVM1) that generates DAn with the A9 phenotype. We have previously found that the forced expression of Bcl X(L) in these cells enhances DAn generation and improves, short-term, d amphetamine-induced rotation after transplantation in the 6-OH-DA rat model of PD 2-month post-grafting. Since functional maturation of human A9 DAn in vivo requires long survival times, in the present study we investigated the behavioral amelioration induced by the transplantation of these precursors (naive and Bcl X(L)-modified) in the striatum of Parkinsonian rats for up to 5 months. The main findings observed are an improvement on drug-induced behaviour and importantly, in spontaneous behavior tests for both cell-transplanted groups. Finally, we have also tested whether the grafts could ameliorate cognitive performance in PD, in addition to motor deficits. Significant difference was observed for T-maze alternation test in the cell-transplanted animals as compared to sham operated ones. To our knowledge, this is the first report showing an amelioration in spontaneous motor behavior and in cognitive performance in Parkinsonian animals after receiving human VM neural stem cell grafts. Histological studies confirmed that the grafts generated mature dopaminergic cells. PMID- 22537774 TI - Long-lasting effects of chronic rTMS to treat chronic rodent model of depression. AB - Repetitive transcranial magnetic stimulation (rTMS) has been demonstrated in the pre-clinical and clinical settings to have an antidepressant effect. However, studies on the long-lasting effect of rTMS, especially when the effect is measured after treatment has ceased for a few weeks is lacking. We examined this question in a chronic unpredicted mild stress (CUMS) rat model of depression. We gave 3 weeks of high frequency (15 Hz) rTMS, venlafaxine, or these two treatments combined to a modified CUMS paradigm, and then investigated the prolonged effect of treatments. Behavioral testing (sucrose preference test, open field test, forced swimming test, novelty suppressed feeding test), plasma hormone level, hippocampal BrdU labeling, and amount of related neurotropic factors were used to assess the effects of stress and treatments. Long-term chronic rTMS significantly reversed andehonic-like behavior, increased hippocampus cell proliferation, BDNF protein level, phosphorylation of ERK1/2 compared with CUMS rats two weeks after the cessation of rTMS treatment. However, the changes in plasma hormone level were not sustained for that amount of time. Venlafaxine had no interaction with the physical stimulation. Our results suggest that high frequency rTMS has long lasting effects, which may have some relationship with neuroplasticity. PMID- 22537775 TI - Hippocampal c-Fos activation in normal and LPA1-null mice after two object recognition tasks with different memory demands. AB - Normal and LPA1-null mice, that have well reported hippocampal deficits, were assessed in an episodic-like what-when-where memory task or in a comparable task designed to test memory for familiar objects and locations by discriminating them from novels. Both genotypes performed the novelty recognition task but failed to learn the what-when-where task. However, normal mice showed what-when memory that was impaired in nulls. Each task elicited a different pattern of c-Fos expression. In normal mice, the what-when-where task induced more hippocampal c Fos activation in the CA1 area than the novelty-based task, correlating with the what-when memory. LPA1-null mice displayed a basal c-Fos hyperactivity in the hippocampus and in the medial prefrontal cortex, which was regulated differently by the two behavioural tasks employed. Both tasks were matched in exploratory behaviour and c-Fos activation in stress-related brain areas for both genotypes. This study shows that the what-when-where memory task differs from a comparable novelty-based task in both the learning demands and the neuronal correlates. Moreover, results also stress the role of the LPA1 receptor in hippocampal functioning. PMID- 22537776 TI - Lipopolysaccharide inhibits the simultaneous establishment of LiCl-induced anticipatory nausea and intravascularly conditioned taste avoidance in the rat. AB - This study examined the effects of the bacterial endotoxin, lipopolysaccharide (LPS), on the establishment of anticipatory nausea and conditioned taste avoidance in a simultaneous conditioning paradigm using an intravascular/intraperitoneal saccharin taste. 83 naive adult male Long-Evans rats were injected (intraperitoneal) with either 200 MUg/kg LPS or 0.9% saline (NaCl), 90 min prior to ip treatment with either 64 mg/kg LiCl, 64 mg/kg LiCl+2.0% saccharin, 0.9% NaCl, or 0.9% NaCl+2.0% saccharin, and immediately placed into a distinctive context for 30 min (repeated over 4 conditioning days, spaced 72 h apart). 72 h following the final conditioning day, each animal was re exposed to the context on a drug-free test day where orofacial responding was recorded. The next day, animals received a 24 h 2-bottle preference test with a choice between water and a palatable 0.2% saccharin solution. Results showed that LPS exposure, prior to LiCl or LiCl+Saccharin treatment, inhibited the establishment of anticipatory nausea, as evidenced by significantly lower conditioned gaping frequencies relative to animals pre-treated with NaCl followed by LiCl or LiCl+Saccharin. LPS pre-treatment also inhibited the formation of LiCl induced taste avoidance, as evidence by significantly higher saccharin preferences in Group LPS-LiCl+Saccharin relative to Group NaCl-LiCl+Saccharin. The results of the current study provide additional evidence for the deleterious effects of LPS on learning and memory in aversive conditioning. PMID- 22537777 TI - [Classification of disposable medical plastics and search for alternatives without polyvinyl chloride in the Hospital Virgen de las Nieves (Granada, Spain)]. AB - OBJECTIVES: To identify and classify disposable hospital products containing polyvinyl chloride (PVC), including the search and evaluation of cost-effective sustainable alternative products free of PVC. METHODS: A descriptive observational analysis was performed, after classifying the latest research in major databases, and disposable products that could contain PVC. These were divided into 5 groups: cannulas, catheters, tubes, bags, and equipment, purchased in the period 2008-2009, differentiating between the technical and economic assessment of the materials. RESULTS: In the analysis of the composition of 492 articles selected, 234 (47.5%) contained PVC, and 19.4% were considered PVC-free alternatives, with only 11.3% of these being economically viable. CONCLUSIONS: This study highlights the advantages of the classification of PVC products, by showing that safe and efficient alternatives exist for some product lines that are consistent with patient safety and quality in the work by doctors. PMID- 22537778 TI - Evaluation of the antioxidative capability of commonly used antioxidants in dermocosmetics by in vivo detection of protein carbonylation in human stratum corneum. AB - We present an in vivo test platform to evaluate the antioxidative capability of seven frequently used dermocosmetic antioxidants on the human stratum corneum (SC). It has been reported that the protein carbonylation could be used as a biomarker for oxidative stress. The current study detects the change of the level of exposed protein carbonyl group in the most outer layer of human SC. The concentration of the antioxidant in each subject emulsion formulation was 0.5% (w/w). The data indicated that alpha-tocopherol (alpha-Vit E) and ascorbic acid (Vit C) have excellent antioxidative capability and alpha-Vit E-acetate possesses better than the average antioxidative capability. The bioconversion of alpha-Vit E-acetate to alpha-Vit E may occur in the human SC during a less than 2 weeks time course test. Lipoic acid possessed moderate antioxidative capability. Ascorbyl 6-palmitate had a low antioxidative capability. Ascorbic acid 2 glucoside represented an insignificant antioxidative capability. Glutathion (GSH) had no effect on reducing oxidative damage to human SC proteins, implying that the GSH recycling system could be absent in human SC. This test platform is an useful tool to evaluate the antioxidative efficiency of antioxidants on human SC proteins. PMID- 22537779 TI - Reduction of low-density lipoprotein receptor-related protein (LRP1) in hippocampal neurons does not proportionately reduce, or otherwise alter, amyloid deposition in APPswe/PS1dE9 transgenic mice. AB - INTRODUCTION: The low-density lipoprotein receptor-related protein (LRP1) and its family members have been implicated in the pathogenesis of Alzheimer's disease. Multiple susceptibility factors converge to metabolic pathways that involve LRP1, including modulation of the processing of amyloid precursor protein (APP) and the clearance of Abeta peptide. METHODS: We used the Cre-lox system to lower LRP1 levels in hippocampal neurons of mice that develop Alzheimer-type amyloid by crosses between mice that express Cre recombinase under the transcriptional control of the GFAP promoter, mice that harbor loxp sites in the LRP1 gene, and the APPswe/PS1dE9 transgenic model. We compared amyloid plaque numbers in APPswe/PS1dE9 mice lacking LRP1 expression in hippocampus (n = 13) to mice with normal levels of LRP1 (n = 12). Student t-test was used to test whether there were significant differences in plaque numbers and amyloid levels between the groups. A regression model was used to fit two regression lines for these groups, and to compare the rates of Abeta accumulation. RESULTS: Immunohistochemical analyses demonstrated efficient elimination of LRP1 expression in the CA fields and dentate gyrus of the hippocampus. Within hippocampus, we observed no effect on the severity of amyloid deposition, the rate of Abeta40/42 accumulation, or the architecture of amyloid plaques when LRP1 levels were reduced. CONCLUSIONS: Expression of LRP1 by neurons in proximity to senile amyloid plaques does not appear to play a major role in modulating the formation of these proximal deposits or in the appearance of the associated neuritic pathology. PMID- 22537780 TI - Latest chemical peel innovations. AB - For decades, chemical peels have remained a trusted option for treatment of aging facial skin. However, emerging technologies are being adopted by many practitioners who may not have had sufficient opportunity to learn the art of chemical peeling. Properly performed peels can improve the condition of the skin, are less expensive than light-based machines, and exfoliate the skin without the thermal damage associated with light-based machines. This article presents a new variation of a trusted method, using a series of low-strength trichloroacetic acid peels and proper skin preparation that is cost-effective and produces excellent results in selected patients. PMID- 22537781 TI - Latest innovations for tattoo and permanent makeup removal. AB - The goal of this article is to reveal the latest techniques and advances in laser removal of both amateur and professional tattoos, as well as cosmetic tattoos and permanent makeup. Each pose different challenges to the removing physician, but the goal is always the same: removal without sequelae. The authors' technique is detailed, and discussion of basic principles of light reflection, ink properties, effects of laser energy and heat, and outcomes and complications of tattoo removal are presented. PMID- 22537782 TI - Combined fractionated CO2 and low-power erbium:YAG laser treatments. AB - This article addresses the use of fractionated CO(2) laser and erbium:YAG laser for facial rejuvenation. Outcomes and limitations of these techniques are discussed, along with a stepwise summary of techniques as they are used in clinical practice. An evaluation of patient satisfaction is presented for a group of patients who underwent combined fractional CO(2) and erbium:YAG facial resurfacing. PMID- 22537783 TI - Plasma skin resurfacing: personal experience and long-term results. AB - This article presents a comprehensive clinical approach to plasma resurfacing for skin regeneration. Plasma technology, preoperative protocols, resurfacing technique, postoperative care, clinical outcomes, evidence-based results, and appropriate candidates for this procedure are discussed. Specific penetration depth and specific laser energy measurements are provided. Nitrogen plasma skin regeneration is a skin-resurfacing technique that offers excellent improvement of mild to moderate skin wrinkles and overall skin rejuvenation. It also provides excellent improvement in uniformity of skin color and texture in patients with hyperpigmentation with Fitzpatrick skin types 1 through 4. PMID- 22537784 TI - Ulthera: initial and six month results. AB - The Ulthera system is a facial application of intense focused ultrasound developed for improving noninvasive rejuvenation results. This article describes the Ulthera device, its mechanism of action, the indications and limitations of the device, and the details of treatment. We also review the literature and our personal results, discuss future trends, and conclude with advice for the early user. PMID- 22537785 TI - Platelet-rich fibrin matrix for facial plastic surgery. AB - Platelets are known primarily for their role in hemostasis, but there is increasing interest in the effect of platelets on wound healing. Platelet isolates such as platelet-rich plasma have been advocated to enhance and accelerate wound healing. This article describes the use of a novel preparation, platelet-rich fibrin matrix (PRFM), for facial plastic surgery applications such as volume augmentation, fat transfer supplementation, and as an adjunct to open surgical procedures. PMID- 22537786 TI - Combined laser treatment of actinic sun damage and acne scarring. AB - Since its approval for use in 2007, many surgeons have been using the laser for subcutaneous use, primarily for lipolysis, facial neck and body contouring, and skin tightening. Techniques have recently evolved to enable use of the subcutaneous laser with concurrent skin resurfacing techniques for improvement of photoaging and acne or facial scarring. The technique shows great promise in patients with facial aging and photodamage who are not deemed candidates for rhytidectomy surgery. With strict patient-selection criteria of mild to moderate facial laxity and mild to moderate photoaging, the procedure can be gratifying for the surgeon and patient alike. PMID- 22537787 TI - Combining fractional carbon-dioxide laser resurfacing with face-lift surgery. AB - The human face ages in three different ways: tissues descend; the skin develops rhytides, dyschromia, and numerous lesions; and facial volume is lost. Face-lift surgery and skin resurfacing are two of the mainstays of facial rejuvenation. Today, carbon-dioxide laser resurfacing is, arguably, the gold standard for resurfacing the skin. This article describes the rationale and application of simultaneous fractional laser resurfacing with face-lift surgery. The discussion includes the author's technique, preoperative and postoperative regimens, and experience. PMID- 22537788 TI - Cannulas for facial filler placement. AB - With more physicians performing injections to the face in increasingly sophisticated ways, techniques must evolve accordingly. Injectables are no longer mere wrinkle fillers but true panfacial volumizers that are placed in many different planes and tissues of the face, in contrast to fillers of the past used for the dermis. This development is providing better results previously not achievable with off-the-shelf fillers. Microcannulas represent a step forward in enhancing surgeons' ability to fill the face with less discomfort, edema, and ecchymosis, with faster recovery. Microcannulas will probably play a role in volume replacement for many years to come. PMID- 22537789 TI - Combining laser therapies for optimal outcomes in treating the aging face and acne scars. AB - Aging and sun damage of the skin results in skin laxity, rhytides, texture irregularities, dyspigmentation, and vascular changes. Many different laser devices are frequently used to correct these changes from age and photodamage. This article describes the author's experience in combining laser technologies (different wavelengths and applications) in one treatment session to achieve better outcomes with fewer visits for the patient. PMID- 22537790 TI - Adipocyte-derived stem cells for the face. AB - This review gives a basic overview of the current state of fat transplantation in view of adipose-derived stem cells. Current technologies regarding facial rejuvenation are presented, with a brief review of the procedures. PMID- 22537791 TI - Latest innovations in facial plastic surgery: procedures and technology. PMID- 22537792 TI - Deletion of the Ustilago maydis ortholog of the Aspergillus sporulation regulator medA affects mating and virulence through pheromone response. AB - Mating of compatible haploid cells of Ustilago maydis is essential for infection and disease development in the host. For mating and subsequent filamentous growth and pathogenicity, the transcription factor, prf1 is necessary. Prf1 is in turn regulated by the cAMP and MAPK pathways and other regulators like rop1 and hap1. Here we describe the identification of another putative Prf1 regulator, med1, the ortholog of the Aspergillus nidulans medusa (medA) transcription factor and show that it is required for mating and full virulence in U. maydis. med1 deletion mutants show both pre- and post-mating defects and are unresponsive to external pheromone. The expression of prf1 is down-regulated in Deltamed1 compared to the wild type, suggesting that med1 is upstream of prf1. Additionally, indicative of a role in secondary metabolism regulation, deletion of the med1 gene de-represses the production of glycolipids in U. maydis. PMID- 22537793 TI - Disrupted functional brain connectome in individuals at risk for Alzheimer's disease. AB - BACKGROUND: Alzheimer's disease disrupts the topological architecture of whole brain connectivity (i.e., the connectome); however, whether this disruption is present in amnestic mild cognitive impairment (aMCI), the prodromal stage of Alzheimer's disease, remains largely unknown. METHODS: We employed resting-state functional magnetic resonance imaging and graph theory approaches to systematically investigate the topological organization of the functional connectome of 37 patients with aMCI and 47 healthy control subjects. Frequency dependent brain networks were derived from wavelet-based correlations of both high- and low-resolution parcellation units. RESULTS: In the frequency interval .031-.063 Hz, the aMCI patients showed an overall decreased functional connectivity of their brain connectome compared with control subjects. Further graph theory analyses of this frequency band revealed an increased path length of the connectome in the aMCI group. Moreover, the disease targeted several key nodes predominantly in the default-mode regions and key links primarily in the intramodule connections within the default-mode network and the intermodule connections among different functional systems. Intriguingly, the topological aberrations correlated with the patients' memory performance and differentiated individuals with aMCI from healthy elderly individuals with a sensitivity of 86.5% and a specificity of 85.1%. Finally, we demonstrated a high reproducibility of our findings across different large-scale parcellation schemes and validated the test-retest reliability of our network-based approaches. CONCLUSIONS: This study demonstrates a disruption of whole-brain topological organization of the functional connectome in aMCI. Our finding provides novel insights into the pathophysiological mechanism of aMCI and highlights the potential for using connectome-based metrics as a disease biomarker. PMID- 22537795 TI - Onabotulinumtoxin A for idiopathic overactive bladder: raising the bar. PMID- 22537794 TI - R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse. AB - BACKGROUND: (+/-)-Modafinil has piqued interest as a treatment for attention deficit/hyperactivity disorder and stimulant dependence. The R-enantiomer of modafinil might have unique pharmacological properties that should be further investigated. METHODS: (+/-)-Modafinil and its R-(-)- and S-(+)-enantiomers were synthesized and tested for inhibition of [(3)H] dopamine (DA) uptake and [(3)H]WIN 35428 binding in human dopamine transporter (DAT) wild-type and mutants with altered conformational equilibria. Data were compared with cocaine and the atypical DA uptake inhibitor, JHW 007. R- and S-modafinil were also evaluated in microdialysis studies in the mouse nucleus accumbens shell and in a cocaine discrimination procedure. RESULTS: (+/-)-, R-, and S-modafinil bind to the DAT and inhibit DA uptake less potently than cocaine, with R-modafinil having approximately threefold higher affinity than its S-enantiomer. Molecular docking studies revealed subtle differences in binding modes for the enantiomers. R modafinil was significantly less potent in the DAT Y156F mutant compared with wild-type DAT, whereas S-modafinil was affected less. Studies with the Y335A DAT mutant showed that the R- and S-enantiomers tolerated the inward-facing conformation better than cocaine, which was further supported by [2 (trimethylammonium)ethyl]-methanethiosulfonate reactivity on the DAT E2C I159C. Microdialysis studies demonstrated that both R- and S-modafinil produced increases in extracellular DA concentrations in the nucleus accumbens shell less efficaciously than cocaine and with a longer duration of action. Both enantiomers fully substituted in mice trained to discriminate cocaine from saline. CONCLUSIONS: R-modafinil displays an in vitro profile different from cocaine. Future trials with R-modafinil as a substitute therapy with the potential benefit of cognitive enhancement for psychostimulant addiction are warranted. PMID- 22537796 TI - Does comorbidity influence the risk of myocardial infarction or diabetes during androgen-deprivation therapy for prostate cancer? AB - BACKGROUND: Androgen-deprivation therapy (ADT) for prostate cancer (PCa) may be associated with cardiovascular disease and diabetes. Some data suggest that men with certain conditions may be more susceptible to developing cardiovascular disease than others. OBJECTIVE: To assess whether the risk of myocardial infarction (MI) or diabetes during ADT is modified by specific baseline comorbidities. DESIGN, SETTING, AND PARTICIPANTS: We conducted a population-based observational study of 185 106 US men >=66 yr of age diagnosed with local/regional PCa from 1992 to 2007. We assessed comorbidities monthly over the follow-up period. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cox proportional hazards models with time-varying variables assessing incident diabetes or MI. RESULTS AND LIMITATIONS: A total of 49.9% of the men received ADT during follow up. Among men with no comorbidities, ADT was associated with an increase in the adjusted hazard of MI (adjusted hazard ratio [AHR]: 1.09; 95% confidence interval [CI], 1.02-1.16) and diabetes (AHR: 1.33; 95% CI, 1.27-1.39). Risks of MI and diabetes were similarly increased among men with and without specific comorbid illnesses (p>0.10 for all interactions, with one exception). Previous MI, congestive heart failure, peripheral arterial disease, stroke, hypertension, chronic obstructive pulmonary disease, and renal disease were associated with new MI and diabetes, and obesity and rheumatologic disease were also associated with diabetes. Limitations include the observational study design, reliance on administrative data to ascertain outcomes, and lack of information on risk factors such as smoking and family history. CONCLUSIONS: Traditional risk factors for MI and diabetes were also associated with developing these conditions during ADT but did not significantly modify the risk attributable to ADT. Strategies to screen and prevent diabetes and cardiovascular disease in men with PCa should be similar to the strategies recommended for the general population. PMID- 22537797 TI - Histologic variants of upper tract urothelial carcinoma do not affect response to adjuvant chemotherapy after radical nephroureterectomy. PMID- 22537798 TI - Re: Giorgio Guazzoni, Massimo Lazzeri, Luciano Nava, et al. Preoperative prostate specific antigen isoform p2PSA and its derivatives, %p2PSA and Prostate Health Index, predict pathologic outcomes in patients undergoing radical prostatectomy for prostate cancer. Eur Urol 2012;61:455-66. PMID- 22537799 TI - The global limits and population at risk of soil-transmitted helminth infections in 2010. AB - BACKGROUND: Understanding the global limits of transmission of soil-transmitted helminth (STH) species is essential for quantifying the population at-risk and the burden of disease. This paper aims to define these limits on the basis of environmental and socioeconomic factors, and additionally seeks to investigate the effects of urbanisation and economic development on STH transmission, and estimate numbers at-risk of infection with Ascaris lumbricoides, Trichuris trichiura and hookworm in 2010. METHODS: A total of 4,840 geo-referenced estimates of infection prevalence were abstracted from the Global Atlas of Helminth Infection and related to a range of environmental factors to delineate the biological limits of transmission. The relationship between STH transmission and urbanisation and economic development was investigated using high resolution population surfaces and country-level socioeconomic indicators, respectively. Based on the identified limits, the global population at risk of STH transmission in 2010 was estimated. RESULTS: High and low land surface temperature and extremely arid environments were found to limit STH transmission, with differential limits identified for each species. There was evidence that the prevalence of A. lumbricoides and of T. trichiura infection was statistically greater in peri-urban areas compared to urban and rural areas, whilst the prevalence of hookworm was highest in rural areas. At national levels, no clear socioeconomic correlates of transmission were identified, with the exception that little or no infection was observed for countries with a per capita gross domestic product greater than US$ 20,000. Globally in 2010, an estimated 5.3 billion people, including 1.0 billion school-aged children, lived in areas stable for transmission of at least one STH species, with 69% of these individuals living in Asia. A further 143 million (31.1 million school-aged children) lived in areas of unstable transmission for at least one STH species. CONCLUSIONS: These limits provide the most contemporary, plausible representation of the extent of STH risk globally, and provide an essential basis for estimating the global disease burden due to STH infection. PMID- 22537800 TI - A flow cytometric protocol for enumeration of endothelial progenitor cells and monocyte subsets in human blood. AB - BACKGROUND: Accumulating evidence intensively advises circulating endothelial progenitor cells (EPCs) and monocyte subsets as surrogate cellular biomarkers in cardiovascular and cancer disease. However, a general standard on their quantification is still elusive, thus precluding a routine monitoring and comparative interpretation of clinical studies. OBJECTIVE: We intend to develop an advanced and express flow cytometric protocol for proper ex vivo quantification of monocyte subsets and EPCs in human blood. METHODS: We employ now lyse/no-wash procedure and bead-based determination of absolute cell counts. We use three-color antibody panels at appropriate compensation. Analysis of rare events and low antigen expression in the EPC experiment is strengthening by sequential gating with exclusion of dead cells, as well as by matching high intensity fluorochromes to low-density markers and by implementing the fluorescence-minus-one control. RESULTS: Analysis of peripheral blood of ten healthy donors revealed median (IQR) value of 1.88 (1.35-2.85) viable CD45(dim)CD34)VEGFR2+ EPCs per microliter. Analysis of monocytes revealed 329.5 (264.5-374.8), 16.0 (8.0-22.2) and 26.5 (19.8-36.3) cells per microliter for classical CD14++(high))CD16-, intermediate CD14++CD16+(mid) and non-classical CD14+(low))CD16++ monocytes. CONCLUSION: Our current protocol provides quantitative information under a simple gating logic while using commonly accepted fluorochromes. This assay is therefore highly adapted for routine use. PMID- 22537802 TI - Obesity care strategies in primary care practices. AB - We evaluated pediatric obesity clinics for internal referrals developed at 5 primary care offices. Clinics developed site-specific strategies: 1 group approach and 4 clinics providing individualized care only. Clinicians reported patient/family motivation as an important referral consideration and compliance as the greatest challenge and perceive clinics to have provided some help. PMID- 22537801 TI - Atherosclerotic calcification relates to cognitive function and to brain changes on magnetic resonance imaging. AB - BACKGROUND: Increasing evidence suggests a role of atherosclerosis in the pathogenesis of cognitive impairment and dementia. Calcification volume measured with computed tomography (CT) is a valid marker of atherosclerosis. This study investigates associations of atherosclerosis (measured using CT) at four locations with cognition and brain changes on magnetic resonance imaging (MRI). METHODS: To quantify calcification volume, 2414 nondemented people from the Rotterdam Study underwent CT of the coronary arteries, aortic arch, extracranial carotid arteries, and intracranial carotid arteries. To assess global cognition and performance on memory, executive function, information processing speed, and motor speed, they also underwent neuropsychological tests. In a random subgroup of 844 participants, brain MRI was performed. Automated segmentation and quantification of brain MRI scans yielded brain tissue volumes in milliliters. Diffusion tensor imaging was used to measure the microstructural integrity of the white matter. Relationships of atherosclerotic calcification with cognition, brain tissue volumes, and diffusion tensor imaging measures were assessed with linear regression models and adjusted for relevant confounders. RESULTS: With larger calcification volumes, lower cognitive scores were observed. When calcification volumes were larger, total brain volumes were also smaller. Specifically, larger coronary artery calcification volumes related to smaller gray matter volumes, and extracranial and intracranial carotid calcification volumes related to smaller white matter volumes. Larger calcification volume in all vessel beds was accompanied by worse microstructural integrity of the white matter. CONCLUSIONS: Larger calcification volume is associated with worse cognitive performance. It also relates to smaller brain tissue volumes and worse white matter microstructural integrity, revealing possible mechanisms through which atherosclerosis may lead to poorer cognition. PMID- 22537803 TI - Predictive value of adenosine 5'-monophosphate challenge in preschool children for the diagnosis of asthma 5 years later. AB - We evaluated the predictive values of preschool bronchial challenge with nebulized adenosine 5'-monophosphate (AMP) using the auscultation method for having asthma 5 years later. Preschool AMP challenge had a high negative (90%) and a moderate positive (67%) predictive value for asthma 5 years later. Positive predictive value increased with the age at which the challenge was performed. The degree of preschool response to AMP was associated with the severity of asthma at school age. PMID- 22537804 TI - Characterization of CD34+ thymocytes in newborn dogs. AB - Using two-color flow cytometry, we characterized CD34(+) cells in the newborn canine thymus. CD34(+) thymic cells comprised approximately 5% of cells recovered by thymus tissue teasing and both large and small thymocytes have been present in this population, the former being 7-12 times more frequent. All CD34(+) cells expressed the pan-leukocyte antigen CD45. The expression of CD44 profile on the large and small CD34(+) thymocytes differed: almost all large CD34(+) cells were CD44(+), while only 75% of small CD34(+) thymocytes co-expressed the CD44 antigen. We have previously described that CD172alpha is present on the surface of CD34(+) bone marrow cells in dogs. In the thymus, CD172alpha was expressed on 5-10% and less than 5% of large and small CD34(+) cells, respectively. Some CD34(+) thymocytes also co-expressed T-lineage-specific markers like CD3, CD4, CD8, TCR1 and TCR2. Their expression increased during the large-to-small thymocyte transition. Based on our findings we suggest that thymocyte progenitors enter their primary differentiation center as large CD34(+), CD44(+), CD45(+) and CD172alpha(+) cells. T-cell specific markers appear on their surface at early stages of differentiation. As the size of progenitors decreases with terminal primary differentiation, the CD34, CD44, and CD172alpha surface markers are down regulated. PMID- 22537805 TI - Colon cancer stem cells--from basic to clinical application. AB - Based on cancer stem cell (CSC) concept of carcinogenesis, tumors represent complex heterogeneous organ-like systems with a hierarchical cellular organization, and only minority phenotypic subpopulations with stem-like properties possess a dual ability to self-renew indefinitely and produce all the heterogeneous cell phenotypes comprising the bulk tumor cells. Large experimental and clinical data indicate that conventional anti-cancer therapies cannot eradicate CSCs, and moreover, they usually increase their number leading to cancer recurrence and further drug resistance. In this review, several current controversies in the CSC field and recent studies, which help to shed light on their origin, are discussed. The emerging necessity for the development of complex, multimodal CSC-targeted treatment strategies, which combine conventional therapeutics with promising pathway-specific modulators, and natural compounds, which can improve the efficacy of conventional anti-cancer therapeutics and decrease their undesirable side effects is presented. Also, novel requirements and criteria necessary for evaluation of the CSC-targeted drug efficacy and relevant experimental models are discussed. PMID- 22537806 TI - Lyophilization of cholesterol-free PEGylated liposomes and its impact on drug loading by passive equilibration. AB - The obstacles in translating liposome formulations into marketable products could be attributed to their physical instabilities upon long-term storage as aqueous dispersions. Lyophilization is the most commonly used technique to improve physical stability of liposomes. The development of stable, lyophilized liposomes is focused primarily on the cholesterol-containing liposomes or pure phosphatidylcholine-based liposomes, with minimal studies on cholesterol-free, pegylated (CF-PEG) liposomes which have emerged as an important class of liposome drug carriers. Hence, it is our interest to investigate the effect of lyophilization on CF-PEG liposomes, and specifically, on drug loading via the passive equilibration method. Three different sugar cryoprotectants were used at two different sugar-to-lipid molar ratios (S/L). Our results demonstrated that CF PEG liposomes lyophilized with sucrose at S/L=5:1 yielded the best cryoprotective effect, as characterized by size, polydispersity indices, and microscopic examination upon liposome reconstitution. The lyophilized liposomes had low water content of 2.59 +/- 0.18%. Of note, lyophilized CF-PEG liposomes exhibited two fold increase in drug content when carboplatin was loaded via the passive equilibration method, and the in vitro drug release profile of these liposomes were not different from that of the non-lyophilized counterparts. Taken together, we envisioned that a stable, lyophilized empty CF-PEG liposome system could be coupled to hydrophilic drug loading via the passive equilibration method to produce a liposomal drug kit product. PMID- 22537807 TI - Formation mechanism of a new carbamazepine/malonic acid cocrystal polymorph. AB - A new 2/1 carbamazepine (CBZ)/malonic acid (MA) cocrystal polymorph form C was formed using a vibrational rod mill, whereas the known cocrystal polymorph form A was prepared using a ball mill. IR measurements showed that the interaction between CBZ and MA in cocrystal form C was formed by amide-carboxylic acid heterosynthons, similar to that in cocrystal form A. However, NMR results showed that the molecular states of CBZ at the dibenzazepine ring appeared to be different, which could be due to variation in either the conjugation of the aromatic rings or the pi-pi interaction of CBZ. Factors affecting the formation of cocrystal polymorphs, such as heat and force, were investigated to clarify the formation mechanism. PMID- 22537808 TI - Photodynamic therapy using glycol chitosan grafted fullerenes. AB - Glycol chitosan (GC)-grafted fullerene (GC-g-C(60)) conjugates were developed for use in photodynamic therapy of tumor cells. GC-g-C(60) was synthesized in anhydrous benzene/dimethylsulfoxide (DMSO) co-solvent via the chemical conjugation of free amine groups of GC to CC double bonds of C(60). The GC-g C(60) with 5*10(-4) C(60) molecules per one repeating unit of GC was soluble in water. As C(60) molecules conjugated to GC increased to 0.16 molecules per one repeating unit of GC, GC-g-C(60) started to form supramolecular assemblies (~30 nm) stabilized in phosphate buffer saline (PBS, 150 mM, pH 7.4). Upon 670 nm light illumination, photo-responsive properties of GC-g-C(60) allowed tremendous singlet oxygen generation in tumor cells for super phototoxicity. GC-g-C(60) also showed highly increased tumor accumulation ability for in vivo tumor of KB tumor bearing nude mice. It is expected that our GC-g-C(60) conjugate may be a good candidate for in vivo photodynamic therapy in various malignant tumor cells. PMID- 22537809 TI - Influence of N-linked glycosylation of minor proteins of porcine reproductive and respiratory syndrome virus on infectious virus recovery and receptor interaction. AB - It has been proposed that the N-linked glycan of the minor proteins of porcine reproductive and respiratory syndrome virus (PRRSV) is important for the production of infectious virus. In this study, we showed that N-linked glycosylation of GP2 is not essential for virus viability and none of the individual glycosylation sites in GP3 has a vital effect on the production of infectious virus. Moreover, mutations of single and double glycosylation sites in GP4 are not critically important for infectious virus recovery, triple and quadruple mutations are lethal. The bimolecular fluorescence complementation (BiFC) analysis also showed that GP4, but might be not GP2, is involved in interaction with cellular receptor CD163 and that glycosylation of GP4 might not play a vital role in the interaction with CD163. The study further revealed that none of the N-glycosylation sites in the minor proteins is critical for the susceptibility of mutants to neutralizing antibody. PMID- 22537811 TI - Human herpesvirus 6 glycoprotein M is essential for virus growth and requires glycoprotein N for its maturation. AB - Human herpesvirus 6 (HHV-6) is a T-lymphotropic virus belonging to the betaherpesvirus family. Several HHV-6-encoded glycoproteins are required for cell entry and virion maturation. Glycoprotein M (gM) is conserved among all herpesviruses, and therefore thought to have important functions; however, the HHV-6 g has not been characterized. Here, we examined the expression of HHV-6 g, and examined its function in viral replication, using a mutant and revertant gM. HHV-6 g was expressed on virions as a glycoprotein modified with complex N-linked oligosaccharides. As in other herpesviruses, HHV-6 g formed a complex with glycoprotein N (gN), and was transported from the endoplasmic reticulum to the trans-Golgi network only when part of this complex. Finally, a gM mutant virus in which the gM start codon was destroyed was not reconstituted, although its revertant was, indicating that HHV-6 g is essential for virus production, unlike the gM of alphaherpesviruses. PMID- 22537810 TI - Antibodies targeting dengue virus envelope domain III are not required for serotype-specific protection or prevention of enhancement in vivo. AB - The envelope (E) protein of dengue virus (DENV) is composed of three domains (EDI, EDII, EDIII) and is the main target of neutralizing antibodies. Many monoclonal antibodies that bind EDIII strongly neutralize DENV. However in vitro studies indicate that anti-EDIII antibodies contribute little to the neutralizing potency of human DENV-immune serum. In this study, we assess the role of anti EDIII antibodies in mouse and human DENV-immune serum in neutralizing or enhancing DENV infection in mice. We demonstrate that EDIII-depleted human DENV immune serum was protective against homologous DENV infection in vivo. Although EDIII-depleted DENV-immune mouse serum demonstrated decreased neutralization potency in vitro, reduced protection in some organs, and enhanced disease in vivo, administration of increased volumes of EDIII-depleted serum abrogated these effects. These data indicate that anti-EDIII antibodies contribute to protection and minimize enhancement when present, but can be replaced by neutralizing antibodies targeting other epitopes on the dengue virion. PMID- 22537812 TI - T-tube drainage of the common bile duct choleperitoneum: etiology and management. AB - External drainage of the common bile duct by placement of a T-tube is a common practice after choledochotomy. This practice may result in the specific complication of bile peritonitis due to leakage after removal of the T-tube. This complication has multiple causes: some are patient-related (corticotherapy, chemotherapy, ascites), and others are due to technical factors (inappropriate suturing of the drain to the ductal wall, minimal inflammatory reaction related to some drain materials). The clinical presentation is quite variable depending on the amount and rapidity of intra-peritoneal spread of of bile leakage. Abdominal ultrasound (US), with US-guided needle aspiration and occasionally Technetium(99) scintigraphy are useful for diagnosis. Traditional therapy consists of surgical intervention including peritoneal lavage and re-intubation of the choledochal fistulous tract to allow for a further period of external drainage. When leakage is walled off and well-tolerated, a more nuanced and less invasive conservative therapy may combine percutaneous drainage with endoscopic placement of a trans-ampullary biliary drainage. PMID- 22537813 TI - Posttraumatic stress symptoms in children diagnosed with type 1 diabetes. AB - BACKGROUND: Studies consistently found remarkable rates of posttraumatic stress symptoms (PTSS) in children with chronic diseases. But, only one study had searched PTSS in children with diabetes, until now. So, the present study aimed to examine incidence rate and predictors of PTSS in children with type 1 diabetes. METHOD: PTSS were evaluated by Child Posttraumatic Stress Reaction Index in fifty four children with diabetes (aged between 8-18 years). This assessment was based on hypoglycaemia as the potential traumatic event. Children were also introduced a brief questionnaire about demographic and disease related information. Some other information was obtained from families, medical stuff and records. Among 54 children, forty two had complete information. Hence, to evaluate possible predictive factors related with PTSS, multiple regression analysis was conducted for 42 children. RESULTS: 18.5% of children were reported PTSS at severe or very severe level, and 51.9% were reported PTSS at moderate level or above. Multiple regression analyses were shown that child PTSS were not significantly related with possible predictive factors other than number of hypoglycaemic attacks for the last month. CONCLUSION: The study results support that posttraumatic stress symptoms are not rarely seen in paediatric patients with diabetes, and even if not severe, hypoglycaemic attacks may be perceived as traumatic by the children with diabetes. But, because of some limitations, the results should be carefully interpreted. PMID- 22537814 TI - Evaluation of preparatory psychosocial counselling for medically assisted reproduction. AB - BACKGROUND: This study evaluated couples' perceptions of preparatory psychosocial counselling prior to participation in medically assisted reproduction (MAR). METHODS: Eighty-three couples about to undergo IUI treatment were asked about their expectations regarding a subsequent single psychosocial counselling session and assessed in terms of their levels of infertility-specific stress, anxiety and depressive symptoms. Afterwards, participants rated their satisfaction with different elements of the session. RESULTS: Almost two-thirds of women and one half of men expected counselling to be important, and the majority anticipated that the session would be helpful and informative. Views of preparatory counselling were significantly more positive afterwards, indicating that a focused session addressing issues of treatment concerns, goal setting and managing infertility stress was more beneficial than anticipated. Those experiencing higher levels of infertility-specific stress expected the counselling session to be more important, and elevated stress and greater utilization of social support were predictive of post-counselling satisfaction. CONCLUSIONS: Preparatory psychosocial counselling provided with a specific and practical focus appears to be a potentially important and helpful service prior to MAR. Clinics should not assume that patients can accurately judge the benefits of counselling before actually engaging in the session. Identifying patients most likely to benefit and providing a clear rationale may further increase receptivity to this proactive counselling service. While patients characterize this intervention as beneficial, it is not yet known if these benefits translate into improved management of treatment procedures. PMID- 22537815 TI - Expression of leukaemia inhibitory factor and interleukin 15 in endometrium of women with recurrent implantation failure after IVF; correlation with the number of endometrial natural killer cells. AB - BACKGROUND: Several studies have suggested that endometrial interleukin 15 (IL 15) and the leukaemia inhibitory factor (LIF) may be important in embryo implantation. IL-15 is postulated to play a role in the control of uterine natural killer (uNK) cell proliferation and function, and uNK cells are also known to play a role in implantation. The aims of this study was to (1) compare endometrial levels of IL-15 and the LIF in women with recurrent implantation failure (RIF) after IVF with those in fertile women (controls) and (2) examine the relation of IL-15 and LIF levels to the uNK cell number. METHODS: We investigated IL-15 and LIF in precisely timed endometrial biopsies (days LH + 7 LH + 9, where the day of the LH surge is LH + 0) obtained from control women (n = 15) and women with RIF (n = 45) by immunohistochemistry. A semi-quantitative analysis was performed by the H-score analysis of staining intensity in the stroma, glandular epithelium and luminal epithelium, separately. We also correlated expression of LIF and IL15 with uNK cell numbers (obtained in an earlier study of the same samples). RESULTS: The quantity of the LIF protein in endometrial glandular epithelium in women with RIF [median and range; 179 (70 365)] was lower (P = 0.01) than in control women [median and range; 247 (120 287)]. In contrast, the level of the IL-15 protein in the stroma in women with RIF [median and range; 90 (0-175)] was higher (P = 0.009) than in control women [median and range; 60 (15-150)]. There was a significant correlation between the uNK cell number and stromal expression of IL-15 (r = 0.427, P = 0.001). No correlation between the LIF expression in any compartment and the uNK cell number was seen. CONCLUSIONS: The results show an altered expression of LIF and IL-15 in the endometrium of women with RIF. Despite the limitation of not identifying uNK cells by phenotypic markers, the correlation between the uNK cell number and the stromal cell IL-15 suggests that IL-15 may play a role in the control of endometrial uNK cell function or proliferation. PMID- 22537817 TI - Sperm DNA fragmentation index does not correlate with the sperm or embryo aneuploidy rate in recurrent miscarriage or implantation failure patients. AB - BACKGROUND: The aneuploidy rate is higher in poor-quality sperm samples, which also have higher DNA fragmentation index values. The aim of this study was to assess the relationship between sperm DNA fragmentation in samples from infertile men belonging to couples with recurrent miscarriage or implantation failure and the aneuploidy rate in spermatozoa as well as in embryos from patients. METHODS: This prospective study evaluated DNA damage and the aneuploidy rate in fresh and processed (density gradient centrifugation) ejaculated sperm as well as the aneuploidy rate in biopsied embryos from fertility cycles. Fluorescence in situ hybridization was used for the aneuploidy analysis. Results were compared using linear regression and analysis of variance. RESULTS: A total of 154 embryos were evaluated from 38 patients undergoing PGD cycles; 35.2% of the embryos were chromosomally normal. Analysis of the same sperm samples showed an increased DNA fragmentation after sperm preparation in 76% of the patients. There was no correlation between DNA fragmentation and the aneuploidy rate in embryos or in fresh or processed sperm samples. CONCLUSIONS: Sperm DNA fragmentation is not related to chromosomal anomalies in embryos from patients with recurrent miscarriage or implantation failure. However, we cannot rule out the possibility that a relationship between DNA fragmentation and aneuploidy exists for other causes of infertility. Furthermore, the different methods used to evaluate DNA fragmentation may produce different results. PMID- 22537818 TI - Polymorphisms in adiposity-related genes are associated with age at menarche and menopause in breast cancer patients and healthy women. AB - STUDY QUESTION: Is there any effect of genetic polymorphisms in adiposity-related genes on the timing of menarche and menopause and the total duration of menstruation among Korean women? SUMMARY ANSWER: Our results suggest that the adiposity-related genes LEP, LEPR and PPARgamma may play a role in the onset and cessation of menstruation, and the total duration of menstruation. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Previous candidate-gene approaches have mainly presented the results for genes related to the estrogen metabolism pathway. Most genes of interest that participate in steroid-hormone metabolism, such as estrogen receptor alpha and estrogen receptor beta, have been associated with age at menarche and menopause. This study shows the possibility that adiposity related genes also influence the duration of menstruation. PARTICIPANTS AND SETTING: We recruited 400 breast cancer patients and 452 healthy participants from a case-control study at the Center for Breast Cancer, National Cancer Center in Korea. Ten single nucleotide polymorphisms (SNPs) in the leptin (LEP), leptin receptor (LEPR) and peroxisome proliferator-activated receptor gamma (PPARgamma) genes were investigated to evaluate their possible effects on menstruation. Associations between SNPs and age at menarche, age at menopause and duration of menstruation were evaluated. MAIN RESULTS: Four SNPs (rs2167270 of LEP, rs7602 of LEPR and rs4684846 and rs3856806 of PPARgamma) were associated with late menarche (>= 17-year-old). Four SNPs (rs2167270 of LEP and rs1801282, rs2120825, and rs3856806 of PPARgamma) were associated with early menopause (<40-year-old) among post-menopausal women. In logistic regression models with covariate adjustment, women with the GG genotype of rs7602 (LEPR) had a higher risk for late menarche [odds ratio (OR) = 1.83, 95% confidence interval (CI) = 1.01-3.31] compared with their counterparts carrying the GA or AA genotypes. In addition, the GG genotype of rs2167270 (LEP) was inversely associated with a duration of menstruation of <30 years (OR = 0.59, 95% CI = 0.31-1.00) compared with the GA or AA genotypes. BIAS, LIMITATIONS AND GENERALIZABILITY TO OTHER POPULATIONS: We obtained information on the age at menarche and menopause from self-administered questionnaires, and some participants might have had difficulty in remembering their age at menarche and menopause. However, this is a non-differential misclassification and should not appreciably affect the interpretation of the results of this study. PMID- 22537819 TI - Rapid detection of viable Bacillus pumilus SAFR-032 encapsulated spores using novel propidium monoazide-linked fluorescence in situ hybridization. AB - The survival of Bacillus pumilus SAFR-032 spores to standard industrial clean room sterilization practices necessitates the development of rapid molecular diagnostic tool(s) for detection and enumeration of viable bacterial spores in industrial clean room environments. This is of importance to maintaining the sterility of clean room processing products. This paper describes the effect of propidium monoazide (PMA) on fluorescence in situ hybridization (FISH) for detecting and enumerating B. pumilus SAFR-032 viable spores having been artificially encapsulated within poly(methylmethacrylate) (Lucite, Plexiglas) and released via an organic solvent (PolyGone-500). The results of the PMA-FISH experiments discussed herein indicate that PMA was able to permeate only the compromised coat layers of non-viable spores, identifying PMA treatment of bacterial spores prior to FISH analysis as a novel method for selecting out the fraction of the spore population that is non-viable from fluorescence detection. The ability of novel PMA-FISH to selectively distinguish and enumerate only the living spores present in a sample is of potential significance for development of improved strategies to minimize spore-specific microbial burden in a given environment. PMID- 22537820 TI - Quantification of Pseudomonas aeruginosa hydrogen cyanide production by a polarographic approach. AB - Pseudomonas aeruginosa is an opportunistic pathogen responsible for numerous infections acquired in hospital especially in persons whose immune systems are weakened, such as with patient suffering from AIDS or cystic fibrosis. This bacterium produces a great diversity of virulence factors among them hydrogen cyanide (HCN) which is one of the most potent and toxic. A precise quantification of HCN or CN(-) ion is essential to understand the involvement of this toxin in the pathogenesis of P. aeruginosa. In the present study, we present a new technique based on a polarographic approach to measure the production kinetics of HCN/CN(-) by P. aeruginosa strains, in several media commonly used in microbiology labs. The method was validated using mutants (hcnB- and hcnC-) which are unable to produce detectable HCN/CN(-). The kinetics of HCN/CN(-) production by P. aeruginosa in Luria Bertani (LB) medium showed a parabolic shape with a peak observed at 4, 5 and 8h for strains PA14, PAO1 and MPAO1, respectively. When bacteria were grown in ordinary nutrient broth (ONB) 2.5% medium, a less adapted medium for bacterial growth, the general profile of the kinetics was conserved but peak production was delayed (10 and 12h for PAO1 and MPAO1, respectively). When the bacteria were cultured in minimum medium MMC, bacterial growth was particularly slow and HCN/CN(-) production was markedly reduced. Taken together, this new polarographic method appears as a useful technique to detect and quantify HCN/CN(-) in routine media where the bacteria can express and regulate high amounts of toxins. With this method, we demonstrate that HCN/CN(-) production by P. aeruginosa is maximal at the end of the exponential growth phase and depends on the richness of the growth medium used. PMID- 22537821 TI - A gel-free proteomic-based method for the characterization of Bordetella pertussis clinical isolates. AB - Bordetella pertussis (Bp) is the etiologic agent of pertussis or whooping cough, a highly contagious respiratory disease occurring primarily in infants and young children. Although vaccine preventable, pertussis cases have increased over the years leading researchers to re-evaluate vaccine control strategies. Since bacterial outer membrane proteins, comprising the surfaceome, often play roles in pathogenesis and antibody-mediated immunity, three recent Bp circulating isolates were examined using proteomics to identify any potential changes in surface protein expression. Fractions enriched for outer membrane proteins were digested with trypsin and the peptides analyzed by nano liquid chromatography-electrospray ionization-mass spectrometry (nLC-ESI-MS), followed by database analysis to elucidate the surfaceomes of our three Bp isolates. Furthermore, a less labor intensive non-gel based antibody affinity capture technology in conjunction with MS was employed to assess each Bp strains' immunogenic outer membrane proteins. This novel technique is generally applicable allowing for the identification of immunogenic surface expressed proteins on pertussis and other pathogenic bacteria. PMID- 22537822 TI - Identification of non-specific hybridization using an empirical equation fitted to non-equilibrium dissociation curves. AB - Non-equilibrium dissociation curves (NEDCs) have the potential to identify non specific hybridizations on high throughput, diagnostic microarrays. We report a simple method for the identification of non-specific signals by using a new parameter that does not rely on comparison of perfect match and mismatch dissociations. The parameter is the ratio of specific dissociation temperature (T(d-w)) to theoretical melting temperature (T(m)) and can be obtained by automated fitting of a four-parameter, sigmoid, empirical equation to the thousands of curves generated in a typical experiment. The curves fit perfect match NEDCs from an initial experiment with an R(2) of 0.998+/-0.006 and root mean square of 108+/-91 fluorescent units. Receiver operating characteristic curve analysis showed low temperature hybridization signals (20-48 degrees C) to be as effective as area under the curve as primary data filters. Evaluation of three datasets that target 16S rRNA and functional genes with varying degrees of target sequence similarity showed that filtering out hybridizations with T(d w)/T(m)<0.78 greatly reduced false positive results. In conclusion, T(d-w)/T(m) successfully screened many non-specific hybridizations that could not be identified using single temperature signal intensities alone, while the empirical modeling allowed a simplified approach to the high throughput analysis of thousands of NEDCs. PMID- 22537823 TI - Predicting warfarin dosage from clinical data: a supervised learning approach. AB - OBJECTIVE: Safety of anticoagulant administration has been a primary concern of the Joint Commission on Accreditation of Healthcare Organizations. Among all anticoagulants, warfarin has long been listed among the top ten drugs causing adverse drug events. Due to narrow therapeutic range and significant side effects, warfarin dosage determination becomes a challenging task in clinical practice. For superior clinical decision making, this study attempts to build a warfarin dosage prediction model utilizing a number of supervised learning techniques. METHODS AND MATERIALS: The data consists of complete historical records of 587 Taiwan clinical cases who received warfarin treatment as well as warfarin dose adjustment. A number of supervised learning techniques were investigated, including multilayer perceptron, model tree, k nearest neighbors, and support vector regression (SVR). To achieve higher prediction accuracy, we further consider both homogeneous and heterogeneous ensembles (i.e., bagging and voting). For performance evaluation, the initial dose of warfarin prescribed by clinicians is established as the baseline. The mean absolute error (MAE) and standard deviation of errors (sigma(E)) are considered as evaluation indicators. RESULTS: The overall evaluation results show that all of the learning based systems are significantly more accurate than the baseline (MAE=0.394, sigma(E)=0.558). Among all prediction models, both Bagged Voting (MAE=0.210, sigma(E)=0.357) with four classifiers and Bagged SVR (MAE=0.210, sigma(E)=0.366) are suggested as the two most effective prediction models due to their lower MAE and sigma(E). CONCLUSION: The investigated models can not only facilitate clinicians in dosage decision-making, but also help reduce patient risk from adverse drug events. PMID- 22537825 TI - Making beta cells from adult tissues. AB - beta-Cell replacement represents an attractive prospect for diabetes therapy. Although much hope has been placed on derivation of insulin-producing cells from human pluripotent stem cells, this approach continues to face considerable challenges. Cells from adult human tissues, with both stem/progenitor and mature phenotypes, offer a possible alternative. This review summarizes recent progress in two major strategies based on this cell source, ex vivo expansion of human islet beta cells and conversion of non-beta cells into insulin-producing cells by nuclear reprogramming, and examines the obstacles that remain to be overcome for bringing these strategies closer to clinical application in diabetes therapy. PMID- 22537826 TI - [Oropharyngeal candidiasis and radiotherapy]. AB - The oropharyngeal candidiasis is a common condition in cancer patients treated by irradiation, during and after their treatment. For example, almost 70% of patients treated with chemoradiation for head and neck cancer are colonized, and 40% of symptomatic patients have an oropharyngeal candidiasis. Furthermore, we noticed an increase in non-albicans Candida strains, which are present in almost 50% of samples. Cancer treatments, especially radiation therapy, and comorbidities are risk factors of oropharyngeal candidiasis. Oropharyngeal candidiasis has substantial effects on quality of life, and may limit treatment. Epidemiologic data, physiopathology, clinical diagnosis criteria, consequences and treatment of oropharyngeal candidiasis will be discussed in this article. PMID- 22537824 TI - Smoking interacts with HLA-DRB1 shared epitope in the development of anti citrullinated protein antibody-positive rheumatoid arthritis: results from the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA). AB - INTRODUCTION: Rheumatoid arthritis (RA) is a multifactorial autoimmune disease in which genetic and environmental factors interact in the etiology. In this study, we investigated whether smoking and HLA-DRB1 shared-epitope (SE) alleles interact differently in the development of the two major subgroups of rheumatoid arthritis (RA), anti-citrullinated proteins antibody (ACPA)-positive and ACPA-negative disease, in a multiethnic population of Asian descent. METHODS: A case-control study comprising early diagnosed RA cases was carried out in Malaysia between 2005 and 2009. In total, 1,076 cases and 1,612 matched controls participated in the study. High-resolution HLA-DRB1 genotyping was performed for shared-epitope (SE) alleles. All participants answered a questionnaire on a broad range of issues, including smoking habits. The odds ratio (OR) of developing ACPA-positive and ACPA-negative disease was calculated for smoking and the presence of any SE alleles separately. Potential interaction between smoking history (defined as "ever" and "never" smoking) and HLA-DRB1 SE alleles also was calculated. RESULTS: In our multiethnic study, both the SE alleles and smoking were associated with an increased risk of developing ACPA-positive RA (OR SE alleles, 4.7; 95% confidence interval (CI), 3.6 to 6.2; OR smoking, 4.1; 95% CI, 1.9 to 9.2). SE-positive smokers had an odds ratio of ACPA-positive RA of 25.6 (95% CI, 10.4 to 63.4), compared with SE-negative never-smokers. The interaction between smoking and SE alleles was significant (attributable proportion due to interaction (AP) was 0.7 (95% CI, 0.5 to 1.0)). The HLA-DRB1*04:05 SE allele, which is common in Asian populations, but not among Caucasians, was associated with an increased risk of ACPA-positive RA, and this allele also showed signs of interaction with smoking (AP, 0.4; 95% CI, -0.1 to 0.9). Neither smoking nor SE alleles nor their combination was associated with an increased risk of ACPA-negative RA. CONCLUSIONS: The risk of developing ACPA-positive RA is associated with a strong gene-environment interaction between smoking and HLA-DRB1 SE alleles in a Malaysian multiethnic population of Asian descent. This interaction seems to apply also between smoking and the specific HLA-DRB1*04:05 SE allele, which is common in Asian populations but not in Caucasians. PMID- 22537827 TI - Barrel cortical neurons and astrocytes coordinately respond to an increased whisker stimulus frequency. AB - BACKGROUND: Nerve cells program the brain codes to manage well-organized cognitions and behaviors. It remains unclear how a population of neurons and astrocytes work coordinately to encode their spatial and temporal activity patterns in response to frequency and intensity signals from sensory inputs. RESULTS: With two-photon imaging and electrophysiology to record cellular functions in the barrel cortex in vivo, we analyzed the activity patterns of neurons and astrocytes in response to whisker stimuli with increasing frequency, an environmental stimulus pattern that rodents experience in the accelerated motion. Compared to the resting state, whisker stimulation caused barrel neurons and astrocytes to be activated more synchronously. An increased stimulus frequency up-regulated the activity strength of neurons and astrocytes as well as coordinated their interaction. The coordination among the barrel neurons and astrocytes was fulfilled by increasing their functional connections. CONCLUSIONS: Our study reveals that the nerve cells in the barrel cortex encode frequency messages in whisker tactile inputs through setting their activity coordination. PMID- 22537828 TI - Network dynamics in nociceptive pathways assessed by the neuronal avalanche model. AB - BACKGROUND: Traditional electroencephalography provides a critical assessment of pain responses. The perception of pain, however, may involve a series of signal transmission pathways in higher cortical function. Recent studies have shown that a mathematical method, the neuronal avalanche model, may be applied to evaluate higher-order network dynamics. The neuronal avalanche is a cascade of neuronal activity, the size distribution of which can be approximated by a power law relationship manifested by the slope of a straight line (i.e., the alpha value). We investigated whether the neuronal avalanche could be a useful index for nociceptive assessment. FINDINGS: Neuronal activity was recorded with a 4 * 8 multichannel electrode array in the primary somatosensory cortex (S1) and anterior cingulate cortex (ACC). Under light anesthesia, peripheral pinch stimulation increased the slope of the alpha value in both the ACC and S1, whereas brush stimulation increased the alpha value only in the S1. The increase in alpha values was blocked in both regions under deep anesthesia. The increase in alpha values in the ACC induced by peripheral pinch stimulation was blocked by medial thalamic lesion, but the increase in alpha values in the S1 induced by brush and pinch stimulation was not affected. CONCLUSIONS: The neuronal avalanche model shows a critical state in the cortical network for noxious-related signal processing. The alpha value may provide an index of brain network activity that distinguishes the responses to somatic stimuli from the control state. These network dynamics may be valuable for the evaluation of acute nociceptive processes and may be applied to chronic pathological pain conditions. PMID- 22537829 TI - Distinct time courses of microglial and astrocytic hyperactivation and the glial contribution to pain hypersensitivity in a facial cancer model. AB - Although recent evidence suggests that central glial hyperactivation is involved in cancer-induced persistent pain, the time course of this hyperactivation and the glial contribution to pain hypersensitivity remain unclear. The present study investigated the time-dependent spatial changes of microglial and astrocytic hyperactivation in the trigeminocervical complex, which consists of the medullary (MDH) and upper cervical (UCDH) dorsal horns, and pain-related behaviors in a rat facial cancer model in which Walker 256B-cells are inoculated into the vibrissal pad. In this model, the tumors grew within the vibrissal pad, from which sensory nerve fibers project into the MDH, but did not expand into the infraorbital region, from which fibers project into the UCDH. Nevertheless, mechanical allodynia and thermal hyperalgesia were observed not only in the vibrissal pad but also in the infraorbital region. Western blotting and immunofluorescence studies indicated that microglia were widely activated in the trigeminocervical complex on day 4 and gradually inactivated by day 11. In contrast, astrocytes were only activated in the MDH on day 4; the hyperactivation later expanded into the UCDH. Daily administration of the glial hyperactivation inhibitor propentofylline beginning on day 4 suppressed the glial hyperactivation on later days. Propentofylline treatment largely prevented allodynia/hyperalgesia in the infraorbital region beginning on day 5, although established allodynia/hyperalgesia in the vibrissal pad was less sensitive to the treatment. These results suggest that central glial hyperactivation, transient microglial hyperactivation and persistent astrocytic hyperactivation, contributes to the development of pain hypersensitivity but not to the maintenance of pain in this model. PMID- 22537830 TI - The relationship between subjective wellbeing, low income and substance use among schoolchildren in the north west of England: a cross-sectional study. AB - BACKGROUND: The consumption of tobacco, alcohol and illegal drugs by young people is a public health concern. This study aimed to explore the associations between subjective wellbeing, living in a low-income household and substance use by schoolchildren. METHODS: Data were analysed from a nationally representative cross-sectional survey of schoolchildren in England (Tellus4, 2009). Participants were 3903 children aged 10 and 15 years from two local authorities in the North West. Eligibility for free school meals provided a proxy for living in a low income household. Multiple logistic regression was conducted with the main outcome measure, a composite indicator of self-reported regular substance use. RESULTS: More boys than girls had experimented with drugs or alcohol, but in the fourth year of secondary education, girls were significantly more likely than boys to have been drunk (P <= 0.001). In the multivariate analysis, older age was the most important factor associated with the consumption of substances. Living in a low-income household was associated with substance use, adjusting for age and subjective wellbeing (adj. OR = 1.78, 95% CI = 1.36-2.34). Respondents who reported being happy (adj. OR = 0.67, 95% CI = 0.52-0.86) or able to communicate with their family (adj. OR = 0.51, 95% CI = 0.39-0.65), were less likely to be regular users. CONCLUSIONS: Interventions to prevent regular substance use should be carefully targeted by age. Policies aimed at social determinants may be an important adjunct to individual-level interventions to reduce some inequalities in health associated with substance misuse. PMID- 22537831 TI - Centrally administered bombesin activates COX-containing spinally projecting neurons of the PVN in anesthetized rats. AB - The paraventricular nucleus (PVN) of the hypothalamus has a heterogenous structure containing different types of output neurons that project to the median eminence, posterior pituitary, brain stem autonomic centers and sympathetic preganglionic neurons in the spinal cord. Presympathetic neurons in the PVN send mono- and poly-synaptic projections to the spinal cord. In the present study using urethane-anesthetized rats, we examined the effects of centrally administered bombesin (a homologue of the mammalian gastrin-releasing peptide) on the mono-synaptic spinally projecting PVN neurons pre-labeled with a retrograde tracer Fluoro-Gold (FG) injected into T8 level of the spinal cord, with regard to the immunoreactivity for cyclooxygenase (COX) isozymes (COX-1/COX-2) and Fos (a marker of neuronal activation). FG-labeled spinally projecting neurons were abundantly observed in the dorsal cap, ventral part and posterior part of the PVN. The immunoreactivity of each COX-1 and COX-2 was detected in FG-labeled spinally projecting PVN neurons in the vehicle (10 MUl of saline/animal, i.c.v.) treated group, while bombesin (1 nmol/animal, i.c.v.) had no effect on the number of these immunoreactive neurons for each COX isozyme with labeling of FG. On the other hand, the peptide significantly increased the number of double immunoreactive neurons for Fos and COX-1/COX-2 with FG-labeling in the PVN (except triple-labeled neurons for FG, COX-2 and Fos in the dorsal cap of the PVN), as compared to those of vehicle-treated group. These results suggest that centrally administered bombesin activates spinally projecting PVN neurons containing COX-1 and COX-2 in rats. PMID- 22537832 TI - Ultrastructure of the salivary glands of non-infected and infected glands in Glossina pallidipes by the salivary glands hypertrophy virus. AB - Light, scanning electron, and transmission electron microscopy analyses were conducted to examine the morphology and ultrastructure of the salivary glands of Glossina pallidipes. Three distinct regions, each with a characteristic composition and organization of tissues and cells, were identified: secretory, reabsorptive and proximal. When infected with the salivary gland hypertrophy (SGH) virus, glands showed a severe hypertrophy, accompanied by profound changes in their morphology and ultrastructure. In addition, the muscular fibers surrounding the secretory region of the glands were disrupted. The morphological alterations in the muscular tissue, caused by viral infection, could be an important aspect of the pathology and may shed light on the mode of action of the SGH virus. Results were discussed with regard to the potential effect of viral infection on normal salivation and on the ability of infected tsetse flies to transmit a trypanosome parasite. PMID- 22537834 TI - Status of resistance to Bt maize in Spodoptera frugiperda: lessons from Puerto Rico. AB - In 2006, reports of potential Spodoptera frugiperda resistance to TC1507 maize in Puerto Rico were received. Subsequent investigation confirmed that pest populations collected from several sites in Puerto Rico were largely unaffected by the Cry1F protein in bioassays, with resistance ratios likely in excess of 1000. Since then, we have continued monitoring populations in Puerto Rico and in southern areas of the mainland US. The majority of the collections from Puerto Rico continue to show high levels of Cry1F resistance whereas populations collected from the southern US mainland continue to show full susceptibility to Cry1F and TC1507 maize. It does not appear that resistant populations have spread to any measurable extent from Puerto Rico to mainland US, nor that local selection pressure from Cry1F-expressing maize or cotton production in the southern US has caused a measurable change in population susceptibility. Lessons learned from Puerto Rico are being applied in other parts of the Americas where TC1507 maize is grown and additional steps being taken to protect the long-term durability of Cry1F in maize in areas where similar selection pressure may be expected. Tactics include using locally-adapted germplasm that contain native Spodoptera resistance, a robust education program to teach end-users about the potential for resistance to develop appropriate crop stewardship, resistance monitoring, and the use of insecticides under high S. frugiperda pressure. Perhaps most importantly, pyramided trait products that produce two or more different Bt proteins are being introduced to further delay resistance development to Cry1F. PMID- 22537833 TI - Tissue distribution and transmission routes for the tsetse fly endosymbionts. AB - The tsetse fly Glossina is the vector of the protozoan Trypanosoma brucei spp., which causes Human and Animal African Trypanosomiasis in sub-Saharan African countries. To supplement their unbalanced vertebrate bloodmeal diet, flies permanently harbor the obligate bacterium Wigglesworthia glossinidia, which resides in bacteriocytes in the midgut bacteriome organ as well as in milk gland organ. Tsetse flies also harbor the secondary facultative endosymbionts (S symbiont) Sodalis glossinidius that infects various tissues and Wolbachia that infects germ cells. Tsetse flies display viviparous reproductive biology where a single embryo hatches and completes its entire larval development in utero and receives nourishments in the form of milk secreted by mother's accessory glands (milk glands). To analyze the precise tissue distribution of the three endosymbiotic bacteria and to infer the way by which each symbiotic partner is transmitted from parent to progeny, we conducted a Fluorescence In situ Hybridization (FISH) study to survey bacterial spatial distribution across the fly tissues. We show that bacteriocytes are mono-infected with Wigglesworthia, while both Wigglesworthia and Sodalis are present in the milk gland lumen. Sodalis was further seen in the uterus, spermathecae, fat body, milk and intracellular in the milk gland cells. Contrary to Wigglesworthia and Sodalis, Wolbachia were the only bacteria infecting oocytes, trophocytes, and embryos at early embryonic stages. Furthermore, Wolbachia were not seen in the milk gland and in the fat body. This work further highlights the diversity of symbiont interactions in multipartner associations and supports two maternal routes of symbiont inheritance in the tsetse fly: Wolbachia through oocytes, and, Wigglesworthia and Sodalis by means of milk gland bacterial infection at early post-embryonic stages. PMID- 22537835 TI - Early detection of field-evolved resistance to Bt cotton in China: cotton bollworm and pink bollworm. AB - Transgenic crops producing Bacillus thuringiensis (Bt) toxins kill some major insect pests, but pests can evolve resistance and thereby reduce the effectiveness of such Bt crops. The main approach for slowing pest adaptation to Bt crops uses non-Bt host plants as "refuges" to increase survival of susceptible pests. To delay evolution of pest resistance to cotton producing Bt toxin Cry1Ac, several countries have required refuges of non-Bt cotton, while farmers in China have relied on "natural" refuges of non-Bt host plants other than cotton. This strategy is designed for cotton bollworm (Helicoverpa armigera), which attacks many crops and is the primary target of Bt cotton in China, but it does not apply to pink bollworm (Pectinophora gossypiella), which feeds almost entirely on cotton in China. Here we review evidence of field-evolved resistance to Cry1Ac by cotton bollworm in northern China and by pink bollworm in the Yangtze River Valley of China. For both pests, results of laboratory diet bioassays reveal significantly decreased susceptibility of field populations to Cry1Ac, yet field control failures of Bt cotton have not been reported. The early detection of resistance summarized here may spur countermeasures such as planting Bt cotton that produces two or more distinct toxins, increased planting of non-Bt cotton, and integration of other management tactics together with Bt cotton. PMID- 22537836 TI - Evolution, ecology and management of resistance in Helicoverpa spp. to Bt cotton in Australia. AB - Prior to the widespread adoption of two-gene Bt cotton (Bollgard II(r)) in Australia, the frequency of resistance alleles to one of the deployed proteins (Cry2Ab) was at least 0.001 in the pests targeted namely, Helicoverpa armigera and Helicoverpa punctigera. In the 7 years hence, there has been a statistically significant increase in the frequency of alleles conferring Cry2Ab resistance in field populations of H. punctigera. This paper reviews the history of deploying Bt cotton in Australia, the characteristics of the isolated Cry2Ab resistance that likely impact on resistance evolution, aspects of the efficacy of Bollgard IIchi, and the behavioural ecology of Helicoverpa spp. larvae as it pertains to resistance management. It also presents up-to-date frequencies of resistant alleles for H. punctigera and reviews the same information for H. armigera. This is followed by a discussion of current resistance management strategies. The consequences of the imminent release of a third generation product that utilizes the novel vegetative insecticidal protein Vip3A are then considered. The area planted to Bt-crops is anticipated to continue to rise worldwide and many biotechnical companies intend to add Vip3A to existing products; therefore the information reviewed herein for Australia is likely to be pertinent to other situations. PMID- 22537837 TI - Field-evolved resistance to Bt maize by western corn rootworm: predictions from the laboratory and effects in the field. AB - Crops engineered to produce insecticidal toxins derived from the bacterium Bacillus thuringiensis (Bt) provide an effective management tool for many key insect pests. However, pest species have repeatedly demonstrated their ability to adapt to management practices. Results from laboratory selection experiments illustrate the capacity of pest species to evolve Bt resistance. Furthermore, resistance has been documented to Bt sprays in the field and greenhouse, and more recently, by some pests to Bt crops in the field. In 2009, fields were discovered in Iowa (USA) with populations of western corn rootworm, Diabrotica virgifera virgifera LeConte, that had evolved resistance to maize that produces the Bt toxin Cry3Bb1. Fields with resistant insects in 2009 had been planted to Cry3Bb1 maize for at least three consecutive years and as many as 6years. Computer simulation models predicted that the western corn rootworm might evolve resistance to Bt maize in as few as 3years. Laboratory and field data for interactions between western corn rootworm and Bt maize indicate that currently commercialized products are not high-dose events, which increases the risk of resistance evolution because non-recessive resistance traits may enhance survival on Bt maize. Furthermore, genetic analysis of laboratory strains of western corn rootworm has found non-recessive inheritance of resistance. Field studies conducted in two fields identified as harboring Cry3Bb1-resistant western corn rootworm found that survival of western corn rootworm did not differ between Cry3Bb1 maize and non-Bt maize and that root injury to Cry3Bb1 maize was higher than injury to other types of Bt maize or to maize roots protected with a soil insecticide. These first cases of field-evolved resistance to Bt maize by western corn rootworm provide an early warning and point to the need to apply better integrated pest management practices when using Bt maize to manage western corn rootworm. PMID- 22537839 TI - Validity and reliability of a sensor-enabled intubation trainer: a focus on patient-centered data. AB - BACKGROUND: Prior work using simulation for assessing intubation skills has largely focused on the use of observer-generated performance measures in the form of checklists and global ratings scales. PURPOSE: The purpose of our work was to investigate whether patient-centered simulation data could be used to quantify learner's performance during direct laryngoscopy. METHODS: We designed a pretest/posttest prospective intervention study of residents' (n = 25) intubation skills. RESULTS: When assessing validity, all of the patient-centered simulation variables showed significant correlations with the previously validated observer generated performance measures (r = 0.331-0.463, P <= 0.001). When assessing reliability, there were significant correlations between all of the sensor variables, confirming moderate to high inter-item reliability (r = 0.259-0.794, P <= 0.05). The observer-generated performance measures showed significant improvement in use of the Macintosh blade (T1 = 2.10/5.00, T2 = 3.64/5.00, P = 0.001). However, this was not the case for the Miller blade (T1 = 1.30/5.00, T2 = 1.75/5.00, P = 0.119). Overall, the patient-centered simulation variables provided a high level of detail regarding performance improvement areas. CONCLUSION: This study presents a multilevel analysis of sensor-generated simulation data. As the sensors provide sound, formative data regarding patient contact, the outputs may be used for specific criterion measures and detailed performance feedback. PMID- 22537838 TI - Src/NF-kappaB-targeted inhibition of LPS-induced macrophage activation and dextran sodium sulphate-induced colitis by Archidendron clypearia methanol extract. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Archidendron clypearia Jack. (Fabaceae) has been traditionally used to treat various inflammatory diseases such as pain in the eyes. However, the antiinflammatory mechanism of A. clypearia has not been fully elucidated. This study examined the anti-inflammatory mechanism of a 95% methanol extract (Ac-ME) of A. clypearia in vitro and in vivo. MATERIALS AND METHODS: The effect of Ac-ME on the production of inflammatory mediators in RAW264.7 cells and peritoneal macrophages and on symptoms of colitis in mouse induced by dextran sodium sulphate (DSS) was investigated. Molecular mechanisms underlying the inhibitory effects were elucidated by analyzing the activation of transcription factors and their upstream signaling as well as by evaluating the kinase activity of target enzymes in vitro and in vivo. RESULTS: Ac-ME dose-dependently suppressed the secretion of nitric oxide (NO) and prostaglandin (PG)E2 from RAW264.7 cells and peritoneal macrophages stimulated by lipopolysaccharide (LPS). Ac-ME clearly reduced mRNA expression of inducible NO synthase (iNOS), cyclooxygenase (COX)-2, and tumor necrosis factor (TNF)-alpha by the blockade of nuclear factor (NF)-kappaB activation and its upstream signaling events containing protein tyrosine kinase such as Syk and Src. In agreement with this, Ac-ME directly reduced the kinase activities of Src and Syk as well as the formation of molecular signaling complex including p85. DSS-induced colitis was also remarkably inhibited by this extract through the suppression of Src and IkappaBalpha phosphorylation. CONCLUSION: Ac-ME displays strong anti-inflammatory activity in vivo by suppressing Src/Syk-mediated NF-kappaB activation which is linked to its ethno-pharmacological uses as an anti-gastritis remedy. Through preclinical studies, the potential therapeutic application will be tested further. PMID- 22537840 TI - Merkel cell carcinoma: high recurrence rate despite aggressive treatment. AB - BACKGROUND: Merkel cell carcinoma (MCC) is a rare aggressive neuroendocrine cancer of the skin whose incidence has been increasing. The objective of the study was to evaluate current treatment modalities, including sentinel lymph node (SLN) biopsy and outcomes and identify prognostic factors in patients with MCC. METHODS: A retrospective chart review of patients with MCC. Clinical, pathologic, treatment characteristics, disease status, and survival were collected. All slides were reviewed by a single pathologist, and additional pathologic elements were evaluated for prognosis. RESULTS: Twenty-six patients were identified in the study period. All patients were Caucasian with an average age of 71.3 y. Twenty one patients had tumors in sun-exposed locations, and 13 had a prior history of skin cancer. All nonmetastatic patients underwent wide excision. SLN biopsy was successful in 19 patients. The SLN was positive in 21% of patients. Radiation therapy was used in 13 patients. Average follow-up was 26 mo, and median survival was 29 mo. Recurrence occurred in eight patients: four locoregional, two distant, one combined, and one unknown. Recurrence occurred in five patients with stage I disease. Five patients with negative SLN later developed recurrence. The presence of metastasis to the nodes was significant for recurrence. No other pathologic factor was found to have prognostic significance. CONCLUSIONS: Despite aggressive surgical and radiation treatment, MCC has a high rate of locoregional recurrence, even in early stage disease. SNLB is useful for the staging and management of patients. Further research is needed to identify better prognostic markers. PMID- 22537842 TI - Cricoid split for acute subglottic injury in the older child. AB - OBJECTIVES: To describe our experience of cricoid split in the older child for acquired subglottic stenosis secondary to chemical or thermal burns. METHODS: A retrospective case series. RESULTS: We describe two patients, both two years old, who benefitted from the procedure and had a return to a normal-sized airway. Neither child required a tracheostomy or further airway intervention after the cricoid split. CONCLUSIONS: Laryngotracheal reconstruction (LTR) is the standard treatment for subglottic injuries with associated subglottic stenosis in children, infants and (where possible) neonates. We have found the cricoid split a useful technique in carefully selected older children with acute subglottic injury and associated early subglottic stenosis, where LTR or ballooning is not feasible, where there is limited experience of ballooning, and/or ballooning has failed in the early stages of treatment. Cricoid split is a technique that is part of the airway surgeon's open operative repertoire and therefore should be remembered as a management option. PMID- 22537841 TI - Pulmonary immune changes early after laparoscopic antireflux surgery in lung transplant patients with gastroesophageal reflux disease. AB - BACKGROUND: The biologic mechanisms by which laparoscopic antireflux surgery (LARS) might influence the inflammatory process leading to bronchiolitis obliterans syndrome are unknown. We hypothesized that LARS alters the pulmonary immune profile in lung transplant patients with gastroesophageal reflux disease. METHODS: In 8 lung transplant patients with gastroesophageal reflux disease, we quantified and compared the pulmonary leukocyte differential and the concentration of inflammatory mediators in the bronchoalveolar lavage fluid (BALF) 4 weeks before LARS, 4 weeks after LARS, and 12 months after lung transplantation. Freedom from bronchiolitis obliterans syndrome (graded 1-3 according to the International Society of Heart and Lung Transplantation guidelines), forced expiratory volume in 1 second trends, and survival were also examined. RESULTS: At 4 weeks after LARS, the percentages of neutrophils and lymphocytes in the BALF were reduced (from 6.6% to 2.8%, P = 0.049, and from 10.4% to 2.4%, P = 0.163, respectively). The percentage of macrophages increased (from 74.8% to 94.6%, P = 0.077). Finally, the BALF concentration of myeloperoxide and interleukin-1beta tended to decrease (from 2109 to 1033 U/mg, P = 0.063, and from 4.1 to 0 pg/mg protein, P = 0.031, respectively), and the concentrations of interleukin-13 and interferon-gamma tended to increase (from 7.6 to 30.4 pg/mg protein, P = 0.078 and from 0 to 159.5 pg/mg protein, P = 0.031, respectively). These trends were typically similar at 12 months after transplantation. At a mean follow-up of 19.7 months, the survival rate was 75% and the freedom from bronchiolitis obliterans syndrome was 75%. Overall, the forced expiratory volume in 1 second remained stable during the first year after transplantation. CONCLUSIONS: Our preliminary study has demonstrated that LARS can restore the physiologic balance of pulmonary leukocyte populations and that the BALF concentration of pro-inflammatory mediators is altered early after LARS. These results suggest that LARS could modulate the pulmonary inflammatory milieu in lung transplant patients with gastroesophageal reflux disease. PMID- 22537843 TI - Dexmedetomidine reduces emergence agitation after tonsillectomy in children by sevoflurane anesthesia: a case-control study. AB - OBJECTIVE: To evaluate the efficacy and safety of dexmedetomidine for emergence agitation after tonsillectomy in children. METHODS: 120 ASA physical status I and II children, aged 5-14 years, undergoing anesthesia for tonsillectomy, were randomly divided into 3 groups: Placebo group, the low dexmedetomidine concentration group and the high dexmedetomidine concentration group. Before the entrance of the operating room (OR), all of the children received intravenous injection 40 MUg kg(-1) midazolam to reduce anxiety at first, and then dexmedetomidine was given intravenously at an initial loading dose of 0.5 MUg kg( 1) or 1 MUg/kg over a 10-min period via a computer controlled infusion pump followed by a maintenance infusion of 0.2 MUg kg(-1)h(-1) or 0.4 MUg kg(-1)h( 1)over the surgery. The heart rate, SpO(2) and mean arterial blood pressure were recorded for each patient in both operation room and PACU. The designated time points: at the start of the anesthetic induction, at the discontinuation of inhalational agents, at first opening of eyes, at time to remove endotracheal tube were recorded. After patient arrival at the PACU, VAS score, RSS, the occurrence of emergence agitation were recorded every 5 min for the first 30 min and every 10 min for the next 30 min after endotracheal tube was removed. RESULTS: There was significant difference in the incidence of emergence agitation between Placebo group and the high concentration group when endotracheal tube was removed (P<0.05). There was significant difference in the VAS pain scores and in the RSS between three groups at the time of extubation, as well as 5 min and 10 min after extubation (P<0.05). CONCLUSIONS: Dexmedetomidine appears to be safe and effective to reduce the incidence of early emergence agitation in children after tonsillectomy. Initial loading dose of 1.0 MUg kg(-1) followed by a maintenance infusion of 0.4 MUg kg(-1)h(-1) is better choice for children received tonsillectomy. PMID- 22537844 TI - Transparent exopolymer particle removal in different drinking water production centers. AB - Transparent exopolymer particles (TEP) have recently gained interest in relation to membrane fouling. These sticky, gel-like particles consist of acidic polysaccharides excreted by bacteria and algae. The concentrations, expressed as xanthan gum equivalents L-1 (MUg X(eq) L-1), usually reach hundred up to thousands MUg X(eq) L-1 in natural waters. However, very few research was performed on the occurrence and fate of TEP in drinking water, this far. This study examined three different drinking water production centers, taking in effluent of a sewage treatment plant (STP), surface water and groundwater, respectively. Each treatment step was evaluated on TEP removal and on 13 other chemical and biological parameters. An assessment on TEP removal efficiency of a diverse range of water treatment methods and on correlations between TEP and other parameters was performed. Significant correlations between particulate TEP (>0.4 MUm) and viable cell concentrations were found, as well as between colloidal TEP (0.05-0.4 MUm) and total COD, TOC, total cell or viable cell concentrations. TEP concentrations were very dependent on the raw water source; no TEP was detected in groundwater but the STP effluent contained 1572 MUg X(eq) L-1 and the surface water 699 MUg X(eq) L-1. Over 94% of total TEP in both plants was colloidal TEP, a fraction neglected in nearly every other TEP study. The combination of coagulation and sand filtration was effective to decrease the TEP levels by 67%, while the combination of ultrafiltration and reverse osmosis provided a total TEP removal. Finally, in none of the installations TEP reached the final drinking water distribution system at significant concentrations. Overall, this study described the presence and removal of TEP in drinking water systems. PMID- 22537845 TI - Overexpression of cellular prion protein (PrP(C)) prevents cognitive dysfunction and apoptotic neuronal cell death induced by amyloid-beta (Abeta1-40) administration in mice. AB - The cellular prion protein (PrP(C)) is a neuronal-anchored glycoprotein that has been associated with several functions in the CNS such as synaptic plasticity, learning and memory and neuroprotection. There is great interest in understanding the role of PrP(C) in the deleterious effects induced by the central accumulation of amyloid-beta (Abeta) peptides, a pathological hallmark of Alzheimer's disease, but the existent results are still controversial. Here we compared the effects of a single intracerebroventricular (i.c.v.) injection of aggregated Abeta(1-40) peptide (400pmol/mouse) on the spatial learning and memory performance as well as hippocampal cell death biomarkers in adult wild type (Prnp(+/+)), PrP(C) knockout (Prnp(0/0)) and the PrP(C) overexpressing Tg-20 mice. Tg-20 mice, which present a fivefold increase in PrP(C) expression in comparison to wild type mice, were resistant to the Abeta(1-40)-induced spatial learning and memory impairments as indicated by reduced escape latencies to find the platform and higher percentage of time spent in the correct quadrant during training and probe test sessions of the water maze task. The protection against Abeta(1-40)-induced cognitive impairments observed in Tg-20 mice was accompanied by a significant decrease in the hippocampal expression of the activated caspase-3 protein and Bax/Bcl-2 ratio as well as reduced hippocampal cell damage assessed by MTT and propidium iodide incorporation assays. These findings indicate that the overexpression of PrP(C) prevents Abeta(1-40)-induced spatial learning and memory deficits in mice and that this response is mediated, at least in part, by the modulation of programed cell death pathways. PMID- 22537846 TI - Preservation of the hyperdirect pathway of basal ganglia in a rodent brain slice. AB - Basal ganglia are a network of interconnected nuclei, involved in motor control, goal-directed behaviors and procedural learning. Basal ganglia process information from the cerebral cortex through three main pathways. The striatum is the input nucleus of the direct (cortico-striato-nigral) and indirect (cortico striato-pallido-subthalamo-nigral) pathways while the subthalamic nucleus (STN) is the input structure of the hyperdirect (cortico-subthalamo-nigral) pathway. Despite the fact that the hyperdirect pathway constitutes a central part of most of basal ganglia models, experimental studies concerning its synaptic transmission and plasticity are still lacking. This is mainly because in vitro brain slices do not preserve the hyperdirect pathway. Here, we address this by developing a hyperdirect pathway brain slice where cortico-subthalamo-nigral connections were preserved. We characterized the transmission properties and its monosynaptic features between the frontal cortex and the STN, and between the STN and the substantia nigra pars reticulata (SNr), the output nucleus of the hyperdirect pathway. Cortical stimulation evoked monosynaptic glutamatergic events in STN neurons with a mean latency of 11.3 ms and a mean amplitude of 21 pA. STN stimulations evoked monosynaptic glutamatergic events in SNr neurons with a mean latency of 2.5 ms and a mean amplitude of 116 pA. This brain slice also preserved a part of the direct and indirect pathways such as the cortico-striatal connection. This novel slice configuration containing the hyperdirect pathway is a useful tool to better understand the transmission and plasticity in this pathway and hence the physiology and the pathophysiology of basal ganglia. PMID- 22537847 TI - Crosstalk between cdk5 and MEK-ERK signalling upon opioid receptor stimulation leads to upregulation of activator p25 and MEK1 inhibition in rat brain. AB - Cyclin-dependent kinase 5 (cdk5) participates in opioid receptor signalling through complex molecular mechanisms. The acute effects of selective MU (fentanyl) and delta-(SNC-80) opioid receptor agonists, as well as the chronic effects of morphine (the prototypic opiate agonist mainly acting at MU receptors), modulating cdk5 and activators p35/p25 and their interactions with neurotoxic/apoptotic factors, dopamine- and cAMP-regulated phosphoprotein of 32kDa (DARPP-32) and extracellular signal-regulated kinase (ERK) were quantified (Western Blot analyses) in the rat corpus striatum and/or cerebral cortex. To assess the involved mechanisms, MDL28170 was used to inhibit calpain activity and SL327 to disrupt MEK (ERK kinase)-ERK activation. Acute fentanyl (0.1mg/kg) and SNC-80 (10mg/kg) induced rapid (7-60 min) 2- to 4-fold increases of p25 content, without induction of cdk5/p25 pro-apoptotic c-Jun NH(2)-terminal protein kinase or aberrant cleavage of poly(ADP-ribose)-polymerase-1, a hallmark of apoptosis. In contrast, fentanyl and SNC-80 stimulated cdk5-mediated p-Thr75 DARPP-32 (+116 166%; PKA inhibition) and p-Thr286 MEK1 (+21-82%; MEK inactivation), and this latter effect resulted in uncoupling of MEK to ERK signals. Calpain inhibition with MDL28170 (cleavage of p35 to p25) attenuated fentanyl-induced p25 accumulation (-57%), but not the stimulation of p-Thr286 MEK1 or p-Thr75 DARPP 32. MEK-ERK inhibition with SL327 fully prevented fentanyl-induced p25 upregulation. Notably, chronic morphine treatment (10-100mg/kg for 6 days) also increased p25 content and p25/p35 ratio (and activated/inactivated MEK1) in rat brain cortex, which indicated that p25 upregulation persisted under the sustained stimulation of MU-opioid receptors. The results demonstrate that the acute stimulation of opioid receptors leads to upregulation of p25 activator through a MEK-ERK and calpain-dependent pathway, and to disruption of MEK-ERK signalling by a cdk5/p35-induced MEK1 inhibition. Moreover, the effects induced by the sustained stimulation of MU-receptors with morphine suggest the participation of cdk5/p25 complex in opiate-induced long-term neuroplasticity. PMID- 22537848 TI - The promotional effect of IL-22 on mineralization activity of periodontal ligament cells. AB - OBJECTIVES: Interleukin (IL)-22 acts on non-immune cells to induce anti-microbial responses, protection from tissue damage, and enhance cell regeneration. However, little is known about the involvement of IL-22 in periodontal biology. This study investigated the biological effects of IL-22 on periodontal ligament (PDL) cells as part of studies to assess the involvement of IL-22 in periodontal disease. MATERIALS AND METHODS: Gene expression levels of IL-22 and its receptors in PDL cells and gingival tissue samples were evaluated by real-time PCR. Proliferative responses and mineralized-matrix forming activities of PDL cells were examined in the presence and absence of IL-22. RESULTS: In contrast to the expression of IL 22 receptors detected in PDL tissues and their cell lines, gingival tissues showed modest or no gene expressions of IL-22. The production of several cytokines including IL-11, IL-8 and CCL2 was upregulated by IL-22 treatment of PDL cells in a dose-dependent manner. IL-22 treatment had no effect on the proliferative response in PDL cells. Meanwhile, IL-22 precipitated mineralized nodule formation and induced gene expressions of RUNX2, MSX2 and osteocalcin in PDL cells, suggesting that IL-22 enhances the mineralized matrix-forming activities of PDL cells. CONCLUSION: IL-22 has the potential to promote mineralizing activity in PDL cells and to develop appropriate regenerative therapy. PMID- 22537850 TI - Protein kinase C stimulates human B cell activating factor gene expression through reactive oxygen species-dependent c-Fos in THP-1 pro-monocytic cells. AB - BAFF is associated with various immunological diseases. Previously, we have reported that mouse B cell activating factor (mBAFF) expression was dependent on nuclear localization of co-activator, p300 and the activation of transcription factors including NF-kappaB and CREB. Here, we investigated whether transcription factor, c-Fos, regulates human (h) BAFF expression through promoter activation by PMA-induced reactive oxygen species (ROS) production. We cloned hBAFF promoter into luciferase-expressing pGL3-basic vector. The activity of 1.0 kb hBAFF promoter was higher than that in 0.75, 0.5 or 0.25 kb hBAFF promoter. The existence of three AP-1 binding motifs was computer-analyzed in hBAFF promoter. The stimulation with PMA and ionomycin (IOM) increased 1.0 kb hBAFF promoter activity, time-dependently. PMA/IOM-stimulation rapidly enhanced c-Fos expression in THP-1 human pro-monocytic cells. Binding of c-Fos to hBAFF promoter was detected by chromatin immunoprecipitation (ChIP) assay. hBAFF expression and its promoter activity were decreased by the transfection with small interference (si) RNA of c-Fos. ROS production in THP-1 cells was increased by PMA/IOM-stimulation. In addition, hBAFF activity stimulated by PMA/IOM was reduced by N-acetyl cysteine (NAC), a well-known ROS scavenger. Serum starvation (0.5% FBS) producing ROS and the exogenous H(2)O(2) treatment also enhanced hBAFF promoter activity. c Fos expression and AP-1 binding to oligonucleotide were reduced by the treatment with NAC. H(2)O(2) was not able to induce hBAFF expression in the presence of staurosporine, PKC inhibitor. Data suggest that hBAFF expression could be regulated by promoter activation through c-Fos association, which might be dependent on PMA-induced ROS production. PMID- 22537851 TI - A novel porcine gene, POT1, differentially expressed in the longissimus muscle tissues from Wujin and Large White pigs. AB - The mRNA differential display technique was performed to investigate the differences of gene expression in the longissimus muscle tissues from Wujin and Large White pigs. One novel gene differentially expressed was identified through quantitative real time PCR and the cDNA complete sequence was then obtained using the rapid amplification of cDNA ends (RACE) method. The nucleotide sequence of the gene is not homologous to any of the known porcine genes. The sequence prediction analysis revealed that the open reading frame of this gene encodes a protein of 507 amino acids that shares high homology with the protection of telomeres 1 isoform 4 (POT1) of human (86%)-so that this gene can be defined as swine POT1 gene. This gene is structured in 12 exons and 11 introns as revealed by computer-assisted analysis. The tissue expression analysis indicated that the swine POT1 gene is differentially expressed in tissues including muscle, heart, liver, fat, kidney, lung, pancreas and spleen. Our experiment is the first to establish the primary foundation for further research on the swine POT1 gene. PMID- 22537852 TI - [Comment to "acute arthritis secondary to intravesical bacillus Calmette-Guerin for bladder cancer"]. PMID- 22537849 TI - Discovering cytokines as targets for chemotherapy-induced painful peripheral neuropathy. AB - Chemotherapy-induced peripheral neuropathy (CIPN), a dose-limiting neurotoxic effect of chemotherapy, is the most common reason for early cessation of cancer treatment. This can result in an increased risk of recurrence and decreased survival rate. Inflammatory cascade activation, proinflammatory cytokine upregulation, and neuro-immune communication pathways play essential roles in the initiation and progression of CIPN. Most notably, TNF-alpha, IL-1beta, IL-6, and CCL2 are involved in neuropathic pain. Further elucidation of the role of these cytokines could lead to their development and use as biomarkers for predicting the onset of painful peripheral neuropathy and early axonal damage. In this review, we provide evidence for the involvement of cytokines in CIPN, the possible underlying mechanisms, and their use as potential therapeutic targets and biomarkers to prevent and improve the painful peripheral neuropathy related to chemotherapeutic agents. PMID- 22537854 TI - Familial Aspects of Cancer 2011 Research and Practice: A combined meeting of kConFab, Australian Breast Cancer Family Study, Australian Colorectal Cancer Family Study, Australian Ovarian Cancer Study, Family Cancer Clinics of Australia and New Zealand and kConFab Kingscliff, Australia. 23-26 August 2011. Abstracts. PMID- 22537853 TI - A transcriptional study of acidogenic chemostat cells of Clostridium acetobutylicum--solvent stress caused by a transient n-butanol pulse. AB - The main product of the anaerobic fermentative bacterium Clostridium acetobutylicum is n-butanol, an organic solvent with severe toxic effects on the cells. Therefore, the identification of the molecular factors related to n butanol stress constitutes a major strategy for furthering the understanding of the biotechnological production of n-butanol, an important industrial biofuel. Previous reports concerning n-butanol stress in C. acetobutylicum dealt exclusively with batch cultures. In this study, for the first time a comprehensive transcriptional analysis of n-butanol-stressed C. acetobutylicum was conducted using stable steady state acidogenic chemostat cultures. A total of 358 differentially expressed genes were significantly affected by n-butanol stress. Similarities, such as the upregulation of general stress genes, and differences in gene expression were compared in detail with earlier DNA microarrays performed in batch cultivation experiments. The main result of this analysis was the observation that genes involved in amino acid and nucleotide biosynthesis, as well as genes for specific transport systems were upregulated by n-butanol. Our results exclude any transcriptional response triggered by exogenous pH changes or solventogenic n-butanol formation. Finally, our data suggest that metabolic flux through the glycerolipid biosynthetic pathway increases, confirming that C. acetobutylicum modifies the cytoplasmic membrane composition in response to n-butanol stress. PMID- 22537855 TI - Behaviour profile of Hungarian adolescent outpatients with a dual diagnosis. AB - The behaviour dimensions of 244 Hungarian adolescent psychiatric outpatients with a dual diagnosis (intellectual disability and psychiatric diagnosis) were examined by means of the adapted version of the Behaviour Problem Inventory (BPI, Rojahn, Matson, Lott, Esbensen, & Smalls, 2001). Four IQ subgroups were created: borderline, mild, moderate and profound ID subsamples. Significantly higher means were found in the self-injury/stereotyped behaviour/summarized scale categories both in the frequency and severity of symptoms in the more disabled groups against the samples having milder IQ impairment. Adolescents with a dual diagnosis showed much higher BPI scale means than an adult residential ID sample. ADHD and emotional disorders were the most frequent psychiatric diagnostic comorbidities of ID (20.67% and 11.73%). Academic achievement disorder, depression and psychosis had low occurrences (3.35, 2.23 and 1.17%, respectively) but showed convergency with other authors' data. The comorbid emotional disorders may create challenges for the care of the mildly intellectually disabled group. PMID- 22537856 TI - Validation of a questionnaire on behaviour academic competence among Chinese preschool children. AB - The aim of this study was to validate a questionnaire on academic competence behaviour for use with Chinese preschool children in Hong Kong. A parent version and a teacher version were developed and evaluated. The participants included 457 children (230 boys and 227 girls) aged four and five years old, their preschool teachers and their parents. Besides, 44 children (39 boys and 5 girls) with developmental disabilities were recruited. The children were assessed on the cognitive domain of the Preschool Development Assessment Scale (PDAS). Their parents completed a questionnaire on academic competence behaviour, as well as the Strength and Difficulty Scale (SDQ). Their teachers completed the questionnaire on academic competence behaviour. Rasch analysis results provided support for the unidimensionality of the parent and teacher versions of the scale, with one item deleted. The parent and teacher versions of the revised scale correlated positively with the cognitive domain of the PDAS and the prosocial scale of the SDQ and negatively with SDQ total problem behaviour score. Children with developmental delay were assigned lower scores by their parents and teachers, compared with preschool children, on the revised versions of the academic competence behaviour scale. Reliability estimates (Cronbach's alpha) of the parent and teacher versions of this revised scale were above .80. The results suggested that the two versions of academic competence behaviour scales were promising instruments for the assessment of academic competence behaviour among Chinese preschool children. PMID- 22537857 TI - Technology-aided programs for assisting communication and leisure engagement of persons with amyotrophic lateral sclerosis: two single-case studies. AB - Technology-aided programs for assisting communication and leisure engagement were assessed in single-case studies involving two men with amyotrophic lateral sclerosis (ALS). Study I involved a 51-year-old man with a virtually total loss of his motor repertoire and assessed a technology-aided program aimed at enabling him to (a) write and send out text messages and have incoming messages read to him and (b) establish videophone connections with his children (i.e., establish video contact and communicate with them). Study II involved a 66-year-old man with virtually no motor behavior and apparent depression and assessed a technology-aided program aimed at enabling him to (a) engage in leisure activities and make requests for basic needs and (b) use a low-demand messaging system. The results of both studies were highly encouraging. The participant of Study I could use the technology-aided program for effective communication and social interaction with multiple partners as well as for family interaction. The participant of Study II could use the technology-aided program for leisure engagement, requests, and basic family contacts/communication. The implications of technology for helping persons with severe ALS levels maintain an active and constructive role are discussed. PMID- 22537858 TI - Statins accelerate the onset of collagen type II-induced arthritis in mice. AB - INTRODUCTION: Statins (hydroxymethylglutaryl coenzyme A reductase inhibitors) are effective in reducing the risk of cardiovascular morbidity and mortality in patients with hyperlipidemia, hypertension, or type II diabetes. Next to their cholesterol-lowering activity, statins have immunomodulatory properties. Based on these properties, we hypothesized that statin use may eventually lead to dysregulation of immune responses, possibly resulting in autoimmunity. We have recently shown in an observational study that statin use was associated with an increased risk of developing rheumatoid arthritis. Our objective was to investigate whether a causal relationship could be established for this finding. METHODS: The mouse collagen type II (CII)-induced arthritis (CIA) model was used, with immunization, challenge, and euthanasia at days 0, 21, and 42, respectively. Statins were given orally before (day -28 until day 21) or after (day 21 until day 42) CIA induction. Atorvastatin (0.2 mg/day) or pravastatin (0.8 mg/day) was administered. Arthritis was recorded three times a week. Serum anti-CII autoantibodies and cytokines in supernatants from Concanavalin-A-stimulated lymph node cells and CII-stimulated spleen cells were measured. RESULTS: Statin administration accelerated arthritis onset and resulted in 100% arthritic animals, whereas only seven out of 12 nonstatin control animals developed arthritis. Atorvastatin administration after CIA induction resulted in earlier onset than atorvastatin administration before induction, or than pravastatin administration before or after induction. The arthritic score of animals given pravastatin before CIA induction was similar to that of the nonstatin controls, whereas the other groups that received statins showed higher arthritic scores. Atorvastatin administration, especially before CIA induction, increased anti-CII autoantibody production. IL-2 and IL-17 production by lymph node and spleen cells was higher in CIA animals than in PBS controls, but was not affected by statin administration. While IFNgamma production was not affected by CIA induction, atorvastatin administration before CIA induction increased the production of this cytokine. CONCLUSION: These data support previous results from our observational studies, indicating a role for statins in the induction of autoimmunity. PMID- 22537859 TI - A critical appraisal of cryopreservation (slow cooling versus vitrification) of human oocytes and embryos. AB - BACKGROUND: Vitrification is now a commonly applied technique for cryopreservation in assisted reproductive technology (ART) replacing, in many cases, conventional slow cooling methodology. This review examines evidence relevant to comparison of the two approaches applied to human oocytes and embryos at different developmental stages. METHODS: Critical review of the published literature using PubMed with particular emphasis on studies which include data on survival and implantation rates, data from fresh control groups and evaluation of the two approaches in a single setting. RESULTS: Slow cooling is associated with lower survival rates and compromised development relative to vitrification when applied to metaphase II (MII) oocytes, although the vitrification results have predominantly been obtained using direct contact with liquid nitrogen and there is some evidence that optimal protocols for slow cooling of MII oocytes are yet to be established. There are no prospective randomized controlled trials (RCTs) which support the use of either technique with pronuclear oocytes although vitrification has become the method of choice. Optimal slow cooling, using modifications of traditional methodology, and vitrification can result in high survival rates of early embryos, which implant at the same rate as equivalent fresh counterparts. Many studies report high survival and implantation rates following vitrification of blastocysts. Although slow cooling of blastocysts has been reported to be inferior in some studies, others comparing the two approaches in the same clinical setting have demonstrated comparable results. The variation in the extent of embryo selection applied in studies can lead to apparent differences in clinical efficiency, which may not be significant if expressed on a 'per oocyte used' basis. CONCLUSIONS: Available evidence suggests that vitrification is the current method of choice when cryopreserving MII oocytes. Early cleavage stage embryos can be cryopreserved with equal success using slow cooling and vitrification. Successful blastocyst cryopreservation may be more consistently achieved with vitrification but optimal slow cooling can produce similar results. There are key limitations associated with the available evidence base, including a paucity of RCTs, limited reporting of live birth outcomes and limited reporting of detail which would allow assessment of the impact of differences in female age. While vitrification has a clear role in ART, we support continued research to establish optimal slow cooling methods which may assist in alleviating concerns over safety issues, such as storage, transport and the use of very high cryoprotectant concentrations. PMID- 22537860 TI - alpha-Glucosylated 6-gingerol: chemoenzymatic synthesis using alpha-glucosidase from Halomonas sp. H11, and its physical properties. AB - 6-Gingerol [(S)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)decan-3-one] is a biologically active compound and is abundant in the rhizomes of ginger (Zingiber officinale). It has some beneficial functions in healthcare, but its use is limited because of its insolubility in water and its heat-instability. To improve these physical properties, the glucosylation of 6-gingerol was investigated using alpha-glucosidases (EC. 3.2.1.20) from Aspergillus niger, Aspergillus nidulans ABPU1, Acremonium strictum, Halomonas sp. H11, and Saccharomyces cerevisiae, and cyclodextrin glucanotransferases (CGTase, EC. 2.4.1.19) from Bacillus coagulans, Bacillus sp. No. 38-2, Bacillus clarkii 7364, and Geobacillus stearothermophilus. Among these, only alpha-glucosidase from Halomonas sp. H11 (HaG) transferred a glucosyl moiety to 6-gingerol, and produced glucosylated compounds. The chemical structure of the reaction product, determined by nuclear magnetic resonance spectroscopy and mass spectrometry, was (S)-5-(O-alpha-D-glucopyranosyl)-1-(4 hydroxy-3-methoxyphenyl)decan-3-one (5-alpha-Glc-gingerol). Notably, the regioisomer formed by glucosylation of the phenolic OH was not observed at all, indicating that HaG specifically transferred the glucose moiety to the 5-OH of the beta-hydroxy keto group in 6-gingerol. Almost 60% of the original 6-gingerol was converted into 5-alpha-Glc-gingerol by the reaction. In contrast to 6 gingerol, 5-alpha-Glc-gingerol, in the form of an orange powder prepared by freeze-drying, was water-soluble and stable at room temperature. It was also more stable than 6-gingerol under acidic conditions and to heat. PMID- 22537861 TI - Research on the structure-surface adsorptive activity relationships of triazolyl glycolipid derivatives for mild steel in HCl. AB - Triazolyl glycolipid derivatives constructed via Cu(I)-catalyzed azide-alkyne 1,3 dipolar cycloaddition reaction (Cue-AAC) represent a new range of carbohydrate based scaffolds for use in many fields of the chemical research. Here the surface adsorptive ability of series of our previously prepared C1- or C6-triazole linked gluco- and galactolipid derivatives for mild steel in 1 M HCl was studied via electrochemical impedance spectroscopy (EIS). Results indicated that these monosaccharide-fatty acid conjugates are weak inhibitors against HCl corrosion for mild steel. Moreover, some newly synthesized triazolyl disaccharide (maltose) fatty alcohol conjugates failed to display enhanced activity, meaning that the structural enlargement of the sugar moiety does not favor the iron surface adsorption. However, a bis-triazolyl glycolipid derivative, which was realized by introducing a benzenesulfonamide group via Cue-AAC to the C6-position of a C1 triazolyl glucolipid analog, eventually showed significantly improved adsorptive potency compared to that of its former counterparts. The corrosion inhibitive modality of this compound for mild steel in HCl was subsequently studied via potentiodynamic polarization and thermodynamic calculations. PMID- 22537862 TI - Use of chitosan and chitosan-derivatives to remove arsenic from aqueous solutions -a mini review. AB - Arsenic removal has become a relevant concern due to the final confirmation of its behaviour as chronic human carcinogen, corresponding to an ever-increasing contamination of water, soil and crops in many parts of the world. Developing easily accessible removal strategies is therefore a primary environmental matter. Chitosan and chitosan derivatives show good adsorption performances against arsenic removal and are considered low cost products, easily obtainable. This review provides a summary of recent advances of the application of these compounds in the area of sorption sciences for arsenate and arsenite removal from water, focusing on equilibrium and kinetic mechanisms. PMID- 22537863 TI - Parieto-motor functional connectivity is impaired in Parkinson's disease. AB - BACKGROUND: Bradykinesia in Parkinson's disease is associated with a difficulty in selecting and executing motor actions, likely due to alterations in the functional connectivity of cortico-cortical circuits. OBJECTIVE/HYPOTHESIS: Our aims were to analyse the functional interplay between the posterior parietal cortex and the ipsilateral primary motor area in Parkinson's disease using bifocal transcranial magnetic stimulation, to evaluate its modulation by dopaminergic treatment and its relationship to a simple choice reaction task. METHODS: We studied 12 Parkinson's disease patients with and without dopaminergic treatment and 12 healthy controls. A paired-pulse transcranial magnetic stimulation protocol was applied over the right posterior parietal cortex and the right primary motor area using different conditioning stimulus intensities and interstimulus intervals. Reaction and movement times were studied by a simple choice reaction task. RESULTS: In controls, we observed a significant facilitation of motor evoked potential amplitudes at 4 ms interstimulus interval when conditioning stimulus intensity was set to 90% of resting motor threshold. This functional interaction was not observed in Parkinson's disease patients without dopaminergic treatment and was not restored with treatment. Moreover, correlation analyses revealed that Parkinson's disease patients with less impaired parieto-motor interaction were faster in executing reaching movements in a choice reaction time task, suggesting that the functional parieto-motor impairment described here could be related to bradykinesia observed in Parkinson's disease patients. CONCLUSIONS: Parieto-motor functional connectivity is impaired in Parkinson's disease. The reduced efficacy of this connection could be related to presence of bradykinesia previously observed in Parkinson's disease. PMID- 22537864 TI - Progressive enhancement of alpha activity and visual function in patients with optic neuropathy: a two-week repeated session alternating current stimulation study. AB - INTRODUCTION: Repetitive transorbital alternating current stimulation (rtACS) can improve visual deficits in patients with optic nerve damage. Recent retrospective results suggest that rtACS enhances oscillatory brain activity. The exact mechanisms of rtACS are unclear and little is known about possibly frequency specific neural-plastic mechanisms. An association between bandwidth-confined neural-entrainment and vision recovery maximization could offer a novel therapeutic option for patients with optic neuropathy. OBJECTIVES: The goal of this prospective open-label study was to investigate if the enhancement of rhythmic brain activity over 10 days of consecutive rtACS stimulation is associated with visual field recovery. The secondary goal was to investigate neurophysiological mechanisms related to frequency dependent adaptive plasticity. METHODS: 18 Patients with visual field impairments resulting from pre-chiasmatic partial optic nerve damage received rtACS on 10 consecutive days. Daily, subject specific treatment parameters (<500 MUA, 9-37 Hz, 25-40 min/day) were defined and EEG-spectra collected prior to and after rtACS. Visual field data was collected at day 1 and 10. The change of spectral-power in classic bandwidths were investigated and correlated with visual field deficit recovery. RESULTS: After 10 days of rtACS alpha-power over bilateral occipital electrodes was significantly larger than at baseline (F(Time x alpha-power)p < 0.01). This effect was progressive over subsequent days of stimulation (cubic-fit, R(2) 0.70, RMSE 0.008). Perimetric results improved significantly, but they were not associated with changes in alpha-synchronization. DISCUSSION: rtACS can induce cumulative bandwidth-confined changes in brain rhythms over multiple sessions. These findings are in line with the notion of brain-state dependent [1] and bandwidth confined entrainment [2] as well as rtACS facilitated visual recovery [3]. PMID- 22537865 TI - Extremely low-frequency electromagnetic fields activate the antioxidant pathway Nrf2 in a Huntington's disease-like rat model. AB - Transcranial magnetic stimulation (TMS) is a non-invasive technique used recently to treat different neuropsychiatric and neurodegenerative disorders. Despite its proven value, the mechanisms through which TMS exerts its beneficial action on neuronal function remain unclear. Recent studies have shown that its beneficial effects may be at least partly due to a neuroprotective effect on oxidative and cell damage. This study shows that TMS can modulate the Nrf2 transcriptor factor in a Huntington's disease-like rat model induced by 3-nitropropionic acid (3-NP). Western blot analysis demonstrated that 3-NP caused a reduction in Nrf2 in both cytoplasm and nucleus, while TMS applied to 3-NP-treated rats triggered an increase in cytoplasm and nucleus Nrf2 levels. It was therefore concluded that TMS modulates Nrf2 expression and translocation and that these mechanisms may partly explain the neuroprotective effect of TMS, as well as its antioxidant and cell protection capacity. PMID- 22537866 TI - Translational application of neuromodulation of decision-making. AB - Recent cognitive neuroscience studies indicate that noninvasive brain stimulation can modulate a wide spectrum of behaviors in healthy individuals. Such modulation of behaviors provides novel insights into the fundamentals and neurobiology of cognitive functions in the healthy brain, but also suggests promising prospects for translational applications into clinical populations. One type of behavior that can be modulated with noninvasive brain stimulation is decision-making. For instance, brain stimulation can induce more cautious or riskier behaviors. The capacity of influencing processes involved in decision-making is of particular interest because such processes are at the core of human social and emotional functioning (or dysfunctioning). We review cognitive neuroscience studies that have successfully modulated processes involved in decision-making with transcranial direct current stimulation (tDCS) or transcranial magnetic stimulation (TMS), including risk taking, reward seeking, impulsivity, and fairness consideration. We also discuss potential clinical relevance of these findings for patients who have still unmet therapeutic need and whose alterations in decision-making represent hallmarks of their clinical symptomatology, such as individuals with addictive disorders. PMID- 22537867 TI - Subcortical substrates of TMS induced modulation of the cortico-cortical connectivity. AB - BACKGROUND: Transcranial magnetic stimulation (TMS) can modulate transiently the physiological brain oscillations, e.g. the alpha rhythm. It has been hypothesized that this effect is not limited to the stimulated region but involves subcortical and distant cortical areas. METHODS: We applied single pulse TMS to the primary motor cortex (M1) of healthy subjects to interfere the cortical oscillatory activity recorded by simultaneous EEG and calculated the cortico-cortical coherence and power in the alpha and beta band. To study the structural substrate of the functional connectivity we performed diffusion tensor imaging and fractional anisotropy analysis (FA). To capture the pathways involved we applied probabilistic tractography to reconstruct the entire network. RESULTS: Suprathreshold TMS of M1 induced a consistent enhancement of interhemispheric cortico-cortical alpha band coherence that lasted ca. 175 ms. after the pulse has been applied. The changes were confined to the interhemispheric central EEG electrodes (i.e. C3-C4). There were no consistent changes in the beta band. Power analysis revealed a longer lasting increase in the beta band after TMS pulses. A cluster in the contralateral thalamus showed a linear relationship between regional FA and TMS induced change in alpha band coherence. Probabilistic tractography presents the transcallosal and the contralateral thalamocortical pathways as essential for the observed oscillatory synchronisation. CONCLUSION: TMS induces an enhancement of oscillatory interaction between corresponding central regions of both hemispheres in the alpha band. The contralateral thalamus, transcallosal fibres and the contralateral thalamocortical pathways may constitute critical brain structures mediating the TMS induced change in oscillatory coupling. PMID- 22537868 TI - Facial nerve dysfunction after drainage of cerebrospinal fluid during vestibular schwannoma surgery. PMID- 22537869 TI - Pleural effusion accumulating in the epidural space: recurrent cord compression in a patient with progressive lung adenocarcinoma. PMID- 22537870 TI - The influence of surgery on recurrence pattern of glioblastoma. AB - OBJECTIVES: Glioblastoma recurs within 2 cm from the primary tumor's margins in 90-95% of cases. Natural history of recurrence is not well defined. The aim of this study was to verify if pattern of recurrence can be influenced by the extent of surgery. PATIENTS AND METHODS: 131 patients with glioblastoma underwent tumor removal, followed by standard adjuvant radio-chemotherapy. Depending on the amount of apparently normal white matter measured around the tumor in the surgical specimen, the extent of surgery was classified into: "border resection" (BR, resection margins at the level of tumor border) or "extended resection" (ER, resection margins 1-2 cm far from tumor border). 88 patients had no residual tumor at post-operative MRI. Among these, 60 patients had a local recurrence (LR) - within 2 cm from the primary tumor's margins, 15 patients had a distant recurrence (DR), 13 patients had no recurrence. Survival curves were obtained through the Kaplan-Meier method. Dichotomous data were compared with the chi square test. RESULTS: Patients who underwent ER presented a LR in 67% of cases. Patients who underwent BR presented a LR in 87.5% of cases (p=0.03). Survival for 60 patients with LR was 16 months vs 35 months for 15 patients with DR (p=0.06). PFS for patients with LR was 9 months vs 21 months for patients with DR (p=0.05). CONCLUSIONS: If tumor grows far from eloquent areas, ER may increase the probability to obtain a gross total resection, a greater number of patients with DR and, therefore, a longer survival. PMID- 22537871 TI - Opinion survey of health care providers towards psychogenic non epileptic seizures. AB - OBJECTIVES: Psychogenic non epileptic seizures (PNES) are challenging conditions to diagnose and manage. Previous workers have investigated the opinion of health care providers towards PNES; still several lacunae remain to be stressed. Amongst health care professionals, opinion of nurses has not been adequately explored. We attempted to identify areas which need more emphasis to provide optimal care to the patients. PATIENTS AND METHODS: We approached 417 health care providers (HCP; primary care, neurology and in-patient nurses) with a questionnaire regarding their opinion of PNES. RESULTS: Total 115 respondents responded to our survey. We found one-thirds of respondent favoured "non-epileptic seizure" as the preferred diagnostic term. Although majority (61%) of responders felt that PNES were involuntary, 48% of nurses felt that PNES are 'fake' and patients have voluntary control over them. Neurologists and nurses expressed high level of confidence in managing patients of PNES. About 1/3rd (35%) of responders did not feel video EEG (vEEG) to be always required for the diagnosis of PNES. Only a minority (15%) of healthcare providers favor unrestricted driving by patients of PNES in setting of ongoing seizures. CONCLUSION: Our findings highlight areas where more emphasis needs to be placed regarding PNES amongst HCPs. More emphasis needs to be placed on the involuntary nature of these episodes within the HCP community. It might be necessary to more strongly address the education of nurses and residents for this condition. PMID- 22537872 TI - Direct interaction between GluR2 and GAPDH regulates AMPAR-mediated excitotoxicity. AB - Over-activation of AMPARs (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype glutamate receptors) is implicated in excitotoxic neuronal death associated with acute brain insults, such as ischemic stroke. However, the specific molecular mechanism by which AMPARs, especially the calcium-impermeable AMPARs, induce neuronal death remains poorly understood. Here we report the identification of a previously unrecognized molecular pathway involving a direct protein-protein interaction that underlies GluR2-containing AMPAR-mediated excitotoxicity. Agonist stimulation of AMPARs promotes GluR2/GAPDH (glyceraldehyde-3-phosphate dehydrogenase) complex formation and subsequent internalization. Disruption of GluR2/GAPDH interaction by administration of an interfering peptide prevents AMPAR-mediated excitotoxicity and protects against damage induced by oxygen-glucose deprivation (OGD), an in vitro model of brain ischemia. PMID- 22537873 TI - Diversity and physiology of culturable bacteria associated with a coastal Antarctic ice core. AB - Microbiological studies of polar ice at different depths may provide important comparisons, as they preserve records of microbial cells and past climate. In this study, we examined bacterial abundance, diversity and glaciochemical composition from three depths of an ice core from coastal Dronning Maud Land, East Antarctica. Higher bacterial abundance corresponded with high in situ sea salt Na(+) and dust concentration, suggesting that bacteria might have been transported and deposited into ice along with dust particles and marine aerosols. Fourteen bacterial isolates belonging to the genera Methylobacterium, Brevundimonas, Paenibacillus, Bacillus and Micrococcus were retrieved. Frequent isolation of similar bacterial genera from different cold environments suggests that they possess features that enable survival and metabolism for extended periods of time at sub-zero temperatures. The highest number and diversity of recoverable bacteria was obtained from 49 m depth corresponding to 1926 AD and consisted of bacteria from 4 different genera whereas at 11 m (1989 AD) and 33 m (1953 AD) samples only species belonging to the genera Bacillus was recovered. Among the Bacillus species, Bacillus aryabhattai which has been reported only from the upper stratosphere, was isolated and is the first record from the Earth's surface. Methylobacterium was the most dominant genera at 49 m depth and its prevalence is attributable to a combination of high in situ methanesulfonate concentration, specialized metabolism and environmental hardiness of Methylobacterium. Some of the isolated bacteria were found to respire and grow using methanesulfonate, suggesting that they may utilize this substrate to sustain growth in ice. In addition, NO(3)(-) (2.93-3.69 MUM), NH(4)(+) (1.45-3.90 MUM) and PO(4)(3-) (0.01-0.75 MUM) present in the ice could be potential sources fueling bacterial metabolism in this environment. It could be deduced from the study that variation in bacterial abundance and diversity was probably associated with the prevailing in situ conditions in ice. PMID- 22537874 TI - Mutational analysis of the N-terminal domain of UreR, the positive transcriptional regulator of urease gene expression. AB - The Escherichia coli plasmid-encoded urease, a virulence factor in human and animal infections of the urinary and gastroduodenal tracts, is induced when the substrate urea is present in the growth medium. Urea-dependent urease expression is mediated at the transcriptional level by the AraC-like activator UreR. Previous work has shown that a peptide representing the N-terminal 194 amino-acid residues of UreR binds urea at a single site, full-length UreR forms an oligomer, and the oligomerization motif is thought to reside in the N-terminal portion of the molecule. The C-terminal domain of UreR contains two helix-turn-helix motifs presumed to be necessary for DNA binding. In this study, we exploited mutational analyses at the N-terminal domain of UreR to determine if this domain dimerizes similar to other AraC family members. UreR mutants were analyzed for the ability to activate transcription of lacZ from an ureDp-lacZ transcriptional fusion. A construct encoding the N-terminal 194 amino acids of UreR, eluted as an oligomer by gel filtration and had a dominant negative phenotype over the wild-type ureR allele. We hypothesize that this dominant negative phenotype results from the formation of inactive heterodimers between wild-type and truncated UreR. Dominant negative analysis and cross-linking assays demonstrated that E. coli UreR is active as a dimer and dimerization occurs within the first 180 residues. PMID- 22537875 TI - Lipoxygenases: potential starting biocatalysts for the synthesis of signaling compounds. AB - Lipoxygenases (LOXs) have attracted a great deal of attention as potential starting biocatalysts for synthesizing signaling compounds. Significant advances during the past decade include the discovery of regiospecific LOXs and structural investigation for their diverse regiospecificity. Eight regiospecific (5-, 8-, 9 , 10-, 11-, 12-, 13-, and 15-) LOXs catalyze positional-specific dioxygenation of polyunsaturated fatty acids, forming positional-specific hydroperoxy fatty acids that are further metabolized into signaling compounds. The LOX-derived signaling compounds can be applied not only for clinical uses but also for industrial uses. For example, animal lipoxin LXA4, plant jasmonic acids, plant green leaf volatiles, and bacterial lactones have been used as anti-inflammatory agents, anti-pest agents, flavors, and food additives, respectively. Prostaglandins, as controllers of hormone regulation and cell growth, are also suggested as LOX derived compounds in corals. PMID- 22537876 TI - Recent advances in microbial production of delta-aminolevulinic acid and vitamin B12. AB - delta-aminolevulinate (ALA) is an important intermediate involved in tetrapyrrole synthesis (precursor for vitamin B12, chlorophyll and heme) in vivo. It has been widely applied in agriculture and medicine. On account of many disadvantages of its chemical synthesis, microbial production of ALA has been received much attention as an alternative because of less expensive raw materials, low pollution, and high productivity. Vitamin B12, one of ALA derivatives, which plays a vital role in prevention of anaemia has also attracted intensive works. In this review, recent advances on the production of ALA and vitamin B12 with novel approaches such as whole-cell enzyme-transformation and metabolic engineering are described. Furthermore, the direction for future research and perspective are also summarized. PMID- 22537878 TI - Dietary supplementation of essential fatty acids in larval pikeperch (Sander lucioperca); short and long term effects on stress tolerance and metabolic physiology. AB - The present study examined the effects of feeding pike perch larvae Artemia, enriched with either docosahexanoic acid (DHA), arachidonic acid (ARA), oleic acid (OA), olive oil (OO) or a commercial enrichment DHA Selco (DS) on tissue lipid deposition, stress tolerance, growth and development, and metabolic rate. There was higher tissue retention of ARA than DHA at comparable inclusion levels. No differences were observed between diets on the percentage contribution of ARA or DHA to the fatty acid profile of tissues (head and trunk). Total fatty acid content (mgg(-1)) was significantly higher in the head, reflecting its high content of neural tissue. Observations on larval erratic behaviour and mortality following exposure to salinity stress suggested that high inclusions levels of DHA had an alleviating effect, while ARA did not. Particularly larval groups reared for 16 days on diets enriched with OO and OA had mortality rates approaching 100% within two hours. Interestingly, this tendency, although not as pronounced, was also apparent in juvenile fish after 120 days of rearing on a common diet. Standard metabolic rate in larvae on an OO enriched diet was significantly elevated, but otherwise no groups had significant changes to their respiratory physiology. In addition to increased stress challenge sensitivity, early feeding with OA had long term impact on pike perch neural development indicated by a smaller brain size in juvenile fish. In conclusion, lack of DHA in the diet of pikeperch larvae suggests that this long chain polyunsaturated fatty acid is involved in processes that increase stress tolerance and that lack of dietary DHA in early larval stage caused increased stress sensitivity and long term impaired neural development, while it does not appear to affect metabolic rate at rest. PMID- 22537877 TI - Associations between a neurophysiological marker of central cholinergic activity and cognitive functions in young and older adults. AB - BACKGROUND: The deterioration of the central cholinergic system in aging is hypothesized to underlie declines in several cognitive domains, including memory and executive functions. However, there is surprisingly little direct evidence regarding acetylcholine's specific role(s) in normal human cognitive aging. METHODS: We used short-latency afferent inhibition (SAI) with transcranial magnetic stimulation (TMS) as a putative marker of cholinergic activity in vivo in young (n = 24) and older adults (n = 31). RESULTS: We found a significant age difference in SAI, concordant with other evidence of cholinergic decline in normal aging. We also found clear age differences on several of the memory and one of the executive function measures. Individual differences in SAI levels predicted memory but not executive functions. CONCLUSION: Individual differences in SAI levels were better predictors of memory than executive functions. We discuss cases in which the relations between SAI and cognition might be even stronger, and refer to other age-related biological changes that may interact with cholinergic activity in cognitive aging. PMID- 22537879 TI - Sex-specific changes in the expression of kisspeptin, kisspeptin receptor, gonadotropins and gonadotropin receptors in the Senegalese sole (Solea senegalensis) during a full reproductive cycle. AB - Kisspeptin is thought to have a major role in the control of the onset of puberty in vertebrates. However, our current understanding of its function in fish and how it integrates with other hormones is incomplete due to the high diversity of this group of animals and a still limited amount of available data. This study examined the temporal and spatial changes in expression of kisspeptin, gonadotropins and their respective receptors in the Senegalese sole during a full reproductive cycle. Kiss2 and kiss2r expression was determined by qRT-PCR in the forebrain and midbrain while expression of fshbeta and lhbeta was determined in the pituitary and fshr and lhr in the gonads. Plasma levels of testosterone (T), 11-ketotestosterone (11-KT) and estradiol-17beta were measured by ELISA and gonadal maturation was assessed histologically. In males, kiss2 and kiss2r expression in the brain areas examined was highest towards the end of winter, just before the spawning season, which took place the following spring. This coincided with maximum levels of pituitary fshbeta and lhbeta, plasma T and 11-KT and the highest number of maturing fish. However, these associations were not evident in females, since the highest expression of kiss2, kiss2r and gonadotropins were observed in the fall, winter or spring, depending upon the variable and tissue considered. Taken together, these data show not only temporal and spatial, but also sex-specific differences in the expression of kisspeptin and its receptor. Thus, while expression of kiss2 in Senegalese sole males agrees with what one would expect according to its proposed role as a major regulator of the onset of reproduction, in females the situation was not so clear, since kiss2 and kiss2r expression was highest either before or during the spawning season. PMID- 22537880 TI - Seasonal variations of cellular stress response in the heart and gastrocnemius muscle of the water frog (Pelophylax ridibundus). AB - The present study aimed to investigate the seasonal cellular stress response in the heart and the gastrocnemius muscle of the amphibian Pelophylax ridibundus (former name Rana ridibunda) during an 8 month acclimatization period in the field. Processes studied included heat shock protein expression and protein kinase activation. The cellular stress response was addressed through the expression of Hsp70 and Hsp90 and the phosphorylation of stress-activated protein kinases and particularly p38 mitogen-activated protein kinase (p38 MAPK), the extracellular signal-regulated kinases (ERK-1/2) and c-Jun N-terminal kinases (JNK1/2/3). Due to a general metabolic depression during winter hibernation, the induction of Hsp70 and Hsp90 and the phosphorylation of p38 MAPK, JNKs and ERKs are retained at low levels of expression in the examined tissues of P. ridibundus. Recovery from hibernation induces increased levels of the specific proteins, probably providing stamina to the animals during their arousal. PMID- 22537881 TI - Sustained hydrostatic pressure tolerance of the shallow water shrimp Palaemonetes varians at different temperatures: insights into the colonisation of the deep sea. AB - We investigated the tolerance of adult specimens of the shallow-water shrimp Palaemonetes varians to sustained high hydrostatic pressure (10 MPa) across its thermal tolerance window (from 5 to 27 degrees C) using both behavioural (survival and activity) and molecular (hsp70 gene expression) approaches. To our knowledge, this paper reports the longest elevated hydrostatic pressure exposures ever performed on a shallow-water marine organism. Behavioural analysis showed a 100% survival rate of P. varians after 7 days at 10 MPa and 5 or 10 degrees C, whilst cannibalism was observed at elevated temperature (27 degrees C), suggesting no impairment of specific dynamic action. A significant interaction of pressure and temperature was observed for both behavioural and molecular responses. Elevated pressure was found to exacerbate the effect of temperature on the behaviour of the animals by reducing activity at low temperature and by increasing activity at high temperature. In contrast, only high pressure combined with low temperature increased the expression of hsp70 genes. We suggest that the impressive tolerance of P. varians to sustained elevated pressure may reflect the physiological capability of an ancestral species to colonise the deep sea. Our results also support the hypothesis that deep-sea colonisation may have occurred during geological periods of time when the oceanic water column was warm and vertically homogenous. PMID- 22537883 TI - Lead electrical parameters may not predict integrity of the Sprint Fidelis ICD lead. AB - BACKGROUND: The reported failure rate of the Medtronic Sprint Fidelis defibrillator lead continues to increase over time. Clinicians and patients count on the electrical analysis of leads through device interrogation to determine whether a lead is functioning "normally." Most importantly, this analysis is often the basis for decision making around the ongoing use of this lead at the time of generator change. Can clinicians count on this analysis and feel confident that this "advisory" lead is "normal?" OBJECTIVE: To describe the incidence of unexpected lead abnormalities among Sprint Fidelis leads removed without prior evidence of electrical abnormalities. METHODS: We performed a retrospective cohort study of Medtronic Sprint Fidelis (6930, 6931, 6948, 6949) leads extracted at a single high-volume center. Medtronic analyzed all returned leads for abnormalities. The presence and type of lead abnormalities in addition to patient characteristics, indications for extraction, implant duration, and use of extraction sheath assistance are reported. RESULTS: Between September 2005 and January 2011, 209 Sprint Fidelis leads were extracted from 208 patients. The average duration of implant was 38.9 months (range 0.2-67.2). Of the analyzed leads, the majority of the extracted leads (63.1%) were active, normal functioning leads (83.8% prophylactically, 9.1% infection, and 7.1% other indication) while 36.9% had clinical evidence of a fracture. Extraction was achieved with simple traction in 39.5% of the leads; extraction sheath assistance was employed in 94 cases (59.9%), and surgical extraction at the time of transplant occurred in 1 case. Analysis of the 99 functionally "normal" leads removed determined that 20 leads had evidence of fractures (20.2%) not related to extraction. Of the fractured leads, 4 leads (20%) had more than 1 fracture and 1 lead had 3 separate fracture sites. There were 17 pacing conductor (10 proximal and 7 distal conductor) and 6 high-voltage conductor (1 superior vena cava and 5 right ventricle defibrillator conductor) fractures observed. Five additional leads (5.2%) had evidence of explant damage. CONCLUSIONS: Functionally "normal" Fidelis leads demonstrate an alarmingly high rate of "subclinical" fractures. Recommendations regarding prophylactic Sprint Fidelis lead extraction, especially at the time of generator change, may warrant reconsideration. To aid in the design of better leads, all leads should be returned for analysis, regardless of the indication for extraction. PMID- 22537882 TI - Funding health and social services for older people - a qualitative study of care recipients in the last year of life. AB - OBJECTIVES: This study explores the views of older adults who are receiving health and social care at the end of their lives, on how services should be funded, and describes their health-related expenditure. DESIGN: Qualitative interview study. SETTING: North West England. PARTICIPANTS: 30 people aged 69-93 years, diagnosed with lung cancer, heart failure or stroke and judged by health professionals to be in their last year of life. Sixteen participants lived in disadvantaged areas. MAIN OUTCOME MEASURES: Views of older adults on funding of services. RESULTS: Participants expressed a belief in an earned entitlement to services funded from taxation, based on a broad sense of being a good citizen. Irrespective of social background, older people felt that those who could afford to pay for social care, should do so. Sale of assets and use of children's inheritance to fund care was widely perceived as an injustice. The costs of living with illness are a burden, and families are filling many of the gaps left by welfare provision. People who had worked in low-wage occupations were most concerned to justify their current acceptance of services, and distance themselves from what they described as welfare 'spongers' or 'layabouts.' CONCLUSIONS: There is a gap between the health and social care system that older adults expect and what may be provided by a reformed welfare state at a time of financial stringencies. The values that underpinned the views expressed- mutuality, care for the most needy, and the importance of working to contribute to society--are an important contribution to the debate on welfare funding. PMID- 22537884 TI - A conflict of evidence: AVNRT or junctional tachycardia? PMID- 22537885 TI - Pharmacotherapy in Medicare beneficiaries with atrial fibrillation. AB - BACKGROUND: There are limited data regarding national patterns of pharmacotherapy for atrial fibrillation (AF) among older patients. Drug exposure data are now captured for Medicare beneficiaries enrolled in prescription drug plans. OBJECTIVE: To describe pharmacotherapy for AF among Medicare beneficiaries. METHODS: By using a 5% national sample of Medicare claims data, we compared demographic characteristics, comorbidity, and treatment patterns according to Medicare Part D status among patients with prevalent AF in 2006 and 2007. RESULTS: In 2006, 27,174 patients (29.3%) with prevalent AF were enrolled in Medicare Part D. In 2007, enrollment increased to 45,711 (49.1%). Most enrollees were taking rate-control agents (74.0% in 2007). beta-Blocker use was higher in those with concomitant AF and heart failure and increased with higher CHADS(2) scores (P <.001). Antiarrhythmic use was 18.7% in 2006 and 19.1% in 2007, with amiodarone accounting for more than 50%. Class Ic drugs were used in 3.2% of the patients in 2007. Warfarin use was <60% and declined with increasing stroke risk (P <.001). CONCLUSION: Pharmacotherapy for AF varied according to comorbidity and underlying risk. Amiodarone was the most commonly prescribed antiarrhythmic agent. Postmarketing surveillance using Medicare Part D claims data linked to clinical data may help inform comparative safety, effectiveness, and net clinical benefit of drug therapy for AF in older patients in real-world settings. PMID- 22537886 TI - The voltage-sensitive dye di-4-ANEPPS slows conduction velocity in isolated guinea pig hearts. AB - BACKGROUND: Voltage-sensitive dyes are important tools for mapping electrical activity in the heart. However, little is known about the effects of voltage sensitive dyes on cardiac electrophysiology. OBJECTIVE: To test the hypothesis that the voltage-sensitive dye di-4-ANEPPS modulates cardiac impulse propagation. METHODS: Electrical and optical mapping experiments were performed in isolated Langendorff perfused guinea pig hearts. The effect of di-4-ANEPPS on conduction velocity and anisotropy of propagation was quantified. HeLa cells expressing connexin 43 were used to evaluate the effect of di-4-ANEPPS on gap junctional conductance. RESULTS: In electrical mapping experiments, di-4-ANEPPS (7.5 MUM) was found to decrease both longitudinal and transverse conduction velocities significantly compared with control. No change in the anisotropy of propagation was observed. Similar results were obtained in optical mapping experiments. In these experiments, the effect of di-4-ANEPPS was dose dependent. di-4-ANEPPS had no detectable effect on connexin 43-mediated gap junctional conductance in transfected HeLa cells. CONCLUSION: Our results demonstrate that the voltage sensitive dye di-4-ANEPPS directly and dose-dependently modulates cardiac impulse propagation. The effect is not likely mediated by connexin 43 inhibition. Our results highlight an important caveat that should be taken into account when interpreting data obtained using di-4-ANEPPS in cardiac preparations. PMID- 22537888 TI - Lead contamination and source in Shanghai in the past century using dated sediment cores from urban park lakes. AB - Lead contamination becomes of importance to urban resident health worldwide, especially for child health and growth. Undisturbed lake sediment cores are increasingly employed as a useful tool to backdate environmental contamination history. Five intact sediment cores collected from lakes in five urban parks were dated using (210)Pb and analyzed for total Pb content and isotope ratio to reconstruct the Pb contamination history over the last century in Shanghai, China. Total Pb content in the sediment cores increased by about 2- to 3-fold since 1900s. The profile of Pb flux in each sediment core revealed a remarkable increase of Pb contamination in Shanghai over the past century, especially in the latest three decades when China was experiencing a rapid economic and industrial development. Significant correlations were found between Pb fluxes in sediment cores and Pb emission from coal combustion in Shanghai. Coal combustion emission dominated anthropogenic Pb sources during the past century contributing from 52% to 69% of total Pb in cores, estimated by a three-end member model of Pb isotope ratios. Leaded gasoline emission generally contributed <30% of total Pb, which was banned by 1997 in the Shanghai region. Our results implicate that coal combustion-based energy consumption should be replaced, or at least partially replaced, to reduce health risks of Pb contamination in Shanghai. PMID- 22537887 TI - Tumor heterogeneity and its implication for drug delivery. AB - Evidence continues to accumulate that patient tumors contain heterogeneous cell populations, each of which may contribute differently in extent and mechanism to the progression of malignancy. However, the field of tumor drug delivery research, while continually presenting new and innovative approaches, in many ways continues to operate on the premise that essentially all tumor cells are identical. In some in vivo models, xenograft tumors using cell lines may actually be comparatively homogeneous, and thus result in overly encouraging results when a particular drug or delivery system is reported to successfully treat tumors in mice. It is well known, however, that many drugs that show success in preclinical studies will fail in clinical trials. Tumor heterogeneity is possibly one of the most significant factors that most treatment methods fail to address sufficiently. While a particular drug may exhibit initial success, the eventual relapse of tumor growth is due in many cases to subpopulations of cells that are either not affected by the drug mechanism, possess or acquire a greater drug resistance, or have a localized condition in their microenvironment that enables them to evade or withstand the drug. These various subpopulations may include cancer stem cells, mutated clonal variants, and tumor-associated stromal cells, as well as cells experiencing a spatially different condition such as hypoxia within a diffusion-limited tumor region. This review briefly discusses some of the many aspects of tumor heterogeneity and their potential implications for future drug design and delivery methods. PMID- 22537889 TI - Co-composting of spent coffee ground with olive mill wastewater sludge and poultry manure and effect of Trametes versicolor inoculation on the compost maturity. AB - The co-composting of spent coffee grounds, olive mill wastewater sludge and poultry manure was investigated on a semi-industrial scale. In order to reduce the toxicity of the phenolic fraction and to improve the degree of composting humification, composts were inoculated with the white-rot fungus Trametes versicolor in the early stages of the maturation phase. During composting, a range of physico-chemical parameters (temperature and both organic matter and C/N reduction), total organic carbon, total nitrogen, elemental composition, lignin degradation and spectroscopic characteristics of the humic acids (HAs) were determined; impacts of the composting process on germination index of Hordeum vulgare and Lactuca sativa were assessed. The coffee waste proved to be a highly compostable feedstock, resulting in mature final compost with a germination index of 120% in less than 5 months composting. In addition, inoculation with T. versicolor led to a greater degree of aromatization of HA than in the control pile. Moreover, in the inoculated mixture, lignin degradation was three times greater and HA increased by 30% (P<0.05), compared to the control pile. In the T. versicolor inoculated mixture, the averages of C and N were significantly enhanced in the HA molecules (P<0.05), by 26% and 22%, respectively. This improvement in the degree of humification was confirmed by the ratio of optical densities of HA solutions at 465 and 665 nm which was lower for HA from the treated mixture (4.5) than that from the control pile (5.4). PMID- 22537890 TI - Fate and transport of atorvastatin and simvastatin drugs during conventional wastewater treatment. AB - This research investigates the environmental behavior of two widely prescribed cholesterol-lowering statin drugs that are expected to be present at significant concentrations in wastewater influents, namely: atorvastatin and simvastatin. Batch biodegradation experiments suggest that both statins are well degraded during secondary treatment, and removal rates exhibit a substrate-enhancement model reflecting elements of both first-order behavior and cometabolism. Resulting biodegradation parameters are used in conjunction with literature sorption parameters to construct a mass-balance model of statin concentrations during conventional treatment. Model results exhibit excellent accuracy compared to measurements from a medium-sized WWTP in the Southeastern USA. Influent concentrations of 1.56 MUg L(-1) and 1.23 MUg L(-1) were measured for atorvastatin and simvastatin. Results also suggest that 85-90% of each drug is removed during conventional treatment, with sorption accounting for less than 10% of overall removal. Expected effluent concentrations are orders of magnitude less than previously reported ecotoxicity thresholds for both drugs. Overall, results suggest statin active ingredients do not pose a significant environmental threat. It is recommended that future work characterize the fate of statin metabolites and that the same mass-balance modeling approach be used to assess other highly prescribed pharmaceutical drugs. PMID- 22537891 TI - Phosphorus flame retardants: properties, production, environmental occurrence, toxicity and analysis. AB - Since the ban on some brominated flame retardants (BFRs), phosphorus flame retardants (PFRs), which were responsible for 20% of the flame retardant (FR) consumption in 2006 in Europe, are often proposed as alternatives for BFRs. PFRs can be divided in three main groups, inorganic, organic and halogen containing PFRs. Most of the PFRs have a mechanism of action in the solid phase of burning materials (char formation), but some may also be active in the gas phase. Some PFRs are reactive FRs, which means they are chemically bound to a polymer, whereas others are additive and mixed into the polymer. The focus of this report is limited to the PFRs mentioned in the literature as potential substitutes for BFRs. The physico-chemical properties, applications and production volumes of PFRs are given. Non-halogenated PFRs are often used as plasticisers as well. Limited information is available on the occurrence of PFRs in the environment. For triphenyl phosphate (TPhP), tricresylphosphate (TCP), tris(2 chloroethyl)phosphate (TCEP), tris(chloropropyl)phosphate (TCPP), tris(1,3 dichloro-2-propyl)phosphate (TDCPP), and tetrekis(2 chlorethyl)dichloroisopentyldiphosphate (V6) a number of studies have been performed on their occurrence in air, water and sediment, but limited data were found on their occurrence in biota. Concentrations found for these PFRs in air were up to 47 MUg m(-3), in sediment levels up to 24 mg kg(-1) were found, and in surface water concentrations up to 379 ng L(-1). In all these matrices TCPP was dominant. Concentrations found in dust were up to 67 mg kg(-1), with TDCPP being the dominant PFR. PFR concentrations reported were often higher than polybrominated diphenylether (PBDE) concentrations, and the human exposure due to PFR concentrations in indoor air appears to be higher than exposure due to PBDE concentrations in indoor air. Only the Cl-containing PFRs are carcinogenic. Other negative human health effects were found for Cl-containing PFRs as well as for TCP, which suggest that those PFRs would not be suitable alternatives for BFRs. TPhP, diphenylcresylphosphate (DCP) and TCP would not be suitable alternatives either, because they are considered to be toxic to (aquatic) organisms. Diethylphosphinic acid is, just like TCEP, considered to be very persistent. From an environmental perspective, resorcinol-bis(diphenylphosphate) (RDP), bisphenol A diphenyl phosphate (BADP) and melamine polyphosphate, may be suitable good substitutes for BFRs. Information on PFR analysis in air, water and sediment is limited to TCEP, TCPP, TPhP, TCP and some other organophosphate esters. For air sampling passive samplers have been used as well as solid phase extraction (SPE) membranes, SPE cartridges, and solid phase micro-extraction (SPME). For extraction of PFRs from water SPE is recommended, because this method gives good recoveries (67-105%) and acceptable relative standard deviations (RSDs) (<20%), and offers the option of on-line coupling with a detection system. For the extraction of PFRs from sediment microwave-assisted extraction (MAE) is recommended. The recoveries (78-105%) and RSDs (3-8%) are good and the method is faster and requires less solvent compared to other methods. For the final instrumental analysis of PFRs, gas chromatography-flame photometric detection (GC FPD), GC-nitrogen-phosphorus detection (NPD), GC-atomic emission detection (AED), GC-mass spectrometry (MS) as well as liquid chromatography (LC)-MS/MS and GC Inductively-coupled plasma-MS (ICP-MS) are used. GC-ICP-MS is a promising method, because it provides much less complex chromatograms while offering the same recoveries and limits of detection (LOD) (instrumental LOD is 5-10 ng mL(-1)) compared to GC-NPD and GC-MS, which are frequently used methods for PFR analysis. GC-MS offers a higher selectivity than GC-NPD and the possibility of using isotopically labeled compounds for quantification. PMID- 22537892 TI - [Prevalence of gastroesophageal reflux disease in Uruguay]. AB - BACKGROUND: Gastroesophageal reflux disease (GERD) is a common condition, with wide geographical differences worldwide. There are no epidemiological data on this disease for Uruguay. OBJECTIVE: To estimate the prevalence of GERD in two adult populations in Uruguay (urban and hospital) through the Gastroesophageal reflux disease Questionnaire (GerdQ) questionnaire and evaluation of typical symptoms. MATERIAL AND METHOD: A descriptive, cross-sectional study was carried out through the use of two diagnostic methods administered in two settings: an urban and a hospital setting. The first method consisted of administration of the standardized GerdQ structured questionnaire and the other consisted of evaluating the typical symptoms of GERD. A total of 1141 persons from the urban population, with a mean age of 52 years (+/- 18 years), and 163 persons from a gastroenterology polyclinic, with a mean age of 53 years (+/- 16 years), were included. RESULTS: The prevalence of GERD in Uruguay was 4.69%, (95% CI 2.92 6.46%) when the GerdQ questionnaire was used, but increased to 14.14% (95% CI 12.57-15.71) when only typical symptoms were considered. In the hospital sample, the prevalence was 11.66% (95% CI 6.42-16.89%) and 20.25% (95% CI 14.01-26.48), respectively. CONCLUSION: The prevalence obtained in the urban population of Uruguay with the GerdQ questionnaire in the symptomatic (hospital) population was more than double that in the general population, 11.66% and 4.69%, respectively. Evaluation of symptoms, pyrosis and/or regurgitation systematically yields a higher prevalence. Consensus on the definition of GERD and on the instrument used for its diagnosis are essential to interpret and compare epidemiological studies. PMID- 22537893 TI - Postnatal development of transmural gradients in expression of ion channels and Ca2+-handling proteins in the ventricle. AB - Transmural gradients in myocyte action potential duration (APD) and Ca(2+) handling proteins are argued to be important for both the normal functioning of the ventricle and arrhythmogenesis. In rabbit, the transmural gradient in APD (left ventricular wedge preparation) is minimal in the neonate. During postnatal development, APD increases both in the epicardium and the endocardium, but the prolongation is more substantial in the endocardium leading to a significant transmural gradient. We have investigated changes in the expression of ion channels and also Ca(2+)-handling proteins in the subepicardial and subendocardial layers of the left ventricular free wall in neonatal (2-7 days of age) and adult male (~6 months of age) New Zealand White rabbits using quantitative PCR and also, when possible, in situ hybridisation and immunohistochemistry. In the adult, there were significant and substantial transmural gradients in Ca(v)1.2, KChIP2, ERG, K(v)LQT1, K(ir)2.1, NCX1, SERCA2a and RyR2 at the mRNA and, in some cases, protein level-in every case the mRNA or protein was more abundant in the epicardium than the endocardium. Of the eight transmural gradients seen in the adult, only three were observed in the neonate and, in two of these cases, the gradients were smaller than those in the adult. However, in the neonate there were also transmural gradients not observed in the adult: in HCN4, Na(v)1.5, minK, K(ir)3.1 and Cx40 mRNAs - in every case the mRNA was more abundant in the endocardium than the epicardium. If the postnatal changes in ion channel mRNAs are used to predict changes in ionic conductances, mathematical modelling predicts the changes in APD observed experimentally. It is concluded that many of the well known transmural gradients in the ventricle develop postnatally. PMID- 22537894 TI - [Rugby player with an "elephant's foot" in the chest]. PMID- 22537895 TI - [Total laparoscopic mesorectal excision versus robot-assisted in the treatment of rectal cancer: a meta-analysis]. AB - A systematic literature review and meta-analysis was performed using the MEDLINE, EMBASE and COCHRANE LIBRARY data bases, and identifying clinical trials, published between the years 2005 to 2010, that compared the short term results of conventional laparoscopic total mesorectal excision (L-TME) and robot-assisted total mesorectal excision (RA-TME) in the treatment of non-complicated rectal cancer. Five trials with a total of 380 patients were selected, of whom 169 were subjected to RA-TME and 211 to L-TME. No significant differences were found, although RA-TME was associated with a lower conversion rate, a greater resection margin circumference, and higher number of isolated lymph nodes, as well as a lower overall rate of complications. There was no evidence that RA-TME had advantages that compensated for the longer duration of the surgery and the higher cost of the procedure. More randomised prospective studies and a greater number of patients are needed. PMID- 22537896 TI - [Aortic thrombosis in a patient with essential thrombocythemia]. PMID- 22537897 TI - [Liver abscess due to listeria monocytogenes]. PMID- 22537898 TI - [Cystic hepatic lymphangioma: a rare cause of abdominal pain in the adult]. PMID- 22537899 TI - [Intra-abdominal abcess due to a faecalith after laparoscopic appendicectomy]. PMID- 22537900 TI - Blast-induced moderate neurotrauma (BINT) elicits early complement activation and tumor necrosis factor alpha (TNFalpha) release in a rat brain. AB - Blast-induced neurotrauma (BINT) is a major medical concern yet its etiology is largely undefined. Complement activation may play a role in the development of secondary injury following traumatic brain injury; however, its role in BINT is still undefined. The present study was designed to characterize the complement system and adaptive immune-inflammatory responses in a rat model of moderate BINT. Anesthetized rats were exposed to a moderate blast (120 kPa) using an air driven shock tube. Brain tissue injury, systemic and local complement, cerebral edema, inflammatory cell infiltration, and pro-inflammatory cytokine production were measured at 0.5, 3, 48, 72, 120, and 168 h. Injury to brain tissue was evaluated by histological evaluation. Systemic complement was measured via ELSIA. The remaining measurements were determined by immunohistoflourescent staining. Moderate blast triggers moderate brain injuries, elevated levels of local brain C3/C5b-9 and systemic C5b-9, increased leukocyte infiltration, unregulated tumor necrosis factor alpha (TNFalpha), and aquaporin-4 in rat brain cortex at 3- and 48-hour post blast. Early immune-inflammatory response to BINT involves complement and TNFalpha, which correlates with hippocampus and cerebral cortex damage. Complement and TNFalpha activation may be a novel therapeutic target for reducing the damaging effects of BINT inflammation. PMID- 22537902 TI - Colorectal cancer with synchronous liver metastases: does global management at the same centre improve results? AB - BACKGROUND: Synchronous liver metastases (SLM) occur in 20% of colorectal cancers (CRC). Resection of SLM and CLC can be undertaken at different centres (separate management, SM) or at the same centre (global management, GM). METHODS: Retrospective study of SLM and CRC resections carried out during 01/2000 - 12/2006 by SM or GM, using a combined or delayed strategy. RESULTS: Morphologic characteristics and type of CRC and SLM resection were similar for the GM (n = 45) or SM (n = 66) groups. In patients with delayed liver resection (62 SM, 17 GM), chemotherapy prior to liver surgery was used in 92% and 38% of SM and GM patients (P < 0.0001) and the median delay between procedures was 212 and 182 days, respectively (P = 0.04). First step of liver resection was more often performed during colorectal surgery in the GM group (62 vs. 6% for SM, P < 0.0001) and the mean number of procedures (CRC+SLM) was lower (1.6 vs. 2.3, P = 0.003). Three-month mortality was 3% for GM and 0% for SM (n.s.). Overall survival rates were 67% and 51% for SM and GM at 3 years (n.s.), and 35 and 31% at 5 years (n.s.). Disease-free survival to 5 years was higher in SM patients (14% vs. 11%, P = 0.009). CONCLUSIONS: GM of CRC and SLM was associated with fewer procedures but did not influence overall survival. SM was associated with a longer delay and increased use of chemotherapy between procedures, suggesting that more rigorous selection of SM patients for surgery may explain the higher disease-free survival after SLM resection. PMID- 22537901 TI - CIP2A is a target of bortezomib in human triple negative breast cancer cells. AB - INTRODUCTION: Triple negative breast cancer (TNBC) is very aggressive and currently has no specific therapeutic targets, such as hormone receptors or human epidermal growth factor receptor type 2 (HER2); therefore, prognosis is poor. Bortezomib, a proteasome inhibitor, may exert efficacy in TNBC through its multiple cellular effects. Here, we tested the efficacy of bortezomib and examined the drug mechanism in breast cancer cells. METHODS: Five breast cancer cell lines: TNBC HCC-1937, MDA-MB-231, and MDA-MB-468; HER2-overexpressing MDA-MB 453; and estrogen receptor positive MCF-7 were used for in vitro studies. Apoptosis was examined by both flow cytometry and Western Blot. Signal transduction pathways in cells were assessed by Western Blot. Gene silencing was done by small interfering RNA (siRNA). In vivo efficacy of bortezomib was tested in nude mice with breast cancer xenografts. Immunohistochemical study was performed on tumor tissues from patients with TNBC. RESULTS: Bortezomib induced significant apoptosis, which was independent of its proteasome inhibition, in the three TNBC cell lines, but not in MDA-MB-453 or MCF-7 cells. Furthermore, cancerous inhibitor of protein phosphatase 2A (CIP2A), a cellular inhibitor of protein phosphatase 2A (PP2A), mediated the apoptotic effect of bortezomib. We showed that bortezomib inhibited CIP2A in association with p-Akt downregulation in a dose- and time-dependent manner in all sensitive TNBC cells, whereas no alterations in CIP2A expression and p-Akt were noted in bortezomib-resistant cells. Overexpression of CIP2A upregulated p-Akt and protected MDA-MB-231 and MDA MB-468 cells from bortezomib-induced apoptosis, whereas silencing CIP2A by siRNA overcame the resistance to bortezomib-induced apoptosis in MCF-7 cells. In addition, bortezomib downregulated CIP2A mRNA but did not affect the degradation of CIP2A protein. Furthermore, bortezomib exerted in vivo antitumor activity in HCC-1937 xenografted tumors, but not in MCF-7 tumors. Bortezomib downregulated CIP2A expression in the HCC-1937 tumors but not in the MCF-7 tumors. Importantly, CIP2A expression is readily detectable in tumor samples from TNBC patients. CONCLUSIONS: CIP2A is a major determinant mediating bortezomib-induced apoptosis in TNBC cells. CIP2A may thus be a potential therapeutic target in TNBC. PMID- 22537903 TI - Liver tumours, toxic hepatitis, intestinal failure-associated liver disease in children. AB - Liver cancers in children are primitive (hepatoblastoma, fibrolamellar hepatocarcinoma, sarcomas), or arise on a genetic or viral disease. Their treatment is a combination of chemotherapy (hepatoblastoma) and surgery. Neonatal hemangioendotheliomas may induce heart failure. They are now successfully treated with propranolol. Focal nodular hyperplasia is the most frequent benign tumour in older children and adolescents. Drug hepatotoxicity is not very frequent. Antipyretic drugs may induce severe side effects. Liver failure due to valproic acid is diagnostic of a respiratory chain disorder. The liver side effects of antituberculous and antiretroviral drugs should be monitored. Intestinal failure associated liver disease is common and can be prevented or treated. Early referral to a specialized centre is important for the prognosis. PMID- 22537904 TI - Mind and consciousness: Towards a final answer? AB - A review is given of recent developments in our scientific understanding of consciousness to help guide further progress, leading to a possible final answer to the question of how the brain may create consciousness. The review commences with a brief description of the nature of consciousness, and moves to an overview of various approaches presently being pursued to understand it (quantum mechanics, 40-Hz, dynamical systems theory and complexity, narrative centre of gravity, global workspace, relational mind). To help move the discussion forward we use the fact that attention acts as the gateway to consciousness, implying the need to analyze attention most closely. An engineering control approach is introduced to model the movement of attention, based on experimental data indicating separate sites for attention modulation and for the creation of that modulation: and using the analogy with motor control in the brain, to which an engineering approach has already been applied by others. Simulation and brain imaging results support the presence of several of the relevant attention control modules in the brain. The attention control framework is extended to analyze how consciousness could arise during attentive processing, in terms of the COrollary Discharge of Attention Movement (CODAM) model. The relation between the CODAM model of consciousness and modern approaches to consciousness in the philosophy of mind is then briefly described. An overall summary and a program of future explorations of the CODAM model conclude the review. PMID- 22537905 TI - Prebiological evolution and the physics of the origin of life. AB - The basic tenet of the heterotrophic theory of the origin of life is that the maintenance and reproduction of the first living systems depended primarily on prebiotically synthesized organic molecules. It is unlikely that any single mechanism can account for the wide range of organic compounds that may have accumulated on the primitive Earth, suggesting that the prebiotic soup was formed by contributions from endogenous syntheses in reducing environments, metal sulphide-mediated synthesis in deep-sea vents, and exogenous sources such as comets, meteorites and interplanetary dust. The wide range of experimental conditions under which amino acids and nucleobases can be synthesized suggests that the abiotic syntheses of these monomers did not take place under a narrow range defined by highly selective reaction conditions, but rather under a wide variety of settings. The robustness of this type of chemistry is supported by the occurrence of most of these biochemical compounds in the Murchison meteorite. These results lend strong credence to the hypothesis that the emergence of life was the outcome of a long, but not necessarily slow, evolutionary processes. The origin of life may be best understood in terms of the dynamics and evolution of sets of chemical replicating entities. Whether such entities were enclosed within membranes is not yet clear, but given the prebiotic availability of amphiphilic compounds this may have well been the case. This scheme is not at odds with the theoretical models of self-organized emerging systems, but what is known of biology suggest that the essential traits of living systems could have not emerged in the absence of genetic material able to store, express and, upon replication, transmit to its progeny information capable of undergoing evolutionary change. How such genetic polymer first evolved is a central issue in origin-of-life studies. PMID- 22537907 TI - Toddaculin, a natural coumarin from Toddalia asiatica, induces differentiation and apoptosis in U-937 leukemic cells. AB - Chemotherapeutics represent the main approach for the treatment of leukemia. However, the occurrence of adverse side effects and the complete lack of effectiveness in some cases make it necessary to develop new drugs. As part of our screening program to evaluate the potential chemotherapeutic effect of natural coumarins, we investigated the anti-leukemic activities of a series of six prenylated coumarins isolated from the stem bark of Toddalia asiatica (Rutaceae). Among these, 6-(3-methyl-2-butenyl)-5,7-dimethoxycoumarin (toddaculin) displayed the most potent cytotoxic and anti-proliferative effects in U-937 cells. To determine whether these effects resulted from induction of cell death or differentiation, we further evaluated the expression of several apoptosis and maturation markers. Interestingly, while toddaculin at 250 MUM was able to induce apoptosis in U-937 cells, involving decreased phosphorylation levels of ERK and Akt, 50 MUM toddaculin exerted differentiating effects, inducing both the capacity of U-937 cells to reduce NBT and the expression of differentiation markers CD88 and CD11b, but no change in p-Akt or p-ERK levels. Taken together, these findings indicate that toddaculin displays a dual effect as a cell differentiating agent and apoptosis inducer in U-937 cells, suggesting it may serve as a pharmacological prototype for the development of novel anti leukemic agents. PMID- 22537906 TI - Establishment of a biomarker model for predicting bone metastasis in resected stage III non-small cell lung cancer. AB - BACKGROUND: This study was designed to establish a biomarker risk model for predicting bone metastasis in stage III non-small cell lung cancer (NSCLC). METHODS: The model consists of 105 cases of stage III NSCLC, who were treated and followed up. The patients were divided into bone metastasis group (n = 45) and non-bone metastasis group (other visceral metastasis and those without recurrence) (n = 60). Tissue microarrays were constructed for immunohistochemical study of 10 molecular markers associated with bone metastasis, based on which a model was established via logistic regression analysis for predicting the risk of bone metastases. The model was prospectively validated in another 40 patients with stage III NSCLC. RESULTS: The molecular model for predicting bone metastasis was logit (P) = - 2.538 + 2.808 CXCR4 +1.629 BSP +0.846 OPN-2.939 BMP4. ROC test showed that when P >= 0.408, the sensitivity was up to 71% and specificity of 70%. Model validation in the 40 cases in clinical trial (NCT 01124253) demonstrated that the prediction sensitivity of the model was 85.7%, specificity 66.7%, Kappa: 0.618, with a high degree of consistency. CONCLUSION: The molecular model combining CXCR4, BSP, OPN and BMP4 could help predict the risk of bone metastasis in stage IIIa and IIIb resected NSCLC. PMID- 22537908 TI - Endogenous CO2 may inhibit bacterial growth and induce virulence gene expression in enteropathogenic Escherichia coli. AB - Analysis of the growth kinetics of enteropathogenic Escherichia coli (EPEC) revealed that growth was directly proportional to the ratio between the exposed surface area and the liquid culture volume (SA/V). It was hypothesized that this bacterial behavior was caused by the accumulation of an endogenous volatile growth inhibitor metabolite whose escape from the medium directly depended on the SA/V. The results of this work support the theory that an inhibitor is produced and indicate that it is CO(2). We also report that concomitant to the accumulation of CO(2), there is secretion of the virulence-related EspB and EspC proteins from EPEC. We therefore postulate that endogenous CO(2) may have an effect on both bacterial growth and virulence. PMID- 22537909 TI - Implementation of an evidence-based depression care management program (PEARLS): perspectives from staff and former clients. AB - INTRODUCTION: Although researchers develop evidence-based programs for public health practice, rates of adoption and implementation are often low. This qualitative study aimed to better understand implementation of the Program to Encourage Active, Rewarding Lives for Seniors (PEARLS), a depression care management program at a Seattle-King County area agency on aging. METHODS: We used stratified, purposive sampling in 2008 to identify 38 PEARLS clients and agency staff for participation. In 9 focus groups and 1 one-on-one interview, we asked participants to identify benefits and negative consequences of PEARLS, facilitators of and barriers to program implementation, and strategies for overcoming the barriers. Two independent researchers used thematic analysis to categorize data into key themes and subthemes. RESULTS: PEARLS benefits clients by decreasing depression symptoms and addressing other concerns, such as health problems. For staff, PEARLS provides "another set of eyes" and is a comprehensive program to help them meet clients' mental health needs. Barriers included issues with implementation process (eg, lack of communication) and the perception that eligibility criteria were more rigid than those of other agency programs. Recommended solutions included changing eligibility criteria, providing additional staff training, increasing communication, and clarifying referral procedures, roles, and responsibilities. CONCLUSION: Barriers to PEARLS delivery discourage referrals to what is generally viewed as a beneficial program. Implementing participants' strategies for overcoming these barriers can enhance delivery of PEARLS to a greater number of older adults and help them improve their depression symptoms. PMID- 22537911 TI - Annual conference on hereditary cancers 2011 szczecin, poland. 17-18 november 2011. Abstracts. PMID- 22537910 TI - Policy implications for local application of the 2009 Youth Risk Behavior Survey, Duval County, Florida. AB - INTRODUCTION: Youth Risk Behavior Survey (YRBS) data have rarely been analyzed at the subcounty level. The purpose of this study was to explore the feasibility of such analysis and its potential to inform local policy and resource allocation. METHODS: We administered the 2009 YRBS to 5,860 students from 46 public middle and high schools in Duval County, Florida. In addition to asking core questions, we asked a set of questions customized for local needs, including questions about zip codes. These data were used to simulate subcounty areas consistent with areas identified by behavioral, morbidity, mortality, and health disparity surveillance. We oversampled Duval County and used weighting procedures that adjusted for subcounty areas. RESULTS: Many Duval County health risk behavior rates were higher than those for Florida overall but did not vary significantly within the county. Physical activity and violence-related behaviors were exceptions that reflect major health disparities in parts of the county with a high proportion of racial/ethnic minorities. CONCLUSION: This study demonstrated that collecting subcounty data in large metropolitan areas is feasible and that analysis of these data at the local level has implications for policy. Some health risk behaviors were common across the county, indicating the need for health promotion and disease prevention programs at the school district level. Other health risk behaviors were more prevalent in specific areas of the county and may have been exacerbated by state or local policies such as restrictions on physical education. Health disparities remain a challenge throughout the country; reducing them will require more extensive data-driven problem solving at state and local levels. PMID- 22537912 TI - Structural and functional analysis of native peroxiredoxin 2 in human red blood cells. AB - Peroxiredoxin 2, a typical 2-Cys peroxiredoxin, is the third most abundant protein in erythrocytes. It is understood that the physiologically functional state of peroxiredoxin 2 is the monomer, and that its role in scavenging low levels of H(2)O(2) results in the formation of disulfide-linked dimers, which are reversibly reduced to monomers by the thioredoxin-thioredoxin reductase system. Additionally, peroxiredoxins are highly susceptible to sulfinic acid formation through reactions with various peroxides. This overoxidized form, which is thought to convert peroxiredoxins into molecular chaperones and to be accompanied by a transition to polymeric forms, can be reversed by sulfiredoxins. However, physiological conformational changes and the antioxidant role of erythrocyte peroxiredoxin 2 are still unclear because there is low sulfiredoxin and thioredoxin-thioredoxin reductase activity in erythrocytes. In this study, we examined the structural and redox states of peroxiredoxin 2 in fresh hemolysates and estimated the activities of native and overoxidized peroxiredoxin 2 purified from red blood cells to clear the physiological roles of peroxiredoxin 2 in erythrocyte. Our findings demonstrate that native peroxiredoxin 2 exists as high molecular weight (>160 kDa) oligomers and that decamers or higher order molecular weight oligomers (260-460 kDa) have peroxidase activity. We further showed that peroxiredoxin 2 oligomers, which were predominantly composed of monomers in the reduced form, exert a chaperone activity equal to that of overoxidized peroxiredoxin 2 polymers. These results provide the novel insight that redox active peroxiredoxin 2 functions in human red blood cells as high molecular weight oligomers that possess peroxidase and chaperone activities. PMID- 22537913 TI - Brevican: a key proteoglycan in the perisynaptic extracellular matrix of the brain. AB - Brevican is a neural proteoglycan implicated in a multitude of physiological and pathophysiological plasticity processes in the brain. It localizes to neuronal surfaces and contributes to the formation of specific types of extracellular matrix like the perineuronal nets or the perisynaptic or axon initial segment based matrix in mature neuronal tissue. Via a variable degree of chondroitin sulfate attachment, limited proteolytic cleavage by matrix metalloproteinases, differential splicing and Ca(2+)-dependent binding to interaction partners it acts as a regulator in synaptic plasticity, glioma invasion, post-lesion plasticity or Alzheimer's disease. This review briefly summarizes its gene and protein structure, biochemical interactions and neurobiological functions. PMID- 22537914 TI - Animacy and competition in relative clause production: a cross-linguistic investigation. AB - This work investigates production preferences in different languages. Specifically, it examines how animacy, competition processes, and language specific constraints shape speakers' choices of structure. English, Spanish and Serbian speakers were presented with depicted events in which either an animate or inanimate entity was acted upon by an agent. Questions about the affected participant in these events prompted the production of relative clauses identifying these entities (e.g., the bag the woman is punching). Results indicated that in English, animacy plays a strong role in determining the choice of passive structures. In contrast, it plays a less prominent role in Spanish and Serbian structure choices, where more active structures were produced to varying degrees. Critically, the semantic similarity between the agent and the patient of the event correlated with the omission of the agent in all languages, indicating that competition resulted in the agent's inhibition. Similarity also correlated with different functional choices in Spanish. The results suggest that similarity based competition may influence various stages of production planning but its manifestations are constrained by language-specific grammatical options. Implications for models of sentence production and the relationship between production and comprehension are discussed. PMID- 22537915 TI - Interferon-gamma release assays for the tuberculosis serial testing of health care workers: a systematic review. AB - BACKGROUND: Interferon-gamma release assays (IGRAs) are increasingly used in the tuberculosis (TB) screening of health care workers (HCWs). However, comparatively high rates of conversions and reversion as well as growing evidence of substantial within-subject variability of interferon-gamma responses complicate their interpretation in the serial testing of HCWs. METHODS: We conducted a systematic review on the repeat use of the two commercial IGRAs, the QuantiFERON TB Gold or In-Tube version (QFT) and the T-SPOT.TB (T-SPOT), in the serial testing and its with-subject variability among HCWs in order to provide guidance on how to interpret serial testing results in the context of the periodic screening of subjects with an increased occupational risk of latent TB infection (LTBI) in countries with low and intermediate TB incidence rates. The Medline, Embase, and Cochrane databases were searched without restrictions. Retrieved articles were complemented by additional hand searched records. Only studies that used commercial IGRAs among HCWs apart from contact and outbreak investigations and those fulfilling further predefined criteria were included. RESULTS: Overall, 20 studies, five using the T-SPOT and 19 using the QFT assay, were included. Fifteen studies met eligibility criteria for serial testing and five studies for within-subject variability. Irrespective of TB incidence rates in the study's country of origin, reversion rates were consistently higher than conversion rates (range 22-71% vs. 1-14%). Subjects with baseline results around the diagnostic threshold were more likely to show inconsistent results on retesting. The within subject variability of interferon-gamma responses was considerable across all studies systematically assessing it. CONCLUSIONS: On the basis of reviewed studies we advocate using a borderline zone from 0.2-0.7 IU/ml for the interpretation of repeat QFT results in the routine screening of HCWs with an increased LTBI risk. Subjects with QFT results within this borderline zone, with suspected fresh infection, and those who are considered for preventive chemotherapy should be retested with the QFT within a period of about four weeks before preventive chemotherapy is recommended. However, the available data regarding the use of the T-SPOT in the serial testing of HCWs is remarkably limited and warrants further research. PMID- 22537916 TI - [Which patients benefit the most from hospital geriatric care in the opinion of the geriatricians?]. AB - OBJECTIVE: To assess the most appropriate criteria considered by geriatricians to select patients who might benefit the most from geriatric hospital care. MATERIAL AND METHODS: We carried out a survey that consisted of various socio-demographic, clinical, functional and mental criteria included in the definition of the geriatric and frail elderly patient. The survey was sent to all specialists in geriatrics in the different hospitals of the Madrid Health Service. They were asked to answer to each criterion indicating whether they considered it as high priority, priority, low priority or no priority. The responses were clustered by type of hospital: acute hospitals with or without a post-graduate geriatric program for medical residents, and medium and long stay hospitals. RESULTS: A total of 83 questionnaires were completed (70% of the study population): 42 teaching hospitals a post-graduate geriatric program (74% of possible), 20 of those with an emergency department but without a post-graduate geriatric program (56% of possible), and 21 medium and long stay hospitals (84% of potential). All proposed criteria were considered individually as priority or high-priority by more than 50% of respondents. An age 85 years and over, admission for hip fracture, the presence of severe cognitive or functional impairment, frailty, and unexplained deterioration of health status, were considered individually as criteria for selecting high-priority target population by more than 85% of respondents. CONCLUSIONS: Certain criteria, such as advanced age, or the presence of geriatrics-specific conditions, such as hip fracture or severe functional or cognitive impairment, are identified by geriatricians as useful to select patients to receive geriatric specialist hospital care. PMID- 22537917 TI - Clinical significance of stanniocalcin-1 detected in peripheral blood and bone marrow of esophageal squamous cell carcinoma patients. AB - BACKGROUND: Stanniocalcin-1 (STC-1) is a potential marker of disseminated tumor cells (DTCs). The aim of this study was to examine STC-1 expression in peripheral blood (PB) and bone marrow (BM) of esophageal squamous cell carcinoma (ESCC) patients, and to evaluate its clinical significance. METHODS: A total of 85 ESCC patients treated with radical resection were enrolled in this study. Immunohistochemistry was used to detect STC-1 protein expression in ESCC tissues. Nested RT-PCR was used to detect STC-1 mRNA expression in PB and BM. RESULTS: There were 71 cases (83.5%) showed a higher level of STC-1 protein expression in tumor tissues than in adjacent normal tissues (P < 0.001). Furthermore, the frequencies of STC-1 mRNA expression detected in PB and BM were 37.6% (32/85) and 21.2% (18/85), respectively, and together increased sensitivity to 48.2% (41/85), which was much higher than that in patients with benign esophageal disease (5.0%, 2/40, P < 0.001). In addition, STC-1 mRNA expression either in PB or BM was correlated with lymph metastasis, advanced stage and adverse 2-year progression free survival (PFS). In a multivariate analysis using the Cox proportional hazard model, STC-1 expression in PB and/or BM was an independent unfavorable prognostic factor for ESCC, apart from lymph metastasis and clinical stage. CONCLUSIONS: STC 1 mRNA expression is a reliable marker for detection of DTCs in PB and BM of ESCC patients, and STC-1-positive DTCs may be a promising tool for diagnosis and prognosis assessment in ESCC. PMID- 22537918 TI - Toxicity and inhibition of bacterial growth by series of alkylphenol polyethoxylate nonionic surfactants. AB - Laboratory experiments measured the effects of five alkylphenol polyethoxylate nonionic surfactants on the microbial degradation of glucose and pentachlorophenol (PCP) by a pure culture of Sphingomonas chlorophenolicum RA2 (RA2) that was unable to biodegrade the surfactants. The surfactants with mid range hydrophile-lipophile balance (HLB) values of 13.5-15 were the most biocompatible with substrate degradation. Monomers of the surfactant with the lowest HLB value of 12.3 inhibited RA2 growth on both glucose and PCP. The surfactant with the highest HLB of 17.9 was only inhibitory to glucose biodegradation at 3000mg/L, a concentration well above its CMC. The surfactants were more inhibitory of RA2 biodegradation of PCP compared to glucose, which is likely due to interactions with membrane-associated PCP-degrading enzymes rather than bioavailability limitations. These results may prove helpful in selecting surfactants for use enhancing surfactant-amended remedial applications involving biodegradation or oil dispersion. PMID- 22537919 TI - Immediate and long-term impacts of potassium permanganate on photosynthetic activity, survival and microcystin-LR release risk of Microcystis aeruginosa. AB - The immediate and long-term impacts of potassium permanganate (KMnO(4)) as pre oxidant on Microcystis aeruginosa and microcystin-LR (MC-LR) release risk were investigated. The cell density and the integrity of M. aeruginosa were determined by a flow cytometry, and typical photosynthetic parameters were measured by a pulse amplitude modulated fluorometer. The photosynthetic parameters were reduced to different degrees, accompanied with slight cytoclasis and complete degradation of extracellular MC-LR immediately after various dosages KMnO(4) oxidation (2-20 mg L(-1)). In a 6-d cultivation following 5 mg L(-1) KMnO(4) oxidation, the cell density decreased from 3.9*10(6) to 0.6*10(6) cells mL(-1), and then increased to 0.9*10(6) cells mL(-1), while the extracellular MC-LR increased from 0 to 51.2 MUg L(-1). In the cultivation after 10 mg L(-1) KMnO(4) treatment, the intracellular MC-LR and cell activity significantly declined, while significant cytoclasis (cell density from 3.8*10(6) to 0 cells mL(-1)) and MC-LR release (increase from 0 to 15.2 MUg L(-1)) were observed. The photosynthetic parameters were found to be useful tools to predict the recovery tendency of M. aeruginosa cells, and the MC-LR release risk should be considered during KMnO(4) pre oxidation in water-treatment plants. PMID- 22537920 TI - Enhanced electron transfer and silver-releasing suppression in Ag-AgBr/titanium doped Al2O3 suspensions with visible-light irradiation. AB - Ag-AgBr was deposited onto mesoporous alumina (MA) and titanium-doped MA by a deposition-precipitation method. The photocatalytic activity and the dissolution of Ag(+) from different catalysts were investigated during the photodegradation of 2-chlorophenol (2-CP) and phenol in ultrapure water and tap water with visible light irradiation. With the increase in doped titanium, the Ag(+) dissolution decreased with a decrease in the photocatalytic activity. Ag-AgBr/MA-Ti1 was considered the better catalyst for practical applications because its Ag(+) dissolution was minimal (0.4 mg L(-1) in ultrapure water and 5 MUg L(-1) in tap water), although its photoactivity was slightly less than that of Ag-AgBr/MA. The dissolution of Ag(+) was related to a charge-transfer process based on the study of cyclic voltammetry analyses under a variety of experimental conditions. The results suggested that several types of anions in the water, including CO(3)(2-), SO(4)(2-), and Cl(-), could act as electron donors that trap the photogenerated holes on Ag nanoparticles to facilitate electron circulation; this would decrease the release of Ag(+). Our studies indicated that the catalyst had a higher activity and stability in water purification. PMID- 22537921 TI - Potentiometric determination of trypsin using a polymeric membrane polycation sensitive electrode based on current-controlled reagent delivery. AB - A potentiometric biosensor for the determination of trypsin is described based on current-controlled reagent delivery. A polymeric membrane protamine-sensitive electrode with dinonylnaphthalene sulfonate as cation exchanger is used for in situ generation of protamine. Diffusion of protamine across the polymeric membrane can be controlled precisely by applying an external current. The hydrolysis catalyzed with trypsin in sample solution decreases the concentration of free protamine released at the sample-membrane interface and facilitates the stripping of protamine out of the membrane surface via the ion-exchange process with sodium ions from the sample solution, thus decreasing the membrane potential, by which the protease can be sensed potentiometrically. The influences of anodic current amplitude, current pulse duration and protamine concentration in the inner filling solution on the membrane potential response have been studied. Under optimum conditions, the proposed protamine-sensitive electrode is useful for continuous and reversible detection of trypsin over the concentration range of 0.5-5UmL(-1) with a detection limit of 0.3UmL(-1). The proposed detection strategy provides a rapid and reagentless way for the detection of protease activities and offers great potential in the homogeneous immunoassays using proteases as labels. PMID- 22537922 TI - Nocardia globerula NHB-2 nitrilase catalysed biotransformation of 4-cyanopyridine to isonicotinic acid. AB - Isonicotinic acid (INA) is an important pyridine derivative used in the manufacture of isoniazid (antituberculosatic drug) and other pharmaceutically important drugs. Nitrilase catalysed processes for the synthesis of pharmaceutically important acids from their corresponding nitriles are promising alternative over the cumbersome, hazardous, and energy demanding chemical processes. Nitrilase of Nocardia globerula NHB-2 (NitNHB2) is expressed in presence of isobutyronitrile in the growth medium (1.0% glucose, 0.5% peptone, 0.3% beef extract, and 0.1 % yeast extract, pH 7.5). NitNHB2 hydrolyses 4 cyanopyridine (4-CP) to INA without accumulation of isonicotinamide, which is common in the reaction catalysed via fungal nitrilases. The NitNHB2 suffers from substrate inhibition effect and hydrolysing activity up to 250 mM 4-CP was recorded. Complete conversion of 200 mM 4-CP to INA was achieved in 40 min using resting cell concentration corresponding to 10 U mL-1 nitrilase activity in the reaction. Substrate inhibition effect in the fed batch reaction (200 mM substrate feed/40min) led to formation of only 729 mM INA. In a fed batch reaction (100 mM 4-CP/20min), substrate inhibition effect was encountered after 7th feed and a total of 958 mM INA was produced in 400 min. The fed batch reaction scaled up to 1 L and 100% hydrolysis of 700 mM of 4-CP to INA at 35 degrees C achieved in 140 min. The rate of INA production was 21.1 g h-1 mgDCW-1. This is the fastest biotransformation process ever reported for INA production with time and space productivity of 36 g L-1 h-1 using a bacterial nitrilase. PMID- 22537924 TI - The 2011 nobel prize in physiology or medicine. PMID- 22537923 TI - Diagnostic value of CD103 expression in bronchoalveolar lymphocytes in sarcoidosis. AB - BACKGROUND: Pulmonary sarcoidosis is frequently characterized by a CD4(+)/CD8(+) ratio >=3.5 in bronchoalveolar lavage fluid (BALF), although up to 40% of the cases present a normal or even decreased ratio, pointing out its variability and limitation as a diagnostic marker for sarcoidosis. Lung lymphocytes within the bronchial epithelium, the alveolar walls, and BALF express the integrin CD103. Our aim was to compare the expression of CD103 in BALF T-lymphocytes between sarcoidosis and other interstitial lung diseases (ILD) and to evaluate its relevance as a BALF diagnostic marker for sarcoidosis. METHODS: A total of 86 patients with ILD (mean age +/- standard deviation, 42.6 +/- 16.6 years; 60.5% female), who underwent BALF as part of their initial diagnostic work-up, were enrolled into 2 groups: sarcoidosis (n = 41) and other ILD (n = 45). Area under the receiver operating characteristic (ROC) curve (AUC) was used to describe the performance of CD103 for sarcoidosis diagnosis. RESULTS: Sarcoidosis patients presented a significantly reduced CD103 expression in BALF T-lymphocytes, more pronounced in the CD4(+) subset. The BALF CD103(+)CD4(+)/CD4(+) ratio for a cutoff point of 0.45 was associated with a better diagnostic performance for sarcoidosis (AUC: 0.86 [95% confidence interval (95% CI): 0.78-0.94]; sensitivity: 81%; specificity: 78%), even for those with a CD4(+)/CD8(+) ratio <3.5 (AUC: 0.79 [95% CI: 0.64-0.93]; sensitivity: 75%; specificity: 78%). CONCLUSIONS: Assessment of CD103 expression in BALF CD4(+) T-lymphocytes may be a reliable tool for sarcoidosis diagnosis, independently of CD4(+)/CD8(+) ratio, pointing out the relevance of evaluating the CD103(+)CD4(+)/CD4(+) ratio in the ILD diagnostic work-up. PMID- 22537925 TI - Molecular cytogenetics: an indispensable tool for cancer diagnosis. AB - Cytogenetic aberrations may escape detection or recognition in traditional karyotyping. The past decade has seen an explosion of methodological advances in molecular cytogenetics technology. These cytogenetics techniques add color to the black and white world of conventional banding. Fluorescence in-situ hybridization (FISH) study has emerged as an indispensable tool for both basic and clinical research, as well as diagnostics, in leukemia and cancers. FISH can be used to identify chromosomal abnormalities through fluorescent labeled DNA probes that target specific DNA sequences. Subsequently, FISH-based tests such as multicolor karyotyping, comparative genomic hybridization (CGH) and array CGH have been used in emerging clinical applications as they enable resolution of complex karyotypic aberrations and whole global scanning of genomic imbalances. More recently, crossspecies array CGH analysis has also been employed in cancer gene identification. The clinical impact of FISH is pivotal, especially in the diagnosis, prognosis and treatment decisions for hematological diseases, all of which facilitate the practice of personalized medicine. This review summarizes the methodology and current utilization of these FISH techniques in unraveling chromosomal changes and highlights how the field is moving away from conventional methods towards molecular cytogenetics approaches. In addition, the potential of the more recently developed FISH tests in contributing information to genetic abnormalities is illustrated. PMID- 22537926 TI - Host factors in the replication of positive-strand RNA viruses. AB - Viruses are obligate, intracellular parasites that depend on host cells for successful propagation. Upon infection of host cells, positivestrand RNA viruses exploit and hijack cellular machinery and reprogram these cells into viral "factories" through various protein-protein, protein- RNA, and protein-lipid interactions. The molecular interplay between host factors and invading viruses is a continuous process throughout the entire viral life cycle and determines virus host range and viral pathogenesis, as well as driving viral evolution. Studies of host factors have contributed insights into their normal cellular functions and helped identify attractive targets for antiviral drug development. With the development of high throughput screening, functional genomics, and proteomics technologies, host factors participating in viral life cycles have been identified rapidly in recent years. In this review, we summarize the recent advances in virus-host cell interactions in positive-strand RNA virus infections and focus on host factors that facilitate viral replication. PMID- 22537927 TI - Ultrasound microbubble contrast agents for diagnostic and therapeutic applications: current status and future design. AB - Ultrasound contrast agents are highly echogenic microbubbles with many unique properties. Microbubbles can basically improve the sensitivity of conventional ultrasound imaging to the microcirculation. The resonance of microbubbles in response to an incident ultrasound pulse results in nonlinear harmonic emission that serves as the signature of microbubbles in microbubble-specific imaging. Inertial cavitation and destruction of microbubbles can produce a strong mechanical stress enhancing the permeability of the surrounding tissues, and can further increase the extravasation of drugs from the blood into the cytoplasm or interstitium. Stable cavitation by high-frequency ultrasound can also mildly increase tissue permeability without causing any damage even at a high acoustic pressure. Microbubbles can carry drugs, release them upon ultrasound-mediated microbubble destruction, and simultaneously enhance vascular permeability to increase drug deposition in tissues. Various targeting ligands can be conjugated to the surface of microbubbles to attain ligand-directed and site-specific accumulation for targeted imaging. In addition to current developments in microbubble technology, this review introduces our studies of the applications of microbubble- specific imaging, ultrasound-aided drug delivery, and targeted imaging. These applications are promising but may require further improvement for clinical use. PMID- 22537928 TI - Extract of sporoderm-broken germinating spores of ganoderma lucidum activates human polymorphonuclear neutrophils via the P38 mitogen-activated protein kinase pathway. AB - BACKGROUND: Ganoderma lucidum (G. lucidum) has been used in traditional Chinese medicine for thousands of years because of its immunomodulatory properties. It is believed that G. lucidum enhances the human immune response by improving the function of human polymorphonuclear neutrophils (PMNs); nevertheless, the actual mechanism by which G. lucidum acts on human PMNs remains unknown. In this study, we investigated the molecular pathways through which G. lucidum activates human PMNs. METHODS: The phagocytic activity of PMNs was evaluated with and without treatment with the extract of sporoderm-broken germinating spores of G. lucidum. The same activity was measured after G. lucidum treatment with or without p38 mitogen-activated protein kinase (p38 MAPK) inhibitor. The activation of p38 MAPK was also evaluated with or without treatment with the extract of sporoderm-broken germinating spores of G. lucidum. RESULTS: In this study, we found that the extract of G. lucidum enhanced the phagocytic activity of PMNs in a dose dependent manner, but this response was attenuated by treatment with SB203580, a p38 MAPK inhibitor. The extract of G. lucidum also enhanced activation of p38 MAPK in a dose-dependent manner. CONCLUSION: These results clearly show that the extract of G. lucidum can modulate human immunity by activating human PMNs via the p38 MAPK pathway. These results may be of clinical importance to doctors of traditional Chinese medicine. PMID- 22537929 TI - Etiological analyses of marked neonatal hyperbilirubinemia in a single institution in Taiwan. AB - BACKGROUND: Hyperbilirubinemia is a common disorder during the neonatal period. Severe neonatal hyperbilirubinemia (NH) carries a potential for permanent neurological impairment. The current study analyzed possible etiologies leading to NH. METHODS: A retrospective cohort of neonates with total serum bilirubin (TSB) >= 20 mg/dL was surveyed from 1995 to 2007. Subjects with gestational ages < 34 weeks were excluded, leaving a total of 413 enrolled neonates. RESULTS: The most common etiology in relation to marked NH was breast milk feeding (38.5%), followed by glucose-6-phospahate dehydrogenase (G6PD) deficiency (24.0%), ABO incompatibility (21.8%), extravascular hemorrhage (6.5%), Rh incompatibility (2.9%), bacterial infection (2.2%), hereditary spherocytosis (1.2%), dehydration (1.2%), diabetic mother (1.0%), polycythemia (0.7%), and gastrointestinal obstruction (0.7%). Other rare etiologies included Down syndrome, Chinese herb intake, asphyxia, galactosemia and congenital hypothyroidism. We did not identify any known cause in 63 neonates (15.3%). Neonates with more than one etiology tended to have higher TSB than subjects without a known etiology (p < 0.05). Anemia was more common in those with G6PD deficiency, blood group incompatibility, hereditary spherocytosis, and gastrointestinal obstruction. Neonates fed breast milk tended to have prolonged NH. CONCLUSION: This study depicts the clinical features of marked NH. Breast milk feeding, G6PD deficiency and ABO incompatibility are common etiologies in Taiwan. Prolonged NH is more common in neonates fed breast milk than those who were given formula. PMID- 22537930 TI - Anthropometric study of the bicipital groove in Indians and its clinical implications. AB - BACKGROUND: Since morphometric data on the upper end of the humerus from Indian anatomical samples are scarce, this study was undertaken with reference to orthopedic surgery. The aim was to determine the length, width and depth of the bicipital groove and to find the incidence of a supratubercular ridge of Meyer in an Indian population. METHODS: The study included 104 unpaired dry humeri (48 right side and 56 left) which belonged to the anatomy laboratory of our institution. The length, width and depth of the bicipital groove were measured with a digital vernier caliper. The data were tabulated as mean +/- SD and statistically compared between the right and left sides. RESULTS: The mean length, width and depth of the bicipital groove were 84.6 +/- 10.9 mm, 8.5 +/- 2.3 mm and 4.4 +/- 1.8 mm, respectively, which corresponded to 27.8% of the total length, 32.2% of the transverse width and 17% of the anteroposterior widh of the humerus, respectively. There was no statistically significant difference in these parameters between the left and right sides (p > 0.05). A supratubercular ridge of Meyer was seen in 24 (23.1%) of the humeri. CONCLUSION: The study determined the morphometric parameters of the bicipital groove in an Indian population. We believe that this study will be an important reference for scientific research, and the details are also important for anthropologists and clinical anatomists. PMID- 22537931 TI - Pierce and push: a simplified method to facilitate laparoscopic myomectomy. AB - BACKGROUND: The aim of this study was to present our experience with a novel approach called the pierce and push (PP) method which uses a stainless steel centimeter probe instead of a 5 mm claw forceps to enucleate fibroids in a laparoscopic myomectomy (LM). METHODS: A retrospective chart review of 90 women with symptomatic uterine fibroids who underwent an LM was performed. Cases of LM with the PP method were compared with a matched control group of LM with a 5 mm claw forceps. The operative time, tumor separation time, specimen removal time, amount of blood loss, requirement for blood transfusion and length of hospital stay were compared between groups. RESULTS: The two groups were matched by age, body mass index, previous cesarean delivery, main fibroid size, and number and weight of fibroids. The tumor separation time was significantly shorter in the PP group than the claw forceps group (9.7 +/- 3.1 minutes versus 17.1 +/- 4.4 minutes, p < 0.001). The length of the operation, hospitalization time, specimen removal time, amount of blood loss, and requirement for blood transfusion were not significantly different between groups. CONCLUSION: A stainless steel centimeter probe has an advantage over a 5 mm claw forceps in pushing and pulling fibroids. Our findings indicate that the PP method was much more effective in excision of fibroids than a 5 mm claw grasper in LM. PMID- 22537932 TI - Eccrine angiomatous hamartoma: a retrospective study of 15 cases. AB - BACKGROUND: Eccrine angiomatous hamartoma (EAH) comprises a rare nevoid proliferation of normal eccrine glands and small blood vessels and occasionally other elements in the middle and deep dermis with variable clinical manifestations. Case series have rarely been published except for case reports and literature reviews. The aims of this article were to investigate the clinical and pathologic features of patients with EAH in Taiwan and to compare our results with the results of previous studies. METHODS: A retrospective review of medical records and histopathological findings was performed on patients diagnosed with EAH in a medical center in Taiwan between 1994 and 2010. RESULTS: Fifteen patients with pathologically diagnosed EAH were collected. The mean age at the time of diagnosis was 38.6 years (range, birth to 67 years). The male to female ratio was 3 to 2. In most cases, EAH arose as a single lesion on a lower extremity. The symptoms and signs most commonly associated with EAH were pain (60%), hypertrichosis (13.3%), itching (13.3%) and hyperhidrosis (6.7%). Additional pathological findings included hemangioma (13.3%), verrucous hemangioma (6.7%), arteriovenous malformation (6.7%), and angiokeratoma (6.7%). None of the patients experienced spontaneous regression of the lesions before excision. Excisions were done in one patient under general anesthesia, and ten patients with local anesthesia. Four patients were kept under observation. Tumor recurrences were noted in two out of the eleven patients whose lesions were excised. CONCLUSION: Compared with cases in the literature, we found additional histopathological findings and an increased tumor recurrence risk in our cohort. EAH remains a benign and uncommon hamartomatous condition. Further multi-center, retrospective studies with larger case numbers are needed to better characterize the disease presentation in Asian populations. PMID- 22537933 TI - Surgical resection of centrally located large hepatocellular carcinoma. AB - BACKGROUND: Centrally located large hepatocellular carcinoma (HCC) is a difficult issue in surgery. These HCCs can be treated by hemi-/extended or central hepatectomies. The aim of this study was to analyze the results of hemi-/extended and central hepatectomies. METHODS: One hundred and four patients with centrally located large tumors were retrospectively reviewed. Patients were divided into group 1 (n = 41) with hemi-/extended hepatectomies, and group 2 (n = 63) with central hepatectomies. Characteristics were analyzed between groups and survival rates were calculated. RESULTS: Parenchyma resection was limited in group 2. The resection margin in 92.6% of group 2 patients was < 1 cm, compared with 78.9% of group 1 patients (p = 0.056). The 1- and 5-year disease-free survival rates were 50% and 38.9% for group 1, and 50% and 15% for group 2 (p = 0.279). The 1-, 5 year overall survival rates were 89.5% and 66.2% for group 1 and 87.5% and 53.1% for group 2 (p = 0.786). Cirrhosis, the preoperative aspartate aminotransferase (AST) level and lower resected liver weight were independent factors impairing survival. CONCLUSION: Hemi-/extended and central hepatectomies have comparable complication rates and long-term survival rates for patients with centrally located large HCC. Cirrhosis, the AST level and resected liver weight were independent factors determining long-term survival. PMID- 22537934 TI - Enhanced RAD21 cohesin expression confers poor prognosis in BRCA2 and BRCAX, but not BRCA1 familial breast cancers. AB - INTRODUCTION: The RAD21 gene encodes a key component of the cohesin complex, which is essential for chromosome segregation, and together with BRCA1 and BRCA2, for high-fidelity DNA repair by homologous recombination. Although its expression correlates with early relapse and treatment resistance in sporadic breast cancers, it is unclear whether familial breast cancers behave in a similar manner. METHODS: We performed an immunohistochemical analysis of RAD21 expression in a cohort of 94 familial breast cancers (28 BRCA1, 27 BRCA2, and 39 BRCAX) and correlated these data with genotype and clinicopathologic parameters, including survival. In these cancers, we also correlated RAD21 expression with genomic expression profiling and gene copy-number changes and miRNAs predicted to target RAD21. RESULTS: No significant differences in nuclear RAD21 expression were observed between BRCA1 (12 (43%) of 28), BRCA2 (12 (44%) of 27), and BRCAX cancers (12 (33%) of 39 (p = 0.598). No correlation was found between RAD21 expression and grade, size, or lymph node, ER, or HER2 status (all P > 0.05). As for sporadic breast cancers, RAD21 expression correlated with shorter survival in grade 3 (P = 0.009) and but not in grade 1 (P = 0.065) or 2 cancers (P = 0.090). Expression of RAD21 correlated with poorer survival in patients treated with chemotherapy (P = 0.036) but not with hormonal therapy (P = 0.881). RAD21 expression correlated with shorter survival in BRCA2 (P = 0.006) and BRCAX (P = 0.008), but not BRCA1 cancers (P = 0.713). Changes in RAD21 mRNA were reflected by genomic changes in DNA copy number (P < 0.001) and by RAD21 protein expression, as assessed with immunohistochemistry (P = 0.047). High RAD21 expression was associated with genomic instability, as assessed by the total number of base pairs affected by genomic change (P = 0.048). Of 15 miRNAs predicted to target RAD21, mir-299-5p inversely correlated with RAD21 expression (P = 0.002). CONCLUSIONS: Potential use of RAD21 as a predictive and prognostic marker in familial breast cancers is hence feasible and may therefore take into account the patient's BRCA1/2 mutation status. PMID- 22537936 TI - Introduction to the symposium "New frontiers from marine snakes to marine ecosystems". AB - Interest in sea snakes and mythological "sea serpents" dates to ancient times and is represented in the writings of Aristotle, early voyagers, and explorers, and references in the Bible. Since then, awareness of the myriad species of snakes inhabiting the oceans has grown at a gradual pace. Scientific investigations into the biology of marine snakes-especially those in behavior, physiology, and other disciplines requiring living animals or tissues-have been comparatively challenging owing to difficulties in acquiring, transporting, handling, and husbanding these secondarily marine vertebrates. A broadening perspective with increasing interest in these animals peaked during the 1960s and 1970s, and literature from this period contributed to a growing knowledge that marine snakes comprise a very diverse fauna and are a significant part of marine ecosystems. Two persons figured prominently as influential drivers of research on sea snakes during this period, namely William Dunson and Harold Heatwole, and this symposium recognizes the contributions of these two individuals. Following a decline in scientific publications on sea snakes during the 1980s and 1990s, there has been a renaissance of scientific interest in recent years, and a wealth of new research findings has improved the understanding of phylogeny and diversity of marine snakes while simultaneously recognizing threats to marine ecosystems arising from climate change and other anthropogenic causes. The purposes of the symposium are to (1) illustrate the importance and relevance of sea snakes as contributors to better understanding a range of issues in marine biology, (2) establish and promote the use of marine systems as models for investigating conceptual issues related to environment, changing climate, and persistence of biological communities, with focus on marine snakes as novel or useful examples, (3) promote interest in sea snakes as useful organisms for study by scientists in a range of disciplines who might presently work with other organisms or systems, and (4) identify leading-edge topics for which studies of marine snakes might contribute uniquely to the advancement of research. PMID- 22537935 TI - Analysis of tissue proteomes of the Gulf killifish, Fundulus grandis, by 2D electrophoresis and MALDI-TOF/TOF mass spectrometry. AB - The Gulf killifish, Fundulus grandis, is a small teleost fish that inhabits marshes of the Gulf of Mexico and demonstrates high tolerance of environmental variation, making it an excellent subject for the study of physiological and molecular adaptations to environmental stress. In the present study, two dimensional (2D) gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry were used to resolve and identify proteins from five tissues: skeletal muscle, liver, brain, heart, and gill. Of 864 protein features excised from 2D gels, 424 proteins were identified, corresponding to a 49% identification rate. For any given tissue, several protein features were identified as the same protein, resulting in a total of 254 nonredundant proteins. These nonredundant proteins were categorized into a total of 11 molecular functions, including catalytic activity, structural molecule, binding, and transport. In all tissues, catalytic activity and binding were the most highly represented molecular functions. Comparing across the tissues, proteome coverage was lowest in skeletal muscle, due to a combination of a low number of gel spots excised for analysis and a high redundancy of identifications among these spots. Nevertheless, the identification of a substantial number of proteins with high statistical confidence from other tissues suggests that F. grandis may serve as a model fish for future studies of environmental proteomics and ultimately help to elucidate proteomic responses of fish and other vertebrates to environmental stress. PMID- 22537937 TI - Uncertain link between loneliness and companion animals in rural adolescents. PMID- 22537938 TI - Synthesis, characterization, biological screenings and interaction with calf thymus DNA of a novel azomethine 3-((3,5-dimethylphenylimino)methyl)benzene-1,2 diol. AB - The novel azomethine, 3-((3,5-dimethylphenylimino)methyl)benzene-1,2-diol (HL) was synthesized and characterized by elemental analysis, FT-IR, (1)H, (13)C NMR spectroscopy and single crystal analysis. The title compound has been screened for its biological activities including enzymatic study, antibacterial, antifungal, cytotoxicity, antioxidant and interaction with CTDNA, and showed remarkable activities in each area of research. The titled compound interacts with DNA via two binding modes: intercalation and groove binding. In intercalation the compound inserts itself into the base pairs of DNA and the compound-DNA complex is stabilized by pi-pi stacking. Interaction via groove binding may be due to hydrogen bonding to bases, typically to N3 of adenine and O2 of thymine. The synthesized compound was also found to be an effective antioxidant of 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) and gives percent inhibition (%I) of 90.7 at a concentration level of 31.3MUg/mL. PMID- 22537939 TI - Molecular structure, spectral studies, intra and intermolecular interactions analyses in a novel ethyl 4-[3-(2-chloro-phenyl)-acryloyl]-3,5-dimethyl-1H pyrrole-2-carboxylate and its dimer: A combined DFT and AIM approach. AB - A newly synthesized chalcone, Ethyl 4-[3-(2-chloro-phenyl)-acryloyl]-3,5-dimethyl 1H-pyrrole-2-carboxylate (ECPADMPC) has been characterized by (1)H NMR, (13)C NMR, UV-Vis, FT-IR, Mass spectroscopy and elemental analysis. Quantum chemical calculations have been performed by DFT level of theory using B3LYP functional and 6-31G(d,p) as basis set. The time dependent density functional theory (TD DFT) is used to find the various electronic transitions within molecule. A combined theoretical and experimental wavenumber analysis confirms the existence of dimer. Topological parameters-electron density (rho(BCP)), Laplacian of electron density (?(2)rho(BCP)), energetic parameters-kinetic electron energy density (G(BCP)), potential electron density (V(BCP)) and the total electron energy density (H(BCP)) at the bond critical points (BCP) have been analyzed by 'Atoms in molecules' AIM theory in detail. The intermolecular hydrogen bond energy of dimer is calculated as -12.3kcal/mol using AIM calculations. AIM ellipticity analysis is carried out to confirm the presence of resonance assisted intermolecular hydrogen bonds in stabilization of dimer. The analysis clearly depicts the presence of different kind of interactions in dimer. This dimer may work as model system to understand the H-bonding interaction in biomolecules. The local reactivity descriptor analysis is performed to find the reactive sites within molecule. PMID- 22537940 TI - The origins of language and the evolution of music: A comparative perspective. AB - According to Darwin [Darwin, CR. The descent of man, and selection in relation to sex. London: John Murray; 1871], the human musical faculty 'must be ranked amongst the most mysterious with which he is endowed'. Music is a human cultural universal that serves no obvious adaptive purpose, making its evolution a puzzle for evolutionary biologists. This review examines Darwin's hypothesis of similarities between language and music indicating a shared evolutionary history. In particular, the fact that both are human universals, have phrase structure, and entail learning and cultural transmission, suggests that any theory of the evolution of language will have implications for the evolution of music, and vice versa. The argument starts by describing variable predispositional musical capabilities and the ontogeny of prosodic communication in human infants and young children, presenting comparative data regarding communication systems commonly present in living nonhuman primate species. Like language, the human music faculty is based on a suite of abilities, some of which are shared with other primates and some of which appear to be uniquely human. Each of these subcomponents may have a different evolutionary history, and should be discussed separately. After briefly considering possible functions of human music for language acquisition, the review ends by discussing the phylogenetic history of music. It concludes that many strands of evidence support Darwin's hypothesis of an intermediate stage of human evolutionary history, characterized by a communication system that resembled music more closely than language, but was identical to neither. This pre-linguistic system, which could probably referred to as "prosodic protolanguage", provided a precursor for both modern language and music. PMID- 22537941 TI - Changes in microRNA expression contribute to pancreatic beta-cell dysfunction in prediabetic NOD mice. AB - During the initial phases of type 1 diabetes, pancreatic islets are invaded by immune cells, exposing beta-cells to proinflammatory cytokines. This unfavorable environment results in gene expression modifications leading to loss of beta-cell functions. To study the contribution of microRNAs (miRNAs) in this process, we used microarray analysis to search for changes in miRNA expression in prediabetic NOD mice islets. We found that the levels of miR-29a/b/c increased in islets of NOD mice during the phases preceding diabetes manifestation and in isolated mouse and human islets exposed to proinflammatory cytokines. Overexpression of miR 29a/b/c in MIN6 and dissociated islet cells led to impairment in glucose-induced insulin secretion. Defective insulin release was associated with diminished expression of the transcription factor Onecut2, and a consequent rise of granuphilin, an inhibitor of beta-cell exocytosis. Overexpression of miR-29a/b/c also promoted apoptosis by decreasing the level of the antiapoptotic protein Mcl1. Indeed, a decoy molecule selectively masking the miR-29 binding site on Mcl1 mRNA protected insulin-secreting cells from apoptosis triggered by miR-29 or cytokines. Taken together, our findings suggest that changes in the level of miR 29 family members contribute to cytokine-mediated beta-cell dysfunction occurring during the initial phases of type 1 diabetes. PMID- 22537942 TI - Differential expression of RBM5, EGFR and KRAS mRNA and protein in non-small cell lung cancer tissues. AB - BACKGROUND: RNA binding motif 5 (RBM5) is a tumor suppressor gene that modulates apoptosis through the regulation of alternative splicing of apoptosis-related genes. This study aimed to detect RBM5 expression in non-small cell lung cancer (NSCLC) and to associate RBM5 expression with clinicopathological data from NSCLC patients and EGFR and KRAS expression to better understand the potential role of RBM5 in NSCLC. METHOD: Semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting were performed to detect expression of mRNA and protein, respectively, of RBM5, EGFR and KRAS in 120 paired non-tumor and tumor samples of NSCLC. RESULTS: The data showed that expression of RBM5 mRNA and protein was significantly reduced in NSCLC compared to normal tissues, whereas expression of both EGFR and KRAS genes was increased in NSCLC compared to normal tissues. Furthermore, the reduced RBM5 protein expression correlated with smoking status, tumor stage and lymph node metastasis of NSCLC, while overexpression of EGFR and KRAS proteins correlated with tumor stage and lymph node metastasis of NSCLC. Overexpression of KRAS protein was more frequent in smokers with NSCLC. In addition, expression of RBM5 mRNA and protein was negatively correlated with expression of EGFR and KRAS mRNA and protein in NSCLC tissues. CONCLUSION: This study suggests further evaluation of RBM5 expression is warranted for use of RBM5 as a biomarker for NSCLC patients. PMID- 22537943 TI - Subacute toxicity of antimicrobial peptide S-thanatin in ICR mice. AB - Antibiotics are commonly used for infectious diseases and saved a lot of lives since its discovery, but the emergence of drug-resistant microorganism has brought a tremendous challenge to clinical therapy at present. Antimicrobial peptides, which are of broad antimicrobial spectrum and rare resistance development in pathogens, are expected to replace conventional antibiotics. S thanatin, a novel antimicrobial peptide with 21 amino acid residues, was proved of significant benefit on therapy of pathogens infection. To evaluate the security of S-thanatin, its subacute toxicity was examined in ICR mice by continually intravenous injection with 125, 50, 20 mg/kg (1/4, 1/10, 1/25 LD(50)) or saline with equal volume for two weeks. Results demonstrated that neither significant difference of serum chemistry and hematology, nor pathological changes were changed in major organs caused by S-thanatin between groups. In conclusion, S-thanatin appears to be a safe antimicrobial peptide for further preclinical trials. PMID- 22537944 TI - The retinal renin-angiotensin system: roles of angiotensin II and aldosterone. AB - In the present review we examine the experimental and clinical evidence for the presence of a local renin-angiotensin system within the retina. Interest in a pathogenic role for the renin-angiotensin system in retinal disease originally stemmed from observations that components of the pathway were elevated in retina during the development of certain retinal pathologies. Since then, our knowledge about the contribution of the RAS to retinal disease has greatly expanded. We discuss the known functions of the renin-angiotensin system in retinopathy of prematurity and diabetic retinopathy. This includes the promotion of retinal neovascularization, inflammation, oxidative stress and neuronal and glial dysfunction. The contribution of specific components of the renin-angiotensin system is evaluated with a particular focus on angiotensin II and aldosterone and their cognate receptors. The therapeutic utility of inhibiting key components of the renin-angiotensin system is complex, but may hold promise for the prevention and improvement of vision threatening diseases. PMID- 22537945 TI - [First confirmed cases of human meningoencephalitis due to West Nile virus in Andalusia, Spain]. PMID- 22537946 TI - Examination of PHB Depolymerases in Ralstonia eutropha: Further Elucidation of the Roles of Enzymes in PHB Homeostasis. AB - Polyhydroxyalkanoates (PHA) are biodegradable polymers that are attractive materials for use in tissue engineering and medical device manufacturing. Ralstonia eutropha is regarded as the model organism for PHA biosynthesis. We examined the effects of PHA depolymerase (PhaZ) expression on PHA homeostasis in R. eutropha strains. In order to analyze the impact of PhaZs on R. eutropha granule architecture, we performed electron microscopy on several phaZ knockout strains and the wild type strain grown under PHA production conditions. Analysis of the acquired micrographs was based on stereology: the ratio of granule area and cell area was determined, along with total granule count per full-size cell image. Cells bearing a phaZ2 knockout mutation alone or in conjunction with a phaZ1 mutation were found to have a high granule volume per cell volume and a higher granule count compared to wild type. A phaZ quadruple knockout strain appeared to have a low granule volume per cell volume and a low granule count per cell. Cells bearing a phaZ3 knockout were found to have a higher granule count than the wild type, whereas granule volume per cell volume was similar. Accordingly, we hypothesize that PhaZs have not only an impact on PHA degradation but also on the 3-dimensional granule architecture. Based on our data, PhaZ2 is postulated to affect granule density. This work increased our knowledge about PHA depolymerases in R. eutropha, including enzymes that had previously been uncharacterized. PMID- 22537948 TI - [Intrahepatic cholestasis due to mitochondrial respiratory chain complex I deficiency in a Chinese boy]. AB - Mitochondrial respiratory chain deficiency is a common cause of mitochondrial disease in children. This study aimed to review the clinical, enzymatic and genetic characteristics of a Chinese boy with progressive intrahepatic cholestasis due to mitochondrial respiratory chain complex I deficiency. The boy developed diarrhea from the age of 13 months, followed by progressive body weight loss, jaundice and weakness. His urine organic acids, blood amino acids and acylcarnitines profiles were normal. Mitochondrial respiratory chain complexes I to V activities in peripheral leukocytes were measured using spectrophotometric assay. Complex I activity was reduced. 5821G>A mutation was indentified by gene sequencing on tRNA-cys of mitochondrial gene in the patient and his mother. Vitamin supplements, liver protection, antibiotics and plasma infusion were not effective in the patient. Unfortunately, the boy died at the age of 17 months. Mitochondrial respiratory chain complex I deficiency is the most common mitochondrial respiratory chain disorder. This was the first case of intrahepatic cholestasis due to complex I deficiency confirmed by mitochondrial respiratory chain enzyme activity assay and gene analysis in China. It was concluded that mitochondrial hepatopathy is one of major causes of metabolic hepatopathy. Biochemical assay, mitochondrial respiratory chain complex activities assay and genetic analysis are crucial for the etiological diagnosis of metabolic hepatopathy. PMID- 22537949 TI - [Effect of early protein and energy intake on the growth of premature infants]. AB - OBJECTIVE: To study the effect of early protein and energy intake on early growth velocity of premature infants. METHODS: Clinical data on premature infants with a birth weight of less than 1800 g were collected retrospectively, including records of general status, enteral and parenteral nutrition and growth parameters. These premature infants were divided into two groups according to the timing of amino acid administration: early supplementation (the first 24 hrs of life; EAA group; n=112) and late supplementation (after 24 hrs of life; LAA group; n=52). Protein and energy intake, protein/energy ratio and growth velocity during hospital stay were compared between the two groups. Correlation analysis was used to evaluate the association of early protein and energy intake and protein/energy ratio with growth velocity of infants. RESULTS: Compared with the LAA group, the EAA group presented lower weight loss (6.3% vs 8.8%), shorter time to return to birth weight (7 days vs 9 days), and higher head circumference growth (0.79 +/- 0.25 cm/week vs 0.55 +/- 0.25 cm/week) and weight growth velocity(20 +/- 3 g/kg*d vs 17 +/- 3 g/kg*d) (P<0.05). The correlation analysis indicated that protein and energy intake and protein/energy ratio on the 3rd and 7th days of life were positively correlated with weight growth velocity. The protein and energy intake per week after returning to birth weight was positively correlated with weight growth velocity (r= 0.709, P<0.01). Significant correlations were found between the protein and energy intake and both head circumference and length growth velocity on the 3rd and the 7th days of life. CONCLUSIONS: Early administration of amino acids can reduce weight loss, shorten the time taken to return to birth weight, and increase weight and head circumference growth velocity in premature infants. An appropriate increase in protein intake can improve weight, circumference and length growth velocity. PMID- 22537951 TI - [Genetic factors in the occurrence of neonatal unconjugated hyperbilirubinemia]. AB - OBJECTIVE: To study association of uridine-diphosphate-glucuronosyltransferase1A1 (UGT1A1) Gly71Arg, UGT1A1 promoter TATA-box and glucose-6-phosphate dehydrogenase (G6PD) gene mutations with the occurrence of neonatal unconjugated hyperbilirubinemia. METHODS: The TATA-box, exon 1 and exon 5 of the UGT1A1 gene and the exon 12 of G6PD gene were amplified by PCR. The products of PCR were analyzed by direct DNA sequencing. Clones for the mutations of the UGT1A1 gene and the G6PD gene were constructed in order to identify the results of the products of PCR. Seventy-two neonates with unconjugated hyperbilirubinemia (case group) and 65 healthy neonates (control group) were enrolled. The genotypes and allele frequencies of the polymorphisms of UGT1A1 Gly71Arg and UGT1A1 TATA-box were compared between the two groups. The effects of UGT1A1 Gly71Arg, UGT1A1 promoter TATA-box and G6PD gene mutations on the development of neonatal unconjugated hyperbilirubinemia were estimated using logistic regression models. RESULTS: There were significant differences in the genotype distribution of Gly71Arg polymorphism of UGT1A1 gene between the case and control groups (P<0.01). The Arg allele frequency of the polymorphisms of UGT1A1 gene in the case group was significantly higher than in the control group (P<0.01). There were no significant differences in the genotype distribution of the UGT1A1 promoter TATA-box between the two groups (P>0.05). The OR and 95%CI values of UGT1A1 Gly71Arg, UGT1A1 TATA-box and G6PD gene mutations associated with the development of neonatal unconjugated hyperbilirubinemia were 5.468 (2.274, 12.818), 0.688 (0.266, 1.778) and 5.081 (1.070, 24.133) respectively. CONCLUSIONS: UGT1A1 Gly71Arg and G6PD gene mutations may be involved in the development of neonatal unconjugated hyperbilirubinemia. PMID- 22537947 TI - Global mRNA decay analysis at single nucleotide resolution reveals segmental and positional degradation patterns in a Gram-positive bacterium. AB - BACKGROUND: Recent years have shown a marked increase in the use of next generation sequencing technologies for quantification of gene expression (RNA sequencing, RNA-Seq). The expression level of a gene is a function of both its rate of transcription and RNA decay, and the influence of mRNA decay rates on gene expression in genome-wide studies of Gram-positive bacteria is under investigated. RESULTS: In this work, we employed RNA-Seq in a genome-wide determination of mRNA half-lives in the Gram-positive bacterium Bacillus cereus. By utilizing a newly developed normalization protocol, RNA-Seq was used successfully to determine global mRNA decay rates at the single nucleotide level. The analysis revealed positional degradation patterns, with mRNAs being degraded from both ends of the molecule, indicating that both 5' to 3' and 3' to 5' directions of RNA decay are present in B. cereus. Other operons showed segmental degradation patterns where specific ORFs within polycistrons were degraded at variable rates, underlining the importance of RNA processing in gene regulation. We determined the half-lives for more than 2,700 ORFs in B. cereus ATCC 10987, ranging from less than one minute to more than fifteen minutes, and showed that mRNA decay rate correlates globally with mRNA expression level, GC content, and functional class of the ORF. CONCLUSIONS: To our knowledge, this study presents the first global analysis of mRNA decay in a bacterium at single nucleotide resolution. We provide a proof of principle for using RNA-Seq in bacterial mRNA decay analysis, revealing RNA processing patterns at the single nucleotide level. PMID- 22537950 TI - [Comparisons of efficacy of different pulmonary surfactants for the treatment of neonatal respiratory distress syndrome]. AB - OBJECTIVE: To compare the clinical efficacy of imported pulmonary surfactant (PS) pig lung phospholipids injection (pig PS) and domestic cattle lung surface-active agent (cattle PS) for the treatment of neonatal respiratory distress syndrome (NRDS). METHODS: A total of 180 cases of grade IV NRDS receiving pig PS (n=90) or cattle PS treatment (n=90) were enrolled. The blood gas analysis and chest X-ray results and the incidence of complications after treatment, and hospitalization time and cost were compared between the two treatment groups. RESULTS: The efficiency rate in the pig PS group (97%) was higher than in the catle PS group (83%) (P<0.01). The cure rate in the pig PS group was also higher than in the cattle PS group (84% vs 66%; P<0.01). The incidence of pneumothorax in the pig PS group was lower than in the cattle PS group (3% vs 7%; P<0.05). The hospitalization time in the pig PS group was shorter than in the cattle PS group (21 +/- 4 days vs 23 +/- 4 days; P<0.05). There were no significant differences in the total hospitalization cost between the two groups. CONCLUSIONS: Pig PS seems to be superior to cattle PS in the treatment of grade IV NRDS. PMID- 22537952 TI - [Genetic polymorphism of GST gene in children with infectious mononucleosis and acute lymphocytic leukemia]. AB - OBJECTIVE: To study the relationship between glutathione S-transferase genes GSTT1 and GSTM1 polymorphisms and the susceptibility to infectious mononucleosis (IM) and acute lymphocytic leukemia (ALL) in children. METHODS: The case-control study involved 106 children with IM, 41 children with ALL and a control group of 100 children with non-hematologic and nontumorous diseases. The genetic polymorphisms of GSTT1 and GSTM1 were detected with multiplex polymerase chain reaction (PCR). Distribution of the genotypes in the children was analyzed. RESULTS: The frequency of GSTT1 null genotype in children with IM was significantly higher than in the control group (P<0.05). The risk of IM in children carrying GSTT1 null genotype was 2.186 times higher than in those carrying GSTT1 non-null genotype. The children carrying both GSTT1 and GSTM1 null genotype had a higher risk of suffering from IM compared to those carrying only one of the null genotypes (OR=4.937). The frequency of GSTM1 null genotype in children with ALL was significantly higher than in the control group (P<0.05). The risk of ALL in children carrying GSTM1 null genotype was 2.242 times higher than in those in carrying GSTT1 non-null genotype. Children carrying both GSTT1 and GSTM1 null genotype had a higher risk of suffering from ALL compared with those carrying only one of the null genotypes (OR=8.552). CONCLUSIONS: Children carrying GSTT1 or GSTM1 null genotype have a high risk of suffering from IM or ALL. Still more increased susceptibility to IM or ALL may occur in children who carry both GSTT1 and GSTM1 null genotype. GSTT1 and GSTM1 might play a potential role in the pathogenesis of both IM and ALL. PMID- 22537953 TI - [Spectrum of gene deletion in 471 children with alpha-thalassemia]. AB - OBJECTIVE: To study the distribution of common alpha-thalassemia gene deletion in children. METHODS: Blood cell analysis was performed on children who visited the clinic of the Foshan Women and Children's Hospital. Blood samples (2 mL, EDTA anticoagulant) was collected from children with MCV<82 fl for analysis of alpha thalassemia gene using the GAP-PCR method. RESULTS: MCV<82 fl was found in 1341 children. Of the 1341 children, 471 (35.1%) were diagnosed with alpha thalassemia. The prevalence of alpha-thalassemia increased with increasing age. - SEA was a major type of alpha-thalassemia gene deletion (75.3%), followed by a3.7 (17.0%) and -a4.2 (7.7%) in the 471 patients. The top three genotypes were - SEA/aa (73.2%), aa/-a3.7 (12.5%) and --SEA/-a3.7 (5.5%). CONCLUSIONS: Genetic testing is necessary for the diagnosis of alpha-thalassemia in children with MCV<82 fl. --SEA is a common type of alpha-thalassemia gene deletion, and -SEA/aa is a common gene type of alpha-thalassemia in the subjects of this study. PMID- 22537954 TI - [Hematologic parameters and genotype analysis in 166 children with HbH disease in the North Guangxi region]. AB - OBJECTIVE: To study the characteristics of genotype spectrum and hematologic parameters in children with HbH disease in the North Guangxi region. METHODS: HbH disease was identified by clinical manifestations, routine blood tests and hemoglobin electrophoresis in 166 children who came form the North Guangxi region. Genotypes were determined by Multi-PCR combined with PCR reverse dot blot. DNA sequencing was used when the genotype could not be identified by regular methods. RESULTS: Of the 166 children with HbH disease, 8 genotypes were identified: --SEA/-alpha3.7 (82 cases), --SEA/-alpha4.2 (40 cases), - SEA/alphaCSalpha (38 cases), --SEA/alphaQSalpha (1 case), --SEA/alphaWSalpha (1 case), --SEA/alphaCD43/44 (-C) alpha (1 case), --SEA/-alpha3.7 plus CD17 (A->T) (1 case) and --SEA/-alpha4.2 plus CD41-42(-TTCT) (1 case). One case was confirmed as the heterozygote of --SEA and an unknown mutation. In the 134 cases with complete medical data, 2 had normal hemoglobin levels, 36 manifested mild anemia, 90 manifested moderate anemia, and 6 (genotype: --SEA/alphaCSalpha) showed severe anemia because of the coexistence of infection. Children with the genotype of - SEA/-alpha3.7 (69 cases), --SEA/-alpha4.2 (31 cases) and --SEA/alphaCSalpha (34 cases) had hemoglobin levels of 62-120, 69-127 and 34-110 g/L respectively. The hemoglobin level in the --SEA/alphaCSalpha group was significantly lower than in the deletional HbH disease group (genotypes: --SEA/-alpha3.7 and --SEA/-alpha4.2 ) (P<0.05). In contrast, MCV levels in the --SEA/alphaCSalpha group were significantly higher than in the deletional HbH disease group (P<0.05). CONCLUSIONS: The genotype spectrum of HbH disease is diverse in the North Guangxi region. Deletional genotype is prevalent. The disease is heterogeneous. The children with --SEA/alphaCSalpha HbH disease have severer anemia and higher MCV levels than those with deletional HbH disease. PMID- 22537955 TI - [Clinical application of cardiac output monitoring in children with severe hand foot-mouth disease]. AB - OBJECTIVE: Significant cardiac dysfunction has been found in children with severe hand-foot-mouth disease and heart failure is the major cause of death in these patients. Evaluation of cardiac function is essential for the treatment of severe cases. This study evaluated the clinical value of cardiac output monitoring in children with severe hand-foot-mouth disease. METHODS: A total of 107 children with severe hand-foot-mouth disease admitted to the pediatric intensive care unit from April 2011 to September 2011 were enrolled and divided into three groups by clinical stage: 73 cases in stage 2, 23 cases in stage 3 and 11 cases in stage 4. Cardiac output and stroke volume were measured by ultrasonic cardiac output monitors (USCOM). Ninety-five children received MRI scanning and were grouped according to the results of MRI: 41 cases (medulla oblongata involvements in 9 cases) in abnormal MRI group and 54 cases in normal MRI group. Cardiac output was compared between the children in different clinical stages and between different MRI results. RESULTS: Compared with children in clinical stages 2 and 3, cardiac output in children in clinical stage 4 decreased significantly (P<0.05). There was no differences in cardiac output between the normal and abnormal MRI groups, however cardiac output was significantly lower in children with medulla oblongata involvement than in those with other involvements and normal MRI. CONCLUSIONS: Significant decrease in cardiac output suggests critical conditions and medulla oblongata cardiovascular center involvement in children with severe hand-foot mouth disease. Dynamic measurement of cardiac output is valuable for treatment of the disease. PMID- 22537956 TI - [Application of the head-up tilt table test in children under 6 years old]. AB - OBJECTIVE: To study the clinical value and safety of the head-up tilt table test (HUTT) in children under 6 years old. METHODS: The HUTT results between September 2000 and August 2011 of 144 2 to 6-year-old children (81 boys and 63 girls) with syncope and dizziness of unknown causes were retrospectively studied. RESULTS: Eight children completed the based tilt table test and 136 cases completed the sublingual nitroglycerin tilt table test. No serious side effects were found in these children. Thirty-two (22.2%) of the 144 children had a positive result of HUTT, including 18 boys and 14 girls (P>0.05). When HUTT-induced syncope met positive standards, ECG record and blood pressure recovered to normal levels within 5 minutes by changing the position of the test bed, keeping the airway open, nasal oxygen inhalation and oral milk. CONCLUSIONS: The HUTT is valuable, safe and compliant in children under 6 years old. PMID- 22537957 TI - [Effects of ulinastatin on coagulation in children after cardiopulmonary bypass]. AB - OBJECTIVE: To study the effects of ulinastatin on coagulation in children who underwent open-heart surgery with cardiopulmonary bypass (CPB). METHODS: Fifty children who underwent open-heart surgery for ventricular septal defect were randomly divided into two groups: ulinastatin treatment and control. Before CPB, ulinastatin (1.0*10(4) U/kg) was added to CPB priming fluid only in the ulinastatin treatment group. Activated partial thromboplasin time (APTT), prothrombin time (PT), thrombin time (TT), fibrinogen and international normalized ratio (INR) were measured both before and at 1 hr, 6 hrs and 24 hrs after CPB. RESULTS: The PT in the ulinastatin group was more prolonged than in the control group at 1 hr after CPB (18.7 +/- 0.7 s vs 15.5 +/- 0.5 s) and 6 hrs after CPB (17.5 +/- 0.6 s vs 15.0 +/- 0.6 s). The APTT in the ulinatatin group was also significantly more prolonged than in the control group at 6 hrs after CPB (38.7 +/- 3.1 s vs 35.3 +/- 3.1 s) and 24 hrs after CPB (34.2 +/- 3.0 s vs 31.1 +/- 2.6 s). CONCLUSIONS: Ulinastatin may prolong PT and APTT after CPB, and thus affects coagulation in children. PMID- 22537958 TI - [Results of skin prick test in young children with wheezing or allergic diseases]. AB - OBJECTIVE: To study the characteristics of allergic reactions to common aeroallergens in young children with wheezing or allergic diseases by examining the results of skin prick test in children under 5 years old. METHODS: A total of 196 children under 5 years old, from a district of Changsha City sampled between September 1 to December 31, 2010, were assigned into two groups according to the presence of wheezing or allergic diseases: allergen screening (n=102) and control (n=94). Skin prick tests were performed on both groups. RESULTS: The positive rate of skin prick test in the allergen screening group was 61.8% (63/102), and this was significantly higher than in the control group (9.6%, 9/94; P<0.05). In the allergen screening group, the positive rate of skin prick test in children with both recurrent wheezing and allergic rhinitis was significantly higher than in children with wheezing alone (P<0.05). The frequency of wheezing was positively correlated with a positive skin prick test (r=0.91; P<0.05). The positive rate of skin prick test for mites was significantly higher than for other aeroallergens (24.2% vs 3.5%; P<0.05) in the allergen screening group. Skin prick testing of the children for dermatophagoides farinae showed a higher positive rate than for dermatophagoides pteronyssinus (50.0% vs 14.7%; P<0.05). CONCLUSIONS: Wheezing in early childhood may be associated with the occurrence of asthma. Skin prick testing contributes to the diagnosis of allergic diseases and assessment of allergic reactions to aeroallergens in children with wheezing. PMID- 22537959 TI - [Association of CLOCK gene T3111C polymorphism with attention deficit hyperactivity disorder and related sleep disturbances in children]. AB - OBJECTIVE: To examine the association between CLOCK gene T3111C polymorphism with attention deficit hyperactivity disorder (ADHD) and ADHD related sleep disturbances in children. METHODS: One hundred and sixty-six unrelated children with ADHD diagnosed according to DSM-IV criteria and a control group of 150 normal children were enrolled in this study. Parents filled out the Sleep Disturbance Scale for Children (SDSC). Genotype and allele frequencies of T3111C of the CLOCK gene were examined by PCR-restriction fragment length polymorphisms (PCR-RFLP). RESULTS: There were significant differences in the genotype and allele frequencies of T3111C of the CLOCK gene between the ADHD and control groups (P<0.05). C allele frequency in the ADHD group was significantly higher than in the control group (chi2=7.254, P=0.007, OR=1.740, 95%CI=1.160-2.612). The ADHD children with sleep disturbances were found to have higher C allele frequency than those without sleep disturbances (chi2=13.052, P<0.001, OR=2.766, 95%CI=1.573-4.865). CONCLUSIONS: There is an association between CLOCK gene T3111C polymorphism and both ADHD and related sleep disturbances in children. The individuals with C allele are susceptible to ADHD as well as ADHD related sleep disturbances. PMID- 22537960 TI - [Epidemiological investigation of birth information and physique status in 9 to 15-year-old children from Chengdu City of Sichuan Province]. AB - OBJECTIVE: As the intrauterine environment can affect childhood growth and development, this study aims to understand the relationship between birth gestational age, birth weight and physique development in 9 to 15-year-old children by a cross sectional investigation in Chengdu City, Sichuan Province. METHODS: A total of 7194 9 to 15-year-old school children were classified according to birth gestational age and birth weight: small for gestational age (SGA), appropriate for gestational age (AGA) and large for gestational age (LGA). Their heights and weights were measured. Parents completed a questionnaire. RESULTS: The prevalence of SGA was 6.23% (448 cases), and 5.13% of children in the SGA group did not undergo "catch-up growth" (lower than -2 SD). The mean height in these children at various stages was significantly lower than in the AGA group (P<0.05). The prevalence of LGA was 18.06% (1299 cases). A total of 179 children (13.78%) were found to be overweight and 57 children (4.39%) were found to be obese in the LGA group. The mean weight in the LGA group at various stages was significantly higher than in the AGA group (P<0.05). CONCLUSIONS: Height and weight development in children born SGA and LGA are different from normal children. More attention should be given to aspects of height and weight development in these school children. PMID- 22537961 TI - [Relationship between neurogenic urination and psychological status in school children]. AB - OBJECTIVE: To study whether anxiety and depression are associated with the development of neurogenic urination in children. METHODS: A total of 136 9 to 12 year-old children with neurogenic urination (case group) and 136 age-matched healthy children (control group) were enrolled. The Screen for Children Anxiety Related Emotion Disorders (SCARED) and Depression Self-rating Scale for Children (DSRSC) were used to evaluate the psychological status. The incidences of anxiety and depression as well as the SCARED and DSRSC scores were compared between two groups. Logistic regression analysis model was used to evaluate the relationship between psychological status and the development of neurogenic urination. RESULTS: The case group was found to have a higher incidence of anxiety and depression compared with the control group (P<0.01). The SCARED score in the case group (28.1 +/- 8.6) increased significantly compared with 14.4 +/- 4.9 in the control group (P<0.01). The DSRSC score in the case group was also significantly higher than in the control group (13.5 +/- 4.8 vs 9.1 +/- 3.2; P<0.01). The logistic regression analysis showed that the children with anxiety (SCARED score>23) had a 1.224-fold increased risk for the development of neurogenic urination compared with the children with the SCARED-score<=23 and that the children with depression (DSRSC-score>=15) had a 1.148-fold increased risk for the development of this disorder. CONCLUSIONS: Anxiety and depression participate in the development of neurogenic urination in school children. PMID- 22537962 TI - [Effects of bacterial lipopolysaccharide on serum IL-4, serum IL-8 and pulmonary VEGF expression in mice with asthma]. AB - OBJECTIVE: To study the regulatory role of bacterial lipopolysaccharide (LPS ) in the development of bronchial asthma by examining the effects of LPS on serum IL 4, serum IL-8 and pulmonary vascular endothelial growth factor (VEGF) expression in mice with asthma. METHODS: Twenty-seven BALB/c mice were randomly assigned into control, asthma and LPS-treated asthma groups (n=9 each). Serum IL-4 and IL 8 concentrations were measured using ELISA. VEGF expression in lung tissues was examined using the immunohistochemical method. RESULTS: Serum IL-4 and IL-8 concentrations in the asthma group were significantly higher than in the control group (P<0.05). LPS treatment significantly decreased serum IL-4 and IL-8 concentrations compared with the asthma group (P<0.05), although levels were significantly higher than in the control group (P<0.05). Airway VEGF expression in the asthma group was significantly higher than in the control group (P<0.05). LPS treatment significantly decreased airway VEGF expression compared with the asthma group (P<0.05), although concentrations remained higher than in the control group (P<0.05). CONCLUSIONS: LPS can decrease serum IL-4, serum IL-8 and pulmonary VEGF expression in mice with asthma, and thus can possibly reduce both airway inflammation and airway vascular remodeling. PMID- 22537963 TI - [Protective effect of rosiglitazone against hyperoxia-induced lung injury in neonatal rats]. AB - OBJECTIVE: To study the protective effects of PPAR gamma ligand rosiglitazone (RGZ) against hyperoxia-induced lung injury in neonatal rats. METHODS: Ninety-six neonatal Sprague-Dawley (SD) rats were randomly divided into three groups: control (room air exposure), hyperoxia (85%-90% oxygen exposure) and RGZ treatment [85%-90% oxygen exposure plus RGZ solution injection (2 mg/kg, once daily)]. Rats were sacrificed at 1, 3, 7 and 14 days after exposure. Hematoxylin and eosin staining was used to evaluate histological changes in lung tissues. The contents of malondialdehyde (MDA) and leucocyte count in bronchoalveolar lavage fluid (BALF) were measured. RESULTS: No pathological changes were found in the control group at any time point after exposure. Alveolar epithelial cell swelling, interstitial edema and massive infiltration of inflammatory cells were found in the hyperoxia group 3 days after exposure. At 14 days after exposure, the number of pulmonary alveoli was reduced, alveolus interstitium had thickened and organizational structure had become disordered in the hyperoxia group. The RGZ treatment alleviated significantly the hyperoxia induced alterations in lung pathology. Radial alveoli count (RAC) decreased significantly in the hyperoxia group compared with the control group from 3 days through to 14 days after exposure (P<0.05). The RGZ treatment group showed significantly increased RAC compared with the hyperoxia group at 3, 7 and 14 days after exposure (P<0.05). MDA content and leucocyte count in BALF increased significantly in the hyperoxia group 3 days after exposure (P<0.05), reached a peak 7 days after exposure (P<0.01) and remained higher 14 days after exposure (P<0.05) compared with the control group. The RGZ treatment group significantly decreased MDA content and leucocyte count compared with the hyperoxia group (P<0.05). CONCLUSIONS: Hyperoxia may cause acute and chronic pulmonary injuries in neonatal rats, characterized by acute inflammatory reactions and decreased alveolus in lungs. RGZ may have protective effects against hyperoxia induced lung injury. PMID- 22537964 TI - [Features of pathological changes in the non-myelin sheath of rats with experimental autoimmune encephalomyelitis]. AB - OBJECTIVE: To study the pathological changes in the non-myelin sheath by observing histological damages to the neurofilament protein and apoptosis of neurons in rats with experimental autoimmune encephalomyelitis (EAE). METHODS: Forty-eight Wistar rats were randomly divided into two groups: control and EAE (24 rats in each group). Behavioral changes were observed. Inflammation reactions and demyelination were observed by hematoxylin eosin staining and LOYEZ staining.The level of neurofilament was detected by immunohistochemistry. Apoptosis of the neuron in the spinal cord was detected by TUNEL. RESULTS: Behavioral and histological results confirmed that the model of EAE rats was prepared successfully. In the EAE group, typical morphological features of axonal damage (sparsed axonal density, axonal distortion, axonal transection and even axonal disappearance) were found from the seventh day after immunization and the morphological changes were the most obvious on the fourteenth day. Neurofilament density in the EAE group was significantly lower than in the control group (P<0.01) at 7, 14 and 21 days after immunization. The neuronal apoptosis index in the EAE group at 7, 14 and 21 days after immunization was significantly higher than in the control group (P<0.01). CONCLUSIONS: In addition to inflammatory demyelination, axonal damage and neuronal apoptosis can be observed in the early stage of EAE. Pathological changes may be associated with neurological dysfunction. PMID- 22537965 TI - [Findings of high resolution computerized tomography of the chest in children with interstitial lung disease]. PMID- 22537966 TI - [Kawasaki disease in male cousins: report of two cases]. PMID- 22537967 TI - [Molecular genetics of functional articulation disorder in children]. AB - Genetic factors are an important cause of functional articulation disorder in children. This article reviews some genes and chromosome regions associated with a genetic susceptibility to functional articulation disorders. The forkhead box P2 (FOXP2) gene on chromosome 7 is introduced in details including its structure, expression and function. The relationship between the FOXP2 gene and developmental apraxia of speech is discussed. As a transcription factor, FOXP2 gene regulates the expression of many genes. CNTNAP2 as an important target gene of FOXP2 is a key gene influencing language development. Functional articulation disorder may be developed to dyslexia, therefore some candidate regions and genes related to dyslexia, such as 3p12-13, 15q11-21, 6p22 and 1p34-36, are also introduced. ROBO1 gene in 3p12.3, ZNF280D gene, TCF12 gene, EKN1 gene in 15q21, and KIAA0319 gene in 6p22 have been candidate genes for the study of functional articulation disorder. PMID- 22537968 TI - Evaluation of molecularity of rate-limiting step of pore formation by antimicrobial peptides studied using mitochondria as a biosensor. AB - Toxic agents, derived from bee or hornet venoms and from fungi - melittin, mastoparan, and alamethicin are able to permeabilize biological membranes. We studied the initial steps of pore formation by these peptides in rat liver mitochondria preparations (RLM) generating transmembrane potential (DeltaPsi). RLM has been used as a potassium transmembrane current (PTC) sensor. The PTC induced in RLM depends linearly on the degree of steady-state activation of RLM respiration. The concentration order of such activation by melittin in a "potassium" incubation medium containing 6mM Mg(2+) was 2.01+/-0.15. In the case of mastoparan, the reaction order was 1.83+/-0.23. The first steady-state phase of activation of RLM respiration by alamethicin was not detected in "Tris" incubation medium; it appeared only after addition of KCl. The order of the reaction limiting such activation was 1.92+/-0.07. It is suggested that PTC in this phase is determined by the channels with the lowest degree of oligomerization formed by "dimers". The ratio of equally active membrane concentrations of peptides obviously reflects the ratio of average lifetimes (ALT) for corresponding "dimers" (alamethicin and melittin, 38.5; mastoparan and melittin, 0.32). It is concluded that the results of this investigation may be useful for comparative testing of perspective pharmaceuticals. PMID- 22537969 TI - Ecological quality assessment of small estuaries from the Portuguese coast based on benthic macroinvertebrate assemblages indices. AB - Benthic macroinvertebrates communities are the most consistently emphasized biotic component of aquatic ecosystems and are one of the biological indicators required for assessment by the European Water Framework Directive. In this context, several indices based on these communities have been developed in order to assess ecological quality of estuarine systems. In the present work we used AMBI, M-AMBI, BENTIX and BAT to distinguish ecological status of five small estuarine systems of the Portuguese south and southwest coasts. Although indices outputs did not differ between systems and sampling seasons, results indicated that the metrics in which these indices are based could differentiate community structures as a result of two main gradients that force these communities: the natural variability, and the anthropogenic impact. PMID- 22537970 TI - Geochemistry of organic carbon and nitrogen in surface sediments of coastal Bohai Bay inferred from their ratios and stable isotopic signatures. AB - Total organic carbon (TOC), total nitrogen (TN) and their delta(13)C and delta(15)N values were determined for 42 surface sediments from coastal Bohai Bay in order to determine the concentration and identify the source of organic matter. The sampling sites covered both the marine region of coastal Bohai Bay and the major rivers it connects with. More abundant TOC and TN in sediments from rivers than from the marine region reflect the situation that most of the terrestrial organic matter is deposited before it meets the sea. The spatial variation in delta(13)C and delta(15)N signatures implies that the input of organic matter from anthropogenic activities has a more significant influence on its distribution than that from natural processes. Taking the area as a whole, surface sediments in the marine region of coastal Bohai Bay are dominated by marine derived organic carbon, which on average accounts for 62+/-11% of TOC. PMID- 22537971 TI - Protective effect of a prime-boost strategy with plasmid DNA followed by recombinant adenovirus expressing TgAMA1 as vaccines against Toxoplasma gondii infection in mice. AB - A heterologous prime-boost strategy with priming plasmid DNA followed by recombinant virus expressing relevant antigens is known to stimulate protective immunity against intracellular parasites. In this study, we have evaluated a heterologous prime-boost strategy for immunizing mice against Toxoplasma gondii infection. Our results revealed that the prime-boost strategy using both plasmid DNA and adenoviral vector encoding TgAMA1 may stimulate both humoral and Th1/Th2 cellular immune responses specific for TgAMA1. Moreover, C57BL/6 mice immunized with the pAMA1/Ad5Null, pNull/Ad5AMA1, and pAMA1/Ad5AMA1 constructs showed survival rates of 12.5%, 37.5%, and 50%, respectively. In contrast, all the pNull/Ad5Null immunized mice died after infection with the PLK-GFP strain of T. gondii. Brain cyst burden was reduced by 23% in mice immunized with pAMA1/Ad5AMA1 compared with the pNull/Ad5AMA1 immunized mice. These results demonstrate that the heterologous DNA priming and recombinant adenovirus boost strategy may provide protective immunity against T. gondii infection. PMID- 22537972 TI - Long-term anaerobic digestion of food waste stabilized by trace elements. AB - The purpose of this study was to examine if long-term anaerobic digestion of food waste in a semi-continuous single-stage reactor could be stabilized by supplementing trace elements. Contrary to the failure of anaerobic digestion of food waste alone, stable anaerobic digestion of food waste was achieved for 368 days by supplementing trace elements. Under the conditions of OLR (organic loading rates) of 2.19-6.64 g VS (volatile solid)/L day and 20-30 days of HRT (hydraulic retention time), a high methane yield (352-450 mL CH(4)/g VS(added)) was obtained, and no significant accumulation of volatile fatty acids was observed. The subsequent investigation on effects of individual trace elements (Co, Fe, Mo and Ni) showed that iron was essential for maintaining stable methane production. These results proved that the food waste used in this study was deficient in trace elements. PMID- 22537973 TI - Comparative analysis for the production of fatty acid alkyl esterase using whole cell biocatalyst and purified enzyme from Rhizopus oryzae on waste cooking oil (sunflower oil). AB - The petroleum fuel is nearing the line of extinction. Recent research and technology have provided promising outcomes to rely on biodiesel as the alternative and conventional source of fuel. The use of renewable source - vegetable oil constitutes the main stream of research. In this preliminary study, Waste Cooking Oil (WCO) was used as the substrate for biodiesel production. Lipase enzyme producing fungi Rhizopus oryzae 262 and commercially available pure lipase enzyme were used for comparative study in the production of Fatty Acid Alkyl Esters (FAAE). The whole cell (RO 262) and pure lipase enzyme (PE) were immobilized using calcium alginate beads. Calcium alginate was prepared by optimizing with different molar ratios of calcium chloride and different per cent sodium alginate. Entrapment immobilization was done for whole cell biocatalyst (WCB). PE was also immobilized by entrapment for the transesterification reaction. Seven different solvents - methanol, ethanol, n-propanol, n-butanol, iso-propanol, iso-butanol and iso-amyl alcohol were used as the acyl acceptors. The reaction parameters like temperature (30 degrees C), molar ratio (1:3 - oil:solvent), reaction time (24 h), and amount of enzyme (10% mass ratio to oil) were also optimized for methanol alone. The same parameters were adopted for the other acyl acceptors too. Among the different acyl acceptors - methanol, whose reaction parameters were optimized showed maximum conversion of triglycerides to FAAE-94% with PE and 84% with WCB. On the whole, PE showed better catalytic converting ability with all the acyl acceptor compared to WCB. Gas chromatography analysis (GC) was done to determine the fatty acid composition of WCO (sunflower oil) and FAAE production with different acyl acceptors. PMID- 22537974 TI - Mandibular plasmocytoma with sun-ray periosteal reaction: A unique presentation. AB - INTRODUCTION: Solitary plasmocytoma is a rare plasmacytic cell tumor, which occurs in the head and neck region and rarely involves the mandible. PRESENTATION OF CASE: We present a unique radiographic presentation of solitary bone plasmocytoma (SBP) occurring in the Jaw. A 63-year-old male presented with the left mandibular swelling and on the conventional radiograph we noticed a lytic lesion with a sunray periosteal reaction. Clinical diagnosis was osteosarcoma but histopathology revealed sheets of plasma cells with cartwheel appearance and expansile bony trabecula suggestive for solitary bone plasmocytoma. 5years after complentary treatment by local radiotherapy he developed malaise, weakness and generalized bone pain and bone marrow aspiration revealed more than 90% plasma cell in the marrow and diagnosis of Multiple Myeloma was confirmed. DISCUSSION: SBP is radiographically seen as a well-defined radiolucent expansile lytic lesion with cortical thinning and no periosteal reaction. The imaging appearance of periosteal reaction is determined by the intensity, aggressiveness, and duration of the underlying pathology. Osteosarcoma, Metastasis (especially from sigmoid colon and rectum), Ewing s sarcoma, Haemangioma, meningioma and Tuberculosis are the main differential diagnosis of Sunburst periosteal reaction. CONCLUSION: Sunray periosteal reaction should be included in the differential diagnosis of lytic bone lesion in the mandible. PMID- 22537975 TI - Comparative structural modeling and docking studies of uricase: possible implication in enzyme supplementation therapy for hyperuricemic disorders. AB - Uricase (EC 1.7.3.3, UC) catalyzes the oxidation of uric acid (UA) to more soluble allantoin thereby lowering plasma UA levels. In humans, when concentration of UA exceeds >7mg/dl, it leads to hyperuricemia, gout, nephrolithiasis and urolithiasis. A new remedy to cure such metabolic diseases is the enzyme supplementation therapy by UC but with high degree of antigenic independence. Therefore screening of new uricase sources to expand its usefulness and reduced antigenecity is needed. Present study employed cheminformatics approach to construct models of reported UC from different sources viz. Bacillus megaterium, Streptomyces bingchenggensis BCW-1, Paenibacillus sp, Solibacter usitatus Ellin6076, Truepera radiovictrix DSM 17093 and Ktedonobacter racemifer DSM 4496 in order to study their structure-function relationship for enzyme mass production and modification for improved characteristics. BioMed CAChe version 6.1 was further used to study enzyme-substrate interactions of models with uric acid using docking approach. Results indicated that models for UC of Streptomyces bingchenggensis BCW-1 accounted for better regio-specificity towards UA, supporting the interested metabolism and thus may further be implicated in enzyme supplementation therapy for hyperuricemic associated disorders. PMID- 22537976 TI - Predictors of carotid intima-media thickness and carotid plaque in young Indian adults: the New Delhi birth cohort. AB - BACKGROUND: Carotid intima-media thickness (CIMT) and carotid plaques represent preclinical markers of atherosclerosis. We sought to describe predictors of CIMT and carotid plaques, including early life growth, in a young urban Indian cohort free of clinical cardiovascular disease (CVD). METHODS: In 2006-2009, we performed B-mode carotid ultrasound on 600 participants (mean [SD] age 36 [1.1] years; 45% women) from the New Delhi Birth Cohort to evaluate CIMT and carotid plaques (>1mm). Height and weight were recorded at birth, 2 and 11 years of age. Data on CVD risk factors, anthropometry, medical history, socio-economic position, and lifestyle habits were collected in 1998-2002. RESULTS: Mean (SD) CIMT for men and women was 0.91 (0.12) and 0.86 (0.13) mm, respectively. Carotid plaque was present in 33% of men and 26% of women. Waist circumference in 1998 2002 was positively associated with CIMT (beta coefficient 0.26 mm [0.17, 0.36] per SD) and carotid plaque (OR 1.27 [1.06,1.52] per SD) in 2006-2009. Higher triglycerides, PAI-1, insulin resistance, and diastolic blood pressure, metabolic syndrome, and lower HDL-cholesterol and physical activity predicted higher CIMT and/or plaque (p<0.05). Longer length at 2 years was associated with higher CIMT (p<0.05). These associations were attenuated after adjusting for adult waist circumference. CONCLUSIONS: These are the first prospective data from India showing that early life growth, adult socio-demographics, and CVD risk factors predict future CIMT and/or carotid plaque. These relationships appear primarily mediated through central adiposity, highlighting the importance of maintaining a healthy weight in early adulthood to prevent CVD. PMID- 22537977 TI - Cardiac resynchronization therapy using dual-site left ventricular pacing improves severe left ventricular dysfunction due to ischemic cardiomyopathy and permanent right ventricular apical pacing. PMID- 22537978 TI - Determinants and functional impact of restrictive physiology after repair of tetralogy of Fallot: new insights from magnetic resonance imaging. AB - BACKGROUND: The presence of end-diastolic forward flow (EDFF) in the pulmonary arteries is commonly regarded as a hallmark of restrictive physiology of the right ventricle (RV) which, in turn, has been associated with a better long-term prognosis in patients after TOF repair. However, controversy persists over the beneficial clinical consequences of restrictive physiology. We aimed at determining the clinical relevance of restrictive physiology late after TOF repair. METHODS: Fifty magnetic resonance examinations of 50 patients (age 13.0 +/- 2.8 years, 26 males) with repaired TOF were evaluated. The patients were divided into: Group-1 with and Group-2 without EDFF; Group-A with smaller RVs (<170 ml/m2) and Group-B with larger RVs (>= 170 ml/m2). Maximum oxygen consumption as percent of predicted (VO2max-pred) at a recent exercise test was recorded. RESULTS: Groups-1 and 2 did not differ with regard to their right ventricular end-diastolic volume, pulmonary regurgitant volume, or QRS duration. Patients in Group-1 had a higher VO2max-pred than patients in Group-2 (70.3% versus 54.7% of predicted, p<0.01). In Group-1A versus 2A (RV<170 ml/m(2), with and without EDFF) this difference persisted, but in Group B there was no difference in VO2max-pred between patients with and without EDFF. The flow volume of EDFF correlated with VO2max-pred (r=0.444, p=0.007). CONCLUSIONS: End diastolic forward flow measured by magnetic resonance is present in patients with small and large RVs. The presence of EDFF is associated with better exercise tolerance, but only in patients with relatively small RVs. PMID- 22537980 TI - Essential requirements of a CT colonography service. AB - There are many potential challenges to developing a high quality, efficient CT colonography service. Some are clear and predictable, for example creating CT capacity and securing financial resources, but some are less obvious, such as harnessing local support or changing referral practice amongst clinical colleagues. Notwithstanding, such barriers will need to be overcome to deliver a well-resourced, successful CT colonography programme. This article utilises the authors' experience of developing their own CT colonography service from scratch (now examining >1200 patients per annum) and relevant published articles on 'Standards' of practice and training to recommend how others might provide CT colonography in their own patient communities. We offer a practical guide and will emphasise the need for a multi-disciplinary approach with locally agreed protocols and service objectives. PMID- 22537979 TI - Deltamethrin-induced oxidative stress and biochemical changes in tissues and blood of catfish (Clarias gariepinus): antioxidant defense and role of alpha tocopherol. AB - BACKGROUND: The pyrethroid class of insecticides, including deltamethrin, is being used as substitutes for organochlorines and organophosphates in pest control programs because of their low environmental persistence and toxicity. This study was aimed to investigate the impact of commonly used pesticides (deltamethrin) on the blood and tissue oxidative stress level in catfish (Clarias gariepinus); in addition to the protective effect of alpha-tocopherol on deltamethrin induced oxidative stress. Catfish were divided into three groups, 1st control group include 20 fish divided into two tanks each one contain 10 fish, 2nd deltamethrin group, where Fish exposed to deltamethrin in a concentration (0.75 MUg/l) and 3rd Vitamin E group, Fish exposed to deltamethrin and vitamin E at a dose of 12 MUg/l for successive 4 days.Serum, liver, kidney and Gills were collected for biochemical assays. Tissue oxidative stress biomarkers malondialdhyde (MDA) and catalase activity in liver, kidney and gills tissues, serum liver enzymes (ALT and AST), serum albumin, total protein, urea and creatinine were analysed. RESULTS: Our results showed that 48 h. exposure to 0.75 MUg/l deltamethrin significantly (p < 0.05) increased lipid peroxidation (MDA) in the liver, kidney and gills while catalase activity was significantly decreased in the same tissues. This accompanied by significant increase in serum ALT, AST activity, urea and creatinine and a marked decrease in serum albumin and total proteins. CONCLUSIONS: It could be concluded that deltamethrin is highly toxic to catfish even in very low concentration (0.75 MUg/l). Moreover the effect of deltamethrin was pronounced in the liver of catfish in comparison with kidneys and gills. Moreover fish antioxidants and oxidative stress could be used as biomarkers for aquatic pollution, thus helping in the diagnosis of pollution. Administration of 12 MUg/l alpha-tocopherol restored the quantified tissue and serum parameters, so supplementation of alpha-tocopherol consider an effective way to counter the toxicity of deltamethrin in the catfish. PMID- 22537981 TI - Primary diaphyseal osteosarcoma in long bones: imaging features and tumor characteristics. AB - OBJECTIVE: This study aims to assess retrospectively the imaging features of diaphyseal osteosarcoma and compare its characteristics with that of metaphyseal osteosarcoma. MATERIALS AND METHODS: Eighteen pathologically confirmed diaphyseal osteosarcomas were reviewed. Images of X-ray (n=18), CT (n=12) and MRI (n=15) were evaluated by two radiologists. Differences among common radiologic findings of X-ray, CT and MRI, and between diaphyseal osteosarcomas and metaphyseal osteosarcomas in terms of tumor characteristics were compared. RESULTS: The common imaging features of diaphyseal osteosarcoma were bone destruction, lamellar periosteal reaction with/without Codman triangle, massive soft tissue mass/swelling, neoplastic bone and/or calcification. CT and MRI had a higher detection rate in detecting bone destruction (P=0.001) as compared with that of X ray. X-ray and CT resulted in a higher percentage in detecting periosteal reaction (P=0.018) and neoplastic bone and/or calcification (P=0.043) as compared with that of MRI. There was no difference (P=0.179) in detecting soft tissue mass among three imaging modalities. When comparing metaphyseal osteosarcoma to diaphyseal osteosarcoma, the latter had the following characteristics: a higher age of onset (P=0.022), a larger extent of tumor (P=0.018), a more osteolytic radiographic pattern (P=0.043). CONCLUSION: As compared with metaphyseal osteosarcoma, diaphysial osteosarcoma is a special location of osteosarcoma with a lower incidence, a higher age of onset, a larger extent of tumor, a more osteolytic radiographic pattern. The osteoblastic and mixed types are diagnosed easily, but the osteolytic lesion should be differentiated from Ewing sarcoma. X ray, CT and MRI can show imaging features from different aspects with different detection rates. PMID- 22537982 TI - Activity of selected phytochemicals against Plasmodium falciparum. AB - According to the WHO, in 2008, there were 247 million reported cases of malaria and nearly one million deaths from the disease. Parasite resistance against first line drugs, including artemisinin and mefloquine, is increasing. In this study the plant-derived compounds aglafolin, rocaglamid, kokusaginine, arborine, arborinine and tuberostemonine were investigated for their anti-plasmodial activity in vitro. Fresh Plasmodium falciparum isolates were taken from patients in the area of Mae Sot, north-western Thailand in 2008 and the inhibition of schizont maturation was determined for the respective compounds. With inhibitory concentrations effecting 50%, 90% and 99% inhibition (IC(50), IC(90) and IC(99)) of 60.95 nM, 854.41 nM and 7351.49 nM, respectively, rocaglamid was the most active of the substances, closely followed by aglafoline with 53.49 nM, 864.55 nM and 8354.20 nM. The activity was significantly below that of artemisinin, but moderately higher than that of quinine. Arborine, arborinine, tuberostemonine and kokusaginine showed only marginal activity against P. falciparum characterized by IC(50) and IC(99) values higher than 350 nM and 180 MUM, respectively, and regressions with relatively shallow slopes S>14.38. Analogues of rocaglamid and aglafoline merit further exploration of their anti-plasmodial activity. PMID- 22537983 TI - Viral vectored granulocyte-macrophage colony stimulating factor inhibits vaccine protection in an SIV challenge model: protection correlates with neutralizing antibody. AB - In a previous vaccine study, we reported significant and apparently sterilizing immunity to high-dose, mucosal, simian immunodeficiency virus (SIV) quasi-species challenge. The vaccine consisted of vectors based on vesicular stomatitis virus (VSV) expressing simian immunodeficiency virus (SIV) gag and env genes, a boost with propagating replicon particles expressing the same SIV genes, and a second boost with VSV-based vectors. Concurrent with that published study we had a parallel group of macaques given the same doses of vaccine vectors, but in addition, we included a third VSV vector expressing rhesus macaque GM-CSF in the priming immunization only. We report here that addition of the vector expressing GM-CSF did not enhance CD8 T cell or antibody responses to SIV antigens, and almost completely abolished the vaccine protection against high-dose mucosal challenge with SIV. Expression of GM-CSF may have limited vector replication excessively in the macaque model. Our results suggest caution in the use of GM CSF as a vaccine adjuvant, especially when expressed by a viral vector. Combining vaccine group animals from this study and the previous study we found that there was a marginal but significant positive correlation between the neutralizing antibody to a neutralization resistant SIV Env and protection from infection. PMID- 22537985 TI - Comparison of vaccine efficacy for different antigen delivery systems for infectious pancreatic necrosis virus vaccines in Atlantic salmon (Salmo salar L.) in a cohabitation challenge model. AB - Two strains of IPNV made by reverse genetics on the Norwegian Sp strain NVI-015 (GenBank AY379740) backbone encoding the virulent (T(217)A(221)) and avirulent (P(217)T(221)) motifs were used to prepare inactivated whole virus (IWV), nanoparticle vaccines with whole virus, Escherichia coli subunit encoding truncated VP2-TA and VP2-PT, VP2-TA and VP2-PT fusion antigens with putative translocating domains of Pseudomonas aeruginosa exotoxin, and plasmid DNA encoding segment A of the TA strain. Post challenge survival percentages (PCSP) showed that IWV vaccines conferred highest protection (PCSP=42-53) while nanoparticle, sub-unit recombinant and DNA vaccines fell short of the IWV vaccines in Atlantic salmon (Salmo salar L.) postsmolts challenged with the highly virulent Sp strain NVI-015 (TA strain) of IPNV after 560 degree days post vaccination. Antibody levels induced by these vaccines did not show antigenic differences between the virulent and avirulent motifs for vaccines made with the same antigen dose and delivery system after 8 weeks post vaccination. Our findings show that fish vaccinated with less potent vaccines comprising of nanoparticle, DNA and recombinant vaccines got infected much earlier and yielded to higher infection rates than fish vaccinated with IWV vaccines that were highly potent. Ability of the virulent (T(217)A(221)) and avirulent (P(217)T(221)) motifs to limit establishment of infection showed equal protection for vaccines made of the same antigen dose and delivery systems. Prevention of tissue damage linked to viral infection was eminent in the more potent vaccines than the less protective ones. Hence, there still remains the challenge of developing highly efficacious vaccines with the ability to eliminate the post challenge carrier state in IPNV vaccinology. PMID- 22537986 TI - Intra-cisternal vaccination induces high-level protection against Neospora caninum infection in mice. AB - The efficacy of intra-cisternal (IC) immunization in preventing the dissemination of Neospora caninum tachyzoites into the brain was investigated. Mice were vaccinated intracisternally with tachyzoite extract in artificial cerebrospinal fluid (ACSF). For comparison, other groups were vaccinated via the intraperitoneal (IP) route with crude tachyzoite antigen extract, suspended either in Freund's incomplete adjuvant (FIA) or saponin. Subsequently, the mice were experimentally infected by IP administration of 2*10(6) N. caninum tachyzoites, and were monitored for 30 days. In the IP vaccinated mice, 22 and 33% of the mice from the adjuvant control groups (FIA and saponin, respectively) survived the challenge, and 66% of mice receiving Neospora tachyzoite extract in FIA and 55% of mice immunized with Neospora tachyzoite antigens in saponin. In the IC vaccinated group, all mice (8 out of 8) immunized with Neospora antigen remained clinically healthy, while only 2 out of 8 survived in the group treated with ACSF alone. Analysis of brain tissue showed a significantly reduced cerebral parasite load in IC vaccinated mice. Quantification of NcGRA2 transcripts in the IC vaccinated groups revealed that the viability of tachyzoites was severely impaired. Analysis of the humoral immune responses employing ELISA showed that the increased protection by IC vaccination was associated with a high IgG2a/IgG1 ratio, and analysis of cytokine transcript levels in spleen tissues at the end of the experiment, revealed a significant increase in mRNA coding for interferon gamma. PMID- 22537984 TI - Phase 2 assessment of the safety and immunogenicity of two inactivated pandemic monovalent H1N1 vaccines in adults as a component of the U.S. pandemic preparedness plan in 2009. AB - BACKGROUND: The influenza A/H1N1 pandemic in 2009 created an urgent need to develop vaccines for mass immunization. To guide decisions regarding the optimal immunization dosage and schedule for adults, we evaluated two monovalent, inactivated, unadjuvanted H1N1 influenza vaccines in independent, but simultaneously conducted, multi-center Phase 2 trials of identical design. METHODS: Healthy adults, stratified by age (18-64 years and >=65 years), were randomized (1:1 allocation), in a double-blind, parallel-group design, to receive two intramuscular doses (21 days apart) of vaccine containing approximately 15 MUg or 30 MUg of hemagglutinin (HA). Primary endpoints were safety (reactogenicity for 8 days after each vaccination and vaccine-associated serious adverse events during the 7 month study) and immunogenicity (proportion of subjects, stratified by age, achieving a serum hemagglutination inhibition [HI] antibody titer >=1:40 or a >=4-fold rise in titer after a single injection of either dosage). RESULTS: Both vaccines were well-tolerated. A single 15 MUg dose induced HI titers >=1:40 in 90% of younger adults (95% confidence interval [CI] 82-95%) and 81% of elderly (95% CI 71-88%) who received Sanofi-Pasteur vaccine (subsequently found to contain 24 MUg HA in the standard potency assay), and in 80% of younger adults (95% CI 71-88%) and 60% of elderly (95% CI 50-70%) who received CSL vaccine. Both vaccines were significantly more immunogenic in younger compared with elderly adults by at least one endpoint measure. Increasing the dose to 30 MUg raised the frequency of HI titers >=1:40 in the elderly by approximately 10%. Higher dosage did not significantly enhance immunogenicity in younger adults and a second dose provided little additional benefit to either age group. CONCLUSION: These trials provided evidence for policymakers that a single 15 MUg dose of 2009 A/H1N1 vaccine would likely protect most U.S. adults and suggest a potential benefit of a 30 MUg dose for the elderly. PMID- 22537987 TI - A novel fusion protein containing the receptor binding domains of C. difficile toxin A and toxin B elicits protective immunity against lethal toxin and spore challenge in preclinical efficacy models. AB - Antibodies targeting the Clostridium difficile toxin A and toxin B confer protective immunity to C. difficile associated disease in animal models and provided protection against recurrent C. difficile disease in human subjects. These antibodies are directed against the receptor binding domains (RBD) located in the carboxy-terminal portion of both toxins and inhibit binding of the toxins to their receptors. We have constructed a recombinant fusion protein containing portions of the RBD from both toxin A and toxin B and expressed it in Escherichia coli. The fusion protein induced high levels of serum antibodies to both toxins A and B capable of neutralizing toxin activity both in vitro and in vivo. In a hamster C. difficile infection model, immunization with the fusion protein reduced disease severity and conferred significant protection against a lethal dose of C. difficile spores. Our studies demonstrate the potential of the fusion protein as a vaccine that could provide protection from C. difficile disease in humans. PMID- 22537988 TI - Evaluation of meningococcal serogroup C conjugate vaccine programs in Canadian children: interim analysis. AB - BACKGROUND: To assess antibody titers afforded by meningococcal C- (MenC) tetanus toxoid conjugate vaccine at 12 months of age in three different immunization schedules. METHODS: This prospective study included three similar cohorts of healthy infants from 1-dose, 2-dose and 3-dose MenC infant immunization programs. Infants were enrolled at 12 months of age and given the final scheduled dose of MenC-tetanus toxoid conjugate vaccine with sera collected prior to and 1 month after the vaccination. Serum bactericidal activity (SBA) titers >= 1:8 were considered protective. RESULTS: Before the 12 month dose, participants had significantly different protective titers according to the number of prior doses received: 100% (95% CI 97.6-100%) of infants who had 2 prior doses (at 2 and 4 months) were protected compared to 84.0% (76.7-89.3%) of participants with one dose (at 2 months) and 27.6% (21.0-35.4%) of unvaccinated infants. All subjects were protected after the 12 month MenC dose, but titers were higher with prior priming. CONCLUSIONS: Two MenC doses given in infancy afford optimal protection during the first year of life; however, substantial protection was seen after one dose at 2 months. PMID- 22537989 TI - Bacterium-like particles supplemented with inactivated influenza antigen induce cross-protective influenza-specific antibody responses through intranasal administration. AB - Administration of influenza vaccines through the intranasal (IN) route forms an attractive alternative to conventional intramuscular (IM) injection. It is not only a better accepted form of vaccine administration but it also has the potential to induce, in addition to systemic antibodies, local protective antibodies, i.e. S-IgA. Most commercially available vaccines however are inactivated non-replicating vaccines and have a low immunogenicity when administered intranasally. Local administration of these vaccines would therefore need an adjuvant to boost systemic and local antibody responses. Here we explored the use of a safe adjuvant system, i.e. bacterium-like particles (BLPs) derived from the food-grade bacterium in Lactococcus lactis, in the induction of protective antibody responses after intranasal immunization of mice. Supplementation of H1N1 split vaccine with BLPs significantly increased levels of serum influenza-specific IgG and hemagglutination-inhibiting antibodies: this was dependent on the dose of admixed BLPs and number of immunizations. Admixing BLPs further boosted local influenza-specific S-IgA antibody levels at lung and nasal mucosal sites, but also at distant mucosal sites such as the vaginal mucosal tissue. Mice immunized IN with BLP-adjuvanted vaccine and IM with non-adjuvanted vaccine were protected against weight loss upon homologous infection with H1N1 A/PR/8/34. Full protection against weight loss upon heterologous challenge with H1N1 A/PR/8/34 was seen in mice immunized IN with BLP-adjuvanted H1N1 A/New Caledonia-derived split virus vaccine, but not in those receiving the split virus vaccine IM. Mice immunized IN with BLP-adjuvanted vaccine had significantly lower lung viral titers upon homologous and heterologous challenge when compared to titers detected in mice immunized by IM injection of non-adjuvanted vaccine. Thus, adjuvantation of IN-administered influenza vaccines with BLPs effectively enhances systemic and local antibody responses leading to a superior protection against homologous and heterologous influenza infection compared to conventional IM immunization. PMID- 22537990 TI - Interchangeability and tolerability of two inactivated hepatitis A vaccines in Chinese children. AB - In China, no data are available to evaluate the interchangeability between Chinese domestic inactivated hepatitis A vaccines (Healive) and imported inactivated hepatitis A vaccines (Havrix). A double-blind, randomized controlled study was to compare interchangeability and safety of Healive and Havrix among Chinese children. Vaccine was administered to 303 healthy children at 0 and 6 months in one of four vaccine regimens: Healive-Healive; Healive-Havrix; Havrix Healive or Havrix-Havrix. We collected sera samples at 0 (before vaccination), 6 (before second dose) and 7 months (after second dose), and compared groups in terms of proportion of sero-conversions which is defined as >= 20 mIU/ml, and geometric mean concentrations (GMCs) of anti-hepatitis A virus (HAV) antibody. Seroconversion rates were 133/133 (100%) for those received one dose of Healive and 105/131 (80.2%) for those received one dose of Havrix at 6 months, respectively (P<0.001), GMCs for Healive and Havrix were 126.1 and 40.9 mIU/ml (P<0.001), respectively. At 7 months, the seroconversion rate was 100% among all groups. The GMC after two doses of Healive was 8905.5 mIU/ml compared with 1900.9 mIU/ml after two doses of Havrix (P<0.001). The GMC in the Healive-Havrix group was 3275.8 mIU/ml compared with 4165.8 mIU/ml in the Havrix-Healive group (P=0.058). There is not different of reported adverse reactions across the groups. The present study indicated that both vaccines can be recommended for interchangeable using of immunization among Chinese healthy children. PMID- 22537992 TI - Adaptive pathways of zoonotic influenza viruses: from exposure to establishment in humans. AB - Human influenza viruses have their ultimate origin in avian reservoirs and may adapt, either directly or after passage through another mammalian species, to circulate independently in the human population. Three sets of barriers must be crossed by a zoonotic influenza virus before it can become a human virus: animal to-human transmission barriers; virus-cell interaction barriers; and human-to human transmission barriers. Adaptive changes allowing zoonotic influenza viruses to cross these barriers have been studied extensively, generating key knowledge for improved pandemic preparedness. Most of these adaptive changes link acquired genetic alterations of the virus to specific adaptation mechanisms that can be screened for, both genetically and phenotypically, as part of zoonotic influenza virus surveillance programs. Human-to-human transmission barriers are only sporadically crossed by zoonotic influenza viruses, eventually triggering a worldwide influenza outbreak or pandemic. This is the most devastating consequence of influenza virus cross-species transmission. Progress has been made in identifying some of the determinants of influenza virus transmissibility. However, interdisciplinary research is needed to further characterize these ultimate barriers to the development of influenza pandemics, at both the level of the individual host and that of the population. PMID- 22537991 TI - Factors mediating seasonal and influenza A (H1N1) vaccine acceptance among ethnically diverse populations in the urban south. AB - OBJECTIVE: We examined the acceptability of the influenza A (H1N1) and seasonal vaccinations immediately following government manufacture approval to gauge potential product uptake in minority communities. We studied correlates of vaccine acceptance including attitudes, beliefs, perceptions, and influenza immunization experiences, and sought to identify communication approaches to increase influenza vaccine coverage in community settings. METHODS: Adults >=18 years participated in a cross-sectional survey from September through December 2009. Venue-based sampling was used to recruit participants of racial and ethnic minorities. RESULTS: The sample (N=503) included mostly lower income (81.9%, n=412) participants and African Americans (79.3%, n=399). Respondents expressed greater acceptability of the H1N1 vaccination compared to seasonal flu immunization (t=2.86, p=0.005) although H1N1 vaccine acceptability was moderately low (38%, n=191). Factors associated with acceptance of the H1N1 vaccine included positive attitudes about immunizations [OR=0.23, CI (0.16, 0.33)], community perceptions of H1N1 [OR=2.15, CI (1.57, 2.95)], and having had a flu shot in the past 5 years [OR=2.50, CI (1.52, 4.10). The factors associated with acceptance of the seasonal flu vaccine included positive attitudes about immunization [OR=0.43, CI (0.32, 0.59)], community perceptions of H1N1 [OR=1.53, CI (1.16, 2.01)], and having had the flu shot in the past 5 years [OR=3.53, CI (2.16, 5.78)]. Participants were most likely to be influenced to take a flu shot by physicians [OR=1.94, CI (1.31, 2.86)]. Persons who obtained influenza vaccinations indicated that Facebook (chi(2)=11.7, p=0.02) and Twitter (chi(2)=18.1, p=0.001) could be useful vaccine communication channels and that churches (chi(2)=21.5, p<0.001) and grocery stores (chi(2)=21.5, p<0.001) would be effective "flu shot stops" in their communities. CONCLUSIONS: In this population, positive vaccine attitudes and community perceptions, along with previous flu vaccination, were associated with H1N1 and seasonal influenza vaccine acceptance. Increased immunization coverage in this community may be achieved through physician communication to dispel vaccine conspiracy beliefs and discussion about vaccine protection via social media and in other community venues. PMID- 22537993 TI - How influenza vaccination policy may affect vaccine logistics. AB - BACKGROUND: When policymakers make decision about the target populations and timing of influenza vaccination, they may not consider the impact on the vaccine supply chains, which may in turn affect vaccine availability. PURPOSE: Our goal is to explore the effects on the Thailand vaccine supply chain of introducing influenza vaccines and varying the target populations and immunization time frames. METHODS: We Utilized our custom-designed software HERMES (Highly Extensible Resource for Modeling Supply Chains), we developed a detailed, computational discrete-event simulation model of the Thailand's National Immunization Program (NIP) supply chain in Trang Province, Thailand. A suite of experiments simulated introducing influenza vaccines for different target populations and over different time-frames prior to and during the annual influenza season. RESULTS: Introducing influenza vaccines creates bottlenecks that reduce the availability of both influenza vaccines as well as the other NIP vaccines, with provincial to district transport capacity being the primary constraint. Even covering only 25% of the Advisory Committee on Immunization Practice-recommended population while administering the vaccine over six months hinders overall vaccine availability so that only 62% of arriving patients can receive vaccines. Increasing the target population from 25% to 100% progressively worsens these bottlenecks, while increasing influenza vaccination time-frame from 1 to 6 months decreases these bottlenecks. CONCLUSION: Since the choice of target populations for influenza vaccination and the time-frame to deliver this vaccine can substantially affect the flow of all vaccines, policy-makers may want to consider supply chain effects when choosing target populations for a vaccine. PMID- 22537994 TI - Persistence of functional antibodies to group B streptococcal capsular polysaccharides following immunization with glycoconjugate vaccines. AB - The duration of functional activity of group B streptococcal (GBS) glycoconjugate vaccine-induced capsular polysaccharide-specific (CPS) IgG was evaluated among healthy adult responders. Opsonophagocytic activity declined significantly from a 4-week post-immunization peak, but substantial functional activity, exceeding 1 log(10) reduction in GBS cfu/mL, was retained at 18 months to 2 years post immunization for each GBS type assessed. The persistence of functional antibody activity when GBS CPS-specific IgG concentrations decline, although remaining significantly higher than pre-immunization levels, suggests that long-term protection may be expected from candidate GBS glycoconjugates administered to this population. PMID- 22537995 TI - Electroejaculation increased vocalization and plasma concentrations of cortisol and progesterone, but not substance P, in beef bulls. AB - Electroejaculation is a reliable method of obtaining a semen sample for a bull breeding soundness examination, but is sometimes regarded as painful. Substance P is a neuropeptide involved in the integration of pain, stress, and anxiety. We hypothesized that substance P is a measure of pain in bulls following electroejaculation. The specific objective was to compare vocalization and plasma concentrations of cortisol, progesterone, and substance P immunoreactivity in bulls following electroejaculation. Nine Angus bulls (501.9 +/- 14.3 kg) were used. Blood samples were collected at -60, -30, 0, 2, 10, 20, 30, 45, 60, 75, 90, 120 min relative to treatment. At Time 0, bulls were subject to electroejaculation, rectal probe insertion without electroejaculation, or no manipulation. Treatments were administered contemporaneously to three bulls. Treatments were repeated weekly until each bull had received each treatment in a 3 * 3 Latin square design. More bulls (P = 0.0147) in the electroejaculation group vocalized (5 of 9 bulls; 55.6%) when compared to controls (0 of 9 bulls; 0%). Mean plasma cortisol and progesterone concentration following electroejaculation in bulls were higher (P < 0.05) than concentrations in probed and control bulls through the 45 min sample. However, mean plasma substance P concentration following electroejaculation in bulls (77.2 +/- 17.2 pg/mL) was not different (P = 0.6264) from probed (79.1 +/- 17.2 pg/mL) or control bulls (93.4 +/- 17.2 pg/mL). A significant increase in vocalization and plasma cortisol and progesterone concentrations in bulls following electroejaculation was likely owing to acute stress. However, the lack of a difference in plasma concentrations of substance P after electroejaculation was interpreted as a lack of pain associated with nociception. PMID- 22537996 TI - Oocyte and embryo production and quality after OPU-IVF in dairy heifers given diets varying in their n-6/n-3 fatty acid ratio. AB - Dietary fat supplementation can improve oocyte quality in ruminants. The influence of the type of dietary fat on the number and quality of oocytes collected by ovum pick-up and on the production of embryos in vitro was investigated in Holstein heifers. Heifers were given hay plus one of two dietary supplements for 42 days. The supplements were linseed (L, rich in linolenic acid, C18:3n-3, n = 9) or soya bean (S, rich in linoleic acid, C18:2n-6, n = 9). Oocytes were collected by ovum pick-up (OPU) for 6 wks (2 sessions/wk) and morphologic quality assessed. Half the oocytes were frozen and the other half was used to produce embryos. Blood samples were analyzed for: insulin, insulin-like growth factor-1, glucose, non-esterified fatty acids, beta-hydroxy butyrate and urea and the proportions of fatty acids. Neither growth rate nor plasma hormone and metabolite concentrations were affected by dietary supplement. However, L significantly increased the proportion of plasma C18:3n-3 while S significantly increased the proportion of C18:2n-6(P < 0.001). Neither oocyte characteristics (number, their quality and number fertilized and cleaved per heifer per session) nor embryo characteristics (number and quality per heifer per session) and embryo development stages were affected by dietary treatment. Real-time RT-PCR was performed on immature and mature cumulus-oocyte complexes (COC). Prostaglandin E synthase-1 expression increased in L compared to S heifers. In conclusion, the type of fatty acid did not modify the numbers of oocytes and embryos produced by OPU-IVF and their quality in dairy heifers. Upregulation of prostaglandin E synthase-1 may ensure sufficient PGE(2) production for oocyte maturation even when its precursor is low. PMID- 22537997 TI - Effects of extenders, cryoprotectants and freezing methods on sperm quality of the threatened Brazilian freshwater fish pirapitinga-do-sul Brycon opalinus (Characiformes). AB - The objective was to develop a suitable freezing method to cryopreserve Brycon opalinus (Characiformes) sperm. Extenders (NaCl and glucose at 325 and 365 mOsm/kg), cryoprotectants (dimethyl sulfoxide=dimethyl sulfoxide (DMSO) and methyl glycol=methyl glycol (MG)), equilibration times (15 and 30 min), thawing temperatures (30 and 60 degrees C), and straw sizes (0.5 and 4.0 mL) were tested. Sperm were frozen in a liquid nitrogen vapor vessel at -170 degrees C and subsequently stored in liquid nitrogen. Post-thaw sperm quality was always evaluated in terms of motility (expressed as percentage of motile sperm), duration of motility and vitality (eosin-nigrosin staining, expressed as percentage of intact sperm). The best freezing method was also tested for fertility and hatching (expressed as the percentage of fertilized eggs). Post thaw sperm quality was highest when sperm were cryopreserved in Glucose 365 mOsm/kg and MG, after a 30-min equilibration and thawed at 60 degrees C for 8 s, of regardless straw size: 74+/-7% motile sperm, 47+/-4 s of motility duration, 69+/-3% intact sperm, 64+/-4% fertilization and 63+/-3% hatching. The freezing method developed in the present study was efficient and can be used to maximize larvae production for both aquaculture purposes and for conservational programs, since B. opalinus is a threatened species. PMID- 22537998 TI - Glass wool filtration of bull cryopreserved semen: a rapid and effective method to obtain a high percentage of functional sperm. AB - Frozen-thawed bull sperm are widely used in assisted reproductive technologies, but cryopreservation negatively affects semen quality. Several sperm selection techniques have been developed to separate motile sperm from non-motile cells. The aim of the present study was to evaluate the effectiveness of the glass wool column filtration to select functional sperm from frozen-thawed bull semen samples. Frozen semen from six Holstein bulls was thawed and filtered through a glass wool column, followed by assessment of routine and functional sperm parameters. In a set of experiments, sperm aliquots were also processed by swim up to compare both selection methods. Samples recovered in the glass wool filtrate had high percentages of viable (94 +/- 3%, mean +/- SD), progressively motile (89 +/- 4%), acrosome-intact (98 +/- 1%), and non-capacitated (80 +/- 10%) sperm; these values were higher (P < 0.05) than those obtained after performing the swim up procedure. Moreover, the glass wool filtration yielded 67 +/- 19% motile cells, in comparison with 18 +/- 8% obtained with swim up (P < 0.05), calculated as the concentration of progressively motile cells selected relative to their concentration in the sample before the selection procedure. Glass wool filtered sperm were able to undergo capacitation-related events, based on the increase in the percentage of cells classified as capacitated by CTC staining (B pattern) after incubation with heparin (50 +/- 5%) in comparison with control conditions with no heparin (17 +/- 4%) or heparin + glucose (16 +/- 2%; P < 0.05). Moreover, they underwent acrosomal exocytosis in response to pharmacologic (calcium ionophore A23187 and lysophosphatidylcholine) and physiological (follicular fluid) stimuli, and they fertilized in vitro matured cumulus-oocyte complexes and denuded oocytes (two-cell embryos: 72 +/- 4% and 52 +/- 6%, respectively). We conclude that glass wool filtration is a low-cost, simple, and highly effective procedure to select functionally competent sperm for reproductive technologies in the bull, which may be useful for other domestic and farm animals, as well as for endangered species. PMID- 22537999 TI - The pattern of cervical penetration and the effect of topical treatment with prostaglandin and/or FSH and oxytocin on the depth of cervical penetration in the ewe during the peri-ovulatory period. AB - Artificial insemination in sheep has two major limiting factors: the poor quality of frozen-thawed ram semen and the convoluted anatomy of the sheep cervix that does not allow transcervical passage of an inseminating catheter. It has been demonstrated that in the ewe during estrus, there is a degree of cervical relaxation mediated by ovarian and possibly gonadotrohic hormones, and we set out to investigate factors that might enhance cervical relaxation. Five experiments were conducted on ewes of different breeds to determine: 1) the pattern of cervical penetration during the periovulatory period in ewes of several breeds (Welsh Mountain, Ile-de-France, Vendeenne, Romanov and Sarda); 2) the effect of the "ram effect" a socio-sexual stimulus, on cervical penetration; and 3) the effects of the intracervical administration of follicle-stimulating hormone (FSH), oxytocin and a prostaglandin E agonist (misoprostol) on the depth of cervical penetration during the periovulatory period. The results showed that during the periovulatory period in all breeds examined, there was increased penetration of the cervical canal (P<0.05) by an inseminating catheter. Cervical penetration increased to a maximum 54 h after the removal of progestagen sponges and then gradually declined. Furthermore, the depth of cervical penetration but not its pattern, was affected (P<0.05) by the breed of ewe. The maximum depth of cervical penetration was lower (P<0.05) in the Vendeenne breed compared to the Ile-de-France and Romanov breeds, which did not differ from one another. In the presence of rams, the depth of cervical penetration was increased at 48 and 54 h after removal of sponges (P<0.05) and reduced at 72 h (P<0.05). The local administration of hormones FSH, misoprostol (a PGE agonist) and oxytocin alone and in various combinations did not have any significant effect on the depth of cervical penetration during the periovulatory period. In conclusion, the natural relaxation of the cervix observed in ewes of several breeds occurs at a time during estrus, 54 h after the removal of progestagen sponges, which is the most suitable for artificial insemination. The effect was enhanced by the presence of a ram but not by the local intracervical administration of FSH, misoprostol and oxytocin even though oxytocin and PGE2 are involved in cervical function. The time of maximum cervical penetration in the preovulatory period (54 h) coincides with high LH and estradiol concentrations suggesting they might be responsible for the relaxation of the cervix probably through an oxytocin-PGE mediated pathway. PMID- 22538000 TI - Body growth, hematological profile, and clinical biochemistry of heifer calves sired by a bull or its clone. AB - The aim of this paper was to compare body growth, hematological profile development, and clinical biochemistry in the female progeny of a sire with the female progeny of its clone. Sixteen Friesian female calves, 9 daughters from a tested bull (BULL) and 7 from its somatic cell nuclear transfer clone (CLONE) were monitored from birth to 60 wk of life. Body weight (BW), wither height (WH), hip height (HH), body length (BL), and hearth girth (HG) were measured at birth and 4, 8, 12, 16, 20, 24, 36, and 50 wk. Blood samples were taken from jugular vein at 12 to 48 h from birth and 1, 2, 3, 4, 8, 12, 16, 20, 24, and 36 wks of age, to be analyzed for hematological, serum protein, and metabolic profiles. At the same time, rectal temperature (RT) was recorded. Age at puberty was assessed on surviving heifers by measuring weekly plasma progesterone levels. Data were evaluated using a mixed model, taking into account the repeated measures in time on the calf. For each variable, different covariance structures were tested, choosing the best according to the Akaike's Information Criteria. Significant was set at P < 0.05, and a trend was considered for P < 0.10. At 24 wk of age, WH was lower in CLONE daughters than BULL daughters. Around 20 wk of age, there was a trend for lower BW in CLONE daughters than BULL daughters, confirmed from differences in HG. There was no difference in RT due to sire effect. Blood glucose concentration decreased in both groups during the first 4 wk of life; at birth, only a trend for higher blood glucose in CLONE daughters was recorded, whereas an opposite trend was observed for plasma creatinine. Total leukocyte count did not differ between progenies. Circulating lymphocytes tended to be lower in CLONE than BULL daughters. The neutrophil: lymphocyte ratio tended to be higher in CLONE than BULL calves. No difference was demonstrated for erythrocyte features, whereas mean platelet volume tended to be lower in CLONE than BULL progeny. From these results, there were no differences between progenies from BULL and its clone that suggest welfare problems in the first 6 mo of life. PMID- 22538001 TI - Effect of age and environmental factors on semen quality, glutathione peroxidase activity and oxidative parameters in Simmental bulls. AB - Taking into account that semen quality depends on animal age and climate conditions and that oxidative stress has been reported to be a common cause of infertility, the objective of this study was to monitor indicators of oxidative stress and antioxidant protection during four seasonal periods in service bulls of various age to get better insight into the significance of these factors upon evaluating service bull semen. The research was conducted over a year on 19 Simmental service bulls. Animals were divided into two groups according to age; Group I consisted of younger bulls aged two to four yrs (n=9), and Group II was comprised of older bulls aged five to ten yrs (n=10). Semen samples were obtained once in the middle of every seasonal period and blood samples for biochemical analysis were collected by jugular venipuncture immediately after ejaculate collection. The activity of total glutathione peroxidase (T-GSH-Px), selenium dependent glutathione peroxidase (Se-GSH-Px) and selenium-independent glutathione peroxidase (non-Se-GSH-Px), together with the intensity of lipid peroxidation (thiobarbituric acid reactive substances; TBARS) and oxidative protein damage (protein carbonyl content (PCC)) were measured in seminal plasma. In samples of spermatozoa and blood serum, the activity of Se-GSH-Px and TBARS and PCC concentrations were determined. Older service bulls had significantly higher ejaculate volume in summer in comparison with younger bulls, whereas the number of spermatozoa and progressive motility percentage did not significantly vary with age. Younger animals had lower progressive motility percentage during summer than in spring, with more intensive oxidative processes observed in seminal plasma (TBARS) and spermatozoa (TBARS and PCC). Based on the results presented here, it can be concluded that younger bulls are more sensitive to elevated ambient temperatures during the summer, when intensified prooxidative processes in semen plasma and spermatozoa eventually led to decreased sperm progressive motility with consequential semen quality deterioration. PMID- 22538002 TI - Non-invasive detection of candidate pregnancy protein biomarkers in the feces of captive polar bears (Ursus maritimus). AB - Currently, there is no method of accurately and non-invasively diagnosing pregnancy in polar bears. Specific proteins may exhibit altered profiles in the feces of pregnant bears, but predicting appropriate candidate proteins to investigate is speculative at best. The objective of this study was to identify potential pregnancy biomarker proteins based on their increased abundance in the feces of pregnant polar bears compared to pseudopregnant females (controls) using two-dimensional in-gel electrophoresis (2D-DIGE) and mass spectrometry (MS). Three 2D-DIGE gels were performed to evaluate fecal protein profiles from controls (n=3) and pregnant polar bears (n=3). There were 2224.67+/-52.39 (mean+/ SEM) spots resolved per gel. Of these, only five proteins were elevated in the pregnant group (P<0.05), and seven additional spots tended to be higher (0.0599.9% confidence interval. The 11 spots represented seven distinct proteins, five of which were significantly more abundant in the pregnant group: IgGFc-binding protein, filamin-C, carboxypeptidase B, transthyretin, and immunoglobulin heavy chain variable region. To our knowledge, this was the first study that employed 2D-DIGE to identify differentially expressed proteins in fecal samples to characterize a physiological condition other than those related to gastrointestinal disorders. These promising results provided a strong foundation for ensuing efforts to develop a non-invasive pregnancy assay for use in both captive and wild polar bears. PMID- 22538003 TI - Porcine nuclei in early growing stage do not possess meiotic competence in matured oocytes. AB - To determine whether the nuclei of early growing stage porcine oocytes can mature to the MII stage, we examined meiotic competence of nuclei that had been fused with enucleated GV oocytes using the nuclear transfer method. In vitro matured oocytes were enucleated and then fused with early growing oocytes (30-40 MUm in diameter) from 5 to 7-wk-old piglets using the hemagglutinating virus of Japan (HVJ). Reconstructed oocytes were cultured for 24 h to the MII stage. Although these oocytes extruded the first polar body, they did not contain normal haploid chromosomes, and the spindles were misaligned or absent at the metaphase II (MII) stage. Furthermore, maturation promoting factor (MPF) activity levels were low in oocytes reconstructed with early growing oocytes at metaphase I (MI) and MII. In contrast, mitogen-activated protein kinase (MAPK) activity was detected between the MI and MII stages, although at slightly lower levels. In conclusion, the nuclei of early growing oocytes did not accomplish normal meiotic division in matured oocytes due to misaligned or absent spindle formation. PMID- 22538004 TI - In vivo oocyte IGF-1 priming increases inner cell mass proliferation of in vitro formed bovine blastocysts. AB - Studies addressing the effects of supraphysiological levels of IGF-1 on oocyte developmental competence are relevant for unravelling conditions resulting in high bioavailability of IGF-1, such as the polycystic ovary syndrome (PCOS). This study investigated the effects of supraphysiological levels of IGF-1 during in vivo folliculogenesis on the morula-blastocyst transition in bovine embryos. Compacted morulae were non-surgically collected and frozen for subsequent mRNA expression analysis (IGF1R, IGBP3, TP53, AKT1, SLC2A1, SLC2A3, and SLC2A8), or underwent confocal microscopy analysis for protein localization (IGF1R and TP53), or were cultured in vitro for 24 h. In vitro-formed blastocysts were subjected to differential cell staining. The mRNA expression of SLC2A8 was higher in morulae collected from cows treated with IGF-1. Both IGF1R and TP53 protein were present in the plasma membrane and cytoplasm. IGF-1 treatment did not affect protein localization of both IGF1R and TP53. In vitro-formed blastocysts derived from morulae recovered from IGF-1-treated cows displayed a higher number of cells in the inner cell mass (ICM). Total cell number (TCN) of in vitro-formed blastocysts was not affected. A higher mean ICM/TCN proportion was observed in in vitro formed blastocysts derived from morulae collected from cows treated with IGF-1. The percentage of in vitro-formed blastocysts displaying a low ICM/TCN proportion was decreased by IGF-1 treatment. In vitro-formed blastocysts with a high ICM/TCN proportion were only detected in IGF-1 treated cows. Results show that even a short in vivo exposure of oocytes to a supraphysiological IGF-1 microenvironment can increase ICM cell proliferation in vitro during the morula to blastocyst transition. PMID- 22538005 TI - Cryopreservation of collared peccaries (Tayassu tajacu) semen using a powdered coconut water (ACP-116c) based extender plus various concentrations of egg yolk and glycerol. AB - The objective was to determine the effectiveness of a powdered coconut water based extender (ACP-116c), plus various concentrations of egg-yolk and glycerol, as an alternative for cryopreservation of collared peccary semen. Twelve ejaculates were obtained from captive adult males by electroejaculation, and evaluated for sperm motility, kinetic rating, viability, morphology, and functional membrane integrity. The ejaculates were apportioned into aliquots that were diluted in Tris plus 10% egg yolk and 3% glycerol, or in ACP-116c plus 10 or 20% egg yolk and 1.5 or 3% glycerol. Samples were frozen in liquid nitrogen and, after 1 mo, thawed at 37 degrees C for 1 min. After thawing, samples were evaluated as reported for fresh semen, and also for sperm membrane integrity (fluorescent probes) and kinematic parameters (computerized analysis). Results were presented as means +/- SEM. Freezing and thawing decreased sperm characteristics relative to fresh semen. Overall, ACP-116c plus 20% egg yolk and 3% glycerol provided better (P < 0.05) sperm motility and kinetic rating (48 +/- 6.1% and 2.8 +/- 0.2, respectively) after thawing than Tris extender (30.4 +/- 5.7% and 2.4 +/- 0.2). However, there were no differences (P > 0.05) among treatments with regard to the other sperm characteristics. Based on computerized motion analysis, total (26.5 +/- 5.9%) and progressive (8.1 +/- 2.2%) motility were best preserved (P < 0.05) with the above-mentioned treatment. In conclusion, a coconut water-based extender, ACP-116c, plus 20% egg yolk and 3% glycerol, was effective for cryopreservation of semen from collared peccaries. PMID- 22538007 TI - Improved semen collection method for wild felids: urethral catheterization yields high sperm quality in African lions (Panthera leo). AB - For wild and domestic felids, electroejaculation (EE) is the most common semen collection method. However, the equipment is expensive, there is a risk of urine contamination and animals usually show strong muscular contraction despite general anesthesia. Accordingly, we tested the feasibility of a different approach using urethral catheterization (UC) in seven African lions, previously described for domestic cats only. After general anesthesia with the alpha2 agonist medetomidine (which also stimulates semen release into the urethra) and ketamine, a transrectal ultrasound was performed to locate the prostate. A commercial dog urinary catheter (2.6 or 3.3 mm in diameter) was advanced approximately 30 cm into the urethra to allow semen collection into the lumen of the catheter by capillary forces. After retraction, sperm volumes between of 422.86 +/- 296.07 MUl yielded motility of 88.83 +/- 13.27% (mean +/- SD) with a mean sperm concentration of 1.94 * 10(9)/ml. Here we describe a simple, field friendly and effective method to attain highly concentrated semen samples with excellent motility in lions and potentially other wild felid species as an alternative to electroejaculation. PMID- 22538006 TI - Vetrabutine clorhydrate use in dystocic farrowings minimizes hemodynamic sequels in piglets. AB - The objective was to measure the effects of VC (a uterotonic drug with vasodilator effects) in eutocic and dystocic sows, on the acid-base balance and some vitality traits of piglets at birth. Farrowing was induced with prostaglandin F2alpha. Four groups of sows (20 sows/group) were monitored; Groups 1 and 2 were eutocic sows, whereas Groups 3 and 4 were dam-fetal dystocic sows. Groups 1 and 3 (control) were given saline, whereas Groups 2 and 4 were given VC im (1.66 mg/kg of body weight) after the first piglet was born. Piglets' physio metabolic performance was monitored peripartum. Treatment with VC reduced (P<0.0001) the percentage of intrapartum stillbirths in sows either with eutocic (5.2 vs. 10.0%) and dystocic (7.6 vs. 16.7%) farrowings and increased (P<0.0001) the number of pigs born alive without any evidence of AFS (89.9 vs. 79.9%, eutocic and 81.6 vs. 65.2%, dystocic). In addition, for the group of pigs with no acute fetal suffering (AFS), VC treatment enhanced survival responses with a half point grater vitality score in Group 4; it also reduced the latency to first teat contact by 6 min (P<0.05) in both treated groups compared to controls; and it improved the condition of the pigs' umbilical cord, with more adhered (98 vs. 86% in eutocic and 88 vs. 80% in dystocic; P<0.05) and less ruptured cords. Moreover, VC reduced the severity of adverse physio-metabolic indicators and the acid-base balance of piglets with AFS at birth by lowering blood lactate (89.8 vs. 93.5 mmol/L in eutocic groups and 94.6 vs. 100.2 mmol/L in dystocic groups; P<0.05), PaCO2 and Ca2+, and by increasing blood pH, HCO3 and PaO2 levels (P<0.05). PMID- 22538009 TI - Ex vivo influence of carbetocin on equine myometrial muscles and comparison with oxytocin. AB - To determine the intercyclic effect of oxytocin and carbetocin on equine myometrial tissue, the effect of the drugs was evaluated through pharmacokinetic and pharmacodynamic studies. The complete pharmacokinetic profile for oxytocin was unknown and had to be established. To do so, 25 IU of oxytocin were administered intravenously to six cycling mares and blood samples were collected before and 2, 4, 8, and 15 min after administration. The half-life of oxytocin was determined to be 5.89 min, the clearance rate 11.67 L/min, mean residence time (MRT) 7.78 min. The effective plasma concentration was estimated to be 0.25 ng/mL. This was similar to the concentration achieved for the organ bath study where the concentration that produced 50% of the maximum effect (EC(50)) was calculated at 0.45 ng/mL. To determine the intercyclic effect of oxytocin and carbetocin uterine myometrial samples were collected from slaughtered mares in estrus, diestrus, and anestrus. The samples were mounted in organ baths and exposed to four ascending, cumulative doses of oxytocin and carbetocin. Area under the curve and amplitude, maximum response (E(max)), and concentration that produced 50% of the maximum effect were studied for each agonist and statistically evaluated. The effect of oxytocin on equine myometrial tissue was higher during diestrus, and surprisingly anestrus, than during estrus, whereas the effect of carbetocin was the same independent of the stage of estrous cycle. A significant difference was found for estrous and anestrous samples when oxytocin was used but not when carbetocin was used. PMID- 22538008 TI - Setting tools for the early assessment of the quality of thawed Pacific oyster (Crassostrea gigas) D-larvae. AB - Parameters used to assess the survival of larvae after cryopreservation generally misestimate the damages that prevent larval development. The objectives of the present study were to 1) define the reliability of the survival rate, assessed at 2 and 7 days post fertilization, to estimate Pacific oyster larval quality after thawing, and 2) select complementary tools allowing an early and reliable estimation of their quality. Oyster larvae were reared for 25 h after fertilization at 19 degrees C and cryopreserved at early D-stage. Then, thawed larvae were incubated in 2-L beakers. At 2 days post fertilization, the survival rate of thawed Pacific oyster larvae was lower than that of fresh larvae for only one experiment (Experiment 3) among the four identical experiments carried out in this work (Experiments 1-4). By contrast, the survival of thawed larvae, as assessed 7 days after fertilization, was lower than that of fresh larvae for the four experiments. These results confirm that the quality of thawed larvae is lower than that of fresh larvae and that the survival rate, estimated 2 days post fertilization, is not adapted to a reliable estimation of the subsequent development ability of thawed larvae. Then, complementary parameters were tested at 2 days: the movement characteristics (Experiments 1 and 2) and the morphologic features (Experiments 3 and 4) of thawed larvae. Compared to values observed on fresh larvae, the percentage of thawed motile larvae was different for only one experiment (Experiment 2) of the two. Compared to control, a reduced Average Path Velocity (VAP) of larvae (determined at the D-larval stage using a CASA-Computer Assisted Sperm Analysis-system) was observed after thawing for both experiments (Experiments 1 and 2), suggesting the ability of larval movement velocity to assess the decrease of the quality of thawed oyster larvae. Using an ASMA (Automated Sperm Morphology Analysis) device, a lower area of thawed larvae was observed, compared to control and for the two experiments (Experiments 3 and 4). By contrast, the Crofton perimeter of thawed larvae was lower than that of control larvae for only one experiment (Experiment 3) and no significant difference of circularity between fresh and thawed larvae was recorded for Experiments 3 and 4. In conclusion, changes in the movement velocity (assessed by CASA) and in the area (measured by ASMA) of D-larvae allow an early and reliable estimation of the quality of thawed Pacific oyster larvae. PMID- 22538010 TI - Effect of increasing trypsin concentrations on seminal coagulum dissolution and sperm parameters in spider monkeys (Ateles geoffroyi). AB - Seminal coagulum formation in spider monkeys (Ateles geoffroyi) interferes with the efficient recovery and evaluation of spermatozoa. The main objective was to assess the effect of increasing concentrations of trypsin on dissolution of seminal coagulum and spermatic parameters. Seminal coagulum was incubated at 37 degrees C without trypsin or in the presence of increasing trypsin concentrations (0.1%, 1.0%, and 5.0%). For each sample, coagulum dissolution time was measured, and sperm concentration, viability, motility, and morphology were evaluated using light microscopy and/or transmission electronic microscopy (TEM). Trypsin concentrations of 1.0% and 5.0% more rapidly liquefied seminal coagulum, averaging 32 and 21 min, respectively, compared with nontrypsinized controls, with maintenance of greater sperm viability (70.8% and 72.5%, respectively). Coagulum treated with 1.0% trypsin and the liquid ejaculate fraction averaged higher sperm motility (40.1% and 55.6%, respectively) than control samples, and both 1.0% and 5.0% trypsin treatment allowed recovery of increased numbers of motile spermatozoa. There was greater sperm fragmentation at the head and midpiece level after treatment with 1.0% and 5.0% trypsin (55.8% and 55.9%); however, the percentage of normal morphology in structurally intact spermatozoa did not differ relative to controls. With transmission electronic microscopy imaging, there were similar percentages of spermatozoa with plasma membrane swelling in the midpiece and acrosomal regions in trypsin-treated samples and controls. In conclusion, trypsin treatment of spider monkey seminal coagulum exerted a concentration-dependent effect on dissolution time and various spermatic parameters. Higher trypsin concentrations caused more rapid liquefaction of coagulum and recovery of greater numbers of motile spermatozoa, but may adversely affect fragmentation of spermatozoa and could compromise sperm function and cryopreservation potential. PMID- 22538011 TI - Endogenous prostaglandin F2alpha concentrations in bovine whole semen, seminal plasma, and extended semen. AB - A series of experiments were conducted to quantify PGF2alpha in bovine semen, seminal plasma, and extended semen, and to determine if PGF2alpha was synthesized or released during extension of bovine semen. Concentrations of PGF2alpha were measured in paired samples of whole and extended semen from beef and dairy bulls. Concentrations of PGF2alpha did not differ between beef and dairy (mean+/-SEM, 273.8+/-42.8 vs. 210.3+/-18.5 pg/mL, respectively; P=0.12), but tended (P=0.08) to be greater for whole compared with extended semen (255.5+/-29.8 vs. 194.5+/ 17.0 pg/mL). Whole semen was extended at eight dilution rates (regardless of initial sperm concentration), using a diluent consisting of two fractions. Samples collected after each dilution step resulted in four subsamples. Concentrations of PGF2alpha in subsamples decreased (P<0.001) at higher dilution rates and later steps of extension. Subsequently, whole semen and seminal plasma were extended at three dilution rates. Initial PGF2alpha concentration was greater (P<0.001) for whole semen compared with seminal plasma. During extension, PGF2alpha synthesis or release resulted in less disparity, but the amount synthesized or released was greater (P=0.03) for semen compared with seminal plasma. We concluded that synthesis or release of PGF2alpha during extension resulted in concentrations similar to whole semen. PMID- 22538013 TI - Should we still use the hospital anxiety and depression scale? PMID- 22538012 TI - Family support, medication adherence, and glycemic control among adults with type 2 diabetes. AB - OBJECTIVE: We used a mixed-methods approach to explore the relationships between participants' perceptions of family members' diabetes self-care knowledge, family members' diabetes-specific supportive and nonsupportive behaviors, and participants' medication adherence and glycemic control (A1C). RESEARCH DESIGN AND METHODS: Adults with type 2 diabetes participated in focus group sessions that discussed barriers and facilitators to diabetes management (n = 45) and/or completed surveys (n = 61) to collect demographic information, measures of diabetes medication adherence, perceptions of family members' diabetes self-care knowledge, and perceptions of family members' diabetes-specific supportive and nonsupportive behaviors. Most recent A1C was extracted from the medical record. RESULTS: Perceiving family members were more knowledgeable about diabetes was associated with perceiving family members performed more diabetes-specific supportive behaviors, but was not associated with perceiving family members performed fewer nonsupportive behaviors. Perceiving family members performed more nonsupportive behaviors was associated with being less adherent to one's diabetes medication regimen, and being less adherent was associated with worse glycemic control. In focus groups, participants discussed family member support and gave examples of family members who were informed about diabetes but performed sabotaging or nonsupportive behaviors. CONCLUSIONS: Participant reports of family members' nonsupportive behaviors were associated with being less adherent to one's diabetes medication regimen. Participants emphasized the importance of instrumental help for diabetes self-care behaviors and reported that nonsupportive family behaviors sabotaged their efforts to perform these behaviors. Interventions should inform family members about diabetes and enhance their motivation and behavioral skills around not interfering with one's diabetes self-care efforts. PMID- 22538015 TI - Isoxazolo(aza)naphthoquinones: a new class of cytotoxic Hsp90 inhibitors. AB - A series of 3-aryl-naphtho[2,3-d]isoxazole-4,9-diones and some of their 6-aza analogues were synthesized and found to inhibit the heat shock protein 90 (Hsp90). The compounds were tested for their binding to Hsp90 and for their effects on Hsp90 client proteins expression in a series of human tumour cell lines. Representative compounds (7f, 10c) downregulated the Hsp90 client proteins EGFR, Akt, Cdk4, Raf-1, and survivin, and upregulated Hsp70. Most of the compounds, in particular the alkylated 3-pyridyl derivatives, exhibited potent antiproliferative activity, down to two-digit nanomolar range. Preliminary results indicated in vivo activity of 7f against human epithelial carcinoma A431 model growing as tumour xenograft in nude mice, thus supporting the therapeutic potential of this novel series of Hsp90 inhibitors. PMID- 22538014 TI - Sphingomyelin synthase 2 over-expression induces expression of aortic inflammatory biomarkers and decreases circulating EPCs in ApoE KO mice. AB - AIMS: This study sought to assess the effect of sphingomyelin synthase 2 (SMS2) over-expression on plaque component and endothelial dysfunction in atherosclerosis. MAIN METHODS: We generated recombinant adenovirus vectors containing human SMS2 cDNA (AdV-SMS2) or control gene GFP cDNA (AdV-GFP). Both AdVs were injected (i.v.) into ApoE KO mice to establish SMS2 over-expressing and control mice models, respectively. The mice were fed a high fat diet for 30 days. We then examined their plasma lipid levels, expression levels of aortic inflammatory biomarkers critical for the plaque's stability, and numbers of peripheral endothelial progenitor cells (EPC). KEY FINDINGS: Compared with the control mice, SMS2 over-expression had significantly (1) increased aortic matrix metalloproteinase-2 (MMP-2), monocyte chemoattractant protein-1 (MCP-1), tissue factor (TF) and cyclooxygenase-2 (COX-2) mRNA levels (1.9-fold, 2.2-fold, 2.6 fold and 3.2-fold, respectively, P<0.01) and protein levels (2.2-fold, 1.9-fold, 1.9-fold and 2.1-fold, respectively, P<0.01); (2) increased MMP-2, COX-2 in situ expression in aortic root (2.6-fold and 2.3-fold, respectively, P<0.01); (3) decreased aortic COX-1 mRNA levels (65%, P<0.01) and protein levels (64%, P<0.01); and (4) decreased CD34/KDR-positive cells (33%, P<0.01), circulating angiogenic cells (CACs) (50%, P<0.05), and colony forming units (CFUs) (40%, P<0.05) in circulation. SIGNIFICANCE: SMS2 over-expression was probably associated with increased expression of aortic inflammatory biomarkers, as well as decreased numbers of CD34/KDR-positive cells, CACs and CFUs in circulation. Therefore, SMS2 over-expression might correlate with endothelial dysfunction and aggravate atherosclerotic plaque instability in ApoE KO mice. PMID- 22538016 TI - Synthesis, evaluation of anticancer activity and COMPARE analysis of N bis(trifluoromethyl)alkyl-N'-substituted ureas with pharmacophoric moieties. AB - A series of new synthesized N-bis(trifluoromethyl)alkyl-N'-substituted ureas have been tested in the National Cancer Institute (NCI, Bethesda, USA) by Program NCI 60 DTP Human Tumor Cell Line Screen at a single high dose (10(-5) M). COMPARE analysis has been carried out for all tested compounds. The tested compounds showed antitumor activity against individual cell lines. The most sensitive cell lines relative to the tested compounds are: 5 g Leukemia RPMI-8226 (GI% 52.7), Non-Small Cell Lung cancer HOP-92 (GI % 88.53), NCI-H522 (GI % 64.41), Melanoma UACC-62 (GI% 53.08), SK-MEL-5 (GI % 74.63), Breast cancer MDA-MB-468 (GI% 51.29), T-47D (GI % 65.1), 5b Leukemia K-562 (GI % 55.55), 7 m Leukemia HL-60(TB) (GI % 51.76). PMID- 22538018 TI - Hi-fi simulation--rehearsing for success. PMID- 22538017 TI - Enhancement of radiation response with bevacizumab. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) plays a critical role in tumor angiogenesis. Bevacizumab is a humanized monoclonal antibody that neutralizes VEGF. We examined the impact on radiation response by blocking VEGF signaling with bevacizumab. METHODS: Human umbilical vein endothelial cell (HUVEC) growth inhibition and apoptosis were examined by crystal violet assay and flow cytometry, respectively. In vitro HUVEC tube formation and in vivo Matrigel assays were performed to assess the anti-angiogenic effect. Finally, a series of experiments of growth inhibition on head and neck (H&N) SCC1 and lung H226 tumor xenograft models were conducted to evaluate the impact of bevacizumab on radiation response in concurrent as well as sequential therapy. RESULTS: The anti angiogenic effect of bevacizumab appeared to derive not only from inhibition of endothelial cell growth (40%) but also by interfering with endothelial cell function including mobility, cell-to-cell interaction and the ability to form capillaries as reflected by tube formation. In cell culture, bevacizumab induced a 2 ~ 3 fold increase in endothelial cell apoptosis following radiation. In both SCC1 and H226 xenograft models, the concurrent administration of bevacizumab and radiation reduced tumor blood vessel formation and inhibited tumor growth compared to either modality alone. We observed a siginificant tumor reduction in mice receiving the combination of bevacizumab and radiation in comparison to mice treated with bevacizumab or radiation alone. We investigated the impact of bevacizumab and radiation treatment sequence on tumor response. In the SCC1 model, tumor response was strongest with radiation followed by bevacizumab with less sequence impact observed in the H226 model. CONCLUSIONS: Overall, these data demonstrate enhanced tumor response when bevacizumab is combined with radiation, supporting the emerging clinical investigations that are combining anti angiogenic therapies with radiation. PMID- 22538019 TI - Toward a more uniform use of OMS. PMID- 22538020 TI - Comments on "single-cannula technique for operative arthroscopy using holmium:YAG laser". PMID- 22538022 TI - Endoscopic removal of bilateral supernumerary intranasal teeth. PMID- 22538024 TI - Use of botulinum toxin A for treatment of myofascial pain and dysfunction. PMID- 22538023 TI - Botulinum toxin A in the treatment of myofascial pain and dysfunction: the case against its use. PMID- 22538025 TI - Rehabilitation of reabsorbed maxillae with implants in buttresses in patients with combination syndrome. AB - PURPOSE: To assess the success and marginal bone loss, after 1 year of loading, of implants placed in anatomic buttresses of atrophic maxillae to rehabilitate patients with combination syndrome. MATERIALS AND METHODS: A case series retrospective study of 22 patients with combination syndrome who were treated with implants in anatomic buttresses in the atrophic maxilla was performed. The inclusion criteria were Classes IV and V Cawood and Howell maxillary atrophy, rehabilitation with implants placed in anatomic buttresses, the presence of anterior remnant teeth in the mandible, and a minimum follow-up of 12 months after implant loading. The criteria of Buser et al were used to evaluate implant success, and marginal bone loss was measured on periapical radiographs. Statistical analysis was performed to relate implant success and marginal bone loss to gender, degree of maxillary atrophy, implant technique, and prosthesis type. RESULTS: A total of 18 patients fulfilled the inclusion criteria. A total of 117 implants were placed; 32 were placed with the conventional technique in the alveolar ridges with enough height and width, 35 were positioned palatally, 30 were tilted in the frontomaxillary buttress, 10 were placed in the pterygomaxillary area, 6 were placed in the nasopalatine canal, and 4 were zygomatic implants. The follow-up ranged from 1 to 7 years after implant loading. Of the 117 implants, 7 failed, for an implant success rate of 94%. The mean marginal bone loss was 0.63 mm. A statistically significant relation was found between bone loss and implant placement technique and the level of maxillary atrophy, being greater in tilted implants and in Class V Cawood and Howell maxillary atrophy. CONCLUSIONS: Implants in anatomic buttresses allow rehabilitation of atrophic maxillae in patients with combination syndrome. The implant success rate was high, and a mean marginal bone loss of 0.63 mm was recorded. PMID- 22538026 TI - Lip competence in Class III patients undergoing orthognathic surgery: an electromyographic study. AB - PURPOSE: The aim of this study was to compare the presurgical and postsurgical electromyographic (EMG) activities of the lips in patients with skeletal Class III treated with combined orthognathic surgery and contrast these data with those obtained from a control group with skeletal Class I. PATIENTS AND METHODS: Ten patients with skeletal Class III underwent the registration of EMG activity before an orthognathic surgical procedure and 4 months after surgery. The results were compared with a control group of 11 healthy patients with skeletal Class I and clinical and EMG lip competence. EMG activity was recorded from the upper orbicularis oris and mentalis muscles during swallowing, lips in contact (LC), and lips apart (LA) using bipolar surface electrodes. The competence condition was assessed by determining the difference in the EMG activity of the mentalis muscle (LC-LA <=0 for lip competence). RESULTS: Patients with skeletal Class III showed greater EMG activity than the control group before and after surgery. Patients with skeletal Class III showed a significantly greater difference in LC LA than the control group before surgery for the 2 muscles (P < .05). No significant difference was found between the skeletal Class III group after surgery and the control group for the mentalis muscle (P > .05). CONCLUSIONS: Four months after treatment with orthognathic surgery, patients with skeletal Class III and an initial muscle activity pattern of lip incompetence different from the control group (P < .05) showed EMG values compatible with lip competence. These values were similar to the control group. PMID- 22538027 TI - Microvascular reconstruction of the mouth, jaws, and face: experience of an Australian oral and maxillofacial surgery unit. AB - PURPOSE: Microvascular reconstruction of oncologic surgical and traumatic defects has been globally practiced by plastic and orthopedic surgical disciplines since the early 1970s. During the past 20 years, reconstructive techniques have been progressively incorporated into the purview of oral and maxillofacial and otolaryngology-head and neck surgeons, particularly those practicing in Europe, the United Kingdom, and China. There has also been a steady increase in the adoption of these techniques in North America, South America, and Japan. MATERIALS AND METHODS: We reviewed our experience (during a 5-year period) with microvascular reconstruction of postablative defects in the oral and maxillofacial region. To our knowledge, resection and neck dissection (or neck exploration in benign free tissue transfer); undertaken by an oral and maxillofacial surgeon), and free tissue transfer reconstruction (undertaken by otolaryngology head and neck and oral and maxillofacial surgeons) of ablative defects of the mouth, jaws, and face (managed within an Australian head and neck cancer multidisciplinary care team) have not been previously reported. RESULTS: The study cohort comprised 107 patients who underwent 109 microvascularly anastomosed free tissue transfers. Of the 107 patients, 79 were males and 38 were females. The median age was 62 years (range 15 to 87). The clinicodemographic analyses and the range of complications observed in this patient cohort are reported. The overall flap success rate in our study was 97%. CONCLUSIONS: The surgical outcomes of our study compare favorably with those previously reported. PMID- 22538028 TI - Gender inequalities and poor health outcomes in Pakistan: a need of priority for the national health research agenda. PMID- 22538029 TI - Rotational vs. standard smooth laryngeal mask airway insertion in adults. AB - OBJECTIVE: To compare the ease of insertion between rotational laryngeal mask airway (LMA) insertion and Brain's LMA insertion technique in terms of number of LMA insertion attempts, time duration of LMA insertion and complications: trauma, laryngospasm, and hypoxaemia. STUDY DESIGN: Randomized control study. PLACE AND DURATION OF STUDY: The Aga Khan University Hospital, Karachi, from September 2006 to May 2007. METHODOLOGY: One hundred ASA I and II adults undergoing short elective surgical procedures requiring general anaesthesia with spontaneous breathing were enrolled. Following pre-oxygenation, anaesthesia was induced with propofol 2 mg/kg and fentanyl 2 MUg/kg. Patients were randomly assigned into one of the study groups: rotational-(R) and standard-(S). LMA insertion was performed when patients became apnoeic and adequate LMA insertion depth achieved. Successful placement was confirmed by chest expansion, reservoir bag movement and appearance of capnographic tracing in both spontaneously breathing patients and in apnoeic patients with assisted ventilation. RESULTS: Significant differences were not seen in patient's demographics, Mallampati score, ASA status and pre operative vital signs. Statistically insignificant difference was found for the time duration and number of LMA insertion attempts. The incidence of trauma was significantly noted in standard insertion technique (28%) compared to (6%) in rotational insertion technique (p = 0.003). The hypoxaemia and laryngospasm was not reported among the groups. CONCLUSION: The rotational technique was practically easy while negotiating the back of mouth and it requires little efforts with lowest complication rate. This technique can be considered in adults when encountering difficulty and repetitive failures with standard LMA insertion technique. PMID- 22538030 TI - Effectiveness of premedication at the time of separation from parent and mask induction in paediatric patients coming for congenital heart disease surgery. AB - OBJECTIVE: To compare the effectiveness of oral midazolam and chloral hydrate on anxiety and sedation at various stages of pre-operative period in congenital heart surgery patients. STUDY DESIGN: Cross-sectional comparative study. PLACE AND DURATION OF STUDY: Operating rooms of The Aga Khan University Hospital, Karachi, from October 2009 to December 2010. METHODOLOGY: Sixty-six patients between the ages of 6 months and 6 years received either chloral hydrate (Group C) or midazolam (Group M) pre-operatively. All congenital heart disease patients coming for cardiac surgeries were included while cases of emergency surgery and those patients in whom premedication was not given were excluded. Effect of premedication observed and documented by Anaesthesia Consultant. Documentation included demographics, level of anxiety and sedation at the time of separation from parent and at the time of mask application. RESULTS: Forty study subjects were male (61%) and 26 were females (39%). Eleven patients received oral midazolam while 55 received oral chloral hydrate. Sixteen patients were tearful and anxious (24%) while rests were calm and asleep. Thirty patients in group C (60%) were well sedated at the time of separation. Mask induction was satisfactory in 76% of chloral hydrate patients. Increase dose was suggested in 23 patients by anaesthetizing physician. Out of these 6 belonged to group M (54.5%) while 17 to low dose chloral hydrate group (30.9%) [< 40 mg/kg]. CONCLUSION: Chloral hydrate provides comparable anxiolysis but superior sedation and mask acceptance scores when compared with midazolam. Higher doses of chloral hydrate (50 mg/kg) were required to keep these patients calm and peaceful at the time of mask application for inhalation induction. PMID- 22538031 TI - Gender based differences in symptoms of acute coronary syndrome. AB - OBJECTIVE: To determine gender based differences in presenting symptoms in patients with acute coronary syndrome. STUDY DESIGN: Cross-sectional, comparative study. PLACE AND DURATION OF STUDY: National institute of Cardiovascular Diseases (NICVD), Karachi, from January to June 2010. METHODOLOGY: Information was obtained by questionnaire from the patients who fulfilled the inclusion criteria. Fisher's exact test and Chi-square analysis were used for data testing. A p < 0.05 was considered statistically significant. RESULTS: Four hundred and thirty seven patients included 230 males and 207 females. Among them unstable angina was diagnosed in 112 males and 142 females, Non ST elevation myocardial infarction (NSTEMI) was diagnosed in 37 males and 26 females. ST elevation myocardial infarction (STEMI) was diagnosed in 81 males and 39 females. Retrosternal pain was the presenting feature in 95 males and 100 females, left sided chest pain was noted in 155 males and 127 females, left arm pain was noted in 61 males and 59 females, right chest pain was noted in 74 males and 41 females, lower jaw pain was noted in 11 males and 16 females, abdominal pain was noted in 9 males and 17 females, 76 males and 88 females had dyspnea, 26 males and 38 females had vomiting, 24 males and 26 females had vertigo, 39 males and 28 females complained of sweating, 3 males and 6 females complained of palpitation, 2 males and 1 female complained of loss of consciousness. CONCLUSION: There are gender differences in the symptoms of ACS. These differences may have a bearing on clinical practice, interpretation of available clinical studies and the design of future investigations. PMID- 22538032 TI - Frequency of factor VIII (FVIII) inhibitor in haemophilia A. AB - OBJECTIVE: To determine the frequency of factor VIII specific inhibitors in haemophilia A. STUDY DESIGN: Cross-sectional study. PLACE AND DURATION OF STUDY: National Institute of Blood Disease and Bone Marrow Transplantation, Karachi, from August 2007 to March 2009. METHODOLOGY: Venous blood samples of diagnosed haemophilia A patients were collected in tubes containing 0.109 M (3.2%) trisodium citrate, centrifuged without delay at 1200 G for 15 minutes. Factor VIII inhibitors were screened by APTT based method using 50:50 patients' plasma mixed with normal plasma incubated together for 2 hours at 37 degrees C. Quantitative assay was carried out to measure Bethesda units (BU). Samples were labelled as low titre inhibitor when less than 5 BU detected, while high titre inhibitor when more than 5 BU were detected. RESULTS: A total of 140 Haemophilia A patients were evaluated for allo-antibodies who received treatment with FVIII concentrates / FFP/ cryoprecipitate. Among them 21 patients (15%) were found to have positive screening test results for inhibitors. The mean age of patients with inhibitors was 11.9 + 8.81 years. Thirteen were high responders (62%) while 8 were low responders (38%). The mean inhibitor level in low (titre) responders was 2.46 + 1.31 BU while in high (titre) responders it was 29.15 + 12.81 BU. According to severity of the disease 12/21 with severe haemophilia A (57.2%) developed inhibitors, whereas 8/21 with moderate (38%) and 1/21 with mild haemophilia A (4.7%) showed positive results for inhibitors. CONCLUSION: Fifteen percent haemophilia A patients developed inhibitors in this cohort, majority with severe and moderate haemophilia A. Age and severity of disease were found to be main contributing factors in patients who developed inhibitors. PMID- 22538033 TI - Optimization of the storage conditions for coagulation screening tests. AB - OBJECTIVE: To determine the optimum storage temperature and time for prothrombin time and activated partial thromboplastin time at various intervals at both room temperature and refrigerator. STUDY DESIGN: Experimental study. PLACE AND DURATION OF STUDY: Advanced Medical and Dental Institute (AMDI), Laboratory at University Sains Malaysia (USM), from August 2009 to June 2010. METHODOLOGY: After obtaining the consent, 33 blood samples were collected from AMDI staffs and students. Prothrombin time (PT) was measured at 0, 4, 8 and 24 hours (h). Partial thromboplastin time (APTT) was measured at 0, 2, 6 and 8 h both at room temperature (RT) and refrigerator. RESULTS: Thirty three subjects (14 males and 19 females, aged from 20 to 40 years) were involved. PT showed no significant differences at RT at 4 h, while significant differences after 8 h and 24 h at RT and after 4 h, 8 h and 24 h at refrigerator were observed. APTT showed no statistically significant differences at 2 h but showed significant differences at 6 h, 8 h at both RT and refrigerator. CONCLUSION: Samples for PT testing can be accepted only up to 4 h when kept at RT while the samples cannot be accepted when kept at refrigerator for 4 h and above. APTT samples can be accepted up to 2 h only at RT or refrigerator. PMID- 22538034 TI - Utility of polymerase chain reaction in diagnosis of tuberculosis in our setup: a ten years experience. AB - OBJECTIVE: To evaluate the yield of polymerase chain reaction (PCR) for detection of Mycobacterium tuberculosis from different clinical specimens. STUDY DESIGN: Observational study. PLACE AND DURATION OF STUDY: Department of Microbiology, Armed Forces Institute of Pathology, Rawalpindi, from January 2001 to December 2010. METHODOLOGY: Different clinical specimens received for Mycobacterium tuberculosis PCR were dealt during the study period. Contaminated samples like sputum were processed by the standard N-acetyl L-cysteine (NALC)-NaOH method. PCR protocols were followed as per manufacturer's manual. PCR was performed using a Thermal Cycler (Master Cycler, Eppendorf, Germany): an initial denaturation step at 94 degrees C for 3 minutes was followed by 40 cycles of denaturation at 94 degrees C for 30 seconds, annealing at 60 degrees C for 30 seconds and extension at 72 degrees C for 30 seconds and a final extension at 72 degrees C for 7 minutes. The products were held at 4 degrees C and later run on 1% agarose gel, stained with Ethidium bromide and visualized in ultraviolet (UV) transilluminator. RESULTS: Out of a total 4620 samples for PCR, 299 were positive for Mycobacterium tuberculosis (6.5%). The percentage of samples from male patients were 63.2%. The mean age of patients was 38+11.5 years. Blood was the most frequent specimen received for PCR (46.66%), followed by body fluids (18.41%) and CSF (10.64%). Yield for different clinical samples was 63/471 for sputum (13.4%), 3/29 for endobronchial washings (10.3%), 59/851 for body fluids (6.9%) and 24/400 for urine (6%). Positive yield from blood was the lowest (101/2156, 4.7%). CONCLUSION: PCR for Mycobacterium tuberculosis is a rapid and reliable method for the diagnosis of both pulmonary and extrapulmonary tuberculosis. The highest positive yield was obtained from sputum and lowest from blood specimens. PMID- 22538035 TI - Comparison of different craniofacial patterns with pharyngeal widths. AB - OBJECTIVE: To compare different craniofacial patterns with pharyngeal widths. STUDY DESIGN: Cross-sectional analytical study. PLACE AND DURATION OF STUDY: Orthodontic Clinic at the Aga Khan University Hospital, Karachi, from June 2002 to June 2010. METHODOLOGY: Data were collected using pre-treatment records including orthodontic files and pre-treatment lateral cephalographs of 360 orthodontic patients. The inclusion criteria were subjects of Pakistani origin, aged between 14-20 years and having no pharyngeal pathology or complaints of nasal obstruction at the initial visit. The sample comprised a total of 360 subjects divided into 2 groups: skeletal Class I (n=180) and skeletal Class II (n=180) subdivided according to the vertical pattern into normodivergent, hyperdivergent and hypodivergent facial patterns. Upper and lower pharyngeal airways were measured using McNamara's airway analysis. The intergroup comparison of upper and lower airways was performed with oneway ANOVA and the Tukey test as the second step. RESULTS: There were 172 males and 188 females with average ages of 15.3+/-1.3 and 15.4+/-0.8 years respectively. Hyperdivergent facial pattern subjects belonging either to skeletal Class I or Class II malocclusion showed a statistically significant narrow upper pharyngeal airway width as compared to normodivergent and hypodivergent facial patterns. However, no statistically significant difference was found in lower pharyngeal airway widths in sagittal and various vertical facial patterns. CONCLUSION: Sagittal malocclusion type does not influence upper pharyngeal width. However, hyperdivergent subjects have statistically significant narrower upper pharyngeal width when compared to other two vertical patterns. PMID- 22538036 TI - Reducing the vermilion notch in primary lip repairs: Z-plasty versus the Noordhoff triangular flap. AB - OBJECTIVE: To compare Z-plasty and the Noordhoff flap for reducing notching in the vermilion during primary repair. STUDY DESIGN: Comparative study. PLACE AND DURATION OF STUDY: Plastic Surgery Department, Mayo Hospital, Lahore, from March 2008 to August 2010. METHODOLOGY: Patients presenting for primary unilateral cleft lip repair were included. The modified Millard's technique was used for lip repair. The percentage of the total vermilion thickness notched was recorded at 6 months follow-up. The repair was graded as: < 0.5 mm good, > 0.5 mm but < 1 mm satisfactory and > 1 mm poor. Patient satisfaction was rated on a scale of 1 to 10, with 10 being the happiest patient. RESULTS: In Group 1 (Z-plasty) 25 patients, and in Group 2 (Noordhoff flap), 20 patients achieved a good result. Five patients in Group 1 and 7 patients in Group 2 achieved a satisfactory result. Three patients in Group 2 had a poor result. Patient satisfaction and vermilion repair were comparable when comparison was made between the two groups (p > 0.05). CONCLUSION: The Noordhoff flap needs more expertise and finesse. All 3 poor results were achieved early in the study. Z-plasty was easier to execute and gave a good result in almost all hands. PMID- 22538037 TI - Quality of life and symptoms control in brain metastasis after palliative whole brain radiotherapy using two different protocols. AB - OBJECTIVE: To compare the quality of life and symptomatic improvement after palliative radiotherapy to brain metastasis using two different treatment protocols. STUDY DESIGN: Comparative study. PLACE AND DURATION OF STUDY: Bahawalpur Institute of Nuclear Medicine and Oncology, Bahawalpur, from January 2009 to November 2010. METHODOLOGY: Patients presenting with brain metastasis referred to Bahawalpur Institute of Nuclear Medicine and Oncology, Bahawalpur for whole brain radiotherapy (WBRT) were included. Patients were divided in two groups. In group A WBRT 30 Gys in 10 fractions were given. While in group B 30 Gys in 15 fractions to whole brain followed by 20 Gys in 10 fractions boost to primary metastatic site with 2 cm margins were given. Follow-up was done at 1 and 3 months. RESULTS: A total of 46 patients with brain metastasis were enrolled with median Karnofsky performance score 50. Median age was 64 years. Most common presenting symptoms were headache, weakness, balance problem and early fatigability. Fifty percent of patients had improvement in their presenting symptoms after completion of palliative radiotherapy at one month and three months follow-up. There was a statistically significant improvement in headache, nausea or vomiting, focal weakness, dizziness, balance problem and problems with smell, hearing and tingling sensation in group B patients as compared to group A. CONCLUSION: More controlled and better quality of life was observed in patient given 30 Gys in 15 fractions followed by a boost of 20 fractions to primary metastatic site versus WBRT with 30 Gys in 10 fractions and in patients with metastatic sites are less than three and having difference not more than 2 cm apart between two metastatic sites. PMID- 22538038 TI - Trainees' feedback on the prevailing teaching methods in postgraduate medical institute, Lady Reading Hospital, Peshawar, Pakistan. AB - OBJECTIVE: To determine the feedback of postgraduate (PG) trainees on their current teaching methods and their level of satisfaction with those at a tertiary care hospital in Pakistan. STUDY DESIGN: Cross-sectional study. PLACE AND DURATION OF STUDY: Department of Surgery, Lady Reading Hospital, Peshawar, from January to May 2010. METHODOLOGY: A semi-structured proforma was filled by the trainees regarding teaching methods and preferences. Level of satisfaction was measured by five points Likert scale. Results were processed through SPSS 17.0 for descriptive statistics. RESULTS: The response rate was 260 out of the total 268 trainees. Lecture / tutorials were reported as the major method of teaching by 239 (91.9%), bedside teaching by 229 (88.1%), journal club by 217 (83.5%), e learning by 157 (60.4%), audit meetings by 152 (58.5%), interactive sessions by 144 (55.4%), radiology meeting by 101 (38.8%) and TOACS by 39 (15%) trainees. Out of 28 units, TOACS were practised as a teaching method in 3 units. It was noted that 47 trainees (18.1%) graded the current training to be unsatisfactory, 127 as fair (48.8%), 77 as good (29.6%), 9 as very good (3.5%) while none considered it to be excellent. TOACS was the most preferred method of teaching, reported by 239 PGs (91.9%). Excessive work load as a cause for the dissatisfaction was reported by 229 trainees (88.1%), inadequate teaching by 157 (60.4%), lack of motivation 124 (47.7%), inappropriate teaching 122 (46.9%) and personal problems by 118 (45.4%). CONCLUSION: Lecture is the most commonly used method of teaching in the Lady Reading Hospital, Peshawar, while TOACS is the most preferred method amongst trainees, but it is the least practiced. PMID- 22538039 TI - Pancarditis: a rare complication of tropical pyomyositis. AB - Tropical pyomyositis is a bacterial infection of the skeletal muscles leading to abscess formation, occurring in the tropical areas, often following minor trauma. We report a case of pancarditis as the direct complication of pyomyositis in a 10 year-old girl who presented with painful swelling of her right thigh, high grade fever and impaired consciousness. Echocardiography showed pericardial effusion with strands and a large vegetation in the left ventricle cavity. She was treated successfully with open heart surgical drainage and intravenous antibiotics. We emphasize early diagnosis and prompt treatment of pyomyositis to reduce its associated mortality and morbidities. PMID- 22538040 TI - Infiltrating ductal carcinoma of breast presenting as areolar dermal lesion. AB - Infiltrating ductal carcinoma is the most common form of invasive breast cancer. It accounts for 80% of all types of breast cancer. We report an unusual presentation of histologically proven case of infiltrating ductal carcinoma of breast presented clinically as a small palpable areolar dermal lesion. Well defined hypoechoic cystic lesion in areolar dermis was present on ultrasound with a negative mammogram. PMID- 22538041 TI - Giant pancreatic pseudocyst. AB - A 56 years old man presented with epigastric pain and abdominal distension. He suffered an attack of acute pancreatitis 6 weeks back followed by pseudopancreatic cyst formation. As the cyst kept on enlarging in size despite being on conservative management, the patient was operated after 5 weeks. A huge pancreatic pseudocyst was found containing about 4.5 liters of fluid. Cystogastrostomy was performed and the patient recovered un-eventfully. It was the third largest pancreatic pseudocyst reported so far. PMID- 22538042 TI - Colonic perforation induced by short term use of slow release diclofenac. AB - Upper gastrointestinal (GI) toxicity of non-steroidal anti-inflammatory drugs (NSAIDs) is well characterized. There is also documented data regarding their adverse effects on lower GI tract, like colonic strictures, inflammatory bowel disease and complications of diverticular disease in the form of abscess or perforation. But there are only two case reports published previously that show colonic perforation due to use of NSAIDs solely. We present here a case of colonic perforation induced by short-term use of slow release diclofenac in a young man. Colonic perforation should be considered as the possible diagnosis in patients with acute abdomen and NSAIDs to be one of the differentials if other possibilities are ruled out. PMID- 22538043 TI - Primary billiary cirrhosis (antimitochondrial antibody negative) leading to secondary amyloidosis. AB - A 49 years old lady presented with low-grade fever (99-100 degrees F) for 2 years. During this time she was extensively worked-up for pyrexia of unknown origin but no diagnosis could be established. Her Initial blood work-up was all negative except high alkaline phosphatase and gamma GT (374 IU and 195 IU respectively). She later presented to our tertiary care centre with facial swelling, flushing and bilateral pedal swelling for 3 months. Along with generalized body swelling she had frothy urine. She was diagnosed as nephrotic syndrome on the basis of nephrotic range proteinuria. Her Renal biopsy done for workup of nephrotic was positive for AA amyloid. Also, her gastrointestinal biopsy was suggestive of amyloidosis. As a workup for secondary amyloidosis, her liver biopsy was done which revealed features of primary billiary cirrhosis (PBC). PMID- 22538044 TI - Carcinosarcoma of the breast. AB - Carcinosarcoma of the breast is an extremely rare and aggressive tumour with two distinct cell lines comprising epithelial and mesenchymal components, with few cases reported in the literature. The prognosis of carcinosarcoma breast is less favourable compared to more common types of breast cancers such as infiltrating ductal or lobular carcinomas. These tumours form a diagnostic and therapeutic challenge. A case of carcinosarcoma breast in a 36 years old woman is presented here. PMID- 22538045 TI - Sinonasal teratocarcinosarcoma. AB - A 20 years old Afghan male was suffering from left sided nasal obstruction with headache for one year. On examination, patient had reddish, fleshy mass in left nasal cavity. Carotid angiography was inconclusive so incision biopsy was taken from nasal mass and it was reported as teratocarcinosarcoma. CT scan of PNS was done which showed heterogeneous mass in nasal cavity, paranasal sinuses with intracranial extension. The patient was operated. The approach was a combination of lateral rhinotomy with trans-basal sub-frontal craniotomy. He was treated by Co 60 and received a tumour dose of 56 Gy radiation. He is being followed regularly every 2 months after his final radiotherapy session and he is disease free so far. PMID- 22538046 TI - Forgotten T-tube in the middle ear. AB - Retention within the middle ear cleft is an unusual complication of T-tube insertion. A 40-year-old woman with Kartagener's Syndrome presented with hearing impairment in the right ear. She was found to have a previously inserted Goode T tube lying within the middle ear behind an intact drum. She underwent successful removal of the T-tube via a myringotomy, and a new tube was re-inserted. Migration of a T-tube into the middle ear cleft should always be kept in mind in patients who present with otological symptoms and have a history of T-tube insertion, even in the presence of an intact drum. PMID- 22538047 TI - Coronary artery bypass grafting after percutaneous coronary intervention. AB - Following percutaneous intervention (PCI), restenosis, progression of disease and multi-vessel involvement may require further intervention in the form of surgical revascularization. Patients with coronary artery bypass grafting (CABG) done after PCI were evaluated to find out the reason for the need of surgical revascularization. Over a period of 12 months, 610 patients underwent CABG. Out of them, 34 patients had previous PCI/stenting. Coronary risk factors including hypertension in 85%, diabetes mellitus in 60%, dyslipidemia in 60%, tobacco use in 50% and a positive family history was present in 53% of the patients. All patients were symptomatic. Multi-vessel disease was present in 67% and single vessel in 4.7%. The extent of disease and stenosis of stents were responsible for reintervention. Careful selection of patients is required in presence of multiple risk factors for coronary artery disease to provide maximum benefit by either PCI or CABG. PMID- 22538048 TI - Accuracy of diagnosis and relationship with quality of emergency medicine training program. AB - An indicator for emergency room performance is the ability to establish the correct diagnosis within the emergency room over the years. The authors chose to examine the non-congruence of Emergency Room diagnoses to that established after hospital stay for three selected years. A total of 8488 records were reviewed and all disparate diagnosis were recorded and categorized. Retrospective chart reviews were done from July 2008 to February 2009 at the Aga Khan University Hospital, Karachi. A substantial reduction in the percentage of disparate diagnoses was seen over the years from 41% in the initial year to 14% in the last year evaluated. It was concluded that over the years there has been an improvement in the reliability of Emergency Room diagnoses at the Aga Khan University Hospital, Karachi. PMID- 22538049 TI - Etiology of ocular trauma: a two years cross-sectional study in Tabriz, Iran. PMID- 22538051 TI - Molecular mechanisms of probiotic action: a proteomic perspective. AB - Probiotics are living microorganisms that confer beneficial effects to human health when supplied in adequate amounts, by promoting digestion and uptake of dietary nutrients, strengthening intestinal barrier function, modulating immune response and enhancing antagonism towards pathogens. The purpose of the present article is to focus on microbial proteomics, pointing out its usefulness in the investigation of molecular mechanisms underlying probiotic effects. It deals, in particular, with molecular strategies responsible for adaptation to the harsh physical-chemical environment of the gastro-intestinal tract, bacterial adhesion to host epithelial cells and intestinal mucosa and probiotic immunomodulatory properties, as analyzed by proteomics in the past few years. PMID- 22538050 TI - Anopheles gambiae pathogen susceptibility: the intersection of genetics, immunity and ecology. AB - Mosquitoes are the major arthropod vectors of human diseases such as malaria and viral encephalitis. However, each mosquito species does not transmit every pathogen, owing to reasons that include specific evolutionary histories, mosquito immune system structure, and ecology. Even a competent vector species for a pathogen displays a wide range of variation between individuals for pathogen susceptibility, and therefore efficiency of disease transmission. Understanding the molecular and genetic mechanisms that determine heterogeneities in transmission efficiency within a vector species could help elaborate new vector control strategies. This review discusses mechanisms of host-defense in Anopheles gambiae, and sources of genetic and ecological variation in the operation of these protective factors. Comparison is made between functional studies using Plasmodium or fungus, and we call attention to the limitations of generalizing gene phenotypes from experiments done in a single genetically simple colony. PMID- 22538052 TI - Prediction of the in vivo OATP1B1-mediated drug-drug interaction potential of an investigational drug against a range of statins. AB - To support drug development, the drug-drug interaction potential (DDI) of an investigational drug (AZX) was assessed against the probe estradiol 17beta glucuronide as well as against simvastatin acid, atorvastatin, pravastatin, pitavastatin, fluvastatin, rosuvastatin and estrone 3-sulfate. The inhibitory potentials of the OATP1B1 inhibitors rifamycin SV and gemfibrozil were assessed in parallel. Monolayer cellular uptake assays were used to determine inhibition of human OATP1B1. Apparent K(m) values for the OATP1B1-mediated transport of [(3)H] substrates were determined prior to their use as probes in inhibition studies, and ranged from 0.6 to 29 MUM for statins. The K(m) of lipophilic simvastatin acid could not be determined due to its high passive permeability that masked OATP1B1 transport, and therefore this statin could not be used as a probe. Estrone 3-sulfate exhibited biphasic kinetics, whereas estradiol 17beta glucuronide demonstrated simple Michaelis-Menton kinetics. AZX moderately inhibited OATP1B1-mediated transport of all statins (IC(50)=4.6-9.7 MUM), except fluvastatin, of estradiol 17beta-glucuronide (IC(50)=5.3 MUM), and weakly inhibited estrone 3-sulfate (IC(50)=79 MUM). Rifamycin SV strongly, and gemfibrozil weakly, inhibited the OATP1B1-mediated transport of substrates. Estradiol 17beta-glucuronide was identified as a good surrogate probe for statins when assessing OATP1B1 inhibitory potential using this test system. Inhibition data was used to predict the likelihood of a clinical DDI, using current draft US FDA guidance and recommendations of the International Transporter Consortium. Predictions for AZX indicated the potential for an OATP1B1-mediated DDI in vivo and that a clinical interaction study is warranted to confirm whether AZX is an OATP1B1 inhibitor in the clinic. PMID- 22538053 TI - In vitro &in vivo targeting behaviors of biotinylated Pluronic F127/poly(lactic acid) nanoparticles through biotin-avidin interaction. AB - Biotinylated Pluronic F127/poly(lactic acid) block copolymers (B-F127-PLA) were successfully synthesized previously by our group. In the present study, the release behaviors of paclitaxel-loaded B-F127-PLA nanoparticles and their targeting properties to human ovarian carcinoma cells were investigated. Paclitaxel (pac) loaded in B-F127-PLA nanoparticles shows an initial burst release in the first 6h and followed by a slow release. The in vitro targeting behaviors of B-F127-PLA nanoparticles against human ovarian cancer cells (OVCAR 3, SKOV-3) were investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) tests and fluorescence microscopy (FM) technique. Targeting was based on a three-step biotin-avidin targeting approach using biotinylated anti-CA125 antibody specific for the CA-125 antigen that is highly expressed on OVCAR-3 cells but not expressed on SKOV-3 cells. MTT results show that the anticancer effect of paclitaxel in B-F127-PLA nanoparticles over OVCAR-3 cells was stronger than that over SKOV-3 cells, indicating that B-F127-PLA nanoparticles were delivered more effectively to OVCAR-3 cells than to SKOV-3 cells. The targeting behaviors of B-F127-PLA nanoparticles were further confirmed by FM technique. The intracellular distribution of B-F127-PLA nanoparticles was also studied using a triple-labeling method. It was observed that B-F127-PLA nanoparticles are mainly localized within the cytoplasm of OVCAR-3 cells. The in vivo antitumor efficacy of pac-loaded B-F127-PLA nanoparticles by three-step method as measured by change in tumor volume of OVCAR-3 implanted in Balb/C nude mice was greater than that by one-step method. PMID- 22538054 TI - Differentiating mucosal and hepatic metabolism of budesonide by local pretreatment with increasing doses of ketoconazole in the proximal jejunum. AB - Many drugs undergo first-pass metabolism both in the gut mucosa and the liver, but little is known about the relative efficiency of these two pathways. The objective of this study was to differentiate between mucosal and hepatic metabolism using budesonide as a probe. After a light breakfast, budesonide, 3mg, was infused locally in the proximal jejunum of eight healthy men on seven occasions, on six occasions after administering the CYP3A4 inhibitor ketoconazole 5 min before in the same jejunal position. The dose range of local inhibitor was 1-128 mg, the highest dose also preceded by an oral dose of 200mg given 12h earlier. Simultaneously with intrajejunal budesonide, deuterium-labelled budesonide (0.2mg) was administered intravenously. Pharmacokinetics of unlabelled and labelled budesonide in plasma was evaluated after LC-MS/MS analysis. Bioavailability of budesonide without inhibition was 27(12-42)%. All ketoconazole doses increased budesonide bioavailability. However, systemic clearance of labelled budesonide was unaffected by ketoconazole doses up to 16 mg but decreased significantly at doses of 64 mg and above. At the two highest doses (128 mg and above) bioavailability approached 100%, showing that budesonide was completely absorbed from jejunum. Ketoconazole doses up to 16 mg appeared to inhibit only mucosal enzymes, while higher doses inhibited also hepatic metabolism. Applying sigmoid E(max)-models of the mean inhibitions in mucosa and liver indicated that, in this study performed under fed conditions, their uninhibited extraction ratios of budesonide were approximately 0.32 and 0.60, respectively. Ketoconazole doses that inhibited half the metabolism were estimated at about 1mg in the mucosa and about 50mg in the liver. In conclusion, this study gave a rough estimate of the relation between mucosal and hepatic first-pass metabolism of budesonide. PMID- 22538055 TI - Chemoinformatics in anti-cancer chemotherapy: multi-target QSAR model for the in silico discovery of anti-breast cancer agents. AB - The discovery of new and more efficient anti-cancer chemotherapies is a field of research in expansion and growth. Breast cancer (BC) is one of the most studied cancers because it is the principal cause of cancer deaths in women. In the active area for the search of more potent anti-BC drugs, the use of approaches based on Chemoinformatics has played a very important role. However, until now there is no methodology able to predict anti-BC activity of compounds against more than one BC cell line, which should constitute a greater interest. In this study we introduce the first chemoinformatic multi-target (mt) approach for the in silico design and virtual screening of anti-BC agents against 13 cell lines. Here, an mt-QSAR discriminant model was developed using a large and heterogeneous database of compounds. The model correctly classified 88.47% and 92.75% of active and inactive compounds respectively, in training set. The validation of the model was carried out by using a prediction set which showed 89.79% of correct classification for active and 92.49% for inactive compounds. Some fragments were extracted from the molecules and their contributions to anti-BC activity were calculated. Several fragments were identified as potential substructural features responsible for anti-BC activity and new molecules designed from those fragments with positive contributions were suggested as possible potent and versatile anti BC agents. PMID- 22538056 TI - Highly-sensitive and label-free indium phosphide biosensor for early phytopathogen diagnosis. AB - The development of highly-sensitive and label-free operating semiconductor-based, biomaterial detecting sensors has important applications in areas such as environmental science, biomedical research and medical diagnostics. In the present study, we developed an Indium Phosphide (InP) semiconductor-based resistive biosensor using the change of its electronic properties upon biomaterial adsorption as sensing element. To detect biomaterial at low concentrations, the procedure of functionalization and covalent biomolecule immobilization was also optimized to guarantee high molecule density and high reproducibility which are prerequisite for reliable results. The characterization, such as biomolecular conjugation efficiency, detection concentration limits, receptor:ligand specificity and concentration detection range was analyzed by using three different biological systems: i) synthetic dsDNA and two phytopathogenic diseases, ii) the severe CB-form of Citrus Tristeza Virus (CTV) and iii) Xylella fastidiosa, both causing great economic loss worldwide. The experimental results show a sensitivity of 1 pM for specific ssDNA detection and about 2 nM for the specific detection of surface proteins of CTV and X. fastidiosa phytopathogens. A brief comparison with other semiconductor based biosensors and other methodological approaches is discussed and confirms the high sensitivity and reproducibility of our InP based biosensor which could be suitable for reliable early infection diagnosis in environmental and life sciences. PMID- 22538057 TI - A simple electrochemical aptasensor for ultrasensitive protein detection using cyclic target-induced primer extension. AB - A simple electrochemical aptasensor was developed for ultrasensitive protein detection by combining a novel strategy of cyclic target-induced primer extension (CTIPE) with an aptamer-hairpin probe and enzyme-amplified electrochemical readout. In the presence of protein target, the immobilized aptamer-hairpin probe recognized the protein to trigger primer extension reaction by target-induced conformational transition, which released the protein from replicated DNA duplex. The released target could cyclically bind with other aptamer-hairpin probes and trigger new primer extension, leading to formation of numerous biotin-tagged DNA duplex, which significantly amplified the protein recognition event and facilitated the subsequent enzymatic signal enhancement, leading to an ultrasensitive electrochemical aptasensor. Using human vascular endothelial growth factor as a model protein, the designed aptasensor could detect protein down to 0.82 pg mL(-1) with a linear range from 1 pg mL(-1) to 1 ng mL(-1). The proposed aptasensor was amenable to quantification of protein in complex biological matrixes, and would become a simple and powerful tool for bioanalysis and clinic diagnostic application. PMID- 22538058 TI - Disposable and integrated amperometric immunosensor for direct determination of sulfonamide antibiotics in milk. AB - The preparation and performance of a disposable amperometric immunosensor, based on the use of a selective capture antibody and screen-printed carbon electrodes (SPCEs), for the specific detection and quantification of sulfonamide residues in milk is reported. The antibody was covalently immobilized onto a 4-aminobenzoic acid (4-ABA) film grafted on the disposable electrode, and a direct competitive immunoassay using a tracer with horseradish peroxidase (HRP) for the enzymatic labeling was performed. The amperometric response measured at -0.2 V vs the silver pseudo-reference electrode of the SPCE upon the addition of H(2)O(2) in the presence of hydroquinone (HQ) as mediator was used as transduction signal. The developed methodology showed very low limits of detection (in the low ppb level) for 6 sulfonamide antibiotics tested in untreated milk samples, and a good selectivity against other families of antibiotics residues frequently detected in milk and dairy products. These features, together with the short analysis time (30 min), the simplicity, and easy automation and miniaturization of the required instrumentation make the developed methodology a promising alternative in the development of devices for on-site analysis. PMID- 22538059 TI - [Hepatitis E. Current perspectives]. AB - Infection with hepatitis E virus (HEV) is highly prevalent in developing countries and the WHO estimates one third of the world population has had contact with the virus. Its diagnosis and epidemiology are well known in endemic countries but, recently, there have been sporadic cases in developed countries in patients with no history of travel. Currently in these countries, hepatitis E is considered a zoonosis yet there remain to be known other routes of transmission. Another interesting aspect is that HEV can cause chronic hepatitis in transplanted patients, other immunocompromised patients and even in immunocompetent people. There have also been reported cases of fulminant hepatitis and other extrahepatic manifestations. The diagnosis is based on serological studies and detection of viral RNA in blood and feces. The vaccine is a good option to prevent this infection that affects a large number of people in deprived geographical areas but unfortunately it is not available yet. PMID- 22538060 TI - [Corticotropin-producing pheochromocytoma]. PMID- 22538061 TI - Assessing the influence of risk factors on rates and dynamics of peripheral vein phlebitis: an observational cohort study. AB - BACKGROUND AND OBJECTIVES: To assess the influence of risk factors on the rates and kinetics of peripheral vein phlebitis (PVP) development and its theoretical influence in absolute PVP reduction after catheter replacement. METHODS: All peripheral short intravenous catheters inserted during one month were included (1201 catheters and 967 patients). PVP risk factors were assessed by a Cox proportional hazard model. Cumulative probability, conditional failure of PVP and theoretical estimation of the benefit from replacement at different intervals were performed. RESULTS: Female gender, catheter insertion at the emergency or medical-surgical wards, forearm site, amoxicillin-clavulamate or aminoglycosides were independent predictors of PVP with hazard ratios (95 confidence interval) of 1.46 (1.09-2.15), 1.94 (1.01-3.73), 2.51 (1.29-4.88), 1.93 (1.20-3.01), 2.15 (1.45-3.20) and 2.10 (1.01-4.63), respectively. Maximum phlebitis incidence was reached sooner in patients with >=2 risk factors (days 3-4) than in those with <2 (days 4-5). Conditional failure increased from 0.08 phlebitis/one catheter-day for devices with <=1 risk factors to 0.26 for those with >=3. The greatest benefit of routine catheter exchange was obtained by replacement every 60h. However, this benefit differed according to the number of risk factors: 24.8% reduction with >=3, 13.1% with 2, and 9.2% with <=1. CONCLUSIONS: PVP dynamics is highly influenced by identifiable risk factors which may be used to refine the strategy of catheter management. Routine replacement every 72h seems to be strictly necessary only in high-risk catheters. PMID- 22538062 TI - [Genetics of congenital deafness]. AB - Congenital deafness is defined as the hearing loss which is present at birth and, consequently, before speech development. It is the most prevalent sensor neural disorder in developed countries, and its incidence is estimated between 1-3 children per 1,000 newborns, of which more than 50% are attributable to genetics causes. Deafness can be classified as syndromic or non-syndromic. In the first case, it is associated with outer ear malformations and/or systemic findings. More than 400 syndromes accompanied of deafness have been described, which represent about 30% of cases of congenital hearing loss. The remaining percentage corresponds to non-syndromic cases: 75-85% are autosomal recessive, 15-24% are autosomal dominant, and 1-2% are X-linked. The evaluation of a child with deafness requires a multidisciplinary collaboration among specialists, who must coordinate themselves and give information to the affected family. The aims of establishing a diagnosis are to predict other manifestations that may suggest some syndrome and to anticipate their management, as well as to perform genetic counseling to parents and affected individuals. PMID- 22538063 TI - [Recommendations of good practices for the genetic diagnosis of Duchenne and Becker muscular dystrophies]. PMID- 22538064 TI - [Administrative pathways and ethical and legal requirements to carry out biomedical research with human beings in Spain: a guideline for researchers]. PMID- 22538065 TI - [Impact of blood pressure control on the ankle-brachial index in hypertensive patients]. AB - BACKGROUND AND OBJECTIVE: The guidelines for arterial hypertension recommend a systematic determination of ankle-brachial index (ABI) in the initial risk stratification in hypertensive patients, while not indicating whether controls should be evolutionary. Our aim was to analyze the evolution of the ABI value in hypertensive patients in terms of control of blood pressure (BP) after one year follow-up. PATIENTS AND METHODS: We included 209 hypertensive patients, in whom ABI was determined at baseline and after one year of antihypertensive treatment. Patients were divided into 2 groups in terms of good/poor clinical control of BP (<140/90 mmHg). RESULTS: A total of 82.8% of the population showed a good control of the BP after one year of treatment and it was associated with significant increase in the ABI value (1.081 versus 1.046 at baseline, P=.002). By contrast, there was no difference of ABI value in patients with poor BP control (1.054 versus 1.093 at baseline). CONCLUSIONS: A good clinical control of BP is associated with an increase in the value of the ABI. PMID- 22538066 TI - Evaluation of a heat vulnerability index on abnormally hot days: an environmental public health tracking study. AB - BACKGROUND: Extreme hot weather conditions have been associated with increased morbidity and mortality, but risks are not evenly distributed throughout the population. Previously, a heat vulnerability index (HVI) was created to geographically locate populations with increased vulnerability to heat in metropolitan areas throughout the United States. OBJECTIVES: We sought to determine whether areas with higher heat vulnerability, as characterized by the HVI, experienced higher rates of morbidity and mortality on abnormally hot days. METHODS: We used Poisson regression to model the interaction of HVI and deviant days (days whose deviation of maximum temperature from the 30-year normal maximum temperature is at or above the 95th percentile) on hospitalization and mortality counts in five states participating in the Environmental Public Health Tracking Network for the years 2000 through 2007. RESULTS: The HVI was associated with higher hospitalization and mortality rates in all states on both normal days and deviant days. However, associations were significantly stronger (interaction p value < 0.05) on deviant days for heat-related illness, acute renal failure, electrolyte imbalance, and nephritis in California, heat-related illness in Washington, all-cause mortality in New Mexico, and respiratory hospitalizations in Massachusetts. CONCLUSION: Our results suggest that the HVI may be a marker of health vulnerability in general, although it may indicate greater vulnerability to heat in some cases. PMID- 22538067 TI - Gut dysbiosis in cystic fibrosis. PMID- 22538068 TI - Pilot study on the use of acoustic radiation force impulse imaging in the staging of cystic fibrosis associated liver disease. AB - BACKGROUND: Acoustic radiation force impulse (ARFI) is a novel technique for the measurement of hepatic stiffness, which could be valuable in clinical follow-up of patients affected by cystic fibrosis liver disease (CFLD). METHODS: Seventy five patients with suspected CFLD (35 males) underwent clinical and ultrasonographic evaluations, liver and pulmonary function tests, ARFI investigation, and upper gastrointestinal endoscopy. Ten ARFI measurements were taken at the deep right hepatic lobe to compute median values of Shear Wave Velocity (SWV) for each individual. RESULTS: SWV increased progressively from 1.02m/s (95%, Confidence Interval, CI, 0.92-1.126) in patients with no evidence of CFLD at ultrasonography (N=16), to 1.12 (95%CI 1.049-1.19) in patients with CFLD and no signs of portal hypertension (PHT, N=23), and to 1.25 (95%CI 1.14 1.358) in those with CFLD and signs of PHT (N=28). SWV was 1.63 (95%CI 1.26-1.99) in patients with oesophageal varices (N=8) (p<0.0001). CONCLUSIONS: ARFI may represent an easy, fast and non-invasive tool for the clinical follow-up of patients with cystic fibrosis associated liver disease. PMID- 22538069 TI - Toward a better understanding of brain lesions during metachromatic leukodystrophy evolution. AB - BACKGROUND AND PURPOSE: The prospect of new therapies in MLD stresses the need to refine the indications for treatment. The aim of this study was, therefore, to perform a detailed analysis of MRI brain lesions at diagnosis and follow-up, to better understand the natural history of MLD. MATERIAL AND METHODS: This retrospective case-control study (2005-2010) looked at 13 patients with MLD (2-5 years of age) with 28 MRIs (mean follow-up, 2 years), compared with 39 age- and sex-matched controls. All MRIs were evaluated qualitatively and semiquantitatively. The Student t test, Wilcoxon signed rank test, and Pearson correlation were used for statistical analysis (P < .05). RESULTS: In addition to diffuse symmetric supratentorial WM T2 hyperintensities with a tigroid pattern (70%) and T2 hyperintensities in the CC (100%) and internal capsules (46%), we found significant GM abnormalities such as thalamic T2 hypointensity (92%), thalamic (23%, P < .05, EJ) and caudate nuclei (23%, P < .05, EJ) atrophy, and cerebellar atrophy without WM involvement (15%). The pattern of splenium involvement progression was misleading, with initially diffuse high signal intensity, which later became curvilinear before finally progressing to atrophy (23%, P < .05; EJ). This should not be mistaken for a disease regression. Spectroscopy confirmed a decrease in the NAA/Cr ratio, an increase in the Cho/Cr ratio and in myo-inositol, and a lactate resonance. CONCLUSIONS: Thalamic changes may be a common finding in MLD, raising the prospect of primary GM lesions. This may prove important when evaluating the efficacy of new treatments. PMID- 22538070 TI - Regional gray matter atrophy in patients with Parkinson disease and freezing of gait. AB - BACKGROUND AND PURPOSE: FOG is a troublesome symptom of PD. Despite growing evidence suggesting that FOG in PD may be associated with cognitive dysfunction, the relationship between regional brain atrophy and FOG has been poorly investigated. MATERIALS AND METHODS: Optimized VBM was applied to 3T brain MR images of 24 patients with PD and 12 HC. Patients were classified as either FOG- or FOG+ (n = 12) based on their responses to a validated FOG Questionnaire and clinical observation. All patients with PD also underwent a detailed neuropsychological evaluation. RESULTS: The VBM analysis in patients with FOG+ showed a reduced GM volume in the left cuneus, precuneus, lingual gyrus, and posterior cingulate cortex compared with both patients with FOG- and HC. We did not detect any significant change of GM volume when comparing HC versus all patients with PD (FOG- and FOG+). FOG clinical severity was significantly correlated with GM loss in posterior cortical regions. Finally, patients with FOG+ scored lower on tests of frontal lobe function. CONCLUSIONS: Our findings provide the first evidence that the development of FOG in patients with PD is associated with posterior GM atrophy, which may play a role in the complex pathophysiology of this disabling symptom. PMID- 22538071 TI - Decreased frontal lobe gray matter perfusion in cognitively impaired patients with secondary-progressive multiple sclerosis detected by the bookend technique. AB - BACKGROUND AND PURPOSE: There is increasing evidence implicating microvascular impairment in MS pathogenesis. Perfusion imaging offers a unique opportunity to investigate the functional impact of GM pathology. We sought to quantify differences in MR imaging-based bookend-derived cerebral perfusion between cognitively impaired and nonimpaired patients with SPMS. MATERIALS AND METHODS: Patients were prospectively recruited and assessed using MR imaging and the standard cognitive battery called the Minimal Assessment of Cognitive Function in MS. Patients exhibiting impairment on >= 2 individual tests were classified as cognitively impaired. Healthy controls were prospectively recruited and assessed using MR imaging to validate bookend assumptions. Structural and perfusion scans were coregistered and partitioned into anatomic brain regions and tissue compartments. Clinical and radiologic characteristics were compared between patients with and without impairment to identify potential confounders. A Bonferroni adjusted P value threshold (P < .005) was used for lobar and sublobar level analyses to correct for multiple comparisons. RESULTS: Thirty-seven patients with SPMS (age 56 +/- 9 years; 23 women, 14 men) and 10 age- and sex matched healthy controls were recruited. Bookend assumptions were found to be valid in MS. GM and WM qCBV were all globally reduced in impaired patients. After adjusting for potential confounders while examining sublobar level perfusion, only GM qCBV was significantly different between cognitive groups, and this hypoperfusion localized to the bilateral medial superior frontal regions and left inferior, middle, and superior frontal regions (P < .005) of impaired patients compared with nonimpaired patients. GM qCBV accounted for 22.5% of the model variance compared with a model including only confounders (P = .0007). CONCLUSIONS: Bookend-derived GM qCBV was significantly reduced in cognitively impaired patients with SPMS in functionally relevant brain regions. PMID- 22538072 TI - Localizing seizure-onset zones in presurgical evaluation of drug-resistant epilepsy by electroencephalography/fMRI: effectiveness of alternative thresholding strategies. AB - BACKGROUND AND PURPOSE: Simultaneous EEG/fMRI is an effective noninvasive tool for identifying and localizing the SOZ in patients with focal epilepsy. In this study, we evaluated different thresholding strategies in EEG/fMRI for the assessment of hemodynamic responses to IEDs in the SOZ of drug-resistant epilepsy. MATERIALS AND METHODS: Sixteen patients with focal epilepsy were examined by using simultaneous 92-channel EEG and BOLD fMRI. The temporal fluctuation of epileptiform signals on the EEG was extracted by independent component analysis to predict the hemodynamic responses to the IEDs. We applied 3 different threshold criteria to detect hemodynamic responses within the SOZ: 1) PA, 2) a fixed threshold at P < .05 corrected for multiple comparison (FWE), and 3) FAV (4000 +/- 200 activated voxels within the brain). RESULTS: PA identified the SOZ in 9 of 16 patients; FWE resulted in concordant BOLD signal correlates in 11 of 16, and FAV in 13 of 16 patients. Hemodynamic responses were detected within the resected areas in 5 (PA), 6 (FWE), and 8 (FAV) of 10 patients who remained seizure-free after surgery. CONCLUSIONS: EEG/fMRI is a noninvasive tool for the presurgical work-up of patients with epilepsy, which can be performed during seizure-free periods and is complementary to the ictal electroclinical assessment. Our findings suggest that the effectiveness of EEG/fMRI in delineating the SOZ may be further improved by the additional use of alternative analysis strategies such as FAV. PMID- 22538074 TI - High-resolution diffusion-weighted imaging increases lesion detectability in patients with transient global amnesia. AB - BACKGROUND AND PURPOSE: DWI can detect small punctate hyperintense lesions of the hippocampus in patients with TGA. We investigated whether small TGA lesions can be detected more often by increasing the resolution of DWI. MATERIALS AND METHODS: Of 31 consecutive patients with TGA, 27 underwent DWI, twice at the first visit (range 1.5-22 hours; mean 10 hours) and at follow-up (range 50-87 hours; mean 72.5 hours) after the onset of their symptoms. Each DWI included 2 different spatial resolutions with the same b-value (2000 seconds/mm(2)): conventional resolution in a 128 * 128 matrix with 3-mm section thickness and high resolution in a 220 * 220 matrix with 2-mm section thickness. The number and contrast of hyperintense lesions were compared between the 2 resolutions. RESULTS: Twenty-two of the 27 patients had single or multiple TGA lesions. The total number of lesions detected on conventional and high-resolution DWI was 11 and 22, respectively, at the first visit, and was 24 and 37, respectively, at follow-up. The number of lesions was significantly larger on high-resolution DWI than on conventional resolution at the first visit (P < .01) and at the follow-up (P < .01). Lesion contrast was significantly increased on high-resolution DWI (P < .01). CONCLUSIONS: Higher DWI resolution increased lesion detectability in patients with TGA. Considering the small size of TGA lesions, the resolution of DWI is an important parameter influencing lesion detectability. PMID- 22538073 TI - The contributions of MRI-based measures of gray matter, white matter hyperintensity, and white matter integrity to late-life cognition. AB - BACKGROUND AND PURPOSE: GM volume, WMH volume, and FA are each associated with cognition; however, few studies have detected whether these 3 different types of MR imaging measurements exert independent or additive effects on cognitive performance. To detect their extent of contribution to cognitive performance, we explored the independent and additive contributions of GM atrophy, white matter injury, and white matter integrity to cognition in elderly patients. MATERIALS AND METHODS: Two hundred and 9 elderly patients participated in the study: 97 were CN adults, 65 had MCI, and 47 had dementia. We measured GM on T1-weighted MR imaging, WMH on FLAIR, and FA on DTI, along with psychometrically matched measures of 4 domains of cognitive performance, including semantic memory, episodic memory, executive function, and spatial abilities. RESULTS: As expected, patients with dementia performed significantly more poorly in all 4 cognitive domains, whereas patients with MCI performed generally less poorly than dementia patients, though considerable overlap in performance was present across groups. GM, FA, and WMH each differed significantly between diagnostic groups and were associated with cognitive measures. In multivariate models that included all 3 MR imaging measures (GM, WMH, and FA), GM volume was the strongest determinant of cognitive performance. CONCLUSIONS: These results strongly suggest that MR imaging measures of GM are more closely associated with cognitive function than WM measures across a broad range of cognitive and functional impairment. PMID- 22538075 TI - The effect of intracranial stent implantation on the curvature of the cerebrovasculature. AB - BACKGROUND AND PURPOSE: Recently, the use of stents to assist in the coiling and repair of wide-neck aneurysms has been shown to be highly effective; however, the effect of these stents on the RC of the parent vessel has not been quantified. The purpose of this study was to quantify the effect of intracranial stenting on the RC of the implanted artery using 3D datasets. MATERIALS AND METHODS: Twenty four patients receiving FDA-approved neurovascular stents to support coil embolization of brain aneurysms were chosen for this study. The stents were located in the ICA, ACA, or MCA. We analyzed C-arm rotational angiography and contrast-enhanced cone beam CT datasets before and after stent implantation, respectively, to ascertain changes in vessel curvature. The images were reconstructed, and the vessel centerline was extracted. From the centerline, the RC was calculated. RESULTS: The average implanted stent length was 25.4 +/- 5.8 mm, with a pre-implantation RC of 7.1 +/- 2.1 mm and a postimplantation RC of 10.7 +/- 3.5 mm. This resulted in a 3.6 +/- 2.7 mm change in the RC due to implantation (P < .0001), more than a 50% increase from the pre-implantation value. There was no difference in the change of RC for the different locations studied. The change in RC was not impacted by the extent of coil packing within the aneurysm. CONCLUSIONS: The implantation of neurovascular stents can be shown to have a large impact on the RC of the vessel. This will lead to a change in the local hemodynamics and flow pattern within the aneurysm. PMID- 22538076 TI - Hemorrhage/contrast staining areas after mechanical intra-arterial thrombectomy in acute ischemic stroke: imaging findings and clinical significance. AB - BACKGROUND AND PURPOSE: The aim of this study was to report the CT evolution and clinical significance of HCA after intra-arterial mechanical thrombectomy (revascularization by using retrievers and/or other mechanical devices without concomitant delivery of intra-arterial thrombolytics) in our patients. These lesions are common after intra-arterial thrombolysis, being considered a negative prognostic sign. Their significance after pure mechanical thrombectomy remains unknown. MATERIALS AND METHODS: Forty-eight patients were treated with mechanical thrombectomy by using retrievable stents between April 2010 and February 2011. All patients underwent initial (first 24 hours) and follow-up (48-72 hours) nonenhanced CT. We retrospectively analyzed the clinical and radiologic data of the patients with HCA and compared them with controls. RESULTS: Fifteen of 48 patients presented with HCA. The site of occlusion was the MCA in 7 patients, both the extra- and intracranial segments of the ICA in 6, and the intracranial ICA in 2. In 7 patients, previous intravenous thrombolysis was administered. Complete recanalization (TICI 3) was achieved in 12 patients, and incomplete recanalization (TICI 2b), in 3. The location of HCA was the subarachnoid space in 6 patients, the brain parenchyma in 4 patients, and both in 5 patients. The HCA were asymptomatic in all patients. There was no statistical difference in final NIHSS score reduction (NIHSS pretreatment-NIHSS at discharge) between patients and controls. CONCLUSIONS: In our series, HCA are common after mechanical thrombectomy but do not carry an increased risk of symptomatic hemorrhage or negative prognosis. These data might be related to the high rate of recanalization and the absence of intra-arterial thrombolytics. PMID- 22538077 TI - Clinical and angiographic characteristics of multiple dural arteriovenous shunts. AB - BACKGROUND AND PURPOSE: The pathogenesis and characteristics of multiple DAVSs are not well-known. The purpose of this study was to evaluate the angiographic and clinical characteristics of patients with multiple DAVSs with an emphasis on the pathomechanism. MATERIALS AND METHODS: One hundred seventy-nine patients with DAVS were reviewed. Patients with >= 2 fistulas at anatomically separate sites were included. Multiple DAVSs were categorized into synchronous (simultaneous multiplicity) or metachronous (temporal sequential development of multiplicity) types. The angiographic and clinical characteristics of these lesions were analyzed. RESULTS: Fourteen patients were diagnosed with multiple DAVSs (7.8%; synchronous, n = 7; metachronous, n = 7). Thirteen of the 14 patients showed CVR (93%, Borden type II/III). Multiple DAVSs were frequently associated with dural sinus thrombosis (71.4%, n = 10). Synchronous DAVSs developed in association with an occluded sinus (n = 5). De novo metachronous lesions developed in association with thrombosis of a previously patent dural sinus (n = 3) or reopening of an occluded sinus (n = 2). Multiplicity was associated with aggressive initial symptoms in 64.3% (n = 9). The newly developed lesions in the metachronous types were accompanied by hemorrhage (n = 1), neurologic deficit (n = 1), worsening of the initial benign symptoms (n = 2), and incidental detection (n = 3). The mean time interval between the initial diagnosis and de novo lesion detection was 31.3 +/- 29.8 months (range, 12-92 months). CONCLUSIONS: Multiplicity of DAVSs is associated with poor angiographic and clinical prognosis, requiring an aggressive treatment and management strategy. Sinus thrombosis has a prominent role in the pathomechanism of DAVSs. PMID- 22538078 TI - Persistent diffusion-restricted lesions in bevacizumab-treated malignant gliomas are associated with improved survival compared with matched controls. AB - BACKGROUND AND PURPOSE: A subset of patients with malignant glioma develops conspicuous lesions characterized by persistent restricted diffusion during treatment with bevacizumab. The purpose of the current study was to characterize the evolution of these lesions and to determine their relationship to patient outcome. MATERIALS AND METHODS: Twenty patients with malignant glioma with persistent restricted-diffusion lesions undergoing treatment with bevacizumab were included in the current study. Mean ADC and the volume of restricted diffusion were computed for each patient during serial follow-up. Differences in TTP, TTS, and OS were compared between patients with restricted diffusion and matched controls by using Kaplan-Meier analysis with the logrank test and Cox hazard models. RESULTS: Mean ADC values were generally stable with time (mean, 5.2 +/- 12.6% change from baseline). The volume of restricted diffusion increased a median of 23% from baseline by 6 months. Patients with restricted-diffusion lesions had significantly greater TTP (logrank, P = .013), TTS (logrank, P = .008), and OS (logrank, P = .010) than matched controls. When available, advanced physiologic imaging of restricted-diffusion lesions showed hypovascularity on perfusion MR imaging and decreased amino acid uptake on (18)F-FDOPA PET scans. Atypical gelatinous necrotic tissue was confirmed in the area of restricted diffusion in 1 patient. CONCLUSIONS: Restricted-diffusion lesions in malignant gliomas treated with bevacizumab are generally stable with time and are associated with improved outcomes. These results combined with physiologic imaging and histopathologic data suggest that these lesions are not consistent with aggressive tumor. PMID- 22538080 TI - Royal jelly can diminish secondary neuronal damage after experimental spinal cord injury in rabbits. AB - The aim of this experimental study was to investigate the neuroprotective effect of Royal jelly (RJ) on traumatic spinal cord injury (SCI). Twenty-one New Zealand male rabbits, weighing between 2.5 and 3.0 kg were divided into three groups: Sham (no drug or operation, n = 7), Control (laminectomy+single dose of 1 ml/kg saline orally, after trauma; n = 7) and RJ (laminectomy+100mg/kg RJ, orally, after trauma, n = 7). Laminectomy was perfor med at T10 and balloon catheter was applied extradurally for traumatic SCI. Four and 24h after surgery, rabbits were evaluated according to the Tarlov scoring system. Blood, cerebrospinal fluid and tissue sample from spinal cord were taken for measurements of antioxidant status or detection of apoptosis. Four hours after SCI, all animals in control or RJ treated groups became paraparesic. Significant improvement was observed in RJ treated group, 24h after SCI, with respect to control. Traumatic SCI led to increase in the lipid peroxidation and decrease enzymic or non-enzymic endogenous antioxidative defense systems, and increase in apoptotic cell numbers. RJ treatment mostly prevented lipid peroxidation and also augmented endogenous enzymic or non-enzymic antioxidative defense systems. Again, RJ treatment significantly decreased the apoptotic cell number induced by SCI. PMID- 22538079 TI - Ubiquitous presence of piscidin-1 in Atlantic cod as evidenced by immunolocalisation. AB - BACKGROUND: Antimicrobial peptides (AMPs), the natural antibiotics bestowed upon all forms of life, consist of small molecular weight proteins with a broad spectrum antimicrobial activity against a variety of pathogenic microorganisms. Piscidins are one of the AMP families that are imperative for the innate defence mechanisms of teleosts. Atlantic cod, a basal fish belonging to the superorder Paracanthopterygii also possesses multiple piscidin peptides. Two piscidin paralogues (pis1 and pis2) and a novel alternative splice variant of pis2 of this fish were previously described by us. To shed light on other potent roles of these molecules, now we have mapped the distribution of piscidin 1 (Pis1), in different tissues and organs of cod through immunohistochemistry (IHC) employing an affinity purified polyclonal antibody specific to Pis1. RESULTS: Various cell types and tissues of Atlantic cod including those from the immune organs of naive fish are armed with Pis1 peptide. Different types of the blood leucocytes and phagocytic cells among the leucocytes examined gave a relatively strong indication of Pis1 immunopositivity. In addition, other cell types such as hematopoietic cells, epithelial cells and multi-granular cells located in the mucosal and hematopoietic tissues were also Pis1-immunoreactive. More interestingly, chondrocytes appear to produce Pis1 and this is the first report on the presence of an AMP in cartilage tissue of fish. Furthermore, Pis1 immunopositivity was detected in other tissues and organs of naive fish including neural tissues, exocrine and endocrine glands, compound gland cells, excretory kidney, intestinal and respiratory epithelial cells, swim bladder, skin and hypodermis layer, myosepta, liver, heart, eye and oocytes. CONCLUSIONS: Pis1 peptide is produced by various cell types located in different tissues and organs of Atlantic cod. It is present in all immune-related organs of naive fish and the elevated peptide expression following phagocytosis strongly suggest their involvement in innate defence. Further, its widespread occurrence in non-immune tissues and organs of apparently healthy fish implies that piscidin may have other functions in addition to its role as an immune effector molecule. PMID- 22538081 TI - Inorganic cobalt supplementation: prediction of cobalt levels in whole blood and urine using a biokinetic model. AB - Soluble cobalt (Co) supplements with recommended daily doses up to 1000 MUg Co/day are increasingly being marketed to consumers interested in healthy living practices. For example, some athletes may consider using Co supplements as blood doping agents, as Co is known to stimulate erythropoesis. However, the distribution and excretion kinetics of ingested Co are understood in a limited fashion. We used a Co-specific biokinetic model to estimate whole blood and urine Co levels resulting from oral exposure or ingestion of Co in amounts exceeding typical dietary intake rates. Following 10 days of Co supplementation at a rate of 400 to 1000 MUg/day, predicted adult Co concentrations range from 1.7 to 10 MUg/L in whole blood, and from 20 to 120 MUg/L in urine. Chronic supplementation (>= 1 year) at a rate of 1000 MUg Co/day is predicted to result in blood levels of 5.7 to 13 MUg/L, and in urine levels from 65 to 150 MUg/L. The model predictions are within those measured in humans following ingestion of known doses. The methodology presented in this paper can be used to predict urinary or blood Co levels following acute or chronic occupational incidental ingestion, medicinal therapy, supplemental intake, or other non-occupational exposures. PMID- 22538082 TI - Phloridzin reduces blood glucose levels and alters hepatic gene expression in normal BALB/c mice. AB - We previously showed that a diet containing phloridzin suppressed the blood glucose levels in streptozotocin-induced diabetic mice most likely by inhibiting glucose absorption from the small intestine. In this study, we showed that 0.5% and 1% phloridzin diets significantly reduce the blood glucose levels in healthy normal BALB/c mice after 7 days of feeding. The 0.1% phloridzin diet did not suppress blood glucose levels but induced the alteration of the hepatic gene expressions related to carbohydrate and fatty acid metabolism in mice after 14 days. Ingenuity Pathway Analysis showed that 0.5% and 1% phloridzin diets suppressed the hepatic gene expressions related to the citrate cycle, gluconeogenesis, fatty acid metabolism, and valine, leucine, and isoleucine degradation in mice when compared with mice fed a control diet after 14 days. Thus the diet containing phloridzin reduces the blood glucose levels and the hepatic gene expressions associated with some metabolic functions in mice. PMID- 22538083 TI - Effect of a special carbohydrate-protein cake on oxidative stress markers after exhaustive cycling in humans. AB - Exercise has been associated with oxidative stress that is correlated with muscle fatigue and reduced exercise performance. The aim of this study was to examine the effects of a special cake (consisting of carbohydrate to whey protein 3.5:1) vs an isocaloric carbohydrate cake on biomarkers of oxidative stress in 9 males after exhaustive cycling. A randomized single-blind cross-over study was completed. They performed one trial involving a 2-h exercise on a cycle ergometer at 60-65% VO(2)max followed by a 4-h recovery and then a second trial involved an 1-h exercise at 60-65% VO(2)max which was increased at 95% VO(2)max (time trial). The subjects received 4 experimental or placebo cakes after the first trial (the first immediately after and then one every hour). Blood samples were collected at eight time intervals: pre-exercise, 30 min, 1.5 h and 4 h post-exercise, post time Trial, 1 h, 24 h and 48 h post time Trial. Thiobarbituric Acid Reactive Substances (TBARS), protein carbonyls, total antioxidant capacity (TAC), catalase and glutathione (GSH) were determined spectrophotometrically. The mean time to exhaustion did not differ upon cake consumption. Consumption of the special cake reduced TBARS significantly, but had no effect on other oxidative stress markers. PMID- 22538084 TI - Biomechanical assessments of the effect of visual feedback on cycling for patients with stroke. AB - Stroke patients exhibit abnormal pattern in leg cycling exercise. The aim of this study was to investigate the effects of visual feedback on the control of cycling motion in stroke patients from kinesiological, kinematic and kinetic aspects. The cycling performance derived from cycling electromyography (EMG), cycling cadence, and torque of forty stroke subjects was evaluated under conditions with and without visual feedback of cycling cadence. Kinesiological indices, shape symmetry index (SSI) and area symmetry index (ASI) were extracted from EMG linear envelopes to evaluate the symmetry of muscle firing patterns during cycling. Roughness index (RI) was calculated from cycling cadence to represent cycling smoothness from kinematic aspects. Averaged cycling power (Pav), the product of cadence and torque, was used to represent force output. The rectus femoris EMG showed significantly greater ASI with visual feedback, however, the difference in SSI between the two conditions was not significant. For the biceps femoris, there was a significant decrease in SSI with visual feedback, while the ASI was not affected significantly by the task conditions. The cycling smoothness was better and the average power generated was larger when visual feedback was provided. This study found that the addition of visual feedback improved both neuromuscular control and overall performance. Such improvement is likely to be the result of better control of the rectus femoris muscle activation and coordination of both legs. PMID- 22538085 TI - Language deficits in pre-symptomatic Huntington's disease: evidence from Hungarian. AB - A limited number of studies have investigated language in Huntington's disease (HD). These have generally reported abnormalities in rule-governed (grammatical) aspects of language, in both syntax and morphology. Several studies of verbal inflectional morphology in English and French have reported evidence of over active rule processing, such as over-suffixation errors (e.g., walkeded) and over regularizations (e.g., digged). Here we extend the investigation to noun inflection in Hungarian, a Finno-Ugric agglutinative language with complex morphology, and to genetically proven pre-symptomatic Huntington's disease (pre HD). Although individuals with pre-HD have no clinical, motor or cognitive symptoms, the underlying pathology may already have begun, and thus sensitive behavioral measures might reveal already-present impairments. Indeed, in a Hungarian morphology production task, pre-HD patients made both over-suffixation and over-regularization errors. The findings suggest the generality of over active rule processing in both HD and pre-HD, across languages from different families with different morphological systems, and for both verbal and noun inflection. Because the neuropathology in pre-HD appears to be largely restricted to the caudate nucleus and related structures, the findings further implicate these structures in language, and in rule-processing in particular. Finally, the need for effective treatments in HD, which will likely depend in part on the ability to sensitively measure early changes in the disease, suggests the possibility that inflectional morphology, and perhaps other language measures, may provide useful diagnostic, tracking, and therapeutic tools for assessing and treating early degeneration in pre-HD and HD. PMID- 22538086 TI - The role of the left putamen in multilingual language production. AB - Subcortical structures are a key component of bilingual language processing. For instance, there is now evidence that the head of the left caudate is involved in controlling languages in bilingual individuals. On the other hand, the left putamen is hypothesized to be involved in articulatory processes but little is known on its engagement in bilingual language processing. Here, our hypothesis was that the left putamen of multilinguals is engaged when producing words in the less proficient language. We investigated this issue with event-related functional Magnetic Resonance (er-fMRI) in a group of multilinguals (n = 14) and in monolinguals (n = 14) during a picture-naming task. Further, we hypothesized increased grey matter density in the left putamen as an effect of experience since multilinguals constantly face a major articulatory load (i.e., speaking multiple languages) during life. To test these hypotheses we measured structural differences between multilinguals and monolinguals using voxel-based morphometry (VBM). Our results indicate that multilinguals have increased activation in the left putamen for a non-native language, but only if they are not highly proficient in that language. In addition, we found increased grey matter density in the left putamen of multilinguals compared to monolinguals. These findings highlight that the multilingual brain handles a complex articulatory repertoire (i.e., dealing with multiple languages) by inducing structural plasticity in the left putamen. PMID- 22538087 TI - Tonic GABA(A) receptor-mediated signalling in temporal lobe epilepsy. AB - The tonic activation of extrasynaptic GABAA receptors by extracellular GABA provides a powerful means of regulating neuronal excitability. A consistent finding from studies that have used various models of temporal lobe epilepsy is that tonic GABAA receptor-mediated conductances are largely preserved in epileptic brain (in contrast to synaptic inhibition which is often reduced). Tonic inhibition is therefore an attractive target for antiepileptic drugs. However, the network consequences of a commonly used approach to augment tonic GABAA receptor-mediated conductances by global manipulation of extracellular GABA are difficult to predict without understanding how epileptogenesis alters the pharmacology and GABA sensitivity of tonic inhibition, and how manipulation of tonic conductances modulates the output of individual neurons. Here we review the current literature on epilepsy-associated changes in tonic GABAA receptor mediated signalling, and speculate about possible effects they have at the network level. This article is part of the Special Issue entitled 'New Targets and Approaches to the Treatment of Epilepsy'. PMID- 22538090 TI - Release of pamidronate from poly(ethyleneimine)/cellulose sulphate complex nanoparticle films: an in situ ATR-FTIR study. AB - In situ ATR-FTIR spectroscopy was used as a screening method to quantify the relative release of pamidronate (PAM) from films of polyelectrolyte (PEL) complex (PEC) particles. Stable colloid PEC particles consisting of poly(ethyleneimine) (PEI) and cellulose sulphate (CS) loaded with PAM were obtained by PEL complexation featuring hydrodynamic radii between 60 and 90 nm and a cationic or anionic surface charge dependent on the mixing ratio n-/n+=0.9 or 1.1, respectively. Respective bare unloaded PEC particles showed smaller hydrodynamic radii. PAM loaded PEC particles were casted from dispersion onto Ge model substrates and dried forming stable films in contact to water. By in situ ATR FTIR spectroscopy it could be shown, that PAM/PEC particle films contacting to water resulted in a time dependent retarded release of PAM from the PEC matrix, while PAM from a pure drug film was immediately released. Cationic PAM loaded PEC particles of PEI/CS showed smaller initial burst and long term release compared to anionic one at similar PAM/PEI ratios. With increasing PAM/PEI ratio the initial burst could be minimized to around 30% and the residual long term amount of PAM optimized to 50% for PAM/PEC samples casted from 0.002 M dispersions. A further improvement of the release performance was achieved either by prerinsing the dry film in H(2)O or by rising the PEC concentration from 0.002 M to 0.01 M revealing an initial burst of around 5% and long term residual PAM content of around 75%. ATR-FTIR and TRANS-FTIR analysis of the PAM release from equivalent PEC samples revealed similar kinetic courses and parameters justifying the use of the Ritger/Peppas two parameter model. Applying this model PAM/PEC samples casted from 0.002 M dispersions revealed exponent values of b?0.5 suggesting PAM dissolution in the PEC matrix, while for those casted from 0.01 M b values close to 0.5 were obtained suggesting hindered dissolution and diffusion. A model describing different retention modalities of PAM in PEC particle is suggested. PMID- 22538089 TI - IL-10-producing regulatory B10 cells ameliorate collagen-induced arthritis via suppressing Th17 cell generation. AB - IL-10-producing CD1d(hi)CD5(+) B cells, also known as B10 cells, have been shown to possess a regulatory function in the inhibition of immune responses, but whether and how B10 cells suppress the development of autoimmune arthritis remain largely unclear. In this study, we detected significantly decreased numbers of IL 10-producing B cells, but increased IL-17-producing CD4(+) T (Th17) cells in both spleen and draining lymph nodes of mice during the acute stage of collagen induced arthritis (CIA) when compared with adjuvant-treated control mice. On adoptive transfer of in vitro expanded B10 cells, collagen-immunized mice showed a marked delay of arthritis onset with reduced severity of both clinical symptoms and joint damage, accompanied by a substantial reduction in the number of Th17 cells. To determine whether B10 cells directly inhibit the generation of Th17 cells in culture, naive CD4(+) T cells labeled with carboxyfluorescein succinimidyl ester (CFSE) were co-cultured with B10 cells. These B10 cells suppressed Th17 cell differentiation via the reduction of STAT3 phosphorylation and retinoid-related orphan receptor gammat (RORgammat) expression. Moreover, Th17 cells showed significantly decreased proliferation when co-cultured with B10 cells. Although adoptive transfer of Th17 cells triggered the development of collagen-induced arthritis in IL-17(-/-)DBA/1J mice, co-transfer of B10 cells with Th17 cells profoundly delayed the onset of arthritis. Thus, our findings suggest a novel regulatory role of B10 cells in arthritic progression via the suppression of Th17 cell generation. PMID- 22538088 TI - Plasticity of button-like junctions in the endothelium of airway lymphatics in development and inflammation. AB - Endothelial cells of initial lymphatics have discontinuous button-like junctions (buttons), unlike continuous zipper-like junctions (zippers) of collecting lymphatics and blood vessels. Buttons are thought to act as primary valves for fluid and cell entry into lymphatics. To learn when and how buttons form during development and whether they change in disease, we examined the appearance of buttons in mouse embryos and their plasticity in sustained inflammation. We found that endothelial cells of lymph sacs at embryonic day (E)12.5 and tracheal lymphatics at E16.5 were joined by zippers, not buttons. However, zippers in initial lymphatics decreased rapidly just before birth, as buttons appeared. The proportion of buttons increased from only 6% at E17.5 and 12% at E18.5 to 35% at birth, 50% at postnatal day (P)7, 90% at P28, and 100% at P70. In inflammation, zippers replaced buttons in airway lymphatics at 14 and 28 days after Mycoplasma pulmonis infection of the respiratory tract. The change in lymphatic junctions was reversed by dexamethasone but not by inhibition of vascular endothelial growth factor receptor-3 signaling by antibody mF4-31C1. Dexamethasone also promoted button formation during early postnatal development through a direct effect involving glucocorticoid receptor phosphorylation in lymphatic endothelial cells. These findings demonstrate the plasticity of intercellular junctions in lymphatics during development and inflammation and show that button formation can be promoted by glucocorticoid receptor signaling in lymphatic endothelial cells. PMID- 22538091 TI - Instability of ovine babesiosis in an endemic area in Turkey. AB - This study was designed to determine the endemic status of Babesia ovis in sheep in Turkey. A total of 2000 sheep, from different age groups (i.e. 0-3, 4-6, 6-9, 10-12, and >12 months), were selected randomly from 132 sheep flocks. The presence of specific antibodies against B. ovis was diagnosed by indirect fluorescent antibody test (IFAT). A total of 843 (42.15%) serum samples were determined to be positive. The seropositivity rates in the age groups stated above were 31.90, 31.64, 47.69, 40.22, and 52.99%, respectively. The endemic status of the disease was determined by calculating the inoculation rate (h) of each group. The h value for each group was determined to be lower than 0.005, which revealed that the endemic status of B. ovis was instable. This report may indicate the necessity of vaccination. PMID- 22538092 TI - Potential environmental consequences of administration of ectoparasiticides to sheep. AB - Sheep ectoparasiticides, which include the synthetic pyrethroids, the organophosphates, the 'insect'-growth regulators, the formamidines and the spinocyns, enter into the environment primarily through disposal of dip or fleece scours, as well as with contaminated faeces and urine. Due to the large quantities of spent dip, risks associated with environmental contamination are high. Synthetic pyrethroids and organophosphates pose risks to dung, soil and aquatic fauna; concerns over potential ecotoxicity to vertebrates and invertebrates have resulted in the cessation of their use in many countries. There is very little information regarding the ecotoxicity of 'insect'-growth regulators, formamidines or spinocyns, with no studies focussing on sheep. Here, the impact of sheep ectoparasiticides is discussed in terms of their potential to enter into the environment, their toxicity and their impact on ecosystem functioning. Where there are no data for excretion or toxicity of the ectoparasiticides used in sheep production, examples to demonstrate potential impacts are taken from laboratory ecotoxicity tests and the cattle literature, as well on work with foliar insecticides. Future research priorities are suggested to allow assessment of the environmental consequences of sheep ectoparasiticide treatments, which are essential for future sustainable sheep production. PMID- 22538093 TI - Potential environmental consequences of administration of anthelmintics to sheep. AB - Anthelmintics, veterinary medicines for the control of endoparasites, enter into the environment largely through faeces of the treated animals. Sheep dung is a patchily distributed, ephemeral resource, with a functionally important decomposer community. The nature of this community and the pharmacokinetics of anthelmintics in sheep mean that the ecotoxic impacts of these drugs in sheep dung may differ markedly from those in cattle dung, where most research has been focussed. The period of maximum residue excretion is generally more transient in sheep than cattle dung, but low-level excretion may continue for longer, giving the potential for extended sub-lethal effects. Here, the environmental impacts of sheep anthelmintics, as well as alternative endoparasite control methods are reviewed. Impacts are discussed in terms of the potential for residues to enter into the environment, the toxicity and the impact on ecosystem functioning at an appropriate scale. Future research priorities are also discussed; these include the need for studies of the functional contributions of dung-colonising species, as well as the development of higher-tier ecotoxicological methods bridging the gap between laboratory and field experiments. Large-scale and long-term studies, including the development of appropriate models, are necessary to allow the consequences of anthelmintic administration to be assessed, particularly within the remit of sustainable animal production. PMID- 22538094 TI - Efficacy of major anthelmintics against horse cyathostomins in France. AB - This paper reports a survey conducted in France during 2011 to evaluate the efficacy of commonly used anthelmintics against horse cyathostomins. A total of 40 farms and 1089 horses were screened for the presence of cyathostomins. All farms but one were positive, with an overall animal infection rate of 53.7%, ranging from 9% to 83% on individual farms. On 445 horses from 30 of these farms, a faecal egg count reduction test (FECRT) was performed to evaluate the efficacy of oral formulations of fenbendazole (FBZ), pyrantel embonate (PYR), ivermectin (IVM) and moxidectin (MOX). Calculation of the mean FECR and 95% confidence intervals (95% CI) around the mean was performed using bootstrap analysis. Resistance to FBZ was found on 17 of 18 farms investigated, with a mean reduction of 57% (95% CI: 38.5-71.2%). Suspected resistance for PYR was found on 6 of 30 farms, and confirmed on another 3 of 30 farms, with a mean reduction for PYR of 94.7% (95% CI: 88.9-98.5%). Reduced efficacy simultaneously of FBZ and PYR was found in 7 farms. Reduced efficacy of IVM was found in one animal on one farm and of MOX in one animal on another farm, and was combined with resistance against FBZ and/or PYR. These results indicate that single and multiple drug resistance and reduced efficacy in equine cyathostomins is present in France. Macrocylic lactones proved to be highly effective compounds against cyathostomins, with reduced efficacy for IVM and MOX in two farms only. These results extend present knowledge on the occurrence of drug resistant cyathostomins in Europe, and illustrate the necessity to use anthelmintics in appropriate worm control programmes. PMID- 22538096 TI - Development of a proficiency testing program for molecular diagnosis of influenza viruses. AB - BACKGROUND: The Molecular Virology Proficiency Testing Program at the Wadsworth Center began the assembly and distribution of influenza virus panels to US public health labs (PHLs) in 2008. The program was created to assist PHLs in assessing their performance and in meeting CLIA regulations for mandated proficiency testing (PT). OBJECTIVES: To design and distribute proficiency testing panels containing influenza A virus subtypes H1N1 and H3N2, and influenza B; when H1N1pdm09 emerged it also was incorporated into the panels. A secondary objective was to determine the best matrix for long term storage of the molecular PT samples. STUDY DESIGN: Viruses were quantitated using TCID(50) and quantitative real-time RT-PCR. Reference laboratories were enlisted to verify viral identity in the panels and to help determine viral titers to be used in the PT panels sent to PHLs. RESULTS AND CONCLUSIONS: Of the 29 laboratories that participated the first year, 27 were able to correctly identify all of the virus types in the panel. Fifty-one PHLs participated in the program the second year when pandemic H1N1 was added, and 45 were able to correctly detect, type and subtype all of the viruses in the panel. In the program's third year, 60 laboratories participated; 58 correctly detected and subtyped all of the viruses in the panel. Annual surveys of assay techniques showed that the PHLs had shifted their extraction methods and PCR-thermocycler instrumentation to meet FDA-approved methods. The degradation study revealed that frozen viral stocks were stable for at least 30months, thus allowing ample time to prepare and pre-test panels. PMID- 22538095 TI - Genetic variation of Haemonchus contortus (Trichostrongylidae) in sheep and goats from Malaysia and Yemen. AB - The large stomach worm, Haemonchus contortus, commonly known as "the barber's pole worm", is a blood-sucking nematode found in the abomasa of sheep and goats. This work is the first documentation on the ND4 sequences of H. contortus from sheep and goats in Malaysia and Yemen and the results provide a preliminary insight on the genetic differences of H. contortus found in the two countries. In general, this study showed a high degree of diversity and low population structure of this species within the same country in comparison with higher genetic structuring at a wider geographical scale. The results also showed that the majority of genetic variance was within H. contortus populations. The Malaysian sheep and goat populations investigated appeared to share the same isolate of H. contortus while different isolates may be found in Yemen which must be taken into account in the design of an effective control strategy. Analysis of the internal transcribed spacer-2 (ITS-2) confirmed that all samples investigated in this study belonged to H. contortus. However presence of other Haemonchus species parasitizing these two hosts can only be confirmed by further detailed studies. PMID- 22538097 TI - In vitro and in vivo evaluation of a dry powder endotracheal insufflator device for use in dose-dependent preclinical studies in mice. AB - The aim of this study was to evaluate the ability of the Penn-Century Dry Powder Insufflator for mice (DP-4M) to reproducibly, uniformly, and deeply deliver dry powders for inhalation in the mouse lung. Itraconazole-based dry powder formulations produced by spray-drying were different in terms of composition (different ratios of drug and mannitol, with or without phospholipids), but relatively similar in terms of particle size and mass median aerodynamic diameter. The ability of the dry powder insufflator to disaggregate each formulation was the same, indicated by the absence of a statistically significant difference between the particle size distribution parameters, as measured by laser scattering. The emitted fraction varied in vivo compared to the in vitro condition. Fluorescent particle distribution in the lungs was uniform and reached the alveolar spaces, as visualized by fluorescent microscopy. In terms of drug recovery in lung tissue, a minimum administered powder mass (in this case ~1 mg) was necessary to recover at least 30% of the emitted dose in the lung and to obtain reproducible pulmonary concentrations. To reduce the dose administered in the lung, it was preferable to dilute the active ingredient within the carrier instead of reducing the dry powder mass inserted in the sampling chamber. Dry powder insufflators are devices usable in dose-dependent preclinical trials but have critical parameters to efficiently deliver reproducible doses depending on the type of formulation. PMID- 22538098 TI - Calcipotriol delivery into the skin with PEGylated liposomes. AB - The D-vitamin analogue calcipotriol is commonly used for topical treatment of psoriasis, but skin penetration is required for calcipotriol to reach its pharmacological target: the keratinocytes in the lower epidermis. Liposomes can enhance the delivery of drugs into the skin, but a major challenge for the development of dosage forms containing liposomes is to maintain the colloidal stability in the formulation. The purpose of this study was to investigate the effect of stabilising liposomes with the lipopolymer poly(ethylene glycol) distearoylphosphoethanolamine (PEG-DSPE) on the physicochemical properties of the liposomes and the ability to deliver membrane-intercalated calcipotriol into the skin. Inclusion of 0.5, l and 5 mol% PEG-DSPE in the membrane enhanced the colloidal stability of the liposomes without compromising the delivery of calcipotriol from the vehicle into excised pig skin. Calcipotriol-loaded liposomes with 1 mol% PEG-DSPE did even provide for a significantly increased deposition of calcipotriol into the stratum corneum. The size of the liposomes affected the penetration of calcipotriol into the stratum corneum since small unilamellar vesicles enhanced calcipotriol penetration as compared to large multilamellar vesicles, indicating that the liposomes to some extent migrate as intact vesicles into the stratum corneum. However, calcipotriol penetrated the skin better than the lipid component of the liposomes, suggesting that at least a fraction of the drug is released from the liposomes during skin migration. In conclusion, PEGylation is therefore a promising approach for stabilising calcipotriol-containing liposomal dispersions without compromising their favourable skin accumulation properties. PMID- 22538099 TI - Both column fractures of the acetabulum: epidemiology, operative management and long-term-results. AB - PURPOSE OF THE STUDY: Both column fractures, defined as an acetabular fracture with no articular fragment in connection with the axial skeleton account for approximately 20% of all acetabular fractures. The typical type of a both column acetabular fracture is the C1.2 fracture with a multifragmentary anterior column fracture extending to the iliac crest and a large posterior column fragment in more than half of the patients. MATERIAL AND METHODS: The analysis of 135 surgically treated patients with both column fractures showed that more than half of these patients had associated injuries. The mean age was 40 years, and two thirds of these patients were male. A high energy trauma was the trauma mechanism in 87.4%. The mean ISS was 14.2 points. The mean articular fracture displacement was 14.8 mm. 65.9% of the patients showed a central femoral head dislocation. An associated posterior wall fracture was present in 34.8% and an acetabular roof comminution in 34.1%. 8.9% of patients had a fracture related nerve damage. RESULTS: Osteosynthesis was performed 9.6 days after trauma. Several approaches were used for stabilization with a combination of plate and screw fixation in 71.9%. The mean operative time was 287 minutes with a blood loss of 1796 ml. Post operatively the hip joint was congruent in 94.7% with anatomical or near anatomical joint reconstruction in 75.6%. Iatrogenic nerve injury occurred in 12 patients (8.9%). 89 patients (66.4%) could be followed after a mean of 54.6 months. The average subjective Visual Analog Scale pain score was 27.6. Mild or no pain was seen in 60.7%. The mean Merle d'Aubigne score was 15 with 60.7% of patients having a functionally perfect or good result. 61.8% had no post traumatic osteoarthritic changes of their hip joint. A joint failure was diagnosed in 25.8% of the patients. DISCUSSION: Analysing only patients with anatomically reconstructed hip joints patients had better results with 69,8% having no or mild pain and a good or excellent functional result. Post-traumatic arthrotic changes occued in only 17.5% of these patients. A joint failure was present in 25.4%. In this group, a joint failure was significantly more likely to be present with an additional lesion of the femoral head and severe primary articular fracture displacement. CONCLUSIONS: In contrast to other acetabular fracture types, both column fractures show worser results regarding joint reconstruction, and functional and radiological long-term results. The optimal results can be achieved with anatomic joint reconstruction. PMID- 22538100 TI - Traumatic epiphysiolysis of the proximal femur. AB - PURPOSE OF THE STUDY: Several former studies show the treatment of slipped epiphysis of the femoral head (SEFH). Its reason is rather unknown. On the other hand the rare traumatic SEFH takes place due to a real accident. According to the literature these injuries are treated like chronic SEFHs. The aim of this study is to show the differences in pathology and treatment of an acute traumatic SEFH in relationship to the chronic SEFH. PATIENTS AND METHODS: In 8 patients dislocated traumatic SEFHs were reduced anatomically and stabilized by the means of 3 to 4 Kirschner- (K-) wires or two cancellous screws. Each patient got a plaster-cast fixation for about 6 weeks of the ipsilateral hip and leg and was mobilized with two crutches and partial weight bearing for 12 weeks. The implants were removed 24 weeks after surgery. Four patients with not dislocated SEFHs were immobilized or mobilized with two crutches without weight bearing according to their pain sensation. The final examination of both groups took place 2 Vz to 15 years after the initial treatment. RESULTS: Four patients primarily under 10 years of age showed no or minimal radiological signs of a dislocated femoral head and were without any further inconvenience--the suspected SEFHs revealed as hip contusions. 8 children aged 10 years or older at the time of trauma were treated by closed reduction and internal fixation. Complications occurred in three cases- one necrosis of the femoral head because of a perforating K-wire, one subtrochanteric femur fracture after implant removal of a prophylactically stabilized contralateral femoral head and one minimally dislocated femoral head after postoperative too early full weight bearing. DISCUSSION: The traumatic SEFH is very different to the chronic one regarding the pathology and acute treatment. Technical challenges must be solved. Unilateral K-wiring or screwing for 24 weeks and reduced weight bearing for the first 12 weeks after surgery is a sufficient way of treatment of the traumatic SEFH. CONCLUSIONS: In the case of a traumatic SEFH it needs to be reduced anatomically and stabilized by surgical means in the acute phase. A prophylactic stabilization of the opposite intact side is usually not required. PMID- 22538101 TI - [Surgical treatment for factures of the neck and body of the talus]. AB - PURPOSE OF THE STUDY: To present a retrospective evaluation of the results of our method of open reduction and internal fixation. MATERIAL AND METHODS: A total of 35 patients were surgically treated for talar fractures at our department between 2004 and 2008. There were 27 men and eight women, with an average age of 31 years (range, 21 to 65). Talar neck fractures were recorded in 21 and talar body fractures in 14 patients. The most frequent cause of injury was a fall from height (77%); motorcar accidents were less frequent (14%). Open fractures were found in 8.5% of the patients, and talar fractures as a single trauma were recorded in 80% of them. Indication criteria for surgery included displaced talar neck (Hawkins type II to type IV) and body fractures, with a displacement exceeding 1 mm. The traction screw osteosynthesis used was combined with plate fixation in some patients. .Full weight-bearing of the extremity was allowed from 12 post-operative months. The patients were followed up at 6 weeks, 3, 6 and 12 months and then at yearly intervals. The American Orthopaedic Foot and Ankle Society (AOFAS) scores were used to evaluate the results. RESULTS: Of the 35 fractures, 16 (45.7%) were treated surgically on the day of injury and 19 (54.3%) on subsequent days. The injury-surgery interval ranged from 0 to 12 days (average, 8 days). Primary bone union was recorded in 34 patients (97%) within 16 weeks of surgery; pseudoarthrosis developed in one patient. The results were excellent in eight (23%), good in 11 (31%) and satisfactory in seven (20%) patients. Poor outcome including function was reported by nine (26%) patients. The poor results were mostly due to associated tibial pilon fractures or because of arthrodesis necessary to be performed for management of necrosis or arthritis. Complications were recorded in 22 patients (63%) and included avascular necrosis in six (17%), traumatic arthritis of the tibiotalar and subtalar joints in 14 (40%) patients and pseudoarthrosis in one (3%) patient. This was treated by corticocancellous graft implantation and repeated osteosynthesis, and bone union occurred within 6 months. Traumatic arthritis was managed by arthrodesis in seven patients. DISCUSSION: Dislocated talar neck and body fractures are always indicated for surgery. The surgical procedure used depends on the patient's injury, surgeon's experience and skills, surgical department's system and fracture type. The timing of surgery is related to the type of injury and soft tissue disturbance. The primary demand is to reduce the fracture as soon as possible; a definite treatment may be postponed. Open fractures require urgent management. The treatment should be completed by an experienced surgeon after subsidence of soft tissue oedema when there is no longer the risk of compartment syndrome development. Injury brings about blood flow disturbance, with its extent relative to the type of injury, which may result in avascular necrosis. However, the timing of surgical treatment plays no role in the development of complications such as avascular necrosis or traumatic arthritis. CONCLUSIONS: Surgical management of dislocated talar neck and body fractures by open reduction and osteosynthesis does not achieve very good results. The definitive treatment should be carried out by an experienced surgeon and at a department with routine performance of these procedures. The results show that a delayed treatment by open reduction and stable osteosynthesis has better long-term outcomes than a rash acute operation done by an incomplete or less experienced operating team. PMID- 22538102 TI - [MEDIN implant of the first metatarsophalangeal joint]. AB - PURPOSE OF THE STUDY: Hemiarthoplasty or total replacement of the first metatarsophalangeal (MTP) joint has been used in orthopaedic surgery for the last 60 year, but good post-operative outcomes have been achieved only in the last ten years. Joint replacement is mainly used in stage 3 and stage 4 hallux rigidus conditions for which arthrodesis is not indicated. The operation on the first MTP joint has its place in the present-day orthopaedics. This study describes anatomical measurements and the development of the first Czech implant (MEDIN Orthopaedics) to replace this joint. MATERIAL AND METHODS: Thirty cadaver specimens were used to develop basic shapes of phalangeal and metatarsal components. A standard technique was used for anatomical dissection of the first MTP joint. Fifteen specimens were cut in the sagittal plane and fifteen in the transverse plane in order to open the intramedullary cavity of the proximal phalanx of the great toe and the first metatarsal bone. The basic shapes of phalangeal and metatarseal components were designed based on the shape of cortical bone of their inner surfaces. Data for the shape, size and scale of articular components were obtained by measurement on 58 dry bone specimens of the first metatarsus and on 30 calibrated X-ray images. In order to adjust the scale and size of components, the final shape and the range of implant size were tested on 50 specimens of dissected lower extremities fixed in formaldehyde, acetone, ethyl-alcohol and glycerol. RESULTS: The new type of a first MTP implant designed by us was based on cone-shaped anchor components coated with hydroxyapatite. The implants can be used in hemiarthroplasty or total joint replacement. The metatarsal insert was designed with a declination angle of 20 degrees to facilitate good dorsiflexion and with a flattening to ensure good function of the sesamoid bones, The phalangeal articular insert was made of either CoCr alloy or low-weight polyethylene for use in hemiarthroplasty and total joint replacement, respectively. DISCUSSION: The new implants are designed for treatment of stage 3 or stage 4 hallux rigidus. We recommend to use hemiarthroplasty or total joint replacement only in the case of first metatarsal head destruction or severe joint destruction due to rheumatoid arthritis. CONCLUSIONS: Our anatomical study of the first MTP joint, proximal phalanx of the great toe and first metatarsal bone was used to design the first Czech implant of this joint. PMID- 22538103 TI - [Knee arthroscopy in children and adolescents with trauma histories]. AB - PURPOSE OF THE STUDY: In this retrospective study we analysed the major indications for knee arthroscopy and the diagnoses made using it in children and adolescents who had sustained knee joint injuries. MATERIAL AND METHODS: A total of 731 knee joint artroscopies were performed and retrospectively evaluated in patients under 19 years of age. The group included patients with knee joint injuries treated at our department in the 2000-2010 period. There were 413 boys (58%) and 300 girls (42%) with an average age of 14 years and 2 months. The clinical diagnosis was compared with the arthroscopic diagnosis. RESULTS: The results of our comparative study were divided into three groups. The clinical diagnosis was fully confirmed in 62%, partially confirmed in 17% (combined injuries) and was wrong in 21% of the patients. In this group, the most frequent diagnosis made by arthroscopy was injury to the lateral meniscus. Arthroscopy revealed patellar dislocations in 18%, osteochondral and cartilage lesions in 16%, plica injuries in 15 %, medial meniscus injuries in 14%, anterior cruciate ligament lesions in 12% and lateral meniscus injury in 8% of the patients. DISCUSSION: With the number of knee injuries in children and adolescents increasing every year, the role of arthroscopy in their diagnosis and treatment is becoming increasingly important. The results of our analysis showed gradual improvement in clinical outcomes and subjective evaluation of the arthroscopic technique in children and adolescents with the history of knee injury. Some authors report difficulties with the pre-operative diagnosis at this age; our results were notably better. CONCLUSION: Knee arthroscopy is a safe and effective method of a high diagnostic and therapeutic value and its use in children and adolescents should be recommended. PMID- 22538104 TI - [Arthroscopically-assisted procedures on the hip joint]. AB - PURPOSE OF THE STUDY: Since 2000 arthroscopically-assisted surgery on hip joints has become more widely used. The technique is relatively demanding and should be used only after arthroscopic procedures on other large joints are mastered to perfection. A thorough study on cadaverous specimens should be a prerequisite for adopting it as a routine method. The aim of this study was to evaluate indications for hip arthroscopy as, from the year 2006, this was gradually introduced and more widely used at our department. MATERIAL AND METHODS: Forty two hip joints were assessed out of the 83 hips which had been treated by arthroscopic surgery before the date of evaluation and which had been followed up for at least 2 years. The patient group evaluated consisted of 25 men and 17 women, with an average age of 40.3 years and a range of 21 to 65 years. Patients with a follow-up shorter than 2 years and those subsequently undergoing total hip arthroplasty were not evaluated. Indications for arthroscopic surgery included the presence of intra-articular bodies, labro-cartilaginous lesions and impingement syndromes. Neurovascular disorder affecting the limb and a higher degree of osteoporosis were considered contraindications. The outcome of surgery and its indications were evaluated on the basis of the questionnaire which recorded the patient's objective findings and subjective feelings at 3 and 6 months and then at 1 and 2 years after surgery. RESULTS: The average VAS score was 7.83 points before surgery, and 3.87 points at 3 months and 2.01 points at 2 years after surgery. Nearly all patients (98%) reported their willingness to undergo the surgery again. The complications included transient hyperesthesia in the perineal region completely resolved within 4 weeks of surgery in three cases and subcutaneous extravasation after extensive capsulotomy in one patient. It subsided within 48 hours without compartment syndrome development. DISCUSSION: A good view allowing for comprehensive exploration of the central as well as peripheral compartments enables us to treat all pathologies, which are manageable by arthroscopic intervention, in one procedure. Patient recovery is faster and the risk of intra- and post-operative complications is lower that in open surgery. The avoidance of extensive capsulotomy and the possibility of leaving the femoral head in place with only minimum distractions and without injury to the ligamentum capitis are the most important advantages of this method. Complications were found in 8.4% of the cases, which is in agreement with the literature data. The method can be applied in both the diagnosis and therapy of chronic conditions such as femoroacetabular impingement, as well as in the treatment of post-traumatic conditions ranging from traumatic labral lesions to the correction of incongruence of articular surfaces in acetabular fractures. CONCLUSIONS: Arthroscopically-assisted surgery enables us to achieve very good results, but requires appropriate, high-standard facilities and a well-mastered operative technique. It should be adopted as the method of choice for young adults still free of arthritic changes including hip impingement syndrome. Similarly to arthroscopic procedures on shoulders and knees, it is associated with low risk factors, and rapid recovery allows the patient to return soon to normal daily activities. PMID- 22538105 TI - [Incidence of proximal femur fractures in relation to seasons of the year and weather]. AB - PURPOSE OF THE STUDY: The opinion that proximal femur fractures occur mainly in the winter season and are related to slippery surfaces prevails in both the lay and medical communities. The elucidation of this relationship would lead to a better understanding of the aetiology of these fractures and may help to prevent them in the elderly population. MATERIAL AND METHODS: In a retrospective study conducted at two departments, the occurrence of proximal femur fractures in patients 60+ years old in relation to weather conditions (air temperature and its humidity, atmospheric pressure, rain and mist) between January 1, 2001 and December 31, 2005 was investigated. Patients with high-energy or pathological fractures were excluded. The results were evaluated by Statistika software. RESULTS: A total of 1720 patients were studied, of whom 1313 were women and 407 were men. The numbers of fractures did not differ significantly among either the seasons or months of the year. No correlation was found between the number of fractures and each of the weather characteristics (air temperature and its humidity, atmospheric pressure, wind speed and visibility). DISCUSSION: It is widely believed that hip fractures are connected with winter months and temperatures below zero. This is supported by several facts related to winter characteristics, such as slippery icy pavements, clumsiness due to warm bulky clothes, bodies affected by cold and thus predisposed to a fall and poorer visibility on shorter winter days. The effect of seasonal variation on hip fracture incidence has been investigated in 10 studies of which only one has taken the influence of daily temperature into consideration. All studies were conduced in the countries north of 40 degrees latitude, i.e., in climatic conditions similar to our country, with temperatures falling below zero and ice glazed pavements in winter months. Of them, six have found no relation between proximal femur fractures and weather conditions, two have reported an increased incidence of these fractures in winter months and two in summer months. CONCLUSIONS: Our study did not show any significant relationship between the incidence of proximal femur fractures and weather characteristics. Seasons of the year had no effect on the number of hip fractures or the length of hospital stay due to their treatment. PMID- 22538106 TI - [Percutaneous dynamic interspinous stabilisation for the treatment of juxtafacet cysts of the lumbar spine: prospective study]. AB - PURPOSE OF THE STUDY: To present the authors' philosophy on the surgical treatment of juxtafacet cysts of the lumbosacral (LS) spine, with its primary aim of dynamic lumbar stabilisation with an interspinous implant, inserted by a minimally invasive approach, without concurrent exploration of the spinal canal and cyst removal. MATERIAL AND METHODS: During a 20-month period, ten patients aged between 25 and 70 years (average age, 53.2 years) were indicated for surgical treatment of a juxtafacet cyst by percutaneous insertion of an In-Space interspinous spacer without surgical exploration of the spinal canal. The group comprised six men and four women. At a follow-up of 6 weeks to 18 months, each patient underwent MRI examination of the LS spine and the degree of cyst resorption was assessed. The visual analogue scale (VAS) scores, Oswestry Disability Index (ODI) and range of motion (ROM) values, and a sagittal angle (SA) of the segment treated obtained for the whole group at 3 to 18 months after surgery were compared with the pre-operative va - lues. The surgeon evaluated the effect of surgery on radicular and axial pain. RESULTS: Complete resorption of the cyst was found in seven patients (70%) and three (30%) showed partial resorption. Complete resolution of radicular symptoms was reported by five patients (50%); five experienced partial relief (50%). Lumbago was relieved completely in three (30%) and partially in seven (70%) patients. The average VAS score was 6.7 points (range, 4-10) pre-operatively and 3.5 (0-8) post operatively, i.e. it decreased by 3.2 points, which meant an improvement by 48%. The average ODI value was 58.4% (range, 32-80) pre-operatively and 23.9% (0-70) post-operatively, i.e., it decreased by 34.5 percentage points and was an improvement by 59%. The average ROM measures were 5.65 degrees (range, 2 degrees 10 degrees ) pre-operatively and 5.55 degrees (0 degrees -19 degrees ) post operatively. The average pre- and post-operative sagittal angles in normal lumbar lordosis were 7.1 degrees (1 degrees -13 degrees ) and 6.2 degrees (1 degrees -11 degrees ), respectively. DISCUSSION: The conventional surgical procedure involves cyst extirpation. However, the procedure only relieves nerve root compression but does not remove the cause of juxtafacet cyst development, which is due to facet joint degeneration and instability. This may results in persistent or recurrent clinical symptoms. On the other hand, a reduction of both mobility and loading of the intervertebral joints achieved by implantation of an interspinous spacer is the mechanism allowing for resorption of the cyst and resolution of symptoms. CONCLUSIONS: 1. The original method of treating juxtafacet cysts of the LS spine by an In-Space interspinous spacer, as presented here, was efficient in all patients and resulted in complete, or at least partial, resorption of the cyst. 2. Segmental mobility and spondyloarthritis are the major aetiological factors of juxtafacet cyst development. 3. Dynamic interspinous stabilisation will reduce loading of the intervertebral joints and will thus allow for cyst resorption and clinical symptom resolution. 4. Percutaneous implantation of an "In-Space" interspinous spacer is a minimally invasive method of dynamic stabilisation that means no restrictions in patients' activities and reduces the length of hospital stay. PMID- 22538107 TI - [Spinal cord concussion: a retrospective study of twenty-four patients]. AB - PURPOSE OF THE STUDY: Spinal cord concussion is characterised as fully reversible, temporary inhibition of conductive function due to trauma, without signs of structural changes. Although neurological deficit is usually related to the severity of spinal injury, this is different in spinal cord concussion. The aim of this retrospective study was to evaluate a group of 24 patients with spinal cord concussion, to design a diagnostic algorithm and propose an effective therapy with a good prognosis for the patients. MATERIAL: We reviewed clinical records of 9 768 patients hospitalised at the Department of Spinal Surgery, University Hospital in Motol, from September 2002 till December 2010, and of 457 patients treated at other departments of the Hospital between January 2008 and December 2010; this was a total of 10 225 patients. The data were retrospectively analysed and only the patients with a clear history of trauma and subsequent conservative therapy were selected to comprise a group characterised by the generally known criteria of spinal cord concussion: (1) spinal injury with immediate neurological deficit of varying degree; (2) neurological deficit corresponding to the level of spinal injury; (3) recovery of neurological function within 72 hours of injury; (4) no morphological evidence of injury to the spinal structures obtained by imaging methods. This group comprised 24 patients. METHODS: The patients were followed up from 6 to 95 months, with a mean of 46 months and a median of 48 months, at intervals of 6 and 12 weeks and 6 and 12 months after injury, and then every following year. The recorded information included the patient's age at the time of injury, their gender, the mechanism of injury, reports on alcohol consumption, the first detected neurological deficit, its development immediately after injury, during the hospital stay and at follow ups in the out-patient department, methylprednisolone administration according to the National Acute Spinal Cord Injury Study (NASCIS) 2, and findings of imaging methods, particularly MRI. RESULTS: Our group consisted of 22 men (91.7%) and two women (8.3%), with an average age of 29 years; the average age was 30 years in men and 18.5 years in women. Seven patients (29.2%) were younger than 18 years, with an average of 16.14 years; the remaining 17 patients (70.8%) were older than 18 years, with an average of 34.35 years. The major mechanisms of injury included falls from a height in 10 patients (41.7%) and injury due to alcohol consumption in five patients (20.1%). Clinical findings involved lesions of the medullary cone in 12 (50.0%), cervical spinal cord in seven (29.2%) and thoracic spinal cord in five (20.8%) patients. Motor function deficit was present in all patients, of whom 10 (41.2%) showed a complete loss of motor function. Impaired sensory function was found in 21 (87.5%) patients. One patient had perianal and genital sensory deficit and one (4.2%) had urinary retention. Neither radiograms nor CT scans showed traumatic changes in any of the patients; MRI findings free of any traumatic spinal changes were recorded in 21 patients (87.5%). One patient had oedema of the T5 and T8 vertebral bodies. No complications were recorded. All patients experienced rapid resolution of neurological deficit, which occurred within 6 hours of injury in two (8.4%), within 12 hours in two (8.4%), within 24 hours in 12 (50.0%) and within 48 hours in six (25.0%) patients, and later than 48 hours after injury in two patients (8.4%). However, recovery always occurred within 72 hours of injury. DISCUSSION: A good prognosis for patients with this injury is supported by our findings, because all patients experienced rapid resolution of neurological deficit within 72 hours of injury. This result is in agreement with the relevant international studies reporting no serious complications associated with spinal trauma. There are no clear recommendations for administration of high doses of methylprednisolone according to the NASCIS system. CONCLUSIONS: Spinal cord concussion is not a frequent injury; in our study, it accounted for 3.54% of the patients with trauma histories out of the total number of 678 patients, or for 2.40% out of 997 injured spinal levels. The first steps should be the same as in any other injury to the spinal cord. An early examination of the patient with imaging methods including MRI is of primary importance. At present administration of methylprednisolone according to the NASCIS system is disputable. The patient diagnosed with spinal cord concussion has a good prognosis, with rehabilitation as the main therapeutic approach. PMID- 22538108 TI - [Primary Pyomyositis of the muscles around the hip. case reports and literature review]. AB - The authors present three case reports of primary pyomyositis, a severe but rare disorder involving the muscles around the hip. In three boys, with an average age of 16 years, the disease developed suddenly in association with strenuous sporting activities. The boys had fever, pain and restricted motion at hip joints, haemoculture tests positive for Staphylococcus aureus and the presence of inflammatory markers. Magnetic resonance findings showed infiltrates and abscesses in the muscles around the hip. X-ray and computed tomography (CT) examination of the pelvis revealed bone irregularities near the pubic symphysis due to repeated avulsion injury to the medial group of the thigh muscles in two boys, and a fresh avulsion of the anterior inferior iliac spine in one boy. This patient developed reactive synovitis of the hip and iliopectineal bursitis. All three patients received intravenous antibiotic therapy, first with broad-spectrum and then with specific anti-staphylococcus antibiotics, for 2 to 3 months. Repeated puncture and drainage of the abscesses under CT guidance was performed in one patient; repeated surgery with abscess removal was necessary in two patients. The early diagnosis and combined conservative and surgical treatment prevented development of the third, septic stage of this disease which is commonly associated with serious complications. PMID- 22538109 TI - [Urgent pedal bypass as part of the treatment of an extensive lower-leg injury]. AB - The authors present the case of a subadventitial rupture of the popliteal artery and devastating injury to the crural arteries due to a crush injury to the proximal shank. The arterial injury was treated by urgent popliteo-pedal bypass grafting. Besides the surgical procedure, the authors also discuss revascularisation syndrome. The subadventitial rupture of the popliteal artery is a serious condition associated with a risk of high amputation. PMID- 22538110 TI - [Fracture-separation of the distal humeral epiphysis in a four-month-old infant: case report]. AB - We report the case of a 4-month-old infant with fracture-separation of the distal humeral epiphysis diagnosed on the basis of X-ray examination. Closed reduction was performed under ultrasound guidance. The effect of reduction was checked by computer tomography and magnetic resonance imaging and, under general anaesthesia, the arm was immobilised using a collar-and-cuff. Subsequently, percutaneous osteosynthesis with two 1.2-mm Kirschner wires through the radial condyle was carried out. The fracture was allowed to heal in a normal elbow position with plaster cast for 5 weeks. The duration of immobilisation had to be prolonged and removal of the wires postponed because the infant acquired a respiratory infection; the usual time for fracture union is 3 weeks. At 23 months after injury the outcome was excellent and the baby remained registered for a long-term follow-up. PMID- 22538111 TI - [Metatropic dysplasia as the cause of atlantoaxial instability, spinal stenosis and myelopathy: case report and literature review]. AB - We present the case of a patient, aged 4 years and 10 months, with metatropic dysplasia. The baby had repeated apnoeic episodes, bradycardia and cardiac arrests and was diagnosed with foramen magnum stenosis and atlantodental dislocation. The episodes were markedly associated with neck movements. Considering this clinical presentation, we performed laminectomy of the atlas, foramen magnum enlargement and decompression followed by dorsal C0-C2 stabilisa - tion with allogeneic bone chips. After the operation, apnoeic episodes did not recur. PMID- 22538112 TI - Talus fractures: a current concepts review of diagnoses, treatments, and outcomes. AB - The talus is the key articular segment linking the leg and foot, and as such, is subject to complex loads and may occasionally fracture. Fracture patterns provide clues to the underlying pathomechanics and energy of the injury, both of which can help guide treatment and suggest prognosis. Talus fractures have a wide variety of presentation from low-energy avulsion fractures of the lateral or posterior processes, to high-energy comminuted talar body fractures. Appropriate, expedient treatment provides the patient the best chance of obtaining a good functional outcome. Treatment relies on appropriate diagnosis, which hinges on clinical suspicion provided by the patient's account of pathomechanics, clinical examination, and radiological workup. This current concepts review discusses the pathomechanics, presentation, workup, treatment, and prognosis of fractures of the talar head, neck, body, lateral process, posterior process, and talar extrusions. Key words: talus, fracture, talar neck, talar head, talar body, lateral process, posterior process, talar extrusion, orthopaedic surgery, review. PMID- 22538113 TI - IMRT treatment of anal cancer with a scrotal shield. AB - The risk of sterility in males undergoing radiotherapy in the pelvic region indicates the use of a shielding device, which offers protection to the testes for patients wishing to maintain fertility. The use of such devices in the realm of intensity-modulated radiotherapy (IMRT) in the pelvic region can pose many obstacles during simulation, treatment planning, and delivery of radiotherapy. This work focuses on the development and execution of an IMRT plan for the treatment of anal cancer using a scrotal shielding device on a clinical patient. An IMRT plan was developed using Eclipse treatment planning system (Varian Medical Systems, Palo Alto, CA), using a wide array of gantry angles as well as fixed jaw and fluence editing techniques. When possible, the entire target volume was encompassed by the treatment field. When the beam was incident on the scrotal shield, the jaw was fixed to avoid the device and the collimator rotation optimized to irradiate as much of the target as possible. This technique maximizes genital sparing and allows minimal irradiation of the gonads. When this fixed-jaw technique was found to compromise adequate coverage of the target, manual fluence editing techniques were used to avoid the shielding device. Special procedures for simulation, imaging, and treatment verification were also developed. In vivo dosimetry was used to verify and ensure acceptable dose to the gonads. The combination of these techniques resulted in a highly conformal plan that spares organs and risk and avoids the genitals as well as entrance of primary radiation onto the shielding device. PMID- 22538114 TI - Validation of the French version of the alcohol, smoking and substance involvement screening test (ASSIST) in the elderly. AB - BACKGROUND: Substance use disorders seem to be an under considered health problem amongst the elderly. The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST), was developed by the World Health Organization to detect substance use disorders. The present study evaluates the psychometric properties of the French version of ASSIST in a sample of elderly people attending geriatric outpatient facilities (primary care or psychiatric facilities). METHODS: One hundred persons older than 65 years were recruited from clients attending a geriatric policlinic day care centre and from geriatric psychiatric facilities. Measures included ASSIST, Addiction Severity Index (ASI), Mini-International Neuropsychiatric Interview (MINI-Plus), Alcohol Use Disorders Identification Test (AUDIT), Revised Fagerstrom Tolerance Questionnaire-Smoking (RTQ) and MiniMental State(MMS). RESULTS: Concurrent validity was established with significant correlations between ASSIST scores, scores from ASI, AUDIT, RTQ, and significantly higher ASSIST scores for patients with a MINI-Plus diagnosis of abuse or dependence. The ASSIST questionnaire was found to have high internal consistency for the total substance involvement along with specific substance involvement as assessed by Cronbach's alpha, ranging from 0.66, to 0.89 . CONCLUSIONS: The findings demonstrate that ASSIST is a valid screening test for identifying substance use disorders in elderly. PMID- 22538115 TI - Reduced sulfate plasma concentrations in the BTBR T+tf/J mouse model of autism. AB - Clinical studies have shown that children diagnosed with autism show abnormal sulfate chemistry, which is critical for cellular and metabolic processes. To determine if the inbred BTBR T+tf/J mouse shows autism-relevant aberrations in sulfate chemistry, the present study examined plasma sulfate concentrations in BTBR T+tf/J, inbred C57BL/6J, and outbred CD-1 mice. Results showed that the BTBR T+tf/J mouse exhibits significantly lower plasma sulfate concentrations in comparison to both C57BL/6J and CD-1 mice. These results suggest that the BTBR mouse shows autism-relevant abnormalities in sulfate chemistry and may serve additional utility in examining the role of sulfate and sulfate-dependent systems in relation to autism-relevant behavioral aberrations. PMID- 22538117 TI - Krill powder increases liver lipid catabolism and reduces glucose mobilization in tumor necrosis factor-alpha transgenic mice fed a high-fat diet. AB - A promising approach to ameliorate obesity and obesity-associated diseases is the identification of new sources of dietary ingredients. The present study investigated the hepatic regulation of energy metabolism after feeding a powder isolated from Antarctic krill (Euphausia superba) in a transgenic mouse model of chronic inflammation (human tumor necrosis factor-alpha (hTNFalpha) mice) known to display unfavorable effects on lipid metabolism. Male hTNFalpha mice were fed high-fat diets (23.6%, w/w) with or without krill powder (6.4% lipids, 4.3% protein, w/w) for 6 weeks. Blood, liver lipid, and fatty acid composition, as well as hepatic enzyme activities and gene expressions, were determined. Krill powder fed mice displayed lowered hepatic and plasma triacylglycerol levels compared to mice on a high-fat casein diet. This was accompanied by down regulated hepatic expression of genes involved in lipogenesis and glycerolipid synthesis, and increased beta-oxidation activity. In addition, the krill powder diet lowered plasma levels of cholesterol, as well as hepatic gene expression of sterol regulatory element binding transcription factor 2 (SREBP2) and enzymes involved in cholesterol synthesis. Notably, genes involved in glycolysis and gluconeogenesis were significantly reduced in liver by the krill powder diet, while genes involved in oxidative phosphorylation and uncoupling were not affected. Krill powder also reduced endogenous TNFalpha in liver, indicating an anti-inflammatory effect. In a high-fat mouse model with disturbed lipid metabolism due to persistent hTNFalpha expression, krill powder showed significant effects on hepatic glucose- and lipid metabolism, resulting in an improved lipid status in liver and plasma. PMID- 22538116 TI - Prioritization of biomarker targets in human umbilical cord blood: identification of proteins in infant blood serving as validated biomarkers in adults. AB - BACKGROUND: Early diagnosis represents one of the best lines of defense in the fight against a wide array of human diseases. Umbilical cord blood (UCB) is one of the first easily available diagnostic biofluids and can inform about the health status of newborns. However, compared with adult blood, its diagnostic potential remains largely untapped. OBJECTIVES: Our goal was to accelerate biomarker research on UCB by exploring its detectable protein content and providing a priority list of potential biomarkers based on known proteins involved in disease pathways. METHODS: We explored cord blood serum proteins by profiling a UCB pool of 12 neonates with different backgrounds using a combination of isoelectric focusing and liquid chromatography coupled with matrix assisted laser desorption/ionization tandem mass spectrometry (MALDI-MS/MS) and by comparing results with information contained in metabolic and disease databases available for adult blood. RESULTS: A total of 1,210 UCB proteins were identified with a protein-level false discovery rate of ~ 5% as estimated by naive target-decoy and MAYU approaches, signifying a 6-fold increase in the number of UCB proteins described to date. Identified proteins correspond to 138 different metabolic and disease pathways and provide a platform of mechanistically linked biomarker candidates for tracking disruptions in cellular processes. Moreover, among the identified proteins, 38 were found to be approved biomarkers for adult blood. CONCLUSIONS: The results of this study advance current knowledge of the human cord blood serum proteome. They showcase the potential of UCB as a diagnostic medium for assessing infant health by detection and identification of candidate biomarkers for known disease pathways using a global, nontargeted approach. These biomarkers may inform about mechanisms of exposure-disease relationships. Furthermore, biomarkers approved by the U.S. Food and Drug Administration for screening in adult blood were detected in UCB and represent high-priority targets for immediate validation. PMID- 22538122 TI - Frequency-domain EEG source analysis for acute tonic cold pain perception. AB - OBJECTIVE: To investigate electrocortical responses to tonic cold pain by frequency-domain electroencephalogram (EEG) source analysis, and to identify potential electrocortical indices of acute tonic pain. METHODS: Scalp EEG data were recorded from 26 healthy subjects under tonic cold pain (CP) and no-pain control (NP) conditions. EEG power spectra and the standardized low-resolution brain electromagnetic tomography (sLORETA) localized EEG cortical sources were compared between the two conditions in five frequency bands: 1-4 Hz, 4-8 Hz, 8-12 Hz, 12-18 Hz and 18-30 Hz. RESULTS: In line with the EEG power spectral results, the source power significantly differed between the CP and NP conditions in 8-12 Hz (CPNP) in extensive brain regions. Besides, there were also significantly different 4-8 Hz and 12-18 Hz source activities between the two conditions. Among the significant source activities, the left medial frontal and left superior frontal 4-8 Hz activities, the anterior cingulate 8-12 Hz activity and the posterior cingulate 12-18 Hz activity showed significant negative correlations with subjective pain ratings. CONCLUSIONS: The brain's perception of tonic cold pain was characterized by cortical source power changes across different frequency bands in multiple brain regions. Oscillatory activities that significantly correlated with subjective pain ratings were found in the prefrontal and cingulate regions. SIGNIFICANCE: These findings may offer useful measures for objective pain assessment and provide a basis for pain treatment by modulation of neural oscillations at specific frequencies in specific brain regions. PMID- 22538119 TI - Percutaneous cryoablation of metastatic renal cell carcinoma for local tumor control: feasibility, outcomes, and estimated cost-effectiveness for palliation. AB - PURPOSE: To assess complications, local tumor recurrences, overall survival (OS), and estimates of cost-effectiveness for multisite cryoablation (MCA) of oligometastatic renal cell carcinoma (RCC). MATERIALS AND METHODS: A total of 60 computed tomography- and/or ultrasound-guided percutaneous MCA procedures were performed on 72 tumors in 27 patients (three women and 24 men). Average patient age was 63 years. Tumor location was grouped according to common metastatic sites. Established surgical selection criteria graded patient status. Median OS was determined by Kaplan-Meier method and defined life-years gained (LYGs). Estimates of MCA costs per LYG were compared with established values for systemic therapies. RESULTS: Total number of tumors and cryoablation procedures for each anatomic site are as follows: nephrectomy bed, 11 and 11; adrenal gland, nine and eight; paraaortic, seven and six; lung, 14 and 13; bone, 13 and 13; superficial, 12 and nine; intraperitoneal, five and three; and liver, one and one. A mean of 2.2 procedures per patient were performed, with a median clinical follow-up of 16 months. Major complication and local recurrence rates were 2% (one of 60) and 3% (two of 72), respectively. No patients were graded as having good surgical risk, but median OS was 2.69 years, with an estimated 5-year survival rate of 27%. Cryoablation remained cost-effective with or without the presence of systemic therapies according to historical cost comparisons, with an adjunctive cost effectiveness ratio of $28,312-$59,554 per LYG. CONCLUSIONS: MCA was associated with very low morbidity and local tumor recurrence rates for all anatomic sites, with apparent increased OS. Even as an adjunct to systemic therapies, MCA appeared cost-effective for palliation of oligometastatic RCC. PMID- 22538121 TI - A novel use of 2-octyl-cyanoacrylate: controlling post-hemodialysis site hemorrhage. AB - BACKGROUND: A common complication of hemodialysis is bleeding from the dialysis site. DISCUSSION: To demonstrate the use of 2-octyl-cyanoacrylate in controlling venous bleeding associated with hemodialysis access. CONCLUSION: 2-octyl cyanoacrylate is effective in stopping venous bleeding from hemodialysis sites. PMID- 22538120 TI - Amphetamine abuse in emergency department patients undergoing psychiatric evaluation. AB - BACKGROUND: Amphetamine abuse accounts for numerous Emergency Department (ED) visits and is often associated with psychiatric disease, with many patients requiring involuntary psychiatric hold placement. It is a common practice in EDs to obtain a urine drug screen (UDS) as part of the "medical clearance" process for psychiatric patients. However, the prevalence of amphetamine-positive UDS in ED patients with psychiatric disease is unknown, as is the relationship of the UDS test to the final patient disposition. OBJECTIVES: The objectives of this study were to determine the prevalence of amphetamine-positive UDS in ED patients undergoing psychiatric evaluation, and whether amphetamine-positive UDS is associated with involuntary psychiatric hold placement. METHODS: This was a retrospective study of adult patients seen in a single urban university ED who had a psychiatric evaluation and a UDS over a 1-year period. Eligible patients had results of the UDS, placement of involuntary holds, past psychiatric history, chief complaint, insurance status, and demographic information recorded. Regression analysis was performed, adjusting for the listed covariates, to evaluate the independent association of amphetamine-positive UDS and involuntary psychiatric hold placement. RESULTS: A total of 1207 patients were included for analysis. Amphetamine-positive UDS were found in 14.8% of patients. Multivariate analysis showed no association of a psychiatric hold due to presence of amphetamines on UDS (adjusted odds ratio [OR] 0.76, 95% confidence interval [CI] 0.55-1.05, p=0.1). The only significant factor in placement of an involuntary hold was a past psychiatric history (adjusted OR 1.8, 95% CI 1.2-2.7, p=0.005). CONCLUSIONS: The prevalence of amphetamine-positive UDS was high in the study population; however, there was no independent association of amphetamine-positive UDS with involuntary psychiatric hospitalization. PMID- 22538123 TI - LC-ESI-MS method for the monitoring of Abl 1 tyrosine kinase. AB - A liquid chromatography-electrospray ionization-mass spectrometric (LC-ESI-MS) method was developed and validated to study Abl 1 tyrosine kinase. An online desalting system was adopted, and a transformation of the ratio of product to substrate instead of a deuterated internal standard was introduced to calculate the concentration of product. In this study, the substrate used was Abltide (KKGEAIYAAPFA-NH2). The detection was performed by selected ion monitoring (SIM) mode via positive ESI interface. Chromatographic separation was achieved on a C18 column using an isocratic mobile phase system. The limit of quantification (LOQ) was 10nM for the product and 25 nM for the substrate. The simple ratios of product to substrate maintained a linear relationship (R2=0.9997) over the ratio of 0-50% product. Intra- and inter-day precision was less than 10% and accuracy was from -1.6 to +5.3%. The validated method was applied to the Abl 1 kinase kinetic study and the K(m) and V(max) constants obtained for Abltide were 34.78 MUM and 5.563 MUmol/mg/min and for adenosine triphosphate (ATP) were 43.61 MUM and 5.906 MUmol/mg/min. The enzymatic reaction of Abl 1 tyrosine kinase belongs to ternary-complex mechanism. PMID- 22538127 TI - Journal of Diabetes Science and Technology: evolution of an electronic journal. PMID- 22538124 TI - Influence of the Fukushima Dai-ichi nuclear accident on Spanish environmental radioactivity levels. AB - This paper presents measurements of the effect of the atmospheric radioactive release from the Fukushima Dai-ichi nuclear power station at three sites belonging to the Spanish environmental monitoring system. Measured values varied depending on the locations of the sites in Spain and their respective climatic characteristics. (134)Cs, (136)Cs, (137)Cs, (131)I, and (132)Te activity concentrations in filter samples were studied and associated levels of (131)I fallout were estimated from wet and dry deposition. Particulate aerosol activity concentrations ranges, in MUBq/m(3), were 1.63-3080 ((131)I), 2.8-690 ((137)Cs), 1.3-620 ((134)Cs) and 3.6-330 ((132)Te), while the associated (131)I fallout was roughly estimated to be less than 20 Bq/m(2), Gaseous (131)I was also detected and the (131)I-gaseous/(131)I-total ratio increased at the three stations from approximately 0.75 at the end of March to 0.85-0.9 during the first few days of April. Finally, the presence of (131)I in some crucial parts of the food chain was also studied. (131)I was detected in samples from goat's and cow's milk (maximum levels of 1.11 Bq/L) and in broadleaf plants (maximum level 1.42 Bq/kg). PMID- 22538118 TI - Ginger consumption enhances the thermic effect of food and promotes feelings of satiety without affecting metabolic and hormonal parameters in overweight men: a pilot study. AB - Evidence suggests that ginger consumption has anti-inflammatory, anti hypertensive, glucose-sensitizing, and stimulatory effects on the gastrointestinal tract. This study assessed the effects of a hot ginger beverage on energy expenditure, feelings of appetite and satiety and metabolic risk factors in overweight men. Ten men, age 39.1+/-3.3 y and body mass index (BMI) 27.2+/-0.3 kg/m(2), participated in this randomized crossover study. Resting state energy expenditure was measured using indirect calorimetry and for 6h after consumption of a breakfast meal with or without 2 g ginger powder dissolved in a hot water beverage. Subjective feelings of satiety were assessed hourly using visual analog scales (VAS) and blood samples were taken fasted and for 3 h after breakfast consumption. There was no significant effect of ginger on total resting energy expenditure (P=.43) or respiratory quotient (P=.41). There was a significant effect of ginger on thermic effect of food (ginger vs control=42.7+/ 21.4 kcal/d, P=.049) but the area under the curve was not different (P=.43). VAS ratings showed lower hunger (P=.002), lower prospective food intake (P=.004) and greater fullness (P=.064) with ginger consumption versus control. There were no effects of ginger on glucose, insulin, lipids, or inflammatory markers. The results, showing enhanced thermogenesis and reduced feelings of hunger with ginger consumption, suggest a potential role of ginger in weight management. Additional studies are necessary to confirm these findings. PMID- 22538126 TI - An in vivo role of bone morphogenetic protein-6 in aldosterone production by rat adrenal gland. AB - Aldosterone is synthesized in the zona glomerulosa of the adrenal cortex. We previously reported the presence of a functional BMP system including BMP-6 in human adrenocortical cells. BMP-6 contributes to Ang II-induced aldosterone production by activating Smad signaling, in which endogenous BMP-6 action is negatively controlled by Ang II in vitro. In the present study, we examined the in vivo role of BMP-6 in regulation of aldosterone by neutralizing endogenous BMP 6 in rats treated with immunization against BMP-6. Three-week-old male rats were actively immunized with rat mature BMP-6 antigen conjugated with keyhole limpet hemocyanin (KLH). The immunization treatment had no effect on bilateral adrenal weight or its ratio to body weight. Urinary aldosterone excretion was time dependently increased during the 8-week observation period in the control group. Of note, the level of urinary aldosterone excretion in BMP-6-KLH-immunized rats was significantly reduced compared to that in the control group, suggesting that endogenous BMP-6 contributes to the induction of aldosterone production in vivo. Moreover, the level of urinary aldosterone/creatinine after 8-week treatment was significantly lowered by treatment with BMP-6-KLH. In contrast, with chronic Ang II treatment, urinary aldosterone and creatinine-corrected values at 8 weeks were not significantly different between the two groups, suggesting that the effects of BMP-6-KLH were impaired under the condition of chronic treatment with Ang II. The mRNA levels of Cyp11b2, but not those of Star, P450scc and 3betahsd2, were significantly decreased in adrenal tissues isolated from BMP-6-KLH-immunized rats after 8-week treatment. Furthermore, the ratio of plasma aldosterone level to corticosterone was significantly decreased by immunization with BMP-6-KLH. Collectively, the results indicate that endogenous BMP-6 is functionally linked to aldosterone synthesis by the zona glomerulosa in the adrenal cortex in vivo. PMID- 22538128 TI - Introduction to human factors. AB - This paper provides an introduction to "human factors engineering," an applied science that seeks to optimize usability and safety of systems. Human factors engineering pursues this goal by aligning system design with the perceptual, cognitive, and physical capabilities of users. Human factors issues loom large in the diabetes management domain because patients and health care professionals interact with a complex variety of systems, including medical device hardware and software, which are themselves embedded within larger systems of institutions, people, and processes. Usability considerations must be addressed in these systems and devices to ensure safe and effective diabetes management. PMID- 22538131 TI - Blood glucose meters and accessibility to blind and visually impaired people. AB - In 2007, five blood glucose meters (BGMs) were introduced with integrated speech output necessary for use by persons with vision loss. One of those five meters had fully integrated speech output, allowing a person with vision loss independence in accessing all features and functions of the meter. In comparison, 13 BGMs with integrated speech output were available in 2011. Accessibility attributes of these 11 meters were tabulated and product design features examined. All 13 meters were found to be usable by persons with vision loss to obtain a blood glucose measurement. However, only 4 of them featured the fully integrated speech output necessary for a person with vision loss to access all features and functions independently. PMID- 22538125 TI - Modeling nucleic acids. AB - Nucleic acids are an important class of biological macromolecules that carry out a variety of cellular roles. For many functions, naturally occurring DNA and RNA molecules need to fold into precise three-dimensional structures. Due to their self-assembling characteristics, nucleic acids have also been widely studied in the field of nanotechnology, and a diverse range of intricate three-dimensional nanostructures have been designed and synthesized. Different physical terms such as base-pairing and stacking interactions, tertiary contacts, electrostatic interactions and entropy all affect nucleic acid folding and structure. Here we review general computational approaches developed to model nucleic acid systems. We focus on four key areas of nucleic acid modeling: molecular representation, potential energy function, degrees of freedom and sampling algorithm. Appropriate choices in each of these key areas in nucleic acid modeling can effectively combine to aid interpretation of experimental data and facilitate prediction of nucleic acid structure. PMID- 22538129 TI - Implications of the new Food and Drug Administration draft guidance on human factors engineering for diabetes device manufacturers. AB - This article discusses the implications of the new Food and Drug Administration's draft guidance on human factors and usability engineering for the development of diabetes-related devices. Important considerations include the challenge of identifying users, when the user population is so dramatically broad, and the challenge of identifying use environments when the same can be said for use environments. Another important consideration is that diabetes-related devices, unlike many other medical devices, are used constantly as part of the user's lifestyle--adding complexity to the focus on human factors and ease of use emphasized by the draft guidance. PMID- 22538134 TI - The role of human factors in the design and development of an insulin pump. AB - This article discusses human factors (HF) processes and how they are applied during the development of a medical device to minimize the risk that the user interface design could lead to patient errors, adverse events, and product recalls. This process is best defined as "prevention through design." The HF design process is exemplified by three distinct phases: (1) preliminary analysis, (2) formative design evaluation and modification, and (3) design validation. Additional benefits of employing HF principles during medical device development are briefly reviewed, including reduced patient risk by eliminating design flaws, increased patient adherence through the reduction in the complexity of therapeutic regimes, and reduced likelihood for product recalls. PMID- 22538137 TI - Postprandial glucose monitoring further improved glycemia, lipids, and weight in persons with type 2 diabetes mellitus who had already reached hemoglobin A1c goal. AB - BACKGROUND: Postprandial hyperglycemia contributes to poor glucose control and is associated with increased cardiovascular risk in type 2 diabetes mellitus (T2DM). The objective of the study was to determine the effect of postprandial self monitoring of blood glucose (pp-SMBG) on glucose control, lipids, body weight, and cardiovascular events. METHOD: Subjects with T2DM hemoglobin A1c (A1C) between 6.5 to 7.0% were randomized into the study group (at least two pp-SMBG a day and dietary modification based on glucose readings) and control group (dietary modification based on glucose readings but no mandatory pp-SMBG) for a 6 month, observational study. Oral antidiabetic drugs or insulin regimen was unchanged in either group if A1C remained less than 7.0% during the study. End points included A1C, lipids, body weight, and cardiovascular events. RESULTS: One hundred sixty-nine subjects, mean age 63 years, and body weight 88 kg were recruited. Hemoglobin A1c, weight, low-density lipoprotein (LDL), and triglycerides (TGs) were similar in the groups at baseline. By the end of 6 months, A1C (6.7 +/- 0.1 to 6.4 +/- 0.1%, p < .05), body weight (88.5 +/- 7.3 to 85.2 +/- 6.3 kg, p < .05), LDL (92.3 +/- 2 8.4 to 81.1 +/- 22.6 mg/dl, p < .05), and TGs (141 +/- 21 to 96 +/- 17 mg/dl, p < .05) decreased in the study group, but did not change in the control group. No cardiovascular events were observed in either group during the 6-month study period. CONCLUSIONS: In T2DM subjects who had already reached their A1C goal, pp-SMBG at least twice a day was associated with further improvement in glycemia, lipids, and weight, as well as exercise and dietary habit. We assume that lifestyle modification promoted by postprandial hyperglycemia awareness may underlie these findings. These results substantiate the importance of implementing pp-SMBG into lifestyle modification, and emphasize that pp-SMBG is critical in the control of T2DM. PMID- 22538138 TI - Glucose measurement of intensive care unit patient plasma samples using a fixed wavelength mid-infrared spectroscopy system. AB - OBJECTIVE: Glycemic control is a rapidly developing field in intensive care medicine with the aim of reducing mortality, morbidity, and cost. Current intensive care unit (ICU) glucose measurement technologies are susceptible to interference from medications, volume expanders, and other substances present in critically ill patients. We hypothesized that a fixed-wavelength mid-infrared (mid-IR) spectroscopy system would be accurate for measuring glucose levels of ICU patients. RESEARCH DESIGN AND METHODS: This is a prospective investigation of plasma samples from two different institutions treating a heterogeneous population of ICU patients. The first 292 samples were collected from 86 patients admitted to Stamford Hospital, and the next 352 samples were collected from 75 patients from three ICUs at the University of Maryland. Plasma samples were measured on a Fourier-transform infrared or a proprietary spectrometer, with a glucose prediction algorithm to correct for spectral interference, which were compared with reference measurements taken using a YSI 2300 glucose analyzer. RESULTS: Glucose values ranged from 24 to 343 mg/dl. Numerous medications and injury/disease states were observed in the patient populations, with metoprolol, fentanyl, and multiple organ failure the most prevalent. Despite these interferents, there was a high correlation (r >= 0.94) and low standard error (<=12.8 mg/dl) between the predicted glucose values and those of the YSI 2300 STAT Plus reference instrument in the three studies. A total of 95.1% of the 644 values in the three studies met International Organization for Standardization 15197 criteria. CONCLUSION: These results suggest that a fixed-wavelength mid-IR spectrometer can measure glucose accurately in the plasma of ICU patients. PMID- 22538132 TI - Accessibility attributes of blood glucose meter and home blood pressure monitor displays for visually impaired persons. AB - The vast majority of diabetes-related self-management technology utilizes small visual displays (SVDs) that often produce a low level of contrast and suffer from high levels of reflection (glare). This is a major accessibility issue for the 3.5 million Americans with diabetes who have reduced vision. The purpose of this article is to gather comparative data on the key display attributes of the SVDs used in blood glucose meters (BGMs) and home blood pressure monitors (HBPMs) on the market today and determine which displays offer the best prospect for being accessible to people with reduced vision. Nine BGMs and eight HBPMs were identified for this study on the basis of amount of devices sold, fullfunctionality speech output, and advanced display technologies. An optical instrumentation system obtained contrast, reflection (glare), and font height measurements for all 17 displays. The contrast, reflection, and font-height values for the BGMs and HBPMs varied greatly between models. The Michelson contrast values for the BGMs ranged from 11% to 98% and font heights ranged 0.39 1.00 in. for the measurement results. The HBPMs had Michelson contrast values ranging 55-96% and font height ranging 0.28-0.94 in. for the measurement results. Due largely to the lack of display design standards for the technical requirements of SVDs, there is tremendous variability in the quality and readability of BGM and HBPM displays. There were two BGMs and one HBPM that exhibited high-contrast values and large font heights, but most of the devices exhibited either poor contrast or exceptionally high reflection. PMID- 22538130 TI - Scientific reasons for including persons with disabilities in clinical and translational diabetes research. AB - Despite disparities in health problems and outcomes, people with disabilities are underrepresented in diabetes research. This results in a lack of evidence-based knowledge regarding best approaches in caring for this population. This article addresses the need for research that includes people with disabilities and describes the common reasons persons with disabilities are not included in research, including scientists' concerns regarding threats to a study's internal validity and cost. Arguments are provided as to how involving people with disabilities in research will improve our science and reduce disparities in this population. In addition to the ethical reasons for including persons with disabilities in research, the ability to generalize study findings to this population and thus speed our development and translation of this knowledge for use by clinicians is discussed. The bias in study conclusions that arise from study samples that do not include persons with disabilities and its possible effect on care delivery are presented. Two strategies that researchers can use to increase the inclusion of persons with disabilities in research are described: (1) Universal Design of Research and (2) intervention optimization study designs. Universal Design of Research includes research design processes such as the use of multisensory formats for recruiting participants, approaches to designing and presenting research instruments and interventions, and methods of data collection to promote the inclusion of participants with a wide range of abilities in research studies. Intervention optimization study designs offer an efficient way for scientists to rapidly build the most potent interventions for a wide range of people, including those with disabilities participating in mainstream research. PMID- 22538133 TI - Creating low vision and nonvisual instructions for diabetes technology: an empirically validated process. AB - INTRODUCTION: Nearly 20% of the adults with diagnosed diabetes in the United States also have visual impairment. Many individuals in this group perform routine diabetes self-management tasks independently, often using technology that was not specifically designed for use by people with visual impairment (e.g., insulin pumps and pens). Equitable care for persons with disabilities requires providing instructions in formats accessible for nonreaders. However, instructions in accessible formats, such as recordings, braille, or digital documents that are legible to screen readers, are seldom available. METHOD: This article includes a summary of existing guidelines for creating accessible documents. The guidelines are followed by a description of the production of accessible nonvisual instructions for use of insulin pens used in a study of dosing accuracy. The study results indicate that the instructions were used successfully by 40 persons with visual impairment. DISCUSSION AND CONCLUSIONS: Instructions in accessible formats can increase access to the benefits of diabetes technology for persons with visual impairment. Recorded instructions may also be useful to sighted persons who do not read well, such as those with dyslexia, low literacy, or who use English as a second language. Finally, they may have important benefits for fully sighted people who find it easier to learn to use technology by handling the equipment while listening to instructions. Manufacturers may also benefit from marketing to an increased pool of potential users. PMID- 22538141 TI - Clinical performance of a device that applies local heat to the insulin infusion site: a crossover study. AB - BACKGROUND: Fast-acting insulin analogs have been available since 1996. The absorption rate of these insulins is still too slow to mimic the physiological insulin action in healthy subjects. This study investigates the clinical performance of InsuPatchTM, a local skin-heating device, on postprandial glucose excursion. METHODS: Twenty-four type 1 diabetes mellitus subjects on continuous subcutaneous insulin infusion were included in this crossover study [10 male, 14 female, age: 43.5 +/- 11.3 years, diabetes duration: 18.3 +/- 10.5 years, glycosylated hemoglobin: 7.4 +/- 0.8%, body mass index: 25.0 +/- 3.0 kg/m(2) (mean +/- standard deviation)]. The impact of local skin heating was measured by dividing the two-hour area under the curve by integration time (AUC/t(120)) for blood glucose (BG) above baseline after two standardized breakfast and dinner meal pairs (with and without heating) per subject. For the first breakfast pair, venous insulin concentration was also measured. RESULTS: A significant reduction was found for the AUC/t(120) after breakfast and after dinner meals (42 breakfast meal pairs, AUC/t(120) not heated 66.4 +/- 32.8 mg/dl vs heated 56.8 +/- 34.0 mg/dl, p = .017; 38 dinner meal pairs, AUC/t(120) not heated 30.8 +/- 31.0 mg/dl vs heated 18.4 +/- 23.9 mg/dl, p = .0028). The maximum venous insulin concentration with heating was 27% higher than without heating (n = 23). The number of hypoglycemic events on days with heating (n = 9) was similar to the number of days without heating (n = 13). CONCLUSIONS: Local heating of the skin around the infusion site significantly reduced postprandial BG by enhancing insulin absorption. The heating device was well tolerated, and it could facilitate development of closed-loop systems. PMID- 22538143 TI - Improving patient acceptance of insulin therapy by improving needle design. AB - Improved needle designs could increase patient compliance with insulin therapy. In this issue of Journal of Diabetes Science and Technology, Hirsch and colleagues assessed patient pain and preference for a 5-bevel needle design among diabetes patients. A blinded comparison with traditional 3-bevel needles yielded no significant difference, but patients preferred the 5-bevel needle in unblinded home injection and clinical insertion studies. This suggests that important subjective/contextual factors contribute to preference in conjunction with the fundamental needle design change. While 5-bevel needles may increase patient acceptance, more dramatic changes of needle design, such as microneedles, could enable still greater patient acceptance through reduced pain as well as improved insulin pharmacokinetics. PMID- 22538139 TI - Prediction and prevention of treatment-related inpatient hypoglycemia. AB - BACKGROUND: Prolonged severe hypoglycemia (SH) in hospitalized patients is associated with increased morbidity and mortality. This study was undertaken to identify risk factors for SH, to apply that knowledge to the development of a prediction algorithm, and to institute a prevention program at a tertiary medical center. METHODS: We analyzed SH events for 172 patients and developed computer algorithms to predict SH that were tested on a population of 3028 inpatients who were found to have blood glucose (BG) <90 mg/dl during their hospital stay. Variables with significant bivariate associations were entered into partition analyses to identify interactions. Logistic regression was performed by calculating parameters related to the odds of hypoglycemia below each cut point. Sensitivity and specificity were determined at various cut points. The cut points resulting in 50% sensitivity for each hypoglycemia level were determined. These algorithms were tested against the initial 172 adjudicated patients. RESULTS: Variables related to the BG <40 mg/dl cut off point were basal and adjustment scale insulin doses, weight, and creatinine clearance, while variables related to the 60 mg/dl and 70 mg/dl cut points were basal, prandial, and adjustment scale insulin doses, weight, creatinine clearance, and sulfonylurea use. The 50% sensitivity cut point developed using the <70 mg/dl algorithm correctly identified 71% of the adjudicated cases, while the <60 mg/dl and <40 mg/dl algorithms identified 70% and 55% respectively. CONCLUSIONS: A validated prediction algorithm for SH can aid in the identification of patients at risk for SH and may be useful in the development of prevention strategies. PMID- 22538136 TI - Insulin fibrillation and protein design: topological resistance of single-chain analogs to thermal degradation with application to a pump reservoir. AB - Insulin is susceptible to thermal fibrillation, a misfolding process that leads to nonnative cross-beta assembly analogous to pathological amyloid deposition. Pharmaceutical formulations are ordinarily protected from such degradation by sequestration of the susceptible monomer within native protein assemblies. With respect to the safety and efficacy of insulin pumps, however, this strategy imposes an intrinsic trade-off between pharmacokinetic goals (rapid absorption and clearance) and the requisite physical properties of a formulation (prolonged shelf life and stability within the reservoir). Available rapid-acting formulations are suboptimal in both respects; susceptibility to fibrillation is exacerbated even as absorption is delayed relative to the ideal specifications of a closed-loop system. To circumvent this molecular trade-off, we exploited structural models of insulin fibrils and amyloidogenic intermediates to define an alternative protective mechanism. Single-chain insulin (SCI) analogs were shown to be refractory to thermal fibrillation with maintenance of biological activity for more than 3 months under conditions that promote the rapid fibrillation and inactivation of insulin. The essential idea exploits an intrinsic incompatibility between SCI topology and the geometry of cross-beta assembly. A peptide tether was thus interposed between the A- and B-chains whose length was (a) sufficiently long to provide the "play" needed for induced fit of the hormone on receptor binding and yet (b) sufficiently short to impose a topological barrier to fibrillation. Our findings suggest that ultrastable monomeric SCI analogs may be formulated without protective self-assembly and so permit simultaneous optimization of pharmacokinetics and reservoir life. PMID- 22538135 TI - Intrinsic fibrillation of fast-acting insulin analogs. AB - BACKGROUND: Aggregation of insulin into insoluble fibrils (fibrillation) may lead to complications for diabetes patients such as reduced insulin potency, occlusion of insulin delivery devices, or potentially increased immunological potential. Even after extensive investigation of fibril formation in regular human insulin, there are little published data about the intrinsic fibrillation of fast-acting analogs. This article investigates and compares the intrinsic fibrillation of three fast-acting insulin analogs--lispro, aspart, and glulisine--as a function of their primary protein structure and exclusive of the stabilizing excipients that are added to their respective commercial formulations. METHODS: The insulin analogs underwent a buffer exchange into phosphate-buffered saline to remove formulation excipients and then were heated and agitated to characterize intrinsic fibrillation potentials devoid of excipient stabilizing effects. Different analytical methods were used to determine the amount of intrinsic fibrillation for the analogs. After initial lag times, intrinsic fibrillation was detected by an amyloid-specific stain. Precipitation of insulin was confirmed by ultraviolet analysis of soluble insulin and gravimetric measurement of insoluble insulin. Electron microscopy showed dense fibrous material, with individual fibrils that are shorter than typical insulin fibrils. Higher resolution kinetic analyses were carried out in 96-well plates to provide more accurate measures of lag times and fibril growth rates. RESULTS: All three analogs exhibited longer lag times and slower intrinsic fibrillation rates than human insulin, with glulisine and lispro rates slower than aspart. This is the first study comparing the intrinsic fibrillation of fast-acting insulin analogs without the stabilizing excipients found in their commercial formulations. CONCLUSIONS: Data show different intrinsic fibrillation potentials based on primary molecular structures when the formulation excipients that are critical for stability are absent. Understanding intrinsic fibrillation potential is critical for evaluating insulin analog stability and device compatibility. PMID- 22538144 TI - Performance of a glucose meter with a built-in automated bolus calculator versus manual bolus calculation in insulin-using subjects. AB - BACKGROUND: Patients consider multiple parameters in adjusting prandial insulin doses for optimal glycemic control. Difficulties in calculations can lead to incorrect doses or induce patients to administer fixed doses, rely on empirical estimates, or skip boluses. METHOD: A multicenter study was conducted with 205 diabetes subjects who were on multiple daily injections of rapid/ short-acting insulin. Using the formula provided, the subjects manually calculated two prandial insulin doses based on one high and one normal glucose test result, respectively. They also determined the two doses using the FreeStyle InsuLinx Blood Glucose Monitoring System, which has a built-in, automated bolus calculator. After dose determinations, the subjects completed opinion surveys. RESULTS: Of the 409 insulin doses manually calculated by the subjects, 256 (63%) were incorrect. Only 23 (6%) of the same 409 dose determinations were incorrect using the meter, and these errors were due to either confirmed or potential deviations from the study instructions by the subjects when determining dose with meter. In the survey, 83% of the subjects expressed more confidence in the meter calculated doses than the manually calculated doses. Furthermore, 87% of the subjects preferred to use the meter than manual calculation to determine prandial insulin doses. CONCLUSIONS: Insulin-using patients made errors in more than half of the manually calculated insulin doses. Use of the automated bolus calculator in the FreeStyle InsuLinx meter minimized errors in dose determination. The patients also expressed confidence and preference for using the meter. This may increase adherence and help optimize the use of mealtime insulin. PMID- 22538142 TI - Impact of a modified needle tip geometry on penetration force as well as acceptability, preference, and perceived pain in subjects with diabetes. AB - BACKGROUND: Multiple factors impact subcutaneous insulin injection pain. Injection devices [e.g., syringe or pen needle (PN)] affect pain due to needle length, diameter, needle polishing and lubrication, and needle tip geometry. METHODS: We evaluated a modified 5-bevel PN tip in 32 G * 4 mm 31 G * 5 mm and 8 mm PNs vs the equivalent marketed 3-bevel PNs in laboratory penetration force testing, as well as in insulin-taking subjects for overall acceptability, comparative pain, and preference. The clinical tests were done in three ways: paired insertions with the subjects blinded to PN tip geometry, after brief at home use of 5-bevel PNs, and again with subjects informed about each needle's tip geometry in paired insertions. RESULTS: Average penetration force in a skin substitute was 23% lower with the 5-bevel PNs vs similar 3-bevel PNs (p <= 0.01). In blinded testing and after at-home use, patients rated the 5-bevel needle as acceptable. After shortterm home use, patients rated the 5-bevel PN less painful and preferable to their usual PN (both p < 0.01). In paired, informed testing, the 5-bevel PN was less painful and preferred to subjects' currently used needles (p <= 0.01) and to other marketed PNs (p < 0.01). CONCLUSIONS: Needle tip geometry affects penetration force. When blinded, patients did not distinguish differences in PN tip geometry with fine-gauge PN insertions. A 5-bevel needle tip is perceived as less painful and is preferred by subjects following home use for usual injections. Similar results occurred when patients were informed that they were using a needle with a modified tip. PMID- 22538140 TI - Mobile phone-based video messages for diabetes self-care support. AB - BACKGROUND: This study examined whether mobile phone-based, one-way video messages about diabetes self-care improve hemoglobin A1c (A1C) and self monitoring of blood glucose (SMBG). METHODS: This was a 1-year prospective randomized trial with two groups. The active intervention lasted 6 months. The study enrolled 65 people with A1C >8.0% who were established (>6 months) patients in the endocrinology clinics of the Walter Reed Health Care System. Participants were randomized to receive "usual care" or self-care video messages from their diabetes nurse practitioner. Video messages were sent daily to cell phones of study participants. Hemoglobin A1c and SMBG data were collected at 0, 3, 6, 9, and 12 months. RESULTS: Participants who received the messages had a larger rate of decline in A1C than people who received usual care (0.2% difference over 12 months, adjusting for covariates; p = .002 and p = .004 for the interaction between time and group and for the quadratic effect of time by group, respectively). Hemoglobin A1c decline was greatest among participants who received video messages and viewed >10 a month (0.6% difference over 12 months, adjusting for covariates; p < .001 for the interaction between time and group and the quadratic effect). Self-monitoring of blood glucose metrics were not related to the intervention. CONCLUSIONS: A one-way intervention using mobile phone-based video messages about diabetes self-care can improve A1C. Engagement with the technology is an important predictor of its success. This intervention is simple to implement and sustain. PMID- 22538145 TI - Commentary on "Performance of a glucose meter with a built-in automated bolus calculator versus manual bolus calculation in insulin-using subjects". AB - Since the early 2000s, there has been an exponentially increasing development of new diabetes-applied technology, such as continuous glucose monitoring, bolus calculators, and "smart" pumps, with the expectation of partially overcoming clinical inertia and low patient compliance. However, its long-term efficacy in glucose control has not been unequivocally proven. In this issue of Journal of Diabetes Science and Technology, Sussman and colleagues evaluated a tool for the calculation of the prandial insulin dose. A total of 205 insulin-treated patients were asked to compute a bolus dose in two simulated conditions either manually or with the bolus calculator built into the FreeStyle InsuLinx meter, revealing the high frequency of wrong calculations when performed manually. Although the clinical impact of this study is limited, it highlights the potential implications of low diabetesrelated numeracy in poor glycemic control. Educational programs aiming to increase patients' empowerment and caregivers' knowledge are needed in order to get full benefit of the technology. PMID- 22538147 TI - Interindividual and intraindividual variations in postprandial glycemia peak time complicate precise recommendations for self-monitoring of glucose in persons with type 1 diabetes mellitus. AB - BACKGROUND: In glycemic control, postprandial glycemia may be important to monitor and optimize as it reveals glycemic control quality, and postprandial hyperglycemia partly predicts late diabetic complications. Self-monitoring of blood glucose (SMBG) may be an appropriate technology to use, but recommendations on measurement time are crucial. METHOD: We retrospectively analyzed interindividual and intraindividual variations in postprandial glycemic peak time. Continuous glucose monitoring (CGM) and carbohydrate intake were collected in 22 patients with type 1 diabetes mellitus. Meals were identified from carbohydrate intake data. For each meal, peak time was identified as time from meal to CGM zenith within 40-150 min after meal start. Interindividual (one-way Anova) and intraindividual (intraclass correlation coefficient) variation was calculated. RESULTS: Nineteen patients were included with sufficient meal data quality. Mean peak time was 87 +/- 29 min. Mean peak time differed significantly between patients (p = 0.02). Intraclass correlation coefficient was 0.29. CONCLUSIONS: Significant interindividual and intraindividual variations exist in postprandial glycemia peak time, thus hindering simple and general advice regarding postprandial SMBG for detection of maximum values. PMID- 22538146 TI - Plantar fascia thickness is longitudinally associated with retinopathy and renal dysfunction: a prospective study from adolescence to adulthood. AB - AIM: The aim was to study the longitudinal relationship between plantar fascia thickness (PFT) as a measure of tissue glycation and microvascular (MV) complications in young persons with type 1 diabetes (T1DM). METHODS: We conducted a prospective longitudinal cohort study of 152 (69 male) adolescents with T1DM who underwent repeated MV complications assessments and ultrasound measurements of PFT from baseline (1997-2002) until 2008. Retinopathy was assessed by 7-field stereoscopic fundal photography and nephropathy by albumin excretion rate (AER) from three timed overnight urine specimens. Longitudinal analysis was performed using generalized estimating equations (GEE). RESULTS: Median (interquartile range) age at baseline was 15.1 (13.4-16.8) years, and median follow-up was 8.3 (7.0-9.5) years, with 4 (3-6) visits per patient. Glycemic control improved from baseline to final visit [glycated hemoglobin (HbA1c) 8.5% to 8.0%, respectively; p = .004]. Prevalence of retinopathy increased from 20% to 51% (p < .001) and early elevation of AER (>7.5 MUg/min) increased from 26% to 29% (p = .2). A greater increase in PFT (mm/year) was associated with retinopathy at the final assessment (DeltaPFT 1st vs. 2nd-4th quartiles, chi(2) = 9.87, p = .02). In multivariate GEE, greater PFT was longitudinally associated with retinopathy [odds ratio (OR) 4.6, 95% confidence interval (CI) 2.0-10.3] and early renal dysfunction (OR 3.2, CI 1.3-8.0) after adjusting for gender, blood pressure standard deviation scores, HbA1c, and total cholesterol. CONCLUSIONS: In young people with T1DM, PFT was longitudinally associated with retinopathy and early renal dysfunction, highlighting the importance of early glycemic control and supporting the role of metabolic memory in MV complications. Measurement of PFT by ultrasound offers a noninvasive estimate of glycemic burden and tissue glycation. PMID- 22538151 TI - Analysis of the accuracy and precision of the Axis-Shield Afinion hemoglobin A1c measurement device. AB - Point-of-care (POC) hemoglobin A1c measurement is now used by many physicians to make more timely decisions on therapy changes. A few studies have highlighted the drawbacks of some POC methods, e.g., poor precision and lot-to-lot variability. Evaluating performance in the clinical setting is difficult because there is minimal proficiency testing data on POC methods. In this issue of Journal of Diabetes Science and Technology, Wood and colleagues describe their experience with the Afinion method in a pediatric clinic network, comparing these results to another POC method as well as to a laboratory high-performance liquid chromatography method. Although they conclude that the Afinion exhibits adequate performance, they do not evaluate lot-to-lot variability. As with laboratory methods, potential assay interferences must also be considered. PMID- 22538150 TI - Accuracy and precision of the Axis-Shield Afinion hemoglobin A1c measurement device. AB - BACKGROUND: The Afinion HbA1c (Axis-Shield) is a newer point-of-care device for measurement of hemoglobin A1c (A1C) using a boronate affinity method unlike the more commonly used DCA immunoassay method (Siemens Medical Solutions Diagnostics). The Afinion's accuracy and precision, when compared with high performance liquid chromatography (HPLC) and DCA methods, have not been established in pediatric practice settings. METHODS: Capillary blood was collected from 700 subjects with diabetes mellitus at seven Pediatric Diabetes Consortium sites. Each subject's A1C was measured locally using Afinion and DCA devices, and by a central laboratory (University of Minnesota) using a Tosoh HPLC method. In addition, repeated measurements on six whole blood samples provided by the National Glycohemoglobin Standardization Program (NGSP) were taken at three clinical centers using the Afinion and DCA methods and centrally using the Tosoh HPLC method to assess the precision of each device. RESULTS: The coefficient of variation for measurements of whole blood samples for precision analysis was 2% for Afinion, 3% for DCA, and 1% for HPLC. In the patient samples measured at the seven clinic sites, the Afinion generated higher A1C results than the HPLC (mean difference = +0.15; p < 0.001), while the DCA produced lower values (mean difference = -0.19; p < 0.001). The absolute differences with HPLC were similar for the Afinion and DCA (median 0.2%) with a slight advantage for the Afinion when compared with DCA (p < 0.001 by rank test). The DCA tended to read lower than HPLC, particularly at high A1C levels (p < 0.001), while the Afinion's accuracy did not vary by A1C. CONCLUSIONS: When compared to the central laboratory HPLC method, the differences between the results of the Afinion and DCA devices are clinically insignificant, and the Afinion and DCA have similar accuracy and precision when used in pediatric practice settings. PMID- 22538148 TI - A human pilot study of the fluorescence affinity sensor for continuous glucose monitoring in diabetes. AB - OBJECTIVE: We report results of a pilot clinical study of a subcutaneous fluorescence affinity sensor (FAS) for continuous glucose monitoring conducted in people with type 1 and type 2 diabetes. The device was assessed based on performance, safety, and comfort level under acute conditions (4 h). RESEARCH DESIGN AND METHODS: A second-generation FAS (BioTex Inc., Houston, TX) was subcutaneously implanted in the abdomens of 12 people with diabetes, and its acute performance to excursions in blood glucose was monitored over 4 h. After 30 60 min the subjects, who all had fasting blood glucose levels of less than 200 mg/dl, received a glucose bolus of 75 g/liter dextrose by oral administration. Capillary blood glucose samples were obtained from the finger tip. The FAS data were retrospectively evaluated by linear least squares regression analysis and by the Clarke error grid method. Comfort levels during insertion, operation, and sensor removal were scored by the subjects using an analog pain scale. RESULTS: After retrospective calibration of 17 sensors implanted in 12 subjects, error grid analysis showed 97% of the paired values in zones A and B and 1.5% in zones C and D, respectively. The mean absolute relative error between sensor signal and capillary blood glucose was 13% [+/-15% standard deviation (SD), 100-350 mg/dl] with an average correlation coefficient of 0.84 (+/-0.24 SD). The actual average "warm-up" time for the FAS readings, at which highest correlation with glucose readings was determined, was 65 (+/-32 SD) min. Mean time lag was 4 (+/-5 SD) min during the initial operational hours. Pain levels during insertion and operation were modest. CONCLUSIONS: The in vivo performance of the FAS demonstrates feasibility of the fluorescence affinity technology to determine blood glucose excursions accurately and safely under acute dynamic conditions in humans with type 1 and type 2 diabetes. Specific engineering challenges to sensor and instrumentation robustness remain. Further studies will be required to validate its promising performance over longer implantation duration (5-7 days) in people with diabetes. PMID- 22538152 TI - Comparison of insulin diluent leakage postinjection using two different needle lengths and injection volumes in obese patients with type 1 or type 2 diabetes mellitus. AB - BACKGROUND: Smaller gauge, shorter needles have been shown to be as safe and effective for insulin delivery as longer needles in many patients. However, in obese patients with diabetes, results have been inconsistent with regard to the impact of needle length on leakage of injectate. METHODS: A single-blind, randomized, two-period, crossover study compared injections with 5 mm needles to 8 mm needles regarding leakage, pain, bleeding, and bruising at abdominal injection sites in obese patients with diabetes using 20- and 60-unit (U) volume equivalent injections of sterile insulin diluent. RESULTS: Fifty-six patients (54% male; mean age 56 years; mean body mass index of 36 kg/m(2)) with type 1 (n = 13) or type 2 (n = 43) diabetes participated. Median leakage (U) was similar for both needles [0.04 (5 mm/20 U) vs 0.02 (8 mm/20 U), P = .32; and 0.04 (5 mm/60 U) vs 0.02 (8 mm/60 U), P = .48]. Pain scores (mean) were similar [1.27 (5 mm/20 U) vs 1.14 (8 mm/20 U), P = .75, and 1.68 (5 mm/60 U) vs 0.95 (8 mm/60 U, P = .21)]. The proportion of injections with bleeding [10.8% (5 mm/20 U) vs 5.83% (8 mm/20 U), P = .23, and 4.92% (5 mm/60 U) vs 6.56% (8 mm/60 U), P = .73] and the proportion of patients with bruising [8.11% (5 mm/20 U) vs 10.81% (8 mm/20 U), p = .56, and 21.05% (5 mm/60 U) vs 26.32% (8 mm/60 U), p = .65] at injection sites were similar. Mean bruise size (mm) [0.73 (5 mm/20 U] vs 2.68 (8 mm/20 U), P = .23; and 1.11 (5 mm/60 U) vs 4.21 (8 mm/60 U), P = .08] at injection sites was similar. CONCLUSIONS: This study supports the suitability of the 5 mm needle for the injection of insulin in obese patients with diabetes. PMID- 22538155 TI - Clinical use of U-500 regular insulin: review and meta-analysis. AB - The use of U-500 regular insulin (U-500R) to treat diabetic patients with severe insulin resistance has increased. In this review, we performed a meta-analysis of PubMed studies reporting the use of U-500R to evaluate the effects of U-500R on hemoglobin A1c (HbA1c), body weight, and total daily insulin dose (TDD). These studies included 310 patients using U-500R as multiple daily injections (MDI) and 55 patients using U-500R via continuous subcutaneous insulin infusion (CSII). Overall, the use of U-500R as MDI resulted in a significant HbA1c reduction of 1.59%, a significant weight gain of 4.38 kg, and a significant increase in TDD by 51.9 units. The use of U-500R via CSII resulted in a similarly significant HbA1c reduction of 1.64% but a nonsignificant weight gain and a nonsignificant change in TDD. The use of U-500 regular insulin both as MDI and via CSII was not reported to be associated with severe hypoglycemia but was associated with an increase in patient satisfaction as well as in cost savings. Suggestions in initiating U-500R in the outpatient setting using U-500R in hospitalized patients are reviewed. In addition, precautions for avoiding prescription and patient errors are discussed. PMID- 22538149 TI - The identifiable virtual patient model: comparison of simulation and clinical closed-loop study results. AB - BACKGROUND: Optimizing a closed-loop insulin delivery algorithm for individuals with type 1 diabetes can be potentially facilitated by a mathematical model of the patient. However, model simulation studies that evaluate changes to the control algorithm need to produce conclusions similar to those that would be obtained from a clinical study evaluating the same modification. We evaluated the ability of a low-order identifiable virtual patient (IVP) model to achieve this goal. METHODS: Ten adult subjects (42.5 +/- 11.5 years of age; 18.0 +/- 13.5 years diabetes; 6.9 +/- 0.8% hemoglobin A1c) previously characterized with the IVP model were studied following the procedures independently reported in a pediatric study assessing proportional-integral-derivative control with and without a 50% meal insulin bolus. Peak postprandial glucose levels with and without the meal bolus and use of supplemental carbohydrate to treat hypoglycemia were compared using two-way analysis of variance and chi-square tests, respectively. RESULTS: The meal bolus decreased the peak postprandial glucose levels in both the adult-simulation and pediatricclinical study (231 +/- 38 standard deviation to 205 +/- 33 mg/dl and 226 +/- 51 to 194 +/- 47 mg/dl, respectively; p = .0472). No differences were observed between the peak postprandial levels obtained in the two studies (clinical and simulation study not different, p = .57; interaction p = .83) or in the use of supplemental carbohydrate (3 occurrences in 17 patient days of closed-loop control in the clinical-pediatric study; 7 occurrences over 20 patient days in the adult simulation study, p = .29). CONCLUSIONS: Closed-loop simulations using an IVP model can predict clinical study outcomes in patients studied independently from those used to develop the model. PMID- 22538153 TI - Analysis and perspective: comparison of insulin diluent leakage post-injection using two different needle lengths and injection volumes in obese patients with type 1 or type 2 diabetes mellitus. AB - The effects of needle gauge and length on the efficacy and tolerability of insulin injection therapy are becoming better understood. This analysis discusses some of these effects and comments on a new study by Ignaut and Fu in this issue of Journal of Diabetes Science and Technology on the effects of needle length on insulin diluent leakage from injection sites. PMID- 22538157 TI - Comparison of known food weights with image-based portion-size automated estimation and adolescents' self-reported portion size. AB - BACKGROUND: Diet is a critical element of diabetes self-management. An emerging area of research is the use of images for dietary records using mobile telephones with embedded cameras. These tools are being designed to reduce user burden and to improve accuracy of portion-size estimation through automation. The objectives of this study were to (1) assess the error of automatically determined portion weights compared to known portion weights of foods and (2) to compare the error between automation and human. METHODS: Adolescents (n = 15) captured images of their eating occasions over a 24 h period. All foods and beverages served were weighed. Adolescents self-reported portion sizes for one meal. Image analysis was used to estimate portion weights. Data analysis compared known weights, automated weights, and self-reported portions. RESULTS: For the 19 foods, the mean ratio of automated weight estimate to known weight ranged from 0.89 to 4.61, and 9 foods were within 0.80 to 1.20. The largest error was for lettuce and the most accurate was strawberry jam. The children were fairly accurate with portion estimates for two foods (sausage links, toast) using one type of estimation aid and two foods (sausage links, scrambled eggs) using another aid. The automated method was fairly accurate for two foods (sausage links, jam); however, the 95% confidence intervals for the automated estimates were consistently narrower than human estimates. CONCLUSIONS: The ability of humans to estimate portion sizes of foods remains a problem and a perceived burden. Errors in automated portion-size estimation can be systematically addressed while minimizing the burden on people. Future applications that take over the burden of these processes may translate to better diabetes self-management. PMID- 22538156 TI - Assessing inpatient glycemic control: what are the next steps? AB - Despite the emergence of glucometrics (i.e., systematic analysis of data on blood glucose levels of inpatients) as a subject of high interest, there remains a lack of standardization on how glucose parameters are measured and reported. This dilemma must be resolved before a national benchmarking process can be developed that will allow institutions to track and compare inpatient glucose control performance against established guidelines and that can also be supported by quality care organizations. In this article, we review some of the questions that need to be resolved through consensus and review of the evidence, and discuss some of the limitations in analyzing and reporting inpatient glucose data that must be addressed (or at least accepted as limitations) before hospitals can commit resources to gathering, compiling, and presenting inpatient glucose statistics as a health care quality measure. Standards must include consensus on which measures to report, the unit of analysis, definitions of targets for hyperglycemia treatment, a definition of hypoglycemia, determination of how data should be gathered (from chart review or from laboratory information systems), and which type of sample (blood or point of care) should be used for analysis of glycemic control. Hospitals and/or their representatives should be included in the discussion. For inpatient glucose control to remain a focus of interest, further dialogue and consensus on the topic are needed. PMID- 22538154 TI - Accuracy of point-of-care glucose measurements. AB - Control of blood glucose (BG) in an acceptable range is a major therapy target for diabetes patients in both the hospital and outpatient environments. This review focuses on the state of point-of-care (POC) glucose monitoring and the accuracy of the measurement devices. The accuracy of the POC glucose monitor depends on device methodology and other factors, including sample source and collection and patient characteristics. Patient parameters capable of influencing measurements include variations in pH, blood oxygen, hematocrit, changes in microcirculation, and vasopressor therapy. These elements alone or when combined can significantly impact BG measurement accuracy with POC glucose monitoring devices (POCGMDs). In general, currently available POCGMDs exhibit the greatest accuracy within the range of physiological glucose levels but become less reliable at the lower and higher ranges of BG levels. This issue raises serious safety concerns and the importance of understanding the limitations of POCGMDs. This review will discuss potential interferences and shortcomings of the current POCGMDs and stress when these may impact the reliability of POCGMDs for clinical decision-making. PMID- 22538160 TI - New Criteria for Assessing the Accuracy of Blood Glucose Monitors meeting, October 28, 2011. AB - Glucose meters (GMs) are routinely used for self-monitoring of blood glucose by patients and for point-of-care glucose monitoring by health care providers in outpatient and inpatient settings. Although widely assumed to be accurate, numerous reports of inaccuracies with resulting morbidity and mortality have been noted. Insulin dosing errors based on inaccurate GMs are most critical. On October 28, 2011, the Diabetes Technology Society invited 45 diabetes technology clinicians who were attending the 2011 Diabetes Technology Meeting to participate in a closed-door meeting entitled New Criteria for Assessing the Accuracy of Blood Glucose Monitors. This report reflects the opinions of most of the attendees of that meeting. The Food and Drug Administration (FDA), the public, and several medical societies are currently in dialogue to establish a new standard for GM accuracy. This update to the FDA standard is driven by improved meter accuracy, technological advances (pumps, bolus calculators, continuous glucose monitors, and insulin pens), reports of hospital and outpatient deaths, consumer complaints about inaccuracy, and research studies showing that several approved GMs failed to meet FDA or International Organization for Standardization standards in postapproval testing. These circumstances mandate a set of new GM standards that appropriately match the GMs' analytical accuracy to the clinical accuracy required for their intended use, as well as ensuring their ongoing accuracy following approval. The attendees of the New Criteria for Assessing the Accuracy of Blood Glucose Monitors meeting proposed a graduated standard and other methods to improve GM performance, which are discussed in this meeting report. PMID- 22538162 TI - Do different glucose levels at calibration influence accuracy of continuous glucose monitoring readings in vitro? PMID- 22538159 TI - Clinical requirements for closed-loop control systems. AB - Closed-loop (CL) therapy systems should be safe, efficacious, and easily manageable for type 1 diabetes mellitus patient use. For the first two clinical requirements, noninferiority and superiority criteria must be determined based on current conventional and intensive therapy outcomes. Current frequencies of hypoglycemia and diabetic ketoacidosis are reviewed and safety expectations for CL therapy systems are proposed. Glycosylated hemoglobin levels lower than current American Diabetes Association recommendations for different age groups are proposed as superiority criteria. Measures of glycemic variability are described and the recording of blood glucose levels as percentages within, above, and below a target range are suggested as reasonable alternatives to sophisticated statistical analyses. It is also suggested that Diabetes Quality of Life and Fear of Hypoglycemia surveys should be used to track psychobehavioral outcomes. Manageability requirements for safe and effective clinical management of CL systems are worth being underscored. The weakest part of the infusion system remains the catheter, which is exposed to variable and under-delivery incidents. Detection methods are needed to warn both the system and the patient about altered insulin delivery, including internal pressure and flow alarms. Glucose monitor sensor accuracy is another requirement; it includes the definition of conditions that lead to capillary glucose measurement, eventually followed by sensor recalibration or replacement. The crucial clinical requirement will be a thorough definition of the situations when the patient needs to move from CL to manual management of insulin delivery, or inversely can switch back to CL after a requested interruption. Instructions about these actions will constitute a major part of the education process of the patients before using CL systems and contribute to the manageability of these systems. PMID- 22538163 TI - Minimally invasive enzyme microprobes: an alternative approach for continuous glucose monitoring. PMID- 22538164 TI - User acceptability and perceived benefits of new reports in CareLink Pro 3.0 Therapy Management Software for Diabetes. PMID- 22538158 TI - Accuracy in blood glucose measurement: what will a tightening of requirements yield? AB - Nowadays, almost all persons with diabetes--at least those using antidiabetic drug therapy--use one of a plethora of meters commercially available for self monitoring of blood glucose. The accuracy of blood glucose (BG) measurement using these meters has been presumed to be adequate; that is, the accuracy of these devices was not usually questioned until recently. Health authorities in the United States (Food and Drug Administration) and in other countries are currently endeavoring to tighten the requirements for the accuracy of these meters above the level that is currently stated in the standard ISO 15197. At first glance, this does not appear to be a problem and is hardly worth further consideration, but a closer look reveals a considerable range of critical aspects that will be discussed in this commentary. In summary, one could say that as a result of modern production methods and ongoing technical advances, the demands placed on the quality of measurement results obtained with BG meters can be increased to a certain degree. One should also take into consideration that the system accuracy (which covers many more aspects as the analytical accuracy) required to make correct therapeutical decisions certainly varies for different types of therapy. At the end, in addition to analytical accuracy, thorough and systematic training of patients and regular refresher training is important to minimize errors. Only under such circumstances will patients make appropriate therapeutic interventions to optimize and maintain metabolic control. PMID- 22538161 TI - Accuracy of the Sof-sensor glucose sensor with the iPro calibration algorithm. PMID- 22538168 TI - Prioritizing sensitized heart transplant candidates: a sensitive affair. PMID- 22538167 TI - Monitoring the intracellular pH of Zygosaccharomyces bailii by green fluorescent protein. AB - It is generally known that intracellular pH (pH(i)) plays a vital role in cell physiology and that pH(i) homeostasis is essential for normal cellular functions. Therefore, it is desirable to know the pH(i) during cell life cycle or under various growth conditions. Different methods to measure pH(i) have been developed and among these methods, the use of pH-sensitive green fluorescent protein (GFP) as a pH(i) indicator is a promising technique. By using this approach, not only can more accurate pH(i) results be obtained but also long-term experiments on pH(i) can be performed. In this study, the wild type Zygosaccharomyces bailii, a notorious food spoilage yeast, was transformed with a plasmid encoding a pH sensitive GFP (i.e. pHluorin), enabling the pH(i) of the yeast to be determined based on cellular fluorescent signals. After the transformation, growth and pH(i) of the yeast were investigated in four different acidic conditions at 22 degrees C during 26days. From the experimental results, the transformation effectiveness was verified and a good correlation between yeast growth and pH(i) was noticed. Particularly, it was observed that the yeast has an ability to tolerate a significant pH(i) drop during exponential phase and a subsequent pH(i) recovery in stationary phase, which may underlie the exceptional acid resistance of the yeast. This was the first time that a GFP-based approach for pH(i) measurement was applied in Z. bailii and that the pH(i) of the yeast was monitored during such a long period (26days). It can be expected that greater understanding of the physiological properties and mechanisms behind the special acid resistance of the yeast will be obtained from further studies on this new yeast strain. PMID- 22538166 TI - Colloidal interactions in liquid CO2--a dry-cleaning perspective. AB - Liquid CO(2) is a viable alternative for the toxic and environmentally harmful solvents traditionally used in dry-cleaning industry. Although liquid CO(2) dry cleaning is being applied already at a commercial scale, it is still a relatively young technique which poses many challenges. The focus of this review is on the causes of the existing problems and directions to solve them. After presenting an overview of the state-of-the-art, we analyze the detergency challenges from the fundamentals of colloid and interface science. The properties of liquid CO(2) such as dielectric constant, density, Hamaker constant, refractive index, viscosity and surface tension are presented and in the subsequent chapters their effects on CO(2) dry-cleaning operation are delineated. We show, based on theory, that the van der Waals forces between a model soil (silica) and model fabric (cellulose) through liquid CO(2) are much stronger compared to those across water or the traditional dry-cleaning solvent PERC (perchloroethylene). Prevention of soil particle redeposition in liquid CO(2) by electrostatic stabilization is challenging and the possibility of using electrolytes having large anionic parts is discussed. Furthermore, the role of different additives used in dry-cleaning, such as water, alcohol and surfactants, is reviewed. Water is not only used as an aid to remove polar soils, but also enhances adhesion between fabric and soil by forming capillary bridges. Its role as a minor component in liquid CO(2) is complex as it depends on many factors, such as the chemical nature of fabrics and soil, and also on the state of water itself, whether present as molecular solution in liquid CO(2) or phase separated droplets. The phenomena of wicking and wetting in liquid CO(2) systems are predicted from the Washburn-Lucas equation for fabrics of various surface energies and pore sizes. It is shown that nearly complete wetting is desirable for good detergency. The effect of mechanical action and fluid dynamic conditions on dry-cleaning is analyzed theoretically. From this it follows that in liquid CO(2) an order of magnitude higher Reynold's number is required to exceed the binding forces between fabric and soil as opposed to PERC or water, mainly due to the strong van der Waals forces and the low viscosity of CO(2) at dry-cleaning operational conditions. PMID- 22538165 TI - Evaluation of the performance and stability of a novel A1c-cellular control. PMID- 22538169 TI - Pilot investigation of a novel testing strategy for bleeding in ventricular assist device recipients. AB - PURPOSE: A universal loss of von Willebrand factor (vWF) high-molecular-weight multimers (HMWM) has been demonstrated in continuous-flow left ventricular assist device (HeartMate II) recipients. However, no reliable clinical or laboratory predictors for an increased bleeding tendency in this patient population have been identified. This study evaluated the ability of a new automated latex particle-enhanced immunoturbidimetric vWF activity assay (ALPEIVA) to predict non surgical bleeding risk in HeartMate II recipients. METHODS: As part of a prospective multicenter trial, pre-surgical, 7-day, and 30-day post-implantation blood samples were collected from 24 patients. ALPEIVA-assessed vWF activities were compared among patients with and without non-surgical bleeding complications after HeartMate II implantation. Additional laboratory testing included factor VIII activity (FVIII:C), vWF antigen (vWFAg), vWF ristocetin cofactor activity (vWF:RCo), and vWF multimer analysis. RESULTS: All 24 patients had HMWM losses after HeartMate II implantation. Five patients (20%) developed non-surgical bleeding complications between 14 days and 6 months after HeartMate II implantation. Among various laboratory variables, only mean ALPEIVA/vWFAg ratios (referred to as the "bleeding ratio") were significantly lower in patients with clinically relevant bleeding (mean, 0.70 +/- 0.06) compared with patients without bleeding (mean, 0.78 +/- 0.09; p = 0.02) when measured at 30 days. CONCLUSIONS: The post-surgical bleeding ratio could potentially predict non-surgical bleeding risk and guide anti-platelet and anti-coagulation strategies in HeartMate II recipients. PMID- 22538172 TI - Predictors of methadone program non-retention for opioid analgesic dependent patients. AB - This study evaluates loss to follow-up in a methadone maintenance treatment (MMT) program for patients dependent on opioid analgesics in a community in eastern Canada. Data were collected using the Addiction Severity Index Lite. The probability of loss to follow-up was evaluated using a time-to-event analysis. Involuntary and voluntary program discharges were treated separately as the outcomes of interest. Multivariate Cox proportional hazards models were used to explore the role of various patient-related attributes. The probabilities of involuntary and voluntary discharges at 1 year were 20% and 14%, respectively. In this exploratory analysis, determinants of loss to follow-up were characteristics related to drug use history (e.g., use of sedatives) and its consequences (e.g., number of lifetime arrests), and differed for each outcome. Some determinants of involuntary discharge were modified by sex. Understanding predictors of specific loss to follow-up outcomes may help MMT programs improve patient retention. PMID- 22538174 TI - Exercise training to improve health related quality of life in long term survivors of major burn injury: a matched controlled study. AB - OBJECTIVE: Patients often experience reduced health-related quality of life (HRQOL) following burn injury. Exercise training has been demonstrated to improve HRQOL in a number of clinical populations, yet it is unknown whether exercise can improve HRQOL in burns patients. PROCEDURES: Nine burn-injured participants (42+/ 18.38%TBSA: 6.56+/-3.68 years after injury) and 9 matched controls participated in a 12-week exercise programme. HRQOL was assessed via the Burn Specific Health Scale-Brief (BSHS-B) and the Medical Outcomes Study 36-Item Short Form (SF-36). Activity limitation was measured using the quick Disabilities of the Arm, Shoulder and Hand (QuickDASH). RESULTS: The burns group had decreased HRQOL compared to the controls at baseline, as reported by the BSHS-B (t (16)=3.51, p=0.003) and some domains of the SF-36 including role physical (t (16)=3.79, p=0.002). Burned participants reported decreased activity levels compared to the controls as measured by the QuickDASH (t (16)=2.19, p=0.044). Exercise training improved SF-36 scores in both burn (t (8)=3.77, p=0.005) and control groups (t (8)=2.71, p=0.027). Following training there was no difference between the groups on the SF-36 or QuickDASH. CONCLUSION: Exercise training improves HRQOL and activity limitations in burn-injured patients to a level that is equivalent to that of their uninjured counterparts. PMID- 22538175 TI - Putting adolescents at the centre of health and development. PMID- 22538171 TI - VI-14, a novel flavonoid derivative, inhibits migration and invasion of human breast cancer cells. AB - It has been well characterized that flavonoids possess pronounced anticancer potentials including anti-angiogenesis, anti-metastasis, and pro-apoptosis. Herein, we report, for the first time, that VI-14, a novel flavonoid derivative, possesses anti-cancer properties. The purpose of this study is to investigate the anti-migration and anti-invasion activities of VI-14 in breast cancer cells. Our data indicate that VI-14 inhibits adhesion, migration and invasion of MDA-MB-231 and MDA-MB-435 human breast cancer cells. MDA-MB-231 cells treated with VI-14 display reduced activities and expressions of ECM degradation-associated proteins including matrix metalloproteinase 2 (MMP-2) and 9 (MMP-9) at both the protein and mRNA levels. Meanwhile, VI-14 treatment induces an up-regulated expression of tissue inhibitor of metalloproteinase 1 (TIMP-1) and 2 (TIMP-2) in MDA-MB-231 cells. Western blotting results show that phosphorylation levels of critical components of the MAPK signaling pathway, including ERK, JNK and P38, are dramatically decreased in VI-14-treated MDA-MB-231 cells. Furthermore, treatment of VI-14 significantly decreases the nuclear levels and the binding ability of nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1). Taken together, our data suggest that VI-14 treatment suppresses migration and motility of breast cancer cells, and VI-14 may be a potential compound for cancer therapy. PMID- 22538176 TI - Seizing the opportunities of adolescent health. PMID- 22538170 TI - Oxidative stress is involved in Dasatinib-induced apoptosis in rat primary hepatocytes. AB - Dasatinib, a multitargeted inhibitor of BCR-ABL and SRC kinases, exhibits antitumor activity and extends the survival of patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). However, some patients suffer from hepatotoxicity, which occurs through an unknown mechanism. In the present study, we found that Dasatinib could induce hepatotoxicity both in vitro and in vivo. Dasatinib reduced the cell viability of rat primary hepatocytes, induced the release of alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) in vitro, and triggered the ballooning degeneration of hepatocytes in Sprague-Dawley rats in vivo. Apoptotic markers (chromatin condensation, cleaved caspase-3 and cleaved PARP) were detected to indicate that the injury induced by Dasatinib in hepatocytes in vitro was mediated by apoptosis. This result was further validated in vivo using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays. Here we found that Dasatinib dramatically increased the level of reactive oxygen species (ROS) in hepatocytes, reduced the intracellular glutathione (GSH) content, attenuated the activity of superoxide dismutase (SOD), generated malondialdehyde (MDA), a product of lipid peroxidation, decreased the mitochondrial membrane potential, and activated nuclear factor erythroid 2 related factor 2 (Nrf2) and mitogen-activated protein kinases (MAPK) related to oxidative stress and survival. These results confirm that oxidative stress plays a pivotal role in Dasatinib-mediated hepatotoxicity. N-acetylcysteine (NAC), a typical antioxidant, can scavenge free radicals, attenuate oxidative stress, and protect hepatocytes against Dasatinib-induced injury. Thus, relieving oxidative stress is a viable strategy for reducing Dasatinib-induced hepatotoxicity. PMID- 22538173 TI - Patient characteristics and availability of onsite non-rapid and rapid HIV testing in US substance use disorder treatment programs. AB - Racial and ethnic minorities and injection drug users (IDUs) are at increased risk of HIV infection. However, the associations between these caseload characteristics and the availability of onsite HIV testing in substance use disorder treatment programs are unknown. This study uses data collected in 2008 2009 from 198 program administrators of treatment programs participating in the National Institute on Drug Abuse's Clinical Trials Network to address this gap in the literature. Results show positive associations between the percentages of African American, Hispanic, and IDU patients and the odds of offering non-rapid onsite HIV testing versus no onsite testing. The associations between racial/ethnic composition and the availability of rapid HIV testing were more complicated. These findings suggest that many programs are responding to the needs of at-risk populations. However, programs and their patients may benefit from greater adoption of rapid testing which is less costly and better ensures that patients receive their results. PMID- 22538177 TI - Adolescent health in the 21st century. PMID- 22538178 TI - Adolescence: a foundation for future health. AB - Adolescence is a life phase in which the opportunities for health are great and future patterns of adult health are established. Health in adolescence is the result of interactions between prenatal and early childhood development and the specific biological and social-role changes that accompany puberty, shaped by social determinants and risk and protective factors that affect the uptake of health-related behaviours. The shape of adolescence is rapidly changing-the age of onset of puberty is decreasing and the age at which mature social roles are achieved is rising. New understandings of the diverse and dynamic effects on adolescent health include insights into the effects of puberty and brain development, together with social media. A focus on adolescence is central to the success of many public health agendas, including the Millennium Development Goals aiming to reduce child and maternal mortality and HIV/AIDS, and the more recent emphases on mental health, injuries, and non-communicable diseases. Greater attention to adolescence is needed within each of these public health domains if global health targets are to be met. Strategies that place the adolescent years centre stage-rather than focusing only on specific health agendas-provide important opportunities to improve health, both in adolescence and later in life. PMID- 22538179 TI - Adolescence and the social determinants of health. AB - The health of adolescents is strongly affected by social factors at personal, family, community, and national levels. Nations present young people with structures of opportunity as they grow up. Since health and health behaviours correspond strongly from adolescence into adult life, the way that these social determinants affect adolescent health are crucial to the health of the whole population and the economic development of nations. During adolescence, developmental effects related to puberty and brain development lead to new sets of behaviours and capacities that enable transitions in family, peer, and educational domains, and in health behaviours. These transitions modify childhood trajectories towards health and wellbeing and are modified by economic and social factors within countries, leading to inequalities. We review existing data on the effects of social determinants on health in adolescence, and present findings from country-level ecological analyses on the health of young people aged 10-24 years. The strongest determinants of adolescent health worldwide are structural factors such as national wealth, income inequality, and access to education. Furthermore, safe and supportive families, safe and supportive schools, together with positive and supportive peers are crucial to helping young people develop to their full potential and attain the best health in the transition to adulthood. Improving adolescent health worldwide requires improving young people's daily life with families and peers and in schools, addressing risk and protective factors in the social environment at a population level, and focusing on factors that are protective across various health outcomes. The most effective interventions are probably structural changes to improve access to education and employment for young people and to reduce the risk of transport-related injury. PMID- 22538181 TI - Health of the world's adolescents: a synthesis of internationally comparable data. AB - Adolescence and young adulthood offer opportunities for health gains both through prevention and early clinical intervention. Yet development of health information systems to support this work has been weak and so far lagged behind those for early childhood and adulthood. With falls in the number of deaths in earlier childhood in many countries and a shifting emphasis to non-communicable disease risks, injuries, and mental health, there are good reasons to assess the present sources of health information for young people. We derive indicators from the conceptual framework for the Series on adolescent health and assess the available data to describe them. We selected indicators for their public health importance and their coverage of major health outcomes in young people, health risk behaviours and states, risk and protective factors, social role transitions relevant to health, and health service inputs. We then specify definitions that maximise international comparability. Even with this optimisation of data usage, only seven of the 25 indicators, covered at least 50% of the world's adolescents. The worst adolescent health profiles are in sub-Saharan Africa, with persisting high mortality from maternal and infectious causes. Risks for non-communicable diseases are spreading rapidly, with the highest rates of tobacco use and overweight, and lowest rates of physical activity, predominantly in adolescents living in low-income and middle-income countries. Even for present global health agendas, such as HIV infection and maternal mortality, data sources are incomplete for adolescents. We propose a series of steps that include better coordination and use of data collected across countries, greater harmonisation of school-based surveys, further development of strategies for socially marginalised youth, targeted research into the validity and use of these health indicators, advocating for adolescent-health information within new global health initiatives, and a recommendation that every country produce a regular report on the health of its adolescents. PMID- 22538180 TI - Worldwide application of prevention science in adolescent health. AB - The burden of morbidity and mortality from non-communicable disease has risen worldwide and is accelerating in low-income and middle-income countries, whereas the burden from infectious diseases has declined. Since this transition, the prevention of non-communicable disease as well as communicable disease causes of adolescent mortality has risen in importance. Problem behaviours that increase the short-term or long-term likelihood of morbidity and mortality, including alcohol, tobacco, and other drug misuse, mental health problems, unsafe sex, risky and unsafe driving, and violence are largely preventable. In the past 30 years new discoveries have led to prevention science being established as a discipline designed to mitigate these problem behaviours. Longitudinal studies have provided an understanding of risk and protective factors across the life course for many of these problem behaviours. Risks cluster across development to produce early accumulation of risk in childhood and more pervasive risk in adolescence. This understanding has led to the construction of developmentally appropriate prevention policies and programmes that have shown short-term and long-term reductions in these adolescent problem behaviours. We describe the principles of prevention science, provide examples of efficacious preventive interventions, describe challenges and potential solutions to take efficacious prevention policies and programmes to scale, and conclude with recommendations to reduce the burden of adolescent mortality and morbidity worldwide through preventive intervention. PMID- 22538182 TI - Progress for children: a report card on adolescents. PMID- 22538183 TI - 12-month follow-up of an exploratory 'brief intervention' for high-frequency cannabis users among Canadian university students. AB - BACKGROUND: One in three young people use cannabis in Canada. Cannabis use can be associated with a variety of health problems which occur primarily among intensive/frequent users. Availability and effectiveness of conventional treatment for cannabis use is limited. While Brief Interventions (BIs) have been shown to result in short-term reductions of cannabis use risks or problems, few studies have assessed their longer-term effects. The present study examined 12 month follow-up outcomes for BIs in a cohort of young Canadian high-frequency cannabis users where select short-term effects (3 months) had previously been assessed and demonstrated. FINDINGS: N=134 frequent cannabis users were recruited from among university students in Toronto, randomized to either an oral or a written cannabis BI, or corresponding health controls, and assessed in-person at baseline, 3-months, and 12-months. N=72 (54%) of the original sample were retained for follow-up analyses at 12-months where reductions in 'deep inhalation/breathholding' (Q=13.1; p< .05) and 'driving after cannabis use' (Q=9.3; p< .05) were observed in the experimental groups. Reductions for these indicators had been shown at 3-months in the experimental groups; these reductions were maintained over the year. Other indicators assessed remained overall stable in both experimental and control groups. CONCLUSIONS: The results confirm findings from select other studies indicating the potential for longer term and sustained risk reduction effects of BIs for cannabis use. While further research is needed on the long-term effects of BIs, these may be a valuable - and efficient - intervention tool in a public health approach to high-risk cannabis use. PMID- 22538184 TI - Formation of one-way-structured cultured neuronal networks in microfluidic devices combining with micropatterning techniques. AB - We present a simple method to regulate the direction of axon development in cultured neurons using microfabrication and microfluidics techniques. We fabricate a PDMS-based device and place it onto a chemically micropatterned glass substrate. We confirm that cultured neurons extend neurites along the medium flow direction and the micropatterned regions. PMID- 22538186 TI - Incentive moderates the impact of implicit anger vs. sadness cues on effort related cardiac response. AB - This experiment investigated the combined effect of implicit affect and monetary success incentive on effort-related cardiac response in a 2 (Affect Prime: anger vs. sadness)*2 (Incentive: low vs. high) between-person design. Sixty-two participants were exposed to affect primes during an objectively difficult short term memory task. As predicted, by our theorizing about affect primes' systematic impact on subjectively experienced task demand and corresponding effort mobilization, sadness primes led to a weak cardiac pre-ejection period (PEP) response when incentive was low (disengagement), but to a very strong PEP response when incentive was high (high effort). PEP responses were moderate in the anger-prime conditions (low effort). HR responses largely corresponded to those of PEP. The results demonstrate for the first time that high incentive can compensate the effort mobilization deficit of individuals who process sadness primes during a difficult task. PMID- 22538187 TI - Specific-site methylation of tumour suppressor ANKRD11 in breast cancer. AB - ANKRD11 is a putative tumour suppressor gene in breast cancer, which has been shown in our laboratory to be a co-activator of p53. Our data suggest that down regulation of ANKRD11 is associated with breast tumourigenesis. Breast cancer cell lines treated with DNA demethylating agents resulted in up-regulation of ANKRD11 expression suggesting that promoter DNA methylation may be responsible for its down-regulation. The transcriptional activity of a CpG-rich region 2kb upstream of the transcription initiation site of ANKRD11 was investigated using dual-luciferase reporter assays. The constructs carrying -661 to -571 bp promoter sequence showed significant transcriptional activity. Using the SEQUENOM Epityper Platform, the region between -770 and +399 bp was analysed in 25 breast tumours, four normal breast tissues and five normal blood samples. The region between -770 and -323 bp was shown to be frequently methylated in breast tumours. The methylation patterns of all analysed CpGs in this region were identical in the normal and tumour samples, except for a 19 bp region containing three CpG sites. These sites had significantly higher levels of methylation in tumours (40%) compared to normal samples (6%). Our findings support the role of ANKRD11 as a tumour suppressor gene and suggest that aberrant DNA methylation of three CpGs in a 19 bp region within the ANKRD11 promoter may be responsible for its down regulation in breast cancer. PMID- 22538188 TI - Amplification of the STOML3, FREM2, and LHFP genes is associated with mesenchymal differentiation in gliosarcoma. AB - Gliosarcoma is a rare glioblastoma variant characterized by a biphasic tissue pattern with alternating areas that display either glial (glial fibrillary acidic protein-positive) or mesenchymal (reticulin-positive) differentiation. Previous analyses have shown identical genetic alterations in glial and mesenchymal tumor areas, suggesting that gliosarcomas are genetically monoclonal, and mesenchymal differentiation was considered to reflect the elevated genomic instability of glioblastomas. In the present study, we compared genome-wide chromosomal imbalances using array comparative genomic hybridization in glial and mesenchymal tumor areas of 13 gliosarcomas. The patterns of gain and loss were similar, except that the gain at 13q13.3-q14.1 (log(2) ratio >3.0), containing the STOML3, FREM2, and LHFP genes, which was restricted to the mesenchymal tumor area of a gliosarcoma. Further analyses of 64 cases of gliosarcoma using quantitative PCR showed amplification of the STOML3, FREM2, and LHFP genes in 14 (22%), 10 (16%), and 7 (11%) mesenchymal tumor areas, respectively, but not in glial tumor areas. Results of IHC analysis confirmed that overexpression of STOML3 and FREM2 was more extensive in mesenchymal than in glial tumor areas. These results suggest that the mesenchymal components in a small fraction of gliosarcomas may be derived from glial cells with additional genetic alterations. PMID- 22538189 TI - Phosphorylation of sst2 receptors in neuroendocrine tumors after octreotide treatment of patients. AB - Somatostatin analogues, which are used to treat neuroendocrine tumors, target the high levels of somatostatin receptor subtype 2 (SSTR1; alias sst2) expressed in these cancers. However, some tumors are resistant to somatostatin analogues, and it is unknown whether the defect lies in sst2 activation or downstream signaling events. Because sst2 phosphorylation occurs rapidly after receptor activation, we examined whether sst2 is phosphorylated in neuroendocrine tumors. The sst2 receptor phosphorylation was evaluated by IHC and Western blot analysis with the new Ra-1124 antibody specific for the sst2 receptor phosphorylated at Ser341/343 in receptor-positive neuroendocrine tumors obtained from 10 octreotide-treated and 7 octreotide-naive patients. The specificity, time course, and subcellular localization of sst2 receptor phosphorylation were examined in human embryo kinase-sst2 cell cultures by immunofluorescence and confocal microscopy. All seven octreotide-naive tumors displayed exclusively nonphosphorylated cell surface sst2 expression. In contrast, 9 of the 10 octreotide-treated tumors contained phosphorylated sst2 that was predominantly internalized. Western blot analysis confirmed the IHC data. Octreotide treatment of human embryo kinase-sst2 cells in culture demonstrated that phosphorylated sst2 was localized at the plasma membrane after 10 seconds of stimulation and was subsequently internalized into endocytic vesicles. These data show, for the first time to our knowledge, that phosphorylated sst2 is present in most gastrointestinal neuroendocrine tumors from patients treated with octreotide but that a striking variability exists in the subcellular distribution of phosphorylated receptors among such tumors. PMID- 22538190 TI - A novel, dual role of CCN3 in experimental glomerulonephritis: pro-angiogenic and antimesangioproliferative effects. AB - In contrast to factors that promote mesangial cell proliferation, little is known about their endogenous inhibitors. During experimental mesangioproliferative nephritis, expression of the glomerular CCN3 (nephroblastoma overexpressed gene [NOV]) gene is reduced before the proliferative phase and increased in glomeruli and serum when mesangial cell proliferation subsides. To further elucidate its role in mesangioproliferative glomerulonephritis, CCN3 systemically was overexpressed by muscle electroporation in healthy or nephritic rats. This increased CCN3 serum concentrations more than threefold for up to 56 days. At day 5 after disease induction, CCN3-transfected rats showed an increase in glomerular endothelial area and in mRNA levels of the pro-angiogenic factors vascular endothelial growth factor and PDGF-C. At day 7, CCN3 overexpression decreased mesangial cell proliferation, including expression of alpha-smooth muscle actin and matrix accumulation of fibronectin and type IV collagen. In progressive nephritis (day 56), overexpression of CCN3 resulted in decreased albuminuria, glomerulosclerosis, and reduced cortical collagen type I accumulation. In healthy rat kidneys, overexpression of CCN3 induced no morphologic changes but regulated glomerular gene transcripts (reduced transcription of PDGF-B, PDGF-D, PDGF receptor-beta, and fibronectin, and increased PDGF-receptor-alpha and PDGF-C mRNA). These data identify a dual role for CCN3 in experimental glomerulonephritis with pro-angiogenic and antimesangioproliferative effects. Manipulation of CCN3 may represent a novel approach to help repair glomerular endothelial damage and mesangioproliferative changes. PMID- 22538192 TI - Familial risk of sleep-disordered breathing. AB - OBJECTIVE: To estimate the incidence of hospitalization for paediatric obstructive sleep apnoea syndrome (OSAS) or sleep-disordered breathing (SDB) caused by adenotonsillar or tonsillar hypertrophy without infection in children with a parent affected by OSAS. PATIENTS AND METHODS: Using the MigMed database at Lund University, hospital data on all children aged 0-18 years in Sweden between 1997 and 2007 (total of 3 million individuals) were used to identify all first hospital admissions for OSAS or either adenotonsillar or tonsillar hypertrophy. Next, individuals were categorized as either having or not having a parent affected by OSAS. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were estimated for boys and girls with a parent affected by OSAS. Children with OSAS or adenotonsillar or tonsillar hypertrophy without a parent affected by OSAS acted as the reference group (SIR=1). RESULTS: After accounting for socio-economic status, age, and geographic region, the SIRs of OSAS in boys and girls with a parent affected by OSAS were 3.09 (95% CI 1.83-4.90) and 4.46 (95% CI 2.68-6.98), respectively. The SIRs of adenotonsillar or tonsillar hypertrophy in boys and girls with a parent affected by OSAS were 1.82 (95% CI 1.54-2.14) and 1.56 (95% CI 1.30-1.87), respectively. CONCLUSION: This study indicates familial clustering of sleep-disordered breathing, which is important information for clinicians. PMID- 22538191 TI - Immune modulation of vascular resident cells by Axl orchestrates carotid intima media thickening. AB - Cellular mechanisms of carotid intima-media thickening (IMT) are largely unknown. The receptor tyrosine kinase Axl is essential for function of both bone marrow (BM) and non-BM cells. We studied the mechanisms by which Axl expression in BM derived cells (compared with non-BM-derived cells) mediates carotid IMT. Partial ligation of the left carotid artery resulted in a similar carotid blood flow reduction in Axl chimeras. Neither irradiation nor bone marrow transplantation had any effect on the 40% difference in carotid IMT between Axl genotypes. Axl dependent survival is very important for intimal leukocytes; however, Axl expression in BM cells contributes to <30% of carotid IMT. Axl in non-BM cells has a greater effect on carotid remodeling. Expression of Axl in non-BM cells is crucial for the up-regulation of several key proinflammatory signals (eg, IL-1) in the carotid. We found that Axl is involved in immune activation of cultured smooth muscle cells and in immune heterogeneity of medial cells (measured by major histocompatibility complex class II) after carotid injury. Finally, a lack of Axl in non-BM cells increased collagen Ialpha expression, which may play a critical role in carotid remodeling. Our data suggest that Axl contributes to carotid remodeling not only by inhibition of apoptosis but also via regulation of immune heterogeneity of vascular cells, cytokine/chemokine expression, and extracellular matrix remodeling. PMID- 22538193 TI - Maintaining Coral Snakes (Micrurus nigrocinctus, Serpentes: Elapidae) for venom production on an alternative fish-based diet. AB - American Elapid snakes (Coral Snakes) comprise the genera Leptomicrurus, Micruroides and Micrurus, which form a vast taxonomic assembly of 330 species distributed from the South of United States to the southern region of South America. In order to obtain venom for animal immunizations aimed at antivenom production, Coral Snakes must be kept in captivity and submitted periodically to venom extraction procedures. Thus, to maintain a snake colony in good health for this purpose, a complete alternative diet utilizing an easily obtained prey animal is desirable. The development of a diet based on fish is compared to the wild diet based on colubrid snakes, and assessed in terms of gain in body weight rate (g/week), longevity (weeks), venom yield (mg/individual), venom median lethal dose (LD50) and venom chromatographic profiles. The animals fed with the fish-based diet gained more weight, lived longer, and produced similar amount of venom whose biological and biochemical characteristics were similar to those of venom collected from specimens fed with the wild diet. This fish-based diet appears to be suitable (and preferable to the wild diet) to supply the nutritional requirements of a Micrurus nigrocinctus snake collection for the production of antivenom. PMID- 22538194 TI - Establishment and first experiences of the National Serum Depot in the Netherlands. AB - Since 2008, a National Serum Depot is operational in the Netherlands, guaranteeing antivenom supply, 24 h per day, during medical emergencies. In this article the organisation structure, choice of antivenoms, problems encountered during the establishment, and the results from establishment in 2008 till December 2011 are discussed. The Serum Depot is organised by the National Institute for Public Health and the Environment in cooperation with the Dutch National Poisons Information Center. During establishing and maintaining of the Serum Depot several antivenom purchase difficulties were encountered. Some antivenom producers did not respond upon (initial) contact and some antivenoms were (temporarily) unavailable. Good contacts with professional herpetologists are necessary in order to keep the content of the depot up-to-date. At the same time, it is important to remain well informed concerning the safety and efficacy of the currently available antivenoms and development of new antivenoms. During the first four years of the National Serum Depot, the Dutch National Poisons Information Center was consulted on average 10 times a year about exotic venomous bites and stings in which antivenom treatment might play a role. Almost half of these consultations were related to bites by venomous exotic snakes, the other half to scorpion and fish stings. Antivenom was delivered in five cases, all after a bite by an exotic venomous snake, and actually administered twice because of the severity of local effects. To reduce costs and extend coverage of the Serum Depot of antivenoms for more unfamiliar snake species, international cooperation between the various owners of the antivenom Serum Depots in Europe is recommended. PMID- 22538195 TI - Brown spider (Loxosceles intermedia) venom triggers endothelial cells death by anoikis. AB - Brown spider (Loxosceles sp.) venom affects the endothelium of vessels and triggers disruptive activity in the subendothelial matrix. The vascular disorders observed after venom exposure include leukocyte and platelet activation, disseminated intravascular coagulation, an increase in vessel permeability and hemorrhage into the dermis. In this study, we report additional evidence regarding the mechanism of endothelial cell cytotoxicity induced by Loxosceles intermedia venom. Exposure to venom led to endothelial cell detachment in a time dependent manner. Loss of cell anchorage and cell-cell adhesion following venom exposure was accompanied by changes in the distribution of the alpha5beta1 integrin and VE-cadherin. An ultrastructural analysis of cells treated with venom revealed morphological alterations characteristic of apoptosis. Moreover, after venom exposure, the ratio between Bax and Bcl-2 proteins was disturbed in favor of Bax. In addition, late apoptosis was only observed in cells detached by the action of venom. Accordingly, there was no increase in apoptosis when cells were exposed to L. intermedia venom in suspension, suggesting that the loss of cell anchorage provides the signal to initiate apoptosis. Thus, L. intermedia venom likely triggers endothelial cell death indirectly through an apoptotic mechanism known as anoikis. PMID- 22538197 TI - Combined use of rapamycin and leflunomide in prevention of acute cardiac allografts rejection in rats. AB - This study aimed to evaluate the role of combined use of rapamycin and leflunomide(Lef) on the prevention of acute allograft rejection in rats. After cardiac transplantations, rats were randomly divided into untreated group, rapamycin group, Lef group and rapamycin+Lef group. The drugs were given by gavage from day 0 to day 9 after transplantations. Graft survival time was observed. Some grafts were harvested for histopathological investigation on day 10 after transplantations. The levels of CD(4)(+) and CD(8)(+) T lymphocytes and the concentrations of interleukin 2(IL-2) and interferon (IFN)gamma in peripheral blood were examined on day 10 after transplantations. At the same time, the body weight, the hepatic function, renal function and the haemoglobin of the recipients were also examined. The graft survival time of untreated group was 7.14 +/- 1.07 days. Rapamycin group was 11.14 +/- 1.35 days. Lef group was 11.29 +/- 1.80 days. While in rapamycin+Lef group, the graft survival time was prolonged to 13.86 +/- 1.57 days(P<0.05). Histological changes of the allografts in rapamycin+Lef group were much milder than either of the two single drug groups. The absolute number and the percentage of CD(4)(+) T lymphocytes in peripheral blood in rapamycin+Lef group were lower than those of rapamycin or Lef group on day 10 after transplantations(P<0.05), while the percentage of CD(8)(+) T lymphocytes in rapamycin+Lef group was higher than that of rapamycin or Lef group(P<0.05). The absolute number of CD(8)(+) T lymphocytes was not significantly different among rapamycin group, Lef group and rapamycin+Lef group. The levels of IL-2 and IFN-gamma in rapamycin+Lef group were significantly lower than that of rapamycin group or Lef group(P<0.05). The body weight, the hepatic function, renal function and the haemoglobin were not significantly different among rapamycin group, Lef group and rapamycin+Lef group (P>0.05). Combined use of rapamycin and Lef had better effect on the prevention of acute cardiac allografts rejection in rats than monotherapy. PMID- 22538198 TI - Protein polymer hydrogels by in situ, rapid and reversible self-gelation. AB - Protein-based biomaterials are an important class of materials for applications in biotechnology and medicine. The exquisite control of their composition, stereochemistry, and chain length offers unique opportunities to engineer biofunctionality, biocompatibility, and biodegradability into these materials. Here, we report the synthesis of a thermally responsive peptide polymer-based hydrogel composed of a recombinant elastin-like polypeptide (ELP) that rapidly forms a reversibly cross-linked hydrogel by the formation of intermolecular disulfide cross-links. To do so, we designed and synthesized ELPs that incorporate periodic cysteine residues (cELPs), and show that cELPs are thermally responsive protein polymers that display rapid gelation under physiologically relevant, mild oxidative conditions. Gelation of cELPs, at concentrations as low as 2.5 wt%, occurs in ~ 2.5 min upon addition a low concentration of hydrogen peroxide (0.3 wt%). We show the utility of these hydrogels for the sustained release of a model protein in vitro, and demonstrate the ability of this injectable biomaterial to pervade tumors to maximize tumor coverage and retention time upon intratumoral injection. cELPs represent a new class of injectable reversibly cross-linked hydrogels with properties intermediate between ELP coacervates and chemically cross-linked ELP hydrogels that will find useful applications in drug delivery and tissue engineering. PMID- 22538200 TI - Highly efficient visible light photocatalysis of novel CuS/ZnO heterostructure nanowire arrays. AB - Here, a facile approach for the fabrication of CuS nanoparticle (NP)/ZnO nanowire (NW) heterostructures on a mesh substrate through a simple two-step solution method is demonstrated. Successive ionic layer adsorption and reaction (SILAR) was employed to uniformly deposit CuS NPs on the hydrothermally grown ZnO NW array. The synthesized CuS/ZnO heterostructure NWs exhibited superior photocatalytic activity under visible light compared to bare ZnO NWs. This strong photocatalytic activity under visible light is due to the interfacial charge transfer (IFCT) from the valence band of the ZnO NW to the CuS NP, which reduces CuS to Cu(2)S. After repeated cycles of photodecolorization of Acid Orange 7 (AO7), the photocatalytic behavior of CuS/ZnO heterostructure NWs exhibited no significant loss of activity. Furthermore, our CuS/ZnO NWs/mesh photocatalyst floats in solution via partial superhydrophobic modification of the NWs. PMID- 22538199 TI - A NaYbF4: Tm3+ nanoprobe for CT and NIR-to-NIR fluorescent bimodal imaging. AB - Early diagnosis that combines the high-resolutional CT and sensitive NIR fluorescence bioimaging could provide more accurate information for cancerous tissues, which, however, remain a big challenge. Here we report a simple bimodal imaging platform based on PEGylated NaYbF(4): Tm(3+) nanoparticles (NPs) of less than 20 nm in diameter for both CT and NIR-fluorescence bioimaging. The as designed nanoprobes showed excellent in vitro and in vivo performances in the dual-bioimaging, very low cytotoxicity and no detectable tissue damage in one month. Remarkably, the Yb(3+) in the lattice of NaYbF(4): Tm(3+) NPs functions not only as a promising CT contrast medium due to its high X-ray absorption coefficiency, but also an excellent sensitizer contributing to the strong NIR fluorescent emissions for its large NIR absorption cross-section. In addition, these NPs could be easily excreted mainly via feces without detectable remnant in the animal bodies. PMID- 22538196 TI - Receptor-targeting mechanisms of pain-causing toxins: How ow? AB - Venoms often target vital processes to cause paralysis or death, but many types of venom also elicit notoriously intense pain. While these pain-producing effects can result as a byproduct of generalized tissue trauma, there are now multiple examples of venom-derived toxins that target somatosensory nerve terminals in order to activate nociceptive (pain-sensing) neural pathways. Intriguingly, investigation of the venom components that are responsible for evoking pain has revealed novel roles and/or configurations of well-studied toxin motifs. This review serves to highlight pain-producing toxins that target the capsaicin receptor, TRPV1, or members of the acid-sensing ion channel family, and to discuss the utility of venom-derived multivalent and multimeric complexes. PMID- 22538201 TI - Extragenital endometrial stromal sarcoma arising in endometriosis. AB - The diagnosis rate of deep pelvic endometriosis is increasing. Endometrial stromal sarcoma (ESS) is a rare neoplasm. Extragenital ESS is an extremely uncommon event. Very few cases of extragenital ESS have been reported to date. The diagnosis of this entity is very difficult in some instances. Knowledge about its management is also limited. In this paper, we review the current literature on the clinical management, histology, immunohistochemistry, treatment and outcome of ESS arising in pelvic endometriosis. PMID- 22538202 TI - [Selection of patients for transcatheter aortic valve implantation]. AB - A good selection of patients is a crucial step before transcatheter aortic valve implantation (TAVI) in order to select the good indications and choose the access route. TAVI should be considered only in patients with symptomatic severe aortic stenosis and either contraindication or high surgical risk. Indication for TAVI should be discussed in a multidisciplinary team meeting. Echocardiography and/or CT scan are mandatory to evaluate the aortic annulus size and select the good prosthesis size. The possibility of transfemoral implantation is evaluated by angiography and CT scan, and based on the arterial diameters, but also on the presence of tortuosities and arterial calcifications. PMID- 22538205 TI - Safety of methotrexate for inflammatory bowel disease. PMID- 22538204 TI - Management of cytomegalovirus infection in inflammatory bowel diseases. AB - Cytomegalovirus is a deoxyribonucleic acid virus that infects a large part of the human population; after primary infection, it develops a latent state and can be reactivated, notably after a decrease in host immune defences. In patients with inflammatory bowel diseases, cytomegalovirus is frequently involved, either as an agent of colitis or through local asymptomatic reactivation. Due to the immune context of inflammatory bowel diseases and to the immunosuppressive therapies that are used to treat them, cytomegalovirus entertains complex relationships with these diseases. Whereas Crohn's disease seems little impacted by cytomegalovirus, this agent interferes strongly with the natural progression of ulcerative colitis. While immune treatments have a clear influence on the occurrence of cytomegalovirus colitis in ulcerative colitis (favourable for steroids and cyclosporine and rather inhibitory for infliximab), the role of cytomegalovirus infection on ulcerative colitis is more debated with roles ranging from innocent bystander to key pathogen suggested. There is however growing evidence for a participation of intestinal cytomegalovirus infection in the resistance of ulcerative colitis to steroids and the investigation of cytomegalovirus infection in intestinal biopsies by immunohistochemistry or quantitative polymerase chain reaction assay is strongly recommended. In several studies, treatment of cytomegalovirus infection by ganciclovir was shown to restore the response to immunomodulatory therapies and even to prevent the need for colectomy. All of these recently acquired data need to be validated by randomised clinical trials conducted on a large panel of ulcerative colitis patients. PMID- 22538203 TI - Integrated molecular analysis indicates undetectable change in DNA damage in mice after continuous irradiation at ~ 400-fold natural background radiation. AB - BACKGROUND: In the event of a nuclear accident, people are exposed to elevated levels of continuous low dose-rate radiation. Nevertheless, most of the literature describes the biological effects of acute radiation. OBJECTIVES: DNA damage and mutations are well established for their carcinogenic effects. We assessed several key markers of DNA damage and DNA damage responses in mice exposed to low dose-rate radiation to reveal potential genotoxic effects associated with low dose-rate radiation. METHODS: We studied low dose-rate radiation using a variable low dose-rate irradiator consisting of flood phantoms filled with 125Iodine-containing buffer. Mice were exposed to 0.0002 cGy/min (~ 400-fold background radiation) continuously over 5 weeks. We assessed base lesions, micronuclei, homologous recombination (HR; using fluorescent yellow direct repeat mice), and transcript levels for several radiation-sensitive genes. RESULTS: We did not observe any changes in the levels of the DNA nucleobase damage products hypoxanthine, 8-oxo-7,8-dihydroguanine, 1,N6-ethenoadenine, or 3,N4-ethenocytosine above background levels under low dose-rate conditions. The micronucleus assay revealed no evidence that low dose-rate radiation induced DNA fragmentation, and there was no evidence of double strand break-induced HR. Furthermore, low dose-rate radiation did not induce Cdkn1a, Gadd45a, Mdm2, Atm, or Dbd2. Importantly, the same total dose, when delivered acutely, induced micronuclei and transcriptional responses. CONCLUSIONS: These results demonstrate in an in vivo animal model that lowering the dose-rate suppresses the potentially deleterious impact of radiation and calls attention to the need for a deeper understanding of the biological impact of low dose-rate radiation. PMID- 22538206 TI - Hepatitis C in the elderly: a multicentre cross-sectional study by the Italian Association for the Study of the Liver. AB - BACKGROUND: The prevalence of hepatitis C virus infection increases with advancing age, but elderly hepatitis C virus patients remain an understudied population. AIM: To define the virological, epidemiological and clinical profiles of Italian outpatients aged 65 years and over infected by hepatitis C virus. METHODS: We evaluated 1544 anti-hepatitis C virus positive patients aged >=65 years referred to 34 Italian outpatient specialty clinics over a two-year period. RESULTS: The study population included 1134 (73%) early elderly (65-74 years) and 410 (27%) late elderly patients (>=75 years). Late elderly subjects were less likely to have their virus genotyped, their viral load assessed or a histological evaluation of liver disease. Overall, 30% of patients had advanced liver disease whose prevalence increased with increasing age. In both age groups, about 40% of patients had normal transaminase levels. Excluding patients with past infection, 51% had not received any antiviral treatment and only 25% were treated after the age of 65. Late elderly patients, women and patients with advanced liver diseases had been less frequently treated. The main reason for exclusion from treatment was age followed by the presence of comorbid conditions. CONCLUSIONS: Elderly hepatitis C virus patients referred to Italian specialty clinics have advanced and underestimated liver disease. Nevertheless, they are progressively understudied in parallel with increasing age. PMID- 22538207 TI - Isolation, molecular characterization, and phylogenetic analysis of porcine encephalomyocarditis virus strain HB10 in China. AB - Encephalomyocarditis virus (EMCV) can cause myocarditis, respiratory failure, reproductive failure, and mortality in pregnant sows, fetuses, and ablactating piglets. Diseases caused by EMCV currently affect the swine industry worldwide. A virus was isolated from organs of dead piglets that presented with acute myocarditis in northern China. The production of a specific cytopathic effect on susceptible cells and the results of hemagglutination inhibition (HI) assay, PCR, electron microscopy (EM), and sequencing indicated that the pathogen was EMCV; the strain was named HB10. Other pathogenic agents causing myocarditis and death were excluded as possible pathogenic agents. Phylogenetic analyses of the capsid coding region and the VP3/VP1 genes using the neighbour-joining method revealed that EMCV isolates cluster into two groups (groups 1 and 2) with two sub-clusters within group 1 (group 1a and b). HB10 belongs to group 1a, along with strains CBNU, GX0601, BJC3, NJ08, and BEL-2887A/91. Five strains isolated from Sus scrofa belong to group 2. The results of this and previous studies indicate that HB10 and other EMCV strains cause myocarditis of pigs in China. PMID- 22538208 TI - Hepatitis B virus genotypes from European origin explains the high endemicity found in some areas from southern Brazil. AB - Southern Brazil is considered an area of low Hepatitis B endemicity, but some areas of higher endemicity have been described in the Southwest of Parana and Santa Catarina states. The aim of this study was to evaluate viral genotypes circulating throughout Parana state. PCR amplification and partial sequencing of the S gene was carried out in 228 samples from HBsAg positive candidate blood donors. Samples have been collected in seven different counties (Cascavel, Curitiba, Foz do Iguacu, Francisco Beltrao, Maringa, Londrina and Paranagua). The most common HBV genotype in Parana state was D (82.9%; 189/228), followed by A (14.1%; 32/228). Genotypes F (1.3%; 3/228), C (1.3%; 3/228) and H (0.4%; 1/228) were also found. Distribution of genotypes was different in the studied counties, but genotype D was the most frequent in all of them. In Francisco Beltrao, all studied samples belonged to genotype D. The high prevalence of HBV genotype D in South of Brazil is explained by the intense migration of settlers from Europeans countries. Subgenotypes A1 and A2 were identified circulating in all cities where HBV/A was found. As observed in other areas of Brazil, HBV/A1 is more frequent than the HBV/A2 in Parana state and its presence was significantly larger in black and mulatto individuals. Genotype C was found only in individuals with Asian ancestry from Londrina and Maringa. Most HBV/F sequences identified in this study were classified as subgenotype F2a that was previously described in Brazil. The sole case of subgenotype F4 was from Foz do Iguacu city, near to Northern Argentina, where F4 is highly prevalent. The single genotype H sample was from Curitiba. This is the first case of this genotype described in Brazil. Further studies should be carried out to determine if more genotype H samples can be found in other populations from Brazil. PMID- 22538209 TI - Medial prefrontal cortex activity during the extinction of conditioned fear: an investigation using functional near-infrared spectroscopy. AB - The majority of fear conditioning studies in humans have focused on fear acquisition rather than fear extinction. For this reason only a few functional imaging studies on fear extinction are available. A large number of animal studies indicate the medial prefrontal cortex (mPFC) as neuronal substrate of extinction. We therefore determined mPFC contribution during extinction learning after a discriminative fear conditioning in 34 healthy human subjects by using functional near-infrared spectroscopy. During the extinction training, a previously conditioned neutral face (conditioned stimulus, CS+) no longer predicted an aversive scream (unconditioned stimulus, UCS). Considering differential valence and arousal ratings as well as skin conductance responses during the acquisition phase, we found a CS+ related increase in oxygenated haemoglobin concentration changes within the mPFC over the time course of extinction. Late CS+ trials further revealed higher activation than CS- trials in a cluster of probe set channels covering the mPFC. These results are in line with previous findings on extinction and further emphasize the mPFC as significant for associative learning processes. During extinction, the diminished fear association between a former CS+ and a UCS is inversely correlated with mPFC activity--a process presumably dysfunctional in anxiety disorders. PMID- 22538210 TI - Influence of health providers on pediatrics' immunization rate. AB - To identify the immunization providers' characteristics associated with immunization rate in children younger than 2 years. A cohort and a cluster sampling design were implemented; 528 children between 18 and 70 months of age were sampled in five public health clinics in Mosul-Iraq. Providers' characterizations were obtained. Immunization rate for the children was assessed. Risk factors for partial immunization were explored using both bivariate analyses and multi-level logistic regression models. Less than half of the children had one or more than one missed dose, considered as partial immunization cases. The study found significant association of immunization rate with provider's type. Two factors were found that strongly impacted on immunization rate in the presence of other factors: birthplace and immunization providers' type. PMID- 22538211 TI - A retrospective analysis of the sentence writing component of the Mini Mental State Examination: cognitive and affective aspects. AB - BACKGROUND: One of the components of the Mini Mental State Examination (MMSE) is the request to write a sentence. We investigated the relationship between the characteristics of the written sentence of the MMSE and the cognitive and affective status of elderly patients. METHODS: The characteristics of the sentence were compared to the total MMSE score, sociodemographic characteristics, tests evaluating cognition and affective status, and diagnoses. RESULTS: The number of words was significantly associated with the degree of cognitive impairment, whereas the emotional polarity of sentences and concerns about health were associated with depression. CONCLUSIONS: Characteristics of the MMSE sentence may provide important additional information regarding both cognition and affect when assessing older people. PMID- 22538212 TI - Concomitant drug- and infection-induced antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis with multispecific ANCA. AB - OBJECTIVE: To report the first case of concomitant drug- and infection-induced antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) in a patient treated with propylthiouracil (PTU) and suffering from tuberculosis. PRESENTATION AND INTERVENTION: A 28-year-old woman with PTU-treated hyperthyroidism presented with fever, purpura, pulmonary cavitations and ANCA to myeloperoxidase, bactericidal/permeability-increasing protein (BPI), proteinase-3 and elastase. Skin histopathology confirmed vasculitis. However, sputum examination revealed Mycobacterium tuberculosis. Remission was achieved after PTU withdrawal and treatment with antituberculosis drugs. CONCLUSION: Our case confirmed that BPI-ANCA are elevated in active tuberculosis. Multispecific ANCA were helpful for the diagnosis of concomitant PTU- and M. tuberculosis-induced AAV. PMID- 22538213 TI - First postoperative day intraocular pressure rise in resident-performed cataract surgery. PMID- 22538214 TI - Association of outer retinal layer morphology with visual acuity in patients with retinal vein occlusion: SCORE Study Report 13. AB - PURPOSE: To assess associations between visual acuity (VA) and the status of the photoreceptor inner segment-outer segment (IS-OS) junction in a subset of patients in the Standard Care vs COrticosteroid for REtinal Vein Occlusion (SCORE) Study. METHODOLOGY: High-resolution time domain optical coherence tomography (OCT) scans of study eyes from a single site participating in the SCORE Study were evaluated. Integrity of the IS-OS junction in the central subfield was evaluated using a three-step scale: absent, abnormal or normal. Associations of the IS-OS status with ETDRS VA letter score and center point thickness (CPT) were investigated. RESULTS: Baseline OCTs of 42 eyes were evaluated. The IS-OS junction was absent in 30 (71%) and abnormal in 12 (29%). At month 12, the IS-OS junction was absent in 18 (43%), abnormal in 12 (28%), and normal in 12 (28%) eyes. At baseline, IS-OS status was significantly associated with CPT, but not with VA. At month 12, IS-OS status was significantly associated with CPT and VA, that is, absent or abnormal IS-OS was associated with increased CPT and worse VA. Change in IS-OS status was not associated with change in CPT (P=0.8). Worsening of IS-OS status was associated with loss of VA and improvement in IS-OS status to normal was associated with gain in VA (P=0.03). CONCLUSION: In this data set with long-term follow-up of OCTs as part of the SCORE Study, there is a correlation between change in IS-OS status and VA. This supports further evaluation of outer retinal morphology in larger data sets. PMID- 22538216 TI - Local anaesthesia for ophthalmic surgery--new guidelines from the Royal College of Anaesthetists and the Royal College of Ophthalmologists. PMID- 22538217 TI - In vivo confocal microscopy study of climatic droplet keratopathy. PMID- 22538218 TI - Spectral-domain OCT in anti-VEGF treatment of myopic choroidal neovascularization. AB - PURPOSE: To evaluate changes in macular morphology due to myopic choroidal neovascularization (CNV), using spectral-domain optical coherence tomography (SD OCT). METHODS: In all, 22 eyes with recent-onset untreated CNV underwent 1 intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF), followed by a pro-re-nata regimen. SD-OCT was performed at baseline (before first administration of anti-VEGF treatment) and month 1, and 2; macular morphologic changes and outer retina characteristics (SD-OCT findings) associated with CNV activity were evaluated. Sensitivity and specificity were calculated for SD-OCT findings using fluorescein angiography (FA) as standard reference. RESULTS: Mean central retinal thickness (CRT) showed no significant reduction from baseline (284+/-98 MUm) to month 1 (257+/-74 MUm) and month 2 (263+/-72 MUm). A hyper reflective lesion with fuzzy borders (fuzzy area), and 'absent or altered' IS/OS junction were the only SD-OCT findings associated with CNV activity (P<0.0001). Both these SD-OCT findings showed good sensitivity and specificity (95.1 and 96.0% (95% CI: 0.87-0.89), respectively, for the fuzzy area; 87.9 and 66.7% (95% CI: 0.65-0.87), respectively, for 'absent or altered' IS/OS junction) when compared with FA leakage (standard reference). CONCLUSIONS: Outer retina characteristics (ie, hyper-reflective lesion with fuzzy borders, and 'absent or altered' IS/OS junction) appear more meaningful than CRT in the evaluation of myopic CNV activity. These SD-OCT findings show overall good sensitivity and specificity when compared with FA leakage (standard reference), and could be considered as an alternative diagnostic tool to FA for myopic CNV monitoring. PMID- 22538220 TI - IgG4 orbitopathy: unravelling a multisystem diagnostic challenge. PMID- 22538219 TI - Safety, tolerability, and bioavailability of topical SAR 1118, a novel antagonist of lymphocyte function-associated antigen-1: a phase 1b study. AB - PURPOSE: A growing body of evidence points to a role for inflammation mediated by lymphocyte function-associated antigen-1 (LFA-1) and its ligand intercellular adhesion molecule-1 in the pathogenesis of diabetic macular oedema. This phase 1b clinical trial assessed the safety, tolerability, and pharmacokinetics of topically administered SAR 1118, a novel LFA-1 antagonist, in human subjects. METHODS: In this prospective, randomized, double-masked trial, 13 subjects scheduled for vitrectomy received one of three concentrations of topical SAR 1118 (0.1, 1.0, or 5.0%) twice daily for 1 week before surgery. Undiluted aqueous and vitreous samples were collected at surgery and analysed for the concentration of the medication. RESULTS: All subjects completed the entire course of medication. The only adverse events reported were instillation site irritation (4/13, 31%) and dysgeusia (3/13, 23%). These were mild and transient, occurring at the highest dose. Mean concentrations (ng/ml) of SAR 1118 in the aqueous humour were 0.25, 37.2, and 101.1 for the 0.1%, 1.0%, and 5.0% dose groups, respectively. SAR 1118 was below the level of detection (0.5 ng/ml) for all vitreous samples except in a single subject who had a history of prior vitrectomy and a dislocated intraocular lens. CONCLUSIONS: Topical SAR 1118 was safe and well tolerated, and dose-dependent levels of drug were detected in aqueous. However, vitreous levels were below the threshold of detection with the concentrations tested. Further investigation of this medication for posterior segment applications would require intravitreal delivery or chemical modification of the drug. PMID- 22538221 TI - Loss of cortical GABA terminals in Unverricht-Lundborg disease. AB - Unverricht-Lundborg disease (ULD) is the most common progressive myoclonic epilepsy. Its etiology has been identified in a defect of a protease inhibitor, cystatin B (CSTB), but the mechanism(s) by which this defect translates in the clinical manifestations of the disease are still obscure. We tested the hypothesis that ULD is accompanied by a loss of cortical GABA inhibition in a murine model (the CSTB knockout mouse) and in a human case. Cortical GABA signaling has been investigated measuring VGAT immunohistochemistry (a histological marker of the density of GABA terminals), GABA release from synaptosomes and paired-pulse stimulation. In CSTB knockout mice, a progressive decrease in neocortex thickness was found, associated with a prevalent loss of GABA interneurons. A marked reduction in VGAT labeling was found in the cortex of both CSTB knockout mice and an ULD patient. This implicates a reduction in GABA synaptic transmission, which was confirmed in the mouse model as reduction in GABA release from isolated nerve terminals and as loss of electrophysiologically measured GABA inhibition. The alterations in VGAT immunolabeling progressed in time, paralleling the worsening of myoclonus. These results provide direct evidence that loss of cortical GABA input occurs in a relevant animal model and in a case of human ULD, leading to a condition of latent hyperexcitability that favors myoclonus and seizures. These findings contribute to the understanding of the pathogenic mechanism of ULD and of the neurobiological basis of the effect of currently employed drugs. PMID- 22538222 TI - Foveal color perception: minimal thresholds at a boundary between perceptual categories. AB - Human color vision depends on the relative rates at which photons are absorbed by the three classes of retinal cone cell. The ratios of these cone absorptions can be represented in a continuous two-dimensional space, but human perception imposes discrete hue categories on this space. We ask whether discrimination is enhanced at the boundary between color categories, as it is at the boundary between speech sounds. Measuring foveal color discrimination under neutral conditions of adaptation, we find a region of enhanced discrimination in color space that corresponds approximately to the subjective category boundary between reddish and greenish hues. We suggest that these chromaticities are ones at which an opponent neural channel is in equilibrium. This channel would be 'non cardinal', in that its signals would not correspond to either axis of the MacLeod Boynton chromaticity diagram. PMID- 22538223 TI - GM in the media. PMID- 22538224 TI - Development of Agrobacterium-mediated transformation technology for mature seed derived callus tissues of indica rice cultivar IR64. AB - Indica rice cultivar IR64 is most recalcitrant to regenerate, which affects the transformation efficiency especially when mature seed-derived callus tissues are used as explants. Therefore, a simple, rapid and improved genetic transformation protocol has been developed for the indica rice cultivar IR64 using Agrobacterium mediated genetic transformation. With different hormonal combination tested, the maximum callus induction was observed on MS medium supplemented with 2.5 mg/l 2,4 D and 0.15 mg/l BAP from the scutellum explants. Three weeks old scutellum derived callus explants were immersed in Agrobacterium suspension (strain LBA4404, OD600=1.0) and co-cultured at 26+/-2 degrees C in dark for 2 d. The maximum transformation efficiency (12%) was achieved with infection of callus explants for 20 min along with use of 150 MUm acetosyringone. The maximum plant regeneration was observed on MS medium supplemented with 3 mg/l BAP, 1 mg/l Kinetin and 0.5 mg/l NAA. The maximum root induction was observed on MS medium along with 10 g/l glucose and 20 g/l sucrose. The integration of the transgene in T1 transgenic plants was confirmed by polymerase chain reaction and Southern blot analyses. The copy number of transgenes has been found to vary from 1 to 2 in transgenic plants. By using this improved method we have successfully raised transgenic rice plants within 3 mo from seed inoculation to plant regeneration. PMID- 22538225 TI - Indian farmers need help to feed over 1.5 billion people in 2030. AB - In view of the enormous challenge and pressure on farmers to feed 9 billion plus people and billions of animals who are going to be living in our planet in 2050, new technologies must be invented, assessed and adapted. Farmer welfare and provision of resources required for their work is of paramount importance. India has benefited from Bt cotton technology and will certainly benefit from other biotech crops that have been carefully developed and assessed for consumption and environmental safety. PMID- 22538226 TI - Surveying of pollen-mediated crop-to-crop gene flow from a wheat field trial as a biosafety measure. AB - Outcrosses from genetically modified (GM) to conventional crops by pollen mediated gene flow (PMGF) are a concern when growing GM crops close to non-GM fields. This also applies to the experimental releases of GM plants in field trials. Therefore, biosafety measures such as isolation distances and surveying of PMGF are required by the regulatory authorities in Switzerland. For two and three years, respectively, we monitored crop-to-crop PMGF from GM wheat field trials in two locations in Switzerland. The pollen donors were two GM spring wheat lines with enhanced fungal resistance and a herbicide tolerance as a selection marker. Seeds from the experimental plots were sampled to test the detection method for outcrosses. Two outcrosses were found adjacent to a transgenic plot within the experimental area. For the survey of PMGF, pollen receptor plots of the conventional wheat variety Frisal used for transformation were planted in the border crop and around the experimental field up to a distance of 200 m. Although the environmental conditions were favorable and the donor and receptor plots flowered at the same time, only three outcrosses were found in approximately 185,000 tested seedlings from seeds collected outside the experimental area. All three hybrids were found in the border crop surrounding the experimental area, but none outside the field. We conclude that a pollen barrier (border crop) and an additional isolation distance of 5 m is a sufficient measure to reduce PMGF from a GM wheat field trial to cleistogamous varieties in commercial fields below a level that can be detected. PMID- 22538227 TI - Effects of different combinations of benzyl adenine and indole acetic acid concentrations on in vitro plant regeneration in hexaploid wheat. AB - Development of a reliable in vitro plant regeneration procedure for hexaploid bread wheat (Triticum aestivum L.) is a prerequisite for its improvement by genetic transformation. Here, we report the effects of two growth regulators, benzyl adenine (BA) and indole acetic acid (IAA) on callus induction and plant regeneration from scutellum cultures of two commercial bread wheat cultivars: Giza 164 and Sakha 69. Callus induction was obtained from isolated embryos cultured on modified Murashige and Skoog (MS) basal medium. After four weeks of callus induction, all calli were plated on MS basal medium for regeneration. Wheat genotype and callus induction medium played a dominant role in plantlet regeneration. 2.0 mg/L BA and 0.2 mg/L IAA were the best combinations for inducing callus and let to highest regeneration frequency (81.67%) across the cultivars. Overall, based on our medium conditions, Giza 164 displayed higher regeneration frequency (81.11%) than Sakha 69. These results will facilitate genetic transformation for the economic varieties Giza 164 and Sakha 69. PMID- 22538228 TI - Power, progress and prevarication: local knowledge and GE papaya in Thailand. AB - Genetically engineered (GE) papaya was developed in the 1990s to improve the livelihoods of small scale farmers in Thailand. Yet these farmers have been excluded from the discourse around its deregulation and deployment. While elite stakeholders continue to debate in Bangkok, little is known about small scale farmers' understanding of biotechnology, their perceptions of the technology and whether or not they are likely to be adopters if it became available. In this case study, I report on farmer knowledge of agricultural biotechnology and genetically engineered papaya in northeast Thailand. Forty farmers in four villages were surveyed with regard to their knowledge and perceptions of GE papaya. A qualitative grounded theory approach was employed to understand their responses, from which three themes emerged: progress, power and prevarication. From these themes, the decision-making process of farmers seems to be dominated by their existing local knowledge and their interest in progressing their economic status. The responses of small-scale Isaan farmers provide a new perspective on the debate over GE virus-resistant papaya in Thailand. Based on the results of this study, we can conclude that this small subset of Thai papaya growers perceive GE virus-resistant papaya as a compatible innovation that is likely to be adopted by Thai farmers if it becomes available. PMID- 22538229 TI - Raised uterine artery impedance is associated with increased maternal arterial stiffness in the late second trimester. AB - OBJECTIVE: To assess the relationship between uterine artery Doppler pulsatility index (PI) and maternal global arterial stiffness and aortic stiffness in women at high a priori risk of preeclampsia in the late second trimester of pregnancy. METHODS: A prospective cohort study was performed. 99 women were recruited from the high-risk obstetric ultrasound clinic in the second trimester; median (+/ IQR) age and gestation were 33 (29-37) years and 23(+6) (23(+3)-24(+4)) weeks respectively. Transabdominal uterine artery Doppler was performed and mean values recorded. Women returned at a later date, median gestation (+/-IQR) 26(+5) (25(+6)-28(+0)) weeks, for measurement of blood pressure, augmentation index (AIx) and aortic pulse wave velocity (aPWV). RESULTS: Uterine artery PI is positively associated with both AIx (r = 0.4, P <0.0001, 95% CI: 0.22-0.55) and aPWV (r = 0.22, P = 0.03, 95% CI: 0.02-0.40). No relationship was found between uterine artery PI and mean arterial pressure or pulse pressure. AIx was significantly higher in women with uterine artery PI > 1.45 (P = 0.003, 95% CI: 3.1-14.9) but not aPWV (P = 0.45). AIx, but not aPWV, was significantly higher in women who developed preeclampsia (14% vs 9%, 95% CI: 2.0-8.6, P = 0.0018) or IUGR (11% vs 9%, 95% CI: 0.3-4.2, P = 0.027). AIx showed a negative correlation with birth weight z-score (r = -0.25, 95% CI: -0.43 to -0.06, P = 0.013). CONCLUSION: Increasing uterine artery Doppler PI reflects impaired placentation and increasing risk of preeclampsia. We show a positive association between uterine artery Doppler PI and both global arterial and aortic stiffness. We also show that increased maternal arterial stiffness is associated with a lower birth weight. These findings may represent evidence of an early effect of impaired placentation on the maternal vasculature. Alternatively, given the association between preeclampsia and later cardiovascular disease, ineffective placentation may result from impaired arterial function. PMID- 22538230 TI - Multiple injections of anti-mouse beta2glycoprotein 1 antibody induce FcRgamma dependent fetal growth restriction (FGR) in mice. AB - OBJECTIVES: The antiphospholipid syndrome (APS) is characterized by the presence of circulating antiphospholipid antibodies (aPLs), is a leading cause for thromboembolic events, repeated miscarriage, fetal loss and is a major risk factor for fetal growth restriction (FGR) and preeclampsia. In human, anti-beta2 glycoprotein I (abeta2GPI) antibody is one of the aPLs and considered to be a specific and important marker for APS. However, pathophysiological changes induced by abeta2GPI antibodies in FGR are largely unknown. METHODS: In the present study, we developed a murine FGR model induced by multiple injections of WBCAL-1, a well-characterized mouse abeta2GPI monoclonal antibody. RESULTS: Administration of WBCAL-1, but not the isotype control antibody and saline, into pregnant mice specifically decreased the size of fetuses and placentas without affecting the number of delivered pups. Also, a significant increase in urinary albumin and electron microscopic changes, such as splitting layers of basal membranes in the placental labyrinth and rearrangement of pores in glomerular endothelial cells, were observed in WBCAL-1 treated mice. WBCAL-1 injection did not induce any changes in blood pressure and typical parameters of blood thromboembolic symptoms. Furthermore, FcRgamma deficiency protected the fetuses from abeta2GPI antibody-induced injuries. CONCLUSIONS: Our present findings suggest that proteinuria is a symptom associated with APS-related FGR with placental and renal tissue injuries, and that FcRgamma might be a molecular target for prevention of abeta2GPI antibody-mediated obstetrical pathologies. PMID- 22538231 TI - Role of calcium in activation of hyperpolarization-activated cyclic nucleotide gated channels caused by cholecystokinin octapeptide in interstitial cells of cajal. AB - BACKGROUND: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate pacemaker activity in some cardiac cells and neurons. Little is known about the effects of cholecystokinin octapeptide (CCK-8) on HCN channels and excitability of murine interstitial cells of Cajal (ICCs). METHODS: In the present study, the effects and mechanisms of CCK-8 on HCN channels were investigated by measuring mechanical contraction of smooth muscle strips and ionic channels of ICCs in murine gastric antrum. RESULTS: Sulfated CCK-8 (CCK-8S) was used, and we found that CCK-8S increased the contraction of smooth muscle strips in the gastric antrum, which could be suppressed by specific HCN channel blockers CsCl and ZD7288. Extracellular calcium could also intensify the contraction. Under the same conditions, when antral strips were exposed to calcium ion (Ca2+)-free solution, no significant changes could be recorded with CCK-8S or ZD7288. Isolated ICCs from the murine gastric antrum identified by specific c-Kit antibody primers were chosen for electrophysiological recordings. HCN current (I(h)) of cultured ICCs was studied by whole-cell patch clamp techniques. A spontaneous transient inward current was recorded in ICCs, which could be inhibited by addition of CsCl and ZD7288; the current proved to be I(h). CCK-8S-facilitated I(h) in cultured ICCs could be inhibited by CsCl and ZD7288. When cultured ICCs were exposed to Ca2+-free solution, no significant changes could be recorded by application of CCK-8S on I(h), which proved extracellular calcium might have an excitatory effect on HCN channels. CONCLUSION: We demonstrate that HCN channels are present in ICCs in the murine gastric antrum; they might be an important regulator of ICC excitability and pacemaker activity and are strongly affected by CCK-8S. Extracellular calcium might be a trigger in the activation of HCN channels caused by CCK-8S in cultured ICCs. PMID- 22538232 TI - The ionic conductivity in lithium-boron oxide materials and its relation to structural, electronic and defect properties: insights from theory. AB - We review recent theoretical studies on ion diffusion in (Li(2)O)(x)(B(2)O(3))(1 x) compounds and at the interfaces of Li(2)O :B(2)O(3) nanocomposite. The investigations were performed theoretically using DFT and HF/DFT hybrid methods with VASP and CRYSTAL codes. For the pure compound B(2)O(3), it was theoretically confirmed that the low-pressure phase B(2)O(3)-I has space group P3(1)21. For the first time, the structure, stability and electronic properties of various low index surfaces of trigonal B(2)O(3)-I were investigated at the same theoretical level. The (101) surface is the most stable among the considered surfaces. Ionic conductivity was investigated systematically in Li(2)O, LiBO(2), and Li(2)B(4)O(7) solids and in Li(2)O:B(2)O(3) nanocomposites by calculating the activation energy (E(A)) for cation diffusion. The Li(+) ion migrates in an almost straight line in Li(2)O bulk whereas it moves in a zig-zag pathway along a direction parallel to the surface plane in Li(2)O surfaces. For LiBO(2), the migration along the c direction (E(A) = 0.55 eV) is slightly less preferable than that in the xy plane (E(A) = 0.43-0.54 eV). In Li(2)B(4)O(7), the Li(+) ion migrates through the large triangular faces of the two nearest oxygen five-vertex polyhedra facing each other where E(A) is in the range of 0.27-0.37 eV. A two dimensional model system of the Li(2)O :B(2)O(3) interface region was created by the combination of supercells of the Li(2)O (111) surface and the B(2)O(3) (001) surface. It was found that the interface region of the Li(2)O:B(2)O(3) nanocomposite is more defective than Li(2)O bulk, which facilitates the conductivity in this region. In addition, the activation energy (E(A )) for local hopping processes is smaller in the Li(2)O :B(2)O(3) nanocomposite compared to the Li(2)O bulk. This confirms that the Li(2)O:B(2)O(3) nanocomposite shows enhanced conductivity along the phase boundary compared to that in the nanocrystalline Li(2)O. PMID- 22538233 TI - Fetal and maternal analgesia/anesthesia for fetal procedures. AB - For many prenatally diagnosed conditions, treatment is possible before birth. These fetal procedures can range from minimal invasive punctions to full open fetal surgery. Providing anesthesia for these procedures is a challenge, where care has to be taken for both mother and fetus. There are specific physiologic changes that occur with pregnancy that have an impact on the anesthetic management of the mother. When providing maternal anesthesia, there is also an impact on the fetus, with concerns for potential negative side effects of the anesthetic regimen used. The question whether the fetus is capable of feeling pain is difficult to answer, but there are indications that nociceptive stimuli have a physiologic reaction. This nociceptive stimulation of the fetus also has the potential for longer-term effects, so there is a need for fetal analgesic treatment. The extent to which a fetus is influenced by the maternal anesthesia depends on the type of anesthesia, with different needs for extra fetal anesthesia or analgesia. When providing fetal anesthesia, the potential negative consequences have to be balanced against the intended benefits of blocking the physiologic fetal responses to nociceptive stimulation. PMID- 22538234 TI - Genetically engineered vegetables expressing proteins from Bacillus thuringiensis for insect resistance: successes, disappointments, challenges and ways to move forward. AB - Genetically engineered (GE) insect-resistant crops that express proteins from Bacillus thuringiensis (Bt) have been widely adopted in the two field crops currently commercially available, Bt cotton and Bt corn. However, the development and commercialization of Bt vegetables has lagged in comparison, which is unfortunate since vegetables tend to be insecticide-intensive crops due to high pest pressure and cosmetic standards required for the market. While it is often stated that consumer choice has played a major role in companies avoiding development of Bt vegetables, this concept requires re-evaluation. In market studies in North America when consumers have been provided basic information about Bt genetic engineering, then given a choice between Bt and conventional sweet corn, they have often preferred the former. Likewise, 77% of consumers in a US survey said they would likely purchase foods produced through biotechnology for their ability to reduce pesticide use. Presently, however, the only commercialized Bt vegetable is sweet corn. Perhaps more critical obstacles to Bt vegetables are their relatively smaller acreages and the cost of government biosafety regulations that inadvertently favor large acreage of field crops because companies can obtain a better return on investment. In developing countries, private-public partnerships may provide the vehicle to bring Bt vegetables to market. However, these can be subverted by misinformation from anti biotech campaigns, as is the case with Bt eggplant in India. Without the use of Bt vegetables as a tool for integrated pest management, farmers and the general public will not be able to realize the substantial environmental and economic benefits that have been well documented with Bt cotton and Bt corn. PMID- 22538235 TI - The effects of levodopa and deep brain stimulation on subthalamic local field low frequency oscillations in Parkinson's disease. AB - New adaptive systems for deep brain stimulation (DBS) could in the near future optimize stimulation settings online so as to achieve better control over the clinical fluctuations in Parkinson's disease (PD). Local field potentials (LFPs) recorded from the subthalamic nucleus (STN) in PD patients show that levodopa and DBS modulate STN oscillations. Because previous research has shown that levodopa and DBS variably influence beta LFP activity (8-20 Hz), we designed this study to find out how they affect low-frequency (LF) oscillations (2-7 Hz). STN LFPs were recorded in 19 patients with PD during DBS, after levodopa medication, and during DBS and levodopa intake combined. We investigated the relationship between LF modulations, DBS duration and levodopa intake. We also studied whether LF power depended on disease severity, the patient's clinical condition and whether LF modulations were related to electrode impedances. LF power increased during DBS, after levodopa intake and under both experimental conditions combined. The LF power increase correlated with the levodopa-induced clinical improvement and the higher the electrode impedance, the greater was the LF power change. These data suggest that the LF band could be useful as a control neurosignal for developing novel adaptive DBS systems for patients with PD. PMID- 22538236 TI - Chronic coexistence of two troponin T isoforms in adult transgenic mouse cardiomyocytes decreased contractile kinetics and caused dilatative remodeling. AB - Our previous in vivo and ex vivo studies suggested that coexistence of two or more troponin T (TnT) isoforms in adult cardiac muscle decreased cardiac function and efficiency (Huang QQ, Feng HZ, Liu J, Du J, Stull LB, Moravec CS, Huang X, Jin JP, Am J Physiol Cell Physiol 294: C213-C22, 2008; Feng HZ, Jin JP, Am J Physiol Heart Circ Physiol 299: H97-H105, 2010). Here we characterized Ca(2+) regulated contractility of isolated adult cardiomyocytes from transgenic mice coexpressing a fast skeletal muscle TnT together with the endogenous cardiac TnT. Without the influence of extracellular matrix, coexistence of the two TnT isoforms resulted in lower shortening amplitude, slower shortening and relengthening velocities, and longer relengthening time. The level of resting cytosolic Ca(2+) was unchanged, but the peak Ca(2+) transient was lowered and the durations of Ca(2+) rising and decaying were longer in the transgenic mouse cardiomyocytes vs. the wild-type controls. Isoproterenol treatment diminished the differences in shortening amplitude and shortening and relengthening velocities, whereas the prolonged durations of relengthening and Ca(2+) transient in the transgenic cardiomyocytes remained. At rigor state, a result from depletion of Ca(2+), resting sarcomere length of the transgenic cardiomyocytes became shorter than that in wild-type cells. Inhibition of myosin motor diminished this effect of TnT function on cross bridges. The length but not width of transgenic cardiomyocytes was significantly increased compared with the wild-type controls, corresponding to longitudinal addition of sarcomeres and dilatative remodeling at the cellular level. These dominantly negative effects of normal fast TnT demonstrated that chronic coexistence of functionally distinct variants of TnT in adult cardiomyocytes reduces contractile performance with pathological consequences. PMID- 22538238 TI - Automated region of interest analysis of dynamic Ca2+ signals in image sequences. AB - Ca(2+) signals are commonly measured using fluorescent Ca(2+) indicators and microscopy techniques, but manual analysis of Ca(2+) measurements is time consuming and subject to bias. Automated region of interest (ROI) detection algorithms have been employed for identification of Ca(2+) signals in one dimensional line scan images, but currently there is no process to integrate acquisition and analysis of ROIs within two-dimensional time lapse image sequences. Therefore we devised a novel algorithm for rapid ROI identification and measurement based on the analysis of best-fit ellipses assigned to signals within noise-filtered image sequences. This algorithm was implemented as a plugin for ImageJ software (National Institutes of Health, Bethesda, MD). We evaluated the ability of our algorithm to detect synthetic Gaussian signal pulses embedded in background noise. The algorithm placed ROIs very near to the center of a range of signal pulses, resulting in mean signal amplitude measurements of 99.06 +/- 4.11% of true amplitude values. As a practical application, we evaluated both agonist-induced Ca(2+) responses in cultured endothelial cell monolayers, and subtle basal endothelial Ca(2+) dynamics in opened artery preparations. Our algorithm enabled comprehensive measurement of individual and localized cellular responses within cultured cell monolayers. It also accurately identified characteristic Ca(2+) transients, or Ca(2+) pulsars, within the endothelium of intact mouse mesenteric arteries and revealed the distribution of this basal Ca(2+) signal modality to be non-Gaussian with respect to amplitude, duration, and spatial spread. We propose that large-scale statistical evaluations made possible by our algorithm will lead to a more efficient and complete characterization of physiologic Ca(2+)-dependent signaling. PMID- 22538237 TI - Reciprocal regulation controlling the expression of CPI-17, a specific inhibitor protein for the myosin light chain phosphatase in vascular smooth muscle cells. AB - Cellular activity of the myosin light chain phosphatase (MLCP) determines agonist induced force development of smooth muscle (SM). CPI-17 is an endogenous inhibitor protein for MLCP, responsible for mediating G-protein signaling into SM contraction. Fluctuations in CPI-17 expression occur in response to pathological stresses, altering excitation-contraction coupling in SM. Here, we determined the signaling pathways regulating CPI-17 expression in rat aorta tissues and the cell culture using a pharmacological approach. CPI-17 transcription was suppressed in response to the proliferative stimulus with platelet-derived growth factor (PDGF) through the ERK1/2 pathway, whereas it was elevated in response to inflammatory, stress-induced and excitatory stimuli with transforming growth factor-beta, IL 1beta, TNFalpha, sorbitol, and serotonin. CPI-17 transcription was repressed by inhibition of JNK, p38, PKC, and Rho-kinase (ROCK). The mouse and human CPI-17 gene promoters were governed by the proximal GC-boxes at the 5'-flanking region, where Sp1/Sp3 transcription factors bound. Sp1 binding to the region was more prominent in intact aorta tissues, compared with the SM cell culture, where the CPI-17 gene is repressed. The 173-bp proximal promoter activity was negatively and positively regulated through PDGF-induced ERK1/2 and sorbitol-induced p38/JNK pathways, respectively. By contrast, PKC and ROCK inhibitors failed to repress the 173-bp promoter activity, suggesting distal enhancer elements. CPI-17 transcription was insensitive to knockdown of myocardin/Kruppel-like factor 4 small interfering RNA or histone deacetylase inhibition. The reciprocal regulation of Sp1/Sp3-driven CPI-17 expression through multiple kinases may be responsible for the adaptation of MLCP signal and SM tone to environmental changes. PMID- 22538240 TI - Binding of carbonic anhydrase IX to extracellular loop 4 of the NBCe1 Na+/HCO3- cotransporter enhances NBCe1-mediated HCO3- influx in the rat heart. AB - Na(+)/HCO(3)(-) cotransporter (NBC)e1 catalyze the electrogenic movement of 1 Na(+):2 HCO(3)(-) into cardiomyocytes cytosol. NBC proteins associate with carbonic anhydrases (CA), CAII, and CAIV, forming a HCO(3)(-) transport metabolon. Herein, we examined the physical/functional interaction of NBCe1 and transmembrane CAIX in cardiac muscle. NBCe1 and CAIX physical association was examined by coimmunoprecipitation, using rat ventricular lysates. NBCe1 coimmunoprecipitated with anti-CAIX antibody, indicating NBCe1 and CAIX interaction in the myocardium. Glutathione-S-transferase (GST) pull-down assays with predicted extracellular loops (EC) of NBCe1 revealed that NBCe1-EC4 mediated interaction with CAIX. Functional NBCe1/CAIX interaction was examined using fluorescence measurements of BCECF in rat cardiomyocytes to monitor cytosolic pH. NBCe1 transport activity was evaluated after membrane depolarization with high extracellular K(+) in the presence or absence of the CA inhibitors, benzolamide (BZ; 100 MUM) or 6-ethoxyzolamide (ETZ; 100 MUM) (*P < 0.05). This depolarization protocol produced an intracellular pH (pH(i)) increase of 0.17 +/- 0.01 (n = 11), which was inhibited by BZ (0.11 +/- 0.02; n = 7) or ETZ (0.06 +/- 0.01; n = 6). NBCe1 activity was also measured by changes of pH(i) in NBCe1-transfected human embryonic kidney 293 cells subjected to acid loads. Cotransfection of CAIX with NBCe1 increased the rate of pH(i) recovery (in mM/min) by about fourfold (12.1 +/ 0.8; n = 9) compared with cells expressing NBCe1 alone (3.1 +/- 0.5; n = 7), which was inhibited by BZ (7.5 +/- 0.3; n = 9). We demonstrated that CAIX forms a complex with EC4 of NBCe1, which activates NBCe1-mediated HCO(3)(-) influx in the myocardium. CAIX and NBCe1 have been linked to tumorigenesis and cardiac cell growth, respectively. Thus inhibition of CA activity might be useful to prevent activation of NBCe1 under these pathological conditions. PMID- 22538239 TI - Hair cell BK channels interact with RACK1, and PKC increases its expression on the cell surface by indirect phosphorylation. AB - Large conductance (BK) calcium activated potassium channels (Slo) are ubiquitous and implicated in a number of human diseases including hypertension and epilepsy. BK channels consist of a pore forming alpha-subunit (Slo) and a number of accessory subunits. In hair cells of nonmammalian vertebrates these channels play a critical role in electrical resonance, a mechanism of frequency selectivity. Hair cell BK channel clusters on the surface and currents increase along the tonotopic axis and contribute significantly to the responsiveness of these hair cells to sounds of high frequency. In contrast, messenger RNA levels encoding the Slo gene show an opposite decrease in high frequency hair cells. To understand the molecular events underlying this paradox, we used a yeast two-hybrid screen to isolate binding partners of Slo. We identified Rack1 as a Slo binding partner and demonstrate that PKC activation increases Slo surface expression. We also establish that increased Slo recycling of endocytosed Slo is at least partially responsible for the increased surface expression of Slo. Moreover, analysis of several PKC phosphorylation site mutants confirms that the effects of PKC on Slo surface expression are likely indirect. Finally, we show that Slo clusters on the surface of hair cells are also increased by increased PKC activity and may contribute to the increasing amounts of channel clusters on the surface of high frequency hair cells. PMID- 22538242 TI - [Health and vitamin D: an incomplete puzzle]. PMID- 22538243 TI - Vertical ZnO nanowire growth on metal substrates. AB - Vertical growth of ZnO nanowires is usually achieved on lattice-matched substrates such as ZnO or sapphire using various vapor transport techniques. Accomplishing this on silicon substrates requires thick ZnO buffer layers. Here we demonstrate growth of vertical ZnO nanowires on FeCrAl substrates. The pre annealing prior to growth appears to preferentially segregate Al and O to the surface, thus leading to a self-forming, thin pseudo-buffer layer, which then results in vertical nanowire growth as on sapphire substrates. Metal substrates are more suitable and cheaper than others for applications in piezoelectric devices, and thin self-forming layers can also reduce interfacial resistance to electrical and thermal conduction. PMID- 22538241 TI - Relation of cumulative low-level lead exposure to depressive and phobic anxiety symptom scores in middle-age and elderly women. AB - BACKGROUND: Different lines of evidence suggest that low-level lead exposure could be a modifiable risk factor for adverse psychological symptoms, but little work has explored this relation. OBJECTIVE: We assessed whether bone lead--a biomarker of cumulative lead exposure--is associated with depression and anxiety symptoms among middle-age and elderly women. METHODS: Participants were 617 Nurses' Health Study participants with K-shell X-ray fluorescence bone lead measures and who had completed at last one Mental Health Index 5-item scale (MHI 5) and the phobic anxiety scale of the Crown-Crisp Index (CCI) assessment at mean +/- SD age of 59 +/- 9 years (range, 41-83 years). With exposure expressed as tertiles of bone lead, we analyzed MHI-5 scores as a continuous variable using linear regression and estimated the odds ratio (OR) of a CCI score >= 4 using generalized estimating equations. RESULTS: There were no significant associations between lead and either outcome in the full sample, but associations were found among premenopausal women and women who consistently took hormone replacement therapy (HRT) between menopause and bone lead measurement (n = 142). Compared with women in the lowest tertile of tibia lead, those in the highest scored 7.78 points worse [95% confidence interval (CI): -11.73, -3.83] on the MHI-5 (p-trend = 0.0001). The corresponding OR for CCI >= 4 was 2.79 (95% CI: 1.02, 7.59; p trend = 0.05). No consistent associations were found with patella lead. CONCLUSIONS: These results provide support for an association of low-level cumulative lead exposure with increased depressive and phobic anxiety symptoms among older women who are premenopausal or who consistently take postmenopausal HRT. PMID- 22538244 TI - Advances in the treatment of hepatitis C virus infection. AB - Since 2007, the annual age-adjusted mortality rate in hepatitis C virus (HCV) infection in the United States has been greater than that in HIV disease, reflecting the continuing decline in HIV-related mortality and the continuing increase in HCV-related mortality. The approval of 2 new direct-acting antivirals within the past year, as well as the promise offered by numerous other direct acting agents in development, provides hope that we will be able to markedly improve our ability to cure HCV disease. The addition of a protease inhibitor (PI) to what has been the standard HCV therapy of peginterferon alfa and ribavirin dramatically improves sustained virologic response rates in treatment naive patients with genotype 1 infection. Similar results have been observed in some treatment-experienced patients in whom prior peginterferon alfa/ribavirin therapy has failed. The use of these new agents has also permitted response guided therapy, wherein early sustained virologic response to treatment allows for a shortened treatment duration. However, these new PIs add cost and adverse effects to HCV therapy. Boceprevir is associated with increased risk of anemia and dysgeusia, and telaprevir is associated with increased risk of anemia and skin and gastrointestinal adverse effects. Early studies indicate that the addition of PIs results in high response rates in patients with HCV/HIV coinfection. Other studies suggest that combinations of PIs and other direct acting antivirals may ultimately permit cure when used in interferon sparing regimens. This article summarizes a presentation by David L. Thomas, MD, MPH, at the IAS-USA live continuing medical education course held in New York City in October 2011. PMID- 22538245 TI - Sexually transmitted infections and HIV: diagnosis and treatment. AB - Accurate assessment, diagnosis, and treatment of sexually transmitted infections (STIs) in HIV-infected persons can identify sexual risk behaviors and specific STIs that may increase transmission of STIs and HIV. HIV-infected men and women should be screened annually for syphilis and urogenital gonorrhea and chlamydia. Serologic testing for hepatitis A, B, and C viruses should also be performed. Women should be tested for trichomoniasis and undergo a cervical Papanicolaou test annually. Men who report receptive anal intercourse with men during the preceding year should be screened for rectal gonorrhea and chlamydia. Men who report receptive oral intercourse with men during the preceding year should be screened for oropharyngeal gonorrhea. More frequent screening at 3- to 6-month intervals may be indicated for men who have sex with men who have numerous or anonymous partners. STIs may have unusual presentations in HIV-infected patients. Aspects of diagnosis and management of common STIs will be discussed in this article. This article summarizes a presentation by Kimberly A. Workowski, MD, at the IAS-USA live continuing medical education course held in New York City in October 2011. PMID- 22538246 TI - Hepatitis C virus therapeutics: at the end of the beginning. PMID- 22538247 TI - Increase in serum brain-derived neurotrophic factor in met allele carriers of the BDNF Val66Met polymorphism is specific to males. AB - BACKGROUND: Association studies of the Val66Met polymorphism and serum brain derived neurotrophic factor (BDNF) levels have yielded conflicting results. Recently, sex-specific differences in BDNF levels were demonstrated. As these might explain the reported inconsistencies, we tested sex interactions with the Val66Met genotype on serum BDNF level. METHODS: Participants (n = 548, age range 50-72 years; mean 62.8 +/- 5.4 years, 267 males) were tested for rs6265 genotype and serum BDNF levels [Hardy-Weinberg equilibrium (HWE), p = 0.04]. A regression analysis with BDNF level as the dependent variable and BDNF Val66Met genotype as an independent variable was used to test the sex interaction corrected for age, smoking and depressive symptoms. Subsequently, we examined the effect of genotype on BDNF levels stratified for sex. RESULTS: We found a significant interaction between sex and genotype on BDNF levels (p = 0.02). Male Met carriers had significantly higher BDNF levels than Val/Val homozygotes (beta = 0.17, p = 0.013), while in females no effect of Val66Met genotype was found (beta = -0.07, p = 0.28). CONCLUSION: Our findings may partly explain the inconsistent findings of earlier studies where results were influenced by male-female ratios. Replication is warranted, however, as our sample was not in HWE. PMID- 22538248 TI - Collagen adhesin-nanoparticle interaction impairs adhesin's ligand binding mechanism. AB - BACKGROUND: Pathogenic bacteria specifically recognize extracellular matrix (ECM) molecules of the host (e.g. collagen, fibrinogen and fibronectin) through their surface proteins known as MSCRAMMs (Microbial Surface Components Recognizing Adhesive Matrix Molecules) and initiate colonization. On implantation, biomaterials easily get coated with these ECM molecules and the MSCRAMMs mediate bacterial adherence to biomaterials. With the rapid rise in antibiotic resistance, designing alternative strategies to reduce/eliminate bacterial colonization is absolutely essential. METHODS: The Rhusiopathiae surface protein B (RspB) is a collagen-binding MSCRAMM of Erysipelothrix rhusiopathiae. It also binds to abiotic surfaces. The crystal structure of the collagen-binding region of RspB (rRspB31-348) reported here revealed that RspB also binds collagen by a unique ligand binding mechanism called "Collagen Hug" which is a common theme for collagen-binding MSCRAMMs of many Gram-positive bacteria. Here, we report the interaction studies between rRspB31-348 and silver nanoparticles using methods like gel shift assay, gel permeation chromatography and circular dichroism spectroscopy. RESULTS: The "Collagen Hug" mechanism was inhibited in the presence of silver nanoparticles as rRspB31-348 was unable to bind to collagen. The total loss of binding was likely because of rRspB31-348 and silver nanoparticle protein corona formation and not due to the loss of the structural integrity of rRspB31 348 on binding with nanoparticles as observed from circular dichroism experiments. GENERAL SIGNIFICANCE: Interaction of rRspB31-348 with silver nanoparticle impaired its ligand binding mechanism. Details of this inhibition mechanism may be useful for the development of antimicrobial materials and antiadhesion drugs. PMID- 22538249 TI - Dynamic chiral-at-metal stability of tetrakis(d/l-hfc)Ln(III) complexes capped with an alkali metal cation in solution. AB - Chiral tetrakis(beta-diketonate) Ln(III) complexes Delta-[NaLa(d hfc)(4)(CH(3)CN)] (1) and Lambda-[NaLa(l-hfc)(4) (CH(3)CN)] (2) (d/l-hfc(-) = 3 heptafluo-robutylryl-(+)/(-)-camphorate) are a pair of enantiomers and crystallize in the same Sohncke space group (P2(1)2(1)2(1)) with dodecahedral (DD) geometry. Typically positive and negative exciton splitting patterns around 320 nm were observed in the solid-state circular dichroism (CD) spectra of complexes 1 and 2, which indicate that their shell configurational chiralities are Delta and Lambda, respectively. The apparent bisignate couplets in the solid state CD spectra of [CsLn(d-hfc)(4)(H(2)O)] [Ln = La (3), Yb (5)] and [CsLn(l hfc)(4)(H(2)O)] [Ln = La (4), Yb (6)] show that they are a pair of enantiomers and their absolute configurations are denoted Delta and Lambda, respectively. The crystallographic data of 5 reveals that its coordination polyhedron is the square antiprism (SAP) geometry and it undergoes a phase transition from triclinic (alpha phase, P1) to monoclinic (beta phase, C2) upon cooling. The difference between the two phases is brought about by the temperature dependent behaviour of the coordination water molecules, but this did not affect the configurational chirality of the Delta-SAP-[Yb(d-hfc)(4)](-) moiety. Furthermore, time-dependent CD, UV-vis and (19)F NMR were applied to study the solution behavior of these complexes. It was found that the chiral-at-metal stability of the three pairs of complexes is different and affected by both the Ln(3+) and M(+) ion size. The results show that the Cs(+) cation can retain the metal center chirality and stablize the structures of [Ln(d/l-hfc)(4)](-) or the dissociated tris(d/l hfc)Ln(III) species in solution for a longer time than that of the Na(+) cation, and it is important that the Cs(+) ion successfully lock the configurational chirality around the Yb(3+) center of the complex species in solution. This is reasoned by the short Cs(+)...FC, Cs(+)...O-Yb and Cs(+)...Yb(3+) interactions observed in the crystal structure of alpha-5 and further confirmed by the chiral self-assembly of 5 or 6 from [Yb(H(2)O)(d/l-hfc)(3)] induced by CsI in a CHCl(3) solution. PMID- 22538250 TI - Are conventional reconstruction plates equivalent to precontoured locking plates for distal humerus fracture fixation? A biomechanics cadaver study. AB - BACKGROUND: The optimal plate type and configuration for distal humerus fracture fixation has yet to be defined. Available biomechanical studies show conflicting results. No existing studies compare conventional reconstruction plates to newer precontoured distal humerus locking plates in both parallel and perpendicular configurations. METHODS: Three groups of humerus specimens were compared via biomechanical testing in a cadaver model simulating metaphyseal comminution. Group 1 consisted of conventional reconstruction plates in a perpendicular configuration. Group 2 used precontoured locking plates in a perpendicular configuration. Group 3 used precontoured locking plates in a parallel configuration. Each group was tested for stiffness in anterior bending, posterior bending, axial compression, and torsion. The specimens then underwent cyclic loading followed by single load to failure in posterior bending. FINDINGS: There was no significant difference between the three groups for anterior bending, posterior bending, axial compression, or torsional stiffness. There was no significant difference in load to failure for any of the three groups. Screw loosening was significantly higher in Group 1 when compared to Groups 2 and 3 after cyclic loading. INTERPRETATION: In the early postoperative period, less expensive perpendicular conventional reconstruction plate constructs provide similar stiffness and load to failure properties to newer precontoured locking plate systems regardless of plate configuration. PMID- 22538251 TI - Mitochondrial tRNA mutations associated with deafness. AB - Mitochondrial tRNA mutations are one of the important causes of both syndromic and non-syndromic deafness. Of those, syndromic deafness-associated tRNA mutations such as tRNA(Leu(UUR)) 3243A>G are often present in heteroplasmy, while non-syndromic deafness-associated tRNA mutations including tRNA(Ser(UCN)) 7445A>G often occur in homplasmy or in high levels of heteroplasmy. These tRNA mutations are the primary mutations leading to hearing loss. However, other tRNA mutations such as tRNA(Thr) 15927G>A and tRNA(Ser(UCN)) 7444G>A may act in synergy with the primary mitochondrial DNA mutations, modulating the phenotypic manifestation of the primary mitochondrial DNA mutations. Theses tRNA mutations cause structural and functional alteration. A failure in tRNA metabolism caused by these tRNA mutations impaired mitochondrial translation and respiration, thereby causing mitochondrial dysfunctions responsible for deafness. These data offer valuable information for the early diagnosis, management and treatment of maternally inherited deafness. PMID- 22538252 TI - alpha1 and alpha2-adrenoceptors in the medial amygdaloid nucleus modulate differently the cardiovascular responses to restraint stress in rats. AB - Medial amygdaloid nucleus (MeA) neurotransmission has an inhibitory influence on cardiovascular responses in rats submitted to restraint, which are characterized by both elevated blood pressure (BP) and intense heart rate (HR) increase. In the present study, we investigated the involvement of MeA adrenoceptors in the modulation of cardiovascular responses that are observed during an acute restraint. Male Wistar rats received bilateral microinjections of the selective alpha1-adrenoceptor antagonist WB4101 (10, 15, and 20 nmol/100 nL) or the selective alpha2-adrenoceptor antagonist RX821002 (10, 15, and 20 nmol/nL) into the MeA, before the exposure to acute restraint. The injection of WB4101 reduced the restraint-evoked tachycardia. In contrast, the injection of RX821002 increased the tachycardia. Both drugs had no influence on BP increases observed during the acute restraint. Our findings indicate that alpha1 and alpha2 adrenoceptors in the MeA play different roles in the modulation of the HR increase evoked by restraint stress in rats. Results suggest that alpha1 adrenoceptors and alpha2-adrenoceptors mediate the MeA-related facilitatory and inhibitory influences on restraint-related HR responses, respectively. PMID- 22538253 TI - Osteoprotegerin is associated with hip fracture incidence: the Tromso Study. AB - BACKGROUND: Osteoprotegerin (OPG) is a cytokine essential for the regulation of bone resorption, but large longitudinal studies on its relationship to fracture risk in humans are lacking. In this population-based study of 2740 men and 2857 post-menopausal women, it was examined whether serum OPG was associated with hip fracture incidence. The participants were followed for 15 years. METHODS: Baseline measurements included height, weight and serum OPG, and information about lifestyle, prevalent diseases and use of medication. RESULTS: Men with OPG in the highest quartile were 2.79-fold [95% confidence interval (CI) 1.34-5.82] more likely to have a hip fracture during follow-up, compared with those with OPG in the lowest quartile (P-trend over OPG quartiles <= 0.001, after adjustments for age and other confounders). In women not using post-menopausal hormone therapy (HT), the risk of hip fracture was 1.64-fold higher (95% CI 0.94-2.86) in the highest quartile compared with the lowest OPG quartile (P-trend over OPG quartiles = 0.05). No relationship was found in post-menopausal women using HT (P trend over OPG quartiles = 0.23). CONCLUSIONS: In men, OPG was positively associated with the incidence of hip fracture. In post-menopausal women not using HT a similar, but weaker, relationship was found. PMID- 22538255 TI - Preferences for opt-in and opt-out enrollment and consent models in biobank research: a national survey of Veterans Administration patients. AB - PURPOSE: In 2006, the Department of Veterans Affairs launched the Genomic Medicine Program with the goal of using genomic information to personalize and improve health care for veterans. A step toward this goal is the Million Veteran Program, which aims to enroll a million veterans in a longitudinal cohort study and establish a database with genomic, lifestyle, military-exposure, and health information. Before the launch of the Million Veteran Program, a survey of Department of Veterans Affairs patients was conducted to measure preferences for opt-in and opt-out models of enrollment and consent. METHODS: An online survey was conducted with a random sample of 451 veterans. The survey described the proposed Million Veteran Program database and asked respondents about the acceptability of opt-in and opt-out models of enrollment. The study examined differences in responses among demographic groups and relationships between beliefs about each model and willingness to participate. RESULTS: Most respondents were willing to participate under both opt-in (80%) and opt-out (69%) models. Nearly 80% said they would be comfortable providing access to residual clinical samples for research. At least half of respondents did not strongly favor one model over the other; of those who expressed a preference, significantly more people said they would participate in a study using opt-in methods. Stronger preferences for the opt-in approach were expressed among younger patients and Hispanic patients. CONCLUSION: Support for the study and willingness to participate were high for both enrollment models. The use of an opt-out model could impede recruitment of certain demographic groups, including Hispanic patients and patients under the age of 55 years. PMID- 22538256 TI - Uniparental disomy: can SNP array data be used for diagnosis? AB - Purpose:Single-nucleotide polymorphism microarray analysis identifies copy-number variants and blocks of homozygosity, suggestive of consanguinity or uniparental disomy. The purpose of this study was to validate chromosomal microarray analysis for the identification of uniparental disomy in a clinical laboratory.Methods:In phase I of this retrospective study, nine cases with uniparental disomy for chromosomes 7 (n = 1), 14 (n = 1), and 15 (n = 7), identified by conventional polymorphic microsatellite marker analysis were analyzed on the Affymetrix 6.0 single-nucleotide polymorphism array. In phase II, four cases of uniparental disomy 15 showing heterozygosity for all microsatellite markers were analyzed using the same array.Results:Chromosomal microarray analysis detected blocks of homozygosity in eight of the nine cases in phase I. Phase II analysis of molecularly defined heterodisomy failed to detect blocks of homozygosity in three of the four cases. The four cases in which microarray did not detect blocks of homozygosity all involved chromosome 15.Conclusion:A failure to recombine may predispose to nondisjunction and, therefore, to uniparental disomy. Four cases of heterodisomy 15 were not detected by array, suggesting a lack of recombination. Therefore, a normal chromosomal microarray result for chromosome 15 does not exclude the possibility of uniparental disomy. This observation may apply to other chromosomes; however, further study is needed.Genet Med advance online publication 26 April 2012. PMID- 22538254 TI - The emerging phenotype of long-term survivors with infantile Pompe disease. AB - PURPOSE: Enzyme replacement therapy with alglucosidase alfa for infantile Pompe disease has improved survival creating new management challenges. We describe an emerging phenotype in a retrospective review of long-term survivors. METHODS: Inclusion criteria included ventilator-free status and age <=6 months at treatment initiation, and survival to age >=5 years. Clinical outcome measures included invasive ventilator-free survival and parameters for cardiac, pulmonary, musculoskeletal, gross motor, and ambulatory status; growth; speech, hearing, and swallowing; and gastrointestinal and nutritional status. RESULTS: Eleven of 17 patients met study criteria. All were cross-reactive immunologic material positive, alive, and invasive ventilator-free at most recent assessment, with a median age of 8.0 years (range: 5.4-12.0 years). All had marked improvements in cardiac parameters. Commonly present were gross motor weakness, motor speech deficits, sensorineural and/or conductive hearing loss, osteopenia, gastroesophageal reflux, and dysphagia with aspiration risk. Seven of 11 patients were independently ambulatory and four required the use of assistive ambulatory devices. All long-term survivors had low or undetectable anti-alglucosidase alfa antibody titers. CONCLUSION: Long-term survivors exhibited sustained improvements in cardiac parameters and gross motor function. Residual muscle weakness, hearing loss, risk for arrhythmias, hypernasal speech, dysphagia with risk for aspiration, and osteopenia were commonly observed findings. PMID- 22538257 TI - Efficient promotion of phosphate diester cleavage by a face-to-face cyclodextrin dimer without metal. AB - An organic face-to-face cyclodextrin dimer promotes the cleavage of bis(4 nitrophenyl) phosphate efficiently in neutral pH without the addition of metal. Both of the phosphate diester bonds can be cleaved. PMID- 22538258 TI - Angiogenesis in neuroendocrine tumors: therapeutic applications. AB - The considerable research efforts devoted to the understanding of the mechanisms of tumor angiogenesis have resulted in the development of targeted anti angiogenic therapies and finally in their introduction in clinical practice. Neuroendocrine tumors (NETs), which are characterized by a high vascular supply and a strong expression of VEGF-A, one of the most potent pro-angiogenic factors, are an attractive indication for these new treatments. However, several lines of evidence show that the dense vascular networks associated with low-grade NETs are more likely to be a marker of differentiation than a marker of aggressiveness, as in other epithelial tumors. These observations form the basis for the so-called 'neuroendocrine paradox', according to which the most vascularized are the most differentiated and the less angiogenic NETs. This must be kept in mind when discussing the role of anti-angiogenic strategies in the treatment of NETs. Nevertheless, several targeted therapies, with direct or indirect anti-angiogenic properties, including anti-VEGF antibodies, tyrosine kinase inhibitors (sunitinib) and mTOR inhibitors (everolimus), have recently proven to be of clinical benefit. In addition, some drugs already used in NET treatment, such as somatostatin analogues and interferon-alpha, may also have anti-angiogenic properties. The main challenges for the next future are to validate biomarkers for the selection of patients and the prediction of their response to refine the indications of anti-angiogenic targeted therapies and to overcome the mechanisms of resistance, which explain the limited duration of action of most of these treatments. PMID- 22538259 TI - A further piece of the puzzle: positive FOBT, colonoscopy, aspirin and the prevention of colorectal cancer. PMID- 22538261 TI - Men's sexual issues after breast cancer in their wives: a qualitative study. AB - BACKGROUND: Husbands of women with breast cancer may experience problems in their sexual relationships with their wives. Adjustment to sexual issues can be affected by cultural norms and beliefs. Understanding men's perceptions and responses to their new sexual status after diagnosis of their wife's disease and during its treatment may help clinicians to better support the couple. OBJECTIVE: The objective of this study was to explore the sexual issues of Iranian men after breast cancer in their wives. METHODS: A qualitative research method based on the grounded theory approach was used. In-depth interviews were conducted with a purposive sampling of Iranian men experiencing breast cancer in their wives. Data analysis was based on the constant comparative method. RESULTS: Eighteen men were interviewed. Five main themes emerged: sexual relationship changes, sexual avoidance, sexual abstinence, sexual restraint, and efforts to normalize the relationship. CONCLUSIONS: The participants experienced problems in their sex lives. Because cultural and religious beliefs were important factors affecting the men's sexual adjustment, health system providers should encourage husbands to tolerate and adjust to their sexual issues in the context of their culture and religion. IMPLICATIONS FOR PRACTICE: The findings of this study could help nurses and other healthcare professionals recognize sexual issues in the husbands of women with breast cancer and promote the couples' healthy sexual life. PMID- 22538260 TI - The burdensome and depressive experience of caring: what cancer, schizophrenia, and Alzheimer's disease caregivers have in common. AB - BACKGROUND: Family members of patients with chronic illnesses experience distress as a result of caregiving roles, which can be manifested as burden and depression, but cross-disease studies on how caring is experienced are limited. OBJECTIVE: The present study was designed to examine the burden and psychiatric morbidity in the form of depression experienced by Cypriot families caring for a relative with one of the following: cancer, Alzheimer's disease, or schizophrenia. METHODS: This study was cross-sectional, descriptive, and correlational. A total of 410 caregivers were recruited from the community. The research instruments included the Greek version of the Burden Interview and the Center of Epidemiological Studies-Depression Scale. Descriptive statistics, 1-way analysis of variance, and post hoc Tukey pairwise comparisons were used to examine significant differences between the 3 groups. RESULTS: The results indicate a high level of burden and depression among all caregivers. Significant differences (P < .001, F = 26.11) between the 3 caregiving groups were detected in terms of burden, with the highest reported for Alzheimer's disease caregivers. One-way analysis of variance showed significant differences (P = .008, F = 4.85) between the 3 caregiving groups in terms of depression, with the highest depression levels being for cancer caregivers. CONCLUSIONS: The findings increase our understanding about burden and emotional well-being in family caring for relatives with cancer and other chronic illnesses. IMPLICATIONS FOR PRACTICE: The findings may be useful for health professionals to plan intervention strategies focusing on each domain of burden. The lessons learned from the caregiving role of family caregivers of patients with Alzheimer's disease or schizophrenia can be used to improve the caregiving process of patients with cancer. PMID- 22538262 TI - Family interaction patterns and their association with family support among women with breast cancer. AB - BACKGROUND: Family support often plays a major role in helping women accept, cope with, and recover from breast cancer, and yet its association with specific family interaction patterns among racially diverse women facing breast cancer has been insufficiently examined. OBJECTIVE: The aim of the study was to examine what specific family interaction patterns exist among diverse women with breast cancer and determine if these family interaction patterns are significantly associated with levels of perceived family support and family support satisfaction reported by these women. METHODS: Participants were 73 white women and 18 African American women with breast cancer. RESULTS: Three different family interaction patterns were identified (ie, cohesive-expressive, conflictual, and nonexpressive). Also, (a) the African American women in cohesive-expressive families versus conflictual families were more satisfied with their emotional family support, (b) the non Hispanic white women in conflictual families versus nonexpressive families perceived that they received significantly more tangible family support, and (c) the non-Hispanic white women in cohesive-expressive families and those in conflictual families perceived that they received significantly more emotional support from their family members than did non-Hispanic white women in nonexpressive families. CONCLUSIONS: Three main family interaction patterns were found among African American and non-Hispanic white women with breast cancer, which were associated with levels of satisfaction with family support or perceived family support. IMPLICATIONS FOR PRACTICE: Findings from this study can be used to (a) more accurately assess the levels of satisfaction with family support experienced by diverse women with breast cancer and (b) implement family interventions to increase family support for these women. PMID- 22538263 TI - The unmet needs of emerging adults with a cancer diagnosis: a qualitative study. AB - BACKGROUND: Emerging adulthood is the life stage between adolescence and young adulthood, and it has been associated with several important developmental milestones. A cancer diagnosis has the potential to disrupt the normal achievement of these milestones. Many psychosocial themes relevant to emerging adults living with cancer have been identified, but there has been only limited research into the needs of this group. OBJECTIVE: The present study seeks to contribute to this limited research base and inform our understanding of the needs of emerging adults with a diagnosis of cancer from a developmental perspective that appreciates the key transitional tasks of emerging adulthood. METHODS: This needs-based qualitative study was conducted with 14 young people with a diagnosis of cancer, aged 20 to 25 years. Nine participated in a focus group, and the remaining 5 participated in 1-on-1 telephone interviews. RESULTS: The needs of these emerging adults in relation to their cancer experience were grouped into 6 themes: information, healthcare provision, daily living, interpersonal support, identity renegotiation, and emotional distress. CONCLUSION: A cancer experience poses the potential for significant impact on the 4 main requirements for the achievement of adulthood: accepting responsibility for oneself, deciding on personal beliefs and values, establishing relationships with parents as equals, and becoming financially independent. IMPLICATIONS FOR PRACTICE: This study provides a useful framework for understanding the needs of emerging adults with a diagnosis of cancer that will assist healthcare professionals in the development and delivery of more targeted supportive care and interventions. PMID- 22538264 TI - Two-pulse excitation for efficient formation of an sp3 nanodomain with frozen shear in a graphite crystal. AB - We propose a two-pulse excitation to efficiently form a novel sp(3)-bonded nanosize domain with frozen shear in a graphite crystal. This sp(3) structure is well stabilized by shear displacement between two neighboring graphite layers. The shearing motion is induced transiently by the first laser pulse, and is frozen by the second pulse before disappearing, resulting in the efficient formation of the sp(3)-bonded domain with frozen shear. We show this dynamical process qualitatively by molecular dynamics calculations. PMID- 22538265 TI - Simultaneous emergence of entecavir resistance mutations in a nucleoside-naive chronic hepatitis B patient. AB - BACKGROUND: Entecavir (ETV) has potent antiviral activity against hepatitis B virus (HBV), and the emergence of drug resistance is rare in nucleoside-naive patients. Resistance requires simultaneous appearance of three mutations which account for the very low resistance profile of ETV. We experienced one case of genotypic ETV resistance with viral rebound during ETV treatment of nucleoside naive patients with chronic hepatitis B (CHB). CASE: A 50-year-old HBV e antigen positive man received ETV 0.5 mg/day for 120 weeks. The level of HBV DNA was 9.0 log(10) copies/ml at baseline, declined to a nadir of 2.7 at week 60 and then rebounded to 6.0 at week 108 and 7.5 at week 120. The serum alanine aminotransferase level did not increase during ETV treatment. The ETV resistance related substitution (T184A) and lamivudine resistance-related substitutions (L180M and M204V) were detected by sequence analysis at week 96. CONCLUSIONS: The three substitutions associated with ETV and lamivudine resistance developed simultaneously without complete suppression in a nucleoside-naive CHB patient after extended therapy. In spite of the extremely rare chance of viral mutation during ETV treatment, treatment-naive patients with high pretreatment viral loads and detectable HBV DNA during treatment should be carefully monitored or undergo targeted surveillance for resistance. PMID- 22538267 TI - Effects of tissue conductivity and electrode area on internal electric fields in a numerical human model for ELF contact current exposures. AB - Contact currents flow through the human body when a conducting object with different potential is touched. There are limited reports on numerical dosimetry for contact current exposure compared with electromagnetic field exposures. In this study, using an anatomical human adult male model, we performed numerical calculation of internal electric fields resulting from 60 Hz contact current flowing from the left hand to the left foot as a basis case. Next, we performed a variety of similar calculations with varying tissue conductivity and contact area, and compared the results with the basis case. We found that very low conductivity of skin and a small electrode size enhanced the internal fields in the muscle, subcutaneous fat and skin close to the contact region. The 99th percentile value of the fields in a particular tissue type did not reliably account for these fields near the electrode. In the arm and leg, the internal fields for the muscle anisotropy were identical to those in the isotropy case using a conductivity value longitudinal to the muscle fibre. Furthermore, the internal fields in the tissues abreast of the joints such as the wrist and the elbow, including low conductivity tissues, as well as the electrode contact region, exceeded the ICNIRP basic restriction for the general public with contact current as the reference level value. PMID- 22538266 TI - Estimated effects of Asian dust storms on spatiotemporal distributions of clinic visits for respiratory diseases in Taipei children (Taiwan). AB - BACKGROUND: Increases in certain cause-specific hospital admissions have been reported during Asian dust storms (ADS), which primarily originate from north and northwest China during winter and spring. However, few studies have investigated the relationship between the ADS and clinic visits for respiratory diseases in children. OBJECTIVE: We investigated the general impact to children's health across space and time by analyzing daily clinic visits for respiratory diseases among preschool and schoolchildren registered in 12 districts of Taipei City during 1997-2007 from the National Health Insurance dataset. METHODS: We applied a structural additive regression model to estimate the association between ADS episodes and children's clinic visits for respiratory diseases, controlling for space and time variations. RESULTS: Compared with weeks before ADS events, the rate of clinic visits during weeks after ADS events increased 2.54% (95% credible interval = 2.43, 2.66) for preschool children (<= 6 years of age) and 5.03% (95% credible interval = 4.87, 5.20) for schoolchildren (7-14 years of age). Spatial heterogeneity in relative rates of clinic visits was also identified. Compared with the mean level of Taipei City, higher relative rates appeared in districts with or near large hospitals and medical centers. CONCLUSION: To our knowledge, this is the first population-based study to assess the impact of ADS on children's respiratory health. Our analysis suggests that children's respiratory health was affected by ADS events across all of Taipei, especially among schoolchildren. PMID- 22538268 TI - From contemporary rehabilitation to restorative neurology. AB - Recent years have witnessed significant advances in the treatment of neurological injuries such as stroke, traumatic brain injuries (TBI), and spinal cord injuries (SCI). The current approach includes acute intervention to curb the primary insult, prevention of secondary complications and early rehabilitation to optimize residual function to ultimately enhance quality of life and independence. While this is effective in providing a degree of independence to many patients, we believe that further functional gains are possible for many patients who have plateaued followed a contemporary rehabilitation program. Complementary methods are available today that are not widely used, but have demonstrated great promise in augmenting function and quality of life in patients who cannot benefit further from currently available treatment options. PMID- 22538269 TI - Evidences and controversies about recurrence of diabetic foot osteomyelitis: a personal view and an illustrated guide for understanding. AB - Recurrence is one of the most worrying issues when dealing with diabetic foot osteomyelitis (DFO). In accordance with expert opinion in other areas of bone infection, it is accepted that very late relapse of apparently successfully treated osteomyelitis is not uncommon. However, the physiopathology of infections in large bones secondary to hematogenous osteomyelitis, infected prostheses, and open fractures is quite different from what is seen in the feet of patients with diabetes. The anatomy of the bones, the mechanism of infection and alterations in host defenses that are frequently seen in patients with diabetes may condition the onset, clinical course, and outcomes. Apparent eradication, disappearance of inflammatory signs, wound healing, bone healing based on image studies, and no recurrences during follow-up are common terms used for defining the success of therapy for DFO. Failure of initial surgical treatment, readmission to hospital, and new episodes of infection at the same or a contiguous site are considered as recurrence of osteomyelitis. Theoretically, bacteria living in the bone could be the source of clinical recurrence, but is it possible to obtain complete healing while bacteria remain alive in the bone in the feet of patients with diabetes? Can these bacteria grow and spread from the bone to the skin after years of healing? In the author's opinion, this type of long-term recurrence of DFO has not been well documented in the medical literature. It is the aim of this illustrated guide to review the evidence and controversies regarding the recurrence of DFO. PMID- 22538270 TI - Effect of gemfibrozil on the metabolism of brivaracetam in vitro and in human subjects. AB - Brivaracetam (BRV) is a new high-affinity synaptic vesicle protein 2A ligand in phase III for epilepsy. Initial studies suggested that the hydroxylation of BRV into BRV-OH is supported by CYP2C8. Other metabolic routes include hydrolysis into a carboxylic acid derivative (BRV-AC), which could be further oxidized into a hydroxy acid derivative (BRV-OHAC). The aim of the present study was to investigate the effect of gemfibrozil (CYP2C9 inhibitor) and its 1-O-beta glucuronide (CYP2C8 inhibitor) on BRV disposition both in vivo (healthy participants) and in vitro (human liver microsomes and hepatocytes). In a two period randomized crossover study, 26 healthy male participants received a single oral dose of 150 mg of BRV alone or at steady state of gemfibrozil (600 mg b.i.d). Gemfibrozil did not modify plasma and urinary excreted BRV, BRV-OH, or BRV-AC. The only observed change was a modest decrease (approximately -40%) in plasma and urinary BRV-OHAC. In human hepatocytes and/or liver microsomes, gemfibrozil potently inhibited the hydroxylation of BRV-AC into BRV-OHAC (K(I) 12 MUM) while having a marginal effect on BRV-OH formation (K(I) >=153 MUM). Gemfibrozil-1-O-beta-glucuronide had no relevant effect on either reaction (K(I) >200 MUM). In conclusion, gemfibrozil did not influence the pharmacokinetics of BRV and its hydroxylation into BRV-OH. Overall, in vitro and in vivo data suggest that CYP2C8 and CYP2C9 are not involved in BRV hydroxylation, whereas hydroxylation of BRV-AC to BRV-OHAC is likely to be mediated by CYP2C9. PMID- 22538271 TI - EEG vigilance regulation patterns and their discriminative power to separate patients with major depression from healthy controls. AB - BACKGROUND/AIM: Recently, a framework has been presented that links vigilance regulation, i.e. tonic brain arousal, with clinical symptoms of affective disorders. Against this background, the aim of this study was to deepen the knowledge of vigilance regulation by (1) identifying different patterns of vigilance regulation at rest in healthy subjects (n = 141) and (2) comparing the frequency distribution of these patterns between unmedicated patients with major depression (MD; n = 30) and healthy controls (HCs; n = 30). METHOD: Each 1-second segment of 15-min resting EEGs from 141 healthy subjects was classified as 1 of 7 different vigilance stages using the Vigilance Algorithm Leipzig. K-means clustering was used to distinguish different patterns of EEG vigilance regulation. The frequency distribution of these patterns was analyzed in independent data of 30 unmedicated MD patients and 30 matched HCs using a chi2 test. RESULTS: The 3-cluster solution with a stable, a slowly declining and an unstable vigilance regulation pattern yielded the highest mathematical quality and performed best for separation of MD patients and HCs (chi2 = 13.34; p < 0.001). Patterns with stable vigilance regulation were found significantly more often in patients with MD than in HCs. CONCLUSION: A stable vigilance regulation pattern, derived from a large sample of HCs, characterizes most patients with MD and separates them from matched HCs with a sensitivity between 67 and 73% and a specificity between 67 and 80%. The pattern of vigilance regulation might be a useful biomarker for delineating MD subgroups, e.g. for treatment prediction. PMID- 22538273 TI - Surface decorated platinum carbonyl clusters. AB - Four molecular Pt-carbonyl clusters decorated by Cd-Br fragments, i.e., [Pt(13)(CO)(12){Cd(5)(MU-Br)(5)Br(2)(dmf)(3)}(2)](2-) (1), [Pt(19)(CO)(17){Cd(5)(MU-Br)(5)Br(3)(Me(2)CO)(2)}{Cd(5)(MU Br)(5)Br(Me(2)CO)(4)}](2-) (2), [H(2)Pt(26)(CO)(20)(CdBr)(12)](8-) (3) and [H(4)Pt(26)(CO)(20)(CdBr)(12)(PtBr)(x)](6-) (4) (x = 0-2), have been obtained from the reactions between [Pt(3n)(CO)(6n)](2-) (n = 2-6) and CdBr(2).H(2)O in dmf at 120 degrees C. The structures of these molecular clusters with diameters of 1.5-2 nm have been determined by X-ray crystallography. Both 1 and 2 are composed of icosahedral or bis-icosahedral Pt-CO cores decorated on the surface by Cd-Br motifs, whereas 3 and 4 display a cubic close packed Pt(26)Cd(12) metal frame decorated by CO and Br ligands. An oversimplified and unifying approach to interpret the electron count of these surface decorated platinum carbonyl clusters is suggested, and extended to other low-valent organometallic clusters and Au-thiolate nanoclusters. PMID- 22538272 TI - Nothing in medicine makes sense, except in the light of evolution. AB - The practice of medicine is a fruitful marriage of classic diagnostic and healing arts with modern advancements in many relevant sciences. The scientific aspects of medicine are rooted in understanding the biology of our species and those of other organisms that interact with us in health and disease. Thus, it is reasonable to paraphrase Dobzhansky, stating that, "nothing in the biological aspects of medicine makes sense except in the light of evolution." However, the art and science of medicine are also rooted in the unusual cognitive abilities of humans and the cultural evolutionary processes arising. This explains the rather bold and inclusive title of this essay. The near complete absence of evolution in medical school curricula is a historical anomaly that needs correction. Otherwise, we will continue to train generations of physicians who lack understanding of some fundamental principles that should guide both medical practice and research. I here recount my attempts to correct this deficiency at my own medical school and the lessons learned. I also attempt to summarize what I teach in the limited amount of time allowed for the purpose. Particular attention is given to the value of comparing human physiology and disease with those of other closely related species. There is a long way to go before the teaching of evolution can be placed in its rightful context within the medical curriculum. However, the trend is in the right direction. Let us aim for a day when an essay like this will no longer be relevant. PMID- 22538274 TI - Alveolar gas exchange and tissue deoxygenation during exercise in type 1 diabetes patients and healthy controls. AB - We used near-infrared spectroscopy to investigate whether leg and arm skeletal muscle and cerebral deoxygenation differ during incremental cycling exercise in men with type 1 diabetes (T1D, n=10, mean+/-SD age 33+/-7 years) and healthy control men (matched by age, anthrometry, and self-reported physical activity, CON, n=10, 32+/-7 years) to seek an explanation for lower aerobic capacity (VO2peak) often reported in T1D. T1D had lower VO2peak (35+/-4mlkg(-1)min(-1) vs. 43+/-8mlkg(-1)min(-1), P<0.01) and peak work rate (219+/-33W vs. 290+/-44W, P<0.001) than CON. Leg muscle deoxygenation (? [deoxyhemoglobin]; ? tissue saturation index) was greater in T1D than CON at a given absolute submaximal work rate, but not at peak exercise, while arm muscle and cerebral deoxygenation were similar. Thus, in T1D compared with CON, faster leg muscle deoxygenation suggests limited circulatory ability to increase O(2) delivery as a plausible explanation for lower VO2peak and earlier fatigue in T1D. PMID- 22538275 TI - Is ultracision knife safe and efficient for breast capsulectomy? A preliminary study. AB - BACKGROUND: Silicone breast implants are used to a wide extent in the field of plastic surgery. However, capsular contracture remains a considerable concern. This study aimed to analyze the effectiveness and applicability of an ultracision knife for capsulectomy breast surgery. METHODS: A prospective, single-center, randomized study was performed in 2009. The inclusion criteria specified female patients 20-80 years of age with capsular contracture (Baker 3-4). Ventral capsulectomy was performed using an ultracision knife on one side and the conventional Metzenbaum-type scissors and surgical knife on the collateral side of the breast. Measurements of the resected capsular ventral fragment, operative time, remaining breast tissue, drainage time, seroma and hematoma formation, visual analog scale pain score, and sensory function of the nipple-areola complex were assessed. In addition, histologic analysis of the resected capsule was performed. RESULTS: Five patients (median age, 59.2 years) were included in this study with a mean follow-up period of 6 months. Three patients had Baker grade 3 capsular contracture, and two patients had Baker grade 4 capsular contracture. The ultracision knife was associated with a significantly lower pain score, shorter operative time, smaller drainage volume, and shorter drainage time and resulted in a larger amount of remaining breast tissue. Histologic analysis of the resected capsule showed no apoptotic cells in the study group or control group. CONCLUSIONS: The results suggest that ventral capsulectomy with Baker grade 3 or 4 contracture using the ultracision knife is feasible, safe, and more efficient than blunt dissection and monopolar cutting diathermy and has a short learning curve. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266. PMID- 22538276 TI - New classification for correction of alar retraction using the alar spreader graft. AB - BACKGROUND: Identifying the cause of alar retraction is essential for proper correction of this deformity. In secondary surgery, aimed primarily at cephalic orientation and medialization of the lateral crus, corrections involving spreading and lateralization of the lateral crus can achieve a more horizontal orientation. In their clinic, the authors have practiced the use of an alar spreader graft to support the spread of the lateral crus. For the lateral crus to move freely without any resistance, it is critical to release the nasal hinge and pyriform ligament. A frontal view of the alar notching and the direction of the lateral crus are highly important factors needed to determine the cause of alar retraction. This report describes a new classification system for alar retractions viewed from the front to aid in determining the cause of the retraction and the surgical management. METHODS: From March 2008 to July 2010, 31 alar retractions were corrected using alar spreader grafts for patients showing clear alar retractions in frontal views. RESULTS: Satisfactory results without severe complications were obtained in 30 cases, with undercorrection in only 1 case. The alar cartilage was completely released to facilitate lateralization and caudal mobilization. An alar spreader graft then was used to support the lateral crus until a biologic scar cast was formed. CONCLUSION: The use of alar spreader grafts to correct alar retractions provided consistently good results. The attempt also was made to enhance the treatment strategy based on this classification system derived from frontal views of alar retraction. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266 . PMID- 22538277 TI - Striae distensae after breast augmentation. AB - BACKGROUND: One known but not fully understood complication after breast augmentation is the new onset of stretch marks (striae distensae) on the surgically treated breast. To date, all publications on this subject have been case reports. No report has fully described the actual incidence, risk factors, or management of striae distensae after breast surgery. METHODS: This study prospectively followed patients who underwent primary breast augmentation using silicone implants in a single group practice from 2007 to 2011. New-onset striae distensae were actively investigated. Time from surgery to the moment of striae onset, patient age, nulliparity, use of oral contraceptives, overweight, personal history of stretch marks, and other variables were evaluated. RESULTS: A total of 409 patients were included in the study. In 19 cases (4.6%), new-onset striae distensae after breast augmentation were observed. The population with striae distensae was significantly younger than the total population (29.56 vs 20.91 years; p=0.012). Striae distensae also were more common in nulliparous than in multiparous women (8.29 vs 0.52%; p=0.006), overweight women (17.77 vs 3.02%; p=0.016), women using oral contraceptives (7.89 vs 0.55%; p=0.008), and women with a personal history of stretch marks (8.97 vs 3.36%; p=0.031). No relation was shown regarding implant pocket type, size, or profile. CONCLUSION: Striae distensae may be a common but underreported complication after breast augmentation. In this series, striae distensae developed in 4.6% of the patients within 1 year after breast augmentation. Severity may vary from inconspicuous small marks (classifications 1 and 2) to wide red and active striae rubra (classifications 3 and 4). Nulliparity, use of oral contraceptives, overweight, personal history of stretch marks, and younger age were related to a higher incidence of striae distensae. The increased rates in these groups may be associated with their exposure to higher estrogen levels and the important role of this hormone in facilitating the formation of striae distensae. Further studies are needed to show whether changes in these risk factors (i.e., weight loss, contraceptive withdrawal) may help to decrease striae distensae rates is these populations. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266. PMID- 22538278 TI - Tretinoin cyclodextrin complex (RA/CyD) causes less irritation with an equal antiwrinkle effect compared with conventional tretinoin: clinical and histologic studies of photoaged skin. AB - BACKGROUND: Topical tretinoin [all-trans-retinoic acid (RA)] currently is widely used to treat photoaged skin. However, undesirable side effects such as erythema, irritation, and scaling are unavoidable and limit the use of tretinoin. To address these issues, the authors developed the tretinoin cyclodextrin complex (RA/CyD), which is tretinoin encapsulated by cyclodextrin. Cyclodextrins are cyclic oligosaccharides commonly used in food additives and fabric fresheners. This study aimed to evaluate the antiwrinkle effect of RA/CyD and alleviation of the side effects compared with RA treatment alone. METHODS: In this study, 12 photoaged patients completed an 8 week study using RA and RA/CyD in a double blind manner. Before and after the treatment, the patients' evaluations, wrinkle scores, skin elasticity, and wrinkle area measurement using skin replica were evaluated. Three men were recruited for histologic analysis. RESULTS: The patients reported that undesirable irritant reactions were more moderate with RA/CyD than with RA. In the assessment of wrinkle scores, skin elasticity, and wrinkle area measurement, RA/CyD demonstrated an antiwrinkle effect statistically equal to that of RA. In histology, both RA/CyD and RA demonstrated epidermal hyperplasia. In immunohistochemistry, inflammation induced by RA/CyD was more moderate than that induced by RA. CONCLUSION: The findings show that RA and RA/CyD result in the equivalent clinical improvement for patients with photoaging. The use of RA/CyD overcomes the drawbacks of RA while possessing equal effect. It is expected that CyD will broaden tretinoin treatment. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266. PMID- 22538280 TI - [Advance of spinal instrumentation]. PMID- 22538279 TI - The influence of vibration type, frequency, body position and additional load on the neuromuscular activity during whole body vibration. AB - This study aimed to assess the influence of different whole body vibration (WBV) determinants on the electromyographic (EMG) activity during WBV in order to identify those training conditions that cause highest neuromuscular responses and therefore provide optimal training conditions. In a randomized cross-over study, the EMG activity of six leg muscles was analyzed in 18 subjects with respect to the following determinants: (1) vibration type (side-alternating vibration (SV) vs. synchronous vibration (SyV), (2) frequency (5-10-15-20-25-30 Hz), (3) knee flexion angle (10 degrees -30 degrees -60 degrees ), (4) stance condition (forefoot vs. normal stance) and (5) load variation (no extra load vs. additional load equal to one-third of the body weight). The results are: (1) neuromuscular activity during SV was enhanced compared to SyV (P < 0.05); (2) a progressive increase in frequency caused a progressive increase in EMG activity (P < 0.05); (3) the EMG activity was highest for the knee extensors when the knee joint was 60 degrees flexed (P < 0.05); (4) for the plantar flexors in the forefoot stance condition (P < 0.05); and (5) additional load caused an increase in neuromuscular activation (P < 0.05). In conclusion, large variations of the EMG activation could be observed across conditions. However, with an appropriate adjustment of specific WBV determinants, high EMG activations and therefore high activation intensities could be achieved in the selected muscles. The combination of high vibration frequencies with additional load on an SV platform led to highest EMG activities. Regarding the body position, a knee flexion of 60 degrees and forefoot stance appear to be beneficial for the knee extensors and the plantar flexors, respectively. PMID- 22538281 TI - [Resistance to antiplatelet agents assessed by a point-of-care platelet function test and thromboembolic adverse events in neurointervention]. AB - OBJECTIVE: To clarify the frequency of Japanese patients who are resistant to antiplatelet agents, and then clarify correlations between resistance and thromboembolic adverse events in neurointervention. METHODS: Blood samples were collected from 163 patients who were taking antiplatelet agents and received neurointervention, with 128 samples collected just before neurointervention. Residual platelet function was measured using a point-of-care platelet function test, VerifyNow(r), and then the frequency of patients resistant to drugs (low responders), correlations between resistance and thromboembolic events, and effects of adding cilostazol to clopidogrel administration were analyzed. Cut-off values were defined as 550 Aspirin Reaction Units (ARU), 230 P2Y12 Reaction Units (PRU), and 50%inhibition of P2Y12, respectively. RESULTS: Three of 105 patients (2.9%) taking aspirin at 100 mg/day were low-responders, whereas 48 (41.0%, as measured by PRU) or 80 (68.4%, as measured by %inhibition) of 117 patients taking clopidogrel at 75 mg/day were low-responders. Among the 19 patients taking cilostazol 200 mg/day in addition to clopidogrel 75 mg/day, platelet functions were significantly more strongly inhibited compared to patients taking clopidogrel alone (p=0.02 by PRU, p=0.005 by %inhibition). Thromboembolic adverse events occurred in 7 patients. Among these 7 patients, 6 who were taking aspirin were all responders to aspirin, while 4 of the 6 patients taking clopidogrel were low-responders to clopidogrel. In 69 patients who received aneurysmal transarterial embolization, 2 thromboembolic complications occurred among low responders (p=0.09). CONCLUSION: Aspirin resistance is rare in Japanese individuals. With aneurysmal transarterial embolization, thromboembolic events tended to occur among clopidogrel low-responders. Addition of cilostazol may offer one method of overcoming clopidogrel resistance. PMID- 22538282 TI - [A cranial reconstruction using an autologous split calvarial bone combined with a free graft of temporal loose areolar tissue]. AB - We report a new simple method of cranial reconstruction using an autologous split calvarial bone, combined with free graft of temporal loose areolar tissue. A 58 year-old woman suffered from a cranium defect on her left side. The originating bone infection happened after initial brain tumor surgery. Part of the left side of her scalp just above the damaged cranial area had become very thin due to previous cranioplasty, which involved a titanium mesh plate and postoperative infections. We performed a cranial reconstruction with an autologous split calvarial bone, combined with loose areolar tissue free graft, for the damaged area with skin from the inner side. In our case, we expect that the addition of the free graft of loose areolar tissue to the autologous calvarial bone graft will effectively contribute to the skin's healing and provide good cosmetic results in our short follow-up period. A free graft of loose areolar tissue for the damaged skin area may be a new optional method for cranial reconstruction in a patient with skin trouble. PMID- 22538283 TI - [Subclavian artery stenting using gadolinium contrast medium in a case with iodine allergy]. AB - The authors reported a subclavian artery stenting (SAS) using gadolinium contrast medium. The patient was a 65-year-old female who presented dizziness and right upper extremity pain with movement. Digital subtraction angiography revealed right subclavian artery occlusion with subclavian steal phenomenon. We tried to treat this lesion using SAS. However, iodinated contrast medium caused the allergy in this patient and the treatment was discontinued. Therefore, SAS was performed with gadolinium contrast medium. Using gadolinium contrast medium, it is possible to confirm large arteries like innominate artery and subclavian artery. The stenting procedure was performed without complication. The usage of gadolinium contrast medium has the limit and some strategies are important to reduce the usage of gadolinium contrast medium in SAS. First, PercuSurge GuardWire(r) was placed in the right internal carotid artery to confirm the anatomy, to decide working angle, and to treat the common carotid artery in case of dissection. Second, a "U" shaped guide wire was placed in the distal end from the brachial artery. Guide wire from femoral side was able to pass the lesion at midpoint of the "U" shaped one. SAS using gadolinium contrast medium may be an alternative treatment if a patient with subclavian artery stenosis or occlusion is allergic to iodinated contrast medium. PMID- 22538284 TI - [A case of a penetrating brain injury due to an explosion of a construction machine]. AB - Penetrating brain injury caused by a high speed projectile is rather rare in Japan, known for its strict gun-control laws. We report a case of a 55-year-old male, who was transferred to our hospital with a foreign body in the brain due to penetrating head injury, which was caused by an explosion of a construction machine. Neurological examination demonstrated severe motor aphagia with no apparent motor paresis. The patient had a scalp laceration on his left forehead with exposed cerebral tissue and CSF leakage. Head CT scan and plain skull X-ray revealed a 20 mm*25 mm bolt which had penetrated due to the explosion of the machine. The anterior wall of the left frontal sinus was fractured resulting in dural laceration, and scattered bone fragments were seen along the trajectory of the bolt. Digital subtraction angiography showed no significant vascular injuries including superior sagittal sinus. We performed open surgery, and successfully removed the bolt along with the damaged frontal lobe. The patient had no infection or seizure after the surgery, and was transferred for further rehabilitation therapy. We performed a cosmetic cranioplasty six months later. Surgical debridement of the damaged cerebral tissue along the trajectory led to successful removal of the bolt with no further neurological deficit. PMID- 22538285 TI - [Abducens palsy due to unruptured aneurysms of the internal carotid artery in a patient with systemic lupus erythematosus]. AB - We report a rare case of unruptured aneurysms in systemic lupus erythematosus (SLE). A 28-year-old female who had suffered from SLE for 5 years was admitted to our hospital because she noticed diplopia three weeks before. She presented with left abducens palsy on admission. CT scans revealed intracranial multiple calcified lesions. MRA and the cerebral angiography showed multiple saccular aneurysms from the cavernous segment to the petrous segment of the left internal carotid artery (ICA). These findings suggested that left abducens palsy was related to cranial nerve compression due to the aneurysm at the cavernous segment of the left ICA. As balloon occlusion test for 15 minutes of the left ICA with 99mTc-HMPAO SPECT was tolerable, the patient underwent the endovascular trapping of multiple aneurysms from the cavernous segment to the petrous segment of the left ICA with detachable coils. Postoperative course was uneventful and left abducens palsy fully recovered. She was discharged with no neurological deficits. This is the first report presenting left abducens palsy due to unruptured aneurysms in SLE. We summarized the previous reports of cerebral aneurysms in SLE. PMID- 22538286 TI - [Intracranial hemorrhage associated with injury of the critical diploic venous system in clipping for unruptured cerebral aneurysm: a case report]. AB - A case of intracranial hemorrhage associated with injury of a critical diploic venous system in clipping for an unruptured cerebral aneurysm was reported. A 67 year-old female presented with a sense of floating. Magnetic resonance angiography (MRA) showed a C1-2 portion aneurysm of the left internal carotid artery 13 mm in size projecting supero-laterally. Three-dimensional CT angiography (3DCTA) volume rendering revealed a developed left fronto-anterior temporal diploic venous system draining the frontal cortical venous return. Because of the large and wide-necked aneurysm, we planned clipping surgery for the purpose of a complete cure. The operation was performed with left fronto temporal craniotomy at the expense of the diploic venous system. Using techniques such as bipolar coagulation and suction decompression, neck clipping was accomplished via the distal trans-sylvian approach. After the operation, the patient was noticed to be delirious, and post-operative CT demonstrated intracranial hemorrhage in the left frontal lobe with severe brain edema. Motor aphasia was remarkable, but it was gradually relieved, and she left our hospital with no motor weakness. 3 months after the operation, her aphasia was faintly perceptible but she could live independently. We concluded that the injury of a diploic venous system could cause intracranial hemorrhage with intractable brain edema by critically interrupting the frontal venous return. PMID- 22538287 TI - [A case of internal carotid artery stenosis with discontinuance of carotid endarterectomy due to the tight adhesions around the internal carotid artery]. AB - A 73-year-old female visited her local doctor after repeatedly experiencing temporary weakness in her left upper and lower extremities. The patient underwent a cervical magnetic resonance imaging (MRI) scan and was diagnosed with right internal carotid artery stenosis. Despite administration of antiplatelet drugs, her symptoms continued, and she was referred to our department for medical treatment. Her medical history revealed hypertension, hyperlipidemia, and cholesteatoma. We diagnosed symptomatic internal carotid artery stenosis and performed carotid endarterectomy (CEA). However, tight adhesions between the carotid artery and surrounding tissue made separation difficult, and surgery had to be discontinued. Some of the extracted adherent tissue consisted of hyalinized fibrous tissue that had the appearance of soft tissue which had organized because of inflammation. Although there have been no reports of cholesteatoma directly causing adhesion around the internal carotid artery, it has been reported to have led to abscess formation in the parapharyngeal space adjacent to the carotid space. Because the boundaries of the parapharyngeal space and carotid space are anatomically incomplete, inflammation often affects the area between them. As far as we know, this report, which also includes a discussion of the literature, is the first to indicate that cholesteatoma causes strong adhesions around the carotid artery. PMID- 22538288 TI - [Brain metastasis from papillary thyroid carcinoma with acute intracerebral hemorrhage: a surgical case report]. AB - We report a rare case of brain metastasis from papillary thyroid carcinoma with intracerebral hemorrhage. A 79-year-old woman presented with sudden headache and monoplegia of the right upper limb 10 years after diagnosis of thyroid papillary adenocarcinoma. Despite the known metastatic lesions in the cervical lymph nodes and lungs, she had been well for 10 years since thyroidectomy, focal irradiation and internal radiation of 131I. CT demonstrated intracerebral hemorrhage in the left temporal lobe. Magnetic resonance imaging showed marked signal heterogeneity. She underwent radical surgery on the day of the onset and the histological diagnosis was metastatic brain tumor of thyroid papillary carcinoma. Postoperative course was uneventful, and the monoplegia was improved. Papillary thyroid carcinoma has a relatively benign course, and surgical removal of the brain metastasis is able to contribute to longer survival times for patients. PMID- 22538289 TI - Computer-aided analysis of star shot films for high-accuracy radiation therapy treatment units. AB - As mechanical stability of radiation therapy treatment devices has gone beyond sub-millimeter levels, there is a rising demand for simple yet highly accurate measurement techniques to support the routine quality control of these devices. A combination of using high-resolution radiosensitive film and computer-aided analysis could provide an answer. One generally known technique is the acquisition of star shot films to determine the mechanical stability of rotations of gantries and the therapeutic beam. With computer-aided analysis, mechanical performance can be quantified as a radiation isocenter radius size. In this work, computer-aided analysis of star shot film is further refined by applying an analytical solution for the smallest intersecting circle problem, in contrast to the gradient optimization approaches used until today. An algorithm is presented and subjected to a performance test using two different types of radiosensitive film, the Kodak EDR2 radiographic film and the ISP EBT2 radiochromic film. Artificial star shots with a priori known radiation isocenter size are used to determine the systematic errors introduced by the digitization of the film and the computer analysis. The estimated uncertainty on the isocenter size measurement with the presented technique was 0.04 mm (2sigma) and 0.06 mm (2sigma) for radiographic and radiochromic films, respectively. As an application of the technique, a study was conducted to compare the mechanical stability of O ring gantry systems with C-arm-based gantries. In total ten systems of five different institutions were included in this study and star shots were acquired for gantry, collimator, ring, couch rotations and gantry wobble. It was not possible to draw general conclusions about differences in mechanical performance between O-ring and C-arm gantry systems, mainly due to differences in the beam MLC alignment procedure accuracy. Nevertheless, the best performing O-ring system in this study, a BrainLab/MHI Vero system, and the best performing C-arm system, a Varian Truebeam system, showed comparable mechanical performance: gantry isocenter radius of 0.12 and 0.09 mm, respectively, ring/couch rotation of below 0.10 mm for both systems and a wobble of 0.06 and 0.18 mm, respectively. The methodology described in this work can be used to monitor mechanical performance constancy of high-accuracy treatment devices, with means available in a clinical radiation therapy environment. PMID- 22538292 TI - Self-assembled one dimensional functionalized metal-organic nanotubes (MONTs) for proton conduction. AB - Two self-assembled isostructural functionalized metal-organic nanotubes have been synthesized using 5-triazole isophthalic acid (5-TIA) with In(III) and Cd(II). In and Cd-5TIA possess one-dimensional (1D) nanotubular architecture and show proton conductivity along regular 1D channels, measured as 5.35 * 10(-5) and 3.61 * 10(-3) S cm(-1) respectively. PMID- 22538291 TI - Estrogen receptors and the regulation of neural stress responses. AB - It is now well established that estrogens can influence a panoply of physiological and behavioral functions. In many instances, the effects of estrogens are mediated by the 'classical' actions of two different estrogen receptors (ERs), ERalpha or ERbeta. ERalpha and ERbeta appear to have opposing actions in the control of stress responses and modulate different neurotransmitter or neuropeptide systems. Studies elucidating the molecular mechanisms for such regulatory processes are currently in progress. Furthermore, the use of ERalpha and ERbeta knockout mouse lines has allowed the exploration of the importance of these receptors in behavioral responses such as anxiety-like and depressive-like behaviors. This review examines some of the recent advances in our knowledge of hormonal control of neuroendocrine and behavioral responses to stress and underscore the importance of these receptors as future therapeutic targets for control of stress-related signaling pathways. PMID- 22538293 TI - A review of the binding-change mechanism for proton-translocating transhydrogenase. AB - Proton-translocating transhydrogenase is found in the inner membranes of animal mitochondria, and in the cytoplasmic membranes of many bacteria. It catalyses hydride transfer from NADH to NADP(+) coupled to inward proton translocation. Evidence is reviewed suggesting the enzyme operates by a "binding-change" mechanism. Experiments with Escherichia coli transhydrogenase indicate the enzyme is driven between "open" and "occluded" states by protonation and deprotonation reactions associated with proton translocation. In the open states NADP(+)/NADPH can rapidly associate with, or dissociate from, the enzyme, and hydride transfer is prevented. In the occluded states bound NADP(+)/NADPH cannot dissociate, and hydride transfer is allowed. Crystal structures of a complex of the nucleotide binding components of Rhodospirillum rubrum transhydrogenase show how hydride transfer is enabled and disabled at appropriate steps in catalysis, and how release of NADP(+)/NADPH is restricted in the occluded state. Thermodynamic and kinetic studies indicate that the equilibrium constant for hydride transfer on the enzyme is elevated as a consequence of the tight binding of NADPH relative to NADP(+). The protonation site in the translocation pathway must face the outside if NADP(+) is bound, the inside if NADPH is bound. Chemical shift changes detected by NMR may show where alterations in protein conformation resulting from NADP(+) reduction are initiated. This article is part of a Special Issue entitled: 17th European Bioenergetics Conference (EBEC 2012). PMID- 22538294 TI - Proton transfer in the quinol-dependent nitric oxide reductase from Geobacillus stearothermophilus during reduction of oxygen. AB - Bacterial nitric oxide reductases (NOR) are integral membrane proteins that catalyse the reduction of nitric oxide to nitrous oxide, often as a step in the process of denitrification. Most functional data has been obtained with NORs that receive their electrons from a soluble cytochrome c in the periplasm and are hence termed cNOR. Very recently, the structure of a different type of NOR, the quinol-dependent (q)-NOR from the thermophilic bacterium Geobacillus stearothermophilus was solved to atomic resolution [Y. Matsumoto, T. Tosha, A.V. Pisliakov, T. Hino, H. Sugimoto, S. Nagano, Y. Sugita and Y. Shiro, Nat. Struct. Mol. Biol. 19 (2012) 238-246]. In this study, we have investigated the reaction between this qNOR and oxygen. Our results show that, like some cNORs, the G. stearothermophilus qNOR is capable of O(2) reduction with a turnover of ~3electronss(-1) at 40 degrees C. Furthermore, using the so-called flow-flash technique, we show that the fully reduced (with three available electrons) qNOR reacts with oxygen in a reaction with a time constant of 1.8ms that oxidises the low-spin heme b. This reaction is coupled to proton uptake from solution and presumably forms a ferryl intermediate at the active site. The pH dependence of the reaction is markedly different from a corresponding reaction in cNOR from Paracoccus denitrificans, indicating that possibly the proton uptake mechanism and/or pathway differs between qNOR and cNOR. This study furthermore forms the basis for investigation of the proton transfer pathway in qNOR using both variants with putative proton transfer elements modified and measurements of the vectorial nature of the proton transfer. This article is part of a Special Issue entitled: 17th European Bioenergetics Conference (EBEC 2012). PMID- 22538296 TI - Conversion of {Fe(NO)2}10 dinitrosyl iron to nitrato iron(III) species by molecular oxygen. AB - A new {Fe(NO)(2)}(10) dinitrosyl iron complex possessing a 2,9-dimethyl-1,10 phenanthroline ligand has been prepared. This complex exhibits dioxygenase activity, converting NO to nitrate (NO(3)(-)) anions. During the oxygenation reaction, formation of reactive nitrating species is implicated, as shown in the effective o-nitration with a phenolic substrate. PMID- 22538295 TI - Mitochondrial and ion channel gene alterations in autism. AB - To evaluate the potential importance in autistic subjects of copy number variants (CNVs) that alter genes of relevance to bioenergetics, ionic metabolism, and synaptic function, we conducted a detailed microarray analysis of 69 autism probands and 35 parents, compared to 89 CEU HapMap controls. This revealed that the frequency CNVs of>=100kb and CNVs of>=10 Kb were markedly increased in probands over parents and in probands and parents over controls. Evaluation of CNVs>=1Mb by chromosomal FISH confirmed the molecular identity of a subset of the CNVs, some of which were associated with chromosomal rearrangements. In a number of the cases, CNVs were found to alter the copy number of genes that are important in mitochondrial oxidative phosphorylation (OXPHOS), ion and especially calcium transport, and synaptic structure. Hence, autism might result from alterations in multiple bioenergetic and metabolic genes required for mental function. This article is part of a Special Issue entitled: 17th European Bioenergetics Conference (EBEC 2012). PMID- 22538297 TI - Three-dimensional hierarchical flower-like Mg-Al-layered double hydroxides: highly efficient adsorbents for As(V) and Cr(VI) removal. AB - 3D hierarchical flower-like Mg-Al-layered double hydroxides (Mg-Al-LDHs) were synthesized by a simple solvothermal method in a mixed solution of ethylene glycol (EG) and water. The formation mechanism of the flower-like Mg-Al-LDHs was proposed. After calcination, the flower-like morphology could be completely preserved. With relatively high specific surface areas, Mg-Al-LDHs and calcined Mg-Al-LDHs with 3D hierarchical nanostructures were tested for their application in water purification. When tested as adsorbents in As(V) and Cr(VI) removal, the as-prepared calcined Mg-Al-LDHs showed excellent performance, and the adsorption capacities of calcined Mg-Al-LDHs for As(V) and Cr(VI) were better than those of Mg-Al-LDHs. The adsorption isotherms, kinetics and mechanisms for As(V) and Cr(VI) onto calcined Mg-Al-LDHs were also investigated. The high uptake capability of the as-prepared novel 3D hierarchical calcined Mg-Al-LDHs make it a potentially attractive adsorbent in water purification. Also, this facile strategy may be extended to synthesize other LDHs with 3D hierarchical nanostructures, which may find many other applications due to their novel structural features. PMID- 22538298 TI - Heart rate variability in association with frequent use of household sprays and scented products in SAPALDIA. AB - BACKGROUND: Household cleaning products are associated with adverse respiratory health outcomes, but the cardiovascular health effects are largely unknown. OBJECTIVE: We determined if long-term use of household sprays and scented products at home was associated with reduced heart rate variability (HRV), a marker of autonomic cardiac dysfunction. METHODS: We recorded 24-hr electrocardiograms in a cross-sectional survey of 581 Swiss adults, >= 50 years of age, who answered a detailed questionnaire regarding their use of household cleaning products in their homes. The adjusted average percent changes in standard deviation of all normal-to-normal intervals in 24 hr (24-hr SDNN) and total power (TP) were estimated in multiple linear regression in association with frequency [< 1, 1-3, or 4-7 days/week, unexposed (reference)] of using cleaning sprays, air freshening sprays, and scented products. RESULTS: Decreases in 24-hr SDNN and TP were observed with frequent use of all product types, but the strongest reductions were associated with air freshening sprays. Compared with unexposed participants, we found that using air freshening sprays 4-7 days/week was associated with 11% [95% confidence interval (CI): -20%, -2%] and 29% (95% CI: -46%, -8%) decreases in 24-hr SDNN and TP, respectively. Inverse associations of 24-SDNN and TP with increased use of cleaning sprays, air freshening sprays, and scented products were observed mainly in participants with obstructive lung disease (p < 0.05 for interactions). CONCLUSIONS: In predominantly older adult women, long-term frequent use of household spray and scented products was associated with reduced HRV, which suggests an increased risk of cardiovascular health hazards. People with preexisting pulmonary conditions may be more susceptible. PMID- 22538299 TI - Neuropeptide-S evoked arousal with electroencephalogram slow-wave compensatory drive in rats. AB - OBJECTIVES: Neuropeptide S (NPS) exerts a dual arousal and anxiolytic effect in rodents, which may indicate the potential of a novel class of therapeutic agents in psychiatry. The purpose of this study is to fully describe the nature of electroencephalogram (EEG)-defined waking that mediates these arousal effects. METHODS: Effects of the intracerebroventricular infusion of NPS at 2 different doses were characterized over 20 h on sleep-wake architecture and EEG spectral components in rats that were chronically implanted with epidural electrodes for continuous measurement of sleep polygraphic and EEG variables. RESULTS: NPS (1 and 10 nmol) increased active waking (+88 and +87%, respectively), decreased light slow-wave sleep (lSWS) (-84 and -68%, respectively), deep slow-wave sleep (dSWS) (-47 and -33%, respectively) and rapid-eye-movement sleep (-71 and -70%, respectively) during the first 2 h after infusion. The wake-promoting effect of NPS is consistent with a marked lengthening in latency to sleep onset, a decrease in the number of state transitions from wakefulness to lSWS, and a delayed lSWS compensatory response. Interestingly, NPS significantly enhanced waking EEG theta oscillations and slow wave activity during dSWS. CONCLUSION: The findings suggest that NPS enhanced a consolidated waking associated with a subsequent compensatory EEG slow-wave homeostatic drive rather than rebound sleep duration. The characteristics of NPS-induced waking coupled with enhanced EEG theta oscillations without rebound in sleep are desirable therapeutic features in wake promoting agents. PMID- 22538300 TI - Periventricular demyelination and axonal pathology is associated with subependymal virus spread in a murine model for multiple sclerosis. AB - OBJECTIVES: Theiler's murine encephalomyelitis virus (TMEV) infection of mice is a widely used animal model for demyelinating disorders, such as multiple sclerosis (MS). The aim of the present study was to identify topographical differences of TMEV spread and demyelination in the brain of experimentally infected susceptible SJL/J mice and resistant C57BL/6 mice. METHODS: Demyelination was confirmed by Luxol fast blue and cresyl violet staining and axonal damage by neurofilament-specific and beta-amyloid precursor protein specific immunohistochemistry. Viral dissemination within the central nervous system (CNS) was quantified by immunohistochemistry and in situ hybridization. Further, the phenotype of infected cells was determined by confocal laser scanning microscopy. RESULTS: An early transient infection of periventricular cells followed by demyelination and axonopathies around the fourth ventricle in SJL/J mice was noticed. Periventricular and brain stem demyelination was associated with a predominant infection of microglia/macrophages and oligodendrocytes. CONCLUSIONS: Summarized, the demonstration of ependymal infection and subjacent spread into the brain parenchyma as well as regional virus clearance despite ongoing demyelination and axonal damage in other CNS compartments allows new insights into TME pathogenesis. This novel aspect of TMEV CNS interaction will enhance the understanding of region-specific susceptibilities to injury and regenerative capacities of the brain in this MS model. PMID- 22538301 TI - Aspirin users attending for NHS bowel cancer screening have less colorectal neoplasia: chemoprevention or false-positive faecal occult blood testing? AB - OBJECTIVE: The NHS Bowel Cancer Screening Programme (BCSP) uses faecal occult blood (FOB) testing to select patients aged 60-69 years for colonoscopy. AIM: To examine the association between aspirin use and the detection of colorectal neoplasia in screened patients undergoing colonoscopy. METHODS: Data were collected prospectively on individuals who underwent colonoscopy following a positive FOB test in the South of Tyne area between February 2007 and 2009. The relationship between the presence of colorectal neoplasia and age, gender, body mass index (BMI) and current aspirin use were evaluated using logistic regression analysis. RESULTS: 701 individuals underwent colonoscopy. 414 (59.1%) were male and 358 (51.1%) aged over 65 years. Males had a higher incidence of colorectal neoplasia (relative risk 2.26, 95% CI 1.65-3.10, p < 0.001). Current aspirin use was associated with a lower neoplasia detection rate (relative risk 0.79, 95% CI 0.50-0.98, p = 0.039). Increased age and BMI were not significantly associated with higher neoplasia detection. CONCLUSION: Amongst individuals undergoing colonoscopy following a positive FOB test in the BCSP, current aspirin use was associated with a lower incidence of colorectal neoplasia. This may represent the chemopreventative effect of aspirin or increased false positivity of FOB testing. Further work is needed to clarify the contribution of each and could reduce the number of unnecessary colonoscopies. PMID- 22538303 TI - Electronic structure of transparent oxides with the Tran-Blaha modified Becke Johnson potential. AB - We present electronic band structures of transparent oxides calculated using the Tran-Blaha modified Becke-Johnson (TB-mBJ) potential. We studied the basic n-type conducting binary oxides In(2)O(3), ZnO, CdO and SnO(2) along with the p-type conducting ternary oxides delafossite CuXO(2) (X=Al, Ga, In) and spinel ZnX(2)O(4) (X=Co, Rh, Ir). The results are presented for calculated band gaps and effective electron masses. We discuss the improvements in the band gap determination using TB-mBJ compared to the standard generalized gradient approximation (GGA) in density functional theory (DFT) and also compare the electronic band structure with available results from the quasiparticle GW method. It is shown that the calculated band gaps compare well with the experimental and GW results, although the electron effective mass is generally overestimated. PMID- 22538302 TI - Profiling the erythrocyte membrane proteome isolated from patients diagnosed with chronic obstructive pulmonary disease. AB - Structural and metabolic alterations in erythrocytes play an important role in the pathophysiology of Chronic Obstructive Pulmonary Disease (COPD). Whether these dysfunctions are related to the modulation of erythrocyte membrane proteins in patients diagnosed with COPD remains to be determined. Herein, a comparative proteomic profiling of the erythrocyte membrane fraction isolated from peripheral blood of smokers diagnosed with COPD and smokers with no COPD was performed using differential (16)O/(18)O stable isotope labeling. A total of 219 proteins were quantified as being significantly differentially expressed within the erythrocyte membrane proteomes of smokers with COPD and healthy smokers. Functional pathway analysis showed that the most enriched biofunctions were related to cell-to-cell signaling and interaction, hematological system development, immune response, oxidative stress and cytoskeleton. Chorein (VPS13A), a cytoskeleton related protein whose defects had been associated with the presence of cell membrane deformation of circulating erythrocytes was found to be down-regulated in the membrane fraction of erythrocytes obtained from COPD patients. Methemoglobin reductase (CYB5R3) was also found to be underexpressed in these cells, suggesting that COPD patients may be at higher risk for developing methemoglobinemia. This article is part of a Special Issue entitled: Integrated omics. PMID- 22538304 TI - Clinical and imaging findings in three patients with advanced inflammatory demyelinating polyradiculoneuropathy associated with nerve root hypertrophy. AB - OBJECTIVES: Chronic inflammatory demyelinating polyradiculoneuropathy is a treatable neuropathy that is challenging to diagnose and has a broad spectrum of presentations. We report the clinical, electrodiagnostic, and radiographic presentations in three patients whose workup revealed hypertrophic nerve roots. METHODS: We retrospectively reviewed the clinical, electrodiagnostic, and imaging data for patients diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy over a 3-year period. RESULTS: All patients had features of proximal and distal neuropathy with progressive or recurrent courses. Diagnosis and management were significantly altered by the concomitant clinical findings and/or radiographic findings. CONCLUSIONS: Our cases highlight the use of magnetic resonance imaging to evaluate for nerve root hypertrophy as an additional tool to electrodiagnostic testing in the setting of refractory or atypical neuropathy condition. Awareness of the radiographic features will assist in confirmation of the diagnosis, institution of the appropriate therapy, and prevention of inadequate or delay of treatment. PMID- 22538305 TI - Neuromuscular pathology case. PMID- 22538306 TI - Muscle restricted vasculitis causing dropped head syndrome: a case report and review of the literature. AB - A 52-year-old man presented with a severe head drop and proximal extremity weakness. Magnetic resonance imaging of the cervical spine showed T2 hyperintensity in cervical paraspinal muscles. Electrodiagnostic studies revealed an axial myopathy isolated to paraspinal muscles. A splenius capitis muscle biopsy confirmed an acute myopathy associated with nonsystemic vasculitis. The patient improved on steroids, intravenous immunoglobulin, and monthly pulse doses of cyclophosphamide. Our case emphasizes that a subgroup of patients with dropped head syndrome have treatable conditions. PMID- 22538307 TI - Exertional rhabdomyolysis: a clinical review with a focus on genetic influences. AB - In this review, the clinical and laboratory features of exertional rhabdomyolysis (ER) are discussed in detail, emphasizing the full clinical spectrum from physiological elevations of serum creatine kinase after exertion to life threatening rhabdomyolysis with acute kidney injury and associated systemic complications. Laboratory markers used to diagnose both ER and rhabdomyolysis are very sensitive, but not very specific, and imperfectly distinguish "subclinical" or asymptomatic from severe, life-threatening illness. However, genetic factors, both recognized and yet to be discovered, likely influence this diverse clinical spectrum of disease and response to exercise. Genetic mutations causative for McArdle disease, carnitine palmitoyl transferase deficiency 2, myoadenylate deaminase deficiency, and malignant hyperthermia have all been associated with ER. Polymorphic variations in the myosin light chain kinase, alpha-actin 3, creatine kinase-muscle isoform, angiotensin I-converting enzyme, heat shock protein, and interleukin-6 genes have also been associated with either ER or exercise-induced serum creatine kinase elevations typical of ER. The prognosis for ER is significantly better than that for other etiologies of rhabdomyolysis, but the risk of recurrence after an initial episode is unknown. Guidelines for management are provided. PMID- 22538308 TI - Peripheral neuropathic symptoms in celiac disease and inflammatory bowel disease. AB - OBJECTIVES: An association between celiac disease (CD) and peripheral neuropathy (PN) has been reported. METHODS: Patients with CD and/or inflammatory bowel disease (IBD) were recruited from the gastroenterology clinics at a medical center and local support groups. Control subjects without CD or IBD were recruited from the staff of the medical center as well as relatives and attendees at support groups. Each participant completed a survey that used two validated PN instruments to define and characterize PN. RESULTS: In the CD group, 38.9% met criteria for PN compared with 38.7% in the IBD group (P = 0.97) and 20.5% in the control group (P < 0.001). On multiple logistic regression, the odds of PN after adjusting for age, gender, diabetes, vitamin B12 deficiency, and cancer history were increased for CD (odds ratio, 2.51; 95% confidence interval, 1.82-3.47) and IBD (odds ratio, 2.78; 95% confidence interval, 1.85-4.18). CONCLUSIONS: PN is more often found in patients with CD and/or IBD than in the general population. PMID- 22538309 TI - Muscle-specific kinase-antibody-positive myasthenia gravis after autologous bone marrow transplantation. AB - A 44-year-old man presented with oculobulbar weakness approximately 5 years after autologous bone marrow transplantation (BMT). His workup led to the diagnosis of muscle-specific kinase-antibody-related myasthenia gravis (MG). There has been only one case report of muscle-specific kinase-antibody-positive MG after BMT, which was allogeneic. We report the first case of autologous BMT-associated MG with muscle-specific kinase antibody. The pathogenic mechanisms of immune dysregulation leading to MG after BMT are discussed. PMID- 22538310 TI - Chronic inflammatory pure sensory polyradiculoneuropathy: a rare CIDP variant with unusual electrophysiology. AB - We describe a patient presenting with progressive upper limb numbness and sensory ataxia of the 4 limbs. Motor nerve conduction studies were completely normal. Sensory electrophysiology showed reduced/absent upper limb sensory action potentials (SAPs). In the lower limbs, SAPs were mostly normal. Sensory conduction velocities were normal. Forearm sensory conduction blocks were present for both median nerves on antidromic testing. The maximal recordable sural SAP was preserved in comparison to maximal recordable radial SAP, consistent with an "abnormal radial normal sural" pattern. Somatosensory evoked potentials were unrecordable for tibial and median nerves. Cerebrospinal fluid protein was raised (0.99 g/L). The patient worsened on oral corticosteroids but subsequently made substantial functional recovery on intravenous immunoglobulins. This case is different to those previously reported of sensory chronic inflammatory demyelinating polyradiculoneuropathy, given its exclusive sensory electrophysiologic presentation, presence of predominant upper limb reduced sensory amplitudes, and detection of sensory conduction blocks. These electrophysiologic features were of paramount importance in establishing diagnosis and effective therapy. PMID- 22538311 TI - Outcome prediction value of nerve conduction studies for endoscopic carpal tunnel surgery. AB - OBJECTIVE: Carpal tunnel syndrome is the most common entrapment neuropathy. We explore the clinical use of nerve conduction study in the outcome prediction and preoperative selection for endoscopic carpal tunnel syndrome surgery. METHODS: Sixty-seven patients with carpal tunnel syndrome were prospectively enrolled. Each patient's clinical symptomatic score at baseline and 3 months postsurgery was compared with nerve conduction study parameters of distal motor latency, motor amplitude, motor conduction velocity, distal sensory latency, sensory amplitude, and sensory conduction velocity. A statistical logistic regression model was used to ascertain outcomes. RESULTS: Endoscopic surgery resulted in significant improvement for all four major symptoms pain, numbness, paresthesia, and weakness. From multivariate logistic regression, a shorter distal sensory latency is associated with a higher likelihood of a good outcome (P = 0.058; odds ratio, 0.912; 95% confidence interval, 0.828-1.0) only for paresthesia. The other factors were not found to be significant (all P > 0.10). The area under the curve (AUC) was 0.69 (95% confidence interval for AUC, 0.50-0.88). A cutoff of 6.0 ms or lower for sensory latency predicts for good outcome (in terms of paresthesia score) with the sensitivity/certainty of 84.6% and positive predictive value of 86.8%. A receiver operating characteristic analysis of baseline paresthesia score for good outcome of the paraesthesia domain showed that the AUC was 0.967 (95% confidence interval for AUC, 0-1.0). At a cutoff of baseline paraesthesia score of 4 or above, prediction for good outcome achieved a sensitivity of 87.2% and positive predictive value of 97.1%. CONCLUSIONS: A shorter distal sensory latency is associated with a higher likelihood of a good outcome for paraesthesia. In addition, patients with baseline of 4 or above had correlated with better surgical outcome than those with less severe symptoms. Our data thus suggest that surgical benefit is best seen in patients with moderate symptoms, in combination with electrophysiological evidence of early demyelination, as a possible therapeutic window. PMID- 22538313 TI - What's in the literature? AB - The neuromuscular literature over the past 3 months has been diverse, including useful information on the epidemiology of several disorders. Our understanding of the genetics of amyotrophic lateral sclerosis continues to grow, and in the process, it makes the distinction between familial and sporadic forms of the disorder increasingly murky. Some interesting articles about peripheral neuropathy provide insight into relationships with diabetes and with Parkinson disease and summarize the state of knowledge of the increasingly complex topic of hereditary neuropathies in children. Epidemiology and electrodiagnosis of lateral femoral cutaneous neuropathy is nicely discussed in 2 articles. Several muscle diseases, including Pompe disease, sporadic inclusion body myositis, and the congenital myopathies, receive attention in articles that provide very useful information for the clinician, and there is a treatment-oriented article on dystrophinopathies, which makes for excellent reading. There are also discussions of several uncommon disorders, including a mitochondrial myopathy, periodic paralysis, and congenital myasthenic syndromes, which are helpful in providing information to clinicians who may see such disorders only infrequently. PMID- 22538312 TI - Electrically silent muscle visible by ultrasound. AB - A 65-year-old woman with multiple chronic cranial neuropathies had spinal accessory innervated muscles that were virtually invisible to electromyography. Ultrasound imaging revealed the extensive atrophy and increased echogenicity that corresponded to the thinness of the muscles and their loss of insertional activity. In patients with severe atrophy of trapezius or sternocleidomastoid muscles, ultrasound may help in identify chronically denervated muscle. PMID- 22538314 TI - Sodium benzoate-rich beverage consumption is associated with increased reporting of ADHD symptoms in college students: a pilot investigation. AB - OBJECTIVE: Sodium benzoate, a common additive in popular beverages, has recently been linked to ADHD. This research examined the relationship between sodium benzoate-rich beverage ingestion and symptoms related to ADHD in college students. METHOD: College students (N = 475) completed an anonymous survey in class in fall 2010. The survey assessed recent intake of a noninclusive list of sodium benzoate-rich beverages and ADHD-related symptoms using a validated screener. RESULTS: Sodium benzoate-rich beverage intake was significantly associated with ADHD-related symptoms (p = .001), and significance was retained after controlling for covariates. Students scoring >=4 on the screener (scores that may be consistent with ADHD; n = 67) reported higher intakes (34.9 +/- 4.4 servings/month) than the remainder of the sample (16.7 +/- 1.1 servings/month). CONCLUSION: These data suggest that a high intake of sodium benzoate-rich beverages may contribute to ADHD-related symptoms in college students and warrants further investigation. PMID- 22538315 TI - Purification of histidine-tagged aequorin with a reactive cysteine residue for chemical conjugations and its application for bioluminescent sandwich immunoassays. AB - Highly purified histidine-tagged aequorin with a reactive cysteine residue (His Cys4-aequorin) was obtained from the periplasmic space of Escherichia coli cells by nickel-chelate affinity chromatography and hydrophobic chromatography. The procedure yielded 40.3mg of His-Cys4-aequorin from 2L of cultured cells with over 95% purity. The chemical conjugates of His-Cys4-aequorin with maleimide-activated streptavidin and maleimide-activated biotin were prepared without significant loss of luminescence activity and were applied to the bioluminescent sandwich immunoassay for alpha-fetoprotein (AFP) as a model analyte. The measurable range of AFP by these conjugates was 0.01-100 ng/ml and the sensitivities were similar to that using aequorin-labeled specific antibody and amino-biotinylated aequorin. PMID- 22538316 TI - Molecular cloning, sequence analysis and expression in Escherichia coli of Camelus dromedarius glucose-6-phosphate dehydrogenase cDNA. AB - This study determined the full length sequence of glucose-6-phosphate dehydrogenase cDNA (G6PD) from the Arabian camel Camelus dromedarius using reverse transcription polymerase chain reaction. The C. dromedarius G6PD has an open reading frame of 1545 bp, and the cDNA encodes a protein of 515 amino acid residues with a molecular weight of 59.0 KDa. The amino acid sequence showed the highest identity with Equus caballus (92%) and Homo sapiens (92%). The G6PD cDNA was cloned and expressed into Escherichia coli as a fusion protein and was purified in a single chromatographic step using nickel affinity gel column. The purity and the molecular weight of the enzyme were checked on SDS-PAGE and the purified enzyme showed a single band on the gel with a molecular weight of 63.0 KDa. The specific activity of G6PD was determined to be 289.6 EU/mg protein with a fold purification of 95.45 and yield of 56.8%. PMID- 22538317 TI - Purification, refolding and characterization of the trimeric Omp2a outer membrane porin from Brucella melitensis. AB - Brucella melitensis is a gram-negative bacteria known to cause brucellosis and to produce severe infections in humans. Whilst brucella's outer membrane proteins have been extensively studied due to their potential role as antigens or virulence factors, their function is still poorly understood at the structural level, as the 3D structure of Brucella beta-barrel membrane proteins are still unknown. In this context, the B. melitensis trimeric Omp2a porin has been overexpressed and refolded in n-dodecyl-beta-d-maltopyranoside. We here show that this refolding process is insensitive to urea but is temperature- and ionic strength-dependent. Reassembled species were characterized by fluorescence, size exclusion chromatography and circular dichroism. A refolding mechanism is proposed, suggesting that Omp2a first refolds under a monomeric form and then self-associates into a trimeric state. This first complete in vitro refolding of a membrane protein from B. melitensis shall eventually lead to functional and 3D structure determination. PMID- 22538319 TI - Determinants of visitor pro-environmental intentions on two small Greek islands: is ecotourism possible at coastal protected areas? AB - A relatively under-researched question is whether there is a possibility of influencing environmentally aware tourists regarding ecotourism at destinations that continue to develop under a pattern of mass 'seaside' tourism. Our objective was to assess the pro-environmental intentions of visitors at two small Greek islands, which are within a Natura 2000 site, specifically Paxoi and Antipaxoi. Intentions involved willingness to receive information about the protected area, willingness to accept pro-environmental limitations on recreational experience, and willingness-to-pay a conditional environmental conservation value added tax. In addition, we aimed to identify determinants of visitor pro-environmental intentions among visitor and visit characteristics, visitor satisfaction, and self-reported environmental knowledge, as well as anticipated outcomes of tourism development and suggestions for protected area management. We randomly collected 324 usable questionnaires during the summer season; 242 (74.69 %) by Greek visitors and 82 (25.31 %) by foreign visitors. Visitor satisfaction was quite high; however, visitors reported low levels of environmental knowledge. Our findings showed that the unique characteristics of the destination were not salient among visitors and that there is a lack of effective outreach campaigns, interpretation, and on-site environmental education programs. However, our study revealed high levels of visitor pro-environmental intentions that might support the promotion of ecotourism on the two islands. We provide recommendations based on determinants of visitor pro-environmental intentions, which might assist towards advancing visitor participation in environmental education projects, environmentally responsible behavior among visitors, and financial contribution to environmental conservation by visitors. PMID- 22538318 TI - Membrane estrogen receptor regulation of hypothalamic function. AB - Over the decades, our understanding of estrogen receptor (ER) function has evolved. Today we are confronted by at least two nuclear ERs, ERalpha and ERbeta, and a number of putative membrane ERs, including ERalpha, ERbeta, ER-X, GPR30 and Gq-mER. These receptors all bind estrogens or at least estrogenic compounds and activate intracellular signaling pathways. In some cases, a well-defined pharmacology and physiology has been discovered. In other cases, the identity or the function remains to be elucidated. This mini-review attempts to synthesize our understanding of 17beta-estradiol membrane signaling within hypothalamic circuits involved in homeostatic functions, focusing on reproduction and energy balance. PMID- 22538320 TI - Use of integrated landscape indicators to evaluate the health of linked watersheds and coral reef environments in the Hawaiian islands. AB - A linkage between the condition of watersheds and adjacent nearshore coral reef communities is an assumed paradigm in the concept of integrated coastal management. However, quantitative evidence for this "catchment to sea" or "ridge to reef" relationship on oceanic islands is lacking and would benefit from the use of appropriate marine and terrestrial landscape indicators to quantify and evaluate ecological status on a large spatial scale. To address this need, our study compared the Hawai'i Watershed Health Index (HI-WHI) and Reef Health Index (HI-RHI) derived independently of each other over the past decade. Comparisons were made across 170 coral reef stations at 52 reef sites adjacent to 42 watersheds throughout the main Hawaiian Islands. A significant positive relationship was shown between the health of watersheds and that of adjacent reef environments when all sites and depths were considered. This relationship was strongest for sites facing in a southerly direction, but diminished for north facing coasts exposed to persistent high surf. High surf conditions along the north shore increase local wave driven currents and flush watershed-derived materials away from nearshore waters. Consequently, reefs in these locales are less vulnerable to the deposition of land derived sediments, nutrients and pollutants transported from watersheds to ocean. Use of integrated landscape health indices can be applied to improve regional-scale conservation and resource management. PMID- 22538321 TI - A combined approach of variance-reduction techniques for the efficient Monte Carlo simulation of linacs. AB - A method based on a combination of the variance-reduction techniques of particle splitting and Russian roulette is presented. This method improves the efficiency of radiation transport through linear accelerator geometries simulated with the Monte Carlo method. The method named as 'splitting-roulette' was implemented on the Monte Carlo code [Formula: see text] and tested on an Elekta linac, although it is general enough to be implemented on any other general-purpose Monte Carlo radiation transport code and linac geometry. Splitting-roulette uses any of the following two modes of splitting: simple splitting and 'selective splitting'. Selective splitting is a new splitting mode based on the angular distribution of bremsstrahlung photons implemented in the Monte Carlo code [Formula: see text]. Splitting-roulette improves the simulation efficiency of an Elekta SL25 linac by a factor of 45. PMID- 22538322 TI - Prenatal screening for sickle cell anemia: awareness among health professionals and medical students at the Lagos University Teaching Hospital and the concept of prevention by termination. AB - Nigeria has the highest population of sickle cell anemia (SCA) patients in the whole world. This condition manifests with frequent episodes of aches and pains, recurrent infections, and frequent hospitalization. Prenatal screening is one of the methods of reducing the prevalence of this disease. The study aimed to determine the awareness and acceptability of prenatal screening for SCA among health professionals and students at the Lagos University Teaching Hospital. It was a descriptive and cross-sectional study carried out between August and September 2006, involving 403 health professionals and students using structured questionnaires. The study revealed that 91.3% of the respondents had heard about prenatal screening for SCA, whereas 8.7% of the respondents had not. In addition, the majority of the respondents (75.3%) knew that SCA can be prevented by prenatal screening for SCA, whereas 13.7% and 11.3% were not aware or not sure, respectively. Up to 48.2% of the respondents were not aware that prenatal screening for SCA is available in Nigeria with the nurses being the least aware (chi=11.9, P=0.00). 42.1% of the respondents will not allow preventive termination of pregnancy if prenatal screening confirms SCA. For those who will not allow preventive termination, up to 79% of them decided on the basis of their religious beliefs. There is a poor level of awareness of the availability of prenatal screening services in Nigeria among health workers in Lagos, and religion is a major factor militating against its acceptability. PMID- 22538323 TI - Crystallization of a Keplerate-type polyoxometalate into a superposed kagome lattice with huge channels. AB - Crystal structures of two Sr(2+) salts of the Keplerate-type polyoxometalate, [Mo(VI)(72)Mo(V)(60)O(372)(CH(3)COO)(30)(H(2)O)(72)](42-), have been determined by single crystal X-ray diffraction. One compound exhibits a superposed kagome lattice with huge channels whose diameters measure approximately 3.0 nm, while the arrangement of the Keplerate anions in the other compound approximates to a distorted cubic close packing. PMID- 22538324 TI - Does retirement affect cognitive functioning? AB - This paper analyses the effect of retirement on cognitive functioning using a longitudinal survey among older Americans, which allows controlling for individual heterogeneity and endogeneity of the retirement decision by using the eligibility age for social security as an instrument. The results highlight a significant negative effect of retirement on cognitive functioning. Our findings suggest that reforms aimed at promoting labour force participation at an older age may not only ensure the sustainability of social security systems but may also create positive health externalities for older individuals. PMID- 22538326 TI - Early caffeine therapy and clinical outcomes in extremely preterm infants. AB - OBJECTIVE: To determine if early caffeine (EC) therapy is associated with decreased bronchopulmonary dysplasia (BPD) or death, decreased treatment of patent ductus arteriosus (PDA), or shortened duration of ventilation. STUDY DESIGN: In a retrospective cohort of 140 neonates <=1250 g at birth, infants receiving EC (initiation <3 days of life) were compared with those receiving late caffeine (LC, initiation >=3 days of life) using logistic regression. RESULT: Of infants receiving EC, 25% (21/83) died or developed BPD compared with 53% (30/57) of infants receiving LC (adjusted odds ratio (aOR) 0.26, 95% confidence interval (CI) 0.09 to 0.70; P<0.01). PDA required treatment in 10% of EC infants versus 36% of LC infants (aOR 0.28, 95%CI 0.10 to 0.73; P=0.01). Duration of mechanical ventilation was shorter in infants receiving EC (EC, 6 days; LC, 22 days; P<0.01). CONCLUSION: Infants receiving EC therapy had improved neonatal outcomes. Further studies are needed to determine if caffeine prophylaxis should be recommended for preterm infants. PMID- 22538325 TI - The effect of massage on heart rate variability in preterm infants. AB - OBJECTIVE: To test the hypothesis that massage would improve autonomic nervous system (ANS) function as measured by heart rate variability (HRV) in preterm infants. STUDY DESIGN: Medically stable, 29- to 32-week preterm infants (17 massage, 20 control) were enrolled in a masked, randomized longitudinal study. Licensed massage therapists provided the massage or control condition twice a day for 4 weeks. Weekly HRV, a measure of ANS development and function, was analyzed using SPSS generalized estimating equations. RESULTS: Infant characteristics were similar between groups. HRV improved in massaged infants but not in the control infants (P<0.05). Massaged males had a greater improvement in HRV than females (P<0.05). HRV in massaged infants was on a trajectory comparable to term-born infants by study completion. CONCLUSION: Massage-improved HRV in a homogeneous sample of hospitalized, medically stable, preterm male infants and may improve infant response to exogenous stressors. We speculate that massage improves ANS function in these infants. PMID- 22538327 TI - Dynamics of brain tissue changes induced by traumatic brain injury assessed with the Marshall, Morris-Marshall, and the Rotterdam classifications and its impact on outcome in a prostacyclin placebo-controlled study. AB - BACKGROUND: The present study evaluates the types and dynamics of intracranial pathological changes in patients with severe traumatic brain injury (sTBI) who participated in a prospective, randomized, double-blinded study of add-on treatment with prostacyclin. Further, the changes of brain CT scan and their correlation to Glasgow Coma Scale score (GCS), maximal intracranial pressure (ICP(max)), minimal cerebral perfusion pressure (CPP(min)), and Glasgow Outcome Score (GOS) at 3, 6, and 12 months were studied. METHODS: Forty-eight subjects with severe traumatic brain injury were treated according to an ICP-targeted therapy protocol based on the Lund concept with the addition of prostacyclin or placebo. The first available CT scans (CT(i)) and follow-up scans nearest to 24 h (CT(24)) were evaluated using the Marshall, Rotterdam, and Morris-Marshall classifications. RESULTS: There was a significant correlation of the initial Marshall, Rotterdam, Morris-Marshall classifications and GOS at 3 and 12 months. The CT(24) Marshall classification did not significantly correlate to GOS while the Rotterdam and the Morris-Marshall classification did. The CT(i) Rotterdam classification predicted outcome evaluated as GOS at 3 and 12 months. Prostacyclin treatment did not influence the dynamic of tissue changes. CONCLUSIONS: The Rotterdam classification seems to be appropriate for describing the evolution of the injuries on the CT scans and contributes in predicting of outcome in patients treated with an ICP-targeted therapy. The Morris-Marshall classification can also be used for prognostication of outcome but it describes only the impact of traumatic subarachnoid hemorrhage (tSAH). PMID- 22538328 TI - New concepts in the assessment of syncope. AB - Significant progress has been made in the past 3 decades in our understanding of the various causes of loss of consciousness thanks to the publication of several important studies and guidelines. In particular, the recent European Society of Cardiology guidelines provide a reference standard for optimal quality service delivery. This paper gives the reader brief guidance on how to manage a patient with syncope, with reference to the above guidelines. Despite the progress made, the management of patients with syncope remains largely unsatisfactory because of the presence of a significant gap between knowledge and its application. Two new concepts aimed at filling that gap are currently under evaluation: syncope facilities with specialist backup and interactive decision-making software. Preliminary data have shown that a standardized syncope assessment, especially when coupled with interactive decision-making software, decreases admission rate and unnecessary testing and improves diagnostic yield, thus reducing cost per diagnosis. The long-term effects of such a new health care model on the rate of diagnosis and survival await future studies. PMID- 22538329 TI - Spotty calcification as a marker of accelerated progression of coronary atherosclerosis: insights from serial intravascular ultrasound. AB - OBJECTIVES: The purpose of this study was to determine atheroma progression in patients with spotty calcification. BACKGROUND: Although extensively calcified atherosclerotic lesions have been proposed to be clinically quiescent, the presence of spotty calcification within plaque has been reported to be associated with an increased incidence of ischemic cardiovascular events. The relationship between spotty calcification and disease progression has not been investigated. METHODS: A total of 1,347 stable patients with angiographic coronary artery disease underwent serial evaluation of atheroma burden with intravascular ultrasound imaging. Patients with spotty calcification were identified based on the presence of lesions (1 to 4 mm in length) containing an arc of calcification of <90 degrees . Clinical characteristics and disease progression were compared between patients with spotty calcification (n = 922) and those with no calcification (n = 425). RESULTS: Patients with spotty calcification were older (age 56 years vs. 54 years; p = 0.001), more likely to be male (68% vs. 54%; p = 0.01), and have a history of diabetes mellitus (30% vs. 24%; p = 0.01) and myocardial infarction (28% vs. 20%; p = 0.004), and have lower on-treatment high density lipoprotein cholesterol levels (48 +/- 16 mg/dl vs. 51 +/- 17 mg/dl; p = 0.001). Patients with spotty calcification demonstrated a greater percent atheroma volume (PAV) (36.0 +/- 7.6% vs. 29.0 +/- 8.5%; p < 0.001) and total atheroma volume (174.6 +/- 71.9 mm(3) vs. 133.9 +/- 64.9 mm(3); p < 0.001). On serial evaluation, spotty calcification was associated with greater progression of PAV (+0.43 +/- 0.07% vs. +0.02 +/- 0.11%; p = 0.002). Although intensive low density lipoprotein cholesterol and blood pressure lowering therapy slowed disease progression, these efficacies were attenuated in patients with spotty calcification. CONCLUSIONS: The presence of spotty calcification is associated with more extensive and diffuse coronary atherosclerosis and accelerated disease progression despite use of medical therapies. PMID- 22538330 TI - Eplerenone and atrial fibrillation in mild systolic heart failure: results from the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure) study. AB - OBJECTIVES: The purpose of this study was to analyze the incidence of new atrial fibrillation or flutter (AFF) in the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure) database. BACKGROUND: Aldosterone antagonism in heart failure might influence atrial fibrosis and remodeling and, therefore, risk of developing AFF. The development of new AFF was a pre-specified secondary endpoint in the EMPHASIS-HF study. METHODS: Patients in New York Heart Association functional class II and with ejection fraction <=35% were eligible for EMPHASIS-HF. History of AFF at baseline was reported by investigators using the study case report form. New onset AFF (in those with no history of AFF at baseline) was reported using a specific endpoint form; in a sensitivity analysis we also examined the effect of eplerenone on AFF reported as an adverse event. RESULTS: New onset AFF was significantly reduced by eplerenone: 25 of 911 (2.7%) versus 40 of 883 (4.5%) in the placebo group (hazard ratio [HR]: 0.58, 95% confidence interval [CI]: 0.35 to 0.96; p = 0.034). The reduction in the primary endpoint with eplerenone was similar among patients with and without AFF at baseline (HR: 0.60, 95% CI: 0.46 to 0.79 vs. HR: 0.70, 95% CI: 0.57 to 0.85, respectively; p for interaction = 0.41). The risk of cardiovascular (CV) death or hospital admission for worsening heart failure, the primary endpoint, was not significantly different in subjects with and without AFF at baseline (both study groups combined: HR: 1.23, 95% CI: 0.81 to 1.86; p = 0.33). CONCLUSIONS: In patients with systolic heart failure and mild symptoms, eplerenone reduced the incidence of new onset AFF. The effects of eplerenone on the reduction of major CV events were similar in patients with and without AFF at baseline. PMID- 22538332 TI - Imaging for infected cardiac implantable electronic devices: a new trick for your pet. PMID- 22538331 TI - Usefulness of fluorine-18 positron emission tomography/computed tomography for identification of cardiovascular implantable electronic device infections. AB - OBJECTIVES: This study evaluated the usefulness of fluorodesoxyglucose marked by fluorine-18 ((18)F-FDG) positron emission tomography (PET) and computed tomography (CT) in patients with suspected cardiovascular implantable electronic device (CIED) infection. BACKGROUND: CIED infection is sometimes challenging to diagnose. Because extraction is associated with significant morbidity/mortality, new imaging modalities to confirm the infection and its dissemination would be of clinical value. METHODS: Three groups were compared. In Group A, 42 patients with suspected CIED infection underwent (18)F-FDG PET/CT. Positive PET/CT was defined as abnormal uptake along cardiac devices. Group B included 12 patients without infection who underwent PET/CT 4 to 8 weeks post-implant. Group C included 12 patients implanted for >6 months without infection who underwent PET/CT for another indication. Semi-quantitative ratio (SQR) was obtained from the ratio between maximal uptake and lung parenchyma uptake. RESULTS: In Group A, 32 of 42 patients with suspected CIED infection had positive PET/CT. Twenty-four patients with positive PET/CT underwent extraction with excellent correlation. In 7 patients with positive PET/CT, 6 were treated as superficial infection with clinical resolution. One patient with positive PET/CT but negative leukocyte scan was considered false positive due to Dacron pouch. Ten patients with negative PET/CT were treated with antibiotics and none has relapsed at 12.9 +/- 1.9 months. In Group B, patients had mild uptake seen at the level of the connector. There was no abnormal uptake in Group C patients. Median SQR was significantly higher in Group A (A = 2.02 vs. B = 1.08 vs. C = 0.57; p < 0.001). CONCLUSIONS: PET/CT is useful in differentiating between CIED infection and recent post implant changes. It may guide appropriate therapy. PMID- 22538333 TI - Metabolomic profile of human myocardial ischemia by nuclear magnetic resonance spectroscopy of peripheral blood serum: a translational study based on transient coronary occlusion models. AB - OBJECTIVES: The aim of this study was to investigate the metabolomic profile of acute myocardial ischemia (MIS) using nuclear magnetic resonance spectroscopy of peripheral blood serum of swine and patients undergoing angioplasty balloon induced transient coronary occlusion. BACKGROUND: Biochemical detection of MIS is a major challenge. The validation of novel biosignatures is of utmost importance. METHODS: High-resolution nuclear magnetic resonance spectroscopy was used to profile 32 blood serum metabolites obtained (before and after controlled ischemia) from swine (n = 9) and patients (n = 20) undergoing transitory MIS in the setting of planned coronary angioplasty. Additionally, blood serum of control patients (n = 10) was sequentially profiled. Preliminary clinical validation of the developed metabolomic biosignature was undertaken in patients with spontaneous acute chest pain (n = 30). RESULTS: Striking differences were detected in the blood profiles of swine and patients immediately after MIS. MIS induced early increases (10 min) of circulating glucose, lactate, glutamine, glycine, glycerol, phenylalanine, tyrosine, and phosphoethanolamine; decreases in choline-containing compounds and triacylglycerols; and a change in the pattern of total, esterified, and nonesterified fatty acids. Creatine increased 2 h after ischemia. Using multivariate analyses, a biosignature was developed that accurately detected patients with MIS both in the setting of angioplasty-related MIS (area under the curve 0.94) and in patients with acute chest pain (negative predictive value 95%). CONCLUSIONS: This study reports, to the authors' knowledge, the first metabolic biosignature of acute MIS developed under highly controlled coronary flow restriction. Metabolic profiling of blood plasma appears to be a promising approach for the early detection of MIS in patients. PMID- 22538334 TI - Metabolomics: seeking a unique biomarker signature for coronary artery syndromes. PMID- 22538335 TI - First in vivo application of microwave radiometry in human carotids: a new noninvasive method for detection of local inflammatory activation. AB - OBJECTIVES: This study investigated whether temperature differences: 1) can be measured in vivo noninvasively by microwave radiometry (MR); and 2) are associated with ultrasound and histological findings. BACKGROUND: Studies of human carotid artery samples showed increased heat production. MR allows in vivo noninvasive measurement of internal temperature of tissues. METHODS: Thirty-four patients undergoing carotid endarterectomy underwent screening of carotid atherosclerosis by ultrasound and MR. Healthy volunteers were enrolled as a control group. During ultrasound study, plaque texture, plaque surface, and plaque echogenicity were analyzed. Temperature difference (DeltaT) was assigned as maximal minus minimum temperature. Association of thermographic with ultrasound and histological findings was performed. RESULTS: DeltaT was higher in atherosclerotic carotid arteries compared with the carotid arteries of controls (p < 0.01). Fatty plaques had higher DeltaT compared with mixed and calcified (p < 0.01) plaques. Plaques with ulcerated surface had higher DeltaT compared with plaques with irregular and regular surface (p < 0.01). Heterogeneous plaques had higher DeltaT compared with homogenous (p < 0.01). Specimens with thin fibrous cap and intense expression of CD3, CD68, and vascular endothelial growth factor (VEGF) had higher DeltaT compared with specimens with thick cap and low expression of CD3, CD68, and VEGF (p < 0.01). CONCLUSIONS: MR provides in vivo noninvasive temperature measurements of carotid plaques, reflecting plaque inflammatory activation. PMID- 22538336 TI - Acute left main coronary artery occlusion after percutaneous aortic valve replacement. PMID- 22538337 TI - President's page: working toward the triple aim in cardiovascular health care. PMID- 22538339 TI - Is ventilation efficiency an additional target of exercise training benefits in heart failure with preserved ejection fraction? PMID- 22538340 TI - Prevalence of J-point elevation in families with sudden arrhythmic death syndrome. PMID- 22538342 TI - Diaphragmatic paralysis after cardiac surgery. PMID- 22538343 TI - Response to gastroesophageal reflux disease therapy: assessment at 4 weeks predicts response/non-response at 8 weeks. AB - BACKGROUND: Many questionnaires that assess subjective symptoms or health-related quality of life (HRQOL) have been developed to confirm the efficacy of treatment in patients with gastroesophageal reflux disease (GERD). However, few reports have correlated early improvements in scale scores with predictions of subsequent therapeutic responses. Our aim was to investigate the appropriate timing for evaluating therapeutic response and subsequent changes in symptoms and HRQOL. METHODS: This was a post hoc analysis of a multicenter prospective cohort study. A total of 5,279 GERD patients with Frequency Scale for the Symptoms of GERD (FSSG) scores >= 8 points at baseline were analyzed. Correlations between HRQOL and FSSG were investigated and logistic regression analysis was performed. RESULTS: The FSSG scores and HRQOL improvements in responders were significantly greater than in non-responders. Positive correlation between FSSG and HRQOL was observed. Based on the analysis, severity of esophagitis at baseline, complications of hypertension, higher HRQOL mental score at baseline, and higher FSSG score at baseline were predictors of responders. Gastrectomy, complication of insomnia, and prior medication with proton pump inhibitors were predictors of non-responders. CONCLUSION: Evaluating patients' symptoms during the fourth week of rabeprazole therapy allows predictions of subsequent changes in subjective symptoms and HRQOL. PMID- 22538344 TI - The influence of extracellular and intracellular calcium on the secretion of renin. AB - Changes in plasma, extracellular, and intracellular calcium can affect renin secretion from the renal juxtaglomerular (JG) cells. Elevated intracellular calcium directly inhibits renin release from JG cells by decreasing the dominant second messenger intracellular cyclic adenosine monophosphate (cAMP) via actions on calcium-inhibitable adenylyl cyclases and calcium-activated phosphodiesterases. Increased extracellular calcium also directly inhibits renin release by stimulating the calcium-sensing receptor (CaSR) on JG cells, resulting in parallel changes in the intracellular environment and decreasing intracellular cAMP. In vivo, acutely elevated plasma calcium inhibits plasma renin activity (PRA) via parathyroid hormone-mediated elevations in renal cortical interstitial calcium that stimulate the JG cell CaSR. However, chronically elevated plasma calcium or CaSR activation may actually stimulate PRA. This elevation in PRA may be a compensatory mechanism resulting from calcium-mediated polyuria. Thus, changing the extracellular calcium in vitro or in vivo results in inversely related acute changes in cAMP, and therefore renin release, but chronic changes in calcium may result in more complex interactions dependent upon the duration of changes and the integration of the body's response to these changes. PMID- 22538345 TI - [Distal femoral fractures]. AB - Fractures of the distal femur still represent injuries that are difficult to treat as they either affect younger patients after a high-energy trauma with soft tissue damage and osseous comminution or elderly people with impaired local vascularity and a poor bone stock. However, exactly these fractures profit from new, biological principles of treatment, which help to diminish additional surgical trauma by indirect fracture reduction and insertion of stabilizing implants via mini-incisions. Basically, these techniques are represented by retrograde intramedullary nails and submuscularilly inserted plates/internal fixateurs. While intramedullary nails are well suited to fix extramedullary and simple articular fractures (C1), plates can also be used to treat complex articular fractures. Nevertheless, any displaced articular fracture component must still be anatomically reduced by an open approach and fixed with absolute stability. Technical advances as well as demographic changes will continue to represent challenges in the treatment of these fractures. PMID- 22538346 TI - Occurrence of 210Po and biological effects of low-level exposure: the need for research. AB - BACKGROUND: Polonium-210 (210Po) concentrations that exceed 1 Bq/L in drinking water supplies have been reported from four widely separated U.S. states where exposure to it went unnoticed for decades. The radionuclide grandparents of 210Po are common in sediments, and segments of the public may be chronically exposed to low levels of 210Po in drinking water or in food products from animals raised in contaminated areas. OBJECTIVES: We summarized information on the environmental behavior, biokinetics, and toxicology of 210Po and identified the need for future research. METHODS: Potential linkages between environmental exposure to 210Po and human health effects were identified in a literature review. DISCUSSION: 210Po accumulates in the ovaries where it kills primary oocytes at low doses. Because of its radiosensitivity and tendency to concentrate 210Po, the ovary may be the critical organ in determining the lowest injurious dose for 210Po. 210Po also accumulates in the yolk sac of the embryo and in the fetal and placental tissues. Low-level exposure to 210Po may have subtle, long-term biological effects because of its tropism towards reproductive and embryonic and fetal tissues where exposure to a single alpha particle may kill or damage critical cells. 210Po is present in cigarettes and maternal smoking has several effects that appear consistent with the toxicology of 210Po. CONCLUSIONS: Much of the important biological and toxicological research on 210Po is more than four decades old. New research is needed to evaluate environmental exposure to 210Po and the biological effects of low-dose exposure to it so that public health officials can develop appropriate mitigation measures where necessary. PMID- 22538347 TI - Design of nanoporous metals with bimodal pore size distributions for enhanced biosensing. AB - Nanoporous gold (np-Au) has shown great potential in catalysis, plasmonics, sensing, etc. In this work, by two-step dealloying a well-designed AuAgAl ternary precursor alloy, np-Au with bimodal ligament/pore size distributions is successfully fabricated. The first dealloying in HCl solution removes Al and generates a nanoporous AuAg alloy which would be mildly annealed at 200 degrees C for 30 min to homogenize the alloy ligament and enlarge the ligament/pore size. Next, the nanoporous AuAg alloy is further dealloyed in a HNO(3) solution to etch Ag and fabricate np-Au with a hierarchical microstructure. This novel bimodal np Au is demonstrated to exhibit enhanced electrocatalytic activity towards H(2)O(2) reduction and be a better support for the fabrication of an oxidase-based biosensor compared with normal np-Au, with a uniform pore/ligament size of 30-40 nm. In a proof-of-concept study, a sensitive glucose biosensor with a linear range up to 21 mM is fabricated by immobilization of glucose oxidase on the bimodal np-Au. PMID- 22538349 TI - Retraction statement. Paper by Takayasu [Oncology 2011;81(suppl 1):105-110]. PMID- 22538348 TI - A general method for detecting protease activity via gelation and its application to artificial clotting. AB - A modular system for detecting protease activity via enzyme-triggered gel formation is described. Protease-specific recognition sequences are utilized to achieve enzyme specificity. Artificial blood clotting is demonstrated by activating endogenous thrombin to trigger gelation in fibrinogen-deficient blood plasma. PMID- 22538350 TI - Characterization of two isoforms of antiliopolysacchride factors (Sp-ALFs) from the mud crab Scylla paramamosain. AB - In the previous study of the mud crab (Scylla paramamosain) hemocyte proteins, which interacted with a bacterium, Vibrio parahaemolyticus, a protein known as antilipopolysaccharide factor (Sp-ALF) was isolated in addition to a serine proteinase homolog (Sp-SPH) protein. In the present study, we further reported the characterization of two isoforms of the mud crab ALF - Sp-ALFs genes (designated as Sp-ALF1 and Sp-ALF2, respectively) based on our previous result. The Sp-ALF1 and Sp-ALF2 cDNA contained 1070 bp and 731 bp, respectively, with 123 deduced amino acid residues. Alignment of deduced amino acid sequences showed that Sp-ALFs possessed high identity with other known ALFs from crustaceans and exhibited an overall similarity of 57.7% to those of ALFs compared. Phylogenetic tree analysis revealed a clear group of each species and also suggested that ALFs from Scylla genus and those from Portunus genus were closely related. Tissue distribution analysis in adult crab implied that both Sp-ALF1 and Sp-ALF2 were mainly expressed in hemocytes. The mRNA transcripts were also found in embryo (I, II, III and V), zoea-I and juvenile crab, but were rarely observed in the megalopa stage. To further identify the biological activity of Sp-ALFs, recombinant proteins (rSp-ALFs: designated as rSp-ALF1 and rSp-ALF2, respectively) were obtained by expression in Pichia pastris, and the synthetic peptide fragments (sSp-ALFs: designated as sSp-ALF1 and sSp-ALF2, respectively) including the putative LPS binding loop were also prepared for antimicrobial test. The results indicated that both rSp-ALFs and sSp-ALFs were highly effective against most of the Gram-positive bacteria and Gram-negative bacteria tested. In contrast to cecropin P1, a membrane integrity assay revealed that Sp-ALFs did not affect the Escherichia coli by disruption of membrane integrity. Additionally, the recombinant Sp-ALFs proteins exhibited strong antiviral activity against an important aquaculture pathogen, white spot syndrome virus, in crustaceans. Taken together, these data suggested that Sp-ALFs might play a key role in immune defense against microbial infection in the mud crab S. paramamosain. PMID- 22538351 TI - The effect of triploidy and vaccination on neutrophils and B-cells in the peripheral blood and head kidney of 0+ and 1+ Atlantic salmon (Salmo salar L.) post-smolts. AB - Sterile triploid fish are being used in aquaculture to prevent early unwanted sexual maturation and the genetic interaction between wild and cultured fish; however, triploid fish are typically considered to be more susceptible to disease than diploid counterparts. Proportions of leucocytes from the head kidney and peripheral blood were identified using monoclonal antibodies and flow cytometry in triploid and diploid, vaccinated and unvaccinated, out-of-season (0+) and 1+ Atlantic salmon (Salmo salar L.) three weeks post seawater transfer. Triploid 1+ fish were significantly (P<0.05) heavier than diploid fish at the time of sampling, whereas triploid 0+ had a significantly lower condition factor than diploids. Ploidy had a significant effect on the proportion of B-cells in the blood of both 0+ and 1+ fish, and the head kidney of 1+ fish, with triploids having lower proportions of B-cells to diploids in both smolt groups. In addition, a significant ploidy*vaccination interaction effect was observed in the response of neutrophils in the blood (vaccinated diploids had a higher mean proportion than diploid unvaccinated) and B-cells in the head kidney (in vaccinated fish, triploids had a lower mean proportion than diploids) in 0+ smolts. Vaccination was found to significantly increase the proportion of B-cells in the head kidney of 1+ smolts in both ploidy. Size (fish weight) was positively correlated with neutrophil proportions in 1+ fish. Our findings are discussed in relation to the physiological differences related to ploidy. The results suggest that ploidy as well as smelting regime influences the immune system of Atlantic salmon post-smolts. PMID- 22538352 TI - Purification and characterization of an antimicrobial histone H1-like protein and its gene from the testes of olive flounder, Paralichthys olivaceus. AB - An approximately 21 kDa antimicrobial protein was purified from an acidified testis extract of olive flounder, Paralichthys olivaceus, by ion-exchange and C(18) reversed-phase HPLC. A comparison of the N-terminal amino acid sequence with those of other known antimicrobial polypeptides revealed high homology between this antimicrobial protein and other histone H1 molecules; thus, it was designated flounder histone H1-like protein (fH1LP). fH1LP showed potent antimicrobial activity against Gram-positive bacteria, including Bacillus subtilis, Staphylococcus aureus, and Streptococcus iniae (minimal effective concentrations [MECs], 2.8-30.0 MUg/ml), Gram-negative bacteria, including Aeromonas hydrophila, Escherichia coli D31, Vibrio parahaemolyticus (MECs, 1.4 12.0 MUg/ml), and Candida albicans (MEC, 2.0 MUg/ml). cDNA cloning and tissue distribution studies of fH1LP indicated that it is constitutively expressed in testis and ovary. The fH1LP expression level was significantly dependent on developmental stage, and decreased dramatically after hatching. However, lipopolysaccharide stimulation did not induce fH1LP mRNA in other immune organs, including the kidney and spleen. These results suggest that fH1LP plays an important role in innate immunity in fish during reproduction, including mating, fertilization, and hatching. PMID- 22538353 TI - Outcomes following robotic radical nephrectomy: a single-center experience. AB - OBJECTIVES: Advancement in technology has led to a decrease in invasiveness for surgical management of malignant renal neoplasms. Laparoscopic radical nephrectomy is an established treatment for renal tumors. Since the introduction of robotic surgery in the realm of urology, many procedures have been done robotically. We evaluated the feasibility, safety, and oncological outcomes of robotic radical nephrectomy (RRN). METHODS: We retrospectively reviewed the records of patients who underwent RRN for renal tumors at our institute from September 2007 to March 2011. Patients with standard indications for a radical nephrectomy were offered a robot-assisted procedure. Intraoperative parameters (operative time, blood loss, transfusion of blood products), postoperative parameters and complications were recorded. RESULTS: Twenty-three patients who underwent RRN were included. Mean operative time was 132.7 min and mean blood loss 270 ml. The majority of patients were able to tolerate liquid diet, were free from drain, and were fit for discharge by postoperative day (POD) 1, POD 2 and POD 3, respectively. After the mean follow-up of 29.4 months, no patient had residual tumor, local recurrence or metastasis. CONCLUSION: We conclude that RRN is a feasible and safe procedure with good oncological outcome on short-term follow-up. PMID- 22538354 TI - Effect of phosphorylation of phosphatidylinositol on myelin basic protein mediated binding of actin filaments to lipid bilayers in vitro. AB - Myelin basic protein (MBP) binds to negatively charged lipids on the cytosolic surface of oligodendrocytes and is believed to be responsible for adhesion of these surfaces in the multilayered myelin sheath. It can also assemble actin filaments and tether them to lipid bilayers through electrostatic interactions. Here we investigate the effect of increased negative charge of the lipid bilayer due to phosphorylation of phosphatidylinositol (PI) on MBP-mediated binding of actin to the lipid bilayer, by substituting phosphatidylinositol 4-phosphate or phosphatidylinositol 4,5-bisphosphate for PI in phosphatidylcholine/phosphatidylglycerol lipid vesicles. Phosphorylation of PI caused dissociation of the MBP/actin complex from the lipid vesicles due to repulsion of the negatively charged complex from the negatively charged membrane surface. An effect of phosphorylation could be detected even if the inositol lipid was only 2mol% of the total lipid. Calcium-calmodulin dissociated actin from the MBP-lipid vesicles and phosphorylation of PI increased the amount dissociated. These results show that changes to the lipid composition of myelin, which could occur during signaling or other physiological events, could regulate the ability of MBP to act as a scaffolding protein and bind actin filaments to the lipid bilayer. PMID- 22538355 TI - Gly(6) of kalata B1 is critical for the selective binding to phosphatidylethanolamine membranes. AB - The membrane interaction of the cyclotide kalata B1, an all-d-analogue and a single alanine substituted analogue (G6A), was studied by surface plasmon resonance (SPR) and atomic force microscopy (AFM). Kalata B1 showed a strong binding selectivity for dimyristoyl-phosphatidylethanolamine (DMPE) compared to dimyristoyl-phoshatidylcholine (DMPC)-containing lipids. However, when the interaction was visualized by AFM the peptide interacted with DMPC and DMPE in a similar manner. There was no apparent change in membrane morphology with either lipid, suggesting that kalata B1 does not act via a carpet-like disruption mechanism. The d-analogue showed similar binding by SPR and the same strong selectivity for DMPE, indicating that the membrane-interaction and lipid selectivity are not stereo-specific. SPR studies of the G6A analogue revealed that it interacted in a similar way to kalata B1 on the DMPC containing lipids, but showed no increased response on the DMPE containing lipids observed for kalata B1 and d-kalata B1. These results indicate that the Gly6 residue directly influences membrane binding as it is located near a putative membrane interacting hydrophobic patch. Overall, the data suggest that very small changes in amino acid composition (with no change in conformation) can influence specific self association in combination with membrane binding and mediate the activity of kalata B1. PMID- 22538356 TI - Neuroprotection and estrogen receptors. AB - This review is intended to assess the state of current knowledge on the role of estrogen receptors (ERs) in the neuroprotective effects of estrogens in models for acute neuronal injury and death. We evaluate the overall evidence that estrogens are neuroprotective in acute injury and critically assess the role of ERalpha, ERbeta, GPR 30, and nonreceptor-mediated mechanisms in these robust neuroprotective effects of this ovarian steroid hormone. We conclude that all three receptors, as well as nonreceptor-mediated mechanisms can be involved in neuroprotection, depending on the model used, the level of estrogen administrated, and the mode of administration of the steroid. Also, the signaling pathways used by both ER-dependent and ER-independent mechanisms to exert neuroprotection are considered. Finally, further studies that are needed to parse out the relative contribution of receptor versus nonreceptor-mediated signaling are discussed. PMID- 22538357 TI - Composition-dependent fluorescence emission of ternary Cd-In-S alloyed quantum dots. AB - This communication describes a new type of alloyed Cd-In-S quantum dots (CdIS QDs) with ultra small particle size and broadly tunable fluorescence emission from 450 to 700 nm. The band gap of CdIS QDs was mainly controlled by their composition rather than their particle size. The CdIS-ZnS core-shell nanocrystals exhibited significantly improved optical properties and chemical stabilities, with the PL quantum yield (QY) of up to 60%. PMID- 22538358 TI - gamma-Aminobutyric acid (GABA) signalling in human pancreatic islets is altered in type 2 diabetes. AB - AIMS/HYPOTHESIS: gamma-Aminobutyric acid (GABA) is a signalling molecule in the interstitial space in pancreatic islets. We examined the expression and function of the GABA signalling system components in human pancreatic islets from normoglycaemic and type 2 diabetic individuals. METHODS: Expression of GABA signalling system components was studied by microarray, quantitative PCR analysis, immunohistochemistry and patch-clamp experiments on cells in intact islets. Hormone release was measured from intact islets. RESULTS: The GABA signalling system was compromised in islets from type 2 diabetic individuals, where the expression of the genes encoding the alpha1, alpha2, beta2 and beta3 GABA(A) channel subunits was downregulated. GABA originating within the islets evoked tonic currents in the cells. The currents were enhanced by pentobarbital and inhibited by the GABA(A) receptor antagonist, SR95531. The effects of SR95531 on hormone release revealed that activation of GABA(A) channels (GABA(A) receptors) decreased both insulin and glucagon secretion. The GABA(B) receptor antagonist, CPG55845, increased insulin release in islets (16.7 mmol/l glucose) from normoglycaemic and type 2 diabetic individuals. CONCLUSIONS/INTERPRETATION: Interstitial GABA activates GABA(A) channels and GABA(B) receptors and effectively modulates hormone release in islets from type 2 diabetic and normoglycaemic individuals. PMID- 22538360 TI - Functional MRI of the hypothalamic response to an oral glucose load. PMID- 22538359 TI - Mechanisms of improved glycaemic control after Roux-en-Y gastric bypass. AB - Roux-en-Y gastric bypass (RYGB) greatly improves glycaemic control in morbidly obese patients with type 2 diabetes, in many even before significant weight loss. Understanding the responsible mechanisms may contribute to our knowledge of the pathophysiology of type 2 diabetes and help identify new drug targets or improve surgical techniques. This review summarises the present knowledge based on pathophysiological studies published during the last decade. Taken together, two main mechanisms seem to be responsible for the early improvement in glycaemic control after RYGB: (1) an increase in hepatic insulin sensitivity induced, at least in part, by energy restriction and (2) improved beta cell function associated with an exaggerated postprandial glucagon-like peptide 1 secretion owing to the altered transit of nutrients. Later a weight loss induced improvement in peripheral insulin sensitivity follows. PMID- 22538361 TI - Multiple genetic variants explain measurable variance in type 2 diabetes-related traits in Pakistanis. AB - AIMS/HYPOTHESIS: Multiple genetic variants are associated with type 2 diabetes related traits in Europeans, but their role in South Asian populations needs further study. We hypothesised that genetic variants associated with diabetes related traits in Europeans would explain a similar proportion of phenotypic variance in a Pakistani population and could be used in Mendelian randomisation analyses. METHODS: We used data from 2,131 individuals from the Control of Blood Pressure and Risk Attenuation Trial (COBRA) in Karachi, Pakistan. Individuals were aged 40 years or older. RESULTS: Combining information from multiple genetic variants showed that fasting glucose, BMI, triacylglycerol, and systolic and diastolic blood pressure variants explained 2.9%, 0.7%, 5.5%, 1.2% and 1.8% of the variance in those traits respectively. Genetic risk scores of fasting glucose, triacylglycerol, BMI, systolic blood pressure and diastolic blood pressure variants were associated with these traits, with per allele SD effects of 0.057 (95% CI 0.041, 0.074), p=3.44 * 10(-12), 0.130 (95% CI 0.105, 0.155), p=2.9 * 10(-21), 0.04 (95% CI 0.014, 0.072), p=0.004, 0.031 (95% CI 0.016, 0.047), p=7.9 * 10(-5), 0.028 (95% CI 0.015, 0.042), p = 5.5 * 10(-5), respectively. These effects are consistent with those observed in Europeans, except that the effect of triacylglycerol variants in South Asians was slightly lower. Mendelian randomisation provided evidence that genetically influenced, raised triacylglycerol levels do not causally affect type 2 diabetes risk to the extent predicted from observational data (p=0.0003 for difference between observed and instrumental variables correlations). CONCLUSIONS/INTERPRETATION: Genetic variants identified in Europeans are associated with type 2 diabetes related traits in Pakistanis, with comparable effect sizes. Larger studies are needed to perform adequately powered Mendelian randomisation and help dissect the relationships between type 2 diabetes-related traits in diverse South Asian subgroups. PMID- 22538362 TI - A novel passive water sampler for in situ sampling of antibiotics. AB - Passive water sampling has several advantages over active methods; it provides time-integrated data, can save on time and cost compared to active methods, and yield high spatial resolution data through co-deployment of simple, cheap units. However, one problem with many sampler designs in current use is that their uptake rates for trace substances of interest are flow-rate dependent, thereby requiring calibration data and other information to enable water concentrations to be derived from the mass per sampler. However, the 'family' of samplers employing the principle of diffusive gradients in thin films (DGT) provides an in situ means of quantitatively measuring labile species in aquatic systems without field calibration. So far, this technique has only been tested and applied in inorganic substances: metals, radionuclides, nutrients, etc. Design and applications of DGT to trace organic contaminants ('o-DGT') would be of widespread interest. This study describes the laboratory testing and performance characteristics of o-DGT, with the antibiotic sulfamethoxazole (SMX) as a model compound and XAD18 as the novel binding agent. o-DGT uptake of SMX increased with time and decreased with diffusion layer thickness, confirming the principle for SMX. XAD18 showed sufficiently high capacity for SMX for routine field applications. o-DGT measurement of SMX was independent of pH (6-9) and ionic strength (0.001-0.1 M) and not affected by flow rate once above static conditions. The diffusion coefficient of SMX in the sampler was measured using an independent diffusion cell and information is presented to allow temperature correction and derivation of aqueous concentrations from deployed samplers. The potential use of o-DGT for in situ measurement of pharmaceutical antibiotics is confirmed by this study and applications are briefly discussed. PMID- 22538363 TI - Metronomic chemotherapy with the COMBAT regimen in advanced pediatric malignancies: a multicenter experience. AB - BACKGROUND: The outcome of children with refractory/relapsed malignancies remains poor and novel therapies are urgently required. One of the promising approaches is metronomic chemotherapy. We present the clinical results of 74 children with advanced solid tumors treated according to treatment recommendation with data registry in three European pediatric centers. METHODS: COMBAT (Combined Oral Metronomic Biodifferentiating Antiangiogenic Treatment) included low-dose daily temozolomide, etoposide, celecoxib, vitamin D, fenofibrate and retinoic acid. From 2004 to 2010, 74 children were enrolled. RESULTS: The 2-year overall survival (OS) was 43.1% (median 15.4, range 1.3-69.9 months). Of the 74 patients, 50 patients (68%) died and 24 are alive: 6 (8%) with progressive disease, 7 (9%) with stable disease/partial response and 11 (15%) in complete response. Median time to response was 6 months. Of 62 patients with initially measurable disease, 25 (40%) had radiological response or stable disease. Fourteen of 25 showing clinical benefit responded within the first 6 months. The treatment was well tolerated on an outpatient basis. Regarding non-hematological toxicity of grade >=2, hepatotoxicity of grade 3 occurred in 8 children and grade 3 cheilitis in 16 children. CONCLUSION: COMBAT is a feasible and effective treatment option for patients with relapsing/refractory malignancies. The treatment is well tolerated with a low acute toxicity profile. PMID- 22538364 TI - Biological markers in osteoarthritis. AB - Osteoarthritis (OA) is considered as a chronic disease with a long "silent" period. The diagnosis is generally based on clinical symptoms and radiographic changes. However X-ray has a poor sensitivity and a relatively large precision error that does not allow an early detection of OA or the monitoring of joint damage progression. The limitations of the tools that are currently available for OA assessment have been the impetus to identify specific biological markers that reflect quantitative and dynamic variations in joint remodeling. Research has focused on the structural components of cartilage matrix, especially type II collagen degradation markers. In spite of a significant increase of some markers in individuals with early stage of OA, the large overlap with control subjects indicates that the current biomarkers used alone have limited diagnostic potential. However, the combination of specific markers seems to improve the prediction of disease progression at the individual level. Several types of treatment have been investigated but the lack of medications with definitively demonstrated chondroprotective activity has limited the assessment of the potential role of biomarkers for monitoring patients' responses to the treatment of OA. In this review, we will use the BIPED classification that appeared in 2006 for OA markers to describe the potential usage of a given marker [5]. This article is part of a Special Issue entitled "Osteoarthritis". PMID- 22538366 TI - 8-Oxo-7,8-dihydrodeoxyadenosine: the first example of a native DNA lesion that stabilizes human telomeric G-quadruplex DNA. AB - Native DNA lesions in general destabilize DNA secondary structures such as duplex and G-quadruplex because they disrupt optimized interactions in DNA defined by nature. In this paper, we report the first example of a native DNA lesion (8-oxo 7,8-dihydrodeoxyadenosine, OxodA) that stabilizes human telomeric G-quadruplex DNA. CD thermal denaturation studies explicitly displayed increased melting temperatures of telomeric G-quadruplex DNAs that contain OxodA(s) in different DNA loops, suggesting enhanced thermal stability. Conformation studies of G quadruplex DNAs containing OxodA(s) in the loops using CD and native PAGE revealed that they adopt a similar antiparallel conformation in Na(+) but have much more versatile conformations in K(+). According to computational calculations, the observed stabilization may result from the tight binding of K(+) into the pocket formed by the O8 of OxodA and its loop. The study reported here may provide better understanding of the effect of DNA lesions on G quadruplex stability and conformation. PMID- 22538365 TI - FOXO1 expression and regulation in endometrial tissue during the menstrual cycle and in early pregnancy decidua. AB - AIMS: To determine FOXO1 (forkhead box O1) expression in the human endometrium during the menstrual cycle and decidua of early pregnancy, as well as FOXO1 regulation in endometrial stromal cells (ESC). METHODS: Immunohistochemistry, RT qPCR, and Western blot analyses evaluated cellular localization and altered FOXO1 expression in the endometrium during the menstrual cycle and decidua of early pregnancy (proliferative phase, n = 12; early-secretory phase, n = 7; mid secretory phase, n = 10; late-secretory phase, n = 10; early pregnancy, n = 12). Using RT-qPCR and Western blot, we studied the regulation of FOXO1 by 8-bromo cAMP, 4-pregnene-3,20-dione, 17beta-estradiol, and human chorionic gonadotrophin in ESC (n = 5). RESULTS: The expression level of FOXO1 in human endometrial tissue fluctuated with the menstrual cycle. If pregnancy occurred, the expression of FOXO1 was further increased (p < 0.05) and cAMP regulated FOXO1 expression in ESC. In addition, 4-pregnene-3,20-dione cooperatively stimulated FOXO1 expression with cAMP. We also observed FOXO1 expression during in vitro cAMP-induced decidualization. CONCLUSIONS: The pattern of FOXO1 expression suggests a potential role for FOXO1 in implantation and decidualization. PMID- 22538367 TI - A beta-sheet structure interacting peptide for intracellular protein delivery into human pluripotent stem cells and their derivatives. AB - The advance in stem cell research relies largely on the efficiency and biocompatibility of technologies used to manipulate stem cells. In our previous study, we had designed an amphipathic peptide RV24 that can deliver proteins into cancer cell lines efficiently without significant side effects. Encouraged by this observation, we moved forward to test whether RV24 could be used to deliver proteins into human embryonic stem cells and human induced pluripotent stem cells. RV24 successfully mediated protein delivery into these pluripotent stem cells, as well as their derivatives including neural stem cells and dendritic cells. Based on NMR studies and particle surface charge measurements, we proposed that hydrophobic domain of RV24 interacts with beta-sheet structures of the proteins, followed by formation of "peptide cage" to facilitate delivery across cellular membrane. These findings suggest the feasibility of using amphipathic peptide to deliver functional proteins intracellularly for stem cell research. PMID- 22538368 TI - Angiopoietin like protein 4 expression is decreased in activated macrophages. AB - Angiopoietin like protein 4 (ANGPTL4) inhibits lipoprotein lipase (LPL) activity. Previous studies have shown that Toll-like Receptor (TLR) activation increases serum levels of ANGPTL4 and expression of ANGPTL4 in liver, heart, muscle, and adipose tissue in mice. ANGPTL4 is expressed in macrophages and is induced by inflammatory saturated fatty acids. The absence of ANGPTL4 leads to the increased uptake of pro-inflammatory saturated fatty acids by macrophages in the mesentery lymph nodes due to the failure of ANGPTL4 to inhibit LPL activity, resulting in peritonitis, intestinal fibrosis, weight loss, and death. Here we determined the effect of TLR activation on the expression of macrophage ANGPTL4. LPS treatment resulted in a 70% decrease in ANGPTL4 expression in mouse spleen, a tissue enriched in macrophages. In mouse peritoneal macrophages, LPS treatment also markedly decreased ANGPTL4 expression. In RAW cells, a macrophage cell line, LPS, zymosan, poly I:C, and imiquimod all inhibited ANGPTL4 expression. In contrast, neither TNF, IL-1, nor IL-6 altered ANGPTL4 expression. Finally, in cholesterol loaded macrophages, LPS treatment still decreased ANGPTL4 expression. Thus, while in most tissues ANGPTL4 expression is stimulated by inflammatory stimuli, in macrophages TLR activators inhibit ANGPTL4 expression, which could lead to a variety of down-stream effects important in host defense and wound repair. PMID- 22538369 TI - All G protein betagamma complexes are capable of translocation on receptor activation. AB - Heterotrimeric G proteins transduce signals sensed by transmembrane G protein coupled receptors (GPCRs). A subfamily of G protein betagamma subunit types has been shown to selectively translocate from the plasma membrane to internal membranes on receptor activation. Using 4D imaging we show here that Gbetagamma translocation is not restricted to some subunit types but rather all 12 members of the family of mammalian gamma subunits are capable of supporting betagamma translocation. Translocation kinetics varies widely depending on the specific gamma subunit type, with t(1/2) ranging from 10s to many minutes. Using fluorescence complementation, we show that the beta and gamma subunits translocate as betagamma dimers with kinetics determined by the gamma subunit type. The expression patterns of endogenous gamma subunit types in HeLa cells, hippocampal neurons and cardiomyocytes are distinctly different. Consistent with these differences, the betagamma translocation rates vary widely. betagamma translocation rates exhibit the same gamma subunit dependent trends regardless of the specific receptor type or cell type showing that the translocation rates are intrinsic to the gamma subunit types. betagamma complexes with widely different rates of translocation had differential effects on muscarinic stimulation of GIRK channel activity. These results show that G protein betagamma translocation is a general response to activation of GPCRs and may play a role in regulating signaling activity. PMID- 22538370 TI - Lamins as mediators of oxidative stress. AB - The nuclear lamina defines both structural and functional properties of the eukaryotic cell nucleus. Mutations in the LMNA gene, encoding A-type lamins, lead to a broad spectrum of diseases termed laminopathies. While different hypotheses have been postulated to explain disease development, there is still no unified view on the mechanistic basis of laminopathies. Recent observations indicate that laminopathies are often accompanied by altered levels of reactive oxygen species and a higher susceptibility to oxidative stress at the cellular level. In this review, we highlight the role of reactive oxygen species for cell function and disease development in the context of laminopathies and present a framework of non-exclusive mechanisms to explain the reciprocal interactions between a dysfunctional lamina and altered redox homeostasis. PMID- 22538371 TI - Isoliquiritigenin isolated from Glycyrrhiza uralensis protects neuronal cells against glutamate-induced mitochondrial dysfunction. AB - Glutamate-mediated excitotoxicity, which is associated with reactive oxygen species (ROS), is hypothesized to be a major contributor to pathological cell death in the mammalian central nervous system, and to be involved in many acute and chronic brain diseases. Here, we showed that isoliquiritigenin (ISL) isolated from Glycyrrhiza uralensis (Gu), one of the most frequently prescribed oriental herbal medicines, protected HT22 hippocampal neuronal cells from glutamate induced oxidative stress. In addition, we clarified the molecular mechanisms by which it protects against glutamate-induced neuronal cell death. ISL reversed glutamate-induced ROS production and mitochondrial depolarization, as well as glutamate-induced changes in expression of the apoptotic regulators Bcl-2 and Bax. Pretreatment of HT22 cells with ISL suppresses the release of apoptosis inducing factor from mitochondria into the cytosol. Taken together, our results suggest that ISL may protect against mitochondrial dysfunction by limiting glutamate-induced oxidative stress. In conclusion, our results demonstrated that ISL isolated from Gu has protective effects against glutamate-induced mitochondrial damage and hippocampal neuronal cell death. We expect ISL to be useful in the development of drugs to prevent or treat neurodegenerative diseases. PMID- 22538372 TI - Gay men who are not getting tested for HIV. AB - Using data from Australian Gay Community Periodic Surveys 1998-2010, we assessed the prevalence, trends and characteristics of gay men not tested for HIV. In 2010, one in eight Australian gay socially-engaged men were never tested for HIV, most of them sexually active and 56.5 % reporting unprotected anal intercourse. The proportion of not tested men was significantly higher in men younger than 30, of non-European origin and living outside of gay metropolitan areas. Although frequency of testing was associated with sexual practices, significant proportions of men with multiple sex partners and reporting unprotected anal intercourse were not tested as recommended. There were issues with using gay friendly testing services in gay metropolitan areas. Despite Australia's success in HIV testing, improvement is needed for early detection of HIV infections. Interventions should encourage regular testing, engage with young gay men, improve access and convenience of testing, train service providers and expand testing options. PMID- 22538373 TI - Cognitive, psychosocial, and sociodemographic predictors of willingness to use HIV pre-exposure prophylaxis among Chinese men who have sex with men. AB - This study was designed to identify predictors of lower versus higher willingness to use pre-exposure prophylaxis (PrEP) to reduce HIV among men who have sex with men (MSM) in China. Participants were 570 MSM who completed self-report measures of willingness to use HIV PrEP, beliefs about HIV, psychosocial factors, sexual experiences and sociodemographic characteristics. Results of a hierarchical binary logistic regression analysis indicated that membership in a higher willingness group was predicted by previous consultation about HIV, more reported barriers to using condoms, and elevations in depressive symptoms. Independent of these factors, higher willingness to use HIV PrEP was predicted by beliefs that the intervention was low in stigma and high in potential benefits. In sum, the study highlighted the utility of broad-based assessment of demographic, behavioral, personality, and cognitive factors in identifying Chinese MSM who express willingness to use a promising biologically-based intervention to lower HIV risk. PMID- 22538375 TI - Nanowires for energy. PMID- 22538374 TI - Examining auditory kappa effects through manipulating intensity differences between sequential tones. AB - The auditory kappa effect is a tendency to base the perceived duration of an inter-onset interval (IOI) separating two sequentially presented sounds on the degree of relative pitch distance separating them. Previous research has found that the degree of frequency discrepancy between tones extends the subjective duration of the IOI. In Experiment 1, auditory kappa effects for sound intensity were tested using a three-tone, AXB paradigm (where the intensity of tone X was shifted to be closer to either Tone A or B). Tones closer in intensity level were perceived as occurring closer in time, evidence of an auditory-intensity kappa effect. In Experiments 2 and 3, the auditory motion hypothesis was tested by preceding AXB patterns with null intensity and coherent intensity context sequences, respectively. The auditory motion hypothesis predicts that coherent sequences should enhance the perception of motion and increase the strength of kappa effects. In this study, the presence of context sequences reduced kappa effect strength regardless of the properties of the context tones. PMID- 22538376 TI - How can we minimize barotraumas in our most premature infants? PMID- 22538377 TI - Management of granulomatous common variable immunodeficiency diagnosed in pregnancy: a case report. AB - Common variable immunodeficiency (CVID) is a rare condition that affects women of childbearing age with important implications in pregnancy. It is characterised by low immunoglobulins (Igs), poor antibody response and a susceptibility to recurrent infections. The cornerstone of management of CVID is Ig replacement. As the transfer of IgG across the placenta in the third trimester of pregnancy is necessary for protection of the infant in the first months of life, failure to recognise this condition and treat it appropriately can have adverse consequences for the neonate, as well as the mother. Here we describe the complex perinatal medical management of a 34-year-old woman who was diagnosed with CVID in the 26th week of pregnancy. PMID- 22538378 TI - Mid-aortic syndrome in two preterm infants. AB - We report mid-aortic syndrome (MAC) in two preterm infants. Both infants developed malignant hypertension refractory to medical therapy and died early in infancy. Thus far, this account is of the two youngest patients with MAC. PMID- 22538380 TI - Letter on 'a review of alternatives to di(2-ethylhexyl)phthalate-containing medical devices in the neonatal intensive care unit'. PMID- 22538382 TI - Measurement of guided mode wavenumbers in soft tissue-bone mimicking phantoms using ultrasonic axial transmission. AB - Human soft tissue is an important factor that influences the assessment of human long bones using quantitative ultrasound techniques. To investigate such influence, a series of soft tissue-bone phantoms (a bone-mimicking plate coated with a layer of water, glycerol or silicon rubber) were ultrasonically investigated using a probe with multi-emitter and multi-receiver arrays in an axial transmission configuration. A singular value decomposition signal processing technique was applied to extract the frequency-dependent wavenumbers of several guided modes. The results indicate that the presence of a soft tissue mimicking layer introduces additional guided modes predicted by a fluid waveguide model. The modes propagating in the bone-mimicking plate covered by the soft tissue phantom are only slightly modified compared to their counterparts in the free bone-mimicking plate, and they are still predicted by an elastic transverse isotropic two-dimensional waveguide. Altogether these observations suggest that the soft tissue-bone phantoms can be modeled as two independent waveguides. Even in the presence of the overlying soft tissue-mimicking layer, the modes propagating in the bone-mimicking plate can still be extracted and identified. These results suggest that our approach can be applied for the purpose of the characterization of the material and structural properties of cortical bone. PMID- 22538383 TI - Intrinsic energy dissipation in CVD-grown graphene nanoresonators. AB - We utilize classical molecular dynamics to study the quality (Q)-factors of monolayer CVD-grown graphene nanoresonators. In particular, we focus on the effects of intrinsic grain boundaries of different orientations, which result from the CVD growth process, on the Q-factors. For a range of misorientation angles that are consistent with those seen experimentally in CVD-grown graphene, i.e. 0 degrees to ~20 degrees , we find that the Q-factors for graphene with intrinsic grain boundaries are 1-2 orders of magnitude smaller than that of pristine monolayer graphene. We find that the Q-factor degradation is strongly influenced by both the symmetry and structure of the 5-7 defect pairs that occur at the grain boundary. Because of this, we also demonstrate that the Q-factors of CVD-grown graphene can be significantly elevated, and approach that of pristine graphene, through application of modest (1%) tensile strain. PMID- 22538384 TI - Synthesis and characterization of novel zwitterionic lipids with pH-responsive biophysical properties. AB - We report the synthesis and biophysical characterization of a novel class of zwitterionic lipids (ZL) with head groups containing a 3 degrees or 4 degrees amine and carboxylate. ZL form stable liposomes that exhibit head group dependent, pH-responsive biophysical characteristics. These lipids may be suitable components for drug delivery applications due to their ease of synthesis and unique pH-dependent properties. PMID- 22538386 TI - Sentinel lymph node biopsy predicts lymph node metastasis in early gastric cancer: a retrospective analysis. AB - BACKGROUND/AIMS: Minimally invasive treatments have emerged as the frontline therapy for patients with early gastric cancer (EGC). However, some cT1N0 patients with EGC may have lymph node metastasis because of inadequate evaluation. This study aimed to investigate the diagnostic accuracy of sentinel lymph node (SLN) and tried to find out feasible criteria for SLN-guided minimally invasive surgery for EGC. METHODS: A solitary metastasis lymph node was taken as SLN, the features of lymph node metastasis were analyzed retrospectively in 255 patients with EGC, and the result was then compared with a SLN biopsy in 23 patients with EGC. RESULTS: Depth of invasion and tumor size were independent risk factors for lymph node metastasis in EGC. The lymph node metastasis rate for mucosal carcinoma with a diameter <4 cm was 2.5%, and it was 13.3% when the diameter was >= 4 cm (p = 0.040). For submucosal carcinoma, it was 25.4% when the tumor diameter was <3 cm and 50.5% when the diameter was >= 3 cm (p = 0.003). The accuracy, sensitivity, and specificity of SLN biopsy in EGC was 100%, respectively. The distribution characteristics of SLN were consistent with those of lymph node metastasis in EGC. CONCLUSIONS: SLN-guided minimally invasive surgery could be safely performed in EGC according to feasible criteria. PMID- 22538385 TI - Function and dysfunction of prefrontal brain circuitry in alcoholic Korsakoff's syndrome. AB - The signature symptom of alcohol-induced persisting amnestic disorder, more commonly referred to as alcoholic Korsakoff's syndrome (KS), is anterograde amnesia, or memory loss for recent events, and until the mid 20th Century, the putative brain damage was considered to be in diencephalic and medial temporal lobe structures. Overall intelligence, as measured by standardized IQ tests, usually remains intact. Preservation of IQ occurs because memories formed before the onset of prolonged heavy drinking--the types of information and abilities tapped by intelligence tests--remain relatively well preserved compared with memories recently acquired. However, clinical and experimental evidence has shown that neurobehavioral dysfunction in alcoholic patients with KS does include nonmnemonic abilities, and further brain damage involves extensive frontal and limbic circuitries. Among the abnormalities are confabulation, disruption of elements of executive functioning and cognitive control, and emotional impairments. Here, we discuss the relationship between neurobehavioral impairments in KS and alcoholism-related brain damage. More specifically, we examine the role of damage to prefrontal brain systems in the neuropsychological profile of alcoholic KS. PMID- 22538388 TI - Human biomarkers in breath by photoacoustic spectroscopy. AB - Photoacoustic spectrometry provides a novel approach to the analysis of human breath biomarkers. This unique methodology has specific applications for determination of ethylene oxide, nitrous oxide, ammonia as well as other compounds of interest including sevoflurane, halothane, isoflurane, methane, ethane and propofol. The advantages and disadvantages of photoacoustic spectrometry for this purpose are evaluated. PMID- 22538389 TI - Aging and diets regulate the rat anterior pituitary and hypothalamic transcriptome. AB - Dietary interventions involving caloric restriction represent a powerful strategy to prevent or delay age-related deteriorations and diseases. Their beneficial effects have been observed in several tissues and species. This microarray study investigated the effects of aging, long-term moderate caloric restriction (LTMCR) and long-term dietary soy on the regulation of gene expression in the anterior pituitary and hypothalamus of 20-month-old Sprague-Dawley rats. In both tissues, aging regulated genes mainly involved in cell defense and repair mechanisms related to apoptosis, DNA repair, cellular stress, inflammatory and immune response. In the aging pituitary, the highest upregulated gene was the regenerating islet-derived 3beta (5.77-fold), coding for a secretory protein involved in acute stress and inflammation. A protective effect of LTMCR on age related change of gene expression was observed for 35 pituitary genes. In addition, beneficial effects of LTMCR in the pituitary were observed on new regulated genes mainly involved in cell death and cell stress response. In the hypothalamus, the effects of LTMCR on age-related changes were modest. Finally, changing the quality of dietary protein (20% casein for soy) had a low impact on the regulation of mRNA levels in both tissues. Genes associated with the somatotroph function were also differentially expressed in the aging pituitary. Interestingly, LTMCR prevented the effect of aging on insulin-like growth factor binding protein-3 gene. Altogether, this study proposes novel pituitary and hypothalamic molecular targets and signaling pathways to help in understanding the mechanisms involved in aging processes and LTMCR. PMID- 22538387 TI - Prevalence, correlates, comorbidities, and suicidal tendencies of premenstrual dysphoric disorder in a nationwide sample of Korean women. AB - PURPOSE: We examined the prevalence, correlates, comorbidities, and suicidal tendencies of premenstrual dysphoric disorder (PMDD) according to the DSM-IV criteria in a nationwide sample of Korean women. METHODS: A total of 2,499 women aged 18-64 years participated in this study. Diagnostic assessments were based on the Korean version of the Composite International Diagnostic Interview (CIDI) 2.1 and its 12-month PMDD diagnostic module, which were administered by lay interviewers. The frequencies of DSM-IV psychiatric disorders, insomnia, and suicidal tendency were analyzed among PMDD cases and compared with non-PMDD cases, and both odds ratios and significance levels were calculated. RESULTS: The 12-month prevalence rate of DSM-IV-diagnosed PMDD was 2.4 %. Among subjects with PMDD, 59.3 % had at least one psychiatric illness; in comparison, the control frequency was 21.8 %. Associations between PMDD and alcohol abuse/dependence, major depressive disorder, post-traumatic stress disorder, social phobia, specific phobia, somatoform disorder, insomnia, and suicidality were overwhelmingly positive and significant (p < 0.05), after controlling for age. Physical illness and being underweight were associated with increased risks of PMDD (p < 0.05). CONCLUSIONS: PMDD was prevalent in the nationwide sample of Korean women and was frequently associated with other psychiatric disorders, insomnia, and suicidality, suggesting the need to detect and treat women who experience PMDD. PMID- 22538390 TI - Success and failure for children born with facial clefts in Africa: a 15-year follow-up. AB - BACKGROUND: This study reviews the 15 year program of our Department of Pediatric Surgery for the treatment and follow-up of children born with a cleft in Benin and Togo. METHODS: We analyzed files of children born in Africa with a cleft. They were referred to us through a nongovernmental organization (NGO) between 1993 and 2008 and assessed in Africa by local pediatricians before and after surgery. Operations were performed by our team. RESULTS: Two hundred files were reviewed: 60 cases of unilateral cleft lip, seven of bilateral cleft lip, 44 of unilateral cleft lip palate (UCLP), 29 of bilateral cleft lip palate (BCLP), 53 of cleft palate (CP), three of bilateral oro-ocular cleft, one of unilateral and two of median clefts (Binder), and one of commissural cleft. Sixty-nine (35 %) of these cases were not operated in Africa: 25 (12.5 %) had not shown up, 28 (15 %) were considered unfit for surgery (Down's syndrome, HIV-positive, malnutrition, cardiac malformation), and 16 (7.5 %) were transferred to Switzerland. Palatal fistula occurred in 20 % of UCLP, 30 % of BCLP, and 16 % of CP. Evaluation of speech after palate surgery gave less than 50 % of socially acceptable speech. CONCLUSIONS: Our partnership with a NGO and a local team makes it possible to treat and subsequently follow children born with a cleft in West Africa. Surgery is performed under good conditions. If aesthetic results are a success, functional results after palate surgery need further improvement to promote integration in school and social life. PMID- 22538391 TI - One- and two-year outcomes and predictors of mortality following emergency laparotomy: a consecutive series from a United Kingdom teaching hospital. AB - BACKGROUND: Data on outcomes of patients who underwent emergency laparotomy (EML) are limited. This prospective observational study examined aspects of inpatient care and outcomes following EML with a view to identifying predictors of mortality. METHODS: Data collected from consecutive inpatients who underwent EML in a UK teaching hospital over a 3-month period included perioperative physiology, treatment, morbidity, and mortality (30-day, in-hospital, 12-month, and 24-month). Univariate and multiple logistic regression analyses were used to identify predictors of mortality. RESULTS: Eighty-five patients (44 male) with a mean +/- SD age of 61 +/- 18 years were studied. Postoperatively, 51 % of patients were admitted to the intensive care (ICU) or the high-dependency unit (HDU). 30-day, in-hospital, 12-month, and 24-month mortality was 14, 16.5, 22.4, and 25.9 %, respectively. After adjusting for confounding variables, age >=70 years (odds ratio [OR] = 9.2, P = 0.004) and a need for postoperative ICU/HDU (OR = 15.0, P = 0.014) were independent predictors of 30-day mortality. Independent predictors of in-hospital mortality were age >=70 years (OR = 18.2, P = 0.016), ASA >=III (OR = 22.1, P = 0.034), preoperative sepsis (OR = 20.6, P = 0.045), and need for postoperative ICU/HDU (OR = 21.5, P = 0.038). Independent predictors of 12-month mortality were preoperative urea >7.5 mmol/L (OR = 3.5, P = 0.038) and need for postoperative ICU/HDU (OR = 3.7, P = 0.044). Age >=70 years was the only independent predictor of 24-month mortality (OR = 4.5, P = 0.014). Almost all deaths recorded in the 24 months following surgery resulted from disseminated malignancy. CONCLUSION: Patients who underwent EML had favourable outcomes, with 2-year survival close to 75 %. Age >=70 years and the need for postoperative ICU/HDU care were independent predictors of mortality. PMID- 22538392 TI - The role of simple renal cysts, abdominal wall hernia, and chronic obstructive pulmonary disease as predictive factors for aortoiliac aneurysmatic disease. AB - BACKGROUND: This study was designed to investigate the possible predictive value of simple renal cysts (SRCs), abdominal wall hernia (AWH), and chronic obstructive pulmonary disease (COPD) for the presence of abdominal aortoiliac aneurysms (AAA). METHODS: Between January 2006 and January 2011, we treated 170 consecutive patients with aortoiliac pathology. Patients' data were prospectively collected and were retrospectively analyzed. Of these patients, 110 (study group) had AAA (group 1) and 60 (control group) had aortoiliac occlusive disease (AOD; group 2). Moreover, patients of group 1 were subdivided, according to aneurysm's diameter to subgroup 1A (aortic aneurysm diameter >55 mm and/or common iliac diameter >22 mm; n = 62) and subgroup 1B (aortic aneurysm diameter <= 55 mm and/or common iliac diameter <= 22 mm; n = 48). All patients underwent a computed tomographic angiography, and datasets were analyzed for aortoiliac and SRCs' anatomical data. Additionally collected data were atherosclerotic risk factors, history of previous or current AWH, and COPD. RESULTS: The two groups as well as the two AAA subgroups were homogenous regarding demographics and atherosclerotic risk factors. Univariate analysis showed that incidence of SRCs, AWH, and COPD were significant predictive factors for presence of AAA. Multivariate analysis identified SRCs and AWH as independent predictive factors for the presence of AAA. In association with the aneurysm's size, multivariate analysis failed to show any predictive value of SRCs, AWH, or COPD. CONCLUSIONS: Results of our study showed a positive predictive value of SRCs and AWH for presence of AAA and a strong relationship but not with predictive value between COPD and AAA. These data might be helpful for the early recognition of patients at risk for an aortoiliac aneurysm formation and for establishment of AAAs population-based screening. Further research of pathophysiological commonalities between the four studied entities may be extremely helpful for designing future preventive and treatment strategy of AAAs. PMID- 22538393 TI - A single, global patient-centered measure from the SF-36 instrument to assess surgical outcomes and quality of life: a pilot study. AB - BACKGROUND: Many quality of life (QoL) and patient-reported outcomes (PRO) measures have been developed to assess the effects of disease processes and treatments. Although these instruments are valuable, the process is hampered because of their number and lack of interchangeability. METHODS: We identified a cohort of patients across a variety of operations within 3-12 months postoperatively. Patients completed the SF-36, measuring eight domains of QoL (physical functioning, role-physical, role-emotional, bodily pain, vitality, mental health, social functioning, and general health), plus a health transition item: Compared to one year ago, how would you rate your health in general now?. (1) Much better now than one year ago. (2) Somewhat better now than one year ago. (3) About the same as one year ago. (4) Somewhat worse than one year ago. (5) Much worse than one year ago. Additional data included improvement of preoperative symptoms, the occurrence of any postoperative symptoms, and the occurrence of any postoperative complications. RESULTS: Of 217 patients, 28 % were much better, 28 % somewhat better, 27 % unchanged, 13 % somewhat worse, and 3 % much worse. The health transition results were associated with all SF-36 domains, preoperative symptom change (p = 0.03) and persistent or new postoperative symptoms (p = 0.001), but not postoperative complications. Patients with persistent or new symptoms postoperatively had worse scores in the role emotional (p = 0.01), bodily pain (p = 0.05), social functioning (p = 0.02), and mental health (p = 0.009) domains of the SF-36. CONCLUSIONS: This single, global assessment of health transition may be a promising practical alternative to assess postoperative patient-centered outcomes. Improved patients had better QoL scores, preoperative symptoms elimination, and no operation-related symptoms, but the occurrence of complications did not affect improvement. PMID- 22538394 TI - Inclusion of predeposit autologous blood donation and 33 % hypertonic saline solution in the surgical management of patients with peritoneal echinococcosis. PMID- 22538395 TI - Prevalence of herpes simplex virus type 2 in different risk groups: thirty years after the onset of HIV. AB - BACKGROUND: Herpes simplex virus type 2 (HSV2) is a sexually transmitted disease causing a lifelong persisting infection. OBJECTIVE: To determine the seroprevalence of anti-HSV2-IgG in a German collective. We evaluate the German serological status, point out trends in the chronological spread of HSV2 infection, and position our findings in a global context. METHODS: Serum samples from 29,694 patients at the University Hospital Frankfurt am Main, Germany, were screened for anti-HSV2-IgG using ELISA. We evaluated five defined groups containing patients from the departments of pediatrics (PED), gynecology (GYN), dermatology (DER), psychiatrics (PSY) and patients suffering from HIV/AIDS (HIV). RESULTS: We retrospectively evaluated an overall seropositivity to anti-HSV2-IgG of 13.6% (95% CI 13.1-14.1), with a significantly higher level in females (15.9%, 95% CI 15.4-16.5) than in males (11.4%, 95% CI 10.9-11.9). The highest seroprevalence was detected in HIV (34.7%, 95% CI 30.3-39.3). The lowest rate was observed in PED (9.9%, 95% CI 9.4-10.6) with an estimated number of 18 infections at delivery between 1/1/2000 and 1/1/2011. CONCLUSIONS: HSV2 infections are widespread in Germany with a tremendous health risk for newborns. Therefore, the public's perception of HSV2 should be strengthened and protected sexual intercourse should be propagated. PMID- 22538396 TI - One-step amino acid selective isotope labeling of proteins in prototrophic Escherichia coli strains. AB - Amino acid selective isotope labeling is a useful approach to simplification of nuclear magnetic resonance (NMR) spectra of large proteins. Cell-free protein synthesis offers essentially unlimited flexibility of labeling patterns but is labor-intensive and expensive. In vivo labeling is simple in principle but generally requires auxotrophic strains, inhibitors of amino acid synthesis, or complex media formulations. We describe a simple procedure for amino acid selective labeling of proteins expressed in prototrophic Escherichia coli strains. Excellent labeling selectivity was achieved for histidine, lysine, methionine, and alanine. Simplicity and robustness of this protocol make it a useful tool for protein NMR. PMID- 22538397 TI - Evaluation of metallothionein formation as a proxy for zinc absorption in an in vitro digestion/Caco-2 cell culture model. AB - Caco-2 cell metallothionein (MT) formation was studied to determine if MT could be used as a proxy for zinc (Zn) absorption in a cell culture model. The MT intracellular concentration was determined using a cadmium/hemoglobin affinity assay. The cellular Zn uptake was determined by acid digests (5% HNO(3)) using inductively-coupled argon-plasma emission spectroscopy. The effect of phytic acid (PA) on cellular Zn and MT concentrations was also studied. Cells were treated with a media containing 0, 2, 5, 10, 25, 50, 75 MUmol L(-1) Zn (ZnCl(2)). The effect of varying the Zn:PA molar ratios (1:0, 1:1, 1:5, 1:10, 1:20) on the Zn uptake and MT formation was determined. The results showed a positive linear correlation between Zn-media concentrations and cellular Zn uptake, and MT formation was observed. Zn and MT concentrations in the cells treated with increasing levels of Zn (>25 MUmol L(-1) Zn) were elevated. The Zn and MT concentrations in the cells incubated with Zn (when <10 MUmol L(-1)) were similar to the untreated cells. PA significantly lowered the cellular Zn and MT concentrations. When the Zn:PA molar ratios were >1:5, cellular MT concentrations were no different to untreated cells. When a combined in vitro digestion/cell model was used, the cellular MT concentrations in white or red beans and fish samples were no different to the cell baseline. This study suggests that measurements of cellular Zn and MT concentrations have some limitations (<10 MUmol L(-1) Zn). PA was observed to be a potent inhibitor of Zn uptake. Under the conditions of this in vitro model, Caco-2 cell monolayers are not useful for evaluating the Zn availability from foods. PMID- 22538400 TI - Retraction Note. Erratum to: Treating allergic rhinitis in pregnancy. PMID- 22538398 TI - Clock gene variants in mood and anxiety disorders. AB - Circadian clocks are driven by signals from the habitat to match the solar day and to reset their phase relative to local time. A key function of the circadian clocks allows individuals to anticipate routine environmental conditions and to adjust their behaviors to the change of conditions. In clinical practice mood, anxiety and alcohol use disorders are often comorbid conditions. Clinical data have demonstrated that there are abnormalities in the circadian rhythms in patients with mood disorders and those with alcohol use disorders. Recent findings of molecular genetics have yielded the first insight into the targets of interest. Circadian clock gene variants are a fruitful target for elucidation of the pathogenesis. The findings that have gained support indicate that genetic variants of RORA (rs2028122) and CRY1 (rs2287161) associate with depressive disorder, those of RORB (rs7022435, rs3750420, rs1157358, rs3903529) and NR1D1 (rs2314339) with bipolar disorder, and those of NPAS2 (rs11541353) and CRY2 (rs10838524) with seasonal affective disorder or winter depression. Concerning anxiety disorders and alcohol use disorders, the current findings are preliminary and need further verification to explain the association of ARNTL2, being suggestive only, with social phobia (rs2306073) and with alcohol abuse (rs7958822, rs4964057). PMID- 22538399 TI - Elevated neutrophil to lymphocyte ratio predicts poor prognosis in advanced colorectal cancer patients receiving oxaliplatin-based chemotherapy. AB - BACKGROUND: The aim of this study was to assess whether the neutrophil to lymphocyte ratio (NLR) and other laboratory markers may predict the prognosis of advanced colorectal cancer (CRC) patients receiving palliative chemotherapy. METHODS: The study population included 50 patients with far advanced or recurrent unresectable CRC who received oxaliplatin-based combination chemotherapy as first line treatment in our hospital between June 2005 and November 2010. Seven clinical variables and 7 laboratory indices before chemotherapy were evaluated retrospectively as the possible prognostic factors of overall and progression free survival. RESULTS: During the study period, 27 patients (54%) died of CRC. Elevated NLR (>=4.0) was observed in 15 patients (30%). By univariate analysis, elevated NLR, performance status and hypoalbuminemia were significantly associated with both poor overall and progression-free survivals. Multivariate analysis showed that elevated NLR (hazard ratio 4.39, 95% confidence interval 1.82-10.7; p = 0.0013) and thrombocytosis (hazard ratio 5.02, 95% confidence interval 1.69-13.4; p = 0.0066) were independently associated with overall survival. CONCLUSION: Elevated NLR is a powerful predictor of poor response to oxaliplatin-based chemotherapy in patients with unresectable CRC. The ratio is a simply accessible and inexpensive but useful biomarker in CRC patients receiving chemotherapy. PMID- 22538401 TI - Gut mucosal injury in neonates is marked by macrophage infiltration in contrast to pleomorphic infiltrates in adult: evidence from an animal model. AB - Necrotizing enterocolitis (NEC) is an inflammatory bowel necrosis of premature infants. In tissue samples of NEC, we identified numerous macrophages and a few neutrophils but not many lymphocytes. We hypothesized that these pathoanatomic characteristics of NEC represent a common tissue injury response of the gastrointestinal tract to a variety of insults at a specific stage of gut development. To evaluate developmental changes in mucosal inflammatory response, we used trinitrobenzene sulfonic acid (TNBS)-induced inflammation as a nonspecific insult and compared mucosal injury in newborn vs. adult mice. Enterocolitis was induced in 10-day-old pups and adult mice (n = 25 animals per group) by administering TNBS by gavage and enema. Leukocyte populations were enumerated in human NEC and in murine TNBS-enterocolitis using quantitative immunofluorescence. Chemokine expression was measured using quantitative polymerase chain reaction, immunoblots, and immunohistochemistry. Macrophage recruitment was investigated ex vivo using intestinal tissue-conditioned media and bone marrow-derived macrophages in a microchemotaxis assay. Similar to human NEC, TNBS enterocolitis in pups was marked by a macrophage-rich leukocyte infiltrate in affected tissue. In contrast, TNBS-enterocolitis in adult mice was associated with pleomorphic leukocyte infiltrates. Macrophage precursors were recruited to murine neonatal gastrointestinal tract by the chemokine CXCL5, a known chemoattractant for myeloid cells. We also demonstrated increased expression of CXCL5 in surgically resected tissue samples of human NEC, indicating that a similar pathway was active in NEC. We concluded that gut mucosal injury in the murine neonate is marked by a macrophage-rich leukocyte infiltrate, which contrasts with the pleomorphic leukocyte infiltrates in adult mice. In murine neonatal enterocolitis, macrophages were recruited to the inflamed gut mucosa by the chemokine CXCL5, indicating that CXCL5 and its cognate receptor CXCR2 merit further investigation as potential therapeutic targets in NEC. PMID- 22538405 TI - Ileal smooth muscle dysfunction and remodeling in cystic fibrosis. AB - Patients with cystic fibrosis (CF) often suffer from gastrointestinal cramps and intestinal obstruction. The CF transmembrane conductance regulator (CFTR) channel has been shown to be expressed in vascular and airway smooth muscle (SM). We hypothesized that the absence of CFTR expression alters the gastrointestinal SM function and that these alterations may show strain-related differences in the mouse. The aim of this study was to measure the contractile properties of the ileal SM in two CF mouse models. CFTR(-/-) and CFTR(+/+) mice were studied on BALB/cJ and C57BL/6J backgrounds. Responsiveness of ileal strips to electrical field stimulation (EFS), methacholine (MCh), and isoproterenol was measured. The mass and the cell density of SM layers were measured morphometrically. Finally, the maximal velocity of shortening (Vmax) and the expression of the fast (+)insert myosin isoform were measured in the C57BL/6J ileum. Ileal hyperreactivity was observed in response to EFS and MCh in CFTR(-/-) compared with CFTR(+/+) mice in C57BL/6J background. This latter observation was not reproduced by acute inhibition of CFTR with CFTR(inh)172. BALB/cJ CFTR(-/-) mice exhibited a significant increase of SM mass with a lower density of cells compared with CFTR(+/+), whereas no difference was observed in the C57BL/6J background. In addition, in this latter strain, ileal strips from CFTR(-/-) exhibited a significant increase in Vmax compared with control and expressed a greater proportion of the fast (+)insert SM myosin isoform with respect to total myosin. BALB/cJ CFTR(-/-) ilium had a greater relaxation to isoproterenol than the CFTR(+/+) mice when precontracted with EFS, but no difference was observed in response to exogeneous MCh. In vivo, the lack of CFTR expression induces a different SM ileal phenotype in different mouse strains, supporting the importance of modifier genes in determining intestinal SM properties. PMID- 22538402 TI - Lactobacillus rhamnosus GG culture supernatant ameliorates acute alcohol-induced intestinal permeability and liver injury. AB - Endotoxemia is a contributing cofactor to alcoholic liver disease (ALD), and alcohol-induced increased intestinal permeability is one of the mechanisms of endotoxin absorption. Probiotic bacteria have been shown to promote intestinal epithelial integrity and protect barrier function in inflammatory bowel disease (IBD) and in ALD. Although it is highly possible that some common molecules secreted by probiotics contribute to this action in IBD, the effect of probiotic culture supernatant has not yet been studied in ALD. We examined the effects of Lactobacillus rhamnosus GG culture supernatant (LGG-s) on the acute alcohol induced intestinal integrity and liver injury in a mouse model. Mice on standard chow diet were supplemented with supernatant from LGG culture (10(9) colony forming unit/mouse) for 5 days, and one dose of alcohol at 6 g/kg body wt was administered via gavage. Intestinal permeability was measured by FITC-FD-4 ex vivo. Alcohol-induced liver injury was examined by measuring the activity of alanine aminotransferase (ALT) in plasma, and liver steatosis was evaluated by triglyceride content and Oil Red O staining of the liver sections. LGG-s pretreatment restored alcohol-induced reduction in ileum mRNA levels of claudin 1, intestine trefoil factor (ITF), P-glycoprotein (P-gp), and cathelin-related antimicrobial peptide (CRAMP), which play important roles on intestinal barrier integrity. As a result, LGG-s pretreatment significantly inhibited the alcohol induced intestinal permeability, endotoxemia and subsequently liver injury. Interestingly, LGG-s pretreatment increased ileum mRNA expression of hypoxia inducible factor (HIF)-2alpha, an important transcription factor of ITF, P-gp, and CRAMP. These results suggest that LGG-s ameliorates the acute alcohol-induced liver injury by promoting HIF signaling, leading to the suppression of alcohol induced increased intestinal permeability and endotoxemia. The use of bacteria free LGG culture supernatant provides a novel strategy for prevention of acute alcohol-induced liver injury. PMID- 22538403 TI - CaMKII inhibition hyperpolarizes membrane and blocks nitrergic IJP by closing a Cl(-) conductance in intestinal smooth muscle. AB - The ionic basis of nitrergic "slow'" inhibitory junction potential (sIJP) is not fully understood. The purpose of the present study was to determine the nature and the role of calmodulin-dependent protein kinase II (CaMKII)-dependent ion conductance in nitrergic neurotransmission at the intestinal smooth muscle neuromuscular junction. Studies were performed in guinea pig ileum. The modified Tomita bath technique was used to induce passive hyperpolarizing electrotonic potentials (ETP) and membrane potential change due to sIJP or drug treatment in the same cell. Changes in membrane potential and ETP were recorded in the same smooth muscle cell, using sharp microelectrode. Nitrergic IJP was elicited by electrical field stimulation in nonadrenergic, noncholinergic conditions and chemical block of purinergic IJP. Modification of ETP during hyperpolarization reflected active conductance change in the smooth muscle. Nitrergic IJP was associated with decreased membrane conductance. The CAMKII inhibitor KN93 but not KN92, the Cl(-) channel blocker niflumic acid (NFA), and the K(ATP)-channel opener cromakalim hyperpolarized the membrane. However, KN93 and NFA were associated with decreased and cromakalim was associated with increased membrane conductance. After maximal NFA-induced hyperpolarization, hyperpolarization associated with KN93 or sIJP was not seen, suggesting a saturation block of the Cl(-) channel signaling. These studies suggest that inhibition of CaMKII dependent Cl(-) conductance mediates nitrergic sIJP by causing maximal closure of the Cl(-) conductance. PMID- 22538406 TI - Toward an evidence-based system for innovation support for implementing innovations with quality: tools, training, technical assistance, and quality assurance/quality improvement. AB - An individual or organization that sets out to implement an innovation (e.g., a new technology, program, or policy) generally requires support. In the Interactive Systems Framework for Dissemination and Implementation, a Support System should work with Delivery Systems (national, state and/or local entities such as health and human service organizations, community-based organizations, schools) to enhance their capacity for quality implementation of innovations. The literature on the Support System [corrected] has been underresearched and under developedThis article begins to conceptualize theory, research, and action for an evidence-based system for innovation support (EBSIS). EBSIS describes key priorities for strengthening the science and practice of support. The major goal of EBSIS is to enhance the research and practice of support in order to build capacity in the Delivery System for implementing innovations with quality, and thereby, help the Delivery System achieve outcomes. EBSIS is guided by a logic model that includes four key support components: tools, training, technical assistance, and quality assurance/quality improvement. EBSIS uses the Getting To Outcomes approach to accountability to aid the identification and synthesis of concepts, tools, and evidence for support. We conclude with some discussion of the current status of EBSIS and possible next steps, including the development of collaborative researcher-practitioner-funder-consumer partnerships to accelerate accumulation of knowledge on the Support System. PMID- 22538404 TI - Arachidonic acid stimulates TNFalpha production in Kupffer cells via a reactive oxygen species-pERK1/2-Egr1-dependent mechanism. AB - Kupffer cells are a key source of mediators of alcohol-induced liver damage such as reactive oxygen species, chemokines, growth factors, and eicosanoids. Since diets rich in polyunsaturated fatty acids are a requirement for the development of alcoholic liver disease, we hypothesized that polyunsaturated fatty acids could synergize with ethanol to promote Kupffer cell activation and TNFalpha production, hence, contributing to liver injury. Primary Kupffer cells from control and from ethanol-fed rats incubated with arachidonic acid showed similar proliferation rates than nontreated cells; however, arachidonic acid induced phenotypic changes, lipid peroxidation, hydroperoxides, and superoxide radical generation. Similar effects occurred in human Kupffer cells. These events were greater in Kupffer cells from ethanol-fed rats, and antioxidants and inhibitors of arachidonic acid metabolism prevented them. Arachidonic acid treatment increased NADPH oxidase activity. Inhibitors of NADPH oxidase and of arachidonic acid metabolism partially prevented the increase in oxidant stress. Upon arachidonic acid stimulation, there was a rapid and sustained increase in TNFalpha, which was greater in Kupffer cells from ethanol-fed rats than in Kupffer cells from control rats. Arachidonic acid induced ERK1/2 phosphorylation and nuclear translocation of early growth response-1 (Egr1), and ethanol synergized with arachidonic acid to promote this effect. PD98059, a mitogen extracellular kinase 1/2 inhibitor, and curcumin, an Egr1 inhibitor, blocked the arachidonic acid-mediated upregulation of TNFalpha in Kupffer cells. This study unveils the mechanism whereby arachidonic acid and ethanol increase TNFalpha production in Kupffer cells, thus contributing to alcoholic liver disease. PMID- 22538407 TI - Systems of care: new partnerships for community psychology. AB - For almost two decades, the federal government has supported the development of integrated models of mental health service delivery for children and families, known as systems of care (SOCs), that strive to be child-centered, family focused, community-based, and culturally competent. These efforts align well with the values and principles (e.g., empowerment, collaboration, strengths emphasis, focus on macro-level social/system change) central to community psychology (CP; Kloos et al. in Community psychology, Cengage Learning, Belmont, 2012). Despite the convergence of many core values, CPs have historically been underrepresented in key roles in SOC initiatives. However, this has changed in recent years, with increasing examples of community psychology skills and principles applied to the development, implementation, and evaluation of SOCs. Because successful and sustainable implementation of SOCs requires community and system-level change, and SOCs are increasingly being urged to adopt a stronger "public health" orientation (Miles et al. in A public health approach to children's mental health: a conceptual framework, Georgetown University Center for Child and Human Development, National Technical Assistance Center for Children's Mental Health, Washington, DC, 2010), there is great potential for CPs to play important roles in SOCs. This paper discusses opportunities and roles for CPs in SOCs in applied research and evaluation, community practice, and training. PMID- 22538408 TI - Which clinical errors lead to the referral of UK paediatricians to the National Clinical Assessment Service? AB - The aim of this study was to determine which clinical errors lead to the referral of UK paediatricians to the National Clinical Assessment Service (NCAS). Data for the 10-year period from 1 April 2001 to 31 March 2011 were analysed. Referrals are classified into clinical, behavioural and health related. Clinical referrals can be general, relating to general deficiencies in knowledge and skills, or specific and concerned with a critical incident. Specific clinical referrals were analysed. There were 259 paediatric cases in this period. There were 110 (42 %) clinical concerns in the 259 cases. In 47 of the 110 cases, these were general concerns. There were 63 cases where specific clinical concerns had led to the referral. These were: diagnosis and management of child protection cases, 19; prescribing errors, 13; diagnosis other than child protection cases, 12; treatment incidents, 7; difficulties with transfer of a patient to another unit, 6; poor resuscitation, 4; and slow response to an emergency, 2. In 16 of the cases, the patient died. CONCLUSION: This analysis reveals some different errors to those in other studies of paediatric litigation and complaints. Mistakes in child protection cases were the commonest reason for referral to NCAS. Prescribing errors were the second commonest cause. Difficulties in the diagnosis and treatment of a range of different conditions accounted for the next biggest group of referrals. This study helps highlight areas of paediatrics, such as child protection and prescribing, where training needs to be improved in order to improve patient safety. PMID- 22538410 TI - Copper oxide nanowires: a review of growth. AB - Cuprous oxide (Cu(2)O) and cupric oxide (CuO) nanowires have started playing important roles in energy conversion devices and optoelectronic devices. Although the desired advanced properties have been demonstrated, these materials cannot yet be produced in large-bulk quantities in order to bridge the technological transfer gap for wider use. In this respect, the quest for the most efficient synthesis process which yields not only large quantities but also high quality and advanced material properties continues. This paper gives an extensive review of copper oxide nanowire (NW) synthesis by all methods and routes by which various researchers have obtained their nanomaterial. These methods are critically overviewed, evaluated and compared. Methods of copper oxide NW growth include wet-chemical methods based on pure solution growth, electrochemical and hydrothermal routes as well as thermal and plasma oxidation methods. In terms of advanced nanowire synthesis, the fast thermal method or direct plasma oxidation as well as the combined hybrid wet-chemical method in which copper hydroxide NWs are produced and sequentially transformed by plasma oxidation which produces Cu(2)O NWs are seen as the most promising methods to explore in the near future. These methods not only yield large quantities of NWs, but produce high quality material with advanced properties. PMID- 22538409 TI - Long-term clinical follow-up and molecular genetic findings in eight patients with triple A syndrome. AB - The triple A syndrome (Allgrove syndrome, OMIM #231550) is caused by autosomal recessively inherited mutations in the AAAS gene on chromosome 12q13 encoding the nuclear pore protein ALADIN. This multisystemic disease is characterised by achalasia, alacrima, adrenal insufficiency and neurological impairment. We analyse long-term clinical follow-up and results of sequencing of the AAAS gene in eight patients with triple A syndrome aged from 2 to 35 years. At the time of diagnosis, all patients presented with alacrima, neurological dysfunction, dermatological abnormalities, seven of them with adrenal insufficiency and five of them with achalasia. Sequencing of the AAAS gene identified the p.S263P mutation in five of eight patients, supporting the hypothesis that this mutation is a founder mutation in Slavic population. One of the patients is homozygous for the p.S263P mutation, two are compound heterozygous for the p.S263P and the p.G14fs mutation, two are compound heterozygous for the p.S263Pro mutation and p.S296Y mutation, two are compound heterozygous for the p.G14fs and the p.Q387X mutations and one is homozygous for the p.Q387X mutation. In the course of the follow-up time of 4-29 years, progression of existing and appearance of new symptoms developed. Although severe, many of these symptoms presented in all six young adult patients are often overlooked or neglected: postural hypotension with blurred vision and syncope, hyposalivation resulting with complete edentulosis, talocrular contractures with permanent walking difficulties and erectile dysfunction in male patients. Triple A syndrome is a progressive debilitating disorder which may seriously affect quality of life and even be life-threatening in patients with severe neurological impairment. CONCLUSION: Long-term follow-up of patients with triple A syndrome revealed a variety of the clinical features involving many systems. Progressive natural course of the disease may seriously affect quality of life and even be life-threatening in patients with severe neurological impairment. PMID- 22538411 TI - Formation of engineered bone with adipose stromal cells from buccal fat pad. AB - A robust method for inducing bone formation from adipose-derived stromal cells (ADSCs) has not been established. Moreover, the efficacy of strong osteogenic inducers including BMP-2 for ADSC-mediated bone engineering remains controversial. Meanwhile, the buccal fat pad (BFP), which is found in the oral cavity as an adipose-encapsulated mass, has been shown to have potential as a new accessible source of ADSCs for oral surgeons. However, to date, there have been no reports that define the practical usefulness of ADSCs from BFP (B-ADSCs) for bone engineering. Here, we report an efficient method of generating bone from B ADSCs using rhBMP-2. The analyses show that B-ADSCs can differentiate in vitro toward the osteoblastic lineage by the addition of rhBMP-2 to culture medium, regardless of the presence of osteoinductive reagents (OSR), as demonstrated by measurements of ALP activity, in vitro calcification, and osteogenic gene expression. Interestingly, adipogenic genes were clearly detectable only in cultures with rhBMP-2 and OSR. However, in vivo bone formation was most substantial when B-ADSCs cultured in this condition were transplanted. Thus, B ADSCs reliably formed engineered bone when pre-treated with rhBMP-2 for inducing mature osteoblastic differentiation. This study supports the potential translation for B-ADSC use in the clinical treatment of bone defects. PMID- 22538412 TI - Bernhard Guggenheim--critical mind at the forefront of oral microbiology. AB - Bernhard Guggenheim is a distinguished leader in oral microbiology and immunology and a recipient of many honors. This article outlines his background and scientific career and illuminates some of his important contributions to dental research. At the age of 75, he continues to scrutinize established paradigms and unremittingly fosters demanding biofilm research. PMID- 22538413 TI - Association among vitamin D, oral candidiasis, and calprotectinemia in HIV. AB - Vitamin D deficiency is associated with negative health outcomes, including infections. Vitamin D modulates inflammation and down-regulates the expression of calprotectin, a molecule which influences neutrophil functions and which has been linked to oral candidiasis (OC), the most prevalent oral lesion in human immunodeficiency virus (HIV). We hypothesized a positive association between vitamin D deficiency and OC, and that this effect was partially modulated by calprotectinemia. Plasma calprotectin and serum 25 (OH) vitamin D levels were measured in stored samples from 84 HIV-seropositive Chicago women enrolled in the Oral Substudy of the Women's Interagency HIV Study (WIHS). OC and vitamin D deficiency were diagnosed in, respectively, 14 (16.7%) and 46 (54.8%) of those studied. Vitamin D deficiency was positively associated with OC (p = 0.011) and with higher calprotectinemia (p = 0.019) in univariate analysis. After adjustment for CD4, HIV viral load, HIV treatment, and tobacco and heroin/methadone use, vitamin D deficiency remained a significant predictor of OC (OR 5.66; 95% confidence interval 1.01-31.71). This association weakened after adjustment for calprotectinemia, supporting a role for calprotectinemia as a moderator of this effect. These findings support studies to examine the effect of vitamin D status on calprotectinemia, neutrophil functions, and opportunistic mucosal infections in HIV. PMID- 22538414 TI - Amphotericin B up-regulates lipid A-induced IL-6 production via caspase-8. AB - Amphotericin B, an antifungal drug used to treat candidiasis, has been reported to induce pro-inflammatory cytokine production in cultured cells. This study investigated the effects of amphotericin B on pro-inflammatory cytokine production in response to lipid A, the bioactive component of lipopolysaccharide (LPS) in the cell walls of Gram-negative bacteria. Amphotericin B alone elicited a slight increase in interleukin (IL)-6 and IL-8 production by human gingival fibroblasts. However, amphotericin B synergistically up-regulated lipid A-induced production of IL-6 and IL-8. While amphotericin B minimally activated nuclear factor (NF)-kappaB, it synergistically increased lipid A-induced NF-kappaB activation. Pre-treatment with methyl-beta-cyclodextrin (MbetaCD), a cholesterol binding agent, reduced IL-6 and IL-8 production in human gingival fibroblasts. Cholesterol-saturated MbetaCD also reversed cytokine production, suggesting that the synergistic production of cytokines by amphotericin B and lipid A is dependent on cholesterol-rich microdomains. Amphotericin B activated caspase-8. In addition, a caspase-8 inhibitor inhibited IL-6 production by amphotericin B and lipid A. This suggests that caspase-8 is required for the synergistic production of IL-6 by amphotericin B and lipid A. Collectively, our results suggest that periodontal treatment carried out before amphotericin B treatment may protect against lipid A-induced pro-inflammatory cytokine production. PMID- 22538415 TI - An iron catalyzed regioselective oxidation of terminal alkenes to aldehydes. AB - Fe(BF(4))(2).6H(2)O with pyridine-2,6-dicarboxylic acid and PhIO can efficiently catalyze the regioselective oxidation of terminal alkene derivatives to aldehydes under mild and benign reaction conditions. PMID- 22538416 TI - Proton-induced single electron capture on DNA/RNA bases. AB - In this work, we report total cross sections for the single electron capture process induced on DNA/RNA bases by high-energy protons. The calculations are performed within both the continuum distorted wave and the continuum distorted wave-eikonal initial state approximations. The biological targets are described within the framework of self-consistent methods based on the complete neglect of differential overlap model whose accuracy has first been checked for simpler bio molecules such as water vapour. Furthermore, the multi-electronic problem investigated here is reduced to a mono-electronic one using a version of the independent electron approximation. Finally, the obtained theoretical predictions are confronted with the scarcely available experimental results. PMID- 22538419 TI - [Tuberculosis]. AB - Tuberculosis is still one of the most important infectious disease worldwide. In Germany the tuberculosis incidence has been declining for decades to currently about 4500 new cases per year. A new challenge poses the rising number tuberculosis cases with drug resistant strains of Mycobacterium tuberculosis. Substantiell progress has been achieved in the diagnosis of tuberculosis with new molecular techniques that can lead to a much faster and more reliable identification of cases with acid-fast bacilli smear-negative tuberculosis and in the identification of drug-resistant strains of M. tuberculosis. Tuberculosis caused by drug resistant strains of M. tuberculosis is difficult to treat with the currently available medications and is related to very high costs of care. New therapeutic approaches and drugs are urgently needed. Interferon-gamma tests have made the diagnosis of latent infection with M. tuberculosis more specific, but hardly contribute to the diagnosis of active tuberculosis.This article presents a brief summary of current knowledge concerning the epidemiology, risk factors, diagnosis and treatment of active tuberculosis and latent infection with M. tuberculosis. Moreover, current treatment approaches and economic aspects of care are discussed. PMID- 22538420 TI - Lymphatic dissemination and the role of sentinel lymph node biopsy in early gastric cancer. PMID- 22538421 TI - Treatment with methimazole in a 3-year-old male with thyroid hormone resistance. AB - BACKGROUND: Thyroid hormone resistance syndromes are disorders in which there is decreased end-organ responsiveness to thyroid hormone. Patients typically present with elevated levels of thyroxine and triiodothyronine with a normal or increased serum thyroid-stimulating hormone concentration. Clinical features are variable, and there are no guidelines regarding treatment. PATIENT: The patient was noted to have tachycardia at 6 months of age. He had persistently elevated free thyroxine and normal/mildly elevated thyroid-stimulating hormone for the first 2 years of life. At age 2 years, he was noted to have sinus tachycardia, a mildly enlarged thyroid, hyperactive behavior, subtle developmental delay, and poor weight gain. The patient has a previously described de novo mutation in the thyroid hormone receptor-beta gene. INTERVENTION AND OUTCOMES: He was started on methimazole (0.3-0.5 mg/kg/day) at age 3 years to treat his symptoms. With medication, weight gain, sleep, behavior, and tachycardia improved. Linear growth has remained appropriate for age. Heart rate is in the upper normal range and his thyroid has become more enlarged. CONCLUSIONS: Methimazole has improved thyrotoxic symptoms in a 3-year-old male with thyroid hormone resistance. The use of methimazole should be considered in certain patients. PMID- 22538422 TI - Assessment of macular function for idiopathic epiretinal membranes classified by spectral-domain optical coherence tomography. AB - PURPOSE: To evaluate the functional changes in various morphologic types of idiopathic epiretinal membrane (ERM) by multifocal electroretinography (mfERG) and spectral-domain optical coherence tomography (SD-OCT). METHODS: All patients (n = 71) with unilateral idiopathic ERM underwent complete ophthalmologic examination, including measurements of best-corrected visual acuity (BCVA), SD OCT, and mfERG for both eyes. To classify idiopathic ERM by subtype, the morphologic characteristics of the foveal area on representative scanned images were assessed. The five subtypes by foveal SD-OCT morphology included fovea attached ERM with outer retinal thickening and minimal inner retinal change (Group 1A), outer retinal inward projection and inner retinal thickening (Group 1B), and prominent thickening of inner retinal layer (Group 1C) and foveal sparing ERM with formation of macular pseudohole (Group 2A) and with schisislike, intraretinal splitting (Group 2B). RESULTS: On mfERG, P1 amplitude density in the central ring (R1) and inter-eye (affected eye/fellow eye) response ratio of P1 amplitude density in R1 differed significantly among five groups (P = 0.032 and P = 0.022, respectively). In Group 1 patients, central subfield thickness (CST) and inner retinal layer thickness (IRT) on SD-OCT were strongly correlated with BCVA and P1 amplitude density in R1. A receiver operating characteristic (ROC) curve analysis showed that IRT had high predictive accuracy in distinguishing Groups 1A and 1B (area under the ROC curve [AUROC] = 0.966) and Groups 1B and 1C (AUROC = 1.000). CONCLUSIONS: Multifocal electroretinography can be used to investigate the pathophysiology of ERM and to evaluate the degree of functional demise in the fovea on SD-OCT. PMID- 22538423 TI - Comparison of retinal nerve fiber layer thickness measurement bias and imprecision across three spectral-domain optical coherence tomography devices. AB - PURPOSE: We compared retinal nerve fiber layer (RNFL) bias and imprecision among three spectral-domain optical coherence tomographs (SD-OCT). METHODS: A total of 152 eyes of 83 subjects (96 healthy and 56 glaucomatous eyes) underwent peripapillary RNFL imaging using at least 2 of the following 3 SD-OCT devices on the same day: Cirrus HD-OCT (optic nerve head [ONH]) cube 200 * 200 protocol), RTVue-100 (ONH protocol [12 radial lines and 13 concentric circles]), and 3D OCT 1000 (3D Scan 256 * 256 protocol). Calibration equations, bias and imprecision of RNFL measurements were calculated using structural equation models. RESULTS: The calibration equations for healthy and glaucoma RNFL thickness measurements among the 3 devices were: Cirrus = 2.136 + 0.831*RTVue; Cirrus = -15.521 + 1.056*3D OCT 1000; RTVue = -21.257 + 1.271*3D OCT-1000. Using Cirrus bias as an arbitrary reference, RTVue bias was 1.20 (95% CI 1.09-1.32, P < 0.05) times larger and 3D OCT-1000 was 0.95 (0.87-1.03, P > 0.05) times smaller. Relative to 3D OCT-1000, the RTVue bias was 1.27 (1.13-1.42, P < 0.05). RTVue imprecision (healthy eyes 7.83, 95% CI 6.43-9.58; glaucoma cases 5.71, 4.19-7.64) was statistically significantly higher than both Cirrus (healthy eyes 3.23, 2.11-4.31; glaucoma cases 3.53, 0.69-5.24) and 3D OCT-1000 (healthy eyes 4.07, 3.11-5.35; glaucoma cases 5.33, 3.77-7.67) in healthy eyes. The imprecision also was significantly higher for RTVue measurements in healthy compared to glaucomatous eyes. None of the other comparisons was statistically significant. CONCLUSIONS: RTVue-100 showed higher imprecision (or higher measurement variability) than Cirrus HD-OCT and 3D OCT-1000 RNFL measurements. Three-dimensional cube scanning with post-hoc data sampling may be a factor reducing imprecision. PMID- 22538424 TI - Magnetic resonance compatibility of intraocular lenses measured at 7 Tesla. AB - PURPOSE: To determine whether intraocular lenses (IOLs) are compatible with magnetic resonance imaging (MRI) at a magnetic field strength of 7 Tesla, the highest field strength at which clinical MRI scans are performed. METHODS: A set of 23 intraocular lenses was selected based on the presence of dyes and metals and different geometric shapes. MR compatibility was evaluated in a high-field 7 Tesla MRI scanner according to the American Standard Test Method (ASTM). The magnetically induced displacement was measured via the angular deflection method. The degree of magnetic susceptibility artifact formation was evaluated by positioning the IOLs in a phantom gel for scanning, using a three-dimensional gradient echo (GRE) sequence. All images were visually inspected to determine the spatial extent of any signal voids. Fiber-optic temperature probes were deployed to measure radio-frequency (RF) heating using a GRE sequence with powers 10 times higher than clinical settings. RESULTS: No significant displacement was detected with any of the tested IOLs. A significant magnetic susceptibility artifact was caused by the small platinum component of the Worst Platinum Clip IOL. None of the other 22 IOLs caused measurable susceptibility artifacts. Measurements on RF induced heating showed no significant temperature rise (<0.25 degrees C) of the tested IOLs. CONCLUSIONS: MRI did not induce movement or RF heating of any of the IOLs. We conclude that all the tested intraocular lenses are considered safe for MRI up to and including 7 Tesla. One IOL, the Worst Platinum Clip IOL, caused a significant imaging artifact. PMID- 22538426 TI - Anti-inflammatory effect of the proteasome inhibitor bortezomib on endotoxin induced uveitis in rats. AB - PURPOSE: We evaluated the anti-inflammatory effect of bortezomib (Velcade), a proteasome inhibitor, on endotoxin-induced uveitis (EIU) in rats and lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. METHODS: EIU was induced by footpad injection of LPS into Lewis rats. MG-132 (10 mg/kg), or high-dose (0.2 mg/kg) or low-dose (0.05 mg/kg) bortezomib was given 30 minutes before LPS injection in each treatment group. The rats were sacrificed 24 hours later to observe the inflammatory response in tissues. The expression levels of fractalkine, MCP-1, ICAM-1, and iNOS were evaluated by PCR and Western blot analysis. Immunohistochemical (IHC) studies were used to demonstrate the expression of pro-inflammatory mediators and nuclear factor-kappa B (NF-kappaB) p65 in the iris and ciliary body. The DNA-binding activity of NF-kappaB was evaluated using an electrophoretic mobility shift assay (EMSA). An in vitro study using RAW 264.7 cells was performed to verify the results. RESULTS: Pretreatment with high-dose bortezomib significantly attenuated the inflammatory response of EIU. Reduced expression of inflammatory mediators always was observed in the high dose bortezomib and MG-132 groups, but invariably was not noted in the low-dose bortezomib group. Decreased DNA-binding activity of NF-kappaB was noted in those rats pretreated with high-dose bortezomib or MG-132. In vitro study demonstrated the dose-dependent anti-inflammatory effects of bortezomib in LPS-stimulated RAW cells, consistent with the results obtained in vivo. CONCLUSIONS: Bortezomib inhibits EIU, probably by inhibiting the activation of NF-kappaB, which in turn, down-regulates the expression of the associated inflammatory genes. Proteasome inhibition may be a potential treatment strategy for uveitis. PMID- 22538425 TI - Angiogenesis potential of human limbal stromal niche cells. AB - PURPOSE: The perivascular localization of stem cell (SC) niches suggests the presence of a vascular niche. We aimed to determine the angiogenesis potential of limbal niche cells (NCs). METHODS: Human limbal NCs were isolated and serially passaged on plastic or coated Matrigel in embryonic SC medium containing BFGF and leukemia inhibitory factor before being reseeded in 3D Matrigel. Expression of angiogenesis markers was assessed by RT-qPCR and immunofluorescence staining. Their angiogenesis potential was measured by differentiation into vascular endothelial cells and by supporting vascular tube network formed by human umbilical vein endothelial cells (HUVEC) on Matrigel. Their support of limbal epithelial progenitor cells (LEPC) was examined in sphere growth formed by reunion in 3D Matrigel. RESULTS: On plastic, limbal NC could be cultured only up to four passages before turning into myofibroblasts. In contrast, on coated Matrigel, they could be expanded for up to 12 passages with upregulation of markers suggestive of angiogenesis progenitors when reseeded in 3D Matrigel because they could differentiate into vascular endothelial cells and pericytes stabilizing the tube network formed by HUVEC. Although both expanded limbal NCs and HUVEC rejoined with LEPC to form spheres to upregulate expression of DeltaNp63alpha, CK15, and CEBPdelta, the former but not the latter abolished expression of CK12 keratin. CONCLUSIONS: Human limbal NCs continuously expanded on the basement membrane differentiate into angiogenesis progenitors that prevent differentiation of LEPC/SCs. They may partake in formation of the vascular niche and contribute to angiogenesis during wound healing. PMID- 22538427 TI - Design of a website on nutrition and physical activity for adolescents: results from formative research. AB - BACKGROUND: Teens do not meet guidelines for healthy eating and physical activity. The Internet may be an effective method for delivering programs that help them adopt healthy behaviors. OBJECTIVE: To collect information to design content and structure for a teen-friendly website promoting healthy eating and physical activity behaviors. METHODS: Qualitative research, encompassing both focus group and interview techniques, were used to design the website. Participants were 12-17 year olds in Houston, Texas, and West Lafayette, Indiana. RESULTS: A total of 133 participants took part in 26 focus groups while 15 participated in one-on-one interviews to provide guidance for the development of teen-friendly content and structure for an online behavior change program promoting healthy eating and physical activity to 12-17 year olds. The youth made suggestions to overcome common barriers to healthy eating and physical activity. Their feedback was used to develop "Teen Choice: Food & Fitness," a 12-week online behavior change program, populated by 4 cartoon character role models. CONCLUSIONS: It is critical that members of the target audience be included in formative research to develop behavior change programs that are relevant, appealing, and address their needs and interests. PMID- 22538428 TI - Rhodococcus sp. Q5, a novel agarolytic bacterium isolated from printing and dyeing wastewater. AB - An agar-degrading bacterium, Rhodococcus sp. Q5, was isolated from printing and dyeing wastewater using a mineral salts agar plate containing agar as the sole carbon source. The bacterium grew from pH 4.0 to 9.0, from 15 to 35 degrees C, and in NaCl concentrations of 0-5 %; optimal values were pH 6.0, 30 degrees C, and 1 % NaCl. Maximal agarase production was observed at pH 6.0 and 30 degrees C. The bacterium did not require NaCl for growth or agarase production. The agarase secreted by Q5 was inducible by agar and was repressed by all simple sugars tested except lactose. Strain Q5 could hydrolyze starch but not cellulose or carboxymethyl cellulose. Agarase activity could also be detected in the medium when lactose or starch was the sole source of carbon and energy. Strain Q5 could grow in nitrogen-free mineral media; an organic nitrogen source was more effective than inorganic carbon sources for growth and agarase production. Addition of more organic nitrogen (peptone) to the medium corresponded with reduced agarase activity. PMID- 22538429 TI - Sortilin as a regulator of lipoprotein metabolism. AB - Elevated low-density lipoprotein cholesterol (LDL-C) is associated with increased risk of atherosclerotic cardiovascular disease (ASCVD) and myocardial infarction (MI). Much of the insight into LDL metabolism has been gained through the study of Mendelian disorders of lipid metabolism. Genome-wide associations studies (GWAS) are now being used to identify novel genes and loci that contribute to variations in LDL-C levels, and they have identified the SORT1 gene as an important modulator of LDL-C levels and ASCVD risk. Mechanistic studies in mice and cell culture also suggest that the SORT1 gene is an important regulator of lipoprotein metabolism; however, these studies disagree on the directionality of the effect of Sort1 expression on plasma lipids and the mechanism for the lipid changes. Here we review the identification of the SORT1 locus as a modulator of LDL-C levels and ASCVD risk and the first mechanistic studies that explore the role of Sortilin in lipid metabolism. PMID- 22538431 TI - International epidemiology of intracerebral hemorrhage. AB - Intracerebral hemorrhage is the second most common subtype of stroke. In recent decades our understanding of intracerebral hemorrhage has improved. New risk factors have been identified; more knowledge has been obtained on previously known risk factors; and new imaging techniques allow for in vivo assessment of preclinical markers of intracerebral hemorrhage. In this review the latest developments in research on intracerebral hemorrhage are highlighted from an epidemiologic point of view. Special focus is on frequency, etiologic factors and pre-clinical markers of intracerebral hemorrhage. PMID- 22538433 TI - Evaluation of metal concentrations in mussel M. galloprovincialis in the Dardanelles Strait, Turkey in regard of safe human consumption. AB - Concentrations of the elements were evaluated for the first time in Mytilus galloprovincialis in the Dardanelles (Canakkale Strait-Turkey). The concentration of elements were measured in samples collected in 2007, 2008 and 2009, while the concentrations of Fe and Ni were evaluated in samples taken in 2009. The maximum concentrations of Cd, Cr, Cu, Pb, Zn, Fe, and Ni were found to be 1.59, 6.04, 12.01, 6.03, 319.6, 402.79, and 3.52 mg/kg, respectively. In terms of the nutritional aspect, taking into account the values recommended by world health authorities, the concentration of elements can generally be considered not to be at levels posing a health risk. PMID- 22538432 TI - Determination of lead, mercury and cadmium in wild and farmed Barbus sharpeyi from Shadegan Wetland and Azadegan Aquaculture Site, South of Iran. AB - Lead, mercury and cadmium concentrations were measured in muscle, liver and gill in wild and farmed Barbus sharpeyi from Shadegan Wetland (SW) and Azadegan Aquaculture Site (AAS). Significant variation in metal values were evaluated in Students' tests at p > 0.05. Results showed: In B. sharpeyi high levels of cadmium, lead, and mercury were measured in gill (0.34, 0.68, and 0.06 mg kg(-1) dw). The concentration of metals was not significantly different (p >= 0.05) in the muscle between SW (Cd, 0.24; Pb, 0.49 and Hg, 0.04) and AAS (Cd, 0.23; Pb, 0.49 and Hg, 0.04). Lead concentration was higher than cadmium and mercury in different organs (p > 0.05). Cadmium, mercury and lead in different tissues of SW were higher than AAS and there was no significant difference between them (p >= 0.05). Metal levels in different tissues were higher than WHO standard. PMID- 22538430 TI - Clinical syndromes and management of intracerebral hemorrhage. AB - Spontaneous intracerebral hemorrhage (ICH) is a devastating disease with high morbidity and mortality. Acutely, ICH is associated with a sudden surge in intracranial pressure (ICP), as the volume of hematoma increases the pressure in the closed head, leading to non-specific symptoms of ICP: headache, nausea, vomiting, and alterations in consciousness. In the early phase, damage to the brain tissues surrounding the hematoma causes progression of neurologic symptoms. Expansion of supratentorial ICHs may result in transtentorial herniation, causing mental status deterioration and loss of pupillary light reflex. Compared to ischemic stroke, seizure is more common in ICH. PMID- 22538434 TI - French experts report on MUTYH-associated polyposis (MAP). AB - Recent years have been characterised by an improvement in our knowledge of genetic determinism of adenomatous polyposes and by the description in 2002 of a new entity called "MUTYH-associated polyposis" (MAP), related to biallelic mutations of this gene. Its autosomal recessive mode of inheritance contrasts with the autosomal dominant inheritance of the classical "familial adenomatous polyposis" (FAP), associated with an APC germline mutation. Although some phenotypic features may be of value to distinguish these two conditions, their clinical "spectra" largely overlap and the differential diagnosis may be difficult. The purpose of this expertise conducted under the auspices of the French Institut National du Cancer (INCa) was to assess the current state of knowledge on MUTYH-associated polyposis and to establish some recommendations in the field of molecular analysis (indications of tests and analysis strategies for affected patients and their relatives) and of clinical management based on available data in the literature, on the results from the French molecular genetics laboratories performing MUTYH analysis and on the opinions of biologists and clinicians experts (genetic counsellors and gastroenterologists). The risk of colorectal cancer among relatives carrying a monoallelic MUTYH mutation was also studied. PMID- 22538435 TI - Drug repositioning through incomplete bi-cliques in an integrated drug-target disease network. AB - Recently, there has been much interest in gene-disease networks and polypharmacology as a basis for drug repositioning. Here, we integrate data from structural and chemical databases to create a drug-target-disease network for 147 promiscuous drugs, their 553 protein targets, and 44 disease indications. Visualizing and analyzing such complex networks is still an open problem. We approach it by mining the network for network motifs of bi-cliques. In our case, a bi-clique is a subnetwork in which every drug is linked to every target and disease. Since the data are incomplete, we identify incomplete bi-cliques, whose completion introduces novel, predicted links from drugs to targets and diseases. We demonstrate the power of this approach by repositioning cardiovascular drugs to parasitic diseases, by predicting the cancer-related kinase PIK3CG as a novel target of resveratrol, and by identifying for five drugs a shared binding site in four serine proteases and novel links to cancer, cardiovascular, and parasitic diseases. PMID- 22538436 TI - Chloroquine-mediated lysosomal dysfunction enhances the anticancer effect of nutrient deprivation. AB - PURPOSE: To investigate the ability of chloroquine, a lysosomotropic autophagy inhibitor, to enhance the anticancer effect of nutrient deprivation. METHODS: Serum-deprived U251 glioma, B16 melanoma and L929 fibrosarcoma cells were treated with chloroquine in vitro. Cell viability was measured by crystal violet and MTT assay. Oxidative stress, apoptosis/necrosis and intracellular acidification were analyzed by flow cytometry. Cell morphology was examined by light and electron microscopy. Activation of AMP-activated protein kinase (AMPK) and autophagy were monitored by immunoblotting. RNA interference was used for AMPK and LC3b knockdown. The anticancer efficiency of intraperitoneal chloroquine in calorie restricted mice was assessed using a B16 mouse melanoma model. RESULTS: Chloroquine rapidly killed serum-starved cancer cells in vitro. This effect was not mimicked by autophagy inhibitors or LC3b shRNA, indicating autophagy independent mechanism. Chloroquine-induced lysosomal accumulation and oxidative stress, leading to mitochondrial depolarization, caspase activation and mixed apoptotic/necrotic cell death, were prevented by lysosomal acidification inhibitor bafilomycin. AMPK downregulation participated in chloroquine action, as AMPK activation reduced, and AMPK shRNA mimicked chloroquine toxicity. Chloroquine inhibited melanoma growth in calorie-restricted mice, causing lysosomal accumulation, mitochondrial disintegration and selective necrosis of tumor cells. CONCLUSION: Combined treatment with chloroquine and calorie restriction might be useful in cancer therapy. PMID- 22538438 TI - An outcome measure of functionality and pain in patients with lumbar disc herniation: a validation study of the Japanese Orthopedic Association (JOA) score. AB - BACKGROUND: Lumbar disc hernia (LDH) is a common cause of low back pain and radicular leg pain. The Japanese Orthopedic Association (JOA) score is a very short instrument for measuring functionality and pain in these patients. This study aimed to translate and validate the JOA score for use in Iran. METHODS: This was a prospective clinical validation study. Translation of the English version of the questionnaire was performed in accordance with published guidelines. A sample of patients with LDH was asked to respond to the questionnaire at two points in time--at preoperative and postoperative (6 months follow-up) assessments. To test reliability, the internal consistency was assessed by use of Cronbach's alpha coefficient. Validity was evaluated by use of known-groups comparison. RESULTS: A total of 117 patients with LDH were entered into the study. The mean age of patients was 45 (SD = 11) and Cronbach's alpha coefficients for the JOA score at the preoperative and postoperative assessments were 0.67 and 0.81, respectively. Validity as performed by known-groups analysis also showed the result was satisfactory. The instrument discriminated well between sub-groups of patients who differed in age and in a standard predictive measure of lumbar disc surgery (the Finneson-Cooper score). CONCLUSIONS: In general, the Iranian version of the JOA score performed well and the findings suggest that it is a reliable and valid measure of functionality and pain among LDH patients. PMID- 22538437 TI - Neural progestin receptors and female sexual behavior. AB - The steroid hormone, progesterone (P), modulates neuroendocrine functions in the central nervous system resulting in integration of reproduction and reproductive behaviors in female mammals. Although it is widely recognized that P's effects on female sex behavior are mediated by the classical neural progestin receptors (PRs) functioning as 'ligand-dependent' transcription factors to regulate genes and genomic networks, additional mechanisms of PR activation also contribute to the behavioral response. Cellular and molecular evidence indicates that PRs can be activated in a ligand-independent manner by neurotransmitters, growth factors, cyclic nucleotides, progestin metabolites and mating stimuli. The rapid responses of P may be mediated by a variety of PR types, including membrane-associated PRs or extranuclear PRs. Furthermore, these rapid nonclassical P actions involving cytoplasmic kinase signaling and/or extranuclear PRs also converge with classical PR-mediated transcription-dependent pathways to regulate reproductive behaviors. In this review, we summarize some of the history of the study of the role of PRs in reproductive behaviors and update the status of PR-mediated mechanisms involved in the facilitation of female sex behavior. We present an integrative model of PR activation via crosstalk and convergence of multiple signaling pathways. PMID- 22538439 TI - Regenerative repair of bone defects with osteoinductive hydroxyapatite fabricated to match the defect and implanted with combined use of computer-aided design, computer-aided manufacturing, and computer-assisted surgery systems: a feasibility study in a canine model. AB - BACKGROUND: Currently, regenerative repair of large bone defects that result from bone tumor resection or severe trauma is a challenging issue because of the limited regenerative potential of bone and treatment modalities. The aim of this study was to achieve repair of large bone defects to the original three dimensional (3D) anatomical state by combining computer-aided technologies and local delivery of bone morphogenetic protein (BMP) in a canine model. METHODS: Computed tomography (CT) images of the pelvic bone of each dog were obtained, and an imaginary spherical malignant bone tumor of 15-mm diameter was placed in the left ilium of a canine on the 3D CT image. Resection of the whole tumor with a 10 mm margin of healthy bone was planned preoperatively by using computer-aided design (CAD) software. In addition, an image of the implant to be used to fill the resulting bone defect was constructed on the computer image. A porous hydroxyapatite (HA) implant identical to the imaged bone defect was made by shaving a tetragonal porous apatite block (40 * 20 * 10 mm) with a computer-aided manufacturing system operated by using the CT-image data of the bone defect obtained from the CAD system. To resect the iliac bone as planned preoperatively on the 3D CT image, computer-aided surgery was performed using the CT data. The defect was filled with the HA implant fabricated as described and coated with a putty carrier either with BMP-2 (BMP group, n = 6) or without BMP-2 (control group, n = 6). RESULTS: In the BMP group, new bone formation was noted around each implant on CT images at 3 weeks after surgery and was remodeled to restore the original anatomy of the ilium on serial CT images. At 12 weeks, the implant was enclosed within new bone, and histological analysis revealed bone formation on and within the implant. Little bone formation was noted in the control group. CONCLUSIONS: This new method may enable efficacious and precise regenerative repair of large bone defects without bone grafting. PMID- 22538440 TI - Usefulness of double-balloon enteroscopy for evaluation of duodenal follicular lymphoma. PMID- 22538441 TI - CSMD1 exhibits antitumor activity in A375 melanoma cells through activation of the Smad pathway. AB - In this work, we studied the effects of CUB and Sushi multiple domains 1 gene (CSMD1) expression in A375 melanoma cells in vivo and in vitro. CSDM1 expression decreased proliferation and migration, and increased apoptosis and G(1) arrest in A375 cells in vitro. Expression of CSDM1 in established xenografted tumors decreased tumor size and weight, and decreased the density of intratumor microvessels. The survival rate of mice with tumors expressing CSMD1 was significantly higher than mice with tumors that did not express CSDM1. These results confirm the role of CSDM1 as a tumor suppressor gene in melanoma cells. Furthermore, we found that CSMD1 can interact with Smad3, activate Smad1, Smad2, and Smad3, and increase the expression of Smad4. These results might prove helpful for the development of novel therapies for melanoma treatment. PMID- 22538442 TI - iASPP inhibits p53-independent apoptosis by inhibiting transcriptional activity of p63/p73 on promoters of proapoptotic genes. AB - The ability to induce apoptosis is the most important tumor-suppression function of p53. Inhibitory member of apoptosis-stimulating protein of p53 family (iASPP) is an apoptotic-specific regulator of p53. iASPP suppresses apoptosis by inhibiting the transactivation function of p53 on the promoters of proapoptotic genes; however, the mechanism whereby iASPP influences apoptosis in tumor cells with mutant or deficient p53 has not been completely defined. In this study, we investigated the role of iASPP in the p63/p73 apoptosis pathway. iASPP inhibited apoptosis independently of p53 in tumor cells, mainly by inhibiting the transcriptional activity of p63/p73 on the promoters of proapoptotic genes. Because p63 and p73 are rarely mutated in human cancers, inhibiting the expression of endogenous iASPP may provide a useful strategy for restoring the apoptotic activity of p63 and p73 in human tumors with p53 loss or mutation. These results represent a promising new strategy for the treatment of cancers with non-wild-type p53. PMID- 22538443 TI - Oncology in Cambodia. AB - Cambodia, a country of 14 million inhabitants, was devastated during the Khmer Rouge period and thereafter. The resources of treatment are rare: only one radiotherapy department, renovated in 2003, with an old cobalt machine; few surgeons trained to operate on cancer patients; no hematology; no facilities to use intensive chemotherapy; no nuclear medicine department and no palliative care unit. Cervical cancer incidence is one of the highest in the world, while in men liver cancer ranks first (20% of all male cancers). Cancers are seen at stage 3 or 4 for 70% of patients. There is no prevention program - only a vaccination program against hepatitis B for newborns - and no screening program for cervical cancer or breast cancer. In 2010, oncology, recognized as a full specialty, was created to train the future oncologists on site at the University of Phnom Penh. A new National Cancer Center will be built in 2013 with modern facilities for radiotherapy, medical oncology, hematology and nuclear medicine. Cooperation with foreign countries, especially France, and international organizations has been established and is ongoing. Progress is occurring slowly due to the shortage of money for Cambodian institutions and the lay public. PMID- 22538444 TI - Drug-targeted inhibition of peroxisome proliferator-activated receptor-gamma enhances the chemopreventive effect of anti-estrogen therapy. AB - The peroxisome proliferator-activated receptorgamma (PPARgamma) is a key regulator of metabolism, proliferation, inflammation and differentiation, and upregulates tumor suppressor genes, such as PTEN, BRCA1 and PPARgamma itself. Examination of mammary carcinogenesis in transgenic mice expressing the dominant negative Pax8PPARgamma fusion protein revealed that tumors were estrogen receptoralpha (ER)-positive and sensitive to the ER antagonist, fulvestrant. Here we evaluated whether administration of an irreversible PPARgamma inhibitor in vivo could similarly induce ER expression in otherwise ER-negative mammary tumors following induction of carcinogenesis, and sensitize them to the antitumor effects of fulvestrant. In addition, we wished to determine whether the effect of GW9662 was associated with a PPAR-selective gene expression profile. Mammary carcinogenesis was induced in wild-type FVB mice by treatment with medroxyprogesterone and dimethylbenz(a)anthracene (DMBA) that were subsequently maintained on a diet supplemented with 0.1% GW9662, and tumorigenesis and gene expression profiling of the resulting tumors were determined. Administration of GW9962 resulted in ER+ tumors that were highly sensitive to fulvestrant. Tumors from GW9662-treated animals exhibited reduced expression of a metabolic gene profile indicative of PPARgamma inhibition, including PPARgamma itself. Additionally, GW9662 upregulated the expression of several genes associated with the transcription, processing, splicing and translation of RNA. This study is the first to show that an irreversible PPARgamma inhibitor can mimic a dominant negative PPARgamma transgene to elicit the development of ER-responsive tumors. These findings suggest that it may be possible to pharmacologically influence the responsiveness of tumors to anti-estrogen therapy. PMID- 22538445 TI - Anti-VEGFR2-conjugated PLGA microspheres as an x-ray phase contrast agent for assessing the VEGFR2 expression. AB - The primary goal of this study was to evaluate the feasibility of using anti vascular endothelial growth factor receptor 2 (VEGFR2)-conjugated poly(lactic-co glycolic acid) (PLGA) microspheres as an x-ray phase contrast agent to assess the VEGFR2 expression in cell cultures. The cell lines, mouse LLC (Lewis lung carcinoma) and HUVEC (human umbilical vein endothelial cell), were selected for cell adhesion studies. The bound PLGA microspheres were found to better adhere to LLC cells or HUVECs than unbound ones. Absorption and phase contrast images of PLGA microspheres were acquired and compared in vitro. Phase contrast imaging (PCI) greatly improves the detection of the microspheres as compared to absorption contrast imaging. The cells incubated with PLGA microspheres were imaged by PCI, which provided clear 3D visualization of the beads, indicating the feasibility of using PLGA microspheres as a contrast agent for phase contrast CT. In addition, the microspheres could be clearly distinguished from the wall of the vessel on phase contrast CT images. Therefore, the approach holds promise for assessing the VEGFR2 expression on endothelial cells of tumor-associated vessels. We conclude that PLGA microsphere-based PCI of the VEGFR2 expression might be a novel, promising biomarker for future studies of tumor angiogenesis. PMID- 22538446 TI - [Role of cilostazol in the sequential therapeutic spectrum of the peripheral arterial occlusion disease (PAOD)]. AB - Cilostazol (Pletal((r)), UCB Pharma, Monheim, Deutschland) has been successfully established since its inauguration on the German market in 2007, which is associated with a considerable distribution, in particular, in angiologic patients. However, vascularsurgical specifics in the use of Cilostazol are still lacking. The aim of this very compact short overview is (based on a selective literature search and own clinical experiences over the years) to characterize mechanism of action, use and expectable therapeutic effect of Cilostazol in the challenging management of exclusively vascularsurgcial patients with peripheral arterial occlusion disease (PAOD). Cilostazol inhibits phosphodiesterase 3 and platelet aggregation in a reversible manner with a dose-effect association, has vasodilating potential and a positive inotropic effect but provides a selective effect on the platelets, muscle and endothelial cells of the vascular wall via an intracellular increase of cAMP; in addition, there is an antiproliferative effect, it promotes neoangiogenesis, inhibits apoptosis and generation of endothelial adhesion molecules - taken together, it can be considered antiatherogenic ("anti-arterioscleroticum"). From a clinical point of view, Cilostazol is indicated in stage IIb of PAOD (Fontaine); its recommended dosage is 2x100 (reduced in case of moderate side effects, 2x50) mg with detectable prolongation of subjective (reported by the patient) and objective walking distance (but not in smokers [!]; ABI-based measurement of the effect not suitable) and partially with an improval of the quality of life (associated with a prolonged but steadily improving therapeutic effect from the 4th to the 6th week until the 6th to the 12th month). The profile of side effects is broad but mostly short-term and dominated by headache [~ 30 %] and diarrhoea [~ 15 %]). While Cilostazol not only plays a beneficial role in the setting to be used in the primary arteriosclerotic course of PAOD (called sequential therapeutic preoperative course), it appears also to provide great effect in case of a re manifestation of claudication (approaching stage IIb according to Fontaine's classification) after previous image-guided interventional or vascularsurgical treatment (suitable conservative mid-term intermediate therapy), i) resulting in a flexible physician's tool of the angiologic and vascularsurgical setting of an outpatient clinic, and ii) which reduces significantly the number of re interventions or prolonges the time interval(s) in between. This might finally be relevant in the perspective for an amputation-free survival. PMID- 22538448 TI - Inequities compounded: explaining variations in the transition to adulthood for teen mothers' offspring. AB - Teen mothers as a cohort are disproportionately disadvantaged before pregnancy and are assumed to be further disadvantaged by an early pregnancy. A growing number of studies report that teen mothers and their children are disadvantaged slightly, if at all, by young maternal age. These studies highlight the social determinants of early childbearing but do not reveal the social contexts that shape the transition into adulthood for teen mothers' offspring. This report addresses this gap by presenting two cases from a longitudinal study that investigated how family members' lives unfold in the context of race, class, family practices, and communities. By the sixth wave, two of the mothers' first born children had become teen parents. Both cases showcase the diverse outcomes and cumulative impact of social advantage and disadvantage on the transition into young adulthood. Implications are described in relation to what is known about social inequities in the transition into adulthood. PMID- 22538447 TI - Sexual response in patients treated with sacral neuromodulation for lower urinary tract symptoms or fecal incontinence. AB - OBJECTIVES: To determine whether sacral neuromodulation (SNM) for urinary symptoms or fecal incontinence gives improvement of female sexual function and whether improvement is due to physiological or psychological factors. METHODS: Between 2002 and 2008, 8 patients had an array of questionnaires before and after SNM implantation. The questionnaires were: the Questionnaire for Screening for Sexual Dysfunctions, the Golombok Rust Inventory of Sexual Satisfaction, the Symptom Checklist-90, the Maudsley Marital Questionnaire and the McGill-Mah Orgasm Questionnaire. Three of these 8 patients underwent vaginal plethysmography before and after implantation. RESULTS: No statistically significant changes were found, although there seems to be a trend toward improvement in orgasm scores. In plethysmography all 3 patients showed increased vaginal pulse amplitude with the stimulator turned on with both erotic and non-erotic stimuli. CONCLUSIONS: This study does not show a clear effect of SNM on sexual function, although there seems to be an improvement in orgasm scores. The lack of response on psychological questionnaires and the increase in vaginal pulse amplitude after SNM implantation indicate that there might be a physiological response. PMID- 22538449 TI - Immunological issues in clinical composite tissue allotransplantation: where do we stand today? AB - Composite tissue allografts are made of histogenetically different tissues and although skin seems to be the most antigenic of them, it is unknown whether the dominant immune response is really directed against the skin or we have insufficient information on the involvement of the other components of these allografts. The first clinical signs of acute rejection manifest on the skin and microscopically the earliest lesions consist in a dermal perivascular lymphocytic infiltrate, predominantly made of CD3+/CD4+ T cells. On the basis of the histological changes, a specific score (Banff score 2007) has been established to assess the severity of rejection. Despite the high incidence of acute rejection episodes, they can be completely reversed when promptly diagnosed and treated. C4d deposits in the skin and circulating donor-specific antibodies are rarely detected, suggesting that humoral rejection does not play a significant role in composite tissue allotransplantation. Chronic rejection features are still unknown. The majority of recipients have been maintained on an immunosuppressive regimen consisting of tacrolimus, steroids, and mycophenolate mofetil. The complications in composite tissue allotransplantation are similar to those usually reported after solid organ transplantation and have prompted different strategies to minimize the maintenance immunosuppression or to induce donor specific tolerance. Furthermore, to what extent the immunosuppression can be tapered is unknown, as well as the influence of donor bone-marrow infusion in tolerance and chronic rejection. The increasing number of patients and the longer follow-up hopefully will allow answering these questions. PMID- 22538450 TI - Randomized trial comparing late concentration-controlled calcineurin inhibitor or mycophenolate mofetil withdrawal. AB - BACKGROUND: Early calcineurin inhibitor (CNI) withdrawal with mycophenolate mofetil (MMF) has not become routine practice, due to concerns about excess acute rejection. Therapeutic drug monitoring may be advantageous when the CNI or MMF is withdrawn. METHODS: This prospective, randomized, concentration-controlled withdrawal study enrolled 177 stable renal transplant recipients on maintenance CNI-based immunosuppression, combined with steroids and MMF. After the feasibility phase of the study, patients were randomized to MMF-withdrawal (target area under the time-concentration curve-cyclosporine: 3250 ng.hr/mL or tacrolimus: 120 ng.hr/mL) or CNI-withdrawal (target area under the time concentration curve-mycophenolic acid: 75 MUg.hr/mL). RESULTS: The estimated glomerular filtration rate (modification of diet in renal disease) remained significantly better after CNI elimination (59.5+/-2.1 mL/min vs. 51.1+/-2.1 mL/min, P = 0.006) up to 3 years and resulted in less functional decline, including the subgroup with an estimated glomerular filtration rate less than 50 mL/min at baseline (P = 0.03). At 6 months, one patient in the MMF-withdrawal group (1.3%) and three in the CNI-withdrawal group (3.8%) experienced acute rejection (P = 0.62). The defined higher mycophenolic acid exposure was well tolerated. CONCLUSION: These data indicate that with time the large majority of stable renal transplant recipients can be safely reduced to dual therapy with MMF or CNIs, applying concentration-controlled dosing. CNI-free patients, including those with moderate renal allograft dysfunction, have the benefit of improved renal function, whereas the risk of acute rejection after late withdrawal is low. PMID- 22538451 TI - Repeat true surveillance biopsies in kidney transplantation. AB - BACKGROUND: Protocol biopsies are assigned to fixed points in time after transplantation irrespective of renal function. Usually, it is not known whether there is graft dysfunction at the time of biopsy. This study analyzes repeat protocol biopsies in the absence of any clinical signs of graft dysfunction at the time of biopsy (i.e., "true surveillance biopsy"). METHODS: Observational single center study. Kidney transplant recipients with protocol biopsies after 3 and 6 months were analyzed. RESULTS: Three hundred seventy patients had protocol biopsies after 3 and 6 months. One hundred forty-eight patients (40%; 296 biopsies) with a median follow-up of 3.4 years (range, 0.95-7.7 years), fulfilled the criteria of repeat true surveillance biopsies. Graft survival censored for death was 100% at 1 year, 96% at the end of follow-up. One hundred eighty-four biopsies (62%) revealed pathological findings, mainly subclinical rejection (3/6 months: 41% vs. 45%; P = 0.2) and chronic lesions (3/6 months: 22% vs. 44%; P<0.001). Grafts with repeat pathological findings at 3 and 6 months had a significant decline in graft function at end of follow-up compared with grafts with no or only singular pathology (median delta estimated glomerular filtration rate: -10.24 vs. -0.19; P = 0.005). Ninety-three of 148 patients (63%) had a therapeutic intervention as a consequence of the biopsy. CONCLUSIONS: Less than 50% of protocol biopsies were performed in the absence of any clinical signs of graft dysfunction. A high proportion of these biopsies revealed pathological findings that were associated with a significant decrease in long-term graft function. PMID- 22538452 TI - Organic reactivity in liquid ammonia. AB - Liquid ammonia is a useful solvent for many organic reactions including aliphatic and aromatic nucleophilic substitution and metal-ion catalysed reactions. The acidity of acids is modified in liquid ammonia giving rise to differences from conventional solvents. The ionisation constants of phenols and carbon acids are the product of those for ion-pair formation and dissociation to the free ions. There is a linear relationship between the pK(a) of phenols and carbon acids in liquid ammonia and those in water of slope 1.68 and 0.7, respectively. Aminium ions exist in their unprotonated free base form in liquid ammonia. The rates of solvolysis and aminolysis by neutral amines of substituted benzyl chlorides in liquid ammonia show little or no dependence upon ring substituents, in stark contrast with the hydrolysis rates of substituted benzyl halides in water which vary 10(7) fold. However, the rates of the reaction of phenoxide ions and amine anions with 4-substituted benzyl chlorides gives a Hammett rho = 1.1 and 0.93, respectively. The second order rate constants for the substitution of benzyl chlorides by neutral and anionic amines show a single Bronsted beta(nuc) = 0.21 whereas those for substituted phenoxide ions generate a Bronsted beta(nuc) = 0.40. The rates of aromatic nucleophilic substitution reactions in liquid ammonia are much faster than those in protic solvents indicating that liquid ammonia behaves like a typical dipolar aprotic solvent in its solvent effects on organic reactions. Nitrofluorobenzenes (NFB) readily undergo solvolysis in liquid ammonia but oxygen nucleophiles, such as alkoxide and phenoxide ions, displace the fluorine of 4-NFB in liquid ammonia to give the corresponding substitution product with little or no competing solvolysis product. The Bronsted beta(nuc) for the reaction of 4-NFB with para-substituted phenoxides is 0.91, indicative that the decomposition of the Meisenheimer sigma-intermediate is rate limiting. The aminolysis of 4-NFB occurs without general base catalysis by the amine and the second order rate constants generate a Bronsted beta(nuc) of 0.36, which is also interpreted in terms of rate limiting breakdown of the Meisenheimer sigma intermediate. PMID- 22538453 TI - A potential probe set of fluorescence in situ hybridization for detection of lung cancer in bronchial brushing specimens. AB - PURPOSE: The study aims to find candidate probes of fluorescence in situ hybridization (FISH) for detection of lung cancer with bronchial brushings and to evaluate whether the accuracy of diagnosing lung cancer by cytological deviant and genetic abnormalities is greater than that of cytology alone. METHODS: Centromeric enumeration probes (CEPs) for chromosomes 2, 3, 6, 7, 8, 9, 11, 12, and 17 were analyzed using FISH in 74 surgical resection tissues, 32 operative margin tissues without tumor involvement of lung cancer, and 174 bronchial brushings. RESULTS: The aneuploidy rates of the tested probes were 61.7, 89.1, 80.0, 92.7, 65.0, 70.4, 66.7, 71.8, 68.9 % in tumor tissues, and 29.3, 58.9, 33.3, 69.6, 67.0, 40.3, 38.0, 49.3, 35.1 % in bronchial brushings. The combination of cytology and FISH using the three-probe set for chromosomes 3+7+8 significantly improved the sensitivity of bronchial brushing examination for lung cancer detection (P = 0.00003), especially squamous cell carcinoma (SCC), which increased from 78.0 to 98.2 %. The specificity of the 3+7+8 probe set was 94.6 %. Moreover, a high aneuploidy rate of the probe set in bronchial brushings was detected more often in SCCs (P = 0.029) and late-stage non-small-cell lung cancer (NSCLC) (P = 0.044). Kaplan-Meier curves indicated that adenocarcinoma (ADC) patients with high aneuploidy rate of CEP3 in tissue samples exhibited poorer overall survival (P = 0.016). CONCLUSIONS: FISH performed on cytology preparations is useful for confirmation of cancer diagnosis. The three-probe set, 3+7+8, has potential value for the detection of SCCs in bronchial brushings. PMID- 22538454 TI - Isolation of heat-tolerant myoglobin from Asian swamp eel Monopterus albus. AB - Myoglobin from Asian swamp eel Monopterus albus was purified from fish muscle using salt fractionation followed by column chromatography and molecular filtration. The purified Mb of 0.68 mg/g wet weight of muscle was determined for its molecular mass by MALDI-TOF-MS to be 15,525.18 Da. Using isoelectric focusing technique, the purified Mb showed two derivatives with pI of 6.40 and 7.12. Six peptide fragments of this protein identified by LC-MS/MS were homologous to Mbs of sea raven Hemitripterus americanus, yellowfin tuna Thunnus albacores, blue marlin Makaira nigicans, common carp Cyprinus carpio, and goldfish Carassius auratus. According to the Mb denaturation, the swamp eel Mb had thermal stability higher than walking catfish Clarias batrachus Mb and striped catfish Pangasius hypophthalmus Mb, between 30 and 60 ( degrees )C. For the thermal stability of Mb, the swamp eel Mb showed a biphasic behavior due to the O(2) dissociation and the heme orientation disorder, with the lowest increase in both Kd(f) and Kd(s). The thermal sensitivity of swamp eel Mb was lower than those of the other Mbs for both of fast and slow reaction stages. These results suggest that the swamp eel Mb globin structure is thermally stable, which is consistent with heat-tolerant behavior of the swamp eel particularly in drought habitat. PMID- 22538455 TI - Lung herniation after minimally invasive atrial-septal-defect closure. PMID- 22538458 TI - Anatomic repair for congenitally corrected transposition of the great arteries: easier is better? PMID- 22538457 TI - Natural and modified history of single-ventricle physiology in adult patients. AB - OBJECTIVE: To define the evolution of the single-ventricle (SV) heart in adult patients in terms of morbidity, mortality and quality of life. METHODS: Sixty-two patients with SV physiology and aged older than 16 years were retrospectively reviewed. Three patients (5%) were in natural history, one had received a Blalock Taussig shunt, one a Waterstone anastomosis, one a pulmonary artery banding, three a bidirectional cavopulmonary anastomosis, eight a classic Fontan procedure and 46 a total cavopulmonary connection (TCPC). The morphology of the SV was left in 48 patients (77%), right in nine (14%) and indeterminable in five (8%). Thirty three patients underwent magnetic resonance imaging (MRI) to assess ventricular mass (VM), ventricular systolic function, pulmonary artery branch diameter and potential thrombosis of the conduit. Cardiopulmonary exercise testing (CPTE) was carried out to evaluate exercise tolerance. The quality of life was monitored with two different specific tests, the Short Form-36 (SF-36) and the congenital heart disease-TNO/AZL adult quality of life (CHD-TAAQOL). The mean follow-up time was 8.0 +/- 9.1 years. RESULTS: Two of the three patients in natural history underwent primary TCPC. Re-interventions were necessary in seven patients (11%). Three patients (5%) died during follow-up. Five patients (8%) underwent cardiac transplantation. Protein losing enteropathy appeared in six (10%), while the arrhythmic disorder was detected in 13 patients. On the MRI, the mean end diastolic ventricular volume was 106 +/- 448 ml/m(2), the mean ejection fraction (EF) was 52.3 +/- 10% and VM was 56 +/- 22.1 g/m(2). On CPTE, the peak of oxygen uptake (peak VO(2)) was moderately impaired in 92% of patients, while 4% presented a severely impaired and 4% a normal peak of VO(2). No correlations were found among the peak of VO(2) and the quality-of-life evaluation. CONCLUSIONS: Adult patients with SV are at high risk of reoperations and need of transplant and complications. Nevertheless, in the presence of a moderately reduced peak of VO(2) and a moderate reduction in the EF detected at the MRI, the results of the evaluation of daily quality of life are incredibly high. PMID- 22538459 TI - Improved enzyme activity and stability in polymer microspheres by encapsulation of protein nanospheres. PMID- 22538460 TI - Microreactor with integrated temperature control for the synthesis of CdSe nanocrystals. AB - The recent needs in the nanosciences field have promoted the interest towards the development of miniaturized and highly integrated devices able to improve and automate the current processes associated with efficient nanomaterials production. Herein, a green tape based microfluidic system to perform high temperature controlled synthetic reactions of nanocrystals is presented. The device, which integrates both the microfluidics and a thermally controlled platform, was applied to the automated and continuous synthesis of CdSe quantum dots. Since temperature can be accurately regulated as required, size-controlled and reproducible quantum dots could be obtained by regulating this parameter and the molar ratio of precursors. The obtained nanocrystals were characterized by UV vis and fluorescence spectrophotometry. The band width of the emission peaks obtained indicates a narrow size distribution of the nanocrystals, which confirms the uniform temperature profile applied for each synthetic process, being the optimum temperature at 270 degrees C (full width at half maximum = 40 nm). This approach allows a temperature controlled, easy, low cost and automated method to produce quantum dots in organic media, enhancing its application from laboratory scale to pilot-line scale processes. PMID- 22538461 TI - An ESICM systematic review and meta-analysis of procalcitonin-guided antibiotic therapy algorithms in adult critically ill patients. AB - PURPOSE: We sought to perform a systematic review and meta-analysis of procalcitonin(PCT)-guided antibiotic therapy algorithms for critically ill adult patients. METHODS: We performed a search in PubMed and in the Cochrane Central Register of Controlled Trials. Seven evaluable randomised clinical trials (RCTs) were identified and analysed. Primary outcomes included the duration of antibiotic therapy for the first episode of infection and 28-day mortality. Secondary outcomes included length of ICU stay, length of hospitalisation, antibiotic-free days within the first 28 days of hospitalisation, recurrences, and superinfections. RESULTS: Data on the duration of antibiotic therapy for the first episode of infection were provided in five out of seven included RCTs, while data on 28-day mortality were provided in all of the included RCTs. Duration of antibiotic therapy for the first episode of infection was reduced in favour of PCT-guided treatment [pooled weighted mean difference (WMD) = -3.15 days, random effects model, 95 % confidence interval (CI) -4.36 to -1.95, P < 0.001]. There was no difference in 28-day mortality between the compared arms [fixed effect model (FEM), odds ratio = 0.96, 95 % CI 0.79-1.15, P = 0.63). Antibiotic-free days were increased within the first 28 days of hospitalisation in favour of the PCT-guided treatment arm (pooled WMD = 3.08 days, FEM, 95 % CI 2.06-4.10, P < 0.001). No difference was found regarding the remaining outcomes. Sensitivity analyses including studies of higher quality and studies using the TRACE method to measure PCT yielded similar results. CONCLUSIONS: Procalcitonin guided antibiotic therapy algorithms could help in reducing the duration of antimicrobial administration without having a negative impact on survival. PMID- 22538463 TI - Identification of the lymphatic drainage pathways from the pancreatic head guided by indocyanine green fluorescence imaging during pancreaticoduodenectomy. AB - AIMS: We identified the lymphatic drainage pathways from the pancreatic head guided by indocyanine green (ICG) fluorescence imaging to analyze optimal lymphadectomy for pancreatic cancer. METHODS: The lymphatic pathways in 20 patients undergoing pancreaticoduodenectomy were analyzed. We injected ICG into the parenchyma in the anterior (n = 10) or posterior surface (n = 10) of the pancreas head and observed the intraoperative lymphatic flows by ICG fluorescence imaging. RESULTS: The seven main lymphatic drainage pathways were identified: (1) along the anterior or posterior pancreaticoduodenal arcade, (2) running obliquely down behind the superior mesenteric vein (SMV), (3) reaching the left side of the superior mesenteric artery (SMA), (4) running longitudinally upward between the SMV and SMA, (5) along the middle colic artery toward the transverse colon, (6) reaching the paraaortic (PA) region, and (7) reaching the hepatoduodenal ligament. The lymphatic pathway reaching the left side of the SMA was observed in 4 patients (20%), while that reaching the PA region in 17 patients (85%). The mean time to reach around the SMA was longer than that to reach the PA region. CONCLUSIONS: We found that several lymphatic drainage routes were observed from the pancreatic head, suggesting that a lymphadectomy around the SMA might have a similar oncological impact as that of the PA region. PMID- 22538462 TI - Receptor subtypes and signal transduction mechanisms contributing to the estrogenic attenuation of cannabinoid-induced changes in energy homeostasis. AB - We examined the receptor subtypes and signal transduction mechanisms contributing to the estrogenic modulation of cannabinoid-induced changes in energy balance. Food intake and, in some cases, O2 consumption, CO2 production and the respiratory exchange ratio were evaluated in ovariectomized female guinea pigs treated s.c. with the cannabinoid receptor agonist WIN 55,212-2 or its cremephor/ethanol/0.9% saline vehicle, and either with estradiol benzoate (EB), the estrogen receptor (ER) alpha agonist PPT, the ERbeta agonist DPN, the Gq coupled membrane ER agonist STX, the GPR30 agonist G-1 or their respective vehicles. Patch-clamp recordings were performed in hypothalamic slices. EB, STX, PPT and G-1 decreased daily food intake. Of these, EB, STX and PPT blocked the WIN 55,212-2-induced increase in food intake within 1-4 h. The estrogenic diminution of cannabinoid-induced hyperphagia correlated with a rapid (within 15 min) attenuation of cannabinoid-mediated decreases in glutamatergic synaptic input onto arcuate neurons, which was completely blocked by inhibition of protein kinase C (PKC) and attenuated by inhibition of protein kinase A (PKA). STX, but not PPT, mimicked this rapid estrogenic effect. However, PPT abolished the cannabinoid-induced inhibition of glutamatergic neurotransmission in cells from animals treated 24 h prior. The estrogenic antagonism of this presynaptic inhibition was observed in anorexigenic proopiomelanocortin neurons. These data reveal that estrogens negatively modulate cannabinoid-induced changes in energy balance via Gq-coupled membrane ER- and ERalpha-mediated mechanisms involving activation of PKC and PKA. As such, they further our understanding of the pathways through which estrogens act to temper cannabinoid sensitivity in regulating energy homeostasis in females. PMID- 22538464 TI - Targeting chemokine receptor CCR4 in adult T-cell leukemia-lymphoma and other T cell lymphomas. AB - Peripheral T-cell lymphoma (PTCL) is a group of lymphoid malignancy that remains difficult to treat, as most PTCL becomes refractory or relapses, and thus there is an unmet medical need for novel treatment modalities. CC chemokine receptor 4 (CCR4) is expressed in various types of PTCL including adult T-cell leukemia lymphoma (ATL), which has the worst prognosis among them. A phase II study of a defucosylated, humanized anti-CCR4 monoclonal antibody, mogamulizumab (KW-0761), yielded an overall response rate of 50 % (13/26) and a median progression-free survival of 5.2 months in relapsed patients with CCR4-positive ATL who had been previously treated with chemotherapy. Mogamulizumab also showed potential efficacy for cutaneous T-cell lymphoma in a US phase I/II study. Further preclinical and clinical investigations are needed to examine whether concomitant use of this novel agent with other agents with different mechanisms of action would be more effective for ATL and other PTCLs. PMID- 22538465 TI - Long-lasting inhibition of the intestinal absorption of fexofenadine by cyclosporin A in rats. AB - The purpose of the present study is to examine the long-lasting inhibition of intestinal organic anion transporting polypeptides (Oatps) by cyclosporin A (CsA) in rats using fexofenadine (FEX) as a probe drug. We examined the pharmacokinetics of FEX after its intravenous or oral administration to rats at 3 or 24 h after the oral administration of CsA. When FEX was administered at 3 h after the administration of CsA, its plasma concentration increased regardless of whether it was administered intravenously or orally. When FEX was intravenously administered at 24 h after the oral administration of CsA, its plasma concentration was increased; however, that observed after its oral administration was not significantly different from the vehicle-treated control. When FEX was administered at 3 h after the administration of CsA, the hepatic availability (F(h)) and the fraction absorbed in the intestine as an unchanged form (F(a).F(g)) of FEX were increased, resulting in increased bioavailability (=F(a).F(g).F(h)). At 24 h after the administration of CsA, the F(h) of FEX was increased, whereas its bioavailability was decreased, suggesting that its F(a).F(g) was decreased because of the long-lasting inhibition. In conclusion, CsA has long-lasting inhibitory effects on Oatps in the rat intestine as well as in the liver. PMID- 22538466 TI - Exploring the role of renal pharmacists in outpatient dialysis centres: a qualitative study. AB - BACKGROUND: Pharmacists' involvement in outpatient dialysis centres in Australia is currently limited, despite the positive contribution of pharmacists to renal patients' medication management and health outcomes outlined in the literature. An expanded role for pharmacists in this setting may be required as a consequence of the increasing burden of renal disease in the population. OBJECTIVE: To explore renal-specialised hospital pharmacists' intentions to implement pharmacy services in outpatient dialysis centres. SETTING: Australian renal-specialised hospital pharmacists. METHOD: Semi-structured interviews were conducted with a purposeful sample of renal pharmacists recruited through the Society of Hospital Pharmacists of Australia Renal Special Interest Group. The interview guide was developed based on the theory of planned behaviour. To identify behavioural intention, the three components of the theory-attitudes, subjective norm, and perceived behavioural control-were explored. The interviews were recorded, transcribed verbatim, and thematically content analysed following a qualitative approach. MAIN OUTCOME MEASURES: Pharmacists' views on their potential involvement and perceived ease or difficulty in implementing pharmacy services in outpatient dialysis centres. RESULTS: Thirteen renal pharmacists were interviewed until data saturation achievement. The following services for this setting were suggested: medication reconciliation, medication review, patient education, promotion of compliance, involvement in protocol development with subsequent anaemia/phosphate management. Pharmacists demonstrated positive attitudes towards the implementation of the services. Outcomes expected included benefits to patients, the renal team, and the pharmacy profession, as well as economic savings due to dose optimisation and improvement of patients' adherence. Subjective norm was favourable meaning that nephrologists, nurses and patients were expected to be receptive towards future pharmacy services. Barriers pointed out for the implementation comprised: funding, hospital administrators' approval, time and staff shortage, academic training, relationship with physicians, and attitudes of pharmacists, renal team, and patients. Facilitators mentioned by respondents included: having an interview room with access to information sources, consent from the team, access to patients' profiles, and a full-time pharmacist with a clearly defined role. CONCLUSION: Pharmacists showed positive attitudes, favourable subjective norm and strong perceived behavioural control, which originated a clear behavioural intention to develop pharmacy services in outpatient dialysis centres. The potential barriers and enablers outlined should be taken into account, as well as the holistic approach for the successful implementation of cognitive pharmacy services. PMID- 22538467 TI - Differentiation of Erwinia amylovora and Erwinia pyrifoliae strains with single nucleotide polymorphisms and by synthesis of dihydrophenylalanine. AB - Fire blight has spread from North America to New Zealand, Europe, and the Mediterranean region. We were able to differentiate strains from various origins with a novel PCR method. Three Single Nucleotide Polymorphisms (SNPs) in the Erwinia amylovora genome were characteristic of isolates from North America and could distinguish them from isolates from other parts of the world. They were derived from the galE, acrB, and hrpA genes of strains Ea273 and Ea1/79. These genes were analyzed by conventional PCR (cPCR) and quantitative PCR (qPCR) with differential primer annealing temperatures. North-American E. amylovora strains were further differentiated according to their production of L: -2,5 dihydrophenylalanine (DHP) as tested by growth inhibition of the yeast Rhodotorula glutinis. E. amylovora fruit tree (Maloideae) and raspberry (rubus) strains were also differentiated by Single Strand Conformational Polymorphism analysis. Strains from the related species Erwinia pyrifoliae isolated in Korea and Japan were all DHP positive, but were differentiated from each other by SNPs in the galE gene. Differential PCR is a rapid and simple method to distinguish E. amylovora as well as E. pyrifoliae strains according to their geographical origin. PMID- 22538468 TI - Transcriptional regulation of the genes encoding chitin and beta-1,3-glucan synthases from Ustilago maydis. AB - Transcriptional regulation of genes encoding chitin synthases (CHS) and beta-1,3 glucan synthase (GLS) from Ustilago maydis was studied. Transcript levels were measured during the growth curve of yeast and mycelial forms, in response to ionic and osmotic stress, and during infection of maize plants. Expression of the single GLS gene was constitutive. In contrast, CHS genes expression showed differences depending on environmental conditions. Transcript levels were slightly higher in the mycelial forms, the highest levels occurring at the log phase. Ionic and osmotic stress induced alterations in the expression of CHS genes, but not following a defined pattern, some genes were induced and others repressed by the tested compounds. Changes in transcripts were more apparent during the pathogenic process. At early infection stages, only CHS6 gene showed significant transcript levels, whereas at the period of tumor formation CHS7 and CHS8 genes were also were induced. PMID- 22538469 TI - Inhibitory effects of sulfur nanoparticles on membrane lipids of Aspergillus niger: a novel route of fungistasis. AB - Orthorhombic (spherical; ~10 nm) and monoclinic (cylindrical; ~50 nm) sulfur nanoparticles (SNPs) were synthesized and examined for their effects on the total lipid content and desaturase enzymes of Aspergillus niger. Synthesized SNPs were characterized for size with transmission electron microscopy, elemental composition with energy dispersive X-ray spectroscopy and allotropic nature with X-ray diffraction pattern. Both the SNPs considerably reduced total lipid content of the treated fungal isolates with significant down regulation of the expression of various desaturase enzymes (linoleoyl-CoA desaturase, stearoyl-CoA 9 desaturase and phosphatidylcholine desaturase). Unusual high accumulation of saturated fatty acids with depleted lipid layer can be inferred as one of the major reasons of SNPs mediated fungistasis. PMID- 22538470 TI - Compromised DNA damage repair promotes genetic instability of the genomic magnetosome island in Magnetospirillum magneticum AMB-1. AB - Magnetotactic bacteria (MTB) are capable of synthesizing nano-sized, intracellular membrane-bound magnetosomes. To learn more about the genetic factors involved in magnetosome formation, transposon mutagenesis was carried out by conjugation using a hyperactive mariner transposon to obtain nonmagnetic mutants of Magnetospirillum magneticum AMB-1. A mutant with defect in uvrA gene encoding the DNA binding subunit of the UvrABC complex responsible for the process of nucleotide excision repair, was obtained. Growth, magnetosome formation and maintenance of magnetosome island (MAI) were further analyzed in the absence of UvrA. Interruption of uvrA led to decreased capacity to form magnetosome when cultured in the presence of oxygen. The deficiency in UvrA also resulted in an accelerated loss of the MAI under aerobic conditions indicating that the nucleotide excision repair system guards against the instability of the MAI. The incapacity of MTB to efficiently initiate recombination mediated by RecA rescued the instability of MAI observed in uvrA mutant. Elevated recombination activity resulting from the accumulation of unrepaired mutations may thus account for the instability of MAI in the absence of UvrA. PMID- 22538471 TI - Analysis of aztreonam-inducing proteome changes in nondividing filamentous Helicobacter pylori. AB - When stressed, bacteria can enter various nondividing states. In the present study, nondividing filamentous form in Helicobacter pylori was induced by a beta lactam antibiotic, aztreonam. In order to find possible cell division checkpoints in H. pylori, 2-DE was used to compare the proteomic profile of nondividing filamentous H. pylori with its spiral form. In total, 21 proteins involved in various cellular processes showed differential expression. One protein induced by aztreonam was a cell division inhibitor (minD), related to cell division. We then constructed the deletion mutant of minD in H. pylori 26695. Scanning electron microscope observation showed that the deletion of this protein provoked some bacteria to change into a short rod-shape and the viability of the mutant is lower than that of the wild type. Moreover, sequence comparison showed that minD of H. pylori and that of Escherichia coli share 50 % amino acid identity. This suggested that this protein possibly plays the similar part in H. pylori as in E. coli. PMID- 22538472 TI - Shear bond strength of orthodontic brackets bonded with a new self-adhering flowable resin composite. AB - OBJECTIVES: This study aims to assess the shear bond strength (SBS) to enamel and the distribution of failure modes of brackets bonded using a new self-adhering flowable resin composite (Vertise Flow, VF), with or without preliminary phosphoric acid etching (PAE). MATERIALS AND METHODS: Eighty extracted premolars were randomly divided into four groups (n = 20): (1) etch-and-rinse adhesive (E&R), PAE/Transbond XT Primer/Transbond XT Paste (3M Unitek); (2) self-etch adhesive (SE), Transbond Plus Self-Etching Primer (3M Unitek)/Transbond XT Paste; (3) VF; (4) PAE/VF. In each group, 10 bracketed teeth were debonded within 30 min, while the remaining teeth were subjected to thermocycling before testing. SBS and adhesive remnant index were recorded. RESULTS: SE measured significantly lower early SBS than PAE/VF. Early SBSs recorded by VF were slightly higher yet statistically similar to those of E&R. Such levels of adhesion were achieved by VF regardless of preliminary PAE. After thermocycling, VF measured the lowest SBS. When debonded early, VF and SE tended to leave less residues on enamel surface than E&R. After thermocycling, the failure pattern changed significantly for VF and PAE/VF specimens that all exhibited adhesive failures at the tooth bracket interface. CONCLUSIONS: VF achieved early bracket SBSs similar to E&R. Following thermocycling, VF and PAE/VF manifested a significant decrease in SBS. CLINICAL RELEVANCE: Although the simplified handling and the satisfactory early SBS of VF may prompt its use for bracket bonding, the decrease in retention noted after thermocycling warns that the issue of bond durability should be thoroughly addressed prior to endorsing this clinical application of VF. PMID- 22538474 TI - Convex optimization problem prototyping for image reconstruction in computed tomography with the Chambolle-Pock algorithm. AB - The primal-dual optimization algorithm developed in Chambolle and Pock (CP) (2011 J. Math. Imag. Vis. 40 1-26) is applied to various convex optimization problems of interest in computed tomography (CT) image reconstruction. This algorithm allows for rapid prototyping of optimization problems for the purpose of designing iterative image reconstruction algorithms for CT. The primal-dual algorithm is briefly summarized in this paper, and its potential for prototyping is demonstrated by explicitly deriving CP algorithm instances for many optimization problems relevant to CT. An example application modeling breast CT with low-intensity x-ray illumination is presented. PMID- 22538473 TI - The influence of bone substitute materials on the bone volume after maxillary sinus augmentation: a microcomputerized tomography study. AB - OBJECTIVES: This study aims to evaluate the effect of adding bone substitute materials (BSM) to particulated autogenous bone (PAB) on the volume fraction (Vf) of newly formed bone after maxillary sinus augmentation. MATERIALS AND METHODS: Thirty healthy patients undergoing maxillary sinus augmentation were included. PAB (N = 10), mixtures of PAB and beta-tricalciumphosphate (PAB/beta-TCP) (N = 10), as well as PAB and beta-TCP and hydroxyapatite (PAB/HA/beta-TCP) (N = 10) were randomly used for sinus augmentation. A sample of the graft material was maintained from each patient at time of maxillary sinus augmentation, and Vfs of the PAB and/or BSM in the samples were determined by means of microcomputerized tomography (MU-CT). Five months later, samples of the grafted areas were harvested during implantation using a trephine bur. MU-CT analysis of these samples was performed, and the Vf of bone and BSM were compared with the data obtained 5 months earlier from the original material. RESULTS: The mean Vf of the bone showed a statistically significant increase (p < 0.05) in all groups after a healing period of 5 months without statistically significant difference between the groups. CONCLUSIONS: With regard to the increase of bone volume, it is not relevant if PAB is used alone or combined with beta-TCP or HA/beta-TCP. CLINICAL RELEVANCE: The amount of PAB and associated donor site morbidity may be reduced by adding BSM for maxillary sinus augmentation. PMID- 22538475 TI - Metabolic fingerprinting by 1HNMR for discrimination of the two species used as Radix Bupleuri. AB - Radix Bupleuri is a traditional Chinese medicine harvested from two Bupleurum species (B. chinense and B. scorzonerifolium). It is widely used and is sourced from different regions of China. 1H NMR spectroscopy and multivariate data analysis were applied to 67 Radix Bupleuri samples to discriminate the two species, and explore the influences of habitat and culture method on the quality of Radix Bupleuri based on their metabolomics profiles. Metabolites responsible for the differences between the two species were higher levels of arginine, citric acid, sucrose, saikosaponin b1/b2 analogs, volatile oil with an (E)-2 olefin aldehyde fragment, and fatty acids in B. scoreonerifolium, and more saikosaponin a/c/d analogs in B. chinense. The variances of two cultivation areas were observed due to the higher amount of saikosaponins a/c/d in samples from Shaanxi and lipidsin samples from Shanxi. No obvious difference was detected between cultivars and wild type. 1HNMR metabolomics can simultaneously detect saikosaponins and hydrocarbon aldehydes, and also differentiate the two main saikosaponin skeletons, making it a suitable tool for the species discrimination and quality evaluation of Radix Bupleuri. PMID- 22538476 TI - Antimalarial efficacy of a quantified extract of Nauclea pobeguinii stem bark in human adult volunteers with diagnosed uncomplicated falciparum malaria. Part 2: a clinical phase IIB trial. AB - According to the promising results of the Phase I and Phase IIA clinical trials with the herbal medicinal product PR 259 CT1 consisting of an 80 % ethanolic extract of the stem bark of Nauclea pobeguinii containing 5.6 % strictosamide, a Phase IIB study was conducted as a single blind prospective trial in 65 patients with proven Plasmodium falciparum malaria to evaluate the effectiveness and safety of this herbal drug. The study was carried out simultaneously using an artesunate-amodiaquine combination (Coarsucam(r)) as a positive control. This combination is the standard first-line treatment for uncomplicated malaria recommended by the National Programme of Malaria Control in the Democratic Republic of Congo (DR Congo). With regard to PR 259 CT1, patients were treated with a drug regimen of two 500-mg capsules three times daily for three days in the inpatient clinic, followed by out-patient treatment of one 500-mg capsule three times daily during the next four days; the positive control group received two tablets containing 100 mg artesunate and 270 mg amodiaquine (fixed-dose) once daily during three consecutive days. Antimalarial responses were evaluated according to the WHO 2003 guideline for a 14-day test. The results from the physical and laboratory examinations did not show any significant changes in values of vital signs, ECG, biochemical, and haematological parameters. The study showed a significant decreased parasitaemia in patients treated with PR 29 CT1 and artesunate-amodiaquine with adequate clinical parasitological responses (APCR) at day 14 of 87.9 and 96.9 %, respectively. The former product was better tolerated than the latter since more side effects were observed for the artesunate-amodiaquine combination. These results indicated that PR 259 CT1 can be considered as a promising candidate for the development of a herbal medicine for the treatment of uncomplicated falciparum malaria. PMID- 22538477 TI - Inhibitory effect of beta-sitosterol on TNBS-induced colitis in mice. AB - beta-Sitosterol, a common sterol in herbal medicines, exhibits anti-inflammatory effects beneficial in the treatment of lung inflammation, asthma, and bronchospasm. To evaluate whether beta-sitosterol also has anticolitic benefits, we tested the effect of beta-sitosterol on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice. beta-Sitosterol inhibited colon shortening and led to lowered macroscopic scores and myeloperoxidase activity in TNBS-treated colitic mice. beta-Sitosterol also inhibited the expression of proinflammatory cytokines TNF-alpha, IL-1beta, and IL-6, and an inflammatory enzyme, cyclooxygenase (COX)-2, in the colons of TNBS-induced colitic mice, as well as the activation of NF-kappaB. Based on these findings, beta-sitosterol may ameliorate colitis by inhibiting the NF-kappaB pathway. PMID- 22538478 TI - Notch signaling expands a pre-malignant pool of T-cell acute lymphoblastic leukemia clones without affecting leukemia-propagating cell frequency. AB - NOTCH1 pathway activation contributes to the pathogenesis of over 60% of T-cell acute lymphoblastic leukemia (T-ALL). While Notch is thought to exert the majority of its effects through transcriptional activation of Myc, it also likely has independent roles in T-ALL malignancy. Here, we utilized a zebrafish transgenic model of T-ALL, where Notch does not induce Myc transcription, to identify a novel Notch gene expression signature that is also found in human T ALL and is regulated independently of Myc. Cross-species microarray comparisons between zebrafish and mammalian disease identified a common T-ALL gene signature, suggesting that conserved genetic pathways underlie T-ALL development. Functionally, Notch expression induced a significant expansion of pre-leukemic clones; however, a majority of these clones were not fully transformed and could not induce leukemia when transplanted into recipient animals. Limiting-dilution cell transplantation revealed that Notch signaling does not increase the overall frequency of leukemia-propagating cells (LPCs), either alone or in collaboration with Myc. Taken together, these data indicate that a primary role of Notch signaling in T-ALL is to expand a population of pre-malignant thymocytes, of which a subset acquire the necessary mutations to become fully transformed LPCs. PMID- 22538480 TI - Maternal protein restriction induce skeletal muscle changes without altering the MRFs MyoD and myogenin expression in offspring. AB - Stimuli during pregnancy, such as protein restriction, can affect morphophysiological parameters in the offspring with consequences in adulthood. The phenomenon known as fetal programming can cause short- and long-term changes in the skeletal muscle phenotype. We investigated the morphology and the myogenic regulatory factors (MRFs) MyoD and myogenin expression in soleus, SOL; oxidative and slow twitching and in extensor digitorum longus, EDL; glycolytic and fast twitching muscles in the offspring of dams subjected to protein restriction during pregnancy. Four groups of male Wistar offspring rats were studied. Offspring from dams fed a low-protein diet (6 % protein, LP) and normal protein diet (17 % protein, NP) were euthanized at 30 and 112 days old, and their muscles were removed and kept at -80 degrees C. Muscles histological sections (8 MUm) were submitted to a myofibrillar adenosine triphosphatase histochemistry reaction for morphometric analysis. Gene and protein expression levels of MyoD and myogenin were determined by RT-qPCR and western blotting. The major findings observed were distinct patterns of morphological changes in SOL and EDL muscles in LP offspring at 30 and 112 days old without changes in MRFs MyoD and myogenin expression. Our results indicate that maternal protein restriction followed by normal diet after birth induced morphological changes in muscles with distinct morphofunctional characteristics over the long term, but did not alter the MRFs MyoD and myogenin expression. Further studies are necessary to better understand the mechanisms underlying the maternal protein restriction response on skeletal muscle. PMID- 22538479 TI - Molluscan neurons in culture: shedding light on synapse formation and plasticity. AB - From genes to behaviour, the simple model system approach has played many pivotal roles in deciphering nervous system function in both invertebrates and vertebrates. However, with the advent of sophisticated imaging and recording techniques enabling the direct investigation of single vertebrate neurons, the utility of simple invertebrate organisms as model systems has been put to question. To address this subject meaningfully and comprehensively, we first review the contributions made by invertebrates in the field of neuroscience over the years, paving the way for similar breakthroughs in higher animals. In particular, we focus on molluscan (Lymnaea, Aplysia, and Helisoma) and leech (Hirudo) models and the pivotal roles they have played in elucidating mechanisms of synapse formation and plasticity. While the ultimate goal in neuroscience is to understand the workings of the human brain in both its normal and diseased states, the sheer complexity of most vertebrate models still makes it difficult to define the underlying principles of nervous system function. Investigators have thus turned to invertebrate models, which are unique with respect to their simple nervous systems that are endowed with a finite number of large, individually identifiable neurons of known function. We start off by discussing in vivo and semi-intact preparations, regarding their amenability to simple circuit analysis. Despite the 'simplicity' of invertebrate nervous systems however, it is still difficult to study individual synaptic connections in detail. We therefore emphasize in the next section, the utility of studying identified invertebrate neurons in vitro, to directly examine the development, specificity, and plasticity of synaptic connections in a well-defined environment, at a resolution that it is still unapproachable in the intact brain. We conclude with a discussion of the future of invertebrates in neuroscience in elucidating mechanisms of neurological disease and developing neuron-silicon interfaces. PMID- 22538481 TI - Fly neurons in culture: a model for neural development and pathology. AB - Primary neural cultures from the fruit fly, Drosophila melanogaster, enable a high-resolution glance into cellular processes and neuronal interaction. The development of the culture, along with its vitality and functionality, can be continuously monitored, and the abundance of available tools for D. melanogaster research can greatly assist in characterizing different aspects of the culture. The fly primary neural culture preparation thus offers a promising platform for studying a variety of processes relating to nervous system development, activity and pathology. Our data reveal that neural cultures derived from the CNS of third instar D. melanogaster larvae undergo an organization process that is specific and consistent throughout different cultures, and culminates in the creation of an elaborate neural network. We demonstrate that this process is accompanied by detectable changes in the protein expression profile of the culture, indicating the involvement of multi-protein processes specific to each stage of the network's development. As a further proof of concept, we demonstrate differential expression of a particular protein family, the gap-junction constructing innexin protein family, throughout the network's life. PMID- 22538482 TI - Molecular cloning, expression, and immunolocalization of protein disulfide isomerase in excretory-secretory products from Clonorchis sinensis. AB - Protein disulfide isomerase (PDI) is an essential catalyst of the endoplasmic reticulum with folding and chaperone activities in different biological systems. Here, PDI of Clonorchis sinensis (CsPDI) was isolated from the cDNA library of adult C. sinensis. The open reading frame contains 1,317 bp encoding 438 amino acids and shares 53 %, 49 %, and 43 % identity with PDI from Bos taurus, Homo sapiens, and Schistosoma mansoni, respectively. Two catalytic thioredoxin motifs CxxC were found in this sequence, which were characteristic domains of thioredoxin superfamily. The CsPDI protein was expressed and purified from Escherichia coli BL21 (DE3). According to western blotting analysis, the recombinant CsPDI could be recognized by anti-CsPDI rat serum, anti excretory/secretory products rat serum, and serum of rat infected with C. sinensis, respectively. Quantitative real-time polymerase chain reaction showed that transcription level of CsPDI in the metacercaria stage was six and four times higher than that in the adult worm and egg stage, respectively. Immunolocalization analysis showed CsPDI could be detected in the intestine, vitellarium, and intrauterine eggs of adult worm, as well as in the cyst wall and vitellarium of metacercaria. In addition, the strong fluorescence signal was observed both on the wall of bile duct and in the lumen of liver tissue of C. sinensis-infected cat. Those results demonstrated that CsPDI was a component of C. sinensis excretory-secretory products. The present study will enhance our understanding of biological functions of CsPDI and pave the way for further studies on host-parasite interaction during C. sinensis infection. PMID- 22538484 TI - Acetaldehyde at a low concentration synergistically exacerbates allergic airway inflammation as an endocrine-disrupting chemical and as a volatile organic compound. AB - BACKGROUND: Acetaldehyde is an endocrine-disrupting chemical (EDC) and a volatile organic compound (VOC). It is also a carcinogen and teratogen that causes bronchoconstriction in a subset of asthmatics. However, the mechanism through which acetaldehyde acts as an EDC/VOC causing allergic airway inflammation remains unknown. OBJECTIVES: To determine the effects of a low concentration of acetaldehyde, which itself did not trigger airway inflammation, on extant allergic airway inflammation in a murine model of allergic asthma. METHODS: We compared airway hyperresponsiveness (AHR), lung pathology, serum IgE and airway concentrations of cytokines among four groups of BALB/c mice [control, Dermatophagoides farinae(Df) allergen-sensitized (AS), intranasally acetaldehyde injected (ALD) and AS-ALD mice]. RESULTS: Physiological and histological differences were not evident between ALD and control mice. AS mice developed AHR and allergic airway inflammation characterized by goblet cell hyperplasia and eosinophilic infiltration. Both AHR and airway eosinophilia were significantly enhanced in AS-ALD compared with AS mice. Serum total and Df-specific IgE were significantly increased in both AS and AS-ALD mice compared with control and ALD mice, but comparable between AS and AS-ALD mice. Mite allergen sensitization significantly increased interleukin-5 and granulocyte macrophage colony stimulating factor, and decreased interferon-gamma levels in the airways; injecting acetaldehyde into airways with allergic inflammation significantly increased the levels of these inflammatory cytokines. CONCLUSIONS: Exposure to acetaldehyde can enhance allergic airway inflammation in asthma. PMID- 22538485 TI - An efficient nickel-catalyzed alkenylation of functionalized benzylic halides with alkenylaluminum reagents. AB - Highly efficient and simple coupling reactions of benzylic bromides or chlorides with alkenylaluminum reagents catalyzed by NiCl(2)(PPh(3))(2) are reported. The coupling reactions proceed effectively at room temperature employing low loading of catalyst, 0.5 mol% for benzylic bromides having either electron-donating or withdrawing substituents on the aromatic ring, affording coupling products in excellent yields of up to 94% in short reaction times. The coupling reactions of benzylic chloride require 5 mol% of the catalyst and a longer reaction time of 2 h. PMID- 22538483 TI - The landmark JDRF continuous glucose monitoring randomized trials: a look back at the accumulated evidence. AB - Despite improvements for management of type 1 diabetes (T1D), patients have difficulty achieving glycated hemoglobin (A1c) levels recommended by the Diabetes Control and Complications Trial (DCCT). Two multicenter randomized trials were conducted to evaluate benefit of using a continuous glucose monitor (CGM) with standard glucose monitoring for T1D management. The primary study evaluated benefits of CGM in 322 patients with A1c >7.0%. The secondary study evaluated 129 patients with A1c <7.0%. In the primary study, CGM resulted in improvements in A1c at 6 m in subjects >25 years, but not those <25. However, all subjects using CGM regularly showed benefit. Improved A1c did not come with increased severe hypoglycemia as seen in the DCCT, and benefit was sustained over 1 year. In the secondary study, CGM use helped subjects maintain target A1c levels with reduced exposure to biochemical hypoglycemia. The data collected allowed for other analyses of important factors in T1D management. PMID- 22538486 TI - Inhibitory effects of acetylmelodorinol, chrysin and polycarpol from Mitrella kentii on prostaglandin E2 and Thromboxane B2 production and platelet activating factor receptor binding. AB - Acetylmelodorinol, chrysin and polycarpol, together with benzoic acid, benzoquinone and stigmasterol were isolated from the leaves of Mitrella kentii (Bl.) Miq. The compounds were evaluated for their ability to inhibit prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) production in human whole blood using a radioimmunoassay technique. Their inhibitory effect on platelet activating factor (PAF) receptor binding to rabbit platelet was determined using 3H-PAF as a ligand. Among the compounds tested, chrysin showed a strong dose dependent inhibitory activity on PGE(2) production (IC50 value of 25.5 uM), which might be due to direct inhibition of cyclooxygenase-2 (COX-2) enzymatic activity. Polycarpol, acetylmelodorinol and stigmasterol exhibited significant and concentration-dependent inhibitory effects on TXB2 production with IC50 values of 15.6, 19.1 and 19.4 uM, respectively, suggesting that they strongly inhibited COX 1 activity. Polycarpol and acetylmelodorinol showed strong dose-dependent inhibitory effects on PAF receptor binding with IC50 values of 24.3 and 24.5 uM, respectively. PMID- 22538487 TI - Antimicrobial and antioxidant activities of essential oils of Satureja thymbra growing wild in Libya. AB - The composition of essential oil isolated from Satureja thymbra, growing wild in Libya, was analyzed by GC and GC-MS. The essential oil was characterized by gamma terpinene (39.23%), thymol (25.16%), p-cymene (7.17%) and carvacrol (4.18%) as the major constituents. Antioxidant activity was analyzed using the 2,2-diphenyl 1-picrylhydrazyl (DPPH) free radical scavenging method. It possessed strong antioxidant activity (IC50 = 0.0967 mg/mL). The essential oil was also screened for its antimicrobial activity against eight bacterial and eight fungal species, showing excellent antimicrobial activity against the microorganisms used, in particular against the fungi. The oil of S. thymbra showed bacteriostatic activity at 0.001-0.1 mg/mL and was bactericidal at 0.002-0.2 mg/mL; fungistatic effects at 0.001-0.025 mg/mL and fungicidal effects at 0.001-0.1 mg/mL. The main constituents thymol, carvacrol and gamma-terpinene also showed strong antimicrobial activity. The commercial fungicide bifonazole showed much lower antifungal activity than the tested oil. PMID- 22538488 TI - Superconducting fullerene nanowhiskers. AB - We synthesized superconducting fullerene nanowhiskers (C(60)NWs) by potassium (K) intercalation. They showed large superconducting volume fractions, as high as 80%. The superconducting transition temperature at 17 K was independent of the K content (x) in the range between 1.6 and 6.0 in K-doped C(60) nanowhiskers (K(x)C(60)NWs), while the superconducting volume fractions changed with x. The highest shielding fraction of a full shielding volume was observed in the material of K(3.3)C(60)NW by heating at 200 degrees C. On the other hand, that of a K-doped fullerene (K-C(60)) crystal was less than 1%. We report the superconducting behaviors of our newly synthesized K(x)C(60)NWs in comparison to those of K(x)C(60) crystals, which show superconductivity at 19 K in K(3)C(60). The lattice structures are also discussed, based on the x-ray diffraction (XRD) analyses. PMID- 22538489 TI - The Antimicrobial efficacy of Elaeis guineensis: characterization, in vitro and in vivo studies. AB - The urgent need to treat multi-drug resistant pathogenic microorganisms in chronically infected patients has given rise to the development of new antimicrobials from natural resources. We have tested Elaeis guineensis Jacq (Arecaceae) methanol extract against a variety of bacterial, fungal and yeast strains associated with infections. Our studies have demonstrated that E. guineensis exhibits excellent antimicrobial activity in vitro and in vivo against the bacterial and fungal strains tested. A marked inhibitory effect of the E. guineensis extracts was observed against C. albicans whereby E. guineensis extract at 1/2, 1, or 2 times the MIC significantly inhibited C. albicans growth with a noticeable drop in optical density (OD) of the bacterial culture. This finding confirmed the anticandidal activity of the extract on C. albicans. Imaging using scanning (SEM) and transmission (TEM) electron microscopy was done to determine the major alterations in the microstructure of the extract-treated C. albicans. The main abnormalities noted via SEM and TEM studies were the alteration in morphology of the yeast cells. In vivo antimicrobial activity was studies in mice that had been inoculated with C. albicans and exhibited good anticandidal activity. The authors conclude that the extract may be used as a candidate for the development of anticandidal agent. PMID- 22538491 TI - Get out--and stay out. AB - Leaving the safety of home exposes our vulnerabilities. In this issue of Blood, Uy and coauthors explore the clinical benefit of interrupting the protective niches in which leukemia cells live in an effort to enhance the benefit of chemotherapy in treating patients with acute myeloid leukemia (AML). PMID- 22538490 TI - Modeling Parkinson's disease using induced pluripotent stem cells. AB - Our understanding of the underlying molecular mechanism of Parkinson's disease (PD) is hampered by a lack of access to affected human dopaminergic (DA) neurons on which to base experimental research. Fortunately, the recent development of a PD disease model using induced pluripotent stem cells (iPSCs) provides access to cell types that were previously unobtainable in sufficient quantity or quality, and presents exciting promises for the elucidation of PD etiology and the development of potential therapeutics. To more effectively model PD, we generated two patient-derived iPSC lines: a line carrying a homozygous p.G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene and another carrying a full gene triplication of the alpha-synuclein encoding gene, SNCA. We demonstrated that these PD-linked pluripotent lines were able to differentiate into DA neurons and that these neurons exhibited increased expression of key oxidative stress response genes and alpha-synuclein protein. Moreover, when compared to wild-type DA neurons, LRRK2-G2019S iPSC-derived DA neurons were more sensitive to caspase-3 activation caused by exposure to hydrogen peroxide, MG-132, and 6 hydroxydopamine. In addition, SNCA-triplication iPSC-derived DA neurons formed early ubiquitin-positive puncta and were more sensitive to peak toxicity from hydrogen peroxide-induced stress. These aforementioned findings suggest that LRRK2-G2019S and SNCA-triplication iPSC-derived DA neurons exhibit early phenotypes linked to PD. Given the high penetrance of the homozygous LRRK2 mutation, the expression of wild-type alpha-synuclein protein in the SNCA triplication line, and the clinical resemblance of patients afflicted with these familial disorders to sporadic PD patients, these iPSC-derived neurons may be unique and valuable models for disease diagnostics and development of novel pharmacological agents for alleviation of relevant disease phenotypes. PMID- 22538492 TI - To SWiTCH or not to SWiTCH? AB - In this issue of Blood, Ware and Helms report results from the Stroke With Transfusions Changing To Hydroxyurea (SWiTCH) study designed to determine whether hydroxyurea is as effective as transfusions in preventing recurrent strokes in children with sickle cell anemia. The finding of strokes in 7 of 67 children receiving hydroxyurea but none in 66 children who received transfusions led the authors to conclude that hydroxyurea is not effective in mitigating strokes.1 PMID- 22538493 TI - CARs and cancers: questions and answers. AB - In this issue of Blood, Till et al present 3 patients with relapsed B-cell lymphomas treated with autologous T cells genetically modified to express a CD20 targeted chimeric antigen receptor (CAR) demonstrating both safety and clinical efficacy. PMID- 22538494 TI - Lymphocyte cytotoxicity: tug-of-war on microtubules. AB - Lymphocyte cytotoxicity is essential in immune defense. In this issue of Blood, Kurowska and colleagues define a Rab27a/Slp3/kinesin-1 complex that facilitates anterograde microtubule transport of lytic granules, representing a critical step in lymphocyte granule exocytosis and cytotoxicity. PMID- 22538495 TI - MicroRNAs function on a new level. AB - In this issue of Blood, Zardo et al describe an emerging mechanism by which microRNAs can regulate gene expression in blood cells via transcriptional gene silencing (TGS). The authors provide evidence that miR-223 binds to specific sites within the promoter of its target gene Nfia and represses transcription by influencing epigenetic events. These observations support the notion that multiple mechanisms of miRNA-mediated gene repression exist and should be considered when investigating gene targets of a given miRNA of interest. PMID- 22538496 TI - Platelets and eltrombopag: a not-so-sticky situation. AB - In this issue of Blood, Psaila and colleagues examine the in vivo effects of eltrombopag, a thrombopoietin receptor agonist (TPO-RA), on platelet function and reactivity. PMID- 22538498 TI - The role of cell lines in the study of neuroendocrine tumors. AB - Cell lines originating from neuroendocrine tumors (NETs) represent useful experimental models to assess the control of synthesis and release of different hormones and hormone-like peptides, to evaluate the mechanisms of action of these agents in target tissues at the cellular and subcellular levels, and to study cell proliferation and tumor development, as well as the effect of different drugs on these complex processes. To date, the understanding of NET biology (with regard to their mechanisms of hormone secretion, cell proliferation and metastatic spread) has been hampered by the lack of appropriate animal models or cell lines for their study. In the present review, we aim to summarize the recent in vitro/in vivo data regarding cell lines derived from NETs which are most frequently employed in experimental neuroendocrinology. PMID- 22538500 TI - Meigs' syndrome: a rare cause of recurrent pleural effusion in scleroderma. AB - Meigs' syndrome represents a triad of pleural effusion, ascites, and an ovarian tumor, usually benign, occurring together. We describe here a case of Meigs' syndrome in a patient with systemic sclerosis, the first such report to our knowledge, in systemic sclerosis. A 53-year-old woman with systemic sclerosis presented with recurrent right-sided pleural effusion, which led to symptoms of shortness of breath, chest tightness, and a non-productive cough. Physical examination revealed a palpable, mobile mass in the right lower quadrant, in addition to typical physical features of scleroderma. Thoracentesis yielded exudative pleural fluid with cytology negative for malignancy. Pleural biopsy was consistent with inflammatory changes, but negative for malignancy. CT scan of the chest, abdomen, and pelvis revealed a soft tissue mass in the pelvis, which appeared to arise from the left ovary. The patient's cancer antigen 125 (CA-125) level was elevated at 222 U/mL (normal range, 0-30 U/mL). The patient underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy. Histology of the left ovarian mass was consistent with an ovarian fibrothecoma, a benign tumor of the ovary. At her 1-month follow-up appointment, the patient had complete resolution of the right-sided pleural effusion. To date, at 10 months past the initial presentation, she has not had recurrence of pleural effusion. Although rare, Meigs' syndrome should be considered as a possible cause of recurrent serositis in women with rheumatologic diseases. Removal of the ovarian tumor leads to prompt resolution of the serositis. PMID- 22538502 TI - Nanophotonic lab-on-a-chip platforms including novel bimodal interferometers, microfluidics and grating couplers. AB - One of the main limitations for achieving truly lab-on-a-chip (LOC) devices for point-of-care diagnosis is the incorporation of the "on-chip" detection. Indeed, most of the state-of-the-art LOC devices usually require complex read-out instrumentation, losing the main advantages of portability and simplicity. In this context, we present our last advances towards the achievement of a portable and label-free LOC platform with highly sensitive "on-chip" detection by using nanophotonic biosensors. Bimodal waveguide interferometers fabricated by standard silicon processes have been integrated with sub-micronic grating couplers for efficient light in-coupling, showing a phase resolution of 6.6 * 10(-4)* 2pi rad and a limit of detection of 3.3 * 10(-7) refractive index unit (RIU) in bulk. A 3D network of SU-8 polymer microfluidics monolithically assembled at the wafer level was included, ensuring perfect sealing and compact packaging. To overcome some of the drawbacks inherent to interferometric read-outs, a novel all-optical wavelength modulation system has been implemented, providing a linear response and a direct read-out of the phase variation. Sensitivity, specificity and reproducibility of the wavelength modulated BiMW sensor has been demonstrated through the label-free immunodetection of the human hormone hTSH at picomolar level using a reliable biofunctionalization process. PMID- 22538501 TI - The influence of risk factors on clinical outcomes following anatomical medial patellofemoral ligament (MPFL) reconstruction using the gracilis tendon. AB - PURPOSE: Patellofemoral instability is influenced by ligamentous, boney and neuromuscular factors. The most important variables are trochlea geometry, medial patellofemoral ligament (MPFL), patella height, tibial tuberosity-trochlea groove distance (TT-TG) and the extensor muscles. Treatment is complicated by these multifactorial conditions. This prospective study examined the influence of risk factors on clinical results and athletic activities where treatment was confined to ligamentous procedures only. METHODS: Fifty patients with chronic patellofemoral instability were treated with MPFL reconstruction using an autologous gracilis tendon. Clinical data, radiographs and magnetic resonance imaging (MRI) were prospectively evaluated pre- and postoperative (minimum follow up 12 month) to detect existing risk factors for patellofemoral instability and to evaluate clinical and sport ability scores (Kujala, Valderrabano). RESULTS: There was a low rate of redislocation (2 %) and an average Kujala score of 87 +/- 13 points postoperative. The MRI showed good integration of the reconstructed MPFL and a positive effect regarding the decrease of patella tilt (16.1 degrees to 11.2 degrees ). A negative relationship was found between the degree of trochlear dysplasia and outcomes. 80 % of all patients returned to the same or higher level of physical activity. CONCLUSIONS: Addressing only ligamentous factors through MPFL reconstruction leads to satisfying clinical results and low redislocation rates in most patients. In cases with a high degree of trochlear dysplasia and enlarged TT-TG, additional procedures such as trochleaplasty and tibial tuberosity transfer should be considered as well. LEVEL OF EVIDENCE: IV. PMID- 22538503 TI - Preoperative assessment of respiratory function in severely obese patients undergoing biliopancreatic diversion. AB - Since severe obesity is often associated with a pulmonary function defect and abdominal surgery increases the risks of respiratory postoperative complications (RPC), an increased incidence of RPC might occur after bariatric operations. A cohort of 146 severely obese patients undergoing biliopancreatic diversion (BPD) was retrospectively evaluated for the occurrence of RPC. Respiratory function was evaluated prior to BPD from the quotient between measured and predicted values of forced vital capacity (FVC), forced expiratory volume in 1 s (FEV(1)) and the Tiffeneau index (TI: FEV(1)/FVC). In this cohort of obese individuals the BMI degree prior to the operation was totally unrelated to the standardized values of TI and to the presence of restrictive or obstructive pulmonary disease. Globally, a very low rate of RPC (7.5%) was found; in patients with suspected restrictive pulmonary impairment, a high occurrence of RPC was observed (p < 0.05). When data are controlled for preoperative BMI values, smoking status and presence of sleep apnoea, a logistic regression model indicates that respiratory function data cannot predict the occurrence of RPC after bariatric surgery. PMID- 22538504 TI - A model infant feeding policy for Baby-Friendly designation in the USA. AB - BACKGROUND: In June 2010, the Communities Putting Prevention to Work program (Centers for Disease Control and Prevention) funded a New Jersey (NJ) Office on Nutrition and Fitness, Department of Health and Senior Services project to reduce obesity and increase exclusive breastfeeding by increased implementation of the Baby-Friendly Hospital Initiative in the state of NJ. At baseline, NJ had no Baby Friendly hospitals and no hospital was using an infant feeding policy that conformed to standards required by Baby-Friendly USA for designation. GOAL: To create a model infant feeding policy that would be adaptable for use at multiple NJ hospitals preparing for Baby-Friendly designation. METHODS: Project consultants created a policy based on existent policies from the American Academy of Pediatrics, the Academy of Breastfeeding Medicine, certified Baby-Friendly hospitals, and guidance from Baby-Friendly USA. This policy was submitted to Baby Friendly USA, the US body responsible for Baby-Friendly designation. RESULTS: Baby-Friendly USA requested changes; after adaptations, the policy was made available to targeted NJ hospitals via a statewide portal. The hospitals made relevant adaptations for their setting, and those that were ready submitted the policy during the Baby-Friendly designation process. The policy was acceptable to Baby-Friendly USA. CONCLUSION: A collaborative initiative can use a single breastfeeding policy template as an aid toward Baby-Friendly designation. Such work streamlines the process and saves time and resources. PMID- 22538505 TI - Tobacco outlet density and demographics: a geographically weighted regression analysis. AB - Previous studies have indicated that tobacco outlets seem to be clustered in low income minority neighborhoods. This study utilized a cross-sectional design to examine the relationships among minority status, median household income, population density, commercial land use, and location of tobacco outlets at the census tract level in Polk County, Iowa. Using geographically weighted regression, this study re-examines one previously carried out in the same location by Schneider et al. (Prevention Science 6: 319-325, 2005). Contrary to that and some other previous studies, this research found no relationship between tobacco outlet density and percent Hispanic, and found a negative relationship with regard to two variables-that of being African American and median household income. Positive significant relationships were found with population density and land use. PMID- 22538506 TI - A rotary nano ion pump: a molecular dynamics study. AB - The dynamics of a rotary nano ion pump, inspired by the F (0) part of the F(0)F(1)-ATP synthase biomolecular motor, were investigated. This nanopump is composed of a rotor, which is constructed of two carbon nanotubes with benzene rings, and a stator, which is made of six graphene sheets. The molecular dynamics (MD) method was used to simulate the dynamics of the ion nanopump. When the rotor of the nanopump rotates mechanically, an ion gradient will be generated between the two sides of the nanopump. It is shown that the ion gradient generated by the nanopump is dependant on parameters such as the rotary frequency of the rotor, temperature and the amounts and locations of the positive and negative charges of the stator part of the nanopump. Also, an electrical potential difference is generated between the two sides of the pump as a result of its operation. PMID- 22538507 TI - Structures, energies and bonding in neutral and charged Li microclusters. AB - Structural and chemical properties of charged and neutral Lithium microclusters are investigated for [Formula: see text]. A total of 18 quantum conformational spaces are randomly walked to produce candidate structures for local minima. Very rich potential energy surfaces are produced, with the largest structural complexity predicted for anionic clusters. Analysis of the electron charge distributions using the quantum theory of atoms in molecules (QTAIM) predicts major stabilizing roles of Non-nuclear attractors (NNAs) via NNA...Li interactions with virtually no direct Li...Li interactions, except in the least stable configurations. A transition in behavior for clusters containing more than seven nuclei is observed by using the recently introduced quantum topology to determine in a quantum mechanically consistent fashion the number of spatial dimensions each cluster has. We experiment with a novel scheme for extracting persistent structural motifs with increase in cluster size. The new structural motifs correlate well with the energetic stability, particularly in highlighting the least stable structures. Quantifying the degree of covalent character in Lithium bonding independently agrees with the observation in the transition in cluster behavior for lithium clusters containing more than seven nuclei. Good correlation with available experimental data is obtained for all properties reported in this work. PMID- 22538508 TI - Computational structural analysis of proteins of Mycobacterium tuberculosis and a resource for identifying off-targets. AB - Advancement in technology has helped to solve structures of several proteins including M. tuberculosis (MTB) proteins. Identifying similarity between protein structures could not only yield valuable clues to their function, but can also be employed for motif finding, protein docking and off-target identification. The current study has undertaken analysis of structures of all MTB gene products with available structures was analyzed. Majority of the MTB proteins belonged to the alpha/beta class. 23 different protein folds are used in the MTB protein structures. Of these, the TIM barrel fold was found to be highly conserved even at very low sequence identity. We identified 21 paralogs and 27 analogs of MTB based on domains and EC classification. Our analysis revealed that many of the current drug targets share structural similarity with other proteins within the MTB genome, which could probably be off-targets. Results of this analysis have been made available in the Mycobacterium tuberculosis Structural Database (http://bmi.icmr.org.in/mtbsd/MtbSD.php/search.php) which is a useful resource for current and novel drug targets of MTB. PMID- 22538509 TI - Development and validation of a BEAMnrc component module for a miniature multileaf collimator. AB - A new component module (CM) named mini multileaf collimator (mMLC) was developed for the Monte Carlo code BEAMnrc. It models the geometry of the add-on miniature multileaf collimator ModuLeaf (MRC Systems GmbH, Heidelberg, Germany, now part of Siemens, Erlangen, Germany). The new CM is partly based on the existing CM called DYNVMLC. The development was performed using a modified EGSnrc platform which enables us to work in the Microsoft Visual Studio environment. In order to validate the new CM, the PRIMUS linac with 6 MV x-rays (Siemens OCS, Concord, CA, USA) equipped with the ModuLeaf mMLC was modelled. Validation was performed by two methods: (a) a ray-tracing method to check the correct geometry of the multileaf collimator (MLC) and (b) a comparison of calculated and measured results of the following dosimetrical parameters: output factors, dose profiles, field edge position penumbra, MLC interleaf leakage and transmission values. Excellent agreement was found for all parameters. It was, in particular, found that the relationship between leaf position and field edge depending on the shape of the leaf ends can be investigated with a higher accuracy by this new CM than by measurements demonstrating the usefulness of the new CM. PMID- 22538510 TI - Lipopolysaccharide-induced proliferation of the vasa vasorum in a rabbit model of atherosclerosis as evaluated by contrast-enhanced ultrasound imaging and histology. AB - Whether lipopolysaccharide (LPS) can promote vasa vasorum (VV) proliferation for atherosclerosis in vivo is unclear. Eighteen rabbits with atherosclerosis were randomly assigned into one of three groups of six. Group A received biweekly injections of 10 mL saline after 2 weeks of balloon injury. Groups B and C received biweekly intravenous injections of 3.0 MUg LPS in 10 mL saline at weeks 10 and 4, respectively, until study termination. LPS significantly increased the levels of triglycerides and C-reactive protein and decreased the level of high density lipoprotein cholesterol. Group C had significant larger plaques and more macrophages than group A (p = 0.01 and p < 0.001, respectively). Contrast enhancement ultrasound imaging and histological detection demonstrated that plaques in group C had a significantly higher VV density than that in group A (p = 0.009 and p = 0.002, respectively). In summary, VV proliferation for plaque destabilization can be accelerated by LPS-induced systemic inflammation and changes in lipid profiles. PMID- 22538511 TI - Re: The record power profile to assess performance in elite cyclists. PMID- 22538515 TI - Similar level of impairment in exercise performance and oxygen uptake kinetics in middle-aged men and women with type 2 diabetes. AB - The present study tested the hypothesis that the magnitude of the type 2 diabetes induced impairments in peak oxygen uptake (Vo(2)) and Vo(2) kinetics would be greater in females than males in middle-aged participants. Thirty-two individuals with type 2 diabetes (16 male, 16 female), and 32 age- and body mass index (BMI) matched healthy individuals (16 male, 16 female) were recruited. Initially, the ventilatory threshold (VT) and peak Vo(2) were determined. On a separate day, subjects completed four 6-min bouts of constant-load cycling at 80% VT for the determination of Vo(2) kinetics using standard procedures. Cardiac output (CO) (inert gas rebreathing) was recorded at rest, 30, and 240 s during two additional bouts. Peak Vo(2) (ml.kg(-1).min(-1)) was significantly reduced in men and women with type 2 diabetes compared with their respective nondiabetic counterparts (men, 27.8 +/- 4.4 vs. 31.1 +/- 6.2 ml.kg(-1).min(-1); women, 19.4 +/- 4.1 vs. 21.4 +/- 2.9 ml.kg(-1).min(-1)). The time constant (s) of phase 2 (tau(2)) and mean response time (s) of the Vo(2) response (MRT) were slowed in women with type 2 diabetes compared with healthy women (tau(2), 43.3 +/- 9.8 vs. 33.6 +/- 10.0 s; MRT, 51.7 +/- 9.4 vs. 43.5 +/- 11.4s) and in men with type 2 diabetes compared with nondiabetic men (tau(2), 43.8 +/- 12.0 vs. 35.3 +/- 9.5 s; MRT, 57.6 +/- 8.3 vs. 47.3 +/- 9.3 s). The magnitude of these impairments was not different between males and females. The steady-state CO responses or the dynamic responses of CO were not affected by type 2 diabetes among men or women. The results suggest that the type 2 diabetes-induced impairments in peak Vo(2) and Vo(2) kinetics are not affected by sex in middle aged participants. PMID- 22538513 TI - Renoprotective effects of anti-TGF-beta antibody and antihypertensive therapies in Dahl S rats. AB - This study examined the effects of anti-TGF-beta antibody (1D11) therapy in Dahl S (S) rats fed a 4% NaCl diet. Baseline renal expression of TGF-beta1 and the degree of injury were lower in female than male S rats maintained on a 0.4% NaCl diet. 4% NaCl diet increased mean arterial pressure (MAP), proteinuria, and renal injury to the same extent in both male and female S rats. Chronic treatment with 1D11 had renoprotective effects in both sexes. The ability of 1D11 to oppose the development of proteinuria when given alone or in combination with antihypertensive agents was further studied in 6-wk-old female S rats, since baseline renal injury was less than that seen in male rats. 1D11, diltiazem, and hydrochlorothiazide (HCT) attenuated the development of hypertension, proteinuria, and glomerular injury. 1D11 had no additional effect when given in combination with these antihypertensive agents. We also explored whether 1D11 could reverse renal injury in 9-wk-old male S rats with preexisting renal injury. MAP increased to 197 +/- 4 mmHg and proteinuria rose to >300 mg/day after 3 wk on a 4% NaCl diet. Proteinuria was reduced by 30-40% in rats treated with 1D11, HCT, or captopril + 1D11, but the protective effect was lost in rats fed the 4% NaCl diet for 6 wk. Nevertheless, 1D11, HCT, and captopril + 1D11 still reduced renomedullary and cardiac fibrosis. These results indicate that anti-TGF-beta antibody therapy reduces renal and cardiac fibrosis and affords additional renoprotection when given in combination with various antihypertensive agents in Dahl S rats. PMID- 22538514 TI - Myocardial ischemia, reperfusion, and infarction in chronically instrumented, intact, conscious, and unrestrained mice. AB - In the United States alone, the National Heart, Lung, and Blood Institute (NHLBI) has invested several hundred million dollars in pursuit of myocardial infarct sparing therapies. However, due largely to methodological limitations, this investment has not produced any notable clinical application or cardioprotective therapy. Among the major methodological limitations is the reliance on animal models that do not mimic the clinical situation. In this context, the limited use of conscious animal models is of major concern. In fact, whenever possible, studies of cardiovascular physiology and pathophysiology should be conducted in conscious, complex models to avoid the complications associated with the use of anesthesia and surgical trauma. The mouse has significant advantages over other experimental models for the investigation of infarct-sparing therapies. The mouse is inexpensive, has a high throughput, and presents the ability of one to create genetically modified models. However, successful infarct-sparing therapies in anesthetized mice or isolated mouse hearts may not be successful in more complex models, including conscious mice. Accordingly, a conscious mouse model of myocardial ischemia and reperfusion has the potential to be of major importance for advancing the concepts and methods that drive the development of infarct sparing therapies. Therefore, we describe, for the first time, the use of an intact, conscious, and unrestrained mouse model of myocardial ischemia reperfusion and infarction. The conscious mouse model permits occlusion and reperfusion of the left anterior descending coronary artery in an intact, complex model free of the confounding influences of anesthetics and surgical trauma. This methodology may be adopted for advancing the concepts and ideas that drive cardiovascular research. PMID- 22538516 TI - EBV-positive diffuse large B-cell lymphoma of the elderly is an aggressive post germinal center B-cell neoplasm characterized by prominent nuclear factor-kB activation. AB - Here, we report a retrospective series of 47 EBV-positive diffuse large B-cell lymphoma associated with advanced age. Histopathology allowed to the identification of different histological patterns: cases with polymorphic diffuse large B-cell lymphoma (29 cases), Hodgkin-like (8 cases) and polymorphic lymphoproliferative disorder-like (9 cases) patterns. One case was purely monomorphic diffuse large B-cell lymphoma. We show that this lymphoma type is a neoplasm with prominent classical and alternative nuclear factor-kB pathway activation in neoplastic cells (79% of the cases showed nuclear staining for p105/p50, 74% for p100/p52 and 63% for both proteins), with higher frequency than that observed in a control series of EBV-negative diffuse large B-cell lymphoma (chi(2) <0.001). Most cases showed an activated phenotype (95% non-germinal center (Hans algorithm); 78% activated B cell (Choi algorithm)). Clonality testing demonstrated IgH and/or K/Kde/L monoclonal rearrangements in 64% of cases and clonal T-cell populations in 24% of cases. C-MYC (1 case), BCL6 (2 cases) or IgH (3 cases) translocations were detected by FISH in 18% cases. These tumors had a poor overall survival and progression-free survival (the estimated 2-year overall survival was 40 +/- 10% and the estimated 2-year progression-free survival was 36 +/- 9%). Thus, alternative therapies, based on the tumor biology, need to be tested in patients with EBV-positive diffuse large B-cell lymphoma of the elderly. PMID- 22538517 TI - Severe resistance to weight gain, lack of stored triglycerides in adipose tissue, hypoglycaemia, and increased energy expenditure: a novel disorder of energy homeostasis. AB - BACKGROUND: Growth during childhood is a consequence of the equilibrium of energy balance. Obesity results from a shift of the equilibrium towards increased energy intake over expenditure. A clinical description of extreme leanness and failure to thrive secondary to a shift of the equilibrium towards increased energy expenditure over energy intake has not been previously described in the medical literature. SUBJECTS AND METHODS: We report the case of a female child born premature with a birth weight of 1.1 kg who presented with extreme failure to thrive, persistent hypoglycaemia, paucity of fat in the adipose tissue with increased brown fat and increased resting energy expenditure. RESULTS: Complete cessation of weight and height was noted between 3 months to 3.5 years of age. Hypoglycaemia was secondary to depleted energy stores and increased insulin sensitivity. Increased resting energy expenditure was demonstrated on indirect calorimetric assessment. Biopsy of adipose tissue demonstrated paucity of stored fat with increase in brown fat. No gain in weight and height was demonstrated despite high calorie intake of enteral and parenteral feeds. CONCLUSION: We describe a unique case of extreme failure to thrive with increased energy expenditure and severe hypoglycaemia. Unravelling the molecular basis of this novel disorder has the potential to provide insights into the prevention of obesity. PMID- 22538518 TI - Genetic changes following hybridization and genome doubling in synthetic Brassica napus. AB - Genetic changes were investigated in two sets of independently synthesized Brasscia napus allopolyploids by the AFLP approach in the present study. We found that 1.17 % of the loci showed genetic changes following both hybridization and genome doubling in the synthesized B. napus F04J2 relative to its diploid progenitors, B. rapa (AA genome) and B. oleracea (CC genome). No significant difference between the proportion of A-genome-specific genetic changes and that of C-genome-specific genetic changes was detected in B. napus F04J2. Approximately 0.6 % of the loci displayed genetic changes following somatic genome doubling in the amphidiploid B. napus DCE11 relative to the amphihaploid in the dimorphic plants. This study showed that rapid genetic changes occurred after hybridization and/or genome doubling in synthesized B. napus allopolyploids and indicated that both hybridization and genome doubling could affect the genomic architecture in newly formed allopolyploids. PMID- 22538519 TI - Identification of neurons that express ghrelin receptors in autonomic pathways originating from the spinal cord. AB - Functional studies have shown that subsets of autonomic preganglionic neurons respond to ghrelin and ghrelin mimetics and in situ hybridisation has revealed receptor gene expression in the cell bodies of some preganglionic neurons. Our present goal has been to determine which preganglionic neurons express ghrelin receptors by using mice expressing enhanced green fluorescent protein (EGFP) under the control of the promoter for the ghrelin receptor (also called growth hormone secretagogue receptor). The retrograde tracer Fast Blue was injected into target organs of reporter mice under anaesthesia to identify specific functional subsets of postganglionic sympathetic neurons. Cryo-sections were immunohistochemically stained by using anti-EGFP and antibodies to neuronal markers. EGFP was detected in nerve terminal varicosities in all sympathetic chain, prevertebral and pelvic ganglia and in the adrenal medulla. Non-varicose fibres associated with the ganglia were also immunoreactive. No postganglionic cell bodies contained EGFP. In sympathetic chain ganglia, most neurons were surrounded by EGFP-positive terminals. In the stellate ganglion, neurons with choline acetyltransferase immunoreactivity, some being sudomotor neurons, lacked surrounding ghrelin-receptor-expressing terminals, although these terminals were found around other neurons. In the superior cervical ganglion, the ghrelin receptor terminals innervated subgroups of neurons including neuropeptide Y (NPY) immunoreactive neurons that projected to the anterior chamber of the eye. However, large NPY-negative neurons projecting to the acini of the submaxillary gland were not innervated by EGFP-positive varicosities. In the celiaco-superior mesenteric ganglion, almost all neurons were surrounded by positive terminals but the VIP-immunoreactive terminals of intestinofugal neurons were EGFP-negative. The pelvic ganglia contained groups of neurons without ghrelin receptor terminal innervation and other groups with positive terminals around them. Ghrelin receptors are therefore expressed by subgroups of preganglionic neurons, including those of vasoconstrictor pathways and of pathways controlling gut function, but are absent from some other neurons, including those innervating sweat glands and the secretomotor neurons that supply the submaxillary salivary glands. PMID- 22538520 TI - Regulation of NH-tautomerism in N-confused porphyrin by N-alkylation. AB - A variety of internally N-alkylated N-confused porphyrins were prepared in a stepwise manner through the protection of the reactive peripheral nitrogen atom. NH-Tautomerism in N-confused porphyrins was found to be regulated by N alkylation, which enabled us to obtain discrete information on two important NH tautomers of an N-confused porphyrin. PMID- 22538521 TI - The interaction of biological factors with mechanical signals in bone adaptation: recent developments. AB - Mechanotransduction in bone is fundamental to proper skeletal development. Deficiencies in signaling mechanisms that transduce physical forces to effector cells can have severe consequences for skeletal integrity. Therefore, a solid understanding of the cellular and molecular components of mechanotransduction is crucial for correcting skeletal modeling and remodeling errors and designing effective therapies. In recent years, progress has been made on many fronts regarding our understanding of bone cell mechanotransduction, including subcellular localization of mechanosensitive components in bone cells, the discovery of mechanosensitive G-protein-coupled receptors, identification of new ion channels and larger pores (eg, hemichannels) involved in physical signal transduction, and cell adhesion proteins, among others. These and other recent mechanisms are reviewed to provide a synthesis of recent experimental findings, in the larger context of whole bone adaptation. PMID- 22538522 TI - Drugs for rheumatoid arthritis. PMID- 22538523 TI - Apoptosis-modulating drugs for improved cancer therapy. AB - Resistance to cell death induction has been recognized as a hallmark of cancer. Increasing understanding of the underlying molecular events regulating different cell death mechanisms like apoptosis, endoplasmic reticulum stress, autophagy, necroptosis and others has opened new possibilities for targeted interference with these pathways. While conventional chemotherapeutic agents usually inhibit cell cycle progression, DNA replication or mitosis execution, novel agents like small molecule kinase inhibitors also target survival-related kinases and signaling pathways and contribute to overcome resistance to chemotherapy and apoptosis. Additionally, antibodies targeting cellular death receptors have been described to specifically target tumor cells only. This review briefly highlights the pathways involved in (apoptotic) cell death and summarizes the current state of development of specific modulators of cell death and how they can help to improve the tolerability of chemotherapy regimens and increase survival rates in patients with advanced cancer diseases. PMID- 22538524 TI - ddm1 plants are sensitive to methyl methane sulfonate and NaCl stresses and are deficient in DNA repair. AB - Plant response to stress includes changes in gene expression and chromatin structure. Our previous work showed that Arabidopsis thaliana Dicer-like (DCL) mutants were impaired in transgenerational response to stress that included an increase in recombination frequency, cytosine methylation and stress tolerance. It can be hypothesized that changes in chromatin structure are important for an efficient stress response. To test this hypothesis, we analyzed the stress response of ddm1, a mutant impaired in DDM1, a member of the SWI/SNF family of adenosine triphosphate-dependent chromatin remodeling genes. We exposed Arabidopsis thaliana ddm1 mutants to methyl methane sulfonate (MMS) and NaCl and found that these plants were more sensitive. At the same time, ddm1 plants were similar to wild-type plants in sensitivity to temperature and bleomycin stresses. Direct comparison to met1 plants, deficient in maintenance methyltransferase MET1, showed higher sensitivity of ddm1 plants to NaCl. The level of DNA strand breaks upon exposure to MMS increased in wild-type plants but decreased in ddm1 plants. DNA methylation analysis showed that heterozygous ddm1/DDM1 plants had lower methylation as compared to fourth generation of homozygous ddm1/ddm1 plants. Exposure to MMS resulted in a decrease in methylation in wild-type plants and an increase in ddm1 plants. Finally, in vitro DNA excision repair assay showed lower capacity for ddm1 mutant. Our results provided a new example of a link between genetic genome stability and epigenetic genome stability. KEY MESSAGE: We demonstrate that heterozygous ddm1/DDM1 plants are more sensitive to stress and have more severe changes in methylation than homozygous ddm1/ddm1 plants. PMID- 22538525 TI - Quantum dot enabled thermal imaging of optofluidic devices. AB - Quantum dot thermal imaging has been used to analyse the chromatic dependence of laser-induced thermal effects inside optofluidic devices with monolithically integrated near-infrared waveguides. We demonstrate how microchannel optical local heating plays an important role, which cannot be disregarded within the context of on-chip optical cell manipulation. We also report on the thermal imaging of locally illuminated microchannels when filled with nano-heating particles such as carbon nanotubes. PMID- 22538526 TI - Influence of age, gender and lifestyle in lymphocyte subsets: report from the Spanish Gait-2 Study. AB - INTRODUCTION: Flow cytometry analysis of lymphocyte subsets in peripheral blood is a common technique in diagnostic laboratories. Abnormal values have been identified in prevalent infections, autoimmune disorders and neoplastic diseases. Reference ranges for lymphocyte subsets of a healthy population from Spain are scarce. METHODS: The study was performed on 319 healthy subjects, aged 4-88 years, from 709 individuals enrolled in the GAIT-2 Project (Genetic Analysis of Idiopathic Thrombophilia). Health status, age, sex, fertility, BMI and lifestyle (physical activity, cigarette smoking and ethanol intake) were assessed using standardized criteria. The percentage of lymphocyte subsets was determined using flow cytometry (LymphogramTM). Percentages of CD3+, CD4+, CD8+, CD19+, CD3-CD56+, CD3+CD4-CD8- double-negative (DN) T cells, CD3+CD4+CD8+ double-positive T cells and the CD4+/CD8+ ratio were recorded for each case. RESULTS: Children had a significantly higher percentage of CD19+ and DN cells than adults. Women had a significantly higher percentage of CD3+ and CD4+ and a lower percentage of natural killer cells than men. Increases in BMI were inversely associated with the percentage of DN cells. Physical activity increased the percentage of lymphocytes and DN cells. Alcohol consumers had a lower percentage of CD19+ and DN cells, and a higher percentage of CD4+. CONCLUSION: This study provides reference ranges for lymphocyte subsets of healthy children and adults in a Mediterranean population (Spain) and determines the influence of lifestyle factors on these values. PMID- 22538527 TI - Supplementation of milled chia seeds increases plasma ALA and EPA in postmenopausal women. AB - Ten postmenopausal women (age 55.6 +/- 0.8 years, BMI 24.6 +/- 1.1 kg/m2) ingested 25 g/day milled chia seed during a 7-week period, with six plasma samples collected for measurement of alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA). Subjects operated as their own controls with overnight fasted blood samples taken at baseline (average of two samples), and then after 1, 2, 3, 5, and 7 weeks supplementation. Plasma ALA increased significantly after one week supplementation and was 138 % above baseline levels by the end of the study (overall time effect, P < 0.001). EPA increased 30 % above baseline (overall time effect, P = 0.019) and was correlated across time with ALA (r = 0.84, P = 0.02). No significant change in plasma DPA levels was measured (overall time effect, P = 0.067). Plasma DHA decreased slightly by the end of the study (overall time effect, P = 0.030) and was not correlated with change in ALA. In conclusion, ingestion of 25 g/day milled chia seeds for seven weeks by postmenopausal women resulted in significant increases in plasma ALA and EPA but not DPA and DHA. PMID- 22538528 TI - Combined use of multiple methodologies for the measurement of total antioxidant capacity in UK commercially available vegetable juices. AB - Substantial evidence exists to support the hypothesis that high fruit and vegetable consumption, rich in antioxidants, can reduce the incidence of several disease states. The aim of this study was to compare the results obtained by six spectrophotometric biochemical methods including the ferric reducing antioxidant power (FRAP), 2, 2-diphenyl-1-picryhydrazyl (DPPH*), 2,2-azinobis-3 ethylbenzothiazoline-6-sulfonic acid (ABTS*+), copper (II) reducing capacity (CUPRAC) and Cerium (IV) reducing antioxidant capacity (CERAC) assays as well as Folin-Ciocalteu method (FC) for the measurement of total antioxidant capacity (TAC) and total polyphenols (TP) in different commercially available vegetable juices. There was a significant positive correlation between the results obtained for FRAP, ABTS*+, CUPRAC, CERAC and FC (0.68 <= r <= 0.96, P < 0.01). DPPH* was only correlated with CERAC (r = 0.66, P < 0.01). Beetroot juice had the highest TAC and TP regardless of the method of analysis. PMID- 22538529 TI - Preformulation characterization of an aluminum salt-adjuvanted trivalent recombinant protein-based vaccine candidate against Streptococcus pneumoniae. AB - The preformulation of a trivalent recombinant protein-based vaccine candidate for protection against Streptococcus pneumoniae is described both in the presence and in the absence of aluminum salt adjuvants. The biophysical properties of the three protein-based antigens, fragments of pneumococcal surface adhesion A (PsaA), serine-threonine protein kinase (StkP), and protein required for cell wall separation of group B streptococcus (PcsB), were studied using several spectroscopic and light scattering techniques. An empirical phase diagram was constructed to assess the overall conformational stability of the three antigens as a function of pH and temperatures. A variety of excipients were screened on the basis of their ability to stabilize each antigen using intrinsic fluorescence spectroscopy and circular dichroism spectroscopy. Sorbitol, sucrose, and trehalose stabilized the three proteins in solution. The addition of manganese also showed a drastic increase in the thermal stability of SP1650 in solution. The adsorption and desorption processes of each of the antigens to aluminum salt adjuvants were evaluated, and the stability of the adsorbed proteins was then assessed using intrinsic fluorescence spectroscopy and Fourier transform infrared spectroscopy. All the three proteins showed good adsorption to Alhydrogel. PsaA was destabilized when adsorbed onto Alhydrogel(r) and adding sodium phosphate showed a stabilizing effect. PcsB was found to be stabilized when adsorbed to Alhydrogel(r), and no destabilizing or stabilizing effects were seen in the case of StkP. PMID- 22538530 TI - Contrast enhanced ultrasound (CEUS) and time intensity curve (TIC) analysis in compartment syndrome: first results. AB - OBJECTIVE: Purpose of this study was to monitor changes of microcirculation in acute compartment syndrome using contrast enhanced ultrasound (CEUS) and to assess the modified perfusion with a special quantification software. METHODS: 8 patients with trauma of the lower limb or the upper extremity were enrolled after acute compartment syndrome was diagnosed clinically and by intracompartmental pressure measurement. The qualitative analysis of the corresponding compartment was assessed using B-scan mode and CEUS simultaneously. CEUS was performed using a multifrequence probe (6-9 MHz, LOGIQ E9 GE) after a i.v. bolus injection of 2 * 2.4 ml contrast agent (SonoVue((r)), Bracco, Italy). Digital raw data were stored as cine loops up to 2 minutes. Retrospectively semiquantitative perfusion analysis was performed using time intensity curve analysis and the quantification software QONTRAST((r)). RESULTS: 6 out of 8 patients had to be operated due to clinical symptoms and to a pressure perfusion gradient lower than 30 mm Hg. 2 out of 8 were treated conservatively. In all patients haematomas were seen in B-scan mode. No necrosis could be detected. In the TIC analysis low levels of time to peak (20.0 +/- 12.1) and area under the curve (118.4 +/- 87.8) were observed in acute compartment syndrome. Similarly results have been obtained using the perfusions parameter PEAK (11.1 +/- 5.7), time to PEAK (14.7 +/- 9.7), regional blood volume (257.1 +/- 192.6), and regional blood flow (12.1 +/- 6.5) in QONTRAST((r)) perfusion software. CONCLUSION: CEUS may be capable of differing between acute compartment syndrome and imminent compartment syndrome. PMID- 22538531 TI - Simple, fast and reliable perfusion monitoring of microvascular flaps. AB - BACKGROUND: Free tissue transfer in head and neck reconstructions has a very high success rate, but thrombotic vessel occlusion is still a serious complication occurring in up to 10% of all cases. Thus, a simple, fast and reliable monitoring system for free flaps would be of advantage. OBJECTIVE: The aim of this study was to investigate whether free flap monitoring by measuring perfusion-dependent parameters is a suitable method for discovering vessel thrombosis in free flaps. METHODS: 10 patients requiring tissue reconstruction after tumour surgery or because of chronic wounds were included in this study. 10 microvascular flaps were harvested and transplanted. Perfusion was determined by measuring a fluorescent oxygen sensor foil covering the flap's skin surface by means of a USB handheld fluorescence microscope prototype. The sensor contained an oxygen reservoir which was consumed by the tissue corresponding to the perfusion status of the flap. Measurements were done before explantation, after successful anastomosis and 1 day after surgery. RESULTS: Clinically well-perfused grafts showed slope values between 0.07 and 0.27 (mean: 0.18 +/- 0.07), and clinically poorly perfused grafts showed slope values between 0.35 and 0.75 (mean: 0.52 +/- 0.19). In the present study, we used a threshold slope value of 0.3 for differentiating between well-perfused and poorly perfused flaps. CONCLUSION: Flap monitoring via oxygen imaging by means of fluorescent sensor foils appears to be a fast, non-invasive, cost-effective and thus suitable method for analyzing flap perfusion with the additional advantage of aiding decision making on flap revision. PMID- 22538532 TI - Influence of acetylsalicylic acid (Aspirin) on cutaneous microcirculation. AB - BACKGROUND: The protective effect of acetylsalicylic acid (aspirin) in primary and secondary prophylaxis of cardiovascular events is attributed to the inhibition of platelet cyclooxygenase (COX). However, a recent animal study found a vasodilating and blood pressure lowering effect of aspirin independent of COX, but mediated by inhibition of the RhoA/Rho kinase signaling pathway. METHOD: Prospective, randomized, double-blind, placebo-controlled cross-over study. In each instance 5 healthy volunteers received either aspirin 500 mg/d or placebo for 7 days. Capillary red blood cell velocity (vRBC) at rest and after postischemic hyperemia was determined on day 1 and 7 by means of nailfold capillary microscopy. RESULTS: In the aspirin group after 7 days a significant increase of vRBC was found at rest and during hyperemia. In the placebo group vRBC did not change. The finding was confirmed by the cross-over design of the study. CONCLUSION: Aspirin at a dosage of 500 mg/d has an impact on vasoregulation in the microcirculation. At present, the underlying mode of action in humans is unknown. PMID- 22538533 TI - Influence of different radiographic contrast media on the echinocyte formation of human erythrocytes. AB - Echinocyte formation is associated with a rigidification of the cells that may affect capillary perfusion and, consequently, the tissue oxygen supply. This study examines how many echinocytes appeared after the addition of radiographic contrast media (RCM) (Iodixanol320, Ioversol300, Iopamidol300, and Iomeprol400) compared to red blood cells in autologous plasma and in isotonic saline solution. Isotonic saline solution, Iodixanol, Ioversol, Iopamidol and Iomeprol in concentrations of 10 vol%, 20 vol%, and 40 vol% were added to the plasma of seven healthy subjects. Subsequently, the erythrocytes were resuspended in these plasma/RCM mixtures, incubated for 5 minutes and then examined under the microscope. The concentrations and the RCM in the mixture had a significant effect on the number of discocytes (factor concentration: p < 0.0001; factor RCM: p < 0.0001). The percentage of discocytes for all concentrations depended significantly on the RCM/plasma mixture (concentration * RCM: p < 0.002). Of all RCM/plasma mixtures used, the Iodixanol/plasma mixture showed the most similar discocyte fraction compared to red blood cells in the autologous plasma. Importantly, while Iodixanol differed from all other RCMs, the other RCMs did not differ from one another with respect to the discocyte fraction. PMID- 22538534 TI - Do radiographic contrast media (Iodixanol or Iomeprol) induce a perturbation of human arterial and/or venous endothial cells in vitro on extracellular matrix? AB - After intra-arterial administration of several radiographic contrast media (RCM) a disorder of the downstream microcirculation with regard to blood flow velocity in microvessels and to tissue oxygen partial pressure in the myocardium of the pig heart was described. Iodixanol did not induce such a microcirculatory disorder in the myocardium of the beating heart of pigs. Whether the morphological changes reported in venous endothelial cells after incubation in culture media supplemented with RCM in vitro coincide with a serious endothelial cell dysfunction is not known. In this study we wanted to get information on possible states of dysfunction or perturbation of venous and arterial ECs through the release of prostacyclin, which was shown to follow the perturbation of ECs. Functionally confluent venous endothelial cells on extracellular matrix secreted great amounts of prostacyclin in reaction to the RCMs indicating a clear perturbation of the ECs. This was not the case in arterial EC cultures. The prostacyclin release from arterial ECs exposed to Iodixanol was more than 10-fold higher than that from arterial ECs exposed to Iomeprol. This could be one of the important factors contributing to the undisturbed myocardial microcirculation after injection of Iodixanol despite a slight echinocyte formation. PMID- 22538535 TI - Physically crosslinked gelatins functionalized with tyrosine moieties do not induce angiogenesis or thrombus formation in the developing vasculature in the avian chorioallantoic membrane. AB - Gelatins functionalized with desaminotyrosine or desaminotyrosyl tyrosine form physically crosslinked polymer networks due to the interactions between the introduced aromatic moeties. In the swollen state, their mechanical properties can be tailored in a range similar to the elasticity of soft tissues. The aim of this study was to evaluate their potential as biomaterials by determining whether these materials - in comparison to plain gelatin - induce bleedings, thrombotic processes, or angiogenesis. These investigations were performed using the hen's egg chorioallantoic membrane (HETCAM) assay. These results indicate that the gelatin-based hydrogels did not possess angiogenic effects and also did not induce bleedings, thrombotic processes or vessel destruction (avascular zones). The biocompatibility of the materials in vitro motivates the exploration of their application as matrix in local drug-release systems with short half-life times (1 hour up to several days). PMID- 22538536 TI - Intraoperative high resolution linear contrast enhanced ultrasound (IOUS) for detection of microvascularization of malignant liver lesions before surgery or radiofrequeny ablation. AB - OBJECTIVE: The aim of this study was to evaluate the value of linear contrast enhanced intraoperative ultrasound (CE-IOUS) to improve detection of malign liver tumors lesions before surgery or radiofrequency ablation (RFA). MATERIALS AND METHODS: 50 patients were included for surgery of malignant liver tumors (mean age 61 years (19-80); male n = 35, female n = 15), suffering from HCC (n = 15), colorectal liver-metastasis (n = 28), CCC (n = 2) or other malign liver lesions (n = 5). Preoperative CE-CT (n = 38), CE-MRI (n = 23) or PET-CT (n = 8) confirmed hepatic tumor manifestation. Before undergoing surgery, intraoperative conventional (IOUS) as well as CE-IOUS were performed by one experienced examiner in all cases using multifrequency linear probes (6-9 MHz, 6-15 MHz; LOGIQ E9; GE Healthcare, Milwaukee, WI, USA). CE-IOUS was performed after bolus injection of 5 ml up to 15 ml SonoVue((r)) (Bracco Imaging SpA, Milan, Italy). Digitally stored images of CE-IOUS were compared with fundamental B-Scan and preoperative imaging (CE-CT, CE-MRI and PET-CET). RESULTS: In 28 of 50 patients (56%), additional lesions were found using CE-IOUS (mean tumor size 8 mm, range 4-12 mm). This resulted in a change of surgical strategy or the intraoperative application of RFA in 27 patients (54%). Modification of therapy due to additionally found liver lesions was statistically significant (p < 0.05). Comparing conventional IOUS and CE-IOUS, 14 additional lesions in 10 patients were seen by CE-IOUS. All lesions seen in B-scan could also be detected with CE-IOUS. SUMMARY: This is the first study using contrast-enhanced ultrasound with high resolution linear probes for intraoperative detection of malignant liver lesions. Compared to preoperative imaging and also conventional IOUS more than 50% additional lesions were found leading to therapeutic consequences of patients. A recently started prospective study has to show whether these changes in the surgical or interventional therapy will influence morbidity, mortality and especially the recurrence rate. PMID- 22538537 TI - Multimodality imaging using ultrasound image fusion in renal lesions. AB - OBJECTIVES: To assess the benefit of ultrasound (US) image fusion in the identifiability and assessment of the dignity of renal lesions. MATERIALS AND METHODS: 25 patients with 29 renal lesions were investigated using standard US and CEUS (contrast enhanced US) with image fusion (CT or MRI). Identifiability and assessment of dignity was evaluated using cross-sectional images and US separately as well as using both US-techniques with additional image fusion. The respective modality was rated by two experienced radiologists (10 and 5 years of experience) using a (subjective) 5 point rank scale (1 = best). RESULTS: Using CEUS, image fusion resulted in improved identifiability (score: 1.1 +/- 0.4) and improved assessment of dignity (score 1.0 +/- 0) of renal lesions than using cross sectional images (score 1.8 +/- 1.2 and 3.8 +/- 1.2 respectively) separately. CONCLUSION: Image fusion improved the identifiability and the assessment of the dignity of renal lesions compared to using the respective modalities separately. PMID- 22538538 TI - Elastography: a new diagnostic tool for evaluation of obstructive diseases of the salivary glands; primary results. AB - PURPOSE: Obstructive diseases of the salivary glands, a common problem in the ENT field, are often based on sialolithiasis but can also result from rare circumstances. Due to recent technical innovations, there has been significant development in the treatment of obstructive diseases of the salivary glands such that minimally invasive glandula-sustaining therapy has now become standard. However, there is still no effective technique to assess and monitor the recovery of the parenchyma of the gland. As a result, recurrent infections often lead to modification of the gland in which fibrosis increases and the gland becomes coarse. After treatment, the parenchyma of the gland is able to recover. Thus, to more effectively monitor and promote the success of treatment, we have developed a new method to measure and quantify the stiffness of the glandula tissue using elastography (Virtual Touch TM Application) to assess the degree of recovery. MATERIALS AND METHODS: First, we collected elastography data from 30 healthy volunteers as part of a conventional ultrasound (Siemens, ACUSON, S 2000, Germany) with a multi-frequency linear 9 MHz transducer in order to determine if normal findings are sufficiently quantifiable. We subsequently measured patients with sialolithiasis of the submandibular gland. RESULTS: For healthy volunteers, the average value was 1.96 +/- 0.48 m/s for the glandula submandibularis and 2.66+/- 0.89 for the parotid gland, a statistically significant difference. For patients with sialolithiasis of the submandibular gland, the average value was 2.98 +/- 0.4 m/s, a highly significant difference in comparison to the healthy side of the patient. CONCLUSION: Elastography is an easy to use diagnostic method that shows promise to become a valuable tool for the assessment of disease severity as it provides the possibility to quantify the level of treatment benefit for the patient. PMID- 22538539 TI - Viability, proliferation and adhesion of smooth muscle cells and human umbilical vein endothelial cells on electrospun polymer scaffolds. AB - A major clinical problem of high relevance in the cardiovascular field is late stent thrombosis after implantation of drug eluting stents (DES). Clinical widely used DES currently utilize durable polymer coatings, which can induce persistent arterial wall inflammation and delayed vascular healing resulting in an impaired endothelialization. In this study we explored the interaction of smooth muscle cells (SMC) and human umbilical vein endothelial cells (HUVEC) with electrospun scaffolds prepared from resorbable polyetheresterurethane (PDC) and poly(p dioxanone) (PPDO), as well as polyetherimide (PEI), which can be surface modified, in comparison to poly(vinylidene fluoride-co-hexafluoropropene) (PVDF) as reference material, which is established as coating material of DES in clinical applications. Our results show that adhesion could be improved for HUVEC on PDC, PPDO and PEI compared to PVDF, whereas almost no SMC attached to the scaffolds indicating a cell-specific response of HUVEC towards the different fibrous structures. Proliferation and apoptosis results revealed that PPDO and PEI have no significant negative influence on vitality and cell cycle behaviour compared to PVDF. Hence, they represent promising candidates for temporary blood vessel support that induce HUVEC attachment and prevent SMC proliferation. PMID- 22538540 TI - Alpha smooth muscle actin in the cycling ovary - an immunohistochemical study. AB - In the ovary with its cyclically developing and regressing functional bodies and the associated intense neovascularisation and remodelling, alpha-smooth muscle actin (SMA) immunolocalisation has been frequently used as a marker to establish vessel hierarchy, in angiogenesis studies, or in studies characterising ovarian neoplasms in various species. The present study aims at detection of alpha-SMA immunolocalisation within all structural components of the cycling bovine ovary in order to complement the hitherto available data. 27 ovaries, mainly of dairy cows ranging from 23 to 118 months of age and displaying all major stages of follicle and corpora lutea development, were collected at the abattoir and subjected to routine HE and trichrome staining as well as alpha-SMA immunohistochemistry. For this purpose, the specimens were pooled to form groups of the respective stage of corpus luteum development. The ovarian stroma displayed a notable alpha-SMA-reactivity, particularly surrounding the functional bodies. The study revealed specialised vascular modifications such as multi directionally arranged vascular smooth muscle layers, vascular sphincters and distinct epitheloid modifications of the media in ovarian arteries. Alpha-SMA reactivity of the microcirculation within corpora lutea of various stages allowed inferences on respective angiogenic properties. The findings were discussed focussing on functional interpretations. PMID- 22538541 TI - Immuno-compatibility of soft hydrophobic poly (n-butyl acrylate) networks with elastic moduli for regeneration of functional tissues. AB - The need for engineered devices to treat cardiovascular diseases is increasing due to an aging population and a changing lifestyle. Soft poly(n-butyl acrylate) (cPnBA) networks were recently described as polymer networks with adjustable mechanical properties and suggested as soft substrates for cells, which could potentially be used for cardiovascular implants. Vascular prostheses designed to be implanted in arteries should have an elasticity similar to blood vessels (elastic modulus at body temperature between 100 and 1200 kPa). Therefore, cPnBA networks with E-moduli of 250 kPa (cPnBA0250) and 1100 kPa (cPnBA1100) were developed. Recently, it was shown that both materials were non-cytotoxic for murin fibroblasts, human primary endothelial cells and human monocytes. However, before such newly developed polymers can be used in vivo, it has to be assured that the sterilized materials have a very low endotoxin load to avoid an unspecific activation of the immune system, which otherwise might cause local or systemic inflammatory responses and could lead to severe pathologies. In this study we investigated the immuno-compatibility of sterilized cPnBA0250 and cPnBA1100 with the help of an immuno-competent macrophage cell line as well as with whole human blood. PMID- 22538542 TI - Shear stress patterns affect the secreted chemokine profile in endothelial cells. AB - BACKGROUND: Atherosclerotic plaques are initiated by pro-inflammatory endothelial activation at arterial regions subjected to non-uniform shear stress. We applied the in vitro flow-through cell culture slides to investigate whether different patterns of shear stress affect the secreted cytokine and chemokine profile in endothelial cells. METHODS: Human umbilical vein endothelial cells (ECs) were exposed to 24 h of flow in straight or bifurcating flow-through slides, in some experiments followed by 6 h stimulation with 2.5 ng/mL TNF-alpha. IL-1beta, IL-6, IL-8, IL-12p70, MIP-1alpha, MCP-1 and sICAM-1 were measured in conditioned medium samples by flow cytometry using antibodies conjugated with fluorescent beads. RESULTS: The release of IL-1beta, IL-12p70 and MIP-1alpha from endothelial cells exposed to shear stress was below detectable levels. Strongly increased level of sICAM and significantly increased IL-8 concentration were detected in conditioned medium from endothelial cells exposed to flow in bifurcating slides as compared with cells grown under laminar flow in straight channels. The release of IL-6 and MCP-1 was not significantly induced in bifurcating slides. Treatment with TNF alpha for 6 h induced 2-3 fold increase in secreted chemokines and cytokines. In particular, significantly increased MCP-1 and increased IL-8 levels were released from endothelial cells grown in bifurcating slides. This release was partly prevented in cells grown in straight channels, i.e. under exposure to laminar flow only. CONCLUSIONS: Although the endothelial monolayer areas exposed to non uniform shear stress are relatively small, the activation of cells in these regions is strong enough to produce a detectable change in cytokine and chemokine profile, which represents the earliest step in atherogenic endothelial dysfunction. PMID- 22538546 TI - Comparison of laser diffraction and image analysis for measurement of Streptomyces coelicolor cell clumps and pellets. AB - Morphology is important in industrial processes involving filamentous organisms because it affects the mixing and mass transfer and can be linked to productivity. Image analysis provides detailed information about the morphology but, in practice, it is often laborious including both collection of high quality images and image processing. Laser diffraction is rapid and fully automatic and provides a volume-weighted distribution of the particle sizes. However, it is based on a number of assumptions that do not always apply to samples. We have evaluated laser diffraction to measure cell clumps and pellets of Streptomyces coelicolor compare to image analysis. Samples, taken five times during fed-batch cultivation, were analyzed by image analysis and laser diffraction. The volume weighted size distribution was calculated for each sample. Laser diffraction and image analysis yielded similar size distributions, i.e. unimodal or bimodal distributions. Both techniques produced similar estimations of the population means, whereas the estimates of the standard deviations were generally higher using laser diffraction compared to image analysis. Therefore, laser diffraction measurements are high quality and the technique may be useful when rapid measurements of filamentous cell clumps and pellets are required. PMID- 22538545 TI - Mandibular fracture scoring system: for prediction of complications. AB - INTRODUCTION: Mandibular fractures are one of the most commonly encountered injuries in trauma clinics. Although several widely accepted classification systems exist, these are mostly region specific, differ in the classification criteria used, and are sometimes only correlated with specific treatment modalities, thereby making it impossible to uniformly and comprehensively document facial fracture patterns. In this study, we developed a modified scoring system for mandibular fractures and analyzed the relationship between scoring of fractures that were treated and the incidence of complications after surgical treatment. MATERIALS AND METHODS: To evaluate the suitability of the proposed scoring system, a prospective study on a series of 116 patients was performed. All the fractures were classified using the proposed scoring system. The scoring was based on clinical and radiological evaluation of each fracture. Patients were followed up postoperatively for presence of complications. RESULTS: A good correlation between the proposed scoring system and the incidence of complications was detected. DISCUSSION: This scoring system for mandibular fractures facilitates an objective and standardized assessment of the degree of severity of a fracture, thereby allowing for systematic evaluation of facial fracture outcomes, including assessment of complications. However, it is our understanding that a multicenter study should be performed before the effectiveness of the proposed classification can be clearly stated. PMID- 22538547 TI - Purification and characterization of an organic solvent-tolerant alkaline cellulase from a halophilic isolate of Thalassobacillus. AB - An extracellular cellulase from Thalassobacillus sp. LY18 was purified 4.5-fold with a recovery of 21 % and a specific activity of 52.4 U mg(-1) protein. Its molecular mass was 61 kDa estimated by SDS-PAGE. It was an endoglucanase for soluble cellulose with optimal activity was at 60 degrees C and pH 8 with 10 % (w/v) NaCl. It was stable from 30 to 80 degrees C and from pH 7 to 11 with NaCl from 5 to 17.5 % (w/v). EDTA inhibited activity indicating it was a metalloenzyme. Inhibition by diethyl pyrocarbonate and beta-mercaptoethanol suggested that histidine residues and disulfide bonds may play important roles in its catalytic function. The cellulase was highly active in non-ionic surfactants and was stable in water-insoluble organic solvents with log P (ow) >= 2.13. PMID- 22538548 TI - Gantrez AN nanoparticles for ocular delivery of memantine: in vitro release evaluation in albino rabbits. AB - AIM: To prepare and evaluate the in vitro release of memantine-loaded poly(anhydride) (Gantrez(r)) nanoparticles (NPs). The clinical safety and retinal toxicity caused by unloaded NPs after sub-Tenon and intravitreal ocular injections were also evaluated. METHODS: Preparation and characterization of this type of NP as well as the in vitro release study are described. Twenty-three healthy New Zealand rabbits were used for clinical and histological assessment after sub-Tenon and intravitreal ocular injections of unloaded NPs. RESULTS: The amount of drug associated with NPs was 55 ug of memantine/mg of NP. The release profile of memantine from this type of NPs was characterized by an initial burst effect, followed by continuous release of the drug for at least 15 days. No relevant complications were found during the clinical follow-up. The histological evaluation suggested that Gantrez NPs are well tolerated after sub-Tenon ocular injection and that signs of inflammation during the first days after intravitreal ocular injections can be considered a normal reaction of the eye's defence mechanism. PMID- 22538549 TI - Gross efficiency and energy expenditure in kayak ergometer exercise. AB - We purposed to study energy expenditure, power output and gross efficiency during kayak ergometer exercise in 12 elite sprint kayakers. 6 males (age 24.2+/-4.8 years, height 180.4+/-4.8 cm, body mass 79.7+/-8.5 kg) and 6 females (age 24.3+/ 4.5 years, height 164.5+/-3.9 cm, body mass 65.4+/-3.5 kg), performed an incremental intermittent protocol on kayak ergometer with VO2 and blood lactate concentration assessment, a non-linear increase between power output and energy expenditure being observed. Paddling power output, energy expenditure and gross efficiency corresponding to VO2max averaged 199.92+/-50.41 W, 75.27+/-6.30 ml.kg 1.min - 1, and 10.10+/-1.08%. Male kayakers presented higher VO2max, power output and gross efficiency at the VO2max, and lower heart rate and maximal lactate concentration than females, but no differences were found between genders regarding energy expenditure at VO2max. Aerobic and anaerobic components of energy expenditure evidenced a significant contribution of anaerobic energy sources in sprint kayak performance. Results also suggested the dependence of the gross efficiency on the changes in the amount of the aerobic and anaerobic contributions, at heavy and severe intensities. The inter-individual variance of the relationship between energy expenditure and the corresponding paddling power output revealed a relevant tracking for females (FDgamma=0.73+/-0.06), conversely to the male group (FDgamma=0.27+/-0.08), supporting that some male kayakers are more skilled in some paddling intensities than others. PMID- 22538550 TI - The relationship between three well-characterized polymorphisms of the angiotensin converting enzyme gene and lung cancer risk: a case-control study and a meta-analysis. AB - BACKGROUND AND OBJECTIVE: The gene encoding angiotensin converting enzyme (ACE) is a promising candidate for lung cancer. We aimed to assess three well characterized polymorphisms of the ACE gene (A-240T, I/D, A2350G) and lung cancer in Chinese people, and complete a meta-analysis of the association of I/D polymorphism with lung cancer. METHODS AND RESULTS: In our case-control study, a total of 684 patients with lung cancer and 602 age-matched controls were recruited. Genotyping was performed using polymerase chain reaction (PCR) and ligase detection reactions (LDR) techniques. Single-locus analysis indicated that carriers of the A-240T allele had a significantly increased risk for lung cancer under additive (odds ratio (OR)=1.2; 95% confidence interval (CI): 1.02-1.42; P=0.027) and recessive (OR=1.8; 95% CI: 1.24-2.63; P=0.002) models, and that DD genotype carriers were 1.97 times more likely to develop lung cancer (95% CI: 1.25-3.11; P=0.004) compared with those with the I allele under the recessive model. However, no significance was observed in further haplotype analysis (P>0.05). In a meta-analysis of ACE gene insertion-deletion (I/D) polymorphism from six studies with 1183 lung cancer patients and 1065 controls, we failed to detect any significant association (overall OR=1.09; 95% CI: 0.84-1.41). A low probability of publication bias was observed. CONCLUSIONS: Our results suggest that ACE gene A-240T polymorphism might be a genetic marker for the development of lung cancer in Chinese people. PMID- 22538551 TI - Normal sperm in a 2;2 homologous male translocation carrier. AB - PURPOSE: Carriers of balanced structural chromosomal abnormalities are phenotypically normal but are at high risk of infertility. Translocations usually occur between two non-homologous chromosomes. When occur between homologous chromosomes, an extremely rare event, generally involve acrocentric chromosomes. We present an infertile male referred for genetic analysis with a pure balanced homologous 2;2 translocation and normal sperm in the ejaculate. METHODS: Conventional cytogenetic and fluorescence in situ hybridization (FISH) were used in karyotype and sperm analysis, respectively. RESULTS: Male's karyotype revealed a pure balanced translocation involving homologous chromosomes 2: 46,XY,t(2;2)(p23;q21.2). Sperm analysis by FISH revealed the presence of 15.8 % of normal and 84.2 % of abnormal spermatozoa for chromosome 2. CONCLUSIONS: This is the first report of confined gonadal mosaicism in a pure homologous non acrocentric chromosome translocation carrier. Preimplantation genetic diagnosis for chromosome 2 should be offered as a reproductive option. PMID- 22538552 TI - Phthalates and bisphenol do not accumulate in human follicular fluid. AB - OBJECTIVE: To determine if phthalates and bisphenol A accumulate in human follicular fluid after brief exposure to medical plastics during an IVF cycle STUDY DESIGN: Prospective collection of follicular fluid from five infertile women undergoing oocyte retrieval at a University IVF laboratory and analysis of Phthalate & Bisphenol A levels. RESULTS: All phthalate levels were detected at levels less than 15 ng/mL and Bisphenol A levels were undetectable in all five samples. The concentrations of phthalates are 200-1000 fold less than the minimum levels reported to cause reproductive toxicity in vitro to cumulus-oocyte complexes of laboratory animals. CONCLUSIONS: In reproductive age women undergoing infertility treatments there is little transfer or accumulation of phthalates, phthalate metabolites or bisphenol A into the microenvironment of the human preovulatory oocyte and the levels are not clinically significant. Further investigation of phthalate and bisphenol A accumulation in vivo in human follicular fluid may not be productive. PMID- 22538553 TI - Reoperation for pelvic organ prolapse within 10 years of primary surgery for prolapse. AB - INTRODUCTION AND HYPOTHESIS: A presumed high failure rate of conventional procedures for prolapse has been part of the rationale for new surgical approaches. The aim of the present retrospective cohort study was to estimate the reoperation rate for prolapse within 10 years of primary surgery for prolapse. METHODS: We identified all patients who underwent primary surgery for prolapse at four large regional centers in Austria in 1997 and 1998. Hospital databases were searched to determine whether patients had been reoperated for prolapse through 2008. RESULTS: A total of 456 patients underwent a primary operation for prolapse in 1997 and 1998. The most common primary operation was vaginal hysterectomy with colporrhaphy (89 %). We identified 13 reoperations for prolapse, for a 10-year reoperation rate of (at least) 2.9 %. The median interval between primary and secondary surgery was 5.5 years (range 1.5-10 years). CONCLUSION: The reoperation rate for prolapse after primary vaginal hysterectomy and colporrhaphy appears to be modest in this series of patients. PMID- 22538554 TI - Porcine urinary bladder matrix-polypropylene mesh: a novel scaffold material reduces immunorejection in rat pelvic surgery. AB - INTRODUCTION AND HYPOTHESIS: The present study set out to modify polypropylene vaginal surgical material using porcine urinary bladder matrix (UBM) in order to improve biocompatibility. The aim was to develop a compound scaffold that induced less vaginal erosion and to evaluate host immunoreactivity to this material in vivo. METHODS: Forty-eight Sprague-Dawley rats were randomly divided into four equal groups. One group underwent a sham operation, and the other groups underwent vaginal implantation with different materials: UBM (U); UBM + polypropylene (UP); or polypropylene (P). The host tissue response was determined by macro-observation, and by histological and immunohistochemical methods at 7, 14, 21, or 28 days after surgery. RESULTS: The inflammation reaction was strongest throughout the entire observation time in Group P, but was weaker and had a tendency to decrease with time in Groups U and UP. The presence of the UBM material in the compound scaffold allowed the polypropylene to fuse with newly proliferating surrounding tissue and resulted in less rejection of the material by the host, as indicated by the reduced appearance of CD4-, and CD8-positive cells. CONCLUSIONS: Porcine UBM allowed mechanical isolation of polypropylene, and also reduced the immune reaction to polypropylene. This study suggests that the UBM + polypropylene compound scaffold may be a promising material for clinical use in pelvic reconstruction surgery. PMID- 22538555 TI - Significance of Virchow-Robin spaces in patients newly diagnosed with multiple sclerosis: a case-control study in an Arab population. AB - OBJECTIVE: To assess the frequency and extent of dilatation of Virchow-Robin (VR) spaces at three levels of the brain in patients of Arab ethnicity in Kuwait recently diagnosed with multiple sclerosis (MS) and compare the results with age- and gender-matched controls. METHODS: The magnetic resonance imaging (MRI) scans performed within 3 months of the clinical diagnosis of 80 patients recently diagnosed with active MS were compared to those of 80 age- and gender-matched controls with headache but without any neurological deficits for the frequency and size of VR spaces. MRI was done with noncontrast axial and coronal T(1)W FSE, axial T(2)W FSE, axial T(2)W FLAIR and sagittal FLAIR sequences followed by postcontrast axial and coronal T(1)W sequences. The frequency of VR spaces in MS patients and controls at midbrain, lenticulostriate vessels and supraventricular levels was analyzed using a two-tailed McNemar test. RESULTS: There was no difference in the frequency of VR spaces at the levels of the midbrain, lenticulostriate vessels and supraventricular white matter between MS patients and controls. In the supraventricular region, however, there were 91 dilated VR spaces in 26 (32%) of the MS patients while in the control group, there were 8 dilated VR spaces in 6 (7.5%) patients and the difference was statistically significant (p < 0.0001). CONCLUSION: The data showed that dilated VR spaces in the supraventricular region could potentially be used as a marker for MS and as a prognostic tool. However, further studies with a larger population are needed to further evaluate and confirm this observation. PMID- 22538557 TI - Innovation in cancer imaging. AB - Cancer is rapidly becoming the worldwide leading cause of premature death. Iconographic techniques have traditionally provided information on tumor anatomy. The recent introduction of functional and molecular imaging techniques allows probing tumor physiology and biology in addition to mere anatomical description. In addition to the research implications, these novel imaging techniques offer early response assessment and target visualization which, in the era of personalized medicine, may offer significant advances in cancer therapy. Here, we provide an overview of the most important developments in cancer imaging, with a focus on the clinical applications. PMID- 22538556 TI - Tongue thickness relates to nutritional status in the elderly. AB - Many elderly people under long-term care suffer from malnutrition caused by dysphagia, frequently leading to sarcopenia. Our hypothesis is that sarcopenia may compromise oral function, resulting in dysphagia. The objectives of this study were to evaluate sarcopenia of the lingual muscles by measuring the tongue thickness, and elucidate its relationship with nutritional status. We examined 104 elderly subjects (mean age = 80.3 +/- 7.9 years). Anthropometric data, such as triceps skinfold thickness and midarm muscle area (AMA), were obtained. The tongue thickness of the central part was determined using ultrasonography. Measurement was performed twice and the mean value was obtained. The relationship between tongue thickness and nutritional status was analyzed by Pearson's correlation coefficient and Spearman's rank correlation coefficient. AMA and age were identified by multiple-regression analysis as factors influencing tongue thickness. The results of this study suggest that malnutrition may induce sarcopenia not only in the skeletal muscles but also in the tongue. PMID- 22538558 TI - Bereavement and anxiety. AB - Bereavement, one of life's most difficult experiences, usually triggers acute grief with yearning and longing for the deceased person that is often intense and preoccupying, along with frequent thoughts and memories of the person who died and relatively little interest in anything unrelated to the deceased loved one. Anxiety is a very common feature of grief that is often neglected. Anxiety is a natural response of the attachment system to separation from a loved one, seen in adults as well as children. Confrontation with one's own death is also a natural trigger of anxiety, though we usually protect ourselves from mortality salience using terror management strategies related to cultural values and self-esteem. In addition, loss of a loved one can trigger the onset of a DSM-IV anxiety disorder that, when present, can derail the mourning process and prolong acute grief. Bereavement-related anxiety disorders need to be recognized and treated. PMID- 22538559 TI - A highly efficient one-pot reaction of 2-(gem-dibromovinyl)phenols(thiophenols) with K4Fe(CN)6 to 2-cyanobenzofurans(thiophenes). AB - 2-Cyanobenzofurans and 2-cyanobenzothiophenes were prepared through an efficient one-pot Ullmann-reaction/cyanation reaction. In the presence of CuI/Na(2)CO(3) Pd(OAc)(2)/PPh(3) in DMF, the reaction of 2-(gem-dibromovinyl)phenols and 2-(gem dibromovinyl)thiophenols with K(4)Fe(CN)(6), as non-toxic and user-friendly cyanating reagent, proceeded smoothly to generate the corresponding 2 cyanobenzofurans and 2-cyanobenzothiophenes in good yields. PMID- 22538560 TI - Chase the dragon. PMID- 22538561 TI - For better or worse. PMID- 22538562 TI - Suckers for success. PMID- 22538563 TI - Commercial space flight is a game-changer. PMID- 22538575 TI - Europe loses sight of Earth. PMID- 22538576 TI - A bloody boon for conservation. PMID- 22538577 TI - Space-station rendezvous set to spur research push. PMID- 22538578 TI - RNA studies under fire. PMID- 22538579 TI - Ancient asteroids kept on coming. PMID- 22538580 TI - Mexico sets climate targets. PMID- 22538582 TI - Controversial research: Good science bad science. PMID- 22538583 TI - Superstars of botany: Rare specimens. PMID- 22538584 TI - Research tools: A recipe for disaster. PMID- 22538585 TI - Research tools: Understand how it works. PMID- 22538586 TI - Global issues: Make social sciences relevant. PMID- 22538596 TI - Conservation: Reaping the benefits of no-tillage farming. PMID- 22538597 TI - Molecular biology: Protect the DNA of museum specimens. PMID- 22538598 TI - Traditional Chinese medicine: China's bear farms prompt public outcry. PMID- 22538599 TI - Biobanks: Validate gene findings before telling donors. PMID- 22538600 TI - Indian science: Enhance visibility of India's academies. PMID- 22538601 TI - Forum: Immunology: Allergy challenged. PMID- 22538602 TI - Developmental biology: Heart under construction. PMID- 22538603 TI - Quantum physics: Simulating magnetism. PMID- 22538604 TI - Astrophysics: Stars throw their weight in old galaxies. PMID- 22538605 TI - Protein engineering: Tighter ties that bind. PMID- 22538607 TI - Allergic host defences. AB - Allergies are generally thought to be a detrimental outcome of a mistargeted immune response that evolved to provide immunity to macroparasites. Here we present arguments to suggest that allergic immunity has an important role in host defence against noxious environmental substances, including venoms, haematophagous fluids, environmental xenobiotics and irritants. We argue that appropriately targeted allergic reactions are beneficial, although they can become detrimental when excessive. Furthermore, we suggest that allergic hypersensitivity evolved to elicit anticipatory responses and to promote avoidance of suboptimal environments. PMID- 22538608 TI - Multiple dynamic representations in the motor cortex during sensorimotor learning. AB - The mechanisms linking sensation and action during learning are poorly understood. Layer 2/3 neurons in the motor cortex might participate in sensorimotor integration and learning; they receive input from sensory cortex and excite deep layer neurons, which control movement. Here we imaged activity in the same set of layer 2/3 neurons in the motor cortex over weeks, while mice learned to detect objects with their whiskers and report detection with licking. Spatially intermingled neurons represented sensory (touch) and motor behaviours (whisker movements and licking). With learning, the population-level representation of task-related licking strengthened. In trained mice, population level representations were redundant and stable, despite dynamism of single neuron representations. The activity of a subpopulation of neurons was consistent with touch driving licking behaviour. Our results suggest that ensembles of motor cortex neurons couple sensory input to multiple, related motor programs during learning. PMID- 22538609 TI - Clonally dominant cardiomyocytes direct heart morphogenesis. AB - As vertebrate embryos develop to adulthood, their organs undergo marked changes in size and tissue architecture. The heart acquires muscle mass and matures structurally to fulfil increasing circulatory needs, a process that is incompletely understood. Here we used multicolour clonal analysis to define the contributions of individual cardiomyocytes as the zebrafish heart undergoes morphogenesis from a primitive embryonic structure into its complex adult form. We find that the single-cardiomyocyte-thick wall of the juvenile ventricle forms by lateral expansion of several dozen cardiomyocytes into muscle patches of variable sizes and shapes. As juvenile zebrafish mature into adults, this structure becomes fully enveloped by a new lineage of cortical muscle. Adult cortical muscle originates from a small number of cardiomyocytes--an average of approximately eight per animal--that display clonal dominance reminiscent of stem cell populations. Cortical cardiomyocytes initially emerge from internal myofibres that in rare events breach the juvenile ventricular wall, and then expand over the surface. Our results illuminate the dynamic proliferative behaviours that generate adult cardiac structure, revealing clonal dominance as a key mechanism that shapes a vertebrate organ. PMID- 22538610 TI - Systematic variation of the stellar initial mass function in early-type galaxies. AB - Much of our knowledge of galaxies comes from analysing the radiation emitted by their stars, which depends on the present number of each type of star in the galaxy. The present number depends on the stellar initial mass function (IMF), which describes the distribution of stellar masses when the population formed, and knowledge of it is critical to almost every aspect of galaxy evolution. More than 50 years after the first IMF determination, no consensus has emerged on whether it is universal among different types of galaxies. Previous studies indicated that the IMF and the dark matter fraction in galaxy centres cannot both be universal, but they could not convincingly discriminate between the two possibilities. Only recently were indications found that massive elliptical galaxies may not have the same IMF as the Milky Way. Here we report a study of the two-dimensional stellar kinematics for the large representative ATLAS(3D) sample of nearby early-type galaxies spanning two orders of magnitude in stellar mass, using detailed dynamical models. We find a strong systematic variation in IMF in early-type galaxies as a function of their stellar mass-to-light ratios, producing differences of a factor of up to three in galactic stellar mass. This implies that a galaxy's IMF depends intimately on the galaxy's formation history. PMID- 22538611 TI - Engineered two-dimensional Ising interactions in a trapped-ion quantum simulator with hundreds of spins. AB - The presence of long-range quantum spin correlations underlies a variety of physical phenomena in condensed-matter systems, potentially including high temperature superconductivity. However, many properties of exotic, strongly correlated spin systems, such as spin liquids, have proved difficult to study, in part because calculations involving N-body entanglement become intractable for as few as N ~ 30 particles. Feynman predicted that a quantum simulator--a special purpose 'analogue' processor built using quantum bits (qubits)--would be inherently suited to solving such problems. In the context of quantum magnetism, a number of experiments have demonstrated the feasibility of this approach, but simulations allowing controlled, tunable interactions between spins localized on two- or three-dimensional lattices of more than a few tens of qubits have yet to be demonstrated, in part because of the technical challenge of realizing large scale qubit arrays. Here we demonstrate a variable-range Ising-type spin-spin interaction, J(i,j), on a naturally occurring, two-dimensional triangular crystal lattice of hundreds of spin-half particles (beryllium ions stored in a Penning trap). This is a computationally relevant scale more than an order of magnitude larger than previous experiments. We show that a spin-dependent optical dipole force can produce an antiferromagnetic interaction J(i,j) proportional variant d( a)(i,j), where 0 <= a <= 3 and d(i,j) is the distance between spin pairs. These power laws correspond physically to infinite-range (a = 0), Coulomb-like (a = 1), monopole-dipole (a = 2) and dipole-dipole (a = 3) couplings. Experimentally, we demonstrate excellent agreement with a theory for 0.05 ? a ? 1.4. This demonstration, coupled with the high spin count, excellent quantum control and low technical complexity of the Penning trap, brings within reach the simulation of otherwise computationally intractable problems in quantum magnetism. PMID- 22538612 TI - Thermal and electrical transport across a magnetic quantum critical point. AB - A quantum critical point (QCP) arises when a continuous transition between competing phases occurs at zero temperature. Collective excitations at magnetic QCPs give rise to metallic properties that strongly deviate from the expectations of Landau's Fermi-liquid description, which is the standard theory of electron correlations in metals. Central to this theory is the notion of quasiparticles, electronic excitations that possess the quantum numbers of the non-interacting electrons. Here we report measurements of thermal and electrical transport across the field-induced magnetic QCP in the heavy-fermion compound YbRh(2)Si(2) (refs 2, 3). We show that the ratio of the thermal to electrical conductivities at the zero-temperature limit obeys the Wiedemann-Franz law for magnetic fields above the critical field at which the QCP is attained. This is also expected for magnetic fields below the critical field, where weak antiferromagnetic order and a Fermi-liquid phase form below 0.07 K (at zero field). At the critical field, however, the low-temperature electrical conductivity exceeds the thermal conductivity by about 10 per cent, suggestive of a non-Fermi-liquid ground state. This apparent violation of the Wiedemann-Franz law provides evidence for an unconventional type of QCP at which the fundamental concept of Landau quasiparticles no longer holds. These results imply that Landau quasiparticles break up, and that the origin of this disintegration is inelastic scattering associated with electronic quantum critical fluctuations--these insights could be relevant to understanding other deviations from Fermi-liquid behaviour frequently observed in various classes of correlated materials. PMID- 22538613 TI - Deposition of 1.88-billion-year-old iron formations as a consequence of rapid crustal growth. AB - Iron formations are chemical sedimentary rocks comprising layers of iron-rich and silica-rich minerals whose deposition requires anoxic and iron-rich (ferruginous) sea water. Their demise after the rise in atmospheric oxygen by 2.32 billion years (Gyr) ago has been attributed to the removal of dissolved iron through progressive oxidation or sulphidation of the deep ocean. Therefore, a sudden return of voluminous iron formations nearly 500 million years later poses an apparent conundrum. Most late Palaeoproterozoic iron formations are about 1.88 Gyr old and occur in the Superior region of North America. Major iron formations are also preserved in Australia, but these were apparently deposited after the transition to a sulphidic ocean at 1.84 Gyr ago that should have terminated iron formation deposition, implying that they reflect local marine conditions. Here we date zircons in tuff layers to show that iron formations in the Frere Formation of Western Australia are about 1.88 Gyr old, indicating that the deposition of iron formations from two disparate cratons was coeval and probably reflects global ocean chemistry. The sudden reappearance of major iron formations at 1.88 Gyr ago--contemporaneous with peaks in global mafic-ultramafic magmatism, juvenile continental and oceanic crust formation, mantle depletion and volcanogenic massive sulphide formation--suggests deposition of iron formations as a consequence of major mantle activity and rapid crustal growth. Our findings support the idea that enhanced submarine volcanism and hydrothermal activity linked to a peak in mantle melting released large volumes of ferrous iron and other reductants that overwhelmed the sulphate and oxygen reservoirs of the ocean, decoupling atmospheric and seawater redox states, and causing the return of widespread ferruginous conditions. Iron formations formed on clastic-starved coastal shelves where dissolved iron upwelled and mixed with oxygenated surface water. The disappearance of iron formations after this event may reflect waning mafic-ultramafic magmatism and a diminished flux of hydrothermal iron relative to seawater oxidants. PMID- 22538614 TI - Antarctic ice-sheet loss driven by basal melting of ice shelves. AB - Accurate prediction of global sea-level rise requires that we understand the cause of recent, widespread and intensifying glacier acceleration along Antarctic ice-sheet coastal margins. Atmospheric and oceanic forcing have the potential to reduce the thickness and extent of floating ice shelves, potentially limiting their ability to buttress the flow of grounded tributary glaciers. Indeed, recent ice-shelf collapse led to retreat and acceleration of several glaciers on the Antarctic Peninsula. But the extent and magnitude of ice-shelf thickness change, the underlying causes of such change, and its link to glacier flow rate are so poorly understood that its future impact on the ice sheets cannot yet be predicted. Here we use satellite laser altimetry and modelling of the surface firn layer to reveal the circum-Antarctic pattern of ice-shelf thinning through increased basal melt. We deduce that this increased melt is the primary control of Antarctic ice-sheet loss, through a reduction in buttressing of the adjacent ice sheet leading to accelerated glacier flow. The highest thinning rates occur where warm water at depth can access thick ice shelves via submarine troughs crossing the continental shelf. Wind forcing could explain the dominant patterns of both basal melting and the surface melting and collapse of Antarctic ice shelves, through ocean upwelling in the Amundsen and Bellingshausen seas, and atmospheric warming on the Antarctic Peninsula. This implies that climate forcing through changing winds influences Antarctic ice-sheet mass balance, and hence global sea level, on annual to decadal timescales. PMID- 22538615 TI - NLRP10 is a NOD-like receptor essential to initiate adaptive immunity by dendritic cells. AB - NLRs (nucleotide-binding domain leucine-rich-repeat-containing receptors; NOD like receptors) are a class of pattern recognition receptor (PRR) that respond to host perturbation from either infectious agents or cellular stress. The function of most NLR family members has not been characterized and their role in instructing adaptive immune responses remains unclear. NLRP10 (also known as PYNOD, NALP10, PAN5 and NOD8) is the only NLR lacking the putative ligand-binding leucine-rich-repeat domain, and has been postulated to be a negative regulator of other NLR members, including NLRP3 (refs 4-6). We did not find evidence that NLRP10 functions through an inflammasome to regulate caspase-1 activity nor that it regulates other inflammasomes. Instead, Nlrp10(-/-) mice had a profound defect in helper T-cell-driven immune responses to a diverse array of adjuvants, including lipopolysaccharide, aluminium hydroxide and complete Freund's adjuvant. Adaptive immunity was impaired in the absence of NLRP10 because of a dendritic cell (DC) intrinsic defect in emigration from inflamed tissues, whereas upregulation of DC costimulatory molecules and chemotaxis to CCR7-dependent and independent ligands remained intact. The loss of antigen transport to the draining lymph nodes by a subset of migratory DCs resulted in an almost absolute loss in naive CD4(+) T-cell priming, highlighting the critical link between diverse innate immune stimulation, NLRP10 activity and the immune function of mature DCs. PMID- 22538619 TI - Drug-target interaction prediction by random walk on the heterogeneous network. AB - Predicting potential drug-target interactions from heterogeneous biological data is critical not only for better understanding of the various interactions and biological processes, but also for the development of novel drugs and the improvement of human medicines. In this paper, the method of Network-based Random Walk with Restart on the Heterogeneous network (NRWRH) is developed to predict potential drug-target interactions on a large scale under the hypothesis that similar drugs often target similar target proteins and the framework of Random Walk. Compared with traditional supervised or semi-supervised methods, NRWRH makes full use of the tool of the network for data integration to predict drug target associations. It integrates three different networks (protein-protein similarity network, drug-drug similarity network, and known drug-target interaction networks) into a heterogeneous network by known drug-target interactions and implements the random walk on this heterogeneous network. When applied to four classes of important drug-target interactions including enzymes, ion channels, GPCRs and nuclear receptors, NRWRH significantly improves previous methods in terms of cross-validation and potential drug-target interaction prediction. Excellent performance enables us to suggest a number of new potential drug-target interactions for drug development. PMID- 22538616 TI - Infection regulates pro-resolving mediators that lower antibiotic requirements. AB - Underlying mechanisms for how bacterial infections contribute to active resolution of acute inflammation are unknown. Here, we performed exudate leukocyte trafficking and mediator-metabololipidomics of murine peritoneal Escherichia coli infections with temporal identification of pro-inflammatory (prostaglandins and leukotrienes) and specialized pro-resolving mediators (SPMs). In self-resolving E. coli exudates (10(5) colony forming units, c.f.u.), the dominant SPMs identified were resolvin (Rv) D5 and protectin D1 (PD1), which at 12 h were at significantly greater levels than in exudates from higher titre E. coli (10(7) c.f.u.)-challenged mice. Germ-free mice had endogenous RvD1 and PD1 levels higher than in conventional mice. RvD1 and RvD5 (nanograms per mouse) each reduced bacterial titres in blood and exudates, E. coli-induced hypothermia and increased survival, demonstrating the first actions of RvD5. With human polymorphonuclear neutrophils and macrophages, RvD1, RvD5 and PD1 each directly enhanced phagocytosis of E. coli, and RvD5 counter-regulated a panel of pro inflammatory genes, including NF-kappaB and TNF-alpha. RvD5 activated the RvD1 receptor, GPR32, to enhance phagocytosis. With self-limited E. coli infections, RvD1 and the antibiotic ciprofloxacin accelerated resolution, each shortening resolution intervals (R(i)). Host-directed RvD1 actions enhanced ciprofloxacin's therapeutic actions. In 10(7) c.f.u. E. coli infections, SPMs (RvD1, RvD5, PD1) together with ciprofloxacin also heightened host antimicrobial responses. In skin infections, SPMs enhanced vancomycin clearance of Staphylococcus aureus. These results demonstrate that specific SPMs are temporally and differentially regulated during infections and that they are anti-phlogistic, enhance containment and lower antibiotic requirements for bacterial clearance. PMID- 22538620 TI - In brief: FDA warning about drospirenone in oral contraceptives. PMID- 22538621 TI - Indacterol (Arcapta Neohaler) for COPD. PMID- 22538622 TI - Ingenol mebutate (Picato) for actinic keratosis. PMID- 22538624 TI - In vivo MRI discrimination between live and lysed iron-labelled cells using balanced steady state free precession. AB - OBJECTIVES: The goal of this study was to evaluate the ability of balanced steady state free precession (b-SSFP) magnetic resonance imaging sequence to distinguish between live and lysed iron-labelled cells. METHODS: Human breast cancer cells were labelled with iron oxide nanoparticles. Cells were lysed using sonication. Imaging was performed at 3 T. The timing parameters for b-SSFP and the number of iron-labelled cells in samples were varied to optimise the b-SSFP signal difference between live and lysed iron-labelled cell samples. For in vivo experiments, cells were mixed with Matrigel and implanted into nude mice. Three mice implanted with live labelled cancer cells were irradiated to validate this method. RESULTS: Lysed iron-labelled cells have a significantly higher signal compared with live, intact iron-labelled cells in bSSFP images. The contrast between live and dead cells can be maximised by careful optimisation of timing parameters. A change in the b-SSFP signal was measured 6 days after irradiation, reflecting cell death in vivo. Histology confirmed the presence of dead cells in the implant. CONCLUSIONS: Our results show that the b-SSFP sequence can be optimised to allow for the discrimination of live iron-labelled cells and lysed iron-labelled cells in vitro and in vivo. PMID- 22538625 TI - Analysis of the impact of digital tomosynthesis on the radiological investigation of patients with suspected pulmonary lesions on chest radiography. AB - OBJECTIVE: To assess the impact of digital tomosynthesis (DTS) on the radiological investigation of patients with suspected pulmonary lesions on chest radiography (CXR). METHODS: Three hundred thirty-nine patients (200 male; age, 71.19 +/- 11.9 years) with suspected pulmonary lesion(s) on CXR underwent DTS. Two readers prospectively analysed CXR and DTS images, and recorded their diagnostic confidence: 1 or 2 = definite or probable benign lesion or pseudolesion deserving no further diagnostic workup; 3 = indeterminate; 4 or 5 = probable or definite pulmonary lesion deserving further diagnostic workup by computed tomography (CT). Imaging follow-up by CT (n = 76 patients), CXR (n = 256) or histology (n = 7) was the reference standard. RESULTS: DTS resolved doubtful CXR findings in 256/339 (76 %) patients, while 83/339 (24 %) patients proceeded to CT. The mean interpretation time for DTS (mean +/- SD, 220 +/- 40 s) was higher (P < 0.05; Wilcoxon test) than for CXR (110 +/- 30 s), but lower than CT (600 +/- 150 s). Mean effective dose was 0.06 mSv (range 0.03-0.1 mSv) for CXR, 0.107 mSv (range 0.094-0.12 mSv) for DTS, and 3 mSv (range 2-4 mSv) for CT. CONCLUSIONS: DTS avoided the need for CT in about three-quarters of patients with a slight increase in the interpretation time and effective dose compared to CXR. PMID- 22538626 TI - Long-term follow-up of non-calcified pulmonary nodules (<10 mm) identified during low-dose CT screening for lung cancer. AB - OBJECTIVES: To assess the long-term stability of small (<10 mm) non-calcified pulmonary nodules (NCNs) in high-risk subjects initially screened for lung cancer using low-dose chest computed tomography (LDCCT). METHODS: A total of 449 subjects initially underwent screening with serial LDCCT over a 2-year period. Participants identified as having NCNs >=10 mm were referred for formal lung cancer workup. NCNs <10 mm diameter were followed in accordance with the study protocol. Seven years after baseline screening, subjects with previously documented NCNs <10 mm, which were unchanged in size after the 2-year follow-up period, were re-imaged using LDCCT to assess for interval nodule growth. RESULTS: Eighty-three subjects with previously documented stable NCNs <10 mm underwent LDCCT at 7 years. NCNs were unchanged in 78 subjects and had decreased in size in 4 subjects. There was interval growth of an NCN (from 6 mm to 9 mm) in one subject re-imaged at 7 years, but this nodule has remained stable in size over a further 2-year follow-up period. CONCLUSIONS: Non-calcified pulmonary nodules <10 mm in size that are unchanged in size or smaller after 2 years of follow-up with LDCCT are most likely benign. PMID- 22538627 TI - Radiation exposure and mortality risk from CT and PET imaging of patients with malignant lymphoma. AB - OBJECTIVE: To quantify radiation exposure and mortality risk from computed tomography (CT) and positron emission tomography (PET) imaging with (18)F fluorodeoxyglucose ((18)F-FDG) in patients with malignant lymphoma (Hodgkin's disease [HD] or non-Hodgkin's lymphoma [NHL]). METHODS: First, organ doses were assessed for a typical diagnostic work-up in children with HD and adults with NHL. Subsequently, life tables were constructed for assessment of radiation risks, also taking into account the disease-related mortality. RESULTS: In children with HD, cumulative effective dose from medical imaging ranged from 66 mSv (newborn) to 113 mSv (15 years old). In adults with NHL the cumulative effective dose from medical imaging was 97 mSv. Average fractions of radiation induced deaths for children with HD [without correction for disease-related mortality in brackets] were 0.4% [0.6%] for boys and 0.7% [1.1%] for girls, and for adults with NHL 0.07% [0.28%] for men and 0.09% [0.37%] for women. CONCLUSION: Taking into account the disease-related reduction in life expectancy of patients with malignant lymphoma results in a higher overall mortality but substantial lower incidence of radiation induced deaths. The modest radiation risk that results from imaging with CT and (18)F-FDG PET can be considered as justified, but imaging should be performed with care, especially in children. PMID- 22538628 TI - Magnetic resonance imaging of the knee at 3 and 7 tesla: a comparison using dedicated multi-channel coils and optimised 2D and 3D protocols. AB - OBJECTIVES: To show the feasibility and possible superiority of two 7 Tesla knee protocols ("7 T high resolution" and "7 T quick") using a new 28-channel knee coil compared to an optimised 3 T knee protocol using an 8-channel knee coil. METHODS: The study was approved by the ethics committee. Both 3 T and 7 T MRI of the knee were performed in 10 healthy volunteers (29.6 +/- 7.9 years), with two 2D sequences (PD-TSE and T1-SE) and three isotropic 3D sequences (TRUFI, FLASH and PD-TSE SPACE). Quantitative contrast-to-noise ratio (CNR) and qualitative evaluations were performed by different readers, and intra- and inter-rater agreement was assessed. RESULTS: The signal-to-noise ratio (SNR) as well as the CNR values for cartilage-bone, cartilage-fluid, cartilage-menisci and menisci fluid were, in most cases, higher at 7 T compared to 3 T, and the 7 T quick measurement was slightly superior compared to the 7 T high-resolution measurement. The results of the subjective qualitative analysis were higher for the 7 T measurements compared to the 3 T measurements. Inter- and intra-observer reliability was high (0.884-0.999). CONCLUSIONS: Through higher field strength and an optimal coil, resolution at 7 T can be increased and acquisition time can be reduced, with superior quantitative and comparable qualitative results compared to 3 T. PMID- 22538630 TI - Potential of right to left ventricular volume ratio measured on chest CT for the prediction of pulmonary hypertension: correlation with pulmonary arterial systolic pressure estimated by echocardiography. AB - OBJECTIVES: To investigate the correlation of right ventricular (RV) to left ventricular (LV) volume ratio measured by chest CT with pulmonary arterial systolic pressure (PASP) estimated by echocardiography. METHODS: 104 patients (72.47 +/- 13.64 years; 39 male) who had undergone chest CT and echocardiography were divided into two groups (hypertensive and normotensive) based upon an echocardiography-derived PASP of 25 mmHg. RV to LV volume ratios (RV(V)/LV(V)) were calculated. RV(V)/LV(V) was then correlated with PASP using regression analysis. The Area Under the Curve (AUC) for predicting pulmonary hypertension on chest CT was calculated. RESULTS: In the hypertensive group, the mean PASP was 46.29 +/- 14.42 mmHg (29-98 mmHg) and there was strong correlation between the RV(V)/LV(V) and PASP (R = 0.82, p < 0.001). The intraobserver and interobserver correlation coefficients for RV(V)/LV(V) were 0.990 and 0.892. RV(V)/LV(V) was 1.01 +/- 0.44 (0.51-2.77) in the hypertensive and 0.72 +/- 0.14 (0.52-1.11) in the normotensive group (P <0.05). With 0.9 as the cutoff for RV(V)/LV(V), sensitivity and specificity for predicting pulmonary hypertension over 40 mmHg were 79.5 % and 90 %, respectively. The AUC for predicting pulmonary hypertension was 0.87 CONCLUSION: RV/LV volume ratios on chest CT correlate well with PASP estimated by echocardiography and can be used to predict pulmonary hypertension over 40 mmHg with high sensitivity and specificity. PMID- 22538629 TI - Model-based iterative reconstruction technique for radiation dose reduction in chest CT: comparison with the adaptive statistical iterative reconstruction technique. AB - OBJECTIVES: To prospectively evaluate dose reduction and image quality characteristics of chest CT reconstructed with model-based iterative reconstruction (MBIR) compared with adaptive statistical iterative reconstruction (ASIR). METHODS: One hundred patients underwent reference-dose and low-dose unenhanced chest CT with 64-row multidetector CT. Images were reconstructed with 50 % ASIR-filtered back projection blending (ASIR50) for reference-dose CT, and with ASIR50 and MBIR for low-dose CT. Two radiologists assessed the images in a blinded manner for subjective image noise, artefacts and diagnostic acceptability. Objective image noise was measured in the lung parenchyma. Data were analysed using the sign test and pair-wise Student's t-test. RESULTS: Compared with reference-dose CT, there was a 79.0 % decrease in dose-length product with low-dose CT. Low-dose MBIR images had significantly lower objective image noise (16.93 +/- 3.00) than low-dose ASIR (49.24 +/- 9.11, P < 0.01) and reference-dose ASIR images (24.93 +/- 4.65, P < 0.01). Low-dose MBIR images were all diagnostically acceptable. Unique features of low-dose MBIR images included motion artefacts and pixellated blotchy appearances, which did not adversely affect diagnostic acceptability. CONCLUSION: Diagnostically acceptable chest CT images acquired with nearly 80 % less radiation can be obtained using MBIR. MBIR shows greater potential than ASIR for providing diagnostically acceptable low dose CT images without severely compromising image quality. KEY POINTS: * Model based iterative reconstruction (MBIR) creates high-quality low-dose CT images. * MBIR significantly improves image noise and artefacts over adaptive statistical iterative techniques. * MBIR shows greater potential than ASIR for diagnostically acceptable low-dose CT. * The prolonged processing time of MBIR may currently limit its routine use in clinical practice. PMID- 22538631 TI - Magnetic resonance colonography in severe attacks of ulcerative colitis. AB - OBJECTIVES: To evaluate the ability of MR colonography (MRC) to detect lesions in severe attacks of ulcerative colitis (UC) and to assess its concordance with rectosigmoidoscopy. METHODS: Eighteen patients underwent MRC and rectosigmoidoscopy. MRC consisted of a water-filled colonic procedure followed by T1/T2w images. Image quality was recorded. Inflammatory lesions and the existence of signs of severity were analysed. We calculated MR accuracy in the diagnosis of inflammatory lesions, as well as per segment and per patient concordance depending on the presence or absence of severe lesions. RESULTS: The MR image quality of the 108 segments was satisfactory. Endoscopy was used to study 36 segments (rectum and sigmoid). MRC had a positive predictive value of 100% and a sensitivity of 64% in the diagnosis of inflammatory lesions. Concordance for the diagnosis of severe lesions was excellent for the rectum (k = 0.85) and good for the sigmoid (k = 0.64). MRC diagnosed signs of severity in all patients affected at endoscopy. MRC also disclosed signs of severity located higher in the colon in four patients with nonsevere lesions at rectosigmoidoscopy. CONCLUSIONS: MRC can accurately diagnose inflammatory lesions in severe attacks of UC and significantly correlates with rectosigmoidoscopy in the diagnosis of severe lesions. PMID- 22538632 TI - Prevalence and prognosis of coronary stent gap detected by multi-detector CT: a follow-up study. AB - OBJECTIVES: To evaluate the features of stent gap (SG) and the long-term impact of SG on in-stent restenosis (ISR) in patent stents. METHODS: A total of 347 consecutive patients with 781 stents who underwent MDCT were assessed for SG and ISR. Clinical and stent features were compared between the SG and non-SG groups. In the follow-up study, among 82 patients with 175 patent stents [26 assessed by conventional coronary angiography (CCA) including 6 contacted in a telephone survey, 46 assessed by computed tomography angiography (CTA) and 10 by both], the incidence of ISR was compared between stents with and without SG. RESULTS: Three patients and 13 stents were excluded. SG was observed in 12.5% of patients and 8.6% of stents. ISR detected by CTA was noted in 21.2% of SG, and SG accounted for 23.7% of ISR. Stent number, length, location, overlapping pattern, tortuosity and in-out angle were predisposing factors for SG. During a mean follow-up period of 15 months after detection of SG, the incidence of ISR was significantly higher in the SG group than in the non-SG group (43.8/14.9% by CCA, 33.3/10.1% by CTA and CCA). CONCLUSION: Patent stents with SG detected by CTA had a higher incidence of late restenosis, indicating that long-term follow-up or further intervention is necessary. PMID- 22538633 TI - Evaluation of different magnetic resonance imaging techniques for the assessment of active left atrial emptying. AB - OBJECTIVES: There is currently no agreement on the best method of assessing active left atrial (LA) emptying. This study evaluated the relative merits of cine- and velocity encoded (VENC) magnetic resonance imaging (MRI) for the assessment of active LA emptying. METHODS: Total LA emptying volume (TLAEV) and active LA stroke volume (ALASV) were assessed in 107 consecutive patients using cine-MRI and transmitral flow measurements by VENC-MRI. The fraction of active LA emptying (ALAEF) was calculated as the ratio of ALASV to TLAEV. LA and left ventricular (LV) output were calculated by multiplying TLAEV and LV stroke volume by heart rate, respectively. RESULTS: Intra- and inter-observer variances were significantly larger for cine-MRI than for VENC-MRI measurements of ALASV (24.7 mL(2) vs. 3.7 mL(2) and 57.7 mL(2) vs. 4.2 mL(2); P < 0.0001). Biplane cine-MRI underestimated TLAEV (mean difference -57 +/- 32 %; P < 0.0001) and ALASV (mean difference -24 +/- 51 %; P < 0.0001) but overestimated ALAEF (mean difference 31 +/- 54 %, P < 0.0001) compared with VENC-MRI. There was significantly better agreement between LV output and LA output measured by VENC-MRI compared with LA output measured by cine-MRI (mean difference 0.30 +/- 1.12 L/min vs. -2.05 +/- 1.44 L/min; P < 0.0001). CONCLUSION: VENC-MRI is the more appropriate method of assessing active LA emptying and its use should be favoured. PMID- 22538634 TI - Content-balancing strategy in bifactor computerized adaptive patient-reported outcome measurement. AB - PURPOSE: Most multidimensional patient-reported outcomes (PRO) measures are lengthy to complete. Computerized adaptive testing (CAT) that selects the most informative items can potentially reduce respondent burden without sacrificing measurement accuracy. The commonly used maximum Fisher information item selection method has been reported to lead to highly unbalanced item bank usage and potentially imprecise trait estimation. This study employs the content-balancing strategy in a bifactor-modeled CAT item selection and examines its impact on measurement accuracy and item bank usage. METHODS: Item responses from a population-based SF-36 survey were first calibrated using the bifactor graded response model. Four post hoc CATs using items and responses from the SF-36 data set were then created. The content-balancing strategy was adopted in the item selection procedure of the bifactor-modeled CAT. The measurement accuracy and usage of items of the CAT were compared between the tests with and without the content-balancing strategy. RESULTS: The results indicate that the CAT implemented with the content-balancing strategy offers a better overall measurement accuracy of both the general health status and the two health domains (physical and mental) of the SF-36. CONCLUSIONS: The content-balancing strategy helps the CAT-PRO to balance the selection of items and achieve improved measurement accuracy. Its implementation in real-time CAT administration to measure multidimensional PRO traits merits further studies. PMID- 22538635 TI - Evidence in favor of a severely impaired net intestinal calcium absorption in patients with (early-stage) chronic kidney disease. AB - INTRODUCTION: Calcium and phosphorus are essential to many vital physiological processes. Little is known about the net and fractional intestinal absorption of calcium and phosphorus in patients with chronic kidney disease (CKD) and their clinical and hormonal determinants. METHODS: Blood and 24-hour urine samples were collected in 20 healthy volunteers (HV) and 72 stable CKD stage 1-4 patients and analyzed for parameters of mineral metabolism including calcidiol, calcitriol, and parathyroid hormone (PTH). Dietary intake was assessed by dietary history. RESULTS: The 24-hour urinary calcium excretion, as opposed to the phosphorus excretion, showed a stepwise decrease across CKD stages (median of 219, 84, 40, and 22 mg/day in HV and patients with CKD stages 1-2, 3 and 4, respectively). Younger age, high serum calcitriol, and high estimated GFR were associated with a high 24-hour urinary calcium excretion. High serum calcitriol levels and dietary phosphorus intake were associated with a high 24-hour urinary phosphorus excretion. The fractional intestinal calcium absorption, as estimated by the urinary-to-ingested calcium ratio, decreased across CKD stages. CONCLUSIONS: The 24-hour urinary excretion of calcium, as opposed to phosphorus, is markedly decreased in CKD, even in early-stage disease. This is partly explained by low calcitriol levels and older age. Assuming a neutral calcium balance at the time of urine collection, we infer that net intestinal calcium absorption may be severely impaired in CKD. PMID- 22538636 TI - Health biomarkers in a rat model after intake of organically grown carrots. AB - BACKGROUND: Organic food is perceived as being of better quality and healthier than conventional foods although the scientific research on organic foodstuffs is highly contradictory. The aim of the present study was to investigate if intake of carrots from four different cultivation systems grown in two consecutive years would influence various biomarkers of health in a rat model. All rats were fed a diet with 40% carrot content. The carrots were grown under conventional (C), 'minimalistic' organic (O1), organic (O2), or 'very' organic cultivation systems (O3). A control group (CO) being fed standard rat chow was included. RESULTS: The plasma alpha-tocopherol concentration was higher in the O2 carrot-based diet group than in the C carrot based-diet group in one year, while all other health biomarkers or nutrient content differences were observed between the CO diet and the carrot-based diets. CONCLUSION: This well-controlled field study demonstrated no clear influence of cultivation methods or harvest year on the nutritional quality of carrots or effect of cultivation methods on health-related biomarkers in a sensitive rat model. However, the experimental set-up and selected biomarkers could be used as a framework for further studies of health in relation to organic foodstuff. PMID- 22538637 TI - Invited commentary by E. Nilsson to the use of hernia registers for improving patient outcome (manuscripts by Stechemesser et al. and Muysoms et al.). PMID- 22538638 TI - The effect of the microenvironment created by a titanium mesh cage on subcutaneous experimental bone formation and inhibition of absorption. AB - We attempted to form ectopic bone under the skin of rats without adding any extrinsic bone-inducing growth factors or cytokines using bone marrow stromal cells (BMSCs), a collagen scaffold and a titanium mesh cage. We set up a space made up of a cage inserted into the subcutaneous region of rats' backs, where we could eliminate the possible influence of residual bone tissue on bone induction. We filled this space with a collagen matrix containing BMSCs. At week 8 and month 6 after implantation, the specimens were removed and observed histologically, histochemically and enzyme histochemically. As a result, bone tissue was identified in each case within the titanium cages, even though we had not used bone-inducing chemical substances. Bone generation was not found in test cases without a cage. Enhanced green fluorescence protein (EGFP) labeling of the implanted BMSCs clearly showed that these cells differentiated into osteoblasts and subsequently into osteocytes in the formed bone tissue. Host cells without EGFP labeling were also confirmed to be involved in bone formation. Six months after transplantation, the implanted cells were still present in the generated bone, and no significant resorption of the generated bone was observed. These results indicate that the physically stable spatial microenvironment created by the cage in vivo plays an important role in bone formation and inhibition of its resorption, which we refer to as the 'cage effect'. PMID- 22538639 TI - Roles of hydrogen sulfide and nitric oxide in the alleviation of cadmium-induced oxidative damage in alfalfa seedling roots. AB - Despite hydrogen sulfide (H(2)S) and nitric oxide (NO) are important endogenous signals or bioregulators involved in many vital aspects of plant growth and responses against abiotic stresses, little information was known about their interaction. In the present study, we evaluated the effects of H(2)S and NO on alfalfa (Medicago sativa L.) plants exposed to cadmium (Cd) stress. Pretreatment with an H(2)S donor sodium hydrosulfide (NaHS) and well-known NO donor sodium nitroprusside (SNP) decreased the Cd toxicity. This conclusion was supported by the decreases of lipid peroxidation as well as the amelioration of seedling growth inhibition and Cd accumulation, in comparison with the Cd-stressed alone plants. Total activities and corresponding transcripts of antioxidant enzymes, including superoxide dismutase, peroxidase and ascorbate peroxidase were modulated differentially, thus leading to the alleviation of oxidative damage. Effects of H(2)S above were reversed by 2-(4-carboxyphenyl)-4,4,5,5 tetramethylimidazoline-1-oxyl-3-oxide potassium salt (cPTIO), the specific scavenger of NO. By using laser confocal scanning microscope combined with Greiss reagent method, further results showed that NO production increased significantly after the NaHS pretreatment regardless of whether Cd was applied or not, all of which were obviously inhibited by cPTIO. These decreases of NO production were consistent with the exaggerated syndromes associated with Cd toxicity. Together, above results suggested that NO was involved in the NaHS-induced alleviation of Cd toxicity in alfalfa seedlings, and also indicated that there exists a cross talk between H(2)S and NO responsible for the increased abiotic stress tolerance. PMID- 22538640 TI - Protective role of simvastatin on isolated rabbit atrioventricular node during experimental atrial fibrillation model: role in rate control of ventricular beats. AB - The purpose of the present study was to determine (1) whether simvastatin (SV) modifies the rate-dependent conduction time and refractoriness of the atrioventricular (AV) node and (2) how it can change the protective mechanism of the AV node during atrial fibrillation (AF). Predefined stimulation protocols were applied to detect the electrophysiological parameters of the AV node, including atrial-His conduction time, effective refractory period (ERP), functional refractory period (FRP), concealed conduction, excitable index, and fatigue in two groups of isolated, perfused rabbit AV nodal preparations (N=16). The stimulation protocols (fatigue, recovery) were carried out during control and in the presence of SV (0.5, 0.8, 3, and 10 MUM). Simulated AF was executed in a separate group (N=8), and specific indexes, including H-H mean, zone of concealment (ZOC), and concealed beats were recorded. SV, in a concentration dependent manner, prolonged ERP, FRP, and Wenckebach cycle lengths. It (10 MUM) significantly increased fatigue and the excitable index. In addition, SV elicited prolongation of ZOC and H-H mean at 3 and 10 MUM. SV-evoked prolongation of nodal refractoriness and concealed conduction caused rate-dependent ventricular slowing effects during AF. The ability of simvastatin to decrease the excitable gap by its heterogeneous effects on nodal dual pathways proposes its protective role in AF. PMID- 22538641 TI - Effects of dapoxetine on cloned Kv1.5 channels expressed in CHO cells. AB - The effects of dapoxetine were examined on cloned Kv1.5 channels stably expressed in Chinese hamster ovary cells using the whole-cell patch clamp technique. Dapoxetine decreased the peak amplitude of Kv1.5 currents and accelerated the decay rate of current inactivation in a concentration-dependent manner with an IC ( 50 ) of 11.6 MUM. Kinetic analysis of the time-dependent effects of dapoxetine on Kv1.5 current decay yielded the apparent association (k (+1 )) and dissociation (k (-1 )) rate constants of 2.8 MUM(-1) s(-1) and 34.2 s(-1), respectively. The theoretical K ( D ) value, derived by k (-1 )/k (+1 ), yielded 12.3 MUM, which was reasonably similar to the IC ( 50 ) value obtained from the concentration-response curve. Dapoxetine decreased the tail current amplitude and slowed the deactivation process of Kv1.5, which resulted in a tail crossover phenomenon. The block by dapoxetine is voltage-dependent and steeply increased at potentials between -10 and +10 mV, which correspond to the voltage range of channel activation. At more depolarized potentials, a weaker voltage dependence was observed (delta=0.31). Dapoxetine had no effect on the steady-state activation of Kv1.5 but shifted the steady-state inactivation curves in a hyperpolarizing direction. Dapoxetine produced a use-dependent block of Kv1.5 at frequencies of 1 and 2 Hz and slowed the time course for recovery of inactivation. These effects were reversible after washout of the drug. Our results indicate that dapoxetine blocks Kv1.5 currents by interacting with the channel in both the open and inactivated states of the channel. PMID- 22538642 TI - Topical and subconjunctival bevacizumab for corneal neovascularization in an experimental rat model. AB - AIMS: To evaluate and compare the inhibitory effects of topical and subconjunctival bevacizumab on corneal neovascularization in a rat model. METHODS: Twenty corneas of 20 rats were chemically cauterized with silver nitrate sticks. Animals were randomized into four groups: a control group that received only topical artificial tear drops twice daily, a subconjunctival injection group that received 1.25 mg (0.05 ml) of bevacizumab on the 1st, 4th, and 7th day, and two topical bevacizumab groups that received instillation of 4 or 12.5 mg/ml bevacizumab twice daily. Digital photographs of the cornea were taken and analyzed using an image analysis software program. On the 10th day, corneas were excised and examined histologically. RESULTS: The mean percentage of the vascularized corneal area (%) in the control group was 63.32 +/- 13.10 (mean +/- SD), compared with 30.22 +/- 15.73 in the subconjunctival injection group, 26.76 +/- 10.23 in the 4-mg/ml topical group, and 25.52 +/- 12.45 in the 12.5-mg/ml group. The differences between the control and each treatment group were significant (all p < 0.01). Further, histological examination revealed that each treatment group had fewer vessels than the control group (all p < 0.01). CONCLUSIONS: Both subconjunctival injection and topical use of bevacizumab are effective and safe in controlling corneal neovascularization. PMID- 22538643 TI - Development and validation of an improved algorithm for overlaying flexible molecules. AB - A program for overlaying multiple flexible molecules has been developed. Candidate overlays are generated by a novel fingerprint algorithm, scored on three objective functions (union volume, hydrogen-bond match, and hydrophobic match), and ranked by constrained Pareto ranking. A diverse subset of the best ranked solutions is chosen using an overlay-dissimilarity metric. If necessary, the solutions can be optimised. A multi-objective genetic algorithm can be used to find additional overlays with a given mapping of chemical features but different ligand conformations. The fingerprint algorithm may also be used to produce constrained overlays, in which user-specified chemical groups are forced to be superimposed. The program has been tested on several sets of ligands, for each of which the true overlay is known from protein-ligand crystal structures. Both objective and subjective success criteria indicate that good results are obtained on the majority of these sets. PMID- 22538644 TI - TBC: a clustering algorithm based on prokaryotic taxonomy. AB - High-throughput DNA sequencing technologies have revolutionized the study of microbial ecology. Massive sequencing of PCR amplicons of the 16S rRNA gene has been widely used to understand the microbial community structure of a variety of environmental samples. The resulting sequencing reads are clustered into operational taxonomic units that are then used to calculate various statistical indices that represent the degree of species diversity in a given sample. Several algorithms have been developed to perform this task, but they tend to produce different outcomes. Herein, we propose a novel sequence clustering algorithm, namely Taxonomy-Based Clustering (TBC). This algorithm incorporates the basic concept of prokaryotic taxonomy in which only comparisons to the type strain are made and used to form species while omitting full-scale multiple sequence alignment. The clustering quality of the proposed method was compared with those of MOTHUR, BLASTClust, ESPRIT-Tree, CD-HIT, and UCLUST. A comprehensive comparison using three different experimental datasets produced by pyrosequencing demonstrated that the clustering obtained using TBC is comparable to those obtained using MOTHUR and ESPRIT-Tree and is computationally efficient. The program was written in JAVA and is available from http://sw.ezbiocloud.net/tbc. PMID- 22538645 TI - Identification and enumeration of Microcystis using a sandwich hybridization assay. AB - Based on sequence analyses of phycocyanin intergenic spacers (PC-IGS) from Microcystis, Anabaena, Aphanizomenon, and Planktothrix (Oscillatoria) strains, a genus-specific probe pair TF/TR was designed, and a sandwich hybridization assay was established to quantitatively detect Microcystis. Through BLAST and cyanobacterial culture tests, TF/TR was demonstrated to be specific for Microcystis. A calibration curve for the sandwich hybridization assay was established, and the lowest detected concentration was 100 cell/ml. Laboratory and field samples were analyzed with both sandwich hybridization assay and microscopy. The biotic and abiotic components of the samples were of little disturbance to the sandwich hybridization assay. The results showed no distinct difference between the two methods. In this study, a sandwich hybridization assay was established to detect Microcystis, providing an alternative to traditional microscopic, morphology-based methods. PMID- 22538646 TI - Isolation and characterization of plant growth-promoting rhizobacteria from wheat roots by wheat germ agglutinin labeled with fluorescein isothiocyanate. AB - Thirty-two isolates were obtained from wheat rhizosphere by wheat germ agglutinin (WGA) labeled with fluorescein isothiocyanate (FITC). Most isolates were able to produce indole acetic acid (65.6%) and siderophores (59.3%), as well as exhibited phosphate solubilization (96.8%). Fourteen isolates displayed three plant growth promoting traits. Among these strains, two phosphate-dissolving ones, WS29 and WS31, were evaluated for their beneficial effects on the early growth of wheat (Triticum aestivum Wan33). Strain WS29 and WS31 significantly promoted the development of lateral roots by 34.9% and 27.6%, as well as increased the root dry weight by 25.0% and 25.6%, respectively, compared to those of the control. Based on 16S rRNA gene sequence comparisons and phylogenetic positions, both isolates were determined to belong to the genus Bacillus. The proportion of isolates showing the properties of plant growth-promoting rhizobacteria (PGPR) was higher than in previous reports. The efficiency of the isolation of PGPR strains was also greatly increased by WGA labeled with FITC. The present study indicated that WGA could be used as an effective tool for isolating PGPR strains with high affinity to host plants from wheat roots. The proposed approach could facilitate research on biofertilizers or biocontrol agents. PMID- 22538647 TI - Detecting nonculturable bacteria in the active mycorrhizal zone of the pine mushroom Tricholoma matsutake. AB - The fungus Tricholoma matsutake forms an ectomycorrhizal relationship with pine trees. Its sporocarps often develop in a circle, which is commonly known as a fairy ring. The fungus produces a solid, compact, white aggregate of mycelia and mycorrhizae beneath the fairy ring, which in Japanese is called a 'shiro'. In the present study, we used soil dilution plating and molecular techniques to analyze the bacterial communities within, beneath, and outside the T. matsutake fairy ring. Soil dilution plating confirmed previous reports that bacteria and actinomycetes are seldom present in the soil of the active mycorrhizal zone of the T. matsutake shiro. In addition, the results showed that the absence of bacteria was strongly correlated with the presence of T. matsutake mycorrhizae. The results demonstrate that bacteria, especially aerobic and heterotrophic forms, and actinomycetes, are strongly inhibited by T. matsutake. Indeed, neither bacteria nor actinomycetes were detected in 11.3% of 213 soil samples from the entire shiro area by culture-dependent methods. However, molecular techniques demonstrated that some bacteria, such as individual genera of Sphingomonas and Acidobacterium, were present in the active mycorrhizal zone, even though they were not detected in soil assays using the dilution plating technique. PMID- 22538648 TI - Molecular analysis of spatial variation of iron-reducing bacteria in riverine alluvial aquifers of the Mankyeong River. AB - Alluvial aquifers are one of the mainwater resources in many countries. Iron reduction in alluvial aquifers is often a major anaerobic process involved in bioremediation or causing problems, including the release of As trapped in Fe(III) oxide. We investigated the distribution of potential iron-reducing bacteria (IRB) in riverine alluvial aquifers (B1, B3, and B6 sites) at the Mankyeong River, Republic of Korea. Inactive iron reduction zones, the diversity and abundance of IRB can be examined using a clone library and quantitative PCR analysis of 16S rRNA genes. Geobacter spp. are potential IRB in the iron-reducing zone at the B6 (9 m) site, where high Fe(II) and arsenic (As) concentrations were observed. At the B3 (16 m) site, where low iron reduction activity was predicted, a dominant clone (10.6%) was 99% identical in 16S rRNA gene sequence with Rhodoferax ferrireducens. Although a major clone belonging to Clostridium spp. was found, possible IRB candidates could not be unambiguously determined at the B1 (18 m) site. Acanonical correspondence analysis demonstrated that, among potential IRB, only the Geobacteraceae were well correlated with Fe(II) and As concentrations. Our results indicate high environmental heterogeneity, and thus high spatial variability, in thedistribution of potential IRB in the riverine alluvial aquifersnear the Mankyeong River. PMID- 22538649 TI - Microbial fingerprinting detects unique bacterial communities in the faecal microbiota of rats with experimentally-induced colitis. AB - An abnormal composition of the gut microbiota is believed to be associated with the pathogenesis of inflammatory bowel disease (IBD). We utilized terminal restriction fragment length polymorphism (T-RFLP) analysis to quantify faecal bacterial communities from rats with experimental colitis. Male Sprague Dawley rats (n=10/group) ingested 2% dextran sulfate sodium (DSS) or water for up to 7 days. Rats were killed and colonic tissues collected for histological analysis. Damage severity score in the distal colon was significantly greater (P<0.001) following DSS consumption compared to controls. T-RFLP faecal bacterial profiles generated with either MspI or CfoI revealed a significant difference (P<0.001) in community composition between healthy and colitic rats, with bacterial composition in healthy rats more variable than in rats with colitis. Operational taxonomic units (OTU: taxonomically related groups of bacteria) associated with either the healthy or colitic state were identified. OTU (116, 226, 360, and 948; CfoI) and (118 and 188; MspI) were strongly associated with untreated healthy rats, while OTU (94, 98, 174, and 384; CfoI) and (94 and 914; MspI) were predominantly associated with DSS-treated colitic rats. Phylogenetic OTU assignment suggested that Bacteroidales and Lactobacillus sp. were predominantly associated with the colitic and healthy rats, respectively. These results show that faecal bacterial profiling is a rapid, sensitive and non-invasive tool for detecting and identifying changes in gut microbiota associated with colitis. Restoring microbial homeostasis by targeting colitis-associated OTU through specific microbiological interventions could form the basis of novel therapeutic strategies for IBD. PMID- 22538650 TI - Effect of natural mediators on the stability of Trametes trogii laccase during the decolourization of textile wastewaters. AB - The purpose of the present study was to determine the effect of natural mediators on the stability of the Trametes trogii crude laccase in the process of decolourization of textile effluents. Acetosyringone allowed the highest wastewaters decolourization rate of 25%. At higher concentrations of acetosyringone, the relative activity of laccase decreased approximately by between 38% and 88% after 5 days of incubation. T. trogii laccase was strongly inactivated at 3 mM syringaldehyde, after 3 days of incubation. However, laccase activity is more stable in the presence of the vanillin and m-coumarate. The T. trogii growth on solid effluent-based-medium was examined and evaluated by measuring the colony diameter in cm. T. trogii was completely inhibited on 100:0 and 80:20 effluent:water solid medium, however, colony diameter reached 5 cm on 60:40 effluent:water solid medium after 13-14 days incubation. When the textile effluent was pre-treated with laccase and laccase-acetosyringone system, the colony diameter of 2 cm of T. trogii on 80:20 effluent:water solid medium was reached after 14 and 10 days of incubation respectively. PMID- 22538651 TI - Purification and structure analysis of mycolic acids in Corynebacterium glutamicum. AB - Corynebacterium glutamicum is widely used for producing amino acids. Mycolic acids, the major components in the cell wall of C. glutamicum might be closely related to the secretion of amino acids. In this study, mycolic acids were extracted from 5 strains of C. glutamicum, including ATCC 13032, ATCC 13869, ATCC 14067, L-isoleucine producing strain IWJ-1, and L-valine producing strain VWJ-1. Structures of these mycolic acids were analyzed using thin layer chromatography and electrospray ionization mass spectrometry. More than twenty molecular species of mycolic acid were observed in all 5 strains. They differ in the length (20-40 carbons) and saturation (0-3 double bonds) of their constituent fatty acids. The dominant species of mycolic acid in every strain was different, but their two hydrocarbon chains were similar in length (14-18 carbons), and the meromycolate chain usually contained double bonds. As the growth temperature of cells increased from 30 degrees C to 34 degrees C, the proportion of mycolic acid species containing unsaturated and shorter hydrocarbon chains increased. These results provide new information on mycolic acids in C. glutamicum, and could be useful for modifying the cell wall to increase the production of amino acids. PMID- 22538652 TI - Effects of exopolysaccharide production on liquid vegetative growth, stress survival, and stationary phase recovery in Myxococcus xanthus. AB - Exopolysaccharide (EPS) of Myxococcus xanthus is a well-regulated cell surface component. In addition to its known functions for social motility and fruiting body formation on solid surfaces, EPS has also been proposed to play a role in multi-cellular clumping in liquid medium, though this phenomenon has not been well studied. In this report, we confirmed that M. xanthus clumps formed in liquid were correlated with EPS levels and demonstrated that the EPS encased cell clumps exhibited biofilm-like structures. The clumps protected the cells at physiologically relevant EPS concentrations, while cells lacking EPS exhibited significant reduction in long-term viability and resistance to stressful conditions. However, excess EPS production was counterproductive to vegetative growth and viable cell recovery declined in extended late stationary phase as cells became trapped in the matrix of clumps. Therefore, optimal EPS production by M. xanthus is important for normal physiological functions in liquid. PMID- 22538653 TI - Development of a suicidal vector-cloning system based on butanal susceptibility due to an expression of YqhD aldehyde reductase. AB - Previously, we observed butanal/propanal sensitivity of Escherichia coli K-12 when cells overexpress YqhD protein, a NADPH dependent aldehyde reductase, possibly due to an accumulation of butanol/propanol in vivo as the reaction products. Based on this finding, we developed a suicidal vector-cloning system derived from pUC19, in which lacZ was substituted with the yqhD gene. As a result, when foreign DNA was inserted into its multiple cloning sites by disrupting an expression of YqhD, the recombinants survived on butanal/propanal containing plate, whereas cells containing the YqhD vector died because of the alcohol production by YqhD. The cloning efficiency, estimated based on colony PCR and enzyme digestion, was achieved more than 90% when the suicidal vector system was used. Moreover, the plasmid vector itself was stably maintained in the cell, presumably due to its ability to remove toxic aldehydes being accumulated in E. coli cell by metabolic stress. PMID- 22538654 TI - Effects of mutations in the WD40 domain of alpha-COP on its interaction with the COPI coatomer in Saccharomyces cerevisiae. AB - Replacement of glycine 227 in the fifth WD40 motif of alpha-COP/Ret1p/Soo1p by charged or aromatic amino acids is responsible for the temperature-dependent osmo sensitivity of Saccharomyces cerevisiae, while truncations of WD40 motifs exerted a reduction in cell growth rate and impairment in assembly of cell-wall associated proteins such as enolase and Gas1p. Yeast two-hybrid analysis revealed that the ret1-1/soo1-1 mutation of alpha-COP abolished the interaction with beta- and E-COP, respectively, and that the interaction between alpha-COP and beta-COP relied on the WD40 domain of alpha-COP. Furthermore, although the WD40 domain is dispensable for interaction of alpha-COP with E-COP, structural alterations in the WD40 domain could impair the interaction. PMID- 22538655 TI - Morphological structure of propagules and electrophoretic karyotype analysis of false smut Villosiclava virens in rice. AB - The target pathogen Villosiclava virens (teleomorph: claviceps oryzae-sativae) was isolated from the infected rice, where it caused false smut. In our study, the forming processes of the chlamydospores, chlamydospore balls, conidiospores, and secondary conidiospores during the asexual reproduction were observed more precisely and in greater detail than previous descriptions. The microstructure of the infected rice kernel showed that the outer dense chlamydospores piled around the false smut balls grown on XBZ medium; moreover the sclerotia consisting of dense mycelium were found. The different morphology was observed across the different growing conditions. In addition, we observed the nuclear numbers of both the conidiospores and hyphae using 4',6-diamidino-2-phenylindole (DAPI) staining. Because the fungus has small chromosomes and the numbers were not previously known, we analyzed the electrophoretic karyotype using a pulsed field gel electrophoresis (PFGE) technique. The results showed that V. virens has at least 10 chromosomes ranging in size from 0.6 kb to 6 Mb. The V. virens genome size is estimated to be 23 Mb. Here, we report the morphological characteristics of the fungus and the process of asexual spores forming asexual propagules, along with the first analyze the molecular karyotype of V. virens. These results supply a foundation for further study of the pathogenicity and biology of this devastating pathogen. PMID- 22538656 TI - Protein-protein interactions between histidine kinases and response regulators of Mycobacterium tuberculosis H37Rv. AB - Using yeast two-hybrid assay, we investigated protein-protein interactions between all orthologous histidine kinase (HK)/response regulator (RR) pairs of M. tuberculosis H37Rv and identified potential protein-protein interactions between a noncognate HK/RR pair, DosT/NarL. The protein interaction between DosT and NarL was verified by phosphotransfer reaction from DosT to NarL. Furthermore, we found that the DosT and DosS HKs, which share considerable sequence similarities to each other and form a two-component system with the DosR RR, have different cross interaction capabilities with NarL: DosT interacted with NarL, while DosS did not. The dimerization domains of DosT and DosS were shown to be sufficient to confer specificity for DosR, and the different cross-interaction abilities of DosS and DosT with NarL were demonstrated to be attributable to variations in the amino acid sequences of the alpha2-helices of their dimerization domains. PMID- 22538657 TI - Shedding of viral hemorrhagic septicemia virus (Genotype IVb) by experimentally infected muskellunge (Esox masquinongy). AB - Previous experimental infection demonstrated that juvenile muskellunge (Esox masquinongy) can survive experimental infection of viral hemorrhagic septicemia virus, Genotype IVb (VHSV IVb) at a low concentration of exposure. Herein we report that survivors of experimental infection with VHSV IVb shed the virus into the surrounding environment for an extended period of time. When muskellunge were exposed to VHSV IVb by immersion at a concentration of 1,400 plaque forming units (PFU)/ml, VHSV IVb was detected in the water of surviving fish for up to 15 weeks postexposure (p.e.) with the highest levels of shedding occurring between weeks 1 and 5 p.e. We estimated that each juvenile muskellunge can shed upwards of 1.36*10(5) PFU/fish/h after initial exposure signifying the uptake and amplification of VHSV to several orders of magnitude above the original exposure concentration. Muskellunge surviving low concentration exposure were re-infected with VHSV IVb by immersion at week 22 p.e. at concentrations ranging from 0 to 10(6) PFU/ml. Viral shedding was detected in all re-exposed fish, including mock rechallenged controls up to 15 consecutive weeks. Rates of viral shedding were substantially higher following rechallenge in the first 5 weeks. The highest rate of viral shedding was approximately 4.6*10(6) PFU/fish/h and shedding did not necessarily correspond to the re-exposure VHSV concentration. The results of this study shed new light into the dynamics of VHSV IVb shedding in a highly susceptible host and provide useful insights to fishery managers to design effective control strategies to this deadly virus. PMID- 22538658 TI - KSHV infection of B-cell lymphoma using a modified KSHV BAC36 and coculturing system. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of two B cell lymphoproliferative diseases, namely primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). KSHV infection of B cell lymphoma in vitro has been a long-standing battle in advancing human KSHV biology. In this study, a modified form of KSHV BAC36 named BAC36A significantly increased the fidelity of gene-targeted site-directed mutagenesis in the KSHV genome. This modification eliminates tedious screening steps required to obtain mutant clones when a KSHV BAC36 reverse genetic system is used. Coculturing B-cell lymphoma BJAB cells with KSHV BAC36A stably transfected 293T cells enabled us to infect BJAB cells with a KSHV virion derived from the KSHV BAC36A. The coculture system produced substantial amounts of KSHV infection to BJAB, meaning that KSHV virions were released from 293T cells and then infected neighboring BJAB cells. Owing to our success with the KSHV BAC36A and coculture system, we propose a new genetic system for the study of KSHV gene expression and regulation in B-cell lymphoma. PMID- 22538659 TI - Antiviral activities of flavonoids isolated from the bark of Rhus verniciflua stokes against fish pathogenic viruses In Vitro. AB - An 80% methanolic extract of Rhus verniciflua Stokes bark showed significant anti viral activity against fish pathogenic infectious hematopoietic necrosis virus (IHNV) and viral hemorrhagic septicemia virus (VHSV) in a cell-based assay measuring virus-induced cytopathic effect (CPE). Activity-guided fractionation and isolation for the 80% methanolic extract of R. verniciflua yielded the most active ethyl acetate fraction, and methyl gallate (1) and four flavonoids: fustin (2), fisetin (3), butin (4) and sulfuretin (5). Among them, fisetin (3) exhibited high antiviral activities against both IHNV and VHSV showing EC(50) values of 27.1 and 33.3 MUM with selective indices (SI = CC(50)/EC(50)) more than 15, respectively. Fustin (2) and sulfuretin (5) displayed significant antiviral activities showing EC50 values of 91.2-197.3 MUM against IHNV and VHSV. In addition, the antiviral activity of fisetin against IHNV and VHSV occurred up to 5 hr post-infection and was not associated with direct virucidal effects in a timed addition study using a plaque reduction assay. These results suggested that the bark of R. verniciflua and isolated flavonoids have significant anti-viral activity against IHNV and VHSV, and also have potential to be used as anti-viral therapeutics against fish viral diseases. PMID- 22538660 TI - Modulation of immune response by interleukin-10 in systemic Corynebacterium kutscheri infection in mice. AB - Interleukin (IL)-10 is an anti-inflammatory cytokine that modulates sepsis by decreasing pro-inflammatory cytokine production and chemokine expression. In this study, IL-10-deficient and wild-type (WT) mice were infected with Corynebacterium kutscheri to determine if the absence of IL-10 altered the protective immunity and pathogenesis. After infection, IL-10 knockout (KO) mice had a higher survival rate than WT mice. The decrease of body weight and the increased weight of organs such as liver and spleen were greater in WT mice. Bacterial counts were significantly increased after inoculation in WT mice over those in IL-10 KO mice. WT mice had more granulomatous inflammation and coagulative necrosis in the liver and spleen, lymphocyte depletion in lymphoid follicles, and apoptosis of immune cells in the spleen. WT mice had significantly higher plasma concentrations of aspartate aminotransferase and alanine aminotransferase. Furthermore, more upregulation of tumor necrosis factor-alpha and IL-4 in the plasma, macrophage inflammatory protein-2, keratinocyte-derived chemokine, inducible nitric oxide synthase, and interferon-inducible protein 10 mRNA in the spleen were observed in WT mice after inoculation. These results suggest that the lack of IL-10 contributes to an increase in the systemic clearance of C. kutscheri, and that IL 10 plays a detrimental role in controlling systemic C. kutscheri infection. PMID- 22538661 TI - Porphyromonas gingivalis-derived lipopolysaccharide-mediated activation of MAPK signaling regulates inflammatory response and differentiation in human periodontal ligament fibroblasts. AB - Porphyromonas gingivalis (P.g.), which is a potential pathogen for periodontal diseases, contains lipopolysaccharide (LPS), and this endotoxin stimulates a variety of cellular responses. At present, P.g.-derived LPS-induced cellular responses in human periodontal ligament fibroblasts (PDLFs) are not well characterized. Here, we demonstrate that P.g-derived LPS regulates inflammatory responses, apoptosis and differentiation in PDLFs. Interleukin-6 (IL-6) and -8 (IL-8) were effectively upregulated by treatment of P.g.-derived LPS, and we confirmed apoptosis markers including elevated cytochrome c levels, active caspase-3 and morphological change in the presence of P.g.-derived LPS. Moreover, when PDLFs were cultured with differentiation media, P.g.-derived LPS reduced the expression of differentiation marker genes, as well as reducing alkaline phosphatase (ALP) activity and mineralization. P.g.-derived LPS-mediated these cellular responses were effectively abolished by treatment of mitogen-activated protein kinase (MAPK) inhibitors. Taken together, our results suggest that P.g. derived LPS regulates several cellular responses via activation of MAPK signaling pathways in PDLFs. PMID- 22538663 TI - Expression and purification of lacticin Q by small ubiquitin-related modifier fusion in Escherichia coli. AB - Lacticin Q is a broad-spectrum class II bacteriocin with potential as an alternative to conventional antibiotics. The objective of this study was to produce recombinant lacticin Q using a small ubiquitin-related modifier (SUMO) fusion protein expression system. The 168-bp lacticin Q gene was cloned into the expression vector pET SUMO and transformed into Escherichia coli BL21(DE3). The soluble fusion protein was recovered with a Ni-NTA Sepharose column (95% purity); 130 mg protein was obtained per liter of fermentation culture. The SUMO tag was then proteolytically cleaved from the protein, which was re-applied to the column. Finally, about 32 mg lacticin Q (>=96% purity) was obtained. The recombinant protein exhibited antimicrobial properties similar to that of the native protein, demonstrating that lacticin Q had been successfully expressed by the SUMO fusion system. PMID- 22538662 TI - Cyclic AMP-receptor protein activates aerobactin receptor IutA expression in Vibrio vulnificus. AB - The ferrophilic bacterium Vibrio vulnificus can utilize the siderophore aerobactin of Escherichia coli for iron acquisition via its specific receptor IutA. This siderophore piracy by V. vulnificus may contribute to its survival and proliferation, especially in mixed bacterial environments. In this study, we examined the effects of glucose, cyclic AMP (cAMP), and cAMP-receptor protein (Crp) on iutA expression in V. vulnificus. Glucose dose-dependently repressed iutA expression. A mutation in cya encoding adenylate cyclase required for cAMP synthesis severely repressed iutA expression, and this change was recovered by in trans complementing cya or the addition of exogenous cAMP. Furthermore, a mutation in crp encoding Crp severely repressed iutA expression, and this change was recovered by complementing crp. Accordingly, glucose deprivation under iron limited conditions is an environmental signal for iutA expression, and Crp functions as an activator that regulates iutA expression in response to glucose availability. PMID- 22538664 TI - Heterologous expression of polygalacturonase genes isolated from Galactomyces citri-aurantii IJ-1 in Pichia pastoris. AB - ABSTACT: The objective of this work was to isolate the polygalacturonase genes of Galactomyces citri-aurantii IJ-1 harvested from rotten citrus peels and to heterologously express these genes in Pichia pastoris. Two polygalacturonase (PG) genes from G. citri-aurantii IJ-1 were obtained and tentatively named PG1 and PG2. The genes were cloned into pPICZalphaC, and expressed in Pichia pastoris strain GS115 with a native signal peptide or the alpha-factor secretion signal peptide of Saccharomyces cerevisiae. All of the recombinant proteins were successfully secreted into the culture media and confirmed as a single band with a molecular weight of 35 to 38 kDa by SDS-PAGE. The specific enzyme activities of recombinant PG1 and PG2 purified by His-tag affinity resin were 4,749 and 6,719 U/mg, respectively, with an optimal pH and temperature of pH 4.0 and 50 degrees C. The Michaelis-Menten kinetic constants for PG1 and PG2, K (m), were confirmed to be 0.94 and 0.84 mM, respectively. In the presence of Mn(2+), the activity of PG1 and PG2 were increased to 160.8 and 146.4% of normal levels, respectively. In contrast, Cu(2+) and Fe(3+) acted as strong inhibitors to the PGs. PMID- 22538665 TI - Remodeling of the glycosylation pathway in the methylotrophic yeast Hansenula polymorpha to produce human hybrid-type N-glycans. AB - As a step forward to achieve the generation of human complex-type N-glycans in the methylotrophic yeast Hansenula polymorpha, we here report the modification of the yeast glycosylation pathway by heterologous expression of the human gene encoding beta-1,2-N-acetylglucosaminyltransferase I (GnTI). For the optimal expression of human GnTI in the yeast Golgi compartment, the catalytic domain of the GnTI was fused to various N-terminal leader sequences derived from the yeast type II membrane proteins. The vectors containing GnTI fusion constructs were introduced into the H. polymorpha och1Delta single and och1Deltaalg3Delta double mutant strains expressing the ER-targeted Aspergillus saitoi alpha-1,2 mannosidase, respectively. Both of the glycoengineered Hpoch1Delta and Hpoch1DeltaHpalg3Delta strains were shown to produce successfully the hybrid-type glycans with a monoantennary N-acetylglucosamine (GlcNAc(1)Man(5)GlcNAc(2) and GlcNAc(1)Man(3)GlcNAc(2), respectively) by N-glycan profile analysis of cell wall proteins. Furthermore, by comparative analysis of byproduct formation and the glycosylation site occupancy, we propose that the Hpoch1Delta strain would be more suitable than the Hpoch1DeltaHpalg3Delta strain as a host for the production of recombinant proteins with humanized glycans. PMID- 22538666 TI - Phycicoccus ochangensis sp. nov., isolated from soil of a potato cultivation field. AB - Two novel, Gram-positive, motile, coccal bacteria, strains L1b-b9(T) and B5a-b5, were isolated from a potato cultivation field in Ochang, Korea. These isolates grew at 10-45 degrees C, pH 5.0-10.0, and in the presence of 8% (w/v) NaCl. The diagnostic diamino acid in the cell-wall peptidoglycan was meso-diaminopimelic acid. The major menaquinone was MK-8(H(4)) and the main cellular fatty acids were iso-C(14:0), iso-C(15:0), and anteiso-C(15:0). Polar lipids in strain L1b-b9(T) consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, and an unknown glyco-amino lipid. The G+C content of genomic DNA was 73.6 mol%. A phylogenetic analysis based on 16S rRNA gene sequences showed that strains L1b b9(T) and B5a-b5 shared 99.36% similarity and formed a robust clade with the type species of the genus Phycicoccus. Strain L1b-b9(T) is related most closely to Phycicoccus cremeus V2M29(T) (97.52% 16S rRNA gene sequence similarity). On the basis of phylogenetic characteristics, the name Phycicoccus ochangensis sp. nov. is proposed for strain LIb-b9(T) (=KCTC 19695(T) [corrected] =JCM 17595(T)). PMID- 22538667 TI - Arenimonas aquatica [corrected] sp. nov., a member of the gammaproteobacterium, isolated from a freshwater reservoir. AB - A novel bacterial strain, designated NA-09(T), was isolated from a freshwater sample collected from the Cheonho reservoir, Republic of Korea. Colonies were creamy-white pigmented, translucent, and circular with convex shape. The isolate was Gram-staining negative, strictly aerobic, motile, and rod-shaped. The 16S rRNA gene sequence analysis revealed that strain NA-09(T) belonged to the genus Arenimonas and showed the highest sequence similarities with Arenimonas malthae CC-JY-1(T) (95.4%), A. oryziterrae YC6267(T) (94.9%), A. composti P2-12-1(T) (94.8%), and A. donghaensis H03-R19(T) (94.1%). The major fatty acids were iso C(16:0) (20.8%), iso-C(15:0) (16.9%), summed feature 1 (13.2%), and iso-C(16:1) omega7c alcohol (10.2%). The major isoprenoid quinone of the isolate was ubiquionone-8. On the basis of the data from the polyphasic characterization, the strain NA-09(T) represents a novel species, for which the name Arenimonas aquatica [corrected] sp. nov. is proposed (type strain NA-09(T) =KACC 14663(T) =NBRC 106550(T)). PMID- 22538668 TI - GFP-expressing influenza A virus for evaluation of the efficacy of antiviral agents. AB - To address its value as a screening tool in the development of antiviral drugs, a recombinant influenza virus expressing green fluorescent protein (rPR8-GFP virus) was investigated in vitro and in vivo. The inhibition of viral growth by a neuraminidase inhibitor in the cells or lower respiratory tracts of mice could be visualized by the level of fluorescence. In addition, the rPR8-GFP virus exhibited high pathogenicity in mice. Taken together, these results suggest that the rPR8-GFP virus can be a useful tool for the rapid identification of antiviral drugs active against influenza viruses. PMID- 22538670 TI - Patient-perspective quality of life after laparoscopic and open hernia repair: a controlled randomized trial. AB - BACKGROUND: Laparoscopic hernia repair accounts for 10% of all hernia surgery. Potential benefits include reduction in postoperative pain, rapid recovery, lower recurrence rate, and fewer complications. The outcomes of health-related quality of life and patient perspective after hernia repair are our aim. METHODS: Consecutive patients treated for unilateral uncomplicated groin hernia were enrolled after evaluation for inclusion. Participants were randomly distributed to receive either laparoscopic transabdominal preperitoneal repair (TAPP) (group I) or Lichtenstein repair (group II). Operative and postoperative complications, operative time, hospital stay, and late complications were assessed early postoperatively, at 4 weeks, and every 6 months thereafter. Quality of life was assessed using Short Form-36 questionnaire in the first visit (after 4 weeks). RESULTS: One hundred and eighty-five patients of unilateral uncomplicated groin hernia were included; 88 patients (group I) were treated by TAPP, and 97 patients were treated by Lichtenstein repair (group II) with median follow-up of 17.9 months. Mean hospital stay, mean operative time, operative and postoperative complications were similar in the two groups. Quality of life showed better and significant outcomes in group I for physical function (p <= 0.001), role physical (p <= 0.011), bodily pain (p <= 0.017), general health (p <= 0.047), and total physical health (p <= 0.008). However, mental health showed no statistical significance in its four scales, but with better outcomes in group I. Total quality outcomes showed significantly better outcomes in group I (p <= 0.031). CONCLUSIONS: TAPP hernia repair technique is a safe technique with low complication rate, less postoperative body pain, and better quality-of-life outcomes compared with open technique, being well accepted from the patient's perspective for quality of life. PMID- 22538671 TI - Drain after elective laparoscopic cholecystectomy. A randomized multicentre controlled trial. AB - BACKGROUND: Routine drainage after laparoscopic cholecystectomy is still debatable. The present study was designed to assess the role of drains in laparoscopic cholecystectomy performed for nonacutely inflamed gallbladder. METHODS: After laparoscopic gallbladder removal, 53 patients were randomized to have a suction drain positioned in the subhepatic space and 53 patients to have a sham drain. The primary outcome measure was the presence of subhepatic fluid collection at abdominal ultrasonography, performed 24 h after surgery. Secondary outcome measures were postoperative abdominal and shoulder tip pain, use of analgesics, nausea, vomiting, and morbidity. RESULTS: Subhepatic fluid collection was not found in 45 patients (84.9 %) in group A and in 46 patients (86.8 %) in group B (difference 1.9 (95 % confidence interval -11.37 to 15.17; P = 0.998). No significant difference in visual analogue scale scores with respect to abdominal and shoulder pain, use of parenteral ketorolac, nausea, and vomiting were found in either group. Two (1.9 %) significant hemorrhagic events occurred postoperatively. Wound infection was observed in three patients (5.7 %) in group A and two patients (3.8 %) in group B (difference 1.9 (95 % CI -6.19 to 9.99; P = 0.997). CONCLUSIONS: The present study was unable to prove that the drain was useful in elective, uncomplicated LC. PMID- 22538672 TI - Refractory and new-onset diabetes more than 5 years after gastric bypass for morbid obesity. AB - BACKGROUND: Few studies about long-term glucose homeostasis in bariatric patients are available. In a prospective protocol that included retrospective information, outcome of patients with both impaired and normal fasting blood glucose (FBG) was monitored to assess frequencies and correlates. METHODS: Patients submitted to Roux-en-Y gastric bypass were classified as group I, elevated FBG, and group II, normal controls. Those in group I with improvement in FBG were defined as responsive and the others as refractory. Group II participants progressing to new onset diabetes (NOD) or prediabetes represented NOD cases; the remaining were listed as stable controls. FBG was the main endpoint, but HbA1c results were considered, along with diet composition and general biochemical profile. RESULTS: Among 97 selected patients, 51 belonged to group I (52.4 +/- 10.5 years, 29.6 % males, initial body mass index (BMI) 58.4 +/- 13.4, current BMI 35.1 +/- 8.4 kg/m(2)) and 46 to group II (48.2 +/- 10.5 years, 19.6 % males, initial BMI 55.5 +/- 8.8, current BMI 33.9 +/- 6.9 kg/m(2)). Follow-up was 7-9 years, and 31.4 % (16/51) of group I were classified as refractory, whereas 15.2 % (7/46) of the controls converted to NOD. Multivariate analysis pointed out higher current BMI, older age, consumption of antidiabetic drugs, and male gender as features of refractory cases, whereas NOD participants were not significantly different from non-progressing controls. CONCLUSIONS: This is the first investigation, to the best of our knowledge, to underscore the correlates of refractory and NOD within the bariatric context. Further studies are recommended as such information could be valuable for patient selection, prognostic scoring, and outcome monitoring. PMID- 22538673 TI - Development of novel electrospun absorbable polycaprolactone (PCL) scaffolds for hernia repair applications. AB - INTRODUCTION: Permanent/nonresorbable hernia repair materials rely on profibrotic wound healing, and repair sites are commonly composed of disorganized tissue with inferior mechanical strength and risk of reherniation. Resorbable electrospun scaffolds represent a novel class of biomaterials, which may provide a unique platform for the design of advanced soft tissue repair materials. These materials are simple, inexpensive, nonwoven materials composed of polymer fibers that readily mimic the natural extracellular matrix. The primary goal of the present study was to evaluate the physiomechanical properties of novel electrospun scaffolds to determine their suitability for hernia repair. Based on previous experimentation, scaffolds possessing >= 20 N suture retention strength, >= 20 N tear resistance, and >= 50 N/cm tensile strength are appropriate for hernia repair. METHODS: Six novel electrospun scaffolds were fabricated by varying combinations of polymer concentration (10-12 %) and flow rate (3.5-10 mL/h). Briefly, poly(epsilon-caprolactone) (PCL) was dissolved in a solvent mixture and electrospun onto a planar metal collector, yielding sheets with randomly oriented fibers. Physiomechanical properties were evaluated through scanning electron microscopy, laser micrometry, and mechanical testing. RESULTS: Scanning electron micrographs demonstrated fiber diameters ranging from 1.0 +/- 0.1 MUm (10 % PCL, 3.5 mL/h) to 1.5 +/- 0.2 MUm (12 % PCL, 4 mL/h). Laser micrometry demonstrated thicknesses ranging from 0.72 +/- 0.07 mm (12 % PCL, 10 mL/h) to 0.91 +/- 0.05 mm (10 % PCL, 3.5 mL/h). Mechanical testing identified two scaffolds possessing suture retention strengths >= 20 N (12 % PCL, 10 mL/h and 12 % PCL, 6 mL/h), and no scaffolds possessing tear resistance values >= 20 N (range, 4.7 +/- 0.9 N to 10.6 +/- 1.8 N). Tensile strengths ranged from 35.27 +/- 2.08 N/cm (10 % PCL, 3.5 mL/h) to 81.76 +/- 15.85 N/cm (12 % PCL, 4 mL/h), with three scaffolds possessing strengths >= 50 N/cm (12 % PCL, 10 mL/h; 12 % PCL, 6 mL/h; 12 % PCL, 4 mL/h). CONCLUSIONS: Two electrospun scaffolds (12 % PCL, 10 mL/h and 12 % PCL, 6 mL/h) possessed suture retention and tensile strengths appropriate for hernia repair, justifying evaluation in a large animal model. Additional studies examining advanced methods of fabrication may further improve the unique properties of these scaffolds, propelling them into applications in a variety of clinical settings. PMID- 22538674 TI - Outcome of alimentary tract duplications operated on by minimally invasive surgery: a retrospective multicenter study by the GECI (Groupe d'Etude en Coeliochirurgie Infantile). AB - BACKGROUND: Alimentary tract duplications (ATD) are a rare cause of intestinal obstruction in childhood. There are many case reports but few series about laparoscopy or thoracoscopy for ATD. The aim of our study was to report the outcome of minimally invasive surgery (MIS) for ATD. METHODS: This was a retrospective multicenter study from the GECI (Groupe d'Etude en Coeliochirurgie Infantile). We reviewed the charts of 114 patients operated on by MIS for ATD from 1994 to 2009. RESULTS: Sixty-two patients (54 %) had a prenatal diagnosis. Forty-nine patients (43 %) were symptomatic before surgery: 33 of those patients (63 %) with postnatal diagnosis compared to 16 (25 %) with prenatal diagnosis (P < 0.01). In this last group, the median age at onset of symptoms was 16 days (range = 0-972). One hundred and two patients had laparoscopy (esophageal to rectal duplications) and 12 patients had thoracoscopy for esophageal duplications. The mean operative time was 90 min (range = 82-98). There were 32 (28 %) resection anastomoses, 55 (48 %) enucleations, and 27 (24 %) unroofings. The conversion rate was 32 %, and in a multivariate analysis, it was significantly higher, up to 41 % for patients weighing <10 kg (P < 0.01). Ten patients (8 %) had unintentional perioperative opening of the digestive tract during the dissection. Eight patients had nine postoperative complications, including six small bowel obstructions. The median length of hospital stay was 4 days (range = 1-21) without conversion and 6 days (range = 1-27) with conversion (P = 0.01). The median follow-up was 3 months (range = 1-120). Eighteen of the 27 patients who underwent partial surgery had an ultrasound examination during follow-up. Five (18 %) of them had macroscopic residue. CONCLUSION: This study showed that MIS for ATD is feasible with a low rate of complications. Patients with prenatal diagnosis should have prompt surgery to prevent symptoms, despite a high rate of conversion in small infants. PMID- 22538675 TI - Transoral stapling for Zenker diverticulum: effect of the traction suture assisted technique on long-term outcomes. AB - BACKGROUND: Long-term outcomes and predictors of success after transoral stapling for Zenker diverticulum are still unclear. METHODS: Between 2001 and 2010, 91 patients with Zenker diverticulum underwent transoral stapling under general anesthesia. Since 2008, the technique was modified by applying traction sutures to ease engagement of the common septum inside the stapler jaws. Perioperative variables, distribution of symptoms, and outcome of surgery were analyzed. Long term results were compared between patients undergoing standard versus modified technique of transoral stapling. RESULTS: The transoral approach was successfully completed in 79 (86.8 %) patients with a median age of 74 years. Overall morbidity was 5 %, and there was no mortality. The median length of hospital stay was 2 days. Six patients were lost to follow-up. After a median follow-up of 53 (range, 12-114) months, an improvement of dysphagia and regurgitation scores (p < 0.001) and a reduction in the number of pneumonia episodes per year (p < 0.001) was recorded. The long-term success rate of the procedure was 80.1 %. At a median time of 12 months, 14 patients complained of recurrent symptoms, 7 of whom needed an open (n = 4) or transoral (n = 3) reoperation. Use of traction sutures resulted in a greater long-term success compared with the standard procedure (p = 0.04). CONCLUSIONS: Transoral stapling is a safe and effective technique. A repeat procedure is feasible in case of recurrent diverticulum. The use of traction sutures applied at the apex of the common septum before stapling might increase the long-term success of the technique. PMID- 22538676 TI - Single-incision versus conventional laparoscopic colectomy for colonic neoplasm: a randomized, controlled trial. AB - BACKGROUND: Single-incision laparoscopic colectomy (SILC) is a newly developed procedure with the benefit of better cosmetic outcome and potentially reduced wound pain compared with conventionally laparoscopic colectomy (CLC). However, the application of SILC requires careful evaluation to prove its benefit and safety. This randomized, controlled study compared the operative outcome of patients who underwent SILC and CLC. METHODS: Patients who had small cancer (<4 cm) or adenomatous polyp requiring colectomy were randomized to have SILC or CLC. The patients were blinded to the procedures and the postoperative pain was used as the primary outcome measure. All patients had patient-controlled analgesia with intravenous morphine after the operation and the nominal rating score on days 1-3 and day 14 were recorded by research staff, who did not known the types of operations. Other operative outcomes of the two groups of patients also were recorded prospectively and compared. RESULTS: There were 25 patients in each group. The patients' demographics, tumor characteristics, operating time, blood loss, complication rate, number of lymph nodes harvested, and resection margin have no statistically significant difference between the two groups. There was no operative mortality in both groups. The SILC group had consistently lower median pain score than CLC group in the whole postoperative course and the difference was statistically significant on day 1 (0 (0-5) vs. day 3 (0-6) respectively; p = 0.002) and day 2 (0 (0-3) vs. 2 (0-8) respectively; p = 0.014). The median hospital stay in the SILC group also was shorter the CLC group. CONCLUSIONS: In a selected group of patients with small tumor and good operative risk, SILC is a safe alternative to CLC. Single-port laparoscopic colectomy also is associated with the benefits of less postoperative pain and shorter hospital stay than CLC. PMID- 22538677 TI - Surgeons don't know what they don't know about the safe use of energy in surgery. AB - BACKGROUND: Surgeons are not required to train on energy-based devices or document their knowledge of safety issues related to their use. Their understanding of how to safely use the devices has never formally been tested. This study assessed that knowledge in a cohort of gastrointestinal surgeons and determined if key facts could be learned in a half-day course. METHODS: SAGES piloted a postgraduate CME course on the Fundamental Use of Surgical EnergyTM (FUSE) at the 2011 SAGES meeting. Course faculty prepared an 11-item multiple choice examination (pretest) of critical knowledge. We administered it to members of the SAGES board; Quality, Outcomes and Safety Committee; and FUSE Task Force. Postgraduate course participants took the pretest, and at the end of the course they took a 10-item post-test that covered the same content. Data are expressed as median (interquartile range, IQR). RESULTS: Forty-eight SAGES leaders completed the test: the median percent of correct answers was 59 % (IQR = 55-73 %; range = 0-100 %). Thirty-one percent did not know how to correctly handle a fire on the patient; 31 % could not identify the device least likely to interfere with a pacemaker; 13 % did not know that thermal injury can extend beyond the jaws of a bipolar instrument; and 10 % thought a dispersive pad should be cut to fit a child. Pretest results for 27 participants in the postgraduate course were similar, with a median of 55 % correct (IQR = 46-82 %). Participants were not told the correct answers. At the end of the course, 25 of them completed a different 10-item post-test, with a median of 90 % correct (IQR = 70-90 %). CONCLUSIONS: Many surgeons have knowledge gaps in the safe use of widely used energy-based devices. A formal curriculum in this area can address this gap and contribute to increased safety. PMID- 22538678 TI - Comprehensive proficiency-based inanimate training for robotic surgery: reliability, feasibility, and educational benefit. AB - BACKGROUND: We previously developed a comprehensive proficiency-based robotic training curriculum demonstrating construct, content, and face validity. This study aimed to assess reliability, feasibility, and educational benefit associated with curricular implementation. METHODS: Over an 11-month period, 55 residents, fellows, and faculty (robotic novices) from general surgery, urology, and gynecology were enrolled in a 2-month curriculum: online didactics, half-day hands-on tutorial, and self-practice using nine inanimate exercises. Each trainee completed a questionnaire and performed a single proctored repetition of each task before (pretest) and after (post-test) training. Tasks were scored for time and errors using modified FLS metrics. For inter-rater reliability (IRR), three trainees were scored by two raters and analyzed using intraclass correlation coefficients (ICC). Data from eight experts were analyzed using ICC and Cronbach's alpha to determine test-retest reliability and internal consistency, respectively. Educational benefit was assessed by comparing baseline (pretest) and final (post-test) trainee performance; comparisons used Wilcoxon signed-rank test. RESULTS: Of the 55 trainees that pretested, 53 (96 %) completed all curricular components in 9-17 h and reached proficiency after completing an average of 72 +/- 28 repetitions over 5 +/- 1 h. Trainees indicated minimal prior robotic experience and "poor comfort" with robotic skills at baseline (1.8 +/- 0.9) compared to final testing (3.1 +/- 0.8, p < 0.001). IRR data for the composite score revealed an ICC of 0.96 (p < 0.001). Test-retest reliability was 0.91 (p < 0.001) and internal consistency was 0.81. Performance improved significantly after training for all nine tasks and according to composite scores (548 +/- 176 vs. 914 +/- 81, p < 0.001), demonstrating educational benefit. CONCLUSION: This curriculum is associated with high reliability measures, demonstrated feasibility for a large cohort of trainees, and yielded significant educational benefit. Further studies and adoption of this curriculum are encouraged. PMID- 22538679 TI - Cosmetic outcome is an important parameter when comparing single-incision laparoscopic surgery (SILS) and conventional multiport laparoscopic cholecystectomy (CLC). PMID- 22538681 TI - Surgical evaluation of a novel tethered robotic capsule endoscope using micro patterned treads. AB - BACKGROUND: The state-of-the-art technology for gastrointestinal (GI) tract exploration is a capsule endoscope (CE). Capsule endoscopes are pill-sized devices that provide visual feedback of the GI tract as they move passively through the patient. These passive devices could benefit from a mobility system enabling maneuverability and controllability. Potential benefits of a tethered robotic capsule endoscope (tRCE) include faster travel speeds, reaction force generation for biopsy, and decreased capsule retention. METHODS: In this work, a tethered CE is developed with an active locomotion system for mobility within a collapsed lumen. Micro-patterned polydimethylsiloxane (PDMS) treads are implemented onto a custom capsule housing as a mobility method. The tRCE housing contains a direct current (DC) motor and gear train to drive the treads, a video camera for visual feedback, and two light sources (infrared and visible) for illumination. RESULTS: The device was placed within the insufflated abdomen of a live anesthetized pig to evaluate mobility performance on a planar tissue surface, as well as within the cecum to evaluate mobility performance in a collapsed lumen. The tRCE was capable of forward and reverse mobility for both planar and collapsed lumen tissue environments. Also, using an onboard visual system, the tRCE was capable of demonstrating visual feedback within an insufflated, anesthetized porcine abdomen. CONCLUSION: Proof-of-concept in vivo tRCE mobility using micro-patterned PDMS treads was shown. This suggests that a similar method could be implemented in future smaller, faster, and untethered RCEs. PMID- 22538683 TI - The long-term efficacy of laparoscopic surgery in early and advanced gastric cancer. PMID- 22538682 TI - Perioperative outcomes using LigaSureTM compared to conventional bipolar instruments in laparoscopic salpingo-oophorectomy: a randomized controlled trial. AB - BACKGROUND: The aim of this study was to compare the effects of LigaSureTM versus conventional bipolar techniques on operating time and blood loss during laparoscopic salpingo-oophorectomy in a randomized controlled trial. METHODS: In three teaching hospitals, 100 women undergoing a laparoscopic salpingo oophorectomy were randomized for LigaSure or conventional bipolar instruments. Primary outcome was operating time (from initial skin incision to removal of the specimen). Secondary outcome measures were total operating time (from initial skin incision to skin closure), time to dissect the ovarian and infundibulopelvic ligaments, intraoperative blood loss, and subjective judgment of the instrument used. RESULTS: There were no differences in operating time and total operating time using LigaSure versus conventional bipolar instruments: 41.0 vs. 39.2 min (p = 0.78; 95 % CI = -10.9 to 14.5) and 54.6 vs. 58.6 min (p = 0.46; 95 % CI = -14.8 to 6.8), respectively. The mean blood loss using LigaSure versus conventional bipolar instruments was 38 vs. 33 mL (p = 0.73; 95 % CI = -22.7 to 32.2). Various subjective efficacy and instrument handling parameters of the two instruments varied among participating centers. CONCLUSION: There were no significant differences in operating time and blood loss with the use of LigaSure compared to conventional bipolar instruments during laparoscopic salpingo-oophorectomy, even after correction for potential confounders. PMID- 22538684 TI - Effectiveness of electrothermal bipolar vessel-sealing devices versus other electrothermal and ultrasonic devices for abdominal surgical hemostasis: a systematic review. AB - BACKGROUND: Adequate hemostatic techniques are essential for optimal intra- and postoperative results. A number of different hemostatic techniques and devices have been developed over the past few years, but which device should be preferred during laparoscopic and open abdominal procedures? METHODS: We conducted a systematic search for randomized controlled trials (RCTs) that compared the effectiveness and costs of vessel-sealing devices with those of other electrothermal or ultrasonic devices in abdominal surgical procedures. RESULTS: Seven RCTs that included 554 patients met the inclusion criteria. Various procedures that used a vessel-sealing device (LigaSureTM) (n = 264) were compared to ultrasonic devices (n = 139) and mono- (n = 20) or bipolar devices (n = 130). LigaSure was favored in two studies with respect to less blood loss, shorter operating time, and lower costs. However, no differences were observed in the other studies. Considering the relatively low number of complications, all hemostatic devices used may be considered relatively safe. None of the studies reported on quality of life or cost effectiveness. CONCLUSIONS: Vessel-sealing devices may be considered safe and their use may reduce costs due to reduced blood loss and shorter operating time in some abdominal surgical procedures compared to mono- or bipolar electrothermal devices. Wider-ranging RCTs of sufficient quality that assess (cost) effectiveness are required to make firm conclusions. PMID- 22538685 TI - Effect of enzymatic degradation on the mechanical properties of biological scaffold materials. AB - BACKGROUND: Biological scaffolds must support a complex balance of resisting enzymatic degradation while promoting tissue remodeling. Thus, the purpose of this study was to evaluate the effects of in vitro enzymatic exposure on the mechanical properties of biological scaffolds. It was hypothesized that exposure to an enzyme solution would result in decreased tensile strength and that crosslinked scaffolds would resist enzymatic degradation more effectively than noncrosslinked scaffolds. METHODS: Nine scaffolds were evaluated (four porcine dermis: PermacolTM, CollaMendTM, StratticeTM, XenMatrixTM; two human dermis: AlloMaxTM, FlexHD((r)); two bovine pericardium: Veritas((r)), PeriGuard((r)); and one porcine small intestine submucosa: SurgisisTM). Ten specimens (n = 10) were hydrated in saline at 37 degrees C and subjected to uniaxial testing to establish baseline properties. 50 specimens (n = 50) were incubated in collagenase solution at 37 degrees C for 2, 6, 12, 24, or 30 h (n = 10 each group) followed by uniaxial tensile testing. RESULTS: Tensile strength was significantly reduced after 30 h for CollaMendTM, AlloMaxTM, Veritas((r)), StratticeTM, XenMatrixTM, PermacolTM, and FlexHD((r)) (p < 0.01), while PeriGuard((r)) demonstrated a slight increase in tensile strength (p = 0.0188). Crosslinked bovine pericardium (PeriGuard((r))) maintained greater tensile strength than noncrosslinked bovine pericardium (Veritas((r))) throughout all exposure periods (p < 0.0001). Similarly, crosslinked porcine dermis (PermacolTM) maintained greater tensile strength than noncrosslinked porcine dermis (StratticeTM and XenMatrixTM) throughout all exposure periods (p < 0.0001). CONCLUSIONS: Materials that deteriorate rapidly after in vitro enzymatic exposure may also deteriorate rapidly in vivo, particularly when exposed to a wound environment with elevated levels of matrix metalloproteinases. PermacolTM, CollaMendTM, StratticeTM, FlexHD((r)), and PeriGuard((r)) survived the longest incubation period (30 h) and withstood mechanical testing. XenMatrixTM, AlloMaxTM, Veritas((r)), and SurgisisTM degraded more quickly and did not survive the longer exposure periods. Scaffolds that maintain strength characteristics after in vitro collagenase exposure may be advantageous for long-term hernia repair scenarios where elevated enzyme levels are expected. PMID- 22538686 TI - Gallbladder damage control: compromised procedure for compromised patients. AB - BACKGROUND: The objective of this study was to analyze a population-based database for (1) recent 9-year trends in utilization of partial cholecystectomy (PC), laparoscopic PC, and trocar cholecystostomy (TC), (2) demographics, associated diagnoses, and hospital characteristics, and (3) relevant inpatient outcomes. METHODS: Retrospective cohort analysis of the Nationwide Inpatient Sample (NIS) files from 2000 to 2008 was performed. For the purposes of the study, gallbladder damage control was defined as PC, laparoscopic PC, and TC. RESULTS: A national estimate of 10,872 gallbladder damage control cases was obtained. Procedures performed included PC (47.8 %), laparoscopic PC (27.2 %), TC (25.3 %), and intraoperative cholangiogram (IOC) (19.7 %). A total of 1,479 (13.6 %) postoperative complications were identified, including pulmonary complications (4.3 %), hemorrhage/hematoma/seroma (3.4 %), and accidental puncture or laceration during procedure (3.3 %). Common bile duct injury occurred in 3.3 % overall. Hospital types included nonteaching (82.1 %) and urban (67.8 %), with regional variations of 42.1 % from the South and 45.2 % from the West. Inpatient outcomes included mean length of stay of 11.4 (0.16 SEM) days, mean total hospital charge of $71,296.69 ($1,106.03 SEM), 7.4 % mortality, and 16.8 % discharge to skilled nursing facility. Multivariate logistic regression analysis identified independent risk variables for common bile duct injury: teaching hospitals (OR = 1.517, CI = 1.155-1.991, P = 0.003). IOC (OR = 2.030, CI = 1.590 2.591, P < 0.001) was a commonly associated procedure in the setting of common bile duct injury. CONCLUSION: Various circumstances may require gallbladder damage control with PC and TC. Postoperative complications and common bile duct injury remain significantly high despite limited resection, and the teaching status of the hospital is associated with CBD injury. High morbidity and mortality of gallbladder damage control may reflect both the compromised nature of the procedures and multiple comorbidities. PMID- 22538687 TI - Effect of monopolar radiofrequency energy on pacemaker function. AB - BACKGROUND: This study aimed to quantify the clinical parameters of mono- and bipolar instruments that inhibit pacemaker function. The specific aims were to quantify pacer inhibition resulting from the monopolar instrument by altering the generator power setting, the generator mode, the distance between the active electrode and the pacemaker, and the location of the dispersive electrode. METHODS: A transvenous ventricular lead pacemaker overdrive paced the native heart rate of an anesthetized pig. The primary outcome variable was pacer inhibition quantified as the number of beats dropped by the pacemaker during 5 s of monopolar active electrode activation. RESULTS: Lowering the generator power setting from 60 to 30 W decreased the number of dropped paced events (2.3 +/- 1.2 vs 1.6 +/- 0.8 beats; p = 0.045). At 30 W of power, use of the cut mode decreased the number of dropped paced beats compared with the coagulation mode (0.6 +/- 0.5 vs 1.6 +/- 0.8; p = 0.015). At 30 W coagulation, firing the active electrode at different distances from the pacemaker generator (3.75, 7.5, 15, and 30 cm) did not change the number of dropped paced beats (p = 0.314, analysis of variance [ANOVA]). The dispersive electrode was placed in four locations (right/left gluteus, right/left shoulder). More paced beats were dropped when the current vector traveled through the pacemaker/leads than when it did not (1.5 +/- 1.0 vs 0.2 +/- 0.4; p < 0.001). CONCLUSIONS: Clinical parameters that reduce the inhibition of a pacemaker by monopolar instruments include lowering the generator power setting, using cut (vs coagulation) mode, and locating the dispersive electrode so the current vector does not traverse the pacemaker generator or leads. PMID- 22538688 TI - Gasless transaxillary robotic versus endoscopic thyroidectomy: exploring the frontiers of scarless thyroidectomy through a preliminary comparison study. AB - BACKGROUND: Robot-assisted thyroidectomy has been associated with lengthy operative times due to fussy robot preparation and docking maneuvers. The authors propose an endoscopic transaxillary approach using a novel platform, comparing its results with those of the former approach. METHODS: Eight patients (6 females and 2 males; mean age, 38.8 years) with a favorable body habitus (mean body mass index [BMI], 23.4 kg/m(2)) underwent robot-assisted thyroidectomy through a gasless transaxillary approach using the da Vinci S system. Another four female patients (mean age, 31 years) underwent an endoscopic procedure. The patients' demographic data, operative time, complications, hospital stay, postoperative visual analog pain score (VAPS), and costs were compared. RESULTS: Three lobectomies, two near-total thyroidectomies, two total thyroidectomies, and one total thyroidectomy with lateral lymph node dissection were performed in the robotic group. Two lobectomies and two near total thyroidectomies were performed in the endoscopic group. The mean diameter of the largest nodule in the robotic series was 26.5 mm compared with 42.5 mm in the endoscopic group. The mean total operative time was 211 min for the robotic series compared with 160 min for the endoscopic series. There was one temporary recurrent laryngeal nerve paralysis in the robotic group. Two patients in the robotic group exhibited transient symptomatic hypocalcemia compared with one patient in the endoscopic group. Hypoesthesia in the flap dissection area was experienced by three patients in the robotic group and two patients of the endoscopic group. The mean hospital stay was 1.5 days (range 1-3 days) in both groups. The postoperative VAPS also was similar in the two groups (3.1 vs 2.8). The cost was significantly less for the endoscopic approach. CONCLUSIONS: The preliminary comparison in this study shows that both approaches are safe and feasible, with similar results. They also afford an excellent view of the critical neck anatomy that allows precise tissue handling and dissection. However, the endoscopic approach results in a significantly faster and more convenient thyroidectomy. PMID- 22538689 TI - Personalized medicine for laparoscopic gastrectomy used to treat gastric cancer. PMID- 22538690 TI - Implications of the law on video recording in clinical practice. AB - BACKGROUND: Technological developments allow for a variety of applications of video recording in health care, including endoscopic procedures. Although the value of video registration is recognized, medicolegal concerns regarding the privacy of patients and professionals are growing. A clear understanding of the legal framework is lacking. Therefore, this research aims to provide insight into the juridical position of patients and professionals regarding video recording in health care practice. METHODS: Jurisprudence was searched to exemplify legislation on video recording in health care. In addition, legislation was translated for different applications of video in health care found in the literature. RESULTS: Three principles in Western law are relevant for video recording in health care practice: (1) regulations on privacy regarding personal data, which apply to the gathering and processing of video data in health care settings; (2) the patient record, in which video data can be stored; and (3) professional secrecy, which protects the privacy of patients including video data. Practical implementation of these principles in video recording in health care does not exist. CONCLUSION: Practical regulations on video recording in health care for different specifically defined purposes are needed. Innovations in video capture technology that enable video data to be made anonymous automatically can contribute to protection for the privacy of all the people involved. PMID- 22538691 TI - Surgical treatment of complicated right colonic diverticulitis: laparoscopic versus open surgery. AB - BACKGROUND: Complicated right colonic diverticulitis is more common in Eastern countries. Although this disease entity is treated primarily with surgery, it is uncertain whether the outcomes of laparoscopic treatment also are comparable with those of open surgery. This study aimed to evaluate the outcome for laparoscopic surgical management of complicated right-sided colonic diverticulitis compared with that for open surgery. METHODS: Between 1999 and 2011, 59 patients who underwent extensive surgery for complicated right colonic diverticulitis were enrolled from two hospitals. All the patients were suspected of having a large abscess or perforation with peritonitis symptoms preoperatively. Laparoscopic surgery was performed for 28 consecutive patients in the one hospital, and open surgery was performed for 31 consecutive patients in the other hospital. There was no conversion in the laparoscopic surgery cases. Clinical outcomes were analyzed and compared between the two groups. RESULTS: Laparoscopic surgery had a longer operating time (165 min) than open surgery (132 min) (p = 0.003). The two groups did not differ significantly in terms of postoperative hospital stay (laparoscopy 9.8 +/- 2.7 days versus open surgery 12.8 +/- 8.8 days; p = 0.234) or resumption of diet (laparoscopy 5.5 +/- 2.4 days versus open surgery 6.3 +/- 3.0 days; p = 0.286). Five patients in the laparoscopy group (17.8 %) had complications such as ileus, abscess, and bleeding, one of whom was treated with surgery. Nine patients in the open surgery group (29 %) had complications, two of whom were treated with surgery. CONCLUSIONS: The laparoscopic approach to complicated right colonic diverticulitis may be feasible. The clinical outcomes were comparable with those for open surgery. PMID- 22538692 TI - Quantitative analysis of intraoperative communication in open and laparoscopic surgery. AB - BACKGROUND: Communication is important for patient safety in the operating room (OR). Several studies have assessed OR communications qualitatively or have focused on communication in crisis situations. This study used prospective, quantitative observation based on well-established communication theory to assess similarities and differences in communication patterns between open and laparoscopic surgery. METHODS: Based on communication theory, a standardized proforma was developed for assessment in the OR via real-time observation of communication types, their purpose, their content, and their initiators/recipients. Data were collected prospectively in real time in the OR for 20 open and 20 laparoscopic inguinal hernia repairs. Assessors were trained and calibrated, and their reliability was established statistically. RESULTS: During 1,884 min of operative time, 4,227 communications were observed and analyzed (2,043 laparoscopic vs 2,184 open communications). The mean operative duration (laparoscopic, 48 min vs open, 47 min), mean communication frequency (laparoscopic, 102 communications/procedure vs open, 109 communications/procedure), and mean communication rate (laparoscopic, 2.13 communications/min vs open, 2.23 communications/min) did not differ significantly across laparoscopic and open procedures. Communications were most likely to be initiated by surgeons (80-81 %), to be received by either other surgeons (46-50%) or OR nurses (38-40 %), to be associated with equipment/procedural issues (39-47 %), and to provide direction for the OR team (38-46%) in open and laparoscopic cases. Moreover, communications in laparoscopic cases were significantly more equipment related (laparoscopic, 47 % vs open, 39 %) and aimed significantly more at providing direction (laparoscopic, 46 % vs open, 38 %) and at consulting (laparoscopic, 17 % vs open, 12 %) than at sharing information (laparoscopic, 17 % vs open, 31 %) (P < 0.001 for all). CONCLUSIONS: Numerous intraoperative communications were found in both laparoscopic and open cases during a relatively low-risk procedure (average, 2 communications/min). In the observed cases, surgeons actively directed and led OR teams in the intraoperative phase. The lack of communication between surgeons and anesthesiologists ought to be evaluated further. Simple, inexpensive interventions shown to streamline intraoperative communication and teamworking (preoperative briefing, surgeons' mental practice) should be considered further. PMID- 22538693 TI - The cap-assisted technique enhances colonoscopy training: prospective randomized study of six trainees. AB - BACKGROUND: Colonoscopy and polypectomy procedures have effectively reduced the incidence of colorectal cancer. Currently, competence in colonoscopy is an essential part of the education program for gastrointestinal (GI) trainees. However, considerable training is required for the optimal performance of a colonoscopy. METHODS: This study involved six colonoscopy trainees, three of whom used the cap whereas the others did not. Each trainee managed 100 cases of screening colonoscopy from beginning to end. The cecal intubation success rate, cecal intubation time, polyp detection rate, adenoma detection rate, advanced adenoma detection rate, and adenocarcinoma detection rate were checked. The rate of successful cecal intubation and the cecal intubation time were reviewed every 10 cases. RESULTS: The cecal intubation rate was 80.7 % (242/300) in the cap group and 63.3 % (190/300) in the non-cap group. The average cecal intubation time was 13.7 min in the cap group and 18.7 min in the non-cap group. The statistical analysis of these results suggested that the cap group had a significantly higher success rate (p < 0.001) and a shorter cecal intubation time (p < 0.001) than the non-cap group. However, the two groups did not differ significantly in the detection rate for polyps (45.3 vs 43 %; p = 0.565), adenomas (26.3 vs 25 %; p = 0.709), advanced adenomas (2.6 vs 0.6 %; p = 0.056), or adenocarcinomas (5.3 vs 3 %; p = 0.153). CONCLUSION: Cap-assisted colonoscopies might help to increase the rate of cecal intubation success and shorten the cecal intubation time for GI trainees. PMID- 22538694 TI - The LINX(r) reflux management system: confirmed safety and efficacy now at 4 years. AB - BACKGROUND: Sphincter augmentation with the LINX(r) Reflux Management System is a surgical option for patients with chronic gastroesophageal disease (GERD) and an inadequate response to proton pump inhibitors (PPIs). Clinical experience with sphincter augmentation is now available out to 4 years. METHODS: In a multicenter, prospective, single-arm study, 44 patients underwent a laparoscopic surgical procedure for placement of the LINX System around the gastroesophageal junction (GEJ). Each patient's baseline GERD status served as the control for evaluations post implant. Long-term efficacy measures included esophageal acid exposure, GERD quality-of-life measures, and use of PPIs. Adverse events and long term complications were closely monitored. RESULTS: For esophageal acid exposure, the mean total % time pH < 4 was reduced from 11.9 % at baseline to 3.8 % at 3 years (p < 0.001), with 80 % (18/20) of patients achieving pH normalization (<= 5.3 %). At >= 4 years, 100 % (23/23) of the patients had improved quality-of-life measures for GERD, and 80 % (20/25) had complete cessation of the use of PPIs. There have been no reports of death or long-term device-related complications such as migration or erosion. CONCLUSIONS: Sphincter augmentation with the LINX Reflux Management System provided long-term clinical benefits with no safety issues, as demonstrated by reduced esophageal acid exposure, improved GERD related quality of life, and cessation of dependence on PPIs, with minimal side effects and no safety issues. Patients with inadequate symptom control with acid suppression therapy may benefit from treatment with sphincter augmentation. PMID- 22538695 TI - Stent treatment of malignant gastric outlet obstruction: the effect on rate of gastric emptying, symptoms, and survival. AB - BACKGROUND: Advanced pancreatic cancer and other malignancies located proximal to the small bowel might cause gastric outlet obstruction (GOO) resulting in nausea, vomiting, dehydration, and malnutrition. Self-expandable metal stents (SEMS) to a large extent have replaced surgical treatment, with gastro-entero-anastomosis as palliative treatment for GOO. The aim of the present study was to evaluate the effect of duodenal stenting on the rate of gastric emptying, symptoms, and survival. METHODS: Patients with endoscopically verified malignant obstruction of the proximal duodenum were included. Gastric emptying rate was measured prior to and within 1 week after stent placement using a meal containing (13)C-octanoic acid as a marker. Symptoms related to GOO were assessed by the patients before and 2 weeks after stent treatment and during the gastric emptying tests. All patients were followed up until death. RESULTS: In the patients included (n = 17), all studied variables of gastric emptying improved significantly following treatment, and a reduction in self-reported obstructive symptoms was observed. There was no correlation between survival and the rate of gastric emptying before or after, or the change in the rate of emptying. CONCLUSION: The present study demonstrated that treatment with SEMS results in improved gastric emptying in most patients with GOO and a corresponding reduction in self-reported obstruction symptoms. However, survival and emptying were not related. The present findings provide further evidence that treatment with stents is an effective palliative treatment in patients with GOO. PMID- 22538696 TI - Guidelines for laparoscopic (TAPP) and endoscopic (TEP) treatment of inguinal hernia. PMID- 22538697 TI - Endoscopic ultrasound (EUS)-guided pseudocyst drainage as a one-step procedure using a novel multiple-wire insertion technique (with video). AB - BACKGROUND: The EUS 2008 working group considered the development of equipment and methods to minimize the need for exchanging accessories and to facilitate insertion of multiple transmural stents during endoscopic ultrasound (EUS)-guided pseudocyst drainage as an important advance for therapeutic EUS. The authors aimed to describe their experience with EUS-guided pseudocyst drainage using a novel multiple-wire insertion technique facilitated by the double-lumen biliary cytology brush catheter. METHODS: The study enrolled 10 symptomatic patients undergoing EUS-guided pseudocyst drainage. The EUS-guided pseudocyst drainage was performed as a one-step procedure using graded catheter and balloon dilation of the cystgastrostomy tract and a novel multiple-wire insertion technique facilitated by a modified double-lumen biliary cytology brush catheter. The main outcome measured was technical success. RESULTS: In this study, 10 patients with 11 pseudocysts underwent a EUS-guided pseudocyst using the novel multiple-wire insertion technique. Technical success, defined as successful achievement of access and drainage of pseudocysts, was achieved in all cases (100 %) with no procedural complications. Clinical success was achieved in all cases with complete resolution of pseudocysts. CONCLUSIONS: The novel method of using a modified double-lumen biliary cytology brush catheter allows for a simple and safe one-step EUS-guided drainage of pseudocysts. PMID- 22538698 TI - Evaluation of fibrin sealant for biologic mesh fixation at the hiatus in a porcine model. AB - BACKGROUND: The ideal method to secure biologic mesh during laparoscopic hiatal hernia repair remains uncertain. Suture or tack fixation can be technically difficult, and serious cardiovascular complications have been reported. Fibrin sealant (FS) offers a potential solution to this problem. We hypothesized that FS provides comparable mesh fixation to suture repair during laparoscopic mesh hiatoplasty. STUDY DESIGN: Using a porcine model, laparoscopic hiatal hernia repair was performed with suture reapproximation of the crura and reinforcement with an acellular porcine dermal matrix. Prior to repair, animals were randomized to mesh fixation with sutures (S) or FS. After 30-day survival, an esophagram was performed, the diaphragm harvested, and mesh position, fixation, and incorporation were evaluated histologically and biomechanically using a T-peel test. RESULTS: Twenty (10 S and 10 FS) laparoscopic hiatal hernia repairs were performed. Total operative time was significantly less in the FS group (74.7 versus 127.0 min, p < 0.01). There were no instances of mesh migration in any animal. Mean peel force did not differ significantly between the S and FS groups (0.21 vs. 0.18 N/mm, respectively; p = 0.49). There was no significant difference in cellular repopularization or inflammatory changes around the mesh. CONCLUSIONS: Fibrin sealant offers a reasonable alternative to suturing biologic mesh during laparoscopic hiatal hernia repair with equivalent mesh fixation. At 30 days it provides adhesive strength similar to suture fixation, while significantly reducing operative time. PMID- 22538699 TI - Laparoscopic approach for treatment of multiple hepatocellular carcinomas. AB - BACKGROUND: The aim of this study is to evaluate clinical and oncologic outcomes after laparoscopic surgery for patients with multiple hepatocellular carcinoma (HCC). METHODS: Among the 260 patients who underwent laparoscopic procedures, including laparoscopic liver resection and laparoscopic radiofrequency ablation (LRFA), between September 2003 and December 2009, 107 patients with HCC were included in this retrospective study. According to tumor multiplicity, patients were divided into multiple lesion (n = 23) and single lesion (n = 84) groups. We compared the operative outcomes after the laparoscopic procedures between the single and multiple tumor groups. RESULTS: There was no difference in the clinicopathologic characteristics between the two groups, except the multiple group had more frequent previous history of preoperative transarterial chemoembolization. LRFA was more frequently used in the multiple group as compared with the single group. There was no postoperative mortality in either group. Application of laparoscopic surgery in the multiple group did not increase the operative time, rate of intraoperative transfusion, length of postoperative hospital stay, or postoperative complications, as compared with the single group. After median follow-up of 33.7 months, there was no statistically significant difference of the survival rates between the two groups, although there was a better disease-free survival rate in the single group. CONCLUSIONS: This study shows that laparoscopic surgery, including LH and LRFA, can be safely applied to patients with multiple HCCs, and the survival outcomes are acceptable. PMID- 22538700 TI - The degree of gallbladder wall thickness and its impact on outcomes after laparoscopic cholecystectomy. AB - BACKGROUND: Laparoscopic cholecystectomy is the gold-standard procedure for management of symptomatic gallstone disease. Increased rates of conversion to an open procedure, increased postoperative complications, and longer lengths of stay are seen in thick-walled gallbladders. Previous studies have only evaluated gallbladder walls as being thick or not thick, without looking at the degree of thickness. We hypothesized that, the more severe the wall thickening, the greater the chance of conversions and complications, and the longer the lengths of stay. METHODS: All attempted laparoscopic cholecystectomies in our institution between 2006 and 2009 were retrospectively reviewed. Patients undergoing cholecystectomy for reasons other than gallstones (e.g., polyps or cancer) and those without preoperative ultrasounds were excluded. Patients were divided into four groups based on the degree of gallbladder wall thickness: normal (1-2 mm), mildly thickened (3-4 mm), moderately thickened (5-6 mm), and severely thickened (7 mm and above). Outcomes were compared amongst the groups. RESULTS: 874 patients were included in the study. There were 68 conversions (7.8 %) and 58 complications (6.6 %). The incidence of conversions was 3.1, 5.1, 14.9, and 16.8 % in the four groups, respectively (p < 0.001, chi (2)), and the incidence of complications was 1.8, 6.7, 9.1, and 13.1 %, respectively (p = 0.001, chi (2)). The mean (+/- standard deviation, SD) length of stay in days was 1.09 +/- 1.42, 1.83 +/- 3.24, 2.54 +/- 3.40 and 3.54 +/- 4.61, respectively [p < 0.001, analysis of variance (ANOVA)]. CONCLUSIONS: A greater degree of gallbladder wall thickness is associated with an increased risk of conversion, increased postoperative complications, and longer lengths of stay. Classifying patients according to degree of gallbladder wall thickness gives more accurate assessment of the risk of surgery, as well as potential outcomes. PMID- 22538702 TI - Digital PCR for noninvasive detection of aneuploidy: power analysis equations for feasibility. AB - OBJECTIVE: To determine the feasibility of digital PCR analysis for noninvasive prenatal diagnosis of trisomy 21. METHODS: Through power equations, we modeled the number of wells necessary to determine the feasibility of digital PCR as a practical method for trisomy 21 risk assessment. RESULTS: The number of wells needed is a direct correlate of the ability to isolate free fetal DNA. If a 20% fetal DNA enhancement can be achieved, then 2,609 counts would be sufficient to achieve a 99% detection rate for a 1% false-positive rate and potentially feasible with readily available plates. However, if only a 2% increase is seen, then 220,816 counts will be necessary, and over 110,000 would be needed just to achieve 95% for a 5% false-positive rate - both far beyond current commercially available technology. CONCLUSION: There are several noninvasive prenatal diagnostic methods which may reach commercialization; all have differing potential advantages and disadvantages. Digital PCR is potentially a cheaper methodology for trisomy 21, but it is too early to determine the optimal method. PMID- 22538703 TI - Stereoselective synthesis of (-)-1-epi-ventiloquinone L and (+)-ventiloquinone L, the monomeric unit of cardinalin 3. AB - A stereoselective synthesis of (-)-1-epi-ventiloquinone L and (+)-ventiloquinone L, the monomeric unit of cardinalin 3 has been described. The synthesis is completed in 7 steps with 10.5% and 13% overall yields for (-)-1-epi ventiloquinone L and (+)-ventiloquinone L respectively. The key steps involve Dotz benzannulation of carbene 5 with alkyne 6 to give a substituted naphthalene moiety and oxa-Pictet-Spengler reaction to install the 1,3-dimethylpyran moiety. PMID- 22538704 TI - Neighborhood deprivation and hospitalization for venous thromboembolism in Sweden. AB - Arterial cardiovascular disease and neighborhood deprivation are associated. However, no study has determined whether neighborhood deprivation is associated with venous thromboembolism (VTE). We aimed to determine whether there is an association between neighborhood deprivation and hospitalization for VTE, and whether effects vary across sociodemographic groups. The entire Swedish population aged 25-74 was followed from January 1, 2000 until hospitalization for VTE, death, emigration, or the end of the study period (December 31, 2008). Data were analyzed by multilevel logistic regression, with individual-level characteristics (age, marital status, family income, educational attainment, immigration status, urban/rural status, mobility, and comorbidity) at the first level and level of neighborhood deprivation at the second level. Neighborhood deprivation was significantly associated with VTE hospitalization rate in both men (OR = 1.09) and women (OR = 1.38). In the full model, which took account of individual-level socioeconomic characteristics and comorbidities, the odds of VTE remained significant only in women (OR = 1.12, 95 % CI 1.06-1.20) in the most deprived neighborhoods. Neighborhood characteristics affect odds of hospitalization for VTE, particularly in women. Thus, neighborhood deprivation is a common risk factor for both arterial cardiovascular disease and VTE. This study adds to knowledge of the negative effects of neighborhood deprivation on cardiovascular health. PMID- 22538706 TI - Overview of the Common Core State Standard initiative and educational reform movement from the vantage of speech-language pathologists. AB - Educational reform is sweeping the country. The adoption and the implementation of the Common Core State Standards in almost every state are meant to transform education. It is intended to update the way schools educate, the way students learn, and to ultimately prepare the nation's next generation for the global workplace. This article will describe the Common Core State Standard initiative and the underlying concerns about the quality of education in the United States as well as the opportunities this reform initiative affords speech-language pathologists. PMID- 22538705 TI - Nprl3 is required for normal development of the cardiovascular system. AB - C16orf35 is a conserved and widely expressed gene lying adjacent to the human alpha-globin cluster in all vertebrate species. In-depth sequence analysis shows that C16orf35 (now called NPRL3) is an orthologue of the yeast gene Npr3 (nitrogen permease regulator 3) and, furthermore, is a paralogue of its protein partner Npr2. The yeast Npr2/3 dimeric protein complex senses amino acid starvation and appropriately adjusts cell metabolism via the TOR pathway. Here we have analysed a mouse model in which expression of Nprl3 has been abolished using homologous recombination. The predominant effect on RNA expression appears to involve genes that regulate protein synthesis and cell cycle, consistent with perturbation of the mTOR pathway. Embryos homozygous for this mutation die towards the end of gestation with a range of cardiovascular defects, including outflow tract abnormalities and ventriculoseptal defects consistent with previous observations, showing that perturbation of the mTOR pathway may affect development of the myocardium. NPRL3 is a candidate gene for harbouring mutations in individuals with developmental abnormalities of the cardiovascular system. PMID- 22538707 TI - Speech-language pathologists and the Common Core Standards initiative: an opportunity for leadership and organizational change. AB - The Common Core State Standards initiative within public school education is designed to provide uniform guidelines for academic standards, including more explicit language targets. Speech-language pathologists (SLPs) are highly qualified language experts who may find new leadership roles within their clinical practice using the Common Core Standards. However, determining its usage by SLPs in clinical practice needs to be examined. This article seeks to discover the social context of organizations and organizational change in relation to clinical practice. Specifically, this article presents the diffusion of innovations theory to explain how initiatives move from ideas to institutionalization and the importance of social context in which these initiatives are introduced. Next, the values of both SLPs and organizations will be discussed. Finally, this article provides information on how to affect organizational change through the value of an affirmative, socially based theoretical perspective and methodology, appreciative inquiry. PMID- 22538708 TI - Universal Design for Learning: speech-language pathologists and their teams making the common core curriculum accessible. AB - The Universal Design for Learning (UDL) framework was named in the supporting documents for the Common Core State Standards (CCSS) as a means of helping all students, especially those with disabilities, to meet and exceed the rigorous expectations. This article will describe the principles of UDL, show how educational teams use the framework to design instruction to teach the CCSS with examples from science and English language arts, and finally explore how the implementation of UDL provides an opportunity for speech-language pathologists to play a critical role in school improvement and instructional design and support. PMID- 22538709 TI - Writing instruction in elementary classrooms: making the connection to Common Core State Standards. AB - This study used a survey of primary general education teachers to examine the frequency of writing instructional activities and the genres composed most frequently by students in these classrooms. Surveys were completed by first-, third-, and fifth-grade general education teachers, with questions addressing writing activities, writing instruction, instructional strategies, writing genres, and writing environment. Means of teacher responses were calculated for each grade level to determine how many days per school year each activity occurred. To better understand the changes that occur in writing instructional practices and genres across grade levels, these means are compared and shifts are discussed. Results of this study revealed that the frequency of writing instructional practices and genre usage change across the primary grade levels, but that great variation also exists among teachers at each grade level. Links among the survey results, the Common Core State Standards for writing, and best practices for writing instruction will be made. PMID- 22538710 TI - The linguistic demands of the Common Core State Standards for reading and writing informational text in the primary grades. AB - Forty-five states and four U.S. territories have committed to implementing the new Common Core State Standards, with the goal of graduating students from our K 12 programs who are ready for college and careers. For many, the new standards represent a shift in genre focus, giving much more specific attention to informational genres. Beginning in the primary grades, the standards set high expectations for students' interaction with informational text, many of which are significantly more linguistically demanding than the standards that they replace. These increased demands are likely to pose difficulties not only for students currently receiving language support, but also for students without identified delays or disabilities. This article describes several of the kindergarten through fifth-grade standards related to informational text, highlighting the linguistic demands that each poses. In addition, instructional strategies are provided that teachers and speech-language pathologists can use to support the understanding and formulation of informational text for listening, reading, speaking, and writing. PMID- 22538711 TI - Curriculum-based assessment of oral language and listening comprehension: a tool for intervention and progress monitoring in the Common Core State Standards. AB - The Common Core State Standards and a Response to Intervention framework are movements sweeping the nation. Speech-language pathologists are uniquely positioned to play a pivotal role in supporting successful implementation of these movements. This article explores the assessment tools speech-language pathologists SLPs will need to identify and progress monitor critical language/literacy skills such as listening comprehension and oral narratives skills. Foundational research demonstrates that communication units, total words spoken, and major story components are measures that will discriminate between students with adequate language skills and language disorders and are curriculum based, sensitive to change, and useful to determine the effectiveness of language/literacy interventions. Speech-language pathologist can broaden the impact of their knowledge and skills to improve outcomes for all students. PMID- 22538713 TI - You sound familiar: carrion crows can differentiate between the calls of known and unknown heterospecifics. AB - In group-living animals, it is adaptive to recognize conspecifics on the basis of familiarity or group membership as it allows association with preferred social partners and avoidance of competitors. However, animals do not only associate with conspecifics but also with heterospecifics, for example in mixed-species flocks. Consequently, between-species recognition, based either on familiarity or even individual recognition, is likely to be beneficial. The extent to which animals can distinguish between familiar and unfamiliar heterospecifics is currently unclear. In the present study, we investigated the ability of eight carrion crows to differentiate between the voices and calls of familiar and unfamiliar humans and jackdaws. The crows responded significantly more often to unfamiliar than familiar human playbacks and, conversely, responded more to familiar than unfamiliar jackdaw calls. Our results provide the first evidence that birds can discriminate between familiar and unfamiliar heterospecific individuals using auditory stimuli. PMID- 22538714 TI - A circular dichroism study uncovers a two-step interaction of antitumor azolato bridged dinuclear platinum(II) complexes with calf thymus DNA. AB - The interactions of four antitumor azolato-bridged dinuclear platinum(II) complexes, [{cis-Pt(NH(3))(2)}(2)(MU-OH)(MU-azolato)](2+), with calf thymus DNA were monitored dose- and time-dependently, by using circular dichroism. Complexes 1-4 reacted with DNA via a two-step interaction that comprised a prompt diffusion controlled reaction, which induced a B- to C-form transition, and a relatively slow temperature-dependent reaction. PMID- 22538715 TI - Testing times. PMID- 22538716 TI - Germline RAD51C mutations confer susceptibility to ovarian cancer. PMID- 22538718 TI - Photosensitivity syndrome brings to light a new transcription-coupled DNA repair cofactor. AB - Three teams have applied whole-exome and proteome methods to identify a new cofactor of human RNA polymerase II that is required for the recovery of transcription on damaged templates. The identification of this new factor raises questions about the causal relationships between molecular mechanisms of transcription regulation and excision repair and developmental and neurological disease and nonmalignant skin photosensitivity. PMID- 22538719 TI - Cell type-specific eQTLs in the human immune system. AB - A new study reports the mapping of gene expression in primary immune cell subsets, showing the presence of cell type-specific cis and trans expression quantitative trait loci (eQTLs). The identification of cell type-specific trans regulated networks can inform functional studies of susceptibility loci identified from genome-wide association studies for human complex diseases. PMID- 22538727 TI - Performance of evacuated calcium phosphate microcarriers loaded with mesenchymal stem cells within a rat calvarium defect. AB - Tissue engineering of stem cells in concert with 3-dimensional (3D) scaffolds is a promising approach for regeneration of bone tissues. Bioactive ceramic microspheres are considered effective 3D stem cell carriers for bone tissue engineering. Here we used evacuated calcium phosphate (CaP) microspheres as the carrier of mesenchymal stem cells (MSCs) derived from rat bone marrow. The performance of the CaP-MSCs construct in bone formation within a rat calvarium defect was evaluated. MSCs were first cultured in combination with the evacuated microcarriers for 7 days in an osteogenic medium, which was then implanted in the 6 mm-diameter calvarium defect for 12 weeks. For comparison purposes, a control defect and cell-free CaP microspheres were also evaluated. The osteogenic differentiation of MSCs cultivated in the evacuated CaP microcarriers was confirmed by alkaline phosphatase staining and real time polymerase chain reaction. The in vivo results confirmed the highest bone formation was attained in the CaP microcarriers combined with MSCs, based on microcomputed tomography and histological assays. The results suggest that evacuated CaP microspheres have the potential to be useful as stem cell carriers for bone tissue engineering. PMID- 22538726 TI - In vitro evaluation of polymeric micelles based on hydrophobically-modified sulfated chitosan as a carrier of doxorubicin. AB - Four types of doxorubicin (DOX)-loaded polymeric micelles based on hydrophobically-modified sulfated chitosan (SCTS) were prepared. The hydrophobic group was composed of glycyrrhetinic acid (GA), cholic acid, stearic acid (SA) or lauric aldehyde. DOX encapsulation depended on several parameters, including the degree of substitution of the sulfate group and the hydrophobic group, and the type of hydrophobic group. Of these micelles, GA-SCTS micelles had the best capability to solubilize DOX. In addition, GA-SCTS micelles had the ability to target HepG(2) cells, and the IC50 for DOX-loaded GA-SCTS micelles was 54.7 ng/mL, which was much lower than that of the other micelles. Further studies on the DOX-loaded GA-SCTS micelles showed that they were stable in salt and protein solutions, in cell culture media, and during long-term storage (6 months). Based on these results, these micelles may be a promising DOX-encapsulated formulation, particularly, GA-SCTS as a potential vehicle for liver-targeted delivery. PMID- 22538728 TI - Isolation and characterization of drug delivering potential of type-I collagen from eel fish Evenchelys macrura. AB - Acid soluble collagen (ASC) and pepsin-soluble collagen (PSC) from the outer skin waste of marine eel fish (Evenchelys macrura) were isolated and characterized. The prepared collagen was used to test its effective drug delivering potential in vitro condition. Present results were confirmed as collagen by different physico chemical techniques like SDS-PAGE, HPLC, FTIR and SEM. Further amino acid analysis corroborates isolation of type I collagen. Both ASC and PSC comprising two different alpha-chains (alpha 1 and alpha 2) were characterized as type I and contained imino acid of 190-200 residues, respectively. The denaturation temperatures (T(d)) of ASC and PSC were 38.5 and 35.0 degrees C, respectively, which is promising as an advantage for biomedical application due to closeness in T(d) to mammalian collagen. Furthermore, the gel and film forming capability of collagen samples containing implant standard antibiotic was proved to be a suitable drug delivering system. PMID- 22538729 TI - Dorsal column nuclei projection to the cerebellar caudal vermis in the rabbit revealed by the fluorescent double-labeling method. AB - The organization of the projection from the dorsal column nuclei (DCN) to the lobules of the cerebellar caudal vermis was studied in the rabbit. Following unilateral injections of the retrograde fluorescent tracers fast blue (FB) and diamidino yellow (DY) into the pyramis (Pr) and uvula (Uv), respectively, a great number of single FB- (40%) and DY-labeled (60%) neurons were observed in the ipsilateral (79%) and contralateral (21%) DCN subdivisions. These neurons, as parents for the DCN-Pr and DCN-Uv projections, were numerous in the lateral cuneate nucleus (CuL; 84 and 74%, respectively) and in the complex of the gracile (Gr) and medial cuneate nuclei (CuM; Gr+CuM; 14 and 25%, respectively). A small percentage of the Pr projecting neurons was found in the CuM and Gr nuclei (2% in total). As regards the Uv, a rare and only ipsilateral projection arose from the CuM (1%), and no connection originated from the Gr. The distribution pattern of labeled neurons within individual subnuclei indicates that there are both separate regions and, to a great extent, common regions of the DCN-Pr and DCN-Uv projections. In these common regions, a small population of double FB+DY-labeled neurons (1.2%) was identified. Such neurons, present exclusively in the ipsilateral CuL and Gr+CuM, were the source of projection by way of axonal collaterals to the Pr and Uv simultaneously. It is suggested that the described connections may play a role in coordination of the axial and proximal forelimb muscles. PMID- 22538730 TI - In vitro antioxidant synergism and antagonism between food extracts can lead to similar activities in H2O2-induced cell death, caspase-3 and MMP-2 activities in H9c2 cells. AB - BACKGROUND: The cardio-health-promoting activity of some foods may be due to their specific antioxidant content. The antioxidant activity of a mixture of plant extracts has been shown to differ from the activity of the individual extracts. As a result, the activity of the mixture can be described as synergistic, antagonistic or additive. This in vitro study evaluated the relationship between the in vitro antioxidant capacity of mixtures and their bioactivity when cardiomyocytes (H9c2) were challenged with H(2)O(2). RESULTS: A mixture of raspberry and adzuki bean extracts produced a synergistic response and a mixture of broccoli and soybean extracts produced an antagonistic response in chemical-based antioxidant assays. When these extracts were tested in cell cultures, individually and in mixtures, the mixture of raspberry and adzuki bean protected the cardiomyocytes from H(2)O(2)-induced cell damage significantly better than the individual extracts. Conversely, the mixture of broccoli and soybean extracts was less effective in protecting H9c2 cells. The synergistic and antagonistic effects of the mixtures in protecting cell damage were brought about by enhanced or reduced ability in attenuating caspase-3 and matrix metalloproteinase-2 activities elevated by H(2)O(2). CONCLUSION: Food mixtures with synergistic antioxidant activity and protective property against reactive oxygen species-induced cell death can potentially be incorporated into novel functional foods or beverages with optimum health benefit. The antagonistic effect of food mixtures can be a health concern and thus should be avoided. PMID- 22538731 TI - Responses to alcohol and cigarette use during ecologically assessed drinking episodes. AB - RATIONALE: Tobacco and alcohol are frequently used together, and this may be partly explained by a distinct profile of subjective effects associated with co administration. Ecological momentary assessment studies have examined effects of naturally occurring co-use, but, to date, have not assessed differing effects as alcohol levels rise and fall. OBJECTIVES: The objective of the study was to describe subjective states and appraisals of cigarette and alcohol effects reported during the entirety of real-world drinking episodes. METHODS: Currently smoking frequent drinkers (N = 255) carried electronic diaries for 21 days. Analyses focused on reports made during 2,046 drinking episodes. Signaled prompts intensively oversampled moments in the hours following consumption of the first drink in an episode. Multilevel regression analyses were used to predict ratings of buzz, dizziness, excitement, and sluggishness as a function of person-level and contextual covariates, estimated blood alcohol concentration (eBAC) level, ascending vs. descending eBAC, smoking, and their interactions. Appraisals of cigarette and alcohol effects were also examined within this framework. RESULTS: Buzz, excitement, and pleasure from alcohol and cigarettes were prominent features of real-world drinking episodes. Smoking was associated with enhanced buzz and excitement when eBAC was high and descending. Smoking slightly accentuated the relation between eBAC and ratings of drinking pleasure among women, but this relation was somewhat weakened by smoking among men. CONCLUSIONS: Smoking during drinking episodes may be partly explained by a persistence of stimulant alcohol effects beyond the blood alcohol concentration peak. Acute effects of nicotine and tobacco use on the descending limb deserve further scrutiny in experimental alcohol challenge research. PMID- 22538733 TI - Oxidative protein damage with carbonyl levels and nitrotyrosine expression after chemotherapy in bone marrow transplantation patients. AB - Protein oxidation is defined as the covalent modification ofa protein, induced either directly by reactive oxygen species/reactive nitrogen species or indirectly by reaction with secondary by-products of oxidative stress. Protein carbonyls are the most commonly measured products of protein oxidation. Additionally, nitrotyrosine is a product of tyrosine nitration mediated by reactive nitrogen species such as peroxynitrite anion and nitrogen dioxide. Samples were collected before the preparative regimen (10 days before transplantation; day -10), on transplantation day (day 0), and after transplantation (days 7, 14, and 28) from 16 pediatric allogeneic hematopoietic stem cell transplantation (HSCT) patients.The erythrocyte 3-nitrotyrosine expression was shown to be significantly increased after chemotherapy. In accordance, the mean plasma carbonyl levels on days 14 and 28 were significantly higher than on the other days. High dose chemotherapy applied in the preparative regimen of HSCT may be responsible for this long-term oxidation of plasma proteins. These results show that high-dose chemotherapy resulted in protein oxidation both in plasma and in erythrocytes in HSCT patients. PMID- 22538732 TI - Cerebellar atrophy in patients with subcortical-type vascular cognitive impairment. AB - Recent studies suggest that the role of the cerebellum extends into cognitive regulation and that subcortical vascular dementia (SVaD) can result in cerebellar atrophy. However, there has been no evaluation of the cerebellar volume in the preclinical stage of SVaD. We aimed to compare cerebellar volume among patients with amnestic mild cognitive impairment (aMCI) and subcortical vascular mild cognitive impairment (svMCI) and evaluate which factors could have contributed to the cerebellar volume. Participants were composed of 355 patients with aMCI, svMCI, Alzheimer's disease (AD), and SVaD. Cerebellar volumes were measured using automated methods. A direct comparison of the cerebellar volume in SVaD and AD groups showed that the SVaD group had a statistically smaller cerebellar volume than the AD group. Additionally, the svMCI group had a smaller cerebellar volume than the aMCI group, with the number of lacunes (especially in the supratentorial regions) being associated with cerebellar volume. Cerebellar volumes were associated with some neuropsychological tests, digit span backward and ideomotor apraxia. These findings suggest that cerebellar atrophy may be useful in differentiating subtypes of dementia and the cerebellum plays a potential role in cognition. PMID- 22538734 TI - Relationship between serum asymmetric dimethylarginine and left ventricular structure and function in patients with end-stage renal disease treated with hemodialysis. AB - INTRODUCTION: Asymmetric dimethylarginin (ADMA) is an endogenous inhibitor of endothelial nitric oxide synthase, considered an effector of endothelial dysfunction. Among multiple diseases associated with elevated ADMA, chronic renal disease is often mentioned. ADMA is thought to be related to certain adverse cardiovascular effects of chronic uremia. The association between left ventricular (LV) structure and function and ADMA has been studied in numerous papers, but only few of them addressed this issue in end-stage renal disease (ESRD). OBJECTIVES: The aim of the study was to analyze associations between serum ADMA (sADMA) levels and LV geometry and function in patients with ESRD treated with hemodialysis (HD). PATIENTS AND METHODS: The study group included 56 patients (31 women, 25 men) aged 59.0 +/-13.1 years, treated with HD for 70 +/ 67 months. sADMA and biochemical parameters were measured and echocardiography was performed. sADMA levels were also measured in the control group of healthy individuals matched for age. RESULTS: Mean sADMA levels in patients were 2.39 +/-1.0 MUmol/ and were significantly higher compared with controls (0.55 +/-0.12 MUmol/l; P <0.01). Based on echocardiography, patients were classified into the following groups: normal LV geometry (17.8%), concentric remodeling (8.9%), concentric hypertrophy (35.7%), excentric hypertrophy (37.5%), impaired systolic function (10.7%), and impaired diastolic function (71.4%) (1 patient could be in 1 or more groups). sADMA correlated with mean (r = 0.78; P <0.05) and relative (r = 0.64; P <0.05) LV wall thickness and with the LV mass index (r = 0.65; P <0.05), but not with the indexes of systolic and diastolic function. sADMA was significantly higher in patients with excentric hypertrophy, concentric remodeling, and concentric hypertrophy compared with patients with normal LV geometry, and the highest was in patients with concentric hypertrophy. CONCLUSIONS: Our study demonstrated an association between sADMA and disturbances in LV geometry in patients with ESRD treated with HD. PMID- 22538735 TI - World kidney day 2012: renal transplantation. PMID- 22538736 TI - Sleep behaviour in a sample of preschool children in Singapore. AB - INTRODUCTION: Sleep problems are common in all ages, but may be particularly acute in urban Singapore. This study aims to describe the sleep behaviour of, and to identify any sleep problems in, preschool children. MATERIALS AND METHODS: This was a cross-sectional questionnaire survey of 372 children attending local childcare centers. The questionnaire was based on the Children's Sleep Habits Questionnaire (CSHQ), a validated parent-report sleep screening questionnaire that contains 54 items identifying sleep behaviours in children. RESULTS: A total of 372 (40.0%) children participated. The mean age was 4.1 (SD 1.3) years (range, 2 to 6 years). Average total sleep duration was 10.8 hours (SD 1.1) with average night-time sleep duration of 8.5 hours (SD 0.6) and average nap duration of 1.6 hours (SD 1.0). Co-sleeping was common; 80.9% of children shared a room with someone else. The most common sleep problems were in the domains of sleep resistance and morning behaviour; namely: requiring company to fall asleep (n = 272, 73.1%), being afraid to sleep alone (n = 228, 61.6%) and diffi culty in waking up (n = 165, 44.4%). Among parents, 84.1 % (n = 313) perceived that their child's sleep duration was adequate. CONCLUSION: The duration of sleep in the Singaporean preschool population sampled is signifi cantly lower than recommended values and that of previously described Caucasian populations. Parental perception of sleep adequacy deviates from current recommendations. Given the clear relation of sleep duration with cognitive functioning, learning, and physical growth, this sleep deprivation should be addressed with parental education and opportunistic screening of sleep in well-child follow-ups. PMID- 22538737 TI - Prevalence and impact of mental and physical comorbidity in the adult Singapore population. AB - INTRODUCTION: This study aims to assess the prevalence rates of mental disorders and chronic medical conditions in the Singapore resident population, and examine their association and respective impact on the quality of life. MATERIALS AND METHODS: A household survey was carried out on a nationally representative sample of the adult (18 years and above) resident population. The main instrument used to establish the diagnosis of mental disorders is the World Mental Health Composite International Diagnostic Interview (WMH-CIDI). The mental disorders included in study were major depressive disorder, bipolar disorder, generalised anxiety disorder, obsessive compulsive disorder, alcohol abuse and alcohol dependence. Respondents were asked if they had any of the chronic medical conditions from a list of 15 conditions. Health-related quality of life was assessed with the EQ-5D. RESULTS: Of the 6616 respondents, the lifetime prevalence of mental disorders was 12.0%, and that of chronic medical disorders were 42.6% and those with comorbid mental and medical disorders was 6.1%. The prevalence of any physical disorder in this population was high (42.6%). Among those with chronic physical disorders, 14.3% also had a mental disorder, and among those with mental disorders, more than half (50.6%) had a medical disorder. Most of the mental disorders were not treated. Males, Indians, older people, and those who were separated or divorced were more likely to have comorbidity. The health-related quality of life was significant worse in those with both mental and medical disorders compared to those with either mental or medical disorder. CONCLUSION: Our study re-emphasised the common occurrence of mental and medical disorders and the importance for an integrated care system with the capability to screen and treat both types of disorders. It also identified certain subpopulations which are more likely to have comorbidity for which a more targeted intervention could be planned. PMID- 22538738 TI - The implantable loop recorder-an important addition to the armentarium in the management of unexplained syncope. AB - INTRODUCTION: Unexplained syncope is a common condition with a significant impact both on the patient and on healthcare expenditure. Often, the diagnosis is hampered due to the temporary sporadic nature of the symptoms. Conventional monitoring methods have a low yield for identifying an abnormality during a spontaneous event. The implantable loop recorder (ILR), often underutilised, is an important diagnostic device that may fi ll this void in the early assessment of patients presenting with syncope. MATERIALS AND METHODS: This article begins with 2 case vignettes which highlight the clinical utility of ILRs in making a definitive diagnosis and guiding subsequent management. This is followed by a review of the existing evidence for ILRs, including the recent international guidelines, underpinning the role of ILRs in the present management algorithm of patients presenting with unexplained syncope. The technical aspects and cost implications will also be reviewed. RESULTS: Present evidence-based international guidelines have recommended the early use of ILRs in the management of patients with unexplained syncope. Furthermore, there may also be an important role for ILR use in patients with presumed epilepsy refractory to treatment and in the neurally mediated syncope cohort with recurrent symptoms. Cost benefit analysis also demonstrates advantages with early ILR use. CONCLUSION: The early use of ILR in selected patients remains an accurate, cost-effective, high yield tool for diagnosis and management of patients with unexplained syncope. However, its use should not detract from the importance of taking a detailed medical history and physical examination in the initial assessment to facilitate identification of the aetiology and risk stratification of patients. PMID- 22538739 TI - Incidence of infusion-related reaction to monoclonal antibody rituximab: a national kidney and transplant institute experience. PMID- 22538740 TI - Is contrast enhanced ultrasound a valid alternative diagnostic modality for renal cell carcinoma in patients with renal impairment? PMID- 22538741 TI - Laparoscopic excision of intrathoracic oesophageal duplication cyst in a Singaporean adult male. PMID- 22538742 TI - Ulceration of the scalp: lipogranuloma induced by industrial oils in a decorator woman. PMID- 22538743 TI - Bullous drug eruption secondary to nicotinic acid/laropiprant. PMID- 22538744 TI - Protected time vs service commitment. PMID- 22538745 TI - 'Silent' somatotropinoma. AB - INTRODUCTION: 'Silent' somatotropinomas are defined as GH-immunopositive pituitary adenomas without clinical symptoms of acromegaly and GH elevation in peripheral blood. Such tumours used to be considered as rare. However, recent data has indicated that they are more frequent than previously thought. The present paper shows that pituitary adenomas, diagnosed before surgery as nonfunctioning, often display GH immunopositivity. MATERIAL AND METHODS: Fifty six patients with pituitary adenomas were included in the study. All the patients underwent transphenoidal adenectomy. In 37 patients before the surgery, clinically nonfunctioning pituitary adenomas (CNFPAs) were diagnosed. In 19 patients, acromegaly was diagnosed. All the excised tumours were examined immunohistochemically using the primary antibodies against the pituitary hormones or their subunits. RESULTS: All the adenomas in the patients with acromegaly were immunopositive for GH. Among the pituitary tumours diagnosed before the surgery as clinically nonfunctioning, 45.9% showed GH immunopositivity. Both somatotropinomas with acromegaly and 'silent' GH-immunopositive adenomas most often co-expressed prolactin, whereas GH-immunonegative nonfunctioning adenomas expressed mainly LH and/or FSH. In three cases of 'silent' somatotropinomas, IGF 1 levels were slightly elevated, suggesting that these patients may present a 'low-symptomatic' acromegaly. CONCLUSIONS: GH-immunopositivity occurs in nearly half of 'clinically' nonfunctioning pituitary adenomas. Because of that, IGF-1 determination in blood before the surgery, and immunohistochemical examination of adenoma for GH after the surgery, should be performed as standard in all patients suffering from pituitary tumours, irrespective of the presence or absence of acromegaly symptoms. PMID- 22538747 TI - The effect of overt and subclinical hypothyroidism on the development of non dipper blood pressure. AB - INTRODUCTION: 'Non-dippers' are individuals without the anticipated nocturnal decrease in blood pressure. An increased incidence of target organ damage and a worse outcome in terms of cardiovascular events have been reported in this group of people. The pathogenesis of non-dipper hypertension is not clear at present. We aimed to investigate the effects of overt and subclinical hypothyroidism on the development of a non-dipper blood pressure pattern via 24-hour ambulatory blood pressure monitoring. MATERIAL AND METHODS: 109 normotensive patients with overt and subclinical hypothyroidism were evaluated, and 95 of these patients without reverse dipping and masked hypertension were included in the study. The control group consisted of 75 gender- and age-matched, normotensive, euthyroid healthy individuals. RESULTS: Median serum TSH levels were 7.61 and 1.59 mUmL in patient and control groups, respectively. The number of non-dippers according to systolic, diastolic and mean blood pressure was significantly higher in the patients with hypothyroidism compared to the control group. In linear regression analysis, TSH had a negative effect on the night/day ratio of the systolic, diastolic and mean blood pressures. CONCLUSION: Despite the fact that the effect of hypothyroidism on non-dipper blood pressure pattern is not known, the present study has revealed that elevated TSH levels are likely to increase the risk of non-dipping in normotensive patients with either overt or subclinical hypothyroidism. PMID- 22538746 TI - Serum interleukin-16 and RANTES during treatment of Graves' orbitopathy with corticosteroids and teleradiotherapy. AB - INTRODUCTION: To assess the usefulness of circulating IL-16 and RANTES measurements as markers of Graves' orbitopathy (GO) activity and to estimate the role of these cytokines in GO pathogenesis. MATERIAL AND METHODS: 42 individuals were divided into four groups: Group 1 comprised 15 euthyroid patients with clinical symptoms of GO who underwent corticosteroid therapy consisting of intravenous infusions of methylprednisolone (MP) and teleradiotherapy (TR); Group 2 comprised ten patients with hyperthyroid GD (Gtx); Group 3 comprised ten patients with GD in euthyreosis (Geu); and Group 4 comprised seven healthy volunteers age- and sex-matched to Groups 1-3. Serum samples were collected 24 hours before the first dose of MP, 24 hours after the first dose of MP, before TR, and at the end of therapy. Serum IL-16 and RANTES were determined by ELISA and TSH-Rab by RIA. RESULTS: Serum IL-16 levels in patients with GO were significantly elevated at the end of therapy: 346 pg/mL (257-538) compared to IL 16 values before treatment: 250 ng/mL (211-337) and to the control group. RANTES serum concentrations did not significantly differ between studied groups, and immunosuppressive treatment did not influence its level. A negative correlation between TSH-Rab and RANTES was found in all studied groups (R = -0.32, p < 0.01). CONCLUSIONS: Our data suggests that IL-16 may exert an immunoregulatory effect in Graves' orbitopathy. Serum measurements of both IL-16 and RANTES may be clinically useful; however, establishing their place in the diagnostics and treatment monitoring of GO needs further research. PMID- 22538748 TI - Reference values for thyroid volume established by ultrasound in Polish schoolchildren. AB - INTRODUCTION: A frequency in excess of 5% of goitre in children is an approved WHO marker of iodine deficiency. As thyroid ultrasound remains the main method of thyroid volume (TV) assessment, the choice of adequate normative values is important for the proper interpretation of epidemiologic data. There is disagreement as to whether local or international normative values should be used. The aim of this study was to establish Polish local TV normative values in children aged 6-12 years. MATERIAL AND METHODS: The study was carried out in a group of 642 children aged 6-12 years (312 girls and 330 boys) living in the Polish seaside area with a proven history of best iodine supply. Inclusion criteria were: iodine concentration in casual morning urine samples above 100 MUg/L, no goitre on palpation, no pathological findings on thyroid US, no history of thyroid disorders, no treatment affecting thyroid function, and written informed consent from the child's parents. TV was measured ultrasonographically with a 7.5 MHz linear transducer. Urinary iodine concentration (UIC) was measured in urine spot samples using the Sandell-Kolthoff method. RESULTS: Median UIC ranged according to age from 126.6 to 155.1 MUg/L in girls, and from 132.23 to 157.62 MUg/L in boys. TVs at P97 were: 3.96, 4.23, 4.33, 5.44, 6.07, 9.5, and 10.9 for girls and 3.99, 4.2, 4.79, 6.61, 7.38, 7.89, and 9.35 for boys. They were lower than the 1997 WHO normative values but higher than the 2004 reference currently adopted by the WHO. CONCLUSIONS: The obtained results may be adopted as normative TV values for Polish children. PMID- 22538749 TI - Adenosine receptors expression is elevated in leukocytes of gestational diabetes mellitus (GDM) subjects--a preliminary study. AB - INTRODUCTION: Adenosine receptors (ARs), belonging to the G-protein-coupled receptors (GPCRs), are present in the majority of human cells and tissues. Depending on their biochemical and pharmacologic properties, four subtypes of ARs (i.e. A1, A(2A), A(2B), and A3) have been distinguished. Currently, these receptors are attractive molecular targets for pharmacological interventions in various diseases, including diabetes. The literature published to date has shown an altered expression of ARs in several types of cells under diabetic conditions. However, there has been no publication devoted to the investigation of ARs expression in leukocytes of subjects with gestational diabetes mellitus (GDM). Therefore, this study was aimed to determine the expression level of AR subtypes in leukocytes of GDM patients and its relationship to anthropometric and biochemical parameters. MATERIAL AND METHODS: Gene expression of four AR subtypes in leukocytes of both healthy (n = 34) and GDM (n = 67) subjects in the third trimester of pregnancy (from 24 to 33 weeks) was investigated. Multiple regression analyses were used to assess the association between the expression level of ARs and both anthropometric and biochemical parameters. RESULTS: Statistically significant (p < 0.05) higher levels of A(2A) and A(2B) mRNAs were observed in leukocytes of the GDM subjects compared to the control group. There was a positive correlation of A(2B) mRNA level with glucose concentration at 120 min of oral glucose tolerance test (OGTT) (r = 0.24, p = 0.041). CONCLUSIONS: Overexpression of A2BAR in leukocytes of the GDM subjects and, additionally, the existence of a relationship between its elevated expression level in these cells and abnormal values of glucose concentration at 120 min of OGTT for GDM, suggest that this subtype might be involved in the pathogenesis of GDM. PMID- 22538751 TI - Effect of testosterone supplementation on leptin release in rats after castration and/or unilateral surrenalectomy. AB - INTRODUCTION: The objective of this study was to examine the effect of testosterone supplementation on leptin release in rats which underwent castration and unilateral surrenalectomy. MATERIAL AND METHODS: The study was conducted on 80 adult male Wistar albino rats. Animals were divided into eight groups, with ten animals in each group. Group 1 was the Control group, Group 2 the Testosterone group, Group 3 the Castration group, Group 4 the Surrenalectomy group, Group 5 the Castration and Surrenalectomy group, Group 6 the Castration and Testosterone group, Group 7 the Surrenalectomy and Testosterone group, and Group 8 the Castration, Surrenalectomy and Testosterone group. The animals in Groups 2, 6, 7 and 8 were administered 5 mg/kg/day intramuscular testosterone propionate for four weeks. Blood samples were collected for analyses of leptin, LH, FSH and free and total testosterone levels in plasma. RESULTS: Groups 3 and 5 had the highest leptin and LH levels of all the groups (p < 0.01). Leptin and LH levels in Groups 1 and 4 were higher than those in Groups 2, 6, 7 and 8 (p < 0.01). A comparison of groups with regard to plasma FSH levels showed that the concerned parameter was significantly higher in Groups 3 and 5 than in the other groups (p < 0.01). FSH levels in Groups 1 and 4 were lower than those in all other groups (p < 0.01). The highest testosterone levels were obtained in Groups 2, 6, 7 and 8 (p < 0.01). Testosterone levels in Groups 1 and 4 were higher than those in Groups 3 and 5 (p < 0.01). CONCLUSIONS: This study demonstrates that unilateral surrenalectomy in rats does not have a significant effect on leptin release, while plasma LH levels, rather than testosterone, may be more effective on plasma leptin. PMID- 22538750 TI - Effects of nitric oxide synthase inhibition on diethylstilbestrol-induced hyperprolactinaemia and pituitary tumourigenesis in rats. AB - INTRODUCTION: The overexpression of nitric oxide synthase (NOS) has been found in tumours, including pituitary adenomas. It has also been found that NOS is overexpressed in human spontaneous pituitary adenomas. The question arises whether NOS and its product, nitric oxide (NO), are involved in pituitary tumourigenesis. To investigate this question, in the present paper we examine the effects of NOS inhibition on the development of diethylstilbestrol (DES)-induced prolactin-secreting pituitary tumours in rats. MATERIAL AND METHODS: Thirty male Fisher 344 rats, four weeks old, were submitted to subcutaneous implantation of a silastic capsule containing DES (10 mg/capsule) or of an empty capsule. Six weeks after implantation, some of the DES-treated animals received a NOS inhibitor, N nitro-l-arginine methyl ester (NAME), 1 mg/mL, in their drinking water, for the subsequent 14 days. Eight weeks after the implantation, all the animals were sacrificed, their pituitaries were weighed, and samples of heart blood were collected for prolactin (PRL) and vascular endothelial growth factor (VEGF) measurements. RESULTS: It was found that DES implantation significantly increased pituitary mass, as well as PRL and VEGF concentrations in blood serum. On the other hand, the administration of NAME did not affect significantly either VEGF concentration or pituitary mass. On the other hand, it did induce a further increase in PRL levels. CONCLUSIONS: These findings indicate that NO is involved in oestrogen-induced hyperprolactinaemia, but does not play a crucial role in oestrogen-induced pituitary tumourigenesis. PMID- 22538752 TI - MSI and LOH in the development and prognosis of follicular cell-derived thyroid tumours. AB - Microsatellite instability (MSI) and loss of heterozygosity (LOH) represent molecular disorders acquired by the cell during neoplastic transformation. Both are associated with genetic instability. Functional silencing of tumour suppressor genes may be the consequence of genomic instability, particularly of the globally occurring LOH phenomenon. Numerous studies have confirmed the role of MSI/LOH at both the early and the late stages of thyroid tumourigenesis. This paper reviews the available study results on MSI/LOH significance and prevalence in thyroid neoplasms. Additionally, it summarises the knowledge regarding the practical usage of the study findings on MSI/LOH in aspects of cancer risk assessment as well as the development of prognostic markers for thyroid neoplasms. PMID- 22538753 TI - What might cause pain in the thyroid gland? Report of a patient with subacute thyroiditis of atypical presentation. AB - Subacute granulomatous thyroiditis (SAT), also known as de Quervain's thyroiditis or painful subacute thyroiditis, is the commonest thyroid condition responsible for neck tenderness. Other causes of pain in the thyroid gland should be taken into consideration during differential diagnosis, especially when a patient presents with misleading or equivocal signs and symptoms. We report the case of a 39 year-old woman diagnosed as having SAT whose clinical, biochemical and radiological presentation varied significantly from the common SAT manifestation. A tentative diagnosis of SAT was made based on the presented symptoms, ultrasonography and fine-needle biopsy results. However, biochemical analysis suggested neither inflammatory process nor the presence of thyrotoxicosis. Moreover, technetium scan of the thyroid revealed normal uptake of the isotope and there was neither clinical nor ultasonographic response for corticosteroids. The patient's symptoms, despite being prescribed typical treatment, gradually deteriorated and the pain became increasingly debilitating. Eventually, the patient underwent total thyroidectomy. As a result, she has become free of symptoms, but the macroscopic picture of thyroid gland, noted during the operation, gave a suspicion of neoplastic process. Nevertheless, histological study of flow samples confirmed the tentative diagnosis of de Quervain's thyroiditis, despite all previous findings that were not suggestive of it. This report confirms the likelihood that SAT can present atypically. Additionally, it indicates that surgical treatment may be considered in patients with severe, debilitating, persistent thyroid gland pain connected with SAT clinical course. PMID- 22538755 TI - Adipocytokines and sex hormone disorders in patients with chronic renal failure (CRF). AB - The authors discussed disorders in adipocytokines' function in chronic renal failure (CRF) and their clinical implications. Adipocytokines' concentrations in CRF are in most cases elevated, which is associated with decreased level of their excretion. This may cause number of clinical implications such as inflammation, loss of appetite, development of protein energy wasting (PEW) syndrome and the progress of artherosclerosis, what leads to increased mortality in a group of patients with end-stage renal disease (ESRD). Disturbances in sexual hormones function are also characteristic for CRF. Disorders in fertility, sexual life and decreased quality of life are observed in patients with CRF. Therapeutic procedure is complicated and not fully effective. PMID- 22538754 TI - Mediastinal parathyroid carcinoma: a case report. AB - A 72 year-old woman with primary hyperparathyroidism was operated for parathyroid crisis. PTH serum level was 808 pg/mL. During the operation, only two superior parathyroid glands were found. One was normal, and hypertrophy was revealed in the other. After the surgical procedure, PTH serum level was 726.5 pg/mL. Helical computer tomography examination showed a heterogeneous mass in the anterior mediastinum. The tumour was removed via a sternotomy approach. Histopathological examination revealed parathyroid carcinoma. PTH level dropped to 5.74 pg/mL. Cytofluorometric examination revealed diploidy (DI = 1) in both the hypertrophic and the unchanged upper glands, whereas parathyroid cancer was aneuploid. After the initial operation, the woman was discharged from the hospital on the 27th postoperative day. One year after surgical procedures, she is well. She has to take calcium. PMID- 22538756 TI - Work of the Polish Council for Control of Iodine Deficiency Disorders, and the model of iodine prophylaxis in Poland. AB - The Polish Council for Control of Iodine Deficiency Disorders (PCCIDD) was established in 1991 in Krakow at the Chair and Dept. of Endocrinology, Jagiellonian University, Collegium Medicum, following the example of the International Council for Control of Iodine Deficiency Disorders (ICCIDD) in Charlottesville, USA. The PCCIDD co-operates with the European Co-ordinating Centre in Pisa, Italy. The PCCIDD comprises a group of experts in endocrinology, iodine prophylaxis, the technology of salt and food iodisation, and Polish representatives of several organisations: WHO, UNICEF, the Polish Consumers Federation, and the Spokesman for Children's Rights. The strategic goal of the Polish Council is to solve the problem of iodine deficiency in Poland realising the Programme for Elimination of Iodine Deficiency financed by the Ministry of Health. The Polish model of iodine prophylaxis contains obligatory iodisation of household salt (20-40 mg KI/1 kg) and neonates' formula (10 MUg/100 mL of milk), and additional supplementation for pregnant and breastfeeding women with 150-200 MUg of iodine as pharmacotherapy. The model is very effective: endemic goitre in schoolchildren has been eradicated, the prevalence of goitre in pregnant women has fallen from 80% to 19%, the frequency of transient hypothyroidism in neonates has dropped from 2.0% to 0.16%, and the observed increase of incidence rate of thyroid cancer in women over 40 years old has diminished markedly. In 2008, a WHO Collaborating Centre (WHOCC) for Nutrition was designated at the Department of Endocrinology, UJCM in Krakow. The main goal of the WHOCC is to sustain effective iodine prophylaxis in Poland in the light of the latest WHO recommendations on the necessary reduction of daily salt intake as a risk factor for hypertension and arteriosclerosis. Therefore, additional standardised carriers of iodine (milk, mineral water) have been introduced into the food market. PMID- 22538759 TI - Prognostic value of electroencephalography and evoked potentials in the early course of malignant middle cerebral artery infarction. AB - Space-occupying brain edema may lead to a malignant course in patients with large middle cerebral artery infarction. Decompressive hemicraniectomy has to be initiated early to prevent further tissue damage. In this retrospective study, we analyzed electroencephalography (EEG) and evoked potentials (EPs), obtained within 24 h after onset of stroke, in 22 patients suffering from a large middle cerebral artery infarction. Our findings indicate a prognostic value of EEG and brainstem auditory EP (BAEP): the absence of delta activity and the presence of theta and fast beta frequencies within EEG-focus predicted a non-malignant course. In contrast, diffuse generalized slowing and slow delta activity in the ischemic hemisphere pointed to a malignant course. Likewise, pathological BAEP were correlated with a malignant course. The coexistence of background slowing and pathological BAEP showed the highest level of significance. In conclusion, our findings implicate an additional early application of electrophysiological methods in stroke patients. EEG and EP deliver useful information to select those patients who develop malignant edema. PMID- 22538758 TI - Deferoxamine attenuates iron-induced long-term neurotoxicity in rats with traumatic brain injury. AB - This study investigated whether deferoxamine (DFO), an iron chelator attenuates iron-induced toxicity in rats with traumatic brain injury. In this study, three groups of Sprague-Dawley rats (sham, injury and DFO groups) were examined. Rats were killed on day 28 after Morris water maze testing and brains perfused for either non-heme brain binding or hemosiderin staining. Western blotting was used to measure protein levels of ferritin, transferrin and transient receptor potential canonical channel 6 (TRPC6). In TBI rats, there was a significant increase in brain iron on day 28, ferritin L, ferritin H, transferrin and TRPC6 levels were all significantly elevated post-TB1. There were also deficits in spatial learning and memory; however, DFO administration attenuated these effects in TBI rats supporting the notion that DFO may reduce brain injury accentuated by iron overload. PMID- 22538761 TI - Proinflammatory cytokines in the saliva of patients with active and non-active Crohn's disease. AB - INTRODUCTION: Crohn's disease (CD) involves the entire gastrointestinal tract, including the mouth. Numerous cytokines play a role in the regulation of inflammatory process in CD. OBJECTIVES: The aim of the study was to examine the prevalence of oral lesions in adult patients with CD and to investigate whether salivary concentrations of interleukin 1beta (IL-1beta), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) are associated with the activity and oral manifestations of CD. PATIENTS AND METHODS: A prospective study included 95 adult patients: 52 with active CD and 43 with inactive CD. The control group involved 45 subjects without CD. We performed blood tests, careful oral examination, and measurement of IL-1beta, IL-6, and TNF-alpha in unstimulated whole saliva by enzyme-linked immunosorbent assays. RESULTS: IL-1beta, IL-6, and TNF-alpha were significantly elevated in patients with active CD. IL-1beta levels were 289.8 +/-52.7 in patients with active CD vs. 196.7 +/-42.9 pg/ml in patients with inactive CD (P <0.039), and 196.7 +/-42.9 pg/ml (P <0.01) in controls. IL-6 levels were 13.8 +/-4.2 vs. 7.2 +/-3.1 pg/ml (P <0.041), respectively, and 6.3 +/ 1.4 pg/ml (P <0.001) in controls. TNF-alpha levels were 32.5 +/-8.7 vs. 10.2 +/ 6.3 pg/ml (P <0.002), respectively, and 6.8 +/-2.8 pg/ml (P <0.001) in controls. We observed CD-specific oral lesions: diffuse asymptomatic buccal swelling in 12 patients (23%) and cobblestoning in 5 patients (11.3%). CD-nonspecific lesions were observed in 17 patients (32.7%) with active CD, in 11 patients (25.6%) with inactive CD, and in 6 controls (13.3%). In active CD, higher salivary IL-6 and TNF-alpha and serum C-reactive protein levels correlated with specific oral lesions. CONCLUSIONS: In patients with active CD, salivary IL-1beta, IL-6, and TNF-alpha levels are higher than in patients with inactive disease and controls. Elevated salivary IL-6 and TNF-alpha levels correlate with specific oral lesions. These cytokines may be used as markers of active CD, but the finding should be confirmed in a larger group of patients. PMID- 22538762 TI - Sodium methoxide: a simple but highly efficient catalyst for the direct amidation of esters. AB - A simple NaOMe catalyst provides superior accessibility to a wide variety of functionalized amides including peptides through direct amination of esters in an atom-economical and environmentally benign way. PMID- 22538763 TI - Effects of histamine H4 receptor ligands in a mouse model of gastric ulceration. AB - AIM: In the present study we examined whether histamine H(4) receptors (H(4)Rs) have a role in gastric ulcerogenesis using a mouse model of gastric damage. METHODS: The H(4)R antagonist JNJ7777120 and the H(4)R agonists VUF8430 and VUF10460 were investigated in fasted CD-1 mice against the ulcerogenic effect induced by co-administration of indomethacin(IND, 30 mg/kg s.c.) and bethanechol (BET, 5 mg/kg i.p.). Both macroscopic and histologic lesions were examined. Strain-related differences were investigated by testing JNJ7777120 also in NMRI, BALB/c and C57BL/6J mice. RESULTS: Neither JNJ7777120 nor the H(4)R agonists displayed effects in the normal stomach at any dose tested (10 and 30 mg/kg s.c.). As expected, IND+BET provoked several lesions in the fundic mucosa, which were significantly reduced by JNJ7777120 (10 and 30 mg/kg s.c.). The gastroprotective effect of JNJ7777120 (10 and 30 mg/kg s.c.) was observed in CD 1, NMRI and BALB/c, but not in C57BL/6J, mice. In CD-1 mice, the H(4)R agonists VUF8430 and VUF10460 (both at 10 and 30 mg/kg s.c.) did not modify the damage induced by IND+BET, however VUF8430 (10 mg/kg s.c.) prevented the gastroprotection induced by JNJ7777120 (10 mg/kg s.c.). CONCLUSIONS: Data obtained with selective ligands suggest that the H(4)R may have a role in mouse gastric ulcerogenesis. If confirmed in humans, these data would emphasize the potential advantage of H(4)R blockers as gastrosparing anti-inflammatory drugs. The lack of effects of JNJ7777120 in C57BL/6J mice has to be carefully considered in the pharmacological characterization of H(4)R functions and/or new selective ligands. PMID- 22538764 TI - Isolated cardiac metastasis in a patient with neuroendocrine carcinoma of pancreas discovered on 68Ga-DOTANOC PET/CT. AB - We present an interesting image that demonstrates utility of (68)Ga-DOTANOC PET/CT for demonstrating rare metastatic sites of neuroendocrime tumor. PMID- 22538765 TI - Lessons for Nuclear Cardiology from the DCRI/ACCF/AHA radiation think tank. PMID- 22538766 TI - Use of high-risk features from exercise treadmill testing to identify obstructive left main disease with normal myocardial perfusion imaging. PMID- 22538767 TI - Time for geriatric jurisprudence. AB - Geriatrics and law may not be natural bedfellows. Moreover, law and lawyers were not part of the professions that were the 'founding fathers' of the field of geriatrics. In this short viewpoint we invite the readers to consider a new inter disciplinary research approach that attempts to combine jurisprudence with geriatrics. Geriatric jurisprudence is a special and timely opportunity for doctors and lawyers to come together in a new, different and more united way to jointly conceptualize a medico-legal theory of aging to better serve our shared community: older and aging persons. PMID- 22538768 TI - Methane storage in molecular nanostructures. AB - We survey various molecular structures which have been proposed as possible nanocontainers for methane storage. These are molecular structures that have been investigated through either experiments, molecular dynamics simulations or mathematical modelling. Computational simulation and mathematical modelling play an important role in predicting and verifying experimental outcomes, but both have their limitations. Even though recent advances have greatly improved computations, due to the large number of atoms and force field calculations involved, computational simulations can still be time consuming as compared to an instantaneous mathematical modelling approach. On the other hand, underlying an ideal mathematical model, there are many assumptions and approximations, but such modelling often reveals the key physical parameters and optimal configurations. Here, we review methane adsorption for three conventional nanostructures, namely graphite, single and multi-walled carbon nanotubes, and nanotube bundles (including interstitial and groove sites), and we survey methane adsorption in other molecular structures including metal organic frameworks. We also include an examination of minimum binding energies, equilibrium distances, gravimetric and volumetric uptakes, volume available for adsorption, as well as the effects of temperature and pressure on the adsorption of methane onto these molecular structures. PMID- 22538769 TI - Nanowires for energy generation. AB - As a result of their morphology, nanowires bring new properties and the promise of performance for a range of electronic devices. This review looks into the properties of nanowires and the multiple ways in which they have been exploited for energy generation, from photovoltaics to piezoelectric generators. PMID- 22538770 TI - Mutation profiling identifies numerous rare drug targets and distinct mutation patterns in different clinical subtypes of breast cancers. AB - The mutation pattern of breast cancer molecular subtypes is incompletely understood. The purpose of this study was to identify mutations in genes that may be targeted with currently available investigational drugs in the three major breast cancer subtypes (ER+/HER2-, HER2+, and Triple Negative). We extracted DNA from fine needle aspirations of 267 stage I-III breast cancers. These tumor specimens typically consisted of >80% neoplastic cells. We examined 28 genes for 163 known cancer-related nucleic acid variations by Sequenom technology. We observed at least one mutation in 38 alleles corresponding to 15 genes in 108 (40%) samples, including PIK3CA (16.1% of all samples), FBXW7 (8%), BRAF (3.0%), EGFR (2.6%), AKT1 and CTNNB1 (1.9% each), KIT and KRAS (1.5% each), and PDGFR alpha (1.1%). We also checked for the polymorphism in PHLPP2 that is known to activate AKT and it was found at 13.5% of the patient samples. PIK3CA mutations were more frequent in estrogen receptor-positive cancers compared to triple negative breast cancer (TNBC) (19 vs. 8%, p=0.001). High frequency of PIK3CA mutations (28%) were also found in HER2+ breast tumors. In TNBC, FBXW7 mutations were significantly more frequent compared to ER+ tumors (13 vs. 5%, p=0.037). We performed validation for all mutated alleles with allele-specific PCR or direct sequencing; alleles analyzed by two different sequencing techniques showed 95 100% concordance for mutation status. In conclusion, different breast cancer subtypes harbor different type of mutations and approximately 40 % of tumors contained individually rare mutations in signaling pathways that can be potentially targeted with drugs. Simultaneous testing of many different mutations in a single needle biopsy is feasible and allows the design of prospective clinical trials that could test the functional importance of these mutations in the future. PMID- 22538771 TI - Id4 protein is highly expressed in triple-negative breast carcinomas: possible implications for BRCA1 downregulation. AB - BRCA1 germline mutation carriers usually develop ER, PR and HER2 negative breast carcinoma. Somatic BRCA1 mutations are rare in sporadic breast cancers, but other mechanisms could impair BRCA1 functions in these tumors, particularly in triple negative breast carcinomas (TNBCs). Id4, a helix-loop-helix DNA binding factor, blocks BRCA1 gene transcription in vitro and could downregulate BRCA1 in vivo. We compared Id4 immunoreactivity in 101 TNBCs versus 113 non-TNBCs, and correlated the results with tumor morphology and immunoreactivity for CK5/6, CK14, EGFR, and androgen receptor (AR). Id4 was present in 76 out of 101 (75 %) TNBCs: 40 (40 %) TNBCs displayed Id4 positivity in >50 % of neoplastic cells, 23 (23 %) in 5-50 %, and 13 (13 %) in <5 %. In contrast, only 6 (5 %) of 113 non-TNBCs showed focal Id4 positivity, limited to fewer than 5 % of the tumor (p < 0.0001). Id4 expression significantly associated with high histologic grade (p = 0.0002) and mitotic rate (p = 0.006). Id4 decorated all 12 TNBCs with large central acellular zone of necrosis in our series, with positive staining in 10-90 % of the cells. Id4 signal strongly correlated with cytokeratin CK14 reactivity (p < 0.0001), but not with CK5/6 and EGFR. All apocrine carcinomas in our series were positive for AR and most for EGFR, but they were negative for CK5/6, CK14, and Id4, with only two exceptions. Our results document substantial expression of Id4 in most TNBCs, which could result in functional downregulation of BRCA1 pathways in these tumors. PMID- 22538772 TI - Using the National Institute of Health Stroke Scale to predict dysphagia in acute ischemic stroke. AB - BACKGROUND AND PURPOSE: Oropharyngeal dysphagia is a common manifestation in acute stroke. Aspiration resulting from difficulties in swallowing is a symptom that should be considered due to the frequent occurrence of aspiration pneumonia that could influence the patient's recovery as it causes clinical complications and could even lead to the patient's death. The early clinical evaluation of swallowing disorders can help define approaches and avoid oral feeding, which may be detrimental to the patient. This study aimed to create an algorithm to identify patients at risk of developing dysphagia following acute ischemic stroke in order to be able to decide on the safest way of feeding and minimize the complications of stroke using the National Institutes of Health Stroke Scale (NHISS). METHODS: Clinical assessment of swallowing was performed in 50 patients admitted to the emergency unit of the University Hospital, Faculty of Medicine of Ribeirao Preto, Sao Paulo, Brazil, with a diagnosis of ischemic stroke, within 48 h after the beginning of symptoms. Patients, 25 females and 25 males with a mean age of 64.90 years (range 26-91 years), were evaluated consecutively. An anamnesis was taken before the patient's participation in the study in order to exclude a prior history of deglutition difficulties. For the functional assessment of swallowing, three food consistencies were used, i.e. pasty, liquid and solid. After clinical evaluation, we concluded whether there was dysphagia. For statistical analysis we used the Fisher exact test, verifying the association between the variables. To assess whether the NIHSS score characterizes a risk factor for dysphagia, a receiver operational characteristics curve was constructed to obtain characteristics for sensitivity and specificity. RESULTS: Dysphagia was present in 32% of the patients. The clinical evaluation is a reliable method of detection of swallowing difficulties. However, the predictors of risk for the swallowing function must be balanced, and the level of consciousness and the presence of preexisting comorbidities should be considered. Gender, age and cerebral hemisphere involved were not significantly associated with the presence of dysphagia. NIHSS, Glasgow Coma Scale, and speech and language changes had a statistically significant predictive value for the presence of dysphagia. CONCLUSIONS: The NIHSS is highly sensitive (88%) and specific (85%) in detecting dysphagia; a score of 12 may be considered as the cutoff value. The creation of an algorithm to detect dysphagia in acute ischemic stroke appears to be useful in selecting the optimal feeding route while awaiting a specialized evaluation. PMID- 22538774 TI - Fibrinolytic status in acute coronary syndromes: evidence of differences in relation to clinical features and pathophysiological pathways. AB - Limited data are available on the role of innate fibrinolysis in acute coronary syndromes (ACS). In the present study we evaluated the dynamic alterations of fibrinolytic markers in patients presenting with ACS. Tissue-type-(tPA) and urokinase type-(uPA) plasminogen activators, plasminogen activator inhibitor (PAI 1) antigen and activity and thrombin activatable fibrinolysis inhibitor (TAFI) were analysed in 50 patients with ST elevation myocardial infarction (STEMI), 47 non-STEMI patients (NSTEMI), 40 patients with stable coronary artery disease (CAD) and 39 controls. The parameters were measured on day 1 and days 3, 7 and 30. Counts of monocyte subsets, monocyte-platelet aggregates and plasma inflammatory cytokines were assessed on admission. On day 1, TAFI was higher in NSTEMI vs. STEMI (p<0.001) while PAI-1 activity was higher in STEMI (p<0.001). In STEMI, uPA activity levels was low on day 1 but significantly increased on day 30 (p<0.001). TAFI levels were increased in NSTEMI on day 1 and gradually reduced by day 30 (p<0.05). In STEMI, TAFI levels peaked at day 7 (p<0.05) and dropped significantly by day 30 (p<0.05). CD14++CD16+ monocytes were independently associated with PAI-1 activity in ACS (p=0.03). Monocyte-platelet aggregates rather than platelet-free monocytes were an independent determinant of tPA, PAI-1 antigen and TAFI on a multivariate analysis (p<0.05). There are significant differences in fibrinolytic activity between patients with STEMI and NSTEMI. These changes could reflect the role of these factors in post-MI myocardial healing. Monocyte-platelet interactions are independently associated with the regulation of the fibrinolytic status in ACS. PMID- 22538773 TI - Using novel methods to examine stress among HIV-positive African American men who have sex with men and women. AB - Biomarker composites (BCs) that objectively quantify psychosocial stress independent of self report could help to identify those at greatest risk for negative health outcomes and elucidate mechanisms of stress-related processes. Here, BCs are examined in the context of existing disease progression among HIV positive African American men who have sex with men and women (MSMW) with high stress histories, including childhood sexual abuse. Participants (N = 99) collected 12-h overnight and morning urine samples for assay of cortisol and catecholamines (primary BC) and neopterin (an indicator of HIV disease progression). Data on cumulative psychosocial trauma history (severity, types, frequency, age at first incident), posttraumatic stress disorder (PTSD) symptoms, sexual risk behaviors, and a secondary BC consisting of routine health indicators (heart rate, blood pressure, body mass index, waist-to-hip ratio) were also collected. Lifetime trauma exposure was highly pervasive and significantly greater among those meeting a standard cutoff for PTSD caseness (24 %). After controlling for HIV factors (neopterin levels and years with disease), PTSD was a significant (p < .05) predictor of the primary, but not secondary BC. Those with PTSD also had significantly more sexual partners, sex without a condom, and exchange sex for money or drugs than those without PTSD. Specific trauma characteristics predicted PTSD severity and caseness independently and uniquely in regression models (p's < .05-.001). A primary BC appears sensitive to cumulative trauma burden and PTSD in HIV-positive African American MSMW, providing support for the use of BCs to quantify psychosocial stress and inform novel methods for examining mechanisms of stress influenced health behaviors and disease outcomes in at-risk populations. PMID- 22538775 TI - Determination of pesticide residues in wine by membrane-assisted solvent extraction and high-performance liquid chromatography-tandem mass spectrometry. AB - The determination of pesticides in food products is an essential issue to guarantee food safety and minimise health risks of consumers. A protocol based on membrane-assisted solvent extraction and liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) that allows the determination of 18 pesticides in red wine at minimum labour effort for sample preparation was developed and validated. Ten millilitres of wine were extracted using 100 MUL of toluene filled in a non porous polyethylene membrane bag which is immersed in the wine sample. After 150 min extraction under stirring, an aliquot of the extraction solution is analysed using HPLC-MS/MS. The limits of quantification ranged from 3 ng/L for Pirimicarb to 1.33 MUg/L for Imidacloprid. Quantification by matrix-matched calibration provided relative standard deviations <=16 % for most of the target pesticides. The linearity of calibration was given over three to four orders of magnitude, which enables the reliable measurement of a broad range of pesticide concentrations, and for each target pesticide, the sensitivity of the protocol meets the maximum residue levels set by legislations at least for wine grapes. Good agreement of results was found when the new method was compared with a standard liquid-liquid extraction protocol. In five wine samples analysed, Carbendazim and Metalaxyl were determined at micrograms per litre concentrations, even in some of the organic wines. Tebuconazol and Cyprodinitril were determined at lower abundance and concentration, followed by Spiroxamin and Diuron. PMID- 22538776 TI - Characterization of AhR agonist compounds in roadside snow. AB - Aryl hydrocarbon receptor (AhR) agonistic contaminants were identified in roadside snow samples. Snow was collected in Oslo, Norway, and compared to a background sample collected from a mountain area. The water and particulate fractions were analysed for AhR agonists using a dioxin-responsive, chemically activated luciferase expression (CALUX) cell assay and by gas chromatography coupled to high-resolution time-of-flight mass spectrometry with targeted analysis for polycyclic aromatic hydrocarbons (PAHs) and broad-spectrum non target analysis. The AhR agonist levels in the dissolved fractions in the roadside samples were between 15 and 387 pg/L CALUX toxic equivalents (TEQ(CALUX)). An elevated AhR activity of 221 pg TEQ(CALUX) per litre was detected in the mountain sample. In the particle-bound fractions, the TEQ(CALUX) was between 1,350 and 7,390 pg/L. One possible explanation for the elevated levels in the dissolved fraction of the mountain sample could be the presence of black carbon in the roadside samples, potentially adsorbing dioxin-like compounds and rendering them unavailable for AhR interaction. No polychlorinated dibenzodioxins and dibenzofurans or polychlorinated biphenyls were detected in the samples; the occurrence of PAHs, however, explained up to 9 % of the AhR agonist activity in the samples, whilst comprehensive two-dimensional gas chromatography coupled to mass spectrometry GCxGC-ToF-Ms identified PAH derivatives such as polycyclic aromatic ketones and alkylated, nitrogen sulphur and oxygen PAHs in the particle fractions. The (large) discrepancy between the total and explained activity highlights the fact that there are other as yet unidentified AhR agonists present in the environment. PMID- 22538777 TI - Use of the HS-PTR-MS for online measurements of pyrethroids during indoor insecticide treatments. AB - A high-sensitivity proton transfer reaction mass spectrometer (HS-PTR-MS) has been used to study the temporal evolution of pesticide concentrations in indoor environments. Because of the high time variability of the indoor air concentrations during household pesticide applications, the use of this online high time resolution instrument is found relevant. Four pyrethroid pesticides of the latest generation that are commonly found in electric vaporizer refills, namely, transfluthrin, empenthrin, tetramethrin, and prallethrin, were considered. A controlled pesticide generation system was settled and coupled to a HS-PTR-MS analyzer, and a calibration procedure based on the fragmentation patterns of the protonated molecules was performed. To illustrate the functionality of the method, measurements of the concentration-time profiles of transfluthrin contained in an electric vaporizer were carried out in a full-scale environmental room under air exchange rate-controlled conditions. This study demonstrates that the HS-PTR-MS technique can provide online and high time resolved measurements of semi-volatile organic compounds such as pyrethroid insecticides. PMID- 22538778 TI - Simultaneous quantitation of sphingoid bases and their phosphates in biological samples by liquid chromatography/electrospray ionization tandem mass spectrometry. AB - We developed a liquid chromatography/electrospray ionization tandem mass spectrometry method for the simultaneous quantitative determination of C18 sphingosine (Sph), C18 dihydrosphingosine (dhSph), C18 phytosphingosine (pSph), C18 sphingosine-1-phosphate (S1P), C18 dihydrosphingosine-1-phosphate (dhS1P), and C18 phytosphingosine-1-phosphate (pS1P). Samples were prepared by simple methanol deproteinization and analyzed in selected reaction monitoring modes. No peak tailing was observed on the chromatograms using a Capcell Pak ACR column (1.5 mm i.d. * 250 mm, 3 MUm, Shiseido). The calibration curves of the sphingoids showed good linearity (r > 0.996) over the range of 0.050-5.00 pmol per injection. The accuracy and precision of this method were demonstrated using four representative biological samples (serum, brain, liver, and spleen) from mice that contained known amounts of the sphingoids. Samples of mice tissue such as plasma, brain, eye, testis, liver, kidney, lung, spleen, lymph node, and thymus were examined for their Sph, dhSph, pSph, S1P, dhS1P, and pS1P composition. The results confirmed the usefulness of this method for the physiological and pathological analysis of the composition of important sphingoids. PMID- 22538779 TI - Collaborative study for the detection of toxic compounds in shellfish extracts using cell-based assays. Part I: screening strategy and pre-validation study with lipophilic marine toxins. AB - Human poisoning due to consumption of seafood contaminated with phycotoxins is a worldwide problem, and routine monitoring programs have been implemented in various countries to protect human consumers. Following successive episodes of unexplained shellfish toxicity since 2005 in the Arcachon Bay on the French Atlantic coast, a national research program was set up to investigate these atypical toxic events. Part of this program was devoted to fit-for-purpose cell based assays (CBA) as complementary tools to collect toxicity data on atypical positive-mouse bioassay shellfish extracts. A collaborative study involving five laboratories was conducted. The responses of human hepatic (HepG2), human intestinal (Caco2), and mouse neuronal (Neuro2a) cell lines exposed to three known lipophilic phycotoxins-okadaic acid (OA), azaspiracid-1 (AZA1), and pectenotoxin-2 (PTX2)-were investigated. A screening strategy composed of standard operating procedures and a decision tree for dose-response modeling and assay validation were designed after a round of "trial-and-error" process. For each toxin, the shape of the concentration-response curves and the IC(50) values were determined on the three cell lines. Whereas OA induced a similar response irrespective of the cell line (complete sigmoid), PTX2 was shown to be less toxic. AZA1 induced cytotoxicity only on HepG2 and Neuro2a, but not on Caco2. Intra- and inter-laboratory coefficients of variation of cell responses were large, with mean values ranging from 35 to 54 % and from 37 to 48 %, respectively. Investigating the responses of the selected cell lines to well known toxins is the first step supporting the use of CBA among the panel of methods for characterizing atypical shellfish toxicity. Considering these successful results, the CBA strategy will be further applied to extracts of negative, spiked, and naturally contaminated shellfish tissues. PMID- 22538780 TI - Carbohydrate analysis of hemicelluloses by gas chromatography-mass spectrometry of acetylated methyl glycosides. AB - A method based on gas chromatography-mass spectrometry analysis of acetylated methyl glycosides was developed in order to analyze monosaccharides obtained from various hemicelluloses. The derivatives of monosaccharide standards, arabinose, glucose, and xylose were studied in detail and (13)C-labeled analogues were used for identification and quantitative analysis. Excellent chromatographic separation of the monosaccharide derivatives was found and identification of the anomeric configuration was feasible through a prepared and identified pure methyl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside. The electron ionization mass spectrum and fragmentation path was studied for each monosaccharide derivative. Fragment ion pairs of labeled and unlabeled monosaccharides were used for quantification; m/z 243/248 for glucose, 128/132 for xylose, and 217/218 for arabinose. Using the intensity ratios obtained from the extracted ion chromatograms, accurate quantification of monosaccharide constituents of selected hemicelluloses was demonstrated. PMID- 22538782 TI - [A training program for dementia trainers: does this program have practical relevance?]. AB - BACKGROUND: Specific curricula for professionals working in various settings with persons with dementia have been developed and implemented into practice. In this study, the practical relevance of a teaching program for the M.A.S (Morbus Alzheimer syndrome) dementia trainer was evaluated. The curriculum was developed in 2002 within a scientific project. The goal was that care professionals and noncare professionals learn how to support and train persons with dementia and their caregivers. The task of the trainer is to support the functional and emotional resources of the person with dementia employing stage-specific training according to principles of the theory of retrogenesis. Trainers are also able to support family caregivers in their difficult day-to-day care for the person with dementia. With this training and support program, persons with dementia can train their residual capacities and develop a life perspective which enables them to cope with the long duration of Alzheimer's disease. MATERIALS AND METHODS: The curriculum for the training methodology is based in the theory of retrogenesis. The 1-year training course is held in the form of modules and includes the following topics: (1) stages of dementia and medical aspects, (2) communication with persons with dementia, (3) stage-specific retrogenic training, (4) physical training for the elderly and persons with dementia, (5) coaching family caregivers through the long disease duration, and (6) care issues for persons without education in care. M.A.S trainers were questioned after they had concluded the teaching program successfully and had the chance to apply the content of the teaching program in their practical work. A short questionnaire was sent via e-mail or a telephone interview was performed. RESULTS: A total of 279 trainers graduated and were certified. Of these, 140 persons (53.6% of the population) could be questioned after an average of 2.69 years after completion of the course: 93.6% of trainees were still using the principles of the teaching course successfully; of these, 56% were working in the function of a trainer full time and 44% used the principles within their work environment (mainly in the nursing home environment). CONCLUSION: The study found that the majority of questioned trainers are still using the principles taught in the course successfully with persons with dementia living at home and the content was found to be relevant for practice. The content of the teaching course, applying principles of retrogenesis, which was originally designed for persons with dementia living at home, can also be successfully applied in the nursing home environment. Increasing interest has been shown by institutions employing professionals whose task it is to keep persons with dementia active and interested as well as physically functioning at their best possible level. As a consequence, persons with dementia perceive higher quality of life and exhibit fewer behavior problems which complicate care. More research is needed to accumulate evidence and to support these findings. PMID- 22538781 TI - TNFalpha pathway blockade ameliorates toxic effects of FSGS plasma on podocyte cytoskeleton and beta3 integrin activation. AB - BACKGROUND: In the absence of mutant genes encoding components of the podocyte slit diaphragm, about 30-50 % of children with primary glucocorticoid-resistant focal segmental glomerulosclerosis (FSGS) develop recurrent proteinuria and slowly progressive FSGS lesions following renal transplantation. Recurrence of FSGS in the allograft strongly suggests a circulating factor that disturbs normal podocyte biology. To date, the nature of the circulating factor is unclear, and there is no cure for the recurrent form of FSGS (R-FSGS). METHODS: Cultured differentiated human podocytes were exposed to the plasmapheresis effluent or blood plasma samples from pediatric patients with recurrent or primary FSGS; in some cases, podocytes were pre-incubated with specific antibodies to block the tumor necrosis factor-alpha (TNFalpha) signaling pathway. Integrity of focal adhesion complexes and actin cytoskeleton were investigated by immunofluorescent microscopy. RESULTS: Plasmapheresis effluent from an R-FSGS child or fresh plasma from two children with primary FSGS rapidly disturbed the cytoskeleton of normal human podocytes in vitro. Plasma from a child with R-FSGS also activated beta3 integrin and dispersed focal adhesion complexes. The effects were reversed by pre incubation with antibodies against TNFalpha or either of the two TNFalpha receptors. When our patient with R-FSGS became resistant to plasmapheresis, we initiated treatment with twice weekly etanercept injections and then infliximab. Within 3 weeks of regular anti-TNFalpha therapy, the patient achieved sustained partial remission of proteinuria, allowing us to wean her off plasmapheresis completely. CONCLUSIONS: We suggest that in some FSGS patients, disruption of the podocyte cytoskeleton and beta3 integrin-mediated podocyte attachment are driven by the TNFalpha pathway. PMID- 22538783 TI - [Geriatric multimorbidity in claims data - part 1. Analysis of hospital data and long-term care insurance data]. AB - BACKGROUND: In Germany, typical geriatric multimorbidity is--next to age itself- of special significance for the identification of target groups for specific geriatric care offers. The present article primarily focuses on typical geriatric multimorbidity in the claims data of statutory health insurance and long-term care insurance in Germany. Using the definition of "the geriatric patient" that is agreed on by providers of services as well as by cost bearers, geriatric multimorbidity is defined as the coexistence of at least 2 of 15 typical geriatric conditions. A suggestion made by the German Geriatric Association was to assign ICD-10-GM codes to each of these 15 conditions. Thus, it becomes possible to identify the corresponding geriatric conditions in claims data. METHODS: The article investigates the frequency of geriatric conditions and, thus, of geriatric multimorbidity of patients aged >= 60 years admitted to a hospital with a geriatric ward. Patients treated in a geriatric ward were compared with those who did not receive geriatric care. In anticipation of a high correlation between typical geriatric conditions and specific features that are preconditions for receiving long-term care insurance benefits (such as care levels and status of a nursing home resident), claims data of the long-term care insurance were included for external validation. RESULTS: The analyses showed a distinctly higher proportion of insured people with typical geriatric multimorbidity or rather a certain care level among the geriatrically treated cases than among those patients not receiving geriatric treatment (68.5%/67.9% versus 24.2%/33.4%). The different proportions of typical geriatric multimorbidity coded among the patients with features of a certain care level in the two given groups give rise to the suspicion that typical geriatric multimorbidity is not always statistically recorded--especially in cases of treatment without provision of geriatric care. CONCLUSION: The frequency of cases of typical geriatric multimorbidity and a certain care level shows that--even when a specific geriatric offer exists--a considerable proportion of cases with typical geriatric conditions are treated in other medical departments. PMID- 22538784 TI - [Geriatric multimorbidity in claims data - part 2 : diagnoses of hospitals and diagnoses from physicians in the ambulatory setting]. AB - BACKGROUND: Due to demographics, characteristic multimorbidity in geriatric patients is resulting in increased social, medical, and healthcare challenges. Geriatric multimorbidity (GM) can be defined as the simultaneous occurrence of at least two diseases that require medical care with an interdisciplinary focus on independence in activities of daily living. Typical conditions of GM are, e.g., incontinence, cognitive impairment, frailty, and decubitus. MATERIAL AND METHODS: Part 2 of this study is based on claims data of 240,502 AOK insurants (AOK is one of the major health insurance companies of the German statutory health insurance system) aged >= 60 years with at least one admission to a hospital with a geriatric ward. Geriatric conditions (GCs) were ascertained in two ways: diagnoses from physicians in the ambulant care setting and diagnoses in a hospital setting in 2008. A total of 15 GC were assessed using diagnoses based on ICD-10 codes (as per suggestion from scientific geriatric societies). An insurant was defined as a person with GM, if he/she had at least two GCs. RESULTS: The proportion of GCs in ambulant or inpatient diagnoses of 240,502 insurants varied significantly in most cases. For specific GCs, considerably higher proportions of ambulant diagnoses (e.g., pain, impairment of vision, or hearing) or for inpatient diagnoses (e.g., electrolyte or fluid metabolism disorders, malnutrition, incontinence) were identified. Only on rare occasions were small differences observed comparing the proportions of specific GCs in the diagnoses of the two different care sectors. This finding reduces considerably the accordance between the two care sectors with reference to the presence or absence of a GC for ambulant or inpatient diagnoses. The main agreement was with the non coding of specific GCs, not with ambulant or inpatient diagnoses. Insurants with a geriatric hospital admission or certain care level (level >= 1) generally had higher proportions for specific GCs for inpatient and ambulant diagnoses than non geriatric treated insurants or insurants without a certain care level. Of the geriatric treated insurants and those with certain care levels, 90% were characterized by the presence of GM for both ambulant or inpatient diagnoses. This percentage is remarkably higher than for patients who featured no geriatric treatment or had no certain care level. CONCLUSION: The inclusion of ambulant diagnoses in addition to inpatient diagnosis offers comprehensive possibilities to identify insurants with GM in claims data. The contribution of the diagnoses of both care sectors for the identification of GC and GM varies with regard to attribute and insurant orientation. Furthermore, significant attribute-oriented overlap of insurants claiming geriatric treatments and insurants with certain care levels became visible, which can open new possibilities for simpler identification of a portion of patients with GM. PMID- 22538785 TI - [Quality of life of older women with dependency and abuse experience]. AB - BACKGROUND: Quality of life is largely determined by changing biographical contexts of a person's behavioural action. In later age, health and social relationships are major determinants for a "good life". A decline in health status may lead to the need for support which may result in further dependency; thus, social relations play an even more important role for older people. Relationships characterised by strain and tension may increase the risk of exposure to force and violence. This article investigates the influence of dependency and abuse on the subjective quality of life of older people. MATERIAL AND METHODS: The dataset was drawn from an Austrian survey of 593 home-dwelling older women aged 60 and over (71.0 +/- 8.1 years). Quality of life was assessed by the EUROHIS-QOL Scale, dependency by the degree of need for support with respect to activities of daily living and by the levels of care allowance received by this cohort. Following the Conflict Tactics Scales (CTS), six different types of abuse have been operationalised by 34 indicators. The data were analysed by descriptive statistics, confirmatory factor analysis and structural equation modelling. RESULTS: With increasing dependency the subjective quality of life of older women decreases. At the same time it is reduced by the experience of abuse in the close social environment. Neglect, psychological abuse and the violation of personal liberties and rights can be identified as factors which have a negative impact on quality of life. It is also noted that neglect can be found particularly among women with a greater need for support and a higher level of care allowance, which is a particularly problematic situation. CONCLUSION: Dependency and abuse are major risk factors for low quality of life in old age. The results stress the importance of raising general awareness on violence and highlight the social taboos around the issue of abuse against older people, especially in the case of increasing dependency. In addition, the results point to an increasing demand for specific measures of health promotion and prevention activities addressing vulnerable older people. PMID- 22538786 TI - [People with dementia in acute hospitals. Literature review of prevalence and reasons for hospital admission]. AB - People with dementia who are hospitalized depend on hospital care that is tailored to their particular needs. However, the current structural conditions and standardized care plans are often opposed to the needs for familiarity and orientation that people with dementia have. For the development of dementia specific care concepts, it is important to know the proportion of persons with dementia who are hospitalized as well as the diagnosis that leads to hospital admission. The results of the literature review show prevalence estimates of 3.4 43.3%. The probability or risk of hospitalization for persons with dementia is between 1.4-3.6 times greater than it is for non-dementia persons. In addition, the reasons for admission are different. People with dementia are more frequently hospitalized due to infectious diseases, fractures, or nutritional disorders than non-dementia persons. Based on these results, one can hypothesize that there is a need for cross-sectoral care approaches, since these indicate the necessity for further research in order to establish a reliable database. PMID- 22538787 TI - [Saving motives in young, middle-aged, and older adults. Preliminary results of a new inventory for exploring lifespan saving motives]. AB - There is some research on personal reasons for saving money in the economic sciences. However, not much is known about the age differences of saving motives. In this vein, the future time perspective (FTP) is known to play a critical role for motivation across the life span. In this study, we introduce a new Saving Motive Inventory (SMI), which also covers saving goals after retirement. Furthermore, it is argued that additional saving motives that are not based on economic models of life-cycle saving also exist. In accordance with the socio emotional selectivity theory, we explored age differences in an online survey with 496 participants from young (19-44 years), middle-aged (45-64 years), and older (65-86 years) adulthood, who completed a questionnaire on saving motives, personality, and future-related thinking (e.g., Future Time Perspective Scale, Life Orientation Test). Results of the explorative Factor Analysis (EFA) are consistent with the theoretical expectations. The factors are generativity, educational investment, consumption, indifference, and provision for death and dying. Together these five factors account for 67% of the variance. In general, the inventory is reliable and valid with respect to the expected internal and external criteria. It contributes to better understanding of saving motives over the lifespan, especially with respect to effects of the future time perspective. PMID- 22538788 TI - [Kyphoplasty in the treatment of osteoporotic spine fractures. Experience in over 500 patients]. AB - For over 10 years, kyphoplasty has been established for the treatment of painful osteoporotic vertebral compression fractures. Its effectiveness has been substantiated in multiple clinical studies. Not only is prompt pain reduction achieved, but according to a new, large, long-term study, long-term survival is also increased. Balloon kyphoplasty was performed for 564 patients from 1 January 2008 until 31 July 2011. In all cases, pain was rated more than 6/10 points, and recent fracture was evident on cross-sectional imaging (CT or MRT) performed to supplement spine x-rays. Average patient age was 75.3 years; 71.3% of patients were female. Treated fracture levels ranged from Th3 to L5. A single level was treated in 372 cases, with two levels treated simultaneously in 128 cases, three levels in 48 cases, and four levels in 22 cases. Average operative time for all patients was 36 min. Eight different surgeons performed the procedures. Average convalescence time was 8 days which decreased progressively over the years. Pain was reduced from 8 preoperative to 2.4 points postoperative in the visual analogue scale. Six major complications (1.06%) occurred. Kyphoplasty is a good procedure to treat painful osteoporotic fractures from the lumbar to thoracic spine. Major complications occur seldom after kyphoplasty; however, they must be considered and clarified. PMID- 22538789 TI - Postoperative cognitive dysfunction in geriatric patients. AB - Postoperative cognitive dysfunction (POCD) is a severe long-term complication after surgical procedures. POCD is mainly seen among geriatric patients. Hospitalization, extent of surgery, and systemic inflammatory response might contribute to POCD. The possible influence of the type of anesthesia is discussed. POCD is often not recognized; thus, incidence rates are likely to be underestimated (19-40%). POCD is associated with major consequences for the individual patient, e.g., delayed long-term recovery, reduced quality of life, and an increased mortality rate. Multiple risk factors have been identified over the last decade. However, the exact etiology is still unknown. This mini-review summarizes the recent developments concerning POCD prevention, diagnosis, and treatment. PMID- 22538791 TI - [Memento mori: what can be learned from early paintings and woodcuts about death and dying in former times?]. AB - What was the impression on death and dying from people living in the 15th century? To answer this question written information is rare on this topic, as few people were able to read at that time, but paintings and early woodcuts may be helpful. Danses macabres (Totentanze) could be seen in Tallinn (formerly Reval), Lubeck, Bern and other places: parts of the original dance macabre still exist in Tallinn, but those in Bern and Lubeck are destroyed; copies however may give a decent impression of their former appearance. At all these dances macabre the death invites persons for a dance: the pope, the Kaiser, the king, the queen, various noblemen and citizens, even young women and small children; to dance with the death meant to die. The death does not dance with any old person. At the time of these dances macabre epidemics and famines were frequent causes of untimely early death.--A booklet Ars moriendi was published about 1470 and taught people how to behave at their hour of death; various devils appear at the deathbed haggling for the soul of the dying person. Thereafter an angel convinces him to trust in god and to resist those false promises of the devil.Nowadays dying is quite different. Usually persons die at very old age and are frequently demented, they die in hospitals, even in intensive care units and possibly without attendance of family members. They may have suffered for a long time and have spent years in nursing homes. Today dying may be just a release from very long suffering. PMID- 22538790 TI - An exercise programme for community-dwelling, mobility-restricted and chronically ill older adults with structured support by the general practitioner's practice (HOMEfit). From feasibility to evaluation. AB - Programmes containing health-enhancing physical exercise should be evaluated using standards that are just as rigorous as those required for drug development. In contrast to new medicines, exercise programmes are highly complex. This has to be taken into account when designing the research plan. In order to illustrate the development process of a "complex intervention", we use the example of an exercise programme for community-dwelling, mobility-restricted and chronically ill older adults. Based on a framework for evaluation of complex interventions (Medical Research Council [MRC], UK), a research plan was set up containing the phases: development, feasibility, evaluation, implementation. The development phase resulted in the design of a home-based exercise programme in which the target group is approached and supported via their general practitioner and an exercise therapist. A feasibility study was performed. Three quantitative criteria for feasibility (adoption, safety, continuing participation) were statistically confirmed which permitted the decision to proceed with the research plan. So far, the MRC framework has proved to be valuable for the development of the new programme. PMID- 22538793 TI - [Maintenance of health and relief for caregivers of elderly with dementia by using "initial case management": experiences from the Lighthouse Project on Dementia, Ulm, ULTDEM-study]. AB - BACKGROUND: When facing the well-known demographic development with an increasing number of people suffering from dementia, there is a need of programmes to support nursing relatives and care at home. Many support services have been established in the past few years but they are rarely used by the relatives and the patients. The purpose of the Lighthouse Project Ulm (ULTDEM Study) was to prove the effectiveness of a single advisory approach in order to provide support services after care level classification and to relieve the burden placed on relatives caring for family members suffering from dementia ("initial case management"). METHODS: The ULTDEM Study is a prospective, open, randomized, controlled, interventional study with different parallel outcome measures (burden of caring, quality of life and mood). After the randomization, the interventional group was given comprehensive, individual advice about available treatment possibilities for dementia patients. Control group participants received standard treatment. Inclusion criteria were application of a care level (0 or 1) as well as dementia diagnosis. All participants (patients/relatives) underwent an initial and a 6 month comprehensive assessment. RESULTS: Our results show that a single advisory approach does not lead to a significant difference in outcome measures in interventional and control groups. Those tendencies described have to be interpreted as clinically not relevant. Although utilization of support services increases, it remains similar in both study groups. A confirmatory interpretation has not been possible due to a lack of adjustment to the findings regarding multiple testing and an insufficient degree of recruitment. Possible causes will be discussed such as premature intervention during the course of the disease, a lack of intervention blinding, recruitment bias and lack of an influence on adherence with regard to the use of support services. IMPLICATIONS: The study demonstrates that there is a substantial information deficit for persons affected by dementia and their relatives. Innovative ways still have to be developed to ensure that this information actually reaches the target audience. PMID- 22538794 TI - Are the elderly different? Factors influencing mortality after percutaneous coronary intervention with stent implantation. AB - BACKGROUND: The aim of this study was to investigate factors influencing mortality after percutaneous coronary intervention (PCI) in patients aged >= 75 years compared to younger patients. PATIENTS AND METHODS: A total of 1,809 coronary heart disease (CHD) patients after PCI with stent implantation in our hospital were assessed. Kaplan-Meier analyses with log-rank test and Cox regression analyses were performed on three predefined models concerning primary endpoint of all-cause mortality. Model 1 was a univariate analysis of the influence of age dichotomized by age 75 years on the primary endpoint. Model 2 included age and classical cardiovascular risk factors (CVRFs, e.g., body mass index (BMI), smoking, diabetes, and hypertension). Model 3 consisted of age, classical CVRFs, and additional factors (e.g., medication; hemoglobin, peripheral arterial disease (PAD), low-density lipoprotein cholesterol (LDL-C) and creatinine levels, and left ventricular ejection fraction (LVEF)). RESULTS: In the mean follow-up of 137 +/- 61 weeks 375 patients died. Age >= 75 years was significantly related to mortality in all models. In model 3, previous stroke, PAD, diabetes, elevated levels of serum creatinine, and increased LDL-C were related to elevated mortality, higher hemoglobin levels, and LVEF > 50% were associated with decreased mortality in all patients and in patients < 75 years. In patients >= 75 years arterial hypertension was associated with poor outcome (hazard ratio (HR) 7.989, p = 0.040), previous antiplatelet therapy showed reduced mortality (HR 0.098, p = 0.039). CONCLUSION: Although risk factors such as previous stroke, PAD, diabetes, renal insufficiency, and anemia were predictors for death in all patients and patients < 75 years, in the elderly only arterial hypertension increased, whereas treatment with platelet inhibitors decreased mortality. PMID- 22538795 TI - Anti-inflammatory and anticoagulant properties of the protein C system in inflammatory bowel disease. AB - INTRODUCTION: In patients with inflammatory bowel disease (IBD), disbalance between procoagulant, anticoagulant, and fibrinolytic factors has been shown. The hemostatic system is an indispensable component of the inflammatory process. Deficiencies in the protein C (PC) pathway components not only promote thrombosis, but also exacerbate inflammation. OBJECTIVES: The aim of the study was to assess the components of the PC system and their correlations with disease activity in patients with IBD. PATIENTS AND METHODS: The levels of PC, free protein S (PS), and soluble thrombomodulin (sTM) were measured in 55 consecutive patients with ulcerative colitis (UC), 50 patients with Crohn's disease (CD), and 41 healthy volunteers. Correlations between PC system components and disease activity, hemostatic variables, and inflammatory markers were assessed. RESULTS: sTM levels in patiens with UC were higher compared with controls (24.5 vs. 17.5 ng/ml; P = 0.0042). In patients with IBD, PC activity was higher and PS activity was lower compared with controls (P <0.001). Tumor necrosis factor alpha (TNF alpha) levels were higher in patients with IBD, and interleukin 6 (IL-6) levels were higher only in patients with CD. In patients with UC, a positive correlation was observed between sTM and both PC and PS levels (r = 0.28 and r = 0.34, respectively, P <0.05). Only PC levels correlated with UC activity (r = 0.3, P <0.05). No correlations of TNF-alpha, IL-6, and C-reactive protein with PC, PS, and sTM levels were observed. CONCLUSIONS: The PC pathway is defective in patients with CD and UC. Hypercoagulability in IBD might be associated not only with the inflammatory process but also with disturbances in the anticoagulant system, since defective PC pathway was observed both in active and nonactive disease. PMID- 22538796 TI - Distinctive features between community-acquired pneumonia (CAP) due to Chlamydophila psittaci and CAP due to Legionella pneumophila admitted to the intensive care unit (ICU). AB - The spectrum of community-acquired pneumonia (CAP) due to Chlamydophila psittaci ranges from mild, self-limited CAP, to acute respiratory failure. We performed a retrospective study of 13 consecutive patients with CAP due to C. psittaci and 51 patients with legionellosis admitted in one intensive care unit (ICU) (1993 2011). As compared to patients with legionellosis, patients with psittacosis were younger (median age 48 [38-59] vs. 60 [50-71] years, p = 0.007), less frequently smokers (38 vs. 79 %, p < 0.001), with less chronic disease (15 vs. 57 %, p = 0.02), and longer duration of symptoms before admission (median 6 [5-13] vs. 5 [3 7] days, p = 0.038). They presented with lower Simplified Acute Physiology Score II (median 28 [19-38] vs. 39 [28-46], p = 0.04) and less extensive infiltrates on chest X-rays (median 2 [1-3] vs. 3 [3-4] lobes, p = 0.007). Bird exposure was mentioned in 100 % of psittacosis cases, as compared to 5.9 % of legionellosis cases (p < 0.0001). Extrapulmonary manifestations, biological features, and mortality (15.4 vs. 21.6 %, p = 0.62) were similar in both groups. In conclusion, severe psittacosis shares many features with severe legionellosis, including extrapulmonary manifestations, biological features, and outcome. Psittacosis is an important differential diagnosis for legionellosis, especially in cases of bird exposure, younger age, and more limited disease progression over the initial few days. PMID- 22538797 TI - Epidemiology and evolution of antibiotic resistance of Haemophilus influenzae in children 5 years of age or less in France, 2001-2008: a retrospective database analysis. AB - Trends in the evolution of antimicrobial resistance and mechanisms of resistance of Haemophilus influenzae to beta-lactam antibiotics in France were assessed through a retrospective database review. The antimicrobial resistance of 2,206 H. influenzae strains from children aged <=5 years was studied between 2001 and 2008. Strains were isolated from blood or cerebrospinal fluid (n = 170), bronchial secretions (n = 188), middle ear fluid, and nasopharynx or conjunctiva (n = 1,848). A proportion of 95.1 % (n = 2,097) were non-typeable H. influenzae (NTHi). beta-lactamase production was identified in 27.5 % of NTHi isolates (all TEM-1), while beta-lactamase-negative ampicillin resistance and beta-lactamase negative amoxicillin-clavulanate resistance among NTHi was 16.9 and 6.4 %, respectively. Over time, a statistically significant decrease in beta-lactamase producing strain prevalence (p < 0.0001) and a statistically significant increase in beta-lactamase-negative ampicillin-resistant (BLNAR) strains (p < 0.0001) were observed in NTHi isolates from 2001 to 2008. The largest changes coincided with a campaign to reduce antibiotic use in France. An increasing diversity of amino acid substitution patterns was observed, with the emergence of group III/'III like' patterns linked to high-level resistance. In France, amino acid substitution patterns are increasingly diverse, and strains with high-level antibiotic resistance are emerging. This study highlights the complexity of resistance dynamics within a given country. These results have implications on antibiotic guidelines and illustrate the importance of continued surveillance. PMID- 22538799 TI - Oral mucosal morphea: a new variant. AB - Morphea is a cutaneous disorder characterized by an excessive collagen deposition. While in almost all cases the sclerosing process exclusively affects the skin, there are anecdotal cases in which associated mucosal involvement has been described. We here report the case of a woman developing a whitish indurated plaque over the left upper vestibular mucosa and hard palate leading to dental mobility and exposure of the roots of several teeth. Cone beam computed tomography of the left maxilla showed bone resorption involving the upper cuspid to the second molar region with widened periodontal ligament spaces, while light microscopy studies demonstrated epithelial atrophy and fibrosis of the dermis extending into the submucosa with hyalinization of subepithelial collagen. Our observation expands the spectrum of clinical presentations of morphea and provides the first example of isolated oral morphea. Its recognition is important to avoid significant local complications. PMID- 22538800 TI - Production, health aspects and potential food uses of dairy prebiotic galactooligosaccharides. AB - Galactooligosaccharides are sugars composed of 3-10 molecules of galactose and glucose via a transgalactosylation reaction mediated by the enzyme beta galactosidase. Prebiotics are non-digestible food ingredients that pass through the upper digestive system relatively intact and ferment in the lower colon, producing short-chain fatty acids that support the growth of supplemented or indigenous colonic microbiota. Galactooligosaccharides and other prebiotic ingredients are increasingly being recognized as useful dietary tools for the modulation of the colonic microflora toward a healthy balance. Galactooligosaccharides compare well to other oligosaccharides in terms of their prebiotic, immunomodulation, and functional properties in foods. This review elucidates the galactooligosaccharide production process from refined lactose and/or cheese whey permeates, galactooligosaccharide market share and economic value, their health properties, and potential food applications. PMID- 22538801 TI - Progressive flow-to-volume dysanapsis in cystic fibrosis: a predictor for lung transplantation? AB - RATIONALE: Airways obstruction and lung volume restriction, major features of lung disease in cystic fibrosis (CF), may regress independently, causing dysanapsis between these parameters. OBJECTIVES: To explore the significance of dysanapsis (FEF(25-75)/FVC) ratio in CF. METHODS: Yearly best spirometry data, collected during 8.6 +/- 1 year per patient, was determined from 93 patients with CF. Three groups were formed according to initial FEV(1). Group-N (n = 35; control, FEV(1) above 80%predicted); Group-B (n = 38; FEV(1) below 80% predicted); and Group-LT (n = 20; data collected before lung transplantation). The yearly decline in spirometry indices was defined in relation to the preceding year. Decline exceeding -2 z scores from Group-N in each index was considered "rapid decline." MEASUREMENTS AND MAIN RESULTS: Group-N's yearly decline of FEV(1), FEF(25-75), and FEF(25-75)/FVC were similar and reached -1.88 +/- 2.93%, 1.41 +/- 3.37%, and -1.81 +/- 4.48%, respectively. Rapid decline was equal to 6.5%, -10.8%, and -8.1%, respectively. Group-B's indices declined faster than that of Group-N, but did not exceed 1 z score. Group-LT showed a rapid decline solely in FEF(25-75)/FVC (mean z score = -6.4 +/- 2.5; P < 0.0001), which sprouted abruptly from the regular course of regression 4 +/- 1.3 years before transplantation. The rapid decline in FEF(25-75)/FVC was found in 19 of 20 patients from Group-LT and five patients from other groups (now waiting for transplantation). The phenomenon did not correlate with initial FEV(1) (%predicted) or age. Having airway hyperreactivity increased the risk of rapid decline in FEF(25-75)/FVC. CONCLUSIONS: Roughly 4 years before lung transplantation and independent of FEV(1) (%predicted), FEV(1) decline rate, or age, an abrupt rapid dysanapsis occurs. Findings imply insufficient ventilation/lung volume unit and insinuate a powerful marker for estimating lung translation time in CF. PMID- 22538802 TI - Combination biomarkers to diagnose sepsis in the critically ill patient. AB - RATIONALE: Although the outcome of sepsis benefits from the prompt administration of appropriate antibiotics on correct diagnosis, the assessment of infection in critically ill patients is often a challenge for clinicians. In this setting, simple biomarkers, especially when used in combination, could prove useful. OBJECTIVES: To determine the usefulness of combination biomarkers to diagnose sepsis. METHODS: Three hundred consecutive patients were enrolled to construct a biologic score that was next validated in an independent prospective cohort of 79 critically ill patients from another center. MEASUREMENT AND MAIN RESULTS: Plasma concentrations of soluble triggering receptor expressed on myeloid cells-1 (sTREM 1) and procalcitonin (PCT) were assayed, and the expression of the high-affinity immunoglobulin-Fc fragment receptor I (FcgammaRI) CD64 on neutrophils (polymorphonuclear [PMN] CD64 index) in flow cytometry was measured. A "bioscore" combining these biomarkers was constructed. Serum concentrations of PCT and sTREM 1 and the PMN CD64 index were higher in patients with sepsis compared with all others (P < 0.001 for the three markers). These biomarkers were all independent predictors of infection, the best receiver-operating characteristic curve being obtained for the PMN CD64 index. The performance of the bioscore, better than that of each individual biomarker, was externally confirmed in the validation cohort. CONCLUSIONS: This prospective study, including inceptive and validation cohorts of unselected intensive care unit patients, demonstrates the high performance of a bioscore combining the PMN CD64 index together with PCT and sTREM-1 serum levels in diagnosing sepsis in the critically ill patient. PMID- 22538803 TI - The relationship between lung inflammation and cardiovascular disease. AB - Acute and chronic lung inflammation is an underrecognized risk factor for cardiovascular disease. Yet, there are compelling epidemiological data to indicate that airway exposures to cigarette smoke, air pollution particles, and viral and bacterial pathogens are strongly related to acute ischemic events. Over the past 10 years, there have been important human and animal studies that have provided experimental evidence to support a causal link. In this article, we review the epidemiological data for the relationship between lung inflammation and cardiovascular disease and provide plausible mechanistic pathways by which acute and chronic inflammation contributes to the development of acute cardiovascular syndromes. PMID- 22538804 TI - Examination of the carbon monoxide diffusing capacity (DL(CO)) in relation to its KCO and VA components. AB - The single-breath carbon monoxide diffusing capacity (DL(CO)) is the product of two measurements during breath holding at full inflation: (1) the rate constant for carbon monoxide uptake from alveolar gas (kco [minute(-1)]) and (2) the "accessible" alveolar volume (Va). kco expressed per mm Hg alveolar dry gas pressure (Pb*) as kco/Pb*, and then multiplied by Va, equals Dl(CO); thus, Dl(CO) divided by Va (DL(CO)/Va, also called Kco) is only kco/Pb* in different units, remaining, essentially, a rate constant. The notion that DL(CO)/Va "corrects" DL(CO) for reduced Va is physiologically incorrect, because DL(CO)/Va is not constant as Va changes; thus, the term Kco reflects the physiology more appropriately. Crucially, the same DL(CO) may occur with various combinations of Kco and Va, each suggesting different pathologies. Decreased Kco occurs in alveolar-capillary damage, microvascular pathology, or anemia. Increased Kco occurs with (1) failure to expand normal lungs to predicted full inflation (extrapulmonary restriction); or (2) increased capillary volume and flow, either globally (left-to-right intracardiac shunting) or from flow and volume diversion from lost or damaged units to surviving normal units (e.g., pneumonectomy). Decreased Va occurs in (1) reduced alveolar expansion, (2) alveolar damage or loss, or (3) maldistribution of inspired gases with airflow obstruction. Kco will be greater than 120% predicted in case 1, 100-120% in case 2, and 40-120% in case 3, depending on pathology. Kco and Va values should be available to clinicians, as fundamental to understanding the clinical implications of DL(CO). The diffusing capacity for nitric oxide (DL(NO)), and the DL(NO)/DL(CO) ratio, provide additional insights. PMID- 22538805 TI - Genome-wide association identifies the T gene as a novel asthma pharmacogenetic locus. AB - RATIONALE: To date, most studies aimed at discovering genetic factors influencing treatment response in asthma have focused on biologic candidate genes. Genome wide association studies (GWAS) can rapidly identify novel pharmacogenetic loci. OBJECTIVES: To investigate if GWAS can identify novel pharmacogenetic loci in asthma. METHODS: Using phenotypic and GWAS genotype data available through the NHLBI-funded Single-nucleotide polymorphism Health association-Asthma Resource Project, we analyzed differences in FEV(1) in response to inhaled corticosteroids in 418 white subjects with asthma. Of the 444,088 single nucleotide polymorphisms (SNPs) analyzed, the lowest 50 SNPs by P value were genotyped in an independent clinical trial population of 407 subjects with asthma. MEASUREMENTS AND MAIN RESULTS: The lowest P value for the GWAS analysis was 2.09 * 10(-6). Of the 47 SNPs successfully genotyped in the replication population, three were associated under the same genetic model in the same direction, including two of the top four SNPs ranked by P value. Combined P values for these SNPs were 1.06 * 10(-5) for rs3127412 and 6.13 * 10(-6) for rs6456042. Although these two were not located within a gene, they were tightly correlated with three variants mapping to potentially functional regions within the T gene. After genotyping, each T gene variant was also associated with lung function response to inhaled corticosteroids in each of the trials associated with rs3127412 and rs6456042 in the initial GWAS analysis. On average, there was a twofold to threefold difference in FEV(1) response for those subjects homozygous for the wild-type versus mutant alleles for each T gene SNP. CONCLUSIONS: Genome-wide association has identified the T gene as a novel pharmacogenetic locus for inhaled corticosteroid response in asthma. PMID- 22538809 TI - Enhancement of hematopoiesis and lymphopoiesis in diet-induced obese mice. AB - A rodent model of diet-induced obesity revealed that obesity significantly altered hematopoietic and lymphopoietic functions in the bone marrow and thymus. C57BL/6 mice were fed a mixed high-fat diet (HFD) of 45% fat or 10% fat diet (lean controls) for 180 d. A sustained increase in the numbers of cells found in bone marrow and thymus of HFD mice occurred from day 90 to day 180. However, with the exception of a 10-18% increase in the proportion of lymphocytes, the composition of monocytes, granulocytes, erythrocytes, and mixed progenitor lineages remained normal in the marrow. Likewise, thymuses of HFD mice increased 30-50% in size compared with controls, with analogous increases in thymocyte numbers. The overall thymus cellular composition remained normal. Although increased blood and lymphatic volume in obese mice would play a role in increased hematopoiesis, there were large and disproportionate increases in blood leukocytes of HFD mice, indicating that homeostasis was not maintained. Leptin, which promotes lymphopoiesis and myelopoiesis, reached 100 ng/mL in sera from HFD mice. Moreover, a three- to sixfold increase in adipocytes in marrow resulted in spiked leptin mRNA expression in bones of HFD mice compared with lean controls. Other cytokines and growth factors did not show any increases in obese marrow. The substantial increase in lymphopoietic and hematopoietic processes in HFD mice indicates that the primary tissues are another facet of the immune system dysregulated by obesity, which was perhaps fostered by higher amounts of leptin in marrow and serum. PMID- 22538806 TI - The transcriptional landscape and small RNAs of Salmonella enterica serovar Typhimurium. AB - More than 50 y of research have provided great insight into the physiology, metabolism, and molecular biology of Salmonella enterica serovar Typhimurium (S. Typhimurium), but important gaps in our knowledge remain. It is clear that a precise choreography of gene expression is required for Salmonella infection, but basic genetic information such as the global locations of transcription start sites (TSSs) has been lacking. We combined three RNA-sequencing techniques and two sequencing platforms to generate a robust picture of transcription in S. Typhimurium. Differential RNA sequencing identified 1,873 TSSs on the chromosome of S. Typhimurium SL1344 and 13% of these TSSs initiated antisense transcripts. Unique findings include the TSSs of the virulence regulators phoP, slyA, and invF. Chromatin immunoprecipitation revealed that RNA polymerase was bound to 70% of the TSSs, and two-thirds of these TSSs were associated with sigma(70) (including phoP, slyA, and invF) from which we identified the -10 and -35 motifs of sigma(70)-dependent S. Typhimurium gene promoters. Overall, we corrected the location of important genes and discovered 18 times more promoters than identified previously. S. Typhimurium expresses 140 small regulatory RNAs (sRNAs) at early stationary phase, including 60 newly identified sRNAs. Almost half of the experimentally verified sRNAs were found to be unique to the Salmonella genus, and <20% were found throughout the Enterobacteriaceae. This description of the transcriptional map of SL1344 advances our understanding of S. Typhimurium, arguably the most important bacterial infection model. PMID- 22538807 TI - Janus-faced liposomes enhance antimicrobial innate immune response in Mycobacterium tuberculosis infection. AB - We have generated unique asymmetric liposomes with phosphatidylserine (PS) distributed at the outer membrane surface to resemble apoptotic bodies and phosphatidic acid (PA) at the inner layer as a strategy to enhance innate antimycobacterial activity in phagocytes while limiting the inflammatory response. Results show that these apoptotic body-like liposomes carrying PA (ABL/PA) (i) are more efficiently internalized by human macrophages than by nonprofessional phagocytes, (ii) induce cytosolic Ca(2+) influx, (iii) promote Ca(2+)-dependent maturation of phagolysosomes containing Mycobacterium tuberculosis (MTB), (iv) induce Ca(2+)-dependent reactive oxygen species (ROS) production, (v) inhibit intracellular mycobacterial growth in differentiated THP 1 cells as well as in type-1 and -2 human macrophages, and (vi) down-regulate tumor necrosis factor (TNF)-alpha, interleukin (IL)-12, IL-1beta, IL-18, and IL 23 and up-regulate transforming growth factor (TGF)-beta without altering IL-10, IL-27, and IL-6 mRNA expression. Also, ABL/PA promoted intracellular killing of M. tuberculosis in bronchoalveolar lavage cells from patients with active pulmonary tuberculosis. Furthermore, the treatment of MTB-infected mice with ABL/PA, in combination or not with isoniazid (INH), dramatically reduced lung and, to a lesser extent, liver and spleen mycobacterial loads, with a concomitant 10-fold reduction of serum TNF-alpha, IL-1beta, and IFN-gamma compared with that in untreated mice. Altogether, these results suggest that apoptotic body-like liposomes may be used as a Janus-faced immunotherapeutic platform to deliver polar secondary lipid messengers, such as PA, into phagocytes to improve and recover phagolysosome biogenesis and pathogen killing while limiting the inflammatory response. PMID- 22538810 TI - Anabolic action of parathyroid hormone regulated by the beta2-adrenergic receptor. AB - Parathyroid hormone (PTH), the major calcium-regulating hormone, and norepinephrine (NE), the principal neurotransmitter of sympathetic nerves, regulate bone remodeling by activating distinct cell-surface G protein-coupled receptors in osteoblasts: the parathyroid hormone type 1 receptor (PTHR) and the beta(2)-adrenergic receptor (beta(2)AR), respectively. These receptors activate a common cAMP/PKA signal transduction pathway mediated through the stimulatory heterotrimeric G protein. Activation of beta(2)AR via the sympathetic nervous system decreases bone formation and increases bone resorption. Conversely, daily injection of PTH (1-34), a regimen known as intermittent (i)PTH treatment, increases bone mass through the stimulation of trabecular and cortical bone formation and decreases fracture incidences in severe cases of osteoporosis. Here, we show that iPTH has no osteoanabolic activity in mice lacking the beta(2)AR. beta(2)AR deficiency suppressed both iPTH-induced increase in bone formation and resorption. We showed that the lack of beta(2)AR blocks expression of iPTH-target genes involved in bone formation and resorption that are regulated by the cAMP/PKA pathway. These data implicate an unexpected functional interaction between PTHR and beta(2)AR, two G protein-coupled receptors from distinct families, which control bone formation and PTH anabolism. PMID- 22538808 TI - Protection from liver fibrosis by a peroxisome proliferator-activated receptor delta agonist. AB - Peroxisome proliferator-activated receptor delta (PPARdelta), a member of the nuclear receptor family, is emerging as a key metabolic regulator with pleiotropic actions on various tissues including fat, skeletal muscle, and liver. Here we show that the PPARdelta agonist KD3010, but not the well-validated GW501516, dramatically ameliorates liver injury induced by carbon tetrachloride (CCl(4)) injections. Deposition of extracellular matrix proteins was lower in the KD3010-treated group than in the vehicle- or GW501516-treated group. Interestingly, profibrogenic connective tissue growth factor was induced significantly by GW501516, but not by KD3010, following CCl(4) treatment. The hepatoprotective and antifibrotic effect of KD3010 was confirmed in a model of cholestasis-induced liver injury and fibrosis using bile duct ligation for 3 wk. Primary hepatocytes treated with KD3010 but not GW501516 were protected from starvation or CCl(4)-induced cell death, in part because of reduced reactive oxygen species production. In conclusion, our data demonstrate that an orally active PPARdelta agonist has hepatoprotective and antifibrotic effects in animal models of liver fibrosis, suggesting a possible mechanistic and therapeutic approach in treating patients with chronic liver diseases. PMID- 22538811 TI - Tracking a complete voltage-sensor cycle with metal-ion bridges. AB - Voltage-gated ion channels open and close in response to changes in membrane potential, thereby enabling electrical signaling in excitable cells. The voltage sensitivity is conferred through four voltage-sensor domains (VSDs) where positively charged residues in the fourth transmembrane segment (S4) sense the potential. While an open state is known from the Kv1.2/2.1 X-ray structure, the conformational changes underlying voltage sensing have not been resolved. We present 20 additional interactions in one open and four different closed conformations based on metal-ion bridges between all four segments of the VSD in the voltage-gated Shaker K channel. A subset of the experimental constraints was used to generate Rosetta models of the conformations that were subjected to molecular simulation and tested against the remaining constraints. This achieves a detailed model of intermediate conformations during VSD gating. The results provide molecular insight into the transition, suggesting that S4 slides at least 12 A along its axis to open the channel with a 3(10) helix region present that moves in sequence in S4 in order to occupy the same position in space opposite F290 from open through the three first closed states. PMID- 22538812 TI - Computational design of a protein crystal. AB - Protein crystals have catalytic and materials applications and are central to efforts in structural biology and therapeutic development. Designing predetermined crystal structures can be subtle given the complexity of proteins and the noncovalent interactions that govern crystallization. De novo protein design provides an approach to engineer highly complex nanoscale molecular structures, and often the positions of atoms can be programmed with sub-A precision. Herein, a computational approach is presented for the design of proteins that self-assemble in three dimensions to yield macroscopic crystals. A three-helix coiled-coil protein is designed de novo to form a polar, layered, three-dimensional crystal having the P6 space group, which has a "honeycomb-like" structure and hexameric channels that span the crystal. The approach involves: (i) creating an ensemble of crystalline structures consistent with the targeted symmetry; (ii) characterizing this ensemble to identify "designable" structures from minima in the sequence-structure energy landscape and designing sequences for these structures; (iii) experimentally characterizing candidate proteins. A 2.1 A resolution X-ray crystal structure of one such designed protein exhibits sub-A agreement [backbone root mean square deviation (rmsd)] with the computational model of the crystal. This approach to crystal design has potential applications to the de novo design of nanostructured materials and to the modification of natural proteins to facilitate X-ray crystallographic analysis. PMID- 22538813 TI - Monitoring single-cell bioenergetics via the coarsening of emulsion droplets. AB - Microorganisms are widely used to generate valuable products, and their efficiency is a major industrial focus. Bioreactors are typically composed of billions of cells, and available measurements only reflect the overall performance of the population. However, cells do not equally contribute, and process optimization would therefore benefit from monitoring this intrapopulation diversity. Such monitoring has so far remained difficult because of the inability to probe concentration changes at the single-cell level. Here, we unlock this limitation by taking advantage of the osmotically driven water flux between a droplet containing a living cell toward surrounding empty droplets, within a concentrated inverse emulsion. With proper formulation, excreted products are far more soluble within the continuous hydrophobic phase compared to initial nutrients (carbohydrates and salts). Fast diffusion of products induces an osmotic mismatch, which further relaxes due to slower diffusion of water through hydrophobic interfaces. By measuring droplet volume variations, we can deduce the metabolic activity down to isolated single cells. As a proof of concept, we present the first direct measurement of the maintenance energy of individual yeast cells. This method does not require any added probes and can in principle apply to any osmotically sensitive bioactivity, opening new routes for screening, and sorting large libraries of microorganisms and biomolecules. PMID- 22538814 TI - Impact of chemical heterogeneity on protein self-assembly in water. AB - Hydrophobicity is thought to underlie self-assembly in biological systems. However, the protein surface comprises hydrophobic and hydrophilic patches, and understanding the impact of such a chemical heterogeneity on protein self assembly in water is of fundamental interest. Here, we report structural and thermodynamic investigations on the dimer formation of full-length amyloid-beta proteins in water associated with Alzheimer's disease. Spontaneous dimerization process--from the individual diffusive regime at large separations, through the approach stage in which two proteins come close to each other, to the structural adjustment stage toward compact dimer formation--was captured in full atomic detail via unguided, explicit-water molecular dynamics simulations. The integral equation theory of liquids was then applied to simulated protein structures to analyze hydration thermodynamic properties and the water-mediated interaction between proteins. We demonstrate that hydrophilic residues play a key role in initiating the dimerization process. A long-range hydration force of enthalpic origin acting on the hydrophilic residues provides the major thermodynamic force that drives two proteins to approach from a large separation to a contact distance. After two proteins make atomic contacts, the nature of the water mediated interaction switches from a long-range enthalpic attraction to a short range entropic one. The latter acts both on the hydrophobic and hydrophilic residues. Along with the direct protein-protein interactions that lead to the formation of intermonomer hydrogen bonds and van der Waals contacts, the water mediated attraction of entropic origin brings about structural adjustment of constituent monomer proteins toward the formation of a compact dimer structure. PMID- 22538815 TI - Computational adaptive optics for broadband optical interferometric tomography of biological tissue. AB - Aberrations in optical microscopy reduce image resolution and contrast, and can limit imaging depth when focusing into biological samples. Static correction of aberrations may be achieved through appropriate lens design, but this approach does not offer the flexibility of simultaneously correcting aberrations for all imaging depths, nor the adaptability to correct for sample-specific aberrations for high-quality tomographic optical imaging. Incorporation of adaptive optics (AO) methods have demonstrated considerable improvement in optical image contrast and resolution in noninterferometric microscopy techniques, as well as in optical coherence tomography. Here we present a method to correct aberrations in a tomogram rather than the beam of a broadband optical interferometry system. Based on Fourier optics principles, we correct aberrations of a virtual pupil using Zernike polynomials. When used in conjunction with the computed imaging method interferometric synthetic aperture microscopy, this computational AO enables object reconstruction (within the single scattering limit) with ideal focal-plane resolution at all depths. Tomographic reconstructions of tissue phantoms containing subresolution titanium-dioxide particles and of ex vivo rat lung tissue demonstrate aberration correction in datasets acquired with a highly astigmatic illumination beam. These results also demonstrate that imaging with an aberrated astigmatic beam provides the advantage of a more uniform depth dependent signal compared to imaging with a standard gaussian beam. With further work, computational AO could enable the replacement of complicated and expensive optical hardware components with algorithms implemented on a standard desktop computer, making high-resolution 3D interferometric tomography accessible to a wider group of users and nonspecialists. PMID- 22538816 TI - KLF15 negatively regulates estrogen-induced epithelial cell proliferation by inhibition of DNA replication licensing. AB - In the epithelial compartment of the uterus, estradiol-17beta (E(2)) induces cell proliferation while progesterone (P(4)) inhibits this response and causes differentiation of the cells. In this study, we identified the mechanism whereby E(2) and P(4) reciprocally regulate the expression of minichromosome maintenance (MCM)-2, a protein that is an essential component of the hexameric MCM-2 to 7 complex required for DNA synthesis initiation. We show in the uterine epithelium that Kruppel-like transcription (KLF) factors, KLF 4 and 15, are inversely expressed; most importantly, they bind to the Mcm2 promoter under the regulation of E(2) and P(4)E(2), respectively. After P(4)E(2) exposure and in contrast to E(2) treated mice, the Mcm2 promoter displays increased histone 3 (H3) methylation and the recruitment of histone deacetylase 1 and 3 with the concomitant deacetylation of H3. This increased methylation and decreased acetylation is associated with an inhibition of RNA polymerase II binding, indicating an inactive Mcm2 promoter following P(4)E(2) treatment. Using transient transfection assays in the Ishikawa endometrial cell line, we demonstrate that Mcm2 promoter activity is hormonally stimulated by E(2) and that KLF15 inhibits this E(2) enhanced transcription. KLF15 expression also blocks Ishikawa cell proliferation through inhibition of MCM2 protein level. Importantly, in vivo expression of KLF15 in an estrogenized uterus mimics P(4)'s action by inhibiting E(2)-induced uterine epithelial MCM-2 expression and DNA synthesis. KLF15 is therefore a downstream physiological mediator of progesterone's cell cycle inhibitory action in the uterine epithelium. PMID- 22538818 TI - Tubulin homolog TubZ in a phage-encoded partition system. AB - Partition systems are responsible for the process whereby large and essential plasmids are accurately positioned to daughter cells during bacterial division. They are typically made of three components: a centromere-like DNA zone, an adaptor protein, and an assembling protein that is either a Walker-box ATPase (type I) or an actin-like ATPase (type II). A recently described type III segregation system has a tubulin/FtsZ-like protein, called TubZ, for plasmid movement. Here, we present the 2.3 A structure and dynamic assembly of a TubZ tubulin homolog from a bacteriophage and unravel the Clostridium botulinum phage c-st type III partition system. Using biochemical and biophysical approaches, we prove that a gene upstream from tubZ encodes the partner TubR and localize the centromeric region (tubS), both of which are essential for anchoring phage DNA to the motile TubZ filaments. Finally, we describe a conserved fourth component, TubY, which modulates the TubZ-R-S complex interaction. PMID- 22538820 TI - Imaging prior information in the brain. AB - In making sense of the visual world, the brain's processing is driven by two factors: the physical information provided by the eyes ("bottom-up" data) and the expectancies driven by past experience ("top-down" influences). We use degraded stimuli to tease apart the effects of bottom-up and top-down processes because they are easier to recognize with prior knowledge of undegraded images. Using machine learning algorithms, we quantify the amount of information that brain regions contain about stimuli as the subject learns the coherent images. Our results show that several distinct regions, including high-level visual areas and the retinotopic cortex, contain more information about degraded stimuli with prior knowledge. Critically, these regions are separate from those that exhibit classical priming, indicating that top-down influences are more than feature based attention. Together, our results show how the neural processing of complex imagery is rapidly influenced by fleeting experiences. PMID- 22538823 TI - Capturing CO2 from air. PMID- 22538822 TI - Structural basis for the allosteric inhibitory mechanism of human kidney-type glutaminase (KGA) and its regulation by Raf-Mek-Erk signaling in cancer cell metabolism. AB - Besides thriving on altered glucose metabolism, cancer cells undergo glutaminolysis to meet their energy demands. As the first enzyme in catalyzing glutaminolysis, human kidney-type glutaminase isoform (KGA) is becoming an attractive target for small molecules such as BPTES [bis-2-(5 phenylacetamido-1, 2, 4-thiadiazol-2-yl) ethyl sulfide], although the regulatory mechanism of KGA remains unknown. On the basis of crystal structures, we reveal that BPTES binds to an allosteric pocket at the dimer interface of KGA, triggering a dramatic conformational change of the key loop (Glu312-Pro329) near the catalytic site and rendering it inactive. The binding mode of BPTES on the hydrophobic pocket explains its specificity to KGA. Interestingly, KGA activity in cells is stimulated by EGF, and KGA associates with all three kinase components of the Raf 1/Mek2/Erk signaling module. However, the enhanced activity is abrogated by kinase-dead, dominant negative mutants of Raf-1 (Raf-1-K375M) and Mek2 (Mek2 K101A), protein phosphatase PP2A, and Mek-inhibitor U0126, indicative of phosphorylation-dependent regulation. Furthermore, treating cells that coexpressed Mek2-K101A and KGA with suboptimal level of BPTES leads to synergistic inhibition on cell proliferation. Consequently, mutating the crucial hydrophobic residues at this key loop abrogates KGA activity and cell proliferation, despite the binding of constitutive active Mek2-S222/226D. These studies therefore offer insights into (i) allosteric inhibition of KGA by BPTES, revealing the dynamic nature of KGA's active and inhibitory sites, and (ii) cross talk and regulation of KGA activities by EGF-mediated Raf-Mek-Erk signaling. These findings will help in the design of better inhibitors and strategies for the treatment of cancers addicted with glutamine metabolism. PMID- 22538824 TI - Golden Rule or valence matching? Methodological problems in Hamlin et al. PMID- 22538825 TI - Sorption of lead, copper, and cadmium by calcium alginate. Metal binding stoichiometry and the pH effect. AB - Binding of heavy metal ions by calcium alginate has been described in the literature with many different models. In the present study, two most basic models were used to systematically compare their simultaneous description of metal uptake dependence on pH and metal ion concentration in the bulk solution. The experimental datasets corresponding to the binary sorption systems containing protons and heavy metal ion (cadmium, lead, or copper) were taken from the literature. The applicability and limitations of both models are discussed. Neither of the models gave a completely satisfactory description of all data. The two-site occupancy model yielded better results compared to the one-site occupancy model when considering the coherence of the parameters (e.g., affinity constants) but the quality of the obtained fits is similar in both cases. PMID- 22538826 TI - Phytoremediation of the polluted Waigang River and general survey on variation of phytoplankton population. AB - The Waigang River, a major tributary of the Qinhuai River system, has suffered from long-standing pollution because of lack of management. Restoration was commenced in April 2006 to reduce pollutants and improve water quality. Four ecological areas and ten surface carriers were constructed for the culture of plants (mainly water hyacinth (Eichhornia crassipes) and ryegrass (Lolium perenne L.)) for phytoremediation. Chemical oxygen demand (COD), total suspended solids (TSS), total phosphorus, total nitrogen (TN), ammonia-nitrogen (NH(3)-N), water transparency, and variations in phytoplankton population were investigated to evaluate the effects of restoration. Over 36 months, TSS, COD, TN, and NH(3)-N levels decreased by 91.1, 55.3, 91.5, and 86.5 %, respectively. Transparency increased from 25 cm in 2006 to 165 cm in 2009. Improvements in water quality significantly enhanced the diversity of phytoplankton, which were harmed by pollution stress. Our results show that the water hyacinth and ryegrass cultured in the ecological areas and the surface carriers can be used to restore other heavily polluted rivers with conditions similar to those of the Waigang River, especially in the initial stages of restoration. PMID- 22538827 TI - Thrombotic complication during intracoronary imaging. AB - Intracoronary imaging with intracoronary ultrasound and coherence tomography is often used in the follow-up of coronary stent implantation. The present case shows an infrequent complication of these procedures, suggesting our continued attention to the selective use of these invasive procedures. PMID- 22538828 TI - Einthoven dissertation prizes 2011. PMID- 22538831 TI - Interaction of alfaxalone with the neuronal and the skeletal muscle sodium channel. AB - The neurosteroid alfaxalone exerts potent anesthetic activity in humans and animals. In former studies on myelinated axons, alfaxalone was assumed to produce a local anesthetic-like effect on the peripheral nervous system. Therefore,the present in vitro study aimed to characterize possible modulatory actions of alfaxalone on voltage-gated sodium channels. -Subunits of voltage-gated neuronal (Nav1.2)and skeletal muscle (Nav1.4) sodium channels were stably expressed in human embryonic kidney cells, and in vitro effects of alfaxalone were compared with lidocaine by means of the patch clamp technique. Alfaxalone preferentially blocked slow inactivated channels and therefore could provide membrane stabilizing effects in ischemic/hypoxic tissues where slow inactivation is regarded to play a crucial role. PMID- 22538829 TI - The effects of mycotoxins and selenium deficiency on tissue-engineered cartilage. AB - OBJECTIVE: To investigate the effects of 3 mycotoxins, deoxynivalenol (DON), nivalenol (NIV) and T-2 toxin, in the presence and absence of selenium (Se) on the metabolism of tissue-engineered cartilage to mimic conditions found in Kashin Beck disease (KBD) environments. MATERIALS AND METHODS: Chondrocytes were seeded onto bone matrix gelatin (BMG) to construct engineered cartilage. The 3 toxins were added to the culture media for 3 weeks followed by immunhistochemical analyses of collagens type II and X, aggrecan, matrix metalloproteinases 1 and 3 (MMP-1 and MMP-3), MMP inhibitors 1 and 3 (TIMP-1 and TIMP-3) and alpha(2) macroglobulin (alpha2M). RESULTS: Type II collagen was decreased while type X collagen was increased in response to DON, NIV and T-2 toxin. Aggrecan was reduced by all 3 mycotoxins. Compared with the control, the 3 toxins decreased the expression of alpha2M, TIMP-1 and TIMP-3, and increased the expression of MMP 1 and MMP-3. Se could partially inhibit the effects of DON, NIV and T-2 toxins. CONCLUSION: Under the low Se condition, the 3 mycotoxins produced procatabolic changes in cartilage resulting in the loss of aggrecan and type II collagen and promoted a hypertrophic phenotype of chondrocytes characterized by increasing type-X-collagen expression, enhancing the expression of MMPs, while weakening the TIMPs. Se could partially block the effects mentioned above. These results support the hypothesis that the combination of mycotoxin stress and Se deficiency would be the causative factors for KBD. PMID- 22538830 TI - Doxorubicin loaded silica nanorattles actively seek tumors with improved anti tumor effects. AB - Silica nanorattles (SNs) have proven to be promising vehicles for drug delivery. In order to further enhance efficacy and minimize adverse effects, active targeted delivery to tumors is necessary. In this work, SNs modified with a tumor specific targeting ligand, folic acid (FA), was used as carrier of doxorubicin (DOX) (DOX-FA-SNs). Drug loading, cytotoxicity and cellular uptake of DOX-FA-SNs in vitro in human cervical carcinoma cells (HeLa cells) were evaluated. DOX-FA SNs showed a higher cytotoxicity in human cervical carcinoma cells (HeLa cells) than DOX loaded carboxyl (-COOH) and poly(ethylene glycol) (PEG) modified SNs (DOX-COOH-SNs and DOX-PEG-SNs, respectively). However, DOX-FA-SNs showed lower cytotoxicity in folate receptor negative normal mouse fibroblast cells (L929 cells) compared with free DOX. In vivo tumor-targeted fluorescence imaging indicated specific tumor targeting and uptake of FA-SNs in nude mice bearing subcutaneous HeLa cell-derived xenograft tumors. In vivo anti-tumor experiments demonstrated that DOX-FA-SNs (10 mg kg(-1) of DOX) significantly regressed the tumor growth and reduced toxicity compared with free DOX. These results have great significance in developing and optimizing SNs as effective intracellular delivery and specific tumor targeting vehicles. PMID- 22538833 TI - Fluorescence as an analytical tool for assessing the conversion of oil into biodiesel. AB - In this work fluorescence-based method to assess the biodiesel production from different refined vegetable oils is presented. Four different refined oils (soybean, sunflower, canola, and corn) and their respective biodiesel were used and the fluorescence of the compounds contained in their compositions was taken as a probe. The results show that the fluorescence intensity of the biodiesel is lower than one verified in the vegetable oil. The data achieved point out that the ratio between the fluorescence intensity of biodiesel and oil is about 0.6 regardless of the vegetable oil feedstock investigated. Reduced content of fluorophores as well as low viscosity of the biodiesel regarding the oil have been raised as hypotheses to explain the low fluorescence intensity of the biodiesel. The results obtained may provide the basis for the development of an alternative method able to give fast and accurate information about the conversion of oil into biodiesel without the requirement of dilution or pre treatment of the biodiesel. PMID- 22538835 TI - Enhanced absorption in silicon nanocone arrays for photovoltaics. AB - Silicon nanowire arrays have been shown to demonstrate light trapping properties and promising potential for next-generation photovoltaics. In this paper, we performed systematic and detailed simulation studies on the optical properties of silicon nanocone arrays as compared to nanowires arrays. Nanocone arrays were found to have significantly improved solar absorption and efficiencies over nanowire arrays. Detailed simulations revealed that nanocones have superior absorption due to reduced reflection from their smaller tip and reduced transmission from their larger base. The enhanced efficiencies of silicon nanocone arrays were found to be insensitive to tip diameter, which should facilitate their fabrication. Breaking the vertical mirror symmetry of nanowires results in a broader absorption spectrum such that overall efficiencies are enhanced. We also evaluated the electric field intensity, carrier generation and angle-dependent optical properties of nanocones and nanowires to offer further physical insight into their light trapping properties. PMID- 22538832 TI - Left ventricular remodeling and torsion dynamics in hypertensive patients. AB - Left ventricular (LV) torsion is a fundamental component of wall motion and plays an important role to optimize ventricular ejection fraction. The aim of our study was to calculate by speckle tracking echocardiography LV twist angle in patients with hypertension and LV remodeling, analyzing torsional indices in all patterns of hypertrophy, in comparison to torsional dynamics of age-matched healthy subjects. Hypertensive patients (n = 202) were divided in three groups, patients with concentric remodeling (n = 70), concentric hypertrophy (n = 68) and eccentric hypertrophy (n = 64), in relation to the echocardiographic measurements of relative wall thickness and LV mass, analyzing their torsional patterns by speckle tracking in comparison to age-matched control group. Compared to healthy controls, LV twist angle was increased in patients with hypertension and concentric remodeling (15.2 degrees +/- 1.9 degrees vs. 11.0 degrees +/- 1.6 degrees ; p < 0.001), reaching the highest value in patients with concentric hypertrophy (19.4 degrees +/- 2.6 degrees ); instead LV twist angle presented depressed in the group of patients that presented eccentric hypertrophy (5.0 degrees +/- 1.1 degrees ). Regarding LV untwisting rate, it was higher in the concentric remodeling and concentric hypertrophy groups (-123.1 degrees /s +/- 12.1 degrees /s and -145.1 degrees /s +/- 15.5 degrees /s, respectively) in comparison with the controls (-90.0 degrees /s +/- 10.1 degrees /s; p < 0.0001 for both). Instead, lower values of LV untwisting rate were observed in the eccentric remodeling group (-81.6 degrees /s +/- 8.1 degrees /s), not significantly different to controls' values (p = 0.09). Enhanced LV twist angle appears to be a compensatory mechanism in hypertensive patients during the earlier stages of concentric remodeling and concentric hypertrophy; this hyper torsion is inevitably loss in the more advanced stage of eccentric hypertrophy. PMID- 22538834 TI - Fluorescence emission spectra of calcofluor stained yeast cell suspensions: heuristic assessment of basis spectra for their linear unmixing. AB - Fluorescence emission spectra of yeast cell suspensions stained with calcofluor have recently been identified as promising markers of variations in the quality of yeast cell wall. It is shown in this paper how the raw fluorescence spectra of calcofluor can be transformed to reliable spectral signatures of cell wall quality, which are independent of actual dye-to-cell concentrations of examined cell suspensions. Moreover, the presented approach makes it possible to assess basis fluorescence spectra that allows for the spectral unmixing of raw fluorescence spectra in terms of respective fluorescence contributions of calcofluor solvated in the suspension medium and bound to yeast cell walls. PMID- 22538836 TI - Efficient catalysis by MgCl2 in hydrogen generation via hydrolysis of Mg-based hydride prepared by hydriding combustion synthesis. AB - Magnesium chloride efficiently catalyzed the hydrolysis of Mg-based hydride prepared by hydriding combustion synthesis. Hydrogen yield of 1635 mL g(-1) was obtained (MgH(2)), i.e. with 96% conversion in 30 min at 303 K. PMID- 22538837 TI - Cancer of unknown primary: does treatment modality make a difference? AB - OBJECTIVES/HYPOTHESIS: We systematically reviewed the published experience on the treatment outcomes of patients with head and neck cancer of unknown primary (CUP) to determine if treatment modality affects survival outcomes. STUDY DESIGN: Meta analysis. METHODS: A comprehensive literature search was performed for articles reporting survival outcomes for CUP in the head and neck published within the last 12 years. RESULTS: Eighteen studies with 1,726 patients met the inclusion criteria. All studies reported at least 5-year survival outcomes. Thirteen of the 18 studies also reported 5-year survival based on N stage, and six reported 5 year survival based on presence of extracapsular extension (EC). Overall 5-year survival in the entire group was 48.6%. Five-year survival based on N stage was as follows: N1 = 60.8%, all N2 = 51.1%, N2a = 63.6%, N2b = 42.5%, N2c = 37.5%, and N3 = 26.3%, with P < .001 on multivariate analysis. Patients who underwent surgical treatment with either postoperative radiation or chemoradiation had a 5 year survival of 52.4% compared to 46.6% for those treated with chemoradiation alone; however, this difference was not statistically significant. Patients with EC had a 5-year disease-specific survival of 56.9% compared to 81.5% for those without EC (P = .01). CONCLUSIONS: In patients with CUP, survival outcomes are most significantly influenced by clinical stage at time of diagnosis. No significant 5-year survival difference was seen between patients treated with radiation or chemoradiation alone when compared to patients who also received surgical treatment. PMID- 22538838 TI - Health-related effects of early part-time sick leave due to musculoskeletal disorders: a randomized controlled trial. AB - OBJECTIVE: Previously we reported that early part-time sick leave enhances return to work (RTW) among employees with musculoskeletal disorders (MSD). This paper assesses the health-related effects of this intervention. METHODS: Patients aged 18-60 years who were unable to perform their regular work due to MSD were randomized to part- or full-time sick leave groups. In the former, workload was reduced by halving working time. Using validated questionnaires, we assessed pain intensity and interference with work and sleep, region-specific disability due to MSD, self-rated general health, health-related quality of life (measured via EuroQol), productivity loss, depression, and sleep disturbance at baseline, 1, 3, 8, 12, and 52 weeks. We analyzed the repeated measures data (171-356 observations) with the generalized estimating equation approach. RESULTS: The intervention (part-time sick leave) and control (full-time sick leave) groups did not differ with regard to pain intensity, pain interference with work and sleep, region-specific disability, productivity loss, depression, or sleep disturbance. The intervention group reported better self-rated general health (adjusted P=0.07) and health-related quality of life (adjusted P=0.02) than the control group. In subgroup analyses, the intervention was more effective among the patients whose current problem began occurring <6 weeks before baseline and those with <=30% productivity loss at baseline. CONCLUSIONS: Our findings showed that part-time sick leave did not exacerbate pain-related symptoms and functional disability, but improved self-rated general health and health-related quality of life in the early stage of work disability due to MSD. PMID- 22538839 TI - [The benefits of using patient-reported outcomes in cancer treatment: an overview]. AB - The patient's perspective evaluated by patient-reported outcomes (PROs) gains more and more importance, since treatment efficacy is no longer solely linked to clinical outcomes like cure and overall survival. Ailments like pain, fatigue and social isolation can only be assessed by patients' direct expression without any interpretation made by medical staff. PROs facilitate the disclosure of quality of life issues and patients feel a stronger support due to improved communication. PROs offer many further advantages like saving of time, cost and staff, targeted intervention and sensitizing of clinicians. Also, internationally validated questionnaires are available and the development of electronic PROs eases data-collection, calculation and storage. PROs collected within clinical routine are versatile concerning their applicability: They can be used for scientific analyses, quality assurance, and health technology assessment. PMID- 22538840 TI - Intramedullary gangliocytoma with calcification and multiple intramedullary cysts. PMID- 22538842 TI - Low-level laser therapy in different stages of rheumatoid arthritis: a histological study. AB - Rheumatoid arthritis (RA) is an autoimmune inflammatory disease of unknown etiology. Treatment of RA is very complex, and in the past years, some studies have investigated the use of low-level laser therapy (LLLT) in treatment of RA. However, it remains unknown if LLLT can modulate early and late stages of RA. With this perspective in mind, we evaluated histological aspects of LLLT effects in different RA progression stages in the knee. It was performed a collagen induced RA model, and 20 male Wistar rats were divided into 4 experimental groups: a non-injured and non-treated control group, a RA non-treated group, a group treated with LLLT (780 nm, 22 mW, 0.10 W/cm(2), spot area of 0.214 cm(2), 7.7 J/cm(2), 75 s, 1.65 J per point, continuous mode) from 12th hour after collagen-induced RA, and a group treated with LLLT from 7th day after RA induction with same LLLT parameters. LLLT treatments were performed once per day. All animals were sacrificed at the 14th day from RA induction and articular tissue was collected in order to perform histological analyses related to inflammatory process. We observed that LLLT both at early and late RA progression stages significantly improved mononuclear inflammatory cells, exudate protein, medullary hemorrhage, hyperemia, necrosis, distribution of fibrocartilage, and chondroblasts and osteoblasts compared to RA group (p < 0.05). We can conclude that LLLT is able to modulate inflammatory response both in early as well as in late progression stages of RA. PMID- 22538841 TI - Low-level laser therapy on the treatment of oral and cutaneous pemphigus vulgaris: case report. AB - Pemphigus vulgaris is a chronic autoimmune mucocutaneous disease that initially is manifested by painful intraoral erosions and ulcers which spread to other mucosa and the skin, generally more than 5 months after oral lesion manifestation. The treatment consists of prednisone alone or in combination with an immunosuppressive agent, and the clinical response is perceived within 2 to 4 weeks. Low-level laser therapy has been effective in accelerating the healing of injured tissue, thus inducing cell proliferation and increasing ATP, nucleic acid, and collagen synthesis. We reported two cases of pemphigus vulgaris that received systemic treatment associated with low-level laser therapy for oral and cutaneous lesions. We observed prompt analgesic effect in oral lesions and accelerated healing of oral and cutaneous wounds. Therefore, the present report suggests LLLT as a noninvasive technique that should be considered as an adjuvant therapy in oral and skin disorders in patients with PV. PMID- 22538843 TI - Treatment of actinic keratoses and photodamage with non-contact fractional 1540 nm laser quasi-ablation: an ex vivo and clinical evaluation. AB - The main use of non-ablative fractional photothermolysis today is for the improvement of wrinkles and scars. The purpose of this work was to evaluate the effect of a "classic" non-ablative fractional 1540 nm on facial photodamaged skin and actinic keratoses. Seventeen patients with facial actinic keratoses (AKs) and photodamage underwent two or three laser treatments with fractional 1540-nm erbium glass laser at fluences of 75 mJ, 15 ms pulse duration, and 10-mm spot size in non-contact mode. Two blinded assessors and participants evaluated clinical improvement of treatment areas after 3 months, using a quartile grading scale (no improvement = 0, 1-25% improvement = 1, 26-50% = 2, 51-75% = 3, and 76 100% = 4). Three months after the last treatment, the mean level of improvement was 3.4 +/- 0.72 for AK and 3.3 +/- 0.54 for skin appearance. Adverse events observed after each treatment were moderate erythema, mild edema, erosions (two cases), and mild desquamation. No scarring or post-inflammatory pigmentary changes were observed. The clinical results were supported by histological changes observed in Yucatan pig studies in vivo and ex vivo. The 1540-nm fractional erbium glass laser in the non-contact mode is a safe and effective treatment for facial photodamage and AKs. PMID- 22538845 TI - Quality of medical follow-up of young women with Turner syndrome treated in one clinical center. AB - For Turner syndrome (TS) patients, smooth transition from pediatric to adult health care is a critical point. The study objective was to evaluate the medical follow-up of young women with TS in one clinical center 3 years after the latest guidelines had been introduced by the TS Study Group. A questionnaire study was performed in 59 TS adults selected from a database of 117 patients. Twenty-two of them, aged 23.0 +/- 2.8 years, consented to participate. Nineteen responders (86.4%) were followed up by general practitioners who were not aware of the TS diagnosis in 14 (63.6%) cases. Eight (36.4%) were seen regularly by the relevant specialists. Adequate medical assessment varied from 5% (celiac serology) to 74% (gynecology assessment) and 82% (ear-nose-throat) of participants. None of the patients had undergone all of the recommended investigations according to recommendation. Height deficiency, body mass index, age at TS diagnosis and level of education did not correlate with the number of assessments performed (p = 0.687, p = 0.810, p = 0.641, and p = 0.568, respectively). Three years after the introduction of the current guidelines, medical follow-up in the transition phase is still inadequate. Improvement in transitional health care is warranted through better patient education, referring to physicians caring for adults with TS and better cooperation with general practitioners with wider popularization of the TS recommendations among them. PMID- 22538846 TI - Etiological classifications of transient ischemic attacks: subtype classification by TOAST, CCS and ASCO--a pilot study. AB - BACKGROUND: In patients with transient ischemic attacks (TIA), etiological classification systems are not well studied. The Trial of ORG 10172 in Acute Stroke Treatment (TOAST), the Causative Classification System (CCS), and the Atherosclerosis Small Vessel Disease Cardiac Source Other Cause (ASCO) classification may be useful to determine the underlying etiology. We aimed at testing the feasibility of each of the 3 systems. Furthermore, we studied and compared their prognostic usefulness. METHODS: In a single-center TIA registry prospectively ascertained over 2 years, we applied 3 etiological classification systems. We compared the distribution of underlying etiologies, the rates of patients with determined versus undetermined etiology, and studied whether etiological subtyping distinguished TIA patients with versus without subsequent stroke or TIA within 3 months. RESULTS: The 3 systems were applicable in all 248 patients. A determined etiology with the highest level of causality was assigned similarly often with TOAST (35.9%), CCS (34.3%), and ASCO (38.7%). However, the frequency of undetermined causes differed significantly between the classification systems and was lowest for ASCO (TOAST: 46.4%; CCS: 37.5%; ASCO: 18.5%; p < 0.001). In TOAST, CCS, and ASCO, cardioembolism (19.4/14.5/18.5%) was the most common etiology, followed by atherosclerosis (11.7/12.9/14.5%). At 3 months, 33 patients (13.3%, 95% confidence interval 9.3-18.2%) had recurrent cerebral ischemic events. These were strokes in 13 patients (5.2%; 95% confidence interval 2.8-8.8%) and TIAs in 20 patients (8.1%, 95% confidence interval 5.0 12.2%). Patients with a determined etiology (high level of causality) had higher rates of subsequent strokes than those without a determined etiology [TOAST: 6.7% (95% confidence interval 2.5-14.1%) vs. 4.4% (95% confidence interval 1.8-8.9%); CSS: 9.3% (95% confidence interval 4.1-17.5%) vs. 3.1% (95% confidence interval 1.0-7.1%); ASCO: 9.4% (95% confidence interval 4.4-17.1%) vs. 2.6% (95% confidence interval 0.7-6.6%)]. However, this difference was only significant in the ASCO classification (p = 0.036). Using ASCO, there was neither an increase in risk of subsequent stroke among patients with incomplete diagnostic workup (at least one subtype scored 9) compared with patients with adequate workup (no subtype scored 9), nor among patients with multiple causes compared with patients with a single cause. CONCLUSION: In TIA patients, all etiological classification systems provided a similar distribution of underlying etiologies. The increase in stroke risk in TIA patients with determined versus undetermined etiology was most evident using the ASCO classification. PMID- 22538844 TI - [Critical limb ischemia in systemic sclerosis]. AB - Vascular complications are common in systemic sclerosis (SSc). Critical limb ischemia leading to gangrene or amputation occurs in more than 10% of these patients and hence is a common emergency. This report highlights the different pathogenetic mechanisms leading to critical ischemic events and provides guidance for the diagnosis and therapy. Apart from SSc-associated vasculopathy and peripheral arterial disease, thromboembolic events and rarely also vasculitis may cause critical limb ischemia. An interdisciplinary approach to the diagnosis and therapy of these lesions is mandatory. Therapy goals are the prevention of further ischemia and, if possible, revascularization as well as optimal pain management. PMID- 22538848 TI - Selective synthesis of 3-hydroxy acids from Meldrum's acids using SmI2-H2O. AB - The single-step synthesis of 3-hydroxy carboxylic acids from readily available Meldrum's acids involves a selective monoreduction using a SmI(2)-H(2)O complex to give products in high crude purity, and it represents a considerable advancement over other methods for the synthesis of 3-hydroxy acids. The protocol includes a detailed guide to the preparation of a single electron-reducing SmI(2) H(2)O complex and describes two representative examples of the methodology: monoreduction of a fully saturated Meldrum's acid (5-(4-bromobenzyl)-2,2-dimethyl 1,3-dioxane-4,6-dione) and tandem conjugate reduction-selective monoreduction of alpha,beta-unsaturated Meldrum's acid (5-(4-methoxybenzylidene)-2,2-dimethyl-1,3 dioxane-4,6-dione). The protocol for selective monoreduction of Meldrum's acids takes ~6 h to complete. PMID- 22538847 TI - Microneedle-based analysis of the micromechanics of the metaphase spindle assembled in Xenopus laevis egg extracts. AB - To explain how micrometer-sized cellular structures generate and respond to forces, we need to characterize their micromechanical properties. Here we provide a protocol to build and use a dual force-calibrated microneedle-based setup to quantitatively analyze the micromechanics of a metaphase spindle assembled in Xenopus laevis egg extracts. This cell-free extract system allows for controlled biochemical perturbations of spindle components. We describe how the microneedles are prepared and how they can be used to apply and measure forces. A multimode imaging system allows the tracking of microtubules, chromosomes and needle tips. This setup can be used to analyze the viscoelastic properties of the spindle on timescales ranging from minutes to sub-seconds. A typical experiment, along with data analysis, is also detailed. We anticipate that our protocol can be readily extended to analyze the micromechanics of other cellular structures assembled in cell-free extracts. The entire procedure can take 3-4 d. PMID- 22538849 TI - Cell type-specific chromatin immunoprecipitation from multicellular complex samples using BiTS-ChIP. AB - This protocol describes the batch isolation of tissue-specific chromatin for immunoprecipitation (BiTS-ChIP) for analysis of histone modifications, transcription factor binding, or polymerase occupancy within the context of a multicellular organism or tissue. Embryos expressing a cell type-specific nuclear marker are formaldehyde cross-linked and then subjected to dissociation. Fixed nuclei are isolated and sorted using FACS on the basis of the cell type-specific nuclear marker. Tissue-specific chromatin is extracted, sheared by sonication and used for ChIP-seq or other analyses. The key advantages of this method are the covalent cross-linking before embryo dissociation, which preserves the transcriptional context, and the use of FACS of nuclei, yielding very high purity. The protocol has been optimized for Drosophila, but with minor modifications should be applicable to any model system. The full protocol, including sorting, immunoprecipitation and generation of sequencing libraries, can be completed within 5 d. PMID- 22538850 TI - Video tracking and analysis of sleep in Drosophila melanogaster. AB - In the past decade, Drosophila has emerged as an ideal model organism for studying the genetic components of sleep as well as its regulation and functions. In fruit flies, sleep can be conveniently estimated by measuring the locomotor activity of the flies using techniques and instruments adapted from the field of circadian behavior. However, proper analysis of sleep requires degrees of spatial and temporal resolution higher than is needed by circadian scientists, as well as different algorithms and software for data analysis. Here I describe how to perform sleep experiments in flies using techniques and software (pySolo and pySolo-Video) previously developed in my laboratory. I focus on computer-assisted video tracking to monitor fly activity. I explain how to plan a sleep analysis experiment that covers the basic aspects of sleep, how to prepare the necessary equipment and how to analyze the data. By using this protocol, a typical sleep analysis experiment can be completed in 5-7 d. PMID- 22538851 TI - Bcl-2, Bcl-x(L), and Bcl-w are not equivalent targets of ABT-737 and navitoclax (ABT-263) in lymphoid and leukemic cells. AB - The BH3-mimetic ABT-737 and an orally bioavailable compound of the same class, navitoclax (ABT-263), have shown promising antitumor efficacy in preclinical and early clinical studies. Although both drugs avidly bind Bcl-2, Bcl-x(L), and Bcl w in vitro, we find that Bcl-2 is the critical target in vivo, suggesting that patients with tumors overexpressing Bcl-2 will probably benefit. In human non Hodgkin lymphomas, high expression of Bcl-2 but not Bcl-x(L) predicted sensitivity to ABT-263. Moreover, we show that increasing Bcl-2 sensitized normal and transformed lymphoid cells to ABT-737 by elevating proapoptotic Bim. In striking contrast, increasing Bcl-x(L) or Bcl-w conferred robust resistance to ABT-737, despite also increasing Bim. Cell-based protein redistribution assays unexpectedly revealed that ABT-737 disrupts Bcl-2/Bim complexes more readily than Bcl-x(L)/Bim or Bcl-w/Bim complexes. These results have profound implications for how BH3-mimetics induce apoptosis and how the use of these compounds can be optimized for treating lymphoid malignancies. PMID- 22538853 TI - Prognostic irrelevance of ring sideroblast percentage in World Health Organization-defined myelodysplastic syndromes without excess blasts. AB - The presence of >= 15% bone marrow (BM) ring sideroblasts (RS) and < 5% blasts is required for a diagnosis of refractory anemia with ring sideroblasts. We examined the phenotypic and prognostic relevance of this "15%" RS threshold in 200 patients with myelodysplastic syndromes (MDS) without excess blasts and with >= 1% RS. The impact of RS% was assessed both as a continuous and categorical variable: < 5% (n = 56), 5%-14% (n = 32), 15%-50% (n = 79), and > 50% (n = 33). RS% correlated (P < .05) directly with age, platelet count, transfusion dependency, BM cellularity, and mutant SF3B1 and inversely with hemoglobin level, multilineage dysplasia, and high-risk karyotype; but did not correlate with IDH mutations. At a median follow-up of 33 months, 156 (73%) deaths and 24 (12%) leukemic transformations were documented. Neither univariate nor multivariable analysis showed significant effect for RS% on overall or leukemia-free survival, suggesting the limited prognostic value of quantifying BM RS in MDS. PMID- 22538852 TI - Blockade of XBP1 splicing by inhibition of IRE1alpha is a promising therapeutic option in multiple myeloma. AB - Multiple myeloma (MM) cells are characterized by high protein synthesis resulting in chronic endoplasmic reticulum (ER) stress, which is adaptively managed by the unfolded protein response. Inositol-requiring enzyme 1alpha (IRE1alpha) is activated to splice X-box binding protein 1 (XBP1) mRNA, thereby increasing XBP1s protein, which in turn regulates genes responsible for protein folding and degradation during the unfolded protein response. In this study, we examined whether IRE1alpha-XBP1 pathway is a potential therapeutic target in MM using a small-molecule IRE1alpha endoribonuclease domain inhibitor MKC-3946. MKC-3946 triggered modest growth inhibition in MM cell lines, without toxicity in normal mononuclear cells. Importantly, it significantly enhanced cytotoxicity induced by bortezomib or 17-AAG, even in the presence of bone marrow stromal cells or exogenous IL-6. Both bortezomib and 17-AAG induced ER stress, evidenced by induction of XBP1s, which was blocked by MKC-3946. Apoptosis induced by these agents was enhanced by MKC-3946, associated with increased CHOP. Finally, MKC 3946 inhibited XBP1 splicing in a model of ER stress in vivo, associated with significant growth inhibition of MM cells. Taken together, our results demonstrate that blockade of XBP1 splicing by inhibition of IRE1alpha endoribonuclease domain is a potential therapeutic option in MM. PMID- 22538854 TI - Bleeding risks are higher in children versus adults given prophylactic platelet transfusions for treatment-induced hypoproliferative thrombocytopenia. AB - Age-group analyses were conducted of patients in the prophylactic platelet dose trial (PLADO), which evaluated the relation between platelet dose per transfusion and bleeding. Hospitalized patients with treatment-induced hypoproliferative thrombocytopenia were randomly assigned to 1 of 3 platelet doses: 1.1 * 10(11), 2.2 * 10(11), or 4.4 * 10(11) platelets/m(2) per transfusion, given for morning counts of <= 10 000 platelets/MUL. Daily hemostatic assessments were performed. The primary end point (percentage of patients who developed grade 2 or higher World Health Organization bleeding) was evaluated in 198 children (0-18 years) and 1044 adults. Although platelet dose did not predict bleeding for any age group, children overall had a significantly higher risk of grade 2 or higher bleeding than adults (86%, 88%, 77% vs 67% of patients aged 0-5 years, 6-12 years, 13-18 years, vs adults, respectively) and more days with grade 2 or higher bleeding (median, 3 days in each pediatric group vs 1 day in adults; P < .001). The effect of age on bleeding differed by disease treatment category and was most pronounced among autologous transplant recipients. Pediatric subjects were at higher risk of bleeding over a wide range of platelet counts, indicating that their excess bleeding risk may be because of factors other than platelet counts. PMID- 22538855 TI - Identification and expansion of highly suppressive CD8(+)FoxP3(+) regulatory T cells after experimental allogeneic bone marrow transplantation. AB - FoxP3(+) confers suppressive properties and is confined to regulatory T cells (T(reg)) that potently inhibit autoreactive immune responses. In the transplant setting, natural CD4(+) T(reg) are critical in controlling alloreactivity and the establishment of tolerance. We now identify an important CD8(+) population of FoxP3(+) T(reg) that convert from CD8(+) conventional donor T cells after allogeneic but not syngeneic bone marrow transplantation. These CD8(+) T(reg) undergo conversion in the mesenteric lymph nodes under the influence of recipient dendritic cells and TGF-beta. Importantly, this population is as important for protection from GVHD as the well-studied natural CD4(+)FoxP3(+) population and is more potent in exerting class I-restricted and antigen-specific suppression in vitro and in vivo. Critically, CD8(+)FoxP3(+) T(reg) are exquisitely sensitive to inhibition by cyclosporine but can be massively and specifically expanded in vivo to prevent GVHD by coadministering rapamycin and IL-2 antibody complexes. CD8(+)FoxP3(+) T(reg) thus represent a new regulatory population with considerable potential to preferentially subvert MHC class I-restricted T-cell responses after bone marrow transplantation. PMID- 22538856 TI - DNA-binding factor CTCF and long-range gene interactions in V(D)J recombination and oncogene activation. AB - Regulation of V(D)J recombination events at immunoglobulin (Ig) and T-cell receptor loci in lymphoid cells is complex and achieved via changes in substrate accessibility. Various studies over the last year have identified the DNA-binding zinc-finger protein CCCTC-binding factor (CTCF) as a crucial regulator of long range chromatin interactions. CTCF often controls specific interactions by preventing inappropriate communication between neighboring regulatory elements or independent chromatin domains. Although recent gene targeting experiments demonstrated that the presence of the CTCF protein is not required for the process of V(D)J recombination per se, CTCF turned out to be essential to control order, lineage specificity and to balance the Ig V gene repertoire. Moreover, CTCF was shown to restrict activity of kappa enhancer elements to the Ig kappa locus. In this review, we discuss CTCF function in the regulation of V(D)J recombination on the basis of established knowledge on CTCF-mediated chromatin loop domains in various other loci, including the imprinted H19-Igf2 locus as well as the complex beta-globin, MHC class II and IFN-gamma loci. Moreover, we discuss that loss of CTCF-mediated restriction of enhancer activity may well contribute to oncogenic activation, when in chromosomal translocations Ig enhancer elements and oncogenes appear in a novel genomic context. PMID- 22538857 TI - Positive conversion of negative signaling of CTLA4 potentiates antitumor efficacy of adoptive T-cell therapy in murine tumor models. AB - Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) has been known to be a strong tolerance-inducing inhibitory receptor on T-cell surface. Systemic blocking of CTLA4 function with blocking antibodies has been regarded as an attractive strategy to enhance antitumor immunity. However, this strategy accompanies systemic autoimmune side effects that are sometimes problematic. Therefore, we developed a novel CTLA4 mutant that could be expressed in tumor antigen-specific T cells to enhance antitumor effect without systemic autoimmunity. This mutant, named CTLA4-CD28 chimera, consists of extracellular and transmembrane domains of CTLA4, linked with cytoplasmic CD28 domain. Overexpression of CTLA4-CD28 chimera in T cells delivered stimulatory signals rather than inhibitory signals of CTLA4 and significantly enhanced T-cell reactivity. Although this effect was observed in both CD4 and CD8 T cells, the effect on CD4 T cells was predominant. CTLA4 CD28 chimera gene modification of CD4 T cells significantly enhanced antitumor effect of unmodified CD8 T cells. Nonetheless, the gene modification of CD8 T cells along with CD4 T cells further maximized antitumor effect of T cells in 2 different murine tumor models. Thus, CTLA4-CD28 chimera gene modification of both tumor antigen-specific CD4 and CD8 T cells would be an ideal way of modulating CTLA4 function to enhance tumor-specific T-cell reactivity. PMID- 22538859 TI - Cardiac resuscitation in the operating room: reflections on how we can do better. PMID- 22538858 TI - MicroRNA-22 increases senescence and activates cardiac fibroblasts in the aging heart. AB - MicroRNAs (miRs) are small non- coding RNA molecules controlling a plethora of biological processes such as development, cellular survival and senescence. We here determined miRs differentially regulated during cardiac postnatal development and aging. Cardiac function, morphology and miR expression profiles were determined in neonatal, 4 weeks, 6 months and 19 months old normotensive male healthy C57/Bl6N mice. MiR-22 was most prominently upregulated during cardiac aging. Cardiac expression of its bioinformatically predicted target mimecan (osteoglycin, OGN) was gradually decreased with advanced age. Luciferase reporter assays validated mimecan as a bona fide miR-22 target. Both, miR-22 and its target mimecan were co- expressed in cardiac fibroblasts and smooth muscle cells. Functionally, miR-22 overexpression induced cellular senescence and promoted migratory activity of cardiac fibroblasts. Small interference RNA mediated silencing of mimecan in cardiac fibroblasts mimicked the miR-22-mediated effects. Rescue experiments revealed that the effects of miR-22 on cardiac fibroblasts were only partially mediated by mimecan. In conclusion, miR-22 upregulation in the aging heart contributed at least partly to accelerated cardiac fibroblast senescence and increased migratory activity. Our results suggest an involvement of miR-22 in age-associated cardiac changes, such as cardiac fibrosis. PMID- 22538860 TI - Retromolar tracheal intubation in a pediatric patient with a difficult airway and bilateral nasal stenoses. PMID- 22538861 TI - Industrial graphene metrology. AB - Graphene is an allotrope of carbon whose structure is based on one-atom-thick planar sheets of carbon atoms that are densely packed in a honeycomb crystal lattice. Its unique electrical and optical properties raised worldwide interest towards the design and fabrication of future electronic and optical devices with unmatched performance. At the moment, extensive efforts are underway to evaluate the reliability and performance of a number of such devices. With the recent advances in synthesizing large-area graphene sheets, engineers have begun investigating viable methodologies for conducting graphene metrology and quality control at industrial scales to understand a variety of reliability issues including defects, patternability, electrical, and physical properties. This review summarizes the current state of industrial graphene metrology and provides an overview of graphene metrology techniques. In addition, a recently developed large-area graphene metrology technique based on fluorescence quenching is introduced. For each metrology technique, the industrial metrics it measures are identified--layer thickness, edge structure, defects, Fermi level, and thermal conductivity--and a detailed description is provided as to how the measurements are performed. Additionally, the potential advantages of each technique for industrial use are identified, including throughput, scalability, sensitivity to substrate/environment, and on their demonstrated ability to achieve quantified results. The recently developed fluorescence-quenching metrology technique is shown to meet all the necessary criteria for industrial applications, rendering it the first industry-ready graphene metrology technique. PMID- 22538863 TI - Natural product extract of Dicksonia sellowiana induces endothelium-dependent relaxations by a redox-sensitive Src- and Akt-dependent activation of eNOS in porcine coronary arteries. AB - BACKGROUND/AIMS: The consumption of polyphenol-rich food is associated with a decreased mortality from coronary diseases. This study examined whether a standardized hydroalcoholic extract of Dicksonia sellowiana (HEDS) triggered endothelium-dependent relaxations in porcine coronary artery rings and characterized the underlying mechanism. METHODS: The phosphorylation level of Src, Akt and eNOS was assessed by Western blot analysis, the formation of reactive oxygen species by dihydroethidine staining and the level of eNOS Ser1177 phosphorylation by immunohistochemical staining in sections of coronary arteries. RESULTS: HEDS-induced endothelium-dependent relaxations were strongly reduced by Nomega-nitro-L-arginine, an eNOS inhibitor, and by its combination with charybdotoxin plus apamin, inhibitors of endothelium-derived hyperpolarizing factor-mediated responses. These relaxations were markedly reduced by MnTMPyP (a membrane-permeant mimetic of superoxide dismutase), polyethylene glycol catalase (PEG-catalase; a membrane-permeant analog of catalase), and by wortmannin (an inhibitor of PI3-kinase). HEDS-induced sustained phosphorylation of Akt and eNOS in endothelial cells was abolished by MnTMPyP, PEG-catalase and wortmannin. Oral administration of HEDS induced a significant decrease of mean arterial pressure in spontaneously hypertensive rats. CONCLUSION: These findings indicate that HEDS caused endothelium-dependent relaxations of coronary artery rings through the redox-sensitive activation of the endothelial PI3-kinase/Akt pathway leading to the subsequent activation of eNOS by phosphorylation. HEDS also has antihypertensive properties. PMID- 22538864 TI - Feasibility and reproducibility of fetal lung texture analysis by Automatic Quantitative Ultrasound Analysis and correlation with gestational age. AB - OBJECTIVE: To evaluate the feasibility and reproducibility of fetal lung texture analysis using a novel automatic quantitative ultrasound analysis and to assess its correlation with gestational age. METHODS: Prospective cross-sectional observational study. To evaluate texture features, 957 left and right lung images in a 2D four-cardiac-chamber view plane were previously delineated from fetuses between 20 and 41 weeks of gestation. Quantification of lung texture was performed by the Automatic Quantitative Ultrasound Analysis (AQUA) software to extract image features. A standard learning approach composed of feature transformation and a regression model was used to evaluate the association between texture features and gestational age. RESULTS: The association between weeks of gestation and fetal lung texture quantified by the AQUA software presented a Pearson correlation of 0.97. The association was not influenced by delineation parameters such as region of interest (ROI) localization, ROI size, right/left lung selected or sonographic parameters such as ultrasound equipment or transducer used. CONCLUSIONS: Fetal lung texture analysis measured by the AQUA software demonstrated a strong correlation with gestational age. This supports further research to explore the use of this technology to the noninvasive prediction of fetal lung maturity. PMID- 22538865 TI - Targeting interleukin-4 in asthma: lost in translation? AB - The first discovery that interleukin-4 (IL-4) is crucial in the development of allergic airway inflammation originates from the early 1990s. Whereas initial studies in experimental animal models provided the community with the optimistic view that targeting IL-4 would be the ultimate solution for treating asthma, the translation of these findings to the clinic has not been evident and has not yet fulfilled the expectations. Many technical challenges have been encountered in the attempts to modulate IL-4 expression or activity and in transferring knowledge of preclinical studies to clinical trials. Moreover, biological redundancies between IL-4 and IL-13 have compelled a simultaneous blockade of both cytokines. A number of phase I/II studies are now providing us with clinical evidence that targeting IL-4/IL-13 may provide some clinical benefit. However, the initial view that asthma is a purely Th2-mediated disease had to be revised. Currently, different asthma phenotypes have been described, implying that blocking specifically Th2 cytokines, such as IL-4, IL-5, and IL-13, should be targeted to only a specific subset of patients. Taking this into consideration, IL-4 (together with IL-13) deserves attention as subject of further investigations to treat asthma. In this review, we will address the role of IL-4 in asthma, describe IL-4 signaling, and give an overview of preclinical and clinical studies targeting the IL-4 Receptor pathway. PMID- 22538862 TI - The emerging role of peptides and lipids as antimicrobial epidermal barriers and modulators of local inflammation. AB - Skin is complex and comprised of distinct layers, each layer with unique architecture and immunologic functions. Cells within these layers produce differing amounts of antimicrobial peptides and lipids (sphingoid bases and sebaceous fatty acids) that limit colonization of commensal and opportunistic microorganisms. Furthermore, antimicrobial peptides and lipids have distinct, concentration-dependent ancillary innate and adaptive immune functions. At 0.1 2.0 MUM, antimicrobial peptides induce cell migration and adaptive immune responses to coadministered antigens. At 2.0-6.0 MUM, they induce cell proliferation and enhance wound healing. At 6.0-12.0 MUM, they can regulate chemokine and cytokine production and at their highest concentrations of 15.0 30.0 MUM, antimicrobial peptides can be cytotoxic. At 1-100 nM, lipids enhance cell migration induced by chemokines, suppress apoptosis, and optimize T cell cytotoxicity, and at 0.3-1.0 MUM they inhibit cell migration and attenuate chemokine and pro-inflammatory cytokine responses. Recently, many antimicrobial peptides and lipids at 0.1-2.0 MUM have been found to attenuate the production of chemokines and pro-inflammatory cytokines to microbial antigens. Together, both the antimicrobial and the anti-inflammatory activities of these peptides and lipids may serve to create a strong, overlapping immunologic barrier that not only controls the concentrations of cutaneous commensal flora but also the extent to which they induce a localized inflammatory response. PMID- 22538868 TI - Significance of good collateral compensation in symptomatic intracranial atherosclerosis. AB - BACKGROUND: Collateral circulation stabilizes cerebral blood flow in patients with acute occlusion, but its prognostic role is less studied in intracranial atherosclerosis and appears different in moderate to severe stenosis. We aimed to study the associations between antegrade flow across stenosis, collateral flow via leptomeningeal anastomosis, and the neurological outcome and recurrence risk in patients with symptomatic intracranial stenosis. METHODS: We examined a cohort of consecutive patients admitted for stroke or transient ischemic attack (TIA) with symptomatic intracranial stenosis confirmed by digital subtraction angiography in a single-center retrospective study. Angiograms were graded systematically in a blinded fashion for antegrade and collateral flow, using Thrombolysis in Cerebral Infarction (TICI) and American Society of Intervention and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) grading, respectively, and integrated to a simple composite circulation score. Demographic and clinical variables, modified Rankin Scale (mRS) scores at 3 months, recurrent stroke or TIA in 12 months were collected. Uni- and multivariate analyses were performed to identify independent predictors of good outcome (mRS 0-2) and recurrence in a logistic regression model. RESULTS: Among 69 patients with pure intracranial atherosclerosis >= 50%, compromised antegrade flow (TICI 0-2a) was observed in 26 (36%) patients and was associated with more severe arterial stenosis (mean 86 vs. 74%, p = 0.001). Poor collateral compensation resulting in a poor composite circulation score was observed in 8 (12%) patients. Patients with a good circulation score (n = 61, 88%) had preserved flow, which was associated with more favorable outcome (OR 7.50, 95% CI 1.11-50.7, p = 0.04) and less recurrent TIA or stroke (OR 0.18, 95% CI 0.04-0.96, p = 0.04). Prognosis was not significantly associated with antegrade or collateral grade per se. CONCLUSION: Good collateral compensations are more important in patients with symptomatic intracranial stenosis and compromised antegrade flow, and are associated with favorable outcome and less recurrence risk. The feasibility of composite flow assessment should be explored in future studies to identify high-risk intracranial stenosis with compromised hemodynamics. PMID- 22538866 TI - NF-kappaB activation is required for the transition of pulmonary inflammation to muscle atrophy. AB - Disease exacerbations and muscle wasting comprise negative prognostic factors of chronic obstructive pulmonary disease (COPD). Transient systemic inflammation and malnutrition have been implicated in skeletal muscle wasting after acute exacerbations of COPD. However, the interactions between systemic inflammation and malnutrition in their contributions to muscle atrophy, as well as the molecular basis underlying the transition of systemic inflammation to muscle atrophy, remain unresolved. Pulmonary inflammation was induced in mice by an intratracheal instillation of LPS to model acute disease exacerbation. Systemic inflammation, nutritional intake, and body and muscle weights were determined. Muscle inflammatory signaling and atrophy signaling were examined, and the effect of the muscle-specific inactivation of NF-kappaB on muscle atrophy was assessed in genetically modified mice. The intratracheal LPS instillation was followed by markedly elevated circulating cytokine concentrations and NF-kappaB activation in extrapulmonary tissues, including skeletal muscle. The administration of intratracheal LPS increased the expression of muscle E3 ubiquitin ligases, which govern muscle proteolysis, in particular MuRF1, and caused a rapid loss of muscle mass. Reduced food intake only partly accounted for the observed muscle atrophy, and did not activate NF-kappaB in muscle. Rather, plasma transfer experiments revealed the presence of NF-kappaB-signaling and atrophy-signaling properties in the circulation of intratracheal LPS-treated mice. The genetic inhibition of muscle NF-kappaB activity suppressed intratracheal LPS-induced MuRF1 expression and resulted in a significant sparing of muscle tissue. Systemic inflammation and malnutrition contribute to the muscle wasting induced by acute pulmonary inflammation via distinct mechanisms, and muscle NF-kappaB activation is required for the transition from inflammatory to muscle atrophy signaling. PMID- 22538869 TI - Fabrication and processing of high-strength densely packed carbon nanotube yarns without solution processes. AB - Defects of carbon nanotubes, weak tube-tube interactions, and weak carbon nanotube joints are bottlenecks for obtaining high-strength carbon nanotube yarns. Some solution processes are usually required to overcome these drawbacks. Here we fabricate ultra-long and densely packed pure carbon nanotube yarns by a two-rotator twisting setup with the aid of some tensioning rods. The densely packed structure enhances the tube-tube interactions, thus making high tensile strengths of carbon nanotube yarns up to 1.6 GPa. We further use a sweeping laser to thermally treat as-produced yarns for recovering defects of carbon nanotubes and possibly welding carbon nanotube joints, which improves their Young's modulus by up to ~70%. The spinning and laser sweeping processes are solution-free and capable of being assembled together to produce high-strength yarns continuously as desired. PMID- 22538867 TI - The role of minimally invasive surgery in multifocal renal cell carcinoma. AB - Surgical excision remains the reference standard for treatment of localized renal cell carcinoma (RCC). Laparoscopic and robotic minimally invasive extirpative approaches are being increasingly employed in current urologic practice. Multiple tumors in the same kidney present a unique set of challenges for minimally invasive surgeons. As such, we review recent literature regarding minimally invasive nephron-sparing surgery in patients with synchronous, ipsilateral, multifocal renal tumors. As the experience with these complex operations grows, perioperative, short-term functional and oncologic outcomes appear comparable to traditional open nephron-sparing surgery. Data on surgical approaches to patients with synchronous, ipsilateral, multifocal RCC are emerging. Short-term results suggest minimally invasive nephron-sparing surgery is safe, feasible, and should be considered as a potential treatment option for patients who present with multiple tumors in the same renal unit. PMID- 22538871 TI - Cyclin d1 induces chromosomal instability. AB - We developed mouse model systems to investigate the potential for cyclin D1 to induce CIN in vivo. In a mammary gland specific Tet-inducible model the acute expression profile regulated by cyclin D1 after 7 days was enriched in genes that rank highly with CIN. We also used a mammary gland targeted model (MMTV) to continuously express cyclin D1. The mice started to develop mammary gland tumors at 400 days and the tumor-free incidence was 40% in MMTV-cyclin D1. The gene expression profile of the tumors showed enrichment for the CIN signature. We next compared cyclin D1 expression and the highest ranking CIN genes to a breast cancer expression database and discovered that expression of genes promoting CIN are highly enriched in luminal subtype and that high cyclin D1 and CIN expression correlate specifically in the luminal B subtype. There is increasing interest in employing drugs in the clinic that exploit CIN in tumors. The high CIN expression index in luminal B breast cancer provides a basis for using Cdk and CIN inhibitors as a targeted therapeutic approach. PMID- 22538872 TI - Similar developmental patterns of ghrelin- and glucagon-expressing cells in the human pancreas. AB - The pancreas appears to be a major source of ghrelin during fetal development, but the ontogeny of ghrelin cells in the human pancreas and their developmental relationship with alpha- and beta-cells remain largely unknown. In the present study, we examined the dynamics of ghrelin cell growth, colocalization of ghrelin with major pancreatic hormones and defined the similarities and differences among developmental patterns of ghrelin-, glucagon- and insulin-expressing cells in the human pancreas. To this end, paraffin-embedded pancreatic tissue sections from human embryos and fetuses were assessed by immunohistochemistry. Ghrelin-positive cells were first detected in the pancreas of 11-week-old fetuses. With advancing gestational age, both ghrelin- and glucagon-expressing cells were increasingly observed at the periphery of the developing islets, whereas insulin-containing cells were typically found in the islet core. Double immunohistochemistry showed that ghrelin-expressing cells were clearly separate from insulin-, somatostatin- and pancreatic polypeptide-containing cells. In contrast, cells coexpressing ghrelin and glucagon were sporadically detected during both the early and late fetal periods. Furthermore, morphometric analysis revealed a similar trend in the volume density of ghrelin- and glucagon-positive cells, and a contrasting pattern in beta-cell density at specific time points during the development of the human pancreas. This study demonstrates that the developmental pattern of ghrelin cells, although clearly distinct, is quite similar to that of glucagon-expressing cells. The obtained findings indicate a close lineage relationship between these cell populations, a functional relationship between their secretory products and an auto/paracrine mode of ghrelin-glucagon interaction in pancreatic development. PMID- 22538870 TI - Prolonged stimulation of pancreatic serous secretions by bile and sodium taurocholate in anaesthetized rats. AB - There have been numerous reports that infusion of either natural bile or bile salts into the duodenum evokes a rapid increase in pancreatic secretion through the release of the hormone secretin from the duodenal mucosa. We have extended this observation by the demonstration of an additional late increase in secretion which persisted for many hours and have sought to identify the processes underlying this increase. In anaesthetised rats, infusion of 20 mM taurocholate into the duodenum caused a staircase-like increase in the weight of pancreatic secretion which extended over many hours during which, the HCO[Formula: see text] and protein output of the secretion showed only minimal changes. This effect was also reproduced with intra-duodenal infusion of natural bile which was inferred to act though its taurocholate content. Since the stimulatory action was also obtained with superfusion of taurocholate or natural bile onto the small intestine and by intravenous injection of taurocholate, it was concluded that taurocholate acted by being absorbed into the bloodstream and then by exerting a stimulatory action on the exocrine pancreas. This action was inhibited by puromycin (a protein synthesis inhibitor), by furosemide (a Na( + )/K( + )/2Cl(-) cotransporter inhibitor), though not by SITS (an inhibitor of Cl(-)/HCO[Formula: see text] exchange). The long lasting increase in pancreatic serous secretion would be consistent with the possible activation of gene transcription by taurocholate leading to increased activity of the Na( + )/K( + )/2Cl(-) cotransporter through which the acinar cells increased their secretions. PMID- 22538873 TI - Cosecretion of glycosylated prolactin and non-glycosylated prolactin from childhood to the end of puberty. AB - BACKGROUND: Glycosylated prolactin (G-PRL) is considered as the major post translational modification of prolactin (PRL) showing reduced lactotropic and mitogenic activities compared to non-glycosylated prolactin (NG-PRL). AIM: To evaluate the evolution of G-PRL in normoprolactinemic children and adolescents and to analyze possible variations in glycosylated/total prolactin (T-PRL) ratios. METHODS: T-PRL, G-PRL and NG-PRL were evaluated in 111 healthy female and male children and adolescents (4.1-18 years), classified as group 1 (Tanner I), group 2 (Tanner II-III) and group 3 (Tanner IV-V). G-PRL and NG-PRL were identified by chromatography on concanavalin-A-Sepharose. RESULTS: G-PRL/T-PRL (median-range): females, group 1: 0.59 (0.17-0.77), group 2: 0.56 (0.31-0.78), group 3: 0.60 (0.38-0.79); males, group 1: 0.64 (0.39-0.80), group 2: 0.61 (0.24 0.79), group 3: 0.62 (0.35-0.90); the p value is not significant among the different groups in both genders. G-PRL/T-PRL ratios do not change when comparing low (first quartile) versus high (third quartile) T-PRL levels in the different groups. CONCLUSION: Our study would appear to support cosecretion of G-PRL and NG PRL from childhood to the end of puberty. Such cosecretion would not be dependent on sex steroid levels. It is important to point out that puberty does not change the proportions of G-PRL and NG-PRL. PMID- 22538874 TI - Association between school engagement and disclosure of suicidal ideation to adults among Latino adolescents. AB - We examined associations between Latino adolescents' school engagement and their likelihood of disclosing suicidal ideation (SI) to adults and of asking for help for SI. A first set of analyses was conducted on a total sample of 14 high schools, and a second set of analyses was conducted on 8 "Latino-representative" high schools. The criterion for Latino representation was that >=10% of the school's total student population was Latino. Across all 14 high schools, 17% (110/663) of Latino students reported SI in the past year, compared to 13% (359/2,740) of non-Hispanic White students and 11% (78/719) of African American students. Of Latino students with SI, 24% (26/110) told an adult and 35% (38/110) sought help. In the 8 Latino-representative schools, higher levels of reported school engagement were associated with a greater likelihood of seeking help (OR = 6.17) and disclosure of SI to an adult (OR = 7.64) for Latino males. For Latinas, however, school engagement was not associated with either disclosure of SI to an adult or seeking help. Additional research is needed to clarify the processes, including social connectedness, that contribute to the disclosure of and help seeking for SI among Latino adolescents. PMID- 22538875 TI - Sawbones no longer? PMID- 22538876 TI - No to direct access. PMID- 22538877 TI - Undiagnosed temporal arteritis. PMID- 22538878 TI - Two sides to the story. PMID- 22538879 TI - PA and fish oil. PMID- 22538880 TI - Devastating dentifrices. PMID- 22538881 TI - A fascinating insight. PMID- 22538882 TI - New review needed. PMID- 22538883 TI - An alternative reaction. PMID- 22538884 TI - Controllable fluoride. PMID- 22538885 TI - Struggle for experience. PMID- 22538895 TI - Ethical issues, dilemmas and controversies in 'cosmetic' or aesthetic dentistry. A personal opinion. AB - Stephen Hancocks' elegant editorial of 11 December 2011 raises interesting questions which deserve discussion. Most experienced dentists would agree that the less that is done to teeth for cosmetic reasons, the lesser are the risks of disappointment, failure of expectation, or threat of litigation. Yet there is an increasing number of cases where aesthetics are the primary concern for dentists and patients alike and some patients are consenting to treatment without being properly informed of the destructive nature of the procedures to their sound tooth tissue and structures to achieve the desired 'cosmetic' outcome. This raises ethical issues, as much of this overtreatment is unnecessarily destructive and goes against the healing and caring principles of the dental profession. PMID- 22538896 TI - 3 '2' 1: Orthodontic re-positioning of canines into central incisors. AB - Resorption of lateral incisors caused by impacted maxillary canines is frequently reported. However, resorption of the central incisor is less common and management of such a finding can prove to be a challenge for the clinician. This article reviews the literature of impacted canines and incisor resorption. The management of two cases of severe central incisor resorption caused by an impacted maxillary canine is also described. PMID- 22538897 TI - Amelogenesis imperfecta: an introduction. AB - Amelogenesis imperfecta (AI) is an inherited disorder that is associated with mutations in five genes (AMEL; ENAM; MMP20; KLK4 and FAM83H) with a wide range of clinical presentations (phenotypes). It affects the structure and appearance of enamel of all teeth, both in the primary and secondary dentition. In this review paper, we look at the epidemiology, classification, aetiology, clinical description and diagnosis of AI. In the following three papers of this series, we aim to describe the role of paediatric dentists, orthodontists and restorative dentists in the clinical management of patients with AI. PMID- 22538902 TI - Summary of: the development of a concise questionnaire designed to measure perceived outcomes on the issues of greatest importance to patients. PMID- 22538903 TI - Summary of: the medical and dental attendance pattern of patients attending general dental practices in Warwickshire and their general health risk assessment. PMID- 22538904 TI - The Edinburgh Dental Dispensary 1860 to 1879. AB - The Edinburgh Dental Dispensary began in 1860 as a private charity to provide free treatment for the poor and to teach students. In 1862 the dispensary became a public charity in new premises with a committee of managers. Dental students were admitted in 1864. By 1867 the annual number of patient attendances was about 4,000 and the mainstay of treatment was extraction. Housekeepers were the only support staff. The dispensary was constantly impecunious; in 1869 the managers considered discontinuing the service. In February 1879, following the 1878 Dentists Act, the dispensary was merged into the new Edinburgh Dental Hospital and School. PMID- 22538925 TI - The medical and dental attendance pattern of patients attending general dental practices in Warwickshire and their general health risk assessment. AB - BACKGROUND: The dental team could have an important role to play in general health risk assessment within primary and community healthcare.Aims To describe medical and dental attendance patterns, demographics and health profiles of patients routinely attending general dental practices in Warwickshire. To identify whether a subgroup attend dental practices regularly but attend medical practices infrequently and discuss whether preventive healthcare interventions delivered in general dental practice would be appropriate. METHODS: A self completion questionnaire was administered to patients attending 16 dental practices in Warwickshire. RESULTS: Eight hundred and eleven completed questionnaires were returned (74% response). Seven hundred and eighty-nine (98%) respondents visited their dentist every one to two years or more frequently and of these a subgroup of 121 (15.3%) visited their general medical practice surgery or health centre less often than every two years. In the subgroup 9.5% reported high blood pressure, 17.6% currently smoked, 22% drank above recommended guidelines, 32.1% were overweight and 7.3% obese. DISCUSSION: The data suggest there may be a role for dental practitioners in identifying patients at risk of having undiagnosed or future general health problems and providing appropriate general health advice, screening or signposting the patient to relevant general healthcare facilities either within or external to the dental practice. PMID- 22538926 TI - Metabolic and translational efficiency in microbial organisms. AB - Metabolic efficiency, as a selective force shaping proteomes, has been shown to exist in Escherichia coli and Bacillus subtilis and in a small number of organisms with photoautotrophic and thermophilic lifestyles. Earlier attempts at larger-scale analyses have utilized proxies (such as molecular weight) for biosynthetic cost, and did not consider lifestyle or auxotrophy. This study extends the analysis to all currently sequenced microbial organisms that are amenable to these analyses while utilizing lifestyle specific amino acid biosynthesis pathways (where possible) to determine protein production costs and compensating for auxotrophy. The tendency for highly expressed proteins (with adherence to codon usage bias as a proxy for expressivity) to utilize less biosynthetically expensive amino acids is taken as evidence of cost selection. A comprehensive analysis of sequenced genomes to identify those that exhibit strong translational efficiency bias (389 out of 1,700 sequenced organisms) is also presented. PMID- 22538927 TI - The plausibility of RNA-templated peptides: simultaneous RNA affinity for adjacent peptide side chains. AB - According to the RNA world hypothesis, coded peptide synthesis (translation) must have been first catalyzed by RNAs. Here, we show that small RNA sequences can simultaneously bind the dissimilar amino acids His and Phe in peptide linkage. We used in vitro counterselection/selection to isolate a pool of RNAs that bind the dipeptide NH(2)-His-Phe-COOH with K (D) ranging from 36 to 480 MUM. These sites contact both side chains, usually including the protonated imidazole of His, but bind-free L: -His and L: -Phe with much lower, sometimes undetectable, affinities. The most frequent His-Phe sites do not usually contain previously isolated sites for individual amino acids, and are only ~35 % larger than previously known separate His and Phe sites. Nonetheless, His-Phe sites appear enriched in His anticodons, as previous L: -His sites also were. Accordingly, these data add to existing experimental evidence for a stereochemical genetic code. In these peptide sites, bound amino acids approach each other to a proximity that allows a covalent peptide linkage. Isolation of several RNAs embracing two amino acids with a linking peptide bond supports the idea that a direct-RNA-template could encode primordial peptides, though crucial experiments remain. PMID- 22538928 TI - Prognostic value of self-reported work ability and performance-based lifting tests for sustainable return to work among construction workers. AB - OBJECTIVE: This study aims to evaluate whether performance-based tests have additional prognostic value over self-reported work ability for sustainable return to work (RTW) in physically demanding work. METHODS: A one-year prospective cohort study was performed among 72 construction workers on sick leave for six weeks due to musculoskeletal disorders. The Work Ability Index (WAI) question regarding "current work ability" was used. Three dynamic lifting tests were used from a Functional Capacity Evaluation (FCE). Sustainable RTW was the number of days on sick leave until the first day of returning fully to work for a period of >=4 weeks. Regression models were built to calculate the prognostic values. RESULTS: Self-reported work ability alone predicted sustainable RTW (R=0.31, R (2)=0.09, P=0.009). In combination with one lifting test, the explained variance (R (2)) increased to 0.16 (P=0.001). CONCLUSION: Combining self-reported work ability and a lifting test nearly doubled the explained variance for sustainable RTW in physically demanding work, although the strength remained modest. PMID- 22538929 TI - Vitamin D status is associated with sociodemographic factors, lifestyle and metabolic health. AB - PURPOSE: Low serum 25(OH)D concentration has been shown to predict the occurrence of several chronic diseases. It is, however, still unclear whether the associations are causal or due to confounding. The aim of this study was to investigate the associations between serum 25(OH)D concentration and sociodemographic, lifestyle and metabolic health-related factors. METHODS: The study population comprised 5,714 men and women, aged 30-79 years, from the Health 2000 Survey representing the Finnish population. Serum 25(OH)D concentration was determined by radioimmunoassay from serum samples frozen at -70 degrees C. Sociodemographic, lifestyle and metabolic factors were determined by questionnaires, interviews and measurements. Linear regression was used to assess the associations between serum 25(OH)D and the factors studied. RESULTS: The mean serum 25(OH)D concentration was 45.3 nmol/l and it varied between categories of sociodemographic, lifestyle and metabolic health variables. Older age, being married or cohabiting and higher education were related to higher serum 25(OH)D concentration. Those with the healthiest lifestyle estimated by a lifestyle index based on body mass index, physical activity, smoking, alcohol consumption and diet had 15.8 nmol/l higher serum 25(OH)D concentration compared to those with the unhealthiest lifestyle. Of the indicators of metabolic health, only waist circumference and HDL cholesterol were significantly associated with 25(OH)D after adjustment for sociodemographic, lifestyle and other metabolic health factors. CONCLUSION: This study suggests that serum 25(OH)D concentration is associated with a multitude of sociodemographic, lifestyle and metabolic health factors. Thus, it is possible that such factors confound associations observed between serum 25(OH)D concentration and chronic diseases. PMID- 22538931 TI - Two-dimensional CdS nanosheet-based TFT and LED nanodevices. AB - Semiconductor nanosheets have several unique applications in electronic and optoelectronic nanodevices. We have successfully synthesized single-crystalline n type CdS nanosheets via a chemical vapor deposition (CVD) method in a Cd-enriched ambient. The as-synthesized nanosheets are typically 40-100 nm thick, 10-300 um wide, and up to several millimeters long. Using the nanosheets, we fabricated for the first time (to our knowledge), nano thin-film transistors (nano-TFTs) based on individual CdS nanosheets. A typical unit of such nanosheet TFTs has a high on off ratio (~1.7 *10(9)) and peak transconductance (~14.1uS), which to our knowledge are the best values reported so far for semiconductor nano-TFTs. In addition, we fabricated n-CdS nanosheet/p(+)-Si heterojunction light emitting diodes (LEDs) with a top electrode structure. This structure, where the n-type electrode is directly above the junction, has the advantage of a large active region and injection current favorable for high-efficiency electroluminescence (EL) and lasing. Room-temperature spectra of the LEDs consist of only an intense CdS band-edge emission peak (~507.7 nm) with a full width at half-maximum of about 14 nm. PMID- 22538930 TI - Ellagic acid attenuates high-carbohydrate, high-fat diet-induced metabolic syndrome in rats. AB - BACKGROUND: Fruits and nuts may prevent or reverse common human health conditions such as obesity, diabetes and hypertension; together, these conditions are referred to as metabolic syndrome, an increasing problem. This study has investigated the responses to ellagic acid, present in many fruits and nuts, in a diet-induced rat model of metabolic syndrome. METHODS: Eight- to nine-week-old male Wistar rats were divided into four groups for 16-week feeding with cornstarch diet (C), cornstarch diet supplemented with ellagic acid (CE), high carbohydrate, high-fat diet (H) and high-carbohydrate, high-fat diet supplemented with ellagic acid (HE). CE and HE rats were given 0.8 g/kg ellagic acid in food from week 8 to 16 only. At the end of 16 weeks, cardiovascular, hepatic and metabolic parameters along with protein levels of Nrf2, NF-kappaB and CPT1 in the heart and the liver were characterised. RESULTS: High-carbohydrate, high-fat diet fed rats developed cardiovascular remodelling, impaired ventricular function, impaired glucose tolerance, non-alcoholic fatty liver disease with increased protein levels of NF-kappaB and decreased protein levels of Nrf2 and CPT1 in the heart and the liver. Ellagic acid attenuated these diet-induced symptoms of metabolic syndrome with normalisation of protein levels of Nrf2, NF-kappaB and CPT1. CONCLUSIONS: Ellagic acid derived from nuts and fruits such as raspberries and pomegranates may provide a useful dietary supplement to decrease the characteristic changes in metabolism and in cardiac and hepatic structure and function induced by a high-carbohydrate, high-fat diet by suppressing oxidative stress and inflammation. PMID- 22538934 TI - Conformational dynamics of di-(perylene bisimide acrylate) and its footprints in steady-state, time-resolved, and fluorescence-correlation spectroscopy. AB - Employing steady-state spectroscopy, time-resolved fluorescence spectroscopy, and fluorescence (cross-) correlation spectroscopy we investigated di-(perylene bisimide acrylate) and compared the results with those from monomeric perylene bisimide acrylate. For the dimeric structure two emitting species were found. By comparison with the spectroscopic results from monomeric perylene bisimide one species was assigned to perylene moieties in an isolated, unstacked conformation, whereas the other species is attributed to aggregated pi-stacked perylene moieties. The transition dynamics between these conformations was uncovered by fluorescence (cross) correlation spectroscopy. A consistent description of the various correlation curves is derived for a dynamic model that considers an additional non-fluorescent dark state that is associated exclusively with the aggregated species. PMID- 22538932 TI - Three EST-SSR markers associated with QTL for the growth of the clam Meretrix meretrix revealed by selective genotyping. AB - The clam Meretrix meretrix is a member of widely cultured, commercially important clams. A marker-trait association analysis was performed using expressed sequence tag (EST) simple sequence repeat (SSR) markers for marker-assisted selection in M. meretrix. Three markers, MM1272, MM2034, and MM7721, were found to be significantly associated with quantitative trait loci (QTLs) controlling shell length (P < 0.0001) in clams of a fast-growing population (JSF) and a control population (JSC). The 144-bp allele of MM1272, the 154-bp allele of MM2034, and the 152- and 165-bp alleles of MM7721 showed a significantly higher frequency in the JSF population (17.65, 36.41, 28.67, and 29.33 %) than in the JSC population (4.65, 8.33, 3.47, and 5.56 %). The three markers showed lower values for the number of alleles and observed heterozygosity as well as a higher proportion of homozygotes in JSF than in JSC population. The three markers have been further confirmed in the high and low tails of another population (09G3SPSB); similarly, lower values for the number of alleles and observed heterozygosity as well as a higher proportion of homozygotes were found in 09G3SPSB(H). The putative functions of the three gene fragments containing MM1272, MM2034, and MM7721 also suggested that the three SSR-containing genes might be involved in growth of M. meretrix. All the results suggest that the three EST-SSR markers associated with growth QTLs would be useful for marker-assisted selection in M. meretrix breeding. PMID- 22538933 TI - Genetic positioning of centromeres through half-tetrad analysis in gynogenetic diploid families of the Zhikong scallop (Chlamys farreri). AB - Centromere mapping is a powerful tool for improving linkage maps, investigating crossover events, and understanding chiasma interference during meiosis. Ninety microsatellite markers selected across all linkage groups (LGs) from a previous Chlamys farreri genetic map were studied in three artificially induced meiogynogenetic families for centromere mapping by half-tetrad analysis. Inheritance analyses showed that all 90 microsatellite loci conformed to Mendelian inheritance in the control crosses, while 4.4 % of the microsatellite loci showed segregation departures from an expected 1:1 ratio of two homozygote classes in meiogynogenetic progeny. The second division segregation frequency (y) of the microsatellites ranged from 0.033 to 0.778 with a mean of 0.332, confirming the occurrence of partial chiasma interference in this species. Heterogeneity of y is observed in one of 42 cases in which markers were typed in more than one family, suggesting variation in gene-centromere recombination among families. Centromere location was mostly in accordance with the C. farreri karyotype, but differences in marker order between linkage and centromere maps occurred. Overall, this study makes the genetic linkage map a more complete and informative tool for genomic studies and it will also facilitate future research of the structure and function of the scallop centromeres. PMID- 22538935 TI - Spatiotemporal distribution of neurovascular alignment in remodeling adult rat mesentery microvascular networks. AB - An emerging area of microvascular research focuses on the links between neural and vascular patterning. However, the functional dependence between vascular and neural growth in adult tissues remains underinvestigated. The objective of this study was to determine the spatial and temporal coordination between vascular and neural networks over a time course of adult microvascular growth. Mesentery tissues from adult male Wistar rats were harvested prior to stimulation, and 2, 10 and 30 days after angiogenesis stimulated by mast cell degranulation. Tissues were immunolabeled for PECAM (endothelial cell marker) and class III beta-tubulin (peripheral nerve marker). Neurovascular alignment was quantified per vessel category: arterioles (>20 um), pre-capillary arterioles (10-20 um), post capillary venules (10-20 um), venules (>20 um), capillaries (<10 um) and capillary sprouts. Neurovascular alignment along pre-capillary arterioles, capillaries, post-capillary venules and venules was decreased compared to unstimulated levels on days 2 and 10. These decreases inversely correlated with increases in vessel density per vessel category. By day 30, alignment either returned to unstimulated levels or was increased compared to day 10. These results suggest that neurovascular alignment arises after microvascular network growth and is present along arterioles, venules and even capillaries. PMID- 22538936 TI - [Relationship between the Italian Society of Nephrology and ERA-EDTA: a new way of introducing young nephrologists to Europe (letter from President)]. AB - The Italian Society of Nephrology (SIN) has been working hard to increase contacts between young Italian nephrologists and the ERA-EDTA. In the last two years 120 trainees in nephrology under 24 years of age received a free membership of SIN and ERA-EDTA, including a subscription to the four journals of the two societies (Giornale Italiano di Nefrologia, Journal of Nephrology, Nephrology Dialysis Transplantation and Clinical Kidney Journal). The collaboration will be extended further by the launch of the new initiative among young ERA-EDTA members called ''Young Nephrologists Platform,'' dedicated to facilitating networking, CME, and the exchange of information about working opportunities and the organization of health care in Europe. In 2011 SIN has provided funding for 20 research projects presented by young researchers and in 2012 the society will again offer fellowships to facilitate exchange between groups. PMID- 22538937 TI - [Reflections on the intensity-of-care hospital model]. PMID- 22538938 TI - [Mutant uromodulin is secreted in the urine of patients with familial hyperuricemic nephropathy and induces the formation of extracellular aggregates]. PMID- 22538939 TI - [FGF-23 causes left ventricular hypertrophy!]. PMID- 22538940 TI - [Urinary biomarkers: ''riformulate'' the interstitium?]. PMID- 22538941 TI - [Circulating autoantibodies in asymptomatic patients: coincidence or early diagnosis?]. PMID- 22538942 TI - [Tolvaptan and CKD, a balance is needed: promises and problems of new drugs in a moment of crisis]. PMID- 22538944 TI - [CKD and kidney transplant: different hemoglobin targets?]. PMID- 22538943 TI - [Route of administration of ESA: subcutaneous still valid and correct?]. PMID- 22538945 TI - [Home hemodialysis and peritoneal dialysis compared]. AB - The evolution of home dialysis marked the main steps in the progress of renal replacement therapy. From the origins when home hemodialysis was often the only alternative to death, to the advent and widespread use of peritoneal dialysis, the dream of kidney transplant as a solution to all problems (at least in the young), and ultimately the profound social and organizational changes that have led to a drastic reduction of home hemodialysis, we arrive at the present with the rediscovery of the clinical, rehabilitative and economic advantages of home dialysis. Seven experts from five different centers with different expertise in home dialysis report their opinions on the future of home dialysis in a ''noncontroversial controversy''. Beyond the sterile competition between peritoneal dialysis and home hemodialysis, the shared opinion is that the two methods may complement each other, allowing a tailored treatment for each patient and a tailored organization in each setting. The organizational solutions are many; the authors underline the importance of longer survival and better rehabilitation, and the ethical need of offering each patient a choice among all available treatments. Add to this the importance of dedicated educational programs targeted to physicians, nurses and patients alike and focused on self care and patient empowerment. A new generation of dialysis machines, easier technical solutions, and financial incentives may strengthen motivations and simplify problems; all these elements may in the near future be combined in a joint effort to increase peritoneal dialysis and revive home hemodialysis in Italy. PMID- 22538946 TI - [Statins and kidney disease]. AB - The prevalence of chronic kidney disease (CKD) is increasing worldwide. This clinical and social problem is mainly related to the ongoing epidemic of obesity and metabolic syndrome resulting in hypertension and diabetes mellitus. CKD is a well-recognized risk multiplier for the development of cardiovascular disease (CVD), and it is widely known that CVD is the leading cause of morbidity and mortality in patients with CKD. Lipid metabolism abnormalities are commonly associated with CKD. These consist of increased levels of low-density lipoproteins (LDL), triglycerides, very-low-density lipoproteins (VLDL) and lipoprotein(a), and reduced levels of HDL cholesterol. Lipid abnormalities contribute to cardiovascular morbidity and mortality in CKD patients. Some evidence also suggests that dyslipidemia may contribute to the progression of renal disease associated with type 1 and type 2 diabetic as well as non-diabetic renal disease. In the general population, HMG-CoA reductase inhibitors (statins) reduce the cardiovascular risk and prevent CVD. Similar data from secondary analyses of CKD subgroups of larger prospective trials using statins suggest a beneficial effect on cardiovascular outcomes and - albeit with more conflicting evidence - the progression of renal disease. Statins reduce blood levels of LDL cholesterol but also have multiple effects above and beyond cholesterol lowering, including direct effects on vascular tissue, kidney, bone, and glucose metabolism. The evidence linking dyslipidemia management with statins to cardiovascular disease and the decline in renal function in CKD patients will be presented in this review. PMID- 22538947 TI - [Intestinal and renal transport mechanisms of phosphate]. AB - Since phosphorus plays a critical role in diverse biological processes, regulation of the phosphorus balance and homeostasis are critical to the well being of the organism. Recent findings point to the presence of a phosphate sensing mechanism in the various organs and the presence of novel intestinal effectors that alter the renal phosphate excretion after the ingestion of a phosphate-containing meal. Recent studies have provided strong evidence that the sodium-phosphate cotransporter NaPi-IIb is responsible for sodium-dependent phosphate absorption by the small intestine, and this protein might link changes in dietary phosphate to altered renal phosphate excretion in order to maintain the phosphate balance. It has been established that different regions of the small intestine respond differently to acute or chronic changes in dietary phosphate load and that phosphatonins inhibit both renal and intestinal phosphate transport. PMID- 22538948 TI - [Contrast-induced nephropathy: the VIKISAFE study group statement]. AB - Contrast-induced nephropathy (CIN) has undergone a significant evolution over the years in terms of epidemiology and diagnostic criteria. At present it is defined as CI-AKI (contrast-induced acute kidney injury) and represents a pathologically relevant event for different disciplines. Thus, a multidisciplinary approach is needed to propose and deploy a common strategy to reduce the incidence of CI-AKI. It seems that the use of isoosmolar non-ionic contrast media such as iodixanol can reduce the nephrotoxic effects. However, since these - still controversial - results have been obtained using various diagnostic criteria, they are difficult to compare and pool together. Common criteria are therefore required. The term acute renal failure has been replaced by acute kidney injury (AKI). Thanks to consensus groups such as ADQI (Acute Dialysis Quality Initiative) and AKIN (Acute Kidney Injury Network) and the development of guidelines by KDIGO, the diagnostic criteria for AKI are well defined. Nevertheless, the possibility to utilize new biomarkers of structural kidney damage such as neutrophil gelatinase-associated lipocalin (NGAL) or cystatin C has introduced the concept that AKI may be diagnosed even in the absence of creatinine elevation or decreased urine output. A re-evaluation of the epidemiology of CI-AKI based on new diagnostic criteria is required. In this paper the results of a collaborative multidisciplinary study group are reported from the perspective of different disciplines including nephrology, cardiology, radiology and pharmacology. The findings in a cohort of cardiac patients undergoing imaging procedures using exclusively the isoosmolar non-ionic contrast medium iodixanol are evaluated according to the RIFLE/AKIN criteria. PMID- 22538949 TI - [Human papillomavirus infection and cervical intraepithelial neoplasia in dialyzed patients]. AB - Human papillomavirus (HPV) infection is a risk factor for the development of cervical intraepithelial neoplasia (CIN). The incidence of certain cancers such as HPV-associated CIN is higher among dialysis patients than in the general population. In the literature there are few studies on the prevalence of HPV infection among dialyzed women and almost all of these studies concerned women with positive Pap smears. We enrolled 73 hemodialyzed women attending our center from January 2009 to December 2010; 29 denied informed consent and 44 underwent Pap tests and cervical curettage for HPV (mean age 62 +/- 15 years). We found HPV positivity in 6 women (prevalence 13.6%). The prevalence of CIN in our sample was also 13.6% (6/44), 83.3% of which HPV related. Since cervical curettage for HPV is a cheap and easy to perform test with high specificity and sensitivity, we believe it is worthwhile including it in the pre-transplant workup of such women to lower the incidence of CIN in dialyzed patients and transplant recipients. PMID- 22538950 TI - [Ultrasound and color Doppler in nephrology. Technology and applications]. AB - Advances in digital technology in the last decades have led to a fast development of ultrasound technology. Ultrasound information originating from stationary structures or red blood cells moving into the vessels can be visualized with different imaging modalities. Conventional B-mode sonography provides anatomical details based on acoustic impedance differences. Gray-scale sonography represents the structural echoes as brightness points. Based on the Doppler effect, vascular scattering can be represented as spectral wave velocity depending on time (velocity/time curve), or as dual-scale color mapping depending on the changes in average blood velocity. The flow-in is depicted in red and the flow-out in blue. The analysis of the vascular scattering enhanced by infusion of contrast agents is the basis of contrast-enhanced harmonic imaging. The perfusional pattern of tissues allows the differential diagnosis of expansive lesions. Tissue strain analysis provides a new dimension of diagnostic information. It is used in elastographic imaging to describe relative physical tissue stiffness properties. Tissue stiffness information is complementary to and independent of the acoustic impedance information provided by B-mode imaging as well as the vascular flow information provided by Doppler imaging. Adjacent tissue elements may appear identical using conventional B-mode or Doppler imaging. When stress (axial force) is applied to tissues, they show different degrees of deformation. Comparing the baseline and stress image information, each tissue element may be labeled by its relative stiffness. A lighter shade indicates relatively soft tissue (elastic), while a darker shade indicates relatively stiff tissue (non-elastic). PMID- 22538951 TI - [Uremic pneumonitis: a case report]. AB - Although lung involvement is frequent in patients with renal failure, cases of uremic pneumonitis have become less and less frequent since the introduction of dialysis. We describe the clinical case of a man who had respiratory distress and severe renal impairment when he first came to our observation. Instrumental and laboratory tests resulted in a diagnosis of advanced chronic renal failure together with extensive bronchopneumonia, while further tests revealed more severe lung involvement. After excluding the immunological pathogenesis forms involving the kidneys and lungs, our new diagnosis was uremic pneumonitis complicated by bronchopneumonia. The diagnosis was supported by the tomographic picture of the lung and the severe state of uremic poisoning, as well as an ex juvantibus criterion: intensive dialytic treatment together with broad-spectrum antibiotic therapy resulted in progressive improvement of the clinical picture with concurrent regression of the radiological lesions in the lung. PMID- 22538952 TI - [Prevalence and control of hypertension in chronic hemodialysis patients: results of a single-centre clinical audit]. AB - Hypertension (HTN) is very common in chronic hemodialysis patients, with a prevalence of 72%, a very poor control and an annual mortality of 23%. We report the results of a clinical audit on prevalence and control of HTN in our hemodialysis patients. The following parameters in a cohort of 89 patients were assessed in one-month observational study, conducted in October 2010: blood pressure (BP) before the beginning (preHD BP) and after the end of the treatment (postHD BP), age, sex, comorbidity, serum hemoglobin (Hb) levels, plasma and dialysate sodium levels, interdialytic weight gain (IWG), serum parathyroid hormone (PTH) levels, prescription of erythropoiesis stimulating agents (ESA) and of antihypertensive drugs. In agreeement to the current guidelines, patients with preHD BP <=140/90 mmHg and postHD BP <=130/80 mmHg were considered normortensive. Forty-nine patients (55%) were found to be hypertensive. The following comorbidities, graded as 1+ to 3+, were detected: ischemic/hypertrophic cardiopathy, dyslipidemia, peripheral arteriopathy, diabetes mellitus. Only 14.3% of patients achieved both preHD and postHD BP targets. Compared to patients whose BP was not controlled, those achieving BP targets were younger, had lower dialysate sodium levels and showed a greater IWG. No significant difference there was in serum Hb levels, plasma sodium levels, serum PTH levels, prescription of antihypertensive drugs and ESA. Our data confirm the high prevalence of HTN and the unsatisfactory BP control in hemodialysis patients. A low-salt diet, probing for dry-weight and the antihypertensive medication may help to achieve the BP control. PMID- 22538954 TI - [Interview with Prof. Umberto Buoncristiani: a nephrologist with a mission to invent technologies. Interview by Mario Timio]. PMID- 22538953 TI - [The intensity-of-care model at the Versilia Hospital]. PMID- 22538955 TI - [A dangerous loop]. PMID- 22538956 TI - ARB and cardioprotection. AB - A growing body of evidence has suggested that the use of angiotensin II (Ang II) type 1 (AT1) receptor blockers (ARBs) leads to a significant decrease in mortality and morbidity in patients with congestive heart failure. The AT1 receptor is a seven-transmembrane G protein-coupled receptor, and is involved in regulating the physiological and pathological process of the cardiovascular system. Systemically and locally generated Ang II has agonistic action on AT1 receptor. However, recent in vitro studies have demonstrated that AT1 receptor is structurally flexible and instable, and has significant and varying levels of spontaneous activity in an Ang II-independent manner. Furthermore, mechanical stress activates AT1 receptor by inducing conformational switch without the involvement of Ang II. Experimental studies have demonstrated that Ang II independent activation of AT1 receptor is profoundly relevant to the pathogenesis of cardiac remodeling in vivo, and that these agonist-independent activities of AT1 receptor can be inhibited by inverse agonists, but not by neutral antagonists. Therefore, inverse agonist activity emerges as an important pharmacological parameter that contributes to cardioprotective effects of ARBs through inhibiting both Ang II-dependent and -independent activation of AT1 receptor. PMID- 22538958 TI - MRI is unnecessary for diagnosing acute Achilles tendon ruptures: clinical diagnostic criteria. AB - BACKGROUND: Achilles tendon ruptures are common in middle-aged athletes. Diagnosis is based on clinical examination or imaging. Although MRI is commonly used to document ruptures, there is no literature supporting its routine use and we wondered whether it was necessary. QUESTIONS/PURPOSES: We (1) determined the sensitivity of physical examination in diagnosing acute Achilles ruptures, (2) compared the sensitivity of physical examination with that of MRI, and (3) assessed care delays and impact attributable to MRI. METHODS: We retrospectively compared 66 patients with surgically confirmed acute Achilles ruptures and preoperative MRI with a control group of 66 patients without preoperative MRI. Clinical diagnostic criteria were an abnormal Thompson test, decreased resting tension, and palpable defect. Time to diagnosis and surgical procedures were compared with those of the control group. RESULTS: All patients had all three clinical findings preoperatively and complete ruptures intraoperatively (sensitivity of 100%). MR images were read as complete tears in 60, partial in four, and inconclusive in two patients. It took a mean of 5.1 days to obtain MRI after the injury, 8.8 days for initial evaluation, and 12.4 days for surgical intervention. In the control group, initial evaluation occurred at 2.5 days and surgical intervention at 5.6 days after injury. Nineteen patients in the MRI group had additional procedures whereas none of the control group patients had additional procedures. CONCLUSIONS: Physical examination findings were more sensitive than MRI. MRI is time consuming, expensive, and can lead to treatment delays. Clinicians should rely on the history and physical examination for accurate diagnosis and reserve MRI for ambiguous presentations and subacute or chronic injuries for preoperative planning. LEVEL OF EVIDENCE: Level II, diagnostic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID- 22538959 TI - Assessing the gold standard: a review of 253 two-stage revisions for infected TKA. AB - BACKGROUND: Periprosthetic joint infection has been the leading cause of failure following TKA surgery. The gold standard for infection control has been a two staged revision TKA. There have been few reports on mid- to long-term survivorship, functional outcomes, and fate of patients with a failed two-stage revision TKA. QUESTIONS/PURPOSES: Therefore, we determined (1) the mid-term survivorship of two-stage revision TKA, (2) the function of patients in whom infection was controlled, and (3) the outcome of patients with a failed two-stage revision due to recurrent infection. METHODS: We retrospectively reviewed 239 patients who underwent 253 two-stage revision TKAs for periprosthetic infection. There were 239 patients (253 knees), 104 men and 135 women, with a mean age of 70 +/- 10 years at the time of two-stage revision and a mean BMI of 31.53 +/- 6.74 kg/m2. During followup, we obtained WOMAC and The Knee Society Clinical Rating Scores and radiographs. The minimum followup was 1 year (median, 4 years; range, 1-17 years). RESULTS: Thirty-three patients experienced a failed two-staged TKA. Sixteen patients experienced failure due to recurrent sepsis. There were 17 failures for aseptic causes. CONCLUSION: The overall infection-free survivorship for two-stage revision TKA was 85% at 5 years and 78% at 10 years. LEVEL OF EVIDENCE: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID- 22538960 TI - In brief: The Risser classification: a classic tool for the clinician treating adolescent idiopathic scoliosis. PMID- 22538961 TI - Quantitative 3D-CT anatomy of hamate osteoarticular autograft for reconstruction of the middle phalanx base. AB - BACKGROUND: Hamate osteoarticular autografts are difficult to obtain and it is unclear to what degree the graft matches the joint surface to be replaced and whether a direct ulnar approach might provide a more reliable graft than the standard proximal to distal approach. PURPOSE: We modeled hemihamate osteotomies using quantitative three-dimensional CT (3D-CT) to measure the amount of hamate articular surface used and the match with the native volar base of the middle phalanx. METHODS: In virtual hemihamate osteotomies (standard and direct ulnar) on CTs of 20 patients (11 men and nine women), we measured the percentage of hamate articular surface used for each finger, the match of the articular contour, and the percentage of hamate articular surface removed. RESULTS: The autograft in the standard approach used an average of 26% of the hamate articular surface and had an average 75% match of the articular contour with the volar half of the middle phalanx base. A direct ulnar approach removed an additional small margin of dorsal ulnar hamate with an average maximum width of 2.5 mm and volume of 27 mm(3). CONCLUSIONS: An osteoarticular allograft from the hamate to replace the volar half of the middle phalanx base uses less than 1/3 of the hamate articular surface even if the dorsal ulnar margin of the hamate is taken with the graft. CLINICAL RELEVANCE: These data suggest that it might be feasible to make the deep cut from a direct ulnar approach. PMID- 22538962 TI - Leukoaraiosis predicts poor 90-day outcome after acute large cerebral artery occlusion. AB - BACKGROUND: To date limited information regarding outcome-modifying factors in patients with acute intracranial large artery occlusion (ILAO) in the anterior circulation is available. Leukoaraiosis (LA) is a common finding among patients with ischemic stroke and has been associated with poor post-stroke outcomes but its association with ILAO remains poorly characterized. This study sought to clarify the contribution of baseline LA and other common risk factors to 90-day outcome (modified Rankin Scale, mRS) after stroke due to acute anterior circulation ILAO. METHODS: We retrospectively analyzed 1,153 consecutive patients with imaging-confirmed ischemic stroke during a 4-year period (2007-2010) at a single academic institution. The final study cohort included 87 patients with acute ILAO subjected to multimodal CT imaging within 24 h of symptom onset. LA severity was assessed using the van Swieten scale on non-contrast CT. Leptomeningeal collaterals were graded using CT angiogram source images. Hemorrhagic transformation (HT) was determined on follow-up CT. Multivariate logistic regression controlling for HT, treatment modality, demographic, as well as baseline clinical and imaging characteristics was used to identify independent predictors of a poor outcome (90-day mRS >2). RESULTS: The median National Institutes of Health Stroke Scale (NIHSS) at baseline was 15 (interquartile range 9-21). Twenty-four percent of the studied patients had severe LA. They were more likely to have hypertension (p = 0.028), coronary artery disease (p = 0.015), poor collaterals (p < 0.001), higher baseline NIHSS (p = 0.003), higher mRS at 90 days (p < 0.001), and were older (p = 0.002). Patients with severe LA had a uniformly poor outcome (p < 0.001) irrespective of treatment modality. Poor outcome was independently associated with higher baseline NIHSS (p < 0.001), worse LA (graded and dichotomized, p < 0.001), reduced leptomeningeal collaterals (graded and dichotomized, p < 0.001), presence of HT (p < 0.001), presence of parenchymal hemorrhages (p = 0.01), baseline mRS (p = 0.002), and older age (p = 0.043). The association between severe LA (p = 0.0056; OR 13.86; 95% CI 1.94 infinity) and baseline NIHSS (p = 0.0001; OR 5.11; 95% CI 2.07-14.49 for each 10 point increase) with poor outcome maintained after adjustment for confounders in the final regression model. In this model, there was no significant association between presence of HT and poor outcome (p = 0.0572). CONCLUSION: Coexisting LA may predict poor functional outcome in patients with acute anterior circulation ILAO independent of other known important outcome predictors such as comorbid state, admission functional deficit, collateral status, hemorrhagic conversion, and treatment modality. PMID- 22538963 TI - A highly sensitive electrochemical biosensor based on zinc oxide nanotetrapods for L-lactic acid detection. AB - An amperometric biosensor based on zinc oxide (ZnO) nanotetrapods was designed to detect L-lactic acid. The lactate oxidase was immobilized on the surface of ZnO nanotetrapods by electrostatic adsorption. Unlike traditional detectors, the special four-leg individual ZnO nanostructure, as an adsorption layer, provides multiterminal charge transfer channels. Furthermore, a large amount of ZnO tetrapods are randomly stacked to form a three-dimensional network naturally that facilitates the exchange of electrons and ions in the phosphate buffer solution. Utilizing amperometric response measurements, the prepared ZnO nanotetrapod L lactic acid biosensor displayed a detection limit of 1.2 MUM, a low apparent Michaelis-Menten constant of 0.58 mM, a high sensitivity of 28.0 MUA cm(-2) mM( 1) and a good linear relationship in the range of 3.6 MUM-0.6 mM for the L-lactic acid detection. This study shows that the biosensor based on ZnO tetrapod nanostructures is highly sensitive and able to respond rapidly in detecting lactic acid. PMID- 22538964 TI - Double agents in the war on cancer: leukocytes govern ovarian cancer progression. AB - In conclusion, our work expands our understanding of tumor progression and provides further mechanistic rationale to develop novel interventions targeting immunosuppression. Future studies should unveil other unrecognized aspects of the contribution of the immune system to cancer prevention and progression. PMID- 22538966 TI - Differentiated epidermal cells regain the ability to regenerate a skin equivalent by increasing the level of beta-catenin in the cells. AB - Epidermal stem cells are of major importance for skin regeneration and tissue engineering, but differentiated epidermal cells lost their proliferative capacity and are no longer able to regenerate a skin equivalent. Here, we investigated the role of beta-catenin in regulating regenerative functions of differentiated epidermal cells. Lithium chloride and a highly specific glycogen synthase kinase (GSK)-3beta inhibitor were applied to induce the expression of beta-catenin in differentiated epidermal cells. After a 6-day induction, the large flat-shaped cells with a small nuclear-cytoplasmic ratio had changed into small round-shaped cells with a large nuclear-cytoplasmic ratio. Phenotypic assays showed a remarkably higher expression of CK19, beta(1)-integrin, Oct4 and Nanog in induced cells than in the control group (p < 0.01). In addition, the results of growth and functional investigations demonstrated that the induced epidermal cells exhibited a high colony-forming ability, a long-term proliferative potential and the ability to regenerate a skin equivalent, which were regarded as the most important features of epidermal stem cells. These results suggest that the activation of beta-catenin favors the reversion or dedifferentiation of differentiated epidermal cells to an immature or a less differentiated state. This study may also offer a new approach to yield enough epidermal stem cells for skin regeneration and tissue engineering. PMID- 22538967 TI - Hierarchical weeping willow nano-tree growth and effect of branching on dye sensitized solar cell efficiency. AB - In this paper we have demonstrated the simple, low cost, low temperature, hydrothermal growth of weeping willow ZnO nano-trees with very long branches to realize high efficiency dye-sensitized solar cells (DSSCs). We also discuss the effects of branching on solar cell efficiency. By introducing branched growth on the backbone ZnO nanowires (NWs), the short circuit current density and the overall light conversion efficiency of the branched ZnO NW DSSCs increased to almost four times that for vertically grown ZnO NWs. The efficiency increase is attributed to the increase in surface area for higher dye loading and light harvesting and also to reduced charge recombination through direct conduction along the crystalline ZnO branches. As the length of the branches increased, the branches became flaccid and the increase in solar cell efficiency slowed down because the effective surface area increase was hindered by branch bundling during the drying process and subsequent decrease in the dye loading. PMID- 22538965 TI - The anti-arthritic and anti-oxidative effect of NBD (6-nitro-1,3-benzodioxane) in adjuvant-induced arthritis (AIA) in rats. AB - OBJECTIVES: The present study evaluated the anti-arthritic and anti-oxidative effects of 6-nitro-1,3-benzodioxane in the adjuvant-induced arthritis model in rats. METHODS: Arthritis was induced in female rats by intradermal injection of MT37Ra. Arthritis was evaluated by arthritic score, body weight loss, paw volume measurement, and histological changes. The plantar test was used to evaluate the effect of NBD on hyperalgesia. RESULTS: The hyperalgesia (p < 0.0001) and hind paw inflammation (p < 0.034) was significantly decreased with parallel increase in the body weight of the NBD-treated (25 mg/kg) group compared to arthritic control rats. The antioxidant activity analysis demonstrated that the treatment of NBD significantly suppressed the levels of nitric oxide (p < 0.001) and peroxide (p < 0.002) with a significant increase in the glutathione (p < 0.021) compared to the arthritic control group. Since the IL-1beta and TNF-alpha are key pro-inflammatory cytokines in arthritis, we therefore measured their levels in the serum samples. In comparison to the arthritic control group, the NBD treatment significantly reduced the levels of IL-1beta (p < 0.003) and TNF-alpha (p < 0.026). CONCLUSION: Our results suggests that NBD is an anti-arthritic agent that not only reduces the severity of the disease process but also affects contributing factors of arthritic inflammation including free radicals and inflammatory cytokines production. PMID- 22538968 TI - Processing gapped verbs. AB - The time course was investigated of the processing of "missing" verbs in gapping constructions, such as John ate the hamburger, and Bill __ the hotdog. Native speakers of Dutch silently read Dutch sentences with and without gapping while their EEG was recorded. A left anterior negativity (LAN) was found at the first possible position at which the gapped verb could be detected, at least, for in participants who performed poorly in an end-of-sentence acceptability judgment task. This suggests that some readers do not anticipate the gapped verb, but infer the gapped verb in a bottom-up fashion, resulting in a LAN. Second, a P600 effect was observed for gapping versus no-gapping conditions, the early part of which was unaffected by plausibility. This suggests that the semantic and syntactic integration of a gapped verb is a relatively late process, and involves mechanisms similar to integrating a wh-phrase object with its verb. PMID- 22538969 TI - Antipsychotic-induced hyperprolactinemia and testosterone levels in boys. AB - AIMS: This cross-sectional study investigates the effect of antipsychotic (AP) induced hyperprolactinemia on testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), inhibin B, and puberty in boys with mainly autism spectrum disorders (ASD). METHOD: One hundred and four physically healthy 10- to 19-year-old boys with ASD or disruptive behavior disorder (DBD) were recruited between October 2006 and November 2009. Fifty-six adolescents had been treated with AP for >16 months; 48 had never been exposed to AP. Morning non-fasting levels of serum prolactin, testosterone, LH, FSH and inhibin B were obtained and Tanner pubertal stage was determined. Patients with hyperprolactinemia (n = 28) were compared to those without hyperprolactinemia (n = 76) using non-parametric or parametric tests, as appropriate. RESULTS: Patients with AP-induced hyperprolactinemia had significantly lower testosterone levels with adjustment for age (p = 0.035) compared to patients without hyperprolactinemia and without AP treatment. The difference was not significant within the AP-treated group, and the level of testosterone was within the reference range compared to age- and gender-matched normative data. There was no between-group difference for LH, FSH, inhibin B or Tanner stages. CONCLUSION: AP-induced hyperprolactinemia is related to significantly lower testosterone levels in pubertal boys with ASD and DBD. PMID- 22538970 TI - Nongynecological endometriosis presenting as an acute abdomen. AB - Endometriosis is a highly prevalent disease that affects up to 10 % of menstruating women. Patients commonly present with pelvic pain or infertility, although the range of clinical symptoms varies widely. Affected women may be asymptomatic or experience mild, moderate, or severe pain that fluctuates with hormonal cycles. Patients who suffer extreme pain may seek immediate care and present to the emergency department with clinical signs of an acute abdomen. In the case of patients without a prior history of endometriosis, the differential diagnosis is broad and making the correct clinical and radiologic diagnosis in the emergency setting can be challenging. In some cases, the diagnosis is only made after surgical or histopathological analysis. Prompt and accurate clinical and radiological evaluation is necessary because complications of endometriosis, such as bowel obstruction and appendicitis, may require immediate surgical intervention. This pictorial essay analyzes nongynecological manifestations of endometriosis that may have a clinical presentation of an acute abdominal emergency. Atypical clinical presentations and unusual sites and complications of endometriosis are discussed, as well as the differential diagnostic considerations. The radiologic features of endometriosis are shown on multiple modalities, including computed tomography, magnetic resonance imaging, and ultrasound. PMID- 22538972 TI - Viable circulating tumour cell detection using multiplex RNA in situ hybridisation predicts progression-free survival in metastatic breast cancer patients. AB - BACKGROUND: Current approaches for detecting circulating tumour cells (CTCs) in blood are dependent on CTC enrichment and are based either on surface epithelial markers on CTCs or on cell size differences. The objectives of this study were to develop and characterise an ultrasensitive multiplex fluorescent RNA in situ hybridisation (ISH)-based CTC detection system called CTCscope. This method detects a multitude of tumour-specific markers at single-cell level in blood. METHODS: Healthy blood samples spiked with tumour cell lines were used as a model system for the development and initial characterisation of CTCscope. To demonstrate the feasibility of CTC detection in patient blood, duplicate blood samples were drawn from 45 metastatic breast cancer patients for analysis by CTCscope and the CellSearch system. The association of CTCs with the tumour marker CA15-3 and progression-free survival (PFS) were assessed. RESULTS: CTCscope detected CTC transcripts of eight epithelial markers and three epithelial-mesenchymal-transition (EMT) markers for increased sensitivity. CTCscope was used to detect CTCs with minimal enrichment, and did not detect apoptotic or dead cells. In patient blood samples, CTCs detected by CellSearch, but not CTCscope, were positively correlated with CA15-3 levels. Circulating tumour cells detected by either CTCscope or CellSearch predicted PFS (CTCscope, HR (hazard ratio) 2.26, 95% CI 1.18-4.35, P=0.014; CellSearch, HR 2.50, 95% CI 1.27-4.90, P=0.008). CONCLUSION: CTCscope offers unique advantages over existing CTC detection approaches. By enumerating and characterising only viable CTCs, CTCscope provides additional prognostic and predictive information in therapy monitoring. PMID- 22538971 TI - Evaluation of cell death mechanisms induced by the vascular disrupting agent OXi4503 during a phase I clinical trial. AB - BACKGROUND: OXi4503 is a tubulin-binding vascular disrupting agent that has recently completed a Cancer Research UK-sponsored phase I trial. Preclinical studies demonstrated early drug-induced apoptosis in tumour endothelial cells at 1-3 h and secondary tumour cell necrosis between 6 and 72 h. METHODS: To capture both possible outcomes of OXi4503 treatment on cell death, plasma samples for analysis by M30 and M65 ELISAs, which measure different circulating forms of cytokeratin 18 as biomarkers of apoptosis and necrosis, respectively, were collected from patients entered into the trial at early (4/6 h) and later time points (24h, day 8 and day 15). RESULTS: OXi4503 induced a selective dose dependent elevation in M30 antigen levels (apoptosis) at 4/6 h and a similar elevation in M65 antigen levels at 24 h (necrosis) consistent with its preclinical cell death profile. For the purposes of investigating potential biomarker relationships to patient characteristics, the trial population was divided into three groups based on radiological and clinical response: (a) early progression, (b) progressive disease and (c) stable disease (SD)/partial response. A significant increase in antigen concentrations was measured by M65 at 24 h in the SD group compared with the two other groups (P=0.015, mean increase 30.9%). CONCLUSION: These results provide pharmacodynamic evidence of drug mechanism of action in cancer patients and highlight the M65 ELISA as a potentially useful biomarker assay of response to OXi4503. PMID- 22538973 TI - Therapy of chronic myeloid leukaemia can benefit from the activation of stem cells: simulation studies of different treatment combinations. AB - BACKGROUND: Newly diagnosed patients with chronic myeloid leukaemia (CML) are currently treated with tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib or dasatinib. However, incomplete eradication of residual disease is a general problem of long-term TKI therapy. Activation of mouse haematopoietic stem cells by interferon-alpha (IFNalpha) stimulated the discussion of whether a combination treatment leads to accelerated eradication of the CML clone. METHODS: We base our simulation approach on a mathematical model describing human CML as a competition phenomenon between normal and malignant cells. We amend this model to incorporate the description of IFNalpha activity and simulate different scenarios for potential treatment combinations. RESULTS: We demonstrate that the overall sensitivity of CML stem cells to IFNalpha activation is a crucial determinant for the benefit of a potential combination therapy. We furthermore show that pulsed IFNalpha together with continuous TKI administration is the most promising strategy for a combination treatment in which the therapeutic benefit prevails adverse side effects. CONCLUSION: Our modelling approach is a highly beneficial tool to quantitatively address the competition between normal and leukaemic haematopoiesis in treated CML patients. We derive testable predictions for different experimental settings that are suggested before the clinical implementation of the combination treatment. PMID- 22538974 TI - Aurora kinase A outperforms Ki67 as a prognostic marker in ER-positive breast cancer. AB - BACKGROUND: Proliferation has emerged as a major prognostic factor in luminal breast cancer. The immunohistochemical (IHC) proliferation marker Ki67 has been most extensively investigated but has not gained widespread clinical acceptance. METHODS: We have conducted a head-to-head comparison of a panel of proliferation markers, including Ki67. Our aim was to establish the marker of the greatest prognostic utility. Tumour samples from 3093 women with breast cancer were constructed as tissue microarrays. We used IHC to detect expression of mini chromosome maintenance protein 2, Ki67, aurora kinase A (AURKA), polo-like kinase 1, geminin and phospho-histone H3. We used a Cox proportional-hazards model to investigate the association with 10-year breast cancer-specific survival (BCSS). Missing values were resolved using multiple imputation. RESULTS: The prognostic significance of proliferation was limited to oestrogen receptor (ER)-positive breast cancer. Aurora kinase A emerged as the marker of the greatest prognostic significance in a multivariate model adjusted for the standard clinical and molecular covariates (hazard ratio 1.3; 95% confidence interval 1.1-1.5; P=0.005), outperforming all other markers including Ki67. CONCLUSION: Aurora kinase A outperforms other proliferation markers as an independent predictor of BCSS in ER-positive breast cancer. It has the potential for use in routine clinical practice. PMID- 22538976 TI - Effect of dietary prebiotic (mannan oligosaccharide) supplementation on the caecal bacterial community structure of turkeys. AB - The identification of specific bacterial species influenced by mannan oligosaccharide (MOS) supplementation may assist in the formulation of new and improved diets that promote intestinal health and improve bird performance, offering suitable alternatives to antimicrobials in feed for sustainable poultry production. This study has been conducted to evaluate the use of a MOS compound derived from the yeast cell wall of Saccharomyces cerevisiae on turkey performance, bacterial community structure and their phylogenetic associations. A 42-day turkey trial was carried out on birds fed control and MOS-supplemented diets. Bird performance data (weight gains, feed consumption and feed efficiency ratios) were collected, and caecal contents were extracted from randomly caught poults on days 28, 35 and 42 posthatch. Bird performance data showed no improvements as a result of dietary supplementation. Automated ribosomal intergenic spacer analysis (ARISA) revealed the bacterial community structure to be significantly altered on days 28 and 35 posthatch but not day 42 as a result of dietary supplementation. This technique was coupled with 16S rRNA gene sequence analysis to elucidate phylogenetic identities of bacteria. The dominant bacteria of the caecum on all days in both treatment groups were members of phylum Firmicutes, followed by the Bacteroidetes and Proteobacteria phyla, respectively. Statistical analysis of the 16S rRNA gene libraries showed that the composition of the MOS clone library differed significantly to the control on day 35 posthatch. It can be concluded that MOS alters the bacterial community structure in the turkey caecum. PMID- 22538975 TI - Epithelial-mesenchymal transition biomarkers and support vector machine guided model in preoperatively predicting regional lymph node metastasis for rectal cancer. AB - BACKGROUND: Current imaging modalities are inadequate in preoperatively predicting regional lymph node metastasis (RLNM) status in rectal cancer (RC). Here, we designed support vector machine (SVM) model to address this issue by integrating epithelial-mesenchymal-transition (EMT)-related biomarkers along with clinicopathological variables. METHODS: Using tissue microarrays and immunohistochemistry, the EMT-related biomarkers expression was measured in 193 RC patients. Of which, 74 patients were assigned to the training set to select the robust variables for designing SVM model. The SVM model predictive value was validated in the testing set (119 patients). RESULTS: In training set, eight variables, including six EMT-related biomarkers and two clinicopathological variables, were selected to devise SVM model. In testing set, we identified 63 patients with high risk to RLNM and 56 patients with low risk. The sensitivity, specificity and overall accuracy of SVM in predicting RLNM were 68.3%, 81.1% and 72.3%, respectively. Importantly, multivariate logistic regression analysis showed that SVM model was indeed an independent predictor of RLNM status (odds ratio, 11.536; 95% confidence interval, 4.113-32.361; P<0.0001). CONCLUSION: Our SVM-based model displayed moderately strong predictive power in defining the RLNM status in RC patients, providing an important approach to select RLNM high-risk subgroup for neoadjuvant chemoradiotherapy. PMID- 22538977 TI - Interspecific competition models derived from competition among individuals. AB - This paper demonstrates how discrete-time models describing population dynamics of two competing species can be derived in a bottom-up manner by considering competition for resources among individuals and the spatial distribution of individuals. The competition type of each species is assumed to be either scramble, contest, or an intermediate between them. Individuals of two species are distributed over resource sites or patches following one of three distribution functions. According to the combination of competition types of the two species and the distribution of individuals, various interspecific competition models are derived. Furthermore, a general interspecific competition model that includes various competition models as special cases is derived for each distribution of individuals. Finally, this paper examines dynamics of some of the derived competition models and shows that the likelihood of coexistence of the two species varies greatly, depending on the type of spatial distribution of individuals. PMID- 22538978 TI - Combining perturbations and parameter variation to influence mean first passage times. AB - Perturbations are relatively large shocks to state variables that can drive transitions between stable states, while drift in parameter values gradually alters equilibrium magnitudes. This latter effect can lead to equilibrium bifurcation, the generation, or annihilation of equilibria. Equilibrium annihilations reduce the number of equilibria and so are associated with catastrophic population collapse. We study the combination of perturbations and parameter drift, using a two-species intraguild predation (IGP) model. For example, we use bifurcation analysis to understand how parameter drift affects equilibrium number, showing that both competition and predation rates in this model are bifurcating parameters. We then introduce a stochastic process to model the effects of population perturbations. We demonstrate how to evaluate the joint effects of perturbations and drift using the common currency of mean first passage time to transitions between stable states. Our methods and results are quite general, and for example, can relate to issues in both pest control and sustainable harvest. Our results show that parameter drift (1) does not importantly change the expected time to reach target points within a basin of attraction, but (2) can dramatically change the expected time to shift between basins of attraction, through its effects on equilibrium resilience. PMID- 22538980 TI - Fixed node diffusion Monte Carlo using a genetic algorithm: a study of the CO (4)He(N) complex, N = 1...10. AB - The diffusion Monte Carlo (DMC) method is a widely used algorithm for computing both ground and excited states of many-particle systems; for states without nodes the algorithm is numerically exact. In the presence of nodes approximations must be introduced, for example, the fixed-node approximation. Recently we have developed a genetic algorithm (GA) based approach which allows the computation of nodal surfaces on-the-fly [Ramilowski and Farrelly, Phys. Chem. Chem. Phys., 2010, 12, 12450]. Here GA-DMC is applied to the computation of rovibrational states of CO-(4)He(N) complexes with N<= 10. These complexes have been the subject of recent high resolution microwave and millimeter-wave studies which traced the onset of microscopic superfluidity in a doped (4)He droplet, one atom at a time, up to N = 10 [Surin et al., Phys. Rev. Lett., 2008, 101, 233401; Raston et al., Phys. Chem. Chem. Phys., 2010, 12, 8260]. The frequencies of the a type (microwave) series, which correlate with end-over-end rotation in the CO (4)He dimer, decrease from N = 1 to 3 and then smoothly increase. This signifies the transition from a molecular complex to a quantum solvated system. The frequencies of the b-type (millimeter-wave) series, which evolves from free rotation of the rigid CO molecule, initially increase from N = 0 to N~ 6 before starting to decrease with increasing N. An interesting feature of the b-type series, originally observed in the high resolution infra-red (IR) experiments of Tang and McKellar [J. Chem. Phys., 2003, 119, 754] is that, for N = 7, two lines are observed. The GA-DMC algorithm is found to be in good agreement with experimental results and possibly detects the small (~0.7 cm(-1)) splitting in the b-series line at N = 7. Advantages and disadvantages of GA-DMC are discussed. PMID- 22538979 TI - Metabolic adaptation to chronic hypoxia in cardiac mitochondria. AB - Chronic hypoxia decreases cardiomyocyte respiration, yet the mitochondrial mechanisms remain largely unknown. We investigated the mitochondrial metabolic pathways and enzymes that were decreased following in vivo hypoxia, and questioned whether hypoxic adaptation was protective for the mitochondria. Wistar rats were housed in hypoxia (7 days acclimatisation and 14 days at 11% oxygen), while control rats were housed in normoxia. Chronic exposure to physiological hypoxia increased haematocrit and cardiac vascular endothelial growth factor, in the absence of weight loss and changes in cardiac mass. In both subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria isolated from hypoxic hearts, state 3 respiration rates with fatty acid were decreased by 17-18%, and with pyruvate were decreased by 29-15%, respectively. State 3 respiration rates with electron transport chain (ETC) substrates were decreased only in hypoxic SSM, not in hypoxic IFM. SSM from hypoxic hearts had decreased activities of ETC complexes I, II and IV, which were associated with decreased reactive oxygen species generation and protection against mitochondrial permeability transition pore (MPTP) opening. In contrast, IFM from hypoxic hearts had decreased activity of the Krebs cycle enzyme, aconitase, which did not modify ROS production or MPTP opening. In conclusion, cardiac mitochondrial respiration was decreased following chronic hypoxia, associated with downregulation of different pathways in the two mitochondrial populations, determined by their subcellular location. Hypoxic adaptation was not deleterious for the mitochondria, in fact, SSM acquired increased protection against oxidative damage under the oxygen-limited conditions. PMID- 22538981 TI - Phytochemical investigation of Bidens biternata (Lour.) Merr. and Sheriff.--a nutrient-rich leafy vegetable from Western Ghats of India. AB - Bidens biternata, belonging to the family Asteraceae, is an erect annual herb, up to 1 cm in height, and a widespread weed of cultivated areas. This plant is common, particularly in the Western Ghats regions of Kerala state in India. It is used as a leafy vegetable by the Paniya and Kattunaayika tribes of Waynadu Districts in Kerala and also to cure hepatitis, cold, cough, dysentery, etc. The multiplication and utilization of this leafy vegetable will help to overcome the nutritional deficiency problem and also to maintain the biodiversity. For effective biochemical analysis, plant extract was taken using different solvents. Various phytochemicals like reducing sugar, glycosides, flavonoids, alkaloids, tannins, steroids, terpenoids, coumarins, saponins, anthraquinones, phlobatannins and iridoids were estimated. Different nutritional factors like total carbohydrates, total proteins, total reducing sugar, different amino acids, free fatty acids, crude fibre, lipids, total moisture content, vitamins, etc. were tested by standard estimation methods. Anti-nutritional factors like phytic acid, total phenol, tannic acid, etc., were also estimated. Micronutrients and different pigments were quantified. The present studies revealed that this wild leafy plant has numerous nutritional factors with a low level of anti-nutritional factors. Therefore, this nutritive herb with diverse health-promoting compounds can be effectively utilized to overcome the nutritional deficiency problem around the globe. PMID- 22538983 TI - A simplified filter paper assay method of cellulase enzymes based on HPLC analysis. AB - A simplified filter paper assay (FPA) method of cellulase enzymes was proposed based on high-performance liquid chromatography (HPLC) measurement. The method was according to the sum of glucose and cellobiose concentrations measured by HPLC that was able to be correlated with filter paper units (FPU) of the cellulase enzymes assayed by the traditional FPA method, regardless of the differences in the sources, activities, and components of the cellulases. This simple and quick assay method for the cellulase enzymes provided another parameter of the ratio of glucose to cellobiose (G/C ratio) representing the capacity of cellulase enzymes degrading cellulose into fermentable monomeric sugars. PMID- 22538982 TI - Novel fungal pelletization-assisted technology for algae harvesting and wastewater treatment. AB - A novel fungi pelletization-assisted bioflocculation technology was developed for efficient algae harvesting and wastewater treatment. Microalga Chlorella vulgaris UMN235 and two locally isolated fungal species Aspergillus sp. UMN F01 and UMN F02 were used to study the effect of various cultural conditions on pelletization process for fungi-algae complex. The results showed that pH was the key factor affecting formation of fungi-algae pellet, and pH could be controlled by adjusting glucose concentration and fungal spore number added. The best pelletization happened when adding 20 g/L glucose and approximately 1.2E8/L spores in BG-11 medium, under which almost 100% of algal cells were captured onto the pellets with shorter retention time. The fungi-algae pellets can be easily harvested by simple filtration due to its large size (2-5 mm). The filtered fungi algae pellets were reused as immobilized cells for treatment wastewaters and the nutrient removal rates of 100, 58.85, 89.83, and 62.53 % (for centrate) and 23.23, 44.68, 84.70, and 70.34% (for diluted swine manure wastewater) for ammonium, total nitrogen, total phosphorus, and chemical oxygen demand, respectively, under both 1- and 2-day cultivations. The novel technology developed is highly promising compared with current algae harvesting and biological wastewater treatment technologies in the literature. PMID- 22538984 TI - Reactive extraction of citric acid using tri-n-octylamine in nontoxic natural diluents: part 1--equilibrium studies from aqueous solutions. AB - Use of cheap, nontoxic, and selective solvents could economically provide a solution to the recovery of carboxylic acids produced by the bioroute. In this regard in the present paper, reactive extraction of citric acid was studied. Problems encompassing the recovery of the acid ([H(3)A](aq)(o) = 0.1-0.8) was solved by using tertiary amine (tri-n-octylamine, TOA) in natural diluents (rice bran oil, sunflower oil, soybean oil, and sesame oil). TOA was very effective in removal of acid providing distribution coefficient (D) as high as 18.51 (E% = 95%), 12.82 (E% = 93%), 15.09 (E% = 94%), and 16.28 (E% = 94%) when used with rice bran oil, sunflower oil, soybean oil, and sesame oil, respectively. Overall extraction constants and association numbers for TOA + rice bran oil, TOA + sunflower oil, TOA + soybean oil, and TOA + sesame oil were evaluated to be 35.48 (mol/l)(-1.46), 29.79 (mol/l)(-1.30), 33.79 (mol/l)(-1.51), and 37.64 (mol/l)( 1.65) and 1.46, 1.30, 1.51, and 1.65, respectively. Specific equilibrium complexation constants (K (E(n/m))) were also predicted using mathematical modeling. PMID- 22538985 TI - Effect of gamma irradiation on mechanical properties of human cortical bone: influence of different processing methods. AB - The secondary sterilisation by irradiation reduces the risk of infectious disease transmission with tissue allografts. Achieving sterility of bone tissue grafts compromises its biomechanical properties. There are several factors, including dose and temperature of irradiation, as well as processing conditions, that may influence mechanical properties of a bone graft. The purpose of this study was to evaluate the effect of gamma irradiation with doses of 25 or 35 kGy, performed on dry ice or at ambient temperature, on mechanical properties of non-defatted or defatted compact bone grafts. Left and right femurs from six male cadaveric donors aged from 46 to 54 years, were transversely cut into slices of 10 mm height, parallel to the longitudinal axis of the bone. Compact bone rings were assigned to the eight experimental groups according to the different processing method (defatted or non-defatted), as well as gamma irradiation dose (25 or 35 kGy) and temperature conditions of irradiation (ambient temperature or dry ice). Axial compression testing was performed with a material testing machine. Results obtained for elastic and plastic regions of stress-strain curves examined by univariate analysis are described. Based on multivariate analysis it was found that defatting of bone rings had no significant effect on any mechanical parameter studied, whereas irradiation with both doses decreased significantly the ultimate strain and its derivative toughness. The elastic limit and resilience were significantly increased by irradiation with the dose 25 kGy, but not 35 kGy, when the time of irradiation was longer. Additionally, irradiation at ambient temperature decreased maximum load, elastic limit, resilience, and ultimate stress. As strain in the elastic region was not affected, decreased elastic limit resulted in lower resilience. The opposite phenomenon was observed in the plastic region, where in spite of the lower ultimate stress, the toughness was increased due to the increase in the ultimate strain. The results of our study suggest that there may be an association between mechanical properties of bone tissue grafts and the damage process of collagen structure during gamma irradiation. This collagen damage in cortical bone allografts containing water does not depends on the temperature of irradiation or defatting during processing if dose of gamma irradiation does not exceed 35 kGy. PMID- 22538986 TI - Homograft banking in Singapore: two years of cardiovascular tissue banking in Southeast Asia. AB - Established in 2008, the National Cardiovascular Homograft Bank (NCHB) has been instrumental in creating an available supply of cardiovascular tissues for implantation in Singapore. This article introduces its collaboration with Singapore General Hospital Skin Bank Unit. The procedure of homograft recovery, processing, cryopreservation and quality assurance are presented. Since its establishment, the NCHB has followed the guidelines set by the Ministry of Health Singapore and the American Association of Tissue Banks. A total of 57 homografts had been recovered and 40 homografts were determined to be suitable for clinical use. The most significant reasons for non-clinical use are positive microbiological culture or unsuitable graft condition. Crucial findings prompted reviews and implementation of new procedures to improve the safety of homograft recipients. These include (1) a change in antibiotic decontamination regime from penicillin and streptomycin to amikacin and vancomycin after a review and (2) mandating histopathogical examination since the discovery of cardiac sarcoidosis in a previously undiagnosed donor. Further, the NCHB also routinely performs dengue virus screening, for donors suspected of dengue infection. Cultural factors which affect the donation rate are also briefly explored. By 2010, 31 homografts had been implanted into recipients with congenital or acquired heart valve conditions. More than half of these recipients were children. Post operative outcomes had been encouraging, with no report of adverse events attributed to implanted homografts. PMID- 22538992 TI - Conjugated polymer-silicon nanowire array hybrid Schottky diode for solar cell application. AB - The hybrid Schottky diode based on silicon nanowire arrays (SiNWs) and poly(3,4 ethylenedioxythiophene)/poly(styrenesulfonate) (PEDOT:PSS) has been fabricated for high performance solar cells. The length of SiNWs on a silicon substrate, which is prepared by metal-assisted chemical etching, can be tuned by adjusting the length of the etching time. In addition, the average distances between the adjacent silicon nanowires can be controlled by changing the immersing time in a saturated PCl(5) solution. The hybrid devices are made from the SiNWs with different wire lengths and various distances between adjacent wires by spin casting PEDOT:PSS on the silicon substrates. It is found that the length and density play leading roles in the electric output characteristics. The device made from SiNWs with optimum morphology can achieve a power conversion efficiency of 7.3%, which is much improved in comparison with that of the planar one. The measurement of the transient photovoltage decay and the analysis of the current versus voltage curve indicate that the charge recombination process is a dominant factor on the device performance. PMID- 22538993 TI - Glycated albumin in patients with neonatal diabetes mellitus is apparently low in relation to glycemia compared with that in patients with type 1 diabetes mellitus. AB - BACKGROUND: Although glycated albumin (GA) is a useful glycemic control marker in neonatal diabetes mellitus (NDM), there has been no report comparing GA levels between NDM patients and non-diabetic infants. Moreover, GA in NDM patients may be apparently low in relation to glycemia due to the assumed elevation of albumin metabolism in neonates. METHODS: We compared GA levels between 6 patients with NDM and 18 non-diabetic infants or 14 patients with type 1 diabetes mellitus (T1DM). Mean blood glucose (MBG) was calculated on the basis of self-monitoring of blood glucose for 1 month before GA measurement. RESULTS: GA in NDM patients was significantly higher than that in non-diabetic infants (22.0 +/- 5.8 vs. 10.2 +/- 1.4%; p < 0.0001), and GA levels significantly correlated with MBG in both NDM and T1DM patients. However, GA in NDM patients was significantly lower than in T1DM patients (25.8 +/- 5.3%; p = 0.0046), whereas MBG in NDM patients was significantly higher than in T1DM patients (233 +/- 79 vs. 183 +/- 41 mg/dl; p = 0.0006). CONCLUSION: GA levels in NDM patients were apparently low in relation to glycemia. Therefore, reference values for infants should be used for assessing the GA level in NDM. PMID- 22538994 TI - Macrolide and tetracycline resistance in clinical strains of Streptococcus agalactiae isolated in Tunisia. AB - Between 2007 and 2009, 226 clinical strains of Streptococcus agalactiae, recovered from female genital specimens and from gastric fluid or ear specimens from infected newborns, were isolated at the Laboratory of Microbiology of Charles Nicolle Hospital of Tunis. They were investigated to determine the prevalence of antibiotic resistance and to characterize the mechanisms of resistance to macrolide and tetracycline. All strains were susceptible to penicillin, ampicillin and quinupristin-dalfopristin. They were resistant to chloramphenicol (3.1%), rifampicin (19.1%), erythromycin (40%) and tetracycline (97.3%); 3.1% were highly resistant to streptomycin and 1.3% to gentamicin. Among the erythromycin-resistant isolates, 78.7% showed a constitutive macrolide lincosamide-streptogramin B (MLS(B)) phenotype with high-level resistance to macrolides and clindamycin (MIC(50) >256 ug ml(-1)), 10% showed an inducible MLS(B) phenotype with high MICs of macrolides (MIC(50) >256 ug ml(-1)) and low MICs of clindamycin (MIC(50)=8 ug ml(-1)) and 2.2% showed an M phenotype with a low erythromycin-resistance level (MIC range=12-32 ug ml(-1)) and low MICs of clindamycin (MIC range: 0.75-1 ug ml(-1)). All strains were susceptible to quinupristin-dalfopristin and linezolid (MIC(90): 0.75 ug ml(-1) for each). MLS(B) phenotypes were genotypically confirmed by the presence of the erm(B) gene and the M phenotype by the mef(A) gene. Resistance to tetracycline was mainly due to the tet(M) gene (93.1%) encoding a ribosome protection mechanism. This determinant is commonly associated with the conjugative transposon Tn916 (P<=0.0002). tet(O) and tet(T) existed in a minority (2.2% and 0.4%, respectively). The efflux mechanism presented by tet(L) was less frequently present (4.5%). No significant association was found between erm(B) and tet(M) genes. PMID- 22538995 TI - Vaccines and adjuvants--special issue. PMID- 22538996 TI - Comparison of genetic epidemiology of vancomycin-resistant Enterococcus faecium isolates from humans and poultry. AB - This study was conducted to investigate the molecular characteristics and genetic relatedness of vancomycin-resistant Enterococcus faecium (VREF) isolates obtained from humans and poultry in Korea. A total of 147 VREF isolates from humans (71 clinical isolates) and poultry (76 isolates) in Korea were compared with respect to their antibiotic susceptibilities, organization of the Tn1546 transposon element, detection of virulence genes (esp and hyl), pulsed-field gel electrophoresis (PFGE) typing and multilocus sequence typing (MLST). All of the human and poultry isolates had the vanA gene and 11.3% (8/71) of the clinical isolates showed the VanB phenotype/vanA genotype. PCR mapping of the Tn1546 elements was different for isolates of the two groups: human isolates were classified into five transposon types, whereas all poultry isolates were identical to Tn1546 of E. faecium strain BM4147. The esp gene was detected in both human (93.0%, 66/71) and poultry (26.3%, 20/76) isolates, as was the hyl gene (human isolates: 80.3%, 57/71; poultry isolates: 26.3%, 20/76). Using MLST, the 71 human isolates could be divided into ten sequence types (STs) belonging to clonal complex (CC) 17 (except for one singleton). The 76 poultry isolates were categorized into 14 STs and 88.2% (67/76) of the poultry isolates belonged to CC26. PFGE typing of the human isolates demonstrated diverse PFGE profiles among the strains. However, the PFGE patterns of the poultry isolates were possibly related to the strains collected from individual farms. These data suggest that epidemic clonal groups of human and poultry VREFs in Korea have evolved through different evolutionary processes. PMID- 22538997 TI - Usefulness of 16S rDNA sequencing for the diagnosis of infective endocarditis caused by Corynebacterium diphtheriae. AB - We report a rare case of infective endocarditis caused by Corynebacterium diphtheriae in an 8-year-old boy, 2 years after a right ventricular outflow tract reconstruction with a bovine Contegra valved conduit. The patient recovered well after an RV-PA conduit enblock explantation and replacement with an aortic homograft with antibiotic treatment. All bacteriological cultures of excised tissue and blood were negative. The aetiological agent was identified as C. diphtheriae subsp. gravis by 16s rDNA sequencing. PMID- 22538991 TI - Regulation of eukaryotic gene expression by the untranslated gene regions and other non-coding elements. AB - There is now compelling evidence that the complexity of higher organisms correlates with the relative amount of non-coding RNA rather than the number of protein-coding genes. Previously dismissed as "junk DNA", it is the non-coding regions of the genome that are responsible for regulation, facilitating complex temporal and spatial gene expression through the combinatorial effect of numerous mechanisms and interactions working together to fine-tune gene expression. The major regions involved in regulation of a particular gene are the 5' and 3' untranslated regions and introns. In addition, pervasive transcription of complex genomes produces a variety of non-coding transcripts that interact with these regions and contribute to regulation. This review discusses recent insights into the regulatory roles of the untranslated gene regions and non-coding RNAs in the control of complex gene expression, as well as the implications of this in terms of organism complexity and evolution. PMID- 22538998 TI - Microsatellite analysis of Candida isolates from recurrent vulvovaginal candidiasis. AB - Candida albicans and Candida glabrata are the most common causative agents of both vulvovaginal candidiasis (VVC) and recurrent vulvovaginal candidiasis (RVVC). Studying the population structure and genotype differentiation of Candida species that cause RVVC may lead to a significant improvement in clinical management. A total of 106 isolates were collected from 55 patients who were subdivided into three groups. Group I comprised 15 patients with RVVC (n=50 isolates); group II comprised 16 patients, who had a history of at least two episodes of VVC in the last year (n=32 isolates, two from each patient); and group III comprised 24 patients (n=24 isolates) who had experienced a single episode of VVC in the previous 1 year period. C. albicans microsatellite markers CAI, CAIII and CAIV and C. glabrata RPM2, MTI and ERG3 microsatellites were amplified in a multiplex PCR. All isolates were subjected to population genetic analysis, which provided evidence that there is a predominantly clonal population structure of C. albicans in each group. However, recombination was detected to some degree in C. albicans isolates in group III. A genetic homogeneity between the different C. albicans groups was observed. Although, C. glabrata isolates showed an important genetic differentiation between group I and group III (F(ST)=0.207). Genotype analysis revealed that the dominant genotypes of C. glabrata and C. albicans strains were more prevalent in patients with RVVC. The frequent scenario for cases of recurrent infection in our study was strain replacement (53.3%). In conclusion, the identification of recurrence-associated genotypes and a specific C. glabrata population structure in the RVVC group could be a significant marker for further investigations of virulence factors and RVVC management. PMID- 22538999 TI - Isolation and characterization of a novel recombinant human adenovirus species D. AB - A novel recombinant human adenovirus (HAdV) species D was isolated from the stool of a pharyngitis patient in Japan and genetic characterization was performed by sequencing variable regions between HAdV types. The nucleotide sequences of the penton base gene and loops 1 and 2 in the hexon gene showed 100% identity with that of the recently identified HAdV-56. Although we observed greatest identity for the entire hexon gene sequence with that of HAdV-56, we noted even greater similarity between the partial nucleotide sequence of the conserved region 4 and that of HAdV-37. Furthermore, the fibre gene and early region 3 sequences were completely identical to that of HAdV-37. These results suggest that the strain is a novel adenovirus related to HAdV-37 and HAdV-56. PMID- 22539000 TI - Characteristics of Lactobacillus and Gardnerella vaginalis from women with or without bacterial vaginosis and their relationships in gnotobiotic mice. AB - The objectives of the present study were to evaluate in vitro the production of antagonistic compounds against Gardnerella vaginalis by Lactobacillus strains isolated from women with or without bacterial vaginosis (BV), and to select one of the better Lactobacillus producers of such a substance to be tested in vivo using a gnotobiotic animal model challenged with one of the more sensitive G. vaginalis isolates. A total of 24 isolates from women with and without BV were identified as G. vaginalis. A higher frequency (P<0.05) of this bacterium was observed in women with BV (56.7%) when compared to healthy women (17.6%). A total of 86 strains of Lactobacillus were obtained from healthy women and women with BV. Lactobacillus strains were more frequently present (P<0.05) in healthy women (97.5%) than in women with BV (76.7%). Lactobacillus crispatus was the predominating strain in both healthy women and women with BV. Lactobacillus jensenii, Lactobacillus johnsonii, Lactobacillus gasseri and Lactobacillus vaginalis were isolated with an intermediate frequency in the two groups. In vitro antagonism assays were performed using as indicators 17 reference strains and the G. vaginalis strains isolated from women with BV and from healthy women. Lactobacillus isolated from healthy women showed the higher antagonistic activity against all the indicator strains when compared with isolates from women with BV. Concerning the indicator strains, G. vaginalis found in women with BV was more resistant to the antagonism, particularly when Lactobacillus isolates from women with BV were used as producer strains. A high vaginal population level of G. vaginalis was obtained by intravaginal inoculation of germ-free mice, and this colonization was accompanied by vaginal histopathological lesions. A tenfold decrease in vaginal population level of G. vaginalis and a reduction of histological lesions were observed when the pathogenic challenge was performed in mice previously monoassociated with an L. johnsonii strain. Concluding, results of the present study suggest that progression of G. vaginalis-associated BV depends in part on a simultaneous presence of Lactobacillus populations with a low antagonistic capacity and of a G. vaginalis strain with a high resistance to this antagonism. The results could also explain why G. vaginalis is frequently found in the vaginal ecosystem of healthy women. PMID- 22539001 TI - Room temperature synthesis of hydrophilic Ln(3+)-doped KGdF4 (Ln = Ce, Eu, Tb, Dy) nanoparticles with controllable size: energy transfer, size-dependent and color-tunable luminescence properties. AB - In this paper, we demonstrate a simple, template-free, reproducible and one-step synthesis of hydrophilic KGdF(4): Ln(3+) (Ln = Ce, Eu, Tb and Dy) nanoparticles (NPs) via a solution-based route at room temperature. X-Ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR), photoluminescence (PL) and cathodoluminescence (CL) spectra are used to characterize the samples. The results indicate that the use of water-diethyleneglycol (DEG) solvent mixture as the reaction medium not only allows facile particle size control but also endows the as-prepared samples with good water-solubility. In particular, the mean size of NPs is monotonously reduced with the increase of DEG content, from 215 to 40 nm. The luminescence intensity and absolute quantum yields for KGdF(4): Ce(3+), Tb(3+) NPs increase remarkably with particle sizes ranging from 40 to 215 nm. Additionally, we systematically investigate the magnetic and luminescence properties of KGdF(4): Ln(3+) (Ln = Ce, Eu, Tb and Dy) NPs. They display paramagnetic and superparamagnetic properties with mass magnetic susceptibility values of 1.03 * 10(-4) emu g(-1).Oe and 3.09 * 10(-3) emu g(-1).Oe at 300 K and 2 K, respectively, and multicolor emissions due to the energy transfer (ET) process Ce(3+)-> Gd(3+)-> (Gd(3+))(n)-> Ln(3+), in which Gd(3+) ions play an intermediate role in this process. Representatively, it is shown that the energy transfer from Ce(3+) to Tb(3+) occurs mainly via the dipole-quadrupole interaction by comparison of the theoretical calculation and experimental results. This kind of magnetic/luminescent dual-function materials may have promising applications in multiple biolabels and MR imaging. PMID- 22539002 TI - Two-factor reprogramming of somatic cells to pluripotent stem cells reveals partial functional redundancy of Sox2 and Klf4. AB - Ectopic expression of defined sets of transcription factors in somatic cells enables them to adopt the qualities of pluripotency. Mouse embryonic fibroblasts (MEFs) are the classic target cell used to elucidate the core principles of nuclear reprogramming. However, their phenotypic and functional heterogeneity represents a major hurdle for mechanistic studies aimed at defining the molecular nature of cellular plasticity. We show that reducing the complexity of MEFs by flow cytometry allows the isolation of discrete cell subpopulations that can be efficiently reprogrammed to pluripotency with fewer genes. Using these FACS sorted cells, we performed a systematic side-by-side analysis of the reprogramming efficiency with different two- and three-factor combinations of Oct4, Sox2 and Klf4. We show that introduction of exogenous Oct4 with either Sox2 or Klf4 does not directly convert MEFs to a pluripotent state. Instead, each combination of factors disrupts the normal cellular homeostasis and establishes transient states characterized by the concurrent expression of mixed lineage markers. These cells convert into induced pluripotent stem cells in a stochastic fashion. Our data suggest that there is a partial functional redundancy between Sox2 and Klf4 in the disruption of cellular homeostasis and activation of regulatory networks that define pluripotency. PMID- 22539003 TI - A BMP7 variant inhibits the tumorigenic potential of glioblastoma stem-like cells. AB - Glioblastoma multiforme (GBM) is among the most aggressive tumor types and is essentially an incurable malignancy characterized by resistance to chemo-, radio , and immunotherapy. GBM is maintained by a hierarchical cell organization that includes stem-like, precursor, and differentiated cells. Recurrence and maintenance of the tumor is attributed to a small population of undifferentiated tumor-initiating cells, defined as glioblastoma stem-like cells (GSLCs). This cellular hierarchy offers a potential treatment to induce differentiation of GSLCs away from tumor initiation to a more benign phenotype or to a cell type more amenable to standard therapies. Bone morphogenetic proteins (BMPs), members of the TGF-beta superfamily, have numerous biological activities including control of growth and differentiation. In vitro, a BMP7 variant (BMP7v) decreased primary human GSLC proliferation, endothelial cord formation, and stem cell marker expression while enhancing neuronal and astrocyte differentiation marker expression. In subcutaneous and orthotopic GSLC xenografts, which closely reproduce the human disease, BMP7v decreased tumor growth and stem cell marker expression, while enhancing astrocyte and neuronal differentiation compared with control mice. In addition, BMP7v reduced brain invasion, angiogenesis, and associated mortality in the orthotopic model. Inducing differentiation of GSLCs and inhibiting angiogenesis with BMP7v provides a potentially powerful and novel approach to the treatment of GBM. PMID- 22539004 TI - Two-step activation of FOXO3 by AMPK generates a coherent feed-forward loop determining excitotoxic cell fate. AB - Cerebral ischemia and excitotoxic injury induce transient or permanent bioenergetic failure, and may result in neuronal apoptosis or necrosis. We have previously shown that ATP depletion and activation of AMP-activated protein kinase (AMPK) during excitotoxic injury induces neuronal apoptosis by transcription of the pro-apoptotic BH3-only protein, Bim. AMPK, however, also exerts pro-survival functions in neurons. The molecular switches that determine these differential outcomes are not well understood. Using an approach combining biochemistry, single-cell imaging and computational modeling, we here demonstrate that excitotoxic injury activated the bim promoter in a FOXO3-dependent manner. The activation of AMPK reduced AKT activation, and led to dephosphorylation and nuclear translocation of FOXO3. Subsequent mutation studies indicated that bim gene activation during excitotoxic injury required direct FOXO3 phosphorylation by AMPK in the nucleus as a second activation step. Inhibition of this phosphorylation prevented Bim expression and protected neurons against excitotoxic and oxygen/glucose deprivation-induced injury. Systems analysis and computational modeling revealed that these two activation steps defined a coherent feed-forward loop; a network motif capable of filtering any effects of short-term AMPK activation on bim gene induction. This may prevent unwanted AMPK mediated Bim expression and apoptosis during transient or physiological bioenergetic stress. PMID- 22539005 TI - Effectors of alcohol-induced cell killing in Drosophila. AB - Heavy alcohol consumption provokes an array of degenerative pathologies but the signals that couple alcohol exposure to regulated forms of cell death are poorly understood. Using Drosophila as a model, we genetically establish that the severity of ethanol challenge dictates the type of death that occurs. In contrast to responses seen under acute exposure, cytotoxic responses to milder challenges required gene encoding components of the apoptosome, Dronc and Dark. We conducted a genome-wide RNAi screen to capture targets that specifically mediate ethanol induced cell death. One effector, Drat, encodes a novel protein that contains an ADH domain but lacks essential residues in the catalytic site. In cultured cells and neurons in vivo, depletion of Drat conferred protection from alcohol-induced apoptosis. Adults mutated for Drat showed both improved survival and enhanced propensities toward sedation after alcohol challenge. Together, these findings highlight novel effectors that support regulated cell death incited by alcohol stress in vitro and in vivo. PMID- 22539007 TI - A multi-GPU real-time dose simulation software framework for lung radiotherapy. AB - PURPOSE: Medical simulation frameworks facilitate both the preoperative and postoperative analysis of the patient's pathophysical condition. Of particular importance is the simulation of radiation dose delivery for real-time radiotherapy monitoring and retrospective analyses of the patient's treatment. METHODS: In this paper, a software framework tailored for the development of simulation-based real-time radiation dose monitoring medical applications is discussed. A multi-GPU-based computational framework coupled with inter-process communication methods is introduced for simulating the radiation dose delivery on a deformable 3D volumetric lung model and its real-time visualization. The model deformation and the corresponding dose calculation are allocated among the GPUs in a task-specific manner and is performed in a pipelined manner. Radiation dose calculations are computed on two different GPU hardware architectures. The integration of this computational framework with a front-end software layer and back-end patient database repository is also discussed. RESULTS: Real-time simulation of the dose delivered is achieved at once every 120 ms using the proposed framework. With a linear increase in the number of GPU cores, the computational time of the simulation was linearly decreased. The inter-process communication time also improved with an increase in the hardware memory. Variations in the delivered dose and computational speedup for variations in the data dimensions are investigated using D70 and D90 as well as gEUD as metrics for a set of 14 patients. Computational speed-up increased with an increase in the beam dimensions when compared with a CPU-based commercial software while the error in the dose calculation was <1%. CONCLUSION: Our analyses show that the framework applied to deformable lung model-based radiotherapy is an effective tool for performing both real-time and retrospective analyses. PMID- 22539006 TI - (G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD. AB - (G2019S) mutation of leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause of both familial and sporadic Parkinson's disease (PD) cases. Twelve- to sixteen-month-old (G2019S) LRRK2 transgenic mice prepared by us displayed progressive degeneration of substantia nigra pars compacta (SNpc) dopaminergic neurons and parkinsonism phenotypes of motor dysfunction. LRRK2 is a member of mixed lineage kinase subfamily of mitogen-activated protein kinase kinase kinases (MAPKKKs). We hypothesized that (G2019S) mutation augmented LRRK2 kinase activity, leading to overphosphorylation of downstream MAPK kinase (MKK) and resulting in activation of neuronal death signal pathway. Consistent with our hypothesis, (G2019S) LRRK2 expressed in HEK 293 cells exhibited an augmented kinase activity of phosphorylating MAPK kinase 4 (MKK4) at Ser(257), and protein expression of active phospho-MKK4(Ser257) was upregulated in the SN of (G2019S) LRRK2 transgenic mice. Protein level of active phospho-JNK(Thr183/Tyr185) and phospho-c-Jun(Ser63), downstream targets of phospho-MKK4(Ser257), was increased in the SN of (G2019S) LRRK2 mice. Upregulated mRNA expression of pro-apoptotic Bim and FasL, target genes of phospho-c-Jun(Ser63), and formation of active caspase-9, caspase-8 and caspase-3 were also observed in the SN of (G2019S) LRRK2 transgenic mice. Our results suggest that mutant (G2019S) LRRK2 activates MKK4 JNK-c-Jun pathway in the SN and causes the resulting degeneration of SNpc dopaminergic neurons in PD transgenic mice. PMID- 22539008 TI - An on-board surgical tracking and video augmentation system for C-arm image guidance. AB - PURPOSE: Conventional tracker configurations for surgical navigation carry a variety of limitations, including limited geometric accuracy, line-of-sight obstruction, and mismatch of the view angle with the surgeon's-eye view. This paper presents the development and characterization of a novel tracker configuration (referred to as "Tracker-on-C") intended to address such limitations by incorporating the tracker directly on the gantry of a mobile C-arm for fluoroscopy and cone-beam CT (CBCT). METHODS: A video-based tracker (MicronTracker, Claron Technology Inc., Toronto, ON, Canada) was mounted on the gantry of a prototype mobile isocentric C-arm next to the flat-panel detector. To maintain registration within a dynamically moving reference frame (due to rotation of the C-arm), a reference marker consisting of 6 faces (referred to as a "hex-face marker") was developed to give visibility across the full range of C arm rotation. Three primary functionalities were investigated: surgical tracking, generation of digitally reconstructed radiographs (DRRs) from the perspective of a tracked tool or the current C-arm angle, and augmentation of the tracker video scene with image, DRR, and planning data. Target registration error (TRE) was measured in comparison with the same tracker implemented in a conventional in room configuration. Graphics processing unit (GPU)-accelerated DRRs were generated in real time as an assistant to C-arm positioning (i.e., positioning the C-arm such that target anatomy is in the field-of-view (FOV)), radiographic search (i.e., a virtual X-ray projection preview of target anatomy without X-ray exposure), and localization (i.e., visualizing the location of the surgical target or planning data). Video augmentation included superimposing tracker data, the X-ray FOV, DRRs, planning data, preoperative images, and/or intraoperative CBCT onto the video scene. Geometric accuracy was quantitatively evaluated in each case, and qualitative assessment of clinical feasibility was analyzed by an experienced and fellowship-trained orthopedic spine surgeon within a clinically realistic surgical setup of the Tracker-on-C. RESULTS: The Tracker-on-C configuration demonstrated improved TRE (0.87 +/- 0.25) mm in comparison with a conventional in-room tracker setup (1.92 +/- 0.71) mm (p < 0.0001) attributed primarily to improved depth resolution of the stereoscopic camera placed closer to the surgical field. The hex-face reference marker maintained registration across the 180 degrees C-arm orbit (TRE = 0.70 +/- 0.32 mm). DRRs generated from the perspective of the C-arm X-ray detector demonstrated sub- mm accuracy (0.37 +/- 0.20 mm) in correspondence with the real X-ray image. Planning data and DRRs overlaid on the video scene exhibited accuracy of (0.59 +/- 0.38) pixels and (0.66 +/- 0.36) pixels, respectively. Preclinical assessment suggested potential utility of the Tracker-on-C in a spectrum of interventions, including improved line of sight, an assistant to C-arm positioning, and faster target localization, while reducing X-ray exposure time. CONCLUSIONS: The proposed tracker configuration demonstrated sub- mm TRE from the dynamic reference frame of a rotational C-arm through the use of the multi-face reference marker. Real-time DRRs and video augmentation from a natural perspective over the operating table assisted C-arm setup, simplified radiographic search and localization, and reduced fluoroscopy time. Incorporation of the proposed tracker configuration with C-arm CBCT guidance has the potential to simplify intraoperative registration, improve geometric accuracy, enhance visualization, and reduce radiation exposure. PMID- 22539009 TI - Michael Barany: a recollection. AB - In this special edition of the Journal of Muscle Research and Cell Motility, we recall the lives and scientific contributions of Michael and Kate Barany, who died in 2011. Michael and Kate were Holocaust survivors who went on to become leading researchers in muscle contraction. Their research topics included myosin isoforms, phosphorylation as a regulator of muscle contraction and the application of NMR to study muscle metabolism. They were deeply committed to science and to fostering the careers of young investigators. PMID- 22539010 TI - Early neurodevelopmental outcome of infants with high-risk fetal lung lesions. AB - OBJECTIVE: To evaluate the neurodevelopmental outcome of infants with high-risk fetal lung lesions defined as (1) requiring fetal intervention and/or ex utero intrapartum therapy (EXIT), or (2) acute respiratory decompensation postnatally necessitating emergent resection within 48 h of life. METHODS: We reviewed the medical records of 13 consecutive patients with high-risk fetal lung lesions who were enrolled in our prospective interdisciplinary follow-up program. Neurodevelopmental status was evaluated using the Bayley Scales of Infant Development-III (children <=3 years, n = 12), or the Wechsler Preschool and Primary Scale of Intelligence-III (children >=4 years, n = 1). RESULTS: Eight children (62%) underwent prenatal intervention (EXIT, n = 6; fetal resection, n = 1; intrauterine shunt placement, n = 1), and 5 (38%) required emergent resection postnatally. Median age at evaluation was 25 months (range: 5-80). Average scores for cognitive development were found in all children assessed under 3 years of age. The one child who was tested for cognitive ability at 6 years of age scored in the borderline range of intellectual functioning. For language outcome, 15% scored above average, 54% scored within the average range, and 31% had mild deficits. Overall, 77% scored within the average range for neuromotor outcome, while 23% scored within the mildly delayed range. None of the children had severe delays. Cognitive, language, and psychomotor scores were similar between both groups. Hypotonicity was found in 23%. Autism was suspected in one child who underwent an EXIT procedure and was postnatally diagnosed with mosaic trisomy 18. CONCLUSION: The majority of children with high-risk fetal lung lesions have age appropriate neurodevelopmental scores. PMID- 22539012 TI - Smoking at diagnosis and survival in cancer patients. AB - The effect of smoking on survival in cancer patients is limited by the lack of structured prospective assessments of smoking at diagnosis. To assess the effect of smoking at diagnosis on survival, structured smoking assessments were obtained in a cohort of 5,185 cancer patients within 30 days of a cancer diagnosis between 1982 and 1998. Hazard ratios (HRs) or odds ratios were generated to analyze the effects of smoking at diagnosis on overall mortality (OM) and disease-specific mortality (DSM) in a patient cohort from 13 disease sites containing at least 100 patients in each disease site. With a minimum of 12 years of follow-up, current smoking increased OM risk versus recent quit (HR 1.17), former (HR 1.29) and never smokers (HR 1.38) in the overall cohort. Current smoking increased DSM risk versus former (HR 1.23) and never smokers (HR 1.18). In disease sites with proportionately large (>20%) recent quit cohorts (lung and head/neck), current smoking increased OM and DSM risks as compared with recent quit. Current smoking increased mortality risks in lung, head/neck, prostate and leukemia in men and breast, ovary, uterus and melanoma in women. Current smoking was not associated with any survival benefit in any disease site. Data using prospective structured smoking assessments demonstrate that current smoking increased long-term OM and DSM. Standardized smoking assessment at diagnosis is an important variable for evaluating outcomes in cancer patients. PMID- 22539014 TI - Specialist multidisciplinary team working in the treatment of cancer. PMID- 22539013 TI - Effects of multidisciplinary team working on breast cancer survival: retrospective, comparative, interventional cohort study of 13 722 women. AB - OBJECTIVES: To describe the effect of multidisciplinary care on survival in women treated for breast cancer. DESIGN: Retrospective, comparative, non-randomised, interventional cohort study. SETTING: NHS hospitals, health boards in the west of Scotland, UK. PARTICIPANTS: 14,358 patients diagnosed with symptomatic invasive breast cancer between 1990 and 2000, residing in health board areas in the west of Scotland. 13,722 (95.6%) patients were eligible (excluding 16 diagnoses of inflammatory cancers and 620 diagnoses of breast cancer at death). INTERVENTION: In 1995, multidisciplinary team working was introduced in hospitals throughout one health board area (Greater Glasgow; intervention area), but not in other health board areas in the west of Scotland (non-intervention area). MAIN OUTCOME MEASURES: Breast cancer specific mortality and all cause mortality. RESULTS: Before the introduction of multidisciplinary care (analysed time period January 1990 to September 1995), breast cancer mortality was 11% higher in the intervention area than in the non-intervention area (hazard ratio adjusted for year of incidence, age at diagnosis, and deprivation, 1.11; 95% confidence interval 1.00 to 1.20). After multidisciplinary care was introduced (time period October 1995 to December 2000), breast cancer mortality was 18% lower in the intervention area than in the non-intervention area (0.82, 0.74 to 0.91). All cause mortality did not differ significantly between populations in the earlier period, but was 11% lower in the intervention area than in the non-interventional area in the later period (0.89, 0.82 to 0.97). Interrupted time series analyses showed a significant improvement in breast cancer survival in the intervention area in 1996, compared with the expected survival in the same year had the pre intervention trend continued (P=0.004). This improvement was maintained after the intervention was introduced. CONCLUSION: Introduction of multidisciplinary care was associated with improved survival and reduced variation in survival among hospitals. Further analysis of clinical audit data for multidisciplinary care could identify which aspects of care are most associated with survival benefits. PMID- 22539015 TI - Perioperative fluid therapy. PMID- 22539011 TI - Recent therapeutic strategies for spinal cord injury treatment: possible role of stem cells. AB - Spinal cord injury (SCI) often results in significant dysfunction and disability. A series of treatments have been proposed to prevent and overcome the formation of the glial scar and inhibitory factors to axon regrowth. In the last decade, cell therapy has emerged as a new tool for several diseases of the nervous system. Stem cells act as minipumps providing trophic and immunomodulatory factors to enhance axonal growth, to modulate the environment, and to reduce neuroinflammation. This capability can be boosted by genetical manipulation to deliver trophic molecules. Different types of stem cells have been tested, according to their properties and the therapeutic aims. They differ from each other for origin, developmental stage, stage of differentiation, and fate lineage. Related to this, stem cells differentiating into neurons could be used for cell replacement, even though the feasibility that stem cells after transplantation in the adult lesioned spinal cord can differentiate into neurons, integrate within neural circuits, and emit axons reaching the muscle is quite remote. The timing of cell therapy has been variable, and may be summarized in the acute and chronic phases of disease, when stem cells interact with a completely different environment. Even though further experimental studies are needed to elucidate the mechanisms of action, the therapeutic, and the side effects of cell therapy, several clinical protocols have been tested or are under trial. Here, we report the state-of-the-art of cell therapy in SCI, in terms of feasibility, outcome, and side effects. PMID- 22539016 TI - Health secretary says new commissioning board's first job will be to devolve powers to local groups. PMID- 22539018 TI - Renalase, a novel enzyme involved in blood pressure regulation, is related to kidney function but not to blood pressure in hemodialysis patients. AB - Renalase, secreted by the kidney, degrades catecholamines and may play a role in the regulation of sympathetic tone and blood pressure. The aim of this study was to assess serum renalase levels in hemodialysis patients and their relationship to blood pressure control, type of antihypertensive therapy and the presence of residual renal function. RESULTS: The mean serum renalase in the study cohort was significantly higher than in the control group (27.53 +/- 7.18 vs. 3.86 +/- 0.73 ug/ml, p < 0.001). The serum renalase concentration was significantly lower in patients with residual renal function when compared to the anuric patients. The type of hypotensive treatment (beta-blockers, ACE inhibitors or AT1 receptor blockers) did not affect renalase levels. There was a significant inverse correlation between the serum renalase and age (r = -0.28, p = 0.023) and residual renal function (r = -0.327, p = 0.001). Renalase was not related to blood pressure, heart rate or hemodialysis vintage. CONCLUSION: Elevated renalase levels in HD patients may be due to impaired kidney function. Further studies are needed to prove or disprove the possible role of renalase in the pathogenesis of hypertension in patients with kidney diseases. PMID- 22539017 TI - Neuronal sensitivity to TDP-43 overexpression is dependent on timing of induction. AB - Ubiquitin-immunoreactive neuronal inclusions composed of TAR DNA binding protein of 43 kDa (TDP-43) are a major pathological feature of frontotemporal lobar degeneration (FTLD-TDP). In vivo studies with TDP-43 knockout mice have suggested that TDP-43 plays a critical, although undefined role in development. In the current report, we generated transgenic mice that conditionally express wild-type human TDP-43 (hTDP-43) in the forebrain and established a paradigm to examine the sensitivity of neurons to TDP-43 overexpression at different developmental stages. Continuous TDP-43 expression during early neuronal development produced a complex phenotype, including aggregation of phospho-TDP-43, increased ubiquitin immunoreactivity, mitochondrial abnormalities, neurodegeneration and early lethality. In contrast, later induction of hTDP-43 in the forebrain of weaned mice prevented early death and mitochondrial abnormalities while yielding salient features of FTLD-TDP, including progressive neurodegeneration and ubiquitinated, phospho-TDP-43 neuronal cytoplasmic inclusions. These results suggest that neurons in the developing forebrain are extremely sensitive to TDP-43 overexpression and that timing of TDP-43 overexpression in transgenic mice must be considered when distinguishing normal roles of TDP-43, particularly as they relate to development, from its pathogenic role in FTLD-TDP and other TDP-43 proteinopathies. Finally, our adult induction of hTDP-43 strategy provides a mouse model that develops critical pathological features that are directly relevant for human TDP-43 proteinopathies. PMID- 22539019 TI - Zinc oxide-montmorillonite hybrid influences diarrhea, intestinal mucosal integrity, and digestive enzyme activity in weaned pigs. AB - One hundred-eighty piglets (Duroc * Landrace * Yorkshire), with an average initial weight of 7.4 kg weaned at 27 +/- 1 days of age, were used to evaluate the effects of dietary zinc oxide-montmorillonite hybrid (ZnO-MMT) on growth performance, diarrhea, intestinal mucosal integrity, and digestive enzyme activity. All pigs were allotted to five treatments and fed with the basal diets supplemented with 0, 250, 500, and 750 mg/kg of Zn as ZnO-MMT or 2,000 mg/kg of Zn as ZnO. The results showed that supplementation with 500 or 750 mg/kg of Zn from ZnO-MMT and 2,000 mg/kg of Zn from ZnO improved average daily gain, enhanced average daily feed intake, decreased fecal scores at 4, 8, and 14 days postweaning, reduced intestinal permeability which was evident from the reduced lactulose recovery and urinary lactulose/mannitol ratio, and improved the activities of protease, amylase, lipase, trypsin, and chymotrypsin both in pancreas and small intestinal contents of pigs as compared with the control. Supplemental 250 mg/kg of Zn from ZnO-MMT also decreased fecal scores at 8 and 14 days postweaning, decreased urinary lactulose/mannitol ratio, and improved chymotrypsin activity in pancreas and small intestinal contents as well as protease activity in small intestinal contents compared with control. Moreover, the above indexes of weanling pigs fed with 500 or 750 mg/kg of Zn as ZnO-MMT did not differ from those fed with 2,000 mg/kg of Zn as ZnO. The results demonstrated that supplementation with 500 or 750 mg/kg of Zn from ZnO-MMT was as efficacious as 2,000 mg/kg of Zn from ZnO in improving growth performance, alleviating postweaning diarrhea, and enhancing intestinal mucosal integrity and the digestive enzyme activities in pancreas and small intestinal contents of pigs. The results that feeding lower concentrations of ZnO-MMT to weanling pigs maintained performance will be beneficial for the environment and for sustaining swine production. PMID- 22539020 TI - Short-term effects of sibutramine on mineral status and selected biochemical parameters in obese women. AB - The aim of this study was to assess the effect of sibutramine on mineral status and selected biochemical parameters in obese women. The study was conducted on 24 patients who received 15 mg daily doses of sibutramine for 12 weeks, and on 20 patients who received placebo. At the baseline, after the sixth and twelfth weeks of treatment, body weight and blood pressure were measured, the BMI was calculated, and samples of blood and of first morning urine were collected. Serum lipid profiles, glucose levels, and nitric oxide levels were determined. The iron (Fe), copper (Cu), zinc (Zn), calcium (Ca), and magnesium (Mg) present in the serum and urine samples were assessed. The erythrocyte hemolysate of the patients was use to assay the activity of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD). No changes were observed in BMI, blood pressure, or nitric oxide during the study. After 12 weeks of treatment, a decrease was observed in total cholesterol, LDL cholesterol, triglyceride, glucose, and ferritin levels. GSH-Px and SOD activity increased after 12 weeks of sibutramine treatment. The Mg and Cu increases was observed in serum after the sixth and twelfth weeks of treatment. It was found that the Zn level decreased in serum after the twelfth week. The elimination of Ca, Mg, Fe, Zn, and Cu in urine also declined in the twelfth week. No differences were found in the women taking the placebo. In conclusion, we found that sibutramine had a positive effect on lipid and glucose status in obese women. However, the drug disturbed the balance of minerals, especially Zn and Mg, in the subjects. PMID- 22539021 TI - Changes in tyrosinase specificity by ionic liquids and sodium dodecyl sulfate. AB - Tyrosinase is a member of the type 3 copper enzyme family involved in the production of melanin in a wide range of organisms. The ability of tyrosinases to convert monophenols into diphenols has stimulated studies regarding the production of substituted catechols, important intermediates for the synthesis of pharmaceuticals, agrochemicals, polymerization inhibitors, and antioxidants. Despite its enormous potential, the use of tyrosinases for catechol synthesis has been limited due to the low monophenolase/diphenolase activity ratio. In the presence of two water miscible ionic liquids, [BMIM][BF(4)] and ethylammonium nitrate, the selectivity of a tyrosinase from Bacillus megaterium (TyrBm) was altered, and the ratio of monophenolase/diphenolase activity increased by up to 5 fold. Furthermore, the addition of sodium dodecyl sulphate (SDS) at levels of 2 50 mM increased the activity of TyrBm by 2-fold towards the natural substrates L tyrosine and L-Dopa and 15- to 20-fold towards the non-native phenol and catechol. The R209H tyrosinase variant we previously identified as having a preferential ratio of monophenolase/diphenolase activity was shown to have a 45 fold increase in activity towards phenol in the presence of SDS. We propose that the effect of SDS on the ability of tyrosinase to convert non-natural substrates is due to the interaction of surfactant molecules with residues located at the entrance to the active site, as visualized by the newly determined crystal structure of TyrBm in the presence of SDS. The effect of SDS on R209 may enable less polar substrates such as phenol and catechol, to penetrate more efficiently into the enzyme catalytic pocket. PMID- 22539024 TI - Variation of the by-product spectrum during alpha-ketoglutaric acid production from raw glycerol by overexpression of fumarase and pyruvate carboxylase genes in Yarrowia lipolytica. AB - The yeast Yarrowia lipolytica secretes high amounts of various organic acids, like citric, isocitric, pyruvic (PA), and alpha-ketoglutaric (KGA) acids, triggered by growth limitation and excess of carbon source. This is leading to an increased interest in this non-conventional yeast for biotechnological applications. To improve the KGA production by Y. lipolytica for an industrial application, it is necessary to reduce the amounts of by-products, e.g., fumarate (FU) and PA, because production of by-products is a main disadvantage of the KGA production by this yeast. We have examined whether the concentration of secreted organic acids (main product KGA and PA as major by-product and FU, malate (MA), and succinate (SU) as minor by-products) can be influenced by a gene-dose dependent overexpression of fumarase (FUM) or pyruvate carboxylase (PYC) genes under KGA production conditions. Recombinant Y. lipolytica strains were constructed, which harbor multiple copies of the respective FUM1, PYC1 or FUM1, and PYC1 genes. Overexpression of the genes FUM1 and PYC1 resulted in strongly increased specific enzyme activities during cultivation of these strains on raw glycerol as carbon source in bioreactors. The recombinant Y. lipolytica strains showed different product selectivity of the secreted organic acids KGA, PA, FU, MA, and SU. Concentrations of the by-products FU, MA, SU, and PA decreased significantly at overproduction of FUM and increased at overproduction of PYC and also of FUM and PYC simultaneously. In contrast, the production of KGA with the multicopy strains H355A(FUM1) and H355A(FUM1-PYC1) was comparable with the wild type strain H355 or slightly lower in case of H355(PYC1). KGA productivity was not changed significantly compared with strain H355 whereas product selectivity of the main product KGA was increased in H355A(FUM1). PMID- 22539022 TI - Two-component signal transduction in Corynebacterium glutamicum and other corynebacteria: on the way towards stimuli and targets. AB - In bacteria, adaptation to changing environmental conditions is often mediated by two-component signal transduction systems. In the prototypical case, a specific stimulus is sensed by a membrane-bound histidine kinase and triggers autophosphorylation of a histidine residue. Subsequently, the phosphoryl group is transferred to an aspartate residue of the cognate response regulator, which then becomes active and mediates a specific response, usually by activating and/or repressing a set of target genes. In this review, we summarize the current knowledge on two-component signal transduction in Corynebacterium glutamicum. This Gram-positive soil bacterium is used for the large-scale biotechnological production of amino acids and can also be applied for the synthesis of a wide variety of other products, such as organic acids, biofuels, or proteins. Therefore, C. glutamicum has become an important model organism in industrial biotechnology and in systems biology. The type strain ATCC 13032 possesses 13 two component systems and the role of five has been elucidated in recent years. They are involved in citrate utilization (CitAB), osmoregulation and cell wall homeostasis (MtrAB), adaptation to phosphate starvation (PhoSR), adaptation to copper stress (CopSR), and heme homeostasis (HrrSA). As C. glutamicum does not only face changing conditions in its natural environment, but also during cultivation in industrial bioreactors of up to 500 m(3) volume, adaptability can also be crucial for good performance in biotechnological production processes. Detailed knowledge on two-component signal transduction and regulatory networks therefore will contribute to both the application and the systemic understanding of C. glutamicum and related species. PMID- 22539023 TI - Responses of bacterial and fungal communities to an elevation gradient in a subtropical montane forest of China. AB - Bacteria and fungi are ecologically important contributors to various functioning of forest ecosystems. In this study, we examined simultaneously the bacterial and fungal distributions in response to elevation changes of a forest. By using clone library analysis from genomic DNA extracted from forest humic clay soils, the composition and diversity of bacterial and fungal communities were determined across an elevation gradient from low via medium to high, in a subtropical forest in the Mountain Lushan, China. Our results showed that soil water content and nutrient availability, specifically total carbon, differed significantly with elevation changes. Although the soil acidity did not differ significantly among the three sites, low pH (around 4) could be an important selection factor selecting for acidophilic Acidobacteria and Alphaproteobacteria, which were the most abundant bacterial clones. As the majority of the fungi recovered, both Basidiomycota and Ascomycota, and their relative abundance were most closely associated with the total carbon. Based on the Shannon-Weaver diversity index and ?-libshuff analysis, the soil at medium elevation contained the highest diversity of bacteria compared with those at high and low elevations. However, it is difficult to predict overall fungal diversity along elevation. The extreme high soil moisture content which may lead to the formation of anaerobic microhabitats in the forest soils potentially reduces the overall bacterial and fungal diversity. PMID- 22539025 TI - High-yield export of a native heterologous protein to the periplasm by the tat translocation pathway in Escherichia coli. AB - Numerous high-value recombinant proteins that are produced in bacteria are exported to the periplasm as this approach offers relatively easy downstream processing and purification. Most recombinant proteins are exported by the Sec pathway, which transports them across the plasma membrane in an unfolded state. The twin-arginine translocation (Tat) system operates in parallel with the Sec pathway but transports substrate proteins in a folded state; it therefore has potential to export proteins that are difficult to produce using the Sec pathway. In this study, we have produced a heterologous protein (green fluorescent protein; GFP) in Escherichia coli and have used batch and fed-batch fermentation systems to test the ability of the newly engineered Tat system to export this protein into the periplasm under industrial-type production conditions. GFP cannot be exported by the Sec pathway in an active form. We first tested the ability of five different Tat signal peptides to export GFP, and showed that the TorA signal peptide directed most efficient export. Under batch fermentation conditions, it was found that TorA-GFP was exported efficiently in wild type cells, but a twofold increase in periplasmic GFP was obtained when the TatABC components were co-expressed. In both cases, periplasmic GFP peaked at about the 12 h point during fermentation but decreased thereafter, suggesting that proteolysis was occurring. Typical yields were 60 mg periplasmic GFP per liter culture. The cells over-expressed the tat operon throughout the fermentation process and the Tat system was shown to be highly active over a 48 h induction period. Fed-batch fermentation generated much greater yields: using glycerol feed rates of 0.4, 0.8, and 1.2 mL h(-1), the cultures reached OD(600) values of 180 and periplasmic GFP levels of 0.4, 0.85, and 1.1 g L(-1) culture, respectively. Most or all of the periplasmic GFP was shown to be active. These export values are in line with those obtained in industrial production processes using Sec dependent export approaches. PMID- 22539026 TI - Outsider to insider: resetting the natural host niche of commensal E. coli K-12. AB - The status of E. coli K-12 as an exclusively non-invasive, non-pathogenic bacterium has almost been incontrovertible. Our recent finding that a mutation in one of its main architectural protein, HU, converts E. coli K-12 to an actively invasive form suggests that gaining host cell entry might be an expedient survival tactic for traditional commensals during certain altered host conditions. The mutant E. coli (SK3842) exhibits properties usually associated with pathogenic bacteria: host cell invasion, phagosomal disruption and intracellular replication. However, unlike the situation with some pathogens, internalized SK3842 imparts anti-apoptotic and cyto-protective effects rather than lethality on the host cell, both in vitro and in vivo. Here, we show that SK3842 also provides colonization resistance against other invasive pathogens--a trait not shared by the parental commensal strain. Thus, the altered lifestyle of SK3842 encompasses characteristics both from traditional pathogens as well as beneficial probiotic strains. PMID- 22539027 TI - Antifungal activity of Lactobacillus against Microsporum canis, Microsporum gypseum and Epidermophyton floccosum. AB - A total of 220 lactic acid bacteria isolates were screened for antifungal activity using Aspergillus fumigatus and Aspergillus niger as the target strains. Four Lactobacillus strains exhibited strong inhibitory activity on agar surfaces. All four were also identified as having strong inhibitory activity against the human pathogenic fungi Microsporum canis, Microsporum gypseum and Epidermophyton floccosum. One of the four lactobacilli, namely Lb. reuteri ee1p exhibited the most inhibition against dermatophytes. Cell-free culture supernatants of Lb. reuteri ee1p and of the non-antifungal Lb. reuteri M13 were freeze-dried and used to access and compare antifungal activity in agar plate assays and microtiter plate assays. Addition of the Lb. reuteri ee1p freeze-dried cell-free supernatant powder into the agar medium at concentrations greater than 2% inhibited all fungal colony growth. Addition of the powder at 5% to liquid cultures caused complete inhibition of fungal growth on the basis of turbidity. Freeze-dried supernatant of the non-antifungal Lb. reuteri M13 at the same concentrations had a much lesser effect. As Lb. reuteri M13 is very similar to the antifungal strain ee1p in terms of growth rate and final pH in liquid culture, and as it has little antifungal activity, it is clear that other antifungal compounds must be specifically produced (or produced at higher levels) by the anti-dermatophyte strain Lb. reuteri ee1p. Reuterin was undetectable in all four antifungal strains. The cell free supernatant of Lb. reuteri ee1p was analyzed by LC-FTMS using an Accela LC coupled to an LTQ Orbitrap XL mass spectrometer. The high mass accuracy spectrum produced by compounds in the Lb. reuteri ee1p strain was compared with both a multianalyte chromatogram and individual spectra of standard anti-fungal compounds, which are known to be produced by lactic acid bacteria. Ten antifungal metabolites were detected. PMID- 22539029 TI - A bi-cistronic baculovirus expression vector for improved recombinant protein production. AB - Baculoviruses are one of the most studied insect viruses both in basic virology research and in biotechnology applications. Incorporating an internal ribosome entry site (IRES) into the baculovirus genome generates bi-cistronic baculoviruses expression vectors that produce two genes of interest. The bi cistronic baculoviruses also facilitate recombinant virus isolation and titer determination when the green fluorescent protein was co-expressed. Furthermore, when the secretion proteins were co-expressed with the cytosolic green fluorescent protein, the cell lysis and cytosolic protein released into the culture medium could be monitored by the green fluorescence, thus facilitating purification of the secreted proteins. PMID- 22539028 TI - Development and optimization of an EGFP-based reporter for measuring the general stress response in Listeria monocytogenes. AB - A characteristic of the food-borne pathogen Listeria monocytogenes is its tolerance to the harsh conditions found both in minimally processed foods and the human gastrointestinal tract. This trait is partly under the control of the alternative sigma factor sigma B (sigma(B)). To study the mechanisms that trigger the activation of sigma(B) , and hence the development of stress tolerance, we have developed a fluorescent reporter fusion that allows the real-time activity of sigma(B) to be monitored. The reporter, designated Plmo2230::egfp, fuses the strong sigma(B)-dependent promoter from the lmo2230 gene (which encodes a putative arsenate reductase) to a gene encoding enhanced green fluorescence protein (EGFP). The reporter was integrated into the genomes of the wild-type strain L. monocytogenes EGD-e as well as two mutant derivatives lacking either sigB or rsbV. The resulting strains were used to study sigma(B) activation in response to growth phase and hyperosmotic stress. The wild-type was strongly fluorescent in stationary phase or in cultures with added NaCl and this fluorescence was abolished in both the sigB and rsbV backgrounds, consistent with the sigma(B)-dependency of the lmo2230 promoter. During sudden osmotic upshock (addition of 0.5 M NaCl during growth) a real-time increase in fluorescence was observed microscopically, reaching maximal activation after 30 min. Flow cytometry was used to study the activation of sigma(B) at a population level by hyperosmotic stress during exponential growth. A strong and proportional increase in fluorescence was observed as the salt concentration increased from 0 to 0.9 M NaCl. Interestingly, there was considerable heterogeneity within the population and a significant proportion of cells failed to induce a high level of fluorescence, suggesting that sigma(B) activation occurs stochastically in response to hyperosmotic stress. Thus the Plmo2230::egfp is a powerful tool that will allow the stress response to be better studied in this important human pathogen. PMID- 22539030 TI - Elevated immunoreactivity against class I histone deacetylases in adenomyosis. AB - BACKGROUND/AIMS: Adenomyosis is a common condition with a poorly understood pathogenesis. Recent data suggest that it may be an epigenetic disease. This study investigated the expression and localization of class I histone deacetylases (HDACs) in women with and without adenomyosis. METHODS: The ectopic and homologous eutopic endometrium of 50 women with adenomyosis and the endometrium of 18 age- and menstrual phase-matched women without adenomyosis were used for immunohistochemical analysis. Tissue sections were immunostained with HDAC1, -2, and -3. Microscopic evaluation to assess the presence and localization of HDAC1-3 throughout the menstrual cycle in both eutopic endometrial and endometriotic tissues of women with adenomyosis was performed and compared with the normal endometrium. RESULTS: We found that, compared with the normal endometrium, immunoreactivity against HDAC1 and HDAC3 was higher in both the eutopic and the ectopic endometrium. Increased HDAC2 in the eutopic endometrium was found to be associated with the severity of dysmenorrhea. CONCLUSION: Given the potential wide-ranging effect of histone deacetylation on gene expression, these findings suggest that HDACs may be involved in adenomyosis. They also suggest the possibility that HDAC2 may be involved in dysmenorrhea and its severity and that HDACs may be potential therapeutic targets in adenomyosis. PMID- 22539031 TI - Worms take to the slo lane: a perspective on the mode of action of emodepside. AB - The cyclo-octapdepsipeptide anthelmintic emodepside exerts a profound paralysis on parasitic and free-living nematodes. The neuromuscular junction is a significant determinant of this effect. Pharmacological and electrophysiological analyses in the parasitic nematode Ascaris suum have resolved that emodepside elicits a hyperpolarisation of body wall muscle, which is dependent on extracellular calcium and the efflux of potassium ions. The molecular basis for emodepside's action has been investigated in forward genetic screens in the free living nematode Caenorhabditis elegans. Two screens for emodepside resistance, totalling 20,000 genomes, identified several mutants of slo-1, which encodes a calcium-activated potassium channel homologous to mammalian BK channels. Slo-1 null mutants are more than 1000-fold less sensitive to emodepside than wild-type C. elegans and tissue-specific expression studies show emodepside acts on SLO-1 in neurons regulating feeding and motility as well as acting on SLO-1 in body wall muscle. These genetic data, combined with physiological measurements in C. elegans and the earlier physiological analyses on A. suum, define a pivotal role for SLO-1 in the mode of action of emodepside. Additional signalling pathways have emerged as determinants of emodepside's mode of action through biochemical and hypothesis-driven approaches. Mutant analyses of these pathways suggest a modulatory role for each of them in emodepside's mode of action; however, they impart much more modest changes in the sensitivity to emodepside than mutations in slo-1. Taken together these studies identify SLO-1 as the major determinant of emodepside's anthelmintic activity. Structural information on the BK channels has advanced significantly in the last 2 years. Therefore, we rationalise this possibility by suggesting a model that speculates on the nature of the emodepside pharmacophore within the calcium-activated potassium channels. PMID- 22539032 TI - How I do it: Side-to-side isoperistaltic strictureplasty for extensive Crohn's disease. AB - INTRODUCTION: Bowel-sparing surgical techniques, such as the Heineke-Mikulicz and the Finney strictureplasty, have been proposed as an alternative to lengthy intestinal resection in the treatment of small bowel strictures in Crohn's disease. However, these conventional strictureplasty techniques lend themselves poorly to cases of multiple short strictures closely clustered over a lengthy small bowel segment. DISCUSSION: In this article, we present the surgical technique of the side-to-side isoperistaltic strictureplasty, which is optimal in addressing these specific situations. PMID- 22539033 TI - The halogen analogs of thiolated gold nanoclusters. AB - Is it possible to replace all the thiolates in a thiolated gold nanocluster with halogens while still maintaining the geometry and the electronic structure? In this work, we show from density functional theory that such halogen analogs of thiolated gold nanoclusters are highly likely. Using Au(25)X(18)(-) as an example, where X = F, Cl, Br, or I replaces -SR, we find that Au(25)Cl(18)(-) demonstrates a high similarity to Au(25)(SR)(18)(-) by showing Au-Cl distances, Cl-Au-Cl angles, band gap, and frontier orbitals similar to those in Au(25)(SR)(18)(-). DFT-based global minimization also indicates the energetic preference of staple formation for the Au(25)Cl(18)(-) cluster. The similarity between Au(m)(SR)(n) and Au(m)X(n) could be exploited to make viable Au(m)X(n) clusters and to predict structures for Au(m)(SR)(n). PMID- 22539034 TI - Reversible minimal change nephrotic syndrome and glomerular IgA deposition associated with nonparenteral heroin abuse: a case report. AB - OBJECTIVE: To report for the first time a case of reversible minimal change nephrotic syndrome with immunoglobulin A (IgA) deposition associated with heroin. CLINICAL PRESENTATION AND INTERVENTION: A 29-year-old male heroin abuser who developed nephrotic syndrome was admitted to our clinic. Renal biopsy revealed minimal change disease with IgA deposition. Because spontaneous complete remission was observed after cessation of heroin, a diagnosis of minimal change nephrotic syndrome with IgA deposition associated with heroin abuse was considered. CONCLUSION: This case showed minimal change nephrotic syndrome with IgA deposition that had a benign clinical course. PMID- 22539035 TI - Transverse vaginal septum: a benign reason for elevated serum CA 19-9 and CA 125 levels. PMID- 22539036 TI - AKR1B10 overexpression in breast cancer: association with tumor size, lymph node metastasis and patient survival and its potential as a novel serum marker. AB - Aldo-keto reductase 1B10 (AKR1B10) is a secretory protein that is upregulated with tumorigenic transformation of human mammary epithelial cells. This study demonstrated that AKR1B10 was overexpressed in 20 (71.4%) of 28 ductal carcinomas in situ, 184 (83.6%) of 220 infiltrating carcinomas and 28 (87.5%) of 32 recurrent tumors. AKR1B10 expression in breast cancer was correlated positively with tumor size (p = 0.0012) and lymph node metastasis (p = 0.0123) but inversely with disease-related survival (p = 0.0120). Univariate (p = 0.0077) and multivariate (p = 0.0192) analyses both suggested that AKR1B10, alone or together with tumor size and node status, is a significant prognostic factor for breast cancer. Silencing of AKR1B10 in BT-20 human breast cancer cells inhibited cell growth in culture and tumorigenesis in female nude mice. Importantly, AKR1B10 in the serum of breast cancer patients was significantly increased to 15.18 +/- 9.08 ng/ml [n = 50; 95% confidence interval (CI), 12.60-17.76], with a high level up to 58.4 ng/ml, compared to 3.34 +/- 2.27 ng/ml in healthy donors (n = 60; 95% CI, 2.78-3.90). In these patients, AKR1B10 levels in serum were correlated with its expression in tumors (r = 0.8066; p < 0.0001). Together our data suggests that AKR1B10 is overexpressed in breast cancer and may be a novel prognostic factor and serum marker for this deadly disease. PMID- 22539038 TI - III-nitride core-shell nanowire arrayed solar cells. AB - A solar cell based on a hybrid nanowire-film architecture consisting of a vertically aligned array of InGaN/GaN multi-quantum well core-shell nanowires which are electrically connected by a coalesced p-InGaN canopy layer is demonstrated. This unique hybrid structure allows for standard planar device processing, solving a key challenge with nanowire device integration, while enabling various advantages by the nanowire absorbing region such as higher indium composition InGaN layers by elastic strain relief, more efficient carrier collection in thinner layers, and enhanced light trapping from nano-scale optical index changes. This hybrid structure is fabricated into working solar cells exhibiting photoresponse out to 2.1 eV and short-circuit current densities of ~1 mA cm(-2) under 1 sun AM1.5G. This proof-of-concept nanowire-based device demonstrates a route forward for high-efficiency III-nitride solar cells. PMID- 22539037 TI - Regulation of microRNA-375 by cAMP in pancreatic beta-cells. AB - MicroRNA-375 (miR-375) is necessary for proper formation of pancreatic islets in vertebrates and is necessary for the development of beta-cells in mice, but regulation of miR-375 in these cells is poorly understood. Here, we show that miR 375 is transcriptionally repressed by the cAMP-protein kinase A (PKA) pathway and that this repression is mediated through a block in RNA polymerase II binding to the miR-375 promoter. cAMP analogs that are PKA selective repress miR-375, as do cAMP agonists and the glucagon-like peptide-1 receptor agonist, exendin-4. Repression of the miR-375 precursor occurs rapidly in rat insulinoma INS-1 832/13 cells, within 15 min after cAMP stimulation, although the mature microRNA declines more slowly due to the kinetics of RNA processing. Repression of miR-375 in isolated rat islets by exendin-4 also occurs slowly, after several hours of stimulation. Glucose is another reported antagonist of miR-375 expression, although we demonstrate here that glucose does not target the microRNA through the PKA pathway. As reported previously, miR-375 negatively regulates insulin secretion, and attenuation of miR-375 through the cAMP-PKA pathway may boost the insulin response in pancreatic beta-cells. PMID- 22539039 TI - A shift from colon- to ileum-predominant bacteria in ileal-pouch feces following total proctocolectomy. AB - BACKGROUND: We previously investigated fecal flora of the pouch after total proctocolectomy using terminal restriction fragment polymorphism analysis. Although the results of the cluster analysis demonstrated clearly that bacterial populations, including an unidentified bacteria generating a 213-bp PCR fragment, moved toward a colon-like community in the pouch, it did not track changes in the individual species of fecal bacteria. AIMS: The aim of the present study was to estimate genome copy number of ten bacterial species, clusters, groups, or subgroups (including the bacteria generating 213-bp fragment in the previous study) in feces samples from pouches at various times following ileostomy closure. METHODS: A total of 117 stool samples were collected from patients with ulcerative colitis after surgery as well as healthy volunteers. We used real-time polymerase chain reaction of the 16S rRNA gene to estimate genome copy numbers for the nine bacterial populations and the bacteria generating 213-bp fragment after identification by DNA sequencing. RESULTS: We demonstrated a time-dependent increase in the number of anaerobic and colon-predominant bacteria (such as Clostridium coccoides, C. leptum, Bacteroides fragilis and Atopobium) present in proctocolectomy patients after stoma closure. In contrast, numbers of ileum predominant bacterial species (such as Lactobacillus and Enterococcus faecalis) declined. CONCLUSIONS: Our data confirm previous findings that fecal flora in the pouch after total proctocolectomy changes significantly, and further demonstrate that the number and diversity of ileal bacteria decreases while a more colon-like community develops. The present data are essential for the future analysis of pathological conditions in the ileal pouch. PMID- 22539041 TI - Evaluation of innate, humoral and cell-mediated immunity in mice following in vivo implantation of electrospun polycaprolactone. AB - Electrospun polycaprolactone (EPCL) is currently being investigated for use in tissue engineering applications such as vascular grafts. However, the effects of electrospun polymers on systemic immune responses following in vivo exposure have not previously been examined. The work presented evaluates whether EPCL in either a microfibrous or nanofibrous form affects innate, humoral and/or cell-mediated immunity using a standard immunotoxicological testing battery. Holistic in vivo endpoints examined include the antibody-forming cell assay (AFC or plaque assay) and the delayed-type hypersensitivity response to Candida albicans. In addition, natural killer cell cytotoxic activity was assessed using an ex vivo assay and splenic cell population phenotypes were analyzed by flow cytometry for material exposure-related changes. Results indicated that 28 day subcutaneous implantation of EPCL, either in microfibrous or nanofibrous form, did not affect the systemic functions of the immune system in 12-16 week old female B6C3F1 mice. PMID- 22539042 TI - The dynamics of the calcium-induced chain-chain association in the polyuronate systems. AB - The calcium-induced formation of strong, hydrophilic gels is the important feature of polyuronates, connected with most of their practical applications. The insight into the molecular details of gelling process dynamics is hardly feasible for both experimental and theoretical methods. Here, the application of the transition path sampling method for studying this problem is reported; the focus was on the poly(alpha-L-guluronate) systems, treated as the representative for all polyuronate-containing systems. The results allowed for identifying several distinct local minima of the free energy lying on the transition paths and visited by the system during the process of chain-chain association. These minima usually correspond to the intermediate structures in which the water molecules bridge calcium ion and carboxyl groups. This work emphasizes the importance of water and provides more complete understanding of the calcium binding by the polyuronate chains. PMID- 22539040 TI - Hepatic stimulator substance alleviates toxin-induced and immune-mediated liver injury and fibrosis in rats. AB - BACKGROUND: Liver fibrosis is a common scarring response to chronic liver injury. It is a precursor to cirrhosis and liver carcinoma. Hepatic stimulator substance (HSS), a known liver-specific but species-nonspecific growth factor, has been shown to protect hepatocytes from various toxins. METHODS: We have investigated the effects of HSS therapy on carbon tetrachloride (CCl(4))-induced and porcine serum-mediated hepatic injury and fibrosis. We hypothesize that HSS might attenuate liver injury and fibrosis by suppressing oxidative stress, down regulating profibrogenic factors, and blocking HSCs activation. RESULTS: This report demonstrated that HSS therapy diminished alpha-smooth muscle actin expression, decreased intrahepatic reactive oxygen species (ROS) level, and down regulated transforming growth factor (TGF)-beta1, platelet-derived growth factor (PDGF)-BB, and tissue inhibitor of metalloproteinase (TIMP)-1 expression. In addition, HSS treatment significantly protected the liver from injury by improving liver function tests and histological architecture of the liver. CONCLUSIONS: These results provided novel insights into the mechanisms of HSS in the protection of the liver. Our results suggested that HSS might be a therapeutic antifibrotic agent for the treatment of liver fibrosis. PMID- 22539043 TI - Alleviating monoterpene toxicity using a two-phase extractive fermentation for the bioproduction of jet fuel mixtures in Saccharomyces cerevisiae. AB - Monoterpenes are a diverse class of compounds with applications as flavors and fragrances, pharmaceuticals and more recently, jet fuels. Engineering biosynthetic pathways for monoterpene production in microbial hosts has received increasing attention. However, monoterpenes are highly toxic to many microorganisms including Saccharomyces cerevisiae, a widely used industrial biocatalyst. In this work, the minimum inhibitory concentration (MIC) for S. cerevisiae was determined for five monoterpenes: beta-pinene, limonene, myrcene, gamma-terpinene, and terpinolene (1.52, 0.44, 2.12, 0.70, 0.53 mM, respectively). Given the low MIC for all compounds tested, a liquid two-phase solvent extraction system to alleviate toxicity during fermentation was evaluated. Ten solvents were tested for biocompatibility, monoterpene distribution, phase separation, and price. The solvents dioctyl phthalate, dibutyl phthalate, isopropyl myristate, and farnesene showed greater than 100-fold increase in the MIC compared to the monoterpenes in a solvent-free system. In particular, the MIC for limonene in dibutyl phthalate showed a 702-fold (308 mM, 42.1 g L(-1) of limonene) improvement while cell viability was maintained above 90%, demonstrating that extractive fermentation is a suitable tool for the reduction of monoterpene toxicity. Finally, we estimated that a limonane to farnesane ratio of 1:9 has physicochemical properties similar to traditional Jet-A aviation fuel. Since farnesene is currently produced in S. cerevisiae, its use as a co-product and extractant for microbial terpene-based jet fuel production in a two-phase system offers an attractive bioprocessing option. PMID- 22539044 TI - Multi-modality imaging findings of splenic hamartoma: a report of nine cases and review of the literature. AB - PURPOSE: To investigate the presentation of splenic hamartomas (SHs) on ultrasonography (US), CT and MRI. METHODS: Nine patients (5 males and 4 females, mean age, 52.8 years) with pathologically proven SHs were included in this study. US, CT and MRI images were analyzed retrospectively, and imaging features were correlated with pathological findings. RESULTS: SHs appeared solitary lesion (n = 8) and multiple lesions (n = 1) in the present study. (1) In 8 cases of solitary lesion, the lesions appeared as solid nodules or masses with well-defined margins and varying echogenicity (hyperecho = 5, hypoecho = 2, strong echo = 1) on ultrasound. The lesions showed iso-attenuation (n = 3) or slightly hypo attenuation (n = 4) on unenhanced CT, and calcification were revealed in 3 lesions. MRI showed isointensity (n = 3) or hypointensity (n = 2) on the T1 weighted image, and heterogeneous hypointensity (n = 2), slightly hyperintensity (n = 2) and hyperintensity (n = 1) on the T2-weighted image. The enhanced patterns of SHs showed mild diffuse heterogeneous enhancement (n = 6) and prominent enhancement (n = 1) during arterial phase and above 7 lesions were demonstrated progressive enhancement at delayed phase on enhanced CT. One lesion without any enhancement was revealed in another patient. (2) One case of multiple lesions included 1 cystic lesion with irregular calcification and 7 solid lesions with progressive enhancement on CT images. CONCLUSIONS: Combination of a variety of imaging modalities could more fully reflect the pathological characteristics and contribute to the diagnosis of SH. PMID- 22539045 TI - Missed lesions at CT colonography: lessons learned. AB - Misinterpretation at CT colonography (CTC) can result in either a colorectal lesion being missed (false-negative) or a false-positive diagnosis. This review will largely focus on potential missed lesions-and ways to avoid such misses. The general causes of false-negative interpretation at CTC can be broadly characterized and grouped into discrete categories related to suboptimal study technique, specific lesion characteristics, anatomic location, and imaging artifacts. Overlapping causes further increase the likelihood of missing a clinically relevant lesion. In the end, if the technical factors of bowel preparation, colonic distention, and robust CTC software are adequately addressed on a consistent basis, and the reader is aware of all the potential pitfalls at CTC, important lesions will seldom be missed. PMID- 22539046 TI - A mechanobiological model of orthodontic tooth movement. AB - Orthodontic tooth movement is achieved by the process of repeated alveolar bone resorption on the pressure side and new bone formation on the tension side. In order to optimize orthodontic treatment, it is important to identify and study the biological processes involved. This article presents a mechanobiological model using partial differential equations to describe cell densities, growth factor concentrations, and matrix densities occurring during orthodontic tooth movement. We hypothesize that such a model can predict tooth movement based on the mechanobiological activity of cells in the PDL. The developed model consists of nine coupled non-linear partial differential equations, and two distinct signaling pathways were modeled: the RANKL-RANK-OPG pathway regulating the communication between osteoblasts and osteoclasts and the TGF-beta pathway mediating the differentiation of mesenchymal stem cells into osteoblasts. The predicted concentrations and densities were qualitatively validated by comparing the results to experiments reported in the literature. In the current form, the model supports our hypothesis, as it is capable of conceptually simulating important features of the biological interactions in the alveolar bone-PDL complex during orthodontic tooth movement. PMID- 22539047 TI - A facile route to boronic acid functional polymeric microspheres via epoxide ring opening. AB - Boronic acid-functionalized microspheres are prepared for the first time via mild epoxide ring opening based on porous cross-linked polymeric microspheres (diameter ~ 10 MUm, porosity ~ 1000 A). Quantitative chemical analysis by XPS and EA evidences that there is a greater functionalization with boronic acid when employing a sequential synthetic method [1.7 atom% boron (XPS); 1.12 wt% nitrogen (EA)] versus a one-pot synthetic method [0.2 atom% boron (XPS); 0.60 wt% nitrogen (EA)] yielding grafting densities ranging from approximately 2.5 molecules of boronic acid per nm(2) to 1 molecule of boronic acid per nm(2), respectively. Furthermore, the boronic acid-functionalized microspheres are conjugated with a novel fluorescent glucose molecule demonstrating a homogeneous spatial distribution of boronic acid. PMID- 22539048 TI - Sliding on a nanotube: interplay of friction, deformations and structure. AB - The frictional properties of individual carbon nanotubes (CNTs) are studied by sliding an atomic force microscopy tip across and along its principle axis. This direction-dependent frictional behavior is found to correlate strongly with the presence of structural defects, surface chemistry, and CNT chirality. This study shows that it is experimentally possible to tune the frictional/adhesion properties of a CNT by controlling the CNT structure and surface chemistry, as well as use friction force to predict its structural and chemical properties. PMID- 22539049 TI - Management of cutaneous adverse events induced by anti-EGFR (epidermal growth factor receptor): a French interdisciplinary therapeutic algorithm. AB - PURPOSE: Cutaneous adverse events induced by epidermal growth factor receptor (EGFR) inhibitors can hamper the patients' quality of life. The aim of our work was to draft an algorithm for the optimised management of this skin toxicity. METHODS: This algorithm was built in three steps under the responsibility of a steering committee. Step I: a systematic literature analysis (SLA) has been performed. Step II: the collection of information about practices was performed through a questionnaire.These questions were asked during regional meetings to which oncologists, gastro-enterologists, radiotherapists, and dermatologists were invited. Step III: a final meeting was organised involving the bibliography group and the steering committee and regional scientific committees for proposing a final algorithm. RESULTS: Step I: 14 publications were selected to evaluate the use of cyclines as curative or prophylactic treatment of the folliculitis induced by EGFR inhibitors. Nineteen publications were retained for the topical treatment of the folliculitis. Forty-six articles were selected for the management of the cutaneous lesions in link with appendages and 12 for xerosis and pruritus. Step II: 96 delegates attended the seven regional meetings and 67 questionnaires were analysed. Step III: a final algorithm was proposed on the basis of the conclusions of the first two steps and expert opinions present at this final meeting. The different propositions were unanimously approved by the 14 experts who voted. CONCLUSIONS: This multidisciplinary study summarising published data and current practices produced a therapeutic algorithm, which should facilitate the standardised, optimised management of skin toxicity associated with EGFR inhibitors in France. PMID- 22539050 TI - Interpreting results from oncology clinical trials: a comparison of denosumab to zoledronic acid for the prevention of skeletal-related events in cancer patients. AB - BACKGROUND: Critically reviewing the design, endpoints, and results of clinical trials can be challenging to health care professionals. This paper will review the basic methods of presenting clinical outcomes in randomized trials and will focus on the number needed to treat (NNT) concept. NNT will then be applied to the case of bone-targeted therapies denosumab and zoledronic acid, which are used for the prevention of skeletal-related events (SREs) in a variety of disease sites. METHODS: A Medline search was performed to identify randomized trials comparing denosumab to zoledronic acid for the prevention of SREs in patients with advanced breast, prostate, and other cancer sites. The data were extracted, and point estimates for the primary and secondary trial endpoints were converted into the NNT parameter. RESULTS: NNT represents the number of patients that need to be treated with a new intervention in order to avoid one additional patient developing the event and is a powerful approach that can be used to make sense of numerical results from clinical trials. In patients with advanced breast, prostate, and other cancer sites, 18, 22, and 21 patients, respectively, would need to be treated with denosumab for at least 24 months to avoid one patient developing an SRE. CONCLUSIONS: The NNT approach is a simple and effective method to express the findings of randomized trials in a clinically meaningful way. In this analysis, the incremental benefits of denosumab would be realized when a minimum of 18 to 22 patients are treated for a prolonged duration. Clinicians would have to weigh the costs and benefits between denosumab and zoledronic acid when bone-targeted therapy is indicated. PMID- 22539052 TI - Lung cancer and rehabilitation--what are the barriers? Results of a questionnaire survey and the development of regional lung cancer rehabilitation standards and guidelines. AB - BACKGROUND: Evidence supports the role of rehabilitation in the management of lung cancer symptoms. Previous research reports that rehabilitation needs are inadequately recognised and managed, which may adversely affect patients' quality of-life and create burden for caregivers. AIMS: This study aims to explore the perceptions of palliative care and respiratory multidisciplinary team (MDT) members about the role of rehabilitation for lung cancer patients, examine patterns of referral for lung cancer patients to rehabilitation services, and highlight the barriers which prevent the referral of lung cancer patients to rehabilitation services. METHODS: Questionnaires were completed by MDT members within a regional cancer network during June 2010. RESULTS: Fifty-nine healthcare professionals participated. Ninety-four per cent of respondents perceived their patients had rehabilitation needs. Referral most commonly occurred during the palliative (29.6 %) and post-treatment (23.7 %) disease phases. Barriers to referral included "lack of knowledge of services or referral mechanisms" (28.8 %), "waiting lists" (28.8 %) and the perception that patients "do not desire rehabilitation" (22 %). Rehabilitation needs were most frequently discussed at palliative in-patient MDT meetings [reported as "often" by 37 (62.7 %) respondents] and least discussed at lung MDTs (half of respondents reporting that rehabilitation was "never" discussed). Rehabilitation services were considered adequate by 39 % of respondents. CONCLUSIONS: Long waiting times and lack of knowledge of services are among several factors that may prevent lung cancer patients being offered rehabilitation. In order to improve the quality of care delivered to cancer patients, it is important to remove barriers that affect delivery of rehabilitation services. PMID- 22539051 TI - Short post-infusion scalp cooling time in the prevention of docetaxel-induced alopecia. AB - PURPOSE: The patient impact of chemotherapy-induced alopecia (CIA) is high. Scalp cooling is applied to reduce CIA. The potential optimum post-infusion cooling times (PICTs) are currently unknown. METHODS: Scalp cooling was applied in 53 patients receiving docetaxel chemotherapy with 90-min PICT (observational part). Also 15 non-scalp-cooled patients were included. If hair preservation was observed in >80 % of the patients, randomisation between 45 and 90-min PICT was planned. Patients reported tolerance of scalp cooling and use of head covering. RESULTS: Observational study: 81 % of scalp-cooled patients did not require head covering versus 27 % of non-scalp-cooled patients. Randomised study: 79 % of 38 patients with 90-min PICT did not need head covering versus 95 % of 38 patients with 45-min PICT (p = 0.04). Scalp cooling was very well tolerated (visual analogue scale = 79). CONCLUSION: A 45-min PICT can be recommended in 3-weekly docetaxel regimens with a dose of 75 or 100 mg/m(2), administered in 60 min. The shorter PICT is a major advantage in time investment for patients. Patients (women and men) who receive docetaxel, except combined with doxorubicin and cyclophosphamide (taxotere, adriamycin and cyclophosphamide (TAC)) should be informed about the protective effect and high tolerability of scalp cooling in avoiding CIA. PMID- 22539053 TI - Predictive index for lymph node management of major salivary gland cancer. AB - OBJECTIVES/HYPOTHESIS: To find the risk factors of lymph node (LN) metastasis of salivary gland cancer and draw a scheme for LN management. STUDY DESIGN: Hospital based retrospective study. METHODS: The records of salivary gland cancer patients treated at the Department of Head and Neck Surgery, Cancer Hospital, Fudan University, were entered in a database, and 219 consecutive patients with carcinomas of major salivary glands primarily operated on between January 1998 and January 2011 were chosen for univariate and multivariate analysis to identify risk factors for LN involvement. RESULTS: Fifty-eight (26.5%) patients had LN involvement. Factors associated with cervical LN involvement on univariate analysis included pathologic type, male sex, shorter duration of preoperative course, facial paralysis, advanced T stage, and major nerve, soft tissue, lymphatic/vascular (L/V), neural/perineural, and extracapsular invasion. Multivariate analysis identified major nerve invasion, histologic type, L/V invasion, and extracapsular invasion as significant factors for LN involvement. The proportion of patients with LN involvement with low (105), middle (61), high (34), and super high (19) predictive index scores based on the four risk factors were 3.8%, 27.9%, 55.9%, and 94.7%, respectively. CONCLUSIONS: A predictive index using the clinicopathologic factors described in this report can effectively stratify patients into risk groups for nodal metastasis. Comprehensive management based on this risk index should improve treatment outcomes for patients with salivary gland cancer. PMID- 22539054 TI - Promoting international cancer education: report from the 2012 European association for cancer education. PMID- 22539055 TI - Feasibility of training oncology residents in shared decision making: a pilot study. AB - Although shared decision making (SDM) is the crux of patient-centered care, physicians are not formally trained in SDM. We conducted a pre-/post-test study with oncology residents to evaluate the feasibility and acceptability of a SDM training intervention. Of 20 medical residents approached, 11 participated and rated the SDM workshop favorably. Quality of SDM provided to simulated patients were median 3.5 out of 10 (range, 1-6) at baseline, eight (4-10) within 1 month, and four (2-10) within 3 months of the workshop with higher scores reflecting more elements of SDM demonstrated. Three months after the workshop, participants reported increased sense of control over providing SDM and higher perceived expectations from others to do so. It was feasible to provide SDM training and findings suggest it increased their SDM skills. Changes in behavioral intentions appear to be influenced through the pathways of perceived behavioral control and social norms. PMID- 22539056 TI - Responsiveness-to-intervention: a decade later. AB - In this introduction to this special issue, "A Decade Later," we provide an overview of the accomplishments as well as the persistent questions surrounding RTI. We organize this discussion within 3 categories: assessment, instruction, and policy. Within each of these sections, we also highlight how the articles in the present special issue expand upon the key issues. Developed initially for the early grades (kindergarten through third grade) and primarily in the area of reading, many-although not all-of these issues speak to the expansion of RTI to address a broader set of academic content areas and the full range of grade levels. PMID- 22539057 TI - First-grade cognitive abilities as long-term predictors of reading comprehension and disability status. AB - In a sample of 195 first graders selected for poor reading performance, the authors explored four cognitive predictors of later reading comprehension and reading disability (RD) status. In fall of first grade, the authors measured the children's phonological processing, rapid automatized naming (RAN), oral language comprehension, and nonverbal reasoning. Throughout first grade, they also modeled the students' reading progress by means of weekly Word Identification Fluency (WIF) tests to derive December and May intercepts. The authors assessed their reading comprehension in the spring of Grades 1-5. With the four cognitive variables and the WIF December intercept as predictors, 50.3% of the variance in fifth-grade reading comprehension was explained: 52.1% of this 50.3% was unique to the cognitive variables, 13.1% to the WIF December intercept, and 34.8% was shared. All five predictors were statistically significant. The same four cognitive variables with the May (rather than December) WIF intercept produced a model that explained 62.1% of the variance. Of this amount, the cognitive variables and May WIF intercept accounted for 34.5% and 27.7%, respectively; they shared 37.8%. All predictors in this model were statistically significant except RAN. Logistic regression analyses indicated that the accuracy with which the cognitive variables predicted end-of-fifth-grade RD status was 73.9%. The May WIF intercept contributed reliably to this prediction; the December WIF intercept did not. Results are discussed in terms of a role for cognitive abilities in identifying, classifying, and instructing students with severe reading problems. PMID- 22539058 TI - A glass half full: a commentary on the special issue. PMID- 22539059 TI - Photocatalytic reduction of nitrite to dinitrogen in aqueous suspensions of metal loaded titanium(IV) oxide in the presence of a hole scavenger: an ensemble effect of silver and palladium co-catalysts. AB - Nitrite (NO(2)(-)) was photocatalytically reduced to dinitrogen (N(2)) in an aqueous suspension of two kinds of titanium(iv) oxide particles loaded with palladium and silver (Pd-TiO(2) and Ag-TiO(2)) at pH 8 under irradiation of UV light in the presence of sodium oxalate as a hole scavenger. The two metal-loaded TiO(2) photocatalysts had different roles in conversion of NO(2)(-) to N(2) and worked in an effective ensemble without conflict: (1) Pd-TiO(2) induced photocatalytic disproportionation of NO(2)(-) to N(2) and nitrate (NO(3)(-)) and (2) Ag-TiO(2) selectively reduced the thus-formed NO(3)(-) back to NO(2)(-) (partially to N(2)) with oxalate acting as a hole scavenger. When Pd-TiO(2) was used alone for NO(3)(-) reduction in the presence of sodium oxalate, Pd-TiO(2) induced fruitless photocatalytic decomposition of oxalate to carbon dioxide and dihydrogen. The presence of Ag-TiO(2) suppressed the fruitless decomposition of oxalate by Pd-TiO(2) because Ag-TiO(2) continuously provided NO(2)(-) in the reaction system using oxalate as a hole scavenger and Pd-TiO(2) therefore only worked as a photocatalyst for disproportionation of NO(2)(-) to N(2) and NO(3)(-) as it did when used alone. PMID- 22539060 TI - Susto, coraje, and abuse: depression and beliefs about diabetes. AB - Mexican immigrants in the US often incorporate folk beliefs into diabetes etiologies but little is known about the relationship between such beliefs and depression. This study examines the relationship of diabetes beliefs and depression among 404 first- and second-generation Mexican immigrants seeking diabetes care in safety-net clinics in Chicago and San Francisco. We used multivariate linear regression to compare the association of depression with beliefs that susto (fright), coraje (anger), and/or interpersonal abuse cause diabetes, adjusting for gender, age, income, education, diabetes duration, co morbidities, language preference, and acculturation. We incorporated the belief that abuse causes diabetes based on previous ethnographic research. Individuals reporting belief that abuse contributes to diabetes were significantly more likely to report symptoms of depression before (beta = 1.37; p < 0.05) and after adjustment (beta = 2.03; p < 0.001). Believing that susto and/or coraje cause diabetes was not significantly associated with depression before or after adjustment. The significant association between depression and belief that abuse contributes to diabetes onset suggests that belief in a specific form of social distress may be more closely associated with depression among people with diabetes than a folk belief such as susto or coraje. PMID- 22539061 TI - Interactions and relationships in long term care: photography and narratives by direct care workers. AB - The challenge of hiring and retaining well-trained caregivers for the growing numbers of elders in need of care is a global concern. This study was designed to understand the views of direct care workers and included 15 nurse aides and med techs working in an assisted living and special care assisted living community for people with dementia. Each participant was provided with a digital camera and asked to take photographs "to show what caregiving means to you." Analysis is based on group discussions about the full set of photographs created by the direct care workers and individual written and oral narratives about four photographs chosen by each participant. The categories generated from these data represent the direct care workers' perceptions of the approaches to quality caregiving and the relationships involved in doing their jobs well. By focusing on the essential relationships and interactions, rather than primarily on the required care, we can begin to imagine the caregiving experience in terms of a communal rather than an institutional experience. We can then productively turn our focus to the people involved rather than emphasize their roles as providers or recipients of care. PMID- 22539062 TI - Activation of a glioma-specific immune response by oncolytic parvovirus Minute Virus of Mice infection. AB - Rodent autonomous parvoviruses (PVs) are endowed with oncotropic properties and represent virotherapeutics with inherent oncolytic features. This work aimed to evaluate the capacity of Minute Virus of Mice (MVMp) to act as an adjuvant stimulating a mouse glioblastoma-specific immune response. MVMp was shown to induce cell death through apoptosis in glioma GL261 cells. Antigen-presenting cells (APCs) provide the initial cue for innate and adaptive immune responses, and thus MVMp-infected GL261 cells were tested for their ability to activate dendritic cells (DCs) and microglia (MG), two distinct cell types that are able to act as APCs. MG and discrete DC subsets were activated after co-culture with MVMp-infected glioma GL261 cells, as evidenced by upregulation of specific activation markers (CD80, CD86) and release of proinflammatory cytokines (tumor necrosis factor-alpha and interleukin-6). The in vivo analysis of immunodeficient and immunocompetent mice revealed a clear difference in their susceptibility to MVMp-mediated tumor suppression. Immunocompetent mice were fully protected from tumor outgrowth of GL261 cells infected ex vivo with MVMp. In contrast, immunodeficient animals were less competent for MVMp-dependent tumor inhibition, with only 20% of the recipients being protected, arguing for an additional immune component to allow full tumor suppression. In keeping with this conclusion, immunocompetent mice engrafted with MVMp-infected glioma cells developed a level of anti-tumor immunity with isolated splenocytes producing elevated levels of interferon-gamma. In rechallenge experiments using uninfected GL261 cells, we could show complete protection against the tumor, arguing for the induction of a T-cell-mediated, tumor-specific, long-term memory response. These findings indicate that the anticancer effect of PVs can be traced back not only for their direct oncolytic effect, but also to their ability to break tumor tolerance. PMID- 22539063 TI - IL15 combined with Caspy2 provides enhanced therapeutic efficiency against murine malignant neoplasm growth and metastasis. AB - Interleukin-15 (IL15) is a potential immunotherapeutic treatment for cancer. Caspy2 is an active zebra caspase for inducing apoptosis and immune response in murine tumors. In this study, we aim to evaluate the potential of gene therapy using IL15 and Caspy2 against the murine tumors. Plasmid expressing both Caspy2 and IL15 genes was constructed, encapsulated in DOTAP/cholesterol cationic liposome and injected intratumorally into the mice bearing CT26, B16-F10 and 4T1 carcinoma. We found that coexpression of IL15 and Caspy2 could significant inhibit tumor growth and prolong survival of the mice bearing CT26 or B16F10 tumor. A significant reduction in spontaneous lung metastasis was observed in the 4T1 tumor model. In CT26 model, the mice treated with IL15 and Caspy2 acquired a long-time protective immunity against the parental tumor cell rechallenge. Cytotoxic T lymphocytes and terminal deoxynucleotidyltransferase-mediated nick end labelling assays showed that the combination of capsy2 and IL15 could enhance both the apoptosis and immune response induction, which may account for its extraordinary antitumor effect. Furthermore, we showed that the observed tumor suppression by IL15 and Caspy2 concurred with the Caspy2-mediated downregulation of IL10 and upregulation of interferon-gamma and tumor necrosis factor-alpha. Our results therefore suggested that the combination regimen might be a novel and effective strategy for cancer treatment. PMID- 22539064 TI - Histoplasmosis presenting with ulcers on the soft palate. PMID- 22539065 TI - Screening colonoscopy in the US: attitudes and practices of primary care physicians. AB - BACKGROUND: Rising colorectal cancer (CRC) screening rates in the last decade are attributable almost entirely to increased colonoscopy use. Little is known about factors driving the increase, but primary care physicians (PCPs) play a central role in CRC screening delivery. OBJECTIVE: Explore PCP attitudes toward screening colonoscopy and their associations with CRC screening practice patterns. DESIGN: Cross-sectional analysis of data from a nationally representative survey conducted in 2006-2007. PARTICIPANTS: 1,266 family physicians, general practitioners, general internists, and obstetrician-gynecologists. MAIN MEASURES: Physician-reported changes in the volume of screening tests ordered, performed or supervised in the past 3 years, attitudes toward colonoscopy, the influence of evidence and perceived norms on their recommendations, challenges to screening, and practice characteristics. RESULTS: The cooperation rate (excludes physicians without valid contact information) was 75%; 28% reported their volume of FOBT ordering had increased substantially or somewhat, and the majority (53%) reported their sigmoidoscopy volume decreased either substantially or somewhat. A majority (73%) reported that colonoscopy volume increased somewhat or substantially. The majority (86%) strongly agreed that colonoscopy was the best of the available CRC screening tests; 69% thought it was readily available for their patients; 59% strongly or somewhat agreed that they might be sued if they did not offer colonoscopy to their patients. All three attitudes were significantly related to substantial increases in colonoscopy ordering. CONCLUSIONS: PCPs report greatly increased colonoscopy recommendation relative to other screening tests, and highly favorable attitudes about colonoscopy. Greater emphasis is needed on informed decision-making with patients about preferences for test options. PMID- 22539066 TI - Do first opinions affect second opinions? AB - BACKGROUND: Second medical opinions have become commonplace and even mandatory in some health-care systems, as variations in diagnosis, treatment or prognosis may emerge among physicians. OBJECTIVE: To evaluate whether physicians' judgment is affected by another medical opinion given to a patient. DESIGN: Orthopedic surgeons and neurologists filled out questionnaires presenting eight hypothetical clinical scenarios with suggested treatments. One group of physicians (in each specialty) was told what the other physician's opinion was (study group), and the other group was not told what it was (control group). PARTICIPANTS: A convenience sample of 332 physicians in Israel: 172 orthopedic surgeons (45.9% of their population) and 160 neurologists (64.0% of their population). MEASUREMENTS: Scoring was by choice of less or more interventional treatment in the scenarios. We used chi(2) tests and repeated measures ANOVA to compare these scores between the two groups. We also fitted a cumulative ordinal regression to account for the dependence within each physician's responses. RESULTS: Orthopedic surgeons in the study group chose a more interventionist treatment when the other physician suggested an intervention than those in the control group [F (1, 170) =4.6, p=0.03; OR=1.437, 95% CI 1.115-1.852]. Evaluating this effect separately in each scenario showed that in four out of the eight scenarios, they chose a more interventional treatment when the other physician suggested an intervention (scenario 1, p=0.039; scenario 2, p<0.001; scenario 3, p=0.033; scenario 6, p<0.001). These effects were insignificant among the neurologists [F (1,158) =0.44, p=0.51; OR=1.087, 95% CI 0.811-1.458]. In both specialties there were no differences in responses by level of clinical experience [orthopedic surgeons: F (2, 166) =0.752, p=0.473; neurologists: F (2,154) =1.951, p=0.146]. CONCLUSIONS: The exploratory survey showed that in some cases physicians' judgments may be affected by other physicians' opinions, but unaffected in other cases. Weighing previous opinions may yield a more informed clinical decision, yet physicians may be unintentionally influenced by previous opinions. Second opinion has the potential to improve the clinical decision-making processes, and mechanisms are needed to reconcile discrepant opinions. PMID- 22539067 TI - Descriptive study of educated African American women successful at weight-loss maintenance through lifestyle changes. AB - BACKGROUND: Interventions to address obesity and weight loss maintenance among African Americans have yielded modest results. There is limited data on African Americans who have achieved successful long-term weight loss maintenance. OBJECTIVE: To identify a large sample of African American adults who intentionally achieved clinically significant weight loss of 10 %; to describe weight-loss and maintenance efforts of African Americans through a cross sectional survey; to determine the feasibility of establishing a registry of African American adults who have successfully lost weight. DESIGN, SETTING, AND PARTICIPANTS: African American volunteers from the United States >= 18 years of age were invited to complete a cross-sectional survey about weight, weight-loss, weight-loss maintenance or regain. Participants were invited to submit contact information to be maintained in a secure registry. MAIN MEASURES: Percentage of participants who achieved long-term weight-loss maintenance reporting various dietary and physical activity strategies, motivations for and social-cognitive influences on weight loss and maintenance, current eating patterns, and self monitoring practices compared to African Americans who lost weight but regained it. Participants also completed the Short International Physical Activity Questionnaire. KEY RESULTS: Of 3,414 individuals screened, 1,280 were eligible and completed surveys. Ninety-percent were women. This descriptive analysis includes 1,110 women who lost weight through non-surgical means. Over 90 % of respondents had at least some college education. Twenty-eight percent of respondents were weight-loss maintainers. Maintainers lost an average of 24 % of their body weight and had maintained >= 10 % weight loss for an average of 5.1 years. Maintainers were more likely to limit their fat intake, eat breakfast most days of the week, avoid fast food restaurants, engage in moderate to high levels of physical activity, and use a scale to monitor their weight. CONCLUSIONS: Influences and practices differ among educated African American women who maintain weight loss compared to those who regain it. PMID- 22539068 TI - Foreign body-induced abscess resembling pancreatic neoplasia. AB - We report the case of a 44-year-old man presenting with abdominal pain and leukocytosis. His initial computed tomography demonstrated a pancreatic head mass concerning for pancreatic adenocarcinoma. However, on further review of the patient's imaging, the mass was determined to be an abscess caused by foreign body ingestion and gastric perforation rather than cancer. This report describes the clinical and radiographic distinctions between pancreatic neoplasia and abscess. It also reviews the pertinent medical literature on how such viscus perforations affect subsequent prognostication and clinical management. PMID- 22539069 TI - Association of sweetened beverage intake with incident hypertension. AB - BACKGROUND: Consumption of sugar-sweetened beverages (SSBs) is associated with an increased risk of hypertension in cross-sectional studies. However, prospective data are limited. OBJECTIVE: To examine the associations between SSBs and artificially sweetened beverages (ASBs) with incident hypertension. DESIGN AND SETTING: Prospective analysis using Cox proportional hazards regression to examine the association between SSBs and ASBs with incident hypertension in three large, prospective cohorts, the Nurses' Health Studies I (n = 88,540 women) and II (n = 97,991 women) and the Health Professionals' Follow-Up Study (n = 37,360 men). MEASUREMENTS: Adjusted hazard ratios for incident clinically diagnosed hypertension. RESULTS: Higher SSB and ASB intake was associated with an increased risk of developing hypertension in all three cohorts. In a pooled analysis, participants who consumed at least one SSB daily had an adjusted HR for incident hypertension of 1.13 (95 % CI, 1.09-1.17) compared with those who did not consume SSBs; for persons who drank at least one ASB daily, the adjusted HR was 1.14 (95 % CI, 1.09-1.18). The association between sweetened beverage intake and hypertension was stronger for carbonated beverages versus non-carbonated beverages, and for cola-containing versus non-cola beverages in the NHS I and NHS II cohorts only. Higher fructose intake from SSBs as a percentage of daily calories was associated with increased hypertension risk in NHS I and NHS II (p trend = 0.001 in both groups), while higher fructose intake from sources other than SSBs was associated with a decrease in hypertension risk in NHS II participants (p-trend = 0.006). LIMITATIONS: Residual confounding factors may interfere with the interpretation of results. CONCLUSIONS: SSBs and ASBs are independently associated with an increased risk of incident hypertension after controlling for multiple potential confounders. These associations may be mediated by factors common to both SSBs and ASBs (e.g., carbonation or cola), but are unlikely to be due to fructose. PMID- 22539071 TI - Chitin nanofibers: preparations, modifications, and applications. AB - Chitin nanofibers are prepared from the exoskeletons of crabs and prawns by a simple mechanical treatment after the removal of proteins and minerals. The obtained nanofibers have fine nanofiber networks with a uniform width of approximately 10-20 nm and a high aspect ratio. The method used for chitin nanofiber isolation is also successfully applied to the cell walls of mushrooms. They form a complex with glucans on the fiber surface. A grinder, a Star Burst atomization system, and a high speed blender are all used in the mechanical treatment to convert chitin to nanofibers. Mechanical treatment under acidic conditions is the key to facilitate fibrillation. At pH 3-4, the cationization of amino groups on the fiber surface assists nano-fibrillation by electrostatic repulsive force. By applying this finding, we also prepared chitin nanofibers from dry chitin powder. Chitin nanofibers are acetylated to modify their surfaces. The acetyl DS can be controlled from 1 to 3 by changing the reaction time. An acetyl group is introduced heterogeneously from the surface to the core. Nanofiber morphology is maintained even in the case of high acetyl DS. Optically transparent chitin nanofiber composites are prepared with 11 different types of acrylic resins. Due to the nano-sized structure, all of the composites are highly transparent. Chitin nanofibers significantly increase the Young's moduli and the tensile strengths and decrease the thermal expansion of all acrylic resins due to the reinforcement effect of chitin nanofibers. Chitin nanofibers show chiral separation ability. The chitin nanofiber membrane transports the d-isomer of glutamic acid, phenylalanine, and lysine from the corresponding racemic amino acid mixtures faster than the corresponding l-isomer. The chitin nanofibers improve clinical symptoms and suppress ulcerative colitis in a DSS-induced mouse model of acute ulcerative colitis. Moreover, chitin nanofibers suppress myeloperoxidase activation in the colon and decrease serum interleukin-6 concentrations. PMID- 22539072 TI - Effect of glycolysis inhibition on mitochondrial function in rat brain. AB - Inhibition of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase enhances the neural vulnerability to excitotoxicity both in vivo and in vitro through an unknown mechanism possibly related to mitochondrial failure. However, as the effect of glycolysis inhibition on mitochondrial function in brain has not been studied, the aim of the present work was to evaluate the effect of glycolysis inhibition induced by iodoacetate on mitochondrial function and oxidative stress in brain. Mitochondria were isolated from brain cortex, striatum and cerebellum of rats treated systemically with iodoacetate (25 mg/kg/day for 3 days). Oxygen consumption, ATP synthesis, transmembrane potential, reactive oxygen species production, lipoperoxidation, glutathione levels, and aconitase activity were assessed. Oxygen consumption and aconitase activity decreased in the brain cortex and striatum, showing that glycolysis inhibition did not trigger severe mitochondrial impairment, but a slight mitochondrial malfunction and oxidative stress were present. PMID- 22539073 TI - Prospective study of ultraviolet radiation exposure and risk of cancer in the United States. AB - Ecologic studies have reported that solar ultraviolet radiation (UVR) exposure is associated with cancer; however, little evidence is available from prospective studies. We aimed to assess the association between an objective measure of ambient UVR exposure and risk of total and site-specific cancer in a large, regionally diverse cohort [450,934 white, non-Hispanic subjects (50-71 years) in the prospective National Institutes of Health (NIH)-AARP Diet and Health Study] after accounting for individual-level confounding risk factors. Estimated erythemal UVR exposure from satellite Total Ozone Mapping Spectrometer (TOMS) data from NASA was linked to the US Census Bureau 2000 census tract (centroid) of baseline residence for each subject. We used Cox proportional hazards models adjusted for multiple potential confounders to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for quartiles of UVR exposure. Restricted cubic splines examined nonlinear relationships. Over 9 years of follow-up, UVR exposure was inversely associated with total cancer risk (N = 75,917; highest versus lowest quartile; HR = 0.97, 95% CI = 0.95-0.99; p-trend < 0.001). In site specific cancer analyses, UVR exposure was associated with increased melanoma risk (highest versus lowest quartile; HR = 1.22, 95% CI = 1.13-1.32; p-trend < 0.001) and decreased risk of non-Hodgkin's lymphoma (HR = 0.82, 95% CI = 0.74 0.92) and colon (HR = 0.88, 95% CI = 0.82-0.96), squamous cell lung (HR = 0.86, 95% CI = 0.75-0.98), pleural (HR = 0.57, 95% CI = 0.38-0.84), prostate (HR = 0.91, 95% CI = 0.88-0.95), kidney (HR = 0.83, 95% CI = 0.73-0.94) and bladder (HR = 0.88, 95% CI = 0.81-0.96) cancers (all p-trend < 0.05). We also found nonlinear associations for some cancer sites, including the thyroid and pancreas. Our results add to mounting evidence for the influential role of UVR exposure on cancer. PMID- 22539074 TI - Highly regio- and stereoselective dirhodium vinylcarbene induced nitrone cycloaddition with subsequent cascade carbenoid aromatic cycloaddition/N-O cleavage and rearrangement. PMID- 22539075 TI - Solution-free and catalyst-free synthesis of ZnO-based nanostructured TCOs by PED and vapor phase growth techniques. AB - Zinc oxide (ZnO) is one of the most promising materials for realizing three dimensional (3D) nanostructured transparent conducting oxides (TCOs) on large scale, because it is cheap, it can be modified with large concentrations of trivalent elements (such Al, Ga or In) and it is characterized by good electron mobility, wide bandgap and visible-range transparency. But, above all, it can be easily obtained in the form of different nanostructures with a large number of growth techniques. A solution-free and catalyst-free approach has been explored here by the vapor phase synthesis of vertically aligned ZnO nanorods on ZnO:Al (AZO) films grown by pulsed electron deposition (PED). The obtained nanostructured TCOs resulted to be homogeneous on large areas and easily patternable by means of mechanical masks. The morphology, crystalline structure, electrical and optical properties of the obtained samples have been characterized in depth. The possible use of such a nanostructured TCO in excitonic (e.g. DSSC) or low-reflectivity traditional solar cells is discussed. PMID- 22539076 TI - Near-infrared light-triggered, targeted drug delivery to cancer cells by aptamer gated nanovehicles. AB - A novel cell-targeting, near-infrared light-responsive drug delivery platform based on mesoporous silica-coated gold nanorods that are surface-functionalized with aptamer DNA is constructed. Aptamer DNA is used as both capping and targeting agent. In vitro studies show the feasibility of using this nanocarrier for targeted and noninvasive remote controlled drug delivery and photothermal therapy. PMID- 22539077 TI - The effect of flashlamp pulsed dye laser on the expression of connective tissue growth factor in keloids. AB - OBJECTIVE: To investigate connective tissue growth factor (CTGF) expression before and after pulsed dye laser (PDL, 595 nm) treatment, and to better understand the mechanism of PDL treatment of keloids. METHOD: Twenty-six patients with keloids were recruited for this study. For each patient, two keloids of similar anatomic location, duration, texture, and appearance were chosen for study; one of these keloids was treated and the other served as a control. Three sessions of PDL treatment, with pulse duration of 1.5 milliseconds, spot size 7 mm, DCD duration 20 milliseconds/delay 10 milliseconds and fluence of 10 J/cm(2), were performed on the keloids at 3- to 4-week intervals. Punch biopsies were performed both on the treated and untreated keloids prior to the first treatment and after the final treatment. The specimens underwent realtime polymerase chain reaction (PCR) and immunohistochemistry (IHC) to investigate the CTGF mRNA and protein expression after PDL treatment. RESULTS: According to realtime PCR, the CTGF mRNA was significantly down-regulated after PDL treatment in 80.77% of patients as compared to the control group. IHC investigation showed that after treatment the CTGF positive cells also significantly decreased in number as compared to the control group in 80.77% of patients. Using the Vancouver scar scale (VSS), there was an average decrease of 20.85 +/- 12.33% after PDL treatment. CONCLUSIONS: Pulsed dye laser treatment of keloids significantly down regulates the expression of CTGF in most cases. This may partially explain the mechanism of action of PDL treatment of keloids. PMID- 22539078 TI - Correlation of thrombosis growth rate to pathological wall shear rate during platelet accumulation. AB - Local hemodynamics may strongly influence atherothrombosis, which can lead to acute myocardial infarction and stroke. The relationship between hemodynamics and thrombosis during platelet accumulation was studied through an in vitro flow system consisting of a stenosis. Specifically, wall shear rates (WSR) ranging from 0 to 100,000 s(-1) were ascertained through computations and compared with thrombus growth rates found by image analysis for over 5,000 individual observation points per experiment. A positive correlation (P < 0.0001) was found between thrombus accumulation rates and WSR up to 6,000 s(-1), with a decrease in growth rates at WSR >6,000 s(-1) (P < 0.0001). Furthermore, growth rates at pathological shear rates were found to be two to four times greater than for physiological arterial shear rates below 400 s(-1). Platelets did not accumulate for the first minute of perfusion. The initial lag time, before discernible thrombus growth could be found, diminished with shear (P < 0.0001). These studies show the quantitative increase in thrombus growth rates with very high shear rates in stenoses onto a collagen substrate. PMID- 22539079 TI - Survey non-response in an internet-mediated, longitudinal autism research study. AB - OBJECTIVE: To evaluate non-response rates to follow-up online surveys using a prospective cohort of parents raising at least one child with an autism spectrum disorder. A secondary objective was to investigate predictors of non-response over time. MATERIALS AND METHODS: Data were collected from a US-based online research database, the Interactive Autism Network (IAN). A total of 19,497 youths, aged 1.9-19 years (mean 9 years, SD 3.94), were included in the present study. Response to three follow-up surveys, solicited from parents after baseline enrollment, served as the outcome measures. Multivariate binary logistic regression models were then used to examine predictors of non-response. RESULTS: 31,216 survey instances were examined, of which 8772 or 28.1% were partly or completely responded to. Results from the multivariate model found non-response of baseline surveys (OR 28.0), years since enrollment in the online protocol (OR 2.06), and numerous sociodemographic characteristics were associated with non response to follow-up surveys (all p<0.05). DISCUSSION: Consistent with the current literature, response rates to online surveys were somewhat low. While many demographic characteristics were associated with non-response, time since registration and participation at baseline played the greatest role in predicting follow-up survey non-response. CONCLUSION: An important hazard to the generalizability of findings from research is non-response bias; however, little is known about this problem in longitudinal internet-mediated research (IMR). This study sheds new light on important predictors of longitudinal response rates that should be considered before launching a prospective IMR study. PMID- 22539080 TI - Pneumonia identification using statistical feature selection. AB - OBJECTIVE: This paper describes a natural language processing system for the task of pneumonia identification. Based on the information extracted from the narrative reports associated with a patient, the task is to identify whether or not the patient is positive for pneumonia. DESIGN: A binary classifier was employed to identify pneumonia from a dataset of multiple types of clinical notes created for 426 patients during their stay in the intensive care unit. For this purpose, three types of features were considered: (1) word n-grams, (2) Unified Medical Language System (UMLS) concepts, and (3) assertion values associated with pneumonia expressions. System performance was greatly increased by a feature selection approach which uses statistical significance testing to rank features based on their association with the two categories of pneumonia identification. RESULTS: Besides testing our system on the entire cohort of 426 patients (unrestricted dataset), we also used a smaller subset of 236 patients (restricted dataset). The performance of the system was compared with the results of a baseline previously proposed for these two datasets. The best results achieved by the system (85.71 and 81.67 F1-measure) are significantly better than the baseline results (50.70 and 49.10 F1-measure) on the restricted and unrestricted datasets, respectively. CONCLUSION: Using a statistical feature selection approach that allows the feature extractor to consider only the most informative features from the feature space significantly improves the performance over a baseline that uses all the features from the same feature space. Extracting the assertion value for pneumonia expressions further improves the system performance. PMID- 22539081 TI - Evaluating the reliability, validity, acceptability, and practicality of SMS text messaging as a tool to collect research data: results from the Feeding Your Baby project. AB - OBJECTIVE: To test the reliability, validity, acceptability, and practicality of short message service (SMS) messaging for collection of research data. MATERIALS AND METHODS: The studies were carried out in a cohort of recently delivered women in Tayside, Scotland, UK, who were asked about their current infant feeding method and future feeding plans. Reliability was assessed by comparison of their responses to two SMS messages sent 1 day apart. Validity was assessed by comparison of their responses to text questions and the same question administered by phone 1 day later, by comparison with the same data collected from other sources, and by correlation with other related measures. Acceptability was evaluated using quantitative and qualitative questions, and practicality by analysis of a researcher log. RESULTS: Reliability of the factual SMS message gave perfect agreement. Reliabilities for the numerical question were reasonable, with kappa between 0.76 (95% CI 0.56 to 0.96) and 0.80 (95% CI 0.59 to 1.00). Validity for data compared with that collected by phone within 24 h (kappa =0.92 (95% CI 0.84 to 1.00)) and with health visitor data (kappa =0.85 (95% CI 0.73 to 0.97)) was excellent. Correlation validity between the text responses and other related demographic and clinical measures was as expected. Participants found the method a convenient and acceptable way of providing data. For researchers, SMS text messaging provided an easy and functional method of gathering a large volume of data. CONCLUSION: In this sample and for these questions, SMS was a reliable and valid method for capturing research data. PMID- 22539082 TI - Deriving rules and assertions from pharmacogenomics knowledge resources in support of patient drug metabolism efficacy predictions. AB - OBJECTIVE: Pharmacogenomics evaluations of variability in drug metabolic processes may be useful for making individual drug response predictions. We present an approach to deriving 'phenotype scores' based on existing pharmacogenomics knowledge and a patient's genomics data. Pharmacogenomics plays an important role in the bioactivation of tamoxifen, a prodrug administered to patients for breast cancer treatment. Tamoxifen is therefore considered a model for many drugs requiring bioactivation. We investigate whether this knowledge based approach can be applied to produce a phenotype score that is predictive of the endoxifen/N-desmethyltamoxifen (NDM) plasma concentration ratio in patients taking tamoxifen. MATERIALS AND METHODS: We implement a knowledge-based model for calculating phenotype scores from patient-specific genotype data. These data include allelic variants of genes encoding enzymes involved in the bioactivation of tamoxifen. We performed quantile linear regression to evaluate whether six phenotype scoring algorithms are predictive of patient endoxifen/NDM plasma concentration ratio, and validate our scoring methods. RESULTS: Our model illustrates a knowledge-based approach to predict drug metabolism efficacy given patient genomics data. Results showed that for one phenotype scoring algorithm, scores were weakly correlated with patient endoxifen/NDM plasma concentration ratios. This algorithm performed better than simple metrics for variation in individual and multiple genes. DISCUSSION: We discuss advantages of the model, challenges to its implementation in a personalized medicine context, and provide example future directions. CONCLUSIONS: We demonstrate the utility of our model in a tamoxifen case study context. We also provide evidence that more complicated polygenic models are needed to represent heterogeneity in clinical outcomes. PMID- 22539083 TI - High-priority drug-drug interactions for use in electronic health records. AB - OBJECTIVE: To develop a set of high-severity, clinically significant drug-drug interactions (DDIs) for use in electronic health records (EHRs). METHODS: A panel of experts was convened with the goal of identifying critical DDIs that should be used for generating medication-related decision support alerts in all EHRs. Panelists included medication knowledge base vendors, EHR vendors, in-house knowledge base developers from academic medical centers, and both federal and private agencies involved in the regulation of medication use. Candidate DDIs were assessed by the panel based on the consequence of the interaction, severity levels assigned to them across various medication knowledge bases, availability of therapeutic alternatives, monitoring/management options, predisposing factors, and the probability of the interaction based on the strength of evidence available in the literature. RESULTS: Of 31 DDIs considered to be high risk, the panel approved a final list of 15 interactions. Panelists agreed that this list represented drugs that are contraindicated for concurrent use, though it does not necessarily represent a complete list of all such interacting drug pairs. For other drug interactions, severity may depend on additional factors, such as patient conditions or timing of co-administration. DISCUSSION: The panel provided recommendations on the creation, maintenance, and implementation of a central repository of high severity interactions. CONCLUSIONS: A set of highly clinically significant drug-drug interactions was identified, for which warnings should be generated in all EHRs. The panel highlighted the complexity of issues surrounding development and implementation of such a list. PMID- 22539084 TI - A short-term high-dose administration of sodium pivalate impairs pyruvate metabolism without affecting cardiac function. AB - The pivalate moiety of some oral antibiotics enhances their intestinal absorption, but liberated pivalic acid decreases tissue carnitine concentration and could lead to impaired energy metabolism. The present study investigated the effects of short-term sodium pivalate administration on cardiac functionality and mitochondrial energy metabolism. Wistar rats received sodium pivalate (40 mM) in their drinking water for 14 days, and the carnitine content was measured in heart tissues. The activities of carnitine-dependent enzymes, including carnitine acetyltransferase (CrAT) and carnitine palmitoyltransferase I (CPT I), and the mitochondrial respiration rate were also measured. The isolated rat heart ischemia-reperfusion injury assay was performed based on the Langendorff technique through the reversible occlusion of the left anterior descending coronary artery. The administration of sodium pivalate decreased carnitine concentration in the myocardium by 37 %. Sodium pivalate significantly decreased mitochondrial respiration on pyruvate/malate by 28 %. The activities of CrAT and CPT I in sodium pivalate-treated animals were decreased by 34 and 30 %, respectively. No differences were observed in the infarct size or in the heart functional parameters between the groups. Together, these results indicate that the short-term administration of a high dose of sodium pivalate impairs cardiac mitochondrial energy metabolism without depressing cardiac function during ischemia-reperfusion injury. PMID- 22539085 TI - Combining synthetic carbohydrate vaccines with cancer cell glycoengineering for effective cancer immunotherapy. AB - Tumor-associated carbohydrate antigens (TACAs) are useful targets for the development of cancer vaccines or immunotherapies. However, a major obstacle in this application of TACAs is their poor immunogenicity. To overcome the problem, a new immunotherapeutic strategy combining synthetic vaccines made of artificial TACA derivatives and metabolic glycoengineering of cancer cells to express the artificial TACA derivatives was explored. Using a murine leukemia model FBL3 with GM3 antigen as the target, it was shown that artificial GM3 N-phenylacetyl derivative (GM3NPhAc) elicited robust antigen-specific T cell-dependent immunity and that N-phenylacetyl-D-mannosamine (ManNPhAc) as the biosynthetic precursor of GM3NPhAc selectively glycoengineered cancer cells to express GM3NPhAc both in vitro and in vivo. It was also demonstrated that GM3NPhAc-specific antisera and antibodies mediated strong cytotoxicity to ManNPhAc-treated FBL3 cell. Furthermore, vaccination with a conjugate vaccine made of GM3NPhAc followed by ManNPhAc treatment could significantly suppress tumor growth and prolong the survival of tumor-bearing mouse. These results have proved the feasibility of the new cancer immunotherapeutic strategy, as well as its efficacy to cure cancer, which is of general significance. PMID- 22539086 TI - Biplanar MRI for the assessment of the spinal cord in multiple sclerosis. AB - OBJECTIVE: To investigate the entire spinal cord (SC) of multiple sclerosis (MS) patients with biplanar MRI and to relate these MRI findings to clinical functional scores. METHODS: Two hundred and two patients (140 women, 62 men 24-74 years, Expanded Disability Status Scale (EDSS) scores 0-7.5) were investigated clinically and with biplanar MRI. Sagittal and axial proton density weighted (PDw) and T2 weighted (T2w) images of the whole SC were obtained employing parallel imaging. Data were analyzed by consensus reading using a standardized reporting scheme. Different combinations of findings were compared to EDSS scores with Spearman's rank correlation coefficient (rho). RESULTS: The combined analysis of sagittal and axial planes demonstrated slightly differing results in 97/202 (48%) patients. There were 9% additional lesions identified, leading to a higher lesion count in 28% of these patients, but also rejection of equivocal abnormality leading to a lower lesion count in 11% of patients. Considering both sagittal and axial images, SC abnormalities were found in 167/202 (83%) patients. When compared with EDSS scores, the combination of focal lesions, signs of atrophy and diffuse abnormalities showed a moderate correlation (rho=0.52), that precludes its use for individual patient assessment. CONCLUSION: Biplanar MRI facilitates a comprehensive identification, localization, and grading of pathological SC findings in MS patients. This improves the confidence and utility of SC imaging. PMID- 22539087 TI - Fate of metastatic foci after chemotherapy and usefulness of contrast-enhanced intraoperative ultrasonography to detect minute hepatic lesions. AB - BACKGROUND/PURPOSE: Along with advances in the chemotherapy for colorectal cancer, the strategy for hepatic metastasis has been changed. One of the most striking issues is that initially unresectable hepatic metastases can be resectable after chemotherapy with considerably high frequency. In addition, advanced chemotherapy leads to the downsizing of the metastatic foci in the liver, which is sometimes difficult to detect with conventional intraoperative ultrasonography (IOUS). To discover the undetectable hepatic lesions with IOUS, we have introduced contrast-enhanced intraoperative ultrasonography (CEIOUS). In the present study, we present evidence that viable cancer cells exist in even the shrunken tumors with high frequency and that CEIOUS contributes to detecting the minute foci. METHODS: This study was composed of eight patients; four of them had initially unresectable metastasis, and the remaining four had either H2 or H3 status of hepatic metastases. All of them underwent hepatic resection after chemotherapy. RESULTS: A total of 57 metastatic lesions were detected before chemotherapy. Thirty lesions were demonstrated by CEIOUS with perflubutane and resected. In the pathological examination, tumor cells were not found in 12 of the 30 resected lesions. The degree of pathological liver damage was grade 1 or less in all patients, and no serious complication occurred after surgery in any of the patients. CONCLUSION: The present study showed that viable cancer cells remained with high frequency, even in the minute hepatic metastasis which was reduced in size after chemotherapy, and CEIOUS was a useful examination for detecting the minute hepatic foci. PMID- 22539088 TI - Hemostasis using a fully covered self-expandable metal stent for marked bleeding from the bile duct following stent removal (with videos). AB - We describe a case of life-threatening hemorrhage from the bile duct following stent removal. Eventually, hemostasis was achieved by tamponade using a fully covered self-expandable metal stent. PMID- 22539090 TI - Circulating vascular endothelial growth factor receptor 2/pAkt-positive cells as a functional pharmacodynamic marker in metastatic colorectal cancers treated with antiangiogenic agent. AB - OBJECTIVE: The anti-vascular endothelial growth factor (VEGF) antibody bevacizumab has received considerable attention as a first-line treatment of advanced colorectal cancers. Difficulties associated with effectively monitoring the activity of this drug have prompted us to seek a pharmacodynamic marker suitable for defining the optimum biological dose and schedule of bevacizumab administration against colon cancer in early clinical trials. METHODS: We evaluated inhibitory effects of bevacizumab on VEGF signaling and tumor growth in vitro and in vivo, and assessed phosphorylation of VEGF receptor 2 (VEGFR2) and downstream signaling in endothelial cells as pharmacodynamic markers using phospho-flow cytometry. We also validated markers in patients with metastatic colorectal cancer (mCRC) treated with bevacizumab-based chemotherapy. RESULTS: In in vitro studies, bevacizumab inhibited proliferation of human umbilical vein endothelial cells in association with reduced VEGF signaling. Notably, bevacizumab inhibited VEGF-induced phosphorylation of VEGFR-2, Akt, and extracellular signal-regulated kinase (ERK). In vivo, treatment with bevacizumab inhibited growth of xenografted tumors and attenuated VEGF-induced phosphorylation of Akt and ERK. The median percentages of VEGFR2 + pAkt + and VEGFR2 + pERK + cells, determined by phospho-flow cytometry, were approximately 3 fold higher in mCRC patients than in healthy controls. Bevacizumab treatment decreased VEGFR2 + pAkt + cells in 18 of 24 patients on day 3. CONCLUSION: Bevacizumab combined with chemotherapy decreased the number of VEGFR2 + pAkt + cells, reflecting impaired VEGFR2 signaling. Together, these data suggest that changes in the proportion of circulating VEGFR2 + pAkt + cells may be a potential pharmacodynamic marker of the efficacy of antiangiogenic agents, and could prove valuable in determining drug dosage and administration schedule. PMID- 22539092 TI - Effect of electrochemical structuring of Ti6Al4V on osteoblast behaviour in vitro. AB - Topography and surface chemistry have a profound effect on the way in which cells interact with an implant, which in turn impacts on clinical use and performance. In this paper we examine an electrochemical polishing approach in H2SO4/methanol that can be applied to the widely used orthopaedic/dentistry implant material, Ti6Al4V, to produce structured surfaces. The surface roughness, as characterized by R(a), was found to be dependent on the time of electropolishing but not on the voltage parameters used here. The surface chemistry, however, was dependent on the applied electrochemical potential. It was found that the chemical composition of the surface layer was modified during the electrochemical process, and at high potentials (9.0 V) a pure TiO2 layer of at least 10 nm was created on top of the bulk alloy. Characterization of these surfaces with rat cells from the osteoblast lineage provided further evidence of contact guidance by microscale topography with morphology analysis correlating with surface roughness (R(a) 300-550 nm). Formation of a bone-like matrix after long-term culture on these surfaces was not strongly dependent upon R(a) values but followed the voltage parameter. These findings suggest that the surfaces created by treatment at higher voltages (9.0 V) produced a nanoscale layer of pure TiO2 on the Ti6Al4V surface that influenced the programme of cellular differentiation culminating in osteogenesis. PMID- 22539091 TI - A phase II study of tasisulam sodium (LY573636 sodium) as second-line or third line treatment for patients with unresectable or metastatic soft tissue sarcoma. AB - BACKGROUND: Tasisulam sodium (hereafter tasisulam), a novel anticancer agent, is being studied in a broad range of tumors. The primary objective of this phase II study was to determine progression-free survival (PFS) in patients with 1 or 2 prior chemotherapy regimens for unresectable/metastatic soft tissue sarcoma (STS). Secondary objectives included objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS), pharmacokinetics, and safety. METHODS: Tasisulam was administered intravenously on day 1 of 21-day cycles according to a lean body weight-based dosing algorithm targeting a peak plasma concentration (C(max)) of 420 MUg/mL; a 360-MUg/mL dose level was also explored. RESULTS: The median age of patients treated at 420 MUg/mL was 58.3 years (range, 18.6-80.4; n = 63). Median PFS was 2.64 months (90 % CI, 1.41-3.38), with a 6-month PFS rate of 11 % (90 % CI, 4-17). Median OS was 8.71 months (90 % CI, 7.39-16.23); ORR, 3.2 %; and CBR, 46.0 % (stable disease, n = 27; partial response/confirmed, n = 2 [angiosarcoma and leiomyosarcoma]; partial response/unconfirmed, n = 1 [desmoplastic small round cell tumor]). The most frequent drug-related grade 3/4 toxicities in patients treated at 420 MUg/mL were thrombocytopenia (27.0 %) and neutropenia (22.2 %). Incidences of grade 4 thrombocytopenia and/or neutropenia were 20.6 % in patients treated at 420 MUg/mL and 15.8 % in those treated at 360 MUg/mL (n = 38). CONCLUSIONS: Tasisulam at a target C(max) of 420 MUg/mL on day 1 of 21-day cycles demonstrated modest activity as second-/third-line treatment in patients with STS. Grade 4 hematologic toxicity posed some challenges in these heavily pre-treated patients. Tasisulam dosing continues to be refined. PMID- 22539093 TI - Cochlear implant performance in geriatric patients. AB - OBJECTIVES/HYPOTHESIS: To evaluate the hearing performance with cochlear implants (CIs) in patients who were 70 years or older at the time of implantation (geriatric patients) and compare it with the performance in younger adults. STUDY DESIGN: Individual, retrospective, cohort study. METHODS: A cohort of 1,005 postlingually deafened adults was selected for this study. According to their age at the time of cochlear implantation, patients were divided into four age groups: group 1, 18 to 39 years; group 2, 40 to 59 years; group 3, 60 to 69 years; and group 4, 70 years and older). The test battery was composed of four standard German speech tests: Freiburger Monosyllabic Test, Speech Tracking Test, and Hochmair-Schulz-Moser (HSM) Sentence Test in quiet and in 10 dB noise. RESULTS: Geriatric patients showed a similar learning curve as the younger adults in the first 2 years after implantation. The direct comparison of speech perception in the Freiburger Monosyllabic Test, Speech Tracking Test, and HSM Test in quiet revealed no differences between the average performance of the geriatric patients and younger adults. However, in the HSM Test in noise, the performance of the geriatric group was significantly lower than the younger adults. CONCLUSIONS: Geriatric CI patients have a similar learning curve to younger adults, and in speech tests in quiet they show a comparable performance. However, their performance is significantly lower in noisy surroundings. This may be due to the central presbycusis in patients older than 70 years and should be taken into account in postoperative fitting of these patients. Further prospective studies are required to evaluate the role of special rehabilitation methods and cognitive training to improve the speech perception in noise in geriatric CI patients. PMID- 22539094 TI - SILS cholecystectomy, early experience of a single institution: pilot study of 21 cases. AB - Many surgeons have attempted to reduce the number and the size of ports in laparoscopic cholecystectomy to decrease parietal trauma and pain, and to improve cosmetic results. We report a series of laparoscopic cholecystectomies using a single-port technique (SILS) through an umbilical incision in a pilot group of 21 cases. Our goal was to validate and develop the single-port access as a viable option. All the operations were performed using an umbilical SILS port (Ethicon). Most reported techniques utilize special purpose-made instruments. This article provides a stepwise description of the procedure using all straight instruments. No special reticulating instruments or flexible telescopes were used. We report our early difficulties and concerns about the procedure and propose solutions to the problems. Patients' request for improved cosmesis impels surgeons toward the application of SILS, but the true advantage of the technique should be assessed by more evidences. For this reason, we are planning a single-institution, prospective randomized controlled trial to compare postoperative pain, operating time and cosmetic result between one port and standard laparoscopic surgery. PMID- 22539095 TI - Correlation between coping strategies and subjective assessment of the voice related quality of life of patients after resection of T1 and T2 laryngeal tumours. AB - When coming to terms with a diagnosis of laryngeal cancer, patients find different ways of coping with their illness. These may or may not be related to communication. Vocal aspects of quality of life are particularly important with cancer of the larynx. The correlation between coping and subjective assessment of the voice-related quality of life was assessed in a cross-sectional study of patients after resection of T1 and T2 laryngeal tumours. As part of follow-up care, 55 male cancer patients with partial laryngectomy were asked about their voice-related quality of life and their coping strategies. The Voice-Related Quality of Life Questionnaire (V-RQOL) and the Trier Coping Scales (TCS) were used as survey instruments. The voice-related quality of life of the patients was assessed on average as medium to good. The coping strategy most frequently chosen by patients was 'threat prevention', followed by 'search for social integration', 'rumination', 'search for information and experience exchange' and 'search for support in religion'. Correlations between coping strategy and the voice-related quality of life were weak to moderate and somewhat inconsistent in this patient population. There was no consistent or strong correlation between voice-related quality of life and coping strategies in male patients with partial laryngectomy, so that individual differences appeared to be more important in coping with illness than primarily voice-related factors such as the voice-related quality of life. PMID- 22539096 TI - [New anticoagulants for stroke prevention in atrial fibrillation]. AB - Oral anticoagulation with vitamin K antagonists (warfarin, phenprocoumon) is successful in both primary and secondary stroke prevention for patients with atrial fibrillation (AF), yielding a 60-70% relative reduction in stroke risk compared with placebo and a mortality reduction of 26%. However, these agents have a number of well documented shortcomings. This review describes the current landscape and developments in stroke prevention in patients with AF with special reference to secondary prevention. A number of new drugs for oral anticoagulation that do not exhibit the limitations of vitamin K antagonists are under investigation. These include direct factor Xa inhibitors and direct thrombin inhibitors. Recent studies (RE-LY, ROCKET-AF, AVERROES, ARISTOTLE) provide promising results for these new agents including higher efficacy and significantly lower incidences of intracranial bleeding compared with warfarin. The new substances show similar results in secondary as well as in primary stroke prevention in patients with AF. The new anticoagulants add to the therapeutic options for patients with AF and offer a number of advantages over warfarin for both clinician and patient, including a favorable bleeding profile and convenience of use. Consideration of these new anticoagulants will improve clinical decision-making. PMID- 22539097 TI - [New anticoagulant drugs for atrial fibrillation. Feasibility and necessity of monitoring]. AB - Two novel oral anticoagulants, namely the direct thrombin inhibitor dabigatran and the direct factor Xa inhibitor rivaroxaban, have recently been approved for treatment of atrial fibrillation. They differ in many ways from vitamin K antagonists, including rapid onset of action, shorter half-life, fewer drug-drug interactions, lack of a need for monitoring and no need for titration or dose adjustments. Commonly available global coagulation time assessments (e.g. prothrombin time and activated partial thromboplastin time) are highly influenced by rivaroxaban and dabigatran but these assays are relatively insensitive. Ideally these anticoagulant agents would be assessable using a sensitive and standardized test with a linear dose-response curve. Optimized assays are currently under investigation and may quantify the anticoagulant effect. At present the therapeutic ranges for dose adjustment have not yet been established. PMID- 22539098 TI - [Role of vitamin K antagonists from a hepatologist's point of view]. AB - Vitamin K antagonists are often used as oral anticoagulants for primary and secondary prevention of thromboembolic events. Vitamin K antagonists induce an anticoagulant effect by interfering with the vitamin K metabolism in the liver. Well-known complications are bleeding events and skin necrosis. Recent data indicate increasing numbers of cases with hepatic complications due to vitamin K antagonists ranging from mild hepatopathy to acute liver failure with high mortality. Hepatotoxicity is usually developed after a few months of latency, which is associated with unspecific symptoms, jaundice, elevated transaminase levels as well as cholestatic enzymes. Hepatotoxicity due to vitamin K antagonists is seldom; however, it should be considered in cases of elevated liver enzymes. In this case coumarin therapy should be discontinued. Caution is needed when changing to another coumarin derivative because cross-reactivity has been described. PMID- 22539099 TI - [Interventional left atrial appendage occlusion. A reasonable alternative to oral anticoagulation - even in the era of the new substances?]. AB - As a potential alternative to long-term oral anticoagulation with vitamin K antagonists in patients with atrial fibrillation, the interventional left atrial appendage occlusion has shown to be non-inferior regarding neurological events. With the new oral direct factor II and factor Xa inhibitors playing an emerging role in stroke prophylaxis, an individual treatment strategy has to be found weighing bleeding and stroke risk against the peri-interventional complication rate based on established risk scores. PMID- 22539100 TI - The effect of slice thickness on the assessment of bone defect volumes by the Cavalieri principle using cone beam computed tomography. AB - The purpose of this study was to investigate the possible effects of section thickness on volume estimations obtained by cone beam computed tomography. Intraosseal cavities representing bone defects on vestibular sides of the two dry sheep mandibles were scanned by a cone beam computed tomography system. Consecutive sections at 0.2, 0.6, 1, 1.4, and 2.2 mm thickness were used to estimate the volumes of the cavities using the Cavalieri principle of stereological methods. Estimated volumes are then compared with the volumes obtained by the Archimedean principle. In 0.2-, 0.6-, and 1-mm-thick slices, the volumes estimated by the Cavalieri principle did not differ from the volumes by the Archimedean principle (p > 0.05). The 0.2 mm slice-thickness group had the highest asymptotic significance value (p = 0.6). Although the thinnest slice appears to provide the most accurate values, slice thickness up to 1 mm can be chosen for volume calculations on CBCT images. PMID- 22539107 TI - Challenges to the development of bryostatin-type anticancer drugs based on the activation mechanism of protein kinase Cdelta. AB - Protein kinase C (PKC) isozymes are widely recognized as targets for anticancer therapy, and recent investigations demonstrated that PKC activators are potential therapeutic candidates for Alzheimer's disease and acquired immune deficiency syndrome. However, concerns exist about their therapeutic uses because most PKC activators are potent tumor promoters. Bryostatin 1 (bryo-1) is a unique PKC activator with little tumor-promoting activities. Bryo-1 is currently undergoing clinical trials for the treatment of cancer. However, its limited availability from natural sources and difficulty in the synthesis hamper further studies on its mode of action and structural optimization. Although excellent practical methods for synthesizing several bryo-1-related compounds have been developed, the identification of synthetically more accessible compounds with bryo-1-like activity also provides a promising way to circumvent the problem of supply. The authors focused on the bryo-1's unique mechanism of activating PKCdelta that plays a tumor suppressor role, and found that a simple and less lipophilic analogue (aplog-1) of the tumor-promoting aplysiatoxin showed PKCdelta-activating behavior similar to bryo-1. Aplog-1 was easily synthesized in only 22 steps using standard reactions. Moreover, its tumor-promoting activity in vitro was very weak, and its cell growth-inhibitory activities were comparable to those of bryo 1. These data suggest that aplog-1 could become another therapeutic lead for cancer. PMID- 22539102 TI - Infectious causes of posterior uveitis and panuveitis in Thailand. AB - PURPOSE: To determine the infectious causes of posterior uveitis (PU) and panuveitis (panU) in Thailand. METHODS: We investigated the infectious causes of uveitis involving the posterior segment of the eye by using real-time polymerase chain reaction (PCR) for cytomegalovirus (CMV), herpes simplex virus (HSV-1, HSV 2), varicella zoster virus and Toxoplasma gondii (T. gondii) DNA in intraocular samples of 80 human immunodeficiency virus (HIV)-negative patients. Additionally, in 61 patients, we performed Goldmann-Witmer coefficient (GWC) analysis for T. gondii. RESULTS: Twenty-four (30 %) patients with PU and/or panU had a positive PCR result. Overall, CMV was the most frequently identified organism. While CMV was the most common cause of uveitis in the patients on immunosuppressive medications for nonocular disorders, HSV was the most common cause of posterior and panuveitis in the patients not receiving such medication. In 38 PU patients, CMV was the most common detected pathogen. In 42 panU patients, CMV and HSV-2 were the most frequently identified pathogens. Out of 61 paired samples analyzed for T. gondii by GWC analysis, only 1 revealed a positive result. There was no difference in PCR results between aqueous humor and vitreous samples. CONCLUSIONS: CMV was the most frequently identified infectious organism in posterior and panuveitis of HIV-1-negative Thai patients. Aqueous humor and vitreous samples showed similar diagnostic values in PCR analysis. PMID- 22539101 TI - Blocking IL-25 signalling protects against gut inflammation in a type-2 model of colitis by suppressing nuocyte and NKT derived IL-13. AB - BACKGROUND: Interleukin-25 (IL-25) is a potent activator of type-2 immune responses. Mucosal inflammation in ulcerative colitis is driven by type-2 cytokines. We have previously shown that a neutralizing anti-IL-25 antibody abrogated airways hyperreactivity in an experimental model of lung allergy. Therefore, we asked whether blocking IL-25 via neutralizing antibodies against the ligand or its receptor IL-17BR could protect against inflammation in an oxazolone-induced mouse model of colitis. METHODS: Neutralizing antibodies to IL 25 or IL-17BR were administered to mice with oxazolone-induced colitis, a model of ulcerative colitis. The disease onset was evaluated by weight loss and degree of colon ulceration. Also, lamina propria and mesenteric lymph node (MLN) infiltrates were assessed for mucosal inflammation and cultured in vitro to determine cytokine production. RESULTS: We found that in oxazolone colitis IL-25 production derives from intestinal epithelial cells and that IL-17BR(+) IL-13 producing natural killer T (NKT) cells and nuocytes drive the intestinal inflammation. Blocking IL-25 signalling considerably improved the clinical aspects of the disease, including weight loss and colon ulceration, and resulted in fewer nuocytes and NKT cells infiltrating the mucosa. The improved pathology correlated with a decrease in IL-13 production by lamina propria cells, a decrease in the production of other type-2 cytokines by MLN cells, and a decrease in blood eosinophilia and IgE. CONCLUSION: IL-25 plays a pro-inflammatory role in the oxazolone colitis model, and neutralizing antibodies to IL-25 or IL-17BR can slow the ongoing inflammation in this disease. Because this model mimics aspects of human ulcerative colitis, these antibodies may represent potential therapeutics for reducing gut inflammation in patients. PMID- 22539108 TI - Recognition of damaged DNA: structure and dynamic markers. AB - DNA damage, a consequence of external factors and inherent metabolic processes, is omnipresent. Nature has devised multiple strategies to safeguard the genetic information and developed intricate repair mechanisms and pathways to reverse an array of different DNA lesions, including mismatches. Failure of the DNA repair systems may result in mutation, premature ageing, and cancer. In this review, we focus on structural and dynamic aspects of detection of lesions in base excision and mismatch repair. A thorough understanding of repair, pathways, and regulation is necessary to develop strategies for targeting DNA-related pathologies. PMID- 22539109 TI - Efficient nonlinear optical properties of dyes confined in interlayer nanospaces of clay minerals. AB - Nonlinear optical (NLO) responses from organic dyes can be maximized when the dyes are aligned in appropriate manners in bulk materials. The use of restricted nanospaces provided by interlayer spacing of inorganic layered materials is a promising strategy for imposing suitable molecular alignments for NLO materials on dyes. The hybrid materials thus obtained exhibit salient NLO responses owing to the improved molecular orientation. In some cases, extension of the pi electron system as a consequence of improved molecular planarity, obtained by the intercalation of a dye into the 2-dimensional interlayer space of an inorganic layered material, is also observed as a factor that enhances NLO responses of chromophores at the molecular level. This review focuses on recent progress in the strategies for controlling the molecular orientation of NLO-phores by employing clay minerals, which are one of the typical inorganic layered materials. In addition, development of a means for fabricating composites that satisfy the properties of an optical material, such as a sufficient size and thickness, a flat surface, and low light-scattering characteristics is required to utilize the superior NLO properties observed for clay/dye hybrid materials for practical applications. A novel means for obtaining such a hybrid material is also outlined. PMID- 22539110 TI - Photoelectrochemical activity of as-grown, alpha-Fe2O3 nanowire array electrodes for water splitting. AB - Undoped hematite nanowire arrays grown using plasma oxidation of iron foils show significant photoactivity (~0.38 mA cm(-2) at 1.5 V versus reversible hydrogen electrode in 1 M KOH). In contrast, thermally oxidized nanowire arrays grown on iron exhibit no photoactivity due to the formation of a thick (>7 MUm Fe(1-x)O) interfacial layer. An atmospheric plasma oxidation process required only a few minutes to synthesize hematite nanowire arrays with a 1-5 MUm interfacial layer of magnetite between the nanowire arrays and the iron substrate. An amorphous oxide surface layer on hematite nanowires, if present, is shown to decrease the resulting photoactivity of as-synthesized, plasma grown nanowire arrays. The photocurrent onset potential is improved after removing the amorphous surface on the nanowires using an acid etch. A two-step method involving high temperature nucleation followed by growth at low temperature is shown to produce a highly dense and uniform coverage of nanowire arrays. PMID- 22539111 TI - [Negative influence of undertreatment in elderly patients with breast cancer]. PMID- 22539112 TI - Covalently bound benzyl ligand promotes selective palladium-catalyzed oxidative esterification of aldehydes with alcohols. PMID- 22539113 TI - Distinct expression and activity of GSK-3alpha and GSK-3beta in prostate cancer. AB - Glycogen synthase kinase (GSK-3) is upregulated in many types of tumor, including prostate cancer. GSK-3 inhibitors reduce prostate tumor cell growth; however, it is not clear if both isoforms, GSK-3alpha and GSK-3beta, are involved. Here, we compared their expression in prostate tumors and used gene silencing to study their functions in 22Rv1 prostate cancer cells. Compared to normal prostate, GSK 3alpha and GSK-3beta were upregulated in 25/79 and 24/79 cases of prostate cancer, respectively, with GSK-3alpha elevated in low Gleason sum score tumors and GSK-3beta expressed in high Gleason tumors, and both isoforms correlating with high expression of the androgen receptor (AR). Gene silencing of GSK-3alpha and, to a lesser extent, GSK-3beta reduced AR transcriptional activity. In addition, silencing of GSK-3beta, but not GSK-3alpha, reduced Akt phosphorylation. Acute and chronic silencing of either isoform reduced 22Rv1 growth in colony formation assays; however, this did not correlate with effects on AR activity. The GSK-3 inhibitor CHIR99021 reduced 22Rv1 colony formation by 50% in normal growth medium and by 15% in hormone-depleted medium, suggesting that GSK-3 is required both for hormone-dependent and hormone-independent proliferation. In addition, CHIR99021 enhanced growth inhibition by the AR antagonists bicalutamide and MDV3100. Finally, expression of GSK3A and GSK3B mRNAs correlated with a gene expression signature for androgen-regulated genes. Our observations highlight the importance of the GSK-3/AR signaling axis in prostate cancer and support the case for development of isoform-specific GSK-3 inhibitors and their use, in combination with AR antagonists, to treat patients with prostate cancer. PMID- 22539114 TI - Rod-coating: towards large-area fabrication of uniform reduced graphene oxide films for flexible touch screens. AB - A novel strategy is developed for the large-scale fabrication of reduced graphene oxide films directly on flexible substrates in a controlled manner by the combination of a rod-coating technique and room-temperature reduction of graphene oxide. The as-prepared films display excellent uniformity, good transparency and conductivity, and great flexibility in a touch screen. PMID- 22539115 TI - Effects of the organophosphate fenthion for control of the red-billed quelea Quelea quelea on cholinesterase and haemoglobin concentrations in the blood of target and non-target birds. AB - The red-billed quelea bird Quelea quelea is one of sub-Saharan Africa's most damaging pests, attacking small-grain crops throughout semi-arid zones. It is routinely controlled by spraying its breeding colonies and roosts with organophosphate pesticides, actions often associated with detrimental effects on non-target organisms. Attributions of mortality and morbidity of non-targets to the sprays are difficult to confirm unequivocally but can be achieved by assessing depressions in cholinesterase activities since these are reduced by exposure to organophosphates. Here we report on surveys of birds caught before and after sprays that were examined for their blood cholinesterase activities to assess the extent to which these became depressed. Blood samples from birds were taken before and after sprays with fenthion against red-billed quelea in colonies or roosts, and at other unsprayed sites, in Botswana and Tanzania and analysed for levels of haemoglobin (Hb) and activities of whole blood acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Background activities of AChE, BChE and Hb concentrations varied with bird species, subspecies, mass, age and gender. Contrary to expectation, since avian erythrocytes are often reported to lack cholinesterases, acetylcholinesterase activities in pre-spray samples of adult birds were positively correlated with Hb concentrations. When these factors were taken into account there were highly significant declines (P < 0.0001) in AChE and BChE and increases in Hb after contact with fenthion in both target and non target birds. BChE generally declined further (up to 87 % depression) from baseline levels than AChE (up to 83 % depression) but did so at a slower rate in a sample of quelea nestlings. Baseline activities of AChE and BChE and levels of Hb were higher in the East African subspecies of the red-billed quelea Q. q. aethiopica than in the southern African subspecies Q. q. lathamii, with the exception of BChE activities for adult males which were equivalent. PMID- 22539116 TI - Short-term uptake of microcystin-LR by Coregonus lavaretus: GST activity and genotoxicity. AB - In the present study, juvenile whitefish weighing 2 g were exposed by force feeding to two ecologically relevant doses (0.05 and 0.5 MUg per fish) of microcystin-LR (MC-LR). Then over 96 h the MC uptake in fish liver and muscle was measured, as the activity of the detoxification enzyme glutathione S-transferase (GST) in the liver, and the genotoxicity impact on red blood cells. Results show that (1) the MC-LR equivalent concentrations increased for both doses and in both organs of whitefish with approximately threefold lower concentrations for the low dose compared to the high dose in both organs and threefold lower concentrations in the muscle compared to the liver for each dose (2) the liver GST activity increased during the first 48 h of exposure with fivefold higher GST activity for the highest dose at 48 h compared to control and (3) MC-LR leads to deoxyribonucleic acid strand breaks that were detected by the comet assay and shown to be partially repaired. This work demonstrates that European whitefish could be impacted by cyanobacteria toxins due to rapid microcystin uptake, especially in the context of chronic contamination, which can occur during long bloom episodes. PMID- 22539117 TI - Direct and indirect effects of the glyphosate formulation Glifosato Atanor(r) on freshwater microbial communities. AB - Glyphosate-based formulations are among the most widely used herbicides in the world. The effect of the formulation Glifosato Atanor((r)) on freshwater microbial communities (phytoplankton, bacterioplankton, periphyton and zooplankton) was assessed through a manipulative experiment using six small outdoor microcosms of small volume. Three of the microcosms were added with 3.5 mg l(-1) of glyphosate whereas the other three were left as controls without the herbicide. The treated microcosms showed a significant increase in total phosphorus, not fully explained by the glyphosate present in the Glifosato Atanor((r)). Therefore, part of the phosphorus should have come from the surfactants of the formulation. The results showed significant direct and indirect effects of Glifosato Atanor((r)) on the microbial communities. A single application of the herbicide caused a fast increase both in the abundance of bacterioplankton and planktonic picocyanobacteria and in chlorophyll a concentration in the water column. Although metabolic alterations related to oxidative stress were induced in the periphyton community, the herbicide favored its development, with a large contribution of filamentous algae typical of nutrient-rich systems, with shallow and calm waters. An indirect effect of the herbicide on the zooplankton was observed due to the increase in the abundance of the rotifer Lecane spp. as a consequence of the improved food availability given by picocyanobacteria and bacteria. The formulation affected directly a fraction of copepods as a target. It was concluded that the Glifosato Atanor((r)) accelerates the deterioration of the water quality, especially when considering small-volume water systems. PMID- 22539118 TI - Cellular signal transduction can be induced by TRAIL conjugated to microcapsules. AB - The extracellular agent tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in tumor cells but spare normal cells. Ligation of TRAIL to a nanoparticle would serve to facilitate targeting to an extravascular site. Polymeric ultrasound contrast agents (UCA) (microencapsulated gas bubbles) can be tracked by ultrasound imaging, and fragmented into nanoparticles by focused ultrasound. This tumor-targeted delivery system has been shown to deliver more efficiently than solid nanoparticles. Additionally, small molecule inhibitors such as bortezomib, shown to sensitize TRAIL-resistant cells, could be co-administered within these UCA. In this pilot study, TRAIL was conjugated to UCA while preserving the agent's sensitivity to ultrasound. Human cancer cell lines, OVCAR-3 and A2058, were bathed with the TRAIL-UCA with and without the addition of bortezomib. Apoptosis was quantified using flow cytometry. OVCAR-3 treated with TRAIL-UCA exhibit significant (p < 0.05) apoptotosis compared to unmodified UCA, equal to positive controls, but no synergistic effect when combined with bortezomib. A2058 cells treated with TRAIL-UCA also exhibited significant apoptosis (p < 0.01) compared to unmodified UCA, similar to positive controls and bortezomib significantly increased apoptosis in combination with TRAIL-UCA. We conclude that TRAIL-ligated UCA show exciting potential as a new therapy. PMID- 22539119 TI - Systematic review of total pancreatectomy and islet autotransplantation for chronic pancreatitis (Br J Surg 2012; 99: 761-766). PMID- 22539120 TI - Clinical and biomarker profile of trauma-induced secondary cardiac injury (Br J Surg 2012; 99: 789-797). PMID- 22539121 TI - Comparison of liver transplantation outcomes from adult split liver and circulatory death donors (Br J Surg 2012; 99: 839-847). PMID- 22539122 TI - Hepatic venous pressure gradient in the assessment of portal hypertension before liver resection in patients with cirrhosis (Br J Surg 2012; 99: 855-863). PMID- 22539123 TI - Population-based study of the need for cholecystectomy after obesity surgery (Br J Surg 2012; 99: 864-869). PMID- 22539124 TI - Outcomes following surgery without radiotherapy for rectal cancer (Br J Surg 2012 99 137-143). PMID- 22539126 TI - Case-controlled study of critical care or surgical ward care after elective open colorectal surgery (Br J Surg 2012 99 295-299). PMID- 22539127 TI - Systematic review of exercise training or percutaneous transluminal angioplasty for intermittent claudication (Br J Surg 2012 99 16-28). PMID- 22539131 TI - A role for anti-CD45RB monoclonal antibody treatment upon dendritic cells. AB - Selective interference with CD45RB isoform by monoclonal antibody (anti CD45RBmAb) reliably induces donor-specific tolerance. Dendritic cells (DCs) are the most potent antigen-presenting cells that are capable of activating naive T cells. The purposes of the present study were to investigate the roles of anti CD45RBmAb on the phenotypes and functioning of DCs and to further illustrate the mechanism of anti-CD45RBmAb-inducing immunologic tolerance. DCs from C57BL/6 mice were cultured and treated with various doses of anti-CD45RB monoclonal antibody. Cell phenotype, cycle and phagocytic ability were detected by flow cytometry. The production of IL-10 and IL-12 in the supernatants of mature DCs was measured with ELISA. Exosomes (Dex) were recovered from the supernatant of DCs cultured for 6 days in depleted medium, and effects of DCs and Dex on the ability of T-cell proliferation were detected by mixed lymphocyte culture. Anti-CD45RBmAb could inhibit DCs maturation in a dose-dependent manner, and the effects of exosomes (Dex) on DCs enhance or inhibition proliferation of T cells were also in a dose dependent manner. Anti-CD45RBmAb could profoundly inhibit the maturation and functioning of DCs and generate tolerogenic dendritic cells (tDCs) as well as Dex, suggesting mechanistic contributions to tolerance development from the DCs through interactions with T cells. PMID- 22539133 TI - Cu2ZnSnS4 (CZTS) nanoparticle based nontoxic and earth-abundant hybrid pn junction solar cells. AB - A heterojunction between a layer of CZTS nanoparticles and a layer of fullerene derivatives forms a pn-junction. We have used such an inorganic-organic hybrid pn junction device for solar cell applications. As routes to optimize device performance, interdot separation has been reduced by replacing long-chain ligands of the quantum dots with short-chain ligands and thickness of the CZTS layer has been varied. We have shown that the CZTS-fullerene interface could dissociate photogenerated excitons due to the depletion region formed at the pn-junction. From capacitance-voltage characteristics, we have determined the width of the depletion region, and compared it with the parameters of devices based on the components of the heterojunction. The results demonstrate solar cell applications based on nontoxic and earth-abundant materials. PMID- 22539132 TI - Prevention and treatment of allergic inflammation by an Fcgamma-Der f2 fusion protein in a murine model of dust mite-induced asthma. AB - The immunoglobulin E (IgE) high-affinity receptor FcepsilonRI expressed on mast cells and basophils plays a critical role in triggering allergic disease. The co aggregation of the FcepsilonRI and FcgammaRIIb receptors is inhibitory to FcepsilonRI signaling and holds great potential for the treatment of IgE-mediated allergies. In China, Dermatophagoides farinae is a common anaphylaxis trigger. Therefore, in this study, the FcgammaRIIb-mediated immunomodulating activity of recombinant Fcgamma-Der f2 fusion protein was tested in a Der f2-allergic murine model. Following the treatment, bronchoalveolar lavage fluid (BALF) was collected to measure the expression of several Th1/Th2-type cytokines (IL-5, TNF-alpha, IL 12p70, IL-4, IL-10, IFN-gamma and IL-18) and histamine, while blood was used to detect the specific IgE and IgG-types anti-Der f2 antibodies, for measurement. In contrast to the saline-treated allergic mice, the levels of Der f2-specific IgE, cytokines and histamine were lowered in the Fcgamma-Der f2-treated allergic mice, in addition to the rare inflammatory cell infiltration in the airways and blood vessels revealed by histopathological examination. The recombinant Fcgamma-Der f2 protein was demonstrated to function as an effective immunotherapeutic agent, suggesting that chimeric human Fcgamma-allergen proteins could be used in the development of antigen-specific immunotherapy for human allergic diseases. PMID- 22539134 TI - Plausibility and evidence: the case of homeopathy. AB - Homeopathy is controversial and hotly debated. The conclusions of systematic reviews of randomised controlled trials of homeopathy vary from 'comparable to conventional medicine' to 'no evidence of effects beyond placebo'. It is claimed that homeopathy conflicts with scientific laws and that homoeopaths reject the naturalistic outlook, but no evidence has been cited. We are homeopathic physicians and researchers who do not reject the scientific outlook; we believe that examination of the prior beliefs underlying this enduring stand-off can advance the debate. We show that interpretations of the same set of evidence--for homeopathy and for conventional medicine--can diverge. Prior disbelief in homeopathy is rooted in the perceived implausibility of any conceivable mechanism of action. Using the 'crossword analogy', we demonstrate that plausibility bias impedes assessment of the clinical evidence. Sweeping statements about the scientific impossibility of homeopathy are themselves unscientific: scientific statements must be precise and testable. There is growing evidence that homeopathic preparations can exert biological effects; due consideration of such research would reduce the influence of prior beliefs on the assessment of systematic review evidence. PMID- 22539135 TI - [The PALLAS study]. PMID- 22539136 TI - [Almanac 2011: Cardiac arrhythmias and pacing. Review of selected studies that have driven recent advances in clinical cardiology -- by the Editors of the Network Task Force of the European Society of Cardiology]. PMID- 22539138 TI - [Between guidelines and regulatory decisions: the odyssey of dronedarone]. PMID- 22539139 TI - [Acute aortic syndromes: an assessment]. AB - The term "acute aortic syndrome" describes a range of severe, painful, potentially life-threatening abnormalities of the aorta. This review discusses the pathophysiology and risk factors, classification schemes, epidemiology, clinical presentations, diagnostic modalities, management options, and outcomes of various aortic conditions, including acute aortic dissection (AD) and its variants intramural hematoma and penetrating atherosclerotic ulcer. The common denominator of acute aortic syndromes is disruption of the media layer of the aorta, with bleeding within the layers (intramural hematoma), along the aortic media resulting in separation of the layers (AD), or transmurally through the wall in the case of ruptured penetrating atherosclerotic ulcer or trauma. The incidence of AD ranges from 2 to 3.5 cases per 100 000 person-years; hypertension and a variety of genetic disorders with altered connective tissues are the most prevalent risk conditions. Recent advances in imaging techniques have helped in understanding the natural history and dynamics of this condition. Prognosis is clearly related to undelayed diagnosis and appropriate surgical repair in case of proximal involvement of the aorta; the advent of endovascular treatment has opened new perspectives in the management of acute aortic syndromes affecting the descending aorta, since this can modify its natural history and improve prognosis. PMID- 22539140 TI - [Treatment of aortic arch disease: state of the art and future perspectives]. AB - Patients with dissecting or aneurysmal disease of the aortic arch represent a unique challenge for the cardiac surgeon, and the employment of valid surgical and endovascular techniques and appropriate methods of cerebral protection is crucial for obtaining satisfactory postoperative results. Open surgical repair remains the approach of choice, even if supported by increasingly improved endovascular procedures. At present, a wide range of surgical, endovascular and hybrid procedures is available for the treatment of these high-risk patients. The aim of this review is to describe the different procedures used in patients with aortic arch pathology and to review the main results available in the literature. PMID- 22539137 TI - [Dronedarone: a real innovation or a mere second-best choice? How to find the way among guidelines, regulatory agencies and daily clinical practice]. AB - Dronedarone is the antiarrhythmic drug with the most complete and wide literature preceding its marketing. Most of these studies showed a good efficacy along with an excellent risk profile, especially in low- and medium-risk patients. Recently, updates of European, American and even Italian guidelines gave dronedarone its own spot into the antiarrhythmic armamentarium, recommending its use both for rhythm control and rate control in non-permanent atrial fibrillation. In Italy, however, dronedarone prescription is still possible only when amiodarone is not tolerated, making dronedarone a mere second choice of its older "relative". Moreover, patients taking dronedarone must undergo a strict alanine aminotransferase and bilirubin follow-up, which usefulness in predicting drug induced liver damage (probably idiosyncratic in nature and therefore unpredictable) is far from demonstrated. The aim of this review is to sum up actual evidences on dronedarone, describe how these evidences had been differently transposed by panel of experts and drug agencies into guidelines and recommendations, and define the current difficulties encountered by the cardiologist in the correct use of this new antiarrhythmic agent in clinical practice. PMID- 22539141 TI - [Percutaneous repair of mitral regurgitation: a new tool in the armamentarium for advanced heart failure?]. AB - Mitral regurgitation (MR) is the second most common heart valve disease worldwide, requiring surgical intervention in Europe. The current gold-standard treatment is surgical repair or replacement. Despite clear international guidelines, many patients do not undergo surgical intervention due to comorbidities, real or perceived high risk for cardiac surgery. The treatment of patients with functional MR in advanced heart failure has unsatisfactory results in terms of long-term survival as shown by retrospective small surgical experiences even if there is weak evidence for beneficial effects on left ventricular remodeling and functional capacity. Nevertheless, the appropriateness and timing of valve surgery in patients with advanced heart failure remain controversial. Based on these results, the focus of research has shifted in recent years to the development of percutaneous approaches to treat severe MR, in order to restore valve function in a minimally invasive fashion. Currently, various percutaneous techniques are under investigation in clinical trials and others have been developed, based on the surgical principles of mitral valve repair. This article focuses on the percutaneous mitral valve repair procedure using the MitraClip system (Abbott Vascular, Abbott Park, Illinois, USA). This approach that reproduces the edge-to-edge technique described by Alfieri, is safe and effective in improving functional class and reducing rehospitalization rates for heart failure patients. PMID- 22539142 TI - [Functional mitral regurgitation in heart failure: an unmet clinical need?]. PMID- 22539143 TI - [Cardiac resynchronization therapy: mortality, rehospitalization, and procedure related complications. A three-year single-center observational study within the Italian Health System]. AB - BACKGROUND: The aim of this study was to evaluate whether the benefit of cardiac resynchronization therapy with an implantable defibrillator (CRT-D) may differ among classes of indications to device therapy. METHODS: All-cause mortality, first hospitalization for non-fatal heart failure, stable improvement of NYHA functional class (responders), and implant-related complications were evaluated retrospectively in 103 patients selected among those (n = 133) who received consecutively CRT-D between 2006 and 2009. Patients were divided into three groups: group IA (n = 65) included patients receiving CRT-D for a class IA indication; group IIa (n = 26) included patients with atrial fibrillation and QRS >= 130 ms receiving CRT-D for a class IA indication; nonconventional group (NC) (n = 12) included patients with an indication to defibrillator implantation extended to CRT-D because of NYHA class III-IV and echocardiographic evidence of electromechanical dyssynchrony. Echocardiographic examination was performed in all patients to identify wall target for left-side lead placement. RESULTS: Group IIa patients were slightly older than group IA patients (p<0.05); gender distribution, left ventricular ejection fraction at implantation, ischemic etiology, and heart failure treatment were comparable among groups (all p>0.5), except for a higher digitalis use in group IIa patients (p<0.05). In a mean observation period of 3 years (up to December 2010), the rates of fatal events (IA: 22%, IIa: 23%, NC: 20%), rehospitalization for worsening heart failure (IA: 30%, IIa: 33%, NC: 22%), clinical responders (IA: 78%, IIa: 78%, NC: 78%), implant-related complications requiring reintervention (IA: 15%, IIa: 19%, NC: 25%), including pocket or catheter infections (IA: 5%, IIa: 11%, NC: 8%) were comparable among groups (all p>0.5). CONCLUSIONS: In the "real world", the benefit of CRT-D in advanced heart failure patients might be comparable among class IA, IIa or NC indication. PMID- 22539144 TI - [Coronary ventricular fistula as a late complication of permanent pacing]. AB - A coronary angiography performed for the occurrence of atypical chest pain allowed us to discover a coronary-right ventricular fistula as a rare complication of myocardial penetration by a tined ventricular catheter implanted some years earlier. PMID- 22539145 TI - Validation of a claims-based diagnostic code for Stevens-Johnson syndrome in a commercially insured population. AB - PURPOSE: To validate the administrative claims identification of a diagnosis of Stevens-Johnson syndrome (SJS) using medical records as the "gold standard" in a large, commercially insured US population. METHODS: Patients with >1 medical claim with the International Classification of Diseases, Ninth Revision, Clinical Modification code 695.1x between 1 July 2000 and 31 May 2007 were queried in the HealthCore Integrated Research Database(SM) , which contains administrative claims data for 14 commercial health insurance plans. Trained nurses and pharmacists abstracted pertinent information from the identified patients' medical records, which were then reviewed by two independent dermatologists to identify criteria to determine SJS diagnosis. Positive predictive values (PPVs) based on the claims and chart data were computed for all the cases. RESULTS: Medical charts for 200 claims-identified cases, with the International Classification of Diseases, Ninth Revision, Clinical Modification code 695.1x, were abstracted and reviewed by the dermatologists. A total of five cases (PPV = 2.50%, 95%CI = 0.8%-5.7%) were determined to be SJS with clinical certainty. PPVs varied with data stratification: PPV for inpatient claims only (PPV = 2.00%, 95%CI = 0.24%-7.04%), inpatient claims with 695.1x in first diagnosis field (PPV = 4.11%, 95%CI = 0.86%-11.54%), and final decisions of either clinical certainty or probable cases of SJS (PPV = 6.00%, 95%CI = 3.14%-10.25%). CONCLUSION: These findings demonstrate the difficulties associated with identifying rare disorders, which lack specific diagnostic criteria, within administrative claims databases. They underscore the challenges of using claims data to monitor ill-defined clinical conditions as well as the need to validate claims-identified cases with information from other sources, such as medical charts. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 22539146 TI - Investigation of scrambled ions in tandem mass spectra. Part 1. Statistical characterization. AB - Scrambled ions have become the focus of recent investigations of peptide fragmentation. Here, an investigation of more than 390,000 high quality CID mass spectra is presented to explore the extent of scrambled ions in mass spectra and the possible fragmentation rules during scramble reactions. For the former, scrambled ions generally make up more than 10 % of mass spectra in number, although the abundances are less than 0.1 of the base peak. For the latter, relatively preferential re-opening sites were found for aliphatic residues Ala, Ile, Leu, and other residues such as Met, Gln, Ser, Phe, and Thr, whereas disfavored sites were found for basic residues Arg, Lys, and His, and Trp for both scrambled b and a ions. Similar preferential order in re-opening reaction was found in the reaction of losing internal residues when cleavage occurs at C terminal side of 20 residues. However, when cleavage occurs at N-terminal side, Glu, Phe, and Trp become the most preferential sites. These results provide a deep insight into cleavage rules during scramble reactions for prediction of peptide mass spectra. Also, an additional investigation of whether scrambled ions could help discriminate false identifications from correct identifications was performed. Probing the number fraction of scrambled ions in falsely and correctly interpreted spectra and analyzing the correlation between scrambled ions and SEQUEST scores XCorr and Sp showed scrambled ions could at some extent help improve the discrimination in singly charged identifications, whereas no improvement was found for multiply charged results. PMID- 22539147 TI - Human CD4+ lymphocytes for antigen quantification: characterization using conventional flow cytometry and mass cytometry. AB - To transform the linear fluorescence intensity scale obtained with fluorescent microspheres to an antibody bound per cell (ABC) scale, a biological cell reference material is needed. Optimally, this material should have a reproducible and tight ABC value for the expression of a known clinical reference biomarker. In this study, we characterized commercially available cryopreserved peripheral blood mononuclear cells (PBMCs) and two lyophilized PBMC preparations, Cyto-Trol and PBMC-National Institute for Biological Standard and Control (NIBSC) relative to freshly prepared PBMC and whole blood samples. It was found that the ABC values for CD4 expression on cryopreserved PBMC were consistent with those of freshly obtained PBMC and whole blood samples. By comparison, the ABC value for CD4 expression on Cyto-Trol is lower and the value on PBMC-NIBSC is much lower than those of freshly prepared cell samples using both conventional flow cytometry and CyTOFTM mass cytometry. By performing simultaneous surface and intracellular staining measurements on these two cell samples, we found that both cell membranes are mostly intact. Moreover, CD4(+) cell diameters from both lyophilized cell preparations are smaller than those of PBMC and whole blood. This could result in steric interference in antibody binding to the lyophilized cells. Further investigation of the fixation effect on the detected CD4 expression suggests that the very low ABC value obtained for CD4(+) cells from lyophilized PBMC-NIBSC is largely due to paraformaldehyde fixation; this significantly decreases available antibody binding sites. This study provides confirmation that the results obtained from the newly developed mass cytometry are directly comparable to the results from conventional flow cytometry when both methods are standardized using the same ABC approach. PMID- 22539150 TI - Stochastic system identification of skin properties: linear and wiener static nonlinear methods. AB - Wiener static nonlinear system identification was used to study the linear dynamics and static nonlinearities in the response of skin and underlying tissue under indentation in vivo. A device capable of measuring the dynamic mechanical properties of bulk skin tissue was developed and it incorporates a custom-built Lorentz force actuator that measures the dynamic compliance between the input force (<12 N) and the output displacement (<20 mm). A simple linear stochastic system identification technique produced a variance accounted for (VAF) of 75-81% and Wiener static nonlinear techniques increased the VAF by 5%. Localized linear techniques increased the VAF to 85-95% with longer tests. Indentation experiments were conducted on 16 test subjects to determine device sensitivity and repeatability. Using the device, the coefficient of variation of test metrics was found to be as low as 2% for a single test location. The measured tissue stiffness was 300 N/m near the surface and 4.5 kN/m for high compression. The damping ranged from 5 to 23 N s/m. The bulk skin properties were also shown to vary significantly with gender and body mass index. The device and techniques used in this research can be applied to consumer product analysis, medical diagnosis and tissue research. PMID- 22539148 TI - Structural systems biology and multiscale signaling models. AB - We review current advances in experimental as well as computational modeling and simulation approaches to structural systems biology, whose overall aim is to build quantitative models of signaling networks while retaining the crucial elements of molecular specificity. We briefly discuss the current and emerging experimental and computational methods, particularly focusing on hybrid and multiscale methods, and highlight several applications in cell signaling with quantitative and predictive capabilities. The scope of such models range from delineating protein-protein interactions to describing clinical implications. PMID- 22539149 TI - Patient-specific multiscale modeling of blood flow for coronary artery bypass graft surgery. AB - We present a computational framework for multiscale modeling and simulation of blood flow in coronary artery bypass graft (CABG) patients. Using this framework, only CT and non-invasive clinical measurements are required without the need to assume pressure and/or flow waveforms in the coronaries and we can capture global circulatory dynamics. We demonstrate this methodology in a case study of a patient with multiple CABGs. A patient-specific model of the blood vessels is constructed from CT image data to include the aorta, aortic branch vessels (brachiocephalic artery and carotids), the coronary arteries and multiple bypass grafts. The rest of the circulatory system is modeled using a lumped parameter network (LPN) 0 dimensional (0D) system comprised of resistances, capacitors (compliance), inductors (inertance), elastance and diodes (valves) that are tuned to match patient-specific clinical data. A finite element solver is used to compute blood flow and pressure in the 3D (3 dimensional) model, and this solver is implicitly coupled to the 0D LPN code at all inlets and outlets. By systematically parameterizing the graft geometry, we evaluate the influence of graft shape on the local hemodynamics, and global circulatory dynamics. Virtual manipulation of graft geometry is automated using Bezier splines and control points along the pathlines. Using this framework, we quantify wall shear stress, wall shear stress gradients and oscillatory shear index for different surgical geometries. We also compare pressures, flow rates and ventricular pressure-volume loops pre- and post-bypass graft surgery. We observe that PV loops do not change significantly after CABG but that both coronary perfusion and local hemodynamic parameters near the anastomosis region change substantially. Implications for future patient-specific optimization of CABG are discussed. PMID- 22539152 TI - Solar energy harnessing in hexagonally arranged Si nanowire arrays and effects of array symmetry on optical characteristics. AB - Investigation of solar energy harvesting in hexagonally arranged Si nanowire (NW) arrays is performed through optimizing the structural parameters, such as array periodicity (P), Si NW diameter (D) and length (L). The results demonstrate that there exist wide P and D/P 'windows' for the Si NW arrays, locating around 600 nm and 0.833 (i.e., D=500 nm), respectively, for achieving enhanced light absorption compared to their thin film counterparts with the same thickness, but with much less materials consumption. Calculation of the ultimate efficiency (UE) indicates that the light trapping capability is not monotonically increased with L, and that UE vibration is found when L is >1000 nm. Comparison of the light absorption spectra for hexagonally and squarely arranged Si NW arrays demonstrates that these two most widely employed array symmetries in practice have little impact on the light trapping capability. PMID- 22539151 TI - A designed functional metalloenzyme that reduces O2 to H2O with over one thousand turnovers. PMID- 22539153 TI - Effect of percutaneous tracheostomy on intracerebral pressure and perfusion pressure in patients with acute cerebral dysfunction (TIP Trial): an observational study. AB - BACKGROUND: Bedside percutaneous tracheostomy (PT) is very commonly used for patients who require prolonged mechanical ventilation. The effect of tracheostomy on intracranial pressure (ICP) is currently a subject of controversy. The aim of our study is to clarify the relation between PT and its effect on ICP and cerebral perfusion pressure. METHODS: 38 patients on our intensive care unit were included prospectively in an observational study. We examined mean values of HF, SpO(2), ICP, CPP, and MAP for changes over five different phases of the procedure using paired Mann-Whitney U tests. A p value of <0.05 was considered significant. p values were Bonferroni corrected for multiple testing. RESULTS: PT was performed on 38 patients (f = 19, m = 19; mean = 56 years). Median ICP before intervention was 9 mmHg. During positioning of the patient, ICP had risen to 14, during bronchoscopy to 16, and during tracheostomy to 18 mmHg, all being significantly higher than baseline level. Monitoring of MAP showed a significant increase to 101 mmHg only during tracheostomy. SpO(2) and HF did not show any significant changes. Mean duration of positioning, bronchoscopy and tracheostomy was 19, 10, and 17 min. 8 patients received osmotherapy due to a rise of ICP of more than 30 mmHg. CONCLUSION: PT only leads to a significant rise of ICP during the procedure. Nevertheless, therapy of ICP is necessary in some patients. From our point of view, therefore, tracheostomy should only be performed under continuous monitoring of ICP and CPP in patients with severe cerebral dysfunctions and critically elevated ICP. PMID- 22539154 TI - Critical appraisal of the 'wait and see' approach in rectal cancer for clinical complete responders after chemoradiation. AB - BACKGROUND: Some 10-20 per cent of patients with locally advanced rectal cancer achieve a pathological complete response (pCR) at surgery following preoperative chemoradiation (CRT). Some demonstrate a sustained clinical complete response (cCR), defined as absence of clinically detectable residual tumour after CRT, and do not undergo resection. The aim of this review was to evaluate non-operative treatment of rectal cancer after CRT, and the outcome of patients observed without radical surgery. METHODS: A systematic computerized search identified 30 publications (9 series, 650 patients) evaluating a non-operative approach after CRT. Original data were extracted and tabulated, and study quality evaluated. The primary outcome measure was cCR. Secondary outcome measures included locoregional failure rate, disease-free survival and overall survival. RESULTS: The most recent Habr-Gama series reported a low locoregional failure rate of 4.6 per cent, with 5-year overall and disease-free survival rates of 96 and 72 per cent respectively. These findings were supported by a small prospective Dutch study. However, other retrospective series have described higher recurrence rates. All studies were heterogeneous in staging, inclusion criteria, study design and rigour of follow-up after CRT, which might explain the different outcomes. The definition of cCR was inconsistent, with only partial concordance with pCR. The results suggested that patients who are observed, but subsequently fail to sustain a cCR, may fare worse than those who undergo immediate tumour resection. CONCLUSION: The rationale of a 'wait and see' policy relies mainly on retrospective observations from a single series. Proof of principle in small low rectal cancers, where clinical assessment is easy, should not be extrapolated uncritically to more advanced cancers where nodal involvement is common. Long term prospective observational studies with more uniform inclusion criteria are required to evaluate the risk versus benefit. PMID- 22539155 TI - Paper-based, capacitive touch pads. AB - Metallized paper is patterned to create touch pads of arrayed buttons that are sensitive to contact with both bare and gloved fingers. The paper-based keypad detects the change in capacitance associated with the touch of a finger to one of its buttons. Mounted on an alarmed cardboard box, the keypad requires the appropriate sequence of touches to disarm the system. PMID- 22539156 TI - Long fusions to the sacrum in elderly patients with spinal deformity. AB - PURPOSE: Long spinal deformity fusions in elderly patients continue to be controversial. However, there is a growing population of elderly patients with spinal deformities that may be optimally treated by reconstructive surgery requiring a long fusion to the sacrum. This study evaluated clinical outcomes in elderly (>65) adult deformity patients who underwent posterior instrumented reconstruction consisting of fusion from the thoracic spine to the sacrum with iliac fixation. METHODS: Patients in a prospective database for adult spinal deformity who had a posterior reconstruction with an instrumented fusion from the thoracic spine to the sacrum that included iliac fixation with minimum 2-year follow-up were identified. Two cohorts were compared: patients 65 years and older and patients 55 years and younger. Student's t test for independent groups was used to determine any significant differences between continuous variables. Chi square was used to compare categorical demographic variables between the two groups. RESULTS: The 65 and older group consisted of 15 patients with an average age of 71 years (range 65-78 years). The 55 and younger group consisted of 25 patients with an average age of 45 years (range 30-55 years). The older group had a worse mean co-morbidity score (4.6 vs. 2.1). Baseline SRS scores were similar between groups. Baseline SF-12 data showed worse PCS (22.1 vs. 32.0, p = 0.009) yet better MCS (63.6 vs. 48.4, p < 0.0001) in the older group. Although major curve magnitude was similar (47.1 degrees vs. 42.6 degrees ), the older group had more positive sagittal imbalance at baseline (115.7 vs. 54.2 mm, p = 0.02). Number of levels fused, operative time, blood loss, and incidence of complications were similar between groups. Two-year improvements in SRS subscores, SF-12 PCS, and MCS were not significantly different between groups. CONCLUSIONS: Properly selected patients 65 years of age and older who have substantial sagittal imbalance, a considerable disease burden, and a lesser degree of mental distress can obtain as much clinical benefit as their younger counterparts (<=55 years of age) 2 years following spinal deformity surgery that requires fusion from the thoracic spine to the sacrum with segmental instrumentation and iliac fixation. PMID- 22539157 TI - Toxic effects of microcystin-LR on the HepG2 cell line under hypoxic and normoxic conditions. AB - Microcystins (MCs) are highly liver-specific and evidenced as a liver tumor promoter. Oxidative stress is one of the most important toxicity mechanisms of MCs, which is tightly related to oxygen concentration. The effects of MCs on animals and cell lines in normoxia and the mechanisms have been well studied, but such effects in different oxygen conditions were still unclear. The aim of the present study was to explore the cellular response of the human hepatocellular carcinoma cell line (HepG2) to MC-LR exposure under hypoxic (1% O2 ) and normoxic (21% O2 ) conditions. We examined cell viability, mitochondrial membrane potential (MMP), superoxide dismutase (SOD) activity and gene expression posttoxin exposure. Cell viability was increased by MC-LR in normoxia although decreased in hypoxia. MC-LR markedly induced MMP loss under hypoxic condition but only slightly MMP loss under normoxic condition. SOD activity was significantly induced by MC-LR in hypoxia, indicating prolonged oxidative stress. Inhibitory apoptosis protein (c-IAP2) was significantly up-regulated by MC-LR under normoxic condition, suggesting that c-IAP2 played an important role in the promotion of cell proliferation by MC-LR. These results indicate that MC-LR promotes cell proliferation under normoxic condition whereas induces cell apoptosis under hypoxic condition. PMID- 22539158 TI - A general approach to mesoporous metal oxide microspheres loaded with noble metal nanoparticles. AB - Catalytic microspheres: A general approach is demonstrated for the facile preparation of mesoporous metal oxide microspheres loaded with noble metal nanoparticles (see TEM image in the picture). Among 18 oxide/noble metal catalysts, TiO(2)/0.1 mol % Pd microspheres showed the highest turnover frequency in NaBH(4) reduction of 4-nitrophenol (see picture). PMID- 22539159 TI - Resting energy expenditure after Fontan surgery in children with single-ventricle heart defects. AB - BACKGROUND: Data on resting energy expenditure (REE) and oxygen consumption (VO(2)) after pediatric cardiopulmonary bypass (CPB) will facilitate optimal nutrient prescription. METHODS: The authors measured continuous REE and VO(2), using an in-line indirect calorimetery (IC) in 30 consecutive children with single-ventricle physiology immediately after Fontan surgery. REE during steady state at 8 hours after surgery was compared with standard equation-estimated energy expenditure (EEE). Patients were classified into 3 groups: hypermetabolic (measured REE [MREE]/EEE ratio >1.2), hypometabolic (MREE/EEE ratio <0.8), and normometabolic (MREE/EEE ratio 0.8-1.2). Demographic, anthropometric, and perioperative clinical characteristics were examined for their correlation with metabolic status. RESULTS: In 26 of 30 patients with completed IC, mean REE at 8 hours after surgery was 57 +/- 20 kcal/kg/d, and mean VO(2) was 110 +/- 35 mL/min. Mean values of VO(2) and REE did not change within the first 24 hours after surgery. There was poor correlation between MREE at 8 hours and the EEE using the World Health Organization equation (r = 0.32, P = .11). Most patients (n = 19, 73%) were either normometabolic or hypometabolic. Lack of hypermetabolism was significantly associated with higher intraoperative serum lactate level and positive fluid balance compared with the rest of the group. CONCLUSIONS: The authors report a low prevalence of hypermetabolism in children with single-ventricle defects after Fontan surgery. Measured REE had poor correlation with equation-estimated energy expenditure in a majority of the cohort. The absence of increased energy expenditure after CPB will influence energy prescription in this group. PMID- 22539161 TI - Comment on Sewell and Eastwood: Screening and treatment in developmental dysplasia of the hip--where do we go from here? PMID- 22539160 TI - Improvement of intertrochanteric bone quality in osteoporotic female rats after injection of polylactic acid-polyglycolic acid copolymer/collagen type I microspheres combined with bone mesenchymal stem cells. AB - PURPOSE: Osteoporosis mainly involves cancellous bone, and the spine and hip, with their relatively high cancellous bone to cortical bone ratio, are severely affected. Studies of bone mesenchymal stem cells (BMSCs) from osteoporotic patients and animal models have revealed that osteoporosis is often associated with reduction of BMSCs' proliferation and osteogenic differentiation. Our aim was to test whether polylactic acid-polyglycolic acid copolymer(PLGA)/collagen type I(CoI) microspheres combined with BMSCs could be used as injectable scaffolds to improve bone quality in osteoporotic female rats. METHODS: PLGA microspheres were coated with CoI. BMSCs of the third passage and were cultured with PLGA/CoI microspheres for seven days. Forty three-month-old female non pregnant SD rats were ovariectomized to establish osteoporotic animal models. Three months after being ovariectomized, the osteoporotic rats were randomly divided into five groups: SHAM group, PBS group, cell group, microsphere (MS) group, and cell+MS group. Varying materials were injected into the intertrochanters of each group's rats. Twenty rats were sacrificed at one month and three months post-op, respectively. The femora were harvested in order to measure the intertrochanteric bone mineral density (BMD) with DEXA and trabecular thickness (Tb.Th), percentage of trabecular area (%Tb.Ar), bone volume fraction (BV/TV) and trabecular spacing (Tb.Sp) with Micro CT. One-way ANOVA and Kruskal Wallis tests were used. RESULTS: BMSCs seeded on PLGA/CoI microspheres had a nice adhesion and proliferation. At one month post-op, the BMD (0.33 +/- 0.01 g/cm(2)), Tb.Th (459.65 +/- 28.31 MUm), %Tb.Ar (9.61 +/- 0.29 %) and Tb.Sp (2645.81 +/- 94.91 MUm) of the cell+ MS group were better than those of the SHAM group and the cell group. At three months post-op, the BMD (0.32 +/- 0.01 g/cm(2)), Tb.Th (372.81 +/- 38.45 MUm), %Tb.Ar (6.65 +/- 0.25 %), BV/TV (6.62 +/- 0.25 %) and Tb.Sp (1559.03 +/- 57.06 MUm) of the cell + MS group were also better than those of the SHAM group and the cell group. CONCLUSION: The PLGA/CoI microspheres combined with BMSCs can repair bone defects more quickly. This means that PLGA/CoI microspheres combined with BMSCs can promote trabecular reconstruction and improve bone quality in osteoporotic rats. This scaffold can provide a promising minimally invasive surgical tool for enhancement of bone fracture healing or prevention of fracture occurrence which will in turn minimize complications endemic to patients with osteoporosis. PMID- 22539162 TI - Differential regulation of phenazine biosynthesis by RpeA and RpeB in Pseudomonas chlororaphis 30-84. AB - RpeA is a two-component sensor protein that negatively controls biosynthesis of phenazines, which are required for biological control activity by Pseudomonas chlororaphis 30-84. In this study, we identified the cognate response regulator RpeB and investigated how RpeA and RpeB interact with the PhzR/PhzI quorum sensing system and other known regulatory genes to control phenazine production. Quantitative real-time PCR revealed that, in contrast with an rpeA mutant, expression of the phenazine biosynthetic genes as well as the pip and phzR genes were significantly reduced in an rpeB mutant, suggesting positive control of phenazines by RpeB. Complementation assays showed that overexpression of pip in trans rescued phenazine production in an rpeB mutant, whereas multiple copies of rpeB genes were unable to restore phenazine production in a pip or phzR mutant. These results indicate that RpeA and RpeB differentially regulate phenazine production and act upstream of Pip and PhzR in the phenazine regulatory network. The differential regulatory functions for RpeA and RpeB also affected the capacity of 30-84 for fungal inhibition. Based on these results, a model is proposed to illustrate the relationship of RpeA/RpeB to other regulatory genes controlling phenazine biosynthesis in P. chlororaphis 30-84, a regulatory hierarchy that may be conserved in other pseudomonads and may play a role in stress response. PMID- 22539163 TI - Phylogenetic clustering of Bradyrhizobium symbionts on legumes indigenous to North America. AB - To analyse determinants of biogeographic structure in members of the genus Bradyrhizobium, isolates were obtained from 41 legume genera, originating from North American sites spanning 48.5 degrees of latitude (Alaska to Panama). Sequencing of portions of six gene loci (3674 bp) in 203 isolates showed that there was only a weak trend towards higher nucleotide diversity in tropical regions. Phylogenetic relationships for nifD, in the symbiosis island region of the Bradyrhizobium chromosome, conflicted substantially with a tree inferred for five housekeeping gene loci. For both nifD and housekeeping gene trees, bacteria from each region were significantly more similar, on average, than would be expected if the source location was permuted at random on the tree. Within-region permutation tests also showed that bacteria clustered significantly on particular host plant clades at all levels in the phylogeny of legumes (from genus up to subfamily). Nevertheless, some bacterial groups were dispersed across multiple regions and were associated with diverse legume host lineages. These results indicate that migration, horizontal gene transfer and host interactions have all influenced the geographical divergence of Bradyrhizobium populations on a continental scale. PMID- 22539164 TI - Structures of free-living and protozoa-associated methanogen communities in the bovine rumen differ according to comparative analysis of 16S rRNA and mcrA genes. AB - Structures of free-living and protozoa-associated methanogen (PAM) communities from forage-fed cattle were investigated by comparative sequence analysis of 16S rRNA and methyl coenzyme M reductase (mcrA) gene clone libraries. The free-living and protozoa-associated communities were composed of the same three genera [namely Methanobrevibacter, Methanomicrobium and rumen cluster C (RCC), which is distantly related to Thermoplasma]; however, the distribution of the methanogen genera differed between the two communities. Despite previous reports of potential bias for the degenerate mcrA primer set, the 16S rRNA (n = 100 clones) and mcrA (n = 92 clones) gene libraries exhibited a similar distribution pattern for the three methanogenic genera. RCC was more abundant in the free-living community and represented 72 and 42 % of the 16S rRNA and mrcA gene sequences, respectively, versus 54 and 13 % of the 16S rRNA and mrcA gene sequences from the PAM community, respectively. The majority of RCC sequences from the free-living and protozoa-associated communities belonged to different species-level operational taxonomic units. Methanobrevibacter species were more abundant in the PAM community and represented 42 and 79 % of clones for the 16S rRNA and mrcA gene libraries, respectively, versus 9 and 27 % of 16S rRNA and mrcA gene clones from the free-living community, respectively. Methanomicrobium species were predominantly free-living. Primers for quantitative PCR were designed to target specific methanogen groups and used to assess the effect of a high-grain diet on methanogen species composition. Switching the ruminant diet from forage to high grain resulted in reduced protozoal diversity, along with a profound overall reduction in the relative abundance of RCC and an increase in the relative abundance of free-living Methanobrevibacter spp. It was unclear whether the reduced abundance of RCC in grain-fed animals was due to the loss of symbiotic protozoa species or due to broader changes in the rumen environment that affected both RCC and protozoa. Importantly, results from this study emphasize the need to consider the different methanogen communities when developing strategies for mitigating methane emissions in ruminants. PMID- 22539165 TI - Deletion of manC in Corynebacterium glutamicum results in a phospho-myo-inositol mannoside- and lipoglycan-deficient mutant. AB - Mannose is an important constituent of the immunomodulatory glycoconjugates of the mycobacterial cell wall: lipoarabinomannan (LAM), lipomannan (LM) and the related phospho-myo-inositol mannosides (PIMs). In Mycobacterium tuberculosis and the related bacillus Corynebacterium glutamicum, mannose is either imported from the medium or derived from glycolysis, and is subsequently converted into the nucleotide-based sugar donor guanosine diphosphomannose (GDP-mannose). This can be utilized by the glycosyltranferases of the GT-A/B superfamily or converted to the lipid-based donor polyprenyl monophosphomannose, and used as a substrate by the transmembrane glycosyltransferases of the GT-C superfamily. To investigate GDP-mannose biosynthesis in detail, the gene encoding a putative ManC in C. glutamicum was deleted. Deletion of manC resulted in a slow-growing mutant, with reduced but not totally abrogated guanosine diphosphomannose pyrophosphorylase activity. However, a comprehensive cell wall analysis revealed that C. glutamicumDeltamanC is deficient in PIMs and LM/LAM. Closer inspection suggests that promiscuous ManC activity is contributed by additional putative nucleotidyltransferases, PmmB, WbbL1, GalU and GlmU, and a hypothetical protein, NCgl0715. Furthermore, complementation analyses of C. glutamicumDeltamanC with Rv3264c suggested that it is a true homologue of ManC in M. tuberculosis, and the essentiality of PIMs in M. tuberculosis makes it an attractive drug target. PMID- 22539166 TI - Flow-mediated dilation and cardiovascular disease. PMID- 22539167 TI - Assessing potential errors of MRI-based measurements of pulmonary blood flow using a detailed network flow model. AB - MRI images of pulmonary blood flow using arterial spin labeling (ASL) measure the delivery of magnetically tagged blood to an image plane during one systolic ejection period. However, the method potentially suffers from two problems, each of which may depend on the imaging plane location: 1) the inversion plane is thicker than the imaging plane, resulting in a gap that blood must cross to be detected in the image; and 2) ASL includes signal contributions from tagged blood in conduit vessels (arterial and venous). By using an in silico model of the pulmonary circulation we found the gap reduced the ASL signal to 64-74% of that in the absence of a gap in the sagittal plane and 53-84% in the coronal. The contribution of the conduit vessels varied markedly as a function of image plane ranging from ~90% of the overall signal in image planes that encompass the central hilar vessels to <20% in peripheral image planes. A threshold cutoff removing voxels with intensities >35% of maximum reduced the conduit vessel contribution to the total ASL signal to ~20% on average; however, planes with large contributions from conduit vessels underestimate acinar flow due to a high proportion of in-plane flow, making ASL measurements of perfusion impractical. In other image planes, perfusion dominated the resulting ASL images with good agreement between ASL and acinar flow. Similarly, heterogeneity of the ASL signal as measured by relative dispersion is a reliable measure of heterogeneity of the acinar flow distribution in the same image planes. PMID- 22539168 TI - Mechanical loading and TGF-beta change the expression of multiple miRNAs in tendon fibroblasts. AB - Tendons link skeletal muscles to bones and are important components of the musculoskeletal system. There has been much interest in the role of microRNA (miRNA) in the regulation of musculoskeletal tissues to mechanical loading, inactivity, and disease, but it was unknown whether miRNA is involved in the adaptation of tendons to mechanical loading. We hypothesized that mechanical loading and transforming growth factor-beta (TGF-beta) treatment would regulate the expression of several miRNA molecules with known roles in cell proliferation and extracellular matrix synthesis. To test our hypothesis, we subjected untrained adult rats to a single session of mechanical loading and measured the expression of several miRNA transcripts in Achilles tendons. Additionally, as TGF beta is known to be an important regulator of tendon growth and adaptation, we treated primary tendon fibroblasts with TGF-beta and measured miRNA expression. Both mechanical loading and TGF-beta treatment modulated the expression of several miRNAs that regulate cell proliferation and extracellular matrix synthesis. We also identified mechanosensitive miRNAs that may bind to the 3' untranslated region of the basic helix-loop-helix transcription factor scleraxis, which is a master regulator of limb tendon development. The results from this study provide novel insight into the mechanobiology of tendons and indicate that miRNA could play an important role in the adaptation of tendons to growth stimuli. PMID- 22539169 TI - Cardiovascular effects of partial sleep deprivation in healthy volunteers. AB - Sleep deprivation is common in Western societies and is associated with increased cardiovascular morbidity and mortality in epidemiological studies. However, the effects of partial sleep deprivation on the cardiovascular system are poorly understood. In the present study, we evaluated 13 healthy male volunteers (age: 31 +/- 2 yr) monitoring sleep diary and wrist actigraphy during their daily routine for 12 nights. The subjects were randomized and crossover to 5 nights of control sleep (>7 h) or 5 nights of partial sleep deprivation (<5 h), interposed by 2 nights of unrestricted sleep. At the end of control and partial sleep deprivation periods, heart rate variability (HRV), blood pressure variability (BPV), serum norepinephrine, and venous endothelial function (dorsal hand vein technique) were measured at rest in a supine position. The subjects slept 8.0 +/- 0.5 and 4.5 +/- 0.3 h during control and partial sleep deprivation periods, respectively (P < 0.01). Compared with control, sleep deprivation caused significant increase in sympathetic activity as evidenced by increase in percent low-frequency (50 +/- 15 vs. 59 +/- 8) and a decrease in percent high-frequency (50 +/- 10 vs. 41 +/- 8) components of HRV, increase in low-frequency band of BPV, and increase in serum norepinephrine (119 +/- 46 vs. 162 +/- 58 ng/ml), as well as a reduction in maximum endothelial dependent venodilatation (100 +/- 22 vs. 41 +/- 20%; P < 0.05 for all comparisons). In conclusion, 5 nights of partial sleep deprivation is sufficient to cause significant increase in sympathetic activity and venous endothelial dysfunction. These results may help to explain the association between short sleep and increased cardiovascular risk in epidemiological studies. PMID- 22539170 TI - Identification of novel mouse genes conferring posthypoxic pauses. AB - Although central to the susceptibility of adult diseases characterized by abnormal rhythmogenesis, characterizing the genes involved is a challenge. We took advantage of the C57BL/6J (B6) trait of hypoxia-induced periodic breathing and its absence in the C57BL/6J-Chr 1(A/J)/NaJ chromosome substitution strain to test the feasibility of gene discovery for this abnormality. Beginning with a genetic and phenotypic analysis of an intercross study between these strains, we discovered three quantitative trait loci (QTLs) on mouse chromosome 1, with phenotypic effects. Fine-mapping reduced the genomic intervals and gene content, and the introgression of one QTL region back onto the C57BL/6J-Chr 1(A/J)/NaJ restored the trait. mRNA expression of non-synonymous genes in the introgressed region in the medulla and pons found evidence for differential expression of three genes, the highest of which was apolipoprotein A2, a lipase regulator; the apo a2 peptide fragment (THEQLTPLVR), highly expressed in the liver, was expressed in low amounts in the medulla but did not correlate with trait expression. This work directly demonstrates the impact of elements on mouse chromosome 1 in respiratory rhythmogenesis. PMID- 22539171 TI - Leg intramuscular pressures and in vivo knee forces during lower body positive and negative pressure treadmill exercise. AB - Quantifying muscle and joint forces over a broad range of weight bearing loads during exercise may provide data required to improve prosthetic materials and better protect against muscle and bone loss. Collectively, leg intramuscular pressure (IMP), ground reaction force (GRF), and the instrumented tibial tray force measurements provide a comprehensive assessment of leg muscle and joint biomechanical effects of gravity during exercise. Titration of body weight (BW) by lower body negative pressure (LBNP) and lower body positive pressure (LBPP) can reproducibly modulate IMP within leg muscle compartments. In addition, previous studies document peak tibial forces during various daily activities of 2.2 to 2.5 BW. The study objective was to determine the IMPs of the leg, axial compressive force on the tibia in vivo, vertical GRF, and knee range of motion during altered BW levels using LBPP and LBNP treadmill exercise. We hypothesize that peak GRF, peak tibial forces, and peak IMPs of the leg correlate linearly with percent BW, as generated across a broad range of upright LBPP and supine LBNP exercise. When running at 2.24 m/s the leg IMPs significantly increased over the loading range of 60% to 140% BW with LBPP and LBNP (P < 0.001); as expected, leg IMPs were significantly higher when running compared with standing (P < 0.001). During upright LBPP, total axial force at the knee increased linearly as a function of BW at 0.67 m/s (R(2) = 0.90) and 1.34 m/s (R(2) = 0.98). During supine LBNP, total axial force at the knee increased linearly as a function of BW at 0.67 m/s (R(2) = 0.98) and 1.34 m/s (R(2) = 0.91). The present study is the first to measure IMPs and peak tibial forces in vivo during upright LBPP, upright LBNP, and supine LBNP exercise. These data will aid the development of rehabilitation exercise hardware and prescriptions for patients and astronauts. PMID- 22539172 TI - Effectiveness of a diabetes education and self management programme (DESMOND) for people with newly diagnosed type 2 diabetes mellitus: three year follow-up of a cluster randomised controlled trial in primary care. AB - OBJECTIVE: To measure whether the benefits of a single education and self management structured programme for people with newly diagnosed type 2 diabetes mellitus are sustained at three years. DESIGN: Three year follow-up of a multicentre cluster randomised controlled trial in primary care, with randomisation at practice level. SETTING: 207 general practices in 13 primary care sites in the United Kingdom. PARTICIPANTS: 731 of the 824 participants included in the original trial were eligible for follow-up. Biomedical data were collected on 604 (82.6%) and questionnaire data on 513 (70.1%) participants. INTERVENTION: A structured group education programme for six hours delivered in the community by two trained healthcare professional educators compared with usual care. MAIN OUTCOME MEASURES: The primary outcome was glycated haemoglobin (HbA(1c)) levels. The secondary outcomes were blood pressure, weight, blood lipid levels, smoking status, physical activity, quality of life, beliefs about illness, depression, emotional impact of diabetes, and drug use at three years. RESULTS: HbA(1c) levels at three years had decreased in both groups. After adjusting for baseline and cluster the difference was not significant (difference -0.02, 95% confidence interval -0.22 to 0.17). The groups did not differ for the other biomedical and lifestyle outcomes and drug use. The significant benefits in the intervention group across four out of five health beliefs seen at 12 months were sustained at three years (P<0.01). Depression scores and quality of life did not differ at three years. CONCLUSION: A single programme for people with newly diagnosed type 2 diabetes mellitus showed no difference in biomedical or lifestyle outcomes at three years although there were sustained improvements in some illness beliefs. TRIAL REGISTRATION: Current Controlled Trials ISRCTN17844016. PMID- 22539174 TI - Dismantling the signposts to public health? NHS data under the Health and Social Care Act 2012. PMID- 22539173 TI - The effect of the Talking Diabetes consulting skills intervention on glycaemic control and quality of life in children with type 1 diabetes: cluster randomised controlled trial (DEPICTED study). AB - OBJECTIVE: To evaluate the effectiveness on glycaemic control of a training programme in consultation skills for paediatric diabetes teams. DESIGN: Pragmatic cluster randomised controlled trial. SETTING: 26 UK secondary and tertiary care paediatric diabetes services. PARTICIPANTS: 79 healthcare practitioners (13 teams) trained in the intervention (359 young people with type 1 diabetes aged 4 15 years and their main carers) and 13 teams allocated to the control group (334 children and their main carers). INTERVENTION: Talking Diabetes programme, which promotes shared agenda setting and guiding communication style, through flexible menu of consultation strategies to support patient led behaviour change. MAIN OUTCOME MEASURES: The primary outcome was glycated haemoglobin (HbA(1c)) level one year after training. Secondary outcomes were clinical measures (hypoglycaemic episodes, body mass index, insulin regimen), general and diabetes specific quality of life, self reported and proxy reported self care and enablement, perceptions of the diabetes team, self reported and carer reported importance of, and confidence in, undertaking diabetes self management measured over one year. Analysis was by intention to treat. An integrated process evaluation included audio recording a sample of 86 routine consultations to assess skills shortly after training (intervention group) and at one year follow-up (intervention and control group). Two key domains of skill assessment were use of the guiding communication style and shared agenda setting. RESULTS: 660/693 patients (95.2%) provided blood samples at follow-up. Training diabetes care teams had no effect on HbA(1c) levels (intervention effect 0.01, 95% confidence interval -0.02 to 0.04, P=0.5), even after adjusting for age and sex of the participants. At follow up, trained staff (n=29) were more capable than controls (n=29) in guiding (difference in means 1.14, P<0.001) and agenda setting (difference in proportions 0.45, 95% confidence interval 0.22 to 0.62). Although skills waned over time for the trained practitioners, the reduction was not significant for either guiding (difference in means -0.33, P=0.128) or use of agenda setting (difference in proportions -0.20, -0.42 to 0.05). 390 patients (56%) and 441 carers (64%) completed follow-up questionnaires. Some aspects of diabetes specific quality of life improved in controls: reduced problems with treatment barriers (mean difference -4.6, 95% confidence interval -8.5 to -0.6, P=0.03) and with treatment adherence (-3.1, -6.3 to -0.01, P=0.05). Short term ability to cope with diabetes increased in patients in intervention clinics (10.4, 0.5 to 20.4, P=0.04). Carers in the intervention arm reported greater excitement about clinic visits (1.9, 1.05 to 3.43, P=0.03) and improved continuity of care (0.2, 0.1 to 0.3, P=0.01). CONCLUSIONS: Improving glycaemic control in children attending specialist diabetes clinics may not be possible through brief, team-wide training in consultation skills. TRIAL REGISTRATION: Current Controlled Trials ISRCTN61568050. PMID- 22539175 TI - Self management education and good professional consultation skills for patients with diabetes. PMID- 22539177 TI - A teenager with a cough, fever, and poor appetite. PMID- 22539176 TI - Bullying victimisation and risk of self harm in early adolescence: longitudinal cohort study. AB - OBJECTIVES: To test whether frequent bullying victimisation in childhood increases the likelihood of self harming in early adolescence, and to identify which bullied children are at highest risk of self harm. DESIGN: The Environmental Risk (E-Risk) longitudinal study of a nationally representative UK cohort of 1116 twin pairs born in 1994-95 (2232 children). SETTING: England and Wales, United Kingdom. PARTICIPANTS: Children assessed at 5, 7, 10, and 12 years of age. MAIN OUTCOME MEASURES: Relative risks of children's self harming behaviour in the six months before their 12th birthday. RESULTS: Self harm data were available for 2141 children. Among children aged 12 who had self harmed (2.9%; n=62), more than half were victims of frequent bullying (56%; n=35). Exposure to frequent bullying predicted higher rates of self harm even after children's pre-morbid emotional and behavioural problems, low IQ, and family environmental risks were taken into account (bullying victimisation reported by mother: adjusted relative risk 1.92, 95% confidence interval 1.18 to 3.12; bullying victimisation reported by child: 2.44, 1.36 to 4.40). Victimised twins were more likely to self harm than were their non-victimised twin sibling (bullying victimisation reported by mother: 13/162 v 3/162, ratio=4.3, 95% confidence interval 1.3 to 14.0; bullying victimisation reported by child: 12/144 v 7/144, ratio=1.7, 0.71 to 4.1). Compared with bullied children who did not self harm, bullied children who self harmed were distinguished by a family history of attempted/completed suicide, concurrent mental health problems, and a history of physical maltreatment by an adult. CONCLUSIONS: Prevention of non-suicidal self injury in young adolescents should focus on helping bullied children to cope more appropriately with their distress. Programmes should target children who have additional mental health problems, have a family history of attempted/completed suicide, or have been maltreated by an adult. PMID- 22539178 TI - What will a doctor bring to the World Bank? PMID- 22539179 TI - "Slick" cigarette packaging encourages children to smoke, UK charity says. PMID- 22539180 TI - Confusion is widespread about the role and aim of clinical senates, conference hears. PMID- 22539181 TI - The role of extraesophageal reflux in medically and surgically refractory rhinosinusitis. AB - OBJECTIVES/HYPOTHESIS: To clarify the relationship between chronic rhinosinusitis (CRS) and extraesophageal reflux (EER) using state-of-the-art technology. We hypothesized that patients with medically and surgically refractory CRS would have a greater prevalence of EER. We also hypothesized that there would be evidence of gastric refluxate reaching the nasopharynx and paranasal sinuses. STUDY DESIGN: Case-control analysis. METHODS: Twenty-two patients with medically and surgically refractory rhinosinusitis were enrolled in the study. Subjects all underwent comprehensive testing for EER including 24-hour pharyngeal pH probe, aerosolized nasopharyngeal pH testing, and nasopharyngeal tissue biopsy for pepsin analysis. In addition, the last five subjects underwent nasal lavage pepsin analysis. A control group of healthy subjects underwent the same nasal secretion pepsin analysis. RESULTS: Twenty subjects completed the study. The pharyngeal pH probe results were positive in 19/20 (95%), where the DeMeester score was positive in 9/19 (47%). The nasopharyngeal pH probe data were available in 17/20 patients and correlated poorly with the pharyngeal pH probe testing. In all 20 subjects, nasopharyngeal tissue biopsies were negative for pepsin. However, in the five subjects who underwent nasal lavage pepsin analysis, all were pepsin positive while five healthy control nasal lavage pepsin analysis were negative. CONCLUSIONS: This study supports an association of EER with medically and surgically refractory CRS. The finding of pepsin in nasal lavages suggests that direct contact of the refluxate with the paranasal sinus mucosa may play a role in the pathophysiology of CRS in this patient population. Finally, evaluation for pepsin in nasal fluid may be a viable method for determining the presence of refluxate in the nose and paranasal sinuses. PMID- 22539182 TI - Synthesis, spectroscopic characterization, photochemical and photophysical properties and biological activities of ruthenium complexes with mono- and bi dentate histamine ligand. AB - The monodentate cis-[Ru(phen)(2)(hist)(2)](2+)1R and the bidentate cis [Ru(phen)(2)(hist)](2+)2A complexes were prepared and characterized using spectroscopic ((1)H, ((1)H-(1)H)COSY and ((1)H-(13)C)HSQC NMR, UV-vis, luminescence) techniques. The complexes presented absorption and emission in the visible region, as well as a tri-exponential emission decay. The complexes are soluble in aqueous and non-aqueous solution with solubility in a buffer solution of pH 7.4 of 1.14 * 10(-3) mol L(-1) for (1R + 2A) and 6.43 * 10(-4) mol L(-1) for 2A and lipophilicity measured in an aqueous-octanol solution of -1.14 and 0.96, respectively. Photolysis in the visible region in CH(3)CN converted the starting complexes into cis-[Ru(phen)(2)(CH(3)CN)(2)](2+). Histamine photorelease was also observed in pure water and in the presence of BSA (1.0 * 10(-6) mol L( 1)). The bidentate coordination of the histamine to the ruthenium center in relation to the monodentate coordination increased the photosubstitution quantum yield by a factor of 3. Pharmacological studies showed that the complexes present a moderate inhibition of AChE with an IC(50) of 21 MUmol L(-1) (referred to risvagtini, IC(50) 181 MUmol L(-1) and galantamine IC(50) 0.006 MUmol L(-1)) with no appreciable cytotoxicity toward to the HeLa cells (50% cell viability at 925 MUmol L(-1)). Cell uptake of the complexes into HeLa cells was detected by fluorescence confocal microscopy. Overall, the observation of a luminescent complex that penetrates the cell wall and has low cytotoxicity, but is reactive photochemically, releasing histamine when irradiated with visible light, are interesting features for application of these complexes as phototherapeutic agents. PMID- 22539183 TI - Genetic polymorphisms of glutathione S-transferase T1 (GSTT1) and M1 (GSTM1) in selected populations of Afghanistan. AB - Genetic polymorphisms in genes encoding glutathione S-transferase T1 (GSTT1, a member of class theta) and M1 (GSTM1, a member of class mu) have been defined. Previous studies have revealed that there was significant difference between populations for allelic frequency of several members of GSTs. In order to find the prevalence of null genotypes of GSTM1 and GSTT1 in Afghanis populations the present study was carried out. The total study subjects consisted of 656 unrelated healthy Afghanis refugees living in Fars province (southern Iran). From these 257, 217, 120, and 62 individuals were Pashtuns, Tajiks, Hazaras, and Uzbeks, respectively. Genetic polymorphisms for GSTT1 and GSTM1 were detected by multiplex PCR. The prevalence of null genotype of GSTM1 in Pashtuns, Tajiks, Hazaras, and Uzbeks was 42.4, 48.4, 52.5, and 40.3 %, respectively. There was no significant difference between these populations for the genotypic distribution of the GSTM1 polymorphism (chi(2) = 4.67, df = 3, P = 0.197). The frequency of GSTT1 null genotype in Pashtuns, Tajiks, Hazaras, and Uzbeks was 7.4, 25.3, 25.0, and 29.0 %, respectively. The observed difference between populations for prevalence of GSTT1 null genotype was statistically significant (chi(2) = 35.54, df = 3, P < 0.001). In comparison with European and Asian populations, Afghanistan populations like Iranian populations showed intermediate frequency for GSTT1 and GSTM1 null genotypes. PMID- 22539184 TI - Overexpression of the halophyte Kalidium foliatum H+-pyrophosphatase gene confers salt and drought tolerance in Arabidopsis thaliana. AB - According to sequences of H(+)-pyrophosphatase genes from GenBank, a new H(+) pyrophosphatase gene (KfVP1) from the halophyte Kalidium foliatum, a very salt tolerant shrub that is highly succulent, was obtained by using reverse transcription PCR and rapid amplification of cDNA ends methods. The obtained KfVP1 cDNA contained a 2295 bp ORF and a 242 bp 3'-untranslated region. It encoded 764 amino acids with a calculated molecular mass of 79.78 kDa. The deduced amino acid sequence showed high identity to those of H(+)-PPase of some Chenopodiaceae plant species. Semi-quantitative PCR results revealed that transcription of KfVP1 in K. foliatum was induced by NaCl, ABA and PEG stress. Transgenic lines of A. thaliana with 35S::KfVP1 were generated. Three transgenic lines grew more vigorous than the wild type (ecotype Col-0) under salt and drought stress. Moreover, the transgenic plants accumulated more Na(+) in the leaves compared to wild type plants. These results demonstrated that KfVP1 from K. foliatum may be a functional tonoplast H(+)-pyrophosphatase in contributing to salt and drought tolerance. PMID- 22539185 TI - BcNRT1, a plasma membrane-localized nitrate transporter from non-heading Chinese cabbage. AB - A nitrate transporter, BcNRT1, was isolated from non-heading Chinese cabbage (Brassica campestris ssp. chinensis Makino) cultivar 'Suzhouqing'. The full length cDNA was obtained using the rapid amplification of cDNA ends technique and contains an open reading frame of 1,770 bp that predicts a protein of 589 acid residues that possesses 12 putative transmembrane domains. Using the GUS marker gene driven by the BcNRT1 promoter, we found BcNRT1 expression to be concentrated in primary and lateral root tips and in shoots of transgenic Arabidopsis plants. The YFP fused to BcNRT1 and transformed into cabbage protoplasts indicated that BcNRT1 was localized to the plasma membrane. The expression of BcNRT1 in roots was induced by exposure to 25 mM nitrate, and the BcNRT1 cRNA heterologously expressed in Xenopus laevis oocytes showed nitrate conductance when nitrate was included in the medium. Moreover, mutant chl1-5 plants harboring 35S::BcNRT1 showed sensitivity to chlorate treatment and exhibited restored nitrate uptake. In conclusion, the results indicate that BcNRT1 functions as a low affinity nitrate transporter in non-heading Chinese cabbage. PMID- 22539187 TI - Overexpressing MhNPR1 in transgenic Fuji apples enhances resistance to apple powdery mildew. AB - Fuji is susceptible to fungal diseases like apple powdery mildew. Non-expressor of pathogenesis-related gene 1 (NPR1) plays a key role in regulating salicylic acid (SA)-mediated systemic acquired resistance (SAR). Previous studies show that overexpressing the Malus hupehensis-derived NPR1 (MhNPR1) gene in tobacco induces the transcript expression of pathogenesis-related genes (PRs) and resistance to the fungus Botrytis cinerea. In this study we introduced the MhNPR1 gene into the 'Fuji' apple via Agrobacterium-mediated transformation. Four transgenic apple lines were verified by PCR and RT-PCR. The semi-quantitative RT-PCR results showed that transcript overexpression of the MhNPR1 gene induced the expression of MdPRs and MdMLO genes known to interact with powdery mildew. Furthermore, the transgenic apple plants resisted infection by apple powdery mildew better than the wild-type plants. As a result, transcript overexpression of the MhNPR1 gene induced SAR and enhanced the Fuji apple's resistance to fungal disease. PMID- 22539188 TI - Radial junction amorphous silicon solar cells on PECVD-grown silicon nanowires. AB - Constructing radial junction hydrogenated amorphous silicon (a-Si:H) solar cells on top of silicon nanowires (SiNWs) represents a promising approach towards high performance and cost-effective thin film photovoltaics. We here develop an all-in situ strategy to grow SiNWs, via a vapour-liquid-solid (VLS) mechanism on top of ZnO-coated glass substrate, in a plasma-enhanced chemical vapour deposition (PECVD) reactor. Controlling the distribution of indium catalyst drops allows us to tailor the as-grown SiNW arrays into suitable size and density, which in turn results in both a sufficient light trapping effect and a suitable arrangement allowing for conformal coverage of SiNWs by subsequent a-Si:H layers. We then demonstrate the fabrication of radial junction solar cells and carry on a parametric study designed to shed light on the absorption and quantum efficiency response, as functions of the intrinsic a-Si:H layer thickness and the density of SiNWs. These results lay a solid foundation for future structural optimization and performance ramp-up of the radial junction thin film a-Si:H photovoltaics. PMID- 22539186 TI - Identification and characterization of a novel calcyclin binding protein (CacyBP) gene from Apis cerana cerana. AB - Calcyclin binding protein (CacyBP), a homolog of Sgt1, was shown to interact with some S100 proteins, Skp1, tubulin, actin and ERK1/2 kinases. Studies have also shown that CacyBP is a neuronal protein in mammals. Limited information is available regarding the properties and functions of CacyBP in insects. Here, we cloned and characterized a novel CacyBP gene, named AccCacyBP, from honeybee (Apis cerana cerana). Bioinformatic analysis indicated that AccCacyBP was highly conserved and closely related to the CacyBP of other insects. Promoter analysis revealed a number of putative tissue, development and stress-related transcription factor-binding sites. RT-qPCR demonstrated that AccCacyBP was expressed at all of the stages of development, especially in the brains of honeybees. Moreover, immunohistochemistry analysis showed the presence of AccCacyBP in the brain. The transcript levels of AccCacyBP in the brains of honeybees were developmentally induced and upregulated by exposure to oxidative stresses, including UV-light, acetamiprid and HgCl(2). This study demonstrates that the CacyBP gene in honeybees may be a neuronal protein involved in the developmental regulation and the stress-response of the brain of honeybees. PMID- 22539190 TI - Negative emotional photographs are identified more slowly than positive photographs. AB - In three experiments, we investigated whether the emotional valence of a photograph influenced the amount of time required to initially identify the contents of the image. In Experiment 1, participants saw a slideshow consisting of positive, neutral, and negative photographs that were balanced for arousal. During the slideshow, presentation time was substantially limited (60 ms), and the images were followed by masks. Immediately following the slideshows, participants were given a recognition memory test. Memory performance was best for positive images and worst for negative images (Experiment 1). In Experiment 2, two simultaneous photographs were briefly presented and masked. On a trial-by trial basis, participants indicated whether the two images were identical or not, thus removing the need for memory storage and retrieval. Again, performance was worst for negative images. The results of Experiment 3 suggested that these valence-based differences were not related attentional effects (Experiment 3). We argue that the valence of an image is detected rapidly and, in the case of negative images, interferes with processing the identity of the scene. PMID- 22539192 TI - Use of bevacizumab for macular edema secondary to branch retinal vein occlusion: a systematic review. AB - INTRODUCTION: This systematic review assesses the effectiveness of intravitreal bevacizumab (IVB) versus a comparison group in the treatment of branch retinal vein occlusion (BRVO)-associated macular edema, and explores its effects on visual acuity (VA) and central macular thickness (CMT). METHODS: The authors searched the following databases: Medline (1950-October week 3, 2011), The Cochrane Library (Issue 10, 2011), EMBASE (up to 24 October 2011), and the TRIP Database (up to 24 October 2011), using no language or other limits. Trials that were included consisted of patients with BRVO-associated macular edema, those comparing a 1.25 mg IVB injection with a comparison group, those reporting both VA and CMT outcomes, and those having a minimum follow-up of 4 weeks. RESULTS: In the four trials comparing IVB with a comparison group, IVB was effective in improving VA and CMT values in the long-term (12 weeks) in patients with BRVO associated macular edema. Furthermore, statistically significant improvements in VA in the short-term (4 weeks) could also be seen. DISCUSSION: Clinicians should use this review as an indicator that IVB is effective in improving VA and CMT values in the long-term in patients with BRVO-associated macular edema. It is important to note, however, that statistically significant improvements in VA in the short term could be seen. This review's main aim was to serve as an evidence base for potentially using other modalities, such as IVB, which seems to be reserved for certain cases. PMID- 22539193 TI - Changes in PACAP immunoreactivity in human milk and presence of PAC1 receptor in mammary gland during lactation. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with widespread occurrence in the nervous system and peripheral organs, including the mammary gland. Previously, we have shown that PACAP38 is present in the human milk at higher levels than in respective blood samples. However, it is not known how PACAP levels and the expression of PAC1 receptor change during lactation. Therefore, the aim of our study was to investigate PACAP38-like immunoreactivity (PACAP38-LI) in human colostrums and transitional and mature milk during lactation and to compare the expression of PAC1 receptors in lactating and non lactating mammary glands. We found that PACAP38-LI was significantly higher in human colostrum samples than in the transitional and mature milk. PACAP38-LI did not show any significant changes within the first 10-month period of lactation, but a significant increase was observed thereafter, up to the examined 17th month. Weak expression of PAC1 receptors was detected in non-lactating sheep and human mammary glands, but a significant increase was observed in the lactating sheep samples. In summary, the present study is the first to show changes of PACAP levels in human milk during lactation. The presence of PACAP in the milk suggests a potential role in the development of newborn, while the increased expressions of PAC1 receptors on lactating breast may indicate a PACAP38/PAC1 interaction in the mammary gland during lactation. PMID- 22539195 TI - Hierarchically tunable helical assembly of achiral porphyrin-incorporated alkoxysilane. AB - A general assembly approach is developed to construct hierarchically tunable helical superstructures from an achiral porphyrin-incorporated alkoxysilane. The resulting superstructures can be controlled from film, rice, spindle, ribbon, to fiber in morphology and from nonhelical to helical in structure at a multiscale with excellent optoelectronic, electrical, and thermal properties. PMID- 22539196 TI - A hybrid photocatalytic system comprising ZnS as light harvester and an [Fe(2)S(2)] hydrogenase mimic as hydrogen evolution catalyst. AB - Photo opportunity: A highly efficient and stable hybrid artificial photosynthetic H(2) evolution system is assembled by using a semiconductor (ZnS) as light harvester and an [Fe(2)S(2)] hydrogenase mimic ([(MU-SPh-4-NH(2) )(2) Fe(2) (CO)(6)]) as catalyst for H(2) evolution. Photocatalytic H(2) production is achieved with more than 2607 turnovers (based on [Fe(2)S(2)]) and an initial turnover frequency of 100 h(-1) through the efficient transfer of photogenerated electrons from ZnS to the [Fe(2)S(2)] complex. PMID- 22539197 TI - Study of pharmaceutical coatings by means of NMR cryoporometry and SEM image analysis. AB - Nuclear magnetic resonance (NMR) cryoporometry and scanning electron microscopy (SEM) image analysis have been used to investigate the size and shape distribution of pores in pharmaceutical coatings. The coatings were made from a mixture of hydroxypropylcellulose (HPC) and ethylcellulose (EC). Upon solvent evaporation from a solution consisting of both the polymers, a solid polymer film is formed, which after removal of the water-soluble HPC consists of a skeleton of EC. A change in the amount of HPC enables modification of the water permeability through the films. By means of NMR cryoporometry, the presence of small pores (radius below 400 nm) was revealed with no significant change in the pore size distribution (PSD) as the HPC content in the films were changed. NMR cryoporometry showed the presence of channels of a characteristic 30-nm length scale in the films that contained more than 22% HPC. Below this threshold, the lack of interconnecting channels seems to prevent complete HPC dissolution and thereby the water permeability. SEM image analysis showed pore sizes that ranged from hundreds of nanometers up to few micrometers. Above the 22% threshold, further increase of HPC in the films resulted in an increased pore volume and wider PSD. PMID- 22539198 TI - The preventive effect of garlicin on a porcine model of myocardial infarction reperfusion no-reflow. AB - OBJECTIVE: To evaluate whether garlicin can prevent reperfusion no-reflow in a catheter-based porcine model of acute myocardial infarction (AMI). METHODS: Twenty-two male Chinese mini swines were randomized into 3 groups: sham-operation group (n=6), control group (n=8), and garlicin group (n=8). The distal part of left anterior descending coronary artery (LAD) in swines of the latter two groups was completely occluded by dilated balloon for 2 h and a successful AMI model was confirmed by coronary angiography (CAG) and electrocardiograph (ECG), which was then reperfused for 3 h. In the sham-operation group, balloon was placed in LAD without dilatation. Garlicin at a dosage of 1.88 mg/kg was injected 10 min before LAD occlusion until reperfusion for 1 h in the garlicin group. To assess serial cardiac function, hemodynamic data were examined by catheter method before AMI, 2 h after occlusion and 1, 2, and 3 h after reperfusion. Myocardial contrast echocardiography (MCE) and double staining with Evans blue and thioflavin-S were performed to evaluate myocardial no-reflow area (NRA) and risk area (RA). RESULTS: Left ventricular systolic pressure and left ventricular end-diastolic pressure significantly improved in the garlicin group after reperfusion compared with the control group P<0.05) and 2 h after AMI (P<0.05). MCE showed garlicin decreased reperfusion NRA after AMI compared with the control group (P <0.05). In double staining, NRA/RA in the garlicin group was 18.78%, significantly lower than that of the control group (49.84%, P<0.01). CONCLUSIONS: Garlicin has a preventive effect on the porcine model of myocardial infarction reperfusion no reflow by improving hemodynamics and decreasing NRA. PMID- 22539199 TI - Evaluation of the conjoint efficacy in Chinese medicine with the longitudinal latent variable linear mixed model. AB - Chinese medicine (CM) clinical efficacy evaluation research involves the longitudinal multivariate measurement which means that patients are measured repeatedly and each patient is measured by several indicators on each fixed cross section. Although each indicator can be evaluated separately with a longitudinal linear mixed model, it is important to consider all the endpoints together especially when researchers pay special attention to the change of the conjoint efficacy for several indicators in one patient. In this article, we introduce a latent variable linear mixed model to the CM conjoint efficacy evaluation and discuss why and how to analyze the longitudinal multivariate endpoint data in the clinical CM efficacy evaluation research. It may lead to the new insight of using such methodology in the field of conjoint efficacy evaluating of CM study. And with the definition of syndrome and symptom in the CM theory, the applied discussion brings the insight of CM syndrome evaluating in future. We illustrate this methodology using an example of CM efficacy evaluation from an ischemic stroke research. PMID- 22539200 TI - Selective hepatic vascular exclusion versus Pringle manoeuvre in liver resection for tumours encroaching on major hepatic veins. AB - BACKGROUND: Control of bleeding is crucial during liver resection, and several techniques have been developed to achieve this. This study compared the safety and efficacy of selective hepatic vascular exclusion (SHVE) and Pringle manoeuvre in partial hepatectomy for liver tumours compressing or involving major hepatic veins. METHODS: All patients undergoing liver resection between January 2003 and December 2010 for liver tumours compressing or involving one or more major hepatic veins were identified retrospectively from a prospective institutional database. Either SHVE or Pringle manoeuvre was used to minimize blood loss during hepatectomy. Data on demographics and the intraoperative and postoperative course were analysed. RESULTS: From the database of 3900 patients, 1420 were identified who underwent liver resection for tumours encroaching on major hepatic veins using either SHVE (550) or the Pringle manoeuvre (870). Intraoperative blood loss (mean(s.d.) 480(210) versus 830(340) ml; P = 0.007) and transfusion requirements (mean(s.d.) 1.3(0.6) versus 2.9(1.4) units; P = 0.008) were significantly less in the SHVE group. In the Pringle group, hepatic vein injury resulted in major intraoperative bleeding of over 1000 ml in 65 patients (7.5 per cent) and air embolism in 14 (1.6 per cent), and three patients (0.3 per cent) died during surgery, whereas there was no major bleeding, air embolism or intraoperative death in the SHVE group. Postoperative liver failure, multiple organ failure and in-hospital death were significantly more common in the Pringle group (P = 0.019, P = 0.032 and P = 0.004 respectively). CONCLUSION: SHVE was more efficacious than the Pringle manoeuvre in minimizing intraoperative bleeding and air embolism during partial hepatectomy for tumours encroaching on major hepatic veins, and decreased the postoperative liver failure rate. PMID- 22539201 TI - High-temperature-resistant chiral silica generated on chiral crystalline templates at neutral pH and ambient conditions. PMID- 22539202 TI - Prostasomes are heterogeneous regarding size and appearance but affiliated to one DNA-containing exosome family. AB - BACKGROUND: Prostate acinar epithelial cells release microvesicles (prostasomes) that possess pleiotropic biological effects relevant for successful fertilization. Prostasomes are formed in a similar way as exosomes but are heterogeneous as regards size and appearance. Like exosomes they are thought to be mediators of intercellular communication. METHODS: We prepared seminal prostasomes in accordance with the prevailing protocol for exosome preparation including passage through a 0.2 um filter and centrifugation in a sucrose gradient. RESULTS: We compared the "filterable prostasomes" with those trapped on the filter ("nonfilterable prostasomes") and, qualitatively, no conspicuous differences were apparent regarding ultrastructure and SDS-PAGE banding pattern. Moreover, both types of prostasomes contained DNA fragments and Western blot revealed presence of prostate specific membrane antigen (PSMA), CD38, and annexin A1. CONCLUSIONS: Reasonably, prostasomes could be included in the exosome family and be regarded as one entity containing chromosomal DNA. PMID- 22539203 TI - On the recurrence of occupational injuries and workers' compensation claims. AB - This paper represents the first study to estimate counts of individual occupational injuries and claims over long spells of working life (up to 13 years) in the USA. It explores data from the National Longitudinal Survey of Youth 1979. I found that 37% of all surveyed workers who had experienced one on the-job accident reported at least one additional injury, but only 56% of all occupational injuries and illnesses resulted in workers' compensation claims. I estimated different count models to assess the effect of different individual worker and job characteristics on individual injury counts and workers' compensation claims counts. Lower educational levels, less tenure, work in dangerous industries and unskilled occupations, and job demands are found to be important determinants of multiple on-the-job injuries. The most interesting results, however, refer to the role played by individuals' pre-injury characteristics: early exposure to dangerous jobs is among the main determinants of higher counts of occupational injuries later in life. Early health limitations are also significant predictors of recurrent workers' compensation claims. These results provide new evidence about the important role played by both the health and the socioeconomic status of young people as determinants of their future occupational injuries. PMID- 22539204 TI - Inferior turbinate surgery in children: a survey of practice patterns. AB - OBJECTIVES/HYPOTHESIS: A variety of techniques for inferior turbinate reduction have been used in children, but to date practice patterns have not been studied. The purpose of this survey was to study the practice of inferior turbinate surgery among pediatric otolaryngologists. STUDY DESIGN: Cross-sectional survey study. METHODS: A questionnaire was sent electronically to American Society of Pediatric Otolaryngologists members. RESULTS: A total of 249 questionnaires were sent, and 103 (41%) were completed. Six questionnaires were eliminated due to incompleteness. Seventy-nine (81%) respondents performed inferior turbinate surgery. The most common reason for not performing the procedure was lack of outcomes data. Coblation was the most common technique used in 51% of respondents. A change in surgical technique in the last 2 to 5 years, most commonly to coblation or microdebridement, was reported by 53% of respondents. Nasal obstruction was the primary indication for turbinate reduction (81%), followed by sleep-disordered breathing (16%). Respondents reported that 20% of turbinate reductions were sole procedures, and 80% were with other procedures: adenotonsillectomy, septoplasty, and sinus surgery. Fifty-six (71%) responders were either satisfied or very satisfied with the results of pediatric turbinate surgery. Failure of the procedure, epistaxis, and nasal crusting were commonly reported complications, and 9% reported major complications. CONCLUSIONS: A high proportion of pediatric otolaryngologists perform inferior turbinate surgery, most commonly for nasal obstruction. Coblation is the most common technique used, and complications are mostly minor. Physician satisfaction rates are high despite a paucity of outcomes data on the procedure. PMID- 22539207 TI - MPF2-like MADS-box genes affecting expression of SOC1 and MAF1 are recruited to control flowering time. AB - A complex and intricate network of genes responding to various developmental and environmental signals control floral transition in plants. MADS-box genes are the key regulators and major contributors with regard to flowering time determination. Previously, MPF2-like genes belonging to the STMADS11 superclade were duplicated into MPF2-like-A and MPF2-like-B in Withania (WSA206 and WSB206) and Tubocapsicum (TAB 201). The present study was conducted to determine the effect of MPF2-like genes on flowering time by analyzing 35S:MPF2-like transgenic Arabidopsis plants as well as to probe their effects on the expression of SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (SOC1, a floral promoter) and MADS AFFECTING FLOWERING 1 (MAF1, a floral repressor) genes. The overexpression of WSA206 (35S:MPF2-like-A) moderately promoted flowering, while that of WSB206 and TAB 201 (35S:MPF2-like-B) exhibited no effects on floral transition. Concomitantly, an elevation in SOC1 transcript abundance and a reduction for MAF1 transcript levels were observed in 35S:WSA206 transgenic plants. Nucleotide diversity analysis indicated an extraordinary 8 aa extension at the C-terminus of the WSA206 protein. Ectopic expression of a truncated WSA206-version without these 8 aa (WSA206DeltaC246) and of MPF2-like-B-versions elongated by these 8 aa (WSB206?C257 and TAB 201?C257) in Arabidopsis revealed an ambiguous role of the 8 aa signature in floral transition. It may influence a protein's ability to modulate flowering time but is neither sufficient nor strictly necessary for early flowering. Nevertheless, the 8 aa extension influences the expression of SOC1 and MAF1 in MPF2-like derivative constructs. Our studies provide insight into the role of MPF2-like genes in phase transition by interacting with SOC1 and MAF1 genes, thereby also pointing to their significance as potential candidates for modifying flowering in crop plants in the future. PMID- 22539208 TI - Experimental analysis of perching in the European starling (Sturnus vulgaris: Passeriformes; Passeres), and the automatic perching mechanism of birds. AB - The avian automatic perching mechanism (APM) involves the automatic digital flexor mechanism (ADFM) and the digital tendon-locking mechanism (DTLM). When birds squat on a perch to sleep, the increased tendon travel distance due to flexion of the knee and ankle supposedly causes the toes to grip the perch (ADFM) and engage the DTLM so perching while sleeping involves no muscular effort. However, the knees and ankles of sleeping European starlings (Sturnus vulgaris) are only slightly flexed and, except for occasional balancing adjustments, the distal two-thirds of the toes are not flexed to grip a 6-mm-diameter perch. The cranial ankle angle (CAA) is ~120 degrees and the foot forms an inverted "U" that, with the mostly unflexed toes, provides a saddle-like structure so the bird balances its weight over the central pad of the foot (during day weight further back and digits actively grasp perch). In the region of the pad, the tendon sheath of many birds is unribbed, or only very slightly so, and it is always separated from the tendon of the M. flexor digitorum longus by tendons of the other toe flexor muscles. Passive leg flexion produces no toe flexion in anesthetized Starlings and only after 15-20 min, at the onset of rigor mortis, in freshly sacrificed Starlings. Anesthetized Starlings could not remain perched upon becoming unconscious (ADFM, DTLM intact). Birds whose digital flexor tendons were severed or the locking mechanism eliminated surgically (no ADFM or DTLM), so without ability to flex their toes, slept on the perch in a manner similar to unoperated Starlings (except CAA ~90 degrees -110 degrees ). Consequently, there is no APM or ADFM and the DTLM, although involved in lots of other activities, only acts in perching with active contraction of the digital flexor muscles. PMID- 22539209 TI - Temperature preference during forelimb regeneration in the red-spotted newt Notophthalmus viridescens. AB - Red-spotted newts (Notophthalmus viridescens) are model organisms for regenerative research. These animals can regenerate limbs, tails, jaws, spinal cords, as well as the lens of the eye. Newts are small ectotherms that are aquatic as adults; as ectotherms, they naturally conform to the temperature of their surroundings. Environmental temperatures, however, can increase or decrease the red-spotted newt's metabolic processes, including their rate of tissue regeneration; whether an optimal temperature for this rate of regeneration exists is unknown. However, newts do exhibit behavioral preferences for certain temperatures, and these thermal preferences can change with season or with acclimation. Given this flexibility in behavioral thermoregulation, we hypothesized that the process of tissue regeneration could also affect thermal preference, given the metabolic costs or altered temperature sensitivities of tissue regrowth. It was predicted that regenerating newts would select an environmental temperature that maximized the rate of regeneration, however, this prediction was not fully supported. Thermal preference trials revealed that newts consistently selected temperatures between 24 and 25 degrees C throughout regeneration. This temperature selection was warmer than that of uninjured conspecifics, but was lower than temperatures that would have further augmented the rate of regeneration. Interestingly, regenerating newts maintained a more stable temperature preference than sham newts, suggesting that accuracy in thermoregulation may be more important to regenerating individuals, than to noninjured individuals. PMID- 22539211 TI - Keratinophilic fungi isolated from soils of long-term fold-grazed, degraded pastures in national parks of Slovakia. AB - A total of 939 isolates of 11 genera representing 15 species of keratinophilic fungi were isolated and identified from the soils of three long-term fold-grazed pastures in national parks of Slovakia (Pod Ploskou, Strungovy prislop, and Pod Keckou) and one non-fold-grazed pasture in sierra Stolicke vrchy (Diel) using the hair-baiting technique. Keratinophilic fungi were present in all soil samples with a prevalence of Trichophyton ajelloi and Paecilomyces lilacinus. These fungi were more abundant in soil from fold-grazed pasture (Strungovy prislop) compared to non-fold-grazed pasture (Diel). The occurrence of the other keratinophilic fungi was substantially lower, likely because of low pH in some soils. PMID- 22539212 TI - Temperature-dependent nonradiative recombination processes in GaN-based nanowire white-light-emitting diodes on silicon. AB - In this paper, we have performed a detailed investigation of the temperature- and current-dependent emission characteristics of nanowire light-emitting diodes, wherein InGaN/GaN dot-in-a-wire nanoscale heterostructures and a p-doped AlGaN electron blocking layer are incorporated in the device's active region to achieve white-light emission and to prevent electron overflow, respectively. Through these studies, the Auger coefficient is estimated to be in the range of ~10(-34) cm(6) s(-1) or less, which is nearly four orders of magnitude smaller than the commonly reported values of planar InGaN/GaN heterostructures, suggesting Auger recombination plays an essentially negligible role in the performance of GaN based nanowire light-emitting diodes. It is observed, however, that the performance of such nanowire LEDs suffers severely from Shockley-Read-Hall recombination, which can account for nearly 40% of the total carrier recombination under moderate injection conditions (~100 A cm(-2)) at room temperature. The Shockley-Read-Hall nonradiative lifetime is estimated to be in the range of a few nanoseconds at room temperature, which correlates well with the surface recombination velocity of GaN and the wire diameters used in this experiment. PMID- 22539213 TI - Super-stretchable spring-like carbon nanotube ropes. AB - Spring-like carbon nanotube ropes consisting of perfectly arranged loops are fabricated by spinning single-walled nanotube films, and can sustain tensile strains as high as 285%. PMID- 22539214 TI - Using FlAsH to probe conformational changes in a large HEAT repeat protein. AB - We have investigated the use of FlAsH, a small fluorogenic molecule that binds to tetracysteine motifs, to probe folding of the 15-HEAT repeat protein PR65A. PR65A is one of a special class of modular non-globular proteins known as tandem repeat proteins, which are composed of small structural motifs that stack to form elongated, one-dimensional architectures. We were able to introduce linear and bipartite tetracysteine motifs at several sites along the alpha-helical HEAT array of PR65A without disrupting the structure or stability. When the linear tetracysteine motif CCPGCC was used, FlAsH fluorescence reported globally on the folding of the protein. When the tetracysteine motif was displayed in bipartite mode through the engineering of pairs of cysteines on adjacent HEAT repeats, FlAsH fluorescence became a reporter of local conformation and of oligomerisation. Thus, by designing FlAsH-binding sites at different locations along the repeat array one can interrogate specific properties of PR65A, paving the way for structure-function analysis of this protein both in vitro and in the cell. PMID- 22539206 TI - Bioengineering for salinity tolerance in plants: state of the art. AB - Genetic engineering of plants for abiotic stress tolerance is a challenging task because of its multifarious nature. Comprehensive studies for developing abiotic stress tolerance are in progress, involving genes from different pathways including osmolyte synthesis, ion homeostasis, antioxidative pathways, and regulatory genes. In the last decade, several attempts have been made to substantiate the role of "single-function" gene(s) as well as transcription factor(s) for abiotic stress tolerance. Since, the abiotic stress tolerance is multigenic in nature, therefore, the recent trend is shifting towards genetic transformation of multiple genes or transcription factors. A large number of crop plants are being engineered by abiotic stress tolerant genes and have shown the stress tolerance mostly at laboratory level. This review presents a mechanistic view of different pathways and emphasizes the function of different genes in conferring salt tolerance by genetic engineering approach. It also highlights the details of successes achieved in developing salt tolerance in plants thus far. PMID- 22539215 TI - Intersubjective model of value transmission: parents using perceived norms as reference when socializing children. AB - What values do parents want to transmit to children? The intersubjective model of value transmission posits that parents want to transmit not only the values they personally endorse but also the values they perceive to be normatively important in the society. The present research shows support to this premise. Furthermore, Studies 1 and 2 revealed that the use of perceived norms is moderated by families' social contexts and parents' personality: It was particularly pronounced among parents who were immigrants, who had a stronger need for closure, and who were more conforming. In addition, Studies 3 and 4 demonstrated that parents' perceived norms can explain actual value transmission: Values parents perceived to be normatively important were to some extent internalized by children. The intersubjective model paves some new directions for value transmission research, contributes to the understanding of cultural transmission and cultural change, and extends the intersubjective approach to culture. PMID- 22539216 TI - The David and Goliath principle: cultural, ideological, and attitudinal underpinnings of the normative protection of low-status groups from criticism. AB - Two studies documented the "David and Goliath" rule--the tendency for people to perceive criticism of "David" groups (groups with low power and status) as less normatively permissible than criticism of "Goliath" groups (groups with high power and status). The authors confirmed the existence of the David and Goliath rule across Western and Chinese cultures (Study 1). However, the rule was endorsed more strongly in Western than in Chinese cultures, an effect mediated by cultural differences in power distance. Study 2 identified the psychological underpinnings of this rule in an Australian sample. Lower social dominance orientation (SDO) was associated with greater endorsement of the rule, an effect mediated through the differential attribution of stereotypes. Specifically, those low in SDO were more likely to attribute traits of warmth and incompetence to David versus Goliath groups, a pattern of stereotypes that was related to the protection of David groups from criticism. PMID- 22539218 TI - Heterobimetallic lanthanide-gold coordination polymers: structure and emissive properties of isomorphous [(n)Bu4N]2[Ln(NO3)4Au(CN)2] 1-D chains. AB - A new series of lanthanide-containing dicyanoaurate coordination polymers, [(n)Bu(4)N](2)[Ln(NO(3))(4)Au(CN)(2)] (Ln = Nd, Eu, Gd or Tb), were synthesized and structurally characterized. They form an isomorphous series, crystallizing in the space group I2(1)2(1)2(1). The structure is composed of a one dimensional zigzag of Ln-N-C-Au-C-N-Ln chains with no intra- or inter-chain aurophilic interactions. The series is related to and can be described as a reduced dimensionality analogue of the previously studied Ln[Au(CN)(2)](3).3H(2)O. Unlike the Ln[Au(CN)(2)](3).3H(2)O series, there is no efficient energy transfer between dicyanoaurate and the lanthanide metal centers in the complexes and they essentially act as two separate emissive chromophores. PMID- 22539217 TI - Methotrexate (MTX)-cIBR conjugate for targeting MTX to leukocytes: conjugate stability and in vivo efficacy in suppressing rheumatoid arthritis. AB - Methotrexate (MTX) has been used to treat rheumatoid arthritis at low doses and leukemia at high doses; however, this drug can produce severe side effects. Our hypothesis is that MTX side effects can be attenuated by directing the drug to the target cells (i.e., leukocytes) using (cyclo(1,12)PenPRGGSVLVTGC) peptide (cIBR). To test this hypothesis, MTX was conjugated to the N-terminus of cIBR peptide to give MTX-cIBR conjugate. MTX-cIBR (5.0 mg/kg) suppressed joint arthritis in adjuvant arthritis rats and prevented periarticular inflammation and bone resorption of the limb joints. In vitro, the toxicity of MTX-cIBR peptide against Molt-3 T cells was inhibited by anti-lymphocyte function-associated antigen-1 (LFA-1) antibody and cIBR peptide in a concentration-dependent manner, suggesting that the uptake of MTX-cIBR was partially mediated by LFA-1. Chemical stability studies indicated that MTX-cIBR was most stable at pH 6.0. The MTX portion of MTX-cIBR was unstable under acidic conditions, whereas the cIBR portion was unstable under basic conditions. In biological media, MTX-cIBR had short half lives in rat plasma (44 min) and homogenized rat heart tissue (38 min). This low plasma stability may contribute to the low in vivo efficacy of MTX cIBR; therefore, there is a need to design a more stable conjugate to improve the in vivo efficacy. PMID- 22539219 TI - Diagnosis of postoperative pancreatic fistula. AB - BACKGROUND: Pancreatic fistula (PF) is a major source of morbidity after pancreatectomy. The International Study Group on Pancreatic Fistula (ISGPF) defines postoperative fistula by an amylase concentration in the abdominal drain of more than three times the serum value on day 3 or more after surgery. However, this definition fails to identify some clinical fistulas. This study examined the association between lipase measured in abdominal drainage fluid and PF. METHODS: Amylase and lipase levels in the abdominal drain were measured 3 days after pancreatic resection. Grade B and C fistulas were classified as clinical fistulas, regardless of whether the measured amylase concentration was considered positive or negative. The PF group included patients with a clinical fistula and/or those with positive amylase according to the ISGPF definition. RESULTS: Sixty-five patients were included. The median level of lipase was higher in patients with positive amylase than in those with negative amylase: 12,176 versus 64 units/l (P < 0.001). The lipase level was 16,500 units/l in patients with a clinical fistula and 224 units/l in those without a clinical fistula (P = 0.001). Patients with a PF had a higher lipase concentration than those without: 7852 versus 64 units/l (P < 0.001). A lipase level higher than 500 units/l yielded a sensitivity of 88 per cent and a specificity of 75 per cent for PF. For clinical fistulas the sensitivity was 93 per cent and specificity 77 per cent when the threshold for lipase was 1000 units/l. CONCLUSION: Lipase concentration in the abdominal drain correlated with PF. A threshold of 1000 units/l yielded a high sensitivity and specificity for the diagnosis of clinical PF. PMID- 22539220 TI - Spring water quality and usability in the Mount Cameroon area revealed by hydrogeochemistry. AB - Groundwater is the only reliable water resource for drinking, domestic, and agricultural purposes for the people living in the Mount Cameroon area. Hydrogeochemical and R-mode factor analysis were used to identify hydrogeochemical processes controlling spring water quality and assess its usability for the above uses. Main water types in the study area are Ca-Mg-HCO(3) and Na-HCO(3). This study reveals that three processes are controlling the spring water quality. CO(2)-driven silicate weathering and reverse cation exchange are the most important processes affecting the hydrochemistry of the spring waters. While tropical oceanic monsoon chloride-rich/sulfate-rich rainwater seems to affect spring water chemistry at low-altitude areas, strong correlations exist between major ions, dissolved silica and the altitude of springs. In general, the spring waters are suitable for drinking and domestic uses. Total hardness (TH) values indicate a general softness of the waters, which is linked to the development of cardiovascular diseases. Based on Na %, residual sodium carbonate, sodium adsorption ratio, and the USSL classification, the spring waters are considered suitable for irrigation. Though there is wide spread use of chemical fertilizers and intense urban settlements at the lower flanks of the volcano, anthropogenic activities for now seem to have little impact on the spring water quality. PMID- 22539221 TI - Groundwater fluoride and dental fluorosis in southwestern Nigeria. AB - This study was carried out to assess the fluoride levels of groundwater from open wells, consumed by the residents of three communities located in two distinct geological terrains of southwestern Nigeria. Fluoride concentration was determined using spectrophotometric technique, while analysis of other parameters like temperature, pH and total dissolve solids followed standard methods. Results of the analysis indicated that groundwater samples from Abeokuta Metropolis (i.e., basement complex terrain) had fluoride content in the range of 0.65 +/- 0.21 and 1.20 +/- 0.14. These values were found to be lower than the fluoride contents in the groundwater samples from Ewekoro peri-urban and Lagos metropolis where the values ranged between 1.10 +/- 0.14-1.45 +/- 0.07 and 0.15 +/- 0.07 2.20 +/- 1.41 mg/l, respectively. The fluoride contents in almost all locations were generally higher than the WHO recommended 0.6 mg/l. Analysis of Duncan multiple range test indicated that there is similarity in the level of significance of fluoride contents between different locations of same geological terrain at p <= 0.05. It was also observed that fluoride distribution of groundwater samples from the different geological terrain was more dependent on factors like pH and TDS than on temperature. The result of the analyzed social demographic characteristics of the residents indicated that the adults (between the age of 20 and >40 years) showed dental decay than the adolescent (<20 years). This signifies incidence of dental fluorosis by the high fluoride content in the drinking water of the populace. Further investigation on all sources of drinking water and other causes of tooth decay in the area is suggested. PMID- 22539222 TI - Values for alphabeta and gammadelta T-lymphocytes and CD4+, CD8+, and CD56+ subsets in healthy adult subjects: assessment by age and gender. AB - BACKGROUND: Normal reference values in healthy subjects for T-lymphocytes for both types of receptors, alphabeta and gammadelta, and their subsets are yet to be defined. The aim of this study was to measure peripheral blood alphabeta and gammadelta total T-lymphocytes and their subsets in a population of healthy subjects, in order to obtain valid reference values for studies in human pathology. METHODS: We studied a total of 157 healthy subjects, 78 men and 79 women, establishing their levels of CD3+, CD4+, CD8+, CD56+, alphabetaCD3+, alphabetaCD3+CD4+, alphabetaCD3+CD8+, alphabetaCD3+CD56+, gammadeltaCD3+, gammadeltaCD3+CD4-CD8-, gammadeltaCD3+CD8+, and gammadeltaCD3+CD56+ T-cells by flow cytometry. The T-cell subsets were compared for different age and gender groups. RESULTS: A significant decrease in CD3+, CD3+CD4+, CD3+CD4+ alphabeta, and CD3+ gammadelta T-cells was observed in elderly subjects. CD3+, CD3+ alphabeta, and CD3+CD4+ alphabeta T-cells increased in women, while CD3+CD56+ alphabeta T-cells increased in men. CONCLUSIONS.: These reference values could be useful in further research studies for assessing changes that occur in the different alphabeta and gammadelta T subsets in human pathology. PMID- 22539223 TI - Activation of silenced tumor suppressor genes in prostate cancer cells by a novel energy restriction-mimetic agent. AB - BACKGROUND: Targeting tumor metabolism by energy restriction-mimetic agents (ERMAs) has emerged as a strategy for cancer therapy/prevention. Evidence suggests a mechanistic link between ERMA-mediated antitumor effects and epigenetic gene regulation. METHODS: Microarray analysis showed that a novel thiazolidinedione-derived ERMA, CG-12, and glucose deprivation could suppress DNA methyltransferase (DNMT)1 expression and reactivate DNA methylation-silenced tumor suppressor genes in LNCaP prostate cancer cells. Thus, we investigated the effects of a potent CG-12 derivative, CG-5, vis-a-vis 2-deoxyglucose, glucose deprivation and/or 5-aza-deoxycytidine, on DNMT isoform expression (Western blotting, RT-PCR), DNMT1 transcriptional activation (luciferase reporter assay), and expression of genes frequently hypermethylated in prostate cancer (quantitative real-time PCR). Promoter methylation was assessed by pyrosequencing analysis. SiRNA-mediated knockdown and ectopic expression of DNMT1 were used to validate DNMT1 as a target of CG-5. RESULTS: CG-5 and glucose deprivation upregulated the expression of DNA methylation-silenced tumor suppressor genes, including GADD45a, GADD45b, IGFBP3, LAMB3, BASP1, GPX3, and GSTP1, but also downregulated methylated tumor/invasion-promoting genes, including CD44, S100A4, and TACSTD2. In contrast, 5-aza-deoxycytidine induced global reactivation of these genes. CG-5 mediated these epigenetic effects by transcriptional repression of DNMT1, which was associated with reduced expression of Sp1 and E2F1. SiRNA mediated knockdown and ectopic expression of DNMT1 corroborated DNMT1's role in the modulation of gene expression by CG-5. Pyrosequencing revealed differential effects of CG-5 versus 5-aza-deoxycytidine on promoter methylation in these genes. CONCLUSIONS: These findings reveal a previously uncharacterized epigenetic effect of ERMAs on DNA methylation-silenced tumor suppressor genes, which may foster novel strategies for prostate cancer therapy. PMID- 22539224 TI - Androgen receptor directed therapies in castration-resistant metastatic prostate cancer. AB - OPINION STATEMENT: Recent results of phase III randomized studies confirm that targeting the androgen receptor (AR)-through inhibition of androgen synthesis or through AR targeting directly-can improve survival for patients with metastatic castration-resistant prostate cancer (mCRPC), a condition previously considered to be "refractory" to further hormonal manipulation. These data validate in the clinical setting much of the scientific work of the previous decade that has demonstrated the extent of and mechanisms behind retained AR signaling in advanced prostate cancer. The convergence of these observations effectively changes the perspective with which androgen deprivation is utilized in prostate cancer, and forms the basis for further expansion of systemic therapy in the disease. In this review, the rationale for and clinical results with these new therapies will be discussed as will the future directions required to fully leverage these therapeutic modalities to the maximum clinical benefit for patients. PMID- 22539225 TI - In reference to effective use of physician extenders in an outpatient otolaryngology setting. PMID- 22539226 TI - Genotoxicity profile of fexinidazole--a drug candidate in clinical development for human African trypanomiasis (sleeping sickness). AB - The parasitic disease human African trypanomiasis (HAT), also known as sleeping sickness, is a highly neglected fatal condition endemic in sub-Saharan Africa, which is poorly treated with medicines that are toxic, no longer effective or very difficult to administer. New, safe, effective and easy-to-use treatments are urgently needed. Many nitroimidazoles possess antibacterial and antiprotozoal activity and examples such as tinidazole are used to treat trichomoniasis and guardiasis, but concerns about toxicity including genotoxicity limit their usefulness. Fexinidazole, a 2-substituted 5-nitroimidazole rediscovered by the Drugs for Neglected Diseases initiative (DNDi) after extensive compound mining of public and pharmaceutical company databases, has the potential to become a short course, safe and effective oral treatment, curing both acute and chronic HAT. This paper describes the genotoxicity profile of fexinidazole and its two active metabolites, the sulfoxide and sulfone derivatives. All the three compounds are mutagenic in the Salmonella/Ames test; however, mutagenicity is either attenuated or lost in Ames Salmonella strains that lack one or more nitroreductase(s). It is known that these enzymes can nitroreduce compounds with low redox potentials, whereas their mammalian cell counterparts cannot, under normal conditions. Fexinidazole and its metabolites have low redox potentials and all mammalian cell assays to detect genetic toxicity, conducted for this study either in vitro (micronucleus test in human lymphocytes) or in vivo (ex vivo unscheduled DNA synthesis in rats; bone marrow micronucleus test in mice), were negative. Thus, fexinidazole does not pose a genotoxic hazard to patients and represents a promising drug candidate for HAT. Fexinidazole is expected to enter Phase II clinical trials in 2012. PMID- 22539227 TI - Electrocatalytic and photocatalytic hydrogen production in aqueous solution by a molecular cobalt complex. PMID- 22539228 TI - Characteristics of patients seeking outpatient rehabilitation for pelvic-floor dysfunction. AB - BACKGROUND: Pelvic-floor dysfunction (PFD) affects a substantial proportion of individuals, especially women. OBJECTIVE: The purposes of this study were: (1) to describe the characteristics of individuals with disorders associated with PFD who were seeking outpatient physical therapy services and (2) to identify the prevalence of specific pelvic-floor disorders in the group. DESIGN: This was a prospective, longitudinal, cohort study of 2,452 patients (mean age=50 years, SD=16, range=18-91) being treated in 109 outpatient physical therapy clinics in 26 states (United States) for their PFD. METHODS: This study examined patient demographic variables and summarized patient self-reported responses to questions related to urinary and bowel functioning at admission prior to receiving the therapy for their PFD disorders. RESULTS: Patients primarily were female (92%), were under 65 years of age (39%: 18 to <45 years; 39%: 45 to <65 years; 21%: 65 years or older), and had chronic symptoms (74%). Overall, 67% of the patients reported that they had urinary problems, 27% reported bowel problems, and 39% had pelvic pain. Among those who had urinary or bowel disorders, 32% and 54% reported leakage and constipation, respectively, as their only problem. Among patients who had pelvic pain, most (56%) reported that the pain was in the abdominal area. Combinations of urinary, bowel, or pelvic-floor pain disorders occurred in 31% of the patients. LIMITATIONS: Because this study was a secondary analysis of data collected prospectively, the researchers were not in control of the data collection procedure. Missing data were common. CONCLUSIONS: Data suggested most patients with PFD receiving outpatient physical therapy services were female, younger than 65 years, and had disorders lasting for more than 90 days. Combinations of urinary, bowel, or pelvic-floor pain disorders were not uncommon. PMID- 22539229 TI - Treadmill training for individuals with Parkinson disease. PMID- 22539230 TI - Recognizing vocal emotions in Mandarin Chinese: a validated database of Chinese vocal emotional stimuli. AB - To establish a valid database of vocal emotional stimuli in Mandarin Chinese, a set of Chinese pseudosentences (i.e., semantically meaningless sentences that resembled real Chinese) were produced by four native Mandarin speakers to express seven emotional meanings: anger, disgust, fear, sadness, happiness, pleasant surprise, and neutrality. These expressions were identified by a group of native Mandarin listeners in a seven-alternative forced choice task, and items reaching a recognition rate of at least three times chance performance in the seven-choice task were selected as a valid database and then subjected to acoustic analysis. The results demonstrated expected variations in both perceptual and acoustic patterns of the seven vocal emotions in Mandarin. For instance, fear, anger, sadness, and neutrality were associated with relatively high recognition, whereas happiness, disgust, and pleasant surprise were recognized less accurately. Acoustically, anger and pleasant surprise exhibited relatively high mean f0 values and large variation in f0 and amplitude; in contrast, sadness, disgust, fear, and neutrality exhibited relatively low mean f0 values and small amplitude variations, and happiness exhibited a moderate mean f0 value and f0 variation. Emotional expressions varied systematically in speech rate and harmonics-to-noise ratio values as well. This validated database is available to the research community and will contribute to future studies of emotional prosody for a number of purposes. To access the database, please contact pan.liu@mail.mcgill.ca. PMID- 22539232 TI - Ion-selective electrodes to monitor osteoblast-like cellular influence on the extracellular concentration of calcium. AB - In bone tissue engineering, the composition of the ionic extracellular environment (IEE) can determine both cellular fate and a biomaterial's development and performance. Therefore, precise control of the IEE and a perfect understanding of the dynamic changes that it can be subject to due to cellular activity is highly desired. To achieve this, we initially monitored how two standard osteoblast-like cell models that expressed either high or low alkaline phosphatase activity - SAOS-2 and MG63 cells, respectively - affected the extracellular concentrations of calcium and phosphate during long-term cultures. It was observed that cellular influence on the IEE varied greatly between the two models and could be linked to the capacity of cells to deposit calcium in the extracellular matrix. Miniaturized ion-selective electrodes that could allow for real-time monitoring of calcium in a minimally invasive way were then constructed. The electrodes were characterized in standard in vitro cell culture environments, prior to being successfully applied for periods of 24 h, to record the dynamics of cell-induced deposition of calcium in the extracellular matrix, while using osteogenic media of either high or low concentrations of phosphate. As a result, this study provides the background and technological means for the non-destructive evaluation of the IEE in vitro and allows for the optimization and development of better models of bone tissue construction. PMID- 22539233 TI - A PEG-based oligomer as a backbone replacement for surface-exposed loops in a protein tertiary structure. AB - PEGged out: Poly(ethylene glycol), a simple biocompatible polymer, can replace natural loop segments in a 56-residue protein domain with a well-defined tertiary structure. Biophysical characterization of chimeras of the protein GB1 coupled with molecular dynamics simulations show that PEG enhances local backbone torsional freedom without compromising the overall protein fold or function. PMID- 22539231 TI - Glutathione S-transferase pi mediates MPTP-induced c-Jun N-terminal kinase activation in the nigrostriatal pathway. AB - Parkinson's disease (PD) is a progressive movement disorder resulting from the death of dopaminergic neurons in the substantia nigra. Neurotoxin-based models of PD using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) recapitulate the neurological features of the disease, triggering a cascade of deleterious events through the activation of the c-Jun N-terminal kinase (JNK). The molecular mechanisms underlying the regulation of JNK activity under cellular stress conditions involve the activation of several upstream kinases along with the fine tuning of different endogenous JNK repressors. Glutathione S-transferase pi (GSTP), a phase II detoxifying enzyme, has been shown to inhibit JNK-activated signaling by protein-protein interactions, preventing c-Jun phosphorylation and the subsequent trigger of the cell death cascade. Here, we use C57BL/6 wild-type and GSTP knockout mice treated with MPTP to evaluate the regulation of JNK signaling by GSTP in both the substantia nigra and the striatum. The results presented herein show that GSTP knockout mice are more susceptible to the neurotoxic effects of MPTP than their wild-type counterparts. Indeed, the administration of MPTP induces a progressive demise of nigral dopaminergic neurons together with the degeneration of striatal fibers at an earlier time point in the GSTP knockout mice when compared to the wild-type mice. Also, MPTP treatment leads to increased p-JNK levels and JNK catalytic activity in both wild type and GSTP knockout mice midbrain and striatum. Moreover, our results demonstrate that in vivo GSTP acts as an endogenous regulator of the MPTP-induced cellular stress response by controlling JNK activity through protein-protein interactions. PMID- 22539234 TI - Metal on metal oxide nanowire Co-catalyzed Si photocathode for solar water splitting. AB - We report a systematic study of Si|ZnO and Si|ZnO| metal photocathodes for effective photoelectrochemical cells and hydrogen generation. Both ZnO nanocrystalline thin films and vertical nanowire arrays were studied. Si|ZnO electrodes showed increased cathodic photocurrents due to improved charge separation by the formation of a p/n junction, and Si|ZnO:Al (n(+)-ZnO) and Si|ZnO(N(2)) (thin films prepared in N(2)/Ar gas) lead to a further increase in cathodic photocurrents. Si|ZnONW (nanowire array) photocathodes dramatically increased the photocurrents and thus photoelectrochemical conversion efficiency due to the enhanced light absorption and enlarged surface area. The ZnO film thickness and ZnO nanowire length were important to the enhancements. A thin metal coating on ZnO showed increased photocurrent due to a catalyzed hydrogen evolution reaction and Ni metal showed comparable catalytic activities to those of Pt and Pd. Moreover, photoelectrochemical instability of Si|ZnO electrodes was minimized by metal co-catalysts. Our results indicate that the metal and ZnO on p type Si serve as co-catalysts for photoelectrochemical water splitting, which can provide a possible low-cost and scalable method to fabricate high efficiency photocathodes for practical applications in clean solar energy harvesting. PMID- 22539235 TI - Total synthesis of bistramide A and its 36(Z) isomers: differential effect on cell division, differentiation, and apoptosis. AB - The total synthesis of bistramide A and its 36(Z),39(S) and 36(Z),39(R) isomers shows that these compounds have different effects on cell division and apoptosis. The synthesis relies on a novel enol ether-forming reaction for the spiroketal fragment, a kinetic oxa-Michael cyclization reaction for the tetrahydropyran fragment, and an asymmetric crotonylation reaction for the amino acid fragment. Preliminary biological studies show a distinct pattern of influence of each of the three compounds on cell division, differentiation, and apoptosis in HL-60 cells, thus suggesting that these effects are independent activities of the natural product. PMID- 22539236 TI - Type 1 diabetes and celiac disease in adults: glycemic control and diabetic complications. AB - The prevalence of celiac disease (CD) in patients with type 1 diabetes mellitus (T1DM) is 4.5 %. Objective of the study is to investigate (1) the course of glycemic control at CD diagnosis and after the initiation of a gluten-free diet (GFD) in T1DM patients; (2) the prevalence of diabetic complications in T1DM patients with adult onset of CD. In 20 hospitals in the Netherlands, we identified T1DM patients diagnosed with CD at adult age. We retrospectively collected glycated hemoglobin (HbA1c) levels before CD diagnosis, at CD diagnosis, and the most recent HbA1c levels as well as the presence of nephropathy and retinopathy. The control group consisted of patients with T1DM and negative CD serology matched for age, gender, T1DM duration, and HbA1c levels. Thirty-one patients were eligible with a median duration of T1DM and CD of 27 years (IQR 14-37) and 3 years (IQR 1-8), respectively. The matched control group consisted of 46 patients. HbA1c levels at the moment of CD diagnosis were 7.5 % (IQR 7.1-8) [58 mmol/mol] and at the most recent visit 7.4 % (IQR 6.9-7.9, P = 0.15) [57 mmol/mol] indicating no difference. Prevalence of retinopathy was lower in T1DM + CD group compared with controls, (38.7 vs 67.4 %, P < 0.05), whereas no difference in the prevalence of nephropathy was found between the groups (P = 0.09). In conclusion, T1DM + CD patients have less retinopathy compared to T1DM patients without CD. A GFD possibly favorable affects the development of vascular complications in T1DM patients. PMID- 22539237 TI - Influence of heart rate at rest for predicting the metabolic syndrome in older Chinese adults. AB - The aim of this study was to examine the relationship between seated resting heart rate and the metabolic syndrome (MetS) among older residents of Guangzhou, South China. A total of 30,519 older participants (>=50 years) from the Guangzhou Biobank Cohort Study were stratified into quartiles based on seated resting heart rate. The associations between each quartile and the MetS were assessed using multivariable logistic regression. A total of 6,907 (22.8 %) individuals were diagnosed as having the MetS, which was significantly associated with increasing heart rate quartiles (P < 0.001). Participants in the uppermost quartile (mean resting heart rate 91 +/- 8 beats/min) of this cardiovascular proxy had an almost twofold increased adjusted risk (odds ratio (95 % CI) = 1.94 (1.79, 2.11), P < 0.001) for the MetS, as compared to those in the lowest quartile (mean resting heart rate, 63 +/- 4 beats/min). Heart rate, which is an inexpensive and simple clinical measure, was independently associated with the MetS in older Chinese adults. We hope these observations will spur further studies to examine the usefulness of resting heart rate as a means of risk stratification in such populations, for which targeted interventions should be implemented. PMID- 22539238 TI - Nutrition and physical activity guidelines for cancer survivors. AB - Cancer survivors are often highly motivated to seek information about food choices, physical activity, and dietary supplements to improve their treatment outcomes, quality of life, and overall survival. To address these concerns, the American Cancer Society (ACS) convened a group of experts in nutrition, physical activity, and cancer survivorship to evaluate the scientific evidence and best clinical practices related to optimal nutrition and physical activity after the diagnosis of cancer. This report summarizes their findings and is intended to present health care providers with the best possible information with which to help cancer survivors and their families make informed choices related to nutrition and physical activity. The report discusses nutrition and physical activity guidelines during the continuum of cancer care, briefly highlighting important issues during cancer treatment and for patients with advanced cancer, but focusing largely on the needs of the population of individuals who are disease free or who have stable disease following their recovery from treatment. It also discusses select nutrition and physical activity issues such as body weight, food choices, food safety, and dietary supplements; issues related to selected cancer sites; and common questions about diet, physical activity, and cancer survivorship. PMID- 22539239 TI - Prevalence of over-the-counter and complementary medication use in the otolaryngology preoperative patient: a patient safety initiative. AB - OBJECTIVES/HYPOTHESIS: To determine the prevalence of over-the-counter and complementary and alternative medication use in the preoperative otolaryngology patient population. STUDY DESIGN: Cross-sectional survey. METHODS: Data were collected from preoperative surveys given to all patients undergoing surgery by a single physician with an academic practice over a 6-month period from March to September 2010. Responses were compiled and combined with demographic information obtained from the computer-based chart system. RESULTS: A total of 92 patients, with ages ranging from 5 to 84 years old (average, 41), completed the survey. Fifty-three (58%) patients were female, and 39 (42%) were male. Forty-two (46%) patients reported the use of nonprescription medications, and 48% reported the use of multiple medications. Of those who reported using medication, 11 (26%) were male and 31 (74%) were female. The average age of nonprescription medication users was 49 years. The most commonly reported over-the-counter medications were aspirin and ibuprofen. The most commonly reported complementary and alternative medications were green tea, fish oil, and vitamin E. CONCLUSIONS: The use of nonprescription medications in the otolaryngology preoperative population is very common, especially in the female patient. The most commonly reported medications are associated with serious potential complications, and awareness of their use is critical before the patient undergoes surgery. PMID- 22539240 TI - Does pregnancy or pregnancy loss increase later maternal risk of diabetes? AB - Evidence that childbearing is associated with future development of diabetes remains conflicting and the role of pregnancy loss in this association has not been investigated. We aimed to examine whether pregnancy and/or pregnancy loss (miscarriage, abortion, or stillbirth) are associated with maternal higher risk of diabetes later in life, using a population-based prospective cohort study (mean follow-up = 10.7 years), including 13,612 women (aged 35-65 at baseline). We found pregnancy per se did not change the risk of diabetes after considering the effect of education, smoking, alcohol consumption, physical activity, BMI, waist/hip ratio, hypertension, and hyperlipidemia (fully-adjusted OR: 1.04, 95 % CI: 0.82-1.31). Having more than four live births was associated with around two times higher risk of diabetes later in life (fully-adjusted OR: 1.77, 95 % CI: 1.12-2.80). Having more than two miscarriages was associated with about two-fold higher risk of diabetes (fully-adjusted Odd ratio (OR): 1.85, 95 % CI: 1.17 2.93). After further adjustment for parity, the higher risk of diabetes in those who had history of more than two miscarriages did not change substantially (OR: 1.82; 95 % CI: 1.15-2.88), but the association between more than four live births and diabetes disappeared when the role of pregnancy loss was considered (fully adjusted HR: 1.06; 95 % CI: 0.54-2.08). No significant association was found between abortion, stillbirth and risk of maternal diabetes. Pregnancy per se did not increase risk of diabetes. Women who experience more than two miscarriages are at around two times higher risk of diabetes later in life. The association between high parity and diabetes is mediated by history of miscarriages and known risk factors of diabetes. The underlying reason for association between miscarriage and diabetes needs further investigation. PMID- 22539242 TI - One-electron Ni(II)/(I) redox couple: potential role in hydrogen activation and production. AB - The three-coordinate Ni(I) complex Ni(Cl)(P(2)), where P(2) is the diphosphine (iPr)DPDBFphos, reacts with the acids HCl.(dioxane) and 2,6-lutidinium chloride to generate Ni(H)(Cl)(P(2)) and Ni(Cl)(2)(P(2)). Photolysis of the Ni(H)(X)(P(2)) (for X = Cl, Br) results in formation of H(2) and the Ni(I) halide. This reaction also proceeds in reverse when heated. PMID- 22539241 TI - Socioeconomic position and the incidence of type 2 diabetes: the ELSA study. AB - We examined the associations between childhood and adult socioeconomic position (SEP) and incident diabetes in 7,432 individuals aged 50 or older from the English Longitudinal Study of Ageing (ELSA). We identified 174 and 189 cases of incident diabetes, in men and women, respectively, over 5.3 years of follow-up. Cox models were estimated. In women, childhood SEP, education, occupational class, income, wealth, and subjective social status (SSS) were related to incident diabetes. Occupational class, income, and SSS did not remain significantly related to incident diabetes after adjustment for individual sets of covariates (i.e. unhealthy behaviours, obesity, or psychosocial factors). Wealth (HR: 1.65, 95 % CI: 1.05, 2.60, poorest vs. wealthiest tertile) remained significantly related to incident diabetes after adjustment for all covariates, but education (HR: 1.46, 95 % CI: 0.92, 2.33, lowest vs. highest category) and childhood SEP (HR: 1.47, 95 % CI: 0.98, 2.19, lowest vs. highest category) did not. In men, only wealth and SSS were related to incident diabetes. SSS remained significantly related to incident diabetes after adjustment for all covariates (HR: 2.46, 95 % CI: 1.32, 4.68, lowest vs. highest category), but wealth did not (HR: 1.42, 95 % CI: 0.94, 2.15, poorest vs. wealthiest tertile). Additional adjustment for wealth did not greatly affect the association between incident diabetes and SSS in men. Incident diabetes in older women is associated with SEP from all life stages, while in older men only with current SEP. Psychosocial factors (in women), unhealthy behaviours, and obesity partly mediate these associations. PMID- 22539244 TI - Magnetic resonance imaging in Sydenham chorea. PMID- 22539243 TI - Neurotoxicity of intra-CSF liposomal cytarabine (DepoCyt) administered for the treatment of leptomeningeal metastases: a retrospective case series. AB - Treatment of leptomeningeal metastasis (LMD) remains challenging due to advanced systemic disease at presentation and limited treatment options. All patients underwent standard pre-treatment LMD evaluation including CSF assessment (cytology or flow cytometry), brain and spine MR imaging, and radioisotope CSF flow study. DepoCyt (liposomal cytarabine) was administered intraventricularly (n = 80) or intralumbar (n = 40) at 50 mg every 2 weeks * 4 and then every 4 weeks * 6 in responding patients. Dexamethasone (4 mg orally twice per day * 5 days) was co-administered with each DepoCyt treatment. Patients were seen with each DepoCyt treatment and assessed for toxicity. 120 adult patients [median age 51 years (range 33-68)] with LMD were treated with DepoCyt. DepoCyt Common Toxicity Criteria >= Grade 3 neurotoxicity was seen in 60 cycles (11.5 %) in 28 patients (23.3 %). Toxicity included bacterial meningitis (3.75 % of ventricular treatments: 0 % of lumbar treatments); chemical meningitis (17.5:15 %); communicating hydrocephalus (3.75:5 %); conus medullaris/cauda equina syndrome (5:5 %); decreased visual acuity (5:2.5 %); encephalopathy (5:5 %); leukoencephalopathy (7.5:2.5 %); myelopathy (2.5:2.5 %); radiculopathy (1.25:5 %); and seizures (1.25:2.5 %). Distribution of toxicity was similar regardless of route of administration (ventricular vs. lumbar). Toxicities were transient in 34 episodes (57 %) and permanent in 26 (43 %). There were no treatment-related deaths however 20 treatment-related toxicities (32.2 %) required hospitalization. In this retrospective case series, DepoCyt is generally well tolerated however a subset of patients (12.5 %) not easily identified pre-treatment, develop serious treatment-related neurological complications that may be persistent and impact quality of life. PMID- 22539245 TI - Difficult differential diagnosis of Unverricht-Lundborg disease with spontaneous kinesogenic myoclonus and movement disorder. PMID- 22539246 TI - Epilepsy and psychiatric problems in a patient with a large intracranial mass. PMID- 22539247 TI - Redox-active metal-centered oxalato phosphate open framework cathode materials for lithium ion batteries. PMID- 22539248 TI - Introduction to the special issue in honor of Ira B. Black. PMID- 22539249 TI - Flow cytometric detection of liposomal cytarabine in cerebrospinal fluid of patients treated with intrathecal chemotherapy. AB - We report the unusual flow cytometric detection of liposomes in the cerebrospinal fluid of patients with aggressive non-Hodgkin's lymphoma and acute myeloid leukemia, treated with intrathecal liposomal cytarabine. PMID- 22539250 TI - Intravascular large B-cell lymphoma with diffuse FDG uptake in the lung by 18FDG PET/CT without chest CT findings. AB - We report a rare case of intravascular large B-cell lymphoma (IVLBCL) with diffuse fluorodeoxyglucose (FDG) uptake in the lung by (18)FDG-positron emission tomography/computed tomography (PET/CT). CT showed nodular shadow, whereas diffuse FDG uptake in PET/CT suggested IVLBCL in the lung. A random skin biopsy provided histological evidence of IVLBCL. The patient responded well to combination chemotherapy. Only two cases of IVLBCL in which diffuse pulmonary FDG uptake was demonstrated have been reported previously. FDG-PET/CT plus random skin biopsy may be useful for the early diagnosis of IVLBCL with pulmonary involvement even without convincing radiological findings in the lung. PMID- 22539251 TI - Suture erosion after gastric bypass surgery. PMID- 22539252 TI - Poly(N-isopropylacrylamide)-based microgels and their assemblies for organic molecule removal from water. AB - We review our recent efforts utilizing poly(N-isopropylacrylamide)-co-acrylic acid (pNIPAm-co-AAc) microgels and their assemblies for the removal of an azo-dye molecule, 4-(2-Hyrodxy-1-napthylazo) benzenesulfonic acid sodium salt (Orange II), from aqueous solutions. First, the ability of dispersed, single microgels to remove Orange II from aqueous solutions at room temperature is discussed. Uptake efficiency (i.e., the amount of Orange II removed from water) increased with AAc composition in the microgels, yielding a maximum uptake efficiency of 29.5% for pNIPAm microgels with 10% AAc. Assemblies of microgels (aggregates) were also investigated for their removal efficiency, which yielded a maximum uptake efficiency of 44.1% at room temperature. Removal efficiencies for the microgels and their aggregates were also monitored at elevated temperatures, and a maximum of 56.6% removal efficiency was achieved for unaggregated microgels, while aggregates were able to remove 73.1% Orange II. To further explore the impact of the microgel system's structure on function, we investigated the role microgel size in the aggregates plays on the uptake efficiency. Initial observations showed that the aggregates composed of microgels with large diameter yielded improved uptake efficiency over the aggregates composed of small diameter microgels. Langmuir sorption isotherms were fit to the data for the dye removal by the unaggregated and aggregated microgels, which showed good fits in all cases. PMID- 22539254 TI - Reductive azidation of carbonyl compounds via tosylhydrazone intermediates using sodium azide. PMID- 22539253 TI - Evidence-based medicine should be practiced for primary prevention and secondary prevention of cardiovascular disease. PMID- 22539255 TI - Aggregation and supramolecular membrane interactions that influence anion transport in tryptophan-containing synthetic peptides. AB - Self-assembly is a desired property in supramolecular chemistry, but extensive aggregation may be counterproductive. Rigid systems typically have better organization, but are inherently less dynamic. This work shows that ion transport by amphiphilic heptapeptides (synthetic anion transporters or SATs) is affected by aggregation of the monomers in the bulk aqueous phase to which they are added and within the bilayer. Ion transport was assessed for all compounds by assay of Cl(-) release from liposomes. The mechanism of ion transport was confirmed by planar bilayer conductance studies for two compounds at opposite ends of the efficacy scale. Dynamic light scattering, the Langmuir trough, transmission electron microscopy, ion release from liposomes, and planar bilayer conductance studies were used to assess the importance of self-assembly versus aggregation in ion transport. Generally, greater aggregation was has an adverse effect on the transport, although at least dimerization is required for amphiphilic heptapeptides to readily transport Cl(-). Anion transport in these systems was found to be sensitive to changes in the C-terminal portion of the (Gly)(3)Pro(Gly)(3) sequence. Moreover, a significant difference in transport efficacy was apparent when L-Trp was replaced by D-Trp in the same position. PMID- 22539256 TI - Energetic payoff of tool use for capuchin monkeys in the caatinga: variation by season and habitat type. AB - In this paper, we analyze predictions from the energetic bottleneck and opportunity models to explain the use of stones to crack open encased fruit by capuchins in dry environments. The energetic bottleneck model argues that tool use derives from the need to crack open hard-encased fruits which are key resources during periods of food scarcity. The opportunity model argues that tool use by capuchins derives from simultaneous access to stones and encased fruits. The study was conducted in the Caatinga biome, northeastern Brazil, at two areas where capuchin monkeys (Sapajus libidinosus and Sapajus spp.) regularly use stones to crack open encased fruit of Syagrus cearensis and Manihot dichotoma. Energetic gains were inferred based on the number of tool-use sites used and the mass of encased fruit consumed per month, and compared across seasons and areas occupied by the two groups. For the drier habitat, a significant increase in frequency of tool use (N(dry) = 329 vs. N(wet) = 59) and in the mean monthly mass of fruits consumed in the dry season (mean(dry) = 193g vs. mean(wet) = 13.5 g) offered support for the energetic bottleneck model. However, our inference of low energetic payoffs for tool using individuals (in the drier caatinga habitat from 13 to 193 cal.ind(-1) .month(-1) and in the wetter caatinga habitat from 805 to 1150 cal.ind(-1) .month(-1) ) offer support for the opportunity model. Finally, our analyses indicate that consumption of six S. cearensis fruits would equal the daily requirements of capuchins for beta-carotene, and the consumption of 1.22 g.day(-1) of M. dichotoma encased fruit or 1.0 g.day(-1) of S. cearensis can supply capuchin's daily requirement of vitamin C. So, specific nutritional requirements may play a role in explaining the continuous consumption of encased fruit and customary use of stones to crack open encased fruit. PMID- 22539257 TI - Quantitative evaluation of the human subventricular zone. PMID- 22539258 TI - Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis. AB - Classical paraneoplastic encephalitis syndromes with 'onconeural' antibodies directed to intracellular antigens, and the recently described paraneoplastic or non-paraneoplastic encephalitides and antibodies against both neural surface antigens (voltage-gated potassium channel-complexes, N-methyl-d-aspartate receptors) and intracellular antigens (glutamic acid decarboxylase-65), constitute an increasingly recognized group of immune-mediated brain diseases. Evidence for specific immune mechanisms, however, is scarce. Here, we report qualitative and quantitative immunopathology in brain tissue (biopsy or autopsy material) of 17 cases with encephalitis and antibodies to either intracellular (Hu, Ma2, glutamic acid decarboxylase) or surface antigenic targets (voltage gated potassium channel-complex or N-methyl-d-aspartate receptors). We hypothesized that the encephalitides with antibodies against intracellular antigens (intracellular antigen-onconeural and intracellular antigen-glutamic acid decarboxylase groups) would show neurodegeneration mediated by T cell cytotoxicity and the encephalitides with antibodies against surface antigens would be antibody-mediated and would show less T cell involvement. We found a higher CD8/CD3 ratio and more frequent appositions of granzyme-B(+) cytotoxic T cells to neurons, with associated neuronal loss, in the intracellular antigen onconeural group (anti-Hu and anti-Ma2 cases) compared to the patients with surface antigens (anti-N-methyl-d-aspartate receptors and anti-voltage-gated potassium channel complex cases). One of the glutamic acid decarboxylase antibody encephalitis cases (intracellular antigen-glutamic acid decarboxylase group) showed multiple appositions of GrB-positive T cells to neurons. Generally, however, the glutamic acid decarboxylase antibody cases showed less intense inflammation and also had relatively low CD8/CD3 ratios compared with the intracellular antigen-onconeural cases. Conversely, we found complement C9neo deposition on neurons associated with acute neuronal cell death in the surface antigen group only, specifically in the voltage-gated potassium channel-complex antibody patients. N-methyl-d-aspartate receptors-antibody cases showed no evidence of antibody and complement-mediated tissue injury and were distinguished from all other encephalitides by the absence of clear neuronal pathology and a low density of inflammatory cells. Although tissue samples varied in location and in the stage of disease, our findings strongly support a central role for T cell mediated neuronal cytotoxicity in encephalitides with antibodies against intracellular antigens. In voltage-gated potassium channel-complex encephalitis, a subset of the surface antigen antibody encephalitides, an antibody- and complement-mediated immune response appears to be responsible for neuronal loss and cerebral atrophy; the apparent absence of these mechanisms in N-methyl-d aspartate receptors antibody encephalitis is intriguing and requires further study. PMID- 22539260 TI - The neurological syndrome in adults during the 2011 northern German E. coli serotype O104:H4 outbreak. AB - The aim of this study was to describe the neurological syndrome in the largest cohort of adult patients with a complicated Shiga toxin-producing Escherichia coli infection. The recent outbreak of Shiga toxin-producing E. coli serotype O104:H4 in northern Germany affected more than 3842 patients, 22% of whom developed haemolytic uraemic syndrome. The proportion of adult patients was unusually high, and neurological complications were frequent and severe. In three hospitals, population-based evaluation of 217 patients with complicated Shiga toxin-producing E. coli infection was carried out, including neurological, neuroradiological, neurophysiological, cerebrospinal fluid and neuropathological analyses. Of the 217 patients with complicated Shiga toxin-producing E. coli infection, 104 (48%) developed neurological symptoms. Neurological symptoms occurred 5.3 days (mean) after first diarrhoea and 4 days after onset of haemolytic uraemic syndrome. Of the infected patients with neurological symptoms, 67.3% presented with cognitive impairment or aphasia. During the course of the disease, 20% of the patients developed epileptic seizures. The onset of neurological symptoms was paralleled by increases in blood urea nitrogen and serum creatinine. In 70 patients with cerebral magnetic resonance imaging, the most common findings were symmetrical hyperintensities in the region of abducens nucleus and lateral thalamus. On follow-up scans, these abnormalities were resolved. Neuropathological analysis revealed regionally accentuated astrogliosis and microgliosis, more predominant in the thalamus and brainstem than in the cortex, and neuronal expression of globotriaosylceramide. There were no signs of microbleeds, thrombotic vessel occlusion or ischaemic infarction. The neurological syndrome in adult patients with complicated Shiga toxin-producing E. coli infection is a rapidly progressive and potentially life-threatening disease necessitating intensive care unit treatment and intubation in >30% of cases. The outcome of neurological patients in the 2011 northern German Shiga toxin producing E. coli O104:H4 outbreak was surprisingly good. Magnetic resonance imaging and neuropathological findings point to a mixed toxic and inflammatory pathomechanism leading to largely reversible damage of neuronal function. PMID- 22539259 TI - Microcystic macular oedema in multiple sclerosis is associated with disease severity. AB - Macular oedema typically results from blood-retinal barrier disruption. It has recently been reported that patients with multiple sclerosis treated with FTY-720 (fingolimod) may exhibit macular oedema. Multiple sclerosis is not otherwise thought to be associated with macular oedema except in the context of comorbid clinical uveitis. Despite a lack of myelin, the retina is a site of inflammation and microglial activation in multiple sclerosis and demonstrates significant neuronal and axonal loss. We unexpectedly observed microcystic macular oedema using spectral domain optical coherence tomography in patients with multiple sclerosis who did not have another reason for macular oedema. We therefore evaluated spectral domain optical coherence tomography images in consecutive patients with multiple sclerosis for microcystic macular oedema and examined correlations between macular oedema and visual and ambulatory disability in a cross-sectional analysis. Participants were excluded if there was a comorbidity that could account for the presence of macular oedema, such as uveitis, diabetes or other retinal disease. A microcystic pattern of macular oedema was observed on optical coherence tomography in 15 of 318 (4.7%) patients with multiple sclerosis. No macular oedema was identified in 52 healthy controls assessed over the same period. The microcystic oedema predominantly involved the inner nuclear layer of the retina and tended to occur in small, discrete patches. Patients with multiple sclerosis with microcystic macular oedema had significantly worse disability [median Expanded Disability Score Scale 4 (interquartile range 3-6)] than patients without macular oedema [median Expanded Disability Score Scale 2 (interquartile range 1.5-3.5)], P = 0.0002. Patients with multiple sclerosis with microcystic macular oedema also had higher Multiple Sclerosis Severity Scores, a measure of disease progression, than those without oedema [median of 6.47 (interquartile range 4.96-7.98) versus 3.65 (interquartile range 1.92-5.87), P = 0.0009]. Microcystic macular oedema occurred more commonly in eyes with prior optic neuritis than eyes without prior optic neuritis (50 versus 27%) and was associated with lower visual acuity (median logMAR acuity of 0.17 versus -0.1) and a thinner retinal nerve fibre layer. The presence of microcystic macular oedema in multiple sclerosis suggests that there may be breakdown of the blood retinal barrier and tight junction integrity in a part of the nervous system that lacks myelin. Microcystic macular oedema may also contribute to visual dysfunction beyond that explained by nerve fibre layer loss. Microcystic changes need to be assessed, and potentially adjusted for, in clinical trials that evaluate macular volume as a marker of retinal ganglion cell survival. These findings also have implications for clinical monitoring in patients with multiple sclerosis on sphingosine 1-phosphate receptor modulating agents. PMID- 22539262 TI - Adaptive actions of young infants in the task of reaching for objects. AB - Although several studies have investigated how movement trajectory and arm/hand configuration are adjusted to environmental affordances, the influence of specific object properties on early adjustments has not been studied. In this study, we aimed to determine the combined effect of object size and rigidity on reaching movements in young infants. Sixteen typically developing infants were assessed at 4, 5, and 6 months of age. The infants were presented with four objects: two soft and two rigid, which were either small or large. The results indicate that with age reaching movements became straighter, the arm control during the final phase was improved, and the grasping success increased. Object size and rigidity collectively influenced the proximal adjustments, grasping, adjustment time, and the number of movement units. The results suggest that early in the infants are able to modify their movement strategies based on object affordances. PMID- 22539261 TI - Close association of olfactory placode precursors and cranial neural crest cells does not predestine cell mixing. AB - Vertebrate sensory organs originate from both cranial neural crest cells (CNCCs) and placodes. Previously, we have shown that the olfactory placode (OP) forms from a large field of cells extending caudally to the premigratory neural crest domain, and that OPs form through cell movements and not cell division. Concurrent with OP formation, CNCCs migrate rostrally to populate the frontal mass. However, little is known about the interactions between CNCCs and the placodes that form the olfactory sensory system. Previous reports suggest that the OP can generate cell types more typical of neural crest lineages such as neuroendocrine cells and glia, thus marking the OP as an unusual sensory placode. One possible explanation for this exception is that the neural crest origin of glia and neurons has been overlooked due to the intimate association of these two fields during migration. Using molecular markers and live imaging, we followed the development of OP precursors and of dorsally migrating CNCCs in zebrafish embryos. We generated a six4b:mCherry line (OP precursors) that, with a sox10:EGFP line (CNCCs), was used to follow cell migration. Our analyses showed that CNCCs associate with and eventually surround the forming OP with limited cell mixing occurring during this process. PMID- 22539263 TI - Electromagnetic interference and implanted cardiac devices: the medical environment (part II). AB - Electromagnetic interference produced by medical equipment can interact with implanted cardiac devices such as pacemakers and implantable cardioverter defibrillators. The most commonly observed interaction is in the operating room with electrosurgery. The risk of interactions can often be mitigated by close communication between the cardiac-device specialist and the anesthesiology/surgical team to develop a patient-specific strategy that accounts for factors such as type of device, type of surgery, and whether the patient is pacemaker dependent. Although magnetic resonance imaging should generally not be used in patients with implanted cardiac devices, several published guidelines provide strategies and recommendations for managing risks if magnetic resonance imaging is required with no suitable diagnostic alternatives. Other common sources of electromagnetic interference in the medical environment are ionizing radiation and left ventricular assist devices. PMID- 22539264 TI - Automated 3D structure composition for large RNAs. AB - Understanding the numerous functions that RNAs play in living cells depends critically on knowledge of their three-dimensional structure. Due to the difficulties in experimentally assessing structures of large RNAs, there is currently great demand for new high-resolution structure prediction methods. We present the novel method for the fully automated prediction of RNA 3D structures from a user-defined secondary structure. The concept is founded on the machine translation system. The translation engine operates on the RNA FRABASE database tailored to the dictionary relating the RNA secondary structure and tertiary structure elements. The translation algorithm is very fast. Initial 3D structure is composed in a range of seconds on a single processor. The method assures the prediction of large RNA 3D structures of high quality. Our approach needs neither structural templates nor RNA sequence alignment, required for comparative methods. This enables the building of unresolved yet native and artificial RNA structures. The method is implemented in a publicly available, user-friendly server RNAComposer. It works in an interactive mode and a batch mode. The batch mode is designed for large-scale modelling and accepts atomic distance restraints. Presently, the server is set to build RNA structures of up to 500 residues. PMID- 22539266 TI - One-step synthesis of SnO2 and TiO2 hollow nanostructures with various shapes and their enhanced lithium storage properties. AB - A versatile one-step method for the general synthesis of metal oxide hollow nanostructures is demonstrated. This method involves the controlled deposition of metal oxides on shaped alpha-Fe(2)O(3) crystals which are simultaneously dissolved. A variety of uniform SnO(2) hollow nanostructures, such as nanococoons, nanoboxes, hollow nanorings, and nanospheres, can be readily generated. The method is also applicable to the synthesis of shaped TiO(2) hollow nanostructures. As a demonstration of the potential applications of these hollow nanostructures, the lithium storage capability of SnO(2) hollow structures is investigated. The results show that such derived SnO(2) hollow structures exhibit stable capacity retention of 600-700 mA h g(-1) for 50 cycles at a 0.2 C rate and good rate capability at 0.5-1 C, perhaps benefiting from the unique structural characteristics. PMID- 22539267 TI - Tandem cross-dimerisation/oxonia-cope reaction of carbonyl compounds to homoallylic esters and lactones. PMID- 22539265 TI - DeltaPhage--a novel helper phage for high-valence pIX phagemid display. AB - Phage display has been instrumental in discovery of novel binding peptides and folded domains for the past two decades. We recently reported a novel pIX phagemid display system that is characterized by a strong preference for phagemid packaging combined with low display levels, two key features that support highly efficient affinity selection. However, high diversity in selected repertoires are intimately coupled to high display levels during initial selection rounds. To incorporate this additional feature into the pIX display system, we have developed a novel helper phage termed DeltaPhage that allows for high-valence display on pIX. This was obtained by inserting two amber mutations close to the pIX start codon, but after the pVII translational stop, conditionally inactivating the helper phage encoded pIX. Until now, the general notion has been that display on pIX is dependent on wild-type complementation, making high valence display unachievable. However, we found that DeltaPhage does facilitate high-valence pIX display when used with a non-suppressor host. Here, we report a side-by-side comparison with pIII display, and we find that this novel helper phage complements existing pIX phagemid display systems to allow both low and high-valence display, making pIX display a complete and efficient alternative to existing pIII phagemid display systems. PMID- 22539268 TI - Social processes and disease in nonhuman primates: introduction to the special section. AB - Most nonhuman primate species are remarkably social, but their social nature presents many challenges, including increased opportunities for pathogen transmission and development of disease (both physical and psychological). An interdisciplinary symposium was convened at the 2010 annual meeting of the American Society of Primatologists on the topic of social processes and disease in nonhuman primates, and four articles from that session, as well as a fifth that was separately solicited, appear in this special section. The articles reflect a variety of disciplines and perspectives that highlight the many ways that social processes can impact disease processes (and vice versa) in this highly social taxon. This is an increasingly active area of research interest as a consequence of technological developments and the availability of long-term field data. The continuing loss of primate habitat in the wild, climate change, and the need to manage high densities of primates in captivity, however, all add urgency to our need to better understand the bidirectional relationship between social factors and disease processes. PMID- 22539269 TI - Primate disease ecology in comparative and theoretical perspective. AB - Infectious disease plays a major role in the lives of wild primates, and the past decade has witnessed significant strides in our understanding of primate disease ecology. In this review, I briefly describe some key findings from phylogenetic comparative approaches, focusing on analyses of parasite richness that use the Global Mammal Parasite Database. While these studies have provided new answers to fundamental questions, new questions have arisen, including questions about the underlying epidemiological mechanisms that produce the broader phylogenetic patterns. I discuss two examples in which theoretical models have given us new traction on these comparative questions. First, drawing on findings of a positive association between range use intensity and the richness of helminth parasites, we developed a spatially explicit agent-based model to investigate the underlying drivers of this pattern. From this model, we are gaining deeper understanding of how range use intensity results in greater exposure to parasites, thus producing higher prevalence in the simulated populations-and, plausibly, higher parasite richness in comparative analyses. Second, I show how a model of disease spread on social networks provides solid theoretical foundations for understanding the effects of sociality and group size on parasitism across primate species. This study further revealed that larger social groups are more subdivided, which should slow the spread of infectious diseases. This effect could offset the increased disease risk expected in larger social groups, which has yet to receive strong empirical support in our comparative analyses. In addition to these examples, I discuss the need for more meta-analyses of individual-level phenomena documented in the field, and for greater linkage between theoretical modeling and field research. PMID- 22539270 TI - Microsatellite variation in two subspecies of cynomolgus monkeys (Macaca fascicularis). AB - To estimate the genetic variability of two subspecies of cynomolgus monkeys (Macaca fascicularis fascicularis and M. f. aurea) using microsatellite markers, 26 microsatellite markers were selected from previous reports. Seventeen markers showed high polymorphism in a subset of monkeys and were used for the assessment of genetic diversity in the larger sample. The effective number of alleles, the polymorphism information content (PIC) and the expected heterozygosity of M. f. aurea monkeys were all statistically significantly higher than those of M. f. fascicularis monkeys (P < 0.05), suggesting the M. f. aurea monkeys had a higher degree of genetic variation than the M. f. fascicularis monkeys. Substantial differences in allele distribution were also detected between the two subspecies of cynomolgus monkeys. Private alleles restricted to the M. f. fascicularis or the M. f. aurea monkeys were found throughout the selected 17 loci. These private alleles may allow the discrimination of the two subspecies of cynomolgus monkeys. The selected markers could also be used to estimate the genetic variation for other subspecies of cynomolgus monkeys. Further work using additional animals obtained from native or independent sources will be important for a more complete understanding of the genetic differences between these two subgroups. PMID- 22539271 TI - Grooming reciprocity in female tibetan macaques macaca thibetana. AB - Grooming among nonhuman primates is widespread and may represent an important service commodity that is exchanged within a biological marketplace. In this study, using focal animal sampling methods, we recorded grooming relationships among 12 adult females in a free-ranging group of Tibetan macaques (Macaca thibetana) at Huangshan, China, to determine the influence of rank and kinship on grooming relationships, and whether females act as reciprocal traders (exchange grooming received for grooming given) or interchange traders (interchange grooming for social tolerance or other commodities). The results showed that: (1) grooming given was positively correlated with grooming received; (2) kinship did not exert a significant influence on grooming reciprocity; and (3) grooming reciprocity occurred principally between individuals of adjacent rank; however, when females of different rank groomed, females tended to groom up the hierarchy (lower ranking individuals groomed higher ranking individuals more than vice versa). Our results support the contention that both grooming reciprocity and the interchange of grooming for tolerance represent important social tactics used by female Tibetan macaques. PMID- 22539272 TI - Demography of Simakobu (Simias concolor) and the impact of human disturbance. AB - Asian colobines typically live in small one-male groups (OMGs) averaging five adult females, but Simias concolor (simakobu or pig-tailed langur) is considered an exception because mostly adult male-female pairs have been reported. However, based on their phylogenetic position and marked sexual dimorphism, simakobu are also expected to form OMGs with multiple females. The preponderance of small groups could be the result of human disturbance (hunting or habitat disturbance) reducing group size in the recent past. To investigate this possibility, we documented the demography of ten wild simakobu groups from January 2007 until December 2008 at an undisturbed site, the Peleonan Forest, Siberut Island, Indonesia. We assessed the population-specific size and composition of groups and documented demographic changes due to births, disappearances, and dispersals throughout our 2-year study. We found OMGs with 3.0 adult females on average in addition to all-male groups, but no adult male-female pairs. The ratio of 0.5 infants per adult female (and 0.64 births per female-year in focal groups) suggested that birth rates were similar to those of other Asian colobines. In 5.1 group-years, we observed six dispersal events and six temporary presences (i.e., less than 3 months' residency). Both males and females dispersed, and juveniles seemed to disperse more frequently than adults. To assess the impact of human disturbance on simakobu demography, we compiled data for seven additional populations from the literature and compared them using multiple regressions. Adult sex ratio and the number of immatures per group were influenced negatively by hunting and positively by habitat disturbance while reproductive rates were not significantly affected by either variable. These findings suggest that adult male-female pairs may result from hunting pressure reducing group size, and that conservation action to reduce hunting in the Mentawai Islands is needed to ensure the survival of this critically endangered species. PMID- 22539273 TI - Transgenic mouse analysis of Sry expression during the pre- and peri-implantation stage. AB - BACKGROUND: The SRY/Sry gene is expressed in pre-Sertoli cells of the male genital ridge and functions as the mammalian testis determining factor (TDF). In addition, expression of SRY/Sry outside the genital ridge has been reported, including preimplantation embryos, although the functional significance of this is not well understood. RESULTS: Using Cre-mediated lineage studies and transgenic reporter mouse models, we now show that promoter sequences of human, pig and mouse SRY drive robust reporter gene expression in epiblast cells of peri implantation embryos between embryonic day (E) 4.5 and E6.5. Analysis of endogenous Sry expression revealed that linear transcripts are produced by means of multiple polyadenylation sites in E4.5 embryos. Within the epiblast, SRY reporter expression mimics the expression seen using a Gata4 reporter model, but is dissimilar to that seen using an Oct4 reporter model. In addition, we report that overexpression of mouse Sry in embryonic stem cells leads to down-regulation of the core pluripotency markers Sox2 and Nanog. CONCLUSION: We propose that SRY/Sry may function as a male-specific maturation factor in the peri implantation mammalian embryo, providing a genetic mechanism to help explain the observation that male embryos are developmentally more advanced compared with female embryos, and suggesting a role for SRY beyond that of TDF. PMID- 22539274 TI - Amide-forming ligation of acyltrifluoroborates and hydroxylamines in water. PMID- 22539275 TI - Enantioselective intramolecular [2+2] photocycloaddition reactions of 4 substituted coumarins catalyzed by a chiral Lewis acid. AB - Eight coumarins, which carry a terminal alkene tethered by a CH(2)XCH(2) group to their 4-position (X = CH(2), CMe(2), O, S, NBoc, NZ, NTs, NBn), were synthesized in overall yields of 51-80 %. Starting materials for the syntheses were either commercially available 4-hydroxycoumarin or 4-formylcoumarin. The intramolecular [2+2] photocycloaddition of these coumarins gave diastereoselectively products with a tetracyclic 3,3a,4,4a-tetrahydro-1H-cyclopenta[2,3]cyclobuta[1,2-c]chromen 5(2H)-one skeleton. Direct irradiation at lambda = 300 nm in dichloromethane (c = 10 mM) led to product formation in good yields for most substrates, presumably via a singlet excited state intermediate. Due to the low coumarin absorption at lambda >350 nm the photocycloaddition was slow upon irradiation at lambda = 366 nm. Addition of a chiral oxazaborolidine-based Lewis acid (50 mol %) increased the reaction rate at lambda = 366 nm and induced a significant enantioselectivity in the [2+2] photocycloaddition. Six out of eight coumarin substrates (X = CH(2), CMe(2), O, NBoc, NZ, NTs) gave the respective products in yields of 72-96 % and with 74-90 % enantiomeric excess (ee) upon irradiation in dichloromethane (c = 20 mM) at -75 degrees C. The Lewis acid presumably acts by coordination to the coumarin carbonyl oxygen atom, which leads to a bathochromic shift (redshift) of the UV absorption and which increases the singlet state lifetime. A second electrostatic interaction of the hydrogen atom at C3 with the oxygen atom of the oxazaborolidine is likely. PMID- 22539278 TI - EFIS-EJI African International Conference on Immunity (AICI). PMID- 22539280 TI - Molecular control over thymic involution: from cytokines and microRNA to aging and adipose tissue. AB - The thymus is the primary organ for T-cell differentiation and maturation. Unlike other major organs, the thymus is highly dynamic, capable of undergoing multiple rounds of almost complete atrophy followed by rapid restoration. The process of thymic atrophy, or involution, results in decreased thymopoiesis and emigration of naive T cells to the periphery. Multiple processes can trigger transient thymic involution, including bacterial and viral infection(s), aging, pregnancy and stress. Intense investigations into the mechanisms that underlie thymic involution have revealed diverse cellular and molecular mediators, with elaborate control mechanisms. This review outlines the disparate pathways through which involution can be mediated, from the transient infection-mediated pathway, tightly controlled by microRNA, to the chronic changes that occur through aging. PMID- 22539281 TI - From crucial to negligible: functional CD8+ T-cell responses and their dependence on CD4+ T-cell help. AB - CD8(+) T cells play an important role in controlling pathogenic infections and are therefore key players in the immune response. It has been shown that among other factors CD4(+) T cells can shape the magnitude as well as the quality of primary and/or secondary CD8(+) T-cell responses. However, due to the complexity and the differences among diverse immunization or infection models, the overall requirement, the time points, as well as the specific mechanism(s) of CD4(+) T cell help may differ substantially. Here, we summarize current knowledge about the differential requirement of CD4(+) T-cell help in promoting primary CD8(+) T-cell responses as well as establishing functional memory CD8(+) T cells in various experimental settings. PMID- 22539282 TI - Innate immunity's path to the Nobel Prize 2011 and beyond. AB - The 2011 Nobel Prize in Physiology/Medicine to Ralph Steinmann, Jules Hoffmann, and Bruce Beutler recognized a paradigm shift in our understanding of innate immunity, and its impact on adaptive immunity. The Prize highlighted the initial discoveries of Toll's role in immunity in flies, Toll-like receptors in mammals, and the establishment of dendritic cells as the initiators of adaptive immunity. This historical Commentary focuses on the developments in our understanding of innate immunity. PMID- 22539283 TI - Type 2 innate lymphoid cells-new members of the "type 2 franchise" that mediate allergic airway inflammation. AB - Type 2 innate lymphoid cells (ILC2s) are members of an ILC family, which contains NK cells and Rorgammat(+) ILCs, the latter including lymphoid tissue inducer (LTi) cells and ILCs producing IL-17 and IL-22. ILC2s are dedicated to the production of IL-5 and IL-13 and, as such, ILC2s provide an early and important source of type 2 cytokines critical for helminth expulsion in the gut. Several studies have also demonstrated a role for ILC2s in airway inflammation. In this issue of the European Journal of Immunology, Klein Wolterink et al. [Eur. J. Immunol. 2012. 42: 1106-1116] show that ILC2s are instrumental in several models of experimental asthma where they significantly contribute to production of IL-5 and IL-13, key cytokines in airway inflammation. This study sheds light over the relative contribution of ILC2s versus T helper type 2 cells (Th2) in type 2 mediated allergen-specific inflammation in the airways as discussed in this commentary. PMID- 22539284 TI - Driving IL-17+ gammadelta T-cell migration in allergic reactions: a new "inflammatory" role for the "homeostatic" chemokine CCL25. AB - Chemokines are traditionally classified as homeostatic or inflammatory depending on whether they direct leukocyte migration in the absence or presence of inflammatory stimuli. CC chemokine ligand (CCL)25, a ligand for CC chemokine receptor (CCR)9, has mostly been characterized as a homeostatic chemokine that determines the migration pathway of T-cell progenitors within the thymus, and the recruitment of various lymphocyte subsets to the intestinal mucosa. In this issue of the European Journal of Immunology, Costa et al. [Eur. J. Immunol. 2012. 42: 1250-1260] describe a new inflammatory role for CCL25/CCR9 in controlling the migration of a subset of gammadelta T cells committed to IL-17 production (gammadelta17 cells) in a model of allergic pleurisy. Interestingly, the effect of CCL25 was selective for gammadelta17 cells, as it did not extend to other gammadelta or alphabeta T-cell subsets, and resulted in a specific increase of IL 17 (but not IL-4 or IFN-gamma) levels in the allergic pleura. In this commentary, I discuss these results in the context of chemokine-mediated recruitment of gammadelta T cells to inflammatory sites, and the as yet unclear and controversial role of IL-17 in allergic reactions. PMID- 22539285 TI - The unwavering commitment of regulatory T cells in the suppression of autoimmune encephalomyelitis: another aspect of immune privilege in the CNS. AB - FoxP3(+) regulatory T (Treg) cells accumulate in the central nervous system (CNS) during experimental autoimmune encephalomyelitis and have been shown to limit the extent of neuroinflammation and to facilitate clinical recovery. The recent demonstration that Treg cells lose FoxP3 expression and assume effector cell characteristics upon stimulation with proinflammatory cytokines has raised questions about their stability in the inflamed CNS. In this issue of the European Journal of Immunology, O'Connor et al. [Eur. J. Immunol. 2012. 42: 1164 1173] show that CNS-infiltrating Treg cells maintain their suppressor phenotype by downregulating the IL-6 receptor. This commentary discusses the finding particularly with relevance to therapy of multiple sclerosis. PMID- 22539286 TI - Pulmonary innate lymphoid cells are major producers of IL-5 and IL-13 in murine models of allergic asthma. AB - Allergic asthma is characterized by chronic airway inflammation and hyperreactivity and is thought to be mediated by an adaptive T helper-2 (Th2) cell-type immune response. Here, we demonstrate that type 2 pulmonary innate lymphoid cells (ILC2s) significantly contribute to production of the key cytokines IL-5 and IL-13 in experimental asthma. In naive mice, lineage-marker negative ILC2s expressing IL-7Ralpha, CD25, Sca-1, and T1/ST2(IL-33R) were present in lungs and mediastinal lymph nodes (MedLNs), but not in broncho alveolar lavage (BAL) fluid. Upon intranasal administration of IL-25 or IL-33, an asthma phenotype was induced, whereby ILC2s accumulated in lungs, MedLNs, and BAL fluid. After IL-25 and IL-33 administration, ILC2s constituted ~50 and ~80% of IL 5(+) /IL-13(+) cells in lung and BAL, respectively. Also in house dust mite induced or ovalbumin-induced allergic asthma, the ILC2 population in lung and BAL fluid increased significantly in size and ILC2s were a major source of IL-5 or IL 13. Particularly in OVA-induced asthma, the contribution of ILC2s to the total population of intracellular IL-5(+) and IL-13(+) cells in the lung was in the same range as found for Th2 cells. We conclude that both ILC2s and Th2 cells produce large amounts of IL-5 and IL-13 that contribute to allergic airway inflammation. PMID- 22539287 TI - Ambivalent effects of dendritic cells displaying prostaglandin E2-induced indoleamine 2,3-dioxygenase. AB - Prostaglandin E2 (PGE(2)), an abundantly produced lipid messenger in mammalian organisms, has been attributed to possess potent albeit ambivalent immunological functions. Recently, PGE(2) has been reported to stimulate the commonly believed immunosuppressive indoleamine 2,3-dioxygenase (IDO) pathway in human dendritic cells (DCs), but without promoting DC immunosuppressive activity. Here, we report that PGE(2) used as a DC maturation agent apparently has more diverse functions. PGE(2)-matured DCs acquired powerful IDO activity, which was sustained even after removing PGE(2). These IDO-competent DCs were able to stimulate allogeneic T-cell proliferation, but achieved inhibitory activity as their content in DC/T-cell co cultures increased. The DC inhibitory activity was reversed upon blockade of IDO activity, confirming that the suppressive effect was in fact mediated by IDO and occurred in a dose-dependent fashion. IDO-mediated T-cell suppression was restored upon re-stimulation of T cells in the absence of IDO activity, confirming its reversibility. T cells stimulated by PGE(2)-matured IDO-competent DCs were sensitized to produce multiple cytokines, comprising Th1, Th2, and Th17 phenotypes. Collectively, these data suggest that T cells stimulated by PGE(2) matured DCs are not terminally differentiated and their ultimate type of response may be formed by microenvironmental conditions. PMID- 22539288 TI - IL-15 inhibits IL-7Ralpha expression by memory-phenotype CD8+ T cells in the bone marrow. AB - CD127 is the IL-7 receptor alpha-chain and its expression is tightly regulated during T-cell differentiation. We previously showed that the bone marrow (BM) is a key organ for proliferation and maintenance of both antigen-specific and CD44(high) memory CD8(+) T cells. Interestingly, BM memory CD8(+) T cells express lower levels of membrane CD127 than do the corresponding spleen and lymph node cells. We investigated the requirements for CD127 downmodulation by CD44(high) memory-phenotype CD8(+) T cells in the BM of C57BL/6 mice. By comparing genetically modified (i.e. CD127tg, IL-7 KO, IL-15 KO, IL-15Ralpha KO) with wild-type (WT) mice, we found that the key molecule regulating CD127 downmodulation was IL-15 but not IL-7, and that the intact CD127 gene was required, including the promoter. Indeed, CD127 mRNA transcript levels were lower in CD44(high) CD8(+) T cells from the BM than in those from the spleen of WT mice, indicating organ-specific regulation. Although levels of the CD127 transactivator Foxo1 were low in BM CD44(high) CD8(+) T cells, Foxo1 was not involved in IL-15-induced CD127 downmodulation. Thus, recirculating CD44(high) CD8(+) T cells passing through the BM transiently downregulate CD127 in response to IL-15, with implications for human therapies acting on the IL-7/CD127 axis, for example cytokine treatments in cancer patients. PMID- 22539289 TI - Activation of the adenosine A2A receptor attenuates experimental autoimmune myasthenia gravis severity. AB - The adenosine A2A receptor (A2AR) is the major cellular adenosine receptor commonly associated with immunosuppression. Here, we investigated whether A2AR activation holds the potential for impacting the severity of experimental autoimmune myasthenia gravis (EAMG) induced following immunization of Lewis rats with the acetylcholine receptor (AChR) R97-116 peptide. This report demonstrates reduced A2AR expression by both T cells and B cells residing in spleen and lymph nodes following EAMG induction. A2AR stimulation inhibited anti-AChR antibody production and proliferation of AChR-specific lymphocytes in vitro. Inhibition was blocked with the A2AR antagonists or protein kinase A inhibitor. We also determined that the development of EAMG was accompanied by a T-helper cell imbalance that could be restored following A2AR stimulation that resulted in increased Treg cell levels and a reduction in Th1-, Th2-, and Th17-cell subtypes. An EAMG-preventive treatment regimen was established that consisted of (2-(p-(2 carbonylethyl)phenylethylamino)-5-N-ethylcarboxamidoadenosine) (CGS21680; A2AR agonist) administration 1 day prior to EAMG induction. Administration of CGS21680 29 days post EAMG induction (therapeutic treatment) also ameliorated disease severity. We conclude that A2AR agonists may represent a new class of compounds that can be developed for use in the treatment of myasthenia gravis or other T cell- and B-cell-mediated autoimmune diseases. PMID- 22539290 TI - Activation of CD4+ Foxp3+ regulatory T cells proceeds normally in the absence of B cells during EAE. AB - B cells and regulatory T (Treg) cells can both facilitate remission from experimental auto immune encephalomyelitis (EAE), a disease of the central nervous system (CNS) used as a model for multiple sclerosis (MS). Considering that B-cell-depletion therapy (BCDT) is used to treat MS patients, we asked whether Treg-cell activation depended on B cells during EAE. Treg-cell proliferation, accumulation in CNS, and augmentation of suppressive activity in the CNS were normal in B-cell-deficient mice, indicating that B cells are not essential for activation of the protective Treg-cell response and thus provide an independent layer of regulation. This function of B cells involved early suppression of the encephalitogenic CD4(+) T-cell response, which was enhanced in B-cell-deficient mice. CD4(+) T-cell depletion was sufficient to intercept the transition from acute-to-chronic EAE when applied to B-cell-deficient animals that just reached the peak of disease severity. Intriguingly, this treatment did not improve disease when applied later, implying that chronic disability was ultimately maintained independently of pathogenic CD4(+) T cells. Collectively, our data indicate that BCDT is unlikely to impair Treg-cell function, yet it might produce undesirable effects on T-cell-mediated autoimmune pathogenesis. PMID- 22539291 TI - Foxp3+ Treg cells in the inflamed CNS are insensitive to IL-6-driven IL-17 production. AB - Foxp3(+) T regulatory (Treg) cells can be induced to produce interleukin (IL)-17 by in vitro exposure to proinflammatory cytokines, drawing into question their functional stability at sites of inflammation. Unlike their splenic counterparts, Treg cells from the inflamed central nervous system (CNS-Treg cells) during EAE resisted conversion to IL-17 production when exposed to IL-6. We show that the highly activated phenotype of CNS-Treg cells includes elevated expression of the Th1-associated molecules CXCR3 and T-bet, but reduced expression of the IL-6 receptor alpha chain (CD126) and the signaling chain gp130. We found a lack of IL 6 receptor on all CNS CD4(+) T cells, which was reflected by an absence of both classical and trans-IL-6 signaling in CNS CD4(+) cells, compared with their splenic counterparts. We propose that extinguished responsiveness to IL-6 (via down-regulation of CD126 and gp130) stabilizes the regulatory phenotype of activated Treg cells at sites of autoimmune inflammation. PMID- 22539292 TI - Blockade of Tim-3 signaling restores the virus-specific CD8+ T-cell response in patients with chronic hepatitis B. AB - Chronic hepatitis B (CHB) is characterized by functionally impaired virus specific CD8(+) T-cell responses. However, the mechanism underlying this dysfunction has not been fully clarified. We examined the role of a newly identified protein, T-cell immunoglobulin domain and mucin domain-containing molecule-3 (Tim-3), in regulating the antiviral CD8(+) T-cell response in CHB patients. Tim-3 expression on peripheral virus-specific CD8(+) T cells from 20 CHB patients and 20 healthy controls was determined by flow cytometry. The phenotypes and cytokine-producing capacity were compared between Tim-3(+) CD8(+) and Tim-3(-) CD8(+) T cells. The impact of Tim-3 signaling on cellular proliferation and cytokine-producing capacity was also studied. Tim-3 expression on hepatitis B virus (HBV)-specific CD8(+) T cells was higher than expression on cytomegalovirus (CMV)-specific CD8(+) T cells. Tim-3(+) CD8(+) T cells exhibited proliferative senescence phenotypes and decreased cytokine production upon antigen challenge. Finally, blocking the Tim-3 pathway significantly improved proliferation and antiviral cytokine secretion of CD8(+) T cells in response to HBV-specific antigen peptides. Tim-3 negatively regulates antiviral responses of CD8(+) T cells isolated from CHB patients, and this response is reversed by blocking the Tim-3 pathway. PMID- 22539293 TI - Mycobacteria-infected bystander macrophages trigger maturation of dendritic cells and enhance their ability to mediate HIV transinfection. AB - Synergistic interplay between Mycobacterium tuberculosis (Mtb) and HIV in coinfected individuals leads to the acceleration of both tuberculosis and HIV disease. Mtb, as well as HIV, may modulate the function of many immune cells, including DCs. To dissect the bystander impact of Mphis infected with Mtb on DC functionality, we here investigated changes in DC phenotype, cytokine profiles, and HIV-1 transinfecting ability. An in vitro system was used in which human monocyte-derived DCs were exposed to soluble factors released by Mphis infected with mycobacteria, including virulent clinical Mtb isolates and nonvirulent BCG. Soluble factors secreted from Mtb-infected Mphis, and to a lesser extent BCG infected Mphis, resulted in the production of proinflammatory cytokines and partial upregulation of DC maturation markers. Interestingly, the HIV-1 transinfecting ability of DCs was enhanced upon exposure to soluble factors released by Mtb-infected Mphis. In summary, our study shows that DCs exposed to soluble factors released by mycobacteria-infected Mphis undergo maturation and display an augmented ability to transmit HIV-1 in trans. These findings highlight the important role of bystander effects during the course of Mtb-HIV coinfection and suggest that Mtb-infected Mphis may contribute to an environment that supports DC-mediated spread and amplification of HIV in coinfected individuals. PMID- 22539294 TI - Double negative Treg cells promote nonmyeloablative bone marrow chimerism by inducing T-cell clonal deletion and suppressing NK cell function. AB - The establishment of immune tolerance and prevention of chronic rejection remain major goals in clinical transplantation. In bone marrow (BM) transplantation, T cells and NK cells play important roles for graft rejection. In addition, graft versus-host-disease (GVHD) remains a major obstacle for BM transplantation. In this study, we aimed to establish mixed chimerism in an irradiation-free condition. Our data indicate that adoptive transfer of donor-derived T-cell receptor (TCR) alphabeta(+) CD3(+) CD4(-) CD8(-) NK1.1(-) (double negative, DN) Treg cells prior to C57BL/6 to BALB/c BM transplantation, in combination with cyclophosphamide, induced a stable-mixed chimerism and acceptance of C57BL/6 skin allografts but rejection of third-party C3H (H-2k) skin grafts. Adoptive transfer of CD4(+) and CD8(+) T cells, but not DN Treg cells, induced GVHD in this regimen. The recipient T-cell alloreactive responsiveness was reduced in the DN Treg cell-treated group and clonal deletions of TCRVbeta2, 7, 8.1/2, and 8.3 were observed in both CD4(+) and CD8(+) T cells. Furthermore, DN Treg-cell treatment suppressed NK cell-mediated BM rejection in a perforin-dependent manner. Taken together, our results suggest that adoptive transfer of DN Treg cells can control both adoptive and innate immunities and promote stable-mixed chimerism and donor specific tolerance in the irradiation-free regimen. PMID- 22539295 TI - Influence of hypoxia-inducible factor 1alpha on dendritic cell differentiation and migration. AB - Dendritic cells(DCs) are important sentinels of the immune system and frequently reside in areas of low oxygen availability, in particular in the course of inflammatory processes. Hypoxia-inducible transcription factor (HIF)1alpha is responsible for major alterations in gene expression as part of the cellular adaptation to low oxygen concentration. In this study, we generated mice with a conditional deletion of HIF1alpha in DCs. Bone marrow-derived DCs from WT and conditional mutant mice expressed elevated levels of major histocompatibility complex class II and CD86 when grown in a hypoxic environment, whereas production of the cytokines interleukin (IL)-12p70, IL-10, IL-6, TNF-alpha, IL-1beta, and IL 23 was reduced, both independent of HIF1alpha expression. In contrast, secretion of IL-22 was strongly enhanced under hypoxic conditions in an HIF1alpha-dependent manner. The chemokine receptor CCR7 was expressed at higher levels in wild-type DCs compared with HIF1alpha-deficient DCs, whereas the production of CCL17 and CCL22 was increased in conditions of low oxygen. Using in vitro as well as in vivo migration assays, we observed an enhanced migratory capability of DCs generated under hypoxia, which was HIF1alpha-dependent. Taken together, our data indicate that HIF1alpha plays an important role for DC differentiation and migration in a low oxygen environment. PMID- 22539296 TI - Foxp3-independent loss of regulatory CD4+ T-cell suppressive capacities induced by self-deprivation. AB - In the periphery, Foxp3 expression is considered sufficient to maintain natural regulatory CD4(+) T-cell suppressive function. In this study, we challenge this model. Indeed, in mouse chimeras in which major histocompatibility complex (MHC) class II expression is restricted to the thymus, peripheral regulatory CD4(+) T cells lack suppressive activity. In addition, regulatory CD4(+) T cells recovered 5 days after transfer into recipient mice lacking expression of MHC class II molecules (self-deprived) are unable to inhibit the proliferative response of conventional CD4(+) T cells both in vitro and in vivo. Disruption of TCR/MHC class II interactions rapidly leads to alterations in the regulatory CD4(+) T-cell phenotype, the ability to respond to stimulation and to produce interleukin-10, and the transcriptional signature. Interestingly, self deprivation does not affect Foxp3 expression indicating that in regulatory CD4(+) T cells, self-recognition induces unique transcriptional and functional features that do not rely on Foxp3 expression. PMID- 22539297 TI - CCL25 induces alpha4beta7 integrin-dependent migration of IL-17+ gammadelta T lymphocytes during an allergic reaction. AB - Herein, we provide evidence that during allergic inflammation, CCL25 induces the selective migration of IL-17(+) gammadelta T cells mediated by alpha(4) beta(7) integrin. Intrapleural injection of CCL25 into ovalbumin (OVA)-immunized C57BL/6 mice triggered the accumulation of gammadelta T lymphocytes expressing CCR9 (CCL25 receptor) and alpha(4) beta(7) integrin in the pleura, but failed to attract alphabeta T lymphocytes. CCL25 attracted CCR6(+) gammadelta T cells producing IL-17 (but not IFN-gamma or IL-4). OVA challenge triggered increased production of CCL25 followed by the accumulation of CCR9(+) , alpha(4) beta(7) (+) , and CCR6(+) /IL-17(+) gammadelta T cells into the pleural cavities of OVA immunized mice, which was inhibited by the in vivo neutralization of CCL25. The in vivo blockade of alpha(4) beta(7) integrin also inhibited the migration of IL 17(+) gammadelta T lymphocytes (but not of alphabeta T lymphocytes) into mouse pleura after OVA challenge, suggesting that the CCL25/alpha(4) beta(7) integrin pathway is selective for gammadelta T cells. In addition, alpha(4) beta(7) integrin blockade impaired the in vitro transmigration of gammadelta T cells across endothelium (which expresses alpha(4) beta(7) ligands VCAM-1 and MadCAM 1), which was induced by CCL25 and by cell-free pleural washes recovered from OVA challenged mice. Our results reveal that during an allergic reaction, CCL25 drives IL-17(+) gammadelta T-cell mobilization to inflamed tissue via alpha(4) beta(7) integrin and modulates IL-17 levels. PMID- 22539298 TI - NKp46 expression discriminates porcine NK cells with different functional properties. AB - So far little is known about natural killer (NK) cells in the pig due to the lack of NK cell-specific markers. In this study, we identified the activating receptor NKp46 (CD335) in swine with newly developed monoclonal antibodies (mAbs) for more detailed studies on NK cells in this species. The NKp46 mAbs showed a specific reactivity with a distinct population of perforin(+) CD2(+) CD3(-) CD8alpha(+) CD16(+) lymphocytes. In spleen and liver, an additional subset of CD8alpha(dim/ ) lymphocytes with increased NKp46 expression was observed. Surprisingly, we could identify NKp46(-) cells with an NK cell phenotype in all animals analyzed. These lymphocytes showed comparable cytolytic activity against xenogeneic and allogeneic target cells as NKp46(+) NK cells. In contrast, NKp46(+) NK cells produced several fold higher levels of interferon-gamma (IFN-gamma) than the NKp46(-) cells after cytokine stimulation. Furthermore, an activation-dependent induction of NKp46 expression in formerly NKp46(-) cells after stimulation with interleukin-2 (IL-2), IL-12, and IL-18 could be shown. In summary, our data indicate that NKp46 is not expressed by all porcine NK cells and that NKp46 discriminates porcine NK cells differing in regard to cytokine production, which challenges the paradigm of NKp46 as a comprehensive marker for NK cells across different mammalian species. PMID- 22539299 TI - Innate NKTgammadelta and NKTalphabeta cells exert similar functions and compete for a thymic niche. AB - The transcriptional regulator promyelocytic leukemia zinc finger (PLZF) is highly expressed during the differentiation of natural killer T (NKT) cells and is essential for the acquisition of their effector/memory innate-like phenotype. Staining with anti-PLZF and anti-NK1.1 Abs allows the definition of two subsets of NKTalphabeta and NKTgammadelta thymocytes that differ phenotypically and functionally: a PLZF(+) NK1.1(-) subset composed of mostly quiescent cells that secrete more IL-4 than IFN-gamma upon activation and a PLZF(+/-) NK1.1(+) subset that expresses CD127, NK1.1, and other NK-cell markers, secrete more IFN-gamma than IL-4 upon activation and contains a sizable fraction of dividing cells. The size of the NK1.1(+) population is very tightly regulated and NK1.1(+) alphabeta and gammadelta thymocytes compete for a thymic niche. Furthermore, the relative representation of the PLZF(+) and NK1.1(+) subsets varies in a strain specific manner with C57BL/6 (B6) mice containing more NK1.1(+) cells and (B6 * DBA/2)F1 (B6D2F1) mice more PLZF(+) cells. Consequently, activation of NKT cells in vivo is expected to result in higher levels of IL-4 secreted in B6D2F1 mice than in B6 mice. Consistent with this possibility, B6D2F1 mice, when compared with B6 mice, contain more "innate" CD8(+) thymocytes, the generation of which depends on IL-4 secreted by NKT cells. PMID- 22539300 TI - Glucocorticoid-induced leucine zipper is downregulated in human alveolar macrophages upon Toll-like receptor activation. AB - Induction of the glucocorticoid-induced leucine zipper (GILZ) by glucocorticoids plays a role in their antiinflammatory action, whereas GILZ expression is reduced under inflammatory conditions. The mechanisms regulating GILZ expression during inflammation, however, have not yet been characterized. Here, we investigated GILZ expression in human alveolar macrophages (AMs) following Toll-like receptor (TLR) activation. Macrophages were shown to predominantly express GILZ transcript variant 2. Lipopolysaccharide-treated AMs, THP-1 cells, and lungs of lipopolysaccharide-exposed mice displayed decreased GILZ protein and mRNA levels. The effect was strictly dependent on the adapter molecule MyD88, as shown by using specific ligands or a knockdown strategy. Investigations on the functional significance of GILZ downregulation performed by GILZ knockdown revealed a proinflammatory response, as indicated by increased cytokine expression and NF kappaB activity. We found that TLR activation reduced GILZ mRNA stability, which was mediated via the GILZ 3'-untranslated region. Finally, involvement of the mRNA-binding protein tristetraprolin (TTP) is suggested, since TTP overexpression or knockdown modulated GILZ expression and TTP was induced in a MyD88-dependent fashion. Taken together, our data show a MyD88- and TTP-dependent GILZ downreg ulation in human macrophages upon TLR activation. Suppression of GILZ is mediated by mRNA destabilization, which might represent a regulatory mechanism in macrophage activation. PMID- 22539301 TI - Mice deficient in hepatocyte-specific IL-1Ra show delayed resolution of concanavalin A-induced hepatitis. AB - Interleukin-1 receptor antagonist (IL-1Ra) is a specific IL-1 inhibitor that possesses anti-inflammatory activities. Several studies in human and mouse suggested a protective role for IL-1Ra in liver inflammation, and we previously demonstrated that hepatocytes produce high levels of IL-1Ra in response to inflammatory challenge in vitro and in vivo. In the present study, we investigated the production and the biological function of hepatocyte-derived IL 1Ra in concanavalin A (ConA)-induced hepatitis in mice. We show that the injured liver produces large amounts of IL-1Ra and that secreted and intracellular IL-1Ra isoforms are produced with different kinetics during the course of hepatitis. By using hepatocyte-specific IL-1Ra-deficient mice (IL-1Ra(DeltaH)), we demonstrate that hepatocytes represent the major cellular source of local IL-1Ra. Most interestingly, hepatic necrosis and inflammation were increased in IL-1Ra(DeltaH) as compared with wild-type mice during the late phase of the disease, leading to a delayed resolution of hepatitis in IL-1Ra(DeltaH) mice. In conclusion, our results show that the local production of IL-1Ra by hepatocytes contributes to the resolution of hepatitis. PMID- 22539302 TI - IL-6 promotes immune responses in human ulcerative colitis and induces a skin homing phenotype in the dendritic cells and Tcells they stimulate. AB - Dendritic cells (DCs) control the type and location of immune responses. Ulcerative colitis (UC) is considered a Th2 disease mediated by IL-13 where up to one third of patients can develop extraintestinal manifestations. Colonic biopsies from inflamed and noninflamed areas of UC patients were cultured in vitro and their supernatants were used to condition human blood enriched DCs from healthy controls. Levels of IL-13 in the culture supernatants were below the detection limit in most cases and the cytokine profile suggested a mixed profile rather than a Th2 cytokine profile. IL-6 was the predominant cytokine found in inflamed areas from UC patients and its concentration correlated with the Mayo endoscopic score for severity of disease. DCs conditioned with noninflamed culture supernatants acquired a regulatory phenotype with decreased stimulatory capacity. However, DCs conditioned with inflamed culture supernatants acquired a proinflammatory phenotype with increased expression of the skin-homing chemokine CCR8. These DCs did not have decreased T-cell stimulatory capacity and primed T cells with the skin-homing CLA molecule in an IL-6-dependent mechanism. Our results highlight the role of IL-6 in UC and question the concept of UC as a Th2 disease and the relevance of IL-13 in its etiology. PMID- 22539303 TI - Detection of weak receptor-ligand interactions using IgM and J-chain-based fusion proteins. PMID- 22539305 TI - Electromagnetic interference and implanted cardiac devices: the nonmedical environment (part I). AB - The number of patients with cardiovascular implantable electronic devices (CIEDs), such as permanent pacemakers and implantable cardioverter defibrillators, is dramatically rising due to an aging population and recent clinical trials showing benefits in mortality and morbidity. Coupled with this increase in the number of patients with CIEDs is the proliferation of technology that emits electromagnetic signals, which can potentially interfere with CIED function through electromagnetic interference (EMI). Despite continuous efforts of manufacturers to create "EMI-proof" CIEDs, adverse events from EMI still occur. Physicians caring for patients with CIEDs should be aware of potential sources of EMI and appropriate management options. This 2-part review aims to provide a contemporary overview of the current knowledge regarding risks attributable to EMI interactions from the most common nonmedical (Part I) and medical (Part II) sources. PMID- 22539306 TI - A novel nuclear FGF Receptor-1 partnership with retinoid and Nur receptors during developmental gene programming of embryonic stem cells. AB - FGF Receptor-1 (FGFR1), a membrane-targeted protein, is also involved in independent direct nuclear signaling. We show that nuclear accumulation of FGFR1 is a common response to retinoic acid (RA) in pluripotent embryonic stem cells (ESC) and neural progenitors and is both necessary and sufficient for neuronal like differentiation and accompanying neuritic outgrowth. Dominant negative nuclear FGFR1, which lacks the tyrosine kinase domain, prevents RA-induced differentiation while full-length nuclear FGFR1 elicits differentiation in the absence of RA. Immunoprecipitation and GST assays demonstrate that FGFR1 interacts with RXR, RAR and their Nur77 and Nurr1 partners. Conditions that promote these interactions decrease the mobility of nuclear FGFR1 and RXR in live cells. RXR and FGFR1 co-associate with 5'-Fluorouridine-labeled transcription sites and with RA Responsive Elements (RARE). RA activation of neuronal (tyrosine hydroxylase) and neurogenic (fgf-2 and fgfr1) genes is accompanied by increased FGFR1, Nur, and histone H3.3 binding to their regulatory sequences. Reporter-gene assays show synergistic activations of RARE, NBRE, and NurRE by FGFR1, RAR/RXR, and Nurs. As shown for mESC differentiation, FGFR1 mediates gene activation by RA and augments transcription in the absence of RA. Cooperation of FGFR1 with RXR/RAR and Nurs at targeted genomic sequences offers a new mechanism in developmental gene regulation. PMID- 22539307 TI - Expanded bacteriochlorins. PMID- 22539308 TI - Solution-processed, undoped, deep-blue organic light-emitting diodes based on starburst oligofluorenes with a planar triphenylamine core. AB - A series of starburst oligomers (T1-T3) that contained a fully diarylmethene bridged triphenylamine core and oligofluorene arms were designed and synthesized through Suzuki cross-coupling reactions. Their thermal, photophysical, and electrochemical properties were also investigated. These materials showed high glass transition, in the range of 123-129 degrees C, and good film-forming abilities. They displayed deep-blue emission both in solution and as thin films. Solution-processed devices based on these oligomers exhibited highly efficient deep-blue electroluminescence and the device performances were significantly enhanced with the extension of the oligofluorene arms. The double-layered device that contained T3 as an emitter showed a maximum current efficiency of 3.83 cd A( 1) and a maximum external quantum efficiency of 4.19% with CIE coordinates of (0.16, 0.09), which are among the highest values for undoped deep-blue OLEDs that are based on solution-processable starburst oligomers. PMID- 22539309 TI - Cardiopulmonary assessment of patients with end-stage kidney disease. PMID- 22539310 TI - Outcome of the living kidney donor. PMID- 22539311 TI - Capillary electrophoretic analysis of whole blood samples for hemoglobin-based oxygen carriers without the use of immunoprecipitation. AB - Hemoglobin-based oxygen carriers (HBOCs) are blood substitutes, synthesized by polymerizing hemoglobin, which are being developed and investigated as alternatives to blood for medical purposes. However, due to their ability to increase the oxygen carrying capacity when taken by healthy individuals, HBOCs have been used as a doping agent among endurance athletes and are included in the World Anti-Doping Agency's Prohibited List. To maintain the fairness of competitions and continue the battle against doping, it is essential to be able to detect HBOCs if present in an athlete's blood. To achieve this goal, it is necessary to differentiate HBOCs from the native hemoglobin and to do so in a cost and time effective manner. We have developed a rapid capillary zone electrophoresis (CZE), UV absorbance, method capable of detecting HBOCs, in whole blood samples, at levels below those considered necessary to provide a performance enhancement. Our approach to the analysis for HBOCs utilizes the whole blood sample, not just the plasma, and does not require the use of immunoprecipitants to ensure accurate analysis. By lysing the red blood cells and using centrifugal filtration, followed by our CZE separation, we are able to effectively distinguish between native hemoglobin and HBOCs. Through this method, we have been able to reliably detect concentrations of HBOCs at the equivalent of 5.5 g/L, the equivalent to a 3.5% increase in blood hemoglobin concentration for an athlete. PMID- 22539313 TI - A comparative survey of proteins from recalcitrant tissues of a non-model gymnosperm, Douglas-fir. AB - Most research in plants and other organisms has, for the sake of convenience, focused on the use of model species to identify mechanisms that are conserved throughout the whole kingdom. Nevertheless, unique features and processes such as those related to plant cell wall and fiber formation, and to wood quality, sometimes need to be studied directly in the non-model organism of interest. Such organisms, like the economically and ecologically important gymnosperm Douglas fir (Pseudotsuga menziesii), which is one of the crucial softwood timber species in Northern America, are often difficult to investigate. High phenolic, resin, and tannin contents in the woody tissues, as well as an incompletely sequenced genome, have contributed greatly to the species' recalcitrance for molecular biology investigations. In this study, we present a complete procedure detailing protein sample preparation, separation, and proteomic analysis based on cross species identification of Douglas-fir. Proteins from the cambial zone, mature needles, and in vitro callus were extracted, purified, and separated via 1D and 2D SDS-PAGE. One-dimensional electrophoresis coupled with ESI-MS/MS was used for cross-species protein identification in order to evaluate the potential of this approach and reveal major differences in protein profiles among tested tissues. Identified proteins were functionally and developmentally compared. The likely contribution of these proteins to the properties of the cell wall and wood is indicated and discussed. PMID- 22539312 TI - A facile electrophoretic technique to monitor phosphoenolpyruvate-dependent kinases. AB - Phosphoenolpyruvate (PEP)-dependent kinases are central to numerous metabolic processes and mediate the production of adenosine triphosphate (ATP) by substrate level phosphorylation (SLP). While pyruvate kinase (PK, EC: 2.7.1.40), the final enzyme of the glycolytic pathway is critical in the anaerobic synthesis of ATP from ADP, pyruvate phosphate dikinase (PPDK, EC: 2.7.9.1), and phosphoenolpyruvate synthase (PEPS, EC: 2.7.9.2) help generate ATP from AMP coupled to PEP as a substrate. Here we demonstrate an inexpensive and effective electrophoretic technology to determine the activities of these enzymes by blue native polyacrylamide gel electrophoresis (BN-PAGE). The generation of pyruvate is linked to exogenous lactate dehydrogenase (LDH), and the oxidation of reduced nicotinamide adenine dinucleotide (NADH) coupled to 2,6-dichloroindophenol (DCIP) and iodonitrotetrazolium chloride (INT) results in a formazan precipitate which is easily quantifiable. The selectivity of the enzymes is ensured by including either AMP or ADP and pyrophosphate (PP(i) ) or inorganic phosphate (P(i) ). Activity bands were readily obtained after incubation in the respective reaction mixtures for 20-30 min. Cell-free extract concentrations as low as 20 MUg protein equivalent yielded activity bands and substrate levels were manipulated to optimize sensitivity of this analytical technique. High-pressure liquid chromatography (HPLC), two-dimensional (2-D) SDS-PAGE (where SDS is sodium dodecyl sulfate), and immunoblot studies of the excised activity band help further characterize these PEP-dependent kinases. Furthermore, these enzymes were readily identified on the same gel by incubating it sequentially in the respective reaction mixtures. This technique provides a facile method to elucidate these kinases in biological systems. PMID- 22539314 TI - Analysis of alpha-1-acid glycoprotein isoforms using CE-LIF with fluorescent thiol derivatization. AB - The analysis of glycoprotein isoforms is of high interest in the biomedical field and clinical chemistry. Many studies have demonstrated that some glycoprotein isoforms could serve as biomarkers for several major diseases, such as cancers and vascular diseases, among others. Capillary zone electrophoresis (CZE) is a well-established technique to separate glycoprotein isoforms, however, it suffers from limited sensitivity when UV-Vis detection is used. On the other hand, with laser-induced fluorescence (LIF) detection, derivatization reaction to render the proteins fluorescent can destroy the resolution of the isoforms. In this work, a derivatization procedure through the thiol groups of glycoproteins using either 5 (iodoacetamide) fluorescein (5-IAF) or BODIPY iodoacetamide is presented with the model protein of alpha-1-acid glycoprotein (AGP). The derivatization process presented enabled high-resolution analysis of AGP isoforms by CZE-LIF. The derivatization procedure was successfully applied to label AGP from samples of serum and secretome of artery tissue, enabling the separation of the AGP isoforms by CE-LIF in natural samples at different concentration levels. PMID- 22539315 TI - Cationic detergents enable the separation of membrane proteins of Plasmodium falciparum-infected erythrocytes by 2D gel electrophoresis. AB - The intraerythrocytic stage of Plasmodium falciparum alters the characteristics of its host cell by exporting selected plasmodial proteins. Although it is clear that the physicochemical and immunobiological properties of the host cell are modulated during parasite development, the involved plasmodial proteins and their mode of action are not completely known. Using cetyltrimethylammonium bromide (CTAB) or benzyldimethyl-n-hexadecylammonium chloride (16-BAC) for the first dimension and SDS for the second dimension, we separated proteins from membranes of human erythrocytes and of erythrocytes infected with the malaria parasite P. falciparum. Protein spots were analyzed by MALDI-TOF/TOF MS and annotated in respective 2D master gels. By using the alternative 2D approach, characteristic host cell membrane proteins and, more importantly, membrane-associated and exported plasmodial proteins were identified that might play a role in parasite induced host cell modulation. PMID- 22539316 TI - Proteomics study of rice embryogenesis: discovery of the embryogenesis-dependent globulins. AB - The plant embryo is the germination center of the seed. How an embryo forms during seed maturation remains unclear, especially in the case of monocotyledonous plants. Generally, the complex processes of embryogenesis result from the action of a coordinated network of genes. Thus, a large-scale survey of changes in protein abundance during embryogenesis is an effective approach to study the molecular events of embryogenesis. In this study, two-dimensional gel electrophoresis (2DE) was applied to separate rice embryo proteins collected during the three phases of embryogenesis: 6 days after pollination (DAP), 12 DAP, and 18 DAP. We then employed matrix-assisted laser desorption-ionization time of flight/time of flight mass spectrometry(MALDI TOF/TOF MS) to identify the phase dependent differential 2DE spots. A total of 66 spots were discovered to be regulated during embryogenesis, and of these spots, 53 spots were identified. These proteins were further categorized into several functional classes, including storage, embryo development, stress response, glycolysis, and protein metabolism. Intriguingly, the major differential spots originated from three globulins. We further examined the possible mechanism underlying the globulins' multiple forms using Western blotting, proteolysis, and blue native gel electrophoresis techniques and found that the multiple forms of globulins were produced as a result of enhanced proteolysis during embryogenesis, indicating that these globulin forms may serve as chaperone proteins participating in the formation of multiple protein complexes during embryogenesis. PMID- 22539317 TI - Proteomic investigation of anti-tumor activities exerted by sinularin against A2058 melanoma cells. AB - The extracts from soft corals have been increasingly investigated for biomedical and therapeutic purposes. The aim of this study is to examine and analyze the anti-tumor effects of the genus Sinularia extract sinularin on A2058 melanoma cells using MTT assay, cell migration assay, wound healing assay, flow cytometric analysis, and proteomic analysis. Sinularin dose-dependently (1-5 MUg/mL) inhibited melanoma cell proliferation while the treatment at identical concentrations suppressed cell migration. Sinularin dose-dependently enhanced apoptotic melanoma cells and caused tumor cell accumulation at G2/M phase, indicating that sinularin exerts apoptosis-induced and cell cycle-delayed activities in A2058 melanoma cells. Comparative proteomic analysis was conducted to investigate the effects of sinularin at the molecular level by comparison between the protein profiling of melanoma cells treated with sinularin and without the treatment. Thirty-five differential proteins (13 upregulated and 22 downregulated) concerning the treatment were identified by liquid chromatography tandem mass spectrometry. Proteomic data and Western blot displayed the levels of several tumor inhibitory or apoptosis-associated proteins including annexin A1, voltage-dependent anion-selective channel protein 1 and prohibitin (upregulated), heat shock protein 60, heat shock protein beta-1, and peroxiredoxin-2 (downregulated) in A2058 melanoma cells exposed to sinularin. Increased expression of p53, cleaved-caspase-3, cleaved-caspase-8, cleaved-caspase-9, p21, and Bax and decreased expression of Bcl-2 in sinularin-treated melanoma cells suggest that the anti-tumor activities of sinularin against melanoma cells are particularly correlated with these pro-apoptotic factors. These data provide important information for the mechanisms of anti-tumor effects of sinularin on melanoma cells and may be helpful for drug development and progression monitoring of human melanoma. PMID- 22539318 TI - Separation of multiply charged anions by capillary electrophoresis using alkyl phosphonium pairing agents. AB - Two newly developed UV transparent phosphonium-based cationic reagents were evaluated as background electrolyte additives for capillary electrophoresis for the separation of multiply charged anions, including several complex anions. These cationic reagents showed moderate suppression of the electroosmotic flow, interacted with the analytes to improve their separation and often improved the peak shape. The effects of the additives and their concentration on the separation were studied, as well as the buffer type, pH, and voltage. The dicationic reagent effectively separated eight divalent anions within 17 min and the tetracationic reagent best separated nine trivalent anions, as well as a mixture of all the anions. PMID- 22539319 TI - Separation principles of cycling temperature capillary electrophoresis. AB - High throughput means to detect and quantify low-frequency mutations (<10(-2) ) in the DNA-coding sequences of human tissues and pathological lesions are required to discover the kinds, numbers, and rates of genetic mutations that (i) confer inherited risk for disease or (ii) arise in somatic tissues as events required for clonal diseases such as cancers and atherosclerotic plaque.While throughput of linear DNA sequencing methods has increased dramatically, such methods are limited by high error rates (>10(-3) ) rendering them unsuitable for the detection of low-frequency risk-conferring mutations among the many neutral mutations carried in the general population or formed in tissue growth and development. In contrast, constant denaturing capillary electrophoresis (CDCE), coupled with high-fidelity PCR, achieved a point mutation detection limit of <10( 5) in exon-sized sequences from human tissue or pooled blood samples. However, increasing CDCE throughput proved difficult due to the need for precise temperature control and the time-consuming optimization steps for each DNA sequence probed. Both of these problems have been solved by the method of cycling temperature capillary electrophoresis (CTCE). The data presented here provide a deeper understanding of the separation principles involved in CTCE and address several elements of a previously presented two-state transport model. PMID- 22539320 TI - A chemometric approach for the elucidation of the parameter impact in the hyphenation of field-enhanced sample injection and sweeping in capillary electrophoresis. AB - The aim of this work was to elucidate the impacts of parameters influencing cation-selective exhaustive injection coupled to sweeping and micellar electrokinetic chromatography (MEKC). A chemometric approach using cationic compounds, acidic conditions (phosphate buffer, pH 2.3) and polyacrylamide-coated capillaries to suppress electroosmotic flow were used. It was demonstrated that the water plug was not useful because of long electrokinetic injections. If conductivity of the high conductivity buffer (HCB) and the HCB to sample conductivity ratio are sufficiently high (>1.66 S/m and >30, respectively), variations of HCB conductivity do not impact sensitivity. The length of the HCB must be long enough so that the most mobile cation remains stacked in this zone for a given injection time. SDS concentration should be as high as possible (the maximum concentration is dictated by MEKC, here 90 mM), so sensitivity is not impacted. We have shown analytes can be lost after electrokinetic injection, when the polarity of the voltage is reversed. Introducing a plug of micellar electrolyte before polarity reversal avoids these losses. Following these recommendations only injection time and sample conductivity impacted sensitivity enhancement. Sample conductivity had to be the lowest as possible and controlled in real case analyses to obtain repeatable enrichment factors. PMID- 22539321 TI - Electroosmotic flow modulation in capillary electrophoresis by organic cations from ionic liquids. AB - This paper describes the ability of several ionic liquids cations for electroosmotic flow modulation in capillary electrophoresis. Organic salts based on phosphonium, sulfonium, cysteinium, ammonium, and guanidinium cations were selected to study this property. In addition, the synergistic effect of these compounds in cyclodextrin chiral separation was also evaluated. In comparison with most studied imidazolium-based ionic liquids, several of the cations studied, are stronger modifiers in terms of electroosmotic flow (EOF) modulation. Phosphonium-based compounds and tri-octyl methylammonium chloride ([Aliquat]Cl) had the strongest ability to reverse EOF both in acidic and in basic conditions and had the lowest EOF reversal concentrations in the presence of hydroxypropyl beta-cyclodextrin. EOF modulation ability of phosphonium cations also contributed to the improvement of chiral separation of DL-propranolol by hydroxypropyl-beta cyclodextrin at lower concentrations in comparison with most commonly used EOF modulators such as tetrabutylammonium phosphate. PMID- 22539322 TI - Bi-directional flow induced by an AC electroosmotic micropump with DC voltage bias. AB - This paper discusses the principle of biased alternating current electroosmosis (ACEO) and its application to move the bulk fluid in a microchannel, as an alternative to mechanical pumping methods. Previous EO-driven flow research has looked at the effect of electrode asymmetry and transverse traveling wave forms on the performance of electroosmotic pumps. This paper presents an analysis that was conducted to assess the effect of combining an AC signal with a DC (direct current) bias when generating the electric field needed to impart electroosmosis (EO) within a microchannel. The results presented here are numerical and experimental. The numerical results were generated through simulations performed using COMSOL 3.5a. Currently available theoretical models for EO flows were embedded in the software and solved numerically to evaluate the effects of channel geometry, frequency of excitation, electrode array geometry, and AC signal with a DC bias on the flow imparted on an electrically conducting fluid. Simulations of the ACEO flow driven by a constant magnitude of AC voltage over symmetric electrodes did not indicate relevant net flows. However, superimposing a DC signal over the AC signal on the same symmetric electrode array leads to a noticeable net forward flow. Moreover, changing the polarity of electrical signal creates a bi-directional flow on symmetrical electrode array. Experimental flow measurements were performed on several electrode array configurations. The mismatch between the numerical and experimental results revealed the limitations of the currently available models for the biased EO. However, they confirm that using a symmetric electrode array excited by an AC signal with a DC bias leads to a significant improvement in flow rates in comparison to the flow rates obtained in an asymmetric electrode array configuration excited just with an AC signal. PMID- 22539323 TI - Microchip electrophoresis coupled with on-line magnetic separation and chemiluminescence detection for multiplexed immunoassay. AB - A facile and universal strategy for multiplexed immunoassay is proposed. The strategy is based on microchip electrophoresis (MCE) coupled with on-line magnetic separation and chemiluminescence (CL) detection. The system consisted of a microchip, an electromagnet, and a photomultiplier. The realization of multiplexed immunoassay protocol involves sampling magnetic nanoparticles (MNPs) labeled antibodies, N-(4-aminobutyl)-N-ethyl-isoluminol (ABEI) labeled antigens and free antigens in the precolumn reactor, on-line immunoreaction, capturing the MNPs-immunocomplexes, and the separation of unconjugated ABEI-labeled antigens. After on-line magnetic separation, the free ABEI-labeled antigens were transported into the separation channel, and mixed with hydrogen peroxide (H(2) O(2) ) in the presence of horseradish peroxidase in the postcolumn reactor, and producing CL emission. Using this arrangement, multiple analytes could be measured simultaneously by performing the technical operations for a single assay. As a proof-of-concept, the multiplexed immunoassay was evaluated for the simultaneous determination of five model analytes (i.e. hydrocortisone, corticosterone, digoxin, testosterone, and estriol). The results exhibited excellent precision and sensitivity, the relative standard deviations for nine times detection were lower than 4.7% for all the five components, and the detection limits of five analytes were in the range of 3.6-4.9 nM. The MCE system was validated using two human serum-based control samples containing five analytes. PMID- 22539324 TI - High-performance capillary electrophoretic separation of double-stranded oligonucleotides using a poly-(ethylpyrrolidine methacrylate-co methylmethacrylate)-coated capillary. AB - Here we describe a capillary electrophoretic method for the separation of double stranded oligonucleotides (ds-ODNs) ranging from 16-20 bp with 2 bp resolution using a low concentration of poly(ethylpyrrolidine methacrylate-co-methyl methacrylate) (PEPyM-co-PMMA) copolymer physically adsorbed to a capillary surface. Contrary to traditional DNA separations, we show that the ds-ODN with the highest molecular size eluted first and propose that this phenomena is due to a screening effect by the PEPyM-co-PMMA coating on the smaller ds-ODNs negative charge during elution. Key to the performance of this separation was a sample preparation time of less than 1 h and analysis time of 40 min. Repeatability of intraday migration time for the mixtures was typically < 1% relative standard deviation (n = 3). In addition, we demonstrate that the coating has an acceptable capillary lifetime of over 70 injections. PMID- 22539325 TI - Designing of sequencing assay assisted by capillary electrophoresis based on DNA folding analysis: an application to the VCAM1 gene. AB - In this work, we describe a fast standardized molecular method for DNA sequencing assisted by capillary electrophoresis with a particular emphasis on bioinformatic approaches to avoid sequencing errors due to complex DNA regions. In this case, the method was applied on the human vascular adhesion molecule 1 (VCAM1) gene. VCAM1 sequence, in fact, shows many thermodynamically critical parameters such as very low GC content (30-40%), many nucleotide stack areas, i.e. hairpins, self complementary regions. With a traditional primer design approach it was difficult to design correct PCR oligonucleotides, thus sometimes, the chromatogram showed an illegible profile. By a strategy involving various bioinformatic tools (Mfold, Oligo, Highter), we investigated the role of the DNA-folding analysis in the assistance of primer design for the DNA sequencing of fragments with high -DeltaG stem-loop regions. This new approach allowed us to sequence nine different VCAM1 regions each containing the respective exon. Our results, based on different DNA samples recruited from oral brushes taken from ten different subjects, identified four different SNPs (c.662-7C/T, c.1793-79A>G, c.2079C/T, c.2208A>G) with high reproducibility. PMID- 22539326 TI - An improved silver stain for the visualization of lipopolysaccharides on polyacrylamide gels. AB - A sensitive, brief, and user-friendly silver stain to meet the needs in high efficiency detection of lipopolysaccharides (LPS) on polyacrylamide gels is described. In this study, the most commonly used formaldehyde-based LPS silver stain, which is potentially hazardous to the operator, is replaced by ascorbic acid (Vc) in alkaline sodium thiosulfate solution. It takes only about 35 min to complete all the protocol, with a detection limit of 4 ng of total LPS. The results indicate that this user-friendly method could be a good choice for LPS visualization on polyacrylamide gels. PMID- 22539332 TI - A short-term testing effect in cross-language recognition. AB - Taking a memory test after an initial study phase produces better long-term retention than restudying the items, a phenomenon known as the testing effect. We propose that this effect emerges because testing strengthens semantic features of items' memory traces, whereas restudying strengthens surface features of items' memory traces. This novel account predicts that a testing effect should be observed even after a short retention interval when a language switch occurs between the learning phase and the final test phase. We assessed this prediction with Dutch-English bilinguals who learned Dutch Deese-Roediger-McDermott word lists through restudying or through testing (retrieval practice). Five minutes after this learning phase, they took a recognition test in Dutch (within-language condition) or in English (across-language condition). We observed a testing effect in the across-language condition, but not in the within-language condition. These findings corroborate our novel account of the testing effect. PMID- 22539333 TI - Discrimination and categorization of actions by pigeons. AB - Recognizing and categorizing behavior is essential for animals (e.g., during mate selection, courtship, and avoidance of predators). In a study examining if and how animals classify different actions, a go/no-go procedure was used to train 4 pigeons to discriminate among "walking" and "running" digital animal models (each portrayed from 12 different viewpoints). Action discrimination acquired for two models significantly transferred to six novel animal models moving in novel and biomechanically characteristic ways. Randomization of frame order in the animated sequences, stimulus inversion, and static presentation all disrupted this discrimination, whereas changes in the direction and speed (both increases and decreases) of the actions did not. These results suggest that the pigeons discriminated the behaviors on the basis of generalized recognition of the models' sequence of poses across time and provide the best evidence yet that animals use action categories to identify contrasting behavioral units. PMID- 22539334 TI - Instrumentality boosts appreciation: helpers are more appreciated while they are useful. AB - We propose that in social interactions, appreciation of a helper depends on that helper's instrumentality: The more motivated one is to accomplish a goal, and the more one perceives a helper as able to facilitate that goal, the more appreciation one will feel for that helper. Four experiments supported this instrumentality-boost hypothesis by showing that beneficiaries felt more appreciation of their helpers while they were receiving help toward an ongoing task than after that task was completed or after the helper was deemed no longer instrumental. This finding held for both the positive side of appreciation (gratitude) and the negative side (feelings of indebtedness) and also across a range of relationships (complete strangers, newly acquainted partners, and friends). This pattern of appreciation is counterintuitive for helpers, and so a mismatch arises between the time courses of beneficiaries' experienced appreciation and helpers' expectations of appreciation. PMID- 22539335 TI - The causal role of phoneme awareness and letter-sound knowledge in learning to read: combining intervention studies with mediation analyses. AB - There is good evidence that phoneme awareness and letter-sound knowledge are reliable longitudinal predictors of learning to read, though whether they have a causal effect remains uncertain. In this article, we present the results of a mediation analysis using data from a previous large-scale intervention study. We found that a phonology and reading intervention that taught letter-sound knowledge and phoneme awareness produced significant improvements in these two skills and in later word-level reading and spelling skills. Improvements in letter-sound knowledge and phoneme awareness at the end of the intervention fully mediated the improvements seen in children's word-level literacy skills 5 months after the intervention finished. Our findings support the conclusion that letter sound knowledge and phoneme awareness are two causal influences on the development of children's early literacy skills. PMID- 22539337 TI - Modeling zeolites with metal-supported two-dimensional aluminosilicate films. PMID- 22539336 TI - Further delineation of CANT1 phenotypic spectrum and demonstration of its role in proteoglycan synthesis. AB - Desbuquois dysplasia (DD) is characterized by antenatal and postnatal short stature, multiple dislocations, and advanced carpal ossification. Two forms have been distinguished on the basis of the presence (type 1) or the absence (type 2) of characteristic hand anomalies. We have identified mutations in calcium activated nucleotidase 1 gene (CANT1) in DD type 1. Recently, CANT1 mutations have been reported in the Kim variant of DD, characterized by short metacarpals and elongated phalanges. DD has overlapping features with spondyloepiphyseal dysplasia with congenital joint dislocations (SDCD) due to Carbohydrate (chondroitin 6) Sulfotransferase 3 (CHST3) mutations. We screened CANT1 and CHST3 in 38 DD cases (6 type 1 patients, 1 Kim variant, and 31 type 2 patients) and found CANT1 mutations in all DD type 1 cases, the Kim variant and in one atypical DD type 2 expanding the clinical spectrum of hand anomalies observed with CANT1 mutations. We also identified in one DD type 2 case CHST3 mutation supporting the phenotype overlap with SDCD. To further define function of CANT1, we studied proteoglycan synthesis in CANT1 mutated patient fibroblasts, and found significant reduced GAG synthesis in presence of beta-D-xyloside, suggesting that CANT1 plays a role in proteoglycan metabolism. PMID- 22539338 TI - Predicting poor physical performance after total knee arthroplasty. AB - The purpose of this study was to develop a preliminary decision algorithm predicting functional performance outcomes to aid in the decision of when to undergo total knee arthroplasty (TKA). One hundred and nineteen patients undergoing primary unilateral TKA were evaluated before and 6 months after TKA. A regression tree analysis using a recursive partitioning function was performed with the Timed Up and Go (TUG) time, Six-Minute Walk (6MW) distance, and Stair Climbing Test (SCT) time as measured 6 months after TKA as the primary outcomes. Preoperative measures of functional performance, joint performance, anthropometrics, demographics, and self-reported status were evaluated as predictors of the primary outcomes 6 months after surgery. Individuals taking >=10.1 s on the TUG and aged 72 years or older before surgery had the poorest performance on the TUG 6 months after surgery. Individuals walking <314 meters on the 6MW before surgery had the poorest performance on the 6MW test 6 months after surgery. Individuals taking >=17 s to complete the SCT and scoring <40 on the SF 36 mental component score before surgery had the poorest performance on the SCT 6 months after surgery. Poorer performance preoperatively on the 6MW, SCT, and TUG, was related to poorer performance in the same measure after TKA. Age and decreased mental health were secondary predictors of poorer performance at 6 months on the TUG and SCT, respectively. These measures may help further develop models predicting thresholds for poor outcomes after TKA. PMID- 22539339 TI - Radiotherapy and temozolomide in anaplastic astrocytoma: a retrospective multicenter study by the Central Nervous System Study Group of AIRO (Italian Association of Radiation Oncology). AB - Although the evidence for the benefit of adding temozolomide (TMZ) to radiotherapy (RT) is limited to glioblastoma patients, there is currently a trend toward treating anaplastic astrocytomas (AAs) with combined RT + TMZ. The aim of the present study was to describe the patterns of care of patients affected by AA and, particularly, to compare the outcome of patients treated exclusively with RT with those treated with RT + TMZ. Data of 295 newly diagnosed AAs treated with postoperative RT +/- TMZ in the period from 2002 to 2007 were reviewed. More than 75% of patients underwent a surgical removal. All the patients had postoperative RT; 86.1% of them were treated with 3D-conformal RT (3D-CRT). Sixty-seven percent of the entire group received postoperative chemotherapy with TMZ (n = 198). One hundred sixty-six patients received both concomitant and sequential TMZ. Prescription of postoperative TMZ increased in the most recent period (2005 2007). One- and 4-year survival rates were 70.2% and 28.6%, respectively. No statistically significant improvement in survival was observed with the addition of TMZ to RT (P = .59). Multivariate analysis showed the statistical significance of age, presence of seizures, Recursive Partitioning Analysis classes I-III, extent of surgical removal, and 3D-CRT. Changes in the care of AA over the past years are documented. Currently there is not evidence to justify the addition of TMZ to postoperative RT for patients with newly diagnosed AA outside a clinical trial. Results of prospective and randomized trials are needed. PMID- 22539340 TI - LTBP2 mutations cause Weill-Marchesani and Weill-Marchesani-like syndrome and affect disruptions in the extracellular matrix. AB - Latent transforming growth factor (TGF) beta-binding protein 2 (LTBP2) is an extracellular matrix (ECM) protein that associates with fibrillin-1 containing microfibrils. Various factors prompted considering LTBP2 in the etiology of isolated ectopia lentis and associated conditions such as Weill-Marchesani syndrome (WMS) and Marfan syndrome (MFS). LTBP2 was screened in 30 unrelated Iranian patients. Mutations were found only in one WMS proband and one MFS proband. Homozygous c.3529G>A (p.Val1177Met) was shown to cause autosomal recessive WMS or WM-like syndrome by several approaches, including homozygosity mapping. Light, fluorescent, and electron microscopy evidenced disruptions of the microfibrillar network in the ECM of the proband's skin. In conjunction with recent findings regarding other ECM proteins, the results presented strongly support the contention that anomalies in WMS patients are due to disruptions in the ECM. Heterozygous c.1642C >T (p.Arg548*) possibly contributed to MFS-related phenotypes, including ocular manifestations, mitral valve prolapse, and pectus excavatum, but was not cause of MFS. PMID- 22539341 TI - Pteros: fast and easy to use open-source C++ library for molecular analysis. AB - An open-source Pteros library for molecular modeling and analysis of molecular dynamics trajectories for C++ programming language is introduced. Pteros provides a number of routine analysis operations ranging from reading and writing trajectory files and geometry transformations to structural alignment and computation of nonbonded interaction energies. The library features asynchronous trajectory reading and parallel execution of several analysis routines, which greatly simplifies development of computationally intensive trajectory analysis algorithms. Pteros programming interface is very simple and intuitive while the source code is well documented and easily extendible. Pteros is available for free under open-source Artistic License from http://sourceforge.net/projects/pteros/. PMID- 22539344 TI - Increased activation of hereditary pancreatitis-associated human cationic trypsinogen mutants in presence of chymotrypsin C. AB - Mutations in human cationic trypsinogen (PRSS1) cause autosomal dominant hereditary pancreatitis. Increased intrapancreatic autoactivation of trypsinogen mutants has been hypothesized to initiate the disease. Autoactivation of cationic trypsinogen is proteolytically regulated by chymotrypsin C (CTRC), which mitigates the development of trypsin activity by promoting degradation of both trypsinogen and trypsin. Paradoxically, CTRC also increases the rate of autoactivation by processing the trypsinogen activation peptide to a shorter form. The aim of this study was to investigate the effect of CTRC on the autoactivation of clinically relevant trypsinogen mutants. We found that in the presence of CTRC, trypsinogen mutants associated with classic hereditary pancreatitis (N29I, N29T, V39A, R122C, and R122H) autoactivated at increased rates and reached markedly higher active trypsin levels compared with wild-type cationic trypsinogen. The A16V mutant, known for its variable disease penetrance, exhibited a smaller increase in autoactivation. The mechanistic basis of increased activation was mutation-specific and involved resistance to degradation (N29I, N29T, V39A, R122C, and R122H) and/or increased N-terminal processing by CTRC (A16V and N29I). These observations indicate that hereditary pancreatitis is caused by CTRC-dependent dysregulation of cationic trypsinogen autoactivation, which results in elevated trypsin levels in the pancreas. PMID- 22539343 TI - Tau isoform composition influences rate and extent of filament formation. AB - The risk of developing tauopathic neurodegenerative disease depends in part on the levels and composition of six naturally occurring Tau isoforms in human brain. These proteins, which form filamentous aggregates in disease, vary only by the presence or absence of three inserts encoded by alternatively spliced exons 2, 3, and 10 of the Tau gene (MAPT). To determine the contribution of alternatively spliced segments to Tau aggregation propensity, the aggregation kinetics of six unmodified, recombinant human Tau isoforms were examined in vitro using electron microscopy assay methods. Aggregation propensity was then compared at the level of elementary rate constants for nucleation and extension phases. We found that all three alternatively spliced segments modulated Tau aggregation but through differing kinetic mechanisms that could synergize or compete depending on sequence context. Overall, segments encoded by exons 2 and 10 promoted aggregation, whereas the segment encoded by exon 3 depressed it with its efficacy dependent on the presence or absence of a fourth microtubule binding repeat. In general, aggregation propensity correlated with genetic risk reported for multiple tauopathies, implicating aggregation as one candidate mechanism rationalizing the correlation between Tau expression patterns and disease. PMID- 22539346 TI - Role of phosphatidylinositol clathrin assembly lymphoid-myeloid leukemia (PICALM) in intracellular amyloid precursor protein (APP) processing and amyloid plaque pathogenesis. AB - One of the pathological hallmarks of Alzheimer disease is the accumulation of amyloid plaques in the extracellular space in the brain. Amyloid plaques are primarily composed of aggregated amyloid beta peptide (Abeta), a proteolytic fragment of the transmembrane amyloid precursor protein (APP). For APP to be proteolytically cleaved into Abeta, it must be internalized into the cell and trafficked to endosomes where specific protease complexes can cleave APP. Several recent genome-wide association studies have reported that several single nucleotide polymorphisms (SNPs) in the phosphatidylinositol clathrin assembly lymphoid-myeloid leukemia (PICALM) gene were significantly associated with Alzheimer disease, suggesting a role in APP endocytosis and Abeta generation. Here, we show that PICALM co-localizes with APP in intracellular vesicles of N2a APP cells after endocytosis is initiated. PICALM knockdown resulted in reduced APP internalization and Abeta generation. Conversely, PICALM overexpression increased APP internalization and Abeta production. In vivo, PICALM was found to be expressed in neurons and co-localized with APP throughout the cortex and hippocampus in APP/PS1 mice. PICALM expression was altered using AAV8 gene transfer of PICALM shRNA or PICALM cDNA into the hippocampus of 6-month-old APP/PS1 mice. PICALM knockdown decreased soluble and insoluble Abeta levels and amyloid plaque load in the hippocampus. Conversely, PICALM overexpression increased Abeta levels and amyloid plaque load. These data indicate that PICALM, an adaptor protein involved in clathrin-mediated endocytosis, regulates APP internalization and subsequent Abeta generation. PICALM contributes to amyloid plaque load in brain likely via its effect on Abeta metabolism. PMID- 22539345 TI - Modulation of ceramide synthase activity via dimerization. AB - Ceramide, the backbone of all sphingolipids, is synthesized by a family of ceramide synthases (CerS) that each use acyl-CoAs of defined chain length for N acylation of the sphingoid long chain base. CerS mRNA expression and enzymatic activity do not always correlate with the sphingolipid acyl chain composition of a particular tissue, suggesting post-translational mechanism(s) of regulation of CerS activity. We now demonstrate that CerS activity can be modulated by dimer formation. Under suitable conditions, high M(r) CerS complexes can be detected by Western blotting, and various CerS co-immunoprecipitate. CerS5 activity is inhibited in a dominant-negative fashion by co-expression with catalytically inactive CerS5, and CerS2 activity is enhanced by co-expression with a catalytically active form of CerS5 or CerS6. In a constitutive heterodimer comprising CerS5 and CerS2, the activity of CerS2 depends on the catalytic activity of CerS5. Finally, CerS dimers are formed upon rapid stimulation of ceramide synthesis by curcumin. Together, these data demonstrate that ceramide synthesis can be regulated by the formation of CerS dimers and suggest a novel way to generate the acyl chain composition of ceramide (and downstream sphingolipids), which may depend on the interaction of CerS with each other. PMID- 22539347 TI - Characterization of gut-associated cathepsin D hemoglobinase from tick Ixodes ricinus (IrCD1). AB - To identify the gut-associated tick aspartic hemoglobinase, this work focuses on the functional diversity of multiple Ixodes ricinus cathepsin D forms (IrCDs). Out of three encoding genes representing Ixodes scapularis genome paralogs, IrCD1 is the most distinct enzyme with a shortened propeptide region and a unique pattern of predicted post-translational modifications. IrCD1 gene transcription is induced by tick feeding and is restricted to the gut tissue. The hemoglobinolytic role of IrCD1 was further supported by immunolocalization of IrCD1 in the vesicles of tick gut cells. Properties of recombinantly expressed rIrCD1 are consistent with the endo-lysosomal environment because the zymogen is autoactivated and remains optimally active in acidic conditions. Hemoglobin cleavage pattern of rIrCD1 is identical to that produced by the native enzyme. The preference for hydrophobic residues at the P1 and P1' position was confirmed by screening a novel synthetic tetradecapeptidyl substrate library. Outside the S1-S1' regions, rIrCD1 tolerates most amino acids but displays a preference for tyrosine at P3 and alanine at P2'. Further analysis of the cleavage site location within the peptide substrate indicated that IrCD1 is a true endopeptidase. The role in hemoglobinolysis was verified with RNAi knockdown of IrCD1 that decreased gut extract cathepsin D activity by >90%. IrCD1 was newly characterized as a unique hemoglobinolytic cathepsin D contributing to the complex intestinal proteolytic network of mainly cysteine peptidases in ticks. PMID- 22539348 TI - Isonicotinamide enhances Sir2 protein-mediated silencing and longevity in yeast by raising intracellular NAD+ concentration. AB - Sirtuins are an evolutionarily conserved family of NAD(+)-dependent protein deacetylases that function in the regulation of gene transcription, cellular metabolism, and aging. Their activity requires the maintenance of an adequate intracellular NAD(+) concentration through the combined action of NAD(+) biosynthesis and salvage pathways. Nicotinamide (NAM) is a key NAD(+) precursor that is also a byproduct and feedback inhibitor of the deacetylation reaction. In Saccharomyces cerevisiae, the nicotinamidase Pnc1 converts NAM to nicotinic acid (NA), which is then used as a substrate by the NAD(+) salvage pathway enzyme NA phosphoribosyltransferase (Npt1). Isonicotinamide (INAM) is an isostere of NAM that stimulates yeast Sir2 deacetylase activity in vitro by alleviating the NAM inhibition. In this study, we determined that INAM stimulates Sir2 through an additional mechanism in vivo, which involves elevation of the intracellular NAD(+) concentration. INAM enhanced normal silencing at the rDNA locus but only partially suppressed the silencing defects of an npt1Delta mutant. Yeast cells grown in media lacking NA had a short replicative life span, which was extended by INAM in a SIR2-dependent manner and correlated with increased NAD(+). The INAM induced increase in NAD(+) was strongly dependent on Pnc1 and Npt1, suggesting that INAM increases flux through the NAD(+) salvage pathway. Part of this effect was mediated by the NR salvage pathways, which generate NAM as a product and require Pnc1 to produce NAD(+). We also provide evidence suggesting that INAM influences the expression of multiple NAD(+) biosynthesis and salvage pathways to promote homeostasis during stationary phase. PMID- 22539349 TI - Highly potent inhibitors of proprotein convertase furin as potential drugs for treatment of infectious diseases. AB - Optimization of our previously described peptidomimetic furin inhibitors was performed and yielded several analogs with a significantly improved activity. The most potent compounds containing an N-terminal 4- or 3 (guanidinomethyl)phenylacetyl residue inhibit furin with K(i) values of 16 and 8 pM, respectively. These analogs inhibit other proprotein convertases, such as PC1/3, PC4, PACE4, and PC5/6, with similar potency, whereas PC2, PC7, and trypsin like serine proteases are poorly affected. Incubation of selected compounds with Madin-Darby canine kidney cells over a period of 96 h revealed that they exhibit great stability, making them suitable candidates for further studies in cell culture. Two of the most potent derivatives were used to inhibit the hemagglutinin cleavage and viral propagation of a highly pathogenic avian H7N1 influenza virus strain. The treatment with inhibitor 24 (4 (guanidinomethyl)phenylacetyl-Arg-Val-Arg-4-amidinobenzylamide) resulted in significantly delayed virus propagation compared with an inhibitor-free control. The same analog was also effective in inhibiting Shiga toxin activation in HEp-2 cells. This antiviral effect, as well as the protective effect against a bacterial toxin, suggests that inhibitors of furin or furin-like proprotein convertases could represent promising lead structures for future drug development, in particular for the treatment of infectious diseases. PMID- 22539350 TI - Expression of mitochondrial non-coding RNAs (ncRNAs) is modulated by high risk human papillomavirus (HPV) oncogenes. AB - The study of RNA and DNA oncogenic viruses has proved invaluable in the discovery of key cellular pathways that are rendered dysfunctional during cancer progression. An example is high risk human papillomavirus (HPV), the etiological agent of cervical cancer. The role of HPV oncogenes in cellular immortalization and transformation has been extensively investigated. We reported the differential expression of a family of human mitochondrial non-coding RNAs (ncRNAs) between normal and cancer cells. Normal cells express a sense mitochondrial ncRNA (SncmtRNA) that seems to be required for cell proliferation and two antisense transcripts (ASncmtRNAs). In contrast, the ASncmtRNAs are down regulated in cancer cells. To shed some light on the mechanisms that trigger down regulation of the ASncmtRNAs, we studied human keratinocytes (HFK) immortalized with HPV. Here we show that immortalization of HFK with HPV-16 or 18 causes down regulation of the ASncmtRNAs and induces the expression of a new sense transcript named SncmtRNA-2. Transduction of HFK with both E6 and E7 is sufficient to induce expression of SncmtRNA-2. Moreover, E2 oncogene is involved in down-regulation of the ASncmtRNAs. Knockdown of E2 in immortalized cells reestablishes in a reversible manner the expression of the ASncmtRNAs, suggesting that endogenous cellular factors(s) could play functions analogous to E2 during non-HPV-induced oncogenesis. PMID- 22539351 TI - Ceramide levels regulated by carnitine palmitoyltransferase 1C control dendritic spine maturation and cognition. AB - The brain-specific isoform carnitine palmitoyltransferase 1C (CPT1C) has been implicated in the hypothalamic regulation of food intake and energy homeostasis. Nevertheless, its molecular function is not completely understood, and its role in other brain areas is unknown. We demonstrate that CPT1C is expressed in pyramidal neurons of the hippocampus and is located in the endoplasmic reticulum throughout the neuron, even inside dendritic spines. We used molecular, cellular, and behavioral approaches to determine CPT1C function. First, we analyzed the implication of CPT1C in ceramide metabolism. CPT1C overexpression in primary hippocampal cultured neurons increased ceramide levels, whereas in CPT1C deficient neurons, ceramide levels were diminished. Correspondingly, CPT1C knock out (KO) mice showed reduced ceramide levels in the hippocampus. At the cellular level, CPT1C deficiency altered dendritic spine morphology by increasing immature filopodia and reducing mature mushroom and stubby spines. Total protrusion density and spine head area in mature spines were unaffected. Treatment of cultured neurons with exogenous ceramide reverted the KO phenotype, as did ectopic overexpression of CPT1C, indicating that CPT1C regulation of spine maturation is mediated by ceramide. To study the repercussions of the KO phenotype on cognition, we performed the hippocampus-dependent Morris water maze test on mice. Results show that CPT1C deficiency strongly impairs spatial learning. All of these results demonstrate that CPT1C regulates the levels of ceramide in the endoplasmic reticulum of hippocampal neurons, and this is a relevant mechanism for the correct maturation of dendritic spines and for proper spatial learning. PMID- 22539353 TI - A novel classification system to predict the pathogenic effects of CHD7 missense variants in CHARGE syndrome. AB - CHARGE syndrome is characterized by the variable occurrence of multisensory impairment, congenital anomalies, and developmental delay, and is caused by heterozygous mutations in the CHD7 gene. Correct interpretation of CHD7 variants is essential for genetic counseling. This is particularly difficult for missense variants because most variants in the CHD7 gene are private and a functional assay is not yet available. We have therefore developed a novel classification system to predict the pathogenic effects of CHD7 missense variants that can be used in a diagnostic setting. Our classification system combines the results from two computational algorithms (PolyPhen-2 and Align-GVGD) and the prediction of a newly developed structural model of the chromo- and helicase domains of CHD7 with segregation and phenotypic data. The combination of different variables will lead to a more confident prediction of pathogenicity than was previously possible. We have used our system to classify 145 CHD7 missense variants. Our data show that pathogenic missense mutations are mainly present in the middle of the CHD7 gene, whereas benign variants are mainly clustered in the 5' and 3' regions. Finally, we show that CHD7 missense mutations are, in general, associated with a milder phenotype than truncating mutations. PMID- 22539354 TI - Ultrashort TE T1rho magic angle imaging. AB - An ultrashort TE T(1)rho sequence was used to measure T(1) rho of the goat posterior cruciate ligament (n = 1) and human Achilles tendon specimens (n = 6) at a series of angles relative to the B(0) field and spin-lock field strengths to investigate the contribution of dipole-dipole interaction to T(1)rho relaxation. Preliminary results showed a significant magic angle effect. T(1)rho of the posterior cruciate ligament increased from 6.9 +/- 1.3 ms at 0 degrees to 36 +/- 5 ms at 55 degrees and then gradually reduced to 12 +/- 3 ms at 90 degrees . Mean T(1)rho of the Achilles tendon increased from 5.5 +/- 2.2 ms at 0 degrees to 40 +/- 5 ms at 55 degrees . T(1)rho dispersion study showed a significant T(1)rho increase from 2.3 +/- 0.9 ms to 11 +/- 3 ms at 0 degrees as the spin lock field strength increased from 150 Hz to 1 kHz, and from 30 +/- 3 ms to 42 +/ 4 ms at 55 degrees as the spin-lock field strength increased from 100 to 500 Hz. These results suggest that dipolar interaction is the dominant T(1)rho relaxation mechanism in tendons and ligaments. PMID- 22539355 TI - DFT study of the mechanism of hydroamination of ethylene with ammonia catalyzed by diplatinum(II) complexes: inner- or outer-sphere? AB - A detailed analysis of the reaction profiles of the hydroamination reaction between ethylene and ammonia catalyzed by the diplatinum(II) [{Pt(NH(2))(MU H)(PPh(3))}(2)] complex is presented herein using density functional theory computational techniques. The coordinatively unsaturated 14e T-shaped [Pt(NH(2))(PPh(3))H] species resulted from the dissociation of the diplatinum [{Pt(NH(2))(MU-H)(PPh(3))}(2)] precatalyst are identified as the active catalytic species. All possible reaction pathways that constitute the entire catalytic cycle have exhaustively been investigated. Overall, the rate-determining step of all catalytic cycles constructed was found to be the oxidative addition of ammonia that leads to the regeneration of the catalyst. According to the energy span model, the outer-sphere mechanism for the hydroamination of ethylene with ammonia catalyzed by the diplatinum complexes is favored over the inner-sphere one, whereas TOF values are in favor of the inner-sphere mechanism. PMID- 22539352 TI - RAP80 protein is important for genomic stability and is required for stabilizing BRCA1-A complex at DNA damage sites in vivo. AB - RAP80 (receptor-associated protein 80) is a ubiquitin-binding protein that can specifically recognize and bind to Lys-63-linked polyubiquitin chains, thus targeting the BRCA1-A complex to DNA damage sites. To study the role of RAP80 in vivo, we generated RAP80-deficient mice. The deficient mice are prone to B-cell lymphomagenesis. B-cell lymphomas in RAP80-deficient mice are nearly diploid but harbor clonal chromosome translocations. Moreover, the deficient mice are hypersensitive to ionizing radiation. Repair of ionizing radiation-induced DNA double-strand breaks is impaired in RAP80-deficient mouse embryonic fibroblasts. Mechanistically, loss of RAP80 suppresses recruitment of the BRCA1-A complex to DNA damage sites and abrogates the DNA damage repair process at DNA damage sites. Taken together, these results reveal that RAP80 plays a crucial role in the DNA damage response and in maintaining genomic integrity. PMID- 22539356 TI - Photoluminescent graphene oxide ink to print sensors onto microporous membranes for versatile visualization bioassays. PMID- 22539357 TI - Contractile efficacy of various prostaglandins in pregnant rat myometrium pretreated with oxytocin. AB - Oxytocin pretreatment of pregnant rat myometrium has been shown to reduce the contractions produced by further administration of oxytocin, as a function of the desensitization phenomenon. It is unclear whether this phenomenon affects the contractions produced by various prostaglandins that are used in the management of postpartum hemorrhage. The objective of this study was to investigate the contractile effects of various prostaglandins after oxytocin pretreatment and to compare their relative efficacies in vitro on pregnant rat myometrial strips. Myometrial samples from 29 pregnant Wistar rats at term were isolated and pretreated with oxytocin (10(-8) mol/L, experimental group) or physiological salt solution (control group) for 1 hour. They were then subjected to dose-response testing with oxytocin (n = 32), PGF2alpha (n = 16), dinoprostone (n = 14), alprostadil (n = 14), or misoprostol (n = 15) with cumulative increases in the organ bath concentrations from 10(-10) to 10(-5) mol/L. The contractile efficacies of various prostaglandins and oxytocin during the dose response were analyzed using mixed linear modeling and compared between the groups. There was no significant difference in the amplitude, frequency, motility index (amplitude * frequency), or area under the curve of all prostaglandins between the groups pretreated with oxytocin and the control group. However, there was a significant decrease in the frequency (P = .02) and motility index (P = .05) in the dose response curves of oxytocin in the groups pretreated with oxytocin compared with the control groups. Overall, oxytocin produced superior contractions compared with all other prostaglandins, while dinoprostone and misoprostol produced the weakest contractions. The uterotonic effects of various prostaglandins are not affected by oxytocin desensitization; and despite desensitization, oxytocin provides superior contractions compared with the prostaglandins. PMID- 22539359 TI - A simple flow cytometric assay for routine paroxysmal nocturnal hemoglobinuria testing based on immature reticulocytes and granulocytes. AB - BACKGROUND: The aim of this study was to test an easy-to-perform flow cytometric (FCM) assay for the routine investigation for diagnosis of paroxysmal nocturnal hemoglobinuria (PNH), through the simultaneous detection of PNH clones on immature reticulocytes (i-RET) and granulocytes. METHODS: During the last 5 years, eight patients were diagnosed with PNH in our laboratory, among 90 patients prospectively studied for PNH. The determination of glycosylphosphatidylinositol (GPI) deficient cells on the erythroid lineage was made with a two-color FCM assay of CD71 and CD59, evaluating the PNH clone on i RET. Three color combinations based on CD66b/CD16/CD45 and CD59/CD24/CD45 were used for the determination of GPI-deficient granulocytes. RESULTS: In all the patients with PNH, the PNH clones determined with CD71(+)CD59(-) red blood cells (RBC) were nearly identical to the respective clones determined with CD16(dim/ )/CD66b(-) and CD59(-)/CD24(-) granulocytes, in contrast to the clones determined with CD59-deficient erythrocytes only, which were significantly lower. CONCLUSIONS: Our results indicate that the simultaneous assessment of the PNH clone on CD71(+)/CD59(-)i-RET and CD16(dim/-)/CD66b(-) granulocytes, could offer a reliable method of two series PNH screening, at low cost and with ease of application. PMID- 22539358 TI - High lymph vessel density and expression of lymphatic growth factors in peritoneal endometriosis. AB - To investigate the occurrence of lymph vessels and lymphangiogenic growth factors in peritoneal lesions, we performed immunohistochemical staining of peritoneal lesions of 37 patients with antibodies against podoplanin (D2-40), lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), prospero homeobox protein 1 (Prox-1), vascular epithelial growth factor (VEGF)-C/VEGF-D. Overall, 10 lesions were double stained against D2-40 and von Willebrand factor. The lymph vessel density in peritoneal lesion was significantly higher in comparison with healthy peritoneum. All lymph vessel makers could be detected, whereby the lymph vessel density of LYVE-1- and Prox-1-positive lymph vessels was significantly higher than the lymph vessel density of D2-40-positive lymph vessels. Endometriotic epithelial cells and stromal cells (SCs) showed a moderate-to-strong VEGF-C/VEGF D expression. The VEGF-C-/VEGF-D-positive macrophages in endometriotic SCs could be observed. The lymphatic vasculature seems to form a further component of peritoneal lesions and could be involved in the inflammatory process. These data demonstrated a further step in the clarification of the pathogenesis of endometriosis. PMID- 22539360 TI - Development of budesonide nanocluster dry powder aerosols: processing. AB - Aerosolized medicine is one of the fastest growing areas in the pharmaceutical industry. Dry powder aerosols of pharmaceutical compounds are particularly attractive for the prevention and treatment of respiratory diseases but are also emerging as a treatment option for systemic diseases. Engineering particles in dry powder formulations can overcome many of the limitations of traditional inhaled pharmaceuticals. Here, a wet milling process for producing agglomerated budesonide nanoparticles (i.e., "NanoClusters") was explored. Parameters such as milling time and drug concentration were investigated, and the aerosol performance of dried budesonide NanoClusters was characterized. The wet milling process was able to produce aerosol particles composed entirely of budesonide. High emitted fraction and a large fine particle fraction suggested that the NanoCluster budesonide formulation would offer highly efficient delivery of drug throughout the lung. PMID- 22539361 TI - InP nanowires from surfactant-free thermolysis of single molecule precursors. AB - Indium phosphide nanofibres were grown from a single-molecule precursor, [(PhCH(2))(2)InP(SiMe(3))(2)](2), using hot injection techniques by a solution liquid-solid (SLS) process, under "surfactant-free" conditions and without the use of protic additives. The fibres are 85-95 nm in diameter and grow from In metal droplets of 100 nm diameter. The length of the nanofibres is a function of the precursor injection temperature (rather than the growth temperature) and can be varied from 6000 nm at 210 degrees C to 1000 nm at 310 degrees C. The indium metal tip can be readily removed under mild, non-etching conditions by treatment with thiophenol-P(SiMe(3))(3) mixtures. PMID- 22539362 TI - Effects of hypoxia and HIFs on cancer metabolism. AB - Cancer cells are characterized by rapid proliferation and require adaptive metabolic responses to allow continued biosynthesis and cell growth in the setting of decreased oxygen (O(2)) and nutrient availability. The hypoxia inducible factors (HIFs) are a common link between adaptation to low O(2), changes in cancer metabolism, and malignant progression. The HIF-alpha subunits differentially regulate metabolic enzymes and other key factors involved in glycolysis, changes in redox status, and oxidative phosphorylation. Importantly, metabolic changes can, in turn, regulate HIF activity. Finally, changes in metabolism under hypoxia lead to important crosstalk between cancer cells and the stromal compartment of the microenvironment. PMID- 22539363 TI - Roles of the hypoxia response system in hematopoietic and leukemic stem cells. AB - Stem cells exhibit a number of characteristic features, including the capacity for self-renewal and differentiation into multiple cell types, stress resistance, and drug efflux activity. These specific biological characteristics are supported by signals from the surrounding niche and the stemcell-specific transcription factor set, including hypoxia and the machinery that senses low oxygen levels. These properties are essential for normal stem cells, and when defective may induce cellular senescence and tumorigenesis. In contrast, cancer stem cells in tumor tissue utilize these biological characters driven by stemcell-specific molecular mechanisms and acquire indefinite self-renewal capacity, drug resistance, and metastatic ability. A fuller understanding of the differences between normal and malignant stem cells in the biological and molecular context is, therefore, necessary to the development of therapies against cancer stem cells. In this review, we discuss the effect of hypoxic microenvironment on normal and malignant stem cells and describe their molecular machinery with an emphasis on hematopoietic stem cells and their malignant counterparts, leukemic stem cells. PMID- 22539364 TI - Detection of serum tumor markers in multiple myeloma using the CLINPROT system. AB - The discovery of biomarkers unique to multiple myeloma (MM) is of great importance to clinical practice. This study was designed to identify serum tumor marker candidates of MM in the mass range of 700-10000 Da. Serum samples from 48 MM patients and 74 healthy controls were collected and classified into a training dataset (MM/controls: 26/26) and a testing dataset (MM/controls: 22/48). Weak cation exchange magnetic beads, MALDI-TOF MS and analytic software in the CLINPROT system were used to do serum sample pre-fractionation, data acquisition and data analysis. Peak statistics were performed using Welch's t test. Mass spectra from the two model generation cohorts in the training dataset were analyzed by the Supervised Neural Network Algorithm (SNNA) in ClinProTools((TM)) to identify the mass peaks with the highest separation power. The resulting diagnostic model was subsequently validated in the testing dataset. A total of 89 discriminating mass peaks were detected by ClinProTools((TM)) in the range of 700 10000 Da using a signal to noise threshold of 3.0. Of these, 49 peaks had statistical significance (P < 0.0001) and four peaks with the highest separation power were picked up by SNNA to form a diagnostic model. This model achieved high sensitivity (86.36 %) and specificity (87.5 %) in the validation in the testing dataset. Using CLINPROT system and MB-WCX we found four novel biomarker candidates. The diagnostic model built by the four peaks achieved high sensitivity and specificity in validation. CLINPROT system is a powerful and reliable tool for clinical proteomic research. PMID- 22539365 TI - The prevalence of priapism in children and adolescents with sickle cell disease in Brazil. AB - To evaluate priapism rates in individuals <18 years of age with sickle cell disease (SCD) at a referral center. An evaluation was made of 599 consecutive male patients with SCD, separated according to type of hemoglobinopathy (HbSS, HbSC and HbS-beta-thalassemia). Age at first episode and number of episodes were recorded. Cases of sickle cell trait were excluded. Mean age was similar in all groups. Overall, priapism occurred in 3.6 % of patients (5.6 % of those with HbSS and 1.1 % of those with HbSC; P = 0.01). In HbSS patients, the prevalence rate of priapism was from 3.5 (CI 95 % 0.94-13.4) when compared with patients with HbSC. No patient with beta-thalassemia had priapism. Mean follow-up was 39.7 months (range 1-202 months). Since 91 % of patients with priapism had HbSS, this group was evaluated separately, revealing a rate of priapism of 1.6 % in patients <10 years and 8.3 % in those >= 10 years of age (P = 0.002). Regarding priapism in HbSS patients >= 10 years (8.3 %) when compared with patients <10 years (1.6 %), the prevalence rate was from 3.3 (CI 95 % 1.1-9.5). Duration of follow-up was not correlated with priapism (P = 0.774). Forty-seven patients were lost to follow up. Telephone contact was successful with 14/22 patients with priapism, 50 % of whom had required hospital treatment. Most episodes (86 %) occurred at night, always during sleep. Medical interventions were required in 13 cases as follows: intravenous hydration (n = 4), corpora cavernosa puncture and drainage (n = 7) and corpus cavernosum-corpus spongiosum shunts (n = 2). The prevalence of priapism in children <18 years of age with SCD was 3.6 %, lower than previously reported. Prevalence was higher in HbSS patients, increasing in patients >10 years of age. Most episodes occurred at night and half of the patients required some form of urological procedure. PMID- 22539366 TI - Neurogenesis and progenitor cells in the adult human brain: a comparison between hippocampal and subventricular progenitor proliferation. AB - For more than a decade, we have known that the human brain harbors progenitor cells capable of becoming mature neurons in the adult human brain. Since the original landmark article by Eriksson et al. in 1998 (Nat Med 4:1313-1317), there have been many studies investigating the effect that depression, epilepsy, Alzheimer's disease, Huntington's disease, and Parkinson's disease have on the germinal zones in the adult human brain. Of particular interest is the demonstration that there are far fewer progenitor cells in the hippocampal subgranular zone (SGZ) compared with the subventricular zone (SVZ) in the human brain. Furthermore, the quantity of progenitor cell proliferation in human neurodegenerative diseases differs from that of animal models of neurodegenerative diseases; there is minimal progenitor proliferation in the SGZ and extensive proliferation in the SVZ in the human. In this review, we will present the data from a range of human and rodent studies from which we can compare the amount of proliferation of cells in the SVZ and SGZ in different neurodegenerative diseases. PMID- 22539367 TI - Recent developments in atom transfer radical polymerization (ATRP): methods to reduce metal catalyst concentrations. AB - Atom transfer radical polymerization (ATRP) was initially developed in the mid 1990s, and with continued refinement and use has led to significant discoveries in new materials. However, metal contamination of the polymer product is an issue that has proven detrimental to widespread industrial application of ATRP. The laboratories of K. Matyjaszewski have made significant progress towards removing this impediment, leading the development of "activators regenerated by electron transfer" ATRP (ARGET ATRP) and electrochemically mediated ATRP (eATRP) technologies. These variants of ATRP allow polymers to be produced with great molecular weight and functionality control but at significantly reduced catalyst concentrations, typically at parts per million levels. This Concept examines these polymerizations in terms of their mechanism and outcomes, and is aimed at giving the reader an overview of recent developments in the field of ATRP. PMID- 22539368 TI - A three-phase model of the social emotional functioning in eating disorders. AB - BACKGROUND: Problems with social emotional functioning are an important part of eating disorder psychopathology. AIM: This study aimed to propose a model of social emotional functioning before and during the illness and to explain the consequences for those involved. METHOD: We propose a three-phase model of social and emotional processes as both causal and maintaining factors in anorexia nervosa. The predictions from this model are examined, and we consider the relevance for treatment. RESULTS: The evidence base for the theoretical model is presented: Phase 1 describes causal predispositions and environments, Phase 2 notes the way in which the symptoms themselves impact on brain function and social cognition and Phase 3 explains the reactions of close others. CONCLUSIONS: A three-phase model including interpersonal and socio-emotional elements can be used to shape and plan treatment interventions. Understanding causal chains and consequences can give a rationale for change and frame therapeutic interventions. PMID- 22539369 TI - [Prevention and treatment of postoperative complications following gastrointestinal surgery]. AB - Gastrointestinal cancers include gastric cancer, small intestinal cancer and colorectal cancer. In China, the majority of hospitals at central cities even at county hospitals are providing surgical intervention for patients with gastrointestinal cancer. However, the complications after gastrointestinal cancer surgery pose significant burden to the patients and their relatives because of increased hospital cost and law suit. Acute bleeding, obstruction, anastomotic leakage are major complications after gastrointestinal surgery. Therefore it is important to deal with complications after gastrointestinal surgery. PMID- 22539370 TI - [Enterostomy and associated problems]. AB - Stoma has been used in colorectal surgery for various indications. Stoma type and stoma location are associated with stoma complications and quality of life with a stoma. The question regarding how to avoid stoma complication and improve quality of life should be considered when stoma creation is planned. The benefit of stoma should be balanced with complications brought about by stoma creation. PMID- 22539371 TI - [Measures to prevent ureteric injury in rectal cancer surgery]. AB - The majority of ureteric injury is iatrogenic during surgical procedures especially pelvic and retroperitoneal operations. Approximately 10% of ureteric injury is associated with colorectal procedures. The major cause is anatomical anomaly. The types of injuries mainly include contusion, clamp injury, ligation injury, cautery, cut injury and distorted traction to an acute angle. The injuries are mainly located in the lower segment of the ureter. An accurate evaluation of the risk of ureteric injury before rectal cancer operation, a better understanding of anatomy in both normal and abnormal conditions, and ureteral stent placement, are important methods to prevent ureteric injury. Primary repair is the best treatment option. PMID- 22539372 TI - [Diagnosis and treatment of abdominal chyle leak after resection of colorectal cancer]. AB - Chyle leak is a rare complication after abdominal surgery. According to the statistical results from our center, we summarized the experiences in the diagnosis, treatment and prevention of abdominal chyle leak after radical resection of colorectal cancer. Early prevention, early diagnosis, and early treatment may result in earlier recovery, shorter hospital stay, lower incidence, and better prognosis. PMID- 22539373 TI - [Complications of laparoscopic gastrectomy for gastric cancer and the management]. AB - In recent years, laparoscopic gastrectomy has developed rapidly for both early and advanced gastric cancer. Most studies showed that the operative complication rate is comparable between laparoscopic and open surgery. The common complications related to laparoscopic gastrectomy are anastomotic leakage, stenosis, intra-abdominal bleeding, pancreatic leakage, bowel obstruction, etc. This article provides insights into the reasons, classification, management, and prevention of the complications related to laparoscopic gastrectomy. PMID- 22539374 TI - [Risk factors of postoperative chyle leak following complete mesocolic excision for colon cancer]. AB - OBJECTIVE: To investigate the incidence, risk factors and preventative methods associated with chyle leak following complete mesocolic excision(CME) for colon cancer. METHODS: Clinical data of 592 patients with colon cancer undergoing CME in the department of Colorectal Surgery in the Fujian Medical University Union Hospital from September 2000 to September 2011 were analyzed retrospectively. RESULTS: Chyle leak occurred in 46 patients(7.7%). The incidence of postoperative chyle leak following right CME hemicolectomy was 13.3%(30/226), significantly higher than that after left CME hemicolectomy (4.4%). On univariate analysis, chyle leak following CME was associated with tumor size(P<0.05), tumor location(P<0.01), and lymph nodes harvested(P<0.01). Multivariate logistic regression revealed that tumor location and lymph nodes harvested were independent risk factors associated with chyle leak following CME(P<0.05). CONCLUSIONS: Tumor location and lymph nodes harvested are independent risk factors for chyle leak following complete mesocolic excision for colon cancer. When the drainage output suddenly increases after oral intake resumption, the chyle test of ascitic fluid should be performed for early diagnosis and prompt management. PMID- 22539375 TI - [Impacts of preoperative radiochemotherapy on operation and postoperative complications in patients with mid-low rectal carcinomas]. AB - OBJECTIVE: To investigate the impact of preoperative radiochemotherapy on postoperative complications in patients with mid-low rectal carcinomas. METHODS: Clinicopathologic data of T3 and T4 patients with mid-low rectal carcinomas in the Department of Colorectal Surgery at the Changhai Hospital of The Second Military Medical University from January 2009 to December 2010 were analyzed retrospectively. This cohort included 81 patients treated with preoperative radiochemotherapy followed by operation(radiochemotherapy group) and 93 cases who underwent surgery alone(control group). RESULTS: Both resection rate and sphincter preservation rate were higher in the radiochemotherapy group(100% and 86.4%) than those in the control group(94.6% and 73.1%), and the difference in sphincter preservation rate was statistically significant(P=0.039). There were no significant differences in the mean operative time [(130+/-15) min vs.(125+/-20) min, P>0.05] and mean amount of bleeding [(100+/-15) ml vs. (95+/-10) ml, P>0.05] between the two groups. The overall incidence of postoperative complications was similar(9.9% vs. 9.7%, P>0.05). CONCLUSIONS: Preoperative radiochemotherapy can significantly increase sphincter preservation rate of mid-low rectal carcinomas, and does not increase the difficulty in surgical procedure and postoperative complications. PMID- 22539376 TI - [Vascular anatomy of the right colon and vascular complications during laparoscopic surgery]. AB - OBJECTIVE: To analyze the vascular anatomy and complications of the right colon under laparoscope. METHODS: Videotapes of 55 laparoscopic extended right hemicolectomy with D3 lymphadenectomy were reviewed and the anatomic relationship and bleeding vessels were determined. RESULTS: The superior mesenteric vein, superior mesenteric artery, ileocolic artery, and middle colic artery were present in all the patients. The right colic artery was present in 45.5%(25/55) of the patients. The incidence of the gastrocolic venous trunk was 74.5%. The overall incidence of intraoperative bleeding was 43.6%. Vessels in the pre pancreatic region including the right gastroepiploic artery, the gastrocolic venous trunk, and its tributaries had a higher risk of bleeding than the middle colic vein and artery (16.4% vs. 14.5%). Intraoperative bleeding significantly prolonged the overall operative time and lymphadenectomy time. CONCLUSIONS: The vascular anatomy of the right colon is intricate and variable and laparoscopic extended right hemicolectomy with D3 lymphadenectomy is associated with a high risk of hemorrhage. Understanding the vessels anatomic relationship of the right colon is valuable to decrease vascular complication. PMID- 22539377 TI - [Association between number of lymphadenectomy and postoperative complication in surgery for esophageal carcinoma]. AB - OBJECTIVE: To investigate the association between the number of lymph nodes retrieval and the incidence of postoperative complications in patients with esophageal carcinoma. METHOD: From January 2008 to December 2009, 794 patients with esophageal carcinoma underwent esophagectomy and lymphadenectomy in the Department of Thoracic Surgery at the West China Hospital of Sichuan University. The clinical data, surgeons, the extent of lymphadenectomy and its association with operative morbidity were retrospectively analyzed. RESULTS: There was no operative death. A total of 84 patients with complication(10.6%) were documented. There were 11,770 lymph nodes harvested in total with an average of 14.8. Multivariate logistic regression showed that gender, number of metastatic lymph nodes, level of anastomosis, and surgeons' experience were risk factors associated with postoperative complications (all P<0.05), while the number and group of lymph node resection were not(all P>0.05). CONCLUSION: Within a rational range of lymphadenectomy(<50) following esophagectomy, the postoperative complications are significantly associated with the gender, extent of regional lymph nodes metastasis, site of anastomosis and the expertise of the surgeons, but not associated with the number and group of lymph nodes resection. PMID- 22539378 TI - [Necessity of defunctioning stoma in low anterior resection for rectal cancer: a meta-analysis]. AB - OBJECTIVE: To evaluate the necessity of defunctioning stoma in low anterior resection for rectal cancer below peritoneal reflection. METHODS: The databases of Medline, Embase, Cochrane Library, Wanfang and CNKI were searched. The eligible studies were identified for pooled analyses. RESULTS: Six randomized controlled trials with 648 cases(332 patients with defunctioning stoma and 316 without stoma) and 25 retrospective controlled trials with 10,722 cases(4,470 patients with defunctioning stoma and 6,252 without stoma) were included. Combined analyses showed that defunctioning stoma was effective for decreasing risk of postoperative anastomotic leakage (RR=0.33 and 95% CI:0.21-0.53 for RCTs, OR=0.60 and 95% CI:0.42-0.85 for retrospective studies), reoperation (RR=0.30, 95% CI:0.16-0.53 for RCTs, OR=0.26 and 95% CI:0.21-0.32 for retrospective studies) and mortality(OR=0.41, 95% CI:0.27-0.62 for retrospective studies). CONCLUSION: Defunctioning stoma should be routinely performed in low anterior resection for high-risk patients. PMID- 22539379 TI - [Impact of hemocoagulase on coagulatory function and deep venous thrombosis after abdominal surgery]. AB - OBJECTIVE: To investigate the impact of hemocoagulase on coagulatory function and deep venous thrombosis after abdominal surgery. METHODS: From June 2008 to January 2009, 60 cases (gastric cancer 20 cases, colonic cancer 40 cases) undergoing gastrointestinal surgery at the Union Hospital of Fujian Medical University were randomized to the hemocoagulase group and the control group(n=30 in each group). Intravenous hemocoagulase at a daily dose of 2U was used on the same day and the next day postoperatively in the hemocoagulase group. D-dimer(D D), tissue plasminogen activator(t-PA), plasminogen activator inhibitor-1(PAI-1), PT, APTT, TT, platelet count were measured before and after operation. Doppler ultrasound examination was carried out to exclude deep venous thrombosis on the 5th to 7th days after operation. RESULTS: Significant increased D-D, t-PA, PAI-1, prolonged PT, APTT, shortened TT and lower platelet count after surgery were noticed as compared to the baseline in both groups(P<0.05, P<0.01). PT, APTT, D D, t-PA, and PAI-1 significantly increased, and TT significantly shortened in the hemocoagulase group as compared to the control group after surgery(P<0.05, P<0.01). Deep venous thrombosis in the left lower limbs was noticed in 7 patients(23.3%) in the hemocoagulase group and 3 cases(10.0%) in the control group, however the difference was not statistically significant(P>0.05). CONCLUSIONS: Hypercoagulable state usually appears after abdominal surgery and use of hemocoagulase may aggravate hypercoagulability and increase the incidence of deep venous thrombosis in lower limbs after abdominal surgery. Preventative use of hemocoagulase must be administered with caution. PMID- 22539380 TI - [Association of early diarrhea after the low anterior resection of rectal cancer and anastomotic leakage]. AB - OBJECTIVE: To evaluate the association of early diarrhea(postoperative day 1 to 7) and anastomotic leakage after low anterior resection for rectal cancer. METHODS: Clinical data of 192 cases (group A, tumor from the anal verge 4-7 cm) from May 2004 to May 2007 and 236 cases(group B) from July 2007 to May 2010 in our hospital who received low anterior resection of rectal cancer were analyzed retrospectively. RESULTS: In group A, the incidence of early postoperative diarrhea was 19.3%(37/192), of which 9 cases were treated with anti-diarrhea drugs. The morbidity of anastomotic leakage in patients with diarrhea was significantly higher than those without early diarrhea(16.2% vs. 5.2%, P<0.05). In group B, the incidence of early postoperative diarrhea was 16.5%(39/236). All the patients were treated with anti-diarrhea drugs. There was no difference in the morbidity of anastomotic leakage between patients with diarrhea and those without early diarrhea(16.2% vs. 5.2%, P<0.05). There was no difference in early diarrhea between groups A and B(P>0.05). However, the incidence of anastomotic leakage in patients with early diarrhea was lower in group B(P<0.05). CONCLUSIONS: Early diarrhea after the low anterior resection of rectal cancer may indicate anastomotic leakage. Treatment of early postoperative diarrhea may reduce the risk of anastomotic leakage. PMID- 22539381 TI - [Management of postoperative chyle leak after surgery for digestive malignancies]. AB - OBJECTIVE: To investigate the treatment of postoperative chyle leak after surgery for digestive malignancies. METHODS: From December 2008 to February 2012, in the Sun Yat-sen Memorial Hospital of Sun Yat-sen University, clinical data of 19 patients with chyle leak after digestive system cancer surgery were retrospective analyzed. RESULTS: Nineteen cases of chyle leak were all identified between the second and the fourth postoperative day and were all initially managed with conservative treatment including early fasting, parenteral nutrition(PN), 24-hour continuous infusion of somatostatin, and low pressure suction drainage. Eight patients were treated successfully for 6 to 10 days with a significant reduction of the daily drainage volume. Ten patients had enteral nutrition(EN) and their drain tubes were repeatedly washed with 30 ml of compound meglumine diatrizoate injection every day until the drainage volume decreased to 200 ml/day. The time to resolution of chyle leak in these ten patients ranged from 12 to 24 days. One patient had no significant decrease in fluid drainage and developed abdominal distension after one week of conservative treatment. Surgical closure of chyle leak was performed on the 11th postoperative day, abdominal cavity drainage tube was removed on the 4th postoperative day. The patient was discharged home in good condition. CONCLUSION: Most postoperative chyle leak after surgery for digestive malignancies can be successfully managed with conservative treatment. Somatostatin and the drainage are the main therapeutic approaches. When chyle leak is not resolved with conservative treatment, surgical treatment should be considered to prevent serious complications. PMID- 22539382 TI - [Association of tumor budding with clinicopathological characteristics and prognosis in T2 rectal cancer]. AB - OBJECTIVE: To demonstrate the association of tumor budding with clinicopathological features and prognosis in T2 rectal cancer. METHODS: Clinicopathological data of 123 patients who underwent potentially curative resection for T2 rectal carcinoma between 2001 and 2005 at the Changhai Hospital were collected. All pathology slides were stained with hematoxylin and eosin for microscopic examinations. The maximum value of tumor buds(MV) and average value of tumor buds(AV) were calculated, which were classified as low value (<=5), median value (5 < bud value < 10), and high value (>=10). RESULTS: Univariate analysis and multivariate analysis revealed that MV(P=0.000), AV(P=0.001), and lymphatic invasion (P=0.006) were independent predictors for lymph node metastasis in T2 rectal cancer. Neural invasion and poorly differentiation were significantly associated with MV(P<0.05). Neural invasion, vascular invasion and poorly differentiation were were significantly associated to AV (P<0.01). Disease free survival (DFS) of patients with low AV, median AV and high AV was 110.5 months, 95.8 months, and 60.0 months respectively. There were significance differences in DFS of low AV with median and high AV(P<0.05). DFS of patients with low MV, median MV and high MV was 115.1 months, 98.5 months, and 86.0 months respectively. There were significance differences in DFS between low and high AV, and median and high MV(P<0.01 and P<0.05), while no significant difference existed between low and median MV. CONCLUSION: Tumor budding is a useful marker to indicate high invasiveness of rectal cancer and a valuable prognostic predictor. PMID- 22539383 TI - [Effect of closed high-pressure suction drainage on primary healing of perineal wound after abdominoperineal resection for rectal cancer]. AB - OBJECTIVE: To evaluate the impact of closed high-pressure suction drainage on the healing of the perineal wound after abdominoperineal resection. METHODS: Patients undergoing rectal abdominoperineal resection in the Wuhan Tongji Hospital from January 2009 to January 2011 were randomized into two groups including the study group(n=61, closed high-pressure suction drainage) and the control group(n=59, presacral drainage). The drainage volume, primary healing rate, and the healing time of perineal wounds were compared. RESULTS: The total volume of the drainage in the first 3 days was (448.1+/-142.9) ml in the study group and (548.3+/-190.6) ml in the control group, the volume of the drainage on the third day was (28.1+/ 12.7) ml and (125.9+/-84.3) ml respectively. The primary healing rate was 93.4%(57/61) in the study group and 74.6% (44/59) in the control group, the healing time was (13.5+/-3.5) days and (20.1+/-5.1) days respectively. CONCLUSION: Closed high-pressure suction drainage may promote perineal wound healing following rectal abdominoperineal resection. PMID- 22539384 TI - [Hepatectomy combined with cryoablation and ethanol injection for unresectable multiple liver metastases from colorectal cancer]. AB - OBJECTIVE: To evaluate the efficacy and safety of hepatectomy combined with cryoablation and ethanol injection in patients with unresectable multiple liver metastases from colorectal cancer. METHODS: Clinical data of 23 patients with multiple liver metastases form colorectal cancer in the Affiliated Tumor Hospital of Guangzhou Medical College between January 2005 and December 2010 were analyzed retrospectively. There were 15 males and 8 females with average age of 52.2 years. All the patients underwent hepatectomy combined with ultrasound-guided cryoablation and ethanol injection intraoperatively. RESULTS: Among 98 lesions in 23 patients, 45 were removed intraoperatively and 53 were treated by cryoablation and ethanol injection. Operative time for liver lesions ranged from 27 to 96 minutes and intraoperative blood loss 50 to 450 ml. One patient developed pleural effusion and 1 myoglobinuria after operation. All the patients were followed up with a median follow-up time of 34 months(8 to 70 months). The 1-, 3-, and 5-year survival rates were 83.2%, 45.5% and 37.6% respectively. CONCLUSION: Hepatectomy combined with cryoablation and ethanol injection is an effective and safe treatment option for patients with unresectable multiple liver metastases from colorectal cancer. PMID- 22539385 TI - [Comparison of surgical outcomes after different surgical approach for middle or lower thoracic esophageal squamous cancer]. AB - OBJECTIVE: To compare outcomes of left and right thoracic incision for middle and lower thoracic esophageal squamous cancer, and to determine reasonable surgical approach for thoracic esophageal squamous carcinoma. METHODS: One hundred and twenty patients with middle or lower thoracic esophageal squamous cancer who received esophagectomy plus lymphadenectomy between January 2004 and December 2007 were divided into two groups including left(n=60) and right thoracic(n=60) approach. Clinical data were analyzed including the results of surgical resection, lymphadenectomy, postoperative complication, recurrence, and survival. RESULTS: The rate of surgical resection was 91.7%(55/60) in the left approach group and 95%(57/60) in the right approach group. There was no significant difference(P>0.05). But the average number of lymph nodes resected (4.60 vs. 8.32) and metastatic lymph nodes(0.57 vs. 1.33) were both significantly higher in the right approach group(P<0.01). There was no statistical difference in postoperative complications[26.7%(16/60) vs. 31.7%(19/60), P>0.05] between the two groups. However, the incidence of local recurrence was lower[43.3%(26/60) vs. 23.3%(14/60), P<0.05] in the right approach group than that in left-approach group. There was no significant difference in distant metastasis(P>0.05). CONCLUSIONS: The resection rate is comparable between left and right approach for thoracic esophageal cancer. However, it is easier to perform systemic lymphadenectomy via right thoracic approach and therefore the local recurrence is reduced and long-term survival improved. PMID- 22539386 TI - [Fluorouracil implants for colorectal cancer: a systematic review and meta analysis]. AB - OBJECTIVE: To evaluate the benefit and safety of fluorouracil implants on colorectal cancer. METHODS: Based on the methods of Cochrane systematic reviews, databases including CBM(1982 to March 2011), CNKI(1911 to March 2011), EMBASE(1966 to March 2011), and Medline(1950 to March 2011) were searched to identify randomized controlled trials assessing the benefit of fluorouracil implants on colorectal cancer. The quality of the included studies was assessed using the Cochrane's tool for assessing bias. RevMan5.0 was used for meta analysis. RESULTS: Sixteen studies were included(n=1223). The quality of included studies was moderate. Fluorouracil implants could reduce the 2-year mortality(RR=0.33. 95% CI:0.18-0.59), 2-year metastasis rate(RR=0.35, 95% CI: 0.19-0.66), and 2-year recurrence rate(RR=0.48, 95% CI:0.36-0.65). There were no significant differences in complications and adverse effects between fluorouracil implants and the control group. CONCLUSIONS: Current evidence demonstrates that fluorouracil implants may modestly improve the outcome of colorectal cancer patients without increasing its adverse events. However, the results should be interpreted with caution due to the risk of bias of included studies. PMID- 22539387 TI - [Influencing factors related to lymphatic metastasis of T2 rectal carcinoma]. AB - OBJECTIVE: To study the risk factors associated with lymphatic metastasis of T2 rectal carcinoma. METHODS: A consecutive series of 122 patients with T2 rectal cancer who underwent radical surgery in the First Affiliated Hospital of Fujian Medical University from 2006 to 2011 were included for retrospective analysis. Risk factors associated with lymphatic metastasis were investigated. RESULTS: The rate of lymph node metastasis was 21.3% (26/122). Distance to anal verge(P<0.05), morphological type(P<0.05), histological type(P<0.05), tumor differentiation(P<0.05), and depth of invasion(P<0.05) were risk factors for lymph node metastasis in T2 rectal cancer by univariate analysis. The depth of invasion remained statistically significant by multivariate analysis. The rate of lymph node metastasis was 13%(7/54) in patients with shallow muscularis propria involvement, and 28%(19/68) in those with deep muscularis involvement. CONCLUSION: For T2 rectal cancer with shallow muscularis involvement, the risk of lymph node metastasis is low and transanal excision should be considered. PMID- 22539388 TI - [Clinicopathological features and prognosis of colorectal cancer patients with preoperative cancer-related anemia]. AB - OBJECTIVE: To analyze the clinicopathological features and prognosis of colorectal cancer patients with preoperative cancer-related anemia. METHODS: Clinical data of 354 patients with colorectal cancer in the Second Affiliated Hospital of Guangzhou Medical College from January 2003 to July 2009 were analyzed retrospectively. Those with hemoglobin(Hb)<120 g/L before surgery were defined as cancer-related anemia. RESULTS: Of the 354 colorectal cancer cases, 195 were males and 159 were females. The median age was 65(range 22-92) years. Preoperative cancer-related anemia tended to be occurred in female(P<0.01) and those with preoperative albumin <=35 g/L (P<0.01), right colon cancer(P<0.01) and full-thickness invasion(P<0.05). Cox regression analysis showed preoperative cancer-related anemia was an independent unfavorable factor for overall survival (HR=1.60, 95% CI:1.05-2.44; P<0.05), but not for disease-free survival (HR=1.43, 95% CI:0.97-2.12; P>0.05) in colorectal cancer. CONCLUSIONS: Preoperative cancer related anemia plays an important role in the development and prognosis of colorectal cancer and great attention should be paid to clinical practice. PMID- 22539389 TI - [Screening and identification of genes associated with multi-drug resistance in colonic cancer]. AB - OBJECTIVE: To identify novel multi-drug resistance-related genes, and to explore the mechanisms of multi-drug resistance. METHODS: Multi-drug resistant cell line Lovo/5-FU was established by incubation with increasing dose of 5-FU. The sensitivity to 5-FU and cis-diaminodichloroplatinum (CDDP) was measured by MTT assay. Two dimensional electrophoresis plus mass spectrum(2-DE/MS) was used to identify the differentially expressed protein between Lovo and Lovo/5-FU. The identified protein was then verified by Western blot analysis. RESULTS: The IC50 concentrations of Lovo/5-FU to 5-FU and CDDP were increased by 31 and 3 times, compared with Lovo (both P<0.01). 2DE-MS showed that CAP-G and RhoGDI2 were up regulated, whereas 6-PGL, DCI, Prdx-6 and Maspin were down-regulated in Lovo/5 FU. Western blot analysis confirmed that the expression levels of RhoGDI2 and CAP G in Lovo/5-FU were increased by 6.14 and 2.98 fold respectively (both P<0.01), whereas Maspin was decreased to 5.2% of Lovo(P<0.01). CONCLUSIONS: Multi-gene and multi-pathway are involved in the development of multi-drug resistance of colorectal cancer cells. CAP-G, RhoGDI2 and Maspin are potential multi-drug resistant genes. PMID- 22539390 TI - [Expression and clinical significance of fibroblast activation protein in colorectal carcinoma tissue]. AB - OBJECTIVE: To detect the expression of fibroblast activation protein(FAP) in colorectal cancer tissue, and to investigate the association between expression of FAP with pathological parameters. METHODS: Fifty-five cancer tissues and 50 normal colorectal samples were examined using immunohistochemistry with anti-FAP polyclonal antibody. The distribution of positive cells in different tissues, and associations of positive cell number with tumor staging, lymph node metastasis and tumor invasion were investigated to evaluate the effects of FAP on pathological progress in colorectal cancer. RESULTS: No FAP expression was observed in 50 normal colorectal tissue samples. FAP positive cells were seen in carcinoma associated fibroblasts(CAFs), and in few colorectal cancer cells. The numbers of FAP positive cells in tissue samples of TNM III(-IIII((40.1+/-15.9) was significantly greater than that of TNMI(-II( (18.3+/-7.7)(P<0.01). Furthermore, the number of FAP positive cells in tissue samples with lymph node metastasis (44.4+/-13.3) was also significantly higher than those without lymph node metastasis (18.5+/-8.1)(P<0.01). Significant positive correlations were found between the number of FAP-positive cells with the tumor TNM staging and lymph node metastasis(r=0.544 and r=0.793, respectively)(P<0.01). The number of FAP-positive cells was 25.2+/-8.9 in T2, 32.41+/-19.30 in T3, and 29.2+/-16.5 in T4. The association between number of positive cells and depth of invasion was not statistically significant(P>0.05). CONCLUSIONS: The FAP mainly expresses in CAFs locating in colorectal cancer tissues. The number of FAP positive cells is positively correlated with TNM staging of colorectal cancer and lymph node metastasis. PMID- 22539391 TI - [Expression of JAG1 and DLL1 genes in colorectal cancer and its clinical significance]. AB - OBJECTIVE: To study the expression of JAG1 and DLL1 in colorectal cancer and its clinical significance. METHODS: Patients with colorectal cancer were treated in the Center of Colorectal Surgery of the Third Affiliated Hospital of Nanjing University of TCM were collected prospectively and followed up. A tissue microarray was made and expressions of JAG1 and DLL1 were detected by immunohistochemical staining. RESULTS: A total of 146 cases with colorectal cancer were included. The differences in JAG1 expression were significant among different tumor differentiation types and the differences in DLL1 expression were significant among different tumor locations(all P<0.05). There were no significant differences in the expression of the two genes and microsatellite instability(MSI)(P>0.05). One hundred and thirty-four (91.8%) cases were followed up and the mean follow-up time was (42.3+/-13.3) months. Tumor-free survival was noticed in 86 patients. The overall survival was 93% at 1 year, 74% in 3 years, and 67% in 5 years. Multivariate analysis showed that long-term survival rate was related to TMN stage, pathology types, MSI status and expression of JAG1. The prognosis of patients with high expression of JAG1 was better than those with low and negative expression(P<0.05). CONCLUSIONS: The expressions of JAG1 and DLL1 are related to tumor differentiation and tumor location. The expression of JAG1 gene is associated with long-term survival. PMID- 22539392 TI - [Association of the IL-18 gene polymorphism with susceptibility to colorectal cancer]. AB - OBJECTIVE: To investigate single nucleotide polymorphisms(SNPs) and haplotypes of interleukin-18(IL-18) gene associated with the susceptibility to colorectal cancer(CRC). METHODS: Two SNPs of IL-18 gene promoter -137G/C and -607C/A in 170 patients with CRC and 160 healthy controls matched by age and sex in a Chinese population were analyzed using polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) strategy. Frequency of haplotypes and linkage disequilibrium of IL-18 gene in different groups were analyzed by SHEsis programs. RESULTS: The distributions of IL-18 gene -607C/A polymorphism did not differ between CRC patients and healthy controls, but IL-18 gene -137G/C polymorphism was significantly different(P<0.05). The relative risk of C allele for CRC was 1.814 times of the G allele (OR=1.814,95% CI:1.246-2.642). Consistent with the results of the genotyping analyses, IL-18 -137G/C and -607C/A polymorphisms showed strong linkage disequilibrium(|D'|=0.945), frequency of the 137C/-607A haplotype in patients with CRC was significantly higher than that in healthy controls(P<0.05). The -137C/-607A haplotype was associated with a significantly increased risk of CRC(OR=1.637, 95% CI:1.100-2.437). CONCLUSIONS: IL-18 gene -137G/C polymorphism and -137C/-607A haplotype are associated with CRC. -137C allele may be an important genetic susceptibility gene for CRC. PMID- 22539393 TI - [Diagnosis and treatment of pouchitis and pouch dysfunction]. AB - Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) has become the surgical treatment of choice for patients with medically refractory ulcerative colitis (UC) or UC with dysplasia and for the majority of patients with familial adenomatous polyposis. However, UC patients with IPAA are susceptible to a number of inflammatory and non-inflammatory sequelae, such as pouchitis, Crohn disease(CD) of the pouch, cuffitis, and irritable pouch syndrome, in addition to common surgery-associated complications, which adversely affect the surgical outcome and compromise patient's health-related quality of life. Pouchitis is the most frequent long-term complication of IPAA in patients with UC, with a cumulative prevalence of up to 50%. Pouchitis may be classified based on the etiopathogenesis into "idiopathic" and "secondary" types and the management is often different. Pouchoscopy is the most important tool for the diagnosis and differential diagnosis in patients with pouch dysfunction. Antibiotic therapy is the main stay of treatment for active pouchitis. Some patients may develop dependency on antibiotics, requiring long-term maintenance therapy. While management of antibiotic-dependent or antibiotic-refractory pouchitis has been challenging, secondary etiology for pouchitis should be evaluated and modified, if possible. PMID- 22539394 TI - Self-assembled germanium/carbon nanostructures as high-power anode material for the lithium-ion battery. PMID- 22539396 TI - hTERT cancer risk genotypes are associated with telomere length. AB - Telomere biology is associated with cancer initiation and prognosis. Collected data suggest that blood cell telomere length (TL) can change over time, which may be related to development of common disorders, such as cardiovascular diseases and cancer. Recently, single nucleotide polymorphisms in the region of the human telomerase reverse transcriptase (hTERT) gene were associated with various malignancies, including glioma, lung and urinary bladder cancer, and telomerase RNA gene hTERC genotypes were recently linked to TL. In the present study a hypothetical association between identified genotypes in hTERT and hTERC genes and TL were investigated. We analyzed 21 polymorphisms, covering 90% of the genetic variance, in the hTERT gene, two genetic variants in hTERC, and relative TL(RTL) at average age 50 and 60 in 959 individuals with repeated blood samples. Mean RTL at age 60 was associated with four genetic variants of the hTERT gene (rs2736100, rs2853672, rs2853677, and rs2853676), two of which reported to be associated with cancer risk. Two alleles (rs12696304, rs16847897) near the hTERC gene were confirmed as also being associated with RTL at age 60. Our data suggest that hTERT and hTERC genotypes have an impact on TL of potential relevance and detectable first at higher ages, which gives us further insight to the complex regulation of TL. PMID- 22539397 TI - An integrative segmentation method for detecting germline copy number variations in SNP arrays. AB - Germline copy number variations (CNVs) are a major source of genetic variation in humans. In large-scale studies of complex diseases, CNVs are usually detected from data generated by single nucleotide polymorphism (SNP) genotyping arrays. In this paper, we develop an integrative segmentation method, SegCNV, for detecting CNVs integrating both log R ratio (LRR) and B allele frequency (BAF). Based on simulation studies, SegCNV had modestly better power to detect deletions and substantially better power to detect duplications compared with circular binary segmentation (CBS) that relies purely on LRRs; and it had better power to detect deletions and a comparable performance to detect duplications compared with PennCNV and QuantiSNP. In two Hapmap subjects with deep sequence data available as a gold standard, SegCNV detected more true short deletions than PennCNV and QuantiSNP. For 21 short duplications validated experimentally in the AGRE dataset, SegCNV, QuantiSNP, and PennCNV detected all of them while CBS detected only three. SegCNV is much faster than the HMM-based (where HMM is hidden Markov model) methods, taking only several seconds to analyze genome-wide data for one subject. PMID- 22539398 TI - Mn-loaded apoferritin: a highly sensitive MRI imaging probe for the detection and characterization of hepatocarcinoma lesions in a transgenic mouse model. AB - Mn-Apo is a highly sensitive MRI contrast agent consisting of ca. 1000 manganese atoms entrapped in the inner cavity of apoferritin. Part of the metallic payload is in the form of Mn(2+) ions that endow the nano-sized system with a very high relaxivity that can be exploited to detect hepatocellular carcinoma in mice. Cellular studies showed that Mn-Apo is readily taken up by normal hepatocytes via the ferritin transporting route. Conversely, hepatoma cells (HTC) displayed a markedly reduced ability to entrap Mn-Apo from the culture medium. The i.v. administration of Mn-Apo into C57BL/6 J mice resulted in a marked liver tissue hyperintensity in T(1)-weighted MR image 20 min after injection. When injected into HBV-tg transgenic mice that spontaneously develop hepatocellular carcinoma (HCC), Mn-Apo allowed a clear delineation of healthy liver tissue and tumor lesions as hyperintense and hypointense T(1)-weighted MR images, respectively. Immunohistochemistry analysis correlated Mn-Apo cellular uptake to SCARA5 receptor expression. When the MRI contrast induced by Mn-Apo was compared with that induced by Gd-BOPTA (a commercial contrast agent known to enter mouse hepatocytes through organic anion transporters) it was found that only some of the lesions were detected by both agents while others could only be visualized by one of the two. These results suggest that Mn-Apo may be useful to detect otherwise invisible lesions and that the extent of its uptake directly reports the expression/regulation of SCARA5 receptors. Mn-Apo contrast-enhanced MR images may therefore contribute to improving HCC lesion detection and characterization. PMID- 22539399 TI - Comparison of near-infrared fluorescent deoxyglucose probes with different dyes for tumor diagnosis in vivo. AB - Glucose plays a central role in the cellular energy metabolism. Malignant tumors exhibit an elevated rate of glycolysis over normal tissues. In this study, two near-infrared fluorescent dyes, Cypate and ICG-Der-02, with different water solubility, were conjugated to 2-amino-2-deoxy-D-glucose (2DG) to form Cypate-2DG and ICG-Der-02-2DG, respectively, for NIR fluorescent imaging of tumors in nude mice. The clear routes and tumor targeting abilities of the two NIR fluorescent 2DG probes were compared. Results showed that ICG-Der-02-2DG with higher hydrophilicity was cleared faster by kidneys than the more lipophilic Cypate-2DG. Cypate-2DG had slower but stronger tumor targeting ability compared with ICG-Der 02-2DG. To investigate the correlation between the targeting ability of the probe and the glucose transporter (GLUT1) expression levels of cancer cells, the accumulation of Cypate-2DG in tumors was assessed in MCF-7/estradiol, U87MG, MCF 7 and MDA-MB-435 tumor xenografts, which express different levels of GLUT1. The results show that both Cypate-2DG and ICG-Der-02-2DG possess tumor targeting ability on all the tumors examined, with a proportional correlation to GLUT1 expression. The findings demonstrate the broad applicability of these molecular probes for optical imaging of tumors and glucose-related pathologies. PMID- 22539400 TI - Electron paramagnetic resonance as a sensitive tool to assess the iron oxide content in cells for MRI cell labeling studies. AB - MRI cell tracking is a promising technique to track various cell types (stem cells, tumor cells, etc.) in living animals. Usually, cells are incubated with iron oxides (T(2) contrast agent) in order to take up the particles before being injected in vivo. Iron oxide quantification is important in such studies for validating the labeling protocols and assessing the dilution of the particles with cell proliferation. We here propose to implement electron paramagnetic resonance (EPR) as a very sensitive method to quantify iron oxide concentration in cells. Iron oxide particles exhibit a unique EPR spectrum, which directly reflects the number of particles in a sample. In order to compare EPR with existing methods (Perls's Prussian blue reaction, ICP-MS and fluorimetry), we labeled tumor cells (melanoma and renal adenocarcinoma cell lines) and fibroblasts with fluorescent iron oxide particles, and determined the limits of detection of the different techniques. We show that EPR is a very sensitive technique and is specific for iron oxide quantification as measurements are not affected by endogenous iron. As a consequence, EPR is well adapted to perform ex vivo analysis of tissues after cell tracking experiments in order to confirm MRI results. PMID- 22539401 TI - Imaging of Her2-targeted magnetic nanoparticles for breast cancer detection: comparison of SQUID-detected magnetic relaxometry and MRI. AB - Both magnetic relaxometry and magnetic resonance imaging (MRI) can be used to detect and locate targeted magnetic nanoparticles, noninvasively and without ionizing radiation. Magnetic relaxometry offers advantages in terms of its specificity (only nanoparticles are detected) and the linear dependence of the relaxometry signal on the number of nanoparticles present. In this study, detection of single-core iron oxide nanoparticles by superconducting quantum interference device (SQUID)-detected magnetic relaxometry and standard 4.7 T MRI are compared. The nanoparticles were conjugated to a Her2 monoclonal antibody and targeted to Her2-expressing MCF7/Her2-18 (breast cancer cells); binding of the nanoparticles to the cells was assessed by magnetic relaxometry and iron assay. The same nanoparticle-labeled cells, serially diluted, were used to assess the detection limits and MR relaxivities. The detection limit of magnetic relaxometry was 125 000 nanoparticle-labeled cells at 3 cm from the SQUID sensors. T(2) weighted MRI yielded a detection limit of 15 600 cells in a 150 ul volume, with r(1) = 1.1 mm(-1) s(-1) and r(2) = 166 mm(-1) s(-1). Her2-targeted nanoparticles were directly injected into xenograft MCF7/Her2-18 tumors in nude mice, and magnetic relaxometry imaging and 4.7 T MRI were performed, enabling direct comparison of the two techniques. Co-registration of relaxometry images and MRI of mice resulted in good agreement. A method for obtaining accurate quantification of microgram quantities of iron in the tumors and liver by relaxometry was also demonstrated. These results demonstrate the potential of SQUID-detected magnetic relaxometry imaging for the specific detection of breast cancer and the monitoring of magnetic nanoparticle-based therapies. PMID- 22539402 TI - Prolonged in vivo circulation time by zwitterionic modification of magnetite nanoparticles for blood pool contrast agents. AB - Long circulation time is critical for blood pool contrast agents used in high resolution magnetic resonance angiography. For iron oxide particle contrast agents, size and surface properties significantly influence their in vivo performance. We developed a novel long-circulating blood pool contrast agent by introducing zwitterionic structure onto the particle surface. Zwitterionic structure was fabricated by 3-(diethylamino)propylamine (DEAPA) grafted onto the surface of ployacrylic acid coated magnetite nanoparticles via EDC/NHS [N-(3 dimethylaminopropyl)-N'-ethylcarbo-diimide hydrochloride/N-hydroxysuccinimide] coupling chemistry. Zwitterionic particles demonstrated five times lower macrophage cell uptake than the original particles and low cell toxicity. Magnetic resonance angiography indicated that zwitterionic nanoparticles had much longer in vivo circulation time than the original particles and were an ideal candidate for blood pool contrast agent. We suppose that zwitterionic modification by DEAPA and EDC/NHS can be used generally for coating nanoparticles with carboxyl surface and to prolong their circulating time. PMID- 22539403 TI - Impact of H-aggregation on activatable MMP-2-specific probes for optical imaging. AB - In order to target and image MMP-2 activity using optical imaging, we developed a panel of new MMP-2 probes based on Cy5 and QSY21 as fluorophore/quencher FRET partners, separated by various MMP-2 specific peptide substrates. We compared these probes for their specificity against other MMPs, their rate of activation by MMP-2 and their initial quenching. PMID- 22539395 TI - Smoking and genetic risk variation across populations of European, Asian, and African American ancestry--a meta-analysis of chromosome 15q25. AB - Recent meta-analyses of European ancestry subjects show strong evidence for association between smoking quantity and multiple genetic variants on chromosome 15q25. This meta-analysis extends the examination of association between distinct genes in the CHRNA5-CHRNA3-CHRNB4 region and smoking quantity to Asian and African American populations to confirm and refine specific reported associations. Association results for a dichotomized cigarettes smoked per day phenotype in 27 datasets (European ancestry (N = 14,786), Asian (N = 6,889), and African American (N = 10,912) for a total of 32,587 smokers) were meta-analyzed by population and results were compared across all three populations. We demonstrate association between smoking quantity and markers in the chromosome 15q25 region across all three populations, and narrow the region of association. Of the variants tested, only rs16969968 is associated with smoking (P < 0.01) in each of these three populations (odds ratio [OR] = 1.33, 95% CI = 1.25-1.42, P = 1.1 * 10(-17) in meta-analysis across all population samples). Additional variants displayed a consistent signal in both European ancestry and Asian datasets, but not in African Americans. The observed consistent association of rs16969968 with heavy smoking across multiple populations, combined with its known biological significance, suggests rs16969968 is most likely a functional variant that alters risk for heavy smoking. We interpret additional association results that differ across populations as providing evidence for additional functional variants, but we are unable to further localize the source of this association. Using the cross-population study paradigm provides valuable insights to narrow regions of interest and inform future biological experiments. PMID- 22539404 TI - Quantifying multimodal contrast agent biological activity using near-infrared flow cytometry. AB - Prior to imaging agent use in preclinical studies and clinical diagnostics, biological activity must be validated. The Lindmo assay has been used conventionally to quantify radiolabeled antibody (Ab) immunoreactivity, although published findings suggest it does not provide consistently accurate results. We developed and tested a near-infrared (NIR) flow cytometry (FC) method for quantifying biological activity of a dual-labeled Ab for use as a multimodal contrast agent in small animal and human positron emission tomography and NIR fluorescence imaging. Antibody specific for epithelial cell adhesion molecule was conjugated to DOTA-NHS-ester, labeled with IRDye 800CW and further labeled with (64)Cu or nonradioactive Cu prior to reacting with human prostate cancer cells for testing by the Lindmo or FC method, respectively. Immunoreactivity of the dual-labeled agent was found to be 76.4 +/- 15.7% by the Lindmo assay. When tested with and without Cu labeling using NIR FC, the biological activity was found to be 73.1 +/- 7.7 and 79.4 +/- 8.1%, respectively. No significant differences were found between these activity levels (p > 0.05), supporting NIR FC as an alternative method for measuring immunoreactivity and demonstrating that Cu labeling does not significantly affect the agent's ability to bind to its target. Biological activity was significantly reduced when the NIR dye-to-protein ratio was increased 3- to 4-fold in agent preparations when tested by FC and the Lindmo assay. In summary, NIR FC is an alternative with similar specificity and sensitivity, and greater reproducibility relative to the Lindmo assay for quantifying biological activity of NIR fluorophore-labeled, multimodal imaging agents. PMID- 22539405 TI - Does quantification of USPIO uptake-related signal loss allow differentiation of benign and malignant normal-sized pelvic lymph nodes? AB - Ultrasmall superparamagnetic iron oxide (USPIO) particles are promising contrast media, especially for molecular and cellular imaging besides lymph node staging owing to their superior NMR efficacy, macrophage uptake and lymphotropic properties. The goal of the present prospective clinical work was to validate quantification of signal decrease on high-resolution T(2)-weighted MR sequences before and 24-36 h after USPIO administration for accurate differentiation between benign and malignant normal-sized pelvic lymph nodes. Fifty-eight patients with bladder or prostate cancer were examined on a 3 T MR unit and their respective lymph node signal intensities (SI), signal-to-noise (SNR) and contrast to-noise (CNR) were determined on pre- and post-contrast 3D T(2)-weighted turbo spin echo (TSE) images. Based on histology and/or localization, USPIO-uptake related SI/SNR decrease of benign vs malignant and pelvic vs inguinal lymph nodes was compared. Out of 2182 resected lymph nodes 366 were selected for MRI post processing. Benign pelvic lymph nodes showed a significantly higher SI/SNR decrease compared with malignant nodes (p < 0.0001). Inguinal lymph nodes in comparison to pelvic lymph nodes presented a reduced SI/SNR decrease (p < 0.0001). CNR did not differ significantly between benign and malignant lymph nodes. The receiver operating curve analysis yielded an area under the curve of 0.96, and the point with optimal accuracy was found at a threshold value of 13.5% SNR decrease. Overlap of SI and SNR changes between benign and malignant lymph nodes were attributed to partial voluming, lipomatosis, histiocytosis or focal lymphoreticular hyperplasia. USPIO-enhanced MRI improves the diagnostic ability of lymph node staging in normal-sized lymph nodes, although some overlap of SI/SNR-changes remained. Quantification of USPIO-dependent SNR decrease will enable the validation of this promising technique with the final goal of improving and individualizing patient care. PMID- 22539406 TI - Paramagnetic self-assembled nanoparticles as supramolecular MRI contrast agents. AB - Nanometer-sized materials offer a wide range of applications in biomedical technologies, particularly imaging and diagnostics. Current scaffolds in the nanometer range predominantly make use of inorganic particles, organic polymers or natural peptide-based macromolecules. In contrast we hereby report a supramolecular approach for the preparation of self-assembled dendritic-like nanoparticles for applications as MRI contrast agents. This strategy combines the benefits from low molecular weight imaging agents with the ones of high molecular weight. Their in vitro properties are confirmed by in vivo measurements: post injection of well-defined and meta-stable nanoparticles allows for high resolution blood-pool imaging, even at very low Gd(III) doses. These dynamic and modular imaging agents are an important addition to the young field of supramolecular medicine using well-defined nanometer-sized assemblies. PMID- 22539408 TI - In situ monitoring of proteins during lyophilization using micro-Raman spectroscopy: a description of structural changes induced by dehydration. AB - Raman investigations were carried out in situ in real time during the lyophilization of three proteins (beta-lactoglobulin, bovine serum albumin, and chymotrypsinogen) characterized by different structural properties. Structural changes in the proteins were only and systematically detected after the primary drying step of the lyophilization, through a frequency shift and a general broadening of amide I and III bands. These spectral changes have been interpreted in terms of local disordering related to the distortion of the structural elements induced by ice desorption. Structural changes of the secondary structure were found almost reversible upon rehydration, whereas changes in the solvent accessibility to protein residues are detected and related to the alteration of the tertiary and/or quaternary structures. The influence of the lyophilization parameters, corresponding to different stress conditions, on the degree of protein denaturation has been analyzed. PMID- 22539409 TI - Weigners fixative-an alternative to formalin fixation for histology with improved preservation of nucleic acids. AB - Formalin fixation and paraffin embedding (FFPE) is the standard method for tissue storage in histopathology. However, FFPE has disadvantages in terms of user health, environment, and nucleic acid integrity. Weigners fixative has been suggested as an alternative for embalming cadavers in human and veterinary anatomy. The present study tested the applicability of Weigners for histology and immunohistochemistry and the preservation of nucleic acids. To this end, a set of organs was fixed for 2 days and up to 6 months in Weigners (WFPE) or formalin. WFPE tissues from the skin, brain, lymphatic tissues, liver, and muscle had good morphologic preservation, comparable to formalin fixation. The quality of kidney and lung samples was inferior to FFPE material due to less accentuated nuclear staining and retention of proteinaceous interstitial fluids. Azan, Turnbull blue, toluidin, and immunohistochemical stainings for CD79a, cytokeratin, vimentin, and von Willebrand factor led to comparable results with both fixates. Of note, immunohistochemical detection of CD3 was possible after 6 months in WFPE but not in FFPE tissues. mRNA, miRNA, and DNA from WFPE tissues had superior quality and allowed for amplification of miRNA, 400-bp-long mRNA, and 1000-bp-long DNA fragments after 6 months of fixation in WFPE. In summary, Weigners fixative is a nonhazardous alternative to formalin, which provides a good morphologic preservation of most organs, a similar sensitivity for protein detection, and a superior preservation of nucleic acids. Weigners may therefore be a promising alternative to cryopreservation and may be embraced by people affected by formalin allergies. PMID- 22539410 TI - Adult periventricular neural stem cells: outstanding progress and outstanding issues. AB - Twenty years have past since the existence of neural stem cells (NSCs) within the walls of the adult lateral ventricles was discovered. During this period of time, great strides have been made in every facet of our understanding of this adult periventricular NSC population. In this review, some of the fields' major advancements regarding the nature and function of adult periventricular NSCs are examined. We bring attention to issues related to NSC identity, potential, and the role of Notch signaling in regulating quiescence and activation that warrant further investigation. Progress in the understanding of human adult NSCs will aid in the development of tools required to advance therapies not only for brain repair after injury or disease but may also lead to novel therapeutics for brain tumors. PMID- 22539411 TI - A simple method for identifying image orientation of chest radiographs by use of the center of gravity of the image. AB - Bedside chest radiography is a frequent X-ray examination when patients are physically incapacitated. An X-ray cassette with an imaging plate is inserted below the patient's body, and the image orientation of the radiograph is determined by the direction of insertion. Therefore, an incorrect direction of insertion would yield an incorrect image orientation for diagnosis, if no correction was performed on the resulting image data. We aimed to develop a computerized method that identifies the image orientation of chest radiographs by using the center of gravity (COG) of the images in terms of pixel values. To develop the computerized method, we used 247 chest images contained in the Japanese Society of Radiological Technology database as training cases, and 1833 bedside chest radiographs obtained in our institution for validation testing. As a result for the 247 training images, the angles which were obtained from directions between the COG of pixel values and the center of the image were distributed between 162.7 degrees and 224.4 degrees in a clockwise direction. We used the angle of the COG to identify the correct view orientation. The range of angles (139.1 degrees -229.0 degrees ) for the COG in the chest image with correct image orientation was determined with a 99 % confidence interval for the angles of the COGs obtained from the training images. As a result of the validation test based on the range of angles determined, 99.7 % of the 1833 test images were identified correctly. PMID- 22539412 TI - 13C GIAO DFT calculation as a tool for configuration prediction of N-O group in saturated heterocyclic N-oxides. AB - Tropane, tropinone, pseudopelletierine and cocaine were oxidized in situ in a nuclear magnetic resonance (NMR) tube providing mixtures of exo/endo N-oxides. Observed (13)C chemical shifts were correlated with values calculated by gauge including atomic orbitals density functional theory (DFT) OPBE/6-31G* method using DFT B3LYP/6-31G* optimized geometries. The same method of (13)C chemical shift calculation was applied on series of methyl-substituted 1-methylpiperidines and their epimeric N-oxides described in literature. The results show that using this undemanding calculation method enables assignment of configuration of N-O group in N-epimeric saturated heterocyclic N-oxides. The approach enables assigning of the configuration with high degree of certainty even if NMR data of only one isomer are available. An improved method of in situ oxidation of starting amines in an NMR tube is also described. PMID- 22539413 TI - Drawing sticky adeno-associated viruses on surfaces for spatially patterned gene expression. PMID- 22539414 TI - Cobalt-mediated crystallographic etching of graphite from defects. AB - Herein is reported a study of Co-assisted crystallographic etching of graphite in hydrogen environment at temperatures above 750 degrees C. Unlike nanoparticle etching of graphite surface that leaves trenches, the Co could fill the hexagonal or triangular etch-pits that progressively enlarge, before finally balling-up, leaving well-defined etched pits enclosed by edges oriented at 60 degrees or 120 degrees relative to each other. The morphology and chirality of the etched edges have been carefully studied by transmission electron microscopy and Raman analysis, the latter indicating zigzag edges. By introducing defects to the graphite using an oxygen plasma or by utilizing the edges of graphene/graphite flakes (which are considered as defects), an ability to define the position of the etched edges is demonstrated. Based on these results, graphite strips are successfully etched from the edges and graphitic ribbons are fabricated which are enclosed by purely zigzag edges. These fabricated graphitic ribbons could potentially be isolated layer-by-layer and transferred to a device substrate for further processing into graphene nanoribbon transistors. PMID- 22539415 TI - CT-guided stereotactic targeting accuracy of osteoid osteoma. AB - BACKGROUND: The aim of this study was to evaluate the CT-guided stereotactic targeting accuracy for radiofrequency ablation of osteoid osteoma (OO), a small, benign but painful osseous lesion. METHODS: Patient and extremity were fixed in a vacuum cushion. The OO was targeted using an optical navigation system with a stereotactic targeting device. For evaluation of targeting errors, the control CT with the needle in place was fused with the planning CT. RESULTS: In 16 consecutive patients, nine OOs in the femur, four in the tibia, one in the spine, one in the ulna and one in the pubic bone were successfully targeted without complications. The mean +/- SD lateral targeting error was 2.6 +/- 1.7 mm at the needle entry and 1.9 +/- 1.2 mm at the needle tip, and the mean angular error was 2.0 +/- 1.3 degrees . CONCLUSION: Stereotaxy allows for accurate and safe targeting of OOs in various bone regions. PMID- 22539416 TI - Guidepost neurons for the lateral olfactory tract: expression of metabotropic glutamate receptor 1 and innervation by glutamatergic olfactory bulb axons. AB - The guidepost neurons for the lateral olfactory tract, which are called lot cells, are the earliest-generated neurons in the neocortex. They migrate tangentially and ventrally further down this tract, and provide scaffolding for the olfactory bulb axons projecting into this pathway. The molecular profiles of the lot cells are largely uncharacterized. We found that lot cells specifically express metabotropic glutamate receptor subtype-1 at a very early stage of development. This receptor is functionally competent and responds to a metabotropic glutamate receptor agonist with a transient increase in the intracellular calcium ion concentration. When the glutamatergic olfactory bulb axons were electrically stimulated, lot cells responded to the stimulation with a calcium increase mainly via ionotropic glutamate receptors, suggesting potential neurotransmission between the axons and lot cells during early development. Together with the finding that lot cells themselves are glutamatergic excitatory neurons, our results provide another notable example of precocious interactions between the projecting axons and their intermediate targets. PMID- 22539417 TI - Copper-catalyzed tandem C-N bond formation: an efficient annulative synthesis of functionalized cinnolines. PMID- 22539418 TI - 13C NMR quantification of mono and diacylglycerols obtained through the solvent free lipase-catalyzed esterification of saturated fatty acids. AB - In the present investigation, we studied the enzymatic synthesis of monoacylglycerols (MAG) and diacylglycerols (DAG) via the esterification of saturated fatty acids (stearic, palmitic and an industrial residue containing 87% palmitic acid) and glycerol in a solvent-free system. Three immobilized lipases (Lipozyme RM IM, Lipozyme TL IM and Novozym 435) and different reaction conditions were evaluated. Under the optimal reaction conditions, esterifications catalyzed by Lipozyme RM IM resulted in a mixture of MAG and DAG at high conversion rates for all of the substrates. In addition, except for the reaction of industrial residue at atmospheric pressure, all of these products met the World Health Organization and European Union directives for acylglycerol mixtures for use in food applications. The products were quantified by (13)C NMR, with the aid of an external reference signal which was generated from a sealed coaxial tube filled with acetonitrile-d3. After calibrating the area of this signal using the classical external reference method, the same coaxial tube was used repeatedly to quantify the reaction products. PMID- 22539419 TI - Ultra-thin and flat mica as gate dielectric layers. PMID- 22539420 TI - Mucosal healing in Crohn's disease: a systematic review. AB - The traditional goals of Crohn's disease therapy, to induce and maintain clinical remission, have not clearly changed its natural history. In contrast, emerging evidence suggests that achieving and maintaining mucosal healing may alter the natural history of Crohn's disease, as it has been associated with more sustained clinical remission and reduced rates of hospitalization and surgical resection. Induction and maintenance of mucosal healing should therefore be a goal toward which therapy is now directed. Unresolved issues pertain to the benefit of achieving mucosal healing at different stages of the disease, the relationship between mucosal healing and transmural inflammation, the intensity of treatment needed to achieve mucosal healing when it has not been obtained using standard therapy, and the means by which mucosal healing is defined using current endoscopic disease activity indices. The main clinical challenge relates to defining the means of achieving high rates of mucosal healing in clinical practice. PMID- 22539421 TI - Effect of triptolide on T-cell receptor beta variable gene mRNA expression in rats with collagen-induced arthritis. AB - Triptolide (TP) has been used in the treatment of rheumatoid arthritis (RA), but its mechanism of action is not understood. T-cell activation and associated release of cytokines appear to be major factors in the pathogenesis of RA. The overexpression of T-cell receptor (TCR) variable gene (V gene) fragments can cause the activation and infiltration of autoreactive T cells. This study examines the effects of TP on rats with collagen-induced arthritis (CIA). The levels of interleukin-10 (IL-10) in the serum were examined with ELISA. Compared to the CIA group, the levels of IL-10 were greater in the TP treatment group. Real-time quantitative polymerase chain reaction confirmed that the expression of TCR V beta (BV) 15 and TCR BV19 was increased in the CIA group, whereas in the TP treatment group, the expression was decreased. In this study, TP was found to enhance IL-10 levels and decrease the expression levels of TCR BV15 and TCR BV19. These changes might help explain the effectiveness of TP in the treatment of RA. PMID- 22539426 TI - HUPO 2011: The new Cardiovascular Initiative - integrating proteomics and cardiovascular biology in health and disease. AB - A newly reorganized HUPO Cardiovascular Initiative was announced at the HUPO 2011 Cardiovascular Initiative Workshop at Geneva. The new initiative is now part of the biology- and disease-driven component of the HUPO Human Proteome Project (B/D HPP). Here we report the recent achievements and future directions of the initiative, and offer a perspective on the present challenges of cardiovascular proteomics and its integration with the cardiovascular biology community at large. PMID- 22539427 TI - Enabling proteomic studies with RNA-Seq: The proteome of tomato pollen as a test case. AB - Effective proteome profiling is generally considered to depend heavily on the availability of a high-quality DNA reference database. As such, proteomics has long been taxonomically restricted, with limited inroads being made into the proteomes of "non-model" organisms. However, next generation sequencing (NGS), and particularly RNA-Seq, now allows deep coverage detection of expressed genes at low cost, which in turn potentially facilitates the matching of peptide mass spectra with cognate gene sequence. To test this, we performed a quantitative analysis of the proteomes of pollen from domesticated tomato (Solanum lycopersicum) and two wild relatives that exhibit differences in mating systems and in interspecific reproductive barriers. Using a custom tomato RNA-Seq database created through 454 pyrosequencing, more than 1200 proteins were identified, with subsets showing expression differences between genotypes or in the accumulation of the corresponding transcripts. Importantly, no major qualitative or quantitative differences were observed in the characterized proteomes when mass spectra were used to interrogate either a highly curated community database of tomato sequences generated through traditional sequencing technologies, or the RNA-Seq database. We conclude that RNA-Seq provides a cost effective and robust platform for protein identification and will be increasingly valuable to the field of proteomics. PMID- 22539428 TI - Proteome characterization of the unsequenced psychrophile Pedobacter cryoconitis using 15N metabolic labeling, tandem mass spectrometry, and a new bioinformatic workflow. AB - Organisms without a sequenced genome and lacking a complete protein database encounter an added level of complexity to protein identification and quantitation. De novo sequencing, new bioinformatics tools, and mass spectrometry (MS) techniques allow for advances in this area. Here, the proteomic characterization of an unsequenced psychrophilic bacterium, Pedobacter cryoconitis, is presented employing a novel workflow based on (15) N metabolic labelling, 2DE, MS/MS, and bioinformatics tools. Two bioinformatics pipelines, based on nitrogen constraint (N-constraint), ortholog searching, and de novo peptide sequencing with N-constraint similarity database search, are compared based on proteome coverage and throughput. Results demonstrate the effect of different growth temperatures (1 degrees C, 20 degrees C) and different carbon sources (glucose, maltose) on the proteome. Seventy-six and 69 proteins were identified and validated from the glucose- and maltose-grown bacterium, respectively, from which 21 and 22 were differentially expressed at different growth temperatures. Differentially expressed proteins are involved in stress response and carbohydrate metabolism, with higher expression at 20 degrees C than at 1 degrees C, while antioxidants were upregulated at 1 degrees C. This study provides an alternative workflow to identify, validate, and quantify proteins from unsequenced organisms distantly related to other species in the protein database. Furthermore, it provides further understanding on bacterial adaptation mechanisms to cold environments, and a comparative proteomic analyses with other psychrophilic microorganisms. PMID- 22539429 TI - jmzIdentML API: A Java interface to the mzIdentML standard for peptide and protein identification data. AB - We present a Java application programming interface (API), jmzIdentML, for the Human Proteome Organisation (HUPO) Proteomics Standards Initiative (PSI) mzIdentML standard for peptide and protein identification data. The API combines the power of Java Architecture of XML Binding (JAXB) and an XPath-based random access indexer to allow a fast and efficient mapping of extensible markup language (XML) elements to Java objects. The internal references in the mzIdentML files are resolved in an on-demand manner, where the whole file is accessed as a random-access swap file, and only the relevant piece of XMLis selected for mapping to its corresponding Java object. The APIis highly efficient in its memory usage and can handle files of arbitrary sizes. The APIfollows the official release of the mzIdentML (version 1.1) specifications and is available in the public domain under a permissive licence at http://www.code.google.com/p/jmzidentml/. PMID- 22539430 TI - jmzReader: A Java parser library to process and visualize multiple text and XML based mass spectrometry data formats. AB - We here present the jmzReader library: a collection of Java application programming interfaces (APIs) to parse the most commonly used peak list and XML based mass spectrometry (MS) data formats: DTA, MS2, MGF, PKL, mzXML, mzData, and mzML (based on the already existing API jmzML). The library is optimized to be used in conjunction with mzIdentML, the recently released standard data format for reporting protein and peptide identifications, developed by the HUPO proteomics standards initiative (PSI). mzIdentML files do not contain spectra data but contain references to different kinds of external MS data files. As a key functionality, all parsers implement a common interface that supports the various methods used by mzIdentML to reference external spectra. Thus, when developing software for mzIdentML, programmers no longer have to support multiple MS data file formats but only this one interface. The library (which includes a viewer) is open source and, together with detailed documentation, can be downloaded from http://code.google.com/p/jmzreader/. PMID- 22539431 TI - Separation of kallikrein 6 glycoprotein subpopulations in biological fluids by anion-exchange chromatography coupled to ELISA and identification by mass spectrometry. AB - Kallikrein 6 (KLK6) has been shown to be aberrantly glycosylated in ovarian cancer. Here, we report a novel HPLC anion exchange method, coupled to a KLK6 specific ELISA, capable of differentiating KLK6 glycoform subgroups in biological fluids. Biological fluids were fractionated using anion exchange and resulting fractions were analyzed for KLK6 content by ELISA producing a four-peak elution profile. Using this assay, the KLK6 elution profile and distribution across peaks of a set (n = 7) of ovarian cancer patient matched serum and ascites fluid samples was found to be different than the profile of serum and cerebrospinal fluid (CSF) of normal individuals (n = 7). Glycosylation patterns of recombinant KLK6 (rKLK6) were characterized using tandem mass spectrometry (MS/MS), and found to consist of a highly heterogeneous KLK6 population. This protein was found to contain all of the four diagnostic KLK6 peaks present in the previously assayed biological fluids. The rKLK6 glycoform composition of each peak was assessed by lectin affinity and MS/MS based glycopeptide quantification by product ion monitoring. The combined results showed an increase in terminal alpha 2-6 linked sialic acid in the N-glycans found on KLK6 from ovarian cancer serum and ascites, as opposed to CSF and serum of normal individuals. PMID- 22539432 TI - Proteomic analysis of the effects of baicalein on colorectal cancer cells. AB - Baicalein is the flavonoids with multiple pharmacological activities. The aim of our study was to investigate the effects of baicalein on colorectal cancer (CRC) and to recognize the targets of baicalein treatment. To better understand baicalein's target, proteomic approaches were used to purify and identify the protein substrates using 2D difference gel electrophoresis (2D SDS-PAGE) to elucidate proteins differential display. Results from this study investigate that baicalein treatment of CRC cells results in reduced cell proliferation. As a result, differential protein displays between baicalein-treated and untreated CRC were determined and validated. There were 11 differentially expressed proteins between baicalein-treated and untreated CRC. Furthermore, we demonstrate that baicalein inhibits cancer cell proliferation and reduced reactive oxygen species (ROS) by up-regulating the levels of peroxiredoxin-6 (PRDX6). Knockdown of PRDX6 in baicalein-treated CRC cells by specific small interfering RNA resulted in ROS production and proliferation, opposite of the baicalein treatment scenario as indicated by cell cycle distribution. These results illustrate that baicalein up regulates the expression of PRDX6, which attenuates the generation of ROS and inhibits the growth of CRC cells, whereas baicalein treatment have no effect on normal epithelial cells. PMID- 22539433 TI - Immunoproteomics of Brucella abortus reveals differential antibody profiles between S19-vaccinated and naturally infected cattle. AB - Brucella abortus is a Gram-negative intracellular bacterium that causes infectious abortion in food-producing animals and chronic infection in humans. This study aimed to characterize a B. abortus S19 antigen preparation obtained by Triton X-114 (TX-114) extraction through immunoproteomics to differentiate infected from vaccinated cattle. Three groups of bovine sera were studied: GI, 30 naturally infected cows; GII, 30 S19-vaccinated heifers; and GIII, 30 nonvaccinated seronegative cows. One-dimensional (1D) and two-dimensional electrophoretic profiles of TX-114 hydrophilic phase antigen revealed a broad spectrum of polypeptides (10-79 kDa). 1D immunoblot showed widespread seroreactivity profile in GI compared with restricted profile in GII. Three antigenic components (10, 12, 17 kDa) were recognized exclusively by GI sera, representing potential markers of infection and excluding vaccinal response. The proteomic characterization revealed 56 protein spots, 27 of which were antigenic spots showing differential seroreactivity profile between GI and GII, especially polypeptides <20 kDa that were recognized exclusively by GI. MS/MS analysis identified five B. abortus S19 proteins (Invasion protein B, Sod, Dps, Ndk, and Bfr), which were related with antigenicity in naturally infected cattle. In conclusion, immunoproteomics of this new antigen preparation enabled the characterization of proteins that could be used as tools to develop sensitive and specific immunoassays for serodiagnosis of bovine brucellosis, with emphasis on differentiation between S19 vaccinated and infected cattle. PMID- 22539434 TI - A proteogenomic approach to map the proteome of an unsequenced pathogen - Leishmania donovani. AB - Visceral leishmaniasis or kala azar is the most severe form of leishmaniasis and is caused by the protozoan parasite Leishmania donovani. There is no published report on L. donovani genome sequence available till date, although the genome sequences of three related Leishmania species are already available. Thus, we took a proteogenomic approach to identify proteins from two different life stages of L. donovani. From our analysis of the promastigote (insect) and amastigote (human) stages of L. donovani, we identified a total of 22,322 unique peptides from a homology-based search against proteins from three Leishmania species. These peptides were assigned to 3711 proteins in L. infantum, 3287 proteins in L. major, and 2433 proteins in L. braziliensis. Of the 3711 L. donovani proteins that were identified, the expression of 1387 proteins was detectable in both life stages of the parasite, while 901 and 1423 proteins were identified only in promastigotes and amastigotes life stages, respectively. In addition, we also identified 13 N-terminally and one C-terminally extended proteins based on the proteomic data search against the six-frame translated genome of the three related Leishmania species. Here, we report results from proteomic profiling of L. donovani, an organism with an unsequenced genome. PMID- 22539435 TI - Comparative membrane proteome analysis of three Borrelia species. AB - The versatility of the surface of Borrelia, the causative agent of Lyme borreliosis, is very important in host-pathogen interactions allowing bacteria to survive in ticks and to persist in a mammalian environment. To identify the surface proteome of Borrelia, we have performed a large comparative proteomic analysis on the three most important pathogenic Borrelia species, namely B. burgdorferi (strain B31), B. afzelii (strain K78), and B. garinii (strain PBi). Isolation of membrane proteins was performed by using three different approaches: (i) a detergent-based fractionation of outer membrane proteins; (ii) a trypsin based partial shedding of outer cell surface proteins; (iii) biotinylation of membrane proteins and preparation of the biotin-labelled fraction using streptavidin. Proteins derived from the detergent-based fractionation were further sub-fractionated by heparin affinity chromatography since heparin-like molecules play an important role for microbial entry into human cells. All isolated proteins were analysed using either a gel-based liquid chromatography (LC)-MS/MS technique or by two-dimensional (2D)-LC-MS/MS resulting in the identification of 286 unique proteins. Ninety seven of these were found in all three Borrelia species, representing potential targets for a broad coverage vaccine for the prevention of Lyme borreliosis caused by the different Borrelia species. PMID- 22539436 TI - Two-dimensional proteome reference map of Rhizobium tropici PRF 81 reveals several symbiotic determinants and strong resemblance with agrobacteria. AB - Rhizobium tropici strain PRF 81 is used in commercial inoculants for common-bean crops in Brazil because of its high efficiency in nitrogen fixation and, as in other strains belonging to this species, its tolerance of environmental stresses, representing a useful biological alternative to chemical nitrogen fertilizers. In this study, a proteomic reference map of PRF 81 was obtained by two-dimensional gel electrophoresis and MALDI-TOF/TOF-TOF mass spectrometry. In total, 115 spots representing 109 different proteins were successfully identified, contributing to a better understanding of the rhizobia-legume symbiosis and supporting, at proteomics level, a strong resemblance with agrobacteria. PMID- 22539437 TI - Differential regulation of aquaporins, small GTPases and V-ATPases proteins in rice leaves subjected to drought stress and recovery. AB - Mechanisms of drought tolerance are complex, interacting, and polygenic. This paper describes patterns of gene expression at precise physiological stages of drought in 35-day-old seedlings of Oryza sativa cv. Nipponbare. Drought was imposed gradually for up to 15 days, causing abscisic acid levels to rise and growth to cease, and plants were then re-watered. Proteins were identified from leaf samples after moderate drought, extreme drought, and 3 and 6 days of re watering. Label-free quantitative shotgun proteomics resulted in identification of 1548 non-redundant proteins. More proteins were down-regulated in early stages of drought but more were up-regulated as severe drought developed. After re watering, there was notable down regulation, suggesting that stress-related proteins were being degraded. Proteins involved in signalling and transport became dominant as severe drought took hold but decreased again on re-watering. Most of the nine aquaporins identified were responsive to drought, with six decreasing rapidly in abundance as plants were re-watered. Nine G-proteins appeared in large amounts during severe drought and dramatically degraded once plants were re-watered. We speculate that water transport and drought signalling are critical elements of the overall response to drought in rice and might be the key to biotechnological approaches to drought tolerance. PMID- 22539438 TI - Secretome analysis of Magnaporthe oryzae using in vitro systems. AB - Magnaporthe oryzae is a devastating blast fungal pathogen of rice (Oryza sativa L.) that causes dramatic decreases in seed yield and quality. During the early stages of infection by this pathogen, the fungal spore senses the rice leaf surface, germinates, and penetrates the cell via an infectious structure known as an appressorium. During this process, M. oryzae secretes several proteins; however, these proteins are largely unknown mainly due to the lack of a suitable method for isolating secreted proteins during germination and appressoria formation. We examined the secretome of M. oryzae by mimicking the early stages of infection in vitro using a glass plate (GP), PVDF membrane, and liquid culture medium (LCM). Microscopic observation of M. oryzae growth revealed appressorium formation on the GP and PVDF membrane resembling natural M. oryzae-rice interactions; however, appresorium formation was not observed in the LCM. Secreted proteins were collected from the GP (3, 8, and 24 h), PVDF membrane (24 h), and LCM (48 h) and identified by two-dimensional gel electrophoresis (2DE) followed by tandem mass spectrometry. The GP, PVDF membrane, and LCM-derived 2D gels showed distinct protein patterns, indicating that they are complementary approaches. Collectively, 53 nonredundant proteins including previously known and novel secreted proteins were identified. Six biological functions were assigned to the proteins, with the predominant functional classes being cell wall modification, reactive oxygen species detoxification, lipid modification, metabolism, and protein modification. The in vitro system using GPs and PVDF membranes applied in this study to survey the M. oryzae secretome, can be used to further our understanding of the early interactions between M. oryzae and rice leaves. PMID- 22539439 TI - Proteomic analysis of latex from the rubber-producing plant Taraxacum brevicorniculatum. AB - Many plants produce latex, a specialized, metabolically active cytoplasm. This is generally regarded as a defensive trait but latex may also possess additional functions. We investigated the role of latex in the dandelion species Taraxacum brevicorniculatum that contains considerable amounts of high-quality natural rubber by carrying out a comprehensive analysis of the latex proteome. We developed reliable protocols for the preparation of protein samples for one dimensional gel electrophoresis, two-dimensional gel electrophoresis, and subsequent mass spectrometry analysis, which led to 278 unique identifications. A gene ontology classification system based on comparisons with known Arabidopsis thaliana root proteins showed that dandelion proteins involved in lipid metabolism and transport were enriched in the latex proteome, whereas those involved in stress responses were not. We also found that proteins involved in rubber biosynthesis were distributed among different fractions of the latex proteome. PMID- 22539440 TI - Quantitative proteomics of heavy metal stress responses in Sydney rock oysters. AB - Currently, there are few predictive biomarkers in key biomonitoring species, such as oysters, that can detect heavy metal pollution in coastal waterways. Several attributes make oysters superior to other organisms for positive biomonitoring of heavy metal pollution. In particular, they are filter feeders with a high capacity for bioaccumulation. In this study, we used two proteomics approaches, namely label-free shotgun proteomics based on SDS-PAGE gel separation and gas phase fractionation, to investigate the heavy metal stress responses of Sydney rock oysters. Protein samples were prepared from haemolymph of oysters exposed to 100 MUg/L of PbCl(2), CuCl(2), or ZnCl(2) for 4 days in closed aquaria. Peptides were identified using a Bivalvia protein sequence database, due to the unavailability of a complete oyster genome sequence. Statistical analysis revealed 56 potential biomarker proteins, as well as several protein biosynthetic pathways to be greatly impacted by metal stress. These have the potential to be incorporated into bioassays for prevention and monitoring of heavy metal pollution in Australian oyster beds. The study confirms that proteomic analysis of biomonitoring species is a promising approach for assessing the effects of environmental pollution, and our experiments have provided insights into the molecular mechanisms underlying oyster stress responses. PMID- 22539441 TI - Structure and NMR spectra of cyclophanes with unsaturated bridges (cyclophenes). AB - The calculated structures of several known and hypothetical cyclophanes with ethylene bridges (cyclophenes) are reported together with experimental and calculated values of their NMR parameters. Of the exchange-correlation functionals and basis sets used in this work, only the omegaB97X-D/6 311++G(2d,2p) and omegaB97X-D/cc-pVQZ yielded values of the C(sp3)-C(sp3) bond length close to the experimental data, although significant differences still remain. As far as the NMR parameters are concerned, except for close-lying signals, chemical shifts and coupling constants calculated at the omegaB97X-D/cc pVQZ level reproduce in most cases the experimental trends. Contrary to the calculations of geometries, an agreement between the values of the NMR parameters obtained at omegaB97X-D/cc-pVQZ level and the experimental ones is the poorest compared with that of the omegaB97X-D/6-311++G(2d,2p) one. Taking into account that the results of the different calculations show the same qualitative trends in most cases, we believe that they correctly describe the structure and properties of the hypothetical molecules studied here. PMID- 22539442 TI - N-Heterocyclic carbene catalyzed oxidative macrolactonization: total synthesis of (+)-dactylolide. PMID- 22539443 TI - The association studies of ADIPOQ with type 2 diabetes mellitus in Chinese populations. AB - Adiponectin, which is secreted by the white adipose tissue, plays an important role in type 2 diabetes mellitus (T2DM) and its complications. Since 2002, many investigators explored the association between ADIPOQ single nucleotide polymorphisms and T2DM in different ethnic populations from different regions. In China, the results of numerous studies of the association between ADIPOQ and T2DM were not consistent, which may be caused by population-specific effects or environmental effects. This review describes the association between ADIPOQ and T2DM, the metabolic characteristics and the complications of T2DM in Chinese populations. PMID- 22539444 TI - Synthesis of Ni-Ru alloy nanoparticles and their high catalytic activity in dehydrogenation of ammonia borane. AB - We report the synthesis and characterization of new Ni(x)Ru(1-x) (x = 0.56-0.74) alloy nanoparticles (NPs) and their catalytic activity for hydrogen release in the ammonia borane hydrolysis process. The alloy NPs were obtained by wet chemistry method using a rapid lithium triethylborohydride reduction of Ni(2+) and Ru(3+) precursors in oleylamine. The nature of each alloy sample was fully characterized by TEM, XRD, energy dispersive X-ray spectroscopy (EDX), and X-ray photoelectron spectroscopy (XPS). We found that the as-prepared Ni-Ru alloy NPs exhibited exceptional catalytic activity for the ammonia borane hydrolysis reaction for hydrogen release. All Ni-Ru alloy NPs, and in particular the Ni(0.74)Ru(0.26) sample, outperform the activity of similar size monometallic Ni and Ru NPs, and even of Ni@Ru core-shell NPs. The hydrolysis activation energy for the Ni(0.74)Ru(0.26) alloy catalyst was measured to be approximately 37 kJ mol(-1). This value is considerably lower than the values measured for monometallic Ni (~70 kJ mol(-1)) and Ru NPs (~49 kJ mol(-1)), and for Ni@Ru (~44 kJ mol(-1)), and is also lower than the values of most noble-metal-containing bimetallic NPs reported in the literature. Thus, a remarkable improvement of catalytic activity of Ru in the dehydrogenation of ammonia borane was obtained by alloying Ru with a Ni, which is a relatively cheap metal. PMID- 22539445 TI - The impact of pain in polyneuropathy. PMID- 22539446 TI - Stochastic processes in the development of pluripotency in vivo. AB - The divergence of the pluripotent inner cell mass and extraembryonic trophectoderm from an apparently homogenous population of cells is a decisive event in mammalian preimplantation development. While three models have been proposed to explain early cellular differentiation in the mouse embryo, the initial cue generating asymmetry within the embryo remains elusive. Recently, unexpected heterogeneity in the expression of crucial transcription factors within the blastocyst has raised the intriguing possibility that a stochastic component is involved in lineage divergence. Unraveling the molecular dynamics and developmental function of the observed heterogeneity awaits further investigations at the single-cell level using quantitative live-imaging with appropriate reporter lines. The possible involvement of dynamic heterogeneity in the establishment, maintenance and resolution of pluripotency makes this topic highly relevant not only to developmental biology, but also to stem cell research and regenerative medicine. In this review, we discuss the possible involvement of stochastic processes in lineage divergence and the establishment of pluripotency in vivo, based on recent data from mouse embryology and stem cell research. PMID- 22539448 TI - Neutral Nazarov-type cyclization catalyzed by palladium(0). PMID- 22539449 TI - Synthesis and characterisation of anionic and neutral gallium(I) N-heterocyclic carbene analogues. AB - A high yield synthesis of a new, extremely bulky anionic gallium(I) N heterocyclic carbene analogue, [(DAB*)Ga:](-) (DAB* = {N(Ar*)C(H)}(2), Ar* = C(6)H(2){C(H)Ph(2)}(2)Me-2,6,4) has been developed and four monomeric sodium complexes of the heterocycle have been crystallographically characterised. The gallium(I) heterocycle has been utilised in the preparations of the heteroleptic zinc and cadmium gallyl complexes, [(DAB*)GaMX(tmeda)] (M = Zn or Cd, X = Br or I), which were crystallographically characterised. In addition, [(DAB*)Ga:](-) was oxidatively coupled to give the diamagnetic digallane(4), [(DAB*)GaGa(DAB*)]. The moderate yield synthesis of the six-membered gallium(I) heterocycle, [((But)MesNacnac)Ga:] ((But)MesNacnac = [(MesNCBu(t))(2)CH](-), Mes = mesityl), is described, and the compound found to be a monomer in the solid state by an X ray crystallographic analysis. A low yield by-product from this synthesis, [Ga(5)I(4)((But)MesNacnac)(3)], was also isolated and shown by X-ray crystallography to be a rare example of a compound bearing a group 13 metal-metal bonded chain stabilised by beta-diketiminate ligands. A preliminary analysis of the bonding in the compound was carried out using DFT calculations. PMID- 22539447 TI - Plasma neopterin level as a marker of peripheral immune activation in amnestic mild cognitive impairment and Alzheimer's disease. AB - OBJECTIVE: Alterations of the immune system play important roles in Alzheimer's disease (AD). The primary purpose of this study was to compare the plasma levels of neopterin, a marker of cellular immune activity, in amnestic mild cognitive impairment (aMCI), early (mild to moderate) AD, and cognitively normal controls. In addition, the correlation of plasma neopterin with interferon-gamma (IFN gamma) and interleukin-6 (IL-6) was also examined. METHODS: Plasma samples from patients with mild-to-moderate AD (N = 34), aMCI (N = 27), and cognitively normal controls (N = 30) were obtained from the Johns Hopkins Alzheimer's Disease Research Center. Plasma neopterin, IFN-gamma, and IL-6 levels were measured using commercially available ELISAs. Multiple linear regression was performed to study differences in the baseline neopterin levels between normal, aMCI, and AD patients. Pearson correlation coefficients were estimated for neopterin and IFN gamma and IL-6 levels. All analyses were conducted using SAS (SAS Institute, Inc., Cary, NC) and GraphPad Prism version 5.00 for Window (GraphPad Software, San Diego, CA, USA). RESULTS: AD subjects had significantly higher neopterin values compared with aMCI (beta = 0.202, p = 0.004) and normal (beta = 0.263, p = 0.0004) subjects. There was no statistically significant difference between normal and aMCI subjects. Significant associations between neopterin and IFN gamma (r = 0.41, p < 0.0001) and IL-6 (r = 0.35, p = 0.0006) levels were found. CONCLUSIONS: Our study demonstrates that peripheral immune response may be stronger in later stages of AD pathophysiology, when dementia has developed. PMID- 22539450 TI - The influence of maximum running speed on eye size: a test of Leuckart's Law in mammals. AB - Vertebrate eye size is influenced by many factors, including body or head size, diet, and activity pattern. Locomotor speed has also been suggested to influence eye size in a relationship known as Leuckart's Law. Leuckart's Law proposes that animals capable of achieving fast locomotor speeds require large eyes to enhance visual acuity and avoid collisions with environmental obstacles. The selective influence of rapid flight has been invoked to explain the relatively large eyes of birds, but Leuckart's Law remains untested in nonavian vertebrates. This study investigates the relationship between eye size and maximum running speed in a diverse sample of mammals. Measures of axial eye diameter, maximum running speed, and body mass were collected from the published literature for 50 species from 10 mammalian orders. This analysis reveals that absolute eye size is significantly positively correlated with maximum running speed in mammals. Moreover, the relationship between eye size and running speed remains significant when the potentially confounding effects of body mass and phylogeny are statistically controlled. The results of this analysis are therefore consistent with the expectations of Leuckart's Law and demonstrate that faster-moving mammals have larger eyes than their slower-moving close relatives. Accordingly, we conclude that maximum running speed is one of several key selective factors that have influenced the evolution of eye size in mammals. PMID- 22539451 TI - How charging corannulene with one and two electrons affects its geometry and aggregation with sodium and potassium cations. AB - Bowl-shaped mono- and dianions are prepared by reduction of corannulene (C(20)H(10), 1) with sodium and potassium metals in the presence of [18]crown-6 ether. Single-crystal X-ray diffraction studies of two sodium salts, [Na(THF)(2)([18]crown-6)](+)[1(-)] (2a) and [Na([18]crown-6)](+)[1(-)] (2b), reveal the presence of naked corannulene monoanions 1(-) in both cases. In contrast, the potassium adduct, [K([18]crown-6)](+)[1(-)] (3), shows an eta(2) binding of the K(+) ion to the convex face of 1(-). For the first time, corannulene dianions have been isolated as salts with sodium, [Na(2)([18]crown 6)](2+)[1(2-)] (4a) and [Na(THF)(2)([18]crown-6)](+)[Na([18]crown-6)](+)[1(2-)] (4b), and potassium counterions, [K([18]crown-6)](2)(+)[1(2-)] (5). Their structural characterization reveals geometry perturbations upon addition of two electrons to a bowl-shaped polyarene. It also demonstrates eta(5)- or eta(6) binding of metals to the curved carbon surface of 1(2-), depending on the crystallization conditions. Both mono- and doubly-charged corannulene bowls show the preferential exo binding of Na(+) and K(+) ions in all investigated compounds. Various types of C-H...pi interactions are found in the crystals of 2 5. The UV/Vis, ESR, and (1)H NMR spectroscopic studies of 2-5 indicate different coordination environment of corannulene anions in solution, depending on the metal ion. PMID- 22539452 TI - Double cyclization/aryl migration across an alkyne bond enabled by organoboryl and diarylplatinum groups. PMID- 22539453 TI - Calf thymus DNA binding studies of the new neodymium-naproxen complex. AB - Fluorescence spectroscopy in combination with UV absorption spectroscopy was carried out to investigate the interaction between the neodymium-naproxen complex (Nd-NAP) and calf thymus DNA (ctDNA). The experimental results showed that Nd-NAP intercalated with the ctDNA base pairs. Analysis of fluorescence quenching data of Nd-NAP by ctDNA at different temperatures using a Stern-Volmer equation revealed that dynamic and static quenching occurred simultaneously. The binding constants and the number of binding sites at 293 and 310 K were obtained as 2.904 * 10(4) L mol(-1), 1.172 and 2.432 * 10(4) L mol(-1), 1.143, respectively. The thermodynamic parameters DeltaG, DeltaH, and DeltaS calculated at different temperatures indicated that hydrogen bonding and van der Waals force were the main binding forces. PMID- 22539454 TI - Potential mechanisms explaining why hydrolyzed casein-based diets outclass single amino acid-based diets in the prevention of autoimmune diabetes in diabetes-prone BB rats. AB - BACKGROUND: It remains controversial whether avoidance of dietary diabetogenic triggers, such as cow's milk proteins, can prevent type 1 diabetes in genetically susceptible individuals. Here, different extensive casein hydrolysates (HC) and single amino acid (AA) formulations were tested for their effect on mechanisms underlying autoimmune diabetes pathogenesis in diabetes-prone BioBreeding rats. Intestinal integrity, gut microbiota composition and mucosal immune reactivity were studies to assess whether these formulations have differential effects in autoimmune diabetes prevention. METHODS: Diabetes-prone BioBreeding rats received diets in which the protein fraction was exchanged for the different hydrolysates or AA compositions, starting from weaning until the end of the experiment (d150). Diabetes development was monitored, and faecal and ileal samples were collected. Gut microbiota composition and cytokine/tight junction mRNA expression were measured by quantitative polymerase chain reaction. Cytokine levels of ileum explant cultures were measured by ELISA, and intestinal permeability was measured in vivo by lactulose-mannitol assay. RESULTS: Both HC-diet fed groups revealed remarkable reduction of diabetes incidence with the most pronounced effect in Nutramigen(r)-fed animals. Interestingly, AA-fed rats only showed delayed autoimmune diabetes development. Furthermore, both HC-fed groups had improved intestinal barrier function when compared with control chow or AA-fed animals. Interestingly, higher IL-10 levels were measured in ileum tissue explants from Nutramigen(r)-fed rats. Beneficial gut microbiota changes (increased Lactobacilli and reduced Bacteroides spp. levels) were found associated especially with HC diet interventions. CONCLUSIONS: Casein hydrolysates were found superior to AA mix in autoimmune diabetes prevention. This suggests the presence of specific peptides that beneficially affect mechanisms that may play a critical role in autoimmune diabetes pathogenesis. PMID- 22539456 TI - Investigation of the synthesis, activation, and isosteric heats of CO2 adsorption of the isostructural series of metal-organic frameworks M3(BTC)2 (M = Cr, Fe, Ni, Cu, Mo, Ru). AB - The synthesis, activation, and heats of CO(2) adsorption for the known members of the M(3)(BTC)(2) (HKUST-1) isostructural series (M = Cr, Fe, Ni, Zn, Ni, Cu, Mo) were investigated to gain insight into the impact of CO(2)-metal interactions for CO(2) storage/separation applications. With the use of modified syntheses and activation procedures, improved BET surface areas were obtained for M = Ni, Mo, and Ru. The zero-coverage isosteric heats of CO(2) adsorption were measured for the Cu, Cr, Ni, Mo, and Ru analogues and gave values consistent with those reported for MOFs containing coordinatively unsaturated metal sites, but lower than for amine functionalized materials. Notably, the Ni and Ru congeners exhibited the highest CO(2) affinities in the studied series. These behaviors were attributed to the presence of residual guest molecules in the case of Ni(3)(BTC)(2)(Me(2)NH)(2)(H(2)O) and the increased charge of the dimetal secondary building unit in [Ru(3)(BTC)(2)][BTC](0.5). PMID- 22539455 TI - Single polymer-based ternary electronic memory material and device. AB - A ternary polymer memory device based on a single polymer with on-chain Ir(III) complexes is fabricated by combining multiple memory mechanisms into one system. Excellent ternary memory performances-low reading, writing, and erasing voltages and good stability for all three states-are achieved. PMID- 22539457 TI - The microvascular anatomy of the trachea in adult Xenopus laevis Daudin (Lissamphibia; Anura): scanning electron microscopy of vascular corrosion casts and correlative light microscopy. AB - Studies on the amphibian respiratory tract microvascular anatomy are few and contradictory. Using scanning electron microscopy of vascular corrosion casts, correlative light microscopy of paraplast-embedded Goldner-stained serial tissue sections, and three-dimensional morphometry, we studied the topographic microvascular anatomy in the trachea of the adult South African Clawed Toad, Xenopus laevis Daudin. Histomorphology showed that the cartilaginous portion of the trachea contained irregularly shaped hyaline cartilage plates in its cranial and caudal portions and C-shaped hyaline cartilage rings in the middle portion. Tracheal cartilages formed large continuous plates on the ventral circumference, numerous small discontinuous plates on the dorsal circumference, and large vertical plates on the caudolateral circumference. The muscular portion of the trachea consisted of bands of smooth muscle that joined the free ends of cartilage plates. The supply of the trachea was via pulmonal artery tracheobronchial trunk artery-tracheobronchial artery-tracheal artery. The subepithelial capillary network consisted of rectangular meshes which are in the area of the tracheal cartilages located between the cartilages and the respiratory epithelium. Small tracheal veins merged into a single tracheal vein that emptied into the pulmonary vein. Because of its dense subepithelial capillary network and its drainage into the pulmonal vein, the trachea could actively take part in respiration. PMID- 22539458 TI - Hepatic lipase activity is increased in non-alcoholic fatty liver disease beyond insulin resistance. AB - BACKGROUND AND OBJECTIVE: Hepatic lipase is a lipolytic enzyme mostly synthesized and localized at the surface of liver sinusoidal capillaries, which hydrolyses triglycerides and phospholipids of intermediate density, large low density (LDL) and high density lipoproteins. Hepatic lipase activity is increased in insulin resistant states. Non-alcoholic fatty liver disease (NAFLD) is characterized by insulin resistance. However, at present, no data are available regarding the behaviour of hepatic lipase with regard to the degree of hepatic steatosis. Our aim was to evaluate hepatic lipase activity in NAFLD patients and its relationship to the severity of hepatic steatosis. DESIGN AND PATIENTS: We studied 48 patients with NAFLD (diagnosed by ultrasonography and confirmed by liver biopsy) and 30 controls. Steatosis was semi-quantitatively assessed and considered as mild or grade 1, moderate or grade 2 and severe or grade 3. MEASUREMENTS: hepatic lipase activity, lipid and lipoprotein profile (including intermediate density lipoproteins and dense LDL), adiponectin, insulin, glucose and high sensitivity C-reactive protein were measured. Homeostasis model assessment for insulin resistance (HOMA) index was calculated. RESULTS: Patients with hepatic steatosis presented with higher hepatic lipase activity, HOMA and dense LDL and lower levels of adiponectin, high density lipoproteins, cholesterol and apoA-I. Hepatic lipase activity positively correlated significantly with the severity of hepatic steatosis. Hepatic lipase correlated with a more atherogenic profile and persisted higher in patients even after corrected for age, gender, body mass index, HOMA and adiponectin. CONCLUSION: The higher hepatic lipase activity in NAFLD patients contributes to a more atherogenic profile linked to increased cardiovascular risk, beyond the insulin resistance and the reduction in adiponectin. PMID- 22539459 TI - Rh(II)2-catalyzed synthesis of alpha-, beta-, or delta-carbolines from aryl azides. PMID- 22539460 TI - Efficient macrocyclization by a novel oxy-oxonia-Cope reaction: synthesis and olfactory properties of new macrocyclic musks. PMID- 22539462 TI - Photoinduced energy transfer processes in hybrid organic-inorganic multichromophoric arrays arranged on a truxene-based platform. AB - The synthesis, photophysical characterization and energy-transfer features of a series of hybrid truxene derivatives peripherally decorated with inorganic Os containing polypyridine units and organic Bodipy dyes are reported. The photoactive terminal units are coupled to the central truxene scaffold by rigid ethynyl linkers in a star-shaped arrangement. The absorption range widely covers the UV-Vis spectrum and the Os (3)MLCT or the Bodipy triplet act as final collectors of the absorbed energy. PMID- 22539461 TI - Rapid detection and quantification of specific proteins by immunodepletion and microfluidic separation. AB - Conventional immunoblotting techniques are labor intensive, time consuming and rely on the elution of target protein after depletion. Here we describe a new method for detection and quantification of proteins, independent of washing and elution. In this method, the target protein is first captured by immunodepletion with antibody-coated microbeads. In the second step, both the supernatant after immunodepletion and the untreated protein sample are directly analyzed by microfluidic electrophoresis without further processing. Subsequently, the detection and quantification are performed by comparing the electropherograms of these two samples. This method was tested using an Escherichia coli lysate with a FLAG-tagged protein and anti-FLAG magnetic beads. An incubation of as short as one min was sufficient for detectable depletion (66%) by microchip electrophoresis. Longer incubation (up to 60 min) resulted in more depletion of the target band (82%). Our results show that only 19% of the target is recovered after elution from the beads. By eliminating multiple wash and elution steps, our method is faster, less labor intensive, and highly reproducible. The target protein can still be easily identified even in the case of nonspecific binding at low concentrations. This work highlights the advantages of integrating immunodepletion techniques on a microfluidic platform. PMID- 22539463 TI - Cadmium-induced hepatotoxicity and its abrogation by thymoquinone. AB - Cadmium (Cd(2+) ) causes alteration of the cellular homeostasis and oxidative damage. The aim of the present study was to investigate the possible protective role of thymoquinone (TQ), a predominant bioactive component present in black seed oil (Nigella sativa) on the hepatotoxicity of Cd(2+) with special reference to its protection against perturbation of nonenzymatic and enzymatic antioxidants. The effect of TQ pretreatment was examined in postnuclear supernatant prepared from liver of Swiss albino mice under in vitro conditions. CdCl(2) treatment (5 mM) resulted in a significant increase in antioxidant enzymatic activities. It also caused a significant (p < 0.001) increase in protein carbonyl and reduced glutathione content. Pretreatment with TQ (10 MUM) showed a significant protection as manifested by noticed attenuation of protein oxidation and rejuvenation of the depleted antioxidants of cellular fraction. These results strengthen the hypothesis that TQ exerts modulatory influence on the antioxidant defense system on being subjected to toxic insult. PMID- 22539464 TI - Adipokines and metabolic syndrome risk factors in women with previous gestational diabetes mellitus. AB - BACKGROUND: Gestational diabetes mellitus (GDM) has been recognized as a significant risk factor for metabolic syndrome and CVD. The aim of the study was to evaluate the relationships between levels of cytokines, components of metabolic syndrome and cardiovascular risk markers in women with previous gestational diabetes. METHODS: Women (n = 41) with gestational diabetes background (cases) and 21 healthy women (controls) in the postpartum period were enrolled. Demographic and clinical data, lipid and carbohydrate metabolism and uric acid and adipokine levels (TNF-alpha, IL-6, leptin and adiponectin) were compared and their relationships analysed. Metabolic syndrome prevalence was calculated by WHO and NCEP-ATPIII definitions. RESULTS: There were significant differences between cases and controls: body mass index (kg/m(2) ) 27.4 +/- 5.6 vs 23.9 +/- 3.6 (p = 0.013), waist circumference (cm) 85.2 +/- 12.9 vs 77.5 +/- 9.0 (p = 0.017), metabolic syndrome (WHO definition) 14.6% vs 0% (p = 0.012), metabolic syndrome (NCEP-ATPIII definition) 22% vs 0% (p = 0.002), low HDL 36.6% vs 9.5% (p = 0.024), fasting glucose (mmol/L) 5.4 +/- 0.6 vs 4.9 +/- 0.2 (p < 0.001), glucose 120' oral glucose tolerance test (mmol/L) 5.8 +/- 1.7vs 4.7 +/- 0.8 (p = 0.007), fasting insulin (MUU/mL) 13.4 +/- 8.1 vs 8.4 +/- 4.3 (p = 0.004), HOMA index 3.3 +/- 2.3 vs 1.8 +/- 1.0 (p = 0.002), HbA(1c) (%) 5.4 +/- 0.2 vs 5.2 +/- 0.2 (p = 0.021), uric acid (mg/dL) 4.1 +/- 1 vs 3.5 +/- 0.6 (p = 0.009), leptin (ng/mL) 32 025.5 +/- 19 917.3 vs 20 258.9 +/- 16 359.9 (p = 0.023), respectively. CONCLUSIONS: Women with previous gestational diabetes have central adiposity, atherogenic lipid profile, carbohydrate intolerance and adverse adipokine profile, all of which are risk factors for the future development of metabolic disease and CVD. PMID- 22539465 TI - The translucent cadaver: an evaluation of the use of full body digital X-ray images and drawings in surface anatomy education. AB - It has been noted by staff at the Faculty of Health Sciences, Stellenbosch University that medical students neglect the study of surface anatomy during dissection. This study reports on the novel use of Lodox((r)) Statscan((r)) images in anatomical education, particularly the teaching of surface anatomy. Full body digital X-ray images (Lodox Statscan) of each cadaver (n = 40) were provided to second year medical students. During dissection students were asked to visualize landmarks, organs, and structures on the digital X-ray and their cadaver, as well as palpate these landmarks and structures on themselves, their colleagues, and the cadaver. To stimulate student engagement with surface anatomy, dissection groups were required to draw both the normal and actual position of organs on a laminated image provided. The accuracy of the drawings was subsequently assessed and students were further assessed by means of practical identification tests. In addition, students were asked to complete an anonymous questionnaire. A response rate of 79% was obtained for the student questionnaire. From the questionnaire it was gathered that students found the digital X-ray images beneficial for viewing most systems' organs, except for the pelvic organs. Although it appears that students still struggle with the study of surface anatomy, most students believed that the digital X-rays were beneficial to their studies and supported their continued use in the future. PMID- 22539466 TI - Identification of novel antibacterial peptides isolated from a commercially available casein hydrolysate by autofocusing technique. AB - Autofocusing, as a simple and safe technique, was used to fractionate casein hydrolysate based on the amphoteric nature of its peptides. The antibacterial activity of casein hydrolysate and its autofocusing fractions (A1-10) was examined against Escherichia coli and Bacillus subtilis. The basic fraction A9 exhibited the highest activity with minimum inhibitory concentration (MIC) of 150 MUg/mL, whereas casein hydrolysate showed MIC values ranging from 2000 to 8000 MUg/mL. The antibacterial peptides in A9 were purified by using a series of size exclusion and reversed phase chromatographies. Three peptides exhibited the most potent antibacterial activity with MIC values ranging from 12.5 to 100 MUg/mL. These peptides were generated from alpha(s2)-casein, alpha(s1)-casein, and kappa casein and identified as K165 KISQRYQKFALPQYLKTVYQHQK188, I6KHQGLPQEV15, and T136EAVESTVATL146, respectively. Therefore, the results revealed that casein hydrolysate had potent antibacterial peptides that could be isolated by autofocusing technique. PMID- 22539467 TI - Using the Cre/lox system for targeted integration into the human genome: loxFAS loxP pairing and delayed introduction of Cre DNA improve gene swapping efficiency. AB - Cre recombinase is a commonly-used genome editing tool suitable for site-specific integrations in mammalian genomes; however, the efficiency of transgenic swapping events compared to excision remains limited. Here we sought to identify important parameters and limiting factors that influence swapping propensity in this system, especially when using one wild-type loxP site. To modulate and increase the occurrence of swapping events, we identified two novel parameters. First, we identified the loxFAS-loxP pairing, a sequence never before used in mammalian systems, as the best choice for increasing swapping events in human cell lines. Second, for the first time we implicate the importance of delayed introduction of Cre DNA for optimal swapping efficiency. This same modification could potentially be of use to other systems catalyzing trimolecular reactions such as PhiC31 integrase and FLP recombinase where we hypothesize that transport of the exchange cassette is likewise initially rate limiting. The total number of recombination events, but not the ratio of swapping to excision, was found to be influenced by the quantity of Cre DNA transfected. Through this study, we were able to obtain Cre-mediated swapping frequencies of 8-12% without antibiotic enrichment, which represents nearly an order of magnitude increase over prior reports in the literature. PMID- 22539468 TI - Comparative analysis of the humoral immune response to Moraxella catarrhalis and Streptococcus pneumoniae surface antigens in children suffering from recurrent acute otitis media and chronic otitis media with effusion. AB - A prospective clinical cohort study was established to investigate the humoral immune response in middle ear fluids (MEF) and serum against bacterial surface proteins in children suffering from recurrent acute otitis media (rAOM) and chronic otitis media with effusion (COME), using Luminex xMAP technology. The association between the humoral immune response and the presence of Moraxella catarrhalis and Streptococcus pneumoniae in the nasopharynx and middle ear was also studied. The levels of antigen-specific IgG, IgA, and IgM showed extensive interindividual variation. No significant differences in anti-M. catarrhalis and anti-S. pneumoniae serum and MEF median fluorescence intensity (MFI) values (anti M. catarrhalis and antipneumococcal IgG levels) were observed between the rAOM or COME groups for all antigens tested. No significant differences were observed for M. catarrhalis and S. pneumoniae colonization and serum IgG levels against the Moraxella and pneumococcal antigens. Similar to the antibody response in serum, no significant differences in IgG, IgA, and IgM levels in MEF were observed for all M. catarrhalis and S. pneumoniae antigens between OM M. catarrhalis- or S. pneumoniae-positive and OM M. catarrhalis- or S. pneumonia-negative children suffering from either rAOM or COME. Finally, results indicated a strong correlation between antigen-specific serum and MEF IgG levels. We observed no significant in vivo expressed anti-M. catarrhalis or anti-S. pneumoniae humoral immune responses using a range of putative vaccine candidate proteins. Other factors, such as Eustachian tube dysfunction, viral load, and genetic and environmental factors, may play a more important role in the pathogenesis of OM and in particular in the development of rAOM or COME. PMID- 22539469 TI - Does tetanus-diphtheria-acellular pertussis vaccination interfere with serodiagnosis of pertussis infection? AB - An anti-pertussis toxin (PT) IgG enzyme-linked immunosorbent assay (ELISA) was analytically validated for the diagnosis of pertussis at a cutoff of 94 ELISA units (EU)/ml. Little was known about the performance of this ELISA in the diagnosis of adults recently vaccinated with tetanus-diphtheria-acellular pertussis (Tdap) vaccine, which contains PT. The goal of this study was to determine when the assay can be used following Tdap vaccination. A cohort of 102 asymptomatic health care personnel (HCP) vaccinated with Tdap (Adacel; Sanofi Pasteur) were aged 19 to 79 years (median, 47 years) at vaccination. For each HCP, specimens were available for evaluation at 2 to 10 time points (prevaccination to 24 months postvaccination), and geometric mean concentrations (GMC) for the cohort were calculated at each time point. Among 97 HCP who responded to vaccination, a mixed-model analysis with prediction and tolerance intervals was performed to estimate the time at which serodiagnosis can be used following vaccination. The GMCs were 8, 21, and 9 EU/ml at prevaccination and 4 and 12 months postvaccination, respectively. Eight (8%) of the 102 HCP reached antibody titers of >=94 EU/ml during their peak response, but none had these titers by 6 months postvaccination. The calculated prediction and tolerance intervals were <94 EU/ml by 45 and 75 days postvaccination, respectively. Tdap vaccination 6 months prior to testing did not confound result interpretation. This seroassay remains a valuable diagnostic tool for adult pertussis. PMID- 22539470 TI - Expression and immunogenicity of recombinant immunoreactive surface protein 2 of Anaplasma phagocytophilum. AB - Human granulocytic anaplasmosis (HGA), caused by Anaplasma phagocytophilum, is an emerging tick-borne zoonotic disease throughout the world. The first HGA cases in China were documented in 2008, and the greatest challenge posed by the disease is rapid and accurate diagnosis during the acute phage of illness. In this study, we successfully cloned and expressed an A. phagocytophilum immunoreactive surface protein (major surface protein 2 [MSP2]) and demonstrated that this recombinant protein has natural immunogenicity by Western blotting and enzyme-linked immunosorbent assay (ELISA) using human HGA-positive sera and reference rabbit HGA-positive sera. The rabbit antisera against the recombinant protein also reacted actively with the natural antigen of A. phagocytophilum by immunofluorescence assay (IFA). No cross-reaction was observed between the recombinant protein and rabbit antisera against 10 common members of the order Rickettsiales by ELISA when the sera were diluted more than 1:100. We concluded that the recombinant MSP2 protein exhibited excellent antigenicity and specificity, results that should lay the foundation for the development of a simple and rapid diagnostic reagent and a vaccination for anaplasmosis. PMID- 22539471 TI - Reassessment of immune correlates in human visceral leishmaniasis as defined by cytokine release in whole blood. AB - Depressed cell-mediated immunity in human visceral leishmaniasis (VL) (also known as kala-azar), revealed as the inability of peripheral blood mononuclear cells (PBMCs) to respond to Leishmania antigen, remains a hallmark of and is thought to underlie the progressive nature of this disease. We recently reported the ability of a whole-blood, gamma interferon (IFN-gamma) release assay to detect subclinical infections among healthy individuals living in an area where kala azar is endemic (Bihar, India) and the surprising result that patients with active VL also secreted significant levels of antigen-specific IFN-gamma in this assay. We were interested in ascertaining whether these findings would be true for a larger cohort of subjects and in employing the whole-blood assay to detect additional cytokines that might better correlate with the disease status of infected individuals. We evaluated IFN-gamma, tumor necrosis factor alpha (TNF alpha), and interleukin-10 (IL-10) release in 35 patients with active VL, 54 patients with VL who were cured, 27 patients with other diseases, 52 healthy controls who lived in regions where VL or kala-azar is not endemic (NEHCs [for nonendemic healthy controls]), and 147 healthy controls who lived in regions where kala-azar is endemic (EHCs [for endemic healthy controls]). The cellular responses of the EHCs were correlated with their serological antibody titers against Leishmania donovani and Phlebotomus argentipes saliva. The whole-blood cells from the majority of both active (80%) and cured (85%) VL patients, as well as 24% of EHCs with presumed subclinical infections, produced significantly elevated levels of IFN-gamma. The findings do not support a severe Th1 response defect in kala-azar. Importantly, only the patients with active VL also produced IL-10, which in conjunction with IFN-gamma better reflects the immune responses that distinguish individuals with active disease from cured or subclinically infected, immune individuals. PMID- 22539472 TI - Immune response to Haemophilus influenzae type b vaccination in patients with chronic renal failure. AB - Adult chronic renal failure patients undergoing hemodialysis are at an increased risk of invasive Haemophilus influenzae type b (Hib) disease due to the lack of functionally active anti-Hib antibodies. The pediatric Hib polysaccharide-protein conjugate vaccine is highly immunogenic in these patients and can provide protection against invasive Hib infection for at least 1 year. PMID- 22539473 TI - PspA family distribution, unlike capsular serotype, remains unaltered following introduction of the heptavalent pneumococcal conjugate vaccine. AB - Pneumococcal conjugate vaccines (PCVs) are recommended for the prevention of invasive pneumococcal disease (IPD) in young children. Since the introduction of the heptavalent pneumococcal vaccine (PCV7) in 2000, IPD caused by serotypes in the vaccine has almost been eliminated, and previously uncommon capsular serotypes now cause most cases of pediatric IPD in the United States. One way to protect against these strains would be to add cross-reactive protein antigens to new vaccines. One such protein is pneumococcal surface protein A (PspA). Prior to 2000, PspA families 1 and 2 were expressed by 94% of isolates. Because PCV7 vaccine pressure has resulted in IPD caused by capsular serotypes that were previously uncommon and unstudied for PspA expression, it was possible that many of the new strains expressed different PspA antigens or even lacked PspA. Of 157 pediatric invasive pneumococcal isolates collected at a large pediatric hospital in Alabama between 2002 and 2010, only 60.5% had capsular serotypes included in PCV13, which came into general use in Alabama after our strains were collected. These isolates included 17 serotypes that were not covered by PCV13. Nonetheless, pneumococcal capsular serotype replacement was not associated with changes in PspA expression; 96% of strains in this collection expressed PspA family 1 or 2. Continued surveillance will be critical to vaccine strategies to further reduce IPD. PMID- 22539475 TI - PET imaging of beta-cell mass: is it feasible? PMID- 22539476 TI - Intracerebral injection of human mesenchymal stem cells impacts cerebral microvasculature after experimental stroke: MRI study. AB - Stroke, the leading cause of disability, lacks treatment beyond thrombolysis. The acute injection of human mesenchymal stem cells (hMSCs) provides a benefit which could be mediated by an enhancement of angiogenesis. A clinical autologous graft requires an hMSC culture delay incompatible with an acute administration. This study evaluates the cerebral microvascular changes after a delayed injection of hMSCs. At day 8 after middle cerebral artery occlusion (MCAo), two groups of rats received an intracerebral injection in the damaged brain of either 10 MUL of cell suspension medium (MCAo-PBS, n = 4) or 4 * 105 hMSCs (MCAo-hMSC, n = 5). Two control groups of healthy rats underwent the same injection procedures in the right hemisphere (control-PBS, n = 6; control-hMSC, n = 5). The effect of hMSCs on the microvasculature was assessed by MRI using three parameters: apparent diffusion coefficient (ADC), cerebral blood volume (CBV) and vessel size index (VSI). At day 9, eight additional rats were euthanised for a histological study of the microvascular parameters (CBV, VSI and vascular fraction). No ADC difference was observed between MCAo groups. One day after intracerebral injection, hMSCs abolished the CBV increase observed in the lesion (MCAo-hMSC: 1.7 +/- 0.1% versus MCAo-PBS: 2.2 +/- 0.2%) and delayed the VSI increase (vasodilation) secondary to cerebral ischaemia. Histological analysis at day 9 confirmed that hMSCs modified the microvascular parameters (CBV, VSI and vascular fraction) in the lesion. No ADC, CBV or VSI differences were observed between control groups. At the stroke post-acute phase, hMSC intracerebral injection rapidly and transiently modifies the cerebral microvasculature. This microvascular effect can be monitored in vivo by MRI. PMID- 22539474 TI - Performance of two commercially available automated immunoassays for the determination of Epstein-Barr virus serological status. AB - This study evaluated the performance of two automated Vidas (V) and Liaison (L) immunoassays for Epstein-Barr virus (EBV) serology. The detection of the viral capsid antigen (VCA) IgM, the VCA/early antigen (VCA/EA) IgG, and the Epstein Barr nuclear antigen (EBNA) IgG was assessed on 526 sera collected for routine EBV testing in immunocompetent subjects. The determination of expected EBV status (186 EBV primary infections, 183 past EBV infections, and 157 EBV-seronegative individuals) was based on results of routine laboratory enzyme immunoassays (EIAs) together with clinical data. The sensitivity and specificity of each individual marker were determined in comparison to the expected EBV status. The agreement between the V and L profiles and the expected EBV status was established through the interpretation of combinations of the different EBV markers. Statistically significant differences between the two tests were found for the specificity of the VCA IgM marker (96.2% for V versus 93.2% for L), the sensitivity of the VCA/EA IgG marker (89% for V versus 94% for L), and the specificity of the EBNA IgG marker (96.5% for V versus 74.2% for L). The results determined for the two assays with respect to overall agreement with the established expected EBV status were not significantly different (89.7% for V versus 88.2% for L), with discrepancies mainly observed in sera referenced as primary infections. These findings demonstrated the similar performances of the Vidas and the Liaison assays for the establishment of an EBV serological status using the VCA, EA, and EBNA markers. PMID- 22539477 TI - Prevalence of systemic sclerosis in south-east Norway. AB - OBJECTIVE: To assess the prevalence of SSc in south-east Norway. METHODS: The survey was conducted in south-east Norway with a denominator population of 2,707,012, 56% of the total Norwegian population. All SSc patients living in the study area between 1 January 1999 and 31 December 2009 were included. Patients were identified by five overlapping acquisition routes, including all the rheumatology departments, private rheumatologists and the dermatology department in the study area. Only cases meeting the 1980 ACR and/or the Medsger and LeRoy classification criteria were included. The patients were assigned to three clinical subsets: limited SSc, lcSSc or dcSSc. RESULTS: At the end of the study period, a total of 269 patients fulfilled the ACR and/or the Medsger and LeRoy SSc criteria, giving a point prevalence of 9.9/100,000 (95% CI 8.8, 11.2). The estimated prevalences of lSSc, lcSSc and dcSSc were 1.3/100,000, 6.9/100,000 and 1.8/100,000 (95% CIs 0.9, 1.8; 5.8, 7.8; 1.4, 2.5), respectively. The mean age at onset was 47 years and the female:male ratio was 3.8:1. The prevalence estimates of SSc in the 10 different counties in south-east Norway varied between 5.2 and 14.4/100,000 (95% CIs 2.8, 8.8; 10.3, 19.6). CONCLUSION: This study establishes baseline estimates of the occurrence and disease characteristics in a large, unselected group of Norwegian SSc patients. Our data suggest that the prevalence of SSc in Norway is comparable with other northern European countries, supporting the notion of a north-south gradient of SSc in Europe with the lowest prevalence in northern Europe. PMID- 22539478 TI - Physical activity and energy expenditure in rheumatoid arthritis patients and matched controls. AB - OBJECTIVES: To compare daily energy expenditure between RA patients and matched controls, and to explore the relationship between daily energy expenditure or sedentariness and disease-related scores. METHODS: One hundred and ten patients with RA and 440 age- and sex-matched controls were included in this study. Energy expenditure was assessed using the validated physical activity (PA) frequency questionnaire. Disease-related scores included disease activity (DAS-28), functional status (HAQ), pain visual analogue scale (VAS) and fatigue VAS. Total energy expenditure (TEE) and the amount of energy spent in low- (TEE-low), moderate- (TEE-mod) and high-intensity (TEE-high) PAs were calculated. Sedentariness was defined as expending <10% of TEE in TEE-mod or TEE-high activities. Between-group comparisons were computed using conditional logistic regression. The effect of disease-related scores on TEE was investigated using linear regression. RESULTS: TEE was significantly lower for RA patients compared with controls [2392 kcal/day (95% CI 2295, 2490) and 2494 kcal/day (2446, 2543), respectively, P = 0.003]. A significant difference was found between groups in TEE-mod (P = 0.015), but not TEE-low (P = 0.242) and TEE-high (P = 0.146). All disease-related scores were significantly poorer in sedentary compared with active patients. TEE was inversely associated with age (P < 0.001), DAS-28 (P = 0.032) and fatigue VAS (P = 0.029), but not with HAQ and pain VAS. CONCLUSION: Daily energy expenditure is significantly lower in RA patients compared with matched controls, mainly due to less moderate-intensity PAs performed. Disease activity and fatigue are important contributing factors. These points need to be addressed if promoting PA in RA patients is a health goal. Trial registration. ClinicalTrials.gov, http://clinicaltrials.gov, NCT01228812. PMID- 22539480 TI - Joint replacement in China: progress and challenges. PMID- 22539479 TI - Two-year direct and indirect costs for patients with inflammatory rheumatic joint diseases: data from real-life follow-up of patients in the NOR-DMARD registry. AB - OBJECTIVE: The overall aim of this study was to estimate the total costs for patients with RA, AS and psoriatic arthritis (PsA) treated with DMARDs. Specific aims were to compare the costs across diagnoses and over time. METHODS: The main data source was the Norwegian DMARD register (NOR-DMARD) that captures outcomes and resource use among patients starting therapy with synthetic and biologic DMARDs. Costs were estimated for four 6-month periods from the start of a DMARD regimen. We included RA (n=1152), AS (n=186) and PsA (n=374) patients with available 2-year data. Direct costs included pharmaceuticals, imaging examinations, in-hospital and out-hospital care, stays in rehabilitation units and visits to general practitioners, private rheumatologists and physiotherapists. Indirect cost included patients' work absenteeism. Differences in costs across diagnoses were tested by Kruskal-Wallis equality-of-populations rank test and changes in costs between first and fourth 6-month periods were tested by paired t-tests. RESULTS: Total 2-year costs were similar across diagnoses for patients on synthetic treatment (RA/AS/PsA ?64,300/63,200/64,500) and on biologic treatment (?121,900/115,319/111,200). The largest cost component was productivity loss. Total costs decreased significantly from the first to the fourth 6-month periods for all diagnoses, and this decrease was influenced by reductions both in direct and indirect costs. CONCLUSION: Total costs were similar across the main inflammatory rheumatic diseases. Biologic DMARD treatment entails considerable drug cost, but the total costs decline during the first 2 years on treatment in both RA, AS and PsA. PMID- 22539481 TI - Quality assurance study of the use of preventative therapies in glucocorticoid induced osteoporosis in early inflammatory arthritis: results from the CATCH cohort. AB - OBJECTIVE: To characterize steroid use and compliance with glucocorticoid-induced osteoporosis (GIOP) guidelines within a large early inflammatory arthritis cohort. METHODS: Using the Canadian Early Arthritis Cohort (CATCH) database, patients with inflammatory arthritis on glucocorticoids (oral, IA and i.m.) were identified. Consecutive steroid exposure was defined as using glucocorticoids for two consecutive clinic visits (at least 90 days apart). The primary outcome was the proportion of patients receiving calcium, vitamin D and a bisphosphonate among patients treated with consecutive oral glucocorticoids. RESULTS: Six hundred and fifty-five patients were in the CATCH database, where 273 patients were identified as glucocorticoid users, of whom 48% were on oral prednisone, 38% received i.m. or IA and 13% both. The median oral daily dose of prednisone was 5 mg (interquartile range 2.5-10). Consecutive users (CUs, n = 78) compared with non-consecutive users (NUs, n = 532) showed that CUs were older (56 vs 50 years, P = 0.001); females were fewer (63% vs 74%, P = 0.04), but a similar proportion were RF positive (51% in CU vs 56% in NU, P = 0.73). For the primary outcome, rates of prophylaxis for users of consecutive oral steroids were as follows: 53% were treated with calcium, 47% with vitamin D and 25% were on a bisphosphonate. For users of oral prednisone at doses >=7.5 mg/day, rates of prophylaxis were as follows: 64% were treated with calcium, 57% with vitamin D and 21% were on a bisphosphonate. CONCLUSION: Glucocorticoid therapy is frequently used in early inflammatory arthritis. The use of calcium, vitamin D or a bisphosphonate was low among chronic glucocorticoid users and illustrates the need for more diligence in patients receiving glucocorticoids to prevent GIOP. PMID- 22539482 TI - Clinical features of anti-TIF1-alpha antibody-positive dermatomyositis patients are closely associated with coexistent dermatomyositis-specific autoantibodies and anti-TIF1-gamma or anti-Mi-2 autoantibodies. AB - OBJECTIVE: Myositis-specific autoantibodies (MSAs), which characterize certain forms of inflammatory myopathy, are useful in the diagnosis and prediction of prognosis in DM/PM. Anti-transcriptional intermediary factor 1-alpha (TIF1-alpha) antibodies were recently reported to be associated with cancer-associated DM in conjunction with anti-TIF1-gamma antibodies. This study aimed to identify a subset of DM patients who have anti-TIF1-alpha antibodies by using biotinylated recombinant proteins and to clarify the clinical and other serological features of DM patients with these antibodies. METHODS: Sera from 202 Japanese patients with CTDs, including 108 with DM and 20 healthy controls, were screened for anti TIF1-alpha antibodies by our novel ELISAs. Positive sera were further examined by immunoprecipitation and also investigated for the detection of anti-TIF1-gamma and anti-Mi-2 antibodies. RESULTS: Sera from 12 patients with DM were confirmed to be positive for anti-TIF1-alpha antibodies. None of the patients with other CTDs and none of the healthy controls had the antibodies. Seven anti-TIF1-alpha positive patients simultaneously had anti-TIF1-gamma antibodies and the other five had anti-Mi-2 antibodies, both of which are well known to be MSAs. These double-positive patients with anti-TIF1-alpha and anti-gamma antibodies included three JDM and two cancer-associated adult DM patients, whereas all the double positive patients with anti-TIF1-alpha and anti-Mi-2 antibodies were classical adult DM. CONCLUSION: Although MSAs have been regarded as mutually exclusive, anti-Mi-2 antibody-positive patients simultaneously have anti-TIF1-alpha antibodies. Anti-Mi-2 antibody-positive patients are associated with classical DM without cancer even with the simultaneous presence of anti-TIF1-alpha antibodies. PMID- 22539483 TI - Novel compound heterozygous mutations in ENPP1 cause hypophosphataemic rickets with anterior spinal ligament ossification. PMID- 22539484 TI - Methotrexate in peripheral spondyloarthritis including psoriatic arthritis: a need for further evaluation. PMID- 22539486 TI - Furosemide increases plasma oxypurinol without lowering serum urate--a complex drug interaction: implications for clinical practice. AB - OBJECTIVE: To determine the effects of furosemide on serum urate (SU), plasma oxypurinol and urinary urate. METHODS: Twenty-three cases with gout receiving furosemide and allopurinol were recruited. Twenty-three controls with gout receiving allopurinol but no diuretics were matched on age, gender, estimated glomerular filtration rate and allopurinol dose. SU, plasma oxypurinol and urinary urate were assessed on a single occasion. The effects of a single dose of furosemide 40 mg were examined in a separate group of 10 patients receiving allopurinol but not diuretic. RESULTS: Cases had significantly higher SU and plasma oxypurinol compared with controls despite receiving similar doses of allopurinol. There was no difference in urinary urate excretion. There was a significant increase in area under the curve (AUC)(0-24) for oxypurinol after administration of furosemide 40 mg. CONCLUSION: The interaction between allopurinol and furosemide results in increased SU and plasma oxypurinol. The exact mechanisms remain unclear but complex interactions that result in attenuation of the hypouricaemic effects of oxypurinol are likely. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, www.anzctr.org.au, 12609000529246. PMID- 22539487 TI - The prevalence of clinical remission in RA patients treated with anti-TNF: results from the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry. AB - OBJECTIVES: To evaluate the prevalence of clinical remission and minimal disease activity according to the ACR/European League Against Rheumatism (EULAR) remission, DAS-28 <2.6 and minimal disease activity (MDA) criteria, and to compare the extent of residual disease activity with disability in RA patients after 6 months of treatment with anti-TNF. METHODS: In the Dutch Rheumatoid Arthritis Monitoring (DREAM) biologic registry the prevalence of DAS-28 <2.6, MDA and ACR/EULAR remission criteria was assessed. Residual disease activity during MDA or remission was assessed as the percentage of patients with swollen and tender joints, elevated acute-phase reactants and general health on a visual analogue scale (VAS). Disability was evaluated with the HAQ score. RESULTS: Prevalence of DAS-28 <2.6 was 27%, prevalence of MDA was 34% and ACR/EULAR remission was reached by 6% of patients. Residual disease activity was present mostly in the most lenient criteria and occurred most frequently on the level of swollen joint count and VAS score: at least one swollen joint in DAS-28 <2.6, MDA and ACR/EULAR remission was present in, respectively, 51, 54 and 34% of the patients. VAS >1 occurred in, respectively, 67, 69 and 0% of the patients. Modification of the cut-point of the patient-reported outcome increased the prevalence of ACR/EULAR remission, but also the level of disability. CONCLUSION: MDA and DAS-28 <2.6 are reachable treatment targets in RA with anti-TNF, although residual disease activity might still be present. In turn, ACR/EULAR remission criteria leave little residual disease activity, but might be too stringent for use in daily clinical practice due to the strict cut-point in the patient reported outcome. PMID- 22539488 TI - MicroRNA-181b targets cAMP responsive element binding protein 1 in gastric adenocarcinomas. AB - MicroRNAs are a class of small endogenous non-coding RNAs that function as post transcriptional regulators. In our previous study, we found that miR-181b was significantly downregulated in human gastric adenocarcinoma tissue samples compared to the adjacent normal gastric tissues. In this study, we confirm the down-regulation of miR-181b in human gastric cancer cell lines versus the gastric epithelial cells. Overexpression of miR-181b suppressed the proliferation and colony formation rate of gastric cancer cells. miR-181b downregulated the expression of cAMP responsive element binding protein 1 (CREB1) by binding its 3' untranslated region. Overexpression of CREB1 counteracted the suppression of growth in gastric cancer cells caused by ectopic expression of miR-181b. These results indicate that miR-181b may function as a tumor suppressor in gastric adenocarcinoma cells through negative regulation of CREB1. PMID- 22539489 TI - A quick one-tube nested PCR-protocol for EPO transgene detection. AB - The practice of doping threatens fair competition in sports. With the very recent reports on successful gene therapies for several diseases, the likelihood for abuse of gene transfer techniques in elite sports is rapidly increasing. It is therefore very important to develop valid detection techniques for transgenic DNA (tDNA) with ultimate sensitivity and specificity. To date, three slightly different procedures have been reported to reliably detect tDNA with sufficiently high sensitivity. Two utilize a real-time PCR-based approach and one uses a primer-internal, intron-spanning PCR approach (spiPCR). The specificity and sensitivity of these techniques, however, is still a matter of debate. Based on spiPCR, here we present a novel one-tube nested PCR approach that minimizes the chances for cross-contamination and shows increased sensitivity compared to non nested PCR techniques. To further reduce the occurrence of false-positives based on cross-contamination, a multi-functional 19bp extended erythropoietin standard (EPO) was cloned which can be easily differentiated from transgenic EPO DNA (tEPO) and can be used as an internal or external positive control in PCR-based applications. We found that one-tube nested PCR is superior in terms of sensitivity and specificity compared to conventional PCR, and shows similar sensitivity compared to real-time based PCR assays. Although it did not reach sensitivity of spiPCR, the one-tube nested PCR technique described here is less laborious, less expensive and much faster than spiPCR. This technique might therefore be useful as a pre-screening tool for gene doping in the future. PMID- 22539490 TI - Synthesis, structure analysis, and antitumor evaluation of 3,6-dimethyl-1,2,4,5 tetrazine-1,4-dicarboxamide derivatives. AB - 3,6-Dimethyl-1,2,4,5-tetrazine-1,4-dicarboxamide derivatives were synthesized, and their structures were confirmed by single-crystal X-ray diffraction. This reaction yields the 1,4-dicarboxamide derivatives rather than the 1,2 dicarboxamide derivatives. Their in vitro antitumor activities were evaluated against SGC-7901, HO-8910, MCF-7, and A-549 cells. The results showed several compounds to be endowed with cytotoxicity in the low micromolar range. One compound (IC(50) =0.57 MUM) was further evaluated in vivo against an A-549 xenograft in BALB/cA nude mice; it effected 76.4% inhibition of tumor weight through intraperitoneal (i.p.) administration of 40 mgkg(-1) body weight. Moreover, its acute toxicity was evaluated, and the i.p. LD(50) value was 325 mgkg(-1) in mice. PMID- 22539492 TI - Do we really need a screening test for open spina bifida? PMID- 22539491 TI - Prediction of pulmonary hypoplasia in mid-trimester preterm prelabor rupture of membranes: research or clinical practice? PMID- 22539493 TI - Re: Microarray application in prenatal diagnosis: a position statement from the cytogenetics working group of the Italian Society of Human Genetics (SIGU), November 2011. PMID- 22539494 TI - Re: Microarray application in prenatal diagnosis: a position statement from the cytogenetics working group of the Italian Society of Human Genetics (SIGU), November 2011. PMID- 22539496 TI - Generation of Nkx2.2:lacZ mice using recombination-mediated cassette exchange technology. AB - Nkx2.2 encodes a homeodomain transcription factor required for the correct specification and/or differentiation of cells in the pancreas, intestine, and central nervous system (CNS). To follow the fate of cells deleted for Nkx2.2 within these tissues, we generated Nkx2.2:lacZ knockin mice using a recombination mediated cassette exchange (RMCE) approach. Expression analysis of lacZ and/or beta-galactosidase in Nkx2.2(lacZ/+) heterozygote embryos and adults demonstrates that lacZ faithfully recapitulates endogenous Nkx2.2 expression. Furthermore, the Nkx2.2(lacZ/lacZ) homozygous embryos display phenotypes indistinguishable from the previously characterized Nkx2.2(-/-) strain. LacZ expression analyses in the Nkx2.2(lacZ/lacZ) homozygous embryos indicate that Nkx2.2-expressing progenitor cells within the pancreas are generated in their normal numbers and are not mislocalized within the pancreatic ductal epithelium or developing islets. In the CNS of Nkx2.2(lacZ/lacZ) embryos, LacZ-expressing cells within the ventral P3 progenitor domain display different migration properties depending on the developmental stage and their respective differentiation potential. PMID- 22539498 TI - "Assessing the RAFT equilibrium constant via model systems: an EPR study"- response to a comment. AB - We have presented an EPR-based approach for deducing the RAFT equilibrium constant, K(eq), of a dithiobenzoate-mediated system [Meiser, W. and Buback M. Macromol. Rapid Commun. 2011, 32, 1490]. Our value is by four orders of magnitude below K(eq) from ab initio calculations for the identical monomer-free system. Junkers et al. [Macromol. Rapid Commun. 2011, 32, 1891] claim that our EPR approach would be model dependent and our data could be equally well fitted by assuming slow addition of radicals to the RAFT agent and slow fragmentation of the so-obtained intermediate radical as well as high cross-termination rate. By identification of all side products, our EPR-based method is shown to be model independent and to provide reliable K(eq) values, which demonstrate the validity of the intermediate radical termination model. PMID- 22539497 TI - O-linked triazolotriazines: potent and selective c-Met inhibitors. AB - The HGF/c-Met signaling pathway mediates a variety of important biological activities, but dysregulation of the pathway is also closely associated with poor prognosis in a wide range of human cancers. c-Met is considered to be among the most promising therapeutic targets for anticancer drug discovery. Herein we report the discovery of a series of O-linked triazolotriazines that show sub nanomolar inhibition of c-Met activity. Among these new compounds, 6 a exhibits high c-Met inhibitory potency in both enzymatic and cellular assays with great selectivity. PMID- 22539499 TI - Synthesis of end-capped regioregular poly(3-hexylthiophene)s via direct arylation. AB - The synthesis of regioregular head-to-tail poly(3-hexylthiophene)s capped with aryl groups (Ar-HT-P3HTs) has been accomplished by palladium-catalyzed polycondensation of 2-bromo-3-hexylthiophene (1) via direct arylation. A variety of aryl groups are installed at the initiated end in 86%-98% selectivity using aryl bromides and iodides as capping agents. The polymerization proceeds via a two-stage process. Before monomer 1 is consumed, the competitive formation of end capped and non-capped HT-P3HTs is operative, where the molecular weight increases linearly with monomer conversion. After 1 is consumed, the resulting polymers are coupled with each other to afford highly end-capped HT-P3HTs. PMID- 22539503 TI - Ikuo Yamashina: a pioneer who established the basis of current glycobiology. AB - Ikuo Yamashina determined the two notable structures of N-glycans, N acetylglucosaminylasparagine and beta-mannosidic linkages, which are generally present in sugar-amino acid and innermost mannose residue of the N-glycans, respectively. He detected mucins with unusual O-glycans and proteoheparan sulphate in the plasma membranes of AH66 ascites hepatoma cells. Unusual O glycans were identified as tumour-associated carbohydrate antigens after the development of monoclonal antibodies against these O-glycans. Epitopic structures of some antigens were determined to comprise clusters of short O-glycans aligned on the core peptide, which may be not only antigenic but also functional in relation to tumour behaviour. With respect to proteoheparan sulphate, this finding led to study on membrane-bound proteoglycans. PMID- 22539500 TI - The osteoinductive potential of printable, cell-laden hydrogel-ceramic composites. AB - Hydrogels used as injectables or in organ printing often lack the appropriate stimuli to direct osteogenic differentiation of embedded multipotent stromal cells (MSCs), resulting in limited bone formation in these matrices. Addition of calcium phosphate (CaP) particles to the printing mixture is hypothesized to overcome this drawback. In this study we have investigated the effect of CaP particles on the osteoinductive potential of cell-laden hydrogel-CaP composite matrices. To this end, apatitic nanoparticles have been included in Matrigel constructs where after the viability of embedded progenitor cells was assessed in vitro. In addition, the osteoinductive potential of cell-laden Matrigel containing apatitic nanoparticles was investigated in vivo and compared with composites containing osteoinductive biphasic calcium phosphate (BCP) microparticles after subcutaneous implantation in immunodeficient mice. Histological and immunohistochemical analysis of the tissue response as well as in vivo bone formation revealed that apatitic nanoparticles were osteoinductive and induced osteoclast activation, but without bone formation. The BCP particles were more effective in inducing elaborate bone formation at the ectopic location. PMID- 22539504 TI - Microsatellite development for the relictual conifer Araucaria araucana (Araucariaceae) using next-generation sequencing. AB - PREMISE OF THE STUDY: In this study, the 454 GS-FLX genome sequence system was used for the identification and characterization of microsatellites in Araucaria araucana, one of the most important and endangered species of Chilean and Argentinean native forests. METHODS AND RESULTS: A total of 35876 reads were identified, 96% of which were within the size range selected for further analysis. Of these, 1563 contained a microsatellite insert suitable for primer design. Ten simple sequence repeat (SSR) markers provided easily interpretable patterns and were used to evaluate the genetic diversity in four populations of the species. The 10 microsatellites showed high polymorphism levels, with a total of 99 alleles and 32 private alleles. The observed heterozygosity was high and ranged from 0.513 to 0.723. CONCLUSIONS: The primers presented in this study display high genetic diversity and may provide useful information for the design of conservation strategies in Araucaria araucana. PMID- 22539505 TI - Growth responses, biomass partitioning, and nitrogen isotopes of prairie legumes in response to elevated temperature and varying nitrogen source in a growth chamber experiment. AB - PREMISE OF THE STUDY: Because legumes can add nitrogen (N) to ecosystems through symbiotic fixation, they play important roles in many plant communities, such as prairies and grasslands. However, very little research has examined the effect of projected climate change on legume growth and function. Our goal was to study the effects of temperature on growth, nodulation, and N chemistry of prairie legumes and determine whether these effects are mediated by source of N. METHODS: We grew seedlings of Amorpha canescens, Dalea purpurea, Lespedeza capitata, and Lupinus perennis at 25/20 degrees C (day/night) or 28/23 degrees C with and without rhizobia and mineral N in controlled-environment growth chambers. Biomass, leaf area, nodule number and mass, and shoot N concentration and delta(15)N values were measured after 12 wk of growth. KEY RESULTS: Both temperature and N-source affected responses in a species-specific manner. Lespedeza showed increased growth and higher shoot N content at 28 degrees C. Lupinus showed decreases in nodulation and lower shoot N concentration at 28 degrees C. The effect of temperature on shoot N concentration occurred only in individuals whose sole N source was N(2)-fixation, but there was no effect of temperature on delta(15)N values in these plants. CONCLUSIONS: Elevated temperature enhanced seedling growth of some species, while inhibiting nodulation in another. Temperature induced shifts in legume composition or nitrogen dynamics may be another potential mechanism through which climate change affects unmanaged ecosystems. PMID- 22539506 TI - Isolation and characterization of microsatellite markers for Plathymenia reticulata (Fabaceae). AB - PREMISE OF THE STUDY: Microsatellite loci were isolated and characterized for use in population genetic studies of Plathymenia reticulata (Fabaceae), a tropical tree widespread in the Atlantic Forest and cerrado biomes of South America. METHODS AND RESULTS: Nine microsatellite markers were developed using a simple sequence repeat-enriched library. Polymorphism was analyzed in 51 individuals from two populations. All loci were polymorphic, with the number of alleles per loci ranging from five to 15 (mean number of alleles: 10.22). Observed and expected heterozygosities per loci and population ranged from 0.313 to 1.000 and 0.280 to 0.869, respectively. CONCLUSIONS: These highly informative loci are potentially useful to estimate population genetic structure and to understand evolutionary processes and taxonomy of the species. PMID- 22539508 TI - Microsatellite primers in the endangered quillwort Isoetes hypsophila (Isoetaceae) and cross-amplification in I. sinensis. AB - PREMISE OF THE STUDY: The first microsatellite primers were developed for Isoetes hypsophila, an endangered quillwort species endemic to the Qinghai-Tibetan Plateau in China, to further describe its genetic variability and population structure. We also examined their cross-amplification in a congeneric species, I. sinensis. METHODS AND RESULTS: Using the Fast Isolation by AFLP of Sequences COntaining Repeats (FIASCO) protocol, nine microsatellite loci were isolated and characterized in 32 samples from four natural populations of I. hypsophila. The primers amplified di- and hexanucleotide repeats with three to 11 alleles per locus. Seven of nine primers were cross-amplified in I. sinensis with two to seven alleles per locus. CONCLUSION: The microsatellite loci primers will be useful for studies of genetic diversity and gene flow in natural populations of Isoetes species. PMID- 22539509 TI - Development of polymorphic microsatellite markers for Cymbidium goeringii (Orchidaceae). AB - PREMISE OF THE STUDY: Microsatellite markers were developed in Cymbidium goeringii to investigate its genetic diversity and population genetic structure. METHODS AND RESULTS: From a microsatellite-enriched genomic library, 21 novel polymorphic microsatellites were isolated. The polymorphic patterns were verified in four populations (East Korea, West Korea, China, and Japan). The number of alleles per locus ranged from 11 to 29 with a mean of 20.29. The observed and expected heterozygosities varied from 0.272 to 0.799 and from 0.461 to 0.911, respectively. CONCLUSIONS: These microsatellite markers will be useful tools for understanding genetic variation and population ecogenetic structure in C. goeringii. PMID- 22539510 TI - Development and characterization of 38 polymorphic microsatellite markers from an economically important fruit tree, the Indian jujube. AB - PREMISE OF THE STUDY: A total of 38 polymorphic microsatellite loci of the Indian jujube (Ziziphus mauritiana), an economically important fruit tree, were developed to evaluate genetic diversity and aid in the identification of cultivars. METHODS AND RESULTS: The 38 microsatellite markers were isolated from the Indian jujube using a magnetic bead enrichment method, and polymorphisms were identified in 24 Indian jujube cultivars. The number of alleles ranged from two to 13, with expected heterozygosity ranging from 0.261 to 0.898. The polymorphism information content ranged from 0.248 to 0.889, with a mean of 0.616. Of these 38 simple sequence repeat loci, 20 loci from Z. jujuba (Chinese jujube) were successfully amplified using the simple sequence repeat primer sets. CONCLUSIONS: These polymorphic loci should be useful in further studies of the genetic diversity and the identification of cultivars of both the Indian jujube and the Chinese jujube. PMID- 22539511 TI - Development of polymorphic microsatellite markers in Camellia chekiangoleosa (Theaceae) using 454-ESTs. AB - PREMISE OF THE STUDY: A set of microsatellite markers for Camellia chekiangoleosa was developed and characterized using 454 sequencing technology to study the population genetic structure and the diversity of germplasm collections. METHODS AND RESULTS: Eighteen polymorphic microsatellite markers were identified and tested in 150 individuals from three natural populations of C. chekiangoleosa. Alleles numbered from two to seven, and the observed and expected heterozygosities ranged from 0.100 to 0.760 and 0.133 to 0.809, respectively. CONCLUSIONS: These markers will potentially be conducive to further genetic studies on C. chekiangoleosa. PMID- 22539512 TI - Intercarpellary growth of pollen tubes in the extragynoecial compitum and its contribution to fruit set in an apocarpous species, Schisandra sphenanthera (Schisandraceae). AB - PREMISE OF THE STUDY: Apocarpous plants possess carpels that are separated in the gynoecium. Extragynoecial compita, commonly occurring in basal angiosperms, have been proposed to have the potential to increase offspring quantity in apocarpous species through the intercarpellary growth of pollen tubes. To date, the impact of an extragynoecial compitum on fruit or seed set has not been studied in any species. This study investigated the pollen tube pathway between adjacent carpels and its contribution to fruit set in Schisandra sphenanthera. METHODS: We investigated the fruit set ratio in the field and collected hundreds of gynoecia at their full flowering stage. Pollinated carpel ratio and pollen tube pathway observations were performed using fluorescence optics. KEY RESULTS: Pollen grains germinated and tubes extended along the pseudostyle surface. Some of them turned and entered the ovules at the end of the stigmatic crest, whereas others subsequently grew into neighboring carpels through promontory connections located at the base of the unfused carpels. No tubes were found growing on the surface of the receptacle. More than 24 carpels could be fertilized by pollen tubes from one carpel through hand pollination. The pollinated carpel ratio was significantly lower than the fruit set ratio under natural conditions. CONCLUSIONS: Pollen tubes from one carpel can easily cross in the extragynoecial compitum between the adjacent carpels of S. sphenanthera, and this intercarpellary growth of pollen tubes can significantly increase the fruit set of apocarpous species, at least in S. sphenanthera. PMID- 22539513 TI - Portable microsatellite primers for Ficus (Moraceae). AB - PREMISE OF THE STUDY: Highly portable microsatellite primers were developed for Ficus to facilitate investigation of genetic structure of complete regional floras using a single set of markers. METHODS AND RESULTS: Pyrosequencing of five species of Ficus produced a library of 5723 potential primers. Potential primers found in at least two species and presenting identical annealing temperatures were tested on a set of five additional Ficus species. A set of 20 primer pairs producing well-defined and easily readable peaks was retained and tests showed their potential utility for analyzing population genetic structure of 24 Ficus species from Taiwan. Numbers of alleles per locus ranged from one to six in the least variable species and from one to 17 in the most variable species. CONCLUSIONS: The results indicate that our set of primers can be used to analyze polymorphism and compare levels of polymorphism among Ficus species. PMID- 22539514 TI - Low levels of climate niche conservatism may explain clade diversity patterns in the South African genus Pelargonium (Geraniaceae). AB - PREMISE OF THE STUDY: Sharp climatic gradients in South Africa and in particular in the Cape Floristic Region (CFR) provide a diversity of niches over short distances that may have promoted ecological diversification in local clades. Here we measured the extent to which closely related species occupy divergent climates and test whether niche lability is correlated with higher species diversity in the genus. METHOD: We integrated phylogenetic information and environmental niche models (ENM) to assess the levels of climate niche conservatism. ENMs for 113 species of Pelargonium were calculated using maximum entropy. We used two tests, one assessing climate niche equivalency and the other testing niche similarity between sister species and within sections. We also examined whether niche similarity was correlated with phylogenetic relatedness across the genus. KEY RESULTS: Niche similarity was mostly independent of phylogenetic relationships. Compared to random expectations, 23% of closely related species pairs had climate niches that were more similar, and only 6.5% were more disparate; the remaining 70% of comparisons had similarities that fell within random expectations. Similar trends were observed when analyses were restricted to only sister species pairs. Although the overall proportion of niche divergence was low, this was significantly related to sectional diversity. We also found a negative relationship between diversity and the proportion of random niches. CONCLUSIONS: Lack of widespread niche conservatism in a highly heterogeneous landscape and few instances of significant climate niche lability suggest that an adaptive divergence process was implicated in the Pelargonium radiation. PMID- 22539515 TI - Development of microsatellite markers for the dove tree, Davidia involucrata (Nyssaceae), a rare endemic from China. AB - PREMISE OF THE STUDY: Microsatellite primers were developed for the endangered Davidia involucrata to assess the population genetics and infer its evolutionary history. METHODS AND RESULTS: Using both the modified magnetic bead hybridization method and the dual-suppression PCR method, we isolated and characterized 12 polymorphic microsatellite loci using 134 individuals from five populations in southwestern China. The number of alleles per locus ranged from six to 21 (mean = 10.8). The expected heterozygosity per locus ranged from 0.404 to 0.918 and observed heterozygosity ranged from 0.015 to 0.821. CONCLUSIONS: All of the 12 microsatellite markers developed for D. involucrata are polymorphic, and lay a solid foundation for further studies of the population genetics of this famous tree. PMID- 22539516 TI - Edaphic adaptation maintains the coexistence of two cryptic species on serpentine soils. AB - PREMISE OF THE STUDY: Divergent edaphic adaptation can contribute to reproductive isolation and coexistence between closely related species, yet we know little about how small-scale continuous edaphic gradients contribute to this phenomenon. We investigated edaphic adaptation between two cryptic species of California wildflower, Lasthenia californica and L. gracilis (Asteraceae), which grow in close parapatry on serpentine soil. METHODS: We reciprocally transplanted both species into the center of each species' habitat and the transition zone between species. We quantified multiple components of fitness and used aster models to predict fitness based on environmental variables. We sampled soil across the ridge throughout the growing season to document edaphic changes through time. We sampled naturally germinating seedlings to determine whether there was dispersal into the adjacent habitat and to help pinpoint the timing of any selection against migrants. KEY RESULTS: We documented within-serpentine adaptation contributing to habitat isolation between close relatives. Both species were adapted to the edaphic conditions in their native region and suffered fitness trade-offs when moved outside that region. However, observed fitness values did not perfectly match those predicted by edaphic variables alone, indicating that other factors, such as competition, also contributed to plant fitness. Soil water content and concentrations of calcium, magnesium, sodium, and potassium were likely drivers of differential fitness. Plants either had limited dispersal ability or migrants experienced early-season mortality outside their native region. CONCLUSIONS: Demonstrating that continuous habitats can support differently adapted, yet closely related, taxa is important to a broader understanding of how species are generated and maintained in nature. PMID- 22539517 TI - Phylogenetics, biogeography, and staminal evolution in the tribe Mentheae (Lamiaceae). AB - PREMISE OF THE STUDY: The mint family (Lamiaceae) is the sixth largest family of flowering plants, with the tribe Mentheae containing about a third of the species. We present a detailed perspective on the evolution of the tribe Mentheae based on a phylogenetic analysis of cpDNA and nrDNA that is the most comprehensive to date, a biogeographic set of analyses using a fossil-calibrated chronogram, and an examination of staminal evolution. METHODS: Data from four cpDNA and two nrDNA markers representing all extant genera within the tribe Mentheae were analyzed using the programs BEAST, Lagrange, S-DIVA, and BayesTraits. BEAST was used to simultaneously estimate phylogeny and divergence times, Lagrange and S-DIVA were used for biogeographical reconstruction, and BayesTraits was used to infer staminal evolution within the tribe. KEY RESULTS: Currently accepted subtribal delimitations are shown to be invalid and are updated. The Mentheae and all five of its subtribes have a Mediterranean origin and have dispersed to the New World multiple times. The vast majority of New World species of subtribe Menthinae are the product of a single dispersal event in the mid-late Miocene. At least four transitions from four stamens to two stamens have occurred within Mentheae, once in the subtribe Salviinae, once in the subtribe Lycopinae, and at least twice in the subtribe Menthinae. CONCLUSIONS: Worldwide cooling trends probably played a large role in the diversification and present day distribution of the tribe Mentheae. Additional work is needed to ascertain relationships within some Mentheae genera, especially in the subtribe Menthinae. PMID- 22539507 TI - Host and geographic structure of endophytic and endolichenic fungi at a continental scale. AB - PREMISE OF THE STUDY: Endophytic and endolichenic fungi occur in healthy tissues of plants and lichens, respectively, playing potentially important roles in the ecology and evolution of their hosts. However, previous sampling has not comprehensively evaluated the biotic, biogeographic, and abiotic factors that structure their communities. METHODS: Using molecular data we examined the diversity, composition, and distributions of 4154 endophytic and endolichenic Ascomycota cultured from replicate surveys of ca. 20 plant and lichen species in each of five North American sites (Madrean coniferous forest, Arizona; montane semideciduous forest, North Carolina; scrub forest, Florida; Beringian tundra and forest, western Alaska; subalpine tundra, eastern central Alaska). KEY RESULTS: Endolichenic fungi were more abundant and diverse per host species than endophytes, but communities of endophytes were more diverse overall, reflecting high diversity in mosses and lycophytes. Endophytes of vascular plants were largely distinct from fungal communities that inhabit mosses and lichens. Fungi from closely related hosts from different regions were similar in higher taxonomy, but differed at shallow taxonomic levels. These differences reflected climate factors more strongly than geographic distance alone. CONCLUSIONS: Our study provides a first evaluation of endophytic and endolichenic fungal associations with their hosts at a continental scale. Both plants and lichens harbor abundant and diverse fungal communities whose incidence, diversity, and composition reflect the interplay of climatic patterns, geographic separation, host type, and host lineage. Although culture-free methods will inform future work, our study sets the stage for empirical assessments of ecological specificity, metabolic capability, and comparative genomics. PMID- 22539518 TI - Purging of inbreeding depression within a population of Oxalis alpina (Oxalidaceae). AB - PREMISE OF THE STUDY: Variation among individuals in levels of inbreeding depression associated with selfing levels could influence mating system evolution by purging deleterious alleles, but empirical evidence for this association is limited. METHODS: We investigated the association of family-level inbreeding depression and presumed inbreeding history in a tristylous population of Oxalis alpina (Oxalidaceae). KEY RESULTS: Mid-styled individuals possessed the greatest degree of self-compatibility (SC) and produced more autogamous capsules than short- or long-styled individuals. Offspring of highly self-compatible mid-styled individuals showed reduced inbreeding depression. Mid-styled plants that produced capsules autogamously exhibited reduced stigma-anther separation compared to mid styled plants that produced no capsules autogamously. Reduced inbreeding depression was not correlated with stigma-anther separation, suggesting that self compatibility and autogamy evolve before morphological changes in stigma-anther separation. CONCLUSIONS: Purging of inbreeding depression occurred in SC mid styled maternal families. Low inbreeding depression in SC mid-styled plants may lead to retention of the mid-styled morph in populations, despite the occurrence of higher selfing rates in mid-styled relative to short- or long-styled morphs. Variation among individuals in levels of self-fertilization within populations may lead to associations between inbreeding lineages and lower levels of inbreeding depression, influencing the evolution of mating systems. PMID- 22539519 TI - Microsatellite markers for Grosmannia alacris (Ophiostomataceae, Ascomycota) and other species in the G. serpens complex. AB - PREMISE OF THE STUDY: Polymorphic microsatellite markers were developed for the pine-infecting fungus, Grosmannia alacris. METHODS AND RESULTS: Sixteen microsatellite markers were developed by using inter-simple sequence repeat (ISSR)-PCRs and 454 sequencing methods. Seven of these markers showed polymorphisms for a South African population of G. alacris, and 13 markers showed polymorphism when European isolates were included. Most of the primer pairs also amplified four closely related species: G. serpens, Leptographium gibbsii, L. castellanum, and L. yamaokae. CONCLUSIONS: These new markers will be useful for population studies of G. alacris and other species in the G. serpens complex. PMID- 22539520 TI - Phylogeny of Opuntia s.s. (Cactaceae): clade delineation, geographic origins, and reticulate evolution. AB - PREMISE OF THE STUDY: The opuntias (nopales, prickly pears) are not only culturally, ecologically, economically, and medicinally important, but are renowned for their taxonomic difficulty due to interspecific hybridization, polyploidy, and morphological variability. Evolutionary relationships in these stem succulents have been insufficiently studied; thus, delimitation of Opuntia s.s. and major subclades, as well as the biogeographic history of this enigmatic group, remain unresolved. METHODS: We sequenced the plastid intergenic spacers atpB-rbcL, ndhF-rpl32, psbJ-petA, and trnL-trnF, the plastid genes matK and ycf1, the nuclear gene ppc, and ITS to reconstruct the phylogeny of tribe Opuntieae, including Opuntia s.s. We used phylogenetic hypotheses to infer the biogeographic history, divergence times, and potential reticulate evolution of Opuntieae. KEY RESULTS: Within Opuntieae, a clade of Tacinga, Opuntia lilae, Brasiliopuntia, and O. schickendantzii is sister to a well-supported Opuntia s.s., which includes Nopalea. Opuntia s.s. originated in southwestern South America (SA) and then expanded to the Central Andean Valleys and the desert region of western North America (NA). Two major clades evolved in NA, which subsequently diversified into eight subclades. These expanded north to Canada and south to Central America and the Caribbean, eventually returning back to SA primarily via allopolyploid taxa. Dating approaches suggest that most of the major subclades in Opuntia s.s. originated during the Pliocene. CONCLUSIONS: Opuntia s.s. is a well-supported clade that includes Nopalea. The clade originated in southwestern SA, but the NA radiation was the most extensive, resulting in broad morphological diversity and frequent species formation through reticulate evolution and polyploidy. PMID- 22539521 TI - Phylogeny of the Asparagales based on three plastid and two mitochondrial genes. AB - PREMISE OF THE STUDY: The Asparagales, with ca. 40% of all monocotyledons, include a host of commercially important ornamentals in families such as Orchidaceae, Alliaceae, and Iridaceae, and several important crop species in genera such as Allium, Aloe, Asparagus, Crocus, and Vanilla. Though the order is well defined, the number of recognized families, their circumscription, and relationships are somewhat controversial. METHODS: Phylogenetic analyses of Asparagales were based on parsimony and maximum likelihood using nucleotide sequence variation in three plastid genes (matK, ndhF, and rbcL) and two mitochondrial genes (atp1 and cob). Branch support was assessed using both jackknife analysis implementing strict-consensus (SC) and bootstrap analysis implementing frequency-within-replicates (FWR). The contribution of edited sites in the mitochondrial genes to topology and branch support was investigated. KEY RESULTS: The topologies recovered largely agree with previous results, though some clades remain poorly resolved (e.g., Ruscaceae). When the edited sites were included in the analysis, the plastid and mitochondrial genes were highly incongruent. However, when the edited sites were removed, the two partitions became congruent. CONCLUSIONS: Some deeper nodes in the Asparagales tree remain poorly resolved or unresolved as do the relationships of certain monogeneric families (e.g., Aphyllanthaceae, Ixioliriaceae, Doryanthaceae), whereas support for many families increases. However, the increased support is dominated by plastid data, and the potential influence of mitochondrial and biparentially inherited single or low-copy nuclear genes should be investigated. PMID- 22539522 TI - Development of a siRNA and shRNA screening system based on a kinase fusion protein. AB - RNA interference (RNAi) is one of the processes in the cell that regulates mRNA expression levels. RNAi can be exploited to experimentally knockdown the expression of one or more genes in cell lines or even in cells in vivo and also became an interesting tool to develop new therapeutic approaches. One of the major challenges of using RNAi is selecting effective shRNAs or siRNAs that sufficiently down-regulate the expression of the target gene. Here, we describe a system to select functional shRNAs or siRNAs that makes use of the leukemia cell line Ba/F3 that is dependent on the expression of a mutant form of the PDGFRalpha kinase for its proliferation and survival. The basis of this system is the generation of an expression construct, where part of the open reading frame of the gene of interest is linked to the mutant PDGFRalpha. Thus, shRNAs or siRNAs that effectively target the gene of interest also result in a reduction of the expression of the mutant PDGFRalpha protein, which can be detected by a reduction of the proliferation of the cells. We demonstrate that this validation system can be used for the selection of effective siRNAs as well as shRNAs. Unlike other systems, the system described here is not dependent on obtaining high transduction efficiencies, and nonspecific effects of the siRNAs or shRNAs can be detected by comparing the effects in the presence or absence of the growth factor interleukin-3. PMID- 22539523 TI - Metal-ion rescue revisited: biochemical detection of site-bound metal ions important for RNA folding. AB - Within the three-dimensional architectures of RNA molecules, divalent metal ions populate specific locations, shedding their water molecules to form chelates. These interactions help the RNA adopt and maintain specific conformations and frequently make essential contributions to function. Defining the locations of these site-bound metal ions remains challenging despite the growing database of RNA structures. Metal-ion rescue experiments have provided a powerful approach to identify and distinguish catalytic metal ions within RNA active sites, but the ability of such experiments to identify metal ions that contribute to tertiary structure acquisition and structural stability is less developed and has been challenged. Herein, we use the well-defined P4-P6 RNA domain of the Tetrahymena group I intron to reevaluate prior evidence against the discriminatory power of metal-ion rescue experiments and to advance thermodynamic descriptions necessary for interpreting these experiments. The approach successfully identifies ligands within the RNA that occupy the inner coordination sphere of divalent metal ions and distinguishes them from ligands that occupy the outer coordination sphere. Our results underscore the importance of obtaining complete folding isotherms and establishing and evaluating thermodynamic models in order to draw conclusions from metal-ion rescue experiments. These results establish metal-ion rescue as a rigorous tool for identifying and dissecting energetically important metal-ion interactions in RNAs that are noncatalytic but critical for RNA tertiary structure. PMID- 22539524 TI - Determination of ribonuclease sequence-specificity using Pentaprobes and mass spectrometry. AB - The VapBC toxin-antitoxin (TA) family is the largest of nine identified TA families. The toxin, VapC, is a metal-dependent ribonuclease that is inhibited by its cognate antitoxin, VapB. Although the VapBCs are the largest TA family, little is known about their biological roles. Here we describe a new general method for the overexpression and purification of toxic VapC proteins and subsequent determination of their RNase sequence-specificity. Functional VapC was isolated by expression of the nontoxic VapBC complex, followed by removal of the labile antitoxin (VapB) using limited trypsin digestion. We have then developed a sensitive and robust method for determining VapC ribonuclease sequence specificity. This technique employs the use of Pentaprobes as substrates for VapC. These are RNA sequences encoding every combination of five bases. We combine the RNase reaction with MALDI-TOF MS to detect and analyze the cleavage products and thus determine the RNA cut sites. Successful MALDI-TOF MS analysis of RNA fragments is acutely dependent on sample preparation methods. The sequence specificity of four VapC proteins from two different organisms (VapC(PAE0151) and VapC(PAE2754) from Pyrobaculum aerophilum, and VapC(Rv0065) and VapC(Rv0617) from Mycobacterium tuberculosis) was successfully determined using the described strategy. This rapid and sensitive method can be applied to determine the sequence-specificity of VapC ribonucleases along with other RNA interferases (such as MazF) from a range of organisms. PMID- 22539525 TI - Structure and folding of a rare, natural kink turn in RNA with an A*A pair at the 2b*2n position. AB - The kink turn (k-turn) is a frequently occurring motif, comprising a bulge followed by G*A and A*G pairs that introduces a sharp axial bend in duplex RNA. Natural k-turn sequences exhibit significant departures from the consensus, including the A*G pairs that form critical interactions stabilizing the core of the structure. Kt-23 found in the small ribosomal subunit differs from the consensus in many organisms, particularly in the second A*G pair distal to the bulge (2b*2n). Analysis of many Kt-23 sequences shows that the frequency of occurrence at the 2n position (i.e., on the nonbulged strand, normally G in standard k-turns) is U>C>G>A. Less than 1% of sequences have A at the 2n position, but one such example occurs in Thelohania solenopsae Kt-23. This sequence folds only weakly in the presence of Mg2+ ions but is induced to fold normally by the binding of L7Ae protein. Introduction of this sequence into the SAM-I riboswitch resulted in normal binding of SAM ligand, indicating that tertiary RNA contacts have resulted in k-turn folding. X-ray crystallography shows that the T. solenopsae Kt-23 adopts a standard k-turn geometry, making the key, conserved hydrogen bonds in the core and orienting the 1n (of the bulge proximal A*G pair) and 2b adenine nucleobases in position facing the opposing minor groove. The 2b and 2n adenine nucleobases are not directly hydrogen bonded, but each makes hydrogen bonds to their opposing strands. PMID- 22539526 TI - RNA secondary structure mediates alternative 3'ss selection in Saccharomyces cerevisiae. AB - Alternative splicing is the mechanism by which different combinations of exons in the pre-mRNA give rise to distinct mature mRNAs. This process is mediated by splicing factors that bind the pre-mRNA and affect the recognition of its splicing signals. Saccharomyces species lack many of the regulatory factors present in metazoans. Accordingly, it is generally assumed that the amount of alternative splicing is limited. However, there is recent compelling evidence that yeast have functional alternative splicing, mainly in response to environmental conditions. We have previously shown that sequence and structure properties of the pre-mRNA could explain the selection of 3' splice sites (ss) in Saccharomyces cerevisiae. In this work, we extend our previous observations to build a computational classifier that explains most of the annotated 3'ss in the CDS and 5' UTR of this organism. Moreover, we show that the same rules can explain the selection of alternative 3'ss. Experimental validation of a number of predicted alternative 3'ss shows that their usage is low compared to annotated 3'ss. The majority of these alternative 3'ss introduce premature termination codons (PTCs), suggesting a role in expression regulation. Furthermore, a genome wide analysis of the effect of temperature, followed by experimental validation, yields only a small number of changes, indicating that this type of regulation is not widespread. Our results are consistent with the presence of alternative 3'ss selection in yeast mediated by the pre-mRNA structure, which can be responsive to external cues, like temperature, and is possibly related to the control of gene expression. PMID- 22539528 TI - More on the immune privilege of glioblastoma. PMID- 22539527 TI - Meiosis-induced alterations in transcript architecture and noncoding RNA expression in S. cerevisiae. AB - Changes in transcript architecture can have powerful effects on protein expression. Regulation of the transcriptome is often dramatically revealed during dynamic conditions such as development. To examine changes in transcript architecture we analyzed the expression and transcript boundaries of protein coding and noncoding RNAs over the developmental process of meiosis in Saccharomyces cerevisiae. Custom-designed, high-resolution tiling arrays were used to define the time-resolved transcriptome of cells undergoing meiosis and sporulation. These arrays were specifically designed for the S. cerevisiae strain SK1 that sporulates with high efficiency and synchrony. In addition, new methods were created to define transcript boundaries and to identify dynamic changes in transcript expression and architecture over time. Of 8407 total segments, 699 (8.3%) were identified by our algorithm as regions containing potential transcript architecture changes. Our analyses reveal extensive changes to both the coding and noncoding transcriptome, including altered 5' ends, 3' ends, and splice sites. Additionally, 3910 (46.5%) unannotated expressed segments were identified. Interestingly, subsets of unannotated RNAs are located across from introns (anti-introns) or across from the junction between two genes (anti intergenic junctions). Many of these unannotated RNAs are abundant and exhibit sporulation-specific changes in expression patterns. All work, including heat maps of the tiling array, annotation for the SK1 strain, and phastCONS conservation analysis, is available at http://groups.molbiosci.northwestern.edu/sontheimer/sk1meiosis.php. Our high resolution transcriptome analyses reveal that coding and noncoding transcript architectures are exceptionally dynamic in S. cerevisiae and suggest a vast array of novel transcriptional and post-transcriptional control mechanisms that are activated upon meiosis and sporulation. PMID- 22539532 TI - Calibration and features of air-kerma length product meters. AB - Pencil-type air-kerma length product meters are generally used for quality control and radiation exposure measurements in computed tomography. To ensure reliable results, these meters should be calibrated so that measurements are traceable to international standards. Suitable calibration procedures, together with the properties of these meters, were examined and compared with the international standards and recommendations. The calibration procedure and setup used in this study were slightly modified compared with international recommendations. The special collimator system was found to cause less scatter than similar setups in earlier studies. The energy dependence of the meter response was investigated for several types of meters with standard radiation qualities. With most tested meter types, the total variation due to energy dependence was <4 %, but some had strong energy dependence and the variation was up to 15 % or higher. This highlights the importance of a proper calibration. The response of one semiconductor meter type varied up to 8 % when rotating the meter around its axis; this should be taken into account when making calibrations with a static setup. PMID- 22539533 TI - Distribution of low-level natural radioactivity in a populated marine region of the Eastern Mediterranean Sea. AB - The levels of natural radioactivity have been evaluated in the water column of an eastern Mediterranean region (Saronikos Gulf), with respect to the relevant environmental parameters. A novel methodology was used for the determination of natural radionuclides, which substitutes the time-consuming radiochemical analysis, based on an in situ sample preconcentration using ion-selective manganese fibres placed on pumping systems. With regard to the results obtained, (238)U-series radionuclides were found at the same level or lower than those observed previously in Mediterranean regions indicating the absence of technologically enhanced naturally occurring radioactive material (TENORM) activities in the area. Similar results were observed for the (232)Th-series radionuclides and (40)K in the water column in comparison with the relevant literature on the Mediterranean Sea. The calculated ratios of (238)U-(232)Th and (40)K-(232)Th verified the lack of TENORM contribution in the Saronikos Gulf. Finally, a rough estimation was attempted concerning the residence times of fresh water inputs from a treatment plant of domestic wastes (Waste Water Treatment Plant of Psitalia) showing that fresh waters need a maximum of 15.7+/-7.6 d to be mixed with the open sea water. PMID- 22539531 TI - Head, neck, and brain tumor embolization guidelines. AB - BACKGROUND: Management of vascular tumors of the head, neck, and brain is often complex and requires a multidisciplinary approach. Peri-operative embolization of vascular tumors may help to reduce intra-operative bleeding and operative times and have thus become an integral part of the management of these tumors. Advances in catheter and non-catheter based techniques in conjunction with the growing field of neurointerventional surgery is likely to expand the number of peri operative embolizations performed. The goal of this article is to provide consensus reporting standards and guidelines for embolization treatment of vascular head, neck, and brain tumors. SUMMARY: This article was produced by a writing group comprised of members of the Society of Neurointerventional Surgery. A computerized literature search using the National Library of Medicine database (Pubmed) was conducted for relevant articles published between 1 January 1990 and 31 December 2010. The article summarizes the effectiveness and safety of peri operative vascular tumor embolization. In addition, this document provides consensus definitions and reporting standards as well as guidelines not intended to represent the standard of care, but rather to provide uniformity in subsequent trials and studies involving embolization of vascular head and neck as well as brain tumors. CONCLUSIONS: Peri-operative embolization of vascular head, neck, and brain tumors is an effective and safe adjuvant to surgical resection. Major complications reported in the literature are rare when these procedures are performed by operators with appropriate training and knowledge of the relevant vascular and surgical anatomy. These standards may help to standardize reporting and publication in future studies. PMID- 22539534 TI - The role of age and sex in symptoms, neurocognitive performance, and postural stability in athletes after concussion. AB - BACKGROUND: Researchers have begun to focus on age and sex differences in concussion outcomes. Results suggest that younger athletes and female athletes may take longer to recover from a concussion. However, little is known about the interactive effects of age and sex on symptoms, neurocognitive testing (NCT), and postural stability. HYPOTHESIS/PURPOSE: The purpose of the study was to examine sex and age differences in symptoms, NCT, and postural stability following concussion. We hypothesized that high school and female athletes would have worse symptoms, NCT, and postural stability than college and male athletes, respectively. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A total of 296 concussed athletes from a multistate, 2-year study were enrolled in this study. Participants completed the Immediate Post-Concussion Assessment and Cognitive Test (ImPACT) and Post-Concussion Symptom Scale (PCSS) at baseline and again at 2, 7, and 14 days after concussion. Participants completed the Balance Error Scoring System (BESS) at 1, 2, and 3 days after concussion. RESULTS: Female athletes performed worse than male athletes on visual memory (mean, 65.1% and 70.1%, respectively; P = .049) and reported more symptoms (mean, 14.4 and 10.1, respectively) after concussion (P = .035). High school athletes performed worse than college athletes on verbal (mean, 78.8% and 82.7%, respectively; P = .001) and visual (mean, 65.8% and 69.4%, respectively; P = .01) memory. High school athletes were still impaired on verbal memory 7 days after concussion compared with collegiate athletes (P = .001). High school male athletes scored worse on the BESS than college male athletes (mean, 18.8 and 13.0, respectively; P = .001). College female athletes scored worse on the BESS than high school female athletes (mean, 21.1 and 16.9, respectively; P = .001). CONCLUSION: The results of the current study supported age differences in memory and sex differences in memory and symptoms and an interaction between age and sex on postural stability after concussion that warrant consideration from clinicians and researchers when interpreting symptoms, specific components of NCT, and postural stability tests. Future research should develop and assess interventions tailored to age and sex differences and include younger (<14 years) participants. PMID- 22539535 TI - Arthroscopic treatment of synovial chondromatosis of the hip. AB - BACKGROUND: Recently, arthroscopic loose body removal and synovectomy have been performed as treatments for synovial chondromatosis of the hip joint. However, to date, no reports have been published on the outcomes of arthroscopic treatments. HYPOTHESIS: Arthroscopic treatment is effective for synovial chondromatosis of the hip joint and has advantages such as low recurrence rates, faster return to activities of daily life, and few surgical complications. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: From June 1996 to July 2008, 24 patients with synovial chondromatosis of the hip who were followed up after arthroscopic removal of loose bodies and synovectomy were evaluated. The common arthroscopic portals were the anterior, anterolateral, and posterolateral portals. In some cases, we applied a medial portal for removal of loose bodies in the posteromedial pouch. Preoperative and postoperative assessments were made through simple radiographs, 3-dimensional computed tomography, magnetic resonance imaging, visual analog scale (VAS) for pain, range of motion of the joint, Harris Hip Score, and Merle D'Aubigne and Postel score. RESULTS: Postoperative mean follow-up period was 41 months. There were no major complications. Patients were able to walk weightbearing on average 2 days after surgery and were discharged in an average of 3.5 days (range, 3-5 days) after surgery. In postoperative radiological imaging, 4 patients showed progression of joint osteoarthritis, and 1 of them underwent total hip arthroplasty. The VAS score before surgery was 8.1 +/- 1.3 and after surgery was 3.1 +/- 1.4. Range of motion of the hip joint before surgery was increased after surgery, except in 1 patient who required a third operation. Harris Hip Score before surgery was an average of 39 +/- 6.9 and improved to an average of 82 +/- 10.2 after surgery. Eighteen patients (75%) had good or excellent outcomes. Symptomatic disease recurred in 4 patients (16.7%), and 1 of these 4 patients showed a subsequent recurrence. CONCLUSION: The treatment of synovial chondromatosis of the hip using arthroscopic loose body removal and synovectomy is relatively successful, and rehabilitation of patients is fast, therefore making it an effective treatment with satisfactory postsurgical results. However, a technical limitation of arthroscopy is the difficulty in approaching the posterolateral and posteromedial areas of the peripheral compartment. PMID- 22539536 TI - A randomized trial comparing accelerated and traditional approaches to postoperative weightbearing rehabilitation after matrix-induced autologous chondrocyte implantation: findings at 5 years. AB - BACKGROUND: While structured postoperative rehabilitation after matrix-induced autologous chondrocyte implantation (MACI) is considered critical, very little has been made available on how best to progressively increase weightbearing and exercise after surgery. HYPOTHESIS: A significant improvement will exist in clinical and magnetic resonance imaging (MRI)-based scoring measures to 5 years after surgery. Furthermore, there will be no significant differences in outcomes in MACI patients at 5 years when comparing a traditional and an accelerated postoperative weightbearing regimen. Finally, patient demographics, cartilage defect parameters, and injury/surgery history will be associated with graft outcome. STUDY DESIGN: Randomized controlled trial; level of evidence, 1. METHODS: Clinical and radiological outcomes were studied in 70 patients who underwent MACI to the medial or lateral femoral condyle, in conjunction with either an "accelerated" or a "traditional" approach to postoperative weightbearing rehabilitation. Under the accelerated protocol, patients reached full weightbearing at 8 weeks after surgery, compared with 11 weeks for the traditional group. Clinical measures (knee injury and osteoarthritis outcome score [KOOS], short-form health survey [SF-36], visual analog scale [VAS], 6 minute walk test, and knee range of motion) were assessed before surgery and at 3, 6, 12, and 24 months and 5 years after surgery. High-resolution MRI was undertaken at 3, 12, and 24 months and 5 years after surgery and assessed 8 previously defined pertinent parameters of graft repair as well as a combined MRI composite score. The association between clinical and MRI-based outcomes, patient demographics, chondral defect parameters, and injury/surgery history was investigated. RESULTS: Of the 70 patients recruited, 63 (31 accelerated, 32 traditional) underwent clinical follow-up at 5 years; 58 (29 accelerated, 29 traditional) also underwent radiological assessment. A significant time effect (P < .05) was demonstrated for all clinical and MRI-based scores over the 5-year period. While the VAS demonstrated significantly less frequent pain at 5 years in the accelerated group, there were no other significant differences between the 2 groups. Between 24 months and 5 years, a significant improvement (P < .05) in both groups was observed for the sport and recreation subscale of the KOOS as well as a significant decrease (P < .05) in active knee extension for the traditional group. There were no significant differences (P > .05) in the MRI based scores between 24 months and 5 years after surgery. Patient age and defect size exhibited significant negative correlations (P < .05) with several MRI-based outcomes at 5 years, while there were no significant correlations (P > .05) between clinical and MRI-based outcomes. At 5 years after surgery, 94% and 95% were satisfied with the ability of MACI to relieve their knee pain and improve their ability to undertake daily activities, respectively. CONCLUSION: The outcomes of this randomized trial demonstrate a safe and effective accelerated rehabilitation protocol as well as a regimen that provides comparable, if not superior, clinical outcomes to patients throughout the postoperative timeline. PMID- 22539538 TI - Anatomic characteristics and radiographic references of the anterolateral and posteromedial bundles of the posterior cruciate ligament. AB - BACKGROUND: Anatomic graft tunnel placement is reported to be essential in double bundle posterior cruciate ligament (PCL) reconstruction. A measurement system that correlates anatomy and radiographs is lacking so far. PURPOSE: To define the femoral and tibial attachments of the anterolateral (AL) and posteromedial (PM) bundles and to correlate them with digital and radiographic images to establish a radiographic anatomy based on anatomic landmarks and evaluate whether radiographs can serve as an accurate method for intraoperative and postoperative assessments of tunnel placement. STUDY DESIGN: Descriptive laboratory study. METHODS: Fifteen human cadaveric knee specimens were used. After preparation, the insertion areas of the 2 fiber bundles were marked with colorants, and high-definition digital images were obtained. With radiopaque tubes placed in the center of each bundle's footprint, anteroposterior and lateral radiographs were created. A measurement grid system was superimposed to determine the position of the AL and PM bundles' femoral and tibial insertion areas on both digital images and radiographs. The measurement zones were numbered 1 to 16, starting in the anterosuperior corner and ending in the posteroinferior corner. RESULTS: On radiographs and digital images, the femoral centers of the AL and PM bundles were found in zones 2 and 7, respectively. The tibial centers of the AL and PM bundles were found at 47.88% and 50.93%, respectively, of the total mediolateral diameter, 83.09% and 92.29%, respectively, of the total anteroposterior diameter, and 3.53 mm and 8.57 mm, respectively, inferior from the tibial plateau on radiographs. CONCLUSION: This study provides a geometric characterization of the AL and PM bundles of the PCL and establishes a reliable and feasible correlation system between anatomy and radiography based on anatomic landmarks. CLINICAL RELEVANCE: Accurate definition of the insertion sites of the PCL is essential for anatomic double-bundle reconstruction. The results of our study may be used as a reference for intraoperative and postoperative assessments of correct femoral and tibial tunnel placements. PMID- 22539537 TI - In vivo evidence for tibial plateau slope as a risk factor for anterior cruciate ligament injury: a systematic review and meta-analysis. AB - BACKGROUND: In vivo studies reporting tibial plateau slope as a risk factor for anterior cruciate ligament (ACL) injury have been published with greatly increasing frequency. PURPOSE: To examine and summarize the in vivo evidence comparing tibial slope in ACL-injured and uninjured populations. STUDY DESIGN: Systematic review and meta-analysis. METHODS: We reviewed publications in Scopus, SPORTDiscus, CINAHL, and PubMed to identify all studies reporting a measure of tibial plateau slope between ACL-injured groups and controls. A meta-analysis was performed including calculation of effect size and 95% confidence interval as well as 95% confidence intervals for the mean values of the measurement in each study. RESULTS: Fourteen studies met our inclusion/exclusion criteria. Five of 6 radiographic studies reporting medial tibial plateau slope (MTPS) demonstrated significant differences between controls and ACL-injured groups, while only 1 of 7 magnetic resonance imaging (MRI) studies reported significant differences between groups. Mean MTPS measurements and standard deviations reported for controls ranged from 2.9 degrees +/- 2.8 degrees anterior to 9.5 degrees +/- 3 degrees posterior. For ACL-injured patients, MTPS ranged from 1.8 degrees +/- 3.5 degrees anterior to 12.1 degrees +/- 3.3 degrees posterior. Lateral tibial plateau slope (LTPS) was reported to be significantly greater in ACL-injured groups in all 5 MRI-based studies reporting group comparisons. Mean values for LTPS in controls ranged from 0.3 degrees +/- 3.6 degrees anterior slope to 9 degrees +/- 4 degrees posterior slope. In ACL-injured groups, mean reported LTPS values ranged from 1.8 degrees +/- 3.2 degrees to 11.5 degrees +/- 3.54 degrees posterior slope. CONCLUSION: Despite high measures of reliability for the various methods reported in current studies, there is vast disagreement regarding the actual values of the slope that would be considered "at risk." Reported tibial slope values for control groups vary greatly between studies. In many cases, the study-to-study differences in "normal" tibial slope exceed the difference between controls and ACL-injured patients. The clinical utility of imaging-based measurement methods for the determination of ACL injury risk requires more reliable techniques that demonstrate consistency between studies. PMID- 22539539 TI - The relative impact on leg symptoms of fears of getting varicose veins and of great saphenous vein reflux. AB - OBJECTIVE: To assess possible links between fears of getting varicose veins and unknown great saphenous vein reflux with the prevalence and features of leg symptoms in healthy people and patients with varicose veins. METHODS: Questionnaire and venous ultrasound in healthy volunteers and patients with great saphenous vein (GSV) incompetence. RESULTS: Intensity of feelings of swelling and heaviness (S&H; scale 0-3) was 0.26 (+/-0.51) in healthy people without fears of varicose veins (n = 162), 0.56 (+/-0.72) in the presence of GSV reflux (n = 39, P = 0.001), 0.73 (+/-0.77) in the presence of fears of varicose veins (n = 43, P < 0.001), 0.95 (+/-0.98) in the presence of both findings (n = 10, P = 0.002) and 0.73 (+/-0.91) in patients (n = 40, P < 0.001). Intensity of S&H was higher in women (P < 0.001) and in the presence of a family history of varicose veins (P = 0.003). Fears had a large influence on S&H (F = 12.38, P < 0.001) while GSV reflux was less important (F = 4.58, P = 0.033). Fears and GSV reflux were not related to each other (r = -0.01, P = 0.933). The prevalence of a crawling sensation was equal in all study groups and cramps were more frequent in volunteers than in patients with GSV reflux (P < 0.001). CONCLUSIONS: Healthy people with fears of getting varicose veins experience feelings of leg S&H as frequently as subjects with previously unknown GSV incompetence and patients with manifest varicose veins. PMID- 22539540 TI - What are the implications of variation in root hair length on tolerance to phosphorus deficiency in combination with water stress in barley (Hordeum vulgare)? AB - BACKGROUND AND AIMS: Phosphorus commonly limits crop yield and is frequently applied as fertilizer; however, supplies of quality rock phosphate for fertilizer production are diminishing. Plants have evolved many mechanisms to increase their P-fertilizer use efficiency, and an understanding of these traits could result in improved long-term sustainability of agriculture. Here a mutant population is utilized to assess the impact of root hair length on P acquisition and yield under P-deficient conditions alone or when combined with drought. METHODS: Mutants with various root hair phenotypes were grown in the glasshouse in pots filled with soil representing sufficient and deficient P treatments and, in one experiment, a range of water availability was also imposed. Plants were variously harvested at 7 d, 8 weeks and 14 weeks, and variables including root hair length, rhizosheath weight, biomass, P accumulation and yield were measured. KEY RESULTS: The results confirmed the robustness of the root hair phenotypes in soils and their relationship to rhizosheath production. The data demonstrated that root hair length is important for shoot P accumulation and biomass, while only the presence of root hairs is critical for yield. Root hair presence was also critical for tolerance to extreme combined P deficit and drought stress, with genotypes with no root hairs suffering extreme growth retardation in comparison with those with root hairs. CONCLUSIONS: The results suggest that although root hair length is not important for maintaining yield, the presence of root hairs is implicit to sustainable yield of barley under P-deficient conditions and when combined with extreme drought. Root hairs are a trait that should be maintained in future germplasm. PMID- 22539541 TI - Peperomia leaf cell wall interface between the multiple hypodermis and crystal containing photosynthetic layer displays unusual pit fields. AB - BACKGROUND AND AIMS: Leaves of succulent Peperomia obtusifolia (Piperaceae), and its related species, contain a large multilayered hypodermis (epidermis) subtended by a very small single-layered photosynthetic palisade parenchyma, the latter containing spherical aggregates of crystals called druses. Each druse is in a central vacuole surrounded by chloroplasts. All hypodermal cell walls are thin, except for thick lowermost periclinal walls associated with the upper periclinal walls of the subtending palisade cells. These thick walls display 'quilted' impressions (mounds) formed by many subtending palisade cells. Conspicuous depressions occur in most mounds, and each depression contains what appear to be many plasmodesmata. These depressions are opposite similar regions in adjacent thin palisade periclinal walls, and they can be considered special pit fields that represent thin translucent regions ('windows' or 'skylights'). Druses in the vacuoles of palisade cells occur below these pit field regions and are surrounded by conspicuous cytoplasmic chloroplasts with massive grana oriented perpendicular to the crystals, probably providing for an efficient photosynthetic system under low-intensity light. METHODS: Leaf clearings and fractures, light microscopy and crossed polarizers, general and histochemical staining, and transmission and scanning electron microscopy were used to examine these structures. KEY RESULTS: Druses in the vacuoles of palisade cells occur below the thin pit field regions in the wall interface, suggesting an interesting physical relationship that could provide a pathway for light waves, filtered through the multiple hypodermis. The light waves pass into the palisade cells and are collected and dispersed by the druses to surrounding chloroplasts with large grana. CONCLUSIONS: These results imply an intriguing possible efficient photosynthetic adaptation for species growing in low-light environments, and provide an opportunity for future research on how evolution through environmental adaptation aids plants containing crystals associated with photosynthetic tissues to exist under low-light intensity and with other stresses. PMID- 22539543 TI - Wasting stroke prevention resources. PMID- 22539542 TI - Phylogenetics of tribe Orchideae (Orchidaceae: Orchidoideae) based on combined DNA matrices: inferences regarding timing of diversification and evolution of pollination syndromes. AB - BACKGROUND AND AIMS: Tribe Orchideae (Orchidaceae: Orchidoideae) comprises around 62 mostly terrestrial genera, which are well represented in the Northern Temperate Zone and less frequently in tropical areas of both the Old and New Worlds. Phylogenetic relationships within this tribe have been studied previously using only nuclear ribosomal DNA (nuclear ribosomal internal transcribed spacer, nrITS). However, different parts of the phylogenetic tree in these analyses were weakly supported, and integrating information from different plant genomes is clearly necessary in orchids, where reticulate evolution events are putatively common. The aims of this study were to: (1) obtain a well-supported and dated phylogenetic hypothesis for tribe Orchideae, (ii) assess appropriateness of recent nomenclatural changes in this tribe in the last decade, (3) detect possible examples of reticulate evolution and (4) analyse in a temporal context evolutionary trends for subtribe Orchidinae with special emphasis on pollination systems. METHODS: The analyses included 118 samples, belonging to 103 species and 25 genera, for three DNA regions (nrITS, mitochondrial cox1 intron and plastid rpl16 intron). Bayesian and maximum-parsimony methods were used to construct a well-supported and dated tree. Evolutionary trends in the subtribe were analysed using Bayesian and maximum-likelihood methods of character evolution. KEY RESULTS: The dated phylogenetic tree strongly supported the recently recircumscribed generic concepts of Bateman and collaborators. Moreover, it was found that Orchidinae have diversified in the Mediterranean basin during the last 15 million years, and one potential example of reticulate evolution in the subtribe was identified. In Orchidinae, pollination systems have shifted on numerous occasions during the last 23 million years. CONCLUSIONS: The results indicate that ancestral Orchidinae were hymenopteran-pollinated, food-deceptive plants and that these traits have been dominant throughout the evolutionary history of the subtribe in the Mediterranean. Evidence was also obtained that the onset of sexual deception might be linked to an increase in labellum size, and the possibility is discussed that diversification in Orchidinae developed in parallel with diversification of bees and wasps from the Miocene onwards. PMID- 22539544 TI - Times from symptom onset to hospital arrival in the Get with the Guidelines- Stroke Program 2002 to 2009: temporal trends and implications. AB - BACKGROUND AND PURPOSE: Time from symptom onset to hospital arrival is the most important factor in determining eligibility for intravenous tissue-type plasminogen activator. We used data from a large contemporary nationwide study to determine temporal trends in the proportions of patients arriving within time windows for potential acute ischemic stroke therapies. METHODS: Trends in symptom onset to hospital arrival time ("onset-to-door time") for patients with acute ischemic stroke in the Get With The Guidelines-Stroke (GWTG-Stroke) program were analyzed between 2003 and 2009. Factors associated with early onset-to-door time (<=2 hours) were also examined. RESULTS: Between April 2003 and March 2009, 1287 hospitals submitted data on 413 147 patients with acute ischemic stroke of whom 194 352 (47.0%) had a specific onset time documented. Among all 413 147 patients, onset-to-door time was documented as <=2 hours in 20.6%, <=3 hours in 25.1%, <=3.5 hours in 26.8%, and <=8 hours in 35.8%. Early arrival within 2 hours was significantly associated with emergency medical services transport (P<0.0001). There was no substantial change in onset-to-door time over the 6-year study period. Expansion of the tissue-type plasminogen activator treatment window from 3 to 4.5 hours (allowing 60 minutes for provision of tissue-type plasminogen activator) increases the pool of potentially eligible patients by 6.3% (30.1% relative increase). CONCLUSIONS: More than one fourth of patients with ischemic stroke arrive within the time window for tissue-type plasminogen activator therapy; however, this percentage has remained unchanged over recent years. Further efforts are needed to increase the portion of patients with acute ischemic stroke presenting within the time window for acute interventions. PMID- 22539545 TI - Association between changes in lipid profiles and progression of symptomatic intracranial atherosclerotic stenosis: a prospective multicenter study. AB - BACKGROUND AND PURPOSE: Predictors of progression of intracranial atherosclerotic stenosis have not been clearly identified. We investigated whether poststroke changes in lipid profiles would affect the prognosis of symptomatic intracranial atherosclerotic stenosis. METHODS: This is a substudy of Trial of cilOstazol in Symptomatic intracranial Stenosis 2 (TOSS-2). From 10 centers we enrolled 230 subjects with acute symptomatic stenosis in the M1 segment of the middle cerebral artery or basilar artery. At baseline and 7 months after stroke, subjects underwent MR angiogram and assessment of cardiovascular risk factors including lipoprotein levels. Progression of intracranial atherosclerotic stenosis was determined by comparing stenosis on the baseline and follow-up MR angiograms. RESULTS: Cilostazol treatment was more frequently seen in the nonprogression group (109 of 198 [55.1%]) than in the progression group (11 of 32 [34.4%]). At 7 months after stroke when compared with baseline, low-density lipoprotein cholesterol and total cholesterol levels decreased in both groups. However, only nonprogressors showed increase in high-density lipoprotein cholesterol levels between baseline and follow-up. Changes in apolipoprotein B/apolipoprotein A-I levels were not different between the groups, although apolipoprotein B/A-I at 7 months was higher in progressors than in nonprogressors. Remnant lipoprotein cholesterol levels decreased in nonprogressors, whereas they did not change in progressors. In multivariable analyses, after adjusting for cilostazol treatment and remnant lipoprotein cholesterol reduction or apolipoprotein B/A-I at 7 months, high-density lipoprotein cholesterol elevation remained as a significant predictor for the nonprogression. CONCLUSIONS: This is the first prospective multicenter study to demonstrate that high-density lipoprotein cholesterol elevation, along with remnant lipoprotein cholesterol reduction and low apolipoprotein B/A-I, is associated with prevention of angiographic progression of symptomatic intracranial atherosclerotic stenosis. CLINICAL TRIAL REGISTRATION INFORMATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00130039. PMID- 22539546 TI - Thirty-day mortality after ischemic stroke and intracranial hemorrhage in patients with atrial fibrillation on and off anticoagulants. AB - BACKGROUND AND PURPOSE: Prescribing warfarin for atrial fibrillation depends in large part on the expected reduction in ischemic stroke risk versus the expected increased risk of intracranial hemorrhage (ICH). However, the anticoagulation decision also depends on the relative severity of such events. We assessed the impact of anticoagulation on 30-day mortality from ischemic stroke versus ICH in a large community-based cohort of patients with atrial fibrillation. METHODS: We followed 13,559 patients with atrial fibrillation enrolled in an integrated healthcare delivery system for a median 6 years. Incident ischemic strokes and ICHs were identified from computerized databases and validated through medical record review. The association of warfarin and international normalized ratio at presentation with 30-day mortality was modeled using multivariable logistic regression adjusting for clinical factors. RESULTS: We identified 1025 incident ischemic strokes and 299 ICHs during follow-up. Compared with no antithrombotic therapy, warfarin was associated with reduced Rankin score and lower 30-day mortality from ischemic stroke (adjusted OR, 0.64; 95% CI, 0.45-0.91) but a higher mortality from ICH (OR, 1.62; 95% CI, 0.88-2.98). Therapeutic international normalized ratios (2-3) were associated with an especially low ischemic stroke mortality (OR, 0.38; 95% CI, 0.20-0.70), whereas international normalized ratios>3 increased the odds of dying of ICH by 2.66-fold (95% CI, 1.21 5.86). CONCLUSIONS: Warfarin reduces 30-day mortality from ischemic stroke but increases ICH-related mortality. Both effects on event severity as well as on event rates need to be incorporated into rational decision-making about anticoagulants for atrial fibrillation. PMID- 22539547 TI - Letter by Freeman and Taussky regarding article, "Near infrared spectroscopy for the detection of desaturations in vulnerable ischemic brain tissue: a pilot study at the stroke unit bedside". PMID- 22539549 TI - Letter by Labovitz and Bhupali regarding article, "transient ischemic attack in Joinville, Brazil, 2010: a population-based study". PMID- 22539548 TI - Comparison of arterial spin labeling and bolus perfusion-weighted imaging for detecting mismatch in acute stroke. AB - BACKGROUND AND PURPOSE: The perfusion-weighted imaging (PWI)-diffusion-weighted imaging (DWI) mismatch paradigm is widely used in stroke imaging studies. Arterial spin labeling (ASL) is an alternative perfusion method that does not require contrast. This study compares the agreement of ASL-DWI and PWI-DWI mismatch classification in patients with stroke. METHODS: This was a retrospective study drawn from all 1.5-T MRI studies performed in 2010 at a single institution. Inclusion criteria were: symptom onset<5 days, DWI lesion>10 mL, and acquisition of both PWI and ASL. DWI and PWI time to maximum>6 seconds lesion volumes were determined using automated software. Patients were classified into reperfused, matched, or mismatch groups. Two radiologists classified ASL-DWI qualitatively into the same categories blinded to DWI-PWI. Agreement between both individual readers and methods was assessed. RESULTS: Fifty-one studies met the inclusion criteria. Seven cases were excluded (1 due to PWI susceptibility artifact, 2 due to motion, and 4 due to severe ASL border zone sign), resulting in 44 studies for comparison. Interrater agreement for ASL-DWI mismatch status was high (kappa=0.92; 95% CI, 0.80-1.00). ASL-DWI and PWI-DWI mismatch categories agreed in 25 of 44 cases (57%). In the 16 of 19 discrepant cases (84%), ASL overestimated the PWI lesion size. In 34 of 44 cases (77%), they agreed regarding the presence of mismatch versus no mismatch. CONCLUSIONS: Mismatch classification based on ASL and PWI agrees frequently but not perfectly. ASL tends to overestimate the PWI time to maximum lesion volume. Improved ASL methodologies and/or higher field strength are necessary before ASL can be recommended for routine use in acute stroke. PMID- 22539550 TI - Defining the role of PET-CT in staging early breast cancer. AB - INTRODUCTION: Currently, there is a lack of data on the role of combined positron emission tomography-computed tomography (PET-CT) in the staging of early invasive primary breast cancer. We therefore evaluated the role of (18)F fluorodeoxyglucose ((18)F-FDG)-PET-CT in this patient population. METHODS: We prospectively recruited 70 consecutive patients (69 women, one man; mean age, 61.9 +/- 8.1 years) with early primary breast cancer for staging with (18)F-FDG PET-CT. All PET-CT images were interpreted by two readers (independently of each other). A third reader adjudicated any discrepancies. All readers had >=5 years of specific experience. Ethics board approval and informed consent were obtained. RESULTS: The mean clinical follow-up was 22.7 +/- 12.6 months. The primary tumor was identified with PET-CT in 64 of 70 patients. Of the unidentified lesions, surgical pathology revealed two intraductal carcinomas, one invasive tubular carcinoma, and three invasive lobular carcinomas. Undiagnosed multifocal breast disease was shown in seven of 70 patients. PET-CT identified avid axillary lymph nodes in 19 of 70 patients, compared with 24 of 70 confirmed during surgery. There were four patients who were axillary node positive on PET but had no axillary disease at surgery. Five patients were reported with avid metastases. Two of those patients were treated for metastatic disease (nodal, lung, and liver in one and bone metastases in the other) following further imaging and clinical assessment. In the other three patients, lesions (lung, n = 1; pleural, n = 1; paratrachael node, n = 1) were subsequently diagnosed as benign lesions. CONCLUSION: Integrated (18)F-FDG-PET-CT may have a role in staging patients presenting with early breast cancer. PMID- 22539551 TI - The crystal structure of human Argonaute2. AB - Argonaute proteins form the functional core of the RNA-induced silencing complexes that mediate RNA silencing in eukaryotes. The 2.3 angstrom resolution crystal structure of human Argonaute2 (Ago2) reveals a bilobed molecule with a central cleft for binding guide and target RNAs. Nucleotides 2 to 6 of a heterogeneous mixture of guide RNAs are positioned in an A-form conformation for base pairing with target messenger RNAs. Between nucleotides 6 and 7, there is a kink that may function in microRNA target recognition or release of sliced RNA products. Tandem tryptophan-binding pockets in the PIWI domain define a likely interaction surface for recruitment of glycine-tryptophan-182 (GW182) or other tryptophan-rich cofactors. These results will enable structure-based approaches for harnessing the untapped therapeutic potential of RNA silencing in humans. PMID- 22539552 TI - AID-driven deletion causes immunoglobulin heavy chain locus suicide recombination in B cells. AB - Remodeling of immunoglobulin genes by activation-induced deaminase (AID) is required for affinity maturation and class-switch recombination in mature B lymphocytes. In the immunoglobulin heavy chain locus, these processes are predominantly controlled by the 3' cis-regulatory region. We now show that this region is transcribed and undergoes AID-mediated mutation and recombination around phylogenetically conserved switchlike DNA repeats. Such recombination, which we term locus suicide recombination, deletes the whole constant region gene cluster and thus stops expression of the immunoglobulin of the B cell surface, which is critical for B cell survival. The frequency of this event is approaching that of class switching and makes it a potential regulator of B cell homeostasis. PMID- 22539553 TI - Evolutionary trade-offs, Pareto optimality, and the geometry of phenotype space. AB - Biological systems that perform multiple tasks face a fundamental trade-off: A given phenotype cannot be optimal at all tasks. Here we ask how trade-offs affect the range of phenotypes found in nature. Using the Pareto front concept from economics and engineering, we find that best-trade-off phenotypes are weighted averages of archetypes--phenotypes specialized for single tasks. For two tasks, phenotypes fall on the line connecting the two archetypes, which could explain linear trait correlations, allometric relationships, as well as bacterial gene expression patterns. For three tasks, phenotypes fall within a triangle in phenotype space, whose vertices are the archetypes, as evident in morphological studies, including on Darwin's finches. Tasks can be inferred from measured phenotypes based on the behavior of organisms nearest the archetypes. PMID- 22539554 TI - Neural correlates of a magnetic sense. AB - Many animals rely on Earth's magnetic field for spatial orientation and navigation. However, how the brain receives and interprets magnetic field information is unknown. Support for the existence of magnetic receptors in the vertebrate retina, beak, nose, and inner ear has been proposed, and immediate gene expression markers have identified several brain regions activated by magnetic stimulation, but the central neural mechanisms underlying magnetoreception remain unknown. Here we describe neuronal responses in the pigeon's brainstem that show how single cells encode magnetic field direction, intensity, and polarity; qualities that are necessary to derive an internal model representing directional heading and geosurface location. Our findings demonstrate that there is a neural substrate for a vertebrate magnetic sense. PMID- 22539555 TI - Quantitative sequencing of 5-methylcytosine and 5-hydroxymethylcytosine at single base resolution. AB - 5-Methylcytosine can be converted to 5-hydroxymethylcytosine (5hmC) in mammalian DNA by the ten-eleven translocation (TET) enzymes. We introduce oxidative bisulfite sequencing (oxBS-Seq), the first method for quantitative mapping of 5hmC in genomic DNA at single-nucleotide resolution. Selective chemical oxidation of 5hmC to 5-formylcytosine (5fC) enables bisulfite conversion of 5fC to uracil. We demonstrate the utility of oxBS-Seq to map and quantify 5hmC at CpG islands (CGIs) in mouse embryonic stem (ES) cells and identify 800 5hmC-containing CGIs that have on average 3.3% hydroxymethylation. High levels of 5hmC were found in CGIs associated with transcriptional regulators and in long interspersed nuclear elements, suggesting that these regions might undergo epigenetic reprogramming in ES cells. Our results open new questions on 5hmC dynamics and sequence-specific targeting by TETs. PMID- 22539557 TI - Workplace field testing of the pressure drop of particulate respirators using welding fumes. AB - In a previous study, we concluded that respirator testing with a sodium chloride aerosol gave a conservative estimate of filter penetration for welding fume aerosols. A rapid increase in the pressure drop (PD) of some respirators was observed as fumes accumulated on the filters. The present study evaluated particulate respirator PD based on workplace field tests. A field PD tester was designed and validated using the TSI 8130 Automatic Filter Tester, designed in compliance with National Institute for Occupational and Safety and Health regulation 42 CFR part 84. Three models (two replaceable dual-type filters and one replaceable single-type filter) were evaluated against CO(2) gas arc welding on mild steel in confined booths in the workplace. Field tests were performed under four airborne concentrations (27.5, 15.4, 7.9, and 2.1 mg m(-3)). The mass concentration was measured by the gravimetric method, and number concentration was monitored using P-Trak (Model 8525, TSI, USA). Additionally, photos and scanning electron microscopy-energy dispersive X-ray spectroscopy were used to visualize and analyze the composition of welding fumes trapped in the filters. The field PD tester showed no significant difference compared with the TSI tester. There was no significant difference in the initial PD between laboratory and field results. The PD increased as a function of fume load on the respirator filters for all tested models. The increasing PD trend differed by models, and PD increased rapidly at high concentrations because greater amount of fumes accumulated on the filters in a given time. The increase in PD as a function of fume load on the filters showed a similar pattern as fume load varied for a particular model, but different patterns were observed for different models. Images and elemental analyses of fumes trapped on the respirator filters showed that most welding fumes were trapped within the first layer, outer web cover, and second layer, in order, while no fumes were observed beneath the fourth layer of the tested respirators. The current findings contribute substantially to our understanding of respirator PD in the presence of welding fumes. PMID- 22539556 TI - Retrospective exposure assessment of perfluorooctanoic acid serum concentrations at a fluoropolymer manufacturing plant. AB - Perfluorooctanoic acid (PFOA) is a suspect human carcinogen, causes neonatal loss, liver enlargement, and a variety of tumors in rodents, and has been associated with increased cholesterol levels in humans. Mortality analyses of worker cohorts have not been conclusive or consistent. As part of a series of epidemiologic studies of workers in a West Virginia plant that manufactures fluoropolymers, estimates of serum PFOA for the worker cohort were developed for the period of 1950-2004. An existing database of 2125 worker biomarker measurements of serum PFOA was used to model retrospective exposures. Historical PFOA serum levels for eight job category/job group combinations were modeled using linear mixed models to account for repeated measures, along with exposure determinants such as cumulative years worked in potentially exposed jobs, the amount of C8 used or emitted by the plant over time, as well as a four-knot restricted cubic spline function to reflect the influence of process changes over calendar time on exposure. The modeled biomarker levels matched well with measured levels, including those collected independently as part of a community study of PFOA levels (Spearman correlations of 0.8 for internal data comparisons and 0.6 for external data comparisons). These annualized PFOA serum estimates will be used in a series of morbidity and mortality studies of this worker cohort. PMID- 22539558 TI - Prostate cancer and occupational whole-body vibration exposure. AB - Prostate cancer is common and its etiology largely unknown; therefore, it is important to explore all potential risk factors that are biologically plausible. Recent literature suggests a relationship between whole-body vibration (WBV) and prostate cancer risk. The aim of this study was to determine whether occupational WBV was a risk factor for prostate cancer. Existing data, collected on 447 incident cases and 532 population controls (or their proxies), in Montreal, Canada, were used to evaluate this question. Personal interviews collected detailed job descriptions for every job held, the tasks involved, and type of equipment used. For each job, experts assessed the intensity and daily duration of WBV exposure. Inter-rater agreement for WBV ratings was examined using the kappa statistic, with values that ranged from 0.83 to 0.94. Logistic regression models explored the relationship between WBV exposure and prostate cancer, using various combinations of intensity, daily duration, and years of exposure. Potential confounders were also examined. Occupations with WBV exposure demonstrated an increased statistically non-significant risk [odds ratio (OR) = 1.44, 95% confidence interval (CI): 0.99-2.09]. The risk for transport equipment operation, a job with WBV exposure, was significantly elevated (OR = 1.90, 95% CI: 1.07-3.39). These results, together with those of an earlier study, suggest that workers in heavy equipment and transport equipment operation may have increased risk of prostate cancer. Further investigation is warranted. PMID- 22539559 TI - Exposure to inhalable, respirable, and ultrafine particles in welding fume. AB - This investigation aims to explore determinants of exposure to particle size specific welding fume. Area sampling of ultrafine particles (UFP) was performed at 33 worksites in parallel with the collection of respirable particles. Personal sampling of respirable and inhalable particles was carried out in the breathing zone of 241 welders. Median mass concentrations were 2.48 mg m(-3) for inhalable and 1.29 mg m(-3) for respirable particles when excluding 26 users of powered air purifying respirators (PAPRs). Mass concentrations were highest when flux-cored arc welding (FCAW) with gas was applied (median of inhalable particles: 11.6 mg m(-3)). Measurements of particles were frequently below the limit of detection (LOD), especially inside PAPRs or during tungsten inert gas welding (TIG). However, TIG generated a high number of small particles, including UFP. We imputed measurements = 5 times/month. MS was self-reported and confirmed by medical record review. RESULTS: Among women with MS, the prevalence of RLS and severe RLS (15+ times/month) were 15.5% and 9.9% in 2005, respectively, relative to 6.4% and 2.6% among women without MS. After adjustment for potential confounders and the presence of other sleep disorders, women with MS had a higher likelihood of having RLS (odds ratio [OR] = 2.72, 95% confidence interval [CI] 1.89-3.93), severe RLS (OR = 4.12, 95% CI 2.65-6.42), and daily daytime sleepiness (OR = 2.11, 95% CI 1.31-3.42) compared with women without MS. Among the 172 women who had MS and were free of RLS in 2005, 9 developed RLS (5.2%) during a 4-year period and all had severe RLS. The adjusted relative risk of severe RLS was 3.58 (95% CI 1.53-8.35), comparing women with MS at baseline with those without MS. CONCLUSION: Women with MS had a significantly higher prevalence of RLS and daytime sleepiness and an increased risk of developing RLS in the future. PMID- 22539568 TI - Treatment of chronic tinnitus with theta burst stimulation: a randomized controlled trial. AB - OBJECTIVE: To test whether 4 weeks of bilateral repetitive transcranial magnetic stimulation (rTMS) to the temporal or temporoparietal cortex is effective and safe in the treatment of chronic tinnitus. METHODS: In this controlled 3-armed trial, 48 patients with chronic tinnitus were treated with 4 weeks (20 sessions) of bilateral continuous theta burst stimulation (cTBS) at the Tubingen University Hospital. They were randomized to stimulation above the temporal cortex, the temporoparietal cortex, or as sham condition behind the mastoid. Patients were masked for the stimulation condition. Tinnitus severity was assessed after 2 and primarily 4 weeks of treatment and at 3 months follow-up with the tinnitus questionnaire and by a tinnitus change score. Audiologic safety was monitored by pure-tone and speech audiometry after 2 and 4 weeks of cTBS. RESULTS: Tinnitus severity was slightly reduced from baseline by a mean (SD) 2.6 (8.2) after sham, 2.4 (8.0) after temporoparietal, 2.2 (8.3) after temporal treatment of 16 patients each, but there was no significant difference between sham treatments and temporal (confidence interval [CI] -5.4 to +6.7) or temporoparietal cTBS (CI 5.9 to +6.3) or real cTBS (CI -7 to +5.1). Patients' global evaluation of tinnitus change after treatment did not indicate any effects. Audiologic measures were unaffected by treatment. CONCLUSIONS: Treating chronic tinnitus for 4 weeks by applying cTBS to the temporal or temporoparietal cortex of both hemispheres appears to be safe but not more effective than sham stimulation. However, these results are not to be generalized to all forms of rTMS treatments for tinnitus. PMID- 22539569 TI - Early thalamic lesions in patients with sleep-potentiated epileptiform activity. AB - OBJECTIVE: To compare the prevalence and type of early developmental lesions in patients with a clinical presentation consistent with electrical status epilepticus in sleep either with or without prominent sleep-potentiated epileptiform activity (PSPEA). METHODS: We performed a case-control study and enrolled patients with 1) clinical features consistent with electrical status epilepticus in sleep, 2) >=1 brain MRI scan, and 3) >=1 overnight EEG recording. We quantified epileptiform activity using spike percentage, the percentage of 1 second bins in the EEG tracing containing at least 1 spike. PSPEA was present when spike percentage during non-REM sleep was >=50% than spike percentage during wakefulness. RESULTS: One hundred patients with PSPEA (cases) and 47 patients without PSPEA (controls) met the inclusion criteria during a 14-year period. Both groups were comparable in terms of clinical and epidemiologic features. Early developmental lesions were more frequent in cases (48% vs 19.2%, p = 0.002). Thalamic lesions were more frequent in cases (14% vs 2.1%, p = 0.037). The main types of early developmental lesions found in cases were vascular lesions (14%), periventricular leukomalacia (9%), and malformation of cortical development (5%). Vascular lesions were the only type of early developmental lesions that were more frequent in cases (14% vs 0%, p = 0.005). CONCLUSIONS: Patients with PSPEA have a higher frequency of early developmental lesions and thalamic lesions than a comparable population of patients without PSPEA. Vascular lesions were the type of early developmental lesions most related to PSPEA. PMID- 22539570 TI - Nav1.7-related small fiber neuropathy: impaired slow-inactivation and DRG neuron hyperexcitability. AB - OBJECTIVES: Although small fiber neuropathy (SFN) often occurs without apparent cause, the molecular etiology of idiopathic SFN (I-SFN) has remained enigmatic. Sodium channel Na(v)1.7 is preferentially expressed within dorsal root ganglion (DRG) and sympathetic ganglion neurons and their small-diameter peripheral axons. We recently reported the presence of Na(v)1.7 variants that produce gain-of function changes in channel properties in 28% of patients with painful I-SFN and demonstrated impaired slow-inactivation in one of these mutations after expression within HEK293 cells. Here we show that the I739V Na(v)1.7 variant in a patient with biopsy-confirmed I-SFN impairs slow-inactivation within DRG neurons and increases their excitability. METHODS: A patient with SFN symptoms including pain, and no identifiable underlying cause, was evaluated by skin biopsy, quantitative sensory testing, nerve conduction studies, screening of genomic DNA for variants in SCN9A, and functional analysis. RESULTS: Voltage-clamp analysis following expression within DRG neurons revealed that the Na(v)1.7/I739V substitution impairs slow-inactivation, depolarizing the midpoint (V(1/2)) by 5.6 mV, and increasing the noninactivating component at 10 mV from 16.5% to 22.2%. Expression of I739V channels within DRG neurons rendered these cells hyperexcitable, reducing current threshold and increasing the frequency of firing evoked by graded suprathreshold stimuli. CONCLUSIONS: These observations provide support, from a patient with biopsy-confirmed SFN, for the suggestion that functional variants of Na(v)1.7 that impair slow-inactivation can produce DRG neuron hyperexcitability that contributes to pain in SFN. Na(v)1.7 channelopathy associated SFN should be considered in the differential diagnosis of cases of SFN in which no other cause is found. PMID- 22539571 TI - Small fiber neuropathy: a bit less idiopathic? PMID- 22539572 TI - Clinical features of Parkinson disease when onset of diabetes came first: A case control study. AB - OBJECTIVE: Recent literature suggests that diabetes is a risk factor for Parkinson disease (PD). We investigated the clinical features of patients with idiopathic PD (IPD) in whom the onset of diabetes came first. METHODS: We designed a case-control study. From the cohort of all new patients with IPD free of vascular disease (n = 783) admitted and evaluated at our institute over a 3 year period (2007-2010), we included all the patients with a diagnosis of diabetes prior to PD onset (n = 89) and a control group (n = 89) matched (1:1) for gender, body mass index (+/- 1 kg/m(2)), and duration of PD (+/- 1 year). The Unified Parkinson's Disease Rating Scale (UPDRS) motor score was the primary endpoint. RESULTS: At study entry, patients with diabetes were similar to controls in terms of most demographic, lifestyle, and general medical features with exception of statins (18% vs 3.4%; p = 0.003). However, diabetes was associated with higher UPDRS motor (22.3 +/- 9.0 vs 19.3 +/- 7.9; p = 0.019) and activities of daily living (9.7 +/- 5.1 vs 8.3 +/- 4.3; p = 0.049) scores, more severe Hoehn & Yahr staging (p = 0.009), and higher treatment doses of levodopa (mg/day, 448 +/- 265 vs 300 +/- 213; p < 0.0001; mg/kg/day, 5.8 +/- 4.0 vs 3.8 +/ 2.9; p < 0.0001). CONCLUSIONS: Onset of diabetes before the onset of PD appears to be a risk factor for more severe PD symptoms. These findings support the hypothesis that diabetes has a role in the etiopathogenesis of PD. Neurologists should be aware of the potential impact of diabetes on overall PD management. PMID- 22539573 TI - Sleep-potentiated epileptic discharges, language regression, and pediatric thalamic lesions. PMID- 22539574 TI - Contribution of EEG/fMRI to the definition of the epileptic focus. AB - OBJECTIVES: To evaluate the clinical relevance of EEG/fMRI in patients with focal epilepsy, by assessing the information it adds to the scalp EEG in the definition of the epileptic focus. METHODS: Forty-three patients with focal epilepsy were studied with EEG/fMRI using a 3-T scanner. Blood oxygen level-dependent (BOLD) signal changes related to interictal epileptic discharges (IEDs) were classified as concordant or not concordant with the scalp EEG spike field and as contributory if the BOLD signal provided additional information to the scalp EEG about the epileptic focus or not contributory if it did not. We considered patients having intracerebral EEG or a focal lesion on MRI as having independent validation. RESULTS: Thirty-three patients had at least 3 IEDs during the EEG/fMRI acquisition (active EEG), and all had a BOLD response. In 29 of 33 (88%) patients, the BOLD response was concordant, and in 21 of 33 (64%) patients, the BOLD response was contributory. Fourteen patients had an independent validation: in 12 of these 14, the BOLD responses were validated and in 2 they were invalidated. CONCLUSIONS: A BOLD response was present in all patients with active EEG, and more specific localization of the epileptic focus was gained from EEG/fMRI in half of the patients who were scanned, when compared with scalp EEG alone. This study demonstrates that EEG/fMRI, in the context of a clinical practice, may contribute to the localization of the interictal epileptic generator in patients with focal epilepsy. PMID- 22539576 TI - A young man with hemiplegia after inhaling the bath salt "Ivory wave". PMID- 22539575 TI - Characterizing contrast-enhancing and re-enhancing lesions in multiple sclerosis. AB - OBJECTIVES: In multiple sclerosis (MS), contrast-enhancing lesions (CELs) in T1 weighted postcontrast MRI are considered markers of blood-brain barrier breakdown. It remains unknown if re-enhancement can be considered a radiologic indicator of different pathology in CELs. We investigated 1) the incidence of re enhancing lesions (re-CELs) from chronic lesions; 2) differences in size, magnetization transfer ratio (MTR), and likelihood to appear as acute black holes (aBHs) between new lesions (n-CELs) and re-CELs; and 3) associations between re CELs and features indicating more advanced disease. METHODS: In this retrospective natural history study, we examined 264 monthly MRI scans performed at month 1 (M1), month 2 (M2), and month 3 (M3) for 88 patients with MS. CELs were defined as n-CELs if not present in the M1 T2W MRI and re-CELs if present in the M1 T2W MRI. RESULTS: A total of 311 (82.7%) n-CELs and 65 (17.3%) re-CELs were identified. Of the 88 patients, 54 presented only n-CELs, 8 presented only re-CELs, and 26 presented both CEL types. Patients with both lesion types presented more CELs than those presenting only one type (p = 0.01). Re-CELs were larger (z = 2.72, p = 0.007) and had lower MTR (z = -2.80, p = 0.005) than n-CELs but the estimated proportion of aBHs from n-CELs was similar (z = -0.09, p = 0.1) from the proportion of aBHs from re-CELs. CONCLUSIONS: Nearly 20% of CELs represent the reoccurrence of enhancement in chronic plaques. Re-CELs represent larger areas of inflammation, not necessarily associated with larger areas of edema. PMID- 22539577 TI - Cognitive outcome of patients with classic infantile Pompe disease receiving enzyme therapy. AB - OBJECTIVE: Classic infantile Pompe disease affects many tissues, including the brain. Untreated infants die within their first year. Although enzyme-replacement therapy (ERT) significantly increases survival, its potential limitation is that the drug cannot cross the blood-brain barrier. We therefore investigated long term cognitive development in patients treated with ERT. METHODS: We prospectively assessed cognitive functioning in 10 children with classic infantile Pompe disease who had been treated with ERT since 1999. Brain imaging was performed in 6 children. RESULTS: During the first 4 years of life, developmental scores in 10 children ranged from above-average development to severe developmental delay; they were influenced by the type of intelligence test used, severity of motor problems, speech/language difficulties, and age at start of therapy. Five of the children were also tested from 5 years onward. Among them were 2 tetraplegic children whose earlier scores had indicated severe developmental delay. These scores now ranged between normal and mild developmental delay and indicated that at young age poor motor functioning may interfere with proper assessment of cognition. We found delayed processing speed in 2 children. Brain imaging revealed periventricular white matter abnormalities in 4 children. CONCLUSIONS: Cognitive development at school age ranged between normal and mildly delayed in our long-term survivors with classic infantile Pompe disease treated with ERT. The oldest was 12 years. We found that cognition is easily underestimated in children younger than 5 years with poor motor functioning. PMID- 22539579 TI - Autonomic changes with seizures correlate with postictal EEG suppression. AB - OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) poses a poorly understood but considerable risk to people with uncontrolled epilepsy. There is controversy regarding the significance of postictal generalized EEG suppression as a biomarker for SUDEP risk, and it remains unknown whether postictal EEG suppression has a neurologic correlate. Here, we examined the profile of autonomic alterations accompanying seizures with a wrist-worn biosensor and explored the relationship between autonomic dysregulation and postictal EEG suppression. METHODS: We used custom-built wrist-worn sensors to continuously record the sympathetically mediated electrodermal activity (EDA) of patients with refractory epilepsy admitted to the long-term video-EEG monitoring unit. Parasympathetic-modulated high-frequency (HF) power of heart rate variability was measured from concurrent EKG recordings. RESULTS: A total of 34 seizures comprising 22 complex partial and 12 tonic-clonic seizures from 11 patients were analyzed. The postictal period was characterized by a surge in EDA and heightened heart rate coinciding with persistent suppression of HF power. An increase in the EDA response amplitude correlated with an increase in the duration of EEG suppression (r = 0.81, p = 0.003). Decreased HF power correlated with an increase in the duration of EEG suppression (r = -0.87, p = 0.002). CONCLUSION: The magnitude of both sympathetic activation and parasympathetic suppression increases with duration of EEG suppression after tonic-clonic seizures. These results provide autonomic correlates of postictal EEG suppression and highlight a critical window of postictal autonomic dysregulation that may be relevant in the pathogenesis of SUDEP. PMID- 22539580 TI - Phenotype and genotype analysis in amyotrophic lateral sclerosis with TARDBP gene mutations. AB - OBJECTIVE: To describe the phenotype and phenotype-genotype correlations in patients with amyotrophic lateral sclerosis (ALS) with TARDBP gene mutations. METHODS: French TARDBP+ patients with ALS (n = 28) were compared first to 3 cohorts: 737 sporadic ALS (SALS), 192 nonmutated familial ALS (FALS), and 58 SOD1 + FALS, and then to 117 TARDBP+ cases from the literature. Genotype-phenotype correlations were studied for the most frequent TARDBP mutations. RESULTS: In TARDBP+ patients, onset was earlier (p = 0.0003), upper limb (UL) onset was predominant (p = 0.002), and duration was longer (p = 0.0001) than in patients with SALS. TARDBP+ and SOD1+ groups had the longest duration but diverged for site of onset: 64.3% UL onset for TARDBP+ and 74.1% on lower limbs for SOD1+ (p < 0.0001). The clinical characteristics of our 28 patients were similar to the 117 cases from the literature. In Caucasians, 51.3% of had UL onset, while 58.8% of Asians had bulbar onset (p = 0.02). The type of mutation influenced survival (p < 0.0001), and the G298S1, lying in the TARDBP super rich glycine-residue domain, was associated with the worst survival (27 months). CONCLUSION: Differences in phenotype between the groups as well as the differential influence of TARBDP mutations on survival may help physicians in ALS management and allow refining the strategy of genetic diagnosis. PMID- 22539578 TI - Genotype patterns at PICALM, CR1, BIN1, CLU, and APOE genes are associated with episodic memory. AB - OBJECTIVE: Several genome-wide association studies (GWAS) have associated variants in late-onset Alzheimer disease (LOAD) susceptibility genes; however, these single nucleotide polymorphisms (SNPs) have very modest effects, suggesting that single SNP approaches may be inadequate to identify genetic risks. An alternative approach is the use of multilocus genotype patterns (MLGPs) that combine SNPs at different susceptibility genes. METHODS: Using data from 1,365 subjects in the National Institute on Aging Late-Onset Alzheimer's Disease Family Study, we conducted a family-based association study in which we tabulated MLGPs for SNPs at CR1, BIN1, CLU, PICALM, and APOE. We used generalized estimating equations to model episodic memory as the dependent endophenotype of LOAD and the MLGPs as predictors while adjusting for sex, age, and education. RESULTS: Several genotype patterns influenced episodic memory performance. A pattern that included PICALM and CLU was the strongest genotypic profile for lower memory performance (beta = -0.32, SE = 0.19, p = 0.021). The effect was stronger after addition of APOE (p = 0.016). Two additional patterns involving PICALM, CR1, and APOE and another pattern involving PICALM, BIN1, and APOE were also associated with significantly poorer memory performance (beta = -0.44, SE = 0.09, p = 0.009 and beta = -0.29, SE = 0.07, p = 0.012) even after exclusion of patients with LOAD. We also identified genotype pattern involving variants in PICALM, CLU, and APOE as a predictor of better memory performance (beta = 0.26, SE = 0.10, p = 0.010). CONCLUSIONS: MLGPs provide an alternative analytical approach to predict an individual's genetic risk for episodic memory performance, a surrogate indicator of LOAD. Identifying genotypic patterns contributing to the decline of an individual's cognitive performance may be a critical step along the road to preclinical detection of Alzheimer disease. PMID- 22539581 TI - Diurnal pattern of seizures outside the hospital: is there a time of circadian vulnerability? AB - OBJECTIVE: To evaluate whether the distribution of seizures throughout the day is the same in ambulatory outpatient conditions as observed in inpatient conditions. METHODS: We analyzed records from consecutive patients who had ambulatory EEG monitoring for 24 to 72 hours using DigitraceTM EEG recording system. The participants maintained a log of symptoms and signaled the time when symptoms occurred by pushing an event button. Additionally, automatic seizure and spike detection was performed on each record using Persyst detection software. RESULTS: Of 831 reports analyzed, 44 unique patients had definite ictal events. There were a total of 129 electrographic seizures (34 subclinical) with timing as follows: frontal (31), temporal (71), and generalized, posterior, or central (27). Frontal lobe seizures occurred more frequently between 12 am and 12 pm as compared to temporal lobe seizures, which occurred more frequently between 12 pm and 12 am (p = 0.017). Analysis of frontal lobe seizures revealed a cluster of 10 seizures centered at 6:33 am (range 5:15-7:30 am) with p = 0.0064. Temporal lobe seizures had a cluster of 24 seizures centered at 8:49 pm (range 6:45-11:56 pm) with p = 0.0437. CONCLUSION: In ambulatory outpatient conditions, electrographic seizures follow day/night patterns similar to those observed in hospital conditions. Frontal seizures occur preferentially in the early morning hours and temporal lobe seizures occur in the early evening hours. PMID- 22539582 TI - Transcranial magnetic stimulation for tinnitus: no better than sham treatment? PMID- 22539583 TI - Telomere abnormalities and chromosome fragility in patients affected by familial papillary thyroid cancer. AB - INTRODUCTION: Genomic instability has been proposed to play a role in cancer development and can occur through different mechanisms including telomere association and telomere loss. Studies carried out in our unit have demonstrated that familial papillary thyroid cancer (fPTC) patients display an imbalance, at the germinal level, in telomere-telomerase complex. AIM: We aimed to verify whether familial fPTC patients show an increased spontaneous chromosome fragility. METHODS: To this purpose, we compared telomeric fusions and associations as well as other chromosomal fragility features by conventional and molecular cytogenetic analyses, in phytohemagglutinin stimulated T-lymphocytes from fPTC patients, unaffected family members, sporadic papillary thyroid cancer patients, and healthy subjects. RESULTS: We demonstrate that fPTC patients have a significant increase in spontaneous telomeric associations and telomeric fusions compared with healthy subjects and sporadic cases in the frame of an otherwise common spontaneous chromosome fragility pattern. A quantitative fluorescence in situ hybridization analysis demonstrates that familial cases display a significant decrease in the telomeric peptide nucleic acid-fluorescence in situ hybridization signal intensity in the metaphase chromosome. Moreover, three copies of the hTERT gene were found only in familial cases, although the result was not statistically significant. CONCLUSIONS: These results contribute in defining familial thyroid cancer as a clinical entity characterized by an altered telomere stability, which may be associated with the predisposition to develop the familial form of thyroid cancer. PMID- 22539584 TI - Dynamic change of serum FGF21 levels in response to glucose challenge in human. AB - AIMS: Fibroblast growth factor 21 (FGF21), an endocrine factor predominantly secreted from liver, possesses multiple beneficial effect on energy metabolism and insulin sensitivity in animals. This study aimed to investigate the acute change of serum FGF21 in response to glucose challenge in humans. METHODS: A 75-g oral glucose tolerance test was performed among 20 healthy subjects, 18 with impaired glucose tolerance (IGT) and 21 with type 2 diabetes mellitus (T2DM). Blood samples were collected for measurement of FGF21 and other biochemical parameters. The associations of FGF21 with insulin and other metabolic parameters were analyzed. RESULTS: Fasting serum FGF21 levels increased progressively from healthy, IGT to T2DM subjects (P < 0.05 for global trend). After oral glucose administration, the serum FGF21 level showed a similar biphasic change in all three groups. It declined to a nadir level at 60 min and then increased gradually to its peak level at 180 min. FGF21 levels at different time points of oral glucose tolerance test negatively correlated with glucose levels in all subjects, and the fold change of serum FGF21 at different time points (compared with the basal level) were inversely associated with fold changes of insulin (P = 0.012) and C-peptide (P = 0.043) levels in healthy subjects but not in IGT and T2DM patients. CONCLUSIONS: The dynamic change of circulating FGF21 was associated with alterations in insulin levels in response to glucose challenge in humans. These findings support the role of FGF21 as a potential regulator of insulin secretion and glucose metabolism in humans. PMID- 22539585 TI - Lymphocytic thyroiditis on histology correlates with serum thyroglobulin autoantibodies in patients with papillary thyroid carcinoma: impact on detection of serum thyroglobulin. AB - CONTEXT: Serum thyroglobulin (Tg), the marker of residual tumor in papillary thyroid carcinoma, can be underestimated in patients with Tg autoantibodies (TgAb). TgAb are due to a coexistent lymphocytic thyroiditis (LT) or the papillary thyroid carcinoma per se. TgAb assays are highly discordant. DESIGN: We evaluated 141 patients with a clinical diagnosis of nodular thyroid disease, 32 of Hashimoto's thyroiditis, and four of Graves' disease, who underwent total thyroidectomy for an associated papillary thyroid carcinoma. Patients were classified as papillary thyroid carcinoma-lymphocytic thyroiditis (PTC-T) and papillary thyroid carcinoma (PTC) according to the presence or absence of LT on histology. Tg was measured before thyroid remnant ablation, when it is expectedly detectable, by an immunometric assay (IMA) and TgAb by three noncompetitive IMA and three competitive radioimmunoassays (RIA). The number of lymphocytes was compared with TgAb concentration. RESULTS: Seventy-two of 177 patients (40.7%) were classified as PTC-T and 105 (59.3%) as PTC. Although the tumor stage was similar in the two groups, Tg was undetectable in more PTC-T (37 of 72) than PTC (12 of 105) (P < 0.01), and Tg values were lower in the former (0; 0-4.7 ng/ml) (median; 25th to 75th percentiles) than in the latter group (9.7; 2.7-24.2) (P < 0.01). Accordingly, the percent of positive TgAb by the six assays resulted in higher PTC-T (29.2-50.0%) than PTC (1.9-6.7%) (P < 0.01). Among 49 patients with undetectable Tg, TgAb were more frequently positive by IMA (57.1-63.3%) than RIA (30.6-42.9%). The number of lymphocytes correlated with TgAb concentration in all six assays (0.34 < Rho < 0.46) (all P < 0.01). CONCLUSIONS: In papillary thyroid carcinoma, LT on histology must be carefully searched for because it is frequently associated with TgAb and therefore mistakenly low or undetectable Tg. TgAb can be missed by some assays. In absence of LT, TgAb are rare. PMID- 22539586 TI - Vitamin D3 therapy corrects the tissue sensitivity to angiotensin ii akin to the action of a converting enzyme inhibitor in obese hypertensives: an interventional study. AB - CONTEXT: Vitamin D deficiency and obesity are associated with increased tissue renin-angiotensin system (RAS) activity. OBJECTIVE: The objective of the study was to evaluate whether vitamin D(3) therapy in obesity reduces tissue-RAS activity, as indicated by an increase in tissue sensitivity to angiotensin II (AngII). PARTICIPANTS: Participants included obese subjects with hypertension and 25-hydroxyvitamin D less than 25 ng/ml. DESIGN: Subjects were studied before and after 1 month of vitamin D(3) 15,000 IU/d, while in dietary sodium balance, and off all interfering medications. Fourteen subjects successfully completed all study procedures. SETTING: The study was conducted at a clinical research center. OUTCOME MEASURES: At each study visit, tissue sensitivity to AngII was assessed by measuring renal plasma flow (RPF), mean arterial pressure (MAP), and adrenal secretion of aldosterone during an infusion of AngII. Subjects were then given captopril, and a second AngII infusion to evaluate the effect of captopril on tissue-RAS activity. RESULTS: Vitamin D(3) therapy increased 25-hydroxyvitamin D (18 to 52 ng/ml) and basal RPF (+5%) and lowered supine MAP (-3%) (all P < 0.01). There was a greater decline in RPF and higher stimulation of aldosterone with AngII infusion after vitamin D(3) therapy (both P < 0.05). As anticipated, captopril increased the renal-vascular, MAP, and adrenal sensitivity to AngII, but this effect was much smaller after vitamin D(3) therapy, indicating that vitamin D(3) therapy corrected the tissue sensitivity to AngII akin to captopril. CONCLUSIONS: Vitamin D(3) therapy in obese hypertensives modified RPF, MAP, and tissue sensitivity to AngII similar to converting enzyme inhibition. Whether chronic vitamin D(3) therapy abrogates the development of diseases associated with excess RAS activity warrants investigation. PMID- 22539587 TI - Oral octreotide absorption in human subjects: comparable pharmacokinetics to parenteral octreotide and effective growth hormone suppression. AB - CONTEXT: Oral administration of a novel octreotide formulation enabled its absorption to the systemic circulation, exhibiting blood concentrations comparable to those observed with injected octreotide and maintaining its biological activity. OBJECTIVES: The aim of the study was to determine oral octreotide absorption and effects on pituitary GH secretion compared to sc octreotide injection. DESIGN: Four single-dose studies were conducted in 75 healthy volunteers. INTERVENTION: Oral doses of 3, 10, or 20 mg octreotide and a single sc injection of 100 MUg octreotide were administered. MAIN OUTCOME MEASURE: We measured the pharmacokinetic profile of orally administrated octreotide and the effect of octreotide on basal and stimulated GH secretion. RESULTS: Both oral and sc treatments were well tolerated. Oral octreotide absorption to the circulation was apparent within 1 h after dose administration. Escalating oral octreotide doses resulted in dose-dependent increased plasma octreotide concentrations, with an observed rate of plasma decay similar to parenteral administration. Both 20 mg oral octreotide and injection of 0.1 mg sc octreotide resulted in equivalent pharmacokinetic parameters [mean peak plasma concentration, 3.77 +/- 0.25 vs. 3.97 +/- 0.19 ng/ml; mean area under the curve, 16.2 +/- 1.25 vs. 12.1 +/- 0.45 h * ng/ml); and median time >= 0.5 ng/ml, 7.67 vs. 5.88 h, respectively). A single dose of 20 mg oral octreotide resulted in basal (P < 0.05) and GHRH-stimulated (P < 0.001) mean GH levels suppressed by 49 and 80%, respectively. CONCLUSIONS: The results support an oral octreotide alternative to parenteral octreotide treatment for patients with acromegaly. PMID- 22539588 TI - Serum vaspin concentrations are closely related to insulin resistance, and rs77060950 at SERPINA12 genetically defines distinct group with higher serum levels in Japanese population. AB - CONTEXT: Vaspin is an adipokine with insulin-sensitizing effects identified from visceral adipose tissues of genetically obese rats. OBJECTIVE: We investigated genetic and nongenetic factors that define serum concentrations of vaspin. DESIGN, SETTING AND PARTICIPANTS: Vaspin levels were measured with RIA in Japanese subjects with normal fasting plasma glucose (NFG; n = 259) and type 2 diabetes patients (T2D; n = 275). Single nucleotide polymorphisms (SNP) at SERPINA12 (vaspin) gene locus were discovered, and five SNP were genotyped in the subjects with varied body mass index (n = 1138). RESULTS: The level of serum vaspin in 93% of the samples was found to vary from 0.2 to nearly 2 ng/ml in NFG subjects (n = 259) and from 0.2 to nearly 3 ng/ml in T2D patients (n = 275) (Vaspin(Low) group), whereas a significant subpopulation (7%) in both groups displayed much higher levels of 10-40 ng/ml (Vaspin(High) group). In the Vaspin(Low) group, serum vaspin levels in T2D were significantly higher than healthy subjects (0.99 +/- 0.04 vs. 0.86 +/- 0.02 ng/ml; P < 0.01). Both in T2D and genotyped Japanese population, serum vaspin levels closely correlated with homeostasis model of assessment for insulin resistance rather than anthropometric parameters. By genotyping, rs77060950 tightly linked to serum vaspin levels, i.e. CC (0.6 +/- 0.4 ng/ml), CA (18.4 +/- 9.6 ng/ml), and AA (30.5 +/- 5.1 ng/ml) (P < 2 * 10(-16)). Putative GATA-2 and GATA-3 binding consensus site was found at rs77060950. CONCLUSIONS: Serum vaspin levels were related to insulin resistance, and higher levels of serum vaspin in 7% of the Japanese population are closely linked to minor allele sequence (A) of rs77060950. PMID- 22539590 TI - Efficacy and safety of taspoglutide in patients with type 2 diabetes inadequately controlled with metformin plus pioglitazone over 24 weeks: T-Emerge 3 trial. AB - OBJECTIVE: This study assessed the efficacy and safety of once-weekly taspoglutide in patients with type 2 diabetes mellitus inadequately controlled with metformin plus pioglitazone compared with placebo. DESIGN: In this randomized, double-blind, parallel-group, placebo-controlled trial (T-emerge 3), 326 patients were randomized to once-weekly sc injections of taspoglutide 10 mg, taspoglutide 20 mg (10 mg for first 4 wk), or placebo. The primary endpoint was change from baseline in glycosylated hemoglobin (HbA1c) at 24 wk. RESULTS: A significant reduction in HbA1c was observed with taspoglutide 10 mg and 20 mg vs. placebo (least square mean -1.35 and -1.40% vs. -0.45%, respectively; P < 0.0001). A greater proportion of taspoglutide-treated patients reached HbA1c target 7% or less (69.8 and 76.1% vs. 35.1%). With taspoglutide 10 mg and 20 mg vs. placebo, significantly greater reductions in fasting plasma glucose [-1.87 mmol/liter (-34 mg/dl) and -2.12 mmol/liter (-38 mg/dl) vs. -0.57 mmol/liter (-10 mg/dl); P < 0.0001], improvements in homeostasis model assessment of beta-cell function score (20.65 and 33.52 vs. -2.03; P < 0.0001), and significant weight loss (-0.64 kg and -1.04 kg vs. 0.59 kg; P < 0.01) were observed. Adverse events were generally mild to moderate; the most frequent adverse events with taspoglutide 10 mg, taspoglutide 20 mg, and placebo were nausea (35, 44, and 10%), vomiting (21, 24, and 2%), and injection site reactions (24, 24, and 5%). CONCLUSIONS: Taspoglutide provided glycemic control with weight loss as add-on therapy to metformin plus pioglitazone for inadequately controlled type 2 diabetes mellitus. PMID- 22539589 TI - Liposuction induces a compensatory increase of visceral fat which is effectively counteracted by physical activity: a randomized trial. AB - CONTEXT: Liposuction is suggested to result in long-term body fat regain that could lead to increased cardiometabolic risk. We hypothesized that physical activity could prevent this effect. OBJECTIVE: Our objective was to investigate the effects of liposuction on body fat distribution and cardiometabolic risk factors in women who were either exercise trained or not after surgery. DESIGN, SETTING, AND PARTICIPANTS: Thirty-six healthy normal-weight women participated in this 6-month randomized controlled trial at the University of Sao Paulo, Sao Paulo, Brazil. INTERVENTIONS: Patients underwent a small-volume abdominal liposuction. Two months after surgery, the subjects were randomly allocated into two groups: trained (TR, n = 18, 4-month exercise program) and nontrained (NT, n = 18). MAIN OUTCOME MEASURES: Body fat distribution (assessed by computed tomography) was assessed before the intervention (PRE) and 2 months (POST2), and 6 months (POST6) after surgery. Secondary outcome measures included body composition, metabolic parameters and dietary intake, assessed at PRE, POST2, and POST6, and total energy expenditure, physical capacity, and sc adipocyte size and lipid metabolism-related gene expression, assessed at PRE and POST6. RESULTS: Liposuction was effective in reducing sc abdominal fat (PRE vs. POST2, P = 0.0001). Despite the sustained sc abdominal fat decrement at POST6 (P = 0.0001), the NT group showed a significant 10% increase in visceral fat from PRE to POST6 (P = 0.04; effect size = -0.72) and decreased energy expenditure (P = 0.01; effect size = 0.95) when compared with TR. Dietary intake, adipocyte size, and gene expression were unchanged over time. CONCLUSION: Abdominal liposuction does not induce regrowth of fat, but it does trigger a compensatory increase of visceral fat, which is effectively counteracted by physical activity. PMID- 22539591 TI - SNP array profiling of childhood adrenocortical tumors reveals distinct pathways of tumorigenesis and highlights candidate driver genes. AB - CONTEXT: Childhood adrenocortical tumors (ACT) are rare malignancies, except in southern Brazil, where a higher incidence rate is associated to a high frequency of the founder R337H TP53 mutation. To date, copy number alterations in these tumors have only been analyzed by low-resolution comparative genomic hybridization. OBJECTIVE: We analyzed an international series of 25 childhood ACT using high-resolution single nucleotide polymorphism arrays to: 1) detect focal copy number alterations highlighting candidate driver genes; and 2) compare genetic alterations between Brazilian patients carrying the R337H TP53 mutation and non-Brazilian patients. RESULTS: We identified 16 significantly recurrent chromosomal alterations (q-value < 0.05), the most frequent being -4q34, +9q33 q34, +19p, loss of heterozygosity (LOH) of chromosome 17 and 11p15. Focal amplifications and homozygous deletions comprising well-known oncogenes (MYC, MDM2, PDGFRA, KIT, MCL1, BCL2L1) and tumor suppressors (TP53, RB1, RPH3AL) were identified. In addition, eight focal deletions were detected at 4q34, defining a sharp peak region around the noncoding RNA LINC00290 gene. Although non-Brazilian tumors with a mutated TP53 were similar to Brazilian tumors, those with a wild type TP53 displayed distinct genomic profiles, with significantly fewer rearrangements (P = 0.019). In particular, three alterations (LOH of chromosome 17, +9q33-q34, and -4q34) were significantly more frequent in TP53-mutated samples. Finally, two of four TP53 wild-type tumors displayed as sole rearrangement a copy-neutral LOH of the imprinted region at 11p15, supporting a major role for this region in ACT development. CONCLUSIONS: Our findings highlight potential driver genes and cellular pathways implicated in childhood ACT and demonstrate the existence of different oncogenic routes in this pathology. PMID- 22539592 TI - The effectiveness of laceback ligatures during initial orthodontic alignment: a systematic review and meta-analysis. AB - Lacebacks may be used to limit unwanted incisor proclination during initial orthodontic alignment; however, their use has not met with universal approval. This systematic review aims to appraise the evidence in relation to the effectiveness of lacebacks in controlling incisor position during initial alignment. Electronic database searches of published literature (MEDLINE via Ovid, Cochrane Central Register of Controlled Trials, LILACS, and IBECS) and unpublished literature were performed. Search terms used included randomized controlled trial, controlled clinical trial, random allocation, double blind method, orthodontics, and laceback. Data were extracted using custom forms. Risk of bias assessment was made using the Cochrane Collaboration risk of bias tool. The quality of the evidence was also assessed using GRADE. Mean differences in incisor inclination and antero-posterior changes in incisor and molar position during alignment were calculated. Two studies involving 97 participants were found to be at low risk of bias and were included in the quantitative synthesis. The random effects meta-analysis demonstrated that the use of lacebacks was associated with 0.5 mm greater posterior movement of the incisors during alignment; this finding was of limited clinical importance and statistically non significant [95 per cent confidence interval (CI): -1.25, 0.25, P = 0.19]. Little difference (0.46 mm) was also found between laceback and non-laceback groups with regards to mesial molar movement (95 per cent CI: -0.33, 1.24, P = 0.26). According to the GRADE assessment, the overall quality of evidence relating to the use of lacebacks was high. There is no evidence to support the use of lacebacks for the control of the sagittal position of the incisors during initial orthodontic alignment. PMID- 22539593 TI - Vascular endothelial growth factor-induced neovascularization rescues cardiac function but not adverse remodeling at advanced ischemic heart disease. AB - OBJECTIVE: Proangiogenic therapy is a promising avenue for the treatment for chronic heart failure and a potentially powerful modality for reversing adverse cardiac remodeling. There is a concern, however, that adverse remodeling might enter an irreversible stage, and become refractory to treatments. The present study aims to determine whether neovascularization therapy is feasible at end stage heart failure and its capacity to reverse adverse cardiac remodeling during progressive disease stages. METHODS AND RESULTS: Using a conditional transgenic mouse system for generating escalating levels of myocardium-specific vascular deficit and resultant stepwise development of heart remodeling, we show that left ventricular dilatation and fibrosis precede ventricular hypertrophy, but that interstitial fibrosis is progressive and eventually results in heart failure. Vascular endothelial growth factor-mediated neovascularization was efficient even at the end stage of disease, and rescued compromised contractile function. Remarkably, remodeling was also fully reversed by neovascularization during early and late stages. Adverse remodeling could not be rescued, however, at the end stage of the disease, thus defining a point of no return and indentifying a critical level of fibrosis as the key determinant to be considered in intended reversal. CONCLUSIONS: The study supports the notion of a restricted golden time for remodeling reversal but not for vascular endothelial growth factor-induced neovascularization, which is feasible even during advanced disease stages. PMID- 22539594 TI - Staphylococcal extracellular adherence protein induces platelet activation by stimulation of thiol isomerases. AB - OBJECTIVE: Staphylococcus aureus can induce platelet aggregation. The rapidity and degree of this correlates with the severity of disseminated intravascular coagulation, and depends on platelet peptidoglycans. Surface-located thiol isomerases play an important role in platelet activation. The staphylococcal extracellular adherence protein (Eap) functions as an adhesin for host plasma proteins. Therefore we tested the effect of Eap on platelets. METHODS AND RESULTS: We found a strong stimulation of the platelet-surface thiol isomerases protein disulfide isomerase and endoplasmic reticulum stress proteins 57 and 72 by Eap. Eap induced thiol isomerase-dependent glycoprotein IIb/IIIa activation, granule secretion, and platelet aggregation. Treatment of platelets with thiol blockers, bacitracin, and anti-protein disulfide isomerase antibody inhibited Eap induced platelet activation. The effect of Eap on platelets and protein disulfide isomerase activity was completely blocked by glycosaminoglycans. Inhibition by the hydrophobic probe bis(1-anilinonaphthalene 8-sulfonate) suggested the involvement of hydrophobic sites in protein disulfide isomerase and platelet activation by Eap. CONCLUSIONS: In the present study, we found an additional and yet unknown mechanism of platelet activation by a bacterial adhesin, involving stimulation of thiol isomerases. The thiol isomerase stimulatory and prothrombotic features of a microbial secreted protein are probably not restricted to S aureus and Eap. Because many microorganisms are coated with amyloidogenic proteins, it is likely that the observed mechanism is a more general one. PMID- 22539596 TI - Cadherin 6 has a functional role in platelet aggregation and thrombus formation. AB - OBJECTIVE: Thrombosis occurs at sites of vascular injury when platelets adhere to subendothelial matrix proteins and to each other. Platelets express many surface receptor proteins, the function of several of these remains poorly characterized. Cadherin 6 is expressed on the platelet surface and contains an arginine-glycine aspartic acid motif, suggesting that it might have a supportive role in thrombus formation. The aim of this study was to characterize the role of cadherin 6 in platelet function. METHODS AND RESULTS: Platelet aggregation was inhibited by both antibodies and exogenous soluble cadherin 6. Platelet adhesion to immobilized cadherin 6 was inhibited by arginine-glycine-aspartic acid-serine tetrapeptides. Antibodies to alpha(IIb)beta(3) inhibited platelet adhesion to cadherin 6. Because platelet aggregation occurs in fibrinogen and von Willebrand factor double-deficient mice, we investigated whether cadherin 6 is an alternative ligand for the integrin alpha(IIb)beta(3). Platelet aggregation in fibrinogen and von Willebrand factor double-deficient mice was significantly inhibited by an antibody to cadherin 6. In flow-based assays, inhibition of cadherin 6 caused a marked reduction in thrombus formation in both human and mouse blood. CONCLUSIONS: This study demonstrates the role of cadherin 6 as a novel ligand for alpha(IIb)beta(3) and highlights its function in thrombus formation. PMID- 22539595 TI - alpha1AMP-activated protein kinase mediates vascular protective effects of exercise. AB - OBJECTIVE: We investigated whether AMP-activated protein kinase (AMPK) may be involved in the signaling processes leading to exercise-mediated vascular protection. METHODS AND RESULTS: The effects of voluntary exercise on AMPK activity, endothelial NO synthase expression and phosphorylation, vascular reactive oxygen species formation, and cell senescence were tested in alpha1AMPK knockout and corresponding wild-type mice. Exercise significantly improved endothelial function, and increased plasma nitrite production in wild-type mice, associated with an activation of aortic AMPK assessed by its phosphorylation at threonine 172. In addition, regular physical activity resulted in an upregulation of endothelial NO synthase protein, serine 1177 endothelial NO synthase phosphorylation, and an increase of circulating Tie-2(+)Sca-1(+)Flk-1(+) myeloid progenitor cells. All these changes were absent after alpha1AMPK deletion. In addition, exercise increased the expression of important regulators of the antioxidative defense including heme oxygenase-1 and peroxisome proliferator activated receptor gamma coactivator 1alpha, decreased aortic reactive oxygen species levels, and prevented endothelial cell senescence in an alpha1AMPK dependent manner. CONCLUSIONS: Intact alpha1AMPK signaling is required for the signaling events leading to the manifestation of vascular protective effects during exercise. Pharmacological AMPK activation might be a novel approach in the near future to simulate the beneficial vascular effects of physical activity. PMID- 22539597 TI - Endoplasmic reticulum stress is involved in cardiac damage and vascular endothelial dysfunction in hypertensive mice. AB - OBJECTIVE: Cardiac damage and vascular dysfunction are major causes of morbidity and mortality in hypertension. In the present study, we explored the beneficial therapeutic effect of endoplasmic reticulum (ER) stress inhibition on cardiac damage and vascular dysfunction in hypertension. METHODS AND RESULTS: Mice were infused with angiotensin II (400 ng/kg per minute) with or without ER stress inhibitors (taurine-conjugated ursodeoxycholic acid and 4-phenylbutyric acid) for 2 weeks. Mice infused with angiotensin II displayed an increase in blood pressure, cardiac hypertrophy and fibrosis associated with enhanced collagen I content, transforming growth factor-beta1 (TGF-beta1) activity, and ER stress markers, which were blunted after ER stress inhibition. Hypertension induced ER stress in aorta and mesenteric resistance arteries (MRA), enhanced TGF-beta1 activity in aorta but not in MRA, and reduced endothelial NO synthase phosphorylation and endothelium-dependent relaxation (EDR) in aorta and MRA. The inhibition of ER stress significantly reduced TGF-beta1 activity, enhanced endothelial NO synthase phosphorylation, and improved EDR. The inhibition of TGF beta1 pathway improved EDR in aorta but not in MRA, whereas the reduction in reactive oxygen species levels ameliorated EDR in MRA only. Infusion of tunicamycin in control mice induced ER stress in aorta and MRA, and reduced EDR by a TGF-beta1-dependent mechanism in aorta and reactive oxygen species-dependent mechanism in MRA. CONCLUSIONS: ER stress inhibition reduces cardiac damage and improves vascular function in hypertension. Therefore, ER stress could be a potential target for cardiovascular diseases. PMID- 22539598 TI - Pro- and antiatherogenic effects of a dominant-negative P465L mutation of peroxisome proliferator-activated receptor-gamma in apolipoprotein E-Null mice. AB - OBJECTIVE: The dominant-negative mutation, P467L, in peroxisome proliferator activated receptor-gamma (PPARgamma) affects adipose tissue distribution, insulin sensitivity, and blood pressure in heterozygous humans. We hypothesized that the equivalent mutation, PPARgamma-P465L, in mice will worsen atherosclerosis. METHODS AND RESULTS: Apolipoprotein E-null mice with and without PPARgamma-P465L mutation were bred in 129S6 inbred genetic background. Mild hypertension and lipodystrophy of PPARgamma-P465L persisted in the apolipoprotein E-null background. Glucose homeostasis was normal, but plasma adiponectin was significantly lower and resistin was higher in PPARgamma-P465L mice. Plasma cholesterol and lipoprotein distribution were not different, but plasma triglycerides tended to be reduced. Surprisingly, there were no overall changes in the atherosclerotic plaque size or composition. PPARgamma-P465L macrophages had a small decrease in CD36 mRNA and a small yet significant reduction in very low-density lipoprotein uptake in culture. In unloaded apolipoprotein E-null macrophages with PPARgamma-P465L, cholesterol uptake was reduced whereas apolipoprotein AI-mediated efflux was increased. However, when cells were cholesterol loaded in the presence of acetylated low-density lipoprotein, no genotype difference in uptake or efflux was apparent. A reduction of vascular cell adhesion molecule-1 expression in aorta suggests a relatively antiatherogenic vascular environment in mice with PPARgamma-P465L. CONCLUSIONS: Small, competing pro- and antiatherogenic effects of PPARgamma-P465L mutation result in unchanged plaque development in apolipoprotein E-deficient mice. PMID- 22539600 TI - Renin-angiotensin-system modulators and the incidence of atrial fibrillation following hospitalization for coronary artery disease. AB - AIMS: Previous studies have suggested that upstream medical therapy to modulate the renin-angiotensin axis may facilitate left atrial remodelling and thereby prevent new-onset atrial fibrillation (AF). The purpose of this study was to evaluate the association between angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blockers (ARB) on new-onset AF in a large cohort of patients with coronary artery disease (CAD). METHODS AND RESULTS: This was a population-based study of 28 620 patients, from community-dwelling Medicare beneficiaries who had been hospitalized for acute myocardial infarction or coronary revascularization (1995-2004). All patients, 65 years and older, had a mean follow-up period of upto 3.8 +/- 3.0 years. Patients with a history of AF before and during hospitalization were excluded. We compared the incidence of new onset AF between patients who were (N= 10 918) and were not (N= 17 702) prescribed ACEI and/or ARB within 1 month of hospital discharge following cardiac event. New-onset AF within 5 and 10 years was 39.1 and 61.1%, respectively, in patients who received ACEI/ARB, compared 34.9 and 53.6% in patients who did not receive them [unadjusted hazard ratio (HR): 1.16; 95% confidence interval (CI): 1.11, 1.21]. Multivariable analysis adjusting for patient- and hospital-related characteristics indicated that ACEI/ARB use independently had no impact on the risk of developing new-onset AF compared with non-users (adjusted HR: 0.99; 95% CI: 0.94, 1.04). Adjustment for propensity-score and health-seeking behaviours yielded nearly identical results. CONCLUSION: Angiotensin converting enzyme inhibitor/ARB therapy initiated within 1 month after hospital discharge is not associated with a reduction in the risk of new-onset AF after myocardial infarction or coronary revascularization. PMID- 22539601 TI - Prevalence, mutation spectrum, and cardiac phenotype of the Jervell and Lange Nielsen syndrome in Sweden. AB - AIMS: To explore the national prevalence, mutation spectrum, cardiac phenotype, and outcome of the uncommon Jervell and Lange-Nielsen syndrome (JLNS), associated with a high risk of sudden cardiac death. METHODS AND RESULTS: A national inventory of clinical JLNS cases was performed. Genotype and area of origin were ascertained in index families. Retrospective clinical data were collected from medical records and interviews. We identified 19 cases in 13 Swedish families. A JLNS prevalence >1:200 000 was revealed (five living cases <10 years of age). The mutation spectrum consisted of eight KCNQ1 mutations, whereof p.R518X in 12/24 alleles. Geographic clustering of four mutations (20/24 alleles) and similarities to Norway's mutation spectrum were seen. A high prevalence of heterozygotes was suggested. Three paediatric cases on beta-blockers since birth were as yet asymptomatic. Seven symptomatic cases had suffered an aborted cardiac arrest and four had died suddenly. QTc prolongation was significantly longer in symptomatic cases (mean 605 +/- 62 vs. 518 +/- 50 ms, P = 0.016). beta-Blockers reduced, but did not abolish, cardiac events in any previously symptomatic case. beta-Blocker type, dosage, and compliance probably affect outcome significantly. Implantable cardioverter-defibrillator therapy (ICD, n = 6) was associated with certain complications; however, no case of sudden death. CONCLUSION: Founder effects could explain 83% of the Swedish JLNS mutation spectrum and probably contribute to the high JLNS prevalence found in preadolescent Swedish children. Due to the severe cardiac phenotype in JLNS, the importance of stringent beta-blocker therapy and compliance, and consideration of ICD implantation in the case of therapy failure is stressed. PMID- 22539599 TI - Potential quantitative magnetic resonance imaging biomarkers of coronary remodeling in older hypertensive patients. AB - OBJECTIVE: To detect differences in potential magnetic resonance imaging biomarkers of coronary remodeling between older hypertensive patients and healthy controls. METHODS AND RESULTS: Two-dimensional black-blood coronary wall magnetic resonance imaging and 3-dimensional whole-heart coronary magnetic resonance angiography were performed on 130 participants (65-84 years), including 65 hypertensive patients and 65 healthy controls. Coronary segments derived from hypertensive participants had a higher mean coronary wall thickness, a smaller vessel area, a smaller coronary wall area, a smaller lumen area, a lower coronary distensibility index, and a higher percent of the coronary wall occupying the vessel area (PWOV) than those from healthy controls. When the average PWOV was set as an ad hoc cutoff point, coronary segments with a high PWOV had a significantly higher mean wall thickness, a higher maximum wall thickness, a smaller vessel area, a smaller lumen area, a lower coronary distensibility index, and a higher coronary plaque index compared with coronary segments with a low PWOV. CONCLUSIONS: Magnetic resonance techniques are able to noninvasively detect significant differences in potential imaging biomarkers of coronary remodeling between older hypertensive patients and healthy controls. The PWOV is a promising remodeling feature for quantitatively evaluating the progression of coronary atherosclerosis. PMID- 22539602 TI - Rotating night shift work and mammographic density. AB - BACKGROUND: An increased risk of breast cancer has been observed in night shift workers. Exposure to artificial light at night and disruption of the endogenous circadian rhythm with suppression of the melatonin synthesis have been suggested mechanisms. We investigated the hypothesis that rotating night shift work is associated with mammographic density. METHODS: We conducted a cross-sectional study on the association between rotating night shift work characteristics, 6 sulfatoxymelatonin (MT6s) creatinine adjusted in a spot morning urine sample, and a computer-assisted measure of mammographic density in 640 nurses and midwives ages 40 to 60 years. The associations were evaluated using regression models adjusted for age, body mass index, menopausal status, age at menopause, age at menarche, smoking, and the calendar season of the year when mammography was conducted. RESULTS: The adjusted means of percentage of mammographic density and absolute density were slightly higher among women working rotating night shifts but not statistically significant [percentage of mammographic density = 23.6%, 95% confidence interval (CI), 21.9%-25.4% vs. 22.5%, 95% CI, 20.8%-24.3%; absolute density = 23.9 cm(2), 95% CI, 21.4-26.4 cm(2) vs. 21.8 cm(2), 95% CI, 19.4-24.3 cm(2) in rotating night shift and day shift nurses, respectively). There were no significant associations between the current or cumulative rotating night shift work exposure metrics and mammographic density. No association was observed between morning MT6s and mammographic density. CONCLUSIONS: The hypothesis on the link between rotating night shift work, melatonin synthesis disruption, and mammographic density is not supported by the results of the present study. IMPACT: It is unlikely that the development of breast cancer in nurses working rotating night shifts is mediated by an increase in mammographic density. PMID- 22539603 TI - Pathway analyses identify TGFBR2 as potential breast cancer susceptibility gene: results from a consortium study among Asians. AB - BACKGROUND: The TGF-beta signaling pathway plays a significant role in the carcinogenic process of breast cancer. METHODS: We systematically evaluated associations of common variants in TGF-beta signaling pathway genes with breast cancer risk using a multistage, case-control study among Asian women. RESULTS: In the first stage, 341 single-nucleotide polymorphisms with minor allele frequencies >= 0.05 across 11 genes were evaluated among 2,926 cases and 2,380 controls recruited as a part of the Shanghai Breast Cancer Genetics Study (SBCGS). In the second stage, 20 SNPs with promising associations were evaluated among an additional 1,890 cases and 2,000 controls from the SBCGS. One variant, TGFBR2 rs1078985, had highly consistent and significant associations with breast cancer risk among participants in both study stages, as well as promising results from in silico analysis. Additional genotyping was carried out among 2,475 cases and 2,343 controls from the SBCGS, as well as among 5,077 cases and 5,384 controls from six studies in the Asian Breast Cancer Consortium (stage III). Pooled analysis of all data indicated that minor allele homozygotes (GG) of TGFBR2 rs1078985 had a 24% reduced risk of breast cancer compared with major allele carriers (AG or AA; OR, 0.76; 95% CI, 0.65-0.89; P = 8.42 * 10(-4)). CONCLUSION: These findings support a role for common genetic variation in TGF beta signaling pathway genes, specifically in TGFBR2, in breast cancer susceptibility. IMPACT: These findings may provide new insights into the etiology of breast cancer as well as future potential therapeutic targets. PMID- 22539604 TI - Association of the 15q25 and 5p15 lung cancer susceptibility regions with gene expression in lung tumor tissue. AB - BACKGROUND: Genome-wide association studies have identified two independent lung cancer susceptibility loci at chromosome 15q25 and one locus at 5p15. We examined the association of genetic variants in these regions with gene expression in lung tumor tissue, in an effort to elucidate carcinogenic mechanisms by which these variants influence lung cancer risk. METHODS: We used data from 2 independent studies of non-small cell lung carcinoma patients: the JBR.10 clinical trial (n = 131) and a University Health Network (UHN) patient sample in Toronto (n = 181). We genotyped seven 15q25 and five 5p15 variants and examined their association with expression profiles of genes in the corresponding regions, measured by Affymetrix HG-U133A. RESULTS: The minor allele (C) of a variant representing one of the two loci at 15q25 (rs2036534) was associated with increased iron responsive element binding protein 2 (IREB2) expression in both studies (JBR.10 P = 0.042; UHN P = 0.002). A false discovery rate of 0.05 or less in the UHN sample increased our confidence in this association. The association appears to be more prominent among lung adenocarcinoma patients. We did not detect an association between genotype and expression profile for the other 15q25 locus or for 5p15 variants. CONCLUSIONS: In contrast to previous studies that indicate 15q25 variants are associated with lung cancer risk through an effect on smoking behavior, our results suggest these variants may influence risk through a second mechanism, involving modulation of IREB2 expression. IMPACT: This finding expands on potential mechanisms through which 15q25 variants influence lung cancer risk and may have implications for future research on chemoprevention strategies. PMID- 22539605 TI - Inference about causation from examination of familial confounding: application to longitudinal twin data on mammographic density measures that predict breast cancer risk. AB - BACKGROUND: Mammographic density is a strong risk factor for breast cancer. It is unknown whether there are different causes of variation in mammographic density at different ages. METHODS: Mammograms and questionnaires were obtained on average 8 years apart from 327 Australian female twin pairs (204 monozygous and 123 dizygous). Mammographic dense area and percentage dense area were measured using a computer-assisted method. The correlational structure of the longitudinal twin data was estimated under a multivariate normal model using FISHER. Inference about causation from examination of familial confounding was made by regressing each twin's recent mammographic density measure against one or both of her and her co-twin's past measures. RESULTS: For square root dense area and percentage dense area (age- and body mass index-adjusted), the correlations over time within twins were 0.86 and 0.82, and the cross-twin correlations were 0.71 and 0.65 for monozygous pairs and 0.25 and 0.20 for dizygous pairs, respectively. As a predictor of a twin's recent dense area, the regression coefficient (SE) for the co-twin's past dense area reduced after adjusting for her own past measure from 0.84 (0.03) to 0.09 (0.03) for monozygous pairs and from 0.63 (0.04) to 0.04 (0.03) for dizygous pairs. Corresponding estimates for percentage dense area were 0.73 (0.04), 0.10 (0.03), 0.42 (0.05), and 0.03 (0.03). CONCLUSION: Mammographic density measures are highly correlated over time and the familial/genetic components of their variation are established before mid-life. IMPACT: Mammographic density of young women could provide a means for breast cancer control. PMID- 22539606 TI - Residential radon exposure, histologic types, and lung cancer risk. A case control study in Galicia, Spain. AB - BACKGROUND: Lung cancer is an important public health problem, and tobacco is the main risk factor followed by residential radon exposure. Recommended exposure levels have been progressively lowered. Galicia, the study area, has high residential radon concentrations. We aim (i) to assess the risk of lung cancer linked to airborne residential radon exposure, (ii) to ascertain whether tobacco modifies radon risk, and (iii) to know whether there is a lung cancer histologic type more susceptible to radon. METHODS: A hospital-based case-control design was conducted in two Spanish hospitals. Consecutive cases with histologic diagnosis of lung cancer and controls undergoing trivial surgery not tobacco-related were included. Residential radon was measured using standard procedures. Results were obtained using logistic regression. RESULTS: Three hundred and forty-nine cases and 513 controls were included. Radon exposure posed a risk even with a low exposure, with those exposed to 50 to 100 Bq/m(3) having an OR of 1.87 [95% confidence interval (CI), 1.21-2.88] and of 2.21 (95% CI, 1.33-3.69) for those exposed to 148 Bq/m(3) or more. Tobacco increased appreciably the risk posed by radon, with an OR of 73 (95% CI, 19.88-268.14) for heavy smokers exposed to more than 147 Bq/m(3). Less frequent histologic types (including large cell carcinomas), followed by small cell lung cancer, had the highest risk associated with radon exposure. CONCLUSIONS: The presence of airborne radon even at low concentrations poses a risk of developing lung cancer, with tobacco habit increasing considerably this risk. IMPACT: Public health initiatives should address the higher risk of lung cancer for smokers exposed to radon. PMID- 22539608 TI - Markers of the APC/beta-catenin signaling pathway as potential treatable, preneoplastic biomarkers of risk for colorectal neoplasms. AB - BACKGROUND: Malfunctioning of the adenomatous polyposis coli (APC)/beta-catenin signaling pathway is both an early and common event in sporadic colorectal cancer. To assess the potential of APC/beta-catenin signaling pathway markers as treatable, preneoplastic biomarkers of risk for colorectal neoplasms, we conducted a pilot colonoscopy-based case-control study (51 cases and 154 controls) of incident, sporadic colorectal adenoma. METHODS: We evaluated APC, beta-catenin, and E-cadherin expression in normal mucosa from the rectum and ascending and sigmoid colon using automated immunohistochemical and quantitative image analysis. Diet, lifestyle, and medical history were assessed with validated questionnaires. RESULTS: In the normal rectal mucosa, the ratio of the proportion of APC expression in the upper 40% of crypts with total beta-catenin expression (APC/beta-catenin score) was 14.3% greater in controls than in cases [P = 0.02; OR, 0.40; 95% confidence interval (CI), 0.14-1.14]. Compared with controls, in cases, APC expression was 3.2% lower, beta-catenin expression was 3.0% higher, and E-cadherin expression was 0.7% lower; however, none of these differences were statistically significant. The APC/beta-catenin score statistically significantly differed according to categories of plausible risk factors for colorectal cancer [e.g., it was 17.7% higher among those with 25(OH) vitamin D(3) concentrations >= 27 ng/mL]. CONCLUSIONS: These preliminary data suggest that the combined expression of APC and beta-catenin in the normal rectal mucosa may be associated with risk for incident, sporadic colorectal neoplasms, as well as with modifiable risk factors for colorectal neoplasms. IMPACT: Our results may help advance the development of treatable, preneoplastic biomarkers of risk for colorectal neoplasms. PMID- 22539607 TI - Correlation of LINE-1 methylation levels in patient-matched buffy coat, serum, buccal cell, and bladder tumor tissue DNA samples. AB - BACKGROUND: Evidence suggests that global methylation levels in blood cell DNA may be a biomarker for cancer risk. To date, most studies have used genomic DNA isolated from blood or urine as a surrogate marker of global DNA methylation levels in bladder tumor tissue. METHODS: A subset of 50 bladder cancer cases was selected from the New England Bladder Cancer Case-Control Study. Genomic DNA was isolated from buffy coat, buccal cells, serum, and formalin-fixed, paraffin embedded tissue for each participant. DNA methylation at four CpG sites within the long interspersed nucleotide element (LINE-1) repetitive element was quantified using pyrosequencing and expressed as a mean methylation level across sites. RESULTS: Overall, the mean percent (%) LINE-1 5-methylcytosine (%5MeC) level was highest in serum (80.47% +/- 1.44%) and lowest in bladder tumor DNA (61.36% +/- 12.74%) and levels varied significantly across tissue types (P = 0.001). An inverse association between LINE-1 mean %5MeC and tumor stage (P = 0.001) and grade (P = 0.002) was observed. A moderate correlation between patient matched serum and buffy coat DNA LINE-1 %5MeC levels was found (r = 0.32, P = 0.03) but levels were uncorrelated among other matched genomic DNA samples. CONCLUSIONS: The mean promoter LINE-1 %5MeC measurements were correlated between buffy coat and serum DNA samples. No correlation was observed between genomic DNA sources and tumor tissues; however a significant inverse association between tumor percent LINE-1 methylation and tumor stage/grade was found. IMPACT: LINE-1 methylation measured in case blood DNA did not reflect that observed in bladder tumor tissue but may represent other factors associated with carcinogenesis. PMID- 22539609 TI - Parental age, family size, and offspring's risk of childhood and adult acute leukemia. AB - BACKGROUND: An association between childhood acute leukemia and advanced parental age was observed more than 50 years ago, and the association has been repeated in several, but not all, subsequent studies. In contrast to the many studies addressing childhood leukemia, few have included adult patients. METHODS: In this register-based case-control study, we examined the association between parental age and incidence of acute leukemia in 2,660 childhood cases and 4,412 adult cases of acute leukemia, compared with 28,288 age-matched controls selected from a population-based register. Relative risks were estimated with conditional logistic regression. RESULTS: We found a small increased risk of childhood acute lymphoblastic leukemia with increasing paternal age (adjusted OR, 1.05 per 5-year increase in age). Risk estimates were similar for childhood acute myeloid leukemia (AML), whereas no association was found with adult leukemia. Meanwhile, we observed a decreased risk of adult AML with increasing number of siblings, both older and younger. CONCLUSIONS: The results support the idea of a prenatal etiology of leukemia but indicate that parental age effects are limited to childhood cases. IMPACT: This is the first large study on parental age and leukemia risk, which includes adult cases. The finding on family size and risk of adult AML needs to be validated in future studies. PMID- 22539610 TI - Evolution of animal Piwi-interacting RNAs and prokaryotic CRISPRs. AB - Piwi-interacting RNAs (piRNAs) and CRISPR RNAs (crRNAs) are two recently discovered classes of small noncoding RNA that are found in animals and prokaryotes, respectively. Both of these novel RNA species function as components of adaptive immune systems that protect their hosts from foreign nucleic acids piRNAs repress transposable elements in animal germlines, whereas crRNAs protect their bacterial hosts from phage and plasmids. The piRNA and CRISPR systems are nonhomologous but rather have independently evolved into logically similar defense mechanisms based on the specificity of targeting via nucleic acid base complementarity. Here we review what is known about the piRNA and CRISPR systems with a focus on comparing their evolutionary properties. In particular, we highlight the importance of several factors on the pattern of piRNA and CRISPR evolution, including the population genetic environment, the role of alternate defense systems and the mechanisms of acquisition of new piRNAs and CRISPRs. PMID- 22539612 TI - Gold nanoparticles uptake and cytotoxicity assessed on rat liver precision-cut slices. AB - A major obstacle in the field of nanotoxicology is the development of an in vitro model that accurately predicts an in vivo response. To address this concern, rat liver precision-cut slices were used to assess the impact of 5-nm gold nanoparticles (GNPs) coated with polyvinylpyrrolidone (PVP) on the mammalian liver, following exposure to different concentrations and for a duration of up to 24 h. The presence of GNPs inside endocytotic vesicles of hepatocytes was appreciable within 30 min of their addition. After 2 h, GNPs were clearly visualized inside endosome-like vesicles within the slice, not only in hepatocytes but also in endothelial and Kupffer cells located within the first two cellular layers. This uptake did not translate into modifications of either phase I or phase II of 7-ethoxycoumarin metabolism or alter activities of cytochrome P450 toward marker substrates. Furthermore, although the GNPs were rapidly internalized, no overt signs of cytotoxicity, assessed through lactate dehydrogenase release, reduction of methylthiazolyldiphenyl tetrazolium bromide, and glutathione levels, were observed. In conclusion, the use of rat liver slices successfully enhanced nanomaterial screening and determined that PVP-coated 5-nm GNPs were biocompatible with rat liver cells. PMID- 22539611 TI - Process versus product in social learning: comparative diffusion tensor imaging of neural systems for action execution-observation matching in macaques, chimpanzees, and humans. AB - Social learning varies among primate species. Macaques only copy the product of observed actions, or emulate, while humans and chimpanzees also copy the process, or imitate. In humans, imitation is linked to the mirror system. Here we compare mirror system connectivity across these species using diffusion tensor imaging. In macaques and chimpanzees, the preponderance of this circuitry consists of frontal-temporal connections via the extreme/external capsules. In contrast, humans have more substantial temporal-parietal and frontal-parietal connections via the middle/inferior longitudinal fasciculi and the third branch of the superior longitudinal fasciculus. In chimpanzees and humans, but not in macaques, this circuitry includes connections with inferior temporal cortex. In humans alone, connections with superior parietal cortex were also detected. We suggest a model linking species differences in mirror system connectivity and responsivity with species differences in behavior, including adaptations for imitation and social learning of tool use. PMID- 22539613 TI - Pregabalin induces hepatic hypoxia and increases endothelial cell proliferation in mice, a process inhibited by dietary vitamin E supplementation. AB - The preceding article identified key components of pregabalin's mode of action on nongenotoxic hemangiosarcoma formation in mice, including increased serum bicarbonate leading to decreased respiratory rate, increased blood pH, increased venous oxygen saturation, increased vascular endothelial growth factor and basic fibroblast growth factor expression, increased hepatic vascular endothelial growth factor receptor 2 expression, and increased iron-laden macrophages. Increased platelet count and platelet activation were early, species-specific biomarkers in mice. Dysregulated erythropoiesis, macrophage activation, and elevations of tissue growth factors were consistent with the unified mode of action for nongenotoxic hemangiosarcoma recently proposed at an international hemangiosarcoma workshop (Cohen, S. M., Storer, R. D., Criswell, K. A., Doerrer, N. G., Dellarco, V. L., Pegg, D. G., Wojcinski, Z. W., Malarkey, D. E., Jacobs, A. C., Klaunig, J. E., et al. (2009). Hemangiosarcoma in rodents: Mode-of-action evaluation and human relevance. Toxicol. Sci. 111, 4-18). In this article, we present evidence that pregabalin induces hypoxia and increases endothelial cell (EC) proliferation in a species-specific manner. Dietary administration of pregabalin produced a significant 35% increase in an immunohistochemical stain for hypoxia (Hypoxyprobe) in livers from pregabalin-treated mice. Increased Hypoxyprobe staining was not observed in the liver, bone marrow, or spleen of rats, supporting the hypothesis that pregabalin produces local tissue hypoxia in a species-specific manner. Transcriptional analysis supports that rats, unlike mice, adapt to pregabalin-induced hypoxia. Using a dual-label method, increased EC proliferation was observed as early as 2 weeks in mouse liver and 12 weeks in bone marrow following pregabalin administration. These same assays showed decreased EC proliferation in hepatic ECs of rats, further supporting species specificity. Dietary supplementation with vitamin E, which is known to have antioxidant and antiangiogenic activity, inhibited pregabalin-induced increases in mouse hepatic EC proliferation, providing confirmatory evidence for the proposed mode of action and its species-specific response. PMID- 22539614 TI - Chemically exacerbated chronic progressive nephropathy not associated with renal tubular tumor induction in rats: an evaluation based on 60 carcinogenicity studies by the national toxicology program. AB - Chronic progressive nephropathy (CPN) is a common age-related degenerative regenerative disease of the kidney that occurs in both sexes of most strains of rats. Recently, claims have been made that enhanced CPN is a mode of action for chemically induced kidney tumors in male rats and that renal tubular tumors (RTTs) induced by chemicals that concomitantly exacerbate CPN are not relevant for human cancer risk assessments. Although CPN is an observable histopathological lesion that may be modified by diet, the etiology of this disease and the mechanisms for its exacerbation by chemicals are unknown, and it fails to meet fundamental principles for defining carcinogenic modes of action and human relevance. Our comprehensive evaluation of possible relationships between exacerbated CPN and induction of RTTs in 58 carcinogenicity studies, conducted by the National Toxicology Program, in male and 11 studies in female F344 rats using 60 chemicals revealed widespread inconsistency in the claimed association. Because the proposed hypothesis lacks evidence of biological plausibility, and due to inconsistent relationships between exacerbated CPN and kidney tumor incidence in carcinogenicity studies in rats, dismissing the human relevance of kidney tumors induced by chemicals that also exacerbate CPN in rats would be wrong. PMID- 22539615 TI - Hemangiosarcoma in mice administered pregabalin: analysis of genotoxicity, tumor incidence, and tumor genetics. AB - Pregabalin, (S)-3-(aminomethyl)-5-methylhexanoic acid, binds with high affinity to the alpha(2)delta subunit of voltage-gated calcium channels and exerts analgesic, anxiolytic, and antiseizure activities. Two-year carcinogenicity studies were completed in B6C3F1 and CD-1 mice and two separate studies in Wistar rats. Doses in mice were 200, 1000, and 5000 mg/kg/day, with systemic exposures (AUC(0-24 h)) up to 31 times the mean exposure in humans, given the maximum recommended clinical dose. In rats, doses were 50, 150, and 450 mg/kg/day in males and 100, 300, and 900 mg/kg/day in females; systemic exposures up to 24 times were achieved in clinical trials. In both strains of mice, pregabalin treatment was associated with an increased incidence of hemangiosarcoma primarily in liver, spleen, and bone marrow. The incidence of hemangiosarcoma was higher in B6C3F1 mice than in CD-1 mice, consistent with its spontaneous incidence. Pregabalin did not increase the incidence of any other tumor type in rats and was not genotoxic, based on an extensive battery of in vivo and in vitro tests in bacterial and mammalian systems. Thus, pregabalin is a single-species, single tumor-type, nongenotoxic mouse carcinogen. Hemangiosarcomas occurring in mice treated with pregabalin were genotypically distinct from hemangiosarcomas induced by genotoxic carcinogens in humans with respect to ras and p53 mutation patterns and were similar to spontaneous tumors. Furthermore, there was a strong association between pregabalin treatment and bone marrow changes in these studies in mice, suggesting a possible link between the effects observed in bone marrow and the increase in tumor incidence in pregabalin-treated mice. PMID- 22539616 TI - Contributions of aryl hydrocarbon receptor genetic variants to the risk of glioma and PAH-DNA adducts. AB - The aryl hydrocarbon receptor (AHR) gene is involved in the response to polycyclic aromatic hydrocarbon (PAH) exposure. To investigate the hypothesis that the genetic variants in the AHR gene might be a causal genetic susceptibility to PAH-DNA adduct formation and glioma risk, we conducted a case control study of 384 glioma cases and 384 cancer-free controls to explore the association between six common single-nucleotide polymorphisms of the AHR gene and glioma risk. Using PAH-DNA adducts as biomarkers, we then evaluated the association between PAH-DNA adduct levels and glioma risk based on a tissue microarray including 11 controls and 77 glioma patients. We further explored the contributions of the glioma risk-associated AHR polymorphisms to the levels of PAH-DNA adducts in glioma tissues based on 77 glioma patients. We found that PAH DNA adduct staining existed in normal brain tissues and grades I-IV gliomas, and the staining intensity was significantly associated with the glioma grade. Two AHR polymorphisms (rs2066853 and rs2158041) demonstrated significant association with glioma risk. Intriguingly, we also found statistically significant associations between these two variants and PAH-DNA adduct levels in glioma tissue. These data suggest the contributions of AHR rs2066853 and rs2158041 to glioma risk and the PAH-DNA adduct levels, which shed new light on gene environment interactions in the etiology of glioma. Further studies with a larger sample size and ethnically diverse populations are required to elucidate the potential biological mechanism for, as well as the impact of, the susceptibility to glioma due to genetic variants of AHR. PMID- 22539617 TI - Pro-oxidant induced DNA damage in human lymphoblastoid cells: homeostatic mechanisms of genotoxic tolerance. AB - Oxidative stress contributes to many disease etiologies including ageing, neurodegeneration, and cancer, partly through DNA damage induction (genotoxicity). Understanding the i nteractions of free radicals with DNA is fundamental to discern mutation risks. In genetic toxicology, regulatory authorities consider that most genotoxins exhibit a linear relationship between dose and mutagenic response. Yet, homeostatic mechanisms, including DNA repair, that allow cells to tolerate low levels of genotoxic exposure exist. Acceptance of thresholds for genotoxicity has widespread consequences in terms of understanding cancer risk and regulating human exposure to chemicals/drugs. Three pro-oxidant chemicals, hydrogen peroxide (H(2)O(2)), potassium bromate (KBrO(3)), and menadione, were examined for low dose-response curves in human lymphoblastoid cells. DNA repair and antioxidant capacity were assessed as possible threshold mechanisms. H(2)O(2) and KBrO(3), but not menadione, exhibited thresholded responses, containing a range of nongenotoxic low doses. Levels of the DNA glycosylase 8-oxoguanine glycosylase were unchanged in response to pro- oxidant stress. DNA repair-focused gene expression arrays reported changes in ATM and BRCA1, involved in double-strand break repair, in response to low-dose pro oxidant exposure; however, these alterations were not substantiated at the protein level. Determination of oxidatively induced DNA damage in H(2)O(2) treated AHH-1 cells reported accumulation of thymine glycol above the genotoxic threshold. Further, the H(2)O(2) dose-response curve was shifted by modulating the antioxidant glutathione. Hence, observed pro- oxidant thresholds were due to protective capacities of base excision repair enzymes and antioxidants against DNA damage, highlighting the importance of homeostatic mechanisms in "genotoxic tolerance." PMID- 22539618 TI - A single neonatal exposure to aflatoxin b1 induces prolonged genetic damage in two loci of mouse liver. AB - Aflatoxin B (1) (AFB(1)) is a risk factor for hepatocellular carcinoma in humans. Infant, but not adult, mice are sensitive to AFB(1)-induced liver carcinogenesis; a single dose during the neonatal period leads to hepatocellular carcinoma in adulthood. Earlier work defined the mutational spectrum in the gpt gene of gpt delta B6C3F1 mice 3 weeks after exposure to aflatoxin. In the present study, we examined the gpt spectrum 10 weeks postdosing and expanded the study to examine, at 3 and 10 weeks, the spectrum at a second locus, the red/gam genes of the mouse lambdaEG10 transgene. Whereas the gpt locus is typically used to define local base changes, the red/gam genes, via the Spi(-) assay, often are used to detect more global mutations such as large deletions and rearrangements. Three weeks after dosing with AFB(1), there was a 10-fold increase over the control in the Spi(-) mutant fraction (MF) in liver DNA; after 10 weeks, a further increase was observed. The MF in the gpt gene was also increased at 10 weeks compared with the MF at 3 weeks. No gender-specific differences were found in the Spi(-) or gpt MFs. Whereas Spi(-) mutations often signal large genetic changes, they did not in this specific case. The Spi(-) spectrum was dominated by GC to TA transversions, with one exceptionally strong hotspot at position 314. Using two genetic loci, the data show a strong preference for the induction of GC to TA mutations in mice, which is the dominant mutation seen in people exposed to aflatoxin. PMID- 22539619 TI - Modulation of PC12 cell viability by forskolin-induced cyclic AMP levels through ERK and JNK pathways: an implication for L-DOPA-induced cytotoxicity in nigrostriatal dopamine neurons. AB - The intracellular levels of cyclic AMP (cAMP) increase in response to cytotoxic concentrations of L-DOPA in PC12 cells, and forskolin that induces intracellular cAMP levels either protects PC12 cells from L-DOPA-induced cytotoxicity or enhances cytotoxicity in a concentration-dependent manner. This study investigated the effects of cAMP induced by forskolin on cell viability of PC12 cells, relevant to L-DOPA-induced cytotoxicity in Parkinson's disease therapy. The low levels of forskolin (0.01 and 0.1 MUM)-induced cAMP increased dopamine biosynthesis and tyrosine hydroxylase (TH) phosphorylation, and induced transient phosphorylation of ERK1/2 within 1 h. However, at the high levels of forskolin (1.0 and 10 MUM)-induced cAMP, dopamine biosynthesis and TH phosphorylation did not increase, but rapid differentiation in neurite-like formation was observed with a steady state. The high levels of forskolin-induced cAMP also induced sustained increase in ERK1/2 phosphorylation within 0.25-6 h and then led to apoptosis, which was apparently mediated by JNK1/2 and caspase-3 activation. Multiple treatment of PC12 cells with nontoxic L-DOPA (20 MUM) for 4-6 days induced neurite-like formation and decreased intracellular dopamine levels by reducing TH phosphorylation. These results suggest that the low levels of forskolin-induced cAMP increased dopamine biosynthesis in cell survival via transient ERK1/2 phosphorylation. In contrast, the high levels of forskolin induced cAMP induced differentiation via sustained ERK1/2 phosphorylation and then led to apoptosis. Taken together, the intracellular levels of cAMP play a dual role in cell survival and death through the ERK1/2 and JNK1/2 pathways in PC12 cells. PMID- 22539620 TI - Mode of action associated with development of hemangiosarcoma in mice given pregabalin and assessment of human relevance. AB - Pregabalin increased the incidence of hemangiosarcomas in carcinogenicity studies of 2-year mice but was not tumorigenic in rats. Serum bicarbonate increased within 24 h of pregabalin administration in mice and rats. Rats compensated appropriately, but mice developed metabolic alkalosis and increased blood pH. Local tissue hypoxia and increased endothelial cell proliferation were also confirmed in mice alone. The combination of hypoxia and sustained increases in endothelial cell proliferation, angiogenic growth factors, dysregulated erythropoiesis, and macrophage activation is proposed as the key event in the mode of action (MOA) for hemangiosarcoma formation. Hemangiosarcomas occur spontaneously in untreated control mice but occur only rarely in humans. The International Programme on Chemical Safety and International Life Sciences Institute developed a Human Relevance Framework (HRF) analysis whereby presence or absence of key events can be used to assess human relevance. The HRF combines the MOA with an assessment of biologic plausibility in humans to assess human relevance. This manuscript compares the proposed MOA with Hill criteria, a component of the HRF, for strength, consistency, specificity, temporality, and dose response, with an assessment of key biomarkers in humans, species differences in response to disease conditions, and spontaneous incidence of hemangiosarcoma to evaluate human relevance. Lack of key biomarker events in the MOA in rats, monkeys, and humans supports a species-specific process and demonstrates that the tumor findings in mice are not relevant to humans at the clinical dose of pregabalin. Based on this collective dataset, clinical use of pregabalin would not pose an increased risk for hemangiosarcoma to humans. PMID- 22539621 TI - Assessment of possible carcinogenicity of oxyfluorfen to humans using mode of action analysis of rodent liver effects. AB - Oxyfluorfen is a herbicide that is not genotoxic and produces liver toxicity in rodents, following repeated administration at high dose levels. Lifetime rodent feeding studies reported in 1977 with low-purity oxyfluorfen (85%) showed no increase in any tumor type in rats (800 ppm, high dose) and only a marginally increased incidence of hepatocellular tumors in male CD-1 mice at the highest dose (200 ppm). To evaluate the potential carcinogenicity of the currently registered oxyfluorfen (> 98% purity), we conducted a series of short-term liver mode of action (MOA) toxicology studies in male CD-1 mice administered dietary doses of 0, 40, 200, 800, and 1600 ppm for durations of 3, 7, 10, or 28 days. MOA endpoints examined included liver weight, histopathology, cell proliferation, nuclear receptor-mediated gene expression, and other peroxisome proliferator specific endpoints and their reversibility. Minimal liver effects were observed in mice administered doses at or below 200 ppm for up to 28 days. Increased liver weight, single-cell necrosis, cell proliferation, and peroxisomal acyl-CoA oxidase (ACO) were observed at 800 ppm after 28 days, but there was no increase in peroxisomes. Expression of Cyp2b10 and Cyp4a10 transcripts, markers of constitutive androstane receptor and peroxisome proliferator activated receptor alpha nuclear receptor activation, respectively, were increased at 800 and 1600 ppm after 3 or 10 days. Collectively, these data along with the negative genotoxicity demonstrate that oxyfluorfen (> 98% purity) has the potential to induce mouse liver tumors through a nongenotoxic, mitogenic MOA with a clear threshold and is not predicted to be carcinogenic in humans at relevant exposure levels. PMID- 22539622 TI - Release of apoptotic cytochrome C from mitochondria by dimethylarsinous acid occurs through interaction with voltage-dependent anion channel in vitro. AB - Arsenic is known to be a human carcinogen as well as one of the most effective drugs for treatment of patients with acute promyelocytic leukemia. The intermediate metabolites of arsenic, monomethylarsonous acid (MMA(III)) and dimethylarsinous acid (DMA(III)), are formed by methylation reactions, and they are more reactive and toxic than the inorganic precursor arsenite (iAs(III)); however, the detailed mechanism of toxicity is poorly understood. Here, we studied the effects of three arsenic compounds (i.e., iAs(III), MMA(III), and DMA(III)) on mitochondrial permeability transition pore (mPTP) and release of apoptotic cytochrome c (Cyt c) after incubating with rat liver mitochondria. Inorganic iAs(III) had no effect on mitochondrial swelling even at higher concentrations ranging up to 100 MUM, but swelling was significantly induced in the presence of Ca(2+). Additionally, mitochondrial swelling was strongly induced by exposure to the methylated forms of MMA(III) and DMA(III) in a dose-dependent manner in the absence of Ca(2+), suggesting that the methylated forms may have potent effects on cellular mitochondria. Although mitochondrial swelling was completely inhibited in the presence of cyclosporin-A (an inhibitor of mitochondrial permeability transition) or ruthenium red (an inhibitor of Ca(2+) uniporter) following exposure to methylated arsenicals, the release of apoptotic Cyt c from mitochondria was not inhibited, indicating that release of Cyt c is probably not dependent on mPTP opening. In addition, inhibitors of Bax (e.g., Bax inhibiting peptide) did not reduce the release of Cyt c from the mitochondria by formation of Bax-voltage-dependent anion channel (VDAC) complex, whereas the recombinant Bcl-x(L )proteins significantly reduced the release of Cyt c after exposure to DMA(III), suggesting that dimethylated DMA(III) directly interacted with the VDAC in mitochondria and caused the release of Cyt c from mitochondria. PMID- 22539623 TI - Gene expression in liver injury caused by long-term exposure to titanium dioxide nanoparticles in mice. AB - Although liver toxicity induced by titanium dioxide nanoparticles (TiO(2) NPs) has been demonstrated, very little is known about the molecular mechanisms of multiple genes working together underlying this type of liver injury in mice. In this study, we used the whole-genome microarray analysis technique to determine the gene expression profile in the livers of mice exposed to 10 mg/kg body weight TiO(2) NPs for 90 days. The findings showed that long-term exposure to TiO(2) NPs resulted in obvious titanium accumulation in the liver and TiO(2) NP aggregation in hepatocyte nuclei, an inflammatory response, hepatocyte apoptosis, and liver dysfunction. Furthermore, microarray data showed striking changes in the expression of 785 genes related to the immune/inflammatory response, apoptosis, oxidative stress, the metabolic process, response to stress, cell cycle, ion transport, signal transduction, cell proliferation, cytoskeleton, and cell differentiation in TiO(2) NP-exposed livers. In particular, a significant reduction in complement factor D (Cfd) expression following long-term exposure to TiO(2) NPs resulted in autoimmune and inflammatory disease states in mice. Therefore, Cfd may be a potential biomarker of liver toxicity caused by TiO(2) NPs exposure. PMID- 22539624 TI - Dietary fat is a lipid source in 2,3,7,8-tetrachlorodibenzo-rho-dioxin (TCDD) elicited hepatic steatosis in C57BL/6 mice. AB - 2,3,7,8-Tetrachlorodibenzo-rho-dioxin (TCDD) increases fatty acid (FA) transport and FA levels resulting in hepatic steatosis in mice. Diet as a source of lipids was investigated using customized diets, stearoyl-CoA desaturase 1 (Scd1) null mice, and (14)C-oleate (18:1n9) uptake studies. C57BL/6 mice fed with 5, 10, or 15% fat or 50, 60 or 70% carbohydrate diets exhibited increased relative liver weight following gavage with 30 ug/kg TCDD for 168 h. Hepatic lipid extract analysis from mice fed with 5, 10, and 15% fat diets identified a dose-dependent increase in total FAs induced by TCDD. Mice fed with fat diet also exhibited a dose-dependent increase in the dietary essential linoleic (18:2n6) and alpha linolenic (18:3n3) acids. No dose-dependent FA increase was detected on carbohydrate diets, suggesting dietary fat as a source of lipids in TCDD-induced steatosis as opposed to de novo lipogenesis. TCDD also induced oleate levels threefold in Scd1 null mice that are incapable of desaturating stearate (18:0). This is consistent with oleate representing > 90% of all monounsaturated FAs in rodent chow. Moreover, TCDD increased hepatic (14)C-oleate levels twofold in wild type and 2.4-fold in Scd1 null mice concurrent with the induction of intestinal and hepatic lipid transport genes (Slc27a, Fabp, Ldlr, Cd36, and Apob). In addition, computational scanning identified putative dioxin response elements and in vivo ChIP-chip analysis revealed regions of aryl hydrocarbon receptor (AhR) enrichment in lipid transport genes differentially regulated by TCDD. Collectively, these results suggest the AhR mediates increased uptake of dietary fats that contribute to TCDD-elicited hepatic steatosis. PMID- 22539625 TI - Key components of the mode of action for hemangiosarcoma induction in pregabalin treated mice: evidence of increased bicarbonate, dysregulated erythropoiesis, macrophage activation, and increased angiogenic growth factors in mice but not in rats. AB - In carcinogenicity studies, pregabalin increased hemangiosarcoma incidence in mice but not in rats. Investigative studies, ranging in length from 24 h to 12 months, were conducted in mice (1000 or 5000 mg/kg) and rats (900 mg/kg) to evaluate a potential mode-of-action scheme for tumor formation. Three areas were evaluated: (1) hematopoiesis (because endothelial and hematopoietic cells arise from the same precursor and hemangiosarcomas are primarily located in mouse hematopoietic tissues), (2) angiogenic growth factors (because increased angiogenic growth factors may stimulate vascular tumors), and (3) pulmonary/blood gas parameters (because hypoxia is a known driver for endothelial cell proliferation). In mice, pregabalin rapidly increased platelet and megakaryocyte counts, activated platelets and bone marrow erythrophages, decreased the myeloid to-erythroid (M:E) ratio (49%), and produced bone marrow and splenic congestion and extramedullary hematopoiesis (EMH). Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor immunohistochemical staining were also increased in mouse bone marrow and spleen and vascular endothelial growth factor receptor 2 immunolabeling was increased in liver. Serum bicarbonate was increased within 24 h of pregabalin administration, persisted over time, and was accompanied by decreased respiratory rate (up to 34%) and increased partial pressure of carbon dioxide (pCO(2)), resulting in sustained metabolic alkalosis and elevated blood pH in mice. In contrast, in rats, pregabalin decreased overall bone marrow cellularity, including decreased number of megakaryocytes (24%) with no evidence of erythrophages, no change in M:E ratio, no EMH, and no increase in angiogenic growth factors or blood pH. Persistent alterations in serum bicarbonate, respiratory function, and blood gas parameters in mice, without adequate compensatory mechanisms, has the potential to create chronic tissue hypoxia, an accepted driver of endothelial cell proliferation. PMID- 22539626 TI - Rationale for further medical and health research on high-potency sweeteners. AB - High-potency or artificial sweeteners have historically been considered inert compounds without physiological consequences other than taste sensations. However, recent data suggest that some of these sweeteners have biological effects that may impact human health. Furthermore, there are significant gaps in our current knowledge of the pharmacokinetics of these sweeteners, their potential for "sweetener-drug interactions" and their impact on appetite and body weight regulation. Nine research needs are described that address some of the major unknown issues associated with ingestion of high-potency sweeteners. PMID- 22539627 TI - Early Service leavers: a study of the factors associated with premature separation from the UK Armed Forces and the mental health of those that leave early. AB - BACKGROUND: Approximately 18,000 personnel leave the UK Armed Forces annually. Those leaving before completing the minimum term of their contracts are called early Service leavers (ESLs). This study aims to identify characteristics associated with being an ESL, and compare the post-discharge mental health of ESLs and other Service leavers (non-ESLs). METHOD: A cross-sectional study used data on ex-Serving UK Armed Forces personnel. ESLs were personnel leaving before completing their 3-4.5 years minimum Service contracts and were compared with non ESLs. Multivariable logistic regression was used to estimate odds ratios and 95% confidence intervals for the associations between Service leaving status with socio-demographics, military characteristics and mental health outcomes. RESULTS: Of 845 Service leavers, 80 (9.5%) were ESLs. Being an ESL was associated with younger age, female sex, not being in a relationship, lower rank, serving in the Army and with a trend of reporting higher levels of childhood adversity, but not with deployment to Iraq. ESLs were at an increased risk of probable post traumatic stress disorder (PTSD), common mental disorders, fatigue and multiple physical symptoms, but not alcohol misuse. CONCLUSIONS: The study suggests that operational Service is not a factor causing personnel to become an ESL. Current mental health problems were more commonly reported among ESLs than other Service leavers. There may be a need to target interventions to ESLs on leaving Service to smooth their transition to civilian life and prevent the negative mental health outcomes experienced by ESLs further down the line. PMID- 22539628 TI - The effect of cancer on suicide in ethnic groups with a differential suicide risk. AB - This study examined the suicide risk among persons with cancer in ethnic groups with differential suicide mortality in the general population. We calculated the suicide standardized incidence ratios (SIRs) among Europe-America and Asia-North Africa-born Israelis with cancer, relative to the respective rates in the general population. The SIRs were higher in the European-American group [men: 1.96, 95% confidence interval (CI) 1.62-2.30; women: 2.03, 95% CI 1.51-2.56], but not significantly different in the Asian-North African group (men: 0.86, 95% CI 0.52 1.20; women: 0.80, 95% CI 0.10-1.50). Assessment of suicide risk must consider the 'suicide culture' of the person with cancer. PMID- 22539629 TI - Nutritional screening in a population-based cohort of community-dwelling older people. AB - BACKGROUND: The risk of malnutrition is widely recognized in institutional settings but few studies have been conducted among community-dwelling older people. The objective of this study was to describe the nutritional status and factors associated with possible malnutrition among community-dwelling older people. METHODS: A randomly selected sample (n = 696) of persons aged >= 75 years were included in the study. Baseline information was obtained for nutritional status (mini nutritional assessment short-form MNA-SF), depressive symptoms (15 item geriatric depression scale), cognitive status (mini-mental state examination MMSE) and daily activities (Barthel ADL index and Lawton and Brody IADL scale), self-reported health, oral health and medication use. Univariate and multivariate regression analyses were conducted to identify demographical, clinical and functional factors associated with possible malnutrition. RESULTS: Of the 696 participants, 15% had possible malnutrition. In the univariate analysis, low MNA SF scores were associated with advanced age, poor self-rated health, dry mouth/chewing problems, depressive symptoms and an increasing number of drugs in regular use. Higher albumin level, ADL, IADL and MMSE scores, and the ability to walk 400 m independently were inversely associated with possible malnutrition. In the multivariate analysis, dry mouth/chewing problems (OR 2.01, 95% CI: 1.14 3.54), IADL (OR 0.85, 95% CI: 0.75-0.96) and MMSE scores (OR 0.90, 95% 0.85-0.96) were independently associated with possible malnutrition. CONCLUSION: Being at risk of malnutrition was common among community-dwelling older people. Problems with mouth, IADL and cognitive impairments were linked to possible nutritional risks. PMID- 22539630 TI - Health screening of people in police custody--evaluation of current police screening procedures in London, UK. AB - BACKGROUND: Previous research has highlighted excess health morbidity in offender populations. A small number of studies have described health problems within police custody settings. The efficacy of police screening procedures has not been evaluated. METHODS: Prospective clinical interviews with custody detainees in London were conducted. Clinical findings were compared with those recorded in police health screening documentation. RESULTS: High levels of health morbidity were observed. The sensitivity and specificity of the current screen with respect to its ability to trigger a call for a health-care professional (HCP), regardless of the reason, was 70 and 66%, respectively. Fifty-one percent of the detainees with asthma, 36% with diabetes mellitus and 40% with epilepsy were not picked up by the screen. Fewer than one-half of the detainees at risk of alcohol withdrawal syndrome had 'alcohol' documented on their screen, although 81% saw the HCP. The police screen missed heroin use in 28% and crack cocaine use in 68% of users. A HCP was called in 84 and 64% of the cases, respectively, for any reason. Two of the 12 detainees (17%) who described a head injury with serious-associated symptoms were detected; 9 had a HCP called for any reason. Whereas mental disturbance was detected in 79% of the detainees with serious mental illness, one third of the detainees with a risk history of suicide and one-half of the detainees with suicidal ideation were not documented as such on the police screen. CONCLUSION: Given the amounts of morbidity and the need for reliable triage, improvement in the health screening procedures used by the police is needed. PMID- 22539631 TI - The development and validation of two prediction models to identify employees at risk of high sickness absence. AB - BACKGROUND: Sickness absence (SA) is a public health risk marker for morbidity and mortality. The aim of this study was to develop and validate prediction models to identify employees at risk of high SA. METHODS: Two prediction models were developed using self-rated health (SRH) and prior SA as predictors. SRH was measured by the categories excellent, good, fair and poor in a convenience sample of 535 hospital employees. Prior SA was retrieved from the employer's register. The predictive performance of the models was assessed by logistic regression analysis with high (>= 90 th percentile) vs. non-high (<90th percentile) SA days and SA episodes as outcome variables and by using bootstrapping techniques to validate the models. RESULTS: The overall performance as reflected in the Nagelkerke's pseudo R(2) was 11.7% for the model identifying employees with high SA days and 31.8% for the model identifying employees with high SA episodes. The discriminative ability, represented by the area (AUC) under the receiver operating characteristic (ROC), was 0.729 (95% CI 0.667-0.809) for the model identifying employees with high SA days and 0.831 (95% CI 0.784-0.877) for the model identifying employees with high SA episodes. The Hosmer-Lemeshow test showed acceptable calibration for both models. CONCLUSIONS: The prediction models identified employees at risk of high SA, but need further external validation in other settings and working populations before applying them in public and occupational health research and care. PMID- 22539632 TI - Long-term trends in obesity among Austrian adults and its relation with the social gradient: 1973-2007. AB - BACKGROUND: The prevalence of obesity is steadily increasing. There is little empirical evidence for the development of obesity in Austria. Therefore, the present study investigated long-term trends in the prevalence of obesity across different age and educational groups in Austrian adults. METHODS: Self-reported data were derived from five nationally representative cross-sectional interview surveys (n = 178,818) in the years 1973, 1983, 1991, 1999 and 2006-07 in private homes and long-term care facilities for Austrian adults aged 20-99 years. An adjustment of the self-reported BMI was performed. Obesity was defined as BMI >= 30 kg m(-2). RESULTS: The age-adjusted prevalence of obesity was 11% during the study period (women: 11.3%, 95% CI 11.2-11.6; men: 9.9%, 95% CI 9.7-10.2). Obesity and a high mean BMI were most prevalent among subjects aged 55-74 years and among those with low educational status. The absolute change in obesity prevalence during the study period was significantly highest (P < 0.001) among women aged >= 75 years (3.0%), and among men aged 55-75 years (3.6%). Concerning educational level, the largest increase in obesity was seen in those with a low educational level (women: 4.1%, men: 2.6%; P < 0.001), whereas the aetiologic fraction was highest in middle-educated men. Relative inequalities for obesity showed a tendency to increase during the study period. CONCLUSION: Examining trends in subpopulations is important when planning accurate target group specific prevention strategies. Therefore, in Austria targeted preventive measures should be designed according to age and educational level. PMID- 22539633 TI - Longer work careers through tackling socioeconomic inequalities in disability retirement. PMID- 22539634 TI - Mistletoe effects on Scots pine decline following drought events: insights from within-tree spatial patterns, growth and carbohydrates. AB - Forest decline has been attributed to the interaction of several stressors including biotic factors such as mistletoes and climate-induced drought stress. However, few data exist on how mistletoes are spatially arranged within trees and how this spatial pattern is related to changes in radial growth, responses to drought stress and carbon use. We used dendrochronology to quantify how mistletoe (Viscum album L.) infestation and drought stress affected long-term growth patterns in Pinus sylvestris L. at different heights. Basal area increment (BAI) trends and comparisons between trees of three different infestation degrees (without mistletoe, ID1; moderately infested trees, ID2; and severely infested trees, ID3) were performed using linear mixed-effects models. To identify the main climatic drivers of tree growth tree-ring widths were converted into indexed chronologies and related to climate data using correlation functions. We performed spatial analyses of the 3D distribution of mistletoe individuals and their ages within the crowns of three severely infested pines to describe their patterns. Lastly, we quantified carbohydrate and nitrogen concentrations in needles and sapwood of branches from severely infested trees and from trees without mistletoe. Mistletoe individuals formed strongly clustered groups of similar age within tree crowns and their age increased towards the crown apex. Mistletoe infestation negatively impacted growth but this effect was stronger near the tree apex than in the rest of sampled heights, causing an average loss of 64% in BAI (loss of BAI was ~51% at 1.3 m or near the tree base). We found that BAI of severely infested trees and moderately or non-infested trees diverged since 2001 and such divergence was magnified by drought. Infested trees had lower concentrations of soluble sugars in their needles than non-infested ones. We conclude that mistletoe infestation causes growth decline and increases the sensitivity of trees to drought stress. PMID- 22539635 TI - Size-mediated tree transpiration along soil drainage gradients in a boreal black spruce forest wildfire chronosequence. AB - Boreal forests are crucial to climate change predictions because of their large land area and ability to sequester and store carbon, which is controlled by water availability. Heterogeneity of these forests is predicted to increase with climate change through more frequent wildfires, warmer, longer growing seasons and potential drainage of forested wetlands. This study aims at quantifying controls over tree transpiration with drainage condition, stand age and species in a central Canadian black spruce boreal forest. Heat dissipation sensors were installed in 2007 and data were collected through 2008 on 118 trees (69 Picea mariana (Mill.) Britton, Sterns & Poggenb. (black spruce), 25 Populus tremuloides Michx. (trembling aspen), 19 Pinus banksiana Lamb. (jack pine), 3 Larix laricina (Du Roi) K. Koch (tamarack) and 2 Salix spp. (willow)) at four stand ages (18, 43, 77 and 157 years old) each containing a well- and poorly-drained stand. Transpiration estimates from sap flux were expressed per unit xylem area, J(S), per unit ground area, E(C) and per unit leaf area, E(L), using sapwood (A(S)) and leaf (A(L)) area calculated from stand- and species-specific allometry. Soil drainage differences in transpiration were variable; only the 43- and 157-year old poorly-drained stands had ~ 50% higher total stand E(C) than well-drained locations. Total stand E(C) tended to decrease with stand age after an initial increase between the 18- and 43-year-old stands. Soil drainage differences in transpiration were controlled primarily by short-term physiological drivers such as vapor pressure deficit and soil moisture whereas stand age differences were controlled by successional species shifts and changes in tree size (i.e., A(S)). Future predictions of boreal climate change must include stand age, species and soil drainage heterogeneity to avoid biased estimates of forest water loss and latent energy exchanges. PMID- 22539636 TI - Stomatal patchiness in the Mediterranean holm oak (Quercus ilex L.) under water stress in the nursery and in the forest. AB - The evergreen holm oak Quercus ilex L. is the most representative tree in Mediterranean forests. Accurate estimation of the limiting factors of photosynthesis for Q. ilex and the prediction of ecosystem water-use efficiency by mechanistic models can be achieved only by establishing whether this species shows heterogenic stomatal aperture, and, if so, the circumstances in which this occurs. Here, we collected gas-exchange and chlorophyll fluorescence data in Q. ilex leaves from a nursery to measure the effects of stomatal oscillations on PSII quantum yield (Phi(PSII)) under water stress. Stomatal conductance (g(s)) was used as an integrative indicator of the degree of water stress. Images of chlorophyll fluorescence showed heterogeneous Phi(PSII) when g(s) was <50 mmol H(2)O m(-2) s(-1), representative of severe drought and corresponding to a container capacity <45%. Stomatal patchiness was related to a coefficient of variation (CV) of Phi(PSII) values >2.5%. A parallel study in the forest confirmed heterogeneous Phi(PSII) values in leaves in response to declining water availability. Three kinds of Q. ilex individuals were distinguished: those resprouting after a clear-cut (resprouts, R); intact individuals growing in the same clear-cut area as resprouts (controls, C); and intact individuals in a nearby, undisturbed area (forest controls, CF). Patchiness increased in C and CF in response to increasing drought from early May to late July, whereas in R, Phi(PSII) values were maintained as a result of their improved water relations since the pre-existing roots were associated with a smaller aerial biomass. Patchiness was related to a % CV of Phi(PSII) values >4 and associated in the summer with mean g(s) values of 30 mmol H(2)O m(-2) s(-1). Under milder drought in spring, Phi(PSII) patchiness was less strictly related to g(s) variations, pointing to biochemical limitants of photosynthesis. The occurrence of heterogenic photosynthesis caused by patchy stomatal closure in Q. ilex during severe drought should be taken into account in ecosystem modelling in which harsher water stress conditions associated with climate change are predicted. PMID- 22539637 TI - Using combined measurements for comparison of light induction of stomatal conductance, electron transport rate and CO2 fixation in woody and fern species adapted to different light regimes. AB - We aimed to understand the relation of photosynthetic rate (A) with g(s) and electron transport rate (ETR) in species of great taxonomic range and light adaptation capability during photosynthetic light induction. We studied three woody species (Alnus formosana, Ardisia crenata and Ardisia cornudentata) and four fern species (Pyrrosia lingus, Asplenium antiquum, Diplazium donianum and Archangiopteris somai) with different light adaptation capabilities. Pot-grown materials received 100 and/or 10% sunlight according to their light adaptation capabilities. At least 4 months after light acclimation, CO(2) and H(2)O exchange and chlorophyll fluorescence were measured simultaneously by equipment in the laboratory. In plants adapted or acclimated to low light, dark-adapted leaves exposed to 500 or 2000 umol m(-2) s(-1) photosynthetic photon flux (PPF) for 30 min showed low gross photosynthetic rate (P(g)) and short time required to reach 90% of maximum P(g) (). At the initiation of illumination, two broad-leaved understory shrubs and the four ferns, especially ferns adapted to heavy shade, showed higher stomatal conductance (g(s)) than pioneer tree species; materials with higher g(s) had short at both 500 and 2000 umol m(-2) s(-1) PPF. With 500 or 2000 umol m(-2) s(-1) PPF, the g(s) for the three woody species increased from 2 to 30 min after the start of illumination, but little change in the g(s) of the four ferns. Thus, P(g) and g(s) were not correlated for all material measured at the same PPF and induction time. However, P(g) was positively correlated with ETR, even though CO(2) assimilation may be influenced by stomatal, biochemical and photoinhibitory limitations. In addition, was closely related to time required to reach 90% maximal ETR for all materials and with two levels of PPF combined. Thus, ETR is a good indicator for estimating the light induction of photosynthetic rate of species, across a wide taxonomic range and light adaptation and acclimation capability. PMID- 22539638 TI - Novel insights into the regulation of malarial calcium-dependent protein kinase 1. AB - Calcium-dependent protein kinases (CDPKs) are major effectors of calcium signaling in apicomplexan parasites like Toxoplasma and Plasmodium and control important processes of the parasite life cycle. Despite recently reported crystal structures of Toxoplasma gondii (Tg)CDPKs, several important questions about their regulation remain unanswered. Plasmodium falciparum (Pf)CDPK1 has emerged as a key player in the life cycle of the malaria parasite, as it may be involved in the invasion of the host cells. Molecular modeling and site-directed mutagenesis studies on PfCDPK1 suggested that several residues in the regulatory domain play a dual role, as they seem to contribute to the stabilization of both the active and inactive kinase. Mass spectrometry revealed that PfCDPK1 was autophosphorylated at several sites; some of these were placed at strategic locations and therefore were found to be critical for kinase activation. The N terminal extension of PfCDPK1 was found to be important for PfCDPK1 activation. Unexpectedly, an ATP binding site in the NTE of PfCDPK1 was identified. Our studies highlight several novel features of PfCDPK1 regulation, which may be shared by other members of the CDPK family. These findings may also aid design of inhibitors against these important targets, which are absent from the host. PMID- 22539639 TI - Maternal low-protein diet up-regulates the neuropeptide Y system in visceral fat and leads to abdominal obesity and glucose intolerance in a sex- and time specific manner. AB - Neuropeptide Y (NPY) mediates stress-induced obesity in adult male mice by activating its Y2 receptor (Y2R) in visceral adipose tissue (VAT). Here, we studied whether the NPY-Y2R system is also activated by maternal low-protein diet (LPD) and linked to obesity in offspring. Prenatal LPD offspring had lower birth weights compared to normal-protein diet (NPD) offspring. Female prenatal and lactation stress (PLS) offspring from mothers fed an LPD developed abdominal adiposity and glucose intolerance associated with a 5-fold up-regulation of NPY mRNA and a 6-fold up-regulation of Y2R mRNA specifically in VAT, in addition to elevated platelet-rich-plasma (PRP) NPY, compared to control females fed a high fat diet (HFD). Conversely, PLS male offspring showed lower NPY in PRP, a 10-fold decrease of Y2R mRNA in VAT, lower adiposity, and improved glucose tolerance compared to control males. Interestingly, prenatal LPD offspring cross-fostered to control lactating mothers had completely inverse metabolic and NPY phenotypes. Taken together, these findings suggested that maternal LPD activates the VAT NPY Y2R system and increases abdominal adiposity and glucose intolerance in a sex- and time-specific fashion, suggesting that the peripheral NPY system is a potential mediator of programming for the offspring's vulnerability to obesity and metabolic syndrome. PMID- 22539640 TI - The presentation and natural history of asbestos-induced diffuse pleural thickening. AB - BACKGROUND: Three forms of asbestos-related benign pleural disease are recognized: discrete pleural plaques, pleural effusions and diffuse pleural fibrosis. Of these, diffuse pleural fibrosis is the most significant on account of its chronicity and associated morbidity. AIMS: The objectives of this study were to determine the latency of asbestos-induced diffuse pleural fibrosis, its presenting features and its clinical course once established. METHODS: We conducted a retrospective review of 75 patients with asbestos-induced diffuse pleural fibrosis referred for assessment at our institution from 1992 to 2007. Diffuse pleural fibrosis was considered to be present if there was obliteration of the costophrenic angle in continuity with at least 3-mm pleural thickening, in accordance with the International Labour Organization 2000 Classification. RESULTS: The median latency for development of diffuse pleural fibrosis from first asbestos exposure was 34 years. Seventy-three per cent of patients had unilateral disease at presentation and 24% of these were observed to develop contralateral disease after a median of 2 years. Unilateral pleural disease was commonest on the right. Forty per cent of patients presented with pleural effusions preceding the development of diffuse pleural thickening. The median latency for development of pleural effusions from onset of exposures was 38 years. Eighty per cent of the pleural effusions were unilateral. Once established, pleural thickening was reported to have remained stable in 91% on the ipsilateral side. CONCLUSIONS: The findings of this study may help in providing further insight into the natural history of diffuse pleural fibrosis to guide the clinician in the management of this condition. PMID- 22539642 TI - Is the incidence of heparin-induced thrombocytopenia affected by the increased use of heparin for VTE prophylaxis? AB - BACKGROUND: The increased exposure to heparin products for thromboprophylaxis against VTE in hospitalized patients raises concerns for an increase in the incidence of heparin-induced thrombocytopenia(HIT). METHODS: We analyzed, among 90,875 patients exposed to heparin products between 2005 and 2009, the number of hematologic consultations for thrombocytopenia, requests for heparin induced antibodies by enzyme-linked immunosorbent assay, and cases given a diagnosis of HIT by the hematology consult service. RESULTS: We observed that despite a doubling in the number of patients receiving pharmacoprophylaxis with heparin, there was no significant increase in the number of consultations for thrombocytopenia,the number of requests for HIT tests, the number of positive HIT test results, or the number of HIT diagnoses. The number of cases of HIT was low and represented < 0.1% of patients exposed to heparin. CONCLUSIONS: We conclude that concerns about HIT should not be a limiting factor for the systematic implementation of heparin-based VTE prophylaxis. PMID- 22539643 TI - Obamacare's (3) Day(s) in Court. AB - Before the oral arguments in late March, the vast majority of legal scholars felt confident that the Supreme Court of the United States would uphold the individual mandate against the constitutional challenge that 26 states have levied against it. Since the oral arguments, that confidence has been severely shaken. This article asks why legal scholars were so confident before the argument and what has made us so concerned since the argument. The article posits that certain fundamental characteristics of health insurance, particularly its unusual role in steering health-care consumption decisions, which distinguishes health insurance from standard kinds of indemnity insurance, should make the constitutional question easy, but the Obama Administration's legal team was understandably hesitant to highlight those unique characteristics in its arguments. Because the Supreme Court justices seemed not to understand the uniqueness of health insurance without the government's help and because the justices seemed unusually willing to adopt a new constitutional constraint in this case, the individual mandate appears to be in far greater jeopardy than we legal scholars anticipated. PMID- 22539645 TI - Reversed halo sign in invasive fungal infections: criteria for differentiation from organizing pneumonia. AB - BACKGROUND: The purpose of this study was to identify CT scan findings that differentiate the reversed halo sign (RHS) caused by invasive fungal infection (IFI) from the RHS caused by organizing pneumonia (OP). METHODS: We retrospectively reviewed CT scans of patients with RHS caused by IFI or OP. The study included 15 patients with proven or probable IFI (eight men and seven women) and 25 patients with biopsy-proven OP (13 women and 12 men). The CT images were reviewed individually by two chest radiologists who were blinded to the final diagnosis. RESULTS: Reticulation inside the RHS was observed in 14 of the 15 patients with IFI (93%) and in no patient with OP. The maximal thickness of the consolidation rim was 2.04 +/- 0.85 cm for IFI and 0.50 +/- 0.22 cm for OP. Pleural effusion was noted in 11 of the 15 patients with IFI (73%) and in no patient with OP. Other parenchymal abnormalities, such as consolidation and ground-glass and linear opacities, were observed in both groups. The number of lesions showing the RHS did not differentiate IFI and OP. CONCLUSION: The presence of reticulation inside the RHS, outer rim thickness > 1 cm, and associated pleural effusion strongly suggest the diagnosis of IFI rather than OP. PMID- 22539644 TI - Comparison and agreement between the Richmond Agitation-Sedation Scale and the Riker Sedation-Agitation Scale in evaluating patients' eligibility for delirium assessment in the ICU. AB - BACKGROUND: Delirium evaluation in patients in the ICU requires the use of an arousal/sedation assessment tool prior to assessing consciousness. The Richmond Agitation-Sedation Scale (RASS) and the Riker Sedation-Agitation Scale (SAS) are well-validated arousal/sedation tools. We sought to assess the concordance of RASS and SAS assessments in determining eligibility of patients in the ICU for delirium screening using the confusion assessment method for the ICU (CAM-ICU). METHODS: We performed a prospective cohort study in the adult medical, surgical, and progressive (step-down) ICUs of a tertiary care, university-affiliated, urban hospital in Indianapolis, Indiana. The cohort included 975 admissions to the ICU between January and October 2009. RESULTS: The outcome measures of interest were the correlation and agreement between RASS and SAS measurements. In 2,469 RASS and SAS paired screens, the rank correlation using the Spearman correlation coefficient was 0.91, and the agreement between the two screening tools for assessing CAM-ICU eligibility as estimated by the kappa coefficient was 0.93. Analysis showed that 70.1% of screens were eligible for CAM-ICU assessment using RASS (7.1% sedated [RASS -3 to -1]; 62.6% calm [0]; and 0.4% restless, agitated [+1 to +3]), compared with 72.1% using SAS (5% sedated [SAS 3]; 66.5% calm [4]; and 0.6% anxious, agitated [5, 6]). In the mechanically ventilated subgroup, RASS identified 19.1% CAM-ICU eligible patients compared with 24.6% by SAS. The correlation coefficient in this subgroup was 0.70 and the agreement was 0.81. CONCLUSION: Both SAS and RASS led to similar rates of delirium assessment using the CAM-ICU. PMID- 22539646 TI - Drug-associated acute lung injury: a population-based cohort study. AB - BACKGROUND: A number of drugs have been reported as risk factors for acute lung injury (ALI) and ARDS. However, evidence is largely limited to case reports, and there is a paucity of data on the incidence and outcome of drug-associated ALI (DALI). METHODS: Using a population-based retrospective cohort study design, critically ill patients with a diagnosis of ALI were studied. These patients were classified as having DALI or non-DALI, based on whether they were exposed to prespecified drugs prior to development of ALI. Outcomes were compared between the two groups and frequencies and incidences reported. RESULTS: Among 514 patients with ALI, 49 (9.5%) had DALI with an estimated population-based incidence of 6.6 (95% CI, 4.8-8.5) per 100,000 person-years. Of the 49 patients with DALI,36 received chemotherapeutic/antiinflammatory agents, and 14 received amiodarone. Twelve patients had no additional risk factors for ALI (probable DALI), whereas 37 had alternative risk factors (possible DALI). Patients with and without DALI had similar baseline characteristics. However, the APACHE (Acute Physiology and Chronic Health Evaluation) III scores (median, 83 vs 70, P 5 .03), ICU mortality (35% vs 20%, P 5 .03), and hospital mortality (63% vs 32%, P , .001)were significantly higher in the DALI group compared with those of the non DALI group. Hospital mortality remained significantly higher after adjusting for APACHE III score on admission and the presence of malignancy in logistic regression analysis (OR, 2.8; 95% CI, 1.3-6.4; P 5 .009). CONCLUSIONS: Drugs are important risk factors for ALI, and recognizing them as such may have important implications for early identification of patients at risk, discontinuation of the offending agent, and prognosis. PMID- 22539647 TI - Exercise stress echocardiography of the pulmonary circulation: limits of normal and sex differences. AB - BACKGROUND: Exercise stress echocardiography has not been recommended in the diagnostic workup of pulmonary hypertension because of insufficient certainty about feasibility and limits of normal. METHODS: Doppler echocardiography pulmonary hemodynamic measurements were performed at a progressively increased workload in 56 healthy male and 57 healthy female volunteers aged 19 to 63 years. Mean pulmonary artery pressure (mPAP) was estimated from the maximal tricuspid regurgitation jet velocity. Cardiac index was calculated from the left ventricular outflow velocity-time integral. Pulmonary vascular distensibility a index, the percentage change of vessel diameter permm Hg of mPAP, was calculated from multipoint mPAP-cardiac output (CO) plots. RESULTS: Peak exercise at 175 +/ 50 W was associated with an mPAP of 33+/-7 mm Hg and a CO of 18 +/-5 L/min. The slope of mPAP-CO relationships was 1.5 +/- 0.5 mm Hg/L/min, and the distensibility coefficient ( alpha ) was 1.3%+/- 1.0%/mm Hg. Maximal workload and cardiac index were higher in men than in women ( P , .05), but mPAP-cardiac index relationships were not different. However,women had a higher a (1.6%+/- 1.3%/mm Hg vs 1.1%+/- 0.6%/mm Hg, P < .05). The average mPAP-cardiac index slope was higher and a lower in subjects >=50 years old. Upper limits of normal of mPAP at exercise were 34 mm Hg at a CO , 10 L/min, 45 mm Hg at a CO <20 L/min, and 52 mm Hg at a CO<30 L/min. These values are in keeping with previously reported invasive measurements. CONCLUSIONS: Exercise stress echocardiography of the pulmonary circulation is feasible and allows for fl ow-corrected definition of upper limits of normal. Women have a more distensible pulmonary circulation. PMID- 22539648 TI - The impact of birth weight on peak lung function in young adults. AB - BACKGROUND: Poor fetal growth rate, as indicated by lower birth weight, is associated with lower respiratory function in childhood; however, findings in adult life remain inconsistent. A birth cohort provides the opportunity to study the association between birth weight and adult respiratory function. METHODS: The present study data are from a longitudinal birth cohort, the Mater-University of Queensland Study of Pregnancy. Prospective data were available from 2,368 young adults who underwent standard spirometry when 21 years old. Pregnancy and birth related variables collected were birth weight, placental weight, parental height, maternal educational status, maternal smoking history in pregnancy, and maternal history of alcohol, tea, and coffee consumption during pregnancy. The impact of birth weight on adult lung function was assessed using univariate and multivariate analyses. RESULTS: For every 100-g increase in birth weight, FVC (95% CI) at 21 years increased by 24 mL (15-32) in men and 20 mL (13-27) in women, and the increase in FEV1 (CI) was 22 mL (15-30) and 16 mL (11-22), respectively. These associations remain after adjusting for lifestyle factors during pregnancy, current smoking, and parental height. However, further adjustment for adult height reduces the strength of association and remains significant for FEV1: 8 mL (1-14) in men and 5 mL (1-10) in women, but not for FVC: 7 mL (-1-14) in men and 5 mL (-1-11) in women. CONCLUSION: Our longitudinal cohort study provides evidence of robust links between birth weight and adult lung function at the age of 21 years. Various estimates of the effect size in the literature may be related to the age at assessment. PMID- 22539649 TI - Ultrashort and progressive 4sU-tagging reveals key characteristics of RNA processing at nucleotide resolution. AB - RNA synthesis and decay rates determine the steady-state levels of cellular RNAs. Metabolic tagging of newly transcribed RNA by 4-thiouridine (4sU) can reveal the relative contributions of RNA synthesis and decay rates. The kinetics of RNA processing, however, had so far remained unresolved. Here, we show that ultrashort 4sU-tagging not only provides snapshot pictures of eukaryotic gene expression but, when combined with progressive 4sU-tagging and RNA-seq, reveals global RNA processing kinetics at nucleotide resolution. Using this method, we identified classes of rapidly and slowly spliced/degraded introns. Interestingly, each class of splicing kinetics was characterized by a distinct association with intron length, gene length, and splice site strength. For a large group of introns, we also observed long lasting retention in the primary transcript, but efficient secondary splicing or degradation at later time points. Finally, we show that processing of most, but not all small nucleolar (sno)RNA-containing introns is remarkably inefficient with the majority of introns being spliced and degraded rather than processed into mature snoRNAs. In summary, our study yields unparalleled insights into the kinetics of RNA processing and provides the tools to study molecular mechanisms of RNA processing and their contribution to the regulation of gene expression. PMID- 22539653 TI - Possible interaction between milnacipran and warfarin potassium. PMID- 22539650 TI - Nutritional control of mRNA isoform expression during developmental arrest and recovery in C. elegans. AB - Nutrient availability profoundly influences gene expression. Many animal genes encode multiple transcript isoforms, yet the effect of nutrient availability on transcript isoform expression has not been studied in genome-wide fashion. When Caenorhabditis elegans larvae hatch without food, they arrest development in the first larval stage (L1 arrest). Starved larvae can survive L1 arrest for weeks, but growth and post-embryonic development are rapidly initiated in response to feeding. We used RNA-seq to characterize the transcriptome during L1 arrest and over time after feeding. Twenty-seven percent of detectable protein-coding genes were differentially expressed during recovery from L1 arrest, with the majority of changes initiating within the first hour, demonstrating widespread, acute effects of nutrient availability on gene expression. We used two independent approaches to track expression of individual exons and mRNA isoforms, and we connected changes in expression to functional consequences by mining a variety of databases. These two approaches identified an overlapping set of genes with alternative isoform expression, and they converged on common functional patterns. Genes affecting mRNA splicing and translation are regulated by alternative isoform expression, revealing post-transcriptional consequences of nutrient availability on gene regulation. We also found that phosphorylation sites are often alternatively expressed, revealing a common mode by which alternative isoform expression modifies protein function and signal transduction. Our results detail rich changes in C. elegans gene expression as larvae initiate growth and post-embryonic development, and they provide an excellent resource for ongoing investigation of transcriptional regulation and developmental physiology. PMID- 22539651 TI - Exploring the DNA-recognition potential of homeodomains. AB - The recognition potential of most families of DNA-binding domains (DBDs) remains relatively unexplored. Homeodomains (HDs), like many other families of DBDs, display limited diversity in their preferred recognition sequences. To explore the recognition potential of HDs, we utilized a bacterial selection system to isolate HD variants, from a randomized library, that are compatible with each of the 64 possible 3' triplet sites (i.e., TAANNN). The majority of these selections yielded sets of HDs with overrepresented residues at specific recognition positions, implying the selection of specific binders. The DNA-binding specificity of 151 representative HD variants was subsequently characterized, identifying HDs that preferentially recognize 44 of these target sites. Many of these variants contain novel combinations of specificity determinants that are uncommon or absent in extant HDs. These novel determinants, when grafted into different HD backbones, produce a corresponding alteration in specificity. This information was used to create more explicit HD recognition models, which can inform the prediction of transcriptional regulatory networks for extant HDs or the engineering of HDs with novel DNA-recognition potential. The diversity of recovered HD recognition sequences raises important questions about the fitness barrier that restricts the evolution of alternate recognition modalities in natural systems. PMID- 22539654 TI - Cognitive and physical functions as determinants of delayed age at onset and progression of disability. AB - BACKGROUND: This study examined the association of cognitive and physical functions with age-related transition and progression of activities of daily living (ADL) disability in a population-based longitudinal cohort of nondisabled older adults. METHODS: A longitudinal population-based cohort study of 5,317 initially nondisabled older adults with an average age of 73.6 years of an urban Chicago community were interviewed annually for up to 8 years from 2000 through 2008. Cognitive function was assessed using a standardized global cognitive score and physical function using a combination of measured walk, tandem stand, and chair stand. A novel two-part model was used to access the relationship between cognitive and physical functions and age at onset and progression of ADL disability. RESULTS: The sample consisted of 5,317 participants, 65% blacks, and 61% females. Twenty-five percent reported an onset of ADL disability during follow-up. After adjusting for confounders, lower cognitive and physical functions were associated with an increased risk for lower age at onset. Lower cognitive function was longitudinally associated with increased rate of progression of disability after onset. However, lower physical function did not alter the rate of progression of ADL disability. CONCLUSIONS: Cognitive and physical functions were associated with age at onset. However, only cognitive function was associated with the rate of progression of ADL disability. PMID- 22539655 TI - Persistent respiratory symptoms in clean-up workers 5 years after the Prestige oil spill. AB - OBJECTIVES: Fishermen who had participated in clean-up activities of the Prestige oil spill showed an excess risk of respiratory symptoms 1-2 years later, but the long-term persistence of these health effects is unclear. The aim of this study was to evaluate the persistence of these respiratory symptoms 5 years after clean up work. METHODS: Subgroups of 501 fishermen who had been exposed to clean-up work and 177 non-exposed individuals were re-interviewed by telephone in 2008, including the same symptom questions as in the initial survey. Associations between participation in clean-up work and respiratory symptoms were assessed using log-binomial and multinomial regression analyses adjusting for sex, age and smoking. RESULTS: Information from 466 exposed (93%) and 156 non-exposed (88%) fishermen was obtained. The prevalence of lower respiratory tract symptoms (including wheeze, shortness of breath, cough and phlegm) had slightly decreased in both groups, but remained higher among the exposed (RR 1.4, 95% CI 1.1 to 1.9). The risk of having persistent respiratory symptoms (reported both at baseline and at follow-up) increased with the degree of exposure: RR ratio 1.7 (95% CI 0.9 to 3.1) and 3.3 (95% CI 1.8 to 6.2) for moderately and highly exposed, respectively, when compared with those without any symptoms. Findings for nasal symptoms and for respiratory medication usage were similar. CONCLUSIONS: Participation in clean-up activities of oil spills may result in respiratory symptoms that persist up to 5 years after exposure. Guidelines for preventive measures and a continued surveillance of clean-up workers of oil spills are necessary. PMID- 22539656 TI - Physical workload, leisure-time physical activity, obesity and smoking as predictors of multisite musculoskeletal pain. A 2-year prospective study of kitchen workers. AB - OBJECTIVES: The aim of this prospective study was to examine the role of physical workload, leisure-time physical activity, obesity and smoking in predicting the occurrence and course of multisite musculoskeletal pain (MSP). METHODS: Data on physical and psychosocial workload, lifestyle factors and MSP were based on questionnaire surveys of 385 Finnish female kitchen workers. MSP (defined as pain at three or more of seven sites) during the past 3 months was measured repeatedly at 3-month intervals over 2 years. Four different patterns (trajectories) in the course of MSP were identified. The authors analysed whether the determinants at baseline predicted the occurrence of MSP (1) at the 2-year follow-up and (2) over the total of nine measurements during the 2 years by exploiting the MSP trajectories. Logistic regression was used. RESULTS: High physical workload at baseline was an independent predictor of MSP at the 2-year follow-up (OR 3.8, 95% CI 1.7 to 8.5) in a model allowing for age, psychosocial factors at work and lifestyle. High physical workload (OR 2.0, 95% CI 1.0 to 4.0) and moderate (OR 2.4, 95% CI 1.2 to 4.9) or low (OR 2.3, 95% CI 1.1 to 4.7) physical activity predicted persistent MSP. Obesity (OR 2.8, 95% CI 1.0 to 7.8) predicted an increased, and not being obese (OR 3.7, 95% CI 1.1 to 12.7) a decreased, prevalence of MSP in models similarly including all covariates. Smoking had no effect. CONCLUSION: The results emphasise the importance of high physical workload, low to moderate physical activity and obesity as potential modifiable risk factors for the occurrence and course of MSP over time. PMID- 22539657 TI - High lead exposure is associated with telomere length shortening in Chinese battery manufacturing plant workers. AB - OBJECTIVES: Critically shortening of telomere length caused by various factors including environmental pollutants results in genome instability and age associated diseases. Lead is one of the ubiquitous environmental and occupational pollutants, potentially affecting public health even at a low level. However, it is still unclear whether lead exposure affects telomere length. This study aims to investigate the association between lead exposure and peripheral white blood cell telomere length (PWBTL) in Chinese battery manufacturing plant workers. METHODS: Lead levels in blood (BLL) and urine (ULL) were evaluated using flame atomic absorption spectrometry and lead mobilisation test for body lead burden (BLB) assessment, respectively. Quantitative PCR was employed to determine relative PWBTL. Univariate and multivariate analyses were performed to examine the associations of telomere length and other variables. RESULTS: PWBTL averaged 1.76 (telomere/single-copy gene of albumin, T/S) in 144 battery plant workers. Significantly shorter PWBTL was observed in the workers with abnormal BLL and/or ULL than those with normal ones (1.66+/-0.63 vs 1.91+/-0.46, p=0.010). In all workers, PWBTL was in negative correlations with BLL, ULL, time working at the plant (working length) and body mass index. A strong inverse correlation was observed between PWBTL and BLB (r=-0.70, p<0.0001) in those with abnormal BLL and ULL. GLMSELECT model showed in the subgroup of inpatient workers, working length and BLB were significantly in inverse associations with PWBTL, while BLL was in weak positive association with PWBTL. CONCLUSIONS: These findings suggest that PWBTL shortening is associated with long-term lead exposure and that PWBTL may be one of the targets damaged by lead toxicity. PMID- 22539658 TI - Epidemiologic investigation of an occupational illness of tobacco harvesters in southern Brazil, a worldwide leader in tobacco production. AB - OBJECTIVES: As part of smoking surveillance, the authors conducted an epidemiologic investigation in southern Brazil to identify the occurrence of Green Tobacco Sickness and risk factors for illness and to recommend control and prevention measures. METHODS: A 1:2 case-control study matched by subjects' smoking habits. The study population was residents of Candelaria, Rio Grande do Sul state, who farm tobacco and provided a urine sample for cotinine measurement by high-performance liquid chromatography. Confirmed cases were persons with compatible clinical presentation (headache, nausea, vomit, dizziness or weakness) and cotinine level >10 ng/ml. Controls were persons without compatible signs or symptoms. The association measure was the matched OR with 95% CIs and p<0.05. RESULTS: Of 33 confirmed cases, 64% were men, average age was 33 years (SD +/- 11.8 years) and 57% were landowners. Cases have had similar illness in the past and were likelier to be workers hired by farmers-landowners than controls. Multivariate analysis yielded independent association between these variables and illness, controlled for age and sex. Contact with pesticides and working with wet tobacco leaves were not associated with illness. CONCLUSIONS: The authors confirmed Green Tobacco Sickness in southern Brazil; the authors recommend investigation of its prevalence in tobacco-growing regions and monitoring of and education about the disease and its prevention by occupational health authorities. PMID- 22539659 TI - Dementia in documentary film: mum by Adelheid Roosen. AB - This article draws attention to the fact that documentaries do not simply reproduce the reality that film and audience share but always present a particular view of this reality. This implies that organizations in Alzheimer care, education, and research that often recommend documentaries to inform people about dementia should take into account that these films might reinforce negative stereotypes inducing fear of dementia. An in-depth analysis of the Dutch short documentary Mum (2009), directed by feminist artist Adelheid Roosen, illustrates that the reasoning of the personhood movement in dementia research can be translated into an artistic form. By highlighting instead of veiling its means of production, Mum stimulates viewers to imagine people with dementia as other than lost selves. PMID- 22539660 TI - The importance of being ironic: narrative openness and personal resilience in later life. AB - This essay applies a narrative perspective to the topic of resilience. On various fronts (physical, social, biographical), aging itself, it argues, pushes us past a perception of aging as intrinsically tragic and toward a more ironic stance instead, one marked by increased acceptance of uncertainty and ambiguity. Moreover, intentional engagement in narrative reflection-by means of integrative reminiscence, life review, and the like-fosters such a stance directly by facilitating narrative openness and, with it, "a good strong story" for coping with the challenges of later life. PMID- 22539661 TI - A sentinel platform to evaluate influenza vaccine effectiveness and new variant circulation, Canada 2010-2011 season. AB - BACKGROUND: During the 2010-2011 winter, a large number of outbreaks due to influenza A/H3N2 at long-term care facilities, including higher-than-expected attack rates among vaccinated staff, were reported in some regions of Canada. Interim analysis from the community-based sentinel surveillance system showed circulating H3N2 variants and suboptimal vaccine effectiveness (VE), assessed here for the entire season's data set. METHODS: Nasal/nasopharyngeal swabs and epidemiologic details were collected from patients presenting to sentinel sites within 7 days of onset of influenza-like illness. Cases tested positive for influenza by real-time reverse-transcription polymerase chain reaction; controls tested negative. Odds ratios for medically attended, laboratory-confirmed influenza in vaccinated vs nonvaccinated participants were used to derive adjusted VE. Viruses were characterized by hemagglutination inhibition (HI), and the hemagglutinin genes of a subset were sequenced to explore vaccine relatedness. RESULTS: Final 2010-2011 VE analysis included 1718 participants (half aged 20-49 years), 93 with A(H1N1)pdm09, 408 with A/H3N2, and 199 with influenza B. Among adults aged 20-49 years, adjusted VE was 65% (95% confidence interval [CI], 8%-87%) for A(H1N1)pdm09 and 66% (95% CI, 10%-87%) for influenza B. Vaccine effectiveness was substantially lower for A/H3N2, at 39% (95% CI, 0% 63%). Phylogenetic analysis identified 2 circulating H3N2 variant clades, A/HongKong/2121/2010 (87%) and A/Victoria/208/2009 (11%), bearing multiple amino acid substitutions at antigenic sites (12 and 8, respectively) compared with the H3N2 vaccine component used in Canada (A/Victoria/210/2009[NYMC X-187]). However, HI characterized all H3N2 isolates as well matched to the vaccine. CONCLUSIONS: Public health observations of increased facility H3N2 outbreaks were consistent with the sentinel network's detection of genetic variants and suboptimal VE but not with conventional HI characterization. We highlight the utility of a multicomponent sentinel surveillance platform that incorporates genotypic, phenotypic, and epidemiologic indicators into the assessment of influenza virus, new variant circulation, vaccine relatedness, and VE. PMID- 22539662 TI - Early primary cytomegalovirus infection in pregnancy: maternal hyperimmunoglobulin therapy improves outcomes among infants at 1 year of age. AB - BACKGROUND: Primary cytomegalovirus (CMV) infection during pregnancy is the leading infectious cause of congenital neurological disabilities. Early CMV infection carries a higher risk of adverse neonatal outcome (sensorineural hearing loss or neurological deficits). Intravenous hyperimmunoglobulin (HIG) therapy seems to be promising, but its efficacy needs further investigation. METHODS: Since 2002, we have enrolled consecutively all pregnant women with early (ie, before gestational week 17) CMV infection. Beginning in 2007, all women were offered treatment with HIG (200 UI per kilogram of maternal weight, in a single intravenous administration). Outcome of infants was evaluated at the age of 1 year. RESULTS: Of the 592 women with early primary CMV infection, amniocentesis for CMV DNA detection was performed for 446. Of the 92 CMV-positive fetuses, pregnancy was terminated for 24, HIG was administered to mothers of 31, and no treatment was received by mothers of 37. Fetuses of treated mothers did not differ from fetuses of nontreated mothers according to mother's age, gestational week of infection, CMV load, or detection of abnormal ultrasonography findings. At the 1-year evaluation, 4 of 31 infants with treated mothers (13%; 95% confidence interval [CI], 1%-25%) and 16 of 37 infants with nontreated mothers (43%; 95% CI, 27%-59%) presented with poor outcomes (P < .01, by the 2-tailed Fisher exact test). CONCLUSIONS: HIG treatment improved the outcome of fetuses from women who had primary CMV infection before gestational week 17. PMID- 22539663 TI - Editorial commentary: Primary maternal cytomegalovirus infection during pregnancy: do we have a treatment option? PMID- 22539664 TI - Prediction of treatment failure using 2010 World Health Organization Guidelines is associated with high misclassification rates and drug resistance among HIV infected Cambodian children. AB - BACKGROUND: Antiretroviral therapy (ART) in resource-limited settings (RLSs) is monitored clinically and immunologically, according to World Health Organization (WHO) or national guidelines. Revised WHO pediatric guidelines were published in 2010, but their ability to accurately identify virological failure is unclear. METHODS: We evaluated performance of WHO 2010 guidelines and compared them with WHO 2006 and Cambodia 2011 guidelines among children on >=6 months of first-line ART at Angkor Hospital for Children between January 2005 and September 2010. We determined sensitivity, specificity, positive and negative predictive values, and accuracy using bootstrap resampling to account for multiple tests per child. Human immunodeficiency virus (HIV) resistance was compared between those correctly and incorrectly identified by each guideline. RESULTS: Among 457 children with 1079 viral loads (VLs), 20% had >400 copies/mL. For children with WHO stage 1/2 HIV, misclassification as failure (met CD4 failure criteria, but VL undetectable) was 64% for WHO 2006 guidelines, 33% for WHO 2010 guidelines, and 81% for Cambodia 2011 guidelines; misclassification as success (did not meet CD4 failure, but VL detectable) was 11%, 12%, and 12%, respectively. For children with WHO stage 3/4 HIV, misclassification as failure was 35% for WHO 2006 guidelines, 40% for WHO 2010 guidelines, and 43% for Cambodia 2011 guidelines; misclassification as success was 13%, 24%, and 21%, respectively. Compared with WHO 2006 guidelines, WHO 2010 guidelines significantly increased the risk of misclassification as success in stage 3/4 HIV (P < .05). The WHO 2010 guidelines failed to identify 98% of children with extensive reverse-transcriptase resistance. CONCLUSIONS: In our cohort, lack of virological monitoring would result in unacceptable treatment failure misclassification, leading to premature ART switch and resistance accumulation. Affordable virological monitoring suitable for use in RLSs is desperately needed. PMID- 22539665 TI - Agreement in classifying bloodstream infections among multiple reviewers conducting surveillance. AB - BACKGROUND: Mandatory reporting of healthcare-associated infections (HAIs) is increasing. Evidence for agreement among different reviewers applying HAI surveillance criteria is limited. We aim to characterize agreement among infection preventionists (IPs) conducting surveillance for central line associated bloodstream infection (CLABSI) with each other and as compared with simplified laboratory-based definitions. METHODS: Abstracted electronic health records were assembled from inpatients with positive blood cultures at a tertiary care Veterans Affairs (VA) hospital over a 5-year period. Identical patient records were made available to VA IPs from different facilities to report on CLABSI using their usual surveillance methods. Positive blood cultures were also evaluated using laboratory-based definitions. Standard indices of interrater agreement, expressed as a kappa statistic, were computed between IPs, and between IPs and simplified laboratory-based methods. RESULTS: Overall, 114 patient records were reviewed by 18 IPs, the majority of whom specified they followed National Healthcare Safety Network criteria. The overall agreement among IPs by kappa statistic was 0.42 (standard error [SE], 0.06). IPs had better agreement with a simple laboratory-based definition with an average kappa of 0.55 (SE, 0.05). The proportion of patient records that 18 IPs reported with CLABSI ranged from 14% to 39% (overall mean, 28% with a coefficient of variation of 25%). When simple laboratory-based methods were applied to different sets of patient records, classification was more consistent with CLABSI assigned in a proportion ranging from 36% to 42% (overall mean, 39%). CONCLUSIONS: Reliability of IP conducted surveillance to identify HAI may not be ideal for public reporting goals of interhospital comparisons. PMID- 22539666 TI - PSI-Search: iterative HOE-reduced profile SSEARCH searching. AB - Iterative similarity searches with PSI-BLAST position-specific score matrices (PSSMs) find many more homologs than single searches, but PSSMs can be contaminated when homologous alignments are extended into unrelated protein domains-homologous over-extension (HOE). PSI-Search combines an optimal Smith Waterman local alignment sequence search, using SSEARCH, with the PSI-BLAST profile construction strategy. An optional sequence boundary-masking procedure, which prevents alignments from being extended after they are initially included, can reduce HOE errors in the PSSM profile. Preventing HOE improves selectivity for both PSI-BLAST and PSI-Search, but PSI-Search has ~4-fold better selectivity than PSI-BLAST and similar sensitivity at 50% and 60% family coverage. PSI-Search is also produces 2- for 4-fold fewer false-positives than JackHMMER, but is ~5% less sensitive. AVAILABILITY AND IMPLEMENTATION: PSI-Search is available from the authors as a standalone implementation written in Perl for Linux-compatible platforms. It is also available through a web interface (www.ebi.ac.uk/Tools/sss/psisearch) and SOAP and REST Web Services (www.ebi.ac.uk/Tools/webservices). PMID- 22539667 TI - CNVRuler: a copy number variation-based case-control association analysis tool. AB - SUMMARY: The method for genome-wide association study (GWAS) based on copy number variation (CNV) is not as well established as that for single nucleotide polymorphism (SNP)-GWAS. Although there are several tools for CNV association studies, most of them do not provide appropriate definitions of CNV regions (CNVRs), which are essential for CNV-association studies. Here we present a user friendly program called CNVRuler for CNV-association studies. Outputs from the 10 most common CNV defining algorithms can be directly used as input files for determining the three different definitions of CNVRs. Once CNVRs are defined, CNVRuler supports four kinds of statistical association tests and options for population stratification. CNVRuler is based on the open-source programs R and Java from Sun Microsystems. AVAILABILITY: CNVRuler software is available with an online manual at the website, www.ircgp.com/CNVRuler/index.html. PMID- 22539668 TI - Boosting automatic event extraction from the literature using domain adaptation and coreference resolution. AB - MOTIVATION: In recent years, several biomedical event extraction (EE) systems have been developed. However, the nature of the annotated training corpora, as well as the training process itself, can limit the performance levels of the trained EE systems. In particular, most event-annotated corpora do not deal adequately with coreference. This impacts on the trained systems' ability to recognize biomedical entities, thus affecting their performance in extracting events accurately. Additionally, the fact that most EE systems are trained on a single annotated corpus further restricts their coverage. RESULTS: We have enhanced our existing EE system, EventMine, in two ways. First, we developed a new coreference resolution (CR) system and integrated it with EventMine. The standalone performance of our CR system in resolving anaphoric references to proteins is considerably higher than the best ranked system in the COREF subtask of the BioNLP'11 Shared Task. Secondly, the improved EventMine incorporates domain adaptation (DA) methods, which extend EE coverage by allowing several different annotated corpora to be used during training. Combined with a novel set of methods to increase the generality and efficiency of EventMine, the integration of both CR and DA have resulted in significant improvements in EE, ranging between 0.5% and 3.4% F-Score. The enhanced EventMine outperforms the highest ranked systems from the BioNLP'09 shared task, and from the GENIA and Infectious Diseases subtasks of the BioNLP'11 shared task. AVAILABILITY: The improved version of EventMine, incorporating the CR system and DA methods, is available at: http://www.nactem.ac.uk/EventMine/. PMID- 22539669 TI - Statistical interpretation of machine learning-based feature importance scores for biomarker discovery. AB - MOTIVATION: Univariate statistical tests are widely used for biomarker discovery in bioinformatics. These procedures are simple, fast and their output is easily interpretable by biologists but they can only identify variables that provide a significant amount of information in isolation from the other variables. As biological processes are expected to involve complex interactions between variables, univariate methods thus potentially miss some informative biomarkers. Variable relevance scores provided by machine learning techniques, however, are potentially able to highlight multivariate interacting effects, but unlike the p values returned by univariate tests, these relevance scores are usually not statistically interpretable. This lack of interpretability hampers the determination of a relevance threshold for extracting a feature subset from the rankings and also prevents the wide adoption of these methods by practicians. RESULTS: We evaluated several, existing and novel, procedures that extract relevant features from rankings derived from machine learning approaches. These procedures replace the relevance scores with measures that can be interpreted in a statistical way, such as p-values, false discovery rates, or family wise error rates, for which it is easier to determine a significance level. Experiments were performed on several artificial problems as well as on real microarray datasets. Although the methods differ in terms of computing times and the tradeoff, they achieve in terms of false positives and false negatives, some of them greatly help in the extraction of truly relevant biomarkers and should thus be of great practical interest for biologists and physicians. As a side conclusion, our experiments also clearly highlight that using model performance as a criterion for feature selection is often counter-productive. AVAILABILITY AND IMPLEMENTATION: Python source codes of all tested methods, as well as the MATLAB scripts used for data simulation, can be found in the Supplementary Material. PMID- 22539670 TI - RNA-SeQC: RNA-seq metrics for quality control and process optimization. AB - RNA-seq, the application of next-generation sequencing to RNA, provides transcriptome-wide characterization of cellular activity. Assessment of sequencing performance and library quality is critical to the interpretation of RNA-seq data, yet few tools exist to address this issue. We introduce RNA-SeQC, a program which provides key measures of data quality. These metrics include yield, alignment and duplication rates; GC bias, rRNA content, regions of alignment (exon, intron and intragenic), continuity of coverage, 3'/5' bias and count of detectable transcripts, among others. The software provides multi-sample evaluation of library construction protocols, input materials and other experimental parameters. The modularity of the software enables pipeline integration and the routine monitoring of key measures of data quality such as the number of alignable reads, duplication rates and rRNA contamination. RNA-SeQC allows investigators to make informed decisions about sample inclusion in downstream analysis. In summary, RNA-SeQC provides quality control measures critical to experiment design, process optimization and downstream computational analysis. AVAILABILITY AND IMPLEMENTATION: See www.genepattern.org to run online, or www.broadinstitute.org/rna-seqc/ for a command line tool. PMID- 22539671 TI - DecoyFinder: an easy-to-use python GUI application for building target-specific decoy sets. AB - Decoys are molecules that are presumed to be inactive against a target (i.e. will not likely bind to the target) and are used to validate the performance of molecular docking or a virtual screening workflow. The Directory of Useful Decoys database (http://dud.docking.org/) provides a free directory of decoys for use in virtual screening, though it only contains a limited set of decoys for 40 targets.To overcome this limitation, we have developed an application called DecoyFinder that selects, for a given collection of active ligands of a target, a set of decoys from a database of compounds. Decoys are selected if they are similar to active ligands according to five physical descriptors (molecular weight, number of rotational bonds, total hydrogen bond donors, total hydrogen bond acceptors and the octanol-water partition coefficient) without being chemically similar to any of the active ligands used as an input (according to the Tanimoto coefficient between MACCS fingerprints). To the best of our knowledge, DecoyFinder is the first application designed to build target-specific decoy sets. AVAILABILITY: A complete description of the software is included on the application home page. A validation of DecoyFinder on 10 DUD targets is provided as Supplementary Table S1. DecoyFinder is freely available at http://URVnutrigenomica-CTNS.github.com/DecoyFinder. PMID- 22539672 TI - e-Drug3D: 3D structure collections dedicated to drug repurposing and fragment based drug design. AB - MOTIVATION: In the drug discovery field, new uses for old drugs, selective optimization of side activities and fragment-based drug design (FBDD) have proved to be successful alternatives to high-throughput screening. e-Drug3D is a database of 3D chemical structures of drugs that provides several collections of ready-to-screen SD files of drugs and commercial drug fragments. They are natural inputs in studies dedicated to drug repurposing and FBDD. AVAILABILITY: e-Drug3D collections are freely available at http://chemoinfo.ipmc.cnrs.fr/e-drug3d.html either for download or for direct in silico web-based screenings. PMID- 22539673 TI - Improving the TFold test for differential shotgun proteomics. AB - We present an updated version of the TFold software for pinpointing differentially expressed proteins in shotgun proteomics experiments. Given an FDR bound, the updated approach uses a theoretical FDR estimator to maximize the number of identifications that satisfy both a fold-change cutoff that varies with the t-test P-value as a power law and a stringency criterion that aims to detect lowly abundant proteins. The new version has yielded significant improvements in sensitivity over the previous one. AVAILABILITY: Freely available for academic use at http://pcarvalho.com/patternlab. PMID- 22539674 TI - State and parameter estimation of the heat shock response system using Kalman and particle filters. AB - MOTIVATION: Traditional models of systems biology describe dynamic biological phenomena as solutions to ordinary differential equations, which, when parameters in them are set to correct values, faithfully mimic observations. Often parameter values are tweaked by hand until desired results are achieved, or computed from biochemical experiments carried out in vitro. Of interest in this article, is the use of probabilistic modelling tools with which parameters and unobserved variables, modelled as hidden states, can be estimated from limited noisy observations of parts of a dynamical system. RESULTS: Here we focus on sequential filtering methods and take a detailed look at the capabilities of three members of this family: (i) extended Kalman filter (EKF), (ii) unscented Kalman filter (UKF) and (iii) the particle filter, in estimating parameters and unobserved states of cellular response to sudden temperature elevation of the bacterium Escherichia coli. While previous literature has studied this system with the EKF, we show that parameter estimation is only possible with this method when the initial guesses are sufficiently close to the true values. The same turns out to be true for the UKF. In this thorough empirical exploration, we show that the non parametric method of particle filtering is able to reliably estimate parameters and states, converging from initial distributions relatively far away from the underlying true values. AVAILABILITY AND IMPLEMENTATION: Software implementation of the three filters on this problem can be freely downloaded from http://users.ecs.soton.ac.uk/mn/HeatShock PMID- 22539676 TI - Characterization of recombinant murine binder of sperm protein homolog 1 and its role in capacitation. AB - Sperm capacitation is a maturation step that is deemed to be essential for sperm to fertilize an oocyte. A family of proteins, the binder of sperm (BSP), are known to bind choline phospholipids on sperm membranes and promote capacitation in bulls and boars. Recently, BSP-homologous genes have been identified in the epididymal tissues of human (BSPH1) and mouse (Bsph1, Bsph2). The aim of this study was to determine the binding characteristics of the murine binder of sperm protein homolog 1 (BSPH1) and evaluate its effects on sperm capacitation. Since it is not possible to purify the native BSP proteins from human and mouse in sufficient quantity, a murine recombinant BSPH1 (rec-BSPH1) was produced and used for the functional studies. Similarly to BSP proteins from other species, rec BSPH1 bound to gelatin, heparin, phosphatidylcholine liposomes, and sperm. Both native BSPH1 and rec-BSPH1 were detected on the head and the midpiece region of sperm, although a stronger signal was detected on the midpiece region when sperm were incubated in a capacitating media containing bovine serum albumin. More importantly, murine rec-BSPH1 was able to capacitate sperm, but was unable to induce the acrosome reaction. These results show that murine epididymal BSPH1 shares many biochemical and functional characteristics with BSP proteins secreted by seminal vesicles of ungulates, and suggest that it might play a similar role in sperm functions. PMID- 22539675 TI - Semantic integration of physiology phenotypes with an application to the Cellular Phenotype Ontology. AB - MOTIVATION: The systematic observation of phenotypes has become a crucial tool of functional genomics, and several large international projects are currently underway to identify and characterize the phenotypes that are associated with genotypes in several species. To integrate phenotype descriptions within and across species, phenotype ontologies have been developed. Applying ontologies to unify phenotype descriptions in the domain of physiology has been a particular challenge due to the high complexity of the underlying domain. RESULTS: In this study, we present the outline of a theory and its implementation for an ontology of physiology-related phenotypes. We provide a formal description of process attributes and relate them to the attributes of their temporal parts and participants. We apply our theory to create the Cellular Phenotype Ontology (CPO). The CPO is an ontology of morphological and physiological phenotypic characteristics of cells, cell components and cellular processes. Its prime application is to provide terms and uniform definition patterns for the annotation of cellular phenotypes. The CPO can be used for the annotation of observed abnormalities in domains, such as systems microscopy, in which cellular abnormalities are observed and for which no phenotype ontology has been created. AVAILABILITY AND IMPLEMENTATION: The CPO and the source code we generated to create the CPO are freely available on http://cell-phenotype.googlecode.com. PMID- 22539677 TI - Thyroid hormone limits postnatal Sertoli cell proliferation in vivo by activation of its alpha1 isoform receptor (TRalpha1) present in these cells and by regulation of Cdk4/JunD/c-myc mRNA levels in mice. AB - Hypo- and hyperthyroidism alter testicular functions in the young. Among T3 receptors, TRalpha1 is ubiquitous, and its previously described knockout leads to an increase in testis weight and sperm production. We tested, for the first time, the hypothesis that TRalpha1-dependent regulation of Sertoli cell (SC) proliferation was directly regulated by TRalpha1 present in these cells. Thus, after crossing with the AMH-Cre line, we generated and analyzed a new line that expressed a dominant-negative TRalpha1 isoform (TRalpha(AMI)) in SCs only. So called TRalpha(AMI)-SC (TRalpha(AMI/+) Cre(+)) mice exhibited similar phenotypic features to the knockout line: heavier testicular weight and higher sperm reserve, in comparison with their adequate controls (TRalpha(AMI/+) Cre(-)). SC density increased significantly as a result of a higher proliferative index at ages Postnatal Day (P) 0 and P3. When explants of control testes were cultured (at age P3), a significant decrease in the proliferation of SCs was observed in response to an excess of T3. This response was not observed in the TRalpha(AMI) SC and knockout lines. Finally, when TRalpha(AMI) is present in SCs, the phenotype observed is similar to that of the knockout line. This study demonstrates that T3 limits postnatal SC proliferation by activation of TRalpha1 present in these cells. Moreover, quantitative RT-PCR provided evidence that regulation of the Cdk4/JunD/c-myc pathway was involved in this negative control. PMID- 22539678 TI - Induction of autophagy promotes preattachment development of bovine embryos by reducing endoplasmic reticulum stress. AB - The coupling of autophagy and endoplasmic reticulum (ER) stress has been implicated in a variety of biological processes; however, little is known regarding the involvement of the autophagy/ER stress pathway in early embryogenesis or the underlying mechanism(s). Here, we showed that the developmental competence of in vitro-produced (IVP) bovine embryos was highly dependent on the autophagy/ER stress balance. Although relative abundances of autophagy-associated gene transcripts, including LC3, Atg5, and Atg7 transcripts, were high in oocytes and throughout the early stages of preattachment development, extensive autophagosome formation was only detected in fertilized embryos. Using an inducer and inhibitor of autophagy, we showed that transient elevation of autophagic activity during early preattachment development greatly increased the blastocyst development rate, trophectoderm cell numbers, and blastomere survival; these same parameters were reduced by both inhibition and prolonged induction of autophagy. Interestingly, the induction of autophagy reduced ER stress and associated damage, while the developmental defects in autophagy-inhibited embryos were significantly alleviated by ER stress inhibitor treatment, indicating that autophagy is a negative regulator of ER stress in early embryos. Collectively, these results suggest that early embryogenesis of IVP bovine embryos depends on an appropriate balance between autophagy and ER stress. These findings may increase our understanding of important early developmental events by providing compelling evidence concerning the tight association between autophagy and ER stress, and may contribute to the development of strategies for the production of IVP bovine blastocysts with high developmental competence. PMID- 22539679 TI - Endometrial receptivity defects and impaired implantation in diabetic NOD mice. AB - Implantation failure is a major hurdle to a successful pregnancy. The high rate of postimplantation fetal loss in nonobese diabetic (NOD) mice is believed to be related to an abnormal decidual production of interferon (IFN)gamma. To address whether diabetes alters the natural events associated with successful implantation, certain morphological and molecular features of uterine receptivity in diabetic NOD (dNOD) mice were examined in normally mated pregnancy and in concanavalin A (ConA)-induced pseudopregnancy. As opposed to normoglycemic NOD (cNOD) mice, dNOD mice expressed retarded maturation of their uterine pinopodes and overexpressed MUC1 mucin at implantation sites (P < 0.001). Uterine production of leukemia inhibitory factor (LIF) and phosphorylation of uterine NFkappaBp65 and STAT3-Ty705 were found to be low (P < 0.01) during Day 4.5 postcoitum, whereas IFNgamma was aberrantly overexpressed. Loss of temporal regulation of progesterone receptor A (PR A) and PR B, together with aberrantly increased expression of the protein inhibitor of activated STAT-y (PIASy) (P < 0.01) and reduced recruitment (P < 0.01) of the latter to nuclear progesterone receptor sites were prominent features of decidualization failure occurring at peri-implantation in dNOD mice. In conclusion, the aberrant expression of endometrial IFNgamma in dNOD mice is associated with a nonreceptive endometrial milieu contributing to peri-implantation embryo loss in type 1 diabetes. PMID- 22539680 TI - Masculine epigenetic sex marks of the CYP19A1/aromatase promoter in genetically male chicken embryonic gonads are resistant to estrogen-induced phenotypic sex conversion. AB - Sex of birds is genetically determined through inheritance of the ZW sex chromosomes (ZZ males and ZW females). Although the mechanisms of avian sex determination remains unknown, the genetic sex is experimentally reversible by in ovo exposure to exogenous estrogens (ZZ-male feminization) or aromatase inhibitors (ZW-female masculinization). Expression of various testis- and ovary specific marker genes during the normal and reversed gonadal sex differentiation in chicken embryos has been extensively studied, but the roles of sex-specific epigenetic marks in sex differentiation are unknown. In this study, we show that a 170-nt region in the promoter of CYP19A1/aromatase, a key gene required for ovarian estrogen biosynthesis and feminization of chicken embryonic gonads, contains highly quantitative, nucleotide base-level epigenetic marks that reflect phenotypic gonadal sex differentiation. We developed a protocol to feminize ZZ male chicken embryonic gonads in a highly quantitative manner by direct injection of emulsified ethynylestradiol into yolk at various developmental stages. Taking advantage of this experimental sex reversal model, we show that the epigenetic sex marks in the CYP19A1/aromatase promoter involving DNA methylation and histone lysine methylation are feminized significantly but only partially in sex converted gonads even when morphological and transcriptional marks of sex differentiation show complete feminization, being indistinguishable from gonads of normal ZW females. Our study suggests that the epigenetic sex of chicken embryonic gonads is more stable than the morphologically or transcriptionally characterized sex differentiation, suggesting the importance of the nucleotide base-level epigenetic sex in gonadal sex differentiation. PMID- 22539683 TI - Driven by basic research. PMID- 22539688 TI - Cancer. California weighs tobacco tax hike to fund research. PMID- 22539681 TI - Developmental programming: impact of prenatal testosterone excess on ovarian cell proliferation and apoptotic factors in sheep. AB - Prenatal testosterone (T) excess leads to reproductive dysfunctions in sheep, which include increased ovarian follicular recruitment and persistence. To test the hypothesis that follicular disruptions in T sheep stem from changes in the developmental ontogeny of ovarian proliferation and apoptotic factors, pregnant Suffolk sheep were injected twice weekly with T propionate or dihydrotestosterone propionate (DHT; a nonaromatizable androgen) from Days 30 to 90 of gestation. Changes in developmental expression of proliferating cell nuclear antigen (PCNA), BCL2, BAX, activated CASP3, and FAS/FASLG were determined at Fetal Days 90 and 140, 22 wk, 10 mo, and 21 mo of age by immunocytochemisty. Prenatal T treatment induced changes in expression of proliferative and apoptotic markers in a follicle-, age-, and steroid-specific manner. Changes in BAX were evident only during fetal life and PCNA, BCL2, and CASP3 only postnatally. Prenatal T and not DHT increased PCNA and decreased BCL2 in granulosa/theca cells of antral follicles at 10 and 21 mo but decreased CASP3 in granulosa/theca cells of antral follicles at 22 wk (prepubertal) and 10 and 21 mo. Both treatments decreased BAX immunostaining in granulosa cells of Fetal Day 90 primordial/primary follicles. Neither treatment affected FAS expression at any developmental time point in any follicular compartment. Effects on BAX appear to be programmed by androgenic actions and PCNA, BCL2, and CASP3 by estrogenic actions of T. Overall, the findings demonstrate that fetal exposure to excess T disrupts the ovarian proliferation/apoptosis balance, thus providing a basis for the follicular disruptions evidenced in these females. PMID- 22539690 TI - U.S. science budget. Spending panels back boosts for NSF, NASA, NIST programs. PMID- 22539689 TI - Archaeology. Ancient migrants brought farming way of life to Europe. PMID- 22539682 TI - Zinc maintains prophase I arrest in mouse oocytes through regulation of the MOS MAPK pathway. AB - Meiosis in mammalian females is marked by two arrest points, at prophase I and metaphase II, which must be tightly regulated in order to produce a haploid gamete at the time of fertilization. The transition metal zinc has emerged as a necessary and dynamic regulator of the establishment, maintenance, and exit from metaphase II arrest, but the roles of zinc during prophase I arrest are largely unknown. In this study, we investigate the mechanisms of zinc regulation during the first meiotic arrest. Disrupting zinc availability in the prophase I arrested oocyte by treatment with the heavy metal chelator N,N,N',N'-tetrakis-(2 pyridylmethyl)-ethylenediamine (TPEN) causes meiotic resumption even in the presence of pharmacological inhibitors of meiosis. We further show that the MOS MAPK pathway mediates zinc-dependent prophase I arrest, as the pathway prematurely activates during TPEN-induced meiotic resumption. Conversely, inhibition of the MOS-MAPK pathway maintains prophase I arrest. While prolonged zinc insufficiency ultimately results in telophase I arrest, early and transient exposure of oocytes to TPEN is sufficient to induce meiotic resumption and bypass the telophase I block, allowing the formation of developmentally competent eggs upon parthenogenetic activation. These results establish zinc as a crucial regulator of meiosis throughout the entirety of oocyte maturation, including the maintenance of and release from the first and second meiotic arrest points. PMID- 22539691 TI - Public health. Despite gains, malnutrition among China's rural poor sparks concern. PMID- 22539692 TI - France. Sarkozy's foe would soften reforms, overturn stem cell law. PMID- 22539694 TI - Global warming. The greenhouse is making the water-poor even poorer. PMID- 22539693 TI - Physics. Textbook electrodynamics may contradict relativity. PMID- 22539695 TI - Public health. Europe's embarrassing problem. PMID- 22539696 TI - Public health. After a successful decade, global fight appears stalled. PMID- 22539697 TI - Evolution of language. Experiments probe language's origins and development. PMID- 22539698 TI - Evolution of language. Where time goes up and down. PMID- 22539699 TI - Chile's research planning falls short. PMID- 22539700 TI - Don't jump to conclusions on fraud. PMID- 22539701 TI - Finding balance in fisheries management. PMID- 22539703 TI - Comment on "Universality in the evolution of orientation columns in the visual cortex". AB - Kaschube et al. (Reports, 19 November 2010, p. 1113) argue that pinwheel density in three mammalian species follows a universal constant of pi as predicted by their orientation-selective suppressive long-range connectivity model. We dispute their conclusions and suggest that a simple brain size-pinwheel density scaling law suffices in predicting the self-organized and disorganized orientation maps from primates to rodents. PMID- 22539705 TI - Public health. Monitoring EU emerging infectious disease risk due to climate change. PMID- 22539706 TI - Immunology. Select inflammasome assembly. PMID- 22539707 TI - Physics. Two atomic clocks ticking as one. PMID- 22539708 TI - Evolution. Microbial evolution in the wild. PMID- 22539709 TI - Cell Biology. Using cell-to-cell variability--a new era in molecular biology. PMID- 22539710 TI - Geochemistry. A hard life for cyanobacteria. PMID- 22539711 TI - Molecular biology. Reprogramming the genetic code. PMID- 22539712 TI - IBI* series winner. Engaging undergraduates in global health technology innovation. PMID- 22539713 TI - Multiblock polymers: panacea or Pandora's box? AB - Advances in synthetic polymer chemistry have unleashed seemingly unlimited strategies for producing block polymers with arbitrary numbers (n) and types (k) of unique sequences of repeating units. Increasing (k,n) leads to a geometric expansion of possible molecular architectures, beyond conventional ABA-type triblock copolymers (k = 2, n = 3), offering alluring opportunities to generate exquisitely tailored materials with unparalleled control over nanoscale-domain geometry, packing symmetry, and chemical composition. Transforming this potential into targeted structures endowed with useful properties hinges on imaginative molecular designs guided by predictive theory and computer simulation. Here, we review recent developments in the field of block polymers. PMID- 22539714 TI - A 920-kilometer optical fiber link for frequency metrology at the 19th decimal place. AB - Optical clocks show unprecedented accuracy, surpassing that of previously available clock systems by more than one order of magnitude. Precise intercomparisons will enable a variety of experiments, including tests of fundamental quantum physics and cosmology and applications in geodesy and navigation. Well-established, satellite-based techniques for microwave dissemination are not adequate to compare optical clocks. Here, we present phase stabilized distribution of an optical frequency over 920 kilometers of telecommunication fiber. We used two antiparallel fiber links to determine their fractional frequency instability (modified Allan deviation) to 5 * 10(-15) in a 1 second integration time, reaching 10(-18) in less than 1000 seconds. For long integration times tau, the deviation from the expected frequency value has been constrained to within 4 * 10(-19). The link may serve as part of a Europe-wide optical frequency dissemination network. PMID- 22539715 TI - Revealing the angular symmetry of chemical bonds by atomic force microscopy. AB - We have measured the angular dependence of chemical bonding forces between a carbon monoxide molecule that is adsorbed to a copper surface and the terminal atom of the metallic tip of a combined scanning tunneling microscope and atomic force microscope. We provide tomographic maps of force and current as a function of distance that revealed the emergence of strongly directional chemical bonds as tip and sample approach. The force maps show pronounced single, dual, or triple minima depending on the orientation of the tip atom, whereas tunneling current maps showed a single minimum for all three tip conditions. We introduce an angular dependent model for the bonding energy that maps the observed experimental data for all observed orientations and distances. PMID- 22539716 TI - Coils and polygonal crust in the Athabasca Valles region, Mars, as evidence for a volcanic history. AB - Athabasca Valles is a near-equatorial martian outflow channel that contains many well-preserved features whose formation and composition have been a point of contention. Large plates of terrain that have clearly fractured and drifted may have once been ice rafts or the rocky solidification crust of a large lava flow. We have identified 269 spiral coils ranging from 5 to 30 meters wide on the polygonally patterned interplate terrain that are morphologically consistent with terrestrial lava coils that form in zones of flow shear. This patterned terrain also exhibits signs of fracture and drift, indicating that it is platelike as well. The coils in the Athabasca region are inconsistent with ice rheology, and the plates, spirals, and polygons are interpreted to be of volcanic origin. PMID- 22539717 TI - Ocean salinities reveal strong global water cycle intensification during 1950 to 2000. AB - Fundamental thermodynamics and climate models suggest that dry regions will become drier and wet regions will become wetter in response to warming. Efforts to detect this long-term response in sparse surface observations of rainfall and evaporation remain ambiguous. We show that ocean salinity patterns express an identifiable fingerprint of an intensifying water cycle. Our 50-year observed global surface salinity changes, combined with changes from global climate models, present robust evidence of an intensified global water cycle at a rate of 8 +/- 5% per degree of surface warming. This rate is double the response projected by current-generation climate models and suggests that a substantial (16 to 24%) intensification of the global water cycle will occur in a future 2 degrees to 3 degrees warmer world. PMID- 22539718 TI - An early-branching microbialite cyanobacterium forms intracellular carbonates. AB - Cyanobacteria have affected major geochemical cycles (carbon, nitrogen, and oxygen) on Earth for billions of years. In particular, they have played a major role in the formation of calcium carbonates (i.e., calcification), which has been considered to be an extracellular process. We identified a cyanobacterium in modern microbialites in Lake Alchichica (Mexico) that forms intracellular amorphous calcium-magnesium-strontium-barium carbonate inclusions about 270 nanometers in average diameter, revealing an unexplored pathway for calcification. Phylogenetic analyses place this cyanobacterium within the deeply divergent order Gloeobacterales. The chemical composition and structure of the intracellular precipitates suggest some level of cellular control on the biomineralization process. This discovery expands the diversity of organisms capable of forming amorphous calcium carbonates. PMID- 22539719 TI - In situ evolutionary rate measurements show ecological success of recently emerged bacterial hybrids. AB - Few data are available on how quickly free-living microorganisms evolve. We analyzed biofilms collected from a well-defined acid mine drainage system over 9 years to investigate the processes and determine rates of bacterial evolution directly in the environment. Population metagenomic analyses of the dominant primary producer yielded the nucleotide substitution rate, which we used to show that proliferation of a series of recombinant bacterial strains occurred over the past few decades. The ecological success of hybrid bacterial types highlights the role of evolutionary processes in rapid adaptation within natural microbial communities. PMID- 22539720 TI - Origins and genetic legacy of Neolithic farmers and hunter-gatherers in Europe. AB - The farming way of life originated in the Near East some 11,000 years ago and had reached most of the European continent 5000 years later. However, the impact of the agricultural revolution on demography and patterns of genomic variation in Europe remains unknown. We obtained 249 million base pairs of genomic DNA from ~5000-year-old remains of three hunter-gatherers and one farmer excavated in Scandinavia and find that the farmer is genetically most similar to extant southern Europeans, contrasting sharply to the hunter-gatherers, whose distinct genetic signature is most similar to that of extant northern Europeans. Our results suggest that migration from southern Europe catalyzed the spread of agriculture and that admixture in the wake of this expansion eventually shaped the genomic landscape of modern-day Europe. PMID- 22539721 TI - Endogenous protein S-Nitrosylation in E. coli: regulation by OxyR. AB - Endogenous S-nitrosylation of proteins, a principal mechanism of cellular signaling in eukaryotes, has not been observed in microbes. We report that protein S-nitrosylation is an obligate concomitant of anaerobic respiration on nitrate in Escherichia coli. Endogenous S-nitrosylation during anaerobic respiration is controlled by the transcription factor OxyR, previously thought to operate only under aerobic conditions. Deletion of OxyR resulted in large increases in protein S-nitrosylation, and S-nitrosylation of OxyR induced transcription from a regulon that is distinct from the regulon induced by OxyR oxidation. Furthermore, products unique to the anaerobic regulon protected against S-nitrosothiols, and anaerobic growth of E. coli lacking OxyR was impaired on nitrate. Thus, OxyR serves as a master regulator of S-nitrosylation, and alternative posttranslational modifications of OxyR control distinct transcriptional responses. PMID- 22539722 TI - Function and molecular mechanism of acetylation in autophagy regulation. AB - Protein acetylation emerged as a key regulatory mechanism for many cellular processes. We used genetic analysis of Saccharomyces cerevisiae to identify Esa1 as a histone acetyltransferase required for autophagy. We further identified the autophagy signaling component Atg3 as a substrate for Esa1. Specifically, acetylation of K19 and K48 of Atg3 regulated autophagy by controlling Atg3 and Atg8 interaction and lipidation of Atg8. Starvation induced transient K19-K48 acetylation through spatial and temporal regulation of the localization of acetylase Esa1 and the deacetylase Rpd3 on pre-autophagosomal structures (PASs) and their interaction with Atg3. Attenuation of K19-K48 acetylation was associated with attenuation of autophagy. Increased K19-K48 acetylation after deletion of the deacetylase Rpd3 caused increased autophagy. Thus, protein acetylation contributes to control of autophagy. PMID- 22539724 TI - The inhibitory receptor PD-1 regulates IgA selection and bacterial composition in the gut. AB - Immunoglobulin A (IgA) is essential to maintain the symbiotic balance between gut bacterial communities and the host immune system. Here we provide evidence that the inhibitory co-receptor programmed cell death-1 (PD-1) regulates the gut microbiota through appropriate selection of IgA plasma cell repertoires. PD-1 deficiency generates an excess number of T follicular helper (T(FH)) cells with altered phenotypes, which results in dysregulated selection of IgA precursor cells in the germinal center of Peyer's patches. Consequently, the IgAs produced in PD-1-deficient mice have reduced bacteria-binding capacity, which causes alterations of microbial communities in the gut. Thus, PD-1 plays a critical role in regulation of antibody diversification required for the maintenance of intact mucosal barrier. PMID- 22539723 TI - GSK3-TIP60-ULK1 signaling pathway links growth factor deprivation to autophagy. AB - In metazoans, cells depend on extracellular growth factors for energy homeostasis. We found that glycogen synthase kinase-3 (GSK3), when deinhibited by default in cells deprived of growth factors, activates acetyltransferase TIP60 through phosphorylating TIP60-Ser(86), which directly acetylates and stimulates the protein kinase ULK1, which is required for autophagy. Cells engineered to express TIP60(S86A) that cannot be phosphorylated by GSK3 could not undergo serum deprivation-induced autophagy. An acetylation-defective mutant of ULK1 failed to rescue autophagy in ULK1(-/-) mouse embryonic fibroblasts. Cells used signaling from GSK3 to TIP60 and ULK1 to regulate autophagy when deprived of serum but not glucose. These findings uncover an activating pathway that integrates protein phosphorylation and acetylation to connect growth factor deprivation to autophagy. PMID- 22539725 TI - Analytic thinking promotes religious disbelief. AB - Scientific interest in the cognitive underpinnings of religious belief has grown in recent years. However, to date, little experimental research has focused on the cognitive processes that may promote religious disbelief. The present studies apply a dual-process model of cognitive processing to this problem, testing the hypothesis that analytic processing promotes religious disbelief. Individual differences in the tendency to analytically override initially flawed intuitions in reasoning were associated with increased religious disbelief. Four additional experiments provided evidence of causation, as subtle manipulations known to trigger analytic processing also encouraged religious disbelief. Combined, these studies indicate that analytic processing is one factor (presumably among several) that promotes religious disbelief. Although these findings do not speak directly to conversations about the inherent rationality, value, or truth of religious beliefs, they illuminate one cognitive factor that may influence such discussions. PMID- 22539726 TI - 'Instantaneous' metabolic measurement. PMID- 22539727 TI - The impacts of repeated cold exposure on insects. AB - Insects experience repeated cold exposure (RCE) on multiple time scales in natural environments, yet the majority of studies of the effects of cold on insects involve only a single exposure. Three broad groups of experimental designs have been employed to examine the effects of RCE on insect physiology and fitness, defined by the control treatments: 'RCE vs cold', which compares RCE with constant cold conditions; 'RCE vs warm', which compares RCE with constant warm conditions; and 'RCE vs matched cold' which compares RCE with a prolonged period of cold matched by time to the RCE condition. RCE are generally beneficial to immediate survival, and increase cold hardiness relative to insects receiving a single prolonged cold exposure. However, the effects of RCE depend on the study design, and RCE vs warm studies cannot differentiate between the effects of cold exposure in general vs RCE in particular. Recent studies of gene transcription, immune function, feeding and reproductive output show that the responses of insects to RCE are distinct from the responses to single cold exposures. We suggest that future research should attempt to elucidate the mechanistic link between physiological responses and fitness parameters. We also recommend that future RCE experiments match the time spent at the stressful low temperature in all experimental groups, include age controls where appropriate, incorporate a pilot study to determine time and intensity of exposure, and measure sub-lethal impacts on fitness. PMID- 22539728 TI - Redox biology of exercise: an integrative and comparative consideration of some overlooked issues. AB - The central aim of this review is to address the highly multidisciplinary topic of redox biology as related to exercise using an integrative and comparative approach rather than focusing on blood, skeletal muscle or humans. An attempt is also made to re-define 'oxidative stress' as well as to introduce the term 'alterations in redox homeostasis' to describe changes in redox homeostasis indicating oxidative stress, reductive stress or both. The literature analysis shows that the effects of non-muscle-damaging exercise and muscle-damaging exercise on redox homeostasis are completely different. Non-muscle-damaging exercise induces alterations in redox homeostasis that last a few hours post exercise, whereas muscle-damaging exercise causes alterations in redox homeostasis that may persist for and/or appear several days post exercise. Both exhaustive maximal exercise lasting only 30 s and isometric exercise lasting 1-3 min (the latter activating in addition a small muscle mass) induce systemic oxidative stress. With the necessary modifications, exercise is capable of inducing redox homeostasis alterations in all fluids, cells, tissues and organs studied so far, irrespective of strains and species. More importantly, 'exercise induced oxidative stress' is not an 'oddity' associated with a particular type of exercise, tissue or species. Rather, oxidative stress constitutes a ubiquitous fundamental biological response to the alteration of redox homeostasis imposed by exercise. The hormesis concept could provide an interpretative framework to reconcile differences that emerge among studies in the field of exercise redox biology. Integrative and comparative approaches can help determine the interactions of key redox responses at multiple levels of biological organization. PMID- 22539729 TI - Evaluation of a tandem gas chromatography/time-of-flight mass spectrometry metabolomics platform as a single method to investigate the effect of starvation on whole-animal metabolism in rainbow trout (Oncorhynchus mykiss). AB - This study was conducted to evaluate the use of a two-dimensional gas chromatography/time-of-flight mass spectrometry (GC*GC/TOF-MS) metabolomic platform to comprehensively analyze the effect of starvation on whole-animal metabolism in rainbow trout (Oncorhynchus mykiss). Trout were either fed a commercial diet at 2% body mass twice daily or starved for 4 weeks. Metabolomic analysis was conducted on serum, liver and muscle tissue from each fish. Database searching and statistical analysis revealed that concentrations of more than 50 positively identified molecules changed significantly (P<0.05) as a result of starvation. Our results indicate that starving rainbow trout for 4 weeks promotes increased utilization of select tissue fatty acids in liver and muscle. However, starvation did not significantly affect protein catabolism in peripheral tissues, as indicated by reductions in the level of serum amino acids in starved fish. In contrast, starvation appears to promote protein catabolism in liver as the level of methionine, proline and lysine metabolite 2-piperidine carboxylic acid increased significantly. Also, starvation resulted in significant changes in the level of numerous xenobiotics that could indicate the origin of particular feed ingredients and selective retention of these molecules in tissues. We suggest that metabolomic analysis using GC*GC/TOF-MS is an effective tool in studying whole-animal metabolism and the fate of important xenobiotic compounds in rainbow trout as numerous polar and non-polar metabolites were rapidly and accurately profiled using a single method. PMID- 22539730 TI - Waggle dance effect: dancing in autumn reduces the mass loss of a honeybee colony. AB - A honeybee informs her nestmates about the location of a profitable food source that she has visited by means of a waggle dance: a round dance and a figure-of eight dance for a short- and long-distance food source, respectively. Consequently, the colony achieves an effective collection of food. However, it is still not fully understood how much effect the dance behavior has on the food collection, because most of the relevant experiments have been performed only in limited locations under limited experimental conditions. Here, we examined the efficacy of the waggle dances by physically preventing bees from dancing and then analyzing the changes in daily mass of the hive as an index of daily food collection. To eliminate place- and year-specific effects, the experiments were performed under fully natural conditions in three different cities in Japan from mid September to early October in three different years. Because the experiments were performed in autumn, all six of the tested colonies lost mass on most of the experimental days. When the dance was prevented, the daily reduction in mass change was greater than when the dance was allowed, i.e. the dance inhibited the reduction of the hive mass. This indicates that dance is effective for food collection. Furthermore, clear inhibition was observed on the first two days of the experiments; after that, inhibition was no longer evident. This result suggests that the bee colony adapted to the new environment. PMID- 22539731 TI - The determination of nest depth in founding queens of leaf-cutting ants (Atta vollenweideri): idiothetic and temporal control. AB - Leaf-cutting ant queens excavate a founding nest consisting of a vertical tunnel and a final horizontal chamber. Nest foundation is very time consuming, and colony success depends on the excavated depth. Although shallow nests may be energetically cheaper to dig, queens may be more exposed to the changing environment. Deeper chambers, in contrast, may be climatically more stable, but are more expensive to dig. We investigated the mechanisms underlying the control of nest depth in queens of the leaf-cutting ant Atta vollenweideri. We focused on the use of internal information for the control of nest depth, and therefore maintained the soil and environmental conditions invariant during the different laboratory experiments. We compared the tunnel lengths excavated by queens that were able to complete their nests earlier, faster or slower than under standard conditions. An earlier and faster nest completion was obtained by offering queens either pre-excavated tunnels of different lengths, soils at different temperatures, or soft sandy soils. A slower nest excavation was induced by offering queens harder dry soils, and by delaying the start of digging several days after the nuptial flight. Results indicate that the determination of nest depth was a regulated process involving the use of internal references: queens excavated their tunnels either until a particular depth was reached or for some predetermined length of time. Queens appear to monitor their movements while walking up und down the tunnel, and to compare this sensory information with a motor command that represents a preset tunnel length to be excavated before switching to chamber digging. In addition to this form of idiothetic control, results indicate that the elapsed digging time also feeds back onto the control system. It is argued that the determination of nest depth, i.e. the transition from tunnel to chamber digging, is initiated either after a preset tunnel length is reached, or as soon as a maximal time interval has elapsed, irrespective of the excavated tunnel length. A control system using both idiothetic and temporal information, as demonstrated in the present study, allows queens to flexibly react to different soil conditions, and therefore avoid excessive time and energy investments. Possible mechanisms underlying the control of chamber size are also discussed. PMID- 22539732 TI - Within-lifetime trade-offs but evolutionary freedom for hormonal and immunological traits: evidence from mice bred for high voluntary exercise. AB - Chronic increases in circulating corticosterone (CORT) generally suppress immune function, but it is not known whether evolved increases necessarily have similar adverse effects. Moreover, the evolution of immune function might be constrained by the sharing of signaling molecules, such as CORT, across numerous physiological systems. Laboratory house mice (Mus domesticus Linnaeus) from four replicate lines selectively bred for high voluntary wheel running (HR lines) generally had baseline circulating CORT approximately twofold higher than in four non-selected control (C) lines. To test whether elevated baseline CORT suppresses the inflammatory response in HR mice, we injected females with lipopolysaccharide (LPS). All mice injected with LPS exhibited classic signs of an inflammatory response, including sickness behavior, loss of body mass, reduced locomotor activity (i.e. voluntary wheel running), enlarged spleens and livers, elevated hematocrit and elevated inflammatory cytokines. However, as compared with C mice, the inflammatory response was not suppressed in HR mice. Our results, and those of a previous study, suggest that selective breeding for high voluntary exercise has not altered immune function. They also suggest that the effects of evolved differences in baseline CORT levels may differ greatly from effects of environmental factors (often viewed as 'stressors') that alter baseline CORT during an individual's lifetime. In particular, evolved increases in circulating levels of 'stress hormones' are not necessarily associated with detrimental suppression of the inflammatory response, presumably as a result of correlated evolution of other physiological systems (counter-measures). Our results have important implications for the interpretation of elevated stress hormones and of immune indicators in natural populations. PMID- 22539733 TI - Small organ size contributes to the slow pace of life in tropical birds. AB - Attributes of an animal's life history, such as reproductive rate or longevity, typically fall along a 'slow-fast' continuum. Animals at the fast end of this continuum, such as temperate birds, are thought to experience high rates of mortality and invest more resources in reproduction, whereas animals at the slow end, such as tropical birds, live longer, have fewer offspring and invest more resources in self-maintenance. We have previously shown that tropical birds, compared with temperate species, have a reduced basal (BMR) and peak metabolic rate (PMR), patterns consistent with a slow pace of life. Here, we elucidate a fundamental linkage between the smaller mass of central organs of tropical species and their reduced BMR, and between their smaller flight muscles and reduced PMR. Analyses of up to 408 species from the literature showed that the heart, flight muscles, liver, pancreas and kidneys were smaller in tropical species. Direct measurements on 49 species showed smaller heart, lungs, flight muscles, liver, kidneys, ovaries and testes in tropical species, as well as lower feather mass. In combination, our results indicate that the benign tropical environment imposes a relaxed selection pressure on high levels of sustained metabolic performance, permitting species to reduce the mass of organs that are energetically costly to maintain. Brain, gizzard and intestine were exceptions, even though energy turnover of brain and intestine are high. Feather mass was 37% lower in tropical species compared with similar-sized temperate birds, supporting the idea that temperate birds require more insulation for thermoregulation. PMID- 22539734 TI - Plant odour stimuli reshape pheromonal representation in neurons of the antennal lobe macroglomerular complex of a male moth. AB - Male moths are confronted with complex odour mixtures in a natural environment when flying towards a female-emitted sex pheromone source. Whereas synergistic effects of sex pheromones and plant odours have been observed at the behavioural level, most investigations at the peripheral level have shown an inhibition of pheromone responses by plant volatiles, suggesting a potential role of the central nervous system in reshaping the peripheral information. We thus investigated the interactions between sex pheromone and a behaviourally active plant volatile, heptanal, and their effects on responses of neurons in the pheromone-processing centre of the antennal lobe, the macroglomerular complex, in the moth Agrotis ipsilon. Our results show that most of these pheromone-sensitive neurons responded to the plant odour. Most neurons responded to the pheromone with a multiphasic pattern and were anatomically identified as projection neurons. They responded either with excitation or pure inhibition to heptanal, and the response to the mixture pheromone + heptanal was generally weaker than to the pheromone alone, showing a suppressive effect of heptanal. However, these neurons responded with a better resolution to pulsed stimuli. The other neurons with either purely excitatory or inhibitory responses to all three stimuli did not exhibit significant differences in responses between stimuli. Although the suppression of the pheromone responses in AL neurons by the plant odour is counter-intuitive at first glance, the observed better resolution of pulsed stimuli is probably more important than high sensitivity to the localization of a calling female. PMID- 22539735 TI - Auditory processing at two time scales by the cricket Gryllus bimaculatus. AB - The acoustic display of many cricket species consists of series of pulses grouped into chirps, and thus information is distributed over both short and long time scales. Here we investigated the temporal cues that females of the cricket Gryllus bimaculatus used to detect a chirp pattern on a longer time scale than the fast pulse pattern. First, over a range of chirp and pause durations (100-400 ms), the duty cycle of the chirp pattern emerged as the most important cue for detection. The songs of males showed a distribution at lower duty cycles than preferred by females. The duty cycle also limited the responses of females at very short durations and pauses (below 80 ms). Second, by systematic variation of pulse and chirp periods of stimuli, an intermediate response field emerged that revealed the best responses of female crickets to patterns with amplitude modulations on both short and long time scales. On average, females also responded weakly to stimuli that contained amplitude modulations of only one time scale. Third, test patterns were constructed by addition of modulation frequencies rather than rectangular pulses. These tests showed that female crickets processed the chirp pattern in the time domain and tolerated noise levels up to a modulation depth of 50%. The combined evidence from all three approaches indicated inhibitory effects of unattractive patterns on both time scales. The fusion of short and long time scales during auditory processing by female crickets corresponded to a weighted AND-like operation of two processing modules, the pulse and the chirp filter. PMID- 22539736 TI - Control of luminescence from pygmy shark (Squaliolus aliae) photophores. AB - The smalleye pygmy shark (Squaliolus aliae) is a dwarf pelagic shark from the Dalatiidae family that harbours thousands of tiny photophores. In this work, we studied the organisation and physiological control of these photogenic organs. Results show that they are mainly situated on the ventral side of the shark, forming a homogeneous ventral photogenic area that appears well suited for counterillumination, a well-known camouflage technique of pelagic organisms. Isolated ventral skin patches containing photophores did not respond to classical neurotransmitters and nitric oxide but produced light after melatonin (MT) application. Prolactin and alpha-melanocyte-stimulating hormone inhibited this hormonally induced luminescence as well as the spontaneous luminescence from the photogenic tissue. The action of MT seems to be mediated by binding to the MT(2) receptor subtype, as the MT(2) receptor agonist 4P-PDOT inhibited the luminescence induced by this hormone. Binding to this receptor probably decreases the intracellular cAMP concentration because forskolin inhibited spontaneous and MT-induced luminescence. In addition, a GABA inhibitory tonus seems to be present in the photogenic tissue as well, as GABA inhibited MT-induced luminescence and the application of bicuculline provoked luminescence from S. aliae photophores. Similarly to what has been found in Etmopteridae, the other luminous shark family, the main target of the luminescence control appears to be the melanophores covering the photocytes. Results suggest that bioluminescence first appeared in Dalatiidae when they adopted a pelagic style at the Cretaceous/Tertiary boundary, and was modified by Etmopteridae when they started to colonize deep-water niches and rely on this light for intraspecific behaviours. PMID- 22539737 TI - Oesophageal chemoreceptors of blue crabs, Callinectes sapidus, sense chemical deterrents and can block ingestion of food. AB - Decapod crustaceans such as blue crabs possess a variety of chemoreceptors that control different stages of the feeding process. All these chemoreceptors are putative targets for feeding deterrents that cause animals to avoid or reject otherwise palatable food. As a first step towards characterizing the chemoreceptors that mediate the effect of deterrents, we used a behavioral approach to investigate their precise location. Data presented here demonstrate that chemoreceptors located on the antennules, pereiopods and mouthparts do not mediate the food-rejection effects of a variety of deterrents, both natural and artificial to crabs. Crabs always searched for deterrent-laced food and took it to their oral region. The deterrent effect was manifested as either rejection or extensive manipulation, but in both cases crabs bit the food. The biting behavior is relevant because the introduction of food into the oral cavity ensured that the deterrents gained access to the oesophageal taste receptors, and so we conclude that they are the ones mediating rejection. Additional support comes from the fact that a variety of deterrent compounds evoked oesophageal dilatation, which is mediated by oesophageal receptors and has been linked to food rejection. Further, there is a positive correlation between a compound's ability to elicit rejection and its ability to evoke oesophageal dilatation. The fact that deterrents do not act at a distance is in accordance with the limited solubility of most known feeding deterrents, and likely influences predator-prey interactions and their outcome: prey organisms will be attacked and bitten before deterrents become relevant. PMID- 22539738 TI - A long-latency aversive learning mechanism enables locusts to avoid odours associated with the consequences of ingesting toxic food. AB - Avoiding food that contains toxins is crucial for the survival of many animals, particularly herbivores, because many plants defend themselves with toxins. Some animals can learn to avoid food containing toxins not through its taste but by the toxins' effects following ingestion, though how they do so remains unclear. We studied how desert locusts (Schistocerca gregaria), which are generalist herbivores, form post-ingestive aversive memories and use them to make appropriate olfactory-based decisions in a Y-maze. Locusts form an aversion gradually to an odour paired with food containing the toxin nicotine hydrogen tartrate (NHT), suggesting the involvement of a long-latency associative mechanism. Pairing of odour and toxin-free food accompanied by NHT injections at different latencies showed that locusts could form an association between an odour and toxic malaise, which could be separated by up to 30 min. Tasting but not swallowing the food, or the temporal separation of odour and food, prevents the formation of these long-latency associations, showing that they are post ingestive. A second associative mechanism not contingent upon feeding operates only when odour presentation is simultaneous with NHT injection. Post-ingestive memory formation is not disrupted by exposure to a novel odour alone but can be if the odour is accompanied by simultaneous NHT injection. Thus, the timing with which food, odour and toxin are encountered whilst foraging is likely to influence memory formation and subsequent foraging decisions. Therefore, locusts can form specific long-lasting aversive olfactory associations that they can use to avoid toxin-containing foods whilst foraging. PMID- 22539739 TI - Regulation of the mTOR signaling network in hibernating thirteen-lined ground squirrels. AB - For many small mammals, survival over the winter months is a serious challenge because of low environmental temperatures and limited food availability. The solution for many species, such as thirteen-lined ground squirrels (Ictidomys tridecemlineatus), is hibernation, an altered physiological state characterized by seasonal heterothermy and entry into long periods of torpor that are interspersed with short arousals back to euthermia. During torpor, metabolic rate is strongly reduced to achieve major energy savings, and a coordinated depression of non-essential ATP-expensive functions such as protein synthesis takes place. This study examines the mammalian target of rapamycin (mTOR) signaling pathway, a crucial component of the insulin receptor network, over six stages of the torpor arousal cycle of hibernation. Immunoblots showed that the phosphorylation state of mTOR(Ser2448) was strongly reduced in skeletal muscle (by 55%) during late torpor but increased by 200% during early arousal compared with euthermia. However, the phosphorylation state of this residue remained relatively constant in cardiac muscle during torpor but was enhanced during entrance into torpor and early arousal from torpor stages (by 2.9- and 3.2-fold, respectively). Phosphorylation states of upstream regulators of mTOR, p-Akt(Thr473) and p TSC2(Thr1462), were also suppressed in skeletal muscle by 55 and 51%, respectively, during late torpor, as were selected downstream substrates--p-4E BP1(Thr46) and p-S6(Ser235) contents dropped by 74 and 41%, respectively. Overall, the results indicate suppressed mTOR signaling in skeletal muscle, but not cardiac muscle, during torpor. By contrast, activation of mTOR and other components of the mTORC1 complex (p-PRAS40(Thr246) and GbetaL) occurred during early arousal in both skeletal and cardiac muscle. PMID- 22539740 TI - The gaits of primates: center of mass mechanics in walking, cantering and galloping ring-tailed lemurs, Lemur catta. AB - Most primates, including lemurs, have a broad range of locomotor capabilities, yet much of the time, they walk at slow speeds and amble, canter or gallop at intermediate and fast speeds. Although numerous studies have investigated limb function during primate quadrupedalism, how the center of mass (COM) moves is not well understood. Here, we examined COM energy, work and power during walking, cantering and galloping in ring-tailed lemurs, Lemur catta (N=5), over a broad speed range (0.43-2.91 m s(-1)). COM energy recoveries were substantial during walking (35-71%) but lower during canters and gallops (10-51%). COM work, power and collisional losses increased with speed. The positive COM works were 0.625 J kg(-1) m(-1) for walks and 1.661 J kg(-1) m(-1) for canters and gallops, which are in the middle range of published values for terrestrial animals. Although some discontinuities in COM mechanics were evident between walking and cantering, there was no apparent analog to the trot-gallop transition across the intermediate and fast speed range (dimensionless v>0.75, Fr>0.5). A phenomenological model of a lemur cantering and trotting at the same speed shows that canters ensure continuous contact of the body with the substrate while reducing peak vertical COM forces, COM stiffness and COM collisions. We suggest that cantering, rather than trotting, at intermediate speeds may be tied to the arboreal origins of the Order Primates. These data allow us to better understand the mechanics of primate gaits and shed new light on primate locomotor evolution. PMID- 22539742 TI - Tarantulas do not shoot silk from their legs: experimental evidence in four species of New World tarantulas. AB - Theraphosid tarantulas, like all other spiders, secrete silk from spigots on the abdominal spinnerets. A few years ago, it was proposed that the large tarantula Aphonopelma seemanni could extrude silk from specialized spigots on the tarsi to help adhesion to vertical surfaces. This suggestion was later questioned because silk was not observed after the spinnerets had been sealed. Recently, experiments with the tarantula Grammostola rosea again suggested tarsal silk secretion. All observations of the supposed tarsal silk were made in spiders with functional spinnerets, thus contamination with silk coming from the spinnerets could not be excluded. Recent morphological arguments also questioned putative tarsal spigots and proposed that they are actually contact chemoreceptors. We here test the supposed tarsal silk secretion in Aphonopelma seemanni, Avicularia avicularia, Brachypelma vagans and Grammostola mollicoma using similar experimental conditions as the previous authors, but with sealed spinnerets. Our results clearly demonstrate that when spinnerets are sealed, tarantulas do not show any tarsal silk secretion. We reinterpret those putative tarsal spigots and discuss possible evolutionary implications of these findings. PMID- 22539741 TI - Odorant tuning of olfactory crypt cells from juvenile and adult rainbow trout. AB - Teleost fish lack independent olfactory organs for odorant and pheromone detection. Instead, they have a single sensory epithelium with two populations of receptor neurons, ciliated and microvillous, that are conserved among vertebrates, and a unique receptor cell type named the olfactory crypt cell. Crypt cells were shown to be chemosensory neurons that project to specific areas in the olfactory bulb, but their odorant tuning and overall function remain unclear. Reproduction in fish is generally synchronized by sex pheromonal signaling between males and females, but the sensors responsible for pheromone detection remain unknown. In crucian carp, a seasonal variation in the population of olfactory crypt cells and their brain projections pathways, involved in reproduction, led to the hypothesis of a role as sex pheromone detectors. In the present study, morphology and localization of olfactory crypt cells were compared between juvenile and mature rainbow trout of both sexes, and calcium imaging was used to visualize responses of crypt cells from the three groups to common social and food-related odorants, sex hormones and conspecific tissue extracts. Crypt cells from mature trout were found to be larger than those of juvenile specimens, and preferentially localized to the apical surface of the olfactory epithelium. Although a fraction of crypt cells of all groups responded to common odorants such as amino acids and bile salts, cells from mature trout showed a characteristic preference for gonadal extracts and hormones from the opposite sex. These results support an involvement of olfactory crypt cells in reproduction-related olfactory signaling in fishes. PMID- 22539743 TI - Constraints-based stoichiometric analysis of hypoxic stress on steroidogenesis in fathead minnows, Pimephales promelas. AB - In this study, an in silico genome-scale metabolic model of steroidogenesis was used to investigate the effects of hypoxic stress on steroid hormone productions in fish. Adult female fathead minnows (Pimephales promelas) were exposed to hypoxia for 7 days with fish sub-sampled on days 1, 3 and 7 of exposure. At each time point, selected steroid enzyme gene expressions and steroid hormone productions were quantified in ovaries. Fold changes in steroid enzyme gene expressions were used to qualitatively scale transcript enzyme reaction constraints (akin to the range of an enzyme's catalytic activity) in the in silico model. Subsequently, in silico predicted steroid hormone productions were qualitatively compared with experimental results. Key findings were as follows. (1) In silico gene deletion analysis identified highly conserved 'essential' genes required for steroid hormone productions. These agreed well (75%) with literature-published genes downregulated in vertebrates (fish and mammal) exposed to hypoxia. (2) Quantification of steroid hormones produced ex vivo from ovaries showed a significant reduction for 17beta-estradiol and 17alpha,20beta dihydroxypregnenone production after 24 h (day 1) of exposure. This lowered 17beta-estradiol production was concomitant with downregulation of cyp19a1a gene expression in ovaries. In silico predictions showed agreement with experimentation by predicting effects on estrogen (17beta-estradiol and estrone) production. (3) Stochastic sampling of in silico reactions indicated that cholesterol uptake and catalysis to pregnenolone along with estrogen methyltransferase and glucuronidation reactions were also impacted by hypoxia. Taken together, this in silico analysis introduces a powerful model for pathway analysis that can lend insights on the effects of various stressor scenarios on metabolic functions. PMID- 22539744 TI - Neuromuscular control of free-flight yaw turns in the hawkmoth Manduca sexta. AB - The biomechanical properties of an animal's locomotor structures profoundly influence the relationship between neuromuscular inputs and body movements. In particular, passive stability properties are of interest as they may offer a non neural mechanism for simplifying control of locomotion. Here, we hypothesized that a passive stability property of animal flight, flapping counter-torque (FCT), allows hawkmoths to control planar yaw turns in a damping-dominated framework that makes rotational velocity directly proportional to neuromuscular activity. This contrasts with a more familiar inertia-dominated framework where acceleration is proportional to force and neuromuscular activity. To test our hypothesis, we collected flight muscle activation timing, yaw velocity and acceleration data from freely flying hawkmoths engaged in planar yaw turns. Statistical models built from these data then allowed us to infer the degree to which the moths inhabit either damping- or inertia-dominated control domains. Contrary to our hypothesis, a combined model corresponding to inertia-dominated control of yaw but including substantial damping effects best linked the neuromuscular and kinematic data. This result shows the importance of including passive stability properties in neuromechanical models of flight control and reveals possible trade-offs between manoeuvrability and stability derived from damping. PMID- 22539745 TI - Vigorous SO4(2-) influx via the gills is balanced by enhanced SO4(2-) excretion by the kidney in eels after seawater adaptation. AB - Sulfate (SO(4)(2-)) is maintained at ~1 mmol(-1) l(-1) in teleost fishes that are exposed to media of varying SO(4)(2-) concentrations. We first measured plasma SO(4)(2-) concentration in euryhaline fishes that adapt to both SO(4)(2-)-poor freshwater (<0.5 mmol l) and SO(4)(2-)-enriched seawater (30 mmol l(-1)). Unlike Mozambique tilapia and chum salmon, Japanese eels maintained higher plasma SO(4)(2-) concentration in freshwater (6.2+/-2.3 mmol l(-1)) than in seawater (0.7+/-0.1 mmol l(-1)). We then analyzed the whole-body SO(4)(2-) budget using (35)SO(4)(2-). (35)SO(4)(2-) influx in seawater-adapted eels occurred by 84.5% via body surfaces and 15.5% via digestive tracts. The SO(4)(2-) influx was higher in seawater eels (1.55 MUmol kg(-1) h(-1)) than in freshwater eels (0.09 MUmol kg(-1) min(-1)), but it was facilitated in freshwater eels when the difference in SO(4)(2-) concentrations between plasma and environment was taken into account (freshwater eels, 6.2 vs 0.3 mmol l(-1); seawater eels, 0.7 vs 30 mmol l(-1)). One hour after injection of (35)SO(4)(2-) into the blood of seawater eels, the kidney excreted ~97% of the ionized form, whereas the radioactivity increased gradually in the medium and the rectal fluid more than 3 h after injection. As the radioactivity was poorly adsorbed by anion-exchange resin, (35)SO(4)(2-) in the blood may be incorporated into cells and excreted by the intestine, gills and skin, probably as mucus. These results show that freshwater eels take up SO(4)(2 ) actively from the environment, but seawater eels cope with the obligatory influx of SO(4)(2-) through the gills by excreting excess SO(4)(2-) via the kidney and in mucus. PMID- 22539747 TI - Efficacy of a remote based computerised visual acuity measurement. AB - AIM: To determine the efficacy of a remotely operated computer-based logarithmic (logMAR) visual acuity chart. METHODS: Visual acuity was tested using a laptop or computer-based logMAR chart (COMPlog) for all subjects by two different methods. The methods differed by the physical presence and absence (remote) of an optometrist and in the mode of instructions provided. Remote access was obtained through the internet, using Teamviewer software to control the system linked to COMPlog and instructions were provided by telephone. The order of measurements and the eye to be tested was randomised. logMAR visual acuity and time taken were recorded. A questionnaire was used to assess the participant's feedback. RESULTS: Intraclass correlation for visual acuity between the two methods (alpha=0.964, 95% CI 0.937 to 0.979). There was no statistically significant difference (p=0.648) in the median visual acuity measurement between the two methods (median difference 0.00, IQR 0.20 logMAR). The time taken between the two methods was not statistically significant (p=0.457). There was no significant difference in the responses to the questionnaire between the study methods (p=0.119). CONCLUSIONS: Tele (remotely controlled) visual acuity measurement is as reliable as that measured with the physical presence of an optometrist. PMID- 22539748 TI - Actions of bevacizumab and ranibizumab on microvascular retinal endothelial cells: similarities and differences. AB - BACKGROUND: Retinal endothelial cells are crucially involved in the genesis of diabetic retinopathy which is treated with vascular endothelial growth factor (VEGF) inhibitors. Of these, ranibizumab can completely restore VEGF-induced effects on immortalised bovine retinal endothelial cells (iBREC). In most experiments supporting diabetic retinopathy therapy with bevacizumab, only non retinal EC or retinal pigment epithelial cells have been used. Also, bevacizumab but not ranibizumab can accumulate in retinal pigment epithelial cells. OBJECTIVE: To investigate the effects of bevacizumab on VEGF-induced changes of iBREC properties and potential uptake and accumulation of both inhibitors. METHODS: Uptake of VEGF inhibitors by iBREC with or without pretreatment with VEGF(165) was visualised by immunofluorescence staining and western blot analyses. Measured transendothelial resistance (TER) of iBREC (+/-VEGF(165)) showed effects on permeability, indicated also by the western blot-determined tight junction protein claudin-1. The influence of bevacizumab on proliferation and migration of iBREC was studied in the presence and absence of VEGF(165). RESULTS: Bevacizumab strongly inhibited VEGF-stimulated and basal migration, but was less efficient than ranibizumab in inhibiting VEGF-induced proliferation or restoring the VEGF-induced decrease of TER and claudin-1. This ability was completely lost after storage of bevacizumab for 4 weeks at 4 degrees C. Ranibizumab and bevacizumab were detectable in whole cell extracts after treatment for at least 1 h; bevacizumab accumulated during prolonged treatment. Ranibizumab was found in the membrane/organelle fraction, whereas bevacizumab was associated with the cytoskeleton. CONCLUSION: Both inhibitors had similar effects on retinal endothelial cells; however, some differences were recognised. Although barrier properties were not affected by internalised bevacizumab in vitro, potential adverse effects due to accumulation after repetitive intravitreal injections remain to be investigated. PMID- 22539749 TI - Allogeneic serum eye drops: time these became the norm? PMID- 22539746 TI - mTOR inhibitors synergize on regression, reversal of gene expression, and autophagy in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) affects more than half a million people worldwide and is the third most common cause of cancer deaths. Because mammalian target of rapamycin (mTOR) signaling is up-regulated in 50% of HCCs, we compared the effects of the U.S. Food and Drug Administration-approved mTOR-allosteric inhibitor, RAD001, with a new-generation phosphatidylinositol 3-kinase/mTOR adenosine triphosphate-site competitive inhibitor, BEZ235. Unexpectedly, the two drugs acted synergistically in inhibiting the proliferation of cultured HCC cells. The synergistic effect closely paralleled eukaryotic initiation factor 4E binding protein 1 (4E-BP1) dephosphorylation, which is implicated in the suppression of tumor cell proliferation. In a mouse model approximating human HCC, the drugs in combination, but not singly, induced a marked regression in tumor burden. However, in the tumor, BEZ235 alone was as effective as the combination in inhibiting 4E-BP1 phosphorylation, which suggests that additional target(s) may also be involved. Microarray analyses revealed a large number of genes that reverted to normal liver tissue expression in mice treated with both drugs, but not either drug alone. These analyses also revealed the down regulation of autophagy genes in tumors compared to normal liver. Moreover, in HCC patients, altered expression of autophagy genes was associated with poor prognosis. Consistent with these findings, the drug combination had a profound effect on UNC51-like kinase 1 (ULK1) dephosphorylation and autophagy in culture, independent of 4E-BP1, and in parallel induced tumor mitophagy, a tumor suppressor process in liver. These observations have led to an investigator initiated phase 1B-2 dose escalation trial with RAD001 combined with BEZ235 in patients with HCC and other advanced solid tumors. PMID- 22539750 TI - Endothelial keratoplasty in children: surgical challenges and early outcomes. PMID- 22539751 TI - Enhancing the potential of cardiac progenitor cells: pushing forward with Pim-1. PMID- 22539752 TI - Platelets provide a bounty of potential targets for therapy in multiple sclerosis. PMID- 22539753 TI - Vascular Nox4: a multifarious NADPH oxidase. PMID- 22539754 TI - Noncoding RNA scaffolds in pluripotency. PMID- 22539755 TI - John Ross: epitome of a medical triple-threat. PMID- 22539757 TI - FOXOs and sirtuins in vascular growth, maintenance, and aging. AB - Blood vessels form the first organ in the developing embryo and build extensive networks that supply all cells with nutrients and oxygen throughout life. As blood vessels get older, they often become abnormal in structure and function, thereby contributing to numerous age-associated diseases including ischemic heart and brain disease, neurodegeneration, or cancer. First described as regulators of the aging process in invertebrate model organisms, Forkhead box "O" (FOXO) transcription factors and sirtuin deacetylases are now emerging as key regulators of mammalian vascular development and disease. The integration of individual FOXO and sirtuin family members into various aspects of vessel growth, maintenance, and function provides new perspectives on disease mechanisms of aging, the most important risk factor for medical maladies of the vascular system. PMID- 22539756 TI - Telomeres and mitochondria in the aging heart. AB - Studies in humans and in mice have highlighted the importance of short telomeres and impaired mitochondrial function in driving age-related functional decline in the heart. Although telomere and mitochondrial dysfunction have been viewed mainly in isolation, recent studies in telomerase-deficient mice have provided evidence for an intimate link between these two processes. Telomere dysfunction induces a profound p53-dependent repression of the master regulators of mitochondrial biogenesis and function, peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha and PGC-1beta in the heart, which leads to bioenergetic compromise due to impaired oxidative phosphorylation and ATP generation. This telomere-p53-PGC mitochondrial/metabolic axis integrates many factors linked to heart aging including increased DNA damage, p53 activation, mitochondrial, and metabolic dysfunction and provides a molecular basis of how dysfunctional telomeres can compromise cardiomyocytes and stem cell compartments in the heart to precipitate cardiac aging. PMID- 22539759 TI - Macrophage subsets in human atherosclerosis. PMID- 22539758 TI - Effects of aging on angiogenesis. AB - Aging is a dominant risk factor for most forms of cardiovascular disease. Impaired angiogenesis and endothelial dysfunction likely contribute to the increased prevalence of both cardiovascular diseases and their adverse sequelae in the elderly. Angiogenesis is both an essential adaptive response to physiological stress and an endogenous repair mechanism after ischemic injury. In addition, induction of angiogenesis is a promising therapeutic approach for ischemic diseases. For these reasons, understanding the basis of age-related impairment of angiogenesis and endothelial function has important implications for understanding and managing cardiovascular disease. In this review, we discuss the molecular mechanisms that contribute to impaired angiogenesis in the elderly and potential therapeutic approaches to improving vascular function and angiogenesis in aging patients. PMID- 22539760 TI - Finding the real culprit between circadian rhythm and "out of hours effect" to explain the higher myocardial infarction size among patients with symptom onset occurring at night. PMID- 22539765 TI - MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes. AB - RATIONALE: Repopulation of the injured heart with new, functional cardiomyocytes remains a daunting challenge for cardiac regenerative medicine. An ideal therapeutic approach would involve an effective method at achieving direct conversion of injured areas to functional tissue in situ. OBJECTIVE: The aim of this study was to develop a strategy that identified and evaluated the potential of specific micro (mi)RNAs capable of inducing reprogramming of cardiac fibroblasts directly to cardiomyocytes in vitro and in vivo. METHODS AND RESULTS: Using a combinatorial strategy, we identified a combination of miRNAs 1, 133, 208, and 499 capable of inducing direct cellular reprogramming of fibroblasts to cardiomyocyte-like cells in vitro. Detailed studies of the reprogrammed cells demonstrated that a single transient transfection of the miRNAs can direct a switch in cell fate as documented by expression of mature cardiomyocyte markers, sarcomeric organization, and exhibition of spontaneous calcium flux characteristic of a cardiomyocyte-like phenotype. Interestingly, we also found that miRNA-mediated reprogramming was enhanced 10-fold on JAK inhibitor I treatment. Importantly, administration of miRNAs into ischemic mouse myocardium resulted in evidence of direct conversion of cardiac fibroblasts to cardiomyocytes in situ. Genetic tracing analysis using Fsp1Cre-traced fibroblasts from both cardiac and noncardiac cell sources strongly suggests that induced cells are most likely of fibroblastic origin. CONCLUSIONS: The findings from this study provide proof-of-concept that miRNAs have the capability of directly converting fibroblasts to a cardiomyocyte-like phenotype in vitro. Also of significance is that this is the first report of direct cardiac reprogramming in vivo. Our approach may have broad and important implications for therapeutic tissue regeneration in general. PMID- 22539767 TI - Transient exposure of neonatal female mice to testosterone abrogates the sexual dimorphism of abdominal aortic aneurysms. AB - RATIONALE: Abdominal aortic aneurysms (AAAs) exhibit marked sexual dimorphism with higher prevalence in men. Similarly, AAAs induced by angiotensin II (AngII) infusion into mice exhibit a higher prevalence in males. Testosterone promotes AAA pathology in adult male mice through regulation of angiotensin type 1A receptors (AT1aR) in abdominal aortas. However, mechanisms for sexual dimorphism of regional aortic angiotensin receptor expression and AAA formation are unknown. OBJECTIVE: To define the role of developmental testosterone exposures in sexual dimorphism of AAAs, we determined if exposure of neonatal female mice to testosterone confers adult susceptibility to AngII-induced AAAs. METHODS AND RESULTS: One-day-old female hypercholesterolemic mice were administered a single dose of either vehicle or testosterone. Neonatal testosterone administration increased abdominal aortic AT1aR mRNA abundance and promoted a striking increase in AngII-induced AAAs in adult females exhibiting low serum testosterone concentrations. AngII-induced atherosclerosis and ascending aortic aneurysms were also increased by testosterone administration to neonatal females. In contrast, neonatal testosterone administration in males had no effect on AngII-induced vascular pathologies. Deficiency of AT1aR in smooth muscle cells reduced effects of neonatal testosterone to promote AAAs in adult females but did not alter atherosclerosis or ascending aortic aneurysms. Testosterone increased AT1aR mRNA abundance and hydrogen peroxide generation in cultured abdominal aortic SMCs. Increased AT1aR mRNA abundance was maintained during progressive passaging of female smooth muscle cells. CONCLUSIONS: These data reveal an unrecognized role of transient sex hormone exposures during neonatal development as long-lasting mediators of regional aortic AT1aR expression and sexual dimorphism of AAAs. PMID- 22539766 TI - Role of RhoB in the regulation of pulmonary endothelial and smooth muscle cell responses to hypoxia. AB - RATIONALE: RhoA and Rho kinase contribute to pulmonary vasoconstriction and vascular remodeling in pulmonary hypertension. RhoB, a protein homologous to RhoA and activated by hypoxia, regulates neoplastic growth and vasoconstriction but its role in the regulation of pulmonary vascular function is not known. OBJECTIVE: To determine the role of RhoB in pulmonary endothelial and smooth muscle cell responses to hypoxia and in pulmonary vascular remodeling in chronic hypoxia-induced pulmonary hypertension. METHODS AND RESULTS: Hypoxia increased expression and activity of RhoB in human pulmonary artery endothelial and smooth muscle cells, coincidental with activation of RhoA. Hypoxia or adenoviral overexpression of constitutively activated RhoB increased actomyosin contractility, induced endothelial permeability, and promoted cell growth; dominant negative RhoB or manumycin, a farnesyltransferase inhibitor that targets the vascular function of RhoB, inhibited the effects of hypoxia. Coordinated activation of RhoA and RhoB maximized the hypoxia-induced stress fiber formation caused by RhoB/mammalian homolog of Drosophila diaphanous-induced actin polymerization and RhoA/Rho kinase-induced phosphorylation of myosin light chain on Ser19. Notably, RhoB was specifically required for hypoxia-induced factor 1alpha stabilization and for hypoxia- and platelet-derived growth factor-induced cell proliferation and migration. RhoB deficiency in mice markedly attenuated development of chronic hypoxia-induced pulmonary hypertension, despite compensatory expression of RhoA in the lung. CONCLUSIONS: RhoB mediates adaptational changes to acute hypoxia in the vasculature, but its continual activation by chronic hypoxia can accentuate vascular remodeling to promote development of pulmonary hypertension. RhoB is a potential target for novel approaches (eg, farnesyltransferase inhibitors) aimed at regulating pulmonary vascular tone and structure. PMID- 22539769 TI - Thoroughly modern risk prediction? AB - Researchers use a data-driven technique called statistical learning to fashion risk prediction algorithms for clinical situations with low event rates. PMID- 22539768 TI - Local beta-adrenergic stimulation overcomes source-sink mismatch to generate focal arrhythmia. AB - RATIONALE: beta-Adrenergic receptor stimulation produces sarcoplasmic reticulum Ca(2+) overload and delayed afterdepolarizations in isolated ventricular myocytes. How delayed afterdepolarizations are synchronized to overcome the source-sink mismatch and produce focal arrhythmia in the intact heart remains unknown. OBJECTIVE: To determine whether local beta-adrenergic receptor stimulation produces spatiotemporal synchronization of delayed afterdepolarizations and to examine the effects of tissue geometry and cell-cell coupling on the induction of focal arrhythmia. METHODS AND RESULTS: Simultaneous optical mapping of transmembrane potential and Ca(2+) transients was performed in normal rabbit hearts during subepicardial injections (50 MUL) of norepinephrine (NE) or control (normal Tyrode's solution). Local NE produced premature ventricular complexes (PVCs) from the injection site that were dose-dependent (low-dose [30-60 MUmol/L], 0.45+/-0.62 PVCs per injection; high-dose [125-250 MUmol/L], 1.33+/-1.46 PVCs per injection; P<0.0001) and were inhibited by propranolol. NE-induced PVCs exhibited abnormal voltage-Ca(2+) delay at the initiation site and were inhibited by either sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase inhibition or reduced perfusate [Ca(2+)], which indicates a Ca(2+) mediated mechanism. NE-induced PVCs were more common at right ventricular than at left ventricular sites (1.48+/-1.50 versus 0.55+/-0.89, P<0.01), and this was unchanged after chemical ablation of endocardial Purkinje fibers, which suggests that source-sink interactions may contribute to the greater propensity to right ventricular PVCs. Partial gap junction uncoupling with carbenoxolone (25 MUmol/L) increased focal activity (2.18+/-1.43 versus 1.33+/-1.46 PVCs per injection, P<0.05), which further supports source-sink balance as a critical mediator of Ca(2+)-induced PVCs. CONCLUSIONS: These data provide the first experimental demonstration that localized beta-adrenergic receptor stimulation produces spatiotemporal synchronization of sarcoplasmic reticulum Ca(2+) overload and release in the intact heart and highlight the critical nature of source-sink balance in initiating focal arrhythmias. PMID- 22539770 TI - Tweaking the social network. AB - Paving the way for clinical trials, a new study shows that a glutamate receptor antagonist reduces repetitive behavior and social deficits in a mouse model of autism spectrum disorder. PMID- 22539771 TI - Comment on "a peptidomimetic targeting white fat causes weight loss and improved insulin resistance in obese monkeys". AB - A study reporting that a peptidomimetic adipotide reduces weight loss in obese monkeys by inducing apoptosis of blood vessels surrounding white adipose tissue may instead reflect a direct effect of adipotide on food consumption. PMID- 22539773 TI - Looking beyond historical patient outcomes to improve clinical models. AB - Conventional algorithms for modeling clinical events focus on characterizing the differences between patients with varying outcomes in historical data sets used for the model derivation. For many clinical conditions with low prevalence and where small data sets are available, this approach to developing models is challenging due to the limited number of positive (that is, event) examples available for model training. Here, we investigate how the approach of developing clinical models might be improved across three distinct patient populations (patients with acute coronary syndrome enrolled in the DISPERSE2-TIMI33 and MERLIN-TIMI36 trials, patients undergoing inpatient surgery in the National Surgical Quality Improvement Program registry, and patients undergoing percutaneous coronary intervention in the Blue Cross Blue Shield of Michigan Cardiovascular Consortium registry). For each of these cases, we supplement an incomplete characterization of patient outcomes in the derivation data set (uncensored view of the data) with an additional characterization of the extent to which patients differ from the statistical support of their clinical characteristics (censored view of the data). Our approach exploits the same training data within the derivation cohort in multiple ways to improve the accuracy of prediction. We position this approach within the context of traditional supervised (2-class) and unsupervised (1-class) learning methods and present a 1.5-class approach for clinical decision-making. We describe a 1.5 class support vector machine (SVM) classification algorithm that implements this approach, and report on its performance relative to logistic regression and 2 class SVM classification with cost-sensitive weighting and oversampling. The 1.5 class SVM algorithm improved prediction accuracy relative to other approaches and may have value in predicting clinical events both at the bedside and for risk adjusted quality of care assessment. PMID- 22539774 TI - Suppression of phosphoinositide 3-kinase signaling and alteration of multiple ion currents in drug-induced long QT syndrome. AB - Many drugs, including some commonly used medications, can cause abnormal heart rhythms and sudden death, as manifest by a prolonged QT interval in the electrocardiogram. Cardiac arrhythmias caused by drug-induced long QT syndrome are thought to result mainly from reductions in the delayed rectifier potassium ion (K(+)) current I(Kr). Here, we report a mechanism for drug-induced QT prolongation that involves changes in multiple ion currents caused by a decrease in phosphoinositide 3-kinase (PI3K) signaling. Treatment of canine cardiac myocytes with inhibitors of tyrosine kinases or PI3Ks caused an increase in action potential duration that was reversed by intracellular infusion of phosphatidylinositol 3,4,5-trisphosphate. The inhibitors decreased the delayed rectifier K(+) currents I(Kr) and I(Ks), the L-type calcium ion (Ca(2+)) current I(Ca,L), and the peak sodium ion (Na(+)) current I(Na) and increased the persistent Na(+) current I(NaP). Computer modeling of the canine ventricular action potential showed that the drug-induced change in any one current accounted for less than 50% of the increase in action potential duration. Mouse hearts lacking the PI3K p110alpha catalytic subunit exhibited a prolonged action potential and QT interval that were at least partly a result of an increase in I(NaP). These results indicate that down-regulation of PI3K signaling directly or indirectly via tyrosine kinase inhibition prolongs the QT interval by affecting multiple ion channels. This mechanism may explain why some tyrosine kinase inhibitors in clinical use are associated with increased risk of life-threatening arrhythmias. PMID- 22539776 TI - Neural basis of autobiographical memory retrieval in schizophrenia. AB - BACKGROUND: Autobiographical memory retrieval is impaired in schizophrenia. AIMS: To determine the neural basis of this impairment. METHOD: Thirteen patients with schizophrenia and 14 healthy controls performed an autobiographical memory retrieval task based on cue words during functional magnetic resonance imaging. Patients were selected on the basis of their ability to perform the task and all participants received training. RESULTS: Although patients and controls activated a similar brain network during autobiographical memory retrieval, patients displayed decreased activation in several of these regions, including the anterior cingulate cortex, left lateral prefrontal cortex, right cerebellum and ventral tegmental area (k>=10, P<0.001, uncorrected). In addition, activation of the caudate nuclei was negatively correlated with retrieval performance in controls but positively correlated with performance in patients. CONCLUSIONS: The autobiographical memory retrieval brain network is impaired in schizophrenia. Patients with schizophrenia display decreased activation of the cognitive control network during retrieval, possibly due to aberrant functioning of the dorsal striatum. PMID- 22539777 TI - Brain structure and joint hypermobility: relevance to the expression of psychiatric symptoms. AB - Joint hypermobility is overrepresented among people with anxiety and can be associated with abnormal autonomic reactivity. We tested for associations between regional cerebral grey matter and hypermobility in 72 healthy volunteers using voxel-based morphometry of structural brain scans. Strikingly, bilateral amygdala volume distinguished those with from those without hypermobility. The hypermobility group scored higher for interoceptive sensitivity yet were not significantly more anxious. Our findings specifically link hypermobility to the structural integrity of a brain centre implicated in normal and abnormal emotions and physiological responses. Our observations endorse hypermobility as a multisystem phenotype and suggest potential mechanisms mediating clinical vulnerability to neuropsychiatric symptoms. PMID- 22539775 TI - Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism. AB - Neurodevelopmental disorders such as autism and fragile X syndrome were long thought to be medically untreatable, on the assumption that brain dysfunctions were immutably hardwired before diagnosis. Recent revelations that many cases of autism are caused by mutations in genes that control the ongoing formation and maturation of synapses have challenged this dogma. Antagonists of metabotropic glutamate receptor subtype 5 (mGluR5), which modulate excitatory neurotransmission, are in clinical trials for fragile X syndrome, a major genetic cause of intellectual disabilities. About 30% of patients with fragile X syndrome meet the diagnostic criteria for autism. Reasoning by analogy, we considered the mGluR5 receptor as a potential target for intervention in autism. We used BTBR T+tf/J (BTBR) mice, an established model with robust behavioral phenotypes relevant to the three diagnostic behavioral symptoms of autism--unusual social interactions, impaired communication, and repetitive behaviors--to probe the efficacy of a selective negative allosteric modulator of the mGluR5 receptor, GRN 529. GRN-529 reduced repetitive behaviors in three cohorts of BTBR mice at doses that did not induce sedation in control assays of open field locomotion. In addition, the same nonsedating doses reduced the spontaneous stereotyped jumping that characterizes a second inbred strain of mice, C58/J. Further, GRN-529 partially reversed the striking lack of sociability in BTBR mice on some parameters of social approach and reciprocal social interactions. These findings raise the possibility that a single targeted pharmacological intervention may alleviate multiple diagnostic behavioral symptoms of autism. PMID- 22539778 TI - Effects of home on the mental health of British forces serving in Iraq and Afghanistan. AB - BACKGROUND: Most studies of the mental health of UK armed forces focus on retrospective accounts of deployment and few sample personnel while they are deployed. AIMS: This study reports the results of a survey of deployed personnel, examining the perceived impact of events at home and military support for the family on current mental health during the deployment. METHOD: Surveys were conducted with 2042 British forces personnel serving in Iraq and Afghanistan. Prevalence of common mental disorders was assessed with the 12-item General Health Questionnaire (GHQ-12) and post-traumatic stress disorder (PTSD) was assessed with the PTSD Checklist - Civilian version (PCL-C). RESULTS: The prevalence of common mental disorders was 17.8% and of probable PTSD was 2.8%. Perceived home difficulties significantly influenced the mental health of deployed personnel; the greater the perception of negative events in the home environment, the greater the reporting of adverse mental health effects. This finding was independent of combat exposure and was only partially mitigated by being well led and reporting subjectively good unit cohesion; however, the effect of the totality of home-front events was not improved by the latter. Poor perceived military support for the family had a detrimental impact on deployment mental health. CONCLUSIONS: The armed forces offer many support services to the partners and families of deployed personnel and ensuring that the efforts being made on their behalf are well communicated might improve the mental health of deployed personnel. PMID- 22539780 TI - Cognitive-behavioural group treatment for a range of functional somatic syndromes: randomised trial. AB - BACKGROUND: Many specialty-specific functional somatic syndrome diagnoses exist to describe people who are experiencing so-called medically unexplained symptoms. Although cognitive-behavioural therapy can be effective in the management of such syndromes, it is rarely available. A cognitive-behavioural therapy suitable for group treatment of people with different functional somatic syndromes could address this problem. AIMS: To test the efficacy of a cognitive-behavioural therapy (Specialised Treatment for Severe Bodily Distress Syndromes, STreSS) designed for patients with a range of severe functional somatic syndromes. METHOD: A randomised controlled trial (clinicaltrials.gov, NCT00132197) compared STreSS (nine 3.5 h sessions over 4 months, n = 54) with enhanced usual care (management by primary care physician or medical specialist, n = 66). The primary outcome was improvement in aggregate score on subscales of the 36-item Short Form Health Survey (physical functioning, bodily pain and vitality) at 16 months. RESULTS: Participants receiving STreSS had a greater improvement on the primary outcome (adjusted mean difference 4.0, 95% CI 1.4-6.6, P = 0.002) and on most secondary outcomes. CONCLUSIONS: In the management of functional somatic syndromes, a cognitive-behavioural group treatment was more effective than enhanced usual care. PMID- 22539779 TI - Role of common mental and physical disorders in partial disability around the world. AB - BACKGROUND: Mental and physical disorders are associated with total disability, but their effects on days with partial disability (i.e. the ability to perform some, but not full-role, functioning in daily life) are not well understood. AIMS: To estimate individual (i.e. the consequences for an individual with a disorder) and societal effects (i.e. the avoidable partial disability in the society due to disorders) of mental and physical disorders on days with partial disability around the world. METHOD: Respondents from 26 nationally representative samples (n = 61 259, age 18+) were interviewed regarding mental and physical disorders, and day-to-day functioning. The Composite International Diagnostic Interview, version 3.0 (CIDI 3.0) was used to assess mental disorders; partial disability (expressed in full day equivalents) was assessed with the World Health Organization Disability Assessment Schedule in the CIDI 3.0. RESULTS: Respondents with disorders reported about 1.58 additional disability days per month compared with respondents without disorders. At the individual level, mental disorders (especially post-traumatic stress disorder, depression and bipolar disorder) yielded a higher number of days with disability than physical disorders. At the societal level, the population attributable risk proportion due to physical and mental disorders was 49% and 15% respectively. CONCLUSIONS: Mental and physical disorders have a considerable impact on partial disability, at both the individual and at the societal level. Physical disorders yielded higher effects on partial disability than mental disorders. PMID- 22539781 TI - Effects of emotion perception training on mood in undergraduate students: randomised controlled trial. AB - We investigated the effects of emotion perception training on depressive symptoms and mood in young adults reporting high levels of depressive symptoms (trial registration: ISRCTN02532638). Participants were randomised to an intervention procedure designed to increase the perception of happiness over sadness in ambiguous facial expressions or a control procedure, and completed self-report measures of depressive symptoms and mood. Those in the intervention condition had lower depressive symptoms and negative mood at 2-week follow-up, but there was no statistical evidence for a difference. There was some evidence for increased positive mood. Modification of emotional perception may lead to an increase in positive affect. PMID- 22539782 TI - Deja vu all over again. PMID- 22539783 TI - Lipids and lipoproteins and risk of different vascular events in the MRC/BHF Heart Protection Study. AB - BACKGROUND: Low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol are established risk factors for vascular disease, but lipoprotein particle concentrations may be stronger determinants of risk. METHODS AND RESULTS: Associations between vascular events and baseline concentrations of cholesterol fractions, apolipoproteins B and A(1), and lipoprotein particles assessed by nuclear magnetic resonance were considered in the Heart Protection Study randomized trial of simvastatin versus placebo (>5000 vascular events during 5.3 years of follow-up among 20 000 participants). Major occlusive coronary events were equally strongly associated with the cholesterol- and particle-based total LDL measures; adjusted hazard ratios per 1-SD-higher level were 1.25 (95% confidence interval [CI], 1.16-1.34) for LDL cholesterol, 1.22 (95% CI, 1.14-1.32) for non-HDL cholesterol, 1.23 (95% CI, 1.15-1.33) for apolipoprotein B, and 1.25 (95% CI, 1.16-1.35) for LDL particle number. Given the total LDL particle number, the distribution between small and large particles did not add predictive value. Associations of these different LDL-related measures were similar with arterial revascularization procedures but much weaker or nonexistent with ischemic stroke and other cardiac events (mainly heart failure). After adjustment for LDL particle number, the hazard ratios for major occlusive coronary event per 1-SD-higher level were 0.91 (95% CI, 0.86-0.96) for HDL cholesterol and 0.89 (95% CI, 0.85-0.93) for HDL particle number. Other cardiac events were inversely associated with total (hazard ratio, 0.84; 95% CI, 0.79 0.90) and small (0.82; 95% CI, 0.76-0.89) HDL particle number but only very weakly associated with HDL cholesterol (0.94; 95% CI, 0.88-1.00). CONCLUSIONS: In a population at 2% average coronary event risk per year, cholesterol, apolipoprotein, and particle measures of LDL were strongly correlated and had similar predictive values for incident major occlusive vascular events. It is unclear whether the associations between HDL particle numbers and other cardiac events represent a causal or reverse-causal effect. PMID- 22539784 TI - Kinetics and activation requirements of contact-dependent immune suppression by human regulatory T cells. AB - Naturally occurring regulatory T cells (Tregs) maintain self tolerance by dominant suppression of potentially self-reactive T cells in peripheral tissues. However, the activation requirements, the temporal aspects of the suppressive activity, and mode of action of human Tregs are subjects of controversy. In this study, we show that Tregs display significant variability in the suppressive activity ex vivo as 54% of healthy blood donors examined had fully suppressive Tregs spontaneously, whereas in the remaining donors, anti-CD3/CD2/CD28 stimulation was required for Treg suppressive activity. Furthermore, anti CD3/CD2/CD28 stimulation for 6 h and subsequent fixation in paraformaldehyde rendered the Tregs fully suppressive in all donors. The fixation-resistant suppressive activity of Tregs operated in a contact-dependent manner that was not dependent on APCs, but could be fully obliterated by trypsin treatment, indicating that a cell surface protein is directly involved. By add-back of active, fixed Tregs at different time points after activation of responding T cells, the responder cells were susceptible to Treg-mediated immune suppression up to 24 h after stimulation. This defines a time window in which effector T cells are susceptible to Treg-mediated immune suppression. Lastly, we examined the effect of a set of signaling inhibitors that perturb effector T cell activation and found that none of the examined inhibitors affected Treg activation, indicating pathway redundancy or that Treg activation proceeds by signaling mechanisms distinct from those of effector T cells. PMID- 22539785 TI - PTPN22 alters the development of regulatory T cells in the thymus. AB - PTPN22 encodes a tyrosine phosphatase that inhibits Src-family kinases responsible for Ag receptor signaling in lymphocytes and is strongly linked with susceptibility to a number of autoimmune diseases. As strength of TCR signal is critical to the thymic selection of regulatory T cells (Tregs), we examined the effect of murine PTPN22 deficiency on Treg development and function. In the thymus, numbers of pre-Tregs and Tregs increased inversely with the level of PTPN22. This increase in Tregs persisted in the periphery and could play a key part in the reduced severity observed in the PTPN22-deficient mice of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. This could explain the lack of association of certain autoimmune conditions with PTPN22 risk alleles. PMID- 22539786 TI - Tripartite motif-containing protein 38 negatively regulates TLR3/4- and RIG-I mediated IFN-beta production and antiviral response by targeting NAP1. AB - Recognition of RNA virus through TLR and RIG-I-like receptor results in rapid expression of type I IFNs, which play an essential role in host antiviral responses. However, the mechanisms to terminate the production of type I IFNs are not well defined. In the current study, we identified a member of the tripartite motif (TRIM) family, TRIM38, as a negative regulator in TLR3/4- and RIG-I mediated IFN-beta signaling. Knockdown of TRIM38 expression by small interfering RNA resulted in augmented activation of IFN regulatory factor 3 and enhanced expression of IFN-beta, whereas overexpression of TRIM38 had opposite effects. Coimmunoprecipitation and colocalization experiments demonstrated that TRIM38 interacted with NF-kappaB-activating kinase-associated protein 1 (NAP1), which is required for TLR-induced IFN regulatory factor 3 activation and IFN-beta production. As an E3 ligase, TRIM38 promoted K48-linked polyubiquitination and proteasomal degradation of NAP1. Thus, knockdown of TRIM38 expression resulted in higher protein level of NAP1 in primary macrophages. Consistent with the inhibitory roles in TLR3/4- and RIG-I-mediated IFN-beta signaling, knockdown of TRIM38 significantly inhibited the replication of vesicular stomatitis virus. Overexpression of TRIM38 resulted in enhanced replication of vesicular stomatitis virus. Therefore, our results demonstrate that TRIM38 is a negative regulator for TLR and RIG-I-mediated IFN-beta production by targeting NAP1 for ubiquitination and subsequent proteasome-mediated degradation. PMID- 22539787 TI - Fyn promotes Th17 differentiation by regulating the kinetics of RORgammat and Foxp3 expression. AB - Th17 cells constitute a proinflammatory CD4(+) T cell subset that is important for microbial clearance, but also are implicated as propagators of various autoimmune pathologies. Evidence suggests that Th17 cells share common progenitors with immunosuppressive CD4(+) inducible regulatory T cells (T(REG)) and that the developmental pathways of these two subsets are reciprocally regulated. In this study, we show evidence that the Src family tyrosine kinase Fyn helps regulate this Th17/T(REG) balance. When placed under Th17-skewing conditions, CD4(+) T cells from fyn(-/-) mice had decreased levels of IL-17, but increased expression of the T(REG) transcription factor Foxp3. The defect in IL 17 expression occurred independently of the ectopic Foxp3 expression and correlated with a delay in retinoic acid-related orphan receptor gammat upregulation and an inability to maintain normal STAT3 activation. Fyn-deficient Th17 cells also exhibited delayed upregulation of Il23r, Il21, Rora, and Irf4, as well as aberrant expression of Socs3, suggesting that Fyn may function upstream of a variety of molecular pathways that contribute to Th17 polarization. The fyn( /-) mice had fewer IL-17(+)CD4(+) T cells in the large intestinal lamina propria compared with littermate controls. Furthermore, after transfer of either wild type or fyn(-/-) naive CD4(+) T cells into Rag1(-/-) hosts, recipients receiving fyn(-/-) cells had fewer IL-17-producing T cells, indicating that Fyn may also regulate Th17 differentiation in vivo. These results identify Fyn as a possible novel regulator of the developmental balance between the Th17 cell and T(REG) subsets. PMID- 22539788 TI - Dendritic cell-specific ablation of the protein tyrosine phosphatase Shp1 promotes Th1 cell differentiation and induces autoimmunity. AB - Dendritic cells (DCs) promote immune responses to foreign Ags and immune tolerance to self-Ags. Deregulation of DCs is implicated in autoimmunity, but the molecules that regulate DCs to protect against autoimmunity have remained unknown. In this study, we show that mice lacking the protein tyrosine phosphatase Shp1 specifically in DCs develop splenomegaly associated with more CD11c(+) DCs. Splenic DCs from the mutant mice showed upregulation of CD86 and CCR7 expression and of LPS-induced production of proinflammatory cytokines. The mice manifested more splenic Th1 cells, consistent with the increased ability of their DCs to induce production of IFN-gamma by Ag-specific T cells in vitro. The number of splenic CD5(+)CD19(+) B-1a cells and the serum concentrations of Igs M and G2a were also increased in the mutant mice. Moreover, aged mutant mice developed glomerulonephritis and interstitial pneumonitis together with increased serum concentrations of autoantibodies. Shp1 is thus a key regulator of DC functions that protects against autoimmunity. PMID- 22539789 TI - ATP binding cassette transporter G1 deletion induces IL-17-dependent dysregulation of pulmonary adaptive immunity. AB - Mice with genetic deletion of the cholesterol transporter ATP binding cassette G1 (ABCG1) have pulmonary lipidosis and enhanced innate immune responses in the airway. Whether ABCG1 regulates adaptive immune responses to the environment is unknown. To this end, Abcg1(+/+) and Abcg1(-/-) mice were sensitized to OVA via the airway using low-dose LPS as an adjuvant, and then challenged with OVA aerosol. Naive Abcg1(-/-) mice displayed increased B cells, CD4(+) T cells, CD8(+) T cells, and dendritic cells (DCs) in lung and lung-draining mediastinal lymph nodes, with lung CD11b(+) DCs displaying increased CD80 and CD86. Upon allergen sensitization and challenge, the Abcg1(-/-) airway, compared with Abcg1(+/+), displayed reduced Th2 responses (IL-4, IL-5, eosinophils), increased neutrophils and IL-17, but equivalent airway hyperresponsiveness. Reduced Th2 responses were also found using standard i.p. OVA sensitization with aluminum hydroxide adjuvant. Mediastinal lymph nodes from airway-sensitized Abcg1(-/-) mice produced reduced IL-5 upon ex vivo OVA challenge. Abcg1(-/-) CD4(+) T cells displayed normal ex vivo differentiation, whereas Abcg1(-/-) DCs were found paradoxically to promote Th2 polarization. Th17 cells, IL-17(+) gammadeltaT cells, and IL-17(+) neutrophils were all increased in Abcg1(-/-) lungs, suggesting Th17 and non-Th17 sources of IL-17 excess. Neutralization of IL-17 prior to challenge normalized eosinophils and reduced neutrophilia in the Abcg1( /-) airway. We conclude that Abcg1(-/-) mice display IL-17-mediated suppression of eosinophilia and enhancement of neutrophilia in the airway following allergen sensitization and challenge. These findings identify ABCG1 as a novel integrator of cholesterol homeostasis and adaptive immune programs. PMID- 22539790 TI - Role of CD25+ dendritic cells in the generation of Th17 autoreactive T cells in autoimmune experimental uveitis. AB - In the current study, we showed that in vivo administration of an anti-CD25 Ab (PC61) decreased the Th17 response in C57BL/6 mice immunized with the uveitogenic peptide interphotoreceptor retinoid-binding protein, while enhancing the autoreactive Th1 response. The depressed Th17 response was closely associated with decreased numbers of a splenic dendritic cell (DC) subset expressing CD11c(+)CD3(-)CD25(+) and decreased expansion of gammadelta T cells. We demonstrated that ablation of the CD25(+) DC subset accounted for the decreased activation and the expansion of gammadelta T cells, leading to decreased activation of IL-17(+) interphotoreceptor retinoid-binding protein-specific T cells. Our results show that an enhanced Th17 response in an autoimmune disease is associated with the appearance of a DC subset expressing CD25 and that treatment of mice with anti-CD25 Ab causes functional alterations in a number of immune cell types, namely DCs and gammadelta T cells, in addition to CD25(+)alphabetaTCR(+) regulatory T cells. PMID- 22539791 TI - Complement C3a-induced IL-17 plays a critical role in an IgE-mediated late-phase asthmatic response and airway hyperresponsiveness via neutrophilic inflammation in mice. AB - Allergen-specific IgE plays an essential role in the pathogenesis of allergic asthma. Although there has been increasing evidence suggesting the involvement of IL-17 in the disease, the relationship between IL-17 and IgE-mediated asthmatic responses has not yet been defined. In this study, we attempted to elucidate the contribution of IL-17 to an IgE-mediated late-phase asthmatic response and airway hyperresponsiveness (AHR). BALB/c mice passively sensitized with an OVA-specific IgE mAb were challenged with OVA intratracheally four times. The fourth challenge caused a late-phase increase in airway resistance associated with elevated levels of IL-17(+)CD4(+) cells in the lungs. Multiple treatments with a C3a receptor antagonist or anti-C3a mAb during the challenges inhibited the increase in IL 17(+)CD4(+) cells. Meanwhile, a single treatment with the antagonist or the mAb at the fourth challenge suppressed the late-phase increase in airway resistance, AHR, and infiltration by neutrophils in bronchoalveolar lavage fluid. Because IL 17 production in the lungs was significantly repressed by both treatments, the effect of an anti-IL-17 mAb was examined. The late-phase increase in airway resistance, AHR, and infiltration by neutrophils in bronchoalveolar lavage fluid was inhibited. Furthermore, an anti-Gr-1 mAb had a similar effect. Collectively, we found that IgE mediated the increase of IL-17(+)CD4(+) cells in the lungs caused by repeated Ag challenges via C3a. The mechanisms leading to the IgE mediated late-phase asthmatic response and AHR are closely associated with neutrophilic inflammation through the production of IL-17 induced by C3a. PMID- 22539792 TI - Dendritic cells activated by IFN-gamma/STAT1 express IL-31 receptor and release proinflammatory mediators upon IL-31 treatment. AB - IL-31 is a T cell-derived cytokine that signals via a heterodimeric receptor composed of IL-31Ralpha and oncostatin M receptor beta. Although several studies have aimed to investigate IL-31-mediated effects, the biological functions of this cytokine are currently not well understood. IL-31 expression correlates with the expression of IL-4 and IL-13 and is associated with atopic dermatitis in humans, indicating that IL-31 is involved in Th2-mediated skin inflammation. Because dendritic cells are the main activators of Th cell responses, we posed the question of whether dendritic cells express the IL-31R complex and govern immune responses triggered by IL-31. In the current study, we report that primary human CD1c(+) as well as monocyte-derived dendritic cells significantly upregulate the IL-31Ralpha receptor chain upon stimulation with IFN-gamma. EMSAs, chromatin immunoprecipitation assays, and small interfering RNA-based silencing assays revealed that STAT1 is the main transcription factor involved in IFN-gamma dependent IL-31Ralpha expression. Subsequent IL-31 stimulation resulted in a dose dependent release of proinflammatory mediators, including TNF-alpha, IL-6, CXCL8, CCL2, CCL5, and CCL22. Because these cytokines are crucially involved in skin inflammation, we hypothesize that IL-31-specific activation of dendritic cells may be part of a positive feedback loop driving the progression of inflammatory skin diseases. PMID- 22539793 TI - Human Th17 cells express high levels of enzymatically active dipeptidylpeptidase IV (CD26). AB - Dipeptidylpeptidase IV (CD26) is a multifunctional ectoenzyme involved in T cell activation that has been implicated in autoimmune pathophysiology. Because IL-17 producing CD4(+) T cells (Th17 cells) are important mediators of autoimmune disease, we analyzed the expression of CD26 and its enzymatic function on human Th17 cells. Analysis of CD26 expression on different CD4(+) T helper subsets showed that CD26 expression is highest on CD4(+) T cells producing type 17 cytokines (e.g., IL-22, IL-17, GM-CSF, or TNF) compared with Th1, Th2, and regulatory T cells. Phenotypic analysis revealed that CD26(++)CD4(+) T cells express the type 17 differentiation molecules CD161, CCR6, lL-23R, and retinoic acid-related orphan receptor-gammat. Furthermore, sorted CD26(++)CD4(+) T cells contain >90-98% of Th17 cells, indicating that CD26(++) T cells harbor the Th17 lineage. A comparison with CD161 and CCR6 indicated that analysis of CD26 coexpression may improve the phenotypic characterization of Th17 cells. Of note, CD26(++) Th17 cells are enriched in the inflamed tissue of patients with hepatitis and inflammatory bowel disease. Functional analysis in migration assays revealed that CD26 expressed on Th17 cells is enzymatically active. Indeed, CD26 negatively regulates the chemotactic CD4(+) T cell response to the inflammatory chemokines CXCL9-12 that can be restored by pharmacological blockade of the enzymatic center of CD26. In summary, these results strongly suggest that CD26 may contribute to the orchestration of the immune response by Th17 cells in human inflammatory diseases. They also suggest that the phenotypic analysis of Th17 cells may be facilitated by determination of CD26 expression. PMID- 22539796 TI - Regulation of cytosolic phospholipase A2 phosphorylation by proteolytic cleavage of annexin A1 in activated mast cells. AB - Annexin A1 (ANXA1) is cleaved at the N terminal in some activated cells, such as macrophages, neutrophils, and epithelial cells. We previously observed that ANXA1 was proteolytically cleaved in lung extracts prepared from a murine OVA-induced asthma model. However, the cleavage and regulatory mechanisms of ANXA1 in the allergic response remain unclear. In this study, we found that ANXA1 was cleaved in both Ag-induced activated rat basophilic leukemia 2H3 (RBL-2H3) cells and bone marrow-derived mast cells. This cleavage event was inhibited when intracellular Ca(2+) signaling was blocked. ANXA1-knockdown RBL-2H3 cells produced a greater amount of eicosanoids with simultaneous upregulation of cytosolic phospholipase A(2) (cPLA(2)) activity. However, there were no changes in degranulation activity or cytokine production in the knockdown cells. We also found that cPLA(2) interacted with either full-length or cleaved ANXA1 in activated mast cells. cPLA(2) mainly interacted with full-length ANXA1 in the cytosol and cleaved ANXA1 in the membrane fraction. In addition, introduction of a cleavage-resistant ANXA1 mutant had inhibitory effects on both the phosphorylation of cPLA(2) and release of eicosanoids during the activation of RBL-2H3 cells and bone marrow-derived mast cells. These data suggest that cleavage of ANXA1 causes proinflammatory reactions by increasing the phosphorylation of cPLA(2) and production of eicosanoids during mast-cell activation. PMID- 22539794 TI - Protein kinase C-theta inhibits inducible regulatory T cell differentiation via an AKT-Foxo1/3a-dependent pathway. AB - Protein kinase C (PKC)-theta has been shown to be a critical TCR signaling molecule that promotes the activation and differentiation of naive T cells into inflammatory effector T cells. In this study, we demonstrate that PKC-theta mediated signals inhibit inducible regulatory T cell (iTreg) differentiation via an AKT-Foxo1/3A pathway. TGF-beta-induced iTreg differentiation was enhanced in PKC-theta(-/-) T cells or wild-type cells treated with a specific PKC-theta inhibitor, but was inhibited by the PKC-theta activator PMA, or by CD28 crosslinking, which enhances PKC-theta activation. PKC-theta(-/-) T cells had reduced activity of the AKT kinase, and the expression of a constitutively active form of AKT in PKC-theta(-/-) T cells restored the ability to inhibit iTreg differentiation. Furthermore, knockdown or overexpression of the AKT downstream targets Foxo1 and Foxo3a was found to inhibit or promote iTreg differentiation in PKC-theta(-/-) T cells accordingly, indicating that the AKT-Foxo1/3A pathway is responsible for the inhibition of iTreg differentiation of iTregs downstream of PKC-theta. We conclude that PKC-theta is able to control T cell-mediated immune responses by shifting the balance between the differentiation of effector T cells and inhibitory Tregs. PMID- 22539797 TI - Evaluation of the B-SAFE campaign to reduce clinically significant warfarin-drug interactions among fee-for-service Medicare beneficiaries. AB - The objective of this study was to evaluate the effectiveness of a health communication campaign designed to reduce the rate of serious warfarin-related drug interactions. The B-SAFE campaign was conducted in 2009 to educate patients located in a Michigan hospital's service area about the risk of serious adverse drug events associated with warfarin. The rate of warfarin-related drug interactions among Medicare fee-for-service (FFS) patients admitted to the exposed hospital with hemorrhagic complications was compared with the rate of warfarin-related drug interactions among a similar cohort admitted to a control hospital before and after the campaign. The chi(2) test and logistic regression were used to analyze differences. The authors observed a marginally significant decline in the rate of warfarin-related drug interactions (odds ratio [OR] = 0.66; 95% confidence interval [CI] = 0.33-1.29) among FFS Medicare patients admitted for bleeding complications to the hospital targeted by the B-SAFE campaign. The same association was not observed in the control hospital (OR = 1.15; CI = 0.42-3.14). These findings suggest that patient exposure to the B-SAFE campaign may have resulted in a decrease in the rate of clinically significant warfarin-related drug interactions. PMID- 22539795 TI - Beyond HLA-A*0201: new HLA-transgenic nonobese diabetic mouse models of type 1 diabetes identify the insulin C-peptide as a rich source of CD8+ T cell epitopes. AB - Type 1 diabetes is an autoimmune disease characterized by T cell responses to beta cell Ags, including insulin. Investigations employing the NOD mouse model of the disease have revealed an essential role for beta cell-specific CD8(+) T cells in the pathogenic process. As CD8(+) T cells specific for beta cell Ags are also present in patients, these reactivities have the potential to serve as therapeutic targets or markers for autoimmune activity. NOD mice transgenic for human class I MHC molecules have previously been employed to identify T cell epitopes having important relevance to the human disease. However, most studies have focused exclusively on HLA-A*0201. To broaden the reach of epitope-based monitoring and therapeutic strategies, we have looked beyond this allele and developed NOD mice expressing human beta(2)-microglobulin and HLA-A*1101 or HLA B*0702, which are representative members of the A3 and B7 HLA supertypes, respectively. We have used islet-infiltrating T cells spontaneously arising in these strains to identify beta cell peptides recognized in the context of the transgenic HLA molecules. This work has identified the insulin C-peptide as an abundant source of CD8(+) T cell epitopes. Responses to these epitopes should be of considerable utility for immune monitoring, as they cannot reflect an immune reaction to exogenously administered insulin, which lacks the C-peptide. Because the peptides bound by one supertype member were found to bind certain other members also, the epitopes identified in this study have the potential to result in therapeutic and monitoring tools applicable to large numbers of patients and at-risk individuals. PMID- 22539799 TI - Using theory and evidence to guide the use of educational outreach to improve patient care. AB - Educational outreach is a common quality improvement (QI) strategy used alone and in combination with other interventions. However, a meta-analysis of educational outreach has failed to identify reasons for variation in its impact. To better understand such variation in findings, a more comprehensive set of characteristics about educational outreach is needed. This article describes the contribution that diffusion of innovations theory and evidence-based continuing education practices can make toward standardizing a set of characteristics to guide QI and research efforts using educational outreach. The article offers a set of characteristics and describes the implications of the set for research and QI efforts. PMID- 22539798 TI - Serious mental illness and acute hospital readmission in diabetic patients. AB - Patients with serious mental illness (SMI), particularly those with other chronic illnesses, may be vulnerable to unplanned hospital readmission. The authors hypothesized that SMI would be associated with increased 30-day hospital readmission in a cohort of adult patients with comorbid diabetes admitted to a tertiary care facility from 2005 to 2009. SMI was defined by International Classification of Diseases, Ninth Revision, discharge diagnosis codes for schizophrenia, schizoaffective, bipolar, manic, or major depressive disorders, or other psychosis. The primary outcome was 30-day readmission to the index hospital. Among 26 878 eligible admissions, the prevalence of SMI was 6% and the incidence of 30-day hospital admission was 16%. Among patients aged <35 years, SMI was significantly associated with decreased odds of 30-day hospital readmission (odds ratio [OR] = 0.39; 95% confidence interval [CI] = 0.17, 0.91). However, among patients >=35 years, SMI was not significantly associated with 30 day hospital readmission (OR = 1.11; 95% CI = 0.86, 1.42). SMI may not be associated with increased odds of 30-day hospital readmission in this population. PMID- 22539800 TI - Inappropriately ordered echocardiograms are related to socioeconomic status. AB - Although the appropriateness of ordering tests is increasingly measured, the demographic characteristics of patients receiving inappropriate cardiac tests, such as echocardiograms, have seldom been studied. The authors hypothesized that particular patient characteristics might influence the frequency of inappropriate echocardiogram ordering. Demographics and appropriateness were examined in a consecutive series of 535 inpatients receiving echocardiograms at a metropolitan hospital; inappropriate tests were ordered in 9% of cases. Disabled patients received a significantly higher proportion of inappropriate echocardiograms compared to both retired and employed patients. Among patients receiving repeat echocardiograms, Medicaid patients were significantly more likely to receive inappropriately ordered echocardiograms than patients with either Medicare or private insurance. In conclusion, certain socioeconomic and demographic characteristics are associated with a higher incidence of inappropriate test ordering. Further research into the causal factors behind this association may be useful to reduce inappropriate test ordering. PMID- 22539801 TI - Profiling three-dimensional nuclear telomeric architecture of myelodysplastic syndromes and acute myeloid leukemia defines patient subgroups. AB - PURPOSE: Myelodysplastic syndromes (MDS) are a group of disorders characterized by cytopenias, with a propensity for evolution into acute myeloid leukemias (AML). This transformation is driven by genomic instability, but mechanisms remain unknown. Telomere dysfunction might generate genomic instability leading to cytopenias and disease progression. EXPERIMENTAL DESIGN: We undertook a pilot study of 94 patients with MDS (56 patients) and AML (38 patients). The MDS cohort consisted of refractory cytopenia with multilineage dysplasia (32 cases), refractory anemia (12 cases), refractory anemia with excess of blasts (RAEB)1 (8 cases), RAEB2 (1 case), refractory anemia with ring sideroblasts (2 cases), and MDS with isolated del(5q) (1 case). The AML cohort was composed of AML-M4 (12 cases), AML-M2 (10 cases), AML-M5 (5 cases), AML-M0 (5 cases), AML-M1 (2 cases), AML-M4eo (1 case), and AML with multidysplasia-related changes (1 case). Three dimensional quantitative FISH of telomeres was carried out on nuclei from bone marrow samples and analyzed using TeloView. RESULTS: We defined three-dimensional nuclear telomeric profiles on the basis of telomere numbers, telomeric aggregates, telomere signal intensities, nuclear volumes, and nuclear telomere distribution. Using these parameters, we blindly subdivided the MDS patients into nine subgroups and the AML patients into six subgroups. Each of the parameters showed significant differences between MDS and AML. Combining all parameters revealed significant differences between all subgroups. Three-dimensional telomeric profiles are linked to the evolution of telomere dysfunction, defining a model of progression from MDS to AML. CONCLUSIONS: Our results show distinct three-dimensional telomeric profiles specific to patients with MDS and AML that help subgroup patients based on the severity of telomere dysfunction highlighted in the profiles. PMID- 22539802 TI - Impact of MiRSNPs on survival and progression in patients with multiple myeloma undergoing autologous stem cell transplantation. AB - PURPOSE: A distinctive new group of polymorphisms is constituted by single nucleotide polymorphism (SNP) in miRNA processing machinery in miRNA precursor molecules and in miRNA-binding sites, known as miRSNPs. The aim of this study was to ascertain the prognostic impact of six miRSNPs in patients with multiple myeloma and analyze the functional consequences. EXPERIMENTAL DESIGN: One hundred and thirty-seven patients with chemosensitive multiple myeloma (73M/64F) intensified with autologous stem cell transplantation (ASCT) were studied. The median follow-up was 4 years. The genes and SNPs evaluated in genomic DNA by allelic discrimination were KRT81 (rs3660), AFF1 (rs17703261), FAM179b (rs1053667), and MIR196A2 (rs11614913) for miRNA target genes and TRBP (rs784567) and XPO5 (rs11077) for miRNA biogenesis pathway. RESULTS: Overall survival (OS) was significantly longer in patients with KRT81 rs3660 C/C variant (P = 0.037). Functional analysis showed that the presence of C variant in KRT81 3' untranslated region (UTR) is related with a reduction of the protein levels. Moreover, the reduction of KRT81 protein levels by siRNA in multiple myeloma cell lines is related to a decreased proliferation. On the other hand, OS was significantly longer in patients with C/C or A/C variant in XPO5 rs11077 (P = 0.012). There was also a significantly longer progression-free survival (PFS) for this SNP (P = 0.013). This SNP retained its prognostic impact on PFS and OS in a multivariate regression analysis (P = 0.028 and P = 0.014, respectively). CONCLUSION: This is the first report that relates miRSNPs with prognosis in multiple myeloma either in a keratin gene (KRT81), target of diverse miRNA multiple myeloma clusters, or in the miRNA biogenesis pathway-related protein exportin-5. PMID- 22539803 TI - Changes in small dense low-density lipoprotein levels following acute coronary syndrome. AB - Low-density lipoprotein (LDL), especially small dense LDL (sdLDL), plays a role in atherogenesis. We compared baseline sdLDL levels between healthy controls and patients with acute coronary syndrome (ACS). Blood samples were taken from patients diagnosed with myocardial infarction ([MI] n = 104) and unstable angina ([UA] n = 100). Both sdLDL and high-sensitivity C-reactive protein (hsCRP) levels were determined on admission and in the next 24 hours after the onset of symptoms. Baseline concentration of sdLDL was significantly higher in patients presenting with ACS than controls (P < .05). In the 24 hours following ACS, the sdLDL levels decreased insignificantly in both groups of patients with ACS (P > .05). The changes in sdLDL values were not significantly different between MI and UA participants (P > .05). Patients with ACS have higher concentration of sdLDL compared with the controls. PMID- 22539804 TI - Substitute care in child welfare and the risk of arrest: does the reason for placement matter? AB - This study sought to investigate whether the reason for placement was associated with the subsequent risk of arrest. The author has focused on youth entering care for reasons of maltreatment and for child behavioral problems. The author stratified the sample based on a history of juvenile delinquency. The sample was diverse and included youth between 8 and 16 years of age with at least one episode in a substitute care child welfare setting (n = 5,528). Approximately 23% of youth were placed in child welfare for reasons others than maltreatment; specifically child behavioral problems. Youth placed for behavioral problems were significantly more likely to live in congregate care facilities, experience placement instability, and more likely to experience at least one arrest. A prevailing argument is that child welfare offers a broader range of family-based services as compared with the secure settings of juvenile justice. High rates of congregate care placement reported in the current study indicate that family based services are infrequently associated with youth placed for behavioral problems in child welfare. High rates of subsequent arrest indicate that the congregate care approach for youth with behavioral problems in child welfare is limited. PMID- 22539805 TI - The geography of drug market activities and child maltreatment. AB - This study examines how drug market activities place children at risk of maltreatment over space and time. Data were collected for 95 Census tracts in Sacramento, California, over 7 years and were analyzed using Bayesian space-time models. Referrals for child maltreatment investigations were less likely to occur in places where current drug market activity was present. However, past-year local and spatially lagged drugs sales were positively related to referrals. After the investigative phase, Census tracts with more drug sales had higher numbers of substantiations, and those with more possessions also had more entries into foster care. The temporal delay between drug sales and child maltreatment referrals may indicate that the surveillance systems designed to protect children may not be responsive to changing neighborhood conditions or be indicative of the time it takes for the detrimental effects of the drug use to appear. PMID- 22539806 TI - Plasma prolylcarboxypeptidase (angiotensinase C) is increased in obesity and diabetes mellitus and related to cardiovascular dysfunction. AB - BACKGROUND: Prolylcarboxypeptidase (PRCP) (angiotensinase C) has 3 major targets, angiotensin II, prekallikrein, and alpha-melanocyte stimulating hormone(1-13). The truncation of the latter leads to loss in appetite regulation and obesity in experimental animals. The objectives of this study were to purify PRCP from a native source, establish a sensitive immunoassay for PRCP, and relate plasma PRCP concentrations to signs and symptoms of obesity, diabetes mellitus, and cardiovascular dysfunction. METHODS: Purification of PRCP from human neutrophils and establishment of a sensitive ELISA was carried out with the use of samples from study participants. Three cohorts were studied: healthy individuals (n = 40); a chest pain cohort (Fast Assessment of Thoracic Pain by Neural Networks) (n = 165); and a community-based cohort [Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS)] (n = 1004). RESULTS: PRCP was purified to homogeneity. Mean (SD) plasma concentrations in healthy individuals were 12.9 (3.2) MUg/L and were increased in patients with chest pain and in patients with obesity and/or diabetes mellitus (P < 0.0001). In the PIVUS cohort the concentrations were related to several measures of arterial plaque formation, thickness of arterial intima media and posterior wall of the heart (P = 0.04 0.000005); the Framingham score (r = 0.14, P < 0.0001); and concentrations of C reactive protein (r = 0.16, P < 0.0001) and N-terminal pro B-type natriuretic peptide (r = -0.13, P < 0.0001). CONCLUSIONS: Plasma concentrations of PRCP may be used to reflect metabolic conditions in individuals with obesity and diabetes mellitus. The associations of PRCP concentrations with signs of cardiovascular dysfunction and cardiovascular abnormalities suggest a pivotal role of the enzyme in disease. PMID- 22539807 TI - Accuracy of first and second generation testosterone assays and improvement through sample extraction. PMID- 22539808 TI - Improving the success and reliability of adrenal venous sampling: focus on intraprocedural cortisol measurement. PMID- 22539809 TI - Increased hemoglobin A(1c) in obese pregnant women after exclusion of gestational diabetes. PMID- 22539810 TI - Hospital delay in South Asian patients with acute ST-elevation myocardial infarction in the UK. AB - BACKGROUND: South Asians presenting with chest pain in the UK experience disproportionately greater delays with respect to diagnosis and treatment for acute myocardial infarction (AMI). The duration of time between symptom onset and hospital intervention is a critical delay for AMI but there are limited data amongst South Asians. The objectives of this study were to investigate ethnic differences in hospital delay and to look at short-term outcomes in South Asian and White patients presenting with AMI. METHODS: Between 2004 and 2009, data were collected from 672 AMI patients with ST elevation who subsequently received percutaneous coronary intervention at Sandwell and West Birmingham Hospitals NHS Trust (UK). The hospital delay between the onset of symptoms and arrival time (pre-hospital), and between arrival time and intervention (post-hospital) was calculated. RESULTS: South Asians were more likely to be in the upper tertile of hospital delay (pre-hospital odds ratio, OR, 1.44, 95% CI 0.93-2.24, p = 0.06; post-hospital OR 1.83, 95% CI 1.05-3.21, p = 0.015), contributing to an overall hospital delay that was longer (median 314, interquartile range, IQR, 195-679 min) than in Whites (median 240, IQR 182-468 min). Women were more likely to be in the upper tertile for pre-hospital delay than men (p = 0.01) and South Asian ethnicity was an independent predictor of post-hospital delay (p = 0.003). CONCLUSIONS: While the reasons for ethnic differences in AMI-related hospital delay are likely to be multifactorial and complex, there is an urgent need to promote change in both the South Asian patient (delays in arrival) and their treatment (delays in intervention). PMID- 22539811 TI - Investigation of the first laboratory-acquired human cowpox virus infection in the United States. AB - BACKGROUND: Cowpox virus is an Orthopoxvirus that can cause infections in humans and a variety of animals. Infections occur in Eurasia; infections in humans and animals have not been reported in the United States. This report describes the occurrence of the first known human case of laboratory-acquired cowpox virus infection in the United States and the ensuing investigation. METHODS: The patient and laboratory personnel were interviewed, and laboratory activities were reviewed. Real-time polymerase chain reaction (PCR) and serologic assays were used to test the patient's specimens. PCR assays were used to test specimens obtained during the investigation. RESULTS: A specimen from the patient's lesion tested positive for cowpox virus DNA. Genome sequencing revealed a recombinant region consistent with a strain of cowpox virus stored in the research laboratory's freezer. Cowpox virus contamination was detected in 6 additional laboratory stocks of viruses. Orthopoxvirus DNA was present in 3 of 20 environmental swabs taken from laboratory surfaces. CONCLUSIONS: The handling of contaminated reagents or contact with contaminated surfaces was likely the mode of transmission. Delays in recognition and diagnosis of this infection in a laboratory researcher underscore the importance of a thorough patient history including occupational information-and laboratory testing in facilitating a prompt investigation and application of control and remediation measures. PMID- 22539812 TI - Trends in intussusception hospitalizations among US infants before and after implementation of the rotavirus vaccination program, 2000-2009. AB - BACKGROUND: Although US data have not documented an intussusception risk with current rotavirus vaccines, international data indicate a possible low risk, primarily after the first dose. METHODS: Among infants in 26 US states comprising 75% of the birth cohort, we examined age-specific trends in population-level intussusception hospitalization rates before (2000-2005) and after (2007-2009) rotavirus vaccine introduction. RESULTS: Compared with 2000-2005 (35.3 per 100,000), the rate was greater in 2007 (39.0 per 100,000; rate ratio [RR], 1.10; 95% confidence interval [CI], 1.04-1.18), similar in 2008 (33.4 per 100,000; RR, 0.95; 95% CI, .89-1.01), and lower in 2009 (32.9 per 100,000; RR, 0.93; 95% CI, .87-.99). Among infants aged 8-11 weeks, compared with 2000-2005 (6.9 per 100,000), a small, significant increase was observed in each of 2007 (11.4 per 100,000; RR, 1.64; 95% CI, 1.08-2.50), 2008 (12.2 per 100,000; RR, 1.76; 95% CI, 1.17-2.65), and 2009 (11.0 per 100,000; RR, 1.59; 95% CI, 1.04-2.44). CONCLUSIONS: Following rotavirus vaccine introduction, a small increase in intussusception rates was seen among US infants aged 8-11 weeks, to whom most first doses of vaccine are given; no sustained population-level change in overall rates was observed. PMID- 22539813 TI - PD-1-mediated attrition of polyfunctional memory CD8+ T cells in chronic toxoplasma infection. AB - We reported earlier that during chronic toxoplasmosis CD8(+) T cells become functionally exhausted with concomitant PD-1 upregulation, leading to eventual host mortality. However, how immune exhaustion specifically mediates attrition of CD8 polyfunctionality, a hallmark of potent T-cell response, during persistent infections has not been addressed. In this study, we demonstrate that PD-1 is preferentially expressed on polyfunctional memory CD8(+) T cells, which renders them susceptible to apoptosis. In vitro blockade of the PD-1-PD-L1 pathway dramatically reduces apoptosis of polyfunctional and interferon gamma(+)/granzyme B(-) memory but not effector CD8(+) T cells. In summary, the present report underscores the critical role of the PD-1-PD-L1 pathway in mediating attrition of this important CD8(+) T-cell subset and addresses the mechanistic basis of how alphaPD-L1 therapy reinvigorates polyfunctional CD8 response during chronic infections. The conclusions of this study can have profound immunotherapeutic implications in combating recrudescent toxoplasmosis as well other chronic infections. PMID- 22539814 TI - Penicillin-binding protein of Ehrlichia chaffeensis: cytokine induction through MyD88-dependent pathway. AB - BACKGROUND: Human monocytic ehrlichiosis is one of the most prevalent tick-borne zoonoses caused by infection with Ehrlichia chaffeensis. Although E. chaffeensis lacks entire lipopolysaccharide and most peptidoglycan biosynthesis genes, it induces inflammatory cytokines and chemokines. Ehrlichia chaffeensis components that induce inflammation and the responsive host cell pathway are not known. METHODS: Expression of penicillin-binding protein (PBP) in E. chaffeensis was analyzed by reverse-transcription polymerase chain reaction and Bocillin FL binding assay. Next, recombinant PBP, which was high-pressure liquid chromatography purified, and native PBP of E. chaffeensis were investigated for their ability to induce proinflammatory cytokines in the human monocytic leukemia cell line THP-1 and bone marrow-derived macrophages (BMDMs) from wild-type and MyD88 knockout mice. RESULTS: Expression of PBP by E. chaffeensis was upregulated during its intracellular life cycle. PBP induced interleukin 8 or CXCL2, tumor necrosis factor alpha, interleukin 1beta, and interleukin 10 in THP-1 cells and BMDMs. Cytokine induction by PBP was MyD88-dependent. Removal of PBP from E. chaffeensis lysate using penicillin affinity column and a complementation assay confirmed cytokine-inducing activity of native PBP. CONCLUSIONS: The cytokine inducing activity by E. chaffeensis PBP provides novel insights into pathogen associated molecular patterns and pathogenesis of E. chaffeensis infection. PMID- 22539816 TI - Rotavirus vaccination for prevention of serious acute gastroenteritis and the importance of postlicensure safety monitoring. PMID- 22539815 TI - Genital human papillomavirus (HPV) concordance in heterosexual couples. AB - BACKGROUND: Few studies have assessed genital human papillomavirus (HPV) concordance and factors associated with concordance among asymptomatic heterosexual couples. METHODS: Genotyping for HPV was conducted with male and female sex partners aged 18-70 years from Tampa, Florida. Eligibility included no history of HPV-associated disease. Type-specific positive concordance (partners with >= 1 genotype in common) and negative concordance (neither partner had HPV) were assessed for 88 couples. Factors associated with concordance were assessed with Fisher exact tests and tests for trend. RESULTS: Couples reported engaging in sexual intercourse for a median of 1.7 years (range, 0.1-49 years), and 75% reported being in the same monogamous relationship for the past 6 months. Almost 1 in 4 couples had type-specific positive concordance, and 35% had negative concordance for all types tested, for a total concordance of 59%. Concordance was not associated with monogamy. Type-specific positive concordance was associated with an increasing difference in partners' lifetime number of sex partners and inversely associated with an increasing difference in age. Negative concordance was inversely associated with both the couple's sum of lifetime number of sex partners and the difference in the partners' lifetime number of sex partners. CONCLUSIONS: Genital HPV concordance was common. Viral infectiousness and number of sex partners may help explain concordance among heterosexual partners. PMID- 22539817 TI - Effects of statin monotherapy versus statin plus ezetimibe combination on serum uric acid levels. AB - BACKGROUND: Uric acid is considered a risk factor for cardiovascular disease (CVD). The effect of statins and ezetimibe on serum uric acid levels has not been yet clarified. OBJECTIVE: To compare the effect of simvastatin/ezetimibe 10/10 mg, simvastatin 40 mg, and rosuvastatin 10 mg daily on serum uric acid levels in patients with dyslipidemia. METHODS: This was a prospective, randomized, open label, blinded end point (PROBE) study. Following a 3-month dietary intervention, patients with hypercholesterolemia received simvastatin/ezetimibe 10/10 mg or simvastatin 40 mg or rosuvastatin 10 mg. Changes in serum levels of uric acid and fractional renal excretion of uric acid as well as changes in electrolyte and renal function parameters were assessed after 12 weeks of treatment. RESULTS: One hundred fifty-three patients (56 male) were included. At week 12, a significant reduction in serum uric acid levels was seen in all treatment groups (simvastatin/ezetimibe 10/10 mg: -3.8%, simvastatin 40 mg: -5.7%, and rosuvastatin 10 mg: -3.8%; P < .05 compared with baseline; P = not significant [NS] for comparison between groups). Fractional excretion of uric acid nonsignificantly increased in all groups (simvastatin/ezetimibe 10/10 mg: +6.8%, simvastatin 40 mg: +6.8%, and rosuvastatin 10 mg: +5.9%). The reduction in serum uric acid levels correlated with the increase in fractional excretion of uric acid and baseline uric acid levels. Renal function parameters as well as serum levels and fractional excretions of electrolytes remained unchanged in all groups. Changes in serum lipids were similar across groups. CONCLUSION: Simvastatin/ezetimibe 10/10 mg, simvastatin 40 mg, and rosuvastatin 10 mg exhibit a similar uric acid-lowering effect. PMID- 22539818 TI - The relative impact of microstimulation parameters on movement generation. AB - Microstimulation is widely used in neurophysiology to characterize brain areas with behavior and in clinical therapeutics to treat neurological disorder. Current intensity and frequency, which respectively influence activation patterns in spatial and temporal domains, are typically selected to elicit a desired response, but their effective influence on behavior has not been thoroughly examined. We delivered microstimulation to the primate superior colliculus while systematically varying each parameter to capture effects of a large range of parameter space. We found that frequency was more effective in driving output properties, whereas properties changed gradually with intensity. Interestingly, when different parameter combinations were matched for total charge, effects on behavioral properties became seemingly equivalent. This study provides a first level resource for choosing desired parameter ranges to effectively manipulate behavior. It also provides insights into interchangeability of parameters, which can assist clinical microstimulation that looks to appropriately control behavior within designated constraints, such as power consumption. PMID- 22539820 TI - The human brain representation of odor identification. AB - Odor identification (OI) tests are increasingly used clinically as biomarkers for Alzheimer's disease and schizophrenia. The aim of this study was to directly compare the neuronal correlates to identified odors vs. nonidentified odors. Seventeen females with normal olfactory function underwent a functional magnetic resonance imaging (fMRI) experiment with postscanning assessment of spontaneous uncued OI. An event-related analysis was performed to compare within-subject activity to spontaneously identified vs. nonidentified odors at the whole brain level, and in anatomic and functional regions of interest (ROIs) in the medial temporal lobe (MTL). Parameter estimate values and blood oxygenated level dependent (BOLD) signal curves for correctly identified and nonidentified odors were derived from functional ROIs in hippocampus, entorhinal, piriform, and orbitofrontal cortices. Number of activated voxels and max parameter estimate values were obtained from anatomic ROIs in the hippocampus and the entorhinal cortex. At the whole brain level the correct OI gave rise to increased activity in the left entorhinal cortex and secondary olfactory structures, including the orbitofrontal cortex. Increased activation was also observed in fusiform, primary visual, and auditory cortices, inferior frontal plus inferior temporal gyri. The anatomic MTL ROI analysis showed increased activation in the left entorhinal cortex, right hippocampus, and posterior parahippocampal gyri in correct OI. In the entorhinal cortex and hippocampus the BOLD signal increased specifically in response to identified odors and decreased for nonidentified odors. In orbitofrontal and piriform cortices both identified and nonidentified odors gave rise to an increased BOLD signal, but the response to identified odors was significantly greater than that for nonidentified odors. These results support a specific role for entorhinal cortex and hippocampus in OI, whereas piriform and orbitofrontal cortices are active in both smelling and OI. Moreover, episodic as well as semantic memory systems appeared to support OI. PMID- 22539819 TI - Analysis of functional neuronal connectivity in the Drosophila brain. AB - Drosophila melanogaster is a valuable model system for the neural basis of complex behavior, but an inability to routinely interrogate physiologic connections within central neural networks of the fly brain remains a fundamental barrier to progress in the field. To address this problem, we have introduced a simple method of measuring functional connectivity based on the independent expression of the mammalian P2X2 purinoreceptor and genetically encoded Ca(2+) and cAMP sensors within separate genetically defined subsets of neurons in the adult brain. We show that such independent expression is capable of specifically rendering defined sets of neurons excitable by pulses of bath-applied ATP in a manner compatible with high-resolution Ca(2+) and cAMP imaging in putative follower neurons. Furthermore, we establish that this approach is sufficiently sensitive for the detection of excitatory and modulatory connections deep within larval and adult brains. This technically facile approach can now be used in wild type and mutant genetic backgrounds to address functional connectivity within neuronal networks governing a wide range of complex behaviors in the fly. Furthermore, the effectiveness of this approach in the fly brain suggests that similar methods using appropriate heterologous receptors might be adopted for other widely used model systems. PMID- 22539821 TI - Impaired long-range synchronization of gamma oscillations in the neocortex of a mouse lacking Kv3.2 potassium channels. AB - Inhibitory interneurons play a critical role in the generation of gamma (20-50 Hz) oscillations, either by forming mutually inhibitory networks or as part of recurrent networks with pyramidal cells. A key property of fast spiking interneurons is their ability to generate brief spikes and high-frequency spike trains with little accommodation. However, the role of their firing properties in network oscillations has not been tested in vivo. Studies in hippocampus in vitro have shown that high-frequency spike doublets in interneurons play a key role in the long-range synchronization of gamma oscillations with little phase lag despite long axonal conduction delays. We generated a knockout (KO) mouse lacking Kv3.2 potassium channel subunits, where infragranular inhibitory interneurons lose the ability both to sustain high-frequency firing and reliably generate high frequency spike doublets. We recorded cortical local field potentials in anesthetized and awake, restrained mice. Spontaneous activity of the KO and the wild-type (WT) showed similar content of gamma and slow (0.1-15 Hz) frequencies, but the KO showed a significantly larger decay of synchronization of gamma oscillations with distance. Coronal cuts in the cortex of WT mice decreased synchronization to values similar to the intact KO. The synchronization of the slow oscillation showed little decay with distance in both mice and was largely reduced after coronal cuts. Our results show that the firing properties of inhibitory interneurons are critical for long-range synchronization of gamma oscillations, and emphasize that intrinsic electrophysiological properties of single cells may play a key role in the spatiotemporal characteristics of network activity. PMID- 22539822 TI - Pitfalls in the dipolar model for the neocortical EEG sources. AB - For about six decades, primary current sources of the electroencephalogram (EEG) have been assumed dipolar in nature. In this study, we used electrophysiological recordings from anesthetized Wistar rats undergoing repeated whisker deflections to revise the biophysical foundations of the EEG dipolar model. In a first experiment, we performed three-dimensional recordings of extracellular potentials from a large portion of the barrel field to estimate intracortical multipolar moments generated either by single spiking neurons (i.e., pyramidal cells, PC; spiny stellate cells, SS) or by populations of them while experiencing synchronized postsynaptic potentials. As expected, backpropagating spikes along PC dendrites caused dipolar field components larger in the direction perpendicular to the cortical surface (49.7 +/- 22.0 nA.mm). In agreement with the fact that SS cells have "close-field" configurations, their dipolar moment at any direction was negligible. Surprisingly, monopolar field components were detectable both at the level of single units (i.e., -11.7 +/- 3.4 nA for PC) and at the mesoscopic level of mixed neuronal populations receiving extended synaptic inputs within either a cortical column (-0.44 +/- 0.20 MUA) or a 2.5-m(3)-voxel volume (-3.32 +/- 1.20 MUA). To evaluate the relationship between the macroscopically defined EEG equivalent dipole and the mesoscopic intracortical multipolar moments, we performed concurrent recordings of high-resolution skull EEG and laminar local field potentials. From this second experiment, we estimated the time-varying EEG equivalent dipole for the entire barrel field using either a multiple dipole fitting or a distributed type of EEG inverse solution. We demonstrated that mesoscopic multipolar components are altogether absorbed by any equivalent dipole in both types of inverse solutions. We conclude that the primary current sources of the EEG in the neocortex of rodents are not precisely represented by a single equivalent dipole and that the existence of monopolar components must be also considered at the mesoscopic level. PMID- 22539823 TI - Sympathoexcitation during chemoreflex active expiration is mediated by L glutamate in the RVLM/Botzinger complex of rats. AB - The involvement of glutamatergic neurotransmission in the rostral ventrolateral medulla/Botzinger/pre-Botzinger complexes (RVLM/BotC/pre-BotC) on the respiratory modulation of sympathoexcitatory response to peripheral chemoreflex activation (chemoreflex) was evaluated in the working heart-brain stem preparation of juvenile rats. We identified different types of baro- and chemosensitive presympathetic and respiratory neurons intermingled within the RVLM/BotC/pre BotC. Bilateral microinjections of kynurenic acid (KYN) into the rostral aspect of RVLM (RVLM/BotC) produced an additional increase in frequency of the phrenic nerve (PN: 0.38 +/- 0.02 vs. 1 +/- 0.08 Hz; P < 0.05; n = 18) and hypoglossal (HN) inspiratory response (41 +/- 2 vs. 82 +/- 2%; P < 0.05; n = 8), but decreased postinspiratory (35 +/- 3 vs. 12 +/- 2%; P < 0.05) and late-expiratory (24 +/- 4 vs. 2 +/-1%; P < 0.05; n = 5) abdominal (AbN) responses to chemoreflex. Likewise, expiratory vagal (cVN; 67 +/- 6 vs. 40 +/- 2%; P < 0.05; n = 5) and expiratory component of sympathoexcitatory (77 +/- 8 vs. 26 +/- 5%; P < 0.05; n = 18) responses to chemoreflex were reduced after KYN microinjections into RVLM/BotC. KYN microinjected into the caudal aspect of the RVLM (RVLM/pre-BotC; n = 16) abolished inspiratory responses [PN (n = 16) and HN (n = 6)], and no changes in magnitude of sympathoexcitatory (n = 16) and expiratory (AbN and cVN; n = 10) responses to chemoreflex, producing similar and phase-locked vagal, abdominal, and sympathetic responses. We conclude that in relation to chemoreflex activation 1) ionotropic glutamate receptors in RVLM/BotC and RVLM/pre-BotC are pivotal to expiratory and inspiratory responses, respectively; and 2) activation of ionotropic glutamate receptors in RVLM/BotC is essential to the coupling of active expiration and sympathoexcitatory response. PMID- 22539824 TI - Calcitonin gene-related peptide receptors in rat trigeminal ganglion do not control spinal trigeminal activity. AB - Calcitonin gene-related peptide (CGRP) is regarded as a key mediator in the generation of primary headaches. CGRP receptor antagonists reduce migraine pain in clinical trials and spinal trigeminal activity in animal experiments. The site of CGRP receptor inhibition causing these effects is debated. Activation and inhibition of CGRP receptors in the trigeminal ganglion may influence the activity of trigeminal afferents and hence of spinal trigeminal neurons. In anesthetized rats extracellular activity was recorded from neurons with meningeal afferent input in the spinal trigeminal nucleus caudalis. Mechanical stimuli were applied at regular intervals to receptive fields located in the exposed cranial dura mater. alpha-CGRP (10(-5) M), the CGRP receptor antagonist olcegepant (10( 3) M), or vehicle was injected through the infraorbital canal into the trigeminal ganglion. The injection of volumes caused transient discharges, but vehicle, CGRP, or olcegepant injection was not followed by significant changes in ongoing or mechanically evoked activity. In animals pretreated intravenously with the nitric oxide donor glyceryl trinitrate (GTN, 250 MUg/kg) the mechanically evoked activity decreased after injection of CGRP and increased after injection of olcegepant. In conclusion, the activity of spinal trigeminal neurons with meningeal afferent input is normally not controlled by CGRP receptor activation or inhibition in the trigeminal ganglion. CGRP receptors in the trigeminal ganglion may influence neuronal activity evoked by mechanical stimulation of meningeal afferents only after pretreatment with GTN. Since it has previously been shown that olcegepant applied to the cranial dura mater is ineffective, trigeminal activity driven by meningeal afferent input is more likely to be controlled by CGRP receptors located centrally to the trigeminal ganglion. PMID- 22539826 TI - Repertoire of high voltage-activated Ca2+ channels in the lateral superior olive: functional analysis in wild-type, Ca(v)1.3(-/-), and Ca(v)1.2DHP(-/-) mice. AB - Voltage-gated Ca(2+) (Ca(v))1.3 alpha-subunits of high voltage-activated Ca(2+) channels (HVACCs) are essential for Ca(2+) influx and transmitter release in cochlear inner hair cells and therefore for signal transmission into the central auditory pathway. Their absence leads to deafness and to striking structural changes in the auditory brain stem, particularly in the lateral superior olive (LSO). Here, we analyzed the contribution of various types of HVACCs to the total Ca(2+) current (I(Ca)) in developing mouse LSO neurons to address several questions: do LSO neurons express functional Ca(v)1.3 channels? What other types of HVACCs are expressed? Are there developmental changes? Do LSO neurons of Ca(v)1.3(-/-) mice show any compensatory responses, namely, upregulation of other HVACCs? Our electrophysiological and pharmacological results showed the presence of functional Ca(v)1.3 and Ca(v)1.2 channels at both postnatal days 4 and 12. Aside from these L-type channels, LSO neurons also expressed functional P/Q-type, N-type, and, most likely, R-type channels. The relative contribution of the four different subtypes to I(Ca) appeared to be 45%, 29%, 22%, and 4% at postnatal day 12, respectively. The physiological results were flanked and extended by quantitative RT-PCR data. Altogether, LSO neurons displayed a broad repertoire of HVACC subtypes. Genetic ablation of Ca(v)1.3 resulted in functional reorganization of some other HVACCs but did not restore normal I(Ca) properties. Together, our results suggest that several types of HVACCs are of functional relevance for the developing LSO. Whether on-site loss of Ca(v)1.3, i.e., in LSO neurons, contributes to the recently described malformation of the LSO needs to be determined by using tissue-specific Ca(v)1.3(-/-) animals. PMID- 22539825 TI - Low error discrimination using a correlated population code. AB - We explored the manner in which spatial information is encoded by retinal ganglion cell populations. We flashed a set of 36 shape stimuli onto the tiger salamander retina and used different decoding algorithms to read out information from a population of 162 ganglion cells. We compared the discrimination performance of linear decoders, which ignore correlation induced by common stimulation, with nonlinear decoders, which can accurately model these correlations. Similar to previous studies, decoders that ignored correlation suffered only a modest drop in discrimination performance for groups of up to ~30 cells. However, for more realistic groups of 100+ cells, we found order-of magnitude differences in the error rate. We also compared decoders that used only the presence of a single spike from each cell with more complex decoders that included information from multiple spike counts and multiple time bins. More complex decoders substantially outperformed simpler decoders, showing the importance of spike timing information. Particularly effective was the first spike latency representation, which allowed zero discrimination errors for the majority of shape stimuli. Furthermore, the performance of nonlinear decoders showed even greater enhancement compared with linear decoders for these complex representations. Finally, decoders that approximated the correlation structure in the population by matching all pairwise correlations with a maximum entropy model fit to all 162 neurons were quite successful, especially for the spike latency representation. Together, these results suggest a picture in which linear decoders allow a coarse categorization of shape stimuli, whereas nonlinear decoders, which take advantage of both correlation and spike timing, are needed to achieve high-fidelity discrimination. PMID- 22539827 TI - Prefrontal cortical mechanisms underlying delayed alternation in mice. AB - The prefrontal cortex (PFC) has been implicated in the maintenance of task relevant information during goal-directed behavior. Using a combination of lesions, local inactivation, and optogenetics, we investigated the functional role of the medial prefrontal cortex (mPFC) in mice with a novel operant delayed alternation task. Task difficulty was manipulated by changing the duration of the delay between two sequential actions. In experiment 1, we showed that excitotoxic lesions of the mPFC impaired acquisition of delayed alternation with long delays (16 s), whereas lesions of the dorsal hippocampus and ventral striatum, areas connected with the PFC, did not produce any deficits. Lesions of dorsal hippocampus, however, significantly impaired reversal learning when the rule was changed from alternation to repetition. In experiment 2, we showed that local infusions of muscimol (an agonist of the GABA(A) receptor) into mPFC impaired performance even when the animal was well trained, suggesting that the mPFC is critical not only for acquisition but also for successful performance. In experiment 3, to examine the mechanisms underlying the role of GABAergic inhibition, we used Cre-inducible Channelrhodopsin-2 to activate parvalbumin (PV) expressing GABAergic interneurons in the mPFC of PV-Cre transgenic mice as they performed the task. Using whole cell patch-clamp recording, we demonstrated that activation of PV-expressing interneurons in vitro with blue light in brain slices reliably produced spiking and inhibited nearby pyramidal projection neurons. With similar stimulation parameters, in vivo stimulation significantly impaired delayed alternation performance. Together these results demonstrate a critical role for the mPFC in the acquisition and performance of the delayed alternation task. PMID- 22539828 TI - Visuomotor feedback gains upregulate during the learning of novel dynamics. AB - At an early stage of learning novel dynamics, changes in muscle activity are mainly due to corrective feedback responses. These feedback contributions to the overall motor command are gradually reduced as feedforward control is learned. The temporary increased use of feedback could arise simply from the large errors in early learning with either unaltered gains or even slightly downregulated gains, or from an upregulation of the feedback gains when feedforward prediction is insufficient. We therefore investigated whether the sensorimotor control system alters feedback gains during adaptation to a novel force field generated by a robotic manipulandum. To probe the feedback gains throughout learning, we measured the magnitude of involuntary rapid visuomotor responses to rapid shifts in the visual location of the hand during reaching movements. We found large increases in the magnitude of the rapid visuomotor response whenever the dynamics changed: both when the force field was first presented, and when it was removed. We confirmed that these changes in feedback gain are not simply a byproduct of the change in background load, by demonstrating that this rapid visuomotor response is not load sensitive. Our results suggest that when the sensorimotor control system experiences errors, it increases the gain of the visuomotor feedback pathways to deal with the unexpected disturbances until the feedforward controller learns the appropriate dynamics. We suggest that these feedback gains are upregulated with increased uncertainty in the knowledge of the dynamics to counteract any errors or disturbances and ensure accurate and skillful movements. PMID- 22539831 TI - Racial disparities in access to pediatric kidney transplantation since share 35. AB - Share 35 was enacted in 2005 to shorten transplant wait times and provide high quality donors to children with ESRD. To investigate the possible effect of this policy on racial disparities in access to pediatric transplantation, we analyzed data from the US Renal Data System before and after Share 35. Among 4766 pediatric patients with incident ESRD, the probability of receiving a deceased donor kidney transplant increased 46% after Share 35, with Hispanics experiencing the greatest improvements (increases of 81% for Hispanics, 45% for blacks, and 37% for whites). On average, patients received a deceased-donor kidney transplant earlier after Share 35, but this finding varied by race: 63 days earlier for whites, 90 days earlier for blacks, and 201 days earlier for Hispanics. Furthermore, a shift from living- to deceased-donor sources occurred with Share 35 for all races, with a 25% reduction in living donors for whites compared with 48% and 46% reductions for Hispanics and blacks, respectively. In summary, Share 35 seems to have attenuated racial disparities in the time to and probability of children receiving a deceased-donor kidney transplant. These changes coincided with changes in the rates of living-donor sources, which vary by race. Future studies should explore how these changes may impact racial differences in long term graft outcomes. PMID- 22539832 TI - Improving the potential of neuroplasticity. PMID- 22539830 TI - Corticosteroid therapy in IgA nephropathy. AB - The benefits and risks of steroids for the treatment of IgA nephropathy remain uncertain. We systematically searched MEDLINE, EMBASE, and the Cochrane Library for randomized, controlled trials of corticosteroid therapy for IgA nephropathy published between 1966 and March 2011. We identified nine relevant trials that included 536 patients who had urinary protein excretion >1 g/d and normal renal function. Forty-six (8.6%) of these patients developed a kidney failure event, defined as doubling of the serum creatinine/halving of the GFR or ESRD. Overall, steroid therapy was associated with a lower risk for kidney failure (relative risk, 0.32 [95% confidence interval [CI], 0.15-0.67]; P=0.002) and a reduction in proteinuria (weighted mean difference, -0.46 g/d [95% CI, -0.63 to -0.29 g/d]), with no evidence of heterogeneity in these outcomes. Subgroup analysis suggested that the dose modifies the effect of steroids for renal protection (P for heterogeneity=0.030): Relatively high-dose and short-term therapy (prednisone >30 mg/d or high-dose pulse intravenous methylprednisolone with duration <=1 year) produced significant renal protection, whereas low-dose, long-term steroid use did not. Steroid therapy was associated with a 55% higher risk for adverse events. The quality of included studies was low, however, limiting the generalizability of the results. In conclusion, steroids appear to provide renal protection in patients with IgA nephropathy but increase the risk for adverse events. Reliably defining the efficacy and safety of steroids in IgA nephropathy requires a high-quality trial with a large sample size. PMID- 22539829 TI - Effect of online hemodiafiltration on all-cause mortality and cardiovascular outcomes. AB - In patients with ESRD, the effects of online hemodiafiltration on all-cause mortality and cardiovascular events are unclear. In this prospective study, we randomly assigned 714 chronic hemodialysis patients to online postdilution hemodiafiltration (n=358) or to continue low-flux hemodialysis (n=356). The primary outcome measure was all-cause mortality. The main secondary endpoint was a composite of major cardiovascular events, including death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, therapeutic coronary intervention, therapeutic carotid intervention, vascular intervention, or amputation. After a mean 3.0 years of follow-up (range, 0.4-6.6 years), we did not detect a significant difference between treatment groups with regard to all cause mortality (121 versus 127 deaths per 1000 person-years in the online hemodiafiltration and low-flux hemodialysis groups, respectively; hazard ratio, 0.95; 95% confidence interval, 0.75-1.20). The incidences of cardiovascular events were 127 and 116 per 1000 person-years, respectively (hazard ratio, 1.07; 95% confidence interval, 0.83-1.39). Receiving high-volume hemodiafiltration during the trial associated with lower all-cause mortality, a finding that persisted after adjusting for potential confounders and dialysis facility. In conclusion, this trial did not detect a beneficial effect of hemodiafiltration on all-cause mortality and cardiovascular events compared with low-flux hemodialysis. On-treatment analysis suggests the possibility of a survival benefit among patients who receive high-volume hemodiafiltration, although this subgroup finding requires confirmation. PMID- 22539833 TI - Benzodiazepines modulate GABAA receptors by regulating the preactivation step after GABA binding. AB - GABA(A) receptors (GABA(A)Rs) composed of alphabetagamma subunits are allosterically modulated by the benzodiazepines (BDZs). Agonists at the BDZ binding site potentiate submaximal GABA responses by increasing the apparent affinity of GABA(A)Rs for GABA. Although BDZs were initially thought to affect the binding of GABA agonists, recent studies suggest an effect on receptor gating; however, the involvement of preactivation steps in the modulation by BDZs has not been considered. Consequently, we examined whether BDZ agonists could exert their modulatory effect by displacing the equilibrium between resting and preactivated states of recombinant alpha1beta2gamma2 GABA(A)Rs expressed in Xenopus oocytes. For GABA and the partial agonists 4,5,6,7 tetrahydroisoxazolo[5,4-c]pyridin-3-ol and piperidine-4-sulfonic acid, we examined BDZ modulation using a simple three-step model incorporating agonist binding, receptor preactivation, and channel opening. The model accounted for diazepam modulation simply by increasing the preactivation constant by approximately fourfold. To assess whether BDZs preferentially affected a specific GABA binding site, pentameric concatamers were used. This demonstrated that single GABA-binding site mutant receptors were equally sensitive to modulation by BDZs compared with wild-type counterparts. Overall, our results suggest that BDZs affect the preactivation step to cause a global conformational rearrangement of GABA(A)Rs, thereby modulating receptor function. PMID- 22539834 TI - The sodium channel accessory subunit Navbeta1 regulates neuronal excitability through modulation of repolarizing voltage-gated K+ channels. AB - The channel pore-forming alpha subunit Kv4.2 is a major constituent of A-type (I(A)) potassium currents and a key regulator of neuronal membrane excitability. Multiple mechanisms regulate the properties, subcellular targeting, and cell surface expression of Kv4.2-encoded channels. In the present study, shotgun proteomic analyses of immunoprecipitated mouse brain Kv4.2 channel complexes unexpectedly identified the voltage-gated Na+ channel accessory subunit Navbeta1. Voltage-clamp and current-clamp recordings revealed that knockdown of Navbeta1 decreases I(A) densities in isolated cortical neurons and that action potential waveforms are prolonged and repetitive firing is increased in Scn1b-null cortical pyramidal neurons lacking Navbeta1. Biochemical and voltage-clamp experiments further demonstrated that Navbeta1 interacts with and increases the stability of the heterologously expressed Kv4.2 protein, resulting in greater total and cell surface Kv4.2 protein expression and in larger Kv4.2-encoded current densities. Together, the results presented here identify Navbeta1 as a component of native neuronal Kv4.2-encoded I(A) channel complexes and a novel regulator of I(A) channel densities and neuronal excitability. PMID- 22539835 TI - Imaging microglial/macrophage activation in spinal cords of experimental autoimmune encephalomyelitis rats by positron emission tomography using the mitochondrial 18 kDa translocator protein radioligand [18F]DPA-714. AB - Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. Activated microglia/macrophages play a key role in the immunopathogenesis of MS and its corresponding animal models, experimental autoimmune encephalomyelitis (EAE). Microglia activation begins at early stages of the disease and is associated with elevated expression of the 18 kDa mitochondrial translocator protein (TSPO). Thus, positron emission tomography (PET) imaging of microglial activation using TSPO-specific radioligands could be valuable for monitoring disease-associated neuroinflammatory processes. EAE was induced in rats using a fragment of myelin basic protein, yielding acute clinical disease that reflects extensive spinal cord inflammation. Enhanced TSPO expression in spinal cords of EAE rats versus those of controls was confirmed by Western blot and immunohistochemistry. Biodistribution studies in control and EAE rats were performed using the TSPO radioligand [18F]DPA-714 [N,N-diethyl-2-(2-(4-(2 fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide]. At 1 h after injection, almost fivefold higher levels of [18F]DPA-714 were measured in spinal cords of EAE rats versus controls. The specific binding of [18F]DPA-714 to TSPO in spinal cords was confirmed in competition studies, using unlabeled (R,S) PK11195 [(R,S)-N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)isoquinoline-3 carboxamide)] or DPA-714 in excess. MicroPET studies affirm that this differential radioactivity uptake in spinal cords of EAE versus control rats could be detected and quantified. Using [18F]DPA-714, neuroinflammation in spinal cords of EAE-induced rats could be visualized by PET, offering a sensitive technique for monitoring neuroinflammatory lesions in the CNS and particularly in the spinal cord. In addition to current MRI protocols, this approach could provide molecular images of neuroinflammation for detection, monitoring, and research in MS. PMID- 22539836 TI - NMDA receptor-dependent synaptic activation of TRPC channels in olfactory bulb granule cells. AB - Canonical transient receptor potential (TRPC) channels are widely expressed throughout the nervous system including the olfactory bulb where their function is largely unknown. Here, we describe their contribution to central synaptic processing at the reciprocal mitral and tufted cell-granule cell microcircuit, the most abundant synapse of the mammalian olfactory bulb. Suprathreshold activation of the synapse causes sodium action potentials in mouse granule cells and a subsequent long-lasting depolarization (LLD) linked to a global dendritic postsynaptic calcium signal recorded with two-photon laser-scanning microscopy. These signals are not observed after action potentials evoked by current injection in the same cells. The LLD persists in the presence of group I metabotropic glutamate receptor antagonists but is entirely absent from granule cells deficient for the NMDA receptor subunit NR1. Moreover, both depolarization and Ca2+ rise are sensitive to the blockade of NMDA receptors. The LLD and the accompanying Ca2+ rise are also absent in granule cells from mice deficient for both TRPC channel subtypes 1 and 4, whereas the deletion of either TRPC1 or TRPC4 results in only a partial reduction of the LLD. Recordings from mitral cells in the absence of both subunits reveal a reduction of asynchronous neurotransmitter release from the granule cells during recurrent inhibition. We conclude that TRPC1 and TRPC4 can be activated downstream of NMDA receptor activation and contribute to slow synaptic transmission in the olfactory bulb, including the calcium dynamics required for asynchronous release from the granule cell spine. PMID- 22539838 TI - Axonal patterns and targets of dA1 interneurons in the chick hindbrain. AB - Hindbrain dorsal interneurons that comprise the rhombic lip relay sensory information and coordinate motor outputs. The progenitor dA1 subgroup of interneurons, which is formed along the dorsal-most region of the caudal rhombic lip, gives rise to the cochlear and precerebellar nuclei. These centers project sensory inputs toward upper-brain regions. The fundamental role of dA1 interneurons in the assembly and function of these brainstem nuclei is well characterized. However, the precise en route axonal patterns and synaptic targets of dA1 interneurons are not clear as of yet. Novel genetic tools were used to label dA1 neurons and trace their axonal trajectories and synaptic connections at various stages of chick embryos. Using dA1-specific enhancers, two contralateral ascending axonal projection patterns were identified; one derived from rhombomeres 6-7 that elongated in the dorsal funiculus, while the other originated from rhombomeres 2-5 and extended in the lateral funiculus. Targets of dA1 axons were followed at later stages using PiggyBac-mediated DNA transposition. dA1 axons were found to project and form synapses in the auditory nuclei and cerebellum. Investigation of mechanisms that regulate the patterns of dA1 axons revealed a fundamental role of Lim-homeodomain (HD) proteins. Switch in the expression of the specific dA1 Lim-HD proteins Lhx2/9 into Lhx1, which is typically expressed in dB1 interneurons, modified dA1 axonal patterns to project along the routes of dB1 subgroup. Together, the results of this research provided new tools and knowledge to the assembly of trajectories and connectivity of hindbrain dA1 interneurons and of molecular mechanisms that control these patterns. PMID- 22539837 TI - Abnormalities in hippocampal functioning with persistent pain. AB - Chronic pain patients exhibit increased anxiety, depression, and deficits in learning and memory. Yet how persistent pain affects the key brain area regulating these behaviors, the hippocampus, has remained minimally explored. In this study we investigated the impact of spared nerve injury (SNI) neuropathic pain in mice on hippocampal-dependent behavior and underlying cellular and molecular changes. In parallel, we measured the hippocampal volume of three groups of chronic pain patients. We found that SNI animals were unable to extinguish contextual fear and showed increased anxiety-like behavior. Additionally, SNI mice compared with Sham animals exhibited hippocampal (1) reduced extracellular signal-regulated kinase expression and phosphorylation, (2) decreased neurogenesis, and (3) altered short-term synaptic plasticity. To relate the observed hippocampal abnormalities with human chronic pain, we measured the volume of human hippocampus in chronic back pain (CBP), complex regional pain syndrome (CRPS), and osteoarthritis patients (OA). Compared with controls, CBP and CRPS, but not OA, had significantly less bilateral hippocampal volume. These results indicate that hippocampus-mediated behavior, synaptic plasticity, and neurogenesis are abnormal in neuropathic rodents. The changes may be related to the reduction in hippocampal volume we see in chronic pain patients, and these abnormalities may underlie learning and emotional deficits commonly observed in such patients. PMID- 22539839 TI - Antennal lobe processing correlates to moth olfactory behavior. AB - Animals typically perceive their olfactory environment as a complex blend of natural odor cues. In insects, the initial processing of odors occurs in the antennal lobe (AL). Afferent peripheral input from olfactory sensory neurons (OSNs) is modified via mostly inhibitory local interneurons (LNs) and transferred by projection neurons (PNs) to higher brain centers. Here we performed optophysiological studies in the AL of the moth, Manduca sexta, and recorded odor evoked calcium changes in response to antennal stimulation with five monomolecular host volatiles and their artificial mixture. In a double staining approach, we simultaneously measured OSN network input in concert with PN output across the glomerular array. By comparing odor-evoked activity patterns and response intensities between the two processing levels, we show that host mixtures could generally be predicted from the linear summation of their components at the input of the AL, but output neurons established a unique, nonlinear spatial pattern separate from individual component identities. We then assessed whether particularly high levels of signal modulation correspond to behavioral relevance. One of our mixture components, phenyl acetaldehyde, evoked significant levels of nonlinear input-output modulation in observed spatiotemporal activation patterns that were unique from the other individual odorants tested. This compound also accelerated behavioral activity in subsequent wind tunnel tests, whereas another compound that did not exhibit high levels of modulation also did not affect behavior. These results suggest that the high degree of input-output modulation exhibited by the AL for specific odors can correlate to behavioral output. PMID- 22539840 TI - Microtubule redistribution in growth cones elicited by focal inactivation of kinesin-5. AB - In order for growth cones to turn, microtubules from the central domain must preferentially invade the peripheral domain in the direction of the turn. Recent studies suggest that kinesin-5 (also called Eg5 or kif11) suppresses the invasion of microtubules into the peripheral domain on the side of the growth cone opposite the direction of turning. In theory, kinesin-5 could elicit these effects by acting on the microtubules within the peripheral domain itself, by acting on microtubules in the central domain, or in the transition zone between these two domains. In rat neurons expressing kinesin-5, we documented the presence of kinesin-5 in both domains of the growth cone and especially enriched in the transition zone. We then focally inactivated kinesin-5 in various regions of the growth cone, using micro-chromophore-assisted laser inactivation. We found that a greater invasion of microtubules into the peripheral domain occurred when kinesin-5 was inactivated specifically in the transition zone. However, there was no effect on microtubule invasion into the peripheral domain when kinesin-5 was inactivated in the peripheral domain itself or in the central domain. In other experiments, frog growth cones were observed to turn toward a gradient of a drug that inhibits kinesin-5, confirming that asymmetric inactivation of kinesin-5 can cause the growth cone to turn. Finally, expression of a phospho-mutant of kinesin 5 resulted in greater microtubule invasion throughout the peripheral domain and an inhibition of growth cone turning, implicating phosphorylation as a means by which kinesin-5 is regulated in the growth cone. PMID- 22539841 TI - The effect of object state-changes on event processing: do objects compete with themselves? AB - When an object is described as changing state during an event, do the representations of those states compete? The distinct states they represent cannot coexist at any one moment in time, yet each representation must be retrievable at the cost of suppressing the other possible object states. We used functional magnetic resonance imaging of human participants to test whether such competition does occur, and whether this competition between object states recruits brain areas sensitive to other forms of conflict. In Experiment 1, the same object was changed either substantially or minimally by one of two actions. In Experiment 2, the same action either substantially or minimally changed one of two objects. On a subject-specific basis, we identified voxels most responsive to conflict in a Stroop color-word interference task. Voxels in left posterior ventrolateral prefrontal cortex most responsive to Stroop conflict were also responsive to our object state-change manipulation, and were not responsive to the imageability of the described action. In contrast, voxels in left middle frontal gyrus responsive to Stroop conflict were not responsive even to language, and voxels in left middle temporal gyrus that were responsive to language and imageability were not responsive to object state-change. Results suggest that, when representing object state-change, multiple incompatible representations of an object compete, and the greater the difference between the initial state and the end state of an object, the greater the conflict. PMID- 22539842 TI - The native serotonin 5-HT(5A) receptor: electrophysiological characterization in rodent cortex and 5-HT(1A)-mediated compensatory plasticity in the knock-out mouse. AB - The 5-HT(5A) receptor is the least understood serotonin (5-HT) receptor. Here, we electrophysiologically identify and characterize a native 5-HT(5A) receptor current in acute ex vivo brain slices of adult rodent prefrontal cortex. In the presence of antagonists for the previously characterized 5-HT(1A) and 5-HT2 receptors, a proportion of layer V pyramidal neurons continue to show 5-HT elicited outward currents in both rats and mice. These 5-HT currents are suppressed by the selective 5-HT(5A) antagonist, SB-699551, and are not observed in 5-HT(5A) receptor knock-out mice. Further characterization reveals that the 5 HT(5A) current is activated by submicromolar concentrations of 5-HT, is inwardly rectifying with a reversal potential near the equilibrium potential for K+ ions, and is suppressed by blockers of Kir3 channels. Finally, we observe that genetic deletion of the inhibitory 5-HT(5A) receptor results in an unexpected, large increase in the inhibitory 5-HT(1A) receptor currents. The presence of functional prefrontal 5-HT(5A) receptors in normal rodents along with compensatory plasticity in 5-HT(5A) receptor knock-out mice testifies to the significance of this receptor in the healthy prefrontal cortex. PMID- 22539843 TI - Effective sensory modality activating an escape triggering neuron switches during early development in zebrafish. AB - Developing nervous systems grow to integrate sensory signals from different modalities and to respond through various behaviors. Here, we examined the development of escape behavior in zebrafish [45-170 h postfertilization (hpf)] to study how developing sensory inputs are integrated into sensorimotor circuits. Mature fish exhibit fast escape upon both auditory/vestibular (AV) and head tactile stimuli. Newly hatched larvae, however, do not respond to AV stimuli before 75 hpf. Because AV-induced fast escape in mature fish is triggered by a pair of hindbrain neurons known as Mauthner (M) cells, we studied functional development of the M-cell circuit accounting for late acquisition of AV-induced escape. In fast escape elicited by head-directed water jet, minimum onset latency decreased throughout development (5 ms at 45-59 hpf, 3 ms after 75 hpf). After 75 hpf, lesioning the otic vesicle (OV) to eliminate AV input resulted in loss of short-latency (<5 ms) fast escape, whereas ablation of the sensory trigeminal ganglion (gV) to block head-tactile input did not. Before 75 hpf, however, fast escape persisted after OV lesion but disappeared after gV ablation. Laser ablation of the M-cell and Ca2+ imaging of the M-cell during escape demonstrated that M-cell firing is required to initiate short-latency fast escapes at every developmental stage and further suggest that head-tactile input activates the M cell before 75 hpf, but that after this point AV input activates the M-cell instead. Thus, a switch in the effective sensory input to the M-cells mediates the acquisition of a novel modality for initiating fast escape. PMID- 22539844 TI - A reversible early oxidized redox state that precedes macromolecular ROS damage in aging nontransgenic and 3xTg-AD mouse neurons. AB - The brain depends on redox electrons from nicotinamide adenine dinucleotide (reduced form; NADH) to produce ATP and oxyradicals (reactive oxygen species [ROS]). Because ROS damage and mitochondrial dysregulation are prominent in aging and Alzheimer's disease (AD) and their relationship to the redox state is unclear, we wanted to know whether an oxidative redox shift precedes these markers and leads to macromolecular damage in a mouse model of AD. We used the 3xTg-AD mouse model, which displays cognitive deficits beginning at 4 months. Hippocampal/cortical neurons were isolated across the age span and cultured in common nutrients to control for possible hormonal and vascular differences. We found an increase of NAD(P)H levels and redox state in nontransgenic (non-Tg) neurons until middle age, followed by a decline in old age. The 3xTg-AD neurons maintained much lower resting NAD(P)H and redox states after 4 months, but the NADH regenerating capacity continuously declined with age beginning at 2 months. These redox characteristics were partially reversible with nicotinamide, a biosynthetic precursor of NAD+. Nicotinamide also protected against glutamate excitotoxicity. Compared with non-Tg neurons, 3xTg-AD neurons had more mitochondria/neuron and lower glutathione (GSH) levels that preceded age-related increases in ROS levels. These GSH deficits were again reversible with nicotinamide in 3xTg-AD neurons. Surprisingly, low macromolecular ROS damage was only elevated after 4 months in the 3xTg-AD neurons if antioxidants were removed. The present data suggest that a more oxidized redox state and a lower antioxidant GSH defense can be dissociated from neuronal ROS damage, changes that precede the onset of cognitive deficits in the 3xTg-AD model. PMID- 22539845 TI - Serotonin selectively modulates reward value in human decision-making. AB - Establishing a function for the neuromodulator serotonin in human decision-making has proved remarkably difficult because if its complex role in reward and punishment processing. In a novel choice task where actions led concurrently and independently to the stochastic delivery of both money and pain, we studied the impact of decreased brain serotonin induced by acute dietary tryptophan depletion. Depletion selectively impaired both behavioral and neural representations of reward outcome value, and hence the effective exchange rate by which rewards and punishments were compared. This effect was computationally and anatomically distinct from a separate effect on increasing outcome-independent choice perseveration. Our results provide evidence for a surprising role for serotonin in reward processing, while illustrating its complex and multifarious effects. PMID- 22539846 TI - Dysregulation of D2-mediated dopamine transmission in monkeys after chronic escalating methamphetamine exposure. AB - Compulsive drug-seeking and drug-taking are important substance-abuse behaviors that have been linked to alterations in dopaminergic neurotransmission and to impaired inhibitory control. Evidence supports the notions that abnormal D2 receptor-mediated dopamine transmission and inhibitory control may be heritable risk factors for addictions, and that they also reflect drug-induced neuroadaptations. To provide a mechanistic explanation for the drug-induced emergence of inhibitory-control deficits, this study examined how a chronic, escalating-dose regimen of methamphetamine administration affected dopaminergic neurochemistry and cognition in monkeys. Dopamine D2-like receptor and dopamine transporter (DAT) availability and reversal-learning performance were measured before and after exposure to methamphetamine (or saline), and brain dopamine levels were assayed at the conclusion of the study. Exposure to methamphetamine reduced dopamine D2-like receptor and DAT availability and produced transient, selective impairments in the reversal of a stimulus-outcome association. Furthermore, individual differences in the change in D2-like receptor availability in the striatum were related to the change in response to positive feedback. These data provide evidence that chronic, escalating-dose methamphetamine administration alters the dopamine system in a manner similar to that observed in methamphetamine-dependent humans. They also implicate alterations in positive-feedback sensitivity associated with D2-like receptor dysfunction as the mechanism by which inhibitory control deficits emerge in stimulant-dependent individuals. Finally, a significant degree of neurochemical and behavioral variation in response to methamphetamine was detected, indicating that individual differences affect the degree to which drugs of abuse alter these processes. Identification of these factors ultimately may assist in the development of individualized treatments for substance dependence. PMID- 22539848 TI - Site-specific synapsin I phosphorylation participates in the expression of post tetanic potentiation and its enhancement by BDNF. AB - A large amount of experimental evidence has highlighted the rapid changes in synaptic efficacy induced by high-frequency stimulation and BDNF at central excitatory synapses. We clarified the quantal mechanisms and the involvement of Synapsin I (SynI) phosphorylation in the expression of post-tetanic potentiation (PTP) and in its modulation by BDNF in mouse glutamatergic autapses. We found that PTP is associated with an elevation in the probability of release and a concomitant increase in the size of the readily releasable pool (RRP). The latter component was virtually absent in SynI knock-out (KO) neurons, which indeed displayed impaired PTP. PTP was fully rescued by the expression of wild-type SynI, but not of its dephosphomimetic mutants in the phosphorylation sites for cAMP-dependent protein kinase and Ca2+/calmodulin-dependent protein kinases I/II. BDNF potently enhanced PTP through a further increase in the RRP size, which was missing in SynI KO neurons. In these neurons, the BDNF-induced PTP enhancement was rescued by the expression of wild-type SynI, but not of its dephosphomimetic mutant at the mitogen-dependent protein kinase sites. The results indicate that the increase in RRP size necessary for the full expression of PTP, and its sensitivity to BDNF, involve phosphorylation of SynI at distinct sites, thus implicating SynI as an essential downstream effector for the expression of PTP and for its enhancement by BDNF. PMID- 22539847 TI - Setting the time course of inhibitory synaptic currents by mixing multiple GABA(A) receptor alpha subunit isoforms. AB - The kinetics of IPSCs influence many neuronal processes, such as the frequencies of oscillations and the duration of shunting inhibition. The subunit composition of recombinant GABA(A) receptors (GABA(A)Rs) strongly affects the deactivation kinetics of GABA-evoked currents. However, for GABAergic synapses, the relationship between subunit composition and IPSC decay is less clear. Here we addressed this by combining whole-cell recordings of miniature IPSCs (mIPSCs) and quantitative immunolocalization of synaptic GABA(A)R subunits. In cerebellar stellate, thalamic relay, and main olfactory bulb (MOB) deep short-axon cells of Wistar rats, the only synaptic alpha subunit was alpha1, and zolpidem-sensitive mIPSCs had weighted decay time constants (tau(w)) of 4-6 ms. Nucleus reticularis thalami neurons expressed only alpha3 as the synaptic alpha subunit and exhibited slow (tau(w) = 28 ms), zolpidem-insensitive mIPSCs. By contrast, MOB external tufted cells contained two alpha subunit types (alpha1 and alpha3) at their synapses. Quantitative analysis of multiple immunolabeled images revealed small within-cell, but large between-cell, variability in synaptic alpha1/alpha3 ratios. This corresponded to large cell-to-cell variability in the decay (tau(w) = 3-30 ms) and zolpidem sensitivity of mIPSCs. Currents evoked by rapid application of GABA to patches excised from HEK cells expressing different mixtures of alpha1 and alpha3 subunits displayed highly variable deactivation times that correlated with the alpha1/alpha3 cDNA ratio. Our results demonstrate that diversity in the decay of IPSCs can be generated by varying the expression of different GABA(A)R subunits that alone confer different decay kinetics, allowing the time course of inhibition to be tuned to individual cellular requirements. PMID- 22539849 TI - Pten deletion in adult hippocampal neural stem/progenitor cells causes cellular abnormalities and alters neurogenesis. AB - Adult neurogenesis persists throughout life in restricted brain regions in mammals and is affected by various physiological and pathological conditions. The tumor suppressor gene Pten is involved in adult neurogenesis and is mutated in a subset of autism patients with macrocephaly; however, the link between the role of PTEN in adult neurogenesis and the etiology of autism has not been studied before. Moreover, the role of hippocampus, one of the brain regions where adult neurogenesis occurs, in development of autism is not clear. Here, we show that ablating Pten in adult neural stem cells in the subgranular zone of hippocampal dentate gyrus results in higher proliferation rate and accelerated differentiation of the stem/progenitor cells, leading to depletion of the neural stem cell pool and increased differentiation toward the astrocytic lineage at later stages. Pten-deleted stem/progenitor cells develop into hypertrophied neurons with abnormal polarity. Additionally, Pten mutant mice have macrocephaly and exhibit impairment in social interactions and seizure activity. Our data reveal a novel function for PTEN in adult hippocampal neurogenesis and indicate a role in the pathogenesis of abnormal social behaviors. PMID- 22539850 TI - Evidence for neuronal desynchrony in the aged suprachiasmatic nucleus clock. AB - Aging is associated with a deterioration of daily (circadian) rhythms in physiology and behavior. Deficits in the function of the central circadian pacemaker in the suprachiasmatic nucleus (SCN) have been implicated, but the responsible mechanisms have not been clearly delineated. In this report, we characterize the progression of rhythm deterioration in mice to 900 d of age. Longitudinal behavioral and sleep-wake recordings in up to 30-month-old mice showed strong fragmentation of rhythms, starting at the age of 700 d. Patch-clamp recordings in this age group revealed deficits in membrane properties and GABAergic postsynaptic current amplitude. A selective loss of circadian modulation of fast delayed-rectifier and A-type K+ currents was observed. At the tissue level, phase synchrony of SCN neurons was grossly disturbed, with some subpopulations peaking in anti-phase and a reduction in amplitude of the overall multiunit activity rhythm. We propose that aberrant SCN rhythmicity in old animals--with electrophysiological arrhythmia at the single-cell level and phase desynchronization at the network level--can account for defective circadian function with aging. PMID- 22539852 TI - Transformation from a pure time delay to a mixed time and phase delay representation in the auditory forebrain pathway. AB - Birds and mammals exploit interaural time differences (ITDs) for sound localization. Subsequent to ITD detection by brainstem neurons, ITD processing continues in parallel midbrain and forebrain pathways. In the barn owl, both ITD detection and processing in the midbrain are specialized to extract ITDs independent of frequency, which amounts to a pure time delay representation. Recent results have elucidated different mechanisms of ITD detection in mammals, which lead to a representation of small ITDs in high-frequency channels and large ITDs in low-frequency channels, resembling a phase delay representation. However, the detection mechanism does not prevent a change in ITD representation at higher processing stages. Here we analyze ITD tuning across frequency channels with pure tone and noise stimuli in neurons of the barn owl's auditory arcopallium, a nucleus at the endpoint of the forebrain pathway. To extend the analysis of ITD representation across frequency bands to a large neural population, we employed Fourier analysis for the spectral decomposition of ITD curves recorded with noise stimuli. This method was validated using physiological as well as model data. We found that low frequencies convey sensitivity to large ITDs, whereas high frequencies convey sensitivity to small ITDs. Moreover, different linear phase frequency regimes in the high-frequency and low-frequency ranges suggested an independent convergence of inputs from these frequency channels. Our results are consistent with ITD being remodeled toward a phase delay representation along the forebrain pathway. This indicates that sensory representations may undergo substantial reorganization, presumably in relation to specific behavioral output. PMID- 22539851 TI - Galpha(olf) mutation allows parsing the role of cAMP-dependent and extracellular signal-regulated kinase-dependent signaling in L-3,4-dihydroxyphenylalanine induced dyskinesia. AB - Although L-3,4-dihydroxyphenylalanine (L-DOPA) remains the reference treatment of Parkinson's disease, its long-term beneficial effects are hindered by L-DOPA induced dyskinesia (LID). In the dopamine (DA)-denervated striatum, L-DOPA activates DA D1 receptor(D1R) signaling, including cAMP-dependent protein kinase A (PKA) and extracellular signal-regulated kinase (ERK), two responses associated with LID. However, the cause of PKA and ERK activation, their respective contribution to LID, and their relationship are not known. In striatal neurons, D1R activates adenylyl-cyclase through Galpha(olf), a protein upregulated after lesion of DA neurons in rats and inpatients. We report here that increased Galpha(olf) levels in hemiparkinsonian mice are correlated with LID after chronic L-DOPA treatment. To determine the role of this upregulation, we performed unilateral lesion in mice lacking one allele of the Gnal gene coding for Galpha(olf) (Gnal+/-). Despite an increase in the lesioned striatum,Galpha(olf) levels remained below those of unlesioned wild-type mice. In Gnal+/- mice, the lesion-induced L-DOPA stimulation of cAMP/PKA-mediated phosphorylation of GluA1 Ser845 and DARPP-32 (32 kDa DA- and cAMP-regulated phosphoprotein) Thr34 was dramatically reduced, whereas ERK activation was preserved. LID occurrence was similar in Gnal+/+ and Gnal+/- mice after a 10-d L-DOPA (20 mg/kg) treatment. Thus, in lesioned animals, Galpha(olf) upregulation is critical for the activation by L-DOPA of D1R-stimulated cAMP/PKA but not ERK signaling. Although the cAMP/PKA pathway appears to be required for LID development, our results indicate that its activation is unlikely to be the main source of LID. In contrast, the persistence of L-DOPA-induced ERK activation in Gnal+/- mice supports its causal role in LID development. PMID- 22539853 TI - Evidence for a fragile X mental retardation protein-mediated translational switch in metabotropic glutamate receptor-triggered Arc translation and long-term depression. AB - Group 1 metabotropic glutamate receptor (mGluR)-stimulated protein synthesis and long-term synaptic depression (mGluR-LTD) are altered in the mouse model of fragile X syndrome, Fmr1 knock-out (KO) mice. Fmr1 encodes fragile X mental retardation protein (FMRP), a dendritic RNA binding protein that functions, in part, as a translational suppressor. It is unknown whether and how FMRP acutely regulates LTD and/or the rapid synthesis of new proteins required for LTD, such as the activity-regulated cytoskeletal-associated protein (Arc). The protein phosphatase PP2A dephosphorylates FMRP, which contributes to translational activation of some target mRNAs. Here, we report that PP2A and dephosphorylation of FMRP at S500 are required for an mGluR-induced, rapid (5 min) increase in dendritic Arc protein and LTD in rat and mouse hippocampal neurons. In Fmr1 KO neurons, basal, dendritic Arc protein levels and mGluR-LTD are enhanced, but mGluR-triggered Arc synthesis is absent. Lentiviral-mediated expression of wild type FMRP in Fmr1 KO neurons suppresses basal dendritic Arc levels and mGluR-LTD, and restores rapid mGluR-triggered Arc synthesis. A phosphomimic of FMRP (S500D) suppresses steady-state dendritic Arc levels but does not rescue mGluR-induced Arc synthesis. A dephosphomimic of FMRP (S500A) neither suppresses dendritic Arc nor supports mGluR-induced Arc synthesis. Accordingly, S500D-FMRP expression in Fmr1 KO neurons suppresses mGluR-LTD, whereas S500A-FMRP has no effect. These data support a model in which phosphorylated FMRP functions to suppress steady state translation of Arc and LTD. Upon mGluR activation of PP2A, FMRP is rapidly dephosphorylated, which contributes to rapid new synthesis of Arc and mGluR-LTD. PMID- 22539854 TI - The intronic GABRG2 mutation, IVS6+2T->G, associated with childhood absence epilepsy altered subunit mRNA intron splicing, activated nonsense-mediated decay, and produced a stable truncated gamma2 subunit. AB - The intronic GABRG2 mutation, IVS6+2T->G, was identified in an Australian family with childhood absence epilepsy and febrile seizures (Kananura et al., 2002). The GABRG2 intron 6 splice donor site was found to be mutated from GT to GG. We generated wild-type and mutant gamma2 subunit bacterial artificial chromosomes (BACs) driven by a CMV promoter and expressed them in HEK293T cells and expressed wild-type and mutant gamma2 subunit BACs containing the endogenous hGABRG2 promoter in transgenic mice. Wild-type and mutant GABRG2 mRNA splicing patterns were determined in both BAC-transfected HEK293T cells and transgenic mouse brain, and in both, the mutation abolished intron 6 splicing at the donor site, activated a cryptic splice site, generated partial intron 6 retention, and produced a frameshift in exon 7 that created a premature translation termination codon (PTC). The resultant mutant mRNA was either degraded partially by nonsense mediated mRNA decay or translated to a stable, truncated subunit (the gamma2-PTC subunit) containing the first six GABRG2 exons and a novel frameshifted 29 aa C terminal tail. The gamma2-PTC subunit was homologous to the mollusk AChBP (acetylcholine binding protein) but was not secreted from cells. It was retained in the ER and not expressed on the surface membrane, but it did oligomerize with alpha1 and beta2 subunits. These results suggested that the GABRG2 mutation, IVS6+2T->G, reduced surface alphabetagamma2 receptor levels, thus reducing GABAergic inhibition, by reducing GABRG2 transcript level and producing a stable, nonfunctional truncated subunit that had a dominant-negative effect on alphabetagamma2 receptor assembly. PMID- 22539855 TI - Impaired short-term plasticity in mossy fiber synapses caused by mitochondrial dysfunction of dentate granule cells is the earliest synaptic deficit in a mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) in the early stages is characterized by memory impairment, which may be attributable to synaptic dysfunction. Oxidative stress, mitochondrial dysfunction, and Ca2+ dysregulation are key factors in the pathogenesis of AD, but the causal relationship between these factors and synaptic dysfunction is not clearly understood. We found that in the hippocampus of an AD mouse model (Tg2576), mitochondrial Ca2+ handling in dentate granule cells was impaired as early as the second postnatal month, and this Ca2+ dysregulation caused an impairment of post-tetanic potentiation in mossy fiber CA3 synapses. The alteration of cellular Ca2+ clearance in Tg2576 mice is region specific within hippocampus because in another region, CA1 pyramidal neuron, no significant difference in Ca2+ clearance was detected between wild-type and Tg2576 mice at this early stage. Impairment of mitochondrial Ca2+ uptake was associated with increased mitochondrial reactive oxygen species and depolarization of mitochondrial membrane potential. Mitochondrial dysfunctions in dentate granule cells and impairment of post-tetanic potentiation in mossy fiber CA3 synapses were fully restored when brain slices obtained from Tg2576 were pretreated with antioxidant, suggesting that mitochondrial oxidative stress initiates other dysfunctions. Reversibility of early dysfunctions by antioxidants at the preclinical stage of AD highlights the importance of early diagnosis and antioxidant therapy to delay or prevent the disease processes. PMID- 22539856 TI - Relationship of a variant in the NTRK1 gene to white matter microstructure in young adults. AB - The NTRK1 gene (also known as TRKA) encodes a high-affinity receptor for NGF, a neurotrophin involved in nervous system development and myelination. NTRK1 has been implicated in neurological function via links between the T allele at rs6336 (NTRK1-T) and schizophrenia risk. A variant in the neurotrophin gene, BDNF, was previously associated with white matter integrity in young adults, highlighting the importance of neurotrophins to white matter development. We hypothesized that NTRK1-T would relate to lower fractional anisotropy in healthy adults. We scanned 391 healthy adult human twins and their siblings (mean age: 23.6 +/- 2.2 years; 31 NTRK1-T carriers, 360 non-carriers) using 105-gradient diffusion tensor imaging at 4 tesla. We evaluated in brain white matter how NTRK1-T and NTRK1 rs4661063 allele A (rs4661063-A, which is in moderate linkage disequilibrium with rs6336) related to voxelwise fractional anisotropy-a common diffusion tensor imaging measure of white matter microstructure. We used mixed-model regression to control for family relatedness, age, and sex. The sample was split in half to test reproducibility of results. The false discovery rate method corrected for voxelwise multiple comparisons. NTRK1-T and rs4661063-A correlated with lower white matter fractional anisotropy, independent of age and sex (multiple comparisons corrected: false discovery rate critical p = 0.038 for NTRK1-T and 0.013 for rs4661063-A). In each half-sample, the NTRK1-T effect was replicated in the cingulum, corpus callosum, superior and inferior longitudinal fasciculi, inferior fronto-occipital fasciculus, superior corona radiata, and uncinate fasciculus. Our results suggest that NTRK1-T is important for developing white matter microstructure. PMID- 22539858 TI - Social interaction enhances motor resonance for observed human actions. AB - Understanding the neural basis of social behavior has become an important goal for cognitive neuroscience and a key aim is to link neural processes observed in the laboratory to more naturalistic social behaviors in real-world contexts. Although it is accepted that mirror mechanisms contribute to the occurrence of motor resonance (MR) and are common to action execution, observation, and imitation, questions remain about mirror (and MR) involvement in real social behavior and in processing nonhuman actions. To determine whether social interaction primes the MR system, groups of participants engaged or did not engage in a social interaction before observing human or robotic actions. During observation, MR was assessed via motor-evoked potentials elicited with transcranial magnetic stimulation. Compared with participants who did not engage in a prior social interaction, participants who engaged in the social interaction showed a significant increase in MR for human actions. In contrast, social interaction did not increase MR for robot actions. Thus, naturalistic social interaction and laboratory action observation tasks appear to involve common MR mechanisms, and recent experience tunes the system to particular agent types. PMID- 22539857 TI - Cervical spinal erythropoietin induces phrenic motor facilitation via extracellular signal-regulated protein kinase and Akt signaling. AB - Erythropoietin (EPO) is typically known for its role in erythropoiesis but is also a potent neurotrophic/neuroprotective factor for spinal motor neurons. Another trophic factor regulated by hypoxia-inducible factor-1, vascular endothelial growth factor (VEGF), signals via ERK and Akt activation to elicit long-lasting phrenic motor facilitation (pMF). Because EPO also signals via ERK and Akt activation, we tested the hypothesis that EPO elicits similar pMF. Using retrograde labeling and immunohistochemical techniques, we demonstrate in adult, male, Sprague Dawley rats that EPO and its receptor, EPO-R, are expressed in identified phrenic motor neurons. Intrathecal EPO at C4 elicits long-lasting pMF; integrated phrenic nerve burst amplitude increased >90 min after injection (63 +/ 12% baseline 90 min after injection; p < 0.001). EPO increased phosphorylation (and presumed activation) of ERK (1.6-fold vs controls; p < 0.05) in phrenic motor neurons; EPO also increased pAkt (1.6-fold vs controls; p < 0.05). EPO induced pMF was abolished by the MEK/ERK inhibitor U0126 [1,4-diamino-2,3-dicyano 1,4-bis(o-aminophenylmercapto)butadiene] and the phosphatidylinositol 3 kinase/Akt inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4 one], demonstrating that ERK MAP kinases and Akt are both required for EPO induced pMF. Pretreatment with U0126 and LY294002 decreased both pERK and pAkt in phrenic motor neurons (p < 0.05), indicating a complex interaction between these kinases. We conclude that EPO elicits spinal plasticity in respiratory motor control. Because EPO expression is hypoxia sensitive, it may play a role in respiratory plasticity in conditions of prolonged or recurrent low oxygen. PMID- 22539859 TI - The subthalamic nucleus is one of multiple innervation sites for long-range corticofugal axons: a single-axon tracing study in the rat. AB - The frontal cortex provides strong excitatory inputs to the subthalamic nucleus (STN), and these cortico-STN inputs play critical roles in the control of basal ganglia activity. It has been assumed from anatomical and physiological studies that STN is innervated mainly by collaterals of thick and fast conducting pyramidal tract axons originating from the frontal cortex deep layer V neurons, implying that STN directly receives efferent copies of motor commands. To more closely examine this assumption, we performed biotinylated dextran amine anterograde tracing studies in rats to examine the cortical layer of origin, the sizes of parent axons, and whether or not the cortical axons emit any other collaterals to brain areas other than STN. This study revealed that the cortico STN projection is formed mostly by collaterals of a small fraction of small-to medium-sized long-range corticofugal axons, which also emit collaterals that innervate multiple other brain sites including the striatum, associative thalamic nuclei, superior colliculus, zona incerta, pontine nucleus, multiple other brainstem areas, and the spinal cord. The results imply that some layer V neurons are involved in associative control of movement through multiple brain innervation sites and that the cortico-STN projection is one part of this multiple corticofugal system. PMID- 22539861 TI - Adaptor protein complexes 1 and 3 are essential for generation of synaptic vesicles from activity-dependent bulk endosomes. AB - Activity-dependent bulk endocytosis is the dominant synaptic vesicle retrieval mode during high intensity stimulation in central nerve terminals. A key event in this endocytosis mode is the generation of new vesicles from bulk endosomes, which replenish the reserve vesicle pool. We have identified an essential requirement for both adaptor protein complexes 1 and 3 in this process by employing morphological and optical tracking of bulk endosome-derived synaptic vesicles in rat primary neuronal cultures. We show that brefeldin A inhibits synaptic vesicle generation from bulk endosomes and that both brefeldin A knockdown and shRNA knockdown of either adaptor protein 1 or 3 subunits inhibit reserve pool replenishment from bulk endosomes. Conversely, no plasma membrane function was found for adaptor protein 1 or 3 in either bulk endosome formation or clathrin-mediated endocytosis. Simultaneous knockdown of both adaptor proteins 1 and 3 indicated that they generated the same population of synaptic vesicles. Thus, adaptor protein complexes 1 and 3 play an essential dual role in generation of synaptic vesicles during activity-dependent bulk endocytosis. PMID- 22539860 TI - The density of EAAC1 (EAAT3) glutamate transporters expressed by neurons in the mammalian CNS. AB - The extracellular levels of excitatory amino acids are kept low by the action of the glutamate transporters. Glutamate/aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1) are the most abundant subtypes and are essential for the functioning of the mammalian CNS, but the contribution of the EAAC1 subtype in the clearance of synaptic glutamate has remained controversial, because the density of this transporter in different tissues has not been determined. We used purified EAAC1 protein as a standard during immunoblotting to measure the concentration of EAAC1 in different CNS regions. The highest EAAC1 levels were found in the young adult rat hippocampus. Here, the concentration of EAAC1 was ~0.013 mg/g tissue (~130 molecules MUm-3), 100 times lower than that of GLT-1. Unlike GLT-1 expression, which increases in parallel with circuit formation, only minor changes in the concentration of EAAC1 were observed from E18 to adulthood. In hippocampal slices, photolysis of MNI-D-aspartate (4-methoxy-7-nitroindolinyl D-aspartate) failed to elicit EAAC1-mediated transporter currents in CA1 pyramidal neurons, and D-aspartate uptake was not detected electron microscopically in spines. Using EAAC1 knock-out mice as negative controls to establish antibody specificity, we show that these relatively small amounts of EAAC1 protein are widely distributed in somata and dendrites of all hippocampal neurons. These findings raise new questions about how so few transporters can influence the activation of NMDA receptors at excitatory synapses. PMID- 22539864 TI - Microsaccades and blinks trigger illusory rotation in the "rotating snakes" illusion. AB - Certain repetitive arrangements of luminance gradients elicit the perception of strong illusory motion. Among them, the "Rotating Snakes Illusion" has generated a large amount of interest in the visual neurosciences, as well as in the public. Prior evidence indicates that the Rotating Snakes illusion depends critically on eye movements, yet the specific eye movement types involved and their associated neural mechanisms remain controversial. According to recent reports, slow ocular drift--a nonsaccadic type of fixational eye movement--drives the illusion, whereas microsaccades produced during attempted fixation fail to do so. Here, we asked human subjects to indicate the presence or absence of rotation during the observation of the illusion while we simultaneously recorded their eye movements with high precision. We found a strong quantitative link between microsaccade and blink production and illusory rotation. These results suggest that transient oculomotor events such as microsaccades, saccades, and blinks, rather than continuous drift, act to trigger the illusory motion in the Rotating Snakes illusion. PMID- 22539863 TI - Intrinsic and extrinsic mechanisms control the termination of cortical interneuron migration. AB - During development, neurons migrate from their site of origin to their final destinations. Upon reaching this destination, the termination of their migration is crucial for building functional architectures such as laminated structures and nuclei. How this termination is regulated, however, is not clear. Here, we investigated the contribution of cell-intrinsic mechanisms and extrinsic factors. Using GAD67-GFP knock-in mice and in utero electroporation cell labeling, we visualized GABAergic neurons and analyzed their motility in vitro. We find that the motility of GABAergic neurons in cortical slices gradually decreases as development proceeds and is almost abolished by the end of the first postnatal week. Consistent with this, a reduction of embryonic interneuron motility occurred in dissociated cultures. This is in part due to cell-intrinsic mechanisms, as a reduction in motility is observed during long-term culturing on glial feeder cells. Cell-intrinsic regulation is further supported by observations that interneurons labeled in early stages migrated more actively than those labeled in late stages in the same cortical explant. We found evidence suggesting that upregulation of the potassium-chloride cotransporter KCC2 underlies this intrinsic regulation. Reduced motility is also observed when embryonic interneurons are plated on postnatal cortical feeder cells, suggesting extrinsic factors derived from the postnatal cortex too contribute to termination. These factors should include secreted molecules, as cultured postnatal cortical cells could exercise this effect without directly contacting the interneuron. These findings suggest that intrinsic mechanisms and extrinsic factors coordinate to reduce the motility of migrating neurons, thereby leading to the termination of migration. PMID- 22539862 TI - BOLD responses in somatosensory cortices better reflect heat sensation than pain. AB - The discovery of cortical networks that participate in pain processing has led to the common generalization that blood oxygen level-dependent (BOLD) responses in these areas indicate the processing of pain. Physical stimuli have fundamental properties that elicit sensations distinguishable from pain, such as heat. We hypothesized that pain intensity coding may reflect the intensity coding of heat sensation during the presentation of thermal stimuli during fMRI. Six 3T fMRI heat scans were collected for 16 healthy subjects, corresponding to perceptual levels of "low innocuous heat," "moderate innocuous heat," "high innocuous heat," "low painful heat," "moderate painful heat," and "high painful heat" delivered by a contact thermode to the face. Subjects rated pain and heat intensity separately after each scan. A general linear model analysis detected different patterns of brain activation for the different phases of the biphasic response to heat. During high painful heat, the early phase was associated with significant anterior insula and anterior cingulate cortex activation. Persistent responses were detected in the right dorsolateral prefrontal cortex and inferior parietal lobule. Only the late phase showed significant correlations with perceptual ratings. Significant heat intensity correlated activation was identified in contralateral primary and secondary somatosensory cortices, motor cortex, and superior temporal lobe. These areas were significantly more related to heat ratings than pain. These results indicate that heat intensity is encoded by the somatosensory cortices, and that pain evaluation may either arise from multimodal evaluative processes, or is a distributed process. PMID- 22539865 TI - The aftereffect of a spatial offset between Gabor patches depends on carrier orientations. AB - This study explored the orientation connectivity in a contrast modulation processing mechanism, modeled as two filtering stages with nonlinear processing in between, by investigating how a negative aftereffect of a contrast-defined spatial offset is influenced by carrier orientations in the adapting stimulus. After adaptation to multiple, globally presented pairs of Gabor patches with a specific horizontal offset, subjects perceived a vertically aligned test pair of patches as offset in the orientation opposite to that of the adaptor. Although the orientations of the carrier gratings in the adaptor pairs were irrelevant to the task, the aftereffect magnitude depended on them. A large aftereffect was observed when the carrier orientations were parallel and/or perpendicular to the contrast-defined orientation, supporting the notion that second-stage filters receive strong inputs from first-stage filters with parallel and perpendicular orientation preferences. Furthermore, the aftereffect was also large when the carrier for only one patch was parallel or perpendicular, and no significant difference in the aftereffect magnitude was observed whether the adaptor pair contained one or two such patches. These results suggest that connectivity is not strictly selective to parallel and perpendicular relationships. Spatially heterogeneous connectivity might explain the observed effect. PMID- 22539866 TI - Synthesis of Heterobactins A and B and Nocardia Heterobactin. AB - The synthesis of the Rhodococcus erythropolis siderophores heterobactins A and B, and the structurally related Nocardia heterobactin, is described. Two approaches for the assembly of these asymmetric ligand donor chelators are explored. In the first approach, a scheme predicated on the biosynthesis of the Paracoccus denitrificans siderophore, parabactin, is employed. In this approach, the central donor synthon is added last. In the second scheme, the central donor and the terminal 2,3-dihydroxybenzoyl fragment are first fixed to the ligand's D ornithine backbone. This is followed by condensation with the cyclic ornithine hydroxamate glycine segment. The schemes offer a flexible approach to other heterobactins. Job's plots suggest that heterobactin A and Nocardia heterobactin form 1:1 ligand/metal complexes, while heterobactin B forms a 3:2 ligand/metal complex. PMID- 22539867 TI - An Initial Investigation into Naturally Occurring Loss- and Gain-Framed Memorable Breast Cancer Messages. AB - Memorable message research examines interpersonal messages "...remembered for extremely long periods of time and which people perceive as a major influence on the course of their lives" (Knapp, Stohl, & Reardon, 1981, p. 27). They can also guide actions, such as health behaviors. This exploratory research examined self reported memorable messages about breast cancer to determine if they were framed, emphasizing either the benefits (gain-framed) or the costs (loss-framed) of a behavior. About one-fourth of the messages were framed, with most being gain framed. The messages tended to emphasize early detection actions. Study limitations and implications for future research are discussed. PMID- 22539868 TI - Getting Personal: Progress and Pitfalls in HIV Prevention Among Latinas. PMID- 22539869 TI - Curcumin protects retinal pigment epithelial cells against oxidative stress via induction of heme oxygenase-1 expression and reduction of reactive oxygen. AB - PURPOSE: To determine whether curcumin induces expression of the defensive enzyme heme oxygenase-1 (HO-1) and protects cells against oxidative stress in cultured human retinal pigment epithelial cells. METHODS: Effective concentrations and toxicities of curcumin were determined after 3 h of curcumin treatment with the 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Confluent human retinal pigment epithelium cell lines (ARPE-19) were preincubated with curcumin and oxidatively challenged with H(2)O(2). HO-1 expression was determined with western blot analysis. To confirm the protective role of HO-1 in oxidative stress, small interfering RNA (siRNA) against HO-1 or inhibitor of HO-1 was treated with curcumin in retinal pigment epithelium cells. Intracellular levels of reactive oxygen species (ROS) were measured with flow cytometry and confocal microscopy. Apoptosis was evaluated with Annexin V-fluoroscein isothiocyanate staining. RESULTS: Curcumin had little cytotoxicity at concentrations less than 30 MUM, and HO-1 expression was the highest at the 15 MUM concentration. At this concentration, curcumin also increased the cytoprotective effect against the oxidative stress of H(2)O(2) through the reduction of ROS levels in human retinal pigment epithelial cells. Curcumin's effect on the reduction of ROS was mediated by the increase in HO-1 expression. CONCLUSIONS: Curcumin upregulated the oxidative stress defense enzyme HO-1 and may protect human retinal pigment epithelial cells against oxidative stress by reducing ROS levels. PMID- 22539870 TI - Combination of blood oxygen level-dependent functional magnetic resonance imaging and visual evoked potential recordings for abnormal visual cortex in two types of amblyopia. AB - PURPOSE: To elucidate the different neuromechanisms of subjects with strabismic and anisometropic amblyopia compared with normal vision subjects using blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI) and pattern-reversal visual evoked potential (PR-VEP). METHODS: Fifty-three subjects, age range seven to 12 years, diagnosed with strabismic amblyopia (17 cases), anisometropic amblyopia (20 cases), and normal vision (16 cases), were examined using the BOLD-fMRI and PR-VEP of UTAS-E3000 techniques. Cortical activation by binocular viewing of reversal checkerboard patterns was examined in terms of the calcarine region of interest (ROI)-based and spatial frequency-dependent analysis. The correlation of cortical activation in fMRI and the P(100) amplitude in VEP were analyzed using the SPSS 12.0 software package. RESULTS: In the BOLD fMRI procedure, reduced areas and decreased activation levels were found in Brodmann area (BA) 17 and other extrastriate areas in subjects with amblyopia compared with the normal vision group. In general, the reduced areas mainly resided in the striate visual cortex in subjects with anisometropic amblyopia. In subjects with strabismic amblyopia, a more significant cortical impairment was found in bilateral BA 18 and BA 19 than that in subjects with anisometropic amblyopia. The activation by high-spatial-frequency stimuli was reduced in bilateral BA 18 and 19 as well as BA 17 in subjects with anisometropic amblyopia, whereas the activation was mainly reduced in BA 18 and BA 19 in subjects with strabismic amblyopia. These findings were further confirmed by the ROI-based analysis of BA 17. During spatial frequency-dependent VEP detection, subjects with anisometropic amblyopia had reduced sensitivity for high spatial frequency compared to subjects with strabismic amblyopia. The cortical activation in fMRI with the calcarine ROI-based analysis of BA 17 was significantly correlated with the P(100) amplitude in VEP recording. CONCLUSIONS: This study suggested that different types of amblyopia had different cortical responses and combinations of spatial frequency-dependent BOLD-fMRI with PR-VEP could differentiate among various kinds of amblyopia according to the different cortical responses. This study can supply new methods for amblyopia neurology study. PMID- 22539872 TI - Study of a US cohort supports the role of ZNF644 and high-grade myopia susceptibility. AB - PURPOSE: Myopia, or nearsightedness, is highly prevalent in Asian countries and is considered a serious public health issue globally. High-grade myopia can predispose individuals to myopic maculopathy, premature cataracts, retinal detachment, and glaucoma. A recent study implicated zinc finger protein 644 isoform 1 (ZNF644) variants with non-syndromic high-grade myopia in a Chinese Asian population. Herein we focused on investigating the role for ZNF644 variants in high-grade myopia in a United States (US) cohort. METHODS: DNA from a case cohort of 131 subject participants diagnosed with high-grade myopia was screened for ZNF644 variants. Spherical refractive error of -<=-6.00 diopters (D) in at least one eye was defined as affected. All coding, intron/exon boundaries were screened using Sanger sequencing. Single nucleotide allele frequencies were determined by screening 672 ethnically matched controls. RESULTS: Sequencing analysis did not detect previously reported mutations. However, our analysis identified 2 novel single nucleotide variants (c.725C>T, c.821A>T) in 2 high grade myopia individuals- one Caucasian and one African American, respectively. These variants were not found in normal controls. A rare variant - dbsSNP132 (rs12117237->c.2119A>G) - with a minor allele frequency of 0.2% was present in 6 additional cases, but was also present in 5 controls. CONCLUSIONS: Our study has identified two novel variants in ZNF644 associated with high-grade myopia in a US cohort. Our results suggest that ZNF644 may play a role in myopia development. PMID- 22539871 TI - Long-term survival and differentiation of retinal neurons derived from human embryonic stem cell lines in un-immunosuppressed mouse retina. AB - PURPOSE: To examine the potential of NIH-maintained human embryonic stem cell (hESC) lines TE03 and UC06 to differentiate into retinal progenitor cells (hESC RPCs) using the noggin/Dkk-1/IGF-1/FGF9 protocol. An additional goal is to examine the in vivo dynamics of maturation and retinal integration of subretinal and epiretinal (vitreous space) hESC-RPC grafts without immunosuppression. METHODS: hESCs were neuralized in vitro with noggin for 2 weeks and expanded to derive neuroepithelial cells (hESC-neural precursors, NPs). Wnt (Integration 1 and wingless) blocking morphogens Dickkopf-1 (Dkk-1) and Insulin-like growth factor 1 (IGF-1) were used to direct NPs to a rostral neural fate, and fibroblast growth factor 9 (FGF9)/fibroblast growth factor-basic (bFGF) were added to bias the differentiation of developing anterior neuroectoderm cells to neural retina (NR) rather than retinal pigment epithelium (RPE). Cells were dissociated and grafted into the subretinal and epiretinal space of young adult (4-6-week-old) mice (C57BL/6J x129/Sv mixed background). Remaining cells were replated for (i) immunocytochemical analysis and (ii) used for quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis. Mice were sacrificed 3 weeks or 3 months after grafting, and the grafts were examined by histology and immunohistochemistry for survival of hESC-RPCs, presence of mature neuronal and retinal markers, and the dynamics of in vivo maturation and integration into the host retina. RESULTS: At the time of grafting, hESC-RPCs exhibited immature neural/neuronal immunophenotypes represented by nestin and neuronal class III beta-tubulin, with about half of the cells positive for cell proliferation marker Kiel University -raised antibody number 67 (Ki67), and no recoverin-positive (recoverin [+]) cells. The grafted cells expressed eye field markers paired box 6 (PAX6), retina and anterior neural fold homeobox (RAX), sine oculis homeobox homolog 6 (SIX6), LIM homeobox 2 (LHX2), early NR markers (Ceh-10 homeodomain containing homolog [CHX10], achaete-scute complex homolog 1 [MASH1], mouse atonal homolog 5 [MATH5], neurogenic differentiation 1 [NEUROD1]), and some retinal cell fate markers (brain-specific homeobox/POU domain transcription factor 3B [BRN3B], prospero homeobox 1 [PROX1], and recoverin). The cells in the subretinal grafts matured to predominantly recoverin [+] phenotype by 3 months and survived in a xenogenic environment without immunosuppression as long as the blood-retinal barrier was not breached by the transplantation procedure. The epiretinal grafts survived but did not express markers of mature retinal cells. Retinal integration into the retinal ganglion cell (RGC) layer and the inner nuclear layer (INL) was efficient from the epiretinal but not subretinal grafts. The subretinal grafts showed limited ability to structurally integrate into the host retina and only in cases when NR was damaged during grafting. Only limited synaptogenesis and no tumorigenicity was observed in grafts. CONCLUSIONS: Our studies show that (i) immunosuppression is not mandatory to xenogenic graft survival in the retina, (ii) the subretinal but not the epiretinal niche can promote maturation of hESC RPCs to photoreceptors, and (iii) the hESC-RPCs from epiretinal but not subretinal grafts can efficiently integrate into the RGC layer and INL. The latter could be of value for long-lasting neuroprotection of retina in some degenerative conditions and glaucoma. Overall, our results provide new insights into the technical aspects associated with cell-based therapy in the retina. PMID- 22539874 TI - Pax6 interacts with SPARC and TGF-beta in murine eyes. AB - PURPOSE: To understand the mechanism of the function of paired box 6 (Pax6), a master regulator of eye development and functions, Pax6-interacting proteins were studied. It is presumed that the interaction of Pax6 with proteins in terms of morphogenesis and the maintenance of the functional anatomy of the eyes cannot be ignored. The interaction of Pax6 with matricellular protein and transforming growth factors (TGFs) is explored and presented in this report. METHODS: Co localization was studied through fluorescence microscopy. The physical interaction of Pax6 interacting proteins was explored through co immunoprecipitation assay of samples from murine eyes. RESULTS: It was interesting to observe the co-localization and physical interaction of Pax6, transforming growth factor-beta (TGF-beta), and secreted protein acidic and rich in cysteine (SPARC) in murine eyes. CONCLUSIONS: The interaction of Pax6, TGF beta, and SPARC in murine eyes indicates that Pax6 function is regulated through TGF-beta, and SPARC influences the shuttling of Pax6 via the TGF-beta/Smad signaling pathway. PMID- 22539873 TI - A novel FBN1 mutation in a Chinese family with isolated ectopia lentis. AB - PURPOSE: To identify the genetic defect in an autosomal dominant isolated ectopia lentis (EL) family. METHODS: Detailed family history and clinical data were collected from the family including sixteen patients with isolated EL. Blood samples of nine patients, one normal person and two unknown children's were collected. Genomic DNA was extracted from leukocytes of peripheral blood. Genotyping was performed by microsatellite markers and logarithm-of-odds (LOD) scores were calculated using the LINKAGE Programs. Mutation screening in the candidate gene, fibrillin-1 (FBN1), was performed by direct sequencing. RESULTS: Linkage to the FBN1 locus is verified. Mutation screening in FBN1 identified a C>T transition at nucleotide position c.2920. This nucleotide change results in the cysteine substitution for highly conserved arginine at codon 974 (p.R974C). This mutation is identified in all affected individuals but is not found in 50 control healthy people. CONCLUSIONS: A novel mutation of FBN1 results in an arginine to cysteine residue (p.R974C) substitution, which is responsible for the patients with isolated EL in this Chinese family. PMID- 22539876 TI - Ohio USA stoneflies (Insecta, Plecoptera): species richness estimation, distribution of functional niche traits, drainage affiliations, and relationships to other states. AB - Ohio is an eastern USA state that historically was >70% covered in upland and mixed coniferous forest; about 60% of it glaciated by the Wisconsinan glacial episode. Its stonefly fauna has been studied in piecemeal fashion until now. The assemblage of Ohio stoneflies was assessed from over 4,000 records accumulated from 18 institutions, new collections, and trusted literature sources. Species richness totaled 102 with estimators Chao2 and ICE Mean predicting 105.6 and 106.4, respectively. Singletons and doubletons totaled 18 species. All North American families were represented with Perlidae accounted for the highest number of species at 34. The family Peltoperlidae contributed a single species. Most species had univoltine-fast life cycles with the vast majority emerging in summer, although there was a significant component of winter stoneflies. Nine United States Geological Survey hierarchical drainage units level 6 (HUC6) were used to stratify specimen data. Species richness was significantly related to the number of unique HUC6 locations, but there was no relationship with HUC6 drainage area. A nonparametric multidimensional scaling analysis found that larger HUC6s in the western part of the state had similar assemblages with lower species richness that were found to align with more savanna and wetland habitat. Other drainages having richer assemblages were aligned with upland deciduous and mixed coniferous forests of the east and south where slopes were higher. The Ohio assemblage was most similar to the well-studied fauna of Indiana (88 spp.) and Kentucky (108 spp.), two neighboring states. Many rare species and several high quality stream reaches should be considered for greater protection. PMID- 22539877 TI - The soil mite genus Conchogneta (Acari, Oribatida, Autognetidae), with new findings from Mongolia. AB - This work deals with taxonomy, geographical distribution as well as known ecology of oribatid mites of the genus Conchogneta Grandjean, 1963 in the world. The majority of species belonging to this genus is known to be widely distributed in Europe, but only three of them are found in other areas of the northern hemisphere. Most species of Conchogneta are inhabitants of litter of various types of forestas, terricolous and epiphytic bryophytes, epiphytic lichens, and soil of steppe, river valleys, moor, oligotrophic bogs, floodland assemblages etc. A new species, Conchogneta glabrisensillatasp. n. is described, and another species, Conchogneta traegardhi (Forsslund, 1947) is redescribed from the northern and western parts of Mongolia, respectively. Conchogneta is recorded for the first time for the fauna of Mongolia. The species status of Conchogneta dalecarlica (Forsslund, 1947) is discussed. Species descriptions are accompanied with detailed illustrations. Furthermore, a key is provided for the identification of adults of the known species of Conchogneta in the world. PMID- 22539875 TI - Present and Prospective Pharmacotherapy for the Management of Patients with Type 2 Diabetes. AB - Diabetes Mellitus is a chronic condition prevalent worldwide. Type 2 diabetes is the most common form of diabetes, comprising 90% to 95% of all cases. Over the last few decades, the importance of glycemic control and its impact on prevention of diabetes-related complications has been documented in multiple clinical trials. As most patients with type 2 diabetes will require pharmacologic intervention to achieve and maintain appropriate glycemic control, new medications targeting different aspects of the pathophysiology of type 2 diabetes have been a significant focus of research and development. During the last decade, multiple new medications for diabetes management have become available: these medications have novel mechanisms of action, differences in effectiveness, and varying side effect profiles which will be reviewed in this article. Some of these newer medications, such as the GLP-1 analogues and DPP-4 inhibitors, have become widely accepted as therapeutic options for the management of type 2 diabetes.Additional classes of glucose-lowering medications are expected to become available in the near future. This manuscript will summarize available data regarding these newer and prospective medications for the management of type 2 diabetes. PMID- 22539878 TI - Description of two new species of Clivina Latreille (Coleoptera, Carabidae, Clivinini) from southeastern United States. AB - Two new species of the genus Clivina Latreille are described. One, Clivina choatei Bousquet & Skelley, belongs to the nominotypical subgenus and is known from six specimens collected in northern Florida. The species is structurally similar to Clivina myops Bousquet, known only from the holotype found in North Carolina, but differs among others by its smaller size and wider elytral striae. The second species, Clivina alabama Bousquet, belongs to the subgenus Antroforceps Barr and is known from two specimens collected in north-central Alabama. The species is structurally most similar to Clivina sasajii Ball, known only from Latimer County in Oklahoma, but differs among others in the absence of eyes and in having the pronotum and elytra proportionally wider. PMID- 22539879 TI - A remarkable new species of Euragallia from Peru (Insecta, Hemiptera, Cicadellidae, Agalliini), including the description of a peculiar structure of the male genitalia. AB - A new species of Euragallia Oman, 1938 from Peru (Pasco Department) is described and illustrated. Euragallia batmanisp. n. can be distinguished from the other species of the genus by the very posteriorly pronounced male pygofer, with an apical hook-like projection, and by the well-developed dorsal area of the aedeagal base, resembling the open wings of a bat. With the addition of Euragallia batmani sp. n., the number of Euragallia species is increased to 21. Only one additional species of the genus is recorded from Peru (Euragallia prion Kramer, 1976). A comparison between the new species and Euragallia prion is provided. A conspicuous structure, which connects the subgenital plates to the styles, is described in detail and named. PMID- 22539880 TI - Diversity of the strongly rheophilous tadpoles of Malagasy tree frogs, genus Boophis (Anura, Mantellidae), and identification of new candidate species via larval DNA sequence and morphology. AB - This study provides detailed morphological descriptions of previously unknown tadpoles of the treefrog genus Boophis Tschudi and analyses of habitat preferences of several of these tadpoles in Ranomafana National Park. A total of twenty-two tadpoles determined via DNA barcoding are characterized morphologically herein, fourteen of them for the first time. Twelve of these tadpoles belong to taxonomically undescribed candidate species which in several cases are so far only known from their larval stages. Our data show that the larvae of some of these candidate species occur syntopically yet maintaining a clearly correlated genetic and morphological identity, suggesting that they indeed are true biological and evolutionary species. Tadpoles considered to belong to the "adherent" ecomorphological guild inhabit fast-running waters and their oral disc is commonly to continuously attached to the rocky substrate, supposedly to keep their position in the water current. Some of these species are characterized by the presence of a dorsal gap of papillae and the absence of an upper jaw sheath. This guild includes the tadpoles of the Boophis albipuncatus group (Boophis ankaratra, Boophis schuboeae, Boophis albipunctatus, Boophis sibilans, Boophis luciae), and of the Boophis mandraka group (Boophis sambirano and six candidate species related to this species and to Boophis mandraka). Tadpoles considered belonging to the "suctorial" guild inhabit fast-running waters where they use frequently their oral disc to attach to the substrate. They have an enlarged oral disc without any dorsal gap, including two nominal species (Boophis marojezensis, Boophis vittatus), and five candidate species related to Boophis marojezensis. An ecological analysis of the tadpoles of Boophis luciae, Boophis schuboeae and Boophis marojezensis [Ca51 JQ518198] from Ranomafana National Park did not provide evidence for a clear preference of these tadpoles to the fast flowing microhabitat sections of the stream, although the tadpoles discussed in this study are typically caught in this habitat. PMID- 22539881 TI - New Coleoptera records from New Brunswick, Canada: Gyrinidae, Carabidae, and Dytiscidae. AB - Dineutus assimilis Kirby and Dineutus discolor Aube of the Family Gyrinidae are newly reported from New Brunswick, Canada. Four species of Carabidae, Agonum (Agonum) piceolum (LeConte), Bembidion (Pseudoperyphus) rufotinctum Chaudoir, Harpalus (Harpalus) opacipennis (Haldeman), and Pterostichus (Melanius) castor Goulet & Bousquet are newly reported from New Brunswick and the Maritime provinces, and one species of Dytiscidae, Liodessus noviaffinis Miller, is newly recorded for the province. Collection, habitat data, and distribution maps are presented for each species. PMID- 22539882 TI - New Coleoptera records from New Brunswick, Canada: Histeridae. AB - Eighteen species of Histeridae are newly reported from New Brunswick, Canada. This brings the total number of species known from New Brunswick to 42. Seven of these species, Acritus exguus (Erichson), Euspilotus rossi (Wenzel), Hypocaccus fitchi (Marseul), Dendrophilus kiteleyi Bousquet and Laplante, Platysoma cylindricum (Paykull), Atholus sedecimstriatus (Say), and Margarinotus harrisii (Kirby) are recorded from the Maritime provinces for the first time. Collection and bionomic data are presented for these species. PMID- 22539883 TI - New Coleoptera records from New Brunswick, Canada: Geotrupidae and Scarabaeidae. AB - Two species of Geotrupidae, Geotrupes splendidus splendidus (Fabricius) and Odonteus liebecki (Wallis), are newly reported for New Brunswick, Canada. Twelve species of Scarabaeidae are added to the faunal list of the province, including Aegialia criddlei Brown, Caelius humeralis (Brown), Dialytellus dialytoides (Fall), Diapterna omissa (LeConte), Diapterna pinguis (Haldeman), Planolinoides aenictus (Cooper and Gordon), Stenotothorax badipes (Melsheimer), and Ataenius strigatus (Say), which are also newly recorded for the Maritime provinces. Collection data, habitat data, and distribution maps are presented for each species. PMID- 22539884 TI - New Coleoptera records from New Brunswick, Canada: Eucinetidae and Scirtidae. AB - We report two species of Eucinetidae, Nycteus oviformis (LeConte) and Nycteus punctulatus (LeConte), new to New Brunswick, Canada and confirm the presence of Nycteus testaceus (LeConte). Nycteus oviformis is newly recorded from the Maritime provinces. Additional locality data are provided for Eucinetus haemorrhoidalis (Germar) and Eucinetus morio LeConte. Five species of Scirtidae, Cyphon ruficollis (Say),Prionocyphon discoideus (Say), Sacodes pulchella (Guerin Meneville), Elodes maculicollis Horn, and Sarabandus robustus (LeConte) are added to the New Brunswick faunal list. Sarabandus robustus is newly recorded from Canada; Cyphon ruficollis, Prionocyphon discoideus and Sacodes pulchella are new for the Maritime provinces. Collection and habitat data, and distribution maps are presented for these species. PMID- 22539885 TI - New Coleoptera records from New Brunswick, Canada: Buprestidae. AB - Nine species of Buprestidae; Agrilus bilineatus (Weber), Agrilus crinicornis Horn, Agrilus obsoletoguttatus Gory, Agrilus putillus putillus Say, Brachys ovatus (Weber), Buprestis sulcicollis (LeConte), Chalcophora liberta (Germar), Phaenops aeneola (Melsheimer), and Taphrocerus gracilis (Say) are newly recorded for New Brunswick, Canada. Agrilus bilineatus, A. crinicornis, A. obsoletoguttatus,and B. ovatus are also newly reported for the Maritime provinces. Lindgren 12-funnel traps do not appear to be an effective tool for sampling the Bupresidae. Collection, habitat notes, and distribution maps are presented for each species. PMID- 22539886 TI - New Coleoptera records from New Brunswick, Canada: Dryopidae, Elmidae, Psephenidae, and Ptilodactylidae. AB - We report five new species records for New Brunswick, Canada from the Coleoptera families Dryopidae, Elimidae, Psephenidae, and Ptilodactylidae. Dryops viennensis (Heer) (Dryopidae) and Promoresia elegans (LeConte) (Elmidae) are added to the faunal list for New Brunswick and the Maritime provinces. Two Psephenidae species, Ectopria nervosa (Melsheimer) and Ectopria thoracica (Ziegler) are reported for the first time for New Brunswick, and the latter species is also new for the Maritime provinces. Anchytarsus bicolor (Melsheimer) and the family Ptilodactylidae are newly recorded for New Brunswick and the Maritime provinces. Collection, habitat data, and distribution maps are presented for all of these species. PMID- 22539887 TI - New Coleoptera records from New Brunswick, Canada: Eucnemidae. AB - We report nine species of Eucnemidae new to the province and additional records for Onichodon canadensis (Brown) and Dromaeolus harringtoni Horn. Five species, Xylophilus cylindriformis (Horn), Entomophthalmus rufiolus (LeConte), Stethon pectorosus LeConte, Onichodon orchesides Newman, and Isarthrus rufipes (Melsheimer), are newly recorded for the Maritime provinces. This brings the total number of Eucnemidae recorded from New Brunswick to 15 species. Lindgren funnel traps are an effective tool for sampling the Eucnemidae. PMID- 22539888 TI - New Coleoptera records from New Brunswick, Canada: Elateridae. AB - Twenty-two species of Elateridae are newly reported for New Brunswick, Canada. Negastrius exiguus (Randall) is removed from the faunal list and Agriotes pubescens Melsheimer is re-instated as a member of the New Brunswick fauna. Agriotes pubescens Melsheimer, Dalopius brevicornis W. J. Brown, Danosoma obtectum (Say) and Megapenthes solitarius Fall are newly reported for the Maritime provinces. Collection data, bionomic data, and distribution maps are presented for all these species. PMID- 22539889 TI - New Coleoptera records from New Brunswick, Canada: Lycidae. AB - Eight species of Lycidae are newly recorded from New Brunswick, Canada, bringing the total number of species known from the province to 16. The first documented records from New Brunswick are provided for Greenarius thoracicus (Randall) Erotides scuptilis (Say), and Calopteron terminale (Say) reported by Majka et al. (2011). Eropterus arculus Green, Lopheros crenatus (Germar), and Calochromus perfacetus (Say) are reported for the first time in the Maritime provinces. Collection data, habitat data, and distribution maps are presented for all these species. PMID- 22539890 TI - New Coleoptera records from New Brunswick, Canada: Dermestidae, Endecatomidae, Bostrichidae, and Ptinidae. AB - We report ten new species records for the Coleoptera fauna of New Brunswick, Canada from the families Dermestidae, Endecatomidae, Bostrichidae, and Ptinidae. Anthrenus fuscus Olivier and Anthrenus museorum (Linnaeus) of the family Dermestidae are newly recorded for New Brunswick. Endecatomus rugosus (Randall) and the family Endecatomidae are recorded for the first time for New Brunswick and the Maritime provinces. Two Bostrichidae, the adventive Dinoderus minutus (Fabricius) and the native Stephanopachys substriatus (Paykull), are newly recorded for the province. Five species of Ptinidae, the adventive Anobium punctatum (DeGeer) and Microbregma emarginatum emarginatum (Duftschmid), and the native Hadrobregmus notatus (Say), Ptilinus lobatus Casey, and Ptilinus ruficornis Say are added to the faunal list of New Brunswick. Collection data, habitat data, and distribution maps are presented for all these species. PMID- 22539891 TI - New Coleoptera records from New Brunswick, Canada: Trogossitidae, Cleridae, and Melyridae, with an addition to the fauna of Nova Scotia. AB - Grynocharis quadrilineata (Melsheimer) and Tenebroides corticalis (Melsheimer) of the family Trogossitidae are newly recorded for New Brunswick, Canada. Additional records of the recently reported Calitys scabra (Thunberg)and Ostoma fraterna (Randall) are presented for the province. The record of Ostoma fraterna is the first recent record of this species from New Brunswick. Additional New Brunswick records of the thaneroclerine, Zenodosus sanguineus (Say), are given, indicting that this species is common and widespread in the province. One species of Cleridae, Cymatodera bicolor (Say),is newly reported from New Brunswick, and the adventive Thanasimus formicarius Linnaeus is newly recorded from Nova Scotia and the Maritime provinces. Attalus morulus (LeConte) and Dolichosoma foveicolle (Kirby), family Melyridae, are reported for the first time for New Brunswick and the Maritime provinces. Collection, habitat data, and distribution maps are presented for these species. PMID- 22539892 TI - New Coleoptera records from New Brunswick, Canada: Silvanidae and Laemophloeidae. AB - One species of Silvanidae, Silvanus muticus Sharp, is newly recorded from New Brunswick, Canada and the Maritime provinces; Ahasverus longulus (Blatchley) is re-instated to the faunal list of the province, and we report the first recent provincial records of Dendrophagus cygnaei Mannerheim. Five species of Laemophloeidae (Charaphloeus convexulus (LeConte), Charaphloeus undescribed species (near adustus), Leptophloeus angustulus (LeConte), Placonotus zimmermanni (LeConte), and an undescribed Leptophloeus species) are added to the faunal list of New Brunswick. Collection data, bionomic data, and distribution maps are presented for all these species. PMID- 22539893 TI - New Coleoptera records from New Brunswick, Canada: Sphindidae, Erotylidae, Monotomidae, and Cryptophagidae. AB - Two species of Sphindidae, Odontosphindus denticollis LeConteand Sphindus trinifer Casey, are reported for the first time for New Brunswick. Another species, Sphindus near americanus LeConte is reported from the province but may be an undescribed species, pending further study. Five species of Erotylidae are newly recorded for the province, including Tritoma humeralis Fabricius and Tritoma sanguinipennis (Say), which are new to the Maritime provinces. Three species of Monotomidae are added to the New Brunswick faunal list, including Pycnotomina cavicollis (Horn), which is newly recorded for the Maritime provinces. Six additional species of Cryptophagidae are reported for the province and the presence of Antherophagus convexulus LeContein New Brunswick is confirmed. Cryptophagus pilosus Gyllenhal and Myrmedophila americana (LeConte) are newly reported to the Maritime provinces. PMID- 22539894 TI - New Coleoptera records for New Brunswick, Canada: Kateretidae, Nitidulidae, Cerylonidae, Endomychidae, Coccinellidae, and Latridiidae. AB - We report 20 new species records for the Coleoptera fauna in New Brunswick, Canada, five of which are new records for the Maritime provinces, including one species that is new for Canada. One species of Kateretidae, Kateretes pusillus (Thunberg) is newly recorded for New Brunswick and the Maritime provinces. Stelidota octomaculata (Say), Phenolia grossa (Fabricius), andCryptarcha strigatula Parsons of the family Nitidulidae are added to the faunal list of New Brunswick; the latter species is new to the Maritime provinces. Two species of Cerylonidae, Philothermus glabriculus LeConte and Cerylon unicolor (Ziegler), are reported for the first time for New Brunswick. Philothermus glabriculus is new for the Maritime provinces. Two species of Endomychidae, Hadromychus chandleri Bousquet and Leschen and Danae testacea (Ziegler) are newly recorded for New Brunswick. Three species of Coccinelidae, Stethorus punctum punctum (LeConte), Naemia seriata seriata Melsheimer, and Macronaemia episcopalis (Kirby) are added to the provincial list. Macronaemia episcopalis (Kirby) is a species new to the Maritime provinces. Nine species of Latridiidae, Cartodere nodifer (Westwood), Dienerella ruficollis (Marsham), Enicmus aterrimus Motschulsky, Enicmus fictus Fall, Encimus histrio Jay and Tomlin, Lathridius minutus (Linnaeus), Stephostethus productus Rosenhauer, Corticaria elongata (Gyllenhal), and Corticarina longipennis (LeConte) are newly recorded for New Brunswick. Stephostehus productus is newly recorded from Canada. Collection and habitat data are presented for all these species. PMID- 22539895 TI - New Coleoptera records from New Brunswick, Canada: Mycetophagidae, Tetratomidae, and Melandryidae. AB - We report 21 new species records for the Coleoptera fauna of New Brunswick, Canada, seven of which are new records for the Maritime provinces. Four species of Mycetophagidae (Litargus didesmus Say, Litargus tetrapilotus LeConte, Mycetophagus punctatus Say, and Mycetophagus quadriguttatus Muller) are newly reported for the province of New Brunswick. Litargus didesmus is newly recorded for the Maritime provinces. Seven species of Tetratomidae are added to the faunal list of New Brunswick: Eustrophus tomentosus Say, Penthe obliquata (Fabricius), and Tetratoma tessellata Melsheimer are new to New Brunswick: Hallomenus serricornis LeConte, Pisenus humeralis Kirby, Synstrophus repandus (Horn), and Tetratoma variegata Casey, which are newly recorded for New Brunswick and the Maritime provinces. Ten additional species of Melandryidae are reported from New Brunswick, of which Orchesia cultriformis Laliberte, Orchesia ovata Laliberte, Phloeotrya fusca (LeConte), Scotochroides antennatus Mank, Spilotus quadripustulatus (Melsheimer), Symphora flavicollis (Haldeman), Symphora rugosa (Haldeman), and Zilora hispida LeConte are new for the province, and Microscapha clavicornis LeConte and Zilora nuda Provancher are newly recorded for the Maritime provinces. In addition, we report numerous additional records for three species of Mycetophagidae and one species of Melandryidae previously recorded from New Brunswick that suggest these species are more widely distributed than previously known. Collection, habitat data, and distribution maps are presented for all these species. PMID- 22539896 TI - New Coleoptera records from New Brunswick, Canada: Mordellidae and Ripiphoridae. AB - Eleven species of Mordellidae are newly recorded for New Brunswick, Canada. Six of these, Falsomordellistena discolor (Melsheimer), Falsomordellistena pubescens (Fabricius), Mordellistena ornata (Melsheimer), Mordellaria undulata (Melsheimer), Tomoxia inclusa LeConte, and Yakuhananomia bidentata (Say)are new for the Maritime provinces. Falsomordellistena pubescens is new to Canada. Pelecotoma flavipes Melsheimer (family Ripiphoridae) is reported for the first time for New Brunswick and the Maritime provinces. Collection and habitat data are presented for all these species. PMID- 22539897 TI - New Coleoptera records from New Brunswick, Canada: Tenebrionidae and Zopheridae. AB - Thirteen species of Tenebrionidae are newly reported for New Brunswick, Canada. Paratenetus punctatus Spinola, Pseudocistela brevis (Say), Mycetochara foveata (LeConte), and Xylopinus aenescens LeConte are recorded for the first time from the Maritime provinces. Platydema excavatum (Say) is removed from the faunal list of New Brunswick, and the presence of Platydema americanum Laporte and Brulle for the province is confirmed. This brings the total number of species of Tenebrionidae known from New Brunswick to 42. Two species of Zopheridae, Bitoma crenata Fabricius and Synchita fuliginosa Melsheimer, are newly recorded for New Brunswick, bringing the number of species known from the province to four. Bitoma crenata is new to the Maritime provinces. Collection and habitat data are presented for these species. PMID- 22539898 TI - New Coleoptera records from New Brunswick, Canada: Stenotrachelidae, Oedemeridae, Meloidae, Myceteridae, Boridae, Pythidae, Pyrochroidae, Anthicidae, and Aderidae. AB - We report 19 new species records for the faunal list of Coleoptera in New Brunswick, Canada, six of which are new records for the Maritime provinces, and one of which is new Canadian record. We also provide the first recent records for five additional species in New Brunswick. One new species of Stenotrachelidae, Cephaloon ungulare LeConte, is added to the New Brunswick faunal list. Additional records are provided for Cephaloon lepturides Newman, as well the first recent record of Nematoplus collaris LeConte. Two species of Oedemeridae, Asclera puncticollis (Say) and Asclera ruficollis (Say), are newly reported for New Brunswick, and additional locality and bionomic data are provided for Calopus angustus LeConte and Ditylus caeruleus (Randall). The records of Ditylus caerulus are the first recent records for the province. Three species of Meloidae, Epicauta pestifera Werner, Lytta sayi LeConte, and Meloe augustcollis Say are reported the first time for New Brunswick; Epicauta pestifera is newly recorded in Canada. Lacconotus punctatus LeConte and the family Mycteridaeis newly recorded for New Brunswick. The first recent records of Borus unicolor Say (Boridae) are reported from the province. One new species of Pythidae, Pytho siedlitzi Blair, and the first recent records of Pytho niger Kirby are added to the faunal list of New Brunswick. Three species of Pyrochroidae are newly reported for the province, including Pedilus canaliculatus (LeConte) and Pedilus elegans (Hentz), which are new for the Maritime provinces. Five species of Anthicidae and the first recent record of Anthicus cervinus LaFerte-Senectere are newly reported for New Brunswick. Anthicus melancholicus LaFerte-Senectere, Sapintus pubescens (LaFerte-Senectere), Notoxus bifasciatus (LeConte), and Stereopalpus rufipes Casey are new to the Maritime provinces faunal list. Ambyderus granularis (LeConte) is removed from the faunal list of the province. Three species of Aderidae, Vanonus huronicus Casey, Zonantes fasciatus (Melsheimer), and Zonantes pallidusWerner, are newly recorded for New Brunswick; Zonantes fasciatus and Vanonus huronicus are new for the Maritime provinces' faunal list. Collection data, bionomic data, and distribution maps are presented for all these species. PMID- 22539899 TI - New Coleoptera records from New Brunswick, Canada: Cerambycidae. AB - Five species of Cerambycidae, Acmaeops discoideus (Haldeman), Anelaphus villosus (Fabricius), Phymatodes species (CNC sp. n. #1), Sarosesthes fulminans (Fabricius), and Urgleptus signatus (LeConte) are newly recorded for New Brunswick, Canada. All but Acmaeops villosus are new to the Maritime provinces. Phymatodes testaceus (Linnaeus) is removed from the faunal list of the province as a result of mislabeled specimens, records of Phymatodes maculicollis LeConte are presented confirming the presence of this species in New Brunswick, and the first recent records ofNeospondylis upiformis (Mannerheim) are presented. Additional records are given for the recently recorded Phymatodes aereus (Newman), indicating a wider distribution in the province. Collection data, habitat data, and distribution maps are presented for each species. PMID- 22539900 TI - New Coleoptera records from New Brunswick, Canada: Megalopodidae and Chrysomelidae. AB - Zeugophora varians Crotch and the family Megalopodidae are newly recorded for New Brunswick, Canada. Twenty-eight species of Chrysomelidae are newly recorded for New Brunswick, including Acalymma gouldi Barber, Altica knabii Blatchley, Altica rosae Woods, Altica woodsi Isely, Bassareus mammifer (Newman), Chrysolina marginata (Linnaeus), Chrysomela laurentia Brown, Crepidodera violacea Melsheimer, Cryptocephalus venustus Fabricius, Neohaemonia melsheimeri (Lacordaire), Neohaemonia nigricornis (Kirby), Pachybrachis bivittatus (Say), Pachybrachis m-nigrum (Melsheimer), Phyllobrotica limbata (Fabricius), Psylliodes affinis (Paykull), Odontota dorsalis (Thunberg), Ophraella communa (LeSage), Ophraella cribrata (LeConte), Ophraella notata (Fabricius), Systena hudsonias (Forster), Tricholochmaea ribicola (Brown), and Tricholochmaea rufosanguinea (Say), which are also newly recorded for the Maritime provinces. Collection data, habitat data, and distribution maps are presented for all these species. PMID- 22539901 TI - New Coleoptera records from New Brunswick, Canada: Anthribidae, Brentidae, Dryophthoridae, Brachyceridae, and Curculionidae, with additions to the fauna of Quebec, Nova Scotia and Prince Edward Island. AB - We report 63 species of Curculionoidea that are new to New Brunswick (three species of Anthribidae, four species of Brentidae, three species of Dryophthoridae, three species of Brachyceridae, 50 species of Curculionidae). Among these are 27 species (two Anthribidae, two Brenthidae, one Brachyceridae, 22 Curculionidae) that are also newly recorded for the Maritime provinces, and one species, Plesiobaris disjuncta Casey (Curculionidae) that is newly recorded for Canada from New Brunswick and Quebec. Bagous planatus LeConte is reinstated to the faunal list of New Brunswick. Two species of Curculionidae are newly recorded from Nova Scotia and the Maritime provinces, and two others are reported for the first time for Prince Edward Island. PMID- 22539902 TI - A new species of Enterognathus (Copepoda, Cyclopoida, Enterognathidae) collected from the Seto Inland Sea, western Japan. AB - A new species of the endoparasitic copepod Enterognathus (Cyclopoida, Enterognathidae) is described from a crinoid host in the Seto Inland Sea, western Japan. This is a third species of the genus and its first occurrence in the Pacific Ocean. The new species is distinguished from two previously known congeners by the morphology of the body somites, caudal rami, antennae and legs. Crinoid parasites belonging to Enterognathus and the closely related genus Parenterognathus have a broad distribution from the northeastern Atlantic through the Red Sea to the West Pacific. PMID- 22539903 TI - A new genus, two new species and a new record of subfamily Cecidophyinae (Acari, Eriophyidae) from China. AB - A new genus and two new species belonging to subfamily Cecidophyinae, namely Kyllocarus reticulatusgen.n., sp. n. infesting Lithocarpus brevicaudatus (Skan) Hay. (Fagaceae) and Gammaphytoptus schimaesp. n.infesting Schima superba Gardn. et Champ. (Theaceae) are described and illustrated. Both new species are vagrants on their respective host plants. Cecidophyes digephyrusKeifer, 1966 is newly recorded for China. PMID- 22539904 TI - Immature stages and ecology of two species of the South African genus Stripsipher Gory & Percheron, 1833 (Coleoptera, Scarabaeidae, Cetoniinae, Trichiini). AB - Based on the study of newly accessible type material, Stripsipher drakensbergi Ricchiardi, 1998, is demoted to a junior synonym of Stripsipher jansoni Peringuey, 1908. The genus Stripsipher Gory & Percheron, 1833, thus, currently includes 12 species, but for none of these are larval stages and/or pupae currently known. The immature stages of Stripsipher orientalis Ricchiardi, 2008 and Stripsipher jansoni are described here for the first time and updated observations on distribution and ecology of both species are provided. Morphological affinities of Stripsipher with other Trichiini larvae are presented and the main diagnostic differences discussed. The larvae of both species are very similar to those of other representatives of the tribe Trichiini, with key differences found on the epipharynx. Based on the morphology of larvae and adults, it is suggested that Stripsipher is a member of the clade composed of Valgini, Trichiini and Cryptodontini. PMID- 22539905 TI - Taxonomic study of the genus Prorophora Ragonot, 1887 (Lepidoptera, Pyralidae, Phycitinae) in China, with description of a new species. AB - The genus Prorophora Ragonot, 1887 is newly recorded for China. Of the three species treated here, Prorophora (Reisserempista) binacanthasp. n. is described as new; Prorophora (Prorophora) albidogilvella Roesler, 1970 and Prorophora (Reisserempista) mongolica Roesler, 1970 are diagnosed and newly recorded for China. Images of adults and illustrations of genital structures are provided, along with a key to the known species. PMID- 22539906 TI - Two new freshwater fish species of the genus Telestes (Actinopterygii, Cyprinidae) from karst poljes in Eastern Herzegovina and Dubrovnik littoral (Bosnia and Herzegovina and Croatia). AB - Two new species, Telestes dabar and Telestes miloradi, are described on the basis of morphological comparisons of isolated geographical populations of fishes identified earlier as Telestes metohiensis. A lectotype is designated for Telestes metohiensis, whose range is shown to include waters of Gatacko, Cernicko, and Nevesinjsko poljes in Eastern Herzegovina. Telestes dabar from Dabarsko Polje (Eastern Herzegovina) and Telestes miloradi from Konavosko Polje (south Croatia) share with Telestes metohiensis the following combination of characters that distinguish them from the rest of the genus Telestes: pharyngeal teeth in one row, usually 5-4; preoperculo-mandibular canal not communicating with the infraorbital canal; mouth subterminal, the tip of the mouth cleft on or below the level of the ventral margin of the eye; postcleithrum minute or absent; ventral portion of the trunk with a dark stripe on a pale background; and dorsal portion of trunk uniformly dark and bordered ventrally by a dark midlateral stripe. Telestes dabar and Telestes miloradi are distinguishable from Telestes metohiensis in usually having 81/2 branched dorsal-fin rays (vs. usually 71/2), 9 or 10 gill rakers (vs. 7-10, usually 8), and the dark stripe on the ventral portion of the trunk below the main pigmented area of the back narrow and usually not reaching posteriorly to the caudal peduncle (vs. dark stripe wide and extending posteriorly to the caudal peduncle). Telestes dabar is distinguished from Telestes miloradi by having scales on most of the body situated close to one another and overlapping in a region behind the pectoral girdle and usually on the caudal peduncle (vs. overlapping scales on most of the body); the lateral line usually incomplete and interrupted, with 24-69, usually 54-65, total scales (vs. lateral line usually complete, with 55-67 total scales); scales above and below the lateral line slightly smaller than lateral-line scales (vs. of about equal size); head width 43-52% HL (vs. 48-58% HL); and lower jaw length 10-12% SL or 36 41% HL (vs. 8-10% SL or 33-38% HL). Telestes miloradi, a very local endemic species,is known only by historical samples. Telestes dabar is an abundant fish in Dabarsko Polje, but its range is critically restricted during the dry season by a few permanent sources. Nothing is known about its occurrence in underground karst waters. PMID- 22539907 TI - A new species of Fauveliopsidae (Annelida) from the North Sea. AB - A new species of the genus Laubieriopsis Petersen, 2000 is described based on 28 specimens collected in the north-east part of the North Sea. It is characterized by fixed number of chaetigers (22), paired genital papillae, bidentate neurochaeta of chaetigers 1-4, the absence of acicular chaetae on chaetigers 5-21 and, on the last chaetiger, one acicular and three capillary chaetae enlarged and directed backward. The present study brings the number of known species of Laubieriopsis to five and the number of Northeast Atlantic species of this genus to two. PMID- 22539908 TI - Description of a new species of Sternocoelis from Morocco with proposal of the Sternocoelis marseulii species group (Coleoptera, Histeridae). AB - TheSternocoelis marseulii species group is proposed based on antennal and prosternal characters. Five species are included in the group:Sternocoelis marseulii (Brisout de Barneville, 1866)(Spain), Sternocoelis viaticus Lewis, 1892 (Algeria), Sternocoelis vaucheri Lewis, 1896 (Morocco), Sternocoelis berberus Lackner & Yelamos, 2001 (Morocco)and Sternocoelis yelamosisp. n. (Morocco). The external morphology of Sternocoelis yelamosisp. n. is described and illustrated, the illustrations of genitalia of all species of the group (except for Sternocoelis vaucheri) are provided and a key to the species of the group is given. PMID- 22539909 TI - A synopsis of the genus Cypholoba Chaudoir (Coleoptera, Carabidae, Anthiini) known to occur in the Republic of South Africa. AB - Nearly one third of the described species of Cypholoba Chaudoir (Coleoptera: Carabidae) are known to inhabit the Republic of South Africa. A key and diagnostic notes are provided for their identification, as well as notes about way of life for some of the species based on observations in the Kruger National Park. Fifteen species and subspecies of the genus are recorded from the Republic of South Africa; adult specimens of each species and subspecies are illustrated and information about the distribution of each species in the Republic of South Africa is summarized and mapped: Cypholoba alstoni (Peringuey), Cypholoba alveolata (Breme), Cypholoba amatonga Peringuey, Cypholoba fritschi (Chaudoir), Cypholoba gracilis gracilis (Dejean), Cypholoba gracilis scrobiculata (Bertoloni), Cypholoba gracilis zuluana Basilewsky, Cypholoba graphipteroides graphipteroides (Guerin-Meneville), Cypholoba leucospilota semilaevis (Chaudoir), Cypholoba macilenta (Olivier), Cypholoba notata (Perroud), Cypholoba oberthueri seruana Strohmeyer, Cypholoba opulenta (Boheman), Cypholoba rutata (Peringuey), and Cypholoba tenuicollis aenigma (Dohrn). PMID- 22539910 TI - First report of Melittobia australica Girault in Europe and new record of M. acasta (Walker) for Italy. AB - Melittobia acasta and Melittobia australica are newly recorded from Sicily, Italy, and the second species is reported in Europe for the first time. A short historical background about Melittobia parasitoid wasps, their hosts, and distribution, with emphasis in those two species is presented together with illustrations to facilitate their identification. Brief discussion about the presence and possible distribution of the species in Sicily is also included. PMID- 22539911 TI - Sinocorophium hangangense sp. n. (Crustacea, Amphipoda, Corophiidae), a new species from Korea, with a key to the genus Sinocorophium. AB - A new species of the corophiid gammaridean amphipod belonging to the genus Sinocorophium Bousfield & Hoover was collected from the lower reaches of the Han River in Gyeonggi-do, Korea. A relatively large body size and morphology of the uropods 1 and 3 are the major characteristics which serve to distinguish the new species from its congeners. The new species is fully illustrated and extensively compared with related species. A key to the species of (Sinocorophium is also provided. PMID- 22539912 TI - On the species status of the root-knot nematode Meloidogyne mayaguensis Rammah & Hirschmann, 1988. AB - Holo- and paratypes of the root-knot nematodes Meloidogyne mayaguensis Rammah & Hirschmann, 1988 and Meloidogyne enterolobii Yang & Eisenback, 1983 were morphometrically and morphologically compared. All observed female, male and second-stage juvenile morphometrical and morphological characters are identical for the two studied species. Additionally, contradictions between the original species descriptions were unravelled.The present study of holo- and paratypes confirms the taxonomical status of Meloidogyne mayaguensis as a junior synonym for Meloidogyne enterolobii. PMID- 22539913 TI - A new sexannulate species of Orobdella (Hirudinida, Arhynchobdellida, Orobdellidae) from Yakushima Island, Japan. AB - A new sexannulate species of the genus Orobdella Oka, 1895, Orobdella mononokesp. n., is described on the basis of five specimens collected from Yakushima Island, Japan. Orobdella mononokesp. n. differs from other sexannulate Orobdella species in its possessing the following combination of characters: dorsal surface bicolor in life, I-XIII, XXVII and caudal sucker grayish purple, XIV-XXVI amber, male gonopore at XI c11/c12, female gonopore at XIII b2, 8 + 1/2 between gonopores, tubular but bulbous at junction with crop gastroporal duct, epididymides in XV XIX, and atrial cornua ovate. Phylogenetic analyses using nuclear 18S rDNA and histone H3, and mitochondrial COI, tRNA(Cys), tRNA(Met), 12S rDNA, tRNA(Val) and 16S rDNA markers show that Orobdella mononokesp. n. is closely related to Orobdella esulcata Nakano, 2010 from Kyushu, Japan, and two species, Orobdella dolichopharynx Nakano, 2011 and Orobdella shimadae Nakano, 2011, from the Ryukyu Archipelago, Japan. PMID- 22539914 TI - Annotated type catalogue of the Bothriembryontidae and Odontostomidae (Mollusca, Gastropoda, Orthalicoidea) in the Natural History Museum, London. AB - The type status is described for specimens of 84 taxa classified within the families Bothriembryontidae and Odontostomidae (superfamily Orthalicoidea) and kept in the Natural History Museum, London. Lectotypes are designated for Bulimus (Liparus) brazieri Angas, 1871; Bulimus broderipii Sowerby I, 1832; Bulimus fuligineus Pfeiffer, 1853; Helix guarani d'Orbigny, 1835; Bulimus (Tomigerus) ramagei E.A. Smith, 1890; Helix rhodinostoma d'Orbigny, 1835; Bulimus (Bulimulus) ridleyi E.A. Smith, 1890. The type status of the following taxa is changed to lectotype in accordance with Art. 74.6 ICZN: Placostylus (Euplacostylus) cylindricus Fulton, 1907; Bulimus pyrostomus Pfeiffer, 1860; Bulimus turneri Pfeiffer, 1860. The following taxon is synonymised: Bulimus oblitus Reeve, 1848 = Bahiensis neglectus (Pfeiffer, 1847). PMID- 22539915 TI - The caddisfly fauna (Insecta, Trichoptera) of the rivers of the Black Sea basin in Kosovo with distributional data for some rare species. AB - Adult caddisflies were collected from 12 stations in the Black Sea basin in Kosovo using UV light traps. Sixty-five of the seventy-six species reported in this paper are first records for the Kosovo caddisfly fauna. The unexpected discovery of several species during this investigation: Agapetus delicatulus McLachlan, 1884, Psychomyia klapaleki Malicky, 1995, Tinodes janssensi Jacquemart, 1957, Hydropsyche emarginata Navas, 1923, Drusus botosaneanui Kumanski, 1968, Potamophylax rotundipennis (Brauer, 1857), Potamophylax schmidi Marinkovic-Gospodnetic, 1970, Ceraclea albimacula (Rambur, 1842), Helicopsyche bacescui Orghidan & Botosaneanu, 1953, Adicella filicornis (Pictet, 1834), Beraea maurus (Curtis, 1834) and Beraeamyia hrabei Mayer, 1937 illustrates that collections from poorly investigated areas in Europe will almost certainly revise the existing knowledge on the distribution of these and other species. PMID- 22539916 TI - The genus Shirozuella Sasaji (Coleoptera, Coccinellidae, Shirozuellini) from the Chinese mainland. AB - The genus Shirozuella Sasaji, 1967 from the Chinese mainland is reviewed. Eight species are recognized, including four new species: Shirozuella motuoensissp. n., Shirozuella tibetinasp. n., Shirozuella unciformasp. n., and Shirozuella guoyueisp. n. Male genitalia of Shirozuella parenthesis Yu and Shirozuella quadrimacularis are described for the first time. All species are described and illustrated. A key and distribution map to the known species from the Chinese mainland are given. PMID- 22539917 TI - Arsenic removal via ZVI in a hybrid spouted vessel/fixed bed filter system. AB - The description and operation of a novel, hybrid spouted vessel/fixed bed filter system for the removal of arsenic from water are presented. The system utilizes zero-valent iron (ZVI) particles circulating in a spouted vessel that continuously generates active colloidal iron corrosion products via the "self polishing" action between ZVI source particles rolling in the moving bed that forms on the conical bottom of the spouted vessel. This action also serves as a "surface renewal" mechanism for the particles that provides for maximum utilization of the ZVI material. (Results of batch experiments conducted to examine this mechanism are also presented.) The colloidal material produced in this fashion is continuously captured and concentrated in a fixed bed filter located within the spouted vessel reservoir wherein arsenic complexation occurs. It is demonstrated that this system is very effective for arsenic removal in the microgram per liter arsenic concentration (i.e., drinking water treatment) range, reducing 100 MUg/L of arsenic to below detectable levels (?10 MUg/L) in less than an hour.A mechanistic analysis of arsenic behavior in the system is presented, identifying the principal components of the population of active colloidal material for arsenic removal that explains the experimental observations and working principles of the system. It is concluded that the apparent kinetic behavior of arsenic in systems where colloidal (i.e., micro/nano) iron corrosion products are dominant can be complex and may not be explained by simple first or zeroth order kinetics. PMID- 22539918 TI - Visual cortex combines a stimulus and an error-like signal with a proportion that is dependent on time, space, and stimulus contrast. AB - Even though the visual cortex is one of the most studied brain areas, the neuronal code in this area is still not fully understood. In the literature, two codes are commonly hypothesized, namely stimulus and predictive (error) codes. Here, we examined whether and how these two codes can coexist in a neuron. To this end, we assumed that neurons could predict a constant stimulus across time or space, since this is the most fundamental type of prediction. Prediction was examined in time using electrophysiology and voltage-sensitive dye imaging in the supragranular layers in area 18 of the anesthetized cat, and in space using a computer model. The distinction into stimulus and error code was made by means of the orientation tuning of the recorded unit. The stimulus was constructed as such that a maximum response to the non-preferred orientation indicated an error signal, and the maximum response to the preferred orientation indicated a stimulus signal. We demonstrate that a single neuron combines stimulus and error like coding. In addition, we observed that the duration of the error coding varies as a function of stimulus contrast. For low contrast the error-like coding was prolonged by around 60-100%. Finally, the combination of stimulus and error leads to a suboptimal free energy in a recent predictive coding model. We therefore suggest a straightforward modification that can be applied to the free energy model and other predictive coding models. Combining stimulus and error might be advantageous because the stimulus code enables a direct stimulus recognition that is free of assumptions whereas the error code enables an experience dependent inference of ambiguous and non-salient stimuli. PMID- 22539919 TI - Bacillary prostatitis after intravesical immunotherapy: a rare adverse effect. AB - Nowadays, the most efficient form of intravesical immunotherapy for superficial transitional cell carcinoma of the urinary bladder is the instillation of bacillus Calmette-Guerin (BCG), proceeding from an attenuated strain of Mycobacterium bovis. In up to 40% of cases, its instillation is associated with significantly elevated prostate-specific antigen (PSA) levels. In these cases, prostate biopsy should be withheld for 3 months and PSA should be monitored. Bacillary prostatitis is a rare occurrence in patients treated with intravesical BCG immunotherapy. Although symptomatic bacillary prostatitis is even rarer, it is the worst type of this condition. The aims of this study are to report a case of bacillary prostatitis as a rare adverse effect of intravesical BCG immunotherapy and to make a theoretical review about how to manage this complication. A 58-year-old man, former smoker, underwent a transurethral resection of the bladder in February 2004 because of a papillary transitional cell carcinoma of the bladder (pT1G2N0M0). After surgery, BCG instillation therapy was given in a total of 15 instillations, the last one in March 2007. In the last 3 months of therapy, until May 2007, a progressive increase in his PSA level was registered, and he underwent a prostate biopsy revealing granulomatous prostatitis of bacillary etiology. The semen culture was positive for M. bovis. After 3 months of a two-drug (isoniazid and rifampin) antituberculous regimen, the semen culture became negative and the PSA level decreased. The early identification of intravesical BCG immunotherapy complications allows their effective treatment. However, when a histological diagnosis of asymptomatic granulomatous prostatitis is made, the execution and type of treatment are controversial. PMID- 22539920 TI - Multifocal epithelioid hemangioendothelioma derived from the spine region: case report and literature review. AB - BACKGROUND: Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor with malignant biological behavior. It arises from endothelial cells, usually within soft tissues, and can occur in almost all locations. CASE REPORT: We report a unique case of a 25-year-old man who presented with sudden attacks of severe back pain followed by acute non-traumatic paraplegia. Emergency diagnostics revealed a pathologic fracture of the T7 vertebra with tumor tissue invasion of the spinal canal. Furthermore, multifocal metastases were found. RESULTS: To achieve en bloc resection, interdisciplinary surgical approaches were indicated. Despite multimodal therapy concepts, including radiotherapy and chemotherapy as well as endovascular embolization, the patient died within 8 weeks. CONCLUSION: Prognosis of EHE is unpredictable and mainly determined by its location. The lesions are potentially aggressive; therefore, en bloc resection should be attempted whenever possible. However, as shown in the literature, only 15% of patients are suitable for total resection. PMID- 22539921 TI - A radial sclerosing lesion mimicking breast cancer on mammography in a young woman. AB - A spiculated mass on a mammogram is highly suggestive of malignancy. We report the case of a 32-year-old woman with a radial sclerosing lesion that mimicked breast cancer on mammography. She visited her physician after palpating a lump in her left breast. Mammography showed architectural distortion in the upper inner quadrant of the left breast. Ultrasonography showed a low echoic area with an ambiguous boundary. Core needle biopsy was performed because of the suspicion of malignancy. Histological examination did not reveal any malignant cells. After 6 months, the breast lump became larger and the patient was referred to our hospital. Mammography performed in our hospital showed a spiculated mass, and therefore mammotome biopsy was performed. Histological examination revealed dense fibroelastic stroma with a wide variety of mastopathic changes, leading to a diagnosis of a radial sclerosing lesion. One year after the biopsy, the lump on her left breast had disappeared and mammography showed no spiculated mass. PMID- 22539922 TI - Fatal pneumonitis induced by oxaliplatin: description of three cases. AB - We describe 3 fatal cases of interstitial pneumonitis rapidly evolving to pulmonary fibrosis and death after the administration of oxaliplatin as part of the FOLFOX regimen. Due to the widespread use of oxaliplatin in oncology, clinicians should be aware of the risk and severity of oxalipatin-induced interstitial pneumonia. PMID- 22539923 TI - Successful Treatment of Pure Red Cell Aplasia with Rituximab in Patients after ABO-Compatible Allogeneic Hematopoietic Stem Cell Transplantation. AB - Pure red cell aplasia (PRCA) following allogeneic hematopoietic stem cell transplantation (HSCT) has been mostly reported in situations involving major ABO incompatibility between donor and recipient. Conventional treatments such as plasma exchange, erythropoietin, and steroid are often unsatisfactory. Rituximab has been reported to be highly effective for PRCA following major ABO incompatible allogeneic HSCT. A 49-year-old woman with PRCA following ABO-matched allogeneic HSCT for acute lymphoblastic leukemia, refractory to erythropoietin treatment, received 4 doses of rituximab 375 mg/m(2) weekly. After the 3rd dose of rituximab, she exhibited a striking rise in her reticulocyte count with an increase in her hemoglobin level. To our knowledge, this is the first case of PRCA following major ABO-compatible allogeneic HSCT resolving completely after rituximab treatment. PMID- 22539924 TI - Unfolded protein stress in the endoplasmic reticulum and mitochondria: a role in neurodegeneration. AB - Protein-folding occurs in several intracellular locations including the endoplasmic reticulum and mitochondria. In normal conditions there is a balance between the levels of unfolded proteins and protein folding machinery. Disruption of homeostasis and an accumulation of unfolded proteins trigger stress responses, or unfolded protein responses (UPR), in these organelles. These pathways signal to increase the folding capacity, inhibit protein import or expression, increase protein degradation, and potentially trigger cell death. Many aging-related neurodegenerative diseases involve the accumulation of misfolded proteins in both the endoplasmic reticulum and mitochondria. The exact participation of the UPRs in the onset of neurodegeneration is unclear, but there is significant evidence for the alteration of these pathways in the endoplasmic reticulum and mitochondria. Here we will discuss the involvement of endoplasmic reticulum and mitochondrial stress and the possible contributions of the UPR in these organelles to the development of two neurodegenerative diseases, Parkinson's disease (PD) and Alzheimer's disease (AD). PMID- 22539925 TI - S100 calcium binding proteins and ion channels. AB - S100 Ca(2+)-binding proteins have been associated with a multitude of intracellular Ca(2+)-dependent functions including regulation of the cell cycle, cell differentiation, cell motility and apoptosis, modulation of membrane cytoskeletal interactions, transduction of intracellular Ca(2+) signals, and in mediating learning and memory. S100 proteins are fine tuned to read the intracellular free Ca(2+) concentration and affect protein phosphorylation, which makes them candidates to modulate certain ion channels and neuronal electrical behavior. Certain S100s are secreted from cells and are found in extracellular fluids where they exert unique extracellular functions. In addition to their neurotrophic activity, some S100 proteins modulate neuronal electrical discharge activity and appear to act directly on ion channels. The first reports regarding these effects suggested S100-mediated alterations in Ca(2+) fluxes, K(+) currents, and neuronal discharge activity. Recent reports revealed direct and indirect interactions with Ca(2+), K(+), Cl(-), and ligand activated channels. This review focuses on studies of the physical and functional interactions of S100 proteins and ion channels. PMID- 22539926 TI - Stem Cell Fate Determination during Development and Regeneration of Ectodermal Organs. AB - The development of ectoderm-derived appendages results in a large variety of highly specialized organs such as hair follicles, mammary glands, salivary glands, and teeth. Despite varying in number, shape, and function, all these ectodermal organs develop through continuous and reciprocal epithelial mesenchymal interactions, sharing common morphological and molecular features especially during their embryonic development. Diseases such as ectodermal dysplasias can affect simultaneously these organs, suggesting that they may arise from common multipotent precursors residing in the embryonic ectoderm. During embryogenesis, these putative ectodermal stem cells may adopt different fates and consequently be able to generate a variety of tissue-specific stem cells, which are the sources for the various cell lineages that form the diverse organs. The specification of those common epithelial precursors, as well as their further lineage commitment to tissue-specific stem cells, might be controlled by specific signals. It has been well documented that Notch, Wnt, bone morphogenetic protein, and fibroblast growth factor signaling pathways regulate cell fate decisions during the various stages of ectodermal organ development. However, the in vivo spatial and temporal dynamics of these signaling pathways are not yet well understood. Improving the current knowledge on the mechanisms involved in stem cell fate determination during organogenesis and homeostasis of ectodermal organs is crucial to develop effective stem cell-based therapies in order to regenerate or replace pathological and damaged tissues. PMID- 22539928 TI - On Discriminating between Geometric Strategies of Surface-Based Orientation. AB - Recently, a debate has manifested in the spatial learning literature regarding the shape parameters by which mobile organisms orient with respect to the environment. On one hand are principal-axis-based strategies which suggest that organisms extract the major and minor principal axes of space which pass through the centroid and approximate length and width of the entire space, respectively. On the other hand are medial-axis-based strategies which suggest that organisms extract a trunk-and-branch system similar to the skeleton of a shape. With competing explanations comes the necessity to devise experiments capable of producing divergent predictions. Here, we suggest that a recent experiment (i.e., Sturz and Bodily, 2011a) may be able to shed empirical light on this debate. Specifically, we suggest that a reevaluation of the design reveals that the enclosures used for training and testing appear to produce divergent predictions between these strategies. We suggest that the obtained data appear inconsistent with a medial-axis-based strategy and that the study may provide an example of the types of designs capable of discriminating between these geometric strategies of surface-based orientation. Such an approach appears critical to fundamental issues regarding the nature of space and spatial perception. PMID- 22539927 TI - The Emerging Role of microRNAs in Schizophrenia and Autism Spectrum Disorders. AB - MicroRNAs (miRNAs) are small non-coding RNAs conserved throughout evolution whose perceived importance for brain development and maturation is increasingly being understood. Although a plethora of new discoveries have provided novel insights into miRNA-mediated molecular mechanisms that influence brain plasticity, their relevance for neuropsychiatric diseases with known deficits in synaptic plasticity, such as schizophrenia and autism, has not been adequately explored. In this review we discuss the intersection between current and old knowledge on the role of miRNAs in brain plasticity and function with a focus in the potential involvement of brain expressed miRNAs in the pathophysiology of neuropsychiatric disorders. PMID- 22539929 TI - Early deafness increases the face inversion effect but does not modulate the composite face effect. AB - Early deprivation in audition can have striking effects on the development of visual processing. Here we investigated whether early deafness induces changes in holistic/configural face processing. To this end, we compared the results of a group of early deaf participants to those of a group of hearing participants in an inversion-matching task (Experiment 1) and a composite face task (Experiment 2). We hypothesized that deaf individuals would show an enhanced inversion effect and/or an increased composite face effect compared to hearing controls in case of enhanced holistic/configural face processing. Conversely, these effects would be reduced if they rely more on facial features than hearing controls. As a result, we found that deaf individuals showed an increased inversion effect for faces, but not for non-face objects. They were also significantly slower than hearing controls to match inverted faces. However, the two populations did not differ regarding the overall size of their composite face effect. Altogether these results suggest that early deafness does not enhance or reduce the amount of holistic/configural processing devoted to faces but may increase the dependency on this mode of processing. PMID- 22539930 TI - Does "task difficulty" explain "task-induced deactivation?". AB - The "default mode network" is commonly described as a set of brain regions in which activity is suppressed during relatively demanding, or difficult, tasks. But what sort of tasks are these? We review some of the contrasting ways in which a task might be assessed as being difficult, such as error rate, response time, propensity to interfere with performance of other tasks, and requirement for transformation of internal representations versus accumulation of perceptual information. We then describe a fMRI study in which 18 participants performed two "stimulus-oriented" tasks, where responses were directly cued by visual stimuli, alongside a "stimulus-independent" task, with a greater reliance on internally generated information. When indexed by response time and error rate, the stimulus independent task was intermediate in difficulty between the two stimulus-oriented tasks. Nevertheless, BOLD signal in medial rostral prefrontal cortex (MPFC) - a prominent part of the default mode network - was reduced in the stimulus independent condition in comparison with both the more difficult and the less difficult stimulus-oriented conditions. By contrast, other regions of the default mode network showed greatest deactivation in the difficult stimulus-oriented condition. There was therefore significant functional heterogeneity between different default mode regions. We conclude that task difficulty - as measured by response time and error rate - does not provide an adequate account of signal change in MPFC. At least in some circumstances, a better predictor of MPFC activity is the requirement of a task for transformation and manipulation of internally represented information, with greatest MPFC activity in situations predominantly requiring attention to perceptual information. PMID- 22539931 TI - Predicting cerebral amyloid angiopathy-related intracerebral hemorrhages and other cerebrovascular disorders in Alzheimer's disease. AB - Cerebral amyloid angiopathy (CAA) of amyloid beta-protein (Abeta) type is common in Alzheimer's disease (AD). Abeta immunotherapies have been reported to induce CAA-related intracerebral hemorrhages (ICH) or vasogenic edema. For the purpose of developing a method to predict CAA-related ICH and other cerebrovascular disorders in AD, the biomarkers, and risk factors are reviewed. The biomarkers include (1) greater occipital uptake on amyloid positron emission tomography imaging and a decrease of cerebrospinal fluid Abeta40 levels as markers suggestive of CAA, and (2) symptomatic lobar ICH, lobar microhemorrhages, focal subarachnoidal hemorrhages/superficial siderosis, cortical microinfarcts, and subacute encephalopathy (caused by CAA-related inflammation or angiitis) as imaging findings of CAA-related ICH and other disorders. The risk factors include (1) old age and AD, (2) CAA-related gene mutations and apolipoprotein E genotype as genetic factors, (3) thrombolytic, anti-coagulation, and anti-platelet therapies, hypertension, and minor head trauma as hemorrhage-inducing factors, and (4) anti-amyloid therapies. Positive findings for one or more biomarkers plus one or more risk factors would be associated with a significant risk of CAA related ICH and other cerebrovascular disorders. To establish a method to predict future occurrence of CAA-related ICH and other cerebrovascular disorders in AD, prospective studies with a large number of AD patients are necessary, which will allow us to statistically evaluate to what extent each biomarker or risk factor would increase the risk. In addition, further studies with progress of technologies are necessary to more precisely detect CAA and CAA-related cerebrovascular disorders. PMID- 22539932 TI - Microbial transformations of nitrogen, sulfur, and iron dictate vegetation composition in wetlands: a review. AB - The majority of studies on rhizospheric interactions focus on pathogens, mycorrhizal symbiosis, or carbon transformations. Although the biogeochemical transformations of N, S, and Fe have profound effects on vegetation, these effects have received far less attention. This review, meant for microbiologists, biogeochemists, and plant scientists includes a call for interdisciplinary research by providing a number of challenging topics for future ecosystem research. Firstly, all three elements are plant nutrients, and microbial activity significantly changes their availability. Secondly, microbial oxidation with oxygen supplied by radial oxygen loss from roots in wetlands causes acidification, while reduction using alternative electron acceptors leads to generation of alkalinity, affecting pH in the rhizosphere, and hence plant composition. Thirdly, reduced species of all three elements may become phytotoxic. In addition, Fe cycling is tightly linked to that of S and P. As water level fluctuations are very common in wetlands, rapid changes in the availability of oxygen and alternative terminal electron acceptors will result in strong changes in the prevalent microbial redox reactions, with significant effects on plant growth. Depending on geological and hydrological settings, these interacting microbial transformations change the conditions and resource availability for plants, which are both strong drivers of vegetation development and composition by changing relative competitive strengths. Conversely, microbial composition is strongly driven by vegetation composition. Therefore, the combination of microbiological and plant ecological knowledge is essential to understand the biogeochemical and biological key factors driving heterogeneity and total (i.e., microorganisms and vegetation) community composition at different spatial and temporal scales. PMID- 22539933 TI - Dark matter RNA: an intelligent scaffold for the dynamic regulation of the nuclear information landscape. AB - Perhaps no other topic in contemporary genomics has inspired such diverse viewpoints as the 95+% of the genome, previously known as "junk DNA," that does not code for proteins. Here, we present a theory in which dark matter RNA plays a role in the generation of a landscape of spatial micro-domains coupled to the information signaling matrix of the nuclear landscape. Within and between these micro-domains, dark matter RNAs additionally function to tether RNA interacting proteins and complexes of many different types, and by doing so, allow for a higher performance of the various processes requiring them at ultra-fast rates. This improves signal to noise characteristics of RNA processing, trafficking, and epigenetic signaling, where competition and differential RNA binding among proteins drives the computational decisions inherent in regulatory events. PMID- 22539935 TI - Sodium iodide symporter for nuclear molecular imaging and gene therapy: from bedside to bench and back. AB - Molecular imaging, defined as the visual representation, characterization and quantification of biological processes at the cellular and subcellular levels within intact living organisms, can be obtained by various imaging technologies, including nuclear imaging methods. Imaging of normal thyroid tissue and differentiated thyroid cancer, and treatment of thyroid cancer with radioiodine rely on the expression of the sodium iodide symporter (NIS) in these cells. NIS is an intrinsic membrane protein with 13 transmembrane domains and it takes up iodide into the cytosol from the extracellular fluid. By transferring NIS function to various cells via gene transfer, the cells can be visualized with gamma or positron emitting radioisotopes such as Tc-99m, I-123, I-131, I-124 and F-18 tetrafluoroborate, which are accumulated by NIS. They can also be treated with beta- or alpha-emitting radionuclides, such as I-131, Re-186, Re-188 and At 211, which are also accumulated by NIS. This article demonstrates the diagnostic and therapeutic applications of NIS as a radionuclide-based reporter gene for trafficking cells and a therapeutic gene for treating cancers. PMID- 22539934 TI - Applications for next-generation sequencing in fish ecotoxicogenomics. AB - The new technologies for next-generation sequencing (NGS) and global gene expression analyses that are widely used in molecular medicine are increasingly applied to the field of fish biology. This has facilitated new directions to address research areas that could not be previously considered due to the lack of molecular information for ecologically relevant species. Over the past decade, the cost of NGS has decreased significantly, making it possible to use non-model fish species to investigate emerging environmental issues. NGS technologies have permitted researchers to obtain large amounts of raw data in short periods of time. There have also been significant improvements in bioinformatics to assemble the sequences and annotate the genes, thus facilitating the management of these large datasets.The combination of DNA sequencing and bioinformatics has improved our abilities to design custom microarrays and study the genome and transcriptome of a wide variety of organisms. Despite the promising results obtained using these techniques in fish studies, NGS technologies are currently underused in ecotoxicogenomics and few studies have employed these methods. These issues should be addressed in order to exploit the full potential of NGS in ecotoxicological studies and expand our understanding of the biology of non-model organisms. PMID- 22539936 TI - Magnetic resonance reporter gene imaging. AB - Molecular imaging has undergone an explosive advancement in recent years, due to the tremendous research efforts made to understand and visualize biological processes. Molecular imaging by definition assesses cellular and molecular processes in living subjects, with the targets of following metabolic, genomic, and proteomic events. Furthermore, reporter gene imaging plays a central role in this field. Many different approaches have been used to visualize genetic events in living subjects, such as, optical, radionuclide, and magnetic resonance imaging. Compared with the other techniques, magnetic resonance (MR)-based reporter gene imaging has not occupied center stage, despite its superior three dimensional depictions of anatomical details. In this article, the authors review the principles and applications of various types of MR reporter gene imaging technologies and discuss their advantages and disadvantages. PMID- 22539937 TI - Molecular imaging with activatable reporter systems. AB - Molecular imaging is a newly emerged multiple disciplinary field that aims to visualize, characterize and quantitatively measure biological processes at cellular and molecular levels in humans and other living systems. A reporter gene is a piece of DNA encoding reporter protein, which presents as a readily measurable phenotype that can be distinguished easily from the background of endogenous protein. After being transferred into cells of organ systems (transgenes), the reporter gene can be utilized to visualize transcriptional and posttranscriptional regulation of gene expression, protein-protein interactions, or trafficking of proteins or cells in living subjects. Herein, we review previous classification of reporter genes and regroup the reporter gene based imaging as basic, inducible and activatable, based on the regulation of reporter gene transcription and post-translational modification of reporter proteins. We then focus on activatable reporters, in which the signal can be activated at the posttranslational level for visualizing protein-protein interactions, protein phosphorylation or tertiary structure changes. The applications of several types of activatable reporters will also be summarized. We conclude that activatable reporter imaging can benefit both basic biomedical research and drug development. PMID- 22539938 TI - Tetrastatin, the NC1 domain of the alpha4(IV) collagen chain: a novel potent anti tumor matrikine. AB - BACKGROUND: NC1 domains from alpha1, alpha2, alpha3 and alpha6(IV) collagen chains were shown to exert anti-tumor or anti-angiogenic activities, whereas the NC1 domain of the alpha4(IV) chain did not show such activities so far. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrate in the present paper that the NC1 alpha4(IV) domain exerts a potent anti-tumor activity both in vitro and in an experimental human melanoma model in vivo. The overexpression of NC1 alpha4(IV) in human UACC-903 melanoma cells strongly inhibited their in vitro proliferative (-38%) and invasive (-52%) properties. MT1-MMP activation was largely decreased and its cellular distribution was modified, resulting in a loss of expression at the migration front associated with a loss of migratory phenotype. In an in vivo xenograft model in athymic nude mice, the subcutaneous injection of NC1 alpha4(IV)-overexpressing melanoma cells induced significantly smaller tumors ( 80% tumor volume) than the Mock cells, due to a strong inhibition of tumor growth. Exogenously added recombinant human NC1 alpha4(IV) reproduced the inhibitory effects of NC1 alpha4(IV) overexpression in UACC-903 cells but not in dermal fibroblasts. An anti-alphavbeta3 integrin blocking antibody inhibited cell adhesion on recombinant human NC1 alpha4(IV) substratum. The involvement of alphavbeta3 integrin in mediating NC1 alpha4(IV) effect was confirmed by surface plasmon resonance (SPR) binding assays showing that recombinant human NC1 alpha4(IV) binds to alphavbeta3 integrin (K(D) = 148 +/- 9.54 nM). CONCLUSION/SIGNIFICANCE: Collectively, our results demonstrate that the NC1 alpha4(IV) domain, named tetrastatin, is a new endogenous anti-tumor matrikine. PMID- 22539939 TI - Integration of DNA copy number alterations and transcriptional expression analysis in human gastric cancer. AB - BACKGROUND: Genomic instability with frequent DNA copy number alterations is one of the key hallmarks of carcinogenesis. The chromosomal regions with frequent DNA copy number gain and loss in human gastric cancer are still poorly defined. It remains unknown how the DNA copy number variations contributes to the changes of gene expression profiles, especially on the global level. PRINCIPAL FINDINGS: We analyzed DNA copy number alterations in 64 human gastric cancer samples and 8 gastric cancer cell lines using bacterial artificial chromosome (BAC) arrays based comparative genomic hybridization (aCGH). Statistical analysis was applied to correlate previously published gene expression data obtained from cDNA microarrays with corresponding DNA copy number variation data to identify candidate oncogenes and tumor suppressor genes. We found that gastric cancer samples showed recurrent DNA copy number variations, including gains at 5p, 8q, 20p, 20q, and losses at 4q, 9p, 18q, 21q. The most frequent regions of amplification were 20q12 (7/72), 20q12-20q13.1 (12/72), 20q13.1-20q13.2 (11/72) and 20q13.2-20q13.3 (6/72). The most frequent deleted region was 9p21 (8/72). Correlating gene expression array data with aCGH identified 321 candidate oncogenes, which were overexpressed and showed frequent DNA copy number gains; and 12 candidate tumor suppressor genes which were down-regulated and showed frequent DNA copy number losses in human gastric cancers. Three networks of significantly expressed genes in gastric cancer samples were identified by ingenuity pathway analysis. CONCLUSIONS: This study provides insight into DNA copy number variations and their contribution to altered gene expression profiles during human gastric cancer development. It provides novel candidate driver oncogenes or tumor suppressor genes for human gastric cancer, useful pathway maps for the future understanding of the molecular pathogenesis of this malignancy, and the construction of new therapeutic targets. PMID- 22539940 TI - A novel biclustering approach to association rule mining for predicting HIV-1 human protein interactions. AB - Identification of potential viral-host protein interactions is a vital and useful approach towards development of new drugs targeting those interactions. In recent days, computational tools are being utilized for predicting viral-host interactions. Recently a database containing records of experimentally validated interactions between a set of HIV-1 proteins and a set of human proteins has been published. The problem of predicting new interactions based on this database is usually posed as a classification problem. However, posing the problem as a classification one suffers from the lack of biologically validated negative interactions. Therefore it will be beneficial to use the existing database for predicting new viral-host interactions without the need of negative samples. Motivated by this, in this article, the HIV-1-human protein interaction database has been analyzed using association rule mining. The main objective is to identify a set of association rules both among the HIV-1 proteins and among the human proteins, and use these rules for predicting new interactions. In this regard, a novel association rule mining technique based on biclustering has been proposed for discovering frequent closed itemsets followed by the association rules from the adjacency matrix of the HIV-1-human interaction network. Novel HIV 1-human interactions have been predicted based on the discovered association rules and tested for biological significance. For validation of the predicted new interactions, gene ontology-based and pathway-based studies have been performed. These studies show that the human proteins which are predicted to interact with a particular viral protein share many common biological activities. Moreover, literature survey has been used for validation purpose to identify some predicted interactions that are already validated experimentally but not present in the database. Comparison with other prediction methods is also discussed. PMID- 22539941 TI - Gender differences in traditional Chinese medicine use among adults in Taiwan. AB - OBJECTIVES: The increasing use of complementary, alternative medicine (CAM) and traditional Chinese medicine (TCM) has attracted attention. We report on the gender difference in TCM use among the general population in Taiwan in a population-based, cross-sectional study. METHODS: We collected data on socio demographic factors, lifestyle and health behavior from the 2001 Taiwan National Health Interview Survey. The medical records of interviewees aged 20-69 years were obtained from National Health Insurance claims data with informed consent. The prevalence of TCM use and the average frequency of TCM use were compared between women and men. RESULTS: Among 14,064 eligible participants, the one-year prevalence of TCM use for women and men was 31.8% and 22.4%, respectively. Compared with men, women had a higher average TCM use frequency (1.55 visits vs. 1.04 visits, p<0.001). This significant difference remained evident after excluding gender-specific diseases (1.43 visits vs. 1.03 visits, p<0.001). The average TCM use frequency was significantly higher in women than in men across all age groups. TCM use correlates differed for women and men. Marital status (odds ratio [OR] = 1.55, 95% confidence interval [CI] = 1.30-1.85), family income and unhealthy lifestyle (OR = 1.50, 95% CI = 1.30-1.74) were factors associated with TCM use in men but not in women. CONCLUSIONS: In Taiwan, women used more TCM services than men and the gender differences in the TCM use profile persisted across age groups. PMID- 22539943 TI - Study on multicellular systems using a phase field model. AB - A model of multicellular systems with several types of cells is developed from the phase field model. The model is presented as a set of partial differential equations of the field variables, each of which expresses the shape of one cell. The dynamics of each cell is based on the criteria for minimizing the surface area and retaining a certain volume. The effects of cell adhesion and excluded volume are also taken into account. The proposed model can be used to find the position of the membrane and/or the cortex of each cell without the need to adopt extra variables. This model is suitable for numerical simulations of a system having a large number of cells. The two-dimensional results of cell division, cell adhesion, rearrangement of a cell cluster, chemotaxis, and cell sorting as well as the three-dimensional results of cell clusters on the substrate are presented. PMID- 22539942 TI - A proteomic view at T cell costimulation. AB - The "two-signal paradigm" in T cell activation predicts that the cooperation of "signal 1," provided by the T cell receptor (TCR) through engagement of major histocompatility complex (MHC)-presented peptide, with "signal 2" provided by costimulatory molecules, the prototype of which is CD28, is required to induce T cell effector functions. While the individual signalling pathways are well understood, little is known about global changes in the proteome pattern during TCR/CD28-mediated activation. Therefore, comparative 2-DE-based proteome analyses of CD3(+) CD69(-) resting T cells versus cells incubated with (i) the agonistic anti-CD3 antibody OKT3 mimicking signal 1 in absence or presence of IL-2 and/or with (ii) the agonistic antibody 15E8 triggering CD28-mediated signaling were performed. Differentially regulated spots were defined leading to the identification of proteins involved in the regulation of the metabolism, shaping and maintenance of the cytoskeleton and signal transduction. Representative members of the differentially expressed protein families, such as calmodulin (CALM), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), L-lactate dehydrogenase (LDH), Rho GDP-dissociation inhibitor 2 (GDIR2), and platelet basic protein (CXCL7), were independently verified by flow cytometry. Data provide a detailed map of individual protein alterations at the global proteome level in response to TCR/CD28-mediated T cell activation. PMID- 22539944 TI - Consistently low prevalence of syphilis among female sex workers in Jinan, China: findings from two consecutive respondent driven sampling surveys. AB - BACKGROUND: Routine surveillance using convenient sampling found low prevalence of HIV and syphilis among female sex workers in China. Two consecutive surveys using respondent driven sampling were conducted in 2008 and 2009 to examine the prevalence of HIV and syphilis among female sex workers in Jinan, China. METHODS: A face-to-face interview was conducted to collect demographic, behavioral and service utilization information using a structured questionnaire. Blood samples were drawn for serological tests of HIV-1 antibody and syphilis antibody. Respondent Driven Sampling Analysis Tool was used to generate population level estimates. RESULTS: In 2008 and in 2009, 363 and 432 subjects were recruited and surveyed respectively. Prevalence of syphilis was 2.8% in 2008 and 2.2% in 2009, while no HIV case was found in both years. Results are comparable to those from routine sentinel surveillance system in the city. Only 60.8% subjects in 2008 and 48.3% in 2009 reported a consistent condom use with clients during the past month. Over 50% subjects had not been covered by any HIV-related services in the past year, with only 15.6% subjects in 2008 and 13.1% in 2009 ever tested for HIV. CONCLUSIONS: Despite the low prevalence of syphilis and HIV, risk behaviors are common. Targeted interventions to promote the safe sex and utilization of existing intervention services are still needed to keep the epidemic from growing. PMID- 22539945 TI - Survival or revival: long-term preservation induces a reversible viable but non culturable state in methane-oxidizing bacteria. AB - Knowledge on long-term preservation of micro-organisms is limited and research in the field is scarce despite its importance for microbial biodiversity and biotechnological innovation. Preservation of fastidious organisms such as methane oxidizing bacteria (MOB) has proven difficult. Most MOB do not survive lyophilization and only some can be cryopreserved successfully for short periods. A large-scale study was designed for a diverse set of MOB applying fifteen cryopreservation or lyophilization conditions. After three, six and twelve months of preservation, the viability (via live-dead flow cytometry) and culturability (via most-probable number analysis and plating) of the cells were assessed. All strains could be cryopreserved without a significant loss in culturability using 1% trehalose in 10-fold diluted TSB (TT) as preservation medium and 5% DMSO as cryoprotectant. Several other cryopreservation and lyophilization conditions, all of which involved the use of TT medium, also allowed successful preservation but showed a considerable loss in culturability. We demonstrate here that most of these non-culturables survived preservation according to viability assessment indicating that preservation induces a viable but non-culturable (VBNC) state in a significant fraction of cells. Since this state is reversible, these findings have major implications shifting the emphasis from survival to revival of cells in a preservation protocol. We showed that MOB cells could be significantly resuscitated from the VBNC state using the TT preservation medium. PMID- 22539946 TI - Synthetic biology: mapping the scientific landscape. AB - This article uses data from Thomson Reuters Web of Science to map and analyse the scientific landscape for synthetic biology. The article draws on recent advances in data visualisation and analytics with the aim of informing upcoming international policy debates on the governance of synthetic biology by the Subsidiary Body on Scientific, Technical and Technological Advice (SBSTTA) of the United Nations Convention on Biological Diversity. We use mapping techniques to identify how synthetic biology can best be understood and the range of institutions, researchers and funding agencies involved. Debates under the Convention are likely to focus on a possible moratorium on the field release of synthetic organisms, cells or genomes. Based on the empirical evidence we propose that guidance could be provided to funding agencies to respect the letter and spirit of the Convention on Biological Diversity in making research investments. Building on the recommendations of the United States Presidential Commission for the Study of Bioethical Issues we demonstrate that it is possible to promote independent and transparent monitoring of developments in synthetic biology using modern information tools. In particular, public and policy understanding and engagement with synthetic biology can be enhanced through the use of online interactive tools. As a step forward in this process we make existing data on the scientific literature on synthetic biology available in an online interactive workbook so that researchers, policy makers and civil society can explore the data and draw conclusions for themselves. PMID- 22539947 TI - Outside-in signalling generated by a constitutively activated integrin alphaIIbbeta3 impairs proplatelet formation in human megakaryocytes. AB - BACKGROUND: The interaction of megakaryocytes with matrix proteins of the osteoblastic and vascular niche is essential for megakaryocyte maturation and proplatelet formation. Fibrinogen is present in the vascular niche and the fibrinogen receptor alpha(IIb)beta(3) is abundantly expressed on megakaryocytes, however the role of the interaction between fibrinogen and alpha(IIb)beta(3) in proplatelet formation in humans is not yet fully understood. We have recently reported a novel congenital macrothrombocytopenia associated with a heterozygous mutation of the beta(3) subunit of alpha(IIb)beta(3). The origin of thrombocytopenia in this condition remains unclear and this may represent an interesting natural model to get further insight into the role of the megakaryocyte fibrinogen receptor in megakaryopoiesis. METHODOLOGY/PRINCIPAL FINDINGS: Patients' peripheral blood CD45+ cells in culture were differentiated into primary megakaryocytes and their maturation, spreading on different extracellular matrix proteins, and proplatelet formation were analyzed. Megakaryocyte maturation was normal but proplatelet formation was severely impaired, with tips decreased in number and larger in size than those of controls. Moreover, megakaryocyte spreading on fibrinogen was abnormal, with 50% of spread cells showing disordered actin distribution and more evident focal adhesion points than stress fibres. Integrin alpha(IIb)beta(3) expression was reduced but the receptor was constitutively activated and a sustained, and substrate-independent, activation of proteins of the outside-in signalling was observed. In addition, platelet maturation from preplatelets was impaired. CONCLUSIONS/SIGNIFICANCE: Our data show that constitutive activation of alpha(IIb)beta(3)-mediated outside-in signalling in human megakaryocytes negatively influences proplatelet formation, leading to macrothombocytopenia. PMID- 22539949 TI - How does spatial study design influence density estimates from spatial capture recapture models? AB - When estimating population density from data collected on non-invasive detector arrays, recently developed spatial capture-recapture (SCR) models present an advance over non-spatial models by accounting for individual movement. While these models should be more robust to changes in trapping designs, they have not been well tested. Here we investigate how the spatial arrangement and size of the trapping array influence parameter estimates for SCR models. We analysed black bear data collected with 123 hair snares with an SCR model accounting for differences in detection and movement between sexes and across the trapping occasions. To see how the size of the trap array and trap dispersion influence parameter estimates, we repeated analysis for data from subsets of traps: 50% chosen at random, 50% in the centre of the array and 20% in the South of the array. Additionally, we simulated and analysed data under a suite of trap designs and home range sizes. In the black bear study, we found that results were similar across trap arrays, except when only 20% of the array was used. Black bear density was approximately 10 individuals per 100 km(2). Our simulation study showed that SCR models performed well as long as the extent of the trap array was similar to or larger than the extent of individual movement during the study period, and movement was at least half the distance between traps. SCR models performed well across a range of spatial trap setups and animal movements. Contrary to non-spatial capture-recapture models, they do not require the trapping grid to cover an area several times the average home range of the studied species. This renders SCR models more appropriate for the study of wide ranging mammals and more flexible to design studies targeting multiple species. PMID- 22539948 TI - Natural CD4+ T-cell responses against indoleamine 2,3-dioxygenase. AB - BACKGROUND: The enzyme indoleamine 2,3-dioxygenase (IDO) contributes to immune tolerance in a variety of settings. In cancer IDO is expressed within the tumor itself as well as in antigen-presenting cells in tumor-draining lymph nodes, where it endorses the establishment of peripheral immune tolerance to tumor antigens. Recently, we described cytotoxic CD8(+) T-cell reactivity towards IDO derived peptides. METHODS AND FINDINGS: In the present study, we show that CD4(+) helper T cells additionally spontaneously recognize IDO. Hence, we scrutinized the vicinity of the previously described HLA-A*0201-restricted IDO-epitope for CD4(+) T-cell epitopes. We demonstrated the presence of naturally occurring IDO specific CD4(+) T cells in cancer patients and to a lesser extent in healthy donors by cytokine release ELISPOT. IDO-reactive CD4(+) T cells released IFN gamma, TNF-alpha, as well as IL-17. We confirm HLA class II-restriction by the addition of HLA class II specific blocking antibodies. In addition, we detected a trend between class I- and class II-restricted IDO responses and detected an association between IDO-specific CD4(+) T cells and CD8(+) CMV-responses. Finally, we could detect IL-10 releasing IDO-reactive CD4(+) T cells. CONCLUSION: IDO is spontaneously recognized by HLA class II-restricted, CD4(+) T cells in cancer patients and in healthy individuals. IDO-specific T cells may participate in immune-regulatory networks where the activation of pro-inflammatory IDO specific CD4(+) responses may well overcome or delay the immune suppressive actions of the IDO-protein, which are otherwise a consequence of the early expression of IDO in maturing antigen presenting cells. In contrast, IDO-specific regulatory T cells may enhance IDO-mediated immune suppression. PMID- 22539950 TI - Dasatinib as a bone-modifying agent: anabolic and anti-resorptive effects. AB - BACKGROUND: Bone loss, in malignant or non-malignant diseases, is caused by increased osteoclast resorption and/or reduced osteoblast bone formation, and is commonly associated with skeletal complications. Thus, there is a need to identify new agents capable of influencing bone remodeling. We aimed to further pre-clinically evaluate the effects of dasatinib (BMS-354825), a multitargeted tyrosine kinase inhibitor, on osteoblast and osteoclast differentiation and function. METHODS: For studies on osteoblasts, primary human bone marrow mensenchymal stem cells (hMSCs) together with the hMSC-TERT and the MG-63 cell lines were employed. Osteoclasts were generated from peripheral blood mononuclear cells (PBMC) of healthy volunteers. Skeletally-immature CD1 mice were used in the in vivo model. RESULTS: Dasatinib inhibited the platelet derived growth factor receptor-beta (PDGFR-beta), c-Src and c-Kit phosphorylation in hMSC-TERT and MG 63 cell lines, which was associated with decreased cell proliferation and activation of canonical Wnt signaling. Treatment of MSCs from healthy donors, but also from multiple myeloma patients with low doses of dasatinib (2-5 nM), promoted its osteogenic differentiation and matrix mineralization. The bone anabolic effect of dasatinib was also observed in vivo by targeting endogenous osteoprogenitors, as assessed by elevated serum levels of bone formation markers, and increased trabecular microarchitecture and number of osteoblast-like cells. By in vitro exposure of hemopoietic progenitors to a similar range of dasatinib concentrations (1-2 nM), novel biological sequelae relative to inhibition of osteoclast formation and resorptive function were identified, including F-actin ring disruption, reduced levels of c-Fos and of nuclear factor of activated T cells 1 (NFATc1) in the nucleus, together with lowered cathepsin K, alphaVbeta3 integrin and CCR1 expression. CONCLUSIONS: Low dasatinib concentrations show convergent bone anabolic and reduced bone resorption effects, which suggests its potential use for the treatment of bone diseases such as osteoporosis, osteolytic bone metastasis and myeloma bone disease. PMID- 22539952 TI - Vitamin D and physical performance in elderly subjects: the Pro.V.A study. AB - BACKGROUND: The role of Vitamin D in musculoskeletal functionality among elderly people is still controversial. We investigated the association between serum 25 hydroxyvitamin D (25OHD) levels and physical performance in older adults. METHODS: 2694 community-dwelling elderly women and men from the Progetto Veneto Anziani (Pro.V.A.) were included. Physical performances were assessed by: tandem test, 5 timed chair stands (TCS), gait speed, 6-minute walking (6 mW) distance, handgrip strength, and quadriceps strength. For each test, separate general linear models and loess plots were obtained in both genders, in relation to serum 25OHD concentrations, controlling for several potential confounders. RESULTS: Linear associations with 25OHD levels were observed for TCS, gait speed, 6 mW test and handgrip strength, but not for tandem test and quadriceps strength. After adjusting for potential confounders, linear associations with 25OHD levels were still evident for the 6 mW distance in both genders (p = .0002 in women; <.0001 in men), for TCS in women (p = .004) and for gait speed (p = .0006) and handgrip strength (p = .03) in men. In loess analyses, performance in TCS in women, in gait speed and handgrip strength in men and in 6 mW in both genders, improved with increasing levels of 25OHD, with most of the improvements occurring for 25OHD levels from 20 to 100 nmol/L. CONCLUSION: lower 25OHD levels are associated with a worse coordination and weaker strength (TCS) in women, a slower walking time and a lower upper limb strength in men, and a weaker aerobic capacity (6 mW) in both genders. For optimal physical performances, 25OHD concentrations of 100 nmol/L appear to be more advantageous in elderly men and women, and Vitamin D supplementation should be encouraged to maintain their 25OHD levels as high as this threshold. PMID- 22539951 TI - Otitis media in a new mouse model for CHARGE syndrome with a deletion in the Chd7 gene. AB - Otitis media is a middle ear disease common in children under three years old. Otitis media can occur in normal individuals with no other symptoms or syndromes, but it is often seen in individuals clinically diagnosed with genetic diseases such as CHARGE syndrome, a complex genetic disease caused by mutation in the Chd7 gene and characterized by multiple birth defects. Although otitis media is common in human CHARGE syndrome patients, it has not been reported in mouse models of CHARGE syndrome. In this study, we report a mouse model with a spontaneous deletion mutation in the Chd7 gene and with chronic otitis media of early onset age accompanied by hearing loss. These mice also exhibit morphological alteration in the Eustachian tubes, dysregulation of epithelial proliferation, and decreased density of middle ear cilia. Gene expression profiling revealed up-regulation of Muc5ac, Muc5b and Tgf-beta1 transcripts, the products of which are involved in mucin production and TGF pathway regulation. This is the first mouse model of CHARGE syndrome reported to show otitis media with effusion and it will be valuable for studying the etiology of otitis media and other symptoms in CHARGE syndrome. PMID- 22539953 TI - Anticipating spring: wild populations of great tits (Parus major) differ in expression of key genes for photoperiodic time measurement. AB - Measuring day length is critical for timing annual changes in physiology and behavior in many species. Recently, rapid changes in several photoperiodically controlled genes following exposure to a single long day have been described. Components of this 'first day release' model have so far only been tested in highly domesticated species: quail, sheep, goats and rodents. Because artificial selection accompanying domestication acts on genes related to photoperiodicity, we must also study this phenomenon in wild organisms for it to be accepted as universal. In a songbird, the great tit (Parus major), we tested whether a) these genes are involved in photoperiodic time measurement (PTM) in a wild species, and b) whether predictable species and population differences in expression patterns exist. Using quantitative RT-PCR, we compared gene expression after a single long day in male great tits from Sweden (57 degrees 42'N) with that from a German (47 degrees 43'N) population. Hypothalamic gene expression key for PTM changed only in the northern population, and occurred earlier after dawn during the single long day than demonstrated in quail; however, gonadotropins (secretion and synthesis) were stimulated in both populations, albeit with different timing. Our data are the first to show acute changes in gene expression in response to photostimulation in any wild species not selected for study of photoperiodism. The pronounced differences in gene expression in response to a single long day between two populations raise exciting new questions about potential environmental selection on photoperiodic cue sensitivity. PMID- 22539954 TI - Interplay between cell migration and neurite outgrowth determines SH2B1beta enhanced neurite regeneration of differentiated PC12 cells. AB - The regulation of neurite outgrowth is crucial in developing strategies to promote neurite regeneration after nerve injury and in degenerative diseases. In this study, we demonstrate that overexpression of an adaptor/scaffolding protein SH2B1beta promotes neurite re-growth of differentiated PC12 cells, an established neuronal model, using wound healing (scraping) assays. Cell migration and the subsequent remodeling are crucial determinants during neurite regeneration. We provide evidence suggesting that overexpressing SH2B1beta enhances protein kinase C (PKC)-dependent cell migration and phosphatidylinositol 3-kinase (PI3K)-AKT-, mitogen activated protein kinase (MAPK)/extracellular signal-regulated protein kinase (ERK) kinase (MEK)-ERK-dependent neurite re-growth. Our results further reveal a cross-talk between pathways involving PKC and ERK1/2 in regulating neurite re-growth and cell migration. We conclude that temporal regulation of cell migration and neurite outgrowth by SH2B1beta contributes to the enhanced regeneration of differentiated PC12 cells. PMID- 22539955 TI - Streptococcus pneumoniae carriage in the Gaza strip. AB - BACKGROUND: Pneumococcal infections cause major morbidity and mortality in developing countries. We report the epidemiology of S. pneumoniae carriage in a developing region, the Gaza strip, and evaluate the theoretical coverage of carriage strains by pneumococcal conjugate vaccines (PCVs). METHODOLOGY: In 2009 we conducted a cross-sectional survey of S. pneumoniae carriage in healthy children and their parents, living throughout the Gaza strip. Data were collected and nasopharyngeal swabs were obtained. Antibiotic susceptibilities were determined by Vitek-2 and serotypes by the Quellung reaction. PRINCIPAL FINDINGS: S. pneumoniae carriage was detected in 189/379 (50%) of children and 30/376 (8%) of parents. Carriage prevalence was highest in children <6 months of age (63%). Significant predictors for child carriage were number of household members and DCC attendance. The proportion of pediatric and adults isolates with serotypes included in PCV7 were 32% and 20% respectively, and 46% and 33% in PCV13 respectively. The most prominent non-vaccine serotypes (NVT) were 35B, 15B/C and 23B. Penicillin-nonsusceptible strains were carried by 70% of carriers, penicillin-resistant strains (PRSP) by 13% and Multi-drug-resistant (MDR) by 30%. Of all PRSP isolates 54% belonged to serotypes included in PCV7 and 71% in the PCV13. Similarly, 59% and 73% of MDR-SP isolates, would theoretically be covered by PCV7 and PCV13, respectively. CONCLUSIONS: This study demonstrates that, PCV13 included strains were carried by 46% and 33% of pediatric and adult subjects respectively. In the absence of definitive data regarding the virulence of the NVT strains, it is difficult to predict the effect of PCVs on IPD in this region. PMID- 22539956 TI - Cellular host responses to gliomas. AB - BACKGROUND: Glioblastoma multiforme (GBM) is the most aggressive type of malignant primary brain tumors in adults. Molecular and genetic analysis has advanced our understanding of glioma biology, however mapping the cellular composition of the tumor microenvironment is crucial for understanding the pathology of this dreaded brain cancer. In this study we identified major cell populations attracted by glioma using orthotopic rodent models of human glioma xenografts. Marker-specific, anatomical and morphological analyses revealed a robust influx of host cells into the main tumor bed and tumor satellites. METHODOLOGY/PRINCIPAL FINDINGS: Human glioma cell lines and glioma spheroid orthotopic implants were used in rodents. In both models, the xenografts recruited large numbers of host nestin-expressing cells, which formed a 'network' with glioma. The host nestin-expressing cells appeared to originate in the subventricular zone ipsilateral to the tumor, and were clearly distinguishable from pericytes that expressed smooth muscle actin. These distinct cell populations established close physical contact in a 'pair-wise' manner and migrated together to the deeper layers of tumor satellites and gave rise to tumor vasculature. The GBM biopsy xenografts displayed two different phenotypes: (a) low-generation tumors (first in vivo passage in rats) were highly invasive and non-angiogenic, and host nestin-positive cells that infiltrated into these tumors displayed astrocytic or elongated bipolar morphology; (b) high-generation xenografts (fifth passage) had pronounced cellularity, were angiogenic with 'glomerulus-like' microvascular proliferations that contained host nestin positive cells. Stromal cell-derived factor-1 and its receptor CXCR4 were highly expressed in and around glioma xenografts, suggesting their role in glioma progression and invasion. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate a robust migration of nestin-expressing host cells to glioma, which together with pericytes give rise to tumor vasculature. Mapping the cellular composition of glioma microenvironment and deciphering the complex 'crosstalk' between tumor and host may ultimately aid the development of novel anti-glioma therapies. PMID- 22539958 TI - Different reactions to adverse neighborhoods in games of cooperation. AB - In social dilemmas, cooperation among randomly interacting individuals is often difficult to achieve. The situation changes if interactions take place in a network where the network structure jointly evolves with the behavioral strategies of the interacting individuals. In particular, cooperation can be stabilized if individuals tend to cut interaction links when facing adverse neighborhoods. Here we consider two different types of reaction to adverse neighborhoods, and all possible mixtures between these reactions. When faced with a gloomy outlook, players can either choose to cut and rewire some of their links to other individuals, or they can migrate to another location and establish new links in the new local neighborhood. We find that in general local rewiring is more favorable for the evolution of cooperation than emigration from adverse neighborhoods. Rewiring helps to maintain the diversity in the degree distribution of players and favors the spontaneous emergence of cooperative clusters. Both properties are known to favor the evolution of cooperation on networks. Interestingly, a mixture of migration and rewiring is even more favorable for the evolution of cooperation than rewiring on its own. While most models only consider a single type of reaction to adverse neighborhoods, the coexistence of several such reactions may actually be an optimal setting for the evolution of cooperation. PMID- 22539957 TI - Quorum sensing signaling molecules produced by reference and emerging soft-rot bacteria (Dickeya and Pectobacterium spp.). AB - BACKGROUND: Several small diffusible molecules are involved in bacterial quorum sensing and virulence. The production of autoinducers-1 and -2, quinolone, indole and gamma-amino butyrate signaling molecules was investigated in a set of soft rot bacteria belonging to six Dickeya or Pectobacterium species including recent or emerging potato isolates. METHODOLOGY/PRINCIPAL FINDINGS: Using bacterial biosensors, immunoassay, and chromatographic analysis, we showed that soft-rot bacteria have the common ability to produce transiently during their exponential phase of growth the N-3-oxo-hexanoyl- or the N-3-oxo-octanoyl-l-homoserine lactones and a molecule of the autoinducer-2 family. Dickeya spp. produced in addition the indole-3-acetic acid in tryptophan-rich conditions. All these signaling molecules have been identified for the first time in the novel Dickeya solani species. In contrast, quinolone and gamma-amino butyrate signals were not identified and the corresponding synthases are not present in the available genomes of soft-rot bacteria. To determine if the variations of signal production according to growth phase could result from expression modifications of the corresponding synthase gene, the respective mRNA levels were estimated by reverse transcriptase-PCR. While the N-acyl-homoserine lactone production is systematically correlated to the synthase expression, that of the autoinducer-2 follows the expression of an enzyme upstream in the activated methyl cycle and providing its precursor, rather than the expression of its own synthase. CONCLUSIONS/SIGNIFICANCE: Despite sharing the S-adenosylmethionine precursor, no strong link was detected between the production kinetics or metabolic pathways of autoinducers-1 and -2. In contrast, the signaling pathway of autoinducer-2 seems to be switched off by the indole-3-acetic acid pathway under tryptophan control. It therefore appears that the two genera of soft-rot bacteria have similarities but also differences in the mechanisms of communication via the diffusible molecules. Our results designate autoinducer-1 lactones as the main targets for a global biocontrol of soft-rot bacteria communications, including those of emerging isolates. PMID- 22539959 TI - Manipulation of plant defense responses by the tomato psyllid (Bactericerca cockerelli) and its associated endosymbiont Candidatus Liberibacter psyllaurous. AB - Some plant pathogens form obligate relationships with their insect vector and are vertically transmitted via eggs analogous to insect endosymbionts. Whether insect endosymbionts manipulate plant defenses to benefit their insect host remains unclear. The tomato psyllid, Bactericerca cockerelli (Sulc), vectors the endosymbiont "Candidatus Liberibacter psyllaurous" (Lps) during feeding on tomato (Solanum lycopersicum L.). Lps titer in psyllids varied relative to the psyllid developmental stage with younger psyllids harboring smaller Lps populations compared to older psyllids. In the present study, feeding by different life stages of B. cockerelli infected with Lps, resulted in distinct tomato transcript profiles. Feeding by young psyllid nymphs, with lower Lps levels, induced tomato genes regulated by jasmonic acid (JA) and salicylic acid (SA) (Allene oxide synthase, Proteinase inhibitor 2, Phenylalanine ammonia-lyase 5, Pathogenesis related protein 1) compared to feeding by older nymphs and adults, where higher Lps titers were found. In addition, inoculation of Lps without insect hosts suppressed accumulation of these defense transcripts. Collectively, these data suggest that the endosymbiont-like pathogen Lps manipulates plant signaling and defensive responses to benefit themselves and the success of their obligate insect vector on their host plant. PMID- 22539960 TI - Targeted overexpression of amelotin disrupts the microstructure of dental enamel. AB - We have previously identified amelotin (AMTN) as a novel protein expressed predominantly during the late stages of dental enamel formation, but its role during amelogenesis remains to be determined. In this study we generated transgenic mice that produce AMTN under the amelogenin (Amel) gene promoter to study the effect of AMTN overexpression on enamel formation in vivo. The specific overexpression of AMTN in secretory stage ameloblasts was confirmed by Western blot and immunohistochemistry. The gross histological appearance of ameloblasts or supporting cellular structures as well as the expression of the enamel proteins amelogenin (AMEL) and ameloblastin (AMBN) was not altered by AMTN overexpression, suggesting that protein production, processing and secretion occurred normally in transgenic mice. The expression of Odontogenic, Ameloblast Associated (ODAM) was slightly increased in secretory stage ameloblasts of transgenic animals. The enamel in AMTN-overexpressing mice was much thinner and displayed a highly irregular surface structure compared to wild type littermates. Teeth of transgenic animals underwent rapid attrition due to the brittleness of the enamel layer. The microstructure of enamel, normally a highly ordered arrangement of hydroxyapatite crystals, was completely disorganized. Tomes' process, the hallmark of secretory stage ameloblasts, did not form in transgenic mice. Collectively our data demonstrate that the overexpression of amelotin has a profound effect on enamel structure by disrupting the formation of Tomes' process and the orderly growth of enamel prisms. PMID- 22539961 TI - Phylogeography of Rift Valley Fever virus in Africa reveals multiple introductions in Senegal and Mauritania. AB - Rift Valley Fever (RVF) virus (Family Bunyaviridae) is an arthropod-borne RNA virus that infects primarily domestic ruminants and occasionally humans. RVF epizootics are characterized by numerous abortions and mortality among young animals. In humans, the illness is usually characterized by a mild self-limited febrile illness, which could progress to more serious complications. RVF virus is widespread and endemic in many regions of Africa. In Western Africa, several outbreaks have been reported since 1987 when the first major one occurred at the frontier of Senegal and Mauritania. Aiming to evaluate the spreading and molecular epidemiology in these countries, RVFV isolates from 1944 to 2008 obtained from 18 localities in Senegal and Mauritania and 15 other countries were investigated. Our results suggest that a more intense viral activity possibly took place during the last century compared to the recent past and that at least 5 introductions of RVFV took place in Senegal and Mauritania from distant African regions. Moreover, Barkedji in Senegal was possibly a hub associated with the three distinct entries of RVFV in West Africa. PMID- 22539962 TI - Integrative subtype discovery in glioblastoma using iCluster. AB - Large-scale cancer genome projects, such as the Cancer Genome Atlas (TCGA) project, are comprehensive molecular characterization efforts to accelerate our understanding of cancer biology and the discovery of new therapeutic targets. The accumulating wealth of multidimensional data provides a new paradigm for important research problems including cancer subtype discovery. The current standard approach relies on separate clustering analyses followed by manual integration. Results can be highly data type dependent, restricting the ability to discover new insights from multidimensional data. In this study, we present an integrative subtype analysis of the TCGA glioblastoma (GBM) data set. Our analysis revealed new insights through integrated subtype characterization. We found three distinct integrated tumor subtypes. Subtype 1 lacks the classical GBM events of chr 7 gain and chr 10 loss. This subclass is enriched for the G-CIMP phenotype and shows hypermethylation of genes involved in brain development and neuronal differentiation. The tumors in this subclass display a Proneural expression profile. Subtype 2 is characterized by a near complete association with EGFR amplification, overrepresentation of promoter methylation of homeobox and G-protein signaling genes, and a Classical expression profile. Subtype 3 is characterized by NF1 and PTEN alterations and exhibits a Mesenchymal-like expression profile. The data analysis workflow we propose provides a unified and computationally scalable framework to harness the full potential of large-scale integrated cancer genomic data for integrative subtype discovery. PMID- 22539963 TI - Mixed acid-base disorders, hydroelectrolyte imbalance and lactate production in hypercapnic respiratory failure: the role of noninvasive ventilation. AB - BACKGROUND: Hypercapnic Chronic Obstructive Pulmonary Disease (COPD) exacerbation in patients with comorbidities and multidrug therapy is complicated by mixed acid base, hydro-electrolyte and lactate disorders. Aim of this study was to determine the relationships of these disorders with the requirement for and duration of noninvasive ventilation (NIV) when treating hypercapnic respiratory failure. METHODS: Sixty-seven consecutive patients who were hospitalized for hypercapnic COPD exacerbation had their clinical condition, respiratory function, blood chemistry, arterial blood gases, blood lactate and volemic state assessed. Heart and respiratory rates, pH, PaO(2) and PaCO(2) and blood lactate were checked at the 1st, 2nd, 6th and 24th hours after starting NIV. RESULTS: Nine patients were transferred to the intensive care unit. NIV was performed in 11/17 (64.7%) mixed respiratory acidosis-metabolic alkalosis, 10/36 (27.8%) respiratory acidosis and 3/5 (60%) mixed respiratory-metabolic acidosis patients (p = 0.026), with durations of 45.1 +/- 9.8, 36.2 +/- 8.9 and 53.3 +/- 4.1 hours, respectively (p = 0.016). The duration of ventilation was associated with higher blood lactate (p<0.001), lower pH (p = 0.016), lower serum sodium (p = 0.014) and lower chloride (p = 0.038). Hyponatremia without hypervolemic hypochloremia occurred in 11 respiratory acidosis patients. Hypovolemic hyponatremia with hypochloremia and hypokalemia occurred in 10 mixed respiratory acidosis-metabolic alkalosis patients, and euvolemic hypochloremia occurred in the other 7 patients with this mixed acid-base disorder. CONCLUSIONS: Mixed acid-base and lactate disorders during hypercapnic COPD exacerbations predict the need for and longer duration of NIV. The combination of mixed acid-base disorders and hydro-electrolyte disturbances should be further investigated. PMID- 22539965 TI - Sulforaphane potentiates RNA damage induced by different xenobiotics. AB - BACKGROUND: The isothiocyanate sulforaphane (SFN) possesses interesting anticancer activities. However, recent studies reported that SFN promotes the formation of reactive oxygen species (ROS) as well as DNA breakage. METHODOLOGY/PRINCIPAL FINDINGS: We investigated whether SFN is able to damage RNA, whose loss of integrity was demonstrated in different chronic diseases. Considering the ability of SFN to protect from genotoxicity, we also examined whether SFN is able to protect from RNA damage induced by different chemicals (doxorubicin, spermine, S-nitroso-N-acetylpenicillamine, H(2)O(2)). We observed that SFN was devoid of either RNA damaging and RNA protective activity in human leukemic cells. It was able to potentiate the RNA damage by doxorubicin and spermine. In the first case, the effect was attributable to its ability of modulating the bioreductive activation of doxorubicin. For spermine, the effects were mainly due to its modulation of ROS levels produced by spermine metabolism. As to the cytotoxic relevance of the RNA damage, we found that the treatment of cells with a mixture of spermine or doxorubicin plus SFN increased their proapoptotic potential. Thus it is conceivable that the presence of RNA damage might concur to the overall toxic response induced by a chemical agent in targeted cells. CONCLUSIONS/SIGNIFICANCE: Since RNA is emerging as a potential target for anticancer drugs, its ability to enhance spermine- and doxorubicin induced RNA damage and cytotoxicity could represent an additional mechanism for the potentiating effects of SFN associated with anticancer drugs. PMID- 22539964 TI - Ets-1 is essential for connective tissue growth factor (CTGF/CCN2) induction by TGF-beta1 in osteoblasts. AB - BACKGROUND: Ets-1 controls osteoblast differentiation and bone development; however, its downstream mechanism of action in osteoblasts remains largely undetermined. CCN2 acts as an anabolic growth factor to regulate osteoblast differentiation and function. CCN2 is induced by TGF-beta1 and acts as a mediator of TGF-beta1 induced matrix production in osteoblasts; however, the molecular mechanisms that control CCN2 induction are poorly understood. In this study, we investigated the role of Ets-1 for CCN2 induction by TGF-beta1 in primary osteoblasts. RESULTS: We demonstrated that Ets-1 is expressed and induced by TGF beta1 treatment in osteoblasts, and that Ets-1 over-expression induces CCN2 protein expression and promoter activity at a level similar to TGF-beta1 treatment alone. Additionally, we found that simultaneous Ets-1 over-expression and TGF-beta1 treatment synergize to enhance CCN2 induction, and that CCN2 induction by TGF-beta1 treatment was impaired using Ets-1 siRNA, demonstrating the requirement of Ets-1 for CCN2 induction by TGF-beta1. Site-directed mutagenesis of eight putative Ets-1 motifs (EBE) in the CCN2 promoter demonstrated that specific EBE sites are required for CCN2 induction, and that mutation of EBE sites in closer proximity to TRE or SBE (two sites previously shown to regulate CCN2 induction by TGF-beta1) had a greater effect on CCN2 induction, suggesting potential synergetic interaction among these sites for CCN2 induction. In addition, mutation of EBE sites prevented protein complex binding, and this protein complex formation was also inhibited by addition of Ets-1 antibody or Smad 3 antibody, demonstrating that protein binding to EBE motifs as a result of TGF-beta1 treatment require synergy between Ets-1 and Smad 3. CONCLUSIONS: This study demonstrates that Ets-1 is an essential downstream signaling component for CCN2 induction by TGF-beta1 in osteoblasts, and that specific EBE sites in the CCN2 promoter are required for CCN2 promoter transactivation in osteoblasts. PMID- 22539966 TI - Mitochondrial lysyl-tRNA synthetase independent import of tRNA lysine into yeast mitochondria. AB - Aminoacyl tRNA synthetases play a central role in protein synthesis by charging tRNAs with amino acids. Yeast mitochondrial lysyl tRNA synthetase (Msk1), in addition to the aminoacylation of mitochondrial tRNA, also functions as a chaperone to facilitate the import of cytosolic lysyl tRNA. In this report, we show that human mitochondrial Kars (lysyl tRNA synthetase) can complement the growth defect associated with the loss of yeast Msk1 and can additionally facilitate the in vitro import of tRNA into mitochondria. Surprisingly, the import of lysyl tRNA can occur independent of Msk1 in vivo. This suggests that an alternative mechanism is present for the import of lysyl tRNA in yeast. PMID- 22539967 TI - Synaptotagmin-2 is a reliable marker for parvalbumin positive inhibitory boutons in the mouse visual cortex. AB - BACKGROUND: Inhibitory innervation by parvalbumin (PV) expressing interneurons has been implicated in the onset of the sensitive period of visual plasticity. Immunohistochemical analysis of the development and plasticity of these inhibitory inputs is difficult because PV expression is low in young animals and strongly influenced by neuronal activity. Moreover, the synaptic boutons that PV neurons form onto each other cannot be distinguished from the innervated cell bodies by immunostaining for this protein because it is present throughout the cells. These problems call for the availability of a synaptic, activity independent marker for PV+ inhibitory boutons that is expressed before sensitive period onset. We investigated whether synaptotagmin-2 (Syt2) fulfills these properties in the visual cortex. Syt2 is a synaptic vesicle protein involved in fast Ca(2+) dependent neurotransmitter release. Its mRNA expression follows a pattern similar to that of PV throughout the brain and is present in 30-40% of hippocampal PV expressing basket cells. Up to now, no quantitative analyses of Syt2 expression in the visual cortex have been carried out. METHODOLOGY/PRINCIPAL FINDINGS: We used immunohistochemistry to analyze colocalization of Syt2 with multiple interneuron markers including vesicular GABA transporter VGAT, calbindin, calretinin, somatostatin and PV in the primary visual cortex of mice during development and after dark-rearing. CONCLUSIONS/SIGNIFICANCE: We show that in the adult visual cortex Syt2 is only found in inhibitory, VGAT positive boutons. Practically all Syt2 positive boutons also contain PV and vice versa. During development, Syt2 expression can be detected in synaptic boutons prior to PV and in contrast to PV expression, Syt2 is not down-regulated by dark-rearing. These properties of Syt2 make it an excellent marker for analyzing the development and plasticity of perisomatic inhibitory innervations onto both excitatory and inhibitory neurons in the visual cortex. PMID- 22539968 TI - ANG-1 TIE-2 and BMPR signalling defects are not seen in the nitrofen model of pulmonary hypertension and congenital diaphragmatic hernia. AB - BACKGROUND: Pulmonary hypertension (PH) is a lethal disease that is associated with characteristic histological abnormalities of the lung vasculature and defects of angiopoetin-1 (ANG-1), TIE-2 and bone morphogenetic protein receptor (BMPR)-related signalling. We hypothesized that if these signalling defects cause PH generically, they will be readily identifiable perinatally in congenital diaphragmatic hernia (CDH), where the typical pulmonary vascular changes are present before birth and are accompanied by PH after birth. METHODS: CDH (predominantly left-sided, LCDH) was created in Sprague-Dawley rat pups by e9.5 maternal nitrofen administration. Left lungs from normal and LCDH pups were compared at fetal and postnatal time points for ANG-1, TIE-2, phosphorylated-TIE 2, phosphorylated-SMAD1/5/8 and phosphorylated-ERK1/2 by immunoprecipitation and Western blotting of lung protein extracts and by immunohistochemistry on lung sections. RESULTS: In normal lung, pulmonary ANG-1 protein levels fall between fetal and postnatal life, while TIE-2 levels increase. Over the corresponding time period, LCDH lung retained normal expression of ANG-1, TIE-2, phosphorylated TIE-2 and, downstream of BMPR, phosphorylated-SMAD1/5/8 and phosphorylated p44/42. CONCLUSION: In PH and CDH defects of ANG-1/TIE-2/BMPR-related signalling are not essential for the lethal vasculopathy. PMID- 22539969 TI - Nonuniform cardiac denervation observed by 11C-meta-hydroxyephedrine PET in 6 OHDA-treated monkeys. AB - Parkinson's disease presents nonmotor complications such as autonomic dysfunction that do not respond to traditional anti-parkinsonian therapies. The lack of established preclinical monkey models of Parkinson's disease with cardiac dysfunction hampers development and testing of new treatments to alleviate or prevent this feature. This study aimed to assess the feasibility of developing a model of cardiac dysautonomia in nonhuman primates and preclinical evaluations tools. Five rhesus monkeys received intravenous injections of 6-hydroxydopamine (total dose: 50 mg/kg). The animals were evaluated before and after with a battery of tests, including positron emission tomography with the norepinephrine analog (11)C-meta-hydroxyephedrine. Imaging 1 week after neurotoxin treatment revealed nearly complete loss of specific radioligand uptake. Partial progressive recovery of cardiac uptake found between 1 and 10 weeks remained stable between 10 and 14 weeks. In all five animals, examination of the pattern of uptake (using Logan plot analysis to create distribution volume maps) revealed a persistent region-specific significant loss in the inferior wall of the left ventricle at 10 (P<0.001) and 14 weeks (P<0.01) relative to the anterior wall. Blood levels of dopamine, norepinephrine (P<0.05), epinephrine, and 3,4-dihydroxyphenylacetic acid (P<0.01) were notably decreased after 6-hydroxydopamine at all time points. These results demonstrate that systemic injection of 6-hydroxydopamine in nonhuman primates creates a nonuniform but reproducible pattern of cardiac denervation as well as a persistent loss of circulating catecholamines, supporting the use of this method to further develop a monkey model of cardiac dysautonomia. PMID- 22539970 TI - Mutational analysis of Cvab, an ABC transporter involved in the secretion of active colicin V. AB - CvaB is the central membrane transporter of the colicin V secretion system that belongs to an ATP-binding cassette superfamily. Previous data showed that the N terminal and C-terminal domains of CvaB are essential for the function of CvaB. N terminal domain of CvaB possesses Ca(2+)-dependent cysteine proteolytic activity, and two critical residues, Cys32 and His105, have been identified. In this study, we also identify Asp121 as being the third residue of the putative catalytic triad within the active site of the enzyme. The Asp121 mutants lose both their colicin V secretion activity and N-terminal proteolytic activity. The adjacent residue Pro122 also appears to play a critical role in the colicin V secretion. However, the reversal of the two residues D121P - P122D results in loss of activity. Based on molecular modeling and protein sequence alignment, several residues adjacent to the critical residues, Cys32 and His105, were also examined and characterized. Site-directed mutagenesis of Trp101, Asp102, Val108, Leu76, Gly77, and Gln26 indicate that the neighboring residues around the catalytic triad affect colicin V secretion. Several mutated CvaB proteins with defective secretion were also tested, including Asp121 and Pro122, and were found to be structurally stable. These results indicate that the residues surrounding the identified catalytic triad are functionally involved in the secretion of biologically active colicin V. PMID- 22539973 TI - Competitive reporter monitored amplification (CMA)--quantification of molecular targets by real time monitoring of competitive reporter hybridization. AB - BACKGROUND: State of the art molecular diagnostic tests are based on the sensitive detection and quantification of nucleic acids. However, currently established diagnostic tests are characterized by elaborate and expensive technical solutions hindering the development of simple, affordable and compact point-of-care molecular tests. METHODOLOGY AND PRINCIPAL FINDINGS: The described competitive reporter monitored amplification allows the simultaneous amplification and quantification of multiple nucleic acid targets by polymerase chain reaction. Target quantification is accomplished by real-time detection of amplified nucleic acids utilizing a capture probe array and specific reporter probes. The reporter probes are fluorescently labeled oligonucleotides that are complementary to the respective capture probes on the array and to the respective sites of the target nucleic acids in solution. Capture probes and amplified target compete for reporter probes. Increasing amplicon concentration leads to decreased fluorescence signal at the respective capture probe position on the array which is measured after each cycle of amplification. In order to observe reporter probe hybridization in real-time without any additional washing steps, we have developed a mechanical fluorescence background displacement technique. CONCLUSIONS AND SIGNIFICANCE: The system presented in this paper enables simultaneous detection and quantification of multiple targets. Moreover, the presented fluorescence background displacement technique provides a generic solution for real time monitoring of binding events of fluorescently labelled ligands to surface immobilized probes. With the model assay for the detection of human immunodeficiency virus type 1 and 2 (HIV 1/2), we have been able to observe the amplification kinetics of five targets simultaneously and accommodate two additional hybridization controls with a simple instrument set-up. The ability to accommodate multiple controls and targets into a single assay and to perform the assay on simple and robust instrumentation is a prerequisite for the development of novel molecular point of care tests. PMID- 22539972 TI - Timeliness of childhood vaccinations in Kampala Uganda: a community-based cross sectional study. AB - BACKGROUND: Child survival is dependent on several factors including high vaccination coverage. Timely receipt of vaccines ensures optimal immune response to the vaccines. Yet timeliness is not usually emphasized in estimating population immunity. In addition to examining timeliness of the recommended Expanded Programme for Immunisation (EPI) vaccines, this paper identifies predictors of untimely vaccination among children aged 10 to 23 months in Kampala. METHODS: In addition to the household survey interview questions, additional data sources for variables included data collection of child's weight and length. Vaccination dates were obtained from child health cards. Timeliness of vaccinations were assessed with Kaplan-Meier time-to-event analysis for each vaccine based on the following time ranges (lowest-highest target age): BCG (birth-8 weeks), polio 0 (birth-4 weeks), three polio and three pentavalent vaccines (4 weeks-2 months; 8 weeks-4 months; 12 weeks-6 months) and measles vaccine (38 weeks-12 months). Cox regression analysis was used to identify factors associated with vaccination timeliness. RESULTS: About half of 821 children received all vaccines within the recommended time ranges (45.6%; 95% CI 39.8-51.2). Timely receipt of vaccinations was lowest for measles (67.5%; 95% CI 60.5-73.8) and highest for BCG vaccine (92.7%: 95% CI 88.1-95.6). For measles, 10.7% (95% CI 6.8-16.4) of the vaccinations were administered earlier than the recommended time. Vaccinations that were not received within the recommended age ranges were associated with increasing number of children per woman (adjusted hazard ratio (AHR); 1.84, 95% CI 1.29-2.64), non-delivery at health facilities (AHR 1.58, 95% CI 1.02-2.46), being unmarried (AHR 1.49, 95% CI 1.15-1.94) or being in the lowest wealth quintile (AHR 1.38, 95% CI 1.11-1.72). CONCLUSIONS: Strategies to improve vaccination practices among the poorest, single, multiparous women and among mothers who do not deliver at health facilities are necessary to improve timeliness of vaccinations. PMID- 22539971 TI - DCLK1 variants are associated across schizophrenia and attention deficit/hyperactivity disorder. AB - Doublecortin and calmodulin like kinase 1 (DCLK1) is implicated in synaptic plasticity and neurodevelopment. Genetic variants in DCLK1 are associated with cognitive traits, specifically verbal memory and general cognition. We investigated the role of DCLK1 variants in three psychiatric disorders that have neuro-cognitive dysfunctions: schizophrenia (SCZ), bipolar affective disorder (BP) and attention deficit/hyperactivity disorder (ADHD). We mined six genome wide association studies (GWASs) that were available publically or through collaboration; three for BP, two for SCZ and one for ADHD. We also genotyped the DCLK1 region in additional samples of cases with SCZ, BP or ADHD and controls that had not been whole-genome typed. In total, 9895 subjects were analysed, including 5308 normal controls and 4,587 patients (1,125 with SCZ, 2,496 with BP and 966 with ADHD). Several DCLK1 variants were associated with disease phenotypes in the different samples. The main effect was observed for rs7989807 in intron 3, which was strongly associated with SCZ alone and even more so when cases with SCZ and ADHD were combined (P-value = 4 * 10(-5) and 4 * 10(-6), respectively). Associations were also observed with additional markers in intron 3 (combination of SCZ, ADHD and BP), intron 19 (SCZ+BP) and the 3'UTR (SCZ+BP). Our results suggest that genetic variants in DCLK1 are associated with SCZ and, to a lesser extent, with ADHD and BP. Interestingly the association is strongest when SCZ and ADHD are considered together, suggesting common genetic susceptibility. Given that DCLK1 variants were previously found to be associated with cognitive traits, these results are consistent with the role of DCLK1 in neurodevelopment and synaptic plasticity. PMID- 22539974 TI - Renal function at hospital admission and mortality due to acute kidney injury after myocardial infarction. AB - BACKGROUND: The role of an impaired estimated glomerular filtration rate (eGFR) at hospital admission in the outcome of acute kidney injury (AKI) after acute myocardial infarction (AMI) has been underreported. The aim of this study was to assess the influence of an admission eGFR<60 mL/min/1.73 m(2) on the incidence and early and late mortality of AMI-associated AKI. METHODS: A prospective study of 828 AMI patients was performed. AKI was defined as a serum creatinine increase of >= 50% from the time of admission (RIFLE criteria) in the first 7 days of hospitalization. Patients were divided into subgroups according to their eGFR upon hospital admission (MDRD formula, mL/min/1.73 m(2)) and the development of AKI: eGFR >= 60 without AKI, eGFR<60 without AKI, eGFR >= 60 with AKI and eGFR<60 with AKI. RESULTS: Overall, 14.6% of the patients in this study developed AKI. The admission eGFR had no impact on the incidence of AKI. However, the admission eGFR was associated with the outcome of AMI-associated AKI. The adjusted hazard ratios (AHR, Cox multivariate analysis) for 30-day mortality were 2.00 (95% CI 1.11-3.61) for eGFR<60 without AKI, 4.76 (95% CI 2.45-9.26) for eGFR >= 60 with AKI and 6.27 (95% CI 3.20-12.29) for eGFR<60 with AKI. Only an admission eGFR of <60 with AKI was significantly associated with a 30-day to 1-year mortality hazard (AHR 3.05, 95% CI 1.50-6.19). CONCLUSIONS: AKI development was associated with an increased early mortality hazard in AMI patients with either preserved or impaired admission eGFR. Only the association of impaired admission eGFR and AKI was associated with an increased hazard for late mortality among these patients. PMID- 22539976 TI - Activation of regulatory T cells during inflammatory response is not an exclusive property of stem cells. AB - BACKGROUND: Sepsis and systemic-inflammatory-response-syndrome (SIRS) remain major causes for fatalities on intensive care units despite up-to-date therapy. It is well accepted that stem cells have immunomodulatory properties during inflammation and sepsis, including the activation of regulatory T cells and the attenuation of distant organ damage. Evidence from recent work suggests that these properties may not be exclusively attributed to stem cells. This study was designed to evaluate the immunomodulatory potency of cellular treatment during acute inflammation in a model of sublethal endotoxemia and to investigate the hypothesis that immunomodulations by cellular treatment during inflammatory response is not stem cell specific. METHODOLOGY/PRINCIPAL FINDINGS: Endotoxemia was induced via intra-peritoneal injection of lipopolysaccharide (LPS) in wild type mice (C3H/HeN). Mice were treated with either vital or homogenized amniotic fluid stem cells (AFS) and sacrificed for specimen collection 24 h after LPS injection. Endpoints were plasma cytokine levels (BDTM Cytometric Bead Arrays), T cell subpopulations (flow-cytometry) and pulmonary neutrophil influx (immunohistochemistry). To define stem cell specific effects, treatment with either vital or homogenized human-embryonic-kidney-cells (HEK) was investigated in a second subset of experiments. Mice treated with homogenized AFS cells showed significantly increased percentages of regulatory T cells and Interleukin-2 as well as decreased amounts of pulmonary neutrophils compared to saline-treated controls. These results could be reproduced in mice treated with vital HEK cells. No further differences were observed between plasma cytokine levels of endotoxemic mice. CONCLUSIONS/SIGNIFICANCE: The results revealed that both AFS and HEK cells modulate cellular immune response and distant organ damage during sublethal endotoxemia. The observed effects support the hypothesis, that immunomodulations are not exclusive attributes of stem cells. PMID- 22539975 TI - Functional and topological properties in hepatocellular carcinoma transcriptome. AB - Hepatocellular carcinoma (HCC) is a leading cause of global cancer mortality. However, little is known about the precise molecular mechanisms involved in tumor formation and pathogenesis. The primary goal of this study was to elucidate genome-wide molecular networks involved in development of HCC with multiple etiologies by exploring high quality microarray data. We undertook a comparative network analysis across 264 human microarray profiles monitoring transcript changes in healthy liver, liver cirrhosis, and HCC with viral and alcoholic etiologies. Gene co-expression profiling was used to derive a consensus gene relevance network of HCC progression that consisted of 798 genes and 2,012 links. The HCC interactome was further confirmed to be phenotype-specific and non random. Additionally, we confirmed that co-expressed genes are more likely to share biological function, but not sub-cellular localization. Analysis of individual HCC genes revealed that they are topologically central in a human protein-protein interaction network. We used quantitative RT-PCR in a cohort of normal liver tissue (n = 8), hepatitis C virus (HCV)-induced chronic liver disease (n = 9), and HCC (n = 7) to validate co-expressions of several well connected genes, namely ASPM, CDKN3, NEK2, RACGAP1, and TOP2A. We show that HCC is a heterogeneous disorder, underpinned by complex cross talk between immune response, cell cycle, and mRNA translation pathways. Our work provides a systems wide resource for deeper understanding of molecular mechanisms in HCC progression and may be used further to define novel targets for efficient treatment or diagnosis of this disease. PMID- 22539977 TI - Role of Dlg5/lp-dlg, a membrane-associated guanylate kinase family protein, in epithelial-mesenchymal transition in LLc-PK1 renal epithelial cells. AB - Discs large homolog 5 (Dlg5) is a member of the membrane-associated guanylate kinase adaptor family of proteins, some of which are involved in the regulation of epithelial-to-mesenchymal transition (EMT). Dlg5 has been described as a susceptibility gene for Crohn's disease; however, the physiological function of Dlg5 is unknown. We show here that transforming growth factor-beta (TGF-beta) induced EMT suppresses Dlg5 expression in LLc-PK1 cells. Depletion of Dlg5 expression by knockdown promoted the expression of the mesenchymal marker proteins, fibronectin and alpha-smooth muscle actin, and suppressed the expression of E-cadherin. In addition, activation of JNK and p38, which are stimulated by TGF-beta, was enhanced by Dlg5 depletion. Furthermore, inhibition of the TGF-beta receptor suppressed the effects of Dlg5 depletion. These observations suggest that Dlg5 is involved in the regulation of TGF-betareceptor dependent signals and EMT. PMID- 22539978 TI - The anaphase-promoting complex or cyclosome supports cell survival in response to endoplasmic reticulum stress. AB - The anaphase-promoting complex or cyclosome (APC/C) is a multi-subunit ubiquitin ligase that regulates exit from mitosis and G1 phase of the cell cycle. Although the regulation and function of APC/C(Cdh1) in the unperturbed cell cycle is well studied, little is known of its role in non-genotoxic stress responses. Here, we demonstrate the role of APC/C(Cdh1) (APC/C activated by Cdh1 protein) in cellular protection from endoplasmic reticulum (ER) stress. Activation of APC/C(Cdh1) under ER stress conditions is evidenced by Cdh1-dependent degradation of its substrates. Importantly, the activity of APC/C(Cdh1) maintains the ER stress checkpoint, as depletion of Cdh1 by RNAi impairs cell cycle arrest and accelerates cell death following ER stress. Our findings identify APC/C(Cdh1) as a regulator of cell cycle checkpoint and cell survival in response to proteotoxic insults. PMID- 22539979 TI - Identification and functional analysis of variant haplotypes in the 5'-flanking region of protein phosphatase 2A-Bdelta gene. AB - Serine-threonine protein phosphatase 2A (PP2A) is a trimeric holoenzyme that plays an integral role in the regulation of cell growth, differentiation, and apoptosis. The substrate specificity and (sub)cellular localization of the PP2A holoenzymes are highly regulated by interaction with a family of regulatory B subunits (PP2A-Bs). The regulatory subunit PP2A-B/PR55delta (PP2A-Bdelta) is involving in the dephosphorylation of PP2A substrates and is crucial for controlling entry into and exit from mitosis. The molecular mechanisms involved in the regulation of expression of PP2A-Bdelta gene (PPP2R2D) remain largely unknown. To explore genetic variations in the 5'-flanking region of PPP2R2D gene as well as their frequent haplotypes in the Han Chinese population and determine whether such variations have an impact on transcriptional activity, DNA samples were collected from 70 healthy Chinese donors and sequenced for identifying genetic variants in the 5'-flanking region of PPP2R2D. Four genetic variants were identified in the 1836 bp 5'-flanking region of PPP2R2D. Linkage disequilibrium (LD) patterns and haplotype profiles were constructed for the genetic variants. Using serially truncated human PPP2R2D promoter luciferase constructs, we found that a 601 bp (-540 nt to +61 nt) fragment constitutes the core promoter region. The subcloning of individual 5'-flanking fragment revealed the existence of three haplotypes in the distal promoter of PPP2R2D. The luciferase reporter assay showed that different haplotypes exhibited distinct promoter activities. The EMSA revealed that the -462 G>A variant influences DNA-protein interactions involving the nuclear factor 1 (NF1). In vitro reporter gene assay indicated that cotransfection of NF1/B expression plasmid could positively regulate the activity of PPP2R2D proximal promoter. Introduction of exogenous NF1/B expression plasmid further confirmed that the NF1 involves in the regulation of PPP2R2D gene expression. Our findings suggest that functional genetic variants and their haplotypes in the 5'-flanking region of PPP2R2D are critical for transcriptional regulation of PP2A-Bdelta. PMID- 22539980 TI - Widespread contribution of Gdf7 lineage to cerebellar cell types and implications for hedgehog-driven medulloblastoma formation. AB - The roof plate is a specialized embryonic midline tissue of the central nervous system that functions as a signaling center regulating dorsal neural patterning. In the developing hindbrain, roof plate cells express Gdf7 and previous genetic fate mapping studies showed that these cells contribute mostly to non-neural choroid plexus epithelium. We demonstrate here that constitutive activation of the Sonic hedgehog signaling pathway in the Gdf7 lineage invariably leads to medulloblastoma. Lineage tracing analysis reveals that Gdf7-lineage cells not only are a source of choroid plexus epithelial cells, but are also present in the cerebellar rhombic lip and contribute to a subset of cerebellar granule neuron precursors, the presumed cell-of-origin for Sonic hedgehog-driven medulloblastoma. We further show that Gdf7-lineage cells also contribute to multiple neuronal and glial cell types in the cerebellum, including glutamatergic granule neurons, unipolar brush cells, Purkinje neurons, GABAergic interneurons, Bergmann glial cells, and white matter astrocytes. These findings establish hindbrain roof plate as a novel source of diverse neural cell types in the cerebellum that is also susceptible to oncogenic transformation by deregulated Sonic hedgehog signaling. PMID- 22539981 TI - Altered synaptic properties during integration of adult-born hippocampal neurons following a seizure insult. AB - Pathological conditions affect several stages of neurogenesis in the adult brain, including proliferation, survival, cell fate, migration, and functional integration. Here we explored how a pathological environment modulates the heterogeneous afferent synaptic input that shapes the functional properties of newly formed neurons. We analyzed the expression of adhesion molecules and other synaptic proteins on adult-born hippocampal neurons formed after electrically induced partial status epilepticus (pSE). New cells were labeled with a GFP retroviral vector one week after pSE. One and three weeks thereafter, synaptic proteins were present on dendritic spines and shafts, but without differences between pSE and control group. In contrast, at six weeks, we found fewer dendritic spines and decreased expression of the scaffolding protein PSD-95 on spines, without changes in expression of the adhesion molecules N-cadherin or neuroligin-1, primarily located at excitatory synapses. Moreover, we detected an increased expression of the inhibitory scaffolding protein gephyrin in newborn but not mature neurons after SE. However, this increase was not accompanied by a difference in GABA expression, and there was even a region-specific decrease in the adhesion molecule neuroligin-2 expression, both in newborn and mature neurons. Neuroligin-2 clusters co-localized with presynaptic cholecystokinin terminals, which were also reduced. The expression of neuroligin-4 and glycine receptor was unchanged. Increased postsynaptic clustering of gephyrin, without an accompanying increase in GABAergic input or neuroligin-2 and -4 expression, the latter important for clustering of GABA(A) and glycine receptors, respectively, could imply an increased but altered inhibitory connectivity specific for newborn neurons. The changes were transient and expression of both gephyrin and NL-2 was normalized 3 months post-SE. Our findings indicate that seizure-induced brain pathology alters the sub-cellular expression of synaptic adhesion molecules and scaffolding proteins related to particularly inhibitory but also excitatory synapses, which may yield functional consequences for the integration of adult born neurons. PMID- 22539982 TI - Length and amino acid sequence of peptides substituted for the 5-HT3A receptor M3M4 loop may affect channel expression and desensitization. AB - 5-HT3A receptors are pentameric neurotransmitter-gated ion channels in the Cys loop receptor family. Each subunit contains an extracellular domain, four transmembrane segments (M1, M2, M3, M4) and a 115 residue intracellular loop between M3 and M4. In contrast, the M3M4 loop in prokaryotic homologues is <15 residues. To investigate the limits of M3M4 loop length and composition on channel function we replaced the 5-HT3A M3M4 loop with two to seven alanine residues (5-HT3A-A(n = 2-7)). Mutants were expressed in Xenopus laevis oocytes and characterized using two electrode voltage clamp recording. All mutants were functional. The 5-HT EC(50)'s were at most 5-fold greater than wild-type (WT). The desensitization rate differed significantly among the mutants. Desensitization rates for 5-HT3A-A(2), 5-HT3A-A(4), 5-HT3A-A(6), and 5-HT3A-A(7) were similar to WT. In contrast, 5-HT3A-A(3) and 5-HT3A-A(5) had desensitization rates at least an order of magnitude faster than WT. The one Ala loop construct, 5-HT3A-A(1), entered a non-functional state from which it did not recover after the first 5-HT application. These results suggest that the large M3M4 loop of eukaryotic Cys-loop channels is not required for receptor assembly or function. However, loop length and amino acid composition can effect channel expression and desensitization. We infer that the cytoplasmic ends of the M3 and M4 segments may undergo conformational changes during channel gating and desensitization and/or the loop may influence the position and mobility of these segments as they undergo gating-induced conformational changes. Altering structure or conformational mobility of the cytoplasmic ends of M3 and M4 may be the basis by which phosphorylation or protein binding to the cytoplasmic loop alters channel function. PMID- 22539983 TI - Test of colonisation scenarios reveals complex invasion history of the red tomato spider mite Tetranychus evansi. AB - The spider mite Tetranychus evansi is an emerging pest of solanaceous crops worldwide. Like many other emerging pests, its small size, confusing taxonomy, complex history of associations with humans, and propensity to start new populations from small inocula, make the study of its invasion biology difficult. Here, we use recent developments in Approximate Bayesian Computation (ABC) and variation in multi-locus genetic markers to reconstruct the complex historical demography of this cryptic invasive pest. By distinguishing among multiple pathways and timing of introductions, we find evidence for the "bridgehead effect", in which one invasion serves as source for subsequent invasions. Tetranychus evansi populations in Europe and Africa resulted from at least three independent introductions from South America and involved mites from two distinct sources in Brazil, corresponding to highly divergent mitochondrial DNA lineages. Mites from southwest Brazil (BR-SW) colonized the African continent, and from there Europe through two pathways in a "bridgehead" type pattern. One pathway resulted in a widespread invasion, not only to Europe, but also to other regions in Africa, southern Europe and eastern Asia. The second pathway involved the mixture with a second introduction from BR-SW leading to an admixed population in southern Spain. Admixture was also detected between invasive populations in Portugal. A third introduction from the Brazilian Atlantic region resulted in only a limited invasion in Europe. This study illustrates that ABC methods can provide insights into, and distinguish among, complex invasion scenarios. These processes are critical not only in understanding the biology of invasions, but also in refining management strategies for invasive species. For example, while reported observations of the mite and outbreaks in the invaded areas were largely consistent with estimates of geographical expansion from the ABC approach, historical observations failed to recognize the complex pathways involved and the corresponding effects on genetic diversity. PMID- 22539984 TI - Comprehensive evaluation of corticospinal tract metabolites in amyotrophic lateral sclerosis using whole-brain 1H MR spectroscopy. AB - Changes in the distribution of the proton magnetic resonance spectroscopy (MRS) observed metabolites N-acetyl aspartate (NAA), total-choline (Cho), and total creatine (Cre) in the entire intracranial corticospinal tract (CST) including the primary motor cortex were evaluated in patients with amyotrophic lateral sclerosis (ALS). The study included 38 sporadic definite-ALS subjects and 70 age matched control subjects. All received whole-brain MR imaging and spectroscopic imaging scans at 3T and clinical neurological assessments including percentage maximum forced vital capacity (FVC) and upper motor neuron (UMN) function. Differences in each individual metabolite and its ratio distributions were evaluated in the entire intracranial CST and in five segments along the length of the CST (at the levels of precentral gyrus (PCG), centrum semiovale (CS), corona radiata (CR), posterior limb of internal capsule (PLIC) and cerebral peduncle (CP)). Major findings included significantly decreased NAA and increased Cho and Cho/NAA in the entire intracranial CST, with the largest differences for Cho/NAA in all the groups. Significant correlations between Cho/NAA in the entire intracranial CST and the right finger tap rate were noted. Of the ten bilateral CST segments, significantly decreased NAA in 4 segments, increased Cho in 5 segments and increased Cho/NAA in all the segments were found. Significant left versus right CST asymmetries were found only in ALS for Cho/NAA in the CS. Among the significant correlations found between Cho/NAA and the clinical assessments included the left-PCG versus FVC and right finger tap rate, left -CR versus FVC and right finger tap rate, and left PLIC versus FVC and right foot tap rate. These results demonstrate that a significant and bilaterally asymmetric alteration of metabolites occurs along the length of the entire intracranial CST in ALS, and the MRS metrics in the segments correlate with measures of disease severity and UMN function. PMID- 22539985 TI - Mammalian niche conservation through deep time. AB - Climate change alters species distributions, causing plants and animals to move north or to higher elevations with current warming. Bioclimatic models predict species distributions based on extant realized niches and assume niche conservation. Here, we evaluate if proxies for niches (i.e., range areas) are conserved at the family level through deep time, from the Eocene to the Pleistocene. We analyze the occurrence of all mammalian families in the continental USA, calculating range area, percent range area occupied, range area rank, and range polygon centroids during each epoch. Percent range area occupied significantly increases from the Oligocene to the Miocene and again from the Pliocene to the Pleistocene; however, mammalian families maintain statistical concordance between rank orders across time. Families with greater taxonomic diversity occupy a greater percent of available range area during each epoch and net changes in taxonomic diversity are significantly positively related to changes in percent range area occupied from the Eocene to the Pleistocene. Furthermore, gains and losses in generic and species diversity are remarkably consistent with ~2.3 species gained per generic increase. Centroids demonstrate southeastern shifts from the Eocene through the Pleistocene that may correspond to major environmental events and/or climate changes during the Cenozoic. These results demonstrate range conservation at the family level and support the idea that niche conservation at higher taxonomic levels operates over deep time and may be controlled by life history traits. Furthermore, families containing megafauna and/or terminal Pleistocene extinction victims do not incur significantly greater declines in range area rank than families containing only smaller taxa and/or only survivors, from the Pliocene to Pleistocene. Collectively, these data evince the resilience of families to climate and/or environmental change in deep time, the absence of terminal Pleistocene "extinction prone" families, and provide valuable insights to understanding mammalian responses to current climate change. PMID- 22539986 TI - Effect of angiogenesis inhibitor bevacizumab on survival in patients with cancer: a meta-analysis of the published literature. AB - Bevacizumab is a recombinant humanized monoclonal antibody against vascular endothelial growth factor which has been used in conjunction with other anti cancer agents in the treatment of patients with many cancers. It remains controversial whether bevacizumab can prolong survival in cancer patients. This meta-analysis was therefore performed to evaluate effect of bevacizumab on survival in cancer patients. PubMed, EMBASE, and Web of Science databases were searched for English-language studies of randomized controlled trials comparing bevacizumab with control therapy published through February 8, 2012. Progression free survival, overall survival, and one-year survival rate were analyzed using random- or fixed-effects model. Thirty one assessable randomized controlled trials were identified. A significant improvement in progression-free survival in cancer patients was attributable to bevacizumab compared with control therapy (hazard ratio, 0.72; 95% confidence interval, 0.68 to 0.76; p<0.001). Overall survival was also significantly longer in patients were treated with bevacizumab (hazard ratio, 0.87; 95% confidence interval, 0.83 to 0.91; p<0.001). The significant benefit in one-year survival rate was further seen in cancer patients receiving bevacizumab (odds ratio, 1.30; 95% confidence interval, 1.20 to 1.41; p<0.001). Current evidences showed that bevacizumab prolong progression-free survival and overall survival, and increase one-year survival rate in cancer patients as compared with control therapy. PMID- 22539987 TI - Mixed emotional experience is associated with and precedes improvements in psychological well-being. AB - BACKGROUND: The relationships between positive and negative emotional experience and physical and psychological well-being have been well-documented. The present study examines the prospective positive relationship between concurrent positive and negative emotional experience and psychological well-being in the context of psychotherapy. METHODS: 47 adults undergoing psychotherapy completed measures of psychological well-being and wrote private narratives that were coded by trained raters for emotional content. RESULTS: The specific concurrent experience of happiness and sadness was associated with improvements in psychological well being above and beyond the impact of the passage of time, personality traits, or the independent effects of happiness and sadness. Changes in mixed emotional experience preceded improvements in well-being. CONCLUSIONS: Experiencing happiness alongside sadness in psychotherapy may be a harbinger of improvement in psychological well-being. PMID- 22539988 TI - Evaluation of the metabochip genotyping array in African Americans and implications for fine mapping of GWAS-identified loci: the PAGE study. AB - The Metabochip is a custom genotyping array designed for replication and fine mapping of metabolic, cardiovascular, and anthropometric trait loci and includes low frequency variation content identified from the 1000 Genomes Project. It has 196,725 SNPs concentrated in 257 genomic regions. We evaluated the Metabochip in 5,863 African Americans; 89% of all SNPs passed rigorous quality control with a call rate of 99.9%. Two examples illustrate the value of fine mapping with the Metabochip in African-ancestry populations. At CELSR2/PSRC1/SORT1, we found the strongest associated SNP for LDL-C to be rs12740374 (p = 3.5 * 10(-11)), a SNP indistinguishable from multiple SNPs in European ancestry samples due to high correlation. Its distinct signal supports functional studies elsewhere suggesting a causal role in LDL-C. At CETP we found rs17231520, with risk allele frequency 0.07 in African Americans, to be associated with HDL-C (p = 7.2 * 10(-36)). This variant is very rare in Europeans and not tagged in common GWAS arrays, but was identified as associated with HDL-C in African Americans in a single-gene study. Our results, one narrowing the risk interval and the other revealing an associated variant not found in Europeans, demonstrate the advantages of high density genotyping of common and rare variation for fine mapping of trait loci in African American samples. PMID- 22539989 TI - Evaluation of Leishmania donovani protein disulfide isomerase as a potential immunogenic protein/vaccine candidate against visceral Leishmaniasis. AB - In Leishmania species, Protein disulfide isomerase (PDI)--a redox chaperone, is reported to be involved in its virulence and survival. This protein has also been identified, through proteomics, as a Th1 stimulatory protein in the soluble lysate of a clinical isolate of Leishmania donovani (LdPDI). In the present study, the molecular characterization of LdPDI was carried out and the immunogenicity of recombinant LdPDI (rLdPDI) was assessed by lymphocyte proliferation assay (LTT), nitric oxide (NO) production, estimation of Th1 cytokines (IFN-gamma and IL-12) as well as IL-10 in PBMCs of cured/endemic/infected Leishmania patients and cured L. donovani infected hamsters. A significantly higher proliferative response against rLdPDI as well as elevated levels of IFN-gamma and IL-12 were observed. The level of IL-10 was found to be highly down regulated in response to rLdPDI. A significant increase in the level of NO production in stimulated hamster macrophages as well as IgG2 antibody and a low level of IgG1 in cured patient's serum was observed. Higher level of IgG2 antibody indicated its Th1 stimulatory potential. The efficacy of pcDNA-LdPDI construct was further evaluated for its prophylactic potential. Vaccination with this construct conferred remarkably good prophylactic efficacy (~90%) and generated a robust cellular immune response with significant increases in the levels of iNOS transcript as well as TNF-alpha, IFN-gamma and IL-12 cytokines. This was further supported by the high level of IgG2 antibody in vaccinated animals. The in vitro as well as in vivo results thus indicate that LdPDI may be exploited as a potential vaccine candidate against visceral Leishmaniasis (VL). PMID- 22539990 TI - Decreased levels of active SMAD2 correlate with poor prognosis in gastric cancer. AB - BACKGROUND: TGF-beta plays a dual role in the progression of human cancer. During the early stages of carcinogenesis, TGF-beta functions as a tumor suppressor. During the late stages of tumor development, however, TGF-beta can promote tumor growth and metastasis. A shift in Smad2/3 phosphorylation from the carboxy terminus to linker sites is a key event determining biological function of TGF beta in colorectal and hepatocellular carcinoma. In the present study, we investigated the potential role of differential Smad2/3 phosphorylation in gastric adenocarcinoma. METHODOLOGY: Immunohistochemical staining with anti-P Smad2/3C and P-Smad2/3L antibodies was performed on 130 paraffin-embedded gastric adenocarcinoma specimens. The relationship between P-Smad2/3C and P-Smad2/3L immunohistochemical score and clinicopathologic characteristics of patients was analyzed. Real time PCR was used to measure mRNA expression of Smad2 and Smad3 in cancer and surrounding non-tumor tissue. PRINCIPAL FINDINGS: No significant P Smad2L and/or P-Smad3L positive staining was detected in the majority of specimens (positive staining in 18/130 samples). Positive P-Smad2/3L staining was not associated with a decrease in carboxyterminal phosphorylation staining. Loss of P-Smad2C remarkably correlated with depth of tumor infiltration and poor differentiation of cancer cells in patients with gastric cancer. No correlation was detectable between P-Smad3C and clinicopathologic characteristics of gastric adenocarcinoma. However, co-staining analysis revealed that P-Smad3C co-localised with alpha-SMA and collagen I in gastric cancer cells, indicating a potential link between P-Smad3C and epithelial-to-mesenchymal transition of cancer. Real time PCR demonstrated reduced mRNA expression of Smad2 in gastric cancer when compared with surrounding non-tumor tissue in 15/16 patients. CONCLUSIONS: Loss of P-Smad2C tightly correlated with cancer invasion and poor differentiation in gastric cancer. Contrary to colorectal and hepatocellular carcinoma, canonical carboxy-terminal phosphorylation, but not linker phosphorylation, of Smad2 is critical for gastric cancer. PMID- 22539991 TI - An interspecific Nicotiana hybrid as a useful and cost-effective platform for production of animal vaccines. AB - The use of transgenic plants to produce novel products has great biotechnological potential as the relatively inexpensive inputs of light, water, and nutrients are utilised in return for potentially valuable bioactive metabolites, diagnostic proteins and vaccines. Extensive research is ongoing in this area internationally with the aim of producing plant-made vaccines of importance for both animals and humans. Vaccine purification is generally regarded as being integral to the preparation of safe and effective vaccines for use in humans. However, the use of crude plant extracts for animal immunisation may enable plant-made vaccines to become a cost-effective and efficacious approach to safely immunise large numbers of farm animals against diseases such as avian influenza. Since the technology associated with genetic transformation and large-scale propagation is very well established in Nicotiana, the genus has attributes well-suited for the production of plant-made vaccines. However the presence of potentially toxic alkaloids in Nicotiana extracts impedes their use as crude vaccine preparations. In the current study we describe a Nicotiana tabacum and N. glauca hybrid that expresses the HA glycoprotein of influenza A in its leaves but does not synthesize alkaloids. We demonstrate that injection with crude leaf extracts from these interspecific hybrid plants is a safe and effective approach for immunising mice. Moreover, this antigen-producing alkaloid-free, transgenic interspecific hybrid is vigorous, with a high capacity for vegetative shoot regeneration after harvesting. These plants are easily propagated by vegetative cuttings and have the added benefit of not producing viable pollen, thus reducing potential problems associated with bio-containment. Hence, these Nicotiana hybrids provide an advantageous production platform for partially purified, plant-made vaccines which may be particularly well suited for use in veterinary immunization programs. PMID- 22539992 TI - Are metastases from metastases clinical relevant? Computer modelling of cancer spread in a case of hepatocellular carcinoma. AB - BACKGROUND: Metastasis formation remains an enigmatic process and one of the main questions recently asked is whether metastases are able to generate further metastases. Different models have been proposed to answer this question; however, their clinical significance remains unclear. Therefore a computer model was developed that permits comparison of the different models quantitatively with clinical data and that additionally predicts the outcome of treatment interventions. METHODS: The computer model is based on discrete events simulation approach. On the basis of a case from an untreated patient with hepatocellular carcinoma and its multiple metastases in the liver, it was evaluated whether metastases are able to metastasise and in particular if late disseminated tumour cells are still capable to form metastases. Additionally, the resection of the primary tumour was simulated. The simulation results were compared with clinical data. RESULTS: The simulation results reveal that the number of metastases varies significantly between scenarios where metastases metastasise and scenarios where they do not. In contrast, the total tumour mass is nearly unaffected by the two different modes of metastasis formation. Furthermore, the results provide evidence that metastasis formation is an early event and that late disseminated tumour cells are still capable of forming metastases. Simulations also allow estimating how the resection of the primary tumour delays the patient's death. CONCLUSION: The simulation results indicate that for this particular case of a hepatocellular carcinoma late metastases, i.e., metastases from metastases, are irrelevant in terms of total tumour mass. Hence metastases seeded from metastases are clinically irrelevant in our model system. Only the first metastases seeded from the primary tumour contribute significantly to the tumour burden and thus cause the patient's death. PMID- 22539993 TI - Mechanical strain regulates osteoblast proliferation through integrin-mediated ERK activation. AB - Mechanical strain plays a critical role in the proliferation, differentiation and maturation of bone cells. As mechanical receptor cells, osteoblasts perceive and respond to stress force, such as those associated with compression, strain and shear stress. However, the underlying molecular mechanisms of this process remain unclear. Using a four-point bending device, mouse MC3T3-E1 cells was exposed to mechanical tensile strain. Cell proliferation was determined to be most efficient when stimulated once a day by mechanical strain at a frequency of 0.5 Hz and intensities of 2500 uepsilon with once a day, and a periodicity of 1 h/day for 3 days. The applied mechanical strain resulted in the altered expression of 1992 genes, 41 of which are involved in the mitogen-activated protein kinase (MAPK) signaling pathway. Activation of ERK by mechanical strain promoted cell proliferation and inactivation of ERK by PD98059 suppressed proliferation, confirming that ERK plays an important role in the response to mechanical strain. Furthermore, the membrane-associated receptors integrin beta1 and integrin beta5 were determined to regulate ERK activity and the proliferation of mechanical strain-treated MC3T3-E1 cells in opposite ways. The knockdown of integrin beta1 led to the inhibition of ERK activity and cell proliferation, whereas the knockdown of integrin beta5 led to the enhancement of both processes. This study proposes a novel mechanism by which mechanical strain regulates bone growth and remodeling. PMID- 22539994 TI - Resveratrol mediated modulation of Sirt-1/Runx2 promotes osteogenic differentiation of mesenchymal stem cells: potential role of Runx2 deacetylation. AB - OBJECTIVE: Osteogenic repair in response to bone injury is characterized by activation and differentiation of mesenchymal stem cells (MSCs) to osteoblasts. This study determined whether activation of Sirt-1 (a NAD(+)-dependent histone deacetylase) by the phytoestrogen resveratrol affects osteogenic differentiation. METHODS: Monolayer and high-density cultures of MSCs and pre-osteoblastic cells were treated with an osteogenic induction medium with/without the Sirt-1 inhibitor nicotinamide or/and resveratrol in a concentration dependent manner. RESULTS: MSCs and pre-osteoblastic cells differentiated to osteoblasts when exposed to osteogenic-induction medium. The osteogenic response was blocked by nicotinamide, resulting in adipogenic differentiation and expression of the adipose transcription regulator PPAR-gamma (peroxisome proliferator-activated receptor). However, in nicotinamide-treated cultures, pre-treatment with resveratrol significantly enhanced osteogenesis by increasing expression of Runx2 (bone specific transcription factor) and decreasing expression of PPAR-gamma. Activation of Sirt-1 by resveratrol in MSCs increased its binding to PPAR-gamma and repressed PPAR-gamma activity by involving its cofactor NCoR (nuclear receptor co-repressor). The modulatory effects of resveratrol on nicotinamide induced expression of PPAR-gamma and its cofactor NCoR were found to be mediated, at least in part, by Sirt-1/Runx2 association and deacetylation of Runx2. Finally, knockdown of Sirt-1 by using antisense oligonucleotides downregulated the expression of Sirt-1 protein and abolished the inhibitory effects of resveratrol, namely nicotinamide-induced Sirt-1 suppression and Runx2 acetylation, suggesting that the acetylated content of Runx2 is related to downregulated Sirt-1 expression. CONCLUSION: These data support a critical role for Runx2 acetylation/deacetylation during osteogenic differentiation in MSCs in vitro. (242 words in abstract). PMID- 22539995 TI - PIAS1 is a GATA4 SUMO ligase that regulates GATA4-dependent intestinal promoters independent of SUMO ligase activity and GATA4 sumoylation. AB - GATA4 confers cell type-specific gene expression on genes expressed in cardiovascular, gastro-intestinal, endocrine and neuronal tissues by interacting with various ubiquitous and cell-type-restricted transcriptional regulators. By using yeast two-hybrid screening approach, we have identified PIAS1 as an intestine-expressed GATA4 interacting protein. The physical interaction between GATA4 and PIAS1 was confirmed in mammalian cells by coimmunoprecipitation and two hybrid analysis. The interacting domains were mapped to the second zinc finger and the adjacent C-terminal basic region of GATA4 and the RING finger and the adjoining C-terminal 60 amino acids of PIAS1. PIAS1 and GATA4 synergistically activated IFABP and SI promoters but not LPH promoters suggesting that PIAS1 differentially activates GATA4 targeted promoters. In primary murine enterocytes PIAS1 was recruited to the GATA4-regulated IFABP promoter. PIAS1 promoted SUMO-1 modification of GATA4 on lysine 366. However, sumoylation was not required for the nuclear localization and stability of GATA4. Further, neither GATA4 sumoylation nor the SUMO ligase activity of PIAS1 was required for coactivation of IFABP promoter by GATA4 and PIAS1. Together, our results demonstrate that PIAS1 is a SUMO ligase for GATA4 that differentially regulates GATA4 transcriptional activity independent of SUMO ligase activity and GATA4 sumoylation. PMID- 22539996 TI - Performance in physical education and health impairment 30 years later--a community based cohort study. AB - OBJECTIVE: A main purpose of physical education (PE) in school is to promote future health. However, there is very limited evidence of the effects of PE on the adult health. We hypothesized that a low performance in PE was associated with an increased risk of health impairment by middle age. METHODS: We performed a cohort study in a community-based setting in Sweden spanning over three decades. We followed up on 1712 of 2225 students (76.9%) who in 1974-1976 graduated with a grade in PE after 9 years of education (mean subject age 16 years). The grade in PE (compulsory subject) was retrieved from municipal archives. We defined three proxies for health impairment: total number of visits to primary care physicians in 2003-2007, having been hospitalized 2003-2007, and total number of days with sick leave in 2004-2007. Using binomial regression models, we adjusted the risk estimates for level of education and occupation. Subjects with an average grade in PE served as reference category. RESULTS: In both the crude and adjusted model, women with a low grade in PE had more physician visits (adjusted IRR 1.30, 95% confidence interval 1.06-1.60) and an increased number of days with sick leave (adjusted IRR 1.44, 1.05-1.95). An increased, although not significant, risk was also observed for having received in-patient care (adjusted RR 1.26; 0.88-1.80). No significant results or similar pattern were observed in men. CONCLUSION: Women with a low grade in PE in adolescence seem to have an increased risk of health impairment by middle age, raising the question of early primary prevention towards these students in particular. PMID- 22539997 TI - Impact of climate change on voltinism and prospective diapause induction of a global pest insect--Cydia pomonella (L.). AB - Global warming will lead to earlier beginnings and prolongation of growing seasons in temperate regions and will have pronounced effects on phenology and life-history adaptation in many species. These changes were not easy to simulate for actual phenologies because of the rudimentary temporal (season) and spatial (regional) resolution of climate model projections. We investigate the effect of climate change on the regional incidence of a pest insect with nearly worldwide distribution and very high potential for adaptation to season length and temperature--the Codling Moth, Cydia pomonella. Seasonal and regional climate change signals were downscaled to the hourly temporal scale of a pest phenology model and the spatial scale of pest habitats using a stochastic weather generator operating at daily scale in combination with a re-sampling approach for simulation of hourly weather data. Under future conditions of increased temperatures (2045-2074), the present risk of below 20% for a pronounced second generation (peak larval emergence) in Switzerland will increase to 70-100%. The risk of an additional third generation will increase from presently 0-2% to 100%. We identified a significant two-week shift to earlier dates in phenological stages, such as overwintering adult flight. The relative extent (magnitude) of first generation pupae and all later stages will significantly increase. The presence of first generation pupae and later stages will be prolonged. A significant decrease in the length of overlap of first and second generation larval emergence was identified. Such shifts in phenology may induce changes in life-history traits regulating the life cycle. An accordingly life-history adaptation in photoperiodic diapause induction to shorter day-length is expected and would thereby even more increase the risk of an additional generation. With respect to Codling Moth management, the shifts in phenology and voltinism projected here will require adaptations of plant protection strategies to maintain their sustainability. PMID- 22539998 TI - The relationships among trait anxiety, state anxiety and the goal performance of penalty shoot-out by university soccer players. AB - The present study examined how the level of trait anxiety, which is a personality characteristic, influences state anxiety and penalty shoot-out performance under pressure by instruction. The high and low trait anxiety groups were selected by using Spielberger's Trait Anxiety Scale, with trait anxiety scores, and control and pressure conditions manipulated by instructions. The participants were two groups of eight university male soccer players. They individually performed 20 shots from the penalty shoot-out point, aiming at the top right and top left corner areas in the soccer goal. Each condition had 10 trials in a within-subject design. The dependent measures comprised the number of successful goals and the state anxiety scores under each instructional condition. The result showed a significant main effect of instruction. State anxiety scores increased more and the number of successful goals decreased more in high trait anxiety groups than in low trait anxiety groups under pressure instructional condition. These findings suggest that players with higher trait anxiety scores tend to experience increased state anxiety under a pressure-laden condition, and higher state anxiety interferes with goal performance. PMID- 22539999 TI - Leaf trait-environment relationships in a subtropical broadleaved forest in South East China. AB - Although trait analyses have become more important in community ecology, trait environment correlations have rarely been studied along successional gradients. We asked which environmental variables had the strongest impact on intraspecific and interspecific trait variation in the community and which traits were most responsive to the environment. We established a series of plots in a secondary forest in the Chinese subtropics, stratified by successional stages that were defined by the time elapsed since the last logging activities. On a total of 27 plots all woody plants were recorded and a set of individuals of every species was analysed for leaf traits, resulting in a trait matrix of 26 leaf traits for 122 species. A Fourth Corner Analysis revealed that the mean values of many leaf traits were tightly related to the successional gradient. Most shifts in traits followed the leaf economics spectrum with decreasing specific leaf area and leaf nutrient contents with successional time. Beside succession, few additional environmental variables resulted in significant trait relationships, such as soil moisture and soil C and N content as well as topographical variables. Not all traits were related to the leaf economics spectrum, and thus, to the successional gradient, such as stomata size and density. By comparing different permutation models in the Fourth Corner Analysis, we found that the trait-environment link was based more on the association of species with the environment than of the communities with species traits. The strong species-environment association was brought about by a clear gradient in species composition along the succession series, while communities were not well differentiated in mean trait composition. In contrast, intraspecific trait variation did not show close environmental relationships. The study confirmed the role of environmental trait filtering in subtropical forests, with traits associated with the leaf economics spectrum being the most responsive ones. PMID- 22540000 TI - Morphometry based on effective and accurate correspondences of localized patterns (MEACOLP). AB - Local features in volumetric images have been used to identify correspondences of localized anatomical structures for brain morphometry. However, the correspondences are often sparse thus ineffective in reflecting the underlying structures, making it unreliable to evaluate specific morphological differences. This paper presents a morphometry method (MEACOLP) based on correspondences with improved effectiveness and accuracy. A novel two-level scale-invariant feature transform is used to enhance the detection repeatability of local features and to recall the correspondences that might be missed in previous studies. Template patterns whose correspondences could be commonly identified in each group are constructed to serve as the basis for morphometric analysis. A matching algorithm is developed to reduce the identification errors by comparing neighboring local features and rejecting unreliable matches. The two-sample t-test is finally adopted to analyze specific properties of the template patterns. Experiments are performed on the public OASIS database to clinically analyze brain images of Alzheimer's disease (AD) and normal controls (NC). MEACOLP automatically identifies known morphological differences between AD and NC brains, and characterizes the differences well as the scaling and translation of underlying structures. Most of the significant differences are identified in only a single hemisphere, indicating that AD-related structures are characterized by strong anatomical asymmetry. In addition, classification trials to differentiate AD subjects from NC confirm that the morphological differences are reliably related to the groups of interest. PMID- 22540001 TI - Role of H- and D- MATE-type transporters from multidrug resistant clinical isolates of Vibrio fluvialis in conferring fluoroquinolone resistance. AB - BACKGROUND: The study seeks to understand the role of efflux pumps in multidrug resistance displayed by the clinical isolates of Vibrio fluvialis, a pathogen known to cause cholera-like diarrhoea. METHODOLOGY: Two putative MATE family efflux pumps (H- and D-type) were PCR amplified from clinical isolates of V. fluvialis obtained from Kolkata, India, in 2006 and sequenced. Bioinformatic analysis of these proteins was done to predict protein structures. Subsequently, the genes were cloned and expressed in a drug hypersusceptible Escherichia coli strain KAM32 using the vector pBR322. The recombinant clones were tested for the functionality of the efflux pump proteins by MIC determination and drug transport assays using fluorimeter. RESULTS: The sequences of the genes were found to be around 99% identical to their counterparts in V. cholerae. Protein structure predicting servers TMHMM and I-TASSER depicted ten-twelve membrane helical structures for both type of pumps. Real time PCR showed that these genes were expressed in the native V. fluvialis isolates. In the drug transport assays, the V. fluvialis clinical isolates as well as recombinant E. coli harbouring the efflux pump genes showed the energy-dependent and sodium ion-dependent drug transport activity. KAM32 cells harbouring the recombinant plasmids showed elevated MIC to the fluoroquinolones, norfloxacin and ciprofloxacin but H-type pumps VCH and VFH from V. cholerae and V. fluvialis respectively, showed decreased MIC to aminoglycosides like gentamicin, kanamycin and streptomycin. Decrease in MIC was also observed for acriflavin, ethidium bromide, safranin and nalidixic acid. SIGNIFICANCE: Increased resistance towards fluoroquinolones exhibited due to these efflux pumps from multidrug resistant clinical isolates of V. fluvialis implies that treatment procedure may become more elaborate for this simple but highly infectious disease. To the best of our knowledge, this is the first report of cloning and characterization of efflux pumps from multidrug resistant clinical isolates of V. fluvialis. PMID- 22540002 TI - Cyr61/CCN1 is regulated by Wnt/beta-catenin signaling and plays an important role in the progression of hepatocellular carcinoma. AB - Abnormal activation of the canonical Wnt signaling pathway has been implicated in carcinogenesis. Transcription of Wnt target genes is regulated by nuclear beta catenin, whose over-expression is observed in Hepatocellular Carcinoma (HCC) tissue. Cyr61, a member of the CCN complex family of multifunctional proteins, is also found over-expressed in many types of tumor and plays dramatically different roles in tumorigenesis. In this study, we investigated the relationship between Cyr61 and beta-catenin in HCC. We found that while Cyr61 protein was not expressed at a detectable level in the liver tissue of healthy individuals, its expression level was elevated in the HCC and HCC adjacent tissues and was markedly increased in cancer-adjacent hepatic cirrhosis tissue. Over-expression of Cyr61 was positively correlated with increased levels of beta-catenin in human HCC samples. Activation of beta-catenin signaling elevated the mRNA level of Cyr61 in HepG2 cells, while inhibition of beta-catenin signaling reduced both mRNA and protein levels of Cyr61. We identified two TCF4-binding elements in the promoter region of human Cyr61 gene and demonstrated that beta-catenin/TCF4 complex specifically bound to the Cyr61 promoter in vivo and directly regulated its promoter activity. Furthermore, we found that over-expression of Cyr61 in HepG2 cells promoted the progression of HCC xenografts in SCID mice. These findings indicate that Cyr61 is a direct target of beta-catenin signaling in HCC and may play an important role in the progression of HCC. PMID- 22540003 TI - Diversity analysis of streptomycetes and associated phosphotranspherase genes in soil. AB - An attempt was made to verify the observation that Streptomyces griseus was prevalent in soil based on isolation work. A genus-specific PCR was developed for Streptomyces based on the housekeeping gene atpD and used to investigate species diversity within selected soils. The presence of S. griseus was investigated to determine coexistence of resistance-only streptomycin phosphotransferase (strA) in the same soil as streptomycin producers. Two additional PCR-based assays were developed; one specific for strA in association with production, the other for more diverse strA and other related phosphotranferases. Both the S. griseus atpD and strA genes were below the PCR detection limit in all soils examined. A number of more diverse phosphotransferase genes were amplified, a minority of which may be associated with streptomycin production. We conclude that neither streptomycin producers nor S. griseus are prevalent in the fresh or chitin and starch-amended soils examined (less than 0.1% of soil actinobacteria). One of the soil sites had received plantomycin (active ingredient: streptomycin) and diversity studies suggested that this altered the streptomycete populations present in the soil. PMID- 22540004 TI - Molecular analysis and risk factors for Escherichia coli producing extended spectrum beta-lactamase bloodstream infection in hematological malignancies. AB - INTRODUCTION: Patients with hematologic malignancies have greater risk-factors for primary bloodstream infections (BSI). METHODS: From 2004-2009, we analyzed bacteremia caused by extended-spectrum beta-lactamase Escherichia coli (ESBL-EC) (n = 100) and we compared with bacteremia caused by cephalosporin-susceptible E. coli (n = 100) in patients with hematologic malignancies. OBJECTIVE: To assess the clinical features, risk factors, and outcome of ESBL-EC BSI in patients with hematologic malignancies, and to study the molecular epidemiology of ESBL-EC isolates. RESULTS: The main diagnosis was acute leukemia in 115 patients (57.5%). Death-related E. coli infection was significantly increased with ESBL-EC (34% vs. control group, 19%; p = 0.03). Treatment for BSI was considered appropriate in 64 patients with ESBL-EC (mean survival, 245 +/- 345 days), and in 45 control patients this was 443 +/- 613 (p = 0.03). In patients not receiving appropriate antimicrobial treatment, survival was significantly decreased in cases compared with controls (26 +/- 122 vs. 276 +/- 442; p = 0.001). Fifty six of the ESBL-EC isolates were characterized by molecular analysis: 47 (84%) expressed CTX-M-15, two (3.6%) SHV, and seven (12.5%) did not correspond to either of these two ESBL enzymes. No TLA-1 enzyme was detected. CONCLUSIONS: Patients who had been previously hospitalized and who received cephalosporins during the previous month, have an increased risk of ESBL-EC bacteremia. Mortality was significantly increased in patients with ESBL-EC BSI. A polyclonal trend was detected, which reflects non-cross transmission of multiresistant E.coli isolates. PMID- 22540005 TI - Prenatal hypoxic-ischemic insult changes the distribution and number of NADPH diaphorase cells in the cerebellum. AB - Astrogliosis, oligodendroglial death and motor deficits have been observed in the offspring of female rats that had their uterine arteries clamped at the 18(th) gestational day. Since nitric oxide has important roles in several inflammatory and developmental events, here we evaluated NADPH-diaphorase (NADPH-d) distribution in the cerebellum of rats submitted to this hypoxia-ischemia (HI) model. At postnatal (P) day 9, Purkinje cells of SHAM and non-manipulated (NM) animals showed NADPH-d+ labeling both in the cell body and dendritic arborization in folia 1 to 8, while HI animals presented a weaker labeling in both cellular structures. NADPH-d+ labeling in the molecular (ML), and in both the external and internal granular layer, was unaffected by HI at this age. At P23, labeling in Purkinje cells was absent in all three groups. Ectopic NADPH-d+ cells in the ML of folia 1 to 4 and folium 10 were present exclusively in HI animals. This labeling pattern was maintained up to P90 in folium 10. In the cerebellar white matter (WM), at P9 and P23, microglial (ED1+) NADPH-d+ cells, were observed in all groups. At P23, only HI animals presented NADPH-d labeling in the cell body and processes of reactive astrocytes (GFAP+). At P9 and P23, the number of NADPH d+ cells in the WM was higher in HI animals than in SHAM and NM ones. At P45 and at P90 no NADPH-d+ cells were observed in the WM of the three groups. Our results indicate that HI insults lead to long-lasting alterations in nitric oxide synthase expression in the cerebellum. Such alterations in cerebellar differentiation might explain, at least in part, the motor deficits that are commonly observed in this model. PMID- 22540006 TI - Evolution of outcrossing in experimental populations of Caenorhabditis elegans. AB - Caenorhabditis elegans can reproduce exclusively by self-fertilization. Yet, males can be maintained in laboratory populations, a phenomenon that continues to puzzle biologists. In this study we evaluated the role of males in facilitating adaptation to novel environments. For this, we contrasted the evolution of a fitness component exclusive to outcrossing in experimental populations of different mating systems. We introgressed a modifier of outcrossing into a hybrid population derived from several wild isolates to transform the wild-type androdioecious mating system into a dioecious mating system. By genotyping 375 single-nucleotide polymorphisms we show that the two populations had similar standing genetic diversity available for adaptation, despite the occurrence of selection during their derivation. We then performed replicated experimental evolution under the two mating systems from starting conditions of either high or low levels of diversity, under defined environmental conditions of discrete non overlapping generations, constant density at high population sizes (N = 10(4)), no obvious spatial structure and abundant food resources. During 100 generations measurements of sex ratios and male competitive performance showed: 1) adaptation to the novel environment; 2) directional selection on male frequency under androdioecy; 3) optimal outcrossing rates of 0.5 under androdioecy; 4) the existence of initial inbreeding depression; and finally 5) that the strength of directional selection on male competitive performance does not depend on male frequencies. Taken together, these results suggest that androdioecious males are maintained at intermediate frequencies because outcrossing is adaptive. PMID- 22540007 TI - Diammonium glycyrrhizinate upregulates PGC-1alpha and protects against Abeta1-42 induced neurotoxicity. AB - Mitochondrial dysfunction is a hallmark of beta-amyloid (Abeta)-induced neurotoxicity in Alzheimer's disease (AD), and is considered an early event in AD pathology. Diammonium glycyrrhizinate (DG), the salt form of Glycyrrhizin, is known for its anti-inflammatory effects, resistance to biologic oxidation and membranous protection. In the present study, the neuroprotective effects of DG on Abeta(1-42)-induced toxicity and its potential mechanisms in primary cortical neurons were investigated. Exposure of neurons to 2 uM Abeta(1-42) resulted in significant viability loss and cell apoptosis. Accumulation of reactive oxygen species (ROS), decreased mitochondrial membrane potential, and activation of caspase-9 and caspase-3 were also observed after Abeta(1-42) exposure. All these effects induced by Abeta(1-42) were markedly reversed by DG treatment. In addition, DG could alleviate lipid peroxidation and partially restore the mitochondrial function in Abeta(1-42)-induced AD mice. DG also significantly increased the PGC-1alpha expression in vivo and in vitro, while knocking down PGC 1alpha partially blocked the protective effects, which indicated that PGC-1alpha contributed to the neuroprotective effects of DG. Furthermore, DG significantly decreased the escape latency and search distance and increased the target crossing times of Abeta(1-42)-induced AD mice in the Morris water maze test. Therefore, these results demonstrated that DG could attenuate Abeta(1-42)-induced neuronal injury by preventing mitochondrial dysfunction and oxidative stress and improved cognitive impairment in Abeta(1-42)-induced AD mice, indicating that DG exerted potential beneficial effects on AD. PMID- 22540008 TI - Pleiotropy of glycogen synthase kinase-3 inhibition by CHIR99021 promotes self renewal of embryonic stem cells from refractory mouse strains. AB - BACKGROUND: Inhibition of glycogen synthase kinase-3 (GSK-3) improves the efficiency of embryonic stem (ES) cell derivation from various strains of mice and rats, as well as dramatically promotes ES cell self-renewal potential. beta catenin has been reported to be involved in the maintenance of self-renewal of ES cells through TCF dependent and independent pathway. But the intrinsic difference between ES cell lines from different species and strains has not been characterized. Here, we dissect the mechanism of GSK-3 inhibition by CHIR99021 in mouse ES cells from refractory mouse strains. METHODOLOGY/PRINCIPAL FINDINGS: We found that CHIR99021, a GSK-3 specific inhibitor, promotes self-renewal of ES cells from recalcitrant C57BL/6 (B6) and BALB/c mouse strains through stabilization of beta-catenin and c-Myc protein levels. Stabilized beta-catenin promoted ES self-renewal through two mechanisms. First, beta-catenin translocated into the nucleus to maintain stem cell pluripotency in a lymphoid-enhancing factor/T-cell factor-independent manner. Second, beta-catenin binds plasma membrane-localized E-cadherin, which ensures a compact, spherical morphology, a hallmark of ES cells. Further, elevated c-Myc protein levels did not contribute significantly to CH-mediated ES cell self-renewal. Instead, the role of c-Myc is dependent on its transformation activity and can be replaced by N-Myc but not L Myc. beta-catenin and c-Myc have similar effects on ES cells derived from both B6 and BALB/c mice. CONCLUSIONS/SIGNIFICANCE: Our data demonstrated that GSK-3 inhibition by CH promotes self-renewal of mouse ES cells with non-permissive genetic backgrounds by regulation of multiple signaling pathways. These findings would be useful to improve the availability of normally non-permissive mouse strains as research tools. PMID- 22540009 TI - Farnesoid X receptor induces murine scavenger receptor Class B type I via intron binding. AB - Farnesoid X receptor (FXR) is a nuclear receptor and a key regulator of liver cholesterol and triglyceride homeostasis. Scavenger receptor class B type I (SR BI) is critical for reverse cholesterol transport (RCT) by transporting high density lipoprotein (HDL) into liver. FXR induces SR-BI, however, the underlying molecular mechanism of this induction is not known. The current study confirmed induction of SR-BI mRNA by activated FXR in mouse livers, a human hepatoma cell line, and primary human hepatocytes. Genome-wide FXR binding analysis in mouse livers identified 4 putative FXR response elements in the form of inverse repeat separated by one nucleotide (IR1) at the first intron and 1 IR1 at the downstream of the mouse Sr-bi gene. ChIP-qPCR analysis revealed FXR binding to only the intronic IR1s, but not the downstream one. Luciferase assays and site-directed mutagenesis further showed that 3 out of 4 IR1s were able to activate gene transcription. A 16-week high-fat diet (HFD) feeding in mice increased hepatic Sr bi gene expression in a FXR-dependent manner. In addition, FXR bound to the 3 bona fide IR1s in vivo, which was increased following HFD feeding. Serum total and HDL cholesterol levels were increased in FXR knockout mice fed the HFD, compared to wild-type mice. In conclusion, the Sr-bi/SR-BI gene is confirmed as a FXR target gene in both mice and humans, and at least in mice, induction of Sr-bi by FXR is via binding to intronic IR1s. This study suggests that FXR may serve as a promising molecular target for increasing reverse cholesterol transport. PMID- 22540010 TI - Differential transcription of bacteriophage phiX174 genes at 37 degrees C and 42 degrees C. AB - To investigate how high temperature affects viral transcription, the absolute amounts of mRNA for six bacteriophage phiX174 genes were compared at 37 degrees C and 42 degrees C using Q-PCR. At 37 degrees C, mRNA levels for all genes were consistent with previous studies, but at 42 degrees C mRNA levels for four genes were significantly different from levels at 37 degrees C. Transcript levels were higher for genes B and D; the promoter before gene B appears to be up-regulated at high temperature. Levels for genes F and G were reduced at high temperature, possibly due to increased efficiency of the transcription termination signal immediately upstream of gene F. These functional changes in phiX174 gene regulation at high temperature have not been described previously. Studies of phage evolution at high temperatures indicate that this difference in transcript levels is subject to adaptation. PMID- 22540011 TI - Dynamic interaction of cBid with detergents, liposomes and mitochondria. AB - The BH3-only protein Bid plays a key role in the induction of mitochondrial apoptosis, but its mechanism of action is still not completely understood. Here we studied the two main activation events of Bid: Caspase-8 cleavage and interaction with the membrane bilayer. We found a striking reversible behaviour of the dissociation-association events between the Bid fragments p15 and p7. Caspase-8 cleavage does not induce per se separation of the two Bid fragments, which remain in a stable complex resembling the full length Bid. Detergents trigger a complete dissociation, which can be fully reversed by detergent removal in a range of protein concentrations from 100 uM down to 500 nM. Incubation of cBid with cardiolipin-containing liposomes leads to partial dissociation of the complex. Only p15 (tBid) fragments are found at the membrane, while p7 shows no tendency to interact with the bilayer, but complete removal of p7 strongly increases the propensity of tBid to become membrane-associated. Despite the striking structural similarities of inactive Bid and Bax, Bid does not form oligomers and reacts differently in the presence of detergents and membranes, highlighting clear differences in the modes of action of the two proteins. The partial dissociation of cBid triggered by the membrane is suggested to depend on the strong and specific interaction between p15 and p7. The reversible disassembly and re-assembly of the cBid molecules at the membrane was as well proven by EPR using spin labeled cBid in the presence of isolated mitochondria. The observed dynamic dissociation of the two Bid fragments could allow the assistance to the pore-forming Bax to occur repeatedly and may explain the proposed "hit-and-run" mode of action of Bid at the bilayer. PMID- 22540012 TI - Interactions of the human MCM-BP protein with MCM complex components and Dbf4. AB - MCM-BP was discovered as a protein that co-purified from human cells with MCM proteins 3 through 7; results which were recapitulated in frogs, yeast and plants. Evidence in all of these organisms supports an important role for MCM-BP in DNA replication, including contributions to MCM complex unloading. However the mechanisms by which MCM-BP functions and associates with MCM complexes are not well understood. Here we show that human MCM-BP is capable of interacting with individual MCM proteins 2 through 7 when co-expressed in insect cells and can greatly increase the recovery of some recombinant MCM proteins. Glycerol gradient sedimentation analysis indicated that MCM-BP interacts most strongly with MCM4 and MCM7. Similar gradient analyses of human cell lysates showed that only a small amount of MCM-BP overlapped with the migration of MCM complexes and that MCM complexes were disrupted by exogenous MCM-BP. In addition, large complexes containing MCM-BP and MCM proteins were detected at mid to late S phase, suggesting that the formation of specific MCM-BP complexes is cell cycle regulated. We also identified an interaction between MCM-BP and the Dbf4 regulatory component of the DDK kinase in both yeast 2-hybrid and insect cell co expression assays, and this interaction was verified by co-immunoprecipitation of endogenous proteins from human cells. In vitro kinase assays showed that MCM-BP was not a substrate for DDK but could inhibit DDK phosphorylation of MCM4,6,7 within MCM4,6,7 or MCM2-7 complexes, with little effect on DDK phosphorylation of MCM2. Since DDK is known to activate DNA replication through phosphorylation of these MCM proteins, our results suggest that MCM-BP may affect DNA replication in part by regulating MCM phosphorylation by DDK. PMID- 22540013 TI - The association between OGG1 Ser326Cys polymorphism and lung cancer susceptibility: a meta-analysis of 27 studies. AB - BACKGROUND: Numerous studies have investigated association of OGG1 Ser326Cys polymorphism with lung cancer susceptibility; however, the findings are inconsistent. Therefore, we performed a meta-analysis based on 27 publications encompass 9663 cases and 11348 controls to comprehensively evaluate such associations. METHODS: We searched publications from MEDLINE and EMBASE which were assessing the associations between OGG1 Ser326Cys polymorphism and lung cancer risk. We calculated pooled odds ratio (OR) and 95% confidence interval (CI) by using either fixed-effects or random-effects model. We used genotype based mRNA expression data from HapMap for SNP rs1052133 in normal cell lines among 270 subjects with four different ethnicities. RESULTS: The results showed that individuals carrying the Cys/Cys genotype did not have significantly increased risk for lung cancer (OR = 1.15, 95% CI = 0.98-1.36) when compared with the Ser/Ser genotype; similarly, no significant association was found in recessive, dominant or heterozygous co-dominant model (Ser/Cys vs. Cys/Cys). However, markedly increased risks were found in relatively large sample size (Ser/Ser vs. Cys/Cys: OR = 1.29, 95% CI = 1.13-1.48, and recessive model: OR = 1.19, 95% CI = 1.07-1.32). As to histological types, we found the Cys/Cys was associated with adenocarcinoma risk (Ser/Ser vs. Cys/Cys: OR = 1.32, 95% CI = 1.12-1.56; Ser/Cys vs. Cys/Cys: OR = 1.19, 95% CI = 1.04-1.37, and recessive model OR = 1.23, 95% CI = 1.08-1.40). No significant difference of OGG1 mRNA expression was found among genotypes between different ethnicities. CONCLUSIONS: Despite some limitations, this meta-analysis established solid statistical evidence for an association between the OGG1 Cys/Cys genotype and lung cancer risk, particularly for studies with large sample size and adenocarcinoma, but this association warrants additional validation in larger and well designed studies. PMID- 22540014 TI - The potential of TaqMan Array Cards for detection of multiple biological agents by real-time PCR. AB - The TaqMan Array Card architecture, normally used for gene expression studies, was evaluated for its potential to detect multiple bacterial agents by real-time PCR. Ten PCR assays targeting five biological agents (Bacillus anthracis, Burkholderia mallei, Burkholderia pseudomallei, Francisella tularensis, and Yersinia pestis) were incorporated onto Array Cards. A comparison of PCR performance of each PCR in Array Card and singleplex format was conducted using DNA extracted from pure bacterial cultures. When 100 fg of agent DNA was added to Array Card channels the following levels of agent detection (where at least one agent PCR replicate returned a positive result) were observed: Y. pestis 100%, B. mallei & F. tularensis 93%; B. anthracis 71%; B. pseudomallei 43%. For B. mallei & pseudomallei detection the BPM2 PCR, which detects both species, outperformed PCR assays specific to each organism indicating identification of the respective species would not be reproducible at the 100 fg level. Near 100% levels of detection were observed when 100 fg of DNA was added to each PCR in singleplex format with singleplex PCRs also returning sporadic positives at the 10 fg per PCR level. Before evaluating the use of Array Cards for the testing of environmental and clinical sample types, with potential levels of background DNA and PCR inhibitors, users would therefore have to accept a 10-fold reduction in sensitivity of PCR assays on the Array Card format, in order to benefit for the capacity to test multiple samples for multiple agents. A two PCR per agent strategy would allow the testing of 7 samples for the presence of 11 biological agents or 3 samples for 23 biological agents per card (with negative control channels). PMID- 22540015 TI - The proline rich homeodomain protein PRH/Hhex forms stable oligomers that are highly resistant to denaturation. AB - BACKGROUND: Many transcription factors control gene expression by binding to specific DNA sequences at or near the genes that they regulate. However, some transcription factors play more global roles in the control of gene expression by altering the architecture of sections of chromatin or even the whole genome. The ability to form oligomeric protein assemblies allows many of these proteins to manipulate extensive segments of DNA or chromatin via the formation of structures such as DNA loops or protein-DNA fibres. PRINCIPAL FINDINGS: Here we show that the proline rich homeodomain protein PRH/Hhex forms predominantly octameric and/or hexadecameric species in solution as well as larger assemblies. We show that these assemblies are highly stable resisting denaturation by temperature and chemical denaturants. CONCLUSION: These data indicate that PRH is functionally and structurally related to the Lrp/AsnC family of proteins, a group of proteins that are known to act globally to control gene expression in bacteria and archaea. PMID- 22540016 TI - The effect of enzymatically polymerised polyphenols on CD4 binding and cytokine production in murine splenocytes. AB - High-molecular weight polymerised polyphenols have been shown to exhibit anti influenza virus, anti-HIV, and anti-cancer activities. The purpose of this study was to evaluate the immunomodulating activities of enzymatically polymerised polyphenols, and to clarify the underlying mechanisms of their effects. The cytokine-inducing activity of the enzymatically polymerised polyphenols derived from caffeic acid (CA), ferulic acid (FA), and p-coumaric acid (CoA) was investigated using murine splenocytes. Polymerised polyphenols, but not non polymerised polyphenols, induced cytokine synthesis in murine splenocytes. Polymerised polyphenols induced several cytokines in murine splenocytes, with interferon-gamma (IFN-gamma) and granulocyte-macrophage colony-stimulating factor (GM-CSF) being the most prominent. The underlying mechanisms of the effects of the polymerised polyphenols were then studied using neutralising antibodies and fluorescent-activated cell sorting (FACS) analysis. Our results show that polymerised polyphenols increased IFN-gamma and GM-CSF production in splenocytes. In addition, the anti-CD4 neutralised monoclonal antibody (mAb) inhibited polymerised polyphenol-induced IFN-gamma and GM-CSF secretion. Moreover, polymerised polyphenols bound directly to a recombinant CD4 protein, and FACS analysis confirmed that interaction occurs between polymerised polyphenols and CD4 molecules expressed on the cell surface. In this study, we clearly demonstrated that enzymatic polymerisation confers immunoactivating potential to phenylpropanoic acids, and CD4 plays a key role in their cytokine-inducing activity. PMID- 22540017 TI - Role of neural NO synthase (nNOS) uncoupling in the dysfunctional nitrergic vasorelaxation of penile arteries from insulin-resistant obese Zucker rats. AB - OBJECTIVE: Erectile dysfunction (ED) is considered as an early sign of vascular disease due to its high prevalence in patients with cardiovascular risk factors. Endothelial and neural dysfunction involving nitric oxide (NO) are usually implicated in the pathophysiology of the diabetic ED, but the underlying mechanisms are unclear. The present study assessed the role of oxidative stress in the dysfunctional neural vasodilator responses of penile arteries in the obese Zucker rat (OZR), an experimental model of metabolic syndrome/prediabetes. METHODS AND RESULTS: Electrical field stimulation (EFS) under non-adrenergic non cholinergic (NANC) conditions evoked relaxations that were significantly reduced in penile arteries of OZR compared with those of lean Zucker rats (LZR). Blockade of NO synthase (NOS) inhibited neural relaxations in both LZR and OZR, while saturating concentrations of the NOS substrate L-arginine reversed the inhibition and restored relaxations in OZR to levels in arteries from LZR. nNOS expression was unchanged in arteries from OZR compared to LZR and nNOS selective inhibition decreased the EFS relaxations in LZR but not in OZR, while endothelium removal did not alter these responses in either strain. Superoxide anion production and nitro-tyrosine immunostaining were elevated in the erectile tissue from OZR. Treatment with the NADPH oxidase inhibitor apocynin or acute incubation with the NOS cofactor tetrahydrobiopterin (BH4) restored neural relaxations in OZR to levels in control arteries, while inhibition of the enzyme of BH4 synthesis GTP cyclohydrolase (GCH) reduced neural relaxations in arteries from LZR but not OZR. The NO donor SNAP induced decreases in intracellular calcium that were impaired in arteries from OZR compared to controls. CONCLUSIONS: The present study demonstrates nitrergic dysfunction and impaired neural NO signalling due to oxidative stress and nNOS uncoupling in penile arteries under conditions of insulin resistance. This dysfunction likely contributes to the metabolic syndrome associated ED, along with the endothelial dysfunction also involving altered NO signalling. PMID- 22540018 TI - Structure of metaphase chromosomes: a role for effects of macromolecular crowding. AB - In metaphase chromosomes, chromatin is compacted to a concentration of several hundred mg/ml by mechanisms which remain elusive. Effects mediated by the ionic environment are considered most frequently because mono- and di-valent cations cause polynucleosome chains to form compact ~30-nm diameter fibres in vitro, but this conformation is not detected in chromosomes in situ. A further unconsidered factor is predicted to influence the compaction of chromosomes, namely the forces which arise from crowding by macromolecules in the surrounding cytoplasm whose measured concentration is 100-200 mg/ml. To mimic these conditions, chromosomes were released from mitotic CHO cells in solutions containing an inert volume occupying macromolecule (8 kDa polyethylene glycol, 10.5 kDa dextran, or 70 kDa Ficoll) in 100 uM K-Hepes buffer, with contaminating cations at only low micromolar concentrations. Optical and electron microscopy showed that these chromosomes conserved their characteristic structure and compaction, and their volume varied inversely with the concentration of a crowding macromolecule. They showed a canonical nucleosomal structure and contained the characteristic proteins topoisomerase IIalpha and the condensin subunit SMC2. These observations, together with evidence that the cytoplasm is crowded in vivo, suggest that macromolecular crowding effects should be considered a significant and perhaps major factor in compacting chromosomes. This model may explain why ~30-nm fibres characteristic of cation-mediated compaction are not seen in chromosomes in situ. Considering that crowding by cytoplasmic macromolecules maintains the compaction of bacterial chromosomes and has been proposed to form the liquid crystalline chromosomes of dinoflagellates, a crowded environment may be an essential characteristic of all genomes. PMID- 22540020 TI - Electronic Properties of Vinylene-Linked Heterocyclic Conducting Polymers: Predictive Design and Rational Guidance from DFT Calculations. AB - The band structure and electronic properties in a series of vinylene-linked heterocyclic conducting polymers are investigated using density functional theory (DFT). In order to accurately calculate electronic band gaps, we utilize hybrid functionals with fully periodic boundary conditions to understand the effect of chemical functionalization on the electronic structure of these materials. The use of predictive first-principles calculations coupled with simple chemical arguments highlights the critical role that aromaticity plays in obtaining a low band gap polymer. Contrary to some approaches which erroneously attempt to lower the band gap by increasing the aromaticity of the polymer backbone, we show that being aromatic (or quinoidal) in itself does not ensure a low band gap. Rather, an iterative approach which destabilizes the ground state of the parent polymer toward the aromatic <-> quinoidal level crossing on the potential energy surface is a more effective way of lowering the band gap in these conjugated systems. Our results highlight the use of predictive calculations guided by rational chemical intuition for designing low band gap polymers in photovoltaic materials. PMID- 22540019 TI - The expression of irx7 in the inner nuclear layer of zebrafish retina is essential for a proper retinal development and lamination. AB - Irx7, a member in the zebrafish iroquois transcription factor (TF) family, has been shown to control brain patterning. During retinal development, irx7's expression was found to appear exclusively in the inner nuclear layer (INL) as soon as the prospective INL cells withdraw from the cell cycle and during retinal lamination. In Irx7-deficient retinas, the formation of a proper retinal lamination was disrupted and the differentiation of INL cell types, including amacrine, horizontal, bipolar and Muller cells, was compromised. Despite irx7's exclusive expression in the INL, photoreceptors differentiation was also compromised in Irx7-deficient retinas. Compared with other retinal cell types, ganglion cells differentiated relatively well in these retinas, except for their dendritic projections into the inner plexiform layer (IPL). In fact, the neuronal projections of amacrine and bipolar cells into the IPL were also diminished. These indicate that the retinal lamination issue in the Irx7-deficient retinas is likely caused by the attenuation of the neurite outgrowth. Since the expression of known TFs that can specify specific retinal cell type was also altered in Irx7 deficient retinas, thus the irx7 gene network is possibly a novel regulatory circuit for retinal development and lamination. PMID- 22540021 TI - Statins May Reduce Breast Cancer Risk, Particularly Hormone Receptor-Negative Disease. AB - Estrogen and progesterone receptor-negative breast cancer disproportionately affects young women and African Americans, has a poor prognosis, and lacks an effective chemoprevention agent. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, known as "statins," are appealing candidate agents for breast cancer chemoprevention because of their demonstrated safety after decades of widespread use. In preclinical studies, statins inhibit multiple cancer associated pathways in both hormone receptor (HR)-negative and HR-positive cell lines. Epidemiologic studies of statins and breast cancer show inconsistent results, with some suggesting a reduction in HR-negative breast cancer incidence in lipophilic statin users. However, large meta-analyses show no association between statin use and overall risk of breast cancer, although most did not evaluate tumor HR status. Multiple phase 1 and 2 prevention studies of statins for breast cancer risk reduction are ongoing. If results are promising, they may justify a randomized trial of statins for breast cancer chemoprevention, with a focus on HR-negative disease. PMID- 22540022 TI - Modulation of chromatin access during adipocyte differentiation. AB - Cellular development requires reprogramming of the genome to modulate the gene program of the undifferentiated cell and allow expression of the gene program unique to differentiated cells. A number of key transcription factors involved in this reprogramming of preadipocytes to adipocytes have been identified; however, it is not until recently that we have begun to understand how these factors act at a genome-wide scale. In a recent publication we have mapped the genome-wide changes in chromatin structure during differentiation of 3T3-L1 preadipocytes and shown that a major reorganization of the chromatin landscape occurs within few hours following the addition of the adipogenic cocktail. In addition, we have mapped the genome-wide profiles of several of the early adipogenic transcription factors and shown that they act in a highly cooperative manner to drive this dramatic remodeling process. PMID- 22540023 TI - Integrated regulation of PIKK-mediated stress responses by AAA+ proteins RUVBL1 and RUVBL2. AB - Proteins of the phosphatidylinositol 3-kinase-related protein kinase (PIKK) family are activated by various cellular stresses, including DNA damage, premature termination codon and nutritional status, and induce appropriate cellular responses. The importance of PIKK functions in the maintenance of genome integrity, accurate gene expression and the proper control of cell growth/proliferation is established. Recently, ATPase associated diverse cellular activities (AAA+) proteins RUVBL1 and RUVBL2 (RUVBL1/2) have been shown to be common regulators of PIKKs. The RUVBL1/2 complex regulates PIKK-mediated stress responses through physical interactions with PIKKs and by controlling PIKK mRNA levels. In this review, the functions of PIKKs in stress responses are outlined and the physiological significance of the integrated regulation of PIKKs by the RUVBL1/2 complex is presented. We also discuss a putative "PIKK regulatory chaperone complex" including other PIKK regulators, Hsp90 and the Tel2 complex. PMID- 22540026 TI - Fine-scale temporal dynamics of a fragmented lotic microbial ecosystem. AB - Microbial ecosystems are often assumed to be relatively stable over short periods of time, but this assumption is seldom tested. An urban stream influenced by both flow and varying levels of anthropogenic influences is expected to have high temporal variability in microbial composition, and short-term ecological instability. Thus, we analyzed the bacterioplankton composition of a weir fragmented urban stream using Automated rRNA Intergenic Spacer Analysis (ARISA). A total of 46 sequential samples were collected in July 2009 for 7 days, every 7 hours, from both the up-stream side of the weir (stream water) and the downstream side of the weir (estuarine) water. Bray-Curtis similarity based analysis showed a clear division between upstream and downstream communities. A sudden pH drop induced change in both communities, but composition stability partially recovered within less than a day. Thus, our results show that microbial ecosystems can change rapidly, but re-establish a new equilibrium relatively quickly. PMID- 22540024 TI - Fission yeast Lem2 and Man1 perform fundamental functions of the animal cell nuclear lamina. AB - In animal cells the nuclear lamina, which consists of lamins and lamin-associated proteins, serves several functions: it provides a structural scaffold for the nuclear envelope and tethers proteins and heterochromatin to the nuclear periphery. In yeast, proteins and large heterochromatic domains including telomeres are also peripherally localized, but there is no evidence that yeast have lamins or a fibrous nuclear envelope scaffold. Nonetheless, we found that the Lem2 and Man1 proteins of the fission yeast Schizosaccharomyces pombe, evolutionarily distant relatives of the Lap2/Emerin/Man1 (LEM) sub-family of animal cell lamin-associated proteins, perform fundamental functions of the animal cell lamina. These integral inner nuclear membrane localized proteins, with nuclear localized DNA binding Helix-Extension-Helix (HEH) domains, impact nuclear envelope structure and integrity, are essential for the enrichment of telomeres at the nuclear periphery and by means of their HEH domains anchor chromatin, most likely transcriptionally repressed heterochromatin, to the nuclear periphery. These data indicate that the core functions of the nuclear lamina are conserved between fungi and animal cells and can be performed in fission yeast, without lamins or other intermediate filament proteins. PMID- 22540027 TI - Single mode lasing from hybrid hemispherical microresonators. AB - Enormous attention has been paid to optical microresonators which hold a great promise for microlasers as well as fundamental studies in cavity quantum electrodynamics. Here we demonstrate a three-dimensional (3D) hybrid microresonator combining self-assembled hemispherical structure with a planar reflector. By incorporating dye molecules into the hemisphere, optically pumped lasing phenomenon is observed at room temperature. We have studied the lasing behaviors with different cavity sizes, and particularly single longitudinal mode lasing from hemispheres with diameter ~15 MUm is achieved. Detailed characterizations indicate that the lasing modes shift under varying pump densities, which can be well-explained by frequency shift and mode hopping. This work provides a versatile approach for 3D confined microresonators and opens an opportunity to realize tunable single mode microlasers. PMID- 22540025 TI - CENP-C facilitates the recruitment of M18BP1 to centromeric chromatin. AB - Centromeres are important structural constituents of chromosomes that ensure proper chromosome segregation during mitosis by providing defined sites for kinetochore attachment. In higher eukaryotes, centromeres have no specific DNA sequence and thus, they are rather determined through epigenetic mechanisms. A fundamental process in centromere establishment is the incorporation of the histone variant CENP-A into centromeric chromatin, which provides a binding platform for the other centromeric proteins. The Mis18 complex, and, in particular, its member M18BP1 was shown to be essential for both incorporation and maintenance of CENP-A. Here we show that M18BP1 displays a cell cycle regulated association with centromeric chromatin in mouse embryonic stem cells. M18BP1 is highly enriched at centromeric regions from late anaphase through to G1 phase. An interaction screen against 16 core centromeric proteins revealed a novel interaction of M18BP1 with CENP-C. We mapped the interaction domain in M18BP1 to a central region containing a conserved SANT domain and in CENP-C to the C-terminus. Knock-down of CENP-C leads to reduced M18BP1 association and lower CENP-A levels at centromeres, suggesting that CENP-C works as an important factor for centromeric M18BP1 recruitment and thus for maintaining centromeric CENP-A. PMID- 22540028 TI - From father to son: transgenerational effect of tetracycline on sperm viability. AB - The broad-spectrum antibiotic tetracycline is used in animal production, antimicrobial therapy, and for curing arthropods infected with bacterial endosymbionts such as Wolbachia. Tetracycline inhibits mitochondrial translation, and recent evidence indicates that male reproductive traits may be particularly sensitive to this antibiotic. Here, we report the first multi-generation investigation of tetracycline's effects on ejaculate traits. In a study of the pseudoscorpion, Cordylochernes scorpioides, in which siblings were randomly assigned to control and tetracycline treatments across replicate full-sibling families, tetracycline did not affect body size in either sex, female reproduction or sperm number. However, tetracycline-treated males exhibited significantly reduced sperm viability compared to control males, and transmitted this toxic effect of tetracycline on sperm to their untreated sons but not to their F2 grandsons. These results are consistent with tetracycline-induced epigenetic changes in the male germline, and suggest the need for further investigation of transgenerational effects of tetracycline on male reproductive function. PMID- 22540029 TI - Presence of amorphous carbon nanoparticles in food caramels. AB - We report the finding of the presence of carbon nanoparticles (CNPs) in different carbohydrate based food caramels, viz. bread, jaggery, sugar caramel, corn flakes and biscuits, where the preparation involves heating of the starting material. The CNPs were amorphous in nature; the particles were spherical having sizes in the range of 4-30 nm, depending upon the source of extraction. The results also indicated that particles formed at higher temperature were smaller than those formed at lower temperature. Excitation tuneable photoluminescence was observed for all the samples with quantum yield (QY) 1.2, 0.55 and 0.63%, for CNPs from bread, jaggery and sugar caramels respectively. The present discovery suggests potential usefulness of CNPs for various biological applications, as the sources of extraction are regular food items, some of which have been consumed by humans for centuries, and thus they can be considered as safe. PMID- 22540032 TI - Setting the Standard: A Special Focus on Genomic Selection in GENETICS and G3. PMID- 22540030 TI - Oxytocin attenuates feelings of hostility depending on emotional context and individuals' characteristics. AB - In humans, oxytocin (OT) enhances prosocial behaviour. However, it is still unclear how the prosocial effects of OT are modulated by emotional features and/or individuals' characteristics. In a placebo-controlled design, we tested 20 healthy male volunteers to investigate these behavioural and neurophysiological modulations using magnetoencephalography. As an index of the individuals' characteristics, we used the empathy quotient (EQ), the autism spectrum quotient (AQ), and the systemising quotient (SQ). Only during the perception of another person's angry face was a higher SQ a significant predictor of OT-induced prosocial change, both in the behavioural and neurophysiological indicators. In addition, a lower EQ was only a significant predictor of OT-induced prosocial changes in the neurophysiological indicators during the perception of angry faces. Both on the behavioural and the neurophysiological level, the effects of OT were specific for anger and correlated with a higher SQ. PMID- 22540033 TI - Simulated data for genomic selection and genome-wide association studies using a combination of coalescent and gene drop methods. AB - An approach is described for simulating data sequence, genotype, and phenotype data to study genomic selection and genome-wide association studies (GWAS). The simulation method, implemented in a software package called AlphaDrop, can be used to simulate genomic data and phenotypes with flexibility in terms of the historical population structure, recent pedigree structure, distribution of quantitative trait loci effects, and with sequence and single nucleotide polymorphism-phased alleles and genotypes. Ten replicates of a representative scenario used to study genomic selection in livestock were generated and have been made publically available. The simulated data sets were structured to encompass a spectrum of additive quantitative trait loci effect distributions, relationship structures, and single nucleotide polymorphism chip densities. PMID- 22540034 TI - A common dataset for genomic analysis of livestock populations. AB - Although common datasets are an important resource for the scientific community and can be used to address important questions, genomic datasets of a meaningful size have not generally been available in livestock species. We describe a pig dataset that PIC (a Genus company) has made available for comparing genomic prediction methods. We also describe genomic evaluation of the data using methods that PIC considers best practice for predicting and validating genomic breeding values, and we discuss the impact of data structure on accuracy. The dataset contains 3534 individuals with high-density genotypes, phenotypes, and estimated breeding values for five traits. Genomic breeding values were calculated using BayesB, with phenotypes and de-regressed breeding values, and using a single-step genomic BLUP approach that combines information from genotyped and un-genotyped animals. The genomic breeding value accuracy increased with increased trait heritability and with increased relationship between training and validation. In nearly all cases, BayesB using de-regressed breeding values outperformed the other approaches, but the single-step evaluation performed only slightly worse. This dataset was useful for comparing methods for genomic prediction using real data. Our results indicate that validation approaches accounting for relatedness between populations can correct for potential overestimation of genomic breeding value accuracies, with implications for genotyping strategies to carry out genomic selection programs. PMID- 22540035 TI - A Systematic Genetic Screen to Dissect the MicroRNA Pathway in Drosophila. AB - A central goal of microRNA biology is to elucidate the genetic program of miRNA function and regulation. However, relatively few of the effectors that execute miRNA repression have been identified. Because such genes may function in many developmental processes, mutations in them are expected to be pleiotropic and thus are discarded in most standard genetic screens. Here, we describe a systematic screen designed to identify all Drosophila genes in ~40% of the genome that function in the miRNA pathway. To identify potentially pleiotropic genes, the screen analyzed clones of homozygous mutant cells in heterozygous animals. We identified 45 mutations representing 24 genes, and we molecularly characterized 9 genes. These include 4 previously known genes that encode core components of the miRNA pathway, including Drosha, Pasha, Dicer-1, and Ago1. The rest are new genes that function through chromatin remodeling, signaling, and mRNA decapping. The results suggest genetic screens that use clonal analysis can elucidate the miRNA program and that ~100 genes are required to execute the miRNA program. PMID- 22540036 TI - FASTER MT: Isolation of Pure Populations of a and alpha Ascospores from Saccharomycescerevisiae. AB - The budding yeast Saccharomyces cerevisiae has many traits that make it useful for studies of quantitative inheritance. Genome-wide association studies and bulk segregant analyses often serve as first steps toward the identification of quantitative trait loci. These approaches benefit from having large numbers of ascospores pooled by mating type without contamination by vegetative cells. To this end, we inserted a gene encoding red fluorescent protein into the MATa locus. Red fluorescent protein expression caused MATa and a/alpha diploid vegetative cells and MATa ascospores to fluoresce; MATalpha cells without the gene did not fluoresce. Heterozygous diploids segregated fluorescent and nonfluorescent ascospores 2:2 in tetrads and bulk populations. The two populations of spores were separable by fluorescence-activated cell sorting with little cross contamination or contamination with diploid vegetative cells. This approach, which we call Fluorescent Ascospore Technique for Efficient Recovery of Mating Type (FASTER MT), should be applicable to laboratory, industrial, and undomesticated, strains. PMID- 22540037 TI - Predicting the fission yeast protein interaction network. AB - A systems-level understanding of biological processes and information flow requires the mapping of cellular component interactions, among which protein protein interactions are particularly important. Fission yeast (Schizosaccharomyces pombe) is a valuable model organism for which no systematic protein-interaction data are available. We exploited gene and protein properties, global genome regulation datasets, and conservation of interactions between budding and fission yeast to predict fission yeast protein interactions in silico. We have extensively tested our method in three ways: first, by predicting with 70-80% accuracy a selected high-confidence test set; second, by recapitulating interactions between members of the well-characterized SAGA co activator complex; and third, by verifying predicted interactions of the Cbf11 transcription factor using mass spectrometry of TAP-purified protein complexes. Given the importance of the pathway in cell physiology and human disease, we explore the predicted sub-networks centered on the Tor1/2 kinases. Moreover, we predict the histidine kinases Mak1/2/3 to be vital hubs in the fission yeast stress response network, and we suggest interactors of argonaute 1, the principal component of the siRNA-mediated gene silencing pathway, lost in budding yeast but preserved in S. pombe. Of the new high-quality interactions that were discovered after we started this work, 73% were found in our predictions. Even though any predicted interactome is imperfect, the protein network presented here can provide a valuable basis to explore biological processes and to guide wet-lab experiments in fission yeast and beyond. Our predicted protein interactions are freely available through PInt, an online resource on our website (www.bahlerlab.info/PInt). PMID- 22540038 TI - Conserved Motifs and Prediction of Regulatory Modules in Caenorhabditis elegans. AB - Transcriptional regulation, a primary mechanism for controlling the development of multicellular organisms, is carried out by transcription factors (TFs) that recognize and bind to their cognate binding sites. In Caenorhabditis elegans, our knowledge of which genes are regulated by which TFs, through binding to specific sites, is still very limited. To expand our knowledge about the C. elegans regulatory network, we performed a comprehensive analysis of the C. elegans, Caenorhabditis briggsae, and Caenorhabditis remanei genomes to identify regulatory elements that are conserved in all genomes. Our analysis identified 4959 elements that are significantly conserved across the genomes and that each occur multiple times within each genome, both hallmarks of functional regulatory sites. Our motifs show significant matches to known core promoter elements, TF binding sites, splice sites, and poly-A signals as well as many putative regulatory sites. Many of the motifs are significantly correlated with various types of experimental data, including gene expression patterns, tissue-specific expression patterns, and binding site location analysis as well as enrichment in specific functional classes of genes. Many can also be significantly associated with specific TFs. Combinations of motif occurrences allow us to predict the location of cis-regulatory modules and we show that many of them significantly overlap experimentally determined enhancers. We provide access to the predicted binding sites, their associated motifs, and the predicted cis-regulatory modules across the whole genome through a web-accessible database and as tracks for genome browsers. PMID- 22540039 TI - Contrasting mutation rates from specific-locus and long-term mutation accumulation procedures. AB - Until recently, the two predominant ways to estimate mutation rates were the specific-locus method and the mutation-accumulation (Bateman-Mukai) method. Both involve seeding a number of parallel lines from a small, genetically uniform population, growing as long as is feasible but not so long as to allow selection to perturb mutant frequencies, and sometimes using extreme bottlenecks to facilitate the retention of deleterious mutations. In the specific-locus method, mutations are selected according to their specific phenotypes and are confirmed by sequencing. In older versions of the mutation-accumulation method, the increase in variance of a quantitative fitness trait is measured and converted into a mutation rate. More recently, a variation on the mutation-accumulation method has become possible based on phenotype-blind genomic sequencing, which might (or might not) provide improved sampling breadth, usually at the expense of sample size. In a recent study, genomic sequencing was applied to Escherichia coli lines propagated for 40,000 generations and passaged daily via 5,000,000 cells. To mitigate the impact of selection, the only targets employed for rate calculations were putatively neutral synonymous mutations. The mutation rate estimate was about 6-fold lower than obtained previously with a robust specific locus method. Here I argue that purifying selection acting to shape the strong codon preferences of E. coli is the probable cause of the lower estimate, rather than, for instance, a lower mutation rate in nature than in the laboratory. PMID- 22540040 TI - Surveillance of 3' Noncoding Transcripts Requires FIERY1 and XRN3 in Arabidopsis. AB - Eukaryotes possess several RNA surveillance mechanisms that prevent undesirable aberrant RNAs from accumulating. Arabidopsis XRN2, XRN3, and XRN4 are three orthologs of the yeast 5'-to-3' exoribonuclease, Rat1/Xrn2, that function in multiple RNA decay pathways. XRN activity is maintained by FIERY1 (FRY1), which converts the XRN inhibitor, adenosine 3', 5'-bisphosphate (PAP), into 5'AMP. To identify the roles of XRNs and FRY1 in suppression of non-coding RNAs, strand specific genome-wide tiling arrays and deep strand-specific RNA-Seq analyses were carried out in fry1 and xrn single and double mutants. In fry1-6, about 2000 new transcripts were identified that extended the 3' end of specific mRNAs; many of these were also observed in genotypes that possess the xrn3-3 mutation, a partial loss-of-function allele. Mutations in XRN2 and XRN4 in combination with xrn3-3 revealed only a minor effect on 3' extensions, indicating that these genes may be partially redundant with XRN3. We also observed the accumulation of 3' remnants of many DCL1-processed microRNA (miRNA) precursors in fry1-6 and xrn3-3. These findings suggest that XRN3, in combination with FRY1, is required to prevent the accumulation of 3' extensions that arise from thousands of mRNA and miRNA precursor transcripts. PMID- 22540041 TI - Hypopigmentation and maternal-zygotic embryonic lethality caused by a hypomorphic mbtps1 mutation in mice. AB - The site 1 protease, encoded by Mbtps1, mediates the initial cleavage of site 2 protease substrates, including sterol regulatory element binding proteins and CREB/ATF transcription factors. We demonstrate that a hypomorphic mutation of Mbtps1 called woodrat (wrt) caused hypocholesterolemia, as well as progressive hypopigmentation of the coat, that appears to be mechanistically unrelated. Hypopigmentation was rescued by transgenic expression of wild-type Mbtps1, and reciprocal grafting studies showed that normal pigmentation depended upon both cell-intrinsic or paracrine factors, as well as factors that act systemically, both of which are lacking in wrt homozygotes. Mbtps1 exhibited a maternal-zygotic effect characterized by fully penetrant embryonic lethality of maternal-zygotic wrt mutant offspring and partial embryonic lethality (~40%) of zygotic wrt mutant offspring. Mbtps1 is one of two maternal-zygotic effect genes identified in mammals to date. It functions nonredundantly in pigmentation and embryogenesis. PMID- 22540042 TI - Ploidy and Hybridity Effects on Growth Vigor and Gene Expression in Arabidopsis thaliana Hybrids and Their Parents. AB - Both ploidy and hybridity affect cell size and growth vigor in plants and animals, but the relative effects of genome dosage and hybridization on biomass, fitness, and gene expression changes have not been systematically examined. Here we performed the first comparative analysis of seed, cell, and flower sizes, starch and chlorophyll content, biomass, and gene expression changes in diploid, triploid, and tetraploid hybrids and their respective parents in three Arabidopsis thaliana ecotypes: Columbia, C24, and Landsberg erecta (Ler). Ploidy affects many morphological and fitness traits, including stomatal size, flower size, and seed weight, whereas hybridization between the ecotypes leads to altered expression of central circadian clock genes and increased starch and chlorophyll content, biomass, and seed weight. However, varying ploidy levels has subtle effects on biomass, circadian clock gene expression, and chlorophyll and starch content. Interestingly, biomass, starch content, and seed weight are significantly different between the reciprocal hybrids at all ploidy levels tested, with the lowest and highest levels found in the reciprocal triploid hybrids, suggesting parent-of-origin effects on biomass, starch content, and seed weight. These findings provide new insights into molecular events of polyploidy and heterosis, as well as complex agronomic traits that are important to biomass and seed production in hybrid and polyploid crops. PMID- 22540043 TI - Regulation of muscle microcirculation in health and diabetes. AB - Insulin increases microvascular perfusion and substrate exchange surface area in muscle, which is pivotal for hormone action and substrate exchange, by activating insulin signaling cascade in the endothelial cells to produce nitric oxide. This action of insulin is closely coupled with its metabolic action and type 2 diabetes is associated with both metabolic and microvascular insulin resistance. Muscle microvascular perfusion/volume can be assessed by 1-methylxanthine metabolism, contrast-enhanced ultrasound and positron emission tomography. In addition to insulin, several factors have been shown to recruit muscle microvasculature, including exercise or muscle contraction, mixed meals, glucagon like peptide 1 and angiotensin II type 1 receptor (AT(1)R) blocker. On the other hand, factors that cause metabolic insulin resistance, such as inflammatory cytokines, free fatty acids, and selective activation of the AT(1)R, are capable of causing microvascular insulin resistance. Therapies targeting microvascular insulin resistance may help prevent or control diabetes and decrease the associated cardiovascular morbidity and mortality. PMID- 22540044 TI - Challenges in diagnosing type 1 diabetes in different populations. AB - Diabetes affects today an estimated 366 million people world-wide, including 20 million to 40 million of patients with type 1 diabetes (T1D). While T1D accounts for 5% to 20% of those with diabetes, it is associated with higher morbidity, mortality and health care cost than the more prevalent type 2 diabetes. Patients with T1D require exogenous insulin for survival and should be identified as soon as possible after diagnosis to avoid high morbidity due to a delay in insulin treatment. It is also important to present to the patient correct prognosis that differs by the type of diabetes. From the research point of view, correct classification should help to identify the etiologies and to develop specific prevention for T1D. This review summarizes evidence that may be helpful in diagnosing T1D in various ethnic groups. Challenges in interpretation of results commonly used to determine the type of diabetes are highlighted. PMID- 22540045 TI - The roles of glycated albumin as intermediate glycation index and pathogenic protein. AB - The conventional glycemic indices used in management of diabetic patients includes A1c, fructosamine, 1,5-anhydroglucitol, and glycated albumin (GA). Among these indices, A1c is currently used as the gold standard. However, A1c cannot reflect the glycemic change over a relatively short period of time, and its accuracy is known to decrease when abnormalities in hemoglobin metabolism, such as anemia, coexist. When considering these weaknesses, there have been needs for finding a novel glycemic index for diagnosing and managing diabetes, as well as for predicting diabetic complications properly. Recently, several studies have suggested the potential of GA as an intermediate-term glycation index in covering the short-term effect of treatment. Furthermore, its role as a pathogenic protein affecting the worsening of diabetes and occurrence of diabetic complications is receiving attention as well. Therefore, in this article, we wanted to review the recent status of GA as a glycemic index and as a pathogenic protein. PMID- 22540047 TI - Latent Autoimmune Diabetes in Adults: Autoimmune Diabetes in Adults with Slowly Progressive beta-cell Failure. PMID- 22540048 TI - Perception of clinicians and diabetic patients on the importance of postprandial glucose control and diabetes education status: a cross sectional survey. AB - BACKGROUND: Recent studies have shown the importance of postprandial glucose (PPG) in the development of diabetes complications. This study was conducted in order to survey the perceptions of clinicians and diabetic patients with respect to PPG management and the current status of diabetes education. METHODS: This was a cross-sectional study involving face-to-face interviews and an open questionnaire survey conducted in Korea. A total of 300 patients and 130 clinicians completed questionnaires, which included current education status, self monitoring of blood glucose (SMBG), criteria of diagnosis and management, and perceptions relating to PPG management. RESULTS: While there was a significantly higher perceived need for diabetes education, the sufficiency of the current education was considered to be severely lacking. Fasting plasma glucose (FPG), PPG, and glycosylated hemoglobin (HbA1c) were all important considerations for clinicians when making a diagnosis of diabetes, although PPG was considered less important than FPG or HbA1c in the treatment of diabetes. Most clinicians and patients were aware of the importance of PPG, but actual education on the importance of PPG was not actively being delivered. CONCLUSION: Our study showed that the current status of diabetes education is insufficient to meet the needs of the Korean population. A considerable gap was found to exist between awareness and what was actually taught in the current education program in regard to the importance of PPG. These results suggest that clinicians need to be more active in patient education, especially in regard to the importance of PPG. PMID- 22540046 TI - Alcoholism and diabetes mellitus. AB - Chronic use of alcohol is considered to be a potential risk factor for the incidence of type 2 diabetes mellitus (T2DM), which causes insulin resistance and pancreatic beta-cell dysfunction that is a prerequisite for the development of diabetes. However, alcohol consumption in diabetes has been controversial and more detailed information on the diabetogenic impact of alcohol seems warranted. Diabetes, especially T2DM, causes dysregulation of various metabolic processes, which includes a defect in the insulin-mediated glucose function of adipocytes, and an impaired insulin action in the liver. In addition, neurobiological profiles of alcoholism are linked to the effects of a disruption of glucose homeostasis and of insulin resistance, which are affected by altered appetite that regulates the peptides and neurotrophic factors. Since conditions, which precede the onset of diabetes that are associated with alcoholism is one of the crucial public problems, researches in efforts to prevent and treat diabetes with alcohol dependence, receives special clinical interest. Therefore, the purpose of this mini-review is to provide the recent progress and current theories in the interplay between alcoholism and diabetes. Further, the purpose of this study also includes summarizing the pathophysiological mechanisms in the neurobiology of alcoholism. PMID- 22540049 TI - Effect of eplerenone, a selective aldosterone blocker, on the development of diabetic nephropathy in type 2 diabetic rats. AB - BACKGROUND: Aldosterone antagonists are reported to have beneficial effects on diabetic nephropathy by effective blocking of the renin-angiotensin-aldosterone system. We investigated the renoprotective effect of the selective aldosterone receptor blocker eplerenone, the angiotensin converting enzyme inhibitor lisinopril, and combined eplerenone and lisinopril treatment in type 2 diabetic rats. METHODS: ANIMALS WERE DIVIDED INTO SIX GROUPS AS FOLLOWS: Otsuka Long-Evans Tokushima Fatty (OLETF) rat control, OLETF rats treated with a low dose of eplerenone (50 mg/kg/day), OLETF rats treated with a high dose of eplerenone (200 mg/kg/day), OLETF rats treated with lisinopril (10 mg/kg/day), OLETF rats treated with a combination of both drugs (eplerenone 200 mg/kg/day and lisinopril 10 mg/kg/day), and obese non-diabetic Long-Evans Tokushima Otsuka rats for 26 weeks. RESULTS: Urinary albumin excretion was significantly lower in the lisinopril group, but not in the eplerenone group. Urinary albumin excretion was decreased in the combination group than in the lisinopril group. Glomerulosclerosis and renal expression of type I and type IV collagen, plasminogen activator inhibitor 1, transforming growth factor-beta1, connective tissue growth factor, and fibronectin mRNA were markedly decreased in the lisinopril, eplerenone, and combination groups. CONCLUSION: Eplerenone and lisinopril combination showed additional benefits on type 2 diabetic nephropathy compared to monotherapy of each drug. PMID- 22540050 TI - Prevalence and clinical characteristics of recently diagnosed type 2 diabetes patients with positive anti-glutamic Acid decarboxylase antibody. AB - BACKGROUND: Latent autoimmune diabetes in adults (LADA) refers to a specific type of diabetes characterized by adult onset, presence of islet auto-antibodies, insulin independence at the time of diagnosis, and rapid decline in beta-cell function. The prevalence of LADA among patients with type 2 diabetes varies from 2% to 20% according to the study population. Since most studies on the prevalence of LADA performed in Korea were conducted in patients who had been tested for anti-glutamic acid decarboxylase antibody (GADAb), a selection bias could not be excluded. In this study, we examined the prevalence and clinical characteristics of LADA among adult patients recently diagnosed with type 2 diabetes. METHODS: We included 462 patients who were diagnosed with type 2 diabetes within 5 years from the time this study was performed. We measured GADAb, fasting insulin level, fasting C-peptide level, fasting plasma glucose level, HbA1c, and serum lipid profiles and collected data on clinical characteristics. RESULTS: The prevalence of LADA was 4.3% (20/462) among adult patients with newly diagnosed type 2 diabetes. Compared with the GADAb-negative patients, the GADAb-positive patients had lower fasting C-peptide levels (1.2+/-0.8 ng/mL vs. 2.0+/-1.2 ng/mL, P=0.004). Other metabolic features were not significantly different between the two groups. CONCLUSION: The prevalence of LADA is 4.3% among Korean adult patients with recently diagnosed type 2 diabetes. The Korean LADA patients exhibited decreased insulin secretory capacity as reflected by lower C-peptide levels. PMID- 22540051 TI - Fracture incidence and risk of osteoporosis in female type 2 diabetic patients in Korea. AB - BACKGROUND: There are no published data regarding fracture risk in type 2 diabetic patients in Korea. In this study, we compared the fracture incidence and risk of osteoporosis of type 2 diabetic female patients with those in a non diabetic hypertensive cohort. METHODS: The incidence of fracture in a type 2 diabetic cohort was compared with that in a non-diabetic hypertensive cohort over the course of 7 years. Female type 2 diabetic and non-diabetic hypertensive patients who visited Eulji General Hospital outpatient clinic from January 2004 to April 2004 were assigned to the diabetic cohort and the non-diabetic hypertensive cohort, respectively. Surveys on fracture event, use of anti osteoporosis medications, and bone mineral density were performed. RESULTS: The number of fractures was 88 in the female diabetic cohort (n=1,268, 60.6+/-11.5 years) and 57 in the female non-diabetic hypertensive cohort (n=1,014, 61.4+/ 11.7 years). The RR in the diabetic cohort was 1.38 (P=0.064; 95% confidence interval [CI], 0.98 to 1.94) when adjusted for age. Diabetic patients with microvascular complications (61.0%) showed a higher RR of 1.81 (P=0.014; 95% CI, 1.13 to 2.92) compared with those without these complications. The prevalence of osteoporosis was comparable between the groups, while use of anti-osteoporosis medication was more common in the diabetic cohort (12.8%) than in the hypertensive cohort (4.5%) (P<0.001). CONCLUSION: In our study, a higher fracture risk was observed in female type 2 diabetics with microvascular complications. Special concern for this risk group is warranted. PMID- 22540052 TI - Impact of HbA1c Criterion on the Detection of Subjects with Increased Risk for Diabetes among Health Check-Up Recipients in Korea. AB - BACKGROUND: We performed the study to examine the impact of hemoglobin A1c (HbA1c) criterion on the screening of increased risk for diabetes among health check-up subjects in Korea. METHODS: We retrospectively analyzed clinical and laboratory data of 37,754 Korean adults (age, 20 to 89 years; 41% women) which were measured during regular health check-ups. After excluding subjects with previously diagnosed diabetes mellitus (n=1,812) and with overt anemia (n=318), 35,624 subjects (21,201 men and 14,423 women) were included in the analysis. RESULTS: Among the 35,624 subjects, 11,316 (31.8%) subjects were categorized as increased risk for diabetes (IRD) by fasting plasma glucose (FPG) criteria, 6,531 (18.1%) subjects by HbA1c criteria, and 13,556 (38.1%) subjects by combined criteria. Therefore, although HbA1c criteria alone identifies 42% [(11,316 6,531)/11,316] fewer subjects with IRD than does FPG criteria, about 20% [(13,556 11,316)/11,316] more subjects could be detected by including new HbA1c criteria in addition to FPG criteria. Among the 13,556 subjects with IRD, 7,025 (51.8%) met FPG criteria only, 2,240 (16.5%) met HbA1c criteria only, and 4,291 (31.7%) met both criteria. Among subjects with impaired fasting glucose, 65% were normal, 32% were IRD, and 3% were diabetes by HbA1c criterion. In receiver operating characteristic curve analysis, cutoff point of HbA1c with optimal sensitivity and specificity for identifying IRD was 5.4%. CONCLUSION: Although HbA1c criteria alone identifies fewer subjects with IRD than does FPG criteria, about 20% more could be detected by addition of HbA1c criteria. Further studies are needed to define optimal cutoff point of HbA1c and to establish screening and management guidelines for IRD. PMID- 22540054 TI - Letter: Prevalence of Dyslipidemia among Korean Adults: Korea National Health and Nutrition Survey 1998-2005 (Diabetes Metab J 2012;36:43-55). PMID- 22540055 TI - Response: Prevalence of Dyslipidemia among Korean Adults: Korea National Health and Nutrition Survey 1998-2005 (Diabetes Metab J 2012;36:43-55). PMID- 22540053 TI - Relationship between Opium Abuse and Severity of Depression in Type 2 Diabetic Patients. AB - BACKGROUND: Opium use in diabetic populations is associated with major depressive disorder (MDD). This study was designed to investigate the relationship between opium use and severity of depression in Iranian diabetic patients. METHODS: In this case-control study, 642 type 2 diabetic patients were recruited from those presenting at two outpatient clinics at the Akhavan Hospital in Kashan, Iran; of them, 600 diabetic patients were included in the study and divided into two groups: opium-abusers (150 patients) and non-opium-abusers (450 patients). Clinical and demographic information was obtained through a detailed questionnaire. Depression symptomalogy and severity were assessed with the Beck Depression Inventory (BDI), and a corresponding diagnosis was made based on the Diagnostic and Statistical Manual of Mental Disorders-IV, Text Revision, 2000 (DSM-IV TR) criteria. RESULTS: The mean depression score was higher in the opium abuse group than in the non-abuser group (29.27+/-1.44 vs. 18.29+/-1.31, P<0.001). In general, a significant association was found between opium abuse and depression among patients (odds ratio [OR], 4.54; 95% confidence interval [CI], 2.87 to 7.44; P=0.001). No significant relationship was found between dysthymia and opium abuse (OR, 0.68; 95% CI, 0.18 to 1.192; P=0.155), while MDD was significantly higher in the opium abuser group (OR, 7.32; 95% CI, 5.20 to 12.01; P<0.001). CONCLUSION: Depression is more frequent in opium-dependent diabetic patients, and its severity is also greater. Given these findings, opium-dependent diabetic patients should be advised about the increased risks of depression and related comorbidities. PMID- 22540056 TI - Pancreatic cancer: chemotherapy and radiotherapy. AB - Pancreatic cancer in many cases appears in a non-curatively resectable stage when the diagnosis is made. Palliative treatment become an option in the patients with advanced stage. The present article reviewed chemotherapy and radiotherapy in various advanced stage of pancreatic cancer. PMID- 22540057 TI - Natural products and body weight control. AB - The purpose of the review was to summarise the effect of some commonly available natural products used for body weight management. We collected data from PubMed and scientific journals. There are numerous publications on this topic, however we have summarized the most commonly available and potent natural products from recent 53 publications. The natural products analyzed in this paper include catechins, capsaicin, conjugated linoleic acid, fucoxanthin, soy isoflavone, glabridin, astaxanthin and cyaniding-3-glucoside. These natural products are effective and safe for body weight management. Further studies need to be conducted to investigate the mechanism of action, metabolism, long term safety and side effects of these natural products, as well as interactions between these natural products with dietary components. PMID- 22540058 TI - Mindfulness-based stress reduction: a non-pharmacological approach for chronic illnesses. AB - BACKGROUND: Mindfulness Based Stress Reduction (MBSR) therapy is a meditation therapy, though originally designed for stress management, it is being used for treating a variety of illnesses such as depression, anxiety, chronic pain, cancer, diabetes mellitus, hypertension, skin and immune disorders. AIM: The aim of this systematic review is to determine the efficacy of MBSR in the treatment of chronic illnesses; it's mechanism of action and adverse effects. It describes an alternative method of treatment for physicians and patients that may help patients cope with their diseases in a more effective way. MATERIALS AND METHODS: COCHRANE, EMBASE and MEDLINE were systematically searched for data on outcome of treatment with MBSR used alone or in conjunction with other treatments. The data available on prevention of diseases through MBSR was also analyzed. RESULTS: All the 18 studies included in this systematic review showed improvement in the condition of patients after MBSR therapy. These studies were focused on patients with chronic diseases like cancer, hypertension, diabetes, HIV/AIDS, chronic pain and skin disorders, before and after MBSR therapy. CONCLUSIONS: Although the research on MBSR is sparse, the results of these researches indicate that MBSR improves the condition of patients suffering from chronic illnesses and helps them cope with a wide variety of clinical problems. PMID- 22540059 TI - A survey of blood pressure in Lebanese children and adolescence. AB - BACKGROUND: Blood pressure varies between populations due to ethnic and environmental factors. Therefore, normal blood pressure values should be determined for different populations. AIMS: The aim of this survey was to produce blood pressure nomograms for Lebanese children in order to establish distribution curves of blood pressure by age and sex. SUBJECTS AND METHODS: We conducted a survey of blood pressure in 5710 Lebanese schoolchildren aged 5 to 15 years (2918 boys and 2792 girls), and studied the distribution of systolic and diastolic blood pressure in these children and adolescents. Blood pressure was measured with a mercury sphygmomanometer using a standardized technique. RESULTS: Both systolic and diastolic blood pressure had a positive correlation with weight, height, age, and body mass index (r= 0.648, 0.643, 0.582, and 0.44, respectively) (P < .001). There was no significant difference in the systolic and diastolic blood pressure in boys compared to girls of corresponding ages. However, the average annual increase in systolic blood pressure was 2.86 mm Hg in boys and 2.63 mm Hg in girls, whereas the annual increase in diastolic blood pressure was 1.72 mm Hg in boys and 1.48 mm Hg in girls. The prevalence of high and high normal blood pressure at the upper limit of normal (between the 90(th) and 95(th) percentile, at risk of future hypertension if not managed adequately), was 10.5% in boys and 6.9% in girls, with similar distributions among the two sexes. CONCLUSIONS: We present the first age-specific reference values for blood pressure of Lebanese children aged 5 to 15 years based on a good representative sample. The use of these reference values should help pediatricians identify children with normal, high-normal and high blood pressure. PMID- 22540060 TI - A significant association between intestinal helminth infection and anaemia burden in children in rural communities of Edo state, Nigeria. AB - BACKGROUND: Anaemia is estimated to affect half the school-age children and adolescents in developing countries. AIM: This study aimed to determine the prevalence of anaemia and evaluate the relationship of intestinal helminth infection on the anaemia status of children in the rural communities of Evbuomore, Isiohor, and Ekosodin. in the Ovia North East local government area of Edo State, Nigeria. SUBJECTS AND METHODS: Faecal samples and blood samples were obtained from 316 children aged 1-15 years. Faecal samples were examined using standard parasitological techniques, and anaemia was defined as blood haemoglobin <11 g/dL. RESULTS: Of the 316 children, 38.6% were anaemic: 75.9% of children in Evbuomore, 42.3% in Isiohor and 26.8% in Ekosodin. The overall parasite prevalence in the three communities were: Ascaris lumbricoides (75.6%), hookworm (16.19%) and Trichuris trichiura (7.3%). Malnutrition was patent; 37.0% of the children were stunted, 19.3% wasted, and 44.0% underweight. There was a statistically significant association between hookworm and Ascaris lumbricoides infection and anaemia (P < .001). Serum ferritin levels were more sensitive than haemoglobin in detecting anemia and were correlated with intestinal helminth infection. CONCLUSION: Intestinal helminth infection in a concomitant state of malnutrition is observed in this population. Intervention programmes should be aimed at control of intestinal helminth infection and iron supplementation. PMID- 22540061 TI - A Survey of prevalence of serum antibodies to human immunodeficiency deficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) among blood donors. AB - BACKGROUND: It is a well known fact that HIV, HBV and HCV are global infectious pathogens contributing to mortality and morbidity in all ages thereby making them infections of grievous public health importance. As donor's potend a possible risk of transfusing these infections of global importance, it makes it imperative for the screening of blood and blood products for these pathogens. AIM: This study aims at determining the seroprevalence of HIV, HBV and HCV among intending blood donors. SUBJECTS AND METHODS: A retrospective data analysis for seroprevalence of antibodies to HIV, HBV and HCV was carried out between the 2(nd) of January and 15(th) of June 2010 among intending blood donors aged 18-45 and the association of these infections with age group and blood group were analyzed. Sterile venous anticoagulated blood was collected from each of the donors and analyzed for HIV, HBV and HCV using highly sensitive and specific kits. All the positive samples for HIV- 1/2 were sent for reconfirmation using polymerase chain reaction. RESULTS: Of the 427 samples analyzed, 203 were positive for HIV, 200 for HBV and 24 for HCV, representing a prevalence of 47.54%, 46.83% and 5.71% respectively among intending blood donors. Among them, blood group O "positive" was the most common blood group with 59.25% followed by blood group B "positive", A "positive" and O "negative" respectively (p<0.001). The analysis of relationship showed a tendency of high association of these infections in subjects with O "positive" blood group. CONCLUSION: This study emphasizes the need for proper screening of blood donors for HIV, HBV and HCV. PMID- 22540062 TI - Thyroid carcinoma presenting as a dural metastasis mimicking a meningioma: A case report. AB - CONTEXT: Follicular thyroid cancer rarely manifests itself as a distant metastatic lesion. CASE REPORT: We report a case of a 41-year old man presented with a solid mass located in the left temporo-occipital region. The 3D computed tomography showed a large solid mass with high vascularity, skull erosion and supra-infratentorial epidural mass effect. After magnetic resonance imaging (MRI) a suspect diagnosis of meningioma was made. The patient underwent surgery where a soft mass with transverse sinus invasion was encountered; the tumour was successfully resected employing microsurgical techniques. Histological examination revealed a thyroid follicular neoplasm with positive staining for follicular carcinoma in immunohistochemical analysis. Postoperatively levels of thyroid hormones were normal. Treatment was planned for the thyroid gland, patient receiving 6 courses of chemotherapy including paclitaxel. CONCLUSIONS: The present case emphasizes that although they are uncommon, dural metastasis can be mistaken for meningiomas. The definitive diagnosis of a meningioma should be established only after the histopathological analysis. Thyroid follicular carcinoma should be included in the differential diagnosis in cases of extrinsic tumoral lesions. PMID- 22540063 TI - Radiotherapy on hidradenocarcinoma. AB - CONTEXT: Clear cell Hidradenocarcinoma is a rare carcinoma arising from sweat glands. It is an aggressive tumor that most metastasizes to regional lymph nodes and distant viscera; surgery with safe margins is the mainstay of treatment. CASE REPORT: We report a case of 68-year-old woman who presented with an invasive clear cell hidradenocarcinoma situated in the left parotid area which recurred 5 months after surgery, this recurrence was managed successfully by high-dose irradiation of the tumor bed (66 Gy) and regional lymphatic chains (50 Gy), after a follow-up of more than 15 months, the patient is in good local control without significant toxicity. CONCLUSION: POST OPERATIVE RADIOTHERAPY ALLOWS BETTER LOCAL CONTROL AND SHOULD BE MANDATORY WHEN HISTOLOGICAL FEATURES PREDICTIVE OF RECURRENCE ARE PRESENT: positive margins, histology poorly differentiated, perineural invasion, vascular and lymphatic invasion, lymph node involvement, and extracapsular spread. PMID- 22540064 TI - Pancreaticojejunostomy in proximal pancreatic transection: A viable option. AB - Complete pancreatic transection following blunt abdominal trauma is not a common injury. Distal pancreatectomy with or without splenectomy is routinely performed if the transection is to the left of the superior mesenteric vessels. We performed pancreaticojejunostomy on a six-year-old female patient who presented with complete transection at the pancreatic neck following blunt abdominal trauma. The aim was to preserve the pancreatic parenchyma and the spleen and assess the feasibility of the procedure. The patient has been followed for more than one year and is doing well. We conclude that the procedure should be considered in proximal pancreatic transection, particularly in the pediatric age group. PMID- 22540065 TI - Comparative effects of Rauwolfia vomitoria and chlorpromazine on social behaviour and pain. AB - BACKGROUND: Rauwolfia vomitoria has been used in Nigeria to manage psychiatric disorders despite orthodox medicine. AIMS: This research was therefore aimed at comparing the effects of R. vomitoria, chlorpromazine and reserpine on social behaviour and pain in mice. MATERIALS AND METHODS: Ninety male CD-1 mice (32 - 38g body weight) were grouped into 3 with 5 subgroups (n=6) each. Mice were given chlorpromazine (0.0, 0.25, 1.0, 2.0, 4.0 mg/kg i.p.), 30 minutes before testing and R. vomitoria (0.0, 0.25, 1.0, 2.0, 4.0 mg/kg, i.p.) and reserpine (0.0, 0.1, 0.4, 0.8, 1.6 mg/kg, i.p) 24 hours before testing. Nesting score assessed social behaviour while the tail flick and hot plate analgesiometers assessed pain. RESULTS: Chlorpromazine dose-dependently decreased nesting score (F(4,25) = 5.5660; p< 0.01), indicating decreased social behaviour (social loss) in the mice. Although R. vomitoria did not affect nesting score, reserpine decreased the nesting score (social loss). In the pain test, chlorpromazine did not alter tail flick latency but decreased hind paw lick latency in the hot plate at 2.0 and 4.0 mg/kg (p< 0.01), indicating increased pain sensitivity at these doses which may indirectly increase social withdrawal and thus aggravating depression. R. vomitoria however, increased tail flick and hind paw lick latencies in the hot plate test (p< 0.05) indicating decreased pain sensitivity. Reserpine, like R. vomitoria, increased latency of hind paw lick in the hot plate. CONCLUSION: R. vomitoria has a high potential as an antipsychotic and may have advantage over chlorpromazine; it is not necessary to isolate active components from this herb. PMID- 22540066 TI - Non-pancreatic cancer tumors in the pancreatic region. AB - Most of tumors found in the pancreas are adenocarcinoma of the pancreas. A small number of tumors in the pancreas, such as islet cell tumors or neuroendocrine tumors, papillary cystic neoplasms, lymphoma, acinar cell tumors, metastatic tumors to the pancreas often, have a far better prognosis, and the majority of these tumors are non-malignant or benign. The author reviewed the recent literatures, and summarized where the tumor comes originally in the pancreas, what is the type of the tumor, and how to treat the tumor. PMID- 22540067 TI - Ventilatory response to high inspired carbon dioxide concentrations in anesthetized dogs. AB - BACKGROUND: The ventilation ( ) response to inspired CO(2) has been extensively studied, but rarely with concentrations >10%. AIMS: These experiments were performed to determine whether would increase correspondingly to higher concentrations and according to conventional chemoreceptor time delays. MATERIALS AND METHODS: We exposed anesthetized dogs acutely, with and without vagotomy and electrical stimulation of the right vagus, to 20-100% CO(2)-balance O(2) and to 0 and 10% O(2)-balance N(2). RESULTS: The time delays decreased and response magnitude increased with increasing concentrations (p<0.01), but at higher concentrations the time delays were shorter than expected, i.e., 0.5 s to double at 100% CO(2), with the response to 0% O(2) being ~3 s slower. Right vagotomy significantly reduced baseline breathing frequency (fR), increased tidal volume (VT) and increased the time delay by ~3 s. Bilateral vagotomy further reduced baseline fR and , and reduced the response to CO(2) and increased the time delay by ~12 s. Electro-stimulation of the peripheral right vagus while inspiring CO(2) caused a 13 s asystole and further reduced and delayed the response, especially after bilateral vagotomy, shifting the mode from VT to fR. CONCLUSIONS: Results indicate that airway or lung receptors responded to the rapid increase in lung H(+) and that vagal afferents and unimpaired circulation seem necessary for the initial rapid response to high CO(2) concentrations by receptors upstream from the aortic bodies. PMID- 22540068 TI - Heart rate and heart rate variability responses to Tai Chi and jogging in Beijing and Graz. AB - BACKGROUND: Tai Chi is a famous training method in China, and jogging is a popular kind of exercise both in Austria and China. Nevertheless, there is little information concerning online monitoring of biosignals during both training activities in parallel. Within the last years innovative scientific monitoring tools for evaluating features of neurocardial fitness have been developed. AIMS: The goal of this study was to demonstrate heart rate and heart rate variability analysis for the first time during Tai Chi and jogging. VOLUNTEERS AND METHODS: Continuous electrocardiographic monitoring over a period of 75 minutes was performed simultaneously in two healthy volunteers using the same type of equipment (medilog AR12 systems). Two healthy persons (both male, 49 years and 52 years, respectively), both hobby sportsmen, were monitored continuously during two resting periods before and after active sport and also during Tai Chi and jogging, respectively. RESULTS: Data acquisition was performed without any technical problems in both subjects. Poincare plots of sequential R-R intervals (beat to beat variability) show two ellipses of different shape and magnitude. During resting periods blood pressure effects can be clearly seen in one subject (jogging). The same effects, however reduced, are obvious in the other volunteer during Tai Chi. CONCLUSIONS: The present investigations during Tai Chi and jogging highlight the potential value of heart rate and heart rate variability monitoring even under difficult conditions. The innovative kind of analysis helps to show how well the human body reacts to sport, stress and recovery. PMID- 22540069 TI - Urinary tract infection in a rural community of Nigeria. AB - AIM: To determine the prevalence of urinary tract infection (UTI) in Okada, a rural community in Nigeria, and the effect of age and gender on its prevalence as well as the etiologic agents and the susceptibility profile of the bacterial agents. PATIENTS AND METHOD: Clean-catch midstream urine was collected from 514 patients (49 males and 465 females). The urine samples were processed and microbial isolates identified. Susceptibility testing was performed on all bacterial isolates. RESULT: The prevalence of urinary tract infection was significantly higher in females compared to males (female vs. male: 42.80% vs. 10.20%; OR = 6.583. 95% CI = 2.563,16.909; P < 0.0001). Age had no effect on the prevalence of UTI. Escherichia coli was the most prevalent isolate generally and in females, while Staphylococcus aureus was the predominant isolate causing urinary tract infection in males. The flouroquinnolones were the most active antibacterial agents. CONCLUSION: An overall prevalence of 39.69% was observed in this study. Females had a 3 to 17 fold increase risk of acquiring UTI, than their male counterpart. Escherichia coli were the predominant isolates causing UTI. PMID- 22540070 TI - Risk of transfusion-transmitted syphilis in a tertiary hospital in Nigeria. AB - BACKGROUND: Every year, millions of people are exposed to avoidable, life threatening risks through the trans-fusion of unsafe blood. AIM: To determine the sero-prevalence of Syphilis among pre-transfused blood in the University of Benin Teaching Hospital, Benin-City, Nigeria. MATERIAL AND METHODS: The detection of Treponema pallidum IgG/IgM was based on the principle of double antigen sandwich immunoassay, in which purified recombinant antigens are employed sufficiently to identify antibodies to Syphilis. The outcomes of interest included the proportion of Syphilis positive units of pre-transfused donor blood, the source of blood and the total number of units of blood processed in the hospital blood bank. RESULTS: Two hundred proportionally selected commercial and targeted donors' blood samples were screened for Treponema pallidum, and 8% (n = 16) were found to be positive (95% confidence intervals 9.21-22.79). Syphilis seropositivity was found to be significantly higher in commercial donors (p<0.05). The likely risk of iatrogenic transfusion related Treponema pallidum infection was estimated to be 384 cases/ year at the present rate of utilization of donor blood at the University of Benin Teaching Hospital. CONCLUSION: There is a risk of iatrogenic transfusion transmitted Treponema pallidum in the study hospital. There is, therefore, a need for screening blood donors for circulating antibodies to syphilis infection and other transfusion transmissible infections prior to allogeneic transfusion both in Nigeria and the world over, which may help in avoiding transfusion related Syphilis and its probable long-term effects. Blood that is positive for Syphilis should be discarded, and the affected donor treated appropriately. PMID- 22540071 TI - Bullous allergic drug eruption with presence of myeloperoxidase and reorganization of the dermal vessels observed by using CD34 and collagen IV antibodies. AB - CONTEXT: Bullous allergic reactions are inflammatory skin disorders, presenting usually as a result of some type of reaction to medication. CASE REPORT: A 67 year-old female was evaluated for the presence of diffuse patches of erythema, microvesiculation, vesicles, crusts, and oozing of sudden appearance on the extremities and on the rest of the body after taking sulfamethoxazole in combination with trimethoprim. Skin biopsies for hematoxylin and eosin examination, as well as for direct immunofluorescence and immunohistochemistry analysis were performed. H&E staining demonstrated classic features. Direct immunofluorescence revealed strong deposits of fibrinogen in the vessels of the skin. The immunohistochemistry stain showed strong positivity of myeloperoxidase within the blister cavity. The distribution of the vessels around the inflammatory process were noticed by using antibodies to CD34 as well to collagen IV. CONCLUSIONS: sulfamethoxazole is catalysed by CYP2C9 and/or myeloperoxidase. Thus, myeloperoxidase appears to be of importance in this disorder. PMID- 22540072 TI - Comparison of suture material and technique of closure of subcutaneous fat and skin in caesarean section. AB - BACKGROUND: A large number of women undergo caesarean section throughout the world. These women pass through a period of post operative pain and a morbidity period. These women translate into a substantial portion of population and hence there is a load on the financial resources of healthcare system. Use of the appropriate technique to approximate the wound after caesarean section would not only avoid financial load but also help in early recovery of the patient. AIM: The aim of this study is to compare the effects of alternative techniques for closure of subcutaneous fat and skin on maternal health and use of healthcare resources in caesarean section. MATERIALS AND METHODS: Patients undergoing Caesarean section were divided in two groups of one thousand patients each. Patients with hematological disorders or a malignancy, diabetes, septicemia or chorioamnionitis were excluded from the study. In all the patients, after stitching the uterus, the rectus sheath was stitched with thread vicryl No.1 (synthetic absorbable braided sutures with polyglycolic acid, polycaprolactone and calcium stearate coating), using a round body needle. Then the patients were divided into two groups. In group I, vicryl No.1 thread used in stitching of the rectus sheath was continued into the skin with application of subcuticular stitches, after securing the edges with a knot. In group II, after stitching the rectus sheath with vicryl No. 1, the thread was cut and interrupted sutures were applied in subcutaneous fat with thread vicryl No. 2. Skin was stitched with subcuticular stitches using proline 2, a non-absorbable propylene suture. The two groups of patients were observed for the duration of surgery, post-operative pain in stitches, patient satisfaction about removal of stitches, evidence of wound infection or seroma, and cosmetic results. RESULTS: It was noted that the duration of surgery in group I was on average 7.5 minutes less as compared to the duration in group II. Patients in group I were more satisfied with the results of the surgery and were relieved to know that their stitches did not need to be removed. CONCLUSION: Although no difference was found in the rates of wound infection and formation of scar tissue between the group I and group II, the duration of surgery was less and the patients were more satisfied in group I. PMID- 22540073 TI - Primary motives for demand of ivermectin drug in mass distribution programmes to control onchocerciasis. AB - BACKGROUND: Onchocerciasis is a disease with a spectrum of manifestations suffered by different infected people. Based on individual perceptions and manifestations presented, demand for the drug Ivermectin was due to different motives and priorities during mass distribution programmes. SUBJECTS AND METHOD: This study presents findings from a sample of 594 persons out of a total of 35,763 treated individuals who voluntarily demanded Ivermectin treatment during a community-based Ivermectin distribution exercise. The distribution, which took place in 2008, was mass distribution of the microfilaricide to control onchocerciasis in endemic communities of Ezinihitte in the Imo River Basin of Nigeria. The subjects who were selected by quota sampling procedure on the basis of community and gender, were asked to rank-order six plausible reasons for seeking treatment in terms of their order of importance in motivating them to demand Ivermectin. RESULTS: "To gain treatment and prevention of Skin Problems" and "Desire to be De-wormed" ranked first and second respectively. "To gain promotion of general wellbeing" and "To improve state of vision and prevent blindness" ranked third and fourth respectively. In the fifth and sixth rank order positions were "To prevent hanging groin" and "to prevent/relieve enlargement of the scrotum or clitoris" in that order. A test of hypothesis to determine if there was significant agreement among treated persons on the rank order of importance of their reasons for demanding Ivermectin gave a Kendall's Coefficient of Concordance of W = 0.62, p <.001. CONCLUSION: The findings are interpreted within the framework of the major postulations of the health belief model with consideration to perceptions of severity of the conditions and belief that submitting to treatment will abate the perceived risk of the conditions. The role of endemicity of specific manifestations of onchocerciasis in lay assessment of risk of this disease is also discussed. PMID- 22540074 TI - Etiologic agents of otitis media in Benin city, Nigeria. AB - BACKGROUND: Otitis Media continues to be a major presentation in the ear, nose and throat clinic. AIM: This study aimed to isolate, characterize and identify the bacteriological and mycological etiologic agents of otitis media in Benin city. PATIENTS AND METHODS: Ear discharge from 569 (299 males and 270 females) patients diagnosed clinically of otitis media between August 2009 and August 2010 were processed to recover the bacterial and fungal etiologic agents. Susceptibility test was performed on all bacterial isolate. RESULT: Pseudomonas aeruginosa (28.3%) was the predominant bacteria isolate causing otitis media followed by Staphylococcus aureus (21.0%), Klebsiella sp (8.9%), Proteus sp (8.2%), Alkaligenes spp (4.3%), Streptococcus pneumoniae (3.9%), Escherichia coli (3.0%) and Citrobacter freundi (1.7%). Fungi isolated were Aspergillus niger (9.2%), Candida albicans (5.4%), Candida tropicalis (3.0%), Aspergillus flavus (2.1%) and Candida parasilopsis (1.5%). 413 had a single organism isolated from the middle ear culture while twenty (3.51%) patients had mixed organisms isolated. Infection was highest among 0 - 5 years, and lowest among aged 18 - 23. All bacterial isolates were poorly susceptible to the antibacterial agents. CONCLUSION: The study uncovers a high frequency of bacteria associated otitis media with the finding of fungi too as a significant etiologic agent. PMID- 22540075 TI - Spontaneous massive hemoperitoneum: A potentially life threatening presentation of the wandering spleen. AB - CONTEXT: Wandering spleen is an unusual condition characterized by the absence or maldevelopment of one or all of the ligaments securing the spleen in its normal position in the left upper abdomen. Pedicular tortion with a complete vascular disruption is a rare but known potential complication of this mostly congenital disorder. Spontaneous hemoperitoneum with acute abdomen however, is a life threatening situation that has not been adequately reported in the adult literature. CASE REPORT: A forty four year old man presented to the emergency department with an acutely distended and rigid abdomen. His past medical history was only significant for mild mental retardation. The patient denies prior abdominal operation or recent trauma. On initial examination, he appeared to be anxious, pale, and tachycardic. Fullness in the midpelvic region was easily appreciated on palpation. An enlarged pelvic spleen and free intraperitoneal fluid consistent with blood were seen on a CT scan. The patient was promptly taken for an exploratory laparotomy where a large rush of blood was encountered upon entering the abdomen. A volvulus of the splenic pedicle with an infarcted spleen was found mandating a splenectomy. CONCLUSIONS: Abnormally located spleen, splenomegaly, and finding of hemoperitoneum are highly suggestive of wandering spleen with tortioned pedicle. Despite its life threatening presentation, immediate laparotomy and splenectomy invariably result in good outcome. PMID- 22540076 TI - Hapten may play an important role in food allergen-related intestinal immune inflammation. AB - There has been a significant increase in the prevalence of allergic diseases especially over the past 2 to 3 decades. However, the etiology and pathogenesis of food allergy are not fully understood. In recent years, with the huge increase in atopic disease, there has also been an increase in dietary hapten exposure. Allergic reactions to chemical haptens occur, in the overwhelming majority of cases, as an inflammatory reaction in the skin to direct contact with haptens. While reactions to haptens on other epithelial surfaces have only rarely been investigated; it is still not clear whether haptens can combine the food antigens and play a role in the induction of food allergen-related inflammation in the intestine. Further research is needed to reveal the underlying mechanism. PMID- 22540077 TI - Ki-67 biomarker in breast cancer of Indian women. AB - BACKGROUND: Biological markers that reliably predict clinical or pathological response to primary systemic therapy early during a course of chemotherapy may have considerable clinical potential. AIMS: Aims of study to evaluated changes in Ki-67 (MIB-1) labeling index and apoptotic index (AI) before, during, and after neoadjuvant anthracycline chemotherapy in breast cancer in Indian women. MATERIALS AND METHODS: Breast cancer tissues were collected from Grant Medical College and Sir J.J. Group of Hospitals, Mumbai, India. Twenty-seven patients receiving neoadjuvant FEC (5-fluorouracil, epirubicin, and cyclophosphamide) chemotherapy for operable breast cancer underwent repeat core biopsy after 21 days of treatment. RESULTS: The objective clinical response rate was 56%. Eight patients (31%) achieved a pathological response by histopathological criteria; two patients had a near-complete pathological response. Increased day-21 AI was a statistically significant predictor of pathological response (p = 0.049). A strong trend for predicting pathological response was seen with higher Ki-67 indices at day 21 and AI at surgery (p = 0.06 and 0.06, respectively). CONCLUSION: The clinical utility of early changes in biological marker expression during chemotherapy remains unclear. Until further prospectively validated evidence confirming the reliability of predictive biomarkers is available, clinical decision-making should not be based upon individual biological tumor biomarker profiles. PMID- 22540078 TI - Prevalence of beta-hemolytic groups C and F streptococci in patients with acute pharyngitis. AB - BACKGROUND: The roles of group C and F streptococci in causing endemic pharyngitis are still controversial, although group C streptococci are implicated in the outbreaks of pharyngitis and associated disorders. AIM: The aim of this study was to determine the prevalence and the role of these groups of beta hemolytic streptococci in acute pharyngitis with emphasis on the Streptococcus anginosus group. The antimicrobial susceptibility profile of these bacterial isolates and their ability to produce some virulence factors was also determined. MATERIALS AND METHODS: Throat swab specimens were collected from 177 patients suffering from acute pharyngitis who had been admitted to the Hilla Teaching Hospital, Hilla, Iraq, during October 2009 to January 2010. The necessary biochemical tests were conducted and the organisms identified using standard procedures. Susceptibility of isolates pathogens to several antibiotics was examined using standard susceptibility testing. Virulence factors of these isolates were also determined using standard methods. RESULTS: Results revealed that a total of 67 isolates belonged to beta-hemolytic streptococci, of which 11(16.4%) isolates belonged to anginosus group streptococci, which possessed Lancefield group C and F antigens. Most of these bacterial isolates have the ability to produce more than one virulence factor such as capsule, hemolysin, CFA III, and lipase enzyme. The bacterial isolates were highly resistant to ampicillin, cefotaxime, and cefepime while they exhibited moderate resistance to tetracycline, ceftriaxone, and ciprofloxacin. On the other hand, they showed a high sensitivity to vancomycin, ofloxacin, and clindamycin. CONCLUSION: This study concluded that groups C and F Streptococci were implicated as a cause of acute pharyngitis in 6.2% of the specimens among other groups of streptococci. Most of these isolates have the ability to produce more than one virulence factor. There was a high rate of resistance among isolates for beta-lactam antibiotics; however, they were highly susceptible to vancomycin, ofloxacin, and clindamycin. PMID- 22540079 TI - Submicroscopic and multiple plasmodium falciparum infections in pregnant Sudanese women. AB - BACKGROUND: Control of malaria during pregnancy remains a major public health challenge in developing countries. Microscopic parasite detection represents a pivotal step in malaria control, while modern molecular techniques are deemed to improve detection rates markedly. AIMS: This study aimed to investigate the frequency of submicroscopic and multiple Plasmodium falciparum (P. falciparum) infections during pregnancy, using the P. falciparum merozoite surface protein1 (MSP-1) gene as a polymorphic marker. MATERIALS AND METHODS: The study was a cross-sectional, analytical study that was conducted at Omdurman Maternity Hospital, Sudan, between July 2003 and December 2004. Following informed consent, 836 pregnant women between the ages of 16-47 years with different gestational ages were enrolled in the study. Thin and thick blood films were stained with Giemsa and examined by experienced microscopists. Parasite DNA was extracted using Chelex method. Nested polymerase chain reaction (PCR) assays specific for P. falciparum were carried out to detect infections below the threshold of microscopy and to genotype different strains in the samples using merozoite surface protein-1. RESULTS: More than a quarter of the study participants (219/836; 26.2%) were smear-positive for malaria infection. The results of the PCR-based assays showed that 41.8 % (257/617) of the smear-negative women were PCR positive and therefore had submicroscopic infections. The mean number of genetically different P. falciparum parasites detected was 2.7 (range 1-9). The multiplicity of infection identified by at least two alleles of MSP-1 was significantly higher among paucigravidae (45.6%) compared to multigravidae (28.9%), with mean number of alleles of 2.4 and 1.9, respectively (p=0.009). This likely indicates the gradual acquisition of immunity. CONCLUSION: Conventional microscopy underestimates the actual extent of malaria infections during pregnancy in endemic regions. Multiplicity of infection may be an important factor in the gradual acquisition of strain-specific immunity. PMID- 22540080 TI - The relationship between helicobacter pylori infection and gastro-esophageal reflux disease. AB - BACKGROUND: Gastro-esophageal reflux disease is a common condition, affecting 25% 40% of the population. Increasing attention has been paid to the relationship between Helicobacter pylori infection and reflux esophagitis. AIM: The aim of this study was to investigate the association between CagA+ H. pylori and endoscopically proven gastro-esophageal reflux disease. PATIENTS AND METHODS: The study group included 60 hospital patients with gastro-esophageal reflux disease between 2007 and 2009 as compared with 30 healthy patients from a control group that was age and sex matched. Helicobacter pylori CagA+ was identified by an immunological test (Immunochromatography test) (ACON, USA). RESULTS: Helicobacter pyloriCagA+ was present in 42/60 (70%) of the patients with gastro-esophageal reflux disease and in 11/30 (36.6%) patients in the control group (p=0.002). The Odds ratio = 0.8004 with 95% Confidence Interval = from 0.3188 to 2.0094. The relative risk=1.35 that indicates an association between Helicobacter pylori and disease. CONCLUSIONS: The presence of Helicobacter pylori is significantly increased in patients with gastro-esophageal reflux disease as compared with the control group. PMID- 22540081 TI - Length of postnatal hospital stay in healthy newborns and re-hospitalization following early discharge. AB - BACKGROUND: The length of postnatal hospital stay for healthy newborns remains controversial. Proponents of early hospital discharge claim that it is safe, decreases the risk of iatrogenic infection, promotes family bonding and attachment, and reduces hospitalization care and patient costs. Disadvantages include delayed breastfeeding, manifestation of new conditions affecting newborns after early discharge, and improper discharge planning. AIM: The main aim of the study was to compare early discharge versus late discharge with the risk of readmission. PATIENTS AND METHODS: The length of hospital stay was recorded for all healthy newborns and infants and followed by investigation of any medical problem arising after discharge. Factors associated with readmission to the hospital were analyzed by Chi square and Mantel-Haenszel Common Odds Ratio Estimate (OR) with Confidence Limits (CL). RESULTS: A total of 478 babies were enrolled, of which 307 were discharged <= 48 hours. The overall length of stay was 39 hours (1.6 days). Thirty-eight (7.9%) newborns were re-hospitalized, with the most common cause being neonatal jaundice. Factors associated with readmission for jaundice were breastfeeding (OR: 10.3 CL3.10to32.20) and length of stay <= 48 hours (OR: 13.8, CL4.04 to 47.05). CONCLUSION: Hospital discharge at any time <= 48 hours significantly increases the risk for readmission as well as the risk for readmission due to hyperbilirubinemia. Planning and implementing a structured program for follow up of infants who are discharged <= 48 hours are vital in order to decrease the risk for readmission, morbidity and neonatal mortality. PMID- 22540082 TI - The use of C-reactive protein in predicting bacterial co-Infection in children with bronchiolitis. AB - BACKGROUND: Bronchiolitis is a potentially life-threatening respiratory illness commonly affecting children who are less than two years of age. Patients with viral lower respiratory tract infection are at risk for co-bacterial infection. AIM: The aim of our study was to evaluate the use of C-reactive protein (CRP) in predicting bacterial co-infection in patients hospitalized for bronchiolitis and to correlate the results with the use of antibiotics. PATIENTS AND METHODS: This is a prospective study that included patients diagnosed with bronchiolitis admitted to Makassed General Hospital in Beirut from October 2008 to April 2009. A tracheal aspirate culture was taken from all patients with bronchiolitis on admission to the hospital. Blood was drawn to test C-reactive protein level, white cell count, transaminases level, and blood sugar level. RESULTS: Forty-nine patients were enrolled in the study and were divided into two groups. Group 1 included patients with positive tracheal aspirate culture and Group 2 included those with negative culture. All patients with a CRP level >=2 mg/dL have had bacterial co-infection. White cell count, transaminases and blood sugar levels were not predictive for bacterial co-infection. The presence of bacterial co infection increased the length of hospital stay in the first group by 2 days compared to those in the second group. CONCLUSION: Bacterial co-infection is frequent in infants with moderate to severe bronchiolitis and requires admission. Our data showed that a CRP level greater than 1.1 mg/dL raised suspicion for bacterial co-infection. Thus, a tracheal aspirate should be investigated microbiologically in all hospitalized patients in order to avoid unnecessary antimicrobial therapy and to shorten the duration of the hospital stay. PMID- 22540083 TI - Serum procalcitonin: Early detection of neonatal bacteremia and septicemia in a tertiary healthcare facility. AB - BACKGROUND: The benefits of procalcitonin measurement in neonatal bacteremia/septicemia with suspected nosocomial infection are unclear and unresearched. AIM: The aim of the study was to assess procalcitonin value as an early or first line diagnosis/prognosis for bacterial neonatal septicemic infection in selected critically ill neonates. PATIENTS AND METHODS: An observational cohort study in a 10-bed intensive care unit was performed. Sixty neonates, with either proven or clinically suspected, but not confirmed, bacterial neonatal septicemic infection were included. Procalcitonin measurements were obtained on the day when the infection was suspected. Neonates with proven septicemic infection were compared to those without. The diagnostic value of procalcitonin was determined through the area under the corresponding receiver operating characteristic curve (AUROCC). In addition, the predictive value of procalcitonin variations preceding the clinical suspicion of infection was also assessed. RESULTS: Procalcitonin was the best early predictor of proven infection in this population of neonates with a clinical suspicion of septicemia (AUROCC = 0.80; 91.6% CI, 0.68-0.91). In contrast, CRP elevation, leukocyte count and fever had a poor predictive value in our population. CONCLUSION: PCT monitoring could be helpful in the early diagnosis of neonatal septicemic infection in the intensive care unit. Both absolute values and variations should be considered and evaluated in further studies. PMID- 22540084 TI - Overexpression of linker for activated T cells, cyclooxygenase-2, CD1a, CD68 and myeloid/histiocyte antigen in an inflamed seborrheic keratosis. AB - CONTEXT: Inflamed seborrheic keratoses are generally associated with the accumulation of variable numbers of lymphocytes and histiocytes in the superficial dermis. The precise immunologic mechanism of this histologic phenomenon is not known CASE REPORT: A 62-year-old male presented with a patch on the right neck with additional features of inflammation. Skin biopsies for hematoxylin and eosin examination, as well as for immunohistochemistry analysis were performed. RESULTS: H&E staining demonstrated classic features of an inflamed seborrheic keratosis. Overexpression of LAT, COX-2, CD1a, and CD68 was noticed in the inflammatory infiltrate. A strong presence of CD1a was also seen in the epidermis suprajacent to the inflammation. Myeloid/histiocyte antigen was strongly expressed by the keratinocytes CONCLUSION: A complex immune response seems to be involved in the pathophysiology of an inflamed seborrheic keratosis. PMID- 22540085 TI - Pancreatic endocrine tumors. AB - Pancreatic endocrine tumours are rare tumours, and arise from the types of pancreatic cells that produce hormones. These tumours may or may not secrete hormones themselves and may or may not be cancerous (malignant). Functioning tumours secrete a particular hormones which may cause various syndromes. The present article reviews the latest reports on the pancreatic endocrine tumours. PMID- 22540086 TI - Systemic treatment and targeted therapy in patients with advanced hepatocellular carcinoma. AB - BACKGROUND: ADVANCED HEPATOCELLULAR CARCINOMA (HCC) IS A MALIGNANCY OF GLOBAL IMPORTANCE: it is the sixth most common cancer and the third most common cause of cancer-related mortality worldwide. Despite decades of efforts by many investigators, systemic chemotherapy or hormone therapy has failed to demonstrate improved survival in patients with HCC.. Ongoing studies are evaluating the efficacy and tolerability of combining Sorafenib with erlotinib and other targeted agents or chemotherapy. AIMS: On the basis of placebo-controlled, randomized phase III trials, Sorafenib has shown improved survival benefits in advanced HCC and has set a new standard for future clinical trials. The successful clinical development of Sorafenib in HCC has ushered in the era of molecularly targeted agents in this disease, which is discussed in this educational review. MATERIAL AND METHODS: Many molecularly targeted agents that inhibit angiogenesis, epidermal growth factor receptor, and mammalian target of rapamycin are at different stages of clinical development in advanced HCC. Future research should continue to unravel the mechanism of hepatocarcinogenesis and to identify key relevant molecular targets for therapeutic intervention. Identification and validation of potential surrogate and predictive biomarkers hold promise to individualize patients' treatment to maximize clinical benefit and minimize the toxicity and cost of targeted agents. RESULTS: Systemic therapy with various classes of agents, including hormone and cytotoxic agents, has provided no or marginal benefits. Improved understanding of the mechanism of hepatocarcinogenesis, coupled with the arrival of many newly developed molecularly targeted agents, has provided the unique opportunity to study some of these novel agents in advanced HCC. CONCLUSIONS: The demonstration of improved survival benefits by Sorafenib in advanced HCC has ushered in the era of molecular-targeted therapy in this disease, with many agents undergoing active clinical development. PMID- 22540087 TI - No association between Val158Met of the COMT gene and susceptibility to schizophrenia in the Syrian population. AB - BACKGROUND: The Val158Met single nucleotide polymorphism of the COMT gene has been implicated in the aetiology of schizophrenia, although results from different populations have been conflicting. AIMS: The aim of the present study was to investigate possible association between schizophrenia and Val158Met in a novel Arab population from Syria. METHODS AND MATERIALS: 71 unrelated schizophrenic subjects (45 men) and 102 unrelated healthy controls (62 men) were recruited to take part in this case- control study. The Val158Met of the COMT gene was genotyped for patients and controls, using a new optimized PCR-RFLP method. RESULTS: the results demonstrated that there is no statistically significant difference between the two groups. CONCLUSION: This study does not support that Val158Met has an influence on susceptibility for schizophrenia in this population. PMID- 22540088 TI - Dipstick urine analysis screening among asymptomatic school children. AB - BACKGROUND: Mass urinary screening is a useful tool to identify children with asymptomatic progressive renal diseases. A dipstick urinalysis screening was conducted to detect such prevalence and to set up a more effective screening program for children. PATIENTS AND METHODS: A cross sectional study was carried out in seven nurseries and primary schools in different regions of Lebanon (Beirut, North Lebanon, and Valley of Bekaa) between February 2010 and March 2010. Eight hundred seventy asymptomatic children were enrolled in this study. First morning mid steam urine samples were obtained from students and were tested by dipstick method. Children with abnormal findings were re-tested after fifteen days. RESULTS: Twenty five (2.9%) children had urinary abnormalities at the first screening; Eighteen (72%) of them still had abnormal results at the second screening. Among all the students, hematuria was the most common abnormality found with a prevalence of 1.5%, followed by nitrituria (0.45%), combined hematuria and nitrituria (0.45%) and proteinuria (0.1%). Urinary abnormalities were more common in females than in males. With respect to age, most positive results were detected at 6 years of age. Hematuria and proteinuria were mainly present in the North of Lebanon. CONCLUSION: Asymptomatic urinary abnormalities might be detected by urine screening program at school age. Further work-up should be offered to define the exact etiology of any abnormal finding and to determine whether early detection of renal disorders in childhood will lead to effective interventions and reduction in the number of individuals who develop end-stage renal disease. PMID- 22540089 TI - Relationship between lactobacilli and opportunistic bacterial pathogens associated with vaginitis. AB - BACKGROUND: Vaginitis, is an infectious inflammation of the vaginal mucosa, which sometimes involves the vulva. The balance of the vaginal flora is maintained by the Lactobacilli and its protective and probiotic role in treating and preventing vaginal infection by producing antagonizing compounds which are regarded as safe for humans. AIM: The aim of this study was to evaluate the protective role of Lactobacilli against common bacterial opportunistic pathogens in vaginitis and study the effects of some antibiotics on Lactobacilli isolates. MATERIALS AND METHODS: In this study (110) vaginal swabs were obtained from women suffering from vaginitis who admitted to Babylon Hospital of Maternity and Paediatrics in Babylon province, Iraq. The study involved the role of intrauterine device among married women with vaginitis and also involved isolation of opportunistic bacterial isolates among pregnant and non pregnant women. This study also involved studying probiotic role of Lactobacilli by production of some defense factors like hydrogen peroxide, bacteriocin, and lactic acid. RESULTS: Results revealed that a total of 130 bacterial isolates were obtained. Intrauterine device was a predisposing factor for vaginitis. The most common opportunistic bacterial isolates were Staphylococcus aureus, Escherichia coli, Streptococcus agalactiae, and Klebsiella pneumoniae. All Lactobacilli were hydrogen peroxide producers while some isolates were bacteriocin producers that inhibited some of opportunistic pathogens (S. aureus, E. coli). Lactobacilli were sensitive to erythromycin while 93.3% of them were resistant to ciprofloxacin and (40%, 53.3%) of them were resistant to amoxicillin and gentamycin respectively. Results revealed that there was an inverse relationship between Lactobacilli presence and organisms causing vaginitis. This may be attributed to the production of defense factors by Lactobacilli. CONCLUSION: The types of antibiotics used to treat vaginitis must be very selective in order not to kill the beneficial bacteria (Lactobacilli) that help in preservation of vaginal health and ecosystem as being one of the probiotic bacteria. PMID- 22540090 TI - Effects of a low level laser on the acceleration of wound healing in rabbits. AB - BACKGROUND: Tissue healing is a complex process that involves local and systemic responses. The use of low level laser therapy for wound healing has been shown to be effective in modulating both local and systemic response. AIM: The aim of this study was to accelerate and facilitate wound healing and reduce scar formation and wound contraction of an open wound by a low level laser. MATERIALS #ENTITYSTARTX00026; METHODS: Twenty adult male rabbits, lepus cuniculus demostica, were brought from a Basrah local market and raised under proper management conditions in Basrah Veterinary Medicine College. The age of these rabbits ranged between 8-10 months and their body weight was 1.5-2 Kg. The rabbits were divided into two groups, group I (Control) and group II (Treated). General anesthesia was provided by a mixture of Xylazine and Ketamine at a ratio of 1:0.5m intramuscularly. Selected sites were shaved, cleaned and disinfected. A wound of 4-cm length and 3-cm depth was made on the gluteal region; six hours later, the wound was treated with gallium aluminum and an arsenide diode laser with a power output of 10m at a wavelength of 890nm in pulsed nods, with a frequency of 20 KLTZ. The wound exposure to the laser was once a day at 890 nm wavelength for 5 minutes over a 7-day period. Histopathological study was obtained regarding the wound depth and edge of the skin on the 3(rd), 7(th) and 14(th) days. RESULTS: The histopathological finding of group I at three days postoperative showed hemorrhage with inflammatory cell infiltration, mainly neutrophils as well as congested blood vessels in the gap. At seven days, the gap contained necrotized neutrophils together with hemolysis and granulation tissue under the dermis tissue. Hemolysis was seen between the muscle fibers. At 14 days, there was irregular fibrous connective tissue proliferation with congested blood vessels seen in the gap with mononuclear cell infiltration. In group II at three days postoperative, severe inflammatory cell infiltration was observed, mainly neutrophils with proliferation of fibroblasts from a few fibrous connective tissues. On the 7(th) day, the main lesion was characterized by severe granulation tissue that consisted of proliferation of fibrous connective tissue and congested blood vessels in the gap of the incision with mononuclear cell infiltration. CONCLUSIONS: The study found that low level laser therapy (II) was effective in open wounds, which showed better regeneration and faster restoration of structural and functional integrity as compared to the control group. PMID- 22540091 TI - Prerequsite result of routine human immunodeficiency virus serology among infertile women before assisted reproduction technology. AB - BACKGROUND: Sexually transmitted diseases such as Human Immunodeficiency Virus (HIV) which causes or induces incurable fatal infections have been transmitted through Assisted Reproduction Technology and from infected mothers to the fetus or new born. AIM: The aim of this study is to determine the prevalence of this chronic viral agent among infertile women recruited for Assisted Reproduction Technique programme in Benin City, Nigeria. MATERIALS AND METHOD: Sera (serum) from Five hundred and Ninety infertile women attending Human Reproduction Research Programme/In-vitro fertilization Center at University of Benin Teaching Hospital were screened for the presence of Human Immunodeficiency Virus antibody using three algorithm or techniques of Determine, Unigold and Stat Pack kits. The age range of the infertile women was 20-49 years. RESULT: 28 (4.7%) out of Five Hundred and fifty infertile women recruited for Assisted Reproduction Technique and screened for Human Immunodeficiency Virus antibody were seropositive with increase in prevalence of 10. 0%, 8.5% and 7.5% among infertile women in age groups of (20 - 24), (25 - 29)yrs and (30 - 34)yrs. Chi-square statistical analysis of data shows insignificance in seroprevalence rate in relation to the number of infertile women screened (P > 0.0001) but the screening of these infertile women for the presence Human Immunodeficiency Virus should continue due to the attendant effects. CONCLUSION: Infertile women who are Human Immunodeficiency Virus carriers give a new dimension to assisted reproductive techniques. This will no doubt help to prevent further spread and adverse pregnancy outcome. PMID- 22540092 TI - Evaluating trial of scar in patients with a history of caesarean section. AB - AIMS: To analyze the outcome of trial of scar in patients with previous caesarean section and to assess the fetal and maternal complications after trial of scar. PATIENTS AND METHODS: The study was conducted at Military Hospital, Rawalpindi, Pakistan, with 375 pregnant patients who had a previous delivery by caesarean and who had regular antenatal checkup. Data were recorded on special pro-forms designed for the purpose. RESULTS: The results from the 375 patients who had one previous lower segment caesarean section due to non-recurrent causes were analyzed and compared with national and international studies. Indications of previous caesarean section (non-recurrent causes) included malpresentations, fetal distress/cord prolapse, failure to progress, severe pregnancy-induced hypertension/eclampsia and twins with abnormal lie of the first twin. 0 218 patients reported spontaneous labor. Among these patients, 176 delivered vaginally and 42 patients had repeat caesarean sections. There were a total of 157 patients who experienced induction of labor. 97 patients were induced by cervical ripening with mechanical method, followed by artificial rupture of membranes and augmentation (if required) with syntocinon infusion. 60 patients were induced with prostaglandin E(2) vaginal tablet. CONCLUSION: This study concludes that females with a prior caesarean are at increased risk for subsequent caesareans, regardless of mode of delivery. Eliminating vaginal-birth after-caesarean will not eliminate the risk. Therefore, vaginal birth after caesarean should be encouraged in selected cases from obstetric units to reduce the risks of repeated caesarean sections. Failed vaginal-birth-after-caesarean can result in increased morbidity than that with elective caesarean section. PMID- 22540093 TI - Acute pancreatitis and fibromyalgia: Cytokine link. AB - CONTEXT: Fibromyalgia is a widespread musculoskeletal pain disorder found in 2% of the general population and with a preponderance of 85% in females, and has both genetic and environmental contribution. Acute pancreatitis is a severe condition and in most cases gallstones disease represents approximately half of the cases of acute pancreatitis, and 20-25% are related to alcohol abuse. Small numbers of cases are caused by a variety of other reasons but a few cases have no obvious cause, referred to as 'idiopathic'. Here we present a case where fibromyalgia might be linked to acute pancreatitis. We believe this has not been reported in this context in literature. CASE REPORT: Fibromyalgia is a widespread musculoskeletal pain disorder found in 2% of the general population and with a preponderance of 85% in females, and has both genetic and environmental contribution. Patient had a cholecystectomy eight years previously. Patient feels tired almost all the time due to her fibromyalgia and requires family support for daily routine. Patient's blood results showed alanine transaminase 527 IU/L, alkaline phosphatase 604 IU/L, bilirubin 34 MUmol/L, amylase 2257 IU/L, C reactive protein 19 mg/L, Gamma-Glutamyl transpeptidase 851 IU/L, renal function and electrolytes were within normal limits. The patient was admitted to the high dependency unit with a diagnosis of acute pancreatitis. CONCLUSION: There is a known increase in levels of cytokines in patients with fibromyalgia. Part of the pathophysiology of acute pancreatitis is related to raised cytokines and immune deregulations. We hypothesize that elevated levels of cytokines in fibromyalgia has led to acute pancreatitis in our patient. Further epidemiological research on the incidence of pancreatitis in cytokine mediated conditions such as fibromyalgia is required. PMID- 22540094 TI - Crohn's disease presenting as acute abdomen: Report of two cases. AB - CONTEXT: Crohn's Disease may involve any part of GI tract leading to inflammation of all the layers of the affected bowel. The symptoms may mimc other intestinal pathologies and at times diagnosis remains a dilemma. Mostly medical therapy remains the mainstay of treatment. However surgical intervention is warranted in cases presenting with acute abdomen. CASE REPORT: We present two such cases of acute abdomen admitted in our hospital and diagnosed as case of intestinal obstruction. Exploratory laparotomy was performed in both cases and diseased resected segments were confirmed as Crohn's Disease on histopathology. CONCLUSION: Crohn's Disease should be kept as a differential diagnosis in patients presenting with acute abdomen especially with a long history of vague abdominal complaints. PMID- 22540096 TI - Ambient maximum temperature as a function of Salmonella food poisoning cases in the Republic of Macedonia. AB - BACKGROUND: Higher temperatures have been associated with higher salmonellosis notifications worldwide. AIMS: The objective of this paper is to assess the seasonal pattern of Salmonella cases among humans. MATERIAL AND METHODS: The relationship between ambient maximum temperature and reports of confirmed cases of Salmonella in the Republic of Macedonia and Skopje during the summer months (i.e. June, July, August and September) beginning in 1998 through 2008 was investigated. The monthly number of reported Salmonella cases and ambient maximum temperatures for Skopje were related to the national number of cases and temperatures recorded during the same timeframe using regression statistical analyses. The Poisson regression model was adapted for the analysis of the data. RESULTS: While a decreasing tendency was registered at the national level, the analysis for Skopje showed an increasing tendency for registration of new salmonella cases. Reported incidents of salmonellosis, were positively associated (P<0.05) with temperature during the summer months. By increasing of the maximum monthly mean temperature of 1 degrees C in Skopje, the salmonellosis incidence increased by 5.2% per month. CONCLUSIONS: THE INCIDENCE OF SALMONELLA CASES IN THE MACEDONIAN POPULATION VARIES SEASONALLY: the highest values of the Seasonal Index for Salmonella cases were registered in the summer months, i.e. June, July, August and September. PMID- 22540095 TI - The potentiality of medicinal plants as the source of new contraceptive principles in males. AB - Rising human population throughout the world especially in developing and underdeveloped countries has detrimental effects on life supporting system on earth. Traditionally, plants have been used to treat different kinds of ailments. The growing importance of phytochemicals in males has been reported. Contraceptive ability of plants has been reported in several animal models. The reversibility of the anti-fertility effects of plants and its active compounds are of potential clinical relevance in the development of male contraceptive. This review attempts to discuss the latest reports on the potentiality of medicinal plants as the source of new contraceptive principles in males. PMID- 22540097 TI - Royal jelly modulates oxidative stress and tissue injury in gamma irradiated male Wister Albino rats. AB - BACKGROUND: Royal jelly is a nutritive secretion produced by the worker bees, rich in proteins, carbohydrates, vitamins and minerals. AIM: The present study was designed to determine the possible protective effects of royal jelly against radiation induced oxidative stress, hematological, biochemical and histological alterations in male Wister albino rats. MATERIALS AND METHODS: Male Wister albino rats were exposed to a fractionated dose of gamma radiation (2 Gy every 3 days up to 8 Gy total doses). Royal jelly was administrated (g/Kg/day) by gavages 14 days before exposure to the 1(st) radiation fraction and the treatment was continued for 15 days after the 1(st) irradiation fraction till the end of the experiment. The rats were sacrificed 3(rd), equivalent to 3rd post 2nd irradiation fraction, and equivalent to 3rd day post last irradiation fraction. RESULTS: In the present study, gamma- irradiation induced hematological, biochemical and histological effects in male Wister albino rats. In royal jelly treated irradiated group, there was a noticeable decrease recorded in thiobarbituric reactive substances concentration when compared to gamma-irradiated group. Also, the serum nitric oxide concentration was significantly improved. The administration of royal jelly to irradiated rats according to the current experimental design significantly ameliorates the changes induced in serum lipid profile. Moreover, in royal jelly treated irradiated group, there was a noticeable amelioration recorded in all hematological parameters along the three experimental intervals. The microscopic examination of cardiac muscle of royal jelly treated irradiated rats demonstrated structural amelioration, improved nuclei and normal features of capillaries and veins in endomysium when compared to gamma-irradiated rats. CONCLUSION: It was suggested that the biochemical, hematological and histological amelioration observed in royal jelly (g/Kg/day) treated irradiated rats might be due to the antioxidant capacity of royal jelly active constituents. PMID- 22540098 TI - Triglycerides, total cholesterol, high density lipoprotein cholesterol and low density lipoprotein cholesterol in rats exposed to premium motor spirit fumes. AB - BACKGROUND: Deliberate and regular exposure to premium motor spirit fumes is common and could be a risk factor for liver disease in those who are occupationally exposed. A possible association between premium motor spirit fumes and plasma levels of triglyceride, total cholesterol, high density lipoprotein cholesterol and low density lipoprotein cholesterol using a rodent model could provide new insights in the pathology of diseases where cellular dysfunction is an established risk factor. AIM: The aim of this study was to evaluate the possible effect of premium motor spirit fumes on lipids and lipoproteins in workers occupationally exposed to premium motor spirit fumes using rodent model. MATERIALS AND METHODS: Twenty-five Wister albino rats (of both sexes) were used for this study between the 4(th) of August and 7(th) of September, 2010. The rats were divided into five groups of five rats each. Group 1 rats were not exposed to premium motor spirit fumes (control group), group 2 rats were exposed for 1 hour daily, group 3 for 3 hours daily, group 4 for 5 hours daily and group 5 for 7 hours daily. The experiment lasted for a period of 4 weeks. Blood samples obtained from all the groups after 4 weeks of exposure were used for the estimation of plasma levels of triglyceride, total cholesterol, high density lipoprotein- cholesterol and low density lipoprotein- cholesterol. RESULT: Results showed significant increase in means of plasma total cholesterol and low density lipoprotein levels (P<0.05). The mean triglyceride and total body weight were significantly lower (P<0.05) in the exposed group when compared with the unexposed. The plasma level of high density lipoprotein, the ratio of low density lipoprotein to high density lipoprotein and the ratio of total cholesterol to high density lipoprotein did not differ significantly in exposed subjects when compared with the control group. CONCLUSION: These results showed that frequent exposure to petrol fumes may be highly deleterious to the liver cells. PMID- 22540099 TI - Direct molecular detection of Mycobacterium tuberculosis complex from clinical samples - An adjunct to cultural method of laboratory diagnosis of tuberculosis. AB - BACKGROUND: Tuberculosis, a communicable disease with significant morbidity and mortality, is the leading cause of death in the world from bacterial infectious disease. Because of its public health importance, there is need for rapid and definitive method of detecting the causative organism. Several approaches have been attempted, but the molecular methods, especially Polymerase Chain Reaction assays are the most promising for rapid detection of Mycobacterium tuberculosis complex from clinical samples. AIM: This study was aimed at using Polymerase Chain Reaction for detection of Mycobacterium tuberculosis complex from clinical samples using universal sample processing methodology. SUBJECTS AND METHODS: Two hundred clinical samples sent to Tuberculosis laboratories in Ibadan and Osogbo, Nigeria, were enrolled in this study. The samples were processed by universal sample processing methodology for PCR; smear microscopy was carried out on sputum samples by Ziehl Nelseen staining technique; and cultured on Middlebrook agar medium containing oleic acid albumin dextrose complex supplement after decontamination of samples. RESULTS: Ninety six (48%) samples were detected positive for M. tuberculosis complex by polymerase chain reaction using the combination of boiling and vortexing and microscopy detected 72 (36%) samples positive for acid fast bacilli. Using culture method as gold standard, it was found that polymerase chain reaction assay was more sensitive (75.5%) and specific (94.8%) than microscopy (sensitivity of 48.5% and specificity of 85.7%) in detecting M. tuberculosis complex from clinical samples. There was significant difference in detecting M. tuberculosis from clinical samples when compared to microscopy (p<0.05). CONCLUSION: The study recommends that direct molecular detection of M. tuberculosis complex is sensitive and specific and polymerase chain reaction method should be used as an adjunct to other methods of laboratory diagnosis of tuberculosis. PMID- 22540100 TI - Isolated type I pelvic cystic echinococcosis mimicking ovarian tumor. AB - CONTEXT: Cystic echinococcosis is an endemic infestation with unique clinical and laboratory manifestations. Isolated pelvic type 1 cystic echinococcosis is a rare form of the disease with diagnostic pitfalls mainly based on non-diagnostic imaging findings. CASE REPORT: We present an isolated pelvic cystic echinococcosis resembling ovarian tumor which was diagnosed during operation. CONCLUSIONS: Characteristic findings of hydatid disease lacks in type 1 and cause diagnostic difficulties. This rare entity should be considered for differential diagnosis due to varied examination findings especially in type 1 cystic echinococcosis. PMID- 22540101 TI - Survivin, p53, MAC, Complement/C3, fibrinogen and HLA-ABC within hair follicles in central and centrifugal cicatricial alopecia. AB - CONTEXT: Central centrifugal cicatricial alopecia (CCCA; originally entitled follicular degeneration syndrome, or hot comb alopecia) was first described in African American women utilizing hot combs and/or strong chemical hair care products. CASE REPORT: A 67 year old African American female was evaluated for the presence of alopecic areas occurring on the scalp vertex, and spreading centrifugally. The alopecic lesions appeared as diffuse patches, including atrophic small areas surrounding individual hair follicles. PATIENTS AND METHODS: Skin biopsies for hematoxylin and eosin examination, as well as for direct immunofluorescence and immunohistochemistry analyses were performed. RESULTS: hematoxylin and eosin staining demonstrated histopathologic findings of premature desquamation of the inner root sheath and eccentric thinning of the follicular epithelium, supporting the diagnosis of CCCA. Direct immunofluorescence revealed strong depositions of Complement/C3, fibrinogen and kappa light chains around the hair follicles. Immunohistochemistry demonstrated increased expressions of HLA ABC (as in African American patients with insulin independent diabetes mellitus). We also detected positive p53, bcl-2 and MAC staining in the hair follicle areas. CONCLUSIONS: Follicular degeneration syndrome may have an important immunological component previously not described, and multicolor immunofluorescence may be useful in establishing an early diagnosis. PMID- 22540102 TI - Anterior interosseous nerve palsy following the use of elbow crutches. AB - CONTEXT: Lesions of the anterior interosseous nerve are rare and comprise less than 1% of all upper extremity nerve palsies. Traumatic causes include blunt trauma, forearm fractures, penetrating injury and local pressure from a plaster cast, but has never before been described in association with crutch use. This is the first reported case of the use of elbow crutches causing symptomatic anterior interosseous nerve compression. CASE REPORT: This case describes a 30-year-old male who developed an inability to pinch with his left hand following the use of elbow crutches for a foot injury. On examination he was unable to flex the interphalangeal joint of his left thumb. A diagnosis of anterior interosseous palsy was made and the patient was treated conservatively and crutch use was ceased. At six weeks follow-up the patient made a complete recovery with full function of his left hand. CONCLUSION: This report highlights the importance of adequate education in the safe use of elbow crutches for all patients. The side effects of inappropriate use should be carefully examined for during follow-up care. PMID- 22540103 TI - Pleomorphic adenoma of the lower lip: A rare site of location. AB - CONTEXT: Pleomorphic adenoma is the most common neoplasm of the minor salivary glands which are uncommon among the entire salivary gland tumors. The lower lip is a very rare site of occurrence for pleomorphic adenoma. We intended to present a case of pleomorphic adenoma of the lower lip. CASE REPORT: A 49-year-old Turkish man presented with the painless mass on his lower lip. A total excision was choiced for the mass by both we and the patient because of some cosmetic reasons. The histopathological evaluation revealed the diagnosis of pleomorphic adenoma and neither complication nor recurrence was observed during a clinical follow-up for 40 months. CONCLUSIONS: A clinician should be vigilant for the possibility of existence of a pleomorphic adenoma located on the lower lip even it is rare. Once it is diagnosed concisely, a wide excision is suggested in general if there is no cosmetic care and no risk of damage to functional structures of head and neck. PMID- 22540104 TI - The dream as space, time and emotion. AB - Human beings, like all living organisms, use energy ceaselessly with whatever they do. Nothing at all happens without spending some energy, not even a glance or a dream. The Author proposes that dreams happen automatically in sleep to help us release unresolved frustration energy and emotional dilemmas left over from the day before. Energy administration is the common denominator behind the manifold workings of dreams, as it is behind all operations of our consciousness in daytime, and this is far more important than one might at first suspect. In summary, if in waking reality the day prior to a dream, a specific sensory composition (a perception or picture) frustrates our mind such that the mind is unable or unwilling to accept this sensory composition, it forms and traps within us an emotional energy charge that lingers inside till that same night when the dream uses it in order to energize from memory analogous sensory components that form a spatiotemporally similar overall representational composition of the daytime waking event. This ends up as the dream we may remember the next day. For example, if in a real event yesterday a red apple between two green apples were in front of us and for some reason we were unable or unwilling to see and accept this perception, in a dream the next time we sleep, we may see promptly a red peach between two green peaches, which will be energized temporarily from our memory to serve the need of our psyche to represent the unprocessed emotion(s) and balance the tensions inside us. The dream always produces more acceptable symbolic perceptions for us to see or sense, and in doing so uses and releases at the same time the unacknowledged emotional energy inside us pending since yesterday's event. PMID- 22540105 TI - Immune enhancing effects of WB365, a novel combination of Ashwagandha (Withania somnifera) and Maitake (Grifola frondosa) extracts. AB - BACKGROUND: Stress has been found to significantly reduce the abilities of the immune system to fight infections. One of the ways to overcome the defects of the immune system is the strengthening of the defense reactions by nutrition. AIMS: TO EVALUATE IMMUNE ENHANCING EFFECTS OF THE FOLLOWING MATERIAL: WB365, a novel combination of Ashwagandha (Withania somnifera) and Maitake (Grifola frondosa) extracts. RESULTS: We found that both glucan-rich maitake extract and WB365 caused a similar stimulation of phagocytic activity. Stress-induced increase of corticosterone production was blocked by feeding with Ashwagandha extract and even more by WB365. Cytokine experiments showed that feeding with WB365 helped overcome the stress-related inhibition of IL-6, IL-12 and IFN-gamma production. CONCLUSION: This study clearly demonstrated that WB365, a combination of Maitake mushroom-derived glucan and Ashwagandha extracts, has strong pleiotropic biological effects related to immune health and stress reduction. PMID- 22540106 TI - Histopathological effects of sub-chronic lamivudine-artesunate co-administration on the liver of diseased adult Wistar rats. AB - BACKGROUND: Lamivudine and artesunate are sometimes co administered in HIV malaria co morbidity. Both drugs are used concurrently in presumptive malaria treatment and simultaneous HIV post exposure prophylaxis. AIM: The aim of this study was to investigate the effect of lamivudine-artesunate co administration on the histology of the liver of diseased adult Wistar rats. MATERIALS AND METHODS: Five groups of rats of both sexes were used for the study and placed on feed and water ad libitum. Disease state consisted of immunosuppression with cyclophosphamide, and infection with Plasmodium berghei. Group 1 animals served as vehicle control, while group 2 were the diseased controls. Group 3 animals received 20 mg/kg lamivudine for three weeks, while group 4 similarly received 20 mg/kg Lamivudine but also received 10 mg/kg artesunate from day 12. Animals in group 5 received 10 mg/kg artesunate from day 12. All drugs were administered intraperitoneally. The animals were treated for twenty-one days, at the end of which they were sacrificed and their livers fixed in 10% formalin for histological studies. RESULT: Results from the study show the presence of regions of focal necrosis and perivascular cuffing with animals that received artesunate. Hemosiderosis was a common feature in all the parasitized groups, while fatty degeneration was observed in the group that received artesunate alone. CONCLUSION: Concurrent lamivudine-artesunate administration resulted in some histopathological changes in the liver. This study suggests there may be considerable histological changes with repeated occurrence of malaria and immunosuppression that may warrant intermittent lamivudine-artesunate administration, and may require evaluation as well as monitoring of liver function during such therapeutic interventions. PMID- 22540107 TI - Survival of Treponema pallidum in banked blood for prevention of Syphilis transmission. AB - BACKGROUND: Every year, millions of people are exposed to avoidable, life threatening risks through the trans-fusion of unsafe blood. AIM: To determine the survival time of Treponema pallidum in banked donor blood. MATERIAL AND METHODS: Two groups of male Wistar rats (group A and B) were inoculated intratesticularly with 0.5ml of artificially infected donor blood (final density of Nichols treponemes: 5*10(5) /ml) stored at 4 degrees C for various periods of time. In group A, a pair each of the rats was injected every 12 hours, starting at 0 hr, up to a maximal storage time of 96 hr. In group B, the rats were injected after 72, 120, 192 and 336 hours of storage of the treponemes-blood mixture. Group C which is a control group was injected with blood only, while group D rats were injected with heat-killed treponemes suspended in blood every 12 hours. The detection of Treponema pallidum IgG/IgM was based on the principle of double antigen sandwich immunoassay, in which purified recombinant antigens are employed sufficiently to identify antibodies to Syphilis. The outcomes of interest included the proportion of Syphilis positive rats and the maximal survival hours of T. pallidum in banked blood. RESULTS: 14 rats (77.8%) out of the 18 rats that were involved in group A developed orchitis and positive serology up to 72 hours of storage time, p<0.05. 2 rats (25%) in group B developed orchitis after 72hrs of storage time. All the 18 rats (100%) in the control group C and D showed neither clinical nor serological changes. CONCLUSION: It was concluded that the survival time of T. pallidum in banked donor blood lies between 72-120hrs in this study. Regardless of blood banking temperature, T. pallidum and other transfusion transmissible infections should be screened for prior to allogeneic transfusion. PMID- 22540108 TI - Whole blood viscosity issue VIII: Comparison of extrapolation method with diagnostic digital viscometer. AB - BACKGROUND: The first issue of this series proposed extrapolation chart with conventional reference range and suggested comparison of results with other methods. AIM: This work sets out to compare interpretative results from the extrapolation method with those from a digital viscometer method. MATERIALS AND METHODS: Five cases in our archived clinical pathology database that were specifically tested for whole blood viscosity by the digital method, and had results for haematocrit and serum proteins were pooled. The values of haematocrit and serum proteins were used to derive extrapolated values. The interpretative results of the extrapolation method were compared with those of digital viscometer-based clinical reports. Non-Newtonian fluids such as whole blood have different viscosities at different shear rates. Comparative statement can only be based on interpreted outcome. RESULTS: Two-fifth absolute concordance and one fifth discordance is observed between extrapolation and viscometer-based clinical reports. The discordance is a case of hyperviscosity in the presence of neither hyperproteinaemia nor polycythemia. CONCLUSION: The extrapolation method may underestimate whole blood viscosity in some patients when compared with digital viscometer, which in turn may suggest hyperviscosity that cannot be explained by hyperproteinaemia or polycythemia concepts. The impact of oxidative stress is highlighted. PMID- 22540109 TI - Ganglioneuroma of the adrenal gland and retroperitoneum: A case report. AB - CONTEXT: Ganglioneuromas are benign tumors of the sympathetic nervous system that rarely arise in the adrenal gland. Majority of cases are detected incidentally since they are usually asymptomatic. Up to the current era of laparoscopic adrenal mass excision, this unusual entity has not been adequately reported in the surgical literature. CASE REPORT: A 51 year old male with history of hypertension was found to have abdominal bruit during a regular physical examination. A 4 cm right adrenal mass with upper pole calcification and a 6 cm retro-pancreatic mass were subsequently found on a computed tomography scan. Endoscopic ultrasound-guided needle biopsy was indeterminate. Preoperative endocrine evaluation showed mildly elevated vanillyl mandelic acid with normal 24 hour cathecolamine, metanephrine and cortisol levels. Histopathologic examination after an uneventful laparoscopic excision was consistent with ganglioneuroma. CONCLUSIONS: Ganglioneuroma occurs rarely in adrenal gland and preoperative diagnosis is difficult since symptoms are usually nonspecific. Due to widespread utilization of abdominal imaging, however, it should be included in differential diagnosis of adrenal or retroperitoneal mass. Histopathologic examination is currently the mainstay of diagnosis. PMID- 22540110 TI - Retained intra-abdominal artery forceps - An unusual cause of intestinal strangulation. AB - CONTEXT: Surgical instruments and materials continue to be retained in the peritoneal cavity despite precautionary measures. Even though uncommon it is also under-reported and carries serious medico-legal consequences. Gauzes and sponges (gossypiboma) are the most commonly retained materials and intra-abdominal retained artery forceps are much rarer but when they do occur lead to chronic abdominal pain and can be a rare cause of intestinal obstruction or strangulation with significant morbidity and mortality. CASE REPORT: We present a case of intraabdominal retained artery forceps in a 70-years-old lady who underwent laparotomy with splenectomy for a large spleen in a peripheral hospital. Upon discharge she continued to complain of intermittent abdominal pain of increasing severity. 12 months later she presented to us with an acute (surgical) abdomen requiring another laparotomy. At laparotomy she had strangulated/gangrenous lower jejunual and upper ileal bowel loops, the small bowel mesentery of this area being tightly trapped between the jaws of the retained artery forceps. She had gut resection and enteroanastomosis. Unfortunately she died from continuing sepsis on the second post-operative day. CONCLUSION: Retained instruments in intra-abdominal surgery can cause serious complication and should be treated surgically. High index of suspicion and appropriate investigations like plain abdominal X-ray, abdominal ultrasound and CT and MRI scans should be instituted in patients who develop chronic abdominal symptoms following laparotomy. Preventive measures against retained instruments must follow strict laid down protocols for surgical instruments handling in theatre. PMID- 22540111 TI - The effect of oxidative stress on human red cells glutathione peroxidase, glutathione reductase level, and prevalence of anemia among diabetics. AB - BACKGROUND: The oxidative stress is considered as major consequence of diabetes mellitus affecting red cell antioxidant enzymes AIM: The present study was conducted to assess the impact of oxidative stress (reduced glutathione) on glutathione peroxidase, and glutathione reductse and prevalence of anemia among diabetic patients. MATERIALS AND METHODS: The study involved 100 adult patients attending Buraidah Central Hospital and 30 healthy controls. Blood samples were collected and analyzed for glutathione (GSH) concentration, glutathione peroxidase (GPO), glutathione reductase (GR), fasting blood sugar (RBS), hemoglobin (HGB), red cell count (RBCs) hematocrit (HCT) mean cell volume (MCV) mean cell hemoglobin (MCH) and mean cell hemoglobin concentration (MCHC) and hemoglobin A1c. Blood urea, serum creatinine, and microalbuminuria were measured to exclude diabetes mellitus nephropathy. RESULTS: were obtained showed significant correlation between deficiency of glutathione peroxidase, glutathione reductase and deficient of glutathione among diabetics, which has significant correlation between low hemoglobin concentration (females <120 g/L, males <130 g/L), also there is low concentration of red cell count and red cell indices (MCV, MCH and MCHC). The prevalence of anemia was 22% in diabetes patients. CONCLUSION: It can be concluded that there is strong significant effect of oxidative stress (reduced glutathione) on glutathione peroxidase, glutathione reductase level these may reduce hemoglobin concentration in diabetic patients. This means oxidative stress of diabetes mellitus is the possible cause of anemia in diabetics without nephropathy. PMID- 22540112 TI - Micronutrient status, immune response and infectious disease in elderly of less developed countries. PMID- 22540113 TI - Variation of the cholesterol content in breast milk during 10 days collection at early stages of lactation. AB - More and more research is done concerning nutritional programming. Human milk nutrients which are consumed by infants can influence their health in later life. High level of cholesterol in human milk paradoxically lowers the cholesterol concentration in blood in adults. During the course of human lactation the cholesterol concentration decreases from 31 mg/100cm(3) (colostrum) to 16 mg/100 cm(3) (mature milk). According to Scopesi et al., 2002, Clin Nutr 21: 379-384, cholesterol concentration in mature milk ranged from 6.5 to 18.4 mg/100 cm(3). The aim of the study was to assess the variations in breast milk cholesterol content during 10 day collection at early lactation. 48 samples of human milk were analyzed. Mean age of women was 31 years. Women were collecting samples during 10 days of an early lactation stage (1-3 months after delivery). An Attenuated Total Reflectance Fourier Transformed Infrared (FTIR-ATR) method for easy and rapid determination of cholesterol in human milk was elaborated. Cholesterol content assessed by the FTIR method ranged from 3.36 to 12.98 mg/100 cm(3). Results indicate that milk cholesterol concentration during 10 consecutive days of early lactation is highly variable. Cholesterol content depends on an individual. Therefore it is suggested that not only the period of lactation but also mother's diet, age, season and place of residence are important factors determining cholesterol content. PMID- 22540114 TI - Prebiotics and bioactive natural substances induce changes of composition and metabolic activities of the colonic microflora in cancerous rats. AB - Prebiotics are defined as selectively fermented food ingredients that induce specific changes in the composition and/or activity in the gastrointestinal microbiota beneficial to the host well-being and health. The aim of the presented experiment was to investigate the effect of a prebiotic applied alone or in combination with Hyppocastani extractum siccum, and Lini oleum virginale in rats with dimethylhydrazine induced colon cancer. Wistar albino rats were fed high fat diet supplemented with the prebiotic alone or in combination with Horse chestnut and flaxseed oil. The activity of faecal glycolytic enzymes, lipid parameters, bile acids, short chain fatty acids and counts of coliforms and lactobacilli were determined. Treatment with the prebiotic alone and in combination with selected substances significantly decreased the activity of glycolytic bacterial enzyme beta-glucuronidase (P<0.001) and increased activities of beta-galactosidase and beta-glucosidase. Bile acids concentration was significantly decreased (P<0.01) except for the combination of the prebiotic with Horse chestnut. The prebiotic alone decreased the lipid parameters (P<0.001) and enhanced production of short chain fatty acids. Application of prebiotic and bioactive natural substances significantly reduced number of coliforms (P<0.05). Prebiotic alone significantly increased the count of lactobacilli (P<0.05). These results show that prebiotics have a protective effect and may be the useful for colon cancer prevention and treatment. PMID- 22540115 TI - Reduction of bilirubin ditaurate by the intestinal bacterium Clostridium perfringens. AB - Bilirubin is degraded in the human gut by microflora into urobilinoids. In our study we investigated whether the bilirubin-reducing strain of Clostridium perfringens can reduce bilirubin ditaurate (BDT), a bile pigment of some lower vertebrates, without hydrolysis of the taurine moiety. C. perfringes was incubated under anaerobic conditions with BDT; reduction products were quantified by spectrophotometry and separated by TLC. Based on Rf values of BDT reduction products and synthetic urobilinogen ditaurate, three novel taurine-conjugated urobilinoids were identified. It is likely that bilirubin-reducing enzyme(s) serve for the effective disposal of electrons produced by fermentolytic processes in these anaerobic bacteria. PMID- 22540116 TI - Quantification of noise sources for amperometric measurement of quantal exocytosis using microelectrodes. AB - Electrochemical microelectrodes are commonly used to record amperometric spikes of current that result from oxidation of transmitter released from individual vesicles during exocytosis. Whereas the exquisite sensitivity of these measurements is well appreciated, a better understanding of the noise sources that limit the resolution of the technique is needed to guide the design of next generation devices. We measured the current power spectral density (S(I)) of electrochemical microelectrodes to understand the physical basis of dominant noise sources and to determine how noise varies with the electrode material and geometry. We find that the current noise is thermal in origin in that S(I) is proportional to the real part of the admittance of the electrode. The admittance of microelectrodes is well described by a constant phase element model such that both the real and imaginary admittance increase with frequency raised to a power of 0.84-0.96. Our results demonstrate that the current standard deviation is proportional to the square root of the area of the working electrode, increases ~linearly with the bandwidth of the recording, and varies with the choice of the electrode material with Au ~ carbon fiber > nitrogen-doped diamond-like carbon > indium-tin-oxide. Contact between a cell and a microelectrode does not appreciably increase noise. Surface-patterned microchip electrodes can have a noise performance that is superior to that of carbon-fiber microelectrodes of the same area. PMID- 22540117 TI - DNA-templated silver nanoclusters-graphene oxide nanohybrid materials: a platform for label-free and sensitive fluorescence turn-on detection of multiple nucleic acid targets. AB - In this study, we develop an efficient method for multiple DNA detection by exploring silver nanoclusters (AgNCs)-graphene oxide (GO) nanohybrid materials. Because of the extraordinarily high quenching efficiency of GO, the ssDNA-AgNCs probe exhibits minimal background fluorescence, while strong emission is observed when it forms a double helix with the specific target DNA, leading to a high signal-to-background ratio. Therefore the AgNCs-GO nanohybrid materials can be successfully applied for DNA detection. The system described here exhibits not only high sensitivity with a detection limit of 1 nM, but also an excellent differentiation ability for single-base mismatched sequences. In addition, by exploring AgNCs as signal reporters and GO as the nanoquencher, this approach avoids labeling the probe DNA or target DNA, which offers the advantages of simplicity and cost efficiency. Moreover, the large planar surface of GO allows adsorption of different DNA-AgNCs probes, each with a distinct emission, leading to a multicolor sensor for the detection of multiple DNA targets in the same solution. PMID- 22540118 TI - Label free colorimetric sensing of thiocyanate based on inducing aggregation of Tween 20-stabilized gold nanoparticles. AB - Based on inducing the aggregation of gold nanoparticles (AuNPs), a simple colorimetric method with high sensitivity and selectivity was developed for the sensing of thiocyanate (SCN(-)) in aqueous solutions. Citrate-capped AuNPs were prepared following a classic method and Tween 20 was subsequently added as a stabilizer. With the addition of SCN(-), citrate ions on AuNPs surfaces were replaced due to the high affinity between SCN(-) and Au. As a result, Tween 20 molecules adsorbed on the AuNPs surfaces were separated and the AuNPs aggregated. The process was accompanied by a visible color change from red to blue within 5 min. The sensing of SCN(-) can therefore be easily achieved by a UV-vis spectrophotometer or even by the naked eye. The potential effects of relevant experimental conditions, including concentration of Tween 20, pH, incubation temperature and time, were evaluated to optimize the method. Under optimized conditions, this method yields excellent sensitivity (LOD = 0.2 MUM or 11.6 ppb) and selectivity toward SCN(-). Our attempt may provide a cost-effective, rapid and simple solution to the inspection of SCN(-) ions in saliva and environmental aqueous samples. PMID- 22540120 TI - Towards copper-free nanocapsules obtained by orthogonal interfacial "click" polymerization in miniemulsion. AB - A facile method to produce nanocapsules by copper-free interfacial "click" polymerization as orthogonal reaction for the encapsulation of functional molecules is successfully performed using stable miniemulsion droplets. Difunctional azides and alkynes have been used for polymerization around the miniemulsion droplets, leading to the formation of nanocapsules. The results were compared with copper-catalyzed systems. PMID- 22540121 TI - Quantum confinement in silver selenide semiconductor nanocrystals. AB - We prepare Ag(2)Se nanocrystals with average diameters between 2.7 and 10.4 nm that exhibit narrow optical absorption features in the near to mid infrared. We demonstrate that these features are broadly tunable due to quantum confinement. They provide the longest wavelength absorption peaks (6.5 MUm) yet reported for colloidal nanocrystals. PMID- 22540119 TI - Facile preparation of amine and amino acid adducts of [60]fullerene using chlorofullerene C60Cl6 as a precursor. AB - We report a general synthetic approach to the preparation of highly functionalized amine and amino acid derivatives of [60]fullerene starting from readily available chlorofullerene C(60)Cl(6). The synthesized water-soluble amino acid derivative of C(60) demonstrated pronounced antiviral activity, while the cationic amine-based compound showed strong antibacterial action in vitro. PMID- 22540122 TI - Immobilisation of quantum dots by bio-orthogonal PCR amplification and labelling for direct gene detection and quantitation. AB - A sensitive and versatile detection scheme based on quantum dot immobilisation on a solid support through bio-orthogonal PCR amplification and labelling has been developed for detection and quantification of gene targets in complex DNA mixtures. PMID- 22540123 TI - A dimethoxytriazine type glycosyl donor enables a facile chemo-enzymatic route toward alpha-linked N-acetylglucosaminyl-galactose disaccharide unit from gastric mucin. AB - An efficient chemo-enzymatic process for construction of the alpha-linked disaccharide unit (GlcNAcalpha1-4Gal) found in gastric mucin has been developed. The process consists of a one-step preparation of a novel triazine type glycosyl donor in water and the subsequent transglycosylation to a galactose derivative catalysed by alpha-N-acetylglucosaminidase. PMID- 22540124 TI - Development of a carbon quantum dots-based fluorescent Cu2+ probe suitable for living cell imaging. AB - An efficient strategy for selective fluorescent detection of Cu(2+) was developed based on the carbon quantum dots (CQDs) nanoconjugated with a specific organic molecule, amino TPEA, and further applied to intracellular sensing and imaging of Cu(2+) as a consequence of the fluorescence properties and the established low cytotoxicity of CQDs. PMID- 22540125 TI - Controlled growth of narrowly dispersed nanosize hexagonal MOF rods from Mn(III) porphyrin and In(NO3)3 and their application in olefin oxidation. AB - A new class of narrowly dispersed nanosize hexagonal MOF rods from Mn(III) porphyrin and In(III) was obtained. The length of MOF rods was controlled by simple change of reaction times. Furthermore, the oxidation of styrene has been successfully demonstrated with Mn(III)-porphyrin MOF rods and their reusability has been also tested. PMID- 22540126 TI - A novel oxidative transformation of alcohols to nitriles: an efficient utility of azides as a nitrogen source. AB - An efficient methodology to oxidize benzylic and cinnamyl alcohols to their corresponding nitriles in excellent yields has been developed. This methodology employs DDQ as an oxidant and TMSN(3) as a source of nitrogen in the presence of a catalytic amount of Cu(ClO(4))(2).6H(2)O. PMID- 22540127 TI - NTCDA-TTF first axial fusion: emergent panchromatic, NIR optical, multi-state redox and high optical contrast photooxidation. AB - The first synthetic entry into axially fused NTCDA/PMDA-TTF multipolar molecules demonstrates a high optical contrast photooxidation, panchromism, low HOMO-LUMO gap, generation of a stable radical cation, NIR absorption/emission beyond 2150/800 nm and theoretically calculated NLO activity. PMID- 22540128 TI - Stepping towards highly flexible aptamers: enzymatic recognition studies of unlocked nucleic acid nucleotides. AB - Enzymatic recognition of unlocked nucleic acid (UNA) nucleotides was successfully accomplished. Therminator DNA polymerase was found to be an efficient enzyme in primer extension reactions. Polymerase chain reaction (PCR) amplification of a 81 mer UNA-modified DNA library was efficiently achieved by KOD DNA polymerase. PMID- 22540129 TI - Characterization of [8-ethyl]-chlorophyll c3 from Emiliania huxleyi. AB - We report herein the isolation and complete characterization of a member of the chlorophyll c family, designated as [8-ethyl]-chlorophyll c(3) ([8-ethyl]-chl c(3)). Structural elucidation of this pigment rested on the analysis of mono- and bidimensional NMR, UV-VIS spectroscopy and ESI-MS data, and the configuration at the 13(2) position on chiral HPLC analysis. PMID- 22540130 TI - STEP cement: Solar Thermal Electrochemical Production of CaO without CO2 emission. AB - New molten salt chemistry allows solar thermal energy to drive calcium oxide production without any carbon dioxide emission. This is accomplished in a one pot synthesis, and at lower projected cost than the existing cement industry process, which after power production, is the largest contributor to anthropogenic greenhouse gas emissions. PMID- 22540131 TI - Aryl-aryl interactions as directing motifs in the stereodivergent iron-catalyzed hydrosilylation of internal alkynes. AB - The defined Fe hydride complex FeH(CO)(NO)(Ph(3)P)(2) is highly active as a catalyst for selective hydrosilylation of internal alkynes to vinylsilanes. Depending on the silane employed either E- or Z-selective hydrosilylation products were formed in excellent yields and good to excellent stereoselectivities. PMID- 22540132 TI - Novel catalytic effects of Mn3O4 for all vanadium redox flow batteries. AB - A new approach for enhancing the electrochemical performance of carbon felt electrodes by employing non-precious metal oxides is designed. The outstanding electro-catalytic activity and mechanical stability of Mn(3)O(4) are advantageous in facilitating the redox reaction of vanadium ions, leading to efficient operation of a vanadium redox flow battery. PMID- 22540133 TI - [Reduced salt intake and risk of increased mortality]. PMID- 22540134 TI - [Non-rational recommendation for pioglitazone in diabetic steatohepatitis]. PMID- 22540135 TI - Guest editors' introduction. PMID- 22540136 TI - [Virtual worlds, virtual microscopy]. PMID- 22540137 TI - Do burn centers provide juvenile firesetter intervention? AB - Juvenile firesetting activity accounts for a significant number of annual injuries and property damage, yet there is sparse information on intervention in the burn literature. To quantify juvenile firesetting intervention (JFSI) in burn centers, a 23-question survey was sent to all directors listed in the American Burn Association Burn Care Facilities Directory.Sixty-four out of 112 (57%) surveys were returned. This represents responses from 79% of currently verified burn centers. When queried on interventions provided to a juvenile firesetter admitted to their unit, 38% report having their own JFSI program and 38% refer the child to fire services. Two thirds of units without a JFSI program treat pediatric patients. Units that previously had a JFSI program report lack of staffing and funding as most common reasons for program discontinuation. Almost all (95%) stated that a visual tool demonstrating legal, financial, social, future, and career ramifications associated with juvenile firesetting would be beneficial to their unit. Many burn units that treat pediatric patients do not have JFSI and rely on external programs operated by fire services. Existing JFSI programs vary greatly in structure and method of delivery. Burn centers should be involved in JFSI, and most units would benefit from a new video toolkit to assist in providing appropriate JFSI. Study results highlight a need for burn centers to collaborate on evaluating effectiveness of JFSI programs and providing consistent intervention materials based on outcomes research. PMID- 22540139 TI - Lactation biology. PMID- 22540138 TI - In vivo molecular imaging of murine embryonic stem cells delivered to a burn wound surface via Integra(r) scaffolding. AB - It has been demonstrated that restoration of function to compromised tissue can be accomplished by transplantation of bone marrow stem cells and/or embryonic stem cells (ESCs). One limitation to this approach has been the lack of noninvasive techniques to longitudinally monitor stem cell attachment and proliferation. Recently, murine ESC lines that express green fluorescent protein (GFP), luciferase (LV), and herpes simplex thymidine kinase (HVTK) were developed for detection of actively growing cells in vivo by imaging. In this study, the authors investigated the use of these ESC lines in a burned mouse model using Integra(r) as a delivery scaffolding/matrix. Two different cell lines were used: one expressing GFP and LV and the other expressing GFP, LV, and HVTK. Burn wounds were produced by application of a brass block (2 * 2 cm kept in boiling water before application) to the dorsal surface of SV129 mice for 10 seconds. Twenty four hours after injury, Integra(r) with adherent stem cells was engrafted onto a burn wound immediately after excision of eschar. The stem cells were monitored in vivo by measuring bioluminescence with a charge-coupled device camera and immunocytochemistry of excised tissue. Bioluminescence progressively increased in intensity over the time course of the study, and GFP-positive cells growing into the Integra(r) were detected. These studies demonstrate the feasibility of using Integra(r) as a scaffolding, or matrix, for the delivery of stem cells to burn wounds as well as the utility of bioluminescence for monitoring in vivo cellular tracking of stably transfected ESC cells. PMID- 22540140 TI - Metal-graphene-metal sandwich contacts for enhanced interface bonding and work function control. AB - Only a small fraction of all available metals has been used as electrode materials for carbon-based devices due to metal-graphene interface debonding problems. We report an enhancement of the bonding energy of weakly interacting metals by using a metal-graphene-metal sandwich geometry, without sacrificing the intrinsic pi-electron dispersions of graphene that is usually undermined by strong metal-graphene interface hybridization. This sandwich structure further makes it possible to effectively tune the doping of graphene with an appropriate selection of metals. Density functional theory calculations reveal that the strengthening of the interface interaction is ascribed to an enhancement of interface dipole-dipole interactions. Raman scattering studies of metal-graphene copper sandwiches are used to validate the theoretically predicted tuning of graphene doping through sandwich structures. PMID- 22540141 TI - Vagus nerve stimulation in children with intractable epilepsy: a randomized controlled trial. AB - AIM: The aim of this study was to evaluate the effects of vagus nerve stimulation (VNS) in children with intractable epilepsy on seizure frequency and severity and in terms of tolerability and safety. METHOD: In this study, the first randomized active controlled trial of its kind in children, 41 children (23 males; 18 females; mean age at implantation 11y 2mo, SD 4y 2mo, range 3y 10mo-17y 8mo) were included. Thirty-five participants had localization-related epilepsy (25 symptomatic; 10 cryptogenic), while six participants had generalized epilepsy (four symptomatic; two idiopathic). During a baseline period of 12 weeks, seizure frequency and severity were recorded using seizure diaries and the adapted Chalfont Seizure Severity Scale (NHS3), after which the participants entered a blinded active controlled phase of 20 weeks. During this phase, half of the participants received high-output VNS (maximally 1.75mA) and the other half received low-output stimulation (0.25mA). Finally, all participants received high output stimulation for 19 weeks. For both phases, seizure frequency and severity were assessed as during the baseline period. Overall satisfaction and adverse events were assessed by semi-structured interviews. RESULTS: At the end of the randomized controlled blinded phase, seizure frequency reduction of 50% or more occurred in 16% of the high-output stimulation group and in 21% of the low-output stimulation group (p=1.00). There was no significant difference in the decrease in seizure severity between participants in the stimulation groups. Overall, VNS reduced seizure frequency by 50% or more in 26% of participants at the end of the add-on phase The overall seizure severity also improved (p<0.001). INTERPRETATION: VNS is a safe and well-tolerated adjunctive treatment of epilepsy in children. Our results suggest that the effect of VNS on seizure frequency in children is limited. However, the possible reduction in seizure severity and improvement in well-being makes this treatment worth considering in individual children with intractable epilepsy. PMID- 22540142 TI - The correlation between size of renal cell carcinoma and its histopathological characteristics: a single center study of 1867 renal cell carcinoma cases. AB - What's known on the subject? and What does the study add? We had known from former studies of RCC that the risks of high grade tumours increased with tumour size and probability of localized tumour decreased with tumour size increasing. Our study had provided large and detailed data about pathologic features of RCC. We also examined the exactly changing of probabilities of different subtypes with diameter increasing and evaluated the effects of hemorrhage, necrosis and cystic degeneration on pathologic subtypes. OBJECTIVE: * To investigate the correlation between tumour size and histopathological characteristics of renal cell carcinoma (RCC). PATIENTS AND METHODS: * A total of 1867 patients who underwent surgical operation between January 2002 and March 2010 due to RCC were included. According to 1997 WHO recommendation about Fuhrman nuclear grading of RCC which criteria we used, tumours were stratified by the largest pathologic diameter into 5 groups, the discrepancy of tumour grade between different groups and whether tumour size could predict histological subtype were analyzed. RESULTS: * The largest diameter (mean +/- sd) of G1, G2, and G3 tumours were 3.27 +/- 1.46 cm,4.87 +/- 2.23 cm, and 7.39 +/- 3.11 cm, respectively. The percentage of extracapsular extension tumours in 2 cm or less, 2.1 and 4.0 cm, 4.1 to 7 cm, 7.1 to 10 cm, and more than 10 cm group were 0.5%, 4.3%, 19.8%, 57.9%, and 91.9%, respectively. The distribution of G1 tumours shows a decreasing trend with the diameter becoming larger, while the G3 tumours shows an opposite trend (P < 0.05). Logistic regression analysis predicted that the odds of papillary, chromophobe, and other types vs clear cell decreased with increase in tumour size. If the tumour was complicated with hemorrhage or necrosis, the chance of being chromophobe was higher, while the probability of being papillary and chromophobe decreased when a tumour with cystic degeneration. CONCLUSION: * There was a significant correlation between tumour size and tumour grade and stage; Larger tumours were prone to have higher grade and stage, and the probability of being clear cell carcinoma grew higher as the tumour size increased. PMID- 22540143 TI - Synthesis of monodisperse, hierarchically mesoporous, silica microspheres embedded with magnetic nanoparticles. AB - We report a preparation method for the synthesis of monodisperse magnetic polymer/silica hybrid microspheres using polymer microspheres incorporated with magnetic nanoparticles as a novel template. Monodisperse, hierarchically mesoporous, silica microspheres embedded with magnetic nanoparticles were successfully fabricated after the calcination of the hybrid microspheres. The magnetic nanoparticles were encapsulated in silica and distributed over the whole area of the porous microspheres without leakage. The resulting inorganic materials possess highly useful properties such as high magnetic nanoparticle loading, high surface area, and large pore volumes. The hierarchically mesoporous magnetic silica microspheres resulted in a high bovine serum albumin (BSA) protein adsorption capacity (260 mg/g) and a fast adsorption rate (reaching equilibrium with 8 h). PMID- 22540144 TI - Rational synthesis and characterization of the mixed-metal organometallic polyoxometalates [Cp*Mo(x)W(6-x)O18]- (x = 0, 1, 5, 6). AB - The reaction between the oxometallic complexes Cp*(2)M(2)O(5) and Na(2)M'O(4) (M, M' = Mo, W) in a 1:10 molar ratio in an acidic aqueous medium constitutes a mild and selective entry into the anionic Lindqvist-type hexametallic organometallic mixed oxides [Cp*Mo(x)W(6-x)O(18)](-) [x = 6 (1), 5 (2), 1 (3), 0 (4)]. All of these compounds have been isolated as salts of nBu(4)N(+) (a), nBu(4)P(+) (b), and Ph(4)P(+) (c) cations and two of them (1 and 3) also with the n butylpyridinium (nBuPyr(+), d) cation. The compounds have been characterized by elemental analyses, thermogravimetric analyses, electrospray mass spectrometry, and IR spectroscopy. The molecular identity and geometry of compounds 1c, 2a, and 2c have been confirmed by single-crystal X-ray diffraction. Density functional theory calculations on models obtained by replacing Cp* with Cp (I-IV) have provided information on the assignment of the terminal M?O and bridging M-O-M vibrations. PMID- 22540145 TI - 5'-Ectonucleotidase-knockout mice lack non-REM sleep responses to sleep deprivation. AB - Adenosine and extracellular adenosine triphosphate (ATP) have multiple physiological central nervous system actions including regulation of cerebral blood flow, inflammation and sleep. However, their exact sleep regulatory mechanisms remain unknown. Extracellular ATP and adenosine diphosphate are converted to adenosine monophosphate (AMP) by the enzyme ectonucleoside triphosphate diphosphohydrolase 1, also known as CD39, and extracellular AMP is in turn converted to adenosine by the 5'-ectonuleotidase enzyme CD73. We investigated the role of CD73 in sleep regulation. Duration of spontaneous non rapid eye movement sleep (NREMS) was greater in CD73-knockout (KO) mice than in C57BL/6 controls whether determined in our laboratory or by others. After sleep deprivation (SD), NREMS was enhanced in controls but not CD73-KO mice. Interleukin-1 beta (IL1beta) enhanced NREMS in both strains, indicating that the CD73-KO mice were capable of sleep responses. Electroencephalographic power spectra during NREMS in the 1.0-2.5 Hz frequency range was significantly enhanced after SD in both CD73-KO and WT mice; the increases were significantly greater in the WT mice than in the CD73-KO mice. Rapid eye movement sleep did not differ between strains in any of the experimental conditions. With the exception of CD73 mRNA, the effects of SD on various adenosine-related mRNAs were small and similar in the two strains. These data suggest that sleep is regulated, in part, by extracellular adenosine derived from the actions of CD73. PMID- 22540146 TI - Structural, physical, and chemical modifications induced by microwave heating on native agar-like galactans. AB - Native agars from Gracilaria vermiculophylla produced in sustainable aquaculture systems (IMTA) were extracted under conventional (TWE) and microwave (MAE) heating. The optimal extracts from both processes were compared in terms of their properties. The agars' structure was further investigated through Fourier transform infrared and NMR spectroscopy. Both samples showed a regular structure with an identical backbone, beta-d-galactose (G) and 3,6-anhydro-alpha-l galactose (LA) units; a considerable degree of methylation was found at C6 of the G units and, to a lesser extent, at C2 of the LA residues. The methylation degree in the G units was lower for MAE(opt) agar; the sulfate content was also reduced. MAE led to higher agar recoveries with drastic extraction time and solvent volume reductions. Two times lower values of [eta] and M(v) obtained for the MAE(opt) sample indicate substantial depolymerization of the polysaccharide backbone; this was reflected in its gelling properties; yet it was clearly appropriate for commercial application in soft-texture food products. PMID- 22540147 TI - Characterization of the heparin-binding site of the protein z-dependent protease inhibitor. AB - High-molecular weight heparins promote the protein Z-dependent protease inhibitor (ZPI) inhibition of factors Xa (FXa) and XIa (FXIa) by a template mechanism. To map the heparin-binding site of ZPI, the role of basic residues of the D-helix (residues Lys-113, Lys-116, and Lys-125) in the interaction with heparin was evaluated by either substituting these residues with Ala (ZPI-3A) or replacing the D-helix with the corresponding loop of the non-heparin-binding serpin alpha(1)-proteinase inhibitor (ZPI-D-helix(alpha1-PI)). Furthermore, both the C helix (contains two basic residues, Lys-104 and Arg-105) and the D-helix of ZPI were substituted with the corresponding loops of alpha(1)-proteinase inhibitor (ZPI-CD-helix(alpha1-PI)). All mutants exhibited near normal reactivity with FXa and FXIa in the absence of cofactors and in the presence of protein Z and membrane cofactors. By contrast, the mutants interacted with heparin with a lower affinity and the ~48-fold heparin-mediated enhancement in the rate of FXa inhibition by ZPI was reduced to ~30-fold for ZPI-3A, ~15-fold for ZPI-D helix(alpha1-PI), and ~8-fold for ZPI-CD-helix(alpha1-PI). Consistent with a template mechanism for heparin cofactor action, ZPI-CD-helix(alpha1-PI) inhibition of a FXa mutant containing a mutation in the heparin-binding site (FXa R240A) was minimally affected by heparin. A significant decrease (~2-5-fold) in the heparin template effect was also observed for the inhibition of FXIa by ZPI mutants. Interestingly, ZPI derivatives exhibited a markedly elevated stoichiometry of inhibition with FXIa in the absence of heparin. These results suggest that basic residues of both helices C and D of ZPI interact with heparin to modulate the inhibitory function of the serpin. PMID- 22540149 TI - EUCAST technical note on Aspergillus and amphotericin B, itraconazole, and posaconazole. AB - The European Committee on Antimicrobial Susceptibility Testing Subcommittee on Antifungal Susceptibility Testing (EUCAST-AFST) has determined breakpoints for amphotericin B, itraconazole and posaconazole for Aspergillus species. This Technical Note is based on the EUCAST amphotericin B, itraconazole and posaconazole rationale documents (available on the EUCAST website: http://www.eucast.org/antifungal_susceptibility_testing_afst/rationale_documents_ or_antifungals/). The amphotericin B and itraconazole breakpoints are based on epidemiological cut-off values and clinical experience. The posaconazole breakpoints are also based on pharmacokinetic and pharmacodynamic data. Breakpoints will be reviewed regularly or when new data emerge. PMID- 22540150 TI - Is it necessary to place a Double J catheter after laparoscopic ureterolithotomy? A four-year experience. AB - PURPOSE: To assess the necessity of placing a ureteral stent after transperitoneal laparoscopic ureterolithotomy (TPLU). PATIENTS AND METHODS: In the period from May 2006 to November 2010, 46 patients underwent TPLU. There were 13 females and 33 males. All patients had an impacted stone larger than 1.5 cm in the upper and middle parts of the ureter. TPLU was performed as either a primary therapy or as a salvage therapy in patients in whom another treatment had failed. The exclusion criteria were pregnancy, a body mass index more than 35, and patients with abnormal results on coagulative tests. In all cases, after removing the stone, the ureter was sutured. In the first 23 patients, no ureteral catheter was placed, but in the second 23 patients, a Double J catheter was inserted through the ureter. RESULTS: In one case, the stone was pushed back. The stone free rate was 97.8%. There were four cases of prolonged urinary leakage after the surgery. All of them were in the group in whose members the Double J catheter had not been placed. The problem was resolved in one patient spontaneously after 4 days, but for the other three patients, a Double J catheter was placed and the leakage was stopped in 24 hours. There was no case of urinary leakage in the second group of patients with a placed Double J catheter. CONCLUSION: Placing a Double J catheter during surgery does not increase the time of operation and may play a role in prevention of urinary extravasation after laparoscopic ureterolithotomy. PMID- 22540148 TI - Aire promotes the self-renewal of embryonic stem cells through Lin28. AB - Abstract Autoimmune regulator (Aire) is one of the most well-characterized molecules in autoimmunity, but its function outside the immune system is largely unknown. The recent discovery of Aire expression in stem cells and early embryonic cells and its function in the self-renewal of embryonic stem (ES) cells highlight the importance of Aire in these cells. In this study, we present evidence that Aire promotes the expression of the pluripotent factor Lin28 and the self-renewal of ES cells. We presented the first evidence that the let-7 microRNA family contributed to the self-renewal promoting effect of Aire on ES cells. Moreover, we showed that Aire and Lin28 are co-expressed in the genital ridge, oocytes, and cleavage-stage embryos, and the expression level of Lin28 is correlated with the expression level of Aire. Although it is widely considered to be a promiscuous gene expression activator, these results indicated that Aire promotes the self-renewal of ES cells through a specific pathway (i.e., the activation of Lin28 and the inhibition of the let-7 microRNA family). The correlation between Aire and Lin28 expression in germ cells and early embryos indicated an in vivo function for Aire in toti- and pluripotent stem cells. This study presents the first molecular pathway that incorporates Aire into the pluripotency network. Moreover, it presents the first evidence that microRNAs contribute to the regulatory function of Aire and highlights a novel function of Aire in stem cell biology and reproduction. These functions reveal novel perspectives for studying the molecular mechanisms behind the establishment and sustenance of pluripotent identity. PMID- 22540151 TI - Cutaneous side effects of inhibitors of the RAS/RAF/MEK/ERK signalling pathway and their management. AB - Mutations in genes encoding for proteins along the RAS-RAF-MEK-ERK pathway have been detected in a variety of tumor entities, including malignant melanoma, thyroid, colonic and ovarian carcinomas, and some sarcomas. Thus, a number of inhibitors of this pathway have been developed, whose antitumor potential is currently being assessed in different clinical trials. Up to now one drug of this category (vemurafenib) has been approved by the FDA and the European Commission for late-stage melanoma. Although these new targeted anticancer therapies are generally considered to be safe and well tolerated, certain toxicities have been attributed to them, with cutaneous side effects being perhaps the most frequent amongst them. Based on results of clinical trials and on case series, a distinct profile of cutaneous toxicity has been observed, which is similar to that of EGFR and multikinase inhibitors. As exanthema, palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, xerosis, pruritus, photosensitivity, and paronychia, can be controlled in most cases with common conservative modalities, special attention should be given to the early detection of epithelial skin tumors (mainly keratoakanthomas) that can be induced during therapy with these agents. This report reviews all current published data on cutaneous side effects of RAS RAF-MEK-ERK pathway inhibitors, and attempts to provide the clinician with clear hints for their management. PMID- 22540152 TI - Genome-wide linkage analyses identify Hfhl1 and Hfhl3 with frequency-specific effects on the hearing spectrum of NIH Swiss mice. AB - BACKGROUND: The mammalian cochlea receives and analyzes sound at specific places along the cochlea coil, commonly referred to as the tonotopic map. Although much is known about the cell-level molecular defects responsible for severe hearing loss, the genetics responsible for less severe and frequency-specific hearing loss remains unclear. We recently identified quantitative trait loci (QTLs) Hfhl1 and Hfhl2 that affect high-frequency hearing loss in NIH Swiss mice. Here we used 2f1-f2 distortion product otoacoustic emissions (DPOAE) measurements to refine the hearing loss phenotype. We crossed the high frequency hearing loss (HFHL) line of NIH Swiss mice to three different inbred strains and performed linkage analysis on the DPOAE data obtained from the second-generation populations. RESULTS: We identified a QTL of moderate effect on chromosome 7 that affected 2f1 f2 emissions intensities (Hfhl1), confirming the results of our previous study that used auditory brainstem response (ABR) thresholds to identify QTLs affecting HFHL. We also identified a novel significant QTL on chromosome 9 (Hfhl3) with moderate effects on 2f1-f2 emissions intensities. By partitioning the DPOAE data into frequency subsets, we determined that Hfhl1 and Hfhl3 affect hearing primarily at frequencies above 24 kHz and 35 kHz, respectively. Furthermore, we uncovered additional QTLs with small effects on isolated portions of the DPOAE spectrum. CONCLUSIONS: This study identifies QTLs with effects that are isolated to limited portions of the frequency map. Our results support the hypothesis that frequency-specific hearing loss results from variation in gene activity along the cochlear partition and suggest a strategy for creating a map of cochlear genes that influence differences in hearing sensitivity and/or vulnerability in restricted portions of the cochlea. PMID- 22540154 TI - Enantioselective synthesis of tetrahydroisoquinolines via iridium-catalyzed intramolecular Friedel-Crafts-type allylic alkylation of phenols. AB - An efficient iridium-catalyzed intramolecular Friedel-Crafts-type allylic alkylation reaction of phenols was developed, affording tetrahydroisoquinolines with moderate to excellent yields, enantioselectivity, and good regioselectivity. PMID- 22540155 TI - Is lithium an effective adjunct therapy for radioiodine therapy for hyperthyroidism? PMID- 22540153 TI - T1 mapping of the myocardium: intra-individual assessment of post-contrast T1 time evolution and extracellular volume fraction at 3T for Gd-DTPA and Gd-BOPTA. AB - PURPOSE: Myocardial T1 relaxation time (T1 time) and extracellular volume fraction (ECV) are altered in patients with diffuse myocardial fibrosis. The purpose of this study was to perform an intra-individual assessment of normal T1 time and ECV for two different contrast agents. METHODS: A modified Look-Locker Inversion Recovery (MOLLI) sequence was acquired at 3 T in 24 healthy subjects (8 men; 28 +/- 6 years) at mid-ventricular short axis pre-contrast and every 5 min between 5-45 min after injection of a bolus of 0.15 mmol/kg gadopentetate dimeglumine (Gd-DTPA; Magnevist(r)) (exam 1) and 0.1 mmol/kg gadobenate dimeglumine (Gd-BOPTA; Multihance(r)) (exam 2) during two separate scanning sessions. T1 times were measured in myocardium and blood on generated T1 maps. ECVs were calculated as DeltaR1 myocardium/DeltaR1 blood*1-hematocrit. RESULTS: Mean pre-contrast T1 relaxation times for myocardium and blood were similar for both the first and second CMR exam (p > 0.5). Overall mean post-contrast myocardial T1 time was 15 +/- 2 ms (2.5 +/- 0.7%) shorter for Gd-DTPA at 0.15 mmol/kg compared to Gd-BOPTA at 0.1 mmol/kg (p < 0.01) while there was no significant difference for T1 time of blood pool (p > 0.05). Between 5 and 45 minutes after contrast injection, mean ECV values increased linearly with time for both contrast agents from 0.27 +/- 0.03 to 0.30 +/- 0.03 (p < 0.0001). Mean ECV values were slightly higher (by 0.01, p < 0.05) for Gd-DTPA compared to Gd BOPTA. Inter-individual variation of ECV was higher (CV 8.7% [exam 1, Gd-DTPA] and 9.4% [exam 2, Gd-BOPTA], respectively) compared to variation of pre-contrast myocardial T1 relaxation time (CV 4.5% [exam 1] and 3.0% [exam 2], respectively). ECV with Gd-DTPA was highly correlated to ECV by Gd-BOPTA (r = 0.803; p < 0.0001). CONCLUSION: In comparison to pre-contrast myocardial T1 relaxation time, variation in ECV values of normal subjects is larger. However, absolute differences in ECV between Gd-DTPA and Gd-BOPTA were small and rank correlation was high. There is a small and linear increase in ECV over time, therefore ideally images should be acquired at the same delay after contrast injection. PMID- 22540156 TI - Utility of corneal confocal microscopy for assessing mild diabetic neuropathy: baseline findings of the LANDMark study. AB - BACKGROUND: For those in the field of managing diabetic complications, the accurate diagnosis and monitoring of diabetic peripheral neuropathy (DPN) continues to be a challenge. Assessment of sub-basal corneal nerve morphology has recently shown promise as a novel ophthalmic marker for the detection of DPN. METHODS: Two hundred and thirty-one individuals with diabetes with predominantly mild or no neuropathy and 61 controls underwent evaluation of diabetic neuropathy symptom score, neuropathy disability score, testing with 10 g monofilament, quantitative sensory testing (warm, cold, vibration detection) and nerve conduction studies. Corneal nerve fibre length, branch density and tortuosity were measured using corneal confocal microscopy. Differences in corneal nerve morphology between individuals with and without DPN and controls were investigated using analysis of variance and correlations were determined between corneal morphology and established tests of, and risk factors for, DPN. RESULTS: Corneal nerve fibre length was significantly reduced in diabetic individuals with mild DPN compared with both controls (p < 0.001) and diabetic individuals without DPN (p = 0.012). Corneal nerve branch density was significantly reduced in individuals with mild DPN compared with controls (p = 0.032). Corneal nerve fibre tortuosity did not show significant differences. Corneal nerve fibre length and corneal nerve branch density showed modest correlations to most measures of neuropathy, with the strongest correlations to nerve conduction study parameters (r = 0.15 to 0.25). Corneal nerve fibre tortuosity showed only a weak correlation to the vibration detection threshold. Corneal nerve fibre length was inversely correlated to glycated haemoglobin (r = -0.24) and duration of diabetes (r = 0.20). CONCLUSION: Assessment of corneal nerve morphology is a non-invasive, rapid test capable of showing differences between individuals with and without DPN. Corneal nerve fibre length shows the strongest associations with other diagnostic tests of neuropathy and with established risk factors for neuropathy. PMID- 22540157 TI - The Australian community overwhelmingly approves IVF to treat subfertility, with increasing support over three decades. AB - Fifteen Australia-wide interview surveys between July 1981 and February 2011 on the community's attitudes to in vitro fertilisation (IVF) were carried out as part of regular Morgan polls. Each survey involved between 650 and 1000 respondents in urban and rural locations. The proportion of respondents who 'approved' or 'disapproved' of various aspects of IVF treatment were determined. Support for IVF to help infertile married couples increased from 77% in 1981 to 91% in 2011. Approval for IVF procedures being supported by Medicare funding rose from 70% in 1981 to 79% in 2000 and was unchanged in 2011. There has also been a marked increase in the support for single women and lesbians using donor sperm. PMID- 22540159 TI - Decreased aztreonam susceptibility among Pseudomonas aeruginosa isolates from hospital effluent treatment system and clinical samples. AB - The aim of this study was to evaluate the antimicrobial resistance patterns of Pseudomonas aeruginosa isolates from hospital wastewater treatment system (HWTS) and clinical specimens in a hospital of Rio de Janeiro city, Brazil. Forty-three isolates obtained from four of the five steps of the HWTS (n = 27) and clinical samples (n = 16) from patients were analyzed regarding their susceptibility profiles to 12 antibiotics. Clinical isolates exhibited higher resistance profiles to antibiotics than wastewater isolates. However, out of 27 isolates from sewage, 62.9% showed decreased susceptibility to aztreonam while 50% of clinical isolates were resistant to this antibiotic. Isolates were not detected at the chlorination stage but they were obtained from the following stage of the treatment revealing the capacity of regrowth after chlorinated sewage effluent. To our knowledge, this is the first study reporting decreased aztreonam susceptibility among P. aeruginosa isolates from a hospital wastewater treatment system. Further investigations are being conducted by our laboratory including a larger sampling program in order to obtain more data. PMID- 22540158 TI - Temporal trends of sulphadoxine-pyrimethamine (SP) drug-resistance molecular markers in Plasmodium falciparum parasites from pregnant women in western Kenya. AB - BACKGROUND: Resistance to sulphadoxine-pyrimethamine (SP) in Plasmodium falciparum parasites is associated with mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes and has spread worldwide. SP remains the recommended drug for intermittent preventive treatment for malaria in pregnancy (IPTp) and information on population prevalence of the SP resistance molecular markers in pregnant women is limited. METHODS: Temporal trends of SP resistance molecular markers were investigated in 489 parasite samples collected from pregnant women at delivery from three different observational studies between 1996 and 2009 in Kenya, where SP was adopted for both IPTp and case treatment policies in 1998. Using real-time polymerase chain reaction, pyrosequencing and direct sequencing, 10 single-nucleotide polymorphisms (SNPs) of SP resistance molecular markers were assayed. RESULTS: The prevalence of quintuple mutant (dhfr N51I/C59R/S108N and dhps A437G/K540E combined genotype) increased from 7% in the first study (1996-2000) to 88% in the third study (2008 2009). When further stratified by sample collection year and adoption of IPTp policy, the prevalence of the quintuple mutant increased from 2.4% in 1998 to 44.4% three years after IPTp policy adoption, seemingly in parallel with the increase in percentage of SP use in pregnancy. However, in the 1996-2000 study, more mutations in the combined dhfr/dhps genotype were associated with SP use during pregnancy only in univariable analysis and no associations were detected in the 2002-2008 and 2008-2009 studies. In addition, in the 2008-2009 study, 5.3% of the parasite samples carried the dhps triple mutant (A437G/K540E/A581G). There were no differences in the prevalence of SP mutant genotypes between the parasite samples from HIV + and HIV- women over time and between paired peripheral and placental samples. CONCLUSIONS: There was a significant increase in dhfr/dhps quintuple mutant and the emergence of new genotype containing dhps 581 in the parasites from pregnant women in western Kenya over 13 years. IPTp adoption and SP use in pregnancy only played a minor role in the increased drug-resistant parasites in the pregnant women over time. Most likely, other major factors, such as the high prevalence of resistant parasites selected by the use of SP for case management in large non-pregnant population, might have contributed to the temporally increased prevalence of SP resistant parasites in pregnant women. Further investigations are needed to determine the linkage between SP drug resistance markers and efficacy of IPTp-SP. PMID- 22540160 TI - Cerebrospinal fluid levels of high-mobility group box 1 and cytochrome C predict outcome after pediatric traumatic brain injury. AB - High-mobility group box 1 (HMGB1) is a ubiquitous nuclear protein that is passively released from damaged and necrotic cells, and actively released from immune cells. In contrast, cytochrome c is released from mitochondria in apoptotic cells, and is considered a reliable biomarker of apoptosis. Thus, HMGB1 and cytochrome c may in part reflect the degree of necrosis and apoptosis present after traumatic brain injury (TBI), where both are felt to contribute to cell death and neurological morbidity. Ventricular cerebrospinal fluid (CSF) was obtained from children admitted to the intensive care unit (ICU) after TBI (n=37). CSF levels of HMGB1 and cytochrome c were determined at four time intervals (0-24 h, 25-48 h, 49-72 h, and>72 h after injury) using enzyme-linked immunosorbent assay (ELISA). Lumbar CSF from children without TBI served as controls (n=12). CSF HMGB1 levels were: control=1.78+/-0.29, 0-24 h=5.73+/-1.45, 25-48 h=5.16+/-1.73, 49-72 h=4.13+/-0.75,>72 h=3.80+/-0.90 ng/mL (mean+/-SEM). Peak HMGB1 levels were inversely and independently associated with favorable Glasgow Outcome Scale (GOS) scores at 6 mo (0.49 [0.24-0.97]; OR [5-95% CI]). CSF cytochrome c levels were: control=0.37+/-0.10, 0-24 h=0.69+/-0.15, 25-48 h=0.82+/ 0.48, 49-72 h=1.52+/-1.08,>72 h=1.38+/-1.02 ng/mL (mean+/-SEM). Peak cytochrome c levels were independently associated with abusive head trauma (AHT; 24.29 [1.77 334.03]) and inversely and independently associated with favorable GOS scores (0.42 [0.18-0.99]). In conclusion, increased CSF levels of HMGB1 and cytochrome c were associated with poor outcome after TBI in infants and children. These data are also consistent with the designation of HMGB1 as a "danger signal." Distinctly increased CSF cytochrome c levels in infants and children with AHT and poor outcome suggests that apoptosis may play an important role in this unique patient population. PMID- 22540161 TI - Antidote strategies to reverse anticoagulation with TB-402, a long-acting partial inhibitor of factor VIII. AB - BACKGROUND: TB-402 is a partially inhibiting antibody of factor VIII that is under development as a long-acting anticoagulant. PATIENTS AND METHODS: The reversibility of FVIII inhibition by TB-402 was evaluated in vitro after spiking with recombinant human FVIII (rhFVIII), human plasma-derived FVIII (hpdFVIII), recombinant activated human FVII (rhFVIIa), FVIII inhibitor bypassing activity (FEIBA), and prothrombin complex concentrate (PCC). Twelve subjects were randomized to placebo or 35 or 70 IU kg(-1) rhFVIII 48 h after a single dose of 620 MUg kg(-1) TB-402. TB-402 concentrations, FVIII activity (FVIII:C), activated partial thromboplastin time (APTT) and thrombin generation were measured over a period of 8 weeks. RESULTS: In spiked samples, TB-402 inhibited FVIII:C by 30%, prolonged APTT by 4.5 s, and reduced the peak height in the thrombin generation assay to 56% +/- 13% of the control value. In the presence of 10 MUg mL(-1) TB 402, rhFVIII restored FVIII:C and APTT to the values obtained in the absence of TB-402. The inhibitory effect of TB-402 on thrombin generation was entirely reversed by rhFVIII, hpdFVIII, rhFVIIa, FEIBA, and PCC. In men, the mean half life (t(1/2) ) of TB-402 was 14.2 days. TB-402 lowered the endogenous thrombin potential by 23% for ~ 35 days. Infusion of 35 IU kg(-1) rhFVIII had a marginal effect, whereas 70 IU kg(-1) rhFVIII restored FVIII:C, reduced APTT back to baseline for 9 h, and restored thrombin generation for ~ 3 h. CONCLUSIONS: TB-402 resulted in a stable long-term anticoagulant effect. rhFVIII and other procoagulants counteracted the effect of TB-402 temporarily, and may be effective antidotes for future clinical practice. PMID- 22540163 TI - Column theme: 50th year tribute to modeling: past, current, and future. PMID- 22540162 TI - Using thioamides to site-specifically interrogate the dynamics of hydrogen bond formation in beta-sheet folding. AB - Thioamides are sterically almost identical to their oxoamide counterparts, but they are weaker hydrogen bond acceptors. Therefore, thioamide amino acids are excellent candidates for perturbing the energetics of backbone-backbone H-bonds in proteins and hence should be useful in elucidating protein folding mechanisms in a site-specific manner. Herein, we validate this approach by applying it to probe the dynamic role of interstrand H-bond formation in the folding kinetics of a well-studied beta-hairpin, tryptophan zipper. Our results show that reducing the strength of the peptide's backbone-backbone H-bonds, except the one directly next to the beta-turn, does not change the folding rate, suggesting that most native interstrand H-bonds in beta-hairpins are formed only after the folding transition state. PMID- 22540164 TI - Modeling groundwater flow--the beginnings. PMID- 22540165 TI - The current state of modeling. PMID- 22540166 TI - Future of groundwater modeling. PMID- 22540167 TI - Health-economic review of zoledronic acid for the management of skeletal-related events in bone-metastatic prostate cancer. AB - Zoledronic acid is the only bisphosphonate approved for the prevention or delay of skeletal-related events in patients with bone metastases secondary to prostate cancer. Recently, the US FDA and the EMA approved denosumab (a fully human monoclonal antibody) to treat skeletal-related events in bone-metastatic prostate cancer. This article summarizes the cost-effectiveness literature pertaining to these two agents when used in the prevention of skeletal-related events secondary to malignancy. Zoledronic acid (and denosumab in comparison with zoledronic acid) have been found to be cost effective and cost ineffective depending on the analytical perspective and model parameters. PMID- 22540168 TI - Incidental durotomy after spinal surgery: a prospective study in an academic institution. AB - OBJECT: Incidental durotomies (IDs) are an unfortunate but anticipated potential complication of spinal surgery. The authors surveyed the frequency of IDs for a single spine surgeon and analyzed the major risk factors as well as the impact on long-term patient outcomes. METHODS: The authors conducted a prospective review of elective spinal surgeries performed over a 15-year period. Any surgery involving peripheral nerve only, intradural procedures, or dural tears due to trauma were excluded from analysis. The incidence of ID was categorized by surgery type including primary surgery, revision surgery, and so forth. Incidence of ID was also examined in the context of years of physician experience and training. Furthermore, the incidence and types of sequelae were examined in patients with an ID. RESULTS: Among 3000 elective spinal surgery cases, 3.5% (104) had an ID. The incidence of ID during minimally invasive procedures (3.3%) was similar, but no patients experienced long-term sequelae. The incidence of ID during revision surgery (6.5%) was higher. There was a marked difference in incidence between cervical (1.3%) and thoracolumbar (5.1%) cases. The incidence was lower for cases involving instrumentation (2.4%). When physician training was examined, residents were responsible for 49% of all IDs, whereas fellows were responsible for 26% and the attending for 25%. Among all of the cases that involved an ID, 7.7% of patients went on to experience a neurological deficit as compared with 1.5% of those without an ID. The overall failure rate of dural repair was 6.9%, and failure was almost 3 times higher (13%) in revision surgery as compared with a primary procedure (5%). CONCLUSIONS: The authors established a reliable baseline incidence for durotomy after spine surgery: 3.5%. They also identified risk factors that can increase the likelihood of a durotomy, including location of the spinal procedure, type of procedure performed, and the implementation of a new procedure. The years of physician training or resident experience did not appear to be a major risk for ID. PMID- 22540169 TI - Three-dimensional measurement of intervertebral range of motion in ossification of the posterior longitudinal ligament: are there mobile segments in the continuous type? AB - OBJECT: In this paper, the authors' goals were to determine the extent of the effect of continuous-type ossification of the posterior longitudinal ligament (OPLL) of the cervical spine on intervertebral range of motion (ROM) and to examine the relationship between the 3D morphology of OPLL and intervertebral ROM. METHODS: The authors evaluated 5 intervertebral segments in each of 20 patients (11 men and 9 women) with continuous-type OPLL, for a total of 100 intervertebral segments, using functional CT in anteroposterior (AP) flexion and right and left axial rotation. Three-dimensional kinematics were evaluated using the voxel-based registration method. Ossification was classified on the basis of 3D kinematics and morphology. RESULTS: The authors found 49 ossifications that were obviously of the continuous type. They were divided into 2 types: 1) bridging (13 instances), with thick, continuous ossification of the anterior or posterior longitudinal ligament bridging intervertebral segments and with an ROM of 0.3 degrees in AP flexion and 0.2 degrees in rotation; and 2) nonbridging (36 instances), with a minute gap in the ossification itself or between the ossification and vertebra and with an ROM of 4.9 degrees in AP flexion and 4.0 degrees in rotation. There were 8 stalagmite-type ossifications in the nonbridging group that had the unique kinematics of restricted AP flexion and normal axial rotation. CONCLUSIONS: The authors' findings indicate that most continuous-type ossifications that are categorized using the conventional radiographic classification system have mobile segments. The discrimination between bridging and nonbridging on CT scans can be a useful predictive index for dynamic factors. PMID- 22540170 TI - Is congenital bony stenosis of the cervical spine associated with lumbar spine stenosis? An anatomical study of 1072 human cadaveric specimens. AB - OBJECT: Congenital cervical and lumbar stenosis occurs when the bony anatomy of the spinal canal is smaller than expected, predisposing an individual to symptomatic neural compression. While tandem stenosis is known to occur in 5%-25% of individuals, it is not known whether this relationship is due to an increased risk of degenerative disease in these individuals or whether this finding is due to the tandem presence of a congenitally small cervical and lumbar canal. The purpose of the present study was to determine if the presence of congenital cervical stenosis is associated with congenital lumbar stenosis. METHODS: One thousand seventy-two adult skeletal specimens from the Hamann-Todd Collection in the Cleveland Museum of Natural History were selected. The canal area at each level was calculated using a formula that was verified by computerized measurements. Values that were 2 standard deviations below the mean were considered to represent congenitally stenotic regions. Linear regression analysis was used to determine the association between the sum of canal areas at all levels in the cervical and lumbar spine. Logistic regression was used to calculate odds ratios for congenital stenosis in one area if congenital stenosis was present in the other. RESULTS: A positive association was found between the additive area of all cervical (that is, the sum of C3-7) and lumbar (that is, the sum of L1-5) levels (p < 0.01). A positive association was also found between the number of cervical and lumbar levels affected by congenital stenosis (p < 0.01). Logistic regression also demonstrated a significant association between congenital stenosis in the cervical and lumbar spine, with an odds ratio of 0.2 (p < 0.05). CONCLUSIONS: Based on the authors' findings in a large population of adult skeletal specimens, it appears that congenital stenosis of the cervical spine is associated with congenital stenosis of the lumbar spine. Thus, the presence of tandem stenosis appears to be, at least in part, related to the tandem presence of a congenitally small cervical and lumbar canal. PMID- 22540172 TI - No autoimmune safety signal after vaccination with quadrivalent HPV vaccine Gardasil? PMID- 22540171 TI - Sagittal spinopelvic parameters in children with achondroplasia: identification of 2 distinct groups. AB - OBJECT: Spinopelvic parameters in children with achondroplasia have not been described. Because they observed a unique sagittal spinopelvic phenotype in some achondroplastic children with very horizontal sacrums, the authors sought to quantify the spinopelvic parameters in a pediatric patient population. METHODS: A retrospective review was performed to identify all children (age range 1 month-10 years) with a diagnosis of achondroplasia between 2004 and 2009. Clinical and radiographic data were analyzed for age, sex, lumbar lordosis (LL), thoracic kyphosis (TK), thoracolumbar kyphosis (TLK), sacral slope (SS), pelvic tilt (PT), and pelvic incidence (PI). Differences among these variables were analyzed using a 2-tailed, unpaired Student t-test. RESULTS: Forty children, 23 males and 17 females, with achondroplasia were identified during the study period. The mean age was 2.6 years. Two groups of patients were identified based on PT (that is, negative or positive tilt and horizontal or not horizontal sacrum). A negative PT was identified in all children with an extremely horizontal sacrum. Seventeen children had a negative PT (mean -16.6 degrees ), and the mean parameters in this group were 65.4 degrees for LL, 31.7 degrees for TLK, 18.5 degrees for TK, 43.3 degrees for SS, and 26.4 degrees for PI. Twenty-three children had a positive PT (mean 17.9 degrees ), and the mean parameters in this group were 53.4 degrees for LL, 41.5 degrees for TLK, 9.6 degrees for TK, 30.8 degrees for SS, and 43.8 degrees for PI. A statistically significant difference was observed for LL (p = 0.01), TLK (p = 0.05), SS (p = 0.006), PT (p = 0.006), and PI (0.0002). CONCLUSIONS: Spinopelvic parameters in achondroplasia are potentially dichotomous. The future implications of this observation are not known and will need to be explored in future long-term studies that follow pediatric patients with achondroplasia through adulthood. PMID- 22540173 TI - Twisted imide bond in noncyclic imides. Synthesis and structural and vibrational properties of N,N-bis(furan-2-carbonyl)-4-chloroaniline. AB - A novel imide compound (C(16)H(10)ClNO(4)) was synthesized in a single step by the reaction of 2-furoic acid with 4-chloroaniline in a 2:1 molar ratio using carbonyldiimidazole (CDI) in dry THF. The structure was supported by spectroscopic and elemental analyses and the single-crystal X-ray diffraction data. Crystallographic studies revealed that the compound crystallized in a monoclinic system with space group P2(1)/c and unit cell dimensions a = 12.2575(5) A, b = 7.7596(2) A, c = 15.0234(7) A, alpha = gamma = 90 degrees , beta = 92.771(4) degrees , V = 1427.25(10) A(3), Z = 4. The imide bond is twisted, and the O?C-N-C(O) units deviate significantly from planarity with dihedral angles around the imide group reaching ca. -150.3 degrees (C1-N1-C2-O21 = -148.8 degrees and C2-N1-C1-O11 = -151.9 degrees ). The nonplanarity of the imide moiety and the related conformational properties are discussed in a combined approach that includes the analysis of the vibrational spectra together with theoretical calculation methods, especially in terms of natural bond orbital (NBO) calculations. PMID- 22540174 TI - What's a proper push? The Valsalva manoeuvre revisited. AB - In daily practice, the Valsalva manoeuvre is used to assess pelvic organ prolapse, virtually always without standardisation of pressure. We undertook a study to determine maximum pressures reached and pressures required to obtain 80% of maximal pelvic organ descent, to investigate the need for such standardisation. Clinical data and ultrasound data sets of 75 women seen for urodynamic testing were reviewed retrospectively, with three Valsalva manoeuvres registered per patient. Maximum rectal pressures generated during Valsalva were 107 cm H (2) O on average (range, 45-190 cm H (2) O). Ninety-seven percent of all women managed to reach pressures >=60 cm H (2) O. On average, 80% of maximal bladder neck descent was reached at 56 cm H (2) O, 80% of maximal pelvic organ descent at 38 cm H (2) O. Our results imply that virtually all patients were able to generate pressures resulting in >=80% of maximal pelvic organ descent. This implies that standardisation of Valsalva pressures for prolapse assessment may be unnecessary. PMID- 22540176 TI - Pregnancy complicated by uterine sacculation due to a huge myoma. AB - Uterine sacculation is rare complication affecting the pregnant uterus, and is difficult to diagnose. Sacculation consists of a transitory pouch or sac-like structure caused by inverted uterine polarity. Vaginal delivery is difficult, and even cesarean section can be difficult because of peculiar risks associated with uterine sacculation. We report a pregnant patient with posterior sacculation due to a huge myoma in the lower anterior uterine segment. Sacculation, especially that complicated by a huge myoma, is very difficult to accurately diagnose and makes cesarean section surgery challenging. Because of the myoma in our present case, opening the lower uterine segment was impossible with cesarean section. The uterus was instead opened by corporeal vertical cesarean section. Myomectomy was not performed and the giant myoma thus remained. Postoperative assessment revealed the uterus to still be retroverted. The giant myoma was the cause of sacculation in this case. PMID- 22540177 TI - Absolute configuration for 1,n-glycols: a nonempirical approach to long-range stereochemical determination. AB - The absolute configurations of 1,n-glycols (n = 2-12, 16) bearing two chiral centers were rapidly determined via exciton-coupled circular dichroism (ECCD) using a tris(pentafluorophenyl)porphyrin (TPFP porphyrin) tweezer system in a nonempirical fashion devoid of chemical derivatization. A unique "side-on" approach of the porphyrin tweezer relative to the diol guest molecule is suggested as the mode of complexation. PMID- 22540178 TI - Making contact with microparticles. PMID- 22540175 TI - The anaemia of Plasmodium vivax malaria. AB - Plasmodium vivax threatens nearly half the world's population and is a significant impediment to achievement of the millennium development goals. It is an important, but incompletely understood, cause of anaemia. This review synthesizes current evidence on the epidemiology, pathogenesis, treatment and consequences of vivax-associated anaemia. Young children are at high risk of clinically significant and potentially severe vivax-associated anaemia, particularly in countries where transmission is intense and relapses are frequent. Despite reaching lower densities than Plasmodium falciparum, Plasmodium vivax causes similar absolute reduction in red blood cell mass because it results in proportionately greater removal of uninfected red blood cells. Severe vivax anaemia is associated with substantial indirect mortality and morbidity through impaired resilience to co-morbidities, obstetric complications and requirement for blood transfusion. Anaemia can be averted by early and effective anti malarial treatment. PMID- 22540179 TI - Important surgical considerations in the management of renal cell carcinoma (RCC) with inferior vena cava (IVC) tumour thrombus. AB - What's known on the subject? and What does the study add? Historically, the surgical management of renal tumours with intravascular tumour thrombus has been associated with high morbidity and mortality. In addition, few cases are treated, and typically at tertiary care referral centres, hence little is known and published about the ideal surgical management of such complex cases. The present comprehensive review details how a multidisciplinary surgical approach to renal tumours with intravascular tumour thrombus can optimise patient outcomes. Similarly, we have developed a treatment algorithm in this review that can be used in the surgical planning of such cases. OBJECTIVES: To detail the perioperative and technical considerations essential to the surgical management of renal cell carcinoma (RCC) with inferior vena cava (IVC) tumour thrombus, as historically patients with RCC and IVC tumour thrombus have had an adverse clinical outcome. * Recent surgical and perioperative advances have for the most part optimized the clinical outcome of such patients. MATERIALS AND METHODS: A comprehensive review of the scientific literature was conducted using MEDLINE from 1990 to present using as the keywords 'renal cell carcinoma' and 'IVC tumor thrombus'. * In all, 62 manuscripts were reviewed, 58 of which were in English. Of these, 25 peer-reviewed articles were deemed of scientific merit and were assessed in detail as part of this comprehensive review. * These articles consist of medium to large (>=25 patients) peer-reviewed studies containing contemporary data pertaining to the surgical management of RCC and IVC tumour thrombus. * Many of these studies highlight important surgical techniques and considerations in the management of such patients and report on their respective clinical outcomes. RESULTS: Careful preoperative planning is essential to optimising the outcomes within this patient cohort. High quality and detailed preoperative imaging studies help delineate the proximal extension of the IVC tumour thrombus and possible caval wall direct invasion while determining the potential necessity for intraoperative vascular bypass. * The surgical management of RCC and IVC tumour thrombus (particularly for level III or IV) often requires the commitment of a multidisciplinary surgical team to optimise patient surgical outcomes. * Despite significant improvements in surgical techniques and perioperative care, the 5 year overall survival remains only between 32% and 69%, highlighting the adverse prognosis of such locally advanced tumours. * Important prognostic factors within this patient cohort include pathological stage, nuclear grade, tumour histology, lymph node and distant metastatic status, preoperative performance status, Charlson comorbidity index, and nutritional status. CONCLUSIONS: The multidisciplinary surgical care of RCC and IVC tumour thrombus (particularly high level thrombi) is pivotal to optimising the surgical outcome of such patients. * Similarly, important preoperative, perioperative, and postoperative considerations can improve the surgical outcome of patients. PMID- 22540184 TI - Distribution of class 1 integrons among enteropathogenic Escherichia coli. AB - The aim of this study was to investigate the incidence of and resistance gene content of class 1 integrons among enteropathogenic Escherichia coli (EPEC) and non-EPEC and to investigate intraspecies genetic diversity of EPEC strains isolated from children with diarrhea in Iran. Twenty-eight EPEC and 16 non-EPEC strains isolated from children with diarrhea were tested for the presence of a class 1 integron associated integrase gene (int1). Sequence analysis was performed to identify the resistance gene content of integrons. Genetic diversity and cluster analysis of EPEC isolates were also investigated using enterobacterial repetitive intergenic concensus-polymerase chain reaction (ERIC PCR) fingerprinting. Twenty-three (82%) EPEC isolates and 11 (68.7%) non-EPEC isolates harbored the int1 gene specific to the conserved integrase region of class 1 integrons. Sequence analysis revealed the dominance of dfrA and aadA gene cassettes among the isolates of both groups. ERIC-PCR fingerprinting of EPEC isolates revealed a high diversity among these isolates. The widespread distribution of 2 resistance gene families (dfrA and aadA) among both groups of EPEC and non-EPEC isolates indicates the significance of integrons in antibiotic resistance transfer among these bacteria. Furthermore, clonal diversity of EPEC isolates harbouring a class 1 integron also suggests the circulation of these mobile elements among a diverse population of EPEC in this country. PMID- 22540185 TI - Distinct muscarinic acetylcholine receptor subtypes mediate pre- and postsynaptic effects in rat neocortex. AB - BACKGROUND: Cholinergic transmission has been implicated in learning, memory and cognition. However, the cellular effects induced by muscarinic acetylcholine receptors (mAChRs) activation are poorly understood in the neocortex. We investigated the effects of the cholinergic agonist carbachol (CCh) and various agonists and antagonists on neuronal activity in rat neocortical slices using intracellular (sharp microelectrode) and field potential recordings. RESULTS: CCh increased neuronal firing but reduced synaptic transmission. The increase of neuronal firing was antagonized by pirenzepine (M1/M4 mAChRs antagonist) but not by AF-DX 116 (M2/M4 mAChRs antagonist). Pirenzepine reversed the depressant effect of CCh on excitatory postsynaptic potential (EPSP) but had marginal effects when applied before CCh. AF-DX 116 antagonized the depression of EPSP when applied before or during CCh. CCh also decreased the paired-pulse inhibition of field potentials and the inhibitory conductances mediated by GABA(A) and GABA(B) receptors. The depression of paired-pulse inhibition was antagonized or prevented by AF-DX 116 or atropine but only marginally by pirenzepine. The inhibitory conductances were unaltered by xanomeline (M1/M4 mAChRs agonist), yet the CCh-induced depression was antagonized by AF-DX 116. Linopirdine, a selective M-current blocker, mimicked the effect of CCh on neuronal firing. However, linopirdine had no effect on the amplitude of EPSP or on the paired-pulse inhibition, indicating that M-current is involved in the increase of neuronal excitability but neither in the depression of EPSP nor paired-pulse inhibition. CONCLUSIONS: These data indicate that the three effects are mediated by different mAChRs, the increase in firing being mediated by M1 mAChR, decrease of inhibition by M2 mAChR and depression of excitatory transmission by M4 mAChR. The depression of EPSP and increase of neuronal firing might enhance the signal-to-noise ratio, whereas the concomitant depression of inhibition would facilitate long-term potentiation. Thus, this triade of effects may represent a "neuronal correlate" of attention and learning. PMID- 22540186 TI - A descriptive analysis of work-related fatal injury in older workers in Australia 2000-2009. AB - The objective of this study is to describe the extent, nature, age distribution and external causes of older-worker fatalities and to provide baseline data for future studies. The methods included retrospective descriptive cohort study using existing population-based mortality data. The study examined work-related fatalities aged 55 years and older, 2000-2009, in Australia following coronial investigation. Of the 336 fatalities identified, almost all (96.3%) were male. The industry with most deaths was agriculture, forestry and fishing (37.8%), followed by transport, postal and warehousing (19.3%) and construction (16.6%). The most frequent injury mechanism was transport-related (40.4%). With predicted workforce ageing, older-worker deaths will become a significant public health issue. Employers and authorities will need to understand older-workers characteristics and vulnerabilities to enable appropriate injury prevention strategy implementation. PMID- 22540187 TI - Structure, function, and chemical synthesis of Vaejovis mexicanus peptide 24: a novel potent blocker of Kv1.3 potassium channels of human T lymphocytes. AB - Animal venoms are rich sources of ligands for studying ion channels and other pharmacological targets. Proteomic analyses of the soluble venom from the Mexican scorpion Vaejovis mexicanus smithi showed that it contains more than 200 different components. Among them, a 36-residue peptide with a molecular mass of 3864 Da (named Vm24) was shown to be a potent blocker of Kv1.3 of human lymphocytes (K(d) ~ 3 pM). The three-dimensional solution structure of Vm24 was determined by nuclear magnetic resonance, showing the peptide folds into a distorted cystine-stabilized alpha/beta motif consisting of a single-turn alpha helix and a three-stranded antiparallel beta-sheet, stabilized by four disulfide bridges. The disulfide pairs are formed between Cys6 and Cys26, Cys12 and Cys31, Cys16 and Cys33, and Cys21 and Cys36. Sequence analyses identified Vm24 as the first example of a new subfamily of alpha-type K(+) channel blockers (systematic number alpha-KTx 23.1). Comparison with other Kv1.3 blockers isolated from scorpions suggests a number of structural features that could explain the remarkable affinity and specificity of Vm24 toward Kv1.3 channels of lymphocytes. PMID- 22540188 TI - Risk factors for symptomatic hyperlactatemia and lactic acidosis among combination antiretroviral therapy-treated adults in Botswana: results from a clinical trial. AB - Nucleoside analogue reverse transcriptase inhibitors are an integral component of combination antiretroviral treatment regimens. However, their ability to inhibit polymerase-gamma has been associated with several mitochondrial toxicities, including potentially life-threatening lactic acidosis. A total of 650 antiretroviral-naive adults (69% female) initiated combination antiretroviral therapy (cART) and were intensively screened for toxicities including lactic acidosis as part of a 3-year clinical trial in Botswana. Patients were categorized as no lactic acidosis symptoms, minor symptoms but lactate <4.4 mmol/liter, and symptoms with lactate >= 4.4 mmol/liter [moderate to severe symptomatic hyperlactatemia (SH) or lactic acidosis (LA)]. Of 650 participants 111 (17.1%) developed symptoms and/or laboratory results suggestive of lactic acidosis and had a serum lactate drawn; 97 (87.4%) of these were female. There were 20 events, 13 having SH and 7 with LA; all 20 (100%) were female (p<0.001). Cox proportional hazard analysis limited to the 451 females revealed that having a higher baseline BMI was predictive for the development of SH/LA [aHR=1.17 per one-unit increase (1.08-1.25), p<0.0001]. Ordered logistic regression performed among all 650 patients revealed that having a lower baseline hemoglobin [aOR=1.28 per one-unit decrease (1.1-1.49), p=0.002] and being randomized to d4T/3TC-based cART [aOR=1.76 relative to ZDV/3TC (1.03-3.01), p=0.04] were predictive of the symptoms and/or the development of SH/LA. cART-treated women in sub-Saharan Africa, especially those having higher body mass indices, should receive additional monitoring for SH/LA. Women presently receiving d4T/3TC-based cART in such settings also warrant more intensive monitoring. PMID- 22540189 TI - Aphanamixoid A, a potent defensive limonoid, with a new carbon skeleton from Aphanamixis polystachya. AB - Aphanamixoid A (1), a limonoid with a new carbon skeleton, along with its biogenetically related limonoid aphanamixoid B (2), was isolated from the leaves and twigs of Aphanamixis polystachya . Their structures with the absolute stereochemistry were determined by spectroscopic analysis, X-ray crystallography and computational methods. The significant antifeedant activity of 1 against the generalist plant-feeding insect Helicoverpa armigera (EC50 = 0.015 MUmol/cm(2)) suggested it may be a potent defensive component of A. polystachya. PMID- 22540190 TI - Comparison of the diagnostic accuracy of combined elastosonography and BRAF analysis vs cytology and ultrasonography for thyroid nodule suspected of malignancy. AB - OBJECTIVE: Diagnosing thyroid nodules preoperatively using traditional diagnostic tools - ultrasonography (US) and cytology - still carries a considerable degree of uncertainty, and surgery is recommended for a far from negligible number of patients simply for diagnostic purposes. Thyroid elastosonography (USE) and BRAF analysis have recently proved useful in detecting thyroid malignancies. The aim of this study is to establish whether combining USE and BRAF testing ameliorates preoperative diagnosis of thyroid nodule candidates for intervention by conventional approaches, thereby avoiding the need for diagnostic surgical procedures. DESIGN AND PATIENTS: We retrospectively analysed the files of 155 consecutive patients with 164 nodules, all assessed by ultrasonography, cytology, USE and BRAF testing, who underwent thyroid surgery. RESULTS: Of the 164 nodules, 74 (45%) were benign and 90 (55%) were malignant at final histology. Combining ultrasonography and cytology identified 21 (13%) as benign, 93 (57%) as malignant or probably malignant and 50 (30%) as 'suspended' (when the combined test was not able to classify the node as benign or malignant) with a 99% sensitivity, 28% specificity, 63% PPV, 95% NPV and 67% accuracy. Combining USE and BRAF testing indicated that 59 (36%) were benign, 74 (45%) were malignant and 31 (19%) were in a 'suspended' category, with a 95% sensitivity, 74% specificity, 82% PPV, 93% NPV and 86% accuracy. CONCLUSIONS: In assessing thyroid nodules suspected of malignancy, the combined analysis of USE and BRAF is equally sensitive and more specific than conventional procedures, achieving more accurate preoperative diagnoses than US and cytology combined. USE and BRAF analysis for thyroid nodule evaluation might reduce the number of unnecessary surgical procedures. PMID- 22540191 TI - A multilevel memetic algorithm for large SAT-encoded problems. AB - Many researchers have focused on the satisfiability problem and on many of its variants due to its applicability in many areas of artificial intelligence. This NP-complete problem refers to the task of finding a satisfying assignment that makes a Boolean expression evaluate to True. In this work, we introduce a memetic algorithm that makes use of the multilevel paradigm. The multilevel paradigm refers to the process of dividing large and difficult problems into smaller ones, which are hopefully much easier to solve, and then work backward toward the solution of the original problem, using a solution from a previous level as a starting solution at the next level. Results comparing the memetic with and without the multilevel paradigm are presented using problem instances drawn from real industrial hardware designs. PMID- 22540192 TI - Regulation of transcription through light-activation and light-deactivation of triplex-forming oligonucleotides in mammalian cells. AB - Triplex-forming oligonucleotides (TFOs) are efficient tools to regulate gene expression through the inhibition of transcription. Here, nucleobase-caging technology was applied to the temporal regulation of transcription through light activated TFOs. Through site-specific incorporation of caged thymidine nucleotides, the TFO:DNA triplex formation is blocked, rendering the TFO inactive. However, after a brief UV irradiation, the caging groups are removed, activating the TFO and leading to the inhibition of transcription. Furthermore, the synthesis and site-specific incorporation of caged deoxycytidine nucleotides within TFO inhibitor sequences was developed, allowing for the light-deactivation of TFO function and thus photochemical activation of gene expression. After UV induced removal of the caging groups, the TFO forms a DNA dumbbell structure, rendering it inactive, releasing it from the DNA, and activating transcription. These are the first examples of light-regulated TFOs and their application in the photochemical activation and deactivation of gene expression. In addition, hairpin loop structures were found to significantly increase the efficacy of phosphodiester DNA-based TFOs in tissue culture. PMID- 22540194 TI - Clinical course of drug-induced hypersensitivity syndrome treated without systemic corticosteroids. AB - BACKGROUND/AIM: Drug-induced hypersensitivity syndrome (DIHS) is a severe reaction to drugs which characteristically occurs after a long latency period. In addition, human herpes virus 6 (HHV-6) reactivation is a characteristic finding in DIHS, which has been known to be related to disease severity. Because DIHS has generally been treated by systemic corticosteroids, the natural clinical course is not clear. METHODS: Data for patients with both DIHS and HHV-6 reactivation were retrospectively collected from four hospitals. RESULTS: Data were collected on 12 patients ranging in age from 21 to 76 years (median, 65.5). All cases had been suspected of DIHS at their initial visit, and the elevation of serum anti HHV-6 antibody had been confirmed (4-256 times: median; 32). The culprit drugs were carbamazepine (6), salazosulfapyridine (4), mexiletine (1) and zonisamide (1). The period of latency from the first administration of the drug ranged from 15 to 50 days (median, 30). All patients were treated conservatively for DIHS without systemic corticosteroids. The peaks of the patients' symptoms and laboratory findings were as follows (days from the onset of skin lesions): fever, 4-16 (median, 10.5); liver abnormality, 3-22 (median, 7.5); leukocytosis, 7-20 (median, 9). All patients recovered without pneumonia, myocarditis, nephritis or other systemic disease, from 7 to 37 days (median, 18) after withdrawal of the drug and from 11 to 44 days (median, 21) after the onset of skin lesions. CONCLUSION: It might be unnecessary to give systemic corticosteroids immediately to all patients suspected of having DIHS. PMID- 22540193 TI - BMP2 and mechanical loading cooperatively regulate immediate early signalling events in the BMP pathway. AB - BACKGROUND: Efficient osteogenic differentiation is highly dependent on coordinated signals arising from growth factor signalling and mechanical forces. Bone morphogenetic proteins (BMPs) are secreted proteins that trigger Smad and non-Smad pathways and thereby influence transcriptional and non-transcriptional differentiation cues. Crosstalk at multiple levels allows for promotion or attenuation of signalling intensity and specificity. Similar to BMPs, mechanical stimulation enhances bone formation. However, the molecular mechanism by which mechanical forces crosstalk to biochemical signals is still unclear. RESULTS: Here, we use a three-dimensional bioreactor system to describe how mechanical forces are integrated into the BMP pathway. Time-dependent phosphorylation of Smad, mitogen-activated protein kinases and Akt in human fetal osteoblasts was investigated under loading and/or BMP2 stimulation conditions. The phosphorylation of R-Smads is increased both in intensity and duration under BMP2 stimulation with concurrent mechanical loading. Interestingly, the synergistic effect of both stimuli on immediate early Smad phosphorylation is reflected in the transcription of only a subset of BMP target genes, while others are differently affected. Together this results in a cooperative regulation of osteogenesis that is guided by both signalling pathways. CONCLUSIONS: Mechanical signals are integrated into the BMP signalling pathway by enhancing immediate early steps within the Smad pathway, independent of autocrine ligand secretion. This suggests a direct crosstalk of both mechanotransduction and BMP signalling, most likely at the level of the cell surface receptors. Furthermore, the crosstalk of both pathways over longer time periods might occur on several signalling levels. PMID- 22540195 TI - What is the value of a regional headache society? Introduction. PMID- 22540196 TI - Introduction to the Southern Headache Society. PMID- 22540197 TI - Management of migraine: the challenges we face and how to meet them. PMID- 22540198 TI - Current topics and controversies in menstrual migraine. AB - As menstrual-related migraine (MRM) has been reported to be longer, more disabling, less responsive to acute therapy, and more prone to recurrence than nonmenstrual migraine attacks, effective preventive strategies are key to their management. Some combined hormonal contraceptives have been suggested as specific preventives for MRM. This article takes a closer look at some of these products, including concerns surrounding them, non-contraceptive benefits, and their potential role as preventive agents for MRM. PMID- 22540199 TI - Southern Headache Society supplement: the neurobiology of throbbing pain in migraine. AB - Virtually everyone can recall an experience, migraine or not, in which pain had a throbbing, pulsatile quality, particularly in association with intense pain. Its pulsatile character strongly reinforces the common presumption that it coincides with the heartbeat. For migraine, a cerebral vascular origin of the throbbing quality is a central tenet of the prevailing scientific view of migraine pain. However, recent data challenge this perspective, with implications for our understanding of throbbing pain not only for migraine but also for the pathophysiology of throbbing pain in other conditions as well. PMID- 22540200 TI - Sports-related concussion: the role of the headache specialist. AB - Over the past few years, sports-related concussion has received significant media attention making it one of the most, if not highest profile neurological disorder. Thirty-one states now have passed sports concussion laws, with 14 states pending legislation. Most concussions are managed by primary care physicians, ie, family practice trained sports medicine physicians and pediatricians. Symptoms are usually short lived and do not require treatment. The one exception is headache, which is usually present from onset and is often the last symptom to resolve. Headache is the most common reason for referral to a specialist, and therefore it is imperative that the headache specialist have at least a basic understanding of all aspects of sports concussion as they are likely going to be called upon to evaluate these athletes, especially the more refractory cases. PMID- 22540201 TI - Temporomandibular disorders, facial pain, and headaches. AB - Headaches and facial pain are common in the general population. In many cases, facial pain can be resultant from temporomandibular joint disorders. Studies have identified an association between headaches and temporomandibular joint disorders suggesting the possibility of shared pathophysiologic mechanisms of these 2 maladies. The aim of this paper is to elucidate potential commonalities of these disorders and to provide a brief overview of an examination protocol that may benefit the headache clinician in daily practice. PMID- 22540202 TI - Psychiatric screening for headache patients. AB - There are numerous reasons to consider psychiatric screening for migraine patients, as well as valid objections to screening. Although psychiatric comorbidity has been consistently described for migraine patients, there is no evidence that treatment of psychiatric comorbidity influences headache outcomes. The author presents his perspectives on psychiatric screening, offers insight into currently available screening instruments, as well as some clinical pearls for screening. PMID- 22540203 TI - Opioids should not be used in migraine. AB - Opioids should not be used for the treatment of migraine. This brief review explores why not. Alternative acute and preventive agents should always be explored. Opioids do not work well clinically in migraine. No randomized controlled study shows pain-free results with opioids in the treatment of migraine. Saper and colleagues' 5-year study showed minimal effectiveness, with many contract violations, interfering with the therapeutic alliance. The physiologic consequences of opioid use are adverse, occur quickly, and can be permanent. Decreased gray matter, release of calcitonin gene-related peptide, dynorphin, and pro-inflammatory peptides, and activation of excitatory glutamate receptors are all associated with opioid exposure. Opioids are pro-nociceptive, prevent reversal of migraine central sensitization, and interfere with triptan effectiveness. Opioids precipitate bad clinical outcomes, especially transformation to daily headache. They cause disease progression, comorbidity, and excessive health care consumption. Use of opioids in migraine is pennywise and pound foolish. PMID- 22540204 TI - The case for opiate/opioid therapy in the management of headache. PMID- 22540205 TI - Conclusions on opioids. PMID- 22540206 TI - New daily persistent headache. AB - Primary new daily persistent headache is a rare disorder of children and adults defined by the onset of daily and unremitting headaches within 3 days of onset lasting 4 hours or more daily. There may be a link between a preceding flu-like or upper respiratory infection in about 15%, a stressful life event in 10%, or extracranial surgery in 10%. Migraine symptoms may be present in over 50%. The headache is generalized in most but may be unilateral in 11% and may be localized to any head region. The diagnosis is one of exclusion as many secondary etiologies can cause similar headaches. The pathophysiology of the primary type is unknown. There are no prospective placebo controlled trials of preventive treatment so prevention is empiric using the same medications for the phenotype of chronic migraine or tension-type headache. Most patients have persistent headaches, although about 15% will remit, and 8% will have a relapsing-remitting type. PMID- 22540208 TI - Advanced interventions for headache. AB - Many headache patients present when medications fail, are inadequate, are contraindicated, or are not tolerated. These are patients with severe disability. Most have daily headaches, including chronic migraine, trigeminal autonomic cephalalgias, or other primary headaches. This brief review addresses, in broad strokes, some thoughts about alternatives beyond the usual daily oral preventive therapies. Do not proceed to more invasive or elaborate approaches until the big 3 are done: diagnosis is established, onabotulinumtoxinA administered when appropriate, that is, if the patient has chronic migraine, and wean is accomplished if the patient has medication overuse headache. Large numbers of patients are helped without the need for more arcane and unproven treatments by following these initial approaches. Simple nerve blocks can be useful in the initial steps, but more invasive blocks and stimulators are not recommended until the big 3 are completed. Wean of overused medications must be absolute and may require an intravenous bridge over several days, either in an infusion unit or inpatient in a medical model. Wean should be accompanied by establishing onabotulinumtoxinA or daily prevention from the beginning. Consider referral to a structured multidisciplinary headache program. This is for patients who require an interdisciplinary approach and may be day-hospital or inpatient. Invasive blocks and stimulators may be appropriate, and the latter are currently being studied in controlled studies. The most promise, with the best balance of efficacy vs adverse event prospects, may be occipital nerve stimulators or sphenopalatine ganglion stimulators. PMID- 22540209 TI - FTIR spectra of algal species can be used as physiological fingerprints to assess their actual growth potential. AB - Fourier transform infrared (FTIR) spectra were measured from cells of Microcystis aeruginosa and Protoceratium reticulatum, whose growth rates were manipulated by the availability of nutrients or light. As expected, the macromolecular composition changed in response to the treatments. These changes were species specific and depended on the type of perturbation applied to the growth regime. Microcystis aeruginosa showed an increase in the carbohydrate-to-protein ratio with decreased growth rates, under nutrient limitation, whereas light limitation induced a decrease of the carbohydrate-to-protein ratio with decreasing proliferation rates. The macromolecular pools of P. reticulatum showed a higher degree of compositional homeostasis. Only when the lowest light irradiance and nutrient availability were supplied, an increase of the carbohydrate-to-protein FTIR absorbance ratio was observed. A species-specific partial least squares (PLS) model was developed using the whole FTIR spectra. This model afforded a very high correlation between the predicted and the measured growth rates, regardless of the growth conditions. On the contrary, the prediction based on absorption band ratios generally used in FTIR studies would strongly depend on growth conditions. This new computational method could constitute a substantial improvement in the early warning systems of algal blooms and, in general, for the study of algal growth, e.g. in biotechnology. Furthermore, these results confirm the suitability of FTIR spectroscopy as a tool to map complex biological processes like growth under different environmental conditions. PMID- 22540210 TI - Successful treatment of pure red cell aplasia with a single low dose of rituximab in two patients after major ABO incompatible peripheral blood allogeneic stem cell transplantation. PMID- 22540211 TI - Pilot study of intense pulsed light for the treatment of systemic sclerosis related telangiectases. AB - BACKGROUND: Telangiectases represent microvascular changes inherent in the systemic sclerosis (SSc) disease process. Intense pulsed light (IPL) is an effective treatment for non-SSc-related cutaneous telangiectases. OBJECTIVES: This pilot study aimed to examine the efficacy, safety and tolerability of IPL treatment in an open study of patients with SSc. METHODS: Patients underwent three treatments of IPL at monthly intervals and attended follow-up examinations at 1, 6 and 12 months after final treatment. Photographs, laser Doppler imaging (LDI) and thermography were used to measure changes at each visit. RESULTS: Seventeen patients completed the study. Photographs were graded (compared with baseline) as: at 1-month follow-up, four 'no change', four 'improved' and eight 'much improved'; at 6-month follow-up, four 'no change', eight 'improved'; and four 'much improved'; and at 12-month follow-up (eight images were available), three 'no change', two 'improved' and three 'much improved'. Perfusion as measured by LDI (perfusion units) was significantly reduced, compared with baseline [median 2.66, interquartile range (1.78-3.93)], at 1 month [1.70 (1.07 2.55), P = 0.006] and 6 months [2.05 (1.42-2.36), P = 0.008] post-treatment, but not at 12 months [1.61 (1.14-3.22), P =0.088]. No differences were found in skin temperature between baseline and follow-up visits. CONCLUSIONS: In this pilot study (the first of IPL treatment for SSc-related telangiectases) most patients improved after IPL treatment. However, the degree of improvement was not maintained in all patients at 6-12 months, suggesting that further treatments may be necessary. Longer term studies of this novel treatment approach are now required. PMID- 22540212 TI - Cross coupling between sp3-carbon and sp3-carbon using a diborylmethane derivative at room temperature. AB - A novel example of the Suzuki-Miyaura cross-coupling reaction between sp(3) carbon and sp(3)-carbon is described. The reaction of a diborylmethane derivative with allyl halides or benzyl halides proceeded efficiently in the presence of appropriate Pd-catalysts at room temperature. The present approaches provide functionalized homoallylboronates and alkylboronates with excellent regio- and chemoselectivities. PMID- 22540213 TI - AMPA receptors regulate exocytosis and insulin release in pancreatic beta cells. AB - Ionotropic glutamate receptors (iGluRs) are expressed in islets and insulinoma cells and involved in insulin secretion. However, the exact roles that iGluRs play in beta cells remain unclear. Here, we demonstrated that GluR2-containing alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) were expressed in mouse beta cells. Glutamate application increased both cytosolic calcium and the number of docked insulin-containing granules, which resulted in augmentation of depolarization-induced exocytosis and high-glucose-stimulated insulin release. While glutamate application directly depolarized beta cells, it also induced an enormous depolarization when K(ATP) channels were available. Glutamate application reduced the conductance of K(ATP) channels and increased voltage oscillations. Moreover, actions of AMPARs were absent in Kir6.2 knock-out mice. The effects of AMPARs on K(ATP) channels were mediated by cytosolic cGMP. Taken together, our experiments uncovered a novel mechanism by which AMPARs participate in insulin release. PMID- 22540214 TI - Imported Plasmodium falciparum malaria in HIV-infected patients: a report of two cases. AB - As HIV becomes a chronic infection, an increasing number of HIV-infected patients are travelling to malaria-endemic areas. Association of malaria with HIV/AIDS can be clinically severe. Severe falciparum malaria is a medical emergency that is associated with a high mortality, even when treated in an Intensive Care Unit. This article describes two cases of HIV-positive patients, who returned from malaria-endemic areas and presented a parasitaemia > 5% of erythrocytes and clinical signs of severe falciparum malaria, both with > 350 CD4 cell count/MUl, absence of chemoprophylaxis and successful response. Factors like drug interactions and the possible implication of anti-malarial therapy bioavailability are all especially interesting in HIV-malaria co-infections. PMID- 22540215 TI - Physical, psychological and sexual effects in multi-ethnic Malaysian women who have undergone hysterectomy. AB - AIM: The postoperative effects on Asian women after hysterectomy have not been fully explored. This study was undertaken to investigate the physical, psychological and sexual functioning effects in multi-ethnic Malaysian women who have undergone hysterectomy. MATERIAL AND METHODS: A cross-sectional questionnaire-based study was conducted on women who underwent hysterectomy at the Gynecological Outpatient Clinic, University of Malaya Medical Center between November 2008 and October 2009. RESULTS: Postoperative physical and psychological effects were common. Participants with higher household income had a significantly lower number of physical and psychological problems. Young women were more likely to experience psychological effects. There were significant differences between ethnic groups in physical and psychological symptoms. A multivariate model to determine factors associated with sexual functioning identified the importance of sexual relationship, spouse or partner's attitudes, and ethnic groups as significant covariates. CONCLUSION: The findings underscore the importance of ethnic-based approaches to counseling to mitigate the psychological effects of hysterectomy and to focus on young women with low socioeconomic status. PMID- 22540216 TI - Surprising acid/base and ion-sequestration chemistry of Sn9(4-): HSn9(3-), Ni@HSn9(3-), and the Sn9(3-) ion revisited. AB - K(4)Sn(9) dissolves in ethylenediamine (en) to give equilibrium mixtures of the diamagnetic HSn(9)(3-) ion along with K(x)Sn(9)((4-x)-) ion pairs, where x = 0, 1, 2, 3. The HSn(9)(3-) cluster is formed from the deprotonation of the en solvent and is the conjugate acid of Sn(9)(4-). DFT studies show that the structure is quite similar to the known isoelectronic RSn(9)(3-) ions (e.g., R = i-Pr). The hydrogen atom of HSn(9)(3-) (delta = 6.18 ppm) rapidly migrates among all nine Sn atoms in an intramolecular fashion; the Sn(9) core is also highly dynamic on the NMR time scale. The HSn(9)(3-) cluster reacts with Ni(cod)(2) to give the Ni@HSn(9)(3-) ion containing a hydridic hydrogen (delta = -28.3 ppm) that also scrambles across the Sn(9) cluster. The Sn(9)(4-) ion competes effectively with 2,2,2-crypt for binding K(+) in en solutions, and the pK(a) of HSn(9)(3-) is similar to that of en (i.e., Sn(9)(4-) is a very strong Bronsted base with a pK(b) comparable to that of the NH(2)CH(2)CH(2)NH(-) anion). Competition studies show that the HSn(9)(3-) ? Sn(9)(4-) + H(+) equilibrium is fully reversible. The HSn(9)(3-) anion is present in significant concentrations in en solutions containing 2,2,2-crypt, yet it has gone undetected for over 30 years. PMID- 22540217 TI - Patients with disorders of sex development (DSD) at risk of gonadal tumour development: management based on laparoscopic biopsy and molecular diagnosis. AB - Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? In some individuals with disorders of sex development (DSD), gonadal tumour risk is increased. The individual risk is estimated based on the molecular diagnosis and the age and approaches 30% in the high-risk group. In the past, early gonadectomy has been advised for all individuals with 46XY DSD. Gonadectomy clearly represents an overtreatment for many individuals with 46XY DSD. Thus, further clinical indicators of individual tumour risk are urgently needed. The present study provides a comprehensive description of gonadal morphology, as seen during laparoscopy. For the first time, laparoscopic features, molecular diagnosis and histopathological findings are presented in a comprehensive context. The present study adds a detailed morphological description of the variability found in different subgroups of 46XY DSD. As three of four detected tumours were microscopic, early diagnosis by inspection appears unfeasible. Biopsy, gonadopexy and precise localisation of the gonad will potentially allow for gonadal preservation in well-defined clinical situations. OBJECTIVE: * To investigate the role of laparoscopy for the early detection of gonadal tumours, with emphasis on gonadal preservation, in patients with 46XY disorders of sex development (DSD). In patients with DSD, gonadectomy is frequently recommended and depending on the age and the molecular diagnosis, an increased gonadal tumour risk exists and undesired hormone effects may arise. However, gonadectomy is irreversible and impacts considerably on body image. It represents an overtreatment for some patients and should be considered after a comprehensive diagnostic evaluation. Laparoscopy is an important technique, because it is able to retrieve small gonads and allows guided biopsies. PATIENTS AND METHODS: * We performed laparoscopic assessment of the gonads in 40 patients with various 46XY DSD. * In all, 77 gonads were evaluated, images were analysed and compared with histological findings. * Laparoscopic procedures included gonadectomy, biopsy, laparoscopic orchidolysis or the Fowler-Stephens procedure as well as the removal or splitting of uterine remnants. RESULTS: * In all, 19 patients underwent gonadectomy and tumours were discovered in four. * Three patients had only microscopic evidence of tumour, in one the tumour was diagnosed intraoperatively. * In 21 patients, biopsies were taken and the gonads preserved. * Laparoscopic biopsy and gonadopexy was performed in six patients with complete androgen insensitivity syndrome (CAIS). CONCLUSION: * Laparoscopy and biopsy detected three microscopic tumours, one tumour was macroscopically evident. * In CAIS, gonadopexy improved the visibility of the gonads on postoperative ultrasonography. This procedure facilitated the examination of the gonad at follow-up. * In complete gonadal dysgenesis, a highly variable morphology of the gonads was found. Laparoscopy improved exposure of gonads and Mullerian structures, and facilitated biopsies and organ-preserving procedures. PMID- 22540218 TI - Aspirin twice a day keeps new COX-1 at bay. PMID- 22540220 TI - Protective immune responses in mice induced by intramuscular and intranasal immunization with a Mycoplasma pneumoniae P1C DNA vaccine. AB - Mycoplasma pneumoniae is an important causative agent of atypical pneumonia. This study was to determine the ability of a DNA expression vector, which encodes the carboxy terminal region of the M. pneumoniae P1 protein (P1C), to induce humoral and cellular immune responses and to protect against M. pneumoniae infection in BALB/c mice. Mice were immunized with pcDNA3.1/P1C by either intramuscular injection (i.m.) or intranasal inoculation (i.n.). Our results showed that p1c DNA immunization generates detectable antibodies specific to M. pneumoniae, and elicits high levels of IgG1, IgG2a, and IgG2b isotypes (P < 0.01). The levels of IFN-gamma and IL-4 in spleen cells of the immunized mice were significantly elevated by immunization via both the i.m. and i.n. methods. Moreover, p1c DNA-immunized mice exhibited detectable protection against M. pneumoniae infection. The lung tissue inflammation was relieved and the histopathologic score (HPS) of pcDNA3.1/P1C-immunized mice was significantly decreased than those in phosphate-buffed saline (PBS) or vaccine-vector-immunized mice (P < 0.01), whereas there were no significant differences in HPS between i.m. and i.n. vaccination (P > 0.05). Our results suggest that pcDNA3.1/P1C could be useful for developing a vaccine against M. pneumoniae infection. PMID- 22540222 TI - Scoring higher the second time around: meta-analyses of practice effects in neuropsychological assessment. AB - In neuropsychological assessment, and many areas of research, it is common for the same test to be administered on more than one occasion to measure change. Measured changes are presumed to reflect true changes in the construct being measured by the test; for example, cognitive changes due to processes such as aging, advancing neurological disease, or treatment interventions. However, practice effects, defined as score increases due to factors such as memory for specific test items, learned strategies, or test sophistication, complicate the interpretation of change. This review presents meta-analyses of nearly 1600 individual effect sizes representing changes in mean-level performance on tests commonly used to assess core domains of neuropsychological function, with the goal of quantitatively summarizing the magnitude of practice effects on such tests. The use of alternate forms, the ages of participants, clinical diagnoses of study participants, and length of the test-retest interval were associated with the magnitude of change in many cases. These findings have important implications for the practice of clinical neuropsychology, as well as for research applications, and highlight the need for practice effects to be taken into account in interpreting change across time with multiple measurements. PMID- 22540224 TI - Morphology effects on the biofunctionalization of nanostructured ZnO. AB - A stepwise surface functionalization methodology was applied to nanostructured ZnO films grown by metal organic chemical vapor deposition (MOCVD) having three different surface morphologies (i.e., nanorod layers (ZnO films-N), rough surface films (ZnO films-R), and planar surface films (ZnO films-P). The films were grown on glass substrates and on the sensing area of a quartz crystal microbalance (nano-QCM). 16-(2-Pyridyldithiol)-hexadecanoic acid (PDHA) was bound to ZnO films N, -R, and -P through the carboxylic acid unit, followed by a nucleophilic displacement of the 2-pyridyldithiol moiety by single-stranded DNA capped with a thiol group (SH-ssDNA). The resulting ssDNA-functionalized films were hybridized with complementary ssDNA tagged with fluorescein (ssDNA-Fl). In a selectivity control experiment, no hybridization occurred upon treatment with non complementary DNA. The ZnO films' surface functionalization, characterized by FT IR-ATR and fluorescence spectroscopy and detected on the nano-QCM, was successful on films-N and -R but was barely detectable on the planar surface of films-P. PMID- 22540223 TI - Empiric guideline-recommended weight-based vancomycin dosing and mortality in methicillin-resistant Staphylococcus aureus bacteremia: a retrospective cohort study. AB - BACKGROUND: No studies have evaluated the effect of guideline-recommended weight based dosing on in-hospital mortality of patients with methicillin-resistant Staphylococcus aureus bacteremia. METHODS: This was a multicenter, retrospective, cohort study of patients with methicillin-resistant Staphylococcus aureus bacteremia receiving at least 48 hours of empiric vancomycin therapy between 01/07/2002 and 30/06/2008. We compared in-hospital mortality for patients treated empirically with weight-based, guideline-recommended vancomycin doses (at least 15 mg/kg/dose) to those treated with less than 15 mg/kg/dose. We used a general linear mixed multivariable model analysis with variables identified a priori through a conceptual framework based on the literature. RESULTS: A total of 337 patients who were admitted to the three hospitals were included in the cohort. One-third of patients received vancomycin empirically at the guideline recommended dose. Guideline-recommended dosing was not associated with in hospital mortality in the univariable (16% vs. 13%, OR 1.26 [95%CI 0.67-2.39]) or multivariable (OR 0.71, 95%CI 0.33-1.55) analysis. Independent predictors of in hospital mortality were ICU admission, Pitt bacteremia score of 4 or greater, age 53 years or greater, and nephrotoxicity. CONCLUSIONS: Empiric use of weight based, guideline-recommended empiric vancomycin dosing was not associated with reduced mortality in this multicenter study. PMID- 22540225 TI - Solid organ transplantation for non-TTR hereditary amyloidosis: report from the 1st International Workshop on the Hereditary Renal Amyloidoses. AB - Fibrinogen A alpha-chain (AFib) and apolipoprotein AI (AApoAI) amyloidosis due to variants in the AFib and ApoAI genes are the most common types of hereditary amyloidosis in Europe and the United States. Liver is the exclusive source of the aberrant amyloidogenic protein in AFib and responsible for supplying approximately half of the circulating variant ApoAI. Nephrotic syndrome and renal impairment due to renal amyloidosis are common disease manifestations; however, recent research provides evidence to support a more diverse and systemic disease phenotype, which in turn has implications in the management of the hereditary amyloidoses with solid organ transplantation and, in particular, liver transplantation. PMID- 22540226 TI - High-performance liquid chromatography under partially denaturing conditions (dHPLC) is a fast and cost-effective method for screening molecular defects: four novel mutations found in X-linked chronic granulomatous disease. AB - Implementing precise techniques in routine diagnosis of chronic granulomatous disease (CGD), which expedite the screening of molecular defects, may be critical for a quick assumption of patient prognosis. This study compared the efficacy of single-strand conformation polymorphism analysis (SSCP) and high-performance liquid chromatography under partially denaturing conditions (dHPLC) for screening mutations in CGD patients. We selected 10 male CGD patients with a clinical history of severe recurrent infections and abnormal respiratory burst function. gDNA, mRNA and cDNA samples were prepared by standard methods. CYBB exons were amplified by PCR and screened by SSCP or dHPLC. Abnormal DNA fragments were sequenced to reveal the nature of the mutations. The SSCP and dHPLC methods showed DNA abnormalities, respectively, in 55% and 100% of the cases. Sequencing of the abnormal DNA samples confirmed mutations in all cases. Four novel mutations in CYBB were identified which were picked up only by the dHPLC screening (c.904 insC, c.141+5 g>t, c.553 T>C, and c.665 A>T). This work highlights the relevance of dHPLC, a sensitive, fast, reliable and cost-effective method for screening mutations in CGD, which in combination with functional assays assessing the phagocyte respiratory burst will contribute to expedite the definitive diagnosis of X-linked CGD, direct treatment, genetic counselling and to have a clear assumption of the prognosis. This strategy is especially suitable for developing countries. PMID- 22540227 TI - Stable carbon and nitrogen isotope signatures of root-holoparasitic Cynomorium songaricum and its hosts at the Tibetan plateau and the surrounding Gobi desert in China. AB - We first measured the delta(13)C and delta(15)N values of root holoparasite Cynomorium songaricum and its hosts from 19 sites across four provinces in northwest China, in an attempt to investigate their nutritional relationship at the Tibetan plateau and the surrounding Gobi desert. Our study showed that the delta(13)C of C. songaricum closely mirrored the values of its hosts, Nitraria tangutorum and N. sibirica across all sampling sites. C. songaricum was significantly depleted in (13)C compared to host plants at the Tibetan plateau, showing an average parasite/host delta(13)C difference of-0.6 0/00. In contrast, (15)N of C. songaricum was significantly enriched by+1.3 0/00 compared to the hosts, implying that these holoparasites had other nitrogen resources. Although no difference in the delta(13)C and delta(15)N values between holoparasites and hosts was detected, the delta(13)C and delta(15)N values of holoparasites were significantly correlated with those of their hosts at the Gobi desert. The delta(13)C versus delta(15)N values were significantly but negatively correlated for the hosts; however, holoparasite/host variation in delta(13)C was not correlated with the variation in delta(15)N. The delta(13)C versus delta(15)N values were negatively correlated in C. songaricum, and this relationship tended to be magnified along the increasing elevations independent of the host plants. C. songaricum at the Tibetan plateau exhibited different delta(13)C and delta(15)N signatures compared with those at the Gobi desert. Furthermore, both delta(13)C and delta(15)N values of C. songaricum and its host plants in salt marshes at the Tibetan plateau were different from those in sand sites at the Tibetan plateau and the Gobi desert. Our results indicate that the isotopic difference depends on the different altitudes and habitats and is host-specific. PMID- 22540230 TI - The current need for family and replacement donation in sub-Saharan Africa should not hide the difficulties of its management. PMID- 22540228 TI - Proteolytic activation of proapoptotic kinase protein kinase Cdelta by tumor necrosis factor alpha death receptor signaling in dopaminergic neurons during neuroinflammation. AB - BACKGROUND: The mechanisms of progressive dopaminergic neuronal loss in Parkinson's disease (PD) remain poorly understood, largely due to the complex etiology and multifactorial nature of disease pathogenesis. Several lines of evidence from human studies and experimental models over the last decade have identified neuroinflammation as a potential pathophysiological mechanism contributing to disease progression. Tumor necrosis factor alpha (TNF) has recently emerged as the primary neuroinflammatory mediator that can elicit dopaminergic cell death in PD. However, the signaling pathways by which TNF mediates dopaminergic cell death have not been completely elucidated. METHODS: In this study we used a dopaminergic neuronal cell model and recombinant TNF to characterize intracellular signaling pathways activated during TNF-induced dopaminergic neurotoxicity. Etanercept and neutralizing antibodies to tumor necrosis factor receptor 1 (TNFR1) were used to block TNF signaling. We confirmed the results from our mechanistic studies in primary embryonic mesencephalic cultures and in vivo using the stereotaxic lipopolysaccharide (LPS) model of nigral dopaminergic degeneration. RESULTS: TNF signaling in dopaminergic neuronal cells triggered the activation of protein kinase Cdelta (PKCdelta), an isoform of the novel PKC family, by caspase-3 and caspase-8 dependent proteolytic cleavage. Both TNFR1 neutralizing antibodies and the soluble TNF receptor Etanercept blocked TNF-induced PKCdelta proteolytic activation. Proteolytic activation of PKCdelta was accompanied by translocation of the kinase to the nucleus. Notably, inhibition of PKCdelta signaling by small interfering (si)RNA or overexpression of a PKCdelta cleavage-resistant mutant protected against TNF-induced dopaminergic neuronal cell death. Further, primary dopaminergic neurons obtained from PKCdelta knockout (-/-) mice were resistant to TNF toxicity. The proteolytic activation of PKCdelta in the mouse substantia nigra in the neuroinflammatory LPS model was also observed. CONCLUSIONS: Collectively, these results identify proteolytic activation of PKCdelta proapoptotic signaling as a key downstream effector of dopaminergic cell death induced by TNF. These findings also provide a rationale for therapeutically targeting PKCdelta to mitigate progressive dopaminergic degeneration resulting from chronic neuroinflammatory processes. PMID- 22540229 TI - Retromer guides STxB and CD8-M6PR from early to recycling endosomes, EHD1 guides STxB from recycling endosome to Golgi. AB - Retrograde trafficking transports proteins, lipids and toxins from the plasma membrane to the Golgi and endoplasmic reticulum (ER). To reach the Golgi, these cargos must transit the endosomal system, consisting of early endosomes (EE), recycling endosomes, late endosomes and lysosomes. All cargos pass through EE, but may take different routes to the Golgi. Retromer-dependent cargos bypass the late endosomes to reach the Golgi. We compared how two very different retromer dependent cargos negotiate the endosomal sorting system. Shiga toxin B, bound to the external layer of the plasma membrane, and chimeric CD8-mannose-6-phosphate receptor (CI-M6PR), which is anchored via a transmembrane domain. Both appear to pass through the recycling endosome. Ablation of the recycling endosome diverted both of these cargos to an aberrant compartment and prevented them from reaching the Golgi. Once in the recycling endosome, Shiga toxin required EHD1 to traffic to the TGN, while the CI-M6PR was not significantly dependent on EHD1. Knockdown of retromer components left cargo in the EE, suggesting that it is required for retrograde exit from this compartment. This work establishes the recycling endosome as a required step in retrograde traffic of at least these two retromer dependent cargos. Along this pathway, retromer is associated with EE to recycling endosome traffic, while EHD1 is associated with recycling endosome to TGN traffic of STxB. PMID- 22540231 TI - Evaluation of diel patterns of relative changes in cell turgor of tomato plants using leaf patch clamp pressure probes. AB - Relative changes in cell turgor of leaves of well-watered tomato plants were evaluated using the leaf patch clamp pressure probe (LPCP) under dynamic greenhouse climate conditions. LPCP changes, a measure for relative changes in cell turgor, were monitored at three different heights of transpiring and non transpiring leaves of tomato plants on sunny and cloudy days simultaneously with whole plant water uptake. Clear diel patterns were observed for relative changes of cell turgor of both transpiring and non-transpiring leaves, which were stronger on sunny days than on cloudy days. A clear effect of canopy height was also observed. Non-transpiring leaves showed relative changes in cell turgor that closely followed plant water uptake throughout the day. However, in the afternoon the relative changes of cell turgor of the transpiring leaves displayed a delayed response in comparison to plant water uptake. Subsequent recovery of cell turgor loss of transpiring leaves during the following night appeared insufficient, as the pre-dawn turgescent state similar to the previous night was not attained. PMID- 22540232 TI - Inhibitory effect of Allium sativum and Zingiber officinale extracts on clinically important drug resistant pathogenic bacteria. AB - BACKGROUND: Herbs and spices are very important and useful as therapeutic agent against many pathological infections. Increasing multidrug resistance of pathogens forces to find alternative compounds for treatment of infectious diseases. METHODS: In the present study the antimicrobial potency of garlic and ginger has been investigated against eight local clinical bacterial isolates. Three types of extracts of each garlic and ginger including aqueous extract, methanol extract and ethanol extract had been assayed separately against drug resistant Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, Staphylococcus aureus, Klebsiella pneumoniae, Shigella sonnei, Staphylococcusepidermidis and Salmonella typhi. The antibacterial activity was determined by disc diffusion method. RESULTS: All tested bacterial strains were most susceptible to the garlic aqueous extract and showed poor susceptibility to the ginger aqueous extract. The (minimum inhibitory concentration) MIC of different bacterial species varied from 0.05 mg/ml to 1.0 mg/ml. CONCLUSION: In the light of several socioeconomic factors of Pakistan mainly poverty and poor hygienic condition, present study encourages the use of spices as alternative or supplementary medicine to reduce the burden of high cost, side effects and progressively increasing drug resistance of pathogens. PMID- 22540234 TI - Venous malformations treated with dual wavelength 595 and 1064 nm laser system. AB - BACKGROUND & OBJECTIVE: Venous malformations (VM) represent a localized error in the embryological development of the venous branch of the circulation. The management of VM is complex and challenging. The aim of this study was to assess the efficacy and safety of combined sequential pulsed dye laser (PDL)-Nd:YAG laser in patients with cutaneous or mucosal VM. METHODS: Thirty patients (age from 8 to 65 years) with cutaneous or mucosal VM treated with dual wavelength PDL Nd:YAG laser were retrospectively analyzed. Laser parameters were 10 mm spot size with 10 ms pulse and 8-10 J/cm(2) of PDL, followed with a second delay by Nd:YAG with 15 or 20 ms at 35-70 J/cm(2); or 7 mm spot size with 10 ms pulse and 5-10.5 J/cm(2) of PDL, followed with a second delay by Nd:YAG with 15 or 20 ms at 50-100 J/cm(2). Laser sessions were repeated approximately every 2-6 months. Air cooling was applied during treatment. Three dermatologists evaluated treatment effectiveness by means of photographs of the patients before and after laser treatment (scale from 0 to 4). Differences in the degree of clinical improvement between patients with cutaneous or mucosal VM were also assessed. Adverse events were registered. Patient satisfaction was also assessed in 19 cases (scale from 0 to 10). RESULTS: Mean global improvement was rated as 3.37. Mean improvement in patients with cutaneous VM was 3.35 and 3.38 in patients with mucosal VM. No significant difference between both groups was observed (P = 0.53). Long-lasting side effects included partial epilation of the eyelashes in one patient, ulceration in two patients and permanent scarring in three patients. Mean patient satisfaction was 8.55. CONCLUSIONS: Our study concludes that dual wavelength PDL Nd:YAG laser was effective for treatment of the superficial component of cutaneous and mucosal VM. PMID- 22540233 TI - Augmented production of soluble CD93 in patients with systemic sclerosis and clinical association with severity of skin sclerosis. AB - BACKGROUND: The cell surface protein CD93, expressed on endothelial and myeloid cells, mediates phagocytosis, inflammation and cell adhesion. A soluble form of CD93 (sCD93) is released during inflammation. OBJECTIVES: To determine the serum sCD93 level and its association with clinical parameters in patients with systemic sclerosis (SSc). METHODS: Serum sCD93 levels were examined by enzyme linked immunosorbent assay in 59 patients with SSc, 24 patients with systemic lupus erythematosus and 47 healthy individuals. The expression of CD93 in skin tissues was examined immunohistochemically. In a retrospective longitudinal study, sera from 11 patients with SSc were analysed. RESULTS: Serum sCD93 levels were increased in patients with SSc compared with healthy individuals (P<0.001). Patients with diffuse cutaneous SSc showed greater levels of sCD93 than those with limited cutaneous SSc (P<0.01) or systemic lupus erythematosus (P<0.01). Serum sCD93 levels correlated positively with the severity of skin sclerosis. Strong CD93 immunostaining was observed on endothelial cells in lesional skin tissues. In the longitudinal study, sCD93 levels decreased in parallel with improvement in skin sclerosis. CONCLUSIONS: Serum sCD93 levels are increased in patients with SSc and correlate with the severity and activity of skin sclerosis. CD93 may contribute to the development of skin fibrosis in SSc. PMID- 22540235 TI - Resource utilization and outcomes in patients with atrial fibrillation: a case control study. AB - BACKGROUND: Atrial fibrillation (AF) is the most common sustained disorder of cardiac rhythm. Various new anticoagulation and antiarrythmic treatments are being investigated for the treatment of AF. Before novel treatments can be used widely in actual clinical practice, the cost effectiveness of such novel treatments may need to be determined. OBJECTIVE: The objectives of the study were to describe resource utilization for AF and control patients, and estimate the incidence of mortality. METHODS: This case control study evaluated 6 months of primary and secondary care resource utilization and mortality rates for patients within the period 01 April 2001 to 31 March 2006. Cases included 15 373 adults with a record of AF in the General Practice Research Database (GPRD) within the study period. The index date was randomly selected between 6 months after the AF record and end of data collection. Cases were matched to controls by age, gender, general practice and time. RESULTS: AF patients had significantly higher resource utilization than controls. Resource utilization increased with greater National Institute for Clinical Excellence (NICE) stroke risk strata (graded as low, moderate or high based on associated risk factors). Both current warfarin and aspirin users had higher resource utilization than control patients. Resource utilization remained high amongst AF patients who discontinued therapy. The mortality rate was significantly higher in AF patients than controls, deaths due to circulatory system disease were increased 4-fold and cancer deaths were doubled. All-cause and circulatory mortality rates, as well as rates of clinical outcomes, were related to the NICE stroke risk schema. CONCLUSIONS: There was large heterogeneity in resource utilization between AF patients, although overall, this was still higher than controls without AF. Higher resource utilization was evident in patients at higher risk of stroke, and remained where antithrombotic therapy was discontinued. The mortality risk in AF was increased substantially, both for cardiovascular and non-cardiovascular causes of death, indicating a large unmet medical need. PMID- 22540236 TI - Prostate-specific antigen vs prostate-specific antigen density as a predictor of upgrading in men diagnosed with Gleason 6 prostate cancer by contemporary multicore prostate biopsy. AB - What's known on the subject? and What does the study add? Previously, it has been reported that PSA may not perform as accurately as PSA density (PSAD) in predicting outcomes after radical prostatectomy among patients with Gleason score 6 prostate cancer. However, there have been few studies comparing the usefulness of PSA and PSAD in predicting upgrading after surgery. Also, most published studies on the prediction of upgrading included significant proportions of subjects who did not undergo contemporary multicore prostate biopsy. Moreover, most studies from major academic centres on the potential usefulness of PSAD as a preoperative predictor of pathological and/or biochemical outcomes after surgery have not included detailed biopsy core-related data. Even when accounting for detailed biopsy core data, this study found that PSAD may be a significantly more accurate preoperative predictor of upgrading than PSA in the current era of extended prostate biopsies. This finding supports the inclusion of PSAD into the risk stratification system for patients with prostate cancer seeking less invasive treatment, such as active surveillance. OBJECTIVE: * To compare the accuracies of prostate-specific antigen (PSA) and PSA density (PSAD) in predicting Gleason score upgrading after radical prostatectomy (RP) in men who have undergone contemporary multicore prostate biopsy and for whom detailed biopsy core data are available. PATIENTS AND METHODS: * We analysed prospectively collected data on 505 patients who were diagnosed with Gleason 6 prostate cancer after multicore (>= 12 cores) biopsy and who underwent RP without neoadjuvant treatment. * Receiver operating characteristic curves were used to analyse the predictive accuracies of multivariate logistic regression models. RESULTS: * When multivariate models were constructed incorporating either PSA or PSAD along with other upgrading predictors, including biopsy core, both PSA and PSAD were observed to be independent predictors of upgrading in all versions of models (all P < 0.05). * When predictive accuracies of multivariate models including PSA and PSAD were compared, the PSAD model was found to have significantly higher accuracy than the PSA model in three out of four versions of models analysed (model 1, P= 0.048; model 2, P= 0.002; model 3, P= 0.201; model 4, P= 0.044). CONCLUSION: * According to our analysis of prospectively collected data, PSAD may be a significantly more accurate preoperative predictor of upgrading than PSA, even when accounting for detailed biopsy core data in the current era of extended prostate biopsies. * Our findings would support the inclusion of PSAD, rather than PSA, into the risk stratification system for patients seeking less invasive treatment for prostate cancer. PMID- 22540245 TI - Long-term patterns of humoral and cellular response after vaccination against influenza A (H1N1) in patients with hematologic malignancies. AB - OBJECTIVES: The efficacy of a novel vaccine against influenza virus A (H1N1) in patients with hematologic malignancies is largely unknown. METHODS: We prospectively evaluated the humoral and cellular immune responses after one injection of monovalent adjuvanted 2009 H1N1 vaccine in 47 adults with hematologic malignancies and 77 controls by hemagglutination-inhibition assay and flow-cytometry analysis on day 0, 28, 50, and 90. RESULTS: On day 28 postvaccination, patients had lower seroprotection (95.2% vs. 75.2%, P < 0.01) and seroconversion (88.7% vs. 51.1%, P < 0.01) rates, as well as geometric mean titer (GMT; 256 vs. 134, P < 0.05), relative to controls. Response to vaccination varied according to the evaluated time point and the patient status: Patients not receiving chemotherapy had seroprotection and GMTs similar to controls in all time points, while patients receiving chemotherapy or allogeneic hematopoietic stem cell transplant (HSCT) had lower seroprotection and seroconversion levels than controls on day 28 and 50. EMEA cutoffs for efficacy were reached from day 28 by patients in follow-up or under treatment and only from day 90 by those with HSCT, especially if still under immunosuppressants. Patients treated with immunomodulatory drugs had higher antibody responses in terms of seroprotection and GMTs. T- and NK cell-mediated responses mounted from day 50 and did not differ between patients and controls. CONCLUSIONS: According to EMEA recommendation, H1N1 vaccination strategy was effective at protecting most of the hematologic patients, but needed to be improved in those more immunocompromised. PMID- 22540246 TI - Crystal structure of the native plasminogen reveals an activation-resistant compact conformation. AB - BACKGROUND: Plasminogen is the zymogen form of plasmin and the precursor of angiostatin. It has been implicated in a variety of disease states, including thrombosis, bleeding and cancers. The native plasminogen, known as Glu plasminogen, contains seven domains comprising the N-terminal peptide domain (NTP), five kringle domains (K1-K5) and the C-terminal serine protease domain (SP). Previous studies have established that the lysine binding site (LBS) of the conserved kringle domains plays a crucial role in mediating the regulation of plasminogen function. However, details of the related conformational mechanism are unknown. OBJECTIVES: We aim to understand in more detail the conformational mechanism of plasminogen activation involving the kringles. METHODS: We crystallized the native plasminogen under physiologically relevant conditions and determined the structure at 3.5 A resolution. We performed structural analyses and related these to the literature data to gain critical understanding of the plasminogen activation. RESULTS AND CONCLUSIONS: The structure reveals the precise architecture of the quaternary complex. It shows that the Glu-plasminogen renders its compact form as an activation-resistant conformation for the proteolytic activation. The LBSs of all kringles, except K1, are engaged in intra molecular interactions while only K1-LBS is readily available for ligand binding or receptor anchorage. The structure also provides insights into the interactions between plasminogen and alpha2-antiplasmin, the primary physiological inhibitor of plasmin. Furthermore, the data presented explain why a conformational transition to the open form is necessary for plasminogen activation as well as angiostatin generation, and provide a rationale for the functional hierarchy of the different kringles. PMID- 22540247 TI - Mechanism and stereoselectivity of a dual amino-catalyzed robinson annulation: rare duumvirate stereocontrol. AB - Computational study of the mechanisms and stereoselectivities of a dual amino catalyzed synthesis of cyclohexenones containing all-carbon gamma-quaternary and ?-tertiary stereocenters is reported. Extensive conformational search with density functional theory optimizations, the high-accuracy SCS-MP2/cc-pVinfinityZ energies, and PCM solvation corrections were used to characterize all intermediates and transition states. Six mechanisms were considered, all consistent with available experiments. The reaction proceeds via sequential Michael and Mannich conjugate additions whereby the primary amine activates the aldehyde and the catalyst activates the pentenone. We have discovered a rare duumvirate stereocontrol: the Michael reaction sets the enantioselectivity, but both the Michael and the Mannich reactions control the diastereoselectivity. PMID- 22540248 TI - Bladder drainage during labor: a randomized controlled trial. AB - AIM: To compare two bladder draining methods during labor on time to delivery, cost and nursing preference. MATERIAL AND METHODS: This trial randomized 139 women with singleton pregnancies in active labor or undergoing induction of labor. Eligibility required an anticipated vaginal delivery with a clinical indication for bladder catheterization (epidural). Participants were randomly assigned to either indwelling or intermittent catheterization. The primary outcome was time to delivery; secondary outcomes were nurse preference, cost and route of delivery. A sample size of 138 women would be needed for 80% power to detect a 30 min difference in the time to delivery interval with a 0.05 alpha error. RESULTS: Outcome data was available for 138 patients (72 indwelling and 66 intermittent). The time to delivery was similar among the two groups (13.8 h for indwelling and 14.4 h for intermittent). Route of delivery and cost estimate was similar in both groups; however, nurses preferred the indwelling method. CONCLUSION: Indwelling catheterization is recommended as the standard method for bladder drainage in laboring women with epidural. PMID- 22540249 TI - Nonutility of routine testing of stool for ova and parasites in a tertiary care Canadian centre. AB - BACKGROUND: In many clinical situations, stool examinations for ova and parasites (O&P) are routine in the work-up of patients with acute or chronic diarrhea. Frequently, these tests are found to be negative for pathogens. The purpose of this study was to examine the diagnostic yield of routine stool testing for O&P in a Canadian tertiary care centre and to estimate the potential clinical benefit of a positive result. PATIENTS AND METHODS: All stool samples sent to the central microbiology laboratory at London Health Sciences Centre were reviewed over a 5 year period ending January 2010. Initial screening was done by direct antigen testing using an enzyme immunoassay (EIA) technique followed by direct microscopy for negative results where there was a high index of suspicion and for positive results to rule out any concurrent parasites not included in the EIA kit. Pathogens identified were categorized and their potential susceptibility to metronidazole was estimated. No clinical data were available, as this was purely a utilization study. RESULTS: A total of 5812 stool tests were ordered. Of these, 5681 (97.7%) were completed. The most common reasons for an incomplete test were sample leakage (n = 38) and use of the incorrect collection kit (n = 32). Direct microscopy identified white blood cells in 17% of patients with positive testing. The most common pathogen was Giardia lamblia , which was detected in 45/83 (54%) of positive specimens. Entamoeba histolytica/Entamoeba dispar was identified in 16/83 (19%) and Cryptosporidium spp. in 10/83 (12%) of positive specimens. Microorganisms not thought to be pathogenic were identified in 7/83 (8%). Direct laboratory costs independent of labor were estimated at $1836 per clinically significant organism identified. Of the 77 specimens positive for pathogenic organisms, 62 (81%) were likely to be sensitive to treatment with metronidazole. CONCLUSION: In a tertiary care centre, the diagnostic yield of routine testing of stool for O&P during the evaluation of patients with acute or chronic diarrhea is low. Most clinically significant positive results should be responsive to metronidazole, but empirical treatment is not encouraged. Strategies to identify patients with a higher likelihood of harboring pathogenic parasites and consideration of empiric metronidazole therapy for patients at highest risk merit further research. PMID- 22540251 TI - Modeling metabolic adaptations and energy regulation in humans. AB - Mathematical modeling of human energy regulation and body weight change has recently reached the level of sophistication required for accurate predictions. Mathematical models are beginning to provide a quantitative framework for integrating experimental data in humans and thereby help us better understand the dynamic imbalances of energy and macronutrients that give rise to changes in body weight and composition. This review provides an overview of the various approaches that have been used to model body weight dynamics and energy regulation in humans, highlights several insights that these models have provided, and suggests how mathematical models can serve as a guide for future experimental research. PMID- 22540250 TI - Race-ethnic differences in the association of genetic loci with HbA1c levels and mortality in U.S. adults: the third National Health and Nutrition Examination Survey (NHANES III). AB - BACKGROUND: Hemoglobin A1c (HbA1c) levels diagnose diabetes, predict mortality and are associated with ten single nucleotide polymorphisms (SNPs) in white individuals. Genetic associations in other race groups are not known. We tested the hypotheses that there is race-ethnic variation in 1) HbA1c-associated risk allele frequencies (RAFs) for SNPs near SPTA1, HFE, ANK1, HK1, ATP11A, FN3K, TMPRSS6, G6PC2, GCK, MTNR1B; 2) association of SNPs with HbA1c and 3) association of SNPs with mortality. METHODS: We studied 3,041 non-diabetic individuals in the NHANES (National Health and Nutrition Examination Survey) III. We stratified the analysis by race/ethnicity (NHW: non-Hispanic white; NHB: non-Hispanic black; MA: Mexican American) to calculate RAF, calculated a genotype score by adding risk SNPs, and tested associations with SNPs and the genotype score using an additive genetic model, with type 1 error = 0.05. RESULTS: RAFs varied widely and at six loci race-ethnic differences in RAF were significant (p < 0.0002), with NHB usually the most divergent. For instance, at ATP11A, the SNP RAF was 54% in NHB, 18% in MA and 14% in NHW (p < .0001). The mean genotype score differed by race ethnicity (NHW: 10.4, NHB: 11.0, MA: 10.7, p < .0001), and was associated with increase in HbA1c in NHW (beta = 0.012 HbA1c increase per risk allele, p = 0.04) and MA (beta = 0.021, p = 0.005) but not NHB (beta = 0.007, p = 0.39). The genotype score was not associated with mortality in any group (NHW: OR (per risk allele increase in mortality) = 1.07, p = 0.09; NHB: OR = 1.04, p = 0.39; MA: OR = 1.03, p = 0.71). CONCLUSION: At many HbA1c loci in NHANES III there is substantial RAF race-ethnic heterogeneity. The combined impact of common HbA1c associated variants on HbA1c levels varied by race-ethnicity, but did not influence mortality. PMID- 22540253 TI - Gene-environment interactions in the development of type 2 diabetes: recent progress and continuing challenges. AB - Type 2 diabetes (T2D) is thought to arise from the complex interplay of both genetic and environmental factors. Since the advent of genome-wide association studies (GWAS), we have seen considerable progress in our understanding of the role that genetics and gene-environment interactions play in the development of T2D. Recent work suggests that the adverse effect of several T2D loci may be abolished or at least attenuated by higher physical activity levels or healthy lifestyle, whereas low physical activity and dietary factors characterizing a Western dietary pattern may augment it. However, there still remain inconsistencies warranting further investigation. Lack of statistical power and measurement errors for the environmental factors continue to challenge our efforts for characterizing interactions. Although our recent focus on established T2D loci is reasonable, we may be overlooking many other potential loci not captured by recent T2D GWAS. Agnostic approaches to the discovery of gene and environment interactions may address this possibility, but their application to the field is currently limited and still faces conceptual challenges. Nonetheless, continued investment in gene-environment interaction studies through large collaborative efforts holds promise in furthering our understanding of the interplay between genetic and environmental factors. PMID- 22540252 TI - Obesity in cancer survival. AB - Although obesity is a well-known risk factor for several cancers, its role on cancer survival is poorly understood. We conducted a systematic literature review to assess the current evidence evaluating the impact of body adiposity on the prognosis of the three most common obesity-related cancers: prostate, colorectal, and breast. We included 33 studies of breast cancer, six studies of prostate cancer, and eight studies of colo-rectal cancer. We note that the evidence overrepresents breast cancer survivorship research and is sparse for prostate and colorectal cancers. Overall, most studies support a relationship between body adiposity and site-specific mortality or cancer progression. However, most of the research was not specifically designed to study these outcomes and, therefore, several methodological issues should be considered before integrating their results to draw conclusions. Further research is urgently warranted to assess the long-term impact of obesity among the growing population of cancer survivors. PMID- 22540254 TI - Population-level intervention strategies and examples for obesity prevention in children. AB - With obesity affecting approximately 12.5 million American youth, population level interventions are indicated to help support healthy behaviors. The purpose of this review is to provide a summary of population-level intervention strategies and specific intervention examples that illustrate ways to help prevent and control obesity in children through improving nutrition and physical activity behaviors. Information is summarized within the settings where children live, learn, and play (early care and education, school, community, health care, home). Intervention strategies are activities or changes intended to promote healthful behaviors in children. They were identified from (a) systematic reviews; (b) evidence- and expert consensus-based recommendations, guidelines, or standards from nongovernmental or federal agencies; and finally (c) peer-reviewed synthesis reviews. Intervention examples illustrate how at least one of the strategies was used in a particular setting. To identify interventions examples, we considered (a) peer-reviewed literature as well as (b) additional sources with research-tested and practice-based initiatives. Researchers and practitioners may use this review as they set priorities and promote integration across settings and to find research- and practice-tested intervention examples that can be replicated in their communities for childhood obesity prevention. PMID- 22540255 TI - New roles of HDL in inflammation and hematopoiesis. AB - High-density lipoprotein (HDL) levels are inversely associated with coronary heart disease due to HDL's ability to transport excess cholesterol in arterial macrophages to the liver for excretion [i.e., reverse cholesterol transport (RCT)]. However, recent advances highlight additional atheroprotective roles for HDL beyond bulk cholesterol removal from cells through RCT. By promoting cellular free cholesterol (FC) efflux, HDL and its apolipoproteins (apoA-I and apoE) decrease plasma membrane FC and lipid raft content in immune and hematopoietic stem cells, decreasing inflammatory and cell proliferation signaling pathways. HDL and apoA-I also dampen inflammatory signaling pathways independent of cellular FC efflux. In addition, HDL lipid and protein cargo provide protection against parasitic and bacterial infection, endothelial damage, and oxidant toxicity. Here, current knowledge is reviewed regarding the role of HDL and its apolipoproteins in regulating cellular cholesterol homeostasis, highlighting recent advances on novel functions and mechanisms by which HDLs regulate inflammation and hematopoiesis. PMID- 22540256 TI - Nutritional metabolomics: progress in addressing complexity in diet and health. AB - Nutritional metabolomics is rapidly maturing to use small-molecule chemical profiling to support integration of diet and nutrition in complex biosystems research. These developments are critical to facilitate transition of nutritional sciences from population-based to individual-based criteria for nutritional research, assessment, and management. This review addresses progress in making these approaches manageable for nutrition research. Important concept developments concerning the exposome, predictive health, and complex pathobiology serve to emphasize the central role of diet and nutrition in integrated biosystems models of health and disease. Improved analytic tools and databases for targeted and nontargeted metabolic profiling, along with bioinformatics, pathway mapping, and computational modeling, are now used for nutrition research on diet, metabolism, microbiome, and health associations. These new developments enable metabolome-wide association studies (MWAS) and provide a foundation for nutritional metabolomics, along with genomics, epigenomics, and health phenotyping, to support the integrated models required for personalized diet and nutrition forecasting. PMID- 22540258 TI - Letter to the editor: standardized use of the terms "sedentary" and "sedentary behaviours". PMID- 22540257 TI - Lipoprotein lipase in the brain and nervous system. AB - Lipoprotein lipase (LPL) is rate limiting in the provision of triglyceride-rich lipoprotein-derived lipids into tissues. LPL is also present in the brain, where its function has remained elusive. Recent evidence implicates a role of LPL in the brain in two processes: (a) the regulation of energy balance and body weight and (b) cognition. Mice with neuron-specific deletion of LPL have increases in food intake that lead to obesity, and then reductions in energy expenditure that further contribute to and sustain the phenotype. In other mice with LPL deficiency rescued from neonatal lethality by somatic gene transfer wherein LPL in the brain remains absent, altered cognition ensues. Taking into consideration data that associate LPL mutations with Alzheimer's disease, a role for LPL in learning and memory seems likely. Overall, the time is ripe for new insights into how LPL-mediated lipoprotein metabolism in the brain impacts CNS processes and systems biology. PMID- 22540260 TI - Electrochemical impedance study of the hematite/water interface. AB - Reactions taking place on hematite (alpha-Fe(2)O(3)) surfaces in contact with aqueous solutions are of paramount importance to environmental and technological processes. The electrochemical properties of the hematite/water interface are central to these processes and can be probed by open circuit potentials and cyclic voltammetric measurements of semiconducting electrodes. In this study, electrochemical impedance spectroscopy (EIS) was used to extract resistive and capacitive attributes of this interface on millimeter-sized single-body hematite electrodes. This was carried out by developing equivalent circuit models for impedance data collected on a semiconducting hematite specimen equilibrated in solutions of 0.1 M NaCl and NH(4)Cl at various pH values. These efforts produced distinct sets of capacitance values for the diffuse and compact layers of the interface. Diffuse layer capacitances shift in the pH 3-11 range from 2.32 to 2.50 MUF.cm(-2) in NaCl and from 1.43 to 1.99 MUF.cm(-2) in NH(4)Cl. Furthermore, these values reach a minimum capacitance at pH 9, near a probable point of zero charge for an undefined hematite surface exposing a variety of (hydr)oxo functional groups. Compact layer capacitances pertain to the transfer of ions (charge carriers) from the diffuse layer to surface hydroxyls and are independent of pH in NaCl, with values of 32.57 +/- 0.49 MUF.cm(-2).s(-phi). However, they decrease with pH in NH(4)Cl from 33.77 at pH 3.5 to 21.02 MUF.cm(-2).s(-phi) at pH 10.6 because of the interactions of ammonium species with surface (hydr)oxo groups. Values of phi (0.71-0.73 in NaCl and 0.56-0.67 in NH(4)Cl) denote the nonideal behavior of this capacitor, which is treated here as a constant phase element. Because electrode-based techniques are generally not applicable to the commonly insulating metal (oxyhydr)oxides found in the environment, this study presents opportunities for exploring mineral/water interface chemistry by EIS studies of single-body hematite specimens. PMID- 22540261 TI - Kinetic and solvent deuterium isotope effects in the oxidation of putrescine catalysed by enzyme diamine oxidase. AB - In this study, the kinetic isotope effects and solvent isotope effects in the reaction of the deamination of [(1R)-(2)H ] putrescine--catalysed by enzyme diamine oxidase (EC 1.4.3.6)--were determined using a non-competitive spectroscopic method. Putrescine, stereospecifically labelled with deuterium, was obtained by enzymatic decarboxylation of l-ornithine that was carried out in a fully deuteriated incubation medium. PMID- 22540263 TI - Could an advance practice nurse improve detection of alcohol misuse in the emergency department? AB - Alcohol misuse is a prevalent problem in New Zealand society, and one that exacts a considerable cost in terms of health, social cohesion, and economic productivity. Despite the burden of alcohol misuse, screening, brief assessment, and interventions for alcohol problems are frequently poorly performed within general health services. In this paper we explore the response to alcohol problems in a New Zealand emergency department and discuss difficulties encountered in improving rates of detection by emergency department personnel. We report the results of a clinical audit of alcohol screening and brief assessment and a staff education programme designed to improve practice in this area, but which met with limited success. The potential role for an advanced practice nurse providing a clinical consultation and liaison service to the emergency department staff is explored. We argue that such a role has potential to reduce the health and social costs of alcohol misuse, and to meet the national policy objective of providing a treatment response to people with alcohol-related problems in contact with health services. PMID- 22540264 TI - The rs150311303 polymorphism in FcgammaRIIa enhances IgG binding capacity. AB - Fc gamma receptor (FcgammaR) provides an important link between humoral and cellular immune responses. FcgammaRIIa-H131R polymorphism has been associated with differential binding to IgG subclasses and susceptibility to severe malaria phenotypes among different populations in the malaria endemic world. In this study, the effect of FCGR2A gene polymorphisms on susceptibility to symptomatic malaria among Ghanaian cohort children was investigated. Blood samples from four hundred and 29 (429) healthy Ghanaian children were genotyped for FCGR2A polymorphisms by direct DNA sequencing. Attributable and relative risks to symptomatic malaria were calculated for the polymorphic variants. Two major FCGR2A polymorphisms, rs1801274A/G (FcgammaRIIa-H131R) and rs150311303 (FcgammaRIIa-ins170L), were identified in the study population, and assessment of their risks did not show significant association with susceptibility to symptomatic malaria. The functional significance of these polymorphisms was also examined by evaluating their binding abilities to IgG subclasses using flow cytometric analysis of HEK cells transfected with the FcgammaRIIa haplotype variants. The binding assay revealed the rs150311303, which was observed only among carriers of the FcgammaRIIa-131RR genotype for the rs1801274 to consistently enhance binding capacities to all IgG subclasses. Thus, of the three FcgammaRIIa haplotype variants observed in this study population, the FcgammaRIIa(RL) haplotype variant was observed to have the highest binding ability to IgG1, IgG3 and IgG4. PMID- 22540262 TI - Mitogen activated protein kinase phosphatase-1 prevents the development of tactile sensitivity in a rodent model of neuropathic pain. AB - BACKGROUND: Neuropathic pain due to nerve injury is one of the most difficult types of pain to treat. Following peripheral nerve injury, neuronal and glial plastic changes contribute to central sensitization and perpetuation of mechanical hypersensitivity in rodents. The mitogen activated protein kinase (MAPK) family is pivotal in this spinal cord plasticity. MAPK phosphatases (MKPs) limit inflammatory processes by dephosphorylating MAPKs. For example, MKP-1 preferentially dephosphorylates p-p38. Since spinal p-p38 is pivotal for the development of chronic hypersensitivity in rodent models of pain, and p-p38 inhibitors have shown clinical potential in acute and chronic pain patients, we hypothesize that induction of spinal MKP-1 will prevent the development of peripheral nerve-injury-induced hypersensitivity and p-p38 overexpression. RESULTS: We cloned rat spinal cord MKP-1 and optimize MKP-1 cDNA in vitro using transfections to BV-2 cells. We observed that in vitro overexpression of MKP-1 blocked lipopolysaccharide-induced phosphorylation of p38 (and other MAPKs) as well as release of pro-algesic effectors (i.e., cytokines, chemokines, nitric oxide). Using this cDNA MKP-1 and a non-viral, in vivo nanoparticle transfection approach, we found that spinal cord overexpression of MKP-1 prevented development of peripheral nerve-injury-induced tactile hypersensitivity and reduced pro inflammatory cytokines and chemokines and the phosphorylated form of p38. CONCLUSIONS: Our results indicate that MKP-1, the natural regulator of p-p38, mediates resolution of the spinal cord pro-inflammatory milieu induced by peripheral nerve injury, resulting in prevention of chronic mechanical hypersensitivity. We propose that MKP-1 is a potential therapeutic target for pain treatment or prevention. PMID- 22540265 TI - The risks of red cell transfusion for hip fracture surgery in the elderly. AB - BACKGROUND AND OBJECTIVES: The benefits and indications for blood transfusion among surgical patients are controversial. There is evidence which suggests that blood transfusion is associated with poor clinical outcomes and risks of infection, but there are few data in the elderly population. MATERIALS AND METHODS: Data were collected on haemoglobin concentrations and transfusions in 919 patients undergoing hip fracture repair at a university hospital over a 2 year period. 28-day and 180-day mortality were specified as primary outcomes. A composite infection outcome (chest infections, urinary tract infections and wound infections) was the main secondary outcome. Preoperative, operative and/or postoperative transfusions were the main exposure variable. Regression analyses were used to explore the associations between transfusion and outcomes, adjusting for pre-defined preoperative variables. RESULTS: 300 patients (32.6%) were transfused at least once during their admission. There was no evidence of a significant difference in either 28-day survival or 180-day survival between transfused and non-transfused hip fracture patients. The transfused group had higher adjusted composite infection rate (HR, 1.91; 95% CI, 1.41-2.59, P < 0.001) and prolonged length of stay in hospital than the non-transfused group (HR, 1.15; 95% CI, 1.07, 1.23, P < 0.001). Anaemia at the time of admission, extra capsular fracture and using walking aids in an indoor setting were preoperative variables, which predicted the need for transfusion. CONCLUSION: Among an elderly population with hip fracture, blood transfusion was not associated with changes in mortality, but was associated with an increased rate of postoperative infection. These data add to the wider literature about adverse clinical outcomes in patients receiving blood transfusions and emphasises the need for prospective trials to evaluate the role of transfusion in the elderly. PMID- 22540266 TI - A two-stage cluster sampling method using gridded population data, a GIS, and Google Earth(TM) imagery in a population-based mortality survey in Iraq. AB - BACKGROUND: Mortality estimates can measure and monitor the impacts of conflict on a population, guide humanitarian efforts, and help to better understand the public health impacts of conflict. Vital statistics registration and surveillance systems are rarely functional in conflict settings, posing a challenge of estimating mortality using retrospective population-based surveys. RESULTS: We present a two-stage cluster sampling method for application in population-based mortality surveys. The sampling method utilizes gridded population data and a geographic information system (GIS) to select clusters in the first sampling stage and Google Earth TM imagery and sampling grids to select households in the second sampling stage. The sampling method is implemented in a household mortality study in Iraq in 2011. Factors affecting feasibility and methodological quality are described. CONCLUSION: Sampling is a challenge in retrospective population-based mortality studies and alternatives that improve on the conventional approaches are needed. The sampling strategy presented here was designed to generate a representative sample of the Iraqi population while reducing the potential for bias and considering the context specific challenges of the study setting. This sampling strategy, or variations on it, are adaptable and should be considered and tested in other conflict settings. PMID- 22540267 TI - Validation of a commercial ELISA for the analysis of the insecticide dinotefuran in a variety of analytically challenging vegetables. AB - The main objective of this paper was to assess the suitability of an enzyme linked immunosorbent assay (ELISA) as a rapid and simple screening method for the detection of neonicotinoid insecticide dinotefuran residues in various vegetable samples including carrot, cabbage, green pepper, leek, Japanese mustard spinach (komatsuna), and spinach. Simple dilution of crude sample extracts was effective to circumvent or reduce matrix interference derived from samples. Consequently, ELISA was useful to determine dinotefuran accurately and directly, only requiring methanol extraction and dilution with water. The theoretically estimated limit of detection of dinotefuran for tested samples ranged from 0.06 to 0.12 mg kg(-1). The ELISA gave recovery values close to 100% for all samples except komatsuna, which contained lower concentration levels, and the results of the ELISA agreed well with those obtained with conventional HPLC (r > 0.99). Results show that the ELISA evaluated in this study is suitable for the rapid and simple screening method of dinotefuran residue in agricultural samples even without sample pre treatment. PMID- 22540268 TI - Cutaneous amalgam tattoo in a dental professional: an unreported occupational argyria. PMID- 22540270 TI - Structure elucidation of new fusarins revealing insights in the rearrangement mechanisms of the Fusarium mycotoxin fusarin C. AB - Fusarin C is a Fusarium mycotoxin that rearranges under reversed phase chromatographic conditions. In this study, the rearrangement of fusarin C was examined in detail, and the formation of fusarins under different conditions was optimized. All relevant fusarins including (10Z)-, (8Z)-, and (6Z)-fusarin C were isolated and identified by NMR. To confirm the involvement of the 2-pyrrolidone ring in the rearrangement of fusarin C, 15-methoxy-fusarin C was synthesized. For the first time, the structure of open-chain fusarin C was elucidated, and on the basis of these data, the rearrangement product of fusarin C was identified as epi fusarin C. The results were confirmed by detailed NMR measurements and density functional theory calculations. Furthermore, a new fusarin C like metabolite, which was named dihydrofusarin C, was detected by analysis of the crude extract of fusarin C with high-performance liquid chromatography coupled to UV and Fourier transform mass spectrometry. PMID- 22540269 TI - Bioequivalence and x-ray visibility of a radiopaque etonogestrel implant versus a non-radiopaque implant: a 3-year, randomized, double-blind study. AB - BACKGROUND: The etonogestrel (ENG)-releasing implant is a subdermal progestogen only contraceptive that provides coverage for up to 3 years. This long-acting hormonal contraceptive has been available in Europe since 1998 and in the US since 2006. To date, localization of non-palpable implants at insertion and before removal has been dependent on ultrasound or magnetic resonance imaging by an experienced clinician. To facilitate localization in rare cases of non palpable implants using widely available equipment without the need for a specialist, a radiopaque ENG implant has been developed that is detectable by two dimensional x-ray imaging. OBJECTIVE: This study aimed to establish whether the radiopaque ENG implant is bioequivalent in situ compared with the original non radiopaque ENG implant, and to assess x-ray visibility of the radiopaque ENG implant. METHODS: This was a 3-year, randomized, double-blind, parallel-group study carried out in nine international clinical trial centres. Women aged 18-40 years at the time of screening, with menstrual cycles of a usual length of 24-35 days and a body mass index of between >=18 and <=29 kg/m(2) were included. Women were assigned to either the radiopaque or non-radiopaque ENG implant in a 1 : 1 ratio via a block randomization by centre. Bioequivalence testing was performed based on the peak ENG concentration (C(max)), and the area under the curve (AUC) for ENG at 6, 24 and 36 months (AUC(6 mo), AUC(24 mo) and AUC(36 mo)) after insertion. For this purpose, blood sampling for pharmacokinetic determination was performed prior to insertion and for up to 3 years afterwards. Bioequivalence was defined as the 90% confidence interval (CI) of the ratio radiopaque implant/non radiopaque implant of the geometric means (GMR) within the acceptance range of 0.80-1.25. x-Ray visibility was assessed by two-dimensional x-ray imaging after insertion and before removal of the implant. RESULTS: The pharmacokinetic profiles of ENG indicated that the radiopaque and non-radiopaque implants were bioequivalent with respect to the geometric mean of C(max) (GMR 1.06; 90% CI 0.91, 1.23), AUC(6 mo) (GMR 1.00; 90% CI 0.91, 1.10), AUC(24 mo) (GMR 0.98; 90% CI 0.88, 1.10) and AUC(36 mo) (GMR 1.00; 90% CI 0.89, 1.11). The radiopaque ENG implant was clearly visible in 50 out of 52 women after insertion and in all 52 women before removal, whereas none of the non-radiopaque implants were visible. CONCLUSION: The radiopaque ENG implant is bioequivalent in situ compared with the original non-radiopaque ENG implant and is clearly visible using x-ray imaging. CLINICAL TRIALS REGISTRATION: Registered as ClinicalTrials.gov identifier NCT00620464. PMID- 22540271 TI - Quantification of proteins by functionalized gold nanoparticles using click chemistry. AB - This letter presents a click-chemistry-based assay for proteins (CAP) that allows quantitative determination of the concentration of proteins, using azide- and alkyne-functionalized gold nanoparticles (AuNPs). Compared with conventional methods, CAP has a broader linear range for detection of proteins with good selectivity. CAP enables the analysis of total proteins in various sera and milk samples. PMID- 22540276 TI - Direct simulation of magnetic resonance relaxation rates and line shapes from molecular trajectories. AB - We simulate spin relaxation processes, which may be measured by either continuous wave or pulsed magnetic resonance techniques, using trajectory-based simulation methodologies. The spin-lattice relaxation rates are extracted numerically from the relaxation simulations. The rates obtained from the numerical fitting of the relaxation curves are compared to those obtained by direct simulation from the relaxation Bloch-Wangsness-Abragam-Redfield theory (BWART). We have restricted our study to anisotropic rigid-body rotational processes, and to the chemical shift anisotropy (CSA) and a single spin-spin dipolar (END) coupling mechanisms. Examples using electron paramagnetic resonance (EPR) nitroxide and nuclear magnetic resonance (NMR) deuterium quadrupolar systems are provided. The objective is to compare those rates obtained by numerical simulations with the rates obtained by BWART. There is excellent agreement between the simulated and BWART rates for a Hamiltonian describing a single spin (an electron) interacting with the bath through the chemical shift anisotropy (CSA) mechanism undergoing anisotropic rotational diffusion. In contrast, when the Hamiltonian contains both the chemical shift anisotropy (CSA) and the spin-spin dipolar (END) mechanisms, the decay rate of a single exponential fit of the simulated spin-lattice relaxation rate is up to a factor of 0.2 smaller than that predicted by BWART. When the relaxation curves are fit to a double exponential, the slow and fast rates extracted from the decay curves bound the BWART prediction. An extended BWART theory, in the literature, includes the need for multiple relaxation rates and indicates that the multiexponential decay is due to the combined effects of direct and cross-relaxation mechanisms. PMID- 22540278 TI - Liver function assessment with three (13)C breath tests by two-point measurements. AB - In this study, we performed three breath tests - l-[1-(13)C ]phenylalanine breath test (PBT), l-[1-(13)C ] methionine breath test, and [(13)C]methacetin breath test (MethaBT) - in patients with chronic liver disease to determine the optimal timing of expired air collection for diagnosing chronic liver disease and evaluating the grade of fibrosis. The subjects were 61 adults with normal livers, 98 chronic hepatitis patients, and 91 liver cirrhosis patients. We investigated the relationships of breath test results with routine biochemical tests and the Child-Pugh score, as well as the diagnostic capacities of the breath tests for liver dysfunction/cirrhosis and grade of liver fibrosis. For the diagnosis of liver cirrhosis and correlations with liver fibrosis, the accuracy of the PBT at 30 min (PBT30) was similar to that of the MethaBT at 15 min (Metha15). For liver function assessment by two-point measurement with (13)C breath tests, we recommend the PBT30 and the Metha15. PMID- 22540277 TI - Molecular cycloencapsulation augments solubility and improves therapeutic index of brominated noscapine in prostate cancer cells. AB - We have previously shown that a novel microtubule-modulating noscapinoid, EM011 (9-Br-Nos), displays potent anticancer activity by inhibition of cellular proliferation and induction of apoptosis in prostate cancer cells and preclinical mice models. However, physicochemical and cellular barriers encumber the development of viable formulations for future clinical translation. To circumvent these limitations, we have synthesized EM011-cyclodextrin inclusion complexes to improve solubility and enhance therapeutic index of EM011. Phase solubility analysis indicated that EM011 formed a 1:1 stoichiometric complex with beta-CD and methyl-beta-CD, with a stability constant (K(c)) of 2.42 * 10(-3) M and 4.85 * 10(-3) M, respectively. Fourier transform infrared spectroscopy suggested the penetrance of either a O-CH(2) or OCH(3)-C(6)H(4)-OCH(3) moiety of EM011 in the beta-CD or methyl-beta-CD cavity. In addition, multifarious techniques, namely, differential scanning calorimetry, powder X-ray diffraction, scanning electron microscopy, NMR spectroscopy, and computational studies validated the cage complex of EM011 with beta-CD and methyl-beta-CD. Moreover, rotating frame overhauser enhancement spectroscopy showed that the H(a) proton of the OCH(3) C(6)H(4)-OCH(3) moiety was in close proximity with H3 proton of the beta-CD or methyl-beta-CD cavity. Furthermore, we found that the solubility of EM011 in phosphate buffer saline (pH 7.4) was enhanced by ~11 fold and ~21 fold upon complexation with beta-CD and methyl-beta-CD, respectively. The enhanced dissolution of the drug CD-complexes in aqueous phase remarkably decreased their IC(50) to 28.5 MUM (9-Br-Nos-beta-CD) and 12.5 MUM (9-Br-Nos-methyl-beta-CD) in PC-3 cells compared to free EM011 (~200 MUM). This is the first report to demonstrate the novel construction of cylcodextrin-based nanosupramolecular vehicles for enhanced delivery of EM011 that warrants in vivo evaluation for the superior management of prostate cancer. PMID- 22540279 TI - Effect of time to infusion of autologous stem cells (24 vs. 48 h) after high-dose melphalan in patients with multiple myeloma. AB - High-dose melphalan (HD-Mel) is considered the current standard of care among the preparative regimens used in autologous peripheral blood stem cell transplantation (SCT) for multiple myeloma (MM), but optimal time and schedule of administration is not defined. We retrospectively analyzed outcomes and toxicities of HD-Mel administered on day -2 vs. day -1 before autologous stem cells infusion. A total of 138 consecutive MM patients treated at Penn State Hershey Cancer Institute between 2007 and 2010 were included in this study. No difference in time to hematopoietic recovery, common SCT-related toxicities, and clinical outcomes was seen between patients who received HD-Mel on day -2 (group A, n = 47), and those who received it on day -1 (group B, n = 91). Prompt and full hematopoietic recovery occurred even when stem cells were infused between 8 and 24 h after completion of chemotherapy. In the absence of prospective and randomized data, we conclude that a single I.V. infusion of HD-Mel on day -1 is a safe and effective practice, and the so-called 'day of rest' before the transplant appears not to be necessary. PMID- 22540280 TI - Morphology of basal cell carcinoma in high definition optical coherence tomography: en-face and slice imaging mode, and comparison with histology. AB - BACKGROUND: Optical coherence tomography (OCT) allows real-time, in vivo examination of basal cell carcinoma (BCC). A new high definition OCT with high lateral and axial resolution in a horizontal (en-face) and vertical (slice) imaging mode offers additional information in the diagnosis of BCC and may potentially replace invasive diagnostic biopsies. OBJECTIVES: To define the characteristic morphologic features of BCC by using high definition optical coherence tomography (HD-OCT) compared to conventional histology. METHODS: A total of 22 BCCs were examined preoperatively by HD-OCT in the en-face and slice imaging mode and characteristic features were evaluated in comparison to the histopathological findings. RESULTS: The following features were found in the en face mode of HD-OCT: lobulated nodules (20/22), peripheral rimming (17/22), epidermal disarray (21/22), dilated vessels (11/22) and variably refractile stroma (19/22). In the slice imaging mode the following characteristics were found: grey/dark oval structures (18/22), peripheral rimming (13/22), destruction of layering (22/22), dilated vessels (7/22) and peritumoural bright stroma (11/22). In the en-face mode the lobulated structure of the BCC was more distinct than in the slice mode compared to histology. CONCLUSION: HD-OCT with a horizontal and vertical imaging mode offers additional information in the diagnosis of BCC compared to conventional OCT imaging and enhances the feasibility of non-invasive diagnostics of BCC. PMID- 22540281 TI - H4octapa: an acyclic chelator for 111In radiopharmaceuticals. AB - This preliminary investigation of the octadentate acyclic chelator H(4)octapa (N(4)O(4)) with (111)In/(115)In(3+) has demonstrated it to be an improvement on the shortcomings of the current industry "gold standards" DOTA (N(4)O(4)) and DTPA (N(3)O(5)). The ability of H(4)octapa to radiolabel quantitatively (111)InCl(3) at ambient temperature in 10 min with specific activities as high as 2.3 mCi/nmol (97.5% radiochemical yield) is presented. In vitro mouse serum stability assays have demonstrated the (111)In complex of H(4)octapa to have improved stability when compared to DOTA and DTPA over 24 h. Mouse biodistribution studies have shown that the radiometal complex [(111)In(octapa)]( ) has exceptionally high in vivo stability over 24 h with improved clearance and stability compared to [(111)In(DOTA)](-), demonstrated by lower uptake in the kidneys, liver, and spleen at 24 h. (1)H/(13)C NMR studies of the [In(octapa)](-) complex revealed a 7-coordinate solution structure, which forms a single isomer and exhibits no observable fluxional behavior at ambient temperature, an improvement to the multiple isomers formed by [In(DTPA)](2-) and [In(DOTA)](-) under the same conditions. Potentiometric titrations have determined the thermodynamic formation constant of the [In(octapa)](-) complex to be log K(ML) = 26.8(1). Through the same set of analyses, the [(111/115)In(decapa)](2-) complex was found to have nonoptimal stability, with H(5)decapa (N(5)O(5)) being more suitable for larger metal ions due to its higher potential denticity (e.g., lanthanides and actinides). Our initial investigations have revealed the acyclic chelator H(4)octapa to be a valuable alternative to the macrocycle DOTA for use with (111)In, and a significant improvement to the acyclic chelator DTPA. PMID- 22540282 TI - A tyrosine aminotransferase involved in tocopherol synthesis in Arabidopsis. AB - The metabolic function of the predicted Arabidopsis tyrosine aminotransferase (TAT) encoded by the At5g53970 gene was studied using two independent knock-out mutants. Gas chromatography-mass spectrometry based metabolic profiling revealed a specific increase in tyrosine levels, supporting the proposed function of At5g53970 as a tyrosine-specific aminotransferase not involved in tyrosine biosynthesis, but rather in utilization of tyrosine for other metabolic pathways. The TAT activity of the At5g53970-encoded protein was verified by complementation of the Escherichia coli tyrosine auxotrophic mutant DL39, and in vitro activity of recombinantly expressed and purified At5g53970 was found to be specific for tyrosine. To investigate the physiological role of At5g53970, the consequences of reduction in tyrosine utilization on metabolic pathways having tyrosine as a substrate were analysed. We found that tocopherols were substantially reduced in the mutants and we conclude that At5g53970 encodes a TAT important for the synthesis of tocopherols in Arabidopsis. PMID- 22540283 TI - Local versus systemic anti-tumour necrosis factor-alpha effects of adalimumab in rheumatoid arthritis: pharmacokinetic modelling analysis of interaction between a soluble target and a drug. AB - BACKGROUND AND OBJECTIVE: The pharmacokinetic models that are applied to describe the disposition of therapeutic antibodies assume that the interaction between an antibody and its target takes place in the central compartment. However, an increasing number of therapeutic antibodies are directed towards soluble/mobile targets. A flawed conclusion can be reached if the pharmacokinetic and pharmacodynamic analysis assumes that the interaction between the therapeutic antibody and its target takes place in the central compartment. The objective of this study was to assess the relative importance of local versus systemic interactions between adalimumab and tumour necrosis factor (TNF)-alpha in rheumatoid arthritis (RA), identify localization of the site of adalimumab action and assess the efficacy of local (intra-articular) versus systemic adalimumab administration for treatment of RA. METHODS: The clinical and preclinical data on adalimumab and TNFalpha disposition were analysed using a pharmacokinetic modelling and simulation approach. The disposition of adalimumab and TNFalpha and the interaction between them at the individual compartments (the synovial fluid of the affected joints, central and peripheral compartments) following different routes of adalimumab administration were studied. RESULTS: Outcomes of modelling and simulation using the pharmacokinetic model developed indicate that adalimumab can efficiently permeate from the diseased joints to the central circulation in RA patients. Permeability of TNFalpha, which is excessively secreted in the joints, is even higher than that of adalimumab. As a result, subcutaneous, intravenous and intra-articular administration of the clinically used dose of adalimumab (40 mg) exert similar effects on the time course of TNFalpha concentrations at different locations in the body and efficiently deplete the TNFalpha in all of the compartments for a prolonged period of time (8-10 weeks). At this dose, adalimumab exhibits predominantly systemic anti-TNFalpha effects at the central and peripheral compartments (~93% of the overall effect) and the contribution of the local effects in the rheumatic joints is ~7% for all of the studied routes, including the local intra-articular injections. The major pathway of TNFalpha elimination from the synovial fluid (~77% for subcutaneous administration, and ~72% for intravenous and intra-articular administration of adalimumab 40 mg) is interaction with adalimumab, which reaches the joints following local or systemic administration. CONCLUSIONS: The kinetics of adalimumab permeation to the synovial fluid (0.00422 L/h clearance of permeation) versus the rate of TNFalpha turnover in the affected joints (1.84 pmol/h synthesis rate and 0.877 h(-1) degradation rate constant) are apparently the major parameters that determine the time course of TNFalpha concentrations in the synovial fluid and the TNFalpha-neutralizing effects of adalimumab in RA patients. Outcomes of this study suggest that intra-articular administration of adalimumab is not preferable to subcutaneous or intravenous treatment. Local and systemic permeability, turnover and interactions between the drug and the target should be taken into account for optimization of the use of drugs acting on soluble targets (growth factors, interferons, interleukins, immunoglobulins, etc.). PMID- 22540285 TI - Comparison of fast gas chomatography-surface acoustic wave (FGC-SAW) detection and GC-MS for characterizing blueberry cultivars and maturity. AB - A novel analytical method using fast gas chromatography-surface acoustic wave detection (FGC-SAW) was employed to rapidly characterize blueberry volatile profiles according to genotypes and fruit maturity. Fourteen FGC-SAW peaks were observed and 11 peaks were tentatively identified in the 15 s chromatogram. Peak identifications were confirmed by matching retention index values with similar values from GC-MS analyses of the same samples. Eighty peaks were observed in the 40 min GC-MS analysis of identical samples. Principal component analysis (PCA) score plots of FGC-SAW and GC-MS data both differentiated blueberries according to genotype, maturity stage, and harvest date even though FGC-SAW PCA's used far fewer peak area values. PCA plots clearly separated 'FL02-40', 'Snowchaser', 'Jewel', and 'Primadonna' blueberry cultivars into four quarters using two dimensional PCA projections. FGC-SAW was also successful in differentiating three berry maturity stages in PCA score plots for both 'Jewel' and 'Primadonna' cultivars. FGC-SAW is an effective technique for rapid analysis of major blueberry volatiles, but could not determine many mid- and low-level volatiles as they were often coeluted with higher concentration volatiles. PMID- 22540284 TI - In-depth proteomic analysis of a mollusc shell: acid-soluble and acid-insoluble matrix of the limpet Lottia gigantea. AB - BACKGROUND: Invertebrate biominerals are characterized by their extraordinary functionality and physical properties, such as strength, stiffness and toughness that by far exceed those of the pure mineral component of such composites. This is attributed to the organic matrix, secreted by specialized cells, which pervades and envelops the mineral crystals. Despite the obvious importance of the protein fraction of the organic matrix, only few in-depth proteomic studies have been performed due to the lack of comprehensive protein sequence databases. The recent public release of the gastropod Lottia gigantea genome sequence and the associated protein sequence database provides for the first time the opportunity to do a state-of-the-art proteomic in-depth analysis of the organic matrix of a mollusc shell. RESULTS: Using three different sodium hypochlorite washing protocols before shell demineralization, a total of 569 proteins were identified in Lottia gigantea shell matrix. Of these, 311 were assembled in a consensus proteome comprising identifications contained in all proteomes irrespective of shell cleaning procedure. Some of these proteins were similar in amino acid sequence, amino acid composition, or domain structure to proteins identified previously in different bivalve or gastropod shells, such as BMSP, dermatopontin, nacrein, perlustrin, perlucin, or Pif. In addition there were dozens of previously uncharacterized proteins, many containing repeated short linear motifs or homorepeats. Such proteins may play a role in shell matrix construction or control of mineralization processes. CONCLUSIONS: The organic matrix of Lottia gigantea shells is a complex mixture of proteins comprising possible homologs of some previously characterized mollusc shell proteins, but also many novel proteins with a possible function in biomineralization as framework building blocks or as regulatory components. We hope that this data set, the most comprehensive available at present, will provide a platform for the further exploration of biomineralization processes in molluscs. PMID- 22540286 TI - Qualitative identification of permitted and non-permitted colour additives in food products. AB - Colour additives are dyes, pigments or other substances that can impart colour when added or applied to food, drugs, cosmetics, medical devices, or the human body. The substances must be pre-approved by the US Food and Drug Administration (USFDA) and listed in Title 21 of the US Code of Federal Regulations before they may be used in products marketed in the United States. Some also are required to be batch certified by the USFDA prior to their use. Both domestic and imported products sold in interstate commerce fall under USFDA jurisdiction, and the USFDA's district laboratories use a combination of analytical methods for identifying or confirming the presence of potentially violative colour additives. We have developed a qualitative method for identifying 17 certifiable, certification exempt, and non-permitted colour additives in various food products. The method involves extracting the colour additives from a product and isolating them from non-coloured components with a C(18) Sep-Pak cartridge. The colour additives are then separated and identified by liquid chromatography (LC) with photodiode array detection, using an Xterra RP18 column and gradient elution with aqueous ammonium acetate and methanol. Limits of detection (LODs) ranged from 0.02 to 1.49 mg/l. This qualititative LC method supplements the visible spectrophotometric and thin-layer chromatography methods currently used by the USFDA's district laboratories and is less time-consuming and requires less solvent compared to the other methods. The extraction step in the new LC method is a simple and an efficient process that can be used for most food types. PMID- 22540287 TI - Lamina I NK1 expressing projection neurones are functional in early postnatal rats and contribute to the setting up of adult mechanical sensory thresholds. AB - BACKGROUND: A small proportion of lamina I neurons of the spinal cord project upon the hindbrain and are thought to engage descending pathways that modulate the behavioural response to peripheral injury. Early postnatal development of nociception in rats is associated with exaggerated and diffuse cutaneous reflexes with a gradual refinement of responses over the first postnatal weeks related to increased participation of inhibitory networks. This study examined the postnatal development of lamina I projection neurons from postnatal day 3 (P3) until P48. RESULTS: At P3, a subset of lamina I neurons were found to express the neurokinin 1 (NK1) receptor. Using fluorogold retrograde tracing, we found that the NK1 positive neurons projected upon the parabrachial nucleus (PB) within the hindbrain. Using c-fos immunohistochemistry, we showed that lamina I and PB neurons in P3 rats responded to noxious stimulation of the periphery. Finally, ablation of lamina I neurons with substance-P saporin conjugates at P3 resulted in increased mechanical sensitivity from P45 onwards compared to control animals of the same age. CONCLUSIONS: These results suggest that the lamina I pathway is present and functional at least from P3 and required for establishing and fine tuning mechanical sensitivity in adult rats. PMID- 22540288 TI - CDKD: a clinical database of kidney diseases. AB - BACKGROUND: The main function of the kidneys is to remove waste products and excess water from the blood. Loss of kidney function leads to various health issues, such as anemia, high blood pressure, bone disease, disorders of cholesterol. The main objective of this database system is to store the personal and laboratory investigatory details of patients with kidney disease. The emphasis is on experimental results relevant to quantitative renal physiology, with a particular focus on data relevant for evaluation of parameters in statistical models of renal function. DESCRIPTION: Clinical database of kidney diseases (CDKD) has been developed with patient confidentiality and data security as a top priority. It can make comparative analysis of one or more parameters of patient's record and includes the information of about whole range of data including demographics, medical history, laboratory test results, vital signs, personal statistics like age and weight. CONCLUSIONS: The goal of this database is to make kidney-related physiological data easily available to the scientific community and to maintain & retain patient's record. As a Web based application it permits physician to see, edit and annotate a patient record from anywhere and anytime while maintaining the confidentiality of the personal record. It also allows statistical analysis of all data. PMID- 22540289 TI - Bacterial contamination of tile drainage water and shallow groundwater under different application methods of liquid swine manure. AB - A 2 year field experiment evaluated liquid manure application methods on the movement of manure-borne pathogens (Salmonella sp.) and indicator bacteria (Escherichia coli and Clostridium perfringens) to subsurface water. A combination of application methods including surface application, pre-application tillage, and post-application incorporation were applied in a randomized complete block design on an instrumented field site in spring 2007 and 2008. Tile and shallow groundwater were sampled immediately after manure application and after rainfall events. Bacterial enumeration from water samples showed that the surface-applied manure resulted in the highest concentration of E. coli in tile drainage water. Pre-tillage significantly (p < 0.05) reduced the movement of manure-based E. coli and C. perfringens to tile water and to shallow groundwater within 3 days after manure application (DAM) in 2008 and within 10 DAM in 2007. Pre-tillage also decreased the occurrence of Salmonella sp. in tile water samples. Indicator bacteria and pathogens reached nondetectable levels within 50 DAM. The results suggest that tillage before application of liquid swine manure can minimize the movement of bacteria to tile and groundwater, but is effective only for the drainage events immediately after manure application or initial rainfall associated drainage flows. Furthermore, the study highlights the strong association between bacterial concentrations in subsurface waters and rainfall timing and volume after manure application. PMID- 22540291 TI - A note on Ostericum koreanum. PMID- 22540290 TI - Prevention and control of childhood asthma and allergy in the EU from the public health point of view: Polish Presidency of the European Union. AB - The leading priority for the Polish Presidency of the Council of the European Union was to reduce health inequalities across European societies, and, within its framework, prevention and control of respiratory diseases in children. This very important paper contain proposal of international cooperation on the prevention, early detection and monitoring of asthma and allergic diseases in childhood which will be undertaken by the EU member countries as a result of EU conclusion developed during the Polish Presidency of the Council of the European Union. This will result in collaboration in the field of chronic diseases, particularly respiratory diseases, together with the activity of the network of national institutions and NGOs in this area. Paper also contains extensive analysis of the socio-economic, political, epidemiological, technological and medical factors affecting the prevention and control of childhood asthma and allergy presented during Experts presidential conference organized in Warsaw-Ossa 21-22 September 2011. PMID- 22540292 TI - Stress adaptation of Saccharomyces cerevisiae as monitored via metabolites using two-dimensional NMR spectroscopy. AB - Many studies on yeast metabolism are focused on its response to specific stress conditions because the results can be extended to the human medical issues. Most of those works have been accomplished through functional genomics studies. However, these changes may not show a linear correlation with protein or metabolite levels. For many organisms including yeast, the number of metabolites is far fewer than that of genes or gene products. Thus, metabolic profiling can provide a simpler yet efficient snapshot of the system's physiology. Metabolites of Saccharomyces cerevisiae under various stresses were analyzed and compared with those under the normal, unstressed growth conditions by two-dimensional NMR spectroscopy. At least 31 metabolites were identified for most of the samples. The levels of many identified metabolites showed significant increase or decrease depending on the nature of the stress. The statistical analysis produced a holistic view: different stresses were clustered and isolated from one another with the exception of high pH, heat, and oxidative stresses. This work could provide a link between the metabolite profiles and mRNA or protein profiles under representative and well-studied stress conditions. PMID- 22540293 TI - Is obstructive sleep apnea a cause of idiopathic pulmonary fibrosis? PMID- 22540295 TI - Is the effect of hemolysis on plasma ammonia measurement overrated? PMID- 22540296 TI - Assuring quality in point-of-care testing. PMID- 22540297 TI - Emerging targeted therapies in cancer. PMID- 22540298 TI - Advances in treatment of lung cancer with targeted therapy. AB - CONTEXT: Ongoing preclinical investigations and clinical trials involving new targeted therapies promise to improve survival for patients with lung cancer. Targeted therapeutic agents, based on genetic mutations and signaling pathways altered in lung cancer, have added significantly to our armamentarium for lung cancer treatment while minimizing drug toxicity. To date, 4 targeted therapies have been approved for treatment of lung cancer by the US Food and Drug Administration: gefitinib in 2002, erlotinib in 2003, bevacizumab in 2006, and crizotinib in 2011. OBJECTIVE: To review targeted therapies in lung cancer, the molecular biomarkers that identify patients likely to benefit from these targeted therapies, the basic molecular biology principles, selected molecular diagnostic techniques, and pathologic features correlated with molecular abnormalities in lung cancer. To review new molecular abnormalities described in lung cancer that are predictive for response to novel promising targeted agents in various phases of clinical trials. DATA SOURCES: Review of the literature covering the molecular abnormalities of lung cancer with a focus on the molecular diagnostics and targeted therapy. Special emphasis is placed on summarizing evolving technologies useful in the diagnosis and characterization of lung cancer. CONCLUSIONS: Molecular testing of lung cancer expands the expertise of the pathologist, who will identify the tumor markers that are predictive of sensitivity or resistance to various targeted therapies and allow patients with cancer to be selected for highly effective and less toxic therapies. PMID- 22540299 TI - Somatic deletions of the polyA tract in the 3' untranslated region of epidermal growth factor receptor are common in microsatellite instability-high endometrial and colorectal carcinomas. AB - CONTEXT: Epidermal growth factor receptor (EGFR) is overexpressed in up to 80% of colorectal and endometrial carcinomas. Deletions of the polyA tract in the 3' untranslated region (3' UTR) have been reported in microsatellite instability high (MSI-H) colonic carcinomas, but their impacts on EGFR expression and downstream pathways are unclear. This phenomenon has not been reported in other MSI-H tumors. OBJECTIVE: To assess the 3' UTR polyA tract of EGFR in both endometrial and colorectal carcinomas and the mutational status of EGFR downstream pathways. DESIGN: Ninety-eight colorectal carcinomas and 47 endometrial carcinomas were included. EGFR 3' UTR polyA status was detected by capillary electrophoresis and Sanger sequencing. EGFR gene expression, EGFR copy numbers, and KRAS and BRAF mutation status were analyzed accordingly. RESULTS: The 3' UTR polyA tract was deleted in 18 of 23 (78%) MSI-H versus 0 of 24 microsatellite-stable endometrial carcinomas (P < .001). Similar observations were seen in colorectal carcinomas, in which 29 of 36 (81%) MSI-H, 1 of 62 (1.6%) microsatellite instability-low, and none of the microsatellite-stable tumors harbored the deletion (P < .001). A moderate increase in EGFR mRNA level was observed in endometrial carcinomas with 3' UTR polyA deletions versus those with wild-type polyA tract. Amplification of the EGFR gene was not observed. Deletions in polyA tract do not seem to affect the frequency of KRAS and BRAF mutations. CONCLUSIONS: Deletions of EGFR 3' UTR polyA are frequent in endometrial and colorectal carcinomas, are confined almost exclusively to MSI-H tumors, and do not affect KRAS and BRAF mutations. PMID- 22540300 TI - Multiphoton microscopy in the evaluation of human bladder biopsies. AB - CONTEXT: Multiphoton microscopy (MPM) is a nonlinear imaging approach, providing cellular and subcellular details from fresh (unprocessed) tissue by exciting intrinsic tissue emissions. With miniaturization and substantially decreased cost on the horizon, MPM is an emerging imaging technique with many potential clinical applications. OBJECTIVES: To assess the imaging ability and diagnostic accuracy of MPM for human bladder biopsies. DESIGN: Seventy-seven fresh bladder biopsies were imaged by MPM and subsequently submitted for routine surgical pathology diagnosis. Twelve cases were excluded because of extensive cautery artifact that prohibited definitive diagnosis. Comparison was made between MPM imaging and gold standard sections for each specimen stained with hematoxylin-eosin. RESULTS: In 57 of 65 cases (88%), accurate MPM diagnoses (benign or neoplastic) were given based on the architecture and/or the cytologic grade. The sensitivity and specificity of MPM in our study were 90.4% and 76.9%, respectively. A positive (neoplastic) diagnosis on MPM had a high predictive value (94%), and negative (benign) diagnoses were sustained on histopathology in two-thirds of cases. Architecture (papillary versus flat) was correctly determined in 56 of 65 cases (86%), and cytologic grade (benign/low grade versus high grade) was assigned correctly in 38 of 56 cases (68%). CONCLUSIONS: The MPM images alone provided sufficient detail to classify most lesions as either benign or neoplastic using the same basic diagnostic criteria as histopathology (architecture and cytologic grade). Future developments in MPM technology may provide urologists and pathologists with additional screening and diagnostic tools for early detection of bladder cancer. Additional applications of such emerging technologies warrant exploration. PMID- 22540301 TI - Comparison of analytical and clinical performance of three methods for detection of Clostridium difficile. AB - CONTEXT: Diagnostic laboratory testing for Clostridium difficile infection has undergone considerable and rapid evolution during the last decade. The ideal detection method(s), which should exhibit high analytical and clinical sensitivity and specificity, remains undefined. OBJECTIVE: We sought to evaluate the analytical and clinical performance characteristics of three methods for the laboratory detection of C difficile. DESIGN: This study used 114 consecutive stool samples to compare three methods of C difficile detection: an enzyme immunoassay (EIA) for toxins A/B, a lateral flow membrane immunoassay for glutamate dehydrogenase (GDH), and a qualitative real-time polymerase chain reaction (PCR) assay. Medical records of all patients having >=1 positive test result were reviewed to estimate the clinical likelihood of C difficile infection. RESULTS: Based upon laboratory result consensus values, analytical sensitivity was significantly higher for GDH (94%) and PCR (94%) assays than for toxin EIA (25%). Analytical specificity was significantly higher for PCR (100%) and EIA (100%) than for GDH assay (93%). In contrast, assay performance based upon clinical probability of C difficile infection suggested lower discriminatory power (ie, clinical specificity) of the more analytically sensitive methods. CONCLUSIONS: Higher rates of C difficile detection will be realized upon implementation of GDH assay and/or real-time PCR-based testing algorithms than by testing with EIA alone. Further study is required to elucidate potential downstream costs for higher detection rates. PMID- 22540302 TI - Iron overload in allogeneic hematopoietic stem cell transplant recipients. AB - CONTEXT: Patients who undergo hematopoietic stem cell transplant are at an increased risk of developing iron overload. OBJECTIVES: To describe the effect of hepatic iron overload on hematopoietic stem cell transplant recipients and to validate the utility of histologic scoring system of iron granules in the liver. DESIGN: Records of 154 post allogeneic hematopoietic stem cell transplant patients were reviewed. Forty-nine patients underwent liver biopsy. Histologic hepatic iron overload was defined as a score of 2 or greater (scale, 0-4). RESULTS: Twenty-eight of 49 patients (57%) evaluated by liver biopsy had hepatic iron overload; 17 had moderate to severe hepatic iron overload (score, 3 or 4). In multivariate analysis, a significant correlation was discovered between hepatic iron overload and the number of transfusions (P < .001), posttransplant serum ferritin levels (P=.004), lactate dehydrogenase levels (P=.03), and the development of blood stream infections (P= .02). There was no correlation between hepatic iron overload and abnormal liver function test results. While 37 patients (76%) died after receiving a transplant, mortality was not influenced by hepatic iron overload but was significantly higher in older patients, in patients with lower serum albumin levels, higher serum bilirubin levels, and higher clinical grade of acute graft-versus-host disease (P=.04, P=.001, P=<.001, and P .004, respectively). CONCLUSIONS: Hepatic iron overload is commonly identified in hematopoietic stem cell transplant patients and can be accurately diagnosed by liver biopsy. In addition, hepatic iron overload has been identified in patients receiving as few as 25 units of packed red blood cells, with elevated posttransplant serum ferritin levels, and with blood stream infections. PMID- 22540303 TI - Quantitative assessment and classification of tissue-based biomarker expression with color content analysis. AB - CONTEXT: The use of computer aids has been suggested as a way to reduce interobserver variability that is known to exist in the interpretation of immunohistochemical staining in pathology. Such computer aids should be automated in their usage but also they should be trained in an automated and reproducible fashion. OBJECTIVE: To present a computer aid for the quantitative analysis of tissue-based biomarkers, based on color content analysis. DESIGN: The developed system incorporates an automated algorithm to allow retraining based on the color properties of different training sets. The algorithm first generates a color palette containing the colors present in a training subset. Based on the palette, color histograms are derived and are used as feature vectors to a pattern recognition system, which returns an output proportional to biomarker continuous expression or a categorical classification. The method was evaluated on a database of HER2/neu digital breast cancer slides, for which expression scores from a pathologist panel were available. The system was retrained and evaluated on different transformations of the database, including compression, blurring, and changes in illumination, to examine its robustness to different imaging conditions frequently met in digital pathology. RESULTS: Results showed high agreement between the results of the algorithm and the truth from the pathologist panel as well as robustness to image transformations. CONCLUSIONS: The results of the study are encouraging for the potential of this method as a computer aid to assess biomarker expression in a consistent and reproducible manner. PMID- 22540305 TI - Renal myopericytoma: case report and review of literature. AB - Myopericytoma arising in the visceral organs is rare and only 1 case of renal myopericytoma has been reported in the literature to date. We report the second case of myopericytoma arising in the kidney in a 40-year-old Hispanic woman who presented with pain on the left side of the abdomen and frequent urination. Abdominal computed tomography scan showed an exophytic left-sided renal mass. Partial nephrectomy was performed. The patient remains free of disease at 24 months after diagnosis. Our case is histologically distinct from the previously described case as it lacks the "hemangiopericytic/glomangiopericytoma" pattern. The tumor in our case showed the characteristic pattern of myopericytoma and an additional glomus tumorlike pattern. The tumor cells showed diffuse reactivity for vimentin, smooth muscle actin, smooth muscle myosin heavy chain, and muscle specific actin in both morphologic patterns and strong diffuse CD34 expression in glomus tumorlike focus. This case report adds to the morphologic heterogeneity of myopericytomas. PMID- 22540304 TI - Perceptual analysis of the reading of dermatopathology virtual slides by pathology residents. AB - CONTEXT: The process by which pathologists arrive at a given diagnosis-a combination of their slide exploration strategy, perceptual information gathering, and cognitive decision making-has not been thoroughly explored, and many questions remain unanswered. OBJECTIVE: To determine how pathology residents learn to diagnose inflammatory skin dermatoses, we contrasted the slide exploration strategy, perceptual capture of relevant histopathologic findings, and cognitive integration of identified features between 2 groups of residents, those who had and those who had not undergone their dermatopathology rotation. DESIGN: Residents read a case set of 20 virtual slides (10 depicting nodular and diffuse dermatitis and 10 depicting subepidermal vesicular dermatitis), using an in-house-developed interface. We recorded residents' reports of diagnostic findings, conjectured diagnostic hypotheses, and final (or differential) diagnosis for each case, and time stamped each interaction with the interface. We created search maps of residents' slide exploration strategy. RESULTS: No statistically significant differences were observed between the resident groups in the number of correctly or incorrectly reported diagnostic findings, but residents with dermatopathology training generated significantly more correct hypotheses (mean improvement of 88.5%) and correct diagnoses (70% of all correct diagnoses). CONCLUSIONS: Two types of slide exploration strategy were identified for both groups: (1) a focused and efficient search, observed when the final diagnosis was correct; and (2) a more dispersed, time-consuming strategy, observed when the final diagnosis was incorrect. This difference was statistically significant, and it suggests that initial interpretation of a slide may bias further slide exploration. PMID- 22540306 TI - Uterine hemangioma: a rare pathologic entity. AB - Uterine hemangioma is a rare benign tumor usually presenting with menorrhagia or pregnancy-associated complications. Although the current literature identifies fewer than 50 cases, we in our institution identified 5 similar cases among 3700 patients undergoing total hysterectomy from January 2006 to December 2010. Adenomyosis was the most common preoperative diagnosis among our patients. Vaginal examination, uterine curettage specimens, ultrasonography, and hysterography are usually uninformative, and the definitive diagnosis relies on the final histologic examination. The differential diagnosis includes adenomatoid tumor, lymphangioma, and arteriovenous malformation. Uterine hemangiomas are classified into congenital and acquired. The former is believed to be associated with some hereditary diseases, while the latter is associated with both physical changes and hormone alteration, especially high estrogen level. The best treatment for hemangiomas is unclear. However, it is very important to obtain an accurate diagnosis to prevent overtreatment among reproductive-age women. The prognosis is excellent after hysterectomy. PMID- 22540307 TI - Telangiectatic osteosarcoma. AB - Osteosarcoma is one of the most common primary malignant bone tumors in children and adolescents. Telangiectatic osteosarcoma is an unusual variant of osteosarcoma, forming 3% to 10% of all osteosarcomas. Radiographically, these tumors appear as purely lytic destructive lesions located in the metaphyses of long bones. The location and x-ray appearance of telangiectatic osteosarcomas are reminiscent of an aneurysmal bone cyst and can test the acumen of a diagnostic radiologist. Distinguishing between the two entities microscopically can also be quite challenging. Telangiectatic osteosarcoma shows dilated blood-filled spaces lined or traversed by septa containing atypical stromal cells, with or without production of a lacelike osteoid matrix. This review highlights the diagnostic features of telangiectatic osteosarcoma and discusses differential diagnostic considerations, treatment options, and prognostic implications. PMID- 22540308 TI - Expression of microRNAs in basal cell carcinoma. AB - BACKGROUND: Perturbations in the expression profiles of microRNAs (miRNAs) have been reported for a variety of different cancers. Differentially expressed miRNAs have not been systematically evaluated in basal cell carcinoma (BCC) of the skin. OBJECTIVES: To initiate a microarray-based miRNA profiling study to identify specific miRNA candidates that are differentially expressed in BCC. METHODS: Patients with BCC (n = 7) were included in this study. Punch biopsies were harvested from the tumour centre (lesional, n = 7) and from adjacent nonlesional skin (intraindividual control, n = 7). Microarray-based miRNA expression profiles were obtained on an Agilent platform using miRBase 16 screening for 1205 Homo sapiens (hsa)-miRNA candidates. To validate the microarray data, the expression of seven dysregulated miRNAs was measured by TaqMan quantitative real-time reverse transcription polymerase chain reaction. RESULTS: We identified 16 significantly upregulated (hsa-miR-17, hsa-miR-18a, hsa-miR-18b, hsa-miR-19b, hsa miR-19b-1*, hsa-miR-93, hsa-miR-106b, hsa-miR-125a-5p, hsa-miR-130a, hsa-miR 181c, hsa-miR-181c*, hsa-miR-181d, hsa-miR-182, hsa-miR-455-3p, hsa-miR-455-5p and hsa-miR-542-5p) and 10 significantly downregulated (hsa-miR-29c, hsa-miR 29c*, hsa-miR-139-5p, hsa-miR-140-3p, hsa-miR-145, hsa-miR-378, hsa-miR-572, hsa miR-638, hsa-miR-2861 and hsa-miR-3196) miRNAs in BCC compared with nonlesional skin. Data mining revealed connections to many tumour-promoting pathways, such as the Hedgehog and the mitogen-activated protein kinase/extracellular signal regulated kinase signalling cascades. CONCLUSIONS: This study identified several miRNA candidates that may play a role in the molecular pathogenesis of BCC. PMID- 22540309 TI - Enhanced cellular immune response elicited by a DNA vaccine fused with Ub against Mycobacterium tuberculosis. AB - This study evaluated the immune response elicited by a Ub-fused Ag85A DNA vaccine against Mycobacterium tuberculosis. BALB/c mice were vaccinated with plasmid DNA encoding Ag85A protein, Ub-fused Ag85A DNA vaccine (UbGR-Ag85A) and negative DNA vaccines, respectively. Ag85A DNA vaccine immunization induced a Th(l)-polarized immune response. The production of Th(l)-type cytokine (IFN-gamma) and proliferative T cell responses was enhanced significantly in mice immunized with UbGR-Ag85A fusion DNA vaccine, compared with non-fusion DNA vaccine. Moreover, this fusion DNA vaccine also resulted in an increased relative ratio of IgG(2a) to IgG(l) and the cytotoxicity of T cells. IFN-gamma intracellular staining of splenocytes indicated that UbGR-Ag85A fusion DNA vaccine activated CD4(+) and CD8(+) T cells, particularly CD8(+) T cells. Thus, this study demonstrated that the UbGR-Ag85A fusion DNA vaccine inoculation could improve antigen-specific cellular immune responses, which is helpful for protection against TB infection. PMID- 22540310 TI - Obstetric and gynecological outcome in a patient with traumatic pelvic fracture and perineal injuries. AB - A 19-year-old woman presented with pelvic trauma following a road accident. She was hemodynamically stable. Examination revealed perineal injuries and type C pelvic fracture, which was stabilized with an external fixator. The broken ends of the pubic bone were brought together by an orthopedic wire. The detached vaginal wall and torn anal sphincter were surgically repaired after making a diverting colostomy. The postoperative period was uneventful. Colostomy was reversed after 3 months. Postoperatively the patient developed a cystocele, dyspareunia and vaginal pain. She conceived spontaneously and was planned for an elective cesarean at 37 weeks gestation; however, she presented in labor at 36 weeks and had a normal vaginal delivery. Pelvic fractures may be associated with genitourinary and anal sphincter injuries, which require management by a multidisciplinary team. On recovery the patient may develop prolapse, dyspareunia and persistent local pain. Spontaneous conception and normal vaginal delivery are nevertheless possible. PMID- 22540311 TI - Comparative genomics of methylated amine utilization by marine Roseobacter clade bacteria and development of functional gene markers (tmm, gmaS). AB - The marine Roseobacter clade bacteria comprise up to 20% of the microbial community in coastal surface seawater. Marine Roseobacter clade bacteria are known to catalyse some important biogeochemical transformations in marine carbon and sulfur cycles. Using a comparative genomic approach, this study revealed that many marine Roseobacter clade bacteria have the genetic potential to utilize methylated amines (MAs) as alternative nitrogen sources. These MAs represent a significant pool of dissolved organic carbon and nitrogen in the marine environment. The marine Roseobacter clade bacterial genomes also encode full sets of genes providing them with the potential to generate energy from complete oxidation of the methyl groups of MAs. Representative species of the marine Roseobacter clade were tested and their abilities to use MAs are directly linked to the presence in their genomes of genes encoding key enzymes involved in MA metabolism, including trimethylamine monooxygenase (tmm) and gamma glutamylmethylamide synthetase (gmaS). These two genes were chosen as functional markers for detecting MA-utilizing marine Roseobacter clade bacteria in the environment. PCR primers targeting these two genes were designed and used successfully to retrieve corresponding gene sequences from MA-utilizing isolates of the marine Roseobacter clade, as well as directly from DNA extracted from surface seawater obtained from Station L4 off the coast of Plymouth, UK. Taken together, the results suggest that MAs may serve as important nitrogen and possibly energy sources for marine Roseobacter clade bacteria, which helps to explain their global success in the marine environment. PMID- 22540312 TI - Substrate effect on thermal stability of superconductor thin films in the peritectic melting. AB - Systematic experiments were performed by in situ observation of the YBa(2)Cu(3)O(z) (Y123 or YBCO) melting. Remarkably, the superheating phenomenon was identified to exist in all commonly used YBCO thin films, that is, films deposited on MgO, LaAlO(3) (LAO), and SrTiO(3) (STO) substrates, suggesting a universal superheating mode of the YBCO film. Distinctively, YBCO/LAO films were found to possess the highest level of superheating, over 100 K, mainly attributed to the lattice match effect of LAO substrate, that is, its superior lattice fit with Y123 delaying the Y123 dissolving and inferior lattice matching with Y(2)BaCuO(5) (Y211) delaying the Y211 nucleation. Moreover, strong dependence of the thermal stability on the substrate material for Y123 films was also found to be associated with the substrate wettability by the liquid and the potential element doping from the substrate. Most importantly, the understanding of the superheating behavior is widely valid for more film/substrate constructions that have the same nature as the YBCO film/substrate. PMID- 22540313 TI - Biomedical techniques in context: on the appropriation of biomedical procedures and artifacts. AB - On the assumption that technical practices and artifacts are fundamental constituents of individual and collective attempts to order lives and bodies in health and sickness, in this introduction, we set out three central propositions. First, medical techniques have to take center stage in research on biomedicine. Second, as medical artifacts travel worldwide, they become part of the processes of sociocultural appropriation. Third, anthropologists have to consider how to study the transformations associated with such appropriation and how much they need to know about the technical aspects of their objects of study. The mutual transformative potential of both biomedical artifacts and practices and the new contexts of application have so far been undertheorized in medical anthropology- a gap that we aim to close with our reflections and the collection of empirical studies of various biomedical techniques in this issue. PMID- 22540314 TI - Appropriate and appropriated technology: lessons learned from ultrasound in Tanzania. AB - In "the North" ultrasound has become a standard procedure in reproductive health services. In Sub-Saharan Africa where diagnostic imaging technology is increasingly transferred to, ultrasound is still quite a new technology. Its promotion as "appropriate" technology by international donors, however, overlooks the fact that ultrasound such as any technology when transferred is not automatically doing what it is intended to do. Rather, ultrasound may be used very differently. Hence, what ultrasound will actually do remains an empirical matter. This article offers an insight into the multiple constructions of ultrasound that exist in one hospital in Northwest Tanzania as the technology is appropriated by nurse-midwives, doctors, students, local healers, and pregnant women. If these emerging situated ultrasounds are made explicit, the question of whether a technology is appropriate becomes more complex than the ubiquitous term suggests. PMID- 22540315 TI - The rise of the cosmetic nation: plastic governmentality and hybrid medical practices in Brazil. AB - In this article, I trace the historical and sociopolitical construction of plastic surgery as a basic health need in Brazil. I argue that plastic surgeons deploy "plastic governmentality" in order to portray their work in public settings as humanitarian in nature, while simultaneously using poor patients as experimental subjects to train new surgeons and develop new techniques. This seemingly contradictory positioning is only possible because aesthetic surgeries are relabeled as reconstructive surgeries, producing a pliable form of statecraft that uses statistics and medical discourse to reinforce the support of the state and civil society for the practice. The form of governance I describe elucidates how the state can become instrumentalized in the benefit of private interests under neoliberalism, and how unprofitable public health needs are rendered invisible by the very biopolitical forms of governance that claim to address those needs. PMID- 22540316 TI - Cutting inoperable bodies: particularizing rural sociality to normalize hysterectomies in Balochistan, Pakistan. AB - Drawing on 15 months of ethnographic research in Balochistan, Pakistan (2005 2006), I explore Panjguri midwives' (dinabogs, kawwas, or balloks) narrative links between routine injections of prostaglandins around childbirth and the increasing number of hysterectomies. These techno-medical interventions reflect the postcolonial biomedicalization of women's bodies and reproductive health care, and are reinforced by shifts in Pakistan's public health policy against maternal mortality in a context where about 90 percent of births occur outside of hospitals. Transnational campaigns against maternal mortality further biomedicalize women's lives. Interviews with doctors, midwives, and women, and analysis of women's experiences, illustrate the practical considerations that were used to normalize radical hysterectomies over less invasive procedures. PMID- 22540317 TI - Assisted reproductive technologies and fertility "tourism": examples from global Dubai and the Ivy League. AB - What motivates the global movements of infertile people searching for assisted reproductive technologies (ARTs)? In this article, we attempt to answer this question by exploring infertile patients' practices of so-called "fertility tourism." Based on ethnographic research carried out with nearly 300 infertile travelers in two major ART centers--one in the global hub of the United Arab Emirates and the other at a major East Coast Ivy League university--we examine a diverse set of reasons for reproductive travel. We argue that reproductive "tourism" should be reconceptualized as reproductive "exile" in that infertile couples feel barred from accessing ARTs in their home countries. Listening to reproductive travel stories is key to understanding infertile couples' transnational "quests for conception." Stories of two couples, one from Lebanon and one from Italy, demonstrate the poignancy of these quests and begin to shed light on the complex calculus of factors governing this global movement of reproductive actors. PMID- 22540318 TI - The social life of psychiatric practice: trauma in postwar Kosova. AB - This article traces the social life of psychiatric practice in the context of war and postwar societies. It is argued that although psychiatric knowledge and practice is situated and grounded in particular cultural, social, and political contexts, it is important to examine how transnational networks situate local systems of meaning in much larger settings. I illustrate this claim by examining discourses and observations concerning health-seeking behaviors of Kosovar Albanian women and ways in which Kosovar health practitioners help them by employing, adapting, and changing the psychiatric tools and lessons learned during (trauma) training provided by international health professionals during the Yugoslav war and postwar eras. Thereby, I hope to contribute to a better understanding of how local health beliefs and practices are nested in the processes involved in international health policymaking and, thereby, relate to higher level structures such as international political economy, regional history, and development ideology. PMID- 22540319 TI - Long term follow-up results on severe recalcitrant atopic dermatitis treated with extracorporeal photochemotherapy. PMID- 22540320 TI - Force-reactivity property of a single monomer is sufficient to predict the micromechanical behavior of its polymer. AB - We demonstrate an accurate prediction of the micromechanical behavior of a single chain of cyclopropanated polybutadiene, which is governed by rapid isomerization of the cyclopropane moieties at ~1.2 nN, from the force-rate correlation of this reaction measured in a small series of increasingly strained macrocycles. The data demonstrate that a single physical quantity, force, uniquely defines the dynamics across length scales from >100 to <1 nm and that strain imposed through molecular design and that imposed by micromanipulation techniques have equivalent effects on the kinetics of a chemical reaction. This represents a new method of screening potential monomers for applications in stress-responsive materials that could also facilitate atomistic interpretations of single-molecule force experiments. PMID- 22540321 TI - SLO2, a mitochondrial pentatricopeptide repeat protein affecting several RNA editing sites, is required for energy metabolism. AB - Pentatricopeptide repeat (PPR) proteins belong to a family of approximately 450 members in Arabidopsis, of which few have been characterized. We identified loss of function alleles of SLO2, defective in a PPR protein belonging to the E+ subclass of the P-L-S subfamily. slo2 mutants are characterized by retarded leaf emergence, restricted root growth, and late flowering. This phenotype is enhanced in the absence of sucrose, suggesting a defect in energy metabolism. The slo2 growth retardation phenotypes are largely suppressed by supplying sugars or increasing light dosage or the concentration of CO2. The SLO2 protein is localized in mitochondria. We identified four RNA editing defects and reduced editing at three sites in slo2 mutants. The resulting amino acid changes occur in four mitochondrial proteins belonging to complex I of the electron transport chain. Both the abundance and activity of complex I are highly reduced in the slo2 mutants, as well as the abundance of complexes III and IV. Moreover, ATP, NAD+, and sugar contents were much lower in the mutants. In contrast, the abundance of alternative oxidase was significantly enhanced. We propose that SLO2 is required for carbon energy balance in Arabidopsis by maintaining the abundance and/or activity of complexes I, III, and IV of the mitochondrial electron transport chain. PMID- 22540322 TI - Correction to Inhibition of Hypoxia Inducible Factor 1-Transcription Coactivator Interaction by a Hydrogen Bond Surrogate alpha-Helix. PMID- 22540323 TI - Role of antihypertensive drugs in arterial 'de-stiffening' and central pulsatile hemodynamics. AB - Arterial stiffness is an independent predictor of cardiovascular (CV) morbidity and mortality in patients with hypertension, as well as a potential therapeutic target. There is increasing awareness that the pulsatile hemodynamics (central blood pressure [CBP], pulse pressure [PP], wave reflections [augmentation index or AIx] and pulse wave velocity [PWV]) may provide better insight into the pathophysiology of CV disorders and target organ damage related to hypertension. Different antihypertensive drugs produce diverse effects on arterial stiffness variables, despite similar effects on peripheral (brachial) blood pressure. Identifying the pharmacologic interventions that can improve arterial stiffness ('de-stiffening' treatment) is a promising field of research. PMID- 22540324 TI - Three uncommon adrenal incidentalomas: a 13-year surgical pathology review. AB - BACKGROUND: The discovery of adrenal incidentalomas due to the widespread use of sophisticated abdominal imaging techniques has resulted in an increasing trend of adrenal gland specimens being received in the pathology laboratory. In this context, we encountered three uncommon adrenal incidentalomas.The aim of this manuscript is to report in detail the three index cases of adrenal incidentalomas in the context of a 13-year retrospective surgical pathology review. METHODS: The three index cases were investigated and analyzed in detail with relevant review of the English literature as available in PubMed and Medline. A 13-year retrospective computer-based histopathological surgical review was conducted in our laboratory and the results were analyzed in the context of evidence-based literature on adrenal incidentalomas. RESULTS: A total of 94 adrenal specimens from incidentalomas were identified, accounting for 0.025% of all surgical pathology cases. In all 76.6% were benign and 23.4% were malignant. A total of 53 females (56.4%) and 41 males (43.6%) aged 4 to 85 years were identified. The benign lesions included cortical adenoma (43.1%), pheochromocytoma (29.3%) and inflammation/fibrosis/hemorrhage (8.3%). Metastatic neoplasms were the most common malignant lesions (50%) followed by primary adrenocortical carcinomas (31.8%) and neuroblastoma (13.6%). These cases were discovered as adrenal incidentalomas that led to surgical exploration.The three index cases of adrenal incidentalomas with unusual pathologies were encountered that included (a) adrenal ganglioneuroma, (b) periadrenal schwannoma and (c) primary adrenal pleomorphic leiomyosarcoma. These cases are discussed, with a literature and clinicopathological review. CONCLUSIONS: Adrenal lesions are uncommon surgical specimens in the pathology laboratory. However, higher detection rates of adrenal incidentalomas aided by the ease of laparoscopic adrenalectomy has resulted in increased adrenal surgical specimens leading to unsuspected diagnostic and management dilemmas. Accurate pathological identification of common and uncommon adrenal incidentalomas is essential for optimal patient management. PMID- 22540325 TI - Commercially pure titanium implants with surfaces modified by laser beam with and without chemical deposition of apatite. Biomechanical and topographical analysis in rabbits. AB - OBJECTIVES: The purpose of this study was to evaluate the surfaces of commercially pure titanium (cp Ti) implants modified by laser beam (LS), without and with hydroxyapatite deposition by the biomimetic method (HAB), without (HAB) and with thermal treatment (HABT), and compare them with implants with surfaces modified by acid treatment (AS) and with machined surfaces (MS), employing topographical and biomechanics analysis. METHODS: Forty-five rabbits received 75 implants. After 30, 60, and 90 days, the implants were removed by reverse torque and the surfaces were topographically analyzed. RESULTS: At 30 days, statistically significant difference (P < 0.05) was observed among all the surfaces and the MS, between HAB/HABT and AS and between HAB and LS. At 60 days, the reverse torque of LS, HAB, HABT, and AS differed significantly from MS. At 90 days, difference was observed between HAB and MS. The microtopographic analysis revealed statistical difference between the roughness of LS, HAB, and HABT when compared with AS and MS. CONCLUSIONS: It was concluded that the implants LS, HAB, and HABT presented physicochemical and topographical properties superior to those of AS and MS and favored the osseointegration process in the shorter periods. In addition, HAB showed the best results when compared with other surfaces. PMID- 22540326 TI - In vitro fertilization pregnancy rates in levothyroxine-treated women with hypothyroidism compared to women without thyroid dysfunction disorders. AB - BACKGROUND: Untreated hypothyroidism can lead to ovulatory dysfunction resulting in oligo-amenorrhea. Treatment with levothyroxine can reverse such dysfunction and thus should improve fertility. The purpose of this retrospective study was to assess whether in vitro fertilization (IVF) pregnancy rates differ in levothyroxine-treated women with hypothyroidism compared to women without thyroid dysfunction/disorders. METHODS: Treated hypothyroid and euthyroid women undergoing IVF at an academic IVF center were studied after Institutional Review Board approval. Women with hypothyroidism were treated with levothyroxine 0.025 0.15 mg/day for at least 3 months to maintain baseline thyrotropin (TSH) levels of 0.35-4.0 MUU/mL prior to commencing IVF treatment (HYPO-Rx group). Causes of infertility were similar in both groups with the exception of male factor, which was more common in the HYPO-Rx group. The main outcomes studied were implantation rate, clinical pregnancy rate, clinical miscarriage rate, and live birth rate. RESULTS: We reviewed the first IVF retrieval cycle performed on 240 women aged 37 years or less during the period January 2003 to December 2007. Women with treated hypothyroidism (n=21) had significantly less implantation, clinical pregnancy, and live birth rates than euthyroid women (n=219). CONCLUSIONS: We conclude that, despite levothyroxine treatment, women with hypothyroidism have a significantly decreased chance of achieving a pregnancy following IVF compared to euthyroid patients. A larger prospective study is necessary to assess confounding variables, confirm these findings, and determine the optimal level of TSH prior to and during controlled ovarian hyperstimulation for IVF. PMID- 22540327 TI - Micro-single-photon emission computed tomography image acquisition and quantification of sodium-iodide symporter-mediated radionuclide accumulation in mouse thyroid and salivary glands. AB - BACKGROUND: Micro-single-photon emission computed tomography (SPECT) provides a noninvasive way to evaluate the effects of genetic and/or pharmacological modulation on sodium-iodide symporter (NIS)-mediated radionuclide accumulation in mouse thyroid and salivary glands. However, parameters affecting image acquisition and analysis of mouse thyroids and salivary glands have not been thoroughly investigated. In this study, we investigated the effects of region-of interest (ROI) selection, collimation, scan time, and imaging orbit on image acquisition and quantification of thyroidal and salivary radionuclide accumulation in mice. METHODS: The effects of data window minima and maxima on thyroidal and salivary ROI selection using a visual boundary method were examined in SPECT images acquired from mice injected with (123)I NaI. The effects of collimation, scan time, and imaging orbit on counting linearity and signal intensity were investigated using phantoms filled with various activities of (123)I NaI or Tc-99m pertechnetate. Spatial resolution of target organs in whole animal images was compared between circular orbit with parallel-hole collimation and spiral orbit with five-pinhole collimation. Lastly, the inter-experimental variability of the same mouse scanned multiple times was compared with the intra experimental variability among different mice scanned at the same time. RESULTS: Thyroid ROI was separated from salivary glands by empirically increasing the data window maxima. Counting linearity within the range of 0.5-14.2 MUCi was validated by phantom imaging using single- or multiple-pinhole collimators with circular or spiral imaging orbit. Scanning time could be shortened to 15 minutes per mouse without compromising counting linearity despite proportionally decreased signal intensity. Whole-animal imaging using a spiral orbit with five-pinhole collimators achieved a high spatial resolution and counting linearity. Finally, the extent of inter-experimental variability of NIS-mediated radionuclide accumulation in the thyroid and salivary glands by SPECT imaging in the same mouse was less than the magnitude of variability among the littermates. CONCLUSIONS: The impacts of multiple variables and experimental designs on micro SPECT imaging and quantification of radionuclide accumulation in mouse thyroid and salivary glands can be minimized. This platform will serve as an invaluable tool to screen for pharmacologic reagents that differentially modulate thyroidal and salivary radioiodine accumulation in preclinical mouse models. PMID- 22540328 TI - Aquaporin-4 expression in distal myopathy with rimmed vacuoles. AB - BACKGROUND: Distal myopathy with rimmed vacuoles/hereditary inclusion body myopathy is clinically characterized by the early involvement of distal leg muscles. The striking pathological features of the myopathy are muscle fibers with rimmed vacuoles. To date, the role of aquaporin-4 water channel in distal myopathy with rimmed vacuoles/hereditary inclusion body myopathy has not been studied. CASE PRESENTATION: Here, we studied the expression of aquaporin-4 in muscle fibers of a patient with distal myopathy with rimmed vacuoles/hereditary inclusion body myopathy. Immunohistochemical and immunofluorescence analyses showed that sarcolemmal aquaporin-4 immunoreactivity was reduced in many muscle fibers of the patient. However, the intensity of aquaporin-4 staining was markedly increased at rimmed vacuoles or its surrounding areas and in some muscle fibers. The fast-twitch type 2 fibers were predominantly involved with the strong aquaporin-4-positive rimmed vacuoles and TAR-DNA-binding protein-43 aggregations. Rimmed vacuoles with strong aquaporin-4 expression seen in the distal myopathy with rimmed vacuoles/hereditary inclusion body myopathy patient were not found in control muscles without evidence of neuromuscular disorders and the other disease controls. CONCLUSIONS: Aquaporin-4 might be crucial in determining the survival or degeneration of fast-twitch type 2 fibers in distal myopathy with rimmed vacuoles/hereditary inclusion body myopathy. PMID- 22540329 TI - Predictive factors for poor peripheral blood stem cell mobilization and peak CD34(+) cell count to guide pre-emptive or immediate rescue mobilization. AB - BACKGROUND AIMS: Failure in mobilization of peripheral blood (PB) stem cells is a frequent reason for not performing hematopoietic stem cell transplantation (HSCT). Early identification of poor mobilizers could avoid repeated attempts at mobilization, with the administration of pre-emptive rescue mobilization. METHODS: Data from the first mobilization schedule of 397 patients referred consecutively for autologous HSCT between 2000 and 2010 were collected. Poor mobilization was defined as the collection of < 2 * 10(6) CD34(+)cells/kg body weight (BW). RESULTS: The median age was 53 years (range 4-70) and 228 (57%) were males. Diagnoses were multiple myeloma in 133 cases, non-Hodgkin's lymphoma in 114, acute myeloid leukemia or myelodysplastic syndrome in 81, Hodgkin's lymphoma in 42, solid tumors in 17 and acute lymphoblastic leukemia in 10. The mobilization regimen consisted of recombinant human granulocyte-colony stimulating factor (G-CSF) in 346 patients (87%) and chemotherapy followed by G CSF (C + G-CSF) in 51 (13%). Poor mobilization occurred in 105 patients (29%), without differences according to mobilization schedule. Diagnosis, previous therapy with purine analogs and three or more previous chemotherapy lines were predictive factors for poor mobilization. A CD34(+)cell count in PB > 13.8/MUL was enough to ensure >= 2 * 10(6) CD34(+)cells/kg, with high sensitivity (90%) and specificity (91%). CONCLUSIONS: The prevalence of poor mobilization was high, being associated with disease type, therapy with purine analogs and multiple chemotherapy regimens. The threshold of CD34(+) cell count in PB identified poor mobilizers, in whom the administration of immediate or pre-emptive plerixafor could be useful to avoid a second mobilization. PMID- 22540330 TI - Effects of a manualized short-term treatment of internet and computer game addiction (STICA): study protocol for a randomized controlled trial. AB - BACKGROUND: In the last few years, excessive internet use and computer gaming have increased dramatically. Salience, mood modification, tolerance, withdrawal symptoms, conflict, and relapse have been defined as diagnostic criteria for internet addiction (IA) and computer addiction (CA) in the scientific community. Despite a growing number of individuals seeking help, there are no specific treatments of established efficacy. METHODS/DESIGN: This clinical trial aims to determine the effect of the disorder-specific manualized short-term treatment of IA/CA (STICA). The cognitive behavioural treatment combines individual and group interventions with a total duration of 4 months. Patients will be randomly assigned to STICA treatment or to a wait list control group. Reliable and valid measures of IA/CA and co-morbid mental symptoms (for example social anxiety, depression) will be assessed prior to the beginning, in the middle, at the end, and 6 months after completion of treatment. DISCUSSION: A treatment of IA/CA will establish efficacy and is desperately needed. As this is the first trial to determine efficacy of a disorder specific treatment, a wait list control group will be implemented. Pros and cons of the design were discussed. TRIAL REGISTRATION: ClinicalTrials (NCT01434589). PMID- 22540331 TI - Interleukin-33 induces interleukin-17F in bronchial epithelial cells. AB - BACKGROUND: IL-33 is clearly expressed in the airway of patients with asthma, but its role in asthma has not yet been fully understood. IL-17F is also involved in the pathogenesis of asthma. However, the regulatory mechanisms of IL-17F expression remain to be defined. To further indentify the role of IL-33 in asthma, we investigated the expression of IL-17F by IL-33 in bronchial epithelial cells and its signaling mechanisms. METHODS: Bronchial epithelial cells were stimulated with IL-33. The levels of IL-17F expression were analyzed using real time PCR and ELISA. Next, the involvement of ST2, MAP kinases, and mitogen- and stress-activated protein kinase1 (MSK1) was determined by Western blot analyses. Various kinase inhibitors and anti-ST2 neutralizing Abs were added to the culture to identify the key signaling events leading to the expression of IL-17F, in conjunction with the use of short interfering RNAs (siRNAs) targeting MSK1. RESULTS: IL-33 significantly induced IL-17F gene and protein expression. The receptor for IL-33, ST2, was expressed in bronchial epithelial cells. Among MAP kinases, IL-33 phosphorylated ERK1/2, but not p38MAPK and JNK. It was inhibited by the pretreatment of anti-ST2 neutralizing (blocking) Abs. MEK inhibitor significantly blocked IL-17F production. Moreover, IL-33 phosphorylated MSK1, and MEK inhibitor diminished its phosphorylation. Finally, MSK1 inhibitors and transfection of the siRNAs targeting MSK1 significantly blocked the IL-17F expression. CONCLUSIONS: IL-33 induces IL-17F via ST2-ERK1/2-MSK1 signaling pathway in bronchial epithelial cells. These data suggest that the IL-33/IL-17F axis is involved in allergic airway inflammation and may be a novel therapeutic target. PMID- 22540332 TI - Sprint interval running increases insulin sensitivity in young healthy subjects. AB - High intensity cycling training increases oxidative capacity in skeletal muscles and improves insulin sensitivity. The present study compared the effect of eight weeks of sprint interval running (SIT) and continuous running at moderate intensity (CT) on insulin sensitivity and cholesterol profile in young healthy subjects (age 25.2 +/- 0.7; VO(2max) 49.3 +/- 1.2 ml.kg(-1).min(-1)). SIT and CT increased maximal oxygen uptake by 5.3 +/- 1.8 and 3.8 +/- 1.6%, respectively (p < 0.05 for both). Oral glucose tolerance test (OGTT) was performed before and 60 h after the last training session. SIT, but not CT, reduced glucose area under curve and improved HOMA beta-cell index (p < 0.05). Insulin area under curve did not decrease significantly in any group. SIT, but not CT, reduced LDL and total cholesterol. In conclusion, sprint interval running improves insulin sensitivity and cholesterol profile in healthy subjects, and sprint interval running may be more effective to improve insulin sensitivity than continuous running at moderate intensity. PMID- 22540333 TI - Metformin sensitizes endometrial cancer cells to chemotherapy by repressing glyoxalase I expression. AB - AIM: Metformin plays an important role in the inhibition of cancer cell growth and prolongs remission durations. It reverses progestin-resistance in endometrial cancer cells by downregulating glyoxalase I (GloI) expression. This study aimed to investigate the effect of metformin on endometrial cancer cell chemotherapeutic sensitivity and explore the underlying molecular mechanisms. MATERIAL AND METHODS: MTT assay was performed to determine the rate of cell death after cisplatin and paclitaxel with or without metformin. Western blot was carried out to analyze GloI expression. SiRNA-targeting of GloI was used to knockdown GloI expression before further treatment with chemotherapeutic agents to examine the effect of GloI downregulation on chemotherapy-induced cell killing. In addition, plasmid transfection was used to overexpress GloI and determine whether high GloI levels blocked metformin-enhanced cell sensitivity to chemotherapy. PCR was used to analyze the efficiency of RNA interference and plasmid transfection. RESULTS: The addition of metformin enhanced the sensitivity of endometrial cells to cisplatin and paclitaxel, which was associated with reduced levels of GloI expression. Moreover, low-dose chemotherapeutic drugs alone could not significantly reduce GloI expression, whereas the addition of metformin potently downregulated GloI protein levels. Cisplatin and paclitaxel markedly inhibited the proliferative ability of GloI-depleted endometrial cancer cells. However, the overexpression of GloI abolished the effect of metformin enhanced cell sensitivity to chemotherapeutic drugs. CONCLUSION: Metformin enhances the rate of cell-killing induced by chemotherapeutic agents by repressing GloI expression. PMID- 22540334 TI - Dramatic reduction in sperm parameters following bariatric surgery: report of two cases. AB - Severe obesity constitutes the main public health crisis of the industrialised world. Bariatric surgery has been proposed as the most efficient treatment of obesity. In this study, we report the potential effects of bariatric surgery on semen parameters in male partners of couples undergoing assisted reproduction. These patients had been tested in the context of infertility treatment in two consecutive cycles before and after bariatric surgery. A marked reduction in sperm parameters was observed in a period of twelve to eighteen months after surgery. This unfavourable effect had also remarkable effects on the assisted reproduction outcome, necessitating the counselling of patients before bariatric surgery. PMID- 22540335 TI - Perturbation of the redox site structure of cytochrome c variants upon tyrosine nitration. AB - Post-translational nitration of tyrosine is considered to be an important step in controlling the multiple functions of cytochrome c (Cyt-c). However, the underlying structural basis and mechanism are not yet understood. In this work, human Cyt-c variants in which all but one tyrosine has been substituted by phenylalanine have been studied by resonance Raman and electrochemical methods to probe the consequences of tyrosine nitration on the heme pocket structure and the redox potential. The mutagenic modifications of the protein cause only subtle conformational changes of the protein and small negative shifts of the redox potentials which can be rationalized in terms of long-range electrostatic effects on the heme. The data indicate that the contributions of the individual tyrosines for maintaining the relatively high redox potential of Cyt-c are additive. Nitration of individual tyrosines leads to a destabilization of the axial Fe Met80 bond which causes the substitution of the native Met ligand by a water molecule or a lysine residue for a fraction of the proteins. Electrostatic immobilization of the protein variants on electrodes coated by self-assembled monolayers (SAMs) of mercaptounadecanoic acid destabilizes the heme pocket structure of both the nitrated and non-nitrated variants. Here, the involvement of surface lysines in binding to the SAM surface prevents the replacement of the Met80 ligand by a lysine but instead a His-His coordinated species is formed. The results indicate that structural perturbations of the heme pocket of Cyt-c due to tyrosine nitration and to local electric fields are independent of each other and occur via different molecular mechanisms. The present results are consistent with the view that either tyrosine nitration or electrostatic binding to the inner mitochondrial membrane, or both events together, are responsible for the switch from the redox to the peroxidase function. PMID- 22540336 TI - Photofragmentation translational spectroscopy of methyl azide (CH3N3) photolysis at 193 nm: molecular and radical channel product branching ratio. AB - We describe molecular-beam photofragment translational spectroscopy (PTS) experiments using electron impact (EI) ionization product detection to investigate the 193 nm photodissociation of methyl azide (CH(3)N(3)) under collision-free conditions. These experiments are used to derive the branching ratio between channels 1 and 2 [(1) radical channel: CH(3)N(3) + hnu (lambda = 193 nm) -> CH(3) + N(3); (2) molecular channel: CH(3)N(3) + hnu (lambda = 193 nm) -> CH(3)N + N(2)], which have been reported in a previous VUV-photoionization based PTS study. (1) Using electron impact ionization cross sections and ion fragmentation ratios for the various detected products, we derive the branching ratio (X(CH(3)-N(3)))/(X(CH(3)N-N(2))) = (0.017 +/- 0.004)/(0.983 +/- 0.004). Based on analysis of the kinetic energy release in the radical channel, we find that the cyclic form of N(3) is the dominant product in the radical channel. Only a small fraction of the radical channel produces ground state linear N(3). PMID- 22540337 TI - Excystation signals do not isolate gregarine gene pools: experimental excystation of Blabericola migrator among 11 species of cockroaches. AB - An experimental excystation assay was used to test the potential species isolating effects of excystation signaling among gregarines. Oocysts of a single gregarine species, Blabericola migrator , were tested for activation, excystation, and sporozoite motility by using intestinal extracts from 11 species of cockroaches representing a cohesive phylogeny of 7 genera, 3 subfamilies, and 2 families of Blattodea. Sporozoite activation, excystation, and motility were observed for all excystation assay replications using intestinal fluid from blaberid hosts, but delayed activation or excystation was observed for all assay replications using intestinal fluid from hosts in the family Blattidae. The results illustrate a trend toward a generalized excystation signal among gregarines that is conserved across the host clade at a subfamily or family level but that is unlikely to play a significant role as a species-isolating mechanism among sibling gregarine species. PMID- 22540338 TI - FK506 inhibits the enhancing effects of transforming growth factor (TGF)-beta1 on collagen expression and TGF-beta/Smad signalling in keloid fibroblasts: implication for new therapeutic approach. AB - BACKGROUND: Keloid is a unique proliferative disorder of fibroblasts resulting from derailment of the typical wound healing process. Due to lack of animal models for therapeutic testing, treatment of keloids remains a clinical challenge. Transforming growth factor (TGF)-beta1-related signalling plays a key role in keloid formation. As tacrolimus (FK506) has been reported to inhibit the effects of TGF-beta1 on cultured fibroblasts, we hypothesized that FK506 may be useful in treating keloids. OBJECTIVES: To explore the effects of FK506 on TGF beta1-stimulated keloid fibroblasts (KFs) in terms of proliferation, migration and collagen production and to investigate the regulatory pathways involved. METHODS: Fibroblasts derived from keloids were treated with TGF-beta1 with or without FK506. Relevant assays including 5-bromo-2'-deoxyuridine incorporation assay, in vitro scratch assay, reverse transcription-polymerase chain reaction (PCR), quantitative PCR and Western blotting were performed. RESULTS: The proliferation and migration of KFs were significantly higher than those of normal fibroblasts. FK506 markedly inhibited KF proliferation, migration and collagen production enhanced by TGF-beta1. The increase in TGF-beta receptor I and II expression in TGF-beta1-treated KFs was suppressed by FK506 treatment. TGF-beta1 increased the phosphorylation of Smad2/3 and Smad4 in KFs, and this enhancing effect was abrogated by FK506. In addition, FK506 significantly increased the expression of Smad7 which was suppressed by TGF-beta1 treatment. CONCLUSIONS: Our results demonstrate that FK506 effectively blocks the TGF-beta/Smad signalling pathway in KFs by downregulation of TGF-beta receptors and suggest that FK506 may be included in the armamentarium for treating keloids. PMID- 22540340 TI - Poly-beta-hydroxybutyrate accumulation in bacterial consortia from different environments. AB - The aim of the present study was to examine soil samples from various vegetation zones in terms of physicochemical properties, microbial communities, and isolation and identification (by polymerase chain reaction and transmission electron microscopy) of bacteria producing poly-beta-hydroxybutyrates (PHBs). Soil samples were analysed originating from zones with heterogeneous environmental conditions from the Romanian Carpathian Mountains (mountain zone with alpine meadow, karstic zone with limestone meadow, hill zone with xerophilous meadow, and flood plain zone with hygrophilic meadow). Different bacterial groups involved in the nitrogen cycle (aerobic mesophilic heterotrophs, ammonifiers, denitrifiers, nitrifiers, and free nitrogen-fixing bacteria from Azotobacter genus) were analysed. Soil biological quality was assessed by the bacterial indicator of soil quality, which varied between 4.3 and 4.7. A colony polymerase chain reaction technique was used for screening PHB producers. With different primers, specific bands were obtained in all the soil samples. Some wild types of Azotobacter species were isolated from the 4 studied sites. Biodegradable polymers of PHB were assessed by negative staining in transmission electron microscopy. The maximum PHB granules density was obtained in the strains isolated from the xerophilous meadow (10-18 granules/cell), which was the most stressful environment from all the studied sites, as the physicochemical and microbiological tests proved. PMID- 22540339 TI - Carbon backbone topology of the metabolome of a cell. AB - The complex metabolic makeup of a biological system, such as a cell, is a key determinant of its biological state providing unique insights into its function. Here we characterize the metabolome of a cell by a novel homonuclear (13)C 2D NMR approach applied to a nonfractionated uniformly (13)C-enriched lysate of E. coli cells and determine de novo their carbon backbone topologies that constitute the "topolome". A protocol was developed, which first identifies traces in a constant time (13)C-(13)C TOCSY NMR spectrum that are unique for individual mixture components and then assembles for each trace the corresponding carbon-bond topology network by consensus clustering. This led to the determination of 112 topologies of unique metabolites from a single sample. The topolome is dominated by carbon topologies of carbohydrates (34.8%) and amino acids (45.5%) that can constitute building blocks of more complex structures. PMID- 22540341 TI - ApaI, BsmI, FokI and TaqI polymorphisms in the vitamin D receptor (VDR) gene and the risk of psoriasis: a meta-analysis. AB - OBJECTIVES: To determine whether ApaI, BsmI, FokI or TaqI polymorphisms in vitamin D receptor (VDR) gene confer susceptibility to psoriasis. Methods All related association studies published before January 2012 were retrieved and eligible ones were included in our meta-analysis. For each of the four polymorphisms, we explored the significance of the associations for the allele contrast as well as the recessive and dominant models in overall samples, Caucasians and East Asians. Heterogeneity was identified by sensitivity analysis and publication bias was examined by funnel plot and Egger's test. RESULTS: 12 studies that met our selection criteria were included. For ApaI polymorphism, the dominant model for allele a in Caucasians produced a significant result [heterogeneity chi(2) = 3.46, P = 0.177, I(2) = 42.2%; OR(fixed-effect model) = 1.398 (1.011-1.934), z = 2.03, P = 0.043]. While in East Asians, pooling analysis under any genetic model acquired no-significant result. Significant heterogeneity was identified among East Asian studies and a Korean study accounted mostly for the heterogeneity detected. The heterogeneities were no longer statistically significant after removing this study, and the results of re-analyses in remaining studies have not been affected. Regarding TaqI polymorphism, the allele contrast discovered significant association between allele T and psoriasis susceptibility in Caucasians [heterogeneity chi(2) = 4.35, P = 0.226, I(2) = 31.1%; OR(fixed-effect model) = 1.287 (1.067-1.551), z = 2.64, P = 0.008]. As for the BsmI and FokI polymorphisms, allele contrast, recessive and dominant models produced non-significant results in either Caucasians or East Asians. The funnel plots and Egger's tests found no publication bias presenting in the studies analyzed. CONCLUSIONS: This meta-analysis showed that ApaI, TaqI polymorphisms in VDR gene correlate with psoriasis in Caucasians. PMID- 22540342 TI - Integration of pillar array columns into a gradient elution system for pressure driven liquid chromatography. AB - A gradient elution system for pressure-driven liquid chromatography (LC) on a chip was developed for carrying out faster and more efficient chemical analyses. Through computational fluid dynamics simulations and an experimental study, we found that the use of a cross-Tesla structure with a 3 mm mixing length was effective for mixing two liquids. A gradient elution system using a cross-Tesla mixer was fabricated on a 20 mm * 20 mm silicon chip with a separation channel of pillar array columns and a sample injection channel. A mixed solution of water and fluorescein in methanol was delivered to the separation channel 7 s after the gradient program had been started. Then, the fluorescence intensity increased gradually with the increasing ratio of fluorescein, which showed that the gradient elution worked well. Under the gradient elution condition, the retention times of two coumarin dyes decreased with the gradient time. When the gradient time was 30 s, the analysis could be completed in 30 s, which was only half the time required compared to that required for an isocratic elution. Fluorescent derivatives of aliphatic amines were successfully separated within 110 s. The results show that the proposed system is promising for the analyses of complex biological samples. PMID- 22540343 TI - Molecular dynamics in supercooled liquid and glassy states of antibiotics: azithromycin, clarithromycin and roxithromycin studied by dielectric spectroscopy. Advantages given by the amorphous state. AB - Antibiotics are chemical compounds of extremely important medical role. Their history can be traced back more than one hundred years. Despite the passing time and significant progress made in pharmacy and medicine, treatment of many bacterial infections without antibiotics would be completely impossible. This makes them particularly unique substances and explains the unflagging popularity of antibiotics within the medical community. Herein, using dielectric spectroscopy we have studied the molecular mobility in the supercooled liquid and glassy states of three well-known antibiotic agents: azithromycin, clarithromycin and roxithromycin. Dielectric studies revealed a number of relaxation processes of different molecular origin. Besides the primary alpha-relaxation, observed above the respective glass transition temperatures of antibiotics, two secondary relaxations in the glassy state were identified. Interestingly, the fragility index as well as activation energies of the secondary processes turned out to be practically the same for all three compounds, indicating probably much the same molecular dynamics. Long-term stability of amorphous antibiotics at room temperature was confirmed by X-ray diffraction technique, and calorimetric studies were performed to evaluate the basic thermodynamic parameters. Finally, we have also checked the experimental solubility advantages given by the amorphous form of the examined antibiotics. PMID- 22540344 TI - CodY, a pleiotropic regulator, influences multicellular behaviour and efficient production of virulence factors in Bacillus cereus. AB - In response to nutrient limitation in the environment, the global transcriptional regulator CodY modulates various pathways in low G+C Gram-positive bacteria. In Bacillus subtilis CodY triggers adaptation to starvation by secretion of proteases coupled to the expression of amino acid transporters. Furthermore, it is involved in modulating survival strategies like sporulation, motility, biofilm formation, and CodY is also known to affect virulence factor production in pathogenic bacteria. In this study, the role of CodY in Bacillus cereus ATCC 14579, the enterotoxin-producing type strain, is investigated. A marker-less deletion mutant of codY (DeltacodY) was generated in B.cereus and the transcriptome changes were surveyed using DNA microarrays. Numerous genes involved in biofilm formation and amino acid transport and metabolism were upregulated and genes associated with motility and virulence were repressed upon deletion of codY. Moreover, we found that CodY is important for efficient production of toxins and for adapting from nutrient-rich to nutrient-limited growth conditions of B.cereus. In contrast, biofilm formation is highly induced in the DeltacodY mutant, suggesting that CodY represses biofilm formation. Together, these results indicate that CodY plays a crucial role in the growth and persistence of B.cereus in different environments such as soil, food, insect guts and the human body. PMID- 22540346 TI - A long-term survival case of adult undifferentiated embryonal sarcoma of liver. AB - Undifferentiated embryonal sarcoma of the liver (USEL) is a rare malignant hepatic tumor with a poor prognosis that is usually observed in children (aged 6 to 10 years) and rarely seen in adults. We present a case of USEL in a 27-year old woman with no previous history of the disease. Laboratory tests performed on admission showed that the patient had mildly elevated levels of aspartate aminotransferase, alanine transaminase, alkaline phosphatase, lactate dehydrogenase, and gamma-glutamyl transpeptidase. The levels of viral hepatitis and tumor serum markers were all within normal limits. Computed tomography showed a large mass involving the right lobe and the medial segment of the liver. Right trisectionectomy was performed. Microscopically, the tumor was composed of pleomorphic and polynuclear dyskaryotic cells in a myxoid stroma with focal eosinophilic globules and no clear differentiation to muscle. Histological diagnosis showed undifferentiated embryonal sarcoma. Adjuvant therapy with cisplatin, vincristine, doxorubicin, cyclophosphamide, and actinomycin D was initiated. We administered a high dose of etoposide to extract the patient's peripheral blood stem cells and performed radiation therapy and peripheral blood stem cell transplantation. At 5-year follow-up, the patient was alive without any evidence of recurrence. Here, we describe the clinical and histopathological features of USEL as well as the therapeutic options for USEL in adults with this disease. PMID- 22540347 TI - Prevalence and impact of disability in women who had recently given birth in the UK. AB - BACKGROUND: Maternity services should take into account the needs of all women, including those related to disability. No reliable information, however, exists on the extent and characteristics of disability in this population in the UK. This brief report provides an overview of the prevalence of disability in women giving birth in the UK as measured by the presence of a limiting longstanding illness (LLI). The demographic, socio-economic, lifestyle and pregnancy related characteristics and child health outcomes are summarised to inform maternity and postnatal care service planning, and policy development. METHODS: Secondary analysis of data on 18,231 mother-child pairs from the nationally representative UK Millennium Cohort Study. The baseline interviews with families were carried out in 2001-2002. The LLI prevalence in women who had recently delivered was estimated, and relevant characteristics and differences in outcomes compared using descriptive statistics taking into account the study design and non response. RESULTS: 9.4% (95% CI 8.7-10.0) of women who had recently given birth reported having an LLI. Musculoskeletal, respiratory and mental disorders accounted for most of the health problems. A significantly higher proportion of women with an LLI received means-tested financial benefits, had no educational qualifications and suffered from intimate partner violence compared to women who did not have an LLI (49.3% vs 35.3%, 20.4% vs 15.0%, 6.0% vs 3.3%, respectively). They were also more likely to smoke throughout pregnancy than women without an LLI (29.2% vs 20.8%), have a preterm birth (10.9% vs 6.8%) and be lone parents (19.5% vs 13.9%). Only 25.6% of children of mothers with an LLI were breastfed for more than three months compared to 33.4% of infants of mothers who did not have an LLI. At the age of seven years, 12.0% of children of mothers with an LLI had an activity limiting health problem themselves compared to 6.2% of children of mothers without an LLI. CONCLUSIONS: Disability in women who had recently delivered is relatively common. It is associated with social and economic inequalities and worse pregnancy and child related outcomes. Apart from condition specific support during and after pregnancy, disabled women may require extra help from health professionals to quit smoking, continue breastfeeding, and reduce intimate partner violence. PMID- 22540348 TI - The endoplasmic reticulum localized PIN8 is a pollen-specific auxin carrier involved in intracellular auxin homeostasis. AB - The plant hormone auxin is a mobile signal which affects nuclear transcription by regulating the stability of auxin/indole-3-acetic acid (IAA) repressor proteins. Auxin is transported polarly from cell to cell by auxin efflux proteins of the PIN family, but it is not as yet clear how auxin levels are regulated within cells and how access of auxin to the nucleus may be controlled. The Arabidopsis genome contains eight PINs, encoding proteins with a similar membrane topology. While five of the PINs are typically targeted polarly to the plasma membranes, the smallest members of the family, PIN5 and PIN8, seem to be located not at the plasma membrane but in endomembranes. Here we demonstrate by electron microscopy analysis that PIN8, which is specifically expressed in pollen, resides in the endoplasmic reticulum and that it remains internally localized during pollen tube growth. Transgenic Arabidopsis and tobacco plants were generated overexpressing or ectopically expressing functional PIN8, and its role in control of auxin homeostasis was studied. PIN8 ectopic expression resulted in strong auxin-related phenotypes. The severity of phenotypes depended on PIN8 protein levels, suggesting a rate-limiting activity for PIN8. The observed phenotypes correlated with elevated levels of free IAA and ester-conjugated IAA. Activation of the auxin-regulated synthetic DR5 promoter and of auxin response genes was strongly repressed in seedlings overexpressing PIN8 when exposed to 1-naphthalene acetic acid. Thus, our data show a functional role for endoplasmic reticulum-localized PIN8 and suggest a mechanism whereby PIN8 controls auxin thresholds and access of auxin to the nucleus, thereby regulating auxin-dependent transcriptional activity. PMID- 22540349 TI - Management of seizures following a stroke: what are the options? AB - Post-stroke seizures are a frequent cause of remote symptomatic epilepsy in adults, especially in older age. About 10% of stroke patients will suffer a seizure, depending on risk factors, such as the type, location and severity of the stroke. Previous stroke accounts for 30-40% of all cases of epilepsy in the elderly. Compared with that in younger patients, the appearance of seizures in old age is less specific and may take time before a diagnosis can be proven. The optimal timing and type of antiepileptic drug (AED) treatment for patients with post-stroke seizures is still a controversial issue. Many population- and hospital-based studies have been performed, ending with generalized recommendations, but still the decision to initiate AED treatment after a first or second seizure should be individualized. Prospective studies in the literature showed that immediate treatment after a first unprovoked seizure does not improve the long-term remission rate. However, because of the physical and psychological influences of recurrent seizures, prophylactic treatment should be considered after a first unprovoked event in an elderly person at high risk of recurrence, taking into consideration the individuality of the patient and a discussion with the patient and his/her family about the risks and benefits of both options. The latest studies regarding post-stroke seizure treatment showed that 'new generation' drugs, such as lamotrigine, gabapentin and levetiracetam, in low doses would be reasonable because of their high rate of long-term seizure-free periods, improved safety profile, and fewer interactions with other drugs, especially anticoagulant ones, compared with first-generation AEDs. On the other hand, first-generation drugs, such as phenytoin, carbamazepine and phenobarbital, have the potential to have a harmful impact on recovery, bone health, cognition and blood sodium levels and may interact with other treatments used by the elderly population. The drug chosen for use in the elderly population should possess a wide spectrum of activity and have few side effects. An assessment should be done to identify possible drug-drug interactions, the drug should be started at a low dose and titrated slowly to the lowest maintenance dose possible, and enhanced quality of life should be a focus of treatment. So, in the end, further research is needed to determine, more appropriately, the type of AED therapy, timing and duration of treatment. PMID- 22540351 TI - Human chorionic gonadotrophin (hCG) enhances immunity against L. tropica by stimulating human macrophage functions. AB - During pregnancy, there are important changes in hormone levels such as the huge production of human chorionic gonadotropin (hCG), which is supposed to influence the immune system. The aim of this study was to investigate the effect of hCG on immune response against Leishmania, through the evaluation of the functions of human macrophages infected with L. tropica. This study demonstrated that hCG significantly increased the NO production by rHu-IFNgamma-primed macrophages then infected with L. tropica, which was correlated with decrease in the number of infected macrophages as well as the number of amastigotes per macrophage in a dose-dependent manner; however, the greatest effect was shown with the 250 U/mL concentration. The addition of the same concentration of hCG to rHu-IFNgamma primed macrophages caused also a major increase in both IL-6 and IL-12p40 production. In conclusion, hCG enhances different macrophage functions involved in immunity against L. tropica. PMID- 22540350 TI - Should we reconsider the routine use of placebo controls in clinical research? AB - BACKGROUND: Modern clinical-research practice favors placebo controls over usual care controls whenever a credible placebo exists. An unrecognized consequence of this preference is that clinicians are more limited in their ability to provide the benefits of the non-specific healing effects of placebos in clinical practice. METHODS: We examined the issues in choosing between placebo and usual care controls. We considered why placebo controls place constraints on clinicians and the trade-offs involved in the choice of control groups. RESULTS: We find that, for certain studies, investigators should consider usual-care controls, even if an adequate placebo is available. Employing usual-care controls would be of greatest value for pragmatic trials evaluating treatments to improve clinical care and for which threats to internal validity can be adequately managed without a placebo-control condition. CONCLUSIONS: Intentionally choosing usual-care controls, even when a satisfactory placebo exists, would allow clinicians to capture the value of non-specific therapeutic benefits that are common to all interventions. The result could be more effective, patient-centered care that makes the best use of both specific and non-specific benefits of medical interventions. PMID- 22540352 TI - May-Thurner syndrome resulting in acute iliofemoral deep vein thrombosis during the second trimester of pregnancy. AB - Described is a 27-year-old pregnant woman with May-Thurner syndrome who experienced extensive pelvic and lower extremity thromboses during the antepartum period. The patient was referred for a symptomatic deep venous thrombosis at 23 weeks of gestation. Ultrasonography demonstrated a massive thrombus in the left iliofemoral vein. Heparin was given intravenously. Due to the possibility of pulmonary embolism during or immediately after delivery, a temporary inferior vena cava filter was inserted at 36 weeks of gestation. Labor was induced at 37 + 5 weeks of gestation; labor proceeded uneventfully and a male infant was born. Postpartum computed tomography (CT) demonstrated compression of the left common iliac vein by the right common iliac artery and lumbar vertebra. CT venogram demonstrated poor flow through the common iliac vein and well-developed collateral vessels. Critical stenosis at the origin of the left common iliac vein was consistent with a diagnosis of May-Thurner syndrome. PMID- 22540353 TI - Adipocyte cell size enlargement involves plasma membrane area increase. AB - The adipocyte enlargement is associated with an increase in the cytoplasmic lipid content, but how the plasma membrane area follows this increase is poorly understood. We monitored single-cell membrane surface area fluctuations, which mirror the dynamics of exocytosis and endocytosis. We employed the patch-clamp technique to measure membrane capacitance (C(m)), a parameter linearly related to the plasma membrane area. Specifically, we studied whether insulin affects membrane area dynamics in adipocytes. A five-minute cell exposure to insulin increased resting C(m) by 12 +/- 4%; in controls the change in C(m) was not different from zero. We measured cell diameter of isolated rat adipocytes microscopically. Twenty-four hour exposure of cells to insulin resulted in a significant increase in cell diameter by 5.1 +/- 0.6%. We conclude that insulin induces membrane area increase, which may in chronic hyperinsulinemia promote the enlargement of plasma membrane area, acting in concert with other insulin mediated metabolic effects on adipocytes. PMID- 22540354 TI - Replica exchange statistical temperature molecular dynamics algorithm. AB - The replica exchange statistical temperature molecular dynamics (RESTMD) algorithm is presented, designed to alleviate an extensive increase of the number of replicas required as system size increases in the conventional temperature replica exchange method (tREM), and to obtain improved sampling in individual replicas. RESTMD optimally integrates multiple STMD (Phys. Rev. Lett. 2006, 97, 050601) runs with replica exchanges, giving rise to a flat energy sampling in each replica with a self-adjusting weight determination. The expanded flat energy dynamic sampling range allows the use of significantly fewer STMD replicas while maintaining the desired acceptance probability for replica exchanges. The computational advantages of RESTMD over conventional REM and single-replica STMD are explicitly demonstrated with an application to a coarse-grained protein model. The effect of two different kinetic temperature control schemes on the sampling efficiency is explored for diverse simulation conditions. PMID- 22540355 TI - The influence of HPMC concentration on release of theophylline or hydrocortisone from extended release mini-tablets. AB - CONTEXT: Mini-tablets are compact dosage forms, typically 2-3 mm in diameter, which have potential advantages for paediatric drug delivery. Extended release (ER) oral dosage forms are intended to release drugs continuously at rates that are sufficiently controlled to provide periods of prolonged therapeutic action following each administration, and polymers such as hypromelllose (HPMC) are commonly used to produce ER hydrophilic matrices. OBJECTIVE: To develop ER mini tablets of different sizes for paediatric delivery and to study the effects of HPMC concentration, tablet diameter and drug solubility on release rate. METHODS: The solubility of Hydrocortisone and theophylline was determined. Mini-tablets (2 and 3 mm) and tablets (4 and 7 mm) comprising theophylline or hydrocortisone and HPMC (METHOCELTM K15M) at different concentrations (30, 40, 50 and 60%w/w) were formulated. The effect of tablet size, HPMC concentration and drug solubility on release rate and tensile strength was studied. RESULTS AND DISCUSSION: Increasing the HPMC content and tablet diameter resulted in a significant decrease in drug release rate from ER mini-tablets. In addition, tablets and mini-tablets containing theophylline produced faster drug dissolution than those containing hydrocortisone, illustrating the influence of drug solubility on release from ER matrices. The results indicate that different drug release profiles and doses can be obtained by varying the polymer content and mini-tablet diameter, thus allowing dose flexibility to suit paediatric requirements. CONCLUSION: This work has demonstrated the feasibility of producing ER mini-tablets to sustain drug release rate, thus allowing dose flexibility for paediatric patients. Drug release rate may be tailored by altering the mini-tablet size or the level of HPMC, without compromising tablet strength. PMID- 22540356 TI - Significance of keratinized mucosa around dental implants: a prospective comparative study. AB - OBJECTIVE: The aim of this investigation was to evaluate the significance of keratinized mucosa (KM) around dental implants both clinically and biochemically for 12 months. MATERIAL AND METHODS: Fifteen edentulous patients treated with implant-retained overdentures in edentulous mandible (four implants per patient). Based on the presence of keratinized mucosa on the buccal surfaces, implants were divided into two groups: Implants having minimal 2 mm of KM on their buccal surfaces and implants having no KM on their buccal surfaces. Thirty-six implants were included in the evaluations; 19 implants in 15 patients had minimal 2 mm of KM on their buccal surfaces and 17 implants in 15 patients had no KM on their buccal surfaces. Clinical measurements of Plaque Index, Gingival Index, probing depths, and Bleeding on Probing were performed and peri-implant crevicular fluid (PICF) were collected immediately before loading (baseline) and at 6th, 12th months after loading. Interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha) have been assessed in the crevicular fluid. Results were analyzed by repeated-measures of variance (ANOVA) and Wilcoxon signed rank tests. RESULTS: After 12 months of evaluation the results of ANOVA showed that implants with KM had lower levels of TNF-alpha total amounts than implants without KM (P < 0.05). Additionally, TNF-alpha total amounts were significantly higher at 12(th) month compared to baseline for implants without KM (P < 0.05). Plaque index and Gingival index values were also found significantly higher for implants without KM (P < 0.05). For IL-1 beta and PICF volume levels the differences between the implant groups were non significant, whereas the differences between the periods were significant. (P < 0.05) Additionally, both of the groups had higher levels of PII and BoP scores when compared to baseline (P < 0.05). CONCLUSIONS: The results of this study showed that an adequate band of keratinized mucosa was related with less plaque accumulation and mucosal inflammation as well as pro inflammatuar mediators, suggesting that it may be critical especially for plaque control and plaque associated mucosal lesions around dental implants. PMID- 22540357 TI - Fundamental molecular design for precise control of thermoresponsiveness of organic polymers by using ternary systems. AB - The de novo design of thermosensitive polymers in solution has been achieved by using the addition of small organic molecules (or "effectors"). Hydrogen bonding as an attractive polymer-polymer or polymer-effector interaction substantially dominates the responsivity, causing facile switching between LCST-type and UCST type phase transitions, control of the transition temperature, and further coincidence of the two transitions. Small molecules having a high affinity for the polymer induce UCST-type phase behavior, whereas those having a low affinity for the polymer showed LCST-type phase behavior. PMID- 22540358 TI - Nonlinguistic cognitive treatment for bilingual children with primary language impairment. AB - Substantial evidence points to the presence of subtle weaknesses in the nonlinguistic cognitive processing skills of children with primary (or specific) language impairment (PLI). It is possible that these weaknesses contribute to the language learning difficulties that characterize PLI, and that treating them can improve language skills. To test this premise, we treated two nonlinguistic cognitive processing skills, processing speed and sustained selective attention, in two Spanish-English bilingual children with PLI. The study followed a single subject multiple baseline design, with both repeated measures and standardized pre- and post-testing as outcome measures. Results from the repeated measures tasks showed that both participants made gains in nonlinguistic cognitive processing skills as well as in Spanish and English. These results both replicate and extend prior work showing that nonlinguistic cognitive processing treatment can positively affect language skills in children with PLI. PMID- 22540359 TI - Intra-word inconsistency in apraxic Hebrew-speaking children. AB - Intra-word inconsistency in a child is perceived as an indicator of speech impairment. Because the speech of typically developing children is highly variable, the extent and nature of the inconsistency must be defined when used as a diagnostic marker of speech impairment (McLeod, S., & Hewett, S. R. (2008). Variability in the production of words containing consonant clusters by typical 2 and 3-year-old children. Folia Phoniatrica et Logopaedica, 60(4), 163-172). In this paper, we study inconsistency with reference to the prosodic hierarchy (McCarthy, J. J., & Prince, A. S. (1996). Prosodic morphology 1986. Amherst, MA: University of Massachusetts. Retrieved April 15, 2010, from http://ruccs.rutgers.edu/pub/papers/pm86all.pdf), suggesting a new way to describe this phenomenon in childhood apraxia of speech (CAS). The prosodic hierarchy has been used in recent years to demonstrate the phonological development of typical and atypical populations. Sixteen children diagnosed with CAS (average age 3;11) participated in the study. The data, collected from each child in the course of eight weekly meetings, are drawn from naming single words. The results indicate that inconsistency is dominant for two prosodic levels, the segmental and the syllabic, while the prosodic word level was largely preserved. PMID- 22540360 TI - The use of semantic- and phonological-based feature approaches to treat naming deficits in aphasia. AB - The aim of the study was to compare approaches highlighting either semantic or phonological features to treat naming deficits in aphasia. Treatment focused on improving picture naming. An alternating treatments design was used with a multiple baseline design across stimuli to examine effects of both approaches in two participants with varying degrees of anomia. The features approaches were modified in that three, rather than six, features were used. Significant differential effects were found across participants; this appeared to be a function of each participant's strengths or preferences over the course of treatment. Modest generalization effects were obtained for one participant. Naming error analyses revealed patterns suggestive of increased lexical access for both participants. These findings provide evidence that using a modified features-based protocol can improve naming when incorporating both semantic and phonological feature cues. Naming error patterns can provide additional evidence of improved naming during treatment. PMID- 22540361 TI - Adjective production by Russian-speaking children with specific language impairment. AB - Research on specific language impairment (SLI) has primarily focused on the acquisition of nouns and verbs. Less attention has been given to other content word classes, such as adjectives and adverbs. This article investigates adjective production by 7- to 10-year-old Russian-speaking children with SLI and their typically developing (TD) peers and focuses on the production of antonymous adjectives and degree markers in an elicitation experiment. The results show that degree morphology is more impaired in SLI than antonymy. In antonym production, children with SLI were able to catch up with their TD peers by age 8. In the domain of degree, however, the SLI group lagged behind the TD controls across all ages studied. Error analysis indicates that language-impaired children have particular difficulty with agreement inflection and affixal negations. They also substitute adjectives with specific meanings by more general terms. The implications of this study for the morphological-richness hypothesis are discussed. PMID- 22540364 TI - Ultrastructural study of vitellogenesis of Aphallus tubarium (Rudolphi, 1819) Poche, 1926 (Digenea: Cryptogonimidae), an intestinal parasite of Dentex dentex (Pisces: Teleostei). AB - Vitellogenesis of Aphallus tubarium, an intestinal parasite of Sparidae (Dentex dentex ), was studied by transmission electron microscopy. The ultrastructural features allowed us to distinguish 4 stages in the vitellogenesis process. In stage 1, vitellocytes have a cytoplasm mainly filled with ribosomes, but few mitochondria. In stage 2, there is an increase in amount of endoplasmic reticulum and few Golgi complexes. There is production of shell globules that coalesce into clusters in stage 3; some glycogen particles are observed via the Thiery method. Finally, in stage 4, mature vitellocytes are filled with shell globule clusters and generally contain a large lipid droplet. Glycogen particles are grouped at the periphery of the cell. PMID- 22540365 TI - Avoiding wrong site surgery: how language and technology can help. PMID- 22540366 TI - Investigating the recrystallization behavior of amorphous paracetamol by variable temperature Raman studies and surface Raman mapping. AB - In situ Raman spectroscopy and Raman mapping are used to monitor the crystallization of amorphous paracetamol in both covered and uncovered geometries, for which different crystallization pathways have been reported previously. The results suggest that surface crystallization predominates in the uncovered samples, leading to forms I and II, whereas in the covered samples bulk crystallization dominates and leads to form III. PMID- 22540367 TI - Is the apolipoprotein E4 allele always hazardous? Serum uric acid level as a conflict. AB - Hyperuricemia, dyslipidemia, and apolipoprotein E (apoE) polymorphism are risk factors for cardiovascular diseases (CVDs). This study sought to determine the association of apoE gene polymorphism with hyperuricemia and dyslipidemia in young healthy people. Association of serum uric acid (SUA) and serum lipids with apoE was studied by analysis of variance in 198 healthy southern Iranian candidates. Subjects with an E2/E3 genotype had a lower cholesterol level in comparison with E3/E3 individuals. In addition, male E3/E4 subjects had a lower SUA level in comparison with other men. Lower cholesterol levels in E2 carriers mean a lower risk for CVDs, while SUA, as another risk factor for CVDs, in male E4 carriers was low. Regarding the higher risk for CVDs in men and the known role of SUA and apoE polymorphism in CVDs, it is not simple to guess the net effect of each one of these risk factors. This is the first report to study the association between SUA level and apoE in healthy men. PMID- 22540368 TI - FHY3 promotes shoot branching and stress tolerance in Arabidopsis in an AXR1 dependent manner. AB - The transposase-related transcription factor FAR-RED ELONGATED HYPOCOTYL3 (FHY3) promotes seedling de-etiolation in far-red light, which is perceived by phytochrome A (phyA). In this role, FHY3 indirectly mediates the nuclear import of light-activated phyA, which triggers downstream transcriptional responses. Here, we present genetic evidence for additional roles of FHY3 in plant development and growth. New fhy3 alleles were isolated as suppressors of max2-1 (more axillary branching2-1), a strigolactone-insensitive mutant characterised by highly branched shoots. Branching suppression by fhy3, in both wild-type and max2 1 backgrounds, resulted from inhibition of axillary bud outgrowth. Additional roles in axillary meristem initiation were revealed in the revoluta (rev) fhy3 double mutant, with fhy3 enhancing rev mutant defects in axillary shoot meristem formation, as well as in floral meristem maintenance. fhy3 also affected embryonic and floral patterning with low penetrance, and displayed oxidative stress-related phenotypes of retarded leaf growth and of cell death. The fhy3 phenotypes of axillary bud outgrowth suppression and of stress-induced leaf growth retardation both required the AUXIN-RESISTANT1 gene, and are independent of phyA. Consistent with the recent discovery that FHY3 regulates many Arabidopsis promoters, our results suggest much wider roles for FHY3 in growth and development, either in concert with, or beyond, light signalling. PMID- 22540369 TI - A rare giant gastrointestinal stromal tumor of the stomach traversing the upper abdomen: a case report and literature review. AB - We present the case of a 66-year-old woman with a huge gastrointestinal stromal tumor of the stomach that traversed her upper abdomen. The predominant abdominal sign was a huge, palpable mass, but there were no other distinctive findings in her physical examination or her routine blood workup, including biochemical markers. It was difficult to judge the origin of the mass upon imaging. Furthermore, radiological findings revealed that the mass had a complex relationship with many major blood vessels. An exploratory laparotomy revealed a huge tumor protruding from the anterior wall of the stomach fundus, on the lesser curvature of the stomach, measuring approximately 21 * 34 * 11 cm in diameter and weighing 5.5 kg. A complete resection was performed and the tumor was characterized on immunohistochemistry as a gastrointestinal stromal tumor of the stomach. Preoperative diagnosis of gastrointestinal stromal tumors can be difficult, and we hope that the presentation of this rare case and literature review will benefit other diagnosing clinicians having similar problems. PMID- 22540370 TI - GlycoPep grader: a web-based utility for assigning the composition of N-linked glycopeptides. AB - GlycoPep grader (GPG) is a freely available software tool designed to accelerate the process of accurately determining glycopeptide composition from tandem mass spectrometric data. GPG relies on the identification of unique dissociation patterns shown for high mannose, hybrid, and complex N-linked glycoprotein types, including patterns specific to those structures containing fucose or sialic acid residues. The novel GPG scoring algorithm scores potential candidate compositions of the same nominal mass against MS/MS data through evaluation of the Y(1) ion and other peptide-containing product ions, across multiple charge states, when applicable. In addition to evaluating the peptide portion of a given glycopeptide, the GPG algorithm predicts and scores product ions that result from unique neutral losses of terminal glycans. GPG has been applied to a variety of glycoproteins, including RNase B, asialofetuin, and transferrin, and the HIV envelope glycoprotein, CON-S gp140DeltaCFI. The GPG software is implemented predominantly in PostgreSQL, with PHP as the presentation tier, and is publicly accessible online. Thus far, the algorithm has identified the correct compositional assignment from multiple candidate N-glycopeptides in all tests performed. PMID- 22540371 TI - Prescribing of rosiglitazone and pioglitazone following safety signals: analysis of trends in dispensing patterns in the Netherlands from 1998 to 2008. AB - BACKGROUND: Relevant safety signals in the EU are regularly communicated in so called 'Direct Healthcare Professional Communications' (DHPCs) or European Medicines Agency (EMA) press releases. Trends of a decrease in the use of rosiglitazone following regulatory safety warnings have been described in the US. In the EU, however, relatively little is known about dispensing patterns following DHPCs or other safety signals such as EMA press releases. OBJECTIVE: The objective of this study was to analyse trends in dispensing patterns of rosiglitazone and pioglitazone following DHPCs and EMA press releases in the EU member state, the Netherlands. METHODS: Data for this study were obtained from the PHARMO Record Linking System, which includes drug dispensing records from community pharmacies of approximately 2.5 million individuals in the Netherlands. Over the period 1998-2008 an auto-regressive, integrated, moving average model (ARIMA) was fitted. The DHPC letters or EMA press releases were used as determinants. Adjustments were made for publication of certain literature. Stratification was performed for dispensings prescribed by general practitioners (GPs) and those prescribed by specialists. RESULTS: For rosiglitazone, four EMA press releases and two DHPCs were issued; for pioglitazone, one DHPC was issued. The number of rosiglitazone dispensings prescribed by GPs decreased significantly after publication of DHPCs and EMA press releases concerning the risk of macular oedema and risk of fractures (both p-values 0.001). The number of rosiglitazone dispensings decreased statistically significantly after publication of EMA press releases 2 and 3 concerning cardiovascular risks but not for EMA press release 4. Adjustment for certain publications in the literature reduced the effect of communicated safety issues on the proportion of dispensings. CONCLUSIONS: Although it is difficult to disentangle the effect of DHPCs and EMA press releases from the effect of reports published in the literature, our results suggest that prescribers may react to such safety communications. PMID- 22540373 TI - Scavenger receptor for hemoglobin in preterm prelabor rupture of membranes pregnancies complicated by histological chorioamnionitis. AB - OBJECTIVE: We sought to evaluate the distribution of scavenger receptor for hemoglobin positive (CD163(+)) cells in the placenta and fetal membranes from pregnancies complicated by preterm prelabor rupture of membranes with respect to the presence and absence of histological chorioamnionitis. METHODS: Sixty-two women with singleton pregnancies with a gestational age between 24+0 and 36+6 weeks were included in a prospective cohort study. CD163 was evaluated by immunohistochemistry in the placenta and fetal membranes. The number of CD163(+) cells and neutrophils was counted in the following locations: fetal membranes' amnion, chorion, and decidua, as well as the placenta's amnion, chorionic plate, subchorionic fibrin, stem villi, terminal villi, and decidua. RESULTS: CD163(+) cells were found in all compartments of the placenta and the fetal membranes regardless of the inflammatory status. A positive correlation between the number of CD163(+) cells and neutrophils in the subchorionic fibrin and the chorionic plate was found. The number of CD163(+) cells was higher in the placental subchorionic fibrin and chorionic plate when histological chorioamnionitis was present. CONCLUSION: The presence of histological chorioamnionitis affected the number of CD163(+) cells in the placental chorionic plate and in the subchorionic fibrin but not in the fetal membranes. PMID- 22540372 TI - Pancreatogastrostomy versus pancreatojejunostomy for RECOnstruction after partial PANCreatoduodenectomy (RECOPANC): study protocol of a randomized controlled trial UTN U1111-1117-9588. AB - BACKGROUND: Pancreatoduodenectomy is one of the most complex abdominal operations, usually performed for tumors of the periampullary region and chronic pancreatitis. Leakage of pancreatic juice from the pancreatoenteric anastomosis, called postoperative pancreatic fistula, is the most prominent postoperative complication. Retrospective studies show a significant reduction of fistula rates with pancreatogastrostomy as compared to pancreatojejunostomy, the most frequently employed method of pancreatoenterostomy. Most single-center prospective trials, however, have not validated this finding. A large multicenter trial is needed for clarification. METHODS/DESIGN: RECOPANC is a prospective, randomized, controlled multicenter trial with two treatment arms, pancreatogastrostomy versus pancreatojejunostomy. The trial hypothesis is that postoperative pancreatic fistula rate is lower after pancreatogastrostomy when compared to pancreatojejunostomy. Fourteen academic centers for pancreatic surgery will participate to allocate 360 patients to the trial. The duration of the entire trial is four years including prearrangement and analyses. DISCUSSION: Postoperative pancreatic fistula is the main reason for clinically important postoperative morbidity after pancreatoduodenectomy. The primary goal of the chosen reconstruction technique for pancreatoenteric anastomosis is to minimize postoperative fistula rate. A randomized trial performed at multiple high-volume centers for pancreatic surgery is the best opportunity to investigate one of the most crucial issues in pancreatic surgery. TRIAL REGISTRATION: German Clinical Trials Register DRKS00000767 (2011/03/23), FSI 2011/05/31. Universal Trial Number U1111-1117-9588. PMID- 22540375 TI - Retraction statement. PMID- 22540374 TI - Flavokawain B, a novel, naturally occurring chalcone, exhibits robust apoptotic effects and induces G2/M arrest of a uterine leiomyosarcoma cell line. AB - AIM: To examine the effects of flavokawain B (FKB), a novel kava chalcone, on the growth of uterine leiomyosarcoma (LMS) cells and investigated its utility in the treatment of uterine LMS. MATERIAL AND METHODS: Uterine leiomyosarcoma (SK-LMS 1), endometrial adenocarcinoma (ECC-1) and the non-malignant, human endometrium fibroblast-like (T-HESC) cell lines were cultured and treated with different concentrations of FKB. Cell viability was determined by MTT assays and the IC(50) was estimated. Fluorescent-activated cell sorting (FACS) analysis of apoptosis and cell cycle was performed. Real-time reverse-transcription polymerase chain reaction and western blot analysis were utilized to evaluate differences in the expression of apoptotic markers. RESULTS: FKB preferentially inhibited the growth of SK-LMS-1 and ECC-1 cells compared to T-HESC control cells. FKB significantly increased both early and late apoptosis in SK-LMS-1 and ECC-1 cells relative to control. Cell cycle analysis illustrated an increase in the G2/M fraction in treated cell lines relative to control. Furthermore, FKB induced the expression of pro-apoptotic death receptor 5 (DR5), Bim, and Puma, and decreased expression of an inhibitor of apoptosis, survivin. FKB also acted synergistically when combined with docetaxel and gemcitabine (combination index = 0.260). CONCLUSION: FKB treatment results in cell cycle arrest and a robust induction of apoptosis in SK-LMS-1 and ECC-1 cell lines. This natural product deserved further investigation as a potential therapeutic agent in the treatment of uterine LMS. PMID- 22540376 TI - The evaluation of the infection with Chlamydia trachomatis of the female population in the Suceava area, Romania. PMID- 22540377 TI - A novel approach to the investigation of passive molecular permeation through lipid bilayers from atomistic simulations. AB - Predicting the permeability coefficient (P) of drugs permeating through the cell membrane is of paramount importance in drug discovery. We here propose an approach for calculating P based on bias-exchange metadynamics. The approach allows constructing from atomistic simulations a model of permeation taking explicitly into account not only the "trivial" reaction coordinate, the position of the drug along the direction normal to the lipid membrane plane, but also other degrees of freedom, for example, the torsional angles of the permeating molecule, or variables describing its solvation/desolvation. This allows deriving an accurate picture of the permeation process, and constructing a detailed molecular model of the transition state, making a rational control of permeation properties possible. We benchmarked this approach on the permeation of ethanol molecules through a POPC membrane, showing that the value of P calculated with our model agrees with the one calculated by a long unbiased molecular dynamics of the same system. PMID- 22540378 TI - Influence of polymer blends on the characterization of gliclazide--encapsulated into poly (epsilon-caprolactone) microparticles. AB - Gliclazide (GLZ)-loaded microparticles made with a polymeric blend were prepared by a solvent evaporation technique. Organic solutions of two polymers, poly(epsilon-caprolactone) (PCL) and Eudragit RS (E RS) or ethyl cellulose (EC), in different weight ratios, and 33.3% of GLZ were prepared and dropped into aqueous solution of poly vinyl alcohol, in different experimental conditions, achieving drug-loaded microparticles. The obtained microparticles were characterized in terms of yield of production, shape, size, surface properties, drug content, and in vitro drug release behavior. The physical state of the drugs and the polymer was determined by scanning electron microscopy (SEM), Fourier transform infra red and differential scanning calorimetry. Following the in vitro release studies microparticles made from blends of polymer, PCL/E RS or EC showed slower drug release than microparticles made from single PCL polymer. Surface morphology also revealed presence of porous and spherical structure of microparticles. Microparticles showing sustained release of GLZ were examined in rabbits and plasma GLZ concentrations were calculated using HPLC method of assay. PMID- 22540379 TI - Stem cell and benzene-induced malignancy and hematotoxicity. AB - The biological effect of benzene on the hematopoietic system has been known for over a century. The rapid advancement in understanding the biology of hematopoietic stem cells (HSCs) and cancer stem cells (CSCs) in recent years has renewed interest in investigating the role of stem cells in benzene-induced malignancy and bone marrow depression. The interplay between benzene and stem cells is complex involving the stem cell, progenitor, and HSC niche compartments of the bone marrow. In this prospect, benzene metabolites formed through metabolism in the liver and bone marrow cause damage in hematopoietic cells via multiple mechanisms that, in addition to traditionally recognized chromosomal aberration and covalent binding, incorporate oxidative stress, alteration of gene expression, apoptosis, error-prone DNA repair, epigenetic regulation, and disruption of tumor surveillance. However, benzene-exposed individuals exhibit variable susceptibility to benzene effect that arises, in part, from genetic variations in benzene metabolism, DNA repair, genomic stability, and immune function. These new studies of benzene leukemogenesis and hematotoxicity are expected to provide insights into how environmental and occupational chemicals affect stem cells to cause cancer and toxicity, which impact the risk assessment, permissible level, and therapy of benzene exposure. PMID- 22540381 TI - Race differences in intellectual control beliefs and cognitive functioning. AB - BACKGROUND/STUDY CONTEXT: The current study examined the relationship between intellectual control and cognition and related the results to everyday problem solving in a mixed ethnicity sample of 35% African American and 65% Caucasian elders. METHODS: Participants completed the Personality in Intellectual Aging Contexts Inventory (PIC; Lachman et al., 1982 , Journal of Research in Personality, 16, 485-501), Everyday Cognition Battery (ECB; Allaire & Marsiske, 1999 , Psychology & Aging, 14, 627-644; 2002 , Psychology & Aging, 17, 101-115), and a battery of basic cognitive ability tests assessing memory, inductive reasoning, and verbal meaning. RESULTS: Results indicated that African Americans had significantly lower intellectual control beliefs relative to Caucasian older adults. Regression models suggested that relationship between control beliefs and cognition was moderated by education and race. Decomposing the interactions with simple slope analysis revealed that across cognitive abilities, better cognitive performance was related to higher control beliefs in African Americans with at least 13 years of education. A similar relationship was also found in Caucasian elders with lower education. CONCLUSION: African American elders' reaching a higher level of education may provide a basis for which individual differences in intellectual control beliefs are activated and thereby more strongly associated with cognitive performance. PMID- 22540380 TI - Copper compound induces autophagy and apoptosis of glioma cells by reactive oxygen species and JNK activation. AB - BACKGROUND: Glioblastoma multiforme (GBM) is the most aggressive of the primary brain tumors, with a grim prognosis despite intensive treatment. In the past decades, progress in research has not significantly increased overall survival rate. METHODS: The in vitro antineoplastic effect and mechanism of action of Casiopeina III-ia (Cas III-ia), a copper compound, on rat malignant glioma C6 cells was investigated. RESULTS: Cas III-ia significantly inhibited cell proliferation, inducing autophagy and apoptosis, which correlated with the formation of autophagic vacuoles, overexpression of LC3, Beclin 1, Atg 7, Bax and Bid proteins. A decrease was detected in the mitochondrial membrane potential and in the activity of caspase 3 and 8, together with the generation of intracellular reactive oxygen species (ROS) and increased activity of c-jun NH(2)-terminal kinase (JNK). The presence of 3-methyladenine (as selective autophagy inhibitor) increased the antineoplastic effect of Cas III-ia, while Z-VAD-FMK only showed partial protection from the antineoplastic effect induced by Cas III-ia, and ROS antioxidants (N-acetylcysteine) decreased apoptosis, autophagy and JNK activity. Moreover, the JNK -specific inhibitor SP600125 prevented Cas III-ia-induced cell death. CONCLUSIONS: Our data suggest that Cas III-ia induces cell death by autophagy and apoptosis, in part due to the activation of ROS -dependent JNK signaling. These findings support further studies of Cas III-ia as candidate for treatment of human malignant glioma. PMID- 22540382 TI - Minor physical anomalies, intelligence, and cognitive decline. AB - BACKGROUND/STUDY CONTEXT: Minor physical anomalies are thought to be markers of development and increased frequency of such anomalies has been linked to lower levels of intelligence. Here the authors examine a finger curvature anomaly, and evaluate its potential as a marker of the causes of cognitive aging. METHODS: Participants were members of the Lothian Birth Cohort 1921 (LBC 1921). Intelligence was assessed at ages 11, 79, and 87. In wave 3, at age 87, 192 participants had both hands scanned with a high-resolution flatbed scanner and the curvature of the fifth digit was measured with image editing software. Multiple regression analyses were conducted to examine the proportion of unique variance in cognitive decline that could be explained by the finger curvature anomaly. RESULTS: Finger curvature was significantly associated with cognitive decline across the life span (beta= -.19, p= .02). Curvature was not associated with intelligence at age 11 or with decline during the period age 79 to age 87. CONCLUSION: Continuously varying minor physical anomalies may accumulate to provide a marker of factors impacting life span cognitive change. Curvature anomalies may reflect the common causes underlying cognitive and physical decline. PMID- 22540383 TI - The effect of perceptual cues on inhibiting irrelevant information in older adults using a list-learning method. AB - BACKGROUND/STUDY CONTEXT: The inhibitory deficit hypothesis (Hasher & Zacks, 1988 , The Psychology of Learning and Motivation: Advances in Research and Theory, 22, 193-225) suggests that older adults are more susceptible to interference from irrelevant information because of age-related declines in inhibitory ability. Reading comprehension tasks have found that this deficit can be overcome by salient perceptual cues used to accentuate relevant information (Carlson, Hasher, Connelly, & Zacks, 1995 , Psychology and Aging, 10, 427-436). This study examined the ability of older adults to use perceptual cues to aid inhibition in list learning tasks. METHODS: Sixteen younger (18-24 years of age) and sixteen older (62-79 years of age) adults were asked to remember/ignore presented items based on a pre- or posttrial perceptual cue (i.e., red or green font designated item relevance before or after each trial). The to-be-ignored stimuli could be pseudo words or words taken from the same word pool as the relevant items. A repeated measures analysis of variance (ANOVA) was done to examine age-related differences in recognition of to-be-remembered items. RESULTS: As expected, younger adults showed better performance than older adults when item relevance was designated posttrial. Most importantly, pretrial perceptual cues eliminated age-related differences in performance when the task-irrelevant stimuli were pseudo-words, but not when they were words from the same word pool as the task-relevant stimuli. CONCLUSION: The results suggest that perceptual cues are not reliably sufficient to overcome inhibitory deficits in older adults, and that older adults may continue to process irrelevant information, leading to declines in task performance. This warrants further investigation regarding the extent to which relevant and irrelevant items must be distinguishable, perceptually or semantically, in order to aid inhibitory ability in older adults. PMID- 22540384 TI - Aging, health behaviors, and the diurnal rhythm and awakening response of salivary cortisol. AB - BACKGROUND/STUDY CONTEXT: The cortisol diurnal rhythm has previously been examined in relation to age and health behaviors. However, less is known about the relationship between multiple health behaviors and diurnal cortisol in the context of aging, where it is possible that the impact of health behaviors on cortisol varies as a function of age. This study compared the awakening response and diurnal rhythm of cortisol in young versus older adults in relation to health behaviors. METHODS: Twenty-four young students (aged 18-22) and 48 community dwelling older adults (aged 65-88) completed an assessment of health behaviors (exercise, smoking, sleep, diet, alcohol) over the past year. Salivary cortisol was measured over the course of 1 day: immediately upon awakening, 30 min later, and then 3, 6, 9, and 12 h post awakening. Repeated measures/univariate analysis of variance (ANOVA) was used to test main effects of age and health behaviors, and any interaction effects in relation to diurnal cortisol. RESULTS: Older adults displayed significantly reduced cortisol upon awakening, a lower cortisol awakening response, and a flatter diurnal profile represented by a reduced area under the curve and cortisol slope. There was also a significant interaction of age, cortisol, and diet; younger adults with a higher fat and lower fruit and vegetable intake exhibited the flattened diurnal cortisol phenotype of the older adults. CONCLUSION: These findings suggest that the diurnal rhythm and awakening response of salivary cortisol is significantly reduced in older adults and that variations in the cortisol diurnal rhythm of younger adults are associated with dietary factors. Younger adults with a poor quality of food intake may be vulnerable to a reduction in the amplitude of the cortisol diurnal profile and this may have implications for other aspects of health. PMID- 22540385 TI - Occupational activity and cognitive aging: a case-control study based on the Maastricht Aging Study. AB - BACKGROUND/STUDY CONTEXT: Occupational activity is associated with cognitive functioning in older age. The mental exercise hypothesis attributes this association to differences in mental exercise at work. METHODS: A case-control design was used to test the mental exercise hypothesis. Primary and secondary school teachers (aged between 25.29 and 79.01 years) and non-teacher controls were matched for level of occupation, educational level, age, and gender. Regression analyses were used to analyze the data. Possible confounders (such as precareer intelligence and depressive status) were taken into account. RESULTS: Teachers had superior verbal fluency and working memory scanning abilities. CONCLUSION: The results are in line with the mental exercise hypothesis. PMID- 22540386 TI - Pain and interference of pain with function and mood in elderly adults involved in a motor vehicle collision: a pilot study. AB - BACKGROUND/STUDY CONTEXT: Musculoskeletal pain after motor vehicle collision is a substantial public health problem. The number of elderly individuals experiencing motor vehicle collision is increasing. The authors conducted analyses of data collected as part of a prospective observational study of outcomes after motor vehicle collision to estimates rates of persistent pain, pain interference, and change in physical function in patients 65 or older. METHODS: Adults presenting to one of four emergency departments following motor vehicle collision without severe or life-threatening injury were recruited. Outcomes were assessed using 1 month follow-up surveys. RESULTS: The frequencies of persistent moderate or severe pain resulting from the motor vehicle collision were similar among elderly and nonelderly participants, both in the neck region (27% vs. 30%) and in any region (60% vs. 56%). For both elderly and nonelderly patients, persistent pain was associated with high levels of interference with physical activity and mood. CONCLUSION: Further studies of this vulnerable and rapidly increasing injury population are needed. PMID- 22540387 TI - Quality of 4-hourly ejaculates--levels of calcium and magnesium. AB - A four-hourly ejaculation study was conducted in which eleven normal healthy subjects participated. Five of them discontinued after submitting three samples. One alone was present for submission at the end of 16 h (fifth ejaculate), which was his last submission. Physical exhaustion was the sole reason for all participants for their discontinuation from the study. The result showed a decrease in semen volume and sperm count from first to last ejaculate. The increase in motility was probably due to reduction in exposure time to sperm motility inhibitory factors. In general, total motile spermatozoa as well as actively motile spermatozoa progressively increased from first to last ejaculate at the cost of sluggish spermatozoa. A significant increase in seminal plasma calcium and magnesium was seen as well as a significant increase in magnesium inside the cell from the first to the fourth ejaculate. Considering the quality of semen, which was good in sperm count and excellent in motility, calcium and magnesium may be helpful in cleaning motility inhibitory factors of spermatozoa. PMID- 22540388 TI - Preschool children's observed disruptive behavior: variations across sex, interactional context, and disruptive psychopathology. AB - Sex differences in disruptive behavior and sensitivity to social context are documented, but the intersection between them is rarely examined empirically. This report focuses on sex differences in observed disruptive behavior across interactional contexts and diagnostic status. Preschoolers (n = 327) were classified as nondisruptive (51%), clinically at risk (26%), and disruptive (23%) using parent and teacher reports on developmentally validated measures of disruptive behavior and impairment. Observed disruptive behavior was measured with the Disruptive Behavior Diagnostic Observation Schedule, a developmentally sensitive observational paradigm characterizing variation in preschoolers' disruptive behavior across two interactional contexts (parent and examiner). Repeated measures analyses of variance revealed a three-way interaction of child sex by diagnostic status by interactional context (F = 9.81, p < .001). Disruptive boys were the only subgroup whose behavior was not sensitive to interactional context: They displayed comparable levels of disruptive behavior with parents and examiners. In contrast, disruptive girls demonstrated the strongest context effect of any group. Specifically, with the examiner, disruptive girls' behavior was comparable to nondisruptive boys (though still more elevated than nondisruptive girls). However, in interactions with their mothers, disruptive girls displayed the highest rates of disruptive behavior of any subgroup in any context, although the difference between disruptive boys and disruptive girls in this context was not statistically significant. Findings suggest the importance of sex-specific conceptualizations of disruptive behavior in young children that take patterns across social contexts into account. PMID- 22540389 TI - Topical cis-urocanic acid attenuates oedema and erythema in acute and subacute skin inflammation in the mouse. AB - BACKGROUND: cis-Urocanic acid (cis-UCA) is an endogenous immunosuppressive molecule of the epidermis. OBJECTIVES: We investigated the effects of topical cis-UCA creams (2.5% and 5%) in acute and subacute mouse models of skin inflammation. METHODS: Acute skin irritation was induced by applying dimethyl sulphoxide (DMSO) on the earlobe of CD-1 mice. Topical cis-UCA, hydrocortisone (1%) or tacrolimus (0.1%) were applied 10 min later. In another model, subacute inflammation was provoked and maintained by three applications of 12-O tetradecanoylphorbol-13-acetate (TPA) on the ears of NMRI mice on days 1, 2 and 4. The test products were applied topically twice a day during 6 days. RESULTS: In the acute DMSO model, cis-UCA creams suppressed ear swelling at 1 h significantly more efficiently than hydrocortisone (P < 0.01) and tacrolimus (P < 0.001). Ear swelling was significantly inhibited by cis-UCA (P < 0.001) in the subacute TPA model as well. The 5% cream also decreased erythema, whereas tacrolimus enhanced skin reddening. Treatments with cis-UCA did not affect TPA induced infiltration of neutrophils to the skin. In contrast to hydrocortisone, cis-UCA did not reduce epidermal thickness. CONCLUSIONS: The results suggest that cis-UCA - unlike hydrocortisone and tacrolimus - is efficient in both acute and subacute skin inflammation, attenuating skin oedema and erythema. Topical drug therapy with cis-UCA may provide a safe and effective drug treatment modality in inflammatory skin disorders. PMID- 22540390 TI - Spatial structure of helminth communities in the golden grey mullet, Liza aurata (Actinopterygii: Mugilidae), from the Western Mediterranean. AB - Ecological investigations regarding the parasite fauna of grey mullets are scarce. The present study provides a detailed description of the helminth communities of Liza aurata in the Spanish western Mediterranean and analyzes the role of spatial, temporal, and host variables in shaping the infracommunities. In total, 204 fish were collected in 2 localities, situated ca. 290 km apart, in spring and fall of 2004 and 2005. A non-metric multidimensional scaling (NMDS) was used to visualize an ordination of the infracommunities according to their relative similarities in parasite abundances. The relationship between infracommunity composition and explanatory variables (host size, locality, year, and season of harvest) was examined by permutational analysis of variance (PERMANOVA) applied to species abundances. Permutational tests for homogeneity of multivariate dispersion were used to test the null hypothesis of no differences in dispersion among groups formed by the factors whose effects were significant in PERMANOVA. A total of 33,241 helminth parasites, belonging to 18 species, was collected, i.e., 12 species of adult digeneans (23% of the parasite specimens), 3 digeneans as metacercariae (68%), 1 acanthocephalan (2.1%), and 2 monogeneans (6.5%). An important part of this helminth fauna is specialized to grey mullets, with a sizable portion of the component community restricted to the Mediterranean and northeast Atlantic. The NMDS ordination indicated high heterogeneity among infrapopulations. However, most differences at both the component and infracommunity level were related to geographic locality. In fact, the PERMANOVA showed that, among the explanatory variables considered, sampling locality accounted for the largest share of variation. The geographical differences observed may be related to local environmental characteristics or to the limited spatial dispersal of the species forming the component community. The latter was supported by the significant portion of variation explained by a 3-way interaction term. Thus, the spatial structure of our helminth infracommunities seems to be determined by a combination of differences in local environmental conditions and the transmission ability of each species at small local and time scales. PMID- 22540391 TI - Aerobic endurance training versus relaxation training in patients with migraine (ARMIG): study protocol for a randomized controlled trial. AB - BACKGROUND: Migraine is one of the most frequent headache diseases and impairs patients' quality of life. Up to now, many randomized studies reported efficacy of prophylactic therapy with medications such as beta-blockers or anti-epileptic drugs. Non-medical treatment, like aerobic endurance training, is considered to be an encouraging alternative in migraine prophylaxis. However, there is still a lack of prospective, high-quality randomized trials. We therefore designed a randomized controlled trial to evaluate the efficacy of aerobic endurance training versus relaxation training in patients with migraine (ARMIG). METHODS: This is a single-center, open-label, prospective, randomized trial. Sixty participants with migraine are randomly allocated to either endurance training or a relaxation group. After baseline headache diary documentation over at least 4 weeks, participants in the exercise group will start moderate aerobic endurance training under a sport therapist's supervision at least 3 times a week over a 12 week period. The second group will perform Jacobson's progressive muscle relaxation training guided by a trained relaxation therapist, also at least 3 times a week over a 12-week period. Both study arms will train in groups of up to 10 participants. More frequent individual training is possible. The follow-up period will be 12 weeks after the training period. The general state of health, possible state of anxiety or depression, impairments due to the headache disorder, pain-related disabilities, the headache-specific locus of control, and the motor fitness status are measured with standardized questionnaires. DISCUSSION: The study design is adequate to generate meaningful results. The trial will be helpful in gaining important data on exercise training for non medical migraine prophylaxis. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov: NCT01407861. PMID- 22540392 TI - Anticonvulsant activity of novel 1-(substituted benzylidene)-4-(1 (morpholino/piperidino methyl)-2,3-dioxoindolin-5-yl) semicarbazide derivatives in mice and rats acute seizure models. AB - A series of novel 1-(substituted benzylidene)-4-(1-(morpholino/piperidino methyl) 2,3-dioxoindolin-5-yl) semicarbazides 6a-6t was designed and synthesized on the basis of semicarbazide-based pharmacophoric model to meet the structural requirements necessary for anticonvulsant activity. The compounds were subjected to in vivo antiepileptic evaluation using maximal electroshock test and subcutaneous pentylenetetrazole seizure test methods. The neurotoxicity was determined by rotorod test. In the preliminary screening, compounds 6c, 6d, 6g, 6h, and 6m were found active in maximal electroshock test model, while 6g, 6i, 6m, and 6o showed significant antiepileptic activity in subcutaneous pentylenetetrazole seizure test model. Further, the compounds 6c, 6d, 6g, 6h, 6i, and 6m were administered orally to rats, of which 6c and 6g showed better activity than phenytoin. Among the synthesized compounds, 6g revealed excellent protection in both models with lower neurotoxicity. PMID- 22540393 TI - Monitoring failure rates of commercial implant brands; substantial equivalence in question? AB - OBJECTIVE: The aim of this study was to report on the failure rates of two distinct dental implant systems in a clinical practice setting. MATERIALS AND METHODS: Date of implant placement and loss were entered prospectively in a data registry system. Failure rates of two commercially pure titanium implants, one with a porous oxydized surface (POS) and the other with a chemically altered surface (CAS), were assessed using a quality control chart and survival analyses. RESULTS: A total of 860 POS and 759 CAS implants were placed. A warning of an increased failure rate of the CAS implant was identified by means of the quality control chart. Survival analyses indicated that the CAS implant failure rate was twice that of the POS implant (Hazard Ratio: 2.08; 95% CI: 1.33-3.28, P-value < 0.0012). After adjusting for alternative explanations, the CAS implant remained associated with a 95% increased failure rate (95% CI: 1.14-3.35; P-value = 0.0146). Abandoning the CAS implant and returning to a POS implant was associated with a non-significant 64% drop in the implant failure rate within less than a year (HR: 0.36; 95% CI: 0.12-1.14; P-value < 0.0826). CONCLUSION: The difference between a 4% failure rate with the POS implant and an 8% failure with the CAS implant appears inconsistent with the assumption of substantial equivalence. PMID- 22540395 TI - Narcolepsy-cataplexy: deficient prepulse inhibition of blink reflex suggests pedunculopontine involvement. AB - Hypocretin (orexin) deficiency plays a major role in the pathophysiology of narcolepsy-cataplexy. In animal models, hypocretinergic projections to the pedunculopontine nucleus are directly involved in muscle tone regulation mediating muscle atonia - a hallmark of cataplexy. We hypothesized that pedunculopontine nucleus function, tested with prepulse inhibition of the blink reflex, is altered in human narcolepsy-cataplexy. Twenty patients with narcolepsy cataplexy and 20 healthy controls underwent a neurophysiological study of pedunculopontine nucleus function. Blink reflex, prepulse inhibition of the blink reflex and blink reflex excitability recovery were measured. Blink reflex characteristics (R1 latency and amplitude, and R2 and R2c latency and area under the curve) did not differ between patients and controls (P > 0.05). Prepulse stimulation significantly increased R2 and R2c latencies and reduced R2 and R2c areas in patients and controls. However, the R2 and R2c area suppression was significantly less in patients than in controls (to 69.8 +/- 14.4 and 74.9 +/- 12.6%, respectively, versus 34.5 +/- 28.6 and 43.3 +/- 29.5%, respectively; each P < 0.001). Blink reflex excitability recovery, as measured by paired-pulse stimulation, which is not mediated via the pedunculopontine nucleus, did not differ between patients and controls (P > 0.05). Our data showed that prepulse inhibition is reduced in narcolepsy-cataplexy, whereas unconditioned blink reflex and its excitability recovery are normal. Because the pedunculopontine nucleus is important for prepulse inhibition, these results suggest its functional involvement in narcolepsy-cataplexy. PMID- 22540394 TI - Pharmacoeconomics of the myeloid growth factors: a critical and systematic review. AB - BACKGROUND: The pharmacoeconomics of the myeloid growth factors (MGFs) is an important topic that has received substantial attention in recent years. The use of the MGFs as primary prophylaxis to prevent febrile neutropenia (FN) has grown considerably over the past decade and professional guidelines regarding their use have broadened the settings in which these agents are indicated. Recent data also suggest a potential role for them in reducing infection-related and all-cause mortality. The cost and effectiveness of these agents will continue to gain visibility as companies pursue approval for biosimilar agents in the US, similar to their recent approval in Europe. OBJECTIVES: The objective of this paper is to review the available pharmacoeconomic literature on the MGFs, which is particularly timely in light of the recent passage of healthcare reform and the increasing focus on cost control. The cost of treating cancer in the US is rising faster than the already rapid increase in overall medical expenditure. The clinical utility and cost effectiveness of supportive care measures in oncology must therefore be weighed carefully. This review focuses on the use of different formulations of MGFs for primary and secondary prophylaxis of chemotherapy induced neutropenia. METHODS: A MEDLINE search was performed to find studies that became available since the prior review of this topic was published in Pharmacoeconomics in 2003. RESULTS: Acceptable cost-minimization estimates for primary prophylaxis with the MGFs in patients receiving cancer chemotherapy have been provided by several studies in the US. Of the commonly used agents in the US, pegfilgrastim appears to be superior to the currently recommended dose and schedule of filgrastim in terms of cost minimization, and primary prophylaxis appears to be less costly than secondary prophylaxis. However, the cost benefits of primary prophylaxis in Europe are not as pronounced as in the US, due to the lower costs of medical care. Data continue to emerge suggesting a decreased risk of early mortality from averted infections as well as the possibility of a disease-specific mortality benefit through maintaining the relative dose intensity of chemotherapy with MGF support. CONCLUSION: This evidence will prove valuable in assessing the overall cost effectiveness and cost utility of the MGFs in patients receiving cancer chemotherapy. PMID- 22540396 TI - Factors predictive of papillary thyroid micro-carcinoma with bilateral involvement and central lymph node metastasis: a retrospective study. AB - BACKGROUND: The optimal resection extent for papillary thyroid microcarcinoma (PTMC) remains controversial. The objective of the study was to investigate risk factors of bilateral PTMC and central lymph node metastasis (CLNM) to guide surgical strategies for PTMC patients. METHODS: We retrospectively reviewed 211 PTMC patients who underwent total thyroidectomy (TT) and 122 clinical lymph node negative (cN0) cases that underwent prophylactic central lymph node dissection (CLND) between 2010 and 2011. The frequency, pattern, and predictive factors for bilateral PTMC and CLNM in these patients were studied using univariate and multivariate analysis with respect to the following variables: age, gender, extrathyroidal extension (ETE), T stage, with Hashimoto thyroiditis (HT), tumor size and multifocality based on final pathology, and preoperative evaluation using ultrasonography (US). RESULTS: Fifty-four of 211 (25.6%) patients had bilateral PTMC. In multivariate analysis, multifocality (P < 0.001, OR = 23.900) and tumor size >=7 mm (P = 0.014, OR = 2.398) based on US were independent predictive factors for bilateral PTMC which was also independently associated with multifocality (P < 0.001, OR = 29.657) and tumor size >=7 mm (P = 0.005, OR = 2.863) based on final pathology. Among 122 cN0 patients who underwent prophylactic CLND, we found 49.2% of patients had CLNM. CLNM was independently associated with men, age <50 years and tumor size >=7 mm based on final pathology or preoperative US. CONCLUSIONS: TT should be considered for PTMC patients who are found multifocality and tumor size >=7 mm based on preoperative US. CLND need be considered in cN0 patients who are men, aged <50 years or tumor size >=7 mm based on preoperative US. PMID- 22540397 TI - Acute effects of right ventricular apical pacing on left atrial remodeling and function. AB - BACKGROUND: The acute effects of right ventricular apical (RVA) pacing on left atrial (LA) function in patients with normal ejection fraction are not clear. METHODS: A total of 94 patients (age 68.1 +/- 11.1 years, 26 men) with implanted RVA-based dual-chamber pacemakers were recruited into this study. Patients who were pacemaker-dependent, in persistent atrial fibrillation or left ventricular ejection fraction <45% were excluded. Echocardiography (iE33, Philips, Andover, MA, USA) was performed during intrinsic ventricular conduction (V-sense) and RVA pacing (V-pace) with 15 minutes between switching modes. The total maximal LA volume (LAV(max)), preatrial contraction volume (LAV(pre)), and minimal volume (LAV(min)) were assessed by area-length method. Peak systolic, early diastolic, and peak late diastolic (atrial contractile) velocity (Sm-la, Em-la, and Am-la) and strain (Es-la, Ee-la, and Ea-la) were measured by color-coded tissue Doppler imaging (TDI) in four mid-LA walls at apical four- and two-chamber views. RESULTS: During V-pace, LA volumes increased significantly compared with V-sense (LAV(max): 52.0 +/- 18.8 vs 55.2 +/- 21.1 mL, P = 0.005; LAV(pre): 39.8 +/- 16.4 vs 41.3 +/- 16.6 mL, P = 0.014; LAV(min): 27.4 +/- 14.0 vs 29.1 +/- 15.1 mL, P = 0.001). TDI parameters showed significant reduction in Sm-la and Em-la. Furthermore, Es-la, Ee-la, and Ea-la decreased significantly, especially in patients with preexisting diastolic dysfunction (all P < 0.01). CONCLUSIONS: RVA pacing acutely induced LA enlargement and impaired atrial contractility. Patients with preexisting diastolic dysfunction may be more vulnerable to develop LA dysfunction and remodeling after acute RVA pacing. PMID- 22540398 TI - Timing of clinical grade assessment and poor outcome in patients with aneurysmal subarachnoid hemorrhage. AB - OBJECT: Timing of clinical grading has not been fully studied in patients with aneurysmal subarachnoid hemorrhage (SAH). The primary objective of this study was to identify at which time point clinical assessment using the World Federation of Neurosurgical Societies (WFNS) grading scale and the Glasgow Coma Scale (GCS) is most predictive of poor functional outcome. METHODS: This study is a retrospective cohort study on the association between poor outcome and clinical grading determined at presentation, nadir, and postresuscitation. Poor functional outcome was defined as a Glasgow Outcome Scale score of 1-3 at 6 months after SAH. RESULTS: The authors identified 186 consecutive patients admitted to a teaching hospital between January 2002 and June 2008. The patients' mean age (+/ SD) was 56.9+/-13.7 years, and 63% were women. Twenty-four percent had poor functional outcome (the mortality rate was 17%). On univariable logistic regression analyses, GCS score determined at presentation (OR 0.80, p<0.0001), nadir (OR 0.73, p<0.0001), and postresuscitation (OR 0.53, p<0.0001); modified Fisher scale (OR 2.21, p=0.0013); WFNS grade assessed at presentation (OR 1.92, p<0.0001), nadir (OR 3.51, <0.0001), and postresuscitation (OR 3.91, p<0.0001); intracerebral hematoma on initial CT (OR 4.55, p<0.0002); acute hydrocephalus (OR 2.29, p=0.0375); and cerebral infarction (OR 4.84, p<0.0001) were associated with poor outcome. On multivariable logistic regression analysis, only cerebral infarction (OR 5.80, p=0.0013) and WFNS grade postresuscitation (OR 3.43, p<0.0001) were associated with poor outcome. Receiver operating characteristic/area under the curve (AUC) analysis demonstrated that WFNS grade determined postresuscitation had a stronger association with poor outcome (AUC 0.90) than WFNS grade assessed upon admission or at nadir. CONCLUSIONS: Timing of WFNS grade assessment affects its prognostic value. Outcome after aneurysmal SAH is best predicted by assessing WFNS grade after neurological resuscitation. PMID- 22540399 TI - Preliminary observations on the vasomotor responses to electrical stimulation of the ventrolateral surface of the human medulla. AB - OBJECT: Pulsatile arterial compression (AC) of the ventrolateral medulla (VLM) is hypothesized to produce the hypertension in a subset of patients with essential hypertension. In animals, a network of subpial neuronal aggregates in the VLM has been shown to control cardiovascular functions. Although histochemically similar, neurons have been identified in the retro-olivary sulcus (ROS) of the human VLM, but their function is unclear. METHODS: The authors recorded cardiovascular responses to electrical stimulation at various locations along the VLM surface, including the ROS, in patients who were undergoing posterior fossa surgery for trigeminal neuralgia. This vasomotor mapping of the medullary surface was performed using a bipolar electrode, with stimulation parameters ranging from 5- to 30-second trains (20-100 Hz), constant current (1.5-5 mA), and 0.1-msec pulse durations. Heart rate (HR) and blood pressure (BP) were recorded continuously from baseline (10 seconds before the stimulus) up to 1 minute poststimulus. In 6 patients, 17 stimulation responses in BP and HR were recorded. RESULTS: The frequency threshold for any cardiovascular response was 20 Hz; the stimulation intensity threshold ranged from 1.5 to 3 mA. In the first patient, all stimulation responses were significantly different from sham recordings (which consisted of electrodes placed without stimulations). Repeated stimulations in the lower ROS produced similar responses in 3 other patients. Two additional patients had similar responses to single stimulations in the lower ROS. Olive stimulation produced no response (control). Hypotensive and/or bradycardic responses were consistently followed by a reflex hypertensive response. Slight right/left differences were noted. No patient suffered short- or long-term effects from this stimulation. CONCLUSIONS: This stimulation technique for vasomotor mapping of the human VLM was safe and reproducible. Neuronal aggregates near the surface of the human ROS may be important in cardiovascular regulation. This method of vasomotor mapping with measures of responses in sympathetic tone (microneurography) should yield additional data for understanding the neuronal network that controls cardiovascular functions in the human VLM. Further studies in which a concentric bipolar electrode is used to generate this type of vasomotor map should also increase understanding of the pathophysiological mechanisms of neurogenically mediated hypertension, and assist in the design of studies to prove the hypothesis that it is caused by pulsatile AC of the VLM. PMID- 22540400 TI - Annual rupture risk of growing unruptured cerebral aneurysms detected by magnetic resonance angiography. AB - OBJECT: In this paper, the authors' goals were to clarify the characteristics of growing unruptured cerebral aneurysms detected by serial MR angiography and to establish the recommended follow-up interval. METHODS: A total of 1002 patients with 1325 unruptured cerebral aneurysms were retrospectively identified. These patients had undergone follow-up evaluation at least twice. Aneurysm growth was defined as an increase in maximum aneurysm diameter by 1.5 times or the appearance of a bleb. RESULTS: Aneurysm growth was observed in 18 patients during the period of this study (1.8%/person-year). The annual rupture risk after growth was 18.5%/person-year. The proportion of females among patients with growing aneurysms was significantly larger than those without growing aneurysms (p=0.0281). The aneurysm wall was reddish, thin, and fragile on intraoperative findings. Frequent follow-up examination is recommended to detect aneurysm growth before rupture. CONCLUSIONS: Despite the relatively short period, the annual rupture risk of growing unruptured cerebral aneurysms detected by MR angiography was not as low as previously reported. Surgical or endovascular treatment can be considered if aneurysm growth is detected during the follow-up period. PMID- 22540401 TI - Outcome after aneurysmal subarachnoid hemorrhage. PMID- 22540402 TI - New variant of persistent primitive olfactory artery associated with a ruptured aneurysm. AB - The authors present the case of a 78-year-old man who presented with a subarachnoid hemorrhage due to rupture of an aneurysm at the origin of the persistent primitive olfactory artery (PPOA). Interestingly, the PPOA was originating from the A1 segment of the anterior cerebral artery and coursed anteromedially along the olfactory tract. Moreover, the PPOA in this case had 2 branches: the branch making a hairpin turn and supplying the distal part of the anterior cerebral artery territory (Type 1), and the branch extending to the cribriform plate to supply the nasal cavity (Type 2). To the best of the authors' knowledge, this is a new variant (Type 3) of PPOA associated with a ruptured aneurysm. The clinical implications of this case are discussed in terms of the embryological aspects. PMID- 22540403 TI - Nidal embolization of brain arteriovenous malformations: rates of cure, partial embolization, and clinical outcome. AB - OBJECT: Nidal embolization of brain arteriovenous malformations (bAVMs) has become an increasingly important component of bAVM treatment. However, controversy exists as to the relative efficacy and safety of single-stage versus multistage approaches to bAVM embolization, with recent literature favoring multistage strategies. The authors present a series of consecutive bAVMs embolized at their institution, demonstrating the safety and efficacy of a predominantly single-stage embolization strategy. The safety and efficacy of embolization are reported in the context of predetermined treatment strategies to provide more generalizable insight into treatment outcome. METHODS: One hundred thirty consecutive patients with 131 bAVMs underwent endovascular embolization at a single center. Diagnostic angiography with superselective microcatheterizations was performed in all patients. Postembolization angiograms were reviewed by 3 neuroradiologists for degree of occlusion and angiographic evidence of procedural complications. Patients were divided into cohorts based on the prospectively determined treatment strategy, which included the following: global devascularization of the bAVM (Devasc); targeting of a focal angioarchitectural weakness (Target), typically as an adjunct to surgery or Gamma Knife treatment; and primary occlusion of the bAVM by embolization alone (Occlude). Safety and efficacy were evaluated in the context of these treatment groups. RESULTS: The 131 bAVMs were treated over an average of 1.28 embolization sessions per bAVM; 105 bAVMs (80%) were treated in a single stage. The average percentage devascularization in the Devasc arm was 85.3%, which was statistically significantly greater than the 72% aggregate devascularization reported in 8 modern N-butyl cyanoacrylate and Onyx papers based on 1-sample Wilcoxon rank-sum testing (p<0.001). Focal angioarchitectural weaknesses were successfully embolized for all 24 bAVMs in the Target group, directly with the embolic agent in 23 bAVMs and indirectly in 1 bAVM with a venous aneurysm/pseudoaneurysm by reducing arterial inflow and inducing venous thrombosis. Lesions in all patients in the Occlude arm were 100% occluded with embolization alone. Overall, the bAVMs in the Occlude arm were significantly smaller and required embolization of fewer pedicles than those in the Devasc group. One patient (0.8%) experienced significant morbidity following embolization, and 1 patient in the cohort died (0.8%). CONCLUSIONS: This research communicates the authors' experience in developing a largely single-stage strategy for embolization of bAVMs. The results suggest that an aggressive, single-stage embolization may be implemented with a margin of safety and effectiveness similar to the multistage approaches more commonly reported in the literature. This work additionally introduces the importance of prospective assignment to a treatment strategy in assessing procedural outcome in bAVM embolization, thereby improving generalizability of the results and allowing for more rigorous interpretation of efficacy and safety. PMID- 22540404 TI - Unruptured intracranial aneurysms in the Familial Intracranial Aneurysm and International Study of Unruptured Intracranial Aneurysms cohorts: differences in multiplicity and location. AB - OBJECT: Familial predisposition is a recognized nonmodifiable risk factor for the formation and rupture of intracranial aneurysms (IAs). However, data regarding the characteristics of familial IAs are limited. The authors sought to describe familial IAs more fully, and to compare their characteristics with a large cohort of nonfamilial IAs. METHODS: The Familial Intracranial Aneurysm (FIA) study is a multicenter international study with the goal of identifying genetic and other risk factors for formation and rupture of IAs in a highly enriched population. The authors compared the FIA study cohort with the International Study of Unruptured Intracranial Aneurysms (ISUIA) cohort with regard to patient demographic data, IA location, and IA multiplicity. To improve comparability, all patients in the ISUIA who had a family history of IAs or subarachnoid hemorrhage were excluded, as well as all patients in both cohorts who had a ruptured IA prior to study entry. RESULTS: Of 983 patients enrolled in the FIA study with definite or probable IAs, 511 met the inclusion criteria for this analysis. Of the 4059 patients in the ISUIA study, 983 had a previous IA rupture and 657 of the remainder had a positive family history, leaving 2419 individuals in the analysis. Multiplicity was more common in the FIA patients (35.6% vs 27.9%, p<0.001). The FIA patients had a higher proportion of IAs located in the middle cerebral artery (28.6% vs 24.9%), whereas ISUIA patients had a higher proportion of posterior communicating artery IAs (13.7% vs 8.2%, p=0.016). CONCLUSIONS: Heritable structural vulnerability may account for differences in IA multiplicity and location. Important investigations into the underlying genetic mechanisms of IA formation are ongoing. PMID- 22540405 TI - Calculation and mitigation of isotopic interferences in liquid chromatography mass spectrometry/mass spectrometry assays and its application in supporting microdose absolute bioavailability studies. AB - A methodology for the accurate calculation and mitigation of isotopic interferences in liquid chromatography-mass spectrometry/mass spectrometry (LC MS/MS) assays and its application in supporting microdose absolute bioavailability studies are reported for the first time. For simplicity, this calculation methodology and the strategy to minimize the isotopic interference are demonstrated using a simple molecule entity, then applied to actual development drugs. The exact isotopic interferences calculated with this methodology were often much less than the traditionally used, overestimated isotopic interferences simply based on the molecular isotope abundance. One application of the methodology is the selection of a stable isotopically labeled internal standard (SIL-IS) for an LC-MS/MS bioanalytical assay. The second application is the selection of an SIL analogue for use in intravenous (i.v.) microdosing for the determination of absolute bioavailability. In the case of microdosing, the traditional approach of calculating isotopic interferences can result in selecting a labeling scheme that overlabels the i.v.-dosed drug or leads to incorrect conclusions on the feasibility of using an SIL drug and analysis by LC-MS/MS. The methodology presented here can guide the synthesis by accurately calculating the isotopic interferences when labeling at different positions, using different selective reaction monitoring (SRM) transitions or adding more labeling positions. This methodology has been successfully applied to the selection of the labeled i.v.-dosed drugs for use in two microdose absolute bioavailability studies, before initiating the chemical synthesis. With this methodology, significant time and cost saving can be achieved in supporting microdose absolute bioavailability studies with stable labeled drugs. PMID- 22540406 TI - Limbic system white matter microstructure and long-term treatment outcome in major depressive disorder: a diffusion tensor imaging study using legacy data. AB - OBJECTIVES: Treatment-resistant depression is a common clinical occurrence among patients with major depressive disorder (MDD), but its neurobiology is poorly understood. We used data collected as part of routine clinical care to study white matter integrity of the brain's limbic system and its association to treatment response. METHODS: Electronic medical records of multiple large New England hospitals were screened for patients with an MDD billing diagnosis, and natural language processing was subsequently applied to find those with concurrent diffusion-weighted images, but without any diagnosed brain pathology. Treatment outcome was determined by review of clinical charts. MDD patients (n = 29 non-remitters, n = 26 partial-remitters, and n = 37 full-remitters), and healthy control subjects (n = 58) were analyzed for fractional anisotropy (FA) of the fornix and cingulum bundle. RESULTS: Failure to achieve remission was associated with lower FA among MDD patients, statistically significant for the medial body of the fornix. Moreover, global and regional-selective age-related FA decline was most pronounced in patients with treatment-refractory, non-remitted depression. CONCLUSIONS: These findings suggest that specific brain microstructural white matter abnormalities underlie persistent, treatment resistant depression. They also demonstrate the feasibility of investigating white matter integrity in psychiatric populations using legacy data. PMID- 22540407 TI - A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole for the treatment of acute manic or mixed episodes in Asian patients with bipolar I disorder (the AMAZE study). AB - OBJECTIVES: To investigate the efficacy and safety of aripiprazole in Asian patients with manic or mixed episodes associated with bipolar I disorder. METHODS: Subjects were randomised to aripiprazole (24 mg/day; reduced to 12 mg/day if needed for tolerability; n = 128) or placebo (n = 130) for 3 weeks in this multicentre, double-blind study. The primary efficacy measure was mean change from baseline in Young Mania Rating Scale (YMRS) Total score. RESULTS: A total of 136 patients (aripiprazole 56.3%; placebo 49.2%) completed the study. The majority of patients (92.6%) received aripiprazole 24 mg/day. Aripiprazole produced statistically significant mean improvements in YMRS Total scores compared with placebo from Day 4 through to Week 3 (-11.3 vs. -5.3; P < 0.001). The most common adverse events (> 15% of patients; aripiprazole vs. placebo) were akathisia (22.0 vs. 5.6%) and insomnia (16.3 vs. 9.6%). Aripiprazole treatment resulted in no significant difference from placebo in change in mean body weight from baseline (-0.4 vs. -0.7 kg; P = 0.231). Aripiprazole was not associated with an elevated serum prolactin level. CONCLUSIONS: Aripiprazole had significantly greater efficacy than placebo for the treatment of acute manic or mixed episodes associated with bipolar I disorder in Asian patients. Treatment was generally safe and well tolerated. PMID- 22540408 TI - High-fat taste challenge reveals altered striatal response in women recovered from bulimia nervosa: A pilot study. AB - OBJECTIVES: Individuals with anorexia nervosa (AN) and bulimia nervosa (BN) tend to have disordered thinking and eating behaviours in regards to fat containing foods. This is the first study to investigate neuronal pathways that may contribute to altered fat consumption in eating disordered patients. METHODS: We used functional magnetic resonance imaging (fMRI) to compare responses to a high fat cream stimulus, water, and a non-caloric viscous stimulus (CMC) to control for response to viscosity in individuals recovered from AN (N = 15), BN (N = 14) and a healthy control sample (CW, N = 18). RESULTS: An interaction analysis (ANOVAR) comparing the three groups (AN, BN, CW) and the three conditions (cream, CMC, water) revealed significant differences in the left anterior ventral striatum (AVS). A post hoc analysis displayed a higher magnitude of response for the contrast cream/water in BN compared to AN or CW and for the contrast CMC/water in BN compared to AN. CONCLUSIONS: BN showed an exaggerated AVS response for the cream/water contrast in comparison to AN or CW. Moreover, BN showed an exaggerated AVS response for the CMC/water contrast in comparison to AN. These findings support the possibility that BN have an altered hedonic and/or motivational drive to consume fats. PMID- 22540410 TI - Free energy of separation of structure II clathrate hydrate in water and a light oil. AB - The adhesion forces and free energies of separation of structure II clathrate hydrates in vacuum and submerged in water and a model oil are investigated by molecular dynamics simulation. The water molecules are modeled by the TIP4P/ice model and the alkanes by the OPLS_AA force field. The results are compared with theory and earlier work. It is observed that the adhesive forces between the simulated surfaces have an effective range of no more than 1.5-2 nm. The hydrate hydrate interaction force is attractive in vacuum and oil, larger in vacuum. In water the interaction force is very slightly repulsive on average and much weaker than in the two other systems with a larger uncertainty. In all cases the interaction is largely entropically driven. The separation energies in vacuum and oil (octane) are stronger than predicted by theory, with free energies of approximately 4 and 0.7 aJ, respectively, likely due to lack of polarization effects. The hydrate-hydrate interaction in water is too weak for quantitative comparisons to be made. PMID- 22540411 TI - Cumulative effects of exposure to violence on posttraumatic stress in Palestinian and Israeli youth. AB - We examine cumulative and prospective effects of exposure to conflict and violence across four contexts (ethnic-political, community, family, school) on posttraumatic stress (PTS) symptoms in Palestinian and Israeli youth. Interviews were conducted with 600 Palestinian and 901 Israeli (Jewish and Arab) children (ages 8, 11, and 14) and their parents once a year for 3 consecutive years. Palestinian children, males, and older youth were generally at greatest risk for exposure to conflict/violence across contexts. Regression analysis found unique effects of exposure to ethnic-political (Palestinian sample), school (Palestinian and Israeli Jewish samples), and family conflict/violence (Israeli Arab sample) during the first 2 years on PTS symptoms in Year 3, controlling for prior PTS symptoms. Cumulative exposure to violence in more contexts during the first 2 years predicted higher subsequent PTS symptoms than did exposure to violence in fewer contexts, and this was true regardless of the youth's level of prior PTS symptoms. These results highlight the risk that ongoing exposure to violence across multiple contexts in the social ecology poses for the mental health of children in contexts of ethnic-political violence. Researchers and mental health professionals working with war-exposed youth in a given cultural context must assess both war- and non-war-related stressors affecting youth. Based on this assessment, interventions may not be limited to individual-based, war-trauma focused approaches but also may include school-based, community-based, and family level interventions. PMID- 22540409 TI - Cancer and non-cancer brain and eye effects of chronic low-dose ionizing radiation exposure. AB - BACKGROUND: According to a fundamental law of radiobiology ("Law of Bergonie and Tribondeau", 1906), the brain is a paradigm of a highly differentiated organ with low mitotic activity, and is thus radio-resistant. This assumption has been challenged by recent evidence discussed in the present review. RESULTS: Ionizing radiation is an established environmental cause of brain cancer. Although direct evidence is lacking in contemporary fluoroscopy due to obvious sample size limitation, limited follow-up time and lack of focused research, anecdotal reports of clusters have appeared in the literature, raising the suspicion that brain cancer may be a professional disease of interventional cardiologists. In addition, although terminally differentiated neurons have reduced or mild proliferative capacity, and are therefore not regarded as critical radiation targets, adult neurogenesis occurs in the dentate gyrus of the hippocampus and the olfactory bulb, and is important for mood, learning/memory and normal olfactory function, whose impairment is a recognized early biomarker of neurodegenerative diseases. The head doses involved in radiotherapy are high, usually above 2 Sv, whereas the low-dose range of professional exposure typically involves lifetime cumulative whole-body exposure in the low-dose range of < 200 mSv, but with head exposure which may (in absence of protection) arrive at a head equivalent dose of 1 to 3 Sv after a professional lifetime (corresponding to a brain equivalent dose around 500 mSv). CONCLUSIONS: At this point, a systematic assessment of brain (cancer and non-cancer) effects of chronic low-dose radiation exposure in interventional cardiologists and staff is needed. PMID- 22540412 TI - Impact of platform switching on inter-proximal bone levels around short implants in the posterior region; 1-year results from a randomized clinical trial. AB - AIM: To assess the outcome of short implants (8.5 mm) supplied with a conventional platform-matched implant-abutment connection or a platform-switched design. MATERIALS AND METHODS: Eighty patients with one or more missing teeth in the posterior zone were randomly assigned to be treated with implants with either a conventional (control) or a platform-switched (mismatch 0.35-0.40 mm) implant abutment connection (test). Follow-up visits were conducted 1 month and 1 year after placing the implant crown. Outcome measures were inter-proximal bone loss, using standardized peri-apical radiographs, implant survival, clinical parameters and patients' satisfaction. RESULTS: One year after loading, inter-proximal bone loss around test implants (0.51 +/- 0.51 mm) was significantly less than around control implants (0.73 +/- 0.48 mm) (p = 0.011). Moreover, bone loss was less around 1 versus 2 adjacent implants (p = 0.001), in both the test (0.29 +/- 0.36 versus 0.71 +/- 0.55 mm) and control (0.46 +/- 0.42 versus 0.88 +/- 0.45 mm) group. With regard to implant survival, clinical parameters and patients' satisfaction no differences were observed between the test and control group. CONCLUSION: This study suggested that crestal bone resorption may be reduced by platform switching. One year after loading, inter-proximal bone levels were better maintained at implants restored according to the platform switching concept. PMID- 22540413 TI - Regional anaesthesia: perceptions of competency and an assessment of practice among U.K. dermatology trainees. PMID- 22540414 TI - Oxidative stress measured by carbonyl groups level in postmenopausal women after oral and transdermal hormone therapy. AB - AIM: Menopause is associated with an increased risk of cardiovascular disorders, which are accompanied by oxidative stress. Our study was undertaken to determine whether oxidative stress in menopausal women could be reduced after six months of oral or transdermal hormonal therapy. MATERIAL AND METHODS: Carbonyl groups of proteins in blood plasma were estimated by sensitive ELISA method with anti-DNP antibodies. In this method, protein samples diluted in phosphate-buffered saline were adsorbed to wells of an ELISA plate and then reacted with dinitrophenylhydrazine (DNPH). RESULTS: Plasma protein carbonyl levels of postmenopausal women treated with o-HT and t-HT for six months (o-HT: 1.785 +/- 0.31 nmol/mg; t-HT: 1.838 +/- 0.33 nmol/mg) were lower when compared with the control group (2.232 +/- 0.28 nmol/mg). There was no statistically significant difference in carbonyl levels between women after oral and transdermal HT (P = 0.149). CONCLUSION: Hormonal therapy reduces the level of carbonyl protein, a marker of oxidative stress, suggesting potential protective effect. PMID- 22540415 TI - Active skin immunoreactions lead to significant epidermal Langerhans cells reduction in facial malignant and premalignant skin tumours. PMID- 22540416 TI - A new microphallid (Digenea) species from Lontra provocax (Mammalia: Mustelidae) from freshwater environments of northwestern Patagonia (Argentina). AB - A new microphallid species of Maritrema is described from the native southern river otter, Lontra provocax (Thomas). A naturally infected otter was found dead in the Nahuel Huapi National Park, Argentina. Ovigerous adult worms were recovered from the anterior portion of the intestine. Specimens of Maritrema huillini n. sp. have an unarmed genital pore and glabrous cirrus. They can be distinguished from all other species in the genus by having a long intestinal ceca extending up to three-quarters of the testes length to the level of the posterior border of the testes and a metraterm composed of a proximal sphincter, a non-muscular sac, and a distal muscular portion. This microphallid is the first species recovered from a South American eutherian host and the first digenean recorded for L. provocax. PMID- 22540419 TI - Gingivitis and plaque scores of 8- to 11-year-old Burmese children following participation in a 2-year school-based toothbrushing programme. AB - AIM: The present study assessed whether gingivitis and plaque scores of 8- to 11 year-old school children who participated in a SBTB programme for 2 years were lower than those of children who did not participate in the programme. MATERIAL AND METHODS: The present study was performed using an examiner-blind, parallel group design and was performed in Burma (Myanmar) in 2006. Three of the five schools where daily SBTB programmes took place after lunch and which were performed under teacher supervision were randomly selected; three non participating schools (non-SBTB) from the same area were assigned as controls. Twenty-five children per school were examined for gingivitis (bleeding on marginal probing) and plaque (Quigley & Hein). RESULTS: In total, 150 8- to 11 year-old children participated, with 75 children in either group. The test group (SBTB) exhibited an overall mean bleeding score of 0.76. For the control group (non-SBTB), this score was 0.83. With respect to the overall mean plaque scores, the test group exhibited a score of 2.93, whereas the control group exhibited a score of 2.91. No statistically significant differences between the test and the control group were observed. CONCLUSION: The present study did not reveal a statistically significant effect of daily SBTB programmes in 8- to 11-year-old school children with respect to gingivitis and plaque scores. PMID- 22540417 TI - A study of the effect of the FertilMateTM Scrotum Cooling Patch on male fertility. SCOP trial (scrotal cooling patch) - study protocol for a randomised controlled trial. AB - BACKGROUND: Male infertility is a significant contributor to the need for fertility treatment. Treatment currently involves correcting any identifiable adverse lifestyle factors in men with suboptimal sperm parameters, and if these measures are unsuccessful, assisted conception is offered, which can be quite expensive. Raised scrotal temperature is one of the least studied but easily corrected risk factors for male infertility. In a recent review of the literature, sperm count, motility and morphology improved with scrotal cooling devices. The devices used to achieve testicular cooling were, however, not practical for day-to-day use. A potentially more practical device for scrotal cooling has recently been developed. The Babystart(r) FertilMateTM Scrotum Cooling Patch is a hydrogel pad which allows for comfortable application. The aims of this study were to investigate whether exposing the scrotum to lower temperatures by means of these new patches could improve semen parameters, thereby improving fertility, and to assess the feasibility of a clinical trial. METHODS/DESIGN: This is a randomised controlled trial set in a university teaching hospital in the United Kingdom. The proposed sample size was 40 men with mild, moderate or severe oligoasthenospermia, of whom 20 would be randomised to wearing the scrotum cooling patch for 90 days and 20 men would be acting as controls and not wearing the patches. The primary outcome measure was the change in sperm concentration. Secondary outcome measures included the change in sperm volume, motility and morphology; endocrine parameters; metabolomic biomarkers; testicular volume and blood flow. Reasons for dropping out and non-compliance were also going to be noted and reported. DISCUSSION: The study started recruiting in October 2011 and as of November 2011 four men had been consented and were participating in the study. No operational challenges had been encountered at the time of the submission of this manuscript. Although the study also aimed to evaluate the feasibility of a definitive study, the change in sperm count after 90 days of wearing the scrotal cooling patches was made the primary outcome measure because a statistically significant improvement in sperm parameters with the scrotal patches would in itself be a definitive finding. TRIAL REGISTRATION: Current Controlled Trials ISRCTN94041896. PMID- 22540420 TI - Validation of the Glasgow Facial Palsy Scale for the assessment of smile reanimation surgery in facial paralysis. AB - OBJECTIVES: To evaluate the Glasgow Facial Palsy Scale as a tool to assess facial reanimation surgery in facial palsy. Software analysis of digital video data is used to measure facial movements, comparing the affected to the normal side. We present the first use of the Glasgow Facial Palsy Scale following facial re-animation surgery. DESIGN: A comparison of the Glasgow Facial Palsy Scale against the Nottingham scoring system. Subjects undergoing unilateral surgical smile reanimation procedures were selected. Comparison was made with the Nottingham facial palsy scale and the House-Brackmann Scale pre- and postoperatively. SETTING: Patients were recruited in the facial palsy clinic of Canniesburn Plastic Surgery Unit, Glasgow. PARTICIPANTS: Seven consecutive patients were selected who were due to undergo unilateral facial reanimation. MAIN OUTCOME MEASURES: The difference in pre- and post-surgical facial movement as measured using the Glasgow Facial Palsy Scale with this value being compared to that obtained using the Nottingham scoring system. Note was also taken of the correlation with House-Brackmann system and clinical correlation. RESULTS AND CONCLUSIONS: Statistical analysis indicated a linear relationship between the Glasgow Facial Palsy Scale and the Nottingham System. The Pearson correlation test was used to confirm the relationship between the two methods giving a result of -0.587, which indicates significant correlation between the two methods. We conclude that the Glasgow Facial Palsy Scale is a standardised objective method of assessing the change in facial movement following smile reanimation surgery. We commend it as a useful tool to objectively assess surgical results in this challenging field. PMID- 22540421 TI - Bacillus thuringiensis insecticidal three-domain Cry toxins: mode of action, insect resistance and consequences for crop protection. AB - Bacillus thuringiensis bacteria are insect pathogens that produce different Cry and Cyt toxins to kill their hosts. Here we review the group of three-domain Cry (3d-Cry) toxins. Expression of these 3d-Cry toxins in transgenic crops has contributed to efficient control of insect pests and a reduction in the use of chemical insecticides. The mode of action of 3d-Cry toxins involves sequential interactions with several insect midgut proteins that facilitate the formation of an oligomeric structure and induce its insertion into the membrane, forming a pore that kills midgut cells. We review recent progress in our understanding of the mechanism of action of these Cry toxins and focus our attention on the different mechanisms of resistance that insects have evolved to counter their action, such as mutations in cadherin, APN and ABC transporter genes. Activity of Cry1AMod toxins, which are able to form toxin oligomers in the absence of receptors, against different resistant populations, including those affected in the ABC transporter and the role of dominant negative mutants as antitoxins, supports the hypothesis that toxin oligomerization is a limiting step in the Cry insecticidal activity. Knowledge of the action of 3d-Cry toxin and the resistance mechanisms to these toxins will set the basis for a rational design of novel toxins to overcome insect resistance, extending the useful lifespan of Cry toxins in insect control programs. PMID- 22540423 TI - Collision cross sectional areas from analysis of Fourier transform ion cyclotron resonance line width: a new method for characterizing molecular structure. AB - We demonstrate a technique for determining molecular collision cross sections via measuring the variation of Fourier transform ion cyclotron resonance (FTICR) line width with background damping gas pressure, under conditions where the length of the FTICR transient is pressure limited. Key features of our method include monoisotopic isolation of ions, the pulsed introduction of damping gas to a constant pressure using a pulsed leak valve, short excitation events to minimize collisions during the excitation, and proper choice of damping gas (Xe is superior to He). The measurements are reproducible within a few percent, which is sufficient for distinguishing between many structural possibilities and is comparable to the uncertainty in cross sections calculated from computed molecular structures. These techniques complement drift ion mobility measurements obtained on dedicated instruments. They do not require a specialized instrument, but should be easily performed on any FTICR mass spectrometer equipped with a pulsed leak valve. PMID- 22540422 TI - Guidelines for the pharmacological treatment of anxiety disorders, obsessive compulsive disorder and posttraumatic stress disorder in primary care. AB - OBJECTIVE: Anxiety disorders are frequently under-diagnosed conditions in primary care, although they can be managed effectively by general practitioners. METHODS: This paper is a short and practical summary of the World Federation of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety disorders, obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD) for the treatment in primary care. The recommendations were developed by a task force of 30 international experts in the field and are based on randomized controlled studies. RESULTS: First-line pharmacological treatments for these disorders are selective serotonin reuptake inhibitors (for all disorders), serotonin-norepinephrine reuptake inhibitors (for some) and pregabalin (for generalized anxiety disorder only). A combination of medication and cognitive behavior/exposure therapy was shown to be a clinically desired treatment strategy. CONCLUSIONS: This short version of an evidence-based guideline may improve treatment of anxiety disorders, OCD, and PTSD in primary care. PMID- 22540424 TI - Compliance with referral of sick children: a survey in five districts of Afghanistan. AB - BACKGROUND: Recognition and referral of sick children to a facility where they can obtain appropriate treatment is critical for helping reduce child mortality. A well-functioning referral system and compliance by caretakers with referrals are essential. This paper examines referral patterns for sick children, and factors that influence caretakers' compliance with referral of sick children to higher-level health facilities in Afghanistan. METHODS: The study was conducted in 5 rural districts of 5 Afghan provinces using interviews with parents or caretakers in 492 randomly selected households with a child from 0 to 2 years old who had been sick within the previous 2 weeks with diarrhea, acute respiratory infection (ARI), or fever. Data collectors from local nongovernmental organizations used a questionnaire to assess compliance with a referral recommendation and identify barriers to compliance. RESULTS: The number of referrals, 99 out of 492 cases, was reasonable. We found a high number of referrals by community health workers (CHWs), especially for ARI. Caretakers were more likely to comply with referral recommendations from community members (relative, friend, CHW, traditional healer) than with recommendations from health workers (at public clinics and hospitals or private clinics and pharmacies). Distance and transportation costs did not create barriers for most families of referred sick children. Although the average cost of transportation in a subsample of 75 cases was relatively high (US$11.28), most families (63%) who went to the referral site walked and hence paid nothing. Most caretakers (75%) complied with referral advice. Use of referral slips by health care providers was higher for urgent referrals, and receiving a referral slip significantly increased caretakers' compliance with referral. CONCLUSIONS: Use of referral slips is important to increase compliance with referral recommendations in rural Afghanistan. PMID- 22540425 TI - Comparison of 90-day re-admission rates between open retropubic radical prostatectomy (RRP), laparoscopic RP (LRP) and robot-assisted laparoscopic prostatectomy (RALP). AB - Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? With the increased use of laparoscopic radical prostatectomy (LRP) and robot-assisted laparoscopic prostatectomy (RALP), a growing number of publications have sought to compare these more advanced techniques to retropubic RP (RRP). Many studies have found RALP and LRP to be associated with lower blood loss, postoperative pain, and hospital stay when compared with RRP. The present study showed that, after adjusting for potential confounders, patients undergoing RALP had a lower risk of 90-day re-admission than patients undergoing RRP. However, there was no significant difference in the odds of being re-admitted <= 90 days after RP between patients undergoing a LRP and RRP. OBJECTIVE: * To examine the risk of 90-day re-admission among patients undergoing retropubic radical prostatectomy (RRP), laparoscopic RP (LRP), and robot-assisted laparoscopic prostatectomy (RALP) in Taiwan. PATIENTS AND METHODS: * We identified 2741 hospitalised patients who underwent a RP. Of these 2741 cases, 1773 patients underwent RRP, 694 LRP, and 274 RALP. * We performed a conditional (fixed-effect) logistic regression model to explore the odds of 90 day re-admission from RP among patients undergoing RRP, LRP, and RALP. RESULTS: * In all, 257 of the 2741 (9.4%) sampled subjects were re-admitted <= 90 days of the index RP. * Patients undergoing a RALP had a significantly lower incidence rate of 90-day re-admission than patients undergoing a RRP or LRP (3.6% vs 10.7% vs 8.2%, P < 0.001). * Compared with patients undergoing a RRP, the odds ratio (OR) of 90-day re-admission for patients undergoing a RALP was only 0.35 (95% confidence interval [CI] 0.19-0.68) after adjusting for patient age, geographic region, year of surgery, Charlson Co-morbidity Index score, and surgeon age and the number of RP cases/year. * However, there was no significant difference in the odds of being re-admitted <= 90 days of RP between patients undergoing a LRP and RRP. * The adjusted odds of 90-day re-admission for patients undergoing a RALP were 0.46 (95% CI 0.23-0.94) those of patients undergoing a LRP. CONCLUSIONS: * Our study shows that patients undergoing a RALP had a lower adjusted risk of 90-day re-admission than patients undergoing RRP. However, no significant differences were identified between LRP and RRP. PMID- 22540426 TI - A functional polymorphism in the promoter region of the IL1B gene is associated with risk of multiple myeloma. AB - The cytokine interleukin-1beta (IL1B) is important for anti-tumour immune response. Genetic variation may modify the expression of IL1B and thereby influence the risk of disease. We investigated genetic variations with functional importance in the IL1B and NFKB1 genes in 348 population-based samples of multiple myeloma (MM) and a random sample of 1700 individuals. Carriers of the variant T-allele IL1B C-3737T and carriers of the TGT haplotype were at lower risk of MM [relative risk (RR) 0.58 (95% confidence interval (CI) = 0.41-0.84) and RR 0.59 (95%CI 0.40-0.85), respectively]. No association with risk of MM was found for the NFKB1- 94 ins/del polymorphism. PMID- 22540427 TI - Glutathione-s-transferases as determinants of cell survival and death. AB - SIGNIFICANCE: The family of glutathione S-transferases (GSTs) is part of a cellular Phase II detoxification program composed of multiple isozymes with functional human polymorphisms that have the capacity to influence individual response to drugs and environmental stresses. Catalytic activity is expressed through GST dimer-mediated thioether conjugate formation with resultant detoxification of a variety of small molecule electrophiles. RECENT ADVANCES: More recent work indicates that in addition to the classic catalytic functions, specific GST isozymes have other characteristics that impact cell survival pathways in ways unrelated to detoxification. These characteristics include the following: regulation of mitogen-activated protein kinases; facilitation of the addition of glutathione to cysteine residues in certain proteins (S glutathionylation); as a novel cellular partner of the human papilloma virus-16 E7 oncoprotein playing a pivotal role in preventing cell death in infected human cells; mitogenic influence in myeloproliferative pathways; participant in the process of cocaine addiction. CRITICAL ISSUES: Some of these functions have provided a platform for targeting GST with novel small molecule therapeutics, particularly in cancer where evidence of clinical applications is emerging. FUTURE DIRECTIONS: Our evolving understanding of the GST superfamily and their divergent expression patterns in individuals make them attractive candidates for translational studies in a variety of human pathologies. In addition, their role in regulating cell fate in signaling and cell death pathways has opened up a significant functional complexity that extends well beyond standard detoxification reactions. PMID- 22540428 TI - Mania symptoms and HIV-risk behavior among adolescents in mental health treatment. AB - This study explored whether adolescents with elevated symptoms of mania (ESM+) engage in more HIV risk behaviors than those with other psychiatric disorders and examined factors associated with HIV risk behavior among ESM+ adolescents. Eight hundred forty adolescents (56% female, 58% African American, M age = 14.9 years) who received mental health treatment completed private, computer-based assessments of psychiatric disorders and of sexual and substance use behaviors and provided urine to screen for sexually transmitted infections (STI). Eighty seven percent met criteria for a psychiatric disorder, and among these youth 21% were considered ESM+. Compared to those with other psychiatric disorders, ESM+ were more likely to be sexually active (61.6% vs. 53.6%), have multiple sexual partners (58.6% vs. 37.5%), have unprotected sex (38.4% vs. 28.0%), exchange sex for money (4.7% vs. 1.2%), and test positive for an STI (14.0% vs. 6.3%). Among ESM+ youth, sexual risk behaviors were primarily associated with individual factors (e.g., self-efficacy, impulsivity, and substance use) and varied depending on the type of sexual behavior (e.g., onset of sex, number of partners, and condom use). Adolescents with ESM should be regularly screened for sexual risk behaviors and receive HIV prevention skills. Efforts to increase self efficacy for safer sex, reduce impulsivity, and decrease substance use may be effective targets for sexual risk reduction among adolescents with ESM. PMID- 22540429 TI - Serum levels of ADAM12-S: possible association with the initiation and progression of dermal fibrosis and interstitial lung disease in patients with systemic sclerosis. AB - BACKGROUND: A disintegrin and metalloprotease (ADAM) 12 is one of the metalloproteinase-type ADAMs and possesses extracellular metalloprotease and cell binding functions. ADAM12 is expressed in two alternative forms, such as a membrane-anchored form (ADAM12-L) and a short secreted form (ADAM12-S). OBJECTIVE: To investigate the clinical significance of serum ADAM12-S levels in systemic sclerosis (SSc). METHODS: Serum ADAM12-S levels were determined by a specific enzyme-linked immunosorbent assay in 61 SSc patients and 18 healthy controls. RESULTS: Serum ADAM12-S levels were significantly increased in diffuse cutaneous SSc (dcSSc) patients than in healthy controls (0.417 +/- 0.389 vs. 0.226 +/- 0.065 ng/mL; P < 0.05), while being comparable between limited cutaneous SSc (0.282 +/- 0.258 ng/mL) and healthy controls. Serum ADAM12-S levels significantly elevated in dcSSc patients with disease duration of <= 6 years (0.537 +/- 0.449 ng/mL, P < 0.05), but not in dcSSc with disease duration of >6 years (0.225 +/- 0.049 ng/mL), compared to healthy controls. Furthermore, in dcSSc patients with disease duration of <= 6 years, serum ADAM12-S levels correlated positively with modified Rodnan total skin thickness score, ground glass score, and serum C-reactive protein values, while showed inverse correlation with fibrosis score. CONCLUSION: Elevated serum ADAM12-S levels are associated with elevated serum inflammatory marker, severity of skin fibrosis, and activity of interstitial lung disease in dcSSc, suggesting the possible contribution of ADAM12-S to the pathological events in this disorder. PMID- 22540431 TI - Temporal and geographic patterns in opioid abuse in Texas. AB - Opioid analgesic abuse is an increasing problem in the United States. All opioid analgesic abuse exposures reported to Texas poison centers during 2000-2010 were identified and annual and geographic patterns were examined. The annual number of opioid analgesic abuse cases increased 160% from 441 in 2000 to 1,145 in 2010. The proportion of total opioid analgesic exposures reported to be due to abuse increased 55% from 11.4% in 2000 to 17.8% in 2010. The opioid analgesic rate per 100,000 was highest (90.15) in northeastern Texas and lowest (27.91) in the southern part of the state. PMID- 22540432 TI - Clinical differences between opioid abuse classes ameliorated after 1 year of buprenorphine-medication assisted treatment. AB - This study compared the clinical and demographic profiles of three opioid dependent user groups, and measured their response to 1 year of buprenorphine medication assisted treatment. Opioid prescription, street, and combination (street + prescription) users completed the Addiction Severity Index multiple times over the course of one treatment year. Although groups differed on all measured demographics (P values <.05) and on six of seven Addiction Severity Index composite scores at induction (P values <.05), differences were ameliorated after 1 year. Findings highlight the disparities between the various opioid dependent patient subpopulations and suggest that buprenorphine-medication assisted treatment is an effective treatment across user subtypes. PMID- 22540433 TI - Tramadol versus methadone for treatment of opiate withdrawal: a double-blind, randomized, clinical trial. AB - The aim of this study was to compare the efficacy and safety of tramadol versus methadone for treatment of opiate withdrawal. Seventy patients randomly were assigned in two groups to receive either prescribed methadone (60 mg/day) or tramadol (600 mg/day). The withdrawal syndrome of patients was evaluated before and after rapid opiate detoxification using the Objective Opioid Withdrawal Scale (OOWS). No significant differences existed in overall OOWS scores between two groups (P = 0.11). Dropout rates were similar in both groups. Side effects in the tramadol group were as or less common than in the methadone group, with the exception of perspiration. Tramadol may be as effective as methadone in the control of withdrawal and could be considered as a potential substitute for methadone to manage opioids withdrawal. PMID- 22540434 TI - Comparison of two ASI-based standardized patient placement approaches. AB - This study evaluated the predictive validity of two automated approaches based on the Addiction Severity Index (ASI) to patient placement criteria. Patients (N = 2,429) in 78 substance abuse treatment programs completed an ASI at intake and were assigned a treatment modality based on availability and clinical considerations. Treatment completion and self-reported abstinence 6 months post discharge were collected. Two placement approaches were developed using ASI summary score cut points or problem-specific algorithms from ASI items. Both approaches showed evidence of predictive validity. Given the ASI's widespread use in community programs, evidence is provided in support of its ability to inform clinical judgment and implementation of standardized placement. PMID- 22540435 TI - Race differences in longitudinal associations between adolescent personal and peer marijuana use and adulthood sexually transmitted infection risk. AB - To assess whether adolescent marijuana exposure represents a modifiable predictor of risk of sexually transmitted infections as adults, we used nationally representative, longitudinal data from Waves I (1994-1995, adolescence) and III (2001-2002, adulthood) of the National Longitudinal Study of Adolescent Health (N = 10,738) to examine racial and gender differences in associations between adolescent marijuana use, current use, and peer use and adulthood multiple partnerships, self-reported sexually transmitted infections, and biologically confirmed sexually transmitted infections. The risk of sexually transmitted infections as adults was predicted by adolescent marijuana use in all groups except Black women and by peer marijuana use among Black men. Adolescents who use or have friends who use marijuana constitute priority populations for sexually transmitted infection prevention. PMID- 22540436 TI - Anxiety sensitivity and cognitive-based smoking processes: testing the mediating role of emotion dysregulation among treatment-seeking daily smokers. AB - The current study investigated whether emotion dysregulation (difficulties in the self-regulation of affective states) mediated relationships between anxiety sensitivity (fear of anxiety and related sensations) and cognitive-based smoking processes. Participants (n = 197; 57.5% male; mean age = 38.0 years) were daily smokers recruited as part of a randomized control trial for smoking cessation. Anxiety sensitivity was uniquely associated with all smoking processes. Moreover, emotion dysregulation significantly mediated relationships between anxiety sensitivity and the smoking processes. Findings suggest that emotion dysregulation is an important construct to consider in relationships between anxiety sensitivity and cognitive-based smoking processes among adult treatment seeking smokers. PMID- 22540437 TI - Drinking in the age of the Great Recession. AB - The United States has been experiencing the most severe economic crisis since the Great Depression. This article presents the Life Change Consequences of the Great Recession (LCCGR), an instrument depicting work and personal life-related stressors reflecting the enduring effects of the Great Recession. A national sample of 663 respondents completed a mail survey including this instrument and measures of drinking outcomes. Multiple regression analyses addressed the links between the LCCGR and drinking. Economy-related stressors manifested significant effects on both male and female consumptions patterns, but most LCCGR subscales were more clearly related to problematic drinking patterns in men compared with women. PMID- 22540438 TI - Young People in Alcoholics Anonymous: the role of spiritual orientation and AA member affiliation. AB - Empirical findings characterizing long-term, committed Alcoholics Anonymous (AA) members are limited, particularly among younger members. The authors studied a sample of 266 highly committed attendees (mean age, 27 years) at an annual conference of Young People in Alcoholics Anonymous (YPAA), whose first encounter with AA was 6 years previously. Most (72%) had abused drugs and alcohol, and 36% had never received substance abuse treatment. They now reported a mean duration of abstinence of 44 months and had attended an average of 233 AA meetings in the previous year; 66% had served as AA sponsors, and 92% reported experiencing an AA "spiritual awakening," itself associated with a decreased likelihood of alcohol craving. Scores on AA beliefs, affiliation to other members, and the experience of spiritual awakening were associated with lower depression scores. These findings are discussed to clarify the nature of long-term AA membership. PMID- 22540439 TI - The relationship between universal human values and adolescent problem and pathological gambling. AB - This article derives statistical models relating adolescents' universal human values with their problem and pathological gambling. An adolescent's values are measured by the priority accorded to each value using the Schwartz Values Inventory, whereas problem or pathological gambling, if any, is indicated by his or her answers to the South Oaks Gambling Screen. Among other complex results, statistical analysis suggests that the value subtypes of "non-faith tradition," "faith tradition," and "macro-universalism" and the value type "stimulation" are associated with less problem and pathological gambling. Among other uses, such findings help identify high-risk adolescents. PMID- 22540441 TI - Exact relaxation dynamics of a localized many-body state in the 1D Bose gas. AB - Through an exact method, we numerically solve the time evolution of the density profile for an initially localized state in the one-dimensional bosons with repulsive short-range interactions. We show that a localized state with a density notch is constructed by superposing one-hole excitations. The initial density profile overlaps the plot of the squared amplitude of a dark soliton in the weak coupling regime. We observe the localized state collapsing into a flat profile in equilibrium for a large number of particles such as N=1000. The relaxation time increases as the coupling constant decreases, which suggests the existence of off diagonal long-range order. We show a recurrence phenomenon for a small number of particles such as N=20. PMID- 22540442 TI - Approaching universality in weakly bound three-body systems. AB - Atom-dimer scattering below the three-body breakup threshold is studied for a system of three identical bosons. The atom-dimer scattering length and the energy of the most weakly bound three-body state are shown to be strongly correlated. An appropriate rescaling of the observables reveals the subtlety of the correlation and serves to identify universal trends in the unitary limit of divergent two body scattering length. The correlation provides a new quantitative measure of the degree of universality in three-body systems with short-ranged interactions, as well as a consistency check of effective field theories and other theoretical models. PMID- 22540443 TI - Maximally and minimally correlated states attainable within a closed evolving system. AB - The amount of correlation attainable between the components of a quantum system is constrained if the system is closed. We provide some examples, largely from the field of quantum thermodynamics, where knowing the maximal possible variation in correlations is useful. The optimization problem it raises requires us to search for the maximally and minimally correlated states on a unitary orbit, with and without energy conservation. This is fully solvable for the smallest system of two qubits. For larger systems, the problem is reduced to a manageable, classical optimization. PMID- 22540444 TI - Testing the structure of multipartite entanglement with Bell inequalities. AB - We show that the rich structure of multipartite entanglement can be tested following a device-independent approach. Specifically we present Bell inequalities for distinguishing between different types of multipartite entanglement, without placing any assumptions on the measurement devices used in the protocol, in contrast with usual entanglement witnesses. We first address the case of three qubits and present Bell inequalities that can be violated by W states but not by Greenberger-Horne-Zeilinger states, and vice versa. Next, we devise 'subcorrelation Bell inequalities' for any number of parties, which can provably not be violated by a broad class of multipartite entangled states (generalizations of Greenberger-Horne-Zeilinger states), but for which violations can be obtained for W states. Our results give insight into the nonlocality of W states. The simplicity and robustness of our tests make them appealing for experiments. PMID- 22540445 TI - Preparing projected entangled pair states on a quantum computer. AB - We present a quantum algorithm to prepare injective projected entangled pair states (PEPS) on a quantum computer, a class of open tensor networks representing quantum states. The run time of our algorithm scales polynomially with the inverse of the minimum condition number of the PEPS projectors and, essentially, with the inverse of the spectral gap of the PEPS's parent Hamiltonian. PMID- 22540446 TI - Measuring Trrhon on single copies of rho using random measurements. AB - While it is known that Trrho(n) can be measured directly (i.e., without first reconstructing the density matrix) by performing joint measurements on n copies of the same state rho, it is shown here that random measurements on single copies suffice, too. Averaging over the random measurements directly yields estimates of Trrho(n), even when it is not known what measurements were actually performed (so that rho cannot be reconstructed). PMID- 22540447 TI - Implementing quantum gates by optimal control with doubly exponential convergence. AB - We introduce a novel algorithm for the task of coherently controlling a quantum mechanical system to implement any chosen unitary dynamics. It performs faster than existing state of the art methods by 1 to 3 orders of magnitude (depending on which one we compare to), particularly for quantum information processing purposes. This substantially enhances the ability to both study the control capabilities of physical systems within their coherence times, and constrain solutions for control tasks to lie within experimentally feasible regions. Natural extensions of the algorithm are also discussed. PMID- 22540448 TI - Majorization theory approach to the Gaussian channel minimum entropy conjecture. AB - A long-standing open problem in quantum information theory is to find the classical capacity of an optical communication link, modeled as a Gaussian bosonic channel. It has been conjectured that this capacity is achieved by a random coding of coherent states using an isotropic Gaussian distribution in phase space. We show that proving a Gaussian minimum entropy conjecture for a quantum-limited amplifier is actually sufficient to confirm this capacity conjecture, and we provide a strong argument towards this proof by exploiting a connection between quantum entanglement and majorization theory. PMID- 22540449 TI - Alternatives to eigenstate thermalization. AB - An isolated quantum many-body system in an initial pure state will come to thermal equilibrium if it satisfies the eigenstate thermalization hypothesis (ETH). We consider alternatives to ETH that have been proposed. We first show that von Neumann's quantum ergodic theorem relies on an assumption that is essentially equivalent to ETH. We also investigate whether, following a sudden quench, special classes of pure states can lead to thermal behavior in systems that do not obey ETH, namely, integrable systems. We find examples of this, but only for initial states that obeyed ETH before the quench. PMID- 22540450 TI - Nonequilibrium relaxation and critical aging for driven Ising lattice gases. AB - We employ Monte Carlo simulations to study the nonequilibrium relaxation of driven Ising lattice gases in two dimensions. Whereas the temporal scaling of the density autocorrelation function in the nonequilibrium steady state does not allow a precise measurement of the critical exponents, these can be accurately determined from the aging scaling of the two-time autocorrelations and the order parameter evolution following a quench to the critical point. We obtain excellent agreement with renormalization group predictions based on the standard Langevin representation of driven Ising lattice gases. PMID- 22540451 TI - Thermalization of a strongly interacting closed spin system: from coherent many body dynamics to a Fokker-Planck equation. AB - Thermalization has been shown to occur in a number of closed quantum many-body systems, but the description of the actual thermalization dynamics is prohibitively complex. Here, we present a model-in one and two dimensions-for which we can analytically show that the evolution into thermal equilibrium is governed by a Fokker-Planck equation derived from the underlying quantum dynamics. Our approach does not rely on a formal distinction of weakly coupled bath and system degrees of freedom. The results show that transitions within narrow energy shells lead to a dynamics which is dominated by entropy and establishes detailed balance conditions that determine both the eventual equilibrium state and the nonequilibrium relaxation to it. PMID- 22540452 TI - Weak localization of light in superdiffusive random systems. AB - Levy flights constitute a broad class of random walks that occur in many fields of research, from biology to economy and geophysics. The recent advent of Levy glasses allows us to study Levy flights-and the resultant superdiffusion-using light waves. This raises several questions about the influence of interference on superdiffusive transport. Superdiffusive structures have the extraordinary property that all points are connected via direct jumps, which is expected to have a strong impact on interference effects such as weak and strong localization. Here we report on the experimental observation of weak localization in Levy glasses and compare our results with a recently developed theory for multiple scattering in superdiffusive media. Experimental results are in good agreement with theory and allow us to unveil the light propagation inside a finite-size superdiffusive system. PMID- 22540453 TI - Global Positioning System test of the local position invariance of Planck's constant. AB - Publicly available clock correction data from the Global Positioning System was analyzed and used in combination with the results of terrestrial clock comparison experiments to confirm the local position invariance (LPI) of Planck's constant within the context of general relativity. The results indicate that h is invariant within a limit of |beta(h)|<0.007, where beta(h) is a dimensionless parameter that represents the extent of LPI violation. PMID- 22540454 TI - Rocky core solubility in Jupiter and giant exoplanets. AB - Gas giants are believed to form by the accretion of hydrogen-helium gas around an initial protocore of rock and ice. The question of whether the rocky parts of the core dissolve into the fluid H-He layers following formation has significant implications for planetary structure and evolution. Here we use ab initio calculations to study rock solubility in fluid hydrogen, choosing MgO as a representative example of planetary rocky materials, and find MgO to be highly soluble in H for temperatures in excess of approximately 10,000 K, implying the potential for significant redistribution of rocky core material in Jupiter and larger exoplanets. PMID- 22540455 TI - Bridging the gap by squeezing superfluid matter. AB - Cooper pairing between fermions in dense matter leads to the formation of a gap in the fermionic excitation spectrum and typically exponentially suppresses transport properties. However, we show here that reactions involving conversion between different fermion species, such as Urca reactions in nuclear matter, become strongly enhanced and approach their ungapped level when the matter undergoes density oscillations of sufficiently large amplitude. We study both the neutrino emissivity and the bulk viscosity due to direct Urca processes in hadronic, hyperonic, and quark matter and discuss different superfluid and superconducting pairing patterns. PMID- 22540456 TI - Model independent signatures of new physics in the inflationary power spectrum. AB - We compute the universal generic corrections to the inflationary power spectrum due to unknown high-energy physics. We arrive at this result via a careful integrating out of massive fields in the "in-in" formalism yielding a consistent and predictive low-energy effective description in time-dependent backgrounds. We find that the power spectrum is universally modified at order H/M, where H is the scale of inflation. This is qualitatively different from the universal corrections in time-independent backgrounds, and it suggests that such effects may be present in upcoming cosmological observations. PMID- 22540457 TI - Curvaton scenario within the minimal supersymmetric standard model and predictions for non-Gaussianity. AB - We provide a model in which both the inflaton and the curvaton are obtained from within the minimal supersymmetric standard model, with known gauge and Yukawa interactions. Since now both the inflaton and curvaton fields are successfully embedded within the same sector, their decay products thermalize very quickly before the electroweak scale. This results in two important features of the model: first, there will be no residual isocurvature perturbations, and second, observable non-Gaussianities can be generated with the non-Gaussianity parameter f(NL)~O(5-1000) being determined solely by the combination of weak-scale physics and the standard model Yukawa interactions. PMID- 22540458 TI - Chern-Simons expectation values and quantum horizons from loop quantum gravity and the Duflo map. AB - We report on a new approach to the calculation of Chern-Simons theory expectation values, using the mathematical underpinnings of loop quantum gravity, as well as the Duflo map, a quantization map for functions on Lie algebras. These new developments can be used in the quantum theory for certain types of black hole horizons, and they may offer new insights for loop quantum gravity, Chern-Simons theory and the theory of quantum groups. PMID- 22540459 TI - Scattering amplitudes with open loops. AB - We introduce a new technique to generate scattering amplitudes at one loop. Traditional tree algorithms, which handle diagrams with fixed momenta, are promoted to generators of loop-momentum polynomials that we call open loops. Combining open loops with tensor-integral and Ossola-Papadopoulos-Pittau reduction results in a fully flexible, very fast, and numerically stable one-loop generator. As demonstrated with nontrivial applications, the open-loop approach will permit us to obtain precise predictions for a very wide range of collider processes. PMID- 22540460 TI - Evidence for CP violation in time-integrated D0->h(-)h(+) decay rates. AB - A search for time-integrated CP violation in D(0)->h(-)h(+) (h=K, pi) decays is presented using 0.62 fb(-1) of data collected by LHCb in 2011. The flavor of the charm meson is determined by the charge of the slow pion in the D(*+)->D(0)pi(+) and D(*-)->D[over -](0)pi(-) decay chains. The difference in CP asymmetry between D(0)->K(-)K(+) and D(0)->pi(-)pi(+), DeltaA(CP)=A(CP)(K(-)K(+))-A(CP)(pi( )pi(+)), is measured to be [-0.82+/-0.21(stat)+/-0.11(syst)]%. This differs from the hypothesis of CP conservation by 3.5 standard deviations. PMID- 22540465 TI - Isolating the Lambda(1405) in lattice QCD. AB - The odd-parity ground state of the Lambda baryon lies surprisingly low in mass. At 1405 MeV, it lies lower than the odd-parity ground-state nucleon, even though it has a valence strange quark. Using the PACS-CS (2+1)-flavor full-QCD ensembles, we employ a variational analysis using source and sink smearing to isolate this elusive state. For the first time we reproduce the correct level ordering with respect to nearby scattering thresholds. With a partially quenched strange quark to produce the appropriate kaon mass, we find a low-lying, odd parity mass trend consistent with the experimental value. PMID- 22540466 TI - Examining coupled-channel effects in radiative charmonium transitions. AB - Coupled-channel effects due to coupling of charmonia to the charmed and anticharmed mesons are of current interest in heavy quarkonium physics. However, the effects have not been unambiguously established. In this Letter, a clean method is proposed in order to examine the coupled-channel effects in charmonium transitions. We show that the hindered M1 radiative transitions from the 2P to 1P charmonia are suitable for this purpose. We suggest to measure one or more of the ratios Gamma(h(c)'->chi(cJ)gamma)/Gamma(chi(cJ)'->chi(cJ)pi(0)) and Gamma(chi(cJ)'->h(c)gamma)/Gamma(chi(cJ)'->chi(cJ)pi(0)), for which highly nontrivial and parameter-free predictions are given. The picture can also be tested using both unquenched and quenched lattice calculations. PMID- 22540468 TI - Quadrupole response of a weakly bound bosonic trimer. AB - The inelastic response of a bosonic trimer is explored in the confines of the Borromean region. To this end we model the interaction between the external field and the bosonic system as a photoabsorptionlike process and study the response of the trimer in the quadrupole approximation. We utilize the hyperspherical harmonics expansion to solve the Schrodinger equation and the Lorentz integral transform method to calculate the reaction. It is found that the magnitude of the response function and corresponding sum rules increase exponentially when approaching the 3-body threshold. It is also found that this increase is governed by unnatural exponents. The connection between our results and radio-frequency experiments in ultracold atom systems is made. PMID- 22540470 TI - Highly resolved measurements of Stark-tuned Forster resonances between Rydberg atoms. AB - We report on experiments exploring Stark-tuned Forster resonances between Rydberg atoms with high resolution in the Forster defect. The individual resonances are expected to exhibit different angular dependencies, opening the possibility to tune not only the interaction strength but also the angular dependence of the pair state potentials by an external electric field. We achieve a high resolution by optical Ramsey interferometry for Rydberg atoms combined with electric field pulses. The resonances are detected by a loss of visibility in the Ramsey fringes due to resonances in the interaction. We present measurements of the density dependence as well as of the coherence time at and close to Forster resonances. PMID- 22540469 TI - Measurement of the neutron radius of 208Pb through parity violation in electron scattering. AB - We report the first measurement of the parity-violating asymmetry A(PV) in the elastic scattering of polarized electrons from 208Pb. A(PV) is sensitive to the radius of the neutron distribution (R(n)). The result A(PV)=0.656+/-0.060(stat)+/ 0.014(syst) ppm corresponds to a difference between the radii of the neutron and proton distributions R(n)-R(p)=0.33(-0.18)(+0.16) fm and provides the first electroweak observation of the neutron skin which is expected in a heavy, neutron rich nucleus. PMID- 22540471 TI - Trapped antihydrogen in its ground state. AB - Antihydrogen atoms (H-) are confined in an Ioffe trap for 15-1000 s-long enough to ensure that they reach their ground state. Though reproducibility challenges remain in making large numbers of cold antiprotons (p-) and positrons (e(+)) interact, 5+/-1 simultaneously confined ground-state atoms are produced and observed on average, substantially more than previously reported. Increases in the number of simultaneously trapped H- are critical if laser cooling of trapped H- is to be demonstrated and spectroscopic studies at interesting levels of precision are to be carried out. PMID- 22540472 TI - Statistical theory of a quantum emitter strongly coupled to Anderson-localized modes. AB - A statistical theory of the coupling between a quantum emitter and Anderson localized cavity modes is presented based on a dyadic Green's function formalism. The probability of achieving the strong light-matter coupling regime is extracted for an experimentally realistic system composed of InAs quantum dots embedded in a disordered photonic crystal waveguide. We demonstrate that by engineering the relevant parameters that define the quality of light confinement, i.e., the light localization length and the loss length, strong coupling between a single quantum dot and an Anderson-localized cavity is within experimental reach. As a consequence, confining light by disorder provides a novel platform for quantum electrodynamics experiments. PMID- 22540473 TI - Rapid coherent optical modulation of atomic momenta via pseudoresonances. AB - We show that modulation of an optical field injected into a cavity containing a dilute Bose-Einstein condensate is transformed into a modulation of the population of the atomic momentum states due to pseudoresonances of the resolvent which describes the linearized evolution of the atom-cavity system. This effect is related to the way the atomic momentum states and the cavity optical field are dynamically coupled. The results presented offer new possibilities for rapid modulation of atomic momentum state populations up to 3 orders of magnitude faster than modulation of magnetic trapping potentials. PMID- 22540474 TI - Experimental observation of self-accelerating beams in quadratic nonlinear media. AB - We present the experimental observation of 1D and 2D self-accelerating nonlinear beams in quadratic media, which are also the first nonlinear self-accelerating beams in any symmetric nonlinearity. Notably, we show that the intensity peaks of the first and second harmonics are asynchronous with respect to one another, but the coupled harmonics exhibit joint acceleration within the nonlinear medium. Finally, we demonstrate the impact of self-healing effects on the jointly accelerating first and second harmonics. PMID- 22540475 TI - Attosecond lighthouses: how to use spatiotemporally coupled light fields to generate isolated attosecond pulses. AB - Under the effect of even simple optical components, the spatial properties of femtosecond laser beams can vary over the duration of the light pulse. We show how using such spatiotemporally coupled light fields in high harmonic generation experiments (e.g., in gases or dense plasmas) enables the production of attosecond lighthouses, i.e., sources emitting a collection of angularly well separated light beams, each consisting of an isolated attosecond pulse. This general effect opens the way to a new generation of light sources, particularly suitable for attosecond pump-probe experiments, and provides a new tool for ultrafast metrology, for instance, giving direct access to fluctuations of the carrier-envelope relative phase of even the most intense ultrashort lasers. PMID- 22540476 TI - Extreme acoustic metamaterial by coiling up space. AB - We show that by coiling up space using curled perforations, a two-dimensional acoustic metamaterial can be constructed to give a frequency dispersive spectrum of extreme constitutive parameters, including double negativity, a density near zero, and a large refractive index. Such an approach has band foldings at the effective medium regime without using local resonating subwavelength structures, while the principle can be easily generalized to three dimensions. Negative refraction with a double negative prism and tunneling with a density-near-zero metamaterial are numerically demonstrated. PMID- 22540477 TI - First observation of intrabeam stripping of negative hydrogen in a superconducting linear accelerator. AB - We report on an experiment in which a negative hydrogen ion beam in the Spallation Neutron Source (SNS) linear accelerator was replaced with a beam of protons with similar size and dynamics. Fractional beam loss in the superconducting part of the SNS accelerator was measured to be at least 2*10(-5) for the H(-) beam, and it was an order of magnitude lower for the protons. Also beam loss has a stronger dependence on intensity with H(-) than with proton beams. These measurements verify a recent theoretical explanation of unexpected beam losses in the SNS superconducting linear accelerator based on an intrabeam stripping mechanism for negative hydrogen ions. This previously unidentified mechanism for beam loss is important for the design of new high current linear ion accelerators and the performance improvement of existing machines. PMID- 22540478 TI - Stirring unmagnetized plasma. AB - A new concept for spinning unmagnetized plasma is demonstrated experimentally. Plasma is confined by an axisymmetric multicusp magnetic field and biased cathodes are used to drive currents and impart a torque in the magnetized edge. Measurements show that flow viscously couples momentum from the magnetized edge (where the plasma viscosity is small) into the unmagnetized core (where the viscosity is large) and that the core rotates as a solid body. To be effective, collisional viscosity must overcome the ion-neutral drag due to charge-exchange collisions. PMID- 22540479 TI - Dominance of radiation pressure in ion acceleration with linearly polarized pulses at intensities of 10(21) W cm(-2). AB - A novel regime is proposed where, by employing linearly polarized laser pulses at intensities 10(21) W cm(-2) (2 orders of magnitude lower than discussed in previous work [T. Esirkepov et al., Phys. Rev. Lett. 92, 175003 (2004)]), ions are dominantly accelerated from ultrathin foils by the radiation pressure and have monoenergetic spectra. In this regime, ions accelerated from the hole-boring process quickly catch up with the ions accelerated by target normal sheath acceleration, and they then join in a single bunch, undergoing a hybrid light sail-target normal sheath acceleration. Under an appropriate coupling condition between foil thickness, laser intensity, and pulse duration, laser radiation pressure can be dominant in this hybrid acceleration. Two-dimensional particle-in cell simulations show that 1.26 GeV quasimonoenergetic C(6+) beams are obtained by linearly polarized laser pulses at intensities of 10(21) W cm(-2). PMID- 22540480 TI - Anticorrelation between ion acceleration and nonlinear coherent structures from laser-underdense plasma interaction. AB - In laser-plasma experiments, we observed that ion acceleration from the Coulomb explosion of the plasma channel bored by the laser is prevented when multiple plasma instabilities, such as filamentation and hosing, and nonlinear coherent structures (vortices or postsolitons) appear in the wake of an ultrashort laser pulse. The tailoring of the longitudinal plasma density ramp allows us to control the onset of these instabilities. We deduced that the laser pulse is depleted into these structures in our conditions, when a plasma at about 10% of the critical density exhibits a gradient on the order of 250 MUm (Gaussian fit), thus hindering the acceleration. A promising experimental setup with a long pulse is demonstrated enabling the excitation of an isolated coherent structure for polarimetric measurements and, in further perspectives, parametric studies of ion plasma acceleration efficiency. PMID- 22540482 TI - Dipolar molecules in optical lattices. AB - We study the extended Bose-Hubbard model describing an ultracold gas of dipolar molecules in an optical lattice, taking into account all on-site and nearest neighbor interactions, including occupation-dependent tunneling and pair tunneling terms. Using exact diagonalization and the multiscale entanglement renormalization ansatz, we show that these terms can destroy insulating phases and lead to novel quantum phases. These considerable changes of the phase diagram have to be taken into account in upcoming experiments with dipolar molecules. PMID- 22540481 TI - Hot electron temperature and coupling efficiency scaling with prepulse for cone guided fast ignition. AB - The effect of increasing prepulse energy levels on the energy spectrum and coupling into forward-going electrons is evaluated in a cone-guided fast-ignition relevant geometry using cone-wire targets irradiated with a high intensity (10(20) W/cm(2)) laser pulse. Hot electron temperature and flux are inferred from Kalpha images and yields using hybrid particle-in-cell simulations. A two temperature distribution of hot electrons was required to fit the full profile, with the ratio of energy in a higher energy (MeV) component increasing with a larger prepulse. As prepulse energies were increased from 8 mJ to 1 J, overall coupling from laser to all hot electrons entering the wire was found to fall from 8.4% to 2.5% while coupling into only the 1-3 MeV electrons dropped from 0.57% to 0.03%. PMID- 22540467 TI - Spin-parity analysis of pp- mass threshold structure in J/psi and psi(3686) radiative decays. AB - A partial wave analysis of the pp- mass-threshold enhancement in the reaction J/psi->gammapp- is used to determine its J(PC) quantum numbers to be 0(-+), its peak mass to be below threshold at M=1832(-5)(+19)(stat)(-17)(+18)(syst)+/ 19(model) MeV/c(2), and its total width to be Gamma<76 MeV/c(2) at the 90% C.L. The product of branching ratios is measured to be BR[J/psi->gammaX(pp-)]BR[X(pp-) >pp-]=[9.0(-1.1)(+0.4)(stat)(-5.0)(+1.5)(syst)+/-2.3(model)]*10(-5). A similar analysis performed on psi(3686)->gammapp- decays shows, for the first time, the presence of a corresponding enhancement with a production rate relative to that for J/psi decays of R=[5.08(-0.45)(+0.71)(stat)(-3.58)(+0.67)(syst)+/ 0.12(model)]%. PMID- 22540483 TI - Tunneling theory of two interacting atoms in a trap. AB - A theory for the tunneling of one atom out of a trap containing two interacting cold atoms is developed. The quasiparticle wave function, dressed by the interaction with the companion atom in the trap, replaces the noninteracting orbital at resonance in the tunneling matrix element. The computed decay time for two ^{6}Li atoms agrees with recent experimental results [G. Zurn, F. Serwane, T. Lompe, A. N. Wenz, M. G. Ries, J. E. Bohn, and S. Jochim, Phys. Rev. Lett. 108, 075303 (2012)], unveiling the "fermionization" of the wave function and a novel two-body effect. PMID- 22540484 TI - Spiral growth without dislocations: molecular beam epitaxy of the topological insulator Bi2Se3 on epitaxial graphene/SiC(0001). AB - We report a new mechanism that does not require the formation of interfacial dislocations to mediate spiral growth during molecular beam epitaxy of Bi2Se3. Based on in situ scanning tunneling microscopy observations, we find that Bi2Se3 growth on epitaxial graphene/SiC(0001) initiates with two-dimensional (2D) nucleation, and that the spiral growth ensues with the pinning of the 2D growth fronts at jagged steps of the substrate or at domain boundaries created during the coalescence of the 2D islands. Winding of the as-created growth fronts around these pinning centers leads to spirals. The mechanism can be broadly applied to the growth of other van der Waals materials on weakly interacting substrates. We further confirm, using scanning tunneling spectroscopy, that the one-dimensional helical mode of a line defect is not supported in strong topological insulators such as Bi2Se3. PMID- 22540485 TI - All-electron path integral Monte Carlo simulations of warm dense matter: application to water and carbon plasmas. AB - We develop an all-electron path integral Monte Carlo method with free-particle nodes for warm dense matter and apply it to water and carbon plasmas. We thereby extend path integral Monte Carlo studies beyond hydrogen and helium to elements with core electrons. Path integral Monte Carlo results for pressures, internal energies, and pair-correlation functions compare well with density functional theory molecular dynamics calculations at temperatures of (2.5-7.5)*10(5) K, and both methods together form a coherent equation of state over a density temperature range of 3-12 g/cm(3) and 10(4)-10(9) K. PMID- 22540486 TI - Microscopic origins of the anomalous melting behavior of sodium under high pressure. AB - X-ray diffraction experiments have shown that sodium exhibits a dramatic pressure induced drop in melting temperature, which extends from 1000 K at ~30 GPa to as low as room temperature at ~120 GPa. Despite significant theoretical effort to understand the anomalous melting, its origins are still debated. In this work, we reconstruct the sodium phase diagram by using an ab initio quality neural-network potential. Furthermore, we demonstrate that the reentrant behavior results from the screening of interionic interactions by conduction electrons, which at high pressure induces a softening in the short-range repulsion. PMID- 22540487 TI - Persistent medium-range order and anomalous liquid properties of Al(1-x)Cu(x) alloys. AB - The development of short-to-medium-range order in atomic arrangements has generally been observed in noncrystalline solid systems such as metallic glasses. Whether such medium-range order (MRO) can exist in materials at well above their melting or glass-transition temperature has been a long-standing important scientific issue. Here, using ab initio molecular dynamics simulations, we show that a novel, persistent MRO exists in liquid Al-Cu alloys near the composition of CuAl3. The correlated atomic motions associated with the MRO give rise to a substantially enhanced viscosity in the vicinity of the composition. The component of the MRO liquid state gradually decreases with increasing temperature, and it disappears above a crossover temperature T(LLC). The continuous liquid-liquid crossover through a percolationlike transition leads to a pronounced heat capacity peak at T(LLC). PMID- 22540488 TI - Diffusion of hydrogen in Pd assisted by inelastic ballistic hot electrons. AB - Sykes et al. [Proc. Natl. Acad. Sci. U.S.A. 102, 17907 (2005)] have reported how electrons injected from a scanning tunneling microscope modify the diffusion rates of H buried beneath Pd(111). A key point in that experiment is the symmetry between positive and negative voltages for H extraction, which is difficult to explain in view of the large asymmetry in Pd between the electron and hole densities of states. Combining concepts from the theory of ballistic electron microscopy and electron-phonon scattering we show that H diffusion is driven by the s-band electrons only, which explains the observed symmetry. PMID- 22540489 TI - p doping in expanded phases of ZnO: an ab initio study. AB - The issue of p doping in nanostructured cagelike ZnO is investigated by state-of the-art calculations. Our study is focused on one prototypical structure, namely, sodalite, for which we show that p-type doping is possible for elements of the V, VI, and VII columns of the periodic table. However, some dopants tend to form dimers, thus impairing the stability of this kind of doping. This difference of behavior is discussed, and two criteria are proposed to ensure stable p doping. PMID- 22540490 TI - Selective adsorption of C60 on Ge/Si nanostructures. AB - Selective adsorption of C60 on nanoscale Ge areas can be achieved, while neighboring Si(111) areas remain uncovered, if the whole surface is initially terminated by Bi. Fullerene chemisorption is found at Bi vacancies which form due to partial thermal desorption of the Bi surfactant. The growth rate and temperature dependence of the C60 adsorption were measured using scanning tunneling microscopy and are described consistently by a rate equation model. The selectivity of the C60 adsorption can be traced back to an easier vacancy formation in the Bi layer on top of the Ge areas compared to the Si areas. Furthermore, it is also possible to desorb C60 from Ge areas, allowing the use of C60 as a resist on the nanoscale. PMID- 22540491 TI - How does adhesion induce the formation of telephone cord buckles? AB - Compressively stressed thin films with low adhesion frequently buckle and delaminate simultaneously into telephone cords. Although these buckles have been studied for decades, no complete understanding of their propagation has so far been presented. In this study, we have coupled a nonlinear plate deformation with a cohesive zone model to simulate the kinematics of a propagating telephone cord buckle in very close agreement with experimental observations. Proper inclusion of the dependence of an adhesion upon the mode mixity proved to be central to the success of the approach. The clarification of the mechanism promises better understanding of buckle morphologies. PMID- 22540492 TI - Physical and chemical nature of the scaling relations between adsorption energies of atoms on metal surfaces. AB - Despite their importance in physics and chemistry, the origin and extent of the scaling relations between the energetics of adsorbed species on surfaces remain elusive. We demonstrate here that scalability is not exclusive to adsorbed atoms and their hydrogenated species but rather a general phenomenon between any set of adsorbates bound similarly to the surface. On the example of the near-surface alloys of Pt, we show that scalability is a result of identical variations of adsorption energies with respect to the valence configuration of both the surface components and the adsorbates. PMID- 22540493 TI - Detecting quantum critical points using bipartite fluctuations. AB - We show that the concept of bipartite fluctuations F provides a very efficient tool to detect quantum phase transitions in strongly correlated systems. Using state-of-the-art numerical techniques complemented with analytical arguments, we investigate paradigmatic examples for both quantum spins and bosons. As compared to the von Neumann entanglement entropy, we observe that F allows us to find quantum critical points with much better accuracy in one dimension. We further demonstrate that F can be successfully applied to the detection of quantum criticality in higher dimensions with no prior knowledge of the universality class of the transition. Promising approaches to experimentally access fluctuations are discussed for quantum antiferromagnets and cold gases. PMID- 22540494 TI - Charge-orbital density wave and superconductivity in the strong spin-orbit coupled IrTe2:Pd. AB - Using transmission electron microscopy, the anomalies in resistivity and magnetic susceptibility at ~262 K in IrTe2 are found to accompany the superlattice peaks with q[over q=(1/5,0,-1/5). The wave vector is consistent with our theoretical calculation for the Fermi surface nesting vector, indicating that the ~262 K transition is of the charge-orbital density wave (DW) type. We also discovered that both Pd intercalation and substitution induce bulk superconductivity with T(c) up to ~3 K, which competes with DW in a quantum critical pointlike manner. PMID- 22540495 TI - Two-dimensional polaronic behavior in the binary oxides m-HfO2 and m-ZrO2. AB - We demonstrate that the three-dimensional (3D) binary monoclinic oxides HfO2 and ZrO2 exhibit quasi-2D polaron localization and conductivity, which results from a small difference in the coordination of two oxygen sublattices in these materials. The transition between a 2D large polaron into a zero-dimensional small polaron state requires overcoming a small energetic barrier. These results demonstrate how a small asymmetry in the lattice structure can determine the qualitative character of polaron localization and significantly broaden the realm of quasi-2D polaron systems. PMID- 22540496 TI - Direct measurement of the Fermi energy in graphene using a double-layer heterostructure. AB - We describe a technique which allows a direct measurement of the relative Fermi energy in an electron system by employing a double-layer heterostructure. We illustrate this method by using a graphene double layer to probe the Fermi energy as a function of carrier density in monolayer graphene, at zero and in high magnetic fields. This technique allows us to determine the Fermi velocity, Landau level spacing, and Landau level broadening. We find that the N=0 Landau level broadening is larger by comparison to the broadening of upper and lower Landau levels. PMID- 22540497 TI - Topological surface states in lead-based ternary telluride Pb(Bi(1-x)Sb(x))2Te4. AB - We have performed angle-resolved photoemission spectroscopy on Pb(Bi(1 x)Sb(x))2Te4, which is a member of lead-based ternary tellurides and has been theoretically proposed as a candidate for a new class of three-dimensional topological insulators. In PbBi2Te4, we found a topological surface state with a hexagonally deformed Dirac-cone band dispersion, indicating that this material is a strong topological insulator with a single topological surface state at the Brillouin-zone center. Partial replacement of Bi with Sb causes a marked change in the Dirac carrier concentration, leading to the sign change of Dirac carriers from n type to p type. The Pb(Bi(1-x)Sb(x))2Te4 system with tunable Dirac carriers thus provides a new platform for investigating exotic topological phenomena. PMID- 22540498 TI - Hydrogen-induced surface metallization of SrTiO3(001). AB - Surface metallization of SrTiO3(001) by hydrogen adsorption is experimentally confirmed for the first time by photoemission spectroscopy and surface conductivity measurements. The metallic state is assigned to a quantized state in the space-charge layer induced by electron doping from hydrogen atoms. The measured two-dimensional (2D) conductivity is well above the 2D Ioffe-Regel limit indicating that the system is in a metallic conduction regime. The mean free path of the surface electron is estimated to be several nanometers at room temperature. PMID- 22540499 TI - Inelastic neutron-scattering measurements of incommensurate magnetic excitations on superconducting LiFeAs single crystals. AB - Magnetic correlations in superconducting LiFeAs were studied by elastic and by inelastic neutron-scattering experiments. There is no indication for static magnetic ordering, but inelastic correlations appear at the incommensurate wave vector (0.5+/-delta,0.5-/+delta,0) with delta~0.07 slightly shifted from the commensurate ordering observed in other FeAs-based compounds. The incommensurate magnetic excitations respond to the opening of the superconducting gap by a transfer of spectral weight. PMID- 22540500 TI - Supercurrent through grain boundaries of cuprate superconductors in the presence of strong correlations. AB - Strong correlations are known to severely reduce the mobility of charge carriers near half filling and thus have an important influence on the current carrying properties of grain boundaries in the high-T(c) cuprates. In this Letter we present an extension of the Gutzwiller projection approach to treat electronic correlations below as well as above half filling consistently. We apply this method to investigate the critical current through grain boundaries with a wide range of misalignment angles for electron- and hole-doped systems. For the latter excellent agreement with experimental data is found. We further provide a detailed comparison to an analogous weak-coupling evaluation. PMID- 22540501 TI - Superconducting and ferromagnetic phases in SrTiO3/LaAlO3 oxide interface structures: possibility of finite momentum pairing. AB - We introduce a model to explain the observed ferromagnetism and superconductivity in LAO/STO oxide interface structures. Because of the polar catastrophe mechanism, 1/2 charge per unit cell is transferred to the interface layer. We argue that this charge localizes and orders ferromagnetically via exchange with the conduction electrons. Ordinarily, this ferromagnetism would destroy superconductivity, but, due to strong spin-orbit coupling near the interface, the magnetism and superconductivity can coexist by forming a Fulde-Ferrell-Larkin Ovchinikov-type condensate of Cooper pairs at finite momentum, which is surprisingly robust in the presence of strong disorder. PMID- 22540502 TI - High-pressure structures of disilane and their superconducting properties. AB - A systematic ab initio search for low-enthalpy phases of disilane (Si2H6) at high pressures was performed based on the minima hopping method. We found a novel metallic phase of disilane with Cmcm symmetry, which is enthalpically more favorable than the recently proposed structures of disilane up to 280 GPa, but revealing compositional instability below 190 GPa. The Cmcm phase has a moderate electron-phonon coupling yielding a superconducting transition temperature T(c) of around 20 K at 100 GPa, decreasing to 13 K at 220 GPa. These values are significantly smaller than previously predicted T(c))s for disilane at equivalent pressure. This shows that similar but different crystalline structures of a material can result in dramatically different T(c)'s and stresses the need for a systematic search for a crystalline ground state. PMID- 22540503 TI - Reentrant superconducting phase in conical-ferromagnet-superconductor nanostructures. AB - We study a bilayer consisting of an ordinary superconductor and a magnet with a spiral magnetic structure of the Ho type. We use a self-consistent solution of the Bogolioubov-de Gennes equations to evaluate the pair amplitude, the transition temperature, and the thermodynamic functions, namely, the free energy and entropy. We find that for a range of thicknesses of the magnetic layer the superconductivity is reentrant with temperature T: as one lowers T the system turns superconducting, and when T is further lowered it turns normal again. This behavior is reflected in the condensation free energy and the pair potential, which vanish both above the upper transition and below the lower one. The transition is strictly reentrant: the low and high temperature phases are the same. The entropy further reveals a range of temperatures where the superconducting state is less ordered than the normal one. PMID- 22540504 TI - Diffusive spin dynamics in ferromagnetic thin films with a Rashba interaction. AB - In a ferromagnetic metal layer, the coupled charge and spin diffusion equations are obtained in the presence of both Rashba spin-orbit interaction and magnetism. The misalignment between the magnetization and the nonequilibrium spin density induced by the Rashba field gives rise to Rashba spin torque acting on the ferromagnetic order parameter. In a general form, we find that the Rashba torque consists of both in-plane and out-of-plane components, i.e., T=T(perpendicular)y^*m^+T(parallel)m^*(y^*m^). Numerical simulations on a two dimensional nanowire consider the impact of diffusion on the Rashba torque and reveal a large enhancement to the ratio T(parallel)/T(perpendicular) for thin wires. Our theory provides an explanation for the mechanism driving the magnetization switching in a single ferromagnet as observed in the recent experiments. PMID- 22540506 TI - Using the de Haas-van Alphen effect to map out the closed three-dimensional Fermi surface of natural graphite. AB - The Fermi surface of graphite has been mapped out using de Haas-van Alphen (dHvA) measurements at low temperature with in-situ rotation. For tilt angles theta>60 degrees between the magnetic field and the c axis, the majority electron and hole dHvA periods no longer follow a cos(theta) behavior demonstrating that graphite has a three-dimensional closed Fermi surface. The Fermi surface of graphite is accurately described by highly elongated ellipsoids. A comparison with the calculated Fermi surface suggests that the Slonczewski-Weiss-McClure trigonal warping parameter gamma(3) is significantly larger than previously thought. PMID- 22540505 TI - Magnetic frustration in a quantum spin chain: the case of linarite PbCuSO4(OH)2. AB - We present a combined neutron diffraction and bulk thermodynamic study of the natural mineral linarite PbCuSO4(OH)2, this way establishing the nature of the ground-state magnetic order. An incommensurate magnetic ordering with a propagation vector k=(0,0.186,1/2) was found below T(N)=2.8 K in a zero magnetic field. The analysis of the neutron diffraction data yields an elliptical helical structure, where one component (0.638MU(B)) is in the monoclinic ac plane forming an angle with the a axis of 27(2) degrees , while the other component (0.833MU(B)) points along the b axis. From a detailed thermodynamic study of bulk linarite in magnetic fields up to 12 T, applied along the chain direction, a very rich magnetic phase diagram is established, with multiple field-induced phases, and possibly short-range-order effects occurring in high fields. Our data establish linarite as a model compound of the frustrated one-dimensional spin chain, with ferromagnetic nearest-neighbor and antiferromagnetic next-nearest neighbor interactions. Long-range magnetic order is brought about by interchain coupling 1 order of magnitude smaller than the intrachain coupling. PMID- 22540507 TI - Laser location and manipulation of a single quantum tunneling channel in an InAs quantum dot. AB - We use a femtowatt focused laser beam to locate and manipulate a single quantum tunneling channel associated with an individual InAs quantum dot within an ensemble of dots. The intensity of the directed laser beam tunes the tunneling current through the targeted dot with an effective optical gain of 10(7) and modifies the curvature of the dot's confining potential and the spatial extent of its ground state electron eigenfunction. These observations are explained by the effect of photocreated hole charges which become bound close to the targeted dot, thus acting as an optically induced gate electrode. PMID- 22540508 TI - Ultrafast optical excitation of a persistent surface-state population in the topological insulator Bi2Se3. AB - Using femtosecond time- and angle-resolved photoemission spectroscopy, we investigated the nonequilibrium dynamics of the topological insulator Bi2Se3. We studied p-type Bi2Se3, in which the metallic Dirac surface state and bulk conduction bands are unoccupied. Optical excitation leads to a metastable population at the bulk conduction band edge, which feeds a nonequilibrium population of the surface state persisting for >10 ps. This unusually long-lived population of a metallic Dirac surface state with spin texture may present a channel in which to drive transient spin-polarized currents. PMID- 22540510 TI - Photoemission spectroscopy of magnetic and nonmagnetic impurities on the surface of the Bi2Se3 topological insulator. AB - Dirac-like surface states on surfaces of topological insulators have a chiral spin structure that suppresses backscattering and protects the coherence of these states in the presence of nonmagnetic scatterers. In contrast, magnetic scatterers should open the backscattering channel via the spin-flip processes and degrade the state's coherence. We present angle-resolved photoemission spectroscopy studies of the electronic structure and the scattering rates upon the adsorption of various magnetic and nonmagnetic impurities on the surface of Bi2Se3, a model topological insulator. We reveal a remarkable insensitivity of the topological surface state to both nonmagnetic and magnetic impurities in the low impurity concentration regime. Scattering channels open up with the emergence of hexagonal warping in the high-doping regime, irrespective of the impurity's magnetic moment. PMID- 22540509 TI - Quantum interference between the third and fourth exciton states in semiconducting carbon nanotubes using resonance Raman spectroscopy. AB - We exploit an energy level crossover effect [Haroz et al., Phys. Rev. B 77, 125405 (2008)] to probe quantum interference in the resonance Raman response from carbon nanotube samples highly enriched in the single semiconducting chiralities of (8,6), (9,4), and (10,5). UV Raman excitation profiles of G-band spectra reveal unambiguous signatures of interference between the third and fourth excitonic states (E(33) and E(44)). Both constructive and destructive responses are observed and lead to anomalous intensity ratios in the LO and TO modes. Especially large anomalies for the (10,5) structure result from nearly identical energies found for the two E(ii) transitions. The interference patterns demonstrate that the sign of the exciton-phonon coupling matrix elements changes for the LO mode between the two electronic states, and remains the same for the TO mode. Significant non-Condon contributions to the Raman response are also found. PMID- 22540511 TI - Subband structure of a two-dimensional electron gas formed at the polar surface of the strong spin-orbit perovskite KTaO3. AB - We demonstrate the formation of a two-dimensional electron gas (2DEG) at the (100) surface of the 5d transition-metal oxide KTaO3. From angle-resolved photoemission, we find that quantum confinement lifts the orbital degeneracy of the bulk band structure and leads to a 2DEG composed of ladders of subband states of both light and heavy carriers. Despite the strong spin-orbit coupling, our measurements provide a direct upper bound for the potential Rashba spin splitting of only Deltak(parallel)}~0.02 A(-1) at the Fermi level. The polar nature of the KTaO3(100) surface appears to help mediate the formation of the 2DEG as compared to nonpolar SrTiO3(100). PMID- 22540512 TI - Oscillations, cessations, and circulation reversals of granular convection in a densely filled rotating container. AB - We study spontaneously forming convection in a container that is almost completely filled with a bidisperse granular mixture. The container with an aspect ratio close to 1 rotates slowly about a horizontal axis. In this geometry, single vortex rolls are observed in the cell plane, after a spontaneous symmetry breaking. The circulation of grains produces nonuniform segregation patterns of the mixture that in turn interact with the convective flow. We describe oscillatory modulations of the convection velocity, cessations and spontaneous reversals of the circulation. All these features are absent in multiroll granular convection. PMID- 22540513 TI - Fluid membranes can drive linear aggregation of adsorbed spherical nanoparticles. AB - Using computer simulations, we show that lipid membranes can mediate linear aggregation of spherical nanoparticles binding to it for a wide range of biologically relevant bending rigidities. This result is in net contrast with the isotropic aggregation of nanoparticles on fluid interfaces or the expected clustering of isotropic insertions in biological membranes. We present a phase diagram indicating where linear aggregation is expected and compute explicitly the free-energy barriers associated with linear and isotropic aggregation. Finally, we provide simple scaling arguments to explain this phenomenology. PMID- 22540514 TI - Charging of heated colloidal particles using the electrolyte Seebeck effect. AB - We propose a novel actuation mechanism for colloids, which is based on the Seebeck effect of the electrolyte solution: Laser heating of a nonionic particle accumulates in its vicinity a net charge Q, which is proportional to the excess temperature at the particle surface. The corresponding long-range thermoelectric field E is proportional to 1/r(2) provides a tool for controlled interactions with nearby beads or with additional molecular solutes. An external field E(ext) drags the thermocharged particle at a velocity that depends on its size and absorption properties; the latter point could be particularly relevant for separating carbon nanotubes according to their electronic band structure. PMID- 22540515 TI - New immediate release formulation for deterring abuse of methadone. AB - CONTEXT: Drug abusers are known to take a dosage form containing an opioid analgesic and crush, shear, grind, chew, or dissolve it in water or in alcohol, in order to extract the opioid component. OBJECTIVE: Develop an anti abuse immediate release formulation using methadone as model drug. MATERIALS AND METHODS: Tablets combining methadone and alkalizing agents were manufactured. A methadone assay was used to determine extraction efficiency from tablets in aqueous and alcohol solvents. In vitro dissolution testing was used to determine drug release in different media. RESULTS AND DISCUSSIONS: Meglumine-based formulations prevented extraction of 70 to 100% of methadone from tablets. Addition of this alkalizing agent caused methadone to precipitate out of a solution along with other ingredients and be retained on standard filters. Meglumine-containing and control tablets showed similar dissolution profiles in acidic media, suggesting adequate solubilisation of the drug early in the gastrointestinal tract. Finally, stability upon storage of the formulations for 6 months at 25 degrees C/60%RH and 40 degrees C/75%RH was confirmed. CONCLUSION: Incorporation of an alkalizing agent into methadone tablets significantly reduced the preparation of a methadone solution for intravenous administration and abuse, while allowing the formulation to release methadone in gastric media and provide desired pharmacological effect. PMID- 22540516 TI - Reduced hyperpolarization of endothelial cells following high dietary Na+: effects of enalapril and tempol. AB - 1. High dietary Na(+) is associated with impaired vascular endothelial function. However, the underlying mechanisms are not completely understood. In the present study, we investigated whether the endothelial hyperpolarization response to acetylcholine (ACh) exhibited any abnormalities in Wistar rats fed a high-salt diet (HSD) for 1 month and, if so, whether chronic treatment with the angiotensin converting enzyme inhibitor enalapril or the anti-oxidant tempol could normalize the response. Membrane potential was recorded using the perforated patch-clamp technique on the endothelium of rat aorta. 2. Acetylcholine (2 MUmol/L) produced a hyperpolarization sensitive to TRAM-34, a blocker of intermediate-conductance Ca(2+) -sensitive K(+) channels (IK(Ca)), but not to apamin, a blocker of small conductance Ca(2+)-sensitive K(+) channels (SK(Ca)). NS309 (3 MUmol/L), an activator of SK(Ca) and IK(Ca) channels, produced a hyperpolarization of similar magnitude as ACh. 3. In the HSD group, the ACh-evoked hyperpolarization was significantly attenuated compared with that in the control group, which was fed normal chow rather than an HSD. Similarly, the hyperpolarization produced by NS309 was weaker in tissues from HSD-fed rats. 4. Combination of HSD with chronic enalapril treatment (20 mg/kg per day for 1 month) normalized endothelial hyperpolarizing responses to ACh. Chronic tempol treatment (1 mmol/L in tap water for 1 month) prevented the reduced hyperpolarization to ACh. 5. The results of the present study indicate that excess in dietary Na(+) results in a failure of endothelial cells to generate normal IK(Ca) channel-mediated hyperpolarizing responses. Our observations implicate oxidative stress mediated by increased angiotensin II signalling as a mechanism underlying altered endothelial hyperpolarization during dietary salt loading. PMID- 22540517 TI - A tandem cross-metathesis/semipinacol rearrangement reaction. AB - An efficient and (E)-selective synthesis of a 6-alkylidenebicyclo[3.2.1]octan-8 one has been developed. The key step is a tandem cross-metathesis/semipinacol rearrangement reaction, wherein the Hoveyda-Grubbs II catalyst, or more likely a derivative thereof, serves as the Lewis acid for the rearrangement. Despite the fact that both the starting alkene and the cross-metathesis product are viable rearrangement substrates, only the latter rearranges, suggesting that the Lewis acidic species is generated only after the cross-metathesis reaction is complete. PMID- 22540518 TI - Is micro-computed tomography reliable to determine the microstructure of the maxillary alveolar bone? AB - OBJECTIVES: To analyze the reliability of micro-computed tomography (micro-CT) to assess bone density and the microstructure of the maxillary bones at the alveolar process in human clinics by direct comparison with conventional stereologic-based histomorphometry. MATERIALS AND METHODS: Analysis of osseous microstructural variables including bone volumetric density (BV/TV) of 39 biopsies from the maxillary alveolar bone was performed by micro-CT. Conventional stereologic-based histomorphometry of 10 bone biopsies was performed by optic microscopy (OM) and low-vacuum surface electronic microscopy (SEM). Percentages of bone between micro CT and conventional stereologic-based histomorphometry were compared. RESULTS: Significant positive correlations were observed between BV/TV and the percentage of bone (%Bone) analyzed by SEM (r = 0.933, P < 0.001), by toluidine blue staining OM (r = 0.950, P < 0.001) and by dark field OM (r = 0.667, P = 0.05). The high positive correlation coefficient between BV/TV and trabecular thickness illustrates that a value of BV/TV upper than 50% squares with a bone presenting most of their trabecules thicker than 0.2 mm. The high negative correlation between BV/TV and trabecular separation shows that values of BV/TV upper than 50% squares with a bone presenting most of their trabecules separated less than 0.3 mm each other. CONCLUSION: BV/TV assessed by micro-CT correlates with the percentage of bone assessed by conventional stereologic-based histomorphometry. Micro-CT is a reliable technique to determine the bone density and the microstructure of the maxillary alveolar bone at the site of dental implant insertion. PMID- 22540519 TI - Automatic generation of causal networks linking growth factor stimuli to functional cell state changes. AB - Despite the increasing number of growth factor-related signalling networks, their lack of logical and causal connection to factual changes in cell states frequently impairs the functional interpretation of microarray data. We present a novel method enabling the automatic inference of causal multi-layer networks from such data, allowing the functional interpretation of growth factor stimulation experiments using pathway databases. Our environment of evaluation was hepatocyte growth factor-stimulated cell migration and proliferation in a keratinocyte fibroblast co-culture. The network for this system was obtained by applying the steps: (a) automatic integration of the comprehensive set of all known cellular networks from the Pathway Interaction Database into a master structure; (b) retrieval of an active-network from the master structure, where the network edges that connect nodes with an absent mRNA level were excluded; and (c) reduction of the active-network complexity to a causal subnetwork from a set of seed nodes specific for the microarray experiment. The seed nodes comprised the receptors stimulated in the experiment, the consequently differentially expressed genes, and the expected cell states. The resulting network shows how well-known players, in the context of hepatocyte growth factor stimulation, are mechanistically linked in a pathway triggering functional cell state changes. Using BIOQUALI, we checked and validated the consistency of the network with respect to microarray data by computational simulation. The network has properties that can be classified into different functional layers because it not only shows signal processing down to the transcriptional level, but also the modulation of the network structure by the preceeding stimulation. The software for generating computable objects from the Pathway Interaction Database database, as well as the generated networks, are freely available at: http://www.tiga.uni hd.de/supplements/inferringFromPID.html. PMID- 22540520 TI - Effects of incorporation of organically modified montmorillonite on the reaction mechanism of epoxy/amine cure. AB - The aim of this study is to understand the effect of nonmodified or different organically modified montmorillonites on the reaction mechanism of epoxy/amine cure. The reference material consists of diglycidyl ether of bisphenol A (DGEBA) and 1,3-phenylene diamine (mPDA) in stoichiometric proportions. The reaction with various organically modified montmorillonites (I28E, I34TCN, and MMTm) is compared to highlight the catalytic effect of MMT water content and of the alkylammonium cations on the epoxy/amine reaction mechanism. In the absence of mPDA curing agent, DGEBA develops homopolymerization reactions with I28E, I34TCN, and MMTm. Chemorheological kinetics and advanced isoconversional analysis of epoxy cure are studied by rheometrical measurements and differential scanning calorimetry (DSC). Molecular mobility of the system under curing is modified in the presence of montmorillonites. Finally, the study underlines the role of montmorillonites and the influence of the change in reaction mechanisms on glass transition of the nanocomposites. PMID- 22540521 TI - The effect of a low-carbohydrate/high-monounsaturated fatty acid liquid diet and an isoleucine-containing liquid diet on 24-h glycemic variability in diabetes patients on tube feeding: a comparison by continuous glucose monitoring. AB - OBJECTIVE: This study compare the effect of various liquid diets on 24-h glycemic variability in diabetes patients on tube feeding. PATIENTS AND METHODS: The study included type 2 diabetes patients in whom percutaneous endoscopic gastrostomy had been performed for dysphagia as a sequela of cerebrovascular disease and who had been put on tube feeding with a standard high-carbohydrate liquid diet (HCD). Once stable glycemic control was achieved, these patients were continuously monitored for glucose levels for 5 days on continuous glucose monitoring. Of the 14 patients included, seven were given HCD on day 1, a low-carbohydrate/high monounsaturated fatty acid liquid diet (LCD) on Days 2 and 3, and a isoleucine containing liquid diet (ICD), which is known to promote glycemic uptake by skeletal muscle, thus suppressing increases in glucose levels, on Days 4 and 5, with the remaining seven given the same diets but ICD given on Days 2 and 3 and LCD given on Days 4 and 5. All comparisons were made under the same caloric conditions (caloric intake, 800-1200 kcal/day). RESULTS: The 24-h mean glucose level was significantly lower with LCD and ICD than with HCD but was also significantly lower with LCD than with ICD. On the other hand, the SD of 288 glucose levels over a 24-h period, 24-h total area for glycemic fluctuations, and mean amplitude of glycemic excursion were significantly lower with LCD than with HCD or ICD, whereas they did not differ significantly between HCD and ICD. CONCLUSIONS: LCD and ICD led to significant decreases in mean glucose levels, compared with HCD. However, of the diets compared, LCD had the greatest effect on glycemic variability in these patients on tube feeding. PMID- 22540522 TI - Early detection of kidney disease in type 1 diabetes: what do we really know? PMID- 22540523 TI - Does nutritional education improve the risk factors for cardiovascular diseases among elderly patients with type 2 diabetes? A randomized controlled trial based on an educational model. AB - BACKGROUND: To evaluate the effects of a nutritional education program on cardiovascular risk among elderly patients with type 2 diabetes (T2D). METHODS: Ninety-seven elderly patients with T2D were enrolled in the present randomized controlled educational trial study. Patients were divided into intervention and control groups. The belief, attitude, subjective norm, enabling factors (BASNEF) educational model was used to design the educational intervention. Patients in the control group received their usual care during the study. Anthropometric data, lipid profiles and blood pressure measurements were collected at baseline and Week 12 in each group. RESULTS: Significant declines were observed in the intervention compared with control group in terms of body weight (-1.3 +/- 1.1 vs. 0.11 +/- 0.58 kg, respectively), body mass index (-0.48 +/- 0.37 vs. 0.05 +/- 0.22 kg/m2, respectively), serum triglyceride levels (-18.25 +/- 32.15 vs. -3.67 +/- 22.61 mg/dL, respectively; P < 0.05 for all), and the waist-to-hip ratio (P = 0.03). There were no significant differences between the intervention and control groups in terms of high-density lipoprotein-cholesterol (-1.02 +/- 4.35 vs. -1.10 +/- 6.93 mg/dL, respectively; P = 0.9) or low-density lipoprotein-cholesterol ( 4.04 +/- 11.64 vs. -1.08 +/- 4.35 mg/dL, respectively; P = 0.2). CONCLUSIONS: Short-term nutritional education based on the BASNEF educational model improves serum triglyceride levels and anthropometric indices in elderly patients with T2D. PMID- 22540525 TI - Totally laparoscopic approach for failed conventional orchiopexy. AB - INTRODUCTION: About 0.2-10% of patients with prior orchiopexy will require reoperation for recurrent cryptorchidism. The most common approach for these patients has been an open inguinal repeat orchiopexy. The aim of this report is to show results and feasibility with the totally laparoscopic approach for failed prior open orchiopexy. SUBJECTS AND METHODS: Nine patients with 11 recurrent undescended testes were treated by the totally laparoscopic orchiopexy approach. We used a four-port technique, starting with laparoscopic dissection of the vas deferens and spermatic vessels as high as possible in order to get adequate length of these structures. The inguinal internal ring was opened, and the testis was dissected to finally bring it into the abdominal cavity. A transcrotal trocar was introduced all the way to the abdominal cavity to finally pull through the testis into the scrotum. RESULTS: Laparoscopic orchiopexy was performed satisfactorily in all but 1 case in a mean time of 90 minutes. We did not experience any perioperative complications. In a mean follow-up of 25 months there has not been any recurrent cryptorchidism or atrophic testis. DISCUSSION: Laparoscopy offers the advantage of achieving an extensive mobilization of spermatic vessels and a careful dissection of the vas deferens. The totally laparoscopic approach for a failed orchiopexy represents a feasible, safe, and successful procedure. PMID- 22540524 TI - Thrombelastographic haemostatic status and antiplatelet therapy after coronary artery bypass surgery (TEG-CABG trial): assessing and monitoring the antithrombotic effect of clopidogrel and aspirin versus aspirin alone in hypercoagulable patients: study protocol for a randomized controlled trial. AB - BACKGROUND: Hypercoagulability, assessed by the thrombelastography (TEG) assay, has in several observational studies been associated with an increased risk of post-procedural thromboembolic complications. We hypothesize that intensified antiplatelet therapy with clopidogrel and aspirin, as compared to aspirin alone, will improve saphenous vein graft patency in preoperatively TEG-Hypercoagulable coronary artery bypass surgery (CABG) patients and reduce their risk for thromboembolic complications and death postoperatively. METHODS/DESIGN: This is a prospective randomized clinical trial, with an open-label design with blinded evaluation of graft patency. TEG-Hypercoagulability is defined as a TEG maximum amplitude above 69 mm. Two hundred and fifty TEG-Hypercoagulable patients will be randomized to either an interventional group receiving clopidogrel 75 mg daily for three months (after initial oral bolus of 300 mg) together with aspirin 75 mg or a control group receiving aspirin 75 mg daily alone. Monitoring of antiplatelet efficacy and on-treatment platelet reactivity to clopidogrel and aspirin will be conducted with Multiplate aggregometry. Graft patency will be assessed with Multislice computed tomography (MSCT) at three months after surgery. CONCLUSIONS: The present trial is the first randomized clinical trial to evaluate whether TEG-Hypercoagulable CABG patients will benefit from intensified antiplatelet therapy after surgery. Monitoring of platelet inhibition from instituted antithrombotic therapy will elucidate platelet resistance patterns after CABG surgery. The results could be helpful in redefining how clinicians can evaluate patients preoperatively for their postoperative thromboembolic risk and tailor individualized postoperative antiplatelet therapy. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT01046942. PMID- 22540526 TI - Surgical management of gallstone pancreatitis in children. AB - INTRODUCTION: Because of the low incidence of gallstone pancreatitis in children, we sought to examine effects of varied practice patterns on outcomes. SUBJECTS AND METHODS: A retrospective review was performed on all patients undergoing cholecystectomy for a diagnosis of gallstone pancreatitis from January 2000 to June 2011. Demographics, diagnostic strategies, operative approaches, length of stay, and morbidity were compared between Group 1, who had cholecystectomy performed during the admission of diagnosis, and Group 2, who underwent cholecystectomy subsequently. RESULTS: Cholecystectomy was performed for gallstone pancreatitis in 41 patients, of whom 29 (70.7%) patients were female. Ultrasound was performed in all cases, revealing cholelithiasis in 37 (90.2%). There were 22 patients in Group 1 and 19 in Group 2. Mean age and body mass index did not vary between groups. Endoscopic retrograde cholangiopancreatography was performed in 14 patients (8 in Group 1 and 6 in Group 2), of these procedures 11 were prior to cholecystectomy, 2 were after cholecystectomy, and 1 was both. Total number of hospital days attributed to the diagnosis of gallstone pancreatitis was 8.9 +/- 6.5 in Group 1 compared with 14.0 +/- 14.4 in Group 2 (P = .15). There were 7 patients (36.8%) in Group 2 who required readmission for recurrent pancreatitis prior to their operation. CONCLUSIONS: This represents the largest reported series of cholecystectomy for gallstone pancreatitis in children. Our results support the use of laparoscopic cholecystectomy during the initial hospitalization as is recommended in the adult literature, and this approach may decrease the total hospital stay. PMID- 22540527 TI - A comparison between single-incision and conventional laparoscopic cholecystectomy. AB - BACKGROUND: Single-incision laparoscopic surgery is becoming a more widely accepted surgical approach. However, the feasibility and safety of single incision laparoscopic cholecystectomy (SILC) are yet to be established. The present study compared outcomes following the use of SILC or conventional laparoscopic cholecystectomy (CLC) on patients with gallbladder disease. SUBJECTS AND METHODS: The study involved 190 symptomatic gallbladder disease patients treated between March 2009 and February 2011. Ninety-six patients underwent SILC, and 94 patients underwent CLC. Clinical and surgical outcomes were compared. RESULTS: The SILC and CLC groups were similar in terms of age, gender ratio, body mass index, and diagnoses. The two groups were also found to be similar in terms of postoperative clinical course and complications. The SILC group had a longer operation time, less postoperative pain, and a shorter hospital stay than the CLC group (P<.05 for all variables). CONCLUSIONS: SILC using the OCTO port system (Darim Corp., Korea) was as safe and feasible as CLC. Additionally, SILC is less invasive and more comfortable for patients than CLC. PMID- 22540529 TI - Uterine tamponade using condom catheter balloon in the management of non traumatic postpartum hemorrhage. AB - AIM: To study the efficacy and complications of uterine tamponade using condom catheter balloon in non-traumatic postpartum hemorrhage (PPH). MATERIAL AND METHODS: This prospective study was conducted in a tertiary care teaching hospital in India. Eighteen patients with non-traumatic PPH not responding to medical management were included in the study. Uterine tamponade was achieved by a condom catheter balloon filled with saline and kept in situ for 8-48 h. The main outcome measures were success rate in controlling hemorrhage, time required to stop bleeding, subsequent morbidity and technical difficulties. Data was analyzed using appropriate statistical methods. RESULTS: The success rate of condom catheter balloon in controlling hemorrhage was 94%. The mean amount of fluid filled in the condom catheter balloon was 409 mL. The average time taken to control bleeding was 6.2 min. The mean duration for which condom catheter balloon was left in situ was 27.5 h. The average amount of blood loss was 1330 mL. Five patients (28%) had infective morbidity. CONCLUSION: Condom catheter balloon is effective in controlling non-traumatic PPH in 94% cases. It is effective, simple to use, easily available and is a cheap modality to manage non-traumatic postpartum hemorrhage, especially in limited resource settings. PMID- 22540528 TI - Body dissatisfaction and body mass in girls and boys transitioning from early to mid-adolescence: additional role of self-esteem and eating habits. AB - BACKGROUND: In the transition from early to mid-adolescence, gender differences in pubertal development become significant. Body dissatisfaction is often associated with body mass, low self-esteem and abnormal eating habits. The majority of studies investigating body dissatisfaction and its associations have been conducted on female populations. However, some evidence suggests that males also suffer from these problems and that gender differences might already be observed in adolescence. AIMS: To examine body dissatisfaction and its relationship with body mass, as well as self-esteem and eating habits, in girls and boys in transition from early to mid-adolescence. METHODS: School nurses recorded the heights and weights of 659 girls and 711 boys with a mean age of 14.5 years. The Rosenberg Self-Esteem Scale and the Body Dissatisfaction subscale of the Eating Disorder Inventory were used as self-appraisal scales. Eating data were self-reported. RESULTS: The girls were less satisfied with their bodies than boys were with theirs (mean score (SD): 30.6 (SD 12.2) vs. 18.9 (SD 9.5); p < 0.001). The girls expressed most satisfaction with their bodies when they were underweight, more dissatisfaction when they were of normal weight and most dissatisfaction when they had excess body weight. The boys also expressed most satisfaction when they were underweight and most dissatisfaction when they had excess body weight. The boys reported higher levels of self-esteem than did the girls (mean (SD): 31.3 (4.8) vs. 28.0 (5.9); p < 0.001). The adolescents self reporting abnormal eating habits were less satisfied with their bodies than those describing normal eating habits (mean (SD): 33.0 (12.9) vs. 21.2 (10.2); p < 0.001). CONCLUSIONS: Body mass, self-esteem and eating habits revealed a significant relationship with body dissatisfaction in the transitional phase from early to mid-adolescence in girls and boys, but significant gender differences were also found. PMID- 22540530 TI - Oil and fatty acid contents in seed of Citrullus lanatus Schrad. AB - Intact seed of 475 genebank accessions of Citrullus ( C. lanatus var. lanatus and C. lanatus var. citroides) were analyzed for percent oil content using TD NMR. Extracts from whole seed of 96 accessions of C. lanatus (30 var. citroides, 33 var. lanatus, and 33 egusi), C. colocynthis (n = 3), C. ecirrhosus (n = 1), C. rehmii (n = 1), and Benincasa fistulosa (n = 3) were also analyzed for their fatty acids content. Among the materials analyzed, seed oil content varied from 14.8 to 43.5%. Mean seed oil content in egusi types of C. lanatus was significantly higher (mean = 35.6%) than that of either var. lanatus (mean = 23.2%) or var. citroides (mean = 22.6%). Egusi types of C. lanatus had a significantly lower hull/kernel ratio when compared to other C. lanatus var. lanatus or C. lanatus var. citroides. The principal fatty acid in all C. lanatus materials examined was linoleic acid (43.6-73%). High levels of linoleic acid were also present in the materials of C. colocynthis (71%), C. ecirrhosus (62.7%), C. rehmii (75.8%), and B. fistulosa (73.2%), which were included for comparative purposes. Most all samples contained traces (<0.5%) of arachidonic acid. The data presented provide novel information on the range in oil content and variability in the concentrations of individual fatty acids present in a diverse array of C. lanatus, and its related species, germplasm. PMID- 22540531 TI - Use of potentiometric sensors to study (bio)molecular interactions. AB - Potentiometric sensors were used to study molecular interactions in liquid environments with sensorgram methodology. This is demonstrated with a lipophilic rubber-based and a collagen-based hydrogel sensor coating. The investigated molecules were promazine and tartaric acid, respectively. The sensors were placed in a hydrodynamic wall-jet system for the recording of sensorgrams. Millivolt sensor responses were first converted to a signal, expressing the concentration of adsorbed organic ions. Using a linearization method, a pseudo-first order kinetic model of adsorption was shown to fit the experimental results perfectly. K(assoc), k(on), and k(off) values were calculated. The technique can be used over 4 decades of concentration, and it is very sensitive to low-MW compounds as well as to multiply charged large biomolecules. This study is the first to demonstrate the application of potentiometric sensors as an alternative and complement to surface plasmon resonance methods. PMID- 22540533 TI - Is laparoscopic right colectomy more effective than open resection? A meta analysis of randomized and nonrandomized studies. AB - AIM: The aim of this systematic review was to compare laparoscopic and/or laparoscopic-assisted right colectomy (LRC) with open right colectomy (ORC). Many randomized clinical trial have shown that laparoscopic colectomy benefits patients with improved short-term outcomes and comparable overall survival in respect to the open approach. These results, however, could not be applied to right colectomy owing to its wide range of resection and more complicated vascular regional anatomy. METHOD: We performed a meta-analysis of the literature in order to compare LRC vs ORC by examining 21 end-points including operative and recovery outcomes, early postoperative mortality and morbidity, and oncological parameters. A subgroup analysis of patients undergoing right colectomy for cancer was carried out. The meta-analysis was conducted following all aspects of the Cochrane Handbook for systematic reviews and Preferred Reporting Items for Systematic Reviews and Metanalysis (PRISMA) statement. The search strategies were developed using the following electronic databases: PubMed, EMBASE, OVID, Medline, Cochrane Database of Systematic Reviews, EBM reviews and CINAHL until March 2011. We included randomized and non randomized studies that compared the LRC vs ORC for benign disease and malignant neoplasm irrespective of publication status. Only studies in English, French, German, Spanish and Italian languages were considered for inclusion. Emergency right colectomies were excluded. To perform the statistical analysis we used the odds ratio (OR) for categorical variables and the weighted mean difference (WMD) for continuous variables. An intention-to-treat analysis was performed. RESULTS: Seventeen studies, 15 nonrandomized clinical trials and two randomized clinical trials, involving a total of 1489 patients, were identified. The mean operative time was longer in the group of patients undergoing LRC [weighted mean difference (WMD) = 37.94, 95% CI: 25.01 to 50.88; P < 0.00001]. Intra-operative blood loss (WMD = -96.61; 95% CI: -150.68 to -42.54; P = 0.0005), length of hospital stay (WMD = -2.29; 95% CI: -3.96 to -0.63; P = 0.007) and short-term postoperative morbidity (OR = 0.64; 95% CI: 0.49 to 0.83; P = 0.0009) were significantly in favour of LRC. CONCLUSION: Laparoscopic-assisted right colectomy results in less blood loss, a shorter length of hospital stay and lower postoperative short-term morbidity compared with ORC. PMID- 22540532 TI - Reactive oxygen species and thiol redox signaling in the macrophage biology of atherosclerosis. AB - SIGNIFICANCE: Despite the recent decline in the prevalence of cardiovascular diseases, atherosclerosis remains the leading cause of death in industrialized countries. Monocyte recruitment into the vessel wall is a rate-limiting step in atherogenesis. Death of macrophage-derived foam cells promotes lesion progression and the majority of acute complications of atherosclerotic disease (e.g., myocardial infarction) occur in lesions that are intensely infiltrated with monocyte-derived macrophages, underlining the critical roles monocytes and macrophages play in this complex chronic inflammatory disease. RECENT ADVANCES: A rapidly growing body of literature supports a critical role for reactive oxygen species (ROS) in the regulation of monocyte and macrophage (dys)function associated with atherogenesis and macrophage death in atherosclerotic plaque. CRITICAL ISSUES: In this review we highlight the important roles of NADHP oxidase 4 recently identified in monocytes and macrophages and the role of ROS and (thiol) redox signaling in different aspects of monocytes and macrophage biology associated with atherosclerosis. FUTURE DIRECTIONS: Studies aimed at identifying the intracellular targets of ROS involved in redox signaling in macrophages and at elucidating the redox signaling mechanisms that control differentiation, activation, polarization, and death of monocytes and macrophages may ultimately lead to the development of novel preventive and therapeutic strategies for atherosclerosis. PMID- 22540534 TI - Adolescent suicide risk screening: the effect of communication about type of follow-up on adolescents' screening responses. AB - This experimental study examined the effect of communication about type of screening follow-up (in-person follow-up vs. no in-person follow-up) on adolescents' responses to a self-report suicide risk screen. Participants were 245 adolescents (131 girls, 114 boys; ages 13-17; 80% White, 21.6% Black, 9.8% American Indian, 2.9% Asian) seeking medical emergency services. They were randomized to a screening follow-up condition. Screening measures assessed primary risk factors for suicidal behavior, including suicidal thoughts, depressive symptoms, alcohol use, and aggressive/delinquent behavior. There was no main effect of follow-up condition on adolescents' screening scores; however, significant interactions between follow-up condition and public assistance status were evident. Adolescents whose families received public assistance were less likely to report aggressive-delinquent behavior if assigned to in-person follow up. Adolescents whose families did not receive public assistance reported significantly higher levels of suicidal ideation if assigned to in-person follow up. Findings suggest that response biases impact some adolescents' responses to suicide risk screenings. Because national policy strongly recommends suicide risk screening in emergency settings, and because screening scores are used to make critical decisions regarding risk management and treatment recommendations, findings indicate the importance of improving the reliability and validity of suicide risk screening for adolescents. PMID- 22540536 TI - Combined sewer overflows: an environmental source of hormones and wastewater micropollutants. AB - Data were collected at a wastewater treatment plant (WWTP) in Burlington, Vermont, USA, (serving 30,000 people) to assess the relative contribution of CSO (combined sewer overflow) bypass flows and treated wastewater effluent to the load of steroid hormones and other wastewater micropollutants (WMPs) from a WWTP to a lake. Flow-weighted composite samples were collected over a 13 month period at this WWTP from CSO bypass flows or plant influent flows (n = 28) and treated effluent discharges (n = 22). Although CSO discharges represent 10% of the total annual water discharge (CSO plus treated plant effluent discharges) from the WWTP, CSO discharges contribute 40-90% of the annual load for hormones and WMPs with high (>90%) wastewater treatment removal efficiency. By contrast, compounds with low removal efficiencies (<90%) have less than 10% of annual load contributed by CSO discharges. Concentrations of estrogens, androgens, and WMPs generally are 10 times higher in CSO discharges compared to treated wastewater discharges. Compound concentrations in samples of CSO discharges generally decrease with increasing flow because of wastewater dilution by rainfall runoff. By contrast, concentrations of hormones and many WMPs in samples from treated discharges can increase with increasing flow due to decreasing removal efficiency. PMID- 22540537 TI - Persistent Mullerian duct syndrome: lessons learned from managing a series of eight patients over a 10-year period and review of literature regarding malignant risk from the Mullerian remnants. AB - Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? Approximately 200 cases of persistent Mullerian duct syndrome have been reported over the last 50 years and most authors suggest leaving the Mullerian remnant in situ because of the difficulty in dissection and the presumed absence of risk of malignancy. However, with increasing reports of Mullerian malignancies emerging, we report our 10-year experience of managing patients with persistent Mullerian duct syndrome, with removal of mullerian remnants. This case series shows that there is an increased risk of Mullerian malignancy that was previously unknown. With the laparoscopic approach, orchidopexy with simultaneous removal of Mullerian remnants could be accomplished with minimal surgical trauma and the benefit of no malignancy risk in the future. This is a new technique that has not been previously performed. Considering the current evidence of malignancy in the Mullerian remnant, surgeons would need to discuss with families about removal of remnants or long-term monitoring. OBJECTIVES: * To describe the presentation and management of eight patients with persistent Mullerian duct syndrome (PMDS) seen over a 10-year period at our tertiary centre. * To review the literature of Mullerian malignancies reported in PMDS. PATIENTS AND METHODS: * The hospital records of eight patients with PMDS were retrospectively reviewed between 2001 and 2011. * Extensive PubMed searches for PMDS and Mullerian malignancy were performed. RESULTS: * Eleven cases with PMDS and malignancy of the Mullerian remnants were identified. * From our own PMDS series: five males presented with bilateral undescended testes and three had unilateral undescended testis. * We found that the Mullerian remnants could be removed by laparoscopy and three patients had simultaneous laparoscopic removal of the Mullerian structures and laparoscopic orchidopexy. CONCLUSIONS: * The principle aim of orchidopexy with simultaneous laparoscopic removal of the Mullerian structures can be accomplished with minimal surgical trauma and the benefit of no malignancy risk in the future. * Surgeons should consider excision of the Mullerian remnants where possible. PMID- 22540538 TI - Method for predicting human intestinal first-pass metabolism of UGT substrate compounds. AB - 1. As intestinal glucuronidation has been suggested to generate the low oral bioavailability (F) of drugs, estimating its effects would be valuable for selecting drug candidates. Here, we investigated the absorption and intestinal availability (F(a)F(g)) in animals, and intrinsic clearance via UDP glucuronosyltransferase (UGT) in intestinal microsomes (CL(int,UGT)) for three drug candidates possessing a carboxylic acid group, in an attempt to estimate the impact of intestinal glucuronidation on F and select potential drug candidates with high F in humans. 2. The F(a)F(g) values of the three test compounds were low in rats and monkeys (0.16-0.51), and high in dogs (>=0.81). Correspondingly, the CL(int,UGT) values were high in rats and monkeys (101-731 uL/min/mg), and low in dogs (<= 59.6 uL/min/mg). A good inverse correlation was observed between F(a)F(g) and CL(int,UGT), suggesting that intestinal glucuronidation was a major factor influencing F(a)F(g) of these compounds. 3. By applying this correlation to F(a)F(g) in humans using human CL(int,UGT) values (26.9-114 uL/min/mg), compounds 1-3 were predicted to have relatively high F(a)F(g). 4. Our approach is expected to be useful for estimating the impact of intestinal glucuronidation on F in animals and semiquantitatively predicting human F for drug candidates. PMID- 22540557 TI - Entanglement entropy of highly degenerate States and fractal dimensions. AB - We consider the bipartite entanglement entropy of ground states of extended quantum systems with a large degeneracy. Often, as when there is a spontaneously broken global Lie group symmetry, basis elements of the lowest-energy space form a natural geometrical structure. For instance, the spins of a spin-1/2 representation, pointing in various directions, form a sphere. We show that for subsystems with a large number m of local degrees of freedom, the entanglement entropy diverges as d/2 logm, where d is the fractal dimension of the subset of basis elements with nonzero coefficients. We interpret this result by seeing d as the (not necessarily integer) number of zero-energy Goldstone bosons describing the ground state. We suggest that this result holds quite generally for largely degenerate ground states, with potential applications to spin glasses and quenched disorder. PMID- 22540535 TI - The role of Borrelia burgdorferi outer surface proteins. AB - Human pathogenic spirochetes causing Lyme disease belong to the Borrelia burgdorferi sensu lato complex. Borrelia burgdorferi organisms are extracellular pathogens transmitted to humans through the bite of Ixodes spp. ticks. These spirochetes are unique in that they can cause chronic infection and persist in the infected human, even though a robust humoral and cellular immune response is produced by the infected host. How this extracellular pathogen is able to evade the host immune response for such long periods of time is currently unclear. To gain a better understanding of how this organism persists in the infected human, many laboratories have focused on identifying and characterizing outer surface proteins of B. burgdorferi. As the interface between B. burgdorferi and its human host is its outer surface, proteins localized to the outer membrane must play an important role in dissemination, virulence, tissue tropism, and immune evasion. Over the last two decades, numerous outer surface proteins from B. burgdorferi have been identified, and more recent studies have begun to elucidate the functional role(s) of many borrelial outer surface proteins. This review summarizes the outer surface proteins identified in B. burgdorferi to date and provides detailed insight into the functions of many of these proteins as they relate to the unique parasitic strategy of this spirochetal pathogen. PMID- 22540559 TI - Relativistic Hall effect. AB - We consider the relativistic deformation of quantum waves and mechanical bodies carrying intrinsic angular momentum (AM). When observed in a moving reference frame, the centroid of the object undergoes an AM-dependent transverse shift. This is the relativistic analogue of the spin-Hall effect, which occurs in free space without any external fields. Remarkably, the shifts of the geometric and energy centroids differ by a factor of 2, and both centroids are crucial for the Lorentz transformations of the AM tensor. We examine manifestations of the relativistic Hall effect in quantum vortices and mechanical flywheels and also discuss various fundamental aspects of this phenomenon. The perfect agreement of quantum and relativistic approaches allows applications at strikingly different scales, from elementary spinning particles, through classical light, to rotating black holes. PMID- 22540540 TI - Rodent motor and neuropsychological behaviour measured in home cages using the integrated modular platform SmartCageTM. AB - 1. To facilitate investigation of diverse rodent behaviours in rodents' home cages, we have developed an integrated modular platform, the SmartCage(TM) system (AfaSci, Inc. Burlingame, CA, USA), which enables automated neurobehavioural phenotypic analysis and in vivo drug screening in a relatively higher-throughput and more objective manner. 2, The individual platform consists of an infrared array, a vibration floor sensor and a variety of modular devices. One computer can simultaneously operate up to 16 platforms via USB cables. 3. The SmartCage(TM) detects drug-induced increases and decreases in activity levels, as well as changes in movement patterns. Wake and sleep states of mice can be detected using the vibration floor sensor. The arousal state classification achieved up to 98% accuracy compared with results obtained by electroencephalography and electromyography. More complex behaviours, including motor coordination, anxiety-related behaviours and social approach behaviour, can be assessed using appropriate modular devices and the results obtained are comparable with results obtained using conventional methods. 4. In conclusion, the SmartCage(TM) system provides an automated and accurate tool to quantify various rodent behaviours in a 'stress-free' environment. This system, combined with the validated testing protocols, offers powerful a tool kit for transgenic phenotyping and in vivo drug screening. PMID- 22540558 TI - Entangled and sequential quantum protocols with dephasing. AB - Sequences of commuting quantum operators can be parallelized using entanglement. This transformation is behind some optimal quantum metrology protocols and recent results on quantum circuit complexity. We show that dephasing quantum maps in arbitrary dimension can also be parallelized. This implies that for general dephasing noise the protocol with entanglement is not more fragile than the corresponding sequential protocol and, conversely, the sequential protocol is not less effective than the entangled one. We derive this result using tensor networks. Furthermore, we only use transformations strictly valid within string diagrams in dagger compact closed categories. Therefore, they apply verbatim to other theories, such as geometric quantization and topological quantum field theory. This clarifies and characterizes to some extent the role of entanglement in general quantum theories. PMID- 22540539 TI - Distinct endothelial pathways underlie sexual dimorphism in vascular auto regulation. AB - BACKGROUND AND PURPOSE: Pre-menopausal females have a lower incidence of cardiovascular disease compared with age-matched males, implying differences in the mechanisms and pathways regulating vasoactivity. In small arteries, myogenic tone (constriction in response to raised intraluminal pressure) is a major determinant of vascular resistance. Endothelium-derived dilators, particularly NO, tonically moderate myogenic tone and, because the endothelium is an important target for female sex hormones, we investigated whether NO-mediated moderation of myogenic tone differed between the sexes. EXPERIMENTAL APPROACH: Pressure diameter or relaxation concentration-response curves to the NO donor spermine-NO or soluble guanylate cyclase (sGC) stimulation (BAY41-2272) were constructed before and following drug intervention in murine mesenteric resistance arteries. Hypotensive responses to activators of the NO-sGC pathway were determined. Quantitative PCR and Western blotting were used for expression analysis. KEY RESULTS: NO synthase inhibition enhanced myogenic tone of arteries of both sexes while block of endothelium-derived hyperpolarizing factor (EDHF) enhanced responses in arteries of females only. Spermine-NO concentration-dependently relaxed mesenteric arteries isolated from either sex. However, while inhibition of sGC activity attenuated responses of arteries from male mice only, endothelial denudation attenuated responses of arteries from females only. BAY41-2272 and spermine-NO-induced vasodilatation and hypotension were greater in males than in females. CONCLUSIONS AND IMPLICATIONS: NO moderated myogenic tone in arteries of male mice by a sGC-dependent pathway while EDHF was the predominant endothelial regulator in arteries of females. This is a potentially important sexual dimorphism in NO-mediated reactivity and further implicates EDHF as the predominant endothelial vasodilator in female resistance arteries. PMID- 22540560 TI - Proposal for inverting the quantum cloning of photons. AB - We propose an experiment where a photon is first cloned by stimulated parametric down-conversion, making many (imperfect) copies, and then the cloning transformation is inverted, regenerating the original photon while destroying the copies. Focusing on the case where the initial photon is entangled with another photon, we study the conditions under which entanglement can be proven in the final state. The proposed experiment would provide a clear demonstration that quantum information is preserved in quantum cloning. It would furthermore allow a definitive experimental proof for micro-macro entanglement in the intermediate multiphoton state, which is still an outstanding challenge. Finally, it might provide a quantum detection technique for small differences in transmission (e.g., in biological samples), whose sensitivity scales better with the number of photons used than a classical transmission measurement. PMID- 22540461 TI - Search for signatures of extra dimensions in the diphoton mass spectrum at the large hadron collider. AB - A search for signatures of extra spatial dimensions in the diphoton invariant mass spectrum has been performed with the CMS detector at the LHC. No excess of events above the standard model expectation is observed using a data sample collected in proton-proton collisions at ?s=7 TeV corresponding to an integrated luminosity of 2.2 fb(-1). In the context of the large-extra-dimensions model, lower limits are set on the effective Planck scale in the range of 2.3-3.8 TeV at the 95% confidence level. These limits are the most restrictive bounds on virtual graviton exchange to date. The most restrictive lower limits to date are also set on the mass of the first graviton excitation in the Randall-Sundrum model in the range of 0.86-1.84 TeV, for values of the associated coupling parameter between 0.01 and 0.10. PMID- 22540561 TI - Ultrafast quantum gates in circuit QED. AB - We present a method to implement ultrafast two-qubit gates valid for the ultrastrong coupling and deep strong coupling regimes of light-matter interaction, considering state-of-the-art circuit quantum electrodynamics technology. Our proposal includes a suitable qubit architecture and is based on a four-step sequential displacement of the intracavity field, operating at a time proportional to the inverse of the resonator frequency. Through ab initio calculations, we show that these quantum gates can be performed at subnanosecond time scales while keeping a fidelity above 99%. PMID- 22540562 TI - Discord and nonclassicality in probabilistic theories. AB - Quantum discord quantifies nonclassical correlations in quantum states. We introduce discord for states in causal probabilistic theories, inspired by the original definition proposed by H. Ollivier and W. H. Zurek [Phys. Rev. Lett. 88, 017901 (2001)]. We show that the only probabilistic theory in which all states have null discord is classical probability theory. Non-null discord is then not just a quantum feature, but a generic signature of nonclassicality. PMID- 22540563 TI - Extracting dynamical equations from experimental data is NP hard. AB - The behavior of any physical system is governed by its underlying dynamical equations. Much of physics is concerned with discovering these dynamical equations and understanding their consequences. In this Letter, we show that, remarkably, identifying the underlying dynamical equation from any amount of experimental data, however precise, is a provably computationally hard problem (it is NP hard), both for classical and quantum mechanical systems. As a by product of this work, we give complexity-theoretic answers to both the quantum and classical embedding problems, two long-standing open problems in mathematics (the classical problem, in particular, dating back over 70 years). PMID- 22540564 TI - Inequalities generalizing the second law of thermodynamics for transitions between nonstationary states. AB - We discuss the consequences of a variant of the Hatano-Sasa relation in which a nonstationary distribution is used in place of the usual stationary one. We first show that this nonstationary distribution is related to a difference of traffic between the direct and dual dynamics. With this formalism, we extend the definition of the adiabatic and nonadiabatic entropies introduced by M. Esposito and C. Van den Broeck in Phys. Rev. Lett. 104, 090601 (2010) for the stationary case. We also obtain interesting second-law-like inequalities for transitions between nonstationary states. PMID- 22540565 TI - Cooling by heating: very hot thermal light can significantly cool quantum systems. AB - We introduce the idea of actually cooling quantum systems by means of incoherent thermal light, hence giving rise to a counterintuitive mechanism of "cooling by heating." In this effect, the mere incoherent occupation of a quantum mechanical mode serves as a trigger to enhance the coupling between other modes. This notion of effectively rendering states more coherent by driving with incoherent thermal quantum noise is applied here to the optomechanical setting, where this effect occurs most naturally. We discuss two ways of describing this situation, one of them making use of stochastic sampling of gaussian quantum states with respect to stationary classical stochastic processes. The potential of experimentally demonstrating this counterintuitive effect in optomechanical systems with present technology is sketched. PMID- 22540566 TI - Cooling by heating: refrigeration powered by photons. AB - We propose a new mechanism for refrigeration powered by photons. We identify the strong coupling regime for which maximum efficiency is achieved. In this case, the cooling flux is proportional to T in the low temperature limit T->0. PMID- 22540567 TI - Cavity optomechanical magnetometer. AB - A cavity optomechanical magnetometer is demonstrated. The magnetic-field-induced expansion of a magnetostrictive material is resonantly transduced onto the physical structure of a highly compliant optical microresonator and read out optically with ultrahigh sensitivity. A peak magnetic field sensitivity of 400 nT Hz(-1/2) is achieved, with theoretical modeling predicting the possibility of sensitivities below 1 pT Hz(-1/2). This chip-based magnetometer combines high sensitivity and large dynamic range with small size and room temperature operation. PMID- 22540568 TI - Single-ion nuclear clock for metrology at the 19th decimal place. AB - The 7.6(5) eV nuclear magnetic-dipole transition in a single 229Th3+ ion may provide the foundation for an optical clock of superb accuracy. A virtual clock transition composed of stretched states within the 5F(5/2) electronic ground level of both nuclear ground and isomeric manifolds is proposed. It is shown to offer unprecedented systematic shift suppression, allowing for clock performance with a total fractional inaccuracy approaching 1*10(-19). PMID- 22540569 TI - No-go theorem for critical phenomena in large-N(c) QCD. AB - We derive some rigorous results on the chiral phase transition in QCD and QCD like theories with a large number of colors, N(c), based on the QCD inequalities and the large-N(c) orbifold equivalence. We show that critical phenomena and associated soft modes are forbidden in flavor-symmetric QCD at finite temperature T and finite but not so large quark chemical potential MU for any nonzero quark mass. In particular, the critical point in QCD at a finite baryon chemical potential MU(B)=N(c)MU is ruled out, if the coordinate (T, MU) is outside the pion condensed phase in the corresponding phase diagram of QCD at a finite isospin chemical potential MU(I)=2MU. PMID- 22540570 TI - Next-to-next-to-leading-order charm-quark contribution to the CP violation parameter epsilon(K) and DeltaM(K). AB - The observables epsilon(K) and DeltaM(K) play a prominent role in particle physics due to their sensitivity to new physics at short distances. To take advantage of this potential, a firm theoretical prediction of the standard-model background is essential. The charm-quark contribution is a major source of theoretical uncertainty. We address this issue by performing a next-to-next-to leading-order QCD analysis of the charm-quark contribution eta(cc) to the effective |DeltaS|=2 Hamiltonian in the standard model. We find a large positive shift of 36%, leading to eta(cc)=1.87(76). This result might cast doubt on the validity of the perturbative expansion; we discuss possible solutions. Finally, we give an updated value of the standard-model prediction for |epsilon(K)|=1.81(28)*10(-3) and DeltaM(K)(SD)=3.1(1.2)*10(-15) GeV. PMID- 22540574 TI - Ratio m(c)/m(s) with Wilson fermions. AB - We determine the quark mass ratio m(c)/m(s) on the lattice, using Wilson-type fermions. Configurations with N(f)=2 dynamical clover-improved fermions by the QCDSF Collaboration are used, which were made available through the ILDG. In the valence sector we use a sophisticated, mass-independently O(a)-improved Wilson type action with small cutoff effects even in the charm mass region. After an extrapolation to the physical pion mass, to zero lattice spacing and to infinite box volume, we find m(c)/m(s)=11.27(30)(26). PMID- 22540575 TI - One-loop factorization for inclusive hadron production in p-A collisions in the saturation formalism. AB - We demonstrate the QCD factorization for inclusive hadron production in p-A collisions in the saturation formalism at one-loop order, with explicit calculation of both real and virtual gluon radiation diagrams. In particular, we find that the cross section can be written into a factorization form in the coordinate space at the next-to-leading order, while the naive form of the convolution in the transverse momentum space does not hold. The collinear divergences associated with the incoming parton distribution of the nucleon and the outgoing fragmentation function of the final-state hadron, as well as the rapidity divergence with small-x dipole gluon distribution of the nucleus are factorized into the splittings of the associated parton distribution and fragmentation functions and the energy evolution of the dipole gluon distribution function. The hard coefficient function is evaluated at one-loop order, and contains no divergence. PMID- 22540573 TI - Measurement of the parity-violating asymmetry in inclusive electroproduction of pi- near the Delta0 resonance. AB - The parity-violating (PV) asymmetry of inclusive pi- production in electron scattering from a liquid deuterium target was measured at backward angles. The measurement was conducted as a part of the G0 experiment, at a beam energy of 360 MeV. The physics process dominating pion production for these kinematics is quasifree photoproduction off the neutron via the Delta0 resonance. In the context of heavy-baryon chiral perturbation theory, this asymmetry is related to a low-energy constant d(Delta)- that characterizes the parity-violating gammaNDelta coupling. Zhu et al. calculated d(Delta)- in a model benchmarked by the large asymmetries seen in hyperon weak radiative decays, and predicted potentially large asymmetries for this process, ranging from A(gamma)-=-5.2 to +5.2 ppm. The measurement performed in this work leads to A(gamma)-=-0.36+/ 1.06+/-0.37+/-0.03 ppm (where sources of statistical, systematic and theoretical uncertainties are included), which would disfavor enchancements considered by Zhu et al. proportional to V(ud)/V(us). The measurement is part of a program of inelastic scattering measurements that were conducted by the G0 experiment, seeking to determine the N-Delta axial transition form factors using PV electron scattering. PMID- 22540572 TI - Observation of two charged bottomoniumlike resonances in Upsilon(5S) decays. AB - We report the observation of two narrow structures in the mass spectra of the pi(+/-)Upsilon(nS) (n=1, 2, 3) and pi(+/-)h(b)(mP) (m=1, 2) pairs that are produced in association with a single charged pion in Upsilon(5S) decays. The measured masses and widths of the two structures averaged over the five final states are M(1)=(10,607.2+/-2.0) MeV/c2, Gamma(1)=(18.4+/-2.4) MeV, and M(2)=(10,652.2+/-1.5) MeV/c2, Gamma(2)=(11.5+/-2.2) MeV. The results are obtained with a 121.4 fb(-1) data sample collected with the Belle detector in the vicinity of the Upsilon(5S) resonance at the KEKB asymmetric-energy e+ e- collider. PMID- 22540577 TI - Precision measurement of the 6He half-life and the weak axial current in nuclei. AB - Studies of 6He beta decay along with tritium can play an important role in testing ab initio nuclear wave-function calculations and may allow for fixing low energy constants in effective-field theories. Here, we present an improved determination of the 6He half-life to a relative precision of 3*10(-4). Our value of 806.89+/-0.11(stat)(-0.19syst)(+0.23) ms resolves a major discrepancy between previous measurements. Calculating the statistical rate function we determined the ft value to be 803.04(-0.23)(+0.26) s. The extracted Gamow-Teller matrix element agrees within a few percent with ab initio calculations. PMID- 22540576 TI - Probing configuration mixing in 12Be with Gamow-Teller transition strengths. AB - We present a novel technique for studying the quenching of shell gaps in exotic isotopes. The method is based on extracting Gamow-Teller (DeltaL=0, DeltaS=1) transition strengths [B(GT)] to low-lying states from charge-exchange reactions at intermediate beam energies. These Gamow-Teller strengths are very sensitive to configuration mixing between cross-shell orbitals, and this technique thus provides an important complement to other tools currently used to study cross shell mixing. This work focuses on the N=8 shell gap. We populated the ground and 2.24 MeV 0+ states in 12Be using the 12B(1+) (7Li, 7Be) reaction at 80 MeV/u in inverse kinematics. Using the ground-state B(GT) value from beta-decay measurements (0.184+/-0.007) as a calibration, the B(GT) for the transition to the second 0+ state was determined to be 0.214+/-0.051. Comparing the extracted Gamow-Teller strengths with shell-model calculations, it was determined that the wave functions of the first and second 0+ states in 12Be are composed of 25+/-5% and 60+/-5% (0s)4(0p)8 configurations, respectively. PMID- 22540578 TI - X-ray fluorescence from the element with atomic number Z=120. AB - An atomic clock based on x-ray fluorescence yields has been used to estimate the mean characteristic time for fusion followed by fission in reactions 238U + 64Ni at 6.6 MeV/A. Inner shell vacancies are created during the collisions in the electronic structure of the possibly formed Z=120 compound nuclei. The filling of these vacancies accompanied by a x-ray emission with energies characteristic of Z=120 can take place only if the atomic transitions occur before nuclear fission. Therefore, the x-ray yield characteristic of the united atom with 120 protons is strongly related to the fission time and to the vacancy lifetimes. K x rays from the element with Z=120 have been unambiguously identified from a coupled analysis of the involved nuclear reaction mechanisms and of the measured photon spectra. A minimum mean fission time tau(f)=2.5*10(-18) s has been deduced for Z=120 from the measured x-ray multiplicity. PMID- 22540579 TI - Real-time observation of interference between atomic one-electron and two electron excitations. AB - We present results of real-time tracking of atomic two-electron dynamics in an autoionizing transient wave packet in krypton. A coherent superposition of two Fano resonances is excited with a femtosecond extreme-ultraviolet pulse. The evolution of the corresponding wave packet is subsequently probed with a delayed infrared pulse. In our specific case, we get access to the interference between one- and two-electron excitation channels in the launched wave packet, which is superimposed on its decay through autoionization. A simple model is able to account for the observed dynamical evolution of this wave packet. PMID- 22540580 TI - Controlled Dicke subradiance from a large cloud of two-level systems. AB - Dicke superradiance has been observed in many systems and is based on constructive interferences between many scattered waves. The counterpart of this enhanced dynamics, subradiance, is a destructive interference effect leading to the partial trapping of light in the system. In contrast to the robust superradiance, subradiant states are fragile, and spurious decoherence phenomena hitherto obstructed the observation of such metastable states. We show that a dilute cloud of cold atoms is an ideal system to look for subradiance in free space and study various mechanisms to control this subradiance. PMID- 22540581 TI - Generation of mesoscopic entangled states in a cavity coupled to an atomic ensemble. AB - We propose a novel scheme for the efficient production of entangled states for N photons of the form |N>(a)|0>(b) + |0>(a)|N>(b) (NOON states) based on the resonant interaction of a pair of quantized cavity modes with an ensemble of atoms. We show that, in the strong-coupling regime, the adiabatic evolution of the system tends to a limiting state that describes mesoscopic entanglement between photons and atoms which can easily be converted to a purely photonic or atomic NOON state. We also demonstrate the remarkable property that the efficiency of this scheme increases exponentially with the cavity cooperativity factor, which gives efficient access to high number NOON states. The experimental feasibility of the scheme is discussed, and its efficiency is demonstrated numerically. PMID- 22540582 TI - Giant Goos-Hanchen effect and Fano resonance at photonic crystal surfaces. AB - The Goos-Hanchen effect and Fano resonance are studied in photonic crystals that are considered Fourier counterparts in wave-vector-coordinate space. The Goos Hanchen effect, which is enhanced by the excitation of Bloch surface electromagnetic waves, is visualized using far-field microscopy and measured at the surface of photonic crystals by angular spectroscopy. The maximal Goos Hanchen shift is observed to be 66 MUm. PMID- 22540583 TI - Two-mode correlation of microwave quantum noise generated by parametric down conversion. AB - In this Letter, we report the observation of the correlation between two modes of microwave radiation resulting from the amplification of quantum noise by the Josephson parametric converter. This process, seen from the pump, can be viewed as parametric down-conversion. The correlation is measured by an interference experiment displaying a contrast better than 99% with a number of photons per mode greater than 250,000. Dispersive measurements of mesoscopic systems and quantum encryption can benefit from this development. PMID- 22540584 TI - Generation of elliptically polarized terahertz waves from laser-induced plasma with double helix electrodes. AB - By applying a helical electric field along a plasma region, a revolving electron current is formed along the plasma and an elliptically polarized far-field terahertz wave pattern is observed. The observed terahertz wave polarization reveals the remarkable role of velocity retardation between optical pulses and generated terahertz pulses in the generation process. Extensive simulations, including longitudinal propagation effects, are performed to clarify the mechanisms responsible for polarization control of air-plasma-based terahertz sources. PMID- 22540585 TI - Generation of high-energy few-cycle laser pulses by using the ionization-induced self-compression effect. AB - A mechanism behind the ionization-induced self-compression effect for ultrashort laser pulses propagating in gas-filled capillaries is proposed. It is shown that as a result of excitation of the nonlinear-plasma waveguide laser pulses producing gas ionization can be self-compressed to few-cycle duration. This effect is used for high-energy laser pulses and its scalability to J-level energies is demonstrated. PMID- 22540587 TI - Stability and angular-momentum transport of fluid flows between corotating cylinders. AB - Turbulent transport of angular momentum is a necessary process to explain accretion in astrophysical disks. Although the hydrodynamic stability of disklike flows has been tested in experiments, results are contradictory and suggest either laminar or turbulent flow. Direct numerical simulations reported here show that currently investigated laboratory flows are hydrodynamically unstable and become turbulent at low Reynolds numbers. The underlying instabilities stem from the axial boundary conditions, affect the flow globally, and enhance angular momentum transport. PMID- 22540586 TI - Anisotropic metamaterials for full control of acoustic waves. AB - We study a class of acoustic metamaterials formed by layers of perforated plates and producing negative refraction and backward propagation of sound. A slab of such material is shown to act as a perfect acoustic lens, yielding images with subwavelength resolution over large distances. Our study constitutes a nontrivial extension of similar concepts from optics to acoustics, capable of sustaining negative refraction over extended angular ranges, with potential application to enhanced imaging for medical and detection purposes, acoustofluidics, and sonochemistry. PMID- 22540589 TI - Influence of surface waves on plasma high-order harmonic generation. AB - The influence of surface plasma waves on high-order harmonic generation from the interaction of intense lasers with overdense plasma is analyzed. It is shown that the surface waves lead to the emission of harmonics away from the optical axis, whereas the high-order on-axis harmonics are lowered in intensity. Our simulation results indicate that surface plasma wave generation plays a crucial role in surface high-order harmonic generation experiments. Furthermore, a novel surface plasma wave generation process different from the well-known two-surface wave decay is observed in the highly relativistic regime. PMID- 22540588 TI - Strong flux of low-energy neutrons produced by thunderstorms. AB - We report here for the first time about the registration of an extraordinary high flux of low-energy neutrons generated during thunderstorms. The measured neutron count rate enhancements are directly connected with thunderstorm discharges. The low-energy neutron flux value obtained in our work is a challenge for the photonuclear channel of neutron generation in thunderstorm: the estimated value of the needed high-energy gamma-ray flux is about 3 orders of magnitude higher than that one observed. PMID- 22540571 TI - Search for charged massive long-lived particles. AB - We report on a search for charged massive long-lived particles (CMLLPs), based on 5.2 fb(-1) of integrated luminosity collected with the D0 detector at the Fermilab Tevatron pp collider. We search for events in which one or more particles are reconstructed as muons but have speed and ionization energy loss (dE/dx) inconsistent with muons produced in beam collisions. CMLLPs are predicted in several theories of physics beyond the standard model. We exclude pair produced long-lived gauginolike charginos below 267 GeV and Higgsino-like charginos below 217 GeV at 95% C.L., as well as long-lived scalar top quarks with mass below 285 GeV. PMID- 22540590 TI - Increasing hydrodynamic efficiency by reducing cross-beam energy transfer in direct-drive-implosion experiments. AB - A series of experiments to determine the optimum laser-beam radius by balancing the reduction of cross-beam energy transfer (CBET) with increased illumination nonuniformities shows that the hydrodynamic efficiency is increased by ~35%, which leads to a factor of 2.6 increase in the neutron yield when the laser-spot size is reduced by 20%. Over this range, the absorption is measured to increase by 15%, resulting in a 17% increase in the implosion velocity and a 10% earlier bang time. When reducing the ratio of laser-spot size to a target radius below 0.8, the rms amplitudes of the nonuniformities imposed by the smaller laser spots are measured at a convergence ratio of 2.5 to exceed 8 MUm and the neutron yield saturates despite increasing absorbed energy, implosion velocity, and decreasing bang time. The results agree well with hydrodynamic simulations that include both nonlocal and CBET models. PMID- 22540592 TI - Breaking of longitudinal Akhiezer-Polovin waves. AB - The breaking of longitudinal Akhiezer-Polovin (AP) waves is demonstrated using a one-dimensional simulation based on the Dawson sheet model. It is found that the AP longitudinal waves break through the process of phase mixing at an amplitude well below the breaking amplitude for AP waves, when subjected to arbitrarily small longitudinal perturbations. Results from the simulation show a good agreement with the Dawson phase mixing formula modified to include relativistic mass variation effects. This result may be of direct relevance to the laser- or particle-beam plasma wakefield experiments. PMID- 22540593 TI - Classical impurity ion confinement in a toroidal magnetized fusion plasma. AB - High-resolution measurements of impurity ion dynamics provide first-time evidence of classical ion confinement in a toroidal, magnetically confined plasma. The density profile evolution of fully stripped carbon is measured in MST reversed field pinch plasmas with reduced magnetic turbulence to assess Coulomb collisional transport without the neoclassical enhancement from particle drift effects. The impurity density profile evolves to a hollow shape, consistent with the temperature screening mechanism of classical transport. Corroborating methane pellet injection experiments expose the sensitivity of the impurity particle confinement time to the residual magnetic fluctuation amplitude. PMID- 22540594 TI - Calculation of transport coefficient profiles in modulation experiments as an inverse problem. AB - The calculation of transport profiles from experimental measurements belongs in the category of inverse problems which are known to come with issues of ill conditioning or singularity. A reformulation of the calculation, the matricial approach, is proposed for periodically modulated experiments, within the context of the standard advection-diffusion model where these issues are related to the vanishing of the determinant of a 2*2 matrix. This sheds light on the accuracy of calculations with transport codes, and provides a path for a more precise assessment of the profiles and of the related uncertainty. PMID- 22540595 TI - Spin-orbit-coupled dipolar Bose-Einstein condensates. AB - We propose an experimental scheme to create spin-orbit coupling in spin-3 Cr atoms using Raman processes. By employing the linear Zeeman effect and optical Stark shift, two spin states within the ground electronic manifold are selected, which results in a pseudospin-1/2 model. We further study the ground state structures of a spin-orbit-coupled Cr condensate. We show that, in addition to the stripe structures induced by the spin-orbit coupling, the magnetic dipole dipole interaction gives rise to the vortex phase, in which a spontaneous spin vortex is formed. PMID- 22540591 TI - Focusing of relativistic electrons in dense plasma using a resistivity-gradient generated magnetic switchyard. AB - A method for producing a self-generated magnetic focussing structure for a beam of laser-generated relativistic electrons using a complex array of resistivity gradients is proposed and demonstrated using numerical simulations. The array of resistivity gradients is created by using a target consisting of alternating layers of different Z material. This new scheme is capable of effectively focussing the fast electrons even when the source is highly divergent. The application of this technique to cone-guided fast ignition inertial confinement fusion is considered, and it is shown that it may be possible to deposit over 25% of the fast electron energy into a hot spot even when the fast electron divergence angle is very large (e.g., 70 degrees half-angle). PMID- 22540596 TI - Mixed molecular and atomic phase of dense hydrogen. AB - We used Raman and visible transmission spectroscopy to investigate dense hydrogen (deuterium) up to 315 (275) GPa at 300 K. At around 200 GPa, we observe the phase transformation, which we attribute to phase III, previously observed only at low temperatures. This is succeeded at 220 GPa by a reversible transformation to a new phase, IV, characterized by the simultaneous appearance of the second vibrational fundamental and new low-frequency phonon excitations and a dramatic softening and broadening of the first vibrational fundamental mode. The optical transmission spectra of phase IV show an overall increase of absorption and a closing band gap which reaches 1.8 eV at 315 GPa. Analysis of the Raman spectra suggests that phase IV is a mixture of graphenelike layers, consisting of elongated H2 dimers experiencing large pairing fluctuations, and unbound H2 molecules. PMID- 22540597 TI - Structure of polymeric carbon dioxide CO2-V. AB - The structure of polymeric carbon dioxide (CO2-V) has been solved using synchrotron x-ray powder diffraction, and its evolution followed from 8 to 65 GPa. We compare the experimental results obtained for a 100% CO2 sample and a 1 mol % CO2/He sample. The latter allows us to produce the polymer in a pure form and study its compressibility under hydrostatic conditions. The high quality of the x-ray data enables us to solve the structure directly from experiments. The latter is isomorphic to the beta-cristobalite phase of SiO2 with the space group I42d. Carbon and oxygen atoms are arranged in CO4 tetrahedral units linked by oxygen atoms at the corners. The bulk modulus determined under hydrostatic conditions, B0=136(10) GPa, is much smaller than previously reported. The comparison of our experimental findings with theoretical calculations performed in the present and previous studies shows that density functional theory very well describes polymeric CO2. PMID- 22540598 TI - Systematic study of Au6 to Au12 gold clusters on MgO(100) F centers using density functional theory. AB - We present an optimized genetic algorithm used in conjunction with density functional theory in the search for stable gold clusters and O2 adsorption ensembles in F centers at MgO(100). For Au8 the method recovers known structures and identifies several more stable ones. When O2 adsorption is investigated, the genetic algorithm is used to imitate structural fluxionality, increasing the O2 bond strength by up to 1 eV. Extending the method to Au(6,10,12), strong O2 adsorption configurations are found for all sizes. However, the effect of fluxionality appears to wear off with increasing cluster size. PMID- 22540599 TI - Nonisomorphic nucleation pathways arising from morphological transitions of liquid channels. AB - Motivated by unexpected morphologies of the emerging liquid phase (channels, bulges, droplets) at the edge of thin, melting alkane terraces, we propose a new heterogeneous nucleation pathway. The competition between bulk and interfacial energies and the boundary conditions determine the growth and shape of the liquid phase at the edge of the solid alkane terraces. Calculations and experiments reveal a "precritical" shape transition (channel-to-bulges) of the liquid before reaching its critical volume along a putative shape-conserving path. Bulk liquid emerges from the new shape, and, depending on the degree of supersaturation, the new pathway may have two, one, or zero energy barriers. The findings are broadly relevant for many heterogeneous nucleation processes because the novel pathway is induced by common, widespread surface topologies (scratches, steps, etc.). PMID- 22540600 TI - Frictional figures of merit for single layered nanostructures. AB - We determine the frictional figures of merit for a pair of layered honeycomb nanostructures, such as graphane, fluorographene, MoS2 and WO2 moving over each other, by carrying out ab initio calculations of interlayer interaction under constant loading force. Using the Prandtl-Tomlinson model we derive the critical stiffness required to avoid stick-slip behavior. We show that these layered structures have low critical stiffness even under high loading forces due to their charged surfaces repelling each other. The intrinsic stiffness of these materials exceeds critical stiffness and thereby the materials avoid the stick slip regime and attain nearly dissipationless continuous sliding. Remarkably, tungsten dioxide displays a much better performance relative to others and heralds a potential superlubricant. The absence of mechanical instabilities leading to conservative lateral forces is also confirmed directly by the simulations of sliding layers. PMID- 22540601 TI - Nonequilibrium charge susceptibility and dynamical conductance: identification of scattering processes in quantum transport. AB - We calculate the nonequilibrium charge transport properties of nanoscale junctions in the steady state and extend the concept of charge susceptibility to the nonequilibrium conditions. We show that the nonequilibrium charge susceptibility is related to the nonlinear dynamical conductance. In spectroscopic terms, both contain the same features versus applied bias when charge fluctuation occurs in the corresponding electronic resonances. However, we show that, while the conductance exhibits features at biases corresponding to inelastic scattering with no charge fluctuations, the nonequilibrium charge susceptibility does not. We suggest that measuring both the nonequilibrium conductance and charge susceptibility in the same experiment will permit us to differentiate between different scattering processes in quantum transport. PMID- 22540464 TI - Search for the standard model Higgs boson in the decay channel H->ZZ->4l in pp collisions at ?s=7 TeV. AB - A search for a Higgs boson in the four-lepton decay channel H->ZZ, with each Z boson decaying to an electron or muon pair, is reported. The search covers Higgs boson mass hypotheses in the range of 110100 GeV (with 13 below 160 GeV), while 67.1+/-6.0 (9.5+/-1.3) events are expected from background. The four-lepton mass distribution is consistent with the expectation of standard model background production of ZZ pairs. Upper limits at 95% confidence level exclude the standard model Higgs boson in the ranges of 134-158 GeV, 180-305 GeV, and 340-465 GeV. Small excesses of events are observed around masses of 119, 126, and 320 GeV, making the observed limits weaker than expected in the absence of a signal. PMID- 22540603 TI - Polariton condensation in photonic molecules. AB - We report on polariton condensation in photonic molecules formed by two coupled micropillars. We show that the condensation process is strongly affected by the interaction with the cloud of uncondensed excitons and thus strongly depends on the exact localization of these excitons within the molecule. Under symmetric excitation conditions, condensation is triggered on both binding and antibinding polariton states of the molecule. On the opposite, when the excitonic cloud is injected in one of the two pillars, condensation on a metastable state is observed and a total transfer of the condensate into one of the micropillars can be achieved. Our results highlight the crucial role played by relaxation kinetics in the condensation process. PMID- 22540602 TI - Nonuniform scaling applied to surface energies of transition metals. AB - We construct a generalized gradient approximation of the exchange-correlation energy that satisfies the nonuniform scaling in one dimension and is accurate in the whole quasi-two-dimensional (Q2D) regime. Using spatial and energetic analyses of metal (111) surfaces, we show that the Q2D behavior is important at the surface of most transition metals, and that the here proposed Q2D-generalized gradient approximation functional predicts for these metals accurate surface energies as well as bulk properties. PMID- 22540607 TI - Helicoidal fields and spin polarized currents in carbon nanotube-DNA hybrids. AB - We report on theoretical studies of electronic transport in the archetypical molecular hybrid formed by DNA wrapped around single-walled carbon nanotubes (CNTs). Using a Green's function formalism in a pi-orbital tight-binding representation, we investigate the role that spin-orbit interactions play on the CNT in the case of the helicoidal electric field induced by the polar nature of the adsorbed DNA molecule. We find that spin polarization of the current can take place in the absence of magnetic fields, depending strongly on the direction of the wrapping and length of the helicoidal field. These findings open new routes for using CNTs in spintronic devices. PMID- 22540605 TI - Fractional quantum-Hall liquid spontaneously generated by strongly correlated t(2g) electrons. AB - For topologically nontrivial and very narrow bands, Coulomb repulsion between electrons has been predicted to give rise to a spontaneous fractional quantum Hall (FQH) state in the absence of magnetic fields. Here we show that strongly correlated electrons in a t(2g)-orbital system on a triangular lattice self organize into a spin-chiral magnetic ordering pattern that induces precisely the required topologically nontrivial and flat bands. This behavior is very robust and does not rely on fine-tuning. In order to go beyond mean field and to study the impact of longer-range interactions, we map the low-energy electronic states onto an effective one-band model. Exact diagonalization is then used to establish signatures of a spontaneous FQH state. PMID- 22540606 TI - Phases of the infinite U Hubbard model on square lattices. AB - We apply the density matrix renormalization group to study the phase diagram of the infinite U Hubbard model on 2- to 6-leg ladders. Where the results are largely insensitive to the ladder width, we consider the results representative of the 2D square lattice. We find a fully polarized ferromagnetic Fermi liquid phase when n, the density of electrons per site, is in the range 1>n?0.800. For n=3/4 we find an unexpected insulating checkerboard phase with coexisting bond density order with 4 sites per unit cell and block-spin antiferromagnetic order with 8 sites per unit cell. For 3/4>n, all ladders with width >2 have unpolarized ground states. PMID- 22540608 TI - Exact exponents for the spin quantum Hall transition in the presence of multiple edge channels. AB - Critical properties of quantum Hall systems are affected by the presence of extra edge channels-those that are present, in particular, at higher plateau transitions. We study this phenomenon for the case of the spin quantum Hall transition. Using supersymmetry, we map the corresponding network model to a classical loop model, whose boundary critical behavior was recently determined exactly. We verify predictions of the exact solution by extensive numerical simulations. PMID- 22540604 TI - First-principles optical spectra for F centers in MgO. AB - The study of the oxygen vacancy (F center) in MgO has been aggravated by the fact that the positively charged and the neutral vacancy (F+ and F0, respectively) absorb at practically identical energies. Here we apply many-body perturbation theory in the G0W0 approximation and the Bethe-Salpeter approach to calculate the optical absorption and emission spectrum of the oxygen vacancy in all three charge states. We observe unprecedented agreement between the calculated and the experimental optical absorption spectra for the F0 and F+ center. Our calculations reveal that not only the absorption but also the emission spectra of different charge states peak at nearly the same energy, which leads to a reinterpretation of the F center's optical properties. PMID- 22540609 TI - Dynamical Coulomb blockade observed in nanosized electrical contacts. AB - Electrical contacts between nanoengineered systems are expected to constitute the basic building blocks of future nanoscale electronics. However, the accurate characterization and understanding of electrical contacts at the nanoscale is an experimentally challenging task. Here, we employ low-temperature scanning tunneling spectroscopy to investigate the conductance of individual nanocontacts formed between flat Pb islands and their supporting substrates. We observe a suppression of the differential tunnel conductance at small bias voltages due to dynamical Coulomb blockade effects. The differential conductance spectra allow us to determine the capacitances and resistances of the electrical contacts which depend systematically on the island-substrate contact area. Calculations based on the theory of environmentally assisted tunneling agree well with the measurements. PMID- 22540610 TI - Intrinsic nature of the excess electron distribution at the TiO2(110) surface. AB - The gap state that appears upon reduction of TiO2 plays a key role in many of titania's interesting properties but its origin and spatial localization have remained unclear. In the present work, the TiO2(110) surface is reduced in a chemically controlled way by sodium adsorption. By means of resonant photoelectron diffraction, excess electrons are shown to be distributed mainly on subsurface Ti sites strikingly similar to the defective TiO2(110) surface, while any significant contribution from interstitial Ti ions is discarded. In agreement with first principles calculations, these findings demonstrate that the distribution of the band gap charge is an intrinsic property of TiO2(110), independent of the way excess electrons are produced. PMID- 22540611 TI - Valley-based noise-resistant quantum computation using Si quantum dots. AB - We devise a platform for noise-resistant quantum computing using the valley degree of freedom of Si quantum dots. The qubit is encoded in two polarized (1,1) spin-triplet states with different valley compositions in a double quantum dot, with a Zeeman field enabling unambiguous initialization. A top gate gives a difference in the valley splitting between the dots, allowing controllable interdot tunneling between opposite valley eigenstates, which enables one-qubit rotations. Two-qubit operations rely on a stripline resonator, and readout on charge sensing. Sensitivity to charge and spin fluctuations is determined by intervalley processes and is greatly reduced as compared to conventional spin and charge qubits. We describe a valley echo for further noise suppression. PMID- 22540612 TI - Non-abelian quantum Hall effect in topological flat bands. AB - Inspired by the recent theoretical discovery of robust fractional topological phases without a magnetic field, we search for the non-abelian quantum Hall effect in lattice models with topological flat bands. Through extensive numerical studies on the Haldane model with three-body hard-core bosons loaded into a topological flat band, we find convincing numerical evidence of a stable nu=1 bosonic non-abelian quantum Hall effect, with the characteristic threefold quasidegeneracy of ground states on a torus, a quantized Chern number, and a robust spectrum gap. Moreover, the spectrum for two-quasihole states also shows a finite energy gap, with the number of states in the lower-energy sector satisfying the same counting rule as the Moore-Read pfaffian state. PMID- 22540613 TI - Exchange-coupled donor dimers in nanocrystal quantum dots. AB - Doping of semiconductor nanocrystals (NCs) is expected to enable the control of key NC properties, yet its practical exploitation requires an understanding of exchange interactions when multiple dopants are incorporated in a single NC. Here, we experimentally probe the exchange of donor dimers in NCs via a deviation of their triplet-state magnetic resonance from Curie paramagnetism. We show that the exchange coupling of the closely spaced donors can be well described by effective mass theory, which allows the consideration of statistical effects crucial in NC ensembles. While a dimer induces discrete states in a NC, their energy splitting differs by up to 3 orders of magnitude for randomly placed dimers in a NC ensemble, due to an enormous dependence of the exchange energy on the dimer configuration. PMID- 22540614 TI - Topological insulators in magnetic fields: quantum Hall effect and edge channels with a nonquantized theta term. AB - We investigate how a magnetic field induces one-dimensional edge channels when the two-dimensional surface states of three-dimensional topological insulators become gapped. The Hall effect, measured by contacting those channels, remains quantized even in situations where the theta term in the bulk and the associated surface Hall conductivities, sigma(xy)(S), are not quantized due to the breaking of time-reversal symmetry. The quantization arises as the theta term changes by +/-2pin along a loop around n edge channels. Model calculations show how an interplay of orbital and Zeeman effects leads to quantum Hall transitions, where channels get redistributed along the edges of the crystal. The network of edges opens new possibilities to investigate the coupling of edge channels. PMID- 22540615 TI - Discretization of electronic states in large InAsP/InP multilevel quantum dots probed by scanning tunneling spectroscopy. AB - The topography and the electronic structure of InAsP/InP quantum dots are probed by cross-sectional scanning tunneling microscopy and spectroscopy. The study of the local density of states in such large quantum dots confirms the discrete nature of the electronic levels whose wave functions are measured by differential conductivity mapping. Because of their large dimensions, the energy separation between the discrete electronic levels is low, allowing for quantization in both the lateral and growth directions as well as the observation of the harmonicity of the dot lateral potential. PMID- 22540616 TI - Probing the unconventional superconducting state of LiFeAs by quasiparticle interference. AB - A crucial step in revealing the nature of unconventional superconductivity is to investigate the symmetry of the superconducting order parameter. Scanning tunneling spectroscopy has proven a powerful technique to probe this symmetry by measuring the quasiparticle interference (QPI) which sensitively depends on the superconducting pairing mechanism. A particularly well-suited material to apply this technique is the stoichiometric superconductor LiFeAs as it features clean, charge neutral cleaved surfaces without surface states and a relatively high T(c)~18 K. Our data reveal that in LiFeAs the quasiparticle scattering is governed by a van Hove singularity at the center of the Brillouin zone which is in stark contrast to other pnictide superconductors where nesting is crucial for both scattering and s(+/-) superconductivity. Indeed, within a minimal model and using the most elementary order parameters, calculations of the QPI suggest a dominating role of the holelike bands for the quasiparticle scattering. Our theoretical findings do not support the elementary singlet pairing symmetries s(++), s(+/-), and d wave. This brings to mind that the superconducting pairing mechanism in LiFeAs is based on an unusual pairing symmetry such as an elementary p wave (which provides optimal agreement between the experimental data and QPI simulations) or a more complex order parameter (e.g., s+id wave symmetry). PMID- 22540617 TI - Optimization of spin-triplet supercurrent in ferromagnetic Josephson junctions. AB - We have observed long-range spin-triplet supercurrents in Josephson junctions containing ferromagnetic (F) materials, which are generated by noncollinear magnetizations between a central Co/Ru/Co synthetic antiferromagnet and two outer thin F layers. Here we show that the spin-triplet supercurrent is enhanced up to 20 times after our samples are subject to a large in-plane field. This occurs because the synthetic antiferromagnet undergoes a "spin-flop" transition, whereby the two Co layer magnetizations end up nearly perpendicular to the magnetizations of the two thin F layers. We report direct experimental evidence for the spin flop transition from scanning electron microscopy with polarization analysis and from spin-polarized neutron reflectometry. These results represent a first step toward experimental control of spin-triplet supercurrents. PMID- 22540618 TI - Near-room-temperature colossal magnetodielectricity and multiglass properties in partially disordered La2NiMnO6. AB - We report magnetic, dielectric, and magnetodielectric responses of the pure monoclinic bulk phase of partially disordered La2NiMnO6, exhibiting a spectrum of unusual properties and establish that this compound is an intrinsically multiglass system with a large magnetodielectric coupling (8%-20%) over a wide range of temperatures (150-300 K). Specifically, our results establish a unique way to obtain colossal magnetodielectricity, independent of any striction effects, by engineering the asymmetric hopping contribution to the dielectric constant via the tuning of the relative-spin orientations between neighboring magnetic ions in a transition-metal oxide system. We discuss the role of antisite (Ni-Mn) disorder in emergence of these unusual properties. PMID- 22540619 TI - Antiferromagnetic spin-S chains with exactly dimerized ground states. AB - We show that spin S Heisenberg spin chains with an additional three-body interaction of the form (S(i-1).S(i))(S(i).S(i+1))+H.c. possess fully dimerized ground states if the ratio of the three-body interaction to the bilinear one is equal to 1/[4S(S+1)-2]. This result generalizes the Majumdar-Ghosh point of the J1-J2 chain, to which the present model reduces for S=1/2. For S=1, we use the density matrix renormalization group method to show that the transition between the Haldane and the dimerized phases is continuous with a central charge c=3/2. Finally, we show that such a three-body interaction appears naturally in a strong coupling expansion of the Hubbard model, and we discuss the consequences for the dimerization of actual antiferromagnetic chains. PMID- 22540620 TI - Relevance of the Heisenberg-Kitaev model for the honeycomb lattice iridates A2IrO3. AB - Combining thermodynamic measurements with theoretical calculations we demonstrate that the iridates A2IrO3 (A=Na, Li) are magnetically ordered Mott insulators where the magnetism of the effective spin-orbital S=1/2 moments can be captured by a Heisenberg-Kitaev (HK) model with interactions beyond nearest-neighbor exchange. Experimentally, we observe an increase of the Curie-Weiss temperature from theta~-125 K for Na2IrO3 to theta~-33 K for Li2IrO3, while the ordering temperature remains roughly the same T(N)~15 K. Using functional renormalization group calculations we show that this evolution of theta and T(N) as well as the low temperature zigzag magnetic order can be captured within this extended HK model. We estimate that Na2IrO3 is deep in a magnetically ordered regime, while Li2IrO3 appears to be close to a spin-liquid regime. PMID- 22540621 TI - Spin waves and revised crystal structure of honeycomb iridate Na2IrO3. AB - We report inelastic neutron scattering measurements on Na2IrO3, a candidate for the Kitaev spin model on the honeycomb lattice. We observe spin-wave excitations below 5 meV with a dispersion that can be accounted for by including substantial further-neighbor exchanges that stabilize zigzag magnetic order. The onset of long-range magnetic order below T(N)=15.3 K is confirmed via the observation of oscillations in zero-field muon-spin rotation experiments. Combining single crystal diffraction and density functional calculations we propose a revised crystal structure model with significant departures from the ideal 90 degrees Ir O-Ir bonds required for dominant Kitaev exchange. PMID- 22540622 TI - Role of magnetic circular dichroism in all-optical magnetic recording. AB - Using magneto-optical microscopy in combination with ellipsometry measurements, we show that all-optical switching with polarized femtosecond laser pulses in ferrimagnetic GdFeCo is subjected to a threshold fluence absorbed in the magnetic layer, independent of either the excitation wavelength or the polarization of the laser pulse. Furthermore, we present a quantitative explanation of the intensity window in which all-optical helicity-dependent switching (AO-HDS) occurs, based on magnetic circular dichroism. This explanation is consistent with all the experimental findings on AO-HDS so far, varying from single- to multiple-shot experiments. The presented results give a solid understanding of the origin of AO HDS, and give novel insights into the physics of ultrafast, laser controlled magnetism. PMID- 22540623 TI - Tailoring terahertz near-field enhancement via two-dimensional plasmons. AB - We suggest a novel possibility for electrically tunable terahertz near-field enhancement in flatland electronic materials supporting two-dimensional plasmons, including recently discovered graphene. We employ electric-field effect modulation of electron density in such materials and induce a periodic plasmonic lattice with a defect cavity. We demonstrate that the plasmons resonantly excited in such a periodic plasmonic lattice by an incident terahertz radiation can strongly pump the cavity plasmon modes leading to a deep subwavelength concentration of terahertz energy, beyond lambda/1000, with giant electric-field enhancement factors up to 10(4), which is 2 orders of magnitude higher than achieved previously in metal-based terahertz field concentrators. PMID- 22540624 TI - Plasmon scattering from single subwavelength holes. AB - We map the complex electric fields associated with the scattering of surface plasmon polaritons by single subwavelength holes of different sizes in thick gold films. We identify and quantify the different modes associated with this event, including a radial surface wave with an angularly isotropic amplitude. This wave is shown to arise from the out-of-plane electric dipole induced in the hole, and we quantify the corresponding polarizability, which is in excellent agreement with electromagnetic theory. Time-resolved measurements reveal a time delay of 38+/-18 fs between the surface plasmon polariton and the radial wave, which we attribute to the interaction with a broad hole resonance. PMID- 22540626 TI - Population genetics in compressible flows. AB - We study competition between two biological species advected by a compressible velocity field. Individuals are treated as discrete Lagrangian particles that reproduce or die in a density-dependent fashion. In the absence of a velocity field and fitness advantage, number fluctuations lead to a coarsening dynamics typical of the stochastic Fisher equation. We investigate three examples of compressible advecting fields: a shell model of turbulence, a sinusoidal velocity field and a linear velocity sink. In all cases, advection leads to a striking drop in the fixation time, as well as a large reduction in the global carrying capacity. We find localization on convergence zones, and very rapid extinction compared to well-mixed populations. For a linear velocity sink, one finds a bimodal distribution of fixation times. The long-lived states in this case are demixed configurations with a single interface, whose location depends on the fitness advantage. PMID- 22540627 TI - Exploring maps with greedy navigators. AB - During the last decade of network research focusing on structural and dynamical properties of networks, the role of network users has been more or less underestimated from the bird's-eye view of global perspective. In this era of global positioning system equipped smartphones, however, a user's ability to access local geometric information and find efficient pathways on networks plays a crucial role, rather than the globally optimal pathways. We present a simple greedy spatial navigation strategy as a probe to explore spatial networks. These greedy navigators use directional information in every move they take, without being trapped in a dead end based on their memory about previous routes. We suggest that the centralities measures have to be modified to incorporate the navigators' behavior, and present the intriguing effect of navigators' greediness where removing some edges may actually enhance the routing efficiency, which is reminiscent of Braess's paradox. In addition, using samples of road structures in large cities around the world, it is shown that the navigability measure we define reflects unique structural properties, which are not easy to predict from other topological characteristics. In this respect, we believe that our routing scheme significantly moves the routing problem on networks one step closer to reality, incorporating the inevitable incompleteness of navigators' information. PMID- 22540625 TI - Frequency-dependent Escherichia coli chemotaxis behavior. AB - We study Escherichia coli chemotaxis behavior in environments with spatially and temporally varying attractant sources by developing a unique microfluidic system. Our measurements reveal a frequency-dependent chemotaxis behavior. At low frequency, the E. coli population oscillates in synchrony with the attractant. In contrast, in fast-changing environments, the population response becomes smaller and out of phase with the attractant waveform. These observations are inconsistent with the well-known Keller-Segel chemotaxis equation. A new continuum model is proposed to describe the population level behavior of E. coli chemotaxis based on the underlying pathway dynamics. With the inclusion of a finite adaptation time and an attractant consumption rate, our model successfully explains the microfluidic experiments at different stimulus frequencies. PMID- 22540628 TI - Emergent criticality through adaptive information processing in boolean networks. AB - We study information processing in populations of boolean networks with evolving connectivity and systematically explore the interplay between the learning capability, robustness, the network topology, and the task complexity. We solve a long-standing open question and find computationally that, for large system sizes N, adaptive information processing drives the networks to a critical connectivity K(c)=2. For finite size networks, the connectivity approaches the critical value with a power law of the system size N. We show that network learning and generalization are optimized near criticality, given that the task complexity and the amount of information provided surpass threshold values. Both random and evolved networks exhibit maximal topological diversity near K(c). We hypothesize that this diversity supports efficient exploration and robustness of solutions. Also reflected in our observation is that the variance of the fitness values is maximal in critical network populations. Finally, we discuss implications of our results for determining the optimal topology of adaptive dynamical networks that solve computational tasks. PMID- 22540629 TI - Comment on "Size control of charge-orbital order in half-doped manganite La0:5Ca0:5MnO3. PMID- 22540631 TI - Enantioselective Rh(I)-catalyzed cyclization of arylboron compounds onto ketones. AB - Rhodium complexes based upon chiral sulfinamide-alkene, TADDOL-derived phosphoramidite, or diene ligands catalyze cyclizations of arylboron compounds onto ketones, generating a variety of products containing five-, six-, or seven membered rings with good yields and high enantioselectivities. PMID- 22540462 TI - Search for the Higgs boson in the H->WW(*)->l(+)nul(-)nu decay channel in pp collisions at ?s=7 TeV with the ATLAS detector. AB - A search for the Higgs boson has been performed in the H->WW(*)->l(+)nul( )nu[over -] channel (l=e/MU) with an integrated luminosity of 2.05 fb(-1) of pp collisions at ?s=7 TeV collected with the ATLAS detector at the Large Hadron Collider. No significant excess of events over the expected background is observed and limits on the Higgs boson production cross section are derived for a Higgs boson mass in the range 110 GeV=3 contractures caused by palpable cords. Efficacy assessments were taken 30 days after treatment and adverse events (AEs) were recorded throughout. In the first treatment period, all subjects were injected with a single dose of CCH (0.58 mg) into a single cord. The same subjects entered a second treatment period 30 days later, where two different cords (affected joints) were injected concurrently on the same hand. A finger extension procedure was performed 24 hours after each administration of CCH to disrupt the enzymatically weakened cord. RESULTS: For metacarpophalangeal (MP) joints, mean contracture reduction per joint treated was 29.0 +/- 20.7 degrees following single injection vs 30.3 +/- 10.9 degrees per treated joint following multiple injections. For proximal interphalangeal (PIP) joints, mean reduction in contracture was 30.7 +/- 21.1 and 22.1 +/- 4.9 degrees per treated joint, respectively, for the two periods. All patients (100%) were either "quite satisfied" or "very satisfied" following either treatment cycle. The most common treatment-related AEs were edema peripheral, contusion, and pain in the treated extremity; the differences in severity for local effects of the injections were minimal between treatment periods. No serious treatment-related AEs or systemic complications were reported. CONCLUSION: These results provide preliminary evidence that two cords (affected joints) can be treated concurrently with CCH with similar efficacy and safety as cords treated individually in a sequential fashion. Multiple concurrent injections would eliminate the 30-day wait between single treatments and allow for rapid and effective treatment of patients with multiple affected joints, a significant advantage for both patient and physician. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry #ACTRN12610001045000. PMID- 22540639 TI - Toxic/Hazardous substances and environmental engineering. Foreword. PMID- 22540635 TI - N-Acetylcysteine as an adjuvant to clomiphene citrate for successful induction of ovulation in infertile patients with polycystic ovary syndrome. AB - AIM: The aim of this study was to evaluate the effect of oral N-acetylcysteine (NAC) administration as an adjuvant to clomiphene citrate (CC) on induction of ovulation outcomes in patients with polycystic ovary syndrome (PCOS). MATERIAL AND METHODS: In this placebo-controlled double-blind randomized clinical trial, 180 PCOS infertile patients were randomly divided into two groups for induction of ovulation. Patients in group 1 received CC 100 mg/d plus NAC 1.2 g/d and patients in group 2 received CC plus placebo for 5 days starting at day 3 of the cycle. On the 12th day of the menstrual cycle in the presence of at least one follicle with an 18-20-mm diameter in ultrasound evaluation, 10,000 U hCG was injected intramuscularly and timed intercourse was advised 36 h after hCG injection. Serum beta-hCG level was measured on the 16th day after hCG injection. RESULTS: The number of follicles >18 mm and the mean endometrial thickness on the day of hCG administration were significantly higher among the CC+NAC group (P value = 0.001). The ovulation and pregnancy rates were also significantly higher in the CC+NAC group (P-value = 0.02 and 0.04, respectively). No adverse side effects and no cases of ovarian hyperstimulation syndrome were observed in the group receiving NAC. CONCLUSION: NAC as a safe and well-tolerated adjuvant to CC for induction of ovulation can improve the ovulation and pregnancy rates in PCOS patients. It may also have some beneficial impacts on endometrial thickness. PMID- 22540641 TI - Concentrations of selected trace elements in organs and tissues of livestock from a polluted area. AB - The occurrence of cadmium (Cd), nickel (Ni) and lead (Pb) from industrial emissions were determined in the muscle and liver of cattle from agricultural farms near an industrial plant in Eastern Slovakia. In this study cows (n = 25) were slaughtered and the concentrations of Cd, Ni, Pb were analyzed with a the atomic absorption spectrophotometer. Levels reaching the highest permissible hygiene limits for toxic metals Cd, Pb and Ni were determined in 50 samples. The maximum levels of Cd, Pb and Ni were recorded in the liver (0.865; 2.324; 1.140 mg/kg, respectively) and muscle (0.300; 0.854; 0.700 mg/kg, respectively). It was concluded that the exposure to an industrial plant significantly increases the levels of contaminants in the muscle and organs of cattle, as the most susceptible livestock. PMID- 22540640 TI - Accumulation of risk elements in kidney, liver, testis, uterus and bone of free living wild rodents from a polluted area in Slovakia. AB - Free-living wild rodents are usually used as indicators of pollution, with elements being determined in either whole body or in specific organs. In the present study, the accumulation of cadmium (Cd), copper (Cu), iron (Fe), and zinc (Zn) in kidney, liver, testis, uterus and bone of yellow-necked mice (Apodemus flavicollis) and bank voles (Myodes glareolus) trapped in a polluted area of Novaky, Slovakia was investigated. Yellow-necked mice and bank voles were collected using standard theriological methods for wood ecosystems. All animals were adults in good physical condition. Concentrations of Cd, Cu, Fe, and Zn in all analyzed organs were determined by atomic absorption spectrophotometry. The highest concentrations of Cd and Zn were found in the bone of both species while Cu and Fe accumulated most in the uterus. Significantly higher concentrations of Cd and Cu were detected in the liver of the bank vole in comparison with the yellow-necked mouse (P<0.05). Similar significantly higher levels of Cd and Zn were found in the bone of the bank vole (P<0.05) than in the yellow-necked mouse, while these rodents had significantly higher Cu and Fe concentrations (P<0.05) in the kidney. Significantly higher levels of Fe and Zn were detected in the testis and uterus of bank voles, respectively. On the other hand, significantly higher concentration of Cu was found in the testis of yellow-necked mice. Results of this study suggest that bank voles are more sensitive heavy metal loaded bioindicators than yellow-necked mice. PMID- 22540638 TI - Alcohol email assessment and feedback study dismantling effectiveness for university students (AMADEUS-1): study protocol for a randomized controlled trial. AB - BACKGROUND: Alcohol causes huge problems for population health and for society, which require interventions with individuals as well as populations to prevent and reduce harms. Brief interventions can be effective and increasingly take advantage of the internet to reach high-risk groups such as students. The research literature on the effectiveness of online interventions is developing rapidly and is confronted by methodological challenges common to other areas of e health including attrition and assessment reactivity and in the design of control conditions. METHODS/DESIGN: The study aim is to evaluate the effectiveness of a brief online intervention, employing a randomized controlled trial (RCT) design that takes account of baseline assessment reactivity, and other possible effects of the research process. Outcomes will be evaluated after 3 months both among student populations as a whole including for a randomized no contact control group and among those who are risky drinkers randomized to brief assessment and feedback (routine practice) or to brief assessment only. A three-arm parallel groups trial will also allow exploration of the magnitude of the feedback and assessment component effects. The trial will be undertaken simultaneously in 2 universities randomizing approximately 15,300 students who will all be blinded to trial participation. All participants will be offered routine practice intervention at the end of the study. DISCUSSION: This trial informs the development of routine service delivery in Swedish universities and more broadly contributes a new approach to the study of the effectiveness of online interventions in student populations, with relevance to behaviors other than alcohol consumption. The use of blinding and deception in this study raise ethical issues that warrant further attention. TRIAL REGISTRATION: ISRCTN28328154. PMID- 22540642 TI - Concentration of cadmium, mercury, zinc, copper and cobalt in the tissues of wild boar (Sus scrofa) hunted in the western Slovakia. AB - The aim of this study was to monitor accumulation of cadmium (Cd), mercury (Hg), zinc (Zn), copper (Cu) and cobalt (Co) in the muscle, liver and kidney of wild boar (Sus scrofa scrofa) from hunting place of western Slovakia and the correlations among the observed elements. A total of 120 samples were involved for analyses by atomic absorption spectrophotometry (AAS). The significantly highest accumulation of Cd in the kidney followed by the liver and muscles was found. Zn accumulated mainly in the liver. Significantly lower values were found in the kidney followed by the muscle. The concentration of Cu was significantly lowest in the muscle when compared to the liver and kidney. Hg and Co accumulated mainly in the kidney, followed by the liver and muscle of wild boars, but without significant differences. In the muscle of wild boar moderately positive correlation between Zn and Cu (r = 0.59), Cd and Co (r = 0.51), Cu and Co (r = 0.33), and Zn and Hg (r = 0.36) were found. In the liver moderately positive correlation between Cd and Hg (r = 0.39) was detected. Moderately positive correlation between Zn and Cu (r = 0.40) was noted for the kidney. PMID- 22540643 TI - The occurrence and dynamics of polychlorinated hydrocarbons in brown hare (Lepus europaeus) in south-western Slovakia. AB - This study aimed at obtaining the data on the occurrence, levels and correlations of organic pollutants present in game animals (n = 75, Brown hare, Lepus europaeus Pall.) in the region of south-western Slovakia. The analyses performed included dichlorodiphenyltrichloroethane (DDT), hexachlorobenzen (HCB), alpha- and beta hexachlorocyclohexane (alpha+beta-HCH), gamma-hexachlorocyclohexane (gamma-HCH), and polychlorinated biphenyls (PCB-delor, commercial mixture of PCB congeners). A gas chromatograph with an electron capture detector was used for the analysis. PCB-delor and DDT were accumulated significantly in the highest level (0.105 +/- 0.059 mg/kg; 0.070 mg/kg) in depot fat in brown hares; however maximum permissible limits for the observed pollutants were not exceeded. Significantly higher concentrations of DDT, HCB, gamma-HCH, and PCB-delor were found in adult animals when compared with juvenile hares. Gender and season had no effect on the accumulation of observed pollutants. Moderately positive correlation was found between PCB-delor and DDT (r = 0.59). Monitoring of environmental pollution with polychlorinated hydrocarbons is important with regard to public health, as game animals constitute an important part of food chain also for humans. PMID- 22540644 TI - Age dependency on some physiological and biochemical parameters of male Wistar rats in controlled environment. AB - The aim of the study was to assess the age dependence on some physiological and serum chemistry parameters of male Wistar rats for the estimation of reference values in controlled environment. We are presenting values obtained from a large number of animals such as survival, average life span, body mass, food and water intake, serum chemistry parameters as total protein, albumin, transferrin and ferritin in serum. One part of this work compares the relationship between rat and human age. The maximal life span of our rats was determined to be about 4.4 years. The average life span was 3.75 years. The body weight quickly rose to the 85th week of life and then remained in the range of about 640-660 g up to the 163rd week when it began to decline. Food intake rose from the beginning to the maximum of about 39 g in the 33rd week and then decreased to about 20 g in the 163rd week. The water intake had a similar dynamics (about 43 mL in the 33rd week and 33 mL in the 163rd week). Levels of total protein in serum increased with age, in contrast, albumin levels decreased. Transferrin and ferritin decreased to approximately the 160th week of life and then increased. PMID- 22540645 TI - Accumulation of zinc, nickel, lead and cadmium in some organs of rabbits after dietary nickel and zinc inclusion. AB - This study reports the effect of dietary nickel (Ni) and a combination of Ni and zinc (Zn) on the accumulation of lead (Pb), cadmium (Cd), Ni and Zn in muscles, liver and kidneys of rabbits. Female rabbits (Oryctolagus cuniculus) of experimental groups were fed a granular mixture with addition of various concentrations of Ni or Ni+Zn (E1 - 17.5 g NiCl(2) per 100 kg of feed mixture, group E2 - 35.0 g NiCl(2) per 100 kg of feed mixture, group E3 - 17.5 g NiCl(2) per 100 kg of feed mixture and 30 g ZnCl(2) per 100 kg of feed mixture, group E4 35.0 g NiCl(2) per 100 kg of feed mixture and 30 g ZnCl(2) per 100 kg of feed mixture). Group C without inclusion of Ni or Zn served as control. After the 90 day experimental period biological material (liver, kidney, musculus longissimus dorsi, musculus biceps femoris) was taken from the animals. Samples were analyzed by the AAS method. Ni added to the FM caused an increase in Cd concentration in the kidneys of the rabbits, significantly in the E3 group in comparison with the control group. In the liver an insignificant decrease of Cd concentration was found. Zn addition in the amount of 30 g to the diet caused an increase of Cd level in the kidney as well as in the liver. Ni and Zn treatment caused a significant decrease of Pb accumulation in the m. longissimus dorsi of rabbits. This study indicates that dietary inclusion of Ni and Zn caused specific interactions among the observed metals. PMID- 22540646 TI - The effects of long-term cadmium exposure in turkeys: accumulation and zinc prevention. AB - Experiments with turkeys were conducted to determine the effects of long-term ingestion of Cd (2.0 mg Cd/day/turkey) on its accumulation in the tissues and organs. The cadmium was found especially in the muscles, livers and kidneys. The highest average content of cadmium was found in the kidneys (1.09 mg/kg). The contents of Cd in the kidneys and livers were 19 times and 14 times (respectively) higher compared to the muscles. The administration of Zn (72 mg / day / turkey) along with high doses of Cd, significantly (P < 0.001) reduced the concentrations of Cd in the organs of the experimental animals. The average concentrations of cadmium in the kidneys and livers of turkeys from the CdZn group were 43 % and 48 % (respectively) lower than the average concentrations in the same organs in the turkeys from the group which received only Cd. PMID- 22540463 TI - Search for the standard model Higgs boson in the diphoton decay channel with 4.9 fb(-1) of pp collision data at ?s=7 TeV with ATLAS. AB - A search for the standard model Higgs boson is performed in the diphoton decay channel. The data used correspond to an integrated luminosity of 4.9 fb(-1) collected with the ATLAS detector at the Large Hadron Collider in proton-proton collisions at a center-of-mass energy of ?s=7 TeV. In the diphoton mass range 110 150 GeV, the largest excess with respect to the background-only hypothesis is observed at 126.5 GeV, with a local significance of 2.8 standard deviations. Taking the look-elsewhere effect into account in the range 110-150 GeV, this significance becomes 1.5 standard deviations. The standard model Higgs boson is excluded at 95% confidence level in the mass ranges of 113-115 GeV and 134.5-136 GeV. PMID- 22540647 TI - Changes of the immunological and haematological parameters in rabbits after bendiocarbamate application. AB - The effect of bendiocarbamate application (5 mg/kg b.w.) on the haematological and immunological parameters in rabbits was evaluated. Total leukocyte cell count, erythrocyte cell count, differential cell count were determined during the period of three months of bendiocarbamate application and compared with those in healthy animals. The immunotoxic effect was evaluated by the test of ingestion ability of phagocytes (phagocytic activity and index of phagocytic activity) and proliferation activity of lymphocytes after mitogen stimulation. The significant decrease of total leukocytes, lymphocytosis and neutropaenia were found after bendiocarbamate application. The functional activities of phagocytes (expressed as phagocytic activity) and lymphocytes (proliferative activity) were significantly suppressed in rabbits treated with bendiocarbamate compared with those in control groups and values before the experiment. PMID- 22540648 TI - Reproductive toxicology of nickel - review. AB - The goal of this minireview is to summarize our current knowledge on the reproductive toxicity of soluble nickel salts. We made an attempt to present the most relevant data obtained from in vivo and in vitro experiments performed on mammals, mammalian primary cell cultures and cell lines. Nickel has been demonstrated to disturb the mammalian reproductive functions at several levels of regulation. The results of previous investigations indicate that the hormonal effects may play an important role in the reproductive toxicology of nickel both at the neuroendocrine and gonadal levels in the hypothalamic-pituitary-gonadal (HPG) axis. At the molecular level, it may be important that nickel may substitute certain other metals in metal dependent enzymes, leading to an altered protein function. It readily crosses the cell membrane via calcium channels and competes with calcium for specific receptors. Nickel can cross-link aminoacids to DNA, lead to formation of reactive oxygen species (ROS), moreover mimic hypoxia. These changes may lead to the activation of some signaling pathways, subsequent transcription factors and eventually to alterations in gene expression and cellular metabolism. These events are likely to be involved in the reproductive toxicity of nickel. PMID- 22540650 TI - Distribution of lead in selected organs and its effect on reproduction parameters of pheasants (Phasianus colchicus) after an experimental per oral administration. AB - Lead poisoning has been reported in almost every country on earth. In this study the effect of experimental lead pellet intake (2-6 pellets per week [groups B2, B4, B6] and ad libitum [BAD] accessibility for 10 weeks) on its distribution in liver, kidney, pectoral muscle, ovary, eggs and the effect of selected reproductive parameters (egg weight, fertilization, hatchability) was analyzed in breeding pheasants. Lead pellets were force fed to the digestive tract (struma, ingluvies) and the ingestion was controlled. Concentration of lead was detected using the atomic absorption spectrophotometry. Analysis of the lead concentration in liver showed a significantly higher concentration in all group after the lead pellets intake. The increase of the lead concentration was dose-dependent and the concentration detected in group BAD was similar as in group B2. Very similar tendencies were detected for the lead concentration in kidney. The accumulation of lead in pectoral muscle was lower, in comparison with liver and kidney. Compared to lead concentration detected in ovary of the control group a significant increase was detected in all experimental groups, reaching the maximum in the group B6. Similar significant increase of lead concentration was detected in eggs. The average weight of eggs was 32.01 +/- 2.71 g in the control group and lower in all experimental groups, but this decrease was significant only in the group B6. The fertilization rate was the highest in the control group and a dose-dependent decrease was detected with the lowest value in the group B6. For egg hatching ratio a significant decrease was detected in groups B4 and B6. Results of this study clearly describe accumulation of lead in the body and a its negative effect on the reproductive parameters. In the ad libitum experimental group the most similar results were found as in group B2, suggesting a rate of "natural" lead pellet intake. PMID- 22540649 TI - Selected heavy metals versus antioxidant parameters in bull seminal plasma - a comparative study. AB - To investigate the effects of lead (Pb) and cadmium (Cd) content on basic motility characteristics (motility, progressive motility) and selected antioxidant parameters (total antioxidant status - TAS, superoxide dismutase - SOD, albumin - ALB) in the bovine seminal plasma semen samples were collected from breeding bulls and used in the study. Motility analysis was carried out using the Computer Assisted Sperm Analysis (CASA) system. Subsequently, the samples were centrifuged and fractions of seminal plasma were collected. Pb and Cd concentrations were determined by the voltametric method (ASV), antioxidant parameters were analyzed by UV/VIS spectrophotometry using commercial kits. The analysis showed that the average concentrations of the trace elements were 0.57 +/- 0.01 MUg/mL for Pb and 0.11 +/- 0.01 MUg/mL for Cd. The correlation analysis revealed that both heavy metals were negatively correlated with motility (r = 0.777; P < 0.001 for Pb and r = -0.786; P < 0.001 for Cd), progressive motility (r = -0.763; P < 0.001 for Pb and r = -0.792; P < 0.001 for Cd), TAS (r = -0.375; p > 0.05 and r = -0.334; P > 0.05, respectively), SOD (r = -0.746; P < 0.001 and r = -0.537; P < 0.05, respectively) as well as with ALB (r = -0.609; P < 0.01 and r = -0.699; P < 0.001, respectively). Moreover the samples were categorized in three quality groups (Excellent, Good, Medium) according to their motility values. The lowest Pb and Cd concentrations but the best antioxidant characteristics were found in samples of excellent quality, medium quality samples were described by the highest Pb and Cd concentration and the worst antioxidant power. This study demonstrates that Pb and Cd are serious toxic elements, which are able to increase the risk of oxidative stress development and a subsequent decrease of semen quality. PMID- 22540652 TI - Multigenerational lifetime low-dose exposure to heavy metals on selected reproductive parameters in rats. AB - The aim of the present investigation was to evaluate the effects of multigenerational (P, F1 and F2) exposure to low doses of lead, mercury and cadmium dissolved in tap water on the reproductive potency of Wistar rats and the physical health of their progeny. The animals were divided into 4 groups - control (C) and 3 groups intoxicated by metals (Pb, 100 MUM; Hg, 1 MUM; Cd, 20 MUM, respectively). Females gave births from the 13th to the 78th week of experiment. Parameters of reprotoxicity such as number of litters, total number of neonates (assigned in the birth day), and number of weanlings (28th day after birth) were measured in 13-week intervals. Our data show an increase of most reproductive parameters in parental generation of rats exposed to lead and mercury and a decrease of reproductive parameters of exposed animals in subsequent F1 and F2 generations. Exposure to cadmium had no significant effect on the reproductive parameters in comparison with the control group. PMID- 22540651 TI - Quantitative histological analysis of the mouse testis after the long-term administration of nickel in feed. AB - In this study, the effects of nickel chloride (NiCl(2)) applied per os on testis histopathology and morphometry of mice were investigated. The metal was applied in pellets at a dose of 10 mg NiCl(2)/kg bw to male mice 4 weeks of age. After 3, 6, 9 and 12 weeks of nickel administration, the relative volume of whole seminiferous tubule, germinal epithelium, tubule lumen, interstitium and blood vessels as well as the diameter of seminiferous tubules were determined in the experimental and corresponding control groups. Microscopic examination of testis showed significant changes in all nickel-exposed groups. The degeneration of germinal epithelium, with released germ cells into the lumen of the tubules, and occurrence of empty spaces in the seminiferous epithelium were found in all experimental groups. The changes in the testes were time-dependent. The relative volume of empty spaces in the seminiferous epithelium significantly increased (P < 0.001) in all experimental groups when compared with the corresponding control. A significant decrease in the relative volume of seminiferous epithelium was observed after 6 and 12 weeks of Ni-exposure. The increased luminization of the tubules was found after 6 (P < 0.001), 9 (P < 0.01) and 12 (P < 0.001) weeks. Interstitial tissue significantly decreased after 6 and 9 weeks of Ni exposure and increased after 12 weeks of Ni intake. The seminiferous tubule diameter significantly (P < 0.001) decreased after 12 weeks. Results of this study report a serious, time-dependent changes in the testes, mainly in the germinal epithelium, after a peroral intake of nickel. PMID- 22540653 TI - Protective effect of zinc on cadmium embryotoxicity and antioxidant status of blood plasma in newly hatched chicks. AB - Among the multiple mechanisms of cadmium toxicity proposed, the most common is the disruption of the cellular antioxidant system, which may be limited by pre- or co-treatment with zinc. The aim of this study was to determine if simultaneous zinc supplementation of hen's egg could reduce embryotoxic effect of cadmium. Egg albumen was injected on day 4 of incubation with cadmium alone (50 nmol per egg) or in combination with zinc (100 and 500 nmol). Hatching results and antioxidant activity in plasma of newly hatched chicks were determined by photochemiluminescence (PCL) and FRAP methods. Administration of cadmium markedly reduced hatchabilty (30.2 %), while both zinc doses used were embryotoxic (43.2 and 48.9 %) as compared to the control group (61.9 %). This adverse effect was reduced by simultaneous zinc administration (completely at 10-fold higher molar concentration). This observation was confirmed by examination of the antioxidant capacity in plasma of Cd-treated chicks. A slight decrease in the hydrophilic and lipophilic antioxidant capacity induced by cadmium was compensated by a co treatment with higher zinc dose administration, whereas the exposure of hen embryos to zinc caused an increase in antioxidant potential in the plasma of chicks. It is concluded that Zn supply in conditions of exposure to Cd can protect against Cd-induced oxidative stress in chicken embryos. PMID- 22540654 TI - Dose- and time-dependent effect of copper ions on the viability of bull spermatozoa in different media. AB - The purpose of this in vitro study was to determine the effect of copper (Cu) on the motility and viability of spermatozoa in the presence of different culture media. Specifically, we examined the dose- and time-dependent effect of copper ions (Cu(2+)) on the motility and viability of spermatozoa during different time periods (Time 0 h, 1 h, 24 h). The percentage of motile spermatozoa and progressive motile spermatozoa was determined after exposure to concentrations of 3.9; 7.8; 15.6; 31.2; 62.5; 125; 250; 500; 1000 MUM/L of Cu(2+) using the Sperm Vision(TM) CASA (Computer Assisted Semen Analyzer) system. The cell viability was measured by the MTT (metabolic activity) assay. The initial spermatozoa motility in the presence of Cu(2+) in physiological saline solution (PS) showed slight increased values at doses <31.20 MUM/L of Cu(2+) compared to the control group. The long-term cultivation (Time 24 h) reduced the average motility values in all experimental groups (P < 0.001) in comparison to the control group. Identical spermatozoa motility was detected for the percentage of progressive motile spermatozoa during all time periods. The culture medium containing 20 % bovine serum albumin (BSA), triladyl and 5 % glucose increased the overall percentage of spermatozoa motility after 1 h of cultivation. A concurrently maintained motility of spermatozoa at doses <62.50 MUM/L of Cu(2+) during the long-term in vitro cultivation confirms the protective effect of albumin. The cell viability was decreased significantly (P < 0.001) in all experimental groups with copper administration. The obtained data point out that Cu(2+) at high doses is a toxic element on the spermatozoa motility, which subsequently disrupts the viability of cells. However, using a suitable culture medium containing an energy component- and protein-rich substrate, the spermatozoa motility could increase. PMID- 22540655 TI - In vivo and in vitro effect of bendiocarb on rabbit testicular structure and spermatozoa motility. AB - In this study the effect of bendiocarb on the rabbit testicular structure and spermatozoa motility was investigated. For testicular structure evaluation the animals were fed with bendiocarb tablets daily at a dose of 5 mg/kg of body weight for 13 days. The relative volume of the germinal epithelium, interstitium and lumen was measured. The testicular structure evaluation showed decreased relative volume of germinal epithelium in both experimental groups in comparison with the control group. The relative volume of the interstitium was increased in both experimental groups. An increase of the relative volume of the lumen was registered also in both experimental groups. Qualitative analysis detected a dilatation of blood vessels in the interstitium, undulation of the basal membrane and some empty spaces in the germinal epithelium after bendiocarb administration. The spermatozoa motility was evaluated by the computer assisted semen analyzer (CASA) method in various time intervals (0-180 minutes) and the bendiocarb concentration in the culture medium added to experimental groups varied from 0.054 to 0.268 mg/mL. Spermatozoa motility and progressive motility significantly decreased with increased bendiocarb administration and with extending the period of incubation. For other fine motility parameters, a decrease dependent on the time of incubation and on the bendiocarb concentration almost in all experimental groups in comparison to the control was detected. These results clearly suggest that in vitro also in vivo bendiocarb administration decrease male fertility. PMID- 22540656 TI - Chick development and high dose of bendiocarb. AB - Developmental data of carbamate pesticides are scarce although they generally possess low toxicity for vertebrates. The aim of the study was to investigate the toxicity of bendiocarb to liver and central nervous system of chick embryos. Bendiocarb (1600 MUg/egg) was administered to the embryo through membrana papyracea on embryonic day 3 and 10. In the liver and central nervous system we observed no macroscopic or microscopic changes. These organs were also investigated for caspase activity in regard to application of bendiocarb and no differences in the caspase immunopositivity were observed in comparison with the control. The embryolethality after bendiocarb respective dose was high (94 %) on the embryonic day 3, though following results indicated no toxicity to investigated organs and no increase in the number of apoptotic cells in survived chick embryos on both the early (day 3 of incubation) and the later (day 10 of incubation) developmental stage. PMID- 22540657 TI - Structural and ultrastructural study of the rabbit testes exposed to carbamate insecticide. AB - The present study was conducted to investigate the impact of carbamate insecticide - bendiocarb on the testicular structure of adult rabbits. Bendiocarb was perorally administered daily for 10 and 30 days, at a dose 5 mg/kg of body weight. After the histological sampling the tissues were investigated and compared with control. After the bendiocarb administration the absolute and relative testicular weight decreased significantly (P < 0.001) in both time periods. The testicular parenchyma showed structural changes such the sloughing of developing sex cells, occurrence of vacuoles within Sertoli cells and inside various spermatogenic cells. The interstitial Leydig cells were smaller than their control counterpart and possessed shrivelled nuclei and strongly vacuolar dark cytoplasm. The rate of changes was directly proportional on duration of the experiment. The ultrastructural examination proved presence of various cellular defects across the germinal epithelium as well as within the interstitial Leydig cells in both experimental periods. Morphometric analysis manifested decrease in diameters of seminiferous tubules, increase of the diameters of the tubular lumina due to reduction of height of the seminiferous epithelium. Results of this study show distinct negative effects of bendiocarb on structure of rabbit testes. PMID- 22540658 TI - Resveratrol inhibits reproductive toxicity induced by deoxynivalenol. AB - The aim of this in vitro study was to examine the release of progesterone by porcine ovarian granulosa cells (GCs) after exposure to toxic concentrations of deoxynivalenol (DON), resveratrol (RSV), and their combination (DON with RSV). Ovarian granulosa cells were incubated without (control) or with treatments of natural substances at various doses for 24 h: RSV (10, 30 and 50 MUg/mL) / DON (2000, 3000 and 5000 ng/mL), and their combination (10 MUg/mL of RSV with 2000 ng/mL of DON; 30 MUg/mL of RSV with 3000 ng/mL of DON; 50 MUg/mL of RSV with 5000 ng/mL of DON). Progesterone was determined by radioimmunoassay (RIA). Progesterone release was significantly (P < 0.05) stimulated by RSV at the doses 50 MUg/mL but not at 30 and 10 MUg/mL and by DON treatment at all used doses (2000, 3000 and 5000 ng/mL). RSV in combination with DON stimulated significantly (P < 0.05) the progesterone release by GCs at the highest doses (50 MUg/mL of RSV with 5000 ng/mL of DON). On the other hand, the stimulatory effect of RSV in combination with DON was significantly (P < 0.05) lower in comparison with alone DON effect. In conclusion, our results indicate, (1) the dose-depended stimulatory effects of RSV, DON and combination of RSV with DON on release of steroid hormone progesterone and (2) reduction of the stimulatory effect of DON by RSV. Our in vitro results suggest that reproductive toxicity of animals induced by a mycotoxin - deoxynivalenol can be inhibited by a protective natural substance - resveratrol. PMID- 22540659 TI - Mechanism of phytoestrogen action in Leydig cells of ganders (Anser anser domesticus): Interaction with estrogen receptors and steroidogenic enzymes. AB - Phytoestrogens (PE) are plant-derived compounds that have an estrogen-like activity and they can influence male and female reproduction. The possible mechanisms of PE action may be including: the binding to estrogen receptors (ER) and the interaction with the key steroidogenic enzymes. The aim of this study was to investigate if PE has effect on steroidogenesis of gander testicular cells by above-described pathways. The Leydig cells were isolated from testes of White Koluda ganders at the peak of their reproductive activity (March). These Leydig cells (1 * 10(5)per mL) were pre-incubated with the ER inhibitor - ICI 182, 780 (100 nM) for 3 h and then these cells were incubated with PE (5 and 50 MUM): genistein, daidzein, equol and coumestrol during next 20 h or untreated control and the Leydig cells that were previously treated (20 h) with genistein (5 and 50 MUM) were incubated for next 6 h with steroid intermediates (20 MUM) as testosterone (T) precursors: hydroxycholesterol, pregnenolone, progesterone and androstenedione. Concentrations of T in the samples of incubation medium were measured using radioimmunoassay. Genistein, daidzein, and equol (5 and 50 MUM) decreased (P < 0.05) T secretion by incubated gander Leydig cells and ICI 182, 780 did not eliminate the inhibitory effect of these PE. After genistein (50 MUM) treatment, basal and stimulated with 22R-hydroxycholesterol, pregnenolone, progesterone and androstenedione, T production by testicular cells was decreased (P < 0.05). In contrast, genistein at lower dose (5 MUM) did not affect the stimulatory effects of testosterone precursors. In conclusion, the inhibition of testosterone secretion by the phytoestrogens in gander Leydig cells did not depend on estrogen receptors. The suppression of steroidogenesis in these cells may be in part conducted by interaction of phytoestrogens with key steroidogenic enzymes. However, further studies are required to elucidate the phytoestrogen mechanism of action in gander testicular cells. PMID- 22540661 TI - Fluorescence detection of DNA, adenosine-5'-triphosphate (ATP), and telomerase activity by zinc(II)-protoporphyrin IX/G-quadruplex labels. AB - The zinc(II)-protoporphyrin IX (ZnPPIX) fluorophore binds to G-quadruplexes, and this results in the enhanced fluorescence of the fluorophore. This property enabled the development of DNA sensors, aptasensors, and a sensor following telomerase activity. The DNA sensor is based on the design of a hairpin structure that includes a "caged" inactive G-quadruplex sequence. Upon opening the hairpin by the analyte DNA, the resulting fluorescence of the ZnPPIX/G-quadruplex provides the readout signal for the sensing event (detection limit 5 nM). Addition of Exonuclease III to the system allows the recycling of the analyte and its amplified analysis (detection limit, 200 pM). The association of the ZnPPIX to G-quadruplex aptamer-substrate complexes allowed the detection of adenosine-5' triphosphate (ATP, detection limit 10 MUM). Finally, the association of ZnPPIX to the G-quadruplex repeat units of telomers allowed the detection of telomerase activity originating from 380 +/- 20 cancer 293T cell extract. PMID- 22540662 TI - Electron density distribution in endohedral complexes of fullerene C60, calculated based on the Gauss law. AB - This study demonstrates that different partial charge methodologies, consisting of an attribution of the total electron density to particular atoms of a molecule, generate very divergent results in the case of atoms doped into a fullerene cage. A new method of calculating the density distribution inside and outside fullerene complexes has been proposed and applied in the case of C60, [F@C60]-, [Na@C60]+, and He@C60. It allowed for the calculation of the electron density between surfaces, isomorphic with the C60 cage, lying inside and outside the latter, as well as the charge in the space surrounding the central atom (or the central point in the case of empty C60). PMID- 22540663 TI - Is proteomics a reliable tool to probe the oxidative folding of bacterial membrane proteins? AB - The oxidative folding of proteins involves disulfide bond formation, which is usually catalyzed by thiol-disulfide oxidoreductases (TDORs). In bacteria, this process takes place in the cytoplasmic membrane and other extracytoplasmic compartments. While it is relatively easy to study oxidative folding of water soluble proteins on a proteome-wide scale, this has remained a major challenge for membrane proteins due to their high hydrophobicity. Here, we have assessed whether proteomic techniques can be applied to probe the oxidative folding of membrane proteins using the Gram-positive bacterium Bacillus subtilis as a model organism. Specifically, we investigated the membrane proteome of a B. subtilis bdbCD mutant strain, which lacks the primary TDOR pair BdbC and BdbD, by gel-free mass spectrometry. In total, 18 membrane-associated proteins showed differing behavior in the bdbCD mutant and the parental strain. These included the ProA protein involved in osmoprotection. Consistent with the absence of ProA, the bdbCD mutant was found to be sensitive to osmotic shock. We hypothesize that membrane proteomics is a potentially effective approach to profile oxidative folding of bacterial membrane proteins. PMID- 22540664 TI - Editorial June 2012. Two new developments in the life of Human Fertility. PMID- 22540666 TI - Comparison of efficacy between uncovered and covered self-expanding metallic stents in malignant large bowel obstruction: a systematic review and meta analysis. AB - AIM: Insertion of a self-expandable metallic stent (SEMS) can rapidly relieve colorectal obstruction. This study aimed to compare the efficacy between uncovered and covered SEMSs in the treatment of malignant colorectal obstruction. METHOD: A systematic search in Medline, Embase, the Cochrane controlled trials register and bibliographies of retrieved articles was performed. Randomized controlled trials and other comparative studies comparing uncovered and covered SEMSs for treatment of malignant colorectal obstruction were selected for this systematic review and meta-analysis. The main outcome measures were technical success, clinical success, tumour ingrowth, tumour overgrowth, early migration (<= 7 days), late migration (> 7 days), overall complications and the duration of stent patency. RESULTS: Compared with covered SEMSs, uncovered SEMSs were associated with a lower late migration rate (relative risk 0.25; 95% CI 0.08, 0.80; P = 0.02), a higher tumour ingrowth rate (relative risk 5.99; 95% CI 2.23, 16.10; P = 0.0004) and a prolonged stent patency (weighted mean difference 15.34 days; 95% CI 4.31, 26.37; P = 0.006). There was no significant difference in technical success, clinical success, tumour overgrowth, early migration, perforation or overall complications between the two groups. CONCLUSION: Tumour ingrowth occurred more frequently in the uncovered SEMS group, while late migration was more common in the covered SEMS group. PMID- 22540665 TI - Immunomodulatory effects of potential probiotics in a mouse peanut sensitization model. AB - Peanut allergy accounts for the majority of severe food-related allergic reactions and there is a need for new prevention and treatment strategies. Probiotics may be considered for treatment on the basis of their immunomodulating properties. Cytokine profiles of probiotic strains were determined by in vitro co culture with human PBMCs. Three strains were selected to investigate their prophylactic potential in a peanut sensitization model by analysing peanut specific antibodies, mast cell degranulation and ex vivo cytokine production by splenocytes. The probiotic strains induced highly variable cytokine profiles in PBMCs. L. salivarius HMI001, L. casei Shirota (LCS) and L. plantarum WCFS1 were selected for further investigation owing to their distinct cytokine patterns. Prophylactic treatment with both HMI001 and LCS attenuated the Th2 phenotype (reduced mast cell responses and ex vivo IL-4 and/or IL-5 production). In contrast, WCFS1 augmented the Th2 phenotype (increased mast cell and antibody responses and ex vivo IL-4 production). In vitro PBMC screening was useful in selecting strains with anti-inflammatory and Th1 skewing properties. In case of HMI001 (high IL-10/IL-12 ratio) and LCS (high interferon-gamma and IL-12), partial protection was seen in a mouse peanut allergy model. Strikingly, certain strains may worsen the allergic reaction as shown in the case of WCFS1. PMID- 22540667 TI - Is Vietnam ready for nuclear power? PMID- 22540670 TI - Transient receptor potential vanilloid 1 mediates nerve growth factor-induced bladder hyperactivity and noxious input. AB - OBJECTIVES: To explore the role of transient receptor potential vanilloid 1 (TRPV1) in the excitatory effects of chronic administration of nerve growth factor (NGF) on bladder-generated sensory input and reflex activity. To explore new therapeutic targets for bladder dysfunction. MATERIALS AND METHODS: Wild-type (WT) and TRPV1 knockout (KO) mice received daily intraperitoneal injections of NGF (1 ug/10 g) or saline for a period of 4 days, during which time thermal sensitivity was evaluated daily. On the 5th day, mice were anaesthetized and cystometries were performed. The frequency, amplitude and area under the curve (AUC) of bladder reflex contractions were determined. c-Fos expression was evaluated on L6 spinal cord sections of WT and TRPV1 KO mice treated with saline or chronic NGF by immunohistochemistry. TrkA receptor staining intensity was determined in L6 spinal cord sections and respective dorsal root ganglia of WT and TRPV1 KO mice. RESULTS: Repeated administration of NGF induced thermal hypersensitivity in WT but not in TRPV1 KO mice. The frequency of bladder contractions of saline-treated WT and TRPV1 KO mice was similar, the values respectively being 0.45 +/- 0.12/min and 0.46 +/- 0.16/min. Treatment with NGF enhanced bladder reflex activity in WT mice to 1.23 +/- 0.41/min (P < 0.05). In NGF-treated KO mice, the frequency of bladder contractions was 0.60 +/- 0.05/min. Irrespective of treatment, no differences were observed in the amplitude of bladder contractions of WT and TRPV1 KO mice. The AUC was significantly increased in NGF-treated WT-mice, when compared with saline-treated WT-mice. No changes were found in AUC of saline-treated and NGF-treated TRPV1 KO mice. Chronic administration of NGF resulted in a significant increase of spinal c-Fos expression in WT mice (P < 0.05 vs KO animals), but not in TRPV1 KO animals. TrkA expression was similar in WT and TRPV1 KO mice. CONCLUSIONS: NGF-induced bladder overactivity and noxious input depend on the interaction of NGF with TRPV1. The lack of bladder overactivity in TRPV1 KO mice treated with NGF does not represent loss of TrkA expression. TRPV1 is essential for NGF-driven bladder dysfunction and represents a bottleneck target in bladder pathologies associated with NGF up regulation. PMID- 22540668 TI - Developmental effects of incentives on response inhibition. AB - Inhibitory control and incentive processes underlie decision making, yet few studies have explicitly examined their interaction across development. Here, the effects of potential rewards and losses on inhibitory control in 64 adolescents (13- to 17-year-olds) and 42 young adults (18- to 29-year-olds) were examined using an incentivized antisaccade task. Notably, measures were implemented to minimize age-related differences in reward valuation and potentially confounding motivation effects. Incentives affected antisaccade metrics differently across the age groups. Younger adolescents generated more errors than adults on reward trials, but all groups performed well on loss trials. Adolescent saccade latencies also differed from adults across the range of reward trials. Overall, results suggest persistent immaturities in the integration of reward and inhibitory control processes across adolescence. PMID- 22540672 TI - Correlated ab initio quantum chemical study of the interaction of the Na+, Mg2+, Ca2+, and Zn2+ ions with the tautomers of cytosine. AB - The interaction of the metal ions Na(+), Mg(2+), Ca(2+), and Zn(2+) with cytosine have been reinvestigated at the density functional, Moller-Plesset, and coupled cluster levels of theory, including hitherto unstudied tautomeric forms. It has been found that the interaction of the metal ion has a varying and often significant effect on the stabilities of the various tautomers, in some cases making most stable rare tautomeric forms. The results have been analyzed with respect to method and role of ion in binding, and confirm that, as has been found for the base cytosine tautomers, B3LYP does not give energetics consistent with highly accurate post-SCF methods for their interaction with these metal ions. PMID- 22540671 TI - Nanovalve-controlled cargo release activated by plasmonic heating. AB - The synthesis and operation of a light-operated nanovalve that controls the pore openings of mesoporous silica nanoparticles containing gold nanoparticle cores is described. The nanoparticles, consisting of 20 nm gold cores inside ~150 nm mesoporous silica spheres, were synthesized using a unique one-pot method. The nanovalves consist of cucurbit[6]uril rings encircling stalks that are attached to the ~2 nm pore openings. Plasmonic heating of the gold core raises the local temperature and decreases the ring-stalk binding constant, thereby unblocking the pore and releasing the cargo molecules that were preloaded inside. Bulk heating of the suspended particles to 60 degrees C is required to release the cargo, but no bulk temperature change was observed in the plasmonic heating release experiment. High-intensity irradiation caused thermal damage to the silica particles, but low-intensity illumination caused a local temperature increase sufficient to operate the valves without damaging the nanoparticle containers. These light-stimulated, thermally activated, mechanized nanoparticles represent a new system with potential utility for on-command drug release. PMID- 22540673 TI - Population dynamics and the evolution of antifungal drug resistance in Candida albicans. AB - Candida albicans is an important human fungal pathogen. Resistance to all major antifungal agents has been observed in clinical isolates of Candida spp. and is a major clinical challenge. The rise and expansion of drug-resistant mutants during exposure to antifungal agents occurs through a process of adaptive evolution, with potentially complex population dynamics. Understanding the population dynamics during the emergence of drug resistance is important for determining the fundamental principles of how fungal pathogens evolve for resistance. While few detailed reports that focus on the population dynamics of C. albicans currently exist, several important features on the population structure and adaptive landscape can be elucidated from existing evolutionary studies in in vivo and in vitro systems. PMID- 22540674 TI - Habitat fragmentation impacts mobility in a common and widespread woodland butterfly: do sexes respond differently? AB - BACKGROUND: Theory predicts a nonlinear response of dispersal evolution to habitat fragmentation. First, dispersal will be favoured in line with both decreasing area of habitat patches and increasing inter-patch distances. Next, once these inter-patch distances exceed a critical threshold, dispersal will be counter-selected, unless essential resources no longer co-occur in compact patches but are differently scattered; colonization of empty habitat patches or rescue of declining populations are then increasingly overruled by dispersal costs like mortality risks and loss of time and energy. However, to date, most empirical studies mainly document an increase of dispersal associated with habitat fragmentation. We analyzed dispersal kernels for males and females of the common, widespread woodland butterfly Pararge aegeria in highly fragmented landscape, and for males in landscapes that differed in their degree of habitat fragmentation. RESULTS: The male and female probabilities of moving were considerably lower in the highly fragmented landscapes compared to the male probability of moving in fragmented agricultural and deciduous oak woodland landscapes. We also investigated whether, and to what extent, daily dispersal distance in the highly fragmented landscape was influenced by a set of landscape variables for both males and females, including distance to the nearest woodland, area of the nearest woodland, patch area and abundance of individuals in the patch. We found that daily movement distance decreased with increasing distance to the nearest woodland in both males and females. Daily distances flown by males were related to the area of the woodland capture site, whereas no such effect was observed for females. CONCLUSION: Overall, mobility was strongly reduced in the highly fragmented landscape, and varied considerably among landscapes with different spatial resource distributions. We interpret the results relative to different cost-benefit ratios of movements in fragmented landscapes. PMID- 22540676 TI - Effect of immediate functional loading on osseointegration of implants used for single tooth replacement. A human histological study. AB - OBJECTIVE: To analyze hard tissue reactions to immediate functionally loaded single implants that were installed either with a conventional drill preparation procedure or with an osteotome preparation technique. MATERIALS AND METHODS: Thirteen subjects with two sites requiring single tooth rehabilitation by means of implants volunteered for the study. Each subject received one test (immediate functionally loaded) and one control (non-loaded) implant. In six subjects (group 1) the implants were placed using a conventional drilling procedure, whereas in the remaining seven subjects (group 2) an osteotome preparation procedure was performed. Block biopsies containing test and control implants and peri-implant bone tissues were collected at 1 month in four of the subjects in group 1 and in five subjects of group 2. The remaining implant sites were sampled at 3 months after implant placement. The biopsies were prepared for histological examination. RESULTS: Two implants of the test-2 group (osteotome preparation) representing 1 month of healing and another test-2 implant representing 3 months of healing failed to integrate. A multilevel multivariate statistical analysis demonstrated that no differences in bone-to-implant contact (BIC)% were found in between test and control implants, the density of newly formed peri-implant bone was significantly higher around test than control implants at 1 and 3 months of healing. Sections representing osteotome technique sites showed fractured trabeculae and large amounts of bone particles. CONCLUSIONS: It is suggested that immediate loading of implants does not influence the osseointegration process, whereas the density of newly formed peri-implant bone at such sites appears to be increased in relation to unloaded control implants. The use of an osteotome preparation technique during installation results in damage of peri-implant bone and enhances the risk for failure in osseointegration. PMID- 22540675 TI - Histological assessment of impact of ovarian endometrioma and laparoscopic cystectomy on ovarian reserve. AB - AIM: The rate of oocyte decline follows a biphasic pattern, characterized by acceleration between 32 and 38 years old. Ovarian reserve is also affected by external factors, including ovarian disease and iatrogenic damage. The aim of this study was to histologically evaluate the impact of ovarian endometriomas, laparoscopic cystectomy, and age on follicle reserve in healthy ovarian tissues and in surgically resected cyst walls. MATERIAL AND METHODS: Sixty-one patients were found to have ovarian endometriomas and 42 patients non-endometriotic cysts. A small amount of normal ovarian tissue was obtained during ovarian cystectomy. The follicles in normal ovarian tissue and resected cyst walls were histologically evaluated. RESULTS: The density of follicles in ovarian tissues correlated with the age of the patients in both groups. In women aged <35 years, the relative density of follicles in healthy ovarian tissues was consistently lower in the endometriotic cyst group compared to the non-endometriotic cyst group, with the relative ratio at age 20, 30 and 35 years calculated to be 35.4%, 46.8% and 62.7%, respectively. There was no significant difference between the groups in patients over the age of 35. The resection rate of normal ovarian tissue in cystectomy specimen of the endometriosis group was significantly higher than in the non-endometriotic cyst group (P < 0.001). CONCLUSIONS: Our data suggest that ovarian endometriomas have a detrimental impact on follicle reserve in younger patients. Further, laparoscopic cystectomy for endometriomas may accelerate the rate of oocyte loss associated with aging. PMID- 22540677 TI - Direct and highly enantioselective iso-Pictet-Spengler reactions with alpha ketoamides: access to underexplored indole core structures. AB - Direct, one-pot, operationally simple, and highly enantioselective iso-Pictet Spengler reactions are reported. The reactions involve the condensation of either (1H-indol-4-yl)methanamine or 2-(1H-Indol-1-yl)ethanamine with a variety of alpha ketoamides, followed by the addition of a simple and commercially available chiral silicon Lewis acid. These reactions are the first asymmetric examples of these cyclization modes and provide access to 3,3-disubstituted-1,3,4,5 tetrahydropyrrolo[4,3,2-de]isoquinolines and 1,1-disubstituted-1,2,3,4 tetrahydropyrazino[1,2-a]indoles, respectively, two relatively underexplored indole-based core structure motifs in medicinal chemistry. PMID- 22540678 TI - The value of the pragmatic-explanatory continuum indicator summary wheel in an ongoing study: the bullous pemphigoid steroids and tetracyclines study. AB - BACKGROUND: The Pragmatic-Explanatory Continuum Indicator Summary (PRECIS) tool is intended to be used in the design phase of trials to help investigative teams design trials in-line with their purpose. Our team applied this tool to an ongoing trial (BLISTER) to determine whether the initial suggestion among some team members that the trial could be described as largely pragmatic was the consensus. METHODS: Each of the six members of the BLISTER trial team was sent a blank PRECIS wheel to independently complete. The results obtained were averaged and plotted on a single PRECIS wheel to illustrate the degree of pragmatism of the trial. RESULTS: The trial team found that the design of the trial was closest to the pragmatic end of the pragmatic-explanatory continuum. The strongest consensus was found on the 'flexibility of the comparison intervention' and 'practitioner adherence' domains (SD = 13). The trial team appeared to disagree most on the 'eligibility criteria' (SD = 35) and 'participant compliance' (SD = 31) domains, although the large standard deviations were a result of a single outlier in the two domains. CONCLUSION: The PRECIS tool can be used to retrospectively determine the pragmatism of a trial provided enough expertise and information on the trial is available. Illustrating the design of a trial on the PRECIS wheel can help research users more easily identify studies of interest. We hope our recommendations for applying this useful tool will encourage others to consider using it when designing, conducting and reporting studies. TRIAL REGISTRATION: Current Controlled Trials http://www.controlled trials.com/ISRCTN13704604. PMID- 22540679 TI - Reference-free transcriptome assembly in non-model animals from next-generation sequencing data. AB - Next-generation sequencing (NGS) technologies offer the opportunity for population genomic study of non-model organisms sampled in the wild. The transcriptome is a convenient and popular target for such purposes. However, designing genetic markers from NGS transcriptome data requires assembling gene coding sequences out of short reads. This is a complex task owing to gene duplications, genetic polymorphism, alternative splicing and transcription noise. Typical assembling programmes return thousands of predicted contigs, whose connection to the species true gene content is unclear, and from which SNP definition is uneasy. Here, the transcriptomes of five diverse non-model animal species (hare, turtle, ant, oyster and tunicate) were assembled from newly generated 454 and Illumina sequence reads. In two species for which a reference genome is available, a new procedure was introduced to annotate each predicted contig as either a full-length cDNA, fragment, chimera, allele, paralogue, genomic sequence or other, based on the number of, and overlap between, blast hits to the appropriate reference. Analyses showed that (i) the highest quality assemblies are obtained when 454 and Illumina data are combined, (ii) typical de novo assemblies include a majority of irrelevant cDNA predictions and (iii) assemblies can be appropriately cleaned by filtering contigs based on length and coverage. We conclude that robust, reference-free assembly of thousands of genes from transcriptomic NGS data is possible, opening promising perspectives for transcriptome-based population genomics in animals. A Galaxy pipeline implementing our best-performing assembling strategy is provided. PMID- 22540680 TI - Down-regulation of miR-214 contributes to intrahepatic cholangiocarcinoma metastasis by targeting Twist. AB - miRNAs play an important role in many human diseases, including cancer metastasis. However, the mechanisms by which miRNAs regulate intrahepatic cholangiocarcinoma metastasis remain poorly understood. In the present study, we assayed the expression level of miR-214 in intrahepatic cholangiocarcinoma tissues by real-time PCR, and defined the target gene and biological function by luciferase reporter assay and Western blot analysis. We found that the miR-214 levels were remarkably decreased in metastatic intrahepatic cholangiocarcinoma tissues compared to non-metastatic tissues. Inhibition of miR-214 levels by its inhibitor promoted metastasis of human intrahepatic cholangiocarcinoma cell. We further demonstrated that down-regulation of miR-214 increased the transcript levels of the epithelial-mesenchymal transition-associated gene Twist, and then decreased E-cadherin levels. We confirmed that down-regulation of miR-214 promoted the epithelial-mesenchymal transition by directly targeting the Twist gene. These results suggest an important role for miR-214 in regulating metastasis of intrahepatic cholangiocarcinoma, and potential application of miR 214 in intrahepatic cholangiocarcinoma therapy. PMID- 22540681 TI - Structure of reversible computation determines the self-duality of quantum theory. AB - Predictions for measurement outcomes in physical theories are usually computed by combining two distinct notions: a state, describing the physical system, and an observable, describing the measurement which is performed. In quantum theory, however, both notions are in some sense identical: outcome probabilities are given by the overlap between two state vectors--quantum theory is self-dual. In this Letter, we show that this notion of self-duality can be understood from a dynamical point of view. We prove that self-duality follows from a computational primitive called bit symmetry: every logical bit can be mapped to any other logical bit by a reversible transformation. Specifically, we consider probabilistic theories more general than quantum theory, and prove that every bit symmetric theory must necessarily be self-dual. We also show that bit symmetry yields stronger restrictions on the set of allowed bipartite states than the no signalling principle alone, suggesting reversible time evolution as a possible reason for limitations of nonlocality. PMID- 22540682 TI - Robust quantum enhanced phase estimation in a multimode interferometer [corrected]. AB - By exploiting the correlation properties of ultracold atoms in a multimode interferometer, we show how quantum enhanced measurement precision can be achieved with strong robustness to particle loss. While the potential for enhanced measurement precision is limited for even moderate loss in two-mode schemes, multimode schemes can be more robust. A ring interferometer for sensing rotational motion with noninteracting fermionic atoms can realize an uncertainty scaling of 1/(N?eta) for N particles with a fraction eta remaining after loss, which undercuts the shot-noise limit of two-mode interferometers. A second scheme with strongly interacting bosons achieves a comparable measurement precision and improved readout. PMID- 22540683 TI - Universal dimer in a collisionally opaque medium: experimental observables and Efimov resonances. AB - A universal dimer is subject to secondary collisions with atoms when formed in a cloud of ultracold atoms via three-body recombination. We show that in a collisionally opaque medium, the value of the scattering length that results in the maximum number of secondary collisions may not correspond to the Efimov resonance at the atom-dimer threshold and thus cannot be automatically associated with it. This result explains a number of controversies in recent experimental results on universal three-body states and supports the emerging evidence for the significant finite range corrections to the first excited Efimov energy level. PMID- 22540684 TI - Quantum factorization of 143 on a dipolar-coupling nuclear magnetic resonance system. AB - Quantum algorithms could be much faster than classical ones in solving the factoring problem. Adiabatic quantum computation for this is an alternative approach other than Shor's algorithm. Here we report an improved adiabatic factoring algorithm and its experimental realization to factor the number 143 on a liquid-crystal NMR quantum processor with dipole-dipole couplings. We believe this to be the largest number factored in quantum-computation realizations, which shows the practical importance of adiabatic quantum algorithms. PMID- 22540685 TI - Side-channel-free quantum key distribution. AB - Quantum key distribution (QKD) offers the promise of absolutely secure communications. However, proofs of absolute security often assume perfect implementation from theory to experiment. Thus, existing systems may be prone to insidious side-channel attacks that rely on flaws in experimental implementation. Here we replace all real channels with virtual channels in a QKD protocol, making the relevant detectors and settings inside private spaces inaccessible while simultaneously acting as a Hilbert space filter to eliminate side-channel attacks. By using a quantum memory we find that we are able to bound the secret key rate below by the entanglement-distillation rate computed over the distributed states. PMID- 22540686 TI - Measurement-device-independent quantum key distribution. AB - How to remove detector side channel attacks has been a notoriously hard problem in quantum cryptography. Here, we propose a simple solution to this problem- measurement-device-independent quantum key distribution (QKD). It not only removes all detector side channels, but also doubles the secure distance with conventional lasers. Our proposal can be implemented with standard optical components with low detection efficiency and highly lossy channels. In contrast to the previous solution of full device independent QKD, the realization of our idea does not require detectors of near unity detection efficiency in combination with a qubit amplifier (based on teleportation) or a quantum nondemolition measurement of the number of photons in a pulse. Furthermore, its key generation rate is many orders of magnitude higher than that based on full device independent QKD. The results show that long-distance quantum cryptography over say 200 km will remain secure even with seriously flawed detectors. PMID- 22540687 TI - Quantum interface between an electrical circuit and a single atom. AB - We show how to bridge the divide between atomic systems and electronic devices by engineering a coupling between the motion of a single ion and the quantized electric field of a resonant circuit. Our method can be used to couple the internal state of an ion to the quantized circuit with the same speed as the internal-state coupling between two ions. All the well-known quantum information protocols linking ion internal and motional states can be converted to protocols between circuit photons and ion internal states. Our results enable quantum interfaces between solid state qubits, atomic qubits, and light, and lay the groundwork for a direct quantum connection between electrical and atomic metrology standards. PMID- 22540688 TI - Energy versus angular momentum in black hole binaries. AB - Using accurate numerical-relativity simulations of (nonspinning) black-hole binaries with mass ratios 1:1, 2:1, and 3:1, we compute the gauge-invariant relation between the (reduced) binding energy E and the (reduced) angular momentum j of the system. We show that the relation E(j) is an accurate diagnostic of the dynamics of a black-hole binary in a highly relativistic regime. By comparing the numerical-relativity E(NR)(j) curve with the predictions of several analytic approximation schemes, we find that, while the canonically defined, nonresummed post-Newtonian-expanded E(PN)(j) relation exhibits large and growing deviations from E(NR)(j), the prediction of the effective one body formalism, based purely on known analytical results (without any calibration to numerical relativity), agrees strikingly well with the numerical-relativity results. PMID- 22540689 TI - Island of stability for consistent deformations of Einstein's gravity. AB - We construct deformations of general relativity that are consistent and phenomenologically viable, since they respect, in particular, cosmological backgrounds. These deformations have unique symmetries in accordance with their Minkowski cousins (Fierz-Pauli theory for massive gravitons) and incorporate a background curvature induced self-stabilizing mechanism. Self-stabilization is essential in order to guarantee hyperbolic evolution in and unitarity of the covariantized theory, as well as the deformation's uniqueness. We show that the deformation's parameter space contains islands of absolute stability that are persistent through the entire cosmic evolution. PMID- 22540690 TI - Gravitational self-force correction to the binding energy of compact binary systems. AB - Using the first law of binary black-hole mechanics, we compute the binding energy E and total angular momentum J of two nonspinning compact objects moving on circular orbits with frequency Omega, at leading order beyond the test-particle approximation. By minimizing E(Omega) we recover the exact frequency shift of the Schwarzschild innermost stable circular orbit induced by the conservative piece of the gravitational self-force. Comparing our results for the coordinate invariant relation E(J) to those recently obtained from numerical simulations of comparable-mass nonspinning black-hole binaries, we find a remarkably good agreement, even in the strong-field regime. Our findings confirm that the domain of validity of perturbative calculations may extend well beyond the extreme mass ratio limit. PMID- 22540692 TI - Renormalization group flows, cycles, and c-theorem folklore. AB - Monotonic renormalization group flows of the "c" and "a" functions are often cited as reasons why cyclic or chaotic coupling trajectories cannot occur. It is argued here, based on simple examples, that this is not necessarily true. Simultaneous monotonic and cyclic flows can be compatible if the flow function is multivalued in the couplings. PMID- 22540691 TI - Search for antihelium with the BESS-Polar spectrometer. AB - In two long-duration balloon flights over Antarctica, the Balloon-borne Experiment with a Superconducting Spectrometer (BESS) collaboration has searched for antihelium in the cosmic radiation with the highest sensitivity reported. BESS-Polar I flew in 2004, observing for 8.5 days. BESS-Polar II flew in 2007 2008, observing for 24.5 days. No antihelium candidate was found in BESS-Polar I data among 8.4*10(6) |Z|=2 nuclei from 1.0 to 20 GV or in BESS-Polar II data among 4.0*10(7) |Z|=2 nuclei from 1.0 to 14 GV. Assuming antihelium to have the same spectral shape as helium, a 95% confidence upper limit to the possible abundance of antihelium relative to helium of 6.9*10(-8)} was determined combining all BESS data, including the two BESS-Polar flights. With no assumed antihelium spectrum and a weighted average of the lowest antihelium efficiencies for each flight, an upper limit of 1.0*10(-7) from 1.6 to 14 GV was determined for the combined BESS-Polar data. Under both antihelium spectral assumptions, these are the lowest limits obtained to date. PMID- 22540695 TI - Robust regularity in gamma-soft nuclei and its microscopic realization. AB - gamma softness in atomic nuclei is investigated in the framework of energy density functionals. By mapping constrained microscopic energy surfaces for a set of representative nonaxial medium-heavy and heavy nuclei to a Hamiltonian of the proton-neutron interacting boson model (IBM-2) containing up to three-body interactions, low-lying collective spectra and transition rates are calculated. Observables are analyzed that distinguish between the two limiting geometrical pictures of nonaxial nuclei: the rigid-triaxial rotor and the gamma-unstable rotor. It is shown that neither of these pictures is realized in actual nuclei, and that a microscopic description leads to results that are almost exactly in between the two geometrical limits. This finding points to the optimal choice of the IBM Hamiltonian for gamma-soft nuclei. PMID- 22540696 TI - Quantum simulation of an extra dimension. AB - We present a general strategy to simulate a D+1-dimensional quantum system using a D-dimensional one. We analyze in detail a feasible implementation of our scheme using optical lattice technology. The simplest nontrivial realization of a fourth dimension corresponds to the creation of a bi-volume geometry. We also propose single- and many-particle experimental signatures to detect the effects of the extra dimension. PMID- 22540693 TI - Indication of reactor nu(e) disappearance in the Double Chooz experiment. AB - The Double Chooz experiment presents an indication of reactor electron antineutrino disappearance consistent with neutrino oscillations. An observed-to predicted ratio of events of 0.944+/-0.016(stat)+/-0.040(syst) was obtained in 101 days of running at the Chooz nuclear power plant in France, with two 4.25 GW(th) reactors. The results were obtained from a single 10 m(3) fiducial volume detector located 1050 m from the two reactor cores. The reactor antineutrino flux prediction used the Bugey4 flux measurement after correction for differences in core composition. The deficit can be interpreted as an indication of a nonzero value of the still unmeasured neutrino mixing parameter sin(2)2theta(13). Analyzing both the rate of the prompt positrons and their energy spectrum, we find sin(2)2theta(13)=0.086+/-0.041(stat)+/-0.030(syst), or, at 90% C.L., 0.017 ~ 11,000) irradiated by femtosecond pulses of 850 eV x-ray photons focused to an intensity of up to 10(17) W/cm(2) from the Linac Coherent Light Source were investigated experimentally. Measurements of ion charge-state distributions and energy spectra exhibit strong evidence for the formation of a Xe nanoplasma in the intense x-ray pulse. This x-ray produced Xe nanoplasma is accompanied by a three-body recombination and hydrodynamic expansion. These experimental results appear to be consistent with a model in which a spherically exploding nanoplasma is formed inside the Xe cluster and where the plasma temperature is determined by photoionization heating. PMID- 22540698 TI - Optical spectroscopy of molecular positronium. AB - We report optical spectroscopic measurements of molecular positronium (Ps(2)), performed via a previously unobserved L=1 excited state. Ps(2) molecules created in a porous silica film, and also in vacuum from an Al(111) crystal, were resonantly excited and then photoionized by pulsed lasers, providing conclusive evidence for the production of this molecular matter-antimatter system and its excited state. Future experiments making use of the photoionized vacuum L=1 Ps(2) could provide a source of Ps(+) ions, as well as other multipositronic systems, such as Ps(2)H(-) or Ps(2)O. PMID- 22540699 TI - Optical detection of the quantization of collective atomic motion. AB - We directly measure the quantized collective motion of a gas of thousands of ultracold atoms, coupled to light in a high-finesse optical cavity. We detect strong asymmetries, as high as 3:1, in the intensity of light scattered into low- and high-energy motional sidebands. Owing to high cavity-atom cooperativity, the optical output of the cavity contains a spectroscopic record of the energy exchanged between light and motion, directly quantifying the heat deposited by a quantum position measurement's backaction. Such backaction selectively causes the phonon occupation of the observed collective modes to increase with the measurement rate. These results, in addition to providing a method for calibrating the motion of low-occupation mechanical systems, offer new possibilities for investigating collective modes of degenerate gases and for diagnosing optomechanical measurement backaction. PMID- 22540700 TI - Extracting continuum electron dynamics from high harmonic emission from molecules. AB - We show that high harmonic generation is the most sensitive probe of rotational wave packet revivals, revealing very high-order rotational revivals for the first time using any probe. By fitting high-quality experimental data to an exact theory of high harmonic generation from aligned molecules, we can extract the underlying electronic dipole elements for high harmonic emission and uncover that the electron gains angular momentum from the photon field. PMID- 22540701 TI - Knotted solitons in nonlinear magnetic metamaterials. AB - We demonstrate that nonlinear magnetic metamaterials comprised of a lattice of weakly coupled split-ring resonators driven by an external electromagnetic field may support entirely new classes of spatially localized modes--knotted solitons, which are stable self-localized dissipative structures in the form of closed knotted chains. We demonstrate different topological types of stable knots for the subcritical coupling between resonators and instability-induced breaking of the chains for the supercritical coupling. PMID- 22540702 TI - Synchronization in simple network motifs with negligible correlation and mutual information measures. AB - Can different or even identical coupled oscillators be completely uncorrelated and still be synchronized? What can be concluded from the absence of correlations or even mutual information in networks of dynamical elements about their connectivity? These are fundamental and far-reaching questions arising in many complex systems. In this Letter, we address these two questions and demonstrate in simple and generic network motifs that synchronized behavior in the generalized sense can be realized and constructed such that no correlations and even negligible mutual information remain. Our findings raise new questions, in particular, whether and to what extent indirect connections are being underestimated, since the related collective behavior and even synchronization are less likely to be detected. PMID- 22540703 TI - Discontinuous transition in a laminar fluid flow: a change of flow topology inside a droplet moving in a micron-size channel. AB - Even at moderate values of Reynolds number [e.g., Re=O(1)] a curved interface between liquids can induce an abrupt transition between topologically different configurations of laminar flow. Here we show for the first time direct evidence of a sharp transition in the speed of flow of a droplet upon a small increase of the value of the capillary number above a threshold and the associated change of topology of flow. The quantitative results on the dependence of the threshold capillary number on the contrast of viscosities and on the direction of transition cannot be explained by any of the existing theories and call for a new description. PMID- 22540704 TI - Distribution of particles and bubbles in turbulence at a small Stokes number. AB - The inertia of particles driven by the turbulent flow of the surrounding fluid makes them prefer certain regions of the flow. The heavy particles lag behind the flow and tend to accumulate in the regions with less vorticity, while the light particles do the opposite. As a result of the long-time evolution, the particles distribute over a multifractal attractor in space. We consider this distribution using our recent results on the steady states of chaotic dynamics. We describe the preferential concentration analytically and derive the correlation functions of density and the fractal dimensions of the attractor. The results are obtained for real turbulence and are testable experimentally. PMID- 22540705 TI - Spallation ultracold neutron source of superfluid helium below 1 K. AB - For the production of high-density ultracold neutrons (UCNs), we placed 0.8 K superfluid helium in a cold neutron moderator. We resolved previous heat-load problems in the spallation neutron source that were particularly serious below 1 K. With a proton-beam power of 400 MeV*1 MUA, a UCN production rate of 4 UCN cm( 3) s(-1) at the maximum UCN energy of E(c)=210 neV and a storage lifetime of 81 s were obtained. A cryogenic test showed that the production rate can be increased by a factor of 10 with the same storage lifetime by increasing the proton-beam power as well as (3)He pumping speed. PMID- 22540706 TI - Weibel-induced filamentation during an ultrafast laser-driven plasma expansion. AB - The development of current instabilities behind the front of a cylindrically expanding plasma has been investigated experimentally via proton probing techniques. A multitude of tubelike filamentary structures is observed to form behind the front of a plasma created by irradiating solid-density wire targets with a high-intensity (I ~ 10(19) W/cm(2)), picosecond-duration laser pulse. These filaments exhibit a remarkable degree of stability, persisting for several tens of picoseconds, and appear to be magnetized over a filament length corresponding to several filament radii. Particle-in-cell simulations indicate that their formation can be attributed to a Weibel instability driven by a thermal anisotropy of the electron population. We suggest that these results may have implications in astrophysical scenarios, particularly concerning the problem of the generation of strong, spatially extended and sustained magnetic fields in astrophysical jets. PMID- 22540694 TI - Search for universal extra dimensions in pp collisions. AB - We present a search for Kaluza-Klein (KK) particles predicted by models with universal extra dimensions (UED) using a data set corresponding to an integrated luminosity of 7.3 fb(-1), collected by the D0 detector at a pp center-of-mass energy of 1.96 TeV. The decay chain of KK particles can lead to a final state with two muons of the same charge. This signature is used to set a lower limit on the compactification scale of R(-1)>260 GeV in a minimal UED model. PMID- 22540707 TI - Kinetic instabilities that limit beta in the edge of a tokamak plasma: a picture of an H-mode pedestal. AB - Plasma equilibria reconstructed from the Mega-Amp Spherical Tokamak have sufficient resolution to capture plasma evolution during the short period between edge-localized modes (ELMs). Immediately after the ELM, steep gradients in pressure, P, and density, n(e), form pedestals close to the separatrix, and they then expand into the core. Local gyrokinetic analysis over the ELM cycle reveals the dominant microinstabilities at perpendicular wavelengths of the order of the ion Larmor radius. These are kinetic ballooning modes in the pedestal and microtearing modes in the core close to the pedestal top. The evolving growth rate spectra, supported by gyrokinetic analysis using artificial local equilibrium scans, suggest a new physical picture for the formation and arrest of this pedestal. PMID- 22540708 TI - Stochastic particle acceleration in multiple magnetic islands during reconnection. AB - A nonthermal particle acceleration mechanism involving the interaction of a charged particle with multiple magnetic islands is proposed. The original Fermi acceleration model, which assumes randomly distributed magnetic clouds moving at random velocity V(c) in the interstellar medium, is known to be of second-order acceleration of O(V(c)/c)(2) owing to the combination of head-on and head-tail collisions. In this Letter, we reconsider the original Fermi model by introducing multiple magnetic islands during reconnection instead of magnetic clouds. We discuss that the energetic particles have a tendency to be distributed outside the magnetic islands, and they mainly interact with reconnection outflow jets. As a result, the acceleration efficiency becomes first order of O(V(A)/c), where V(A) and c are the Alfven velocity and the speed of light, respectively. PMID- 22540709 TI - Soft-x-ray harmonic comb from relativistic electron spikes. AB - We demonstrate a new high-order harmonic generation mechanism reaching the "water window" spectral region in experiments with multiterawatt femtosecond lasers irradiating gas jets. A few hundred harmonic orders are resolved, giving MUJ/sr pulses. Harmonics are collectively emitted by an oscillating electron spike formed at the joint of the boundaries of a cavity and bow wave created by a relativistically self-focusing laser in underdense plasma. The spike sharpness and stability are explained by catastrophe theory. The mechanism is corroborated by particle-in-cell simulations. PMID- 22540710 TI - Microstructure of a liquid two-dimensional dusty plasma under shear. AB - The microstructure of a strongly coupled liquid undergoing a shear flow was studied experimentally. The liquid was a shear melted two-dimensional plasma crystal, i.e., a single-layer suspension of micrometer-size particles in a rf discharge plasma. Trajectories of particles were measured using video microscopy. The resulting microstructure was anisotropic, with compressional and extensional axes at around +/-45 degrees to the flow direction. Corresponding ellipticity of the pair correlation function g(r) or static structure factor S(k) gives the (normalized) shear rate of the flow. PMID- 22540711 TI - Direct measurement of energetic electrons coupling to an imploding low-adiabat inertial confinement fusion capsule. AB - We have imaged hard x-ray (>100 keV) bremsstrahlung emission from energetic electrons slowing in a plastic ablator shell during indirectly driven implosions at the National Ignition Facility. We measure 570 J in electrons with E>100 keV impinging on the fusion capsule under ignition drive conditions. This translates into an acceptable increase in the adiabat alpha, defined as the ratio of total deuterium-tritium fuel pressure to Fermi pressure, of 3.5%. The hard x-ray observables are consistent with detailed radiative-hydrodynamics simulations, including the sourcing and transport of these high energy electrons. PMID- 22540712 TI - Families of superhard crystalline carbon allotropes constructed via cold compression of graphite and nanotubes. AB - We report a general scheme to systematically construct two classes of structural families of superhard sp(3) carbon allotropes of cold-compressed graphite through the topological analysis of odd 5+7 or even 4+8 membered carbon rings stemmed from the stacking of zigzag and armchair chains. Our results show that the previously proposed M, bct-C(4), W and Z allotropes belong to our currently proposed families and that depending on the topological arrangement of the native carbon rings numerous other members are found that can help us understand the structural phase transformation of cold-compressed graphite and carbon nanotubes (CNTs). In particular, we predict the existence of two simple allotropes, R and P carbon, which match well the experimental x-ray diffraction patterns of cold compressed graphite and CNTs, respectively, display a transparent wide-gap insulator ground state and possess a large Vickers hardness comparable to diamond. PMID- 22540713 TI - Hot spots in an athermal system. AB - We study experimentally the dynamical heterogeneities occurring at slow shear, in a model amorphous glassy material, i.e., a 3D granular packing. The deformation field is resolved spatially by using a diffusive wave spectroscopy technique. The heterogeneities show up as localized regions of strong deformations spanning a mesoscopic size of about 10 grains and called the "hot spots." The spatial clustering of hot spots is linked to the subsequent emergence of shear bands. Quantitatively, their appearance is associated with the macroscopic plastic deformation, and their rate of occurrence gives a physical meaning to the concept of "fluidity," recently used to describe the local and nonlocal rheology of soft glassy materials. PMID- 22540714 TI - Rapid nondestructive analysis of threading dislocations in wurtzite materials using the scanning electron microscope. AB - We describe the use of electron channeling contrast imaging in the scanning electron microscope to rapidly and reliably image and identify threading dislocations (TDs) in materials with the wurtzite crystal structure. In electron channeling contrast imaging, vertical TDs are revealed as spots with black-white contrast. We have developed a simple geometric procedure which exploits the differences observed in the direction of this black-white contrast for screw, edge, and mixed dislocations for two electron channeling contrast images acquired from two symmetrically equivalent crystal planes whose g vectors are at 120 degrees to each other. Our approach allows unambiguous identification of all TDs without the need to compare results with dynamical simulations of channeling contrast. PMID- 22540715 TI - Charge redistribution mechanisms of ceria reduction. AB - Charge redistribution at low oxygen vacancy concentrations in ceria have been studied in the framework of the density functional theory. We propose a model to approach the dilute limit using the results of supercell calculations. It allows one to reproduce the characteristic experimentally observed behavior of composition versus oxygen pressure dependency. We show that in the dilute limit the charge redistribution is likely to be driven by a mechanism different from the one involving electron localization on cerium atoms. We demonstrate that it can involve charge localization on light element impurities. PMID- 22540716 TI - Noncontact friction and relaxational dynamics of surface defects. AB - The motion of a cantilever near sample surfaces exhibits additional friction even before two bodies come into mechanical contact. Called noncontact friction (NCF), this friction is of great practical importance to the ultrasensitive force detection measurements. The observed large NCF of a micron-scale cantilever found an anomalously large damping that exceeds theoretical predictions by 8-11 orders of magnitude. This finding points to a contribution beyond fluctuating electromagnetic fields within the van der Waals approach. Recent experiments reported by Saitoh et al. [Phys. Rev. Lett. 105, 236103 (2010)] also found a nontrivial distance dependence of NCF. Motivated by these observations, we propose a mechanism based on the coupling of a cantilever to the relaxation dynamics of surface defects. We assume that the surface defects couple to the cantilever tip via spin-spin coupling and their spin relaxation dynamics gives rise to the backaction terms and modifies both the friction coefficient and the spring constant. We explain the magnitude, as well as the distance dependence of the friction due to these backaction terms. Reasonable agreement is found with the experiments. PMID- 22540717 TI - Incoherent scatterer in a Luttinger liquid: a new paradigmatic limit. AB - We address the problem of a Luttinger liquid with a scatterer that allows for both coherent and incoherent scattering channels. The asymptotic behavior at zero temperature is governed by a new stable fixed point: A Goldstone mode dominates the low energy dynamics, leading to universal behavior. This limit is marked by equal probabilities for forward and backward scattering. Notwithstanding this nontrivial scattering pattern, we find that the shot noise as well as cross current correlations vanish. We thus present a paradigmatic picture of an impurity in the Luttinger model, alternative to the Kane-Fisher picture. PMID- 22540718 TI - Ultrafast strain engineering in complex oxide heterostructures. AB - We report on ultrafast optical experiments in which femtosecond midinfrared radiation is used to excite the lattice of complex oxide heterostructures. By tuning the excitation energy to a vibrational mode of the substrate, a long-lived five-order-of-magnitude increase of the electrical conductivity of NdNiO(3) epitaxial thin films is observed as a structural distortion propagates across the interface. Vibrational excitation, extended here to a wide class of heterostructures and interfaces, may be conducive to new strategies for electronic phase control at THz repetition rates. PMID- 22540719 TI - Nonlinear plasmon-photon interaction resolved by k-space spectroscopy. AB - Metallic nanostructures support extreme localization and enhancement of optical fields via surface-plasmon (SP) resonances. Although SP are associated with giant enhancements of nonlinear phenomena such as second-harmonic generation (SHG), the role of SP in the process, whether as a field-enhancing catalyst or as a quasiparticle converted in the interaction, has remained experimentally elusive. We demonstrate how k-space spectroscopy can distinguish between the plasmonic and photonic SHG processes that occur in a metal nanofilm when it is optically driven via the Kretschmann geometry. The results revealed a nonlinear interaction where two SP annihilate to create a second-harmonic photon. This knowledge has implications for realizing the inverse process, plasmonic parametric down conversion, which could act as a coherent source of entangled SP pairs. PMID- 22540720 TI - Localized end states in density modulated quantum wires and rings. AB - We study finite quantum wires and rings in the presence of a charge-density wave gap induced by a periodic modulation of the chemical potential. We show that the Tamm-Shockley bound states emerging at the ends of the wire are stable against weak disorder and interactions, for discrete open chains and for continuum systems. The low-energy physics can be mapped onto the Jackiw-Rebbi equations describing massive Dirac fermions and bound end states. We treat interactions via the continuum model and show that they increase the charge gap and further localize the end states. The electrons placed in the two localized states on the opposite ends of the wire can interact via exchange interactions and this setup can be used as a double quantum dot hosting spin qubits. The existence of these states could be experimentally detected through the presence of an unusual 4pi Aharonov-Bohm periodicity in the spectrum and persistent current as a function of the external flux. PMID- 22540721 TI - Direct imaging of electron states in open quantum dots. AB - We use scanning gate microscopy to probe the ballistic motion of electrons within an open GaAs/AlGaAs quantum dot. Conductance maps are recorded by scanning a biased tip over the open quantum dot while a magnetic field is applied. We show that, for specific magnetic fields, the measured conductance images resemble the classical transmitted and backscattered trajectories and their quantum mechanical analogue. In addition, we prove experimentally, with this direct measurement technique, the existence of pointer states. The demonstrated direct imaging technique is essential for the fundamental understanding of wave function scarring and quantum decoherence theory. PMID- 22540722 TI - Lattice model for the SU(N) Neel to valence-bond solid quantum phase transition at large N. AB - We generalize the SU(N=2) S=1/2 square-lattice quantum magnet with nearest neighbor antiferromagnetic coupling (J(1)) and next-nearest-neighbor ferromagnetic coupling (J(2)) to arbitrary N. For all N>4, the ground state has valence-bond-solid order for J(2)=0 and Neel order for J(2)/J(1)?1, allowing us access to the transition between these types of states for large N. Using quantum Monte Carlo simulations, we show that both order parameters vanish at a single quantum-critical point, whose universal exponents for large enough N (here up to N=12) approach the values obtained in a 1/N expansion of the noncompact CP(N-1) field theory. These results lend strong support to the deconfined quantum criticality theory of the Neel-valence-bond-solid transition. PMID- 22540723 TI - Pseudo Jahn-Teller origin of perovskite multiferroics, magnetic-ferroelectric crossover, and magnetoelectric effects: the d0-d10 problem. AB - The conditions of multiferroicity in d(n) perovskites are derived from the pseudo Jahn-Teller effect, due to which ferroelectric displacements are triggered by vibronic coupling between ground and excited electronic states of opposite parity but same spin multiplicity; it takes place for some specific d(n) configurations and spin states only. In combination with the high-spin-low-spin crossover effect this leads to a novel phenomenon, the magnetic-ferroelectric (multiferroics) crossover which predicts magnetoelectric effects with exciting functionalities including electric magnetization and demagnetization. PMID- 22540724 TI - Electric-field control of nonvolatile magnetization in Co40Fe40B20/Pb(Mg(1/3)Nb(2/3))(0.7)Ti(0.3)O3 structure at room temperature. AB - We report a large and nonvolatile bipolar-electric-field-controlled magnetization at room temperature in a Co(40)Fe(40)B(20)/Pb(Mg(1/3)Nb(2/3))(0.7)Ti(0.3)O(3) structure, which exhibits an electric-field-controlled looplike magnetization. Investigations on the ferroelectric domains and crystal structures with in situ electric fields reveal that the effect is related to the combined action of 109 degrees ferroelastic domain switching and the absence of magnetocrystalline anisotropy in Co(40)Fe(40)B(20). This work provides a route to realize large and nonvolatile magnetoelectric coupling at room temperature and is significant for applications. PMID- 22540725 TI - Direct measurement of the triplet exciton diffusion length in organic semiconductors. AB - We present a new method to measure the triplet exciton diffusion length in organic semiconductors. N,N'-di-[(1-naphthyl)-N,N'-diphenyl]-1,1'-biphenyl)-4,4' diamine (NPD) has been used as a model system. Triplet excitons are injected into a thin film of NPD by a phosphorescent thin film, which is optically excited and forms a sharp interface with the NPD layer. The penetration profile of the triplet excitons density is recorded by measuring the emission intensity of another phosphorescent material (detector), which is doped into the NPD film at variable distances from the injecting interface. From the obtained triplet penetration profile we extracted a triplet exciton diffusion length of 87+/-2.7 nm. For excitation power densities >1 mW/mm(2) triplet-triplet annihilation processes can significantly limit the triplet penetration depth into organic semiconductor. The proposed sample structure can be further used to study excitonic spin degree of freedom. PMID- 22540726 TI - Temperature-pressure scaling for air-fluidized grains near jamming. AB - We present experiments on a monolayer of air-fluidized beads in which a jamming transition is approached by increasing pressure, increasing packing fraction, and decreasing kinetic energy. This is accomplished, along with a noninvasive measurement of pressure, by tilting the system and examining behavior versus depth. We construct an equation of state and analyze relaxation time versus effective temperature. By making time and effective temperature dimensionless using factors of pressure, bead size, and bead mass, we obtain a good collapse of the data but to a functional form that differs from that of thermal hard-sphere systems. The relaxation time appears to diverge only as the effective temperature to pressure ratio goes to zero. PMID- 22540727 TI - Concentration polarization in translocation of DNA through nanopores and nanochannels. AB - In this Letter we provide a theory to show that high-field electrokinetic translocation of DNA through nanopores or nanochannels causes large transient variations of the ionic concentrations in front and at the back of the DNA due to concentration polarization (CP). The CP causes strong local conductivity variations, which can successfully explain the nontrivial current transients and ionic distributions observed in molecular dynamics simulations of nanopore DNA translocations as well as the transient current dips and spikes measured for translocating hairpin DNA. Most importantly, as the future of sequencing of DNA by nanopore translocation will be based on time-varying electrical conductance, CP, must be considered in experimental design and interpretation--currently these studies are mostly based on the incomplete pore conductance models that ignore CP and transients in the electrical conductance. PMID- 22540728 TI - Reorientation of a nonspherical capsule in creeping shear flow. AB - The dynamics of a capsule and a biological cell is of great interest in chemical engineering and bioengineering. Although the dynamics of a rigid spheroid is well understood by Jeffery's theory, that of a spheroidal capsule remains unclear. In this Letter, the motion of a spheroidal capsule or a red blood cell in creeping shear flow is investigated. The results show that the orientation of a nonspherical capsule is variant under time reversal, though that of a rigid spheroid is invariant. Surprisingly, the alignment of a nonspherical capsule over a long time duration shows a transition depending on the shear rate, which can be utilized for a particle-alignment technique. These findings form a fundamental basis of the suspension mechanics of capsules and biological cells. PMID- 22540729 TI - Modulating the precision of recurrent bursts in cultured neural networks. AB - Synchronized bursts are a very common feature in biological neural networks, and they play an important role in various brain functions and neurological diseases. This Letter investigates "recurrent synchronized bursts" induced by a single pulse stimulation in cultured networks of rat cortical neurons. We look at how the precision in their arrival times can be modified by a noble time-delayed stimulation protocol, which we term as "Deltat training." The emergence of recurrent bursts and the change of the precision in their arrival times can be explained by the stochastic resonance of a damped, subthreshold, neural oscillation. PMID- 22540730 TI - Accurate detection of interaural time differences by a population of slowly integrating neurons. AB - For localization of a sound source, animals and humans process the microsecond interaural time differences of arriving sound waves. How nervous systems, consisting of elements with time constants of about and more than 1 ms, can reach such high precision is still an open question. In this Letter we present a hypothesis and show theoretical and computational evidence that a rather large population of slowly integrating neurons with inhibitory and excitatory inputs (EI neurons) can detect minute temporal disparities in input signals which are significantly less than any time constant in the system. PMID- 22540731 TI - Shear-induced deformation of surfactant multilamellar vesicles. AB - Surfactant multilamellar vesicles (SMLVs) play a key role in the formulation of many industrial products, such as detergents, foodstuff, and cosmetics. In this Letter, we present the first quantitative investigation of the flow behavior of single SMLVs in a shearing parallel plate apparatus. We found that SMLVs are deformed and oriented by the action of shear flow while keeping constant volume and exhibit complex dynamic modes (i.e., tumbling, breathing, and tank treading). This behavior can be explained in terms of an excess area (as compared to a sphere of the same volume) and of microstructural defects, which were observed by 3D shape reconstruction through confocal microscopy. Furthermore, the deformation and orientation of SMLVs scale with radius R in analogy with emulsion droplets and elastic capsules (instead of R(3), such as in unilamellar vesicles). A possible application of the physical insight provided by this Letter is in the rationale design of processing methods of surfactant-based systems. PMID- 22540732 TI - Comment on "Energy-dependent excitation cross section measurements of the diagnostic lines of Fe XVII". PMID- 22540734 TI - Comment on "Ar+ and Xe+ velocities near the presheath-sheath boundary in an Ar/Xe discharge". PMID- 22540735 TI - Lactoferrin, a bird's eye view. AB - Lactoferrin is an abundant iron-binding protein in milk. This 80 kDa bilobal glycoprotein is also present in several other secreted bodily fluids, as well as in the secondary granules of neutrophils. The potent iron-binding properties of lactoferrin can locally create iron deficiency, and this is an important factor in host defense as it prevents bacteria from growing and forming biofilms. In addition to having antibacterial activity, lactoferrin is now known to have a long list of other beneficial biological properties. It has direct antiviral, antifungal, and even some anticancer activities. It can also promote wound healing and bone growth, or it can act as an iron carrier. Moreover, lactoferrin displays a cytokine-like "alarmin" activity, and it activates the immune system. Simultaneously, it can bind endotoxin (lipopolysaccharide), and in doing so, it modulates the activity of the host immune response. The majority of these intriguing biological activities reside in the unique positively charged N terminal region of the protein. Interestingly, several peptides, which retain many of the beneficial activities, can be released from this region of lactoferrin. An isoform of the human protein, known as delta-lactoferrin, is expressed inside many cells, where it acts as a transcription factor. Lactoferrin purified from human and bovine milk have very similar but not completely identical properties. Lactoferrin receptors have been identified on the surface of various cells, and some of these can bind both the human and the bovine protein. Because of the extensive health-promoting effects of lactoferrin, there has been considerable interest in the use of bovine or human lactoferrin as a "protein nutraceutical" or as a therapeutic protein. When lactoferrin is used as a "biologic drug", it seems to be orally active in contrast to most other therapeutic proteins. PMID- 22540736 TI - Novel inhibitor discovery through virtual screening against multiple protein conformations generated via ligand-directed modeling: a maternal embryonic leucine zipper kinase example. AB - Kinase targets have been demonstrated to undergo major conformational reorganization upon ligand binding. Such protein conformational plasticity remains a significant challenge in structure-based virtual screening methodology and may be approximated by screening against an ensemble of diverse protein conformations. Maternal embryonic leucine zipper kinase (MELK), a member of serine-threonine kinase family, has been recently found to be involved in the tumerogenic state of glioblastoma, breast, ovarian, and colon cancers. We therefore modeled several conformers of MELK utilizing the available chemogenomic and crystallographic data of homologous kinases. We carried out docking pose prediction and virtual screening enrichment studies with these conformers. The performances of the ensembles were evaluated by their ability to reproduce known inhibitor bioactive conformations and to efficiently recover known active compounds early in the virtual screen when seeded with decoy sets. A few of the individual MELK conformers performed satisfactorily in reproducing the native protein-ligand pharmacophoric interactions up to 50% of the cases. By selecting an ensemble of a few representative conformational states, most of the known inhibitor binding poses could be rationalized. For example, a four conformer ensemble is able to recover 95% of the studied actives, especially with imperfect scoring function(s). The virtual screening enrichment varied considerably among different MELK conformers. Enrichment appears to improve by selection of a proper protein conformation. For example, several holo and unliganded active conformations are better to accommodate diverse chemotypes than ATP-bound conformer. These results prove that using an ensemble of diverse conformations could give a better performance. Applying this approach, we were able to screen a commercially available library of half a million compounds against three conformers to discover three novel inhibitors of MELK, one from each template. Among the three compounds validated via experimental enzyme inhibition assays, one is relatively potent (15; K(d) = 0.37 MUM), one moderately active (12; K(d) = 3.2 MUM), and one weak but very selective (9; K(d) = 18 MUM). These novel hits may be utilized to assist in the development of small molecule therapeutic agents useful in diseases caused by deregulated MELK, and perhaps more importantly, the approach demonstrates the advantages of choosing an appropriate ensemble of a few conformers in pursuing compound potency, selectivity, and novel chemotypes over using single target conformation for structure-based drug design in general. PMID- 22540737 TI - An image-based biosensor assay strategy to screen for modulators of the microRNA 21 biogenesis pathway. AB - microRNAs (miRNAs) are evolutionary conserved, small endogenous non-coding, RNA molecules. Although their mode of action has been extensively studied, little is known about their biogenesis. As their altered expression has been implicated in many diseases, small molecules that would modulate their expression are sought after. They are generated through the concerted action of several complexes which promote their transcription, maturation, export, trafficking, and loading of mature miRNA into silencing complexes. An increasing number of studies have suggested that each of these steps serves as a regulatory junction in the process, and therefore provides an intervention point. For this purpose, we have developed a simple image-based assay strategy to screen for such modulators. Here, we describe its successful implementation which combines the use of a microRNA 21 (miR-21) synthetic mimic together with an EGFP based reporter cell line, where its expression is under the control of miR-21, to monitor EGFP expression in a format suitable for HTS. The strategy was further validated using a small panel of known gene modulators of the miRNA pathway. A screen was performed in duplicate against a library of 6,912 compounds and identified 48 initial positives exhibiting enhanced EGFP fluorescence intensity. 42 compounds were found to be inherently fluorescent in the green channel leaving the remaining 6 as potential inhibitors and with a positive rate of 0.09%. Taken together, this validated strategy offers the opportunity to discover novel and specific inhibitors of the pathway through the screening of diverse chemical libraries. PMID- 22540738 TI - Enhanced handling and positioning in early infancy advances development throughout the first year. AB - Behaviors emerge, in part, from the interplay of infant abilities and caregiver infant interactions. Cross-cultural and developmental studies suggest caregiver handling and positioning influence infant development. In this prospective, longitudinal study, the effects of 3 weeks of enhanced handling and positioning experiences provided to 14 infants versus control experiences provided to 14 infants at 2 months of age were assessed with follow-up through 15 months of age. Behaviors in prone were immediately advanced. Short-term advancements occurred in multiple behaviors, including prone, head control, reaching, and sitting behaviors. Longer term advancements, up to 12 months after the experience period, occurred in object transfer, crawling and walking behaviors. This suggests broad and long-lasting changes can arise via brief periods of change in caregiver infant interactions. PMID- 22540740 TI - Analysis of nerve supply pattern in thoracic duct in young and elderly men. AB - BACKGROUND: Analysis of the innervation pattern of the thoracic duct in young and elderly human subjects has been performed. The subdivision of the vessels in cervical and lumbar region were taken in consideration. METHODS AND RESULTS: Immunostaining for general nerve fibers with a PGP 9.5 marker disclosed a diffuse innervation of the thoracic duct in young subjects, which was strongly reduced in elderly subjects. In young subjects, tyrosine hydroxylase (TH) and neuropeptide Y (NPY) immunoreactive fibers, markers of noradrenergic postganglionic sympathetic fibers, were frequent; choline acetyltransferase (ChAT) immunoreactive fibers, marker of cholinergic parasympathetic nerve fibers, were also well represented. Therefore, the influence of sympathetic and parasympathetic nerve systems on the thoracic duct can be confirmed. The immunoreactivity of vasoactive intestinal peptide (VIP), a neuropeptide frequently present in cholinergic parasympathetic nerve fibers, was scarcely present. Dopamine-positive fibers were observed in few short nerve fibers. Substance P (SP)-positive fibers were widely distributed in the medial and intimal smooth muscle layers, suggesting their involvement as contractile modulating fibers and sensitive fibers. In elderly subjects, an evident reduction of all specific nerve fibers analyzed was detected, the ChAT positive fibers being the most affected. CONCLUSIONS: The lymphatic vessel thoracic duct is able to regulate hydrodynamic lymph flow by intrinsic contraction of its smooth muscle layer. Therefore, analysis of the thoracic duct innervation pattern may be important in assessing the regulation of vessel contraction. These findings called attention to the reduction of lymphatic drainage functionality affecting fluid balance in the elderly. PMID- 22540739 TI - Evidence of increased oxidative stress in aged mesenteric lymphatic vessels. AB - BACKGROUND: We have previously shown that aging is associated with weakened rat mesenteric lymphatic vessel (MLV) contractility. However, the specific mechanisms contributing to this aging-associated contractile degeneration remain unknown. Aging is often associated with elevations in oxidative stress, and reactive oxygen species (ROS) have been shown to reduce the contractility of MLV. Thus in the present study, we sought to assess whether aging is associated with increased levels of oxidative stress and oxidative damage in MLV. METHODS AND RESULTS: MLV were isolated from 9-mo- and 24-mo-old Fischer-344 rats and subjected to the following experimental techniques: measurement of total superoxide dismutase (SOD) activity; estimation of lipid peroxidation levels via measurement of thiobarbituric acid reactive substances (TBARS); detection of superoxide and mitochondrial ROS in live MLV; Western blot analysis, and immunohistochemical labeling of the SOD isoforms and nitro-tyrosine proteins. We found that aging is associated with increased levels of cellular superoxide and mitochondrial ROS concomitant with a reduction in Cu/Zn-SOD protein expression and total SOD enzymatic activity in MLV. This increase in oxidative stress and decrease in antioxidant activity was associated with evidence of increased lipid (as indicated by TBARS) and protein (as indicated by nitro-tyrosine labeling) oxidative damage. CONCLUSIONS: Thus for the first time, we demonstrate that aging associated increases in oxidative stress and oxidative damage is indeed present in the walls of MLV and may contribute to the aging-associated lymphatic pump dysfunction we previously reported. PMID- 22540741 TI - Doxycycline inhibits TREM-1 induction by Porphyromonas gingivalis. AB - The triggering receptor expressed on myeloid cells 1 (TREM-1) is a cell surface receptor of the immunoglobulin superfamily, with the capacity to amplify pro inflammatory cytokine production. Porphyromonas gingivalis is a Gram-negative anaerobic species highly implicated in inflammatory periodontal disease, with potential involvement in systemic inflammation. Porphyromonas gingivalis positively regulates TREM-1 expression and production in monocytic cells. Subantimicrobial doses of doxycycline (SDD) are used as an adjunct treatment in periodontal therapy, because of their anti-inflammatory properties. The aim of this study was to investigate the effect of SDD on P. gingivalis-induced TREM-1 expression and secretion by the myelomonocytic cell line MonoMac-6. After 24 h of challenge, P. gingivalis enhanced TREM-1 gene expression by the cells, with a concomitant increase in soluble TREM-1 release. Nevertheless, SDD concentrations between 2 and 10 MUg mL(-1) abolished TREM-1 expression and release, already after 4 h of administration. Moreover, SDD reduced P. gingivalis-induced interleukin-8 secretion, confirming its anti-inflammatory effects. In conclusion, SDD inhibits bacterially induced TREM-1, and this effect may partly account for its generalized anti-inflammatory properties. This could partly explain the clinical efficacy of SDD as an adjunctive treatment for periodontal disease, but may also indicate that SDD could serve as a suitable modulator of systemic inflammatory responses. PMID- 22540764 TI - Kinetics of the reductive dissolution of lead(IV) oxide by iodide. AB - Lead(IV) oxide (PbO(2)) is a corrosion product found in lead service lines used to convey drinking water. The presence of reductants can accelerate PbO(2) dissolution and enhance lead release to drinking water. The dissolution rate rather than the equilibrium solubility of PbO(2) can control the dissolved lead concentrations in water distributed through pipes containing PbO(2). Iodide, a known reductant for PbO(2), was selected as a model reductant for investigating the kinetics and mechanisms of the reductive dissolution of PbO(2). The dissolution rate of plattnerite (beta-PbO(2)) was determined as a function of pH, iodide concentration, and dissolved inorganic carbon (DIC) concentration using continuously stirred tank reactors. The dissolution rate of plattnerite increased with decreasing pH and increasing iodide concentrations. The presence of 10 mg C/L DIC accelerated plattnerite dissolution, but further increases in DIC concentration did not affect the dissolution rate. The reductive dissolution of PbO(2) can be interpreted as a coupled process involving chemical reduction of Pb(IV) to Pb(II) at the PbO(2) surface followed by detachment of Pb(II) to solution. The data suggest that chemical reduction is the rate-limiting step for PbO(2) dissolution in the presence of iodide. PMID- 22540742 TI - Modulation of bladder afferent signals in normal and spinal cord-injured rats by purinergic P2X3 and P2X2/3 receptors. AB - OBJECTIVE: To evaluate the role of bladder sensory purinergic P2X3 and P2X2/3 receptors on modulating the activity of lumbosacral neurones and urinary bladder contractions in vivo in normal or spinal cord-injured (SCI) rats with neurogenic bladder overactivity. MATERIALS AND METHODS: SCI was induced in female rats by complete transection at T8-T9 and experiments were performed 4 weeks later, when bladder overactivity developed. Non-transected rats were used as controls (normal rats). Neural activity was recorded in the dorsal horn of the spinal cord and field potentials were acquired in response to intravesical pressure steps via a suprapubic catheter. Field potentials were recorded under control conditions, after stimulation of bladder mucosal purinergic receptors with intravesical ATP (1 mm), and after intravenous injection of the P2X3/P2X2/3 antagonist AF-353 (10 mg/kg and 20 mg/kg). Cystometry was performed in urethane-anaesthetised rats intravesically infused with saline. AF-353 (10 mg/kg) was systemically applied after baseline recordings; the rats also received a second dose of AF-353 (20 mg/kg). Changes in the frequency of voiding (VC) and non-voiding (NVC) contractions were evaluated. RESULTS: SCI rats had significantly higher frequencies for field potentials and NVC than NL rats. Intravesical ATP increased field potential frequency in control but not SCI rats, while systemic AF-353 significantly reduced this parameter in both groups. AF-353 also reduced the inter-contractile interval in control but not in SCI rats; however, the frequency of NVC in SCI rats was significantly reduced. CONCLUSION: The P2X3/P2X2/3 receptors on bladder afferent nerves positively regulate sensory activity and NVCs in overactive bladders. PMID- 22540765 TI - Effects of syntactic cueing therapy on picture naming and connected speech in acquired aphasia. AB - Language therapy for word-finding difficulties in aphasia usually involves picture naming of single words with the support of cues. Most studies have addressed nouns in isolation, even though in connected speech nouns are more frequently produced with determiners. We hypothesised that improved word finding in connected speech would be most likely if intervention treated nouns in usual syntactic contexts. Six speakers with aphasia underwent language therapy using a software program developed for the purpose, which provided lexical and syntactic (determiner) cues. Exposure to determiners with nouns would potentially lead to improved picture naming of both treated and untreated nouns, and increased production of determiner plus noun combinations in connected speech. After intervention, picture naming of treated words improved for five of the six speakers, but naming of untreated words was unchanged. The number of determiner plus noun combinations in connected speech increased for four speakers. These findings attest to the close relationship between frequently co-occurring content and function words, and indicate that intervention for word-finding deficits can profitably proceed beyond single word naming, to retrieval in appropriate syntactic contexts. We also examined the relationship between effects of therapy, and amount and intensity of therapy. We found no relationship between immediate effects and amount or intensity of therapy. However, those participants whose naming maintained at follow-up completed the therapy regime in fewer sessions, of relatively longer duration. We explore the relationship between therapy regime and outcomes, and propose future considerations for research. PMID- 22540766 TI - Achieving high quality colonoscopy: using graphical representation to measure performance and reset standards. AB - AIM: Completeness and thoroughness of colonoscopy are measured by the caecal intubation rate (CIR) and the adenoma detection rate (ADR). National standards are >= 90% and >= 10% respectively. Variability in CIR and ADR have been demonstrated but comparison between individuals and units is difficult. We aimed to assess the performance of colonoscopy in endoscopy units in the northeast of England. METHOD: Data on colonoscopy performance and sedation use were collected over 3 months from 12 units. Colonoscopies performed by screening colonoscopists were included for the CIR only. Funnel plots with upper and lower 95% confidence limits for CIR and ADR were created. RESULTS: CIR was 92.5% (n = 5720) and ADR 15.9% (n = 4748). All units and 128 (99.2%) colonoscopists were above the lower limit for CIR. All units achieved the ADR standard with 10 above the upper limit. Ninety-nine (76.7%) colonoscopists were above 10%, 16 (12.4%) above the upper limit and 7 (5.4%) below the lower limit. Median medication doses were 2.2 mg midazolam, 29.4 mg pethidine and 83.3 MUg fentanyl. In all, 15.1% of colonoscopies were unsedated. Complications were bleeding (0.10%) and perforation (0.02%). There was one death possibly related to bowel preparation. CONCLUSION: Results indicate that colonoscopies are performed safely and to a high standard. Funnel plots can highlight variability and areas for improvement. Analyses of ADR presented graphically around the global mean suggest that the national standard should be reset at 15%. PMID- 22540767 TI - Repigmentation of hypopigmented scars using an erbium-doped 1,550-nm fractionated laser and topical bimatoprost. AB - BACKGROUND: Hypopigmented scarring is a challenging condition to treat, with current treatments showing limited efficacy and temporary results. Nonablative fractional resurfacing has been demonstrated to be an effective and safe modality in the treatment of hypopigmented scars. OBJECTIVES: To demonstrate the efficacy and safety of combining fractional resurfacing with topical bimatoprost and topical tretinoin or pimecrolimus for the treatment of hypopigmented scars. MATERIALS AND METHODS: Fourteen patients with hypopigmented scars were treated with a mean of 4.5 sessions of a fractionated 1,550-nm erbium-doped laser at 4- to 8-week intervals and subsequently started topical bimatoprost and tretinoin or pimecrolimus. An independent physician evaluated digital photographs taken before and 4 weeks after the last laser treatment using a quartile grading scale (grade 1, <=25% improvement; grade 2, 26-50% improvement; grade 3, 51-75% improvement; grade 4, >75% improvement). RESULTS: Five patients had >75% improvement in hypopigmentation, and 12 had >50% improvement. After a mean follow-up of 20.1 months, all patients demonstrated prolonged results. Side effects were limited to transitory post-treatment edema and erythema. CONCLUSION: The combination of fractional resurfacing, topical bimatoprost, and tretinoin or pimecrolimus is a potential effective resource for the treatment of hypopigmented scars, with long lasting results. PMID- 22540768 TI - Indicators for root caries in Danish persons with recently diagnosed Alzheimer's disease. AB - OBJECTIVE: To identify indicators of root caries among persons with newly diagnosed Alzheimer's disease (AD). BACKGROUND: Few studies have investigated dental caries in older adults with AD. Previously we found that persons with AD had significantly more root caries compared to persons with dementia other than AD. METHODS: Participants were recruited from two university hospital clinics in Copenhagen, Denmark. A team of neurologists/geriatricians carried out the diagnostic screening. The study included an interview, oral examination and medical records. RESULTS: We evaluated potential indicators of root decay across subjects with 3+ decayed surfaces vs. <3 decayed surfaces. Variables associated with increased odds of root caries were age over 80 years, 2+ decayed coronal surfaces and 5+ filled root surfaces. Among the social variables, living with someone was associated with a nearly 70% reduction in the odds of having 3+ surfaces of untreated caries. DISCUSSION: Root caries is highly prevalent among individuals with new AD and there is still a strong need for active assessment of and attention to oral problems in persons with AD. Our findings document that recently diagnosed AD cases with multiple coronal caries lesions are at elevated risk of having more root caries. Also persons 81+ years and those with multiple root fillings are more likely to have numerous untreated root lesions. PMID- 22540769 TI - Can an alpha-anomer of the trinitro form of D-glucopyranose be more easily hydrolyzed in alkaline environment than the beta-anomer? A detailed theoretical analysis. AB - Comprehensive computational investigations of detailed alkaline hydrolysis reaction pathways of the alpha-anomeric form of nitrocellulose monomer (2,3,6 trinitro-alpha-D-glucopyranose) in the (4)C(1) chair conformation within the S(N)2 framework in the gas phase and in bulk water solution are reported. Geometries of reactant complexes, transition states, intermediates, and completely denitrated product were optimized at the density functional theory (DFT) level using the B3LYP functional and the 6-311G(d,p) basis set both in the gas phase and in the bulk water solution. The effect of bulk water was modeled using the polarizable continuum model (PCM) approach. The nature of the potential energy surface of the local minima and transition states was ascertained through vibrational frequency analysis. Intrinsic reaction coordinate (IRC) calculations were also performed to validate the computed transition state structures. Effect of electron correlation on computed energies was considered through a single point energy calculation at the MP2 level using the cc-pVTZ basis set. It was revealed that the presence of hydrogen bonds between the attacking OH(-) ion and various hydrogen bond donating sites (including CH sites) of monomer was necessary for stabilization of the transition state. It was revealed that the alpha-anomer will be more reactive than the beta-anomer with regard to the denitration reaction. The role of entropy and the denitration ability of various sites are also discussed. PMID- 22540772 TI - Uncertainty relation for photons. AB - The uncertainty relation for the photons in three dimensions that overcomes the difficulties caused by the nonexistence of the photon position operator is derived in quantum electrodynamics. The photon energy density plays the role of the probability density in configuration space. It is shown that the measure of the spatial extension based on the energy distribution in space leads to an inequality that is a natural counterpart of the standard Heisenberg relation. The equation satisfied by the photon wave function in momentum space which saturates the uncertainty relations has the form of the Schrodinger equation in coordinate space in the presence of electric and magnetic charges. PMID- 22540773 TI - Stable periodic density waves in dipolar Bose-Einstein condensates trapped in optical lattices. AB - Density-wave patterns in discrete media with local interactions are known to be unstable. We demonstrate that stable double- and triple-period patterns (DPPs and TPPs), with respect to the period of the underlying lattice, exist in media with nonlocal nonlinearity. This is shown in detail for dipolar Bose-Einstein condensates, loaded into a deep one-dimensional optical lattice. The DPP and TPP emerge via phase transitions of the second and first kind, respectively. The emerging patterns may be stable if the dipole-dipole interactions are repulsive and sufficiently strong, in comparison with the local repulsive nonlinearity. Within the set of the considered states, the TPPs realize a minimum of the free energy. A vast stability region for the TPPs is found in the parameter space, while the DPP stability region is relatively narrow. The same mechanism may create stable density-wave patterns in other physical media featuring nonlocal interactions. PMID- 22540771 TI - Comparison of photographic and visual assessment of occlusal caries with histology as the reference standard. AB - BACKGROUND: The purpose of this study was to compare diagnostic performance for the detection of caries using photographs with an established visual examination method and histological sections as the reference standard. METHODS: 50 extracted permanent teeth were assessed for the presence of occlusal caries by 9 examiners using two methods; traditional visual examination developed by BASCD and photographs produced by an intra-oral camera. For both methods, diagnoses were made at "caries into dentine" level. The teeth were histologically sectioned and the diagnostic decisions using visual and photographic assessment were compared to the histological reference standard. Inter- and intra- examiner reliability for the methods was assessed and weighted kappa values were calculated. RESULTS: The visual examination method had a median sensitivity value of 65.6% and a median specificity value of 82.4%. The photographic assessments method had a median sensitivity of 81.3% and a median specificity of 82.4%. CONCLUSIONS: The photographic assessments method had a higher sensitivity for caries detection than the visual examination. The two methods had comparable specificities and good intra- and inter- examiner reliability. PMID- 22540774 TI - Controlling spin-spin network dynamics by repeated projective measurements. AB - We show that coupled-spin network manipulations can be made highly effective by repeated projections of the evolving quantum states onto diagonal density-matrix states (populations). As opposed to the intricately crafted pulse trains that are often used to fine-tune a complex network's evolution, the strategy hereby presented derives from the "quantum Zeno effect" and provides a highly robust route to guide the evolution by destroying all unwanted correlations (coherences). We exploit these effects by showing that a relaxationlike behavior is endowed to polarization transfers occurring within a N-spin coupled network. Experimental implementations yield coupling constant determinations for complex spin-coupling topologies, as demonstrated within the field of liquid-state nuclear magnetic resonance. PMID- 22540775 TI - Fermion bags, duality, and the three dimensional massless lattice thirring model. AB - The recently proposed fermion-bag approach is a powerful technique to solve some four-fermion lattice field theories. Because of the existence of a duality between strong and weak couplings, the approach leads to efficient Monte Carlo algorithms in both these limits. The new method allows us for the first time to accurately compute quantities close to the quantum critical point in the three dimensional lattice Thirring model with massless fermions on large lattices. The critical exponents at the quantum critical point are found to be nu=0.85(1), eta=0.65(1), and eta(psi)=0.37(1). PMID- 22540776 TI - Dirac semimetal in three dimensions. AB - We show that the pseudorelativistic physics of graphene near the Fermi level can be extended to three dimensional (3D) materials. Unlike in phase transitions from inversion symmetric topological to normal insulators, we show that particular space groups also allow 3D Dirac points as symmetry protected degeneracies. We provide criteria necessary to identify these groups and, as an example, present ab initio calculations of beta-cristobalite BiO(2) which exhibits three Dirac points at the Fermi level. We find that beta-cristobalite BiO(2) is metastable, so it can be physically realized as a 3D analog to graphene. PMID- 22540777 TI - Information trade-offs for optical quantum communication. AB - Recent work has precisely characterized the achievable trade-offs between three key information processing tasks-classical communication (generation or consumption), quantum communication (generation or consumption), and shared entanglement (distribution or consumption), measured in bits, qubits, and ebits per channel use, respectively. Slices and corner points of this three-dimensional region reduce to well-known protocols for quantum channels. A trade-off coding technique can attain any point in the region and can outperform time sharing between the best-known protocols for accomplishing each information processing task by itself. Previously, the benefits of trade-off coding that had been found were too small to be of practical value (viz., for the dephasing and the universal cloning machine channels). In this Letter, we demonstrate that the associated performance gains are in fact remarkably high for several physically relevant bosonic channels that model free-space or fiber-optic links, thermal noise channels, and amplifiers. We show that significant performance gains from trade-off coding also apply when trading photon-number resources between transmitting public and private classical information simultaneously over secret key-assisted bosonic channels. PMID- 22540778 TI - Parallel information transfer in a multinode quantum information processor. AB - We describe a method for coupling disjoint quantum bits (qubits) in different local processing nodes of a distributed node quantum information processor. An effective channel for information transfer between nodes is obtained by moving the system into an interaction frame where all pairs of cross-node qubits are effectively coupled via an exchange interaction between actuator elements of each node. All control is achieved via actuator-only modulation, leading to fast implementations of a universal set of internode quantum gates. The method is expected to be nearly independent of actuator decoherence and may be made insensitive to experimental variations of system parameters by appropriate design of control sequences. We show, in particular, how the induced cross-node coupling channel may be used to swap the complete quantum states of the local processors in parallel. PMID- 22540779 TI - Fast hybrid silicon double-quantum-dot qubit. AB - We propose a quantum dot qubit architecture that has an attractive combination of speed and fabrication simplicity. It consists of a double quantum dot with one electron in one dot and two electrons in the other. The qubit itself is a set of two states with total spin quantum numbers S(2)=3/4 (S=1/2) and S(z)=-1/2, with the two different states being singlet and triplet in the doubly occupied dot. Gate operations can be implemented electrically and the qubit is highly tunable, enabling fast implementation of one- and two-qubit gates in a simpler geometry and with fewer operations than in other proposed quantum dot qubit architectures with fast operations. Moreover, the system has potentially long decoherence times. These are all extremely attractive properties for use in quantum information processing devices. PMID- 22540780 TI - Ergodicity breaking and parametric resonances in systems with long-range interactions. AB - We explore the mechanism responsible for the ergodicity breaking in systems with long-range forces. In thermodynamic limit such systems do not evolve to the Boltzmann-Gibbs equilibrium, but become trapped in an out-of-equilibrium quasi stationary-state. Nevertheless, we show that if the initial distribution satisfies a specific constraint-a generalized virial condition-the quasistationary state is very close to ergodic and can be described by Lynden Bell statistics. On the other hand, if the generalized virial condition is violated, parametric resonances are excited, leading to chaos and ergodicity breaking. PMID- 22540770 TI - UK Dermatology Clinical Trials Network's STOP GAP trial (a multicentre trial of prednisolone versus ciclosporin for pyoderma gangrenosum): protocol for a randomised controlled trial. AB - BACKGROUND: Pyoderma gangrenosum (PG) is a rare inflammatory skin disorder characterised by painful and rapidly progressing skin ulceration. PG can be extremely difficult to treat and patients often require systemic immunosuppression. Recurrent lesions of PG are common, but the relative rarity of this condition means that there is a lack of published evidence regarding its treatment. A systematic review published in 2005 found no randomised controlled trials (RCTs) relating to the treatment of PG. Since this time, one small RCT has been published comparing infliximab to placebo, but none of the commonly used systemic treatments for PG have been formally assessed. The UK Dermatology Clinical Trials Network's STOP GAP Trial has been designed to address this lack of trial evidence. METHODS: The objective is to assess whether oral ciclosporin is more effective than oral prednisolone for the treatment of PG. The trial design is a two-arm, observer-blind, parallel-group, randomised controlled trial comparing ciclosporin (4 mg/kg/day) to prednisolone (0.75 mg/kg/day). A total of 140 participants are to be recruited over a period of 4 years, from up to 50 hospitals in the UK and Eire. Primary outcome of velocity of healing at 6 weeks is assessed blinded to treatment allocation (using digital images of the ulcers). Secondary outcomes include: (i) time to healing; (ii) global assessment of improvement; (iii) PG inflammation assessment scale score; (iv) self-reported pain; (v) health-related quality of life; (vi) time to recurrence; (vii) treatment failures; (viii) adverse reactions to study medications; and (ix) cost effectiveness/utility. Patients with a clinical diagnosis of PG (excluding granulomatous PG); measurable ulceration (that is, not pustular PG); and patients aged over 18 years old who are able to give informed consent are included in the trial. Randomisation is by computer generated code using permuted blocks of randomly varying size, stratified by lesion size, and presence or absence of underlying systemic disease (for example, rheumatoid arthritis).Patients who require topical therapy are asked to enter a parallel observational study (case series). If topical therapy fails and systemic therapy is required, participants are then considered for inclusion in the randomised trial. TRIAL REGISTRATION: Current controlled trials: ISRCTN35898459. Eudract No.2008-008291-14. PMID- 22540781 TI - Reduction of thermal fluctuations in a cryogenic laser interferometric gravitational wave detector. AB - The thermal fluctuation of mirror surfaces is the fundamental limitation for interferometric gravitational wave (GW) detectors. Here, we experimentally demonstrate for the first time a reduction in a mirror's thermal fluctuation in a GW detector with sapphire mirrors from the Cryogenic Laser Interferometer Observatory at 17 and 18 K. The detector sensitivity, which was limited by the mirror's thermal fluctuation at room temperature, was improved in the frequency range of 90 to 240 Hz by cooling the mirrors. The improved sensitivity reached a maximum of 2.2*10(-19) m/?Hz at 165 Hz. PMID- 22540782 TI - Time and a physical Hamiltonian for quantum gravity. AB - We present a nonperturbative quantization of general relativity coupled to dust and other matter fields. The dust provides a natural time variable, leading to a physical Hamiltonian with spatial diffeomorphism symmetry. The surprising feature is that the Hamiltonian is not a square root. This property, together with the kinematical structure of loop quantum gravity, provides a complete theory of quantum gravity, and puts applications to cosmology, quantum gravitational collapse, and Hawking radiation within technical reach. PMID- 22540783 TI - What do gas-rich galaxies actually tell us about modified Newtonian dynamics? AB - It has recently been claimed that measurements of the baryonic Tully-Fisher relation (BTFR), a power-law relationship between the observed baryonic masses and outer rotation velocities of galaxies, support the predictions of modified Newtonian dynamics for the slope and scatter in the relation, while challenging the cold dark matter (CDM) paradigm. We investigate these claims, and find that (1) the scatter in the data used to determine the BTFR is in conflict with observational uncertainties on the data, (2) these data do not make strong distinctions regarding the best-fit BTFR parameters, (3) the literature contains a wide variety of measurements of the BTFR, many of which are discrepant with the recent results, and (4) the claimed CDM "prediction" for the BTFR is a gross oversimplification of the complex galaxy-scale physics involved. We conclude that the BTFR is currently untrustworthy as a test of CDM. PMID- 22540784 TI - K->(pipi)(I=2) decay amplitude from lattice QCD. AB - We report on the first realistic ab initio calculation of a hadronic weak decay, that of the amplitude A(2) for a kaon to decay into two pi mesons with isospin 2. We find ReA(2)=(1.436+/-0.063(stat)+/-0.258(syst))10(-8) GeV in good agreement with the experimental result and for the hitherto unknown imaginary part we find ImA(2)=-(6.83+/-0.51(stat)+/-1.30(syst))10(-13) GeV. Moreover combining our result for ImA(2) with experimental values of ReA(2), ReA(0), and epsilon'/epsilon, we obtain the following value for the unknown ratio ImA(0)/ReA(0) within the standard model: ImA(0)/ReA(0)= 1.63(19)(stat)(20(syst)*10(-4). One consequence of these results is that the contribution from ImA(2) to the direct CP violation parameter epsilon' (the so called Electroweak Penguin contribution) is Re(epsilon'/epsilon)(EWP)=-(6.52+/ 0.49(stat)+/-1.24(syst))*10(-4). We explain why this calculation of A(2) represents a major milestone for lattice QCD and discuss the exciting prospects for a full quantitative understanding of CP violation in kaon decays. PMID- 22540785 TI - Could the excess seen at 124-126 GeV be due to the Randall-Sundrum radion? AB - Current Higgs boson searches in various channels at the LHC point to an excess at around 124-126 GeV due to a possibly standard-model-like Higgs boson. If one examines more closely the channels (gammagamma, WW(*), and ZZ(*)) that have excess, this "Higgs boson" may be the Randall-Sundrum radion phi. Because of the trace anomaly, the radion has stronger couplings to the photon and gluon pairs. Thus, it will enhance the production rates into gg and gammagamma, while those for WW(*), ZZ(*), and b b are reduced relative to their standard model values. We show that it can match well with the data from CMS for m(phi)=124 GeV, and the required scale Lambda(phi)~ is about 0.68 TeV. PMID- 22540787 TI - Nuclear charge radius of 12Be. AB - The nuclear charge radius of (12)Be was precisely determined using the technique of collinear laser spectroscopy on the 2s(1/2)->2p(1/2,3/2) transition in the Be(+) ion. The mean square charge radius increases from (10)Be to (12)Be by delta(10,12)=0.69(5) fm(2) compared to delta(10,11)=0.49(5) fm(2) for the one-neutron halo isotope ^{11}Be. Calculations in the fermionic molecular dynamics approach show a strong sensitivity of the charge radius to the structure of ^{12}Be. The experimental charge radius is consistent with a breakdown of the N=8 shell closure. PMID- 22540788 TI - Abrupt change in radiation-width distribution for 147Sm neutron resonances. AB - We obtained the total radiation widths of s-wave resonances through an R-matrix analysis of (147)Sm(n,gamma) cross sections. Distributions of these widths differ markedly for resonances below and above E(n)=300 eV, which is in stark contrast to long-established theory. We show that this change, as well as a similar change in the neutron-width distribution reported previously, is reflected in abrupt increases in both the average (147)Sm(n,gamma) cross section and fluctuations about the average near 300 eV. Such effects could have important consequences for applications such as nuclear astrophysics and nuclear criticality safety. PMID- 22540789 TI - Evidence for the ground-state resonance of 26O. AB - Evidence for the ground state of the neutron-unbound nucleus (26)O was observed for the first time in the single proton-knockout reaction from a 82 MeV/u (27)F beam. Neutrons were measured in coincidence with (24)O fragments. (26)O was determined to be unbound by 150(-150)(+50) keV from the observation of low-energy neutrons. This result agrees with recent shell-model calculations based on microscopic two- and three-nucleon forces. PMID- 22540790 TI - Frequency metrology of helium around 1083 nm and determination of the nuclear charge radius. AB - We measure the absolute frequency of seven out of the nine allowed transitions between the 2 (3)S and 2 (3)P hyperfine manifolds in a metastable (3)He beam by using an optical frequency comb synthesizer-assisted spectrometer. The relative uncertainty of our measurements ranges from 1*10(-11) to 5*10(-12), which is, to our knowledge, the most precise result for any optical ^{3}He transition to date. The resulting 2 (3)P-2 (3)S centroid frequency is 276,702,827,204.8(2.4) kHz. Comparing this value with the known result for the (4)He centroid and performing ab initio QED calculations of the (4)He-(3)He isotope shift, we extract the difference of the squared nuclear charge radii deltar(2) of (3)He and (4)He. Our result for deltar(2)=1.074(3) fm(2) disagrees by about 4sigma with the recent determination [R. van Rooij et al., Science 333, 196 (2011)]. PMID- 22540791 TI - Muonium emission into vacuum from mesoporous thin films at cryogenic temperatures. AB - We report on muonium (Mu) emission into vacuum following MU(+) implantation in mesoporous thin SiO(2) films. We obtain a yield of Mu into vacuum of (38+/-4)% at 250 K and (20+/-4)% at 100 K for 5 keV MU(+) implantation energy. From the implantation energy dependence of the Mu vacuum yield we determine the Mu diffusion constants in these films: D(Mu)(250 K)=(1.6+/-0.1)*10(-4) cm(2)/s and D(Mu)(100 K)=(4.2+/-0.5)*10(-5) cm(2)/s. Describing the diffusion process as quantum mechanical tunneling from pore to pore, we reproduce the measured temperature dependence ~T(3/2) of the diffusion constant. We extract a potential barrier of (-0.3+/-0.1) eV which is consistent with our computed Mu work function in SiO(2) of [-0.3,-0.9] eV. The high Mu vacuum yield, even at low temperatures, represents an important step toward next generation Mu spectroscopy experiments. PMID- 22540786 TI - Measurement of the neutron F2 structure function via spectator tagging with CLAS. AB - We report on the first measurement of the F(2) structure function of the neutron from the semi-inclusive scattering of electrons from deuterium, with low-momentum protons detected in the backward hemisphere. Restricting the momentum of the spectator protons to ?100 MeV/c and their angles to ?100 degrees relative to the momentum transfer allows an interpretation of the process in terms of scattering from nearly on-shell neutrons. The F(2)(n) data collected cover the nucleon resonance and deep-inelastic regions over a wide range of Bjorken x for 0.651) allowing spatially localized measurements of the ion or electron plasma temperatures and of the plasma bulk velocity. The ablation flow is found to accelerate towards the axis reaching peak velocities of 1.2-1.3*10(7) cm/s in aluminium and ~1*10(7) cm/s in tungsten arrays. Precursor ion temperature measurements made shortly after formation are found to correspond to the kinetic energy of the converging ablation flow. PMID- 22540800 TI - Driven spatially autoresonant stimulated Raman scattering in the kinetic regime. AB - The autoresonant behavior of Langmuir waves excited by stimulated Raman scattering (SRS) is clearly identified in particle-in-cell (PIC) simulations in an inhomogeneous plasma. As previously shown via a 3-wave coupling model [T. Chapman et al., Phys. Plasmas 17, 122317 (2010)], weakly kinetic effects such as trapping can be described via an amplitude-dependent frequency shift that compensates the dephasing of the resonance of SRS due to the inhomogeneity. The autoresonance (AR) leads to phase locking and to growth of the Langmuir wave beyond the spatial amplification expected from Rosenbluth's model in an inhomogeneous profile [M. N. Rosenbluth, Phys. Rev. Lett. 29, 565 (1972)]. Results from PIC simulations and from a 3-wave coupling code show very good agreement, leading to the conclusion that AR arises even beyond the so-called weakly kinetic regime. PMID- 22540801 TI - Parametric amplification of laser-driven electron acceleration in underdense plasma. AB - A new mechanism is reported that increases electron energy gain from a laser beam of ultrarelativistic intensity in underdense plasma. The increase occurs when the laser produces an ion channel that confines accelerated electrons. The frequency of electron oscillations across the channel is strongly modulated by the laser beam, which causes parametric amplification of the oscillations and enhances the electron energy gain. This mechanism has a threshold determined by a product of beam intensity and ion density. PMID- 22540802 TI - Bond order solid of two-dimensional dipolar fermions. AB - The recent experimental realization of dipolar Fermi gases near or below quantum degeneracy provides an opportunity to engineer Hubbard-like models with long range interactions. Motivated by these experiments, we chart out the theoretical phase diagram of interacting dipolar fermions on the square lattice at zero temperature and half filling. We show that, in addition to p-wave superfluid and charge density wave order, two new and exotic types of bond order emerge generically in dipolar fermion systems. These phases feature homogeneous density but periodic modulations of the kinetic hopping energy between nearest or next nearest neighbors. Similar, but manifestly different, phases of two-dimensional correlated electrons have previously only been hypothesized and termed "density waves of nonzero angular momentum." Our results suggest that these phases can be constructed flexibly with dipolar fermions, using currently available experimental techniques. PMID- 22540803 TI - BCS-BEC crossover in 2D Fermi gases with Rashba spin-orbit coupling. AB - We present a systematic theoretical study of the BCS-BEC crossover in two dimensional Fermi gases with Rashba spin-orbit coupling (SOC). By solving the exact two-body problem in the presence of an attractive short-range interaction we show that the SOC enhances the formation of the bound state: the binding energy E(B) and effective mass m(B) of the bound state grows along with the increase of the SOC. For the many-body problem, even at weak attraction, a dilute Fermi gas can evolve from a BCS superfluid state to a Bose condensation of molecules when the SOC becomes comparable to the Fermi momentum. The ground-state properties and the Berezinskii-Kosterlitz-Thouless (BKT) transition temperature are studied, and analytical results are obtained in various limits. For large SOC, the BKT transition temperature recovers that for a Bose gas with an effective mass m(B). We find that the condensate and superfluid densities have distinct behaviors in the presence of SOC: the condensate density is generally enhanced by the SOC due to the increase of the molecule binding; the superfluid density is suppressed because of the nontrivial molecule effective mass m(B). PMID- 22540804 TI - Self-trapping of magnon Bose-Einstein condensates in the ground state and on excited levels: from harmonic to box confinement. AB - Long-lived coherent spin precession of (3)He-B at low temperatures around 0.2T(c) is a manifestation of Bose-Einstein condensation of spin-wave excitations or magnons in a magnetic trap which is formed by the order-parameter texture and can be manipulated experimentally. When the number of magnons increases, the orbital texture reorients under the influence of the spin-orbit interaction and the profile of the trap gradually changes from harmonic to a square well, with walls almost impenetrable to magnons. This is the first experimental example of Bose condensation in a box. By selective rf pumping the trap can be populated with a ground-state condensate or one at any of the excited energy levels. In the latter case the ground state is simultaneously populated by relaxation from the exited level, forming a system of two coexisting condensates. PMID- 22540805 TI - Density instabilities in a two-dimensional dipolar Fermi gas. AB - We study the density instabilities of a two-dimensional gas of dipolar fermions with aligned dipole moments. The random phase approximation (RPA) for the density density response function is never accurate for the dipolar gas, and so we incorporate correlations beyond RPA via an improved version of the Singwi-Tosi Land-Sjolander scheme. In addition to density-wave instabilities, our formalism captures the collapse instability that is expected from Hartree-Fock calculations but is absent from RPA. Crucially, we find that when the dipoles are perpendicular to the layer, the system spontaneously breaks rotational symmetry and forms a stripe phase, in defiance of conventional wisdom. PMID- 22540806 TI - Measurements of Tan's contact in an atomic Bose-Einstein condensate. AB - A powerful set of universal relations, centered on a quantity called the contact, connects the strength of short-range two-body correlations to the thermodynamics of a many-body system with zero-range interactions. We report on measurements of the contact, using rf spectroscopy, for an (85)Rb atomic Bose-Einstein condensate (BEC). For bosons, the fact that contact spectroscopy can be used to probe the gas on short time scales is useful given the decreasing stability of BECs with increasing interactions. A complication is the added possibility, for bosons, of three-body interactions. In investigating this issue, we have located an Efimov resonance for (85)Rb atoms with loss measurements and thus determined the three body interaction parameter. In our contact spectroscopy, in a region of observable beyond-mean-field effects, we find no measurable contribution from three-body physics. PMID- 22540807 TI - Dynamic structure mediated by graphitelike Al nets on the Al2Cu (001) surface. AB - A detailed study of the (001) surface of the Al(2)Cu crystal using both experimental and ab initio computational methods is presented in this work. The combination of both approaches gives many arguments to match the surface plane with a bulk truncated surface model terminated by incomplete Al planes. The missing rows of Al atoms lead to a 2?2*?2R 45 degrees surface reconstruction with two domains rotated by 90 degrees from each other. Ab initio calculations demonstrate that the energetic cost associated with the removal of pairs of Al atoms is the lowest for the two nearest surface Al atoms (covalentlike interaction). They reveal that the remaining atomic rows of various widths are oriented according to the graphitelike Al 6(3) nets used to describe the Al(2)Cu bulk structure. The surface dynamics observed at 300 K at the Al(2)Cu surface is also presented. Finally, configurational and vibrational entropies are introduced to discuss the reduced surface plane density. PMID- 22540808 TI - Field-induced expansion deformation in Pb islands on Cu(111): evidence from energy shift of empty quantum-well states. AB - We use scanning tunneling microscopy and spectroscopy to measure the energy shift of empty quantum-well (QW) states in Pb islands on the Cu(111) surface. It is found that, with an increase of the electric field, the behavior of the energy shift can be grouped into two different modes for most QW states. In the first mode, the state energy moves toward high energy monotonically. In the second mode, the state energy shifts to a lower energy initially and then turns around to a higher energy. Moreover, we have observed that the QW states of higher energy behave in preference to the first mode, but they gradually change to the second mode as the Pb island becomes thicker. This thickness-dependent behavior reflects the existence of local expansion in the Pb islands, due to the electric field, and that the expansion is larger for a thicker island. QW states can thus be used for studying the localized lattice deformation in the nanometer scale. PMID- 22540809 TI - Density-functional theory with screened van der Waals interactions for the modeling of hybrid inorganic-organic systems. AB - The electronic properties and the function of hybrid inorganic-organic systems (HIOS) are intimately linked to their interface geometry. Here we show that the inclusion of the many-body collective response of the substrate electrons inside the inorganic bulk enables us to reliably predict the HIOS geometries and energies. This is achieved by the combination of dispersion-corrected density functional theory (the DFT+ van der Waals approach) [Phys. Rev. Lett. 102, 073005 (2009)], with the Lifshitz-Zaremba-Kohn theory for the nonlocal Coulomb screening within the bulk. Our method yields geometries in remarkable agreement (~0.1 A) with normal incidence x-ray standing wave measurements for the 3, 4, 9, 10 perylene-tetracarboxylic acid dianhydride (C(24)O(6)H(8), PTCDA) molecule on Cu(111), Ag(111), and Au(111) surfaces. Similarly accurate results are obtained for xenon and benzene adsorbed on metal surfaces. PMID- 22540810 TI - Kohn-Sham self-interaction correction in real time. AB - We present a solution scheme for the time-dependent Kohn-Sham self-interaction correction. Based on the generalized optimized effective potential approach, the multiplicative Kohn-Sham potential is constructed in real time and real space for the self-interaction corrected local density approximation. Excitations of different character, including charge-transfer excitations that had been regarded as prime examples for the failure of standard time-dependent density functionals, are described correctly by this approach. We analyze the time-dependent exchange correlation potential and density, revealing features that are decisive for the correct description of the response. PMID- 22540811 TI - Synchrotron infrared measurements of dense hydrogen to 360 GPa. AB - Diamond-anvil-cell techniques have been developed to confine and measure hydrogen samples under static conditions to pressures above 300 GPa from 12 to 300 K using synchrotron infrared and optical absorption techniques. A decreasing absorption threshold in the visible spectrum is observed, but the material remains transparent at photon energies down to 0.1 eV at pressures to 360 GPa over a broad temperature range. The persistence of the strong infrared absorption of the vibron characteristic of phase III indicates the stability of the paired state of hydrogen. There is no evidence for the predicted metallic state over these conditions, in contrast to recent reports, but electronic properties consistent with semimetallic behavior are observed. PMID- 22540812 TI - Spin exciton formation inside the hidden order phase of CeB6. AB - The heavy fermion metal CeB(6) exhibits a hidden order of the antiferroquadrupolar (AFQ) type below T(Q)=3.2 K and a subsequent antiferromagnetic (AFM) order at T(N)=2.3 K. It was interpreted as an ordering of the quadrupole and dipole moments of a Gamma(8) quartet of localized Ce 4f(1) electrons. This established picture has been profoundly shaken by recent inelastic neutron scattering (G. Friemel et al., arXiv:1111.4151) that found the evolution of a feedback spin exciton resonance within the hidden order phase at the AFQ wave vector which is stabilized by the AFM order. We develop an alternative theory based on a fourfold degenerate Anderson lattice model, including both order parameters as particle-hole condensates of itinerant heavy quasiparticles. This explains in a natural way the appearance of the spin exciton resonance and the momentum dependence of its spectral weight, in particular, around the AFQ vector and its rapid disappearance in the disordered phase. Analogies to the feedback effect in unconventional heavy fermion superconductors are pointed out. PMID- 22540813 TI - Direct observation of charge ordering in magnetite using resonant multiwave x-ray diffraction. AB - Charge disproportion at octahedral Fe sites in magnetite was observed at low temperature using two inversion-symmetry related three-wave resonant x-ray diffraction, 022-311 and 002-31, near the iron K edge. Both of the three-wave cases involve the (002) forbidden-weak reflection. The self-normalized three-wave to two-wave (002) diffraction intensity ratio automatically cancels the self absorption effect and leads to direct determination of charge disproportion for magnetite below 120 K. This approach provides a more direct and effective way for extracting charge-ordering information. PMID- 22540814 TI - Computational design of axion insulators based on 5d spinel compounds. AB - Based on density functional calculation using the local density approximation+U method, we predict that osmium compounds such as CaOs(2)O(4) and SrOs(2)O(4) can be stabilized in the geometrically frustrated spinel crystal structure. They show ferromagnetic order in a reasonable range of the on-site Coulomb correlation U and exotic electronic properties, in particular, a large magnetoelectric coupling characteristic of axion electrodynamics. Depending on U, other electronic phases including a 3D Weyl semimetal and Mott insulator are also shown to occur. PMID- 22540815 TI - Detection of vibration-mode scattering in electronic shot noise. AB - We present shot noise measurements on Au nanowires showing very pronounced vibration-mode features. In accordance to recent theoretical predictions the sign of the inelastic signal, i.e., the signal due to vibration excitations, depends on the transmission probability becoming negative below a certain transmission value. We argue that the negative contribution to noise arises from coherent two electron processes mediated by electron-phonon scattering and the Pauli exclusion principle. These signals can provide unique information on the local phonon population and lattice temperature of the nanoscale system. PMID- 22540816 TI - Model of an exotic chiral superconducting phase in a graphene bilayer. AB - We theoretically demonstrate the formation of a new type of unconventional superconductivity in graphene materials, which exhibits a gapless property. The studied superconductivity is based on an interlayer pairing of chiral electrons in bilayer graphene, which results in an exotic s-wave spin-triplet condensate order with anomalous thermodynamic properties. These include the possibility of a temperature-induced condensation causing an increase of the pairing gap with increasing temperature and an entropy of the stable superconducting state which can be higher than its value in the normal state. Our study reveals the analogy of the interlayer superconductivity in graphene materials to the color superconductivity in dense quark matter and the gapless pairing states in nuclear matter and ultracold atomic gases. PMID- 22540817 TI - Electronic correlations and unconventional spectral weight transfer in the high temperature pnictide BaFe(2-x)Co(x)As(2) superconductor using infrared spectroscopy. AB - We report an infrared optical study of the pnictide high-temperature superconductor BaFe(1.84)Co(0.16)As(2) and its parent compound BaFe(2)As(2). We demonstrate that electronic correlations are moderately strong and do not change across the spin-density wave transition or with doping. By examining the energy scale and direction of spectral weight transfer, we argue that Hund's coupling J is the primary mechanism that gives rise to correlations. PMID- 22540818 TI - Topological superconductivity in bilayer Rashba system. AB - We theoretically study a possible topological superconductivity in the interacting two layers of Rashba systems, which can be fabricated by the heterostructures of semiconductors and oxides. The hybridization, which induces the gap in the single particle dispersion, and the electron-electron interaction between the two layers leads to the novel phase diagram of the superconductivity. It is found that the topological superconductivity without breaking time-reversal symmetry is realized when (i) the Fermi energy is within the hybridization gap, and (ii) the interlayer interaction is repulsive, both of which can be satisfied in realistic systems. Edge channels are studied in a tight-binding model numerically, and the several predictions on experiments are also given. PMID- 22540819 TI - Resonance measurement of nonlocal spin torque in a three-terminal magnetic device. AB - A pure spin current generated within a nonlocal spin valve can exert a spin transfer torque on a nanomagnet. This nonlocal torque enables new design schemes for magnetic memory devices that do not require the application of large voltages across tunnel barriers that can suffer electrical breakdown. Here we report a quantitative measurement of this nonlocal spin torque using spin-torque-driven ferromagnetic resonance. Our measurement agrees well with the prediction of an effective circuit model for spin transport. Based on this model, we suggest strategies for optimizing the strength of nonlocal torque. PMID- 22540820 TI - Time-domain observation of the spinmotive force in permalloy nanowires. AB - The spinmotive force associated with a moving domain wall is observed directly in Permalloy nanowires using real time voltage measurements with proper subtraction of the electromotive force. Whereas the wall velocity exhibits nonlinear dependence on magnetic field, the generated voltage increases linearly with the field. We show that the sign of the voltage reverses when the wall propagation direction is altered. Numerical simulations explain quantitatively these features of spinmotive force and indicate that it scales with the field even in a field range where the wall motion is no longer associated with periodic angular rotation of the wall magnetization. PMID- 22540821 TI - Superradiant optical emitters coupled to an array of nanosize metallic antennas. AB - We study the properties of an array of Au ring nanoantennas fed by an ensemble of coherent emitters. The luminescence of the emitters is strongly enhanced at certain wavelengths due to the excitation of two types of resonances-the diffractive Rayleigh anomalies associated with the opening of new diffraction orders and the localized surface plasmons of the nanoantennas. We show that the two families of resonances can spectrally overlap and lead to anticrossings or cumulative enhancements depending on the symmetries of the modes. This rich optical behavior induces marked changes in the linewidth, shape, and amplitude of the peaks and could be potentially used to tune the luminescence of superradiant sources with new flexibility. PMID- 22540822 TI - Monopoles, magnetricity, and the stray field from spin ice. AB - An analysis is presented of the behavior of muons in the low-temperature state in spin ice. It is shown in detail how the behavior observed in some previous muon experiments on spin ice in a weak transverse field may result from the macroscopic stray field of magnetized spin ice. A model is presented which allows these macroscopic field effects to be simulated and the results agree with experiment. The persistent spin dynamics at low temperature originate from the sample and could be a muon-induced implantation effect that is operative in out of-equilibrium systems with long relaxation times. PMID- 22540823 TI - Widely tunable, nondegenerate three-wave mixing microwave device operating near the quantum limit. AB - We present the first experimental realization of a widely frequency tunable, nondegenerate three-wave mixing device for quantum signals at gigahertz frequency. It is based on a new superconducting building block consisting of a ring of four Josephson junctions shunted by a cross of four linear inductances. The phase configuration of the ring remains unique over a wide range of magnetic fluxes threading the loop. It is thus possible to vary the inductance of the ring with flux while retaining a strong, dissipation-free, and noiseless nonlinearity. The device has been operated in amplifier mode, and its noise performance has been evaluated by using the noise spectrum emitted by a voltage-biased tunnel junction at finite frequency as a test signal. The unprecedented accuracy with which the crossover between zero-point fluctuations and shot noise has been measured provides an upper bound for the noise and dissipation intrinsic to the device. PMID- 22540824 TI - Scale-invariant correlations in dynamic bacterial clusters. AB - In Bacillus subtilis colonies, motile bacteria move collectively, spontaneously forming dynamic clusters. These bacterial clusters share similarities with other systems exhibiting polarized collective motion, such as bird flocks or fish schools. Here we study experimentally how velocity and orientation fluctuations within clusters are spatially correlated. For a range of cell density and cluster size, the correlation length is shown to be 30% of the spatial size of clusters, and the correlation functions collapse onto a master curve after rescaling the separation with correlation length. Our results demonstrate that correlations of velocity and orientation fluctuations are scale invariant in dynamic bacterial clusters. PMID- 22540825 TI - Microscale rheology of a soft glassy material close to yielding. AB - Using confocal microscopy, we study the flow of a model soft glassy material: a concentrated emulsion. We demonstrate the micro-macro link between in situ measured movements of droplets during the flow and the macroscopic rheological response of a concentrated emulsion, in the form of scaling relationships connecting the rheological "fluidity" with local standard deviation of the strain rate tensor. Furthermore, we measure correlations between these local fluctuations, thereby extracting a correlation length which increases while approaching the yielding transition, in accordance with recent theoretical predictions. PMID- 22540826 TI - Packing spheres tightly: influence of mechanical stability on close-packed sphere structures. AB - Many experiments and simulations of packings of monodisperse hard spheres report a dominance of the face-centered cubic structure in the hexagonally close-packed limit, even though it has no significant energetic or entropic gain over other close-packed configurations. Combining simulations and experiments, we demonstrate that a simple mechanical instability which occurs during the packing process may play an important role in selecting the face-centered cubic structure over other close-packed alternatives. Our argument is supported by detailed quantitative analyses of key configurations in sphere packings and highlights the importance of the packing dynamics. The proposed mechanism is elementary and should therefore play a role in a wide range of sphere systems. PMID- 22540827 TI - Comment on "Electronic structure of superconducting KC8 and nonsuperconducting LiC6 graphite intercalation compounds: evidence for a graphene-sheet-driven superconducting state". PMID- 22540829 TI - Pillar[6]arene-based photoresponsive host-guest complexation. AB - The trans form of an azobenzene-containing guest can complex with a pillar[6]arene, while it cannot complex with pillar[5]arenes due to the different cavity sizes of the pillar[6]arene and the pillar[5]arenes. The spontaneous aggregation of its host-guest complex with the pillar[6]arene can be reversibly photocontrolled by irradiation with UV and visible light, leading to a switch between irregular aggregates and vesicle-like aggregates. This new pillar[6]arene based photoresponsive host-guest recognition motif can work in organic solvents and is a good supplement to the existing widely used cyclodextrin/azobenzene recognition motif. PMID- 22540830 TI - Nelfinavir inhibits regulated intramembrane proteolysis of sterol regulatory element binding protein-1 and activating transcription factor 6 in castration resistant prostate cancer. AB - Nelfinavir induces apoptosis in liposarcoma by inhibiting site-2 protease (S2P) activity, which leads to suppression of regulated intramembrane proteolysis. We postulate similar effects in castration-resistant prostate cancer because it exhibits a lipogenic phenotype. Nelfinavir inhibited androgen receptor activation in androgen-sensitive prostate cancer and the nuclear translocation of the fusion proteins sterol regulatory element binding protein-1 (SREBP-1)-enhanced green fluorescence protein (EGFP) and activating transcription factor 6 (ATF6)-EGFP in castration-resistant prostate cancer cells, viewed under confocal microscopy. Nelfinavir and site-1 protease (S1P) and S2P small interfering RNAs (siRNAs) reduced the proliferation of castration-resistant prostate cancer and induced apoptosis, which was opposed by autophagy. Inhibition of autophagy with hydroxychloroquine was additive to the apoptotic effect of nelfinavir. Western blotting of S1P and S2P siRNA knockdown and/or nelfinavir-treated cells confirmed the accumulation of precursor SREBP-1 and ATF6. 3,4-Dichloroisocoumarin, an S1P inhibitor, did not affect SREBP-1 processing. In contrast, 1,10-phenanthroline, an S2P inhibitor, reproduced the nelfinavir-treated molecular and biological phenotype. Nelfinavir-mediated inhibition of regulated intramembrane proteolysis led to the accumulation of unprocessed SREBP-1 and ATF6. This resulted in sequential endoplasmic reticulum stress, inhibition of the unfolded protein response, reduced fatty acid synthase expression and apoptosis, which was countered by autophagy. Inhibition of autophagy was at least additive to this pro apoptotic effect. These findings provide new insights into nelfinavir-induced endoplasmic reticulum stress and cancer cell death, and lead us to propose investigating its clinical activity in castration-resistant prostate cancer. This report validates S2P as a therapeutic target in castration-resistant prostate cancer. PMID- 22540832 TI - Influence of protonation on substrate and inhibitor interactions at the active site of human monoamine oxidase-A. AB - Although substrate conversion mediated by human monoaminooxidase (hMAO) has been associated with the deprotonated state of their amine moiety, data regarding the influence of protonation on substrate binding at the active site are scarce. Thus, in order to assess protonation influence, steered molecular dynamics (SMD) runs were carried out. These simulations revealed that the protonated form of the substrate serotonin (5-HT) exhibited stronger interactions at the protein surface compared to the neutral form. The latter displayed stronger interactions in the active site cavity. These observations support the possible role of the deprotonated form in substrate conversion. Multigrid docking studies carried out to rationalize the role of 5-HT protonation in other sites besides the active site indicated two energetically favored docking sites for the protonated form of 5-HT on the enzyme surface. These sites seem to be interconnected with the substrate/inhibitor cavity, as revealed by the tunnels observed by means of CAVER program. pK(a) calculations in the surface loci pointed to Glu327, Asp328, His488, and Asp132 as candidates for a possible in situ deprotonation step. Docking analysis of a group of inhibitors (structurally related to substrates) showed further interactions with the same two docking access sites. Interestingly, the protonated/deprotonated amine moiety of almost all compounds attained different docking poses in the active site, none of them oriented to the flavin moiety, thus producing a more variable and less productive orientations to act as substrates. Our results highlight the role of deprotonation in facilitating substrate conversion and also might reflect the necessity of inhibitor molecules to adopt specific orientations to achieve enzyme inhibition. PMID- 22540831 TI - Candidate gene study of genetic thrombophilic polymorphisms in pre-eclampsia and recurrent pregnancy loss in Sinhalese women. AB - AIM: Genetic thrombophilias are known to contribute to adverse pregnancy outcomes. Studies in Western populations show that 5, 10 methylenetetrahydrofolate reductase (MTHFR) 677C>T and Factor V (F5) 1691G>A (Leiden) polymorphisms are commonly associated with pre-eclampsia and recurrent spontaneous pregnancy loss. The objective of this study was to investigate the association of MTHFR 677C>T (rs1801133); 1298A>C (rs1801131) and F5 1691G>A (rs6025); 4070A>G (rs1800595) polymorphisms with pre-eclampsia and recurrent pregnancy loss among Sinhalese women in Sri Lanka. MATERIAL AND METHODS: Genotype and allele frequencies at each polymorphic site in the MTHFR and F5 genes and the haplotypes defined by them were determined in 175 Sinhalese women with pre eclampsia, 171 normotensive controls, 200 Sinhalese women with two or more recurrent pregnancy losses and 200 controls with two or more living children and no pregnancy losses. Genotyping was done by polymerase chain reaction/restriction fragment length polymorphism. Odds ratios and chi(2) -testing were performed to compare genotype/haplotype frequencies at each polymorphic site for both cases and controls. RESULTS: The genotype frequencies at each polymorphic site in the MTHFR 677C>T; 1298A>C; F5 1691G>A and 4070A>G genes and the haplotypes defined by them were not significantly associated with either pre-eclampsia or recurrent pregnancy loss. There was no significant association of genetic thrombophilia with either early or late pregnancy losses. CONCLUSIONS: The MTHFR and F5 polymorphisms and the haplotypes defined by them were not significantly associated with either pre-eclampsia or recurrent pregnancy loss in this group of Sinhalese women. PMID- 22540833 TI - Performance of the Straumann Bone Level Implant system for anterior single-tooth replacements in augmented and nonaugmented sites: a prospective cohort study with 60 consecutive patients. AB - AIM: The purpose of this prospective study was to evaluate radiographic, clinical and aesthetic outcomes and patient satisfaction of cases treated with platform switched single implant restorations in the aesthetic region of the maxilla. Furthermore, the influence of an augmentation procedure 3 months before implant placement and the type of restoration (screw-retained vs. cement-retained) was evaluated. MATERIAL AND METHODS: Sixty patients with a missing anterior tooth in the maxilla were treated with a Straumann Bone Level Implant. Bone augmentation was performed in 29 patients at 3 months before implant placement. Implants were loaded after 3 months of submerged healing. Follow-up was conducted at 7 and 18 months after implant placement. Peri-implant mucosa and implant crown aesthetic outcomes were determined using the Implant Crown Aesthetic Index (ICAI) and the Pink Esthetic Score-White Esthetic Score (PES-WES). RESULTS: No implants were lost. At 18 months after implant placement, mean bone level change was -0.10 +/- 0.27 mm and mean probing pocket depth was 2.57 mm. No differences were found between augmented and nonaugmented sites (P = 0.28). The ICAI indicated satisfactory mucosa and crown aesthetics in 67% and 75% of the cases, respectively, while the PES score was 14.4. ICAI mucosa (P = 0.004) and PES (P = 0.02) scores were significantly less favourable for augmented sites compared with nonaugmented sites. Patient satisfaction was high (8.9 +/- 1.1 on VAS-score). CONCLUSIONS: From the present prospective, clinical study, it can be concluded that the Straumann Bone Level Implant shows an excellent survival rate, marginal bone stability and good clinical and aesthetic results. Bone augmentation before implant placement does not lead to more marginal bone loss. However, less favourable pink aesthetic outcomes were found in augmented sites compared with nonaugmented sites, while no differences were found between cement-retained and screw-retained restorations. PMID- 22540834 TI - Language-specific developmental differences in speech production: a cross language acoustic study. AB - Speech productions of 40 English- and 40 Japanese-speaking children (aged 2-5) were examined and compared with the speech produced by 20 adult speakers (10 speakers per language). Participants were recorded while repeating words that began with "s" and "sh" sounds. Clear language-specific patterns in adults' speech were found, with English speakers differentiating "s" and "sh" in 1 acoustic dimension (i.e., spectral mean) and Japanese speakers differentiating the 2 categories in 3 acoustic dimensions (i.e., spectral mean, standard deviation, and onset F2 frequency). For both language groups, children's speech exhibited a gradual change from an early undifferentiated form to later differentiated categories. The separation processes, however, only occur in those acoustic dimensions used by adults in the corresponding languages. PMID- 22540835 TI - Mitochondrial proteome heterogeneity between tissues from the vegetative and reproductive stages of Arabidopsis thaliana development. AB - Specialization of the mitochondrial proteome in Arabidopsis has the potential to underlie the roles of these organelles at different developmental time points and in specific organs; however, most research to date has been limited to studies of mitochondrial composition from a few vegetative tissue types. To provide further insight into the extent of mitochondrial heterogeneity in Arabidopsis, mitochondria isolated from six organ/cell types, leaf, root, cell culture, flower, bolt stem, and silique, were analyzed. Of the 286 protein spots on a 2-D gel of the mitochondrial proteome, the abundance of 237 spots was significantly varied between different samples. Identification of these spots revealed a nonredundant set of 83 proteins which were differentially expressed between organ/cell types, and the protein identification information can be analyzed in an integrated manner in an interactive fashion online. A number of mitochondrial protein spots were identified as being derived from the same genes in Arabidopsis but differed in their pI, indicating organ-specific variation in the post translational modifications, or in their MW, suggesting differences in truncated mitochondrial products accumulating in different tissues. Comparisons of the proteomic data for the major isoforms with microarray analysis showed a positive correlation between mRNA and mitochondrial protein abundance and 60-90% concordance between changes in protein and transcript abundance. These analyses demonstrate that, while mitochondrial proteins are controlled transcriptionally by the nucleus, post-transcriptional regulation and/or post-translational modifications play a vital role in modulating the state or regulation of proteins in key biochemical pathways in plant mitochondria for specific functions. The integration of protein abundance and protein modification data with respiratory measurements, enzyme assays, and transcript data sets has allowed the identification of organ-enhanced differences in central carbon and amino acid metabolism pathways and provides ranked lists of mitochondrial proteins that are strongly transcriptionally regulated vs those whose abundance or activity is strongly influenced by a variety of post-transcriptional processes. PMID- 22540836 TI - Unconjugated hyperbilirubinemia is inversely associated with non-alcoholic steatohepatitis (NASH). AB - BACKGROUND: It has been recognised that unconjugated bilirubin contains hepatic anti-fibrogenic and anti-inflammatory properties and is a potent physiological antioxidant cytoprotectant. We believe that unconjugated hyperbilirubinemia may protect against development of non-alcoholic steatohepatitis (NASH). AIM: This study was conducted to assess the association of serum unconjugated bilirubin levels and histological liver damage in non-alcoholic fatty liver disease (NAFLD). METHODS: This was a retrospective analysis involving adult patients from a tertiary medical centre undergoing liver biopsy to evaluate suspected NAFLD or NASH and a control group without NAFLD based on normal liver ultrasound, labs and history. Identification of unconjugated hyperbilirubinemia was based on the presence of predominantly unconjugated bilirubin >=1.0 mg/dL (17.1 MUmol/L) while fasting, in the absence of haemolytic disease or other hepatic function alteration. RESULTS: Six-hundred and forty-one patients were included. Unconjugated hyperbilirubinemia was inversely associated with NASH (OR 16.1, 95% CI 3.7-70.8 P < 0.001). Of the patients without NAFLD (133 patients), 13 (9.8%) had unconjugated hyperbilirubinemia (range 1.0-1.8, mean 1.4). Of the patients with NAFLD without NASH (285 patients), 32 (11.2%) had unconjugated hyperbilirubinemia (range 1.0-3.0, mean 1.4). Of the patients with NASH (223 patients), three (1.3%) had unconjugated hyperbilirubinemia (1.0, 1.1, 1.4). CONCLUSIONS: Unconjugated hyperbilirubinemia is inversely associated with the histopathological severity of liver damage in non-alcoholic fatty liver disease. PMID- 22540837 TI - Laparoscopy in the surgical treatment of rectal cancer in Germany 2000-2009. AB - AIM: The goal of this registry study was to compare open surgery with planned laparoscopy and then with laparoscopic to open conversion for rectal cancer surgery. METHOD: The study included 17,964 rectal cancer patients, operated on between 1 January 2000 and 31 December 2009, from 345 hospitals in Germany. All statistical tests were two-sided, with the chi(2) test (Pearson correlation) for patients and tumour characteristics. Fisher's exact test was used for complications and 30-day mortality. RESULTS: Of the 17,964 rectal cancer patients, 16,308 (90.8%) had an open procedure and 1656 (9.2%) were started with a laparoscopy. The 1455 patients with completed laparoscopic operations had fewer intra-operative and postoperative complications (5.4%vs 7.0%, P = 0.020, and 20.5%vs 25.8%, P < 0.001, respectively) and a lower 30-day mortality rate (1.1%vs 1.9%, P = 0.023). Of the 1656 planned laparoscopies, 201 (12.1%) were converted to open. The converted group suffered more intra-operative complications (18.9%vs 3.6% for completed laparoscopy and 7.0% for open surgery, P < 0.0001) and postoperative complications (32.3%vs 18.9% for completed laparoscopy and 25.8% for open operations, P < 0.0001). The converted group also had a higher 30-day mortality rate (2.0%vs 1.0% for completed laparoscopy and 1.9% for open surgery, P = 0.043). CONCLUSION: The more favourable patient profile provided justification for a laparoscopic procedure. For those converted to an open procedure, however, there were significantly more complications than planned open surgery patients. A move away from the standard open procedure for rectal cancer surgery and towards laparoscopy is not yet feasible. PMID- 22540838 TI - Experimentally determined soil organic matter-water sorption coefficients for different classes of natural toxins and comparison with estimated numbers. AB - Although natural toxins, such as mycotoxins or phytoestrogens are widely studied and were recently identified as micropollutants in the environment, many of their environmentally relevant physicochemical properties have not yet been determined. Here, the sorption affinity to Pahokee peat, a model sorbent for soil organic matter, was investigated for 29 mycotoxins and two phytoestrogens. Sorption coefficients (K(oc)) were determined with a dynamic HPLC-based column method using a fully aqueous mobile phase with 5 mM CaCl(2) at pH 4.5. Sorption coefficients varied from less than 10(0.7) L/kg(oc) (e.g., all type B trichothecenes) to 10(4.0) L/kg(oc) (positively charged ergot alkaloids). For the neutral compounds the experimental sorption data set was compared with predicted sorption coefficients using various models, based on molecular fragment approaches (EPISuite's KOCWIN or SPARC), poly parameter linear free energy relationship (pp-LFER) in combination with predicted descriptors, and quantum chemical based software (COSMOtherm)). None of the available models was able to adequately predict absolute K(oc) numbers and relative differences in sorption affinity for the whole set of neutral toxins, largely because mycotoxins exhibit highly complex structures. Hence, at present, for such compounds fast and consistent experimental techniques for determining sorption coefficients, as the one used in this study, are required. PMID- 22540839 TI - Synthesis of N-alkoxycarbonyl ketimines derived from isatins and their application in enantioselective synthesis of 3-aminooxindoles. AB - A simple and general method in the synthesis of N-alkoxycarbonyl ketimines derived from isatins has been described first. Generally, the enantioselective addition of 1,3-dicarbonyl compounds to this kind of ketimine affords chiral 3 amino oxindoles in high yield and excellent ee. PMID- 22540840 TI - Concentration of free amino acids in human milk of women with gestational diabetes mellitus and healthy women. AB - OBJECTIVE: It is generally agreed that breastfeeding has a positive effect on the metabolic situation in diabetic mothers. However, negative long-term effects are described for breastfed offspring of diabetic women. It is unknown if the composition of free amino acids (FAAs) in breastmilk of women with gestational diabetes mellitus (GDM) differs from that in milk of healthy women. We studied the amount of FAAs in breastmilk of women with GDM and women with normal glucose tolerance (NGT). SUBJECTS AND METHODS: Human milk samples of 68 women (21 GDM and 47 NGT) were analyzed. Contents of FAAs in milk samples, obtained within the first 4 days after delivery (colostrum) and 6 weeks later (mature milk), were analyzed using high-performance liquid chromatography. Total amounts of FAAs in colostrum and in mature milk were compared between the groups. The impact of maternal age, body mass index (BMI), gestational age at birth, birth weight, and diagnosis of GDM on the total amount of FAAs was evaluated. RESULTS: Overall, the total amount of FAAs increased significantly from colostrum to mature milk in both groups (p<0.001). The total amount of FAAs did not significantly differ between GDM and NGT in colostrum and in mature milk (1,560 MUmol/L vs. 1,730 MUmol/L and 2,440 MUmol/L vs. 2,723 MUmol/L, respectively). No significant influence on the total amount of FAAs at both measurements of maternal age, BMI, gestational age at birth, birth weight, and diagnosis of GDM could be observed by regression analyses. CONCLUSION: The content of FAAs of human milk does not significantly differ between women with GDM and women with NGT. PMID- 22540842 TI - Increased oxidative stress condition found in different stages of HIV disease in patients undergoing antiretroviral therapy in Umuahia (Nigeria). AB - CONTEXT: Effective diagnostic tools for management of HIV disease progression in Sub-Saharan Africa is inadequate considering the endemic nature of the infection in the region. OBJECTIVE: To elucidate the clinical implication of oxidative stress (measured as Malondialdehyde, MDA) as additional biomarker of HIV disease progression and its implication in HIV clinical management. MATERIALS AND METHODS: A total of 250 individuals were recruited for the study. FACScan cytometry and spectrophotometric methods were employed in assessing T-lymphocytes (CD3, CD4, CD8) and MDA respectively. RESULTS: MDA concentration increased significantly (P < 0.05) in highly active antiretroviral therapy (HAART) subjects by 12.72% in category 1, 9.75% in III and in category II (4.63%) on comparison with non-HAART subjects. In subjects taking HAART, 22.2%, 56.3%, and 22.2% were found to be in category I, II and III, respectively, with a corresponding non HAART values of 15.6%, 45.6% and 38.9%. However, Spearman's rank correlation (P < 0.001) statistics of MDA and HIV categories showed a negative correlation in all the categories (I, II and III). DISCUSSION AND CONCLUSION: These findings suggest that MDA may be an additional clinical factor in assessing progression of HIV disease; however, necessary fortification of regimen with antioxidant may help reduce the high MDA concentration in the disease progression of the infection. PMID- 22540843 TI - Productive university, industry, and government relationships in preclinical drug discovery and development: considerations toward a synergistic lingua franca. AB - Efficiency and productivity shortfalls conspire with subpar economic return to stigmatize the pharmaceutical industry and jeopardize its viability. This complex and costly innovation-to-commercialization failure, the formidable associated costs, and the relevance of various core competencies endemic to universities, the pharmaceutical industry, and government have been major drivers for establishing preclinical drug-discovery alliances involving these constituencies. Such cross-sector alliances have the potential to help restore at least some of the industry's former health by militating risk, enhancing productivity, and improving the quantity/quality of development candidates. This Editorial will highlight certain characteristics of pharma-industry and non-industrial settings that can jeopardize the effectiveness of these sectors for unified preclinical discovery campaigns capable of generating well-characterized drug candidates that merit human testing. Based on decades of research and development (R&D) and business experience spanning international big-pharma, biotechnology, and academic spheres, the author opines that a synergistic lingua franca is required among involved constituencies in order for such cross-sector discovery alliances to emerge as robust drug-discovery engines fueled by joint intellectual effort. Technology-transfer professionals, postdoctoral trainees, and consultants are discussed as resources for helping establish the university-industry-government triumvirate as a normative innovation network for preclinical drug discovery and development in the 21st century. PMID- 22540844 TI - Phenotypes selected during chronic lung infection in cystic fibrosis patients: implications for the treatment of Pseudomonas aeruginosa biofilm infections. AB - During chronic lung infection of patients with cystic fibrosis, Pseudomonas aeruginosa can survive for long periods of time under the challenging selective pressure imposed by the immune system and antibiotic treatment as a result of its biofilm mode of growth and adaptive evolution mediated by genetic variation. Mucoidy, hypermutability and acquirement of mutational antibiotic resistance are important adaptive phenotypes that are selected during chronic P. aeruginosa infection. This review dicsusses the role played by these phenotypes for the tolerance of biofilms to antibiotics and show that mucoidy and hypermutability change the architecture of in vitro formed biofilms and lead to increase tolerance to antibiotics. Production of high levels of beta-lactamase impairs penetration of beta-lactam antibiotics due to inactivation of the antibiotic. In conclusion, these data underline the importance of biofilm prevention strategies by early aggressive antibiotic prophylaxis or therapy before phenotypic diversification during chronic lung infection of patients with cystic fibrosis. PMID- 22540845 TI - Biometric ratio in estimating widths of maxillary anterior teeth derived after correlating anthropometric measurements with dental measurements. AB - OBJECTIVE: To correlate dental measurements i.e. combined mesiodistal width of six maxillary anterior teeth with facial measurements i.e. inner canthal distance, interpupillary distance and intercommissural width and acquire a biometric ratio to serve as a preliminary guide in selection of the maxillary anterior teeth. BACKGROUND: In the absence of pre-extraction records, the resultant denture can lead to patient dissatisfaction towards the aesthetic appeal of their dentures. The maxillary anterior teeth play a pivotal role in denture aesthetics. Various techniques and biometric ratios have been described in literature for selection of the maxillary anteriors. This study derives a biometric ratio for the same, obtained after correlating anthropometric measurements with dental measurements. MATERIALS AND METHODS: Two standardized digital photographs of the face were generated; one, when the facial muscles were relaxed and the other, when the subject was smiling; thereby, revealing the maxillary anterior teeth upto the canine tip. Inner canthal distance, interpupillary distance, intercommissural distance, distance between the tips of the maxillary canines and distance between the distal surfaces of the canines were measured. On the cast, the distance between tips of maxillary canines and distance between distal surfaces of maxillary canines were noted. The data was analysed using Spearman's rank correlation coefficient. RESULTS: A high correlation was found between the intercommissural measurement with distance between the tips of the canines on the photograph and between the tips of the canines on the cast with the interpupillary distance, giving a biometric ratio of 1:1.35 and 1:1.41 respectively. The least correlation was between the inner canthal distance and the tips of the canines measured on the photograph. CONCLUSIONS: Extra oral anthropometric measurements of the interpupillary distances and the intercommissural distances with the help of standardised photographs can help us determine the combined widths of the anterior teeth accurately, thus aiding their selection in the absence of pre-extraction records. PMID- 22540846 TI - Minimally invasive percutaneous nephrolitholapaxy (PCNL) as an effective and safe procedure for large renal stones. AB - Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? The minimally invasive percutaneous nephrolitholapaxy (MIP) has shown high efficacy and safety for the management of small renal stones. It was initially developed to overcome a gap between the minimally invasive extracorporeal shockwave lithotripsy and invasive conventional percutaneous nephrolitholapaxy (PCNL) in the management of low stone burden but there is debate as to whether the MIP is also effective for larger stones. The present study shows the high efficacy and safety of MIP, which is comparable to conventional PCNL in the treatment of stones of >20 mm, including complex staghorn stones. OBJECTIVE: * To evaluate the safety and efficacy of minimally invasive percutaneous nephrolitholapaxy (MIP) in the management of large and complex renal calculi. PATIENTS AND METHODS: * From January 2007 to March 2011, 73 patients with 83 renal units with large renal stones (>20 mm in diameter) were retrospectively evaluated. * Stones were classified into simple (isolated renal pelvis or isolated calyceal stones) or complex (partial or complete staghorn stones, renal pelvis stones with accompanying calyceal stones). * Stone-free rate, complications according to the modified Clavien system, decrease in haemoglobin, creatinine level, operative duration and hospital stay were compared for simple and complex renal calculi. RESULTS: * The mean (sd) stone size was 36.7 (23.37) mm and mean operative duration was 99.2 (48.3) min. * In all, 65 cases (78.3%) were stone-free after the first procedure and another 14 needed an auxiliary procedure (four second-look percutaneous nephrolitholapaxy, nine ureterorenoscopy, and one extracorporeal shockwave lithotripsy) to become stone free, resulting in a 95.2% stone-free rate. * Complications occurred in 22 procedures (26.5%), 17 of them were Clavien Grade 1 or 2 (20.5%), five were Grade 3 (6%). There were no Grade 4 or 5 complications. * The only significant difference between complex and simple stones was the stone-free rate (96.9% vs 66.7%, P = 0.001). CONCLUSION: * The MIP technique is effective and safe for larger stones with low morbidity, good success rate and reasonable operative duration. PMID- 22540847 TI - The time-course of recovery from interruption during reading: eye movement evidence for the role of interruption lag and spatial memory. AB - Two experiments examined how interruptions impact reading and how interruption lags and the reader's spatial memory affect the recovery from such interruptions. Participants read paragraphs of text and were interrupted unpredictably by a spoken news story while their eye movements were monitored. Time made available for consolidation prior to responding to the interruption did not aid reading resumption. However, providing readers with a visual cue that indicated the interruption location did aid task resumption substantially in Experiment 2. Taken together, the findings show that the recovery from interruptions during reading draws on spatial memory resources and can be aided by processes that support spatial memory. Practical implications are discussed. PMID- 22540848 TI - Physicochemical signatures of natural sea films from Middle Adriatic stations. AB - Monolayer studies and a force-area quantification approach, in combination with electrochemical methods, are applied for physicochemical characterization of surface active substances (SAS) of the sea surface microlayers (MLs) from Middle Adriatic stations. Higher primary production during late spring-early autumn was reflected in the presence of MLs of higher surfactant activity containing on average molecules of lower molecular masses (M(w) = 0.65 +/- 0.27 kDa) and higher miscibility (y = 6.46 +/- 1.33) and elasticity (E(isoth) = 18.33 +/- 2.02 mN m( 1)) modulus in comparison to structural parameters (average M(w) = 2.15 +/- 1.58 kDa; y = 3.51 +/- 1.46; E(isoth) = 6.41 +/- 1.97 mN m(-1)) obtained for MLs from a period of lower production. A higher inhibition effect on the reduction process of Cd(2+) was observed for SAS abundant MLs from a more productive period. This kind of distribution is explained as the consequence of competitive adsorption of hydrophobic lipid-like substances of lower M(w) that act as end-members, highly influencing the surface structural properties of the natural air-water interface forming there segregated surface films during more productive period. PMID- 22540849 TI - Parallel but not equivalent: challenges and solutions for repeated assessment of cognition over time. AB - OBJECTIVE: Analyses of individual differences in change may be unintentionally biased when versions of a neuropsychological test used at different follow-ups are not of equivalent difficulty. This study's objective was to compare mean, linear, and equipercentile equating methods and demonstrate their utility in longitudinal research. STUDY DESIGN AND SETTING: The Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE, N = 1,401) study is a longitudinal randomized trial of cognitive training. The Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 819) is an observational cohort study. Nonequivalent alternate versions of the Auditory Verbal Learning Test (AVLT) were administered in both studies. RESULTS: Using visual displays, raw and mean-equated AVLT scores in both studies showed obvious nonlinear trajectories in reference groups that should show minimal change and poor equivalence over time (ps <= .001), and raw scores demonstrated poor fits in models of within-person change (root mean square errors of approximation, RMSEAs > 0.12). Linear and equipercentile equating produced more similar means in reference groups (ps >= .09) and performed better in growth models (RMSEAs < 0.05). CONCLUSION: Equipercentile equating is the preferred equating method because it accommodates tests more difficult than a reference test at different percentiles of performance and performs well in models of within-person trajectory. The method has broad applications in both clinical and research settings to enhance the ability to use nonequivalent test forms. PMID- 22540850 TI - Development and implementation of an herbal and natural product elective in undergraduate medical education. AB - BACKGROUND: Medical students have consistently expressed interest in learning about alternative healing modalities, especially herbal and natural products. To fill this void in medical education at our institution, a novel elective was developed and implemented for fourth year medical students. This herbal/natural product course uses guest lecturers, classroom presentations, and active learning mechanisms that include experiential rotations, case-based learning, and team based learning to increase student knowledge of herbal/natural product safety and efficacy. METHODS: Knowledge outcomes were evaluated via administration of a pre- and post-course test (paired student t-test). End-of-course evaluations (Likert type questions and narrative responses) were used to assess student opinion of knowledge and skills imparted by the elective and overall course content (mean, standard deviation). RESULTS: Over three academic years, 23 students have enrolled in this elective. More than 60% of participants have been female and nearly half of the students (43%) have pursued residencies in primary care. Completion of the course significantly increased student knowledge of common herbal/natural product mechanisms, uses, adverse effects, and drug-interactions as determined by a pre- and post-course knowledge assessment (45%+/-10% versus 78%+/-6%; p<0.0001). The course was highly rated by enrollees (overall course quality, 4.6 of 5.0+/-0.48) who appreciated the variety of activities to which they were exposed and the open classroom discussions that resulted. While students tended to view some alternative medical systems with skepticism, they still believed it was valuable to learn what these modalities encompass. CONCLUSIONS: Development and implementation of a herbal/natural product elective that engages undergraduate medical students through active learning mechanisms and critical analysis of the literature has proven effective in increasing knowledge outcomes and is deemed to be a valuable curricular addition by student participants. In the future, it will be of interest to explore mechanisms for expanding the course to reach a larger number of students within the time, financial, and logistical constraints that currently exist. PMID- 22540851 TI - Assessing the effectiveness of 'pulse radiofrequency treatment of dorsal root ganglion' in patients with chronic lumbar radicular pain: study protocol for a randomized control trial. AB - BACKGROUND: Chronic lumbar radicular pain can be described as neuropathic pain along the distribution of a particular nerve root. The dorsal root ganglion has been implicated in its pathogenesis by giving rise to abnormal impulse generation as a result of irritation, direct compression and sensitization. Chronic lumbar radicular pain is commonly treated with medications, physiotherapy and epidural steroid injections. Epidural steroid injections are associated with several common and rarer side effects such as spinal cord infarction and death. It is essential and advantageous to look for alternate interventions which could be effective with fewer side effects. Pulse radio frequency is a relatively new technique and is less destructive then conventional radiofrequency. Safety and effectiveness of pulse radio frequency in neuropathic pain has been demonstrated in animal and humans studies. Although its effects on dorsal root ganglion have been studied in animals there is only one randomized control trial in literature demonstrating its effectiveness in cervical radicular pain and none in lumbar radicular pain. Our primary objective is to study the feasibility of a larger trial in terms of recruitment and methodology. Secondary objectives are to compare the treatment effects and side effects. METHODS/DESIGNS: This is a single center, parallel, placebo-controlled, triple-blinded (patients, care-givers, and outcome assessors), randomized control trial. Participants will have a history of chronic lumbar radicular pain for at least 4 months in duration. Once randomized, all patients will have an intervention involving fluoroscopy guided needle placement to appropriate dorsal root ganglion. After test stimulation in both groups; the study group will have a pulse radio frequency treatment at 42 degrees C for 120 s to the dorsal root ganglion, with the control group having only low intensity test stimulation for the same duration. Primary outcome is to recruit at least four patients every month with 80% of eligible patients being recruited. Secondary outcomes would be to assess success of intervention through change in the visual analogue scale measured at 4 weeks post intervention and side effects. Allocation to each group will be a 1:1 ratio with allocation block sizes of 2, 4, and 6. TRIAL REGISTRATION: ClinicalTrials.gov NCT01117870. PMID- 22540852 TI - Blood testosterone in middle aged males heavily exposed to endocrine disruptors is decreasing more with HCB and p,p'-DDE related to BMI and lipids, but not with Sigma15PCBs. AB - OBJECTIVE: This work was aimed to evaluate the fundamental relations between the blood levels of testosterone (TEST) and persistent organochlorinated pollutants (POPs) related to body mass index (BMI) and blood lipids in a cohort of heavily exposed males from Eastern Slovakia. METHODS: In 429 middle aged (41-55 years) males heavily exposed to POPs the levels of 15 polychlorinated biphenyl congeners (Sigma15PCBs), hexachlorobenzene (HCB), and dichlorodiethyl-dichloroethylene (p,p'-DDE) were measured by gas chromatography/mass spectrometry and the total testosterone (TEST) by electrochemiluminiscent immunoassay. RESULTS: After classifying the values of BMI, TEST, HCB, p,p'-DDE, and Sigma15PCBs in quintiles and evaluating mutual interrelations of individual quintile counts in pairs of variables with chi-square, statistically significant interrelation was found for BMI/TEST (<0.0001) and HCB/TEST (p<0.001), but not for p,p'-DDE/TEST (p<0.6036) and Sigma15PCBs/TEST (p<0.3246). Moreover, highly significant negative correlation was found between HCB and TEST by means of both Pearson (p<0.01) and Spearman rank correlations (p<0.0001). However, similar correlations performed between p,p'-DDE and Sigma15PCBs did not reveal statistical significance. Finally, highly significant positive correlations were found between HCB and BMI, age, total lipids, and triglycerides. However, these correlations were less significant for p,p'-DDE and not significant or even negligibly negative for Sigma15PCBs. In contrast, correlations of TEST with BMI and lipid fractions were significantly negative. CONCLUSION: It appears that HCB might play a role in a decrease of TEST in males with relatively narrow age range of males highly exposed to POPs. Highly significant positive correlation of HCB with BMI and blood lipids points out the role of BMI as an imaginary compartment closely related to the total body fat mass and representing a depot of POPs which is closely related to the level of POPs and lipids in blood. However, the differences in the affinity of individual POPs to BMI and blood lipids as well as the mechanism of their different relation to blood TEST levels remain to be still explained. PMID- 22540853 TI - Relationship between disease activity and serum levels of vitamin D and parathyroid hormone in rheumatoid arthritis. AB - OBJECTIVE: Measuring vitamin D and its regulating hormones in the serum might be an accurate method for assessment of rheumatoid arthritis (RA) activity. We tested the hypothesis that the serum levels of vitamin D and parathyroid hormone (PTH) are associated with the grade of disease activity in an unselected cohort of patients with RA. METHODS: A total of 158 patients who met the American College of Rheumatology criteria for RA were examined and categorized as the patients with the active RA (n = 87) and silent RA (n = 71). Blood samples were obtained after at least eight-hour overnight fasting and the levels of 25-OH vitamin D and PTH were measured. RESULTS: The levels of the vitamin D in patients with active RA were significantly lower than in those with silent RA (49.38+/ 38.21 versus 64.64+/-43.61 nmol/l; p = 0.022). The PTH serum level lower than the normal range (< 0.8 nmol/l) was statistically observed similar in the active RA group compared with another ones (10.3 % versus 4.2 %, p = 0.149). Serum levels of vitamin D and PTH were not influenced by patients' gender and age as well as the duration of disease. CONCLUSION: Serum level of vitamin D was inversely related to RA activity and this relationship might be independent of PTH secretion or activity. PMID- 22540854 TI - Dehydroepiandrosterone in the type 1 diabetes mellitus. AB - OBJECTIVE: Dehydroepiandrosterone (DHEA) is believed to exert, besides others, positive effects on the insulin resistance or its secretion and glucose metabolism. There are several reports dealing with the DHEA levels and its effects in the type 2 diabetes mellitus, but less information is available on the type 1 diabetic subjects. Recently, a report dealing with the lack of the age dependent decline of the DHEA levels in the type 2 diabetic subjects was published. The aim of the present study was to answer the question whether a comparable change in the aging pattern of the DHEA and its sulphate could be detected in the type 1 diabetes mellitus. METHODS: The data regarding the DHEA and dehydroepiandrosterone sulphate (DHEA-S) concentrations in the serum obtained from 116 patients with the type 1 diabetes mellitus and 259 controls were gathered from the database of the Institute of Endocrinology (Prague, Czech Republic). RESULTS: No significant differences in the level of the DHEA-S were found between the type 1 diabetics and controls either in men or women. However, lower DHEA levels were found in the type 1 diabetic women, but not in men. The age-dependent declines of both the DHEA and DHEA-S were similar to those in controls. CONCLUSION: In contrast to the type 2 diabetes, the levels of DHEA-S in the type 1 diabetic patients were practically identical with those in controls. In contrast to men, in women, the DHEA basal levels were lower than those seen in controls. The age dependence of both hormones followed the pattern of the decline in controls. PMID- 22540855 TI - Protective effect of GHRP-6 and estrogen supplementation against some cardiometabolic risk factors in ovariectomized rats. AB - OBJECTIVE: This study was aimed to assess the effect of both the estrogen and growth hormone releasing peptide-6 (GHRP-6), on the cardiovascular and metabolic diseases in ovariectomized (OVX) rats. METHOD: Four groups of adult female rats were used: sham operated, OVX, OVX plus estrogen supplemented, and OVX plus GHRP 6 supplemented. After 8 weeks, blood samples were collected from the retro orbital plexus and total cholesterol (TC), triglycerides (TGs), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), glucose and insulin in serum were estimated. RESULTS: The ovariectomy resulted in significant increase of body weight gain, food intake, fasting serum glucose, insulin, insulin resistance, TC, and LDL-C as well as in significant decrease of serum TGs and HDL-C levels. Estrogen supplementation to OVX rats reversed the effect of OVX on all the above mentioned parameters. However, GHRP-6 supplemented to OVX rats failed to produce significant change in both the body weight gain and food intake, but reversed the effect of OVX on fasting serum glucose, insulin, insulin resistance, and the assessed lipid fractions. CONCLUSION: The decrease in ovarian hormones produced by OVX resulted in arising of several risk factors related to carbohydrate metabolism and cardiovascular system. It appeared that such negative effects of OVX can be reversed by estrogen or GHRP-6 supplementation. However, the effect of GHRP-6 on improving dyslipidemia after OVX was more potent than that of estrogen, while the effect of estrogen on improving carbohydrate metabolism after OVX was more potent than that of GHRP-6. PMID- 22540856 TI - Chronic resveratrol administration has beneficial effects in experimental model of type 2 diabetic rats. AB - OBJECTIVE: The present study was designed to evaluate whether long-term resveratrol administration has beneficial effects on the metabolic control and oxidative stress in diabetic rats. METHODS: Male Wistar rats were divided into four groups: normal control, diabetic control, normal treated with resveratrol, and diabetic treated with resveratrol. Diabetes was induced by injection of streptozotocin (50 mg/kg; i.p.), fifteen minutes after the administration of nicotinamide (110 mg/kg; i.p.) in 12 h fasted rats. RESULTS: Four-month oral resveratrol administration (5 mg/kg/day) significantly attenuated the elevated levels of the blood glucose, glycosylated hemoglobin, total protein, albumin, urea, creatinine, and 8-isoprostane in diabetic rats. Moreover, resveratrol administration to diabetic rats improved the reduced levels of glutathione, total antioxidant capacity, and the antioxidant enzymes activities (superoxide dismutase, glutathione peroxidase, and catalase). No significant differences were observed in the activities of plasma aminotransferases (ALT and AST) and insulin levels between diabetic rats treated with resveratrol and diabetic controls. CONCLUSION: The results suggest that chronic resveratrol administration is safe and effective, and may be considered as a beneficial therapeutic compound in diabetes. PMID- 22540857 TI - High fat diet impact on Fos expression in ovariectomized female C57BL/6 mice: effect of colchicine and response of different neuronal phenotypes. AB - OBJECTIVES: Activity of neuropeptide Y (NPY), tyrosine hydroxylase (TH), corticoliberine (CRH), and oxytocin (OXY) producing cells was investigated in the ovariectomized (OVX) female C57BL/6 mice kept on the high fat diet for 16 weeks and their response to colchicine stress in selected brain areas, including the hypothalamic paraventricular (PVN), dorsomedial (DMN) and arcuate (ARC) nuclei, A1/C1 (in the ventrolateral medulla), and A2/C2 (in the nucleus of the solitarii tract, NTS) catecholaminergic cell groups. METHODS: The OVX female C57BL/6 mice kept on high fat diet were sacrificed by transcardial perfusion with fixative 48 h after intracerebroventricular injection of colchicine (18 ug mice). Dual Fos/neuropeptide immunohistochemistry was employed to investigate Fos/neuropeptide colocalizations. RESULTS: In the OVX saline-treated mice (sham control) with standard diet (St diet), no immunopositive CRH and NPY neurons were identified in the PVN and weak Fos immunostainig was visible in TH neurons in the DMN and ARC nuclei. Colchicine treatment in the OVX mice with St diet increased the number of CRH and OXY immunopositive neurons in the PVN as well as the number of NPY and TH neurons in DMN and ARC nuclei and NPY neurons in the middle NTS (mNTS) and A1/C1 cell group. Prolonged HF diet in OVX sham control mice moderately increased the number of Fos/TH neurons in the mNTS and commissural NTS (cNTS) in comparison with St diet mice. However, prolonged HF diet in OVX colchicines-treated mice reduced the number of Fos/NPY neurons in the anterior NTS (aNTS) and A1/C1 cell group in comparison with colchicines-treated animals with St diet as well as Fos-TH neurons in the mNTS and cNTS in comparison with saline-treated animals with HF diet. CONCLUSION: The data of this pilot study indicate that prolonged high fat diet might: 1) represent itself a light/moderate stimulus for activation of TH neurons in the NTS and A1/C1 cell group as well as NPY neurons in the A1/C1 cell group and 2) interfere with colchicines-induced and time-delayed Fos activation in the NPY and TH neurons in both the above mentioned brain nuclei. PMID- 22540858 TI - Impact of Type 2 diabetes on Glucokinase diabetes (GCK-MODY) phenotype in a Roma (Gypsy) family - case report. AB - OBJECTIVES: Glucokinase (GCK) diabetes is a mild form of the monogenic diabetes characterized by the fasting hyperglycemia without signs of metabolic syndrome and very low risk for chronic complications of diabetes. For the Type 2 diabetes (T2D), signs of the metabolic syndrome with high risk for chronic micro- and macro-vascular complications are typical. The prevalence of the GCK-diabetes is estimated from 0.5 to 1% in the diabetic patients. The T2D is the most prevalent type of the diabetes (it encompasses more than 85% of all the diabetic patients). According to the epidemiology, the coincidence of these two diabetes subtypes may occur; nevertheless no case reports on the above mentioned two diabetes subtypes have been published. The aim of the study was: 1) to perform the DNA analysis in three brothers, two of them with the fasting hyperglycemia and one with normal glucose tolerance, and their father with T2D metabolic syndrome and 2) to study the coincidence of the GCK-diabetes with T2D and its effect on the diabetic phenotype. PATIENTS AND METHODS: We report about a Roma (Gypsy) family consisting of three brothers: 17 years old probant and two older brothers (21 and 25 years), and their father. The probant is suffering from fasting hyperglycemia. His 25 years old diabetic brother and their father suffer from obesity, hypertension, dyslipidemia, and hyperglycemia. The glucokinase gene was analyzed by direct sequencing in each of the brothers and their father, and appropriate phenotype characteristics were also carried out on each of the family members. RESULTS: In the proband and his diabetic brother with the fasting hyperglycemia, a heterozygous mutation of the glucokinase gene p.Arg36Trp was found. The proband's phenotype was consistent with the GCK-diabetes, while the diabetic brother displayed already features of the metabolic syndrome. Although, the latter one suffered from the overweight, hypertension, and elevated triglycerides, his fasting hyperglycemia (8.3 mmol/l) was still consistent with the GCK-diabetes. Their father is also a heterozygous mutation carrier of the same mutation displaying all the features of the metabolic syndrome. In his case, the fasting hyperinsulinemia (43.5 MUU/ml) and fasting plasma glucose (10.4 mmol/l) are more typical for the T2D than GCK-diabetes. CONCLUSIONS: We found coincidence between the GCK-diabetes and T2D in the members of a single Roma (Gypsy) family. Since the chronic complications are rare in the GCK-diabetes, the major risk factor for the further morbidity may be in the development of the T2D. The overlapping of the GCK-diabetes with other types of diabetes, particularly the T2D, makes the diagnostics difficult and therefore, it might be one of the reasons why the estimated prevalence of the GCK-diabetes seems to be higher than the real one as it has been reported in several studies. PMID- 22540859 TI - The biochemical complexity of the endocannabinoid system with some remarks on stress and related disorders: a minireview. AB - Nowadays, the endocannabinoid-regulated processes are in the focus of interest, among others, for the treatment of stress-related disorders. In this minireview, we attempt to give some possible explanations for the conflicting results of the cannabinoidergic regulation of the hypothalamo-pituitary-adrenocortical (HPA) axis and related disorders, drawing attention to the complexity of the endocannabinoid system. The endocannabinoid system is a part of an intricate network of lipid pathways and consists of the cannabinoid receptors, their endogenous ligands, and the enzymes catalyzing their formation and degradation. The stress research is focused almost exclusively on the anandamide and 2 arachidonyl glycerol, and the cannabinoid 1 receptor. However, physiological, pathological, and pharmacological perturbations of the interconnected lipid pathways have a profound effect on the regulation of the endocannabinoid signaling system. For example, diet may substantially influence the lipid composition of the body. Recent studies have indicated that beside cannabinoid 1 receptor, the endocannabinoids may act on the cannabinoid 2, peroxisome proliferator-activated, and transient receptor potential of vanilloid type-1 receptors, too. All of these receptors are implicated in the development of stress-related disorders. However, it has to be mentioned that degradation of the endocannabinoids may result in the production of active compounds as well. Since endocannabinoids have a widespread distribution in the body, they may influence a phenomenon at several points. Different effects (stimulatory or inhibitory) at different levels of endocannabinoids (e.g. hypothalamus, hypophysis, adrenal gland in the case of HPA axis) may explain some of their unequivocal results. PMID- 22540861 TI - Significant endothelin release in patients treated with foam sclerotherapy. AB - BACKGROUND: Foam sclerotherapy has been proven to be a safe and effective treatment for superficial venous insufficiency, but transient visual and neurologic disturbances continue to be reported. These side effects have been theorized to be related to the presence of air or gases in the sclerosing foam that results in "bubble" migration into the cerebral circulation. We present a differing hypothesis that significant amounts of endothelin are released from the treated veins, amounts capable of causing these complications. MATERIAL AND METHODS: We tested the release of endothelin 1 (ET-1) in 12 rats after sclerotherapy with sodium tetradecyl sulfate (STS) in liquid and foam preparations. In 11 human subjects, we measured ET-1 in systemic circulation and in a draining vein after foam sclerotherapy with polidocanol. RESULTS: Rats treated with STS showed a significant increase in ET-1 levels 1 and 5 minutes after foam sclerotherapy. Patients treated with foam sclerotherapy showed a marked increase in ET-1 levels that correlated significantly with local ET-1 levels. CONCLUSIONS: Evidence of ET-1 release represents a plausible relationship explaining neurologic and visual disturbances reported after sclerotherapy. PMID- 22540860 TI - A root-knot nematode-secreted protein is injected into giant cells and targeted to the nuclei. AB - Root-knot nematodes (RKNs) are obligate endoparasites that maintain a biotrophic relationship with their hosts over a period of several weeks and induce the differentiation of root cells into specialized feeding cells. Nematode effectors synthesized in the oesophageal glands and injected into the plant tissue through the syringe-like stylet certainly play a central role in these processes. In a search for nematode effectors, we used comparative genomics on expressed sequence tag (EST) datasets to identify Meloidogyne incognita genes encoding proteins potentially secreted upon the early steps of infection. We identified three genes specifically expressed in the oesophageal glands of parasitic juveniles that encode predicted secreted proteins. One of these genes, Mi-EFF1 is a pioneer gene that has no similarity in databases and a predicted nuclear localization signal. We demonstrate that RKNs secrete Mi-EFF1 within the feeding site and show Mi-EFF1 targeting to the nuclei of the feeding cells. RKNs were previously shown to secrete proteins in the apoplasm of infected tissues. Our results show that nematodes sedentarily established at the feeding site also deliver proteins within plant cells through their stylet. The protein Mi-EFF1 injected within the feeding cells is targeted at the nuclei where it may manipulate nuclear functions of the host cell. PMID- 22540862 TI - Prognostic significance of tumor markers in T4a gastric cancer. AB - BACKGROUND: The clinical importance of preoperative tumor markers remain elusive in gastric cancer. The aim of this study was to evaluate the prognostic value of AFP, CEA, CA19-9, and CA50 in T4a stage gastric cancer. METHODS: Two hundred and seventy-three T4a gastric cancer patients who underwent curative D2 gastrectomy between 1996 and 2005 were evaluated. The correlation between tumor markers and clinicopathologic characteristics and prognostic value of preoperative tumor markers were investigated. RESULTS: Correlation analysis showed that AFP was associated with Borrmann type (P = 0.010); CEA with sex (P = 0.029), tumors site (P = 0.014), and N stage (P = 0.001); CA19-9 with age (P = 0.047), tumor site (P = 0.011), lymphovascular invasion (P = 0.004), and N stage (P = 0.000); CA50 with age (P = 0.017), tumor site (P = 0.004), tumor size (P = 0.014), and N stage (P = 0.000). Multivariate analysis showed that the positivity of preoperative CEA, CA19-9, and CA50 were major independent poor prognostic factors of patients with T4a stage gastric cancer. CONCLUSIONS: Preoperative serum tumor marker might be a candidate for the staging system in addition to conventional factors. PMID- 22540863 TI - Optically active, amphiphilic poly(meta-phenylene ethynylene)s: synthesis, hydrogen-bonding enforced helix stability, and direct AFM observation of their helical structures. AB - Optically active, amphiphilic poly(meta-phenylene ethynylene)s (PPEa) bearing L- or D-alanine-derived oligo(ethylene glycol) side chains connected to the backbone via amide linkages were prepared by microwave-assisted polycondensation. PPEa's exhibited an intense Cotton effect in the pi-conjugated main-chain chromophore regions in various polar and nonpolar organic solvents due to a predominantly one handed helical conformation stabilized by an intramolecular hydrogen-bonding network between the amide groups of the pendants. The stable helical structure was retained in the bulk and led to supramolecular column formation from stacked helices in oriented polymer films as evidenced by X-ray diffraction. Atomic force microscopy was used to directly visualize the helical structures of the polymers in two-dimensional crystalline layers with molecular resolution, and, for the first time, their absolute helical senses could unambiguously be determined. PMID- 22540864 TI - Proteomic characterization of the human FTSJ3 preribosomal complexes. AB - In eukaryotes, ribosome biogenesis involves excision of transcribed spacer sequences from the preribosomal RNA, base and ribose covalent modification at specific sites, assembly of ribosomal proteins, and transport of subunits from the nucleolus to the cytoplasm where mature ribosomes engage in mRNA translation. The biochemical reactions throughout ribosome synthesis are mediated by factors that associate transiently to the preribosomal complexes. In this work, we describe the complexes containing the human protein FTSJ3. This protein functions in association with NIP7 in ribosome synthesis and contains a putative RNA-methyl transferase domain (FtsJ) in the N-terminal region and two uncharacterized domains in the central (DUF3381) and C-terminal (Spb1_C) regions. FLAG-tagged FTSJ3 coimmunoprecipitates both RPS and RPL proteins, ribosome synthesis factors, and proteins whose function in ribosome synthesis has not been demonstrated yet. A similar set of proteins coimmunoprecipitates with the Spb1_C domain, suggesting that FTSJ3 interaction with the preribosome complexes is mediated by the Spb1_C domain. Approximately 50% of the components of FTSJ3 complexes are shared by complexes described for RPS19, Par14, nucleolin, and NOP56. A significant number of factors are also found in complexes described for nucleophosmin, SBDS, ISG20L2, and NIP7. These findings provide information on the dynamics of preribosome complexes in human cells. PMID- 22540865 TI - Enhanced biodegradation of carbamazepine after UV/H2O2 advanced oxidation. AB - Carbamazepine is one of the most persistent pharmaceutical compounds in wastewater effluents due to its resistance to biodegradation-based conventional treatment. Advanced oxidation can efficiently degrade carbamazepine, but the toxicity and persistence of the oxidation products may be more relevant than the parent. This study sets out to determine whether the products of advanced oxidation of carbamazepine can be biotransformed and ultimately mineralized by developing a novel methodology to assess these sequential treatment processes. The methodology traces the transformation products of the (14)C-labeled carbamazepine during UV/hydrogen peroxide advanced oxidation and subsequent biotransformation by mixed, undefined cultures using liquid scintillation counting and liquid chromatography with radioactivity, mass spectrometry, and UV detectors. The results show that the oxidation byproducts of carbamazepine containing a hydroxyl or carbonyl group can be fully mineralized by a mixed bacterial inoculum. A tertiary treatment approach that includes oxidation and biotransformation has the potential to synergistically mineralize persistent pharmaceutical compounds in wastewater treatment plant effluents. The methodology developed for this study can be applied to assess the mineralization potential of other persistent organic contaminants. PMID- 22540866 TI - Urinary biopyrrins: potential biomarker for monitoring of the response to treatment with anxiolytics. AB - During periods of psychological stress, excess amounts of free radicals are produced. Bilirubin oxidative metabolites (biopyrrins; BOM) are generated from bilirubin as a result of its scavenging action against free radicals. We investigated whether the urinary excretion of biopyrrins is altered by anxiolytics. In the present study, mice were immobilized for a period of 6 hr. Alprazolam (0.1-1 mg/kg of body-weight) was administered 30 min. before subjecting the animals to acute stress. The BOM concentrations in urine and the corticosterone levels in serum were measured by ELISA with an anti-bilirubin antibody and EIA, respectively. We observed an increase in urinary biopyrrins in stressed mice in comparison with non-stressed mice and a decrease after the treatment of stressed animals with alprazolam. A correlation between urinary BOM and serum corticosterone levels was found. Urinary levels of biopyrrins might be used to assess the response to anxiolytics prescribed during acute stress periods. PMID- 22540867 TI - Nuclear mapping of nanodrug delivery systems in dynamic cellular environments. AB - Nanoformulations have shown great promise for delivering chemotherapeutics and hold tremendous clinical relevance. However nuclear mapping of the chemodrugs is important to predict the success of the nanoformulation. In this study fluorescence microscopy and a subcellular tracking algorithm were used to map the diffusion of chemotherapeutic drugs in cancer cells. Positively charged nanoparticles efficiently carried the chemodrug across the cell membrane. The algorithm helped map free drug and drug-loaded nanoparticles, revealing a varying nuclear diffusion pattern of the chemotherapeutics in drug-sensitive and resistant cells in a live dynamic cellular environment. While the drug-sensitive cells showed an exponential uptake of the drug with time, resistant cells showed random and asymmetric drug distribution. Moreover nanoparticles carrying the drug remained in the perinuclear region, while the drug accumulated in the cell nuclei. The tracking approach has enabled us to predict the therapeutic success of different nanoscale formulations of doxorubicin. PMID- 22540868 TI - Thinking in categories or along a continuum: consequences for children's social judgments. AB - Can young children, forming expectations about the social world, capture differences among people without falling into the pitfalls of categorization? Categorization often leads to exaggerating differences between groups and minimizing differences within groups, resulting in stereotyping. Six studies with 4-year-old children (N = 214) characterized schematic faces or photographs as falling along a continuum (really mean to really nice) or divided into categories (mean vs. nice). Using materials that children naturally group into categories (Study 3), the continuum framing prevented the signature pattern of categorization for similarity judgments (Study 1), inferences about behavior and deservingness (Studies 2 and 5), personal liking and play preferences (Study 4), and stable and internal attributions for behavior (Study 6). When children recognize people as members of continua, they may avoid stereotypes. PMID- 22540869 TI - Meta-analysis: nonsteroidal anti-inflammatory drugs in biliary colic. AB - BACKGROUND: Biliary colic is a common manifestation of cholelithiasis, developing in about one-third of patients. Even if nonsteroid anti-inflammatory drugs (NSAIDs) have widely been used to relieve biliary pain, there is a lack of systematic review of treatments on this issue. AIM: To assess the potential benefits in terms of both pain control and reduction of complications, and the potential harms of NSAIDs in patients with biliary colic. METHODS: Data from randomised clinical trials (RCTs) comparing NSAIDs with no treatment, placebo or other drugs in patients with biliary colic, were collected from Medline and Embase. The outcome measures were expressed as odds ratio and relative risk and then pooled using fixed or random-effect models. RESULTS: Eleven RCTs involving 1076 subjects (268 men, 808 women; 18-86 years), including 442 controls were analysed. In comparison with placebo, NSAIDs led to a significantly higher proportion of patients with complete pain relief (RR 3.77, 95%CI 1.65-8.61; I(2) : 73%) and a significantly lower rate of complications (RR 0.53, 95% CI 0.31 0.89; I(2) : 35%). In comparison with other drugs, NSAIDs were more efficacious in controlling pain than spasmolytics (RR 1.47, 95% CI 1.03-2.10; I(2) : 55%); there was no difference between NSAIDs and opioids (RR 1.05, 95% CI 0.82-1.33; I(2) : 74%). CONCLUSIONS: In patients with biliary colic NSAIDs are the first choice treatments as they control pain with the same efficacy of opioids and significantly reduce the proportion of patients with severe complications. However, the lack of high-quality RCTs and the presence of consistent heterogeneity among studies may partially flaw these results. PMID- 22540870 TI - The influence of lupin seed germination on the chemical composition and standardized ileal digestibility of protein and amino acids in pigs. AB - The germination process can modify the chemical composition of nutrients in seeds, which can influence the digestibility and utilization of sprouts in animal diets compared to raw seeds. The aims of research were to provide controlled germination process of lupin seeds, monitor the changes in seed composition and determine the influence of the germination on the coefficients of standardized ileal digestibility (SID) of crude protein and amino acids in growing pigs, compared to raw lupin seeds. The seeds of two lupin species were used: yellow (RYL) (Lupinus luteus, cv. Lord) and blue (RBL) (Lupinus angustifolius, cv. Graf). Germination was provided in the dark at 24 degrees C for 4 days. Nutritional and antinutritional compositions of raw and germinated seeds (GYL and GBL, respectively) were analysed. Digestibility study was performed on pigs with an average body weight of 25 kg, and the pigs were surgically fitted with a T cannula in the distal ileum, with chromic oxide as an indicator. Seed germination increased the crude protein and fibre concentrations, but reduced the levels of the ether extract, nitrogen-free extracts and all amino acids in protein. The content of alkaloids and raffinose family oligosaccharides decreased in both lupin species. Germination had no positive impact (p>0.05) on the SID of crude protein and amino acids. Germination of lupin seeds negatively influenced the SID of lysine and methionine (p<0.05). The results of the research revealed a decrease in the concentrations of antinutritional factors in the sprouts of yellow and blue lupins compared to raw seeds; however, no positive effect was observed on the coefficients of the standardized ileal apparent digestibility of protein and amino acids. PMID- 22540871 TI - Re: It's the procedure not the patient: the operative approach is independently associated with an increased risk of complications after rectal prolapse repair. PMID- 22540872 TI - Brca1 is involved in establishing murine pigmentation in a p53 and developmentally specific manner. PMID- 22540873 TI - Regioselective synthesis of heteroaryl triflones by LDA (lithium diisopropylamide)-mediated anionic thia-Fries rearrangement. AB - Novel heteroaryl triflones including oxindole, pyrazolone, pyridine, and quinoline derivatives have been regioselectively synthesized by LDA-mediated thia Fries rearrangement for the first time. These reactions are also the first examples of the application of anionic thia-Fries rearrangement in heteroaromatic compounds. PMID- 22540874 TI - Why are defensive toxins so variable? An evolutionary perspective. AB - Defensive toxins are widely used by animals, plants and micro-organisms to deter natural enemies. An important characteristic of such defences is diversity both in the quantity of toxins and the profile of specific defensive chemicals present. Here we evaluate evolutionary and ecological explanations for the persistence of toxin diversity within prey populations, drawing together a range of explanations from the literature, and adding new hypotheses. We consider toxin diversity in three ways: (1) the absence of toxicity in a proportion of individuals in an otherwise toxic prey population (automimicry); (2) broad variation in quantities of toxin within individuals in the same population; (3) variation in the chemical constituents of chemical defence. For each of these phenomena we identify alternative evolutionary explanations for the persistence of variation. One important general explanation is diversifying (frequency- or density-dependent) selection in which either costs of toxicity increase or their benefits decrease with increases in the absolute or relative abundance of toxicity in a prey population. A second major class of explanation is that variation in toxicity profiles is itself nonadaptive. One application of this explanation requires that predator behaviour is not affected by variation in levels or profiles of chemical defence within a prey population, and that there are no cost differences between different quantities or forms of toxins found within a population. Finally, the ecology and life history of the animal may enable some general predictions about toxin variation. For example, in animals which only gain their toxins in their immature forms (e.g. caterpillars on host plants) we may expect a decline in toxicity during adult life (or at least no change). By contrast, when toxins are also acquired during the adult form, we may for example expect the converse, in which young adults have less time to acquire toxicity than older adults. One major conclusion that we draw is that there are good reasons to consider within-species variation in defensive toxins as more than mere ecological noise. Rather there are a number of compelling evolutionary hypotheses which can explain and predict variation in prey toxicity. PMID- 22540875 TI - Electrochemical methods for speciation of trace elements in marine waters. Dynamic aspects. AB - The contribution of electrochemical methods to the knowledge of dynamic speciation of toxic trace elements in marine waters is critically reviewed. Due to the importance of dynamic considerations in the interpretation of the electrochemical signal, the principles and recent developments of kinetic features in the interconversion of metal complex species will be presented. As dynamic electrochemical methods, only stripping techniques (anodic stripping voltammetry and stripping chronopotentiometry) will be used because they are the most important for the determination of trace elements. Competitive ligand exchange-adsorptive cathodic stripping voltammetry, which should be considered an equilibrium technique rather than a dynamic method, will be also discussed because the complexing parameters may be affected by some kinetic limitations if equilibrium before analysis is not attained and/or the flux of the adsorbed complex is influenced by the lability of the natural complexes in the water sample. For a correct data interpretation and system characterization the comparison of results obtained from different techniques seems essential in the articulation of a serious discussion of their meaning. PMID- 22540876 TI - Meiotic segregation study of a novel t(3;6)(q21;q23) in an infertile man using fluorescence in situ hybridization (FISH). AB - Male carriers with balanced reciprocal translocations can produce a variable proportion of unbalanced gametes resulting in reproductive failures. The presence of a structural rearrangement may induce an interchromosomal effect. This is characterized by abnormal bivalents not involved in the reorganization thereby yielding non-disjunction, which would present as aneuploid spermatozoa for these chromosomes. In the present case report segregation analysis of the sperm and investigation of interchromosomal effect were carried out using cytogenetic and fluorescence in situ hybridization (FISH) analysis on blood lymphocytes. The karyotype of the patient was 46,XY,t(3;6)(q21;q23). During sperm segregation analysis a total of 2,002 sperms were evaluated, of which 46.8% showed normal/balanced (alternate segregation mode) and 53.2% of sperm showed an abnormal signal pattern. A significant difference in the frequency of the estimated number of chromosome anomalies was observed in the translocation carrier when compared to the normozoospermic group (P<0.0001) and the oligozoospermic group (P<0.0001). Meiotic segregation analysis of sperm together with aneuploidy assessment for X, Y, and 17 chromosomes using FISH allows for the determination of a reproductive prognosis in male balanced translocation carriers and can be used for appropriate genetic counseling. PMID- 22540877 TI - Clinical capabilities of graduates of an outcomes-based integrated medical program. AB - BACKGROUND: The University of New South Wales (UNSW) Faculty of Medicine replaced its old content-based curriculum with an innovative new 6-year undergraduate entry outcomes-based integrated program in 2004. This paper is an initial evaluation of the perceived and assessed clinical capabilities of recent graduates of the new outcomes-based integrated medical program compared to benchmarks from traditional content-based or process-based programs. METHOD: Self perceived capability in a range of clinical tasks and assessment of medical education as preparation for hospital practice were evaluated in recent graduates after 3 months working as junior doctors. Responses of the 2009 graduates of the UNSW's new outcomes-based integrated medical education program were compared to those of the 2007 graduates of UNSW's previous content-based program, to published data from other Australian medical schools, and to hospital-based supervisor evaluations of their clinical competence. RESULTS: Three months into internship, graduates from UNSW's new outcomes-based integrated program rated themselves to have good clinical and procedural skills, with ratings that indicated significantly greater capability than graduates of the previous UNSW content-based program. New program graduates rated themselves significantly more prepared for hospital practice in the confidence (reflective practice), prevention (social aspects of health), interpersonal skills (communication), and collaboration (teamwork) subscales than old program students, and significantly better or equivalent to published benchmarks of graduates from other Australian medical schools. Clinical supervisors rated new program graduates highly capable for teamwork, reflective practice and communication. CONCLUSIONS: Medical students from an outcomes-based integrated program graduate with excellent self rated and supervisor-evaluated capabilities in a range of clinically-relevant outcomes. The program-wide curriculum reform at UNSW has had a major impact in developing capabilities in new graduates that are important for 21st century medical practice. PMID- 22540878 TI - Endocervical glandular involvement, positive endocervical surgical margin and multicentricity are more often associated with high-grade than low-grade squamous intraepithelial lesion. AB - AIM: The aim of this study was to compare the relative frequencies of endocervical glandular involvement (EGI), multicentricity, positive endocervical surgical margins (ESM) and positive vaginal surgical margins (VSM), and adenocarcinoma in situ of the cervix (AIS) between high-grade and low-grade squamous intraepithelial lesions (HSIL and LSIL, respectively). MATERIAL AND METHODS: We identified 238 patients with squamous intraepithelial lesions/cervical intraepithelial neoplasia (CIN) who were treated by loop electrocautery excision (LEEP) or conventional cold-knife conization (CKC). A total of 223 (72 [32.3%] LSIL/CIN I; 85 [38.1%] HSIL/CIN II; 66 [29.6%] HSIL/CIN III; and 151 [67.7%], HSIL/CIN II + III) LEEP/CKC slides were histologically reviewed. RESULTS: The frequencies of EGI, positive ESM, and multicentricity were significantly higher in the HSIL/CIN II + III group than in the LSIL/CIN I group (P = 0.001, 0.001, and 0.025, respectively). Eighteen of the 72 (25%) LSIL/CIN I patients, 44 of the 85 (51.8%) HSIL/CIN II patients, and 60 of the 66 (90.9%) HSIL/CIN III patients (P = 0.001) showed EGI. In four of the 72 (5.6%) LSIL/CIN I patients, 18 of the 85 (21.2%) HSIL/CIN II patients, and 42 of the 66 (63.6%) HSIL/CIN III patients (P = 0.001), ESM was positive. Two of the 72 (2.8%) LSIL/CIN I patients, seven of the 85 (8.2%) HSIL/CIN II patients, and 11 of the 66 (16.7%) HSIL/CIN III patients (P = 0.016) were multicentric. CONCLUSION: The current study showed that EGI, positive ESM and multicentricity were more often associated with HSIL/CIN II + III than with LSIL/CIN I. Moreover, the frequencies of EGI, multicentricity, and positive ESM increased with increasing severity of the cervical lesion. This result may influence the preference for the type of surgical procedure used for patients with cytological diagnosis of HSIL. PMID- 22540879 TI - Long-acting beta-agonists and the risk of intensive care unit admission in children. AB - OBJECTIVE: A possible association between long-acting beta-agonists (LABA) and severe asthma exacerbations including death remains controversial. We examined whether LABA in the setting of combination therapy with inhaled corticosteroids (ICS) increase the risk of near-fatal asthma in children using a case-control study design. METHODS: Medical records from admissions for asthma exacerbations in children 4-18 years of age during the 2005 calendar year at Children's Hospital of Pittsburgh of UPMC were reviewed. Cases and controls were determined by pediatric intensive care unit (PICU) and floor admission, respectively. Exposure was defined by LABA use in combination with ICS versus ICS alone. RESULTS: Records from 85 PICU and 96 pediatric floor admissions were reviewed. LABA use in combination with ICS did not increase the risk of PICU admission (odds ratio 1.07, 95% CI 0.46-2.52) compared to ICS only without LABA. After adjusting for demographics, asthma severity, history of PICU admissions, and concurrent infection, LABA/ICS use still did not increase the risk of PICU admission (adjusted odds ratio 0.84, 95% CI 0.26-2.76) compared to ICS alone. There were no deaths and five intubations within the study period. CONCLUSIONS: The combination of LABA and ICS did not appear to increase the risk of near-fatal asthma in children. PMID- 22540880 TI - Sources of individual differences in the speed of naming objects and actions: the contribution of executive control. AB - We examined the contribution of executive control to individual differences in response time (RT) for naming objects and actions. Following Miyake et al., executive control was assumed to include updating, shifting, and inhibiting abilities, which were assessed using operation span, task-switching, and stop signal tasks, respectively. Experiment 1 showed that updating ability was significantly correlated with the mean RT of action naming, but not of object naming. This finding was replicated in experiment 2 using a larger stimulus set. Inhibiting ability was significantly correlated with the mean RT of both action and object naming, whereas shifting ability was not correlated with the mean naming RTs. Ex-Gaussian analyses of the RT distributions revealed that updating ability was correlated with the distribution tail of both action and object naming, whereas inhibiting ability was correlated with the leading edge of the distribution for action naming and the tail for object naming. Shifting ability provided no independent contribution. These results indicate that the executive control abilities of updating and inhibiting contribute to the speed of naming objects and actions, although there are differences in the way and extent these abilities are involved. PMID- 22540881 TI - Extraction, characterization of components, and potential thermoplastic applications of camelina meal grafted with vinyl monomers. AB - Camelina meal contains oil, proteins, and carbohydrates that can be used to develop value-added bioproducts. In addition to containing valuable polymers, coproducts generated during the production of biofuels are inexpensive and renewable. Camelina is a preferred oilseed crop for biodiesel production because camelina is easier to grow and provides better yields. In this research, the components in camelina meal were extracted and studied for their composition, structure, and properties. The potential of using the camelina meal to develop thermoplastics was also studied by grafting various vinyl monomers. Oil (19%) extracted from camelina meal could be useful for food and fuel applications, and proteins and cellulose in camelina meal could be useful in the development of films, fibers, and thermoplastics. Thermoplastic films developed from grafted camelina meal had excellent wet tensile properties, unlike thermoplastics developed from other biopolymers. Camelina meal grafted with butylmethacrylate (BMA) had high dry and wet tensile strengths of 53.7 and 17.3 MPa, respectively. PMID- 22540882 TI - Supramolecular polymers as dynamic multicomponent cellular uptake carriers. AB - Supramolecular synthesis represents a flexible approach to the generation of dynamic multicomponent materials with tunable properties. Here, cellular uptake systems based on dynamic supramolecular copolymers have been developed using a combination of differently functionalized discotic molecules. Discotics featuring peripheral amine functionalities that endow the supramolecular polymer with cellular uptake capabilities were readily synthesized. This enabled the uptake of otherwise cell-impermeable discotics via cotransport as a function of supramolecular coassembly. Dynamic multicomponent and multifunctional supramolecular polymers represent a novel and unique platform for modular cellular uptake systems. PMID- 22540883 TI - Exenatide plus metformin compared with metformin alone on beta-cell function in patients with Type 2 diabetes. AB - AIM: To quantify how much exenatide added to metformin improves beta-cell function, and to evaluate the impact on glycaemic control, insulin resistance and inflammation compared with metformin alone. METHODS: A total of 174 patients with Type 2 diabetes with poor glycaemic control were instructed to take metformin for 8 +/- 2 months, then they were randomly assigned to exenatide (5 MUg twice a day for the first 4 weeks and forced titration to 10 MUg twice a day thereafter) or placebo for 12 months. At 12 months we evaluated anthropometric measurements, glycaemic control, insulin resistance and beta-cell function variables, glucagon, adiponectin, high sensitivity-C reactive protein and tumour necrosis factor alpha. Before and after 12 months, patients underwent a combined euglycaemic hyperinsulinaemic and hyperglycaemic clamp, with subsequent arginine stimulation. RESULTS: Exenatide + metformin gave a greater decrease in body weight, glycaemic control, fasting plasma proinsulin and insulin and their ratio, homeostasis model assessment for insulin resistance (HOMA-IR), and glucagon values and a greater increase in C-peptide levels, homeostasis model assessment beta-cell function index (HOMA-beta) and adiponectin compared with placebo + metformin. Exenatide + metformin decreased waist and hip circumference, and reduced concentrations of high sensitivity-C reactive protein and tumour necrosis factor-alpha. Exenatide + metformin gave a greater increase in M value (+34%), and disposition index (+55%) compared with placebo + metformin; first (+21%) and second phase (+34%) C-peptide response to glucose and C-peptide response to arginine (+25%) were also improved by exenatide + metformin treatment, but not by placebo + metformin. CONCLUSION: Exenatide is effective not only on glycaemic control, but also in protecting beta cells and in reducing inflammation. PMID- 22540884 TI - Extragonadal mixed germ cell tumor of the right arm: description of the first case in the literature. AB - BACKGROUND: Extragonadal localization of germ cell tumors (GCTs) is rare; to the best of our knowledge, a location in the soft tissue of the arm has never been previously reported in the literature. CASE PRESENTATION: We report the case of a 37-year-old man who presented with a primary malignant mixed non-seminomatous GCT (teratocarcinoma variety) in the right arm, treated by a combination of cisplatin based chemotherapy and surgery. After 18 months of close follow-up, no locoregional recurrence or distant metastases have been detected. CONCLUSIONS: A combination of chemotherapy and surgery is the most appropriate treatment strategy for extragonadal GCTs, to ensure both local and systemic control. PMID- 22540885 TI - The earliest description of the frontal lobe syndrome in an Edgar Allan Poe tale. PMID- 22540886 TI - Impact assessment of the European Clinical Trials Directive: a longitudinal, prospective, observational study analyzing patterns and trends in clinical drug trial applications submitted since 2001 to regulatory agencies in six EU countries. AB - BACKGROUND: Shifts in clinical trial application rates over time indicate if the attractiveness of a country or region for the conduct of clinical trials is growing or decreasing. The purpose of this observational study was to track changes in drug trial application patterns across several EU countries in order to analyze the medium-term impact of the EU Clinical Trials Directive 2001/20/EC on the conduct of drug trials. METHODS: Rates of Clinical Trial Applications (CTA) for studies with medicinal products in those six countries in the EU, which authorize on average more than 500 trials per year, were analyzed. Publicly available figures on the number of annually submitted CTA, the distribution of trials per phase and the type of sponsorship were tracked; missing data were provided by national drug agencies. RESULTS: Since 2001, the number of CTA in Italy and Spain increased significantly (5.0 and 2.5% average annual growth). For Italy, the gain was driven by a strong increase of applications from academic trial sponsors; Spain's growth was due to a rise in trials run by commercial sponsors. The Netherlands, Germany, France and the UK saw a decline (1.9, 2.3, 3.0 and 5.3% average annual diminution; significant (P < 0.05) except for Germany) in clinical drug trials. The decrease in the UK was caused by a sharp fall in academic trial activities. Across the six analyzed countries, no EU-wide trial-phase-specific patterns or trends were observed. CONCLUSIONS: The EU Clinical Trials Directive 2001/20/EC did not achieve the harmonization of clinical trial requirements across Europe. Rather, it resulted in the leveling of clinical trial activities caused by a continuing decrease in CTA rates in the Netherlands, Germany, France and the UK. Southern European countries, Italy and Spain, benefited to some extent from policy changes introduced by the Directive. In Italy's case, national funding measures helped to considerably promote the conduct of non-commercial trials. On the other hand, the EU Directive-driven transition from liberal policy environments, based on non-explicit trial approval through notifications, towards red-taped processes of trial authorization, contributed to the decreases in trial numbers in Germany and the UK. In the latter case, national research governance concerns had a share in the country's marked decline. However, different EU member states successfully developed best practices, which a new European legislation should take into consideration to resume Europe's attractiveness and international competitiveness for the conduct of clinical trials. PMID- 22540887 TI - Risk of colorectal adenomas and advanced neoplasia in Hispanic, black and white patients undergoing screening colonoscopy. AB - BACKGROUND: Racial and ethnic differences in the risk of premalignant colorectal neoplasia have not been extensively studied. AIM: To measure adenoma prevalence among asymptomatic white, black and Hispanic patients undergoing screening colonoscopy. METHODS: In this cross sectional cohort study, data from individuals >=50 years undergoing first-time colonoscopy since 2006 at a single tertiary-care medical centre were obtained from the electronic medical record. Adenoma prevalence among whites, blacks and Hispanics was calculated; multivariate Poisson and logistic regression were used to identify factors independently associated with adenoma rates and the presence of advanced adenomas. RESULTS: We identified 5075 eligible subjects: 3542 (70%) whites, 942 (18%) Hispanics and 591 (12%) blacks. The mean age was 62.2 years with 58% women. At least one adenoma was detected in 19%, 22% and 26% of whites, Hispanics and blacks respectively (Hispanics vs. whites P = 0.09; blacks vs. whites P = 0.0001). Isolated proximal adenomas were present in 9% of whites, 11% of Hispanics (P = 0.03) and 11% of blacks (P = 0.03). In multivariate analyses, a higher rate of adenomas was present in Hispanics (RR: 1.37, 95% CI: 1.20-1.57) and blacks (RR: 1.76, 95% CI: 1.52-2.04) than whites. Hispanics and blacks also had an increased risk of advanced adenomas compared to whites (OR(Hispanics) : 2.25, 95% CI: 1.62-3.11; OR(blacks) : 1.91, 95% CI: 1.27-2.86). CONCLUSIONS: Adenoma prevalence was higher in blacks and Hispanics than in whites. Both groups were at greater risk of having proximal adenomas in the absence of any distal pathology than whites, where these lesions would have only been detected by colonoscopy. Efforts to promote screening are necessary among diverse, under-represented populations. PMID- 22540888 TI - Histopathologic changes induced by intense pulsed light in the treatment of poikiloderma of Civatte. AB - BACKGROUND: The clinical efficacy of intense pulsed light (IPL) in the treatment of poikiloderma of Civatte (PC) is well documented, but little is known about microscopic changes. OBJECTIVE: To analyze histopathologic findings on the necks of individuals with PC after IPL therapy. MATERIALS AND METHODS: Fourteen patients with PC on the neck underwent three monthly sessions of IPL. Biopsies and clinical photographs were taken before and 60 days after treatment. A dermatopathologist analyzed histopathologic slides stained with hematoxylin and eosin, Masson's trichrome, Verhoeff-van Gieson and Fontana-Masson or processed for CD-34 immunohistochemistry. The slides also underwent digital image analysis. Clinical results were based on the analysis of the pictures by three dermatologists and on patient satisfaction. RESULTS: Intense pulsed light treatment resulted in more-homogeneous melanin distribution; a greater number of fibroblasts and nonfragmented elastic fibers; and greater density (p = .01), color intensity (p = .02), number and thickness of the collagen bundles. No significant changes in vessels' number or diameters were observed. Clinical results were positive in 92.9% of the cases. CONCLUSION: IPL treatment of PC induced a more-homogeneous distribution of melanin and increased nonfragmented elastic fibers, collagen density, and intensity. These changes were related to clinical improvement. PMID- 22540891 TI - Pb particles from tap water: bioaccessibility and contribution to child exposure. AB - High particulate lead (Pb) levels can be measured in tap water, but the hazard linked to particulate Pb ingestion is unknown. An in vitro test was developed to determine the bioaccessibility of Pb particles from tap water, based on the Relative Bioaccessibility Leaching Procedure validated for soils, and applied to lab-generated particles and field particles collected behind the aerator tap. Field particles were found in 43% of the 342 taps investigated equipped with an aerator, and contained significant amounts of Pb (0.003-71%, median 4.7%). The bioaccessibility of lab-generated particles ranged from 2 to 96% depending on the particle type (Pb(II) > Brass > Pb(IV) > solder), while that of field particles was distributed between 1.5 and 100% (median 41%). The hazard of particulate Pb ingestion depends on the amount and concentration ingested, and the bioaccessibility of the particulate Pb forms involved. Using the Integrated Exposure Uptake Biokinetic model, the impact of particulate Pb on the exposure of children aged 0.5-7 for the distribution system studied was the most significant when considering a fraction of the exposure from large buildings. PMID- 22540890 TI - Metformin, an antidiabetic agent reduces growth of cutaneous squamous cell carcinoma by targeting mTOR signaling pathway. AB - The biguanide metformin is widely used for the treatment of Type-II diabetes. Its antiproliferative and pro-apoptotic effects in various tumor cells suggest its potential candidacy for cancer chemoprevention. Herein, we report that metformin significantly inhibited human epidermoid A431 tumor xenograft growth in nu/nu mice, which was associated with a significant reduction in proliferative biomarkers PCNA and cyclins D1/B1. This tumor growth reduction was accompanied by the enhanced apoptotic cell death and an increase in Bax:Bcl2 ratio. The mechanism by which metformin manifests antitumor effects appears to be dependent on the inhibition of nuclear factor kappa B (NFkB) and mTOR signaling pathways. Decreased phosphorylation of NFkB inhibitory protein IKBalpha together with reduced enhancement of NFkB transcriptional target proteins, iNOS/COX-2 were observed. In addition, a decrease in the activation of ERK/p38-driven MAP kinase signaling was seen. Similarly, AKT signaling activation as assessed by the diminished phosphorylation at Ser473 with a concomitant decrease in mTOR signaling pathway was also noted as phosphorylation of mTOR regulatory proteins p70S6K and 4E-BP-1 was significantly reduced. Consistently, decreased phosphorylation of GSK3beta, which is carried out by AKT kinases was also observed. These results suggest that metformin blocks SCC growth by dampening NFkB and mTOR signaling pathways. PMID- 22540892 TI - Size-dependent localization and penetration of ultrasmall gold nanoparticles in cancer cells, multicellular spheroids, and tumors in vivo. AB - This work demonstrated that ultrasmall gold nanoparticles (AuNPs) smaller than 10 nm display unique advantages over nanoparticles larger than 10 nm in terms of localization to, and penetration of, breast cancer cells, multicellular tumor spheroids, and tumors in mice. Au@tiopronin nanoparticles that have tunable sizes from 2 to 15 nm with identical surface coatings of tiopronin and charge were successfully prepared. For monolayer cells, the smaller the Au@tiopronin NPs, the more AuNPs found in each cell. In addition, the accumulation of Au NPs in the ex vivo tumor model was size-dependent: smaller AuNPs were able to penetrate deeply into tumor spheroids, whereas 15 nm nanoparticles were not. Owing to their ultrasmall nanostructure, 2 and 6 nm nanoparticles showed high levels of accumulation in tumor tissue in mice after a single intravenous injection. Surprisingly, both 2 and 6 nm Au@tiopronin nanoparticles were distributed throughout the cytoplasm and nucleus of cancer cells in vitro and in vivo, whereas 15 nm Au@tiopronin nanoparticles were found only in the cytoplasm, where they formed aggregates. The ex vivo multicellular spheroid proved to be a good model to simulate in vivo tumor tissue and evaluate nanoparticle penetration behavior. This work gives important insights into the design and functionalization of nanoparticles to achieve high levels of accumulation in tumors. PMID- 22540893 TI - Inhibition of tryptophan hydroxylase abolishes fatigue induced by central tryptophan in exercising rats. AB - Fatigue during prolonged exercise is related to brain monoamines concentrations, but the mechanisms underlying this relationship have not been fully elucidated. We investigated the effects of increased central tryptophan (TRP) availability on physical performance and thermoregulation in running rats that were pretreated with parachlorophenylalanine (p-CPA), an inhibitor of the conversion of TRP to serotonin. On the 3 days before the experiment, adult male Wistar rats were treated with intraperitoneal (ip) injections of saline or p-CPA. On the day of the experiment, animals received intracerebroventricular (icv) injections of either saline or TRP (20.3 MUM) and underwent a submaximal exercise test until fatigue. Icv TRP-treated rats that received ip saline presented higher heat storage rate and a 69% reduction in time to fatigue compared with the control animals. Pretreatment with ip p-CPA blocked the effects of TRP on thermoregulation and performance. Moreover, ip p-CPA administration accelerated cutaneous heat dissipation when compared with saline-pretreated rats. We conclude that an elevated availability of central TRP interferes with fatigue mechanisms of exercising rats. This response is modulated by serotonergic pathways, because TRP effects were blocked in the presence of p-CPA. Our data also support that a depletion of brain serotonin facilitates heat loss mechanisms during exercise. PMID- 22540894 TI - Effects of induced energy deficiency on lactoferrin concentration in milk and the lactoferrin reaction of primary bovine mammary epithelial cells in vitro. AB - A dietary energy restriction to 49% of total energy requirements was conducted with Red Holstein cows for three weeks in mid-lactation. At the last day of the restriction phase, primary bovine mammary epithelial cells (pbMEC) of eight restriction (RF) and seven control-fed (CF) cows were extracted out of one litre of milk and cultured. In their third passage, an immune challenge with the most prevalent, heat-inactivated mastitis pathogens Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) was conducted. Lactoferrin (LF) was determined on gene expression and protein level. An enzyme-linked immunosorbent assay (ELISA) was developed to determine LF in milk samples taken twice weekly throughout the animal trial, beginning on day 20 pp (post-partum) until day 150 pp, in cell culture total protein and in cell culture supernatant. Milk LF increased throughout the lactation and decreased significantly during the induced energy deficiency in the RF group. At the beginning of realimentation, LF concentration increased immediately in the RF group and reached higher levels than before the induced deficit following the upward trend seen in the CF group. Cell culture data revealed higher levels (up to sevenfold up-regulation in gene expression) and significant higher LF protein concentration in the RF compared to the CF group cells. A further emphasized effect was found in E. coli compared to S. aureus exposed cells. The general elevated LF levels in the RF pbMEC group and the further increase owing to the immune challenge indicate an unexpected memory ability of milk-extracted mammary cells that were transposed into in vitro conditions and even displayed in the third passage of cultivation. The study confirms the suitability of the non-invasive milk-extracted pbMEC culture model to monitor the influence of feeding experiments on immunological situations in vivo. PMID- 22540895 TI - The absence of voiding symptoms in men with a prostate-specific antigen (PSA) concentration of >=3.0 ng/mL is an independent risk factor for prostate cancer: results from the Gothenburg Randomized Screening Trial. AB - What's known on the subject? and What does the study add? There are only a few studies and no consensus concerning the relationship between LUTS and prostate cancer. This paper focuses on 2353 men with an elevated PSA level within the Gothenburg Randomized Screening Trial who underwent biopsy and answered questions regarding LUTS. The main conclusion was that the absence of voiding symptoms is an independent risk factor for prostate cancer detection. OBJECTIVE: To investigate whether men with obstructive voiding symptoms are at increased risk for being diagnosed with prostate cancer within the Gothenburg randomized population-based prostate cancer screening trial. SUBJECTS AND METHODS: In 1995, 20 000 men born between 1930 and 1944 were randomly selected from the population register and randomized to either a screening group (10 000), invited for total prostate-specific antigen (tPSA) testing every second year until they reached an upper age-limit pending between 67 and 71 years, or to a control group not invited (10 000). Men with a PSA concentration of >=3.0 ng/mL were offered further examination with prostate biopsies. Immediately before the physician's examination a self-administered, study-specific questionnaire was completed including one question concerning obstructive voiding symptoms. Multivariate logistic regression modelling was used to estimate odds ratios (ORs) for associations of age, tPSA, free/total PSA (f/tPSA) ratio, prostate volume and the presence of voiding symptoms in prostate cancer risk. A P < 0.05 was considered statistically significant. RESULTS: Between 1995 and 2010 there were 2590 men who had an elevated PSA concentration (>=3.0 ng/mL) at least once during the study. Of these, 2353 men (91%) accepted further clinical examination with transrectal ultrasonography (TRUS) and prostate biopsies. In all, 633/2353 men had prostate cancer (27%) on biopsy and 1720/2353 men (73%) had a benign pathology. Men with prostate cancer reported a lower frequency of voiding symptoms (24% vs 31%, P < 0.001), independent of age and locally advanced tumours (T2b-T4). In the multivariate logistic regression model increasing age and tPSA were positively associated with prostate cancer while prostate volume, f/tPSA ratio and the presence of voiding symptoms were all inversely associated with the risk of detecting prostate cancer in a screening setting. This inverse association of voiding symptoms and prostate cancer detection was restricted to men with large prostates (>37.8 mL); 15% in men with voiding symptoms vs 22% in asymptomatic men (P < 0.001). CONCLUSION: The presence of voiding symptoms should not be a decision tool for deciding which men with an elevated PSA concentration should be offered biopsies of the prostate. PMID- 22540898 TI - The fitness consequences of environmental sex reversal in fish: a quantitative review. AB - Environmental sex reversal (ESR) occurs when environmental factors overpower genetic sex-determining factors. The phenomenon of ESR is observed widely in teleost species, where it can be induced by exposing developing fish to endocrine disrupting chemicals (EDCs). EDC-induced ESR has been exploited by the aquaculture industry, while ecological and evolutionary models are also beginning to elucidate the potential roles that sex-reversed individuals play in influencing population dynamics. However, how EDC exposure affects individual fitness remains relatively unknown. To date, many experimental studies have induced sex reversal in fish and measured fitness-as indicated by related traits such as size, survival and gonadal somatic index (GSI), but the reported results vary. Here, we meta-analytically combine the results of 78 studies of induced ESR to gain insight into the fitness of sex-reversed individuals. Overall, our results suggest that the fitness of fish exposed to EDCs is reduced at the time of exposure, with exposed individuals having a smaller size and likely a smaller GSI. Given a period of non-exposure, fish treated with EDCs can regain a size equal to those not exposed, although GSI remains compromised. Interestingly, survival does not appear to be affected by EDC treatment. The published reports that comprise our dataset are, however, based on captive fish and the general small size resulting from exposure is likely to lead to reduced survival in the wild. Additionally, reduced fitness-related parameters are likely to be due to exposure to EDCs rather than ESR itself. We suggest that theoretical models of ESR should account for the fitness-related effects that we report. Whilst we are able to shed light on the physical fitness of EDC-exposed fish, the behaviour of such individuals remains largely untested and should be the focus of future experimental manipulation. PMID- 22540897 TI - Does doctors' workload impact supervision and ward activities of final-year students? A prospective study. AB - BACKGROUND: Hospital doctors face constantly increasing workloads. Besides caring for patients, their duties also comprise the education of future colleagues. The aim of this study was to objectively investigate whether the workload arising from increased patient care interferes with student supervision and is associated with more non-medical activities of final-year medical students. METHODS: A total of 54 final-year students were asked to keep a diary of their daily activities over a three-week period at the beginning of their internship in Internal Medicine. Students categorized their activities--both medical and non-medical- according to whether they had: (1) only watched, (2) assisted the ward resident, (3) performed the activity themselves under supervision of the ward resident, or (4) performed the activity without supervision. The activities reported on a particular day were matched with a ward specific workload-index derived from the hospital information system, including the number of patients treated on the corresponding ward on that day, a correction factor according to the patient comorbidity complexity level (PCCL), and the number of admissions and discharges. Both students and ward residents were blinded to the study question. RESULTS: A total of 32 diaries (59 %, 442 recorded working days) were handed back. Overall, the students reported 1.2 +/- 1.3 supervised, 1.8 +/- 1.6 medical and 3.6 +/- 1.7 non-medical activities per day. The more supervised activities were reported, the more the number of reported medical activities increased (p < .0001). No relationship between the ward specific workload and number of medical activities could be shown. CONCLUSIONS: There was a significant association between ward doctors' supervision of students and the number of medical activities performed by medical students. The workload had no significant effect on supervision or the number of medical or non-medical activities of final-year students. PMID- 22540896 TI - A prognostic signature of defective p53-dependent G1 checkpoint function in melanoma cell lines. AB - Melanoma cell lines and normal human melanocytes (NHM) were assayed for p53 dependent G1 checkpoint response to ionizing radiation (IR)-induced DNA damage. Sixty-six percent of melanoma cell lines displayed a defective G1 checkpoint. Checkpoint function was correlated with sensitivity to IR with checkpoint defective lines being radio-resistant. Microarray analysis identified 316 probes whose expression was correlated with G1 checkpoint function in melanoma lines (P<=0.007) including p53 transactivation targets CDKN1A, DDB2, and RRM2B. The 316 probe list predicted G1 checkpoint function of the melanoma lines with 86% accuracy using a binary analysis and 91% accuracy using a continuous analysis. When applied to microarray data from primary melanomas, the 316 probe list was prognostic of 4-yr distant metastasis-free survival. Thus, p53 function, radio sensitivity, and metastatic spread may be estimated in melanomas from a signature of gene expression. PMID- 22540899 TI - Through-space control of the persistence of photogenerated o-quinonoid intermediates in naphthalenes containing cofacially oriented chromenes and arenes. AB - Remarkable modulation of the persistence of the photogenerated colored o quinonoid intermediates via a through-space interaction has been demonstrated in chromenes 1-4 based on 1,8-diarylnaphthalenes. Polar/pi interaction is shown to stabilize the closed form of 4 to such an extent that photoinduced coloration is virtually invisible, while the same stabilization in the opened form of 2 permits ready coloration with a long-lived o-quinonoid intermediate. PMID- 22540900 TI - Development of antibiotic and debriding enzyme-loaded PLGA microspheres entrapped in PVA-gelatin hydrogel for complete wound management. AB - A biocompatible moist system was developed for effective and complete wound healing. Optimized PLGA microspheres of gentamicin (GM) and serratiopeptidase (STP) were incorporated into PVA-gelatin slurry and casted into films to prepare multiphase hydrogel. The prepared system was characterized by in vitro and in vivo studies. Results revealed the uniform dispersion of microspheres in three dimensional matrix of the hydrogel. The in vitro release data showed a typical biphasic release pattern. All parameters such as wound contraction, tensile strength, histopathological and biochemical parameters were observed significant (p < 0.05) in comparison to the control group. Results suggested an accelerated re-epithelialization with minimum disturbance of wound bed. PMID- 22540902 TI - Parallel processing of whole words and morphemes in visual word recognition. AB - Models of morphological processing make different predictions about whether morphologically complex written words are initially decomposed and recognized on the basis of their morphemic subunits or whether they can directly be accessed as whole words and at what point semantics begin to influence morphological processing. In this study, we used unprimed and masked primed lexical decision to compare truly suffixed (darkest) and pseudosuffixed words (glossary) with within boundary (drakest/golssary) to across-boundary (darekst/glosasry) letter transpositions. Significant transposed-letter similarity effects were found independently of the morphological position of the letter transposition, demonstrating that, in English, morphologically complex whole-word representations can be directly accessed at initial word processing stages. In a third masked primed lexical decision experiment, the same materials were used in the context of stem target priming, and it was found that truly suffixed primes facilitate the recognition of their stem-target (darkest-DARK) to the same extent as pseudosuffixed primes (glossary-GLOSS), which is consistent with theories of early morpho-orthographic decomposition. Taken together, our findings provide evidence for both whole-word access and morphological decomposition at initial stages of visual word recognition and are discussed in the context of a hybrid account. PMID- 22540901 TI - Automatic flow-batch system for cold vapor atomic absorption spectroscopy determination of mercury in honey from Argentina using online sample treatment. AB - An automatic flow-batch system that includes two borosilicate glass chambers to perform sample digestion and cold vapor atomic absorption spectroscopy determination of mercury in honey samples was designed. The sample digestion was performed by using a low-cost halogen lamp to obtain the optimum temperature. Optimization of the digestion procedure was done using a Box-Behnken experimental design. A linear response was observed from 2.30 to 11.20 MUg Hg L(-1). The relative standard deviation was 3.20% (n = 11, 6.81 MUg Hg L(-1)), the sample throughput was 4 sample h(-1), and the detection limit was 0.68 MUg Hg L(-1). The obtained results with the flow-batch method are in good agreement with those obtained with the reference method. The flow-batch system is simple, allows the use of both chambers simultaneously, is seen as a promising methodology for achieving green chemistry goals, and is a good proposal to improving the quality control of honey. PMID- 22540903 TI - Refining the indications of implantable cardioverter defibrillator in patients with left ventricular dysfunction. AB - Although clinical trials evaluating therapy with implantable cardioverter defibrillators (ICD) have had clear limitations, there are few interventions in which multiple trial settings over a long period have consistently produced a 20% to 30% reduction in total mortality in patients with left ventricular dysfunction. Substantial differences between the Guidelines on ICD implantation have resulted and the number of patients actually implanted following these recommendations remains relatively low. As well as this, different reasons have been proposed to explain why randomized trials of ICD versus control subjects implanted early after myocardial infarction do not show survival benefit. Moreover, many factors in addition to ejection fraction (EF) do influence the prognosis of patients with coronary disease. However, there are few tools to use this information to guide clinical decisions. Recent years have seen an ongoing debate on the further risk stratification of patients who will benefit most from ICD implantation and a combination of a few readily available clinical variables indicating advanced disease and comorbid conditions identifies ICD patients at high risk. In addition, the role of these devices in patients with nonischemic cardiomyopathies, in older patients and females, for prevention of sudden cardiac death (SCD), has long been debated. This review aims to summarize these criticisms and to refine the current indications of ICD implantation in patients with moderate-severe left ventricular dysfunction. PMID- 22540904 TI - Contemporary overview on clinical trials and future prospects of hepato protective herbal medicines. AB - Till date the synthetic hepato-protective agents used in clinical practices are therapeutically non-promising and may itself lead to hepatotoxicity. Herbal medicines and their bioactives are considered to be relatively safe and have been used in the treatment of liver diseases for a long time. The 21st century has seen a paradigm shift towards therapeutic standardization of herbal drugs in hepatic disorders by evidence-based randomized controlled clinical trials to support their clinical efficacy. Even so, the specific hepato-protective clinical trial protocols for herbal medicines are not established till now. So, the efficacy of herbal medicines needs to be evaluated through rigorously designed multicentre clinical studies. In this review, we have enlightened the clinically evaluated hepatoprotective herbals and herbal formulations with respect to their status in different trial stages. Moreover, the problems and their strategic solutions during the development of clinical trial protocol for hepatoprotective herbal medicine are also addressed. PMID- 22540905 TI - Cardiac output by Flotrac/VigileoTM validation trials: are there reliable conclusions? AB - We reviewed the comparative trials of the Flotrac/VigileoTM versus the thermodilution method, published in the last five years. The results about the agreement between the two methods measuring cardiac output are contrasting. We also noticed that almost the whole pertinent literature include studies conducted without a correct statistical design, particularly about the sample size. For this reason we consider that results of the published studies about the agreement between pulse contour analysis for cardiac output measurement and thermodilution method may be not reliable. PMID- 22540906 TI - Anemia and chronic kidney disease: making sense of the recent trials. AB - Anemia is a very common complication of chronic kidney disease (CKD). Anemia confers significant risk of cardiovascular disease and contributes to decreased quality of life. Anemia in CKD patients can be multi-factorial, including but not invariably due to the underlying renal insufficiency. Identifying the type of anemia is important in this group of patients and can often be challenging. Diagnosing anemia of renal disease due to erythropoietin (EPO) deficiency is a diagnosis of exclusion. Erythropoiesis stimulating agents (ESA) are the mainstay for the treatment of anemia secondary to CKD. However, over the last four years the use of ESA in the treatment of anemia in CKD patients has undergone a severe interrogation as several trials have reported adverse outcomes with targeting higher hemoglobin (Hb) levels with these agents. Thereby, this review describes the pathophysiology of anemia in CKD patients, diagnosis and the current role of ESA's as it relates to anemia of CKD as well as safety and efficacy of ESA's. PMID- 22540907 TI - Clinical trials in chemoprevention of head and neck cancers. AB - Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignancies and has significant mortality. Its multi-step cumulative features strongly support early management. Cancer chemoprevention has been accepted as a promising intervention for early management, and has made enormous progresses over the past 30 years due to the large number of research studies including many randomized clinical trials. Overall, chemoprevention is an appealing approach for fighting HNSCC because it is generally safe, cost-effective, and widely available. In this review, we summarize and discuss new findings and evidences from the most recent clinical trials in chemoprevention of HNSCC. Our literature search is limited only to those trials published within the past 10 years (2001 2011). Based on our review, the most extensively studied agents/compounds for chemoprevention continue to be retinoids (e.g., 13-cRA). Additional agents considered include COX inhibitors, Vitamin A and E forms, and green tea and other natural extracts. However, we found disappointing results in the studies using retinoids, COX inhibitors and vitamin forms, while encouraging outcomes were found with most natural extracts. Further study is warranted for validation or improvement of treatment efficacy with current agents and strategies. Future research may include identification of new biomarkers/targets, improvement of bioavailability or tissue penetration, combinations of different compounds (or development of dual-action agents) to act on multiple pathways, and specific study of non-smoking related or other untraditional causes. PMID- 22540908 TI - New treatment approaches in acute myeloid leukemia: review of recent clinical studies. AB - Standard chemotherapy can cure only a fraction (30-40%) of younger and very few older patients with acute myeloid leukemia (AML). While conventional allografting can extend the cure rates, its application remains limited mostly to younger patients and those in remission. Limited efficacy of current therapies and improved understanding of the disease biology provided a spur for clinical trials examining novel agents and therapeutic strategies in AML. Clinical studies with novel chemotherapeutics, antibodies, different signal transduction inhibitors, and epigenetic modulators demonstrated their clinical activity; however, it remains unclear how to successfully integrate novel agents either alone or in combination with chemotherapy into the overall therapeutic schema for AML. Further studies are needed to examine their role in relation to standard chemotherapy and their applicability to select patient populations based on recognition of unique disease and patient characteristics, including the development of predictive biomarkers of response. With increasing use of nonmyeloablative or reduced intensity conditioning and alternative graft sources such as haploidentical donors and cord blood transplants, the benefits of allografting may extend to a broader patient population, including older AML patients and those lacking a HLA-matched donor. We will review here recent clinical studies that examined novel pharmacologic and immunologic approaches to AML therapy. PMID- 22540909 TI - Bone marrow cell therapy in clinical trials: a review of the literature. AB - Spurred by remarkable findings in animal studies, there has been strong interest in evaluating the potential of adult stem cells to improve left ventricular function in the past decade. Driven by the need to treat the increasing number of patients with coronary artery disease, numerous studies have attempted to define a role for bone marrow cell therapy in clinical use. However, the conflicting results of these studies can be confusing. This article will review the landmark trials evaluating bone marrow cell therapy in the past decade and describe the current state of adult stem cell therapy and its future direction herein. PMID- 22540910 TI - Methotrexate vs placebo in early tubal ectopic pregnancy: a multi- centre double blind randomised trial. AB - BACKGROUND: In the 21st century, tubal ectopic pregnancies (EPs) are diagnosed earlier in their natural history due to transvaginal ultrasound technology. More women are haemodynamically stable and therefore can be offered non-invasive outpatient management with systemic Methotrexate (MTX). However there is no evidence that MTX is necessary in all these early EPs, as many may resolve spontaneously in the absence of any treatment. To date there are no published randomized trials comparing systemic MTX with a placebo. The aim of this study is to verify if MTX is more effective than the placebo in women with tubal EP and rising/plateauing serum human chorionic gonadotrophin (hCG) levels. METHODS/DESIGN: This is a multi-centre double-blind randomized controlled trial conducted in Australia. Haemodynamically stable women with a confirmed ultrasound diagnosis of tubal EP and a rising/plateauing serum hCG & < 1500 IU/L are eligible for the trial. Women with a declining serum hCG, hCG > 1500 IU/L at 48 hrs, viable tubal EP, severe abdominal pain, evidence of haemoperitoneum on ultrasound, diagnostic uncertainty, non-tubal ectopic pregnancy, or women with contraindications to MTX will be excluded. Systemic MTX in a single dose intramuscular regimen (50mg/m2) is compared to an identical placebo in an outpatient setting. All women will attend for a serum hCG measurement on day 4. Provided patients are haemodynamically stable, they will attend for another blood test on day 7. If a decline in serum hCG > 15% between days 4 - 7 is observed, weekly blood tests will be scheduled until undetectable hCG levels. If serum hCG levels increase or decrease < 15% between days 4 - 7, a second dose of MTX will be given and weekly blood tests will be scheduled until undetectable serum hCG. If any increase in serum hCG > 15% between days 4 - 7 or at any subsequent follow up, women will be treated with MTX. Primary outcome measure is treatment success, defined as uneventful decline of serum hCG to an undetectable level ( < 5 IU/L) by the initial intervention. Secondary outcome measures are re-interventions (additional systemic MTX injections and/or surgery for haemodynamic instability/trophoblast persistence), treatment complications and length of follow-up. DISCUSSION: This trial will clarify the actual effectiveness of MTX in haemodynamically stable women with an early tubal EPs and rising or plateauing hCG. PMID- 22540911 TI - Evidence for oxygen binding at the active site of particulate methane monooxygenase. AB - Particulate methane monooxygenase (pMMO) is an integral membrane metalloenzyme that converts methane to methanol in methanotrophic bacteria. The enzyme consists of three subunits, pmoB, pmoA, and pmoC, organized in an alpha(3)beta(3)gamma(3) trimer. Studies of intact pMMO and a recombinant soluble fragment of the pmoB subunit (denoted as spmoB) indicate that the active site is located within the soluble region of pmoB at the site of a crystallographically modeled dicopper center. In this work, we have investigated the reactivity of pMMO and spmoB with oxidants. Upon reduction and treatment of spmoB with O(2) or H(2)O(2) or pMMO with H(2)O(2), an absorbance feature at 345 nm is generated. The energy and intensity of this band are similar to those of the MU-eta(2):eta(2)-peroxo Cu(II)(2) species formed in several dicopper enzymes and model compounds. The feature is not observed in inactive spmoB variants in which the dicopper center is disrupted, consistent with O(2) binding to the proposed active site. Reaction of the 345 nm species with CH(4) results in the disappearance of the spectroscopic feature, suggesting that this O(2) intermediate is mechanistically relevant. Taken together, these observations provide strong new support for the identity and location of the pMMO active site. PMID- 22540913 TI - TODAY--a stark glimpse of tomorrow. PMID- 22540914 TI - Total thyroidectomy with ultrasonic dissector for cancer: multicentric experience. AB - BACKGROUND: We conducted an observational multicentric clinical study on a cohort of patients undergoing thyroidectomy for thyroid carcinoma. The aim of this study was to evaluate the benefits of the use of ultrasonic dissector (UAS) vs. the use of a conventional technique (vessel clamp and tie) in patients undergoing thyroid surgery for cancer. METHODS: From June 2009 to May 2010 we evaluated 321 consecutive patients electively admitted to undergo total thyroidectomy for thyroid carcinoma. The first 201 patients (89 males, 112 females) presenting to our Department underwent thyroidectomy with the use of UAS while the following 120 patients (54 males, 66 females) underwent thyroidectomy performed with a conventional technique (CT): vessel clamp and tie. RESULTS: The operative time (mean: 75 min in UAS vs. 113 min in CT, range: 54 to 120 min in UAS vs. 68 to 173 min in CT) was much shorter in the group of thyroidectomies performed with UAS. The incidence of transient laryngeal nerve palsy (UAS 3/201 patients (1.49%); CT 1/120 patients (0.83%)) was higher in the group of UAS; the incidence of permanent laryngeal nerve palsy was similar in the two groups (UAS 2/201 patients (0.99%) vs. CT 2/120 patients (1.66%)). The incidence of transient hypocalcaemia (UAS 17/201 patients (8.4%) vs. CT 9/120 patients (7.5%)) was higher in the UAS group; no relevant differences were reported in the incidence of permanent hypocalcaemia in the two groups (UAS 5/201 patients (2.48%) vs. 2/120 patients (1.66%)). Also the average postoperative length of stay was similar in two groups (2 days). CONCLUSION: The only significant advantage proved by this study is represented by the cost-effectiveness (reduction of the usage of operating room) for patients treated with UAS, secondary to the significant reduction of the operative time. The analysis failed to show any advantages in terms of postoperative transient complications in the group of patients treated with ultrasonic dissector: transient laryngeal nerve palsy (1.49% in UAS vs. 0.83% in CT) and transient hypocalcaemia (8.4% in UAS vs. 7.5%in CT). No significant differences in the incidence of permanent laryngeal nerve palsy (0.8% in UAS vs. 1.04% in CT) and permanent hypocalcaemia (2.6% in UAS vs. 2.04% in CT) were demonstrated. The level of surgeons' expertise is a central factor, which can influence the complications rate; the use of UAS can only help surgical action but cannot replace the experience of the operator. PMID- 22540915 TI - Gestational bodyweight gain among underweight Japanese women related to small-for gestational-age birth. AB - AIM: The prevalence of underweight women, who have an increased risk for small for-gestational-age (SGA) birth, is increasing in Japan. We examined the associations of pre-pregnancy body mass index and gestational weight gain (GWG) with SGA birth among Japanese women. MATERIAL AND METHODS: We conducted a prospective cohort study of 1391 women who delivered full-term singleton babies. SGA was defined as below the 10th percentile of birthweight at each gestational age, baby sex, and parity. We calculated the 5th percentile of birthweight in the same way for another threshold for SGA. According to pre-pregnancy body mass index, we divided the participants into three groups: underweight (<18.5 kg/m(2)), normal weight (18.5-24.9 kg/m(2)), and overweight and obese (>=25.0 kg/m(2)). RESULTS: SGA birth was observed most frequently among the underweight group (13.8%). Underweight was associated with an increased risk of SGA birth. The multiple-adjusted odds ratio for underweight was 1.96 (95% confidence interval, 1.23-3.11) compared with normal weight. Sufficient GWG reduced the incidence and the multiple-adjusted odds ratio for 1-kg increase of GWG was 0.86 (0.81-0.92). The same tendency was observed for the delivery of infants below the 5th birthweight percentile. Women with underweight and normal weight who had 9.0 kg or less of GWG had a significantly higher risk of SGA birth than women with normal weight who had 9.1-11.0 kg of GWG. CONCLUSIONS: Underweight and poor GWG were associated with a higher incidence of SGA birth. However, the incidence of SGA birth among underweight women was not increased significantly if they had sufficient GWG. PMID- 22540919 TI - Pressure-reduction and preservation in custom-made footwear of patients with diabetes and a history of plantar ulceration. AB - AIMS: To assess the value of using in-shoe plantar pressure analysis to improve and preserve the offloading properties of custom-made footwear in patients with diabetes. METHODS: Dynamic in-shoe plantar pressures were measured in new custom made footwear of 117 patients with diabetes, neuropathy, and a healed plantar foot ulcer. In 85 of these patients, high peak pressure locations (peak pressure > 200 kPa) were targeted for pressure reduction (goal: > 25% relief or below an absolute level of 200 kPa) by modifying the footwear. After each of a maximum three rounds of modifications, pressures were measured. In a subgroup of 32 patients, pressures were measured and, if needed, footwear was modified at 3 monthly visits for 1 year. Pressures were compared with those measured in 32 control patients who had no footwear modifications based on pressure analysis. RESULTS: At the previous ulcer location and the highest and second highest pressure locations, peak pressures were significantly reduced by 23%, 21% and 15%, respectively, after modification of footwear. These lowered pressures were maintained or further reduced over time and were significantly lower, by 24-28%, compared with pressures in the control group. CONCLUSION: The offloading capacity of custom-made footwear for high-risk patients can be effectively improved and preserved using in-shoe plantar pressure analysis as guidance tool for footwear modification. This provides a useful approach to obtain better offloading footwear that may reduce the risk for pressure-related diabetic foot ulcers. PMID- 22540920 TI - Three dimensional socket preservation: a technique for soft tissue augmentation along with socket grafting. AB - BACKGROUND: A cursory review of the current socket preservation literatures well depicts the necessity of further esthetic considerations through the corrective procedures of the alveolar ridge upon and post extraction. A new technique has been described here is a rotational pedicle combined epithelialized and connective tissue graft (RPC graft) adjunct with immediate guided tissue regeneration (GBR) procedure. RESULTS: We reviewed this technique through a case report and discuss it's benefit in compare to other socket preservation procedures. CONCLUSION: The main advantages of RPC graft would be summarized as follows: stable primary closure during bone remodeling, saving or crating sufficient vestibular depth, making adequate keratinized gingiva on the buccal surface, and being esthetically pleasant. PMID- 22540921 TI - Punctate leucoderma after low-fluence 1,064-nm quality-switched neodymium-doped yttrium aluminum garnet laser therapy successfully managed using a 308-nm excimer laser. PMID- 22540912 TI - A clinical trial to maintain glycemic control in youth with type 2 diabetes. AB - BACKGROUND: Despite the increasing prevalence of type 2 diabetes in youth, there are few data to guide treatment. We compared the efficacy of three treatment regimens to achieve durable glycemic control in children and adolescents with recent-onset type 2 diabetes. METHODS: Eligible patients 10 to 17 years of age were treated with metformin (at a dose of 1000 mg twice daily) to attain a glycated hemoglobin level of less than 8% and were randomly assigned to continued treatment with metformin alone or to metformin combined with rosiglitazone (4 mg twice a day) or a lifestyle-intervention program focusing on weight loss through eating and activity behaviors. The primary outcome was loss of glycemic control, defined as a glycated hemoglobin level of at least 8% for 6 months or sustained metabolic decompensation requiring insulin. RESULTS: Of the 699 randomly assigned participants (mean duration of diagnosed type 2 diabetes, 7.8 months), 319 (45.6%) reached the primary outcome over an average follow-up of 3.86 years. Rates of failure were 51.7% (120 of 232 participants), 38.6% (90 of 233), and 46.6% (109 of 234) for metformin alone, metformin plus rosiglitazone, and metformin plus lifestyle intervention, respectively. Metformin plus rosiglitazone was superior to metformin alone (P=0.006); metformin plus lifestyle intervention was intermediate but not significantly different from metformin alone or metformin plus rosiglitazone. Prespecified analyses according to sex and race or ethnic group showed differences in sustained effectiveness, with metformin alone least effective in non-Hispanic black participants and metformin plus rosiglitazone most effective in girls. Serious adverse events were reported in 19.2% of participants. CONCLUSIONS: Monotherapy with metformin was associated with durable glycemic control in approximately half of children and adolescents with type 2 diabetes. The addition of rosiglitazone, but not an intensive lifestyle intervention, was superior to metformin alone. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; TODAY ClinicalTrials.gov number, NCT00081328.). PMID- 22540922 TI - Radical prostatectomy vs radiation therapy and androgen-suppression therapy in high-risk prostate cancer. AB - What's known on the subject? and What does the study add? Prostate cancer is generally considered to be high risk when the prostate-specific antigen (PSA) concentration is >20 ng/mL, the Gleason score is >=8 or the American Joint Commission on Cancer (AJCC) tumour (T) category is >=2c. There is no consensus on the best treatment for men with prostate cancer that includes these high-risk features. Options include external beam radiation therapy (EBRT) with androgen suppression therapy (AST), treatment with a combination of brachytherapy, EBRT and AST termed combined-modality therapy (CMT) or radical prostatectomy (RP) followed by adjuvant RT in cases where there are unfavourable pathological features, e.g. positive surgical margin, extracapsular extension and seminal vesicle invasion. While outcomes for both approaches have been published independently these treatments have not been compared in the setting of a prospective RCT where confounding factors related to patient selection for RP or CMT would be minimised. These factors include age, known prostate cancer prognostic factors and comorbidity. RCTs that compare RP to radiation-based regimens have been attempted but failed to accrue. OBJECTIVE: To assess the risk of prostate cancer-specific mortality after therapy with radical prostatectomy (RP) or combined-modality therapy (CMT) with brachytherapy, external beam radiation therapy (EBRT) and androgen-suppression therapy (AST) in men with Gleason score 8-10 prostate cancer. PATIENTS AND METHODS: Men with localised high risk prostate cancer based on a Gleason score of 8-10 were selected for study from Duke University (285 men), treated between January 1988 and October 2008 with RP or from the Chicago Prostate Cancer Center or within the 21st Century Oncology establishment (372) treated between August 1991 and November 2005 with CMT. Fine and Gray multivariable regression was used to assess whether the risk of prostate cancer-specific mortality differed after RP as compared with CMT adjusting for age, cardiac comorbidity and year of treatment, and known prostate cancer prognostic factors. RESULTS: As of January 2009, with a median (interquartile range) follow-up of 4.62 (2.4-8.2) years, there were 21 prostate cancer-specific deaths. Treatment with RP was not associated with an increased risk of prostate cancer-specific mortality compared with CMT (adjusted hazard ratio [HR] 1.8, 95% confidence interval [CI] 0.6-5.6, P = 0.3). Factors associated with an increased risk of prostate cancer-specific mortality were a PSA concentration of <4 ng/mL (adjusted HR 6.1, 95% CI 2.3-16, P < 0.001) as compared with >=4 ng/mL, and clinical category T2b, c (adjusted HR 2.9; 95% CI 1.1-7.2; P = 0.03) as compared with T1c, 2a. CONCLUSION: Initial treatment with RP as compared with CMT was not associated with an increased risk of prostate cancer-specific mortality in men with Gleason score 8-10 prostate cancer. PMID- 22540924 TI - Effective transmission of light for media culture, plates and tubes. AB - The results of many investigations on low-level laser therapy are contradictory and this is due to the large number of illumination parameters as well as the inability to measure the possible effects after irradiation with the necessary objectivity and the fact that the light needs to pass thorough barriers (usually the plastic of the culture dish/plate and culture medium) to reach the cells. In this manner, the objective of this study was to determine the absorption coefficient, penetration depth and effective transmission in materials commonly used in cell cultures. Among the most commonly used wavelengths in low-level laser therapy, the lowest absorption coefficients were reached by DMEM and RPMI (alpha = 0.03 cm(-1)), from 633 to 690 nm, which reach an effective transmission of 93% of incident radiation and penetration depth of 33 cm. Among the solid materials in the same range of the electromagnetic spectrum, the lowest absorption coefficient was obtained for the polystyrene (Petri dish and well plate), with alpha = 1.31 cm(-1), 78% of effective transmission and 0.76 cm of penetration depth. This article also presents a simple equation for estimating the amount of energy that will actually reach the sample. PMID- 22540923 TI - Cockroach allergens induce biphasic asthma-like pulmonary inflammation in outbred mice. AB - OBJECTIVES: The aim of this study is to define the kinetics of the pulmonary inflammatory response in cockroach allergen (CRA) sensitized and challenged outbred mice. METHODS: Asthma-like pulmonary inflammation was induced with three pulmonary exposures to CRA, without the use of adjuvants. Mice were sacrificed at multiple time points and asthma-like pulmonary inflammation quantified. RESULTS: Several pulmonary parameters showed a pronounced biphasic inflammatory response with an early stage (1.5 hours post challenge) and late stage (24 hours). The initial phase was characterized by the production of multiple inflammatory mediators, including CXC chemokines, and the recruitment of neutrophils to the lung. The number of pulmonary eosinophils decreased in the early phase but quickly rebounded. Both the early and late phases had increases in TNF production in addition to airways hyperreactivity. The model also demonstrated early production of mucin with clearance by 12 hours followed by new accumulation of mucin in the pulmonary epithelial cells. Eotaxins within the lung peaked at about 12 hours and the numbers of eosinophils in the lung remained constant throughout the 48 hours of the study. CONCLUSIONS: The pulmonary inflammatory parameters in response to a clinically relevant allergen define a biphasic response. These data may be used to investigate the pathogenesis of the disease and develop targeted therapies for the distinct phases. PMID- 22540926 TI - Visual search performance of patients with vision impairment: effect of JPEG image enhancement. AB - PURPOSE: To measure natural image search performance in patients with central vision impairment. To evaluate the performance effect for a JPEG based image enhancement technique using the visual search task. METHODS: One hundred and fifty JPEG images were presented on a touch screen monitor in either an enhanced or original version to 19 patients (visual acuity 0.4-1.2 logMAR, 6/15 to 6/90, 20/50 to 20/300) and seven normally sighted controls (visual acuity -0.12 to 0.1 logMAR, 6/4.5 to 6/7.5, 20/15 to 20/25). Each image fell into one of three categories: faces, indoors, and collections. The enhancement was realized by moderately boosting a mid-range spatial frequency band in the discrete cosine transform (DCT) coefficients of the image luminance component. Participants pointed to an object in a picture that matched a given target displayed at the upper-left corner of the monitor. Search performance was quantified by the percentage of correct responses, the median search time of correct responses, and an 'integrated performance' measure - the area under the curve of cumulative correct response rate over search time. RESULTS: Patients were able to perform the search tasks but their performance was substantially worse than the controls. Search performances for the three image categories were significantly different (p <= 0.001) for all the participants, with searching for faces being the most difficult. When search time and correct response were analyzed separately, the effect of enhancement led to increase in one measure but decrease in another for many patients. Using the integrated performance, it was found that search performance declined with decrease in acuity (p = 0.005). An improvement with enhancement was found mainly for the patients whose acuity ranged from 0.4 to 0.8 logMAR (6/15 to 6/38, 20/50 to 20/125). Enhancement conferred a small but significant improvement in integrated performance for indoor and collection images (p = 0.025) in the patients. CONCLUSION: Search performance for natural images can be measured in patients with impaired vision to evaluate the effect of image enhancement. Patients with moderate vision loss might benefit from the moderate level of enhancement used here. PMID- 22540925 TI - Artemether resistance in vitro is linked to mutations in PfATP6 that also interact with mutations in PfMDR1 in travellers returning with Plasmodium falciparum infections. AB - BACKGROUND: Monitoring resistance phenotypes for Plasmodium falciparum, using in vitro growth assays, and relating findings to parasite genotype has proved particularly challenging for the study of resistance to artemisinins. METHODS: Plasmodium falciparum isolates cultured from 28 returning travellers diagnosed with malaria were assessed for sensitivity to artemisinin, artemether, dihydroartemisinin and artesunate and findings related to mutations in pfatp6 and pfmdr1. RESULTS: Resistance to artemether in vitro was significantly associated with a pfatp6 haplotype encoding two amino acid substitutions (pfatp6 A623E and S769N; (mean IC50 (95% CI) values of 8.2 (5.7 - 10.7) for A623/S769 versus 623E/769 N 13.5 (9.8 - 17.3) nM with a mean increase of 65%; p = 0.012). Increased copy number of pfmdr1 was not itself associated with increased IC50 values for artemether, but when interactions between the pfatp6 haplotype and increased copy number of pfmdr1 were examined together, a highly significant association was noted with IC50 values for artemether (mean IC50 (95% CI) values of 8.7 (5.9 - 11.6) versus 16.3 (10.7 - 21.8) nM with a mean increase of 87%; p = 0.0068). Previously described SNPs in pfmdr1 are also associated with differences in sensitivity to some artemisinins. CONCLUSIONS: These findings were further explored in molecular modelling experiments that suggest mutations in pfatp6 are unlikely to affect differential binding of artemisinins at their proposed site, whereas there may be differences in such binding associated with mutations in pfmdr1. Implications for a hypothesis that artemisinin resistance may be exacerbated by interactions between PfATP6 and PfMDR1 and for epidemiological studies to monitor emerging resistance are discussed. PMID- 22540927 TI - Total laparoscopic hysterectomy in 1253 patients using an early ureteral identification technique. AB - AIM: The aim of this study was to determine the incidence of perioperative complications and evaluate risk factors for the major complications of total laparoscopic hysterectomy (TLH) using an early ureteral identification technique. We describe the technique we standardized and used for TLH, without exclusion criteria. MATERIAL AND METHODS: A retrospective study was carried out at Kurashiki Medical Center, Japan, based on 1253 TLH procedures performed from January 2005 to March 2009. We reviewed records to identify the major perioperative complications, including bladder, ureteral, and intestinal injuries, and incidences of reoperation. Risk factors for major complications were analyzed using multivariate logistic regression models. RESULTS: A total of 24 patients encountered major complications (1.91%). Complications included 10 intraoperative urologic injuries, five cases of postoperative hydronephrosis, five cases of vaginal dehiscence, one bowel injury, one postoperative hemorrhage, one bowel obstruction, and one ureterovaginal fistula. All 11 cases of intraoperative visceral injury were recognized during the surgery and repaired during the same laparoscopic surgical procedure. Of the risk factors analyzed, a history of abdominal surgery was the only one associated with the occurrence of major complications, with an odds ratio of 2.48 (95% confidence interval 1.23 6.49). CONCLUSION: While complications are inevitable, even in the hands of the most skilled surgeon, they can be minimized without conversion to laparotomy by a sufficiently developed suturing technique and a precise knowledge of pelvic anatomy. The presented data indicate that our method allows for safe TLH and minimization of ureteral injury, without the use of stringent exclusion criteria. PMID- 22540928 TI - Population-level consequences of polymorphism, plasticity and randomized phenotype switching: a review of predictions. AB - The consequences of among-individual phenotypic variation for the performance and ecological success of populations and species has attracted growing interest in recent years. Earlier reviews of this field typically address the consequences for population processes of one specific source of variation (plasticity or polymorphism), or consider one specific aspect of population performance, such as rate of speciation. Here we take a broader approach and study earlier reviews in order to summarize and compare predictions regarding several population-level consequences of phenotypic variation stemming from genetic polymorphism, developmental plasticity or randomized phenotype switching. Unravelling cause dependent consequences of variation may increase our ability to understand the ecological dynamics of natural populations and communities, develop more informed management plans for protection of biodiversity, suggest possible routes to increased productivity and yield in natural and managed biological systems, and resolve inconsistencies in patterns and results seen in studies of different model systems. We find an overall agreement regarding the effects of higher levels of phenotypic variation generated by different sources, but also some differences between fine-grained and coarse-grained environments, modular and unitary organisms, mobile and sessile organisms, and between flexible and fixed traits. We propose ways to test the predictions and identify issues where current knowledge is limited and future lines of investigation promise to provide important novel insights. PMID- 22540929 TI - Glucose biosensor based on the immobilization of glucose oxidase on electrochemically synthesized polypyrrole-poly(vinyl sulphonate) composite film by cross-linking with glutaraldehyde. AB - In this study, a novel amperometric glucose biosensor was developed by immobilizing glucose oxidase (GOX) by cross-linking via glutaraldehyde on electrochemically polymerized polypyrrole-poly(vinyl sulphonate) (PPy-PVS) films on the surface of a platinum (Pt) electrode. Electropolymerization of pyrrole and poly(vinyl sulphonate) on the Pt surface was carried out with an electrochemical cell containing pyrrole and poly(vinyl sulphonate) by cyclic voltammetry between 1.0 and + 2.0 V (vs.Ag/AgCl) at a scan rate of 50 mV/s upon the Pt electrode. The amperometric determination was based on the electrochemical detection of H(2)O(2) generated in enzymatic reaction of glucose. Determination of glucose was carried out by the oxidation of enzymatically produced H(2)O(2) at 0.4 V vs. Ag/AgCl. The effects of pH and temperature were investigated and optimum parameters were found to be 7.5 and 65 degrees C, respectively. The effect of working potential was investigated and optimum potential was determined to be 0.4 V. The operational stability of the enzyme electrode was also studied. The response of the PPy/PVS GOX glucose biosensor exhibited good reproducibility with a relative standard deviation (RSD) of 2.48%. The glucose biosensor retained 63% of initial activity after 93 days when stored in 0.1 M phosphate buffer solution of pH 7.5 at 4 degrees C. With the low operating potential, the biosensor demonstrated little interference from the possible interferants. PMID- 22540931 TI - Hypoxia-inducible factor 1 protects hypoxic astrocytes against glutamate toxicity. AB - Stroke is a major neurological disorder characterized by an increase in the Glu (glutamate) concentration resulting in excitotoxicity and eventually cellular damage and death in the brain. HIF-1 (hypoxia-inducible factor-1), a transcription factor, plays an important protective role in promoting cellular adaptation to hypoxic conditions. It is known that HIF-1alpha, the regulatable subunit of HIF-1, is expressed by astrocytes under severe ischaemia. However, the effect of HIF-1 on astrocytes following Glu toxicity during ischaemia has not been well studied. We investigated the role of HIF-1 in protecting ischaemic astrocytes against Glu toxicity. Immunostaining with GFAP (glial fibrillary acidic protein) confirmed the morphological modification of astrocytes in the presence of 1 mM Glu under normoxia. Interestingly, when the astrocytes were exposed to severe hypoxia (0.1% O2), the altered cell morphology was ameliorated with up-regulation of HIF-1alpha. To ascertain HIF-1's protective role, effects of two HIF-1alpha inhibitors, YC-1 [3-(50-hydroxymethyl-20-furyl)-1 benzylindazole] and 2Me2 (2-methoxyoestradiol), were tested. Both the inhibitors decreased the recovery in astrocyte morphology and increased cell death. Given that ischaemia increases ROS (reactive oxygen species), we examined the role of GSH (reduced glutathione) in the mechanism for this protection. GSH was increased under hypoxia, and this correlated with an increase in HIF-1alpha stabilization in the astrocytes. Furthermore, inhibition of GSH with BSO (l-butathione sulfoximine) decreased HIF-1alpha expression, suggesting its role in the stabilization of HIF-1alpha. Overall, our results indicate that the expression of HIF-1alpha under hypoxia has a protective effect on astrocytes in maintaining cell morphology and viability in response to Glu toxicity. PMID- 22540932 TI - Enhancement of cyclopamine via conjugation with nonmetabolic sugars. AB - The Veratrum alkaloid cyclopamine, an inhibitor of cancer stem cell growth, was used as a representative scaffold to evaluate the inhibitory impact of glycosylation with a group of nonmetabolic saccharides, such as d-threose. In a five-step divergent process, a 32-member glycoside library was created and assayed to determine that glycosides of such sugars notably improved the GI50 value of cyclopamine while metabolic sugars, such as d-glucose, did not. PMID- 22540933 TI - MMP-7 as a potential marker of cardiovascular complications in patients with chronic kidney disease (CKD). PMID- 22540934 TI - Dermoscopic findings in biopsy-proven poromas. PMID- 22540935 TI - 18F-fluoro-deoxy-glucose focal uptake in very small pulmonary nodules: fact or artifact? Case reports. AB - BACKGROUND: 18F-fluoro-deoxy-glucose (18 F-FDG) positron emission tomography integrated/combined with computed tomography (PET-CT) provides the best diagnostic results in the metabolic characterization of undetermined solid pulmonary nodules. The diagnostic performance of 18 F-FDG is similar for nodules measuring at least 1 cm and for larger masses, but few data exist for nodules smaller than 1 cm. CASE PRESENTATION: We report five cases of oncologic patients showing focal lung 18 F-FDG uptake on PET-CT in nodules smaller than 1 cm. We also discuss the most common causes of 18 F-FDG false-positive and false-negative results in the pulmonary parenchyma.In patient 1, contrast-enhanced CT performed 10 days before PET-CT did not show any abnormality in the site of uptake; in patient 2, high-resolution CT performed 1 month after PET showed a bronchiole filled with dense material interpreted as a mucoid impaction; in patient 3, contrast-enhanced CT performed 15 days before PET-CT did not identify any nodules; in patients 4 and 5, contrast-enhanced CT revealed a nodule smaller than 1 cm which could not be characterized. The 18 F-FDG uptake at follow-up confirmed the malignant nature of pulmonary nodules smaller than 1 cm which were undetectable, misinterpreted, not recognized or undetermined at contrast-enhanced CT. CONCLUSION: In all five oncologic patients, 18 F-FDG was able to metabolically characterize as malignant those nodules smaller than 1 cm, underlining that: 18 F-FDG uptake is not only a function of tumor size but it is strongly related to the tumor biology; functional alterations may precede morphologic abnormalities. In the oncologic population, especially in higher-risk patients, PET can be performed even when the nodules are smaller than 1 cm, because it might give an earlier characterization and, sometimes, could guide in the identification of alterations missed on CT. PMID- 22540936 TI - Generic and diabetes-specific well-being in the AT.LANTUS Follow-on study: further psychometric validation of the W-BQ28 indicates its utility in research and clinical practice in Type 2 diabetes in the UK. AB - AIMS: To undertake further psychometric validation of the W-BQ28 to determine its suitability for use in adults with Type 2 diabetes in the UK using data from the AT.LANTUS follow-on study. METHODS: A total of 353 people with Type 2 diabetes participated in the AT.LANTUS Follow-on study, completing measures of well-being (W-BQ28), treatment satisfaction (DTSQ) and self-care (SCI-R). Confirmatory factor analyses was used to confirm the W-BQ28 structure and internal consistency reliability was assessed. Additional statistical tests were conducted to explore convergent, divergent and known-groups validity. Minimal important differences were calculated using distribution and anchor-based techniques. RESULTS: Structure of the W-BQ28 (seven four-item subscales plus 16-item generic and 12 item diabetes-specific scales) was confirmed (comparative fit index = 0.917, root mean square error of approximation (RMSEA) = 0.057). Internal consistency reliability was satisfactory (four-item subscales: alpha = 0.73-0.90; 12/16-item scales: alpha = 0.84-0.90). Convergent validity was supported by expected moderate to high correlations (r(s) = 0.35-0.67) between all W-BQ28 subscales (except Energy); divergent validity was supported by expected low to moderate correlations with treatment satisfaction (r(s) = -0.03-0.52) and self-care (r(s) = 0.02-0.22). Known-groups validity was supported with statistically significant differences by sex, age and HbA(1c) for expected subscales. Minimal important differences were established (range 0.14-2.90). CONCLUSIONS: The W-BQ28 is a valid and reliable measure of generic and diabetes-specific well-being in Type 2 diabetes in the UK. Confirmation of the utility of W-BQ28 (including establishment of minimal important differences) means that its use is indicated in research and clinical practice. PMID- 22540937 TI - Quantitative statistical analysis of dielectric breakdown in zirconia-based self assembled nanodielectrics. AB - Uniformity of the dielectric breakdown voltage distribution for several thicknesses of a zirconia-based self-assembled nanodielectric was characterized using the Weibull distribution. Two regimes of breakdown behavior are observed: self-assembled multilayers >5 nm thick are well described by a single two parameter Weibull distribution, with beta ~ 11. Multilayers <=5 nm thick exhibit kinks on the Weibull plot of dielectric breakdown voltage, suggesting that multiple characteristic mechanisms for dielectric breakdown are present. Both the degree of uniformity and the effective dielectric breakdown field are observed to be greater for one layer than for two layers of Zr-SAND, suggesting that this multilayer is more promising for device applications. PMID- 22540938 TI - Rapid isolation and identification of active antioxidant ingredients from Gongju using HPLC-DAD-ESI-MS(n) and postcolumn derivatization. AB - Flos Chrysanthemi (Gongju, GJ) is used to prepare a herbal tea that is commonly consumed as a health beverage in Asia and is believed to contain abundant beneficial antioxidants. To rapidly identify the chemical constituents and to obtain the profile related to antioxidant activity, an online analytical method combining high-performance liquid chromatography-diode-array detector electrospray ionization-ion-trap time-of-flight mass spectrometry (HPLC-DAD-ESI IT-TOF-MS(n)) and postcolumn derivatization (PCD) has been applied for a precise and thorough identification of the chemical constituents. Meanwhile, the antioxidant profile has also been characterized by directly measuring the scavenging activity of each compound for the free radical produced by DPPH. As a result, 13 compounds have been identified in GJ, 7 of which account for its antioxidant activity. The established LC-MS(n)-PCD system has proved to offer a useful strategy for correlating the chemical profile with the bioactivities of the components without their isolation and purification, and may be used for multicomponent analysis of active substances in other foods and herbs. PMID- 22540939 TI - Preschoolers use intentional and pedagogical cues to guide inductive inferences and exploration. AB - Children are judicious social learners. They may be particularly sensitive to communicative actions done pedagogically for their benefit, as such actions may mark important, generalizable information. Three experiments (N = 224) found striking differences in preschoolers' inductive generalization and exploration of a novel functional property, depending on whether identical evidence for the property was produced accidentally, intentionally, or pedagogically and communicatively. Results also revealed that although 4-year-olds reserved strong generalizations for a property that is pedagogically demonstrated, 3-year-olds made such inferences when it was produced either intentionally or pedagogically. These findings suggest that by age 4 children assess whether evidence is produced for their benefit in gauging generalizability, giving them a powerful tool for acquiring important kind-relevant, generic knowledge. PMID- 22540940 TI - Modeling gas formation and mineral precipitation in a granular iron column. AB - In granular iron permeable reactive barriers (PRBs), hydrogen gas formation, entrapment and release of gas bubbles, and secondary mineral precipitation have been known to affect the permeability and reactivity. The multicomponent reactive transport model MIN3P was enhanced to couple gas formation and release, secondary mineral precipitation, and the effects of these processes on hydraulic properties and iron reactivity. The enhanced model was applied to a granular iron column, which was studied for the treatment of trichloroethene (TCE) in the presence of dissolved CaCO(3). The simulation reasonably reproduced trends in gas formation, secondary mineral precipitation, permeability changes, and reactivity changes observed over time. The simulation showed that the accumulation of secondary minerals reduced the reactivity of the granular iron over time, which in turn decreased the rate of mineral accumulation, and also resulted in a gradual decrease in gas formation over time. This study provides a quantitative assessment of the evolving nature of geochemistry and permeability, resulting from coupled processes of gas formation and mineral precipitation, which leads to a better understanding of the processes controlling the granular iron reactivity, and represents an improved method for incorporating these factors into the design of granular iron PRBs. PMID- 22540941 TI - Microfluidic models of vascular functions. AB - In vitro studies of vascular physiology have traditionally relied on cultures of endothelial cells, smooth muscle cells, and pericytes grown on centimeter-scale plates, filters, and flow chambers. The introduction of microfluidic tools has revolutionized the study of vascular physiology by allowing researchers to create physiologically relevant culture models, at the same time greatly reducing the consumption of expensive reagents. By taking advantage of the small dimensions and laminar flow inherent in microfluidic systems, recent studies have created in vitro models that reproduce many features of the in vivo vascular microenvironment with fine spatial and temporal resolution. In this review, we highlight the advantages of microfluidics in four areas: the investigation of hemodynamics on a capillary length scale, the modulation of fluid streams over vascular cells, angiogenesis induced by the exposure of vascular cells to well defined gradients in growth factors or pressure, and the growth of microvascular networks in biomaterials. Such unique capabilities at the microscale are rapidly advancing the understanding of microcirculatory dynamics, shear responses, and angiogenesis in health and disease as well as the ability to create in vivo-like blood vessels in vitro. PMID- 22540942 TI - Establishment of a coculture model for studying inflammation after pediatric cardiopulmonary bypass: from bench to bedside. AB - Cardiopulmonary bypass (CPB) has been known to induce an inflammatory response that is influenced by various factors. Hypothermia is supposed to reduce inflammation after CPB. We developed an in vitro coculture model for CPB and compared the effects of hypothermia on the inflammatory response in the coculture model with results from a clinical prospective randomized trial. The coculture model consisted of endothelial cells and monocytes. Cells were stimulated with tumor necrosis factor (TNF)-alpha and exposed to deep hypothermia (20 degrees C) or normothermia (37 degrees C). In the clinical trial, 20 patients undergoing CPB for ventricular septum defect receive either normothermic (37 degrees C) or mild hypothermic (32 degrees C) CPB. We observed a significant interleukin (IL)-6 and IL-8 release in the coculture model 2 and 24 h after the experimental start. In the clinical trial, cytokines were significantly increased directly after weaning from CPB and remained elevated until 24 h. IL-8 and IL-6 secretions were similar in the hypothermic and normothermic group of the coculture model and the patients after 24 h. These results demonstrate that the inflammatory reaction observed in our coculture model is comparable with the cytokine increase in the blood of children undergoing CPB. Our coculture model could be useful for studies on the mechanisms of CPB-induced inflammation. PMID- 22540943 TI - Negative regulation of the type I interferon signaling pathway by synthetic Toll like receptor 7 ligands. AB - Ten Toll-like receptor (TLR) family members have been reported in humans. Here, the endoplasmatic receptors TLR9, TLR8, TLR7, and TLR3 respond to nucleic acids and derivatives or to small molecules (TLR7 and 8). Another cytoplasmic RNA receptor, retinoic acid inducible gene I (RIG-I), is stimulated by 5' triphosphate double-stranded RNA. We discovered that TLR7 small-molecule agonists inhibit nucleic acid-mediated TLR3, TLR7, TLR9, or RIG-I-dependent interferon alpha (IFN-alpha) immune response. Other cytokines and chemokines stimulated by nucleic acid agonists remained unaffected. The observed blockage of TLR3, TLR7, TLR9, and RIG-I-mediated IFN-alpha response appears to be driven by a competitive mechanism at the type I IFN pathway. Besides type I IFN, IFN response genes such as IFIT-1, Mx1, OAS1, or IRF7 were affected, which indicates that the key element driving the inhibition is located in the type I IFN pathway. Indeed, the heterotrimeric complex formation of phosphor-signal transducer and activator of transcription factor 1 (STAT1), phosphor-STAT2, and IRF9 (called ISGF3, IFN stimulated gene factor 3) is inhibited through the TLR7 small-molecule agonists by phosphor-STAT2 blockage. These findings provide novel insights into the use of synthetic TLR7 or TLR7/8 small molecules as ligands for immune activation and suppression. PMID- 22540946 TI - Surface-dependent, ligand-mediated photochemical etching of CdSe nanoplatelets. AB - Photochemical etching of CdSe nanoplatelets was studied to establish a relationship between the nanocrystal surface and the photochemical activity of an exciton. Nanoplatelets were synthesized in a mixture of octylamine and oleylamine for the wurtzite (W) lattice or in octadecene containing oleic acid for the zinc blende (ZB) lattice. For photochemical etching, nanoplatelets were dispersed in chloroform containing oleylamine and tributylphosphine in the absence or presence of oleic acid and then irradiated with light at the band-edge absorption maxima. Etching phenomena were characterized using UV-vis absorption spectroscopy and transmission electron microscopy. The absorption spectra of both W and ZB CdSe nanoplatelets showed that the exciton was confined in one dimension along the thickness. However, the two nanoplatelets presented different etching kinetics and erosion patterns. The rate of etching for W CdSe nanoplatelets was much faster than that for ZB nanoplatelets. Small holes were uniformly perforated on the planar surface of W nanoplatelets, whereas the corners and edges of ZB nanoplatelets were massively eroded without a significant perforation on the planar surface. This suggests that the amine-passivated surface of trivalent cadmium atoms on CdSe nanoplatelets is photochemically active, but the carboxylate-passivated surface of divalent cadmium atoms is not. Hence, the ligand, which induces the growth of W or ZB CdSe nanoplatelets, mediates the surface-dependent photochemical etching. This result implies that an electron hole pair can be extracted from the planar surface of amine-passivated W nanoplatelets but from the corners and edges of carboxylate-passivated ZB nanoplatelets. PMID- 22540944 TI - Metabolic network analysis predicts efficacy of FDA-approved drugs targeting the causative agent of a neglected tropical disease. AB - BACKGROUND: Systems biology holds promise as a new approach to drug target identification and drug discovery against neglected tropical diseases. Genome scale metabolic reconstructions, assembled from annotated genomes and a vast array of bioinformatics/biochemical resources, provide a framework for the interrogation of human pathogens and serve as a platform for generation of future experimental hypotheses. In this article, with the application of selection criteria for both Leishmania major targets (e.g. in silico gene lethality) and drugs (e.g. toxicity), a method (MetDP) to rationally focus on a subset of low toxic Food and Drug Administration (FDA)-approved drugs is introduced. RESULTS: This metabolic network-driven approach identified 15 L. major genes as high priority targets, 8 high-priority synthetic lethal targets, and 254 FDA-approved drugs. Results were compared to previous literature findings and existing high throughput screens. Halofantrine, an antimalarial agent that was prioritized using MetDP, showed noticeable antileishmanial activity when experimentally evaluated in vitro against L. major promastigotes. Furthermore, synthetic lethality predictions also aided in the prediction of superadditive drug combinations. For proof-of-concept, double-drug combinations were evaluated in vitro against L. major and four combinations involving the drug disulfiram that showed superadditivity are presented. CONCLUSIONS: A direct metabolic network driven method that incorporates single gene essentiality and synthetic lethality predictions is proposed that generates a set of high-priority L. major targets, which are in turn associated with a select number of FDA-approved drugs that are candidate antileishmanials. Additionally, selection of high-priority double-drug combinations might provide for an attractive and alternative avenue for drug discovery against leishmaniasis. PMID- 22540945 TI - Rational evolution of a novel type of potent and selective proviral integration site in Moloney murine leukemia virus kinase 1 (PIM1) inhibitor from a screening hit compound. AB - Serine/threonine kinase PIM1 is an emerging therapeutic target for hematopoietic and prostate cancer therapy. To develop a novel PIM1 inhibitor, we focused on 1, a metabolically labile, nonselective kinase inhibitor discovered in our previous screening study. We adopted a rational optimization strategy based mainly on structural information for the PIM1-1 complex to improve the potency and selectivity. This approach afforded the potent and metabolically stable PIM1 selective inhibitor 14, which shows only a marginal increase in molecular weight compared with 1 but has a significantly decreased cLogP. The validity of our design concept was confirmed by X-ray structure analysis. In a cellular study, 14 potently inhibited the growth of human leukemia cell line MV4-11 but had a negligible effect on the growth of WI-38 (surrogate for general toxicity). These results demonstrate the effectiveness of our design strategy for evolving the screening-hit compound 1 into a novel type of PIM1 inhibitor, 14. PMID- 22540947 TI - Synthesis of microwave-assisted poly(methyl vinyl ether-co-maleic anhydride) bovine serum albumin bioconjugates. AB - The water-soluble poly(methyl vinyl ether-co-maleic anhydride) copolymer-bovine serum albumin bioconjugates were synthesized in the presence of 1-ethyl-3-(3 dimetilamino-propyl) carbodiimide hydrochloride as cross-linking agents via microwave-assisted and conventional methods and characterized by size-exclusion chromatography and high-performance liquid chromatography. According to size exclusion chromatography and high-performance liquid chromatography results, the bioconjugates synthesized in the microwave-assisted method are more stable and efficient than the conventional method. The reaction time is shortened from 17 hours to 15 minutes by means of the microwave-assisted method. PMID- 22540948 TI - Degradation of two soluble proteins--casein and egg protein by a macro in vitro method. AB - Degradation of casein and egg protein was studied with whole rumen contents (RC) in a macro in vitro system to elucidate previous findings of initial rapid disappearance of soluble proteins in vitro. Five to 7.5 kg of RC from a dry and/or a lactating cow were incubated with buffer and casein or egg protein for 180 min with frequent sampling. Degradation was measured as loss of trichloroacetic acid precipitable N (TCA-N) from the inocula. Normal (39 degrees C) and low (2 degrees C) temperature incubations were examined in Exp. 1, using 1 g of TCA-N from casein. Four levels of casein (0-12 g TCA-N) in Exp. 2 and four levels of egg albumin (0-24 g TCA-N) in Exp. 3 were fermented at 39 degrees C. Initial recovery of casein TCA-N was 106% at 2 degrees C and 56% at 39 degrees C (Exp. 1). Casein (TCA-N) recovered initially increased in Exp. 2 from 21% at 3 g to 86% at 12 g TCA-N, while absolute loss remained relatively constant at 358 mg TCA-N/kg RC (SD=47). Fractional degradation rate was highest (0.03/min) at the intermediate dosage level. In the absence of rumen fluid (Exp. 4), no casein was lost. Initial egg protein recovery was on average 103% (Exp. 3). Recovery seemed unaffected by dosage level, and absolute degradation rate was relatively constant over time and increased with dosage level (p<0.001) from 1.48 to 2.95 mg TCA N/(kg RC * min). Maximum degradation rate [mg TCA-N/(kg RC * min)] and affinity constant (mg TCA-N/kg RC) were estimated at 261 and 1650, respectively. It is concluded that a surprisingly constant amount of casein disappears immediately from warm rumen fluid and that this does not occur either with chilled RC, in the absence of rumen fluid, or when replaced with egg protein. The mechanisms for this disappearance are yet to be discovered. PMID- 22540949 TI - Metabolic and toxicological considerations of botanicals in anticancer therapy. AB - INTRODUCTION: Cancer is a complex disease, characterized by redundant aberrant signaling pathways as a result of genetic perturbations at different levels. Botanicals consist of a complex mixture of constituents and exhibit pharmacological effects by the interaction of many phytochemicals. The multitarget nature of botanicals could, therefore, be a relevant strategy to address the biological complexity that characterizes tumors. AREAS COVERED: This article reviews the current status of botanicals in the oncological field and the challenges associated with their complex nature. EXPERT OPINION: Botanicals are an important new pharmacological strategy, which are potentially exploitable in the oncological area but are characterized by a number of problems still unresolved. Content variation of products is one of the primary problems with botanicals and, consequently, there is a concern about the therapeutic consistency in marketed batches. Furthermore, metabolic interactions with antineoplastic drugs and the genotoxic potential of botanicals need to be properly addressed throughout the various phases of botanical drug development. These issues not only pose a serious problem to the approvability of those botanical products as new drugs but also present as a limitation to their post approval clinical use. PMID- 22540950 TI - A multidisciplinary approach to solving computer related vision problems. AB - PURPOSE: This paper proposes a multidisciplinary approach to solving computer related vision issues by including optometry as a part of the problem-solving team. RECENT FINDINGS: Computer workstation design is increasing in complexity. There are at least ten different professions who contribute to workstation design or who provide advice to improve worker comfort, safety and efficiency. Optometrists have a role identifying and solving computer-related vision issues and in prescribing appropriate optical devices. However, it is possible that advice given by optometrists to improve visual comfort may conflict with other requirements and demands within the workplace. A multidisciplinary approach has been advocated for solving computer related vision issues. There are opportunities for optometrists to collaborate with ergonomists, who coordinate information from physical, cognitive and organisational disciplines to enact holistic solutions to problems. This paper proposes a model of collaboration and examples of successful partnerships at a number of professional levels including individual relationships between optometrists and ergonomists when they have mutual clients/patients, in undergraduate and postgraduate education and in research. There is also scope for dialogue between optometry and ergonomics professional associations. SUMMARY: A multidisciplinary approach offers the opportunity to solve vision related computer issues in a cohesive, rather than fragmented way. Further exploration is required to understand the barriers to these professional relationships. PMID- 22540952 TI - Retraction. Placental alpha-microglobulin-1 rapid immunoassay for detection of premature rupture of membranes. PMID- 22540951 TI - Predicting the outer membrane proteome of Pasteurella multocida based on consensus prediction enhanced by results integration and manual confirmation. AB - BACKGROUND: Outer membrane proteins (OMPs) of Pasteurella multocida have various functions related to virulence and pathogenesis and represent important targets for vaccine development. Various bioinformatic algorithms can predict outer membrane localization and discriminate OMPs by structure or function. The designation of a confident prediction framework by integrating different predictors followed by consensus prediction, results integration and manual confirmation will improve the prediction of the outer membrane proteome. RESULTS: In the present study, we used 10 different predictors classified into three groups (subcellular localization, transmembrane beta-barrel protein and lipoprotein predictors) to identify putative OMPs from two available P. multocida genomes: those of avian strain Pm70 and porcine non-toxigenic strain 3480. Predicted proteins in each group were filtered by optimized criteria for consensus prediction: at least two positive predictions for the subcellular localization predictors, three for the transmembrane beta-barrel protein predictors and one for the lipoprotein predictors. The consensus predicted proteins were integrated from each group into a single list of proteins. We further incorporated a manual confirmation step including a public database search against PubMed and sequence analyses, e.g. sequence and structural homology, conserved motifs/domains, functional prediction, and protein-protein interactions to enhance the confidence of prediction. As a result, we were able to confidently predict 98 putative OMPs from the avian strain genome and 107 OMPs from the porcine strain genome with 83% overlap between the two genomes. CONCLUSIONS: The bioinformatic framework developed in this study has increased the number of putative OMPs identified in P. multocida and allowed these OMPs to be identified with a higher degree of confidence. Our approach can be applied to investigate the outer membrane proteomes of other Gram-negative bacteria. PMID- 22540953 TI - Metallocene-based inhibitors of cancer-associated carbonic anhydrase enzymes IX and XII. AB - In this study, 20 metallocene-based compounds comprising extensive structural diversity were synthesized and evaluated as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. These compounds proved moderate to good CA inhibitors in vitro, with several compounds displaying selectivity for cancer-associated isozymes CA IX and CA XII compared to off-target CA I and CA II. Compound 6 was the most potent ferrocene-based inhibitor with K(i)s of 5.9 and 6.8 nM at CA IX and XII, respectively. A selection of key drug-like parameters comprising Log P, Log D, solubility, and in vitro metabolic stability and permeability were measured for two of the ferrocene-based compounds, regioisomers 1 and 5. Compounds 1 and 5 were found to have characteristics consistent with lipophilic compounds, however, our findings show that the lipophilicity of the ferrocene moiety is not well modeled by replacement with either a naphthyl or a phenyl moiety in software prediction tools. PMID- 22540954 TI - Pharmacokinetics and pharmacodynamics of intravenous artesunate during severe malaria treatment in Ugandan adults. AB - BACKGROUND: Severe malaria is a medical emergency with high mortality. Prompt achievement of therapeutic concentrations of highly effective anti-malarial drugs reduces the risk of death. The aim of this study was to assess the pharmacokinetics and pharmacodynamics of intravenous artesunate in Ugandan adults with severe malaria. METHODS: Fourteen adults with severe falciparum malaria requiring parenteral therapy were treated with 2.4 mg/kg intravenous artesunate. Blood samples were collected after the initial dose and plasma concentrations of artesunate and dihydroartemisinin measured by solid-phase extraction and liquid chromatography-tandem mass spectrometry. The study was approved by the Makerere University Faculty of Medicine Research and Ethics Committee (Ref2010-015) and Uganda National Council of Science and Technology (HS605) and registered with ClinicalTrials.gov (NCT01122134). RESULTS: All study participants achieved prompt resolution of symptoms and complete parasite clearance with median (range) parasite clearance time of 17 (8-24) hours. Median (range) maximal artesunate concentration (Cmax) was 3260 (1020-164000) ng/mL, terminal elimination half-life (T1/2) was 0.25 (0.1-1.8) hours and total artesunate exposure (AUC) was 727 (290 111256) ng.h/mL. Median (range) dihydroartemisinin Cmax was 3140 (1670-9530) ng/mL, with Tmax of 0.14 (0.6 - 6.07) hours and T1/2 of 1.31 (0.8-2.8) hours. Dihydroartemisinin AUC was 3492 (2183-6338) ng.h/mL. None of the participants reported adverse events. CONCLUSIONS: Plasma concentrations of artesunate and dihydroartemisinin were achieved rapidly with rapid and complete symptom resolution and parasite clearance with no adverse events. PMID- 22540955 TI - The impact of routine open nonsuction drainage on fluid accumulation after thyroid surgery: a prospective randomised clinical trial. AB - BACKGROUND: Thyroid drains following thyroid surgery are routinely used despite minimal supportive evidence. Our aim in this study is to determine the impact of routine open drainage of the thyroid bed postoperatively on ultrasound-determined fluid accumulation at 24 hours. METHODS: We conducted a prospective randomised clinical trial on patients undergoing thyroid surgery. Patients were randomly assigned to a drain group (n = 49) or a no-drain group (n = 44) immediately prior to wound closure. Patients underwent a neck ultrasound on day 1 and day 2 postoperatively. After surgery, we evaluated visual analogue scale pain scores, postoperative analgesic requirements, self-reported scar satisfaction at 6 weeks and complications. RESULTS: There was significantly less mean fluid accumulated in the drain group on both day 1, 16.4 versus 25.1 ml (P-value = 0.005), and day 2, 18.4 versus 25.7 ml (P-value = 0.026), following surgery. We found no significant differences between the groups with regard to length of stay, scar satisfaction, visual analogue scale pain score and analgesic requirements. There were four versus one wound infections in the drain versus no-drain groups. This finding was not statistically significant (P = 0.154). No life-threatening bleeds occurred in either group. CONCLUSIONS: Fluid accumulation after thyroid surgery was significantly lessened by drainage. However, this study did not show any clinical benefit associated with this finding in the nonemergent setting. Drains themselves showed a trend indicating that they may augment infection rates. The results of this study suggest that the frequency of acute life-threatening bleeds remains extremely low following abandoning drains. We advocate abandoning routine use of thyroid drains. TRIAL REGISTRATION: ISRCTN94715414. PMID- 22540956 TI - Examining the 'gold standard': a comparative critical analysis of three consecutive decades of monopolar transurethral resection of the prostate (TURP) outcomes. AB - What's known on the subject? and What does the study add? Transurethral resection of the prostate (TURP) remains the dominant and definitive treatment for lower urinary tract symptoms due to benign prostatic hyperplasia (LUTS-BPH), but the widespread use of medical therapies (particularly monotherapies) for rapid symptom improvement has meant that the most common indication for TURP has shifted to moderate-severe medical therapy refractory LUTS to, coupled with abnormal objective parameters, or when complications arise. Patients undergoing TURP as part of contemporary randomised controlled trials are not older but have a larger preoperative prostate volume and reduced major morbidity compared with large cohort studies from successive past eras. Delayed surgery because of prolonged medical monotherapy may explain a higher reported failure to void rate, possibly because of negative impact on detrusor function from unrelieved obstruction. This study examined contemporary TURP for significant changes, specifically regarding prostate size, operative parameters, and outcomes, compared with two preceding decades. Electronic databases PubMed, EMBASE & Cochrane collaboration were searched for English literature on prospective randomized controlled trials, published between 1997 and 2007 using keywords "transurethral resection" and "prostate". Monopolar TURP (M-TURP) cohort data of each study were selectively pooled for analysis, weighting studies according to patient numbers. Where possible, pooled post-operative outcomes data were compared with two large cohort landmark studies of successive preceding decades. A total of 3470 patients from 67 studies were included. Mean patient age (67 years) was unchanged, while mean pre-operative prostate volume of 47.6 g was greater than previously reported. Mean resected prostate tissue (25.8 g) with a resection time of 38.5 minutes suggested improved resection efficiency. A statistically significantly reduced transfusion rate and increased urinary tract infection (UTI) rate were reported. Hospital stay (3.6 days) and initial catheterisation duration (2.5 days) were similar, but post-operative urinary retention rate was slightly higher (6.8%). Contemporary RCTs of M-TURP showed larger prostate volume, and reduced major morbidity, compared with large cohort studies from successive past eras. The higher reported failure to void rate, may possibly reflect worse detrusor function at time of TURP. Delaying surgery by prolonged medical monotherapy may compound this. Trials methodology in this area requires quality improvement and standardisation in future. PMID- 22540957 TI - Effects of prolonged and maintenance strength training on force production, walking, and balance in aging women and men. AB - To examine effects of 21-week twice/week strength training (ST) period followed by an additional 21-week twice or once/week ST period on force production, walking and balance in aging people. Seventy-two women (58 +/- 7 years; W) and 63 (58 +/- 6 years) men (M) were randomized for the first 21-week ST period: STW and STM, control (C) CW and CM. Training participants were randomized for the second 21-week ST period: once/week STWx1 and STMx1, twice/week STWx2 and STMx2. LegPress, isometric leg extension rate of force development (RFD), walking time, and balance. First 21-week ST period: leg press, RFD, balance, and walking improved significantly in STW and STM. Second 21-week ST period: leg press first increased in STMx1 and STMx2, and then decreased to the level of 21 weeks in STMx2 and remained unchanged in STWx2 and decreased in STWx1 and STMx1. Walking and balance improved significantly in STWx1 and STWx2. A progressive 21-week ST period twice/week in aging people can lead to large improvements in maximal strength, walking time, and balance in both genders. A further strength training period with the same amount of training may maintain the strength gains, whereas balance and walking may be maintained with less training. PMID- 22540958 TI - Spectroscopic signature of the superparamagnetic transition and surface spin disorder in CoFe2O4 nanoparticles. AB - Phonons are exquisitely sensitive to finite length scale effects in a wide variety of materials. To investigate confinement in combination with strong magnetoelastic interactions, we measured the infrared vibrational properties of CoFe(2)O(4) nanoparticles and compared our results to trends in the coercivity over the same size range and to the response of the bulk material. Remarkably, the spectroscopic response is sensitive to the size-induced crossover to the superparamagnetic state, which occurs between 7 and 10 nm. A spin-phonon coupling analysis supports the core-shell model. Moreover, it provides an estimate of the magnetically disordered shell thickness, which increases from 0.4 nm in the 14 nm particles to 0.8 nm in the 5 nm particles, demonstrating that the associated local lattice distortions take place on the length scale of the unit cell. These findings are important for understanding finite length scale effects in this and other magnetic oxides where magnetoelastic interactions are important. PMID- 22540959 TI - Changes in the neuronal glutamate transporter EAAT3 in rat brain after exposure to methamphetamine. AB - Methamphetamine (METH), an addictive psychostimulant, can induce glutamate release in several brain areas such as cerebral cortex, hippocampus and striatum. Excess glutamate is ordinarily removed from the synaptic cleft by glutamate transporters for maintaining homoeostasis. EAAT3, a subtype of glutamate transporter expressed mainly by neurons, is a major glutamate transporter in the hippocampus and cortex. Therefore, this study examined the effects of acute and sub-acute METH administration on the expression of the EAAT3 in the hippocampal formation, striatum and frontal cortex. Male Sprague-Dawley rats received vehicle injections (i.p.) for 13 days followed by one injection of METH (8 mg/kg, i.p.) on day 14 in acute group. Animals received METH (4 mg/kg, i.p.) or vehicle for 14 days in sub-acute and control groups, respectively. EAAT3 immunoreactivity was determined by western blotting followed by measurement of the integrated optical density. A significant increase in EAAT3 was found in the hippocampal formation after sub-acute, but not acute, METH administration. Conversely, a significant decrease in EAAT3 in striatum was observed in both acute and sub-acute groups. A trend towards a decrease in EAAT3 was also found in frontal cortex in the sub acute group. Our results of decreased EAAT3 in striatum and frontal cortex suggest deficits of cortico-striatal glutamatergic synapses after METH exposure. Increased EAAT3 expression in the hippocampus may be a compensatory response to possible deficits of glutamatergic neurotransmission induced by METH. Moreover, our findings provide further support for glutamatergic dysfunction with abnormalities involving a transporter important in the regulation of neuronal glutamate. PMID- 22540960 TI - Engineering flax plants to increase their antioxidant capacity and improve oil composition and stability. AB - The composition of polyunsaturated fatty acids in the tissues is very important to human health and strongly depends on dietary intake. Since flax seeds are the richest source of polyunsaturated acids, their consumption might be beneficial for human health. Unfortunately, they are highly susceptible to auto-oxidation, which generates toxic derivatives. The main goal of this study was the generation of genetically modified flax plants with increased antioxidant potential and stable and healthy oil production. Since among phenylpropanoid compounds those belonging to the flavonoid route have the lowest antioxidant capacity, the approach was to inhibit this route of the pathway, which might result in accumulation of other compounds more effective in antioxidation. The suppression of the chalcone synthase gene resulted in hydrolyzable tannin accumulation and thus increased antioxidant status of seeds of the transgenic plant. This was due to the partial redirecting of substrates for flavonoid biosynthesis to the other routes of the phenylpropanoid pathway. Consequently, transgenic plants produced more (20-45%) polyunsaturated fatty acids than the control and mainly alpha linolenic acid. Thus, increasing the antioxidant potential of flax plants has benefits in terms of the yield of suitable oil for human dietary consumption. PMID- 22540961 TI - Ultrasound-guided foam sclerotherapy for treating incompetent great saphenous veins--results of 5 years of analysis and morphologic evolvement study. AB - BACKGROUND: Varicose veins of the lower leg is a common disease and is associated with long-term morbidity. It has been treated using high ligation with stripping and endovenous laser surgery of the great saphenous vein (GSV). OBJECTIVES: To investigate the clinical outcomes of GSV insufficiency after ultrasound-guided foam sclerotherapy (UGFS) using 3% sodium tetradecyl sulfate (STS). METHODS: Between 2005 and 2009, patients with symptomatic varicose veins secondary to GSV insufficiency were enrolled; 3% STS foam was injected into the GSV under ultrasound visualization. Ultrasound examinations and clinical follow-up were performed at 3- to 6-month intervals. Follow-up visits continued through April 2011. RESULTS: Two hundred 88 limbs of 233 patients were enrolled. The mean follow-up interval was 37.8 months. Occlusion was achieved for 89.6% of the incompetent veins in two sessions of UGFS. The mean number of therapy sessions per leg was 1.53. The internal diameters of the treated veins reduced to 66.9% 3 months and 32.7% at 12 months. CONCLUSIONS: UGFS is effective in sealing incompetent GSV segments. It is a minimally invasive procedure and can be redone several times in cases of recurrence. UGFS is simpler and less painful than stripping surgery and endovenous laser treatment. PMID- 22540962 TI - Patient factors and glycaemic control--associations and explanatory power. AB - AIMS: To investigate the association between glycaemic control and patient socio demographics, activation level, diabetes-related distress, assessment of care, knowledge of target HbA(1c), and self-management behaviours, and to determine to what extent these factors explain the variance in HbA(1c) in a large Danish population of patients with Type 2 diabetes. METHODS: Cross-sectional survey and record review of 2045 patients from a specialist diabetes clinic. Validated scales measured patient activation, self-management behaviours, diabetes-related emotional distress, and perceived care. The electronic patient record provided information about HbA(1c), medication, body mass index, and duration of diabetes. Data were analysed using multiple linear regression models with stepwise addition of covariates. RESULTS: The response rate was 54% (n = 1081). Good glycaemic control was significantly associated with older age, higher education, higher patient activation, lower diabetes-related emotional distress, better diet and exercise behaviours, lower body mass index, shorter duration of disease and knowledge of HbA(1c) targets (P < 0.05 for all). Patient socio-demographics, behaviour; perceptions of care and diabetes distress accounted for 14% of the total variance in HbA(1c) levels (P = 0.0134), but the variance explained was higher for respondents treated with medications other than insulin. CONCLUSIONS: Our study emphasizes the complex relationships between patient activation, distress and behaviour, specific treatment modalities and glycaemic control. Knowledge of treatment goals, achieving patient activation in coping with diabetes, and lowering disease-related emotional stress are important patient education goals. However, the large unexplained component of HbA(1c) variance highlights the need for more research to understand the mechanisms of glycaemic control. PMID- 22540963 TI - Evaluation of Biologically Active Compounds from Calendula officinalis Flowers using Spectrophotometry. AB - BACKGROUND: This study aimed to quantify the active biological compounds in C. officinalis flowers. Based on the active principles and biological properties of marigolds flowers reported in the literature, we sought to obtain and characterize the molecular composition of extracts prepared using different solvents. The antioxidant capacities of extracts were assessed by using spectrophotometry to measure both absorbance of the colorimetric free radical scavenger 2,2-diphenyl-1-picrylhydrazyl (DPPH) as well as the total antioxidant potential, using the ferric reducing power (FRAP) assay. RESULTS: Spectrophotometric assays in the ultraviolet-visible (UV-VIS) region enabled identification and characterization of the full range of phenolic and flavonoids acids, and high-performance liquid chromatography (HPLC) was used to identify and quantify phenolic compounds (depending on the method of extraction). Methanol ensured more efficient extraction of flavonoids than the other solvents tested.Antioxidant activity in methanolic extracts was correlated with the polyphenol content. CONCLUSIONS: The UV-VIS spectra of assimilator pigments (e.g. chlorophylls), polyphenols and flavonoids extracted from the C. officinalis flowers consisted in quantitative evaluation of compounds which absorb to wavelengths broader than 360 nm. PMID- 22540964 TI - A rare case of primary sellar lymphoma presenting a diagnostic challenge. AB - Primary sellar lymphoma (PSL) is an exceptional diagnosis, among the most unusual causes of a sellar mass. Distinguishing PSL from other sellar lesions is often difficult as clinical and radiological features are typically non-specific. We present a case in which unusual presentation and previous medical history made diagnosis particularly challenging. PMID- 22540965 TI - Dynamic origin of the stereoselectivity of a nucleophilic substitution reaction. AB - A nucleophilic substitution on a dichlorovinyl ketone was studied experimentally and computationally. A mixture of products is observed experimentally, but a conventional computational analysis does not account for the formation of the minor stereoisomer. Instead, the product mixture is predicted accurately from a dynamic trajectory study on a bifurcating energy surface. The dynamic origin of the stereoselectivity of the reaction is discussed. PMID- 22540966 TI - Quantitative separation of monomeric U(IV) from UO2 in products of U(VI) reduction. AB - The reduction of soluble hexavalent uranium to tetravalent uranium can be catalyzed by bacteria and minerals. The end-product of this reduction is often the mineral uraninite, which was long assumed to be the only product of U(VI) reduction. However, recent studies report the formation of other species including an adsorbed U(IV) species, operationally referred to as monomeric U(IV). The discovery of monomeric U(IV) is important because the species is likely to be more labile and more susceptible to reoxidation than uraninite. Because there is a need to distinguish between these two U(IV) species, we propose here a wet chemical method of differentiating monomeric U(IV) from uraninite in environmental samples. To calibrate the method, U(IV) was extracted from known mixtures of uraninite and monomeric U(IV) and tested using X-ray absorption spectroscopy (XAS). Monomeric U(IV) was efficiently removed from biomass and Fe(II)-bearing phases by bicarbonate extraction, without affecting uraninite stability. After confirming that the method effectively separates monomeric U(IV) and uraninite, it is further evaluated for a system containing those reduced U species and adsorbed U(VI). The method provides a rapid complement, and in some cases alternative, to XAS analyses for quantifying monomeric U(IV), uraninite, and adsorbed U(VI) species in environmental samples. PMID- 22540967 TI - Liposomal clodronate treatment for tumour macrophage depletion in dogs with soft tissue sarcoma. AB - Increased numbers of tumour-associated macrophages correlate with rapid tumour growth and metastasis in tumours. Thus, macrophage depletion has potential as a novel cancer therapy and positive responses have been reported in rodent tumour models. To investigate the effectiveness of this approach in dogs with cancer, we evaluated the effects of the macrophage-depleting agent liposomal clodronate (LC) in dogs with soft-tissue sarcoma (STS). To this end, we conducted a clinical trial of LC therapy in 13 dogs with STS. Repeated LC administration was well tolerated clinically. Preliminary examination of tumour biopsy sets from 5 of the 13 dogs demonstrated that the density of CD11b(+) macrophages was significantly decreased after LC treatment. Circulating concentrations of interleukin-8 were also significantly reduced. These preliminary studies are the first to suggest that LC can be used as a systemic macrophage-depleting agent in dogs to reduce numbers of tumour-associated macrophages. PMID- 22540969 TI - Effects of acupuncture on the outcomes of in vitro fertilization: a systematic review and meta-analysis. AB - OBJECTIVES: The objective of this article was to conduct a systematic review with meta-analysis of the trials of acupuncture during in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment on the outcomes of clinical pregnancy, biochemical pregnancy, ongoing pregnancy, implantation rate, live birth, and miscarriage. SEARCH STRATEGY: The search was conducted by using MEDLINE((r)), SCISEARCH, the Cochrane Menstrual Disorders and Subfertility Group trials register, AMED, Cumulative Index to Nursing and Allied Health Literature, EMBASE, Wanfang Database, China Academic Journal Electronic full text Database in China National Knowledge Infrastructure, Index to Chinese Periodical Literature, ISI Proceedings for conference abstracts, and ISRCTN Register and Meta-register for randomized controlled trials. DATA COLLECTION AND ANALYSIS: Study selection, quality appraisal, and data extraction were performed independently and in duplicate. The measures of treatment effect were the pooled relative risks (RR) of achieving clinical pregnancy, biochemical pregnancy, ongoing pregnancy, implantation rate, live birth, or miscarriage for women in the acupuncture group compared with women in the control group. RESULTS: Using the random-effects model, pooling of the effect estimates from all of the 17 trials showed no significant difference in the clinical pregnancy outcome between the acupuncture and the control groups (RR=1.09, 95% confidence interval (CI) 0.94-1.26, p=0.25). No significant differences in the biochemical pregnancy, ongoing pregnancy, implantation rate, live birth, or miscarriage outcomes were found between the acupuncture and the control groups (biochemical pregnancy: RR=1.01, 95% CI 0.84 1.20, p=0.95; ongoing pregnancy: RR=1.20, 95% CI 0.93-1.56, p=0.16; implantation rate: RR=1.22, 95% CI 0.93-1.62, p=0.16; live birth: RR=1.42, 95% CI 0.92-2.20, p=0.11; miscarriage outcomes: RR=0.94, 95% CI 0.67-1.33, p=0.74). CONCLUSIONS: No significant benefits of acupuncture are found to improve the outcomes of IVF or ICSI. PMID- 22540968 TI - Investigating cell surface galectin-mediated cross-linking on glycoengineered cells. AB - The galectin family of glycan-binding proteins is thought to mediate many cellular processes by oligomerizing cell surface glycoproteins and glycolipids into higher-order aggregates. This hypothesis reflects the known oligomeric states of the galectins themselves and their binding properties with multivalent ligands in vitro, but direct evidence of their ability to cross-link ligands on a cell surface is lacking. A major challenge in fundamental studies of galectin ligand interactions is that their natural ligands comprise a heterogeneous collection of glycoconjugates that share related glycan structures but disparate underlying scaffolds. Consequently, there is no obvious means to selectively monitor the behaviors of natural galectin ligands on live cell surfaces. Here we describe an approach for probing the galectin-induced multimerization of glycoconjugates on cultured cells. Using RAFT polymerization, we synthesized well defined glycopolymers (GPs) functionalized with galectin-binding glycans along the backbone, a lipid group on one end and a fluorophore on the other. After insertion into live cell membranes, the GPs' fluorescence lifetime and diffusion time were measured in the presence and absence of galectin-1. We observed direct evidence for galectin-1-mediated extended cross-linking on the engineered cells, a phenomenon that was dependent on glycan structure. This platform offers a new approach to exploring the "galectin lattice" hypothesis and to defining galectin ligand specificity in a physiologically relevant context. PMID- 22540971 TI - Zingiber officinale (ginger) as an anti-emetic in cancer chemotherapy: a review. AB - Despite significant advances and development of novel anti-emetics, nausea and vomiting (emesis) is a major side-effect of cancer chemotherapy. At times, severe nausea and vomiting may also lead to reduction in adherence to the treatment regimen, and this will concomitantly affect the patient's survival. The rhizome of Zingiber officinale, commonly known as ginger, is globally an important spice. It has been used for centuries in the Indian, Chinese, Arabic, Tibetan, Unani, and Siddha systems of traditional medicine to treat nausea and vomiting induced by different stimuli. Preclinical studies with experimental animals (dogs and rats) have shown that the various extracts of ginger and the ginger juice possess anti-emetic effects against chemotherapy-induced nausea and vomiting. Gingerol, the active principle, is also shown to possess anti-emetic effects in minks. However, with regard to humans, while most studies have been supportive of the preclinical observations, a few have been contradictory. The exact mechanism responsible for the anti-emetic effects of ginger is unknown; however, the ginger phytochemicals, especially 6-gingerol, 8-gingerol, 10-gingerol, and 6-shogaol, may function as a 5-hydroxytryptamine (5-HT3) antagonist, NK1 antagonist, antihistaminic, and possess prokinetic effects. The present review for the first time attempts to address the anti-emetic observations and the variability in response of the anti-emetic effects of ginger in cancer chemotherapy. An attempt is also made to address the lacunae in the published studies and emphasize aspects that need further investigations for ginger to be of use in clinics as an anti-emetic agent in the future. PMID- 22540970 TI - Effects of physical therapy on pain and mood in patients with terminal cancer: a pilot randomized clinical trial. AB - OBJECTIVES: The objective of this study was to determine the effects of physical therapy, including massage and exercise, on pain and mood in patients with advanced terminal cancer. DESIGN: The design was a randomized controlled pilot study. SUBJECTS: Twenty-four (24) patients with terminal cancer were randomly assigned to one of two treatment groups. INTERVENTIONS: Group A received a physiotherapy intervention consisting of several massage techniques, mobilizations, and local and global exercises. Group B received a simple hand contact/touch to areas of pain (cervical area, shoulder, interscapular area, heels, and gastrocnemius), which was maintained for the same period of time as the intervention group. All patients received six sessions of 30-35 minutes in duration over a 2-week period. OUTCOMES: Outcomes were collected at baseline, at 1 week, and at a 2-week follow-up (after treatment completion) by an assessor blinded to the treatment allocation of the participants. Outcomes included the Brief Pain Inventory (BPI, 0-10 scale), Memorial Pain Assessment Card (0-10 scale), and Memorial Symptom Assessment Scale (MSAS Physical, Psychological, 0-4 scale). Baseline between-group differences were assessed with an independent t test. A two-way repeated-measures analysis of variance was used to examine the effects of the intervention. RESULTS: There were no significant between-group baseline differences (p>0.2). A significant group * time interaction with greater improvements in group A was found for BPI worst pain (F=3.5, p=0.036), BPI pain right now (F=3.94, p=0.027), and BPI index (F=13.2, p<0.001), for MSAS Psychological (F=8.480, p=0.001). CONCLUSIONS: The combination of massage and exercises can reduce pain and improve mood in patients with terminal cancer. A sustained effect on pain and psychologic distress existed; however, parameters such as physical distress and the least pain were no greater in the intervention group as compared to the sham. PMID- 22540972 TI - A comparison of the organization of longitudinal and circular contractions during pendular and segmental activity in the duodenum of the rat and guinea pig. AB - BACKGROUND: Little is known of the spatiotemporal organization of pendular duodenal contractions. METHODS: We used longitudinal and radial spatiotemporal mapping to examine and compare pendular and segmental contractile activity in the proximal duodenum of the rat and guinea pig when the lumen was perfused with saline or micellar decanoic acid. KEY RESULTS: Isolated phasic longitudinal contractions occurred along the rat duodenum with a frequency of 36 +/- 2 cpm and strain rate amplitude of 26.8 +/- 8.0% s(-1). These contractions occurred at fixed locations along the duodenum forming columns on the longitudinal strain rate map. The strain rate activity had local maxima at 4-6 points spaced at 7.7 +/- 4.0 mm intervals along the duodenum and were uncoordinated between neighboring domains. Similarly disposed, less distinct, longitudinal contractions occurred in the guinea pig duodenum at a frequency of 25.2 +/- 6.6 cpm with amplitude 6.8 +/- 3.6% s(-1) but these were generally accompanied by numerous circular contractions that were distributed over 4-5 fixed locations and occurred with a frequency of 9 +/- 3 cpm. Isolated static circular muscle contractions also occurred but at a lower rate in the rat than the guinea pig. Both types of contractions propagated after dosage with tetrodotoxin, lidocaine, atropine, or apamin. CONCLUSIONS & INFERENCES: Localized contractions during segmental and pendular activity had some features of the spike patches that are normally associated with slow wave propagation. However, the commencement of propagation following administration of neural blocking agents and cholinergic inhibitors indicates their localization is maintained by inhibitory elements of the enteric nervous system. PMID- 22540973 TI - Differential Plasmodium falciparum infection of Anopheles gambiae s.s. molecular and chromosomal forms in Mali. AB - BACKGROUND: Anopheles gambiae sensu stricto (s.s.) is a primary vector of Plasmodium falciparum in sub-Saharan Africa. Although some physiological differences among molecular and chromosomal forms of this species have been demonstrated, the relative susceptibility to malaria parasite infection among them has not been unequivocally shown. The objective of this study was to investigate P. falciparum circumsporozoite protein infection (CSP) positivity among An. gambiae s.s. chromosomal and molecular forms. METHODS: Wild An. gambiae from two sites Kela (n=464) and Sidarebougou (n=266) in Mali were screened for the presence of P. falciparum CSP using an enzyme-linked immunosorbent assay (ELISA). Samples were then identified to molecular form using multiple PCR diagnostics (n=713) and chromosomal form using chromosomal karyotyping (n=419). RESULTS: Of 730 An. gambiae sensu lato (s.l.) mosquitoes, 89 (12.2%) were CSP ELISA positive. The percentage of positive mosquitoes varied by site: 52 (11.2%) in Kela and 37 (13.9%) in Sidarebougou. Eighty-seven of the positive mosquitoes were identified to molecular form and they consisted of nine Anopheles arabiensis (21.4%), 46 S (10.9%), 31 M (12.8%), and one MS hybrid (14.3%). Sixty of the positive mosquitoes were identified to chromosomal form and they consisted of five An. arabiensis (20.0%), 21 Savanna (15.1%), 21 Mopti (30.4%), 11 Bamako (9.2%), and two hybrids (20.0%). DISCUSSION: In this collection, the prevalence of P. falciparum infection in the M form was equivalent to infection in the S form (no molecular form differential infection). There was a significant differential infection by chromosomal form such that, P. falciparum infection was more prevalent in the Mopti chromosomal forms than in the Bamako or Savanna forms; the Mopti form was also the most underrepresented in the collection. Continued research on the differential P. falciparum infection of An. gambiae s.s. chromosomal and molecular forms may suggest that Plasmodium - An. gambiae interactions play a role in malaria transmission. PMID- 22540974 TI - A new class of highly potent matrix metalloproteinase inhibitors based on triazole-substituted hydroxamates: (radio)synthesis and in vitro and first in vivo evaluation. AB - In vivo imaging of MMPs is of great (pre)clinical interest and can potentially be realized with modern three-dimensional and noninvasive in vivo molecular imaging techniques such as positron emission tomography (PET). Consequently, MMP inhibitors (MMPIs) radiolabeled with positron emitting nuclides (e.g., (18)F) represent a suitable tool for the visualization of activated MMPs with PET. On the basis of our previous work and results regarding radiolabeled and unlabeled derivatives of the nonselective MMPIs, we discovered a new class of fluorinated MMPIs with a triazole-substituted hydroxamate substructure. These novel MMPIs are characterized by an increased hydrophilicity compared with the lead structures and excellent MMP inhibition potencies for MMP-2, MMP-8, MMP-9, and MMP-13 (IC(50) = 0.006-107 nM). Therefore, one promising fluorinated triazole substituted hydroxamate (30b) was selected and resynthesised as its (18)F-labeled version to yield the potential PET radioligand [(18)F]30b. The biodistribution behavior of this novel compound was investigated with small animal PET. PMID- 22540975 TI - Xanthogranuloma of the intrasellar region presenting in pituitary dysfunction: a case report. AB - INTRODUCTION: Differentiation of cystic mass lesions of the sellar and parasellar regions may pose a diagnostic dilemma for physicians, neurosurgeons, radiologists and pathologists involved in treating patients with these entities. A considerable number of tumors previously identified as craniopharyngiomas may, in fact, have been xanthogranulomas. We report a case of pituitary dysfunction caused by xanthogranuloma of the intrasellar region. CASE PRESENTATION: A 47-year old man of Japanese descent presented to our institution with a tumor located exclusively in the intrasellar region which manifested as severe hypopituitarism. MRI revealed a clearly defined intrasellar mass that was heterogeneously hyperintense on T1-weighted images and markedly hypointense on T2-weighted images. We preoperatively diagnosed the patient with Rathke's cleft cyst or non functioning pituitary adenoma. Although the tumor was completely removed using a transsphenoidal approach, the improvement of the patient's endocrine function was marginal, and continued endocrine replacement therapy was needed. Postoperatively, a histological examination revealed the tumor to be a xanthogranuloma of the intrasellar region. His visual field defects and headache improved. CONCLUSION: Because diagnosis depends on surgical intervention and xanthogranulomas of the intrasellar region are very rare, the natural history of xanthogranuloma is still unknown. Therefore, this entity is difficult to diagnose preoperatively. We suggest that xanthogranuloma should be included in the differential diagnosis, even in the case of sellar lesions, to formulate appropriate postoperative management and improve endocrine outcomes. PMID- 22540976 TI - Influence of malt roasting on the oxidative stability of sweet wort. AB - Influence of malt roasting on the oxidative stability of sweet wort was evaluated based on radical intensity, volatile profile, content of transition metals (Fe and Cu) and thiols. Malt roasting had a large influence on the oxidative stability of sweet wort. Light sweet worts were more stable with low radical intensity, low Fe content, and ability to retain volatile compounds when heated. At mild roasting, the Fe content in the wort increased but remained close to constant with further roasting. Dark sweet worts were less stable with high radical intensities, high Fe content, and a decreased ability to retain volatiles. Results suggested that the Maillard reaction compounds formed during the roasting of malt are prooxidants in sweet wort. A thiol-removing capacity was observed in sweet wort, and it was gradually inhibited by malt roasting. It is possibly caused by thiol oxidizing enzymes present in the fresh malt. PMID- 22540977 TI - Comprehensive comparison of graph based multiple protein sequence alignment strategies. AB - BACKGROUND: Alignment of protein sequences (MPSA) is the starting point for a multitude of applications in molecular biology. Here, we present a novel MPSA program based on the SeqAn sequence alignment library. Our implementation has a strict modular structure, which allows to swap different components of the alignment process and, thus, to investigate their contribution to the alignment quality and computation time. We systematically varied information sources, guiding trees, score transformations and iterative refinement options, and evaluated the resulting alignments on BAliBASE and SABmark. RESULTS: Our results indicate the optimal alignment strategy based on the choices compared. First, we show that pairwise global and local alignments contain sufficient information to construct a high quality multiple alignment. Second, single linkage clustering is almost invariably the best algorithm to build a guiding tree for progressive alignment. Third, triplet library extension, with introduction of new edges, is the most efficient consistency transformation of those compared. Alternatively, one can apply tree dependent partitioning as a post processing step, which was shown to be comparable with the best consistency transformation in both time and accuracy. Finally, propagating information beyond four transitive links introduces more noise than signal. CONCLUSIONS: This is the first time multiple protein alignment strategies are comprehensively and clearly compared using a single implementation platform. In particular, we showed which of the existing consistency transformations and iterative refinement techniques are the most valid. Our implementation is freely available at http://ekhidna.biocenter.helsinki.fi/MMSA and as a supplementary file attached to this article (see Additional file 1). PMID- 22540979 TI - Functional consequences of mutations in postsynaptic scaffolding proteins and relevance to psychiatric disorders. AB - Functional studies on postsynaptic scaffolding proteins at excitatory synapses have revealed a plethora of important roles for synaptic structure and function. In addition, a convergence of recent in vivo functional evidence together with human genetics data strongly suggest that mutations in a variety of these postsynaptic scaffolding proteins may contribute to the etiology of diverse human psychiatric disorders such as schizophrenia, autism spectrum disorders, and obsessive-compulsive spectrum disorders. Here we review the most recent evidence for several key postsynaptic scaffolding protein families and explore how mouse genetics and human genetics have intersected to advance our knowledge concerning the contributions of these important players to complex brain function and dysfunction. PMID- 22540980 TI - Identification and management of poor response to growth-promoting therapy in children with short stature. AB - Growth hormone (GH) is widely prescribed for children with short stature across a range of growth disorders. Recombinant human (rh) insulin-like growth factor-1 (rhIGF-1) therapy is approved for severe primary IGF-I deficiency - a state of severe GH resistance. Evidence is increasing for an unacceptably high rate of poor or unsatisfactory response to growth-promoting therapy (i.e. not leading to significant catch up growth) in terms of change in height standard deviation score (SDS) and height velocity (HV) in many approved indications. Consequently, there is a need to define poor response and to prevent or correct it by optimizing treatment regimens within accepted guidelines. Recognition of a poor response is an indication for action by the treating physician, either to modify the therapy or to review the primary diagnosis leading either to discontinuation or change of therapy. This review discusses the optimal investigation of the child who is a candidate for GH or IGF-1 therapy so that a diagnosis-based choice of therapy and dosage can be made. The relevant parameters in the evaluation of growth response are described together with the definitions of poor response. Prevention of poor response is addressed by discussion of strategy for first-year management with GH and IGF-1. Adherence to therapy is reviewed as is the recommended action following the identification of the poorly responding patient. The awareness, recognition and management of poor response to growth-promoting therapy will lead to better patient care, greater cost-effectiveness and increased opportunities for clinical benefit. PMID- 22540978 TI - Cellular pathways of hereditary spastic paraplegia. AB - Human voluntary movement is controlled by the pyramidal motor system, a long CNS pathway comprising corticospinal and lower motor neurons. Hereditary spastic paraplegias (HSPs) are a large, genetically diverse group of inherited neurologic disorders characterized by a length-dependent distal axonopathy of the corticospinal tracts, resulting in lower limb spasticity and weakness. A range of studies are converging on alterations in the shaping of organelles, particularly the endoplasmic reticulum, as well as intracellular membrane trafficking and distribution as primary defects underlying the HSPs, with clear relevance for other long axonopathies affecting peripheral nerves and lower motor neurons. PMID- 22540981 TI - Bland thrombus association with tumour thrombus in renal cell carcinoma: analysis of surgical significance and role of inferior vena caval interruption. AB - What's known on the subject? and What does the study add? The surgical implications of renal cell carcinoma with coexisting bland and tumour thrombi of the inferior vena cava is not well described. In this study we review our experience managing these tumours. On multivariate analysis, we found that the presence of bland thrombus was associated with an increased need for surgical interruption of the inferior vena cava. OBJECTIVE: * To study the role of interruption of the inferior vena cava (IVC) in patients with renal cell carcinoma (RCC) and associated bland and tumour thrombi. METHODS: * We reviewed 129 consecutive patients with the preoperative diagnosis of RCC with tumour thrombus who underwent radical nephrectomy and tumour thrombectomy in one academic institution between May 1997 and February 2011. RESULTS: * Percentages of patients with levels I, II, III and IV tumour thrombus were 29%, 13%, 48% and 9%, respectively. * The perioperative mortality rate was 2.3%. There were 29 (22%) perioperative complications recorded. * In all, 19 patients underwent surgical interruption of the IVC by ligation or segmental resection, including one level II, 14 level III and four level IV thrombi. * A total of 15 patients (12%) had bland thrombus associated with the tumour thrombus; four of these underwent intraoperative IVC filter placement and eight underwent surgical IVC interruption. * Advanced level of tumour thrombus was the only significant factor predicting association of bland thrombus (odds ratio [OR]= 2.09, 95% confidence interval [CI]: 1.082-4.037, P= 0.028). * On multivariate analysis, level of thrombus (OR = 3.1, 95% CI: 1.30-7.74, P= 0.011) and association of bland thrombus (OR = 9.07, 95% CI: 2.42-34.01, P= 0.001) were significant factors for IVC interruption. CONCLUSIONS: * Surgical interruption of the IVC is a feasible option in selected patients with chronic IVC obstruction. Association of bland thrombus with tumour thrombus should alert the surgical team to the potential for a challenging surgery. * Precise preoperative imaging to assess the degree of venous obstruction and to help with differentiation between bland and tumour thrombus is key to achieving a surgical outcome with minimal morbidity. PMID- 22540985 TI - Energy and energy policy: chemistry's role. PMID- 22540983 TI - Dedifferentiation of human epidermal melanocytes into melanoblasts in vitro. AB - Melanoblasts (MB) are also called melanocyte (MC) precursor cells. In recent years, people have successfully cultivated human and mouse MB. Previous studies have shown that EDN3 induces cultivated bird MC to re-differentiate into double potential progenitor cells of MB. However, no study has reported whether in vitro cultivated human MC can be dedifferentiated. Our research on MC that were purified and cultivated in vitro found that adding 10 nm endothelin 1 (EDN1) (ET 1) to the MC medium without phorbol 12-myristate 13-acetate (PMA) induced a few MC to dedifferentiate and become a new type of cell. This new cell type was separated, purified, cloned and identified using multiple approaches. The results show that 88.7%, 8.69% and 2.5% of this new cell type were cells in the G(0) G(1) , G(2) -M and S stages, respectively. The new cell type did not exhibit an apparent apoptotic peak, and its apoptotic rate was 0.09%. Stage I melanosomes were observed in the cytoplasm and were negative for the DOPA reaction. The cell surface antigen expression was positive for tyrosinase-related protein 2, negative or positive for c-kit and negative for S-100 and HMB45, showing that these cells were dedifferentiated MB of MC. Our findings provided evidence for atavism of mature human MC under certain conditions. PMID- 22540986 TI - Algae biodiesel - a feasibility report. AB - BACKGROUND: Algae biofuels have been studied numerous times including the Aquatic Species program in 1978 in the U.S., smaller laboratory research projects and private programs. RESULTS: Using Molina Grima 2003 and Department of Energy figures, captial costs and operating costs of the closed systems and open systems were estimated. Cost per gallon of conservative estimates yielded $1,292.05 and $114.94 for closed and open ponds respectively. Contingency scenarios were generated in which cost per gallon of closed system biofuels would reach $17.54 under the generous conditions of 60% yield, 50% reduction in the capital costs and 50% hexane recovery. Price per gallon of open system produced fuel could reach $1.94 under generous assumptions of 30% yield and $0.2/kg CO2. CONCLUSIONS: Current subsidies could allow biodiesel to be produced economically under the generous conditions specified by the model. PMID- 22540987 TI - Frontier battery development for hybrid vehicles. AB - BACKGROUND: Interest in hybrid-electric vehicles (HEVs) has recently spiked, partly due to an increasingly negative view toward the U.S. foreign oil dependency and environmental concerns. Though HEVs are becoming more common, they have a significant price premium over gasoline-powered vehicles. One of the primary drivers of this "hybrid premium" is the cost of the vehicles' batteries. This paper focuses on these batteries used in hybrid vehicles, examines the types of batteries used for transportation applications and addresses some of the technological, environmental and political drivers in battery development and the deployment of HEVs. METHODS: This paper examines the claim, often voiced by HEV proponents, that by taking into account savings on gasoline and vehicle maintenance, hybrid cars are cheaper than traditional gasoline cars. This is done by a quantitative benefit-cost analysis, in addition to qualitative benefit-cost analysis from political, technological and environmental perspectives. RESULTS: The quantitative benefit-cost analysis shows that, taking account of all costs for the life of the vehicle, hybrid cars are in fact more expensive than gasoline powered vehicles; however, after five years, HEVs will break even with gasoline cars. CONCLUSIONS: Our results show that it is likely that after 5 years, using hybrid vehicles should be cheaper in effect and yield a positive net benefit to society. There are a number of externalities that could significantly impact the total social cost of the car. These externalities can be divided into four categories: environmental, industrial, R&D and political. Despite short-term implications and hurdles, increased HEV usage forecasts a generally favorable long-term net benefit to society. Most notably, increasing HEV usage could decrease greenhouse gas emissions, while also decreasing U.S. dependence on foreign oil. PMID- 22540988 TI - Combined heat and power systems: economic and policy barriers to growth. AB - BACKGROUND: Combined Heat and Power (CHP) systems can provide a range of benefits to users with regards to efficiency, reliability, costs and environmental impact. Furthermore, increasing the amount of electricity generated by CHP systems in the United States has been identified as having significant potential for impressive economic and environmental outcomes on a national scale. Given the benefits from increasing the adoption of CHP technologies, there is value in improving our understanding of how desired increases in CHP adoption can be best achieved. These obstacles are currently understood to stem from regulatory as well as economic and technological barriers. In our research, we answer the following questions: Given the current policy and economic environment facing the CHP industry, what changes need to take place in this space in order for CHP systems to be competitive in the energy market? METHODS: We focus our analysis primarily on Combined Heat and Power Systems that use natural gas turbines. Our analysis takes a two-pronged approach. We first conduct a statistical analysis of the impact of state policies on increases in electricity generated from CHP system. Second, we conduct a Cost-Benefit analysis to determine in which circumstances funding incentives are necessary to make CHP technologies cost-competitive. RESULTS: Our policy analysis shows that regulatory improvements do not explain the growth in adoption of CHP technologies but hold the potential to encourage increases in electricity generated from CHP system in small-scale applications. Our Cost-Benefit analysis shows that CHP systems are only cost competitive in large-scale applications and that funding incentives would be necessary to make CHP technology cost-competitive in small-scale applications. CONCLUSION: From the synthesis of these analyses we conclude that because large-scale applications of natural gas turbines are already cost-competitive, policy initiatives aimed at a CHP market dominated primarily by large-scale (and therefore already cost competitive) systems have not been effectively directed. Our recommendation is that for CHP technologies using natural gas turbines, policy focuses should be on increasing CHP growth in small-scale systems. This result can be best achieved through redirection of state and federal incentives, research and development, adoption of smart grid technology, and outreach and education. PMID- 22540989 TI - The role of natural gas as a primary fuel in the near future, including comparisons of acquisition, transmission and waste handling costs of as with competitive alternatives. AB - Natural gas comprises about a quarter of the United States' energy use. It is more environmentally friendly than oil and coal due to lower carbon dioxide (CO2) emissions per unit, less costly per unit of energy and more readily available domestically in abundant supply. However, due to a number of barriers in the political, infrastructural, pricing and other arenas, the use of natural gas as a significant energy source in the United States has been limited. In our paper, we highlight the favorable qualities of natural gas and its benefits for the consumer, producer, and environment, having compared the costs of the various components of the natural gas business such as drilling and transport to that of coal and oil. Moreover, we touch upon the major issues that have prevented a more prevalent use of the gas, such as the fact that the infrastructure of natural gas is more costly since it is transported though pipelines whereas other energy sources such as oil and coal have flexible systems that use trains, trucks and ships. In addition, the powerful lobbies of the coal and oil businesses, along with the inertia in the congress to pass a national climate change bill further dampens incentives for these industries to invest in natural gas, despite its various attractive qualities. We also include discussions of policy proposals to incentive greater use of natural gas in the future. PMID- 22540990 TI - The smart meter and a smarter consumer: quantifying the benefits of smart meter implementation in the United States. AB - The electric grid in the United States has been suffering from underinvestment for years, and now faces pressing challenges from rising demand and deteriorating infrastructure. High congestion levels in transmission lines are greatly reducing the efficiency of electricity generation and distribution. In this paper, we assess the faults of the current electric grid and quantify the costs of maintaining the current system into the future. While the proposed "smart grid" contains many proposals to upgrade the ailing infrastructure of the electric grid, we argue that smart meter installation in each U.S. household will offer a significant reduction in peak demand on the current system. A smart meter is a device which monitors a household's electricity consumption in real-time, and has the ability to display real-time pricing in each household. We conclude that these devices will provide short-term and long-term benefits to utilities and consumers. The smart meter will enable utilities to closely monitor electricity consumption in real-time, while also allowing households to adjust electricity consumption in response to real-time price adjustments. PMID- 22540991 TI - The place of solar power: an economic analysis of concentrated and distributed solar power. AB - BACKGROUND: This paper examines the cost and benefits, both financial and environmental, of two leading forms of solar power generation, grid-tied photovoltaic cells and Dish Stirling Systems, using conventional carbon-based fuel as a benchmark. METHODS: First we define how these solar technologies will be implemented and why. Then we delineate a model city and its characteristics, which will be used to test the two methods of solar-powered electric distribution. Then we set the constraining assumptions for each technology, which serve as parameters for our calculations. Finally, we calculate the present value of the total cost of conventional energy needed to power our model city and use this as a benchmark when analyzing both solar models' benefits and costs. RESULTS: The preeminent form of distributed electricity generation, grid-tied photovoltaic cells under net-metering, allow individual homeowners a degree of electric self-sufficiency while often turning a profit. However, substantial subsidies are required to make the investment sensible. Meanwhile, large dish Stirling engine installations have a significantly higher potential rate of return, but face a number of pragmatic limitations. CONCLUSIONS: This paper concludes that both technologies are a sensible investment for consumers, but given that the dish Stirling consumer receives 6.37 dollars per watt while the home photovoltaic system consumer receives between 0.9 and 1.70 dollars per watt, the former appears to be a superior option. Despite the large investment, this paper deduces that it is far more feasible to get few strong investors to develop a solar farm of this magnitude, than to get 150,000 households to install photovoltaic arrays in their roofs. Potential implications of the solar farm construction include an environmental impact given the size of land require for this endeavour. However, the positive aspects, which include a large CO2 emission reduction aggregated over the lifespan of the farm, outweigh any minor concerns or potential externalities. PMID- 22540992 TI - The interferon type I signature towards prediction of non-response to rituximab in rheumatoid arthritis patients. AB - INTRODUCTION: B cell depletion therapy is efficacious in rheumatoid arthritis (RA) patients failing on tumor necrosis factor (TNF) blocking agents. However, approximately 40% to 50% of rituximab (RTX) treated RA patients have a poor response. We investigated whether baseline gene expression levels can discriminate between clinical non-responders and responders to RTX. METHODS: In 14 consecutive RA patients starting on RTX (test cohort), gene expression profiling on whole peripheral blood RNA was performed by Illumina(r) HumanHT beadchip microarrays. Supervised cluster analysis was used to identify genes expressed differentially at baseline between responders and non-responders based on both a difference in 28 joints disease activity score (DeltaDAS28 < 1.2) and European League against Rheumatism (EULAR) response criteria after six months RTX. Genes of interest were measured by quantitative real-time PCR and tested for their predictive value using receiver operating characteristics (ROC) curves in an independent validation cohort (n = 26). RESULTS: Genome-wide microarray analysis revealed a marked variation in the peripheral blood cells between RA patients before the start of RTX treatment. Here, we demonstrated that only a cluster consisting of interferon (IFN) type I network genes, represented by a set of IFN type I response genes (IRGs), that is, LY6E, HERC5, IFI44L, ISG15, MxA, MxB, EPSTI1 and RSAD2, was associated with DeltaDAS28 and EULAR response outcome (P = 0.0074 and P = 0.0599, respectively). Based on the eight IRGs an IFN-score was calculated that reached an area under the curve (AUC) of 0.82 to separate non responders from responders in an independent validation cohort of 26 patients using Receiver Operator Characteristics (ROC) curves analysis according to DeltaDAS28 < 1.2 criteria. Advanced classifier analysis yielded a three IRG-set that reached an AUC of 87%. Comparable findings applied to EULAR non-response criteria. CONCLUSIONS: This study demonstrates clinical utility for the use of baseline IRG expression levels as a predictive biomarker for non-response to RTX in RA. PMID- 22540994 TI - Copper-catalyzed formic acid synthesis from CO2 with hydrosilanes and H2O. AB - A copper-catalyzed formic acid synthesis from CO2 with hydrosilanes has been accomplished. The Cu(OAc)2.H2O-1,2-bis(diphenylphosphino)benzene system is highly effective for the formic acid synthesis under 1 atm of CO2. The TON value approached 8100 in 6 h. The reaction pathway was revealed by in situ NMR analysis and isotopic experiments. PMID- 22540993 TI - GnRH agonist versus GnRH antagonist in assisted reproduction cycles: oocyte morphology. AB - BACKGROUND: The selection of developmentally competent human gametes may increase the efficiency of assisted reproduction. Spermatozoa and oocytes are usually assessed according to morphological criteria. Oocyte morphology can be affected by the age, genetic characteristics, and factors related to controlled ovarian stimulation. However, there is a lack of evidence in the literature concerning the effect of gonadotropin-releasing hormone (GnRH) analogues, either agonists or antagonists, on oocyte morphology. The aim of this randomized study was to investigate whether the prevalence of oocyte dysmorphism is influenced by the type of pituitary suppression used in ovarian stimulation. METHODS: A total of 64 patients in the first intracytoplasmic sperm injection (ICSI) cycle were prospectively randomized to receive treatment with either a GnRH agonist with a long-term protocol (n: 32) or a GnRH antagonist with a multi-dose protocol (n: 32). Before being subjected to ICSI, the oocytes at metaphase II from both groups were morphologically analyzed under an inverted light microscope at 400x magnification. The oocytes were classified as follows: normal or with cytoplasmic dysmorphism, extracytoplasmic dysmorphism, or both. The number of dysmorphic oocytes per total number of oocytes was analyzed. RESULTS: Out of a total of 681 oocytes, 189 (27.8%) were morphologically normal, 220 (32.3%) showed cytoplasmic dysmorphism, 124 (18.2%) showed extracytoplasmic alterations, and 148 (21.7%) exhibited both types of dysmorphism. No significant difference in oocyte dysmorphism was observed between the agonist- and antagonist-treated groups (P>0.05). Analysis for each dysmorphism revealed that the most common conditions were alterations in polar body shape (31.3%) and the presence of diffuse cytoplasmic granulations (22.8%), refractile bodies (18.5%) and central cytoplasmic granulations (13.6%). There was no significant difference among individual oocyte dysmorphisms in the agonist- and antagonist-treated groups (P>0.05). CONCLUSIONS: Our randomized data indicate that in terms of the quality of oocyte morphology, there is no difference between the antagonist multi-dose protocol and the long-term agonist protocol. If a GnRH analogue used for pituitary suppression in IVF cycles influences the prevalence of oocyte dysmorphisms, there does not appear to be a difference between the use of an agonist as opposed to an antagonist. PMID- 22540995 TI - An update on treatment of onychomycosis. AB - Onychomycosis (OM) is a fungal infection of the nail plate or nail bed which is highly prevalent in the general population and also responsible for significant morbidity. The condition needs to be treated in view of the physical and emotional handicap it produces. The peculiarities of the nail apparatus in health and disease lead to difficulties in being able to successfully treat this condition. Hence, the very same antifungals which produce high cure rates in skin infections are rendered less efficacious in nail disease. Low cure rates and high relapse rates even with highly efficacious antifungals have lead to an increasing interest in exploring newer treatment options which can ensure drug penetration, drug persistence, mycological cure and effective prevention of relapse. The current review aims to summarize our current status of knowledge about the treatment options for OM. It also summarizes the newer areas of research especially with respect to devices related therapies; physical measures to enhance penetration through nail; and development and evaluation of synergistic combinations. PMID- 22540996 TI - A randomised trial comparing the CEL-100 videolaryngoscope(TM) with the Macintosh laryngoscope blade for insertion of double-lumen tubes. AB - We performed a randomised trial comparing the CEL-100 videolaryngoscope(TM) with the Macintosh laryngoscope blade in 170 patients undergoing double-lumen tube placement for thoracic surgery. Compared with the Macintosh laryngoscope blade, use of the CEL-100 resulted in significantly more patients with a Cormack and Lehane Grade-1 laryngeal view (90.4% vs 61.0%, p < 0.001), a higher rate of successful intubation on the first attempt (92.8% vs 79.3%, p = 0.012), a lower median (IQR [range]) intubation difficulty score (0 (0-0 [0-60]) vs 15 (0-30 [0 80]), p < 0.001), a higher incidence of correct positioning of the tube (90.3% vs 79.2%, p = 0.041) and significantly fewer patients requiring external laryngeal pressure (19.3% vs 32.9%, p = 0.046). Median (IQR [range]) time to successful intubation was 45 (38-55 [22-132]) s with the CEL-100 compared with 51 (40-61 [30 160] s using the Macintosh laryngoscope blade. We conclude that the CEL-100 videolaryngoscope is superior to the Macintosh laryngoscope blade for double lumen tube insertion. PMID- 22540997 TI - Understanding and tuning the catalytic bias of hydrogenase. AB - When enzymes are optimized for biotechnological purposes, the goal often is to increase stability or catalytic efficiency. However, many enzymes reversibly convert their substrate and product, and if one is interested in catalysis in only one direction, it may be necessary to prevent the reverse reaction. In other cases, reversibility may be advantageous because only an enzyme that can operate in both directions can turnover at a high rate even under conditions of low thermodynamic driving force. Therefore, understanding the basic mechanisms of reversibility in complex enzymes should help the rational engineering of these proteins. Here, we focus on NiFe hydrogenase, an enzyme that catalyzes H(2) oxidation and production, and we elucidate the mechanism that governs the catalytic bias (the ratio of maximal rates in the two directions). Unexpectedly, we found that this bias is not mainly determined by redox properties of the active site, but rather by steps which occur on sites of the proteins that are remote from the active site. We evidence a novel strategy for tuning the catalytic bias of an oxidoreductase, which consists in modulating the rate of a step that is limiting only in one direction of the reaction, without modifying the properties of the active site. PMID- 22540999 TI - Autosomal dominant amelogenesis imperfecta associated with ENAM frameshift mutation p.Asn36Ilefs56. PMID- 22540998 TI - Effect of sodium and calcium cations on the ion-exchange affinity of organic cations for soil organic matter. AB - Sorption of organic cations to soil organic matter was studied using dynamic column experiments with different compositions of electrolytes in aqueous eluents. The sorption affinity of the tested variety of charged compounds, including primary, secondary, and tertiary amines and quaternary ammonium compounds, all showed the same response to different medium compositions. The sorption affinity to Pahokee peat (i) strongly decreased with increasing electrolyte concentration, up to a factor 250 due to tested electrolyte compositions alone, (ii) was higher in NaCl solutions than in CaCl(2) solutions of similar ionic strength, and (iii) was more sensitive to a decrease in NaCl than to a decrease in CaCl(2), though the selectivity coefficients were not significantly different. For a weak base that was tested in eluent pH either above or below its pK(a), we demonstrated that the sorption affinity of (iv) the neutral base was hardly affected by different electrolyte compositions, comparable to a neutral reference compound, (v) the protonated weak base was strongly affected by different electrolyte compositions, and (vi) the protonated base was in the same range, or stronger, compared to the neutral base. Mass action law equations for ion-exchange reactions predicted similar trends in a qualitative but not in a quantitative way. More complex models are required to fully account for the contributions of ionic interactions to the sorption of organic cations. These results imply that risk assessment models for organic bases should take ion-exchange processes into account when estimating soil sorption coefficients and bioavailability. PMID- 22541000 TI - Anti-inflammatory active gold(I) complexes involving 6-substituted-purine derivatives. AB - The gold(I) complexes of the general formula [Au(L(n))(PPh(3))].xH(2)O (1-8; n = 1-8 and x = 0-1.5), where L(n) stands for a deprotonated form of the benzyl substituted derivatives of 6-benzylaminopurine, were prepared, thoroughly characterized (elemental analyses, FT-IR, Raman and multinuclear NMR spectroscopy, ESI+ mass spectrometry, conductivity, DFT calculations), and studied for their in vitro cytotoxicity and in vitro and in vivo anti inflammatory effects on LPS-activated macrophages (derived from THP-1 cell line) and using the carrageenan-induced hind paw edema model on rats. The obtained results indicate that the representative complexes (1, 3, 6) exhibit a strong ability to reduce the production of pro-inflammatory cytokines TNF-alpha, IL 1beta and HMGB1 without influence on the secretion of anti-inflammatory cytokine IL-1RA in the LPS-activated macrophages. The complexes also significantly influence the formation of edema, caused by the intraplantar application of polysaccharide lambda-carrageenan to rats in vivo. All the tested complexes showed similar or better biological effects as compared with Auranofin, but contrary to Auranofin they were found to be less cytotoxic in vitro. The obtained results clearly indicate that the gold(I) complexes behave as very effective anti inflammatory agents and could prove to be useful for the treatment of difficult to treat inflammatory diseases such as rheumatoid arthritis. PMID- 22541001 TI - Synthetic cathinone exposures reported to Texas poison centers. AB - BACKGROUND: Among the novel classes of synthetic "designer" drugs that have become increasingly popular among recreational drug users are synthetic cathinones. There is limited information on exposures to these substances. OBJECTIVE: The objective of this investigation was to describe the pattern of synthetic cathinone exposures reported to a statewide poison center network. METHODS: Synthetic cathinone exposures reported to Texas poison centers during 2010-2011 were identified and the distribution by various demographic and clinical factors determined. RESULTS: Of 362 total calls, 84.5% of the patients were 20 years or older and 74.0% male. The route of exposure was 47.8% by inhalation alone and 28.7% by ingestion alone. Other substances were involved in 19.3% of the exposures. The patient was already at or en route to a health-care facility in 75.1% of the exposures. The outcome was serious (moderate, major, potentially toxic, or death) in 74.0% of the exposures. The most frequently reported clinical effects were tachycardia (45.9%), agitation (39.2%), hypertension (21.0%), hallucinations (17.7%), and confusion (13.0%). The most common treatments were IV fluids (53.6%), benzodiazepines (40.9%), oxygen (11.0%), and other sedatives (7.5%). CONCLUSION: Synthetic cathinone exposures reported to Texas poison centers tended to occur through inhalation or ingestion, involve adult and male patients, be managed at health-care facilities, and involve potentially serious outcomes. SCIENTIFIC SIGNIFICANCE: This study adds to the limited information currently available on synthetic cathinone exposures. PMID- 22541003 TI - The journey from despair to hope: an exploration of the phenomenon of psychological distress in women residing in British secure mental health services. AB - This paper reports the findings of a descriptive phenomenological study that aimed to elicit and describe the experience of psychological distress as expressed by a group of women compulsorily detained within secure mental health services in the U.K. A fundamental objective of the study was to contribute to the existing evidence base that supports the care and treatment needs of this severely traumatized and challenging patient group. We argue that service providers and clinical practitioners could be better informed about the unique care and treatment needs of this severely traumatized and challenging patient group when working with them. A descriptive phenomenological approach developed by Giorgi was used to elicit the lived experiences of 'psychological distress' from a sample of female patients resident within a high secure hospital and an independent medium secure hospital. The findings indicate that a treatment plan which includes a combination of prescribed medication, informal support networks, intensive individual therapy and active engagement in a therapeutic life skills programme can be extremely beneficial. Most notably in helping to reduce the frequency of both internally and externally directed violent behaviour in this vulnerable client group. PMID- 22541002 TI - Splicosomal and serine and arginine-rich splicing factors as targets for TGF beta. AB - BACKGROUND: Transforming growth factor-beta1 (TGF-beta1) is a potent regulator of cell growth and differentiation. TGF-beta1 has been shown to be a key player in tissue remodeling processes in a number of disease states by inducing expression of extracellular matrix proteins. In this study a quantitative proteomic analysis was undertaken to investigate if TGF-beta1 contributes to tissue remodeling by mediating mRNA splicing and production of alternative isoforms of proteins. METHODOLOGY/PRINCIPAL FINDINGS: The expression of proteins involved in mRNA splicing from TGF-beta1-stimulated lung fibroblasts was compared to non stimulated cells by employing isotope coded affinity tag (ICATTM) reagent labeling and tandem mass spectrometry. A total of 1733 proteins were identified and quantified with a relative standard deviation of 11% +/- 8 from enriched nuclear fractions. Seventy-six of these proteins were associated with mRNA splicing, including 22 proteins involved in splice site selection. In addition, TGF-beta1 was observed to alter the relative expression of splicing proteins that may be important for alternative splicing of fibronectin. Specifically, TGF-beta1 significantly induced expression of SRp20, and reduced the expression of SRp30C, which has been suggested to be a prerequisite for generation of alternatively spliced fibronectin. The induction of SRp20 was further confirmed by western blot and immunofluorescence. CONCLUSIONS: The results show that TGF-beta1 induces the expression of proteins involved in mRNA splicing and RNA processing in human lung fibroblasts. This may have an impact on the production of alternative isoforms of matrix proteins and can therefore be an important factor in tissue remodeling and disease progression. PMID- 22541005 TI - Evaluation of drying methods and toxicity of rayless goldenrod ( Isocoma pluriflora ) and white snakeroot ( Ageratina altissima ) in goats. AB - White snakeroot and rayless goldenrod cause "trembles" and "milk sickness" in livestock and humans, respectively. The toxin in white snakeroot and rayless goldenrod was identified in 1927 and 1930, respectively, as tremetol. It was reported that the toxin in white snakeroot disappears as it is dried and that completely dried plants were incapable of producing trembles or milk sickness. Conversely, it has been reported that the rayless goldenrod toxin was not destroyed by drying and that the plant is toxic either fresh or dry. In this study the concentrations of tremetone, dehydrotremetone, and structurally similar compounds were determined in white snakeroot and rayless goldenrod before and after various drying conditions. Tremetone, dehydrotremetone, and structurally similar compounds in rayless goldenrod and white snakeroot are most stable upon freeze-drying, followed by air-drying, and least stable upon oven-drying (60 degrees C). Also demonstrated is that tremetone is stable and that dried white snakeroot and rayless goldenrod are capable of inducing toxicosis in livestock. PMID- 22541004 TI - Identical germline mutations in the TMEM127 gene in two unrelated Japanese patients with bilateral pheochromocytoma. AB - OBJECTIVE: Recently, TMEM127 was shown to be a new pheochromocytoma susceptibility gene; this is consistent with its function as a tumour suppressor gene (Journal of Clinical Endocrinology and Metabolism, 2009, 94, 2817). Most pheochromocytomas arise from the adrenal medulla, and in approximately half of the cases, the tumours are bilateral (Journal of Clinical Endocrinology and Metabolism, 2009, 94, 2817; Journal of the American Medical Association, 2004, 292, 943; Human Mutation, 2010, 31, 41; Science, 2009, 325, 1139). The aim of the present study was to determine whether TMEM127 mutations are involved in the pathogenesis of pheochromocytomas/paragangliomas in Japanese subjects. PATIENTS AND METHODS: For this study, 74 unrelated patients with pheochromocytoma/paraganglioma who tested negative for mutations and deletions in RET, VHL, SDHB and SDHD were recruited through a multi-institutional collaborative effort in Japan. The TMEM127 gene sequence was determined in their germline DNA, and tumour DNA was analysed for the loss of heterozygosity. In addition, their TMEM127 gene sequences were compared with sequences from 114 normal healthy, ethnically matched controls. RESULTS: Among the 74 eligible patients, two unrelated patients (2.7%) with bilateral adrenal pheochromocytoma were found to have an identical germline TMEM127 mutation (c.116_119delTGTC, p.Ile41ArgfsX39) associated with 2q deletion loss of heterozygosity, which was also previously described in a Brazilian case (Journal of the American Medical Association, 2004, 292, 943). We also determined that none of the 114 normal healthy controls had this deletion mutation. CONCLUSION: This is the first report showing that TMEM127 mutation plays a pathological role in pheochromocytoma in an Asian population. Although our surveillance is limited, the prevalence and the phenotype of this gene mutation appear to be similar to those reported in previous studies. PMID- 22541007 TI - Determination of trace elements in lithium niobate crystals by solid sampling and solution-based spectrometry methods. AB - Solid sampling (SS) graphite furnace atomic absorption spectrometry (GFAAS) and solution-based (SB) methods of GFAAS, flame atomic absorption spectrometry (FAAS), inductively coupled plasma optical emission spectrometry (ICP-OES) and inductively coupled plasma mass spectrometry (ICP-MS) were elaborated and/or optimized for the determination of Cr, Fe and Mn trace elements used as dopants in lithium niobate optical crystals. The calibration of the SS-GFAAS analysis was possible with the application of the three-point-estimation standard addition method, while the SB methods were mostly calibrated against matrix-matched and/or acidic standards. Spectral and non-spectral interferences were studied in SB GFAAS after digestion of the samples. The SS-GFAAS method required the use of less sensitive spectral lines of the analytes and a higher internal furnace gas (Ar) flow rate to decrease the sensitivity for crystal samples of higher (doped) analyte content. The chemical forms of the matrix produced at various stages of the graphite furnace heating cycle, dispensed either as a solid sample or a solution (after digestion), were studied by means of the X-ray near-edge absorption structure (XANES). These results revealed that the solid matrix vaporized/deposited in the graphite furnace is mostly present in the metallic form, while the dry residue from the solution form mostly vaporized/deposited as the oxide of niobium. PMID- 22541006 TI - Histamine is a modulator of metamorphic competence in Strongylocentrotus purpuratus (Echinodermata: Echinoidea). AB - BACKGROUND: A metamorphic life-history is present in the majority of animal phyla. This developmental mode is particularly prominent among marine invertebrates with a bentho-planktonic life cycle, where a pelagic larval form transforms into a benthic adult. Metamorphic competence (the stage at which a larva is capable to undergo the metamorphic transformation and settlement) is an important adaptation both ecologically and physiologically. The competence period maintains the larval state until suitable settlement sites are encountered, at which point the larvae settle in response to settlement cues. The mechanistic basis for metamorphosis (the morphogenetic transition from a larva to a juvenile including settlement), i.e. the molecular and cellular processes underlying metamorphosis in marine invertebrate species, is poorly understood. Histamine (HA), a neurotransmitter used for various physiological and developmental functions among animals, has a critical role in sea urchin fertilization and in the induction of metamorphosis. Here we test the premise that HA functions as a developmental modulator of metamorphic competence in the sea urchin Strongylocentrotus purpuratus. RESULTS: Our results provide strong evidence that HA leads to the acquisition of metamorphic competence in S. purpuratus larvae. Pharmacological analysis of several HA receptor antagonists and an inhibitor of HA synthesis indicates a function of HA in metamorphic competence as well as programmed cell death (PCD) during arm retraction. Furthermore we identified an extensive network of histaminergic neurons in pre-metamorphic and metamorphically competent larvae. Analysis of this network throughout larval development indicates that the maturation of specific neuronal clusters correlates with the acquisition of metamorphic competence. Moreover, histamine receptor antagonist treatment leads to the induction of caspase mediated apoptosis in competent larvae. CONCLUSIONS: We conclude that HA is a modulator of metamorphic competence in S. purpuratus development and hypothesize that HA may have played an important role in the evolution of settlement strategies in echinoids. Our findings provide novel insights into the evolution of HA signalling and its function in one of the most important and widespread life history transitions in the animal kingdom- metamorphosis. PMID- 22541008 TI - Alignment and clustering strategies for GC*GC-MS features using a cylindrical mapping. AB - Comprehensive two-dimensional gas chromatography coupled to mass spectrometry is a powerful tool to analyze complex samples. For application of the technique in studies like biomarker discovery in which large sets of complex samples have to be analyzed, extensive preprocessing is needed to align the data obtained in several injections (analyses). We developed new alignment and clustering algorithms for this type of data. New in the current procedures is the consistent way in which the phenomenon referred to as wrap-around is treated. The data analysis problems associated with this phenomenon are solved by treating the 2D display as the surface of a three-dimensional cylinder. Based on this transformation we developed a new similarity metric for features as a function of both the cylindrical distance (reflecting similarity in chromatographic behavior) and of the mass spectral correlation (reflecting similarity in chemical structure). The concepts are used in warping and clustering, and include a protection against greedy warping. The methods were applied - for the purpose of an example - to the analysis of 11 replicates of a human urine sample concentrated by solid phase extraction. It is shown that the alignment is well protected against greedy warping which is important with respect to analytical qualities as robustness and repeatability. It is also demonstrated that chemically similar features are clustered together. The paper is organized as follows. First a brief introduction is provided addressing the background of the GC*GC-MS data structure followed by a theoretical section with a conceptual description of the procedures and details of the algorithms. Finally an example is given in the experimental section, illustrating the application of the procedures. PMID- 22541009 TI - A layered magnetic iron/iron oxide nanoscavenger for the analytical enrichment of ng-L(-1) concentration levels of heavy metals from water. AB - Magnetically driven separation techniques have received considerable attention in recent decade because of their great potential application. In this study, we investigate the application of an unmodified layered magnetic Fe/Fe(2)O(3) nanoscavenger for the analytical enrichment and determination of sub-parts per billion concentrations of Cd(II), Pb(II), Ni(II), Cr(VI) and As(V) from water samples. The synthesized nanoscavenger was characterized by BET, TGA, XRD and IR and the parameters influencing the extraction and recovery of the preconcentration process were assessed by atomic absorption spectrometry. The possible mechanism of the enrichment of heavy metals on Fe/Fe(2)O(3) was proposed, which involved the dominant adsorption and reduction. The nanoscale size offers large surface area and high reactivity of sorption and reduction reactions. The obtained limits of detection for the metals studied were in the range of 20-125 ng L(-1) and the applicability of the nanomaterial was verified using a real sample matrix. The method is environmentally friendly as only 15 mg of nanoscavenger are used, no organic solvent is required for the extraction and the experiment is performed without the need for filtration or preparation of packed preconcentration columns. PMID- 22541010 TI - Determination of perfluorocarboxylic acids in water by ion-pair dispersive liquid liquid microextraction and gas chromatography-tandem mass spectrometry with injection port derivatization. AB - A novel technique for derivatization in a gas chromatograph injection port after a one-step extraction of trace perfluorocarboxylic acids (PFCAs) in water with ion pair formation during dispersive liquid-liquid microextraction (DLLME) was investigated. Tetrabutylammonium hydrogen sulfate (TBAHS) was used as the ion pair reagent. PFCA butyl ester derivatives were formed in the GC injection port and then analyzed using gas chromatography coupled to tandem mass spectrometry with negative chemical ionization. According to our analysis, the operative linear range for PFCA detection from 250 pg mL(-1) to 2 MUg mL(-1) with a relative standard derivation (RSD) below 13%. Detection limits were achieved at the level of 37-51 pg mL(-1). This method was successfully applied for the analyzing of PFCAs in river water samples from urban and industrial areas without tedious pretreatment. The concentration range over which PFCAs were detected is from 0.6 ng mL(-1) to 604.9 ng mL(-1). PMID- 22541012 TI - 2-Aminopurine hairpin probes for the detection of ultraviolet-induced DNA damage. AB - Nucleic acid exposure to radiation and chemical insults leads to damage and disease. Thus, detection and understanding DNA damage is important for elucidating molecular mechanisms of disease. However, current methods of DNA damage detection are either time-consuming, destroy the sample, or are too specific to be used for generic detection of damage. In this paper, we develop a fluorescence sensor of 2-aminopurine (2AP), a fluorescent analogue of adenine, incorporated in the loop of a hairpin probe for the quantification of ultraviolet (UV) C-induced nucleic acid damage. Our results show that the selectivity of the 2AP hairpin probe to UV-induced nucleic acid damage is comparable to molecular beacon (MB) probes of DNA damage. The calibration curve for the 2AP hairpin probe shows good linearity (R(2)=0.98) with a limit of detection of 17.2 nM. This probe is a simple, fast and economic fluorescence sensor for the quantification of UV induced damage in DNA. PMID- 22541011 TI - Incorporation of methamphetamine and amphetamine in human hair following controlled oral methamphetamine administration. AB - BACKGROUND: Although hair testing is well established for the assessment of past drug exposure, uncertainties persist about mechanisms of drug incorporation into hair and interpretation of results. The aim of this study was to administer methamphetamine (MAMP) under controlled conditions as a model drug to investigate drug incorporation into human hair. MATERIAL AND METHODS: Seven volunteers with a history of stimulant use received 4*10 mg (low) doses of sustained release S-(+) MAMP HCl within 1 week, with weekly head hair samples collected by shaving. 3 weeks later, 4 of them received 4*20 mg (high) doses. After extensive isopropanol/phosphate buffer washing of the hair, MAMP and its metabolite amphetamine (AMP) concentrations were determined in all weekly hair samples by LC MS-MS in selected reaction monitoring mode with the undeca- and deca-deuterated drugs, respectively, as internal standards (LLOQ, 0.005 ng mg(-1)). RESULTS: MAMP T(max) occurred from 1 to 2 weeks after both doses, with C(max) ranging from 0.6 to 3.5 ng mg(-1) after the low and 1.2 to 5.3 ng mg(-1) after the high MAMP doses. AMP C(max) in hair was 0.1-0.3 ng mg(-1) and 0.2-0.5 ng mg(-1), respectively, for low and high doses. Highly dose-related concentrations within subjects, but large variability between subjects were observed. MAMP concentrations were above the 0.2 ng mg(-1) cut-off for at least 2 weeks following administration of both low and high doses. The overall AMP/MAMP ratio ranged from 0.07 to 0.37 with a mean value of 0.15 +/- 0.07, and a median of 0.13. The percentage of MAMP and AMP removed with the washing procedure decreased with time after administration. A strong correlation was found between area under the curve of MAMP (r(2)=0.90, p=0.00) and AMP (r(2)=0.94, p=0.00) concentrations calculated for the 3-week period following administration and the total melanin concentration in hair. Significant correlations were observed also between C(max) and melanin. CONCLUSIONS: This study demonstrated that despite large inter individual differences, the incorporation of MAMP and AMP into hair is dose related with much of the observed scatter of MAMP and AMP concentrations explained by melanin concentration in hair. PMID- 22541013 TI - Improving the efficiency of ion mobility spectrometry analyses by using multivariate calibration. AB - The simplicity, sensitivity and expeditiousness of ion mobility spectrometry (IMS) make it especially useful for the determination of active principal ingredients (APIs) present at low concentrations in pharmaceuticals. However, the poor resolution of this technique precludes the identification and/or determination of substances with similar molecular weights, which exhibit also similar drift times and give overlapped peaks as a result. Oral contraceptives are pharmaceutical formulations containing two APIs of similar molecular weights at very low concentrations which therefore give strongly overlapped peaks hindering their determination by IMS. In this work, we assessed the potential of IMS for detecting and quantifying the contraceptives ethinylestradiol (ETE) and desogestrel (DES) in commercial tablets. To this end, we used various chemometric techniques including a second-derivative (TN2D) algorithm and the more powerful choice Multivariate Curve Resolution (MCR) to improve the resolution of IMS and enable the determination of both APIs. Quantitation was based on PLS1 models for each API. The models constructed involve a single PLS factor with a Y-explained variance above 98.4%, obtaining a RMSEP of 0.34 and 0.63 for ETE and DES, respectively. The ensuing method, which was validated for use in routine analyses, is quite expeditious (analyses take less than 1 min) and uses very small amounts of sample (a few microliters). Based on the results, IMS has a great potential for the qualitative and quantitative determination of APIs in low doses. PMID- 22541014 TI - Rapid prediction of moisture content of dehydrated prawns using online hyperspectral imaging system. AB - Because the shape of prawn is not round, spectroscopy instruments cannot measure the spectra of the whole prawn without containing background information. In this study, an online hyperspectral imaging system in the spectral region of 380-1100 nm was developed to determine the moisture content of prawns at different dehydrated levels. Hyperspectral images of prawns were acquired at different dehydration periods. The spectra of prawns then were extracted from hyperspectral images based on 'Manual Prawn Mask' and 'Automatic Prawn Mask', respectively. Spectral data were analyzed using partial least squares regression (PLSR) and least-squares support vector machines (LS-SVM) to establish the calibration models, respectively. Successive projections algorithm (SPA) was first applied for the optimal wavelength selection in the hyperspectral image analysis. Out of 482 wavelengths, only twelve wavelengths (428, 445, 544, 569, 629, 672, 697, 760, 827, 917, 958, and 999 nm) were selected by SPA as the optimum wavelengths for moisture prediction. Based on these optimum wavelengths, a multiple linear regression (MLR) calibration model was established and used to obtain the moisture distribution of each prawn. The overall results of this study revealed the potentiality of hyperspectral imaging as an objective and non-destructive method to obtain the content and distribution of moisture of prawns whose shapes are not round. PMID- 22541015 TI - 3,4,9,10-Perylenetetracarboxylic dianhydride functionalized graphene sheet as labels for ultrasensitive electrochemiluminescent detection of thrombin. AB - A novel tracer, 3,4,9,10-perylenetetracarboxylic dianhydride (PTCDA) functionalized graphene sheet (GS) composite (GS-TCDA), is employed to label the secondary anti-thrombin aptamer (TBA) to construct an ultrasensitive electrochemiluminescent sandwich-type aptasensor. The GS provided large surface area for loading abundant PTCDA and TBA with good stability and biocompatibility. Because of the excellent electroconductivity of GS and the desirable optical properties of PTCDA, the as-formed Apt II bioconjugate considerably amplified the electrochmiluminescence (ECL) signal of peroxydisulfate (S(2)O(8)(2-)) and worked as the desirable label for Apt II. On the basis of the considerably amplified ECL signal and sandwich format, an extremely wide range from 1 fM to 1 nM with an ultralow detection limit of 0.33 fM for thrombin was obtained. Additionally, the selectivity and stability of the proposed aptasensor were also excellent. Thus, this procedure has great promise for detection of thrombin present at ultra-trace levels during early stage of diseases. PMID- 22541016 TI - An efficient strategy for unmodified nucleotide-mediated dispersion of magnetic nanoparticles, leading to a highly sensitive MRI-based mercury ion assay. AB - It is highly attractive to develop a detection system that is not only sensitive and selective but also simple, rapid, practical and cost-effective in operation. Here, we report an interesting observation that single-stranded oligonucleotide (ssDNA) can adsorb efficiently on carboxylic acid-functionalized magnetic nanoparticles (CAMNPs) and stabilize the nanoparticles against aggregation in weakly acidic solution. The adsorbing rate closely correlates with the pH of the solution, the temperature and the sequence length of ssDNA. On the basis of this observation, we have designed a highly sensitive, non-sandwich type magnetic relaxation-based detection system for quantitatively probing mercury ion. The assay is independent of the sample's optical properties, requires no covalent modification of the ssDNA or the CAMNPs surfaces, and can be used for high throughput analysis. By varying the concentration of CAMNPs, four orders of dynamic response range and a detection limit of 0.3 nM for Hg(2+) are achieved. Moreover, we developed a multi-sample assay to detect Hg(2+) in real environmental samples with high sensitivity, selectivity and efficiency. PMID- 22541018 TI - Improvement of the homogeneity of protein-imprinted polymer films by orientated immobilization of the template. AB - A method for preparing homogeneous protein-imprinted polymer films with orientated immobilization of template is described. The template methyl parathion hydrolase (MPH) was modified with a peptide linker (Gly-Ser)(5)-Cys and was immobilized on a cover glass with a fixed orientation via the linker. The activity of the fusion enzyme (MPH-L) was evaluated by determining the product's absorbance at 405 nm (A(405)). Both the free and the immobilized MPH-L showed higher retention of the bioactivity than the wide type enzyme (MPH-W) as revealed by the A(405) values for MPH-L(free)/MPH-W(free) (1.159/1.111) and for MPH L(immobilized)/MPH-W(immobilized) (0.348/0.118). The immobilized MPH-L also formed a more homogeneous template stamp compared to the immobilized MPH-W. The molecularly imprinted polymer films prepared with the immobilized MPH-L exhibited high homogeneity with low Std. Deviations of 80 and 200 from the CL intensity mean volumes which were observed for batch-prepared films and an individual film, respectively. MPH-L-imprinted polymer film also had a larger template binding capacity indicated by higher CL intensity mean volume of 3900 INT over 2500 INT for MPH-W-imprinted films. The imprinted film prepared with the orientated immobilization of template showed an imprinting factor of 1.7, while the controls did not show an imprinting effect. PMID- 22541017 TI - Ultrasensitive detection of ovarian cancer marker using immunoliposomes and gold nanoelectrodes. AB - Mucin-16 (MUC16) is the established ovarian cancer marker used to follow the disease during or after treatment for epithelial ovarian cancer. The emerging science of cancer markers also demands for the new sensitive detection methods. In this work, we have developed an electrochemical immunosensor for antigen MUC16 using gold nanoelectrode ensemble (GNEE) and ferrocene carboxylic acid encapsulated liposomes tethered with monoclonal anti-Mucin-16 antibodies (alphaMUC16). GNEEs were fabricated by electroless deposition of the gold within the pores of polycarbonate track-etched membranes. Afterwards, alphaMUC16 were immobilized on preformed self-assembled monolayer of cysteamine on the GNEE via cross-linking with EDC-Sulfo-NHS. A sandwich immunoassay was performed on alphaMUC16 functionalized GNEE with MUC16 and immunoliposomes. The differential pulse voltammetry was employed to quantify the faradic redox response of ferrocene carboxylic acid released from immunoliposomes. The dose-response curve for MUC16 concentration was found between the range of 0.001-300 U mL(-1). The lowest detection limit was found to be 5*10(-4) U mL(-1) (S/N=3). We evaluated the performance of this developed immunosensor with commercial ELISA assay by comparing results obtained from spiked serum samples and real blood serum samples from volunteers. PMID- 22541019 TI - Influence of hole mobility on the response characteristics of p-type nickel oxide thin film based glucose biosensor. AB - RF sputtered p-type nickel oxide (NiO) thin film exhibiting tunable semiconductor character which in turns enhanced its functional properties. NiO thin film with high hole mobility is developed as a potential matrix for the realization of glucose biosensor. NiO thin film prepared under the optimized deposition conditions offer good electrical conductivity (1.5*10(-3) Omega(-1)-cm(-1)) with high hole mobility (2.8 cm(2) V(-1) s(-1)). The bioelectrode (GO(x)/NiO/ITO/glass) exhibits a low value of Michaelis-Menten constant (K(m)=1.05 mM), indicating high affinity of the immobilized GO(x) toward the analyte (glucose). Due to the high surface coverage (2.32*10(-7) mol cm(-2)) of the immobilized enzyme on to the NiO matrix and its high electrocatalytic activity, the prepared biosensor exhibits a high sensitivity of 0.1 mA(mM(-1)-cm( 2)) and a good linearity from 25 to 300 mg dL(-1) of glucose concentration with fast response time of 5 s. Various functional properties of the material (mobility, crystallinity and stress) are found to influence the charge communication feature of NiO thin film matrix to a great extent, resulting in enhanced sensing response characteristics. PMID- 22541020 TI - Carbon nanoparticles from corn stalk soot and its novel application as stationary phase of hydrophilic interaction chromatography and per aqueous liquid chromatography. AB - Carbon nanoparticles (CNPs) (6-18 nm in size) were prepared by refluxing corn stalk soot in nitric acid. The obtained acid-oxidized CNPs are soluble in water due to the existence of carboxylic and hydroxyl groups. (13)C NMR measurement shows the CNPs are mainly of sp(2) and sp(3) carbon structure different from CNPs obtained from candle soot and natural gas soot. Furthermore, these CNPs exhibit unique photoluminescence properties. Interestingly, the CNPs might be exploited to immobilize on the surface of porous silica particles as chromatographic stationary phase. The resultant packing material was evaluated by high performance liquid chromatography, indicating that the new stationary phase could be used in hydrophilic interaction liquid chromatography (HILIC) and per aqueous liquid chromatography (PALC) modes. The separation of five nucleosides, four sulfa compounds and safflower injection was achieved by using the new column in the HILIC and PALC modes, respectively. PMID- 22541021 TI - Pyrogenic inputs of anthropogenic Pb and Hg to sediments of the Hood Canal, Washington, in the 20th century: source evidence from stable Pb isotopes and PAH signatures. AB - Combustion-derived PAHs and stable Pb isotopic signatures ((206)Pb/(207)Pb) in sedimentary records assisted in reconstructing the sources of atmospheric inputs of anthropogenic Pb and Hg to the Hood Canal, Washington. The sediment-focusing corrected peak fluxes of total Pb and Hg (1960-70s) demonstrate that the watershed of Hood Canal has received greater atmospheric inputs of these metals than its mostly rural land use would predict. The tight relationships between the Pb, Hg, and organic markers in the cores indicate that these metals are derived from industrial combustion emissions. Multiple lines of evidence point to the Asarco smelter, located in the Main Basin of Puget Sound, as the major emission source of these metals to the watershed of the Hood Canal. The evidence includes (1) similar PAH isomer ratios in sediment cores from the two basins, (2) the correlations between Pb, Hg, and Cu in sediments and previously studied environmental samples including particulate matter emitted from the Asarco smelter's main stack at the peak of production, and (3) Pb isotope ratios. The natural rate of recovery in Hood Canal since the 1970s, back to preindustrial metal concentrations, was linear and contrasts with recovery rates reported for the Main Basin which slowed post late 1980s. PMID- 22541022 TI - Routine chest x-rays in intensive care units: a systematic review and meta analysis. AB - INTRODUCTION: Chest x-rays (CXRs) are the most frequent radiological tests performed in the intensive care unit (ICU). However, the utility of performing daily routine CXRs is unclear. METHODS: We searched Medline and Embase (1948 to March 2011) for randomized and quasi-randomized controlled trials (RCTs) and before-after observational studies comparing a strategy of routine CXRs to a more restrictive approach with CXRs performed to investigate clinical changes among critically ill adults or children. In duplicate, we extracted data on the CXR strategy, study quality and clinical outcomes (ICU and hospital mortality; duration of mechanical ventilation and ICU and hospital stay). RESULTS: Nine studies (39,358 CXRs; 9,611 patients) were included in the meta-analysis. Three trials (N = 870) of moderate to good quality provided information on the safety of a restrictive routine CXR strategy; only one trial systematically assessed for missed findings. Pooled data from trials showed no evidence of effect of a restrictive approach on ICU mortality (risk ratio [RR] 1.04, 95% confidence interval [CI] 0.84 to 1.28, P = 0.72; two trials, N = 776), hospital mortality (RR 0.98, 95% CI 0.68 to 1.41, P = 0.91; two trials, N = 259), ICU length of stay (weighted mean difference [WMD] -0.86 days, 95% CI -2.38 to 0.66 days, P = 0.27; three trials, N = 870), hospital length of stay (WMD -2.50 days, 95% CI -6.62 to 1.61 days, P = 0.23; two trials, N = 259), or duration of mechanical ventilation (WMD -0.30 days, 95% CI -1.48 to 0.89 days, P = 0.62; three trials, N = 705). Adding data from six observational studies, one of which systematically screened for missed findings, gave similar results. CONCLUSIONS: This meta-analysis did not detect any harm associated with a restrictive chest radiograph strategy. However, confidence intervals were wide and harm was not rigorously assessed. Therefore, the safety of abandoning routine CXRs in patients admitted to the ICU remains uncertain. PMID- 22541023 TI - Identification of a novel microRNA that regulates the proliferation and differentiation in muscle side population cells. AB - Muscle satellite cells are largely responsible for skeletal muscle regeneration following injury. Side population (SP) cells, which are thought to be muscle stem cells, also contribute to muscle regeneration. SP cells exhibit high mesenchymal potential, and are a possible cell source for therapy of muscular dystrophy. However, the mechanism by which muscle SP cells are committed to differentiation is poorly understood. microRNAs (miRNAs) play key roles in modulating a variety of cellular processes through repression of their mRNA targets. In skeletal muscle, miRNAs are known to be involved in myoblast proliferation and differentiation. To investigate mechanisms of SP cell regulation, we profiled miRNA expression in SP cells and main population (MP) cells in muscles using quantitative real-time polymerase chain reaction-based expression assays. We identified a set of miRNAs that was highly expressed in SP cells as compared with MP cells. One miRNA, miR-128a, was elevated in expression in SP cells, but decreased in expression during continued culture in vitro. Overexpression of miR 128a in SP cells resulted in inhibited cell proliferation. The differentiation potential of SP cells was also decreased when miR-128a was overexpressed. MiR 128a was found to regulate the target genes involved in the regulation of adipogenic-, osteogenic- and myogenic genes that include: PPARgamma, Runx1, and Pax3. Overexpression of miR-128a suppressed the activity of a luciferase reporter fused to the 3'-untranslated region of each gene. These results demonstrate that miR-128a contributes to the maintenance of the quiescent state, and it regulates cellular differentiation by repressing individual genes in SP cells. PMID- 22541025 TI - Race, psychiatric comorbidity, and headache characteristics in patients in headache subspecialty treatment clinics. AB - OBJECTIVE: This research examined how race, psychiatric comorbidity, and headache characteristics are inter-related in patients with severe headache disorders. DESIGN: This study used a naturalistic cohort design and assessed 114 Black and 173 White patients receiving treatment in headache subspecialty clinics in Cincinnati, Cleveland, Columbus, and Toledo, OH. Face-to-face interviews yielded headache and psychiatric diagnoses; 30-day daily diaries collected data on headache frequency, severity, and disability; and self-administered surveys obtained data on headache management self-efficacy, headache locus of control, and quality of life. RESULTS: Compared with Whites, Blacks reported more frequent and severe headaches, were more likely to be diagnosed with depressive disorders, and were more likely to be diagnosed with chronic headaches. White and Black patients diagnosed with both depression and anxiety reported the most frequent headache days per month and the lowest levels of life quality and headache management self-efficacy. CONCLUSIONS: Additional research on race, psychiatric comorbidity, and headache characteristics is needed that can inform culturally contextualized interventions for persons with severe headache disorders. PMID- 22541024 TI - Expression of the T regulatory cell transcription factor FoxP3 in peri implantation phase endometrium in infertile women with endometriosis. AB - BACKGROUND: Endometriosis (EM) is highly associated with infertility. The precise mechanism underlying EM-associated infertility remains controversial. This study aimed to investigate the pathogenesis of infertility in women with EM by comparing FoxP3+ T regulatory cells (Tregs) expression in the eutopic endometrium of infertile women with EM and endometrium from healthy fertile women. METHODS: As a marker of Tregs, FoxP3 expression was analyzed in eutopic endometrium during the peri-implantation phase in infertile women with mild EM (n = 7), advanced EM (n = 20), and normally fertile women without EM (n = 20). FoxP3 mRNA expression was analyzed by quantitative real-time RT-PCR. FoxP3 protein expression was assessed by immunohistochemistry. RESULTS: FoxP3 mRNA expression in all infertile patients with EM was significantly higher than the control group (P < 0.05) by non-parametric Mann-Whitney U-test. Further analysis based on the extent of EM revealed that FoxP3 mRNA expression in infertile patients with advanced EM was significantly higher than the mild EM group and the control group (P < 0.05). Immunohistochemistry analysis showed predominant positive staining for FoxP3 protein in the endometrial stroma. In addition, the number of FoxP3+ cells in the eutopic endometrium of infertile women with advanced EM was marginally higher than the mild EM group and the control group, although the differences were not statistically significant (P > 0.05) by two-tailed t-tests. CONCLUSIONS: These findings suggest that FoxP3+ Tregs in the peri-implantation endometrium might participate in the pathogenesis of advanced EM. However, they are not directly involved in the pathogenesis of advanced EM associated with infertility. The differential expression of FoxP3 in infertile women with mild EM and advanced EM implicates that notable differences in the uterine immune status are likely involved in the pathogenesis of mild EM associated with infertility in the peri implantation endometrium. PMID- 22541026 TI - Action anticipation beyond the action observation network: a functional magnetic resonance imaging study in expert basketball players. AB - The ability to predict the actions of others is quintessential for effective social interactions, particularly in competitive contexts (e.g. in sport) when knowledge about upcoming movements allows anticipating rather than reacting to opponents. Studies suggest that we predict what others are doing by using our own motor system as an internal forward model and that the fronto-parietal action observation network (AON) is fundamental for this ability. However, multiple-duty cells dealing with action perception and execution have been found in a variety of cortical regions. Here we used functional magnetic resonance imaging to explore, in expert basketball athletes and novices, whether the ability to make early predictions about the fate of sport-specific actions (i.e. free throws) is underpinned by neural regions beyond the classical AON. We found that, although involved in action prediction, the fronto-parietal AON was similarly activated in novices and experts. Importantly, athletes exhibited relatively greater activity in the extrastriate body area during the prediction task, probably due to their expert reading of the observed action kinematics. Moreover, experts exhibited higher activation in the bilateral inferior frontal gyrus and in the right anterior insular cortex when producing errors, suggesting that they might become aware of their own errors. Correct action prediction induced higher posterior insular cortex activity in experts and higher orbito-frontal activity in novices, suggesting that body awareness is important for performance monitoring in experts, whereas novices rely more on higher-order decision-making strategies. This functional reorganization highlights the tight relationship between action anticipation, error awareness and motor expertise leading to body-related processing and differences in decision-making processes. PMID- 22541028 TI - Molecular logic with a saccharide probe on the few-molecules level. AB - In this Communication we describe a two-component saccharide probe with logic capability. The combination of a boronic acid-appended viologen and perylene diimide was able to perform a complementary implication/not implication logic function. Fluorescence quenching and recovery with fructose was analyzed with fluorescence correlation spectroscopy on the level of a few molecules of the reporting dye. PMID- 22541027 TI - Comparison of perinatal outcomes in small-for-gestational-age infants classified by population-based versus customised birth weight standards. AB - AIMS: The objective of this study was to derive a customised birth weight standard curve in our institute and to compare the perinatal outcomes of small for-gestational-age (SGA) births classified by population-based versus customised birth weight standards. METHODS: We surveyed 9052 normal singleton deliveries and generated customised standards by adjusting for maternal characteristics and neonatal gender. We compared adverse perinatal outcomes between SGA and non-SGA births classified by both standards. RESULTS: According to the population-based standards, mothers of SGA infants were younger, thinner and shorter and had higher rates of nulliparity and female births. We adjusted for these maternal characteristics and neonatal gender in our customised standards. Multivariate analysis revealed that there were no differences in neonatal composite morbidity between the standards. However, infants classified as SGA by the customised standards showed a significantly higher rate of neonatal intensive care unit (NICU) admission than those classified by the population-based standards. CONCLUSION: Our study showed that customised SGA made no significant differences in neonatal composite morbidity, only a modest increase in NICU admission rate compared to population-based standard. To clarify the association of adverse perinatal outcomes with customised SGA, larger studies are required. PMID- 22541029 TI - [Factor Xa inhibition. A new era in oral anticoagulation]. PMID- 22541030 TI - [Old and new oral anticoagulants. Pharmacological perspective]. AB - Oral anticoagulant therapy is changing. In several clinical settings, warfarin and acenocumarol remain the standard oral anticoagulants. However, in view of the limitations of vitamin K antagonists, resulting from its slow onset of pharmacological action, its narrow therapeutic window, its variable metabolism, dependent of citochrome P450, its multiple pharmacological and food interactions and its potential risk for hemorrhagic complications, the last years have witnessed the emergence of new pharmacological groups in oral anticoagulant therapy, that can overcome these problems. At present, pharmacological investigation is focused in the development of new non-peptide molecules, which can inhibit essential moments of the coagulation system (thrombin and factor Xa), with a predictable and consistent pharmacodynamic and pharmacokinetic pattern, administered orally. Of these compounds, three of them (dabigatran, rivaroxaban and apixaban) already have defined (or to be defined) therapeutic indications, built on large interventional phase III studies, while many others are in less advanced development phases. This review summarizes and discusses the pharmacology of warfarin/acenocumarol and of the new direct thrombin and factor Xa inhibitors, exemplifying similarities and stressing differences that help us justify out therapeutic options. PMID- 22541031 TI - [Prevention of thromboembolism in atrial fibrillation]. AB - Atrial fibrillation (AF) is the most prevalent chronic arrhythmia in the general population. The prognosis of AF is mainly marked by the associated thromboembolic phenomena. Of every six ischemic strokes, one is due to AF, but the proportion of ischemic strokes attributable to AF increases with age. Thromboembolic risk stratification is a key component of the clinical evaluation of the AF patient, and a clinical performance measure, and should guide the antithrombotic therapeutic strategy. Oral anticoagulation with vitamin K antagonists is effective for the prevention of ischemic stroke in nonvalvular AF but, due to several reasons, it is largely underutilized in daily clinical practice, and INR values are often sub-therapeutic. The new oral anticoagulants (thrombin inhibitors or factor Xa inhibitors) are easier to manage, and don't require laboratorial monitoring. In phase III clinical trials they have shown to be at least as effective as warfarin, but safer, particularly regarding intracranial bleeding, a complication that is responsible for 90% of warfarin-attributable deaths. These results show a potential to increase the proportion of AF patients adequately anticoagulated, which will represent a significant advance in the prevention of stroke attributable to AF. PMID- 22541032 TI - [Non valvular atrial fibrillation: the neurologist's perspective]. AB - In the last years the incidence of thromboembolic stroke has increased. Better control of other cardiovascular risk factors and the ageing of the population with the consequent augmentation of the prevalence of non valvular atrial fibrillation (NVAF) justify that increase. Although anticoagulation therapy has remarkable efficacy, from the perspective of the neurologist it seems to be underestimated. To support that perspective we present the casuistic of admissions in the Neurology Department of Hospitais da Universidade de Coimbra (HUC) during the first trimester of 2011 and the follow up from one to two years of all the patients that were admitted in the Stroke Unit of the HUC during 2010. We conclude that the introduction in the clinical practice of the new oral anticoagulants will allow a simplification of the proceedings in the patients with NVAF promoting, in the majority of the cases, a more marked reduction of thromboembolic events and also a reduction of their most feared complication, intracranial bleeding. PMID- 22541033 TI - [Bleeding, the Achilles' heel in patients treated with anticoagulants. Approach in patients with atrial fibrillation]. AB - Bleeding is always the Achilles' heel of all antithrombotic therapy, being unthinkable to use this type of therapy ignoring the complications that it may arise. The bleeding risk raises very particular problems, namely how to predict it and how to manage it. The withdrawal of antithrombotic drugs and transfusion are two important practical problems, involving clinical decisions that are generally very difficult. The new oral anticoagulants pose new problems. If on the one hand its bleeding risk appears to be less, specially in what concerns intracranial bleeding and potentially life-threatening bleeding, on the other hand the lack of an antidote or the lack of a quick and effective laboratory test to evaluate its efficacy, are arguments used by the critics. The risk of bleeding is conditioned by several factors, among them old age. The elderly patient is, by definition, the patient that can bleed more but also the one that, due to its ischemic risk, can reap more benefit. In this paper some of the tools used to predict the risk of bleeding and its clinical impact are also presented. PMID- 22541034 TI - [Anticoagulants and dual antiplatelet therapy combined, a challenge to our intelligence]. AB - The combination of antiplatelet and anticoagulant drugs, a common practice in the setting of acute coronary syndromes, constitutes an important practical problem involving difficult decisions, that lack support both in terms of clinical evidence (adequate clinical studies are not available) and strong guidelines. The problem was particularly aggravated from the moment when practically all the patients with acute coronary syndromes started to be submitted to double antiplatelet therapy, especially those treated with drug eluting stents. Simply reminding that 10% of these patients have or will have atrial fibrillation gives us the dimension of the problem. In this paper we discuss the benefits and risks of an eventual triple therapy and present the data obtained from the scarce evidence at our disposal, both from clinical studies and registries. The evidence about the combination of the double antiplatelet therapy with the new anticoagulants is derived from the phase II and phase III studies, conducted with dabigatran, apixaban, darexaban and rivaroxaban. The results from the only phase III study concluded with good results, the ATLAS-ACS 2 TIMI 51 study, conducted with rivaroxaban, are presented. The author also presents some of the recommendations extracted from the consensus document published on this matter by the Working Group on Thrombosis of the European Society of Cardiology. PMID- 22541035 TI - [Prevention and treatment of venous thromboembolism: the place of new oral anticoagulants]. AB - Venous thromboembolism (VTE) is still an important problem of Public Health, due to its impact in terms of morbidity, mortality, resource allocation and associated costs. In the prevention and treatment of VTE, pharmacological therapy is well defined and efficacious but has some inconveniences that leave space for improvement. Several new oral anticoagulants are being developed and tested for the prevention and treatment of VTE. The better studied are the selective Factor Xa inhibitors apixaban, rivaroxaban and edoxaban, and the thrombin antagonist dabigatran. They all are orally administrated, don't have important interactions with food or other drugs, have a convenient fixed-dose regimen and a predictable action, and dispense routine monitoring of their anticoagulant effect. The major part of them has phase III studies concluded and published. Some of them are already approved by de European Medicines Agency (EMA) and the Food and Drug Administration (FDA) and recommended by the international guidelines. Rivaroxaban is approved by the EMA for the treatment of deep venous thrombosis (DVT) and for the prevention of recurrences of DVT and pulmonary embolism. In this article the available evidences are reviewed, the place of the new oral anticoagulants is discussed and future perspectives regarding the prevention and treatment of VTE are outlined. PMID- 22541036 TI - [Anticoagulation clinics, present situation and future perspectives]. AB - There are several modalities to monitor oral anticoagulant therapy, namely: monitoring by a secondary care specialist in the hospital setting; monitoring by the general practitioner/ family doctor in the primary care setting; monitoring by private laboratories of clinical analysis; self-monitoring with point-of-care devices. In Portugal, the most frequent modality is still the hospital monitoring/anticoagulation clinics, although monitoring in the primary care/routine medical care setting has began to be implemented in some areas of the country since five years ago. Anticoagulation clinics are still actually the organizations that optimize better the clinical and laboratorial follow up of the patients anticoagulated with warfarin. In 2011, anticoagulation control quality was evaluated, in the setting of an anticoagulation clinic (Santo Antonio Hospital, Porto Hospital Center) by determining the proportion of INRs within the therapeutic range. The evaluation focused ambulatory patients, during a period of two months, corresponding to 1067 controls from 687 patients (mean age: 69+/-13 years; 54%, n=567, female gender). 71% of controls (n=756) were within the therapeutic range. 27% of controls were outside the therapeutic range, after exclusion of patients with programmed surgery or invasive proceedings. 13.8% of controls were below the therapeutic range and 8.6% (n=92) of the latter had INR <= 1.5. Above therapeutic range were 13.2% (n=139), from which 4.4% (n=46) had an INR between 5-8 and 0.3% (n=4) an INR >= 8. The group of primary care Health Centers (Portuguese acronym ACES) of the Baixo Tamega region conducted, also in 2011, an evaluation of the anticoagulant control quality, by determining the proportion of INRs within the therapeutic range. The results were similar to those found in the anticoagulation clinic of the Hospital de Santo Antonio which shows that the quality of monitoring in the primary care setting can have the same quality of the anticoagulation clinics monitoring. The introduction of the new oral anticoagulants, that don't require laboratorial monitoring constitutes a challenge. In Portugal, there is no experience yet to respond to the question if, in this new context, the anticoagulation clinics will be fundamental for the registration of patients, the evaluation of the hemorrhagic risk, the clinical follow up or the evaluation of the adherence to therapy. PMID- 22541037 TI - Efficacy of an imidacloprid/flumethrin collar against fleas and ticks on cats. AB - BACKGROUND: The objectives of the studies listed here were to ascertain the therapeutic and sustained efficacy of 10% imidacloprid (w/w) and 4.5% flumethrin (w/w) incorporated in a slow-release matrix collar, against laboratory infestations of fleas and ticks on cats. Efficacy was evaluated against the flea Ctenocephalides felis felis, and the ticks Ixodes ricinus, Amblyomma americanum and Rhipicephalus turanicus. The number of studies was so large that only a general overview can be presented in this abstract. METHODS: Preventive efficacy was evaluated by infesting groups of cats (n = 8-10) with C. felis felis and/or I. ricinus, A. americanum or R. turanicus at monthly intervals at least, for a period of up to 8 months. Efficacy against fleas was evaluated 24 to 48 h after treatment and 24 h after infestation, and against ticks at 6 h (repellent) or 48 h (acaricidal) after infestation. Efficacy against flea larvae was evaluated over a period of 8 months by incubating viable flea eggs on blanket samples after cat contact. In all cases efficacy was calculated by comparison with untreated negative control groups. RESULTS: Efficacy against fleas (24 h) generally exceeded 95% until study termination. In vitro efficacy against flea larvae exceeded 92% until Day 90 and then declined to 67% at the conclusion of the study on Day 230.Sustained acaricidal (48 h) efficacy over a period of eight months was consistently 100% against I. ricinus from Day 2 after treatment, 100% against A. americanum, except for 98.5% and 97.7% at two time-points, and between 94% and 100% against R. turanicus.From Day 2 until 8 months after treatment the repellent (6 h), efficacy was consistently 100% against I. ricinus, and between 54.8% and 85.4% against R. turanicus. CONCLUSION: The rapid insecticidal and acaricidal properties of the medicated collars against newly- acquired infestations of fleas and ticks and their sustained high levels of preventive efficacy have been clearly demonstrated. Taking into account the seasonality of fleas and ticks, the collars have the potential to prevent the transmission of vector-borne diseases and other conditions directly associated with infestation throughout the season of parasite abundance. PMID- 22541038 TI - Evaluation of FOXP3 expression in canine mammary gland tumours. AB - The expression of the transcription factor forkhead box P3 (FOXP3) was examined in 62 canine mammary gland tumours via immunohistochemical analysis and association with the known expression of the oestrogen receptor-alpha (ERalpha), progesterone receptor (PR), c-erbB-2 receptor (HER2/neu), and survival. Positive staining for FOXP3 was present in 22.6% of the tumours and was associated with the histological type. Negative staining for FOXP3 was associated with positive ERalpha and PR expression (P < 0.001). The expression of FOXP3 in canine mammary gland tumours was significantly associated with the disease-free survival time (P = 0.029). The FOXP3 expression was not an independent prognostic factor in the multivariate analysis, though. The negative expression of FOXP3 in the canine mammary gland tumours was found to be related to histopathologic benignity and a longer survival time in canine mammary gland tumours. PMID- 22541039 TI - Vocal acoustic biomarkers of depression severity and treatment response. AB - BACKGROUND: Valid, reliable biomarkers of depression severity and treatment response would provide new targets for clinical research. Noticeable differences in speech production between depressed and nondepressed patients have been suggested as a potential biomarker. METHODS: One hundred five adults with major depression were recruited into a 4-week, randomized, double-blind, placebo controlled research methodology study. An exploratory objective of the study was to evaluate the generalizability and repeatability of prior study results indicating vocal acoustic properties in speech may serve as biomarkers for depression severity and response to treatment. Speech samples, collected at baseline and study end point using an automated telephone system, were analyzed as a function of clinician-rated and patient-reported measures of depression severity and treatment response. RESULTS: Regression models of speech pattern changes associated with clinical outcomes in a prior study were found to be reliable and significant predictors of outcome in the current study, despite differences in the methodological design and implementation of the two studies. Results of the current study replicate and support findings from the prior study. Clinical changes in depressive symptoms among patients responding to the treatments provided also reflected significant differences in speech production patterns. Depressed patients who did not improve clinically showed smaller vocal acoustic changes and/or changes that were directionally opposite to treatment responders. CONCLUSIONS: This study supports the feasibility and validity of obtaining clinically important, biologically based vocal acoustic measures of depression severity and treatment response using an automated telephone system. PMID- 22541040 TI - Cigarette smoking predicts differential benefit from naltrexone for alcohol dependence. AB - BACKGROUND: Identifying factors that modify responsiveness to pharmacotherapies for alcohol dependence is important for treatment planning. Cigarette smoking predicts more severe alcohol dependence and poorer treatment response in general. Nevertheless, there is limited research on cigarette smoking as a potential predictor of differential response to pharmacological treatment of alcoholism. METHODS: We examined the association between cigarette smoking and drinking outcomes in the COMBINE (Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence) study, a randomized, double-blind placebo-controlled 16 week trial comparing combinations of medications (i.e., acamprosate and naltrexone) and behavioral interventions (i.e., medical management, combined behavioral therapy) in 1383 alcohol-dependent individuals. RESULTS: Smokers (i.e., more than one half the sample) significantly differed from nonsmokers on several demographic and drinking-related variables at baseline and generally had poorer treatment outcomes than nonsmokers. However, smokers who received naltrexone had better drinking outcomes than smokers who received placebo, whereas alcohol use among nonsmokers did not vary by naltrexone assignment. This pattern of findings occurred independent of whether patients received combined behavioral intervention or medical management and remained after controlling for alcoholism typology and baseline demographic differences. Approximately 9% of smokers quit smoking, and an additional 10% reduced their cigarette intake during treatment. Reductions in smoking did not vary by treatment assignment. CONCLUSIONS: These results suggest that naltrexone might be particularly beneficial for improving alcohol use outcomes in alcohol-dependent smokers. PMID- 22541041 TI - Development of LC-MS/MS-based receptor occupancy tracers and positron emission tomography radioligands for the nociceptin/orphanin FQ (NOP) receptor. AB - Currently, a lack of sufficient tools has limited the understanding of the relationship between neuropsychiatric disorders and the nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor. Herein, we describe the discovery and development of an antagonist NOP receptor occupancy (RO) tracer and a novel positron emission tomography (PET) radioligand suitable to probe the NOP receptor in human clinical studies. A thorough structure-activity relationship (SAR) around the high affinity 3-(2'-fluoro-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]-1 yl)-2-(2-halobenzyl)-N-alkylpropanamide scaffold identified a series of subnanomolar, highly selective NOP antagonists. Subsequently, these unlabeled NOP ligands were evaluated in vivo by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in rat to determine brain uptake, kinetics and specific binding. (S) 27 was identified as a suitable unlabeled preclinical RO tracer to accurately quantify NOP receptor engagement in rat brain. Three compounds were selected for evaluation in nonhuman primates as PET tracers: (-)-26, (-)-30, and (-)-33. Carbon-11 labeling of (+)-31 yielded [(11)C]-(S)-30, which exhibited minimal generation of central nervous system (CNS) penetrant radiometabolites, improved brain uptake, and was an excellent PET radioligand in both rat and monkey. Currently [(11)C]-(S)-30 is being evaluated as a PET radiotracer for the NOP receptor in human subjects. PMID- 22541043 TI - Minimal ovarian stimulation combined with elective single embryo transfer policy: age-specific results of a large, single-centre, Japanese cohort. AB - BACKGROUND: The two main complications associated with the use of assisted reproduction techniques, ovarian hyperstimulation syndrome and multiple pregnancies, could be eliminated by milder ovarian stimulation protocols and the increased use of a single embryo transfer (SET) policy. A retrospective, cohort study was performed in private infertility centre to evaluate the embryological and clinical results of a large exclusively SET program according to patient age (lower or equal 29, 30-34, 35-39, 40-44 and equal or higher 45 years). MATERIALS: A total of 7,244 infertile patients have undergone 20,244 cycles with a clomiphene-based minimal stimulation or natural cycle IVF protocol during 2008. Following oocyte retrieval, fertilization and embryo culture a total of 10,401 fresh or frozen single embryo transfer procedures were performed involving cleavage-stage embryos or blastocysts. RESULTS: Successful oocyte retrieval rate (78.0 %) showed no age-dependent decrease until 45 years. Fertilization (80.3 %) and cleavage (91.1 %) rates were not significantly different between age groups. Blastocyst formation (70.1 % to 22.8 %) and overall live birth rates (35.9 % to 2 %) showed an age-dependent decrease. Frozen-thawed blastocyst transfer cycles gave the highest chance of live birth per embryo transfer (41.3 % to 6.1 %). CONCLUSIONS: High fertilization and cleavage rates were obtained regardless of age whereas blastocyst formation and live birth rates showed an age-dependent decrease. An elective single embryo transfer program based on a minimal ovarian stimulation protocol yields acceptable live birth rates per embryo transfer in infertile patients up until their mid-forties. However in very advanced age patients (equal or higher 45 years old) success rates fall below 1 %. PMID- 22541042 TI - Cooperative interactions in the West Nile virus mutant swarm. AB - BACKGROUND: RNA viruses including arthropod-borne viruses (arboviruses) exist as highly genetically diverse mutant swarms within individual hosts. A more complete understanding of the phenotypic correlates of these diverse swarms is needed in order to equate RNA swarm breadth and composition to specific adaptive and evolutionary outcomes. RESULTS: Here, we determined clonal fitness landscapes of mosquito cell-adapted West Nile virus (WNV) and assessed how altering the capacity for interactions among variants affects mutant swarm dynamics and swarm fitness. Our results demonstrate that although there is significant mutational robustness in the WNV swarm, genetic diversity also corresponds to substantial phenotypic diversity in terms of relative fitness in vitro. In addition, our data demonstrate that increasing levels of co-infection can lead to widespread strain complementation, which acts to maintain high levels of phenotypic and genetic diversity and potentially slow selection for individual variants. Lastly, we show that cooperative interactions may lead to swarm fitness levels which exceed the relative fitness levels of any individual genotype. CONCLUSIONS: These studies demonstrate the profound effects variant interactions can have on arbovirus evolution and adaptation, and provide a baseline by which to study the impact of this phenomenon in natural systems. PMID- 22541045 TI - A new graphical method for the estimation of the corrected QT interval. PMID- 22541044 TI - Novel ECG criteria for right ventricular systolic dysfunction in patients with right bundle branch block. AB - BACKGROUND: Altered hemodynamics of a failing right ventricle (RV) may place stress on the right bundle branch and Purkinje network, which may be evident as conduction delay on surface electrocardiogram (ECG). We hypothesized that prolonged R' duration in lead V1 would be an indicator of RV dysfunction in patients with RBBB. METHODS: The Mayo Clinic Arizona echocardiography database was reviewed from 2007 to 2009 to identify patients with RV dysfunction and coexistent right bundle branch block (RBBB). Specific ECG features of RBBB were compared between the RV dysfunction cohort and a randomly selected control population. Features found to be predictive of RV dysfunction were then tested on 100 consecutive patients with RBBB on ECG between January and June 2010. RESULTS: In lead V1, the QRS duration was longer in the RV dysfunction cohort (164 +/- 22 ms) compared to controls (148 +/- 12 ms), predominantly due to R' prolongation (117 +/- 27 ms vs. 87 +/- 13 ms, p<.001). Retrospective analysis suggested that V1 R' duration >= 100 ms may be 82.3% specific for the presence of RV systolic dysfunction. When applied prospectively, V1 R' duration >= 100 ms yielded sensitivity and specificity of 39.0% and 82.9% respectively for detection of abnormal RV systolic function with a positive predictive value of 76.7%. CONCLUSION: Lead V1 R' duration >= 100 ms is predictive of RV systolic dysfunction in patients with RBBB. PMID- 22541046 TI - Rupatadine 10 mg in the treatment of immediate mosquito-bite allergy. AB - BACKGROUND: People frequently experience wealing and delayed papules from mosquito bites. Wealing is mediated by antisaliva IgE antibodies and histamine. Rupatadine is a new antihistamine effective in allergic rhinitis and urticaria, but the effect on mosquito-bite allergy is not known. OBJECTIVE: To determine the effectiveness of rupatadine in inmediate mosquito-bite allergy-confirmed adult patients. METHODS: A double-blind, placebo-controlled, cross-over study was performed with rupatadine 10 mg and matched placebo in 30 mosquito-bite-sensitive adults. The mean age was 37 years and the subjects had suffered from harmful mosquito bites for a mean of 15 years. Either rupatadine or placebo was taken at 08:00 am for 4 days, followed by a 5 day wash out period and then alternative treatment was given for 4 days. On day 3, in both drug periods the subjects received two Aedes aegypti mosquito-bites on the forearm. The size of lesions and intensity of pruritus [visual analogue scale (VAS)] were measured after 15 min bite reaction. RESULTS: Twenty-six subjects were analysed for efficacy. The size of the 15 min bite reaction under placebo was of 106 mm2 and under rupatadine, of 55 mm2. This is a significant decrease (48%; P=0.0003). The accompanying pruritus decreased from 60 (VAS; median) under placebo to 47.5 under rupatadine, which also is a significant (P=0.019) difference. There was no significant (P=0.263) difference in adverse events under rupatadine and placebo. CONCLUSION: The present placebo-controlled study in mosquito-bite-sensitive adults shows that rupatadine 10 mg prophylactically given is an effective treatment for the mosquito-bite wealing and skin pruritus. PMID- 22541047 TI - Complex fluid-fluid interfaces: rheology and structure. AB - Complex fluid-fluid interfaces are common to living systems, foods, personal products, and the environment. They occur wherever surface-active molecules and particles collect at fluid interfaces and render them nonlinear in their response to flow and deformation. When this occurs, the interfaces acquire a complex microstructure that must be interrogated. Interfacial rheological material properties must be measured to appreciate their role in such varied processes as lung function, cell division, and foam and emulsion stability. This review presents the methods that have been devised to determine the microstructure of complex fluid-fluid interfaces. Complex interfacial microstructure leads to rheological complexity. This behavior is often responsible for stabilizing interfacial systems such as foams and emulsions, and it can also have a profound influence on wetting/dewetting dynamics. Interfacial rheological characterization relies on the development of tools with the sensitivity to respond to small surface stresses in a way that isolates them from bulk stresses. This development is relatively recent, and reviews of methods for both shear and dilatational measurements are offered here. PMID- 22541048 TI - Sustainable engineered processes to mitigate the global arsenic crisis in drinking water: challenges and progress. AB - Millions of people around the world are currently living under the threat of developing serious health problems owing to ingestion of dangerous concentrations of arsenic through their drinking water. In many places, treatment of arsenic contaminated water is an urgent necessity owing to a lack of safe alternative sources. Sustainable production of arsenic-safe water from an arsenic contaminated raw water source is currently a challenge. Despite the successful development in the laboratory of technologies for arsenic remediation, few have been successful in the field. A sustainable arsenic-remediation technology should be robust, composed of local resources, and user-friendly as well as must attach special consideration to the social, economic, cultural, traditional, and environmental aspects of the target community. One such technology is in operation on the Indian subcontinent. Wide-scale replication of this technology with adequate improvisation can solve the arsenic crisis prevalent in the developing world. PMID- 22541049 TI - Transport phenomena in chaotic laminar flows. AB - In many important chemical processes, the laminar flow regime is inescapable and defines the performance of reactors, separators, and analytical instruments. In the emerging field of microchemical process or lab-on-a-chip, this constraint is particularly rigid. Here, we review developments in the use of chaotic laminar flows to improve common transport processes in this regime. We focus on four: mixing, interfacial transfer, axial dispersion, and spatial sampling. Our coverage demonstrates the potential for chaos to improve these processes if implemented appropriately. Throughout, we emphasize the usefulness of familiar theoretical models of transport for processes occurring in chaotic flows. Finally, we point out open challenges and opportunities in the field. PMID- 22541050 TI - Molecular evidence of Culex pipiens form molestus and hybrids pipiens/molestus in Morocco, North Africa. AB - BACKGROUND: Culex pipiens L. is the most widespread mosquito vector in temperate regions including North Africa. Cx. pipiens has two recognized forms or biotypes; pipiens and molestus are morphologically indistinguishable with distinct behavior and physiology that may influence their vectorial status. In our study, we prospected for the different forms of Cx. pipiens in Morocco. METHODS: Cx. pipiens larvae were collected in 9 sites throughout Morocco during summer 2010 and reared until imago stage. Cx. pipiens was identified using diagnostic primers designed for the flanking region of microsatellite CQ11. RESULTS: We established the presence of both forms of Cx. pipiens and their hybrids in Morocco. CONCLUSIONS: Molecular identification provides the first evidence of the presence of Cx. pipiens form molestus in Morocco and hybrids between pipiens and molestus forms in North Africa. The epidemiological implications of our findings are discussed. PMID- 22541051 TI - Synthesis, biological evaluation and molecular docking studies of novel 2-(1,3,4 oxadiazol-2-ylthio)-1-phenylethanone derivatives. AB - In present study, a series of new 2-(1,3,4-oxadiazol-2-ylthio)-1-phenylethanone derivatives (6a-6x) as potential focal adhesion kinase (FAK) inhibitors were synthesized. The bioassay assays demonstrated that compound 6i showed the most potent activity, which inhibited the growth of MCF-7 and A431 cell lines with IC(50) values of 140 +/- 10 nM and 10 +/- 1 nM, respectively. Compound 6i also exhibited significant FAK inhibitory activity (IC(50)=20 +/- 1 nM). Docking simulation was performed to position compound 6i into the active site of FAK to determine the probable binding model. PMID- 22541052 TI - Genetic basis of transcriptome differences between the founder strains of the rat HXB/BXH recombinant inbred panel. AB - BACKGROUND: With the advent of next generation sequencing it has become possible to detect genomic variation on a large scale. However, predicting which genomic variants are damaging to gene function remains a challenge, as knowledge of the effects of genomic variation on gene expression is still limited. Recombinant inbred panels are powerful tools to study the cis and trans effects of genetic variation on molecular phenotypes such as gene expression. RESULTS: We generated a comprehensive inventory of genomic differences between the two founder strains of the rat HXB/BXH recombinant inbred panel: SHR/OlaIpcv and BN-Lx/Cub. We identified 3.2 million single nucleotide variants, 425,924 small insertions and deletions, 907 copy number changes and 1,094 large structural genetic variants. RNA-sequencing analyses on liver tissue of the two strains identified 532 differentially expressed genes and 40 alterations in transcript structure. We identified both coding and non-coding variants that correlate with differential expression and alternative splicing. Furthermore, structural variants, in particular gene duplications, show a strong correlation with transcriptome alterations. CONCLUSIONS: We show that the panel is a good model for assessing the genetic basis of phenotypic heterogeneity and for providing insights into possible underlying molecular mechanisms. Our results reveal a high diversity and complexity underlying quantitative and qualitative transcriptional differences. PMID- 22541053 TI - TaqIA polymorphism in dopamine D2 receptor gene complicates weight maintenance in younger obese patients. AB - OBJECTIVE: The A1 allele of the TaqIA polymorphism in the dopamine D2 receptor gene (rs1800497) has been associated with obesity. However, the effect of the polymorphism on the success in weight loss and/or weight maintenance during weight-loss programs has not been evaluated thus far. METHODS: The rs1800497 was genotyped in 202 (135 female, 67 male) severely obese individuals with an initial body mass index of 41.7 +/- 0.5 kg/m2 who participated in a weight-loss program consisting of a weight-loss phase with a formula diet (12 wk) and a weight maintenance phase (40 wk). Measurements were collected at baseline, after the weight-loss phase, and at the end of the weight-maintenance phase at 1 y. RESULTS: Genotyping revealed 4 A1A1, 67 A1A2, and 131 A2A2 genotype carriers. Of the 202 subjects in the program, 66.8% completed the program and 33.2% terminated prematurely. Neither the attrition rate (P = 0.44) nor the overall weight loss was influenced by the different genotypes (P = 0.96). However, younger A1+ participants (A1A1 and A1A2) had a higher body mass index at all time points (baseline, P = 0.04; after weight loss, P = 0.05; after weight maintenance, P = 0.02). They also showed less overall weight loss (P = 0.05), which derived mainly from a greater weight regain during the maintenance phase (P = 0.02). CONCLUSION: In this program, younger A1+ participants exhibited problems in maintaining weight loss during a weight-loss program. PMID- 22541054 TI - Effect of suboptimal breast-feeding on occurrence of autism: a case-control study. AB - OBJECTIVE: To evaluate the association between suboptimal breast-feeding practices and autism spectrum disorders (ASDs). METHODS: A case-control study was conducted in 102 ASD cases and 102 matched healthy controls. RESULTS: Based on adjusted odds ratios from logistic regression models, ASD was found to be associated with the late initiation of breast-feeding (odds ratio 1.48, 95% confidence interval 1.01-3.1), a non-intake of colostrum (odds ratio 1.7, 95% confidence interval 1.03-4.3), prelacteal feeding, and bottle-feeding. The risk of ASD was found to decrease in a dose-response fashion over increasing periods of exclusive breast-feeding (P for trend = 0.04) and continued breast-feeding (P for trend = 0.001). CONCLUSION: The study indicates that increased ASD risk is generally associated with suboptimal breast-feeding practices. PMID- 22541055 TI - Eicosapentaenoic and docosahexaenoic acids, cognition, and behavior in children with attention-deficit/hyperactivity disorder: a randomized controlled trial. AB - OBJECTIVE: To determine the effects of an eicosapentaenoic acid (EPA)-rich oil and a docosahexaenoic acid (DHA)-rich oil versus an omega-6 polyunsaturated fatty acid-rich safflower oil (control) on literacy and behavior in children with attention-deficit/hyperactivity disorder (ADHD) in a randomized controlled trial. METHODS: Supplements rich in EPA, DHA, or safflower oil were randomly allocated for 4 mo to 90 Australian children 7 to 12 y old with ADHD symptoms higher than the 90th percentile on the Conners Rating Scales. The effect of supplementation on cognition, literacy, and parent-rated behavior was assessed by linear mixed modeling. Pearson correlations determined associations between the changes in outcome measurements and the erythrocyte fatty acid content (percentage of total) from baseline to 4 mo. RESULTS: There were no significant differences between the supplement groups in the primary outcomes after 4 mo. However, the erythrocyte fatty acid profiles indicated that an increased proportion of DHA was associated with improved word reading (r = 0.394) and lower parent ratings of oppositional behavior (r = 0.392). These effects were more evident in a subgroup of 17 children with learning difficulties: an increased erythrocyte DHA was associated with improved word reading (r = 0.683), improved spelling (r = 0.556), an improved ability to divide attention (r = 0.676), and lower parent ratings of oppositional behavior (r = 0.777), hyperactivity (r = 0.702), restlessness (r = 0.705), and overall ADHD symptoms (r = 0.665). CONCLUSION: Increases in erythrocyte omega-3 polyunsaturated fatty acids, specifically DHA, may improve literacy and behavior in children with ADHD. The greatest benefit may be observed in children who have comorbid learning difficulties. PMID- 22541056 TI - Lung anabolic activity in patients with chronic heart failure: potential implications for clinical practice. AB - OBJECTIVE: The proteins in the lungs are in constant flux, undergoing degradation and resynthesis. We investigated pulmonary protein and amino acid metabolism, the biochemical basis of the remodeling process, in individuals with chronic heart failure receiving or not receiving beta-blocker therapy with bisoprolol (BIS). METHODS: Clinically stable rehabilitative patients with chronic heart failure, without metabolic diseases or liver/renal failure, and with a stable weight over the preceding 3 mo underwent right heart catheterization, and radial artery cannulation. Mixed central venous and arterial blood samples were drawn simultaneously to calculate the venous-arterial difference of amino acids (pulmonary uptake and release). RESULTS: Twenty-two patients on BIS therapy and eight not receiving BIS were analyzed. The two groups showed a net pulmonary protein synthesis (i.e., a positive value of phenylalanine [venous-arterial difference] * cardiac index product) and amino acid extraction, the rates of which were significantly lower in patients on BIS therapy. The two groups had pulmonary hypertension (mean pulmonary artery pressure >19 mmHg). Pulmonary vascular resistance was 57% higher in patients not receiving BIS than in those on BIS therapy (6.65 +/- 2.90 versus 4.23 +/- 1.49 mmHg/L . min-1 . m-2, P < 0.05). Pulmonary vascular resistance correlated positively with the pulmonary extraction of total essential amino acids (r = +0.4576, P = 0.01) and leucine (r = +0.5083, P = 0.004), the most important amino acid for protein synthesis. CONCLUSION: Patients with chronic heart failure have increased rates of amino acid extraction and pulmonary protein synthesis, suggesting, at least in part, an increased rate of lung remodeling. Therapy with BIS attenuates lung metabolic abnormalities. PMID- 22541057 TI - Polysaccharides from extracts of Antrodia camphorata mycelia and fruiting bodies modulate inflammatory mediator expression in mice with polymicrobial sepsis. AB - OBJECTIVES: Antrodia camphorata (AC) is a traditional Chinese medicine, and the polysaccharides contained within AC (AC-PSs) are reported to possess various biological functions. This study extracted AC-PSs from mycelia and fruiting bodies and evaluated their influences on inflammatory mediator expressions in septic mice. METHODS: There were one normal control (NC) and three experimental groups. The normal control group underwent a sham operation, whereas the experimental groups underwent cecal ligation and puncture (CLP) to induce sepsis. Mice in the experimental groups were further divided into saline, mycelia, and fruiting body treatment groups. Saline or AC-PSs were injected intraperitoneally twice at 0.5 and 1 h after CLP and the mice were sacrificed at 6 or 16 h after sepsis for further analysis. RESULTS: Compared with the normal control group, interleukin (IL)-6, tumor necrosis factor-alpha, IL-10, and monocyte chemotactic protein-1 levels in plasma and/or peritoneal lavage fluid in the septic mice dramatically increased after CLP. The increased levels of these inflammatory mediators in the two AC-PS-treated groups had decreased by 16 h after CLP. Messenger RNA expressions of tumor necrosis factor-alpha, IL-6, and IL-10 in the splenocytes were lower in the 2 AC-PS-treated groups than in the saline group. Consistent with the results, lung nuclear factor-kappaB expressions decreased and less severe interstitial inflammation was observed in the histologic finding after CLP in mice that had received AC-PSs. The fruiting body group had higher white blood cell counts and lower IL-6 levels in the peritoneal lavage fluid 6 h after CLP, whereas the interferon-gamma level was higher 16 h after CLP than in the saline group. These alterations were not found in mice injected with the mycelia extract. CONCLUSION: The administration of AC-PSs from mycelia or fruiting bodies decreased the inflammatory mediator expressions at the location of injury and in the circulation, especially in the late stage of sepsis. AC-PSs from fruiting bodies seemed to be more effective in decreasing the inflammatory response than those from mycelia. These findings suggest that AC-PSs from mycelia and fruiting bodies have potential protective effects against polymicrobial sepsis. PMID- 22541058 TI - Comparative proteomic analysis of human whole saliva of children with protein energy undernutrition. AB - OBJECTIVE: The aim of the present study was to investigate the protein profile of children with different levels of protein-energy undernutrition (PEU) through a proteomic approach of human whole saliva. METHODS: Initially, saliva samples of children with mild, moderate, and severe PEU were collected and lyophilized. Saliva samples of healthy children were used as controls. Samples were analyzed for total protein using the Bradford method. Saliva samples were analyzed by two dimensional electrophoresis according to their isoelectric point (pI) and their molecular weights (MWs). RESULTS: Comparisons of protein bands among the healthy and mildly, moderately, and severely undernourished children showed significant differences in the MWs (P = 0.001) and pI values (P = 0.03). In total 159 spots were identified in the healthy children; 156, 168, and 221 spots were observed in mildly, moderately, and severely undernourished children, respectively. Mildly undernourished children presented with the spot with the highest MW of 293 kDa (pI = 7.77) and the lowest MW of 5 kDa (pI = 4.83). Moderately undernourished children were the only ones who did not present with a protein band with an MW of 30 kDa. The presence of a protein band with an MW of 123 kDa (pI = 516), possibly a cyclin-dependent protein kinase, was also observed only in this group. CONCLUSION: The protein profile in saliva varies according to the presence or absence of PEU, and these variations are specifically expressed in different grades of undernutrition. Thus, saliva may be an important diagnostic tool for the assessment of PEU. PMID- 22541059 TI - Dietary energy density is favorably associated with dietary diversity score among female university students in Isfahan. AB - OBJECTIVE: To report the relation between dietary energy density and dietary diversity score (DDS) in Isfahanian female university students. METHODS: This cross-sectional study was conducted in 289 healthy females who were randomly chosen by a cluster random sampling method from among students at Isfahan University of Medical Sciences, Isfahan, Iran. A validated semiquantitative food frequency questionnaire was used to assess the usual dietary intake. Dietary energy density was calculated as an individual's reported daily energy intake (kilocalories per day) per total weight of foods (excluding beverages) consumed (grams per day). The DDS was calculated based on the scoring of the five food groups of the Food Guide Pyramid. RESULTS: The mean dietary energy density was 1.60 +/- 0.29 kcal/g. Individuals in the top tertile of dietary energy density had the lowest mean DDS (means among tertiles: first, 9.61 +/- 1.92; second, 6.98 +/- 1.22; third, 3.63 +/- 1.02; P < 0.05) and diversity scores of vegetables (1.91 +/- 0.33, 1.54 +/- 0.26, 1.11 +/- 0.2, P < 0.01) and fruit (1.98 +/- 0.72, 1.89 +/- 0.66, 1.44 +/- 0.3, P < 0.05). Those in the top tertile of the DDS had the lowest mean dietary energy density (2.08 +/- 0.36, 1.69 +/- 0.31, 1.38 +/- 0.25 kcal/g, P < 0.05). There was an inverse and significant association between dietary energy density and DDS (r = -0.3, P = 0.03). CONCLUSION: There was inverse significant association between the DDS and dietary energy density in Isfahanian female university students. Further prospective investigations will be needed to confirm this finding. PMID- 22541060 TI - beta-2 spectrin is involved in hepatocyte proliferation through the interaction of TGFbeta/Smad and PI3K/AKT signalling. AB - BACKGROUND: Transforming growth factor (TGF) beta signalling pathway plays a crucial role in liver regeneration following partial hepatectomy in mice. Evidence demonstrated that beta-2 Spectrin is involved in TGFbeta/Smad signalling pathway as a Smad3/4 adaptor protein. AIM: The aim of this study was to explore the role of beta-2 Spectrin in hepatocyte proliferation. METHODS: beta-2 Spectrin expression was evaluated in mice receiving partial hepatectomy. The effect of siRNA against beta-2 Spectrin on hepatocyte proliferation was determined. The interaction between TGFbeta/Smad and PI3K/Akt signalling was investigated. RESULTS: Hepatic beta-2 Spectrin decreased dramatically 2 days after 70% hepatectomy in mice. In AML-12 cells, hepatocyte proliferation was inhibited after the stimulation of TGF beta1 and a reduction in beta-2 Spectrin mediated by siRNA resulted in increase in proliferative response. Confocal results revealed that beta-2 Spectrin represented a key regulator in TGFbeta/Smad signalling through controlling Smad3/4 subcellular localization. Moreover, Alternation of Akt phosphorylation led to the change in subcellular localization of Smad2, 3, 4 and beta-2 Spectrin, A reduction in Smad2, 3 and 4 mediated by siRNA resulted in the induction of pAkt expression. CONCLUSIONS: These findings reveal that beta-2 Spectrin plays a crucial role in hepatocyte proliferation, which contributes to liver regeneration following hepatectomy in mice. In addition, PI3K/Akt is involved in TGFbeta/Smad signalling pathway through the interaction with Smad proteins and beta-2 Spectrin. PMID- 22541061 TI - Experimental assessment of the influence of beam hardening filters on image quality and patient dose in volumetric 64-slice X-ray CT scanners. AB - Beam hardening filters have long been employed in X-ray Computed Tomography (CT) to preferentially absorb soft and low-energy X-rays having no or little contribution to image formation, thus allowing the reduction of patient dose and beam hardening artefacts. In this work, we studied the influence of additional copper (Cu) and aluminium (Al) flat filters on patient dose and image quality and seek an optimum filter thickness for the GE LightSpeed VCT 64-slice CT scanner using experimental phantom measurements. Different thicknesses of Cu and Al filters (0.5-1.6mm Cu, 0.5-4mm Al) were installed on the scanner's collimator. A planar phantom consisting of 13 slabs of Cu having different thicknesses was designed and scanned to assess the impact of beam filtration on contrast in the intensity domain (CT detector's output). To assess image contrast and image noise, a cylindrical phantom consisting of a polyethylene cylinder having 16 holes filled with different concentrations of K2HPO4 solution mimicking different tissue types was used. The GE performance and the standard head CT dose index (CTDI) phantoms were also used to assess image resolution characterized by the modulation transfer function (MTF) and patient dose defined by the weighted CTDI. A 100mm pencil ionization chamber was used for CTDI measurement. Finally, an optimum filter thickness was determined from an objective figure of merit (FOM) metric. The results show that the contrast is somewhat compromised with filter thickness in both the planar and cylindrical phantoms. The contrast of the K2HPO4 solutions in the cylindrical phantom was degraded by up to 10% for a 0.68mm Cu filter and 6% for a 4.14mm Al filter. It was shown that additional filters increase image noise which impaired the detectability of low density K2HPO4 solutions. It was found that with a 0.48mm Cu filter the 50% MTF value is shifted by about 0.77lp/cm compared to the case where the filter is not used. An added Cu filter with approximately 0.5mm thickness accounts for 50% reduction in radiation absorbed dose as measured by the weighted CTDI. The FOM results indicate that with an additional filter of 0.5mm Cu or minimum 4mm Al, a good compromise between image quality and patient dose is achieved for CT images acquired at tube voltages of 120 and 140kVp. The results seem to indicate that an optimum filter for high kVp acquisitions, routinely used in cardiovascular imaging, should be 0.5mm copper or 4mm aluminium minimum. PMID- 22541062 TI - Other genetic liver diseases in children. AB - Wilson disease is rare but proteiform, and should be suspected in any child with liver disease and older than 3 years of age. The treatment is very efficient, and must be taken life-long. Fifteen percent of patients with alpha-1-antitrypsin deficiency develop a neonatal jaundice, and 3% a cirrhosis in childhood. There is no specific treatment except liver transplantation. Five percent of cystic fibrosis patients develop a cirrhosis, with a very slow progression. Milder abnormalities are frequent, as well as biliary stones. Liver disease in ciliopathies may be a congenital hepatic fibrosis, with risks of portal hypertension and cholangitis, or a more variable biliary disease. Gilbert disease is frequent and benign. Crigler-Najjar syndrome is rare, severe, and may be an indication for liver or liver-cell transplantation. PMID- 22541063 TI - Liver transplantation and liver cell transplantation. AB - Liver transplantation is nowadays the recognized treatment of many liver diseases and liver-based metabolic disorders in childhood. The indications are congenital cholestatic diseases, mainly biliary atresia, metabolic disorders and fulminant hepatic failure. Potential candidates have to be evaluated early in a specialized center, as the survival rate is worse if the child is transplanted with end-stage liver failure. The graft is in most cases partial, either a split liver from a deceased donor (the other part going to an adult recipient), or the left lobe or left liver from a living donor. The patient's survival rate is about 80-90% at 1 year, 70-80% at 10 years, and the graft survival rate 60-70% at 10 years. Immuno suppression depends on a calcineurin inhibitor (cyclosporin or tacrolimus), and either steroids or an induction with a monoclonal antibody against IL2-receptor. Early surgical complications are a non-function of the graft (rare), arterial or portal thrombosis, biliary problems (more frequent with partial grafts), bleeding. Infections with bacteria and fungi are frequent and often severe. CMV infection is prevented, or screened and preemptively treated. EBV infection is frequent and may induce a posttransplant lymphoproliferative disease, that can develop into a lymphoma. Early stages are treated with reduction of immuno suppression and monoclonal antibodies against CD20. Acute rejection is frequent but usually easily controlled. Chronic rejection may be due to poor compliance. Late graft loss is due to chronic rejection or long-standing biliary complications. Long-term complications are progressive graft fibrosis, renal failure due to drug toxicity (mainly calcineurin inhibitors), and cancers (skin and lymphoma). PMID- 22541064 TI - Impact of age over 75 years on outcomes after pancreaticoduodenectomy. AB - BACKGROUND: The risks associated with pancreaticoduodenectomy (PD) in elderly patients continue to be debated. The aim of our study was to assess the incidence of death and postoperative complications following PD and identify the risk factors in patients >75 y. STUDY DESIGN: All patients who underwent PD between January 2000 and September 2009 were analyzed retrospectively. Patients were divided into two groups according to age (Group 1: patients aged <75 y, and Group 2: patients aged >= 75 y). Morbidity and perioperative mortality risk factors were analyzed using univariate and multivariate analyses. RESULTS: Among the 314 patients, 273 were included in Group 1 (sex ratio 1.4) and 41 in Group 2 (sex ratio 1). In multivariate analysis, postoperative hemorrhage (PH) (OR 6.61, IC95% [1.96; 22.31], P = 0.002) and age >75 y proved to be predictive factors for mortality (OR 11.04, IC95% [2.57; 47.49], P = 0.001). When compared with Group 1, Group 2 was associated with increased postoperative deaths (24.4% versus 3.66%, P < 0.001) and pancreatic fistulas (26.8% versus 13.2%, P = 0.041), in particular, Grade C fistulas (14.6% versus 4.4%, P = 0.023). In multivariate analysis, only PH proved to be an independent predictive factor for mortality (OR 12.9, IC95% [1.07; 155.5], P = 0.04). CONCLUSIONS: PD in elderly patients aged over 75 y appears to be associated with an increased risk of postoperative death and pancreatic fistula. No single preoperative factor made it possible to predict this risk. PMID- 22541065 TI - Preoperative mediastinal and hilar nodal staging with diffusion-weighted magnetic resonance imaging and fluorodeoxyglucose positron emission tomography/computed tomography in patients with non-small-cell lung cancer: which is better? AB - BACKGROUND: To compare the diagnostic capability of diffusion-weighted magnetic resonance imaging (DWI) and (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) in the N stage assessment in patients with non-small-cell lung cancer. METHODS: We performed a meta-analysis of all available studies of the diagnostic performance of DWI and (18)F-FDG PET/CT in the N stage assessment of patients with non-small-cell lung cancer. We determined the sensitivity and specificity across studies, calculated the positive and negative likelihood ratios (LR+ and LR-, respectively), and constructed the summary receiver operating characteristic curves using hierarchical regression models. The methodologic quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool. RESULTS: A total of 19 studies met the inclusion criteria and included a total of 2845 pathologically confirmed patients. No publication bias was found. The methodologic quality was relatively high. The pooled sensitivity estimate of DWI (0.72, 95% confidence interval [CI] 0.63-0.80) was not significantly difference between PET/CT (0.75, 95% CI 0.68-0.81; P = 0.09). The pooled specificity estimate for DWI (0.95, 95% CI 0.85-0.98) was significantly greater than (18)F-FDG PET/CT (0.89, 95% CI 0.85 0.91; P = 0.02). For DWI, the overall LR+ was 13.80 (95% CI 4.54-41.95) and the LR- was 0.29 (95% CI 0.21-0.40). For (18)F-FDG PET/CT, LR+ was 6.67 (95% CI 5.20 8.56) and LR- was 0.28 (95% CI 0.22-0.37). CONCLUSIONS: Our study has confirmed that DWI has a high specificity for N staging of non-small-cell lung cancer compared with (18)F-FDG PET/CT and has the potential to be a reliable alternative noninvasive imaging method for the preoperative staging of mediastinal and hilar lymph nodes in patients with non-small-cell lung cancer. PMID- 22541066 TI - Ribonucleotide reductase inhibition restores platinum-sensitivity in platinum resistant ovarian cancer: a Gynecologic Oncology Group Study. AB - BACKGROUND: The potent ribonucleotide reductase (RNR) inhibitor 3-aminopyridine-2 carboxyaldehyde-thiosemicarbazone (3-AP) was tested as a chemosensitizer for restored cisplatin-mediated cytotoxicity in platinum-resistant ovarian cancer. METHODS: Preclinical in vitro platinum-resistant ovarian cancer cell survival, RNR activity, and DNA damage assays were done after cisplatin or cisplatin plus 3 AP treatments. Six women with platinum-resistant ovarian cancer underwent four day 3-AP (96 mg/m(2), day one to four) and cisplatin (25 mg/m(2), day two and three) infusions every 21 days until disease progression or adverse effects prohibited further therapy. Pre-therapy ovarian cancer tissues were analyzed by immunohistochemistry for RNR subunit expression as an indicator of cisplatin plus 3-AP treatment response. RESULTS: 3-AP preceding cisplatin exposure in platinum resistant ovarian cancer cells was not as effective as sequencing cisplatin plus 3-AP together in cell survival assays. Platinum-mediated DNA damage (i.e., gammaH2AX foci) resolved quickly after cisplatin-alone or 3-AP preceding cisplatin exposure, but persisted after a cisplatin plus 3-AP sequence. On trial, 25 four-day overlapping 3-AP and cisplatin cycles were administered to six women (median 4.2 cycles per patient). 3-AP-related methemoglobinemia (range seven to 10%) occurred in two (33%) of six women, halting trial accrual. CONCLUSIONS: When sequenced cisplatin plus 3-AP, RNR inhibition restored platinum-sensitivity in platinum-resistant ovarian cancers. 3-AP (96 mg/m(2)) infusions produced modest methemoglobinemia, the expected consequence of ribonucleotide reductase inhibitors disrupting collateral proteins containing iron. TRIAL REGISTRY: ClinicalTrials.gov NCT00081276. PMID- 22541067 TI - Diagnostics, surveillance and management of sexually transmitted infections in Europe have to be improved: lessons from the European Conference of National Strategies for Chlamydia Trachomatis and Human Papillomavirus (NSCP conference) in Latvia, 2011. AB - BACKGROUND: There is an urgent need for the recognition of sexually transmitted infections (STIs) as a serious public health problem in Europe. The lack of standardization in testing, along with poor reporting and surveillance mechanisms, have resulted in low reported rates of STIs in many European Union (EU) countries, reinforcing the erroneous assumption that STIs are not a major problem. Testing and diagnosis of STIs must therefore be improved and enhanced. RECOMMENDATIONS: Reporting of Chlamydia trachomatis infection, gonorrhoea and syphilis should be mandatory, and an integrated surveillance system for C. trachomatis implemented in all European countries. Implementation of the European Centre for Disease Prevention and Control (ECDC) surveillance mechanisms for STIs in all EU countries is highly recommended. A necessary component for successful introduction of the HPV vaccine, as with any vaccination programme is a well planned and organized information campaign. PMID- 22541068 TI - Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions. AB - The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors. PMID- 22541069 TI - A long ncRNA links copy number variation to a polycomb/trithorax epigenetic switch in FSHD muscular dystrophy. AB - Repetitive sequences account for more than 50% of the human genome. Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disease associated with reduction in the copy number of the D4Z4 repeat mapping to 4q35. By an unknown mechanism, D4Z4 deletion causes an epigenetic switch leading to de repression of 4q35 genes. Here we show that the Polycomb group of epigenetic repressors targets D4Z4 in healthy subjects and that D4Z4 deletion is associated with reduced Polycomb silencing in FSHD patients. We identify DBE-T, a chromatin associated noncoding RNA produced selectively in FSHD patients that coordinates de-repression of 4q35 genes. DBE-T recruits the Trithorax group protein Ash1L to the FSHD locus, driving histone H3 lysine 36 dimethylation, chromatin remodeling, and 4q35 gene transcription. This study provides insights into the biological function of repetitive sequences in regulating gene expression and shows how mutations of such elements can influence the progression of a human genetic disease. PMID- 22541072 TI - [Effects of gossypol acetate on apoptosis in primary cultured cells from patients with lymphoid leukemia and its synergy with dexamethasone]. AB - To investigate the effects of gossypol acetate on apoptosis in primary cultured cells from patients with acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL) and its synergistic effect with dexamethasone. The apoptosis-inducing effect of gossypol acetate on primary cultured leukemia cells was analyzed by flow cytometry (FCM). The effect of gossypol acetate on survival rates of Raji cells and mononuclear cells (MNC) from normal bone marrow were evaluated by MTT assay. After co-treatment with gossypol acetate and dexamethasone, the apoptosis rate of Raji cells was detected by FCM. The results showed that gossypol acetate was able to induce apoptosis in primary cultured ALL cells at concentrations of >= 5 umol/L. The effect was concentration and time dependent. Apoptosis-inducing concentration in CLL cells was higher than that in ALL cells. After exposing to 50 umol/L gossypol acetate for 48 h, the apoptosis rate of ALL and CLL cells were (90.4 +/- 6.2)% and (51.7 +/- 10.3)% separately. No major growth inhibitory effect was observed in MNC from normal bone marrow when they were exposed to gossypol acetate at concentrations lower than 10 umol/L. After exposing for 48 and 72 h, the IC(50) of gossypol acetate for MNC from normal bone marrow was 7.1 and 9.1 times as much as the IC(50) of Raji cells. Co-treatment with 10 umol/L gossypol acetate and dexamethasone remarkably increased the apoptosis rate of Raji cells. It is concluded that the gossypol acetate has apoptosis-inducing activity in primary cultured leukemia cells from patients diagnosed as ALL and CLL in vitro. The inhibitory effect of gossypol acetate on MNC from normal bone marrow is less prominent than that on Raji cells. Co-treatment with gossypol acetate and dexamethasone notably amplified the pro apoptosis activity of the latter in Raji cells. PMID- 22541071 TI - Acute hemodialysis complications in end-stage renal disease patients: the burden and implications for the under-resourced Sub-Saharan African health systems. AB - Little is known about the challenges of routine renal replacement therapy in Sub Saharan Africa. We investigated the fatal and nonfatal acute hemodialysis (HD) complications in patients with end-stage renal disease (ESRD) in two main dialysis centers in Cameroon. 1000 consecutive HD sessions incurred over a 4 month period by 129 patients (96 men, 74%) with ESRD, receiving two weekly HD sessions of 4 hours each, were considered. Personal and clinical profiles before, during, and within 24 hours after HD sessions were used to diagnose complications. Participants were aged 7 to 80 years (mean 46 years). In all, 452 acute complications were recorded in 411 (41%) of the 1000 HD sessions. Of the 11 types of complications, hypotension (25%), muscular cramps (22%), hypertensive crisis (14%), pruritus (10%), and fever (7%) were the most frequent. Three hundred and six complications (67.7%) occurred during understaffed nighttime. The vascular access was the main bleeding site with 64%. Being diabetic and ultrafiltration rate >1000 mL/h were associated with hypotension and muscle cramps. The shorter duration in dialysis was associated with the risk of bleeding and the disequilibrium syndrome while longer duration was associated with muscle cramps. Four deaths (three from bleeding and one from disequilibrium syndrome) occurred, all during nighttime. Nearly half of dialysis sessions in these settings are associated with acute complications, some of which are fatal. Those complications occurred mostly during understaffed periods. Urgent strategies are needed to quickly solve the human capital crisis in the health care sector. PMID- 22541070 TI - DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88. AB - Alu RNA accumulation due to DICER1 deficiency in the retinal pigmented epithelium (RPE) is implicated in geographic atrophy (GA), an advanced form of age-related macular degeneration that causes blindness in millions of individuals. The mechanism of Alu RNA-induced cytotoxicity is unknown. Here we show that DICER1 deficit or Alu RNA exposure activates the NLRP3 inflammasome and triggers TLR independent MyD88 signaling via IL18 in the RPE. Genetic or pharmacological inhibition of inflammasome components (NLRP3, Pycard, Caspase-1), MyD88, or IL18 prevents RPE degeneration induced by DICER1 loss or Alu RNA exposure. These findings, coupled with our observation that human GA RPE contains elevated amounts of NLRP3, PYCARD, and IL18 and evidence of increased Caspase-1 and MyD88 activation, provide a rationale for targeting this pathway in GA. Our findings also reveal a function of the inflammasome outside the immune system and an immunomodulatory action of mobile elements. PMID- 22541073 TI - [Suppression of NAMPT expression enhances the sensitivity of K562 cells to imatinib and its relative mechanism]. AB - The aim of this study was to investigate the effect of suppression of nicotinamide phosphoribosyltransferase (NAMPT) expression on imatinib-sensitivity in chronic myelogenous leukemia (CML) cell line K562 and its mechanisms, NAMPT siRNA was synthesized and transfected into K562 cells. PI/Calcein staining technique was used to determine survival rate of transfected K562 cells at 48th hour after exposure to 1 umol/L imatinib. MTS method was used to determine the proliferation changes of transfected K562 cell at 48th hour after exposure to different doses of imatinib, then half inhibitory concentration (IC(50)) was calculated. Expression of NAMPT at 3rd-48th hour after exposure to 1 umol/L imatinib was determined by Western blot. To explore the effect of NAMPT-siRNA and imatinib on the expression of apoptosis-related genes, the microarray data from NCBI GEO Data-Sets was analyzed, then the results were confirmed by Western blot. The luciferase reporter assay was used to determine the effect of NAMPT and imatinib on transcriptional activity of NF-kappaB transcription factors. The results showed that after exposure to 1 umol/L imatinib for 3 - 48 h, there was no significant change of NAMPT expression in K562 cells. The expression of NAMPT could be effectively inhibited by the NAMPT-siRNA. After exposure to 1 umol/L of imatinib for 48 h, the survival rate of NAMPT-siRNA interference group was lower than that of negative control group (P < 0.05), indicating that suppression of NAMPT expression can increase the sensitivity of K562 cells to imatinib and enhance the killing effect of imatinib on K562 cells. The IC(50) of imatinib in NAMPT-siRNA interference group was the lowest compared with that of control group (P < 0.05) after exposure to different concentrations of imatinib for 48 h, the fitted survival curves showed that the slope of NAMPT-siRNA interference group was the largest ranging between 0.01 - 0.1 umol/L of imatinib. Data mining of expression profiling indicated that the anti-apoptotic factor Bcl-2 decreased in K562 cells treated with either NAMPT-siRNA or imatinib, which was confirmed by Western blot. The inhibitory effect was much more significant when both NAMPT siRNA and imatinib were used. The results of luciferase reporter assay showed that either NAMPT-siRNA or imatinib decreased transcriptional activity of NF kappaB. The decreased effect was much more significant when both NAMPT-siRNA and imatinib were used. It is concluded that survival of K562 cells affected by imatinib may not be due to regulation of expression of NAMPT. When expression of NAMPT decreases, the K562 cells are more sensitive to imatinib, this may be related with the decreased transcriptional activity of NF-kappaB and its downstream effector Bcl-2. PMID- 22541074 TI - [Influence of pre-ALIP number and its distance from trabeculae on AML relapse]. AB - This study was purposed to detect the abnormal quantity and localization of pre ALIP in bone marrow of acute myelocytic leukemia patients (AML) during the complete remission (CR) and investigate their correlation with AML relapse. The bone marrow biopsy and prognosis of 62 patients with CR were retrospectively analyzed. The bone marrow was divided into the pre-relapse group and the no relapse group according to prognosis of patients. In order to clarify the correlation of abnormal quantity and localization of pre-ALIP with AML relapse, the number of single and double-cluster precursor cells and the sum of both were calculated, and their distance from bone trabeculae was surveyed with the computer image segment method. The results showed that the number of pre-ALIP in pre-relapse group (11 +/- 11.71/mm(2)) and no-relapse group (8.33 +/- 9.17/mm(2)) were more than that in normal control group (5.29 +/- 4.00) (P < 0.01). The number of pre-ALIP more than 11/mm(2) was observed in 17 among all AML patients, and out of them 12 patients with pre-ALIP number >11/mm(2) (70.6) were found in the pre-relapse group, which was higher than that in no-relapse group (P < 0.05). While the distance between pre-ALIP and trabeculae [(341.31 +/- 266.16) um] in pre-relapse group showed the tendency of migrating to the intermediate zone of bone trabeculae, compared with that in no-relapse group [(242.41 +/- 174.65) um, P < 0.01]. Moreover, about 77.8 of 18 patients showed the distance of pre-ALIP from trabeculae was more than 341 um in the pre-relapse group, and significantly higher than that in no-relapse group (P < 0.01). It is concluded that the average number of "pre-ALIP" more than 11/mm(2) or the average distance from trabeculae longer than 341 um in bone marrow sections during CR may be the indicators for early relapse of AML. PMID- 22541075 TI - [Effects of advanced glycosylation end products and tetrandrine on proliferation of K562 and K562/A02 cells]. AB - This study was aimed to investigate the effect of advanced glycosylation end products (AGE) on the proliferation of K562 and K562/A02 cells, the effect of tetrandrine (Tet) on proliferation of K562 and K562/A02 cells induced by AGE, and their mechanisms. The effects of AGE on proliferation of K562 and K562/A02 cells and Tet on the proliferation of AGE-induced K562 and K562/A02 cells were assayed by CCK8 kit, the apoptosis rate and the expression of receptor of advanced glycosylation end products (RAGE) in K562 and K562/A02 cells were determined by flow cytometry, the expression of RAGE mRNA was detected by semi-quantitative RT PCR. The results showed that AGE could promote the proliferation of K562 and K562/A02 cells in a concentration-dependent manner, the cell proliferation was enhanced with time increasing in 0 - 48 h, and was higher than control group after 72 h. AGE up-regulated the RAGE mRNA and protein expressions of K562 and K562/A02 cells in a concentration-dependent manner. Treatment of Tet combined with AGE for 48 h could inhibit the proliferation of K562 and K562/A02 cells promoted by AGE in a concentration-dependent manner, which probably by inducing cell apoptosis, however, there was no obvious effect in the up-regulating expression of RAGE mRNA and protein induced by AGE. It is concluded that AGE can promote the proliferation of K562 and K562/A02 cells, which is probably induced by up-regulating the expression of RAGE mRNA and protein. Tet can inhibit the proliferation of K562 and K562/A02 cells induced by AGE, and the mechanism may be not closely associated with changes of the up-regulating expression of RAGE mRNA and protein induced by AGE. PMID- 22541076 TI - [Reversal effect of gambogic acid on multidrug resistance of K562/A02 cell line]. AB - This study was purposed to investigate the reversal effect of gambogic acid (GA) on multidrug resistance of K562/A02 cells and its mechanism. The IC(50) (half maximal inhibitory concentration) of adriamycin (ADM) was evaluated by MTT. Cell apoptosis was detected by flow cytometry. Morphological changes of K562/A02 cells were observed by fluorescent microscopy with DAPI staining. The expressions of Survivin and P-gp were determined by Western blot. The results showed that the IC(50) of ADM on K562 and K562/A02 cell proliferation were (1.42 +/- 0.07) ug/ml and (28.42 +/- 1.40) ug/ml respectively. GA <= 0.0625 umol/L had no inhibitory effect on proliferation of K562 and K562/A02. 0.0625 umol/L GA could enhance the sensitivity of K562/A02 cells to ADM (P < 0.05) and the reversal multiples was 1.53. The apoptotic rate was raised after treating with ADM combined with 0.0625 umol/L GA for 48 h (P < 0.05). Morphological differences were typical and obvious between cells of control and treated groups under fluorescence microscopy using DAPI staining. After treating K562/A02 cells with ADM combined with 0.0625 umol/L GA for 48 h, the expressions of Survivin and P-gp were down-regulated at protein levels. It is concluded that GA can enhance the sensitivity of K562/A02 cells to ADM, which may be related to increasing cell apoptosis and down-regulating expressions of Survivin and P-gp. PMID- 22541078 TI - [Effect of berberine on HL-60 cell proliferation, apoptosis and vascular endothelial growth factor receptor 2 expression]. AB - This study was aimed to investigate the effect of berberine on the proliferation and apoptosis of HL-60 cells, and the expression of vascular endothelial growth factor receptor 2 (VEGFR2) in HL-60 cells. Berberine (6 - 96 ug/ml) was added to the HL-60 cell line culture medium, the CCK-8 method was used to reveal the inhibitory effect on cell proliferation, the flow cytometry was used to determine the apoptosis rate and cell cycle in HL-60 cells treated with berberine. The expression of VEGFR2 mRNA and protein were examined by RT-PCR and Western blot respectively. The results showed that the berberine inhibited the proliferation of HL-60 cells and induced their apoptosis in dose- and time-dependent manners. With the increased concentration of berberine, the percentage of HL-60 cells in G(1) phase of cycle increased significantly, and the percentage of HL-60 cells in S phase decreased significantly. The expression of mRNA and protein of VEGFR2 decreased with the increased concentration of berberine. It is concluded that the berberine can inhibit HL-60 cell proliferation and induce HL-60 cell apoptosis. The expression of mRNA and proteins of VEGFR2 decreased after treatment with berberine. PMID- 22541077 TI - [siRNA-induced down-regulation of Livin expression increases spontaneous apoptosis in K562 cell line]. AB - This study was aimed to observe the effects of siRNA on Livin expression and function in K562 cells. Livin siRNA were designed and synthesized, then were transfected into K562 cells by using AMAXA nucle transfactor. Expressions of Livin mRNA and protein in transfected K562 cells was detected by RT-PCR and Western blot respectively. Non-transfected cells were used as control. The enhanced green fluorescent protein plasmid was used as positive control and the transfection efficiency was detected by flow cytometry. Cell apoptosis was measured by flow cytometry with Annexin V-FITC/PI double staining. The results showed that the transfection efficiency of electroporation method was about 50. The synthesized siRNA inhibited livin expression at both mRNA and protein levels. The rate of K562 cell apoptosis increased from (9.63 +/- 0.89) in control group to (12.07 +/- 1.39) and (27.41 +/- 2.30) at 24 h and 48 h after transfection, respectively (P < 0.05). It is concluded that the siRNA can inhibit anti apoptosis of livin gene via down-regulating livin gene expression, which may provide the new method for anti-leukemia study. PMID- 22541079 TI - [Effects of simvastatin on PI3K/AKT signaling pathway in human acute monocytic leukemia cell line SHI-1]. AB - To investigate the effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin (SV) on proliferation, apoptosis and the PI3K/AKT signaling pathway in human acute monocytic leukemia cell line SHI-1. SHI-1 cells were incubated with different concentrations of SV (5, 10, 15 umol/L). Otherwise, SHI 1 cells without any treatment were used as control. Cells in different groups were collected at 24, 48 and 72 h after incubation for further detection. MTT method was used to assay the growth inhibition rate and flow cytometry was used to detect the early stage apoptosis ratio. The human PI3K-AKT Signaling Pathway RT(2) Profiler(TM) PCR Array was used to detect the expression of 84 genes involved in PI3K-AKT signaling. The results indicated that the SV inhibited the proliferation and inducted the apoptosis of SHI-1 cells in time- and dose dependent manners significantly. The growth inhibition rates of SHI-1 cells treated with 15 umol/L SV for 24, 48 and 72 h were 26.82, 47.09 and 63.92, respectively; and their early stage apoptosis ratios were 5.75, 13.25 and 15.59, respectively. Compared with the control group, expression levels of 39 genes were changed in the group of 15 umol/L SV at 48 h, among them 26 genes were down regulated and 13 genes were up-regulated. It is concluded that the SV can inhibit proliferation and induce apoptosis of SHI-1 cells, and the mechanism may be associated with the changes of gene expression level in PI3K-AKT signaling pathway regulated by SV. PMID- 22541080 TI - [Component I from Agkistrodon acutus venom induces apoptosis of K562/A02 cells by promoting caspase 3 expression]. AB - To investigate the effects of component I from Agkistrodon acutus venom (AAVC-I) on the biological features of chronic myeloid leukemia cells, K562/A02 leukemia cells were cultured in the presence of AAVC-I (6.25 - 100 ug/ml) and the proliferation status was assayed by CCK-8 method. Morphological changes were observed by inversed microscope after Giemsa and Hochest 33258 staining, and cell apoptosis was detected by flow cytometry. Caspase 3 activity was tested by using Chromogenic Activity Assay Kit. The results showed that AAVC-I inhibited the growth of K562/A02 cells in time- and concentration-dependant manners, and the IC(50) at 48 h was 30.988 ug/ml. Giemsa and Hochest 33258 staining showed the typical apoptotic features in K562/A02 cells after induction with AAVC-I for 48 h. Flow cytometric analysis revealed that the percentage of the apoptotic cells reached from 0.88 up to 53.66 as the treated concentration was elevated from 0 to 50 ug/ml. Compared with the control group, the expression of caspase 3 in the tested group was enhanced in a dose-dependent manner (P < 0.05). It is concluded that AAVC-I can effectively inhibit the growth and promote apoptosis of K562/A02 cells. Elevated expression of caspase-3 may be attributed to the apoptosis of K562/A02 cells. PMID- 22541081 TI - [Effects of AZT on leukemia cell line KG-1a proliferation and telomerase activity]. AB - This study was purposed to investigate the effect of 3'-azido-2', 3' dideoxythymidine (AZT)on the proliferation and telomerase activity of human acute myeloid leukemia cell line KG-1a. The effect of proliferation was detected by MTT assay after the KG-1a cell were stimulated for 24, 48 and 72 h with different concentrations of AZT; telomerase activity was detected with TRAP-PCR-ELISA assay; RT-PCR was used to detect telomerase hTERT mRNA expression. The results showed that the proliferation of KG-1a cells was inhibited in a time and concentration dependent manner after exposure to AZT for 24, 48 and 72 h; the KG 1a cells decreased in S phase and increased in G(2)/M phase with the increasing of the concentration of AZT; telomerase activity and hTERT-mRNA expression in the experimental groups decreased after treated with AZT, which was positively correlated with concentration of AZT. It is concluded that AZT inhibits KG-1a cell proliferation and induces apoptosis, which maybe related with its decreasing the telomerase activity and hTERT mRNA expression. PMID- 22541082 TI - [Expression of ICAM-1 (CD54) in pediatric tumor and acute leukemia and its clinic significance in immunotherapy with CIK cell]. AB - This study was aimed to investigate the expression of ICAM-1 (CD54) in pediatric tumor and acute leukemia (AL), so as to understand the distribution of ICAM-1 and its clinical significance. The expression of ICAM-1 in tissues of 46 pediatric tumor patients were detected by immunohistochemistry, and in bone marrow cells of 60 pediatric acute leukemia (AL) patients were detected by flow cytometry. 46 pediatric tumor patients included 10 lymphoma, 3 hepatoblastoma, 6 neuroblastoma, 2 rhabdomyosarcoma, 6 Ewing's bone sarcoma, 2 fibrosarcoma, 5 primitive neuroectodermal tumor, 11 nephroblastoma and 1 osteosarcoma. 60 AL pediatric patients included 20 acute lymphocytic leukemia (ALL) patients and 40 acute nonlymphocytic leukemia (ANLL) patients containing 20 M1, M2, M3 patients and 20 M4, M5. The results indicated that expression of ICAM-1 was more positive in all 3 hepatoblastoma cases, which represent a higher positive rate than that in lymphoma, neuroblastoma, rhabdomyosarcoma, Ewing's sarcoma of bone and osteosarcoma. However, no expression of ICAM-1 was observed in fibrosarcoma, nephroblastoma and primitive neuroectodermal tumor patients. On the other hand, the expression rate of ICAM-1 was 55 in ALL, 65 in ANLL M1, M2, M3, and 50 in ANLL M4, M5. It is concluded that the expression of ICAM-1 in pediatric tumor and AL has variability. The ICAM-1 positive expression is observed in hepatoblastoma and ANLL M1, M2, M3 patients, whereas it is undetectable in fibrosarcoma, nephroblastoma and primitive neuroectodermal tumor patients. PMID- 22541083 TI - [A case of Richter syndrome transformed from chronic lymphocytic leukemia with karyotype aberration of trisomy 12]. AB - This study was aimed to investigate the relationship between Richter's syndrome (RS) transformation and clinical characteristics as well as karyotype of patient with chronic lymphocytic leukemia (CLL). By the follow-up of a patient with CLL, the clinical characteristics, karyotype, treatment pattern and its effect, as well as disease progression were monitored regularly with serological test, flow cytometry and FISH technique. The results indicated that the patient typically presented with history of CLL at initial diagnosis, with expression of CD5(+), CD19(+) and CD23(+), Binet stage C, as well as karyotype aberration of trisomy 12, and poorly responded to 4 cycles of standard chemotherapy of FCR regimen. The disease progression was confirmed at 5 months with the symptoms of fever in the absence of infection, elevated lactate dehydrogenase level and rapidly enlarging lymphnodes which showed typically diffuse large B cell lymphoma by the biopsy. It is concluded that karyotype aberration of trisomy 12 is one of the risk factors for RS transformation, and treatment pattern of the patient with CLL may be associated with the transformation of RS. PMID- 22541084 TI - [Heterogenous abnormality polymorphism of gene PDGFRB in myeloid neoplasms and its clinical characteristics]. AB - Myeloid neoplasms with eosinophilia and abnormalities of PDGFRB gene are a new kind of myeloid disorders in the revised 2008 WHO classification. Out of detected 2000 cases of myeloid cell abnormalities in our hospital, 12 cases of myeloid neoplasms with eosinophilia and abnormalities of PDGFRB were found. This study was purposed to summarize and analyze the clinical and laboratorial characteristics of the 12 cases with PDGFRB gene abnormalities. The results indicated that among 12 cases of myeloid neoplasms with PDGFRB abnormalities, 5 cases with TEL/PDGFRB fusion gene, 2 cases with HEPI/PDGFRB, 1 case with PDGFRB mutation, 1 case with RABAPTIN-5/PDGFRB, 1 case with GIT2/PDGFRB, 1 case with TP53/PDGFRB, 1 case with WDR43/PDGFRB fusion gene were detected, showing the polymorphism of PDGFRB gene abnormalities. Among this kind of myeloid neoplasm patients, almost all patients manifested monocytosis and eosinophilia in different degree, the thrombocytosis mainly was observed in atypical myeloid neoplasms, acute leukemia, chromic myelo-monocytic leukemia patients. The treatment with imatinib mesylate for this kind of patients was effective in some cases. It is concluded that the myeloid neoplasms with PDGFRB gene abnormalities are a kind of heterogenetic myeloid neoplasms, their gene abnormal types and clinical manifestations show polymorphism too. The monocytosis and eosinophilia appear in this kind myeloid neoplasms which may be treated with tyrosine kinase inhibitors such as imatinib mesylate. PMID- 22541085 TI - [Effect of NKG2D in eliminating hematological malignant cell lines by natural killer cells]. AB - The aim of this study was to clarify whether NKG2D plays an activating role in eliminating hematological malignant cells lines by natural killer (NK) cells. Several hematological malignant cell lines (K562, NB4, Kasumi-1 THP-1, MV-4-11, MOLT-4, Jurkat, RS4; 11, Raji) were used as target cells. The expression levels of major histocompatibility complex class I (MHC I)-related molecules A/B (MICA, MICB), whose corresponding ligand was NKG2D, were detected in target cells by flow cytometry. Firstly, the target cell lines were co-incubated with carboxyfluorescein succinimidyl ester (CFSE) for 30 min. In the meanwhile, NK92MI, a kind of NK cell line, was co-incubated respectively with isotype control antibody or blocking antibody, the latter could block NKG2D specifically. Then, NK92MI cells were co-cultured with different target cell lines. After incubation for 2 h, the apoptotic ratio of each target cell line was detected by flow cytometry. The results demonstrated that there was a significant reduction of the apoptotic ratio in Kasumi-1, an acute myeloid leukemia cell line, when NK92MI cells were incubated with NKG2D blocking antibody previously. In contrast, the apoptotic ratio of other cell lines varied minimally. It is concluded that NKG2D can activate NK cells through inducing cytotoxicity to certain target cells. PMID- 22541086 TI - [Expression of homeobox A9 in myeloid leukemia cell line HL-60 and effect of drugs on its expression]. AB - This study was aimed to investigate the homeobox A9 (HOXA9) mRNA and protein expression in myeloid leukemia cell line HL-60 and effect of all-trans retinoic acid (ATRA 1 umol/L) or arsenic trioxide (As2O3 1 umol/L) on its expression, and to explore the pathogenesis of leukemia mediated by HOXA9 at mRNA and protein levels. The expression of HOXA9 mRNA and protein were detected by real-time fluorescent quantitative reverse transcription polymerase chain reaction (FQ-RT PCR) and Western blot, respectively. HL-60 cells were divided into 3 group: normal control added with RPMI 1640 medium, ATRA group and As2O3 group. The results indicated that HOXA9 mRNA expression in each group showed a firstly increasing and then decreasing tendency, in which the expression of HOXA9 mRNA was observed at day 1, increased at day 2, and decreased at day 3; while HOXA9 protein expression in each group was observed at day 1, the expression of HOXA9 protein in control group and ATRA group showed firstly increase and then decrease. The expression of HOXA9 protein in As2O3 group showed a decreased tendency gradually. The expression of HOXA9 mRNA in ATRA groups at day 1-3 was higher than that in control group (P < 0.05). The differences of HOXA9 mRNA expression between As2O3 groups and the control group were not significant at day 1 and day 3, but was higher than that in control group at day 2 (P < 0.05). The expression of HOXA9 protein in ATRA group at day 1- day 3 was higher than that in control group (P < 0.05). Compared with control group, the expression of HOXA9 protein in As2O3 group was higher at day 1 (P < 0.05), lower at day 2 (P < 0.05), and no significant differences at day 3. It is concluded that HOXA9 mRNA and protein express in HL-60 cells. ATRA 1 umol/L can up-regulate the expression of HOXA9 mRNA and protein in HL-60 cells. The mechanisms of treatment of leukemia by ATRA and As2O3 may be associated with the regulation of the HOXA9 mRNA or protein expression. PMID- 22541087 TI - [Expressions of miR-21, miR-155 and miR-210 in plasma of patients with lymphoma and its clinical significance]. AB - This study was purposed to investigate the expressions of miR-21, miR-155 and miR 210 in plasma of patients with lymphoma, and explore their role played in diagnosis, evaluation of chemotherapy effect and prognosis of lymphoma. The expressions of miR-21, miR-155 and miR-210 were assayed by RT-PCR in plasma of 54 cases of lymphoma, 10 cases of lymphonode inflammation and 27 cases of normal controls. The results indicated that the expressions of miR-21, miR-155 and miR 210 in plasma of lymphoma patients were higher than those of control group and lymphonode inflammation group (P < 0.05). The expressions of miR-21 and miR-210 in plasma of control group and lymphonode inflammation group had no significant differences (P > 0.05). The expression of miR-21 in plasma of lymphoma patient group significantly correlated with their serum LDH level. The expressions of miR 21 and miR-210 in plasma of previously untreated lymphoma patient group were higher than those of the patients treated for 6 or more courses (P < 0.05). The diagnostic accuracy of miR-21, miR-155 and miR-210 used for lymphoma patients was 56, 65, 48 respectively, and reached to 83 when combined three of them. It is concluded that the expressions of miR-21, miR-155 and miR-210 in plasma of lymphoma patients were significantly higher. Detection of these 3 miRNA in plasma of patients can contribute to the clinical diagnosis, treatment and prognosis evaluation of lymphoma. PMID- 22541088 TI - [Inhibitory effects of sporoderm-broken Ganoderma lucidum spores on growth of lymphoma implanted in nude mouse]. AB - This study was aimed to investigate the inhibitory effects of sporoderm-broken ganoderma lucidum spores (GLS) on transplanted lymphoma in nude mice and its mechanism. The models of the subcutaneously transplanting tumor were established by N-methylnitrosourea-induced thymus T-cell lymphoma. The cellular apoptosis of tumor tissues in nude mice were observed by transmission electron microscopy (TEM), the mRNA expression of Bax, Bcl-2, Bcl-xl was determined by RT-PCR. The results indicated that the GLS had a certain anti-tumor effect, and the inhibitory rate was 45.8 with the dose of 4 g/kg (ig, once daily for 21 d). Apoptotic cells in lymphoma cells treated with GLS were observed by TEM. RT-PCR analysis showed that the expression of Bax was up-regulated, Bcl-2 and Bcl-xl were down-regulated in T-cell lymphoma cells. It is concluded that GLS can inhibit proliferation of lymphoma cells and induce the lymphoma cell apoptosis, the mechanism of which may be related with up-regulating the expression of Bax and down-regulating the expression of Bcl-2 and Bcl-xl. PMID- 22541089 TI - [Impact of immunochemotherapy on prognostic factors in diffuse large B-cell lymphoma patients]. AB - The international prognostic index (IPI) has been established as one of the best predictors of outcome, and several different immunologic subtypes have been established as independent predictors of diffuse large B-cell lymphoma (DLBCL). This study was aimed to reassess and re-evaluate the useful value of these prognostic predictors in patients treated with immunochemotherapy. A retrospective analysis of clinical records of immuno-chemotherapeutic (rituximab + CHOP, R-CHOP) and route chemotherapeutic (CHOP) groups was carried out. Standard two-step method of immunohistochemical staining was used to assess the expression of CD10, MUM-1, BCL-6 and BCL-2. The different classification models (Han's algorithm and Muris model) were performed for patients with DLBCL according to the immunohistochemical staining results in both R-CHOP and CHOP regimen groups. Then the data of remission and overall survival rate in different groups were analyzed to investigate the effect of these prognostic factors. Total 126 de novo DLBCL patients were collected in this study, including 51 patients with treatment of R-CHOP and the other 75 patients with treatment of CHOP. The results showed that the R-CHOP group had higher complete remission rate (68.8) than CHOP group (58.7). The patients with IPI score <= 2 had significantly higher overall response rate and overall survival rates than the patients with IPI scores > 2 in both groups. The survival rates of different subtypes in Han's and Muris models were not different from each other in R-CHOP group, but were obvious different from each other in CHOP group. It is concluded that IPI is still effective and predictive for identification of different risk groups. Immunochemotherapy can improve the remission and overall survival rate of DLBCL, but weaken the effect of outcome predictor. PMID- 22541090 TI - [Retrospective analysis for 104 cases of early-stage Hodgkin's Lymphoma treated with different modality therapies]. AB - This paper explored the curative effect of combined modality therapy and extended field radiotherapy for early-stage Hodgkin's Lymphoma. 104 cases of early-stage Hodgkin's Lymphoma from Jan 1987 to Dec 2010 in PLA Hospital 307 were retrospectively analyzed, including 76 cases in combined modality therapy group and 28 cases in extended field radiotherapy group, and the long-term efficacy and toxicity of two therapy modalities were evaluated. The results showed that the median survival time of 104 cases was 85.42 months, the complete remission rates of combined modality therapy and extended field radiotherapy groups were 72.4 and 71.4 respectively (P = 0.924); the overall response rates of combined modality therapy and extended field radiotherapy groups were 97.4 and 96.4 respectively (P = 0.779); the 5-year overall survival (OS) rates in the 2 groups were 89.5 and 89.1 respectively, and the 8-year OS rates of the 2 groups were 81.3 and 70.6. No statistical difference was found in above-mentioned 2 groups. Moreover, the 5 year progression free survival (PFS) rates of these 2 groups were 84.2 and 69.0 (P = 0.04), and 8-year PFS rates of these 2 groups were 80.0 and 55.5 (P = 0.04) respectively, the 5-year relapse rates of these 2 groups were 28.1 and 45.6 (P = 0.023) respectively. It is concluded that the combined modality therapy can raise the PFS rate and reduce the relapse rate as compared with extended field radiotherapy for early-stage Hodgkin's Lymphoma, but there is no difference in the overall survival rate between the 2 groups. PMID- 22541091 TI - [Predictive value of tissue factor-associated platelet microparticles in thrombosis of patients with lymphoma]. AB - This study was purposed to investigate the relationship between tissue factor associated platelet microparticles and thrombosis of patients with lymphoma by detecting the density of platelet microparticles and the tissue factor coagulative activity, and to evaluate the possibility of tissue factor coagulative activity for predication of thrombosis in lymphoma patients. This study was divided into 3 groups: A group including 50 healthy persons who did not take any drugs and had no hypercoagulation diseases; B group including 50 cases of lymphoma without thrombosis, and C group including 8 cases of lymphoma with thrombosis. The plasma was isolated from venous blood by centrifugation. The density of platelet microparticles was detected by flow cytometry; the tissue factor coagulative activity of plasma was measured by chromogenic substrate. The results indicated that compared with group A, the density of platelet microparticles increased in group B. Compared with group B, group C had significantly higher density of platelet microparticles and tissue factor coagulative activity (P < 0.01). It is concluded that the density of tissue factor associated platelet microparticle has predictive value for lymphoma with thrombosis, which can be used as target of clinical test. PMID- 22541092 TI - [SUDHL-4 cell culture in vitro and establishment of mouse tumor model]. AB - This study was designed to investigate the biological and immunological characteristics of a human diffuse large B-cell lymphoma (DLBCL) cell line SUDHL 4, and to establish a mouse model for human DLBCL. SUDHL-4 cells were cultured under different conditions. The morphology and in vitro expression of B-cell and tumor-related markers were detected by microscopy and flow cytometry respectively. To establish the transplanted tumor, the cells were injected subcutaneously into SCID mice. Tumor formation and its histomorphology were analyzed. The results showed that the expression of B cell/tumor-related markers was found on cultured SUDHL-4 cells. A stable mouse model of human DLBCL was successfully established in SCID mice by subcutaneous injection of 10(7) SUDHL-4 cells. Tumor tissue from mice exhibited similar histologic manifestation to those of human DLBCL. It is concluded that the SUDHL-4 cells represent a high consistency in immunological characteristics with human DLBCL. Transplantation of SUDHL-4 cells provides a syngeneic mouse model for the study of human DLBCL. PMID- 22541093 TI - [Effects of triptolide on bortezomib-induced apoptosis in multiple myeloma cells]. AB - This study was purposed to investigate the effect of triptolide on bortezomib induced apoptosis in multiple myeloma cell line NCI-H929(H929). MTT assay was applied to detect the inhibitory effects of triptolide and bortezomib alone or combined at different concentrations on H929 cells, the cell apoptosis was assayed by flow cytometry with Annexin V-FITC/PI staining. The results showed that both triptolide (10 - 100 ng/ml) and bortezomib (10 - 100 nmol/L) alone or combination inhibited the proliferation of MM cell line H929 in a concentration dependent manner. The apoptotic rate of H929 cells in group of triptolide combined with bortezomib was much higher than that in groups of single drug or control; moreover, the apoptotic rate of H929 cells treated by non-inhibitory concentration of triptolide (10 ng/ml) combined with bortezomib (40 nmol/L) for 24 h was significantly higher than that by bortezomib alone (P < 0.05). It is concluded that triptolide can significantly enhance the pro-apoptotic activity of bortezomib in MM cells. PMID- 22541094 TI - [Relationship between the catalysis of Bence Jones protein and renal impairment in patients with multiple myeloma]. AB - This study was purposed to investigate the relationship between the catalysis of Bence Jones protein (BJP) in urine of patients with multiple myeloma(MM) and toxicity on the renal proximal tubular cells in vitro, and to explore the potential mechanism for the toxicity of BJP to renal impairment in patients with MM. The Michaelis-Menten constant (K(m)) and catalytic constant (k(cat)) of the amidase activity of BJP was calculated by Hanes equation. The LLC-PK1 cells were cultured with different concentration of BJP for 24 h, then proliferation of the cells were determined by MTT method and apoptosis were determined by flow cytometry. The results showed that the BJP from the MM patients with renal impairment significantly inhibited cell proliferation, as compared with that from MM patients without renal impairment. The BJP with higher k(cat) had higher toxicity to LLC-PK1 cells. BJP could induce apoptosis and necrosis of LLC-PK1 cells when reached a certain concentration and this effect enhanced with increase of BJP concentration. It is concluded that the catalysis of BJP and its toxicity to renal tubular epithelial cells has a positive correlation, and toxic effect of BJP on renal tubular epithelial cells results from inhibiting proliferation and inducing apoptosis and necrosis of the cells, which may be one of renal impairment mechanisms in MM patients. PMID- 22541095 TI - [Clinical significance of serum vascular endothelial growth factor and interleukin-17 in patients with multiple myeloma]. AB - The aim of this study was to investigate the clinical significance of vascular endothelial growth factor (VEGF) and interleukin-17 (IL-17) levels in patients with multiple myeloma (MM). 40 newly diagnosed MM patients were enrolled, including 9 in stage I, 18 in stage II, 13 in stage III. 25 patients were treated with VAD regimen, and 15 patients with the bortezomib and dexamethasone (BD) regimen. 20 healthy individuals as controls were enrolled in this study. The serum VEGF and IL-17 levels were determined by ELISA. The results indicated that the serum VEGF and IL-17 levels in the patients with MM were significantly higher than those in healthy controls (P < 0.01). VEGF and IL-17 levels in stage III was significantly higher than that in stage I and II (P < 0.05). There was a positive correlation between IL-17 and serum calcium beta2-microglobulin or C-reactive protein (P < 0.01), and there was also a positive correlation between VEGF and serum creatinine serum Bene-Jones protein lambda or urinary Bene-Jones protein lambda (P < 0.01). Serum VEGF and IL-17 levels significantly decreased in MM patients after treatment, and the serum levels of VEGF and IL-17 was much lower in MM patients treated with VAD regimen than those in patients treated with BD regimen. It is concluded that the detection of serum VEGF and IL-17 levels is helpful to evaluation of the clinical stages and the severity of MM. PMID- 22541096 TI - [Clinical observation of thalidomide combined with VAD regimen for treatment of osteosclerotic myeloma (POEMS syndrome)]. AB - This study was purposed to analyze the clinical features and evaluate the efficacy of thalidomide combined with VAD regimen for treatment of osteosclerotic myeloma (POEMS syndrome). The data of 27 patients with POEMS syndrome in the First Affiliated Hospital of Zhengzhou University were analyzed retrospectively, including clinical manifestations, laboratory tests, treatments and prognosis. The results showed that the polyneuropathy was observed in 27 patients (27/27), hepato-spleno-lymphadenectasis was found in 15 patients (15/27), endocrinopathy was found in 24 patients (24/27), skin changes was observed in 22 patients (22/27). M protein was found in 23 patients (23/27); in addition to these clinical manifestations, the papilledema serous cavity effusion and sclerotic bone lesion were also frequently observed in patients with POEMS syndrome. The remission rates of treatment of POEMS syndrome with thalidomide combined with VAD regimen for organomegaly, edema, skin changes, and endocrinopathy were 60, 58.3, 41 and 45.8 respectively. The level of serum M protein and the nervous system ODSS value decreased greatly after treatment (P < 0.01). It is concluded that the clinical characteristics of POEMS syndrome are complicated and easy to be misdiagnosed, and the evidence of monoclonal plasma cell hyperplasia should be actively searched for those patients whose serum M protein is negative. Thalidomide combined with VAD regimen for treatment of patients with POEMS syndrome has advantages such as significant curative effects, less side-effects, good tolerance, and higher safety and can be chosen as a preferred approach. PMID- 22541097 TI - [Expression of p57kip2 in patients with de novo myelodysplastic syndrome and its relationship with SDF-1/CXCR4 axis]. AB - This study was purposed to explore the expression of p57kip2 in the bone marrow of patients with de novo myelodysplastic syndrome (MDS) and its role in MDS pathogenesis, as well as the relationship between the expression of p57kip2 and SDF-1/CXCR4 signal. The expression of p57kip2 and CXCR4 in 67 de novo MDS patients was measured by real-time quantitative PCR. The percentage of CD34(+) cells in the bone marrow from MDS patients was measured by flow cytometry. 18 healthy volunteers were recruited for control. The effect of SDF-1 on p57kip2 expression in bone marrow mononuclear cell (BMMNC) from MDS or normal controls was investigated in vitro, and difference between them was compared. The results showed that low-risk MDS and high-risk MDS displayed a significant reduction of p57kip2 mRNA expression in BMMNC compared with that in control group (P < 0.001) and there was a negative correlation between p57kip2 expression and percentage of CD34(+) (r = -0.458, P < 0.001); the patients with abnormal karyotype showed lower expression of p57kip2 gene, compared to patients with normal karyotype (P = 0.045). Although the expression of CXCR4 had no difference between MDS patients and normal controls, a positive correlation between p57kip2 and CXCR4 in MDS patients was still found (r = 0.609, P < 0.001). Moreover, SDF-1 increased p57kip2 expression in normal BMMNC in dose-dependent manner, but BMMNC from MDS patients showed no response to SDF-1. SDF-1-induced p57 expression was blocked by AMD3100. It is concluded that the low expression of p57 gene in MDS may play a role in the pathogenesis of MDS. Furthermore, SDF-1-induced p57kip2 expression in BMMNC, and the decreasing response of BMMNC to SDF-1 may contribute to the low expression of p57kip2 in MDS patients. PMID- 22541098 TI - [Abnormal expression of microRNA-124 in patients with leukemia or myelodysplastic syndrome and its significance]. AB - This study was aimed to investigate the abnormal expression of microRNA-124 (miR 124) in bone marrow cells of patients with leukemia or myelodysplastic syndrome (MDS) and its significance. The relative expression levels of miR-124 in bone marrow mononuclear cells from 33 patients with newly diagnosed leukemia or MDS, and 10 normal donors (as controls) were detected by stem-loop fluorescence real time quantitative RT-PCR. The methylation levels of miR-124 promoter were detected by quantitative methylation specific PCR in partial MDS samples. The results indicated that as compared with normal control, lower levels of miR-124 (<= 1/3) were found in 2/18 of leukemia patients and in 5/15 of MDS patients (among them <= 1/4 in 3/15 MDS patients). No statistically significance difference was observed between leukemia patients and normal controls (P = 0.725). However the difference was statistically significant between MDS group and control group (P = 0.031). Furthermore, an elevated methylation level of miR 124 promoter region in some of MDS patients (7/11) was detected by using quantitative methylation-specific PCR. The expression level of miR-124 was related with methylation level of promoter region (R(2) = 0.339, P = 0.018). It is concluded that the expression of miR-124 in partial MDS patients is inhibited, which may be associated with the abnormal methylation of its promoter. PMID- 22541099 TI - [Relationship between V617F mutation and 46/1 haplotype in JAK2 gene in patients with chronic myeloproliferative diseases and frequencies of 46/1 haplotype in different Chinese nationalities]. AB - Somatic gene V617F mutation in JAK2 is a critical molecular and biological indicator to diagnosis of chronic myeloproliferative disease (MPD). This study was aimed to investigate the genetic background of V617F mutation in 46/1 gene haplotype in Chinese MPD patients, and the frequencies of 46/1 gene haplotype and V617F mutation in three nationalities of Chinese populations. Peripheral blood or bone marrow samples of 150 V617F mutation positive MPD patients, 123 V617F mutation negative MPD patients, 124 healthy Han individuals, 395 healthy Tibetan individuals and 315 healthy Yugu individuals were collected. The allele-specific multiplex PCR method was established, the presence or absence of V617F mutation, the presence or absence of 46/1 haplotype, and the relationship between V617F and 46/1 haplotype were easily identified by agarose gel image. The results showed that the V617F mutation located in the 46/1 haplotype of 88 cases (58.67) among 150 V617F-positive MPD cases. In 814 Chinese healthy individuals including Han, Tibetan, Yugu nationalities, the frequency of the 46/1 gene haplotype was 38.37 without difference in the frequency among different nationalities, and no V617F mutation was found in Chinese healthy populations, The frequency of the 46/1 gene haplotype was 43.09 in V617F mutation negative MPD patients and was 69.33 in V617F mutation positive MPD patients, the latter was obviously higher than former and than that in healthy Han individuals. In conclusion, a multiplex PCR method has been developed that is simple and useful to identify V617F mutation in JAK2 gene and its relationship to the 46/1 haplotype. In more than half of Chinese V617F-positive MPD patients, the V617F mutation locates in 46/1 haplotype in JAK2. The frequencies of 46/1 haplotype are statistically insignificant among Han, Tibetan and Yugu nationality populations. PMID- 22541100 TI - [Effect of erlotinib on proliferation and differentiation of JAK2V617F-positive cells in vitro]. AB - The aim of this study was to investigate the effect of erlotinib on proliferation and differentiation of JAK2V617F-positive cells in vitro, and to provide experimental evidence of erlotinib for potential target therapy in polycythemia vera. Colony forming assays were used to detect the effect of erlotinib on differentiation of hematopoietic progenitor cells from bone marrow of polycythemia vera patients, and MTT method was used to measure the proliferation of HEL cell line containing the JAK2V617F mutation. The results showed that erlotinib 5 umol/L inhibited the differentiation of JAK2V617F-positive hematopoietic progenitor cells into hematopoietic colonies in vitro, while it had almost no effect on normal hematopoietic progenitor cells from the patients. Erlotinib had inhibitory effect on the proliferation of HEL cell line in a dose dependent manner. The IC(50) was 4.1 umol/L. It is concluded that erlotinib can inhibit proliferation and differentiation of JAK2V617F-positive cells to a certain extent in vitro. PMID- 22541101 TI - [Inhibitory effect of gefitinib and lapatinib on proliferation of HEL cells]. AB - This study was aimed to investigate the therapeutic effect of two molecular targeted therapeutic drugs, tyrosine kinase inhibitors gefitinib and lapatinib, on JAK2 V617F positive myeloproliferative disorders (MPD). The human leukemia cell line (HEL cell line) carrying JAK2 V617F mutation was treated with gefitinib (0.5, 1, 5, 10, 25 umol/L) and lapatinib (0.5, 1, 2, 4, 8, 16 umol/L) respectively. MTT method was used to detect HEL cell proliferation. The apoptotic rate and cell cycle were measured by flow cytometry. The results showed that gefitinib could significantly inhibit the proliferation of HEL cells in a dose dependent manner, it's correlation coefficients for 24 and 48 h were 0.991 and 0.895 respectively. IC(50) at 48 h was 5.4 umol/L. Gefitinib could effectively induce apoptosis of HEL cells in a dose-dependent manner (r = 0.896). Otherwise, gefitinib could arrest HEL cells at G(0)/G(1) phase. The inhibitory effect of lapatinib was less than gefitinib, it's IC(50) of inhibiting proliferation of HEL cells was 19.6 umol/L. It is concluded that both gefitinib and lapatinib can inhibit the proliferation of HEL cells. These two tyrosine kinase inhibitors can be used for researching of targeted therapy of JAK2 V617 positive MPD. PMID- 22541102 TI - [In vitro effects of hemocoagulase atrix and its effective components on blood coagulation of patients with bleeding disorders]. AB - This study was aimed to investigate the pro coagulation effects of hemocoagulase atrix and its effective components (batroxobin and factor X activator) on plasma of normal subjects and patients with bleeding disorders and their mechanisms. Activated partial thromboplastin time (APTT) and prothrombin time (PT) were measured. The factor (F)X activation and thrombin generation were analyzed by using chromogenic substrate method. The results showed that the plasma APTT of normal subjects was shortened by hemocoagulase atrix, batroxobin and FX activator, and the effect of FX activator was found to be concentration-dependent (r = 0.889, P < 0.05). The prolonged APTT of plasma from patients with bleeding disorders could be corrected by hemocoagulase atrix, batroxobin and FX activator, but PT showed no great changes resulted from the treatments. FX activator could promote FX activation and thrombin generation, while neither hemocoagulase atrix nor batroxobin showed such abilities. It is concluded that hemocoagulase atrix promotes coagulation process, and corrects coagulation abnormalities in patients with bleeding disorders, its main component batroxobin directly acts on fibrinogen, and FX activator promotes thrombin generation through activating FX. PMID- 22541103 TI - [Analysis on the effectiveness in 727 times of platelet transfusion]. AB - This study was purposed to analyze the efficiency of platelet transfusion and to explore factors influencing platelet transfusion efficiency. 727 times of platelets transfusion in 254 patients in The Third Xiangya Hospital from September 2010 to May 2011 were analyzed retrospectively. Moreover, according to symptoms, times of platelet transfusion, blood types and splenomegaly, the corrected count of increment (CCI) and percentage of platelet recovery (PPR) were calculated for evaluation of platelet transfusion efficiency. The results showed that there were 456 effective transfusions out of 727 transfusions (62.72). Among them, the therapeutic effect of platelet transfusion for patients with acute blood loss anemia and chronic systemic diseases was relatively obvious, specially for chronic renal disease, the effective efficiency of them was 94.12. The patients with splenomegaly showed a significant impact on platelet transfusion efficiency (41.07). Analysis found that the frequency of platelet transfusion negatively correlated with transfusion efficiency. It is concluded that the transfusion frequency and splenomegaly are factors influencing the transfusion efficiency. PMID- 22541104 TI - [Influence of S-nitrosoglutathione on agglutination and nitric oxide concentration in frozen platelets]. AB - The aim of this study was to investigate the influence of S-nitrosoglutathione (GSNO) on agglutination and nitric oxide (NO) concentration in frozen platelets. The agglutination of platelets was detected by using platelet agglutination apparatus, the level of NO in platelets was detected by the nitrate enzyme reduction method. The results showed that the rates of agglutination in freeze platelets and frozen platelets treated with GSNO were (35.47 +/- 2.93) and (24.43 +/- 3.07), which were significantly lower than that in fresh liquid platelets (63.44 +/- 2.96). The level of NO concentration in frozen platelets was (22.16 +/ 6.38), which was significantly lower than that in fresh liquid platelets (31.59 +/- 16.88). The level of NO concentration in frozen platelets treated with GSNO was (45.64 +/- 6.31), which was significantly higher than that in fresh liquid platelets (P < 0.01). It is concluded that GSNO increases the concentration of NO in frozen platelets, inhibits platelet activation and maintains platelet function, thus GSNO can be used as a frozen protective agent. PMID- 22541105 TI - [Changes of mean platelet volume, fibrinogen content and blood rheology in peripheral blood of youth patients with cerebral infarction]. AB - This study was aimed to explore the correlation of mean platelet volume (MPV), fibrinogen (FIB) and blood rheology with the youth patients with cerebral infarction, so as to provide the basis for the clinical early diagnosis and treatment. The 109 patients with cerebral infarction aged between 18 - 45 were divided into three group: the large (> 10 cm(3)), middle (4 - 10 cm(3)) and small (< 4 cm(3)) area infarction; 30 healthy persons were served as control group. All the four groups were subjected to 16 examinations, such as MPV, FIB, and rheology (Letab, Metab, Hetab, etap, Letar, Metar, Hetar, KVE, EAI, ERI, EDI, EEI, HCT, ESR). The results showed that all the MPV, FIB and rheology indexes of the different infarction groups were higher than those of healthy control group (P < 0.05). The MPV, FIB and rheology indexes in the large area infarction group were all higher than those in the small area infarction group (P < 0.05). The indexes of MPV, FIB and rheology in the various cerebral infarction area groups obviously decreased, but those did not reach to the level in the healthy control group (P < 0.05). The MPV, FIB content and rheology level correlated with infarction areas (r = 0.36, 0.29 and 0.48, respectively). It is concluded that the serious intensity of youth patients with cerebral infarction positively correlated with the levels of MPV, FIB and rheology indexes. Regular examination of above mentioned index may be useful to prevent youth patients from cerebral infraction. PMID- 22541106 TI - [Changes of platelet alpha-particle membrane protein, platelet activating factor and platelet parameters in patients with hyperuricemia]. AB - This study was aimed to investigate the changes of the platelet particle membrane protein (GMP-140), platelet activating factor (PAF) and platelet parametes in the patients with hyperuricemia (HUA), ELISA was used to detect the levels of GMP-140 and PAF in 55 patients with HUA and 30 healthy individuals. Platelet parameters were measured with automatic blood cell analyzer, and the biochemical indexes were detected at the same time. The results showed that the levels of serum uric acid, triglycerides (TG) and low density lipoprotein cholesterol (LDL-C) in HUA patients were higher than that in the normal group (P < 0.01). Serum uric acid level of HUA group was higher in men than that in women. The levels of GMP-140 and PAF in HUA patients were much higher than that in the normal group (P < 0.01), the indexes of platelet distribution width (PDW) and platelet-large cell ratio (P-LCR) in HUA patients were higher than that in the normal group (P < 0.01), there was no statistically significant difference in platelet count, plateletcrit (PCT), mean platelet volume (MPV) between the two groups. There was positive correlation between serum uric acid and levels of GMP-140, PAF, P-LCR and PDW, respectively (r = 0.667, 0.879, 0.310, 0.460, P < 0.01 or P < 0.05). Multivariate stepwise regression analysis revealed that serum uric acid, creatinine, P-LCR, urea nitrogen contributed to GMP-140 level (adjusted R(2) = 0.822). Serum uric acid and LDL-C also contributed to PAF level (adjusted R(2) = 0.451). It is concluded that a close relationship exists between HUA and the change of platelet function, and HUA plays a certain role in cardiovascular disease thrombosis complications. PMID- 22541107 TI - [A novel mutation in beta-globin gene of a patient with beta-thalassemia]. AB - This study was aimed to analyze the beta-globin gene mutations in a patient with beta-thalassemia minor. Genomic DNA was extracted from peripheral blood cells of the patient. The full-length DNA sequence coding for beta-globin was amplified by polymerase chain reaction, and the gene mutation was determined by DNA sequencing. The results indicated that a heterogeneous A->G mutation was found at position 129 in intron 1 of the beta-thalassemia minor patient. It is concluded that the IVS-I-129(A->G) mutation is a splicing site mutation leading to a splicing error in immature messenger RNA and a protein translation error for the beta-globin gene. Thus, the IVS-I-129(A->G) is a novel mutation. PMID- 22541108 TI - [Significance of soluble interleukin-2 receptor and NK cell activity in patients with hemophagocytic lymphohistiocytosis]. AB - This study was aimed to detect the level of soluble interleukin-2 receptor (sCD25) and cytotoxic activity of NK lymphocytes in patients with hemophagocytic lymphohistiocytosis (HLH), and to explore their clinical significance in HLH. The enzyme-linked immunosorbent assay was used to detect the sCD25 level in serum of 20 patients with HLH, 15 healthy controls, 20 cases of acute myeloid leukemia and 20 cases of systemic lupus erythematosus. The NK cell cytotoxicity in peripheral blood of patients with HLH and controls were detected by flow cytometry with CD107a antibody labeling and LDH release assay. The results indicated that the level of sCD25 in HLH patients was significantly higher than that in healthy controls and disease groups (P < 0.001). The NK cell cytotoxicity in peripheral blood detected by both methods in patients with HLH were lower than that in healthy controls (P < 0.05), and the results detected by flow cytometry correlated significantly with those by LDH release assay (r = 0.73, P < 0.05). It is concluded that detection of sCD25 levels and NK cell activity in peripheral blood in HLH is of great value. Using flow cytometry following CD107a antibody labeling to measure NK activity is a simple, stability, reproducibility method and can be used for clinical diagnosis of HLH. PMID- 22541109 TI - [Effect of recipient mouse age on occurrence of graft-versus-host disease following allogenic bone marrow transplantation]. AB - This study was aimed to explore the influence of recipient age on the occurrence of acute graft-versus-host disease (aGVHD) in mice. 8 - 10 weeks aged C57BL/6 (H 2K(b)) mice were selected as donors, 18 - 20 weeks aged and 8 - 10 weeks aged BALB/c (H-2K(d)) mice were served as recipients. 18 - 20 weeks and 8 - 10 weeks aged mice were all randomly divided into three groups: normal control group (without any treatment); irradiation alone group [administered a total body irradiation (TBI) without bone marrow transplantation] and model group [infused with bone marrow mononuclear cells 5 * 10(6) and splenocytes 5 * 10(5) from donor C57BL/6 (H-2K(b)) mice through caudal vein no more than 4 h after TBI]. The general state and survival rate of all mice were observed everyday. The factors (the chimerism in peripheral blood, T lymphocyte and their subsets, the percentage of Th1 cells) of mice in model groups were measured by flow cytometry on day 5, 10, 15, 20, 25, 30 after TBI, the leukocytes in peripheral blood were also calculated by direct microscopic counting. The histological examinations of liver, intestine and skin were done by hematoxylin and eosin staining on day 5, 15, and 25 after TBI. All above data were compared between model groups. The results indicated that murine model with aGVHD was established in two model groups. Compared with 8 - 10 weeks aged mice, the 18 - 20 weeks aged mice showed higher survival rate and lower clinical scores (P < 0.05); the reconstitution time of leukocyte and chimerism in peripheral blood were delayed (P < 0.05); The ratio of CD8(+)T lymphocytes and Th1 cells in peripheral blood were lower (P < 0.05); the histological changes of liver, intestine and skin were little. It is concluded that 18 - 20 weeks aged recipient mice exhibited a lower incidence of aGVHD than 8 - 10 weeks aged recipient mice. PMID- 22541110 TI - [Influence of NK cell S1PR5 expression on graft versus host disease in allogeneic hematopoietic stem cell transplantation]. AB - Natural killer (NK) cells can suppress the development of graft vs host disease (GVHD) while retaining antitumor response in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Sphingosine-1-phosphate receptor 5 (S1PR5) can regulate NK cell migration and distribution in vivo by interacting with sphingosine-1-phosphate (S1P). This study was aimed to investigate S1PR5 expression change of NK cells in allo-HSCT and to explore the relationship between S1PR5 change and frequency of acute/chronic graft-versus-host disease (aGVHD/cGVHD). The S1PR5 expression was detected by real time quantitative PCR in the RNA extracted from blood NK cells of 17 couples of donor and recipient one month after allo-HSCT. The results showed that S1PR5 mRNA level variations in NK cells of donors and recipients post-allo-HSCT were not statistically significant (0.235 +/- 0.191 vs 0.330 +/- 0.261, P > 0.05). S1PR5 expression of NK cells was significantly lower in patients with aGVHD than those in patient without aGVHD (0.973 +/- 0.834 vs 6.166 +/- 5.32, P < 0.05). Compared with the corresponding donor, S1PR5 expression levels of patient declined by more than 10 that caused the high incidence of aGVHD. No significant correlation was found between S1PR5 expression of NK cells and cGVHD (3.401 +/- 2.324 vs 2.762 +/- 1.972, P > 0.05). It is concluded that the decreased expression level of NK cells S1PR5 is associated with aGVHD occurrence. Possible mechanism is due to S1PR5 low expression affecting distribution of NK cells in vivo, so affecting the regulation of NK cells for aGVHD. PMID- 22541111 TI - [Clinical analysis for 3 cases of HLA-matched between father and son and 1 case of post-hematopoietic stem cell transplant efficacy]. AB - Getting a HLA-matched donor is a key factor for successful hematopoietic stem cell transplantation. People are almost semi-matched with their parents, while a person HLA-matched with his/her father or mother was rarely seen, if so, usually whose father and mother are genetically related. HLA-low resolution for patients and their relatives were performed using PCR-SSP technique and three patients were found HLA-matched with their father in these results. One of them accepted hematopoietic stem cell transplantation using his HLA-matched father as his donor. The results showed that the chimerism was detected as stable complete donor chimerism, fusing gene of MLL-ENL was detected all negatively in the post transplant period. This case got well hematopoietic reconstruction and GVHD didn't occur, so far he has survived for two years in health conditioning. It is concluded that people HLA-matched with his/her father or mother can be found when there is one identical haplotype of high frequency and strong linkage disequilibrium between father and mother. This case is valuable for hematopoietic stem cell transplantation development. PMID- 22541112 TI - [Effects of interferon-gamma on biological characteristics and immunomodulatory property of human umbilical cord-derived mesenchymal stem cells]. AB - The aim of this study was to investigate the effects of interferon (IFN)-gamma on biological characteristics and immunomodulatory property of human umbilical cord derived mesenchymal stem cells (hUC-MSC). hUC-MSC were treated with IFN-gamma 10 ng/ml (IFN-gamma group) or without IFN-gamma (control group). The phenotype of hUC-MSC was detected by flow cytometry. The proliferation status was detected by CCK-8 method, and its differentiation ability was assessed by oil red O and von Kossa staining. The production of PGE-2 was measured by ELISA, and the mRNA expression levels of COX-2, IDO-1 and IDO-2 in hUC-MSC were detected by real-time quantitative PCR. Furthermore, the proliferation of human peripheral blood mononuclear cells (hPBMNC) was evaluated after co-culture with hUC-MSC, IFN-gamma pretreatment or not. The results showed that after IFN-gamma stimulation, the expression of SSEA-4 on hUC-MSC decreased significantly [(8.15 +/- 2.94) vs (16.42 +/- 8.5), P < 0.05], and the expression of CD54 increased [(96.64 +/- 3.29) vs (84.12 +/- 10.73), P = 0.051]. The immunomodulatory property of hUC-MSC on the proliferation of hPBMNC was enhanced (P < 0.05). All the above mentioned effects were IFN-gamma concentration-dependent. When hUC-MSC were stimulated by IFN-gamma for 24 h, the production of PGE-2 secreted by hUC-MSC decreased significantly (P < 0.01). The mRNA expression level of COX-2 also decreased though the difference did not reach to statistically significant level. Compared with control group, IDO-1 expression level in IFN-gamma group increased significantly (P < 0.01), and the mRNA expression level of IDO-2 remained unchanged. It is concluded that IFN-gamma can influence the phenotype of hUC-MSC and enhance the immunomodulatory property of hUC-MSC. PMID- 22541113 TI - [Transfection of recombinant adenoviral vector with co-expressing keratinocyte growth factor and enhanced green fluorescent protein to murine bone marrow mesenchymal stem cells]. AB - To construct the adenoviral vector with co-expressing keratinocyte growth factor (KGF) and enhanced green fluorescent protein (EGFP) for transfection into the mesenchymal stem cells (MSC), the target gene KGF was cloned into the shuttle plasmid with the report gene EGFP, then the recombinant shuttle plasmid was transformed into DH5a bacteria to recombine with backbone vector pAdxsi. Next, the plasmid pAd-EGFP-mKGF was amplified in H293 cells and the viral titer was determined. The MSC were separated and enriched by using bone marrow adherent culture and identified in vitro to observe the efficiency of transfection. The results indicated that the recombinant shuttle plasmid pShuttle-EGFP-mKGF digested with restriction endonucleases was confirmed by two products which length was about 0.6 kb and 5.1 kb, respectively; the recombinant plasmid pAdxsi EGFP-mKGF digested with restriction endonucleases was confirmed by 7 products; recombinant adenoviral vector Ad-EGFP-mKGF was amplified to titer of 1.6 * 10(10) pfu/ml. At 10 h after transfecting MSC began to express fluorescence at 6 to 8 days later, the fluorescence reached to the peak with infection rate of 92.3, at 28 days the expression of fluorescence was still observed. It is concluded that the recombinant adenoviral vector Ad-EGFP-mKGF is successfully constructed and can transfect MSC effectively and safely. PMID- 22541114 TI - [Human bone marrow mesenchymal stem cells have little preventive or therapeutic effect on rat arthritis induced by collagen]. AB - The aim of this study was to investigate if transfusion of mesenchymal stem cells (MSC) could exhibit beneficial effects on rheumatoid arthritis. Human bone marrow MSC were intraperitoneally injected into Wistar rats with collagen-induced arthritis at a dose of 10(7) on the next day (preventive group) or 2 weeks (treatment group) after collagen II induction, once a week for 2 weeks (preventive group) or 4 weeks (treatment group). The control group was given normal saline (NS) at corresponding time. The symptom scorings were documented weekly from the second week of the induction. On week 6, the hind joints of the rats were pathologically examined and the activation status of splenocytes was analyzed by flow cytometry. The results showed that all the rats developed arthritis and subsequent joint abnormality. On the sixth week, symptom scores of the rats that received MSC preventive (9.5 +/- 0.5) or therapeutic (9.4 +/- 0.6) infusions had no significant difference between each other, but were significantly greater than those of the NS controls (7.6 +/- 0.6, P < 0.05). Consistently, pathological examination on the involved knees showed that the synovitis and arthritis scorings of MSC treated rats were greatly elevated compared with NS controls. Furthermore, the ratios of CD86(+) cells in the spleens of MSC prevention, MSC treatment and NS control groups were (4.16 +/- 1.48), (4.06 +/- 1.97) and (4.15 +/- 2.04) respectively, while those of CD11b/c(+)CD86(+) cells were (1.04 +/- 0.68), (0.95 +/- 0.56) and (0.98 +/- 0.44), all of which were significantly higher than those of healthy controls [(0.97 +/- 0.18) and (0.30 +/- 0.17), P < 0.05 for both parameters]. It is concluded that MSC infusion has little beneficial effects on collagen-induced arthritis in rats, conversely, MSC therapy aggravated the damage of the involved joints, its underlying mechanisms need to be further investigated. PMID- 22541115 TI - [Bone marrow-derived mesenchymal stem cells regulate the proliferation and activity of natural killer cells]. AB - This study was aimed to explore the effect of bone marrow-derived mesenchymal stem cells (MSC) on proliferation and activity of natural killer (NK) and NK-T cells. MSC was co-cultured with peripheral mononuclear cells from healthy donors in presence of IL-2, phytohemagglutinin (PHA) and mouse anti-human CD3 McAb (culture condition known to expand NK cells). The ratio of NK cells and NK-T cells was measured by flow cytometry and the effect of MSC on killing activity of NK cells against K562 cells was detected by MTT method after co-cultured with different densities of MSC. The results showed that MSC inhibited the production of NK cells in a dose-dependent manner generally. At the densities of 0, 1 * 10(5) and 5 * 10(5)/ml, the ratios of NK cells in the co-culture conditions were (16.9 +/- 4.6), (14.0 +/- 8.6) and (6.4 +/- 4.6), respectively (P < 0.05). However, MSC could promote the formation of NK cells at lower MSC density (1 * 10(4)/ml), the ratio of NK cells reached to (20.9 +/- 7.1), which was higher than that of culture condition without MSC (P < 0.05). The different densities of MSC in the co-culture conditions had no much influence on the ratio of NK-T cells (P > 0.05). MTT assay showed that the killing activity of suspended cells in co culture system against K562 cells was parallel with the ratio of NK cells. Different densities of MSC regulated bidirectionally killing activity of NK to K562 cells by regulating bidirectionally ratio of NK cells. It is concluded that the MSC can promote the formation of NK cells and enhance its activity against tumor cells in the lower doses, while suppress the formation of NK cells and attenuate its tumor-killing effect in higher dose condition. PMID- 22541116 TI - [Ultrastructure of human umbilical cord mesenchymal stem cells]. AB - The purpose of this study was to observe the ultrastructure of human umbilical cord mesenchymal stem cells (hUCMSC). hUCMSC from full-term newborn umbilical cord were isolated and cultured by collagenase digestion, and then subcultured, amplification, and cell morphology was observed by microscopy. The immunophenotype and trilineage differentiation potential of hUCMSCs at passage 3 were analyzed. Transmission electron microscopy and scanning electron microscopy were used to observe the ultrastructure of hUCMSC. The results indicated that appearance of hUCMSC was spindle-shaped and polygonal, and nuclei were observed. hUCMSC expressed immunophenotype CD44, CD73, CD105, did not express CD34, CD45, CD31 and human leukocyte antigen HLA-DR. hUCMSC were capable of adipogenic, osteogenic, and cartilage differentiation; the short and thick microvilli processes were seen at the surface of hUCMSC by scanning electron microscope. Two different cell morphologies of hUCMSC were seen under transmission electron microscope, the one was a quiescent period in which a large and round or oval nucleus only one nucleolus were seen, cytoplasmic organelles were less; the other was in a relatively active period in which one or two nuclei in the same one cell were observed, the organelles were rich, structure was clear, expansion of the mitochondria was visible. It is concluded that the cells successfully isolated and cultured from umbilical cord, which possess biological characteristics of MSC and display two different states of ultrastructure. PMID- 22541117 TI - [Culture and pluripotentiality of murine compact bone-derived mesenchymal stem cells]. AB - This study was purposed to culture murine compact bone-derived mesenchymal stem cell (MSC) and analyze the immunological and trilineage differentiation potential. Tibia and femur were extracted. Bone marrow cells were flushed out and compact bone fragments were digested with collagenase. The digested cells were cultured in 6-well plates. The immunophenotype, immunosuppressive function and trilineage differentiation potential were analysed by flow cytometry, mixed lympocyte reaction and Oil red O, von Kossa and alcian blue straining, respectively. The results indicated that the pure compact bone MSC could be isolated with in 3 weeks. The resulting MSC had trilineage differentiation potential and immunosuppressive effect on mixed lymphocyte reaction. The count per minute (CPM) value in control group of BALB/c T cells cocultured with irradiated C57BL/6 T cells was (2.56 +/- 0.31) * 10(4), while CPM values of mixed lymphocyte cocultured with C57BL/6 compact bone MSC at ratios of 100:1 and 10:1 were (0.47 +/- 0.12) * 10(4) and (0.28 +/- 0.09) * 10(4). The CPM value of control group was higher than those of MSC cocultured group (P < 0.001). Compact bone-MSC had an immunosuppressive effect on mixed lymphocyte reaction in a dose dependent manner. It is concluded that murine compact bone has rich MSC and the primary MSC is contaminated with less hematopoietic cells. Murine compact bone MSC have immunosuppressive effect on mixed lymphocyte reaction and trilineage differentiation potential. Compact bone-MSC have promising experimental study value. PMID- 22541118 TI - [Mesenchymal stem cells release membrane microparticles in the process of apoptosis]. AB - Though mesenchymal stem cells (MSC) have been clinically used to repair a variety of damaged tissues, the underlying mechanisms remain elusively as the majority of the ex vivo expanded MSC die shortly after transplantation. To explore the mechanism in which the death cells play tissue repair effect, apoptosis of rat bone marrow MSC was induced by culturing cells in the conditions of hypoxia or/and serum-free medium, and the subcellular structures in the supernatants were analyzed. The results showed that apoptosis occurred in the presence of either hypoxia or serum-free condition as well, and the apoptotic proportion reached up to (17.44 +/- 2.15) after the cells were treated by hypoxia plus serum free culture for 72 hours. The flow cytometric analysis of the sub-cellular substances harvested by ultracentrifugation of the supernatants found that the MSC released substantial amount of membrane microparticles into the supernatants, which expressed CD29, CD44A and Annexin-V-binding phosphatidylserine. It is concluded that the MSC can release membrane microparticles after induction, the amount of these membrane microparticles was around 15-fold of the parent cell numbers. The membrane microparticles is the mediators in the cross-talk between the transplanted cells and their surrounding tissues. This study provides some novel information for the mechanisms of MSC therapy. PMID- 22541119 TI - [Changes of biological characteristics and gene expression profile of umbilical cord mesenchymal stem cells during senescence in culture]. AB - This study was purposed to investigate the changes of biological properties and expression patterns of the aging related genes in umbilical cord mesenchymal stem cells (UC-MSC) during in vitro culture. UC-MSC at passage 3 were served as the control cells and those at passage 15 were considered as the aged cells. The biological features of those two kinds of cells including morphology, proliferation activity and phenotypic profile were observed, and the differences of gene expression were analysed by the whole human genome oligo microarray. Several differential genes were selected for further confirmation by quantitative reverse transcription-polymerase chain reaction. The results showed that UC-MSC at passage 15 were larger in size and their proliferation rate was slower compared with those of cells at passage 3, while the positivity of CD44 and CD105 remained unchanged. Compared with UC-MSC at passage 3, relatively aged cells expressed higher levels of genes that are associated with small subunit of ribosome. Further analysis with Gene Ontology functional categories showed that the up-regulated genes were concentrated in those related to steroid biosynthesis, galactose metabolism and the development of autoimmune diseases and degenerative diseases and the down-regulated genes in UC-MSC at passage 15 were concentrated in cytoskeleton molecules, DNA structure binding, mRNA binding and protein function. Functional analysis with Kyoto Encyclopedia of Genes and Genomes functional pathway revealed that the expression of some genes responsible for ribosome composition was elevated while those of associated with extracellular matrix, focal adhesion and cell cycle progression were down regulated. It is concluded that UC-MSC become senescent due to the declines in metabolism and proliferation activities. PMID- 22541120 TI - [Impact of clopidogrel on gene profile of human umbilical vein endothelial cell line and bioinformatics analysis]. AB - This study was purposed to investigate the effect of clopidogrel on gene expression profile of cultured human umbilical vein endothelial cell (HUVEC) line (EA.hy926), and explore its potential molecule mechanism. A Affymetrix U133 plus 2.0 oligonucleotide microarray was applied to detect the alteration of gene expression profile induced by clopidogrel in HUVEC. Real time RT-PCR was used to verify the result of selected differentially expressing genes. The results showed that total 508 genes (including 139 up-regulated and 369 down-regulated genes) were obtained with differential expression more than 1.5-fold after clopidogrel (10 umol/L) acted on HUVEC for 48 h. Clopidogrel affected the expression levels of genes involved protein binding, transcription factor activity, zinc ion binding, regulation of DNA-dependent transcription, transcription, RNA splicing and so on. It is concluded that the clopidogrel modulate function of endothelial cells by regulating sets of genes through different pathway. PMID- 22541121 TI - [Establishment of a U266 cell line with stable Bmi-1 silencing by lentivirus mediated RNA interference]. AB - This study was aimed to construct lentivirus-mediated shRNA expression vector targeting Bmi-1 and establish a stable cell line U266-li, so as to pave the way for further research on function of Bmi-1 and application of shRNA to gene therapy. One pair of oligonucleotide sequences targeted at human Bmi-1 mRNA were designed and synthesized. The annealed oligonucleotide fragments were subcloned into pLVTHM vector. Virus particles were collected after the control or shRNA vectors were co-transfected with the psPAX2 packaging plasmid and the plasmid pMD2.G was enveloped into HEK-293T cells by using Lipofectamine2000. The U266 cells were transduced with 5 * 10(6) recombinant lentivirus-transducing units plus 6 ug/ml of polybrene. Real-time PCR and Western blot were used respectively to detect the expression of Bmi-1 and P14 after lentivirus transduction. DNA sequencing demonstrated that the lentivirus RNAi vector of Bmi-1 was constructed successfully and the virus was packaged in 293T cells. The titer of virus was 5 * 10(7) TU/ml. Stable transfected U266 cell line was established. As was expected, the mRNA and protein levels of Bmi-1 was reduced significantly in U266 cells after lentivirus transduction, whereas the mRNA and protein levels of P14 was upregulated. It is concluded that the lentiviral RNAi vector of Bmi-1 is constructed, and U266 stable cell line is established. PMID- 22541122 TI - [Clinical analysis on adult acute T-lymphoblastic leukemia]. AB - This study was aimed to summarize and analyze the clinical features and biological characteristics of adult acute T-lymphoblastic leukemia (T-ALL), and compare the efficacy of chemotherapy and transplantation in order to explore the factors influencing the long term survival and prognosis. Twenty-two T-ALL patients, all of whom were initially diagnosed according to MICM classification criteria from May 2000 to May 2010, were enrolled in this study. All patients received VDCLP regimen as the induction chemotherapy. In consolidation stage, some of the patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT) and the others underwent intensive chemotherapy. The clinical and laboratory parameters were summarized and the contribution to survival and efficacy was analyzed by using chi(2) test, Kaplan-Meier method, Cox regression analysis and log-rank test with the aid of SPSS13.0 software. The results showed that: (1) The median age of all 22 patients was 23.5 years (16 - 63 years). 15 patients with splenomegaly had much shorter event-free survival (EFS) period (P = 0.014) and overall survival (OS) period (P = 0.013). The median white blood cell (WBC) count was 148.82 (5.51-546.0) * 10(9)/L. 15 cases out of them had leucocytosis (WBC >= 80 * 10(9)/L), whose EFS period (P = 0.021) and OS time (P = 0.050) were reduced significantly. The similar condition was observed in 6 patients whose blood platelet (Plt) count was no more than 30 * 10(9)/L (P = 0.033 for EFS and P = 0.035 for OS, respectively); (2) Immunophenotypic analysis showed that from 22 cases 2 cases were of pro-T, 14 cases of pre-T, 3 cases of cortical-T and 3 cases of medullary-T. Supposing pro-T and pre-T as earlier period immunophenotype, cortical-T and medullary-T as advanced stage immunophenotype, there were significant differences between earlier period and advanced stage patients in terms of EFS and OS (P = 0.035 for EFS and P = 0.028 for OS, respectively); (3) Chromosome karyotype was analyzed in 19 cases at diagnosis, and among them 12 cases had normal karyotypes while abnormal karyotypes were observed in 7 cases. Correlation analysis showed that there were no significant differences between these two groups in time of EFS and OS; (4) The overall complete remission (CR) rate was 72.7 after the induction chemotherapy. The median CR period was 18.0 months. The EFS and OS rate were 57.9 and 67.1 for 1-year, and 23.0 EFS rate and 22.0 OS rate for 3-years, respectively. Six patients received allo-HSCT and the average EFS time and OS time were both 57.8 months, which were significantly longer than those of the intensive chemotherapy group (P = 0.001 and P = 0.002 for EFS and OS, respectively); (5) Cox regression analysis proved that allo-HSCT treatment was the independent favorable prognostic factor. It is concluded that higher CR rate can be achieved by using intensive induction chemotherapy in adult T-ALL, but the long term survival seems poor by chemotherapy only in consolidation treatment stage. Allo-HSCT is the optimal choice to improve the prognosis and the outcome. PMID- 22541123 TI - [An unusual child case of myeloid/natural killer cell precursor acute leukemia treated successfully with acute myeloid leukemia-oriented chemotherapy]. AB - This study was aimed to identify the characteristics of childhood myeloid/natural killer cell precursor acute leukemia (M/NKPAL), and to summarize the therapeutical experiences of this rare hematologic malignancy. A child case of M/NKPAL accompanied by CNS leukemia was enrolled in this study, the therapeutic regiments and the results of long time following up were analysed and evaluated. The results showed that the unusual child case of M/NKPAL with CNS infiltration was diagnosed, showing immunophenotype of CD7(+), CD33(+), CD34(+), CD56(+), HLA DR(+), MPO(-) and negative for other NK cell, T and B cell differentiation antigens; the chromosomal abnormalities were trisomy 8 and deletion of chromosome 12p. The child case was treated with daunorubicin and cytarabine, and achieved complete remission. Then, 5 courses of acute myeloid leukemia-oriented chemotherapy were given as consolidation chemotherapy, all of the 5 courses contained high dose cytarabine. This child case was given 9 times of lumbar puncture and intrathecal injection, besides these, this case was also given cranial radiotherapy with a dose of 36 Gy. After treated with these methods, the child case achieved long-term complete remission. It is concluded that the M/NKPAL is a rare disease with distinctive immunophenotypic characteristics, acute myeloid leukemia-oriented chemotherapy regimen with high dose of cytarabine may be able to induce long-term remission. PMID- 22541124 TI - [Effects of insulin on expression of insulin receptor and insulin-like growth factor-1 receptor and proliferation in Reh cells]. AB - This study was aimed to explore the effects of insulin on expression of insulin receptor (IR) and insulin-like growth factor-I receptor (IGF-IR) in Reh cells and promoting effect on proliferation of Reh cells. The proliferation of Reh cells were evaluated by CCK-8 assay. The expression levels of IR and IGF-IR mRNA in Reh cells at different times were detected by real-time quantitative polymerase chain reaction. The results showed that insulin promoted the proliferation of Reh cells in dose- and time-dependent manners. Compared with the control group, insulin promoted the proliferation of Reh cells obviously (P < 0.05). When Reh cells were treated with insulin 10(-9) mol/L for 24, 48 and 72 h, the relative quantity of IR expression (2(-DeltaCt1)/2(-DeltaCt2)) was 2.2520 +/- 0.7431, 1.9956 +/- 0.9692 and 3.9766 +/- 1.3189, respectively, the relative quantity of IGF-IR expression was 1.0803 +/- 0.2238, 1.6026 +/- 0.6158 and 3.1013 +/- 0.1008, respectively, compared with the control group. The expression levels of IR and IGF-IR mRNA in Reh cells treated with insulin were obviously increased compared with the control group. It is concluded that insulin promotes the proliferation of Reh cells. The high expression levels of IR and IGF-IR may closely related with the growth of leukemia cells. PMID- 22541125 TI - [Clinical analysis of invasive fungal infections in patients with hematologic malignancies]. AB - The aim of this study was to investigate the clinical situation of invasive fungal infections in patients with hematological malignancies, and discuss the susceptible factors and precautions. 541 patients with hematological malignancies from 2008 Jan to 2011 Dec in hospital 307 of Chinese PLA were statistically retrospectively analyzed in term of clinical manifestation, image examination, culture results of secretions, therapy and so on. The results showed that 63 out of 541 patients got invasive fungal infections. The respiratory tract and intestinal tract were the most common infection sites (62.34 and 19.48, respectively); Candida albicans (66.67) and Candida glabrata (12.82) were the most common pathogens. It is concluded that the main risk factors are as follows: primary diseases, chemotherapy, glucocorticoid, leukopenia after chemotherapy, applications of broad-spectrum antibiotics and aging. It is suggested that a stratification of risk factors is helpful in preventing and treating invasive fungal infections. PMID- 22541126 TI - [An improved protocol of preparing bone marrow cells for fluorescence in situ hybridization]. AB - This study was aimed to establish a smear protocol for preparing bone marrow cells and investigate its effect on fluorescence in situ hybridization (FISH) signal. Probe DNA (C-myc, MDM2, STK6) was labeled with Spectrum Green, PromoFluor 555 and PromoFluor-415 by nick translation. Five bone marrow samples were tested by two methods separately. Traditional method: after removing the erythrocytes by hypoosmotic solution, the bone marrow cells were fixed in methanol/acetic acid (3:1). Improved method: erythrocytes were removed using density gradient centrifugation and fixed in methanol. The samples were then fixed again in 2 formaldehyde for 5 min. The FISH signal was assessed by comparing the relative signal intensity of each fluorophore with the autofluorescence background. The results indicated that improved method greatly increased the ratio of fluorescence signal intensity in the Spectrum Green, PromoFluor-555 and PromoFluor-415 channel (traditional method: 4.3 +/- 0.19, 3.52 +/- 0.04, 3.07 +/- 0.08; improved method: 9.89 +/- 0.41, 7.55 +/- 0.5, 5.67 +/- 0.18, n = 5, P < 0.01) respectively. The signal intensity increased 2.32, 2.14 and 1.85-fold in the Spectrum Green, PromoFluor-555 and PromoFluor-415 channel respectively. In addition, the improved method decreased the split signals [traditional method: (15.8 +/- 1.74), (20.42 +/- 2.88), (23.2 +/- 3.02); improved method: (8.6 +/- 1.2), (12.28 +/- 1.33), (12.6 +/- 2.56), n = 5, P < 0.05]. It is concluded that the improved optimal procedure which facilitates FISH intensity on bone marrow cells is developed, showing potential for wide application in the diagnosis of hematologic diseases. PMID- 22541127 TI - [Separation and amplification of CD4(+)CD25(+) regulatory T cells from sensitized mice]. AB - The aim of this study was to separate and amplify CD4(+)CD25(+)Treg cells from splenocytes of sensitized mice. The percentage of CD4(+)CD25(+)Treg cells was detected by flow cytometry in sensitized and normal control mice. CD4(+)T, CD4(+)CD25(+)Treg and CD4(+)CD25(-) T cells were isolated from mouse splenocytes by MACS. CD4(+)CD25(+)Treg cells were expanded in vitro cultures in addition of CD3/CD28 MACSiBead and IL-2. The activity of cells was detected with 0.4 trypan blue staining. The purity of cells after sorting, the main surface marker and the level of Foxp3 were detected by flow cytometry. The results showed that CD4(+)CD25(+)Treg cell proportion was higher in sensitized mice than normal control mice (P < 0.05). The average purity of CD4(+)CD25(+)Treg cells was 87. The activity of these cells was more than 97, and the expression of Foxp3 in these cells was high. The amplification multiples achieved 42 times after 2 weeks in vitro. The percentage of CD4(+)CD25(+) regulatory T cells was 85.32, and the expression of Foxp3 decreased from (76.92 +/- 1.72) to (75.33 +/- 2.11) (P > 0.05). It is concluded that the sorting of CD4(+)CD25(+)Treg cells is isolated successfully by MACS without affecting the vitality of target cells. The amplification of CD4(+)CD25(+)Treg cells is successful in vitro. Expression of surface markers and Foxp3 gene does not obviously change after amplification, so that to establish a practical method to recover and enlarge the amount of CD4(+)CD25(+)Treg cells in good condition. PMID- 22541129 TI - [New progress of study on hematopoietic stem cell transplantation for myelodysplastic syndromes]. AB - Hematopoietic stem cell transplantation (HSCT) is the only way to cure myelodysplastic syndromes. At present there are several myelodysplastic syndromes scoring systems, including the International Prognostic Scoring System (IPSS), WHO Prognostic Scoring System (WPSS) and Simplified MDS Risk Score. These score systems can not only predict the probability of transplant success, but also help to determine the time of transplantation. For the older patient with serious complication, a suitable conditioning regimen can lower the risk of treatment related mortality. Complication management, individualized conditioning regimen, optimal timing of transplantation and donor selection should improve the curative effect of HSCT. However, post-transplantation relapse and graft-versus-host disease (GVHD) remain to be solved and further investigations are needed. In this review the MDS scoring system, factors influencing HSCT efficacy, the selection of HSCT donors and timing, the preconditioning intensity before HSCT and evaluation of HSCT efficacy are summarized. PMID- 22541128 TI - [Application of bone marrow indirect Coombs test and its clinical significance in diagnosis of immuno-related pancytopenia]. AB - This study was purposed to applicate the bone marrow indirect Coombs test and investigate its clinical significancies in diagnosis of immuno-related pancytopenia (IRP). 30 patients with pancytopenia including 22 cases of IRP and 8 cases of idiopathic cytopenia of undetermined significance (ICUS), and 15 patients with iron-deficiency anemia as controls were enrolled in this study. After incubation of the bone marrow supernatant of IRP patients and bone marrow nucleated cell (BMNC) of controls was used as experiment group, while the incubation of BMNC and bone marrow supernatant of controls was used as control group. After incubation for 45 min, the positive rate of membrane antibodies in bone marrow hematopoietic cells (CD15(+), GlyCoA(+) and CD34(+)cells) was detected by flow cytometry, and correlation analysis of positive rate with clinical data of patients were analyzed. The results showed that among 30 patients with pancytopenia (16 positive and 14 negative for bone marrow direct Coombs test) 16 cases showed positive for bone marrow indirect Coombs test, with positive rate 53.33. In the experiment group, the median positive rate of CD15(+)IgM was 0.34, which was significantly higher than that in control group (0.20, P < 0.05); the median positive rates of CD34(+) IgG and IgM were 0.64 and 0.21 respectively, which were significantly higher than those in control group (0.00, P < 0.05) and (0.00, P < 0.05); the positive rates of GlyCoA(+)IgG and IgM were (0.83 +/- 0.75) and (2.12 +/- 1.98) respectively, which were significantly higher than those in control group [(0.47 +/- 0.43), P < 0.05, (0.68 +/- 0.64), P < 0.01]; the positive rates of CD15(+) IgG and IgM were positively correlated with the ratio of CD5(+)B cells. The positive rates of GlyCoA(+) IgG and IgM negatively correlated with the Hb level, percentage of reticulocytes, the ratio of bone marrow erythroid lineage and DC1/DC2 positively correlated with the ratio of CD5(+)B cells and indirect bilirubin level. It is concluded that antibodies (IgG or IgM) aiming at the bone marrow hematopoietic cells exist in the supernatant of some IRP and ICUS patients, and may act on the membrane protein of the normal BMNC. These antibodies correlate with the prognosis of IRP. PMID- 22541130 TI - [Advancement of insulin effecting signaling pathway of leukemia cell proliferation]. AB - Many reports have documented a role of insulin and insulin-like growth factor 1 (IGF-1) as growth factors in many cancers. The sequence and structure of insulin receptor (IR) and IGF receptor (IGF-1R) are highly similar. Both receptors are overexpressed in leukemia cells.Studies indicate that insulin can enhance the signal of the phosphoinositide 3-kinase/Akt pathways by activating IR or IGF-1R or hybrid IR/IGF-IR receptors, resulting in the proliferation of leukemia cells. High concentration of insulin may inhibit the growth of leukemia cells, the mechanism of which remains to be unclear. Inhibiting IR and IGF-IR can diminish the proliferation of leukemia cells. Therefore, the assumption of IR/IGF-1R as a potential therapeutic target in leukemia appears reasonable. This article summarizes the recent advancement associated with the signaling pathway of insulin effecting the proliferation of leukemia cells. PMID- 22541131 TI - [Research progress of proto-oncogene c-myb in megakaryocyte-erythroid hematopoiesis]. AB - The nuclear proto-oncogene c-myb is an essential regulator of hematopoiesis, it involves in the growth, survival, proliferation and differentiation of hematopoietic cells. More recently, different cell lines and transgenic mouse studies have suggested that c-myb plays a pivotal role in the megakaryocyte erythroid progenitor cell lineage commitment. The deletion of the proto-oncogene c-myb would lead to profoundly impaired definitive erythropoiesis, but little influence in definitive megakaryopoiesis. Moreover, transient transfection and immunoprecipitation studies have demonstrated that c-myb exerts its physiological function in normal hematopoiesis by influencing a network of regulator molecules. Now therefore, insight into the structure, function and related molecular regulation mechanism of c-myb gene can help to further clarify its function in megakaryocyte-erythroid hematopoiesis and can provide new ideas for molecular target therapy of the platelet diseases and red blood cell diseases. In this article, c-myb structure, function and related effects involved in megakaryocyte erythroid hematopoiesis as well as related molecular mechanisms are reviewed. PMID- 22541132 TI - Human ocular filariasis: further evidence on the zoonotic role of Onchocerca lupi. AB - BACKGROUND: Among ocular vector-borne pathogens, Onchocerca volvulus, the agent of the so-called "river blindness", affects about 37 million people globally. Other Onchocerca spp. have been sporadically reported as zoonotic agents. Cases of canine onchocerciasis caused by Onchocerca lupi are on the rise in the United States and Europe. Its zoonotic role has been suspected but only recently ascertained in a single case from Turkey. The present study provides further evidence on the occurrence of O. lupi infesting human eyes in two patients from Turkey (case 1) and Tunisia (case 2). The importance of obtaining a correct sample collection and preparation of nematodes infesting human eyes is highlighted. METHODS: In both cases the parasites were identified with morpho anatomical characters at the gross examination, histological analysis and anatomical description and also molecularly in case 1. RESULTS: The nematode from the first case was obviously O. lupi based on their morphology at the gross examination, histological analysis and anatomical description. In the second case, although the diagnostic cuticular characters were not completely developed, other features were congruent with the identification of O. lupi. Furthermore, the morphological identification was also molecularly confirmed in the Turkish case. CONCLUSIONS: The results of this study suggest that O. lupi infestation is not an occasional finding but it should be considered in the differential diagnosis of other zoonotic helminths causing eye infestation in humans (e.g., D. immitis and Dirofilaria repens). Both cases came from areas where no cases of canine onchocerciasis were previously reported in the literature, suggesting that an in depth appraisal of the infestation in canine populations is necessary. Physicians and ophthalmologists are advised on how to preserve nematode samples recovered surgically, to allow a definitive, correct etiological diagnosis. PMID- 22541133 TI - Occurrence and recurrence of spontaneous chronic subdural haematoma is associated with a factor XIII deficiency. AB - OBJECTIVE: In some patients, chronic subdural haematoma (cSDH) appears to occur spontaneously with frequent re-bleeding events. The pathophysiology of this phenomenon is still poorly understood. Because coagulation factor XIII (FXIII) is known to be involved in vascular integrity, endothelial barrier function and wound healing, we evaluated the role of FXIII in spontaneous cSDH. METHODS: We prospectively scrutinised the origin of cSDH in 117 patients and identified a subgroup of patients suffering from spontaneous cSDH who were included in this study. We analysed the plasma activity of FXIII and standard coagulation parameters and compared these data to age- and sex-matched healthy controls. We assessed the occurrence of re-bleeding events using clinical and imaging data and compared FXIII activity in patients with and without re-bleeding events. RESULTS: Out of 117 cSDH patients, 18 individuals suffered from spontaneous cSDH in this study. The patients with spontaneous cSDH showed significantly lower FXIII activity than the control group (65% [52.75, 80.25] (median [IQR]) vs. 93% [81, 111], P=0.001), whereas standard coagulation parameters did not differ significantly between the groups. Six patients developed re-bleeding events after haematoma evacuation, and these patients expressed significantly lower FXIII activity compared to the other 12 patients (47.5% [33.5, 64] vs. 78.5% [58, 87], P=0.005). The patient group with FXIII<=68.5% differed significantly from the group with FXIII>68.5% when categorised by the occurrence of re-bleeding events (n=6/9 vs. n=0/9, P=0.009). This cut-off value predicted the re-bleeding events with a sensitivity of 100% and a specificity of 75% (positive predictive value: 66%, negative predictive value: 100%). CONCLUSION: FXIII deficiency may play a pathophysiological role in spontaneous cSDH, so we suggest investigating FXIII activity because it may predict re-bleeding events after treatment. In individuals with considerably low FXIII activity, FXIII substitution may mitigate the chronic nature of this disease. PMID- 22541135 TI - Outcomes of patients with end-stage renal disease (ESRD) under chronic hemodialysis requiring continuous renal replacement therapy (CRRT) and patients without ESRD in acute kidney injury requiring CRRT: a single-center study. AB - In most continuous renal replacement therapy (CRRT) studies, end-stage renal disease (ESRD) patients were excluded and the outcomes of patients with ESRD treated with chronic hemodialysis (HD) were unknown. The purposes of this study were to (1) evaluate short-term patient survival and (2) compare the survival of conventional HD patients needing CRRT with the survival of non-ESRD patients in acute kidney injury (AKI) requiring CRRT. We evaluated adults (>18 years) requiring CRRT who were treated in the intensive care unit (ICU) at Kosin University Gospel Hospital from January 1, 2009 to December 31, 2010. A total of 100 (24 ESRD, 76 non-ESRD) patients underwent CRRT during the study period. Patients were divided into two major groups: patients with ESRD requiring chronic dialysis and patients without ESRD (non-ESRD) with AKI. We compared the survival of conventional HD patients requiring CRRT with the survival of non-ESRD patients in AKI requiring CRRT. For non-ESRD patients, the 90-day survival rate was 41.6%. For ESRD patients, the 90-day survival rate was 55.3%. Multivariate Cox proportional hazards analyses demonstrated that conventional HD was not a significant predictor of mortality (hazard ratio [HR]: 0.334, 95% confidence interval [CI]: 0.063-1.763, P = 0.196), after adjustment for age, gender, presence of sepsis, APACHE score, use of vasoactive drugs, number of organ failures, ultrafiltration rate, and arterial pH. The survival rates of non-ESRD and ESRD patients requiring CRRT did not differ; ESRD with conventional HD patients may be not a significant predictor of mortality. PMID- 22541134 TI - Systemic-to-pulmonary collateral flow in patients with palliated univentricular heart physiology: measurement using cardiovascular magnetic resonance 4D velocity acquisition. AB - BACKGROUND: Systemic-to-pulmonary collateral flow (SPCF) may constitute a risk factor for increased morbidity and mortality in patients with single-ventricle physiology (SV). However, clinical research is limited by the complexity of multi vessel two-dimensional (2D) cardiovascular magnetic resonance (CMR) flow measurements. We sought to validate four-dimensional (4D) velocity acquisition sequence for concise quantification of SPCF and flow distribution in patients with SV. METHODS: 29 patients with SV physiology prospectively underwent CMR (1.5 T) (n = 14 bidirectional cavopulmonary connection [BCPC], age 2.9 +/- 1.3 years; and n = 15 Fontan, 14.4 +/- 5.9 years) and 20 healthy volunteers (age, 28.7 +/- 13.1 years) served as controls. A single whole-heart 4D velocity acquisition and five 2D flow acquisitions were performed in the aorta, superior/inferior caval veins, right/left pulmonary arteries to serve as gold-standard. The five 2D velocity acquisition measurements were compared with 4D velocity acquisition for validation of individual vessel flow quantification and time efficiency. The SPCF was calculated by evaluating the disparity between systemic (aortic minus caval vein flows) and pulmonary flows (arterial and venour return). The pulmonary right to left and the systemic lower to upper body flow distribution were also calculated. RESULTS: The comparison between 4D velocity and 2D flow acquisitions showed good Bland-Altman agreement for all individual vessels (mean bias, 0.05 +/ 0.24 l/min/m2), calculated SPCF (-0.02 +/- 0.18 l/min/m2) and significantly shorter 4D velocity acquisition-time (12:34 min/17:28 min,p < 0.01). 4D velocity acquisition in patients versus controls revealed (1) good agreement between systemic versus pulmonary estimator for SPFC; (2) significant SPCF in patients (BCPC 0.79 +/- 0.45 l/min/m2; Fontan 0.62 +/- 0.82 l/min/m2) and not in controls (0.01 + 0.16 l/min/m2), (3) inverse relation of right/left pulmonary artery perfusion and right/left SPCF (Pearson = -0.47,p = 0.01) and (4) upper to lower body flow distribution trend related to the weight (r = 0.742, p < 0.001) similar to the controls. CONCLUSIONS: 4D velocity acquisition is reliable, operator independent and more time-efficient than 2D flow acquisition to quantify SPCF. There is considerable SPCF in BCPC and Fontan patients. SPCF was more pronounced towards the respective lung with less pulmonary arterial flow suggesting more collateral flow where less anterograde branch pulmonary artery perfusion. PMID- 22541136 TI - Therapeutic efficacy of milbemycin oxime/praziquantel oral formulation (Milbemax(r)) against Thelazia callipaeda in naturally infested dogs and cats. AB - BACKGROUND: Over the last few decades, canine and feline thelaziosis caused by Thelazia callipaeda eye worms has gained the attention of the veterinary community due to the spread of this ocular infestation in geographical areas previously regarded as non endemic. The therapeutic efficacy of milbemycin oxime/praziquantel tablets (Milbemax(r)) against T. callipaeda was tested in naturally infested dogs and cats. METHODS: From January 2009 to July 2011 a placebo controlled and randomized field study was conducted in T. callipaeda endemic areas of Switzerland (CH) and Italy (ITA) involving client-owned animals. Dogs (n = 56) and cats (n = 31) were physically examined at enrolment Day 0 (D0) and twice afterwards (D7 and D14). Infested animals were orally treated with Milbemax(r) or with placebo tablets on D0 and, if an animal was found still infested with T. callipaeda, also on D7. On D14 nematodes were flushed from the conjunctiva, identified and counted. RESULTS: Out of 56 dogs, 43 were included in the statistical analysis, whereas 13 were excluded because the products under investigation were not administered with food, as required by the label. On D7 and D14, 72.7% and 90.9% of treated dogs were eye worm free, whereas in the placebo group 95.2% and 76.2% still harbored nematodes, resulting in a mean percentage worm count reduction for the Milbemax(r) group of 86.1% and 96.8%, respectively. Both results were significantly higher (p = 0.0001) than the placebo group. Out of the 31 cats included in the study at D7 and D14, 53.3% and 73.3% treated with Milbemax(r) were free of T. callipaeda, while 81.3% and 73.3 in the placebo group were still harbouring eye worms, resulting in a mean percentage worm count reduction for the treated group of 62.2% and 80.0%, respectively. Both results were significantly higher (p = 0.0106 and p = 0.0043) than the placebo group. CONCLUSIONS: The commercial formulation of milbemycin oxime at the minimal dose of 0.5 mg/kg and 2 mg/k in dogs and cats, respectively, showed a high therapeutic efficacy in curing T. callipaeda infestations. The advantages of an oral application are additionally increased by the large spectrum of activity of praziquantel and milbemycin oxime against Cestodes and Nematodes infesting dogs and cats. PMID- 22541137 TI - N-acetylcysteine may improve residual renal function in hemodialysis patients: a pilot study. AB - Clinical outcomes in chronic dialysis patients are highly dependent on preservation of residual renal function (RRF). N-acetylcysteine (NAC) may have a positive effect on renal function in the setting of nephrotoxic contrast media administration. In our recent study, we showed that NAC may improve RRF in peritoneal dialysis patients. The aim of the present study was to investigate the effect of NAC on RRF in patients treated with chronic hemodialysis. Prevalent chronic hemodialysis patients with a residual urine output of at least 100 mL/24 hours were included. The patients were administered oral NAC 1200 mg twice daily for 2 weeks. Residual renal function was assessed at baseline and at the end of treatment using a midweek interdialytic urine collection for measurement of urine output and calculation of residual renal Kt/V and glomerular filtration rate (GFR). Residual GFR was measured as the mean of urea and creatinine residual renal clearance. Each patient served as his own control. Twenty patients were prospectively enrolled in the study. Administration of NAC 1200 mg twice daily for 2 weeks resulted in significant improvement in RRF: urine volume increased from 320 +/- 199 to 430 +/- 232 mL/24 hours (P < 0.01), residual renal Kt/V increased from 0.19 +/- 0.12 to 0.29 +/- 0.14 (P < 0.01), and residual GFR increased from 1.6 +/- 1.6 to 2.4 +/- 2.3 mL/minute/1.73 m(2) (P < 0.01). N acetylcysteine may improve RRF in patients treated with chronic hemodialysis. PMID- 22541139 TI - Pyogenic liver abscess in the elderly: what we have learned? PMID- 22541138 TI - Spatial and temporal dynamics of malaria transmission in rural Western Kenya. AB - BACKGROUND: Understanding the relationship between Plasmodium falciparum malaria transmission and health outcomes requires accurate estimates of exposure to infectious mosquitoes. However, measures of exposure such as mosquito density and entomological inoculation rate (EIR) are generally aggregated over large areas and time periods, biasing the outcome-exposure relationship. There are few studies examining the extent and drivers of local variation in malaria exposure in endemic areas. METHODS: We describe the spatio-temporal dynamics of malaria transmission intensity measured by mosquito density and EIR in the KEMRI/CDC health and demographic surveillance system using entomological data collected during 2002-2004. Geostatistical zero inflated binomial and negative binomial models were applied to obtain location specific (house) estimates of sporozoite rates and mosquito densities respectively. Model-based predictions were multiplied to estimate the spatial pattern of annual entomological inoculation rate, a measure of the number of infective bites a person receive per unit of time. The models included environmental and climatic predictors extracted from satellite data, harmonic seasonal trends and parameters describing space-time correlation. RESULTS: Anopheles gambiae s.l was the main vector species accounting for 86% (n=2309) of the total mosquitoes collected with the remainder being Anopheles funestus. Sixty eight percent (757/1110) of the surveyed houses had no mosquitoes. Distance to water bodies, vegetation and day temperature were strongly associated with mosquito density. Overall annual point estimates of EIR were 6.7, 9.3 and 9.6 infectious bites per annum for 2002, 2003 and 2004 respectively. Monthly mosquito density and EIR varied over the study period peaking in May during the wet season each year. The predicted and observed densities of mosquitoes and EIR showed a strong seasonal and spatial pattern over the study area. CONCLUSIONS: Spatio-temporal maps of malaria transmission intensity obtained in this study are not only useful in understanding variability in malaria epidemiology over small areas but also provide a high resolution exposure surface that can be used to analyse the impact of transmission on malaria related and all-cause morbidity and mortality. PMID- 22541140 TI - Predictive factors for operation and mortality following renal trauma. PMID- 22541141 TI - Investigation on signal transduction pathways after H(1) receptor activated by histamine in C6 glioma cells: involvement of phosphatidylinositol and arachidonic acid metabolisms. AB - BACKGROUND: Information related to histamine-induced cellular responses in C6 glioma cells through second messenger pathways has not been fully studied, especially the involvement of arachidonic acid (AA) metabolism. In addition, specific labeled ligand binding to histamine receptor sites still needs to be clarified. METHODS: Labeled mepyramine ligand was used to study its binding sites; [(3)H] inositol was used to detect inositol 4-phosphate (IP(1)) formation, and fura-2/AM was used to detect intracellular free calcium ion ([Ca(2+)]i) level activated by the phosphatidylinositol-phospholipase C (PI-PLC) pathway. Also, labeled AA was used to detect the metabolism of AA and its metabolites release via the activation of phospholipase A2 in the presence of histamine. RESULTS: C6 glioma cells incubated with histamine in the presence of 10 mM LiCl for 60 minutes induced an increase of IP(1) and glycerophosphoric-inositol (GPI) accumulation. In addition, histamine caused an increase of extracellular AA with its metabolite release, eliciting a transient and sustained increase of free [Ca(2+)]i. The sustained increase of [Ca(2+)]i was almost or completely blocked by La(3+) and excess ethylene diamine tetraacetic acid. The calcium ion influx associated with the sustained phase required the presence of histamine on the receptor sites, and could be blocked by a H(1) antagonist, chlorpheniramine. CONCLUSION: C6 glioma cells possess histamine H(1) receptors that have affinity towards [(3)H]mepyramine binding, and are coupled to PI-PLC to generate inositol phosphates and to increase [Ca(2+)]i, and they are coupled to phospholipase A2 (PLA2) to generate GPI and AA with its metabolite release. The transient increase in [Ca(2+)]i can be attributed to Ca(2+) release from intracellular stores, whereas the sustained increase in [Ca(2+)]i is due to influx of extracellular calcium ions. The sustained increase in [Ca(2+)]i plays a role in the activation of histamine receptor-coupled PLA2. PMID- 22541142 TI - Long-term follow-up of ulcerative colitis in Taiwan. AB - BACKGROUND: The incidence of ulcerative colitis (UC) has been increasing in Asia recently, but little long-term follow-up data is available. We aimed to understand the clinical characteristics of UC patients in the National Taiwan University Hospital (NTUH), a tertiary referral center in Taiwan. METHODS: A retrospective study was conducted to review data from January 1, 1988 through December 31, 2008 compiled at NTUH. Patients' clinical information, demographic data, endoscopic pictures, treatment regimens, pathologic, and outcome details were reviewed, recorded, and analyzed. RESULTS: A total of 406 patients were included (233 males and 173 females; median age at diagnosis was 36 years). The follow-up period ranged from 0.25 to 40.8 (mean, 7.3) years. The prevalence of UC in Taiwan was at least 7.4/100,000 in 2008. Bloody stool was the most common presentation (77.3%). Total colon was the most common (41.0%) disease involvement and proctitis the least common (21.1%). Six patients (1.5%) died during the follow up. Most of the UC patients (72.4%) could be controlled with 5 aminosalicylic acid alone, but about one third (30.9%) were admitted for treating the UC or UC-related complications. Twenty-three patients (5.5%) were treated surgically. Extra-gastrointestinal tract manifestations were noted in 4.5% of the UC patients, with primary sclerosing cholangitis (6 in 406, 1.5%) the most common. Colon cancer/severe dysplasia occurred in six (1.5%) of the patients. CONCLUSION: The incidence of UC has increased in Taiwan. Interestingly, CRC/dysplasia and PSC occur more frequently here than in other Asian nations. PMID- 22541143 TI - Delayed primary closure versus primary closure for wound management in perforated appendicitis: a prospective randomized controlled trial. AB - BACKGROUND: It is still a matter of debate whether delayed primary closure (DPC) of contaminated abdominal incisions reduces surgical site infections compared with a primary closure (PC). The aim of this study was to determine the optimal method of wound closure for patients with perforated appendicitis. METHODS: A total of 70 patients with perforated appendicitis were included. They were randomized to have their surgical incisions (skin and subcutaneous tissue) either PC or left open with Betadine-soaked gauze packing for DPC on the fifth postoperative day or later if the wound conditions were inappropriate for closure. A wound was considered infected if pus discharged from the incision site. The main outcome measures were the incidence of wound infection and the length of hospital stay (LOS). RESULTS: In the entire series, wound infection developed after incision closure in 21.4% of the patients. The PC group had a higher incidence of wound infection (38.9% vs. 2.9%, p<0.001) and longer LOS (8.4 days vs. 6.3 days, p=0.038). CONCLUSION: Delayed primary closure is the optimal management strategy for perforated appendicitis wounds. It significantly reduces the wound infection rate and length of stay. PMID- 22541144 TI - Magnetic resonance imaging guided biopsy of musculoskeletal lesions. AB - BACKGROUND: Minimally invasive interventional biopsy procedures have the advantages of accurate localization, small incisions, and rapid recovery. The purpose of this study was to clinically test and evaluate the efficacy of the magnetic resonance imaging (MRI)-guidance techniques for obtaining musculoskeletal biopsies using the appropriate imaging modalities and instruments. METHODS: We used MRI-compatible biopsy needles from the Invivo Bone Biopsy Set (Daum, Germany), and a 1.5-T closed-magnet MRI scanner was used to perform the MRI-guided biopsy. The pulse sequences included fast spin echo T1- and T2-weighted imaging and gradient echo imaging. The inclusion criteria included the presence of bone or soft tissue masses, infectious disease, and other nonspecific lesions that required tissue confirmation. Lesions that could not be visualized by computed tomography (CT) or other imaging modalities were preferred. RESULTS: From January 2005 through December 2009, 23 patients (12 males and 11 females, aged 11-82 years) underwent musculoskeletal MRI-guided biopsy. The biopsy locations were as follow: spine (n = 12), tibia (n = 3), pelvis (n = 1), femur (n = 2), scapula (n = 1), humerus (n = 1), ulna (n = 1), scapula (n = 1), and soft tissue mass of the shoulder (n = 1). The final diagnoses included bone metastasis (n = 7), spinal osteomyelitis and discitis (n = 5), osteonecrosis after chemotherapy (n = 4), bone marrow change or benign lesion without malignancy (n = 3), insufficiency fracture (n = 1), long bone osteomyelitis (n = 1), soft tissue metastasis (n = 1), and perineural ganglion cyst (n = 1). In 10 of the 23 cases, the lesions were barely visualized or invisible on CT guidance. Pathologic analysis and laboratory culturing revealed that the lesions were successfully accessed by MRI-guided biopsy in 100% (23/23) of cases. No obvious complications developed during or after the procedures. CONCLUSION: Biopsy under MRI guidance is especially valuable for the localization of bone marrow lesions, viable tumors (after chemotherapy or radiation), and lesions that cannot be visualized using CT. It is both accurate and safe, is a good alternative biopsy method, and may be a good adjunctive technique for the localization of bone lesions for radiofrequency ablation or other interventional procedures. PMID- 22541145 TI - Cefuroxime-impregnated cement and systemic cefazolin for 1 week in primary total knee arthroplasty: an evaluation of 2700 knees. AB - BACKGROUND: Infection is one of the most devastating complications after primary total knee arthroplasty (TKA). Antibiotics-impregnated cement has been used and proven effective in preventing deep infection. This study was to evaluate the long-term results of using cefuroxime-impregnated cement and systemic cefazolin for one week to assess their efficacy in preventing infection of primary TKA. METHODS: From 1999 to 2007, 2700 cases of primary TKA were performed with cemented fixation of all patellar, tibial, and femoral components. Cefuroxime impregnated cement for fixation and systemic cefazolin for one week were selected in all cases. The average follow-up period was 89 months (range, 40-140). The effects of this selected regime in the periprosthetic infection were evaluated. RESULTS: A total of eight infections occurred after primary TKA, including five deep infections (0.19%) and three superficial infections (0.11%) in the 2700 knees. No loosening or osteolysis was noted. CONCLUSION: Comparable with other measurements, cefuroxime-impregnated cement, accompany by systemic cefazolin for 1 week was shown to control postoperative deep infection to 0.19% (after primary TKA was performed in an operative setting without lamina flow and body exhaust suit). PMID- 22541147 TI - Effect of oxidized regenerated cellulose on the healing of pharyngeal wound: an experimental animal study. AB - BACKGROUND: This study aimed to investigate the relationship between oxidized regenerated cellulose (ORC) and mucosa healing in an experimental animal model. METHODS: Fifteen adult Sprague-Dawley rats were randomly divided into three groups that underwent different wound treatments. In Group 1, no pharyngeal wound was created. In Group 2, the pharyngeal wound was sutured with Prolene only. In Group 3, the pharyngeal wound was sutured with Prolene, and covered with one layer of ORC before closure of the skin wound. The animals were euthanized either 5 or 10 days after operation, and wound conditions were inspected and recorded. Specimens including sections of larynx and pharynx/upper esophagus were taken for microscopic and molecular biological examination. RESULTS: The pharyngotomy/esophagotomy wounds achieved good healing outcomes 10 days after operation. Wounds treated with ORC had significantly diminished inflammatory cell infiltration in microscopic examination when compared with that of those without ORC 5 days after operation. The matrix metalloproteinases (MMP) expression level was higher in wounds of Group 2 and Group 3, when compared with that of group 1. In addition, the MMP expression level was lower in the ORC-treated wounds when compared with that of those without ORC. There was no significant difference in fibroblast proliferation, collagen deposition, endothelin-1, alpha-smooth muscle actin, and transforming growth factor beta 1 expression level between wounds treated with ORC and those without ORC. CONCLUSION: Reduced inflammatory response and decreased MMP expression level was observed in ORC-treated wounds. Whether ORC facilitates mucosa healing requires further investigation. PMID- 22541146 TI - Ductus venosus Doppler velocimetry in normal pregnancies from 11 to 13 + 6 weeks' gestation - a Taiwanese study. AB - BACKGROUND: To investigate flow in the ductus venosus at 11-13 + 6 weeks of gestation in women with normal pregnancies in the Taiwanese population. METHODS: Two hundred and fifty-two normal singleton pregnancies with gestational ages ranging from 11 to 13 + 6 weeks were examined in this study. The pulsatility index for veins (PIV), resistance index (RI), peak velocity during ventricular systole (S-wave), and peak velocity during ventricular diastole (D-wave) were recorded from the ductus venosus. RESULTS: We analyzed 252 participants who all fulfilled the inclusion and exclusion criteria of our study. The mean maternal age was 31 (range 19-45 years), with a corresponding gestational age of 12 + 4 weeks (range 11-13 + 6). No significant change was found in the vascular indices as gestational age increased for the S-wave (S-wave = 1.4214 (GA) + 17.448, r = 0.09, P = 0.154), PIV (PIV = -0.0358 (GA) + 1.4143, r = -0.05, P = 0.378) and RI (RI = -0.035 (GA) + 1.1478, r = -0.064, P = 0.468). In contrast, the D-wave behaved differently from the other variables. There was a significant increase (r = 0.155, P = 0.013) in the D-wave with gestational age (D-wave = 1.4896 (GA) - 7.1547). CONCLUSION: D-wave velocity in the ductus venosus increased with gestational age. S-wave peak velocity showed an increasing trend and PIV showed a decreasing trend with gestational age, but they did not reach statistical significance. PMID- 22541148 TI - Foreign body in the ureter: a particle of glue after transarterial embolization of a renal pseudoaneurysm during percutaneous nephrostomy. AB - Reports on foreign bodies within the ureter are extremely rare in the literature. Herein, we present a case of a foreign body in a ureter, specifically a particle of glue resulting from transarterial embolization of a renal pseudoaneurysm secondary to percutaneous nephrostomy. Emergent transarterial embolization was required due to life-threatening active bleeding of the pseudoaneurysm. However, the glue material subsequently fell into the ureter where it became a foreign body, resulting in obstructive uropathy. Several surgical interventions, including endoscopic and laparoscopic methods, were performed to retrieve the foreign body, but these attempts were unsuccessful. Finally, the glue material was spontaneously passed out by chance. To the best of our knowledge, this type of complication (a glue particle left over from an embolization procedure migrating into the urinary collecting system) has never been reported. We recommend close follow-up examinations after transarterial embolization for renal pseudoaneurysm in order to avoid possible obstructive uropathy caused by glue materials or coils. PMID- 22541149 TI - Acute appendicitis with superior mesenteric vein septic thrombophlebitis. AB - Septic thrombophlebitis of the superior mesenteric vein (SMV) is rarely caused by acute appendicitis. The clinical symptoms of SMV thrombophlebitis are varied and atypical, so the diagnosis is commonly delayed, resulting in a reported mortality rate of 30%-50%. We report a case of SMV septic thrombophlebitis caused by acute appendicitis in which the patient was successfully treated with surgical intervention, appropriate antibiotics, and anticoagulation therapy. A follow-up abdominal computed tomography scan after 3 months of treatment showed that the SMV thrombosis had been resolved. PMID- 22541150 TI - Persistent cloaca presenting with a perineal cyst: Prenatal ultrasound and magnetic resonance imaging findings. AB - A 40-year-old, primigravid woman presented at 23 weeks of gestation for evaluation of an extra-abdominal echogenic cystic mass of the fetus. Amniocentesis revealed a karyotype of 46,XX. Prenatal ultrasound showed a two vessel umbilical cord, hydrocolpos, and distended bladder, urethra, and colon, and a perineal cystic mass. The kidneys and amniotic fluid amount were normal. Fetal magnetic resonance imaging revealed ascites, hydrocolpos, distended urinary bladder and colon, high rectum, and a perineal cyst. The fetus postnatally manifested persistent cloaca. The perineum was distended and smooth, without patent anal, vaginal, and urethral openings. The external genitalia were ambiguous with no labia majora, labia minora, or clitoris. The perineal cyst had a very small single orifice. We suggest that cloacal anomalies be considered in any female fetus with hydrocolpos, distended bladder and colon, ascites, and a perineal cyst. PMID- 22541152 TI - Orthoses and sex, changes to expect. PMID- 22541153 TI - Pyrocarbon proximal interphalangeal joint arthroplasty: minimum two-year follow up. AB - PURPOSE: To report the outcome and complications from pyrocarbon proximal interphalangeal (PIP) joint arthroplasty at a minimum of 2 years of follow-up. METHODS: A retrospective case review was performed on 72 patients with an average age of 57 years, and a total of 97 pyrocarbon PIP joint arthroplasties. Patient demographics, diagnosis, implant revisions, and other repeat surgeries were recorded. Subjective outcome was evaluated at latest follow-up with the Disabilities of the Arm, Shoulder, and Hand score; Patient Evaluation Measure; and visual analog scores of pain, satisfaction, and appearance. Objective outcomes included PIP joint range of motion, grip strength, and radiographic assessment of alignment and loosening. RESULTS: The principal diagnosis was primary osteoarthritis in 43 patients(60%), posttraumatic arthritis in 14 (19%), rheumatoid arthritis in 9 (13%), and psoriatic arthritis in 6 (8%). The average follow-up was 60 months (range, 24-108 mo). Twenty-two of 97 digits (23%) had repeat surgery without revision, and 13 digits (13%) had revision at an average of 15 months. There were no significant differences in preoperative and postoperative range of motion. The average Disabilities of the Arm, Shoulder, and Hand score was 22, and the average pain score was zero. Implant migration and loosening was observed but was not related to clinical outcome or revision. CONCLUSIONS: The survival of pyrocarbon PIP joint arthroplasty was 85% (83 of 97) at 5 years of follow-up, with high patient satisfaction. Patients should be advised that the procedure achieves good relief of pain but does not improve range of motion. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 22541154 TI - Radiographic appearance and patient outcome after ulnar shortening osteotomy for idiopathic ulnar impaction syndrome. AB - PURPOSE: Radiographic carpal chondromalacia (RCC) was defined as the presence of cortical sclerosis or subchondral changes, such as a lucent defect or cystic changes in a carpal on plain radiographs. The purpose of this study was to investigate the factors associated with the occurrence of RCC in idiopathic ulnar impaction syndrome and to determine the efficacy of ulnar shortening osteotomy on patient outcome and RCC. METHODS: Thirty-nine patients (42 wrists) with idiopathic ulnar impaction syndrome were treated with either ulnar shortening osteotomy or arthroscopic wafer resection. Patients were divided into 2 groups according to the presence (RCC group; 17 patients, 19 wrists) or absence (non-RCC group: 22 patients, 23 wrists) of RCC on preoperative radiographs. To determine the factors associated with RCC, a comparative analysis of these 2 groups was performed with respect to sex, age, duration of symptoms, positive ulnar variance, pain scores, and Chun and Palmer grading system. The RCC area was measured on serial radiographs taken during follow-up. Progressive changes of RCC area and clinical outcomes were evaluated. RESULTS: Patients in the RCC group were older, exhibited greater positive ulnar variance, and demonstrated a significantly higher mean pain score before surgery. The RCC was found to reverse over the year following ulnar shortening osteotomy and did not recur up to 2 years after surgery. In 3 wrists, RCC had completely disappeared at the last follow-up. All patients showed improved clinical outcomes. CONCLUSIONS: The RCC changes correlated with older age, a positive ulnar variance, and preoperative pain severity. The RCC progressively reversed after ulnar shortening osteotomy, and this reversal of radiographic changes correlated with clinical improvements. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 22541155 TI - Pediatric variants of the transolecranon fracture dislocation: recognition and tension band fixation: report of 3 cases. AB - Anterior transolecranon fracture dislocation of the elbow is relatively uncommon in children. We reviewed the experience over the past 5 years at our institution in treating this injury to identify pediatric variants and outline a rational treatment strategy. We found 2 pediatric variants to the injury pattern and determined that tension band constructs can successfully be used to treat certain pediatric transolecranon fracture dislocations. The pediatric variants identified in this report are fracture dislocations with associated medial epicondyle fracture and radial neck fracture. We recommend a heightened vigilance in looking for a fracture through the ulna when an anterior dislocation is present, as physeal injuries can be challenging to see on plain radiographs. PMID- 22541156 TI - Distal metaphyseal ulnar-shortening osteotomy: surgical technique. AB - Ulnar impaction is a common condition encountered by hand surgeons. Historically, treatment of this condition has been with wafer resection of the distal ulna, by either open or arthroscopic means, or diaphyseal ulnar shortening osteotomy; however, both of these have the potential for prolonged recovery or a need for additional procedures. Wafer procedures, whether done by open or arthroscopic techniques, can result in hemarthrosis, and diaphyseal osteotomies can require hardware removal. Recently, Slade and Gillon described a technique of ulnar shortening in the osteochondral region of the ulnar head, which offers advantages over previously used techniques. The purpose of this manuscript is to describe this technique, as well as pearls and pitfalls associated with the procedure. To more accurately describe the location of the osteotomy, we have changed the name of the procedure from Dr. Slade's original description to distal metaphyseal ulnar-shortening osteotomy. PMID- 22541157 TI - Management of scaphoid nonunion. AB - The primary risk factor for nonunion of the scaphoid is displacement/instability, but delayed or missed diagnosis, inadequate treatment, fracture location, and blood supply are also risk factors. Untreated nonunion leads to degenerative wrist arthritis-the so-called scaphoid nonunion advanced collapse wrist. However, the correlation of symptoms and disease is poor; the true "natural history" is debatable because we evaluate only symptomatic patients presenting for treatment. It is not clear that surgery can change the natural history, even if union is attained. The diagnosis of nonunion is made on radiographs, but computed tomography or magnetic resonance imaging scans can be useful to assess deformity and blood supply. Treatment options vary from percutaneous fixation to open reduction and internal fixation with vascularized or nonvascularized bone grafting to salvage procedures involving excision and/or arthrodesis of carpals. PMID- 22541158 TI - Letter regarding "the effect of botulinum neurotoxin-a on blood flow in rats: a potential mechanism for treatment of Raynaud phenomenon". PMID- 22541160 TI - Partial improvement of Dupuytren contracture following a wasp sting. PMID- 22541162 TI - Avirulent K88 (F4)+ Escherichia coli strains constructed to express modified enterotoxins protect young piglets from challenge with a virulent enterotoxigenic Escherichia coli strain that expresses the same adhesion and enterotoxins. AB - Virulence of enterotoxigenic Escherichia coli (ETEC) is associated with fimbrial adhesins and enterotoxins such as heat-labile (LT) and/or heat-stable (ST) enterotoxins. Previous studies using a cell culture model suggest that exclusion of ETEC from attachment to epithelial cells requires expression of both an adhesin such as K88 (F4) fimbriae, and LT. To test the ability of non-pathogenic E. coli constructs to exclude virulent ETEC sufficiently to prevent clinical disease, we utilized a piglet ETEC challenge model. Thirty-nine 5-day-old piglets were inoculated with a placebo (control), or with either of the three K88(+)E. coli strains isogenic with regard to modified LT expression: 8017 (pBR322 plasmid vector control), non-toxigenic mutant 8221 (LT(R192G)) in pBR322, or 8488, with the LT gene fused to the STb gene in pBR322 (LT(R192G)-STb). Piglets were challenged with virulent ETEC Strain 3030-2 (K88(+)/LT/STb) 24h post-inoculation. K88ac receptor-positive piglets in the control group developed diarrhea and became dehydrated 12-24h post-challenge. Piglets inoculated with 8221 or 8488 did not exhibit clinical signs of ETEC disease; most piglets inoculated with 8017 showed diarrhea. Control pigs exhibited significant weight loss, increased blood total protein, and higher numbers of colony-forming units of 3030-2 E. coli in washed ileum and jejunum than treated pigs. This study shows for the first time that pre-inoculation with an avirulent strain expressing adhesive fimbriae and a non-toxic form of LT provides significant short term protection from challenge with a virulent ETEC strain that expresses the same fimbrial adhesion and enterotoxin. PMID- 22541161 TI - Immunoproteomic analyses of outer membrane antigens of Actinobacillus pleuropneumoniae grown under iron-restricted conditions. AB - Actinobacillus pleuropneumoniae, a bacterial pathogen of swine and agent of porcine pneumonia, causes a highly infectious disease of economic importance in the pig industry. Commercial vaccines for A. pleuropneumoniae include whole-cell bacterins and second generation subunit vaccines but they only confer partial protective immunity. Our search for new vaccine candidates identified antigens that are expressed during conditions that mimic infection; the outer membrane (OM) proteome of A. pleuropneumoniae serotype 5b was examined under iron restriction. Quantitative profiling by 2D-DiGE technology revealed that iron restriction induced expression of previously described transferrin binding proteins (TbpA, TbpB) plus four lipoproteins including spermidine/putrescine binding periplasmic protein 1 precursor (PotD2). Immunoproteomic analyses with antisera from naive animals and from infected pigs were able to differentiate antigens within the OM proteome that were specifically recognized during A. pleuropneumoniae infection. Immunoblots of iron-restricted profiles detected PotD2, heme-binding protein A (HbpA), and capsule polysaccharide export protein (CpxD) as well as surface antigens TbpA, TbpB, and OmlA. These data identify OM proteins that demonstrate immunogenicity and upregulation under conditions mimicking infection, providing emphasis on lipoproteins as an important class of antigens to exploit for vaccine development for A. pleuropneumoniae. PMID- 22541163 TI - Whole genome sequence analyses of three African bovine rotaviruses reveal that they emerged through multiple reassortment events between rotaviruses from different mammalian species. AB - Animal-to-human interspecies transmission is one of the evolutionary mechanisms driving rotavirus strain diversity in humans. Although quite a few studies emanating from Africa revealed evidence of bovine-to-human rotavirus interspecies transmission, whole genome data of African bovine rotavirus strains are not yet available. To gain insight into the complete genome constellation of African bovine rotaviruses, the full genomes of three bovine rotavirus strains were extracted from stool samples collected from calves, amplified using a sequence independent procedure, followed by 454((r)) pyrosequencing. Strains RVA/Cow wt/ZAF/1603/2007/G6P[5] and RVA/Cow-wt/ZAF/1605/2007/G6P[5] were both genotyped as G6-P[5]-I2-R2-C2-M2-A3-N2-T6-E2-H3 and were probably two variants of the same rotavirus due to their close nucleotide sequence similarity. The genotype constellation of strain RVA/Cow-wt/ZAF/1604/2007/G8P[1] was G8-P[1]-I2-R2-C2-M2 A3-N2-T6-E2-H3. The genetic relationships and phylogenetic analyses suggested that these three bovine rotavirus strains may have emerged through multiple reassortment events between bovine, giraffe and antelope rotaviruses. Due to the close relatedness of genome segments 1 (encoding VP1), 7 (NSP2), 9 (VP7) and 10 (NSP4) of strain RVA/Cow-wt/ZAF/1604/2007/G8P[1] to those of the corresponding segments of human rotaviruses, RVA strain 1604 may represent bovine strains that were transmitted to humans and possibly reassorted with human rotaviruses previously. The complete nucleotide sequences of the bovine rotavirus strains reported in this study represent the first whole genome data of bovine rotaviruses from Africa. PMID- 22541164 TI - Comparative genomic analyses of the Taylorellae. AB - Contagious equine metritis (CEM) is an important venereal disease of horses that is of concern to the thoroughbred industry. Taylorella equigenitalis is a causative agent of CEM but very little is known about it or its close relative Taylorella asinigenitalis. To reveal novel information about Taylorella biology, comparative genomic analyses were undertaken. Whole genome sequencing was performed for the T. equigenitalis type strain, NCTC11184. Draft genome sequences were produced for a second T. equigenitalis strain and for a strain of T. asinigenitalis. These genome sequences were analysed and compared to each other and the recently released genome sequence of T. equigenitalis MCE9. These analyses revealed that T. equigenitalis strains appear to be very similar to each other with relatively little strain-specific DNA content. A number of genes were identified that encode putative toxins and adhesins that are possibly involved in infection. Analysis of T. asinigenitalis revealed that it has a very similar gene repertoire to that of T. equigenitalis but shares surprisingly little DNA sequence identity with it. The generation of genome sequence information greatly increases knowledge of these poorly characterised bacteria and greatly facilitates study of them. PMID- 22541165 TI - Effects of daily levels of fatigue and acutely induced fatigue on the visual evoked magnetic response. AB - Fatigue is a common complaint in modern society. As photosensitivity is associated with fatigue, this study aimed to clarify the relationship between neural response to visual stimuli and fatigue using a 160-channel whole-head-type magnetoencephalographic system. Twelve healthy male volunteers were enrolled. Participants were randomly assigned to two groups in a single-blinded, crossover fashion to perform acute fatigue-inducing mental task sessions, i.e., 0-back or 2 back test for 30 min. Visual evoked magnetic field (VEF) intensities were evaluated by standardized low-resolution brain electromagnetic tomography modified for a quantifiable method. VEF consisted of two phases, and although acute fatigue did not alter the VEF intensities and the intensities before the acute fatigue-inducing mental task sessions were not correlated with the Chalder's Fatigue Scale scores in either of the two phases, the intensities after the 0-back test trials for 30 min in Phase 1 and those after the 2-back test trials in Phase 2 were significantly correlated with the fatigue scale scores. The daily level of fatigue was related to VEF intensity after the acute mental fatigue loads. Our findings provide new perspectives to evaluate our daily level of fatigue as well as to clarify the neural mechanisms underlying it. PMID- 22541166 TI - Dysfunctional hippocampal activity affects emotion and cognition in mood disorders. AB - Mood disorders, such as major depressive disorder (MDD), bipolar disorder and generalized anxiety disorder usually comprise mood related as well as cognitive symptoms and the interaction between these symptoms is still not clear. Most antidepressant drugs have a positive effect on mood but do not treat the cognitive dysfunctions or even aggravate the symptoms. In this review we will evaluate the association between mood and cognition in the context of mood disorders. In the first section we will summarize the brain circuits at the intersection between cognition and emotion, highlighting the role of the hippocampus. In the second section, we will survey the contribution of the glutamate and GABA systems in the pathophysiology of mood disorders, making an effort to understand the link between emotions and cognition and how novel therapeutic approaches deal with them. In the third section we will explore the monoamine involvement in the emotion/cognition duality in the context of mood disorders. Finally we will underline the role of synaptic plasticity and neurogenesis in depression. We consider that a broader knowledge about the integrative mechanisms involved in specific aspects of mood disorders is crucial in the development of more powerful and effective antidepressant drugs. This article is part of a Special Issue entitled: Brain Integration. PMID- 22541167 TI - Thirty minute transcutaneous electric acupoint stimulation modulates resting state brain activities: a perfusion and BOLD fMRI study. AB - Increasing neuroimaging studies have focused on the sustained after effects of acupuncture, especially for the changes of brain activities in rest. However, short-period stimuli have mostly been chosen in these works. The present study aimed to investigate how the resting state brain activities in healthy subjects were modulated by relatively long-period (30 min) acupuncture, a widely used modality in clinical practice. Transcutaneous electric acupoint stimulation (TEAS) or intermittent minimal TEAS (MTEAS) were given for 30 min to 40 subjects. Functional MRI (fMRI) data were collected including the pre-stimulation resting state and the post-stimulation resting state, using dual-echo arterial spin labeling (ASL) techniques, representing both cerebral blood flow (CBF) signals and blood oxygen-dependent level (BOLD) signals simultaneously. Following 30 min TEAS, but not MTEAS, the mean global CBF decreased, and a significant decrease of regional CBF was observed in SI, insula, STG, MOG and IFG. Functional connectivity analysis showed more secure and spatially extended connectivity of both the DMN and SMN after 30 min TEAS. Our results implied that modulation of the regional brain activities and network connectivity induced by thirty minute TEAS may associate with the acupuncture-related therapeutic effects. Furthermore, the resting state regional CBF quantified by ASL perfusion fMRI may serve as a potential biomarker in future acupuncture studies. PMID- 22541168 TI - Development and validation of a hydrophilic interaction liquid chromatography tandem mass spectrometry method for the quantification of lipid-related extracellular metabolites in Saccharomyces cerevisiae. AB - A highly sensitive hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS) method was developed and validated for the quantification of glycerophosphoinositol (GroPIns), glycerophosphocholine (GroPCho), glycerol 3-phosphate (GroP), inositol, and choline in the extracellular medium of Saccharomyces cerevisiae. The media samples were pretreated with a single two-phase liquid extraction. Chromatographic separation was achieved on a Waters Xbridge HILIC (150 mm * 4.6 mm, 5 MUm) column under isocratic conditions using a mobile phase composed of acetonitrile/water, 70:30 (v/v) with 10mM ammonium acetate (pH adjusted to 4.5) at a flow-rate of 0.5 mL/min. Using a triple quadrupole tandem mass spectrometer, samples were detected in multiple reaction monitoring (MRM) mode via an electrospray ionization (ESI) source. The calibration curves were linear (r2 >= 0.995) over the range of 0.5 150 nM, with the lower limit of quantitation validated at 0.5 nM for all analytes. The intra- and inter-day precision (calculated by coefficient of variation, CV%) ranged from 1.24 to 5.88% and 2.46 to 9.77%, respectively, and intra- and inter-day accuracy (calculated by relative error, RE%) was between 8.42 to 8.22% and -9.35 to 6.62%, respectively, at all quality control levels. The extracellular metabolites were stable throughout various storage stability studies. The fully validated method was successfully applied to determine the extracellular levels of phospholipid-related metabolites in S. cerevisiae. PMID- 22541169 TI - Validation of a liquid chromatography/tandem mass spectrometry method for the simultaneous quantification of Sotrastaurin and its metabolite N-desmethyl sotrastaurin in human blood. AB - A liquid chromatography/tandem mass spectrometry (HPLC-MS/MS) method was validated for the quantification of Sotrastaurin (AEB071) and N-desmethyl sotrastaurin in human blood. The validation of the analytical procedure was performed according to the latest Food and Drug Administration (FDA) "Guidance for Industry, Bioanalytical Method Validation". Chromatographic separation was performed using an RP C18 (50 mm * 4.6 mm, 5 MUm) column at 40+/-3.0 degrees C with a mobile phase consisted of 2 mM ammonium acetate in water (pH 4.5):methanol:acetonitrile (25:15:60, v/v) of a flow rate of 1 mL/min followed by quantification with tandem mass spectrometer, operated in electrospray ionization (ESI) positive ion mode and applying multiple reaction monitoring (MRM). The validated method described in this paper presents high absolute recovery, with a sensitivity of 3.00 ng/mL as lower limit of quantitation using a sample volume of 300 MUL, low inter-run bias and variability (for Sotrastaurin, -4.4 to 0.4% and 1.8 to 2.5% and for N-desmethyl-sotrastaurin, ranged from 1.6 to 2.3% and 2.7 to 3.9%, respectively) with a short runtime of 3.5 min. The method was validated using K3EDTA as specific anticoagulant and cross-validated using Li-Heparin and Na-Heparin. The method was specific for Sotrastaurin and N-desmethyl-sotrastaurin within the given criteria of acceptance (apparent peak area for Sotrastaurin and N-desmethyl-sotrastaurin in zero samples <= 20% of mean peak area at LLOQ) in human blood. The method was fully validated for the quantitative determination of Sotrastaurin and its metabolite N-desmethyl-sotrastaurin in human blood between the range of 3.00 ng/mL and 1200 ng/mL. PMID- 22541170 TI - Reproduction in chinchilla (Chinchilla lanigera): current status of environmental control of gonadal activity and advances in reproductive techniques. AB - A review of the biology of reproduction of chinchilla, focusing on environmental control of the gonadal activity, is presented. Chinchilla is a South American hystricomorph rodent genus currently considered almost extinct in the wild. However, a domestic form is still widespread in breeding farms around the world. Information regarding their reproductive biology has been obtained from studies on captive animals. In the case of Chinchilla lanigera, a seasonal reproductive pattern has been frequently reported in breeding facilities, but factors that might trigger gonadal activity have not been identified. The available information on reproductive productivity in farms worldwide shows a range of 1.2 to 2.4 deliveries per female per yr (with up to 2.1 weaned young per female per yr). Indeed, as found in all rodents, chinchillas can multiply at high fecundity and fertility rates (4 to 6 follicles mature during estrous cycles). Some new research avenues are postulated to improve the control of gonadal activity by means of environmental and/or pharmacologic factors. Furthermore, reproductive techniques that have been validated in chinchilla are reviewed (noninvasive hormone monitoring, semen collection, sperm cryopreservation, estrus induction), and several technical steps are proposed to be able to achieve AI. Because domesticated chinchilla still share some genomic characteristics with their counterparts in the wild, validated reproductive techniques in chinchilla males and females might contribute to the success of breeding programs. PMID- 22541173 TI - It is the journey, not the destination. PMID- 22541171 TI - Effect of insulin-like growth factor-I on some quality traits and fertility of cryopreserved ovine semen. AB - The objective was to evaluate the effects of insulin-like growth factor-I (IGF-I) on the quality and fertility of frozen/thawed ovine semen. Five rams (five ejaculates/ram) were used for evaluation of semen parameters. Before cryopreservation, ejaculates were divided into four aliquots and extended with Tris alone or supplemented with human IGF-I (50, 100, or 250 ng/mL). Semen was evaluated immediately after thawing (T0), after 1 h (T1) and 2 h (T2) post incubation at 37 degrees C. The percentage of live cells (fluorescence analysis calcein and ethidium), acrosome integrity (NAR) and motility were analyzed, and hypo-osmotic swelling tests (HOST) were used to evaluate membrane resistance. In addition, AI was performed using 121 ewes to compare the optimal concentration of IGF-I vs. Tris alone on pregnancy rates after laparoscopic insemination. Pregnancy diagnosis was performed by transrectal ultrasonography. After 1 and 2 h post-incubation, in every group, percentage motile sperm, NAR and HOST decreased compared to semen at T0. Motility was higher (P < 0.05) in the IGF-I 100 and IGF I 250 groups when compared to the IGF-I 50 and Tris groups (76.2 and 74.4% vs. 66.2 and 64.4 percent, respectively) at T0, after 1 h (67 and 63.6% vs. 56.2 and 54.7%) and 2 h post-incubation (58.2 and 55.8% vs. 48 and 47.2%). Furthermore, viability was higher (P < 0.05) in the insulin-like growth factor-I (IGF-I) 100 and IGF-I 250 groups than in the IGF-I 50 and Tris groups (88.7 and 88.3% vs. 76.6 and 77.6%, respectively) at T0. There was no difference (P > 0.05) in NAR or hypo-osmotic swelling tests (HOST) among groups. There were no differences (P > 0.05) in fertility between the IGF-I 100 and Tris groups. In conclusion, IGF-I improved subjective sperm motility and structural integrity of the plasma membrane without a significant effect on 45-day pregnancy rates after laparoscopic insemination of ewes with frozen-thawed semen. PMID- 22541172 TI - Optimal dose for stroke thrombolysis in Asians: low dose may have similar safety and efficacy as standard dose. AB - BACKGROUND: Although intravenous tissue-type plasminogen activator (t-PA) at a standard dose of 0.9 mg kg(-1) is effective for patients with acute ischemic stroke, concerns have been raised regarding Asians. OBJECTIVES: To compare the safety and efficacy between low and standard doses for stroke thrombolysis. PATIENTS/METHODS: Consecutive patients receiving t-PA treatment were recruited according to the prespecified dosing policy from two medical centers in Taiwan: low dose (0.7 mg kg(-1) ) at National Cheng Kung University Hospital (NCKUH) from August 2006 to June 2009, or standard dose (0.9 mg kg(-1) ) at NCKUH from July 2009 to December 2010 and at Changhua Christian Hospital from May 2008 to December 2010. The primary safety outcome was the occurrence of symptomatic intracerebral hemorrhage (SICH). The secondary efficacy outcome was the proportion of patients with a modified Rankin Scale (mRS) grade of <= 1 at 3 months. RESULTS: From August 2006 to December 2010, 261 patients were recruited, of whom 105 and 156 received low and standard doses, respectively. The occurrence of SICH was non-significantly lower in the standard-dose group than in the low dose group (2.6% vs. 4.8%, respectively; P = 0.34). The favorable outcome of mRS grade of <= 1 at 3 months was similar (38.4% and 41.1%, respectively; P = 0.676). A review of other case series of low vs. standard doses in Asians also showed similar safety and efficacy. CONCLUSION: Our study, as well as other case series on Asians, revealed that standard-dose thrombolysis for acute ischemic stroke in an Asian population carries no increased risk of symptomatic intracerebral hemorrhage when compared with the low dose. PMID- 22541174 TI - Review of case-mix corrected survival curves. AB - Survival is an end point of immense interest in cardiothoracic research. In observational studies, the comparison of survival between groups of patients is usually accomplished using a toolbox that includes Kaplan-Meier survival curves and the Cox model. The Cox model yields comparisons between groups adjusted for case-mix differences, whereas the Kaplan-Meier is a plot of survival over time without adjustment. During the past decade, new methods have emerged for case-mix adjustment of survival curves and are increasingly being used in cardiothoracic research. The purpose of this report is to describe, illustrate, and review several approaches to case-mix adjusted survival (or event-free) curves. PMID- 22541175 TI - Invited commentary. PMID- 22541176 TI - Preoperative statin therapy is not associated with a decrease in the incidence of delirium after cardiac operations. AB - BACKGROUND: Delirium after cardiac operations is associated with significant morbidity and death. Statins have been recently suggested to exert protective cerebral effects. This study investigated whether preoperative statins were associated with decreased incidence of postoperative delirium in patients undergoing coronary artery bypass grafting. METHODS: The study enrolled 4,659 consecutive patients (21% women; age, 67.8+/-9.2 years) undergoing coronary artery bypass grafting. A propensity score-based optimal-matching algorithm was used to match 1,577 patients receiving preoperative statins with a control group (1:1). Patients were screened for delirium in the intensive care unit according to the Confusion Assessment Method for the intensive care unit. RESULTS: Delirium affected 89 patients (3%), and preoperative statin administration was not multivariably associated with a decreased incidence of delirium (odds ratio, 1.52; 95% confidence interval, 0.97 to 2.37; p=0.18) and was also unrelated to a delirium decrease in patient subgroups undergoing isolated coronary artery bypass grafting (odds ratio, 1.31; 95% confidence interval, 0.68 to 2.52; p=0.51) or combined valvular procedures (odds ratio, 1.72; 95% confidence interval, 0.96 to 3.07, p=0.08). Similar results were observed for age groups and cardiopulmonary bypass durations. Patients affected by postoperative delirium experienced a longer hospital stay (25th to 75th percentile) of 11 (7 to 18 days) vs 7 days (7 to 8 days, p<0.001) and 12% hospital mortality vs 1% (p<0.001). CONCLUSIONS: Preoperative statins were not associated with a decreased incidence of delirium in patients undergoing coronary revascularization. PMID- 22541177 TI - Invited commentary. PMID- 22541178 TI - Minimally invasive surgery using bipolar radiofrequency energy is effective treatment for refractory atrial fibrillation. AB - BACKGROUND: A web-based registry was used to prospectively study patients after minimally invasive surgery with monitoring to determine freedom from atrial fibrillation (AF) (clinicaltrials.gov/ct2/show/NCT00747838). This is a report showing the utility and feasibility of the registry. METHODS: All patients had symptomatic AF refractory to medical treatment. Surgical ablation was performed using bipolar radiofrequency (RF) energy with a clamp around pulmonary veins and additional RF was delivered to ablate ganglionic plexi and create linear lesions. After a 3-month blanking period, prolonged electrocardiogram monitoring was done at 6 months, 1 year, and 2 years. Success was defined as no episodes of AF and atrial tachyarrhythmias greater than 30 seconds by monitoring. RESULTS: A total of 118 patients were studied from 4 institutions from June 2006 to February 2011. Seventy-two patients were male (61%). The mean age was 64+/-9 years. CHADS2 (Congestive heart failure, Hypertension, age greater than 75, Diabetes and Stroke score for risk of thromboembolic events in patients with atrial fibrillation) was 1.3. Warfarin was used in 92 (78%), antiarrhythmic medications in 108 (92%), and 35 (30%) had previous catheter ablation. Paroxysmal AF was present in 80 (68%), persistent AF present in 35 (30%), and long-standing persistent present in 3 (2%). The mean left atrial size was 4.4 cm. The surgical approach was bilateral minithoracotomy in 69 (58%) and totally thoracoscopic in 49 (42%). The left atrial appendage was excluded or excised in 112 (95%) patients. There were no deaths related to the procedure. Only 5 (4%) patients required ventilation greater than 24 hours; permanent pacemaker was needed in 3 (2%) patients. Mean length of hospital stay was 5 days. At a mean follow-up of 16.5 months, 80% of patients were free of AF off antiarrhythmic medications with long-term monitoring. Quality of life data showed significant improvement at 6 and 12 months. CONCLUSIONS: The STAR (stable angina in practice) registry is an effective web-based tool for long-term follow-up of patients after surgery for AF. Minimally invasive surgery with lesions created by bipolar RF energy is an effective treatment for AF in carefully selected patients. PMID- 22541179 TI - Invited commentary. PMID- 22541180 TI - Sutureless perceval aortic valve replacement: results of two European centers. AB - BACKGROUND: The Perceval S bioprosthesis (Sorin Biomedica Cardio Srl, Sallugia, Italy) is a self-expanding valve designed to preserve aortic sinuses and sinotubular junction. We report the midterm results of a prospective, multicenter clinical study evaluating the safety and efficacy of this stented bioprosthesis in patients undergoing aortic valve replacement with or without concomitant procedures. METHODS: From January 2007 to September 2011, a total of 208 high risk patients (mean European system for cardiac operative risk evaluation: 8.7+/ 5.3 years) received a Perceval bioprosthesis in 2 European centers. Median follow up was 10+/-20 months and 100% complete, and the total accumulated follow-up was 156 patient-years. Ten patients have reached a 4-year follow-up. Valve function was assessed in all patients. RESULTS: Valve implantation resulted in significant improvement of patients' symptoms. Mean preoperative and postoperative gradients were 48.6+/-18.6 mm Hg and 10.4+/-4.3 mm Hg, respectively, and preoperative and postoperative mean effective orifice areas were 0.7+/-0.2 and 1.4+/-0.4 cm2. Survival at 12 months was 87.1%, success of implantation was 95%, and freedom from reoperation was 96%. In hospital mortality was 2.4%. During follow-up, 9 patients (4%) required reoperation for paravalvular regurgitation; 7 early and 2 late reoperations. Mean cross-clamp time (CCT) and extracorporeal circulation time (ECT) were, respectively, 33+/-14 minutes and 54+/-24 minutes, including 45 patients who underwent surgery through ministernotomy. Concomitant coronary bypass was done in 48 patients with mean CCT 43+/-13 and ECT 68+/-25 minutes. CONCLUSIONS: Perceval sutureless is a safe bioprosthesis that can easily be implanted, including by a minimally invasive technique. It provides excellent hemodynamic with significant clinical improvement. Overall, these data confirm the safety and utility of the Perceval bioprosthesis aortic valve replacement for high-risk patients. PMID- 22541181 TI - Invited commentary. PMID- 22541182 TI - Invited commentary. PMID- 22541183 TI - Invited commentary. PMID- 22541184 TI - Invited commentary. PMID- 22541185 TI - Incidence and management of gastrointestinal bleeding with continuous flow assist devices. AB - BACKGROUND: Continuous flow left ventricular assist devices (CF-LVADs) have emerged as the standard of care for patients in advanced heart failure (HF) requiring long-term mechanical circulatory support. Gastrointestinal (GI) bleeding has been frequently reported within this population. METHODS: A retrospective analysis of 101 patients implanted with the Heart Mate II from January 2005 to August 2011 was performed to identify incidence, etiology, and management of GI bleeding. Univariate and multivariate regression analysis was conducted to identify related risk factors. RESULTS: A significant incidence of GI bleeding (22.8%) occurred in our predominantly destination therapy (DT) (93%) population. Fifty-seven percent of the patients with bleeding episodes bled from the upper GI (UGI) tract (with 54% bleeding from gastric erosions and 37% from ulcers/angiodysplasias), whereas 35% of patients bled from the lower GI (LGI) tract. Previous history of GI bleeding (odds ratio [OR], 22.7; 95% CI, 2.2-228.6; p=0.008), elevated international normalized ratio (INR) (OR, 3.9; CI, 1.2-12.9; p=0.02), and low platelet count (OR, -0.98; CI, 0.98 -0.99; p=0.001) were independent predictors of GI hemorrhage. Recurrent bleeding was more common in older patients (mean, 70 years; p=0.01). The majority of bleeders (60%) rebled from the same site. Management strategies included temporarily withholding anticoagulation, decreasing the speed of LVADs, and using octreotide. Octreotide did not impact the amount of packed red blood cells used, rebleeding rates, length of hospital stay, or all-cause mortality. Only 1 patient died as a direct consequence of GI bleeding. CONCLUSIONS: Multiple factors account for GI bleeding in patients on CF-VADs. A previous history of bleeding increases risk significantly and warrants careful monitoring. PMID- 22541186 TI - Invited commentary. PMID- 22541187 TI - Invited commentary. PMID- 22541188 TI - Neurodevelopmental outcomes after open heart operations before 3 months of age. AB - BACKGROUND: The purpose of this study was to monitor developmental progress and identify predictors of developmental outcomes at 2 years after operation in infants who underwent a surgical procedure with cardiopulmonary bypass (CPB) at less than 3 months of age. METHODS: Patients (N=131 enrolled; N=106 assessed) less than 3 months of age at the time of cardiac operation were prospectively enrolled (years 1999-2003) and assessed at 8, 12, and 24 months after operation. Patients with preexisting conditions independently associated with poor neurodevelopmental outcomes were excluded. Fine and gross motor development was formally assessed at all 3 visits, and parent ratings of development across several domains were obtained. Neurodevelopment was formally assessed at 24 months of age using the Bayley Scales of Infant Development, 2nd edition (BSID II) Mental Development Index score (MDI). RESULTS: Significant gross motor difficulties were identified at 8 months of age (p<0.001) and, although improved by the 24-month assessment, remained lower than average. Fine motor skills showed a significant decrease from 8 to 24 months of age (p=0.001). Factors associated with poorer neurodevelopmental outcome (BSID-II MDI) at 24 months after operation included a diagnosis of univentricular anatomy or complex coarctation of the aorta, higher complexity of the surgical procedure, longer duration of hospital stay, and presence of complications in the postoperative period. CONCLUSIONS: Children undergoing repair of congenital heart disease (CHD) still have impaired development 2 years after the operation. Observed patterns of development were specific to the skill being assessed and related to both anatomic complexity and increased complexity of care received. PMID- 22541189 TI - Invited commentary. PMID- 22541190 TI - Invited commentary. PMID- 22541191 TI - Invited commentary. PMID- 22541192 TI - Invited commentary. PMID- 22541193 TI - Invited commentary. PMID- 22541194 TI - Invited commentary. PMID- 22541195 TI - Interatrial shunting after major thoracic surgery: a rare but clinically significant event. AB - BACKGROUND: Interatrial shunting after thoracic surgery through a patent foramen ovale or previously asymptomatic atrial septal defect has been reported as a rare, clinically significant and potentially treatable condition. The incidence, presentation, management, and outcome after thoracic surgery have yet to be defined. METHODS: We performed a retrospective cohort study of all patients undergoing major thoracic surgery (pneumonectomy, extrapleural pneumonectomy, pleurectomy) at our institution between January 2005 and December 2009. Perioperative records were reviewed up to 1 year postoperatively. The presenting clinical symptoms, and complications were identified, and data from the cardiac investigations (right-side heart catheterization, echocardiogram) were extracted into our database. RESULTS: In all, 581 patients underwent major thoracic surgery during the period of study. We identified 8 cases of postoperative interatrial shunting, of which 7 occurred after right-sided surgery. The most common presentations were dyspnea, increase in oxygen requirements, and platypnea orthodeoxia. Two patients presented with neurologic complications secondary to paradoxic embolism. The median time to presentation was 14 days after the operation. Five patients had increased pulmonary pressures postoperatively. Two patients required intervention, and the symptoms of the rest resolved with conservative management. CONCLUSIONS: Interatrial shunting is a rare but clinically significant complication after thoracic surgery. The presentation is myriad, and can occur immediately postoperatively or more than a month later. Some cases may require interventions, although most resolve with conservative management. PMID- 22541196 TI - Radical pleurectomy and intraoperative photodynamic therapy for malignant pleural mesothelioma. AB - BACKGROUND: Radical pleurectomy (RP) for mesothelioma is often considered either technically unfeasible or an operation limited to patients who would not tolerate a pneumonectomy. The purpose of this study was to review our experience using RP and intraoperative photodynamic therapy (PDT) for mesothelioma. METHODS: Thirty eight patients (42-81 years) underwent RP-PDT. Thirty five of 38 (92%) patients also received systemic therapy. Standard statistical techniques were used for analysis. RESULTS: Thirty seven of 38 (97%) patients had stage III/IV cancer (according to the American Joint Committee on Cancer [AJCC manual 7th Edition, 2010]) and 7/38 (18%) patients had nonepithelial subtypes. Macroscopic complete resection was achieved in 37/38 (97%) patients. There was 1 postoperative mortality (stroke). At a median follow-up of 34.4 months, the median survival was 31.7 months for all 38 patients, 41.2 months for the 31/38 (82%) patients with epithelial subtypes, and 6.8 months for the 7/38 (18%) patients with nonepithelial subtypes. Median progression-free survival (PFS) was 9.6, 15.1, and 4.8 months, respectively. The median survival and PFS for the 20/31 (64%) patients with N2 epithelial disease were 31.7 and 15.1 months, respectively. CONCLUSIONS: It was possible to achieve a macroscopic complete resection using lung-sparing surgery in 97% of these patients with stage III/IV disease. The survival we observed with this approach was unusually long for the patients with the epithelial subtype but, interestingly, the PFS was not. The reason for this prolonged survival despite recurrence is not clear but is potentially related to preservation of the lung or some PDT-induced effect, or both. We conclude that the results of this lung-sparing approach are safe, encouraging, and warrant further investigation. PMID- 22541197 TI - Invited commentary. PMID- 22541198 TI - Invited commentary. PMID- 22541199 TI - Hospital esophageal cancer resection volume does not predict patient mortality risk. AB - BACKGROUND: Insurers often seek to direct esophageal cancer patients to hospitals with high volumes of esophageal resection. However, controversy exists regarding the strength and validity of evidence for the volume-outcome association. The purpose of this study was to evaluate the volume-outcome relationship for esophageal cancer resection in a large population dataset and to compare 3alternative techniques for measuring the effect of volume. METHODS: Esophageal cancer resection patients were identified in the 2007 Nationwide Inpatient Sample. Hospital volume was measured using a continuous linear function, a nonlinear function using restricted cubic splines, and using quintiles of volume. The statistical significance of the relationship between hospital volume and mortality risk was assessed, and adjusted for patient age, for comorbid disease, and for correlated events within hospitals. RESULTS: A total of 6,248 esophageal cancer resection patients from 217 hospitals were identified. All 3 models demonstrated excellent performance characteristics (C index=0.94, Nagelkerke R2=0.62). However, no significant association was demonstrated between hospital procedure volume and in-hospital mortality in any model. Important predictors of mortality included age, hypertension, weight loss, and peripheral vascular disease (p<0.001). CONCLUSIONS: Esophageal cancer resection volume is not a significant predictor of mortality and should not be used as a proxy measure for surgical quality. PMID- 22541200 TI - Three-dimensional replica of a life-sized model of aortic arch aneurysm for preoperative assessments. AB - PURPOSE: In the treatment of extended distal aortic arch aneurysms with open stent grafting, detailed preoperative minute evaluation is essential to determine the optimal operative strategy and reduce the incidence of complications. We describe a three-dimensional replica of a life-sized aortic arch aneurysm model for aiding preoperative assessments. DESCRIPTION: Life-sized replicas of an aortic arch aneurysm were made for 4 patients who underwent total aortic arch replacement with open stent-grafting. These replicas were used to determine the curve of the CLATE, a newly developed open stent delivery system (Senko Medical Instrument Mfg, Co, Ltd, Tokyo, Japan), and the depth of the open stent grafting. The replica and the CLATE system were also used to obtain informed consent from the patients. EVALUATION: Surgeons could simulate the operative procedure precisely. Insertion of the graft was smooth in all patients. Use of the replica made it easier for the patients to understand the form and site of the aneurysm, as well as the operative procedure. CONCLUSIONS: The combination of the three dimensional replica and the CLATE system may be useful for both surgeons and patients in the treatment of extended distal aortic arch aneurysms. PMID- 22541201 TI - Starnes procedure in a neonate with pulmonary atresia and intact ventricular septum. AB - We describe the case of 7-day-old neonate with pulmonary atresia, intact ventricular septum, and severe tricuspid valve (TV) dysplasia who underwent a Starnes right ventricular exclusion procedure (RVEP). The patient had severe tricuspid stenosis and regurgitation and right ventricular dysfunction after perforation and balloon dilation of the pulmonary valve. PMID- 22541202 TI - Pressure necrosis of the outlet septum caused by two adjacent implants. AB - A patient had a history of a Ross-Konno procedure, stenting of the pulmonary homograft, and an aortic valve replacement. Pressure necrosis developed in the tissues in between the stent and the prosthetic valve. This resulted in a defect between the right and left ventricular outflow tracts that required a complex operation for its correction. PMID- 22541203 TI - Bicuspid pulmonary valve with atrial septal defect leading to pulmonary aneurysm. AB - Pulmonary artery aneurysms are rare. We describe 2 adult patients with pulmonary artery aneurysm with normal pulmonary pressure associated with bicuspid pulmonary valve and atrial septal defect. One patient presented with moderate pulmonary valve stenosis and was treated with open surgery; the other patient had a small atrial septal defect and mild pulmonary valve insufficiency and is periodically still being evaluated. Hemodynamic alterations associated with a pulmonary artery aneurysm are described; the influence of additional volume overload and intrinsic wall abnormalities in pulmonary valvular lesions as potential triggers for the development of these aneurysms are analyzed and therapeutic strategies are discussed. PMID- 22541204 TI - Direct transatrial transcatheter SAPIEN valve implantation through right minithoracotomy in a degenerated mitral bioprosthetic valve. AB - Transcatheter valve implantation into failing surgical mitral bioprosthetic valves have been reported. This strategy avoids performing high-risk repeat cardiac surgery in elderly patients with multiple comorbidities. All these patients have been treated by a transapical approach. We report a case of failing bioprosthetic mitral valve in an 82-year-old woman successfully treated with a 29 mm Edwards SAPIEN balloon expandable bioprosthesis (Edwards Lifesciences, Irvine, CA) with direct left atrial approach through a right anterior thoracotomy. Our experience demonstrates the technical feasibility and safety of this approach. Therefore, mitral valve-in-surgical valve implantation may be a viable treatment alternative in carefully selected patients. PMID- 22541205 TI - Total endovascular repair of an aortic arch aneurysm using an externalized transseptal guidewire technique. AB - Total endovascular treatment of complex ascending and arch disease remains extremely challenging with difficulties provided by the curvature of the arch, the variable anatomy of the great vessels, the proximity of the coronary ostia, potential damage to the aortic valve, and ventricle and instability during deployment. Given this background, reports of the total endovascular treatment of aortic arch are sparse. We describe one challenging case using an arch branched endograft that was safely advanced and precisely positioned into the ascending aorta using an externalized transseptal guide wire technique. PMID- 22541206 TI - Intracardiac migration of operatively placed epicardial pacing leads. AB - This study describes intracardiac migration of epicardial pacemaker leads after open heart surgery in 2 patients. Discovery of these pacemaker leads or remnants led to diagnostic confusion until an appropriate diagnosis was established by both invasive and noninvasive means. Intracardiac migration of epicardial pacemaker leads has only rarely been reported. Migration to other noncardiac organs has also been reported infrequently. Awareness of this unusual occurrence should avoid postoperative confusion in recognizing origin of said artifacts. PMID- 22541207 TI - Intracoronary fiducial embolization after percutaneous placement for stereotactic radiosurgery. AB - Although well established for the treatment of intracranial and prostatic pathology, stereotactic radiosurgery has only recently emerged as a modality for the treatment of malignant lung lesions. Utilization of radio-opaque markers, called fiducials, facilitate dose-intensive radiation focused on the tumor with sparing of surrounding normal tissue. There is a paucity of literature regarding complications that occur secondary to placement of these fiducials. The following report details a case in which intracoronary migration resulted in a hemodynamically significant acute coronary syndrome. PMID- 22541209 TI - Lung herniation after supraclavicular thoracic outlet decompression. AB - Lung herniation after first rib resection for thoracic outlet syndrome (TOS) has not been reported to our knowledge. We present a unique case of cervical lung herniation causing displacement of the brachial plexus and chronic pain in a patient who had previously undergone supraclavicular thoracic outlet decompression with first rib resection. This was successfully treated with thoracoscopic reduction and resection of the herniated lung and pleural flap closure of the defect. PMID- 22541208 TI - Tracheal paraganglioma: an unusual neoplasm of the upper airway. AB - Paraganglioma of the trachea is a rare neoplasm, with fewer than 15 cases reported. A 40-year-old man presented with stridor and hemoptysis. Bronchoscopy demonstrated a tumor of the posterior trachea and biopsy initially suggested typical carcinoid. The patient underwent surgical resection uneventfully and made a good recovery. Final pathology disclosed the tumor to be a paraganglioma based on immunohistology. The pathophysiology and treatment of this tumor are discussed. PMID- 22541210 TI - Endobronchial ultrasonography in a patient with a mediastinal thoracic duct cyst. AB - Mediastinal thoracic duct cysts are rare clinical findings. We report the case of a symptomatic 58-year-old woman in whom a thoracic duct cyst was successfully treated with surgical resection. Preoperative endobronchial ultrasonography revealed an oval-shaped hypoechoic area with a distinct, thick pedicle, gradual intermittent flux of the fluid content within the lesion, and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) revealed lymphocyte predominant serous fluid without malignancy, which is consistent with features of a mediastinal thoracic duct cyst. We postulate that EBUS-TBNA can be used as a preoperative diagnostic tool for patients with possible mediastinal thoracic duct cysts. PMID- 22541211 TI - Clear cell chondrosarcoma arising from the sternum: a rare tumor in an uncommon location. AB - A 52-year-old woman presented with bulging of the anterior chest wall. The computed tomographic scan revealed an expansive localized mass based on the sternal manubrium. The patient was successfully treated with en bloc radical resection and reconstruction with clear resection margin. Histopathologic examination of the surgical specimen confirmed the diagnosis of clear cell chondrosarcoma. After the surgery, the patient has been free of disease for 43 months after surgery without other treatment. Our search and review of the literature did not reveal any published cases of clear cell chondrosarcoma arising from the sternum; therefore, we have presented a summary of this novel case with a review of the relevant literature. PMID- 22541212 TI - Gastric conduit resection and jejunal interposition for recurrent esophageal cancer. AB - We describe the case of a 58-year-old man with recurrent adenocarcinoma at the site of an esophagogastrostomy that we treated by radical surgical resection and jejunal interposition. Oral intake was started on the 6th postoperative day and the patient was discharged on the 11th postoperative day. Seven months after the surgical procedure no signs of tumor recurrence were detected. Resection of localized (recurrent) esophageal cancer may well be a valuable treatment option and is therefore an interesting therapeutic option in patients with recurrent disease. However this needs to be investigated in a randomized controlled trial. PMID- 22541213 TI - Gastropericardial fistula: a late complication of esophageal reconstruction. AB - Esophageal replacement for both benign and malignant diseases commonly uses gastric tube reconstruction. A rare but potentially life-threatening late complication is the formation of a gastropericardial fistula. We describe a case of gastropericardial fistula occurring more than 20 years after esophageal reconstruction for congenital esophageal atresia. We report our surgical strategy and review the key concepts in the management of this complication. PMID- 22541214 TI - Stanford type A acute aortic dissection with intimal intussusception. PMID- 22541216 TI - An unusual cause of hemoptysis in a young woman. PMID- 22541215 TI - Scanning the Adamkiewicz artery and collateral supply via dorsal thoracic artery. PMID- 22541217 TI - Transapical endovascular aortic repair to treat complex aortic pathologies. AB - Clinical condition, hostile anatomy, and previous heart/aortic surgery may preclude standard open surgery and standard endovascular interventions in patients with complex aortic pathologies. We report our initial experience using the transapical endovascular approach to treat a type IA endoleak after transfemoral endovascular graft repair for a contained rupture of a penetrating descending aortic ulcer; an ascending aortic anastomotic pseudoaneurysm after open surgical repair of an ascending aortic dissection; and a type A aortic dissection after minimally invasive mitral valve repair. There were no neurologic or cardiovascular complications, and the 30-day mortality was 0%. PMID- 22541219 TI - Vacuum-assisted closure of pleural empyema without classic open-window thoracostomy. AB - A 64-year-old man was diagnosed with complex empyema after a second course of palliative chemotherapy for metastatic lung cancer. Because of the poor general condition of the patient, the decision was made to proceed with vacuum-assisted closure (VAC) therapy of the empyema without Eloesser or Clagett open-window thoracostomy (OWT). Installation and changing of the VAC sponge were performed using the ALEXIS Wound Protector/Retractor (Applied Medical, Rancho Santa Margarita, CA), a flexible polymer membrane tube. After 10 days of VAC treatment, the pleural cavity was sterile and was closed with single stitches. Chemotherapy was resumed 1 week later. PMID- 22541218 TI - Transfer technique of an anomalous coronary artery from the anterior pulmonary artery. AB - We describe a simple rerouting technique for an anteriorly situated anomalous left coronary artery from the pulmonary artery (ALCAPA), extending the left main coronary trunk with autologous aortic and pulmonary tissue. This technique is reproducible. It provides a tension-free aortocoronary anastomosis and a full potential for future growth. PMID- 22541220 TI - Use of the thoracodorsal artery perforator flap for bronchial reinforcement in patients with previous posterolateral thoracotomy. AB - The thoracodorsal artery perforator flap (TDAP flap) allows raising the same cutaneous island as in the classical latissimus dorsi musculocutaneous flap without its muscular part. All patients who underwent a completion pneumonectomy with reinforcement of bronchial stump with a TDAP flap from December 2009 to October 2010 were followed prospectively. The 30-day mortality and the procedure related morbidity as well as bronchial fistula and TDAP flap were analyzed. The TDAP flap was used in 6 cases without failure or fistula formation. At 1 month, all patients were alive, and there was no morbidity (seroma, hematoma, fistula, or shoulder dysfunction). Computed tomography scans were performed at 1 month and 3 months postoperatively and showed viable nonatrophic flap. This type of flap has been described in the field of plastic surgery, and this is the first description of its use in the chest. Deepithelialized fasciocutaneous TDAP flap is safe and reliable. It is available even if the latissimus dorsi has been previously divided. It is now our first-line option to reinforce the bronchial stump. PMID- 22541221 TI - How an aspirin, a throat swab from a chicken, and four Guinea pigs changed thoracic surgery. AB - The development of antituberculous drugs changed thoracic surgery and also markedly lowered the morbidity and mortality of a disease that had epidemic proportions. This article summarizes aspects from 3 important articles that led to the discovery of these drugs. PMID- 22541222 TI - Possible causes of neocord rupture. PMID- 22541225 TI - Low adiponectin level may contribute to higher incidence of postcardiac surgery atrial fibrillation in obese patients. PMID- 22541226 TI - YC-1 induced constrictions: no dependency on other vasoconstrictor. PMID- 22541228 TI - Symmetrical dimethylarginine as a biomarker for acute kidney injury. PMID- 22541230 TI - Totally endoscopic quadruple coronary artery bypass grafting is feasible using robotic technology. AB - Multivessel robotic totally endoscopic coronary artery bypass grafting is currently under development. Quadruple totally endoscopic coronary artery bypass has so far not been reported. A 75-year-old patient with multivessel coronary artery disease underwent daVinci Si-assisted completely endoscopic placement of a left internal mammary artery bypass to the left anterior descending artery and construction of a right internal mammary artery Y-graft off the left internal mammary artery to the posterior descending artery. The left internal mammary artery was also connected to a diagonal branch as a sequential graft. The obtuse marginal branch was revascularized using an endoscopically harvested vein graft originating from the left axillary artery. PMID- 22541231 TI - A rapid structural degeneration of a porcine mitral valve. AB - A 73-year-old woman underwent both mitral and aortic valve replacements with porcine heart valve prostheses because of severe mitral regurgitation and severe aortic regurgitation. Ten months after surgery, maximal flow velocity of the aortic valve reached 4.6 m/sec and moderate mitral regurgitation was detected. Repeated mitral and aortic valve replacements with mechanical heart valves were performed. The excised mitral valve showed thinning of the 3 cusps, and 2 of them were perforated. There was pannus overgrowth on the flow surface of the porcine aortic valve. Histologic examination of the excised mitral valve revealed marked inflammatory changes with macrophages. PMID- 22541232 TI - Synchronous presentation of cardiac and abdominal paragangliomas. AB - A 28-year-old male presenting with a hypertensive crisis was found to have synchronous right atrial and retrocaval masses. Serum normetadrenaline was elevated in keeping with functional paragangliomas. After preoperative optimization both masses were successfully excised, including a saphenous vein graft to the right coronary artery. Serum catecholamines returned to the normal range postoperatively and all antihypertensive therapy was ceased. PMID- 22541233 TI - Novel approach to recurrent cavoatrial renal cell carcinoma. AB - Renal cell carcinoma (RCC) with cavoatrial extension is a rare and complex problem. Complete resection is difficult but correlates with favorable patient outcomes. We present 2 cases of successful reoperative resections of recurrent RCC in patients with level III-IV cavoatrial involvement. We used a thoracoabdominal approach, peripheral cannulation, and hypothermic circulatory arrest. We advocate this novel approach as a successful means of avoiding a more difficult reoperation. PMID- 22541234 TI - A rare case of swyer-james macleod syndrome and a new clinical presentation, acquired lobar emphysema. AB - Swyer-James Macleod syndrome is a radiologic entity characterized by hyperlucency of one or more lobes or of the entire lung, decreased number and diameter of ipsilateral peripheral pulmonary vessels, and difficult visibility of the arterial network and unobstructed bronchial system. A 21-year-old male was admitted to our clinic on the observation of left hemithoracic hyperinflation on chest radiography. Preoperative evaluation revealed an increase of ventilation to the left lower lobe and the deletion of peripheral vascular structures. Scintigraphy revealed a perfusion defect in the left lower lobe. In this patient with congenital left upper lobe hypoplasia and Swyer-James Macleod syndrome in the lower half of the lower lobe, I present the coexistence of these two rare clinical entities and "acquired lobar emphysema." PMID- 22541235 TI - Laparoscopic repair of gastric herniation after extrapleural pneumonectomy for mesothelioma. AB - Acute herniation of intra-abdominal organs into the chest after extrapleural pneumonectomy is an uncommon but morbid and potentially mortal complication. We report a case of acute diaphragmatic hernia after extrapleural pneumonectomy for mesothelioma repaired laparoscopically. This approach is an alternative to repeated thoracotomy and is a viable option for treatment of this difficult problem with potentially less morbidity. PMID- 22541236 TI - Laparoscopic thoracic duct clipping for persistent chylothorax after extrapleural pneumonectomy. AB - We describe a 68-year-old man who was treated by laparoscopic thoracic duct clipping for persistent chylothorax after an extrapleural pneumonectomy for malignant pleural mesothelioma. Initial conservative treatment did not resolve the postoperative chylothorax. A second surgery through the thoracic approach was considered invasive and difficult after extrapleural pneumonectomy. A laparoscopic approach proved effective and resolved the chylothorax. Thus, laparoscopic thoracic duct clipping is considered very useful for treating chylothorax. PMID- 22541237 TI - Echocardiographic, cardiac magnetic resonance imaging, surgical and pathological findings of an unusual right atrial tumor: a giant papillary fibroelastoma. PMID- 22541238 TI - A rare cause of respiratory distress: a huge tracheal diverticulum. PMID- 22541239 TI - Bridging annuloplasty for left atrioventricular valve of partial atrioventricular septal defect. AB - Residual left atrioventricular valve regurgitation after conventional repair technique for partial atrioventricular septal defect most commonly occurs in the central position. We describe here the technique for bridging annuloplasty on the opposing anterior and posterior annuli of the atrioventricular valve in selected patients with short leaflets. PMID- 22541240 TI - Imaging in upper urinary tract infections. AB - Most infections of the upper urinary tract are straightforward and do not require any emergency radiological investigations. A sonogram carried out within 48 hours will in most cases be sufficient to eliminate obstructed pyelonephritis requiring emergency drainage of urine. In complicated cases, or those affecting already weakened areas, an urgent CT scan is necessary, preferably after injection of iodinated contrast medium if renal function permits. CT scanning is far better at diagnosis than sonography as well as at investigating whether there are complications. Furthermore, it is essential that the radiologist is aware of unusual and rare forms of pyelonephritis, especially pseudotumoural forms, so that clinicians can be pointed towards the appropriate treatment, avoiding unnecessary and invasive interventions. PMID- 22541241 TI - [Practical taxonomy of health care containment/disinvestment in non-value-added care in order to have a sustainable NHS]. AB - The environment of severe cost containment has led to the active search of "internal sustainability" of health systems; the disinvestment in all non-value added services is one of the tools used. This article provides the taxonomy to identify ineffective, unsafe, unnecessary, unsuccessful, unkind and unwise care practices and discusses their implications in relation to patients ordered according to their severity, as well as the expected health gains of the intervention. Finally, the feasibility of those disinvestment policies is analysed according to macro-, middle, and micro-management scenarios. PMID- 22541243 TI - Amplification of Toll-like receptor-mediated signaling through spleen tyrosine kinase in human B-cell activation. AB - BACKGROUND: B cells are activated by combined signals through the B-cell receptor (BCR) and CD40. However, the underlying mechanisms by which BCR signals synergize with Toll-like receptor (TLR) signaling in human B cells remain unclear. OBJECTIVE: We sought to elucidate a role of spleen tyrosine kinase (Syk), a key molecule of BCR signaling, in TLR-mediated activation of human B cells. METHODS: Human naive and memory B cells were stimulated with combinations of anti-BCR, soluble CD40 ligand, and CpG. Effects of the Syk inhibitors on several B-cell functions and expression of TLR9, TNF receptor-associated factors (TRAFs), and phospho-nuclear factor kappaB in B cells were assessed. RESULTS: Activation of BCR synergized with CD40- and TLR9-mediated signals in driving robust proliferation, cell-cycle progression, expression of costimulatory molecules, cytokine production, and immunoglobulin production of human B-cell subsets, especially memory B cells. However, the Syk inhibitors remarkably abrogated these B-cell functions. Notably, after stimulation through all 3 receptors, B-cell subsets induced marked expression of TLR9, TRAF6, and phospho-nuclear factor kappaB, which was again significantly abrogated by the Syk inhibitors. CONCLUSION: Syk-mediated BCR signaling is a prerequisite for optimal induction of TLR9 and TRAF6, allowing efficient propagation of TLR9-mediated signaling in memory B cells. These results also underscore the role of Syk in aberrant B-cell activation in patients with autoimmune diseases. PMID- 22541242 TI - Molecular mimicry between cockroach and helminth glutathione S-transferases promotes cross-reactivity and cross-sensitization. AB - BACKGROUND: The extensive similarities between helminth proteins and allergens are thought to contribute to helminth-driven allergic sensitization. OBJECTIVE: The objective of this study was to investigate the cross-reactivity between a major glutathione-S transferase allergen of cockroach (Bla g 5) and the glutathione-S transferase of Wuchereria bancrofti (WbGST), a major lymphatic filarial pathogen of humans. METHODS: We compared the molecular and structural similarities between Bla g 5 and WbGST by in silico analysis and by linear epitope mapping. The levels of IgE, IgG, and IgG(4) antibodies were measured in filarial-infected and filarial-uninfected patients. Mice were infected with Heligmosomoides bakeri, and their skin was tested for cross-reactive allergic responses. RESULTS: These 2 proteins are 30% identical at the amino acid level with remarkable similarity in the N-terminal region and overall structural conservation based on predicted 3-dimensional models. Filarial infection was associated with IgE, IgG, and IgG(4) anti-Bla g 5 antibody production, with a significant correlation between antibodies (irrespective of isotype) to Bla g 5 and WbGST (P< .0003). Preincubation of sera from cockroach-allergic subjects with WbGST partially depleted (by 50%-70%) anti-Bla g 5 IgE, IgG, and IgG(4) antibodies. IgE epitope mapping of Bla g 5 revealed that 2 linear N-terminal epitopes are highly conserved in WbGST corresponding to Bla g 5 peptides partially involved in the inhibition of WbGST binding. Finally, mice infected with H bakeri developed anti-HbGST IgE and showed immediate-type skin test reactivity to Bla g 5. CONCLUSION: These data demonstrate that helminth glutathione-S transferase and the aeroallergen Bla g 5 share epitopes that can induce allergic cross-sensitization. PMID- 22541244 TI - A self-regulation intervention can improve quality of life for families with food allergy. PMID- 22541245 TI - Long-term safety and asthma control measures with a budesonide/formoterol pressurized metered-dose inhaler in African American asthmatic patients: a randomized controlled trial. AB - BACKGROUND: Information surrounding the long-term safety of combination inhaled corticosteroid/long-acting beta(2)-adrenergic agonist medications in African American asthmatic patients is limited. OBJECTIVE: We sought to assess safety and asthma control with a budesonide/formoterol pressurized metered-dose inhaler (pMDI) versus budesonide over 1 year in African American patients. METHODS: This 52-week, randomized, double-blind, parallel-group, multicenter, phase 3B safety study (NCT00419952) was conducted in 742 self-reported African American patients 12 years or older with moderate-to-severe asthma previously receiving medium- to high-dose inhaled corticosteroids. After 2 weeks using a 320 MUg twice-daily budesonide pMDI, patients were randomized 1:1 to 320/9 MUg twice-daily budesonide/formoterol pMDI or 320 MUg twice-daily budesonide pMDI. RESULTS: Both treatments were well tolerated. Asthma exacerbation incidence and rate (per patient-treatment year) were lower with budesonide/formoterol versus budesonide (incidence, 7.7% vs 14.0% [P= .006]; rate ratio, 0.615 [P= .002]). Time to first asthma exacerbation was longer (P= .018) with budesonide/formoterol versus budesonide. The most common adverse events, regardless of study drug relationship, were headache (9.5% and 7.7%), nasopharyngitis (6.9% and 8.0%), sinusitis (4.0% and 6.3%), and viral upper respiratory tract infection (5.8% and 4.4%) for budesonide/formoterol and budesonide, respectively. Serious adverse events occurred in 12 and 15 patients, respectively; none were considered drug related. No substantial or unexpected patterns of abnormalities were observed in laboratory, electrocardiographic, or Holter monitoring assessments. Hospitalization caused by asthma exacerbation occurred in 0 and 4 patients in the budesonide/formoterol and budesonide groups, respectively. Pulmonary function and asthma control measures generally favored budesonide/formoterol. CONCLUSIONS: In this population budesonide/formoterol pMDI was well tolerated over 12 months, with a safety profile similar to that of budesonide; the asthma exacerbation rate was reduced by 38.5% versus budesonide. PMID- 22541247 TI - Inhibitory human antichimeric antibodies to rituximab in a patient with pemphigus. PMID- 22541246 TI - Comparative dietary therapy effectiveness in remission of pediatric eosinophilic esophagitis. AB - BACKGROUND: Eosinophilic esophagitis is a chronic, immune-mediated inflammatory disorder that responds to dietary therapy; however, data evaluating the effectiveness of dietary therapeutic strategies are limited. OBJECTIVE: This study compared the effectiveness of 3 frequently prescribed dietary therapies (elemental, 6-food elimination, and skin prick and atopy patch-directed elimination diets) and assessed the remission predictability of skin tests and their utility in directing dietary planning. METHODS: A retrospective cohort of proton-pump inhibitor-unresponsive, non-glucocorticoid-treated patients with eosinophilic esophagitis who had 2 consecutive endoscopic biopsy specimens associated with dietary intervention was identified. Biopsy histology and remissions (<15 eosinophils/high-power field) after dietary therapy and food reintroductions were evaluated. RESULTS: Ninety-eight of 513 patients met the eligibility criteria. Of these 98 patients, 50% (n= 49), 27% (n= 26), and 23% (n= 23) received elemental, 6-food elimination, and directed diets, respectively. Remission occurred in 96%, 81%, and 65% of patients on elemental, 6-food elimination, and directed diets, respectively. The odds of postdiet remission versus nonremission were 5.6-fold higher (P= .05) on elemental versus 6-food elimination diets and 12.5-fold higher (P= .003) on elemental versus directed diets and were not significantly different (P= .22) on 6-food elimination versus directed diets. After 116 single-food reintroductions, the negative predictive value of skin testing for remission was 40% to 67% (milk, 40%; egg, 56%; soy, 64%; and wheat, 67%). CONCLUSION: All 3 dietary therapies are effective; however, an elemental diet is superior at inducing histologic remission compared with 6 food elimination and skin test-directed diets. Notably, an empiric 6-food elimination diet is as effective as a skin test-directed diet. The negative predictive values of foods most commonly reintroduced in single-food challenges are not sufficient to support the development of dietary advancement plans solely based on skin test results. PMID- 22541249 TI - Determination of dalcetrapib by liquid chromatography-tandem mass spectrometry. AB - The cholesteryl ester transfer protein modulator dalcetrapib is currently under development for the prevention of dyslipidemia and cardiovascular disease. Dalcetrapib, a thioester, is rapidly hydrolyzed in vivo to the corresponding thiophenol which in turn is further oxidized to the dimer and mixed disulfides (where the thiophenol binds to peptides, proteins and other endogenous thiols). These forms co-exist in an oxidation-reduction equilibrium via the thiol and cannot be stabilized without influencing the equilibrium, hence specific determination of individual components, i.e., in order to distinguish between the free thiol, the disulfide dimer and mixed disulfide adducts, was not pursued for routine analysis. The individual forms were quantified collectively as dalcetrapib-thiol (dal-thiol) after reduction under basic conditions with dithiothreitol to break disulfide bonds and derivatization with N-ethylmaleimide to stabilize the free thiol. The S-methyl and S-glucuronide metabolites were determined simultaneously with dal-thiol with no effect from the derivatization procedure. Column-switching liquid chromatography-tandem mass spectrometry provided a simple, fast and robust method for analysis of human and animal plasma and human urine samples. Addition of the surfactant Tween 80 to urine prevented adsorptive compound loss. The lower limits of quantitation (LLOQ) were 5 ng/mL for dal-thiol, and 5 ng/mL for the S-methyl and 50 ng/mL for the S-glucuronide metabolites. Using stable isotope-labeled internal standards, inter- and intra assay precisions were each <15% (<20% at LLOQ) and accuracy was between 85 and 115%. Recovery was close to 100%, and no significant matrix effect was observed. PMID- 22541250 TI - First international conference on animal health surveillance (ICAHS). PMID- 22541248 TI - IL-4 receptor polymorphisms predict reduction in asthma exacerbations during response to an anti-IL-4 receptor alpha antagonist. AB - BACKGROUND: This is the first large pharmacogenetic investigation of the inflammatory IL-4/IL-13 pathway in patients with moderate-to-severe asthma. We analyzed genomic DNA from participants in a 12-week placebo-controlled efficacy trial of pitrakinra (1, 3, or 10 mg twice daily), a novel IL-4/IL-13 pathway antagonist (Clinicaltrials.govNCT00801853). OBJECTIVES: The primary hypothesis for this analysis is that amino acid changes in the 3' end of the IL-4 receptor alpha gene (IL4RA) or closely proximal variants would predict reductions in asthma exacerbations for subjects randomized to pitrakinra therapy. METHODS: Nineteen IL4RA single nucleotide polymorphisms (SNPs) were tested in 407 non Hispanic white subjects for association with the primary clinical end point of asthma exacerbations and changes in secondary end points for asthma symptom scores. RESULTS: The most consistent pharmacogenetic associations were observed for the correlated tagging SNPs rs8832 and rs1029489 in the IL4RA 3' untranslated and proximal regions, respectively. Subjects homozygous for the rs8832 common G allele randomized to pitrakinra (placebo group nonsignificant) had decreased asthma exacerbations and decreased nocturnal awakenings and activities limited by asthma. There was also a significant pitrakinra dose-response relationship (placebo/1 mg/3 mg/10 mg) for exacerbations in subjects homozygous for the common allele in rs1029489 (P = .005) and rs8832 (P= .009) and the intronic SNPs rs3024585, rs3024622, and rs4787956 (P = .03). CONCLUSION: This study demonstrates a significant pharmacogenetic interaction between anti-IL-4 receptor alpha therapy and IL4RA gene variation, identifying an asthma subgroup that is more responsive to therapy with this antagonist. PMID- 22541251 TI - Sequence analysis of the 3'-untranslated region of HSP70 (type I) genes in the genus Leishmania: its usefulness as a molecular marker for species identification. AB - BACKGROUND: The Leishmaniases are a group of clinically diverse diseases caused by parasites of the genus Leishmania. To distinguish between species is crucial for correct diagnosis and prognosis as well as for treatment decisions. Recently, sequencing of the HSP70 coding region has been applied in phylogenetic studies and for identifying of Leishmania species with excellent results. METHODS: In the present study, we analyzed the 3'-untranslated region (UTR) of Leishmania HSP70 type I gene from 24 strains representing eleven Leishmania species in the belief that this non-coding region would have a better discriminatory capacity for species typing than coding regions. RESULTS: It was observed that there was a remarkable degree of sequence conservation in this region, even between species of the subgenus Leishmania and Viannia. In addition, the presence of many microsatellites was a common feature of the 3'-UTR of HSP70-I genes in the Leishmania genus. Finally, we constructed dendrograms based on global sequence alignments of the analyzed Leishmania species and strains, the results indicated that this particular region of HSP70 genes might be useful for species (or species complex) typing, improving for particular species the discrimination capacity of phylogenetic trees based on HSP70 coding sequences. Given the large size variation of the analyzed region between the Leishmania and Viannia subgenera, direct visualization of the PCR amplification product would allow discrimination between subgenera, and a HaeIII-PCR-RFLP analysis might be used for differentiating some species within each subgenera. CONCLUSIONS: Sequence and phylogenetic analyses indicated that this region, which is readily amplified using a single pair of primers from both Old and New World Leishmania species, might be useful as a molecular marker for species discrimination. PMID- 22541252 TI - [Influence of non-alcoholic fatty liver disease on cardiovascular disease]. AB - Non-alcoholic fatty liver disease encompasses a spectrum ranging from simple steatosis to steatohepatitis without excess alcohol intake and is considered to be the hepatic manifestation of metabolic syndrome. Recent studies indicate that non-alcoholic fatty liver disease is closely related to cardiovascular disease, especially to thickening of the intima-media layer of the carotid artery, as the morphostructural manifestation of the presence of subclinical atheromatosis. Therefore, the correct management of non-alcoholic fatty liver disease would allow the natural history of both the liver disease and the atherosclerosis to be modified. PMID- 22541253 TI - The frontotemporal dementias in a tertiary referral center: classification and demographic characteristics in a series of 232 cases. AB - BACKGROUND: Frontotemporal lobar degeneration (FTLD) comprises of behavioral variant frontotemporal dementia (bvFTD) and primary progressive aphasia (PPA) with its 3 main variants, namely nonfluent/agrammatic (naPPA), semantic (svPPA) and logopenic (lvPPA). Recently a clinical syndrome with predominant right temporal atrophy was recognized (rvFTD). FTLD often overlaps with parkinsonism plus syndromes such as corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), as well as with motor neuron disease (FTD-MND). While FTLD syndromes were thought to be rare and difficult to diagnose ante mortem, revised diagnostic criteria as well as recent studies highlighted the plausibility of accurate clinical diagnosis. METHODS: 232 FTLD patients were assessed from January 1, 2003 to December 31, 2010 in the Neurology Department of a tertiary referral center. Patients were classified as bvFTD, naPPA, svPPA, lvPPA, CBD/PSP and rvFTD and their demographic characteristics were analyzed. RESULTS: From the 232 patients, 111 (47.8%) were diagnosed with bvFTD, 56 (24.1%) with naPPA, 21 (9.1%) with svPPA, 6 (2.6%) with lvPPA, 20 (8.6%) with CBD or PSP and 18 (7.8%) with rvFTD. 44% of the patients were under 65 years old at onset of symptoms, while only 4.3% reported family history of dementia. FTLD subgroups did not differ with respect to demographic characteristics, but early onset cases had higher educational level. DISCUSSION: FTLD represents a syndrome with different but clinically distinguishable phenotypes. Cultural, educational and socioeconomic status differences might regulate patients' access to medical care and therefore influence age of reported onset and prevalence of FTLD in clinical studies. High clinical alertness and sensitive neuropsychological tests could lead to timely clinical diagnosis in a common presenile type of dementia. PMID- 22541254 TI - Selective muscle involvement in a family affected by a second LIM domain mutation of fhl1: an imaging study using computed tomography. AB - Mutations in the four-and-a-half LIM domains 1 gene (fhl1) are associated with various phenotypes of hereditary myopathies, including reducing body myopathy. We describe here a mother, daughter and son suffering from FHL1 myopathy with a mutation in the second LIM domain of fhl1. We investigated whether there is a characteristic muscle involvement in both sexes. Despite the variety of symptoms exhibited by the male and female patients, the systemic imaging studies showed a similar pattern: the flexor muscles of the brachium and thigh were affected earlier than the extensor muscle with a profound degeneration of the paraspinal muscles. These findings may include one of the characteristic clinical features for suspecting a mutation in the second LIM domain. PMID- 22541255 TI - An unusual cause of visual impairment in tuberculous meningitis. AB - Impairment of vision is a devastating complication of tuberculous meningitis which may occur as a result of increased intracranial pressure, compression over the visual pathways or vasculitis. We herein present occurrence of neuroretinitis in a 35-year-old lady presenting with low grade fever and headache for one month, and associated with diminution of vision from 3 weeks. She was diagnosed as a case of definite tuberculous meningitis and initiated on anti-tuberculous treatment as per WHO guidelines with supplemental corticosteroids. Marked improvement in vision was observed and at 3 months of follow-up the patient was asymptomatic. Direct ophthalmoscopy, visual field analysis, fluorescein angiography, optical coherence tomography and magnetic resonance imaging of the brain were done to document the ophthalmological findings. Neuroretinitis, being an unusual cause of visual impairment in tuberculous meningitis, must be considered in patients without any evidence of raised intracranial pressure or compression, and with normal fluorescein angiography. We suggest that neuroretinitis may be added to list of causes of visual impairment in patients with tuberculous meningitis. PMID- 22541256 TI - Health conditions for travellers to Saudi Arabia for the Umra and Hajj pilgrimage to Mecca: requirements for 2012 (1433). PMID- 22541257 TI - Cerebro-rhino orbital mucormycosis: an update. AB - Mucormycosis is an uncommon fungal infection which can lead to fulminant necrotizing infection under optimal host condition. Fungi have the ability to invade blood vessels and can affect different parts of the body. The most common, though the most aggressive, form is cerebro-rhino-orbital mucormycosis that occurs in debilitated patients, in conjunction with sinus or para-sinus involvement. Due to increased number of newly diagnosed cases of mucormycosis world-wide resulting from uncontrolled metabolic conditions, this paper intends to widen the reader's scope and knowledge about the nature of the disease and its multicomplexity that require a collaborative effort for careful management. Patients who are at risks both at the onset of the disease and during its management have been identified in the paper. PMID- 22541258 TI - Prevaccination screening of health-care workers for immunity to measles, rubella, mumps, and varicella in a developing country: What do we save? AB - A structured questionnaire was administered to health-care workers (HCWs). The HCWs were also screened for measles, rubella, mumps, and varicella (MMRV) using serological methods. One thousand two hundred and fifty-five HCWs were tested. Of the HCWs examined, 94% were immune to measles, 97% to rubella, 90% to mumps and 98% to varicella. The positive predictive values of histories of measles, mumps, rubella and varicella were 96%, 93%, 100% and 98%, respectively. The negative predictive values of histories of measles, mumps, rubella and varicella were 13%, 17%, 5% and 2%, respectively. The cost of vaccination without screening was significantly more expensive (cost difference: ?24,385) for varicella, although vaccination without screening was cheap (cost difference: ?5693) for MMR. Although the use of cheaper vaccines supports the implementation of vaccination programs without screening, the cost of vaccination should not be calculated based only on the direct costs. The indirect costs associated with lost work time due to vaccination and its side effects and the direct costs of potential side effects should be considered. However, if prescreening is not conducted, some HCWs (2-7%) would be unprotected against these contagious illnesses because of the unreliability of their MMRV history. In conclusion, the screening of HCWs before vaccination continues to be advisable. PMID- 22541259 TI - Bacterial interactions in the nasopharynx - effects of host factors in children attending day-care centers. AB - The nasopharynges of preschool children are often colonized by potentially pathogenic bacteria. The interactions between these common pathogens and certain host factors were investigated in healthy preschool children 1-6 years of age. Nasopharynx samples were collected from all 63 children attending a day-care center that experienced an outbreak of penicillin-resistant Streptococcus pneumoniae. The samples were analyzed for S. pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Group A Streptococci. A model for the risk of carrying these bacteria was established using logistic regression. S. pneumoniae and H. influenzae antagonize each other, whereas M. catarrhalis and S. pneumoniae have a positively association. The risk of carrying M. catarrhalis decreases with age. The time spent in day care each week was not shown to influence the rate of carriage of any of these pathogens. The negative effect of H. influenzae on S. pneumoniae is discussed in relation to the carriage of penicillin-resistant S. pneumoniae, and possible mechanisms involved in this interaction are presented. PMID- 22541260 TI - The analysis of pathological findings for cervical lymph node biopsies in eastern Saudi Arabia. AB - BACKGROUND AND OBJECTIVE: Lymphadenopathy is a common medical problem. A lymph node biopsy may be necessary for definitive diagnosis in selected cases. METHODS: The study group included a retrospective, hospital-based series of patients who had a cervical lymph node biopsy at the Saudi Aramco Medical Services organization between 1997 and 2008. RESULTS: During the study period, there were a total of 452 cervical lymph node biopsies. Biopsies were performed on 122 (27%) children <=18 years and 81 (18%) patients >60 years. The most common histopathological diagnosis was reactive disease (52.2%, n=236), which was followed by granulomatous disease (15.5%, n=70). We detected carcinoma in 14.6% of the patients (n=66), Hodgkin's lymphoma in 8.8% (n=40) and non-Hodgkin's disease in 8.8% (n=40). Malignancy was more common in adults than children (19.5% vs. 1.6%, respectively and reactive disease was more common in children than adults (65.3% vs. 47.3%, respectively). Metastatic disease was more likely in the older age group (17.7% vs. 0%), Hodgkin's disease was found in 12.5% of the adolescents, and non-Hodgkin's disease was present in 10.3% of the adults and elderly. CONCLUSION: The most common histopathological findings for cervical lymph node biopsies in eastern Saudi Arabia were reactive disease and granulomatous disease. PMID- 22541261 TI - Acinetobacter infections in a tertiary level intensive care unit in northern India: epidemiology, clinical profiles and outcomes. AB - BACKGROUND: Nosocomial Acinetobacter infections are an increasing concern in intensive care units (ICU). OBJECTIVES: To study the demographic and clinical characteristics and the outcomes of ICU patients with Acinetobacter infections. METHODS: A retrospective, 1-year audit of all Acinetobacter infections diagnosed in ICU patients between January 1 and December 31, 2009. RESULTS: Acinetobacter infection occurred in 94 patients (108 episodes). The most common site of infection was the respiratory tract (83 patients, 76.85%), with medical patients being more susceptible than surgical patients to Acinetobacter lung infections (P=0.04), particularly late-onset ventilator-associated pneumonia (VAP) (P=0.04). The majority (63.8%) of infections were acquired in the ICU, and patients with ICU acquired infections were intubated significantly longer than the other patients (P=0.02). Seventy percent of the infections were caused by multidrug resistant (MDR) strains, and the overall crude mortality rate was over 70%. The most important factors affecting mortality were the duration of intubation (P=0.001) and the inappropriate use of antibiotics (P=0.021) after diagnosis of the infection. CONCLUSIONS: Acinetobacter infections are highly prevalent in the ICU, with medical patients being more susceptible to lung infections, particularly late-onset VAP. The early and appropriate selection of antibiotics is the most important determinant of survival among these patients. PMID- 22541262 TI - Helicobacter pylori genotypes can predict gastric tissue histopathology: a longitudinal study of Iranian patients. AB - INTRODUCTION: Several factors have been suggested to account for differences in the virulence of Helicobacter pylori infections in various populations. Evidence suggests the existence of different strains of H. pylori with different degrees of virulence. The present study aimed to investigate the gastric histopathology in Iranian patients infected with H. pylori and to investigate the relationship between the severity of gastritis and four different bacterial virulence associated genotypes. METHODS AND MATERIALS: All of the patients with positive results from a pathological examination, a rapid urease test, and PCR analysis for H. pylori infection were consecutively included into the study. The classification and grading of gastritis were performed according to the Sydney System. Esophagitis was classified endoscopically according to the Savary-Miller grading system. The primers used in this study targeted 16S rRNa (521 bp), Urease A (411 bp), Cag A (400 bp), and 26 kDa (303 bp). RESULTS: Twenty-eight patients were included in the study. The presence of Cag A showed a significant relationship with higher gastritis grades (3.0+/-0.7 vs. 2.3+/-0.9, p=0.024) and higher scores for H. pylori infection (3.0+/-0.7 vs. 2.3+/-0.7, p=0.027). The patients infected with 26 kDa-positive H. pylori had significantly higher infection scores (3.5+/-0.6 vs. 2.5+/-0.6, p=0.020). CONCLUSION: This study showed that CagA-positive H. pylori infection is associated with more severe gastritis and with increased bacterial density and inflammation in the biopsy specimens. The 303-bp positive genotype was also significantly associated with higher grades of esophagitis. Additional in-depth trials will be helpful in extending our findings. PMID- 22541263 TI - The prevalence and characteristics of water-pipe smoking among high school students in Saudi Arabia. AB - OBJECTIVE: To identify the prevalence and predictors of the water-pipe (WP) smoking epidemic in the Kingdom of Saudi Arabia (KSA). METHODS: A cross-sectional study conducted with 16-18 year-old high school students in Riyadh, Saudi Arabia. RESULTS: Of the 1272 participants, 414 (33.0%) reported having tried WP smoking. Of this group, 141 (34.1%) were female and 273 (65.9%) were male. Further, 129 (10.2%) students were current WP smokers who had used at least one rock in the past month; 20 were female (1.6%) and 120 were male (8.6%). Regarding age, 276 (68.1%) students who tried WP smoking at least once began when they were over 11 years of age, whereas 129 (31.9%) began WP smoking at or before 11 years of age. Adjusted odds ratios showed that trying WP smoking at least once was associated with smoking after the age of 11 (p=0.021, OR 7.7; CI: 1.4-43.6) and accepting water-pipes from a friend (p=0.024, OR 10.6; CI: 1.4-83.4). CONCLUSION: A high prevalence of WP smoking exists among male and female high schools students in Riyadh, KSA. WP smoking was reported to begin in early adulthood. PMID- 22541264 TI - Point prevalence and risk factors of hospital acquired infections in a cluster of university-affiliated hospitals in Shiraz, Iran. AB - BACKGROUND: Hospital-acquired infections (HAIs) are critical and mostly preventable complications that occur in hospitalized patients and lead to major health and economic burdens. Most of the information on HAI risk factors and the recommended preventive measures is based on data acquired from only a few countries. The aim of this point prevalence HAI study conducted in Shiraz, Iran, was to study the local epidemiology of HAIs and the major risk factors for acquiring HAIs in a Middle-Eastern region. METHODS: The study employed four identical point prevalence surveys in eight university hospitals, each consisting of 60-700 beds. The study was conducted during all four season of 2008-2009. All of the patients admitted for >=48h were studied, although the patients admitted to emergency wards were excluded. A standardized data collection form that included name, age, gender, presence or absence of HAI, administration of any antibiotics, insertion of a central line, use of an endotracheal tube, mechanical ventilation, and use of an urinary catheter was completed for each patient. The HAI definitions used in this study were based on the US National Nosocomial Infection Surveillance (NNIS) guidelines. RESULTS: Data from 3450 patients were prospectively collected and analyzed. The overall HAI prevalence was 9.4%. The most common HAIs were blood stream infections (2.5%), surgical site infections (2.4%), urinary tract infections (1.4%), and pneumonia (1.3%). A logistic regression analysis showed that the odds ratio OR for males rather than females acquiring infections was 1.56 (95% confidence interval [CI] 1.21-2.02). Other HAI risk factors included using a central intravascular catheter, adjusted OR of 3.86 (95% CI 2.38-6.26), and using an urinary catheter, adjusted OR of 3.06 (95% CI 2.19-4.28). Being admitted to an ICU was not an independent HAI risk factor. For all HAIs, the OR of acquiring infection was 3.24 (95% CI 2.34-4.47) in the patients with hospital stays longer than eight days. A high discrepancy between HAIs and antibiotic use was observed. Antibiotics were administered to 71% of the patients, but only 9.4% of the patients also had at least one documented infection. CONCLUSION: This point prevalence study showed that HAIs are frequent in Shiraz university hospitals, and that the proportion of patients receiving antibiotics is high. The results imply that more primary prevention efforts are necessary to address HAIs associated with using indwelling devices and to prevent surgical site infections. PMID- 22541265 TI - Injection practices of healthcare professionals in a Tertiary Care Hospital. AB - BACKGROUND: Unsafe injection practices are prevalent worldwide and may result in spread of infection. Thus the present study was planned to observe the injection practices of healthcare professionals (HCP), including aseptic precautions and disposal of used syringes/needle. MATERIALS AND METHODS: Injection practices were observed in the outpatients and inpatients departments. Questionnaire was designed, tested and administered for this purpose. RESULTS: 130 patients receiving injections were observed. Overall injection practices of the HCP were satisfactory. However, unsafe practices with respect to not washing hands (95.4%), not wearing/changing gloves (61.6%), recapping of needles (12.2%), wiping of needle with swab (15.4%) and breaking of ampoule with solid object (44.4%) were observed. CONCLUSION: The problem of unsafe injections can be successfully addressed by organizing continuing medical education/symposium/workshops for improving the knowledge, attitude and practices of the HCP. Periodic monitoring and such interventions may also further improve safe injection practices. PMID- 22541266 TI - Disposal of syringes, needles, and lancets used by diabetic patients in Pakistan. AB - OBJECTIVE: To assess the use, handling and disposal of insulin injection equipment by diabetic patients in Pakistan. METHODS: We conducted a cross sectional study at diabetic clinics in five tertiary centers in Pakistan. All diabetic patients (type 1/type 2) who were on insulin for more than 1 month, were included. An Urdu (local language)-translated questionnaire was used to collect information on insulin administration equipment, the site and frequency of needle use, insulin syringe/pen/lancet disposal, sharing of needles and knowledge about diseases that are spread by sharing contaminated needles. RESULTS: Of 375 patients, 58% were female. The mean (SD) duration of diabetes was 12.3 (7.3) years, and the duration of insulin use was 4.4 (4.3) years. The majority of the patients used syringes (88.3%) for insulin administration. Additionally, the majority of the patients disposed of used devices (syringes, 92%; pens, 75%; and lancets, 91%) in the household garbage collection bin. About half of the patients (n=185) reported being educated by their physicians about the disposal of sharps. Those who were educated by a physician (adjusted odds ratio (adjOR): 0.36; 95%CI: 0.16-0.81) or could read/write English (adjOR: 0.32; 95%CI: 0.11-0.92) were less likely to dispose of syringes and needles in the household garbage. CONCLUSION: The common disposal of sharps in the household garbage has implications for disease transmission. Education on the safe disposal of sharps may improve the disposal practices. PMID- 22541267 TI - Serological and molecular diagnosis of human brucellosis in Najran, Southwestern Saudi Arabia. AB - This study aimed to investigate the prevalence of human brucellosis in Najran, southwestern Saudi Arabia, and to assess the performances of ELISA and PCR as diagnostic tools for brucellosis with respect to conventional methods. The study included 340 patients with clinical characteristics of brucellosis. Blood samples from cases and controls were subjected to culture, standard tube agglutination test (SAT), ELISA for IgM and IgG, and brucella PCR. The diagnosis of brucellosis was confirmed in 54 (15.9%) of the 340 provisionally diagnosed brucellosis patients. Blood culture identified only 14 (25.9%) cases. The SAT was positive for 50 (92.6%) cases, whereas ELISA IgM, IgG and PCR were found positive in 46, 52 and 38 cases respectively. The sensitivities of ELISA IgM and IgG were 85.2% and 96.3% respectively and the specificity was 100% for each. For PCR, the sensitivity and specificity were 70.4% and 100% respectively. In conclusion, ELISA offers a significant advantage over conventional serological methods in the diagnosis of brucellosis in endemic areas. The PCR test results can be particularly important in patients with clinical signs and symptoms, and negative serological results, allowing the early and rapid confirmation of the brucellosis. PMID- 22541268 TI - Public awareness and practical knowledge regarding Hepatitis A, B, and C: a two country survey. AB - AIM: To assess the level of public awareness and practical knowledge regarding Hepatitis A, B, and C in two low-endemic countries (Germany and The Netherlands). METHODS: Two large-scale surveys (N=1989 and 668). RESULTS: Although public awareness was high, practical knowledge regarding differences in the mode of transmission, consequences, and prevention was very low in both countries, especially among those with a lower level of education. CONCLUSION: Future public health initiatives are warranted to increase knowledge as a first step to empower people, especially those with a lower level of education. PMID- 22541269 TI - The diagnostic challenge of pandemic H1N1 2009 virus in a dengue-endemic region: a case report of combined infection in Jeddah, Kingdom of Saudi Arabia. AB - It is difficult to distinguish dengue fever from other febrile illnesses in a dengue-endemic area. This issue was compounded during the H1N1 2009 pandemic of influenza, which also presents as a febrile illness. This first laboratory confirmed case of co-infection with dengue and influenza A H1N1 2009 strain in Jeddah, Saudi Arabia, highlights the importance of considering co-infections because not only is influenza an ongoing concern in Jeddah, but several viral hemorrhagic fever viruses circulate in this region. PMID- 22541270 TI - An unusual combination of extrapulmonary manifestations of tuberculosis in a child. AB - We report the case of a 10-year-old girl who presented to the emergency department with acute abdominal pain. She was diagnosed as having extrapulmonary tuberculosis (TB) with multifocal osteomyelitis of the spine and ribs, peritonitis and intestinal involvement. We describe the clinical presentation of this unusual constellation of the disease in the absence of pulmonary involvement in a child and discuss the diagnostic challenges and treatment of these rare forms of TB. PMID- 22541271 TI - A patient with HIV infection presenting with diffuse membranous glomerulonephritis in a country with a low HIV prevalence--remarkable remission with therapy. AB - The most common manifestation of HIV in the kidney is HIV-associated nephropathy (HIVAN). In this report, we describe the first documented case of membranous glomerulonephritis in an HIV-positive individual in Turkey, the country with the lowest HIV prevalence in the region. The case occurred in an HIV-positive, hepatitis C (HCV)-negative, and hepatitis B (HBV)-negative Caucasian male, who presented with nephrotic-range proteinuria. The patient had a favorable response to HAART and an angiotensin-receptor blocker. PMID- 22541272 TI - Influenza A (H1N1) 2009 reinfection in Thailand. AB - In 2009, a novel influenza A (H1N1) virus emerged and rapidly spread around the world, leading to a pandemic. In contrast to the high rate of primary infection, reinfection with influenza A (H1N1) 2009 is rather rare. In this report, we describe a case of influenza A (H1N1) 2009 reinfection that occurred within an interval of 5 months in Thailand. PMID- 22541273 TI - An assessment of the Pakistan national HIV/AIDS strategy for sex workers. PMID- 22541274 TI - Tetracycline resistant V. cholerae O1 biotype El Tor serotype Ogawa with classical ctxB from a recent cholera outbreak in Orissa, Eastern India. PMID- 22541276 TI - Carotid intima-media thickness and cardiovascular events. PMID- 22541277 TI - Expression of vitellogenin receptor gene in the ovary of wild and captive Atlantic bluefin tuna (Thunnus thynnus). AB - The cDNA sequences of vitellogenin receptor proteins (VgR(+) and VgR(-)), containing or lacking the O-linked sugar domain, were determined in Atlantic bluefin tuna (Thunnus thynnus L.). VgR(-) gene expression in the ovary was compared in captive-reared and wild Atlantic bluefin tuna during the reproductive cycle. Gonad samples from adult fish were sampled from 2008 to 2010 from stocks reared in captivity at different commercial fattening operations in the Mediterranean Sea and from wild individuals caught either by traditional tuna traps during their migration towards the spawning grounds in the Mediterranean Sea or by the long-line artisanal fishery. In addition, juvenile male and female Atlantic bluefin tuna were sampled from a farming facility, to obtain baseline information and pre-adulthood amounts of VgR(-). The total length of VgR(+) cDNA was 4006 nucleotides (nt) and that of VgR(-) was 3946 nt. Relative amounts of VgR(-) were greater in juvenile females and in those adults having only previtellogenic oocytes (119 +/- 55 and 146 +/- 26 folds more than juvenile males, respectively). Amounts of VgR(-) were less in individuals with yolked oocytes (ripening stage, May-June) and increased after spawning in July (92 +/- 20 and 113 +/- 13 folds more than juvenile males in ripening and post-spawning fish, respectively). These data suggest that regulation of VgR(-) is not under oestrogen control. During the ripening period, greater VgR(-) gene expression was observed in wild fish than in fish reared in captivity, possibly because of (a) differences in water temperature exposure and/or energy storage, and/or (b) an inadequate diet in reared Atlantic bluefin tuna. PMID- 22541275 TI - Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a meta-analysis of individual participant data. AB - BACKGROUND: Carotid intima-media thickness (cIMT) is related to the risk of cardiovascular events in the general population. An association between changes in cIMT and cardiovascular risk is frequently assumed but has rarely been reported. Our aim was to test this association. METHODS: We identified general population studies that assessed cIMT at least twice and followed up participants for myocardial infarction, stroke, or death. The study teams collaborated in an individual participant data meta-analysis. Excluding individuals with previous myocardial infarction or stroke, we assessed the association between cIMT progression and the risk of cardiovascular events (myocardial infarction, stroke, vascular death, or a combination of these) for each study with Cox regression. The log hazard ratios (HRs) per SD difference were pooled by random effects meta analysis. FINDINGS: Of 21 eligible studies, 16 with 36,984 participants were included. During a mean follow-up of 7.0 years, 1519 myocardial infarctions, 1339 strokes, and 2028 combined endpoints (myocardial infarction, stroke, vascular death) occurred. Yearly cIMT progression was derived from two ultrasound visits 2 7 years (median 4 years) apart. For mean common carotid artery intima-media thickness progression, the overall HR of the combined endpoint was 0.97 (95% CI 0.94-1.00) when adjusted for age, sex, and mean common carotid artery intima media thickness, and 0.98 (0.95-1.01) when also adjusted for vascular risk factors. Although we detected no associations with cIMT progression in sensitivity analyses, the mean cIMT of the two ultrasound scans was positively and robustly associated with cardiovascular risk (HR for the combined endpoint 1.16, 95% CI 1.10-1.22, adjusted for age, sex, mean common carotid artery intima media thickness progression, and vascular risk factors). In three studies including 3439 participants who had four ultrasound scans, cIMT progression did not correlate between occassions (reproducibility correlations between r=-0.06 and r=-0.02). INTERPRETATION: The association between cIMT progression assessed from two ultrasound scans and cardiovascular risk in the general population remains unproven. No conclusion can be derived for the use of cIMT progression as a surrogate in clinical trials. FUNDING: Deutsche Forschungsgemeinschaft. PMID- 22541278 TI - Low dose of doxycyline promotes early differentiation of preosteoblasts by partially regulating the expression of estrogen receptors. AB - BACKGROUND: The tetracycline (TC) family, including minocycline and doxycycline (DC), has long been used in the medical field owing to its well-characterized antimicrobial properties. Moreover, TCs have been reported to have effects on bone formation and bone metabolism. Results have shown that more new bone formation is achieved when TCs have been applied in combination with bone graft material. METHODS: In the present study, the effects of TCs (TC, minocycline, and DC) on osteoprecursor cells were evaluated. The cell viability was determined using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. Differentiation and mineralization were evaluated using an alkaline phosphatase activity test and alizarin red-S staining. In addition, the expression of proteins related to bone formation, such as estrogen receptor (ER)-alpha, bone morphogenetic protein receptor-IA, bone morphogenetic protein-2, and phospho Smad1/5, were evaluated by using Western blot analysis. RESULTS: The morphology of the cells seemed normal, and their viability was not affected in the treated groups compared with the control. Alkaline phosphatase activity significantly increased in cultures grown in the presence of 0.1 and 1.0 MUM of DC. No statistically significant increase in the mineralization was seen the treated groups. The results of the Western blot analysis revealed that the addition of DC upregulated ER-alpha, bone morphogenetic protein-2, and phospho-Smad1/5 expression with a statistically significant difference in ER-alpha expression. CONCLUSIONS: From our findings, it was concluded that a low dose of DC could produce positive effects on the differentiation of osteoprecursor cells at an early stage. Our results also suggested that DC has osteoinductive effects that were achieved mainly through the ER pathway by enhancing the expression of ER alpha. PMID- 22541279 TI - Quantitative histological assessment of hepatic ischemia-reperfusion injuries following ischemic pre- and post-conditioning in the rat liver. AB - BACKGROUND: Ischemic preconditioning (IPC) has been shown to protect the liver against ischemia-reperfusion (I/R) injuries. However, ischemic post-conditioning has received little attention. The aim of the present study was to quantify and compare the hepato-protective properties of IPC and IPO, for the first time, using unbiased design-based stereological methods. METHODS: We divided 67 rats into four groups: sham, liver ischemia (LI), IPC, and IPO. Rats were subjected to 60 min LI, followed by 4- or 24-h reperfusion. We performed quantification of (NVR) and apoptotic cell profile number. RESULTS: We observed no significant differences in NVR between ischemic groups after 4 h. After 24-h reperfusion, NVR had increased to 70% in the LI group, compared with 51% (P = 0.02) and 49% (P = 0.01) in the IPC and IPO groups, respectively. After 4-h reperfusion, the apoptotic cell number was significantly higher in all ischemic groups than in the sham group; we detected no difference between ischemic groups. After 24-h reperfusion, we detected a significantly lower number of apoptotic cell profiles in the IPC group than in the LI group (P = 0.02). The mean number of apoptotic cell profiles decreased insignificantly in the IPO group (P = 0.06). Liver parameters were at all time comparable between groups. CONCLUSIONS: After I/R, IPC and IPO reduce the degree of hepatocellular injury. Both methods are equally efficient at preventing hepatocellular necrosis. Furthermore, apoptosis is significantly lower after IPC. PMID- 22541280 TI - Systemic differential gene regulation of the inter-alpha-trypsin inhibitor family in acute necrotizing pancreatitis in mice. AB - BACKGROUND: Therapy for systemic complications in severe necrotizing pancreatitis remains symptomatic owing to the unavailability of more specific therapeutic targets. We investigated the differential gene expression in typically affected organs in a mouse model of severe necrotizing pancreatitis. METHODS: Acute necrotizing pancreatitis was induced in mice by retrograde infusion of taurocholate into the common bile duct. Microarray hybridization was subsequently performed with mRNA isolated from the spleen, liver, intestine, and lungs. Additionally, quantitative real-time polymerase chain reaction was performed to confirm the microarray results. RESULTS: Severe necrotizing pancreatitis induced widespread changes in gene expression, affecting 27.20% of the genes tested in the spleen and 29.07% in the liver. Fewer genes were differentially regulated in the intestine (10.28%) and the lungs (10.75%). Only 10 genes were found to be upregulated in all 4 organs using microarray analysis. This upregulation in all organs was confirmed by quantitative real-time polymerase chain reaction for only 3 molecules. These molecules were lipocalin 2, insulin-like growth factor binding protein 1, and CD14. Additionally we observed significantly aberrant gene regulation of inter-alpha-trypsin inhibitor family members in several organs. CONCLUSIONS: Differential gene regulation in severe necrotizing pancreatitis is far more organ specific than anticipated, with only 3 molecules uniformly regulated systemically. The inter-alpha-trypsin inhibitor family of molecules appears to play a crucial biologic role in the systemic inflammatory response in acute pancreatitis. Finally, owing to its regulation and function, alpha1 microglobulin (or bikunin) may be a suitable predictive marker of the systemic inflammatory response syndrome in acute pancreatitis. PMID- 22541281 TI - Volume-outcome effects for children undergoing resection of renal malignancies. AB - INTRODUCTION: Adults undergoing oncologic resections at low-volume centers experience increased perioperative morbidity and mortality. The volume-outcome effect has not been extensively studied in pediatric oncologic resections. METHODS: To clarify volume-outcome effects in pediatric oncologic resections, we analyzed resection of renal malignancies in children less than 15 y of age. We conducted a cross-sectional analysis of hospital discharges included in the health care utilization project kids' inpatient database from 1997 to 2009, examining in-hospital operative complications, length of stay (LOS), and inflation-adjusted hospital charges. Hospital volume was expressed as low (n = 1 2), medium (n = 3-4), and high (n > 4) annual volume of resections. RESULTS: One thousand five hundred thirty-eight patients underwent renal malignancy resection. Of these, 527 patients had resection in low-, 422 in medium-, and 589 in high volume hospitals. Relative to low-volume hospitals, those resected in medium volume hospitals had an odds ratio of 0.62 (95% confidence interval 0.39-0.99, P = 0.046) for operative complication and those in high-volume hospitals had an odds ratio of 1.02 (95% confidence interval 0.63-1.65, P = 0.95). There was no detectable association with LOS (P = 0.113) or inflation-adjusted charges (P = 0.331). CONCLUSIONS: The number of complications, total charges, and LOS attributable to resection of a childhood renal malignancy did not differ among high-, medium-, or low-operative volume hospitals, although oncologic outcomes could not be determined because of the limited nature of this administrative database. PMID- 22541283 TI - Transfemoral aortic valve implantation in a patient with mitral bioprosthesis: technical features and forethoughts. PMID- 22541282 TI - Rapid point-of-care NT-proBNP optimal cut-off point for heart failure diagnosis in primary care. AB - INTRODUCTION AND OBJECTIVES: Measurement of natriuretic peptides may be recommended prior to echocardiography in patients with suspected heart failure. Cut-off point for heart failure diagnosis in primary care is not well established. We aimed to assess the optimal diagnostic cut-off value of N terminal pro-B-type natriuretic peptide on a community population attended in primary care. METHODS: Prospective diagnostic accuracy study of a rapid point-of care N-terminal pro-B-type natriuretic peptide test in a primary healthcare centre. Consecutive patients referred by their general practitioners to echocardiography due to suspected heart failure were included. Clinical history and physical examination based on Framingham criteria, electrocardiogram, chest X ray, N-terminal pro-B-type natriuretic peptide measurement and echocardiogram were performed. Heart failure diagnosis was made by a cardiologist blinded to N terminal pro-B-type natriuretic peptide value, using the European Society of Cardiology diagnosis criteria (clinical and echocardiographic data). RESULTS: Of 220 patients evaluated (65.5% women; median 74 years [interquartile range 67 81]). Heart failure diagnosis was confirmed in 52 patients (23.6%), 16 (30.8%) with left ventricular ejection fraction <50% (39.6 [5.1]%). Median values of N terminal pro-B-type natriuretic peptide were 715 pg/mL [interquartile range 510.5 1575] and 77.5 pg/mL [interquartile range 58-179.75] for patients with and without heart failure respectively. The best cut-off point was 280 pg/mL, with a receiver operating characteristic curve of 0.94 (95% confidence interval, 0.91 0.97). Six patients with heart failure diagnosis (11.5%) had N-terminal pro-B type natriuretic peptide values <400 pg/mL. Measurement of natriuretic peptides would avoid 67% of requested echocardiograms. CONCLUSIONS: In a community population attended in primary care, the best cut-off point of N-terminal pro-B type natriuretic peptide to rule out heart failure was 280 pg/mL. N-terminal pro B-type natriuretic peptide measurement improve work-out diagnoses and could be cost-effectiveness. PMID- 22541284 TI - Atrial fibrillation ablation. AB - Atrial fibrillation is the commonest cardiac arrhythmia, with significant morbidity related to symptoms, heart failure, and thromboembolism, which is associated with excess mortality. Over the past 10 years, many centers worldwide have reported high success rates and few complications after a single ablation procedure in patients with paroxysmal atrial fibrillation. Recent studies indicate a short-term and long-term superiority of catheter ablation as compared with conventional antiarrhythmic drug therapy in terms of arrhythmia recurrence, quality of life, and arrhythmia progression. As a result, catheter ablation is evolving to a front-line therapy in many patients with atrial fibrillation. However, in patients with persistent long-standing atrial fibrillation catheter ablation strategy is more complex and time-consuming, frequently requiring repeat procedures to achieve success rates as high as in paroxysmal atrial fibrillation. In the near future, however, with growing experience and evolving technology, catheter ablation of atrial fibrillation may be extended also to patients with long-standing atrial fibrillation. PMID- 22541285 TI - Therapeutic approaches in the improvement of cognitive performance in Down syndrome: past, present, and future. AB - Clinical trials with drugs aimed at treatment of Alzheimer disease to decelerate cognitive decline and translated mimetically to demented and young nondemented Down syndrome patients have been unable to demonstrate improvements in cognitive performance and functioning. Unfortunately, results from clinical trials do not support the use of NMDA antagonists like memantine and we should await at the development of safer GABA(A) antagonists to conclude about the efficacy of approaching Down syndrome therapeutics by modulating neurotransmission systems altered in this pathology. The use of folinic acid or antioxidants in DS patients is not supported by scientific evidence and do not provide improvement in cognitive performance to patients. Alternatively to the modulation of neurotransmission systems, future therapeutic approaches should focus at normalizing the expression levels or function of candidate molecules. Epigallocatechin gallate, a green tea polyphenol, that modulates DYRK1A functioning has already shown preliminarily that this approach may prove useful in therapeutics. PMID- 22541286 TI - Genomic determinants in the phenotypic variability of Down syndrome. AB - Down syndrome caused by trisomy 21 is a collection of phenotypes with variable expressivity and penetrance. The significant advances in exploring the human genome now provide the tools to better understand the contribution of trisomy 21 in the different manifestations of Down syndrome, and the functional links between the genome variability and the phenotypic variability. PMID- 22541287 TI - Intellectual disabilities, neuronal posttranscriptional RNA metabolism, and RNA binding proteins: three actors for a complex scenario. AB - Intellectual disability (ID) is the most frequent cause of serious handicap in children and young adults and interests 2-3% of worldwide population, representing a serious problem from the medical, social, and economic points of view. The causes are very heterogeneous. Genes involved in ID have various functions altering different pathways important in neuronal function. Regulation of mRNA metabolism is particularly important in neurons for synaptic structure and function. Here, we review ID due to alteration of mRNA metabolism. Functional absence of some RNA-binding proteins--namely, FMRP, FMR2P, PQBP1, UFP3B, VCX-A- causes different forms of ID. These proteins are involved in different steps of RNA metabolism and, even if a detailed analysis of their RNA targets has been performed so far only for FMRP, it appears clear that they modulate some aspects (translation, stability, transport, and sublocalization) of a subset of RNAs coding for proteins, whose function must be relevant for neurons. Two other proteins, DYRK1A and CDKL5, involved in Down syndrome and Rett syndrome, respectively, have been shown to have an impact on splicing efficiency of specific mRNAs. Both proteins are kinases and their effect is indirect. Interestingly, both are localized in nuclear speckles, the nuclear domains where splicing factors are assembled, stocked, and recycled and influence their biogenesis and/or their organization. PMID- 22541288 TI - Aberrant epigenetic landscape in intellectual disability. AB - In recent decades, epigenetics has emerged as a broad-ranging regulatory layer that modulates the whole genome and transcriptome. It largely determines the firing of transcription start sites, the splicing processes, and the binding of transcription factors, among many other processes. Its wide spectrum of action has provided us with the keys to new doors to investigate many diseases, including intellectual disability syndromes. The involvement of epigenetic factors in Rett syndrome is already well established, and its involvement in alpha-thalassemia/mental retardation-X-linked and Rubinstein-Taybi syndromes is also being elucidated. Down syndrome is not an exception, and the most recent reports suggest that epigenetic factors may play a crucial role in its etiology and also have the potential to provide new panels of biomarkers and tailored treatments. PMID- 22541289 TI - Pathways to cognitive deficits in Down syndrome. AB - Major efforts in Down syndrome (DS) research have been directed at the identification and functional characterization of genes encoded by human chromosome 21 (HSA21). In parallel with this, tissue samples and cell lines derived from individuals with DS have been examined for abnormalities in gene expression and cellular morphology, and mouse models of DS have been characterized for abnormalities at the molecular, cellular, electrophysiological, and behavioral level. One goal of such investigations has been the identification of effective targets for pharmacotherapies that can prevent or correct the abnormalities and, by extension to human clinical trials, prevent or lessen aspects of the cognitive deficits seen in people with DS. Because it is caused by an extra copy of an entire chromosome, DS has been considered by some as too complicated a genetic perturbation to be amenable to postnatal pharmacological interventions. However, recent data from experiments with one mouse model, the Ts65Dn, have clearly demonstrated that several pharmacological interventions can indeed rescue DS-relevant learning and memory deficits. Extension of mouse data to successful human clinical trials will be aided by understanding the molecular basis of successful drug treatments, that is, how increased expression of HSA21 genes perturbs molecular mechanisms that are targeted and rescued by specific drugs. Here, we review information on HSA21 genes, their expression and their likely contributions to the DS phenotype. We then describe results of a bioinformatics effort that integrates information on genes known to cause intellectual disability when mutated, the pathways in which these genes function, and how these pathways are impacted by HSA21 encoded proteins. This pathway approach to the molecular basis of ID in DS aids in understanding why some drug therapies have been successful in the Ts65Dn and in predicting whether these same drugs are likely to be successful in treating ID in DS. These data can be used to design new experiments and interpret information for prediction of additional targets for effective drug treatments. PMID- 22541291 TI - Human and mouse model cognitive phenotypes in Down syndrome: implications for assessment. AB - The study of cognitive function in Down syndrome (DS) has advanced rapidly in the past decade. Mouse models have generated data regarding the neurological basis for the specific cognitive profile of DS (i.e., deficits in aspects of hippocampal, prefrontal, and cerebellar function) and have uncovered pharmacological treatments with the potential to affect this phenotype. Given this progress, the field is at a juncture in which we require assessments that may effectively translate the findings acquired in mouse models to humans with DS. In this chapter, we describe the cognitive profile of humans with DS and associated mouse models, discussing the ways in which we may merge these findings so as to more fully understand cognitive strengths and weaknesses in this population. New directions for approaches to cognitive assessment in mice and humans are discussed. PMID- 22541292 TI - Perturbation of dendritic protrusions in intellectual disability. AB - Intellectual disability (ID) affects 1-3% of the general population and is defined by an intelligence quotient score under 70 and the presence of two or more adaptive behaviors. Learning and memory involves the change in the transmission efficacy at the synapse (synaptic plasticity). Synaptic plasticity is the ability of the connection, or synapse, between two functional neurons to change in strength. Many molecular mechanisms are involved in the change in synaptic strength, which can result in changes in spine morphology. Spines are specialized dendritic protrusions and their change in morphology is implicated in learning and memory. In several cases of ID, the link between spine abnormalities (abnormal in number, size, and shape) and ID is well described, including nonsyndromic ID and Down, Fragile X, and Rett syndromes. This chapter discusses the underlying molecular mechanisms of this altered spine phenotype. PMID- 22541293 TI - The in vivo Down syndrome genomic library in mouse. AB - Mouse models are key elements to better understand the genotype-phenotype relationship and the physiopathology of Down syndrome (DS). Even though the mouse will never recapitulate the whole spectrum of intellectual disabilities observed in the DS, mouse models have been developed over the recent decades and have been used extensively to identify homologous genes or entire regions homologous to the human chromosome 21 (Hsa21) that are necessary or sufficient to induce DS cognitive features. In this chapter, we review the principal mouse DS models which have been selected and engineered over the years either for large genomic regions or for a few or a single gene of interest. Their analyses highlight the complexity of the genetic interactions that are involved in DS cognitive phenotypes and also strengthen the hypothesis on the multigenic nature of DS. This review also addresses future research challenges relative to the making of new models and their combination to go further in the characterization of candidates and modifier of the DS features. PMID- 22541290 TI - Neurological phenotypes for Down syndrome across the life span. AB - This chapter reviews the neurological phenotype of Down syndrome (DS) in early development, childhood, and aging. Neuroanatomic abnormalities in DS are manifested as aberrations in gross brain structure as well as characteristic microdysgenetic changes. As the result of these morphological abnormalities, brain circuitry is impaired. While an intellectual disability is ubiquitous in DS, there is a wide range of variation in cognitive performance and a growing understanding between aberrant brain circuitry and the cognitive phenotype. Hypotonia is most marked at birth, affecting gait and ligamentous laxity. Seizures are bimodal in presentation with infantile spasms common in infancy and generalized seizures associated with cognitive decline observed in later years. While all individuals have the characteristic neuropathology of Alzheimer's disease (AD) by age 40 years, the prevalence of dementia is not universal. The tendency to develop AD is related, in part, to several genes on chromosome 21 that are overexpressed in DS. Intraneuronal accumulation of beta-amyloid appears to trigger a cascade of neurodegeneration resulting in the neuropathological and clinical manifestations of dementia. Functional brain imaging has elucidated the temporal sequence of amyloid deposition and glucose metabolic rate in the development of dementia in DS. Mitochondrial abnormalities contribute to oxidative stress which is part of AD pathogenesis in DS as well as AD in the general population. A variety of medical comorbidities threaten cognitive performance including sleep apnea, abnormalities in thyroid metabolism, and behavioral disturbances. Mouse models for DS are providing a platform for the formulation of clinical trials with intervention targeted to synaptic plasticity, brain biochemistry, and morphological brain alterations. PMID- 22541294 TI - Discoveries in Down syndrome: moving basic science to clinical care. AB - This review describes recent discoveries in neurobiology of Down syndrome (DS) achieved with use of mouse genetic models and provides an overview of experimental approaches aimed at development of pharmacological restoration of cognitive function in people with this developmental disorder. Changes in structure and function of synaptic connections within the hippocampal formation of DS model mice, as well as alterations in innervations of the hippocampus by noradrenergic and cholinergic neuromodulatory systems, provided important clues for potential pharmacological treatments of cognitive disabilities in DS. Possible molecular and cellular mechanisms underlying this genetic disorder have been addressed. We discuss novel mechanisms engaging misprocessing of amyloid precursor protein (App) and other proteins, through their affect on axonal transport and endosomal dysfunction, to "Alzheimer-type" neurodegenerative processes that affect cognition later in life. In conclusion, a number of therapeutic strategies have been defined that may restore cognitive function in mouse models of DS. In the juvenile and young animals, these strategists focus on restoration of synaptic plasticity, rate of adult neurogenesis, and functions of the neuromodulatory subcortical systems. Later in life, the major focus is on recuperation of misprocessed App and related proteins. It is hoped that the identification of an increasing number of potential targets for pharmacotherapy of cognitive deficits in DS will add to the momentum for creating and completing clinical trials. PMID- 22541296 TI - Gene therapy for Down syndrome. AB - The presence of an additional copy of HSA21 chromosome in Down syndrome (DS) individuals leads to the overexpression of 30-50% of HSA21 genes. This upregulation can, in turn, trigger a deregulation on the expression of non-HSA21 genes. Moreover, the overdose of HSA21 microRNAs (miRNAs) may result in the downregulation of its target genes. Additional complexity can also arise from epigenetic changes modulating gene expression. Thus, a myriad of transcriptional and posttranscriptional alterations participate to produce abnormal phenotypes in almost all tissues and organs of DS individuals. The study of the physiological roles of genes dysregulated in DS, as well as their characterization in murine models with gene(s) dosage imbalance, pointed out several genes, and functional noncoding elements to be particularly critical in the etiology of DS. Recent findings indicate that gene therapy strategies-based on the introduction of genetic elements by means of delivery vectors-toward the correction of phenotypic abnormalities in DS are also very promising tool to identify HSA21 and non-HSA21 gene candidates, contributing to DS phenotype. In this chapter, we focus on the impact of normalizing the expression levels of up or downregulated genes to rescue particular phenotypes of DS. Attempts toward gene-based treatment approaches in mouse models will be discussed as new opportunities to ameliorate DS alterations. PMID- 22541297 TI - Preface. PMID- 22541295 TI - A Sonic hedgehog (Shh) response deficit in trisomic cells may be a common denominator for multiple features of Down syndrome. AB - The hedgehog (HH) family of growth factors is involved in many aspects of growth and development, from the establishment of left-right axes at gastrulation to the patterning and formation of multiple structures in essentially every tissue, to the maintenance and regulation of stem cell populations in adults. Sonic hedgehog (Shh) in particular acts as a mitogen, regulating proliferation of target cells, a growth factor that triggers differentiation in target populations, and a morphogen causing cells to respond differently based on their positions along a spatial and temporal concentration gradient. Given its very broad range of effects in development, it is not surprising that many of the structures affected by a disruption in Shh signaling are also affected in Down syndrome (DS). However, recent studies have shown that trisomic cerebellar granule cell precursors have a deficit, compared to their euploid counterparts, in their response to the mitogenic effects of Shh. This deficit substantially contributes to the hypocellular cerebellum in mouse models that parallels the human DS phenotype and can be corrected in early development by a single exposure to a small-molecule agonist of the Shh pathway. Here, we consider how an attenuated Shh response might affect several aspects of development to produce multiple phenotypic outcomes observed in DS. PMID- 22541298 TI - Amino alcohol-modified beta-cyclodextrin inducing biomimetic asymmetric oxidation of thioanisole in water. AB - Inspired by beta-CD, a macrocyclic oligomers of D-(+)-glucopyranose and a renewable material, which could be obtained from starch, that can promote a lot of organic reactions in water, a green solvent, several amino alcohol-modified beta-CDs CD-1 to CD-7 were synthesized in the yields of 36-61%. Their conformations in vacuum and in aqueous solution were optimized by quantum calculation. Their complexes with sodium molybdate prepared in situ were characterized by (1)H NMR and were applied in the asymmetric oxidation of thioanisole. Their performance in inducing enantioselectivity was investigated in detail. For the optimal one, CD-1, moderate enantioselectivity (56% ee) was achieved in aqueous CH(3)COONa-HCl buffer solution (pH 7.0). The abilities of CD 1 to CD-7 to induce asymmetry are highly dependent on the pH value of the reaction medium and the structure of the modifying group. The origin of the moderate enantioselectivity and the reaction mechanism were investigated with the aid of (1)H ROESY NMR studies and quantum calculation. The moderate enantioselectivity was attributed to the two different binding models between CD 1 and thioanisole, which could be defined as intramolecular catalysis and intermolecular catalysis, in which intramolecular catalysis gave (S)-methyl phenyl sulfoxide and intermolecular catalysis gave (R,S)-methyl phenyl sulfoxide. PMID- 22541299 TI - A general route to xyloglucan-peptide conjugates for the activation of cellulose surfaces. AB - Cellulose is an attractive supporting matrix for diverse biotechnological applications, including chromatography, diagnostics, and tissue replacement/scaffolding, due to its renewable resource status, low cost, and low non-specific interaction with biomolecules. In an effort to expand the biofunctionality of cellulose materials, we present here a versatile method for the synthesis of xyloglucan-peptide conjugates that harness the strong xyloglucan cellulose binding interaction for gentle surface modification. Xylogluco oligosaccharide aminoalditols (XGO-NH(2)) were coupled to both linear and cyclic peptides, which contained the endothelial cell epitope Arg-Gly-Asp, in a facile two-step approach employing diethyl squarate cross-linking. Subsequent xyloglucan endo-transglycosylase-mediated coupling of the resulting XGO-GRGDS (Gly-Arg-Gly Asp-Ser) and XGO-c[RGDfK]-PEG-PEG (cyclo[Arg-Gly-Asp-(D-Phe)-Lys]-PEG-PEG; where PEG is 8-amino-3,6-dioxaoctanoic acid) conjugates into high molecular mass xyloglucan yielded xyloglucan-RGD peptide conjugates suitable for cellulose surface activation. Notably, use of XGO-squaramate as a readily accessible, versatile intermediate overcomes previous limitations of solid-phase synthetic approaches to XGO-peptide conjugates, and furthermore allows the method to be generalized to a wide variety of polypeptides and proteins, as well as diverse primary amino compounds. PMID- 22541300 TI - Kinetics of the oxidation of lactose by copper(II) complexed with bipyridyl in alkaline medium using chloro-complex of rhodium(III) in its nano-concentration range as homogeneous catalyst: a spectrophotometric study. AB - Kinetics of the oxidation of lactose by Cu(II) complexed with bipyridyl have been investigated at 40 degrees C for the first time spectrophotometrically using Rh(III) chloride as homogeneous catalyst in aqueous alkaline medium in its nano concentration range. The order of reaction was found to be fractional positive order, when the concentration of Rh(III) chloride was varied from 0.30*10(-9) M to 6.00*10(-9) M. The reaction shows fractional positive-order kinetics with respect to [lactose] and [OH(-)] and zeroth-order kinetics with respect to [Cu(II)]. The reaction also shows slight increase in the rate by decreasing dielectric constant of the medium and remains unaffected by the change in ionic strength of the medium. The reaction was carried out at four different temperatures and observed values of rate constants were utilized to calculate various activation parameters specially the entropy of activation (DeltaS(#)). The species, [RhCl(3)(H(2)O)(2)OH](-), was postulated as the main reactive species of Rh(III) chloride for the oxidation of lactose by Cu(II) in alkaline medium. On the basis of kinetic and equivalence studies together with spectrophotometric information for the formation of a complex, [formula see text] the most appropriate mechanism for the aforesaid reaction has been proposed. Support to the proposed mechanism was also given by the observed activation parameters and multiple regression analysis. Sodium salts of formic acid, arabinonic acid and lyxonic acid were identified as the main oxidation products of the reaction under investigation. PMID- 22541305 TI - Clinical effectiveness of low-level laser therapy as an adjunct to eccentric exercise for the treatment of Achilles' tendinopathy: a randomized controlled trial. AB - OBJECTIVE: To investigate the effectiveness of low-level laser therapy (LLLT) as an adjunct to a program of eccentric exercises for the treatment of Achilles' tendinopathy. DESIGN: Randomized controlled trial with evaluations at baseline and 4, 12, and 52 weeks. SETTING: Primary care clinic. PARTICIPANTS: Participants with midportion Achilles' tendinopathy were randomly assigned to 2 groups (LLLT n=20: mean age +/- SD, 45.6+/-9.1y; placebo n=20: mean age +/- SD, 46.5+/-6.4y). The 12-week evaluation was completed by 36 participants (90%), and 33 participants (82.5%) completed the 52-week evaluation. INTERVENTION: Both groups of participants performed eccentric exercises over a 3-month period. In addition, they received either an active or placebo application of LLLT 3 times per week for the first 4 weeks; the dose was 3J per point. MAIN OUTCOME MEASURES: The primary outcome was the Victorian Institute of Sport Assessment-Achilles' questionnaire (VISA-A) score at 12 weeks; secondary outcome was a visual analog scale for pain. Outcomes were measured at baseline and 4, 12, and 52 weeks. RESULTS: Baseline characteristics exhibited no differences between groups. At the primary outcome point, there was no statistically significant difference in VISA A scores between groups (P>.05). The difference in VISA-A scores at the 4-week point significantly favored the placebo group (F(1)=6.411, sum of squares 783.839; P=.016); all other outcome scores showed no significant difference between the groups at any time point. Observers were blinded to groupings. CONCLUSIONS: The clinical effectiveness of adding LLLT to eccentric exercises for the treatment of Achilles' tendinopathy has not been demonstrated using the parameters in this study. PMID- 22541306 TI - Effectiveness of supported employment for veterans with spinal cord injuries: results from a randomized multisite study. AB - OBJECTIVE: To examine whether supported employment (SE) is more effective than treatment as usual (TAU) in returning veterans to competitive employment after spinal cord injury (SCI). DESIGN: Prospective, randomized, controlled, multisite trial of SE versus TAU for vocational issues with 12 months of follow-up data. SETTING: SCI centers in the Veterans Health Administration. PARTICIPANTS: Subjects (N=201) were enrolled and completed baseline interviews. In interventional sites, subjects were randomly assigned to the SE condition (n=81) or the TAU condition (treatment as usual-interventional site [TAU-IS], n=76). In observational sites where the SE program was not available, 44 subjects were enrolled in a nonrandomized TAU condition (treatment as usual-observational site [TAU-OS]). INTERVENTIONS: The intervention consisted of an SE vocational rehabilitation program called the Spinal Cord Injury Vocational Integration Program, which adhered as closely as possible to principles of SE as developed and described in the individual placement and support model of SE for persons with mental illness. MAIN OUTCOME MEASURES: The primary study outcome measurement was competitive employment in the community. RESULTS: Subjects in the SE group were 2.5 times more likely than the TAU-IS group and 11.4 times more likely than the TAU-OS group to obtain competitive employment. CONCLUSIONS: To the best of our knowledge, this is the first and only controlled study of a specific vocational rehabilitation program to report improved employment outcomes for persons with SCI. SE, a well-prescribed method of integrated vocational care, was superior to usual practices in improving employment outcomes for veterans with SCI. PMID- 22541308 TI - Evaluating intense rehabilitative therapies with and without acupuncture for children with cerebral palsy: a randomized controlled trial. AB - OBJECTIVE: To compare the outcomes of conventional therapies (physical, occupational, and hydrotherapies) plus acupuncture with those without acupuncture when administered intensely in the management of children with spastic cerebral palsy (CP). DESIGN: Evaluation-blind, prospective randomized controlled trial. SETTING: Therapies and video-recorded assessments at a children's hospital in Beijing, China, and blind scoring and data analyses at a university in the United States. PARTICIPANTS: Children (N=75), 12 to 72 months of age, with spastic CP. INTERVENTIONS: Intensely administered (5 times per week for 12wk) physical therapy, occupational therapy, and hydrotherapy either with acupuncture (group 1) or without acupuncture (group 2). To satisfy standard of care, group 2 subsequently received acupuncture (weeks 16-28). MAIN OUTCOME MEASURES: The Gross Motor Function Measure (GMFM)-66 and the Pediatric Evaluation of Disability Inventory (PEDI) assessments at 0, 4, 8, 12, 16, and 28 weeks. RESULTS: At the end of 12 weeks, there was no statistically significant difference between the 2 groups, but when group 2 received acupuncture (16-28wk) there was a shift toward improvement in the GMFM-66 and the PEDI-Functional Skills Self-Care and Mobility domain. When groups were combined, statistically significant improvements after intense therapies occurred from baseline to 12 weeks for each outcome measure at each Gross Motor Function Classification System (GMFCS) level. After adjusting for expected normative maturational gains based on age, the GMFM gains for children with GMFCS II level was statistically significant (P<.05) with a mean gain of 6.5 versus a predicted gain of 3.4. CONCLUSIONS: Intense early administered rehabilitation improves function in children with spastic CP. The contribution from acupuncture was unclear. Children's response varied widely, suggesting the importance of defining clinical profiles that identify which children might benefit most. Further research should explore how this approach might apply in the U.S. PMID- 22541307 TI - Contributions of cognitive function to straight- and curved-path walking in older adults. AB - OBJECTIVE: To determine whether the cognitive function contribution to straight- and curved-path walking differs for older adults. DESIGN: Cross-sectional observational study. SETTING: Ambulatory clinical research training center. PARTICIPANTS: People (N=106) aged 65 to 92 years, able to walk household distances independently with or without an assistive device, and who scored 24 or greater on the Mini-Mental State Examination. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Cognitive function was assessed using the Digit Symbol Substitution Test (DSST) as a measure of psychomotor speed, and Trail Making Test Parts A and B (TMT-A and TMT-B) and the Trail Making Test difference score (TMT-B A) as executive function measures of complex visual scanning and set shifting. Gait speed recorded over an instrumented walkway was used as the measure of straight-path walking. Curved-path walking was assessed using the Figure-of-8 Walk Test (F8W) and recorded as the total time and number of steps for completion. RESULTS: Both DSST and TMT-A independently contributed to usual gait speed (P<.001). TMT-A performance contributed to F8W time (P<.001). Neither TMT-B nor TMT-B-A contributed to usual gait speed or time to complete the F8W. For the number of steps taken to complete the F8W, TMT-A, TMT-B, and TMT-B-A (all P<.001) were independent contributors, while DSST performance was not. CONCLUSIONS: Curved-path walking, as measured by the F8W, involves different cognitive processes compared with straight-path walking. Cognitive flexibility and set shifting processes uniquely contributed to how individuals navigated curved paths. The measure of curved-path walking provides different and meaningful information about daily life walking ability than usual gait speed alone. PMID- 22541309 TI - Predictors of cardiometabolic risk among adults with cerebral palsy. AB - OBJECTIVE: To examine the independent association between various anthropometric indicators and standard clinical markers of cardiometabolic health risk among adults with cerebral palsy (CP). DESIGN: Cross-sectional study. SETTING: Clinical center for CP treatment and rehabilitation. PARTICIPANTS: Adults with CP (N=43) with a mean age +/- SD of 37.3+/-13.2 years, and Gross Motor Function Classification System (GMFCS) levels of I-V. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Adults with CP were assessed for body mass index (BMI), waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR), waist-to height ratio (WtHR), and serum lipid profiles. Data were analyzed with multiple regression analysis and general linear models, and are reported as means +/- SDs. RESULTS: Mean BMI was 29.1+/-7.8kg/m(2). BMI was not associated with any measures of cardiometabolic risk. Using GMFCS categories (2 groups: GMFCS levels I-III and IV-V), BMI was significantly lower among GMFCS levels IV-V (24.2+/-6.2kg/m(2)) versus GMFCS levels I-III (30.1+/-7.6kg/m(2)). WC and WtHR were not correlated with any cardiometabolic outcomes. Conversely, measures of WHR were independently associated with various indices of risk, including total cholesterol to high density lipoprotein (HDL) cholesterol ratio (r=.45; P<.05), HDL cholesterol (r= .51; P<.01), and triglycerides (r=.40; P<.05), suggesting that greater WHR was indicative of elevated risk. CONCLUSIONS: It is likely that WHR represents a stronger predictor of risk, because this measure was robustly and independently associated with 3 primary clinical markers of cardiometabolic health in adults with CP. PMID- 22541310 TI - Computer-aided design of customized foot orthoses: reproducibility and effect of method used to obtain foot shape. AB - OBJECTIVE: To determine, for a number of techniques used to obtain foot shape based around plaster casting, foam box impressions, and 3-dimensional scanning, (1) the effect the technique has on the overall reproducibility of custom foot orthoses (FOs) in terms of inter- and intracaster reliability and (2) the reproducibility of FO design by using computer-aided design (CAD) software in terms of inter- and intra-CAD operator reliability for all these techniques. DESIGN: Cross-sectional study. SETTING: University laboratory. PARTICIPANTS: Convenience sample of individuals (N=22) with noncavus foot types. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Parameters of the FO design (length, width at forefoot, width at rearfoot, and peak medial arch height), the forefoot to rearfoot angle of the foot shape, and overall volume match between device designs. RESULTS: For intra- and intercaster reliability of the different methods of obtaining the foot shape, all methods fell below the reproducibility quality threshold for the medial arch height of the device, and volume matching was <80% for all methods. The more experienced CAD operator was able to achieve excellent reliability (intraclass correlation coefficients >0.75) for all variables with the exception of forefoot to rearfoot angle, with overall volume matches of >87% of the devices. CONCLUSIONS: None of the techniques for obtaining foot shape met all the criteria for excellent reproducibility, with the peak arch height being particularly variable. Additional variability is added at the CAD stage of the FO design process, although with adequate operator experience good to excellent reproducibility may be achieved at this stage. Taking only basic linear or angular measurement parameters from the device may fail to fully capture the variability in FO design. PMID- 22541311 TI - Impact of cerebral palsy on health-related physical fitness in adults: systematic review. AB - OBJECTIVE: To conduct a systematic review of the impact of cerebral palsy (CP) on the level of health-related physical fitness (body composition, cardiorespiratory endurance, flexibility, muscular endurance, and strength) in adults with CP compared with able-bodied adults. DATA SOURCES: The Cochrane Library, MEDLINE, CINAHL, EMBASE, and PEDro were searched up to December 2010 for relevant comparative studies. STUDY SELECTION: Two reviewers independently applied the inclusion criteria (adults, comparative design, components of physical fitness) to select potential relevant studies. DATA EXTRACTION: Two reviewers independently extracted the data and assessed the methodological quality. A consensus method was used to solve disagreements. DATA SYNTHESIS: Pooling data was not possible, but a best-evidence synthesis was conducted. Also, a description of the level of health-related physical fitness in CP was given (expressed as a percentage of able-bodied controls). Nine case-control studies were included (average age +/- SD of subjects with CP, 21+/-3y): 3 investigated body composition; 5, cardiorespiratory endurance; 3, muscular strength; and 1, muscular endurance. Two of the studies investigated multiple fitness components. No studies on flexibility were found. Muscular strength (34%-60%), muscular endurance (27%-52%), and cardiorespiratory endurance (14%) showed significantly lower values in adults with CP compared with able-bodied controls. Studies on body composition reported conflicting results on the impact of CP. CONCLUSIONS: The results of this review point to a reduction in 3 components of health-related physical fitness in young adults with CP compared with controls: muscular strength, muscular endurance, and cardiorespiratory endurance. However, the level of evidence varies from moderate (muscular strength) to limited (muscular endurance and cardiorespiratory endurance). Additional studies of high methodological quality are recommended before firm conclusions can be made. PMID- 22541312 TI - Longitudinal performance of a surgically implanted neuroprosthesis for lower extremity exercise, standing, and transfers after spinal cord injury. AB - OBJECTIVE: To investigate the longitudinal performance of a surgically implanted neuroprosthesis for lower-extremity exercise, standing, and transfers after spinal cord injury. DESIGN: Case series. SETTING: Research or outpatient physical therapy departments of 4 academic hospitals. PARTICIPANTS: Subjects (N=15) with thoracic or low cervical level spinal cord injuries who had received the 8 channel neuroprosthesis for exercise and standing. INTERVENTION: After completing rehabilitation with the device, the subjects were discharged to unrestricted home use of the system. A series of assessments were performed before discharge and at a follow-up appointment approximately 1 year later. MAIN OUTCOME MEASURES: Neuroprosthesis usage, maximum standing time, body weight support, knee strength, knee fatigue index, electrode stability, and component survivability. RESULTS: Levels of maximum standing time, body weight support, knee strength, and knee fatigue index were not statistically different from discharge to follow-up (P>.05). Additionally, neuroprosthesis usage was consistent with subjects choosing to use the system on approximately half of the days during each monitoring period. Although the number of hours using the neuroprosthesis remained constant, subjects shifted their usage to more functional standing versus more maintenance exercise, suggesting that the subjects incorporated the neuroprosthesis into their lives. Safety and reliability of the system were demonstrated by electrode stability and a high component survivability rate (>90%). CONCLUSIONS: This group of 15 subjects is the largest cohort of implanted lower-extremity neuroprosthetic exercise and standing system users. The safety and efficiency data from this group, and acceptance of the neuroprosthesis as demonstrated by continued usage, indicate that future efforts toward commercialization of a similar device may be warranted. PMID- 22541313 TI - Systematic reviews for informing rehabilitation practice: an introduction. AB - The research literature that rehabilitation clinicians need to be familiar with has become too large for anyone to read, and numerous published studies are too complex for many practitioners to understand and fruitfully use. One method to keep up with new findings is through systematic reviews. Systematic reviews can be effective tools that help guide rehabilitation practice by identifying the best research that provides the evidence for enhanced clinical decision-making. This article describes how systematic reviews are created, indicates where rehabilitation clinicians may find them, and refers to a resource that may be of use in evaluating their quality and applicability. PMID- 22541314 TI - The authors respond: balance and ambulation improvements in individuals with chronic incomplete spinal cord injury using locomotor training-based rehabilitation. PMID- 22541315 TI - Quasi-experimental study of weight-supported treadmill training for myelopathy. PMID- 22541316 TI - Effect of vacuum-assisted socket and pin suspensions on socket fit. PMID- 22541317 TI - The authors respond: vacuum-assisted socket suspension systems for lower extremity amputees: effect on fit, activity, and limb volume. PMID- 22541318 TI - A novel method for the diagnosis of bacterial contamination in the anterior vagina of sows based on measurement of biogenic amines by ion mobility spectrometry: A field trial. AB - To determine if postpartum subclinical infection occurs in sows, a novel device was used to diagnose such bacterial contamination of the vagina. The device was based on the measurement of biogenic amines by ion mobility spectrometry (IMS). The device is portable and results are obtained within 1 min. Vaginal swabs were taken from 449 sows before first-estrus insemination and 133 (29.6%) had elevated biogenic amines and were considered positives. Sixty-one percent of the sows became pregnant following post-weaning first estrus insemination. Positive scores had no apparent effect on fertility rate which was 64%. Of the sows that became pregnant, 197 (69.1%) were diagnosed as "negative" and 88 (30.9%) were "positive", of which 37 received treatment with antibiotics and were termed "positive treated". The average live-born piglets litter size of the "positives" was 10.02 which was significantly lower (P = 0.031) than the "negative" sows (11.06) while "positive treated" sow average litter size was close to the "negative" (10.56). In conclusion, it was demonstrated that subclinical anterior vaginal bacterial contamination in lactating sows about 2 wks postpartum is a condition that affects sow litter number and could be determined by the measurement of vaginal biogenic amines with IMS. PMID- 22541319 TI - Molecular mechanisms of a novel selenium-based complementary medicine which confers protection against hyperandrogenism-induced polycystic ovary. AB - The objective was to evaluate ovarian functionality and oxidative response in hyperandrogenism-induced polycystic ovary (PCO) and the protective effects of immunomodulator drug (IMOD), an electromagnetically-treated, selenium-based, herbal medicine. Daily oral administration of letrozole (1 mg/kg) for 21 consecutive days induced ovarian cysts in female rats. An effective dose of IMOD (30 mg/kg per day) was given intraperitoneally for 21 days. Biomarkers of ovarian function, serum concentrations of estradiol, progesterone, testosterone, and ovarian prostaglandin-E (PGE), were analyzed. To determine the role of oxidative stress (OS) in hyperandrogenism-induced PCO, concentrations of cellular lipid peroxidation (LPO), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), peroxynitrite (ONOO), and tumor necrosis factor (TNF)-alpha as a marker of inflammation and apoptosis were measured in serum and ovaries. Letrozole-induced PCO resulted in significant increases in concentrations of lipid peroxidation and peroxynitrite in serum and ovary, but significantly decreased superoxide dismutase, catalase, and glutathione peroxidase. Serum concentrations of testosterone and TNF-alpha, and ovarian prostaglandin-E were increased (P < 0.001) in animals with cysts versus control, whereas estradiol and progesterone were decreased (P < 0.01 and P < 0.001, respectively). When compared with controls, letrozole induced irregular cycles and PCO characterized by a high incidence of subcapsular ovarian cysts with a diminished granulosa cell layer, luteinized granulosa cells in the cyst wall, significantly more atretic preantral and antral follicles, and absence of CL. There were almost no intact primary, secondary, and tertiary follicles in PCO rats. All end points assessed were significantly improved by IMOD and reached close to normal levels. In conclusion, the present study provided evidence that toxic free radicals and TNF-alpha were involved in the pathogenesis of PCO; furthermore, IMOD prevented ovarian histopathologic, endocrine, and biochemical alterations induced by hyperandrogenism. PMID- 22541320 TI - Characterization of the innate immune response in goats after intrauterine infusion of E. coli using histopathological, cytologic and molecular analyses. AB - The objective was to characterize the innate immune response in dairy goats after intrauterine infusion of E. coli. A suspension of Escherichia coli (E. coli; 4 * 10(9) cfu (cfu)/mL; experimental group, n = 6) or 5 mL PBS (control group, n = 6) were infused once into each uterine horn in goats at 25 days postpartum. Blood and endometrial biopsy samples were collected preinoculation (0 h) and at 3, 6, 12, 24, 72, 120, and 168 h post inoculation (pi). Relative gene expression analyses of Toll-like receptor4 (TLR4), tumor necrosis factoralpha (TNF-alpha), beta-defensin2, and interleukins (IL-1beta, IL-6, IL-8) were performed on RNA extracted from endometrial tissue and peripheral white blood cells (WBCs) using quantitative real-time PCR. Endometrial tissue was also used for histopathology and cytology. In experimental goats, the mRNA expression of TLR4 and proinflammatory cytokines were increased within 24 h pi (P < 0.01) in endometrium and WBCs. Similarly, expression of beta-defensin2 was higher at 72 h pi in endometrium (P < 0.001), and at 120 h pi in WBCs (P < 0.05). The %PMNs in the experimental group increased up to 92.16 +/- 3.95% at 3 h pi (P < 0.001). Endometrial histopathology revealed a severe inflammatory response at 3 to 12 h pi, whereas no changes were detected in the control group. In conclusion, intrauterine infusion of E. coli in goats resulted in a rapid activation of the local innate immune response, characterized by infiltration of PMNs into the endometrium and up-regulation of gene expression for TLR4, cytokines and beta defensin2. PMID- 22541321 TI - Expression of luteinizing hormone and follicle-stimulating hormone receptor in the dog prostate. AB - A possible role for gonadotrophins luteinizing hormone (LH) and follicle stimulating hormone (FSH) in the prostate physiology has been suggested in humans and rats. This study aimed at investigating the presence of receptors for LH and FSH (LHR and FSHR) in the canine prostate. Prostates were collected at post mortem from 6 clinically healthy, sexually intact beagles free from any prostatic disorder. Tissue was sampled from dorsal, middle and ventral regions of each prostate. Immunohistochemical localization was performed on wax-embedded sections using polyclonal antibodies for LHR or FSHR. The pattern and intensity of staining in the parenchyma (glandular epithelium) and stroma were determined using a semiquantitative histologic assessment. Receptors for LH and FSH were consistently present in both the glandular epithelium and the stroma in all tissue samples examined. Expression for both receptors was higher in the glandular epithelium than the stroma of all prostatic regions (P < 0.001). In the glandular epithelium, LHR (P < 0.01) and FSHR (P < 0.05) expression was lower in the lateral than the other regions, and there was no difference between dorsal and ventral regions. However, variations in the expression for LHR and FSHR among prostatic regions were not found in the stroma. These findings have demonstrated that LHR and FSHR are expressed in the dog prostate, and the variation observed in their levels of expression among its regions and tissue layers suggests a potential role of gonadotrophins LH and FSH in the regulation of the prostate physiology, particularly the glandular epithelium. PMID- 22541322 TI - Silencing of fat-1 transgene expression in sheep may result from hypermethylation of its driven cytomegalovirus (CMV) promoter. AB - The fat-1 gene was isolated from roundworm Caenorhabditis elegans, and built into pIRES2-EGFP expression vectors driven by cytomegalovirus (CMV) promoter or cytomegalovirus enhancer and chickenbeta-actin (CAG) promoter. Both CMV- and CAG driven expression vectors were transfected to sheep fetal fibroblast cells. Positive transfected cells were used as donors for somatic cell nuclear transfer (SCNT) and the cloned embryos were transferred into the oviducts of synchronized recipient sheep. Two lambs derived from CMV vector and three lambs derived from CAG vector developed to term. Although Southern analyses using tissues from the two lambs derived from CMV vectors indicated integration of fat-1 gene into the genome, fat-1 mRNAs were not detected by RT-PCR. However, there was fat-1 expression (detected by RT-PCR) in tissues from transgenic lambs driven by CAG vectors. To investigate potential mechanisms involved in the two transgene models, methylation state of the vector promoters were examined. In CMV-driven transgenics, CMV promoters had almost no methylation in transfected cells and the resultant cloned embryos, whereas high methylations were detected in tissues and organs in transgenic lambs. In the CAG-driven transgenics, there were almost no methylations in transgenic cells and transgenic cloned embryos, and cloned lambs expressed fat-1 mRNA (detected by RT-PCR). Moreover, although SV40 promoters which drove neo/kan marker gene in CMV vectors were highly methylated in tissues from transgenic lambs, they were without methylation in cells and embryos. Therefore, we concluded that highly methylated CMV promoters induced the silence of fat-1 transgene expression in sheep. Furthermore, CAG promoter, but not CMV promoter was suitable for generation of fat-1 transgenic sheep. PMID- 22541323 TI - Vaccination against gonadotropin-releasing factor (GnRF) with Bopriva significantly decreases testicular development, serum testosterone levels and physical activity in pubertal bulls. AB - The aim of this study was to evaluate the effects of vaccination against gonadotropin-releasing factor (GnRF) on testicular development, testosterone secretion, and physical activity in pubertal bulls. The experiment was performed using 44 bulls aged between 6 and 7 mo. Twenty-three animals were vaccinated twice 4 wk apart with 1 mL of Bopriva (Pfizer, Animal Health, Parkville, Australia) and 21 bulls served as matched controls. Serum GnRF antibody titer and testosterone concentration as well as body weight and scrotal circumference were determined in all bulls for 24 wk from the first vaccination. In addition, physical activity was analyzed in 11 vaccinated and in 10 control animals using the ALPRO DeLaval activity meter system (DeLaval AG, Sursee, Switzerland). The results show that vaccination significantly (P < 0.05) influenced all parameters evaluated except body weight. Antibody titers to GnRF began to rise 2 wk after the first vaccination and reached peak values 2 wk after the second injection. Significant group differences in anti-GnRF titer were present for 22 wk following the first vaccination. Testosterone concentrations were significantly lower between weeks 6 to 24 after first vaccination in bulls with Bopriva compared with control animals. In vaccinated bulls testicular development was impaired after the second injection and scrotal circumference was significantly smaller between weeks 8 to 24 after first vaccination. Physical activity of vaccinated bulls was reduced after the booster injection with significant group differences for a continuous period of 106 days. In conclusion, vaccination against GnRF with Bopriva in pubertal bulls decreased testosterone levels in peripheral blood, testicular development, and physical activity but did not affect weight gain. PMID- 22541324 TI - Sperm cryopreservation affects postthaw motility, but not embryogenesis or larval growth in the Brazilian fish Brycon insignis (Characiformes). AB - Sperm cryopreservation is an important method for preserving genetic information and facilitating artificial reproduction. The objective was to investigate whether the cryopreservation process affects postthaw sperm motility, embryogenesis, and larval growth in the fish Brycon insignis. Sperm was diluted in methyl glycol and Beltsville Thawing solution, frozen in a nitrogen vapor vessel (dry shipper) and stored in liquid nitrogen. Half of the samples were evaluated both subjectively (% of motile sperm and motility quality score arbitrary grading system from 0 [no movement] to 5 [rapidly swimming sperm]) and in a computer-assisted sperm analyzer (CASA; percentage of motile sperm and velocity). The other half was used for fertilization and the evaluation of embryogenesis (cleavage and gastrula stages), hatching rate, percentage of larvae with normal development and larval growth up to 112 days posthatching (dph). Fresh sperm was analyzed subjectively (percentage of motile sperm and motility quality score) and used as the control. In the subjective analysis, sperm motility significantly decreased from 100% motile sperm and quality score of 5 in fresh sperm to 54% motile sperm and quality score of 3 after thawing. Under computer-assisted sperm analyzer evaluation, postthaw sperm had 67% motile sperm, 122 MUm/sec of curvilinear velocity, 87 MUm/sec of straight-line velocity and 103 MUm/sec of average path velocity. There were no significant differences between progenies (pooled data) for the percentage of viable embryos in cleavage (62%) or gastrula stages (24%) or in the hatching rate (24%), percentage of normal hatched larvae (93%), larval body weight (39.8 g), or standard length (12.7 cm) at 112 days posthatching. Based on these findings, cryopreserved sperm can be used as a tool to restore the population of endangered species, such as B. insignis, as well as for aquaculture purposes, without any concern regarding quality of the offspring. PMID- 22541325 TI - Role of hyaluronic acid in maturation and further early embryo development of bovine oocytes. AB - Hyaluronic acid (HA), an important component of the extracellular matrix, plays a crucial role for cumulus cell expansion. Genes and proteins involved in HA synthesis and its receptor CD44 are expressed in cumulus oocyte complexes (COCs) in different animal species and increase during maturation. Hyaluronidase enzymes (Hyal) degrade HA into smaller biologically active HA fragments. To investigate the effects of the molecular size and concentration of HA on oocyte maturation and further embryo development, bovine oocytes were matured in vitro in the presence or absence of HA, Hyal-2 or 4-methylumbelliferone (4-MU); an HA synthesis inhibitor. The rates of oocyte nuclear maturation to metaphase II stage and development of embryos to blastocyst stage and blastocyst quality were recorded. Hyal-2 inhibited cumulus cell expansion without affecting oocyte maturation and further embryo development. Whereas, 4-MU at 1 mm reduced cumulus cell expansion, oocyte maturation rate and further embryo development; an effect which was partially abrogated by exogenous HA supplementation. These data suggest that HA production by cumulus cells during maturation is essential not only for cumulus cell expansion, but also for oocyte maturation and further embryo development. This effect is not affected by HA-degradation by Hyal-2. PMID- 22541326 TI - Computer assisted sperm analysis of motility patterns of postthawed epididymal spermatozoa of springbok (Antidorcas marsupialis), impala (Aepyceros melampus), and blesbok (Damaliscus dorcus phillipsi) incubated under conditions supporting domestic cattle in vitro fertilization. AB - The need for information on the reproductive physiology of different wildlife species is important for ex situ conservation using such methods as in vitro fertilization (IVF). Information on species reproductive physiology and evaluation of sperm quality using accurate, objective, repeatable methods, such as computer-assisted sperm analysis (CASA) for ex situ conservation has become a priority. The aim of this study was to evaluate motility patterns of antelope epididymal spermatozoa incubated for 4 h under conditions that support bovine IVF using CASA. Cauda epididymal spermatozoa were collected postmortem from testicles of springbok (N=38), impala (N=26), and blesbok (N=42), and cryopreserved in biladyl containing 7% glycerol. Spermatozoa were thawed and incubated in Capacitation media and modified Tyrode lactate (m-TL) IVF media using a protocol developed for domestic cattle IVF. The study evaluates 14 motility characteristics of the antelope epididymal sperm at six time points using CASA. Species differences in CASA parameters evaluated under similar conditions were observed. Several differences in individual motility parameters at the time points were reported for each species. Epididymal sperm of the different antelope species responded differently to capacitation agents exhibiting variations in hyperactivity. Motility parameters that describe the vigor of sperm decreased over time. Spermatozoa from the different antelope species have different physiological and optimal capacitation and in vitro culture requirements. The interspecies comparison of kinematic parameters of spermatozoa between the antelopes over several end points contributes to comparative sperm physiology which forms an important step in the development of species specific assisted reproductive techniques (ARTs) for ex situ conservation of these species. PMID- 22541327 TI - Effect of post-fusion holding time, orientation and position of somatic cell cytoplasts during electrofusion on the development of handmade cloned embryos in buffalo (Bubalus bubalis). AB - The present study was conducted primarily to optimize electrofusion conditions for efficient production of zona-free nuclear transfer embryos in buffalos (Bubalus bubalis). We found that 4V AC current for proper triplet alignment and single step fusion method, using a single DC pulse of 3.36 kV/cm for 4-MUs duration, produced the most convincing results for efficient reconstitution of zona-free cloned embryos. Lysis rate was very high (84.28 +/- 2.59%) when triplets were in physical contact with negative electrode after applying DC current, however, cleavage rate and blastocyst rate were found to be similar when the triplets were not in physical contact with either positive or negative electrodes or when they were in physical contact with the positive electrode. Significant improvement in blastocyst production was observed when the somatic cell faced the positive electrode than when it faced the negative electrode (39.17 +/- 2.74% vs. 25.91 +/- 2.00%, respectively) during electrofusion. Similarly, the blastocyst rate (52.0 +/- 3.4%) was found to be significantly higher when reconstructed embryos were activated 6 h post electrofusion as compared to 0, 2, 4 and 8 h (16.04 +/- 6.3%; 18.36 +/- 1.4%; 22.44 +/- 3.7% and 30.02 +/- 4.6%, respectively). This study establishes the application of zona free nuclear transfer procedures for the production of handmade cloned buffalo embryos through optimization of electrofusion parameters and post fusion holding time for enhancing their preimplantation development. PMID- 22541328 TI - Passive transfer of maternal GnRH antibodies does not affect reproductive development in elk (Cervus elaphus nelsoni) calves. AB - Gonadotropin-releasing hormone is intermittently released from the hypothalamus in consistent patterns from before birth to final maturation of the hypothalamic pituitary-gonadal axis at puberty. Disruption of this signaling via GnRH vaccination during the neonatal period can alter reproduction at maturity. The objective of this study was to investigate the long-term effects of GnRH-antibody exposure on reproductive maturation and function in elk calves passively exposed to high concentrations of GnRH antibodies immediately after birth. Fifteen elk calves (eight males and seven females) born to females treated with GnRH vaccine or sham vaccine during midgestation were divided into two groups based on the concentration of serum GnRH antibodies measured during the neonatal period. Those with robust (>15 pmol (125)I-GnRH bound per mL of serum) titers (N = 10; four females and six males) were designated as the exposed group, whereas those with undetectable titers (N = 5; three females and two males) were the unexposed group. Onset of puberty, reproductive development, and endocrine function in antibody-exposed and unexposed male and female elk calves were compared. Neonatal exposure to high concentrations of GnRH antibodies had no effect on body weight (P = 0.968), endocrine profiles (P > 0.05), or gametogenesis in either sex. Likewise, there were no differences between groups in gross or histologic structure of the hypothalamus, pituitary, testes, or ovaries. Pituitary stimulation with a GnRH analog before the second potential reproductive season induced substantial LH secretion in all experimental elk. All females became pregnant during their second reproductive season and all males exhibited similar mature secondary sexual characteristics. There were no differences between exposure groups in hypothalamic GnRH content (P = 0.979), pituitary gonadotropin content (P > 0.05) or gonadal structure. We concluded that suppressing GnRH signaling through immunoneutralization during the neonatal period likely does not alter long-term reproductive function in this species. PMID- 22541329 TI - Changes in histone acetylation during oocyte meiotic maturation in the diabetic mouse. AB - Although there is considerable evidence that diabetes can adversely affect meiosis in mammalian oocytes, acetylation status of oocytes in a diabetic environment remains unclear. The objective was to determine acetylation or deacetylation patterns (based on immunostaining) of H3K9, H3K14, H4K5, H4K8, H4K12, and H4K16 sites at various stages during meiosis in murine oocytes from control and diabetic mice. According to quantitative real time polymerase chain reaction (qPCR), mean +/- SEM relative expression of Gcn5 (1.70 +/- 0.14 at metaphase [M]I and 1.27 +/- 0.01 at MII, respectively), Ep300 (1.74 +/- 0.04 at MI and 1.80 +/- 0.001 at MII), and Pcaf (2.01 +/- 0.03 at MI and 1.41 +/- 0.18 at MII) mRNA in oocytes from diabetic mice were higher than those from controls (P < 0.05), whereas there was no difference (P > 0.05) during the germinal vesicle (GV) stage between the two groups (1.23 +/- 0.04 for Gcn5, 0.82 +/- 0.06 for Ep300, and 0.80 +/- 0.07 for Pcaf). Conversely, relative mRNA expression concentrations of Hdac1, Hdac2, Hdac3, Sirt1 and Sirt2 during the germinal vesicle stage were lower in oocytes of diabetic mice (0.24 +/- 0.03 for Hdac1, 0.11 +/- 0.001 for Hdac2, 0.31 +/- 0.03 for Hdac3, 0.28 +/- 0.02 for Sirt1, and 0.55 +/- 0.02 for Sirt2; P < 0.05). Similarly, the expression concentrations of these genes at the MI stage were lower in oocytes from diabetic mice (0.79 +/- 0.12 for Hdac1, 0.72 +/- 0.001 for Hdac2, 0.02 +/- 0.001 for Sirt1, and 0.84 +/- 0.08 for Sirt2; P < 0.05). Their expression concentrations at the MII stage were also lower in oocytes from diabetic mice (0.46 +/- 0.03 for Hdac1, 0.93 +/- 0.01 for Hdac2, 0.56 +/- 0.01 for Hdac3, 0.01 +/- 0.002 for Sirt1, and 0.84 +/- 0.04 for Sirt2; P < 0.05). At the MI stage, however, there was no difference in the expression of Hdac3 between the two groups of oocytes (0.96 +/- 0.03; P > 0.05). Taken together, diabetes altered the intracellular histone modification system, which may have contributed to changes in histone acetylation, and may be involved in the compromised maturation rate of oocytes in diabetic humans. PMID- 22541330 TI - Kinetics of CMV seroconversion in a Swiss pregnant women population. AB - Retrospective evaluation of the kinetics of cytomegalovirus (CMV) seroconversion with CMV IgM, IgG, and IgG avidity assays, in a Swiss pregnant women population, has shown that the current published CMV serologic diagnostic algorithms were valid and fit for use. In 19% of the cases analyzed, CMV-specific IgM was detected before IgG. PMID- 22541331 TI - Isolation of a capnophilic Escherichia coli strain from an empyemic patient. PMID- 22541332 TI - Recent advances in the genetics and immunology of Stevens-Johnson syndrome and toxic epidermal necrosis. AB - Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) are rare but life-threatening severe cutaneous adverse reactions (SCARs), which are majorly (65-75%) induced by a variety of drugs. SJS/TEN could be recognized as SCARs or drug immune reactions, if the reactions are elicited by drugs. The recent studies suggested that SJS/TEN is a specific immune reaction initiated by the cytotoxic T lymphocytes (CTLs) via human leukocyte antigens (HLAs)-restricted pathway. The patho-mechanism involving HLA-restricted presentation of a drug or its metabolites for T-cell activation is supported by the findings of strong genetic associations with HLA alleles (e.g. HLA-B*15:02 and carbamazepine-SJS/TEN, and HLA-B*58:01 and allopurinol-SJS/TEN). However, the genetic associations of SJS/TEN or drug induced cutaneous immune reactions are complex, which are drug specific and ethnicity specific. The genetic polymorphisms and diversity of HLA alleles may provide different binding affinities for drug antigens to launch the activation of specific CTLs responses, further leading to the unique clinical manifestations in SJS/TEN. Fas-FasL and perforin/granzyme B have been advocated mediating the epidermal necrosis in SJS/TEN. Our recent study showed that granulysin, a cytotoxic protein produced by CTLs or natural killer (NK) cells, is the key mediator for disseminated keratinocyte death in SJS/TEN. From the point of view of a physician, the profounder understanding of the genetic predisposition and patho-mechanism we discover, the better strategies for prevention, clinical management, and therapeutic methods of SJS/TEN we can develop in the near future. PMID- 22541334 TI - Degradation of 17alpha-methyltestosterone by Rhodococcus sp. and Nocardioides sp. isolated from a masculinizing pond of Nile tilapia fry. AB - 17alpha-Methyltestosterone (MT), a synthetic anabolic androgenic steroid, is widely used in aquafarming for the production of an all male fish population such as Nile tilapia. This study isolated, identified and characterized MT-degrading bacteria in the sediment and water from a masculinizing pond of Nile tilapia fry. Based on the phylogeny, physiological properties and cell morphology, the three isolated MT-degrading bacteria were related closely to Rhodococcus equi, Nocardioides aromaticivorans, and Nocardioides nitrophenolicus. Growth of the three isolated strains was found to be inhibited for MT concentrations in the range of 1.0-10mg/L. The inhibition of cell growth was found to be modeled using the Haldane's substrate inhibition model. The kinetic constants ranged from 0.13 to 0.19h(-1) for MU(max), 0.7-24.8mg/L for K(s) and 19.6-76.2mg/L for K(i). Androgenic activity using beta-galactosidase assay showed that all strains degraded MT to the products with no androgenic potency. PMID- 22541333 TI - The conformational flexibility of the C-terminus of histone H4 promotes histone octamer and nucleosome stability and yeast viability. AB - BACKGROUND: The protein anti-silencing function 1 (Asf1) chaperones histones H3/H4 for assembly into nucleosomes every cell cycle as well as during DNA transcription and repair. Asf1 interacts directly with H4 through the C-terminal tail of H4, which itself interacts with the docking domain of H2A in the nucleosome. The structure of this region of the H4 C-terminus differs greatly in these two contexts. RESULTS: To investigate the functional consequence of this structural change in histone H4, we restricted the available conformations of the H4 C-terminus and analyzed its effect in vitro and in vivo in Saccharomyces cerevisiae. One such mutation, H4 G94P, had modest effects on the interaction between H4 and Asf1. However, in yeast, flexibility of the C-terminal tail of H4 has essential functions that extend beyond chromatin assembly and disassembly. The H4 G94P mutation resulted in severely sick yeast, although nucleosomes still formed in vivo albeit yielding diffuse micrococcal nuclease ladders. In vitro, H4G4P had modest effects on nucleosome stability, dramatically reduced histone octamer stability, and altered nucleosome sliding ability. CONCLUSIONS: The functional consequences of altering the conformational flexibility in the C terminal tail of H4 are severe. Interestingly, despite the detrimental effects of the histone H4 G94P mutant on viability, nucleosome formation was not markedly affected in vivo. However, histone octamer stability and nucleosome stability as well as nucleosome sliding ability were altered in vitro. These studies highlight an important role for correct interactions of the histone H4 C-terminal tail within the histone octamer and suggest that maintenance of a stable histone octamer in vivo is an essential feature of chromatin dynamics. PMID- 22541335 TI - Characterization of mass transfer of lower chlorinated benzenes from contaminated sediment into water. AB - Mass transport of chlorinated benzenes as found at the Petro-Processors of Louisiana, Inc. (PPI) Superfund site was characterized for a range of flow rates in small streams. At this site hazardous waste was historically disposed of in unengineered pits. Hexachlorobenzene and lesser chlorinated degradation products were found among other compounds. As waste was being disposed into unengineered pits, it seeped to lagoons and sediments of Baton Rouge Bayou (BRB), which flows through and nearby the former disposal areas. Characterization of the transport and fate of chlorobenzenes at PPI is an integral part of the Monitored Natural Attenuation (MNA) remedy currently underway. Laboratory experimental results and mathematical model predictions of the flux of 1,3-dichlorobenzene (1,3-DCB) from sediments into water are presented. 1,3-DCB was studied as individually and as part of a mixture of four contaminants with 1,2-DCB, chlorobenzene (MCB) and trichlorobenzene (TCB). Surficial sediments were collected, spiked with contaminants and leached to determine flux over time. Two advection-dispersion models were tested and the effect of low, cycling and fast stream flow on the contaminant flux was assessed. Model results suggest that tortuosity and effective diffusivity are related effective system predictors and descriptors. Statistical analysis supports the models' predictive capabilities. PMID- 22541336 TI - A case series of spotted fever rickettsiosis with neurological manifestations in Sri Lanka. AB - BACKGROUND: Spotted fever group (SFG) rickettsial infections are increasingly detected in Sri Lanka. We describe 17 patients with SFG who developed neurological manifestations. METHODS: The cases were studied prospectively from 2008 at the Teaching Hospital, Peradeniya. An immunofluorescent antibody assay (IFA) was used to confirm the diagnosis. RESULTS: All had an IFA IgG titer ranging from 1/64 to 1/4096 and a positive IFA IgM titer against Rickettsia conorii antigen; in 10 (59%) cases the IgG titers were >= 1/256 (definitive cases). The median age of the patients was 62 years (range 26-82 years); 10 were male and seven female. The median duration of fever was 12 days (range 4-35 days). Neurological manifestations on admission were drowsiness or confusion in 14 (82%) and a semi-comatose state in three (18%). Rigidity of the limbs occurred in 14 (82%), bradykinesia and resting tremors in 12 (71%), which persisted after defervescence, neck stiffness in seven (42%), weakness of the limbs in five (29%), deafness in two (12%), and stupor in three (18%). Electroencephalograms in three (18%) showed generalized slow waves. Cerebrospinal fluid examination showed a cellular reaction, predominantly lymphocytes, in three cases. Two patients died (fatality rate 12%). CONCLUSION: We have documented for the first time the neurological features of SFG rickettsioses in the Central Province, Sri Lanka. These were predominantly extrapyramidal features in patients of older age. PMID- 22541337 TI - Systems biotechnology of animal cells: the road to prediction. AB - A central concern of biopharmaceutical R&D is the production of sufficient quantities of recombinant products from manufacturing processes based on animal cell culture. The way in which bioprocess researchers have addressed this question experienced a tremendous shift over the years, progressing from almost empirical to more rational approaches. A step further is the application of systems biotechnology: recent technological advances for large-scale cell state characterization and creative methods for host cell modeling are becoming crucial for next-generation bioprocess optimization. Here we provide an overview of the main trends towards this goal, with a focus on metabolic models as central scaffolds for data integration and prediction of bioprocess outcomes. PMID- 22541338 TI - Process engineering of human pluripotent stem cells for clinical application. AB - Human pluripotent stem cells (hPSCs), including embryonic and induced pluripotent stem cells, constitute an extremely attractive tool for cell therapy. However, flexible platforms for the large-scale production and storage of hPSCs in tightly controlled conditions are necessary to deliver high-quality cells in relevant quantities to satisfy clinical demands. Here we discuss the main principles for the bioprocessing of hPSCs, highlighting the impact of environmental factors, novel 3D culturing approaches and integrated bioreactor strategies for controlling hPSC culture outcome. Knowledge on hPSC bioprocessing accumulated during recent years provides important insights for the establishment of more robust production platforms and should potentiate the implementation of novel hPSC-based therapies. PMID- 22541339 TI - [Microbiological diagnosis of mycoplasma infections]. AB - The microbiological diagnosis of mycoplasma and ureaplasma infections has always been limited due to the fastidious growth of these microorganisms, as well as the lack of commercially prepared growth media, absence of rapid diagnostic procedures, and the clinical perception that these organisms are less significant in the infectious diseases setting. During the last few years, this situation has substantially improved due to the commercial availability of culture media, the development of rapid serological techniques, and, in particular, to the introduction of nucleic acid amplification assays, commercially available or "in house" preparations. Despite the lack of proper standardisation and validation of the molecular and serological techniques, methodological advances have led to an increased detection of these microorganisms and, consequently, a greater appreciation of their clinical relevance. PMID- 22541342 TI - Intractable seizures in a 4-month-old girl. AB - A 4-month-old, 7-kg girl with a 3-day history of mild diarrhea was brought into a rural emergency department (ED) by private vehicle. The patient's parents reported that the child was in her usual state of health until the past several days, when she began having multiple loose stools. After an extensive interview, the family said she was born full term without any complications. She had never been hospitalized and was up to date on all of her immunizations. Family also stated emphatically that there was no alteration in her formula concentration and intake before her presentation. Approximately 30 minutes before her arrival, her parents noticed "shaking of the extremities" consistent with seizure activity. Concurrently, they noted she had irregular respirations and was not acting at her baseline. PMID- 22541343 TI - When is a calendar a kickback? PMID- 22541340 TI - [Prevalence of hepatitis virus infection markers in HIV-infected patients in Southern Spain]. AB - OBJECTIVES: To determine: (a) The prevalence of active infection by the hepatitis C virus (HCV) and hepatitis B virus (HBV) in HIV-infected patients, as well as previous exposure to hepatitis A virus (HAV), HBV and HCV. (b) The proportion of patients who have been vaccinated against HAV and/or HBV. (c) The HCV genotype distribution and the percentage of patients who have started treatment against HCV infection. METHODS: All HIV-infected patients who attended the Infectious Diseases Unit of a tertiary care hospital in Southern Spain between September 2008 and February 2009 were included in a prospective cross-sectional study. RESULTS: A total of 520 patients were included. Three hundred and fifty-eight (69%) patients had positive HCV antibody, while 71% of them showed detectable HCV RNA. The HCV genotype distribution was: 153 (62%) genotype 1, 49 (20%) genotype 3, and 45 (18%) genotype 4. One hundred and thirteen (36.5%) subjects had received treatment against HCV. The prevalence of active HBV infection was 4.4%, while the exposure to HBV was 54.8%. Four hundred and thirty-seven (84%) patients had positive markers of infection of HAV. Of the patients eligible to be vaccinated, 25.6% and 22.3% patients were vaccinated against HAV and HBV, respectively. CONCLUSIONS: The current prevalence of active HCV infection remains high in our area. There were no changes in the HCV genotype distribution. The number of patients with indication for HBV and HAV vaccination and receive these vaccines is low. PMID- 22541345 TI - Simulator training: reducing risk in helicopter rescue. PMID- 22541346 TI - Collective air medical evacuation: the French tool. PMID- 22541347 TI - Unknown, unrecognized, and underreported: flicker vertigo in helicopter emergency medical services. PMID- 22541348 TI - Heliox in children with croup: a strategy to hasten improvement. AB - OBJECTIVE: Upper airway obstruction is responsive to the reduction in airflow turbulence provided by helium/oxygen (heliox) admixture. Our pediatric critical care transport team (PCCTT) has used heliox for children with upper airway obstruction from croup. We sought to describe our experience with heliox on transport and hypothesized that heliox-treated children with croup would show a more rapid clinical improvement. METHODS: Children with croup transported by our PCCTT and admitted to the PICU were evaluated. We analyzed pretransport care, transport interventions, and outcomes. Croup scores (Modified Taussig) were assigned retrospectively according to respiratory therapy charting. Data were analyzed using appropriate statistical tests, including Pearson's chi-square test, Fisher's exact test, Mann-Whitney U rank comparison, and two-sample t-test. RESULTS: Thirty-five children met inclusion criteria. Demographics were similar between groups. The pretransport medical care was similar between groups. Children receiving heliox had a higher baseline croup score [mean (SD) = 5.7(2.3) vs no heliox 2.9 (2.0), P < 0.001]. The improvement in croup scores over the first 60 minutes of transport was more rapid in the heliox-treated children (P < 0.001). There was no difference in the number of children requiring additional nebulized racemic epinephrine during transport. The PICU length of stay (P = 0.59) and hospital length of stay (P = 0.64) were similar between groups. CONCLUSION: Heliox added to standard transport treatment for critically ill children with croup provides a more rapid improvement in croup scores. Heliox for croup during transport does not prolong intensive care unit stay. A prospective clinical trial is warranted to evaluate heliox in pediatric transport. PMID- 22541349 TI - Air medical services must be prepared for massive transfusion. PMID- 22541350 TI - I'll take passion for $1000. PMID- 22541352 TI - The biology of reactive sulfur species (RSS). AB - Sulfur is an essential and quantitatively important element for living organisms. Plants contain on average approximately 1 g S kg-1 dry weight (for comparison plants contain approximately 15 g N kg-1 dry weight). Sulfur is a constituent of many organic molecules, for example amino acids such as cysteine and methionine and the small tripeptide glutathione, but sulfur is also essential in the form of Fe-S clusters for the activity of many enzymes, particularly those involved in redox reactions. Sulfur chemistry is therefore important. In particular, sulfur in the form of thiol groups is central to manifold aspects of metabolism. Because thiol groups are oxidized and reduced easily and reversibly, the redox control of cellular metabolism has become an increasing focus of research. In the same way that oxygen and nitrogen have reactive species (ROS and RNS), sulfur too can form reactive molecular species (RSS), for example when a -SH group is oxidized. Indeed, several redox reactions occur via RSS intermediates. Several naturally occurring S-containing molecules are themselves RSS and because they are physiologically active they make up part of the intrinsic plant defence repertoire against herbivore and pathogen attack. Furthermore, RSS can also be used as redox-active pharmacological tools to study cell metabolism. The aim of this review is to familiarize the general reader with some of the chemical concepts, terminology and biology of selected RSS. PMID- 22541353 TI - The prediction of drug metabolism using scaffold-mediated enhancement of the induced cytochrome P450 activities in fibroblasts by hepatic transcriptional regulators. AB - A reliable, reproducible, and convenient in vitro platform for drug metabolism determination and toxicity prediction is of tremendous value but still lacking. In the present study, a collection of 24 hepatic transcription factors and nuclear receptors in different combinations were surveyed, and 10 among them were finally selected to induce the expression and enzyme activities of cytochrome P450 (CYP) 3A4, 1B1, and 2C9 in human dermal fibroblasts (HDFs). The expression and activities of these CYPs in the induced HDFs were higher than those in commonly used hepatoma cell lines. High CYP expression and activities could be further enhanced by culturing the induced HDFs either as spheroids or into several kinds of scaffolds, particularly the tri-copolymer scaffold composed of gelatin, chondroitin and hyaluronan. More strikingly, there showed a synergistic effect of seeding and culturing the spheroids into the tri-copolymer scaffold. Scanning electron microscopy and confocal microscopy disclosed well accommodation of these spheroids inside the scaffolds and displayed a high survival rate. Moreover, the spheroid/scaffold constructs could metabolize an anti-hypertension drug nifedipine into oxidized nifedipine, showing their applicability in studying drug metabolism. This study presents a strategy to induce the expression and enzyme activities of critical CYPs in HDFs, and may have potential to establish an in vitro platform to study drug metabolism and to predict the possible human risk of drug toxicity. PMID- 22541355 TI - Self-renewal of embryonic stem cells through culture on nanopattern polydimethylsiloxane substrate. AB - Embryonic stem (ES) cells can undergo continual proliferation and differentiation into cells of all somatic cell lineages in vitro; they are an unlimited cell source for regenerative medicine. However, techniques for maintaining undifferentiated ES cells are often inefficient and result in heterogeneous cell populations. Here, we determined effects of nanopattern polydimethylsiloxane (PDMS) as a culture substrate in promoting the self-renewal of mouse ES (mES) cells, compared to commercial plastic culture dishes. After many passages, mES cells efficiently maintained their undifferentiated state on nanopattern PDMS, but randomly differentiated on commercial plastic culture dishes, as indicated by partially altered morphologies and decreases in alkaline phosphatase activity and stage-specific expression of embryonic antigen-1. Under nanopattern PDMS conditions, we found increased activities of STAT3 and Akt, important proteins involved in maintaining the self-renewal of mES cells. The substrate-cell interactions also enhanced leukemia inhibitory factor (LIF)-downstream signaling and inhibited spontaneous differentiation, concomitant with reduced focal adhesion kinase (FAK) signaling. This reduction in FAK signaling was shown to be important for promoting mES cell self-renewal. Thus, our data demonstrates that nanopattern PDMS contributes to maintaining the self-renewal of mES cells and may be applicable in the large-scale production of homogeneously undifferentiated mES cells. PMID- 22541354 TI - Use of polyelectrolyte thin films to modulate osteoblast response to microstructured titanium surfaces. AB - The microstructure and wettability of titanium (Ti) surfaces directly impact osteoblast differentiation in vitro and in vivo. These surface properties are important variables that control initial interactions of an implant with the physiological environment, potentially affecting osseointegration. The objective of this study was to use polyelectrolyte thin films to investigate how surface chemistry modulates response of human MG63 osteoblast-like cells to surface microstructure. Three polyelectrolytes, chitosan, poly(L-glutamic acid), and poly(L-lysine), were used to coat Ti substrates with two different microtopographies (PT, Sa = 0.37 MUm and SLA, Sa = 2.54 MUm). The polyelectrolyte coatings significantly increased wettability of PT and SLA without altering micron-scale roughness or morphology of the surface. Enhanced wettability of all coated PT surfaces was correlated with increased cell numbers whereas cell number was reduced on coated SLA surfaces. Alkaline phosphatase specific activity was increased on coated SLA surfaces than on uncoated SLA whereas no differences in enzyme activity were seen on coated PT compared to uncoated PT. Culture on chitosan-coated SLA enhanced osteocalcin and osteoprotegerin production. Integrin expression on smooth surfaces was sensitive to surface chemistry, but microtexture was the dominant variable in modulating integrin expression on SLA. These results suggest that surface wettability achieved using different thin films has a major role in regulating osteoblast response to Ti, but this is dependent on the microtexture of the substrate. PMID- 22541356 TI - The degradation and clearance of Poly(N-hydroxypropyl-L-glutamine)-DTPA-Gd as a blood pool MRI contrast agent. AB - Although polymeric magnetic resonance imaging (MRI) agents have significantly improved relaxivity and prolonged circulation time in vivo compared with current imaging agents, the potential for long-term toxicity prevents their translation into the clinic. The aim of this study was to develop a new biodegradable, nonionic polymeric blood pool MRI contrast agent with efficient clearance from the body. We synthesized PHPG-DTPA, which possesses two potentially degradable sites in vivo: protein amide bonds of the polymer backbone susceptible to enzymatic degradation and hydrolytically labile ester bonds in the side chains. After chelation with Gd(3+), PHPG-DTPA-Gd displayed an R(1) relaxivity of 15.72 mm(-1)?sec(-1) (3.7 times higher than that of Magnevist(T)). In vitro, DTPA was completely released from PHPG polymer within 48 h when incubated in mouse plasma. In vivo, PHPG-DTPA-Gd was cleared via renal route as shown by micro-single photon emission computed tomography of mice after intravenous injection of (111)In labeled PHPG-DTPA-Gd. MRI of nude rats bearing C6 glioblastoma showed significant enhancement of the tumor periphery after intravenous injection of PHPG-DTPA-Gd. Furthermore, mouse brain angiography was clearly delineated up to 2 h after injection of PHPG-DTPA-Gd. PHPG-DTPA-Gd's biodegradability, efficient clearance, and significantly increased relaxivity make it a promising polymeric blood pool MRI contrast agent. PMID- 22541357 TI - Cooperation between research institutions and journals on research integrity cases: guidance from the Committee on Publication Ethics (COPE). AB - Institutions and journals both have important duties relating to research and publication misconduct. Institutions are responsible for the conduct of their researchers and for encouraging a healthy research environment. Journals are responsible for the conduct of their editors, for safeguarding the research record, and for ensuring the reliability of everything they publish. It is therefore important for institutions and journals to communicate and collaborate effectively on cases relating to research integrity. To achieve this, we make the following recommendations. Institutions should: * have a research integrity officer (or office) and publish their contact details prominently; * inform journals about cases of proven misconduct that affect the reliability or attribution of work that they have published; * respond to journals if they request information about issues, such as disputed authorship, misleading reporting, competing interests, or other factors, including honest errors, that could affect the reliability of published work; * initiate inquiries into allegations of research misconduct or unacceptable publication practice raised by journals; * have policies supporting responsible research conduct and systems in place for investigating suspected research misconduct. Journals should: * publish the contact details of their editor-in-chief who should act as the point of contact for questions relating to research and publication integrity; * inform institutions if they suspect misconduct by their researchers, and provide evidence to support these concerns; * cooperate with investigations and respond to institutions' questions about misconduct allegations; * be prepared to issue retractions or corrections (according to the COPE guidelines on retractions) when provided with findings of misconduct arising from investigations; * have policies for responding to institutions and other organizations that investigate cases of research misconduct. PMID- 22541358 TI - Systematic review of progesterone use by midlife and menopausal women. AB - Progesterone treatment for menopausal symptoms is still controversial. Progesterone levels fall during menopause transition, therefore some menopausal women may benefit from progesterone therapy. A systematic review was conducted of studies published from 2001 reporting on progesterone use to treat symptoms associated with menopause or postmenopausal women. Fourteen data bases were searched using the search terms progesterone, menopause, aged, female and human; exclusions were breast cancer, animal and contraception. Thirteen studies were selected for inclusion (11 clinical trials, 1 cohort study and 1 qualitative study), evaluating progesterone effects on menopausal symptoms, bone, sleep, skin, cognition, plasma lipids and plaque progression. Most studies were of low methodological quality (GRADE low or very low). Progesterone improved vasomotor symptoms and sleep quality, with minimal risk. Large studies designed to identify confounders, such as hormone levels, menopausal status and metabolism are required to understand the place of progesterone in clinical practice. PMID- 22541359 TI - A European perspective on immunotherapy for food allergies. AB - Food allergies are common, and frequently, the only treatment option is strict avoidance. Unfortunately, many patients accidentally ingest allergenic foods, which can result in severe anaphylactic reactions. Several immunotherapies are being developed for food allergies; these involve oral, sublingual, epicutaneous, or subcutaneous administration of small amounts of native or modified allergens to induce immune tolerance. Oral immunotherapy seems to be the most promising approach based on results from small uncontrolled and controlled studies. However, it is a challenge to compare results among immunotherapy trials because of differences in protocols. Studies conducted thus far have tested the most prevalent food allergens: it is not clear whether their results can be extended to other allergens. Sublingual administration of immunotherapy has shown some efficacy and fewer side effects than oral administration in some trials, yet neither approach can be recommended for routine practice. Controlled studies with larger numbers of subjects are needed to determine short- and long-term efficacy and side effects. In Europe immunotherapy trials for food allergies face many ethical and regulatory issues. Guidelines from the European Medicine Agency on the clinical development of products for specific immunotherapy of allergic diseases do not adequately address immunotherapy for food allergies, especially for therapies that orally administer native food or that include pediatric patients. PMID- 22541360 TI - Asthma: the paradox of heterogeneity. PMID- 22541363 TI - Common variable immunodeficiency. PMID- 22541361 TI - The interpersonal and intrapersonal diversity of human-associated microbiota in key body sites. AB - The human body harbors 10 to 100 trillion microbes, mainly bacteria in our gut, which greatly outnumber our own human cells. This bacterial assemblage, referred to as the human microbiota, plays a fundamental role in our well-being. Deviations from healthy microbial compositions (dysbiosis) have been linked with important human diseases, including inflammation-linked disorders, such as allergies, obesity, and inflammatory bowel disease. Characterizing the temporal variations and community membership of the healthy human microbiome is critical to accurately identify the significant deviations from normality that could be associated with disease states. However, the diversity of the human microbiome varies between body sites, between patients, and over time. Environmental differences have also been shown to play a role in shaping the human microbiome in different cultures, requiring that the healthy human microbiome be characterized across life spans, ethnicities, nationalities, cultures, and geographic locales. In this article we summarize our knowledge on the microbial composition of the 5 best-characterized body sites (gut, skin, oral, airways, and vagina), focusing on interpersonal and intrapersonal variations and our current understanding of the sources of this variation. PMID- 22541364 TI - Association of LPL gene variant and LDL, HDL, VLDL cholesterol and triglyceride levels with ischemic stroke and its subtypes. AB - Lipoprotein lipase (LPL) plays an important role in lipid metabolism by hydrolyzing triglycerides in chylomicrons and very low density lipoproteins. An increasing number of studies have suggested an association of LPL gene variants with the risk of cardiovascular and cerebrovascular diseases. The aim of this study was to test whether HindIII polymorphism of LPL gene is associated with ischemic stroke and its subtypes as well as plasma lipid levels in a South Indian population from Andhra Pradesh. Five hundred and twenty five ischemic stroke patients and 500 controls were enrolled in this case-control study. The LPL HindIII polymorphism was determined by PCR-RFLP technique and the lipid levels were estimated using commercially available kits. We found significant difference in the genotypic distribution between patients and controls [for HindIII (+/+) vs. HindIII (-/-), chi(2)=4.916; p=0.02; Odds ratio=1.59 (95%CI; 1.054-2.413); HindIII (+/+) vs. HindIII (-/-) and HindIII (+/-), chi(2)=5.25; p=0.02; Odds ratio=1.24 (95%CI; 1.03-1.503)]. A stepwise multiple logistic regression analysis confirmedthese findings. The relationship between HindIII genotypes and plasma levels of HDL, LDL, VLDL and triglycerides was analyzed using ANOVA and further confirmed by Post-hoc analysis. The levels of triglycerides were found to be elevated in individuals bearing HindIII (+/+) genotype in comparison with HindIII (-/-) genotype. HDL levels were found to be significantly reduced and triglyceride levels significantly elevated in HindIII (+/+) genotype in comparison with HindIII (-/-). However, there was no difference in the levels of LDL and VLDL between the two genotypes. Examining the association of LPL gene HindIII polymorphism with stroke subtypes, we found significant association of HindIII polymorphism with Intracranial large artery atherosclerosis [Odds ratio=2.12 955CI (1.656-2.848); p=0.009]. Our results suggest that the HindIII polymorphism of LPL is significantly associated with ischemic stroke risk and elevated levels of plasma triglycerides and reduced HDL levels. Further, this polymorphism is significantly associated with intracranial large artery atherosclerosis which is the most frequent subtype in our region. PMID- 22541365 TI - Abnormal baseline brain activity in low-grade hepatic encephalopathy: a resting state fMRI study. AB - Resting-state functional magnetic resonance imaging (fMRI) has been used to detect the alterations of spontaneous neuronal activity in various neuropsychiatric diseases, but rarely in low-grade hepatic encephalopathy (HE), a common neuropsychiatric complication of liver cirrhosis. We conducted a resting state fMRI in 19 healthy controls, 18 cirrhotic patients without HE, and 22 cirrhotic patients with low-grade HE. The amplitude of low-frequency fluctuations (ALFF) of fMRI signal was computed to measure the spontaneous neuronal activity. Several regions showing significant ALFF differences among three groups were the precuneus, occipital lobe, left frontal lobe and anterior/middle cingulate cortex, and left cerebellum posterior lobe. Compared to controls or patients without HE, patients with low-grade HE showed decreased ALFF in the precuneus and adjacent cuneus, visual cortex, and left cerebellum posterior lobe. Compared to controls, patients with low-grade HE showed higher ALFF in both cortical and subcortical regions, including the right middle cingulate gyrus, and left anterior/middle cingulate gyrus, inferior frontal gyrus, insula lobe, parahippocampal gyrus, middle temporal gyrus and lentiform nucleus; compared to patients without HE, patients with low-grade HE showed higher ALFF in the left medial frontal gyrus and anterior cingulate gyrus, bilateral superior frontal gyrus, and right middle frontal gyrus. Moreover, correlations between ALFF changes and poor neurocognitive performances were found in patients with low grade HE. These results suggested the existence of aberrant brain activity at the baseline state in low-grade HE, which may be implicated in the neurological pathophysiology underlying HE. PMID- 22541366 TI - The effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease (review of Technology Appraisal No. 111): a systematic review and economic model. AB - BACKGROUND: Alzheimer's disease (AD) is the most commonly occurring form of dementia. It is predominantly a disease of later life, affecting 5% of those over 65 in the UK. OBJECTIVES: Review and update guidance to the NHS in England and Wales on the clinical effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine [acetylcholinesterase inhibitors (AChEIs)] and memantine within their licensed indications for the treatment of AD, which was issued in November 2006 (amended September 2007 and August 2009). DATA SOURCES: Electronic databases were searched for systematic reviews and/or metaanalyses, randomised controlled trials (RCTs) and ongoing research in November 2009 and updated in March 2010; this updated search revealed no new includable studies. The databases searched included The Cochrane Library (2009 Issue 4, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials), MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, PsycINFO, EconLit, ISI Web of Science Databases--Science Citation Index, Conference Proceedings Citation Index, and BIOSIS; the Centre for Reviews and Dissemination (CRD) databases--NHS Economic Evaluation Database, Health Technology Assessment, and Database of Abstracts of Reviews of Effects. REVIEW METHODS: The clinical effectiveness systematic review was undertaken following the principles published by the NHS CRD. We included RCTs whose population was people with AD. The intervention and comparators depended on disease severity, measured by the Mini Mental State Examination (MMSE). INTERVENTIONS: mild AD (MMSE 21-26)--donepezil, galantamine and rivastigmine; moderate AD (MMSE 10-20)- donepezil, galantamine, rivastigmine and memantine; severe AD (MMSE < 10)- memantine. Comparators: mild AD (MMSE 21-26)--placebo or best supportive care (BSC); moderate AD (MMSE 10-20)--donepezil, galantamine, rivastigmine, memantine, placebo or BSC; severe AD (MMSE < 10)--placebo or BSC. The outcomes were clinical, global, functional, behavioural, quality of life, adverse events, costs and cost-effectiveness. Where appropriate, data were pooled using pair-wise meta analysis, multiple outcome measures, metaregression and mixedtreatment comparisons. The decision model was based broadly on the structure of the three state Markov model described in the previous technology assessment report, based upon time to institutionalisation, parameterised with updated estimates of effectiveness, costs and utilities. RESULTS: Notwithstanding the uncertainty of our results, we found in the base case that the AChEIs are probably cost saving at a willingness-to-pay (WTP) of L'30,000 per qualityadjusted life-year (QALY) for people with mild-to-moderate AD. For this class of drugs, there is a > 99% probability that the AChEIs are more cost-effective than BSC. These analyses assume that the AChEIs have no effect on survival. For the AChEIs, in people with mild to moderate AD, the probabilistic sensitivity analyses suggested that donepezil is the most cost-effective, with a 28% probability of being the most cost-effective option at a WTP of L'30,000 per QALY (27% at a WTP of L'20,000 per QALY). In the deterministic results, donepezil dominates the other drugs and BSC, which, along with rivastigmine patches, are associated with greater costs and fewer QALYs. Thus, although galantamine has a slightly cheaper total cost than donepezil (L'69,592 vs L'69,624), the slightly greater QALY gains from donepezil (1.616 vs 1.617) are enough for donepezil to dominate galantamine.The probability that memantine is cost-effective in a moderate to severe cohort compared with BSC at a WTP of L'30,000 per QALY is 38% (and 28% at a WTP of L'20,000 per QALY). The deterministic ICER for memantine is L'32,100 per/QALY and the probabilistic ICER is L'36,700 per/QALY. LIMITATIONS: Trials were of 6 months maximum follow-up, lacked reporting of key outcomes, provided no subgroup analyses and used insensitive measures. Searches were limited to English language, The model does not include behavioural symptoms and there is uncertainty about the model structure and parameters. CONCLUSIONS: The additional clinical effectiveness evidence identified continues to suggest clinical benefit from the AChEIs in alleviating AD symptoms, although there is debate about the magnitude of the effect. Although there is also new evidence on the effectiveness of memantine, it remains less supportive of this drug's use than the evidence for AChEIs. The conclusions concerning cost-effectiveness are quite different from the previous assessment. This is because both the changes in effectiveness and costs between drug use and non-drug use underlying the ICERs are very small. This leads to highly uncertain results, which are very sensitive to change. RESEARCH PRIORITIES: RCTs to include mortality, time to institutionalisation and quality of life, powered for subgroup analysis. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 22541367 TI - Metabolic syndrome markers in wistar rats of different ages. AB - In recent decades, metabolic syndrome has become a public health problem throughout the world. Longitudinal studies in humans have several limitations due to the invasive nature of certain analyses and the size and randomness of the study populations. Thus, animal models that are able to mimic human physiological responses could aid in investigating metabolic disease. Thus, the present study was designed to analyze metabolic syndrome markers in albino Wistar rats (Rattus norvegicus) of different ages. The following parameters were assessed at two (young), four ( adult), six (adult), and twelve (mature) months of age: glucose tolerance (glucose tolerance test); insulin sensitivity (insulin tolerance test); fasting serum glucose, triglycerides, total cholesterol, HDL cholestero, and LDL cholesterol concentrations; glucose uptake in isolated soleus muscle; and total lipid concentration in subcutaneous, mesenteric, and retroperitoneal adipose tissue. We found that aging triggered signs of metabolic syndrome in Wistar rats. For example, mature rats showed a significant increase in body weight that was associated. In addition, mature rats showed an increase in the serum concentration of triglycerides, total cholesterol, and LDL cholesterol, which is characteristic of dyslipidemia. There was also an increase in serum glucose compared with the younger groups of animals. Therefore, aging Wistar rats appear to be an interesting model to study the changes related to metabolic syndrome. PMID- 22541369 TI - Neurocognitive dimensions of lexical complexity in Polish. AB - Neuroimaging studies of English suggest that speech comprehension engages two interdependent systems: a bilateral fronto-temporal network responsible for general perceptual and cognitive processing, and a specialised left-lateralised network supporting specifically linguistic processing. Using fMRI we test this hypothesis in Polish, a Slavic language with rich and diverse morphology. We manipulated general perceptual complexity (presence or absence of an onset embedded stem, e.g. kotlet 'cutlet' vs. kot 'cat') and specifically linguistic complexity (presence of an inflectional affix, e.g. dom 'house, Nom' vs. dom-u 'house, Gen'). Non-linguistic complexity activated a bilateral network, as in English, but we found no differences between inflected and uninflected nouns. Instead, all types of words activated left inferior frontal areas, suggesting that all Polish words can be considered linguistically 'complex' in processing terms. The results support a dual network hypothesis, but highlight differences between languages like English and Polish, and underline the importance of cross linguistic comparisons. PMID- 22541368 TI - Influence of maternal and paternal IQ on offspring health and health behaviours: evidence for some trans-generational associations using the 1958 British birth cohort study. AB - PURPOSE: Individuals scoring poorly on tests of intelligence (IQ) have been reported as having increased risk of morbidity, premature mortality, and risk factors such as obesity, high blood pressure, poor diet, alcohol and cigarette consumption. Very little is known about the impact of parental IQ on the health and health behaviours of their offspring. METHODS: We explored associations of maternal and paternal IQ scores with offspring television viewing, injuries, hospitalisations, long standing illness, height and BMI at ages 4 to 18 using data from the National Child Development Study (1958 birth cohort). RESULTS: Data were available for 1446 mother-offspring and 822 father-offspring pairs. After adjusting for potential confounding/mediating factors, the children of higher IQ parents were less likely to watch TV (odds ratio (95% confidence interval) for watching 3+ vs. less than 3hours per week associated with a standard deviation increase in maternal or paternal IQ: 0.75 (0.64, 0.88) or 0.78 (0.64, 0.95) respectively) and less likely to have one or more injuries requiring hospitalisation (0.77 (0.66, 0.90) or 0.72 (0.56, 0.91) respectively for maternal or paternal IQ). CONCLUSIONS: Children whose parents have low IQ scores may have poorer selected health and health behaviours. Health education might usefully be targeted at these families. PMID- 22541370 TI - The spider acylpolyamine Mygalin is a potent modulator of innate immune responses. AB - Mygalin is an antibacterial molecule isolated from the hemocytes of the spider Acanthoscurria gomesiana. It was identified as bis-acylpolyamine spermidine. We evaluated the modulator effects of synthetic Mygalin in the innate immune response. We demonstrate that Mygalin induces IFN-gamma synthesis by splenocytes increasing the nitrite secretion by splenocytes and macrophages. A specific inhibitor of iNOS abrogated Mygalin-induced nitrite production in macrophages independent of IFN-gamma activation. In addition, Mygalin-activated macrophages produced TNF-alpha but not IL-1beta, demonstrating that Mygalin does not act directly on the inflammasome. Furthermore, this compound did not affect spontaneous or Concanavalin A-induced proliferative responses by murine splenocytes and did not induce IL-5 or apoptosis of splenocytes or bone marrow derived macrophages. These data provide evidence that Mygalin modulates the innate immune response by inducing IFN-gamma and NO synthesis. The combined immune regulatory and antibacterial qualities of Mygalin should be explored as a strategy to enhance immune responses in infection. PMID- 22541371 TI - What is on the horizon? Adding a new item to our list: mechanical connective soft tissue. PMID- 22541372 TI - Ask the authors. PMID- 22541373 TI - Predictors of clinical outcome in fibromyalgia after a brief interdisciplinary fibromyalgia treatment program: single center experience. AB - OBJECTIVE: To determine which patient characteristics are closely associated with a positive response to a brief interdisciplinary fibromyalgia treatment program (FTP). DESIGN: A prospective cohort study. SETTING: FTP at a tertiary medical center. PARTICIPANTS: A total of 536 patients with a confirmed diagnosis of fibromyalgia who underwent the FTP and completed the Fibromyalgia Impact Questionnaire (FIQ) at baseline and 6-12 months after treatment. INTERVENTIONS: A brief 1.5-day interdisciplinary FTP, which included evaluation with a registered nurse and a physician for a diagnosis or confirmation of fibromyalgia, fibromyalgia education, interactive self management session, and physical and occupational therapy. MAIN OUTCOME MEASUREMENTS: The responder definition was an improvement of 14% or more in the FIQ total score from their baseline to 6-12 months after treatment. RESULTS: Mean (standard deviation) age of our patients was 50.3 +/- 13.0 years; 515 women (96%) and 23 men (4%). Two hundred forty-eight patients (46%) met the responder definition at 6-12 months follow-up. In an univariate analysis, younger age (P = .008), college or higher education (P = .02), fewer tender points (P = .048), and higher FIQ depression subscore (P = .02) significantly predicted positive response. In a multivariate analysis, these factors all remained statistically significant. In addition, a positive abuse history became significant (P = .03). There was no significant association for gender, duration of symptoms, marital status, employment, smoking status, or 3 numeric rating scale pain scores. CONCLUSIONS: Patients with younger age, more years of education (with college or graduate degree), higher baseline FIQ depression score, lower tender point count, and absent abuse history experience greater benefit from a brief FTP. PMID- 22541374 TI - Diagnostic accuracy of bedside swallow evaluation versus videofluoroscopy to assess dysphagia in individuals with tetraplegia. AB - OBJECTIVE: To assess the accuracy of bedside swallow evaluation (BSE) compared with videofluorosopic swallow study (VFSS) in diagnosing dysphagia in individuals with tetraplegia due to spinal cord injury (SCI). DESIGN: A prospective diagnostic accuracy study according to STAndards for the Reporting of Diagnostic accuracy studies (STARD) criteria. SETTING: A county hospital with acute inpatient SCI unit. PATIENTS: Thirty-nine subjects with SCI and tetraplegia were enrolled. All of the subjects underwent BSE, and 26 subjects completed the VFSS. METHODS: Individuals with SCI underwent a BSE followed by a VFSS within 72 hours of the BSE. The subjects were diagnosed as having dysphagia if they had positive findings in either BSE or VFSS. MAIN OUTCOME MEASURES: Sensitivity, specificity, and positive and negative predictive values were calculated by using VFSS as the criterion standard. RESULTS: Fifteen subjects (38%) were diagnosed as having dysphagia based on the BSE results. Among the subjects who completed the VFSS, 11 were diagnosed with dysphagia (42%) and 4 were diagnosed with aspiration (10%). Of the 26 subjects who completed both BSE and VFSS, only 1 subject was diagnosed differently compared with BSE (3.8%). Different diet recommendations were made in 4 cases after VFSS versus BSE. Different liquid recommendations were made in 8 cases after VFSS versus BSE. Sensitivity of BSE was 100% (95% confidence interval [CI], 71.5%-100%), specificity was 93.3% (95% CI, 68.1%-99.8%). A positive predictive value of BSE was 91.7% (95% CI, 61.5%-100%), and the negative predictive value was 100% (95% CI, 76.8%-100%). CONCLUSIONS: Dysphagia is present in approximately 38% of individuals with acute tetraplegia. Because only one of the 21 subjects was diagnosed differently based on VFSS, we believe that BSE is an appropriate screening tool for dysphagia for individuals with cervical SCI. However, VFSS provided additional information on diet and liquid recommendations, so there appears to be an important clinical role for the VFSS. PMID- 22541376 TI - "Why can't I move, Doc?" Ethical dilemmas in treating conversion disorders. PMID- 22541375 TI - Recovery of functional status after stroke in a tri-ethnic population. AB - OBJECTIVE: To examine recovery of functional status for white, black, and Hispanic patients who have had a stroke from the time of admission to inpatient medical rehabilitation to 12 months after discharge. DESIGN: A longitudinal study that used information from the Stroke Recovery in Underserved Population database, a prospective observational study of persons with stroke who received inpatient medical rehabilitation services during 2005-2006. SETTING: Eleven inpatient rehabilitation facilities located across diverse regions of the United States, including California, Florida, Iowa, Illinois, Kentucky, New Jersey, New York (2), Texas (2), and Washington, DC. PARTICIPANTS: A total of 990 adults aged 55 years or older who had a stroke and were admitted to 1 of 11 inpatient medical rehabilitation facilities in the United States were interviewed at 4 time points, including admission to and discharge from an inpatient medical rehabilitation facility and 3 and 12 months after discharge. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Functional status as measured by the Functional Independence Measure (FIM). RESULTS: For the total sample, FIM ratings increased from admission to discharge and from discharge to 3-month follow-up, with little recovery occurring between 3 and 12 months. In random effects mixed models, at 3 month follow-up, both black and Hispanic patients had lower FIM ratings than did white patients. At 12-month follow-up, black and white patients were similar; however, Hispanic patients continued to have lower FIM ratings compare with white patients. Racial/ethnic group, age, length of stay, and medical comorbidities were significant predictors of total FIM ratings over the 4 time points. CONCLUSIONS: Persons 55 years and older who have had a stroke, regardless of race/ethnicity, appear to benefit from inpatient medical rehabilitation. Most functional status gains occur during inpatient medical rehabilitation and continue in the first few months after discharge, with little change afterward. PMID- 22541377 TI - The appropriateness of long-term opioids to treat chronic back pain. PMID- 22541378 TI - Salivagram after gland injection of botulinum neurotoxin A in patients with cerebral infarction and cerebral palsy. PMID- 22541379 TI - Ewing sarcoma causing back and leg pain in 2 patients. PMID- 22541380 TI - Can double blinding distort results in randomized controlled trials? PMID- 22541382 TI - Spatio-temporal variation of suspended and sedimentary organic matter quality in the Bay of Marseilles (NW Mediterranean) assessed by biochemical and isotopic analyses. AB - Isotopic and biochemical features of suspended particulate organic matter (POM) in the water column and of sedimentary organic matter (SOM) were investigated seasonally in the Bay of Marseilles. Biochemical compounds (carbohydrates, lipids and proteins) were consistently more concentrated in POM than in SOM, with SOM mainly composed of insoluble carbohydrates. POM displayed lower delta(13)C and higher delta(15)N values than SOM. Phytoplanktonic production represented the major contributor of POM year-round with spatial and seasonal variations. Climatic parameters and wind-induced currents created differences in POM contributions, with more important inputs of terrestrial OM at one sampling site. Spatial and seasonal variations were lower for SOM. The composition of this pool appeared to be linked with the permanent inputs of phytoplankton and Posidonia oceanica detritus. The combined use of biochemical and isotopic analyses was a useful tool to characterize OM pools and would help understanding the trophic functioning of this coastal environment. PMID- 22541388 TI - Complications of percutaneous endoscopic gastrostomy in children: results of an Italian multicenter observational study. AB - BACKGROUND: Percutaneous endoscopic gastrostomy is the preferred way to achieve an artificial feeding route for patients requiring long-term enteral nutrition. Although the procedure is well-standardized, it carries early and late complications. AIM: To establish the mortality and morbidity of this technique in a large cohort of children. METHODS: A multi-centre prospective clinical data collection from children undergoing percutaneous endoscopic gastrostomy tube implantation has been conducted from January 2004 to December 2007. Previous abdominal surgery was the only exclusion criterion. Follow-up visits were carried out at 1, 3, 6, 12, and 24 months after the procedure. RESULTS: 239 children (males, 55.2%; mean age 6.05+/-6.1years) were enrolled from nine tertiary Italian centres. Major complications occurred in 8 patients (3.3%). The cumulative incidence of complications was 47.7% at 24 months. The presence of thoraco abdominal deformity was an independent predictor of complications at 12 months. No risk factors were identified in association to complications during the 1st tube replacement. CONCLUSION: In children undergoing percutaneous endoscopic gastrostomy placement minor complications are common, while severe morbidities are rare. Accurate follow up is essential to recognize every complication, in particular when risk factors such as thoraco-abdominal deformity exist. PMID- 22541389 TI - Individualized estimation of the benefit of radical prostatectomy from the Scandinavian Prostate Cancer Group randomized trial. AB - BACKGROUND: Although there is randomized evidence that radical prostatectomy improves survival, there are few data on how benefit varies by baseline risk. OBJECTIVE: We aimed to create a statistical model to calculate the decrease in risk of death associated with surgery for an individual patient, using stage, grade, prostate-specific antigen, and age as predictors. DESIGN, SETTING, AND PARTICIPANTS: A total of 695 men with T1 or T2 prostate cancer participated in the Scandinavian Prostate Cancer Group 4 trial (SPCG-4). INTERVENTION: Patients in SPCG-4 were randomized to radical prostatectomy or conservative management. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Competing risk models were created separately for the radical prostatectomy and the watchful waiting group, with the difference between model predictions constituting the estimated benefit for an individual patient. RESULTS AND LIMITATIONS: Individualized predictions of surgery benefit varied widely depending on age and tumor characteristics. At 65 yr of age, the absolute 10-yr risk reduction in prostate cancer mortality attributable to radical prostatectomy ranged from 4.5% to 17.2% for low- versus high-risk patients. Little expected benefit was associated with surgery much beyond age 70. Only about a quarter of men had an individualized benefit within even 50% of the mean. A limitation is that estimates from SPCG-4 have to be applied cautiously to contemporary patients. CONCLUSIONS: Our model suggests that it is hard to justify surgery in patients with Gleason 6, T1 disease or in those patients much above 70 yr of age. Conversely, surgery seems unequivocally of benefit for patients who have Gleason 8, or Gleason 7, stage T2. For patients with Gleason 6 T2 and Gleason 7 T1, treatment is more of a judgment call, depending on patient preference and other clinical findings, such as the number of positive biopsy cores and comorbidities. PMID- 22541390 TI - Occurrence and characteristics of methicillin-resistant and -susceptible Staphylococcus aureus and methicillin-resistant coagulase-negative staphylococci from Japanese retail ready-to-eat raw fish. AB - Staphylococci are not part of the normal fish microflora. The presence of staphylococci on fish is an indication of (a) post-harvest contamination due to poor personnel hygiene, or (b) disease in fish. The aim of this study was to determine the prevalence, molecular genetic characteristics, antibiotic resistance and virulence factors of methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA) and methicillin-resistant coagulase-negative staphylococci (MR-CoNS) isolated from 200 samples of retail ready-to-eat raw fish (sashimi) collected from the Japanese prefecture of Hiroshima. We characterized 180 staphylococcal strains. A majority of the grocery stores surveyed (92%, 23/25) contained fish contaminated with Staphylococcus species. We recovered 175 S. aureus isolates from 174 (87%, 174/200) samples, with 170 isolates of MSSA. For the MRSA and MR-CoNS, 10 isolates were obtained from 10 samples (5%, 10/200) collected from 10 shops (40%, 10/25) belonging to four supermarket chains. SCCmec typing revealed the presence of a type IV.1 SCCmec cassette in S. warneri isolates, a type II.1 SCCmec cassette in S. haemolyticus isolates and a cassette in methicillin-resistant S. aureus (MRSA) isolates that could not be typed. Molecular typing of two MRSA isolates by spa sequencing and multilocus sequence typing (MLST) identified t1767 and ST8, respectively. Antibiotic resistance genes that confer resistance to aminoglycosides, tetracyclines, beta-lactams, macrolides, lincosamides and streptogramin B (MLS(B)) antibiotics were detected. Genes encoding one or more of the following virulence factors: staphylococcal enterotoxins (seb, and sed), toxic shock syndrome toxin 1 (tst), exfoliative toxin (etaA) were detected in 14.2% (25/175) of S. aureus isolates. The accessory gene regulator (agr) typing of S. aureus isolates revealed that agr type 1 was most prevalent (96.5%, 169/175) followed by type 2 (2.2%, 4/175) and type 3 (1.1%, 2/175). None of the S. aureus isolates carried the Panton-Valentine leucocidin (PVL) encoding genes, lukF-PV and lukS-PV. To the best of our knowledge, this is the first report to show MRSA and MR-CoNS isolated from retail ready-to-eat food in Japan. Our results showed that sashimi is a likely vehicle for transmission of multidrug resistant and toxigenic staphylococci. PMID- 22541391 TI - In vitro inhibition of expression of virulence genes responsible for colonization and systemic spread of enteric pathogens using Bifidobacterium bifidum secreted molecules. AB - Enteric pathogens such as Salmonella enterica serovar Typhimurium and Enterohaemorrhagic Escherichia coli require an initial indispensable step of attachment or invasion of enterocytes before they can produce systemic disease and translocate to their target organs. Prevention of either of these steps will result in an avirulent state and limit their pathogenicity. In vitro tests demonstrated that molecules secreted by Bifidobacterium bifidum interfere with both attachment and invasion. The main regulatory genes controlling the virulence factors essential for these pathogenicity steps were efficiently down-regulated when treated with chromatographically separated B. bifidum cell free fractions as measured by reporter constructs and confirmed by RT-PCR. Moreover, the ability of both pathogens to colonize eukaryotic cells was significantly reduced, and the capacity of Salmonella to survive and multiply within macrophages was also diminished upon treatment with these bioactive molecules. These results indicate that probiotic Bifidobacteria strains may represent an effective alternative approach to control food-borne enteric pathogens. PMID- 22541392 TI - Disease burden of foodborne pathogens in the Netherlands, 2009. AB - To inform risk management decisions on control, prevention and surveillance of foodborne disease, the disease burden of foodborne pathogens is estimated using Disability Adjusted Life Years as a summary metric of public health. Fourteen pathogens that can be transmitted by food are included in the study (four infectious bacteria, three toxin-producing bacteria, four viruses and three protozoa). Data represent the burden in the Netherlands in 2009. The incidence of community-acquired non-consulting cases, patients consulting their general practitioner, those admitted to hospital, as well as the incidence of sequelae and fatal cases is estimated using surveillance data, cohort studies and published data. Disease burden includes estimates of duration and disability weights for non-fatal cases and loss of statistical life expectancy for fatal cases. Results at pathogen level are combined with data from an expert survey to assess the fraction of cases attributable to food, and the main food groups contributing to transmission. Among 1.8 million cases of disease (approx. 10,600 per 100,000) and 233 deaths (1.4 per 100,000) by these fourteen pathogens, approximately one-third (680,000 cases; 4100 per 100,000) and 78 deaths (0.5 per 100,000) are attributable to foodborne transmission. The total burden is 13,500 DALY (82 DALY per 100,000). On a population level, Toxoplasma gondii, thermophilic Campylobacter spp., rotaviruses, noroviruses and Salmonella spp. cause the highest disease burden. The burden per case is highest for perinatal listeriosis and congenital toxoplasmosis. Approximately 45% of the total burden is attributed to food. T. gondii and Campylobacter spp. appear to be key targets for additional intervention efforts, with a focus on food and environmental pathways. The ranking of foodborne pathogens based on burden is very different compared to when only incidence is considered. The burden of acute disease is a relatively small part of the total burden. In the Netherlands, the burden of foodborne pathogens is similar to the burden of upper respiratory and urinary tract infections. PMID- 22541393 TI - A variant peptide of buffalo colostrum beta-lactoglobulin inhibits angiotensin I converting enzyme activity. AB - beta-lactoglobulin is a rich source of bioactive peptides. The LC-MS separated tryptic peptides of buffalo colostrum beta-lactoglobulin (BLG-col) were computed based on MS-MS fragmentation for de novo sequencing. Among the selected peptides (P1-P8), a variant was detected with methionine at position 74 instead of glutamate. The sequences of two peptides were identical to hypocholesterolemic peptides whereas the remaining peptides were in accordance with buffalo milk beta lactoglobulin. Comparative sequence analysis of BLG-col to milk beta lactoglobulin was carried out using CLUSTALW2 and a molecular model for BLG-col was constructed (PMDB ID-PM0076812). The synthesized variant pentapeptide (IIAMK, m/z-576 Da) was found to inhibit angiotensin I-converting enzyme (ACE) with an IC(50) of 498 +/- 2 MUM, which was rationalized through docking simulations using Molgrow virtual docker. PMID- 22541394 TI - Appraisal of GABA and PABA as linker: design and synthesis of novel benzamide based histone deacetylase inhibitors. AB - Histone deacetylase inhibitors have been actively explored as a new generation of chemotherapeutics for cancers, generally known as epigenetic therapeutics. Two novel series of N-(2-amino-phenyl)-4-{[(2/3/4-substituted-phenylcarbamoyl) methyl]-amino}-butyramide and N-(2-amino-phenyl)-4-{[(2/3/4-substituted phenylcarbamoyl)-methyl]-amino}benzamide were designed and synthesized as novel histone deacetylase inhibitors. The anticancer potential of the compounds were determined in-vitro using MTT assay against HCT-116 and U251 (glioma) cell lines and histone deacetylase inhibitory assay. The synthesized compounds were investigated for anti-tumor activity against Ehrlich ascites carcinoma (EAC) cells in Swiss albino mice. The efforts were also made to ascertain structure activity relationships among test compounds. The results of the present studying represents appraisal of gamma-aminobutyric acid (GABA) and para-aminobenzoic acid (PABA) as linker moiety for development of newer benzamide based histone deacetylase inhibitor. PMID- 22541395 TI - Food allergy: diagnosis and beyond. PMID- 22541396 TI - Vascular ring presenting as asthma in an 8-year-old. PMID- 22541397 TI - Impact of climate change on aeroallergens. PMID- 22541398 TI - Exhaled breath condensate MMP-9 level and its relationship with asthma severity and interleukin-4/10 levels in children. AB - BACKGROUND: Matrix metalloproteases (MMPs) are key mediators in airway remodeling, and MMP- 9 is the main type investigated to discover its implication for the pathogenesis and severity of asthma. OBJECTIVE: To evaluate MMP-9 and its natural tissue inhibitors of metalloproteinases (TIMP-1) levels of exhaled breath condensate (EBC) in children with asthma. We also analyzed any potential relationship between these enzymes and EBC interleukin (IL)-4/10 levels as well as asthma severity. METHODS: Three study groups were formed: group 1, children with persistent asthma (n = 20); group 2, children with intermittent asthma (n = 10), and group 3, healthy controls (n = 12). Pulmonary functions were measured as forced expiratory volume in 1 second (FEV(1)), peak expiratory flow (PEF), and forced expiratory flow from 25% to 75% of vital capacity values by spirometry, and MMP-9, TIMP-1 and IL-4/10 levels in EBC were analyzed by enzyme-linked immunosorbent assay (ELISA). RESULTS: The MMP-9 levels of EBC were found to be 57.7 +/- 17.5, 35.4 +/- 11.7, and 30.6 +/- 3.7 ng/mL in children belonging to group 1, group 2 and group 3, respectively. Children belonging to group 1 and group 2 showed significantly higher MMP-9 levels of EBC in comparison with the controls (P < .001 and P = .047, respectively). No statistically significant difference was found between groups regarding TIMP-1 levels of EBC. EBC MMP-9 levels were inversely correlated with both FEV(1) and PEF values (r = -0.472, P = .011, and r = -0.571, P = .002, respectively) in children with asthma. Positive correlations were also seen between MMP-9 levels and IL-4/10 levels of EBC (r = 0.419, P = .027 and r = 0.405, P = .032, respectively) in children with asthma. CONCLUSION: We showed that MMP-9 levels of EBC are elevated in children with asthma and correlated with lung functions and other inflammatory markers such as IL-4/IL10 in EBC. PMID- 22541399 TI - Asthma in the elderly: risk factors and impact on physical function. AB - BACKGROUND: The incidence rate of asthma has increased in all age groups in the past 40 years. Asthma in older adults is underdiagnosed and undertreated, resulting in suboptimal asthma control. OBJECTIVE: The objectives of the study are to evaluate differences in host characteristics between older patients with asthma and persons who do not have asthma and how these differences impact overall quality of life. METHODS: Patients older than age 60 years were recruited from the general population for this case/control and nested cohort study. A complete medical history, physical examination, skin prick testing (SPT), spirometry, and exhaled nitric oxide (ENO) measurements were performed. Quality of life was assessed through the standardized SF-36v2 questionnaire. Quality of life scores, spirometry, ENO, and aeroallergen sensitization differences were compared between older patients with asthma and control patients. RESULTS: The mean age of the 77 patients evaluated was 68.7 +/- 7.2 years, with 59 (77%) being female. A higher rate of SPT positivity was found in patients with asthma (88.9%) compared with controls (51.2%) (P = .007). The mean percent predicted forced expiratory volume in 1 second (FEV1) at baseline was lower in the asthma group (73.7 +/- 21.9%) compared with controls (89.6 +/- 19.1%) (P = .007). For quality of life assessed by the SF-36v2 questionnaire, the asthma group had worse general health, increased bodily pain, and worse overall physical health compared with controls (P = .02; .021; .01). CONCLUSION: Older adults with asthma have a higher rate of allergic sensitization, decreased lung function, and significantly worse quality of life compared with controls. PMID- 22541400 TI - Using latent class growth analysis to identify childhood wheeze phenotypes in an urban birth cohort. AB - BACKGROUND: To advance asthma cohort research, we need a method that can use longitudinal data, including when collected at irregular intervals, to model multiple phenotypes of wheeze and identify both time-invariant (eg, sex) and time varying (eg, environmental exposure) risk factors. OBJECTIVE: To demonstrate the use of latent class growth analysis (LCGA) in defining phenotypes of wheeze and examining the effects of causative factors, using repeated questionnaires in an urban birth cohort study. METHODS: We gathered repeat questionnaire data on wheeze from 689 children ages 3 through 108 months (n = 7,048 questionnaires) and used LCGA to identify wheeze phenotypes and model the effects of time-invariant (maternal asthma, ethnicity, prenatal environmental tobacco smoke, and child sex) and time-varying (cold/influenza [flu] season) risk factors on prevalence of wheeze in each phenotype. RESULTS: LCGA identified four wheezing phenotypes: never/infrequent (47.1%), early-transient (37.5%), early-persistent (7.6%), and late-onset (7.8%). Compared with children in the never/infrequent phenotype, maternal asthma was a risk factor for the other 3 phenotypes; Dominican versus African American ethnicity was a risk factor for the early-transient phenotype; and male sex was a risk factor for the early-persistent phenotype. The prevalence of wheeze was higher during the cold/flu season than otherwise among children in the early-persistent phenotype (P = .08). CONCLUSION: This is the first application of LCGA to identify wheeze phenotypes in asthma research. Unlike other methods, this modeling technique can accommodate questionnaire data collected at irregularly spaced age intervals and can simultaneously identify multiple trajectories of health outcomes and associations with time-invariant and time-varying causative factors. PMID- 22541401 TI - Respiratory syncytial virus infection increases regulated on activation normal T cell expressed and secreted and monocyte chemotactic protein 1 levels in serum of patients with asthma and in human monocyte cultures. AB - BACKGROUND: Respiratory syncytial virus (RSV) infection is associated to episodic exacerbations of asthma involving alveolar macrophages and chemokine production. OBJECTIVE: The aim of this study was to determine the circulating levels of monocyte chemotactic protein 1 (MCP-1), regulated on activation normal T cell expressed and secreted (RANTES), and substance P (SP) in patients with and without asthma with acute respiratory RSV infection and the chemokine profile in RSV- infected monocyte cultures from normal individuals and individuals with asthma. METHODS: In this regard, 31 adult patients with acute respiratory infection (15 patients with asthma) were studied. MCP-1, RANTES and SP were measured in serum and in supernatants from monocyte cultures by enzyme-linked immunosorbent assay (ELISA). RESULTS: Increased levels of MCP-1 and RANTES were observed in serum from patients with asthma related to RSV infection. RSV infected monocyte cultures from healthy individuals showed increased content of those chemokines, and monocyte cultures from patients with asthma showed increased expression of MCP-1. CONCLUSION: These data show that RSV infection induces increased circulating level of chemokines in patients with asthma, and this finding could be mediated in part by the interaction virus-monocyte. PMID- 22541402 TI - Timing the transfer of responsibilities for anaphylaxis recognition and use of an epinephrine auto-injector from adults to children and teenagers: pediatric allergists' perspective. AB - BACKGROUND: The optimal time for transferring responsibilities for anaphylaxis recognition and epinephrine auto-injector use from adults to children and teenagers has not yet been defined. OBJECTIVE: To determine whether pediatric allergists have age-specific goals for beginning to transfer responsibilities for anaphylaxis recognition and epinephrine auto-injector use from parents and caregivers to children and teenagers at risk of anaphylaxis in the community. METHODS: Members of the American Academy of Pediatrics Section on Allergy and Immunology (AAP-SOAI) were surveyed about when they typically begin to transfer these responsibilities from adults to children and teenagers. RESULTS: Eighty eight allergists responded to the survey, 97.7% of whom provided service to children and teenagers with food allergies. Few allergists expected to begin transferring responsibilities for anaphylaxis recognition and epinephrine auto injector use to children younger than 9 to 11 years. By the time their patients reached age 12 to 14 years, however, most allergists expected them to be able to describe some anaphylaxis symptoms (95.4%), demonstrate how to use an epinephrine auto-injector trainer (93.1%), begin carrying self-injectable epinephrine (88.2%), recognize the need for epinephrine (88.1%), learn to self-inject epinephrine (84.5%), and be able to self-inject epinephrine (78.6%) (cumulative data). The allergists rated the following as "very important" readiness factors for beginning to transfer responsibilities: medical history, developmental level, and ability to demonstrate auto-injector technique. CONCLUSION: Most pediatric allergists expected that by age 12 to 14 years, their patients should begin to share responsibilities with adults for anaphylaxis recognition and epinephrine auto-injector use; however, they individualized the timing based on assessment of patient readiness factors. PMID- 22541403 TI - The natural history of persistent peanut allergy. AB - BACKGROUND: Peanut allergy affects 1% of children, and for those with persistent disease, few data have been published on trends in peanut-specific immunoglobulin E (P-IgE) levels or the value of P-IgE in predicting reaction severity. OBJECTIVE: The primary outcome was the frequency of inadvertent peanut exposure. Secondary outcomes included clinical characteristics, trends in P-IgE, characteristics of accidental exposures, and predictors of reaction severity in patients with persistent peanut allergy. METHODS: Records of patients with persistent peanut allergy were reviewed. Other allergic conditions, P-IgE levels, and peanut exposures were documented. RESULTS: Seven hundred eighty-two patients were studied, 524 of them male. The median age at initial observation was 1.4 years; the median duration of follow-up was 5.3 years. Of the 782 patients, 93.1% were avoiding other foods, 70.8% had atopic dermatitis, 57.3% allergic rhinitis, and 55.8% asthma. The median initial P-IgE was 28.0 kU/L, and the median peak P IgE was 68.1. Six hundred eighty-five exposures were seen among 455 patients: 75.9% ingestion, 13.6% contact, 4.5% airborne. 73.7% resulted in urticaria/angioedema, 22.2% lower respiratory symptoms, 21.2% gastrointestinal symptoms, and 7.7% oral erythema/pruritus. Treatment included antihistamines (33.4%), emergency department visits (16.5%), epinephrine (13.1%), corticosteroids (7.7%), albuterol (3.2%), no treatment (26.3%), and not recorded (29.6%). The rate of postdiagnosis ingestion was 4.7%/year; exposures with severe reactions, 1.6%/year; reactions treated with epinephrine, 1.1%/year. Reaction severity did not change with repeated exposure. Severe reactions were associated with higher P-IgE, but not with age, sex, or asthma. CONCLUSION: In this referral population, the rates of accidental peanut exposures and severe reactions were low. There was a strong association between higher P-IgE levels and reaction severity. PMID- 22541404 TI - Clinical thresholds to egg, hazelnut, milk and peanut: results from a single center study using standardized challenges. AB - BACKGROUND: Large studies of individual thresholds and risk profiles for foods are sparse. Previous reports indicate that thresholds adjusted for the protein content in foods would be comparable. OBJECTIVE: To establish and compare clinical threshold values for egg, hazelnut, milk and peanut, and correlating them to severity of symptoms. METHODS: Seven hundred eighty-one challenges were performed in 487 patients (age range, 0.5-73.5 years). Using interval censoring survival analysis, the dose distribution of thresholds was fitted to a log-normal function. Symptom score was correlated to thresholds. RESULTS: Based on the 405 challenges resulting in objective signs, similar distribution of thresholds for hazelnut, milk, and peanut challenges were found, whereas individuals with egg allergy were bimodally distributed with a high or a low threshold. Eliciting dose in 10% (95% confidence interval) was 42.9 (24-76.8) mg whole eggs, 133.8 (95.9 186.6) mg whole hazelnut, 106.5 (59.7-190.6) mg roasted peanut, and 2.9 (1.5-5.4) mL milk. Adults showed more severe symptoms and signs than children, and peanut caused more severe reactions than the 3 other foods. CONCLUSION: Thresholds for the different foods were not comparable, and eliciting dose for the 4 foods differed, even if adjusted for protein content. Increasing age but not a low threshold dose is associated with severe symptoms on challenge. Peanuts elicit more severe reactions than the other foods. PMID- 22541405 TI - The role of autoimmune testing in chronic idiopathic urticaria. AB - BACKGROUND: The clinical implications of autoimmune testing in chronic idiopathic urticaria (CIU) are not well established. OBJECTIVE: To identify the association of autoimmune biomarkers in CIU with disease severity. METHODS: We retrospectively evaluated 195 patients with a diagnosis of CIU for the presence of antinuclear antibody (ANA), anti-thyroglobulin antibody (ATG), anti thyroperoxidase antibody (ATPO), and Chronic Urticaria (CU) Index. The patients were categorized into controlled and refractory subgroups based on their response to antihistamines with or without a leukotriene receptor antagonist. RESULTS: The percentage of patients with a positive test for ANA (titer>1:160), ATG, ATPO, and CU Index were 29%, 6%, 26%, and 38%, respectively. Among those tested, the percentage of patients categorized as refractory was significantly higher in those with a positive CU index (80% vs 46%; P = .01) or a positive ANA titer (50% vs 30%; P = .04) than those with negative test results; however, a similar relationship was not observed for ATPO or ATG antibodies. Odds ratios of individual or combinations of autoimmune biomarkers in CIU were examined for associations with refractoriness to antihistamines with or without a leukotriene receptor antagonist. The CU Index alone has an odds ratio of 4.5 (P = .005), whereas the combination of ANA, ATG, and ATPO has an odds ratio of 3.1 (P = .01) and ANA alone has an odds ratio of 2.3 (P = .04) for correlating with a refractory outcome. CONCLUSION: Our data indicate the CU Index independently has the strongest correlation with disease severity followed by the combination of ANA, ATG, and ATPO and the ANA alone. PMID- 22541406 TI - Contribution of interleukin 17A to the development and regulation of allergic inflammation in a murine allergic rhinitis model. AB - BACKGROUND: Interleukin (IL) 17A, a key cytokine of T(H)17 cells, is a well-known proinflammatory cytokine. Despite the important role of T(H)17 cells in acute airway inflammation, the role of IL-17A in allergic rhinitis (AR) remains unclear. OBJECTIVE: To investigate the role of IL-17A in the allergic response in AR. METHODS: Wild-type BALB/c and IL-17A-deficient mice were immunized intraperitoneally and were challenged intranasally with ovalbumin. Allergic symptom scores, eosinophil infiltration, serum IgE level, and the levels of several cytokines in nasal lavage fluid and splenocyte supernatants were analyzed. RESULTS: IL-17A levels increased significantly more in ovalbumin sensitized wild-type mice than in the negative control group. IL-17A-deficient mice showed a significant decrease in allergic symptoms, serum IgE levels, and eosinophil infiltration into the nasal mucosa compared with wild-type mice. IL 17A-deficient mice also showed decreased histamine and cysteinyl leukotriene release. Bone marrow-derived mast cells from IL-17A-deficient mice showed significantly lower degranulation and secretion of tumor necrosis factor alpha. Moreover, IL-17A deficiency attenuated the IL-5 level in nasal lavage fluid and its production in response to ovalbumin but did not increase interferon gamma production and its level in nasal lavage fluid. In addition, secretion of IL-17A from spleen cells induced the expression of proinflammatory cytokine messenger RNA in macrophages. The mean level of proinflammatory cytokines, including tumor necrosis factor alpha and IL-17, decreased in IL-17A-deficient mice. CONCLUSION: These results suggest that IL-17A may partly contribute to the development of nasal allergic inflammation in an AR animal model and regulate AR via the activation of proinflammatory cytokines and modulation of T(H)2 cytokine. PMID- 22541407 TI - Efficacy and immunological actions of FAHF-2 in a murine model of multiple food allergies. AB - BACKGROUND: Food Allergy Herbal Formula-2 (FAHF-2) prevents anaphylaxis in a murine model of peanut allergy. Multiple food allergies (MFA) are common and associated with a higher risk of anaphylaxis. No well-characterized murine model of sensitization to multiple food allergens exists, and no satisfactory therapy for MFA is currently available. OBJECTIVE: To determine the effect of FAHF-2 in a murine model of MFA. METHODS: C3H/HeJ mice were orally sensitized to peanut, codfish, and egg concurrently. Oral FAHF-2 treatment commenced 1 day after completing sensitization and continued daily for 7 weeks. Mice were subsequently orally challenged with each allergen. RESULTS: Antibodies in sera from mice simultaneously sensitized with peanut, codfish, and egg recognized major allergens of all 3 foods, demonstrating sensitization to multiple unrelated food allergens (MFA mice). Sham-treated MFA mice exhibited anaphylactic symptoms accompanied by elevation of plasma histamine and hypothermia. In contrast, FAHF-2 treated MFA mice showed no anaphylactic symptoms, normal body temperature, and histamine levels after challenge with each allergen. Protection was accompanied by reduction in allergen-specific immunoglobulin E levels. Allergen-stimulated Th2 cytokine interleukin-4 and interleukin-13 production levels decreased, whereas the Th1 cytokine interferon-gamma levels were elevated in cultured splenocytes and mesenteric lymph node cells in FAHF-2-treated mice. CONCLUSION: We established the first murine model of MFA. FAHF-2 prevents peanut, egg, and fish-induced anaphylactic reactions in this model, suggesting that FAHF-2 may have potential for treating human MFA. PMID- 22541408 TI - Effects of intranasal mometasone furoate on itchy ear and palate in patients with seasonal allergic rhinitis. AB - BACKGROUND: Intranasal steroids relieve nasal symptoms and ocular itch in allergic rhinitis. Itchy ear and palate are also common and bothersome symptoms but have received little attention in clinical trials of allergic rhinitis. OBJECTIVE: To ascertain the efficacy of mometasone furoate nasal spray in alleviating itchy ear and palate in seasonal allergic rhinitis. METHODS: Data were pooled from 4 randomized, double-blind, placebo-controlled trials of mometasone furoate nasal spray, 200 MUg/d. Participants rated ear and palate itching from baseline through treatment day 15 as follows: 0, none; 1, mild; 2, moderate; and 3, severe. RESULTS: A total of 962 study participants received mometasone furoate nasal spray or placebo. Baseline least squares mean itchy ear and palate score was 1.81 for participants receiving mometasone furoate nasal spray (n = 480) and 1.85 for participants receiving placebo (n = 482). Mometasone furoate nasal spray was associated with a greater decrease in itchy and ear palate score vs placebo during the 15-day study period (least squares mean change, -0.73 vs -0.45; P < .001). The difference reached significance on day 2 and persisted through day 15 (P <= .01 for each day). Results were similar in a subgroup of patients (n = 305) with moderate-to-severe symptoms at baseline. Adverse events with mometasone furoate nasal spray were similar to those observed in other studies of intranasal steroid therapy. CONCLUSION: These preliminary findings suggest that mometasone furoate nasal spray effectively treats itchy ear and palate in individuals with seasonal allergic rhinitis. Itchy ear and palate is a relevant end point for future clinical trials of allergic rhinitis. PMID- 22541409 TI - Conservative long-term treatment of children with eosinophilic esophagitis. AB - BACKGROUND: Current treatments of eosinophilic esophagitis (EoE), including restrictive diets or glucocorticoids, provide only transient improvement. Proton pump inhibitor (PPI) use in EoE does not lead to histologic improvement; however, the long-term use of PPI on symptoms and prevention of complications has not been evaluated. OBJECTIVE: To evaluate the use of PPI as maintenance therapy in children with EoE. METHODS: Eosinophilic esophagitis was diagnosed based on initial endoscopic biopsies and persistent eosinophilic inflammation despite PPI therapy. Inclusion criteria included diagnosis of EoE and PPI use as primary maintenance treatment. Patients were excluded if they were treated with dietary or glucocorticoid therapy. Histologic evidence of inflammation as well as degree of subepithelial fibrosis at presentation was compared with most recent biopsies while receiving PPI therapy. RESULTS: Thirty-eight patients (30 males and 8 females; average age 6.7 +/- 5.4 years) fulfilled inclusion criteria. Duration of follow-up was 3.0 +/- 2.4 years. At presentation, vomiting was significantly more frequent in the younger patients, whereas dysphagia occurred more frequently in the older patients. At follow-up, 26 patients were asymptomatic, and the remaining 12 patients' symptoms were significantly improved. No complications of stricture or food impaction were seen. Significant eosinophilic inflammation persisted in 28 patients. No difference in degree of subepithelial fibrosis at diagnosis compared with most recent biopsies. The z-scores of the treated EoE patients significantly improved. CONCLUSION: Patients with EoE treated with PPIs show an improvement in symptoms and z-scores despite persistent eosinophilic inflammation. PPI treatment may be useful maintenance therapy in children with EoE. PMID- 22541410 TI - Component-resolved immunologic modifications, efficacy, and tolerance of latex sublingual immunotherapy in children. AB - BACKGROUND: As the frequency of natural rubber latex (NRL) allergy has increased, attempts have been made to diminish exposure in high-risk patients. Despite some good results, complete NRL avoidance was not possible, so latex immunotherapy was developed. OBJECTIVE: To examine variations in immunologic parameters, clinical efficacy, and safety of NRL sublingual immunotherapy (SLIT). METHODS: This prospective, observational, open, case-control study included 23 patients (18 patients receiving NRL SLIT and 5 controls). Skin prick, conjunctival provocation, and in-use tests with NRL, specific IgE and specific IgG4 to NRL, specific IgE to recombinant NRL allergens, and basophil activation test (BAT) with whole latex, natural, and recombinant allergens were performed before immunotherapy (T0) and at 6 (T1) and 12 months (T2) of treatment. RESULTS: Patients were sensitized to Hev b 5, Hev b 6.01, and Hev b 6.02 proteins, optimal for SLIT. Changes in specific IgE were not significant. Increases in specific IgG4 between T1 and T2 were larger in the active group. BAT determinations showed significant decreases in recombinant Hev b 6.01 and natural Hev b 6.02 in the active group at T1 but not at T2. Both groups had new sensitizations at T1 but not at T2. The active group had significant increases in the response threshold in the in vivo tests at T1 and T2. Adverse effects were limited to local reactions. CONCLUSION: NRL SLIT is effective and safe in children with latex allergy. Our results suggest that specific IgE determinations and BAT measurements to natural and recombinant latex allergens may allow obtaining an allergen-based diagnosis to help determine specific immunotherapy. PMID- 22541411 TI - Survey on immunotherapy practice patterns: dose, dose adjustments, and duration. AB - BACKGROUND: Practical issues dealing with the administration of allergen immunotherapy (AIT) by European and US allergists are not well known. Several concerns are only partially covered by guidelines. OBJECTIVE: To survey AIT practice patterns among worldwide members of the American Academy of Allergy, Asthma and Immunology (AAAAI). METHODS: A web-based survey was conducted among AAAAI members on dosing, dose adjustment after missed doses, and duration of AIT. RESULTS: A total of 1,201 replies (24.7% response rate of which 10% of responses were from non-US and non-Canada members). A total of 57% to 65% of the US Canadian dosing falls within the recommended Practice Parameter ranges (9.4%-19% too low). Dose adjustment after missed doses is based on time elapsed since the last administered dose by 77% of US-Canadian and 58% of non-US-Canadian allergists. Doses are reduced when a patient comes in more than 14 days for 5 weeks after the last administration and initial dosing restarted after more than 30 days for 12 weeks since last administration during the build-up or maintenance stage. After missing 1 to 3 doses, the dosing schedules were mostly followed (build-up phase: repeat last dose, reduce by 1 dose, reduce by 2doses; maintenance phase: reduce by 1 dose, reduce by 2 doses, reduce by 3 doses). AIT is prescribed for a median of 3 years by non-US-Canadian allergists but for a median of 5 years by 75% of US-Canadian allergists. Main reasons for continuing beyond 5 years were "after stopping, symptoms reappeared" or "patient afraid to relapse." CONCLUSION: Many patients receive less than recommended doses. Two areas in which to plan further research are establishment of an optimal dose adjustment plan for missed applications and exploration of the maximum appropriate duration of immunotherapy. PMID- 22541413 TI - Acute coronary thrombosis after anaphylactic shock treatment. PMID- 22541412 TI - Impaired cough-related quality of life in patients with controlled asthma with gastroesophageal reflux disease. PMID- 22541414 TI - A protocol to aid in the diagnosis of occupational asthma to Alaska pollock and Yellowfin sole. PMID- 22541415 TI - Tolerance to cobalt after immunotherapy for cobalt hypersensitivity. PMID- 22541416 TI - Prevention of anaphylaxis related to mast cell activation syndrome with omalizumab. PMID- 22541417 TI - Allergen of the month--ginkgo. PMID- 22541419 TI - Protecting infants of HIV-positive mothers in Malawi. PMID- 22541420 TI - Meta-analysis of accuracy of left ventricular mass measurement by three dimensional echocardiography. AB - Left ventricular (LV) hypertrophy is a fundamental prognostic factor in a variety of cardiac diseases. Three-dimensional echocardiography (3DE) has achieved better estimation of LV mass than 2-dimensional echocardiography. However, significant underestimation has often been reported, and no previous study has synthesized these data. The aim of this meta-analysis was to investigate if there has been improvement in the accuracy in LV mass measurement by 3DE over time. Studies comparing LV mass between 3DE and magnetic resonance imaging were eligible. A cumulative meta-analysis was performed to investigate improvement in accuracy, followed by subgroup and meta-regression analysis to reveal factors affecting the bias. A total of 25 studies including 671 comparisons were analyzed. Studies published in or before 2004 showed high heterogeneity (I(2) = 69%) and significant underestimation of LV mass by 3DE (-5.7 g, 95% confidence interval 11.3 to -0.2, p = 0.04). Studies published from 2005 to 2007 were still heterogenous (I(2) = 60%) but showed less systematic bias (-0.5 g, 95% confidence interval -2.5 to 1.5, p = 0.63). In contrast, studies published in or after 2008 were highly homogenous (I(2) = 3%) and showed excellent accuracy (-0.1 g, 95% confidence interval -2.2 to 1.9, p = 0.90). Investigation of factors affecting the bias revealed that evaluation of cardiac patients compared to healthy volunteers led to larger bias (p <0.05). In conclusion, this meta-analysis elucidates the underestimation of LV mass by 3DE, its improvement over the past decade, and factors affecting the bias. These data provide a more detailed basis for improving the accuracy of 3DE, an indispensable step toward further clinical application. PMID- 22541418 TI - Maternal and infant antiretroviral regimens to prevent postnatal HIV-1 transmission: 48-week follow-up of the BAN randomised controlled trial. AB - BACKGROUND: In resource-limited settings where no safe alternative to breastfeeding exists, WHO recommends that antiretroviral prophylaxis be given to either HIV-infected mothers or infants throughout breastfeeding. We assessed the effect of 28 weeks of maternal or infant antiretroviral prophylaxis on postnatal HIV infection at 48 weeks. METHODS: The Breastfeeding, Antiretrovirals, and Nutrition (BAN) Study was undertaken in Lilongwe, Malawi, between April 21, 2004, and Jan 28, 2010. 2369 HIV-infected breastfeeding mothers with a CD4 count of 250 cells per MUL or more and their newborn babies were randomly assigned with a variable-block design to one of three, 28-week regimens: maternal triple antiretroviral (n=849); daily infant nevirapine (n=852); or control (n=668). Patients and local clinical staff were not masked to treatment allocation, but other study investigators were. All mothers and infants received one dose of nevirapine (mother 200 mg; infant 2 mg/kg) and 7 days of zidovudine (mother 300 mg; infants 2 mg/kg) and lamivudine (mothers 150 mg; infants 4 mg/kg) twice a day. Mothers were advised to wean between 24 weeks and 28 weeks after birth. The primary endpoint was HIV infection by 48 weeks in infants who were not infected at 2 weeks and in all infants randomly assigned with censoring at loss to follow up. This trial is registered with ClinicalTrials.gov, number NCT00164736. FINDINGS: 676 mother-infant pairs completed follow-up to 48 weeks or reached an endpoint in the maternal-antiretroviral group, 680 in the infant-nevirapine group, and 542 in the control group. By 32 weeks post partum, 96% of women in the intervention groups and 88% of those in the control group reported no breastfeeding since their 28-week visit. 30 infants in the maternal antiretroviral group, 25 in the infant-nevirapine group, and 38 in the control group became HIV infected between 2 weeks and 48 weeks of life; 28 (30%) infections occurred after 28 weeks (nine in maternal-antiretroviral, 13 in infant nevirapine, and six in control groups). The cumulative risk of HIV-1 transmission by 48 weeks was significantly higher in the control group (7%, 95% CI 5-9) than in the maternal-antiretroviral (4%, 3-6; p=0.0273) or the infant-nevirapine (4%, 2-5; p=0.0027) groups. The rate of serious adverse events in infants was significantly higher during 29-48 weeks than during the intervention phase (1.1 [95% CI 1.0-1.2] vs 0.7 [0.7-0.8] per 100 person-weeks; p<0.0001), with increased risk of diarrhoea, malaria, growth faltering, tuberculosis, and death. Nine women died between 2 weeks and 48 weeks post partum (one in maternal-antiretroviral group, two in infant-nevirapine group, six in control group). INTERPRETATION: In resource-limited settings where no suitable alternative to breastfeeding is available, antiretroviral prophylaxis given to mothers or infants might decrease HIV transmission. Weaning at 6 months might increase infant morbidity. FUNDING: US Centers for Disease Control and Prevention. PMID- 22541421 TI - Therapeutic hypothermia for acute myocardial infarction and cardiac arrest. AB - This report focuses on cardioprotection and describes the advantages and disadvantages of various methods of inducing therapeutic hypothermia (TH) with regard to neuroprotection and cardioprotection for patients with cardiac arrest and ST-segment elevation myocardial infarction (STEMI). TH is recommended in cardiac arrest guidelines. For patients resuscitated after out-of-hospital cardiac arrest, improvements in survival and neurologic outcomes were observed with relatively slow induction of TH. More rapid induction of TH in patients with cardiac arrest might have a mild to modest incremental impact on neurologic outcomes. TH drastically reduces infarct size in animal models, but achievement of target temperature before reperfusion is essential. Rapid initiation of TH in patients with STEMI is challenging but attainable, and marked infarct size reductions are possible. To induce TH, a variety of devices have recently been developed that require additional study. Of particular interest is transcoronary induction of TH using a catheter or wire lumen, which enables hypothermic reperfusion in the absence of total-body hypothermia. At present, the main methods of inducing and maintaining TH are surface cooling, endovascular heat exchange catheters, and intravenous infusion of cold fluids. Surface cooling or endovascular catheters may be sufficient for induction of TH in patients resuscitated after out-of-hospital cardiac arrest. For patients with STEMI, intravenous infusion of cold fluids achieves target temperature very rapidly but might worsen left ventricular function. More widespread use of TH would improve survival and quality of life for patients with out-of-hospital cardiac arrest; larger studies with more rapid induction of TH are needed in the STEMI population. PMID- 22541422 TI - Dissecting spindle architecture with a laser. AB - Microtubules in spindles are too dense to resolve by light microscopy, even with super-resolution methods. Using a new method based on laser-ablation techniques, Brugues et al. present the first quantitative characterization of the vertebrate meiotic spindle and propose an assembly mechanism for building this architecture. PMID- 22541423 TI - Dialing down SUN1 for laminopathies. AB - Laminopathies, caused by mutations in A-type nuclear lamins, encompass a range of diseases, including forms of progeria and muscular dystrophy. In this issue, Chen et al. provide evidence that elevated expression of the nuclear inner membrane protein SUN1 drives pathology in multiple laminopathies. PMID- 22541424 TI - Does the Bicoid gradient matter? AB - The generation and interpretation of positional information are key processes in developmental systems. In this issue, Chen et al. report discoveries made in the Drosophila embryo that give new insights into how positional information can be produced by patterning gradients. PMID- 22541425 TI - A piRNA to remember. AB - In this issue of Cell, Rajasethupathy et al. report a surprising role for piRNAs, previously thought to act mainly in the animal germline to silence transposons, in transcriptional regulation of plasticity-related genes in the central nervous system of the sea slug Aplysia californica. The findings expand the functions of small RNAs and have important implications for our understanding of how transient signals can give rise to long-term memories. PMID- 22541427 TI - Nucleation and transport organize microtubules in metaphase spindles. AB - Spindles are arrays of microtubules that segregate chromosomes during cell division. It has been difficult to validate models of spindle assembly due to a lack of information on the organization of microtubules in these structures. Here we present a method, based on femtosecond laser ablation, capable of measuring the detailed architecture of spindles. We used this method to study the metaphase spindle in Xenopus laevis egg extracts and found that microtubules are shortest near poles and become progressively longer toward the center of the spindle. These data, in combination with mathematical modeling, imaging, and biochemical perturbations, are sufficient to reject previously proposed mechanisms of spindle assembly. Our results support a model of spindle assembly in which microtubule polymerization dynamics are not spatially regulated, and the proper organization of microtubules in the spindle is determined by nonuniform microtubule nucleation and the local sorting of microtubules by transport. PMID- 22541426 TI - Roles for microRNAs in conferring robustness to biological processes. AB - Biological systems use a variety of mechanisms to maintain their functions in the face of environmental and genetic perturbations. Increasing evidence suggests that, among their roles as posttranscriptional repressors of gene expression, microRNAs (miRNAs) help to confer robustness to biological processes by reinforcing transcriptional programs and attenuating aberrant transcripts, and they may in some network contexts help suppress random fluctuations in transcript copy number. These activities have important consequences for normal development and physiology, disease, and evolution. Here, we will discuss examples and principles of miRNAs that contribute to robustness in animal systems. PMID- 22541428 TI - Accumulation of the inner nuclear envelope protein Sun1 is pathogenic in progeric and dystrophic laminopathies. AB - Human LMNA gene mutations result in laminopathies that include Emery-Dreifuss muscular dystrophy (AD-EDMD) and Hutchinson-Gilford progeria, the premature aging syndrome (HGPS). The Lmna null (Lmna(-/-)) and progeroid LmnaDelta9 mutant mice are models for AD-EDMD and HGPS, respectively. Both animals develop severe tissue pathologies with abbreviated life spans. Like HGPS cells, Lmna(-/-) and LmnaDelta9 fibroblasts have typically misshapen nuclei. Unexpectedly, Lmna(-/-) or LmnaDelta9 mice that are also deficient for the inner nuclear membrane protein Sun1 show markedly reduced tissue pathologies and enhanced longevity. Concordantly, reduction of SUN1 overaccumulation in LMNA mutant fibroblasts and in cells derived from HGPS patients corrected nuclear defects and cellular senescence. Collectively, these findings implicate Sun1 protein accumulation as a common pathogenic event in Lmna(-/-), LmnaDelta9, and HGPS disorders. PMID- 22541429 TI - Hikeshi, a nuclear import carrier for Hsp70s, protects cells from heat shock induced nuclear damage. AB - During heat shock stress, importin beta family-mediated nucleocytoplasmic trafficking is downregulated, whereas nuclear import of the molecular chaperone Hsp70s is upregulated. Here, we identify a nuclear import pathway that operates during heat shock stress and is mediated by an evolutionarily conserved protein named "Hikeshi," which does not belong to the importin beta family. Hikeshi binds to FG-Nups and translocates through nuclear pores on its own, showing characteristic features of nuclear transport carriers. In reconstituted transport, Hikeshi supports the nuclear import of the ATP form of Hsp70s, but not the ADP form, indicating the importance of the Hsp70 ATPase cycle in the import cycle. In living cells, depletion of Hikeshi inhibits heat shock-induced nuclear import of Hsp70s, reduces cell viability after heat shock stress, and significantly delays the attenuation and reversion of multiple heat shock-induced nuclear phenotypes. Nuclear Hsp70s rescue the effect of Hikeshi depletion at least in part. Thus, Hsp70s counteract heat shock-induced damage by acting inside of the nucleus. PMID- 22541430 TI - The transcriptional and epigenomic foundations of ground state pluripotency. AB - Mouse embryonic stem (ES) cells grown in serum exhibit greater heterogeneity in morphology and expression of pluripotency factors than ES cells cultured in defined medium with inhibitors of two kinases (Mek and GSK3), a condition known as "2i" postulated to establish a naive ground state. We show that the transcriptome and epigenome profiles of serum- and 2i-grown ES cells are distinct. 2i-treated cells exhibit lower expression of lineage-affiliated genes, reduced prevalence at promoters of the repressive histone modification H3K27me3, and fewer bivalent domains, which are thought to mark genes poised for either up- or downregulation. Nonetheless, serum- and 2i-grown ES cells have similar differentiation potential. Precocious transcription of developmental genes in 2i is restrained by RNA polymerase II promoter-proximal pausing. These findings suggest that transcriptional potentiation and a permissive chromatin context characterize the ground state and that exit from it may not require a metastable intermediate or multilineage priming. PMID- 22541431 TI - Generation of genetically modified mice by oocyte injection of androgenetic haploid embryonic stem cells. AB - Haploid cells are amenable for genetic analysis. Recent success in the derivation of mouse haploid embryonic stem cells (haESCs) via parthenogenesis has enabled genetic screening in mammalian cells. However, successful generation of live animals from these haESCs, which is needed to extend the genetic analysis to the organism level, has not been achieved. Here, we report the derivation of haESCs from androgenetic blastocysts. These cells, designated as AG-haESCs, partially maintain paternal imprints, express classical ESC pluripotency markers, and contribute to various tissues, including the germline, upon injection into diploid blastocysts. Strikingly, live mice can be obtained upon injection of AG haESCs into MII oocytes, and these mice bear haESC-carried genetic traits and develop into fertile adults. Furthermore, gene targeting via homologous recombination is feasible in the AG-haESCs. Our results demonstrate that AG haESCs can be used as a genetically tractable fertilization agent for the production of live animals via injection into oocytes. PMID- 22541432 TI - A system of repressor gradients spatially organizes the boundaries of Bicoid dependent target genes. AB - The homeodomain (HD) protein Bicoid (Bcd) is thought to function as a gradient morphogen that positions boundaries of target genes via threshold-dependent activation mechanisms. Here, we analyze 66 Bcd-dependent regulatory elements and show that their boundaries are positioned primarily by repressive gradients that antagonize Bcd-mediated activation. A major repressor is the pair-rule protein Runt (Run), which is expressed in an opposing gradient and is necessary and sufficient for limiting Bcd-dependent activation. Evidence is presented that Run functions with the maternal repressor Capicua and the gap protein Kruppel as the principal components of a repression system that correctly orders boundaries throughout the anterior half of the embryo. These results put conceptual limits on the Bcd morphogen hypothesis and demonstrate how the Bcd gradient functions within the gene network that patterns the embryo. PMID- 22541433 TI - Paternal RLIM/Rnf12 is a survival factor for milk-producing alveolar cells. AB - In female mouse embryos, somatic cells undergo a random form of X chromosome inactivation (XCI), whereas extraembryonic trophoblast cells in the placenta undergo imprinted XCI, silencing exclusively the paternal X chromosome. Initiation of imprinted XCI requires a functional maternal allele of the X-linked gene Rnf12, which encodes the ubiquitin ligase Rnf12/RLIM. We find that knockout (KO) of Rnf12 in female mammary glands inhibits alveolar differentiation and milk production upon pregnancy, with alveolar cells that lack RLIM undergoing apoptosis as they begin to differentiate. Genetic analyses demonstrate that these functions are mediated primarily by the paternal Rnf12 allele due to nonrandom maternal XCI in mammary epithelial cells. These results identify paternal Rnf12/RLIM as a critical survival factor for milk-producing alveolar cells and, together with population models, reveal implications of transgenerational epigenetic inheritance. PMID- 22541434 TI - The GATA2 transcriptional network is requisite for RAS oncogene-driven non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) is the most frequent cause of cancer deaths worldwide; nearly half contain mutations in the receptor tyrosine kinase/RAS pathway. Here we show that RAS-pathway mutant NSCLC cells depend on the transcription factor GATA2. Loss of GATA2 reduced the viability of NSCLC cells with RAS-pathway mutations, whereas wild-type cells were unaffected. Integrated gene expression and genome occupancy analyses revealed GATA2 regulation of the proteasome, and IL-1-signaling, and Rho-signaling pathways. These pathways were functionally significant, as reactivation rescued viability after GATA2 depletion. In a Kras-driven NSCLC mouse model, Gata2 loss dramatically reduced tumor development. Furthermore, Gata2 deletion in established Kras mutant tumors induced striking regression. Although GATA2 itself is likely undruggable, combined suppression of GATA2-regulated pathways with clinically approved inhibitors caused marked tumor clearance. Discovery of the nononcogene addiction of KRAS mutant lung cancers to GATA2 presents a network of druggable pathways for therapeutic exploitation. PMID- 22541435 TI - Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. AB - Tumor maintenance relies on continued activity of driver oncogenes, although their rate-limiting role is highly context dependent. Oncogenic Kras mutation is the signature event in pancreatic ductal adenocarcinoma (PDAC), serving a critical role in tumor initiation. Here, an inducible Kras(G12D)-driven PDAC mouse model establishes that advanced PDAC remains strictly dependent on Kras(G12D) expression. Transcriptome and metabolomic analyses indicate that Kras(G12D) serves a vital role in controlling tumor metabolism through stimulation of glucose uptake and channeling of glucose intermediates into the hexosamine biosynthesis and pentose phosphate pathways (PPP). These studies also reveal that oncogenic Kras promotes ribose biogenesis. Unlike canonical models, we demonstrate that Kras(G12D) drives glycolysis intermediates into the nonoxidative PPP, thereby decoupling ribose biogenesis from NADP/NADPH-mediated redox control. Together, this work provides in vivo mechanistic insights into how oncogenic Kras promotes metabolic reprogramming in native tumors and illuminates potential metabolic targets that can be exploited for therapeutic benefit in PDAC. PMID- 22541436 TI - A cardiac microRNA governs systemic energy homeostasis by regulation of MED13. AB - Obesity, type 2 diabetes, and heart failure are associated with aberrant cardiac metabolism. We show that the heart regulates systemic energy homeostasis via MED13, a subunit of the Mediator complex, which controls transcription by thyroid hormone and other nuclear hormone receptors. MED13, in turn, is negatively regulated by a heart-specific microRNA, miR-208a. Cardiac-specific overexpression of MED13 or pharmacologic inhibition of miR-208a in mice confers resistance to high-fat diet-induced obesity and improves systemic insulin sensitivity and glucose tolerance. Conversely, genetic deletion of MED13 specifically in cardiomyocytes enhances obesity in response to high-fat diet and exacerbates metabolic syndrome. The metabolic actions of MED13 result from increased energy expenditure and regulation of numerous genes involved in energy balance in the heart. These findings reveal a role of the heart in systemic metabolic control and point to MED13 and miR-208a as potential therapeutic targets for metabolic disorders. PMID- 22541437 TI - A self-produced trigger for biofilm disassembly that targets exopolysaccharide. AB - Biofilms are structured communities of bacteria that are held together by an extracellular matrix consisting of protein and exopolysaccharide. Biofilms often have a limited lifespan, disassembling as nutrients become exhausted and waste products accumulate. D-amino acids were previously identified as a self-produced factor that mediates biofilm disassembly by causing the release of the protein component of the matrix in Bacillus subtilis. Here we report that B. subtilis produces an additional biofilm-disassembly factor, norspermidine. Dynamic light scattering and scanning electron microscopy experiments indicated that norspermidine interacts directly and specifically with exopolysaccharide. D-amino acids and norspermidine acted together to break down existing biofilms and mutants blocked in the production of both factors formed long-lived biofilms. Norspermidine, but not closely related polyamines, prevented biofilm formation by B. subtilis, Escherichia coli, and Staphylococcus aureus. PMID- 22541438 TI - A role for neuronal piRNAs in the epigenetic control of memory-related synaptic plasticity. AB - Small RNA-mediated gene regulation during development causes long-lasting changes in cellular phenotypes. To determine whether small RNAs of the adult brain can regulate memory storage, a process that requires stable and long-lasting changes in the functional state of neurons, we generated small RNA libraries from the Aplysia CNS. In these libraries, we discovered an unexpectedly abundant expression of a 28 nucleotide sized class of piRNAs in brain, which had been thought to be germline specific. These piRNAs have unique biogenesis patterns, predominant nuclear localization, and robust sensitivity to serotonin, a modulatory transmitter that is important for memory. We find that the Piwi/piRNA complex facilitates serotonin-dependent methylation of a conserved CpG island in the promoter of CREB2, the major inhibitory constraint of memory in Aplysia, leading to enhanced long-term synaptic facilitation. These findings provide a small RNA-mediated gene regulatory mechanism for establishing stable long-term changes in neurons for the persistence of memory. PMID- 22541440 TI - SnapShot: Mitochondrial architecture. PMID- 22541439 TI - Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model. AB - Alzheimer's disease (AD) results in cognitive decline and altered network activity, but the mechanisms are unknown. We studied human amyloid precursor protein (hAPP) transgenic mice, which simulate key aspects of AD. Electroencephalographic recordings in hAPP mice revealed spontaneous epileptiform discharges, indicating network hypersynchrony, primarily during reduced gamma oscillatory activity. Because this oscillatory rhythm is generated by inhibitory parvalbumin (PV) cells, network dysfunction in hAPP mice might arise from impaired PV cells. Supporting this hypothesis, hAPP mice and AD patients had decreased levels of the interneuron-specific and PV cell-predominant voltage gated sodium channel subunit Nav1.1. Restoring Nav1.1 levels in hAPP mice by Nav1.1-BAC expression increased inhibitory synaptic activity and gamma oscillations and reduced hypersynchrony, memory deficits, and premature mortality. We conclude that reduced Nav1.1 levels and PV cell dysfunction critically contribute to abnormalities in oscillatory rhythms, network synchrony, and memory in hAPP mice and possibly in AD. PMID- 22541441 TI - Generalized chorea-ballism in acute non ketotic hyperglycemia: findings from diffusion-weighted magnetic resonance imaging. PMID- 22541442 TI - Integrating outcome data collection into the care of the patient with pain. PMID- 22541443 TI - Enhanced affect/cognition-related brain responses during visceral placebo analgesia in irritable bowel syndrome patients. AB - Placebo analgesia is a psychosocial context effect that is rarely studied in visceral pain. Patients with irritable bowel syndrome (IBS) exhibit visceral hyperalgesia and heightened affective/cognitive brain region activation during visceral stimuli. Psychological factors alter the pain and brain activation pattern, and these changes are more pronounced in IBS patients. Expectation constitutes the major neuropsychological mechanism in the placebo effect. This study confirmed the heightened affective/cognitive brain responses in IBS patients during visceral placebo analgesia using a placebo model with expectation, which was enhanced by suggestion and conditioning. Seventeen IBS patients and 17 age-/sex-matched controls were enrolled. Psychophysical inventories (Hospital Anxiety and Depression Scale [HADS], visual analogue scale, and short-form McGill questionnaire) were completed. Brain activity during placebo intervention and anticipation was assessed in response to rectal distension using 3T-functional magnetic resonance imaging. Suggestion /conditioning-enhanced placebo was used to convince controls/patients of the efficacy of a newly developed intravenous drug (saline, in actuality) for the relief of rectal distension-induced visceral pain. A comparable visceral placebo analgesia was observed in IBS patients and control subjects. IBS patients demonstrated a higher HADS-anxiety score, which was predictive of a weak placebo effect. Suggestion-/conditioning-enhanced placebo evoked more activity in affective/cognitive brain regions (insula, midcingulate cortex, and ventrolateral prefrontal cortex [VLPFC]) in IBS patients than in healthy controls. VLPFC was also more active during anticipation in IBS patients. In conclusion, IBS patients and control subjects achieved comparable placebo analgesia during experimentally induced rectal pain. The visceral placebo analgesia produced heightened activity in affective/cognitive brain regions in IBS patients. PMID- 22541444 TI - Chronic compression or acute dissociation of dorsal root ganglion induces cAMP dependent neuronal hyperexcitability through activation of PAR2. AB - Chronic compression (CCD) or dissociation of dorsal root ganglion (DRG) can induce cyclic adenosine monophosphate (cAMP)-dependent DRG neuronal hyperexcitability and behaviorally expressed hyperalgesia. Here, we report that protease-activated receptor 2 (PAR2) activation after CCD or dissociation mediates the increase of cAMP activity and protein kinase A (PKA) and cAMP dependent hyperexcitability and hyperalgesia in rats. CCD and dissociation, as well as trypsin (a PAR2 activator) treatment, increased level of cAMP concentration, mRNA, and protein expression for PKA subunits PKA-RII and PKA-c and protein expression of PAR2, in addition to producing neuronal hyperexcitability and, in CCD rats, thermal hyperalgesia. The increased expression of PAR2 was colocalized with PKA-c subunit. A PAR2 antagonistic peptide applied before and/or during the treatment, prevented or largely diminished the increased activity of cAMP and PKA, neuronal hyperexcitability, and thermal hyperalgesia. However, posttreatment with the PAR2 antagonistic peptide failed to alter either hyperexcitability or hyperalgesia. In contrast, an adenylyl cyclase inhibitor, SQ22536, administrated after dissociation or CCD, successfully suppressed hyperexcitability and hyperalgesia, in vitro and/or in vivo. Trypsin-induced increase of the intracellular calcium [Ca(2+)](i) was prevented in CCD or dissociation DRG neurons. These alterations were further confirmed by knockdown of PAR2 with siRNA. In addition, trypsin and PAR2 agonistic peptide-induced increase of cAMP was prevented by inhibition of PKC, but not Galphas. These findings suggest that PAR2 activation is critical to induction of nerve injury-induced neuronal hyperexcitability and cAMP-PKA activation. Inhibiting PAR2 activation may be a potential target for preventing/suppressing development of neuropathic pain. PMID- 22541446 TI - [A massive hepatic infarction after radiofrequency ablation]. PMID- 22541445 TI - Structure equals function: cortical correlates of pain. PMID- 22541447 TI - [Idiopathic fibrosing pancreatitis-a uncommon cause of obstructive jaundice in young patients]. PMID- 22541448 TI - [Biological implants in abdominal wall hernia surgery]. AB - Permanent synthetic materials are currently of choice for abdominal wall hernia repair. However, they are not ideal as short- and long-term complications with these have been reported. Extracellular matrix-derived biological implants (EMDBI) have emerged as a result of research and development into new materials. Several types of EMDBI have appeared in the last few years, each with its own manufacture characteristics and different from the rest. The current panorama of the xenogeneic EMDBI available in Spain is analysed, their complications, the unknown factors arising in the long-term, and the clinical experience available on incisional and inguinal hernias. PMID- 22541449 TI - [Standardising sigmoidectomy by single umbilical incision]. AB - The increase in single-incision endoscopic surgery has led to more and more procedures and surgical groups who perform them. Segmental resection is the procedure most likely to benefit from this approach since it achieves a significant minimisation in the parietal access; with umbilical mini-laparotomy the entrance ports are grouped together and extraction of the piece and preparation of the anastomosis can be performed. Among the colorectal procedures, sigmoidectomy seems to be the most appropriate area to start using these techniques by groups with laparoscopic colorectal experience. Our aim is the standardisation of single-incision sigmoidectomy, analysing the process with the support of video sequences, and placing emphasis on the factors where it differs from conventional laparoscopy and on the key points in order to avoid problems during the execution of the process. PMID- 22541450 TI - [Intestinal peritonitis due to non-typhoidal salmonella]. PMID- 22541451 TI - [Calcifying cystic fibrous tumour. A rare form of benign peritoneal carcinomatosis]. PMID- 22541452 TI - [Autologous cephalic duodenopancreatectomy with superior mesenteric vein dissection and reconstruction using the renal vein]. PMID- 22541453 TI - Invited review: The impact of automatic milking systems on dairy cow management, behavior, health, and welfare. AB - Over the last 100 yr, the dairy industry has incorporated technology to maximize yield and profit. Pressure to maximize efficiency and lower inputs has resulted in novel approaches to managing and milking dairy herds, including implementation of automatic milking systems (AMS) to reduce labor associated with milking. Although AMS have been used for almost 20 yr in Europe, they have only recently become more popular in North America. Automatic milking systems have the potential to increase milk production by up to 12%, decrease labor by as much as 18%, and simultaneously improve dairy cow welfare by allowing cows to choose when to be milked. However, producers using AMS may not fully realize these anticipated benefits for a variety of reasons. For example, producers may not see a reduction in labor because some cows do not milk voluntarily or because they have not fully or efficiently incorporated the AMS into their management routines. Following the introduction of AMS on the market in the 1990s, research has been conducted examining AMS systems versus conventional parlors focusing primarily on cow health, milk yield, and milk quality, as well as on some of the economic and social factors related to AMS adoption. Additionally, because AMS rely on cows milking themselves voluntarily, research has also been conducted on the behavior of cows in AMS facilities, with particular attention paid to cow traffic around AMS, cow use of AMS, and cows' motivation to enter the milking stall. However, the sometimes contradictory findings resulting from different studies on the same aspect of AMS suggest that differences in management and farm level variables may be more important to AMS efficiency and milk production than features of the milking system itself. Furthermore, some of the recommendations that have been made regarding AMS facility design and management should be scientifically tested to demonstrate their validity, as not all may work as intended. As updated AMS designs, such as the automatic rotary milking parlor, continue to be introduced to the dairy industry, research must continue to be conducted on AMS to understand the causes and consequences of differences between milking systems as well as the impacts of the different facilities and management systems that surround them on dairy cow behavior, health, and welfare. PMID- 22541454 TI - Effect of highly lipolyzed goat cheese on HL-60 human leukemia cells: antiproliferative activity and induction of apoptotic DNA damage. AB - To establish cheese as a dairy product with health benefits, we embarked on examining the multifunctional role of cheeses, especially in the field of cancer prevention. The current study was designed to investigate whether different types of commercial goat cheeses may possess antiproliferative activity, using an HL-60 human promyelocytic leukemia cell line as a cancer cell model. Among 11 cheese extracts tested at 500MUg/mL, 6 (Crottin de Chavignol, Pouligny Saint-Pierre, Chabichou du Poitou, Valencay, Kavli, and Sainte-Maure de Touraine) resulted in a significant decrease of cell viability, which is consistent with a decrease in viable cell number. Compared with the half-maximal inhibitory concentration (IC(50)) value of individual cheeses in cellular proliferation assays, the Pouligny Saint-Pierre extract showed strong inhibition. Incubation of cells in the presence of Pouligny Saint-Pierre extract resulted in induction of cellular morphological changes and apoptotic DNA fragmentation as well as expression of the active form of caspase-3 protein. Based on the quantification of the ratio of free fatty acids to triglycerides in different cheese samples, a significant correlation was detected between lipolytic ripeness and IC(50) values for antiproliferative capacity tested in HL-60 cells. Collectively, these results support a potential role of highly lipolyzed goat cheeses in the prevention of leukemic cell proliferation. PMID- 22541455 TI - Probiotic yogurts manufactured with increased glucose oxidase levels: postacidification, proteolytic patterns, survival of probiotic microorganisms, production of organic acid and aroma compounds. AB - We investigated the effect of increased glucose oxidase concentration as a technological option to decrease oxidative stress during the processing of probiotic yogurts. Probiotic yogurts were produced with increased concentrations of glucose oxidase (0, 250, 500, 750, or 1,000 mg/kg) and submitted to physicochemical and microbiological analysis at 1, 15, and 30 d of refrigerated storage. Higher concentrations of glucose oxidase (750 and 1,000 mg/kg) and a longer storage time were found to have an influence on the characteristics of the probiotic yogurt, contributing to more extensive postacidification, an increase in the dissolved oxygen level, and higher proteolysis. In addition, increased production of aroma compounds (diacetyl and acetaldehyde) and organic acids (mainly lactic acid) and a decrease in the probiotic bacteria count were reported. The use of glucose oxidase was a feasible option to minimize oxidative stress in probiotic yogurts. However, supplementation with excessive amounts of the enzyme may be ineffective, because insufficient substrate (glucose) is present for its action. Consumer tests should be performed to evaluate changes in the sensory attributes of the probiotic yogurts with increased supplementation of glucose oxidase. In addition, packaging systems with different permeability to oxygen should be evaluated. PMID- 22541456 TI - Effects of hydrolysis on solid-state relaxation and stickiness behavior of sodium caseinate-lactose powders. AB - Hydrolyzed or nonhydrolyzed sodium caseinate-lactose dispersions were spray dried, at a protein: lactose ratio of 0.5, to examine the effects of protein hydrolysis on relaxation behavior and stickiness of model powders. Sodium caseinate (NC) used included a nonhydrolyzed control (DH 0) and 2 hydrolyzed variants (DH 8.3 and DH 15), where DH = degree of hydrolysis (%). Prior to spray drying, apparent viscosities of liquid feeds (at 70 degrees C) at a shear rate of 20/s were 37.6, 3.14, and 3.19 mPa.s, respectively, for DH 0, DH 8, and DH 15 dispersions. Powders containing hydrolyzed casein were more susceptible to sticking than those containing intact NC. The former had also lower bulk densities and powder particle sizes. Scanning electron microscopy showed that hydrolyzed powders had thinner particle walls and were more friable than powders containing intact NC. Secondary structure of caseinates, determined by Fourier transform infrared spectroscopy, was affected by the relative humidity of storage and the presence of lactose as co-solvent rather than its physical state. Glass transition temperatures and lactose crystallization temperatures, determined by differential scanning calorimetry were not affected by caseinate hydrolysis, although the effects of protein hydrolysis on glass-rubber transitions (T(gr)) could be determined by thermo-mechanical analysis. Powders containing hydrolyzed NC had lower T(gr) values (~30 degrees C) following storage at a higher subcrystallization relative humidity (33%) compared with powder with nonhydrolyzed NC (T(gr) value of ~40 degrees C), an effect that reflects more extensive plasticization of powder matrices by moisture. Results support that sodium caseinate-lactose interactions were weak but that relaxation behavior, as determined by the susceptibility of powder to sticking, was affected by hydrolysis of sodium caseinate. PMID- 22541457 TI - Checking into China's cow hotels: have policies following the milk scandal changed the structure of the dairy sector? AB - China's milk scandal is well known for causing the nation's largest food safety crisis and for its effect on thousands of children. Less, however, is known about the effect on the other victim: China's small dairy farmers. Although small backyard producers were not the ones that added melamine to the milk supply, the incomes of dairy farmers fell sharply after the crisis. In response, one of the actions taken by the government was to encourage small dairy producers to check into production complexes that were supposed to supply services, new technologies, and provide for easy/bulk procurement of the milk produced by the cows of the farmers. Because both farmers and their cows were living (and working) away from home, in the rest of the paper we call these complexes cow hotels. In this paper we examine the dynamics of China's dairy production structure before and after the milk scandal. In particular, we seek to gain a better understanding about how China's policies have been successful in encouraging farmers to move from the backyard into cow hotels. We also seek to find if larger or smaller farmers respond differently to these policy measures. Using data from a sample of farmers from dairy-producing villages in Greater Beijing, our empirical analysis finds that 1 yr after the milk scandal, the dairy production structure changed substantially. Approximately one quarter (26%) of the sample checked into cow hotels after the milk scandal, increasing from 2% before the crisis. Our results also demonstrate that the increase in cow hotel production can largely be attributed to China's dairy policies. Finally, our results suggest that the effects of government policy differ across farm sizes; China's dairy policies are more likely to persuade larger farms to join cow hotels. Apparently, larger farms benefit more when they join cow hotels. Overall, these results suggest that during the first year after the crisis, the government policies were effective in moving some of the backyard farmers into cow hotels (although 60% farmers remained backyard producing). PMID- 22541458 TI - No seasonal effect on culturable pseudomonads in fresh milks from cattle herds. AB - Freshly drawn raw milk from 37 single herds on farms manufacturing raw cow cheese under the Protected Designation of Origin (PDO) label were sampled over 13 mo for pseudomonad counts. Coliforms, somatic cells, and coagulase-positive staphylococci were counted and total fat and protein contents measured. For pseudomonad counts, the overall mean value was 3.60*10(3) cfu/mL. We observed very high variation between different producers and within the same producers (average standard deviation 1.30*10(4) cfu/mL), but we did not detect a seasonal effect. The only statistical correlation with other milk quality parameters was with coliforms. A survey of milking practices and milking machine sanitation together with environmental and milk sampling for pseudomonad counts in 7 cheese workshops showed that no real negligence or error could be imputed to producers. The main problems were the presence of non-aeruginosa pseudomonads in potable water and a few isolated failures during the cleaning and rinsing phases of sanitation. PMID- 22541459 TI - Stability of milk fat globule membrane proteins toward human enzymatic gastrointestinal digestion. AB - The milk fat globule membrane (MFGM) fraction refers to the thin film of polar lipids and membrane proteins that surrounds fat globules in milk. It is its unique biochemical composition that renders MFGM with some beneficial biological activities, such as anti-adhesive effects toward pathogens. However, a prerequisite for the putative bioactivity of MFGM is its stability during gastrointestinal digestion. We, therefore, subjected MFGM material, isolated from raw milk, to an in vitro enzymatic gastrointestinal digestion. Sodium dodecyl sulfate PAGE, in combination with 2 staining methods, Coomassie Blue and periodic acid Schiff staining, was used to evaluate polypeptide patterns of the digest, whereas mass spectrometry was used to confirm the presence of specific MFGM proteins. Generally, it was observed that glycoproteins showed higher resistance to endogenous proteases compared with non-glycosylated proteins. Mucin 1 displayed the highest resistance to digestion and a considerable part of this protein was still detected at its original molecular weight after gastric and small intestine digestion. Cluster of differentiation 36 was also quite resistant to pepsin. A significant part of periodic acid Schiff 6/7 survived the gastric digestion, provided that the lipid moiety was not removed from the MFGM material. Overall, MFGM glycoproteins are generally more resistant to gastrointestinal digestion than serum milk proteins and the presence of lipids, besides glycosylation, may protect MFGM glycoproteins from gastrointestinal digestion. This gastrointestinal stability makes MFGM glycoproteins amenable to further studies in which their putative health-promoting effects can be explored. PMID- 22541460 TI - Effects of cooling and freezing storage on the stability of bioactive factors in human colostrum. AB - Breast milk constitutes the best form of newborn alimentation because of its nutritional and immunological properties. Banked human milk is stored at low temperature, which may produce losses of some bioactive milk components. During lactation, colostrum provides the requirements of the newborn during the first days of life. The aim of this study was to evaluate the effect of cooling storage at 4 degrees C and freezing storage at -20 degrees C and -80 degrees C on bioactive factors in human colostrum. For this purpose, the content of IgA, growth factors such as epidermal growth factor, transforming growth factor (TGF) beta1 and TGF-beta2, and some cytokines such as IL-6, IL-8, IL-10, and tumor necrosis factor (TNF)-alpha, and its type I receptor TNF-RI, were quantified. Some colostrum samples were stored for 6, 12, 24, and 48 h at 4 degrees C and others were frozen at -20 degrees C or -80 degrees C for 6 and 12 mo. We quantified IgA, epidermal growth factor, TGF-beta1, and TGF-beta2 by indirect ELISA. Concentrations of IL-6, IL-10, and TNF-alpha cytokines, IL-8 chemokine, and TNF-RI were measured using the BD Cytometric Bead Array (BD Biosciences, Erembodegem, Belgium). Bioactive immunological factors measured in this study were retained in colostrum after cooling storage at 4 degrees C for at least 48h, with the exception of IL-10. None of the initial bioactive factor concentrations was modified after 6 mo of freezing storage at either -20 degrees C or -80 degrees C. However, freezing storage of colostrum at -20 degrees C and -80 degrees C for 12 mo produced a decrease in the concentrations of IgA, IL-8, and TGF-beta1. In summary, colostrum can be stored at 4 degrees C for up to 48 h or at -20 degrees C or -80 degrees C for at least 6 mo without losing its immunological properties. Future studies are necessary to develop quality assurance guidelines for the storage of colostrum in human milk banks, and to focus not only on the microbiological safety but also on the maintenance of the immunological properties of colostrum. PMID- 22541461 TI - Sampling strategies for total bacterial count of unpasteurized bulk milk. AB - The purpose of this study was to assess bulk tank milk sampling strategies for estimating total bacterial count (TBC). Nine large dairies in Wisconsin that produced and shipped at least 1 milk load per day were selected for this study. Total bacteria count was performed for each milk load produced during a 13-mo period. The milk shipment frequency was once (n=3), twice (n=4), or 3 times daily (n=2 farms). A threshold of 8,000 cfu/mL was used to define increased TBC. The proportion of increased TBC (TBCref) during the study period was defined as the reference probability of an increased TBC for each farm. The number of milk loads that would need to be tested to estimate TBCref precisely (TBCref +/- 0.05) in selected time periods (month, quarter, 6 mo, or a year) was calculated assuming independence among TBC measurements. Sampling simulations (systematic or simple random sampling) were used to assess the validity of the independence assumption and compare different sampling schedules (every second, every third, or every seventh milk load) used for estimating TBCref in a 13-mo or 30-d TBC series. The number of milk loads tested to estimate TBCref depended on the time period of interest. For farms with daily milk shipments, at least 94% of all milk loads produced would need to be tested to estimate TBCref during a 30-d period. In contrast, when the period of interest was a year, reductions of up to 88% in the number of milk loads tested could be achieved. As the probability of an increased TBC departed from 0.50 toward 1 or 0, fewer samples were needed to estimate TBCref. A sampling schedule based on TBC performed on every second milk load resulted in 100% of 5,000 random samples (taken from the 13-mo TBC series) within the range of TBCref +/- 0.05, indicating that sampling half of the milk loads would precisely estimate TBCref. Results of this study suggest that dairy consultants and processors can adjust the frequency of testing of milk loads depending on the goal of the milk quality monitoring program. PMID- 22541462 TI - Color of low-fat cheese influences flavor perception and consumer liking. AB - The present study examines the effect of color on low-fat cheese flavor perception and consumer acceptability. To understand the flavor preferences of the consumer population participating in the sensory testing, 4 brands of retail full-fat Cheddar cheeses labeled as mild, medium, or sharp were obtained. These cheeses were evaluated by a trained descriptive panel to generate a flavor profile for each cheese and then by consumer sensory panels. Overall and color liking were measured using a 9-point hedonic scale, and flavor, chewiness, level of sharpness measured using a 5-point just-about-right (JAR) scale (with 1 being not enough, 3 being just about right, and 5 being too much of the attribute). Subsequently, 9 low-fat Cheddar cheeses were manufactured using 3 levels of annatto (0, 7.34, and 22 g/100 kg) and 3 levels of titanium dioxide (0, 7.67, and 40 g/100 kg) using a randomized block design in duplicate. Cheeses were then evaluated by descriptive and consumer sensory panels. Each consumer testing consisted of 120 panelists who were mainly 18 to 35 yr of age (>90% of total populace) with >60% being frequent cheese consumers. Overall liking preference of the consumer group was for mild to medium cheese. Using the JAR scale, the medium cheeses were considered closest to JAR with a mean score of 3.0, compared with 2.4 for mild cheese and 3.6 for sharp cheese. Among low-fat cheeses, color was shown to be important with consumer liking being negatively influenced when the cheese appearance was too translucent (especially when normal levels of annatto were used) or too white. Matching the level of titanium dioxide with the annatto level gave the highest liking scores and flavor perception closest to JAR. This study established a significant effect of color on overall liking of low-fat versions of Cheddar cheese. PMID- 22541463 TI - Short communication: Evidence for methylglyoxal-mediated browning of Parmesan cheese during low temperature storage. AB - Brown pigmentation can occasionally form in Parmesan cheese during the ripening process, creating an unappealing appearance and associated off-flavors. The browning reactions proceed at refrigerated temperatures and in the relative absence of reducing sugar, contrary to typical Maillard browning. Residual sugars, lipid oxidation products, byproducts of fermentation, and (or) enzymes may react with primary amines in cheese to form brown pigmentation and concomitantly generate volatile compounds unique to each of these reactions. Determining the volatile profiles provides a means of understanding the potential substrates involved and causative reaction pathways. This work is divided into 2 segments. The first portion characterized the pigmentation and the browning index of Parmesan cheeses with and without extensive browning. The second phase examined the volatile character of the cheeses using gas chromatography-mass spectrometry. Various pyrazines, such as 2,3,5-trimethylpyrazine and 3,5-diethyl 2-methylpyrazine, were found in the brown cheeses but were not present in the white samples. The formation of pyrazines is proposed to result from the spontaneous condensation of aminoacetone. Aminoacetone can be formed by the Strecker degradation of amino acids with methylglyoxal, the latter a byproduct of sugar fermentation. Evidence is provided to support a browning pathway mediated by the production of methylglyoxal in Parmesan cheese. PMID- 22541464 TI - Low numbers of ovarian follicles >=3 mm in diameter are associated with low fertility in dairy cows. AB - The total number of ovarian follicles >= 3mm in diameter (antral follicle count, AFC) during follicular waves varies among cattle of similar age, but AFC is highly repeatable within individuals. We hypothesized that lower AFC could be associated with reduced fertility in cattle. The AFC was assessed by ultrasonography for 2 d consecutively during the first wave of follicular growth of the estrous cycle, 4.6+/-1.43 d (mean +/- SD) after estrus, in 306 Holstein Friesian dairy cows approximately 70 d postpartum. Cows were classified into 3 groups based on AFC: low (AFC <=15), intermediate (AFC=16 to 24), and high (AFC >=25). During the cycle in which AFC was assessed and in subsequent cycles, cows were artificially inseminated (AI) following detection of estrus, and pregnancy status was assessed using ultrasonography. Cows with high AFC had 3.34 times greater odds of being pregnant at the end of the breeding season compared with cows with low AFC; the odds of a successful pregnancy at first service were 1.75 times greater in the intermediate compared with the low group. The predicted probability of a successful pregnancy by the end of the breeding period (length of breeding season was 86+/-16.3 d) was 94, 88, and 84% for the high, intermediate, and low AFC groups, respectively. No difference was evident among groups in 21-d submission rate (proportion of all cows detected in estrus and submitted for AI in the first 21 d of the breeding season), but the interval from calving to conception was shorter in the high (109.5+/-5.1 d) versus low (117.1+/ 4 d) group, and animals with intermediate AFC received fewer services during the breeding season (2.3+/-0.1) compared with animals with low AFC (2.7+/-0.1). Lactating cows with <=15 ovarian follicles have lower reproductive performance compared with cows with higher numbers of follicles, but the existence of a positive association between high numbers of ovarian follicles and fertility is yet to be established. PMID- 22541465 TI - Metabolic and production profiles of dairy cows in response to decreased nutrient density to increase physiological imbalance at different stages of lactation. AB - Physiological imbalance (PI) is a situation in which physiological parameters deviate from the normal, and cows consequently have an increased risk of developing production diseases and reduced production or reproduction. Our objectives were to (1) determine the effect of stage of lactation and milk yield on metabolic and production responses of cows during a nutrient restriction period to experimentally increase PI; (2) identify major metabolites that relate to degree of PI; and (3) identify potential biomarkers in milk for on-farm detection of PI throughout lactation. Forty-seven Holstein cows in early [n=14; 49+/-22 d in milk (DIM); parity=1.6+/-0.5], mid (n=15; 159+/-39 DIM; parity=1.5+/ 0.5), and late (n=18; 273+/-3 DIM; parity=1.3+/-0.5) lactation were used. Prior to restriction, all cows were fed the same total mixed ration ad libitum. All cows were then nutrient restricted for 4 d by supplementing the ration with 60% wheat straw to induce PI. After restriction, cows returned to full feed. Daily milk yield was recorded and composite milk samples were analyzed for fat, protein, lactose, citrate, somatic cells, uric acid, alkaline phosphatase, beta hydroxybutyrate (BHBA), and milk urea nitrogen. Blood was collected daily and analyzed for metabolites: nonesterified fatty acids (NEFA), BHBA, glucose, plasma urea nitrogen, and insulin. The revised quantitative insulin sensitivity check index (RQUICKI) was calculated for each cow. Liver biopsies collected before and during restriction were analyzed for triglycerides, glycogen, phospholipids, glucose, and total lipid content. A generalized linear mixed model was used to determine the effect of stage of lactation on responses during restriction. Regression analyses were used to examine the effect of pre-restriction levels on changes during restriction. Similar decreases in milk yield among groups indicate that the capacity of individual responses is dependent on milk yield but the coping strategies used are dependent on stage of lactation. Milk yield was a better predictor of feed intake than DIM. Plasma glucose decreased for all cows, and cows in early lactation had increased plasma BHBA, whereas cows in later lactation had increased NEFA during restriction. Milk citrate had the greatest increase (58%) during restriction for all cows. Results reported here identified metabolites (i.e., glucose, NEFA, BHBA, cholesterol) as predictors of PI and identified milk citrate as a promising biomarker for PI on farm. PMID- 22541466 TI - Endogenous and exogenous progesterone influence body temperature in dairy cows. AB - Three experiments were conducted to determine the effect of endogenous progesterone (P4) on body temperature comparing lactating, pregnant with lactating, nonpregnant cows, and to study the effect of exogenous P4 administered via a controlled internal drug release (CIDR) insert on body temperature in lactating dairy cows. Body temperature was measured vaginally and rectally using temperature loggers and a digital thermometer, respectively. In experiment 1, 10 cyclic lactating cows (3 primiparous, 7 multiparous) and 10 lactating, pregnant cows (3 primiparous, 7 multiparous) were included. Vaginal temperatures and serum P4 concentrations were greater in pregnant cows (vaginal: 0.3+/-0.01 degrees C; P4: 5.5+/-0.4 ng/mL) compared with nonpregnant cows. In experiment 2, estrous cycles of 14 postpartum healthy, cyclic, lactating cows (10 primiparous, 4 multiparous) were synchronized, and cows were assigned randomly to 1 of 2 treatments (CIDR-P4 or CIDR-blank). A temperature logger was inserted 1 d after ovulation using a P4-free CIDR (CIDR-blank) and a CIDR containing 1.38g of P4 (CIDR-P4) in the control (n=7) and the P4-treated group (n=7), respectively. On d 3 after P4 treatment, vaginal temperature was 0.3+/-0.03 degrees C greater compared with that on d 1 and d 5. In experiment 3, 9 cyclic multiparous lactating cows were enrolled 1+/-1 d after confirmed ovulation and a temperature logger inserted. Two days later, a CIDR-P4 was inserted on top of the CIDR-blank. On d 5+/-1 and d 7+/-1, respectively, the CIDR-P4 and CIDR-blank with the temperature logger were removed. During the CIDR-P4 treatment (48h), vaginal temperature was 0.2+/-0.05 degrees C and 0.1+/-0.05 degrees C greater than during the pre- and post-treatment periods (48h), respectively. Serum P4 concentration peaked during CIDR-P4 treatment (2.2+/-0.8 ng/mL) and was greater than during the pre-treatment period (0.2+/-0.2 ng/mL) for 48h. An increase in vaginal temperature could be due to endogenous and exogenous P4. However, a correlation between serum P4 concentrations and body temperature did not exist. Further investigations are warranted to better understand the pathways of the thermogenic effect of P4 on body temperature. PMID- 22541467 TI - Relationship between pregnancy per artificial insemination and early luteal concentrations of progesterone and establishment of repeatability estimates for these traits in Holstein-Friesian heifers. AB - Pregnancy per insemination is a major determinant of reproductive efficiency in cattle and is affected by concentrations of progesterone (P4) during early pregnancy. The relationship between pregnancy per artificial insemination (P/AI) and early luteal concentrations of P4, and repeatability of concentrations of P4 was examined on d 4, 5, 6, and 7 (day of standing estrus=d 0) in 118 Holstein Friesian heifers following 2 rounds of AI to 1 high-fertility sire. Repeatability estimates (R(e)) for P/AI were established following 4 rounds of AI. We found a linear and quadratic relationship between P/AI and concentrations of P4 on d 4 to 7 after estrus, as well as a linear and quadratic relationship between P/AI and the change in concentration of P4 from d 4 to 7 and from d 5 to 7. Optimum concentrations of P4 to maximize probability of P/AI were 2.5, 4.0, 5.0, 5.2, and 3.5 ng/mL for d 4, 5, 6, and 7, and the change from d 4 to 7, respectively. Repeatability of P/AI following 4 rounds of AI was low (R(e)=0.07). Repeatability estimates for concentrations of P4 from cycle to cycle indicated low repeatability between d 4 (R(e)=0.05) and 7 (R(e)=0.20). These data indicated the importance of P4 in the early luteal phase for pregnancy survival, but also demonstrated that high concentrations of P4 on these days have a deleterious effect on embryo viability. Early luteal (d 4 to 5) concentrations of P4 were a reasonable predictor of concentrations on d 7 and could be used as a diagnostic tool to identify animals at risk of subsequent embryo loss. PMID- 22541468 TI - Supplemental feeding with glycerol or propylene glycol of dairy cows in early lactation--effects on metabolic status, body condition, and milk yield. AB - The objective of this field study was to evaluate the effect of supplemental feeding with glycerol or propylene glycol to dairy cows in early lactation on metabolic status, body condition and milk yield. In total, 673 newly calved cows from 12 commercial Swedish dairy herds were randomized to daily supplementation with 450 g of glycerol (GLY), 300 g of propylene glycol (PG), or nothing (control, CON). Supplements were fed twice daily from 0 to 21 d in milk (DIM) as a top dress on concentrates. For each cow, data on parity, breed, calving date, monthly test-day milk yield, and cases of diseases were collected. Blood samples were taken at approximately 2, 5, and 8 wk postpartum (pp) and analyzed for glucose, beta-hydroxybutyrate (BHBA), nonesterified fatty acids (NEFA), and insulin. Samples taken within 3 wk pp were also analyzed for insulin-like growth factor 1 (IGF-1). Measurements of body condition score (BCS) and heart girth (HG) were obtained at approximately 2 and 5 wk pp and at time of first insemination. The effects of supplemental feeding with GLY or PG on the plasma concentrations of glucose, NEFA, BHBA, insulin, and IGF-1, and BCS, HG, and occurrence of disease were analyzed. No differences in BCS or HG or in plasma concentrations of glucose, BHBA, NEFA, or IGF-1 were found between the control group and any of the treatment groups. Cows in the GLY group had lower plasma insulin concentrations during DIM 0 to 63 compared with group CON, but no difference in insulin was found between the PG group and the CON group. Cows supplemented with GLY had a higher milk yield (kg of milk and kg of energy-corrected milk) during the first 90 DIM. Cows in the PG group tended to yield more milk during the same period. No differences in the occurrence of diseases were seen between the groups. In conclusion, supplementation with GLY in early lactation did increase milk yield without a subsequent decrease of metabolic status, and supplementation with PG tended to do the same. PMID- 22541469 TI - Liver protein expression in dairy cows with high liver triglycerides in early lactation. AB - Fatty liver is a frequent subclinical health disorder in dairy cows that may lead to disorders related to the liver function. However, the effect of triglyceride (TG) accumulation on liver metabolic pathways is still unclear. The objective was, therefore, to characterize quantitative differences in the liver proteome between early lactation dairy cows with a low or high liver TG content. The liver proteome analysis indicated that a high liver TG content in early lactation dairy cows is associated with increased oxidation of saturated fatty acids, oxidative stress, and urea synthesis and decreased oxidation of unsaturated fatty acids. Furthermore, liver gluconeogenesis is apparently not impaired by an increased liver TG content. Based on correlations between liver proteins and plasma components, we suggest that future studies investigate the sensitivity and specificity of plasma aspartate aminotransferase, beta-hydroxybutyrate, total bilirubin, total bile acids, and gamma-glutamyltransferase for potential use as blood-based biomarkers for early detection of fatty liver in dairy cows. Our study is the first to study the proteome of dairy cows with naturally occurring fatty liver in early lactation. PMID- 22541470 TI - In vitro effects of Escherichia coli lipopolysaccharide on the function and gene expression of neutrophils isolated from the blood of dairy cows. AB - The objectives of this study were to investigate the effect of Escherichia coli lipopolysaccharide (LPS) on the function of bovine neutrophils (PMNL) collected from mid lactation cows and determine the differential effects of LPS on gene expression of PMNL purified from early and mid lactation cows. The PMNL from mid lactation cows (187+/-13 d postpartum) were incubated with 0, 1, 25, and 50 MUg/mL of LPS for 120 min, and the generation of reactive oxygen species (ROS), PMNL extracellular traps (NET), chemotaxis, and killing of Staphylococcus aureus were determined. Incubation of PMNL with 25 MUg/mL of LPS increased intracellular ROS by 79% in mitogen-stimulated PMNL. Addition of 50 MUg/mL of LPS enhanced intracellular ROS by nonstimulated and stimulated PMNL by 184 and 154%, respectively. Nonstimulated PMNL incubated with 25 and 50 MUg/mL of LPS had a 105% increase in NET. Addition of LPS had no effect on subsequent PMNL chemotaxis or killing of Staph. aureus. To examine the effect of LPS on the expression of genes involved in PMNL function and cytokine production, mRNA was purified from PMNL isolated from mid lactation (146+/-2 postpartum; n=10) and early lactation cows (7 d postpartum; n=10), after a 120-min incubation with 0 or 50 MUg/mL of LPS. Amounts of interleukin-8 (IL-8), tumor necrosis factor (TNF), bactericidal/permeability-increasing protein (BPI), myeloperoxidase (MPO), superoxide dismutase 2 (SOD2), NADPH oxidase 4 (NOX4), Cytochrome b-245, alpha polypeptide (CYBA), histone H2A/1 (H2A/1), and histone H2B-like (H2B) mRNA were determined relative to that of beta-actin by real-time quantitative PCR. Regardless of stage of lactation, PMNL incubated with 50 MUg/mL of LPS had 537 and 45% higher mRNA contents of IL-8 and SOD2 compared with 0 MUg/mL LPS, respectively. In addition, LPS augmented the expression of TNF, BPI, and CYBA (2,908, 59, and 158% compared with controls, respectively) only in PMNL from mid lactation cows. Addition of LPS did not affect mRNA levels of MPO, NOX4, H2A/1, or H2B. Independent of LPS treatment, PMNL from mid lactation cows had 99% higher mRNA contents of IL-8 compared with PMNL from early lactation cows. The PMNL from early lactation cows had a 634% increase in MPO mRNA expression relative to that from mid lactation cows. These results support that LPS directly stimulates PMNL to produce ROS and express NET. In addition, LPS enhances the generation of ROS by PMNL in response to other stimuli and increases the expression of genes encoding inflammatory mediators and enzymes involved in the production of ROS. Finally, reduced PMNL gene expression of IL-8 (regardless of LPS activation), TNF, CYBA, and BPI (upon stimulation with LPS) in early lactation may elucidate several mechanisms by which PMNL may become immune-incompetent during this period. PMID- 22541471 TI - The effect of strategic supplementation with trans-10,cis-12 conjugated linoleic acid on the milk production, estrous cycle characteristics, and reproductive performance of lactating dairy cattle. AB - The objective was to determine the effects of a protected (lipid-encapsulated) conjugated linoleic acid (LE-CLA) supplement on milk production, estrous cycle characteristics, and reproductive performance in lactating dairy cows on a pasture-based diet. Spring calving dairy cows (n=409) on a single pasture-based commercial dairy farm were used in a completely randomized block design. Cows were assigned to 1 of 2 dietary supplements [LE-CLA (n=203) or no supplement (control, n=206)]. The LE-CLA cows received 51 g/d of a lipid supplement containing 5 g of both trans-10,cis-12 and cis-9,trans-11 CLA from 0 to 60 d in milk. Milk samples were collected 3 times weekly, and each sample was analyzed for progesterone to determine the interval to first ovulation and estrous cycle characteristics. Milk yield and concentrations of fat, protein, and lactose were measured every 2 wk. Cows were inseminated following visual observation of estrus. The breeding season commenced on April 8, 2009 and continued for 16 wk. Transrectal ultrasonography was carried out at 30 to 36 d and 60 to 66 d post-AI to diagnose pregnancy. The LE-CLA treatment resulted in a decrease in milk fat concentration (36.9+/-0.06 g/kg vs. 30.7+/-0.06 g/kg for control and LE-CLA, respectively) and yield (0.91+/-0.02 kg/d vs. 0.84+/-0.02 kg/d for control and LE CLA, respectively); however, milk yield was increased by LE-CLA supplementation (24.7+/-0.7 kg/d vs. 27.2+/-0.7 kg/d for control and LE-CLA, respectively), resulting in no overall difference in milk energy output. No effect of LE-CLA was observed on any estrous cycle characteristics or measures of reproductive performance. These results support that in pasture-based systems of dairy production, where energy intake limits milk production, energy spared by CLA induced milk fat depression is partitioned toward increasing milk yield rather than toward body reserves. PMID- 22541472 TI - Effects of management and health on the use of activity monitoring for estrus detection in dairy cows. AB - The aim was to investigate 1) the relationship between the physical activity index created for each cow by activity monitoring systems and the identification of the preovulatory follicular phase, and 2) the influence of various production, health, and cow factors on the relationship between physical activity and estrous behavior. Eighty-nine spring calving cows, on pasture, were monitored during the breeding season using the neck-mounted estrous activity monitor Heatime (SCR Engineers Ltd., Netanya, Israel). Milk samples were collected twice weekly for progesterone assay to characterize resumption of reproductive activity. Reproductive tract health was assessed weekly by ultrasonography and vaginal mucus scoring. Body condition score and milk yield were assessed every 2 wk. Heatime identified 72% of preovulatory follicular phases from which 145 inseminations resulted in 69 conceptions; 32% of activity clusters were associated with high-progesterone states (i.e., false positives). By inclusion of a 6 to 8-h duration threshold and maintaining the borderline peak activity threshold, this was improved to 87.5% with 21.3% false positives. Mean (+/- standard error of the mean) peak activity and cluster duration (19.3+/-0.53 and 10.8+/-0.38, respectively) were highest for the second or subsequent preovulatory follicular phases followed, in descending order, by those during first preovulatory follicular phases (14.8+/-2.13 and 8.4+/-1.4, respectively) and high progesterone states (8.0+/-0.47 and 3.0+/-0.42, respectively). The odds of an activity cluster being in a preovulatory follicular phase rather than a high progesterone phase improved by 29% for every 1-unit increase in peak activity and by 91% for every 2-h increase in duration. The probability of an activity cluster detecting a preovulatory follicular phase was improved if it was a second or subsequent follicular phase, if body condition score was 0.25 units higher, if milk yield was 10 kg lower, and uterine infection was absent. Conception rate was influenced by insemination on the same day (52%) or day after a cluster (34.3%); inseminations were carried out using the a.m.-p.m. rule. Advances in the development of more accurate automatic monitoring of the preovulatory follicular phase will aid the timing of insemination and, thus, improve conception rates. PMID- 22541473 TI - Effect of alternative models for increasing stocking density on the short-term behavior and hygiene of Holstein dairy cows. AB - The primary objective of this study was to evaluate short-term responses in lying behavior and hygiene of Holstein dairy cows housed at a stocking density of 100 (1 cow per stall and headlock) or 142% imposed by 1) the denial of access to freestalls and headlocks, 2) the denial of access to freestalls, headlocks, and 26.6 m(2) of alley space, or 3) the addition of a rotating group of 14 cows to the resident group of 34 cows. The secondary objective was to determine the bioequivalence of the 3 methods of experimentally increasing stocking density. Cows (n=136) were assigned to 1 of 4 pens in a 4-row freestall barn and treatments were allocated using a 4*4 Latin square with 14-d periods. Lying time (h/d) and number of bouts/d for 12 focal cows per pen were determined using dataloggers recording at 1-min intervals during the final 5 d of each period. Dry matter intake (DMI) was established from the pen mean over the final 4 d of each period. Feeding and rumination activities on focal cows were determined by direct observation at 10-min intervals for 24h on d 11. Hygiene of focal cows was assessed from the difference in the scores after the legs and udder were cleaned on d 2 of each period and those on d 14. Lying time was greater for 100% stocking density (13.0 h/d) than the 142% stocking density treatments (11.8 h/d), which did not differ. Lying bouts (12.3/d) and bout duration (64.8 min/bout) did not differ among treatments. Short-term responses in DMI (24.6 kg/d) did not differ in response to the treatments. The 3 stocking density treatments decreased, or tended to decrease, the time spent feeding compared with 100% (4.4 versus 4.2 h/d). The stocking density treatments decreased the percentage of rumination occurring within a stall (92.3 versus 85.3%). A treatment effect on udder and leg hygiene scores was not evident on d 14 of each period or in the change from d 2 to 14 of each period. With the exception of rumination time (h/d), the 3 methods for experimentally imposing stocking density were bioequivalent for responses in behaviors, DMI, and hygiene. Future stocking density experiments in 4-row barns should simply deny resting and feeding space to simulate overcrowded housing conditions for lactating dairy cows because it is bioequivalent to more complicated, and potentially confounding, research models. PMID- 22541474 TI - Incidence of subclinical mastitis in Dutch dairy heifers in the first 100 days in lactation and associated risk factors. AB - Heifer mastitis is a problem and risk factors may differ between heifers and older cows. The aim of this study was to estimate the heifer subclinical mastitis (HSCLM) incidence based on elevated somatic cell count (SCC) in the first 100 d in lactation and the associated risk factors in Dutch dairy herds. In 2008, 173 farmers filled in a questionnaire regarding housing and herd management factors potentially related to udder health. In addition, monthly milk production and SCC data from all cattle were provided by the Dutch Royal Cattle Syndicate (CRV, Arnhem, the Netherlands). Heifer subclinical mastitis incidence was calculated at the herd level as the number of heifer cases divided by the number of heifers at risk in the first 100 d in milk. Linear regression models were used for the analyses. On average, 25.5% [95% confidence interval (CI): 23.9 to 27.0%] of the heifers had subclinical mastitis. Heifers with a high SCC (>150,000 cells/mL) on the first test day after calving that returned to SCC levels below the cut-off continued to have a higher SCC throughout the study period compared with heifers with a low SCC (<=150,000 cells/mL) at the first test day after calving. Housing heifers together with lactating cows close to calving was protective from HSCLM incidence compared with separate housing (-4.5%; 95% CI: -8.7 to -0.2%). In addition, herds in which the farmer removed supernumerary teats of calves had a 7.0% (95% CI: 2.8 to 11.3%) lower HSCLM incidence and day and night grazing was also protective (-5.9%; 95% CI: -10.6 to -1.3%). Herds that were milked with an automatic milking system had, on average, a 6.9% (95% CI: 2.2 to 11.5%) higher HSCLM incidence and submitting milk samples for bacteriological culturing in the previous year was also associated with a higher HSCLM incidence (4.1%; 95% CI: 1.1 to 7.1%). Heifer subclinical mastitis is prevalent in all dairy herds, with a large variation in incidence. A high SCC in heifers at the first test day after calving appears to indicate a prolonged effect on udder health. Several management factors were found to be associated with HSCLM incidence that may help in reducing HSCLM. PMID- 22541475 TI - Factors associated with cattle cleanliness on Norwegian dairy farms. AB - Animal cleanliness in dairy herds is essential to ensure hygienic milk production, high microbial quality of carcasses, good hide quality, and animal welfare. The objective of this study was to identify on-farm factors associated with dairy cattle cleanliness. The study also examined differences in risk factors and preventive factors between contrasting herds regarding cattle cleanliness. In total, 60 dairy herds, selected from a national database, were visited by 2 trained assessors during the indoor feeding period in February and March 2009. In Norwegian abattoirs, cattle are assessed and categorized according to hide cleanliness, based on national guidelines, using a 3-category scale. Dirty animals result in deductions in payment to farmers. "Dirty" herds (n=30) were defined as those that had most deductions in payment registered due to dirty animals slaughtered in 2007 and 2008. "Clean" herds (n=30) were those that had similar farm characteristics, but slaughtered only clean animals during 2007 and 2008, and thus had no deductions in payments registered. The dairy farms were located in 4 different areas of Norway. Relevant information, such as housing, bedding, feeding, and management practices concerning cleaning animals and floors, was collected during farm visits. In addition, the cleanliness of each animal over 1 yr of age (4,991 animals) was assessed and scored on a 5-point scale, and later changed to a dichotomous variable during statistical analysis. Milk data (milk yield and somatic cell counts) were obtained from the Norwegian Dairy Herd Recording System. Factors associated with dirty animals in all 60 herds were, in ranked order, high air humidity, many dirty animals slaughtered during the previous 2 yr, lack of preslaughter management practices toward cleaning animals, animal type (heifers and bulls/steers), housing (freestalls and pens without bedding), manure consistency, and lack of efforts directed toward cleaning the animals throughout the year. Additional factors associated with dirty animals in the dirty herds were water leakage from drinking nipples/troughs into lying areas, bedding type, and feed type. In the clean herds, additional risk factors were water leakage from drinking nipples/troughs and low milk yield. PMID- 22541476 TI - Lipolysis in early lactation is associated with an increase in phosphorylation of adenosine monophosphate-activated protein kinase (AMPK)alpha1 in adipose tissue of dairy cows. AB - Adenosine monophosphate-activated protein kinase (AMPK)alpha1 is activated in the context of triacylglycerol hydrolysis in adipose tissue in monogastric animals. This study describes AMPKalpha1 protein expression and the occurrence of its phosphorylated form (pAMPKalpha1) in different adipose tissue depots as influenced by time and postpartum diet in dairy cows. Biopsy samples were obtained from subcutaneous (SCAT) and retroperitoneal (RPAT) adipose tissues of 20 Holstein cows 21 d prepartum (ap) and 1 and 21 d postpartum (pp). After d 1 pp, cows were randomly assigned to 2 groups (n=10) and fed different amounts of concentrate until the third biopsy sampling at 21 d pp. Protein expression of AMPK and the extent of its phosphorylation in adipose tissue were measured by semiquantitative Western blotting. Results were not influenced by postpartum feeding. Therefore, both groups were pooled and data analyzed together. Expression of AMPKalpha1 in SCAT showed a decrease over time, resulting in lower expression at 1d pp compared with 21 d ap. Expression in RPAT was maintained over time. Phosphorylation increased in SCAT, showing a greater extent of phosphorylation at d 21 pp compared with 21 d ap. In RPAT, this could be seen as a trend. The proportion of pAMPKalpha1 to AMPKalpha1 significantly increased over time in both tissues. In the first adipose tissue sampling (21 d ap), AMPKalpha1 protein expression and extent of phosphorylation were significantly higher in RPAT than in SCAT. Lipolysis in early lactation of dairy cows was associated with an increase in phosphorylation of AMPKalpha1 and ratio of pAMPKalpha1 to AMPKalpha1 in bovine adipose tissues. This indicates that AMPKalpha1 may be involved in the regulation of energy metabolism of bovine adipose tissues. PMID- 22541477 TI - A field trial on the effect of propylene glycol on displaced abomasum, removal from herd, and reproduction in fresh cows diagnosed with subclinical ketosis. AB - The purpose was to determine the effect of oral propylene glycol (PG) administration in fresh cows diagnosed with subclinical ketosis (SCK). Measured outcomes were development of displaced abomasum (DA) and removal from herd in the first 30 d in milk (DIM), conception to first service, and time to conception within 150 DIM. Cows from 4 freestall dairy herds (2 in New York and 2 in Wisconsin) were each tested 6 times for SCK from 3 to 16 DIM on Mondays, Wednesdays, and Fridays using the Precision Xtra meter (Abbott Laboratories, Abbott Park, IL). Subclinical ketosis was defined as a blood beta-hydroxybutyrate concentration of 1.2 to 2.9 mmol/L. Cows with SCK were randomized to treatment group (oral PG) or untreated control group (no PG); treatment cows were orally drenched with 300 mL of PG once daily from the day they tested 1.2 to 2.9 mmol/L until the day they tested <1.2 mmol/L. Mixed effects multivariable Poisson regression was used to assess the effect of PG on DA, removal from herd, and conception to first service; a semiparametric proportional hazards model was used to evaluate the days-to-conception outcome. A total of 741 of 1,717 (43.2%) eligible enrolled cows had at least 1 beta-hydroxybutyrate test of 1.2 to 2.9 mmol/L. Of these, 372 were assigned to the PG treatment group and 369 to the control group. Thirty-nine cows (5.3%) developed a DA after testing positive for SCK and 30 cows (4.0%) died or were sold within the first 30 DIM. Based on risk ratios, control cows were 1.6 times more likely [95% confidence interval (CI)=1.3 to 2.0] to develop a DA and 2.1 times more likely (95% CI=1.2 to 3.6) to die or be sold than cows treated with PG. In addition, PG-treated cows were 1.3 times more likely (risk ratio 95% CI=1.1 to 1.5) to conceive at first insemination than control cows in 3 of the herds. No difference was observed in days to conception within 150 DIM between treatment groups (hazard ratio for PG cows=1.1, 95% CI=0.8 to 1.4), with a median time to conception of 100 d (95% CI=93 to 111) and 104 d (95% CI=95 to 114) for PG-treated and control cows, respectively. These results show that intensive detection of SCK, followed by treatment of positive cows with oral PG decreased the risk of developing a DA or leaving the herd within the first 30 DIM and increased the risk of conception to first service. PMID- 22541479 TI - Mastitis alert preferences of farmers milking with automatic milking systems. AB - The aim of this study was to assess farmers' preferences for the performance characteristics of mastitis detection systems. Additionally, we looked at whether certain groups of farmers could be distinguished with specific preferences. Farmers' opinions concerning mastitis detection systems, as well as general information about the farm and the farmer, were investigated with a standard questionnaire. The second part of the questionnaire was specifically aimed at elucidating preferences. Definitions of time windows and performance parameters, such as sensitivity and specificity, were incorporated into characteristics of a detection system (attributes) that reflect farmers' daily experience. Based on data from 139 farmers, we concluded that, on average, they prefer a clinical mastitis detection system that produces a low number of false alerts, while alerting in good time and with emphasis on the more severe cases. These 3 attributes were evaluated as more important than the 3 other attributes, representing the costs of the detection system, the number of missed cases, and how long before clinical signs alerts need to be given. Variation in importance per attribute, however, was high, denoting that farmers' preferences differ considerably. Although some significant relationships were found between farm characteristics and attributes, no clear groups of farmers with specific preferences could be distinguished. Based on these results, we advise making detection systems adaptable for the farmers to satisfy their preferences and to match the circumstances on the farm. Furthermore, these results support that for evaluation of detection algorithms comparisons have to be made at high levels of specificity (e.g., 99%) and time windows have to be kept small (preferably no more than 24 h). PMID- 22541478 TI - Effects of presynchronization and length of proestrus on fertility of grazing dairy cows subjected to a 5-day timed artificial insemination protocol. AB - The objectives were to compare the effects of 2 methods of presynchronization and 2 lengths of proestrus on fertility of grazing dairy cows subjected to a 5-d timed artificial insemination (AI) protocol at initiation of breeding season. Lactating dairy cows (n=1,754) from 3 seasonal grazing farms were blocked within farm by breed, parity, and days in milk (DIM). Study d 0 was considered the day of AI of cows in COS72 (72h of proestrus). Within each block, cows were randomly assigned to 1 of 2 presynchronization treatments: a PGF(2alpha)-based program, Presynch, consisting of 2 injections of PGF(2alpha) administered on d -32 and 18, or a PGF(2alpha)-GnRH-based program, Double-Ovsynch (DO), consisting of GnRH on d -25, PGF(2alpha) on d -18, and GnRH on d -15. Within each of the 2 presynchronization treatments, cows were randomly assigned to 1 of 2 lengths of proestrus within the 5-d timed AI protocol, consisting of GnRH on d -8, PGF(2alpha) on d -3 and -2, and GnRH+AI at either 58 h (COS58) or 72 h (COS72) after the d -3 PGF(2alpha) injection. Ovaries were scanned by ultrasonography twice, on d -42 and -32, to determine estrous cyclicity before enrollment in the study. Blood was sampled and analyzed for concentrations of estradiol on the day of AI. Pregnancies per AI (P/AI) were determined 30 and 65 d after AI. Presynchronization did not affect the concentration of estradiol at AI (DO=6.4 vs. Presynch=5.8 pg/mL), detection of estrus at AI (20.8 vs. 25.9%), or P/AI on d 30 (56.8 vs. 59.1%) and 65 (52.5 vs. 52.4%) after the first AI. Cows receiving COS72 had increased concentration of estradiol (6.6 vs. 5.5 pg/mL) and detection of estrus at AI (28.5 vs. 10.8%) compared with cows receiving COS58. Length of proestrus did not affect P/AI on d 30 (COS72=58.7 vs. COS58=56.1%) but, in Presynch cows, COS58 was detrimental to fertility on d 65 after AI (54.9 vs. 46.5%). Pregnancy loss between gestational d 30 and 65 was greater for Presynch than for DO (7.6 vs. 11.3%), but it was not affected by length of proestrus. Estrous cyclic cows had greater P/AI than anovular cows on d 30 (61.7 vs. 35.1%) and 65 (56.1 vs. 30.7%), but no interaction between estrous cyclic status and treatments was detected. Crossbred Holstein/Jersey cows had superior fertility than their purebred counterparts during the breeding season. The Presynch and DO protocols resulted in similar fertility with no overall difference between the presynchronization methods; however, limiting the length of proestrus to 58 h reduced P/AI in the 5-d timed AI protocol when cows had their estrous cycle presynchronized with Presynch but not with DO. PMID- 22541480 TI - Blocking opioid receptors alters short-term feed intake and oro-sensorial preferences in weaned calves. AB - Opioid peptides may participate in the control of feed intake through mechanisms involving pleasure reward linked to consumption of palatable feed. The objective of this study was to determine whether blocking opioid receptors might void oro sensorial preferences of calves, and affect circulating glucose, insulin, and anorexigenic hormones in fasted and fed calves. Two experiments involved 32 Holstein calves [body weight (BW)=86.5+/-1.73 kg, age=72+/-0.6 d]. In experiment 1, all calves received an ad libitum choice of the same feed either unflavored or flavored with a sweetener (Luctarom SFS-R, Lucta, Montornes del Valles, Spain). Feed consumption was recorded every 2 h from 0800 to 1400 h for 3 consecutive days to verify the establishment of an oro-sensorial preference for sweet feed (SF). The SF was preferred over the control feed (CF) at all recorded times. In experiment 2, calves were subjected to a 2 * 2 factorial design to study the interaction between opioid activity and metabolic state. Half of the calves were fasted for 14 h (FAS), whereas the other half remained well fed (FED). Within each of these groups, at feeding time (0800 h), half of the calves received an i.v. injection of naloxone (NAL, an opioid receptor antagonist; 1 mg/kg of BW) and the other half was injected with saline solution (SAL; 0.9% NaCl). Therefore, treatments were FED-NAL, FED-SAL, FAS-NAL, and FAS-SAL. Blood samples were taken at -10, 20, 180, and 240 min relative to NAL or SAL injections. As expected, cumulative consumption of starter feed was greater in FAS than in FED calves. Total feed consumption 2 h after feeding was lower in NAL than in SAL calves. Calves in the FAS group did not discern between CF and SF during the first 4 h after feed offer. Preference for SF was greater in SAL than in NAL calves. Calves in the FED-SAL treatment preferred SF at 2 and 6 h after feed offer and tended to prefer SF at 4 h after feeding. However, FED-NAL calves did not discern between SF and CF during the first 4 h after feeding and tended to prefer SF only after 6 h from feeding. Plasma glucose, insulin, and cholecystokinin concentrations were greater in FED than in FAS calves. Injection of naloxone decreased plasma glucagon-like peptide-1 (GLP-1) in NAL calves. Blocking opioid receptors reduced intake the first 2 h after naloxone injection in FED calves, altered oro sensorial preferences, and reduced plasma GLP-1 concentration. In conclusion, the opioid peptide system may control short-term feed intake by modulating the oro sensorial response triggered by feed consumption, especially when calves are fed ad libitum. PMID- 22541481 TI - Local and systemic response to intramammary lipopolysaccharide challenge during long-term manipulated plasma glucose and insulin concentrations in dairy cows. AB - The metabolic load during periods of high milk production in dairy cows causes a variety of changes of metabolite blood concentrations including dramatically decreased glucose levels. These changes supposedly impair the immune system. The goal of this study was, therefore, to evaluate adaptations of the cow's immune system in response to an intramammary lipopolysaccharide (LPS) stimulation during a 3-d modification of plasma glucose and insulin induced by different clamp infusions. Seventeen midlactating dairy cows received a hypoglycemic hyperinsulinemic clamp induced by insulin infusion (HypoG; n=5), a euglycemic hyperinsulinemic clamp induced by insulin and glucose infusion (EuG; n=6), or infusion of saline solution (NaCl; n=6) for 56 h. At 48 h of infusion, 2 udder quarters were challenged with 200 MUg of Escherichia coli LPS. At 48 h of infusion (immediately before LPS challenge), tumor necrosis factor alpha, lactoferrin, and serum amyloid A (SAA) mRNA abundance was increased in HypoG and Il-1beta mRNA abundance was decreased in EuG. After LPS challenge, plasma glucose concentration did not decrease, although plasma insulin increased simultaneously in all groups either due to enhanced endogenous release (NaCl) or due to increased insulin infusion rate (HypoG; EuG). Plasma cortisol, rectal temperatures, and milk somatic cell count of challenged quarters increased, whereas plasma nonesterified fatty acid concentrations were similarly decreased across treatments. In mammary biopsies, increased mRNA expression of tumor necrosis factor alpha, IL-1beta, IL-8, and IL-10, and SAA were observed in LPS treated quarters of all groups, with a more pronounced increase in IL-1beta, IL 10, and SAA expression in EuG. Nuclear factor-kappaB mRNA expression was upregulated in NaCl and EuG but not in HypoG in response to LPS. Lactoferrin, toll-like receptor 4, and cyclooxygenase-2 mRNA expression was increased in LPS treated quarters of EuG only, and 5-lipoxygenase mRNA expression was decreased in LPS-treated quarters only in treatments HypoG and NaCl. In conclusion, intramammary LPS induces local and systemic inflammatory responses, as well as systemic insulin resistance. The observed treatment differences of the mammary mRNA expression of several immune parameters both before and after LPS challenge indicate a direct influence of changed glucose and insulin concentrations during the course of lactation on the immune defense against mastitis pathogens. PMID- 22541482 TI - Level of nutrient intake affects mammary gland gene expression profiles in preweaned Holstein heifers. AB - Bovine mammary parenchyma (PAR) and fat pad (MFP) development are responsive to preweaning level of nutrient intake. We studied transcriptome alterations in PAR and MFP from Holstein heifer calves (n=6/treatment) fed different nutrient intakes from birth to ca. 65 d age. Conventional nutrient intake received 441 g of dry matter (DM)/d of a control milk replacer (MR) [CON; 20% crude protein (CP), 20% fat, DM basis]. Calves in the accelerated nutrition groups received 951 g/d of high-protein/low-fat MR (HPLF; 28% CP, 20% fat, DM basis), 951 g/d of high protein/high-fat MR (HPHF; 28% CP, 28% fat, DM basis), or 1,431 g/d of HPHF (HPHF+) MR. Out of 13,000 genes evaluated, over 1,500 differentially expressed genes (DEG) were affected (false discovery rate <0.10) by level of nutrient intake in PAR or MFP. Feeding HPLF versus CON resulted in the most dramatic changes in gene expression, with 278 and 588 DEG having >=1.5-fold change in PAR and MFP. In PAR, the most-altered molecular functions were associated with metabolism of the cell (molecular transport and lipid metabolism) with most of the genes downregulated in HPLF versus CON. In MFP, DEG also were primarily associated with metabolism but changes also occurred in genes linked to cell morphology, cell-to-cell signaling, and immune response. Compared with CON, feeding HPHF or HPHF+ did not result in substantial additional effects on DEG beyond those observed with HPLF. The pentose phosphate, mitochondrial dysfunction, and ubiquinone biosynthesis pathways were among the most enriched due to HPLF versus CON in PAR and were inhibited, whereas glycosphingolipid biosynthesis, arachidonic acid metabolism, and eicosanoid synthesis pathways were among the most enriched due to HPLF versus CON in MFP and were inhibited. These responses suggest that, in PAR, doubling nutrient intake from standard feeding rates inhibited energy metabolism and activity of oxidative pathways that partly serve to protect cells against oxidative stress. The MFP in those heifers appeared to decrease production of lipid-derived metabolites that may play roles in signaling pathways within the adipocyte. Overall, results indicated that prepubertal/preweaned mammary transcriptome is responsive to long-term enhanced nutrient supply to achieve greater growth rates before weaning. The biological significance of these results to future milk production remains to be elucidated. PMID- 22541483 TI - Short communication: Endoplasmic reticulum stress gene network expression in bovine mammary tissue during the lactation cycle. AB - The endoplasmic reticulum (ER) has a crucial role in cellular metabolism. Recent studies in nonruminants discovered that components of the ER stress pathway, induced during the unfolded protein response, play critical roles in regulating lipogenesis. The bovine mammary gland faces extreme metabolic stress at the onset of lactation due primarily to the increase in flux through pathways associated with milk fat and protein synthesis. Our objective was to study, via quantitative real-time PCR, the expression of the ER stress pathway components P58IPK, PERK, XBP1, ATF4, ATF3, ATF6, CHOP, MBTPS1, GRP94, and BiP in mammary tissue (n=7 cows * 5 time points) collected at -15, 1, 15, 60, and 240 d relative to parturition. Expression of P58IPK and ATF4 increased to a peak at d 60, followed by a decrease by d 240 postpartum. Despite the decrease in expression by 240 d, P58IPK remained higher than prepartal levels (d -15). Expression patterns of ATF3 and CHOP were similar and peaked at d 15, followed by a decrease through d 240, at which point CHOP expression was still greater than prepartal levels. The sharp increase in milk production postpartum (d 15) as well as apoptosis during late lactation (240 d) may have induced a pseudo unfolded protein response state. This is supported by the similar expression patterns of P58IPK and PERK. In the context of lactation, however, transcriptional changes in the ER stress pathway at different stages of the lactation cycle are a normal aspect of the tissue's adaptation to the changing physiological state. PMID- 22541484 TI - Short communication: Effect of automatic postmilking teat disinfection and cluster flushing on the milking work routine. AB - The importance of a consistent and comprehensive milking routine as a critical component of any mastitis control program is well documented. However, as pressure on time increases, farmers are faced with 3 options: (1) adjust the milking routine to suit the time available, (2) undertake the task less thoroughly, or (3) examine which elements of the milking routine can be automated and substitute capital expenditure for labor. A study was undertaken on 5 farms in the United Kingdom in October and November 2007 to assess the effect on milking time of installing a commercial automatic postmilking teat disinfection and cluster back flushing system (ADF). Two of the farms recruited for the study were intending to purchase the ADF system in the near future and 3 farms had already invested in the technology. The farms ranged in size from 120 to 550 cows and included three 90 degrees rapid exit parlors, a herringbone parlor, and an abreast parlor. All 5 farms were visited for 2 successive milkings before the ADF was installed or disabled, and a detailed time and motion analysis was undertaken. After ADF was installed or the system reactivated, a further 2 milkings were monitored. All monitored farms showed a measurable reduction in milking time after the ADF system was installed. However, the magnitude of the reduction was greater than would be expected by simply removing the elements of postmilking teat disinfection and cluster sanitization. The benefits of ADF are greater than simply disinfecting teats and back flushing clusters and the time saving obtained may allow a more structured milking routine that may have additional benefits in terms of mastitis prevention and control. PMID- 22541485 TI - Short communication: The effects of experimentally induced Escherichia coli clinical mastitis on lying behavior of dairy cows. AB - Clinical mastitis is a commonly occurring and economically important problem in the dairy industry. Researchers have suggested that changes in lying behavior could be useful as early indicators of cow discomfort and poor welfare. The objective of this study was to determine the associations between the onset of illness resulting from experimentally induced clinical mastitis and measures of lying behavior. Clinical mastitis was induced in 21 lactating dairy cows (parity=2.0+/-1.0, range=1 to 4; days in milk=61+/-18) by intramammary infusion of 25 or 100 MUg of Escherichia coli lipopolysaccharide (LPS) into 1 uninfected mammary quarter. Lying behavior was monitored from 2 d before through 3 d after the LPS challenge by fitting each cow with a data logger. Calculated outcome measures were total lying time, lying time on the side of the intramammary infusion, number of lying bouts, and average lying bout duration. Cows spent less time lying down on the day of the challenge compared with the 2 d before (633.3 vs. 707.0 min/d; SE=29.6), particularly during the 4 to 7h following LPS infusion. However, no significant relationship was found between the mammary quarter challenged and cow preference for lying side throughout the episode of induced clinical mastitis. Given that lying is a high-priority behavior in dairy cows and that increased lying time is an adaptive sickness behavior to facilitate recovery, we infer that this reduction in lying time may present a concern for cows with clinical mastitis. Although additional studies with larger numbers of animals are needed, automated monitoring of lying behavior could be an important component of the on-farm early detection of health problems, such as mastitis, in the future. PMID- 22541486 TI - Technical note: The risk ratio, an alternative to the odds ratio for estimating the association between multiple risk factors and a dichotomous outcome. AB - The objectives were (1) to explain why the risk ratio (RR) is an appropriate measure of association when the outcome of interest is dichotomous (e.g., displaced abomasum or no displaced abomasum) in both cohort studies and randomized trials; and (2) to outline an applied method for estimating the RR using currently available software. Interest in the association between multiple risk factors and a yes or no outcome is very common in the dairy industry; historically, logistic regression, which reports odds ratios (OR), was the method available in common statistical packages to evaluate this kind of association. However, the OR can overestimate the magnitude of the response in cohort studies and randomized trials when the outcome frequency is large. In addition, the interpretation of odds is not intuitive; fortunately, recent advances in statistical software have allowed the estimation of the RR. Because SAS software (SAS Institute Inc., Cary, NC) is commonly used to analyze data, this technical note outlines the basic programming code that may be used to estimate the RR from raw data. Example data from a prospective cohort study was used to compare the OR and RR of developing a displaced abomasum or ketosis or metritis based on multiple predictors, their interaction, and a random effect (e.g., herd). PMID- 22541487 TI - Effects of feeding a calf starter on molecular adaptations in the ruminal epithelium and liver of Holstein dairy calves. AB - The objective of this study was to elucidate the effect of feeding a calf starter on the volatile fatty acid (VFA) profile in the rumen and on expression of genes involved in epithelial intracellular pH regulation, butyrate metabolism, and hepatic urea cycle during the weaning transition. Twenty Holstein bull calves were fed either milk replacer and hay (MR) or milk replacer, hay, and a commercial texturized calf starter (MR+S) in a randomized complete block design. All calves were fed 750 g/d of milk replacer as the basal diet. Calves on the MR+S treatment were also fed starter ad libitum, and the energy intake of calves within blocks was maintained by supplementing the MR group with extra milk replacer that was equivalent to the energy intake from calf starter. Calves were killed 3 d after they consumed 680 g/d of calf starter for 3 consecutive days. Calves fed MR+S had higher VFA concentrations in the rumen (99.1+/-8.1 vs. 64.6+/ 8.6 mM) and a higher molar proportion of butyrate (15.6+/-1.7 vs. 7.9+/-1.9%) than calves fed MR. Relative abundance of mRNA for monocarboxylate transporter isoform 1 was higher (1.45 vs. 0.53), and that of Na(+)/H(+) exchanger isoform 3 (0.37 vs. 0.82) and 3-hydroxy-3-methylglutaryl synthase isoform 1 (0.40 vs. 0.94) lower for the MR+S treatment compared with the MR treatment. In the liver, relative mRNA abundances of argininosuccinate synthetase isoform 1 (2.67 vs. 1.56), argininosuccinate lyase (1.44 vs. 0.99), and arginase isoform 1 (3.21 vs. 1.74) were greater for MR+S than for MR calves. Calf starter consumption appeared to increase fermentation in the rumen and affected expression of genes involved in cholesterol synthesis and intracellular pH regulation in ruminal epithelium, and those involved in urea cycle in the liver. PMID- 22541488 TI - Associations among dairy cow body condition and welfare-associated behavioral traits. AB - Some evidence exists that cow body condition score (BCS) is associated with risks to animal health, and that higher BCS in extensively kept animals provides a buffer against cold conditions or other adverse weather events. Not surprisingly, measures of BCS feature in dairy cattle welfare assessment protocols. However, the degree to which BCS predicts welfare state, particularly in relation to the level of "hunger" experienced, is not well researched. The aim of this study was to examine associations between naturally arising variations in BCS in dairy cattle and time spent engaged in activities used as proxy indicators of hunger. Holstein-Friesian cows (n=113) of either North American or New Zealand ancestry were allocated to 1 of 3 levels of concentrate-feed supplementation (0, 3, or 6 kg of dry matter/d) and also offered pasture in excess of requirements. Body condition score (1 to 10 scale), pasture dry matter intake (DMI), and time budgets for grazing, ruminating, standing, and lying were recorded during early, mid, and late lactation. Body condition score varied over a wide range (2.5 to 8.5) and, within genetic strain and supplementation level, was inversely associated with pasture DMI, rate of DMI, and the proportions of time spent grazing and ruminating. In comparison, variation in BCS (within genetic strain and supplementation level) was directly associated with variations in time spent lying (in late lactation). Nevertheless, pasture DMI and time spent in the key behavioral activities were all within the normal expected limits for pasture-fed dairy cows. Thus, thin cows appeared able to achieve their nutritional requirements. Furthermore, even though thinner cows traded-off a small portion of their lying time in late lactation to forage longer, they still rested for normal periods each day. Based on these results, we found no difference in the welfare status of naturally thin and fat cows when they were offered generous pasture allowances with or without concentrate supplementation. The extent to which this pertains under conditions of persistently low feed allowances that result in reductions in BCS remains to be determined. PMID- 22541489 TI - Enteric methane emissions and lactational performance of Holstein cows fed different concentrations of coconut oil. AB - To determine if dietary medium-chain fatty acids (FA; C(8) to C(14)) may mitigate enteric methane emissions, 24 cows were blocked by body size (n=2) and randomly assigned to 1 sequence of dietary treatments. Diets were fed for 35 d each in 2 consecutive periods. Diets differed in concentrations of coconut oil (CNO; ~75% medium-chain FA): 0.0 (control) or 1.3, 2.7, or 3.3% CNO, dry matter basis. The control diet contained 50% forage (74% from corn silage), 16.5% crude protein (60% from rumen-degradable protein), 34% neutral detergent fiber (NDF; 71% from forage), and 28% starch, dry matter basis. Data and sample collections were from d 29 to 35 in environmentally controlled rooms to measure methane (CH(4)) production. Methane emitted was computed from the difference in concentrations of inlet and outlet air and flux as measured 8 times per day. Control cows emitted 464 g of CH(4)/d, consumed 22.9 kg of DM/d, and produced 34.8 kg of solids corrected milk/d and 1.3 kg of milk fat/d. Treatment with 1.3, 2.7, or 3.3% dietary CNO reduced CH(4) (449, 291, and 253 g/d, respectively), but concomitantly depressed dry matter intake (21.4, 17.9, and 16.2 kg/d, respectively), solids-corrected milk yield (36.3, 28.4, and 26.8 kg/d, respectively), and milk fat yield (1.4, 0.9, and 0.9 kg/d, respectively). The amount of NDF digested in the total tract decreased with increased dietary CNO concentrations; thus, CH(4) emitted per unit of NDF digested rose from 118 to 128, 153, and 166 g/kg across CNO treatments. Dietary CNO did not significantly affect apparent digestibility of CP but increased apparent starch digestibility from 92 to 95%. No FA C(10) or shorter were detected in feces, and apparent digestibility decreased with increasing FA chain length. Coconut oil concentrations of 2.7 or 3.3% decreased yields of milk FA C(14). The highest milk fat concentration (3.69%; 1.3% CNO) was due to the greatest yields of C(12) to C(16) milk FA. Milk FA concentrations of C(18:2 trans-10,cis-12) were related to increased dietary CNO concentrations and presumably to depressed ruminal NDF digestion. Moderate dietary CNO concentrations (e.g., 1.3%) may benefit lactational performance; however, CNO concentrations greater than or equal to 2.7% depressed dry matter intake, milk yield, milk fat yield, and NDF utilization. If mitigation of enteric CH(4) emissions is due to decreased digestion of dietary NDF, then this will lessen a major advantage of ruminants compared with nonruminants in food-production systems. Thus, CNO has limited use for enteric CH(4) mitigation in lactating dairy cows. PMID- 22541490 TI - Nutrient demand interacts with legume particle length to affect digestion responses and rumen pool sizes in dairy cows. AB - Effects of legume particle length on dry matter intake (DMI), milk production, ruminal fermentation and pool sizes, and digestion and passage kinetics, and the relationship of these effects with preliminary DMI (pDMI) were evaluated using 13 ruminally and duodenally cannulated Holstein cows in a crossover design with a 14 d preliminary period and two 19-d treatment periods. During the preliminary period, pDMI of individual cows ranged from 22.8 to 32.4 kg/d (mean=26.5 kg/d) and 3.5% fat-corrected milk yield ranged from 22.9 to 62.4 kg/d (mean=35.1 kg/d). Experimental treatments were diets containing alfalfa silage chopped to (1) 19 mm (long cut, LC) or (2) 10 mm (short cut, SC) theoretical length of cut as the sole forage. Alfalfa silages contained approximately 43% neutral detergent fiber (NDF); diets contained approximately 47% forage and 20% forage NDF. Preliminary DMI, an index of nutrient demand, was determined during the last 4 d of the preliminary period, when cows were fed a common diet, and used as a covariate. Main effects of legume particle length and their interaction with pDMI were tested by ANOVA. Alfalfa particle length and its interaction with pDMI did not affect milk yield or rumen pH. The LC diet decreased milk fat concentration more per kilogram of pDMI increase than the SC diet and increased yields of milk fat and fat-corrected milk less per kilogram of pDMI increase than the SC diet, resulting in a greater benefit for LC at low pDMI and for SC at high pDMI. The LC diet tended to decrease DMI compared with the SC diet. Ruminal digestion and passage rates of feed fractions did not differ between LC and SC and were not related to level of intake. The LC diet tended to decrease the rate of ruminal turnover for NDF but increased NDF rumen pools at a slower rate than the SC diet as pDMI increased. This indicated that the faster NDF turnover rate did not counterbalance the higher DMI for SC, resulting in larger NDF rumen pools for SC than LC. As pDMI increased, LC increased ruminal digestibility of potentially digestible NDF and total NDF, and SC decreased them, but total-tract digestibilities of potentially digestible NDF, total NDF, organic matter, and dry matter were lower for LC than for SC. Ruminal digestibilities of starch and organic matter interacted quadratically with level of intake. When legume silage was the only source of forage in the diet, increasing chop length from 10 to 19 mm tended to decrease DMI but did not negatively affect productivity of cows. PMID- 22541491 TI - Nutrient demand interacts with legume maturity to affect rumen pool sizes in dairy cows. AB - Effects of legume maturity on dry matter intake (DMI), milk production, ruminal fermentation and pool sizes, and digestion and passage kinetics, and the relationship of these effects with preliminary DMI (pDMI) were evaluated using 16 ruminally and duodenally cannulated Holstein cows in a crossover design with a 14 d preliminary period and two 17-d treatment periods. During the preliminary period, the pDMI of individual cows ranged from 22.9 to 30.0 kg/d (mean=25.9 kg/d) and the 3.5% fat-corrected milk yield ranged from 34.1 to 68.2 kg/d (mean=43.7 kg/d). Experimental treatments were diets containing alfalfa silage harvested either a) early-cut, less mature (EC) or b) late-cut, more mature (LC) as the sole forage. Early- and late-cut alfalfa contained 40.8 and 53.1% neutral detergent fiber (NDF) and 23.7 and 18.1% crude protein, respectively. Forage:concentrate ratios were 53:47 and 42:58 for EC and LC, respectively; both diets contained approximately 22% forage NDF and 27% total NDF. Preliminary DMI, an index of nutrient demand, was determined during the last 4d of the preliminary period when cows were fed a common diet and used as a covariate. Main effects of alfalfa maturity and their interaction with pDMI were tested by ANOVA. Alfalfa maturity and its interaction with pDMI did not affect milk yield but EC increased DMI compared with LC; thus, EC had lower efficiency of milk production than LC. The EC diet decreased milk fat concentration more per kilogram of pDMI increase than the LC diet, but milk fat yield was not affected. The lower concentration and faster passage rate of indigestible NDF for EC resulted in lower rumen pools of indigestible NDF, total NDF, and dry matter than did LC, which EC increased at a slower rate than did LC as pDMI increased. The EC diet decreased starch intake and increased ruminal pH compared with the LC diet. The rate of ruminal starch digestion was related to level of intake, but this did not affect ruminal or postruminal starch digestion. Total-tract digestibility of NDF, organic matter, and dry matter was higher for EC than LC. Microbial efficiency tended to be related to pDMI and the response differed by treatment. When alfalfa silage was the only source of forage in the diet, cows supplemented with additional concentrate to account for decreased protein and increased fiber concentrations associated with LC produced similar fat-corrected milk yields with greater efficiency than cows fed EC. PMID- 22541492 TI - Adding liquid feed to a total mixed ration reduces feed sorting behavior and improves productivity of lactating dairy cows. AB - This study was designed to determine the effect of adding a molasses-based liquid feed (LF) supplement to a total mixed ration (TMR) on the feed sorting behavior and production of dairy cows. Twelve lactating Holstein cows (88.2+/-19.5 DIM) were exposed, in a crossover design with 21-d periods, to each of 2 treatment diets: 1) control TMR and 2) control TMR with 4.1% dietary dry matter LF added. Dry matter intake (DMI), sorting, and milk yield were recorded for the last 7 d of each treatment period. Milk samples were collected for composition analysis for the last 3 d of each treatment period; these data were used to calculate 4% fat-corrected milk and energy-corrected milk yield. Sorting was determined by subjecting fresh feed and orts samples to particle separation and expressing the actual intake of each particle fraction as a percentage of the predicted intake of that fraction. Addition of LF did not noticeably change the nutrient composition of the ration, with the exception of an expected increase in dietary sugar concentration (from 4.0 to 5.4%). Liquid feed supplementation affected the particle size distribution of the ration, resulting in a lesser amount of short and a greater amount of fine particles. Cows sorted against the longest ration particles on both treatment diets; the extent of this sorting was greater on the control diet (55.0 vs. 68.8%). Dry matter intake was 1.4 kg/d higher when cows were fed the LF diet as compared with the control diet, resulting in higher acid detergent fiber, neutral-detergent fiber, and sugar intakes. As a result of the increased DMI, cows tended to produce 1.9 kg/d more milk and produced 3.1 and 3.2 kg/d more 4% fat-corrected milk and energy-corrected milk, respectively, on the LF diet. As a result, cows tended to produce more milk fat (0.13 kg/d) and produced more milk protein (0.09 kg/d) on the LF diet. No difference between treatments was observed in the efficiency of milk production. Overall, adding a molasses-based LF to TMR can be used to decrease feed sorting, enhance DMI, and improve milk yield. PMID- 22541493 TI - Excretion pattern of aflatoxin M1 in milk of goats fed a single dose of aflatoxin B1. AB - The feedstuffs used in dairy animals must be able to give consumers confidence about the wholesomeness of milk with regard to aflatoxin contamination. The aim of this study was to determine the excretion patterns of aflatoxin M(1) (AFM1) in the milk of dairy goats fed a single dose of pure aflatoxin B(1) (AFB1), which can occasionally occur if feeds are infected by hot-spot growth of molds that produce aflatoxins. Five dairy goats in midlactation were administered 0.8 mg of AFB1 orally. Individual milk samples were collected for 84 h after AFB1 dosage. Aflatoxin M(1) was found in milk in the highest concentration. In all goats, AFM1 was not detected in milk before AFB1 administration, but was detected in the first milking following AFB1 administration. The excretion pattern of AFM1 concentration in milk was very similar in all goats even if the values of the concentration differed between animals. The peak values for AFM1 concentration in milk was observed in milk collected during the milking at 3 and 6h. After the peak, the AFM1 in milk disappeared with a trend that fitted well a monoexponential decreasing function, and the toxin was not detected after 84 h. Only about 0.17% of the amount of AFB1 administered was detected as AFM1 in milk, and about 50% of this was excreted in the first liter of milk yielded after AFB1 intake. Correct procedures to prevent growth of molds, and consequent AFB1 contamination, on the feedstuffs for lactating goats represent the key to providing consumers a guarantee that milk is not contaminated by AFM1. PMID- 22541494 TI - Meta-analysis reveals threshold level of rapidly fermentable dietary concentrate that triggers systemic inflammation in cattle. AB - This study examined the extent by which changes in the concentrate level and neutral detergent fiber (NDF) content in the diet as well as the severity of acidotic insult, measured as the duration time of rumen pH below 6.0 and daily mean rumen pH, and the concentration of endotoxin in the rumen fluid are involved in the development of inflammatory conditions in cattle. A meta-analytical approach accounting for inter- and intraexperimental variation was used to generate prediction models, and data from recent studies were used to parameterize these models. A total of 10 recently conducted experiments with 43 different dietary treatments fulfilled the criteria for inclusion in this study. Diets of all of the experiments included in this meta-analysis were based on rapidly degradable grain sources, such as barley and wheat, and the findings of this study apply only to these kinds of diets. Data indicated that greater levels of concentrate in the diet were associated with increased concentrations of rumen endotoxin (R(2)=0.27), plasma haptoglobin (R(2)=0.19), and serum amyloid A (SAA) level (R(2)=0.46). Similar correlations, but in opposite directions, were observed between dietary NDF content and rumen endotoxin (R(2)=0.39) and plasma SAA concentrations (R(2)=0.22). The meta-analysis revealed that the relationships between those variables were not linear. Additionally, the breakpoint model fitted to the data of rumen endotoxin, plasma haptoglobin, and SAA indicated the presence of a threshold level of dietary concentrate and NDF, above which those responses became linear to increasing amounts of concentrate or decreasing contents of NDF in the diet. Also, feeding cattle more than 44.1% concentrate or less than 39.2% NDF in the diet was associated with a linear increase in the risk of systemic inflammation. Low daily mean rumen pH (R(2)=0.38) and duration of rumen pH <6.0 (R(2)=0.59) were associated with increased concentrations of endotoxin in the rumen fluid; although those events were not always associated with systemic inflammation. Accordingly, only 15 to 21% of the overall variation in the responses of SAA was explained by variables of rumen pH, whereas the concentrate level in the diet accounted for 46% of this variation. In conclusion, data from this study indicated the presence of thresholds of dietary concentrate and NDF levels in the diets based on rapidly fermentable grains beyond which the risk of systemic inflammation in cattle increases linearly. PMID- 22541495 TI - Effect of rumen-protected niacin on lipid metabolism, oxidative stress, and performance of transition dairy cows. AB - The objective of this study was to evaluate the effect of a rumen-protected niacin product (RPN; 65% nicotinic acid; NiaShure, Balchem Corp., New Hampton, NY) on lipid metabolism, oxidative stress, and performance of transition dairy cows. Thirty nonlactating multiparous Holstein cows in late gestation were paired according to expected calving date and randomly assigned to 12 g/cow per day of RPN product or to an unsupplemented control (CON) diet. Treatment diets were fed from 21 d before expected calving through 21 d after parturition. Blood samples were taken on d -21, -14, -7, 1, 7, 14, and 21 relative to calving for plasma nonesterified fatty acid (NEFA), beta-hydroxybutyrate (BHBA), glucose, and superoxide dismutase (SOD) analyses. Liver samples were taken by biopsy on d 1 and 21 relative to calving for triglyceride (TG) analysis. Data were analyzed for a randomized complete block design with repeated measures. Pre- and postpartum dry matter intake, milk yield, and protein were unaffected by treatment. Milk fat percentage (5.08 vs. 4.44%) and somatic cell score (3.93 vs. 2.48) were reduced for RPN. Treatment * time interactions were observed for energy-corrected milk (ECM) and fat-corrected milk (FCM) yields; RPN reduced ECM and FCM yields by 8.5 and 8.9 kg/cow per day, respectively, in the first week of lactation. Although body weight and condition score decreased during the experimental period, no differences due to treatment were observed. However, calculated postpartum energy balance tended to be improved for RPN because of the reduction in ECM yield. Time and treatment * time effects were observed for plasma NEFA. On d 1 postpartum, NEFA reached 1,138+/-80 MUEq/L for CON compared with 698+/-80 MUEq/L for RPN. Cows supplemented with RPN tended to have lower plasma NEFA concentrations than CON cows on d 7 and 14 postpartum. Plasma BHBA, glucose, and SOD and liver TG concentrations were unaffected by treatment. In conclusion, supplementation with 12 g/cow per day of the RPN product provided a bioavailable source of niacin that modified lipid metabolism but did not affect milk yield over the first 3 wk of lactation or oxidative stress of transition dairy cows. PMID- 22541496 TI - Ruminal escape and intestinal digestibility of ruminally protected lysine supplements differing in oleic acid and lysine concentrations. AB - This trial was conducted to determine the effect of the addition of 2 or 4% oleic acid to an hydrogenated fat coating applied to an experimental supplement with 55 or 58% lysine sulfate on ruminal escape and intestinal absorption of Lys. Two lactating Holstein cows (103 d in milk and 45.1 kg/d of milk) previously fitted with ruminal and duodenal cannulas were individually housed and fed a corn silage based ration. In situ and mobile bag techniques were utilized to evaluate the 4 test products. Twenty bags of each product were incubated for 16 h in each cow to determine ruminal escape. After ruminal incubation, products were repackaged, soaked in pepsin/HCl solution for 2 h, inserted into the duodenum, and subsequently collected in the feces. The percentage of dry matter and fat escaping the rumen decreased as oleic acid increased from 2 to 4% or as the proportion of supplemental Lys increased. An interaction was observed because of a greater reduction of N and Lys escaping ruminal fermentation and flowing to the small intestine for the product with 58% supplemental Lys and 4% oleic acid compared with the other products. No differences were observed in intestinal digestibility of dry matter, N, Lys, or fat or in the amount of Lys digested in the small intestine. Increasing the proportion of oleic acid in the coating applied to supplemental Lys increased ruminal degradation. The extent of the degradation increased as the proportion of Lys in the product increased. PMID- 22541497 TI - Forage proportion and particle length affects the supply of amino acids in lactating dairy cows. AB - This study was conducted to evaluate the effects of dietary factors that alter ruminal fermentability on intake, duodenal flows and intestinal digestibility of individual amino acids (AA) in lactating dairy cows. The experiment was designed as a 4*4 Latin square using 4 ruminally and duodenally cannulated lactating dairy cows. Treatments were arranged in a 2*2 factorial design; 2 forage particle lengths (FPL) of alfalfa silage (short and long) were combined with low (35:65) and high (60:40) forage-to-concentrate ratio (F:C; dry matter basis). Four diets were formulated using 2 cuts of alfalfa silage [short (7.9 mm) and long (19.1mm)], combined with 2 ratios of forage to barley grain concentrate (35:65 and 60:40). Overall, the interactions between dietary F:C and FPL on intake, duodenal flows, and intestinal digestibility of AA were marginal. Intakes of total AA and nonessential AA were not different between low- and high-F:C diets, whereas that of essential AA tended to be less with high-F:C diet as a result of lower intakes of Met, Phe, Arg, and His. The flows of total AA and microbial AA were reduced by 22 and 19%, respectively, with increasing F:C ratio in the diets due to consistently reduced flows of individual AA, whereas AA profiles (% of AA N) of the duodenal protein were not different. Altering F:C from 35:65 to 60:40 decreased the intestinal digestibility of Ile, Leu, Thr, Val, Ala, Cys, and Ser, and consequently, tended to decrease the digestibility of total AA, essential AA, and nonessential AA. Intakes of total AA, essential AA, and nonessential AA were overall not affected by dietary FPL so FPL did not affect the flows or intestinal digestibility of AA. These results indicate that increasing dietary F:C ratio decreased overall AA supply because flow to the duodenum and intestinal digestibility of AA were decreased. However, increasing FPL had no effect on AA supply. The measured duodenal flows of AA were consistent with the predictions of the Cornell Net Carbohydrate and Protein System model for the low-forage diet, and were consistent with the National Research Council model for the high-forage diet. Furthermore, the digestibility of individual AA in the intestine varied considerably, regardless of dietary treatment. The results revealed the necessity to consider the both flows and digestibility of individual AA when optimizing ration formulation to meet AA requirements of dairy cows. PMID- 22541498 TI - Heat treatment of colostrum on commercial dairy farms decreases colostrum microbial counts while maintaining colostrum immunoglobulin G concentrations. AB - This study was conducted on 6 commercial dairy farms in Minnesota and Wisconsin to describe the effect of heat treatment (at 60 degrees C for 60 min) on colostrum, on colostrum bacteria counts, and immunoglobulin G concentrations. First-milking colostrum was collected each day, pooled, divided into 2 aliquots, and then 1 aliquot was heat treated in a commercial batch pasteurizer at 60 degrees C for 60 min. Frozen samples of pre- and post- heat-treated colostrum were submitted for standard microbial culture (total plate count and total coliform count, cfu/mL) and testing for immunoglobulin G concentrations (mg/mL). Data were analyzed from 266 unique batches of colostrum. Linear regression showed that heat treatment decreased colostrum total plate counts (-2.25 log(10)) and coliform counts (-2.49 log(10)), but, overall, did not affect colostrum IgG concentration. Though higher-quality batches of colostrum did experience a greater magnitude of loss of IgG as a result of heat treatment as compared with lower- or intermediate-quality batches of colostrum, the colostral IgG concentrations in these batches remained high overall, and within acceptable limits for feeding. This study demonstrates that batch heat treatment of colostrum at 60 degrees C for 60 min can be successfully conducted on commercial dairy farms by farm staff to decrease colostrum microbial counts while maintaining colostrum IgG concentrations. PMID- 22541499 TI - Short communication: Antioxidant activity of calf milk replacers. AB - A calf milk replacer (CMR) is designed to replace whole, saleable milk as a lower cost nutrient source for calves while striving to nourish a newborn calf, reduce calf mortality, strengthen immunity, and increase animal life span and productivity. Antioxidants (AO) can enhance immune defense by reducing oxidative damage, but CMR are traditionally not formulated for AO activity. The objective of this study was to compare total AO activities of bovine milk and 6 CMR (A to F) that vary in the amount and source of fat and protein. Calf milk replacers were donated by Milk Products LLC (Chilton, WI). Milk was obtained from the Cornell Dairy Research Farm bulk tank, representing milk produced within 24h by 455 cows. Milk replacers were mixed to 150 g/L with 40 degrees C purified water. All samples were extracted in triplicate. Following hexane lipid extraction, both milk and CMR samples were extracted 5 times with ethyl acetate and then evaporated and reconstituted with 70% methanol:water. Samples were assessed for total AO activity using the peroxyl radical scavenging capacity assay where each sample was diluted to 5 descending concentrations, plated in triplicate. Ascorbic and gallic acids were standards for each plate. Type of protein (soy) had a positive effect on AO activity for CMR A, which exhibited the highest total AO activity. Natural bovine milk had the second highest AO activity. Many factors may explain the difference in AO activity between natural milk and formulated CMR, including fat, vitamin, and mineral contents, enzymatic AO, phenolics, flavonoids, fatty acid profile, and AA composition. When comparing AO activity of CMR, it is important to consider the diversity in feeding recommendations, which will alter the vitamin and mineral content, thus influencing AO activity. The opportunity exists to enhance AO activity of CMR to more closely mimic that of bovine milk. Future research is warranted to compare a broader range of CMR using methods that account for total lipophilic and hydrophilic AO activities, as well as to investigate the effect of additional compounds in milk that may affect AO activity. PMID- 22541500 TI - Breed differences over time and heritability estimates for production and reproduction traits of dairy goats in the United States. AB - To aid in improvement of breeding programs for production and reproduction traits of US dairy goats, breed differences over time were documented and genetic parameters were estimated. Data were from herds with >=2 breeds (Alpine, LaMancha, Nubian, Oberhasli, Saanen, or Toggenburg), but only purebred data were analyzed. Three kidding periods were examined: 1976 through 1984, 1985 through 1994, and 1995 through 2005. Univariate repeatability mixed models were used to estimate least squares means by kidding period-breed and genetic parameters for milk, fat, and protein yields, combined fat and protein yield, fat and protein percentages, protein:fat ratio, age at first kidding, and kidding interval. Trends across kidding periods were favorable for most yield traits for all breeds but generally unfavorable for reproduction traits. Saanens had the highest milk (1,063 to 1,125 kg) and protein yields (31 to 33 kg). Nubians had the highest fat yields (37 to 40 kg) and lowest milk yields (791 to 851 kg). Oberhaslis had the lowest fat (31 to 33 kg) and protein (23 to 27 kg) yields. Alpines had the largest increase in milk yield (7.4%); Oberhaslis had the largest increase in protein (17.4%) and combined fat and protein (13.2%) yields. Combined fat and protein yield was higher for Nubians, Saanens, and Alpines (65 to 72 kg) than for LaManchas, Toggenburgs, and Oberhaslis (53 to 67 kg). Nubians had the highest fat (4.7 to 4.8%) and protein (3.6 to 3.8%) percentages. Only Nubians increased in fat percentage (2.1%); protein percentage increased most for Toggenburgs (7.4%) and Alpines (7.1%). Protein:fat ratio was highest for Toggenburgs (0.84 to 0.89) and lowest for Nubians (0.76 to 0.81), but Nubians had the largest increase in protein:fat ratio (6.6%). Saanens were oldest at first kidding (509 to 589 d), and Toggenburgs and LaManchas generally were youngest (435 to 545 d); age at first kidding increased most for Alpines (21.8%) and LaManchas (21.6%). Kidding intervals generally were shorter for Oberhaslis, LaManchas, and Nubians (350 to 377 d) than for Toggenburgs, Alpines, and Saanens (373 to 387 d). Kidding interval increased most for Nubians (3.9%) and Saanens (3.8%) and decreased only for Oberhaslis (5.4%). Heritability estimates across breeds were 0.35 for milk and fat yields, 0.37 for protein yield and protein:fat ratio, 0.36 for combined fat and protein yield, 0.52 for fat percentage, 0.54 for protein percentage, 0.23 for age at first kidding, and 0.05 for kidding interval. Genetic selection within breed is feasible for production and reproduction traits of US dairy goats. PMID- 22541501 TI - Using an incomplete gamma function to quantify the effect of dystocia on the lactation performance of Holstein dairy cows in Iran. AB - The aim of the present study was to estimate the effect of dystocia on lactation performance, using an incomplete gamma function. Data from March 2000 to April 2009 comprising 100,628 lactations of 65,421 cows in 204 dairy herds collected by the Animal Breeding Center of Iran were used. Of 100,628 births, 91.8% required no assistance, whereas 8.2% required assistance of some sort. Factors associated with the presence of dystocia were calving season, calving year, herd, calf sex, parity, and age of dam. Peak yield for primiparous cows with dystocia at calving occurred on d 87.2 [standard error (SE) 0.47], and for primiparous cows with easy calving, the peak of lactation was on d 83.3 (0.25). Peak yield was lowered by 0.39 (SE 0.07), 2.20 (SE 0.15), 2.22 (SE 0.21), and 2.54 (SE 0.32) kg for cows with incidence of dystocia compared with normal cows in parity 1 to 4, respectively. Dystocia was associated with decreased 305-d lactation performance in all parities, mostly in early lactation. Although more difficult births occurred in heifer calvings, loss in lactation performance was greater in second or later lactations following a difficult birth. PMID- 22541502 TI - Genomic selection in the French Lacaune dairy sheep breed. AB - Genomic selection aims to increase accuracy and to decrease generation intervals, thus increasing genetic gains in animal breeding. Using real data of the French Lacaune dairy sheep breed, the purpose of this study was to compare the observed accuracies of genomic estimated breeding values using different models (infinitesimal only, markers only, and joint estimation of infinitesimal and marker effects) and methods [BLUP, Bayes Cpi, partial least squares (PLS), and sparse PLS]. The training data set included results of progeny tests of 1,886 rams born from 1998 to 2006, whereas the validation set had results of 681 rams born in 2007 and 2008. The 3 lactation traits studied (milk yield, fat content, and somatic cell scores) had heritabilities varying from 0.14 to 0.41. The inclusion of molecular information, as compared with traditional schemes, increased accuracies of estimated breeding values of young males at birth from 18 up to 25%, according to the trait. Accuracies of genomic methods varied from 0.4 to 0.6, according to the traits, with minor differences among genomic approaches. In Bayes Cpi, the joint estimation of marker and infinitesimal effects had a slightly favorable effect on the accuracies of genomic estimated breeding values, and were especially beneficial for somatic cell counts, the less heritable trait. Inclusion of infinitesimal effects also improved slopes of predictive regression equations. Methods that select markers implicitly (Bayes Cpi and sparse PLS) were advantageous for some models and traits, and are of interest for further quantitative trait loci studies. PMID- 22541503 TI - Heritability estimates for Mycobacterium avium subspecies paratuberculosis status of German Holstein cows tested by fecal culture. AB - The objective of this study was to estimate genetic manifestation of Mycobacterium avium ssp. paratuberculosis (MAP) infection in German Holstein cows. Incorporated into this study were 11,285 German Holstein herd book cows classified as MAP-positive and MAP-negative animals using fecal culture results and originating from 15 farms in Thuringia, Germany involved in a paratuberculosis voluntary control program from 2008 to 2009. The frequency of MAP-positive animals per farm ranged from 2.7 to 67.6%. The fixed effects of farm and lactation number had a highly significant effect on MAP status. An increase in the frequency of positive animals from the first to the third lactation could be observed. Threshold animal and sire models with sire relationship were used as statistical models to estimate genetic parameters. Heritability estimates of fecal culture varied from 0.157 to 0.228. To analyze the effect of prevalence on genetic parameter estimates, the total data set was divided into 2 subsets of data into farms with prevalence rates below 10% and those above 10%. The data set with prevalence above 10% show higher heritability estimates in both models compared with the data set with prevalence below 10%. For all data sets, the sire model shows higher heritabilities than the equivalent animal model. This study demonstrates that genetic variation exists in dairy cattle for paratuberculosis infection susceptibility and furthermore, leads to the conclusion that MAP detection by fecal culture shows a higher genetic background than ELISA test results. In conclusion, fecal culture seems to be a better trait to control the disease, as well as an appropriate feature for further genomic analyses to detect MAP-associated chromosome regions. PMID- 22541504 TI - Genome-wide association study to identify chromosomal regions associated with antibody response to Mycobacterium avium subspecies paratuberculosis in milk of Dutch Holstein-Friesians. AB - Heritability of susceptibility to Johne's disease in cattle has been shown to vary from 0.041 to 0.159. Although the presence of genetic variation involved in susceptibility to Johne's disease has been demonstrated, the understanding of genes contributing to the genetic variance is far from complete. The objective of this study was to contribute to further understanding of genetic variation involved in susceptibility to Johne's disease by identifying associated chromosomal regions using a genome-wide association approach. Log-transformed ELISA test results of 265,290 individual Holstein-Friesian cows from 3,927 herds from the Netherlands were analyzed to obtain sire estimated breeding values for Mycobacterium avium subspecies paratuberculosis (MAP)-specific antibody response in milk using a sire-maternal grandsire model with fixed effects for parity, year of birth, lactation stage, and herd; a covariate for milk yield on test day; and random effects for sire, maternal grandsire, and error. For 192 sires with estimated breeding values with a minimum reliability of 70%, single nucleotide polymorphism (SNP) typing was conducted by a multiple SNP analysis with a random polygenic effect fitting 37,869 SNP simultaneously. Five SNP associated with MAP specific antibody response in milk were identified distributed over 4 chromosomal regions (chromosome 4, 15, 18, and 28). Thirteen putative SNP associated with MAP specific antibody response in milk were identified distributed over 10 chromosomes (chromosome 4, 14, 16, 18, 19, 20, 21, 26, 27, and 29). This knowledge contributes to the current understanding of genetic variation involved in Johne's disease susceptibility and facilitates control of Johne's disease and improvement of health status by breeding. PMID- 22541505 TI - Milk adulteration: Detection of bovine milk in bulk goat milk produced by smallholders in northeastern Brazil by a duplex PCR assay. AB - The aim of this study was to investigate the adulteration of goat milk produced by smallholders in semiarid northeastern Brazil with bovine milk as an adulterant. The study was requested by the association of smallholder producers in the region to investigate and to inhibit adulteration practices as a need to ensure the quality and safety of goat milk. A duplex PCR assay has been developed and standardized. Further validation was performed in 160 fresh bulk goat milk samples. The detection limit of the duplex PCR was 0.5% bovine milk in goat milk and the results indicated that 41.2% of the goat milk presented to market was positive for bovine milk. Making the test available to the association of producers, together with extension activities, have been applied to reduce adulteration in goat milk sold to small-scale dairy plants and to ensure the species origin for goat milk in the state of Paraiba. PMID- 22541506 TI - Prevalence of respiratory disorders in veal calves and potential risk factors. AB - The study aimed to assess the in vivo and postmortem prevalence of respiratory disorders in veal calves and investigate risk factors associated with them. A cross-sectional study was carried out in 174 farms in the 3 major veal meat producing countries in Europe (50 in France, 100 in the Netherlands, and 24 in Italy). Trained veterinarians visually evaluated individual calves of 1 batch per farm at 3 and 13 wk after arrival and at 2 wk before slaughter to assess the prevalence of hampered respiration, nasal discharge, and coughing. A random sample of lungs belonging to calves of the same batch was monitored at the slaughterhouse for mild to moderate or severe signs of pneumonia, and presence of pleuritis. Data regarding veal calf housing, feeding, and management and specific characteristics of the batch were collected through an interview with the stockperson, and the potential of these as respiratory disease risk factors was assessed. Regardless of the stage of fattening, the prevalence of in vivo signs of respiratory disorders in calves was always <7%. This low prevalence was likely the outcome of the general implementation by veal producers of standardized practices such as prophylaxis, all-in/all-out, and individual daily checks of the calves, which are recognized tools for effective disease prevention and management. However, at postmortem inspection, 13.9% and 7.7% of lungs showed mild to moderate and severe signs of pneumonia, respectively, and 21.4% of the inspected lungs had pleuritis. Thus, even mild clinical signs of respiratory disorder in calves at specific time points during the fattening period may be associated with high prevalence of lungs with lesions at slaughter. Alternatively, clinical symptoms recorded during routine visual inspections of veal calves on-farm may be poor predictors of the true prevalence of respiratory disease in calves. Among all potential risk factors considered, those concerning the characteristics of the batch were predominant but factors related to housing, management and feeding equipment were also relevant. Different risk factors were involved at different stages of the fattening period. Therefore, to overcome respiratory disorders in veal calves, different solutions may apply to different stages of the fattening period. PMID- 22541507 TI - Recording of direct health traits in Austria--experience report with emphasis on aspects of availability for breeding purposes. AB - A project to establish an Austria-wide health-monitoring system for cattle was launched in 2006. Veterinary diagnostic data subject to documentation by law [Law on the Control of Veterinary Medicinal Products (Tierarzneimittelkontrollgesetz)] are standardized, validated, and recorded in a central database. This Austria wide project is a collaboration among agricultural and veterinary organizations as well as universities, and is also supported by the Austrian government. In addition to providing information for herd management and preventive measures, further objectives of the project include estimating breeding values for health traits and monitoring the overall health status of Austria's cattle. To ensure a high level of participation from farmers and veterinarians, data security issues are extremely important. Valid data are the prerequisite for the efficient use of health records. The challenge hereby is to distinguish between farms with low frequencies of diseases and incomplete documentation and recording. Measures were undertaken to establish a routine monitoring system for direct health traits. A routine genetic evaluation for direct health traits as part of the joint breeding value estimation program between Germany and Austria was introduced for Fleckvieh in December 2010, based on diagnostic data from 5,428 farms with 147,764 Fleckvieh cows. In 2010 to 2011, the reporting of direct health traits as a compulsory part of performance recording and the breeding program was introduced as well. The overall challenge is the availability of sufficient valid direct health data for reliable breeding values. Practical experience gained in Austria in setting up a health registration system, focusing mainly on the availability of direct health data for breeding purposes with its successes and difficulties, is described. PMID- 22541508 TI - Increasing readiness to decide and strengthening behavioral intentions: evaluating the impact of a web-based patient decision aid for breast cancer treatment options (BresDex: www.bresdex.com). AB - OBJECTIVES: To undertake a quantitative evaluation of a theory-based, interactive online decision aid (BresDex) to support women choosing surgery for early breast cancer (Stage I and II), based on observations of its use in practice. METHODS: Observational cohort study. Website log-files collected data on the use of BresDex. Online questionnaires assessed knowledge about breast cancer and treatment options, degree to which women were deliberating about their options, and surgery intentions, pre- and post-BresDex. RESULTS: Readiness to make a decision significantly increased after using BresDex (p<.001), although there was no significant improvement in knowledge. Participants that were 'less ready' to make a decision before using BresDex, spent a longer time using BresDex (p<.05). Significant associations between surgery intentions and choices were observed (p<.001), with the majority of participants going on to have BCS. Greater length of time spent on BresDex was associated with stronger intentions to have BCS (p<.05). CONCLUSION: The use of BresDex appears to facilitate readiness to make a decision for surgery, helping to strengthen surgery intentions. PRACTICE IMPLICATIONS: BresDex may prove a useful adjunct to the support provided by the clinical team for women facing surgery for early breast cancer. PMID- 22541509 TI - [Atypical onset of Churg and Strauss syndrome in a child]. AB - We report the case of a 13-year-old boy who had been treated since the age of 6 for moderate asthma. Except asthma, his past medical history was uneventful. The patient was referred for the sudden onset of bilateral leg edemas with peripheral purpuric lesions. Blood tests showed increased blood eosinophilia (9000/mm(3)) with no fever. The antineutrophil cytoplasmic antibodies (ANCA) were negative. The skin biopsy showed extensive ischemic subcutaneous necrosis related to necrotizing vasculitis. The general secondary symptoms occurred with multiorgan involvement (pulmonary infiltrates, peripheral neuropathy, gastrointestinal tract symptoms, and arthralgia). Genital infiltration was also noted. The child's general health was preserved. Neither cardiac nor renal involvement were found. The patient showed favorable clinical progression after oral prednisone therapy. PMID- 22541510 TI - [Streptococcus pneumoniae-induced hemolytic uremic syndrome: a serotype-3 associated case]. AB - Hemolytic uremic syndrome (HUS) is the primary cause of acute renal failure in children younger than 3 years of age. It usually occurs after a diarrheal illness due to Shiga-toxin-producing Escherichia coli. Streptococcus pneumoniae (SP) induced HUS remains rare, involving 5% of all cases of HUS in children, but its frequency has increased over the last decade. The incidence of HUS following invasive pneumococcal infections is estimated at 0.4 to 0.6%. We report here the case of a 3.5-year-old child who presented SP serotype-3-associated HUS. The diagnosis was suspected by the patient's multiple organ failure. The pathogenesis involves the activation of the Thomsen-Friedenreich antigen. To prevent transfusion-associated hemolysis, it is recommended that fresh-frozen plasma or unwashed blood products should be avoided when possible. Our patient was transfused with 4 units of unwashed red blood cell and 2 units of fresh-frozen plasma. No special complication was noted. The risk of immediate complications requires close clinical and biological monitoring, and the possibility of starting dialysis immediately. Twenty-five to 35% of SP-HUS patients exhibit long term renal aftereffects. The acute mortality rate depends on the site of infection. The increased frequency of SP-HUS may be related to the new ecology of serotypes created by widespread Prevenar7((r)) vaccination. PMID- 22541512 TI - Multifaceted roles of interleukin-7 signaling for the development and function of innate lymphoid cells. AB - Recently, additional innate lymphocyte subsets have been identified that express germline encoded immunoreceptors and respond to cytokine cues. Among these, innate lymphoid cells (ILC) at mucosal surfaces are of significant interest because they were found to play important roles for lymphoid organogenesis, tissue homeostasis and repair, for immunity to various infections but also have been involved as disease-promoting cells in models of chronic inflammatory diseases and of autoimmunity. Their functional and transcriptional programs strikingly resemble that of the various T helper cell subsets suggesting that these programs are already pre-formed in the innate immune system and that these may be more conserved than previously appreciated. Interestingly, all ILC subsets express the interleukin 7 receptor alpha chain and IL-7 signaling has been involved in various aspects of their developmental and functional programs. Here, we will review the role of IL-7 signaling for the differentiation, maintenance and function of two important ILC subsets, lymphoid tissue inducer cells (i.e., RORgammat(+) ILC) and natural helper cells (i.e., type 2 ILC). We will also put emphasis on the recently discovered role of IL-7 in controlling plasticity of RORgammat(+) ILC. PMID- 22541513 TI - Cardiopulmonary bypass strategy with low-dose heparin and nafamostat mesilate in cardiac surgery: a safe option for patients with acute stroke. PMID- 22541511 TI - Reliability of the amplitude of low-frequency fluctuations in resting state fMRI in chronic schizophrenia. AB - The resting state amplitude of low frequency fluctuations (ALFF) in functional magnetic resonance imaging has been shown to be reliable in healthy subjects, and to correlate with antipsychotic treatment response in antipsychotic-naive schizophrenia patients. We found moderate to high test-retest stability of ALFF in chronically treated schizophrenia patients assessed twice over a median interval of 2.5 months. PMID- 22541514 TI - Comparison of 30-day outcomes of coronary artery bypass grafting surgery verus hybrid coronary revascularization stratified by SYNTAX and euroSCORE. AB - OBJECTIVE: The optimal treatment of multivessel coronary artery disease is not well established. Hybrid coronary revascularization by combining the left internal mammary artery-left anterior descending artery graft and drug-eluting stents in non-left anterior descending artery territories might offer superior results compared with sole coronary artery bypass grafting or sole percutaneous coronary intervention. METHODS: We retrospectively analyzed the 30-day outcomes of 381 consecutive patients undergoing coronary artery bypass grafting (n = 301) vs hybrid coronary revascularization (n = 80). In a 2 * 2 matrix, the 2 groups were stratified by the Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery (SYNTAX) score (<=32 vs >=33) and the European System for Cardiac Operative Risk Evaluation (euroSCORE) (<5 vs >=5). The composite endpoint (death from any cause, stroke, myocardial infarction, low cardiac output syndrome) and secondary endpoints (worsening postprocedural renal function and bleeding) were determined. RESULTS: After stratification using the SYNTAX and the euroSCORE, the preoperative characteristics were similar within the 4 groups, except for the >=33 SYNTAX/>5 euroSCORE. The hybrid coronary revascularization patients were older (77 vs 65 years, P = .001). The postoperative outcomes using combined SYNTAX and the euroSCORE stratification showed a similar rate of the composite endpoint for all groups except for patients with >=33 SYNTAX/>5 euroSCORE (0% for the coronary artery bypass grafting group vs 33% for the hybrid coronary revascularization group, P = .001). An analysis of the secondary endpoint showed similar results across all groups, except for in the >=33 SYNTAX/>5 euroSCORE group, in which bleeding (re-exploration for bleeding and transfusion >3 packed red blood cell units per patient) was 44% in the hybrid coronary revascularization group vs 11% in the coronary artery bypass grafting group (P = .05). CONCLUSIONS: Hybrid coronary revascularization is a safe alternative to coronary artery bypass grafting in many patients with multivessel coronary artery disease. However, in high-risk patients with complex coronary artery disease (>=33 SYNTAX/>5 euroSCORE), coronary artery bypass grafting is superior to hybrid coronary revascularization. PMID- 22541515 TI - Nurses' strategies to address self-care aspects related to medication adherence and symptom recognition in heart failure patients: an in-depth look. AB - OBJECTIVE: Despite an increasing body of knowledge on self-care in heart failure patients, the need for effective interventions remains. We sought to deepen the understanding of interventions that heart failure nurses use in clinical practice to improve patient adherence to medication and symptom monitoring. METHODS: A qualitative study with a directed content analysis was performed, using data from a selected sample of Dutch-speaking heart failure nurses who completed booklets with two vignettes involving medication adherence and symptom recognition. RESULTS: Nurses regularly assess and reassess patients before they decide on an intervention. They evaluate basic/factual information and barriers in a patient's behavior, and try to find room for improvement in a patient's behavior. Interventions that heart failure nurses use to improve adherence to medication and symptom monitoring were grouped into the themes of increasing knowledge, increasing motivation, and providing patients with practical tools. Nurses also described using technology-based tools, increased social support, alternative communication, partnership approaches, and coordination of care to improve adherence to medications and symptom monitoring. CONCLUSION: Despite a strong focus on educational strategies, nurses also reported other strategies to increase patient adherence. Nurses use several strategies to improve patient adherence that are not incorporated into guidelines. These interventions need to be evaluated for further applications in improving heart failure management. PMID- 22541516 TI - Anti-glutamate receptor delta2 antibody-positive migrating focal encephalitis. PMID- 22541517 TI - Association of mesial temporal sclerosis and moyamoya syndrome. PMID- 22541518 TI - The RAM classification: a novel, systematic approach to the adult-acquired flatfoot. AB - In summary, prior classifications have provided broad guidelines for treating the AAFF without accounting for case-specific variables in determining a treatment plan. The current system breaks down the deformity into three independent levels of involvement: the rearfoot, the ankle, and the midfoot. Via a simple, easy to remember, and reproducible schema based off the original Johnson and Strom classification, each level can be independently evaluated and a patient-specific surgical treatment plan can be formulated based on our most current understanding of the AAFF. PMID- 22541519 TI - The calcaneo-stop procedure. AB - Flexible flatfoot is one of the most common deformities. Arthroereisis procedures are designed to correct this deformity. Among them, the calcaneo-stop is a procedure with both biomechanical and proprioceptive properties. It is designed for pediatric treatment. Results similar to endorthesis procedure are reported. Theoretically the procedure can be applied to adults if combined with other procedures to obtain a stable plantigrade foot, but medium-term follow up studies are missing. PMID- 22541520 TI - Tarsal coalitions in the adult population: does treatment differ from the adolescent? AB - There is a paucity of information on adult coalitions without large, well designed outcome studies. Current recommendations are thus similar to those for adolescents. Based on the available literature, current recommendations include an initial trial of adequate nonoperative treatment in symptomatic coalitions. Unlike adolescent coalitions, nonoperative treatment may be even more effective in the adult patient as many are asymptomatic or discovered after injury. If nonoperative treatment fails, then surgical intervention is considered and tailored to the location of the coalition, existing advanced arthrosis, and any existing deformity. Similar to the adolescent, surgical treatment for adult calcaneonavicular coalitions typically involves an attempt at resection with some type of interposition. Resection can be attempted for talocalcaneal coalitions that do not present with advanced arthrosis or significant hindfoot malalignment. For those patients with advanced arthrosis, more than 50% involvement of the joint hindfoot malalignment, subtalar or triple arthrodesis is recommended. The decision between resection and arthrodesis is controversial in the adolescent population. With few outcome studies in adults, it is even more difficult to make definitive treatment recommendations; however, the indications for resection are likely even more limited. It is likely that the adult subtalar coalition that becomes symptomatic and fails nonoperative treatment will require arthrodesis for full pain relief and improvement in objective outcome measures, such as the AOFAS hindfoot score. Our treatment algorithm focuses first on a trial of nonoperative treatment of at least 3 months regardless of coalition location. After failed nonoperative treatment, calcaneonavicular coalitions are in most cases treated with excision and interpositional fat graft. For talocalcaneal coalitions, resection is offered to patients with neutral hindfoot alignment, some preservation of subtalar joint motion and no adjacent joint arthrosis. The patients are advised that the outcome after resection of talocalcaneal coalitions is less predictable than resection of calcaneonavicular coalitions. Those patients with absent subtalar motion and relatively normal hindfoot alignment are candidates for in situ fusion of the subtalar joint. For those patients with greater than 15 degrees of valgus hindfoot malalignment on a weight-bearing hindfoot alignment view or adjacent joint arthrosis, a triple arthrodesis is recommended with or without medial displacement osteotomy of the calcaneus. Adjacent joint arthrosis may be determined by radiographs, CT scan, or preoperative MRI. PMID- 22541521 TI - Tendon transfer options in managing the adult flexible flatfoot. AB - Patients undergoing surgery for posterior tibial tendon dysfunction may require tendon transfer. The flexor digitorum longus is most commonly transferred, although the flexor hallucis longus and peroneus brevis have also been described in the literature. This article discusses the advantages and disadvantages of the different tendons, the surgical techniques used to perform them, and their results in the literature, concentrating principally on studies in which additional bone procedures were not performed. This article will also discuss the potential role for isolated soft tissue procedures in the treatment of stage 2 posterior tibial tendon dysfunction. PMID- 22541522 TI - Young's procedure for the treatment of valgus flatfoot deformity caused by a posterior tibial tendon dysfunction, stage II. AB - Young's procedure contains an action mechanism that works better than other techniques on the pathophysiology of FFD. It respects the anatomy and biomechanics of the foot to reach the necessary muscular balance. The benefits of this technique include that the ATT is not detached, so its function mechanism is still active; the new trajectory of the ATT provides a powerful sling function at the level of the navicular; and the horizontal trajectory of the ATT and the osteoperiosteal flaps constitute a powerful inner capsular-tendinous-ligamentous support. What is more, an insufficiency of the ATT is created, which results in a predominance of the peroneus lateral longus, that descends and prones the forefoot. Additional procedures, such as medial displacement calcaneal osteotomy, should be considered to correct the entire deformity. The combination of these techniques do not sacrifice the joint mobility. PMID- 22541523 TI - Calcaneal osteotomy in the treatment of adult acquired flatfoot deformity. AB - Calcaneal osteotomies are an essential part of our current armamentarium in the treatment of AAFD. Soft tissue correction or bony realignment alone have failed to adequately correct the deformity; therefore, both procedures are used simultaneously to achieve long-term correction. Medial displacement and lateral column lengthening osteotomies in isolation or in combination and the Malerba osteotomy have been employed along with soft tissue balancing to good effect by various authors. The goal is to create a stable bony configuration with adequate soft tissue balance to maintain dynamic equilibrium in the hindfoot. In "pronatory syndromes," the relation of the osteotomy to the posterior subtalar facet modifies the biomechanics of the hindfoot in different ways. Anterior calcaneal osteotomies correct deformities in the transverse plane (forefoot abduction), whereas posterior tuberosity osteotomies result in "varization" of the calcaneus and correct the frontal plane deformity. The choice of osteotomy depends on the plane of the dominant deformity. If the subtalar axis is more horizontal than normal, transverse plane movement is cancelled out and the frontal plane eversion-inversion is predominant. The patient presents with marked hindfoot valgus without significant forefoot abduction. Conversely, if the subtalar axis is more vertical than normal, transverse plane movement is predominant and the patient presents with forefoot abduction and instability of the medial midtarsal joints, although without significant hindfoot valgus. In this situation, a lateral column lengthening procedure is recommended to decrease the uncovering of the talar head and improve the height of the arch while correcting the forefoot abduction. With a predominant frontal plane deformity, medialization of the calcaneal tuberosity is used to displace the calcaneal weight bearing axis medially, aligning it with the tibial axis and restoring the function of the gastrosoleus as a heel invertor. An essential prerequisite for this is the absence of arthritis affecting the subtalar joint. The Achilles tendon may need to be lengthened at the same time. PMID- 22541524 TI - Lateral column lengthening osteotomies. AB - Lateral column lengthening procedures, either an Evans-type procedure or a calcaneocuboid distraction arthrodesis, clearly have a role to play in the management of a pes planovalgus foot deformity, as is evident from clinical outcome studies. Despite an abundance of literature intricately detailing the biomechanical effects of different operative procedures on the hindfoot, there is no clear consensus as to the best procedure or procedures to perform for a flexible pes planovalgus foot deformity. There is, therefore, no single solution to this problem; the surgeon must treat each patient as an individual and choose the procedure that will work best in their hands for any given foot pathology they are presented with. The surgeon must also be aware that to improve the kinematics of a planovalgus foot deformity, one may often have to perform multiple procedures and not a lateral column lengthening in isolation. PMID- 22541525 TI - Is there a role for subtalar arthroereisis in the management of adult acquired flatfoot? AB - Subtalar arthroereisis, often combined with Achilles tendon lengthening, is a simple and effective way to treat flexible flatfoot in adults. The most common complication is pain in sinus tarsi, which usually disappears after removal of the implant. Midterm results are good and it does not hinder other treatments in the future. PMID- 22541526 TI - Medial column procedures in the correction of adult acquired flatfoot deformity. AB - AAFD is a complex problem with a wide variety of treatment options. No single procedure or group of procedures can be applied to all patients with AAFD because of the variety of underlying etiology and grades of deformity. As the posture of the foot progresses into hindfoot valgus and forefoot abduction through attenuation of the medial structures of the foot, the medial column begins to change shape. The first ray elevates and the joints of the medial column may begin to collapse. Careful physical examination and review of weight-bearing radiographs determines which patients have an associated forefoot varus deformity that may require correction at the time of flatfoot reconstruction. Correction of an AAFD requires a combination of soft-tissue procedures to restore dynamic inversion power and bony procedures to correct the hindfoot and midfoot malalignments. If after these corrections forefoot varus deformity remains, the surgeon should consider use of a medial column procedure to recreate the "triangle of support" of the foot that Cotton described.5 If the elevation of the medial column is identified to be at the first NC or the first TMT joint, then the joint should be carefully examined for evidence of instability, hypermobility, or arthritic change. If none of these problems exist, then the surgeon can consider use of the joint-sparing Cotton medial cuneiform osteotomy to correct residual forefoot varus. However, if instability, hypermobility, or arthritic change is present, then the surgeon should consider use of an arthrodesis of the involved joint to correct residual forefoot varus. Either procedure provides a safe and predictable correction to the medial column as part of a comprehensive surgical correction of AAFD. PMID- 22541527 TI - Management of the recurrent deformity in a flexible foot following failure of tendon transfer: is arthrodesis necessary? AB - Recurrent deformity in the adult flatfoot following previous tendon transfer represents a challenging treatment dilemma for even the most experienced foot and ankle surgeon. The evaluation must be comprehensive, resulting in a clear understanding of the extent to which previous surgical procedures either failed to address the deformity initially or led to progressive recurrence. Particularly in younger, more high-demand patients, every effort to preserve normal joint mechanics while alleviating pain and restoring functional alignment must be made. LCL coupled with MDCO and a comprehensive medial soft tissue reconstruction represents a joint-sparing modality for approaching even the most challenging flexible flatfoot deformities. Care to avoid overcorrection, particularly with a double calcaneal osteotomy, must be taken. In the presence of progressive degenerative changes or patient factors such as morbid obesity and advanced age, hindfoot arthrodesis, particularly realignment subtalar joint arthrodesis, provides a technically straightforward, predictable means of achieving a pain free plantigrade foot. Talonavicular arthrodesis and double arthrodesis, although reliable means of achieving pain relief and functional alignment, do sacrifice considerably more hindfoot motion and are likely more appropriately reserved for elderly, low-demand patients or those with more severe fixed deformities. PMID- 22541528 TI - Management of the rigid arthritic flatfoot in adults: triple arthrodesis. AB - The traditional surgical treatment for adults with a rigid, arthritic flatfoot is a dual-incision triple arthrodesis. Over time, this procedure has proved to be reliable and reproducible in obtaining successful deformity correction through fusion and good clinical results. However, the traditional dual-incision triple arthrodesis is not without shortcomings. Early complications include lateral wound problems, malunion, and nonunion. Long-term follow-up of patients after a triple arthrodesis has shown that many develop adjacent joint arthritis at the ankle or midfoot. This particular problem should be considered an expected consequence, rather than a failure of the procedure. Although the indications for and surgical techniques used in triple arthrodesis have evolved and improved with time (predictably improving results in the intermediate term), the triple arthrodesis should be regarded as a salvage procedure. Certain measures can be taken by the surgeon to avoid some problems. If patients are at risk for lateral wound complications, the arthrodesis could be performed through a single medial incision. However, this can make some aspects of the CC fusion more difficult. Implants would have to be inserted percutaneously, which prevents the surgeon from using either staples or plates. If a patient were to need a lateral column lengthening through a CC distraction fusion, this would not be possible medially. If either the ST or CC joints have minimal degenerative changes, they could be spared through a double or modified double arthrodesis, respectively. Although these procedures that deviate from the traditional triple arthrodesis offer promise, further study is required to better define their role in treatment of the rigid, arthritic AAFD. Triple arthrodesis is, by no means, a simple surgery. It requires preoperative planning, meticulous preparation of bony surfaces, cognizance of hindfoot positioning, and rigidity of fixation. The procedure also requires enough experience on the part of the operating surgeon to anticipate postoperative problems and provide modifications in traditional technique for certain patients. PMID- 22541529 TI - Management of the rigid arthritic flatfoot in the adults: alternatives to triple arthrodesis. AB - Every alternative to triple arthrodesis in the rigid acquired flatfoot deformity is predicated on limiting the patient exposure to the complication associated with triple arthrodesis. When possible, avoiding arthrodesis of either the talonavicular and calcaneocuboid joints, with their higher nonunion rates, seems a cogent option. Successful treatment is dependent on thoughtful patient evaluation and examination, meticulous joint preparation, careful positioning with rigid fixation, and judicious use of adjunctive procedures to achieve the goal of a plantigrade foot that functions well and is minimally painful. PMID- 22541530 TI - Minimizing the role of fusion in the rigid flatfoot. AB - The goals of surgery for the rigid flatfoot are to achieve a painless, stable, functional plantigrade foot. Although triple arthrodesis affords predictable correction and pain relief, the long-term sequelae of extended hindfoot fusions include arthritis and often the need for further, more extensive fusion procedures. We propose that satisfactory results can be achieved in the rigid flatfoot by limiting fusion to joints that are arthritic, and correcting associated deformity with osteotomy and soft tissue reconstruction. PMID- 22541531 TI - Update on stage IV acquired adult flatfoot disorder: when the deltoid ligament becomes dysfunctional. AB - Deltoid ligament complex insufficiency is a fundamental pathologic component of stage IV AAFD. Failure of the deltoid ligament allows the talus to tilt into valgus within the ankle mortise. If left untreated, ankle joint biomechanics are altered and may lead to debilitating tibiotalar arthritis. All surgical treatments that address the valgus talar tilt seen with stage IV AAFD require accompanying procedures to properly realign the hindfoot. Stage IV AAFD can be subdivided into two groups. Patients with a flexible ankle deformity without advanced tibiotalar arthritis (stage IV-A) can be considered for a joint-sparing procedure. A variety of procedures have been described, but longterm follow-up studies have yet to determine which of these techniques is optimal. Patients with a rigid valgus ankle deformity or a flexible deformity accompanied by advanced tibiotalar arthritis (stage IV-B) should be considered for a joint-sacrificing procedure. To date, the most reliable results for stage IV-B AAFD have been reported with either tibiotalocalcaneal or pan-talar arthrodesis. PMID- 22541532 TI - Adult flatfoot. Preface. PMID- 22541533 TI - [Systematic withdrawal of peripheral vein catheters: does it salvage lives or increase costs?]. PMID- 22541535 TI - Changes in adipokines after transjugular intrahepatic porto-systemic shunt indicate an anabolic shift in metabolism. AB - BACKGROUND & AIMS: Decompressing the portal hypertension by inserting a transjugular intrahepatic porto-systemic shunt (TIPS) in undernourished liver cirrhosis patients results in gains in body weight. It is important to understand whether this reflects an advantageous or unfavourable shift in nutrition status. This to some extent can be judged from the changes in the patients' adipokine patterns. We, therefore, examined the circulating levels of the most important adipokines before and after the TIPS procedure. METHODS: Twenty-five liver cirrhosis patients were examined before TIPS insertion and followed for six months after the procedure. Their body composition was determined by the bioimpedance technique. The serum concentrations of adiponectin, retinol binding protein 4 (RBP4), and leptin were measured. RESULTS: The TIPS procedure induced a 12% increase in body cell mass (P = 0.03) but did not change the body fat mass. At six months, serum adiponectin was increased by 60% (mean +/- SD, 10.7 +/- 6.1 vs. 16.9 +/- 8.9 mg/L; P = 0.001), serum RBP4 was decreased by 45% (28.6 +/- 20.0 vs. 16.3 +/- 9.6 mg/L; P = 0.01), and the leptin levels remained unchanged. CONCLUSIONS: The TIPS-related tissue build up was accompanied by increased adiponectin and decreased RBP4. Such changes are associated with an anabolic condition where the adipose tissue possesses residual capacity for energy storage. TIPS, therefore, can be considered to be nutritionally beneficial to cirrhosis patients. PMID- 22541534 TI - Orangutan Alu quiescence reveals possible source element: support for ancient backseat drivers. AB - BACKGROUND: Sequence analysis of the orangutan genome revealed that recent proliferative activity of Alu elements has been uncharacteristically quiescent in the Pongo (orangutan) lineage, compared with all previously studied primate genomes. With relatively few young polymorphic insertions, the genomic landscape of the orangutan seemed like the ideal place to search for a driver, or source element, of Alu retrotransposition. RESULTS: Here we report the identification of a nearly pristine insertion possessing all the known putative hallmarks of a retrotranspositionally competent Alu element. It is located in an intronic sequence of the DGKB gene on chromosome 7 and is highly conserved in Hominidae (the great apes), but absent from Hylobatidae (gibbon and siamang). We provide evidence for the evolution of a lineage-specific subfamily of this shared Alu insertion in orangutans and possibly the lineage leading to humans. In the orangutan genome, this insertion contains three orangutan-specific diagnostic mutations which are characteristic of the youngest polymorphic Alu subfamily, AluYe5b5_Pongo. In the Homininae lineage (human, chimpanzee and gorilla), this insertion has acquired three different mutations which are also found in a single human-specific Alu insertion. CONCLUSIONS: This seemingly stealth-like amplification, ongoing at a very low rate over millions of years of evolution, suggests that this shared insertion may represent an ancient backseat driver of Alu element expansion. PMID- 22541536 TI - Occurrence and phenotypic detection of class A carbapenemases among Escherichia coli and Klebsiella pneumoniae blood isolates at a tertiary care center. AB - BACKGROUND: Resistance to carbapenems is a significant therapeutic threat. The increasing frequency of car bapenemase enzymes among Gram-negative bacilli makes their early detection and differentiation urgent. Carbapenemases belonging to Class A are most commonly produced by members of family Enterobacteriaceae and are inhibited to various degrees by clavulanic acid. The present study is aimed to determine the occurrence and phenotypic detection of Class A carbapenemases in Escherichia coli and Klebsiella pneumoniae blood isolates from septicemic patients. METHODS: A total of 75 isolates of K. pneumoniae and 25 E. coli were screened for resistance to carbapenems by using meropenem and imipenem discs and meropenem E-test. Positive strains were then subjected to a modified Hodge test combined with carbapenemase inhibition tests to phenotypically detect and differentiate Class A serine carbapenemases from other classes of carbapenem hydrolyzing enzymes. RESULTS: The screening test showing the number of isolates resistant to meropenem and imipenem were 41 and 35 for K. pneumoniae and nine and four for E. coli, respectively. A total of 25 (33.3%) K. pneumoniae isolates and two (8.0%) E. coli isolates were classified as Class A carbapenemase producers. Multidrug resistance with coexistence of extended spectrum-beta-lactamases occurred in 44.4% isolates. However, all of the isolates were susceptible to colistin, polymyxin B, and tigecycline by disc diffusion test. CONCLUSION: We conclude from the present study that Class A carbapenemases appear to be the predominant cause of resistance to carbapenems in Enterobacteriaceae at our center and, thus, phenotypic detection based on simple methods should be employed routinely in clinical microbiology laboratories. PMID- 22541537 TI - The expression of sonic hedgehog in diabetic wounds following treatment with poly(methacrylic acid-co-methyl methacrylate) beads. AB - The expression of native sonic hedgehog (Shh) was significantly increased in poly(methacrylic acid-co-methyl methacrylate) bead (MAA) treated wounds at day 4 compared to both poly(methyl methacrylate) bead (PMMA) treated and untreated wounds in diabetic db/db mice. MAA beads also increased the expression of the Shh transcription factor Gli3 at day 4. Previously, topical application of MAA beads (45 mol % methacrylic acid) improved wound closure and blood vessel density in excisional wounds in these mice, while PMMA beads did not. Gene expression within the granulation tissue of healing wounds was studied to provide insight into the mechanism of vessel formation and wound healing in the presence of MAA beads. In addition to the increased expression of Shh, MAA-treated wounds had increased expression of osteopontin (OPN), IL-1beta and TNF-alpha, (at day 7) similar to the previously reported MAA response of macrophage-like and endothelial cells in vitro. PMID- 22541538 TI - Mimicking normal tissue architecture and perturbation in cancer with engineered micro-epidermis. AB - Correct tissue architecture is essential for normal physiology, yet there have been few attempts to recreate tissues using micro-patterning. We have used polymer brush micro-engineering to generate a stratified micro-epidermis with fewer than 10 human keratinocytes. Epidermal stem cells are captured on 100 MUm diameter circular collagen-coated disks. Within 24 h they assemble a stratified micro-tissue, in which differentiated cells have a central suprabasal location. For rings with a non-adhesive centre of up to 40 MUm diameter, cell-cell and cell matrix adhesive interactions together result in correct micro-epidermis assembly. Assembly requires actin polymerization, adherens junctions and desmosomes, but not myosin II-mediated contractility nor coordinated cell movement. Squamous cell carcinoma cells on micro-patterned rings exhibit disturbed architecture that correlates with the characteristics of the original tumours. The micro-epidermis we have generated provides a new platform for screening drugs that modulate tissue assembly, quantifying tissue stratification and investigating the properties of tumour cells. PMID- 22541539 TI - Dual roles of hyaluronic acids in multilayer films capturing nanocarriers for drug-eluting coatings. AB - We developed hyaluronic acid (HA)-based multilayer films capturing polymeric nanocarriers (NCs) for drug delivery. The electrostatic interactions between positively charged linear polyethylene imines (LPEI) and negatively charged HAs are the main driving forces to form multilayers based on the layer-by-layer (LbL) deposition. NCs were easily incorporated within the multilayer film due to intra- and/or inter-hydrogen bonding among HA chains. The amount of NCs captured by the HA chains was varied by the ratio between HAs and NCs as well as the length (i.e., molecular weight) and absolute number density of HAs in solution. Biocompatibility of the NC-capturing HA multilayer films was tested with the human dermal fibroblast (HDF) culture. In addition, the controlled release of paclitaxel (PTX) from the HA multilayer films successfully led to the apoptosis of human aortic smooth muscle cells (hSMC) in vitro, implying that the NC capturing HA multilayer films would be quite useful as drug-eluting stent systems to prevent the restenosis after surgery. PMID- 22541540 TI - Role of male novelty and familiarity in male-induced LH secretion in female sheep. AB - Ewes supposedly need to be separated from rams before male stimuli can increase gonadotrophin secretion and induce ovulation. In the present study, we investigated the LH response of ewes to 'novel' and 'familiar' rams after varying periods of separation. In Experiment 1, ewes (n = 8 per treatment) were separated from familiar rams for 15 min or 1 month and then exposed to either familiar rams, novel rams or novel wethers. After 15 min or 1 month of separation, exposure to novel rams increased pulsatile LH secretion (P < 0.05) and induced an LH surge in all ewes whereas exposure to familiar rams or novel wethers had no effect on LH secretion (P > 0.1). After 1 month of separation, re-exposure to the same familiar rams increased pulsatile LH secretion (P < 0.05) in six of eight ewes, but only induced an LH surge in two of eight ewes. In Experiment 2, familiar rams were removed and returned after 15 min, 1 day or 17 days (n = 5 per treatment). None of these treatments affected LH secretion. We conclude that separation of ewes from rams is a prerequisite for familiar rams to increase LH secretion, but is not necessary if the rams are novel. PMID- 22541541 TI - Quantification of kinetic changes in protein tyrosine phosphorylation and cytosolic Ca2+ concentration in boar spermatozoa during cryopreservation. AB - Protein tyrosine phosphorylation in sperm is associated with capacitation in several mammalian species. Although tyrosine phosphorylated proteins have been demonstrated in cryopreserved sperm, indicating capacitation-like changes during cryopreservation, these changes have not yet been quantified objectively. We monitored tyrosine phosphorylation, intracellular calcium and sperm kinematics throughout the cryopreservation process, and studied the relationships among them in boar spermatozoa. Sperm kinetics changed significantly during cryopreservation: curvilinear velocity, average path velocity and straight line velocity all decreased significantly (P < 0.05). While the percentage of sperm with high intracellular calcium declined (P < 0.05), global phosphorylation increased significantly (P < 0.01). Specifically, cooling to 5 degrees C induced phosphorylation in the spermatozoa. After cooling, a 32-kDa protein not observed in fresh semen appeared and was consistently present throughout the cryopreservation process. While the level of expression of this phosphoprotein decreased after addition of the second extender, frozen-thawed spermatozoa showed an increased expression. The proportion of sperm cells with phosphorylation in the acrosomal area also increased significantly (P < 0.05) during cryopreservation, indicating that phosphorylation might be associated with capacitation-like changes. These results provide the first quantitative evidence of dynamic changes in the subpopulation of boar spermatozoa undergoing tyrosine phosphorylation during cryopreservation. PMID- 22541542 TI - The oviducal protein, heat-shock 70-kDa protein 8, improves the long-term survival of ram spermatozoa during storage at 17 degrees C in a commercial extender. AB - Poor fertility rates are often observed when fresh ram semen stored in conventional extenders is used for cervical artificial insemination (AI). Heat shock 70-kDa protein 8 (HSPA8), found within the oviduct, prolongs boar, ram and bull sperm survival at body temperatures in vitro. Here, we aimed to determine whether supplementing extenders (INRA-96 and RSD-1) with HSPA8 (4 ug mL-1) would improve their performance in maintaining freshly collected ram sperm viability and sperm nuclear DNA integrity during storage over 48 h at 17 degrees C. Sperm function was assessed at 1, 6, 24 and 48h and this experiment was repeated using 25 * 106 and 800 * 106 spermatozoa mL-1. INRA96 supplemented with HSPA8 maintained sperm viability significantly better than INRA96 alone at both sperm concentrations. However, sperm nuclear DNA fragmentation (DF) increased significantly during storage using the higher sperm concentration, irrespective of the extender and the protein treatment used. Increasing levels of sperm nuclear DF over time could explain why poor fertility rates are often observed following cervical AI using stored ram semen. However, further research is required to ascertain whether supplementing the commercially available INRA96 extender with HSPA8 will improve fertility rates following cervical AI using stored ram semen. PMID- 22541543 TI - Temporal candidate gene expression in the sow placenta and embryo during early gestation and effect of maternal Progenos supplementation on embryonic and placental development. AB - The present study characterised gene expression associated with embryonic muscle development and placental vascularisation during early gestation in the pig and examined effects of Progenos supplementation in early pregnancy. Tissues were collected from commercial multiparous sows (n = 48) from Days 16 to 49 of gestation. In the placenta, qPCR revealed that vascular endothelial growth factor (VEGFA) expression did not change from Day 17 to 49 of gestation; however, KDR receptor and angiopoietin-1 and -2 expression were differentially regulated, with periods of high expression corresponding to two critical phases of angiogenesis in the pig. In the embryo, the pattern of myogenesis-related gene expression was consistent with available literature. A commercially available nutritional supplement Progenos (20 g day-1 L-arginine) added to the diet of sows from either Day 15 to 29 (P15-29; n = 33), Day 30 to 44 (n = 29) or from Day 15 to 44 (n = 76) of gestation tended to increase (P = 0.058) embryonic growth rate compared with non-supplemented controls (n = 79) and angiogenin expression was higher (P = 0.028) at Day 30 of gestation in placentae from sows on the P15-29 Progenos treatment. These results are consistent with proposed beneficial effects of l arginine on early embryonic development and placental vascularisation. PMID- 22541544 TI - Could zinc prevent reproductive alterations caused by cigarette smoke in male rats? AB - The aim of the present study was to evaluate the effects of zinc on fertility through semen parameters, testosterone level and oxidative DNA damage to spermatozoa of rats exposed to cigarette smoke. Male Wistar rats (60 days old) were divided into four groups (n = 10 per group): control, cigarette-smoking (20 cigarettes per day), zinc (zinc chloride 20 mg kg-1 day-1) and zinc plus cigarette-smoking (zinc chloride 20 mg kg-1 day-1; 20 cigarettes per day). The treatment was applied for nine weeks and the following parameters were analysed: bodyweight, wet weights of the reproductive organs and the adrenal gland, plasma testosterone concentration, testicular function (seminal analysis and daily sperm production) and sperm DNA oxidative damage. The exposure to cigarette smoke decreased testosterone concentration, the percentage of normal morphology and the motility of spermatozoa. In addition, this exposure increased sperm DNA oxidative damage. Zinc treatment protected against the toxic damage that smoking caused to spermatozoa. This study showed a correlation between smoking and possible male infertility and subfertility, and also that the majority of smoking-induced changes in spermatozoa were prevented by zinc treatment. In conclusion, zinc, an antioxidant and stimulant of cell division, can be indicated as a promising treatment in men with infertility caused by the toxic components of cigarette smoke. PMID- 22541546 TI - Expression, purification and structural analysis of recombinant rBdh-2His6, a spermadhesin from buck (Capra hircus) seminal plasma. AB - Spermadhesins, a family of secretory proteins from the male genital tract of ungulate species, belong to the group of animal lectins. Spermadhesins have a prominent role in different aspects of fertilisation, such as spermatozoid capacitation, acrosomal stabilisation, sperm-oviduct interaction and during sperm oocyte fusion. Proteins (spermadhesins) in buck seminal plasma were described. In the present study, bodhesin Bdh-2 cDNA present in buck seminal plasma was subcloned with the expression plasmid pTrcHis TOPO used to transform Escherichia coli Top10 One shot cells. The recombinant clones were selected by growth in 50 ug mL-1 ampicillin-containing LB broth and polymerase chain reaction amplification. Recombinant rBdh-2His6 synthesis was monitored by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and followed by immunoblotting using monoclonal anti-His antibody. Production of rBdh-2 using low temperatures was not satisfactory. Greater production of rBdh-2 occurred with 1.5mM isopropyl betad thiogalactoside after 2h of induction. The method used to purify rBdh-2 was affinity chromatography on a His-Trap column following ion-exchange chromatography on a DEAE-Sephacel column. The secondary structure of the rBdh 2His6 was evaluated by spectral profile circular dichroism (CD). The prevalence of secondary structures like beta-sheets, with fewer unfolded structures and alpha-helices, was confirmed. The structure of rBdh-2His6 remained stable up to 35 degrees C. However, significant structural changes were observed at temperatures higher than 40 degrees C related to a distortion of the CD spectrum. PMID- 22541545 TI - Zona pellucida birefringence correlates with developmental capacity of bovine oocytes classified by maturational environment, COC morphology and G6PDH activity. AB - In the present study we aimed to analyse structural changes during in vitro maturation of the bovine zona pellucida (ZP) by scanning electron microscopy (SEM) ands zona pellucida birefringence (ZPB). Here we show that alterations during in vitro maturation invasively analysed by SEM are reflected in ZPB. In vivo-matured oocytes displayed significantly lower birefringence parameters and significantly higher blastocyst rates compared with in vitro-derived oocytes (39.1% vs 21.6%). The same was observed for in vitro-matured oocytes with cumulus oocyte complex (COC) Quality 1 (Q1) compared with Q3-COCs with respect to zona birefringence and developmental capacity. Immature oocytes with Q1-COCs displayed higher ZPB values and a higher developmental capacity to the blastocyst stage (27.7% vs 16.9%) compared with immature Q3-COCs. Considering in vitro-matured oocytes, only those with Q1-COC showed a trend for ZPB similar to in vivo-matured oocytes. Therefore, a decreasing trend for ZPB during in vitro maturation seems to be typical for high-quality oocytes and successful cytoplasmic maturation. In accordance, fully-grown immature oocytes reached significantly higher blastocyst rates (32.0% vs 11.5%) and lower ZPB values compared with still-growing ones. In conclusion, we successfully evaluated the applicability of zona imaging to bovine oocytes: alterations during in vitro maturation invasively analysed by scanning electron microscopy were reflected in the birefringence of the zona pellucida of bovine oocytes affecting developmental capacity at the same value. Therefore ZPB measurement by live zona imaging has potential to become a new tool to assess correctness of in vitro maturation and to predict developmental competence. PMID- 22541547 TI - Aberrant expression of E-cadherin and beta-catenin proteins in placenta of bovine embryos derived from somatic cell nuclear transfer. AB - Abnormal placental development is common in the bovine somatic cell nuclear transfer (SCNT)-derived fetus. In the present study, we characterised the expression of E-cadherin and beta-catenin, structural proteins of adherens junctions, in SCNT gestations as a model for impaired placentation. Cotyledonary tissues were separated from pregnant uteri of SCNT (n = 6) and control pregnancies (n = 8) obtained by artificial insemination. Samples were analysed by western blot, quantitative RT-PCR (qRT-PCR) and immunohistochemistry. Bovine trophectoderm cell lines derived from SCNT and control embryos were analysed to compare with the in utero condition. Although no differences in E-cadherin or beta-catenin mRNA abundance were observed in fetal tissues between the two groups, proteins encoded by these genes were markedly under-expressed in SCNT trophoblast cells. Immunohistochemistry revealed a different pattern of E cadherin and total beta-catenin localisation in SCNT placentas compared with controls. No difference was observed in subcellular localisation of dephosphorylated active-beta-catenin protein in SCNT tissues compared with controls. However, qRT-PCR confirmed that the wingless (WNT)/beta-catenin signalling pathway target genes CCND1, CLDN1 and MSX1 were downregulated in SCNT placentas. No differences were detected between two groups of bovine trophectoderm cell lines. Our results suggest that impaired expression of E cadherin and beta-catenin proteins, along with defective beta-catenin signalling during embryo attachment, specifically during placentation, is a molecular mechanism explaining insufficient placentation in the bovine SCNT-derived fetus. PMID- 22541548 TI - Hormonal induction of spermatozoa from amphibians with Rana temporaria and Bufo bufo as anuran models. AB - The use of hormonally induced spermatozoa expressed in urine (HISu) is a valuable component of reproduction technologies for amphibians. Five protocols for sampling HISu from the European common frog (Rana temporaria) were compared: (1) pituitary extracts, (2) 0.12 ug g-1 luteinising hormone-releasing hormone analogue (LHRHa), (3) 1.20 ug g-1 LHRHa, (4) 11.7 IU g-1 human chorionic gonadotrophin (hCG) and (5) 23.4 IU g-1 hCG (g-1 = per gram bodyweight). From 1 to 24h after administration we assessed the number and concentration of spermatozoa in spermic urine and in holding water, and in urine the percentage of motile spermatozoa and their progressive motility. The protocol using 1.20 ug g-1 LHRHa gave the highest total sperm numbers (650 * 106) and the highest percentage (40%) of samples with sperm concentrations above 200 * 106 mL-1. The percentage motility and progressive motility was similar from all protocols. Considerable amounts of spermatozoa were expressed by R. temporaria into their holding water. We tested hormonal priming and spermiation in the common toad (Bufo bufo) using 0.13 ug g-1 LHRHa administered 24h before a final spermiating dose of 12.8 IU g-1 hCG. No spermatozoa were expressed in holding water. Priming resulted in 35% more spermatozoa than without; however, there were no differences in sperm concentrations. Primed B. bufo produced spermatozoa with significantly higher percentage motility, but not progressive motility, membrane integrity, or abnormal spermatozoa than unprimed males. PMID- 22541549 TI - Oocyte quality determines bovine embryo development after fertilisation with hydrogen peroxide-stressed spermatozoa. AB - Exposure of gametes to specific stressors at sublethal levels can enhance the gametes' subsequent performance in processes such as cryopreservation. In the present study, bull spermatozoa were subjected to H2O2 for 4 h at 100-, 200- and 500-MUM levels; computer-assisted sperm analysis (CASA) and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) assay were used for evaluation of subsequent sperm motility and DNA integrity, respectively. Exposure of spermatozoa to H2O2 did not affect sperm motility but DNA integrity was negatively affected by 500 MUM H2O2 compared with mock-exposed spermatozoa, whereas both motility and DNA integrity were affected compared with untreated spermatozoa. Nevertheless, insemination of oocytes with spermatozoa exposed to 200 MUM H2O2 increased fertilisation, cleavage and blastocyst rates (P < 0.05). Furthermore, the higher blastocyst yield after fertilisation of oocytes with spermatozoa exposed to 200 MUM H2O2 was related to oocyte diameter, with large medium oocytes yielding higher blastocyst rates, while small-diameter oocytes consistently failed to develop into blastocysts. In conclusion, the results indicate that exposure of spermatozoa to 200 MUM H2O2 before sperm-oocyte interaction may enhance in vitro embryo production in cattle. However, this increased embryo production is largely dependent on the intrinsic quality of the oocytes. PMID- 22541550 TI - Glycocalyx characterisation and glycoprotein expression of Sus domesticus epididymal sperm surface samples. AB - The sperm surface is covered with a dense coating of carbohydrate-rich molecules. Many of these molecules are involved in the acquisition of fertilising ability. In the present study, eight lectins (i.e. Arachis hypogae (peanut) agglutinin (PNA), Lens culimaris (lentil) agglutinin-A (LCA), Pisum sativum (pea) agglutin (PSA), Triticum vulgari (wheat) germ agglutinin (WGA), Helix pomatia agglutinin (HPA), Phaseolus vulgaris (red kidney bean) leucoagglutinin (PHA-L), Glycine max (soybean) agglutinin (SBA) and Ulex europaeus agglutinin I (UEA-I)) were investigated to identify changes in the nature and localisation of glycoproteins in boar spermatozoa migrating along the epididymal duct. Complementary procedures included measurement of global lectin binding over the surface of the viable sperm population by flow cytometry, analysis of lectin localisation on the membrane of individual spermatozoa using fluorescence microscopy and the electrophoretic characterisation of the major sperm surface glycoprotein receptors involved in lectin binding. A significant increase was found in sperm galactose, glucose/mannose and N-acetyl-d-glucosamine residues distally in the epididymis. Moreover, the sperm head, cytoplasmic droplet and midpiece were recognised by most of the lectins tested, whereas only HPA and WGA bound to the principal piece and end piece of the sperm tail. Fourteen sperm surface proteins were observed with different patterns of lectin expression between epididymal regions. The sperm glycocalyx modifications observed in the present study provide an insight into the molecular modifications associated with epididymal maturation, which may be correlated with the degree of maturation of ejaculated spermatozoa. PMID- 22541551 TI - Effects of a non-steroidal aromatase inhibitor on ovarian function in cattle. AB - Effects of the non-steroidal aromatase inhibitor letrozole on ovarian function in cattle were determined. The hypothesis that letrozole would arrest growth of the dominant follicle, resulting in emergence of a new follicular wave at a predictable post-treatment interval, was tested. Heifers were assigned randomly to four groups 4 days after follicular ablation (~21/2 days after wave emergence) and given intravenous doses of 500 (n = 9), 250 (n = 10), or 125 ug kg-1 (n = 10) letrozole or phosphate-buffered saline (controls; n = 10). Blood was collected and ovarian structures were monitored daily by transrectal ultrasonography. Plasma concentrations of LH and FSH were measured by radioimmunoassay; plasma concentrations of letrozole were determined by high-performance liquid chromatography tandem mass spectrometry. A single intravenous dose of letrozole did not induce regression of the dominant follicle present at the time of treatment, nor did it directly affect FSH release. Conversely, treatment with letrozole increased endogenous concentrations of LH and extended the lifespan of the dominant follicle, which delayed the next FSH surge and subsequent follicular wave emergence. Letrozole continues to have potential as a non-steroidal treatment for controlling ovarian function in cattle. PMID- 22541552 TI - A novel function for BRCA1 in crosslink repair. AB - In this issue of Molecular Cell, Bunting et al. (2012) provide new evidence that BRCA1 plays an important role in DNA interstrand crosslink repair that is distinct from its established function in promoting DNA end resection during homologous recombination. PMID- 22541553 TI - DNA damage response: multilevel proteomics gains momentum. AB - In this issue of Molecular Cell, Beli et al. (2012) introduce a multilevel proteomics approach for parallel quantification of protein phosphorylation, acetylation, and abundance and apply this to the complex signaling network of the DNA damage response. PMID- 22541554 TI - R loops: from transcription byproducts to threats to genome stability. AB - RNA:DNA hybrid structures known as R loops were thought to be rare byproducts of transcription. In the last decade, however, accumulating evidence has pointed to a new view in which R loops form more frequently, impacting transcription and threatening genome integrity as a source of chromosome fragility and a potential cause of disease. Not surprisingly, cells have evolved mechanisms to prevent cotranscriptional R loop formation. Here we discuss the factors and cellular processes that control R loop formation and the mechanisms by which R loops may influence gene expression and the integrity of the genome. PMID- 22541555 TI - Torque generation of kinesin motors is governed by the stability of the neck domain. AB - In long-range transport of cargo, prototypical kinesin-1 steps along a single protofilament on the microtubule, an astonishing behavior given the number of theoretically available binding sites on adjacent protofilaments. Using a laser trap assay, we analyzed the trajectories of several representatives from the kinesin-2 class on freely suspended microtubules. In stark contrast to kinesin-1, these motors display a wide range of left-handed spiraling around microtubules and thus generate torque during cargo transport. We provide direct evidence that kinesin's neck region determines the torque-generating properties. A model system based on kinesin-1 corroborates this result: disrupting the stability of the neck by inserting flexible peptide stretches resulted in pronounced left-handed spiraling. Mimicking neck stability by crosslinking significantly reduced the spiraling of the motor up to the point of protofilament tracking. Finally, we present a model that explains the physical basis of kinesin's spiraling around the microtubule. PMID- 22541556 TI - Reduced expression of ribosomal proteins relieves microRNA-mediated repression. AB - MicroRNAs (miRNAs) regulate physiological and pathological processes by inducing posttranscriptional repression of target messenger RNAs (mRNAs) via incompletely understood mechanisms. To discover factors required for human miRNA activity, we performed an RNAi screen using a reporter cell line of miRNA-mediated repression of translation initiation. We report that reduced expression of ribosomal protein genes (RPGs) dissociated miRNA complexes from target mRNAs, leading to increased polysome association, translation, and stability of miRNA-targeted mRNAs relative to untargeted mRNAs. RNA sequencing of polysomes indicated substantial overlap in sets of genes exhibiting increased or decreased polysomal association after Argonaute or RPG knockdowns, suggesting similarity in affected pathways. miRNA profiling of monosomes and polysomes demonstrated that miRNAs cosediment with ribosomes. RPG knockdowns decreased miRNAs in monosomes and increased their target mRNAs in polysomes. Our data show that most miRNAs repress translation and that the levels of RPGs modulate miRNA-mediated repression of translation initiation. PMID- 22541557 TI - Nitric-oxide supplementation for treatment of long-term complications in argininosuccinic aciduria. AB - Argininosuccinate lyase (ASL) is required for the synthesis and channeling of L arginine to nitric oxide synthase (NOS) for nitric oxide (NO) production. Congenital ASL deficiency causes argininosuccinic aciduria (ASA), the second most common urea-cycle disorder, and leads to deficiency of both ureagenesis and NO production. Subjects with ASA have been reported to develop long-term complications such as hypertension and neurocognitive deficits despite early initiation of therapy and the absence of documented hyperammonemia. In order to distinguish the relative contributions of the hepatic urea-cycle defect from those of the NO deficiency to the phenotype, we performed liver-directed gene therapy in a mouse model of ASA. Whereas the gene therapy corrected the ureagenesis defect, the systemic hypertension in mice could be corrected by treatment with an exogenous NO source. In an ASA subject with severe hypertension refractory to antihypertensive medications, monotherapy with NO supplements resulted in the long-term control of hypertension and a decrease in cardiac hypertrophy. In addition, the NO therapy was associated with an improvement in some neuropsychological parameters pertaining to verbal memory and nonverbal problem solving. Our data show that ASA, in addition to being a classical urea cycle disorder, is also a model of congenital human NO deficiency and that ASA subjects could potentially benefit from NO supplementation. Hence, NO supplementation should be investigated for the long-term treatment of this condition. PMID- 22541558 TI - Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome. AB - Nager syndrome, first described more than 60 years ago, is the archetype of a class of disorders called the acrofacial dysostoses, which are characterized by craniofacial and limb malformations. Despite intensive efforts, no gene for Nager syndrome has yet been identified. In an international collaboration, FORGE Canada and the National Institutes of Health Centers for Mendelian Genomics used exome sequencing as a discovery tool and found that mutations in SF3B4, a component of the U2 pre-mRNA spliceosomal complex, cause Nager syndrome. After Sanger sequencing of SF3B4 in a validation cohort, 20 of 35 (57%) families affected by Nager syndrome had 1 of 18 different mutations, nearly all of which were frameshifts. These results suggest that most cases of Nager syndrome are caused by haploinsufficiency of SF3B4. Our findings add Nager syndrome to a growing list of disorders caused by mutations in genes that encode major components of the spliceosome and also highlight the synergistic potential of international collaboration when exome sequencing is applied in the search for genes responsible for rare Mendelian phenotypes. PMID- 22541559 TI - Mutations in NSUN2 cause autosomal-recessive intellectual disability. AB - With a prevalence between 1 and 3%, hereditary forms of intellectual disability (ID) are among the most important problems in health care. Particularly, autosomal-recessive forms of the disorder have a very heterogeneous molecular basis, and genes with an increased number of disease-causing mutations are not common. Here, we report on three different mutations (two nonsense mutations, c.679C>T [p.Gln227(*)] and c.1114C>T [p.Gln372(*)], as well as one splicing mutation, g.6622224A>C [p.Ile179Argfs(*)192]) that cause a loss of the tRNA methyltransferase-encoding NSUN2 main transcript in homozygotes. We identified the mutations by sequencing exons and exon-intron boundaries within the genomic region where the linkage intervals of three independent consanguineous families of Iranian and Kurdish origin overlapped with the previously described MRT5 locus. In order to gain further evidence concerning the effect of a loss of NSUN2 on memory and learning, we constructed a Drosophila model by deleting the NSUN2 ortholog, CG6133, and investigated the mutants by using molecular and behavioral approaches. When the Drosophila melanogaster NSUN2 ortholog was deleted, severe short-term-memory (STM) deficits were observed; STM could be rescued by re expression of the wild-type protein in the nervous system. The humans homozygous for NSUN2 mutations showed an overlapping phenotype consisting of moderate to severe ID and facial dysmorphism (which includes a long face, characteristic eyebrows, a long nose, and a small chin), suggesting that mutations in this gene might even induce a syndromic form of ID. Moreover, our observations from the Drosophila model point toward an evolutionarily conserved role of RNA methylation in normal cognitive development. PMID- 22541560 TI - Exome sequencing identifies autosomal-dominant SRP72 mutations associated with familial aplasia and myelodysplasia. AB - Aplastic anemia (AA) and myelodysplasia (MDS) are forms of bone marrow failure that are often part of the same progressive underlying disorder. While most cases are simplex and idiopathic, some show a clear pattern of inheritance; therefore, elucidating the underlying genetic cause could lead to a greater understanding of this spectrum of disorders. We used a combination of exome sequencing and SNP haplotype analysis to identify causative mutations in a family with a history of autosomal-dominant AA/MDS. We identified a heterozygous mutation in SRP72, a component of the signal recognition particle (SRP) that is responsible for the translocation of nascent membrane-bound and excreted proteins to the endoplasmic reticulum. A subsequent screen revealed another autosomal-dominant family with an inherited heterozygous SRP72 mutation. Transfection of these sequences into mammalian cells suggested that these proteins localize incorrectly within the cell. Furthermore, coimmunoprecipitation of epitope-tagged SRP72 indicated that the essential RNA component of the SRP did not fully associate with one of the SRP72 variants. These results suggest that inherited mutations in a component of the SRP have a role in the pathophysiology of AA/MDS, identifying a third pathway for developing these disorders alongside transcription factor and telomerase mutations. PMID- 22541561 TI - A genome-wide association study reveals that variants within the HLA region are associated with risk for nonobstructive azoospermia. AB - A genome-wide association study of Han Chinese subjects was conducted to identify genetic susceptibility loci for nonobstructive azoospermia (NOA). In the discovery stage, 802 azoospermia cases and 1,863 controls were screened for genetic variants in the genome. Promising SNPs were subsequently confirmed in two independent sets of subjects: 818 azoospermia cases and 1,755 controls from northern China, and 606 azoospermia cases and 958 controls from central and southern China. We detected variants at human leukocyte antigen (HLA) regions that were independently associated with NOA (HLA-DRA, rs3129878, p(combine) = 3.70 * 10(-16), odds ratio [OR] = 1.37; C6orf10 and BTNL2, rs498422, p(combine) = 2.43 * 10(-12), OR = 1.42). These findings provide additional insight into the pathogenesis of NOA. PMID- 22541563 TI - Social media: how doctors can contribute. PMID- 22541562 TI - Mutation in NSUN2, which encodes an RNA methyltransferase, causes autosomal recessive intellectual disability. AB - Causes of autosomal-recessive intellectual disability (ID) have, until very recently, been under researched because of the high degree of genetic heterogeneity. However, now that genome-wide approaches can be applied to single multiplex consanguineous families, the identification of genes harboring disease causing mutations by autozygosity mapping is expanding rapidly. Here, we have mapped a disease locus in a consanguineous Pakistani family affected by ID and distal myopathy. We genotyped family members on genome-wide SNP microarrays and used the data to determine a single 2.5 Mb homozygosity-by-descent (HBD) locus in region 5p15.32-p15.31; we identified the missense change c.2035G>A (p.Gly679Arg) at a conserved residue within NSUN2. This gene encodes a methyltransferase that catalyzes formation of 5-methylcytosine at C34 of tRNA-leu(CAA) and plays a role in spindle assembly during mitosis as well as chromosome segregation. In mouse brains, we show that NSUN2 localizes to the nucleolus of Purkinje cells in the cerebellum. The effects of the mutation were confirmed by the transfection of wild-type and mutant constructs into cells and subsequent immunohistochemistry. We show that mutation to arginine at this residue causes NSUN2 to fail to localize within the nucleolus. The ID combined with a unique profile of comorbid features presented here makes this an important genetic discovery, and the involvement of NSUN2 highlights the role of RNA methyltransferase in human neurocognitive development. PMID- 22541564 TI - TDR: a time to live or die? PMID- 22541565 TI - Anders Breivik, the public, and psychiatry. PMID- 22541568 TI - Linda Bearinger: creating healthy pathways for adolescents. PMID- 22541569 TI - Omar Ghannoum: an irresistible force for change. PMID- 22541573 TI - Does aspirin really reduce the risk of colon cancer? PMID- 22541575 TI - Does aspirin really reduce the risk of colon cancer? PMID- 22541576 TI - Self-collection of vaginal specimens for HPV testing. PMID- 22541580 TI - Surfactant treatment for spontaneously breathing preterm infants. PMID- 22541581 TI - Dutasteride and active surveillance of low-risk prostate cancer. PMID- 22541582 TI - When is grief a disease? PMID- 22541583 TI - Peripheral neuropathy after hip replacement failure: is vanadium the culprit? PMID- 22541584 TI - The role of intuition and deliberative thinking in experts' superior tactical decision-making. AB - Current theories argue that human decision making is largely based on quick, automatic, and intuitive processes that are occasionally supplemented by slow controlled deliberation. Researchers, therefore, predominantly studied the heuristics of the automatic system in everyday decision making. Our study examines the role of slow deliberation for experts who exhibit superior decision making outcomes in tactical chess problems with clear best moves. Our study uses advanced computer software to measure the objective value of actions preferred at the start versus the conclusion of decision making. It finds that both experts and less skilled individuals benefit significantly from extra deliberation regardless of whether the problem is easy or difficult. Our findings have important implications for the role of training for increasing decision making accuracy in many domains of expertise. PMID- 22541585 TI - Deltamethrin and cypermethrin resistance status of Rhipicephalus (Boophilus) microplus collected from six agro-climatic regions of India. AB - A cross sectional study was conducted to assess the prevalence of synthetic pyrethroids (SP) resistance in Rhipicephalus (Boophilus) microplus in India. Twenty-seven areas located in six agro-climatic regions were selected for the collection of engorged ticks using two stage stratified sampling procedure. Adult immersion test (AIT) and larval packet test (LPT) were optimized using laboratory reared susceptible line of R.(B.) microplus (IVRI-I) for determination of 95% lethal concentration (LC(95)) of deltamethrin (29.6 ppm in AIT and 35.5 ppm in LPT) and cypermethrin (349.1 ppm in AIT and 350.7 ppm in LPT). The AIT with a discriminating dose (2 * LC(95)) was used to detect deltamethrin and cypermethrin resistance in the field isolates of R.(B.) microplus. On the basis of the data generated on three variables viz., mortality, egg masses and reproductive index, the resistance level was categorized as I, II, III and IV. The overall prevalence of SP-resistant R.(B.) microplus among the sampled farms was 66.6% (18/27). Out of these 18 areas, resistance to deltamethrin at level I was detected in 08 areas (resistance factor=2.0-4.9), at level II in 09 areas (RF=5.2-11.8), at level III in 01 area (RF=34.9) and at level IV in 01 area (RF=95.7). The resistance to cypermethrin was detected in 16 areas and level of resistance was detected at level I in 10 areas (RF=2.06-4.64) and at level II in 06 areas (RF=5.13-9.88). The middle-gangetic and trans-gangetic plains revealed higher density of resistant ticks where intensive cross bred cattle population are reared and the SP compounds are commonly used. The data generated on acaricide resistant status in ticks will help in formulating tick control strategy for the country. PMID- 22541586 TI - Introduction to Young Investigator Award Symposium: Symposium XII: Young Investigator Award. PMID- 22541588 TI - Failure to intensify hypertension therapy after rejected aliskiren claims. AB - BACKGROUND: Failure to intensify therapy when indicated is a serious problem in the management of hypertension. Patients having an antihypertensive prescription rejected because of utilization management tools may be at a high risk of failing to intensify their therapy when it is warranted. OBJECTIVE: The goal of this study was to investigate the patterns of therapy change after rejected aliskiren claims because of utilization management tools such as prior authorization, step therapy, and restrictive formulary. METHODS: A retrospective study was conducted using data from a large national pharmacy benefits manager. Patients with a rejected aliskiren claim because of utilization management and who were naive to aliskiren treatment before having a rejected aliskiren claim were included. Patients were followed up for 6 months after the initial rejected aliskiren claim to see whether there was a therapy change. Therapy change was defined as titration of old regimens, fulfillment of aliskiren, or fulfillment of a new antihypertensive medication not used previously. RESULTS: A total of 1955 patients were identified (mean age, 64.5 years; 54.4% female). Six months after having rejected aliskiren claims, 36.8% overcame the utilization management and filled aliskiren; 45.1% filled a new antihypertensive medication not used previously; and 10.8% patients titrated old antihypertensive medications. More than one quarter of patients (28.4%) had no change in their antihypertensive treatment. Logistic regression analysis revealed that patients rejected because of prior authorization (odds ratio = 4.00 [95% CI, 1.89-8.44]) or step therapy (odds ratio = 2.59 [95% CI, 1.26-5.32]) were more likely to have a therapy change compared with patients rejected because of a restrictive formulary. CONCLUSIONS: A significant number of patients had no therapy change 6 months after having rejected aliskiren claims because of utilization management tools, indicating potential clinical inertia or lack of therapy intensification in hypertension management. Patients with restrictive formularies were least likely to have a therapy change. More aggressive follow-up with patients with a rejected claim may be warranted to reduce treatment gaps. PMID- 22541587 TI - Cost-effectiveness analysis of interferon beta-1b for the treatment of patients with a first clinical event suggestive of multiple sclerosis. AB - OBJECTIVES: To assess, from a Swedish societal perspective, the cost effectiveness of interferon beta-1b (IFNB-1b) after an initial clinical event suggestive of multiple sclerosis (MS) (ie, early treatment) compared with treatment after onset of clinically definite MS (CDMS) (ie, delayed treatment). METHODS: A Markov model was developed, using patient level data from the BENEFIT trial and published literature, to estimate health outcomes and costs associated with IFNB-1b for hypothetical cohorts of patients after an initial clinical event suggestive of MS. Health states were defined by Kurtzke Expanded Disability Status Scale (EDSS) scores. Model outcomes included quality-adjusted life years (QALYs), total costs (including both direct and indirect costs), and incremental cost-effectiveness ratios. Sensitivity analyses were performed on key model parameters to assess the robustness of model results. RESULTS: In the base case scenario, early IFNB-1b treatment was economically dominant (ie, less costly and more effective) versus delayed IFNB-1b treatment when QALYs were used as the effectiveness metric. Sensitivity analyses showed that the cost-effectiveness results were sensitive to model time horizon. Compared with the delayed treatment strategy, early treatment of MS was also associated with delayed EDSS progressions, prolonged time to CDMS diagnosis, and a reduction in frequency of relapse. CONCLUSION: Early treatment with IFNB-1b for a first clinical event suggestive of MS was found to improve patient outcomes while controlling costs. PMID- 22541589 TI - [Difficulty in diagnosing infections in cerebrospinal fluid shunts]. PMID- 22541590 TI - Interobserver agreement of the injury diagnoses obtained by postmortem computed tomography of traffic fatality victims and a comparison with autopsy results. AB - The present study investigated the interobserver variation between a radiologist and a forensic pathologist in 994 injury diagnoses obtained by postmortem computed tomography (CT) of 67 traffic fatality victims, and the results were compared with diagnoses obtained by autopsy. The injuries were coded according to the abbreviated injury scale (AIS). We found a low interobserver variability for postmortem CT injury diagnoses, and the variability was the lowest for injuries with a high AIS severity score. The radiologist diagnosed more injuries than the pathologist, especially in the skeletal system, but the pathologist diagnosed more organ injuries. We recommend the use of a radiologist as a consultant for the evaluation of postmortem CT images. Training in radiology should be included in forensic medicine postgraduate training. CT was superior to autopsy in detecting abnormal air accumulations, but autopsy was superior to CT in the detection of organ injuries and aortic ruptures. We recommend a combination of CT and autopsy for the postmortem investigation of traffic fatality victims. PMID- 22541591 TI - Selected papers from the 14th Annual Bio-Ontologies Special Interest Group Meeting. AB - Over the 14 years, the Bio-Ontologies SIG at ISMB has provided a forum for discussion of the latest and most innovative research in the bio-ontologies development, its applications to biomedicine and more generally the organisation, presentation and dissemination of knowledge in biomedicine and the life sciences. The seven papers selected for this supplement span a wide range of topics including: web-based querying over multiple ontologies, integration of data from wikis, innovative methods of annotating and mining electronic health records, advances in annotating web documents and biomedical literature, quality control of ontology alignments, and the ontology support for predictive models about toxicity and open access to the toxicity data. PMID- 22541592 TI - Open semantic annotation of scientific publications using DOMEO. AB - BACKGROUND: Our group has developed a useful shared software framework for performing, versioning, sharing and viewing Web annotations of a number of kinds, using an open representation model. METHODS: The Domeo Annotation Tool was developed in tandem with this open model, the Annotation Ontology (AO). Development of both the Annotation Framework and the open model was driven by requirements of several different types of alpha users, including bench scientists and biomedical curators from university research labs, online scientific communities, publishing and pharmaceutical companies.Several use cases were incrementally implemented by the toolkit. These use cases in biomedical communications include personal note-taking, group document annotation, semantic tagging, claim-evidence-context extraction, reagent tagging, and curation of textmining results from entity extraction algorithms. RESULTS: We report on the Domeo user interface here. Domeo has been deployed in beta release as part of the NIH Neuroscience Information Framework (NIF, http://www.neuinfo.org) and is scheduled for production deployment in the NIF's next full release.Future papers will describe other aspects of this work in detail, including Annotation Framework Services and components for integrating with external textmining services, such as the NCBO Annotator web service, and with other textmining applications using the Apache UIMA framework. PMID- 22541593 TI - A Maximum-Entropy approach for accurate document annotation in the biomedical domain. AB - The increasing number of scientific literature on the Web and the absence of efficient tools used for classifying and searching the documents are the two most important factors that influence the speed of the search and the quality of the results. Previous studies have shown that the usage of ontologies makes it possible to process document and query information at the semantic level, which greatly improves the search for the relevant information and makes one step further towards the Semantic Web. A fundamental step in these approaches is the annotation of documents with ontology concepts, which can also be seen as a classification task. In this paper we address this issue for the biomedical domain and present a new automated and robust method, based on a Maximum Entropy approach, for annotating biomedical literature documents with terms from the Medical Subject Headings (MeSH).The experimental evaluation shows that the suggested Maximum Entropy approach for annotating biomedical documents with MeSH terms is highly accurate, robust to the ambiguity of terms, and can provide very good performance even when a very small number of training documents is used. More precisely, we show that the proposed algorithm obtained an average F-measure of 92.4% (precision 99.41%, recall 86.77%) for the full range of the explored terms (4,078 MeSH terms), and that the algorithm's performance is resilient to terms' ambiguity, achieving an average F-measure of 92.42% (precision 99.32%, recall 86.87%) in the explored MeSH terms which were found to be ambiguous according to the Unified Medical Language System (UMLS) thesaurus. Finally, we compared the results of the suggested methodology with a Naive Bayes and a Decision Trees classification approach, and we show that the Maximum Entropy based approach performed with higher F-Measure in both ambiguous and monosemous MeSH terms. PMID- 22541595 TI - Towards valid and reusable reference alignments - ten basic quality checks for ontology alignments and their application to three different reference data sets. AB - Identifying relationships between hitherto unrelated entities in different ontologies is the key task of ontology alignment. An alignment is either manually created by domain experts or automatically by an alignment system. In recent years, several alignment systems have been made available, each using its own set of methods for relation detection. To evaluate and compare these systems, typically a manually created alignment is used, the so-called reference alignment. Based on our experience with several of these reference alignments we derived requirements and translated them into simple quality checks to ensure the alignments' validity and also their reusability. In this article, these quality checks are applied to a standard reference alignment in the biomedical domain, the Ontology Alignment Evaluation Initiative Anatomy track reference alignment, and two more recent data sets covering multiple domains, including but not restricted to anatomy and biology. PMID- 22541594 TI - Logical Gene Ontology Annotations (GOAL): exploring gene ontology annotations with OWL. AB - MOTIVATION: Ontologies such as the Gene Ontology (GO) and their use in annotations make cross species comparisons of genes possible, along with a wide range of other analytical activities. The bio-ontologies community, in particular the Open Biomedical Ontologies (OBO) community, have provided many other ontologies and an increasingly large volume of annotations of gene products that can be exploited in query and analysis. As many annotations with different ontologies centre upon gene products, there is a possibility to explore gene products through multiple ontological perspectives at the same time. Questions could be asked that link a gene product's function, process, cellular location, phenotype and disease. Current tools, such as AmiGO, allow exploration of genes based on their GO annotations, but not through multiple ontological perspectives. In addition, the semantics of these ontology's representations should be able to, through automated reasoning, afford richer query opportunities of the gene product annotations than is currently possible. RESULTS: To do this multi perspective, richer querying of gene product annotations, we have created the Logical Gene Ontology, or GOAL ontology, in OWL that combines the Gene Ontology, Human Disease Ontology and the Mammalian Phenotype Ontology, together with classes that represent the annotations with these ontologies for mouse gene products. Each mouse gene product is represented as a class, with the appropriate relationships to the GO aspects, phenotype and disease with which it has been annotated. We then use defined classes to query these protein classes through automated reasoning, and to build a complex hierarchy of gene products. We have presented this through a Web interface that allows arbitrary queries to be constructed and the results displayed. CONCLUSION: This standard use of OWL affords a rich interaction with Gene Ontology, Human Disease Ontology and Mammalian Phenotype Ontology annotations for the mouse, to give a fine partitioning of the gene products in the GOAL ontology. OWL in combination with automated reasoning can be effectively used to query across ontologies to ask biologically rich questions. We have demonstrated that automated reasoning can be used to deliver practical on-line querying support for the ontology annotations available for the mouse. AVAILABILITY: The GOAL Web page is to be found at http://owl.cs.manchester.ac.uk/goal. PMID- 22541596 TI - Annotation Analysis for Testing Drug Safety Signals using Unstructured Clinical Notes. AB - BACKGROUND: The electronic surveillance for adverse drug events is largely based upon the analysis of coded data from reporting systems. Yet, the vast majority of electronic health data lies embedded within the free text of clinical notes and is not gathered into centralized repositories. With the increasing access to large volumes of electronic medical data-in particular the clinical notes-it may be possible to computationally encode and to test drug safety signals in an active manner. RESULTS: We describe the application of simple annotation tools on clinical text and the mining of the resulting annotations to compute the risk of getting a myocardial infarction for patients with rheumatoid arthritis that take Vioxx. Our analysis clearly reveals elevated risks for myocardial infarction in rheumatoid arthritis patients taking Vioxx (odds ratio 2.06) before 2005. CONCLUSIONS: Our results show that it is possible to apply annotation analysis methods for testing hypotheses about drug safety using electronic medical records. PMID- 22541597 TI - Linking genes to diseases with a SNPedia-Gene Wiki mashup. AB - BACKGROUND: A variety of topic-focused wikis are used in the biomedical sciences to enable the mass-collaborative synthesis and distribution of diverse bodies of knowledge. To address complex problems such as defining the relationships between genes and disease, it is important to bring the knowledge from many different domains together. Here we show how advances in wiki technology and natural language processing can be used to automatically assemble 'meta-wikis' that present integrated views over the data collaboratively created in multiple source wikis. RESULTS: We produced a semantic meta-wiki called the Gene Wiki+ that automatically mirrors and integrates data from the Gene Wiki and SNPedia. The Gene Wiki+, available at (http://genewikiplus.org/), captures 8,047 distinct gene disease relationships. SNPedia accounts for 4,149 of the gene-disease pairs, the Gene Wiki provides 4,377 and only 479 appear independently in both sources. All of this content is available to query and browse and is provided as linked open data. CONCLUSIONS: Wikis contain increasing amounts of diverse, biological information useful for elucidating the connections between genes and disease. The Gene Wiki+ shows how wiki technology can be used in concert with natural language processing to provide integrated views over diverse underlying data sources. PMID- 22541598 TI - OpenTox predictive toxicology framework: toxicological ontology and semantic media wiki-based OpenToxipedia. AB - BACKGROUND: The OpenTox Framework, developed by the partners in the OpenTox project (http://www.opentox.org), aims at providing a unified access to toxicity data, predictive models and validation procedures. Interoperability of resources is achieved using a common information model, based on the OpenTox ontologies, describing predictive algorithms, models and toxicity data. As toxicological data may come from different, heterogeneous sources, a deployed ontology, unifying the terminology and the resources, is critical for the rational and reliable organization of the data, and its automatic processing. RESULTS: The following related ontologies have been developed for OpenTox: a) Toxicological ontology - listing the toxicological endpoints; b) Organs system and Effects ontology - addressing organs, targets/examinations and effects observed in in vivo studies; c) ToxML ontology - representing semi-automatic conversion of the ToxML schema; d) OpenTox ontology- representation of OpenTox framework components: chemical compounds, datasets, types of algorithms, models and validation web services; e) ToxLink-ToxCast assays ontology and f) OpenToxipedia community knowledge resource on toxicology terminology.OpenTox components are made available through standardized REST web services, where every compound, data set, and predictive method has a unique resolvable address (URI), used to retrieve its Resource Description Framework (RDF) representation, or to initiate the associated calculations and generate new RDF-based resources.The services support the integration of toxicity and chemical data from various sources, the generation and validation of computer models for toxic effects, seamless integration of new algorithms and scientifically sound validation routines and provide a flexible framework, which allows building arbitrary number of applications, tailored to solving different problems by end users (e.g. toxicologists). AVAILABILITY: The OpenTox toxicological ontology projects may be accessed via the OpenTox ontology development page http://www.opentox.org/dev/ontology; the OpenTox ontology is available as OWL at http://opentox.org/api/1 1/opentox.owl, the ToxML - OWL conversion utility is an open source resource available at http://ambit.svn.sourceforge.net/viewvc/ambit/branches/toxml-utils/ PMID- 22541599 TI - Better analyze the determinants of therapeutic inertia to overcome it. PMID- 22541600 TI - Type 2 diabetes treatment intensification in general practice in France in 2008 2009: the DIAttitude Study. AB - AIMS: To evaluate the current procedures in French general practice of intensifying hypoglycaemic treatment in orally treated type 2 diabetic patients, according to the French recommendations. METHODS: Type 2 diabetic patient characteristics, HbA(1c) values, hypoglycaemic treatment and physician characteristics were collected from the electronic records of a panel of French general practitioners. Factors associated with the time until intensification of treatment were studied with the Cox model. RESULTS: Among 17 493 orally treated patients with at least two available HbA(1c) values, 3118 patients (18%) required treatment intensification; 65% were on monotherapy, 31% on bitherapy and 4% on tritherapy. These patients were followed for a maximum of 14 months or until treatment was intensified. Treatment was intensified after the second high HbA(1c) value for 1212 patients (39%); this was immediate for 13% of these patients, within 6 months for 39% and within one year for 59%. Treatment intensification was less likely the older the patient, and more likely the higher the first HbA(1c) value, up to an HbA(1c) threshold of 9%. CONCLUSIONS: Therapeutic inertia in caring for type 2 diabetic patients in France is frequent, at least for patients treated in general practice. This inadequate glycaemic control would be expected to have significant patient and public health consequences, with higher rates of associated diabetic complications. PMID- 22541601 TI - Therapeutic management of orally treated type 2 diabetic patients, by French general practitioners in 2010: the DIAttitude Study. AB - AIM: To describe the behaviour of French general practitioners (GP) regarding intensification of hypoglycaemic agents in orally treated type 2 diabetic (T2D) patients, according to their HbA(1c) level. METHODS: General practitioners were recruited from a panel of office-based general practitioners. T2D patients who had been orally treated for at least 6 months were included in the study; their characteristics were recorded, and their HbA(1c) values and hypoglycaemic treatments over the previous 24 months extracted from electronic records The major reasons for intensification (or no intensification) of hypoglycaemic agents were recorded at the inclusion visit. RESULTS: A total of 236 general practitioners recruited 2109 T2D patients: 1732 had at least one HbA(1c) value recorded in the previous 6 months, and 52%, 33% and 14% had been treated, with oral hypoglycaemic agents in monotherapy, bitherapy or tri-or quadritherapy, respectively. Of these patients, 702 (41%) remained uncontrolled (47%, 39% and 20% respectively) and according to the current French guidelines needed treatment intensification. Only 46 (7%) had their treatment intensified at inclusion. Of those without intensified treatment, 60% were treated with monotherapy; the main reason given by the general practitioners for not intensifying treatment was a satisfactory HbA(1c) level (53%), although 32% had an HbA(1c)>7%. Other reasons were: lifestyle advice had greater priority (20%); decision was postponed until the next visit (11%); HbA(1c) had decreased since last visit (7%; not confirmed by available data in 58% of cases); a medical priority other than diabetes (6%) and other reasons related to the patient (3%). CONCLUSION: For T2D patients managed by French general practitioners, guidelines are not consistently followed: HbA(1c) should be monitored more frequently and treatment adjusted according to HbA(1c) levels. PMID- 22541602 TI - Therapeutic inertia in type 2 diabetes: insights from the PANORAMA study in France. AB - "Therapeutic inertia" is usually defined as the failure to change or uptitrate treatment strategy when a disease is uncontrolled. In patients with type 2 diabetes (T2D) this may occur with antidiabetes treatments and/or treatment for various cardiovascular risk factors. The PANORAMA study (NCT00916513) compared individual HbA(1c) targets and actual HbA(1c) levels in 5817 patients with T2D in nine European countries, and investigated the reasons why therapeutic choices made by physicians sometimes differ from expert guidelines for this disease. Thus it provides an insight into therapeutic inertia, a fashionable paradigm which can be challenged. This article reports data specifically from the French cohort of patients (n=759). We will try to demonstrate that criticising physicians for not strictly applying the expert T2D guidelines would not be beneficial as the clinical background for this apparent therapeutic inertia is complex. It appears that it may be more clinically relevant and useful to understand the reasons why the therapeutic choice made by the physician-patient partnership can sometimes differ from guidelines. This pragmatic approach would not detract from the need to develop and implement expert guidelines as it is essential to have benchmarks to assess temporal trends of quality of healthcare delivered to patients with T2D at the national level. However, these treatment targets must be put into perspective for clinical practice. Following the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, it appears mandatory to individualize glycaemic targets to enable physicians to identify the most appropriate antidiabetes treatment for each patient. PMID- 22541603 TI - Clinical inertia: viewpoints of general practitioners and diabetologists. AB - Large clinical studies have enabled best practice guidelines to be issued. Intended to serve practitioners in their daily practice, the guidelines are also excellent tools for assessing physician performance. It was therefore demonstrated that despite the observation of insufficient glycaemic control, physicians did not systematically increase drug treatments. As a result, they have been accused of clinical inertia! In this journal, we first try to reveal what is behind this concept and to differentiate true inertia from pseudo inertia. Secondly, we consider how general practitioners and diabetologists, through their respective positions, can develop a synergy that is able to fight against inertia but that can especially, improve the glycaemic control of our patients. PMID- 22541604 TI - How to help the patient motivate himself? AB - In order to help a patient with a chronic disease motivate himself, caregivers spontaneously make use of reason with a view to having the patient share the caregivers' point of view, in other words, to some extent, transforming the care recipient into a caregiver. However, it is not unusual for a caregiver suffering from the disease in which he specializes not to treat himself in compliance with the rules he recommends to his patients. Man is a trinity with three instances of the self. In addition to the "rational self" that tends towards the universal, there is also an "animal self" subject to powerful, frequently imperious, primary needs which may be compared to impulsions, compulsions and addictions. Lastly, there is an "identity self", an irreducible singularity, governed by the law of optimizing pleasure or, in any event, avoiding moral distress. The patient has to learn to navigate between objectives oriented by reason, more or less imperious urges and the striving for well-being and avoidance of moral distress. These various instances of the "self" have a distinct relationship with the norm and with time. Psychologists recognize two types of motivation: intrinsic motivation, an activity implemented for itself, and extrinsic motivation, an activity practiced for its secondary beneficial effects. Clearly, caring for oneself derives from an extrinsic motivation. This motivation may be very powerful but is frequently of limited duration. Helping a patient suffering from a chronic disease motivate himself over time thus consists in helping the patient take on board an extrinsic motivation in order for the treatment to become a routine or a source of satisfaction or even pleasure. The physician has to promote the acquisition of self-care skills and a feeling of success in the patient. The physician is also to help the patient negotiate the optimum compromise between his "rational self" and his "identity self" by acting as the advocate of the two parties, while not forgetting to play the devils' advocate. Lastly, the expression of the patient's "identity self" through discussion groups, drawing or writing workshops, or "living theatre" may enable expression of an encysted wound. While progressing in that direction, the patient will modify his representation of the disease and its treatment, and enhance his understanding of who he is and how he functions (metacognition). This is the objective of therapeutic education. However, it is necessary for caregivers to demonstrate real empathy that is not only cognitive but also emotional. PMID- 22541605 TI - Time to stroke magnetic resonance imaging. AB - BACKGROUND: Recent guidelines on stroke neuroimaging from the American Academy of Neurology (AAN) recommend magnetic resonance imaging (MRI) over computed tomography (CT) for stroke diagnosis when patients present within 12 hours of onset. We sought to estimate the proportion of stroke MRI that is performed within 12 hours. METHODS: Using the best available data, we estimated total time from symptom onset to MRI with a Monte Carlo simulation. We modeled 3 times to MRI: time to presentation, time to emergency department (ED) MRI, and time to inpatient MRI. Total time to MRI was estimated by summing these time components while varying model parameters around our base model. Sensitivity analyses assessed the relative importance of model parameters to overall MRI timing. RESULTS: In 2009, we estimate that 66% of stroke patients underwent MRI, 14% received an MRI in the ED, and 68% of all MRIs were obtained on hospital day 0 or 1. We estimate that 29% (95% confidence interval 24-33%) of stroke MRIs are obtained within 12 hours of onset. Sensitivity analyses revealed that even large clinical changes (eg, decreasing time to presentation) would only moderately influence this proportion. For example, if mean time to presentation were reduced to 30 minutes (from the base case estimate of 16 hours), the proportion of stroke MRI performed within 12 hours would only increase to 55.3%. CONCLUSIONS: Stroke guidelines favor the use of MRI over CT only during the first 12 hours from symptom onset, yet less than one-third of stroke MRIs are actually performed within this timeframe. PMID- 22541606 TI - Microembolic signals in patients with acute nonembolic stroke. AB - BACKGROUND: The nature of microembolic signals (MES) in patients without apparent sources of embolism remains elusive. We hypothesize that MES in acute stroke patients without an embolic source may represent a transient phenomenon related to blood rheology or clot dissolving, in which case the characteristics of such MES would differ from those with definitive sources of emboli. METHODS: We compared the intensity and duration of 250 MES in 62 acute nonembolic stroke patients (stroke group) and 217 MES in 57 patients with asymptomatic carotid stenosis (>=50%; carotid group). RESULTS: The duration of MES was significantly different between the 2 groups (24.86 +/- 0.89 ms in the carotid group v 18.8 +/- 0.83 in the stroke group; P < .001). When comparing the groups for MES with an intensity higher than 6 dB, a highly significant difference in the duration of MES was found (27.87 +/- 1.26 ms in the carotid group v 18.57 +/- 1.29 ms in the stroke group; P < .0001). A strong linear relationship between the duration and intensity of MES was found for the carotid group, but not for the stroke group. CONCLUSIONS: There are significant differences between the characteristics of MES in acute stroke patients as compared with MES in patients with carotid plaques. There is a strong correlation between the intensity and duration of MES from a definitive embolic source, which is absent from MES in patients with nonembolic stroke. These findings may point to the different mechanisms of MES origin in the examined groups. PMID- 22541607 TI - Stroke size correlates with functional outcome on the simplified modified Rankin Scale questionnaire. AB - BACKGROUND: Acute stroke size is one of the factors impacting functional outcome. To further validate the simplified modified Rankin Scale questionnaire (smRSq), we tested its correlation with stroke size. METHODS: We screened 60 ischemic stroke patients with acute brain images available for stroke volume measurement who were enrolled in 2 smRSq reliability studies. Inclusion criteria were acute ischemic stroke visible on computed tomography (CT) or magnetic resonance imaging (MRI) and the smRSq scored at least 3 months after stroke. We excluded patients with disabilities from a previous stroke. One investigator who was blinded to the functional outcomes measured stroke volumes with a specialized computer program (Analyze). We used MRI when both MRI and CT were available. We classified strokes into 2 size categories: lacunar type measuring <= 6.28 cm(3), which corresponds to a cylinder with a maximum diameter and height of 2.00 cm, or strokes >6.28 cm(3). The Spearman correlation analysis compared the smRSq between the lacunar type and the larger strokes. RESULTS: Thirty-two patients qualified for this analysis with a mean age of 59 +/- 15 years, and 17 (53%) were men. Lacunar stroke volumes (n = 17) ranged from 0.03 to 4.58 cm(3), and the larger stroke volumes (n = 15) ranged from 11.52 to 250.02 cm(3). Lacunar strokes were associated with lower smRSq scores (median 1) than the larger strokes (median 4; r = 0.68; R(2) = 0.46; P < .001). CONCLUSIONS: Acute stroke size correlates well with the smRSq, supporting its validity in assessing functional outcome after stroke. PMID- 22541608 TI - Bilateral medial medullary infarction: a systematic review. AB - Bilateral infarction of the medial medulla (MMI) is rare. Limited information is available on clinical characteristics, etiology, and prognosis. High-resolution neuroimaging has a major role in elucidating the underlying stroke mechanism. The aim of this systematic review was to analyze the clinical presentations, stroke mechanisms, and outcomes in patients with bilateral MMI. We performed a systematic review of the literature from 1992-2011 that reported on clinical presentations, stroke mechanism, and/or outcomes in patients with magnetic resonance imaging-proven bilateral MMI. Medline, EMBASE, and Web of Science Scholars Portal were searched without language restriction. Two reviewers independently assessed identified studies to determine eligibility, validity, and quality. The primary outcome was inpatient mortality; a secondary outcome was case fatality at 12 months. We identified 138 articles from Medline, EMBASE, and Scholars Portal including the MeSH terms "brainstem infarction," "medulla," and "bilateral." Twenty-nine articles met our inclusion criteria, including a total of 38 cases with bilateral MMI, and included in our study. These 38 patients had a mean age of 62.2 years and were predominately male (74.2%). The most common clinical presentations were motor weakness in 78.4%, dysarthria in 48.6%, and hypoglossal palsy in 40.5%. The most common vascular pathology was vertebral artery atherosclerosis, in 38.5%. The clinical outcome was poor (mortality, 23.8%; dependency, 61.9%). Bilateral medial medullary infarction is a rare stroke syndrome. Clinical presentations were mostly rostral medullary lesions. Large artery atherosclerosis and branch disease were the most common stroke mechanisms. The clinical outcome was usually poor. PMID- 22541609 TI - An unusual feature of yolk sac placentation in Necromys lasiurus (Rodentia, Cricetidae, Sigmodontinae). AB - We studied the development of the inverted yolk sac in a New World rodent, Necromys lasiurus during early placentation. Ten implantation sites were investigated by means of histology, immunohistochemistry and electron microscopy. The yolk sac was villous near its attachment to the placenta. Elsewhere it was non-villous and closely attached to the uterus. The uterine glands were shallow and wide mouthed. They were associated with vessels and filled with secretion, suggesting the release of histotroph. This feature was absent at later stages. The intimate association of the yolk sac with specialized glandular regions of the uterus may represent a derived character condition of Necromys and/or sigmodont rodents. PMID- 22541610 TI - Use of Matrigel in culture affects cell phenotype and gene expression in the first trimester trophoblast cell line HTR8/SVneo. AB - There is inconsistent use of Matrigel for experiments with the HTR8/SVneo first trimester trophoblast and other cell lines. We quantified the effects of Matrigel on the expression of genes considered to be markers of extravillous cytotrophoblast (EVT) differentiation and invasive potential. Culture on Matrigel promoted formation of "endothelial-like" tubes and reduced mRNA expression of matrix metalloproteinase 2 (MMP2), cytokeratin 7 (KRT7) and integrin alpha 1 (ITGA1), while increasing VE-cadherin (CDH5) expression consistent with a vascular phenotype. This process may constitute part of the endothelial cell mimicry exhibited by endovascular EVTs invading the maternal spiral arteries. HTR8/SVneo appears to be phenotypically polymorphic and adopt endovascular morphology on Matrigel. PMID- 22541611 TI - The utility of endocervical curettage: does routine ECC at the time of colposcopy for low-grade cytologic abnormalities improve diagnosis of high-grade disease? AB - OBJECTIVE: To determine the use of endocervical curettage at the time of colposcopy for low-grade cytologic abnormalities. STUDY DESIGN: We conducted a retrospective chart review of women with low-grade Papanicolaou smears who had undergone satisfactory colposcopic examinations with identifiable lesions. We evaluated results during a 2-year period thereafter to determine whether endocervical curettage increased the diagnosis of high-grade dysplasia. RESULTS: The study group consisted of 374 patients. Of these patients, 16 had endocervical curettages suggestive of high-grade dysplasia. Of these 16 patients, 4 did not have concomitant high-grade dysplasia identified on ectocervical biopsy. Therefore, 93 to 94 endocervical curettages needed to be performed to detect 1 case of high-grade dysplasia that would not have been identified otherwise. CONCLUSION: Routine endocervical curettage at the time of satisfactory colposcopy for low-grade cytologic abnormalities with a visible lesion does not significantly improve the diagnosis of high-grade dysplasia. PMID- 22541612 TI - Successful in utero treatment of an oral teratoma via operative fetoscopy: case report and review of the literature. AB - The prenatal diagnosis of a nasopharyngeal teratoma carries a very grave prognosis. Although these tumors constitute only 9% of all teratomas, all previous cases diagnosed antenatally have been associated with either fetal demise or emergent surgery at birth. Of the fetuses that survive to birth, delivery can be associated with airway obstruction and multiple postnatal surgeries. These complications could be averted if the tumor could be safely treated in utero. We hereby report the successful treatment of an oral teratoma via operative fetoscopy, with the birth of a healthy infant at term. PMID- 22541613 TI - Splenic diffuse red pulp small-B cell lymphoma: toward the emergence of a new lymphoma entity. AB - Among splenic lymphomas with circulating cells presenting cytoplasmic projections, a homogeneous clinico-pathological entity has been recently individualized as Splenic Diffuse Red Pulp Lymphomas (SDRPL) and introduced in the provisional "unclassifiable splenic lymphoma" category of the current updated WHO classification until more is known. SDRPL presents characteristic circulating basophilic villous lymphocytes and diffuse infiltration of the splenic red pulp, distinct from Splenic Marginal Zone Lymphoma (SMZL) and Hairy Cell Leukemia (HCL), but reminiscent of HCL-Variant (HCL-V). Series of SDRPL remain sparse in the literature and controversies exist about the relationship with other splenic lymphomas. Distinction of these disorders at diagnosis can be difficult, but an adequate diagnosis is important due to differences in patient management and clinical outcome. Especially, BRAF mutations have been detected in almost all patients with HCL that may have implications for pathogenesis, diagnosis, and targeted therapy. This review will report literature data and discuss the differential diagnosis, particularly with HCL-V. PMID- 22541614 TI - Evolving paradigms for desensitization in managing broadly HLA sensitized transplant candidates. AB - The broadly human leukocyte antigen (HLA) sensitized patient awaiting organ transplantation remains a persistent and significant problem for transplant medicine. Sensitization occurs as a consequence of exposure to HLA antigens through pregnancy, blood and platelet transfusions, and previous transplants. Early experience with desensitization protocols coupled with improved diagnostics for donor-specific antibodies (DSAs) and renal pathology have greatly improved transplant rates and outcomes for patients once considered un-transplantable or at high risk for poor outcomes. More recent advances have occurred through implementation of a national allocation system requiring the entering of unacceptable antigens that reduces the rate of crossmatch positivity. Current desensitization therapies include high-dose intravenous immunoglobulin (IVIG), plasma exchange (PLEX) with low-dose IVIG, and IVIG combined with rituximab. Developing therapies include proteasome inhibitors aimed at plasma cells and modifiers of complement-mediated injury. Here we discuss the important advancements in desensitization including defining the risk for antibody-mediated rejection prior to transplantation and the evolution of therapies aimed at reducing the impact of antibody injury on allografts. PMID- 22541615 TI - Calcium phosphosilicate nanoparticles for imaging and photodynamic therapy of cancer. AB - Photodynamic therapy (PDT) has emerged as an alternative modality for cancer treatment. PDT works by initiating damaging oxidation or redox-sensitive pathways to trigger cell death. PDT can also regulate tumor angiogenesis and modulate systemic antitumor immunity. The drawbacks to PDT--photosensitizer toxicity, a lack of selectivity and efficacy of photosensitizers, and a limited penetrance of light through deep tissues--are the same pitfalls associated with diagnostic imaging. Developments in the field of nanotechnology have generated novel platforms for optimizing the advantages while minimizing the disadvantages of PDT. Calcium phosphosilicate nanoparticles (CPSNPs) represent an optimal nano system for both diagnostic imaging and PDT. In this review, we will discuss how CPSNPs can enhance optical agents and serve as selective, non-toxic, and functionally stable photosensitizers for PDT. We will also examine novel applications of CPSNPs and PDT for the treatment of leukemia to illustrate their potential utility in cancer therapeutics. PMID- 22541616 TI - Recent advances in non-small cell lung cancer biology and clinical management. AB - Despite advances in surgery, chemotherapy, and radiotherapy over the last decades, the death rate from lung cancer has remained largely unchanged, which is mainly due to metastatic disease. Because of the overall poor prognosis, new treatment strategies for lung cancer patients are urgently needed. In this review, we summarize recent advances in non-small cell lung cancer (NSCLC) screening and diagnostic workup. We discuss current clinical management, highlighting stage-specific therapy approaches, chemotherapy options for advanced stage patients, along with new agents such as vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) monoclonal antibodies, and the EGFR-targeting tyrosine kinase inhibitors erlotinib and gefitinib, and the anaplastic lymphoma kinase (ALK) inhibitor crizotinib. Finally, we give an outlook into NSCLC disease biology, focusing on the importance of EGFR activating mutations and the role of the tumor-microenvironment. CXCR4 chemokine receptors expressed on NSCLC cells are a central pathway of NSCLC cross talk with the tumor microenvironment, as they induce activation, migration, and tumor cell adhesion to stromal cells, which in turn provides growth- and drug resistance-signals. Because of the growing evidence that the microenvironment in NSCLC promotes disease progression, we expect that selected molecular pathways of cross talk between NSCLC cells and their microenvironment will become alternative therapeutic targets in the near future. PMID- 22541617 TI - Advances in the evaluation and classification of chronic inflammatory rheumatic diseases. AB - The challenges of diagnosing rheumatic diseases are the high prevalence of certain rheumatic diseases, the existence of orphan disease, and the different pathophysiological backgrounds including infection and autoimmune mechanisms. During recent decades, more and more attention has been drawn to early diagnosis and achievement of full remission. Accordingly, new classification criteria have been developed and more biomarkers introduced into clinical practice. Specific laboratory parameters as well as wider use of functional imaging tools like ultrasound and magnetic resonance further support the early diagnostic process. Besides diagnosis early after disease onset, achievement of remission during follow-up is another important clinical aim of rheumatologists. In parallel with the development of new therapeutic approaches, both quality of life and treatment outcome especially of chronic inflammatory diseases could be improved. Both specific outcome parameters and global disease activity assessments are important to verify treatment goals of (full) remission, and at the same time may also predict response to treatment regimens. PMID- 22541618 TI - Inhibition of interleukin-5 for the treatment of eosinophilic diseases. AB - Elevated numbers of blood and tissue eosinophils are present in allergic diseases and experimental evidence suggests that eosinophils play an important pathogenic role in these conditions. Regulation of eosinophil maturation, recruitment, and survival is under the control of a small group of factors, including interleukin 5 (IL-5). Given the probable importance of eosinophils to allergy and other associated disorders, IL-5 has been proposed as a potential molecular target in the treatment of these diseases. IL-5 antagonist therapies in current development include two monoclonal anti-IL-5 antibodies (mepolizumab, reslizumab), a monoclonal antibody directed at the IL-5 receptor (benralizumab), and anti-sense oligonucleotide therapy (TPI ASM8). Anti-IL5 antibody therapy has been the most extensively studied of these agents, and trials have been performed in patients with bronchial asthma, nasal polyposis, atopic dermatitis, eosinophilic esophagitis, hypereosinophilic syndrome, and Churg-Strauss syndrome. In studies of asthmatics, anti-IL-5 showed minimal efficacy in patients with moderate, controlled asthma. In patients with severe, refractory asthma associated with eosinophilia, however, clinical trials have demonstrated significant reductions in asthma exacerbations. Clinical studies in other disorders, particularly eosinophilic esophagitis and hypereosinophilic syndrome, have also shown significant improvements in blood and/or tissue eosinophilia and variable alterations in clinical disease activity. Strategies aimed at the inhibition of IL-5 may hold great promise in the treatment of eosinophilic diseases. PMID- 22541619 TI - Advances in colonoscopy. AB - There is intense interest in optimizing currently available colonoscopy techniques and developing new methods to improve early detection and prevention of colorectal cancer. These improvements apply to many aspects of colonoscopy, including screening effectiveness, reduced pain and complications, in vivo lesion classification, and easier insertion methods. Inherent characteristics of colonoscopy such as blind spots, residual stool, colonic contractions, and the subtle nature of some polyps present challenges to colonoscopic effectiveness. With the advent of several promising techniques, these issues are being addressed. Wide-angle colonoscopes, retroflexion, and water immersion technique are methods that have been developed. Concurrently, there is a need to reduce complications and improve patient acceptance and comfort. The education of endoscopists has appropriately focused on awareness of potential complications, with recent advances in the ability to manage complications such as bleeding and perforation. Despite its effectiveness, there are key opportunities to further improve colonoscopy including reducing the cost, improving the quality and tolerance of bowel preparation, and upgrading variance in detection and removal of polyps. PMID- 22541620 TI - Noise levels in a burn intensive care unit. AB - INTRODUCTION: Increased noise levels in hospitals, critical care units, and peri operative areas have been associated with higher levels of sleep deprivation and patient stress. The World Health Organization (WHO) guidelines stipulate a limit of 35 decibels (dB(A)) equivalent continuous sound level (LEq) during the day and 30 dB(A) LEq at night in patients' rooms. To date, no quantitative studies of noise levels have been performed in burn units. The objective of this study was to quantify noise levels in a burn critical care unit to ascertain compliance with guidelines in order to minimize this potential insult. METHODS: An A weighted sound pressure level meter was used to measure the ambient noise levels in a burn intensive care unit. Maximum and minimum sound pressure levels were measured at 30-min intervals on 10 days over a 1 month period. Measurements were obtained during shift changes and random times during the day and night-time. Descriptive statistical analyses were performed, to calculate means and standard deviations. Noise measurements at specified times were compared using analysis of variance (ANOVA). RESULTS: Mean dB(A) LEq values for shift changes, day, and night-time were 65.9 +/- 2.8, 65.7 +/- 2.6, and 60.9 +/- 5.2 dB(A), respectively. There was no significant difference in dB(A)(max) or dB(A)(min) between shift changes, day or night-time (p>0.05). However, night-time minimum values were consistently lower. There was no significant difference between sound pressure level (SPL) inside and outside patients' rooms (p>0.05) at any time. CONCLUSIONS: Irrespective of time or location, the mean dB(A) LEq in the burn unit was significantly greater than World Health Organization (WHO), National Institute for Occupational Safety and Health (NIOSH), and the Environmental Protection Agency (EPA) recommendations. Guidelines for decreasing noise exposure are necessary to reduce potential negative effects on patients, visitors, and staff. PMID- 22541621 TI - Resurgence of methamphetamine related burns and injuries: a follow-up study. AB - PURPOSE: Legislation enacted to curb methamphetamine production has only temporarily succeeded. Experiencing a recent increase in burns as a result of the new one-pot method, we compared methamphetamine related burn patients who utilized the previous anhydrous ammonia method of production to current patients who largely used the new one-pot method of production. BASIC PROCEDURES: Patients who were burned as a result of methamphetamine production were retrospectively reviewed. Comparisons were made including demographics, length of stay, injury severity score, hospital charges, total body surface area burned, inhalation injury, intubation, ventilator days, toxicology, fluid volumes, surgeries and complications. MAIN FINDINGS: Eighteen current study patients (88.9% male) were compared to twenty-nine (86.2% male) previous study patients. The groups were similar in age, pattern of burn injury and intubation. Total body surface area burned, injury severity score, inhalation injuries, and ventilator days were not significantly increased in the current study. Longer length of stay and greater hospital charges were incurred by the current group. Burn surgeries per patient were significantly increased in the current group. PRINCIPAL CONCLUSIONS: A new one-pot method has emerged despite legislative attempts to curtail methamphetamine production, and burns have also increased. The reason for more extensive burn surgeries in the current METH related burn patients remains enigmatic. Severity of injury and cost to society remain high. PMID- 22541622 TI - Sinusitis and antibiotics. PMID- 22541623 TI - Lyme disease antiscience. PMID- 22541624 TI - Lyme disease antiscience. PMID- 22541626 TI - Lyme disease antiscience. PMID- 22541627 TI - Post-disaster assessment in Brazzaville, Congo. PMID- 22541628 TI - Research into transmissibility of influenza A H5N1: a practical response to the controversy. PMID- 22541629 TI - Passive immunity in the prevention of rabies. AB - Prevention of clinical disease in those exposed to viral infection is an important goal of human medicine. Using rabies virus infection as an example, we discuss the advances in passive immunoprophylaxis, most notably the shift from the recommended polyclonal human or equine immunoglobulins to monoclonal antibody therapies. The first rabies-specific monoclonal antibodies are undergoing clinical trials, so passive immunisation might finally become an accessible, affordable, and routinely used part of global health practices for rabies. Coupled with an adequate supply of modern tissue-culture vaccines, replacing the less efficient and unsafe nerve-tissue-derived rabies vaccines, the burden of this disease could be substantially reduced. PMID- 22541631 TI - Skin infection and progressive paraparesis. PMID- 22541630 TI - Hepatitis C virus clearance, reinfection, and persistence, with insights from studies of injecting drug users: towards a vaccine. AB - Hepatitis C virus (HCV) was discovered more than two decades ago, but progress towards a vaccine has been slow. HCV infection will spontaneously clear in about 25% of people. Studies of spontaneous HCV clearance in chimpanzees and human beings have identified host and viral factors that could be important in the control of HCV infection and the design of HCV vaccines. Although data from studies of chimpanzees suggest that protection against reinfection is possible after spontaneous clearance, HCV is a human disease. Results from studies of reinfection risk after spontaneous clearance in injecting drug users are conflicting, but some people seem to have protection against HCV persistence. To guide future vaccine development, we assess data from studies of HCV reinfection after spontaneous clearance, discuss flaws in the methods of previous human studies, and suggest essential components for future investigations of control of HCV infection. PMID- 22541632 TI - Detection of clinically significant retinopathy of prematurity using wide-angle digital retinal photography: a report by the American Academy of Ophthalmology. AB - OBJECTIVE: To evaluate the accuracy of detecting clinically significant retinopathy of prematurity (ROP) using wide-angle digital retinal photography. METHODS: Literature searches of PubMed and the Cochrane Library databases were conducted last on December 7, 2010, and yielded 414 unique citations. The authors assessed these 414 citations and marked 82 that potentially met the inclusion criteria. These 82 studies were reviewed in full text; 28 studies met inclusion criteria. The authors extracted from these studies information about study design, interventions, outcomes, and study quality. After data abstraction, 18 were excluded for study deficiencies or because they were superseded by a more recent publication. The methodologist reviewed the remaining 10 studies and assigned ratings of evidence quality; 7 studies were rated level I evidence and 3 studies were rated level III evidence. RESULTS: There is level I evidence from >=5 studies demonstrating that digital retinal photography has high accuracy for detection of clinically significant ROP. Level III studies have reported high accuracy, without any detectable complications, from real-world operational programs intended to detect clinically significant ROP through remote site interpretation of wide-angle retinal photographs. CONCLUSIONS: Wide-angle digital retinal photography has the potential to complement standard ROP care. It may provide advantages through objective documentation of clinical examination findings, improved recognition of disease progression by comparing previous photographs, and the creation of image libraries for education and research. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 22541633 TI - Indications, outcomes, and risk factors for failure in tectonic keratoplasty. AB - PURPOSE: Outcomes of corneal transplantation for tectonic indications and risk factors for (tectonic and physiologic) graft failure. DESIGN: Retrospective cohort study. PARTICIPANTS: Consecutive patients who underwent keratoplasty for tectonic indications at the Singapore National Eye Centre (SNEC) between January 1, 1991, and December 1, 2009. METHODS: Clinical data and donor and recipient characteristics were recorded and analyzed from subjects in the prospective Singapore Corneal Transplant Study. MAIN OUTCOME MEASURES: (1) Tectonic (anatomic) failure defined as recurrence of corneal melt threatening tectonic integrity and requiring additional corneal grafting within 3 months of the primary procedure. (2) Physiologic failure defined as irreversible change in graft clarity preventing recovery in useful vision in grafts initially clear 2 weeks postoperatively. RESULTS: The mean age of the study cohort (n = 362, 193 male and 169 female subjects) was 51.5 +/- 20.2 years, with a mean follow-up of 25.8 +/- 18.7 months. Patients underwent penetrating keratoplasty (PK) (n = 142, 39.2%), anterior lamellar keratoplasty (ALK) (n = 127, 35.1%), or a peripheral corneoscleral patch graft (n = 93, 25.7%) most commonly for inflammation (n = 68, 18.8%), trauma (n = 66, 18.2%), or infection (n = 66, 18.2%). Risk factors for tectonic failure (18/362 eyes, 5.0%) were severe lid disease (odds ratio [OR], 6.1; 95% confidence interval [CI], 1.7-22.1; P = 0.006), central ALK (OR, 7.5; 95% CI, 1.8-32.4; P = 0.007), and peripheral grafts (OR, 5.7; 95% CI, 1.1-28.3; P = 0.035). Among anatomically successful central grafts (n = 223), the mean physiological graft survival was 96 months (95% CI, 83-110); Kaplan-Meier probabilities for survival at 10 years were 66.8% for ALK and 44.2% for PK. Active corneal inflammation (hazard ratio [HR], 2.5; 95% CI, 1.4-4.4; P = 0.003) and larger donor and recipient graft sizes of >= 9 mm (HR, 17.9; 95% CI, 2.3 140.3; P = 0.006) were risk factors for physiologic graft failure in anatomically successful eyes with central tectonic grafts. CONCLUSIONS: Patients with lid disease, central ALK, and peripheral grafts were at higher risk of anatomic failure. For anatomically successful cases with central tectonic grafts, active corneal inflammation and donor size >= 9 mm were risk factors for physiologic failure. In these cases, our results suggest that ALK had better physiologic graft survival outcomes than PK. PMID- 22541634 TI - Medication-related problems occurring in people with diabetes during an admission to an adult teaching hospital: a retrospective cohort study. AB - AIMS: To examine the characteristics of medication-related problems occurring in people with diabetes admitted to hospital and to identify risk factors for medication-related problems. METHODS: A retrospective cohort study of medication related problems occurring in patients admitted to an adult, inner-city Australian teaching hospital was conducted over two-years. The risk factors associated with medication-related problems were identified using random effect logistic regression. RESULTS: There were 9530 admissions of people with diabetes involving 5205 individuals over a two-year period. Medication-related problems were associated with 686 (7.2%) admissions involving 571 individuals (11.0%). The most common medication-related problems were medication errors (64.1%) associated with hypoglycaemia and unintentional overdose. Five factors were significantly associated with medication-related problems: female gender [odds ratio (OR) 1.30, 95% confidence intervals (CI) 1.11-1.52], age of 18-50 years (OR 2.32, CI 1.85 2.91), single marital status (OR 1.46, CI 1.24-1.74), mental and behavioural problems (OR 1.74, 1.43-2.11), and a comorbidity index score of at least one (OR 1.35-1.67). CONCLUSIONS: Five significant risk factors were associated with medication-related problems in people with diabetes admitted to hospital. These risks need to be considered when developing care plans and interventions to prevent medication-related problems for individuals with diabetes. PMID- 22541635 TI - Hormonal contraception and HIV acquisition risk: implications for individual users and public policies. AB - BACKGROUND: A recent observational study among HIV-1 serodiscordant couples (uninfected women living with an infected partner) raised concerns about the safety of injectable contraceptives, especially depot medroxyprogesterone acetate (DMPA). The purpose of this paper is to assess the implications of potentially elevated risk of Human Immunodeficiency Virus (HIV) acquisition with the use of hormonal contraceptives for individual users and public policies. STUDY DESIGN: Two indicators expressing costs (additional unwanted births and additional maternal deaths) in terms of the same unit of benefit (per 100 HIV infections averted) are estimated by using data on competing risks of unwanted birth and HIV acquisition associated with the use of various contraceptive methods. Elevated HIV acquisition risks associated with hormonal contraception observed in the observational studies of family planning users, sex workers and HIV-1 serodiscordant couples are used. Other relevant data for Kenya, South Africa and Zimbabwe are used to illustrate the potential effect of withdrawal of DMPA at the population level. RESULTS: Both the risks of unwanted birth and HIV acquisition with sterilization, intrauterine devices (IUDs) and implants at the individual level are lower than those with DMPA. A shift from DMPA to an oral contraceptive (OC) or male condom by an individual could result in about 600 and a shift to no method in about 5400 additional unwanted births per 100 HIV infections averted. At the population level, the withdrawal of DMPA from Kenya, for example, could result in 7600 annual additional unwanted births and 40 annual additional maternal deaths per 100 HIV infections averted. CONCLUSION: Individual DMPA users may be advised to shift to sterilization, IUD or implant depending upon their reproductive needs and circumstances, but not to no method, OC or even condom alone. At the macro level, the decision to withdraw DMPA from family planning programs in sub-Saharan Africa is not warranted. PMID- 22541636 TI - beta-Amyrin acetate and beta-amyrin palmitate as antidyslipidemic agents from Wrightia tomentosa leaves. AB - The ethanolic extract and fractions of Wrightia tomentosa Roem. & Schult (Apocynaceae) leaves were tested in vivo for their antidyslipidemic activity in high fat diet (HFD) induced dyslipidemic hamsters. Activity guided isolation resulted in identification of antidyslipidemic compounds beta-AA and beta-AP. Compounds beta-AA and beta-AP decrease the levels of LDL by 36% and 44%, and increase the HDL-C/TC ratio by 49% and 28%, respectively, at a dose of 10mg/kg. In addition, the isolated compounds beta-AA and beta-AP showed significant HMG CoA-reductase inhibition, which was further established by docking studies. PMID- 22541637 TI - Molecular docking and enzyme kinetic studies of dihydrotanshinone on metabolism of a model CYP2D6 probe substrate in human liver microsomes. AB - The effects of Danshen and its active components (tanshinone I, tanshinone IIA, dihydrotanshinone and cryptotanshinone) on CYP2D6 activity was investigated by measuring the metabolism of a model CYP2D6 probe substrate, dextromethorphan to dextrorphan in human pooled liver microsomes. The ethanolic extract of crude Danshen (6.25-100 MUg/ml) decreased dextromethorphan O-demethylation in vitro (IC(50)=23.3 MUg/ml) and the water extract of crude Danshen (0.0625-1 mg/ml) showed no inhibition. A commercially available Danshen pill (31.25-500 MUg/ml) also decreased CYP2D6 activity (IC(50)=265.8 MUg/ml). Among the tanshinones, only dihydrotanshinone significantly inhibited CYP2D6 activity (IC(50)=35.4 MUM), compared to quinidine, a specific CYP2D6 inhibitor (IC(50)=0.9 MUM). Crytotanshinone, tanshinone I and tanshinone IIA produced weak inhibition, with IC(20) of 40.8 MUM, 16.5 MUM and 61.4 MUM, respectively. Water soluble components such as salvianolic acid B and danshensu did not affect CYP2D6-mediated metabolism. Enzyme kinetics studies showed that inhibition of CYP2D6 activity by the ethanolic extract of crude Danshen and dihydrotanshinone was concentration dependent, with K(i) values of 4.23 MUg/ml and 2.53 MUM, respectively, compared to quinidine, K(i)=0.41 MUM. Molecular docking study confirmed that dihydrotanshinone and tanshinone I interacted with the Phe120 amino acid residue in the active cavity of CYP2D6 through Pi-Pi interaction, but did not interact with Glu216 and Asp301, the key residues for substrate binding. The logarithm of free binding energy of dihydrotanshinone (-7.6 kcal/mol) to Phe120 was comparable to quinidine (-7.0 kcal/mol) but greater than tanshinone I (-5.4 kcal/mol), indicating dihydrotanshinone has similar affinity to quinidine in binding to the catalytic site on CYP2D6. PMID- 22541638 TI - Liquid-liquid extraction of Pu(IV), U(VI) and Am(III) using malonamide in room temperature ionic liquid as diluent. AB - The extraction behavior of U(VI), Pu(IV) and Am(III) from nitric acid medium by a solution of N,N-dimethyl-N,N-dioctyl-2-(2-hexyloxyethyl)malonamide (DMDOHEMA) in the room temperature ionic liquid, 1-butyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide (C(4)mimNTf(2)), was studied. The distribution ratio of these actinides in DMDOHEMA/C(4)mimNTf(2) was measured as a function of various parameters such as the concentration of nitric acid, DMDOHEMA, NTf(2)(-), alkyl chain length of ionic liquid. The extraction of actinides in the absence of DMDOHEMA was insignificant and the distribution ratio achieved in conjunction with C(4)mimNTf(2), was remarkable. The separation factor of U(VI) and Pu(IV) achieved with the use of DMDOHEMA, ionic liquid was compared with Am(III) and other fission products. The stoichiometry of the metal-solvate was determined to be 1:2 for U(VI) and Pu(IV) and 1:3 for Am(III). PMID- 22541639 TI - The hazardous hexavalent chromium formed on trivalent chromium conversion coating: The origin, influence factors and control measures. AB - In this paper, the effects of processing parameters and constituents of treating agent on the presence of hazardous hexavalent chromium on trivalent chromium conversion coating were studied. Results showed that shorter immersion time, lower bath pH value as well as lower working and baking temperatures retarded the presence of hexavalent chromium. In addition, the concentration of hexavalent chromium on conversion coatings prepared by the oxalic acid treating-agent was far greater than those on conversion coatings prepared by formic acid and acetic acid treating-agents. Results also indicated that the concentration of hexavalent chromium on conversion coatings was enhanced due to the addition of bivalent cobalt and nitrate anion in treating-agent, especially for oxalic acid conversion coating. However, the addition of hydroxyl compound d-gluconic acid in treating agent could reduce the concentration of hexavalent chromium effectively. Moreover, a possible formation mechanism of hexavalent chromium on trivalent conversion coating was proposed. Findings of this study provide a better understanding of the formation of hexavalent chromium on trivalent chromium conversion coating and can facilitate the management of trivalent chromium treating-agents and trivalent chromium fasteners. PMID- 22541640 TI - Formaldehyde emission monitoring from a variety of solid wood, plywood, blockboard and flooring products manufactured for building and furnishing materials. AB - The measurements of formaldehyde emission (FE) from solid wood, plywood, flooring and blockboard used for building and furnishing materials were obtained using the European small-scale chamber (EN 717-1) and gas analysis (EN 717-2) methods to identify the major sources of formaldehyde among construction and wood products in the Czech Republic. The differences in the FE values reported for various wood products were a function of their structural differences. These results showed that the wood species, plywood type and thickness significantly affected the FE measured by EN 717-2 (P<0.001). The FE values from solid wood ranged between 0.0068 and 0.0036ppm and 0.084-0.014mg/m(2)h. The initial FE ranged from 0.006mg/m(3) for engineered flooring with polyvinyl acetate (PVAc) to 0.048mg/m(3) for painted birch blockboard. Furthermore, the FE dropped noticeably by the end of the measuring period, ranging between 0.006mg/m(3) for engineered flooring with PVAc and 0.037mg/m(3) for painted beech blockboard. Additionally, the initial FE was higher for the painted blockboard (0.035-0.048mg/m(3)) than for the uncoated boards (0.022-0.032mg/m(3)). In the first week after manufacturing, the FE was high, but the decrease in FE was noticeable at the two week measurement for all of the materials, especially for the painted blockboards. PMID- 22541641 TI - Mine water treatment with limestone for sulfate removal. AB - Limestone can be an option for sulfate sorption, particularly from neutral mine drainages because calcium ions on the solid surface can bind sulfate ions. This work investigated sulfate removal from mine waters through sorption on limestone. Continuous stirred-tank experiments reduced the sulfate concentration from 588.0mg/L to 87.0mg/L at a 210-min residence time. Batch equilibrium tests showed that sulfate loading on limestone can be described by the Langmuir isotherm, with a maximum loading of 23.7mg/g. Fixed-bed experiments were utilized to produce breakthrough curves at different bed depths. The Bed Depth Service Time (BDST) model was applied, and it indicated sulfate loadings of up to 20.0gSO(4)(2-)/L bed as the flow rate increased from 1 to 10mL/min. Thomas, Yoon-Nelson and dose response models, predicted a maximum particle loading of 19mg/g. Infrared spectrometry indicated the presence of sulfate ions on the limestone surface. Sulfate sorption on limestone seems to be an alternative to treating mine waters with sulfate concentrations below the 1200-2000mg/L range, where lime precipitation is not effective. In addition, this approach does not require alkaline pH values, as in the ettringite process. PMID- 22541642 TI - Plastic pellets as oviposition site and means of dispersal for the ocean-skater insect Halobates. AB - Microplastics are omnipresent in the oceans and generally have negative impacts on the biota. However, flotsam may increase the availability of hard substrates, which are considered a limiting resource for some oceanic species, e.g. as oviposition sites for the ocean insect Halobates. This study describes the use of plastic pellets as an oviposition site for Halobates micans and discusses possible effects on its abundance and dispersion. Inspection of egg masses on stranded particles on beaches revealed that a mean of 24% (from 0% to 62%) of the pellets bore eggs (mean of 5 and max. of 48 eggs per pellet). Most eggs (63%) contained embryos, while 37% were empty egg shells. This shows that even small plastic particles are used as oviposition site by H. micans, and that marine litter may have a positive effect over the abundance and dispersion of this species. PMID- 22541643 TI - Reconstruction of the posterior oblique ligament and the posterior cruciate ligament in knees with posteromedial instability. AB - PURPOSE: Posterior cruciate ligament (PCL) injuries are often associated with injuries of the posteromedial structures of the knee. The motivation for this study was the attempt to test different reconstruction techniques for the structures of the posteromedial corner in a biomechanical experiment. METHODS: Kinematic studies were carried out on 10 cadaveric knees exposed to a 134-N posterior tibial load, 10-Nm valgus torque, and 5-Nm internal torque at 0 degrees , 30 degrees , 60 degrees , and 90 degrees of flexion. The resulting posterior tibial translation (PTT) was determined using a robotic/universal force-moment sensor testing system for (1) intact knees, (2) PCL-deficient knees, (3) knees with deficiency of the PCL and the posteromedial structures, (4) knees with only the PCL reconstructed, (5) knees with the PCL and posterior oblique ligament (POL) reconstructed, and (6) knees with the PCL, medial collateral ligament (MCL), and POL reconstructed. Kinematic data were analyzed by a 2-factor repeated analysis of variance. RESULTS: When both the PCL and the posteromedial structures were cut, PTT increased significantly at all flexion grades under a posterior tibial load (P < .05). Reconstruction of only the PCL could not restore PTT at 0 degrees , 30 degrees , 60 degrees , and 90 degrees of flexion under loading conditions in a knee with combined injury of the PCL and the posteromedial structures (P > .05). Additional reconstruction of the POL improved PTT at all flexion angles in comparison with only the PCL-reconstructed knee. Reconstruction of the MCL had no significant effect on PTT. CONCLUSIONS: This study shows that reconstruction of the POL contributes significantly to the normalization of coupled PTT in knees with combined injury of the PCL and the posteromedial structures under valgus or internal rotational moment. The supplementary reconstruction of the MCL did not provide significant improvement in knee kinematics. CLINICAL RELEVANCE: The POL should be addressed in the patient with combined injuries of the PCL and the posteromedial structures. PMID- 22541644 TI - MyoD-dependent regulation of NF-kappaB activity couples cell-cycle withdrawal to myogenic differentiation. AB - BACKGROUND: Mice lacking MyoD exhibit delayed skeletal muscle regeneration and markedly enhanced numbers of satellite cells. Myoblasts isolated from MyoD-/- myoblasts proliferate more rapidly than wild type myoblasts, display a dramatic delay in differentiation, and continue to incorporate BrdU after serum withdrawal. METHODS: Primary myoblasts isolated from wild type and MyoD-/- mutant mice were examined by microarray analysis and further characterized by cell and molecular experiments in cell culture. RESULTS: We found that NF-kappaB, a key regulator of cell-cycle withdrawal and differentiation, aberrantly maintains nuclear localization and transcriptional activity in MyoD-/- myoblasts. As a result, expression of cyclin D is maintained during serum withdrawal, inhibiting expression of muscle-specific genes and progression through the differentiation program. Sustained nuclear localization of cyclin E, and a concomitant increase in cdk2 activity maintains S-phase entry in MyoD-/- myoblasts even in the absence of mitogens. Importantly, this deficit was rescued by forced expression of IkappaBalphaSR, a non-degradable mutant of IkappaBalpha, indicating that inhibition of NF-kappaB is sufficient to induce terminal myogenic differentiation in the absence of MyoD. CONCLUSION: MyoD-induced cytoplasmic relocalization of NF kappaB is an essential step in linking cell-cycle withdrawal to the terminal differentiation of skeletal myoblasts. These results provide important insight into the unique functions of MyoD in regulating the switch from progenitor proliferation to terminal differentiation. PMID- 22541645 TI - Ovine craniofacial malformation: a morphometrical study. AB - Craniofacial malformation in 64 sheep was phenotypically described as mandibular distoclusion. Digital radiographs were examined in order to determine the degree of morphological changes in certain bones of the skull. Therefore, laterolateral standardised digital radiographs were used to determine anatomic reference points. Subsequently, five reference lines were defined and 16 linear and seven angular measurements were determined to describe malformations in the bones of the skull. Statistical analysis revealed a significant shortening of the rostral part of the corpus mandibulae and of the ramus mandibulae. However, the molar part of the mandible remained unchanged. These morphological changes caused premolar and molar malocclusion. No further craniofacial abnormalities, such as an elongation of the maxilla or of the incisive bone, were identified. In conclusion, the phenotypically observed mandibular distoclusion is caused by a shortening of specific parts of the mandible. This form of ovine craniofacial malformation is therefore best described as brachygnathia inferior. PMID- 22541646 TI - The sense of agency during skill learning in individuals and dyads. AB - The sense of agency has received much attention in the context of individual action but not in the context of joint action. We investigated how the sense of agency developed during individual and dyadic performance while people learned a haptic coordination task. The sense of agency increased with better performance in all groups. Individuals and dyads showed a differential sense of agency after initial task learning, with dyads showing a minimal increase. The sense of agency depended on the context in which the task was first learnt, as transfer from joint to individual performance resulted in an illusory boost in the sense of agency. Whereas the quality of performance related to the sense of agency, the generated forces to achieve the task did not. Our findings are consistent with a predictive model account at the perceptual level, such that the sense of agency relies most strongly on sharable perceptual information. PMID- 22541647 TI - Physiotherapy in the management of disorders of the temporomandibular joint- perceived effectiveness and access to services: a national United Kingdom survey. AB - Up to a quarter of the general population has experienced temporomandibular joint disorder (TMD) at some point in time. Physiotherapy has been used in the management of TMD for many years, but evidence supporting its clinical effectiveness is limited. We investigated the perceived effectiveness of physiotherapy for patients with TMD among consultants in oral and maxillofacial surgery (OMFS) and the accessibility of these services in the United Kingdom (UK). Information was gathered from a postal or electronic questionnaire sent to the 356 OMFS consultants listed on the British Association of Oral and Maxillofacial Surgeons' website. A total of 208 responded (58%) and 72% considered physiotherapy to be effective. Amongst these respondents, jaw exercises (79%), ultrasound (52%), manual therapy (48%), acupuncture (41%) and laser therapy (15%) were considered to be effective. Twenty-eight percent of respondents did not consider physiotherapy to be effective. Reasons for this included lack of knowledge or expertise of the physiotherapist (41%) and lack of awareness of the benefits of physiotherapy (28%). In relation to access to physiotherapy services, 10% of respondents had a designated physiotherapist for patients with TMD, 89% could refer directly to physiotherapy and 7% worked in an environment that provided training for physiotherapists. Patients were prescribed jaw exercises by 69% of respondents. Despite limited evidence to support its effectiveness, approximately three-quarters of OMFS consultants in the UK regard physiotherapy to be beneficial in the management of TMD. PMID- 22541648 TI - Exocytotic fusion pore stability and topological defects in the membrane with orientational degree of ordering. AB - Regulated exocytosis is a process that strongly depends on the formation and stability of the fusion pore. It was indicated experimentally and theoretically that narrow and highly curved fusion pore may be stabilized by accumulation of anisotropic membrane components possessing orientational ordering. On the other hand, narrow fusion pore may also undergo repetitive opening and closing, disruption in the so called kiss and run process or become completely opened in the process of full fusion of the vesicle with the membrane. In this paper we attempt to elucidate the subtle interplay between the stabilizing and destabilizing processes in the fusion neck. A possible physical mechanism which may lead to disruption of the stable fusion pore or complete fusion of the vesicle with the membrane is discussed. It is indicated that topologically driven defects of the in-plane orientational membrane ordering in the region of the fusion pore may disrupt the fusion. Alternatively, it may facilitate repetitive opening and closing of the fusion pore or induce full fusion of the vesicle with the target membrane. PMID- 22541649 TI - Four-year incidence of open-angle glaucoma and ocular hypertension: the Los Angeles Latino Eye Study. AB - PURPOSE: To estimate the 4-year incidence of open-angle glaucoma (OAG) and ocular hypertension (OHT) among adult Latinos 40 years of age and older. DESIGN: Population-based longitudinal study. METHODS: Comprehensive ophthalmologic examinations including intraocular pressure, visual field testing, and stereoscopic fundus photography were performed at both baseline and the 4-year follow-up examination. Incident OAG at the 4-year follow-up examination was defined as the presence of an open angle and a glaucomatous visual field abnormality or evidence of glaucomatous optic disc damage, or both when not present at baseline. Incident OHT was defined as intraocular pressure of more than 21 mm Hg and the absence of optic disc damage or abnormal visual field results at the 4 year follow-up examination when not present at baseline. RESULTS: Among the 3939 participants (mean age, 54.7 +/- 10.5 years) with complete data for a diagnosis of glaucoma at both baseline and follow-up examination, incident OAG at the 4-year follow-up was identified in 87 persons (4 year incidence rate, 2.3%; 95% confidence interval, 1.8% to 2.8%). Incident OHT at the 4-year follow-up was identified in 124 persons (4-year incidence rate, 3.5%; 95% confidence interval, 2.9% to 4.1%). In participants with OAG in 1 eye, the 4-year risk of OAG developing in the fellow eye was 5 times as high as the risk for those without OAG in either eye at baseline. In participants with OHT in 1 eye, the 4-year risk of OHT developing in the fellow eye was 10 times as high as the risk for those without OHT in either eye at baseline. The incidence rates of OAG and OHT were higher in older Latinos than in younger Latinos. CONCLUSIONS: Incidence of OAG in Latinos is higher than in non-Hispanic whites, but lower than in Afro-Caribbeans. The relatively high rate of incident OAG and OHT underscores the need for community screening programs in this fastest growing segment of the United States population. PMID- 22541650 TI - Enhanced circulating soluble LR11 in patients with diabetic retinopathy. AB - PURPOSE: To investigate the relationship of circulating levels of soluble form of LR11 (sLR11; also called SorLA or SORL1), with the progression of proliferative diabetic retinopathy (PDR) in patients with type 2 diabetes mellitus. DESIGN: Cross-sectional study. METHODS: Fifty-four patients with type 2 diabetes mellitus were divided into 2 sex- and age-matched groups: one with PDR (n = 29) and the other with nonproliferative diabetic retinopathy (n = 25). The serum sLR11 levels were measured with an immunodetection system followed by chemifluorescence quantification. RESULTS: The serum sLR11 levels were higher in the PDR group than in the nonproliferative diabetic retinopathy group (5.8 +/- 1.2 U vs 3.7 +/- 1.3 U; P < .01). A multivariate regression analysis showed that circulating sLR11 is a factor contributing to the prediction of PDR independent of other classical risk factors, and an area under the receiver operating characteristic curve analysis revealed that the sensitivity and the specificity were equivalent to or more than those of other factors. Among the classical risk factors for PDR, glycosylated hemoglobin levels showed the highest correlation coefficient (P < .01) for the sLR11 concentrations. CONCLUSIONS: Serum sLR11 concentration may reflect the progression of PDR in patients with type 2 diabetes mellitus. sLR11, released from immature vascular cells and indicating the development of atherosclerosis, is expected to be a novel candidate biomarker indicating diabetic retinopathy in patients with type 2 diabetes mellitus. PMID- 22541651 TI - Discrepancies between fluorescein angiography and optical coherence tomography in macular edema in uveitis. AB - PURPOSE: To assess the frequency and characteristics of discrepant findings between fluorescein angiography (FA) and optical coherence tomography (OCT) in uveitic macular edema (ME). DESIGN: Retrospective cross-sectional study of 112 eyes of 78 patients with uveitic ME on FA, OCT, or both. METHODS: ME was graded on OCT and FA of uveitis patients attending the University Medical Center Utrecht. The frequency and severity of discrepant findings were analyzed, and the clinical findings at the time of imaging were assessed. The imaging studies were compared with the clinical characteristics. RESULTS: Positive results of both imaging methods (FA+/OCT+) were observed in 61 (54%) of 112 eyes, whereas discrepant results occurred in 51 (46%) of 112 eyes. The FA+/OCT- discrepancy occurred in 34 (30%) of 112 eyes, and the FA-/OCT+ discrepancy occurred in 17 (15%) of 112 eyes. No correlations between the discrepant imaging results and age, gender, duration of uveitis or ME, visual acuity, or cause of uveitis were identified. FA+/OCT- and FA-/OCT+ discrepancies comprised typically mild degrees of ME. The FA+/OCT- discrepancy occurred in 50% of eyes with birdshot chorioretinopathy (7/14), and the FA-/OCT+ discrepancy occurred more often in intermediate uveitis than in other anatomic locations. Although the FA+/OCT+ consistency was noted frequently in active uveitis, the FA-/OCT+ discrepancy was common in eyes with inactive uveitis (8/18; 44% of inactive eyes). CONCLUSIONS: Our results emphasize that FA and OCT are complementary investigations, each revealing different aspects of the pathophysiology of uveitic ME. PMID- 22541652 TI - Anti-inflammatory effect of low-molecular-weight heparin in pediatric cataract surgery: a randomized clinical trial. AB - PURPOSE: To determine if intraocular infusion of low-molecular-weight heparin (enoxaparin) reduces postoperative inflammation in pediatric eyes undergoing cataract surgery with IOL implantation. DESIGN: Prospective masked randomized controlled trial. METHODS: setting: Private, institutional practice. study population: Twenty children (40 eyes) undergoing bilateral cataract surgery with IOL implantation were randomized to receive enoxaparin in the intraocular infusion fluid (BSS) (Group I) or not to receive enoxaparin (Group II). The first eye was randomly assigned to 1 of the 2 groups and the second eye received alternate treatment. observation procedure: Patients were followed up in the first week and 1 and 3 months after surgery. main outcome measures: Anterior chamber flare and cells (Hogan's criteria), cell deposits on IOL, posterior synechiae. RESULTS: One week postoperatively, no eyes had >grade 2 flare/cells. Proportion of eyes with grade 2 cells was higher in eyes that did not receive enoxaparin (Group II: 80% vs Group I: 40%, P = .009). In the first week >10 small cell deposits were noted in the eyes that received enoxaparin (Group I: 20%, Group II: none, P = .005). Large cell deposits first appeared at 1 month in 40% of eyes in Group I and 55% of eyes in Group II (P = .34) and increased at 3 months (60% in both groups, P > .999). Posterior synechiae were seen in 10% of eyes in Group I at 1 month, which persisted at 3 months; no eyes in Group II showed posterior synechiae (P = .14). CONCLUSION: The results of our study suggest that there does not seem to be a benefit of using enoxaparin in the infusion fluid with respect to early postoperative inflammation. PMID- 22541653 TI - Prediction of proliferative vitreoretinopathy after retinal detachment surgery: potential of biomarker profiling. AB - PURPOSE: To investigate the potential of a combined assessment of clinical risk factors and biomarker profiling in the prediction of proliferative vitreoretinopathy (PVR) after retinal detachment surgery. DESIGN: Retrospective case-control study. METHODS: Multiplex bead-based immunoassays were used for the simultaneous measurement of 50 biomarkers in subretinal fluid samples obtained from patients who underwent scleral buckling surgery for primary rhegmatogenous retinal detachment (RRD). Of 306 samples that were collected and stored in our BioBank, we selected 21 samples from patients in whom a redetachment developed as a result of PVR within 3 months after reattachment surgery for primary RRD (PVR group). These were compared with age-, sex-, and storage time-matched RRD samples from 54 patients with an uncomplicated postoperative course after primary RRD repair (RRD group). RESULTS: Preoperative PVR was the only clinical variable that was an independent predictor of postoperative PVR development (P = .035) and resulted in an area under the receiver operating characteristic curve of 0.67 (95% confidence interval, 0.51 to 0.83). The addition of the biomarkers chemokine (C-C motif) ligand 22, interleukin-3, and macrophage migration inhibitory factor improved the model significantly (P < .001) and resulted in an area under the receiver operating characteristic curve of 0.93 (95% confidence interval, 0.82 to 1.04). A sensitivity of 94.1% and a specificity of 94.2% were reached, using a cutoff value of 5%. CONCLUSIONS: In combination with preoperative PVR grade, the measurement of a single biomarker or a small multibiomarker panel shows great potential and may predict postoperative PVR development after primary RRD in a highly sensitive and specific manner. PMID- 22541654 TI - Depression, post-traumatic stress disorder, and dry eye syndrome: a study utilizing the national United States Veterans Affairs administrative database. AB - PURPOSE: To study the scope of dry eye syndrome (DES) in veterans on a national level and to evaluate the relationship between psychiatric diagnoses and DES. DESIGN: Case-control study. METHODS: SETTING: Patients were seen in a Veterans Affairs (VA) eye clinic between 2006 and 2011. PATIENT POPULATION: Patients were divided into cases and controls with regard to their dry eye status (cases = ICD 9 code for DES plus dry eye therapy; controls = patients without ICD-9 code plus no therapy). MAIN OUTCOME MEASURES: The prevalence of DES and the influence of psychiatric diagnoses on the risk of DES. RESULTS: A total of 2 454 458 patients were identified as either a dry eye case (n = 462 641) or control (n = 1 991 817). Overall, 19% of male patients and 22% of female patients had a diagnosis of DES, with female sex imparting an increased risk of DES at each decade compared to male sex (odds ratio [OR] 1.22-2.09). Several conditions were found to increase DES risk, including post-traumatic stress disorder (OR 1.92, 95% CI 1.91 1.94) and depression (OR 1.92, 95% CI 1.91-1.94) (analyses adjusted for sex and age). The use of several systemic medications was likewise associated with an increased risk of DES, including antidepressant medications (OR 1.97, 95% CI 1.79 2.17) and antianxiety medication (OR 1.74, 95% CI 1.58-1.91). Multivariate analysis (adjusted for age and sex) revealed that for psychiatric diagnoses, both the use of medication and the diagnosis remained significant risk factors when considered concomitantly, although the magnitude of each association decreased. CONCLUSIONS: DES is a disease associated with depression and post-traumatic stress disorder, and is prevalent among male and female veterans receiving eye care services. The association could be driven by underlying disease physiology or medications used to treat psychiatric conditions. Regardless of the causal link, this suggests that individuals with a known psychiatric diagnosis should be questioned about dry eye symptoms and, if applicable, referred to an eye care physician. PMID- 22541655 TI - Intrachoroidal cavitation in macular area of eyes with pathologic myopia. AB - PURPOSE: To determine the incidence and characteristics of intrachoroidal cavitations in the macular area of eyes with high myopia. DESIGN: Prospective, noninterventional case series. METHODS: We evaluated 56 eyes of 44 patients with pathologic myopia (myopic spherical equivalent >8 diopters) and with patchy chorioretinal atrophy using a swept-source optical coherence tomographic (OCT) system with a center wavelength of 1050 nm. We focused on the changes in the scleral curvature in the area of patchy atrophy. The relationship of the macular intrachoroidal cavitation and retinoschisis was also analyzed. Sixty-eight consecutive patients with pathologic myopia but without patchy atrophy were analyzed as controls. RESULTS: In 31 of 56 eyes (55.4%) with patchy atrophy, the swept-source OCT images showed that the sclera was bowed posteriorly in and around the patchy atrophy compared to neighboring sclera, whereas none of the 68 patients without patchy atrophy showed this finding. Macular intrachoroidal cavitation had OCT features similar to peripapillary intrachoroidal cavitation; the choroid in the macular intrachoroidal cavitation area appeared thickened and the retina was caved into the cavitation. There was a direct communication between the vitreous and intrachoroidal cavitation in 3 eyes. Retinoschisis was observed significantly more frequently in or around the patchy atrophy in eyes with macular intrachoroidal cavitation than in those without cavitation. CONCLUSIONS: These findings suggest that patchy atrophy affects the scleral contour within posterior staphyloma beyond the funduscopically identified patchy atrophy by macular intrachoroidal cavitation. Such deformation of sclera may facilitate the development of retinoschisis in and around the patchy atrophy. PMID- 22541656 TI - Altered expression of CD46 and CD59 on leukocytes in neovascular age-related macular degeneration. AB - PURPOSE: To investigate the expression of the complement regulatory proteins CD46, CD55, and CD59 on peripheral leukocytes in neovascular age-related macular degeneration (AMD). DESIGN: Prospective, case-control study. METHODS: Thirty-five unrelated patients with neovascular AMD and 30 control individuals were included in this case-control study. All participants were subjected to a structured interview and detailed imaging (autofluorescence, digital funduscopy, spectral domain optical coherence tomography, and fluorescein and indocyanine green angiography in patients suspected of having neovascular AMD) was performed. Fresh ethylenediamine-tetraacetic acid blood was obtained and stained with monoclonal antibodies. Using flow cytometry, the percentage of CD14(+) monocytes, CD45(+) lymphocytes, and CD45(+) granulocytes positive for CD46, CD55, and CD59 was determined in patients with neovascular AMD and was compared with that of controls. RESULTS: We found that the expression of CD46 and CD59 was significantly lower on CD14(+) monocytes in patients with neovascular AMD compared with controls (P = .0070). A significantly lower expression of CD46 on lymphocytes was observed in patients with fibrosis compared with patients without fibrosis (P = .010). CONCLUSIONS: Our study suggests that neovascular AMD is associated with an inadequate regulation of the complement system, supporting current evidence on the role of complement dysregulation in the pathogenesis of AMD. PMID- 22541657 TI - Long-term outcomes of vitrectomy for progressive X-linked retinoschisis. AB - PURPOSE: To evaluate the long-term outcomes of vitrectomy for progressive X linked retinoschisis. DESIGN: Prospective, nonrandomized, consecutive, interventional case series. METHODS: Twenty-eight eyes of 22 patients who were diagnosed with progressive X-linked retinoschisis were divided into 2 groups: a nonsurgical group (n = 11) and a vitrectomy group (n = 17). The main outcome measures included best-corrected visual acuity, the area of the macular schisis cavity measured by optical coherence tomography, the retinal anatomic status, and complications. RESULTS: The mean follow-up period was 34.7 months (range, 10 to 68 months). The mean best-corrected visual acuity increased from 20/125 at baseline to 20/55 at the final follow-up in the vitrectomy group (P = .001), but decreased from 20/100 at baseline to 20/400 at the final follow-up in the nonsurgical group (P = .000). In the vitrectomy group, the macular schisis cavity resolved in all 17 eyes; the mean area of the macular schisis cavity decreased from 0.85 mm(2) at baseline to 0.23 mm(2) at the final follow-up (P = .000), and the retinas of 16 eyes (94%) were attached after surgery. In the nonsurgical group, retinal schisis progressively extended in 9 eyes (82%); the mean area of the macular schisis cavity increased from 0.82 mm(2) at baseline to 1.21 mm(2) at the final follow-up (P = .000); in 8 eyes (72%), retinal detachment developed, and 2 eyes (18%) experienced vitreous hemorrhage, which terminated the observations. CONCLUSIONS: Vitrectomy may be an effective and essential treatment for patients with progressive X-linked retinoschisis to prevent a deterioration of vision before severe complications developed in their eyes. PMID- 22541658 TI - Responses to photodynamic therapy in patients with polypoidal choroidal vasculopathy consisting of polyps resembling grape clusters. AB - PURPOSE: To investigate the responses to photodynamic therapy (PDT) in patients with polypoidal choroidal vasculopathy (PCV) that show large aneurysmal dilation with internal angio-architecture consisting of diverse patterns of curvilinear vessels and polyps resembling grape clusters. DESIGN: Retrospective, interventional case series. METHODS: Twenty-two eyes of 22 patients were included. All patients initially received PDT monotreatment. The main outcome measures were the rates of complete polyp regression on indocyanine green angiography and initial favorable responses observed clinically. Also, the rates of recurrent exudative changes were evaluated at the 2-year follow-up. We focused on changes in the vascular features and their clinical association. RESULTS: Complete regression of polypoidal lesions was observed in 21 eyes (95%) after a mean of 1.7 PDTs. However, favorable clinical responses were achieved in only 9 eyes (41%), and 6 of them had recurrent exudation. Main vessels, previously consisting of the polypoidal lesion frame, persisted. Additionally, aberrant vessels with a thin radiating or tortuous configuration were observed in the area where large aneurysmal dilation was present. Leakage from this vascular complex or an expanded vascular complex was observed in a total of 14 eyes (64%) during the 2-year follow-up, contributing to persistent (8 eyes) or recurrent (6 eyes) exudation. This seemed to represent secondary choroidal neovascularization (CNV). In another 4 eyes (18%), fibrous changes developed immediately after PDT. Polyps recurred in 8 eyes (38%). CONCLUSIONS: This PCV pattern frequently evolved into typical CNV after PDT, resulting in persistent or recurrent exudation despite the disappearance of polypoidal structures. PMID- 22541659 TI - Economic evaluation of endothelial keratoplasty techniques and penetrating keratoplasty in the Netherlands. AB - PURPOSE: To evaluate cost-effectiveness of penetrating keratoplasty (PK), femtosecond laser-assisted Descemet stripping endothelial keratoplasty (FS-DSEK), and Descemet stripping automated endothelial keratoplasty (DSAEK). DESIGN: Cost effectiveness analysis based on data from a randomized multicenter clinical trial and a noncomparative prospective study. METHODS: Data of 118 patients with corneal endothelial dysfunction were analyzed in the economic evaluation. Forty patients were included in the PK group, 36 in the FS-DSEK group, and 42 in the DSAEK group. The primary incremental cost-effectiveness ratio (ICER) was the incremental costs per clinically improved patient, defined as a patient with a combined effectiveness of both a clinically improved BSCVA (defined as an improvement of at least 2 lines) and a clinically acceptable refractive astigmatism (defined as less than or equal to 3.0 diopters). Analysis was based on a 1-year follow-up period after transplantation. RESULTS: The percentage of treated patients who met the combined effectiveness measures was 52% for DSAEK, 44% for PK, and 43% for FS-DSEK. Mean total costs per patient were ?6674 (US$7942), ?12 443 (US$14 807), and ?7072 (US$8416) in the PK group, FS-DSEK group, and DSAEK group, respectively. FS-DSEK was less effective and more costly compared to both DSAEK and PK. DSAEK was more costly but also more effective compared to PK, resulting in incremental costs of ?4975 (US$5920) per additional clinically improved patient. CONCLUSIONS: The results of this study show that FS DSEK was not cost-effective compared to PK and DSAEK. DSAEK, on the other hand, was more costly but also more effective compared to PK. Including societal costs, a longer follow-up period and preparation of the lamellar transplant buttons in a national cornea bank could improve the cost-effectiveness of DSAEK. PMID- 22541660 TI - Corneal endothelial morphologic assessment in pediatric cataract surgery with intraocular lens implantation: a comparison of preoperative and early postoperative specular microscopy. AB - PURPOSE: To observe longitudinal changes in the corneal endothelium after pediatric cataract surgery with intraocular lens implantation. DESIGN: Prospective, longitudinal study. METHODS: settings: Iladevi Cataract and IOL Research Centre, Ahmedabad, India. study population: This study included 100 pediatric eyes undergoing cataract surgery with intraocular lens implantation. Posterior capsule management was based on the status of the posterior capsule. Two-port anterior limbal vitrectomy was carried out after posterior capsule plaque peeling. observation procedures: Corneal endothelial morphologic features: endothelial cell density (cell/mm(2)), coefficient of variation, percentage of hexagonality, and central corneal thickness were assessed. main outcome measures: To evaluate whether there is a difference in endothelial cell morphologic features before surgery and 3 months after surgery and also whether pediatric cataract surgery with and without anterior vitrectomy has any impact on the endothelial cell morphologic features. RESULTS: A comparison of preoperative and postoperative specular microscopy is given here: endothelial cell density, 3225.1 +/- 346.8 cells/mm(2) versus 3057.7 +/- 330.1 cells/mm(2) (P < .001); coefficient of variation, 27.5 +/- 10.6 versus 37.7 +/- 16.3 (P < .001); percentage of hexagonality, 58.1 +/- 15.3 versus 48.6 +/- 13.4 (P < .001); and central corneal thickness, 529 +/- 30 MUm versus 527 +/- 34 MUm (P = .64). There was 5.1% decrease in mean endothelial cell loss at 3 months after surgery. No statistically significant difference was noted in the percentage decrease in mean endothelial cell density between eyes undergoing cataract surgery with intact posterior capsules, eyes undergoing manual posterior capsulorrhexis without anterior limbal vitrectomy, and eyes undergoing anterior limbal vitrectomy (P = .543). CONCLUSIONS: Endothelial cell loss with currently practiced techniques of pediatric cataract surgery is within acceptable limits by adhering to the principles of close chamber technique. PMID- 22541661 TI - The changing face of primary open-angle glaucoma in the United States: demographic and geographic changes from 2011 to 2050. AB - PURPOSE: To examine how demographic and geographic variations in US populations from 2011 to 2050 will contribute to estimated numbers of primary open-angle glaucoma (POAG) cases. DESIGN: Cross-sectional study. METHODS: Prevalence rates from selected population-based studies were used to estimate the number of persons aged 40 years and older with POAG in the United States. For calculation, the age-, sex-, and race/ethnicity-specific prevalence rates were multiplied by the US Census estimates and projections from 2011 to 2050. Main outcome measures are estimated numbers of persons with POAG in different age, sex, and racial/ethnic groups and total and per capita POAG rates by state. RESULTS: In 2011, 2.71 million persons in the United States have POAG, with the highest estimated number among populations aged 70 to 79 years (31%), women (53%), and non-Hispanic whites (44%). The largest demographic group is non-Hispanic white women. In 2050, an estimated 7.32 million persons will have POAG, with the highest number among populations aged 70 to 79 years (32%), women (50%), and Hispanics (50%). The largest demographic group will shift to Hispanic men. During the next 40 years, the highest per capita POAG rates will double in New Mexico, Texas, and Florida. CONCLUSIONS: Despite the high prevalence of POAG in African Americans and Hispanics, the largest group in the United States is currently among older non-Hispanic white women but is expected to shift to Hispanic men over the next few decades. Given this shift, the greatest yield from screening programs is likely to be in those states with high numbers of non-Hispanic white women and Hispanic men. PMID- 22541662 TI - Uveal melanoma: molecular pattern, clinical features, and radiation response. AB - PURPOSE: To characterize the clinical spectrum of class 1 and class 2 uveal melanomas and their relationship with intraocular proton radiation response. DESIGN: Masked retrospective case series of uveal melanoma patients with fine needle biopsy-based molecular profiles. METHODS: A total of 197 uveal melanoma patients from a single institution were analyzed for pathology, clinical characteristics, and response to radiation therapy. RESULTS: A total of 126 patients (64%) had class 1 tumors and 71 (36%) had class 2 tumors. Patients with class 2 tumors had more advanced age (mean: 64 years vs 57 years; P = .001), had thicker initial mean ultrasound measurements (7.4 mm vs 5.9 mm; P = .0007), and were more likely to have epithelioid or mixed cells on cytopathology (66% vs 38%; P = .0004). Although mean pretreatment and posttreatment ultrasound thicknesses were significantly different between class 1 and class 2 tumors, there was no difference in the mean change in thickness 24 months after radiation therapy (mean difference: class 1 = -1.64 mm, class 2 = -1.47; P = .47) or in the overall rate of thickness change (slope: P = .64). Class 2 tumors were more likely to metastasize and cause death than class 1 tumors (DSS: P < .0001). CONCLUSIONS: At the time of radiation therapy, thicker tumors, epithelioid pathology, and older patient age are significantly related to class 2 tumors, and class 2 tumors result in higher tumor-related mortality. We found no definitive clinical marker for differentiating class 1 and class 2 tumors. PMID- 22541664 TI - Family size, the physical environment, and socioeconomic effects across the stature distribution. AB - A neglected area in historical stature studies is the relationship between stature and family size. Using robust statistics and a large 19th century data set, this study documents a positive relationship between stature and family size across the stature distribution. The relationship between material inequality and health is the subject of considerable debate, and there was a positive relationship between stature and wealth and an inverse relationship between stature and material inequality. After controlling for family size and wealth variables, the paper reports a positive relationship between the physical environment and stature. PMID- 22541663 TI - DNA aptamer functionalized nanomaterials for intracellular analysis, cancer cell imaging and drug delivery. PMID- 22541665 TI - Pharmacotherapy of autism spectrum disorders. AB - Although no pharmacological or behavioral therapy has currently proven effective for treating all core symptoms of autism, many dysfunctional behaviors may be treated pharmacologically. Drug treatments should always be part of a comprehensive management plan that includes behavioral and educational interventions, and should be focused on specific targets. Several classes of psychotropic medications have been used to decrease the wide range of "maladaptive" or "interfering" behaviors and associated medical problems that can interfere with relationships and physical health and hinder the implementation of various non-pharmacological interventions. Atypical neuroleptics have been shown to be useful in the treatment of behavioral symptoms in autism. Attention deficit and hyperactivity disorder medications may be effective for counteracting the additional features of hyperactivity and short attention span. Antiepileptic drugs and selective serotonin reuptake inhibitors have shown promising results, but there are no specific indications for them as of yet. With respect to potential drug targets, some clinical features are caused by a dysfunction in neurochemical signaling systems, and thus may improve with selective pharmacological interventions acting on specific abnormal neurobiological pathways. Recent animal studies can be useful models for understanding the common pathogenic pathways leading to autism spectrum disorders (ASDs), and have the potential to offer new biologically focused treatment options. PMID- 22541667 TI - Psychometric properties of Yelland and Tiggemann's Drive for Muscularity Scale. AB - The purpose of the current study was to examine the dimensionality and validity of Yelland and Tiggemann's Drive for Muscularity Scale (YT-DMS). Participants were college students (305 women, M(AGE)=20.15 years, SD=4.00; 356 men, M(AGE)=20.24 years, SD=3.85) who completed the YT-DMS, the Drive for Muscularity Attitudes Questionnaire, the Drive for Leanness Scale, the Drive for Thinness Scale, and a socio-demographic questionnaire. Results indicated the YT-DMS had a stable unidimensional factor structure in both genders, and the pattern of relationships generally supported the measure's criterion and construct validity. These results reveal the YT-DMS has promise, but helps identify possible areas for improvement, such as a greater focus on sampling the content domain associated with the drive for muscularity. PMID- 22541666 TI - Novel mutation in SLC9A6 gene in a patient with Christianson syndrome and retinitis pigmentosum. AB - Mutations in the SLC9A6 gene cause Christianson syndrome in boys. This X-linked syndrome is characterized by profound mental retardation with autistic behavior, microcephaly, epilepsy, ophthalmoplegia, and ataxia. Progressive cerebellar atrophy with motor regression is a remarkable feature in some patients. We report on a 22year-old male patient with Christianson syndrome carrying the novel p.Gln306X mutation. The infantile phenotype suggested pervasive developmental disorder, then profound mental retardation ensued. In later childhood, progressive cerebellar atrophy was diagnosed on serial brain MRIs and motor regression occurred. Furthermore, ophthalmological evaluations showed a retinitis pigmentosum previously unreported in this condition. We conclude that the natural history of the disease in this patient tends to confirm the degenerative nature of Christianson syndrome, and that retinal degeneration may be part of the condition. Before the onset of degeneration, the syndromic association of severe mental retardation, autistic behavior, external ophthalmoplegia, and facial dysmorphism in male patients is a clue to the diagnosis. PMID- 22541668 TI - Adjuvant trastuzumab in elderly with HER-2 positive breast cancer: a systematic review of randomized controlled trials. AB - Trastuzumab, in combination with chemotherapy, is the gold standard in the adjuvant treatment of patients with HER2 positive breast cancer. Limited data are available on the role of adjuvant trastuzumab in the elderly population. We performed a systematic review of prospective randomized trials with available data on the use of adjuvant trastuzumab in patients older than 60years, focusing on both the efficacy and the cardiac safety. Data extrapolated from two prospective trials were included for efficacy and cardiac safety. A significant 47% relative risk reduction was observed in elderly patients receiving trastuzumab compared to chemotherapy alone (pooled Hazard Ratio: 0.53; 95% CI, 0.36-0.77). The pooled proportion of cardiac events in elderly patients treated with trastuzumab was 5% (95% CI, 4-7%). The use of trastuzumab should be considered as a standard of care in the adjuvant therapy of elderly patients with HER-2 positive breast cancer. Acute and chronic medical conditions, nutritional status and level of daily activities should be considered. Uncertainty about cardiac safety in the elderly is a major concern. PMID- 22541670 TI - Widespread reproductive variation in North American turtles: temperature, egg size and optimality. AB - Theory predicts the existence of an optimal offspring size that balances the trade-off between offspring fitness and offspring number. However, in wild populations of many species, egg size can still vary from year to year for unknown reasons. Here, we hypothesize that among-year variation in population mean egg size of freshwater turtles is partly a consequence of their gonadal sensitivity to seasonal temperatures, a physiological mechanism which principally functions to synchronize reproduction with a favorable time of year. As part of this process, among-year variation in seasonal temperatures modifies the extent of egg follicle development, and this may translate into variation in mean egg size among years (both at the individual and population level). To test this hypothesis, we applied an information-theoretic approach to model relationships between mean egg mass and the temperatures experienced during discrete periods of follicular development in wild populations of three turtle species (Chrysemys picta, Chelydra serpentina, Glyptemys insculpta) over 12 consecutive years. Because follicular development occurs in the fall for C. serpentina and G. insculpta, whereas it occurs both in the fall and spring for C. picta, we expected only fall temperatures would explain egg size variation in C. serpentina and G. insculpta, whereas both fall and spring temperatures would correlate with egg size variation in C. picta. These predictions were upheld. We then compared among-year variation in within-female egg and clutch sizes of each species in order to evaluate whether such variation might still be consistent with some tenets of optimal egg size theory. In all three species, we found that clutch sizes vary more than egg sizes in spite of temperature-induced egg size variation, and this pattern of relatively high clutch-size variation matches theoretical predictions. Future work should explore the roles of direct and indirect (i.e., nutritional) influences of temperature on egg size in natural settings. PMID- 22541669 TI - miR-206 integrates multiple components of differentiation pathways to control the transition from growth to differentiation in rhabdomyosarcoma cells. AB - BACKGROUND: Similar to replicating myoblasts, many rhabdomyosarcoma cells express the myogenic determination gene MyoD. In contrast to myoblasts, rhabdomyosarcoma cells do not make the transition from a regulative growth phase to terminal differentiation. Previously we demonstrated that the forced expression of MyoD with its E-protein dimerization partner was sufficient to induce differentiation and suppress multiple growth-promoting genes, suggesting that the dimer was targeting a switch that regulated the transition from growth to differentiation. Our data also suggested that a balance between various inhibitory transcription factors and MyoD activity kept rhabdomyosarcomas trapped in a proliferative state. METHODS: Potential myogenic co-factors were tested for their ability to drive differentiation in rhabdomyosarcoma cell culture models, and their relation to MyoD activity determined through molecular biological experiments. RESULTS: Modulation of the transcription factors RUNX1 and ZNF238 can induce differentiation in rhabdomyosarcoma cells and their activity is integrated, at least in part, through the activation of miR-206, which acts as a genetic switch to transition the cell from a proliferative growth phase to differentiation. The inhibitory transcription factor MSC also plays a role in controlling miR-206, appearing to function by occluding a binding site for MyoD in the miR-206 promoter. CONCLUSIONS: These findings support a network model composed of coupled regulatory circuits with miR-206 functioning as a switch regulating the transition from one stable state (growth) to another (differentiation). PMID- 22541671 TI - [Neurophysiological and functional assessment of patients with difficult-to control asthma]. AB - INTRODUCTION: Due to the inadequate response to inhaled corticoids, patients with difficult-to-control asthma (DCA) are submitted to oral corticoids or use of Omalizumab. Although it is necessary to treat these patients, a significant relationship between steroid usage and both peripheral and respiratory weakness muscle, results in implications such as loss of quality of life and compromised lung function. Nonetheless, it is not known whether these patients suffer neurophysiological changes due to drug effect. OBJECTIVE: To investigate the neurophysiological and functional characteristics of patients with DCA in order to gain a better understanding of the condition. METHOD: A cross-sectional study was carried out involving three groups of patients: DCA-C (use of oral corticosteroids), DCA-O (use of omalizumab) and CG (healthy controls matched for age). The assessment involved the six-minute walk test, sit-to-stand test, static balance on a pressure platform, patellar and Achilles reflexes and quadriceps strength in the dominant leg. RESULTS: The results revealed no statistically significant differences between the control group and DCA groups in relation to neurophysiological aspects. However, the DCA groups exhibited a significant reduction in functional capacity [decreased muscle strength (p < 0.05), shorter distance covered on walk test (p < 0.05) and lesser number of repetitions on sit to-stand test (p < 0.05)] in comparison to the control group. CONCLUSION: Individuals with DCA exhibited a reduction in functional capacity. The DCA-C group also demonstrated a reduction in muscle strength when compared with control group, likely caused by the continual use of corticoids. However, no neurophysiological alterations were found in the studied population. PMID- 22541672 TI - [Adaptation of the sleep apnea quality of life index (SAQLI) to Portuguese obstructive sleep apnea syndrome patients]. AB - OBJECTIVE: Obstructive sleep apnea syndrome is a prevalent sleep disorder involving various domains of quality of life that require an objective evaluation. The aim of the present study was to validate a specific measure of health related quality of life in Portuguese sleep apnea patients- the SAQLI. MATERIAL AND METHODS: A sample of 206 Portuguese sleep apnea patients completed a Portuguese version of SAQLI for assessment of its comprehensibility, construct validity and reliability and repeated the same measures after 1 to 3 months CPAP therapy. Hospital Anxiety and Depression Scale (HADS) was also used to test construct validity. RESULTS: Cronbach alpha coefficients of internal validity were above the standard (0.70) in all domains. Factor analysis showed that the items of daily functioning, emotional and symptoms domains all loaded on the hypothesized scales. Longitudinal data showed a significant difference (p<.001) in each SAQLI domain and between total score before and after CPAP use. In terms of external validity, all SAQLI domains were negatively correlated with anxiety and depression scales. CONCLUSIONS: Overall the results of the present study demonstrated that the Portuguese version of SAQLI to be psychometric valid and applicable for evaluate the impact of sleep apnea and CPAP treatment in Portuguese patients. PMID- 22541673 TI - Local structure and dynamics of hemeproteins by X-ray absorption near edge structure spectroscopy. AB - X-ray absorption near edge structure (XANES) spectroscopy is a synchrotron radiation technique sensitive to the local structure and dynamics around the metal site of a heme containing protein. Advances in detection techniques and theoretical/computational platforms in the last 15 years allowed the use of XANES as a quantitative probe of the key structural determinants driving functional changes, both in a concerted way with protein crystallography and EXAFS (extended X-ray absorption fine structure), or as a stand-alone method to apply in the crystal state as well as in solution. Moreover, the local dynamics of the heme site has been deeply investigated, on one hand, coupling XANES to classical photolysis experiments at cryogenic temperatures; on the other hand, the intrinsic property of the synchrotron radiation to induce radiolysis events, has been exploited to investigate specific cryotrapped intermediates, using X-rays both as a pump and a probe. Insights on the XANES method and some specific examples are presented to illustrate these topics. PMID- 22541674 TI - Impact of atherosclerosis on the relationship of glycemic control and mortality in diabetic patients on hemodialysis. AB - OBJECTIVE: The impact of preexisting cardiovascular disease (CVD) on glycemic control-improved survival in hemodialysis patients with diabetes mellitus (DM) was investigated. Glycoalbumin (GA) was used as a glycemic marker. METHODS: A single-center 4-year follow-up study was performed in an observational cohort of 178 DM hemodialysis patients to analyze the relationship between GA and all-cause mortality in patients with (n = 70) and without (n = 108) CVD. The subjects were divided into three categories based on GA value at the start of study. RESULTS: Baseline characteristics did not differ between the two groups of patients. During the 4-year follow-up, 24 of 108 (23.3%) CVD(-) patients and 30 of 70 (42.8%) CVD(+) patients died. The mortality was significantly higher in the CVD(+) group. Multivariate Cox analyses including GA, logCRP, age, gender, hemodialysis duration, albumin, hemoglobin, BMI, SBP, DBP, smoking habit, and SUN as independent variables showed that GA, in addition to logCRP and age, was independently associated with mortality in all patients. Kaplan-Meier analysis showed lower GA levels to be a significant predictor of lower mortality in the CVD(-) group, but not in the CVD(+) group. Multivariable-adjusted Cox proportional hazards models demonstrated a significant association between GA with allcause mortality risk in the CVD(-) group (p = 0.004), in contrast with the CVD(+) group in the same model (p = 0.842). CONCLUSION: These results demonstrate a beneficial effect of improved glycemic control on survival in DM hemodialysis patients, which might be attenuated by the presence of CVD. PMID- 22541675 TI - Vascular access malfunction: towards a more genecentric view. AB - A well-functioning vascular access is the cornerstone for an optimal hemodialysis treatment and an issue of major importance for the outcome of patients on chronic hemodialysis. Over the last few years reports supporting the aspect that mechanisms involved in vascular access malfunction are genetically controlled have been published. Triggered by two cases reported herein, we present a comprehensive review of the literature on an evolving field of particular significance to patients on hemodialysis. PMID- 22541676 TI - Intractable membranous lupus nephritis showing selective improvement of subepithelial deposits with tacrolimus therapy: a case report. AB - A 37-year-old female patient was admitted for evaluation of nephrotic proteinuria refractory to prednisolone and other immunosuppressants in 2004. On admission, urinary protein loss was 16 g/d. Anti-ds DNA antibody was positive and hypocomplementemia was detected. Renal biopsy revealed membranous lupus nephritis. Because 5 cyclophosphamide pulse therapies did not have an effect, tacrolimus was started at 3 mg daily. Proteinuria decreased to 4.8 g/d after 5 months and was < 0.1 g/d in 2009, but antids DNA antibody remained positive and hypocomplementemia persisted. Repeat renal biopsy revealed thinning of the glomerular capillary walls and disappearance of subepithelial electron-dense deposits. However, the subendothelial and mesangial deposits were unchanged. In this patient, proteinuria refractory to various immunosuppressants including cyclosporine A improved after administration of tacrolimus, and selective disappearance of subepithelial deposits was seen histologically. This is the first histological evidence that tacrolimus therapy may cause removal of subepithelial deposits, which are separated from the circulation by the glomerular basement membrane. This finding is supported by experimental data that tacrolimus selectively block the binding of FK-binding protein 12 to transient receptor potential-cation channel 6, resulting in normalization of affected podocytes. PMID- 22541677 TI - Anti-neutrophil cytoplasmic antibody (ANCA) associated small-vessel vasculitis in a patient with diabetic nephropathy and autoimmune polyendocrinopathy syndrome (APS) Type 2: a case report. AB - We present a 42-year-old woman with pre-existing autoimmune polyendocrinopathy syndrome (APS) Type 2 and chronic kidney disease due to Type 1 diabetic nephropathy, who developed a rapid deterioration in renal function due to perinuclear anti-neutrophil cytoplasmic antibody (pANCA)-associated vasculitis. Although possibly a chance occurrence, ANCA have been detected more frequently in patients with a history of certain autoimmune diseases. Such an association may simply reflect an underlying tendency to immune system dysfunction in these patients and the finding of positive ANCA serology does not reliably herald the development of ANCA-associated vasculitis. However, our case illustrates that positive ANCA serology in such circumstances is not always a benign phenomenon and should still be interpreted within the clinical context. Moreover, clinicians managing patients with pre-existing autoimmune disease should maintain a low threshold for appropriate assessment should such patients develop evidence suggestive of vasculitis. PMID- 22541678 TI - Association of a novel in-frame deletion mutation of the MYH9 gene with end-stage renal failure: case report and review of the literature. AB - MYH9 disorders are autosomal dominant diseases characterized by giant platelets, thrombocytopenia, and granulocyte inclusion bodies. These diseases are caused by mutations in the MYH9 gene that encodes nonmuscle myosin heavy chain IIA. We describe the case of a 27-year-old male who presented with macrothrombocytopenia and leukocyte inclusion bodies. Chronic kidney disease, probably due to progressive glomerulosclerosis, and high-tone sensorineural deafness were evident. Although deterioration of renal function necessitated renal replacement therapy in the form of peritoneal dialysis, we reconsidered the etiology of the kidney disease due to the patient's clinical history. We identified an in-frame deletion mutation in exon 24 of the MYH9 gene that resulted in the removal of 21 nucleotides. The patient was diagnosed with an MYH9 disorder. We report this novel abnormality of the nucleotide sequence and compare it with previous cases and their associated phenotypes. PMID- 22541679 TI - Successful treatment of life threatening theophylline intoxication in a pregnant patient by hemodialysis. AB - High-flux hemodialysis is the extracorporeal treatment of choice for various life threatening intoxications. Most published reports support the use of hemoperfusion in the context of severe theophylline poisoning, but the technique is limited by its significant side-effects. We present a potentially life threatening theophylline overdose treated with hemodialysis in a pregnant patient. For the first time the amount of theophylline removed was measured in the total collected spent dialysate, after a 3.75 hour hemodialysis and an 8 hour extended dialysis. PMID- 22541680 TI - Mild proteinuria in a patient with glomerularlimited intravascular large B-cell lymphoma. AB - Intravascular large B-cell lymphoma (IVLBCL) is a rare type of non- Hodgkin lymphoma characterized by a disseminated intravascular proliferation of tumor cells in the lumina of small vessels. Although the kidney is one of the target organs of IVLBCL, lymphoma cells that localize only in glomeruli are extremely rare. We report a 55-year-old Chinese patient diagnosed as glomerular-limited IVLBCL by percutaneous renal biopsy. The patient was referred to our institution for further examination of mild proteinuria and anemia without lymphoma symptoms. He had daily urinary excretion of 0.65 g proteins with normal renal function. Percutaneous renal biopsy showed that lymphoid cell accumulation was encircled within the glomerular capillary lumina only in certain glomeruli, resulting in marked obstruction of capillary structure. However, almost all of the peritubular capillary and tubulointerstitium were intact. Immunohistochemical analysis confirmed the diagnosis of intravascular large B-cell lymphoma. Extensive systemic examinations showed no other organ involvement. With these characteristic changes, glomerularlimited IVLBCL were considered as an exceptional renal manifestation of intravascular lymphoma diagnosised by percutaneous renal biopsy. PMID- 22541681 TI - Stabilization of hepatitis C associated collapsing focal segmental glomerulosclerosis with interferon alpha-2a and ribavirin. AB - Hepatitis C virus (HCV) infection is associated with a variety of glomerular diseases, most notably cryoglobulin associated membranoproliferative glomerulonephritis Type I. Focal segmental glomerulosclerosis has only rarely been reported in association with HCV. More striking are multiple reports of de novo collapsing focal segmental glomerulosclerosis (cFSGS) developing during administration of interferon for treatment of HCV. Herein is presented a case of HCV associated cFSGS stabilized with combination therapy of interferon alpha-2a and ribavirin in a patient with advanced kidney disease. PMID- 22541682 TI - Alteplase for blood flow restoration in hemodialysis catheters: a multicenter, randomized, prospective study comparing "dwell" versus "push" administration. AB - AIMS: Catheter-related thrombosis is a frequent complication of providing hemodialysis via central venous catheters. The primary aim of this study was to compare the efficacy of an alteplase "dwell" protocol over 30 minutes (with an additional 90 minutes where necessary) to a new 30 minute "push" protocol in restoring function to occluded hemodialysis catheters. METHODS: This was a prospective, randomized, parallel arm, multicenter study. Participants included hemodialysis patients using central venous catheters for vascular access. A new alteplase push protocol was the intervention and was compared to an alteplase dwell protocol. The primary outcome of this study was the proportion of patients with pre-thrombolytic blood flows less than 200 ml/min achieving a post thrombolytic blood flow >= 300 ml/ min. Secondary outcomes included recovery of Kt/V and liters processed per hour at the hemodialysis session following the intervention, time from thrombolytic to future catheter interventions, and the presence of serious adverse events. RESULTS: 82 patients were included in the intention-to-treat analysis. 65% (28/43) of catheters receiving the dwell protocol achieved blood flow >= 300 ml/min compared to 82% (32/39) in the push protocol. The difference was not statistically significant despite a 17% separation in the point estimates, p = 0.84. A non-significant result may have been associated with an inability to enrol the required a priori sample size. Kt/V, liters processed per hour and time to next catheter event were not significantly different. There were no serious adverse events attributed to the study medication. CONCLUSIONS: The alteplase push protocol was effective and safe for managing dysfunctional hemodialysis catheters and was more practical than a 2 h dwell. PMID- 22541683 TI - Recovery of kidney function following delayed use of TheraliteTM dialyzer in a patient with myeloma cast nephropathy. AB - We report the case of a 60- year- old man who presented with newly diagnosed multiple myeloma complicated by biopsy-proven acute cast nephropathy, requiring hemodialysis, plasmapheresis and chemotherapy. After remaining dialysis dependent for 5 weeks, a high cut-off (HCO) dialyzer, intended to use for the removal of plasma substances with a molecular weight of up to 45 kDa such as free light chains, was introduced to his outpatient 4-hour hemodialysis regimen with an increase in treatment frequency to 4 sessions per week. Following 6 weeks of dialysis with the HCO dialyzer, serum levels of free kappa light chains declined by more than 75%. Concurrently, he recovered kidney function and discontinued dialysis. He subsequently received a successful autologous stem-cell transplant. We discuss the potential merit of using the HCO dialyzer late in the course of the care of patients with myeloma cast nephropathy who are dialysis dependent. PMID- 22541684 TI - Vascular stiffness in incident peritoneal dialysis patients over time. AB - OBJECTIVE: Vascular stiffness is prevalent in end-stage renal disease patients and predicts adverse events. This study describes the prevalence of vascular stiffness and its associated factors in a cohort of incident peritoneal dialysis (PD) patients. METHODS: In a prospective observational study of 50 patients, carotid-femoral pulse wave velocity (PWV) were conducted at baseline, 3, 6 and 12 months after initiation of PD. Aortic calcification scores (ACS) were derived using plain lateral abdominal films. We examined the association of significant changes in PWV (defined as 1 m/s or 15% change from baseline) over 6 months in conjunction with demographic and clinical data. RESULTS: The mean age was 58 years, 67% were male, and 48% were Caucasian. One third was diabetic, and 23% had pre-existing cardiovascular disease. Median eGFR was 8.7 ml/ min. ACS was strongly correlated with PWV (r = 0.62, p < 0.0001). Over 6 months, 42% demonstrated significant increases, while 23% demonstrated decreases in their PWV. Factors shown to be associated with increasing PWV were Caucasian race (OR = 4.50; CI: 0.97 - 20.83), higher phosphate (OR = 8.36; CI: 1.10 - 63.51) and a lower baseline PWV (OR = 0.67; CI: 0.45 - 0.99). Decrease in PWV was associated with the absence of calcium based phosphate binder usage (OR = 0.11; CI: 0.02 - 0.73). Changes in weight and PWV at 12 months were significantly correlated (p = 0.007, r = 0.57). CONCLUSION: In this group of incident PD patients, we demonstrate a lower prevalence of vascular calcification than in hemodialysis patients, a correlation of calcification with PWV, and an important finding that PWV can change in either direction over a short period of time, which are associated with modifiable risk factors. PMID- 22541685 TI - Do serum hepcidin-25 levels correlate with oxidative stress in patients with chronic kidney disease not receiving dialysis? AB - AIMS: Iron metabolism is an important factor of anemia in chronic kidney disease (CKD). Hepcidin is a regulator of iron homeostasis and has a major role in the anemia of chronic disease (ACD). Oxidative stress (OS) is also associated with iron metabolism. However, the clinical utility of hepcidin, especially its association with OS, in CKD patients not receiving dialysis is still unclear. METHODS: We recruited 117 patients (62 +/- 15 years, 85 males, and median estimated glomerular filtration rate (eGFR) 22 ml/min/1.73 m2) with CKD not receiving dialysis. Serum 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of DNA oxidative injury, and serum hepcidin-25 were measured by ELISA and by liquid chromatography tandem mass spectrometry, respectively. RESULTS: Hepcidin-25 was associated positively with ferritin, high-sensitive C-reactive protein (hsCRP) and 8-OHdG, and negatively with eGFR and hemoglobin. Sex, oral iron, hemoglobin, transferrin saturation (TSAT), ferritin, and hsCRP were independently associated with hepcidin-25 in a multiple regression model. In contrast, neither eGFR nor 8 OHdG independently affected hepcidin- 25. CONCLUSIONS: The close association between hepcidin and serum ferritin, oral iron and hsCRP indicates that it plays a key role in the pathogenesis of anemia in patients with CKD not receiving dialysis. In contrast, effects of eGFR and OS were not apparent. PMID- 22541686 TI - Renal-limited vasculitis in children: a single-center retrospective long-term follow-up analysis. AB - Pauci-immune renal limited vasculitis (RLV) is a rare and aggressive autoimmune disease. We retrospectively analyzed the renal outcome of 6 children with biopsy proven RLV. Median age at diagnosis was 10.6 years (range 7.1 - 14.5) and the median follow-up was 4.4 years (range 2.3 - 6.6). At diagnosis, 5 patients were given induction therapy (methylprednisolone + cyclophosphamide pulses) followed by maintenance treatment (prednisolone + azathioprine) while 1 patient received maintenance treatment only. After induction, 4 patients either retained or recovered normal renal function, and 1 patient, in whom short-term plasma exchange was prescribed to try to rescue her renal function, became free from dialysis. Repeated biopsy showed no disease activity; however, renal scarring was evident in all renal specimens. At last follow-up, 2 patients had normal renal function, 3 patients had mild renal insufficiency, and 1 patient had advanced renal failure. In addition, 5 patients were treated for hypertension. Our case series suggests that an initial favorable response to immunosuppressive therapy might not necessarily prevent the occurrence of renal scarring and highlights the importance of regular follow-up. PMID- 22541687 TI - Maintenance therapy with single-daily, high-dose mizoribine after cyclophosphamide therapy for prepubertal boys with severe steroid-dependent nephrotic syndrome. PMID- 22541689 TI - Long-term outcome of Hepatitis B-positive renal allograft recipients after development of antiviral treatment. AB - BACKGROUND/AIMS: Hepatitis B virus (HBV) infection can adversely affect the clinical outcome of kidney transplantation (KT). Short-term efficacy of lamivudine has been demonstrated for chronic hepatitis B in KT recipients (KTR). METHODS: To clarify the long-term impact of antiviral treatment for HBV-positive KTR, we retrospectively reviewed 94 HBV-positive (male 73%) and 282 age/sex matched HBV-negative patients who underwent KT from February 1997 to November 2009, after lamivudine had come into wide use. RESULTS: Mean follow-up was 75.7 months. 56 patients received antiviral agent for prophylaxis, and other 18 for HBV reactivation. During follow-up, 15 died, with 5 deaths being HBV related. Although the patient survival rate was lower for HBVpositive than HBV-negative KTRs (89% vs. 94% at 5 years, 78% vs. 88% at 10 years, p = 0.031), graft survival was comparable (86% vs. 92% at 5 years, 73% vs. 81% at 10 years, p = 0.113). In multivariate analysis, HBsAg positivity was a significant risk factor for patient death (OR 2.19, 95% CI 1.14 - 4.20, p = 0.019), but not significant for graft loss (OR 1.64, 95% CI 0.94 - 2.86, p = 0.079). Of the 26 hepatitis B e antigen (HBeAg)-positive patients, 14 experienced HBV reactivations, but all survived with stable liver chemistry, except for one who died of hepatocellular carcinoma. Among 57 HBeAg-negative patients, 12 died, whereas the remaining 45 survived without hepatic dysfunction. CONCLUSION: Long-term outcomes of HBV-positive KTRs may be favorable after antiviral agents have been introduced. PMID- 22541688 TI - Therapeutic resistance to ACEI and ARB combination in macroalbuminuric diabetic nephropathy. PMID- 22541690 TI - Long-term impact of prophylactic antiviral treatment in Hepatitis B surface antigen positive renal allograft recipients. AB - BACKGROUND: Antiviral prophylaxis has been shown to prevent hepatic dysfunction in Hepatitis B virus (HBV)-positive kidney transplantation recipients (KTRs). However the long-term effects of antiviral prophylaxis on the patient death, graft loss, or hepatic decompensation have not been determined. METHOD: We therefore retrospectively analyzed outcomes in 94 HBV-positive patients, who underwent KT between February 1997 and November 2009 and were followed-up for a mean 75.7 months. Of the 94 KTRs, 56 received antiviral prophylaxis (Group 1), 51 with lamivudine and 5 with entecavir, and 38 did not (Group 2). RESULT: Of the latter group, 20 experienced HBV reactivation and 18 did not (mean 85 months); of those with reactivation, 16 received lamivudine, 2 received entecavir and 2 received no antiviral treatment. Cox-regression analysis showed that antiviral prophylaxis had no benefit on patient death (OR 1.29, 95% CI 0.37 - 4.49, p = 0.693), graft failure (OR 1.25, 0.45 - 3.46, p = 0.666) or hepatic decompensation (OR 2.01, 0.35 - 11.57, p = 0.434). Lamivudine resistance occurred in 21 lamivudine-treated Group 1 and 4 lamivudine-treated Group 2 patients (p = 0.243), with mean times of resistance after KT of 82 and 132 months, respectively (p = 0.001). CONCLUSION: These findings indicate that lamivudine-based antiviral prophylaxis for HBV-positive renal recipients has no long-term clinical benefits. PMID- 22541692 TI - We only talk about breast feeding: a discourse analysis of infant feeding messages in antenatal group-based education. AB - AIM: the aim of the study was to examine the dominant discourses that midwives draw on to present information on breast feeding in group-based antenatal education sessions. BACKGROUND: breast-feeding initiation rates are high among Australian women however, duration rates are low. Antenatal breast-feeding education is considered a key strategy in promoting breast feeding to childbearing women. The efficacy and effectiveness of such a strategy is equivocal and there is little qualitative work examining group-based antenatal breast-feeding education. METHODS: discourse analysis was used to explore the language and practises of midwives facilitating group antenatal breast-feeding education sessions at two Australian maternity facilities. Nine sessions were observed and tape recorded over a 12 month period. Each session lasted between 60 and 140 mins. FINDINGS: the analysis revealed four dominate discourses midwives used to promote breast feeding during group-based antenatal education session. The predominant discourses 'There is only one feeding option': breast feeding' and 'Selling the 'breast is best' reflected how midwives used their personal and professional commitment to breast feeding, within supportive and protective policy frameworks, to convince as many pregnant women as possible to commit to breast feeding. Sessions were organised to ensure women and their partners were 'armed' with as much information as possible about the value of breastmilk, successful positioning and attachment and practical strategies to deal with early breast-feeding problems. Antenatal commitment to breast feeding was deemed necessary if women were to overcome potential hurdles and maintain a commitment to the supply of breast milk. The latter two discourses, drawn upon to promote the breast-feeding message, presented infants as 'hard wired' to breast feed and male partners as 'protectors' of breast feeding. CONCLUSIONS: midwives clearly demonstrated a passion and enthusiasm for breast-feeding education. Examining the dominant discourses used by midwives during the antenatal sessions revealed, however, that their language and practices were often limited to convincing women to breast feed rather than engaging with them in conversations that facilitated exploration and discovery of how breast feeding might be experienced within the mother-infant relationship and broader social and cultural context. In addition, there was evidence that global breast-feeding policies, in resource rich countries such as Australia, may influence how midwives talk about breast feeding without them being fully cognisant of the potentially coercive nature of the messages women receive. PMID- 22541691 TI - The pan-caspase inhibitor Q-VD-OPh has anti-leukemia effects and can interact with vitamin D analogs to increase HPK1 signaling in AML cells. AB - Caspase function is known to be essential for cell death by apoptosis, but it is now increasingly recognized that these proteases also play important roles in other cellular events. Here we report for the first time that inhibition of cellular caspase activity can induce differentiation of AML blasts, and can enhance vitamin D-induced cell differentiation of these cells. This was studied in blasts obtained from nine patients with AML and one patient with CML by ex vivo culture in the presence of Q-VD-OPh (QVD), a pan caspase inhibitor. Cell differentiation was manifested by the expression of markers of monocytic differentiation CD11b and CD14. Differentiation induced by 1alpha,25 dihydroxyvitamin D3 (1,25D) or its analogs PRI-1906 and PRI-2191 was enhanced by QVD to a varying degree, depending on the subtype of the leukemia. QVD and 1,25D induced differentiation was accompanied by increased signaling by Hematopoietic Progenitor Kinase 1(HPK1), and the expression of transcription factors known to be involved in monocytic differentiation was increased. Although the magnitude and nature of these changes were not invariable, it is clear that caspase inhibitors warrant attention as components of differentiation therapy of leukemia, perhaps in combination with derivatives of vitamin D. PMID- 22541693 TI - Internal cardiac defibrillator implant-associated angiosarcoma presenting as suspected implant pouch infection. AB - Medical implants have been rarely associated with the development of sarcomas. We report, to our knowledge, the first case of a high-grade epithelioid angiosarcoma developing in the capsule of an internal cardiac defibrillator implanted subcutaneously over the abdomen over 20 years ago. Although the internal cardiac defibrillator generator had been exchanged in the intervening years, recently, the patient showed a year-long history of systemic symptoms suspicious for implant infection, necessitating several internal cardiac defibrillator pocket hematoma evacuations, always with negative microbiologic cultures. Final reexploration identified suspicious tissue with excessive bleeding which was biopsied and proven to be angiosarcoma on histologic examination. Subsequent imaging demonstrated precipitous progression to liver and lung metastases. Though rare, foreign-body-related sarcoma should be considered in the differential diagnosis for presentations suggestive of hemorrhagic or infectious sequelae of medical implants; this case broadens the range of medical devices associated with angiosarcoma to include now very commonly used implantable medical devices. PMID- 22541694 TI - Evaluation of elevated liver enzymes. AB - Liver enzymes, including aminotransferases and alkaline phosphatase, are some of the most commonly ordered blood tests in a physician's practice. These enzymes have been valuable in screening for liver disease, as well as in diagnosing and monitoring patients with acute and chronic hepatobiliary disorders. Patients with predominantly aminotransferase elevations are thought to have acute or chronic hepatitis from a variety of causes. In patients with predominantly alkaline phosphatase elevations, imaging evaluation is undertaken upfront to exclude large bile duct disorders and infiltrative/mass lesions. A liver biopsy may be reserved for patients for whom these less invasive investigations are unfruitful. PMID- 22541696 TI - Drug-induced liver disease. AB - Drug-induced liver injury (DILI), also known as hepatotoxicity, refers to liver injury caused by drugs or other chemical agents, and represents a special type of adverse drug reaction. It has been estimated that more than 600 drugs and chemicals have been associated with significant liver injury. Many previous reviews have focused on DILI pathogenesis or have outlined the clinical features of liver injury linked to different drugs. This article briefly touches on several areas that are potentially vexing for both the novice and cognoscenti, with the goal of guiding the consultant through one of the most challenging areas of hepatology. PMID- 22541697 TI - Liver disease in pregnancy. AB - Changes in the liver biochemical profile are normal in pregnancy. However, up to 3% to 5% of all pregnancies are complicated by liver dysfunction. It is important that liver disease during pregnancy is recognized because early diagnosis may improve maternal and fetal outcomes, with resultant decreased morbidity and mortality. Liver diseases that occur in pregnancy can be divided into 3 different groups: liver diseases that are unique to pregnancy, liver diseases that are not unique to pregnancy but can be revealed or exacerbated by pregnancy, and liver diseases that are unrelated to but occur coincidentally during pregnancy. PMID- 22541698 TI - Evaluation of liver lesions. AB - The differential diagnosis of a liver mass is large and requires understanding of the clinical and imaging features of liver lesions. A detailed history, physical examination, hepatic biochemical tests, and imaging studies are all essential in making the diagnosis. Decisions regarding specific imaging modalities for diagnoses, the use of liver biopsy, therapeutic options, and appropriate follow up are all determined by the presentation of the lesion and associated patient characteristics. PMID- 22541695 TI - Approach to a patient with elevated serum alkaline phosphatase. AB - Cholestasis develops either from a defect in bile synthesis, impairment in bile secretion, or obstruction to bile flow, and is characterized by an elevated serum alkaline phosphatase and gamma-glutamyltransferase disproportionate to elevation of aminotransferase enzymes. Key elements to the diagnostic workup include visualization of the biliary tree by cholangiography and evaluation of liver histology. The hope is that recent advances in understanding the genetic factors and immune mechanisms involved in the pathogenesis of cholestasis will lead to newer therapeutic interventions in the treatment of these diseases. PMID- 22541699 TI - Ascites. AB - Ascites is the pathologic accumulation of fluid in the peritoneum. It is the most common complication of cirrhosis, with a prevalence of approximately 10%. Over a 10-year period, 50% of patients with previously compensated cirrhosis are expected to develop ascites. As a marker of hepatic decompensation, ascites is associated with a poor prognosis, with only a 56% survival 3 years after onset. In addition, morbidity is increased because of the risk of additional complications, such as spontaneous bacterial peritonitis and hepatorenal syndrome. Understanding the pathophysiology of ascites is essential for its proper management. PMID- 22541700 TI - Hepatic encephalopathy. AB - Hepatic encephalopathy (HE) represents a continuum of transient and reversible neurologic and psychiatric dysfunction. It is a reversible state of impaired cognitive function or altered consciousness in patients with liver disease or portosystemic shunting. Over the last several years, high-quality studies have been conducted on various pharmacologic therapies for HE; as more data emerge, it is hoped that HE will become a more easily treated complication of decompensated liver disease. In the interim, it is important that physicians continue to screen for minimal HE and treat patients early in addition to continuing to provide current treatments of overt HE. PMID- 22541701 TI - Shortness of breath in the patient with chronic liver disease. AB - Shortness of breath is a common complaint in those with chronic liver disease. The differential diagnosis for this complaint includes primary pulmonary disorders, systemic disorders that affect the liver and lungs, and extrahepatic manifestations of portal hypertension. Orthotopic liver transplant, when appropriate, is the most effective therapy for many patients with dyspnea and chronic liver disease, although therapies to treat the underlying complications of cirrhosis may provide relief. Shortness of breath in patients with cirrhosis often portends a poor prognosis, and these patients should be evaluated for orthotopic liver transplant because this therapy is most likely to provide long lasting benefit. PMID- 22541702 TI - Pruritus in chronic cholestatic liver disease. AB - Pruritus is a troublesome complication in patients with cholestatic liver disease. Several links to its pathogenesis have been proposed, including the role of bile acids, endogenous opioid and serotonins, and lysophosphatidic acid. The management of pruritus in cholestasis is challenging. Medical treatment of the underlying cholestatic condition may provide benefit. Extracorporeal albumin dialysis can be pursued for those who have a poor quality of life and failed the various therapeutic interventions, while awaiting liver transplantation. Experimental interventions, and the management of pruritus in certain conditions such as intrahepatic cholestasis of pregnancy and benign recurrent intrahepatic cholestasis, are also briefly reviewed. PMID- 22541703 TI - Chronic hepatitis B infection. AB - The management of chronic hepatitis B virus (HBV) infection requires understanding the natural history of the disease as well as the risks, benefits, and limitations of the therapeutic options. This article covers the principles governing when to start antiviral therapy, discusses recent advances using hepatitis B surface antigen quantification to better define various phases of infection, describes the use of HBV core, precore, and viral genotyping as well as host IL28B genotyping to predict response to interferon therapy, and reports on the management of HBV in 3 special populations (pregnancy, postliver transplantation, and in the setting of chemotherapy or immunosuppression). PMID- 22541704 TI - Alcoholic hepatitis: a clinician's guide. AB - Alcoholic hepatitis is a frequent reason for admission and a common consultation request for hepatologists and gastroenterologists. Although it seems to occur acutely, it is usually subacute and often superimposed on underlying alcoholic cirrhosis. Typically patients have a background of drinking on a daily basis, but, in response to a life crisis, patients have started drinking massively. PMID- 22541705 TI - Granulomatous liver disease. AB - Hepatic granulomata are not infrequently encountered in liver biopsy and often are associated with systemic disease. The clinical presentation varies with the particular systemic process. From a biochemical standpoint, the most common abnormalities are elevated serum alkaline phosphatase and gamma glutamyltransferase. The observation of granulomata in a liver biopsy specimen warrants workup to identify a possible cause. Clues may be obtained in the medical history, on physical examination, or with specialized blood testing or radiologic studies. Treatment involves therapy of the underlying cause of the disease associated with the development of the granulomatous hepatitis. PMID- 22541706 TI - Nonalcoholic fatty liver disease. AB - As the hepatic manifestation of the metabolic syndrome, nonalcoholic fatty liver disease (NAFLD) has become the most common cause of asymptomatic liver enzyme elevations in Western nations. Although it is easy to diagnose NAFLD, a liver biopsy is currently required to diagnose nonalcoholic steatohepatitis (NASH). Patients with NASH are those at greatest risk of progression to cirrhosis and, thus, treatment efforts are targeted to these individuals. Although currently there are no FDA-approved treatments for NASH, a multidisciplinary approach that addresses comorbid conditions and promotes modest weight loss comprises the backbone of therapy. PMID- 22541707 TI - Surgical clearance for the patient with chronic liver disease. AB - Patients with chronic liver disease face greater risk of perioperative morbidity and mortality, with the greatest risk among patients with cirrhosis. Both the Child-Pugh score and the Model for End-Stage Liver Disease have been evaluated as predictors of postoperative mortality. Other comorbidities, age, and American Society of Anesthesiologists physical status classification are also important predictors of these outcomes. In patients with liver disease, elective surgeries should be delayed to allow complete evaluation of the severity of liver disease, including the role of transplantation in the event of hepatic decompensation postoperatively. PMID- 22541708 TI - Is the patient a candidate for liver transplantation? AB - Identifying whether someone is a good candidate for liver transplantation is a complex process that requires a team approach. There are several medical and psychosocial considerations involved, each of which is thoroughly explored during the evaluation process. Both the indications and contraindications to transplantation can change over time, reflecting advances in understanding of, and ability to treat, certain disease processes. Ultimately, the goal of liver transplantation remains to provide a survival benefit to those with acute or chronic liver diseases. PMID- 22541709 TI - Consultations for liver disease patients. PMID- 22541710 TI - Development and validation of a reliable method for studying the distribution pattern for opiates metabolites in brain. AB - Brain distribution pattern of "street" heroin metabolites (morphine and codeine) was investigated in two fatalities due to "acute narcotism". A suitable sample pretreatment prior to solid-phase-extraction was developed to achieve a good recovery of the analytes and to eliminate the interfering species. After derivatization with MSTFA, samples were analyzed by GC/MS. Specificity, accuracy, precision and linearity of the method were evaluated; LOD and LOQ were, respectively, 10ng/25ng for morphine and 5ng/10ng for codeine. This method was applied to the analysis of six brain areas (hippocampus, frontal lobe, occipital lobe, nuclei, bulb and pons) coming from two cases of heroin-related deaths. No evidence of accumulation of metabolites in a specific brain region was found. PMID- 22541711 TI - Starch turnover: pathways, regulation and role in growth. AB - Many plants store part of their photosynthate as starch during the day and remobilise it to support metabolism and growth at night. Mutants unable to synthesize or degrade starch show strongly impaired growth except in long day conditions. In rapidly growing plants, starch turnover is regulated such that it is almost, but not completely, exhausted at dawn. There is increasing evidence that premature or incomplete exhaustion of starch turnover results in lower rates of plant growth. This review provides an update on the pathways for starch synthesis and degradation. We discuss recent advances in understanding how starch turnover and the use of carbon for growth is regulated during diurnal cycles, with special emphasis on the role of the biological clock. Much of the molecular and genetic research on starch turnover has been performed in the reference system Arabidopsis. This review considers to what extent information gained in this weed species maybe applicable to annual crops and perennial species. PMID- 22541712 TI - Good outcomes with WIC continue. PMID- 22541713 TI - Farm field trips provide sensory-based experiences with fresh, local produce. PMID- 22541714 TI - Unstabilized DNA breaks in HTLV-1 Tax expressing cells correlate with functional targeting of Ku80, not PKcs, XRCC4, or H2AX. AB - BACKGROUND: Expression of the human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein rapidily induces a significant increase of micronuclei (MN) and unstabilized DNA breaks in cells. Unstabilized DNA breaks can have free 3'-OH ends accessible to in situ addition of digoxygenin (DIG)-labeled dUTP using terminal deoxynucleotidyl transferase. In the present work, we used a GFP-Tax (green fluorescent protein) plasmid, which produces a functionally active GFP tagged Tax protein, to detect the cellular target(s) for Tax which might mechanistically explain the clastogenic phenomenon. We examined the induction of MN and unstabilized DNA breaks in wild type cells and cells individually knocked out for Ku80, PKcs, XRCC4, and H2AX proteins. We also assessed in the same cells, the signal strengths produced by DIG-dUTP incorporation at the unstable DNA breaks in the presence and absence of Tax. RESULTS: Cells mutated for PKcs, XRCC4 and H2AX showed increased frequency of MN and unstabilized DNA breaks in response to the expression of Tax, while cells genetically mutated for Ku80 were refractory to Tax's induction of these cytogenetic effects. Moreover, by measuring the size of DIG-dUTP incorporation signal, which indicates the extent of unstable DNA ends, we found that Tax induces larger signals than those in control cells. However, in xrs-6 cells deficient for Ku80, this Tax effect was not seen. CONCLUSIONS: The data here demonstrate that clastogenic DNA damage in Tax expressing cells is explained by Tax targeting of Ku80, but not PKcs, XRCC4 or H2AX, which are all proteins directly or indirectly related to the non homologous end-joining (NHEJ) repair system. Of note, the Ku80 protein plays an important role at the initial stage of the NHEJ repair system, protecting and stabilizing DNA-breaks. Accordingly, HTLV-1 Tax is shown to interfere with a normal cellular protective mechanism for stabilizing DNA breaks. These DNA breaks, unprotected by Ku80, are unstable and are subject to erosion or end-to end fusion, ultimately leading to additional chromosomal aberrations. PMID- 22541716 TI - Short-term hypothyroidism in thyroid cancer patients and cognitive-motor performance relevant for driving. AB - CONTEXT: In patients with differentiated thyroid carcinoma (DTC) who, after thyroidectomy, are to receive radioiodine therapy or diagnostics, a strong TSH stimulus is necessary. Traditionally, this is induced by thyroid hormone withdrawal (THW) over a period of 4-5weeks; alternatively thyroid hormone replacement therapy is continued and recombinant human thyrotropin (rhTSH) is administered. During the hypothyroid state due to THW, patients often report mood disturbances and physical complaints but also an impairment of performance during attention demanding tasks. OBJECTIVE: Based on physiological, self-report and performance test data collected from various studies, we proposed the hypothesis that thyroidectomized DTC patients perform significantly worse in cognitive-motor functions that are relevant for driving when in the THW-induced hypothyroid state compared to when thyroid hormone replacement therapy is continued and rhTSH is administered. METHODS: We compared 41 DTC patients (age 42.3 (9.4) years; 80.5% female) after 4weeks THW with 41 DTC patients after the application of rhTSH, pairwise matched according to age, gender and educational level, with respect to performance in 4 core tests of the Act-React-Testsystem ART-90, a validated test battery for examining fitness to drive. RESULTS: Contrary to our expectations, no statistically relevant impairment of performance could be confirmed in the THW group in comparison to the rhTSH group for any variable (at adjusted alpha). At most there is a tendency in the THW group for slowed reaction times in simple choice reaction tasks; the (standardized) difference to the rhTSH group is however small (d'=0.31). Furthermore, large effects due to THW, as they are suggested by several studies, could be excluded. PMID- 22541715 TI - beta-Estradiol unmasks metabotropic receptor-mediated metaplasticity of NMDA receptor transmission in the female rat dentate gyrus. AB - Loss of estrogen in women following menopause is associated with increased risk for cognitive decline, dementia and depression, all of which can be prevented by estradiol replacement. The dentate gyrus plays an important role in cognition, learning and memory. The gatekeeping function of the dentate gyrus to filter incoming activity into the hippocampus is modulated by estradiol in a frequency dependent manner and involves activation of metabotropic glutamate receptors (mGluR). In the present study, we investigated whether estradiol (EB) modulates the metaplastic effect of inducing synaptic long-term potentiation (LTP) on subsequent propensity for expression of LTP in the dentate gyrus. At medial perforant path-dentate granule cell synapses in hippocampal slices of ovariectomized female rats, EB replacement was critical for an initial induction of LTP to enhance the magnitude of subsequent LTP elicited by a second high frequency stimulation, metaplasticity, which was not present in slices from oil treated control animals. EB enhanced expression of group I mGluRs, and the metaplastic effect of EB on LTP required activation of group I mGluRs that led to Src-family tyrosine kinase-mediated phosphorylation of NR2B subunits of N-methyl d-aspartate receptors (NMDAR) that enhanced the magnitude of NMDAR-dependent LTP. Our data show that EB effects on LTP in the hippocampal dentate gyrus require activation of group I mGluRs, which in turn leads to functional metaplastic regulation of NR2B subunit-containing NMDARs, as opposed to direct effects of EB on NMDARs. PMID- 22541717 TI - Increased level of serum cytokines, chemokines and adipokines in patients with schizophrenia is associated with disease and metabolic syndrome. AB - At present there are strong indications of a shared vulnerability factor for schizophrenia (SZ), diabetes and the metabolic syndrome (metS). In this study we focus on an aberrantly activated monocyte/macrophage system as the shared factor. We measured in SZ patients (n=144), the serum levels of monocyte/macrophage cytokines/chemokines/adipokines CCL2, CCL4, IL-1beta, TNF-alpha, IL-6, PTX3, leptin, adiponectin, PAI-1, OPG and ICAM-1 and compared these levels to healthy controls (HC) (n=138). Using multivariate analysis, we studied the effect of the presence of the disease SZ, the components of the metS including BMI, the levels of lipids (HDL cholesterol and triglycerides (TG)), diabetes (hyperglycemia) and the use of antipsychotic medication, on the serum levels of these immune compounds. We found all measured immune compounds with the exception of PAI-1 and OPG to be elevated in the SZ patient population. Multivariate analysis showed that elevations were linked to gender (ICAM-1, leptin, TNF-alpha and adiponectin), an increased BMI (leptin, adiponectin), hyperglycemia/diabetes (CCL4, and OPG), reduced HDL-cholesterol or increased levels of TG (adiponectin and PTX3) or the metS (CCL2, leptin and adiponectin). IL-1beta and IL-6 were the only immune compounds raised in the serum of patients not affected by any of the included factors. Although many of the immune compounds were found linked to (components of) the metS, the most dominant linkage was found with the disease schizophrenia, confirming earlier reports on increased monocyte/macrophage activation as a key component for understanding the pathogenesis of schizophrenia. PMID- 22541718 TI - Diffuse alveolar hemorrhage in immunocompetent patients: etiologies and prognosis revisited. AB - BACKGROUND: Diffuse alveolar hemorrhage (DAH) represents a diagnostic challenge of acute respiratory failure. Prompt identification of the underlying cause of DAH and initiation of appropriate treatment are required in order to prevent acute respiratory failure and irreversible loss of renal function. More than 100 causes of DAH have been reported. However, the relative frequency and the differential presentation of those causes have been poorly documented, as well as their respective prognosis. METHODS: We retrospectively reviewed the charts of 112 consecutive patients hospitalized for DAH in a tertiary referral center over a 30-year period. RESULTS: Twenty-four causes of DAH were classified into four etiologic groups: immune (n = 39), congestive heart failure (CHF; n = 33), miscellaneous (n = 26), and idiopathic DAH (n = 14). Based on this classification, clinical and laboratory features of DAH differed on hospital admission. Patients with immune DAH had more frequent pulmonary-renal syndrome (p < 0.001), extra-pulmonary symptoms (p < 0.01), and lower blood hemoglobin level than others (p < 0.001). Patients with CHF-related DAH were older and received more anticoagulant treatments than others (p < 0.05). Those with miscellaneous causes of DAH exhibited a shorter prodromal phase (p < 0.001) and had more frequent hemoptysis >200 mL (p < 0.05). Patients with idiopathic DAH had more bronchoalveolar lavage siderophages (p < 0.01). In-hospital mortality was 24.1%, ranging from 7.1% in patients with idiopathic DAH to 36.4% in those with CHF. CONCLUSIONS: Arbitrary classification of DAH in four etiologic groups gives the opportunity to underline distinct presentations and outcomes of various causes of DAH. PMID- 22541719 TI - Smoking cessation and the risk of hospitalization for pneumonia. AB - BACKGROUND: Smoking increases the risk of hospitalization for pneumonia, yet it is unknown if smoking cessation changes this risk. We sought to determine if smoking cessation and the duration of abstinence from tobacco reduce the risk of pneumonia hospitalization. METHODS: We performed secondary analysis of data collected from male United States Veterans participating in a randomized trial. We used Cox proportional-hazard models to estimate risk of hospitalization for pneumonia within one year of enrollment. We adjusted for confounders, including: demographics, comorbidity, alcohol use, prior pneumonia, inhaled corticosteroid use, and intensity of tobacco exposure. Among a restricted cohort excluding never smokers, we assessed for effect modification by a diagnosis of chronic obstructive pulmonary disease (COPD). RESULTS: Of the 25,235 participants, we identified 6720 current, 13,625 former, and 4890 never smokers. Compared to current smokers, never smokers had a decreased (adjusted HR 0.48, 95% CI 0.31 0.74), while former smokers had no difference in (adjusted HR 0.83, 95% CI 0.63 1.09) risk of hospitalization for pneumonia. Among participants without COPD, former smokers had a lower risk of hospitalization (adjusted HR 0.65, 95% CI 0.45 0.95). However, this lower risk was isolated to those who quit tobacco more than 10 years previously (adjusted HR 0.62, 95% CI 0.41-0.93). Among those with COPD, there was no difference in risk with smoking cessation or duration of remaining tobacco-free. CONCLUSIONS: Tobacco cessation is likely important in reducing hospital admissions for pneumonia, but its benefit depends on duration of smoking cessation and is likely attenuated in the presence of COPD. PMID- 22541720 TI - Low-level exposure to ambient particulate matter is associated with systemic inflammation in ischemic heart disease patients. AB - Short-term exposure to ambient air pollution is associated with increased cardiovascular mortality and morbidity. This adverse health effect is suggested to be mediated by inflammatory processes. The purpose of this study was to determine if low levels of particulate matter, typical for smaller cities, are associated with acute systemic inflammation. Fifty-two elderly individuals with ischemic heart disease were followed for six months with biweekly clinical visits in the city of Kotka, Finland. Blood samples were collected for the determination of inflammatory markers interleukin (IL)-1beta, IL-6, IL-8, IL-12, interferon (IFN)gamma, C-reactive protein (CRP), fibrinogen, myeloperoxidase and white blood cell count. Particle number concentration and fine particle (particles with aerodynamic diameters <2.5 MUm (PM(2.5))) as well as thoracic particle (particles with aerodynamic diameters <10 MUm (PM(10))) mass concentration were measured daily at a fixed outdoor measurement site. Light-absorbance of PM(2.5) filter samples, an indicator of combustion derived particles, was measured with a smoke stain reflectometer. In addition, personal exposure to PM(2.5) was measured with portable photometers. During the study period, wildfires in Eastern Europe led to a 12-day air pollution episode, which was excluded from the main analyses. Average ambient PM(2.5) concentration was 8.7 MUg/m(3). Of the studied pollutants, PM(2.5) and absorbance were most strongly associated with increased levels of inflammatory markers; most notably with C-reactive protein and IL-12 within a few days of exposure. There was also some evidence of an effect of particulate air pollution on fibrinogen and myeloperoxidase. The concentration of IL-12 was considerably (227%) higher during than before the forest fire episode. These findings show that even low levels of particulate air pollution from urban sources are associated with acute systemic inflammation. Also particles from wildfires may exhibit pro-inflammatory effects. PMID- 22541721 TI - The environmental impact on air quality and exposure to carbon monoxide from charcoal production in southern Brazil. AB - Black wattle silviculture is an important activity in southern Brazil. Much of the wood is used in the production of charcoal and the pyrolysis products impacts on air quality. This paper estimates the level of atmospheric contamination from the production of charcoal in one region of Brazil. We describe a low-cost charcoal kiln that can capture condensable gases and we estimate the levels of exposure of kiln workers to carbon monoxide. The latter results indicated that exposure to carbon monoxide can be reduced from an average of 950 ppm to 907 ppm and the mass of gases reduced by 16.8%. PMID- 22541722 TI - Validation of the pain sensitivity questionnaire in chronic pain patients. AB - Recently, a self-rating measure for pain perception based on imagined painful daily life situations, the Pain Sensitivity Questionnaire (PSQ), has been developed and shown to correlate with experimentally obtained pain intensity ratings in healthy subjects. Here, we assessed the validity of the PSQ for investigation of general pain perception (ie, pain perception outside the site of clinical pain) in chronic pain patients. PSQ scores were obtained in 134 chronic pain patients and compared to those of 185 healthy control subjects. In a subgroup of 46 chronic pain patients, we performed experimental pain testing outside the clinical pain site, including different modalities (heat, cold, pressure, and pinprick) and different measures (pain thresholds, pain intensity ratings). Results show that PSQ scores were significantly correlated with both experimental pain intensity ratings (Pearson's r=0.71, P<.001) and experimental pain thresholds (r=-0.52, P<.001). In addition, chronic pain patients exhibited significantly elevated PSQ scores as compared to healthy controls, consistent with the generalized increase of experimentally determined pain perception that has repeatedly been reported in chronic pain patients. These results demonstrate that the PSQ constitutes a valid self-rating measure of pain perception outside the clinical pain site in chronic pain patients and might serve as an alternative to experimental assessment of pain perception outside the clinical pain site in situations where experimental pain testing is not feasible. PMID- 22541723 TI - Recombinant bacterial vaccines. AB - Vaccines are currently available for many infectious diseases caused by several microbes and the prevention of disease and death by vaccination has profoundly improved public health globally. However, vaccines are not yet licensed for use against many other infectious diseases and new or improved vaccines are needed to replace suboptimal vaccines, and against newly emerging pathogens. Most of the vaccines currently licensed for human use include live attenuated and inactivated or killed microorganisms. Only a small subset is based on purified components and even fewer are recombinantly produced. Novel approaches in recombinant DNA technology, genomics and structural biology have revolutionized the way vaccine candidates are developed and will make a significant impact in the generation of safer and more effective vaccines. PMID- 22541725 TI - [New light on psoriasis]. PMID- 22541724 TI - The impact of CMV infection on survival in older humans. AB - Dysregulated immunity, 'immunosenescence', in the elderly is thought to contribute to their increased susceptibility to infectious disease and to impact on mortality. Accepted hallmarks of human immunosenescence are low numbers and frequencies of naive T cells and higher numbers and frequencies of memory T cells in the peripheral blood of the elderly compared to the young. The proportion of the population infected with CMV increases with age and markedly influences these parameters. Infection with this persistent beta-herpesvirus may therefore indirectly impact on survival in the elderly. Recent evidence pertaining to this controversial proposal is reviewed here. PMID- 22541726 TI - [Pustular psoriasis]. AB - The pustular forms o f psoriasis make up a heterogeneous entity from a clinical point of view. However, the existence of clinically detectable aseptic pustular lesions is common to all these forms. How they are related to plaque psoriasis, also called psoriasis vulgaris, the most frequent form of psoriasis, and the genetic and molecular mechanisms recently updated in some forms, have renewed interest in these pustular forms, resulting in reconsideration of their place within cutaneous and systemic inflammatory diseases. PMID- 22541727 TI - [Rare or unusual forms of psoriasis]. AB - Apart from plaque-type psoriasis, there are multiple particular or rare clinical presentations, according to signs and symptoms, localization or distribution of lesions. Psoriasis can affect mucous membranes, especially the genital areas of male and female patients, causing pain or burning sensation and decreased quality of life. Geographic tongue is not specific of psoriasis, but is more frequent in this context. Other localizations like the lips and the eylids are rare, but should not be overlooked. Certain lesions have an unusual distribution, like psoriasis gyrata and blaschko linear forms. Pustules are frequently observed on the palms and soles. Acrodermatitis continua is a rare chronic pustular condition affecting the acral areas, mainly the fingers, which is associated with severe nail involvement. Nails can also be involved in the unusual pachydermo periostitis, a clinical form of psoriasis without epidermal lesions, which has characteristic radiologic presentation. PMID- 22541728 TI - [Psoriasis and inflammatory bowel diseases]. AB - Psoriasis and inflammatory bowel diseases (Crohn's disease and ulcerative colitis) are among the immune-mediated inflammatory diseases. This group includes approximately 80 disorders, some of which can at times be associated in a single patient. In psoriasis, Crohn's disease may be observed slightly more frequently, but ulcerative colitis and celiac disease are also an issue. The underlying relations between these disorders comprise: i) genetic data obtained by genome wide association studies that show the involvement of shared predisposing loci and/or genes, for example, in innate immunity; ii) immunological data: these disorders share inflammation effector mechanisms, particularly the activation pathway of Th17 lymphocytes, which explains the efficacy of anti-TNF antibodies and anti-IL-12/23; and iii) environmental co-factors such as smoking, possibly certain food proteins (gliadin, etc.), and bacterial infections that are probably decisive elements in the genesis of these diseases. PMID- 22541729 TI - [Depression and psoriasis]. AB - Psychiatric co-morbidity is very frequently associated with psoriasis and depression is observed in numerous patients with psoriasis. Early detection and treatment are very important. The links between psoriasis and depression are not only psychopathological. Biological factors could also explain this association. There is a vicious circle psoriasis-alteration of quality of life-depression, but psoriasis improvement is not always followed by an improvement of depression. A contrario, it is obvious that a depressive patient has a bad observance of treatment. PMID- 22541730 TI - [Anti-drug antibodies, auto-antibodies and biotherapy in psoriasis]. AB - The approval of substantial numbers of targeted biologic therapies (e.g., monoclonal antibodies, fusion proteins) for treatment of inflammatory diseases has positioned these drugs as important to fight chronic disorders such as psoriasis, rheumatoid arthritis and Crohn's disease. One of the concerns raised with the administration of biologic therapies is that because most of them are immunogenic glycoproteins they induce undesirable immune response leading to the generation of specific anti-drug antibodies (ADA). The development of "self" derived protein therapeutics (comprised of human germline sequence), such as recombinant "human" antibodies, helped to reduce the production of ADA but did not avoid all immunogenicity. Reduced efficacy and safety issues such as anaphylaxis or vasculitis accompany the development of ADA. In addition to immune reactions directed against the biologic therapies as a whole, some of them such as anti-TNFalpha are able to induce auto-immune response, notably antinuclear antibody (ANA). ANA development was associated with induced lupus and in psoriasis it was suggested that it may act as a marker of treatment failure to anti-TNFalpha. With a focus on psoriasis, this paper makes a current point on the consequences and challenges of the development of anti-drug antibodies and auto immunity in patients who receive biologic therapies. PMID- 22541731 TI - [Pathogenesis of psoriasis]. AB - Psoriasis is a polymorphous disease. The multiple ways to combine susceptibility genes, immunological mechanisms and modifying factors which interact toward the development of the lesions contribute widely to this polymorphism. It is elusive to look for the source of the disease in an exclusive disorder of the immune system or in an isolated primitive change of the epithelial or stromal skin cells. It is more likely that various combinations of selective abnormalities of these two compartments give raise to the psoriatic phenotype. Indeed, if in on hand T-cells are essential in the development of psoriatic plaques, the role of innate immunity in this process is better recognized, and numerous psoriasis susceptibility genes are linked to immunity, on the other hand some susceptibility factors related to primitive abnormalities of keratinocytes and some of the most recent murine models of psoriasis are based on modifications targeted to the keratinocytes. This article makes a current point on the physiopathology of the disease. PMID- 22541733 TI - Five questions about Streptococcus mutans: theoretical study of its transmission and colonisation. AB - PURPOSE: This theoretical study aimed to identify the decisive (and controllable) factors involved in Streptococcus mutans (Sm) infection through addressing questions about (i) the time and prevalence pattern (including the raison d'etre of the discrete period for the infection or WI) of initial Sm colonisation and (ii) the infant's selection of bacterial types and their diversity, which are not yet definitely answered by empirical works. METHOD: A model of Sm infection (within-host type) was developed. For questions (i): using the basic model, stochastic simulation was performed to reproduce longitudinal observations of the initial colonisation time. A symmetrical or right-skewed gamma distribution was assumed for the maximum colonisable area (K(max)) and transmission rate (mx). Additionally, 3 or 4 developmental modes of colonisable area [K(t)] were assigned based on the K(max) value. For (ii): by extending the basic model to the two bacterial type model, intraspecific competition analysis focusing on the differences in mx (received by the infancy) and colonisation ability (thetaD) was performed. RESULTS: The basic model simulation showed that mx and K(t) played a pivotal role in determining the individual time of initial colonisation and their variations among infants in forming its prevalence patterns (with or without WI). The competition model simulation showed that higher mx could be more advantageous in competitive colonisation than higher thetaD under repeated invasions. Accordingly, it played a decisive role in infant's selection of initially, persistently and transiently colonising bacterial types, and thus in their diversity. CONCLUSIONS: (i) The mx is the primary and controllable (risk) factor that extensively affects various aspects of the Sm infection process. (ii) Also, the growing carrying capacity, i.e., K(t) is another important factor when considering how to effectively delay the onset of the colonisation. (iii) Thus, currently, the most feasible and effective control measure for the infection should be microbiological interventions in the primary host with concurrent oral hygiene and dietary control in the exposed child. PMID- 22541732 TI - Regulation of chromatin structure by long noncoding RNAs: focus on natural antisense transcripts. AB - In the decade following the publication of the Human Genome, noncoding RNAs (ncRNAs) have reshaped our understanding of the broad landscape of genome regulation. During this period, natural antisense transcripts (NATs), which are transcribed from the opposite strand of either protein or non-protein coding genes, have vaulted to prominence. Recent findings have shown that NATs can exert their regulatory functions by acting as epigenetic regulators of gene expression and chromatin remodeling. Here, we review recent work on the mechanisms of epigenetic modifications by NATs and their emerging role as master regulators of chromatin states. Unlike other long ncRNAs, antisense RNAs usually regulate their counterpart sense mRNA in cis by bridging epigenetic effectors and regulatory complexes at specific genomic loci. Understanding the broad range of effects of NATs will shed light on the complex mechanisms that regulate chromatin remodeling and gene expression in development and disease. PMID- 22541734 TI - Effect of NaCl and sucrose tastants on protein composition of oral fluid analysed by SELDI-TOF-MS. AB - During eating, human saliva is secreted into the oral cavity by salivary glands. The relative contribution of different glands to total salivary flow rate depends, among other factors, on the tastants in the food. Few reports indicated that also the salivary protein composition depends on the tastant make-up of the food. We studied the influence of sodium-chloride- and sucrose solutions on the presence of proteins in the M(r) range 2-20kDa in whole saliva. Upon oral stimulation with a sodium chloride solution, a sucrose solution or water, we collected whole saliva from 14 volunteers after t=1 min, t=11 min and t=20 min. Saliva protein profiles were analysed by SELDI-TOF-MS. SELDI-TOF-MS intensities of m/z values representing different protein masses were compared between subjects, tastants and time conditions. For subsets of the 33 detected masses, significant effects were observed for all factors, with most masses involved in the Subjects effect: m/z(Subjects)>m/z(Time*Stimulus)>m/z(Stimulus)>m/z(Time). Most effects on saliva protein composition were observed at t=1 min, whilst almost no effects were observed at t=11 min and t=20 min. When considering the Stimulus*Time interaction, we identified four different stimulus-response patterns. Proteins identified in the present study, and attributed to specific glands or tissues in literature, were used to associate stimulus-response patterns with tissue provenances. Observed stimulus-response patterns were not uniquely associated to particular glands and tissues. Hence, there was no evidence of the involvement of particular tissues or glands in tastant-specific protein responses. In conclusion, oral stimulation with different tastants affects salivary protein composition in a protein- and stimuli dependent way, which seems not be associated with any specific tissues or glands of origin. PMID- 22541735 TI - Liver X receptor biology and pharmacology: new pathways, challenges and opportunities. AB - Nuclear receptors (NRs) are master regulators of transcriptional programs that integrate the homeostatic control of almost all biological processes. Their direct mode of ligand regulation and genome interaction is at the core of modern pharmacology. The two liver X receptors LXRalpha and LXRbeta are among the emerging newer drug targets within the NR family. LXRs are best known as nuclear oxysterol receptors and physiological regulators of lipid and cholesterol metabolism that also act in an anti-inflammatory way. Because LXRs control diverse pathways in development, reproduction, metabolism, immunity and inflammation, they have potential as therapeutic targets for diseases as diverse as lipid disorders, atherosclerosis, chronic inflammation, autoimmunity, cancer and neurodegenerative diseases. Recent insights into LXR signaling suggest future targeting strategies aiming at increasing LXR subtype and pathway selectivity. This review discusses the current status of our understanding of LXR biology and pharmacology, with an emphasis on the molecular aspects of LXR signaling that constitute the potential of LXRs as drug targets. PMID- 22541736 TI - Necrotising fasciitis of the thigh secondary to colonic perforation: the femoral canal as a route for infective spread. AB - A 57 year-old man with a history of corticosteroid use presented with abdominal pain and diarrhoea. He was initially treated for presumed Clostridium difficile colitis, but later developed a left inguinal mass with spreading erythema. A CT scan showed gas within the retroperitoneal tissues, with surgical emphysema of the left groin. Necrotising fasciitis was diagnosed, and the patient underwent extensive debridement of the left thigh and inguinal region. The femoral vein was covered in infected fascia in the femoral canal, and a laparotomy revealed a posterior perforation of the sigmoid colon. Necrotising fasciitis of the thigh is a rare complication of colonic perforation. Our case highlights the femoral canal as a potential channel for the spread of intra-abdominal infection into the thigh. PMID- 22541737 TI - Association of complete recovery from acute kidney injury with incident CKD stage 3 and all-cause mortality. AB - BACKGROUND: There is a gap of knowledge in the long-term outcomes of patients who have complete recovery of kidney function after an episode of acute kidney injury (AKI). We sought to determine whether complete recovery of kidney function after an episode of AKI is associated with the development of incident stage 3 chronic kidney disease (CKD) and mortality in patients with normal baseline kidney function. DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 3,809 patients from an integrated health care delivery system who had a hospitalization between January 1, 1999, and December 31, 2009, with follow-up through March 31, 2010. PREDICTOR: AKI defined by International Classification of Diseases, Ninth Revision (ICD-9) codes and using the AKI Network (AKIN) definition, with complete recovery defined as a decrease in serum creatinine level to less than 1.10 times the baseline value. OUTCOMES AND MEASUREMENTS: Incident stage 3 CKD persistent for 3 months and all-cause mortality. RESULTS: After a median follow-up of 2.5 years, incident stage 3 CKD occurred in 15% and 3% of those with and without AKI, respectively, with an unadjusted HR of 5.93 (95% CI, 4.49-7.84) and HR of 3.82 (95% CI, 2.81-5.19) in propensity score-stratified analyses. Deaths occurred in 35% and 24% of those with and without AKI, respectively, with an unadjusted HR of 1.46 (95% CI, 1.27-1.68). In propensity score-stratified analyses, HR decreased to 1.08 (95% CI, 0.93-1.27). LIMITATIONS: Measurements of albuminuria were not available. CONCLUSIONS: Complete recovery of kidney function after an episode of AKI in patients with normal baseline kidney function is associated with increased risk of the development of incident stage 3 CKD, but not all-cause mortality. PMID- 22541738 TI - Effects of Mediterranean diets on kidney function: a report from the PREDIMED trial. AB - BACKGROUND: Epidemiologic observations have linked healthy dietary patterns to improved kidney function. STUDY DESIGN: We assessed the effects of the Mediterranean diet (MedDiet) on kidney function in both a cross-sectional assessment and after a 1-year intervention in a cohort of the PREDIMED (Prevencion con Dieta Mediterranea) Study, a multicenter 3-arm randomized clinical trial to determine the efficacy of the MedDiet on primary cardiovascular prevention. SETTING & PARTICIPANTS: Community-dwelling men aged 55-80 years and women aged 60-80 years at high risk of cardiovascular disease from Reus, Spain. INTERVENTION: Participants were randomly assigned to 3 ad libitum diets: a MedDiet supplemented with virgin olive oil (MedDiet + olive oil), a MedDiet supplemented with mixed nuts (MedDiet + nuts), or a control low-fat diet. OUTCOMES: Estimated glomerular filtration rate (eGFR) and urinary albumin creatinine ratio (ACR). MEASUREMENTS: Nutrient intake, adherence to the MedDiet, lifestyle variables, cardiovascular risk factors, serum urea and creatinine concentrations, eGFR, and urinary ACR were evaluated at baseline and after intervention for 1 year. RESULTS: Baseline kidney function markers were similar across quartiles of adherence to the MedDiet in 785 participants (55% women; mean age, 67 years). After a 1-year intervention in 665 participants, the 3 dietary approaches were associated with improved kidney function, with similar average increases in eGFR (4.7 [95% CI, 3.2-6.2], 3.5 [95% CI, 1.9-5.0], and 4.1 [95% CI, 2.8-5.5] mL/min/1.73 m(2) for the MedDiet + olive oil, MedDiet + nuts, and control groups, respectively [P < 0.001 vs baseline for each; P = 0.9 for differences among groups]), but no changes in ACRs after adjustment for various confounders. LIMITATIONS: Generalization of results to other age groups or ethnicities. GFR was not directly measured. CONCLUSIONS: The results do not support the notion that the MedDiet has a beneficial effect on kidney function over and above that of advice for a low-fat diet in elderly individuals at high cardiovascular risk. PMID- 22541740 TI - Heartbeat evoked potentials mirror altered body perception in depressed patients. AB - OBJECTIVE: Awareness of stimuli originating inside of the body (interoceptive awareness) is thought to have an impact on psychopathology. The aim of the present study was to analyze whether heartbeat perception accuracy is reduced in depressed patients. Furthermore, we investigated whether putative differences are reflected in heartbeat-evoked potentials. METHOD: We assessed the heartbeat perception score in 16 depressed patients and in matched healthy controls. A 63 channel EEG was recorded while participants counted pseudo-randomly presented target tones or heartbeats during a fixed number of cardiac cycles. ECG R-waves served as the trigger for EEG averaging. The cardiac-field artifact was minimized using independent component analysis and current-source density. RESULTS: Behaviorally, the depressed sample showed less accurate heartbeat perception in comparison to the control group (p=.011). The two groups also demonstrated psychophysiological differences, showing that heartbeat-evoked potentials were significantly reduced in depressed patients. CONCLUSIONS: Our results suggest that heartbeat evoked potentials are objective markers of altered bodily awareness. Reduced interoception during depression may be linked to alexithymia, as well as to both decreased capacity for decision-making and for cognitive processing. SIGNIFICANCE: It may be helpful to practice interoceptive awareness to improve depressive symptoms, for example by practicing meditation. PMID- 22541739 TI - Mismatch negativity and low frequency oscillations in schizophrenia families. AB - OBJECTIVE: Theta-alpha range oscillations have been associated with MMN in healthy controls. Our previous studies showed that theta-alpha activities are highly heritable in schizophrenia patients' families. We aimed to test the hypothesis that theta-alpha activities may contribute to MMN in schizophrenia patients and their family members. METHODS: We compared MMN and single trial oscillations during MMN in 95 patients, 75 first-degree relatives, 87 controls, and 34 community subjects with schizophrenia spectrum personality (SSP) traits. RESULTS: We found that (1) MMN was reduced in patients (p<0.001) and SSP subjects (p=0.047) but not in relatives (p=0.42); (2) there were augmented 1-20 Hz oscillations in patients (p=0.02 to <0.001) during standard and deviant stimuli; (3) theta-alpha (5-12 Hz) oscillations had the strongest correlation to MMN in controls and relatives (DeltaR(2)=21.4-23.9%, all p<0.001), while delta (<5 Hz) showed the strongest correlation to MMN in schizophrenia and SSP trait subjects; and, (4) MMN (h(2)=0.56, p=0.002) and theta-alpha (h(2)=0.55, p=0.004) were heritable traits. CONCLUSIONS: Low frequency oscillations have a robust relationship with MMN and the relationship appears altered by schizophrenia; and schizophrenia patients showed augmented low frequency activities during the MMN paradigm. SIGNIFICANCE: The results encourage investigation of low frequency oscillations to elucidate the neurophysiological pathology underlying MMN abnormalities in schizophrenia. PMID- 22541741 TI - Age-related changes in the control of perturbation-evoked and voluntary arm movements. AB - OBJECTIVE: This study examined how handrail location predictability affects perturbation-evoked arm responses in young and older adults and whether age related changes in perturbation-evoked arm responses are specific to mechanisms associated with reactive postural control. METHODS: Young and older adults reached for a handrail in response to a support surface translation (perturbation evoked) or to a visual cue (voluntary). For both movement tasks, the handrail location was made predictable or unpredictable to the participant. Electromyographic (EMG) activity and kinematics of the reaching arm were recorded to quantify the arm response. RESULTS: Posterior deltoid EMG activity during perturbation-evoked and voluntary movements were delayed by 15-74 ms (p<0.001) and 16% smaller (p=0.024) when the handrail was in an unpredictable compared to a predictable location. While ageing resulted in a 12-16 ms delayed initiation of EMG activity during perturbation-evoked reaching (p=0.003), the effects of handrail predictability and movement task did not interact with age. CONCLUSIONS: Age-related differences in perturbation-evoked arm responses are independent of both handrail location predictability and movement task. SIGNIFICANCE: Age related differences in perturbation-evoked arm responses cannot be solely attributed to declines in reactive postural control. Rather, ageing leads to a deterioration of neural mechanisms common to both perturbation-evoked and voluntary arm movements. PMID- 22541742 TI - An improved approach to diagnosing and treating conjunctival mucoepidermoid carcinoma. AB - The current case of conjunctival mucoepidermoid carcinoma offers features that expand the biologic spectrum afforded by this tumor. More focused strategies should be developed for its earlier histopathologic diagnosis and improved management (historical recurrence rate of 85%). A 63-year-old woman with a history of rheumatoid arthritis and idiopathic sclerosing cholangitis developed scleral thinning, anterior chamber cells and flare, and uveal prolapse. Biopsies of the epibulbar lesion were initially misinterpreted as a squamous cell carcinoma but on review harbored CK7-positive cells and contained rare goblet cells brought out with Alcian blue and mucicarmine staining. Intraocular extension exhibited micro-and macrocysts with minimal goblet cells. Focal CK7 immunopositivity in any epibulbar squamous dysplasia or in invasive carcinoma should lead to suspicion of a mucoepidermoid carcinoma. Behaviorally aggressive or rapidly recurrent epithelial squamous tumors with "inflammatory" features or unusual clinical characteristics should be initially stained at multiple levels for the detection of parsimonious mucus secretion. Surgical options include wide excision and partial sclerectomy with cryotherapy for superficial invasion and/or interferon therapy. Results with radiotherapy and cryotherapy for deep scleral invasion have been unpredictable or unacceptable compared with surgery. PMID- 22541743 TI - Drug-drug interactions at hospital admission in geriatric patients in a single facility: a retrospective study. AB - BACKGROUND: Individuals older than 60 years of age have multiple simultaneous diseases, for which the average number of medications is greater than five, leading up to 3% possibility of having an adverse reaction event. OBJECTIVE: To detect potential drug-drug interactions (PDDIs) and report the average hospital stay for severity potential PPIs, in adults 60 years of age and older in an Internal Medicine Service. METHODS: This was a retrospective analysis with a review of the clinical records of patients 60 years of age and older. The length of stay, number and type of prescribed daily medications, PDDIs, and number of admission diagnoses for each patient, were reviewed. RESULTS: This study included 342 patients with an average and standard deviation of 6 +/- 3.0 medications per day. The PDDI levels were 27 (7.9%) severe, 94 (27.5%) moderate, and 61 (17.8%) had both types of interactions. Severe interactions, presented a hospital stay of 10 days, and moderate interaction a 13-day stay. CONCLUSION: The most common interactions and their average length of stay may be utilized for quality evaluation of the medication process of such a major patient population as that of the older adult in the hospital setting. PMID- 22541744 TI - Evaluation of myocardial infarction and coronary artery disease in subjects taking lopinavir/ritonavir: a study using clinical trial and pharmacovigilance databases. AB - OBJECTIVE: There is growing interest in studying age-related diseases, such as coronary artery disease (CAD) and resulting myocardial infarction (MI) in HIV infected patients. While some cohort studies indicate that several antiretrovirals (ARVs), including the protease inhibitor lopinavir/ ritonavir (LPV/r), are associated with an increased relative risk (RR) of MI, other studies show a reduction of MI and CAD in subjects taking ARVs when compared with HIV+ patients not taking ARV therapy. This manuscript reviews data from Abbott sponsored clinical trials and pharmacovigilance reporting system. METHODS: A systematic search was performed to retrieve cases of MI and CAD in Abbott's clinical trial and pharmacovigilance safety databases. The rates of MI and CAD, and risk factors for the events were reviewed in detail. RESULTS: The rate of MI and CAD per 1,000 patient treatment years (PTY) was 1.24 (95% CI = 0.40 - 2.90) and 2.74 (95% CI = 1.37 - 4.90), respectively, for subjects taking LPV/r during clinical trials. The frequency of pharmacovigilance reports of MI and CAD were 2.9 per 100,000 PTY and 3.6 per 100,000 PTY, respectively. Most subjects who had MI and CAD events had multiple baseline risk factors. CONCLUSIONS: Relatively few subjects experienced MI or CAD during Abbott-sponsored clinical trials of LPV/r. Analysis of clinical trial and pharmacovigilance data did not indicate an increased risk of MI or CAD associated with LPV/r compared with the general population. In general, the subjects that experienced MI or CAD had known traditional risk factors suggesting that addressing modifiable risk factors could decrease the risk of MI or CAD. ARVs have not been thoroughly studied in subjects at high risk for MI and CAD, and further studies of this population could identify whether starting ARVs affects the incidences of cardic events in subjects with many traditional risk factors PMID- 22541745 TI - Pharmacokinetics and safety of aclidinium bromide in younger and elderly patients with chronic obstructive pulmonary disease. AB - OBJECTIVE: To investigate the pharmacokinetics, safety and tolerability of aclidinium bromide 200 MUg and 400 MUg after a single dose and repeated once daily doses in younger and elderly patients with moderate or severe chronic obstructive pulmonary disease (COPD). METHODS: Younger (40-59 years; n = 12) and elderly (>= 70 years; n = 12) patients were treated with aclidinium via the Genuair(r) inhaler. Patients received once-daily aclidinium 200 MUg for 3 days; after a 7-day washout period, patients received once-daily aclidinium 400 MUg for 3 days. Pharmacokinetic analyses were conducted on plasma and urine on Days 1 and 3 of both treatment periods. Safety and tolerability were assessed. RESULTS: Aclidinium showed similar linear and time-independent pharmacokinetics in younger and elderly patients at each dose level and day of treatment. For both age groups at each dose level and day, aclidinium appeared rapidly in the plasma with a median tmax between 10 and 15 min; concentrations of aclidinium in the plasma declined rapidly with a t1/2 between 1 and 3 h. Plasma exposure with the 400 MUg dose was ~ 2-fold higher than for the 200 MUg dose in both age groups on both days. For both age groups, urinary excretion of aclidinium over 24 h was < 0.15% of the dose at each dose and day. Aclidinium 200 MUg and 400 MUg were safe and well tolerated in both age groups. CONCLUSION: These data suggest that no dose adjustment of aclidinium is required when treating elderly patients with COPD. PMID- 22541746 TI - Human pharmacokinetics of intravenous recombinant human Cu/Zn superoxide dismutase. AB - OBJECTIVE: Oxidative stress plays an important role in human disease, but antioxidant therapies are limited. Under physiological conditions superoxide is controlled by the enzyme superoxide dismutase. A recombinant human Cu/Zn superoxide dismutase (rhSOD) might open new therapeutic possibilities. METHODS: Safety profile and pharmacokinetics in plasma and urine were assessed in an open label phase I study with dose-escalation. 18 healthy male volunteers received a single intravenous 10-minute infusion of 150, 300, or 600 mg rhSOD, respectively (n = 6 per dose group). RESULTS: rhSOD was well tolerated. Peak plasma concentrations (cmax; mean +/- SD) were reached at the end of infusion, with 32.96 +/- 10.31, 51.60 +/- 8.23, and 103.90 +/- 19.02 MUg/ ml, respectively. Non compartmental halflife was 1.06 +/- 0.37, 1.59 +/- 0.64, and 1.63 +/- 0.28 hours. Urinary excretion (10 h) showed dose-dependent relative increases with 11.28 +/- 6.46 (7.5%), 54.93 +/- 15.25 (18.3%), and 191.81 +/- 104.60 mg (32.0%). CONCLUSIONS: Our results show a good safety profile and predictable pharmacokinetics of rhSOD, suggesting that therapeutic exploratory studies might be safely conducted in humans. PMID- 22541747 TI - Pilot and pivotal study to evaluate the bioequivalence of two paroxetine 40 mg tablet formulations in healthy Chinese subjects. AB - The purpose of this study was to conduct a pilot study in order to obtain reliable results for further planning of a well-designed pivotal trial comparing the bioequivalence (BE) of two paroxetine tablet formulations in healthy Chinese subjects. Before conducting the pivotal trial, the pilot trial enrolled 14 subjects to help in study design, establishing the recruitment period, determining pharmacokinetics (PK) time points and sample size, and assessing BE of the two formulations. The single-center, randomized, open-label, single-dose, two period crossover study with a 7-day washout interval was conducted after obtaining information from the fasted pilot trial in 72 healthy volunteers for a pivotal study under fed and fasted conditions, respectively. There were 19 PK sample collection time points employed in both the pilot and pivotal trials. A sensitive and specific liquid chromatography- tandem mass spectrometry (LC-MS/ MS) method was developed and validated for determining paroxetine in human plasma. BE between two articles was determined by calculating 90% confidence intervals (CIs) for the ratio of Cmax 91.38 - 110.39% for the pilot trial, 99.81 114.08% for pivotal trial under fasted condition, and 94.06 - 110.41% for pivotal trial under fed condition, AUC(0-t) 96.06 - 110.52% for pilot study, 100.88 - 113.05% for the pivotal trial under fasted condition, and 97.08 - 106.06% for pivotal study under fed condition, and AUC(0-infinity) 96.17 - 110.42% for the pilot study, 100.85 - 112.81% for the pivotal trial under fasted condition and 97.22 - 106.14% for the pivotal study under fed condition, respectively. These values for the test and reference products are within the 80 125% interval proposed by FDA and EMEA. It was concluded that the proposed method was successfully applied to a PK study in healthy Chinese volunteers, and results showed from both the pilot and pivotal studies that the two paroxetine formulations are bioequivalent in their rates and extent of absorption. PMID- 22541748 TI - Impact of evidence-based cardiac medication on short- and long-term mortality in 7,567 acute coronary syndrome patients in the Gulf RACE-II registry. AB - OBJECTIVE: To evaluate the impact of evidence-based cardiac medications (EBMs) on 1-month and 1-year mortality among discharged acute coronary syndrome (ACS) patients in the Middle East. METHODS: Data were analyzed from 7,567 consecutive ACS patients admitted to 66 hospitals in 6 Middle Eastern countries enrolled in the Gulf RACE II in October 2008 to June 2009. Individual EBMs or concurrent use of the EBM combination consists of an anti-platelet therapy, angiotensin converting enzyme inhibitor (ACEI) (or angiotensin II receptor blocker (ARB)), beta-blocker, and a statin at discharge, were evaluated. Analyses were performed using univariate and multivariate statistical techniques. RESULTS: The mean age of the cohort was 56 +/- 12 years with 79% being males. 65% of the patients received the concurrent EBM combination at discharge. Aspirin, clopidogrel, statins, b-blockers and ACEIs/ARBs use was 96%, 71%, 95%, 82% and 81%, respectively. 70% of the patients were prescribed both aspirin and clopidogrel concurrently at discharge. Adjusting for demographic, clinical, revascularization, and country characteristics, the multivariable logistic regression models demonstrated no differences in mortality at both 1-month (3.0 vs. 3.6%; p = 0.828) and 1-year (3.5 vs. 3.5%; p = 0.976) between the concurrent EBM combination users and non-users. CONCLUSION: The majority of the ACS patients in the Middle East were prescribed the guideline recommended EBM combination at discharge. However, potential still remains for further optimization of management. Further studies are required to examine the long term effect of concurrent use of the EBM combination on mortality in the region. PMID- 22541749 TI - Effectiveness of an integrated CPOE decision-supporting system with clinical pharmacist monitoring practice in preventing antibiotic dosing errors. AB - OBJECTIVE: Computer-prescriber order entry (CPOE) systems that lack clinical decision components actually increase errors and cause harm rather than the opposite. Recent studies have also demonstrated that dosing errors, typing errors, or miscommunication with other systems are the most common CPOE errors. Our objective was to develop an antibiotic dosing calculator and implement it in the CPOE system while integrating the role of the clinical pharmacist in the CPOE in order to minimize dosing errors in the prescription of antibiotics. METHODS: A database was prepared using dosage information for 13 renal function-related antibiotics. The dosages in the database ranged from the standard to the maximum dosage based on various creatinine clearance (CL(cr) levels. The antibiotic dosage monitoring system was developed to screen the entire inpatient database for inappropriate antibiotic dosage regimens and record the results as an Excel document. MAIN OUTCOME MEASURE: We tracked the frequency of calculator utilization by physicians, the acceptance rate of recommendations from the calculator and pharmacists, the inappropriate antibiotic dosage regimen prescriptions, and the antibiotic-related renal function deterioration. The relative risk (RR) with 95% confidence intervals (CI) was used to calculate the risk of inappropriate antibiotic dosage prescription, the deterioration in renal function when antibiotics were used. RESULTS: From 2005 to 2008, 38,647 antibiotic prescriptions were recorded in the CPOE system. The instances of inappropriate antibiotic dosage prescriptions were decreased by ~ 80% after the calculator was implemented (RR, 0.18 - 0.23; p < 0.001), and the incidence rates of renal function deterioration were lowered from 12.39% to 9.47%. The frequency of antibiotic calculator utilization by physicians (from 239 times/ year in 2005 to 3,480 times/year in 2008) and the acceptance rate of the calculator's dosage recommendations (from 68.2% in 2005 to 94.7% in 2008) both increased during the study period. The average acceptance rates of pharmacist recommendations by physicians were 97.65%. CONCLUSIONS: Integration of the CPOE decision-supporting system and the clinical pharmacist monitoring practice can help physicians provide appropriate antibiotic dosage regimens and decrease the incidence of dosing errors that could be decreased concerned patients with impaired renal function. PMID- 22541750 TI - Antipsychotic treatment in older schizophrenia patients with extrapyramidal side effects in Asia (2001 - 2009). AB - OBJECTIVE: This study surveyed the prescribing patterns of antipsychotic medications in Asian older schizophrenia patients with extrapyramidal side effects (EPS) during the period between 2001 and 2009. METHOD: Information on 848 hospitalized patients with schizophrenia aged 60 or older was extracted from the database of the Research on Asian Psychotropic Prescription Patterns (REAP) study (2001 - 2009). Data from those patients with reported EPS from 8 Asian countries and territories including China, Hong Kong, Japan, Korea, Singapore, Taiwan, India and Malaysia were analyzed. The cross-sectional data of sociodemographic and clinical characteristics and antipsychotic prescriptions were collected using a standardized protocol and data collection procedure. RESULTS: Of the 309/848 (36%) patients suffering from EPS, 210 patients (210/309; 68.0%) received at least one type of first generation antipsychotic (FGA), and 99 (99/309; 32.0%) received second generation antipsychotics (SGAs) only. Of SGAs prescribed in patients with EPS, risperidone was the most commonly used (100/309; 32.4%) followed by olanzapine (33/309; 10.7%) and quetiapine (25/309; 8.1%). CONCLUSIONS: FGAs were frequently used in Asian older schizophrenia patients with EPS. Considering the potential adverse effects of FGAs on existing EPS, the reasons for the frequent use of FGAs need to be urgently identified. PMID- 22541752 TI - Phenotyping the activity of drug metabolizing enzymes using limited sampling strategies: perturbations and bias. PMID- 22541751 TI - Evaluation of intravenous midazolam limited sampling models to determine area under the concentration time curve during cytochrome P450 3A baseline, inhibition and induction or activation. AB - OBJECTIVE: This study evaluated if previously published limited sampling models (LSMs) accurately predict midazolam area under the concentration time curve (AUC) during cytochrome P450 (CYP) 3A baseline, inhibition and induction/activation. MATERIALS AND METHODS: Plasma midazolam concentrations (n = 108) were obtained where intravenous midazolam was co-administered alone or concomitantly with ketoconazole, itraconazole, aprepitant, rifampin, or pleconaril. Observed AUC was calculated using noncompartmental analysis. Predicted AUC was calculated from the LSMs. Bias and precision were determined by percent mean prediction error (%MPE), percent mean absolute error (%MAE), and percent root mean squared error (%RMSE). RESULTS: Contrasting results were observed for LSMs in predicting CYP3A baseline activity, with the majority of studies resulting in unacceptable bias and precision. During CYP3A inhibition, unacceptable bias and precision were observed from single- and 2-time point LSMs. %MAE and %RMSE values exceeded acceptable limits during CYP3A induction with rifampin. Contrasting results were observed with pleconaril. CONCLUSION: The contrasting results during CYP3A baseline and induction/activation, as well as the unacceptable bias and precision during CYP3A inhibition, limits the widespread use of the previously published LSMs. PMID- 22541753 TI - Potassium treatment for hypertension in patients with high salt intake: a meta analysis. AB - BACKGROUND: Previous metaanalyses of potassium supplementation in patients with hypertension observed little or no benefit, but failed to account the amount of salt intake. OBJECTIVE: To assess the effect on blood pressure of potassium treatment in patients with high salt intake. METHODS: We meta-analyzed studies of patient populations with both high salt and potassium intake. We searched Medline, Google, major journals, Pubmed. Publication bias, lack of heterogeneity, and lack of robustness were assessed using standard procedures for such purposes. RESULTS: After the exclusion of 32 studies 10 studies were left in the meta analysis. A pooled reduction of systolic blood pressure of -9.5 mmHg (95% confidence interval -10.8 to -8.1) and of diastolic blood pressure -6.4 mmHg ( 7.3 to -5.6) was observed. These results were very heterogeneous (I2-values of 94 and 95%). After exclusion of single authored studies the results fell but remained statistically significant, -7.1 mmHg (-8.5 to -5.7), and -4.9 mmHg (-5.8 to -4.0). Heterogeneity of systolic blood pressure was no longer observed (I2 value 24.3%). Some publication bias was observed. CONCLUSIONS: 1. Potassium treatment reduces the blood pressure substantially in hypertensive patients with salt-rich diets. 2. The difference in magnitude of blood pressure reduction between different studies is probably related to the amount of salt intake. 3. Patients with reduced salt intake benefit little from potassium treatment. 4. Major meta-analyses published to date have severely underestimated the potential benefit of potassium treatment in patients with hypertension. PMID- 22541754 TI - The pharmacokinetics and pharmacodynamics of PF-00734200, a DPP-IV inhibitor, in healthy Japanese subjects. AB - OBJECTIVE: To evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of PF-00734200, a potent dipeptidyl peptidase-IV (DPP-IV) inhibitor, in Japanese subjects, and compare the results with those in Western subjects. MATERIALS AND METHODS: Eight healthy Japanese subjects received a single dose of PF-00734200 10 mg, 100 mg, or placebo. Another 8 subjects received PF-00734200 20 mg or placebo single dose once daily for 6 days. Serum and urine PK, plasma DPP IV activity, and plasma glucagon-like peptide 1 (GLP-1) levels were measured. RESULTS: Linear pharmacokinetics was observed over the single dose range 10 - 100 mg. Following multiple-dose administration, 37.3 +/- 4.33% of the unchanged PF 00734200 was excreted in the urine and renal clearance was calculated as 33.9 +/- 6.56 ml/min. After the standardized meals, GLP- 1 levels increased ~ 2-fold compared with placebo, and no further increase in GLP-1 levels was observed at doses above 10 mg. The steady state DPP-IV inhibition at 24 h was ~ 75%. CONCLUSION: Pharmacokinetics of PF-00734200, inhibition of DPP-IV, and non-linear increases in GLP-1 were similar between healthy Japanese and Western subjects. PMID- 22541755 TI - Pharmacokinetic and bioavailability studies of 5 mg mosapride tablets in healthy Korean volunteers. AB - AIM: Mosapride is a gastroprokinetic agent, a 5-HT4 receptor agonist and 5-HT3 receptor antagonist exhibiting no activity at dopamine D2, 5-HT1 and 5-HT2 receptors. This study was performed to compare basic pharmacokinetic (PK) characteristics of mosapride for Korean young adults and to evaluate the bioequivalence (BE) of two formulations of drugs mosapride. VOLUNTEERS AND METHODS: For pharmacokinetic and bioavailability of 5 mg mosapride tablets in healthy Korean adults, a randomized, two way, crossover bioequivalence study in 23 healthy Korean volunteers (M : F = 16 : 7) was conducted to compare bioavailability of two formulation of 5 mg mosapride citrate tablets, Moprid(r) (Chung Kun Dang Pharm Co., Ltd., Korea) as a test and Gasmotin(r) (Daewoong Pharm Co., Ltd., Korea) as a reference drug. Subjects were administered single dosage of 3 tablets of each formulation with 240 ml water after 10 h overnight fasting on 2 treatment days separated by 1-week washout period. Before and after dosing, blood sample were collected at 0, 0.25, 0.5, 0.8, 1.0, 1.5, 2, 2.5, 3, 4, 6, 8, 12 and 24 h and analyzed by validated liquid chromatography- tandem mass spectrometry (LC-MS/ MS) in the range 1.28 - 192 ng/ml with the lowest limit of quantification of 1.28 ng/ml. RESULTS: Several PK characteristics were determined from the plasma samples, and data from reference and test formulations in the plasma were represented such as AUC0- t (184.4 vs. 179.6 ng*h/ml), AUC0-infinity (192.8 vs. 186.6 ng*h/ml), Cmax (98.9 vs. 84.4 ng/ ml), tmax (0.8 vs. 0.7 h), half-life (2.4 vs. 2.3 h), Ke (0.289 vs. 0.301), respectively. AUC0- t and Cmax were tested for bioequivalence after log-transformation of plasma data. PK characteristics with 90% confidence interval (CI) of test/reference ratio based on ANOVA analysis were 0.842 - 1.163 for AUC0-t and 0.753 - 1.088 for Cmax. PK characteristics with 90% CI were within the bioequivalence range of 80 - 125% of FDA statistical limit. Cmax with 90% CI were not within the bioequivalence range of 80 - 125% of FDA statistical limit. However, this result was assessed to bioequivalence in accordance with the "Bioequivalence Test Guidelines" outlined in No. 2005-31 of the KFDA. CONCLUSION: Therefore, both mosapride formulations were bioequivalent during fasting state in healthy Korean adults. PMID- 22541756 TI - Straightforward thiol-mediated protein labelling with DTPA: Synthesis of a highly active 111In-annexin A5-DTPA tracer. AB - BACKGROUND: Annexin A5 (anxA5) has been found useful for molecular imaging of apoptosis and other biological processes. METHODS: Here, we report an optimised two-step synthesis of annexin A5-diethylene triamine pentaacetic acid (DTPA) (anxA5-DTPA) for positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging with a single purification step. The use of a recombinant annexin A5 (cys-anxA5) with a single thiol group allowed regionally specific coupling, without affecting the binding domain of cys-anxA5. RESULTS: The metal complexing capacity of anxA5-DTPA was investigated by labelling with 111In3+ and Eu3+. Binding of modified anxA5-DTPA to apoptotic cells was tested in competition experiments with a fluorescent anxA5 derivative (anxA5-FITC) using flow cytometry and compared with that of wildtype anxA5 or non-binding anxA5-DTPA (M1234-anxA5-DTPA). The binding affinity to apoptotic cells of the anxA5-DTPA conjugate does not differ from that of wildtype anxA5. CONCLUSIONS: This two-step synthesis of annexin A5-DTPA resulted in biologically active anxA5-DTPA, which can be labelled with radionuclides for use in SPECT and PET imaging. PMID- 22541758 TI - Does cardiology intervention improve mortality for post-operative troponin elevations after emergency orthopaedic-geriatric surgery? A randomised controlled study. AB - OBJECTIVES: Troponin elevations are common after emergency orthopaedic surgery and confer a higher mortality at one year. The objective was to determine if comprehensive cardiology care after emergency orthopaedic surgery reduces mortality at one year in patients who sustain a post-operative troponin elevation versus standard care. METHODS: A randomised controlled trial was conducted at a metropolitan teaching hospital in Melbourne, Australia. 187 consecutive patients were eligible with 70 patients randomised. Troponin I was tested peri-operatively and patients with a troponin elevation were randomised to cardiology care versus standard ward management. The main outcome measure was one year mortality. RESULTS: The incidence of a post-operative troponin elevation was 37.4% (70/187) and these 70 patients were randomised. In-hospital cardiac complications were similar between the randomised groups: standard care (7/35 or 20.0%) versus cardiology care (8/35 or 22.9%). There was no difference in 1 year mortality between the randomised groups (6/35 or 17.1% in each group). Multivariate predictors of 1 year mortality were post-operative troponin elevation OR 4.3 (95% CI, 1.1-16.4, p=0.035), age OR 1.1 (95% CI, 1.02-1.2, p=0.016) and number of comorbidities OR 2.1 (95% CI, 1.3-3.5, p=0.004). At 1 year 35/187 (18.7%) sustained a cardiac complication and 23/35 (65.7%) had a troponin elevation. CONCLUSIONS: There was no difference in mortality between patients with a post operative troponin elevation randomised to cardiology care compared with standard care. Troponin elevation predicted one year mortality. Further research is needed to find an effective intervention to reduce mortality. PMID- 22541757 TI - Nuclear bodies: multifunctional companions of the genome. AB - It has become increasingly apparent that gene expression is regulated by the functional interplay between spatial genome organization and nuclear architecture. Within the nuclear environment a variety of distinct nuclear bodies exist. They are dynamic, self-organizing structures that do not assemble as pre formed entities but rather emerge as a direct reflection of specific activities associated with gene expression and genome maintenance. Here I summarize recent findings on functions of some of the most prominent nuclear bodies, including the nucleolus, Cajal body, PML nuclear body, Polycomb group body and the 53BP1 nuclear body. The emerging view is that their organization is orchestrated by similar principles, and they function in fundamental cellular processes involved in homeostasis, differentiation, development and disease. PMID- 22541759 TI - Costs of falls in an ageing population: a nationwide study from the Netherlands (2007-2009). AB - BACKGROUND: Falls are a common mechanism of injury in the older population, putting an increasing demand on scarce healthcare resources. The objective of this study was to determine healthcare costs due to falls in the older population. METHODS: An incidence-based cost model was used to estimate the annual healthcare costs and costs per case spent on fall-related injuries in patients >= 65 years, The Netherlands (2007-2009). Costs were subdivided by age, gender, nature of injury, and type of resource use. RESULTS: In the period 2007 2009, each year 3% of all persons aged >= 65 years visited the Emergency Department due to a fall incident. Related medical costs were estimated at ?675.4 million annually. Fractures led to 80% (?540 million) of the fall-related healthcare costs. The mean costs per fall were ?9370, and were higher for women (?9990) than men (?7510) and increased with age (from ?3900 at ages 65-69 years to ?14,600 at ages >= 85 year). Persons >= 80 years accounted for 47% of all fall related Emergency Department visits, and 66% of total costs. The costs of long term care at home and in nursing homes showed the largest age-related increases and accounted together for 54% of the fall-related costs in older people. DISCUSSION: Fall-related injuries are leading to a high healthcare consumption and related healthcare costs, which increases with age. Programmes to prevent falls and fractures should be further implemented in order to reduce costs due to falls in the older population and to avoid that healthcare systems become overburdened. PMID- 22541760 TI - CT scanogram for limb length discrepancy in comminuted femoral shaft fractures following IM nailing. AB - INTRODUCTION: Leg length discrepancy (LLD) following intramedullary nailing of femoral fractures is not uncommon. We designed a prospective study to evaluate the efficacy of routine postoperative computed tomography (CT) scanograms for evaluation of limb length discrepancy in patients with comminuted Winquist III or IV femoral shaft fractures treated with intramedullary nailing. METHODS: The study consisted of 15 patients with Winquist III and 13 with a Winquist IV femoral shaft fracture pattern with an average age of 37 years. The mechanisms of injury were motor vehicle collision (13), gunshot wound (12) and falls (three). All patients were treated with a statically locked intramedullary femoral nail (18 antegrade and 10 retrograde). A CT scanogram evaluated limb length in all patients. A discrepancy of greater than 20mm was considered for correction during the same admission. An LLD of 15-20mm was discussed with the patient extensively for correction. RESULTS: In the 28 patients included in our study, the average limb length discrepancy was 9.1mm with a range of -43.5mm short to 10.3mm long. The LLD was less than 10mm in 18 patients (64%), 10-15mm in four patients (14%), 15-20mm in three patients (11%) and more than 20mm in three patients (11%). Measurement of discrepancy as small as 0.5mm showed that 18 patients were fixed with shortening and in 10 patients the operated femur was longer. Tibia lengths were also evaluated separately. Though none of the tibiae had a previous fracture, only three patients (10%) had tibiae of equal length. In 13 patients, an unequal tibia partially corrected the LLD whilst in 12 it added to the discrepancy. Five patients with LLD of greater than 15mm underwent correction. CONCLUSIONS: A postoperative scanogram in patients with comminuted femoral shaft fractures treated with intramedullary nailing is useful to evaluate LLD and allows for early intervention. The ideal length where correction is necessary remains unclear. PMID- 22541761 TI - Management of hospital readmissions in internal medicine. AB - The unplanned hospital readmission ratio is an unusual indicator of health care quality. Hospital readmission could be due to clinical or health care factors, to factors related to the patient and his/her social and familial setting, to factors related to the disease, or to a combination of all of them. The former could be avoided by designing effective interventions for the follow-up of the patients after discharge. We present a case of a male patient with a common clinical problem and propose the measures that could help to avoid his readmission. The article ends with the author's clinical recommendations. PMID- 22541762 TI - Collaboration among nursing organizations. PMID- 22541763 TI - Communication and safety. PMID- 22541764 TI - Nurses' responsibility for the future of nursing. PMID- 22541765 TI - Overcoming barriers to implementing recommended practices. PMID- 22541767 TI - Continuous application of intermittent pneumatic compression devices. PMID- 22541770 TI - Patient safety: break the silence. AB - A culture of patient safety requires commitment and full participation from all staff members. In 2008, results of a culture of patient safety survey conducted in the perioperative division of the Lehigh Valley Health Network in Pennsylvania revealed a lack of patient-centered focus, teamwork, and positive communication. As a result, perioperative leaders assembled a multidisciplinary team that designed a safety training program focusing on Crew Resource Management, TeamSTEPPS, and communication techniques. The team used video vignettes and an audience response system to engage learners and promote participation. Topics included using preprocedural briefings and postprocedural debriefings, conflict resolution, and assertiveness techniques. Postcourse evaluations showed that the majority of respondents believed they were better able to question the decisions or actions of someone with more authority. The facility has experienced a marked decrease in the number of incidents requiring a root cause analysis since the program was conducted. PMID- 22541769 TI - Interruptions and miscommunications in surgery: an observational study. AB - In surgery, as much as 30% of procedure-specific information may be lost as a result of miscommunication. We assessed the relationship between interruptions, team familiarity, and miscommunications across a purposive sample of 160 surgical procedures in 10 specialties during a six-month period. Descriptive analysis was used to quantify interruptions in respect to the source (ie, conversational, procedural) and type of miscommunication (ie, audience, purpose, occasion, content, experience). Results revealed an inverse correlation between the length of time that teams had worked together and the number of miscommunications in surgery (tau = -.33, P < .01). There was a positive correlation between the number of intraoperative interruptions and the number of miscommunications (tau = .30, P < .01). These results may help to inform the development of evidence-based interventions designed to mitigate the effects of miscommunications in surgery. PMID- 22541771 TI - Communication skills training to address disruptive physician behavior. AB - Disruptive behavior among health care providers has been linked to negative patient outcomes. High-stress areas, including the perioperative setting, are especially prone to this behavior. The purpose of this study was to develop, implement, and evaluate an educational communication skills intervention aimed at increasing the perceived self-efficacy of perioperative nurses to address disruptive physician behavior. Seventeen perioperative nurses participated in a two-day communication skills program presented by a certified Crucial Conversations trainer. By using paired t test analysis, I found that there was a statistically significant increase in total mean self-efficacy scores immediately after the intervention and four weeks after the intervention. In addition, four weeks after the intervention, participants reported the ability to address disruptive physician behavior 71% of the time. The results of this study suggest that one intervention strategy to address the serious threat of disruptive physician behavior to patient safety is to educate nurses in communication skills. PMID- 22541772 TI - Implementing AORN Recommended Practices for Laser Safety. AB - Lasers used in the OR pose many risks to both patients and personnel. AORN's "Recommended practices for laser safety in perioperative practice settings" identifies the potential hazards associated with laser use, such as eye damage and fire- and smoke-related injuries. The practice recommendations are intended to be used as a guide for establishing best practices in the workplace and to give perioperative nurses strategies for implementing the recommended safety measures. A laser safety program should include measures to control access to laser use areas; protect staff members and patients from exposure to the laser beam; provide staff members and patients with the appropriate safety eyewear for use in the laser use area; and protect staff members and patients from surgical smoke, electrical, and fire hazards. Measures such as using a safety checklist or creating a laser cart can help perioperative nurses successfully incorporate the practice recommendations. Patient scenarios are included as examples of how to use the document in real-life situations. PMID- 22541773 TI - Suture cost savings in the OR. AB - Materials management personnel at a health care facility in Baltimore, Maryland, were stocking too much suture. They stocked suture requested by surgeons or recommended by suture company representatives, and, because the facility is a teaching institution, they stocked suture requested by residents. No master suture database was available to determine what was needed and what was not. As a result, some suture was rarely used, which cost the facility money and took up inventory space. In response, I created a list of the existing inventory and coordinated with the specialty surgical service coordinators to determine which suture was typically used and in what quantities. I used this information to create a master list, with the goal of eliminating the purchase of suture that was not on this list. I gave the staff members and surgeons two months to assess the list and determine whether the suggested suture was sufficient for their needs. I then asked the materials management personnel to order and maintain suture stock based on the master list. This process took approximately four months and shows how health care providers can take a high-volume item, such as suture, and create cost-saving processes that will serve surgeons' and patients' needs while reducing costs and streamlining stock. PMID- 22541775 TI - Finding voice. PMID- 22541774 TI - Perioperative care of the child with epilepsy. PMID- 22541776 TI - Near infrared fluorescent imaging as a surgical navigation tool: the time has come. PMID- 22541778 TI - Pocket syringe swap. PMID- 22541779 TI - Mixed schwannoma with meningioma - report on 2 cases of unusual tumor with review of literature. AB - We present 2 rare cases of mixed schwannoma with meningioma. The first case was sporadic, in a 38-year-old female in cervical spine (C2). The second case was a 24-year-old female, associated with NF-2, involving bilateral cerebellopontine angle with extension into the left cavernous sinus, sellar region with erosion of the petrous ridge and multiple intradural extramedullary lesions in the spinal cord suggestive of neurofibromas. To date only 12 cases of such tumors are documented in the literature. To the best of our knowledge this is the first case of sporadic mixed schwannoma with meningioma in cervical spine (C2). PMID- 22541781 TI - Binucleated neurons in the pontine nuclei in neuro-Behcet's disease: a study of 3 autopsy cases. AB - Neuropathological findings of three autopsy cases of neuro-Behcet's disease are presented with special reference to the frequent occurrence of binucleated neurons in the pontine nuclei. All 3 patients were men and died after a protracted clinical course characterized by various brain stem symptoms. Autopsies revealed chronic non-specific brain stem encephalitis, which is a typical neuropathological feature of neuro-Behcet's disease. In all cases, many binucleated neurons (19, 20, and 55 neurons in each case) were found in the pontine nuclei. For comparison, the occurrence of binucleated neurons in the pontine nuclei was examined in 67 control cases including various neurological disorders. In 55 cases (82.1%) among them, no binucleated neurons were detected. In the remaining 12 cases (17.9%), the pontine nuclei contained 1 or 2 binucleated neurons. These observations confirmed that the occurrence of many binucleated neurons in the pontine nuclei was a characteristic finding in neuro- Behcet's disease. Although the pathogenetic mechanism for the formation of binucleated neurons is unknown, it is most likely the result of abortive cell division of neurons or fusion of the perikarya of the adjacent neurons. It probably reflects the presence of intense local noxious stimuli affecting neurons in the pontine nuclei. PMID- 22541780 TI - Multiple intracranial de-novo chloromas presenting with Garcin's syndrome. AB - Intracranial occurrence of a chloroma (myeloid sarcoma, MS) in the absence of a preceding hematological malignancy is unusual. We report the case of a 20-year old man who presented with Garcin's syndrome of short duration. MRI revealed multiple extra-axial contrast enhancing lesions: two mirror lesions on the skull base, and one in the right parietal convexity. The parietal lesion was excised and histologically and immunohistochemically proved to be a differentiated variant of MS. Peripheral blood smear and bone marrow biopsy ruled out an underlying leukemia or myeloproliferative disorder. With a diagnosis of intracranial de-novo MS, he was referred for chemotherapy and radiation therapy. 15 months later, his clinical status remained the same while his imaging showed marginal decrease in size of the lesions. A repeat bone marrow biopsy remained normal. This is a first-of-its- kind report of multiple intracranial lesions of a de-novo MS presenting as Garcin's syndrome. Radiological differentials, immunohistochemical variants and management options related to MS are discussed in the light of the reported case. PMID- 22541782 TI - Danon disease caused by two novel mutations of the LAMP2 gene: implications for two ends of the clinical spectrum. AB - Danon disease is caused by mutations of the lysosome-associated membrane protein 2 (LAMP2) gene at Xq24. Male patients usually manifested as severe cardiomyopathy, mild myopathy and mental retardation. We describe two patients: the first patient presented with severe hypertrophic cardiomyopathy, Wolff Parkinson-White syndrome, proximal muscle weakness, and chronic painless diarrhea; the second patient manifested as limb-girdle muscle weakness, mild left ventricular diastolic dysfunction, sub-clinical neuropathy. Muscle biopsies indicated autophagic vacuolar myopathy. Immunologic analysis demonstrated absence of the LAMP2 protein in the first patient, while a smear of expression was detected in the second patient. Two nonsense mutations (p.E298X and p. K402X) were identified in the two cases, respectively located in exon 7 and exon 9B of the LAMP2 gene. Our findings indicated that patients with Danon disease caused by mutations in exon 1 - 8 manifested as a typically severe phenotype, while patients with mutations in exon 9 of the LAMP2B isoform presented with a relatively benign phenotype. PMID- 22541783 TI - Staging of Lewy-related pathology in dementia. AB - OBJECTIVE: Lewy-related pathology is the characteristic feature of Parkinson's disease with and without dementia and dementia with Lewy bodies (DLB). There are two neuropathological staging systems for Lewy-related pathology commonly employed today: the staging system for Parkinson-related pathology by Braak et al., and the staging system by the Consortium on DLB. There are also several modified systems based on these two scales. METHODS: We applied a total of eight different staging systems for Lewy-related pathology to 36 consecutive demented patients with various dementia disorders. RESULTS: The staging systems varied considerably in number of unclassifiable cases (range 0 - 16 out of 36 cases), while the diagnostic agreement between the systems that were able to classify all or the very majority of cases varied only slightly (weighted kappa 0.86 - 0.92 and Spearman's sigma 0.80 - 1.0). CONCLUSION: The different staging systems for Lewy-related pathology that exist today vary in staging procedure and proportion of unclassifiable cases. The choice of system may affect the stage of Lewy related pathology and ultimately final diagnosis. PMID- 22541785 TI - Microvascularization and expression of VEGF and its receptors in recurring meningiomas: pathobiological data in favor of anti-angiogenic therapy approaches. AB - AIM: We studied expression of molecules of the vascular endothelial growth factor (VEGF) pathway and its relation to vascularization, cell proliferation and patient outcome in recurring non-anaplastic meningioma. We studied 29 tumor specimens of 8 patients with recurring meningiomas and of 8 age- and gender matched control patients with non-recurring meningiomas (including meningothelial, transitional, fibroblastic and atypical subtypes) using immunohistochemistry and in-situ hybridization. RESULTS: VEGF protein, VEGF-mRNA, VEGF receptor (VEGFR)-1 mRNA, VEGFR-2 mRNA and hypoxia-inducible factor (HIF)-1 alpha protein were expressed in 27/29 (93%), 20/27 (74%), 9/27 (33.3%), 12/27 (44.4%) and 5/29 (17.2%) specimens, respectively. VEGFR- 2 mRNA expression was found in 6/8 tumors extracted at first operation in patients with recurring tumors and in none of the control cases (p = 0.007). Microvessel density (MVD) and Ki-67 index values were generally higher in meningiomas with expression of angiogenic factors. The association of high Ki-67 index values with VEGF-mRNA expression was significant (p = 0.04). Time to recurrence was shorter in patients with high MVD than in patients with low MVD (p = 0.027). CONCLUSIONS: High MVD correlates with unfavorable prognosis in our series of recurring meningioma. VEGF and its receptors are frequently expressed in meningiomas and seem important for tumor growth and recurrence. Thus, anti-VEGF therapy in aggressive meningioma seems rational from a pathobiological point of view. PMID- 22541786 TI - Multifocal choroid plexus papilloma: a case report. AB - BACKGROUND: Multiple choroid plexus papillomas (CPPs) are rare. Usually, they correspond to villous hypertrophy or metastasis occurring during cerebrospinal dissemination. Multiple CPPs have rarely been reported as synchronous tumors. CASE REPORT: Three synchronous CPPs were resected in a 59-year-old female 6 years after their first imaging description. Pathology showed mucus-producing CPP in all 3, 1 of the 3 presenting some signs of atypia. No p53 or hSNF5/INI1 mutation, or signs of polyoma viruses infection were found. CONCLUSION: Although no clear cause for the multifocality was found, the simultaneous presence of the three tumors and their benign histology suggest that they were synchronous and not metastatic. The issue of differentiating synchronous CPPs from metastatic CPP is discussed. PMID- 22541787 TI - Evaluation of BACTEC Plus aerobic and anaerobic blood culture bottles and BacT/Alert FAN aerobic and anaerobic blood culture bottles for the detection of bacteremia in ICU patients. AB - Blood culture is the most valuable laboratory test for the diagnosis of bacteremia and sepsis. The BACTEC FX and BacT/Alert 3D automated blood culture systems are commonly used in Korean health care facilities. A controlled clinical evaluation of the resin-containing BACTEC Plus aerobic (BA) and anaerobic (BN), and the charcoal-containing FAN aerobic (FA) and anaerobic (FN) bottles using blood from intensive care unit (ICU) patients was designed. The performances of these 2 systems with media containing particle absorbing antimicrobial agents were evaluated using the culture positivity rate and time to detection (TTD). TTD was collected using data management systems, either the Epicenter (BD Diagnostic Systems) or the hospital laboratory information system. A total of 1539 four bottle sets were collected from 270 patients in medical and surgical ICUs. Blood culture samples included 1539 bottles each of BA, BN, FA, and FN, and yielded 113 (7.3%), 90 (5.8%), 104 (6.8%), and 80 (5.2%) positive bacterial or fungal isolates, respectively. There were significant differences between the resin containing BA and BN samples in culture positivity and also between the charcoal containing FA and FN samples, especially for Escherichia coli (25/27 versus 17/27, P < 0.05) and Acinetobacter baumannii (14/15 versus 7/15, P < 0.05). Significantly shorter recovery time was observed in BACTEC Plus aerobic bottles than in FAN aerobic bottles (17.2 and 24.7 h, respectively) (P < 0.001). PMID- 22541789 TI - Detection of Mycoplasma pneumoniae and Chlamydophila pneumoniae directly from respiratory clinical specimens using a rapid real-time polymerase chain reaction assay. AB - We developed a rapid real-time polymerase chain reaction assay for detecting Mycoplasma pneumoniae and Chlamydophila pneumoniae directly from respiratory specimens. This procedure provides over 5 times faster results compared to existing methods while maintaining equivalent detection rates for specimens containing limited target organisms. PMID- 22541790 TI - Clinical value of whole-blood interferon-gamma assay in patients with suspected pulmonary tuberculosis and AFB smear- and polymerase chain reaction-negative bronchial aspirates. AB - Combining a polymerase chain reaction (PCR) test with bronchoscopy is frequently performed to allow a rapid diagnosis of smear-negative pulmonary tuberculosis (PTB). However, limited data are available concerning clinical judgment in patients with suspected PTB and AFB smear- and PCR-negative bronchial aspirates (BA). The present study evaluated the usefulness of whole-blood QuantiFERON-TB Gold In-Tube (QFT) testing in these patients. Of 166 patients with suspected PTB who had undergone bronchoscopy because of smear-negative sputum or inadequate sputum production, 93 (56%) were diagnosed with culture-positive PTB. Seventy four patients were either AFB smear- or PCR-positive. In the 75 patients whose BA AFB smear and PCR results were both negative, 19 were finally diagnosed with PTB by culture. The QFT test had a negative predictive value of 91% for PTB. The QFT test may be useful for excluding PTB in patients with suspected PTB whose BA AFB smear and PCR results are both negative. PMID- 22541788 TI - Development of a multiplex polymerase chain reaction assay for diarrheagenic Escherichia coli and Shigella spp. and its evaluation on colonies, culture broths, and stool. AB - Detection of diarrheagenic Escherichia coli (DEC) typically depends on identification of virulence genes from stool cultures, not on stool itself. We developed a multiplex polymerase chain reaction (PCR) assay that detects key DEC virulence genes (stx1, stx2, eae, bfpA, ipaH, LT, STh, aaiC, aatA). The assay involved a multiplex PCR reaction followed by detection of amplicon(s) using Luminex beads. The assay was evaluated on over 100 colony and broth specimens. We then evaluated the assay using DNA extracted from stool, colony pools, and Gram negative broths, using stool spiked with known quantities of DEC. Performance of the assay on stool DNA was most quantitative, while stool broth DNA offered the lowest limit of detection. The assay was prospectively evaluated on clinical specimens in Tanzania. Stool DNA yielded higher sensitivity than colony pools compared with broth DNA as the standard. We propose using this assay to screen for DEC directly in stool or stool broths. PMID- 22541792 TI - Update: The diagnosis and management of dengue virus infection in North America. AB - Dengue is a mosquito-transmitted infection that poses significant global health risks for travelers and individuals living in the tropics and subtropics. The reported global incidence has increased dramatically in the past century, with dengue now ranking as the most common cause of febrile illness in travelers. While sporadic cases have been reported within the southern United States since 1980, autochthonous outbreaks have now been described in Hawaii, St. Croix (US Virgin Islands), along the Texas-Mexico border, and, most recently, in Key West, Florida. Although many infections are mild or asymptomatic, 5-10% of patients may experience hemorrhagic disease, with shock and even death. Laboratory identification commonly involves serologic and nucleic acid amplification methods. Due to rising incidence worldwide, physicians should be familiar with the clinical manifestations, laboratory diagnosis, and management of this illness. PMID- 22541791 TI - Evaluation of the usefulness of six commercial agglutination assays for serologic diagnosis of toxoplasmosis. AB - Six agglutination tests for detecting Toxoplasma gondii-specific antibodies (immunoglobulin G or M) in serum were performed and compared. In total, 599 sera were examined using direct and indirect agglutination assays. Sensitivity varied from 93.7% to 100% and specificity from 97.1% to 99.2%. In a selected population with interfering diseases, the percentage of false positives ranged from 4.3% to 10.9%. Although an overall agreement of 100% was found for chronic toxoplasmosis, sensitivity for the detection of confirmed acute toxoplasmosis ranged from 86.4% to 97.3%. Regarding the large variability in terms of the performance of the 6 assays, tests based on the hemagglutination principle were found to be better than the other agglutination tests for all the panels evaluated, meaning that they could be used as qualitative or semiquantitative low-cost screening assays. PMID- 22541793 TI - Seroprevalence and isolation of Toxoplasma gondii from free-range chickens from Espirito Santo state, southeastern Brazil. AB - Prevalence of Toxoplasma gondii infection in 510 free-range (FR) chickens (380 from 33 small farms, and 130 from a slaughter house for FR chickens) from Espirito Santo state, southeastern Brazil, was investigated. Antibodies to T. gondii were sought using commercial indirect haemagglutination (IHAT, Imuno-HAI Toxo((r)), Wama Diagnostica, Sao Paulo, Brazil, cut-off 1:16) and the modified agglutination test (MAT, cut-off 1:25) tests. Attempts were made to isolate viable T. gondii from seropositive chickens by bioassay in mice. Pooled samples of brain, heart and quadriceps muscle of one thigh (total 40 g) from 64 chickens with IHAT titers of >= 1:16 were minced, digested in pepsin and bioassayed in mice. Antibodies to T. gondii were found in 40.4% (206/510) FR chickens by IHAT (titer >= 1:16) and 38.8% (198/510) by MAT (titer >= 1:25); concordance between IHAT and MAT was 81.6% (kappa index=0.614). Viable T. gondii was isolated (designated TgCkBr234-281) from 48 of 64 (75%) seropositive (IHAT titers >= 1:32) FR chickens. Most isolates of T. gondii were virulent for mice; 100% of mice inoculated with 44 of 48 isolates died of toxoplasmosis within 30 days post inoculation (p.i). An epidemiological investigation revealed that people living in rural areas have little knowledge about the parasite and about the risk of acquiring it from raw meat. Results indicated that the locally available IHAT was useful for screening of chicken sera for T. gondii antibodies. PMID- 22541795 TI - Persistent efficacy of a long acting injectable formulation of moxidectin against natural infestations of the sheep nasal bot (Oestrus ovis) in Spain. AB - Cydectin((r)) 2% LA Solution for Injection for Sheep (Pfizer Animal Health) is a long-acting (LA) formulation of moxidectin for the treatment and prevention of mixed infections of gastro-intestinal nematodes, respiratory nematodes and certain arthropod parasites in sheep. To evaluate the duration of persistent efficacy against nasal bots (Oestrus ovis), a natural exposure study was conducted in Spain during the summer of 2011. One hundred and twenty nasal bot free, Rasa Aragonesa sheep were randomly allocated to eight groups of 15 animals each. On Day 0, four groups were treated at the recommended dose rate of 1 mg moxidectin/kg bodyweight. Four groups remained untreated as negative controls. All animals were held in nasal bot-proof housing except for exposure to natural challenge when one group of treated sheep and one of group of control animals were transferred to a local pasture at either 0-20, 20-40, 40-60, or 60-80 days after treatment. Following challenge, sheep were scored for clinical signs of bot infestation, necropsied and the heads sectioned for larval recovery. Nasal bot larvae were retrieved from 7 to 11 control sheep following each exposure period indicating that adult bots were active throughout the study. In the first challenge up to 20 days after treatment, when sheep were slaughtered immediately after exposure, the majority of larvae were first instar (L1) and only 3 of the 15 control sheep were infested with second instars (L2). There was 100% efficacy against L2 and 38.1% reduction in the number of live L1 in the treated sheep but mean counts were not significantly different between treatment and control groups (P >= 0.05). For the subsequent exposure periods 20-80 days after treatment (necropsies 7-9 days after challenge), 6-10 sheep were infested with L1 and 9-11 control sheep were infested with L2 and third instars (L3). There was negligible efficacy against L1, but treatment with moxidectin resulted in 100% control of L2 and L3. These results are consistent with the biology of nasal bots and control with a systemic agent, as the slower growing L1 have limited feeding and are therefore less susceptible to systemic parasiticides. The study demonstrated that the persistent efficacy of this long-acting injectable formulation of moxidectin protects against the development of active O. ovis infestations for at least 80 days after treatment. PMID- 22541794 TI - Real-time PCR as a surveillance tool for the detection of Trichinella infection in muscle samples from wildlife. AB - Trichinella nematodes are the causative agent of trichinellosis, a meat-borne zoonosis acquired by consuming undercooked, infected meat. Although most human infections are sourced from the domestic environment, the majority of Trichinella parasites circulate in the natural environment in carnivorous and scavenging wildlife. Surveillance using reliable and accurate diagnostic tools to detect Trichinella parasites in wildlife hosts is necessary to evaluate the prevalence and risk of transmission from wildlife to humans. Real-time PCR assays have previously been developed for the detection of European Trichinella species in commercial pork and wild fox muscle samples. We have expanded on the use of real time PCR in Trichinella detection by developing an improved extraction method and SYBR green assay that detects all known Trichinella species in muscle samples from a greater variety of wildlife. We simulated low-level Trichinella infections in wild pig, fox, saltwater crocodile, wild cat and a native Australian marsupial using Trichinella pseudospiralis or Trichinella papuae ethanol-fixed larvae. Trichinella-specific primers targeted a conserved region of the small subunit of the ribosomal RNA and were tested for specificity against host and other parasite genomic DNAs. The analytical sensitivity of the assay was at least 100 fg using pure genomic T. pseudospiralis DNA serially diluted in water. The diagnostic sensitivity of the assay was evaluated by spiking 10 g of each host muscle with T. pseudospiralis or T. papuae larvae at representative infections of 1.0, 0.5 and 0.1 larvae per gram, and shown to detect larvae at the lowest infection rate. A field sample evaluation on naturally infected muscle samples of wild pigs and Tasmanian devils showed complete agreement with the EU reference artificial digestion method (k-value=1.00). Positive amplification of mouse tissue experimentally infected with T. spiralis indicated the assay could also be used on encapsulated species in situ. This real-time PCR assay offers an alternative highly specific and sensitive diagnostic method for use in Trichinella wildlife surveillance and could be adapted to wildlife hosts of any region. PMID- 22541796 TI - Ovine cutaneous myiasis: effects on production and control. AB - Ovine cutaneous myiasis ('fly strike') remains a major sheep health problem in many areas of the world. Myiasis risk is the result of a complex interaction of factors, such as fly and host abundance, host susceptibility, climate and, critically, husbandry and management strategies, all of which change seasonally in space and time. Given the complexity of the interacting factors, changes in myiasis incidence are hard to predict, as accordingly are the optimal husbandry responses required to manage the problem. Here the important risk factors are briefly reviewed and the future changes in myiasis incidence under conditions of anticipated climate change are considered. It is concluded that future work should focus in particular on evaluating the optimum use of integrated management, such as the combination of insecticide and trap use, in different environments under a range of farming regimes. PMID- 22541797 TI - Successful immunization of naturally reared pigs against porcine cysticercosis with a recombinant oncosphere antigen vaccine. AB - Taenia solium causes cysticercosis in pigs and taeniasis and neurocysticercosis in humans. Oncosphere antigens have proven to be effective as vaccines to protect pigs against an experimental infection with T. solium. A pair-matched vaccination trial field, using a combination of two recombinant antigens, TSOL16 and TSOL18, was undertaken in rural villages of Peru to evaluate the efficacy of this vaccine under natural conditions. Pairs of pigs (n=137) comprising one vaccinated and one control animal, were allocated to local villagers. Animals received two vaccinations with 200 MUg of each of TSOL16 and TSOL18, plus 5mg Quil-A. Necropsies were performed 7 months after the animals were distributed to the farmers. Vaccination reduced 99.7% and 99.9% (p<0.01) the total number of cysts and the number of viable cysts, respectively. Immunization with the TSOL16-TSOL18 vaccines has the potential to control T. solium transmission in areas where the disease is endemic, reducing the source for tapeworm infections in humans. PMID- 22541798 TI - Behaviour change communication targeting four health behaviours in developing countries: a review of change techniques. AB - Behaviour change communication is vital for increasing the enactment of particular behaviours known to promote health and growth. The techniques used to change behaviour are important for determining how successful the intervention is. In order to integrate findings from different interventions, we need to define and organize the techniques previously used and connect them to effectiveness data. This paper reviews 24 interventions and programs implemented to change four health behaviours related to child health in developing countries: the use of bed nets, hand washing, face washing and complementary feeding. The techniques employed are organized under six categories: information, performance, problem solving, social support, materials, and media. The most successful interventions use three or even four categories of techniques, engaging participants at the behavioural, social, sensory, and cognitive levels. We discuss the link between techniques and theories. We propose that program development would be more systematic if researchers considered a menu of technique categories appropriate for the targeted behaviour and audience when designing their studies. PMID- 22541799 TI - Patients' willingness and ability to participate actively in the reduction of clinical errors: a systematic literature review. AB - This systematic review identifies the factors that both support and deter patients from being willing and able to participate actively in reducing clinical errors. Specifically, we add to our understanding of the safety culture in healthcare by engaging with the call for more focus on the relational and subjective factors which enable patients' participation (Iedema, Jorm, & Lum, 2009; Ovretveit, 2009). A systematic search of six databases, ten journals and seven healthcare organisations' web sites resulted in the identification of 2714 studies of which 68 were included in the review. These studies investigated initiatives involving patients in safety or studies of patients' perspectives of being actively involved in the safety of their care. The factors explored varied considerably depending on the scope, setting and context of the study. Using thematic analysis we synthesized the data to build an explanation of why, when and how patients are likely to engage actively in helping to reduce clinical errors. The findings show that the main factors for engaging patients in their own safety can be summarised in four categories: illness; individual cognitive characteristics; the clinician-patient relationship; and organisational factors. We conclude that illness and patients' perceptions of their role and status as subordinate to that of clinicians are the most important barriers to their involvement in error reduction. In sum, patients' fear of being labelled "difficult" and a consequent desire for clinicians' approbation may cause them to assume a passive role as a means of actively protecting their personal safety. PMID- 22541800 TI - Governing at a distance: social marketing and the (bio) politics of responsibility. AB - In the recently published lectures from the College de France series, The Birth of Bio-Politics, Foucault (2009) offers his most explicit analysis of neo-liberal governmentality and its impact upon states and societies in the late twentieth century. Framed in terms of the bio-political as a mode of governance of populations and its relationship to neo-liberalism, these lectures offer a rich seam of theoretical resources with which to interrogate contemporary forms of governmentality. This paper seeks to apply these and some recent critical analysis by Foucauldian scholars, to the study of health governance, with particular reference to the use of social marketing as a strategy to improve the health of populations 'at a distance'. Reflecting a broader decollectivisation of welfare, such strategies are identified as exemplars of neo-liberal methods of governance through inculcating self management and individualisation of responsibility for health and wellbeing. Drawing on original empirical data collected with a sample of fifty long term unemployed men in 2009, this paper critically examines social marketing as a newer feature of health governance and reflects upon participants' responses to it as a strategy in the context of their wider understandings of health, choice and responsibility. PMID- 22541801 TI - Weight of communities: a multilevel analysis of body mass index in 32,814 neighborhoods in 57 low- to middle-income countries (LMICs). AB - The extent to which body mass index (BMI) varies between small areas or neighborhoods in low- to middle-income countries (LMICs) remains unknown. Further, whether such variation is reflective of characteristics of individuals living in these neighborhoods is also not clear. We estimated the extent to which there is variation in BMI is attributable to neighborhoods in 57 LMICs. The data were from non-pregnant women of reproductive age (20-49 y) participating in Demographic and Health Surveys conducted in 57 countries between 1994 and 2008. Body mass index (BMI, weight [in kg] divided by height squared [in m(2)]) was used to assess weight status. Height and weight were measured objectively by trained field investigators. Age, household wealth, education were included as individual covariates and place of residence (urban or rural) as a neighborhood level covariate. We conducted a multilevel analysis of 451,321 women (aged 20-49 y) from 32,814 neighborhoods and 57 countries. We used linear and multinomial models to partition the variation in BMI (in kg/m(2)), underweight (BMI <18.5 kg/m(2)) and overweight (BMI >=25.0 kg/m(2)) at the level of neighborhoods and countries. We also explored the heterogeneity in neighborhood variation by socioeconomic status (SES). Of the total variation in BMI 17.6% was attributable to countries (Standard Deviation [SD] 2.0, 95% credible interval [CI] 1.7, 2.4) and 10.6% (SD 1.56, 95% CI 1.54, 1.58) was attributable to neighborhoods in age adjusted models. Adjusting for individual- and neighborhood-level covariates reduced the SD attributable to countries and neighborhoods to 1.9, and 1.17, respectively. Between-country variation was 13.4% (SD 0.75, 95% CI 0.62-0.90) for underweight and 18.9% (SD 0.92, 95% CI 0.76-1.10) for overweight, and between neighborhood variation was 7.7% (SD 0.57, 95% CI 0.55-0.58) for underweight and 7.1% (SD 0.56, 95% CI 0.55-0.58) for overweight in the fully-adjusted multinomial model. In country-specific models, the neighborhood variation in BMI ranged from 0.4 SD in Central African Republic to 2.7 SD in Sierra Leone in fully-adjusted models. Our results demonstrate a considerable range in neighborhood variation in BMI. In countries with greater neighborhood variation it is possible that BMI is being influenced by local conditions more than others with lesser neighborhood variation. PMID- 22541802 TI - The association between non-medical prescription drug use, depressive symptoms, and suicidality among college students. AB - PURPOSE: Studies have substantiated a relationship between drug use, depression, and suicidality. However, little research has examined this relationship with prescription drugs. Given the prevalence of non-medical prescription drug use (NMPDU) among college students, this study explored the association between general and specific NMPDU, depressive symptoms, and suicidality. METHODS: Data from the Fall 2008 National College Health Assessment (NCHA) was utilized (N=22,783). Five separate logistic regression models were employed, with the first combining any NMPDU (antidepressants, painkillers, sedatives, and stimulants) followed by four additional regressions for each drug, and then separated by gender. Models were estimated before and after control for key covariates. RESULTS: Approximately 13% of participants reported NMPDU. After covariate adjustment, those who reported feeling hopeless, sad, depressed, or considered suicide were 1.22-1.31 times more likely to report NMPDU (p<.05). Those who reported feeling hopeless, sad, or depressed were 1.18-1.43 times more likely to report opioid painkiller use; those who reported feeling sad, depressed, or considered suicide were 1.22-1.38 times more likely to report stimulant use; those who reported being depressed were 1.36 times more likely to report sedative use; and those who reported feeling hopeless or depressed were 1.44 and 1.91 times more likely to report antidepressant use (p<.05). When the adjusted models were repeated separately by gender, results were more pronounced for females, especially for females who reported painkiller use. CONCLUSIONS: Depressive symptoms and suicidality were significantly associated with greater odds of any NMPDU, with painkiller use (especially for females) representing the greatest correlate among college students. Results suggest that students may be inappropriately self-medicating psychological distress with prescription medications. PMID- 22541803 TI - Senescence and steroid hormone receptor reactivities in accessory sex glands of elderly rats (Sprague-Dawley) following exogenous hormonal therapy. AB - The aim of this study was to characterize the stromal and epithelial distribution of AR, ERalpha and ERbeta reactivities in the different accessory sex glands of elderly rats and during strong hormonal changes. Ten month old male rats were divided into six senile groups and submitted to treatment: Senile/Control group (SC); Senile/Testosterone group (ST): Senile/Estrogen group (SE); Castrated group (CA); Castrated/Testosterone group (CT); Castrated/Estrogen group (CE). After a 30-day treatment, the prostatic ventral lobe (VL), dorsal lobe (DL) and coagulating gland (CG) samples were processed for immunohistochemistry and Western Blotting. The results showed that AR immunoreactivity was characterized in the epithelium of VL and DL in senile/control rats and senile rats submitted to exogenous hormonal therapy. AR reactivity in the coagulating gland was verified predominantly in the stromal cells in the different experimental groups. ERalpha reactivity occurred predominantly in the stromal compartment in all accessory sex glands. In the DL and CG, ERalpha immunoreactivities were intense in the groups which received testosterone (ST) and estrogen (SE). ERbeta immunoreactivity in the CG was verified in the stromal compartment in the different experimental groups, showing a positive response to both increased testosterone and estrogen levels. ERbeta reactivity, in the DL, was intensified in the stroma of senile rats with higher serum testosterone levels, and in senile rats with increased serum estrogen levels, especially in the glandular epithelium. Thus, the results revealed different distribution pattern of steroid hormone receptors in each one of the prostatic lobes in senescence, especially in the prostate dorsal lobe and coagulating gland, which is a fundamental factor due to the fact that major prostatic diseases occur in a later period of life. PMID- 22541804 TI - Morphometric analysis of terminal villi and gross morphological changes in the placentae of term idiopathic intrauterine growth restriction. AB - The aim of this study is to compare the gross morphology of the placentae and the morphometry of terminal villi and terminal villous capillaries in pregnancies complicated by idiopathic intrauterine growth restriction (IUGR) with those of normal pregnancies. 75 placentae were collected between April 2010 and March 2011. 50 placentae were associated with idiopathic IUGR and 25 were from controls. Insertion of cords, placental weights and diameters were noted. Hematoxylin and eosin-stained wax sections were analyzed stereologically. Growth of terminal villi and fetal capillaries was assessed by estimating total and mean surface areas. Villous capillarization was monitored using capillary:villus surface ratio. Measurements were done using image analysis system. In comparison with the control group, idiopathic IUGR placentae are significantly smaller (p=0.000) and lighter (p=0.000). In majority of IUGR (68%) and control (60%) cases, eccentric insertion of cord is noted. In idiopathic IUGR group, there is a significant decrease in the total areas of both terminal villi (p=0.048) and their capillaries (p=0.000) and a significant decrease in number of both terminal villi (p=0.000) and their capillaries (p=0.001), also, capillarization index is significantly smaller (p=0.038). Idiopathic IUGR is associated with reduced growth of placental terminal villi and fetal capillaries and this is accompanied by changes in measures of villous capillarization as compared with those of control placentae. Further investigations of idiopathic IUGR placentae are necessary, especially considering the histopathological changes that could affect the fetomaternal exchange, with a note that strict distinction should be made between idiopathic and nonidiopathic IUGR placentae. PMID- 22541808 TI - Bifrontal meningioma presenting as postpartum depression with psychotic features. PMID- 22541809 TI - Comparison of "push" and "pull" methods for impacted fetal head extraction during cesarean delivery. AB - OBJECTIVE: To compare maternal and neonatal outcomes associated with the "push" and "pull" methods for impacted fetal head extraction during cesarean delivery. METHODS: A prospective study was conducted at Imam Reza Hospital, Kermanshah, Iran, from April 2006 to March 2008. After failed vacuum extraction, women with obstructed labor caused by impacted fetal head were randomly assigned to deliver via the push method (n=35) or the pull method (n=37). The outcomes investigated included operation time, operative blood loss, incidence of extension of the uterine incision, and postpartum fever. Data were analyzed using chi(2) and Student t tests. RESULTS: Mean operative time and incidence of extension of the uterine incision were significantly increased in the group that delivered via the push method (P<0.001). There were no significant differences in the other maternal and neonatal morbidities between the groups, although there was 1 case of neonatal femoral fracture in the pull group. CONCLUSION: Although the pull method may lead to some neonatal complications, it is associated with lower maternal morbidity than the push method when used for impacted fetal head extraction during cesarean delivery. PMID- 22541810 TI - DTI reveals hypothalamic and brainstem white matter lesions in patients with idiopathic narcolepsy. AB - BACKGROUND: Symptomatic narcolepsy is often related to hypothalamic, pontine, or mesencephalic lesions. Despite evidence of disturbances of the hypothalamic hypocretin system in patients with idiopathic narcolepsy, neuroimaging in patients with idiopathic narcolepsy revealed conflicting results and there is limited data on possible structural brain changes that might be associated with this disorder. METHODS: We investigated with diffusion tensor imaging (DTI) whether microstructural abnormalities in the brain of eight patients with idiopathic narcolepsy with cataplexy are detectable compared to 12 healthy controls using a 1.5T MRI scanner. Whole-head DTI scans were analyzed without an a priori hypothesis. Voxelwise statistical analysis of fractional anisotropy (FA) data was performed using Tract-Based Spatial Statistics (TBSS), a non-linear analysis approach. RESULTS: Patients with narcolepsy showed microstructural white matter changes in the right hypothalamus as well as in the left mesencephalon, pons, and medulla oblongata. Additionally, areas in the left temporal lobe, the pre- and postcentral gyrus, the frontal and parietal white matter, the corona radiata, the right internal capsule, and the caudate nucleus had altered microstructure in patients with narcolepsy. CONCLUSIONS: Our study shows widespread microstructural white matter changes that are not visible on conventional MRI scans in patients with idiopathic narcolepsy. In support of the evidence from patients with symptomatic narcolepsy, we found microstructural changes in the hypothalamus, mesencephalon, pons, and medulla oblongata. Changes are in accordance with disturbances of the hypothalamic hypocretin system and its projections to mesencephalic and pontine areas regulating REM sleep. PMID- 22541811 TI - Reaction pathway and free energy profile determined for specific recognition of oligosaccharide moiety of carboxypeptidase Y. AB - The interaction of mannose specific lectin (from Lens culinaris, LcL) with the carbohydrate moiety of carboxypeptidase Y (CaY) was studied using both atomic force microscope (AFM) and quartz crystal microbalance with dissipation monitoring (QCM-D). The AFM enables to determine the positions of energy barriers present in the energy landscape of the single complex undergoing dissociation. The QCM-D measurements allow the estimation of the quantitative parameters characterizing the kinetics of the studied molecular interaction (namely the association and dissociation rate constants and the association constant). The use of both methods not only delivers the complementary characterization of kinetic and thermodynamic parameters but also permits to investigate the mechanism of the binding and unbinding of the molecules. The results for LcL were compared with those obtained for concanavalin A i.e. lectin, which interacts with the carbohydrate moiety on a similar way. PMID- 22541812 TI - Gold-nanobeacons for real-time monitoring of RNA synthesis. AB - Measuring RNA synthesis and, when required, the level of inhibition, is crucial towards the development of practical strategies to evaluate silencing efficiency of gene silencing approaches. We developed a direct method to follow RNA synthesis in real time based on gold nanoparticles (AuNPs) functionalized with a fluorophore labeled hairpin-DNA, i.e. gold-nanobeacon (Au-nanobeacon). Under hairpin configuration, proximity to gold nanoparticles leads to fluorescence quenching; hybridization to a complementary target restores fluorescence emission due to the Au-nanobeacons' conformational reorganization that causes the fluorophore and the AuNP to part from each other, yielding a quantitative response. With this reporter Au-nanobeacon we were able to measure the rate of in vitro RNA synthesis (~10.3 fmol of RNA per minute). Then, we designed a second Au nanobeacon targeting the promoter sequence (inhibitor) so as to inhibit transcription whilst simultaneously monitor the number of promoters being silenced. Using the two Au-nanobeacons in the same reaction mixture, we are capable of quantitatively assess in real time the synthesis of RNA and the level of inhibition. The biosensor concept can easily be extended and adapted to situations when real-time quantitative assessment of RNA synthesis and determination of the level of inhibition are required. In fact, this biosensor may assist the in vitro evaluation of silencing potential of a given sequence to be later used for in vivo gene silencing. PMID- 22541813 TI - Label-free, multiplexed detection of bacterial tmRNA using silicon photonic microring resonators. AB - A label-free biosensing method for the sensitive detection and identification of bacterial transfer-messenger RNA (tmRNA) is presented employing arrays of silicon photonic microring resonators. Species specific tmRNA molecules are targeted by complementary DNA capture probes that are covalently attached to the sensor surface. Specific hybridization is monitored in near real-time by observing the resonance wavelength shift of each individual microring. The sensitivity of the biosensing platform allowed for detection down to 53 fmol of Streptococcus pneumoniae tmRNA, equivalent to approximately 3.16*10(7) CFU of bacteria. The simplicity and scalability of this biosensing approach makes it a promising tool for the rapid identification of different bacteria via tmRNA profiling. PMID- 22541815 TI - Automated capillary electrophoresis with on-line preconcentration by solid phase extraction using a sequential injection manifold and contactless conductivity detection. AB - An extension of a capillary electrophoresis instrument coupled to a sequential injection analysis manifold was developed for automated measurements with on-line solid-phase extraction preconcentration. An in-house built capacitively coupled contactless conductivity detector was employed for sensitive detection with narrow capillaries of 25 MUm internal diameter. The system was assembled into standardized 19 in. frames and racks for easy transport and mobile deployment. The system can be left running unattendedly without manual intervention with good operation stability. To demonstrate the application of the system, a method for the determination of four drugs, namely ibuprofen, diclofenac, naproxen and bezafibrate, was developed with enrichment factors of up to several hundreds. Detection of the drug residues down to the nM-scale was found possible and the method was found suitable for the detection of ibuprofen in the waste water of a hospital in Hanoi. PMID- 22541814 TI - Thrombin induces heme oxygenase-1 expression in human synovial fibroblasts through protease-activated receptor signaling pathways. AB - INTRODUCTION: Thrombin is a key factor in the stimulation of fibrin deposition, angiogenesis, and proinflammatory processes. Abnormalities in these processes are primary features of osteoarthritis (OA). Heme oxygenase (HO)-1 is a stress inducible rate-limiting enzyme in heme degradation that confers cytoprotection against oxidative injury. Here, we investigated the intracellular signaling pathways involved in thrombin-induced HO-1 expression in human synovial fibroblasts (SFs). METHODS: Thrombin-mediated HO-1 expression was assessed with quantitative real-time (q)PCR. The mechanisms of action of thrombin in different signaling pathways were studied by using Western blotting. Knockdown of protease activated receptor (PAR) proteins was achieved by transfection with siRNA. Chromatin immunoprecipitation assays were used to study in vivo binding of Nrf2 to the HO-1 promoter. Transient transfection was used to examine HO-1 activity. RESULTS: Osteoarthritis synovial fibroblasts (OASFs) showed significant expression of thrombin, and expression was higher than in normal SFs. OASFs stimulation with thrombin induced concentration- and time-dependent increases in HO-1 expression. Pharmacologic inhibitors or activators and genetic inhibition by siRNA of protease-activated receptors (PARs) revealed that the PAR1 and PAR3 receptors, but not the PAR4 receptor, are involved in thrombin-mediated upregulation of HO-1. Thrombin-mediated HO-1 expression was attenuated by thrombin inhibitor (PPACK), PKCdelta inhibitor (rottlerin), or c-Src inhibitor (PP2). Stimulation of cells with thrombin increased PKCdelta, c-Src, and Nrf2 activation. CONCLUSION: Our results suggest that the interaction between thrombin and PAR1/PAR3 increases HO-1 expression in human synovial fibroblasts through the PKCdelta, c-Src, and Nrf2 signaling pathways. PMID- 22541816 TI - An efficient extraction method for quantitation of adenosine triphosphate in mammalian tissues and cells. AB - Firefly bioluminescence is widely used in the measurement of adenosine 5' triphosphate (ATP) levels in biological materials. For such assays in tissues and cells, ATP must be extracted away from protein in the initial step and extraction efficacy is the main determinant of the assay accuracy. Extraction reagents recommended in the commercially available ATP assay kits are chaotropic reagents, trichloroacetic acid (TCA), perchloric acid (PCA), and ethylene glycol (EG), which extract nucleotides through protein precipitation and/or nucleotidase inactivation. We found that these reagents are particularly useful for measuring ATP levels in materials with relatively low protein concentrations such as blood cells, cultured cells, and bacteria. However, these methods are not suitable for ATP extraction from tissues with high protein concentrations, because some ATP may be co-precipitated with the insolubilized protein during homogenization and extraction, and it could also be precipitated by neutralization in the acid extracts. Here we found that a phenol-based extraction method markedly increased the ATP and other nucleotides extracted from tissues. In addition, phenol extraction does not require neutralization before the luciferin-luciferase assay step. ATP levels analyzed by luciferase assay in various tissues extracted by Tris-EDTA-saturated phenol (phenol-TE) were over 17.8-fold higher than those extracted by TCA and over 550-fold higher than those in EG extracts. Here we report a simple, rapid, and reliable phenol-TE extraction procedure for ATP measurement in tissues and cells by luciferase assay. PMID- 22541817 TI - Fabrication of novel nanoporous array anodic alumina solid-phase microextraction fiber coating and its potential application for headspace sampling of biological volatile organic compounds. AB - In the study, nanoporous array anodic alumina (NAAA) prepared by a simple, rapid and stable two-step anodic oxidization method was introduced as a novel solid phase microextraction (SPME) fiber coating. The regular nanoporous array structure and chemical composition of NAAA SPME fiber coating was characterized and validated by scanning electron microscopy and energy dispersive spectroscopy, respectively. Compared with the commercial polydimethylsiloxane (PDMS) SPME fiber coating, NAAA SPME fiber coating achieved the higher enrichment capability (1.7 4.7 folds) for the mixed standards of volatile organic compounds (VOCs). The selectivity for volatile alcohols by NAAA SPME fiber coating demonstrated an increasing trend with the increasing polarity of alcohols caused by the gradually shortening carbon chains from 1-undecanol to 1-heptanol or the isomerization of carbon chains of some typical volatile alcohols including 2-ethyl hexanol, 1 octanol, 2-phenylethanol, 1-phenylethanol, 5-undecanol, 2-undecanol and 1 undecanol. Finally, NAAA SPME fiber coating was originally applied for the analysis of biological VOCs of Bailan flower, stinkbug and orange peel samples coupled with gas chromatography-mass spectrometry (GC-MS) detection. Thirty, twenty-seven and forty-four VOCs of Bailan flower, stinkbug and orange peel samples were sampled and identified, respectively. Moreover, the contents of trace 1-octanol and nonanal of real orange peel samples were quantified for the further method validation with satisfactory recoveries of 106.5 and 120.5%, respectively. This work proposed a sensitive, rapid, reliable and convenient analytical method for the potential study of trace and small molecular biological VOCs by the novel NAAA SPME fiber coating. PMID- 22541818 TI - Development of a fiber coating based on molecular sol-gel imprinting technology for selective solid-phase micro extraction of caffeine from human serum and determination by gas chromatography/mass spectrometry. AB - In this work, a molecular sol-gel imprinting approach has been introduced to produce a fiber coating for selective direct immersion solid-phase microextraction (SPME) of caffeine. The polymerization mixture was composed of vinyl trimethoxysilane and methacrylic acid as vinyl sol-gel precursor and functional monomer, respectively. Caffeine was used as template molecule during polymerization process. The prepared fibers could be coupled directly to gas chromatography/mass spectrometry (GC/MS) and used for trace analysis of caffeine in a complex sample such as human serum. The parameters influencing SPME such as time, temperature and stirring speed were optimized. The prepared coating showed good selectivity towards caffeine in the presence of some structurally related compounds. Also, it offered high imprinting capability in comparison to bare fiber and non-imprinted coating. Linear range for caffeine detection was 1-80 MUg mL(-1) and the limit of detection was 0.1 MUg mL(-1). The intra-day and inter-day precisions of the peak areas for five replicates were 10 and 16%, respectively. PMID- 22541820 TI - Automatic microemulsion preparation for metals determination in fuel samples using a flow-batch analyzer and graphite furnace atomic absorption spectrometry. AB - The principal thermodynamic advantages of using microemulsions over standard emulsions for flow metal analysis are the greatly increased analyte stability and emulsive homogeneity that improve both the ease of sample preparation, and the analytical result. In this study a piston propelled flow-batch analyzer (PFBA) for the determination of Cu, Cr and Pb in gasoline and naphtha by graphite furnace atomic absorption spectrometry (GF AAS) was explored. Investigative phase modeling for low dilution was conducted both for gasoline and naphtha microemulsions. Rheological considerations were also explored including a mathematical flow derivation to fine tune the system's operational parameters, and the GF AAS coupling. Both manual and automated procedures for microemulsion preparation were compared. The results of the paired t test at a 95% confidence level showed no significant differences between them. Further recovery test results confirmed a negligible matrix effect of the sample on the analyte absorption signals and an efficient stabilization of the samples (with metals) submitted to microemulsion treatment. The accuracy of the developed procedure was attested by good recovery percentages in the ranges of 100.0+/-3.5% for Pb in the naphtha samples, and 100.2+/-3.4% and 100.7+/-4.6% for Cu and Cr, respectively in gasoline samples. PMID- 22541819 TI - An electrochemically enhanced solid-phase microextraction approach based on molecularly imprinted polypyrrole/multi-walled carbon nanotubes composite coating for selective extraction of fluoroquinolones in aqueous samples. AB - In this study, an electrochemically enhanced solid-phase microextraction (EE SPME) approach based on molecularly imprinted polypyrrole/multi-walled carbon nanotubes (MIPPy/MWCNTs) composite coating on Pt wire was developed for selective extraction of fluoroquinolone antibiotics (FQs) in aqueous samples. During the extraction, a direct current potential was applied to the MIPPy/MWCNTs/Pt fiber as working electrode in a standard three-electrode system, FQ ions suffered electrophoretic transfer to the coating surface and then entered into the shape complimentary cavities by hydrogen-bonding and ion-exchange interactions. After EE-SPME extraction, the fiber was desorbed with desorption solvent for high performance liquid chromatography (HPLC) analysis. Some parameters influencing EE SPME extraction such as applied potential, extraction time, solution pH, ionic strength, and desorption solvent were optimized. EE-SPME showed good selectivity and higher extraction efficiency to FQs compared with that of traditional solid phase microextraction. EE-SPME coupled with HPLC to determine FQs in water samples, the limits of detection (S/N=3) for the selected FQs are 0.5-1.9 MUg L( 1). The proposed method was successfully used to the analysis of FQs spiked urine and soil samples, with recoveries of 85.1-94.2% for the urine samples and 89.8 95.5% for the soil samples. PMID- 22541821 TI - A novel approach to the uniform distribution of liquid in multi-channel (electrochemical) flow-through cells. AB - Four-channel flow-through electrochemical cell working in thin-layer regime was designed, fabricated and characterized experimentally and in computational fluid dynamics (CFD) simulations. The new principle of operation allows reproducible splitting of a stream of liquid into multiple flow channels. Systems comprising of 2-, 3-, 4- and 8-channels were tested. The proper function of the cell is given by the ratio of the cross-sections of the fluidic element collecting chamber and the particular flow paths among which the liquid is distributed. Suitable flow rates providing uniform liquid distribution were evaluated and the results were compared to CFD modeling. The flow-through cells designed according to the proposed principle can be simply incorporated in automated routine analysis as only one inlet and one common outlet are required. PMID- 22541822 TI - Multiple reaction monitoring-based determination of bovine alpha-lactalbumin in infant formulas and whey protein concentrates by ultra-high performance liquid chromatography-tandem mass spectrometry using tryptic signature peptides and synthetic peptide standards. AB - The determination of alpha-lactalbumin in various dairy products attracts wide attention in multidiscipline fields because of its nutritional and biological functions. In the present study, we quantified the bovine alpha-lactalbumin in various infant formulas and whey protein concentrates using ultra-high performance liquid chromatography coupled to tandem mass spectrometer in multiple reaction monitoring mode. Bovine alpha-lactalbumin was quantified by employing the synthetic internal standard based on the molar equivalent relationship among the internal standard, bovine alpha-lactalbumin and their signature peptides. This study especially focused on the recovery rates of the sample preparation procedure and robust quantification of total bovine alpha-lactalbumin in its native and thermally denatured form with a synthetic internal standard KILDKVGINNYWLAHKALCSE. The observed recovery rates of bovine alpha-lactalbumin ranged from 95.8 to 100.6% and the reproducibility was excellent (RSD<6%) at different spiking levels. The limit of quantitation is 10 mg/100 g for infant formulas and whey protein concentrates. In order to validate the applicability of the method, 21 brands of infant formulas were analyzed. The acquired contents of bovine alpha-lactalbumin were 0.67-1.84 g/100g in these infant formulas in agreement with their label claimed values. The experiment of heat treatment time showed that the loss of native alpha-lactalbumin enhanced with an increasing intensity of heat treatment. Comparing with Ren's previous method by analysis of only native bovine alpha-lactalbumin, the present method at the peptide level proved to be highly suitable for measuring bovine alpha-lactalbumin in infant formulas and whey protein concentrates, avoiding forgoing the thermally induced denatured alpha-lactalbumin caused by the technological processing. PMID- 22541823 TI - Rapid and precise determination of Sr and Nd isotopic ratios in geological samples from the same filament loading by thermal ionization mass spectrometry employing a single-step separation scheme. AB - Thermal ionization mass spectrometry (TIMS) offers the excellent precision and accuracy of the Sr and Nd isotopic ratio analysis for geological samples, but this method is labour intensive, expensive and time-consuming. In this study, a new analytical protocol by TIMS is presented that aims at improving analytical efficiency and cutting down experimental cost. Using the single-step cation exchange resin technique, mixed Sr and rare earth elements (REEs) fractions were separated from matrix and evaporated to dryness. Afterwards, mixed Sr+REEs fractions were dissolved and loaded onto the same Re filament using 1 MUL of 2 M HCl. Then, Sr and Nd were sequentially measured without venting using TIMS. In contrast to conventional TIMS methods, the merits of this analytical protocol are its cost- and time-saving adaptations. The applicability of our method is evaluated by replicated measurements of (87)Sr/(86)Sr and (143)Nd/(144)Nd for nine international silicate rock reference materials, spanning a wide range of bulk compositions. The typical internal precision in this study is ca. 0.001% (RSE) for (87)Sr/(86)Sr and (143)Nd/(144)Nd; the analytical results obtained for these standard rocks show a good agreement with reported values, indicating the effectiveness of the proposed method. PMID- 22541824 TI - Lateral flow dipstick test for genotyping of 15 beta-globin gene (HBB) mutations with naked-eye detection. AB - For definitive diagnosis of thalassemia carriers and patients, as well as for prenatal diagnosis, genotype analysis is of fundamental importance. We report a dry-reagent, lateral flow dipstick test that enables visual genotyping (detection by naked eye) of 15 mutations common in Mediterranean populations in the beta globin gene (HBB). The method comprises 3 simple steps: (i) PCR amplification of a single 1896 bp segment of the beta globin gene flanking all 15 mutations; (ii) a multiplex (10-plex and/or 30-plex) primer extension reaction of the unpurified amplification product using allele-specific primers. Biotin is incorporated in the extended product; (iii) a dry-reagent multi-allele (10-plex) dipstick assay for visual detection of the primer extension reaction products within minutes. The total time required for PCR, primer extension reaction and the dipstick assay is ~2 h. The method was evaluated by genotyping 45 DNA samples of known genotypes and 54 blind samples. The results were fully concordant with reference methods. The method is simple, rapid, and cost-effective. Detection by the dipstick assay does not require specialized instrumentation or highly qualified personnel. The proposed method could be a particularly useful tool in laboratories with limited resources and a basis for point-of-care diagnostics especially in combination with PCR amplification from whole blood. PMID- 22541825 TI - Graphene oxide-based biosensor for sensitive fluorescence detection of DNA based on exonuclease III-aided signal amplification. AB - Based on the super fluorescence quenching efficiency of graphene oxide and exonuclease III aided signal amplification, we develop a facile, sensitive, rapid and cost-effective method for DNA detection. In the presence of target DNA, the target-probe hybridization forms a double-stranded structure and exonuclease III catalyzes the stepwise removal of mononucleotides from the blunt 3' termini of probe, resulting in the recycling of the target DNA and signal amplification. Therefore, our proposed sensor exhibits a high sensitivity towards target DNA with a detection limit of 20 pM, which was even lower than previously reported GO based DNA sensors without enzymatic amplification, and provides a universal sensing platform for sensitive detection of DNA. PMID- 22541826 TI - Determination of bismuth in open ocean waters by inductively coupled plasma sector-field mass spectrometry after chelating resin column preconcentration. AB - A novel low-blank method is described for the analysis of bismuth in seawater based on preconcentration using an ethylenediaminetriacetic acid chelating resin column followed by determination with inductively coupled plasma sector-field mass spectrometry (ICPSFMS). A sample is siphoned into and drains through the column with the flow rate being kept constant by using a flotation device. Bi in 250 mL of acidified seawater is extracted onto the column in this process and eluted with 2 mL of 3 M HNO(3) followed by 3 mL of ultra-high purity water. The concentration of Bi in the eluate is measured by ICPMS. The benefits of the method compared to others are its simplicity, a smaller amount of seawater, and lower procedural blanks and detection limits at pg kg(-1) levels. Data on dissolved Bi in open ocean reference samples of SAFe and GEOTRACES programs are presented for the first time. PMID- 22541827 TI - Determination of creatine and phosphocreatine in muscle biopsy samples by capillary electrophoresis with contactless conductivity detection. AB - A capillary electrophoresis method with contactless conductivity detection was evaluated as a new approach for quantification of creatine and phosphocreatine in human quadriceps femoris biopsy samples. The running buffers employed consisted of 1 M acetic acid at a pH of 2.3 for the determination of creatine and 50 mM 3 (N-morpholino)propanesulfonic acid/30 mM histidine at a pH of 6.4 for the determination of phosphocreatine in the centrifuged muscle extracts. The limits of detection for creatine and phosphocreatine were found to be 2.5 and 1.0 MUM, respectively. Creatine and phosphocreatine were determined in six human muscle biopsy samples and the results were found comparable to those of a standard enzymatic assay. The procedures developed for creatine and phosphocreatine also allow the determination of creatinine as well as adenosine diphosphate and adenosine triphosphate. PMID- 22541828 TI - Intrasubject repeatability of corneal morphology measurements obtained with a new Scheimpflug photography-based system. AB - PURPOSE: To evaluate in normal healthy eyes the intrasubject repeatability of anterior and posterior corneal curvature measurements and other anatomic anterior segment measurements obtained with a new topography system combining Scheimpflug photography and Placido-disk technology. SETTING: Vissum Corp., Alicante, Spain. DESIGN: Evaluation of technology. METHODS: All eyes received a comprehensive ophthalmologic examination including anterior segment analysis with the Sirius system. Three consecutive measurements were performed with the device to assess the intrasubject repeatability of the following parameters: anterior and posterior corneal curvature and shape factor, white-to-white (WTW) corneal diameter, central and minimum corneal thickness, and anterior chamber depth (ACD). The within-subject standard deviation (S(w)) and intraclass correlation coefficient (ICC) were calculated. RESULTS: This study included 117 eyes of 117 subjects (mean age 42 years; range 7 to 80 years). For anterior and posterior corneal curvatures, the S(w) was 0.04 mm or lower and the ICC was higher than 0.990. For shape-factor measurements, the S(w) was below 0.08 in all cases and ICC values ranged between 0.909 and 0.994. Significantly larger S(w) values were found for the anterior and posterior shape factor calculated for 8.0 mm compared with 4.5 mm (P<.01). An S(w) value below 3 MUm was observed for the central and minimum thickness, with ICC values close to 1. The mean S(w) for ACD and WTW was below 0.1 mm. CONCLUSION: In healthy eyes, the new topography system provided repeatable measurements of several anterior segment parameters, including anterior and posterior curvature and pachymetry. PMID- 22541829 TI - Evidence-based guidelines for cataract surgery: guidelines based on data in the European Registry of Quality Outcomes for Cataract and Refractive Surgery database. AB - In March 2008, the European Registry of Quality Outcomes for Cataract and Refractive Surgery (EUREQUO) commenced. This 3-year project was cofunded by the European Union (EU) and the European Society of Cataract & Refractive Surgeons (ESCRS). The ESCRS became the lead partner in the project with 11 national societies as associated partners. The aims of the project were to improve treatment and standards of care for cataract and refractive surgery and to develop evidence-based guidelines for cataract and refractive surgery across Europe. Surgeons from all participating societies contributed to the database, which contained data on 820,000 cataract surgeries in November 2011. The present guidelines are based on data entered from January 1, 2009, to August 28, 2011 (523,921 cataract extractions). The guidelines include only those steps in the cataract surgery process that can be analyzed by the database. PMID- 22541831 TI - Model evaluation of plant metal content and biomass yield for the phytoextraction of heavy metals by switchgrass. AB - To better understand the ability of switchgrass (Panicum virgatum L.), a perennial grass often relegated to marginal agricultural areas with minimal inputs, to remove cadmium, chromium, and zinc by phytoextraction from contaminated sites, the relationship between plant metal content and biomass yield is expressed in different models to predict the amount of metals switchgrass can extract. These models are reliable in assessing the use of switchgrass for phytoremediation of heavy-metal-contaminated sites. In the present study, linear and exponential decay models are more suitable for presenting the relationship between plant cadmium and dry weight. The maximum extractions of cadmium using switchgrass, as predicted by the linear and exponential decay models, approached 40 and 34 MUg pot(-1), respectively. The log normal model was superior in predicting the relationship between plant chromium and dry weight. The predicted maximum extraction of chromium by switchgrass was about 56 MUg pot(-1). In addition, the exponential decay and log normal models were better than the linear model in predicting the relationship between plant zinc and dry weight. The maximum extractions of zinc by switchgrass, as predicted by the exponential decay and log normal models, were about 358 and 254 MUg pot( 1), respectively. To meet the maximum removal of Cd, Cr, and Zn, one can adopt the optimal timing of harvest as plant Cd, Cr, and Zn approach 450 and 526 mg kg( 1), 266 mg kg(-1), and 3022 and 5000 mg kg(-1), respectively. Due to the well known agronomic characteristics of cultivation and the high biomass production of switchgrass, it is practicable to use switchgrass for the phytoextraction of heavy metals in situ. PMID- 22541830 TI - The protective role of vitamin E on the fatty acid composition of phospholipid structure in gill and liver tissues of Oreochromis niloticus exposed to deltamethrin. AB - Deltamethrin is a commonly used pyrethroid pesticide. Vitamin E is a antioxidant that plays an important role in protecting cells against toxicity by inactivating free radicals generated following pesticides exposure. Therefore, in the present study, it was evaluated whether deltamethrin induced changes on the fatty acid composition of phospholipid in gill and liver tissues in Oreochromis niloticus and, the possible protective effect of vitamin E against deltamethrin was determined. Fish was fed with no pesticide+control diet, no pesticide+vitamin E supplemented diet, 1.45 MUg/l deltamethrin+control diet, 1.45 MUg/l deltamethrin+vitamin E-supplemented diet for twenty days. Pesticide and diet quality made an impact on the fatty acid composition of phospholipid. In treatments of deltamethrin, group fed with control diet showed much greater damage in comparison with group fed with vitamin E supplemented diet. The results indicated that the deltamethrin led to an increase in the percentages of total SFAs (saturated fatty acids) and total MUFAs (monounsaturated fatty acids) and a decrease in total PUFAs (polyunsaturated fatty acids) in the gill tissues. However, coadministration of deltamethrin and vitamin E showed decrease in the percentages of saturated fatty acids and increase in the percentages of polyunsaturated fatty acids in the gill tissues. In group fed with control diet, deltamethrin led to a decrease in the percentage of SFAs and a increase in total MUFAs in the liver. Coadministration of deltamethrin and vitamin E showed increase in the percentages of polyunsaturated fatty acids in the liver tissues. These results have demonstrated that administration of vitamin E along with deltamethrin decreases the peroxidation of unsaturated fatty acids and thus protects the cell membranes. PMID- 22541832 TI - Timing isn't everything: donor heart allocation in the present LVAD era. PMID- 22541833 TI - Transplant registrants with implanted left ventricular assist devices have insufficient risk to justify elective organ procurement and transplantation network status 1A time. AB - OBJECTIVES: The goal of this research was to identify disparities in risk within heart transplant urgency designations. BACKGROUND: Patients with left ventricular assist devices (LVADs) are given 30 days of elective status 1A time. This allowance may create competition for organs between stable LVAD-supported registrants and less stable registrants listed status 1A or 1B. METHODS: The Scientific Registry of Transplant Recipients database was analyzed for all status 1A and 1B listings between 2005 and 2010. Cox models were used to estimate the relative and absolute risk of adverse events (death or delisting as too ill) during status 1A or 1B listing. RESULTS: Status 1A registrants supported with dual inotropes and right heart monitoring had a higher risk of adverse events compared to those supported with implanted LVADs using elective 1A time (hazard ratio: 3.2; 95% confidence interval: 1.8 to 5.7). The 30-day risk of events was 1% (95% confidence interval: 0.1% to 3%) for implanted LVADs using elective 1A time and 6% (95% confidence interval: 4% to 8%) for dual inotrope support. Registrants listed with paracorporeal ventricular assist devices had a higher risk of adverse events (hazard ratio: 9.1; p < 0.0001) compared with registrants with implanted LVADs using elective 1A time. The odds of transplant were higher for implanted LVADs (odds ratio: 1.5; p < 0.0001) compared with dual-inotrope and intra-aortic balloon pump support. CONCLUSIONS: The historic allowance for 30 days of elective status 1A time for implanted LVADs creates disparities in risk among status 1A registrants. The allowance of 30 days of elective status 1A time should not be allocated to stable registrants with implanted LVADs. Registrants supported with paracorporeal ventricular assist devices should be listed status 1A indefinitely. PMID- 22541834 TI - Risk assessment for continuous flow left ventricular assist devices: does the destination therapy risk score work? An analysis of over 1,000 patients. AB - OBJECTIVES: This study sought to assess the utility of the Destination Therapy Risk Score (DTRS) in patients with continuous flow left ventricular assist devices (LVAD). BACKGROUND: The DTRS was developed to predict the risk of 90-day in-hospital mortality with pulsatile flow LVAD as destination therapy (DT). Despite ongoing use in patients with continuous flow devices, its utility has not been studied in such populations. METHODS: The DTRS was determined in 1,124 patients with the continuous flow HeartMate II (Thoratec Corporation, Pleasanton, California) LVAD as a bridge to transplant (BTT, n = 486) and DT (n = 638) and 114 DT patients with the pulsatile flow HeartMate XVE (Thoratec Corporation). Patients were divided into risk groups based on DTRS: low (0-8), medium (9-16), and high (>16). RESULTS: The 90-day in-hospital mortality for low-, medium-, and high-risk groups was 8%, 7%, and 16%, respectively, for BTT patients; 9%, 12%, and 19%, respectively, for DT patients; and 11%, 18%, and 25%, respectively, for XVE DT patients. The high-risk groups had more than a 2-fold increased risk of mortality compared with the low-risk groups. However, the area under the receiver operating characteristic curve for 90-day in-hospital mortality yielded modest values ranging from 0.54 to 0.58 for the HeartMate II BTT and DT groups, respectively. Survival rates over 2 years were statistically significantly different as stratified by the 3 DTRS groups for patients implanted for DT but not for BTT. CONCLUSIONS: DTRS provides poor discrimination of mortality for BTT patients and only modest discrimination for DT patients receiving continuous flow LVAD. PMID- 22541835 TI - Persistence and compliance of medications used in the treatment of osteoporosis- analysis using a large scale, representative, longitudinal German database. AB - OBJECTIVE: Osteoporosis can be effectively treated with a number of medications. However, high persistence and compliance are required to assure efficacy. This study analyses persistence and compliance with a variety of medical interventions including p.o., i.v. and s.c. administrations in Germany. METHODS: This retrospective cohort study used a representative longitudinal database (IMS(r) LRx) comprising longitudinal prescription data for Germany from almost 80% of all German prescriptions of members of the German statutory health insurance system. Persistence is defined as the proportion of patients who remained on their initially prescribed therapy at 1 year. Compliance is measured indirectly based on the medication possession ratio (MPR). RESULTS: A total of more than 1 million patients (1,107,482) for the period 07/2007 - 06/2009 was identified in the database who received a prescription for a bisphosphonate, strontium or PTH. Of these, 268,568 patients fulfilled further inclusion criteria and were included in the persistence and compliance analysis. At 12 months the proportion of patients that remained on treatment were 65.6% for zoledronate 5 mg; 56.6% for ibandronate i.v. 3 mg; 54.7% for PTH (teriparatide and 1-84 PTH), 51.0% for ibandronate 150 mg p.o.; 44.8% for alendronate 70 mg; 43.4% for etidronate. Other values were risedronate plus calcium 42.3%; alendronate plus vitamin D 37.8%; risedronate 35 mg 35.2%; risedronate 5 mg 30.6%; strontium ranelate 31.4% and alendronate 10 mg 17.3%. CONCLUSION: Persistence and compliance during the treatment of osteoporosis were found to be insufficient. Treatment using the intravenous route and PTH showed the highest persistence and compliance rates and daily oral bisphosphonates the lowest. More effort to improve treatment compliance and persistence is needed to assure clinical efficacy. PMID- 22541836 TI - The concentration-dependent binding of linagliptin (BI 1356) and its implication on efficacy and safety. AB - OBJECTIVES: Linagliptin (BI 1356) is a dipeptidyl peptidase-4 (DPP-4) inhibitor for treatment of Type 2 diabetes which recently gained approval in the US, Europe, and Japan. Linagliptin showed nonlinear pharmacokinetics after intravenous and oral administration, which is due to a concentration-dependent protein binding of linagliptin to its target enzyme DPP-4. The aim of this analysis was to investigate this target-mediated binding of linagliptin and its implication on efficacy and safety. METHODS: Pharmacokinetic modeling and simulations were performed using a two-compartment model with concentration dependent binding in the central and in one peripheral compartment. The optimum therapeutic dose with minimal off-target side effects was simulated assuming that an antidiabetic effect of linagliptin was due to the linagliptin concentration bound to DPP-4 and that off-target side effects were related to free linagliptin. RESULTS: The difference between steady state AUCs of specifically bound and free linagliptin was maximized at oral doses of 2 - 5 mg. Since plasma DPP-4 inhibition increased slightly from 2.5 to 10 mg, pharmacokinetic simulations and the pharmacodynamic measurements taken together suggest that 5 mg linagliptin could be considered an optimum dose. Simulations with missed doses and additional doses at steady state showed the effect on DPP-4 bound linagliptin and change in DPP-4 inhibition was minimal after missing one 5 mg oral dose of linagliptin while two doses of 5 mg linagliptin resulted in a less than proportional increase of steady state AUC of free linagliptin. CONCLUSIONS: Results from modeling and simulation support a stable antidiabetic effect of linagliptin over 24 h at steady state and further indicate a low risk for off-target side effects. PMID- 22541837 TI - The effects of xanthine oxidase inhibition by febuxostat on the pharmacokinetics of theophylline. AB - OBJECTIVE: Febuxostat, a non-purine selective xanthine oxidase (XO) inhibitor, may affect the metabolism of theophylline as XO hydroxylates 1-methylxanthine to 1-methyluric acid. The objective of this study was to examine the effects of febuxostat on the pharmacokinetics of theophylline and its metabolites. METHODS: 24 healthy subjects received febuxostat 80 mg (Regimen A) or matching placebo (Regimen B) daily for 7 days along with a single oral dose of theophylline 400 mg on Day 5 in a double-blind, randomized, cross-over fashion (>= 7 day washout between periods) followed by collection of plasma and urine samples for 72 h. RESULTS: For Regimens A and B, mean theophylline Cmax values were 4.4 and 4.1 MUg/ml, respectively, and mean theophylline AUC0-tlqc was 122.3 and 115.2 MUg x h/ml, respectively. The ratios of theophylline Cmax and AUC0-tlqc central values following coadministration with febuxostat or placebo were 1.03 (90% confidence intervals (CIs), 0.917 - 1.149) and 1.04 (90% CI, 0.927 - 1.156). Both 90% CIs fell within the no-effect range of 0.8 and 1.25. Mean excreted amounts in urine for 1-methylxanthine levels were higher in Regimen A vs. B (40.1 vs. 0.1 mg), while 1-methyluric acid levels were lower (3.1 vs. 56.2 mg). Mean excreted amounts of theophylline and other metabolites were comparable between Regimen A and B. CONCLUSIONS: No dose adjustment for theophylline is necessary when coadministered with febuxostat 80 mg, as coadministration does not affect the plasma pharmacokinetics of theophylline and neither 1-methylxanthine nor 1 methyluric have any pharmacological effect. PMID- 22541838 TI - Treatment of tinnitus with cyclobenzaprine: an open-label study. AB - OBJECTIVE: Tinnitus is defined as an intrinsic sound sensation that cannot be attributed to an external sound source. Currently there are no standardized drug therapies for the treatment of tinnitus. Based on the analogy between pain and tinnitus it is suggested that among all antidepressant families that have been used for tinnitus, particular interest should be paid to the tricyclic group of drugs as they have an analgesic effect. The aim of the present study was to investigate the effect of a tricyclic pharmacological agent, namely cyclobenzaprine for the relief of tinnitus complaints. SUBJECTS AND METHODS: 65 patients, who received the drug treatment, were compared to 30 patients on a waiting list, who received no treatment. RESULTS: Analysis shows that cyclobenzaprine offers some benefit to patients with tinnitus on both tinnitus intensity and tinnitus distress, while a waiting list control group does not demonstrate any improvement: 24% of the tinnitus patients showed a clear response to cyclobenzaprine with a reduction of 53% on tinnitus intensity and 25% had a clear response to cyclobenzaprine with a reduction of 55% on tinnitus distress. It was further demonstrated that particular subgroups, namely pure tone tinnitus patients and unilateral tinnitus patients, respond better to cyclobenzaprine. CONCLUSION: Our results indicate that cyclobenzaprine is a promising drug to treat tinnitus particularly in certain subgroups. As there is a good risk-benefit ratio and there are currently no well-established, specific treatments for tinnitus, cyclobenzaprine might be worthwhile to further investigate. PMID- 22541839 TI - Pharmacokinetics and correlation analysis of cilostazol in healthy Korean subjects. AB - BACKGROUND: Cilostazol is frequently used to treat and prevent thrombosis in Korean patients. PATIENTS AND METHODS: We performed the pharmacokinetic and correlation analysis of cilostazol in Korean healthy subjects. A total of male 78 volunteers was subjected to three separate bioequivalence studies in which 100 mg of cilostazol was administered. AUC, t(1/2), and C(max) were 12,100 +/- 4,880 ng*h/ ml, 11.1 +/- 4.4 hours, and 827 +/- 361 ng/ml, respectively. RESULTS: ALT was positively correlated with age and C(max) was positively correlated with AUC, but negatively correlated with body weight. CONCLUSION: We suggest that the unique pharmacokinetic parameters and interrelationship can help to understand the pharmacokinetics of cilostazol in Korean subjects. PMID- 22541840 TI - Bioequivalence study of two losartan tablet formulations with special emphasis on cardiac safety. AB - OBJECTIVES: To study the bioequivalence of Losartan Potassium Tablets 50 mg manufactured by Micro Labs Ltd. India to Cozaar(r) Tablets 50 mg, manufactured by Merck Sharp and Dohme Ltd., UK in normal healthy adult subjects under fasting condition along with the comparative safety evaluation of both treatments. MATERIALS AND METHODS: The in vitro dissolution studies were carried out on 12 units each of test and reference products using the paddle method and dissolution media like water, 0.1 N hydrochloric acid with pH 1.2, pH 4.5 acetate buffer and pH 6.8 phosphate buffer. An open label, randomized, two-treatment, two-period, two-sequence, crossover bioequivalence study with a washout period of 7 days was conducted in 60 healthy Indian male subjects. Serial blood samples were collected after drug administration in each study period. Plasma concentrations of losartan and losartan acid were determined using a validated LC-MS-MS method. The pharmacokinetic parameters of losartan and losartan acid were determined using a non compartmental model. Occurrence of adverse events, change in systolic blood pressure, diastolic blood pressure, heart rate and QT interval from the baseline to 3.50 h post dose were studied and compared between the two treatments as safety parameters. RESULTS: The in vitro study proved the essential similarity of both the formulations as evident from the similarity factor of > 50% in all the dissolution media. The ratios for geometric least square means and 90% confidence intervals were within the acceptance criteria of 80% to 125% for log transformed C(max), AUC(0-t) and AUC(0-infinity) for losartan. No statistically significant difference between the two treatments was observed for either of the safety parameters. CONCLUSIONS: The test product Losartan Potassium tablets 50 mg manufactured by Micro Labs Limited, India was bioequivalent to Cozaar(r) tablets 50 mg, manufactured by Merck Sharp and Dohme Ltd., UK in terms of rate and extent of absorption. Both treatments were well tolerated and had similar non significant effect on the safety parameters. PMID- 22541841 TI - Low absolute bioavailability of oral naloxone in healthy subjects. AB - OBJECTIVE: To determine the absolute bioavailability of naloxone from oral doses ranging from 5 mg to 120 mg. MATERIALS AND METHODS: In this open-label study, 28 healthy subjects received naloxone 1 mg (0.4 mg/ml) as an intravenous infusion (reference treatment), and the following oral doses as prolonged release (PR) naloxone tablets: 5 mg, 20 mg, 40 mg, 80 mg and 120 mg. The pharmacokinetic characteristics of 40 mg administered per rectum were also investigated. Each subject received five of the seven treatments as single doses with a 7 day washout between doses. Pharmacokinetic blood sampling and safety monitoring were performed for 24 h after the intravenous dose, and 72 h after the oral and rectal doses. RESULTS: The mean absolute bioavailability of naloxone from the orally administered PR tablets was very low, ranging from 0.9% for the 5 mg dose to 2% for the 40, 80 and 120 mg doses, based on AUC(t) values. The pharmacokinetics of naloxone were linear across the range of oral doses. Where AUC(inf) values were calculated, these confirmed the results based on AUC(t) values (mean absolute bioavailability ranging from 1.9% to 2.2% for the 20 mg to 120 mg oral doses). The absolute bioavailability of naloxone was higher following rectal administration compared with oral administration, but was still low at 15%. CONCLUSIONS: The mean oral absolute bioavailability of naloxone in this study was <= 2% at doses ranging from 5 mg to 120 mg. PMID- 22541842 TI - Bioequivalence study of two mirtazapine oral tablet formulations in healthy Chinese male volunteers. AB - OBJECTIVE: Mirtazapine is a tetracyclic antidepressant which works relating to noradrenergic and elective serotoninergic receptors. The aim of this study was to assess the pharmacokinetic properties and bioequivalence of a newly developed tablet formulation of mirtazapine with those of an established branded formulation in healthy Chinese male volunteers. MATERIALS AND METHODS: A randomized, open-label, single-dose, 2-way crossover study was conducted in healthy Chinese volunteers under fasting conditions with a washout of 14 days between the study periods. A sensitive and credible high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method was developed and validated to determine mirtazapine in human plasma. RESULTS: The main PK parameters of the mirtazapine test and reference tables were as follows: mean (SD) C(max), 58.715 (23.89) and 58.255 (22.34) ng/ml; AUC(0-t), 591.406 (186.79) and 596.339 (201.25) ng * h/ml; AUC(0-infinity), 627.03 (201.39) and 631.521 (227.32) ng * h/ml; t(1/2), 18.941 (4.79) and 18.285 (3.91) h; t(max) 1.417 (0.61) and 1.424 (0.75) h. The 90% CI for logtransformed ratios of C(max) (88.8 - 112.4%), AUC(0-t) (93.9 - 104.9%) and AUC(0-infinity) (94.5 - 105.3%) for the test and reference formulations respectively, meeting the predetermined criteria for bioequivalence. CONCLUSIONS: Both treatments exhibited similar tolerability and safety. The test product is therefore bioequivalent to the reference product with respect to the rate and extent of mirtazapine pharmacokinetics. PMID- 22541843 TI - Diagnostic performance of 2 h postprandial capillary and venous glucose as a screening test for abnormal glucose tolerance. AB - AIMS: To evaluate the diagnostic performance of postprandial venous and capillary glucose to screen for abnormal glucose tolerance in primary care setting. METHODS: Both post-breakfast venous plasma and capillary blood glucose were taken simultaneously from a consecutive sample of volunteer civil service workers in Khon Kaen, Thailand between June and December 2009. The 75-g oral glucose tolerance test was performed within 3 days of the baseline visit. Both postprandial capillary and venous glucose were assessed for sensitivity, specificity, area under the receiver operating characteristic (ROC) curve and likelihood ratio using the oral glucose tolerance test (OGTT) results for the diagnosis of abnormal glucose tolerance as a gold standard. RESULTS: 1102 volunteers participated, of whom 874 (79.3%) completed the full study protocol. Five-hundred and four (57.8%) of 874 participants were female. The mean age was 39.9 years (SD=12.16) and the mean BMI was 24.3 kg/m(2) (SD=6.86). The sensitivity and specificity at the optimal cut-off point for venous glucose were 68.28% (95% CI 60.04-75.75) and 67.90% (95% CI 64.38-71.28), respectively. The sensitivity and specificity at the optimal cut-off point for capillary glucose were 63.45% (95% CI 55.05-71.28) and 64.06% (95% CI 60.46-67.55), respectively. The area under the ROC curve was 0.73 (95% CI 0.68-0.78) for venous glucose and 0.69 (95% CI 0.64-0.74) for capillary glucose. The subgroup analysis involving individuals with waist circumference>90 cm improved the area under the curve (AUC) to 0.76 (95% CI 0.68-0.83). CONCLUSIONS: Postprandial blood glucose testing had a moderate discriminating characteristic for the diagnosis of abnormal glucose tolerance. Careful consideration is needed when using it to screen for this condition in general population. PMID- 22541844 TI - Are there predicting factors for burn patients that transfer to a rehabilitation center upon completion of acute care? AB - INTRODUCTION: Choosing the right burn patient that transfers to a rehabilitation facility following acute hospitalization is a difficult decision. In our study we characterize demographic, injury and hospitalization related variables that predict a burn patient's transfer to a rehabilitation facility. METHODS: We analyzed the data of 974 burn patients with burns of the second degree and deeper, spanning 20% TBSA (total body surface area) or more, that were admitted to all 5 hospitals that operate a burn unit in Israel, between the years 1998 and 2005. RESULTS: The results of the multivariate logistical regression model in which the predicted variable is discharge to rehabilitation showed that the most predictive variables were inhalation injury, surgical procedures and hospitalization period. Execution of a surgical procedure was the most influential factor over discharge to rehabilitation (odds ratio=6.202) followed by inhalation injury (OR=4.706) and finally, the hospitalization period (OR=1.026) (an increase of 1.026 times in the likelihood to be sent to rehabilitation with any additional day of hospitalization). DISCUSSION: In this study we examined patients who were sent to a rehabilitation facility upon completion of their acute care in an attempt to evaluate common initial clinical variables that assist in making an educated decision regarding the patient rehabilitation transfer. This is one of the first attempts at examining and revealing evidence based parameters that might determine the correct burn patient to send to rehabilitation after his hospitalization. PMID- 22541846 TI - The National Institute for Health and Clinical Excellence (NICE) guidelines for caesarean section, 2011 update: implications for the anaesthetist. AB - In 2004 the first National Institute for Health and Clinical Excellence guidelines on caesarean section were published with the aim of providing evidence based recommendations for best practice. With the publication of new evidence, the guidelines have been revised with the second edition released in 2011. This review highlights the changes that have been made which are of specific relevance to obstetric anaesthetists including planned caesarean section compared with vaginal birth in healthy women with an uncomplicated pregnancy; management of the morbidly adherent placenta; mother-to-child transmission of maternal infections; maternal request for caesarean section; decision-to-delivery interval for emergency caesarean section; timing of antibiotic administration and childbirth after caesarean section. PMID- 22541845 TI - The renal urate transporter SLC17A1 locus: confirmation of association with gout. AB - INTRODUCTION: Two major gout-causing genes have been identified, the urate transport genes SLC2A9 and ABCG2. Variation within the SLC17A1 locus, which encodes sodium-dependent phosphate transporter 1, a renal transporter of uric acid, has also been associated with serum urate concentration. However, evidence for association with gout is equivocal. We investigated the association of the SLC17A1 locus with gout in New Zealand sample sets. METHODS: Five variants (rs1165196, rs1183201, rs9358890, rs3799344, rs12664474) were genotyped across a New Zealand sample set totaling 971 cases and 1,742 controls. Cases were ascertained according to American Rheumatism Association criteria. Two population groups were studied: Caucasian and Polynesian. RESULTS: At rs1183201 (SLC17A1), evidence for association with gout was observed in both the Caucasian (odds ratio (OR) = 0.67, P = 3.0 * 10-6) and Polynesian (OR = 0.74, P = 3.0 * 10-3) groups. Meta-analysis confirmed association of rs1183201 with gout at a genome-wide level of significance (OR = 0.70, P = 3.0 * 10-8). Haplotype analysis suggested the presence of a common protective haplotype. CONCLUSION: We confirm the SLC17A1 locus as the third associated with gout at a genome-wide level of significance. PMID- 22541849 TI - The road to 2020-guest editorial. PMID- 22541847 TI - The quest to identify the ideal patient for early left ventricular assist device implantation as destination therapy. PMID- 22541850 TI - APIC Strategic Plan 2020. PMID- 22541851 TI - The value of certification and the CIC credential. PMID- 22541852 TI - Competency in infection prevention: a conceptual approach to guide current and future practice. AB - Professional competency has traditionally been divided into 2 essential components: knowledge and skill. More recent definitions have recommended additional components such as communication, values, reasoning, and teamwork. A standard, widely accepted, comprehensive definition remains an elusive goal. For infection preventionists (IPs), the requisite elements of competence are most often embedded in the IP position description, which may or may not reference national standards or guidelines. For this reason, there is widespread variation among these elements and the criteria they include. As the demand for IP expertise continues to rapidly expand, the Association for Professionals in Infection Control and Epidemiology, Inc, made a strategic commitment to develop a conceptual model of IP competency that could be applicable in all practice settings. The model was designed to be used in combination with organizational training and evaluation tools already in place. Ideally, the Association for Professionals in Infection Control and Epidemiology, Inc, model will complement similar competency efforts undertaken in non-US countries and/or international organizations. This conceptual model not only describes successful IP practice as it is today but is also meant to be forward thinking by emphasizing those areas that will be especially critical in the next 3 to 5 years. The paper also references a skill assessment resource developed by Community and Hospital Infection Control Association (CHICA)-Canada and a competency model developed by the Infection Prevention Society (IPS), which offer additional support of infection prevention as a global patient safety mission. PMID- 22541853 TI - Performance improvement and implementation science: infection prevention competencies for current and future role development. AB - The Association for Professionals in Infection Control and Epidemiology, Inc, developed its first model of infection preventionist (IP) competency in 2011. The model is based on the principles of patient safety, professional and practice standards, and core competencies identified through research conducted by the Certification Board of Infection Control and Epidemiology, Inc. In addition, the model highlights 4 domains that are predicted to be key areas for future competency development. Performance improvement (PI) and implementation represent 1 of the 4 forward-focused domains. Concurrently, the inclusion of implementation science (IS) in the competency model is consistent with the research goals established by the Association for Professionals in Infection Control and Epidemiology, Inc, in its 2020 strategic plan. This article explains the importance of PI and IS and describes their relevance to the current and future IP role development. Significant challenges such as role delineation and compression are discussed. The need for the IP to acquire new competencies at integrating, as well as differentiating, PI and IS are explored in terms of emerging issues and trends. PMID- 22541854 TI - The APIC research agenda: results from a national survey. AB - BACKGROUND: Research is an integral component of the Association for Professionals in Infection Control and Epidemiology (APIC) Strategic Plan 2020. As the role of the infection preventionist (IP) has evolved toward consumers and implementers of research, it becomes increasingly necessary to assess which topics require further evidence and how best APIC can assist IPs. In 2010, APIC determined that the research priorities first described in 2000 needed to be re evaluated. METHODS: A 33-question Web-based survey was developed and distributed via e-mail to APIC members in March 2011. The survey contained sections inquiring about respondents' demographics, familiarity with implementation science, and infection prevention research priorities. Priorities identified by a Delphi study 10 years ago were re-ranked, and open-ended items were used to identify new research priorities and understand how APIC could best serve its members in relation to research. RESULTS: Seven hundred one members responded. Behavioral management science, surveillance standards, and infection prevention resource optimization were the highest ranked priorities and relatively unchanged from 2000. Proposed additional research topics focused on achieving standardization in infection prevention practices and program resource allocation. The majority of respondents described APIC's role in the field of research as a disseminator of low-cost, highly accessible education to its members. CONCLUSION: This report should be used as a roadmap for APIC leadership as it provides suggestions on how APIC may best direct the association's research program. The major research priorities described and ranked in 2000 continue to challenge IPs. APIC can best serve its members by disseminating research findings in a cost-effective and easily accessed manner. Recurrent assessments of research priorities can help guide researchers and policy makers and help determine which topics will best support successful infection prevention processes and outcomes. PMID- 22541856 TI - Endometrial ablation: postoperative complications. AB - Endometrial ablation as a treatment for abnormal uterine bleeding has evolved considerably over the past several decades. Postoperative complications include the following: (1) pregnancy after endometrial ablation; (2) pain-related obstructed menses (hematometra, postablation tubal sterilization syndrome); (3) failure to control menses (repeat ablation, hysterectomy); (4) risk from preexisting conditions (endometrial neoplasia, cesarean section); and (5) infection. Physicians performing endometrial ablation should be aware of postoperative complications and be able to diagnose and provide treatment for these conditions. PMID- 22541855 TI - Perceived impact of the Medicare policy to adjust payment for health care associated infections. AB - BACKGROUND: In 2008, the Centers for Medicare and Medicaid Services (CMS) ceased additional payment for hospitalizations resulting in complications deemed preventable, including several health care-associated infections. We sought to understand the impact of the CMS payment policy on infection prevention efforts. METHODS: A national survey of infection preventionists from a random sample of US hospitals was conducted in December 2010. RESULTS: Eighty-one percent reported increased attention to HAIs targeted by the CMS policy, whereas one-third reported spending less time on nontargeted HAIs. Only 15% reported increased funding for infection control as a result of the CMS policy, whereas most reported stable (77%) funding. Respondents reported faster removal of urinary (71%) and central venous (50%) catheters as a result of the CMS policy, whereas routine urine and blood cultures on admission occurred infrequently (27% and 13%, respectively). Resource shifting (ie, less time spent on nontargeted HAIs) occurred more commonly in large hospitals (odds ratio, 2.3; 95% confidence interval: 1.0-5.1; P = .038) but less often in hospitals where front-line staff were receptive to changes in clinical processes (odds ratio, 0.5; 95% confidence interval: 0.3-0.8; P = .005). CONCLUSION: Infection preventionists reported greater hospital attention to preventing targeted HAIs as a result of the CMS nonpayment policy. Whether the increased focus and greater engagement in HAI prevention practices has led to better patient outcomes is unclear. PMID- 22541857 TI - An unusual way to give birth: the patient's son was delivered paravaginally while she was en route to the hospital. PMID- 22541858 TI - Leukocyte chemoattractant receptor FPR2 may accelerate atherogenesis. AB - Atherosclerosis is a chronic inflammatory disease and the number one cause of mortality worldwide. The fundamental causes of atherosclerosis have not been precisely delineated, although pathogenesis clearly involves endothelial dysfunction and both innate and adaptive immunity. Recent evidence suggests that formyl peptide receptor 2 (FPR2), a G protein-coupled receptor (GPCR), mediates a range of inflammatory responses including superoxide production in neutrophils, chemotaxis of monocytes and neutrophils, CCL2 production in endothelial cells (ECs) and monocytes, and increased CXCL8 expression in neutrophils, which are all related with atherogenesis. Therefore, we propose that FPR2 may play a pathogenic role in atherogenesis. PMID- 22541859 TI - Geometrical factors as predictors of increased growth rate or increased rupture risk in small aortic aneurysms. AB - Abdominal Aortic Aneurysms (AAAs) are focal dilation of the aorta that can lead to excessive enlargement and rupture over time. Current practice suggests intervention when the maximum diameter exceeds 5.5 cm, since in this diameter range the annual rupture risk outweighs the operative mortality. However, small AAA (<5.5 cm), though infrequently, may rupture or produce symptoms. Evidence from large randomized studies of small AAAs support the heterogeneity in patterns of growth and rupture potential among small AAAs. Elevated wall stress values have been implicated in AAAs rupture and rapid enlargement. Additionally, many studies have identified a strong correlation between certain geometric factors and elevated stress values. In this article we discuss the possibility that geometrical factors may have a predictive value to identify those small AAAs that have an increased risk of rupture or growth rate either during initial examination or during follow-up, making them amenable for early repair. PMID- 22541860 TI - Preeclampsia and gestational diabetes mellitus: pre-conception origins? AB - Preeclampsia (PE) and gestational diabetes mellitus (GDM) are two of the most common medical complications of pregnancy, with risks for both mother and child. Like many other antepartum complications, PE and GDM occur only in pregnancy. However, it is not clear if pregnancy itself is the cause of these complications or it these conditions are caused by factors that existed prior to gestation. In this paper, we hypothesize that although the clinical findings of PE and GDM are first noted during pregnancy, the origins of both conditions may actually precede pregnancy. We further hypothesize that pathophysiologic changes underlying PE and GDM are present prior to pregnancy, but remain undetected in the non-gravid state either because pregnancy is the trigger that makes these pathologies become clinically detectable or because there has been limited prospective longitudinal data comparing the pre-gravid and antepartum status of women that go on to develop these conditions. Rigorous prospective cohort studies in which women undergo serial systematic evaluation in the pre-conception period, throughout pregnancy and into the postpartum are ideally needed to test this hypothesis of pre-conception origins of PE and GDM. In this context, we are creating a pre conception cohort, involving about 5000 couples who plan to have a baby within six months in Liuyang county in the Chinese province of Hunan. Results from this pre-conception cohort program should be able to provide definitive answer to the question of whether the underpinnings of PE and GDM originate prior to pregnancy. Ultimately, the significance of addressing this hypothesis is underscored by its potential implications for targeted interventions that could be designed to (i) prevent the deleterious effects of PE/GDM and (ii) thereby interrupt the vicious cycle of disease that links affected women and their offspring. PMID- 22541861 TI - Translating whole-body cryotherapy into geriatric psychiatry--a proposed strategy for the prevention of Alzheimer's disease. AB - Alzheimer's disease (AD), which is the most common form of dementia, constitutes one of the leading causes of disability and mortality in aging societies. Currently recommended medications used in treating AD include cholinesterase inhibitors and the NMDA antagonist--memantine, but poorly counteract progression of the disease. According to current knowledge, the neuropathological process underlying the etiology of AD begins many years, if not decades, before the development of overt symptoms of dementia. Mild cognitive impairment (MCI) is regarded as the first detectable manifestation of cognitive decline. Nowadays, there is a general consensus that vascular alterations, oxidative stress and inflammatory response contribute to the development of AD. Following these mechanisms and tracing the anti-inflammatory and anti-oxidative effects of cryostimulation, we postulate that whole-body cryotherapy (WBCT) might be utilized as a means of preventing AD. WBCT is a relatively safe and cost effective procedure, which is widely applied in various medical specialties. Thus, there is an urgent necessity to evaluate the long-term effectiveness of WBCT in the prevention of AD in patients with MCI and healthy individuals. PMID- 22541862 TI - Sistemic calciphylaxis and thrombotic microangiopathy in a kidney transplant patient: two mixing fatal syndromes? AB - Abnormalities in calcium and phosphorus metabolism are common and metabolic bone diseases develop often in patients with chronic renal failure (CRF). Effective clinical management includes measures to control phosphorus retention and prevent hyperphosphataemia, to maintain serum calcium concentrations within the normal range and to prevent excess parathyroid hormone (PTH) secretion by the judicious use of vitamin D sterols. Certain of these interventions, however, appear to increase the risk of soft tissue and vascular calcification in patients with End Stage Renal Disease (ESRD), so current therapeutic approaches are thus being re evaluated in an effort to limit these risks. Patients with calciphylaxis have an extremely high mortality rate, diagnosis requires a high degree of clinical suspicion and the role and extent of parathyroidectomy in the management of this condition remain controversial. In some cases renal transplant patients could suffer from a comorbidity in which vascular function is compromised not only by secondary hyperparathyroidism-related calcification but also by other pathological condition as haemolytic uremic syndrome (HUS), leading to a fatal clinical outcome. We postulate that in these cases a secondary hyperparathyroidism not properly diagnosed in an early phase of the renal disease (probably before the kidney transplant) could cause a vascular calcification which, adding to the pre-existing HUS-related vascular compromission, gave rise to catastrophic clinical consequences. In the management of ESRD patients, in particular in the cases of pre-existing angiopathies, could be therefore crucial the early and proper diagnosis of an alteration of calcium-posphorus metabolism and effort of medicine could be oriented in these cases also towards identification of screening methodologies to undoubtedly assess such a diagnosis. PMID- 22541864 TI - Phylogenetic and morphological diversity of novel soil cercomonad species with a description of two new genera (Nucleocercomonas and Metabolomonas). AB - Cercomonads are important components of microbial food webs in soils and aquatic sediments. Here, we investigated the general morphology, behaviour, life cycle and 18S rDNA phylogeny of cercomonad cultures from a German grassland soil habitat. We describe ten new species including two new genera from 23 strains. Three Cercomonas, two Eocercomonas and three Paracercomonas species are described. Based on large phylogenetic distance and distinct morphology, we erect two novel clade B genera near the root of the cercomonad tree. Nucleocercomonas nov. gen. bears a number of characters unusual for cercomonads: Its anterior flagellum is extremely long, it mostly does not glide, and in its most frequent life stage the cell body does not attach to the substratum, but produces unattached pseudopodia. Furthermore, it has a unique nucleus with a peripheral nucleolus that attaches to the nuclear envelope opposite the basal body connection. Metabolomonas nov. gen. is extremely metabolic. It is characterized by a very high beating frequency of the anterior flagellum, fast gliding, rapid changes in shape and strong cytoplasmic streams. A new genus Brevimastigomonas is erected for the previously described species Paracercomonas anaerobica. The general morphology of cercomonad species often does not correspond with their phylogenetic position: closely related species may have a very different morphology. PMID- 22541865 TI - Anatomic direct repair of chronic distal biceps brachii tendon rupture without interposition graft. AB - BACKGROUND: Rupture of the biceps brachii insertion is relatively uncommon and may present late. Chronic ruptures pose a management dilemma, with higher reported complication rates when surgery is delayed, whilst conservatively treated injuries may do badly in active patients. MATERIALS AND METHODS: Six consecutive male patients with delayed presentation of biceps rupture were treated operatively using a limited standard anterior approach, a secondary proximal "retrieval" incision, and EndoButton fixation. This modification of the well-described EndoButton technique for distal biceps reconstruction allows passage of the shortened tendon in maximal elbow flexion and a rehabilitation program without immobilization. The mean interval to repair was 79 days (range, 35-116 days). The mean age at presentation was 47.5 years. The injury mechanisms were unexpected loads on a flexed supinated forearm. RESULTS: Patients were assessed at a mean of 20.2 months. Range of motion was restored to 94% in flexion and 95% in prosupination compared with the uninjured limb. Supination endurance was reduced by 9 repetitions/min compared with the contralateral side (mean, 83.4 repetitions/min). Mayo Elbow Performance Scores were universally 100 and the mean Disabilities of Arm, Shoulder and Hand score was 4. Patient satisfaction was high, with visual analog scores of 92 to 100. No major complications occurred, and all repairs were intact at the final follow-up. CONCLUSIONS: Our outcomes are comparable to acute repair, with restoration of range of motion and function and few complications. PMID- 22541866 TI - The relationship between tear severity, fatty infiltration, and muscle atrophy in the supraspinatus. AB - BACKGROUND: Fatty infiltration and muscle atrophy have been described as interrelated characteristic changes that occur within the muscles of the rotator cuff after cuff tears, and both are independently associated with poor outcomes after surgical repair. We hypothesize that fatty infiltration and muscle atrophy are two distinct processes independently associated with supraspinatus tears. MATERIALS AND METHODS: A retrospective review of 377 patients who underwent shoulder magnetic resonance imaging at one institution was performed. Multivariate analysis was performed based on parameters including age, sex, rotator cuff tear severity, fatty infiltration grade, and muscle atrophy. RESULTS: A total of 116 patients (30.8%) had full-thickness tears of the supraspinatus, 153 (40.6%) had partial thickness tears, and 108 (28.7%) had no evidence of tear. With increasing tear severity, the prevalence of substantial fatty infiltration (grade >=2) increased: 6.5% of patients with no tears vs 41.4% for complete tears (P < .001). Similarly, the prevalence of supraspinatus atrophy increased with worsening tear severity: 36.1% of no tears vs 77.6% of complete tears (P < .001). Multivariate analysis demonstrated a significant independent association between fatty infiltration and muscle atrophy when taking into account sex, age, and tear severity. CONCLUSIONS: Fatty infiltration and muscle atrophy are independently associated processes. Fatty infiltration is also related to increasing age, muscle tear severity, and sex, whereas muscle atrophy is related to increasing age but not tear severity. In patients without rotator cuff tears, fatty infiltration and atrophy prevalence increased independently with increasing age. PMID- 22541867 TI - Functional outcomes and structural integrity after double-pulley suture bridge rotator cuff repair using serial ultrasonographic examination. AB - BACKGROUND: We evaluated the integrity and functional outcomes of rotator cuff tear after performing the double-pulley suture bridge (DPSB) repair technique according to the tear size by using serial ultrasonographic examinations. MATERIALS AND METHODS: The study included 41 consecutive arthroscopic rotator repairs using the DPSB technique. The average follow-up was 28 months. We completed the serial ultrasonographic examinations and compared the results with the functional outcome using the American Shoulder and Elbow Surgeons (ASES) score, the Constant score, the Korean Shoulder Scoring (KSS) system, and the University of California, Los Angeles (UCLA) score. RESULTS: The overall retear rate was 19.5% (8 of 41), comprising 50% (2 of 4) for massive tears, 18% (2 of 11) for large tears, 17% (4 of 23) for medium tears, and no failures for small tears (0 of 3). The retear rate was 17.6% (6 of 34) after complete repair and 28.6% (2 of 7) after repair with gap formation. Seventy-five percent (6 of 8) of retears were identified within 6 months after operation and 25% (2 of 8) were identified more than 1 year after repair. The functional outcomes of the intact group and the retear group according to the ASES score, the Constant score, the KSS, and the UCLA score were 96, 93, 94, and 33, and 90, 82, 87, and 31, respectively (P > .05). CONCLUSION: The overall retear rate after DPSB repair was 19.5% with 2 time periods of retear. The outcome improved independent of the tear size and the cuff integrity. PMID- 22541868 TI - Are there advantages of the combined latissimus-dorsi transfer according to L'Episcopo compared to the isolated latissimus-dorsi transfer according to Herzberg after a mean follow-up of 6 years? A matched-pair analysis. AB - HYPOTHESIS: The aim of the study was to evaluate differences of clinical results between the latissimus-dorsi transfer combined with teres-major transfer (G1) and the isolated latissimus-dorsi transfer (G2) for the treatment of massive irreparable postero-superior rotator cuff tears. METHODS: We performed the combined latissimus-dorsi/teres-major transfer in 17 patients at a mean age of 57 years. Furthermore, 17 patients at a mean age of 61 years were treated using the isolated latissimus-dorsi transfer. Both groups were followed-up clinically, radiologically, and with surface electromyography using the same study protocol. RESULTS: The Constant score (CS) improved significantly from 48.3 points pre-op to 69.5 points post-op after a follow-up of 58 months in G1. The active range of motion improved in G1 sig. for flexion (124 degrees pre-op, 166.5 degrees post op) and for abduction (117 degrees pre-op, 163 degrees post-op). The CS improved significantly from 45.1 points pre-op to 74.2 points post-op after a follow-up of 51 months in G2. The flexion and abduction increased significantly from 133.3 degrees pre-op to 176 degrees post-op, resp. from 113.3 degrees pre op to 173 degrees post-op. The comparison of both surgical techniques showed a significant better active flexion and abduction for G2. CONCLUSION: Both techniques achieved good functional results but the isolated latissimus-dorsi transfer produced a better active abduction and flexion, whereas the combined latissmus-dorsi/teres-major transfer achieved an increase in abduction strength. In contrast to the combined latissimus-dorsi/teres-major transfer, a progression of cuff tear arthropathy was not observed with the isolated latissimus-dorsi transfer. PMID- 22541869 TI - Ganglion cyst of the spinoglenoid notch: comparison between SLAP repair alone and SLAP repair with cyst decompression. AB - BACKGROUND: Some authors have described the ganglion cyst of the spinoglenoidal notch as related to repetitive overhead activities and labral tear caused by trauma, while others have explained lesions of the capsulolabral complex and ganglion cysts to have separate pathologies. The purpose of this study is to compare clinical and radiological outcomes between 2 groups: 1 with superior labrum anterior and posterior (SLAP) repair only and the other with SLAP repair and cyst decompression prospectively. MATERIALS AND METHODS: From August 2000 to March 2007, 28 patients matching the inclusion criteria were selected for the study. They were divided into 2 groups: 1 who received SLAP repair and the other with concomitant SLAP repair and cyst decompression. A visual analogue scale (VAS) and Rowe and Constant scores were used to make evaluation. Preoperative magnetic resonance images (MRIs) of 2 patient groups were compared with 2 follow up MRIs taken 3 months after the operation and at final follow-up. RESULTS: Mean VAS and Constant and Rowe scores in groups I and II improved significantly from mean preoperative score compared to last follow-up score; however, there was no statistically significant difference between the 2 groups (P > .05). Preoperative MRI and arthroscopy revealed type II SLAP lesions and a type V lesion, respectively, as accompanying lesions in 24 cases. CONCLUSION: The hypothesis stating 1-way valve mechanism of SLAP lesion as an initial cause of ganglion cysts has been proved indirectly in this study. Furthermore, direct decompression of the cyst does not lead to different results. PMID- 22541870 TI - Clavicle morphometry revisited: a 3-dimensional study with relevance to operative fixation. AB - BACKGROUND: The advocacy for operative fixation of midshaft clavicle fractures has prompted a reemergence of interest in clavicle anatomy. Three-dimensional (3D) anatomical studies provide more information than 2-dimensional studies, but are currently rare. MATERIAL AND METHODS: Twenty-five skeletonized clavicles were digitized using a laser scanner. Three-dimensional computer software was used to analyze the data. Clavicles were divided into medial, middle, and lateral segments based on the medial and lateral apices of curvature and their lengths and midpoint cortical diameter measured. The angles of medial and lateral curvatures were measured in standardized axial and coronal planes. The medial and lateral curvatures were fitted with circles and the radii of curvature measured. Correlations between the intrinsic dimensions of the clavicle were assessed. RESULTS: The mean length was 136.7 mm. The medial, middle, and lateral segments had mean lengths of 48, 56, and 32.7 mm, respectively. In the axial plane, the mean medial and lateral angles were 149.5 degrees and 145.8 degrees , respectively. In the coronal plane, the mean medial and lateral angles were 178.2 degrees and 174.2 degrees , respectively. The mean midpoint cortical diameter was 10.9 mm. The mean medial and lateral radii of curvature were 66.4 and 33.5 mm, respectively. The length and cortical diameter and length and medial radius of curvature were found to positively correlate, R(2) = .355 and .184, respectively. CONCLUSION: Using standardized measurements, we were able to accurately characterize the dimensions of the clavicle. We found that the length of the clavicle correlates with the midpoint cortical diameter and with the radius of medial curvature. PMID- 22541871 TI - Fixation and durability of a bone-ingrowth component for glenoid bone loss. AB - BACKGROUND: Deficient glenoid bone is a reconstructive challenge in shoulder arthroplasty. One solution is an ingrowth anatomic glenoid with column and screw fixation, with or without supplemental bone graft. This study examines the outcome of patients managed in this manner. MATERIALS AND METHODS: This type of glenoid component was used in 21 shoulder arthroplasties with central or peripheral glenoid bone deficiencies: 13 for bone loss due to arthritic wear and 8 for revision arthroplasty. Patients were monitored clinically for a mean of 11.1 years (range, 7.6-15.1 years) and by x-ray imaging for a mean of 9.1 years (range, 2.2-14.2 years). RESULTS: Revision procedures were needed for 7 shoulders at a mean of 10.4 years (range 5.5-14.3 years), 6 for polyethylene or metal wear leading to glenoid loosening in 4. In the 14 nonrevised shoulders, pain ratings (1 to 5 scale) decreased from a mean of 4.5 to 1.9 (P < .001). Mean active elevation increased from 100 degrees to 125 degrees (P = .02). Mean external rotation increased from 28 degrees to 43 degrees (P = .06). Results assessed by the Neer rating were excellent in 3, satisfactory in 10, and unsatisfactory in 1. In radiographic assessment of the unrevised shoulders, 4 were at risk for glenoid loosening, and 1 was at risk for humeral loosening. CONCLUSIONS: This method of reconstruction can offer pain relief and improved motion. However, the large number of revision procedures and additional adverse changes on x-ray imaging suggest other reconstructive options may be more successful and durable. PMID- 22541872 TI - Speciation by symbiosis. AB - In the Origin of Species, Darwin struggled with how continuous changes within a species lead to the emergence of discrete species. Molecular analyses have since identified nuclear genes and organelles that underpin speciation. In this review, we explore the microbiota as a third genetic component that spurs species formation. We first recall Ivan Wallin's original conception from the early 20th century on the role that bacteria play in speciation. We then describe three fundamental observations that justify a prominent role for microbes in eukaryotic speciation, consolidate exemplar studies of microbe-assisted speciation and incorporate the microbiota into classic models of speciation. PMID- 22541873 TI - Scaling-up attention to nonmalaria acute undifferentiated fever. AB - Studies have reported that only a small fraction of fever cases in malaria endemic areas are actually caused by malaria. Much greater emphasis is now needed to step up attention to the appropriate management of nonmalarial acute undifferentiated febrile illness. There is an overlap at the start of clinical manifestations of different febrile illnesses which makes it difficult to adhere to the clinical guidelines. The development of rigorous guidelines based on high quality research and a consensus from the core group of content experts are needed. An innovative financing mechanism for universal access to such appropriate management should also be considered. PMID- 22541874 TI - Pancreatic beta-cell function relates positively to HDL functionality in well controlled type 2 diabetes mellitus. AB - BACKGROUND: High density lipoproteins (HDLs) have been implicated in glucose homeostasis. Among subjects with normal fasting glucose (NFG), impaired fasting glucose (IFG) and Type 2 diabetes mellitus (T2DM) we tested whether pancreatic beta-cell function relates to HDL functionality, as determined by HDL anti oxidative capacity and cellular cholesterol efflux to plasma. SUBJECTS AND METHODS: HDL anti-oxidative capacity (inhibition of LDL oxidation in vitro), cellular cholesterol efflux (the ability of plasma to stimulate cholesterol efflux out of cultured fibroblasts obtained from a single human donor), glucose and insulin were determined in fasting plasma samples from 37 subjects with NFG, 36 with IFG and 22 with T2DM (no glucose lowering drug or insulin treatment; HbA1c 6.0+/-1.0%). Homeostasis model assessment was used to estimate pancreatic beta-cell function (HOMA-beta) and insulin resistance (HOMAir). RESULTS: HOMA beta was lowest, whereas HOMAir was highest in T2DM (P<0.01 and P<0.001 vs. NFG). HDL anti-oxidative capacity and cellular cholesterol efflux did not differ significantly according to glucose tolerance category. In univariate analysis and after controlling for HOMAir both HDL anti-oxidative capacity (P<0.05) and cellular cholesterol efflux (P<0.01) were positively correlated with HOMA-beta in T2DM, but not in NFG and IFG. In age-, sex- and HOMAir-adjusted analyses, T2DM status interacted positively with HDL anti-oxidative capacity (P=0.001) and cellular cholesterol efflux (P=0.042) on HOMA-beta. HbA1c interacted similarly with HDL functionality measures on HOMA-beta. CONCLUSIONS: Pancreatic beta-cell function relates to pathophysiologically relevant measures of HDL function in T2DM, but not in NFG and IFG. Better HDL functionality may contribute to maintenance of beta-cell function in subjects with well-controlled T2DM. PMID- 22541875 TI - Hospitalizations of older patients with human immunodeficiency virus in the United States. AB - BACKGROUND: Older adults represent a growing percentage of the United States (US) population living with human immunodeficiency virus (HIV). The Emergency Department plays an integral role in the identification and initial evaluation and treatment of patients with HIV. OBJECTIVE: We sought to estimate the number of hospitalizations of older adults (age >= 50 years) with HIV in the United States from 2000 to 2006 and compare features of this population to younger adults with HIV. Clinical and demographic characteristics of the younger cohort (19-49 years) and two older cohorts (ages 50-64 and >= 65 years) were examined and compared. METHODS: Data from the Nationwide Inpatient Sample was used to compare the three groups of HIV-positive patients. Comparisons between the most common discharge diagnoses and primary procedures were also made. RESULTS: Older adults with HIV constitute almost one quarter of the hospitalizations of adults with HIV. Older adults with HIV were more likely to be male, have a significantly higher average hospital charge, and have a longer length of stay than younger adults with HIV. Pneumonia and fluid and electrolyte disorders were common diagnoses among all three age cohorts. CONCLUSIONS: Older HIV patients were more likely to die during hospitalization compared with younger adults with HIV and older adults without HIV. Admissions for older HIV patients almost doubled during the study period and future studies should examine whether this is due to aging of the current HIV population or new infections. PMID- 22541876 TI - Catatonia in the emergency department. PMID- 22541877 TI - Are oral medications effective in the management of acute agitation? AB - BACKGROUND: Current expert guidelines recommend treating agitation with oral medications instead of intramuscular medications if possible. Oral medications are sometimes believed to be inappropriate for the emergency department (ED) as they require patient cooperation and may have a slower onset of action. This review examined published literature for the efficacy of oral agents in agitation. CLINICAL QUESTION: Are oral medications effective at managing acute agitation? METHODS: Structured review of PubMed of articles in which the first timepoints of evaluation were<24 hours (i.e., the typical timecourse in the ED). RESULTS: 11 articles included for final analysis. CONCLUSIONS/CLINICAL BOTTOM LINE: Treatment with oral medications is as effective as intramuscular medications in rapidly reducing psychotic agitation in the ED. Their use is thought to pose less risk to both patient and ED staff and is less coercive. There is little to no evidence about the use of oral medications for ED patients with extreme agitation. PMID- 22541878 TI - Comparison of neurological outcome between tracheal intubation and supraglottic airway device insertion of out-of-hospital cardiac arrest patients: a nationwide, population-based, observational study. AB - BACKGROUND: The effect of prehospital use of supraglottic airway devices as an alternative to tracheal intubation on long-term outcomes of patients with out-of hospital cardiac arrest is unclear. STUDY OBJECTIVES: We compared the neurological outcomes of patients who underwent supraglottic airway device insertion with those who underwent tracheal intubation. METHODS: We conducted a nationwide population-based observational study using a national database containing all out-of-hospital cardiac arrest cases in Japan over a 3-year period (2005-2007). The rates of neurologically favorable 1-month survival (primary outcome) and of 1-month survival and return of spontaneous circulation before hospital arrival (secondary outcomes) were examined. Multiple logistic regression analyses were performed to adjust for potential confounders. Advanced airway devices were used in 138,248 of 318,141 patients, including an endotracheal tube (ETT) in 16,054 patients (12%), a laryngeal mask airway (LMA) in 34,125 patients (25%), and an esophageal obturator airway (EOA) in 88,069 patients (63%). RESULTS: The overall rate of neurologically favorable 1-month survival was 1.03% (1426/137,880). The rates of neurologically favorable 1-month survival were 1.14% (183/16,028) in the ETT group, 0.98% (333/34,059) in the LMA group, and 1.04% (910/87,793) in the EOA group. Compared with the ETT group, the rates were significantly lower in the LMA group (adjusted odds ratio 0.77, 95% confidence interval [CI] 0.64-0.94) and EOA group (adjusted odds ratio 0.81, 95% CI 0.68 0.96). CONCLUSIONS: Prehospital use of supraglottic airway devices was associated with slightly, but significantly, poorer neurological outcomes compared with tracheal intubation, but neurological outcomes remained poor overall. PMID- 22541879 TI - Massive human ingestion of orpiment (arsenic trisulfide). AB - BACKGROUND: Because the toxicity of arsenic is well known, arsenic-containing compounds have frequently been ingested for suicidal purposes. We report a case of attempted suicide by massive ingestion of arsenic trisulfide, an arsenic mineral of low solubility, which resulted in minimal symptoms. CASE REPORT: An asymptomatic 57-year-old man presented to an Emergency Department 13h after his reported ingestion of approximately 84g of arsenic contained in a mineral specimen of orpiment (arsenic trisulfide) that had been crushed and mixed with an alcoholic beverage and food. His only symptom before presentation was nausea. Physical examination was unremarkable, and diagnostic tests included a normal electrolyte panel, a normal serum lactate, and a normal electrocardiogram. An abdominal radiograph revealed hyper-dense material scattered throughout the large intestine. As per the recommendations of the regional poison center, the patient was managed with whole bowel irrigation with a polyethylene glycol solution, maintenance intravenous hydration, and observation on a telemetry unit. Chelation was not performed. A spot urine specimen collected 12h after admission contained 1490MUg of total arsenic per liter (background range<50MUg per liter). The patient remained asymptomatic throughout his hospital course. Follow-up studies revealed a diminution in both intra-abdominal radiopacities and urine arsenic concentration. X-ray diffraction analysis of the specimen confirmed its identity as arsenic trisulfide. CONCLUSIONS: Our experience demonstrates that massive ingestion of a poorly soluble inorganic arsenic compound can be successfully managed with gastrointestinal decontamination alone without chelation, provided that the patient remains asymptomatic during close clinical monitoring. PMID- 22541880 TI - Seroprevalence study using oral rapid HIV testing in a large urban emergency department. AB - BACKGROUND: The Centers for Disease Control (CDC) recommends universal human immunodeficiency virus (HIV) testing for patients aged 13-64 years in health care settings where the seroprevalence is>0.1%. Rapid HIV testing has several advantages; however, recent studies have raised concerns about false positives in populations with low seroprevalence. STUDY OBJECTIVES: To determine the seroprevalence of HIV in our Emergency Department (ED) population, understand patient preferences toward rapid testing in the ED, and evaluate the performance of a rapid oral HIV test. METHODS: A serosurvey offered oral rapid HIV 1/2 testing (OraQuick ADVANCE, Bethlehem, PA) to a convenience sample of 1348 ED patients beginning August 2008. Subjects declining participation were asked to complete an opt-out survey. RESULTS: 1000 patients were tested. Twelve had positive results (1.2%), including one who had newly diagnosed HIV infection; 988 patients tested negative. Of these, 335 (33.3%) had never been tested; 640 had prior history of a negative HIV test. No false-positive rapid HIV results were detected; 98.7% received the results of their preliminary HIV test, including 100% of those who tested positive. Most subjects who declined testing cited either a recent negative HIV test (160/348) or low perceived risk (65/348). A minority cited a concern regarding their privacy (11/348) or that the test might delay their treatment (7/348). CONCLUSIONS: The seroprevalence estimate of 1.2% was above the rate recommended by the CDC for routine universal opt-out testing in our study population. The acceptance rate of rapid HIV testing and the percentage of patients receiving results approximated other recent reports. PMID- 22541881 TI - Emergency ultrasound of the gall bladder: comparison of a concentrated elective experience vs. longitudinal exposure during residency. AB - BACKGROUND: It is unknown how an intensive emergency ultrasound (EUS) experience compares with comparable exposure done over the course of residency training. OBJECTIVE: Our objective was to compare the accuracy of EUS of the gall bladder done by physicians after a 2-week EUS elective with similarly numbered examinations done by physicians longitudinally over several years of residency training. METHODS: This was a secondary analysis of a previously reported prospective study of EUS for biliary disease. The 21(st)-40(th) examinations were compared between those who participated in an EUS elective and those who did not. The gold standard was ultrasound done by the Department of Radiology. RESULTS: Mean time to complete 40 EUS examinations for biliary disease was 14 months for those participating in an EUS elective compared with 29 months for those who did not. One hundred and ninety-one examinations (49%) were done by 19 operators who did not participate in an EUS elective and 202 examinations (51%) were done by 23 operators who completed an EUS elective. There was no statistical difference between the two groups with regard to detecting the presence of gall stones, gall bladder wall thickening, pericholecystic free fluid, ductal dilation, or sludge. CONCLUSIONS: Physicians who participated in a 2-week, semi-structured EUS elective demonstrated EUS accuracy for biliary disease that was comparable with those who performed the same number of examinations over a longer period of time. PMID- 22541882 TI - Information tools for environmental risk assessment of low level presence - an introduction to the reviews of the environmental safety of proteins used in genetically engineered plants. AB - Since the first regulatory approval of a genetically engineered (GE) plant was issued in 1992, hundreds of additional GE plants, thousands of regulatory decisions and millions of tons of GE grain and seed have been produced. In an increasingly global economy, the grain and seeds move relatively freely across national jurisdictions, but the regulatory decisions and associated data and analyses do not. Combined with the realities of agricultural production, this has led to a legal and regulatory challenge due to the low level presence (LLP) of GE grain or seeds that do not have regulatory approvals in the country of destination. In order to assist regulators in conducting environmental risk assessments related to LLP, reviews of environmental safety data, including associated regulatory analyses and decisions, for proteins commonly introduced in GE plants have been produced. PMID- 22541883 TI - A review of the environmental safety of the CP4 EPSPS protein. PMID- 22541886 TI - Tooth agenesis in a Portuguese population. AB - OBJECTIVE: The aim of this retrospective study was to evaluate the prevalence and pattern of hypodontia in the permanent dentition, including and excluding third molars, in a Portuguese sample. PATIENTS AND METHODS: The study group comprised 2888 patients, observed between 2005 and 2009 at the Dentistry Clinic of the Instituto Superior de Ciencias de Saude-Norte (ISCSN, Portugal). The patients were examined for evidence of hypodontia and presence or absence of deciduous teeth in those presenting agenesis. The age range varied from 7 to 21 years. In order to study the absence of the third molar, subjects under 14 years were excluded. Statistical analysis was performed using SPSS((r)). RESULTS: Excluding third molars, the prevalence of tooth agenesis was 6.1% for the Portuguese population. Tooth agenesis was found more frequently in females than in males, although this difference was not statistically significant (P>.05). The most commonly missing tooth was the mandibular second premolar, followed by maxillary lateral incisor, and maxillary second premolar. There was a significantly higher prevalence of missing third molars in the agenesis group than in the non-agenesis group. There was a correlation between second premolar and upper lateral agenesis with presence of their corresponding deciduous teeth. CONCLUSIONS: The prevalence of tooth agenesis was found to be 6.1% for this Portuguese population and there was a correlation between agenesis and presence of deciduous teeth and between agenesis and missing third molars. PMID- 22541887 TI - European college of orthodontics: commission of affiliation and titularisation. AB - Date of birth: 28/4/1977; sex: female. A. PRETREATMENT RECORDS: (4/2006; 29 years). DIAGNOSIS: Tooth-arch discrepancy with bi-maxillary protrusion. TREATMENT: Correction of bi-maxillary protrusion; avulsion of 15, 25, 35 and 45; fixed multi-bracket Incognito bi-maxillary appliance; mini-screw anchorage. B. POST-TREATMENT RECORDS DOCUMENTS: (9/2009; 32 years and 6 months). RETENTION: Permanent retainers using fixed upper and lower bonded wires. C. POST-RETENTION RECORDS: (7/2010; 33 years and 3 months). D. CLINICAL OBSERVATION: Reason for consultation: correction of crooked and "jutting" teeth. Extraoral examination: balanced facial levels; lateral view: predominant lower third; closed nasolabial angle; labial asymmetry with predominant lower lips. Endooral examination: young adult dentition; average dental status; large number of fillings; panorex confirms four devitalized teeth; good periodontal status; V-shaped upper arch with lingually ectopic 12 and 22; lower arch with slight incisor crowding; bi lateral molar and canine Class I; crossbite of 12 and 22; 2-mm deepbite and 1-mm overjet. PMID- 22541889 TI - The role of high dose chemotherapy and autologous stem-cell transplantation in peripheral T-cell lymphoma: a review of the literature and new perspectives. AB - Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin's lymphoma that carries, except for ALK-positive anaplastic large cell lymphoma, a poor prognosis. Only a third of patients live 5years past diagnosis. The incidence of PTCL has been increasing during the last two decades. In recent years, there was a rising interest in PTCL manifested by the abundance of publications dedicated exclusively to this disease. The international T-cell lymphoma project was formed with an aim of unifying efforts towards a better understanding of the diagnosis and management of this disease. Given the poor outcomes of PTCL patients, high-dose chemotherapy and autologous stem-cell transplantation (HDT/ASCT) have been used in the up-front and salvage settings, with different success rates. However, there are no prospective randomized controlled trials addressing the role of HDT/ASCT in a PTCL-restricted population. This article critically reviews the data available from the retrospective and prospective studies addressing this topic. We will emphasize the favorable prognostic factors of HDT/ASCT such as a solid remission at the time of transplantation, a chemotherapy sensitive disease and a low prognostic index score. As novel agents and new therapeutic strategies are introduced, there is a continued need for prospective randomized trials to define the optimal use of HDT/ASCT in managing PTCL. PMID- 22541888 TI - Synovial cytokine expression in psoriatic arthritis and associations with lymphoid neogenesis and clinical features. AB - INTRODUCTION: Psoriatic arthritis (PsA) is an autoantibody-negative immune mediated disease in which synovial lymphoid neogenesis (LN) occurs. We determined whether LN is associated with specific patterns of inflammatory cytokine expression in paired synovial tissue (ST) and fluid (SF) samples and their potential correlation with the clinical characteristics of PsA. METHODS: ST and paired SF samples were obtained from the inflamed knee of PsA patients. ST samples were immunostained with CD3 (T cell), CD20 (B cell), and MECA-79 (high endothelial vessels). Total ST mRNA was extracted, and the gene expression of 21 T-cell-derived and proinflammatory cytokines were measured with quantitative real time PCR. SF concentrations of Th1, Th2, Th17, and proinflammatory cytokines were determined with the Quantibody Human Th17 Array. Clinical and biologic data were collected at inclusion and after a median of 27 months of follow-up. RESULTS: Twenty (43.5%) of 46 patients had LN. Only two genes showed differences (Wilcoxon test, P < 0.06) in ST between LN-positive and LN-negative patients: interleukin 23A (IL-23A) (P = 0.058) and transforming growth factor-beta (TGF-beta1) (P = 0.050). IL-23A expression was higher, and TGF-beta1 expression was lower in LN positive patients. ST IL-15 mRNA showed a nonsignificant trend toward higher expression in LN-positive patients, and SF IL-15 protein levels were significantly higher in LN-positive patients (P = 0.002). In all PsA patients, IL 23A mRNA expression correlated with C-reactive protein (CRP) (r = 0.471; P = 0.001) and swollen-joint count (SJC) (r = 0.350; P = 0.018), whereas SF levels of IL-6 and CC chemokine-ligand 20 (CCL-20) correlated with CRP levels (r = 0.377; P = 0.014 and r = 0.501; P < 0.0001, respectively). CONCLUSIONS: These findings suggest differences in the cytokine profile of PsA patients with LN, with a higher expression of IL-23A and IL-15 and a lower expression of TGF-beta1. In the entire group of patients, IL-23 ST expression and CCL20 SF levels strongly correlated with markers of disease activity. This cytokine pattern was not accompanied by gross clinical or biologic differences between LN-positive and negative patients. Taken together, these results suggest a role of the IL-17/IL 23 cytokine axis in synovial LN in PsA. PMID- 22541890 TI - Comparative study of surface plasmon resonance, electrochemical and electroassisted chemiluminescence methods based immunosensor for the determination of antibodies against human growth hormone. AB - An indirect immunoassay format with human growth hormone (hGH) immobilized on the self-assembled monolayer (SAM) modified surface plasmon resonance (SPR) chip has been shown to detect specific anti-hGH antibodies using the combination of three different physical phenomena in the same channel of the SPR analyzer. For the enhancement of analytical signal and sensitivity of the immunosensor horseradish peroxidase (HRP) labeled secondary antibodies, specifically interacting with the formed immune complexes, were used. The electroassisted chemiluminescence (ECL) protocol offered the limit of detection (LOD) as low as 0.061 nM and this result was very similar to that obtained by SPR, which was 0.051 nM. In the case of anti hGH detection using pulsed amperometry (PA) with 3,3',5,5'-tetramethylbenzidine (TMB) and H(2)O(2) in the electrochemical system the LOD was the lowest - 0.027 nm. Lower reproducibility of the analytical signal and higher limit of detection was observed using cyclic voltammetry (CV) where LOD was 0.056 nM. PA detection shows 1.89, 2.07 and 2.26 times higher sensitivity if compared with SPR, CV and ECL, respectively. This work demonstrates successful simultaneous exploitation of several techniques to detect the specific anti-hGH antibodies using indirect immunoassay format on the same area of the SPR-chip. PMID- 22541892 TI - A high-precision angular control system for HIFU calibration. AB - A design of high-precision angular position control system for calibrating high intensity focused ultrasound (HIFU) is presented with alignment procedures. Two independent angular controls are achieved by combining a worm gear and a belt gear system. The proposed system verifies alignment by comparing simulation data and experimental data with three different transducers and two different types of hydrophones. The performance of the proposed system is compared to that of a commercial system. The results indicate that the proposed system provides high precision angular alignment (e.g., <0.01radians) with robust reproducibility regardless of the hydrophone type. PMID- 22541891 TI - Direct fluorimetric sensing of UV-excited analytes in biological and environmental samples using molecularly imprinted polymer nanoparticles and fluorescence polarization. AB - A rapid, robust, sensitive and economic sensing method, based on a molecularly imprinted polymer (MIP) synthetic antibody mimic, and fluorescence polarization analysis, for the direct detection of UV-excited fluorescent analytes in food and environmental samples was developed. Fluoroquinolone (FQ) antibiotics were used as fluorescent model analytes. Water-compatible MIP nanoparticles were synthesized with enrofloxacin (ENRO) as the imprinting template. Fluorescence polarization measurements then allow the direct determination of the amount of ENRO and other structurally related piperazine-based fluoroquinolones that bind to the MIP. No separation step was required since this technique distinguishes in situ analyte molecules bound to the MIP from the free analyte in solution. This assay was successfully applied for the first time to determine FQs in real samples, i.e. tap water and milk, without any prior concentration step, by simply adding a known amount of MIP. No interference by the sample components was observed even though the excitation was in the UV region. In tap water, a low limit of detection of 0.1 nM for ENRO was achieved with 5 MUg mL(-1) of MIP. In milk, ENRO and danofloxacin, whose MRLs have been fixed at 0.28 MUM and 0.08 MUM, respectively, could be selectively measured and distinguished from other families of antibiotics. The procedure is very easy and practical as it consists of simply precipitating the milk proteins with acetonitrile and adding buffer and MIP to the supernatant before reading the polarization values with a spectrofluorimeter. PMID- 22541893 TI - Trabectedin plus pegylated liposomal doxorubicin (PLD) versus PLD in recurrent ovarian cancer: overall survival analysis. AB - AIM: Trabectedin in combination with pegylated liposomal doxorubicin (PLD) improves progression-free survival (PFS) compared to PLD alone in recurrent ovarian cancer (J Clin Oncol 2010;28:3107-14). METHODS: Women, stratified by performance status (0-1 versus 2) and platinum sensitivity (platinum-free interval [PFI]<6 versus >= 6 months), were randomly assigned to receive PLD 30 mg/m(2) IV followed by a 3-h infusion of trabectedin 1.1mg/m(2) every 3 weeks or PLD 50mg/m(2) every 4 weeks. The study was powered to show a 33% increase in overall survival (OS) after 520 deaths had occurred. RESULTS: After a median follow-up of 47.4 months, there were 522 deaths among 672 subjects. The median OS for trabectedin+PLD and PLD arms was 22.2 and 18.9 months, respectively (hazard ratio [HR]=0.86; 95% confidence interval [CI]: 0.72-1.02; p=0.0835). An unexpected but significant imbalance in the PFI favouring the PLD arm (mean PFI: PLD=13.3 months, trabectedin+PLD=10.6 months) was identified. On the basis of this finding, an unplanned hypothesis generating analysis adjusting for the PFI imbalance and other prognostic factors suggested an improvement in OS associated with the trabectedin+PLD arm (HR=0.82; 95%CI: 0.69-0.98; p=0.0285). In another unplanned exploratory analysis, the subset of patients with a PFI of 6-12 months had the largest difference in OS (HR=0.64; 95%CI: 0.47-0.86; p=0.0027). CONCLUSIONS: The final OS analysis did not meet the protocol-defined criterion for statistical significance. Despite stratification on platinum sensitivity, there was an imbalance in mean platinum free interval that had an effect on OS. PMID- 22541894 TI - Effects on post-prandial glucose and AGE precursors from two initial insulin strategies in patients with type 2 diabetes uncontrolled by oral agents. AB - OBJECTIVE: Progressive beta-cell dysfunction in Type 2 diabetes results in the need for insulin therapy in many patients. Yet the best regimen to prescribe to patients transitioning from oral anti-hyperglycemic drugs (OADs) is not clear. We sought to compare the effects of two standard initial insulin strategies (basal insulin alone versus premixed insulin) on post-prandial glucose metabolism and precursors of advanced glycation end-products in patients with type 2 diabetes suboptimally controlled on OADs. RESEARCH DESIGN AND METHODS: This was a 6-month, open-label, single-center study using a cross-over design. 14 subjects were randomized to one of two protocols: once daily insulin glargine or twice-daily 75%/25% neutral protamine lispro/lispro mix. At 12 weeks, the subjects were crossed-over to the opposite protocol. During each period, insulin doses were titrated to target fasting blood glucose of 90-110 mg/dL. At baseline and after the two 12-week treatment periods, subjects were studied in the Clinical Research Center; they consumed three liquid mixed isocaloric meals at 4-h intervals, and glucose, free fatty acids (FFA), lipids, and alpha-dicarbonyls (3-deoxyglucosone [3-DG] and methylglyoxal [MG]) were measured before and after each meal. Patient data were analyzed in the context of their assigned insulin strategy groups. RESULT: Both insulin regimens led to a significant improvement in glycemic profiles, including fasting glucose and HbA1c, compared to baseline. However, mean post-prandial glucose was lower with lispro mix than with glargine (153 +/- 36 vs. 199 +/- 49 mg/dL, respectively; P=0.001). Likewise, there was a reduction in both fasting (48 +/- 13 vs. 57 +/- 19, P=0.047) and post-prandial (53 +/- 19 vs. 63 +/- 23; P=0.007) 3DG levels with lispro mix as compared to glargine. No differences were noted in MG concentrations. CONCLUSION: In type 2 diabetes patients failing OAD therapy, an initial insulin regimen of twice daily premixed insulin results in significantly improved post-prandial glucose levels as well as a reduction in a precursor of AGEs. The effect of these two initial insulin regimens on long-term diabetic complications requires further study. PMID- 22541895 TI - Antidiabetic effect of S-allylcysteine: effect on thyroid hormone and circulatory antioxidant system in experimental diabetic rats. AB - OBJECTIVE: It is considered that diabetes mellitus and thyroid disease are the two common endocrine disorders and also suggested that insulin and thyroid hormones influence each other actions. The present study was designed to investigate the effect of the administration of S-allylcysteine (SAC), a sulfur containing amino acid derived from garlic on blood glucose, insulin, HbA1C, total protein, albumin, Thyroid hormone (T3, T4), TSH, TBARS and circulatory antioxidant levels (SOD, CAT, GSH and GPx) in STZ-induced diabetic rats. METHODS: SAC was administered orally for 45 days to control and STZ induced diabetic rats. The effects of SAC on glucose, plasma insulin, HbA1C, total protein, albumin, Thyroid hormone, TSH and circulatory antioxidant levels were studied. RESULTS: The levels of glucose, TBARS, hydroperoxide and HbA1C were increased significantly whereas the levels of plasma insulin, reduced glutathione, superoxide dismutase, catalase, GSH, GPx, total protein, albumin, Thyroid hormone and TSH were decreased in STZ induced diabetic rats. Administration of SAC to diabetic rats showed a decrease in plasma glucose, TBARS, hydroperoxide and HbA1C. In addition, the levels of plasma insulin, SOD, CAT, GPx, GSH, total protein, albumin, Thyroid hormone and TSH were increased in SAC treated diabetic rats. The effect of SAC was compared with gliclazide, a well-known antioxidant and antihyperglycemic drug. CONCLUSION: From these findings, it is indicated that SAC might be acting through activation in the synthesis and/or secretion of circulating thyroid hormones which in turn stimulate the synthesis of insulin. PMID- 22541896 TI - Inverse optimization of hydraulic, solute transport, and cation exchange parameters using HP1 and UCODE to simulate cation exchange. AB - Reactive transport modeling is a powerful tool to evaluate systems with complex geochemical relations. However, parameters are not always directly measurable. This study represents one of the first attempts to obtain hydrologic, transport and geochemical parameters from an experimental dataset involving transient unsaturated water flow and solute transport, using an automatic inverse optimization (or calibration) algorithm. The data come from previously published, controlled laboratory experiments on the transport of major cations (Na, K, Mg, Ca) during water absorption into horizontal soil columns that were terminated at different times. Experimental data consisted of the depth profiles of water contents (theta), Cl concentrations, and total aqueous and sorbed concentrations of major cations. The dataset was used to optimize several parameters using the reactive transport model, HP1 and the generic optimization code, UCODE. Although the soil hydraulic and solute transport parameters were also optimized, the study focused mainly on the geochemical parameters because the soil columns were constructed from disturbed soil. The cation exchange capacity and the cation exchange coefficients for two exchange models (Gapon and Rothmund-Kornfeld) were optimized. The results suggest that both calibrated models satisfactorily described the experimental data, although the Rothmund-Kornfeld model fit was slightly better. However, information content and surface response analyses indicated that parameters of the Gapon model are well identifiable, whereas those of the Rothmund-Kornfeld model were strongly correlated. The calibrated geochemical parameters were validated using an independent dataset. In agreement with the identifiability analysis, the Gapon approach was better than the Rothmund-Kornfeld model at calculating the observed concentrations of major cations in the soil solution and on the exchange sites. PMID- 22541897 TI - Inflammation and Barrett's carcinogenesis. AB - Barrett's esophagus (BE) is one of the most common premalignant lesions in which normal squamous epithelium of the esophagus is replaced by metaplastic columnar epithelium. Esophageal adenocarcinoma (EA) develops through progression from BE to low- and high-grade dysplasia (LGD/HGD) and to adenocarcinoma. It is widely accepted that inflammation can increase cancer risk, promoting tumor progression. Therefore, inflammation is regarded as the seventh hallmark of cancer. In recent years, the inflammation-cancer connection of Barrett's carcinogenesis has been intensively studied, unraveling genetic abnormalities. Besides genetic alterations, inflammation is also epigenetically linked to loss of protein expression through transcriptional silencing via promoter methylation. Key mediators linking inflammation and Barrett's carcinogenesis include reactive oxygen species (ROS), NFkappaB, inflammatory cytokines, prostaglandins, and specific microRNAs (miRNAs). Therefore, the decipherment of molecular pathways that contain these and novel inflammatory key mediators is of major importance for diagnosis, therapy, and prognosis. The detailed elucidation of the signaling molecules involved in Barrett's carcinogenesis will be important for the development of pharmaceutical inhibitors. We herein give an overview of the current knowledge of the inflammation-mediated genetic and epigenetic alterations involved in Barrett's carcinogenesis. We highlight the role of oxidative stress and deregulated DNA damage checkpoints besides the NFkappaB pathway. PMID- 22541898 TI - The uses and abuses of rapid bioluminescence-based ATP assays. AB - Bioluminescence-based ATP testing of solid surfaces has become well established in the food processing industry as part of general hazard analysis and critical control points (HACCP) measures. The rise in healthcare associated infections (HAIs) at the turn of the century focussed attention on the environment as a potential reservoir of the agents responsible for such infections. In response to the need for objective methods of assessing the efficiency of cleaning in healthcare establishments and for rapid methods for detecting the presence of the pathogens responsible for HAIs, it was proposed that ATP testing of environmental surfaces be introduced. We examine the basis behind the assumptions inherent in these proposals. Intracellular ATP levels are shown to vary between microbial taxa and according to environmental conditions. Good correlations between microbial numbers and ATP levels have been obtained under certain specific conditions, but never within healthcare settings. Notwithstanding, ATP testing may still have a role in providing reassurance that cleaning regimes are being carried out satisfactorily. However, ATP results should not be interpreted as surrogate indicators for the presence of microbial pathogens. PMID- 22541899 TI - [Current role of lymph node dissection in renal cell carcinoma: review of the literature by the Oncology Committee of the French Association of Urology (CCAFU)]. AB - Nowadays, most of renal cancers are incidental tumors less than 4 cm. Prevalence of lymph node involvement is low and does not require a systematic lymphadenectomy as described by Robson in the 1960s. Radiologic progress and particularly CT scan describe with high precision lymph node involvement in the initial work-up. In renal cancer with a high risk of recurrence, lymphadenectomy has a pronostic interest and therapeutic role in rare situations where lymph node involvement is isolated. In metastatic patients, the role of cytoreductive nephrectomy has to be assessed. PMID- 22541900 TI - [The sacral neuromodulation in double incontinence treatment: a review]. AB - Urinary and fecal incontinence are common conditions which are frequently associated and defining double incontinence. When conservative treatments fail, sacral nerve modulation (SNM) is considered to be a first-line treatment for patients with urge urinary incontinence and for patients with fecal incontinence. The present article aims to determine the effect of SNM on the treatment of double incontinence. A medline search for clinical studies with SNM and double incontinence was carried out, extracted data were reviewed and analysed. The results of SNM in patients with double incontinence has been reported in seven studies (120 patients). The percentage of patients suffering from double incontinence improved on the urinary and fecal incontinence varied between 32% to 75%. This review reports the effectiveness of the SNM on the urinary and fecal incontinence in this population of double incontinence patients. Its main advantage would be to treat two incontinence by a single treatment. The search of predictive factors of success must be given. PMID- 22541901 TI - [The hypofractionated radiotherapy in the treatment of the prostate cancer: radiate less to treat more]. AB - The principle of the hypofractionation in radiotherapy is to deliver a higher dose by session and to reduce the duration of treatment. In the particular case of the cancer of prostate, a hypofractionned protocol allows to deliver an equivalent radiobiological dose identical even higher than a standard plan of irradiation. The hypofractionation is presented as a solution to improve the access to the care (fewer processing times by patient, more patients treated by machine) while increasing the quality of the care: better carcinologic control, less radiotoxicity. The objective of this article is to make a clarification on the hypofractionned radiotherapy in first intention in the treatment of the localized prostate cancer. We count three studies on large cohorts, comparing standard plans to 1.8-2 Gy/session and hypofractionned plans (2.5-3 Gy/session). The inferior carcinologic results of the two first comparative studies with regard to the study of phase I/II of the Cleveland clinic were owed to a sub dosage of hypofractionned plans. The administered equivalent biological doses were lower than the at present recommended total doses and lower than the theoretical doses, calculated on the bases of an erroneous evaluation of the radiosensibility of the prostate cancer. In the comparative study of Arcangeli, the rate of survival without biological recurrence in 4 years (82%) was significantly to the advantage of the hypofractionned group, while reducing the duration of treatment of 3 weeks. Four comparative studies reported aigues/late toxicity, gastrointestinal (GI)/genito-urinary acceptable (GU) even lower with a hypofractionned plan. The hypofractionation is potentially the future of the radiotherapy in the treatment of the localized prostate cancer thanks to the technological innovation, but for all that does not constitute at present a standard. PMID- 22541902 TI - [Prognostic significance of lymphovascular invasion in upper urinary tract carcinoma: a retrospective monocentric analysis]. AB - OBJECTIVE: To analyze the prognostic impact of lymphovascular invasion (LVI) in case of urothelial carcinoma of upper urinary tract (UUT-UC). PATIENTS AND METHODS: Retrospective study of 83 consecutive patients treated surgically for UUT-UC between January 1998 and October 2008. Prognostic interest of histopathological factors (stage, grade, LVI, CIS, tumor architecture, location, nodal status and surgical margins) was assessed in univariate and multivariate Cox regression model. Specific survival (SS), recurrence-free survival (RFS) and metastasis-free survival (MFS) were calculated using Kaplan-Meier method and Log Rank test. RESULTS: LVI was observed in 26.5% of patients after histopathologic reviewing. The SS, RFS and MFS at 2 years were 93%, 76% and 96% respectively in group without LVI compared to 40%, 13% and 38% in group with LVI (P<0.001). In univariate analysis, pathological stage, LVI and margin status were predictive of SS (P<0.05). Pathological stage, LVI and surgical margin status were predictive of RFS (P<0.05). LVI, tumor architecture and status of surgical margins were predictive of MFS (P<0.05). LVI was the only independent predictive factor in multivariate analysis for all survival (P=0.002, 0.002 and 0.001 respectively for the SS, RFS and MFS). CONCLUSION: LVI was a poor prognostic factor in cases of UUT-UC. This criteria should be routinely sought and included in the pathology report. PMID- 22541903 TI - [Long-term outcome of patients with renal transplant and neural tube defect]. AB - PURPOSE: To evaluate the long term outcome of renal transplant in patients with a neural tube defect causing voiding dysfunctions. PATIENT AND METHODS: Between 1993 and 2010, 18 cadaveric renal transplants were performed in 16 patients (5 females and 11 males) older than 15 years with a neural tube defect and voiding dysfunction. RESULTS: The patients had dialysis since the mean age of 27.4 and have been transplanted at the mean age of 32.2. The survival rate of the first kidney transplant was 93.75% at 1 year and 63.3% at 5 and 10 years respectively. With a mean follow-up of 6.67 years, 11 out of 16 first transplants remained functional (68.75%) The median survival of the first transplants was 13.52 years. At the end of the follow-up, 13 out of 18 transplants were still functional (72.2%). The mean serum creatinine level was 123.9 micromol/l with a mean glomerular filtration rate estimated by the simplified MDRD formula of 67 ml/min for the 13 still functional transplants. Before transplantation, 66% of patients had a neuro-urologic assessment versus 100% thereafter. CONCLUSION: Renal transplantation in patients with neural tube defect is feasible without surgical particularities to those of other renal failure causes. These type of patients represented less than 1% of the followed cohort with an average graft survival rate of 63.3% at five and 10 years. The median survival time of the first graft was 13.52 years. PMID- 22541904 TI - [Place of bilateral pulpectomy as a method of androgen suppression therapy in prostate cancer]. AB - PURPOSE: To report the oncologic results and morbidity of bilateral pulpectomy and to identify factors that make this method of androgen suppression therapy the most used in our country. PATIENTS AND METHODS: We conducted a prospective study in the urology department of Aristide Le-Dantec hospital (Dakar) between January 2008 and June 2010 (30 months). It included 84 cases of prostate cancer treated by bilateral pulpectomy under local anesthesia. RESULTS: The mean age of patients was 72.17+/-12.48 years (53-91). The median PSA level was 101 ng/mL (12.18-9990). Metastasis have been detected in 75% of cases. The Gleason score was higher than 7 in 40 patients (47.6%). Three months after pulpectomy, an improvement of performance status was seen in 76 patients (90.4%). The back pain significantly decreased in intensity or disappeared in 65.3% (32/49) of cases. A complete recovery of lower limbs motor deficit was observed in 50% of cases (7/14). The PSA levels decreased in 57 of the 76 patients alive and the mean PSA level was then 72+/-11.7 ng/mL (3.8-2433). At six months, of the 53 patients in urinary retention, 18 had recovered spontaneous and complete urination. The PSA level was below 4 ng/mL in 33.8% (22/65) of cases and between 4 and 10 ng/mL in 52.3% (34/65) of cases. At 12 months, the median PSA nadir was 0.76 ng/mL (0,002-8,17) and 57.4% of the 54 patients alive had a PSA nadir less than 2 ng/mL. The mean follow-up was 11.08+/-10.34 months (1-30). A rising PSA occurred in 17 patients (20.2%) after an mean progression-free survival of 10.5 months (6-25). The overall survival at 6, 12 and 24 months were respectively 77.3, 64.3 and 52.3%. The overall cost of pulpectomy was 50 000 FCFA (76?). The specific morbidity of pulpectomy was two cases (2.4%) of infection of the operative site. CONCLUSION: The bilateral pulpectomy was a method of androgen suppression immediately effective, efficacious with a low morbidity. Its very low cost is the main reason why it is still the most used method in our country. PMID- 22541905 TI - [French translation and linguistic validation of the questionnaire Bladder Cancer Index (BCI)]. AB - OBJECTIVE: Translation and linguistic validation of the French version of Bladder Cancer Index (BCI). MATERIAL AND METHODS: A double-back translation of the original Bladder Cancer Index was performed. First, two urologists translated the English version in French. Then, a first consensus meeting between the translators and a group composed of urologists and nurses was achieved. Back translation of this version was then done by professional translators (Nagpal, Paris) to ensure that no distortion was detected between the two questionnaires. Finally, a pilot study followed by an interview was carried out among one woman and five men having bladder cancer. RESULTS: The consensus version is attached to the article. No difficulties were reported by the pilot population to comprehend or to complete this BCI French version. CONCLUSION: This BCI French version attached to the article-makes it possible for researchers among a French population to use this validated and internationally recognized tool among a French population. The impact of various bladder cancer treatment on quality of life could hence be assessed and compared. PMID- 22541906 TI - [Asynchronous implantation of a penile prosthesis (AMS 700) in patients with an artificial urinary sphincter (AMS 800): what functional outcomes can we expect from the AMS 1500?]. AB - OBJECTIVE: To report the functional results and morbidity after metachronous implantation of an AMS 800 artificial urinary sphincter (AUS) and an AMS 700 inflatable penile prosthesis (IPP). PATIENTS AND METHODS: From the 250 patients treated in our department between 2000 and 2011 for the insertion of an AUS, we retrospectively selected patients who also underwent implantation of an IPP. The following data were recorded: age, aetiology of urinary incontinence (UI) and erectile dysfunction (ED), treatment history of UI/ED, date of insertion of the AUS and the IPP and time gap between the two implants. We evaluated both the pad test and the number of protective pads used per day, before and after AUS insertion. We also analysed the IIEF5 score before and after IPP. Patients were reviewed at 3, 6 and 12 months and annually thereafter. RESULTS: In total, five patients were included. The median age was 69 years. The median follow-up after IPP was 22.6 months and the time gap between the two implants was 50 months. The aetiology of UI and ED was prostate surgery in four cases. Complete continence without leakage was observed in three patients and the IIEF5 score increased from 6.6 preoperatively to 22.2 for four patients. One patient developed a urethral erosion of the AUS cuff 6 months after implantation of the IPP. The AUS cuff has been explanted but the patient remains continent with the IPP cylinders semi inflated. CONCLUSION: From our small study, it appears that the combined use of an AMS 800 AUS and an AMS 700 IPP was a feasible and efficacious option in patients with concomitant refractory UI and ED. PMID- 22541907 TI - [Carcinosarcoma of the renal pelvis in a horseshoe kidney: about a case]. AB - Carcinosarcoma of the renal pelvis is a rare tumor, and its development in a horseshoe kidney makes it even more special. This is the first case reported in the literature of a renal pelvis carcinosarcoma developed in a horseshoe kidney and diagnosed on macroscopic hematuria. PMID- 22541908 TI - [Existence of lymphovascular invasion has to be assessed on pathological report after removal of a tumor of the upper urinary tract]. PMID- 22541909 TI - [Is combined prosthetic surgery a valid option in end stage impotence and male urinary incontinence?]. PMID- 22541910 TI - Atraumatic, symptomatic ankle plica successfully treated by arthroscopic debridement: a case report. AB - Synovial plicae, both symptomatic and asymptomatic, are increasingly being diagnosed with the expansion of arthroscopic procedures in synovial joints. Ankle plicae, however, remain an uncommon diagnosis and have previously only been reported as symptomatic in the post-traumatic ankle. Here the authors present a case report of an atraumatic, symptomatic ankle plica successfully treated with arthroscopic debridement. PMID- 22541911 TI - Temporary joint-spanning external fixation before internal fixation of open intra articular distal humeral fractures: a staged protocol. AB - INTRODUCTION: This study determined outcomes after temporary joint-spanning external fixation before internal fixation of open intra-articular distal humeral fractures. MATERIALS AND METHODS: A retrospective case analysis was done of all patients who were treated between 2000 and 2008 in 3 level I trauma centers with temporary joint-spanning external fixation before internal fixation of an open intra-articular distal humeral fracture. Healing rates, complications, Disabilities of Arm, Shoulder and Hand (DASH), and Smith and Cooney outcome scores were documented. RESULTS: The study included 16 patients. Mean follow-up was 35.2 months. Fractures united after an average of 5.2 months. No complications specifically related to the external fixation occurred. The DASH outcome score averaged 15.1. Although complications occurred in 12 patients (9 patients requiring surgery), 10 of 16 had an excellent/good outcome score. CONCLUSIONS: Temporary joint-spanning external fixation before internal fixation of open intra-articular distal humeral fractures is a safe adjunct. PMID- 22541912 TI - Acromioclavicular joint reconstruction: a comparative biomechanical study of three techniques. AB - BACKGROUND: Acute acromioclavicular joint dislocations indicated for surgery can be treated with several stabilization techniques. This in vitro study evaluated the acromioclavicular joint stability after 3 types of validated repair techniques compared with the native situation. MATERIALS AND METHODS: Nine pairs (right-left) of intact cadaveric shoulder specimens were assigned to 3 study groups with randomly distributed samples according to the coracoclavicular distance. The groups were instrumented with acromioclavicular and coracoclavicular cerclages (CE), a Twin Tail TightRope (TR), or a locking compression superior and anterior clavicle plate (CP). Native and instrumented specimens were tested quasi-static nondestructively (superior: 70 N; anteroposterior: +/- 35 N, 10 mm/min) and cyclically until failure (superior, valley load: 20 N; initial peak load: 70 N; increment: 0.02 N/cycle). RESULTS: The TR study group showed the highest (in N/mm) superoinferior (73.77 +/- 14.04) and anteroposterior (29.58 +/- 1.52) stiffness, followed by CE (superoinferior: 59.73 +/- 10.33; anteroposterior: 24.31 +/- 4.14) and CP (superoinferior: 24.08 +/- 5.29). Instrumentation generally led to increased superoinferior and anteroposterior stiffness in each study group but to a significant superoinferior stiffness reduction for CP (P = .029). Significantly lower coracoclavicular displacement at valley load after 1 and 500 cycles was observed for TR (P = .018) and CE (P = .041) compared with CP. Cycles to failure were significantly higher in CE (7298 +/- 1244 cycles, P = .011) and TR (4434 +/- 727 cycles, P = .031) compared with CP (1683 +/- 509 cycles). CONCLUSIONS: The CE and TR techniques led to similar biomechanical performances. The CE repair might mimic the native acromioclavicular joint stiffness better than the other 2 setups, leading to more physiological stabilization. PMID- 22541913 TI - [Lights and shadows of cytomegalovirus infection in solid organ transplantation]. AB - Cytomegalovirus (CMV) develops in 30-80% of patients undergoing solid organ transplantation (SOT). The incidence and presence of symptomatic disease varies depending on the type of transplant, the presence of associated risk factors, the intensity of immunosuppression, and the prevention strategies used. The impact of CMV on SOT is due not only to the effects of CMV disease per se, but also to its multiple indirect effects resulting from its immunomodulatory role and immunoactivation caused by viral latency. The two prophylactic strategies used (universal prophylaxis and preemptive therapy) are equally useful. Both strategies have advantages and disadvantages, and uncertainties remain on the populations that should receive prophylaxis and for how long. Viral monitoring to detect CMV infection is important for diagnosis, prognosis and evaluation of treatment response. The new real-time polymerase chain reaction techniques have provided numerous advantages but standardization remains an issue and common reference values are required. Specific anti-CMV drugs are available but issues such as the role of valganciclovir versus ganciclovir, the development of resistances and optimal treatment length are still being debated. Complementary therapy with mTOR inhibitors and vaccine strategies against CMV are alternatives for which conclusive data are lacking. PMID- 22541914 TI - [Key definitions and concepts in cytomegalovirus: infection versus disease. Replication, viral load, universal prophylaxis. Preemptive therapy]. AB - Although advances have been made in the prevention, diagnosis and treatment of cytomegalovirus (CMV), this infection continues to be a major complication in transplant recipients, causing considerable morbidity and occasionally mortality. There is wide variability in definitions of CMV infection, which can lead to conceptual errors. The present article attempts to standardize the definitions used, which have recently been revised and recommended by the American Society of Transplantation for the purpose of developing consistent reporting of CMV in clinical trials. The concepts of infection and viral replication, persistence and recurrence of infection, viremia and disease are discussed, together with the diagnostic criteria for febrile syndrome and visceral involvement. Methods for preventing CMV infection, universal prophylaxis and preemptive therapy are also mentioned. PMID- 22541915 TI - [Indirect effects of cytomegalovirus infection]. AB - Despite improvements in prevention strategies, cytomegalovirus (CMV) continues to be the main cause of infection in solid organ transplant recipients. In these patients, in addition to direct effects, such as viral syndrome or invasive organ disease, CMV can cause indirect effects resulting from the interaction of the virus with the host's immune system. This interaction may increase immunosuppression, with a consequent rise in opportunistic infections and the risk of malignancies (Epstein-Barr virus-associated posttransplantation lymphoproliferative disease) and graft dysfunction. Currently, a direct causal relation between CMV and most of the indirect effects described cannot be established. However, numerous experimental and clinical studies have found an association between the development of these effects and CMV. Moreover, some of these effects, such as the development of opportunistic infections, have been reduced by CMV prophylaxis. PMID- 22541916 TI - [Risk factors for cytomegalovirus in solid organ transplant recipients]. AB - Cytomegalovirus (CMV) is the most important opportunistic pathogen in patients undergoing solid organ transplantation and increases mortality due to both direct and indirect effects. The most important risk factor for the development of CMV disease is discordant donor-recipient CMV serology (positive donor and negative recipient), which confers more than 50% risk of developing CMV disease if no prophylaxis is given. The use of highly potent antiviral agents for CMV prophylaxis in high-risk patients has changed the characteristics of CMV disease in this population. Other classical risk factors for CMV disease include acute graft rejection, the type of organ transplanted, coinfection with other herpesviruses and the type of immunosuppressive agents employed. New risk factors for this complication have recently been described, including variations in the CMV genotype between donor and recipient and genetic alterations in the recipient's innate immunity. The present review discusses classical risk factors and the latest findings reported on the development of CMV in organ transplant recipients. PMID- 22541917 TI - [Monitoring techniques in cytomegalovirus infection in solid organ transplant recipients]. AB - The availability of antiviral drugs for cytomegalovirus (CMV) in clinical practice, along with advances in methods of laboratory diagnosis, has substantially alleviated the negative effects of CMV infection in solid organ transplant recipients. Nevertheless, CMV continues to be a significant cause of morbidity and mortality in these patients. Virological monitoring plays a crucial role in controlling these negative consequences. Several diagnostic techniques are now available but not all are applicable in the transplant setting, nor are they all suitable for different clinical situations. Selection of a particular method depends on the clinical objective, the technical profile of the test and the possibilities of the laboratory. Serological tests are useful during pretransplant evaluation of both donor and candidates, the most suitable for this purpose being those that detect IgG antibodies. After transplantation, methods for determining CMV viral load are the cornerstone of diagnosis, prognosis (e.g., as a guide for preemptive therapy), and antiviral treatment monitoring, as well as a first alert on the emergence of drug resistant mutants. The pp65 antigenemia test remains useful as a measure of CMV viral load, but molecular assays are progressively replacing antigenemia in most laboratories because of technical issues. Despite advances in methodological standardization, no reference breakpoint values for viral load interpretation are available, and each center should obtain these values based on their own experience. PMID- 22541918 TI - [Resistance studies: when are they indicated?]. AB - Cytomegalovirus (CMV) resistance to antiviral drugs is an emerging problem and is due to selection of mutations in the viral genome. Although ganciclovir resistance is the most common and widely studied, there is resistance to all antiviral agents. Risk factors for the development of resistance are the absence of preexisting immunity to CMV, lung and pancreas transplantation, high viral loads, intense concomitant immunosuppressive therapy and prolonged exposure to ganciclovir or suboptimal levels of this drug. Antiviral resistance should be suspected when, despite adequate treatment exposure for 2 weeks, an increase in viral load, or persistence or clinical progression of CMV disease are detected. However, failure to respond cannot always be attributed to antiviral resistance nor does resistance always lead to poor clinical outcome. When resistance is suspected, phenotypic and genotypic confirmation is required. The most common mutations are those in the UL97 gene, which confers ganciclovir resistance. However, foscarnet and cidofovir can be used. The UL54 mutation is not uncommon, whether alone or in combination with UL97 mutations. The combination of UL54 and UL97 mutations is associated with high-grade and multiple resistance. Early detection of resistance is essential to prevent unfavorable outcome and the development of multi-drug resistance. In patients with a slow response to treatment and without mutations associated with resistance, plasma ganciclovir levels and specific CMV immunity should be investigated. PMID- 22541919 TI - [Immunological monitoring strategies for cytomegalovirus infection. Immune-based therapies]. AB - T-cell response to cytomegalovirus (CMV) is essential in the control of viral replication. Quantification of functional CD4(+) and CD8(+) T lymphocytes against certain CMV-antigen specificities through flow cytometry, ELISPOT or the QuantiFERON-CMV kit allows fairly accurate estimation of the risk of active infection and CMV disease in solid organ transplantation (SOT). Combined virological and immunological monitoring of CMV infection could allow antiviral treatments to be individually tailored and optimized in SOT, although clinical experience is currently lacking. The adoptive transfer of CMV-specific T cells before selection with multimer HLA peptides or after activation and expansion ex vivo could be an effective therapeutic alternative in the management of active infection or organic CMV disease refractory to antiviral therapy. Several CMV vaccines have been developed, which have been shown to be safe and immunogenic in preclinical and Phase I clinical trials. However, to date, none of these vaccines has been evaluated in Phase III clinical trials and consequently none has been approved for clinical use. PMID- 22541920 TI - [Prevention of cytomegalovirus infection: preemptive therapy versus universal prophylaxis]. AB - Despite the advances made in the diagnosis and treatment of cytomegalovirus (CMV) infection, this pathogen continues to cause substantial morbidity in solid organ transplant (SOT) recipients. The two main strategies for the prevention of CMV disease are universal prophylaxis and preemptive therapy. Several meta-analyses have found that both strategies are effective in the prevention of CMV disease in SOT recipients compared with placebo, each with its own advantages and disadvantages. Nevertheless, few studies have compared the two approaches to CMV disease in SOT recipients. The present article provides a review of the indications of each of these strategies and the main studies on which they are based. PMID- 22541921 TI - [Prophylaxis of cytomegalovirus infection in renal transplantation]. AB - Cytomegalovirus (CMV) infection remains a major problem in renal transplant recipients. CMV produces not only febrile syndromes and/or visceral disease but also contributes to the development of acute rejection and chronic graft failure. Valganciclovir prophylaxis has represented a major advance in controlling this infection, but late CMV infection after prophylaxis can occur, especially when universal prophylaxis is used. The use of valganciclovir prophylaxis for 200 days is more effective than prophylaxis for 100 days but does not completely prevent this problem. Prophylaxis based on the detection of CMV viremia (early prophylaxis or preemptive therapy) may prevent the development of delayed CMV disease, but has the disadvantage of requiring more intensive monitoring of viremia and does not prevent the development of viremia and its potential consequences in the long term. This article reviews current recommendations for prophylaxis of CMV disease in renal transplantation. PMID- 22541922 TI - [Prophylaxis of cytomegalovirus infection in liver transplantation]. AB - CMV prevention strategies in liver transplant recipients should be stratified according to serological status. In donor (D)-/recipient (R)- combinations, no prophylaxis or preemptive therapy is recommended. In the remaining combinations, the most widely used strategies are universal prophylaxis and preemptive therapy. Both strategies are effective compared with placebo but have not been compared with each other in well-designed clinical trials. Preemptive therapy is the preferred strategy in low-risk patients while prophylaxis is the most widely used option in those at high-risk. Delayed CMV disease is an adverse consequence of universal prophylaxis. Prolongation of prophylaxis from 100 to 200 days does not reduce the incidence of CMV disease. CMV-specific cell mediated immunity, facilitated by preemptive therapy and delayed by prophylaxis, has a therapeutic effect by reducing CMV replication. The drug of choice in both strategies is valganciclovir but the duration and dose differ. When preemptive therapy is used, viremia monitoring is required for the first 4 months. The technique of choice is quantitative polymerase chain reaction. Given the lack of conclusive data, the choice of one or other strategy in these patients should be individualized in each patient and center according to the available resources and possibilities of follow-up. PMID- 22541923 TI - [Prevention of cytomegalovirus disease in lung transplantation]. AB - Lung transplant recipients, more than other organ transplant recipients, are at particular risk for cytomegalovirus (CMV) infection and disease. CMV prevention avoids the indirect effects of this virus, such as opportunistic fungal infections and obliterative bronchiolitis, the latter being the major limiting factor in the long-term success of lung-transplantation. CMV prevention strategies have significantly reduced CMV disease and CMV-related mortality. Two major strategies are commonly used for CMV prevention: universal prophylaxis and preemptive therapy. In lung transplant recipients, the efficacy and safety of preemptive treatment have not been studied and therefore, cannot be recommended. Universal prophylaxis is the best strategy for preventing CMV disease in lung transplant recipients. There is no consensus on the optimal duration of prophylaxis, but the recently published GESITRA-SEIMC/REIPI 2011 Guidelines for the management of CMV infection in solid-organ transplant patients recommend 6 months posttransplantation. In D+/R- recipients, this period can be prolonged to 12 months if there are difficulties in monitoring at 6 months posttransplantation. The future of prevention will probably depend on immunoguided strategies. PMID- 22541924 TI - [Prophylaxis of cytomegalovirus infection in heart transplantation]. AB - Cytomegalovirus (CMV) is a common complication after heart transplantation, affecting almost half of all recipients. The clinical spectrum of this infection includes, in order of greater to lesser severity, latent infection, asymptomatic viremia, CMV syndrome and CMV disease. CMV is associated with rejection and vascular graft disease and is a major cause of morbidity and mortality. The factors most frequently involved in susceptibility to this infection and its severity are donor and recipient CMV serological status, the intensity of immunosuppression and the type of immunosuppressive agents used. The management strategies of this infection include universal or targeted prophylaxis, preemptive therapy and treatment of established disease. The use of preventive measures significantly reduces the incidence of symtomatic infection or CMV disease, which has been reported to be less than 3% in some recent series. PMID- 22541925 TI - [Prophylaxis of cytomegalovirus infection in pancreatic transplantation]. AB - Pancreatic transplantation carries a higher risk of cytomegalovirus (CMV) infection than renal transplantation alone. The management of CMV disease in pancreatic transplantation depends on the risk indicated by the donor's and recipient's serological profiles (CMV IgG) and the use of antibodies as immunosuppressive therapy (especially thymoglobulin). Most clinical guidelines recommend the use of prophylaxis in preference to preemptive therapy in both donor (D)+/recipient (R)- and D+/R+ pancreatic transplantations. In combinations with highest risk (D+/R-), prophylaxis with valganciclovir 900mg per day for 3 to 6 months is recommended, adjusted to renal funtion. In D+/R+ combinations, if antibody therapy was used in the transplant or in rejection, valgancioclovir prophylaxis is also recommended for 1 to 3 months. When prophylaxis is finished, in both cases, viral load determination (quantitative polymerase chain reaction of CMV) or antigenemia should be carried out for the first year. In D-/R combinations, preemptive therapy can be considered with determinations of viral load or antigenemia at each follow-up visit during the first year. Once prophylaxis has been suspended, special attention should be paid to the development of delayed CMV disease. PMID- 22541926 TI - [Prophylaxis of cytomegalovirus infection in intestinal transplantation]. AB - Intestinal transplant recipients are at high risk of cytomegalovirus (CMV) disease due to the specific characteristics of the graft and the intense cellular immunosuppression caused by immunosuppressive induction therapy in this type of transplantation. The most frequent form of CMV disease is graft enteritis. Diagnosis of this entity is not always straightforward given that antigenemia for CMV is frequently low grade or negative and the pathological findings can be confused with those of rejection. Diagnosis is aided by immunohistochemistry or molecular biological detection in biopsies of the colon. Current recommendations for the preventive management of CMV disease are based on sporadic experiences and expert opinion, given the lack of specifically-designed, high-quality studies in this type of transplant recipient. In general, universal prophylaxis against CMV is preferred in these patients, initially with intravenous ganciclovir and subsequently with oral valganciclovir for a minimum of 6 months, although this prophylaxis can be prolonged for up to 1 year depending on the type of immunosuppressive therapy used. Several groups also use CMV-specific immunoglobulin. PMID- 22541927 TI - [Treatment of cytomegalovirus disease]. AB - For years, intravenous ganciclovir has been the recommended treatment for cytomegalovirus (CMV) in transplant recipients. Recently, oral valganciclovir has been shown to induce a response to CMV similar to that produced by intravenous ganciclovir and could consequently be an alternative to ganciclovir in patients with non-severe disease. Sequential therapy with ganciclovir followed by valganciclovir, after the onset of clinical improvement, reduces costs and avoids prolonged hospital stays, thus benefitting patients. Optimal treatment duration is guided by clinical response and virological monitoring (polymerase chain reaction or antigenemia) and is maintained until the results are negative. Some groups use secondary prophylaxis in patients with risk factors for recurrence of CMV disease. Reducing the intensity of immunosuppression or complementing antiviral therapy with immunoglobulins can be considered in patients with severe disease or immunodepression. There are no conclusive data on the most effective treatment in ganciclovir-resistant CMV. Therapeutic decisions should be based on genotypic resistance studies, the patient's immune status and disease severity. Treatment consists of foscarnet alone or in combination with ganciclovir in the most severe forms and in high-resistance mutations, or in increasing the dose of ganciclovir in clinical forms or in mild resistance. There are no conclusive data on alternative antiviral drugs or complementary therapy with mTOR inhibitors. Several CMV vaccines are under development and the preclinical results are encouraging. PMID- 22541928 TI - [Special considerations in the management of cytomegalovirus infection in pediatric solid organ transplant recipients]. AB - In pediatric patients, the main risk factor for the development of post transplantation cytomegalovirus (CMV) is the absence of specific immunity to the virus in the pretransplantation period. CMV infection has become less of a problem in pediatric solid organ transplant (SOT) recipients mainly due to the availability of sensitive diagnostic techniques, the development of prevention strategies, and the possibility of starting effective antiviral treatments. Both polymerase chain reaction (PCR) techniques and pp65 antigenemia have proved to be effective in the diagnosis and monitoring of children with CMV infection. However, in some types of transplantation, such as lung transplantation, CMV infection continues to be an important risk factor for mortality or retransplantation in D+/R(-1) patients. Prophylaxis with ganciclovir followed by valganciclovir for between 3 and 6 months is recommended over preemptive therapy. In the treatment of CMV disease, the use of ganciclovir is recommended until a negative weekly result of PCR or pp65 antigenemia is obtained. The total duration of treatment, both in viral syndrome and organ disease, is the same as in adults. Treatment can be completed by substituting intravenous ganciclovir for oral treatment in older children and adolescents. PMID- 22541929 TI - Efficacy of topical blockade of interleukin-1 in experimental dry eye disease. AB - PURPOSE: To evaluate the therapeutic efficacy of topical interleukin-1 receptor antagonist (IL-1Ra) in the treatment of dry eye disease. DESIGN: Laboratory investigation. METHODS: Dry eye disease was induced in C57BL/6 female mice through exposure to a desiccating environment within a controlled environment chamber. Topical formulations containing 5% IL-1Ra, 1% methylprednisolone, 0.05% cyclosporin A, and a vehicle control containing carboxymethylcellulose sodium were applied after the induction of dry eye. Corneal fluorescein staining was performed by a masked observer in the different treatment groups. Immunohistochemical studies were undertaken to enumerate corneal CD11b+ cells, as well as to evaluate corneal lymphangiogenesis. Real-time polymerase reaction was used to quantify the expression of interleukin-1beta in the cornea. RESULTS: A significant decrease in corneal fluorescein staining was observed after topical treatment with 5% IL-1Ra (P < .01), 1% methylprednisolone (P < .01), and 0.05% cyclosporin A (P < .03). Additionally, a significant decrease in the numbers of central corneal CD11b+ cells (P < .05), corneal lymphatic growth (P < .05), and corneal interleukin-1beta expression (P < .003), compared with vehicle treated, were demonstrated only after treatment with 5% IL-1Ra and 1% methylprednisolone, and were absent after cyclosporin A treatment. CONCLUSIONS: Topical treatment with IL-1Ra is effective in ameliorating the clinical signs of the dry eye disease, as well as in reducing underlying inflammation. These effects are comparable with those resulting from treatment with topical methylprednisolone. Topical IL-1Ra may hold promise as a novel therapeutic strategy in the treatment of dry eye. PMID- 22541930 TI - Morphometric spectral-domain optical coherence tomography features of epiretinal membrane correlate with visual acuity in patients with uveitis. AB - PURPOSE: To identify visually significant spectral-domain optical coherence tomography (SD-OCT) features of epiretinal membranes (ERM) in patients with uveitis. DESIGN: Retrospective cohort and cross-sectional study. METHODS: Eighty consecutive eyes with uveitis and SD-OCT-documented ERM were included. Clinical data were collected at the time of diagnosis of ERM and at the final visit. SD OCT images at the last visit were evaluated to identify fovea and ERM configuration and structural changes. Changes of 10% and 20% in central subfield thickness between initial and last SD-OCT were calculated and correlated with visual acuity (VA). An ERM thickness map was created using validated SD-OCT grading software. RESULTS: VA improved significantly in eyes with more than 12 months of follow-up (P = .03). Although inflammation activity and medical treatment methods were no different in eyes with more or less than 12 months of follow-up, 16 eyes in the subset with longer follow-up underwent cataract extraction and intraocular lens implantation. Kaplan-Meier analysis demonstrated few vision losses during the follow-up period. Change in central subfield thickness did not correlate with VA. Foveal center involvement (P < .001), focal attachment of the ERM (P = .003), and foveal inner segment and outer segment junction disruption (P = .006) were associated independently with lower VA. ERM was thinner in eyes with 20/40 or better VA (4.6 +/- 0.6 MUm) compared with eyes with VA of less than 20/200 (P = .02). Longer duration of ERM was associated with thicker ERM (P < .05). CONCLUSIONS: In most eyes with uveitis and ERM, VA remains stable if ocular inflammation and comorbidities are addressed appropriately. PMID- 22541931 TI - The impact of cataract, cataract types, and cataract grades on vision-specific functioning using Rasch analysis. AB - PURPOSE: To determine the impact of cataracts and their types and grades on vision-specific functioning. DESIGN: Prospective population-based cross-sectional study. METHODS: The Singapore Indian Eye Study examined 3400 of 4497 (75.6% response rate) ethnic Indians 40 years of age and older living in Singapore. Three thousand one hundred sixty-eight (93.2%) fulfilled inclusion criteria with complete information for final analysis. Cataracts were assessed on slit-lamp examination and were graded according to the Lens Opacity Classification System III. Vision-specific functioning scores were explored with the Visual Function scale, validated using Rasch analysis. RESULTS: Two hundred sixty-nine (8.5%) and 740 (23.4%) of the study participants had unilateral and bilateral cataracts, respectively, and 329 (10.4%), 800 (25.2%), and 128 (4.1%) participants had nuclear, cortical, and posterior subcapsular (PSC) cataracts, respectively. In multivariate linear regression models, the presence of bilateral rather than unilateral cataract (beta = -0.12; 95% confidence interval, -0.20 to 0.00) was associated independently with poorer vision-specific functioning, even after adjusting for undercorrected refractive error (beta = -0.11; 95% confidence interval, -0.21 to 0.00). Bilateral nuclear, cortical, and PSC cataracts also were associated with poorer vision-specific functioning (beta = -0.31, -0.15, and -1.15, respectively), with combinations of them having even greater impact. Significantly poorer vision-specific functioning occurred at Lens Opacity Classification System grades 4 (nuclear opalescence), 5 (nuclear color), 3 (cortical), and 1 (PSC) or higher. CONCLUSIONS: People with bilateral but not unilateral cataracts experience difficulty with performing vision-specific daily activities independent of refractive error, with PSC cataracts and cataract combinations having the greatest impact. Cataract types cause poorer vision specific functioning beginning at different severity grades. PMID- 22541933 TI - Effects of melatonin on islet neogenesis and beta cell apoptosis in streptozotocin-induced diabetic rats: an immunohistochemical study. AB - This investigation was carried out to explore the antidiabetic, antiapoptotic and neogenetic effects of melatonin (MLT) in streptozotocin-induced diabetic rats. Sixty-four male rats were assigned randomly to one of four groups for periods of 21 and 42 d as follows; i) control, ii) MLT, iii) diabetic (DM), and iv) DM + MLT. Immunohistochemical methods were used -with pancreatic tissue to determine the intensity of insulin, caspase-3 and Bcl-x(L) immune reactivities, and new islet formation. In untreated DM rats, BW loss, increased plasma glucose and MLT concentrations, as well as cytoplasmic degranulation and vacuolization were observed. We also observed a marked increase in the number of apoptotic caspase-3 positive cells and a few insulin- positive cells, but not antiapoptotic Bcl-x(L) positive cells. Observations in the DM + MLT-treated group revealed a high intensity of insulin- and antiapoptotic Bcl-x(L) immune reactivities at 21 and 42 d. Moreover, data indicated that MLT may cause beta cell proliferation and that new small islets originate from cells associated with ductal epithelium and from centroacinar cells by day 21. These data indicate that; i) MLT treatment may stimulate neogenesis in the pancreas of diabetic rats, and ii) MLT's antiapoptotic action may increase beta cell differentiation and caspase-3 inactivation or Bcl-x(L) activation. PMID- 22541932 TI - Improvement of photoreceptor integrity and associated visual outcome in neovascular age-related macular degeneration. AB - PURPOSE: To evaluate the association between improvement of photoreceptor integrity and visual acuity (VA) after anti-vascular endothelial growth factor (anti-VEGF) injections in neovascular age-related macular degeneration (AMD). DESIGN: Retrospective, cross-sectional study. METHODS: Eighty-seven eyes of 84 patients who were newly diagnosed with neovascular AMD and treated with anti-VEGF injections were reviewed retrospectively. Using spectral-domain optical coherence tomography, the status of the inner segment/outer segment photoreceptor junction (IS/OS) was graded and classified into 3 groups at baseline and 1 and 2 months after 3 monthly injections. The proportion of the improved IS/OS line after treatment was analyzed and correlated with VA. RESULTS: The number of eyes in the IS/OS+ group, representing disrupted IS/OS line less than 200 MUm, was increased from 9 (10%) at baseline to 33 (38%) at 1 month. There was a significant difference in the ratio of IS/OS+ group between baseline and 1 month (P < .001). Those in the IS/OS+/- group, showing focal disrupted IS/OS line between 200 and 800 MUm, decreased from 29 (33%) to 22 eyes (25%). Improvement of the IS/OS line at 1 month compared to baseline was noted in 43 eyes (49%) and correlated with better VA (P < .016). No increase of VA was observed in 44 eyes without definite improvement. There was no significant correlation between improvement of the IS/OS line and VA from 1 to 2 months. CONCLUSIONS: Assessing the change of the photoreceptor integrity before and after treatment would be a useful indicator to predict initial response to treatment and visual prognosis in patients with neovascular AMD. PMID- 22541934 TI - Effects of tryptophan supplementation on cashmere fiber characteristics, serum tryptophan, and related hormone concentrations in cashmere goats. AB - This study was designed to investigate the effects of tryptophan (Trp) supplementation on cashmere fiber characteristics and on serum Trp, melatonin (MEL), prolactin (PRL), insulin-like growth factor 1 (IGF-1), triiodothyronine (T3), and thyroxine (T4) concentrations in cashmere goats during the cashmere fast-growth period. Thirty-six Liaoning cashmere wether goats were stratified on the basis of body weight (28+/-0.8 kg) and assigned randomly to 1 of the following 4 rumen-protected Trp treatments: 0, 2.0, 4.0, and 6.0 g per goat per day. The experimental period lasted 137 d. Blood samples were collected monthly during the daytime (8:00 AM) and at night (8:00 PM). Tryptophan supplementation improved cashmere growth rates, cashmere weight, and body weight (P=0.001) and increased serum Trp levels, nighttime MEL concentrations, IGF-1, and T3 and T4 concentrations (P<0.05). Across the treatments and sampling months, a highly positive correlation between cashmere growth rate and nighttime serum MEL concentrations was observed (r=0.879, P=0.001). A moderately negative correlation between cashmere growth rates and serum PRL concentrations during the day and at night (rday=-0.645, P=0.007; rnight=-0.583, P=0.018) was observed. A moderately positive correlation between the cashmere growth rate and the daytime serum IGF-1 concentration (r=0.536, P=0.032) was observed, and no correlation was found between the cashmere growth rate and the other serum hormone concentrations. These data indicate that changes in serum concentrations of MEL, IGF-1, and PRL are related to cashmere growth in Liaoning cashmere goats during the cashmere fast-growth period. Under the experimental conditions of the current trial, we suggest that Trp may promote cashmere growth by increasing daytime IGF-1 and nighttime MEL secretion. PMID- 22541935 TI - Comparing outcome criteria performance in adult strabismus surgery. AB - PURPOSE: To evaluate the performance of motor, diplopia, and health-related quality of life (HRQOL) criteria when analyzing outcomes of adult strabismus surgery. DESIGN: Cohort study. PARTICIPANTS: We studied 159 adults undergoing 171 strabismus surgeries. METHODS: All patients underwent clinical assessment preoperatively and 6 weeks postoperatively, including completion of Adult Strabismus-20 HRQOL questionnaires. Preoperatively, strabismus was classified as either diplopic (n = 117), nondiplopic (n = 38), or atypical diplopic (n = 16). To assess performance of motor, diplopia, and HRQOL criteria, success was defined a priori and applied separately and in combinations. For success: (1) motor criteria, <10 prism diopters by simultaneous prism cover test; (2) diplopia criteria, none or only rare in primary distance and for reading; (3) HRQOL criteria, exceeding previously reported 95% limits of agreement (LOA). MAIN OUTCOME MEASURES: Surgical success rate when applying motor, diplopia, and HRQOL criteria alone and in combinations. RESULTS: Overall, success rates were 90% for motor criteria, 74% for diplopia criteria, and 60% for HRQOL criteria. Combining criteria, the highest success rate was for motor plus diplopia criteria (67%) and the lowest success rate was when combining motor, diplopia, and HRQOL criteria (50%). CONCLUSIONS: Applying motor criteria alone yields the highest success rates when evaluating outcomes in adult strabismus surgery, but motor criteria do not fully represent the patient's postoperative status. Combining diplopia criteria with motor criteria provides a more clinically relevant standard for judging the success of adult strabismus surgery. For HRQOL criteria, exceeding 95% LOA at 6 weeks postoperatively seems to be a difficult hurdle to clear for some individual patients, and evaluating change in HRQOL score may be more useful in cohort studies. PMID- 22541937 TI - Prevention of gut leakiness by a probiotic treatment leads to attenuated HPA response to an acute psychological stress in rats. AB - BACKGROUND AND AIMS: Intestinal barrier impairment is incriminated in the pathophysiology of intestinal gut disorders associated with psychiatric comorbidity. Increased intestinal permeability associated with upload of lipopolysaccharides (LPS) translocation induces depressive symptoms. Gut microbiota and probiotics alter behavior and brain neurochemistry. Since Lactobacillus farciminis suppresses stress-induced hyperpermeability, we examined whether (i) L. farciminis affects the HPA axis stress response, (ii) stress induces changes in LPS translocation and central cytokine expression which may be reversed by L. farciminis, (iii) the prevention of "leaky" gut and LPS upload are involved in these effects. METHODS: At the end of the following treatments female rats were submitted to a partial restraint stress (PRS) or sham-PRS: (i) oral administration of L. farciminis during 2 weeks, (ii) intraperitoneal administration of ML-7 (a specific myosin light chain kinase inhibitor), (iii) antibiotic administration in drinking water during 12 days. After PRS or sham-PRS session, we evaluated LPS levels in portal blood, plasma corticosterone and adrenocorticotropic hormone (ACTH) levels, hypothalamic corticotropin releasing factor (CRF) and pro-inflammatory cytokine mRNA expression, and colonic paracellular permeability (CPP). RESULTS: PRS increased plasma ACTH and corticosterone; hypothalamic CRF and pro-inflammatory cytokine expression; CPP and portal blood concentration of LPS. L. farciminis and ML-7 suppressed stress induced hyperpermeability, endotoxemia and prevented HPA axis stress response and neuroinflammation. Antibiotic reduction of luminal LPS concentration prevented HPA axis stress response and increased hypothalamic expression of pro inflammatory cytokines. CONCLUSION: The attenuation of the HPA axis response to stress by L. farciminis depends upon the prevention of intestinal barrier impairment and decrease of circulating LPS levels. PMID- 22541936 TI - Antimullerian hormone levels are independently related to ovarian hyperandrogenism and polycystic ovaries. AB - OBJECTIVE: To determine the relationship of antimullerian hormone (AMH) levels to polycystic ovaries and ovarian androgenic function. DESIGN: Prospective case control study. SETTING: General clinical research center. PARTICIPANT(S): Eumenorrheic asymptomatic volunteers without (V-NO; n = 19; reference population) or with (V-PCO; n = 28) a polycystic ovary and hyperandrogenemic anovulatory subjects grouped according to ovarian function into typical PCOS (PCOS-T; n = 37) and atypical PCOS (PCOS-A; n = 18). INTERVENTION(S): Pelvic ultrasonography, short dexamethasone androgen-suppression test (SDAST), and GnRH agonist (GnRHag) test. MAIN OUTCOME MEASURE(S): Baseline AMH levels were related to polycystic ovary status, testosterone response to SDAST, and 17-hydroxyprogesterone response to GnRHag test. RESULT(S): AMH levels correlated with SDAST and GnRHag test outcomes. AMH was elevated (>6.2 ng/mL) in 32% of V-PCO versus 5% V-NO. The 21% of V-PCO who met Rotterdam PCOS criteria all had functional ovarian hyperandrogenism, but AMH levels were similar to nonhyperandrogenic V-PCO. AMH >10.7 ng/mL discriminated V-PCO from PCOS with 96% specificity and 41% sensitivity for PCOS-T, and insignificantly for PCOS-A. CONCLUSION(S): AMH levels are independently related to ovarian androgenic function and polycystic ovaries. Very high AMH levels are specific but insensitive for PCOS. In the absence of hyperandrogenism, moderate AMH elevation in women with normal-variant polycystic ovaries seems to indicate an enlarged oocyte pool. PMID- 22541938 TI - HPV-18 E2^E4 chimera: 2 new spliced transcripts and proteins induced by keratinocyte differentiation. AB - The Human Papillomavirus (HPV) E4 is known to be synthesized as an E1^E4 fusion resulting from splice donor and acceptor sites conserved across HPV types. Here we demonstrate the existence of 2 HPV-18 E2^E4 transcripts resulting from 2 splice donor sites in the 5' part of E2, while the splice acceptor site is the one used for E1^E4. Both E2^E4 transcripts are up-regulated by keratinocyte differentiation in vitro and can be detected in clinical samples containing low grade HPV-18-positive cells from Pap smears. They give rise to two fusion proteins in vitro, E2^E4-S and E2^E4-L. Whereas we could not differentiate E2^E4 S from E1^E4 in vivo, E2^E4-L could be formally identified as a 23 kDa protein in raft cultures in which the corresponding transcript was also found, and in a biopsy from a patient with cervical intraepithelial neoplasia stage I-II (CINI II) associated with HPV-18, demonstrating the physiological relevance of E2^E4 products. PMID- 22541940 TI - Construction of healthy arteries using computed tomography and virtual histology intravascular ultrasound. AB - Vessel geometry for numerical analysis is generally obtained by computed tomography (CT) or magnetic resonance imaging (MRI) and intravascular ultrasound (IVUS). Most medical imaging is obtained from patients for hemodynamic analysis due to the properties of vascular disease and the difficulties in angiography. To predict the site where plaque occurs and understand the progression of the lesion, however, it is necessary to take into consideration not only the diseased artery, but also the blood flow characteristics of healthy artery. In order to simulate healthy vessels prior to lesion formation, we performed CT and virtual histology intravascular ultrasound (VH-IVUS) on three actual patients and this data was used to develop criteria for healthy vessel construction, a method that virtually removes all intravascular plaque. The lumen of a vessel generated by CT and the lumen from VH-IVUS were compared, and the cross-sectional areas of plaque components (fibrous, fibrofatty, dense calcium, and necrotic) and the lumen from VH-IVUS were analyzed. Geometric differences in the healthy vessel and diseased vessel were analyzed, and flow characteristics of the healthy vessel and diseased vessel were compared through computational fluid dynamics simulation. Low average wall shear stress (AWSS) was distributed in the site where plaque was removed from the healthy vessel, and a high oscillatory shear index (OSI) was observed in the region proximal to the site where plaque previously existed. Low AWSS and high OSI are widely accepted indicators of plaque formation or the direction of plaque progression. A numerical model that effectively predicts lesion forming sites was also generated based on the healthy vessel construction method presented in this study. PMID- 22541939 TI - Bias in effect size of systemic lupus erythematosus susceptibility loci across Europe: a case-control study. AB - INTRODUCTION: We aimed to investigate whether the effect size of the systemic lupus erythematosus (SLE) risk alleles varies across European subpopulations. METHODS: European SLE patients (n = 1,742) and ethnically matched healthy controls (n = 2,101) were recruited at 17 centres from 10 different countries. Only individuals with self-reported ancestry from the country of origin were included. In addition, participants were genotyped for top ancestry informative markers and for 25 SLE associated SNPs. The results were used to compare effect sizes between the Central Eureopan and Southern European subgroups. RESULTS: Twenty of the 25 SNPs showed independent association with SLE, These SNPs showed a significant bias to larger effect sizes in the Southern subgroup, with 15/20 showing this trend (P = 0.019) and a larger mean odds ratio of the 20 SNPs (1.46 vs. 1.34, P = 0.02) as well as a larger difference in the number of risk alleles (2.06 vs. 1.63, P = 0.027) between SLE patients and controls than for Central Europeans. This bias was reflected in a very significant difference in the cumulative genetic risk score (4.31 vs. 3.48, P = 1.8 * 10-32). Effect size bias was accompanied by a lower number of SLE risk alleles in the Southern subjects, both patients and controls, the difference being more marked between the controls (P = 1.1 * 10-8) than between the Southern and Central European patients (P = 0.016). Seven of these SNPs showed significant allele frequency clines. CONCLUSION: Our findings showed a bias to larger effect sizes of SLE loci in the Southern Europeans relative to the Central Europeans together with clines of SLE risk allele frequencies. These results indicate the need to study risk allele clines and the implications of the polygenic model of inheritance in SLE. PMID- 22541941 TI - Interdependency of stress relaxation and afferent nerve discharge in rat small intestine. AB - BACKGROUND AND AIMS: To be able to characterize intestinal mechano-electrical transduction, i.e. the mechanoreceptor behaviour, quantitative nerve studies with controlled and quantified stimulus are needed. This study aimed to determine the relationship between mechanical stress relaxation and afferent discharge adaptation evoked by fast isovolumetric bag distensions in the rat jejunum. METHODS: Multiunit afferent activity was recorded in vivo from jejunum afferents from five male Wistar rats. The jejunum was distended via a bag at a distension speed of 0.5 ml/s to volumes of 0.2, 0.25, 0.3 and 0.4 ml, respectively. The distension was stopped and the volume was kept constant for 2 min to induce stress relaxation. The pressure in the bag, the afferent discharge (spike rate) and the diameter of the segment during the relaxation time were recorded simultaneously. RESULTS: The afferent discharge responses to distension showed a pattern with a peak during the sudden loading followed by decreasing activity with time. At distension volumes of 0.2, 0.25, 0.3 and 0.4 ml, the afferent discharge declined faster and to a greater extent (94%, 91%,96% and 87%) than the stress decreased (55%, 45%, 59% and 56%) during stress relaxation (p<0.001). Both the stress and the afferent discharge during the constant volume distension were independent of the distension volumes (p>0.5). The stress and the afferent discharge during the distension can be described mathematically on the basis of the quasi-linear theory of viscoelasticity. The association between the stress and the afferent discharge during the constant volume distension is linear with the same slope under various distension volumes. CONCLUSIONS: Intestinal mechanoreceptors were sensitive to the stress stimulus and a linear association between the stress relaxation and afferent discharge adaptation was found. The quasi-linear theory of visco-elasticity can be transferred to analysis of mechanical stimulus evoked afferent discharge. PMID- 22541942 TI - Computational models for wall shear stress estimation in scaffolds: a comparative study of two complete geometries. AB - Fluid mechanical stimuli are known to upregulate cell differentiation and matrix formation. Since wall shear stress plays an important role various studies tried to estimate the scaffold fluid dynamic environment. However, because of the geometrical complexity, nearly all studies created their CFD model based on a submodel of the entire scaffold assuming that the model covers heterogeneity sufficiently. However to the authors' knowledge no study exist providing guidelines in this matter. In a previous study we demonstrated that submodels are influenced by the boundary conditions, inevitable when flow channels are chopped off. For the current study we therefore developed MUCT based models of two complete scaffold geometries (one titanium and one hydroxyapatite). Imposing a 0.04 ml/min flow rate resulted in a surface area averaged wall shear stress of 1.41 mPa for titanium and 1.09 mPa for hydroxyapatite. In order to get insight in required model size we subdivided the domain in regions of different size. From our results we propose a model size between 6 and 10 times the average pore size. The wall shears stress should be calculated on a region at least one pore size away from the boundaries. These guidelines could be of use for computationally more costly simulations where it is not possible to simulate the complete scaffold domain. PMID- 22541943 TI - Older adults have unstable gait kinematics during weight transfer. AB - The present article investigates gait stability of healthy older persons during weight transfer. Ten healthy older persons and ten younger persons walked 10 min each on a treadmill at 3 different gait speeds. The intra-stride change in gait stability was defined by the local divergence exponent lambda(t) estimated by a newly developed method. The intra-stride changes in lambda(t) during weight transfer were identified by separating each stride into a single and double support phase. The intra-stride changes in lambda(t) were also compared to changes in the variation of the gait kinematics, i.e., SD(t). The healthy older persons walked at the same preferred walking speed as the younger persons. However, they exhibited significantly larger lambda(t) (p<0.001) during weight transfer in the double support phase. Local divergence was closely related to intra-stride changes in SD(t) of the feet in the anterior-posterior direction. Furthermore, a high correlation was found between local divergence and the variation in step length and step width for both older (R>0.67, p<0.05) and younger persons (R>0.67, p<0.05). The present results indicate that the gait kinematics of older adults are more dynamical unstable during the weight transfer compared to younger persons. Furthermore, a close relationship exists between intra-stride changes in dynamical stability and variation in step length and step width. Further work will validate the results of the present study using real life perturbations of the gait kinematics of both younger and older adults. PMID- 22541944 TI - The superposition principle applied to grasping an object producing moments outside anatomically-defined axes. AB - The superposition principle suggests that motor commands can be divided into individually controlled components that summate to produce complex motor actions. Previous studies have examined the validity of this principle in human grasping by changing moments acting on an object about a single anatomically-defined axis and asking subjects to hold the object while their forearm was constrained. Superposition was reflected as separate control of the grip force and moments required to prevent object slip and maintain orientation. The objective of this study was to examine the robustness of this principle by: 1) expanding the range of tasks to include those where moments act on an object with respect to moment arms not necessarily in line with the anatomically-defined axes; 2) asking subjects to hold the object in an unconstrained manner. Ten subjects were asked to lift and hold an object vertically under eighteen moment conditions. Force and moment data from all digits were analysed using principal components analysis (PCA). Different PCAs were run for variable sets corresponding to moments about the long axis of the forearm (M(x)), the vertical (M(y)) and grip (M(z)) axes, and for the entire dataset (M(3D)). The PCA showed grip force and moment variables on separate PCs for the M(x), M(y), and M(3D) variable sets. The M(3D) PCA also showed a separation of variables corresponding to moments about each anatomically-defined axis. Thus, the present results show that the superposition principle holds during natural manipulation of an object experiencing external moments outside the anatomically-defined axes. PMID- 22541945 TI - Kinematic adaptations to a variable stiffness shoe: mechanisms for reducing joint loading. AB - A recently described variable-stiffness shoe has been shown to reduce the adduction moment and pain in patients with medial-compartment knee osteoarthritis. The mechanism associated with how this device modifies overall gait patterns to reduce the adduction moment is not well understood. Yet this information is important for applying load modifying intervention for the treatment of knee osteoarthritis. A principal component analysis (PCA) was used to test the hypothesis that there are differences in the frontal plane kinematics that are correlated with differences in the ground reaction forces (GRFs) and center of pressure (COP) for a variable-stiffness compared to a constant stiffness control shoe. Eleven healthy adults were tested in a constant-stiffness control shoe and a variable-stiffness shoe while walking at self-selected speeds. The PCA was performed on trial vectors consisting of all kinematic, GRF and COP data. The projection of trial vectors onto the linear combination of four PCs showed there were significant differences between shoes. The interpretation of the PCs indicated an increase in the ankle eversion, knee abduction and adduction, decreases in the hip adduction and pelvic obliquity angles and reduced excursion of both the COP and peak medial-lateral GRFs for the variable-stiffness compared to the control shoe. The variable-stiffness shoe produced a unique dynamic change in the frontal plane motion of the ankle, hip and pelvis that contributed to changes in the GRF and COP and thus reduced the adduction moment at a critical instant during gait suggesting a different mechanism that was seen with fixed interventions (e.g. wedges). PMID- 22541946 TI - Protracted withdrawal from cocaine self-administration flips the switch on 5 HT(1B) receptor modulation of cocaine abuse-related behaviors. AB - BACKGROUND: The role of serotonin-1B receptors (5-HT(1B)Rs) in modulating cocaine abuse-related behaviors has been controversial due to discrepancies between pharmacological and gene knockout approaches and opposite influences on cocaine self-administration versus cocaine-seeking behavior. We hypothesized that modulation of these behaviors via 5-HT(1B)Rs in the mesolimbic pathway may vary depending on the stage of the addiction cycle. METHODS: To test this hypothesis, we examined the effects of increasing 5-HT(1B)R production by microinfusing a viral vector expressing either green fluorescent protein and 5-HT(1B)R or green fluorescent protein alone into the medial nucleus accumbens shell of rats either during maintenance of cocaine self-administration (i.e., active drug use) or during protracted withdrawal. RESULTS: 5-HT(1B)R receptor gene transfer during maintenance shifted the dose-response curve for cocaine self-administration upward and to the left and increased breakpoints and cocaine intake on a progressive ratio schedule, consistent with enhanced reinforcing effects of cocaine. In contrast, following 21 days of forced abstinence, 5-HT(1B)R gene transfer attenuated breakpoints and cocaine intake on a progressive ratio schedule of reinforcement, as well as cue- and cocaine-primed reinstatement of cocaine-seeking behavior. CONCLUSIONS: This unique pattern of effects suggests that mesolimbic 5-HT(1B)Rs differentially modulate cocaine abuse-related behaviors, with a facilitative influence during periods of active drug use, in striking contrast to an inhibitory influence during protracted withdrawal. These findings suggest that targeting 5-HT(1B)Rs may lead to a novel treatment for cocaine dependence and that the therapeutic efficacy of these treatments may vary depending on the stage of the addiction cycle. PMID- 22541948 TI - A review of the environmental safety of the Cry1Ac protein. PMID- 22541947 TI - Learning and memory depend on fibroblast growth factor receptor 2 functioning in hippocampus. AB - BACKGROUND: Fibroblast growth factor (FGF) signaling controls self-renewal of neural stem cells during embryonic telencephalic development. FGF receptor 2 (FGFR2) has a significant role in the production of cortical neurons during embryogenesis, but its role in the hippocampus during development and in adulthood has not been described. METHODS: Here we dissociate the role of FGFR2 in the hippocampus during development and during adulthood with the use of embryonic knockout and inducible knockout mice. RESULTS: Embryonic knockout of FGFR2 causes a reduction of hippocampal volume and impairment in adult spatial memory in mice. Spatial reference memory, as assessed by performance on the water maze probe trial, was correlated with reduced hippocampal parvalbumin+ cells, whereas short-term learning was correlated with reduction in immature neurons in the dentate gyrus. Furthermore, short-term learning and newly generated neurons in the dentate gyrus were deficient even when FGFR2 was lacking only in adulthood. CONCLUSIONS: Taken together, these findings support a dual role for FGFR2 in hippocampal short-term learning and long-term reference memory, which appear to depend on the abundance of two separate cellular components, parvalbumin interneurons and newly generated granule cells in the hippocampus. PMID- 22541949 TI - A glucose bio-battery prototype based on a GDH/poly(methylene blue) bioanode and a graphite cathode with an iodide/tri-iodide redox couple. AB - A glucose bio-battery prototype independent of oxygen is proposed based on a glucose dehydrogenase (GDH) bioanode and a graphite cathode with an iodide/tri iodide redox couple. At the bioanode, a NADH electrocatalyst, poly(methylene blue) (PMB), which can be easily grown on the electrode (screen-printed carbon paste electrode, SPCE) by electrodeposition, is harnessed and engineered. We find that carboxylated multi-walled carbon nanotubes (MWCNTs) are capable of significantly increasing the deposition amount of PMB and thus enhancing the PMB's electrocatalysis of NADH oxidation and the glucose bio-battery's performance. The choice of the iodide/tri-iodide redox couple eliminates the dependence of oxygen for this bio-battery, thus enabling the bio-battery with a constant current-output feature similar to that of the solar cells. The present glucose bio-battery prototype can attain a maximum power density of 2.4 MUW/cm(2) at 25 degrees C. PMID- 22541950 TI - Influence of growth phase on harvesting of Chlorella zofingiensis by dissolved air flotation. AB - The effects of changes in cellular characteristics and dissolved organic matter (DOM) on dissolved air flotation (DAF) harvesting of Chlorella zofingiensis at the different growth phases were studied. Harvesting efficiency increased with Al(3+) dosage and reached more than 90%, regardless of growth phases. In the absence of DOM, the ratio of Al(3+) dosage to surface functional group concentration determined the harvesting efficiency. DOM in the culture medium competed with algal cell surface functional groups for Al(3+), and more Al(3+) was required for cultures with DOM than for DOM-free cultures to achieve the same harvesting efficiency. As the culture aged, the increase of Al(3+) dosage due to increased DOM was less than the decrease of Al(3+) dosage associated with reduced cell surface functional groups, resulting in overall reduced demand for Al(3+). The interdependency of Al(3+) dosage and harvesting efficiency on concentrations of cell surface functional groups and DOM was successfully modeled. PMID- 22541951 TI - Improvement of thermostability and activity of pectate lyase in the presence of hydroxyapatite nanoparticles. AB - The activity and half-life of pectate lyase (PL) from Bacillus megaterium were nine- and 60-fold, respectively, higher at 90 degrees C in the presence of hydroxyapatite nanoparticles (NP-PLs) than in the presence of 1mM CaCl(2). Thermodynamic analysis of the nanoparticle-induced stability revealed an enhanced entropy-enthalpy compensation by the NP-PLs since a reciprocal linearity of the enthalpy-entropy change to 90 degrees C was observed. Without nanoparticles, the linearity range was 70 degrees C. Such compensation reflected the maintenance of the native structure of proteins. The remarkable enhancement of activity and stability of the NP-PL system at high temperatures may be utilized commercially e.g. in the food industry or the processing of natural fibers that may require a thermotolerant enzyme. PMID- 22541952 TI - Rapid production of maggots as feed supplement and organic fertilizer by the two stage composting of pig manure. AB - A two-stage composting experiment was performed to utilize pig manure for producing maggots as feed supplement and organic fertilizer. Seven-day composting of 1.8 ton fresh manure inoculated with 9 kg mixture of housefly neonates and wheat bran produced 193 kg aging maggots, followed by 12 week composting to maturity. Reaching the thermophilic phase and final maturity faster was characteristic of the maggot-treated compost compared with the same-size natural compost. Upon the transit of the maggot-treated compost to the second stage, the composting temperature maintained around 55 degrees C for 9 days and the moisture decreased to ~40%. Moreover, higher pH, faster detoxification and different activity patterns for some microbial enzymes were observed. There was a strong material loss (35% water-soluble carbon and 16% total nitrogen) caused by the maggot culture in the first stage. Our results highlight a higher economic value of pig manure achieved through the two-stage composting without bulking agents. PMID- 22541953 TI - The membrane biofilm reactor (MBfR) for water and wastewater treatment: principles, applications, and recent developments. AB - The membrane biofilm reactor (MBfR), an emerging technology for water and wastewater treatment, is based on pressurized membranes that supply a gaseous substrate to a biofilm formed on the membrane's exterior. MBfR biofilms behave differently from conventional biofilms due to the counter-diffusion of substrates. MBfRs are uniquely suited for numerous treatment applications, including the removal of carbon and nitrogen when oxygen is supplied, and reduction of oxidized contaminants when hydrogen is supplied. Major benefits include high gas utilization efficiency, low energy consumption, and small reactor footprints. The first commercial MBfR was recently released, and its success may lead to the scale-up of other applications. MBfR development still faces challenges, including biofilm management, the design of scalable reactor configurations, and the identification of cost-effective membranes. If future research and development continue to address these issues, the MBfR may play a key role in the next generation of sustainable treatment systems. PMID- 22541954 TI - Cardiac troponin I increases in female adventure racers. PMID- 22541955 TI - Difference in the incidence of hospitalizations for ST-segment elevation acute myocardial infarction in the last 20 years. PMID- 22541956 TI - Abatacept therapy and safety management. AB - OBJECTIVES: To develop and/or update fact sheets about abatacept treatment, in order to assist physicians in the management of patients with inflammatory joint disease. METHODS: 1. selection by a committee of rheumatology experts of the main topics of interest for which fact sheets were desirable 2. identification and review of publications relevant to each topic 3. development and/or update of fact sheets based on three levels of evidence: evidence-based medicine, official recommendations, and expert opinion. The experts were rheumatologists and invited specialists in other fields (dermatologist, cardiologist, pediatric rheumatologist, endocrinologist, hematologist, immunologist, infectiologist), and they had extensive experience with the management of chronic inflammatory diseases, such as rheumatoid arthritis (RA). They were members of the CRI (Club Rhumatismes et Inflammation), a section of the French Rheumatology Society (Societe Francaise de Rhumatologie). Each fact sheet was revised by several experts and the overall process was coordinated by three experts. RESULTS: Several topics of major interest were selected: contraindications of abatacept treatment; management of adverse effects and concomitant diseases that may develop during abatacept treatment; and management of common situations such as pregnancy, surgery, patient older than 75 years of age, and patients with co morbidities (such as dialysis, hemoglobinopathy, or splenectomy). After a review of the literature and discussion among experts, a consensus was developed about the content of the fact sheets presented here. These fact sheets focus on several points: 1. in RA, initiation and monitoring of the abatacept treatment, management of patients with specific past histories, and specific clinical situations such as pregnancy 2. diseases other than RA, such as juvenile idiopathic arthritis, spondylarthropathies, or autoimmune diseases (systemic lupus erythematosus and other systemic autoimmune diseases) 3. models of letters for informing the rheumatologist and general practitioner 4. patient information about the use of abatacept in RA 5. and data on the new abatacept formulation for subcutaneous administration (approved by the FDA in August 2011 for patients with moderate-to-severe RA). CONCLUSION: These fact sheets built on evidence-based medicine and expert opinion will serve as a practical tool for assisting physicians who manage patients on abatacept. They will be available continuously on www.cri-net.com and will be updated at appropriate intervals. PMID- 22541957 TI - A phase II study of submandibular gland transfer prior to radiation for prevention of radiation-induced xerostomia in head-and-neck cancer (RTOG 0244). AB - PURPOSE: We report the results of a phase II study to determine the reproducibility of a submandibular salivary gland transfer (SGT) surgical technique for prevention of radiation (XRT)-induced xerostomia in a multi institutional setting and to assess severity of xerostomia. METHODS AND MATERIALS: Eligible patients had surgery for primary, neck dissection, and SGT, followed by XRT, during which the transferred salivary gland was shielded. Intensity modulated radiation therapy, amifostine, and pilocarpine were not allowed, but postoperative chemotherapy was allowed. Each operation was reviewed by 2 reviewers and radiation by 1 reviewer. If 13 or more (of 43) were "not per protocol," then the technique would be considered not reproducible as per study design. The secondary endpoint was the rate of acute xerostomia, grade 2 or higher, and a rate of <= 51% was acceptable. RESULTS: Forty-four of the total 49 patients were analyzable: male (81.8%), oropharynx (63.6%), stage IV (61.4%), median age 56.5 years. SGT was "per protocol" or within acceptable variation in 34 patients (77.3%) and XRT in 79.5%. Nine patients (20.9%) developed grade 2 acute xerostomia; 2 had grade 0-1 xerostomia (4.7%) but started on amifostine/pilocarpine. Treatment for these 11 patients (25.6%) was considered a failure for the xerostomia endpoint. Thirteen patients died; median follow-up for 31 surviving patients was 2.9 years. Two-year overall and disease-free survival rates were 76.4% and 71.7%, respectively. CONCLUSIONS: The technique of submandibular SGT is reproducible in a multicenter setting. Seventy-four percent of patients were prevented from XRT-induced acute xerostomia. PMID- 22541958 TI - Accuracy of real-time couch tracking during 3-dimensional conformal radiation therapy, intensity modulated radiation therapy, and volumetric modulated arc therapy for prostate cancer. AB - PURPOSE: To evaluate the accuracy of real-time couch tracking for prostate cancer. METHODS AND MATERIALS: Intrafractional motion trajectories of 15 prostate cancer patients were the basis for this phantom study; prostate motion had been monitored with the Calypso System. An industrial robot moved a phantom along these trajectories, motion was detected via an infrared camera system, and the robotic HexaPOD couch was used for real-time counter-steering. Residual phantom motion during real-time tracking was measured with the infrared camera system. Film dosimetry was performed during delivery of 3-dimensional conformal radiation therapy (3D-CRT), step-and-shoot intensity modulated radiation therapy (IMRT), and volumetric modulated arc therapy (VMAT). RESULTS: Motion of the prostate was largest in the anterior-posterior direction, with systematic (?) and random (sigma) errors of 2.3 mm and 2.9 mm, respectively; the prostate was outside a threshold of 5 mm (3D vector) for 25.0%+/-19.8% of treatment time. Real-time tracking reduced prostate motion to ?=0.01 mm and sigma = 0.55 mm in the anterior posterior direction; the prostate remained within a 1-mm and 5-mm threshold for 93.9%+/-4.6% and 99.7%+/-0.4% of the time, respectively. Without real-time tracking, pass rates based on a gamma index of 2%/2 mm in film dosimetry ranged between 66% and 72% for 3D-CRT, IMRT, and VMAT, on average. Real-time tracking increased pass rates to minimum 98% on average for 3D-CRT, IMRT, and VMAT. CONCLUSIONS: Real-time couch tracking resulted in submillimeter accuracy for prostate cancer, which transferred into high dosimetric accuracy independently of whether 3D-CRT, IMRT, or VMAT was used. PMID- 22541959 TI - Origin of tumor recurrence after intensity modulated radiation therapy for oropharyngeal squamous cell carcinoma. AB - PURPOSE: To model locoregional recurrences of oropharyngeal squamous cell carcinomas (OSCC) treated with primary intensity modulated radiation therapy (IMRT) in order to find the origins from which recurrences grow and relate their location to original target volume borders. METHODS AND MATERIALS: This was a retrospective analysis of OSCC treated with primary IMRT between January 2002 and December 2009. Locoregional recurrence volumes were delineated on diagnostic scans and coregistered rigidly with treatment planning computed tomography scans. Each recurrence was analyzed with two methods. First, overlapping volumes of a recurrence and original target were measured ('volumetric approach') and assessed as 'in-field', 'marginal', or 'out-field'. Then, the center of mass (COM) of a recurrence volume was assumed as the origin from where a recurrence expanded, the COM location was compared with original target volume borders and assessed as 'in field', 'marginal', or 'out-field'. RESULTS: One hundred thirty-one OSCC were assessed. For all patients alive at the end of follow-up, the mean follow-up time was 40 months (range, 12-83 months); 2 patients were lost to follow-up. The locoregional recurrence rate was 27%. Of all recurrences, 51% were local, 23% were regional, and 26% had both local and regional recurrences. Of all recurrences, 74% had imaging available for assessment. Regarding volumetric analysis of local recurrences, 15% were in-field gross tumor volume (GTV), and 65% were in-field clinical tumor volume (CTV). Using the COM approach, we found that 70% of local recurrences were in-field GTV and 90% were in-field CTV. Of the regional recurrences, 25% were volumetrically in-field GTV, and using the COM approach, we found 54% were in-field GTV. The COM of local out-field CTV recurrences were maximally 16 mm outside CTV borders, whereas for regional recurrences, this was 17 mm. CONCLUSIONS: The COM model is practical and specific for recurrence assessment. Most recurrences originated in the GTV. This suggests radioresistance in certain tumor parts. PMID- 22541960 TI - Strain-dependent damage in mouse lung after carbon ion irradiation. AB - PURPOSE: To examine whether inherent factors produce differences in lung morbidity in response to carbon ion (C-ion) irradiation, and to identify the molecules that have a key role in strain-dependent adverse effects in the lung. METHODS AND MATERIALS: Three strains of female mice (C3H/He Slc, C57BL/6J Jms Slc, and A/J Jms Slc) were locally irradiated in the thorax with either C-ion beams (290 MeV/n, in 6 cm spread-out Bragg peak) or with 137Cs gamma-rays as a reference beam. We performed survival assays and histologic examination of the lung with hematoxylin-eosin and Masson's trichrome staining. In addition, we performed immunohistochemical staining for hyaluronic acid (HA), CD44, and Mac3 and assayed for gene expression. RESULTS: The survival data in mice showed a between-strain variance after C-ion irradiation with 10 Gy. The median survival time of C3H/He was significantly shortened after C-ion irradiation at the higher dose of 12.5 Gy. Histologic examination revealed early-phase hemorrhagic pneumonitis in C3H/He and late-phase focal fibrotic lesions in C57BL/6J after C ion irradiation with 10 Gy. Pleural effusion was apparent in C57BL/6J and A/J mice, 168 days after C-ion irradiation with 10 Gy. Microarray analysis of irradiated lung tissue in the three mouse strains identified differential expression changes in growth differentiation factor 15 (Gdf15), which regulates macrophage function, and hyaluronan synthase 1 (Has1), which plays a role in HA metabolism. Immunohistochemistry showed that the number of CD44-positive cells, a surrogate marker for HA accumulation, and Mac3-positive cells, a marker for macrophage infiltration in irradiated lung, varied significantly among the three mouse strains during the early phase. CONCLUSIONS: This study demonstrated a strain-dependent differential response in mice to C-ion thoracic irradiation. Our findings identified candidate molecules that could be implicated in the between strain variance to early hemorrhagic pneumonitis after C-ion irradiation. PMID- 22541961 TI - Statistical validation of normal tissue complication probability models. AB - PURPOSE: To investigate the applicability and value of double cross-validation and permutation tests as established statistical approaches in the validation of normal tissue complication probability (NTCP) models. METHODS AND MATERIALS: A penalized regression method, LASSO (least absolute shrinkage and selection operator), was used to build NTCP models for xerostomia after radiation therapy treatment of head-and-neck cancer. Model assessment was based on the likelihood function and the area under the receiver operating characteristic curve. RESULTS: Repeated double cross-validation showed the uncertainty and instability of the NTCP models and indicated that the statistical significance of model performance can be obtained by permutation testing. CONCLUSION: Repeated double cross validation and permutation tests are recommended to validate NTCP models before clinical use. PMID- 22541962 TI - Impact of concurrent androgen deprivation on fiducial marker migration in external-beam radiation therapy for prostate cancer. AB - PURPOSE: To determine the extent of gold fiducial marker (FM) migration in patients treated for prostate cancer with concurrent androgen deprivation and external-beam radiation therapy (EBRT). METHODS AND MATERIALS: Three or 4 gold FMs were implanted in 37 patients with prostate adenocarcinoma receiving androgen deprivation therapy (ADT) in conjunction with 70-78 Gy. Androgen deprivation therapy was started a median of 3.9 months before EBRT (range, 0.3-12.5 months). To establish the extent of FM migration, the distance between each FM was calculated for 5-8 treatments once per week throughout the EBRT course. For each treatment, the distance between FMs was compared with the distance from the digitally reconstructed radiographs generated from the planning CT. A total of 281 treatments were analyzed. RESULTS: The average daily migration was 0.8 +/- 0.3 mm, with distances ranging from 0.2 mm-2.6 mm. Two of the 281 assessed treatments (0.7%) showed migrations >2 mm. No correlation between FM migration and patient weight or time delay between ADT and start of EBRT was found. There was no correlation between the extent of FM migration and prostate volume. CONCLUSION: This is the largest report of implanted FM migration in patients receiving concomitant ADT. Only 0.7% of the 281 treatments studied had significant marker migrations (>2 mm) throughout the course of EBRT. Consequently, the use of implanted FMs in these patients enables accurate monitoring of prostate gland position during treatment. PMID- 22541963 TI - Semiquantitative analysis using thallium-201 SPECT for differential diagnosis between tumor recurrence and radiation necrosis after gamma knife surgery for malignant brain tumors. AB - PURPOSE: Semiquantitative analysis of thallium-201 chloride single photon emission computed tomography (201Tl SPECT) was evaluated for the discrimination between recurrent brain tumor and delayed radiation necrosis after gamma knife surgery (GKS) for metastatic brain tumors and high-grade gliomas. METHODS AND MATERIALS: The medical records were reviewed of 75 patients, including 48 patients with metastatic brain tumor and 27 patients with high-grade glioma who underwent GKS in our institution, and had suspected tumor recurrence or radiation necrosis on follow-up neuroimaging and deteriorating clinical status after GKS. Analysis of 201Tl SPECT data used the early ratio (ER) and the delayed ratio (DR) calculated as tumor/normal average counts on the early and delayed images, and the retention index (RI) as the ratio of DR to ER. RESULTS: A total of 107 tumors were analyzed with 201Tl SPECT. Nineteen lesions were removed surgically and histological diagnoses established, and the other lesions were evaluated with follow-up clinical and neuroimaging examinations after GKS. The final diagnosis was considered to be recurrent tumor in 65 lesions and radiation necrosis in 42 lesions. Semiquantitative analysis demonstrated significant differences in DR (P=.002) and RI (P<.0001), but not in ER (P=.372), between the tumor recurrence and radiation necrosis groups, and no significant differences between metastatic brain tumors and high-grade gliomas in all indices (P=.926 for ER, P=.263 for DR, and P=.826 for RI). Receiver operating characteristics analysis indicated that RI was the most informative index with the optimum threshold of 0.775, which provided 82.8% sensitivity, 83.7% specificity, and 82.8% accuracy. CONCLUSIONS: Semiquantitative analysis of 201Tl SPECT provides useful information for the differentiation between tumor recurrence and radiation necrosis in metastatic brain tumors and high-grade gliomas after GKS, and the RI may be the most valuable index for this purpose. PMID- 22541964 TI - Implementation of remote 3-dimensional image guided radiation therapy quality assurance for radiation therapy oncology group clinical trials. AB - PURPOSE: To report the process and initial experience of remote credentialing of three-dimensional (3D) image guided radiation therapy (IGRT) as part of the quality assurance (QA) of submitted data for Radiation Therapy Oncology Group (RTOG) clinical trials; and to identify major issues resulting from this process and analyze the review results on patient positioning shifts. METHODS AND MATERIALS: Image guided radiation therapy datasets including in-room positioning CT scans and daily shifts applied were submitted through the Image Guided Therapy QA Center from institutions for the IGRT credentialing process, as required by various RTOG trials. A centralized virtual environment is established at the RTOG Core Laboratory, containing analysis tools and database infrastructure for remote review by the Physics Principal Investigators of each protocol. The appropriateness of IGRT technique and volumetric image registration accuracy were evaluated. Registration accuracy was verified by repeat registration with a third party registration software system. With the accumulated review results, registration differences between those obtained by the Physics Principal Investigators and from the institutions were analyzed for different imaging sites, shift directions, and imaging modalities. RESULTS: The remote review process was successfully carried out for 87 3D cases (out of 137 total cases, including 2-dimensional and 3D) during 2010. Frequent errors in submitted IGRT data and challenges in the review of image registration for some special cases were identified. Workarounds for these issues were developed. The average differences of registration results between reviewers and institutions ranged between 2 mm and 3 mm. Large discrepancies in the superior-inferior direction were found for megavoltage CT cases, owing to low spatial resolution in this direction for most megavoltage CT cases. CONCLUSION: This first experience indicated that remote review for 3D IGRT as part of QA for RTOG clinical trials is feasible and effective. The magnitude of registration discrepancy between institution and reviewer was presented, and the major issues were investigated to further improve this remote evaluation process. PMID- 22541965 TI - Dosimetric analysis of radiation-induced gastric bleeding. AB - PURPOSE: Radiation-induced gastric bleeding has been poorly understood. In this study, we described dosimetric predictors for gastric bleeding after fractionated radiation therapy. METHODS AND MATERIALS: The records of 139 sequential patients treated with 3-dimensional conformal radiation therapy (3D-CRT) for intrahepatic malignancies were reviewed. Median follow-up was 7.4 months. The parameters of a Lyman normal tissue complication probability (NTCP) model for the occurrence of >=grade 3 gastric bleed, adjusted for cirrhosis, were fitted to the data. The principle of maximum likelihood was used to estimate parameters for NTCP models. RESULTS: Sixteen of 116 evaluable patients (14%) developed gastric bleeds at a median time of 4.0 months (mean, 6.5 months; range, 2.1-28.3 months) following completion of RT. The median and mean maximum doses to the stomach were 61 and 63 Gy (range, 46-86 Gy), respectively, after biocorrection of each part of the 3D dose distributions to equivalent 2-Gy daily fractions. The Lyman NTCP model with parameters adjusted for cirrhosis predicted gastric bleed. Best-fit Lyman NTCP model parameters were n=0.10 and m=0.21 and with TD50 (normal) = 56 Gy and TD50 (cirrhosis) = 22 Gy. The low n value is consistent with the importance of maximum dose; a lower TD50 value for the cirrhosis patients points out their greater sensitivity. CONCLUSIONS: This study demonstrates that the Lyman NTCP model has utility for predicting gastric bleeding and that the presence of cirrhosis greatly increases this risk. These findings should facilitate the design of future clinical trials involving high-dose upper abdominal radiation. PMID- 22541968 TI - [Daptomycin in infections caused by gram-positive bacteria. Introduction]. PMID- 22541966 TI - Incorporating single-nucleotide polymorphisms into the Lyman model to improve prediction of radiation pneumonitis. AB - PURPOSE: To determine whether single-nucleotide polymorphisms (SNPs) in genes associated with DNA repair, cell cycle, transforming growth factor-beta, tumor necrosis factor and receptor, folic acid metabolism, and angiogenesis can significantly improve the fit of the Lyman-Kutcher-Burman (LKB) normal-tissue complication probability (NTCP) model of radiation pneumonitis (RP) risk among patients with non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Sixteen SNPs from 10 different genes (XRCC1, XRCC3, APEX1, MDM2, TGFbeta, TNFalpha, TNFR, MTHFR, MTRR, and VEGF) were genotyped in 141 NSCLC patients treated with definitive radiation therapy, with or without chemotherapy. The LKB model was used to estimate the risk of severe (grade>=3) RP as a function of mean lung dose (MLD), with SNPs and patient smoking status incorporated into the model as dose modifying factors. Multivariate analyses were performed by adding significant factors to the MLD model in a forward stepwise procedure, with significance assessed using the likelihood-ratio test. Bootstrap analyses were used to assess the reproducibility of results under variations in the data. RESULTS: Five SNPs were selected for inclusion in the multivariate NTCP model based on MLD alone. SNPs associated with an increased risk of severe RP were in genes for TGFbeta, VEGF, TNFalpha, XRCC1 and APEX1. With smoking status included in the multivariate model, the SNPs significantly associated with increased risk of RP were in genes for TGFbeta, VEGF, and XRCC3. Bootstrap analyses selected a median of 4 SNPs per model fit, with the 6 genes listed above selected most often. CONCLUSIONS: This study provides evidence that SNPs can significantly improve the predictive ability of the Lyman MLD model. With a small number of SNPs, it was possible to distinguish cohorts with >50% risk vs <10% risk of RP when they were exposed to high MLDs. PMID- 22541967 TI - A 5-year investigation of children's adaptive functioning following conformal radiation therapy for localized ependymoma. AB - PURPOSE: Conformal and intensity modulated radiation therapies have the potential to preserve cognitive outcomes in children with ependymoma; however, functional behavior remains uninvestigated. This longitudinal investigation prospectively examined intelligence quotient (IQ) and adaptive functioning during the first 5 years after irradiation in children diagnosed with ependymoma. METHODS AND MATERIALS: The study cohort consisted of 123 children with intracranial ependymoma. Mean age at irradiation was 4.60 years (95% confidence interval [CI], 3.85-5.35). Serial neurocognitive evaluations, including an age-appropriate IQ measure and the Vineland Adaptive Behavior Scales (VABS), were completed before irradiation, 6 months after treatment, and annually for 5 years. A total of 579 neurocognitive evaluations were included in these analyses. RESULTS: Baseline IQ and VABS were below normative means (P<.05), although within the average range. Linear mixed models revealed stable IQ and VABS across the follow-up period, except for the VABS Communication Index, which declined significantly (P=.015). Annual change in IQ (-.04 points) did not correlate with annual change in VABS ( .90 to +.44 points). Clinical factors associated with poorer baseline performance (P<.05) included preirradiation chemotherapy, cerebrospinal fluid shunt placement, number and extent of surgical resections, and younger age at treatment. No clinical factors significantly affected the rate of change in scores. CONCLUSIONS: Conformal and intensity modulated radiation therapies provided relative sparing of functional outcomes including IQ and adaptive behaviors, even in very young children. Communication skills remained vulnerable and should be the target of preventive and rehabilitative interventions. PMID- 22541969 TI - [The EUCORE registry: objectives and general results]. AB - The European Cubicin Outcomes Registry and Experience (EUCORE) is an ongoing, retrospective, European, post-marketing, non-comparative database of daptomycin use in patients that have received at least one daptomycin dose. The primary objective is to evaluate the clinical outcomes of patients treated with this drug. This article presents the analysis of patients included in Spanish institutions from January 2006 to March 2010. A total of 726 patients were included: 66% males, 48.6% aged more than 65 years old, and 70% with comorbidities. Daptomycin was administered in the outpatient setting in 20.3% of the patients. More than 50% of the patients received a dose of 6 mg/kg/day and in 80% daptomycin was administered as a rescue therapy. The median treatment duration was 14 days. The infections treated were bacteremia (32.51%), skin and soft tissue infections (31.4%), infectious endocarditis (14.33%), infections associated with prosthetic materials (10.9%), osteoarticular infections (6.1%), and others. Infections were caused by Staphylococcus aureus (40.5%; 14.4% methicilllin-resistant), coagulase-negative staphylococci (34.5%), enterococci (11.7%) and group viridans streptococci (2.9%). The overall rate of clinical success was 78.4% (81.5% when administered as first-line therapy and 77.6% when administered as rescue therapy). In patients with renal failure, the efficacy of daptomycin was lower. At the end of therapy, 8.7% of patients showed a decrease in creatinine clearance, and in 25 patients creatine kinase values were more than 10 times higher than normal values. Daptomycin is a safe and effective antimicrobial agent for the treatment of severe infections caused by Gram positive bacteria. PMID- 22541970 TI - [Daptomycin in the context of antimicrobial resistance in Gram-positive bacteria]. AB - Infection by antimicrobial-resistant Gram-positive bacteria (GPB) is highly prevalent, especially in the hospital setting. The increase in the use of glycopeptides has a microbiological cost: vancomycin-resistant strains (scarce), strains with intermediate sensitivity, heteroresistant and glycopeptide-tolerant strains and glycopeptide-sensitive strains but with a higher minimal inhibitory concentration require a higher dose of vancomycin, increasing toxicity. Because of its pharmacodynamics profile, linezolide has allowed more effective treatment of localized GPB infections in areas with complex spread and in ischemic tissues with little cost in terms of the selection of resistant strains. Similarly, because of its broad spectrum, tigecycline can be used to treat complex mixed infections caused by resistant pathogens. However, because linezolide and tigecycline are bacteriostatic agents, their use in the initial management of bacteremia, endocarditis and infection in immunocompromised hosts is limited. Because daptomycin has potent early bactericidal activity and has not been affected by heteroresistance or tolerance, this drug is an effective alternative against these severe GPB infections. PMID- 22541971 TI - [Daptomycin therapy in patients with bacteremia]. AB - Community-acquired bacteremias assciated with healthcare and, especially, those of nosocomial origin, are mainly caused by Gram-positive microorganisms. Notable among this group are Staphylococcus spp, with an incidence of methicillin resistance of approximately 30% in S. aureus and of 70% in coagulase-negative staphylococcus, which is higher in patients admitted to intensive care units. Vancomycin has been the most widely used antibiotic in these situations but its toxicity, especially in the kidney, and reports of failure when used for the treatment of methicillin-resistant S. aureus (MRSA) and with a vancomycin MIC > 1 mg/L have led to the search for other treatments. Daptomycin is a new lipopeptide antibiotic that has been shown to be not inferior to vancomycin in a pivotal clinical trial in patients with bacteremia and right endocarditis due to S. aureus. Recent guidelines and consensus documents place daptomycin as an ideal alternative in these situations, indicating its use in MRSA bacteremia with a vancomycin MIC > 1 mg/L, as well as in patients whose renal dysfunction excludes the use of vancomycin therapy. Evidence of worse prognosis in MRSA bacteremia when empirical treatment is inappropriate has led to the recommendation of daptomycin as the first-choice drug in critically ill patients with suspected Gram-positive bacteremic infection and renal dysfunction and/or in hospitals where there is a high prevalence of MRSA with a MIC > 1 mg/L. The recommended dose in severely ill patients should be higher than 6 mg/kg/day. PMID- 22541972 TI - [Challenges in the antimicrobial treatment of infective endocarditis. Role of daptomycin]. AB - Infections caused by Gram-positive organisms are currently a therapeutic problem because of the emergence and spread of strains with multiple resistance to antibiotics used as first-line therapeutic options. Glycopeptides, considered as alternative drugs, have limited effectiveness in the treatment of serious infections caused by these microorganisms, including infective endocarditis. Among the new antimicrobial agents recently licensed for use in human therapy, daptomycin offers a good clinical efficacy profile in both clinical trials and in experiences of clinical use registered after approval. Because of its bactericidal activity and potential synergy with other antimicrobial agents, such as beta-lactams, fosfomycin and aminoglycosides, daptomycin is among the first line options in the treatment of infections caused by staphylococci and probably enterococci with multiple resistance to antibiotics. Daptomycin also offers an excellent safety profile and a very low rate of resistance. Further studies, including many patients with this serious infection, should precisely determine the clinical efficacy of daptomycin in this indication. PMID- 22541973 TI - [Daptomycin in complicated skin and soft tissue infections]. AB - In recent years, Staphylococcus aureus, the most commonly identified infectious agent causing skin and soft tissue infections (SSTIs), has shown an increase in methicillin resistance and decreased susceptibility to vancomycin. Because of its spectrum, microbiological activity, pharmacokinetics, and safety, as well as clinical experience in its use, daptomycin seems to be a highly appropriate antibiotic in the treatment of SSTIs, especially those produced by methicillin resistant S. aureus. PMID- 22541974 TI - [Daptomycin in the treatment of Gram-positive infections in patients with chronic renal failure]. AB - Daptomycin is a cyclic lipopeptide that is effective in the treatment of Gram positive infections, including those caused by multiresistant pathogens. This drug has rapid bactericidal action and low nephrotoxicity. Patients with severe renal failure show a dicrease in its renal clearance and an increase in the elimination half-life. The recommended dose in patients with creatinine clearance (CrCl) < 30 ml/min is 4 mg/kg/48 h in skin and soft tissue infections and is 6 mg/kg/48 h in bacteremia and right endocarditis. Pharmacokinetic studies and data from the CORE Registry have allowed improved the dosing regimen in patients under hemodialysis, peritoneal dialysis and other extrarenal depuration techniques. Patients with a CrCl < 30 ml/ min have rates of efficacy ranging between 69.2% and 96%, these rates being similar to or lower than those observed in patients with a CrCl > 30 ml/min. Patients under hemodialysis may have higher rates of clinical failure. This article presents the preliminary results of the EUCORE in Spain. The presence of renal failure at the start of daptomycin therapy is not associated with an increase in the rates of severe adverse effects. Daptomycin has a good safety and efficacy profile for the treatment of infections in patients with chronic renal insufficiency. The consensus documents of distinct societies have incorporated the use of daptomycin in the treatment of bacteremia due to methicillin-resistant Staphylococcus aureus in patients with renal insufficiency. PMID- 22541975 TI - [Daptomycin in Gram-positive bacterial infections in oncohematological patients and transplant recipients]. AB - Gram-positive infections are a major cause of morbidity and mortality in oncohematological patients and transplant recipients. The most frequently isolated Gram-positive organisms are the coagulase-negative staphylococci, Staphylococcus aureus and Enterococcus spp., and viridans group streptococci. Antibiotic resistance in these organisms is increasing and poses a challenge to clinicians. Daptomycin is rapidly bactericidal against a broad spectrum of gram positive bacteria, including strains resistant to other drugs. The present article reviews some aspects of Gram-positive infections in these immunocompromised patients and provides a detailed analysis of experience with daptomycin in the treatment of these infections. PMID- 22541976 TI - [Safety and efficacy of daptomycin therapy in older adults with pluripathology]. AB - Serious Gram-positive bacterial infections are a major cause of morbidity and mortality among older adults and can pose a significant challenge to clinicians. Although more than 50% of patients treated with daptomycin are > 65 years old, there are few data evaluating the efficacy and safety of daptomcyn in this population. Analysis of data from patients > 65 years old included in the Cubicin Outcomes Registry and Experience (CORE), a multicenter, retrospective registry designed to collect post-marketing clinical data on patients who received daptomycin, and in its European version, the EUCORE, showed similar rates of efficacy and safety in this population to those in younger patients, suggesting that daptomycin is also a valuable option in older patients with serious Gram positive infections. PMID- 22541977 TI - [Daptomycin in diabetic patients]. AB - In diabetic patients, there is a high prevalence of skin or nasal carriage of Staphylococcus aureus, which is associated with an increased risk of local or systemic infections and consequently with greater morbidity and mortality. The microorganisms causing most infections in diabetic ulcers and diabetic foot are S. aureus and Streptococcus pyogenes, although chronic diabetic foot infections are generally polymicrobial, including Pseudomonas aeruginosa and enterobacteria. The present article describes experience with daptomycin in the treatment of the most frequent infectious complications in diabetic patients. The Cubicin Outcomes Registry and Experience (CORE) registry contains information on 60 patients with skin and soft tissue infections treated with daptomycin, with a success rate of 83%. Other recent studies comparing daptomycin with vancomycin or semi-synthetic penicillins have also shown the efficacy and safety of daptomycin with cure rates of between 70% and 80%. In the European version of the CORE registry, the EUROCORE, diabetic patients who developed bacteremia or endocarditis due to Gram positive pathogens and who received daptomycin showed success rates of 76.8% and 72%, respectively. No significant differences were found in a study comparing daptomycin or standard therapy with vancomycin in methicillin-resistant S. aureus (MRSA) or antistaphylococcal penicillin in methicillin-susceptible S. aureus (MSSA) in diabetic patients with bacteremia or endocarditis. Because of its rapid bactericidal action and scarce adverse effects, daptomycin is an attractive antimicrobial agent in the treatment of Gram-positive infections in diabetic patients, whether in monotherapy or in association with other agents. PMID- 22541978 TI - [Daptomycin in outpatient antimicrobial parenteral therapy]. AB - Daptomycin is a cyclic lipopeptide with a rapid bactericidal effect against Gram positive bacteria. The pharmacokinetic properties of this drug allow once-daily intravenous infusion as the best posology (including a 2-minute bolus). Because of its ease of administration and excellent safety profile, daptomycin is a first line agent for use as outpatient antimicrobial parenteral therapy (OPAT). The best evidence supporting this indication exists for the treatment of complicated and uncomplicated skin and soft tissue infections, as well as osteoarticular infections caused by Gram-positive bacteria. For the remaining indications, the use of daptomycin as OPAT should be analyzed in each patient. Information from the EUCORE Registry in Spain indicates that daptomycin has high rates of treatment success in both hospitalized patient and in those included in OPAT programs. PMID- 22541979 TI - Bone mineral density in adult patients treated with various antiepileptic drugs. AB - There is considerable evidence suggesting, that older antiepileptic drugs (AEDs) and some of the newer ones decrease bone mineral density (BMD). However, there is only limited and conflicting data concerning the effect of levetiracetam on BMD. In this cross-sectional study we analysed data from 168 adult consecutive outpatients treated with AEDs for more than 2 years, and who underwent measurement of the BMD. We compared the incidence of decreased BMD among the patients treated with 6 different AEDs: carbamazepine (CBZ), oxcarbazepine (OXC), valproic acid (VPA), lamotrigine (LTG), topiramate (TPM) and levetiracetam (LEV). Among the patients on monotherapy, reduced BMD was present significantly most often in patients treated with LEV and those treated with OXC. In the group of patients on polytherapy there was no significant difference in the incidence of low BMD among patients treated with various AEDs. Our data suggest that patients on long-term treatment with LEV have a higher risk for affection of bone density. PMID- 22541980 TI - Difficulty with surgical site identification: what role does it play in dermatology? AB - BACKGROUND: The potential for wrong-site surgery is a growing concern in dermatology. OBJECTIVE: The purpose of this study was to determine the incidence of difficulty with surgical site identification and possible confounding factors. METHODS: This was a prospective study on 333 Mohs cases performed between April 1, 2009, and February 9, 2010. Data collection forms were used on the day of surgery to record the difficulty associated with surgical site identification and potential confounding factors. RESULTS: Of the 333 patients evaluated, 9% were unable to identify their surgical sites. The majority of cases (88.5%) were located on the head and neck. When comparing patients who were able to identify their site and those who were not, there was a statistically significant difference (P = .035) in the percentage of lesions residing in a location visible to the patient. Those who were able to see their biopsy sites were 3.5 times more likely to identify their surgical site. Of the 47.6% of patients with chart notes, only 5% of these cases were photographs and 23% had high-quality diagrams. Although a delay in treatment of greater than 3 months from the original biopsy site was higher among those with difficulty in identifying their surgical site, this was not found to be statistically significant. LIMITATIONS: We believe our sample size was not large enough to show a significant link between difficulty with surgical site identification and several likely confounding factors. CONCLUSION: We have shown that at least 9% of patients presenting for Mohs micrographic surgery are unable to confidently identify their surgical sites. PMID- 22541981 TI - Relaxin-2 may offer therapeutic advantages in end-stage heart failure. PMID- 22541982 TI - Acute aortic dissection with ongoing right coronary artery and aortic valve involvement. PMID- 22541983 TI - [Anaesthetic management of brain-dead for organ donation: impact on delayed graft function after kidney transplantation]. AB - BACKGROUND: The aim of this study was to report current anaesthetic management brain-dead organ donors and to assess its impact on delayed kidney graft function (DGF). METHODS: To achieve this retrospective multicenter study, brain-dead patient records were analysed for the years 2005 to 2007. Expanded donor criteria, length of stay in ICU, duration of brain death, respect of recommended cold ischemia time, preoperative and intraoperative management, type of anaesthesia, hemodynamic and respiratory parameters during organ retrieval, and impact of anaesthesia on DGF were analysed. RESULTS: One hundred and forty-nine out of 165 files were available. Sixty-two percent of donors received anaesthetic drugs. There were no differences in demographic characteristics between the anaesthesia group (group A) and the no-anaesthesia group (group NA). In group NA, the mean arterial pressure (MAP)>65 mm Hg was more frequent (53% vs. 29%, P<0.01), but did not differ for maximal MAP. In group A, maximal heart rate was higher (120 vs. 105b/min, P=0.02) and donors received significantly more colloids (P<0.01). Independent risk factors of DGF included absence of hydroxyethyl starch infusion during the preoperative period and mechanical ventilation without PEEP. CONCLUSION: During organ retrieval, 62% of organ donors received anaesthetic drugs. Use of anaesthesia lead to lower MAP requiring more fluid challenge with colloids but did not influence the DGF. PMID- 22541984 TI - [Medication error: account the shape but the context too]. PMID- 22541985 TI - Open repair of blunt thoracic aortic injury remains relevant in the endovascular era. AB - BACKGROUND: Thoracic endovascular aneurysm repair (TEVAR) has been a major advance in the treatment of blunt thoracic aortic injury (BTAI), although many patients still undergo open repair. This study was undertaken to evaluate outcomes with open repair and TEVAR for BTAI. STUDY DESIGN: A retrospective review of all patients with BTAI at a single Level I trauma center from 2001 through 2009 was performed. Patients were grouped according to treatment modality, ie, open repair, TEVAR, or medical management. Direct comparison using standard statistical methods was made between patients undergoing open repair and TEVAR since late 2006 when TEVAR began at our institution using standard statistical methods. Outcomes variables included mortality, paraplegia, length of stay, ICU stay, and ventilator requirements. RESULTS: There were 69 patients in the study, with 36 (52.2%) undergoing open repair, 10 receiving TEVAR (14.5%), 10 patients managed medically (14.5%), and 13 (18.8%) who died during triage. Overall mortality in the pre-TEVAR era was 29.6%. Since the introduction of TEVAR, there have been 8 open repairs. Patients undergoing open repair were significantly younger (32 vs 58 years; p = 0.002) and had smaller aortic diameter (18 mm vs 24.5 mm; p < 0.001) than those undergoing TEVAR. Overall mortality since the introduction of TEVAR has dropped to 12.0% (p = 0.097). CONCLUSIONS: TEVAR and open repair should be viewed as complementary rather than competing modalities for the treatment of BTAI. Having both available allows selection of the most appropriate management technique for each patient, with subsequent improvement in outcomes. PMID- 22541986 TI - Intraparenchymal vs extracranial ventricular drain intracranial pressure monitors in traumatic brain injury: less is more? AB - BACKGROUND: Management of severe traumatic brain injury has centered on continuous intracranial pressure (ICP) monitoring with intraparenchymal ICP monitors (IPM) or extracranial ventricular drains (EVD). Our hypothesis was that neurologic outcomes are unaffected by the type of ICP monitoring device. STUDY DESIGN: We reviewed 377 adult patients with traumatic brain injury requiring ICP monitoring. Primary outcome was Glasgow Outcome Score (GOS) 1 month after injury. Secondary outcomes included mortality, monitoring-related complications, and length of ICU and hospital stay. RESULTS: There were 253 patients managed with an IPM and 124 with an EVD. There was no difference in Glasgow Outcome Score (2.7 +/ 1.3 vs 2.5 +/- 1.3, p = 0.45), mortality (30.9% vs 32.2%, p = 0.82), and hospital length of stay (LOS) (15.6 +/- 12.4 days vs 16.4 +/- 10.7 days, p = 0.57). Device-related complications (11.9% vs 31.1%, p < 0.001), duration of ICP monitoring (3.8 +/- 2.6 days vs 7.3 +/- 5.6 days, p < 0.001), and ICU LOS (7.6 +/ 5.6 days vs 9.5 +/- 6.2 days, p = 0.004) were longer in the EVD group. Age, opening ICP, and size of midline shift were independent predictors for neurologic outcomes and mortality, when type and severity of brain injury, as well as overall injury severity were controlled for. Duration of ICP monitoring and opening ICP were independent predictors for hospital LOS and the former predicted prolonged ICU stay. Device-related complications were affected by type of device. CONCLUSIONS: Use of EVDs in adult traumatic brain injury patients is associated with prolonged ICP monitoring, ICU LOS, and more frequent device-related complications. PMID- 22541987 TI - Early tracheostomy is associated with improved outcomes in patients who require prolonged mechanical ventilation after cardiac surgery. AB - BACKGROUND: The best time to perform a tracheostomy in cardiac surgery patients who require prolonged postoperative mechanical ventilation remains unknown. The primary aim of this investigation was to determine if tracheostomy performed before postoperative day 10 improves patient outcomes. STUDY DESIGN: We conducted a retrospective review of prospectively collected patient information obtained from the Anesthesiology Institute Patient Registry on adult patients recovering from coronary artery bypass grafting and/or valve surgery. Demographic and comorbidity patient variables were obtained. Patients were divided into 2 groups based on the timing of their tracheostomy: early (less than 10 days) and late (14 to 28 days). The 2 patient groups were matched using propensity scores and compared on morbidity and in-hospital mortality outcomes. The primary outcomes measures were length of stay, morbidity, and in-hospital mortality. RESULTS: After propensity matching (n = 114 patients/group), early tracheostomy was associated with decreased in-hospital mortality (21.1% vs 40.4%, p = 0.002) and cardiac morbidity (14.0% vs 33.3%, p < 0.001), along with decreased ICU (median difference 7.2 days, p < 0.001) and hospital (median difference 7.5 days, p = 0.010) durations. The occurrence of sternal wound infection (6.0% vs 19.5%, p = 0.009) was less in the early tracheostomy group, but mediastinitis did not differ significantly (3.5% vs 7.0%, p = 0.24). CONCLUSIONS: Tracheostomy within 10 postoperative days in cardiac surgery patients who require prolonged mechanical ventilation was associated with decreased length of stay, morbidity, and mortality. PMID- 22541989 TI - [NGAL, biomarker of acute kidney injury in 2012]. AB - Neutrophil Gelatinase Associated Lipocalin (NGAL) is one of the most promising biomarkers for acute kidney injury (AKI). Although urinary NGAL is intuitively more appropriate to apprehend renal injury, clinical data have accumulated on the potential interest of NGAL measured indifferently in serum or urine. Diagnostic performance of NGAL greatly varies across studies according to different factors such as the type of patients (pediatric versus adult) and the clinical situations (surgery versus intensive care). Overall, NGAL is presented as a useful tool to diagnose and predict AKI outcome but several issues (the absence of a unique pertinent threshold value, the incomplete analytical validation of its measurement and, its apparent limited clinical added value as compared to traditional AKI markers) remain to be addressed in order to definitely recommend its use in clinical practice. PMID- 22541988 TI - [Perception of kidney donation in Senegal and potential donors]. AB - INTRODUCTION: The objective of this study was to explore the potential for kidney donation in the Senegalese population, as a prelude to a proposed kidney transplant from living donors. METHOD: A survey of cross type, and descriptive analysis was conducted from June 15 to September 15, 2010 in Dakar (Senegal). A two-stage sampling was done. The data, collected on the basis of a questionnaire, were captured and analyzed with Epi Info software version 3.3.2 and R version 2.9.2. RESULTS: The study population comprised 400 people with 56.75% of men, a sex ratio of 1.3. The average age was 33.58+/-11 years. It consisted of people between 18 and 30 (48.5%), married (44.25%). The subjects surveyed were mostly Senegalese (91%), students and pupils (24%) and educated (86.75%). The questioned subjects heard of kidney failure (65%). They knew at least one person who died of renal failure or dialyzed respectively in 19% and 24% of cases. The respondents have heard of the graft (47.3%). They knew at least one grafted patient in 5%. The public has expressed a desire to donate a kidney to a relative or friend in treatment of chronic renal failure in 71.5% of cases. The subjects taught at secondary level, higher level and those informed of renal failure were more prone to kidney donation than others. CONCLUSION: This study shows a large pool of potential kidney donors, hence the need to conduct outreach activities to turn them into actual donors. PMID- 22541990 TI - Resistance training to improve power and sports performance in adolescent athletes: a systematic review and meta-analysis. AB - OBJECTIVES: Resistance training in untrained adolescents can positively effect health-related fitness as well as improve muscular power and sports performance. The impact of resistance training on adolescent athletes is less clear. The purpose of this review is to determine the effectiveness of resistance training programs on muscular power and sports performance in adolescent athletes. DESIGN: Systematic review and meta-analysis of previously published studies investigating resistance training in adolescent athlete populations. METHODS: A systematic search of Medline, Embase, and SPORTDiscus databases was conducted on 21st March 2011 to identify studies evaluating resistance training programs on power and sports performance in adolescent athletes. RESULTS: Thirty-four studies were identified. All but two of the studies reported at least one statistically significant improvement in an alactic muscular power outcome. The most common indicators of alactic power were vertical jump (25 studies) and sprint running (13 studies) performance. Fourteen studies provided data to allow for pooling of results in a meta-analysis. A positive effect was detected for resistance training programs on vertical jump performance (mean difference 3.08 [95% CI 1.65, 4.51], Z=4.23 [P<0.0001]). CONCLUSIONS: There is sufficient evidence to conclude that resistance-training interventions can improve muscular power in adolescent athletes. A positive effect on sports performance attributable to participation in resistance training was reported by almost half the included studies, however limited objective evidence to support these claims was found. Improvements in motor performance skills, such as jumping, are widely stated as indicators of improvements in sporting performance. PMID- 22541991 TI - Radiological investigations at the "Taiga" nuclear explosion site, part II: man made gamma-ray emitting radionuclides in the ground and the resultant kerma rate in air. AB - Samples of soil and epigeic lichens were collected from the "Taiga" peaceful nuclear explosion site (61.30 degrees N 56.60 degrees E, the Perm region, Russia) in 2009 and analyzed using high resolution gamma-ray spectrometry. For soil samples obtained at six different plots, two products of fission ((137)Cs and (155)Eu), five products of neutron activation ((60)Co, (94)Nb, (152)Eu, (154)Eu, (207)Bi) and (241)Am have been identified and quantified. The maximal activity concentrations of (60)Co, (137)Cs, and (241)Am for the soils samples were measured as 1650, 7100, and 6800 Bq kg(-1) (d.w.), respectively. The deposit of (137)Cs for the top 20 cm of soil on the tested plots at the "Taiga" site ranged from 30 to 1020 kBq m(-2); the maximal value greatly (by almost 3 orders of magnitude) exceeded the regional background (from global fallout) level of 1.4 kBq m(-2). (137)Cs contributes approximately 57% of the total ground inventory of the man-made gamma-ray emitters for the six plots tested at the "Taiga" site. The other major radionuclides -(241)Am and (60)Co, constitute around 40%. Such radionuclides as (60)Co, (137)Cs, (241)Am, and (207)Bi have also been determined for the epigeic lichens (genera Cladonia) that colonized certain areas at the ground lip produced by the "Taiga" explosion. Maximal activity concentrations (up to 80 Bq kg(-1) for (60)Co, 580 Bq kg(-1) for (137)Cs, 200 Bq kg(-1) for (241)Am, and 5 Bq kg(-1) for (207)Bi; all are given in terms of d.w.) have been detected for the lower dead section of the organisms. The air kerma rates associated with the anthropogenic sources of gamma radiation have been calculated using the data obtained from the laboratory analysis. For the six plots tested, the kerma rates ranged from 50 to 1200 nGy h(-1); on average, 51% of the dose can be attributed to (137)Cs and 45% to (60)Co. These estimates agree reasonably well with the results of the in situ measurements made during our field survey of the "Taiga" site in August 2009. PMID- 22541992 TI - Radionuclides in the ground-level atmosphere in Vilnius, Lithuania, in March 2011, detected by gamma-ray spectrometry. AB - This study presents the ground-level air monitoring results obtained in Vilnius, the capital of Lithuania, on 14 March-14 April 2011 after the recent earthquake and subsequent Tsunami having a crucial impact on Japanese nuclear reactors at the Fukushima Daiichi Nuclear Power Plant (NPP) on 11 March 2011. To collect representative diurnal aerosol samples a powerful sampling system ensuring the air filtration rate of 5500 m(3) h(-1) was used. The following artificial gamma ray emitting radionuclides have been determined: (129m)Te, (132)Te (in equilibrium with its daughter (132)I), (131)I, (134)Cs, (136)Cs and (137)Cs. Activity concentration of the globally distributed fission product (137)Cs has increased from a background value of 1.6 MUBq m(-3) to the value of 0.9 mBq m(-3) at the beginning of April. The activity ratio (134)Cs/(137)Cs was found to be close to 1, with a slightly higher activity of (134)Cs. The maximum aerosol associated (131)I activity concentration of 3.45 mBq m(-3) was by four orders of magnitude lower than that measured at the same location in April-May 1986 as a consequence of the Chernobyl NPP accident. The estimated gaseous fraction of iodine-131 constituted about 70% of the total (131)I activity. PMID- 22541993 TI - Even SAFER handovers in obstetric anaesthesia. PMID- 22541994 TI - A review of the environmental safety of the Cry1Ab protein. PMID- 22541995 TI - The membrane interaction of drugs as one of mechanisms for their enantioselective effects. AB - The discrimination between different enantiomers of chiral compounds by the biological system is medically important as the pharmacological and toxicological effects of enantiomeric drugs significantly differ depending on their stereostructures. One enantiomer is preferred over its enantiomeric counterpart and a racemic mixture for higher activity or lower toxicity. Such enantioselectivity has been exclusively explained by the stereostructure-specific interactions with receptors, channels and enzymes of drugs including general and local anesthetics, sedatives, hypnotics, anti-inflammatory drugs, analgesics and beta-adrenergic antagonists. These drugs can act on not only protein targets but also lipid biomembranes. Almost all of the relevant proteins are embedded in or associated with membrane lipid bilayers. Therefore, we propose one of possible mechanisms that drugs might enantioselectively interact with membrane lipids and induce changes in membrane property like fluidity which are discriminable between enantiomers. If the induced changes are different between enantiomers, enantiomeric drugs would differently influence the membrane lipid environments for receptors, channels and enzymes, resulting in the enantioselectivity of drug effects. The enantioselective membrane interactions of drugs could be mediated by membrane component cholesterol and phospholipids, both of which have chiral centers in structure as well as drug enantiomers. Chiral membrane lipids possibly exhibit the preference for the interactions with drug molecules of either the same chirality or the different chirality, producing the selectivity to one drug enantiomer. The proposed hypothesis may be available to investigate more useful medicines based on the novel concept of drug enantioselectivity. PMID- 22541996 TI - The value of a European registry for pituitary adenomas: the example of Cushing's syndrome registry. AB - In the field of Rare Diseases, patient registries and databases are key instruments for the development of clinical research, improvement of patient care and healthcare planning. They can achieve a sufficient sample size for epidemiological and/or clinical research, to assess feasibility of and facilitate planning of appropriate clinical trials, and support the enrolment of patients to be treated with orphan drugs. Registries of patients treated allow the gathering of evidence on the effectiveness of treatments and possible side effects, since marketing authorisation is often granted when evidence albeit convincing, is limited. The European Registry of Cushing's syndrome (ERCUSYN) database initially funded by the EU, now includes data on over 500 patients. It represents the largest collaboration of endocrine centres in Europe and has potential not only for improving the care of patients with Cushing's syndrome, but also to extend its collaboration into new areas. It may be used as a rare disease registry for an orphan drug to be evaluated, such as a new somatostatin analogue. This academic registry set up before marketing authorization of this new drug as a disease registry, may be liaised to a European Medicines Agency-regulated, industry-required post-marketing surveillance study, to follow safety and efficacy in the long term outcomes in clinical practice conditions. Through the ESE this network may be used to disseminate information and encourage further interaction between endocrinologists across Europe. PMID- 22541997 TI - Diagnostic and therapeutic challenges of acquired thyrotropic deficiency. AB - The acquired thyrotropic deficiency (TD) is a hypothyroid condition due to an insufficient stimulation by thyrotropin (TSH) of an otherwise normal thyroid gland. This disease can be the consequence of disorders affecting either the pituitary gland or the hypothalamus, but most frequently both of them, and is generally called central hypothyroidism (CH). CH is about one thousand folds rarer than primary hypothyroidism (PH) and the thyroid hormone defect is often less severe than in primary forms. Differently to PH, the TD is most frequently characterized by low/normal TSH levels and thyroid hormone replacement is associated with the suppression of residual TSH secretion. Thus, CH diagnosis and management often represent a clinical challenge because physicians cannot rely on the systematic use of the reflex TSH determination. The clinical challenge of CH is further amplified by the frequent combination with other pituitary deficiencies. PMID- 22541998 TI - A general overview on pituitary tumorigenesis. PMID- 22541999 TI - Male acquired hypogonadotropic hypogonadism: diagnosis and treatment. AB - Acquired hypogonadotropic hypogonadism (AHH), contrary to congenital hypogonadotropic hypogonadism (CHH) is characterized by postnatal onset of disorders that damage or alter the function of gonadotropin-releasing hormone (GnRH) neurons and/or pituitary gonadotroph cells. AHH thus prevents the establishment of gonadotropin secretion at puberty, or its post-pubertal maintenance. Thus, postnatal AHH may prevent the onset of puberty or appear during pubertal development, but it usually emerges after the normal age of puberty. Although pituitary tumors, particularly prolactinoma, are the most common cause, sellar tumors or cyst of the hypothalamus or infundibulum, infiltrative, vascular, iron overload and other disorders may also cause AHH. Pituitary surgery and head trauma or cranial/pituitary radiation therapy are also usual causes of AHH. The clinical manifestations of AHH depend on age of onset, the degree of gonadotropin deficiency, the rapidity of its onset and the association to other pituitary function deficiencies or excess. Men with AHH have less stamina, decreased libido, erectile dysfunction and strength, and a worsened sense of well being leading to degraded quality of life. The physical examination is usually normal if hypogonadism is of recent onset. Diminished facial, body hair and muscle mass, fine facial wrinkles, gynecomastia, and hypotrophic testes are observed in long-standing and complete AHH. Spermatogenesis is impaired and the volume of ejaculate is decreased only when gonadotropins and testosterone levels are very low. Men with AHH may have normal or low serum LH and FSH concentrations, but normal gonadotropin values are inappropriate when associated with low serum testosterone. In the majority of AHH patients, serum inhibin B is "normal". The decrease of this sertolian hormone indicates a long-standing and severe gonadotropin deficiency. Symptoms, usually associated with significant testosterone deficiency in men with AHH, improve with testosterone replacement therapy. Replacement therapy is often simple, using an injectable testosterone ester as first line treatment. Fertility can be restored rather quickly, provided there is no independent primary testicular damage and the partner is fertile. PMID- 22542000 TI - Treatment of nonfunctioning pituitary adenomas: what were the contributions of the last 10 years? A critical view. AB - OBJECTIVES: All evidence for treatment and follow-up for nonfunctioning pituitary adenomas (NFMA) is based on observational studies. The objective was to critically review the contributions of the last 10 years on treatment of NFMA. MATERIALS AND METHODS: Systematic review. RESULTS: Transsphenoidal surgery remains the cornerstone of treatment of NFMA. When compared to the microsurgical procedure, some, but not all, studies favor endoscopy, but endocrinological outcome is not different. Radiosurgery results in a high and durable rate of tumor control, including in those previously treated by conventional radiotherapy, but the risk of developing hypopituitarism is comparable to the risk after conventional radiotherapy. In selected patients without visual field defects, a wait-and-see approach with frequent evaluation of visual fields is possible, without the risk of irreversibly compromising visual function. Tumor progression in NFMA is difficult to predict, but the MIB-1 LI is clinically useful and is indicative of invasiveness, but does not predict recurrence. To date, the potential contribution of other proliferation markers still requires further validation, and effective medical treatment strategies are not available. New features are the role of temozolomide and rapamicin as potential therapeutical targets, combined with octreotide. Although chimeric sst-DA analogues effectively inhibit proliferation in vitro, the effects of these molecules have not yet been evaluated in clinical trials with patients with NFMA. CONCLUSION: Surgery, followed by radiotherapy or radiosurgery in case of remnant or recurrence, remains the cornerstone of treatment of NFMA. Currently, medical treatment cannot yet be incorporated in routine clinical practice. PMID- 22542001 TI - MENX. AB - Multiple endocrine neoplasias (MEN) are a group of hereditary disorders characterized by tumors arising in more than one neuroendocrine tissue. There are two major forms which can occur in humans, MEN type 1 (MEN1) and MEN type 2 (MEN2). These syndromes are transmitted as autosomal dominant traits with high penetrance and have a different tumor spectrum. MEN1 and MEN2 are caused by germline mutations in the MEN1 and RET genes, respectively. Recently, a variant of the MEN syndromes was discovered in a rat colony and was named MENX since affected animals develop tumors with a spectrum that shares features with both MEN1 and MEN2 human syndromes. Extensive genetic studies identified a germline mutation in the Cdkn1b gene, encoding the p27 cell cycle inhibitor, as the causative mutation for MENX. Capitalizing on these findings, heterozygous germline mutations in the human homologue, CDKN1B, were searched for and identified in patients with multiple endocrine tumors. As a consequence of this discovery, a novel human MEN syndrome, named MEN4, was recognized which is caused by mutations in p27. Altogether these studies identified Cdkn1b/CDKN1B as a novel tumor susceptibility gene for multiple endocrine tumors in both rats and humans. Here I review the phenotypic features and the genetics of the MENX rat syndrome. I briefly address the main functions of p27 and how they are affected by the MENX associated mutation. Finally, I present examples of how this animal model might be exploited as a translational platform for preclinical studies of pituitary adenomas. PMID- 22542002 TI - Broad neutralization of wild-type dengue virus isolates following immunization in monkeys with a tetravalent dengue vaccine based on chimeric yellow fever 17D/dengue viruses. AB - The objective of the study was to evaluate if the antibodies elicited after immunization with a tetravalent dengue vaccine, based on chimeric yellow fever 17D/dengue viruses, can neutralize a large range of dengue viruses (DENV). A panel of 82 DENVs was developed from viruses collected primarily during the last decade in 30 countries and included the four serotypes and the majority of existing genotypes. Viruses were isolated and minimally amplified before evaluation against a tetravalent polyclonal serum generated during vaccine preclinical evaluation in monkey, a model in which protection efficacy of this vaccine has been previously demonstrated (Guirakhoo et al., 2004). Neutralization was observed across all the DENV serotypes, genotypes, geographical origins and isolation years. These data indicate that antibodies elicited after immunization with this dengue vaccine candidate should widely protect against infection with contemporary DENV lineages circulating in endemic countries. PMID- 22542003 TI - Characterization of cell lines stably transfected with rubella virus replicons. AB - Rubella virus (RUBV) replicons expressing a drug resistance gene and a gene of interest were used to select cell lines uniformly harboring the replicon. Replicons expressing GFP and a virus capsid protein GFP fusion (C-GFP) were compared. Vero or BHK cells transfected with either replicon survived drug selection and grew into a monolayer. However, survival was ~9-fold greater following transfection with the C-GFP-replicon than with the GFP-expressing replicon and while the C-GFP-replicon cells grew similarly to non-transfected cells, the GFP-replicon cells grew slower. Neither was due to the ability of the CP to enhance RNA synthesis but survival during drug selection was correlated with the ability of CP to inhibit apoptosis. Additionally, C-GFP-replicon cells were not cured of the replicon in the absence of drug selection. Interferon-alpha suppressed replicon RNA and protein synthesis, but did not cure the cells, explaining in part the ability of RUBV to establish persistent infections. PMID- 22542004 TI - Quantitative proteomic analysis of HIV-1 infected CD4+ T cells reveals an early host response in important biological pathways: protein synthesis, cell proliferation, and T-cell activation. AB - Human immunodeficiency virus (HIV-1) depends upon host-encoded proteins to facilitate its replication while at the same time inhibiting critical components of innate and/or intrinsic immune response pathways. To characterize the host cell response on protein levels in CD4+ lymphoblastoid SUP-T1 cells after infection with HIV-1 strain LAI, we used mass spectrometry (MS)-based global quantitation with iTRAQ (isobaric tag for relative and absolute quantification). We found 266, 60 and 22 proteins differentially expressed (DE) (P-value <= 0.05) at 4, 8, and 20 hours post-infection (hpi), respectively, compared to time matched mock-infected samples. The majority of changes in protein abundance occurred at an early stage of infection well before the de novo production of viral proteins. Functional analyses of these DE proteins showed enrichment in several biological pathways including protein synthesis, cell proliferation, and T-cell activation. Importantly, these early changes before the time of robust viral production have not been described before. PMID- 22542006 TI - Evaluation of a new interferon-gamma release assay and comparison to tuberculin skin test during a tuberculosis outbreak. AB - BACKGROUND: The tuberculin skin test (TST) is commonly used for the diagnosis of latent tuberculosis infection (LTBI) in non-bacille Calmette-Guerin (BCG) vaccination settings. In recent years, attention has been drawn to interferon gamma release assays (IGRAs), especially in BCG-vaccinated populations. In this study, we evaluated the TST and a new whole blood IGRA in BCG-vaccinated individuals during a tuberculosis (TB) outbreak in China. METHODS: A TB outbreak occurred at a university in Dalian, China from March to November 2010. The TST and a whole blood IGRA were used to screen for TB infection. The correlation between exposure levels, TST, and the IGRA were evaluated. RESULTS: We found that agreement between the IGRA and TST was poor (kappa 0.182-0.290). IGRA positivity was associated with the level of exposure, and IGRA positivity and the level of exposure were risk factors for TB incidence. Neither the IGRA nor the TST alone picked up all TB incidences. However, if a 10 mm cutoff for the TST was used in the highest risk exposure group and IGRA positivity was used in the other risk groups, 19 of the 20 (95%) TB cases were identified. CONCLUSIONS: A recommended preventive treatment regimen for China should be based on the level of exposure in conjunction with IGRA and TST test results. PMID- 22542005 TI - Risk factors for tuberculin skin test conversion among HIV-infected patients in New York City. AB - BACKGROUND: We assessed the incidence of and risk factors for tuberculin skin test (TST) conversion among HIV-infected adults at a New York City clinic. METHODS: All adult HIV-infected patients were eligible for inclusion if they had a negative baseline TST result and at least one subsequent documented TST test result. RESULTS: A total of 414 HIV-infected patients had a negative baseline TST result; 288 (69.6%) were male. Among 348 patients who had a place of birth documented, 50% were born outside of mainland USA. Twenty-two (5.3%) of 414 patients had documented TST conversions, giving a crude incidence rate of 1.77 per 100 person-years. Being a foreign-born Asian individual (p=0.02), having lived in a shelter (p=0.004), and having an increase in CD4 cell count (p=0.02) while under care were independent risk factors for TST conversion. CONCLUSIONS: We found a high TST conversion rate among HIV-infected patients attending an urban clinic. Annual TST testing is particularly important for patients who are foreign-born from high-endemic countries, those with a history of homelessness, and those with an increase in CD4 cell count since the baseline negative TST test. PMID- 22542007 TI - One-step synthesis of water-soluble AgInS2 and ZnS-AgInS2 composite nanocrystals and their photocatalytic activities. AB - Water-soluble AgInS(2) (AIS) nanocrystals (NCs) have been synthesized for the first time in the presence of GSH as capping ligand in aqueous media at low temperature of 95 degrees C. The investigations on the effects of various experimental variables including pH value, GSH/In, In/Ag, and In/S ratios on the optical properties showed that the long time, pH of 8.5 and large GSH/In ratio could increase the intensity of the shorter wavelength (position not changed) emission, while the ratios of In/Ag and In/S could affect the emission wavelength and intensity as well as the intensity ratio of longer to shorter wavelength emission with the shorter wavelength emission tunable from 560 to 660 nm. After modifying with ZnS, the obtained ZnS-AgInS(2) (ZAIS) NCs show both slightly blue shifted stronger PL emission and higher quantum yield increasing to 5 fold. The obtained AIS and ZAIS NCs showed promising photocatalytic activities in the degradation of rhodamine B. PMID- 22542008 TI - Bionanoparticles of amphiphilic copolymers polyacrylate bearing cholesterol and ascorbate for drug delivery. AB - In this study, a series of amphiphilic polymers with poly(ascorbyl acrylate) (PAAA) as hydrophilic blocks and polyacrylate bearing side-chain cholesteryl mesogens (PCholDEGA) as hydrophobic blocks were prepared using a combination of four-step reactions consisting of two consecutive reversible addition fragmentation chain transfer (RAFT), desulfurization, and hydrogenolysis under normal pressure. The thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) as well as wide-angle X-ray diffraction (WAXD) studies showed that the copolymers with PCholDEGA as major block had relatively high stability and clear isotropization temperature (T(i)). Small-angle X-ray diffraction (SAXD) investigation exhibited that the copolymers had bilayer smectic A structure. Their self-assembly behavior was monitored by turbidity change using UV-vis spectrometer, and the morphology and size of the nanoparticles via self-assembly were detected using transmission electron microscopy (TEM) and dynamic light scattering (DLS). The entrapment efficiency and loading capacity of these amphiphilic copolymers were investigated using nile red and drug molecule Ibuprofen. These polymeric micelles with PAAA shell extending into the aqueous solution and strong hydrophobic PCholDEGA core have potential abilities to act as promising nanovehicles with high loading and targeting delivery. PMID- 22542009 TI - Discovery and optimization of benzenesulfonanilide derivatives as a novel class of 11beta-HSD1 inhibitors. AB - A novel series of benzenesulfonanilide derivatives of 11beta-HSD1 inhibitors were identified via modification of the sulfonamide core of the arylsulfonylpiperazine lead structures. The synthesis, in vitro biological evaluation, and structure activity relationship of these compounds are presented. Optimization of this series rapidly resulted in the discovery of compounds (S)-10 and (S)-23 (11beta HSD1 SPA IC(50)=1.8 and 1.4 nM, respectively). PMID- 22542010 TI - Discovery of a novel melanin concentrating hormone receptor 1 (MCHR1) antagonist with reduced hERG inhibition. AB - An initial SAR study resulted in the identification of the novel, potent MCHR1 antagonist 2. After further profiling, compound 2 was discovered to be a potent inhibitor of the hERG potassium channel, which prevented its further development. Additional optimization of this structure resulted in the discovery of the potent MCHR1 antagonist 11 with a dramatically reduced hERG liability. The decrease in hERG activity was confirmed by several in vivo preclinical cardiovascular studies examining QT prolongation. This compound demonstrated good selectivity for MCHR1 and possessed good pharmacokinetic properties across preclinical species. Compound 11 was also efficacious in reducing body weight in two in vivo mouse models. This compound was selected for clinical evaluation and was given the code AMG 076. PMID- 22542011 TI - Synthesis and biological activity of carbamate-linked cationic lipids for gene delivery in vitro. AB - We have introduced a convenient synthesis method for carbamate-linked cationic lipids. Two cationic lipids N-[1-(2,3-didodecylcarbamoyloxy)propyl]-N,N,N trimethylammonium iodide (DDCTMA) and N-[1-(2,3-didodecyl carbamoyloxy)propyl]-N ethyl-N,N-dimethylammonium iodide (DDCEDMA), with identical length of hydrocarbon chains, alternative quaternary ammonium heads, carbamate linkages between hydrocarbon chains and quaternary ammonium heads, were synthesized for liposome mediated gene delivery. Liposomes composed of DDCEDMA and DOPE in 1:1 ratio exhibited a lower zeta potential as compared to those made of pure DDCEDMA alone, which influences their DNA-binding ability. pGFP-N2 plasmid was transferred by cationic liposomes formed from the above cationic lipids into Hela and Hep-2 cells, and the transfection efficiency of some of cationic liposomes was superior or parallel to that of two commercial transfection agents, Lipofectamine2000 and DOTAP. Combined with the results of the agarose gel electrophoresis and transfection experiment, the DNA-binding ability of cationic lipids was too strong to release DNA from complex in the transfection, which could lead to relative low transfection efficiency and high cytotoxicity. PMID- 22542012 TI - The design, synthesis, and biological evaluation of PIM kinase inhibitors. AB - A series of substituted benzofuropyrimidinones with pan-PIM activities and excellent selectivity against a panel of diverse kinases is described. Initial exploration identified aryl benzofuropyrimidinones that were potent, but had cell permeability limitation. Using X-ray crystal structures of the bound PIM-1 complexes with 3, 5m, and 6d, we were able to guide the SAR and identify the alkyl benzofuropyrimidinone (6l) with good PIM potencies, permeability, and oral exposure. PMID- 22542013 TI - Design, synthesis, and evaluation of a novel class of 2,3-disubstituted tetrahydro-beta-carboline derivatives. AB - Several novel tetrahydro-beta-carboline derivatives with amino acid residues at the 2-position and a glucosamine group at the 3-position of the tetrahydro-beta carboline nucleus were synthesized from a readily available starting material, tryptophane, and were evaluated for their anti-inflammatory activity in the present study. Our results showed that all of the derivatives tested exhibited a significant inhibition of xylene-induced inflammation in mice. PMID- 22542014 TI - A new high-yield synthetic route to PET CB1 radioligands [11C]OMAR and its analogs. AB - OMAR analogs reference standards and their corresponding desmethylated precursors were synthesized from substituted anilines either in 4 and 5 steps with 27-32% and 24-31% yield, or in 3 and 4 steps with 21-30% and 19-28% yield, respectively. [(11)C]OMAR and its analog radioligands were prepared from their desmethylated precursors with [(11)C]CH(3)OTf through O-[(11)C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 50-65% radiochemical yields based on [(11)C]CO(2) and decay corrected to end of bombardment (EOB), with 370-740 GBq/MUmol specific activity at EOB. PMID- 22542015 TI - Synthesis, study on anti-arthritic, anti-inflammatory activity and toxicity of some novel bis-oxy cyclophane diamides. AB - A series of bis-oxy cyclophane diamides with bis(aminomethyl)m-terphenyl as spacer have been synthesized and characterized from spectral and analytical data. All the cyclophane diamides exhibit better anti-arthritic activity than the reference drug viz. diclofenac sodium. Some of the cyclophane diamides exhibit good anti-inflammatory activity. The cyclophane amide 4 and 5 do not show any evidence of mutagenicity and cytotoxicity. PMID- 22542016 TI - Synthesis, reactive oxygen species generation and copper-mediated nuclease activity profiles of 2-aryl-3-amino-1,4-naphthoquinones. AB - Here we report a series of 2-aryl-3-amino-1,4-naphthoquinones that generated reactive oxygen species (ROS) such as superoxide and hydrogen peroxide upon incubation in pH 7.4 under ambient aerobic conditions. ROS generation from these compounds was sensitive to structural modifications at the 3-amino position and a 2-aryl substituent promoted ROS generation. A number of these compounds were found to induce DNA damage in the presence of Cu(II) without any added reducing agent. Our data suggests that 2-aryl-3-amino-1,4-naphthoquinones' propensity to produce ROS correlated well with its DNA damage inducing ability. 2-Phenyl-3 pyrrolid-1-yl-1,4-naphthoquinone (22) was found to damage DNA at 1 MUM suggesting that these compounds may have therapeutic relevance in targeting cancers which over-express Cu(II). PMID- 22542017 TI - Bio-inspired synthesis and biological evaluation of a colchicine-related compound library. AB - A bio-inspired investigation of the reactions of substrates of type 1 with VOF(3) and PIFA [phenyliodine(III) bis(trifluoroacetate)] led to a collection of colchicine-like compounds 2-5 and related systems. Biological evaluation revealed that some of the synthesized products had significant cytotoxic properties against the colon cancer cell line HT-29. PMID- 22542018 TI - Exploring the molecular mechanism of karrikins and strigolactones. AB - Karrikins and strigolactones are novel plant growth regulators that contain similar molecular features, but very little is known about how they elicit responses in plants. A tentative molecular mechanism has previously been proposed involving a Michael-type addition for both compounds. Through structure-activity studies with karrikins, we now propose an alternative mechanism for karrikin and strigolactone mode of action that involves hydrolysis of the butenolide ring. PMID- 22542019 TI - Reexamining hydroxamate inhibitors of botulinum neurotoxin serotype A: extending towards the beta-exosite. AB - Botulinum neurotoxins (BoNTs) are the most toxic proteins known to man, exposure to which results in flaccid paralysis. Given their extreme potency, these proteins have become studied as possible weapons of bioterrorism; however, effective treatments that function after intoxication have not progressed to the clinic. Here, we have reexamined one of the most effective inhibitors, 2,4 dichlorocinnamyl hydroxamate, in the context of the known plasticity of the BoNT/A light chain metalloprotease. Our studies have shown that modifications of this compound are tolerated and result in improved inhibitors, with the best compound having an IC(50) of 0.23 MUM. Given the inconsistency of structure activity relationship trends observed across similar compounds, this data argues for caution in extrapolating across structural series. PMID- 22542020 TI - Identification of aryl dihydrouracil derivatives as palm initiation site inhibitors of HCV NS5B polymerase. AB - Aryl dihydrouracil derivatives were identified from high throughput screening as potent inhibitors of HCV NS5B polymerase. The aryl dihydrouracil derivatives were shown to be non-competitive with respect to template RNA and elongation nucleotide substrates. They demonstrated genotype 1 specific activity towards HCV NS5B polymerases. Structure activity relationships and genotype specific activities of aryl dihydrouracil derivatives suggested that they bind to the palm initiation nucleotide pocket, a hypothesis which was confirmed by studies with polymerases containing mutations in various inhibitor binding sites. Therefore, aryl dihydrouracil derivatives represent a novel class of palm initiation site inhibitors of HCV NS5B polymerase. PMID- 22542021 TI - Effects of dietary fish oil on learning function and apoptosis of hippocampal pyramidal neurons in streptozotocin-diabetic rats. AB - Previous research has demonstrated that diabetes induces learning and memory deficits. However, the mechanism of memory impairment induced by diabetes is poorly understood. Dietary fatty acids, especially polyunsaturated fatty acids, have been shown to enhance learning and memory and prevent memory deficits in various experimental conditions. The present study investigated the effects of fish oil supplementation on the neuron apoptosis in the hippocampus of streptozotocin (STZ)-induced diabetes rats. The effects of diabetes and fish oil treatment on the spatial learning and memory were also evaluated using the Morris Water Maze. Diabetes impaired spatial learning and memory of rats. Diabetes increased the expression of Bax and caspase-3, which led the apoptosis of the CA1 pyramidal neurons, and further contributed to the deficits in learning and memory processing. Fish oil dietary supplementation in diabetic rats conducts neuron protective function through an anti-apoptotic pathway and significantly improves the ability of learning and memory. These results partially explain the mechanism of the effect of diabetes and fish oil treatment on learning and memory, supporting a potential role for fish oil as an adjuvant therapy for the prevention and treatment of diabetic complications. PMID- 22542022 TI - Nasopharyngeal swabs of school children, useful in rapid assessment of community antimicrobial resistance patterns in Streptococcus pneumoniae and Haemophilus influenzae. AB - OBJECTIVES: The present study evaluates the feasibility of rapid surveillance of community antimicrobial resistance (AMR) patterns of Streptococcus pneumoniae and Haemophilus influenzae in India using nasopharyngeal swabs (NPSs) of school children. It compares the AMR data obtained with that of invasive and nasopharyngeal (NP) isolates studied previously. No one has done such surveillance since our study so we decided to publish and more clearly demonstrate the feasibility of the methodology we did. STUDY DESIGN AND SETTING: This community-based, cross-sectional, cluster sample study had seven centers; each had two sites distant to them. Two hundred sixty school children per center were enrolled. NP swabbing was performed and isolates identified as S. pneumoniae and H. influenzae at each center were sent to reference laboratories. RESULTS: From January to December 2004, 1,988 NP swabs were processed; 776 S. pneumoniae and 64 H. influenzae were isolated. The AMR patterns for S. pneumoniae to co trimoxazole varied, with sensitivity as low as 6% in Mumbai, 29% in Chennai and Vellore, and 100% in Delhi and Lucknow. For H. influenzae, sensitivity rates to co-trimoxazole ranged from 22% to 62%. The AMR patterns for both bacteria in the present study with data from invasive and NP isolates studied earlier were similar. CONCLUSION: The study demonstrates that it is practical and feasible to rapidly assess the AMR patterns of both S. pneumoniae and H. influenzae in NPSs of school children in different geographic locations all over India. PMID- 22542023 TI - GRADE guidelines: 11. Making an overall rating of confidence in effect estimates for a single outcome and for all outcomes. AB - GRADE requires guideline developers to make an overall rating of confidence in estimates of effect (quality of evidence-high, moderate, low, or very low) for each important or critical outcome. GRADE suggests, for each outcome, the initial separate consideration of five domains of reasons for rating down the confidence in effect estimates, thereby allowing systematic review authors and guideline developers to arrive at an outcome-specific rating of confidence. Although this rating system represents discrete steps on an ordinal scale, it is helpful to view confidence in estimates as a continuum, and the final rating of confidence may differ from that suggested by separate consideration of each domain. An overall rating of confidence in estimates of effect is only relevant in settings when recommendations are being made. In general, it is based on the critical outcome that provides the lowest confidence. PMID- 22542024 TI - Impact of reflection on the fluence rate distribution in a UV reactor with various inner walls as measured using a micro-fluorescent silica detector. AB - An assessment of the impact of ultraviolet (UV) reflection from inner walls is important for the accuracy of model predictions of fluence rate (FR) distribution and for the improvement of reactor efficiency. In this study, the FR distribution in an annular UV reactor with inner walls of various reflectances was measured in situ by using a 360 degrees response micro-fluorescent silica detector. The tests were performed in water with various transmittances ranging from 65% to 99% and with inner reactor walls composed of quartz/aluminum foil, quartz/stainless steel, or quartz/black cloth, whose reflection coefficients were determined to be 80.5%, 26.1% and 11.1%, respectively. The results demonstrate that an inner wall with a high reflection coefficient can lead to a marked increase in the weighted average FRs, thus greatly improving the reactor efficiency. Furthermore, the presently used FR distribution models could have an error of up to 35% for commonly used stainless steel walls as a result of the influence of inner-wall reflection. Finally, it was found that the uniformity of the FR distribution is strongly dependent on the diffuse reflection property of the inner wall, which could lead to a better fluence delivery distribution in the UV reactor. This work has potential application to increase the accuracy of model predictions as well as optimize the design of high-efficiency UV reactors. PMID- 22542025 TI - Influences of pH, heavy metals and phosphate and their co-influences on the sorption of pentachlorophenol on cyanobacterial biomass. AB - Influences of pH, two types of ions of transition metals (Cu2+, Cd2+), Na3PO4 and their co-influences on the sorption of pentachlorophenol (PCP) on cyanobacterial biomass derived from natural bloom were studied. Sorption of PCP significantly decreases with pH in the range of 3.25-9.00. Although sorption coefficient of ionized PCP is 8.51 times lower than that of neutral species, it is the dominant species at environmentally relevant pH and contributes more to the total sorption of PCP. In the presence of low concentration of Cu2+ (<= 40 MUmol L-1), sorption of PCP was much lower than that of the blank. However, it increased gradually with Cu2+, and overpassed the blank when concentration of Cu2+ was higher than 50 MUmol L-1. Compared with the sole influence of pH, coexisted Cu2+ inhibited the sorption of PCP at pH of 3.25 and 4.35, but enhanced it in the pH range of 5.00 9.00. In the presence of Cd2+, sorption of PCP first increased then decreased rapidly and finally increased slightly again with Cd2+. Except for at pH of 9.00, sorption of PCP at other pH in the presence of Cd2+ was much lower than that solely affected by pH. In the presence of Na3PO4, sorption of PCP increased rapidly then maintained with Na3PO4. Under the influence of both Na3PO4 and pH, sorption of PCP at pH from 3.25 to 5.00 was lower than that solely affected by pH, while it increased with pH in the range of 5.00-9.00 and was higher than that solely affected by pH in the range of 6.00-9.00. Ion pairs of pentachlorophenolate-metal facilitated the sorption of PCP, which was largely dependent on pH illustrated by UV-visible and FTIR spectra. Speciations of metals and PCP and the stability constants of ion pairs of pentachlorophenolate-metal greatly affected the sorption. Ionic strength also played an important role for the sorption of PCP. PMID- 22542026 TI - Bacterial burden in the operating room: impact of airflow systems. AB - BACKGROUND: Wound infections present one of the most prevalent and frequent complications associated with surgical procedures. This study analyzes the impact of currently used ventilation systems in the operating room to reduce bacterial contamination during surgical procedures. METHODS: Four ventilation systems (window-based ventilation, supported air nozzle canopy, low-turbulence displacement airflow, and low-turbulence displacement airflow with flow stabilizer) were analyzed. Two hundred seventy-seven surgical procedures in 6 operating rooms of 5 different hospitals were analyzed for this study. RESULTS: Window-based ventilation showed the highest intraoperative contamination (13.3 colony-forming units [CFU]/h) followed by supported air nozzle canopy (6.4 CFU/h; P = .001 vs window-based ventilation) and low-turbulence displacement airflow (3.4 and 0.8 CFU/h; P < .001 vs window-based ventilation and supported air nozzle canopy). The highest protection was provided by the low-turbulence displacement airflow with flow stabilizer (0.7 CFU/h), which showed a highly significant difference compared with the best supported air nozzle canopy theatre (3.9 CFU/h; P < .001). Furthermore, this system showed no increase of contamination in prolonged durations of surgical procedures. CONCLUSION: This study shows that intraoperative contamination can be significantly reduced by the use of adequate ventilation systems. PMID- 22542028 TI - Infections in solid organ transplantation. Prologue. PMID- 22542027 TI - Influence of inoculation time of an autochthonous selected malolactic bacterium on volatile and sensory profile of Tempranillo and Merlot wines. AB - A study was carried out to determine the effect of the inoculation time of the lactic acid bacteria (LAB) on the kinetic of vinification and on chemical and sensory characteristics of Tempranillo and Merlot wines. Traditional vinifications, with LAB inoculated after completion of AF, were compared with vinifications where yeast and bacteria were co-inoculated. Two commercial yeast strains and an autochthonous Oenococcus oeni strain (C22L9) previously identified and selected at our laboratory were used. Monitoring of alcoholic and malolactic fermentations was carried out by yeast and lactic acid bacteria counts and by measuring contents of glucose+fructose, malic acid and lactic acid. The implantation rate of O. oeni C22L9 was calculated by typing isolates obtained from count plates using the RAPD-PCR (Randomly Amplified Polymorphic DNA Polymerase Chain Reaction) technique. Wines were chemically characterised and analysed for biogenic amine and volatile compound contents. A sensory analysis, consisting in a descriptive and a triangular test was also carried out. Results from this study showed that for both grape varieties, the concurrent yeast/bacteria inoculation of musts produced a significant reduction in duration of the process, without a pronounced degradation of malic acid during AF, nor an excessive increase in volatile acidity. Biogenic amine content was also lower in wines produced by co-inoculation. Important differences in volatile compound contents were observed, although there was little impact on the sensorial profile of wines. These results suggest that co-inoculation using O. oeni C22L9 is a worthwhile alternative compared to traditional post AF inoculation for Tempranillo and Merlot winemaking. PMID- 22542029 TI - The role of the clinical microbiology laboratory in solid organ transplantation programs. AB - Infections remain a major complication of solid organ transplantation. For this reason, the clinical microbiology laboratory plays a key role in the success of transplant programs, which must have the support of a qualified laboratory, both technically and professionally. Transplant programs strongly condition the structure and functionality of microbiology laboratories, but at the same time, benefit greatly from the knowledge generated from these programs. The laboratory must make a special effort to implement rapid methods that can respond to the broad spectrum of potential pathogens in solid organ transplant patients. The integration of microbiologists in multidisciplinary teams is highly recommended, as only then can they obtain the highest quality and efficiency in the diagnostic process. This article provides an updated review of the techniques to be used once transplantation has occurred. The role of the microbiologist is also crucial in the pretransplant period, as good microbiological candidate evaluation at this time strongly conditions the success of the transplantation program. PMID- 22542030 TI - Epidemiology and risk factors of infections after solid organ transplantation. AB - Infection remains a significant complication after solid organ transplantation (SOT). The incidence of various pathogens varies widely depending on the presence of specific factors, according to which patients can be classified into different risk categories that may merit tailored prophylaxis strategies. Both the endogenous origin of microorganisms (previous colonization or latent infection) and new acquisition (primary infection from donor or environment) should be considered. Bacterial infections predominate in patients with complex hospital stays or anatomical alterations. Viral infections, caused both by opportunistic (CMV, EBV, BKV, etc.) and common viruses (influenza, respiratory virus, VVZ, etc.), are of great importance, and may contribute to chronic rejection. Fungal infections are uncommon nowadays, but cause high mortality and deserve prophylaxis for a subset of patients. Parasitic infections are a clear threat, mainly in transplanted patients or those travelling to endemic areas. Physicians attending SOT recipients should be aware of these risk factors, which include specific host characteristics, type of transplantation, microorganism and immunosuppressive policy. PMID- 22542031 TI - Evaluating the risk of transmission of infection from donor to recipient of a solid organ transplantation. AB - In the context of solid organ transplantation, screening of potential organ donors is crucial, and should be performed with great rigor to minimize the risk of transmission of certain infectious processes. This review aims to update understanding of the possible pathologies involved, as well as of emerging infections that, as a result of globalization, are gaining increasing prominence on a daily basis. PMID- 22542032 TI - Infection prevention in solid organ transplantation. AB - As complications from infection are a major cause of morbidity and mortality following transplantation, infection prevention is a cornerstone of any modern solid organ transplantation program. There is no doubt that, among other measures, antimicrobial prophylaxis has decreased the incidence and severity of posttransplant infections, and it is a major contributor to the currently improved survival rates of solid organ transplant recipients. This chapter is not a thorough analysis of all studies examining the prevention of infection following organ transplantation, but a practical guide to widely accepted recommendations regarding the prevention of common infections in the transplant setting, such as bacterial infections, including tuberculosis, cytomegalovirus, hepatitis viruses or invasive fungal infections. PMID- 22542033 TI - Tuberculosis in solid organ transplant patients. AB - Tuberculosis is an opportunistic infection with high morbidity and mortality in solid organ transplant patients. The reasons for this high morbidity and mortality lie mostly in diagnostic difficulties, which cause delays in starting treatment, and associated pharmaceutical toxicity. There are still major issues and difficulties in managing tuberculosis in solid organ transplant patients. These include problems due to interactions between antituberculosis and immunosuppressant drugs, the high risk of toxicity of antituberculosis drugs (particularly in liver transplant patients) and the absence of clear indications for the treatment of latent tuberculous infection. This article updates current understanding of tuberculosis in solid organ transplant patients. PMID- 22542034 TI - Multidrug-resistant bacterial infection in solid organ transplant recipients. AB - The most frequent complication from infection after solid organ transplantation is bacterial infection. This complication is more frequent in organ transplantation involving the abdominal cavity, such as liver or pancreas transplantation, and less frequent in heart transplant recipients. The sources, clinical characteristics, antibiotic resistance and clinical outcomes vary according to the time of onset after transplantation. Most bacterial infections during the first month post-transplantation are hospital acquired, and there is usually a high incidence of multidrug-resistant bacterial infections. The higher incidence of complications from bacterial infection in the first month post transplantation may be associated with high morbidity. Of special interest due to their frequency are infections by S. aureus, enterococci, Gram-negative enteric and non-fermentative bacilli. Opportunistic bacterial infections may occur at any time on the posttransplant timeline, but are more frequent between months two and six, the period in which immunosuppression is higher. The most frequent bacterial species causing opportunistic infections in organ transplant recipients are Listeria monocytogenes and Nocardia spp. After month six, posttransplantation solid organ transplant patients usually develop conventional community-acquired bacterial infections, especially urinary tract infections by E. coli and S. pneumoniae pneumonia. In this article we review the clinical characteristics, epidemiology, diagnosis and prognosis of bacterial infections in solid organ transplant patients. PMID- 22542035 TI - Fungal infection in solid organ recipients. AB - In solid organ recipients, as with other immunosuppressed patients, infections by Candida spp. and Aspergillus spp. are the most frequent invasive mycoses. Infections by Cryptococcus spp. and fungi of the Mucorales order are less common. Infections by Fusarium spp. and Scedosporium spp. are very uncommon, except in patients undergoing hematopoietic stem cell transplant and patients with prolonged neutropenia. The risk factors for fungal infection are immunosuppression, surgery, viral co-infection, and environmental exposure. Diagnosis is challenging: blood culture is of little use, except in candidiasis and cryptococcosis, and the poor accuracy of antigen-based techniques, except in cryptococcosis, favors widespread use of empirical therapy. A delay in the initiation of therapy increases the already high mortality of these infections. The agents used to treat fungal infection are azoles, echinocandins, and lipid amphotericin. Administration depends on antifungal activity, drug-drug interactions with calcineurin inhibitors, and safety profiles (effects on grafts and other side effects). PMID- 22542036 TI - Cytomegalovirus infection in solid organ transplantation. AB - Cytomegalovirus infection remains a serious threat to solid transplant recipients. Despite advances in this field, there are still difficulties in the diagnosis of the disease and there are questions about the best and most cost effective strategy to prevent infection and its direct and indirect consequences in the short and long term. All these points are discussed and updated in this chapter. PMID- 22542037 TI - Infections caused by herpes viruses other than cytomegalovirus in solid organ transplant recipients. AB - Despite great advances in solid organ transplantation (SOT) in recent decades, infection remains a major cause of morbidity and mortality among SOT recipients. Members of the herpesvirus family are the most common viral pathogens causing disease in this patient population. Herpes viruses are large enveloped DNA viruses that commonly reactivate during periods of severe immunosuppression. Currently, infections caused by herpes viruses continue to complicate clinical management of transplant patients. Although cytomegalovirus (CMV) is the most important virus of this family and is the subject of active research, herpes simplex virus (HSV) and varicella-zoster virus (VZV) can also lead to severe disease. Epstein-Barr virus (EBV) associated with post-transplant lymphoproliferative disease is increasingly recognized as a major complication of SOT. There is less information available on the role and impact of other viruses of the herpesvirus family, such as the human herpes virus 6 (HHV-6), human herpes virus 7 (HHV-7) and human herpes virus 8 (HHV-8). This review summarizes current knowledge regarding epidemiology, clinical manifestations, diagnosis, treatment and prevention of infections caused by herpes viruses other than CMV in SOT recipients. PMID- 22542038 TI - Other viral infections in solid organ transplantation. AB - Viral infections are a major cause of morbidity and even mortality in solid organ transplant recipients. This article reviews key aspects of infections in solid organ transplant recipients from respiratory viruses, such as influenza, polyomavirus, erythrovirus B19 and measles. PMID- 22542040 TI - Antimicrobial and immunosuppressive drug interactions in solid organ transplant recipients. AB - Infections are frequent and can be severe in recipients of solid organ transplantation. Prevention and treatment are priority objectives of multidisciplinary transplant teams. Interactions between antimicrobials (indicated for prevention and therapy) and immunosuppressants (for preventing rejection) make treatment more complex than in the general population. Co administration of immunosuppressants and antibiotics can cause harmful interactions, modifying the pharmacokinetic and pharmacodynamic characteristics of both groups of drugs. The loss of the transplanted organ due to reduced levels of immunosuppressants is a unique consequence of the often lethal interactions in this group of patients. By contrast, elevated levels of these drugs cause toxicity, and reduced concentrations of antimicrobial treatment fail to contain the infection. Azoles, rifabutin, protease inhibitors, non-nucleoside reverse transcriptase inhibitors and antimicrobial macrolides all interact with immunosuppressants. In this article, we review interactions between antibiotics and immunosuppressants in order to adopt the most appropriate clinical approach (dosage adjustments, close monitoring of plasma levels and organ function) and determine whether they can be used together with any measure of safety. PMID- 22542039 TI - Infections in solid organ transplantation in special situations: HIV-infection and immigration. AB - With the advent of highly active antiretroviral therapy in 1996, patients infected with HIV are now living longer and are dying from illnesses other than acquired immunodeficiency syndrome (AIDS). Liver disease due to chronic hepatitis C is now a leading cause of mortality among HIV-infected patients in the developed world. The prevalence of end-stage kidney or heart disease is also increasing among HIV-infected patients. For these patients, solid organ transplantation (SOT) is the only therapeutic option and HIV infection alone is not a contraindication. Accumulated experience in North America and Europe in the last few years indicates that 3- to 5-year survival in liver recipients coinfected with HIV and HCV is lower than that of HCV-monoinfected recipients. Conversely, 3- to 5-year survival of non-HCV-coinfected liver recipients and kidney recipients was similar to that of HIV-negative patients. Infections in the post-transplant period in HIV-infected recipients are similar to those seen in HIV-negative patients, although the incidence of some of them (e.g. tuberculosis and fungal infections) is higher. In the USA and Europe the number of immigrants from areas with endemic geographically-restricted infections has increased significantly in recent years. These changes in the population profile have led to an increase in the percentage of foreign-born transplant candidates and donors. Organ transplant recipients may develop endemic diseases in four ways: Transmission through the graft; de novo infection; reactivation of dormant infection; and reinfection/reactivation in a healthy graft. In foreign-born recipients, there is the possibility of endemic infections manifesting in the post-transplant period as a consequence of immunosuppression. These issues are modifying the criteria for donor selection and have also expanded pre-transplant screening for infectious diseases in both donors and transplant recipients. Some infectious diseases such as Chagas disease, endemic fungal infections, tuberculosis (which could be multidrug- or extensively drug-resistant according the origin of the recipient), leishmaniasis and other viral and parasitic diseases should always be considered in the differential diagnosis of post transplant infections in foreign-born recipients. PMID- 22542041 TI - Perspectives in interventional electrophysiology in children and those with congenital heart disease: electrophysiology in children. AB - Recent developments in paediatric pacing and ablation of arrhythmia substrate have been characterised by adoption and modification of techniques used in adults. Infants, small children and those of all ages with congenital heart disease are a patient group with a higher risk profile needing a special approach. Current success rates for catheter ablation are high and major complication rates are low. Important issues with respect to long-term outcome include questions about coronary injury, long-term effects of radiation exposure and late recurrence. Non-fluoroscopic electro-anatomical mapping systems (3D systems), cryo-ablation and remote navigation are techniques recently improved such that it is possible to potentially reduce fluoroscopy and complications. Pacing in young children and congenital heart disease often warrants an epicardial approach to avoid embolism, venous occlusion and lead failure related to growth. Defibrillator and resynchronisation therapy are increasingly important tools to reduce mortality, although the indications are not as clear as in adult patients without congenital heart disease. PMID- 22542042 TI - Imaging a boa constrictor--the incomplete double aortic arch syndrome. AB - Incomplete double aortic arch is a rare anomaly resulting from atresia rather than complete involution in the distal left arch resulting in a non-patent fibrous cord between the left arch and descending thoracic aorta. This anatomic anomaly may cause symptomatic vascular rings, leading to stridor, wheezing, or dysphagia, requiring surgical transection of the fibrous cord. Herein, we describe an asymptomatic 59 year-old man presenting for contrast-enhanced CT angiography to assess cardiac anatomy prior to radiofrequency ablation, who was incidentally found to have an incomplete double aortic arch with hypoplasia of the left arch segment and an aortic diverticulum. Recognition of this abnormality by imaging is important to inform both corrective surgery in symptomatic patients, as well as assist in the planning of percutaneous coronary and vascular interventions. PMID- 22542043 TI - Expanding role for transcatheter aortic valve replacement: successful transfemoral implantation of a Medtronic CoreValve for severe aortic regurgitation. AB - Severe aortic regurgitation (AR), when intervention is required, is best managed by surgical aortic valve replacement (SAVR). Transcatheter aortic valve replacement (TAVR) for aortic stenosis has recently shown non-inferiority to SAVR and superiority to medical management. Here we describe a successful TAVR for a patient with severe AR that was unsuitable for SAVR due to her high surgical risk. PMID- 22542044 TI - The toxicity of chemotherapy and radiotherapy on the central nervous system. PMID- 22542045 TI - Central nervous system complications of cancer therapy. AB - As more effective therapies prolong the survival of patients with cancer, therapy related toxicities, particularly those affecting the central nervous system (CNS) become increasingly important. CNS complications can cause significant morbidity and can limit the dose or duration of otherwise effective treatments. Because effects on the CNS are disabling and often permanent and treatments remain limited, it is important that clinicians recognize the effects of cancer therapy on the CNS. Cytotoxic chemotherapy and radiation are well-known causes of neurotoxicity, but there is increasing recognition that novel therapies are also sources of adverse effects on the CNS. This review highlights the CNS complications that result from radiation, chemotherapy, and novel therapeutics. PMID- 22542046 TI - Biomechanical femoral neck fracture experiments--a narrative review. AB - INTRODUCTION: Orthopaedic implants can be introduced in clinical practice if equivalency to an already approved implant can be demonstrated. A preclinical laboratory test can in theory provide the required evidence. Due to the lack of consensus on the optimum design of biomechanical experiments, setups vary considerably. This review aims to make femoral neck fracture models more accessible for evaluation to orthopaedic surgeons without any particular background in biomechanics. Additionally, the clinical relevance of the different setups is discussed. METHODS: This is a narrative review based on a non systematic search in PubMed, Scopus and Cochrane. SUMMARY: Biomechanical femoral neck fracture experiments should aim at optimizing the recreation of the in vivo situation. The bone quality of the experimental femurs should resemble the hip fracture population, hence cadaveric bones should be preferred to the available synthetic replica. The fracture geometry must be carefully selected to avoid bias. The load applied to the specimen should result in forces within the range of in vivo measured values and the magnitude should be related to the actual weight of the donor. A well designed biomechanical experiment can prevent harmful devices from being introduced in clinical practice, however, positive results can never exclude the necessity of subsequent clinical studies. PMID- 22542048 TI - The emerging role of cardiac computed tomography for the assessment of coronary perfusion: a systematic review and meta-analysis. AB - BACKGROUND: Computed tomography perfusion (CTP) is an emerging method which, coupled with the anatomical detail afforded by cardiac computed tomographic angiography (CCTA), may allow for determination of both structural and physiologic significance of coronary stenoses with a single imaging modality. This study was designed to execute a systematic review/meta-analysis to determine the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of CTP as compared with reference standards for detection of significant coronary artery stenoses and impaired perfusion. METHODS: A systematic review identified 13 out of 4368 studies allowing a calculation of sensitivity, specificity, PPV, and NPV on a per patient or per vessel or per segment basis using radionuclide myocardial perfusion imaging (MPI), conventional coronary angiography (CCA), magnetic resonance perfusion imaging (MRPI), or fractional flow reserve (FFR) as the reference standard. Meta-analyses of results were carried out using random effects modelling. RESULTS: Most studies used a maximal vasodilator stress protocol with adenosine, provided information mainly on a per vessel basis, and used myocardial perfusion imaging or CCA as the reference standard. Of the studies comparing combinations of both anatomical and functional imaging, the most rigourous standard was CCA/FFR. Compared with the latter, CCTA/CTP had sensitivity, specificity, PPV, and NPV of 81%, 93%, 87%, and 88%, respectively. CONCLUSIONS: CTP shows promise as an adjunct to CCTA, potentially allowing determination of both structural and physiologic significance with a single imaging modality. PMID- 22542049 TI - Acute biventricular failure as a sequela of multiple autoimmune disorders. AB - In this case, uncharacteristic clinical and laboratory findings led to an unanticipated diagnosis for a 24-year-old woman admitted for new-onset heart failure with features suggesting cardiac tamponade. Concomitant diagnosis of progressive mixed connective tissue disease associated with severe hypothyroidism was made. Despite early recognition (based on clinical and pathologic features) and rapid management (with glucocorticoids, thyroxine, metoprolol, lisinopril, furosemide, and milrinone), she deteriorated and died within 4 weeks. PMID- 22542050 TI - Spectacular evolution of reactive arthritis after early treatment with infliximab. PMID- 22542051 TI - Psychiatric comorbidity and gender differences among suicide attempters in Bangalore, India. AB - BACKGROUND: Suicides are an entirely preventable cause of death, with current suicide rates being 11.4 per 100,000 population in India. The city of Bangalore in India is often called the suicide capital of India because of its high suicide and attempted suicide rate. This study attempted to evaluate the psychiatric comorbidity and gender differences among suicide attempters presenting to a general hospital in the city of Bangalore, India. METHODS: Using a structured questionnaire [Structured Clinical Interview for DSM-IV (SCID)-I and SCID-II], the study gathered data on the psychiatric diagnoses as well as the reasons for and mode of attempted suicides on 100 suicide attempters after taking written informed consent. In addition, the Beck Depression Inventory was also used to evaluate the severity of depression, the most commonly detected psychiatric comorbidity. RESULTS: Forty-two percent of the sample had a psychiatric comorbidity, with depression (14%) and dysthymia (12%) being the most common disorders. Among personality disorders (PDs), borderline PD (5%) and dependent PD (3%) were the most commonly detected. Severe depression was detected in 15% of those with a mood disorder. Gender differences were found in both mode and reasons for attempted suicide. CONCLUSION: The presence of any psychiatric comorbidity was observed to confer a high risk of suicide. All attempters should therefore be comprehensively evaluated by a qualified health care professional, and attempts should be made for continuous follow-up. PMID- 22542052 TI - Peritraumatic distress predicts acute posttraumatic stress disorder symptoms after a first stroke. PMID- 22542053 TI - Lung transplantation in a Japanese patient with schizophrenia from brain-dead donor. AB - We herein report a case of lung transplantation in a patient with schizophrenia. The findings show that patients with schizophrenia can be considered for lung transplant after careful evaluation of psychiatric status and indications. PMID- 22542056 TI - Previous infliximab therapy and postoperative complications after proctocolectomy with ileum pouch anal anastomosis. AB - BACKGROUND AND AIMS: It is unclear whether infliximab treatment induces increased complication rates after surgery for ulcerative colitis. Aim was to compare complication rates after pouch surgery in refractory ulcerative colitis patients with versus without previous infliximab therapy. METHODS: We performed a retrospective study evaluating all patients who underwent an ileoanal J-pouch for refractory ulcerative colitis over a four-year period. Postoperative complications, infliximab use and time between last infliximab administration and restorative surgery were assessed. 1-stage procedures (proctocolectomy with pouch, with or without temporary diversion) and 2-stage procedures (emergency colectomy and subsequent completion proctectomy with pouch, with or without temporary diversion) were analyzed separately. RESULTS: Seventy-two patients were included; 33 underwent 1-stage procedure and 39 had 2-stage surgery. In the 1 stage group, 21 patients (64%) had previous infliximab therapy (median time between last infusion and surgery: 7.1 months (IQR 2.6-8.3)). Infliximab-treated patients had higher incidence of pelvic sepsis (5/21 vs. 0/12; risk difference 24%; 95% CI: 6 to 42, p=0.067) and non-infectious complications (8/21 vs. 1/12; risk difference 30%; 95% CI: 4 to 56, p=0.065). In the 2-stage group, 17 (44%) had previous infliximab therapy (median time between last infusion and surgery: 11.8 months (IQR 7.3-15.5)). Total, infectious, non-infectious complication rates and pelvic sepsis rates were similar for infliximab and non-infliximab patients in the 2-stage group. CONCLUSIONS: This small study suggests that infliximab use prior to 1-stage restorative proctocolectomy in patients with UC is associated with increased incidence of pelvic sepsis. A 2-stage procedure in these patients should be considered. PMID- 22542055 TI - Contrast-enhanced ultrasonography: usefulness in the assessment of postoperative recurrence of Crohn's disease. AB - AIM: The aim of this study was to assess whether the contrast-enhanced ultrasonography (CEUS) can increase the value of the ultrasonography in the study of postoperative recurrence of Crohn's disease (CD). MATERIALS AND METHODS: 60 patients with CD who had previously undergone ileocolic resection underwent prospectively both CEUS and colonoscopy within a 3-day period. The sonographic examination included evaluation of bowel wall thickness, transmural complications, colour Doppler grade and contrast-enhanced US. In addition a sonographic score was established. The capacity of CEUS to diagnose endoscopic recurrence, as well as its severity, was assessed by calculating the sensitivity, specificity and positive and negative predictive values, accuracy and odds ratio, with their respective 95% confidence intervals. The areas under the receiver operating characteristic (ROC) curves were also calculated. RESULTS: 49 out of 60 patients showed endoscopic postoperative recurrence. Severe endoscopic recurrence was present in 34 patients (57%). Classic ultrasound parameters (wall thickness >3mm and colour Doppler flow) revealed an accuracy of 88.3% for the diagnosis of recurrence. Sonographic score 2, including thickness >5mm or contrast enhancement >46%, improved the results with a sensitivity, specificity and accuracy of 98%, 100% and 98.3%, respectively, in the diagnosis of endoscopic recurrence. The area under the ROC curve was 0.99, in remarkable agreement with endoscopy (k: 0.946). Sonographic score 3, including thickness >5mm, contrast enhancement >70% or fistula identified 32 out of 34 (94.1%) severe endoscopic recurrences. The area under the ROC curve was 0.836, in good agreement with endoscopy (k: 0.688). CONCLUSION: CEUS shows excellent sensitivity and specificity for the diagnosis of postoperative recurrence in CD and can also detect severe recurrences. PMID- 22542057 TI - Incidence of inflammatory bowel disease in the province of Styria, Austria, from 1997 to 2007: a population-based study. AB - BACKGROUND: The incidence of inflammatory bowel disease (IBD) varies widely between different countries. This large variation is also observed for the incidence of its main two forms, ulcerative colitis (UC) and Crohn's disease (CD). Controversy exists whether IBD incidence is increasing, especially in western countries. Currently no data are available for Austria. This study therefore aimed to evaluate for the first time the incidence of IBD over an eleven-year period in Styria, a province of Austria with a population of 1.2 million. METHODS: All patients with an initial diagnosis of IBD between 1997 and 2007, who were Styrian residents, were eligible for this retrospective study. Data were acquired from electronically stored hospital discharge reports and individual reports by patients and physicians. According to population density Styria was divided into two rural and one urban area. RESULTS: Throughout the study period 1527 patients with an initial diagnosis of IBD were identified. The average annual incidence was 6.7 (95% CI 6.2-7.1) per 100,000 persons per year for CD and 4.8 (95% CI 4.5-5.2) for UC. The average annual incidence increased significantly (p<0.01) for both diseases during the 11 year study period. Median age at initial diagnosis was 29 years (range 3-87) for CD and 39 years (range 3 94) for UC. At diagnosis, 8.5% of all IBD patients were <18 years of age. The incidence of both CD and UC was significantly higher in the urban area than in rural areas (CD: 8.8, 95% CI 7.8-9.8 versus 5.5, 95% CI 4.7-6.4 and 5.9, 95% CI 5.3-6.7; [p<0.001]; UC: 5.8, 95% CI 5.1-6.6 versus 4.0, 95% CI 3.4-4.7 and 4.7, 95% CI 4.1-5.4; [p=0.04]). CONCLUSION: We observed an overall increase in the incidence of ulcerative colitis and Crohn's disease in a part of Austria during an eleven year period. IBD was more predominant in the largest urban area than in rural areas. PMID- 22542058 TI - Children's understanding of ambiguous idioms and conversational perspective taking. AB - The aim of this study was to test the hypothesis that conversational perspective taking is a determinant of unfamiliar ambiguous idiom comprehension. We investigated two types of ambiguous idiom, decomposable and nondecomposable expressions, which differ in the degree to which the literal meanings of the individual words contribute to the overall idiomatic meaning. We designed an experiment to assess the relationship between the acquisition of figurative comprehension and conversational perspective-taking. Our sample of children aged 5-7 years performed three conversational perspective-taking tasks (language acts, shared/unshared information, and conversational maxims). They then listened to decomposable and nondecomposable idiomatic expressions presented in context before performing a multiple-choice task (figurative, literal, and contextual responses). Results indicated that decomposable idiom comprehension was predicted by conversational perspective-taking scores and language skills, whereas nondecomposable idiom comprehension was predicted solely by language skills. We discuss our findings with respect to verbal and pragmatic skills. PMID- 22542059 TI - Biomechanical properties of fixed-angle volar distal radius plates under dynamic loading. AB - PURPOSE: To evaluate and compare the biomechanical properties of 8 different locked fixed-angle volar distal radius plates under conditions designed to reflect forces seen in early fracture healing and postoperative rehabilitation. METHODS: We evaluated the Acumed Acu-Loc (Acumed, Hillsboro, OR), Hand Innovations DVR (Hand Innovations, Miami, FL), SBi SCS volar distal radial plate (Small Bone Innovations, Morrisville, PA), Synthes volar distal radius plate and EA extra-articular volar distal radius plate (Synthes, Paoli, PA), Stryker Matrix SmartLock (Stryker Leibinger, Kalamazoo, MI), Wright Medical Technology Locon VLS (Wright Medical Technology, Arlington, TN), and Zimmer periarticular distal radius locking plate (Zimmer, Warsaw, IN). After affixing each plate to a synthetic corticocancellous radius, we created a standardized dorsal wedge osteotomy. Each construct had cyclic loading of 100 N, 200 N, and 300 N for a total of 6000 cycles. Outcomes, including load deformation curves, displacement, and ultimate yield strengths, were collected for each construct. RESULTS: The Wright plate was significantly stiffer at the 100 N load than the Zimmer plate and was stiffer at the 300 N load than 4 other plates. The Zimmer and Hand Innovations plates had the highest yield strengths and significantly higher yield strengths than the Wright, SBi, Stryker, and Synthes EA plates. CONCLUSIONS: Given the biomechanical properties of the plates tested, in light of the loads transmitted across the native wrist, all plate constructs met the anticipated demands. It seems clear that fracture configuration, screw placement, cost, and surgeon familiarity with instrumentation should take priority in selecting a plating system for distal radius fracture treatment. CLINICAL RELEVANCE: This study provides further information to surgeons regarding the relative strengths of different plate options for the treatment of distal radius fractures. PMID- 22542060 TI - Spontaneous rupture of the extensor carpi radialis brevis in a 51-year-old man: case report. AB - Dorsal hand osteophytes are common findings in the general population, frequently presenting with dorsal pain and treated with surgical excision. We report the spontaneous rupture of the extensor carpi radialis brevis in association with a previously asymptomatic dorsal scaphoid spur. Following conservative management, surgical excision of dorsal hand osteophytes should be considered for both resolution of pain and prevention of attritional tendon rupture. PMID- 22542061 TI - Enchondromas of the hand: factors affecting recurrence, healing, motion, and malignant transformation. AB - PURPOSE: Enchondromas represent the most common primary bone tumor in the hand. Despite their frequency, a standardized treatment protocol is lacking. This study examines the outcome of surgically treated enchondromas of the hand with regard to tumor location, graft choice, and presence or absence of fracture. METHODS: We retrospectively reviewed 102 enchondromas in 80 patients, identified between 1991 and 2008, with a mean clinical follow-up of 38 months. We assessed the effects of age, tumor location, and graft choice on outcomes for all lesions. Patients presenting with Ollier disease, Maffucci syndrome, pathologic fractures, or recurrent disease were separated for additional analysis. RESULTS: Of the 102 lesions, 62 (61%) achieved complete radiographic healing in a median time of 6 months. Full range of motion was achieved following treatment of 68 lesions (67%) in a median time of 3 months. A total of 95 lesions (93%) remained recurrence free following surgery. One case of malignant transformation occurred in a patient with Maffucci syndrome. Tumor location and graft choice did not affect healing grade, time to healing, range of motion, or recurrence rate. Age at presentation greater than 30 was associated with more rapid healing. Monocentric, nonexpanding lesions were associated with improved postoperative range of motion. Patients with a diagnosis of multiple enchondromas had a higher rate of recurrence following surgery, and patients presenting with a recurrent lesion had a higher rate of complications. Following pathologic fracture, no differences in outcomes were observed when enchondromas were treated primarily or following fracture healing. CONCLUSIONS: Following surgical treatment of enchondromas in the hand, the majority of patients achieve complete bony healing and full range of motion, regardless of the graft material used. Malignant transformation is rare, and aggressive follow-up measures should be reserved for patients with a diagnosis of multiple enchondromas. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 22542062 TI - Overview of injectable corticosteroids. PMID- 22542063 TI - Reactivation performance of aerobic granules under different storage strategies. AB - Aerobic granules storage process is complicated and the affective mechanism is not very clear, which is influenced by storage temperature, storage substrate and storage time. The effects of storage temperature (-25 degrees C, 4 degrees C and room temperature) and storage substrate (distilled water and 400 mg/L glucose solution) on long-term storage and subsequently reactivation performance of aerobic granules were investigated in this study. The results showed that storage temperature had huge impact on the morphology and physical properties and storage substrate had relatively small influence on granules. Granules reactivation was a re-stability process of granules structure, physical properties and microbial communities. Storage at 4 degrees C was more suitable for maintenance of structural integrity and granules long-term stability storage. Granules stored at -25 degrees C achieved excellent settling ability after reactivation and PN/PS ratio was basically unchanged, which demonstrated that storage at -25 degrees Cwas more suitable for the maintenance of the internal microstructure. Aerobic granules under different storage conditions could be reactivated after 10 days operation and the microbial activity (SOUR) could be fully restored. Furthermore granules stored at 4 degrees C obtained the best recovery performance, and granules at room temperature presented the worst restoration performance. In conclusion, no matter what the storage temperature or the storage substrate is, aerobic granules after long-term storage (8 months) could be restored within 10 days and stored granules could be successfully used as bioseed for reactor fast startup. PMID- 22542064 TI - Sequential versus concurrent anthracyclines and taxanes as adjuvant chemotherapy of early breast cancer: a meta-analysis of phase III randomized control trials. AB - PURPOSE: We performed a meta-analysis of Phase III randomized trials to compare treatment outcomes for early-stage breast cancer patients receiving adjuvant chemotherapy with sequential or concurrent anthracyclines and taxanes. METHODS: All Phase III randomized trials comparing adjuvant chemotherapy of sequential or concurrent anthracyclines and taxanes in early-stage breast cancer patients were considered eligible. A total of three trials that enrolled 8728 women were analyzed. A pooled analysis was accomplished and event-based risk ratios (RR) with 95% confidence intervals (95%CI) were derived. The significant differences in disease-free survival (DFS) and overall survival (OS) were explored. A heterogeneity test was applied as well. RESULTS: Among three eligible trials, significant differences in favor of sequential regimen were seen in DFS (RR: 0.90; 95%CI: 0.84 to 0.98; P=0.01) and in OS (RR: 0.88; 95%CI: 0.79 to 0.98; P=0.02). CONCLUSION: Considering all the available Phase III trials, sequential adjuvant chemotherapy for early breast cancer seems to add a significant benefit in both DFS and OS over concurrent regimens. PMID- 22542066 TI - Off-pump coronary surgery may reduce stroke, respiratory failure, and mortality in octogenarians. AB - BACKGROUND: Octogenarians are a challenging group of patients referred for cardiac surgery. The aim of this study is to assess early outcomes of coronary artery bypass grafting (CABG) performed in the elderly population. METHODS: We performed a meta-analysis of all published observational studies comparing early results of conventional CABG surgery and off-pump CABG surgery in patients aged 80 years or older. The outcomes of interest were mortality, stroke, respiratory failure, renal failure, incidence of support with intraaortic balloon pump, and incidence of postoperative atrial fibrillation. The random effects model was used. RESULTS: Fourteen studies were analyzed. The total number of included subjects was 4,991, of whom 3,113 underwent conventional CABG surgery (62.4%), and 1,878 (37.6%) underwent off-pump CABG surgery. The rates of mortality, stroke, and respiratory failure were significantly higher in the conventional CABG surgery group. CONCLUSIONS: These results confirm that off-pump CABG surgery remains a valuable option of surgical myocardial revascularization, and may optimize the outcome in senior patients. PMID- 22542065 TI - An LED light source and novel fluorophore combinations improve fluorescence laparoscopic detection of metastatic pancreatic cancer in orthotopic mouse models. AB - BACKGROUND: The aim of this study was to improve fluorescence laparoscopy of pancreatic cancer in an orthotopic mouse model with the use of a light-emitting diode (LED) light source and optimal fluorophore combinations. STUDY DESIGN: Human pancreatic cancer models were established with fluorescent FG-RFP, MiaPaca2 GFP, BxPC-3-RFP, and BxPC-3 cancer cells implanted in 6-week-old female athymic mice. Two weeks postimplantation, diagnostic laparoscopy was performed with a Stryker L9000 LED light source or a Stryker X8000 xenon light source 24 hours after tail-vein injection of CEA antibodies conjugated with Alexa 488 or Alexa 555. Cancer lesions were detected and localized under each light mode. Intravital images were also obtained with the OV-100 Olympus and Maestro CRI Small Animal Imaging Systems, serving as a positive control. Tumors were collected for histologic analysis. RESULTS: Fluorescence laparoscopy with a 495-nm emission filter and an LED light source enabled real-time visualization of the fluorescence-labeled tumor deposits in the peritoneal cavity. The simultaneous use of different fluorophores (Alexa 488 and Alexa 555), conjugated to antibodies, brightened the fluorescence signal, enhancing detection of submillimeter lesions without compromising background illumination. Adjustments to the LED light source permitted simultaneous detection of tumor lesions of different fluorescent colors and surrounding structures with minimal autofluorescence. CONCLUSIONS: Using an LED light source with adjustments to the red, blue, and green wavelengths, it is possible to simultaneously identify tumor metastases expressing fluorescent proteins of different wavelengths, which greatly enhanced the signal without compromising background illumination. Development of this fluorescence laparoscopy technology for clinical use can improve staging and resection of pancreatic cancer. PMID- 22542067 TI - Regional changes in coaptation geometry after reduction annuloplasty for functional mitral regurgitation. AB - BACKGROUND: While it is known that band annuloplasty for functional mitral regurgitation (FMR) improves leaflet coaptation, the effect on regional coaptation geometry has not previously been well defined. We used three dimensional transesophageal echocardiography (3D-TEE) to analyze the regional effects of semirigid band annuloplasty on annular geometry and leaflet coaptation zones of patients with FMR. METHODS: Sixteen patients with severe FMR underwent a semirigid band annuloplasty. Intraoperative full volume 3D-TEE datasets were acquired pre valve and post valve repair. Offline analysis assessed annular dimensions and regional coaptation zone geometry. The regions were defined as R1 (A1-P1), R2 (A2-P2), and R3 (A3-P3); coaptation distance, coaptation depth, and coaptation length were measured in each region. Differences were analyzed with repeated measures within a general linear model. RESULTS: Band annuloplasty decreased mitral regurgitation grade from 3.7 to 0.1 (scale 0 to 4). Annular septolateral dimension (p<0.01) and coaptation distance (p<0.01) decreased significantly in all regions. Likewise, anterior and posterior leaflet coaptation lengths increased in all regions (p<0.01 and p=0.05, respectively), with region 2 showing the greatest increase (p=0.01). Changes in coaptation depth were not significant. CONCLUSIONS: Semirigid band annuloplasty for FMR produces significant regional remodeling of leaflet coaptation zones, with region 2 showing the greatest increase in leaflet coaptation length. This regional analysis of annular geometry and leaflet coaptation creates a framework to better understand the mechanisms of surgical success or failure of annuloplasty for FMR. PMID- 22542068 TI - Peripheral extracorporeal membrane oxygenation: comprehensive therapy for high risk massive pulmonary embolism. AB - BACKGROUND: Although commonly reserved as a last line of defense, experienced centers have reported excellent results with pulmonary embolectomy for massive and submassive pulmonary embolism (PE). We present a contemporary surgical series for PE that demonstrates the utility of peripheral extracorporeal membrane oxygenation (pECMO) for high-risk surgical candidates. METHODS: Between June 2005 and April 2011, 29 patients were treated for massive or submassive pulmonary embolism, with surgical embolectomy performed in 26. Four high-risk patients were placed on pECMO, established by percutaneously cannulating the right atrium through a femoral vein and perfusing by a Dacron graft anastomosed to the axillary artery. A small, extracorporeal, rotary assist device was used, interposing a compact oxygenator in the circuit, and maintaining anticoagulation with heparin. RESULTS: Extracorporeal membrane oxygenation was weaned in 3 of 4 patients after 5.3 days (5, 5, and 6), with normalization of right ventricular dysfunction and pulmonary artery pressure (44.0 +/- 2.0 to 24.5 +/- 5.5 mm Hg) by ECHO. Follow-up computed tomographies showed several peripheral, nearly resorbed emboli in 1 case and complete resolution in 2 others. The fourth patient, not improving after 10 days, underwent surgery where an embolic liposarcoma was extracted. For all 29 cases, hospital and 30-day mortality was 0% and all patients were discharged, with average postoperative length of stay of 15 days for embolectomy and 17 days for pECMO. CONCLUSIONS: Heparin therapy with pECMO support is a rapid, effective option for patients who might benefit from pulmonary embolectomy but are at high risk for surgery. PMID- 22542069 TI - Midterm outcome of off-pump bypass procedures versus drug-eluting stent for unprotected left main coronary artery disease. AB - BACKGROUND: Although surgical revascularization is recommended for the treatment of left main coronary artery (LMCA) disease, percutaneous coronary intervention (PCI) attempts have increased, especially after the introduction of the drug eluting stent. The goal of this study was to compare the midterm outcomes between drug-eluting stenting and off-pump coronary artery bypass (OPCAB) grafting in LMCA disease. METHODS: Five hundred twelve consecutive patients with unprotected LMCA disease who underwent OPCAB (N = 269) or drug-eluting stenting (N = 243) were enrolled. We compared major cardiac and cerebrovascular events (MACCEs) in a real-world cohort and in a matching patient cohort (N = 256). The duration of mean follow-up was 38 +/- 20 months, and the follow-up rate was 97.7%. RESULTS: In a real-world comparison, the OPCAB group showed better 5-year freedom from MACCEs compared with the stenting group (71.5% +/- 4.4% versus 67.6% +/- 4.0%; p = 0.031), despite worse patient characteristics. After patient matching, the OPCAB group showed more distinct benefit in 5-year freedom from MACCEs (75.3% +/- 6.6% versus 62.8% +/- 5.4; p < 0.001), including a significantly lower target vessel revascularization (TVR) rate (p < 0.001). In a subgroup analysis, the benefit of OPCAB regarding 5-year freedom from MACCEs was more clearly defined for lesions of the distal LCMA and in LMCA lesions with multivessel disease (p = 0.015, p = 0.004, respectively). CONCLUSIONS: Patients with LMCA disease who were treated with OPCAB showed better 5-year freedom from MACCEs in a real-world practice and in a patient matching cohort compared with the drug-eluting stenting group. TVR was the main factor that made the difference. The benefit of OPCAB was more prominent in distal LMCA lesions and in LMCA lesions with multivessel involvement. PMID- 22542070 TI - Tumor recurrence after complete resection for non-small cell lung cancer. AB - BACKGROUND: Long-term survival after R0 resection for non-small cell lung cancer (NSCLC) is less than 50%. The majority of mortality after resection is related to tumor recurrence. The purpose of this study was to identify independent perioperative and pathologic variables that are associated with NSCLC recurrence after complete surgical resection. METHODS: A retrospective examination was performed of a prospectively maintained database of patients who underwent resection for NSCLC from July 1999 to August 2008 at a single institution. Clinicopathologic variables were evaluated for their influence on time to recurrence. Cox's proportional regression hazard model examined the association of recurrence in NSCLC. RESULTS: A total of 1,143 patients met inclusion criteria and had complete follow-up information. Of these patients, 378 (33.1%) had recurrence of the primary cancer. Median follow-up was 24 months (range, 3-134 months). Preoperative tumor maximum standardized uptake value (SUVmax) greater than 5 was associated with increased risk of recurrence (hazard ratio [HR], 1.81; p=0.01). Preoperative radiation was independently associated with recurrence (HR, 1.98; p=0.05) as well as the presence of pathologic stage II and stage III disease (stage II: HR, 2.53; p=0.05; stage III: HR, 6.49; p=0.006). Subgroup analysis found that sublobar resection was also associated with locoregional recurrence after resection (HR, 4.17; p=0.02) and lymphovascular invasion of distant recurrence (HR, 4.21; p=0.002). CONCLUSIONS: In the largest series reported to date on postresectional recurrence of NSCLC, SUVmax greater than 5, increasing pathologic stage, and the administration of preoperative radiation were independently associated with NSCLC recurrence after resection. Sublobar resection was independently associated with locoregional recurrence, and lymphovascular invasion was associated with distant recurrence. PMID- 22542071 TI - Transmyocardial revascularization induces mesenchymal stem cell engraftment in infarcted hearts. AB - BACKGROUND: Transmyocardial revascularization (TMR) prior to mesenchymal stem cell (MSC) transplantation augments repair of infarcted hearts. We evaluated the effects of TMR on homing and engraftment of circulating MSCs and mediators of this effect. METHODS: Three weeks after left anterior descending coronary artery ligation in female rats, 10-channel needle TMR was performed in the infarct, followed by daily intravenous injections of 1 million male MSCs for 5 days. Control rats had MSC infusions without TMR (n=16/group). Donor MSC survival was evaluated at 3 days and at 1 week by quantitative polymerase chain reaction, as well as expression of stem cell factor (SCF), stromal derived factor-1 (SDF-1), c kit, and chemokine receptor type 4 (CXCR4). RESULTS: The MSCs engrafted into the infarct, clustering around TMR channels. The MSC engraftment was greater in TMR hearts at 3 days and at 1 week. Both SCF (p=0.03) and c-kit (p=0.01) were upregulated by TMR at 3 days, but their levels fell at 1 week (p=0.3, p=0.5, respectively). The SDF-1 levels were higher in TMR hearts at both 3 days (p=0.04) and at 1 week (p=0.04). The CXCR4 was upregulated early by TMR (p=0.0002) but levels dropped dramatically at 1 week (p=0.045). CONCLUSIONS: Transmyocardial revascularization induces transmigration and engraftment of circulating MSCs. Post TMR, the transcription of SCF and c-kit is rapid and corresponds temporally to MSC engraftment, while SDF-1 levels rise slowly. The CXCR4 is also transiently upregulated. The TMR-augmented repair of infarcted hearts by stem cell transplantation may be mediated by a novel mechanism: transmigration and engraftment of circulating progenitor cells. PMID- 22542072 TI - First 102 patients with the BioValsalva conduit for aortic root replacement. AB - BACKGROUND: We retrospectively evaluated our results with the BioValsalva Conduit (Vascutek Terumo, Renfrewshire Scotland), a stentless porcine valve incorporated in a 3-layered prosthetic graft. METHODS: From July 2008 through April 2011, 102 patients with a mean age of 70.9 +/- 7.3 years underwent aortic root replacement with a BioValsalva conduit. The indication for surgery was aneurysmal disease of the aorta in 81 patients (79.4%), aortic valve endocarditis in 15 patients (14.7%), acute type A aortic dissection in 4 patients (3.9%), and other causes in 2 patients (2.0%). In 26 patients (25.5%), the intervention was a reoperation. RESULTS: Overall hospital mortality was 4.9% (n = 5; 95% confidence limit [CL], 1.6%-11.1%). Cause of death was cardiac failure in 2 patients, multiple organ or renal failure in 2 patients, and tamponade in 1 patient. Mean follow-up was 8.1 months. During follow-up, 3 deaths occurred (3.1%) because of mediastinitis, cardiac ischemia, and arrhythmia. The overall survival at 3 and 12 months was 95.9% (95% CL, 92.0% -99.9%) and 92.1% (95% CL, 85.7% -98.9%) respectively. Three patients (3.1%) had new-onset endocarditis of the BioValsalva conduit; 2 of these patients required reoperation and 1 patient received antibiotic treatment only. CONCLUSIONS: Retrospective analysis of the BioValsalva conduit for aortic root replacement in more than 100 consecutive patients demonstrated satisfactory initial results, with low mortality and acceptable low morbidity rates. Follow-up is mandatory and long-term results are to be awaited. PMID- 22542073 TI - Complications of modeling glycosylation reactions: can the anomeric conformation of a donor determine the glycopyranosyl oxacarbenium ring conformation? AB - That the ring conformation of glycopyranosyl oxacarbenium ions can influence the stereochemical outcome of glycosylation reactions has been postulated for some time. Some new ionization calculations show that the ultimate conformation (4)H(3) or (5)S(1) of D-glucopyranosyl oxacarbenium ions depends on the initial phi(H) (CH-1-C-1-S(+)-SCH(3)) conformation of anomeric thiosulfonium ions. Evidence is also presented that nucleophile:electrophile hydrogen bonded complexes, 1,6-anhydro-carbenium ions and electron rich carbon nucleophile:oxacarbenium ion complexes are all probably artifacts of neglecting counter ions or nucleophiles in the DFT calculation. All three cationic species are likely important for glycosylation reaction side reactions but not as productive species. PMID- 22542074 TI - Low-fat pork liver pates enriched with n-3 PUFA/konjac gel: dynamic rheological properties and technological behaviour during chill storage. AB - Low-fat pork liver pates enriched with n-3 PUFA/konjac gel were formulated by replacing (total or partially) pork backfat by a combination of healthier oils (olive, linseed and fish oils) and konjac gel. Dynamic rheological properties and technological behaviour of pates during chill storage (2 degrees C, 85 days) were analysed. Cooking yields were affected (P<0.05) by formulation, with percentages ranging between 88 and 98%. According to the frequency sweep test, pates presented a gel/emulsion-like pattern with a loosely-structured network and the consistency of a viscoelastic gel. Thermal processing caused the formation of a protein gel network with a considerable element of emulsion-like characteristics. Pates became lighter and less red (P<0.05) during chill storage. Purge losses of around 1% were observed at the end of the storage period, irrespective of formulation. Textural parameters of pates were affected by formulation and storage time. The results suggest that the replacement of pork back fat by oil-in-water emulsion and the incorporation of konjac gel could provide a mixture of ingredients that effectively mimics the normal animal fat content in pates. PMID- 22542075 TI - The restriction of grazing duration does not compromise lamb meat colour and oxidative stability. AB - Over 72 days, 33 lambs were fed: concentrates in stall (S), grass at pasture for 8 hours (8 h), or grass at pasture for 4 hours in the afternoon (4h-PM). The 4h PM treatment did not affect the carcass yield compared to the 8h treatment. Meat colour development after blooming was unaffected by the treatments. The 4 h-PM treatment increased the proportion of polyunsaturated fatty acids (PUFA; P<0.0005) and of the highly peroxidizable fatty acids (HP-PUFA; P<0.001) in meat compared to the 8h treatment. The S treatment increased lipid oxidation (higher TBARS values) and impaired colour stability (higher H* values) of meat over storage compared to the 8h and 4 h-PM treatments (P<0.0005 and P=0.003, respectively). No difference in meat oxidative stability was found between the 8h and the 4h-PM treatments. In conclusion, growing lambs can tolerate a restriction of grazing duration without detrimental effects on performances and meat oxidative stability. PMID- 22542076 TI - Role of alpha methylacyl-coenzyme A racemase in differentiating hepatocellular carcinoma from dysplastic and nondysplastic liver cell lesions. AB - Distinction of hepatocellular carcinoma (HCC) from liver cell dysplasia (LCD) is one of the problems faced by pathologists. In spite of various methods claimed to differentiate between these 2 lesions, no reliable marker is available until now. The aim of the study was to assess the value of alpha methylacyl-coenzyme A (COA) racemase (AMACR) in distinguishing HCC from LCD. Formalin-fixed, paraffin embedded tissue sections from 30 HCCs and 30 nonneoplastic liver tissues (12 dysplastic and 18 nondysplastic lesions) were immunostained for AMACR. Staining intensity was interpreted as low (negative, mild) and high expressions (moderate, marked). Alpha methylacyl-COA racemase showed high expression in 21 (70%) of 30 HCCs and 7 (58.3%) of 12 LCDs. All 18 nondysplastic lesions revealed low AMACR expression. The percentage of high AMACR expression was significantly more in HCC and LCD as compared with nondysplastic lesions (P = .001 in each). There was no significant difference in AMACR expression between HCC and LCD. Furthermore, the pattern of AMACR immunostaining was coarsely granular cytoplasmic positivity in HCC as well as LCD in comparison with the weak finely granular in nondysplastic lesions. Alpha methylacyl-COA racemase cannot discriminate HCC from LCD, although it can separate HCC and LCD from nondysplastic lesions. PMID- 22542077 TI - Clinicopathologic correlation of vitamin D receptor expression with retinoid X receptor and MIB-1 expression in primary and metastatic osteosarcoma. AB - Vitamin D, in addition to its effects on bone, is important in cell cycle regulation. Vitamin D receptor (VDR) has been identified in breast, prostate, and colon cancers, as well as in canine and human osteosarcoma (OS) cell lines; however, it has not been well investigated in human OS-archived specimens. We correlated VDR, retinoid X receptor (RXR), and MIB-1 (Ki-67) expression in 110 archived OS cases with several clinicopathologic parameters including patient's age, sex, tumor location, tumor grade, and type and metastatic status. The expression of VDR and RXR was identified in human OS tissue obtained from primary and metastatic OS archival tissue. No statistically significant difference was found in VDR expression in relation with tumor grade, type, age, sex, or location. The expression of RXR was highest in higher-grade (P = .0006) and metastatic tumors but remained unchanged when correlated with tumor type, age, sex, or location. The expression of MIB-1 was statistically elevated in higher grade tumors (P = .001), patients 25 years or younger (P = .04), tumors located in extremities (P = .005), and metastatic lesions, but was not impacted by tumor type or patient's sex. Proliferative activity was significantly reduced after treatment, as the mean MIB-1 expression dropped from 11% in primary biopsy samples to 6% in resection specimens. There appears to be a relationship between proliferative tumor activity and tumor grade, location, and metastasis. Additional studies on the analysis of the effects of vitamin D and RXR on OS proliferation, apoptosis, and differentiation are critical to further evaluate their potential role in OS treatment. PMID- 22542078 TI - Effects of maxillary advancement and impaction on nasal airway function. AB - The effects of Le Fort I osteotomy on the nasal airway are controversial. This study aimed to evaluate nasal airway changes after Le Fort I. 25 patients underwent conventional Le Fort I osteotomy and were separated into three groups depending on the type of surgery they underwent. 11 patients needed maxillary impaction, 9 underwent maxillary advancement, and 5 had both maxillary impaction and advancement. Rhinological examinations, anterior rhinomanometry and acoustic rhinometry were carried out 1 week before surgery and 3 months after that. Wilcoxon and chi(2) tests were used for data analysis. The samples included 19 females and 6 males with a mean age of 22.4 +/- 3.32 years. Rhinomanometric assessment showed that total nasal airflow was increased from 406 +/- 202 ml/s to 543 +/- 268 ml/s in all three groups. Significant decrease in nasal airway resistance was seen in all three groups. Acoustic rhinometry revealed a significant decrease in total nasal volume but an increase in the cross-sectional areas of isthmus nasi (IN) and inferior concha. The rhinomanometric measurements showed improvements in the total nasal airflow after Le Fort I osteotomy with alar base cinch suture in cases where the impaction was not higher than 5.5mm. PMID- 22542079 TI - Success rate of dental implants inserted in horizontal and vertical guided bone regenerated areas: a systematic review. AB - This study assessed the success rate of implants placed in horizontal and vertical guided bone regenerated areas. A systematic review was carried out of all prospective and retrospective studies, involving at least five consecutively treated patients, that analysed the success rate of implants placed simultaneously or as second surgery following ridge augmentation by means of a guided bone regeneration (GBR) technique. Studies reporting only the survival rate of implants and studies with a post-loading follow up less than 6 months were excluded. From 323 potentially relevant studies, 32 full text publications were screened and 8 were identified as fulfilling the inclusion criteria. The success rate of implants placed in GBR augmented ridges ranged from 61.5% to 100%; all studies, apart from three, reported a success rate higher than 90% (range 90-100%). The data obtained demonstrated that GBR is a predictable technique that allows the placement of implants in atrophic areas. Despite that, studies with well-defined implant success criteria after a longer follow-up are required. PMID- 22542080 TI - Signs and symptoms of parotid gland carcinoma and their prognostic value. AB - The aim of this study was to analyse signs and symptoms present in patients with parotid gland carcinoma and to assess their prognostic value. A retrospective study of data from 131 patients who were treated surgically was performed. Evaluation of prognostic factors was possible in 109 patients who completed a minimum 5 year follow up. The most common sign and symptoms were parotid mass (96.9%), pain (40.4%), enlarged cervical lymph nodes (32.0%), facial nerve palsy (20.6%) and overlying skin infiltration (19.8%). In 20% of all cases there were no symptoms of tumour malignancy. The average duration of symptoms suggesting malignancy was 4 months. In univariate analysis, the strongest prognostic value was found for facial nerve palsy; it reduced nearly tenfold (9.7) the 5-year disease-free survival. The subsequent poor prognostic factors were: skin infiltration, enlarged cervical lymph nodes, tumour fixation and tumour size (>4 cm). Pain and the dynamics of tumour growth were not statistically significant for survival rate. Significant difference in 5-year disease free survival rate was found between the groups of patients, according to the number of symptoms suggesting malignancy. The multivariate analysis showed that only facial nerve palsy and skin infiltration were independent prognostic factors. PMID- 22542081 TI - Contamination and potential sources of polybrominated diphenyl ethers (PBDEs) in water and sediment from the artificial Lake Shihwa, Korea. AB - Concentrations of polybrominated diphenyl ethers (PBDEs) were determined in water and sediment collected from the artificial Lake Shihwa and surrounding creeks. Total concentrations of 23 PBDE congeners in water and sediment ranged from 0.16 to 11.0ngL(-1) and from 1.3 to 18700ngg(-1)dryweight, respectively. The concentrations of BDE 209 in water and sediment were 1-2 orders of magnitude higher than the total concentrations of other PBDE congeners. The concentrations of total PBDEs and BDE 209 in sediments were the highest compared to previously reported worldwide levels. The highest concentrations of PBDEs in water and sediments were found in creeks near industrial complexes. The PBDE concentrations gradually decreased with increasing distance from the creeks to the inshore and then offshore regions of the lake. BDE 209 was a major congener, accounting for 80% of the total PBDEs in water and sediment, consistent with a high consumption of deca-BDE for the brominated flame retardant market in Korea. Non-parametric multidimensional scaling ordination showed that surrounding creeks are major pathways of PBDE contamination associated with deca-BDE technical mixtures used in industrial complexes around Lake Shihwa. A significant correlation between total organic carbon and total PBDE concentration was found in sediments, and the correlation coefficients for individual PBDE congeners relatively increased from lower to higher brominated congeners. PMID- 22542082 TI - Combined approaches to determine the impact of wood fire on PCDD/F and PCB contamination of the environment: a case study. AB - Fires might be the source of persistent organic pollutants (POPs) such as dioxins, furans (PCDD/Fs) and/or polychlorobiphenyls (PCBs) in the environment. In the perspective of defining legal responsibilities a thorough characterization of the impact of such an event should be carried out. However, such characterization is not easy as the environment integrates both local and diffuse sources of such molecules. Thus, a combined approach, which includes gathering field surveys, modeling and laboratory experiments, should be conducted. The objective of this work is to illustrate different approaches to give sufficient insight to determine the actual impact of wood fire on the environment. The work was carried out at the vicinity of a burnt down parcel. The fired material was a mixture of wood and PCB-contaminated soils as the site was a former pyralene disposal site. Modeling, soil and lichen sampling and experimental combustion were carried out to delineate the contamination for each chemical and to define the area within the fire that was responsible for the environmental contamination. Concentrations of PCDD/F and PCBs were very high on the burnt plot. The combined approach determined that the furans were the predominant compounds in the smoke emitted by the fire. Based on this tracer, it was possible to demonstrate that in terms of environmental contamination of PCDD/F, the impact of the fire was restricted to a 2km radius from the burnt down plot. For PCBs, no specific tracer was identified. In this case, the delineation of the impact could only be empirical, based on the total concentration of the chemicals. PMID- 22542083 TI - [Prevalence of plasmid-mediated quinolone resistance determinant aac(6')-Ib-cr among ESBL producing enterobacteria isolates from Chilean hospitals]. AB - INTRODUCTION: The frequency of aac(6')-Ib-cr gene in ESBL-producing strains of Klebsiella pneumoniae and Escherichia coli is unknown, in Chile. METHODOLOGY: The aac(6')-Ib and aac(6')-Ib-cr genes were investigated using polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP), and sequencing, in strains isolated from 10 Chilean hospitals between 2008-2009. RESULTS: The aac(6')-Ib-cr gene was detected in 54% of K. pneumoniae and 74% of E. coli strains. The CIM(50) of CIP was higher among strains harboring aac(6')-Ib-cr, 8 times higher in K. pneumoniae and 4 times higher in E. coli. Moreover, both aac(6')-Ib and aac(6')-Ib-cr were simultaneously found in 13 K. pneumoniae and 3 E. coli isolates. CONCLUSION: This is the first report of aac(6')-Ib-cr in ESBL producing strains of K. pneumoniae and E. coli isolated from in-patients in Chilean hospitals located along an area of more than 2,800 Km. PMID- 22542084 TI - The influence of staff nurse perception of leadership style on satisfaction with leadership: a cross-sectional survey of pediatric nurses. AB - BACKGROUND: There is evidence that transformational leadership style promotes nursing excellence. Differences in how supervisees and supervisors perceive the supervisor's leadership style may also be related to satisfaction with leadership. Research demonstrates that satisfaction with leadership is a critical element in the retention of nurses. OBJECTIVE: To evaluate staff nurse and nurse leader perceptions of leadership style. METHODS: 16 supervisors and 179 supervisees completed the Multifactor Leadership Questionnaire and a demographic survey. Data were analyzed using parametric statistical techniques. RESULTS: Although staff perceived leaders as employing largely transformative leadership strategies, differences existed in leader-staff congruence in interpretation of leadership style and as related to the role of the leader. CONCLUSIONS: Differences in interpretation of leadership style between supervisors and supervisees were associated with diminished satisfaction with leadership. In addition, those serving in a direct operational role (assistant nurse manager) were viewed as less transformative than leaders who maintained broader administrative responsibilities. PMID- 22542085 TI - Burnout during nursing education predicts lower occupational preparedness and future clinical performance: a longitudinal study. AB - BACKGROUND: Early-career burnout among nurses can influence health and professional development, as well as quality of care. However, the prospective occupational consequences of study burnout have not previously been investigated in a national sample using a longitudinal design. OBJECTIVES: To prospectively monitor study burnout for a national sample of nursing students during their years in higher education and at follow-up 1 year post graduation. Further, to relate the possible development of study burnout to prospective health and life outcomes, as well as student and occupational outcomes. DESIGN: A longitudinal cohort of Swedish nursing students (within the population-based LANE (Longitudinal Analysis of Nursing Education/Entry) study) from all sites of education in Sweden was surveyed annually. Data were collected at four points in time over 4 years: three times during higher education and 1 year post graduation. PARTICIPANTS: : A longitudinal sample of 1702 respondents was prospectively followed from late autumn 2002 to spring 2006. METHODS: Mean level changes of study burnout (as measured by the Oldenburg Burnout Inventory, i.e. the Exhaustion and Disengagement subscales) across time, as well as prospective effects of baseline study burnout and changes in study burnout levels, were estimated using Latent Growth Curve Modeling. RESULTS: An increase in study burnout (from 30% to 41%) across 3 years in higher education was found, and levels of both Exhaustion and Disengagement increased significantly across the years in education (p<0.001). Baseline levels, as well as development of study burnout, predicted lower levels of in-class learner engagement and occupational preparedness in the final year. At follow-up 1 year post graduation, earlier development of study burnout was related to lower mastery of occupational tasks, less research utilization in everyday clinical practice and higher turnover intentions. CONCLUSIONS: The results suggest that study burnout may have interfered with learning and psychological well-being. Aspects related to work skills and intention to leave the profession were also affected. Thus, burnout development during higher education may be an important concern, and effective preventive measures to counteract burnout development may be necessary already at the outset of nursing education. PMID- 22542086 TI - Stem cells in breast tumours: are they ready for the clinic? AB - The concept of stem-like cells in cancer has been gaining currency over the last decade or so since evidence for stem cell activity in human leukaemia and solid tumours, including breast cancer, was first published. The evidence established that sub-populations of cells identified by antibodies to cell surface markers behaved like developmental stem cells in their capacity to re-grow the human tumour for several generations in experimental immune-deficient hosts. The experiments established that cells with tumourigenic capacity expressed 'cancer stem cell' (CSC) markers and that activity could also be measured by self-renewal of tumour sphere colonies in culture. In breast and other cancers, there is good evidence that CSCs are relatively resistant to radio- and chemotherapy indicating that novel CSC-targeted therapies are needed. Several pathways are promising targets in breast CSCs. There are several ways of combating CSC activity including inducing their apoptosis, inhibiting stem cell self-renewal to either stop their division or to promote their differentiation, or targeting the CSC niche that supports them. The first challenge for developing novel CSC therapies is to ascertain which of these CSC properties is being targeted. The second challenge is to determine suitable CSC biomarkers to measure the efficacy of the novel CSC therapies. We propose using biomarkers as a means to identify and assess CSC activity in clinical trials. This is likely to be demanding but feasible in the near future. Thus, we asked if CSCs are ready for the clinic, however, the emerging question becomes: is the clinic ready for cancer stem cells? PMID- 22542088 TI - Words of wisdom: Re: Hedgehog/Wnt feedback supports regenerative proliferation of epithelial stem cells in bladder. PMID- 22542087 TI - Fractal temporal organisation of motricity is altered in major depression. AB - OBJECTIVE: Motor changes in major depression (MD) may represent potential markers of treatment response. Physiological rhythms (heart rate/gait cycle/hand movements) have been recently shown to be neither random nor regular but to display a fractal temporal organisation, possibly reflecting a unique central "internal clock" control. Sleep and mood circadian rhythm modifications observed in MD also suggest a role for this "internal clock". We set out to examine the fractal pattern of motor activity in MD. METHODS: Ten depressed patients (46+/-20 years) and ten age- and gender-matched healthy controls (48+/-21 years) underwent a 6-h ambulatory monitoring of spontaneous hand activity with a validated wireless device. Fractal scaling exponent (alpha) was analysed. An alpha value close to 1 means the pattern is fractal. RESULTS: Healthy controls displayed a fractal pattern of spontaneous motor hand activity (alpha: 1.0+/-0.1), whereas depressed patients showed an alteration of that pattern (alpha:1.2+/-0.15, p<0.01), towards a smoother organisation. CONCLUSION: The alteration of fractal pattern of hand activity by depression further supports the role of a central internal clock in the temporal organisation of movements. This novel way of studying motor changes in depression might have an important role in the detection of endophenotypes and potential predictors of treatment response. PMID- 22542089 TI - Words of wisdom: Re: Alkaline citrate reduces stone recurrence and regrowth after shockwave lithotripsy and percutaneous nephrolithotomy. PMID- 22542090 TI - Words of wisdom: Re: Baseline prostate-specific antigen testing at a young age. PMID- 22542091 TI - Words of wisdom: Re: Dutasteride in localised prostate cancer management: the REDEEM randomised, double-blind, placebo-controlled trial. PMID- 22542092 TI - Words of wisdom: Re: Super extended versus extended pelvic lymph node dissection in patients undergoing radical cystectomy for bladder cancer: a comparative study. PMID- 22542093 TI - Words of wisdom: Re: Can a durable disease-free survival be achieved with surgical resection in patients with pathological node positive renal cell carcinoma? PMID- 22542094 TI - Fall frequency and risk assessment in early Parkinson's disease. AB - BACKGROUND: We sought to define the frequency of falls in early PD and assess potential risk factors for falls in this population. METHODS: We analyzed the data from two randomized, placebo controlled trials (NET-PD FS1 and FS-TOO) of 413 individuals with early PD over 18 months of follow-up in FS1 and 12 months in FS-TOO. Falls were defined as any report of falls on the UPDRS or the adverse event log. We assessed the frequency of falls overall and by age. The relationship between prespecified fall risk markers and the probability of falling was assessed using logistic and multiple logistic regression. A hurdle Poisson model was used to jointly model the probability of remaining fall-free and the number of falls. RESULTS: During the follow-up period, 23% of participants fell, and 11% were habitual fallers. In a multiple logistic regression model, age, baseline UPDRS Falling score, and baseline PDQ-39 scores were associated with subsequent fall risk (p < 0.001). Similarly, in a hurdle Poisson regression model, age, baseline UPDRS falling item, and baseline PDQ-39 were all significantly related to the probability of falling, but only UPDRS falling >0 was associated with the number of falls. CONCLUSION: Falls are frequent and are associated with impaired quality of life, even in early PD. Current standard rating scales do not sufficiently explain future fall risk in the absence of a prior fall history. New assessment methods for falls and postural instability are required to better evaluate this important problem in clinical trials and clinical practice. PMID- 22542095 TI - [Smoking prevalence in Portuguese school-aged adolescents by gender: can we be optimistic?]. AB - INTRODUCTION: According to the MPOWER approach adopted in 2008 by the WHO, monitoring smoking epidemics is necessary in order to assess the effectiveness of the preventive measures used in smoking control in adolescents and adults. OBJECTIVES: To determine the prevalence of smoking in Portuguese school-aged adolescents by region. MATERIAL AND METHODS: The sample is made up of 8764 students, 4060 boys and 4704 girls, and is representative of the Portuguese students in regular public education. The data was collected in the 2008/2009 academic year, through a quantitative self-report questionnaire. RESULTS: In the total sample, 10.2% of boys and 9.1% of girls are regular smokers. Smoking increases with age. At 15 years old 12.3% of the boys and 8.6% of the girls are regular smokers and 6.1% of the boys and 4.0% of the girls are occasional smokers. Looking at prevalence by region, the highest prevalence of regular smoking is found in Alentejo (14.7%), followed by Azores (11.8%) and the lowest is found in Algarve (4.1%). CONCLUSIONS: The prevalence of smokers among Portuguese school-aged adolescents varies within the several regions of the country, similar to what happens in the adult Portuguese population. PMID- 22542096 TI - [Jarde Act: non-interventional research in deadlock?]. PMID- 22542097 TI - [Cystic pancreatic lesion with a history of abdominal trauma 20 years ago]. PMID- 22542098 TI - The interface of animal and human vaccines. PMID- 22542099 TI - Pathogenesis of rhinovirus infection. AB - Since its discovery in 1956, rhinovirus (RV) has been recognized as the most important virus producing the common cold syndrome. Despite its ubiquity, little is known concerning the pathogenesis of RV infections, and some of the research in this area has led to contradictions regarding the molecular and cellular mechanisms of RV-induced illness. In this article, we discuss the pathogenesis of this virus as it relates to RV-induced illness in the upper and lower airway, an issue of considerable interest in view of the minimal cytopathology associated with RV infection. We endeavor to explain why many infected individuals exhibit minimal symptoms or remain asymptomatic, while others, especially those with asthma, may have severe, even life-threatening, complications (sequelae). Finally, we discuss the immune responses to RV in the normal and asthmatic host focusing on RV infection and epithelial barrier integrity and maintenance as well as the impact of the innate and adaptive immune responses to RV on epithelial function. PMID- 22542100 TI - Localized products of futile cycle/lrmp promote centrosome-nucleus attachment in the zebrafish zygote. AB - BACKGROUND: The centrosome has a well-established role as a microtubule organizer during mitosis and cytokinesis. In addition, it facilitates the union of parental haploid genomes following fertilization by nucleating a microtubule aster along which the female pronucleus migrates toward the male pronucleus. Stable associations between the sperm aster and the pronuclei are essential during this directed movement. RESULTS: Our studies reveal that the zebrafish gene futile cycle (fue) is required in the zygote for male pronucleus-centrosome attachment and female pronuclear migration. We show that fue encodes a novel, maternally provided long form of lymphoid-restricted membrane protein (lrmp), a vertebrate specific gene of unknown function. Both maternal lrmp messenger RNA (mRNA) and protein are highly localized in the zygote, in a largely overlapping pattern at nuclear membranes, centrosomes, and spindles. Truncated Lrmp-EGFP fusion proteins identified subcellular targeting signals in the C terminus of Lrmp; however, endogenous mRNA localization is likely important to ensure strict spatial expression of the protein. Localization of both Lrmp protein and lrmp RNA is defective in fue mutant embryos, indicating that correct targeting of lrmp gene products is dependent on Lrmp function. CONCLUSIONS: Lrmp is a conserved vertebrate gene whose maternally inherited products are essential for nucleus centrosome attachment and pronuclear congression during fertilization. Precise subcellular localization of lrmp products also suggests a requirement for strict spatiotemporal regulation of their function in the early embryo. PMID- 22542101 TI - Kendrin is a novel substrate for separase involved in the licensing of centriole duplication. AB - The centrosome, consisting of a pair of centrioles surrounded by pericentriolar material, directs the formation of bipolar spindles during mitosis. Aberrant centrosome number can promote chromosome instability, which is implicated in tumorigenesis. Thus, centrosome duplication needs to be tightly regulated to occur only once per cell cycle. Separase, a cysteine protease that triggers sister chromatid separation, is involved in centriole disengagement, which licenses centrosomes for the next round of duplication. However, at least two questions remain unsolved: what is the substrate relevant to the disengagement, and how does separase, activated at anaphase onset, act on the disengagement that occurs during late mitosis. Here, we show that kendrin, also named pericentrin, is cleaved by activated separase at a consensus site in vivo and in vitro, and this leads to the delayed release of kendrin from the centrosome later in mitosis. Furthermore, we demonstrate that expression of a noncleavable kendrin mutant suppresses centriole disengagement and subsequent centriole duplication. Based on these results, we propose that kendrin is a novel and crucial substrate for separase at the centrosome, protecting the engaged centrioles from premature disengagement and thereby blocking reduplication until the cell passes through mitosis. PMID- 22542102 TI - The Caenorhabditis elegans RDE-10/RDE-11 complex regulates RNAi by promoting secondary siRNA amplification. AB - BACKGROUND: In nematodes, plants, and fungi, RNAi is remarkably potent and persistent due to the amplification of initial silencing signals by RNA-dependent RNA polymerases (RdRPs). In Caenorhabditis elegans (C. elegans), the interaction between the RNA-induced silencing complex (RISC) loaded with primary small interfering RNAs (siRNAs) and the target messenger RNA (mRNA) leads to the recruitment of RdRPs and synthesis of secondary siRNAs using the target mRNA as the template. The mechanism and genetic requirements for secondary siRNA accumulation are not well understood. RESULTS: From a forward genetic screen for C. elegans genes required for RNAi, we identified rde-10, and through proteomic analysis of RDE-10-interacting proteins, we identified a protein complex containing the new RNAi factor RDE-11, the known RNAi factors RSD-2 and ERGO-1, and other candidate RNAi factors. The RNAi defective genes rde-10 and rde-11 encode a novel protein and a RING-type zinc finger domain protein, respectively. Mutations in rde-10 and rde-11 genes cause dosage-sensitive RNAi deficiencies: these mutants are resistant to low dosage but sensitive to high dosage of double stranded RNAs. We assessed the roles of rde-10, rde-11, and other dosage sensitive RNAi-defective genes rsd-2, rsd-6, and haf-6 in both exogenous and endogenous small RNA pathways using high-throughput sequencing and qRT-PCR. These genes are required for the accumulation of secondary siRNAs in both exogenous and endogenous RNAi pathways. CONCLUSIONS: The RDE-10/RDE-11 complex is essential for the amplification of RNAi in C. elegans by promoting secondary siRNA accumulation. PMID- 22542103 TI - Origin of immunoglobulin isotype switching. AB - BACKGROUND: From humans to frogs, immunoglobulin class switching introduces different effector functions to antibodies through an intrachromosomal DNA recombination process at the heavy-chain locus. Although there are two conventional antibody classes (IgM, IgW) in sharks, their heavy chains are encoded by 20 to >100 miniloci. These representatives of the earliest jawed vertebrates possess a primordial immunoglobulin gene organization where each gene cluster is autonomous and contains a few rearranging gene segments (VH-D1-D2-JH) with one constant region, MU or omega. RESULTS: V(D)J rearrangement always takes place within the MU cluster, but here we show that the VDJ can be expressed with constant regions from different clusters, although IgH genes are spatially distant, at >120 kb. Moreover, reciprocal exchanges take place between Igomega and IgMU genes. Switching is augmented with deliberate immunization and is concomitant with somatic hypermutation activity. Because switching occurs independently of the partners' linkage position, some events involve transchromosomal recombination. The switch sites consist of direct joins between two genes in the 3' intron flanking JH. CONCLUSIONS: Our data are consistent with a mechanism of cutting or joining of distal DNA lesions initiated by activation induced cytidine deaminase (AID), in the absence of mammalian-type switch regions. We suggest that, in shark, with its many autonomous IgH targeted by programmed DNA breakage, factors predisposing broken DNA ends to translocate configured the earliest version of class switch recombination. PMID- 22542104 TI - Highly selective inhibitors of monoacylglycerol lipase bearing a reactive group that is bioisosteric with endocannabinoid substrates. AB - The endocannabinoids 2-arachidonoyl glycerol (2-AG) and N-arachidonoyl ethanolamine (anandamide) are principally degraded by monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), respectively. The recent discovery of O-aryl carbamates such as JZL184 as selective MAGL inhibitors has enabled functional investigation of 2-AG signaling pathways in vivo. Nonetheless, JZL184 and other reported MAGL inhibitors still display low-level cross-reactivity with FAAH and peripheral carboxylesterases, which can complicate their use in certain biological studies. Here, we report a distinct class of O-hexafluoroisopropyl (HFIP) carbamates that inhibits MAGL in vitro and in vivo with excellent potency and greatly improved selectivity, including showing no detectable cross reactivity with FAAH. These findings designate HFIP carbamates as a versatile chemotype for inhibiting MAGL and should encourage the pursuit of other serine hydrolase inhibitors that bear reactive groups resembling the structures of natural substrates. PMID- 22542105 TI - Synthesis, antitumor activity and SAR study of novel [1,2,4]triazino[4,5 a]benzimidazole derivatives. AB - A series of novel 1,2,3,4-tetrahydro[1,2,4]triazino[4,5-a]benzimidazoles carrying variety of aryl and heteroaryl groups at position 1 were synthesized. The newly synthesized compounds were tested in vitro on human breast adenocarcinoma cell line (MCF7). Some of the test compounds showed potent antitumor activity, especially compound 3c [1-(2-chlorophenyl) derivative] which displayed the highest activity among the test compounds. PMID- 22542106 TI - Synthesis and antitumor activity of lapathoside D and its analogs. AB - Phenylpropanoid sucrose esters are important class of plant-derived natural products and have greater potential to be leads for new drugs because of their structural diversity and broad-array of pharmacological and biological activities. Regio- and chemo-selective acylation of 2,1':4,6-O-di-isopropylidene sucrose 4 with cinnamoyl chloride 5 and p-acetoxycinnamoyl chloride 6 afforded mono-, di-, tri- and tetra- variant PSEs in moderate yields. The first total synthesis of di-substituted PSE, lapathoside D 1' has been achieved successfully in short and simple synthetic steps from sucrose 3 as an inexpensive starting material. Lapathoside D 1 and a set of selected synthesized PSEs were tested for in vitro cytotoxicity against human cervical epithelioid carcinoma (HeLa) cell lines. Most of the compounds exhibited significant antitumor activity with their IC(50) values ranging from 0.05 to 7.63 MUM. The primary screening results indicated that PSEs might be valuable source for new potent anticancer drug candidates. PMID- 22542107 TI - Synthesis and molecular modelling studies of novel carbapeptide analogs for inhibition of HIV-1 protease. AB - Novel glycopeptides containing amino acids such as valine and alanine were designed, synthesized and tested for inhibition of the wild type C-SA HIV-1 protease enzyme. The incorporation of dipeptide sequences Val-Ala/Ala-Val to the sugar B-amino acid at two side chain positions resulted in a series of nine novel compounds. Compounds 3a, 3b, 3c, 3d, 4a, 4b and 5 displayed significant activities against the HIV protease enzyme. The glycopeptides are orders of magnitude less toxic to human MT-4 cells than lopinavir. Computational results were in good agreement with the experimental HIV-PR activity. The sugar hydroxyl group at the C(3) position interacts with the enzymatic Asp25/Asp25' residues. The docked position of the inhibitor is preserved during MD simulations and at least five hydrogen bond forms between the inhibitor and the enzymatic pocket. The results provide a platform for the progress of more effective carbohydrate supported inhibitors of HIV-1 and other aspartic proteases. PMID- 22542108 TI - Genetic up-regulation and overexpression of PLEKHA7 differentiates invasive lobular carcinomas from invasive ductal carcinomas. AB - Molecular differentiation between invasive lobular carcinomas (ILCs) and invasive ductal carcinomas (IDCs) of the breast has not been well defined. We investigated gene expression differences between ILCs and IDCs and their correlation with variations in invasiveness and tumor growth. Total RNA was isolated from 30 frozen tumor samples: 10 from ILCs and 20 from IDCs. Gene expression was investigated using the Affymetrix GeneChip Human Gene 1.0 ST Array (Affymetrix, Santa Clara, CA). Data and validation were performed by reverse transcriptase polymerase chain reaction and immunohistochemistry. Gene expression differences between ILCs and IDCs were found in 140 genes. Overall, ILCs showed up-regulation of genes related with cell migration, lipid and fatty acid metabolism, and some transcription factors and showed down-regulation of cell adhesion, actin cytoskeleton, cell proliferation, and energetic metabolism of the tumor cells. Our reverse transcriptase polymerase chain reaction results showed that PLEKHA and TMSB10 expression discriminated ILCs from luminal A IDCs, whereas PLEKHA7, TMSB10, PRDX4, and SERPINB5 discriminated ILCs from luminal B IDCs. At the protein level, Plekha7 was overexpressed in ILCs but not in normal tissue or low grade IDCs. Moreover, Plekha7 overexpression had an inverse relation with E cadherin expression. The gene expression profile in ILCs and IDCs differs in several signaling pathways. Our findings suggest that overexpression of PLEKHA7 is common in ILCs and could be a molecular marker to differentiate ILCs from IDCs. PMID- 22542109 TI - Shugoshins: from protectors of cohesion to versatile adaptors at the centromere. AB - Sister chromatids are held together by a protein complex named cohesin. Shugoshin proteins protect cohesin from cleavage by separase during meiosis I in eukaryotes and from phosphorylation-mediated removal during mitosis in vertebrates. This protection is crucial for chromosome segregation during mitosis and meiosis. Mechanistically, shugoshins shield cohesin by forming a complex with the phosphatase PP2A, which dephosphorylates cohesin, leading to its retention at centromeres during the onset of meiotic anaphase and vertebrate mitotic prophase I. In addition to this canonical function, shugoshins have evolved novel, species specific cellular functions, the mechanisms of which remain a subject of intense debate, but are likely to involve spatio-temporally coordinated interactions with the chromosome passenger complex, the spindle checkpoint and the anaphase promoting complex. Here, we compare and contrast these remarkable features of shugoshins in model organisms and humans. PMID- 22542111 TI - The new American Journal of Obstetrics and Gynecology, 5 years later: looking back and moving forward. PMID- 22542112 TI - Maternal-fetal care starts and ends with the mother. PMID- 22542113 TI - Progesterone and preterm birth prevention: translating clinical trials data into clinical practice. AB - OBJECTIVE: We sought to provide evidence-based guidelines for using progestogens for the prevention of preterm birth (PTB). METHODS: Relevant documents, in particular randomized trials, were identified using PubMed (US National Library of Medicine, 1983 through February 2012) publications, written in English, which evaluate the effectiveness of progestogens for prevention of PTB. Progestogens evaluated were, in particular, vaginal progesterone and 17-alpha-hydroxy progesterone caproate. Additionally, the Cochrane Library, organizational guidelines, and studies identified through review of the above were utilized to identify relevant articles. Data were evaluated according to population studied, with separate analyses for singleton vs multiple gestations, prior PTB, or short transvaginal ultrasound cervical length (CL), and combinations of these factors. Consistent with US Preventive Task Force suggestions, references were evaluated for quality based on the highest level of evidence, and recommendations were graded. RESULTS AND RECOMMENDATIONS: Summary of randomized studies indicates that in women with singleton gestations, no prior PTB, and short CL <= 20 mm at <= 24 weeks, vaginal progesterone, either 90-mg gel or 200-mg suppository, is associated with reduction in PTB and perinatal morbidity and mortality, and can be offered in these cases. The issue of universal CL screening of singleton gestations without prior PTB for the prevention of PTB remains an object of debate. CL screening in singleton gestations without prior PTB cannot yet be universally mandated. Nonetheless, implementation of such a screening strategy can be viewed as reasonable, and can be considered by individual practitioners, following strict guidelines. In singleton gestations with prior PTB 20-36 6/7 weeks, 17-alpha-hydroxy-progesterone caproate 250 mg intramuscularly weekly, preferably starting at 16-20 weeks until 36 weeks, is recommended. In these women with prior PTB, if the transvaginal ultrasound CL shortens to < 25 mm at < 24 weeks, cervical cerclage may be offered. Progestogens have not been associated with prevention of PTB in women who have in the current pregnancy multiple gestations, preterm labor, or preterm premature rupture of membranes. There is insufficient evidence to recommend the use of progestogens in women with any of these risk factors, with or without a short CL. PMID- 22542115 TI - The effect of CenteringPregnancy group prenatal care on preterm birth in a low income population. AB - OBJECTIVE: The purpose of this study was to evaluate the impact of group prenatal care on rates of preterm birth. STUDY DESIGN: We conducted a retrospective cohort study of 316 women in group prenatal care that was compared with 3767 women in traditional prenatal care. Women self-selected participation in group care. RESULTS: Risk factors for preterm birth were similar for group prenatal care vs traditional prenatal care: smoking (16.9% vs 20%; P = .17), sexually transmitted diseases (15.8% vs 13.7%; P = .29), and previous preterm birth (3.2% vs 5.4%; P = .08). Preterm delivery (<37 weeks' gestation) was lower in group care than traditional care (7.9% vs 12.7%; P = .01), as was delivery at <32 weeks' gestation (1.3% vs 3.1%; P = .03). Adjusted odds ratio for preterm birth for participants in group care was 0.53 (95% confidence interval, 0.34-0.81). The racial disparity in preterm birth for black women, relative to white and Hispanic women, was diminished for the women in group care. CONCLUSION: Among low-risk women, participation in group care improves the rate of preterm birth compared with traditional care, especially among black women. Randomized studies are needed to eliminate selection bias. PMID- 22542116 TI - Maternal superobesity and perinatal outcomes. AB - OBJECTIVE: The purpose of this study was to determine the effect of maternal superobesity (body mass index [BMI], >= 50 kg/m(2)) compared with morbid obesity (BMI, 40-49.9 kg/m(2)) or obesity (BMI, 30-39.9 kg/m(2)) on perinatal outcomes. STUDY DESIGN: We conducted a retrospective cohort study of birth records that were linked to hospital discharge data for all liveborn singleton term infants who were born to obese Missouri residents from 2000-2006. We excluded major congenital anomalies and women with diabetes mellitus or chronic hypertension. RESULTS: There were 64,272 births that met the study criteria, which included 1185 superobese mothers (1.8%). Superobese women were significantly more likely than obese women to have preeclampsia (adjusted relative risk [aRR], 1.7; 95% confidence interval [CI], 1.4-2.1), macrosomia (aRR, 1.8; 95% CI, 1.3-2.5), and cesarean delivery (aRR, 1.8; 95% CI, 1.5-2.1). Almost one-half of all superobese women (49.1%) delivered by cesarean section, and 33.8% of superobese nulliparous women underwent scheduled primary cesarean delivery. CONCLUSION: Women with a BMI of >= 50 kg/m(2) are at significantly increased risk for perinatal complications compared with obese women with a lower BMI. PMID- 22542117 TI - Changes in labor patterns over 50 years. AB - OBJECTIVE: The objective of the study was to examine differences in labor patterns in a modern cohort compared with the 1960s in the United States. STUDY DESIGN: Data from pregnancies at term, in spontaneous labor, with cephalic, singleton fetuses were compared between the Collaborative Perinatal Project (CPP, n = 39,491 delivering 1959-1966) and the Consortium on Safe Labor (CSL; n = 98,359 delivering 2002-2008). RESULTS: Compared with the CPP, women in the CSL were older (26.8 +/- 6.0 vs 24.1 +/- 6.0 years), heavier (body mass index 29.9 +/ 5.0 vs 26.3 +/- 4.1 kg/m(2)), had higher epidural (55% vs 4%) and oxytocin use (31% vs 12%), and cesarean delivery (12% vs 3%). First stage of labor in the CSL was longer by a median of 2.6 hours in nulliparas and 2.0 hours in multiparas, even after adjusting for maternal and pregnancy characteristics, suggesting that the prolonged labor is mostly due to changes in practice patterns. CONCLUSION: Labor is longer in the modern obstetrical cohort. The benefit of extensive interventions needs further evaluation. PMID- 22542119 TI - Prepregnancy obesity and complement system activation in early pregnancy and the subsequent development of preeclampsia. AB - OBJECTIVE: We hypothesized that women who are obese before they become pregnant and also have elevations of complement Bb and C3a in the top quartile in early pregnancy would have the highest risk of preeclampsia compared with a referent group of women who were not obese and had levels of complement less than the top quartile. STUDY DESIGN: This was a prospective study of 1013 women recruited at less than 20 weeks' gestation. An EDTA-plasma sample was obtained, and complement fragments were measured using enzyme-linked immunosorbent assays. The data were analyzed using univariable and multivariable logistic regression analysis. RESULTS: Women who were obese with levels of Bb or C3a in the top quartile were 10.0 (95% confidence interval, 3.3-30) and 8.8 (95% confidence interval, 3-24) times, respectively, more likely to develop preeclampsia compared with the referent group. CONCLUSION: We demonstrate a combined impact of obesity and elevated complement on the development of preeclampsia. PMID- 22542120 TI - Improving patient understanding of preeclampsia: a randomized controlled trial. AB - OBJECTIVE: We developed a standardized educational tool to inform women about preeclampsia. The objective of this study was to assess whether exposure to this tool led to superior understanding of the syndrome. STUDY DESIGN: This was a randomized controlled trial in which 120 women were assigned to (1) a newly developed preeclampsia educational tool, (2) a standard pamphlet addressing preeclampsia that had been created by the American College of Obstetricians and Gynecologists, or (3) no additional information. Preeclampsia knowledge was assessed with the use of a previously validated questionnaire. RESULTS: There were no demographic differences among the groups. Patients who received the tool scored significantly better on the preeclampsia questionnaire than those who received the American College of Obstetricians and Gynecologists pamphlet or no additional information (71%, 63%, 49%, respectively; P < .05). This improved understanding was evident equally among women with and without adequate health literacy (interaction: P > .05). CONCLUSION: Patients who were exposed to a graphics-based educational tool demonstrated superior preeclampsia-related knowledge, compared with those patients who were exposed to standard materials or no education. PMID- 22542121 TI - Interrater reliability of the International Continence Society and International Urogynecological Association (ICS/IUGA) classification system for mesh-related complications. AB - OBJECTIVE: We sought to assess interrater reliability of the International Continence Society (ICS)/International Urogynecological Association (IUGA) classification system of vaginal mesh-related complications and compare this with several other available complication classification systems. STUDY DESIGN: This was a retrospective analysis of mesh-related complications in patients presenting after pelvic organ prolapse or incontinence surgery. The complications were classified by 2 independent reviewers using the ICS/IUGA classification system as well as 3 other available classification systems. Interrater reliability was assessed using percent agreement and the weighted kappa statistic. RESULTS: The ICS/IUGA mesh complication classification system was found to have poor interrater reliability (kappa = 0.15-0.78). The other systems yielded a kappa that ranged from 0.18-0.60, but were too general or could only be applied to 68% of the complications. CONCLUSION: The complexity of the ICS/IUGA mesh complication system, the large number of categories, and lack of clarity likely contribute to its poor interrater reliability. PMID- 22542118 TI - Fetal male gender and the benefits of treatment of mild gestational diabetes mellitus. AB - OBJECTIVE: We evaluated whether improvements in pregnancy outcomes after treatment of mild gestational diabetes mellitus differed in magnitude on the basis of fetal gender. STUDY DESIGN: This is a secondary analysis of a masked randomized controlled trial of treatment for mild gestational diabetes mellitus. The results included preeclampsia or gestational hypertension, birthweight, neonatal fat mass, and composite adverse outcomes for both neonate (preterm birth, small for gestational age, or neonatal intensive care unit admission) and mother (labor induction, cesarean delivery, preeclampsia, or gestational hypertension). After stratification according to fetal gender, the interaction of gender with treatment status was estimated for these outcomes. RESULTS: Of the 469 pregnancies with male fetuses, 244 pregnancies were assigned randomly to treatment, and 225 pregnancies were assigned randomly to routine care. Of the 463 pregnancies with female fetuses, 233 pregnancies were assigned randomly to treatment, and 230 pregnancies were assigned randomly to routine care. The interaction of gender with treatment status was significant for fat mass (P = .04) and birthweight percentile (P = .02). Among women who were assigned to the treatment group, male offspring were significantly more likely to have both a lower birthweight percentile (50.7 +/- 29.2 vs 62.5 +/- 30.2 percentile; P < .0001) and less neonatal fat mass (487 +/- 229.6 g vs 416.6 +/- 172.8 g; P = .0005,) whereas these differences were not significant among female offspring. There was no interaction between fetal gender and treatment group with regard to other outcomes. CONCLUSION: The magnitude of the reduction of a newborn's birthweight percentile and neonatal fat mass that were related to the treatment of mild gestational diabetes mellitus appears greater for male neonates. PMID- 22542123 TI - A novel bridge between oxidative stress and immunity: the interaction between hydrogen peroxide and human leukocyte antigen G in placental trophoblasts during preeclampsia. AB - OBJECTIVE: The aim of this study was to investigate a possible association between hydrogen peroxide and human leukocyte antigen G (HLA-G) in preeclampsia. STUDY DESIGN: We explored the correlation between HLA-G and hydrogen peroxide in preeclamptic (n = 30) and normotensive (n = 30) placentas, which was confirmed by in vitro experiments. Furthermore, RNA interference was used to explore the influence of HLA-G on the proliferation, apoptosis and invasion of HTR-8/SVneo cells when exposed to hydrogen peroxide. RESULTS: We found an inverse correlation between hydrogen peroxide and HLA-G expression in preeclamptic placentas. High levels of hydrogen peroxide could down-regulate HLA-G expression in HTR-8/SVneo. Compared with HLA-G knockdown HTR-8/SVneo, increased proliferation inhibition, higher apoptosis, and decreased cell invasion were found in the cell expressing HLA-G when exposed to hydrogen peroxide. CONCLUSION: Our findings highlight that high levels of hydrogen peroxide can down-regulate HLA-G expression in trophoblasts during preeclampsia and trophoblasts expressing HLA-G are vulnerable to oxidative stress. PMID- 22542122 TI - Pharmacologic treatment for urgency-predominant urinary incontinence in women diagnosed using a simplified algorithm: a randomized trial. AB - OBJECTIVE: The purpose of this study was to evaluate clinical outcomes associated with the initiation of treatment for urgency-predominant incontinence in women diagnosed by a simple 3-item questionnaire. STUDY DESIGN: We conducted a multicenter, double-blinded, 12-week randomized trial of pharmacologic therapy for urgency-predominant incontinence in ambulatory women diagnosed by the simple 3-item questionnaire. Participants (N = 645) were assigned randomly to fesoterodine therapy (4-8 mg daily) or placebo. Urinary incontinence was assessed with the use of voiding diaries; postvoid residual volume was measured after treatment. RESULTS: After 12 weeks, women who had been assigned randomly to fesoterodine therapy reported 0.9 fewer urgency and 1.0 fewer total incontinence episodes/day, compared with placebo (P <= .001). Four serious adverse events occurred in each group, none of which was related to treatment. No participant had postvoid residual volume of >= 250 mL after treatment. CONCLUSION: Among ambulatory women with urgency-predominant incontinence diagnosed with a simple 3 item questionnaire, pharmacologic therapy resulted in a moderate decrease in incontinence frequency without increasing significant urinary retention or serious adverse events, which provides support for a streamlined algorithm for diagnosis and treatment of female urgency-predominant incontinence. PMID- 22542125 TI - Discussion: 'A new method for assessing uterine activity' by Haran et al. AB - In the roundtable that follows, clinicians discuss a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. Article discussed: Haran G, Elbaz M, Fejgin MD, et al. A comparison of surface acquired uterine electromyography and intrauterine pressure catheter to assess uterine activity. Am J Obstet Gynecol 2012;206:412.e1 5. PMID- 22542124 TI - Human amnion epithelial cells reduce ventilation-induced preterm lung injury in fetal sheep. AB - OBJECTIVE: The objective of the study was to explore whether human amnion epithelial cells (hAECs) can mitigate ventilation-induced lung injury. STUDY DESIGN: An established in utero ovine model of ventilation-induced lung injury was used. At day 110 of gestation, singleton fetal lambs either had sham in utero ventilation (IUV) (n = 4), 12 hours of IUV alone (n = 4), or 12 hours of IUV and hAEC administration (n = 5). The primary outcome, structural lung injury, was assessed 1 week later. RESULTS: Compared with sham controls, IUV alone was associated with significant lung injury: increased collagen (P = .03), elastin (P = .02), fibrosis (P = .02), and reduced secondary-septal crests (P = .009). This effect of IUV was significantly mitigated by the administration of hAECs: less collagen (P = .03), elastin (P = .04), fibrosis (P = .02), normalized secondary septal crests (P = .02). The hAECs were immunolocalized within the fetal lung and had differentiated into type I and II alveolar cells. CONCLUSION: The hAECs mitigate ventilation-induced lung injury and differentiated into alveolar cells in vivo. PMID- 22542126 TI - Histologic grading of urothelial carcinoma: a reappraisal. AB - A uniform grading system for bladder cancer will allow for valid comparison of treatment results among different centers. The introduction of the World Health Organization (2004)/International Society of Urological Pathology classification is a welcome step toward standardization of treatment and follow-up regimens. The greatest source of controversy with the World Health Organization (2004)/International Society of Urological Pathology classification system centers on the diagnosis of papillary urothelial neoplasm of low malignant potential. Some feel that papillary urothelial neoplasm of low malignant potential terminology increases the complexity of histologic grading and does not accurately reflect biologic potential. Papillary urothelial neoplasm of low malignant potential is a low-grade papillary urothelial neoplasm with a substantial incidence of recurrence and progression. In the distinction of papillary urothelial neoplasm of low malignant potential from noninvasive low grade papillary urothelial carcinoma, there is considerable interobserver variability. For these reasons, some investigators believe that papillary urothelial neoplasm of low malignant potential is, in essence, an entity that was previously designated grade 1 urothelial carcinoma in the World Health Organization 1973 grading system. In addition, treatment and follow-up regimens for patients with papillary urothelial neoplasm of low malignant potential do not typically differ from those prescribed for low-grade, noninvasive urothelial carcinoma, further minimizing the clinical need for the papillary urothelial neoplasm of low malignant potential distinction to be made. We propose abandonment of the terminology "papillary urothelial neoplasm of low malignant potential" in bladder tumor classification. Full-genome searches for prognostic and predictive molecular gene expression signatures as cancer markers have shown significant promise. Recent advances in the molecular grading of these tumors may eventually supplant traditional morphologic grading systems, allowing a more precise and objective assessment of the tumors' biologic potentials. PMID- 22542127 TI - Mucin 16 (cancer antigen 125) expression in human tissues and cell lines and correlation with clinical outcome in adenocarcinomas of the pancreas, esophagus, stomach, and colon. AB - Mucin 16 (cancer antigen 125) is a cell surface glycoprotein that plays a role in promoting cancer cell growth in ovarian cancer. The aims of this study were to examine mucin 16 expression in a large number of digestive tract adenocarcinomas and precursors and to determine whether mucin 16 up-regulation is correlated with patient outcome. Tissue microarrays were constructed using surgical resection tissues and included pancreatic (115 normal, 29 precursors, 200 pancreatic ductal adenocarcinomas), esophageal (86 normal, 104 precursors, 95 esophageal adenocarcinomas, 35 lymph node metastases), gastric (211 normal, 8 precursors, 119 gastric adenocarcinomas, 62 lymph node metastases), and colorectal (34 normal, 17 precursors, 39 colorectal adenocarcinomas) tissues. Mucin 16 was detected in 81.5%, 69.9%, 41.2%, and 64.1% of the pancreatic ductal adenocarcinomas, esophageal adenocarcinomas, gastric adenocarcinomas, and colorectal adenocarcinomas, respectively. Mucin 16 was seen in a subset of the precursors. On multivariate analysis, moderate/diffuse mucin 16 in pancreatic ductal adenocarcinomas was strongly associated with poor survival (P < .001), independent of other prognosis predictors. A similar trend was observed for esophageal adenocarcinomas (P = .160) and gastric adenocarcinomas (P = .080). Focal mucin 16 in colorectal adenocarcinomas was significantly correlated (P = .044) with a better patient outcome, when compared with mucin 16-negative cases. Using Western blot analysis, we found mucin 16 expression in 3 of 6 pancreatic ductal adenocarcinoma and 1 of 2 esophageal adenocarcinoma cell lines. We conclude that most of the digestive tract adenocarcinomas and a subset of their precursors express mucin 16. Mucin 16 expression is an independent predictor of poor outcome in pancreatic ductal adenocarcinomas and potentially in esophageal adenocarcinomas and gastric adenocarcinomas. We propose that mucin 16 may function as a prognostic marker and therapeutic target in the future. PMID- 22542129 TI - Staining for acid-fast bacilli in surgical pathology: practice patterns and variations. AB - Analysis of acid-fast bacilli stains on sputum smears for the diagnosis of tuberculosis has a long history, but quality control for acid-fast bacilli in histologic sections is not as well established. In tissues, necrotizing granulomas are closely linked to positive cultures for mycobacteria. However, the practices of pathologists examining acid-fast bacilli in surgical specimens are not well described in the literature. This study characterizes practice patterns related to the histologic interpretation of acid-fast bacilli stains. A survey invitation was sent to 1299 pathologists including members of the Pulmonary Pathology Society and randomly selected fellows of the College of American Pathologists. Twenty-one questions inquired about demographics, ordering and interpreting acid-fast bacilli stains, reporting, and correlation. Of the 392 responses (30.2% response rate), 363 respondents review acid-fast bacilli stains on histologic sections. Approximately half of respondents practice in an academic setting, with the other half in community practice. Most respondents examine the entire acid-fast bacilli slide with the *40 objective; approximately half confirm the organisms under oil immersion at *100. There was considerable variation in when an acid-fast bacilli stain is ordered, as well as possible additional workup for negative cases, reporting of results, correlation with clinical and culture findings, and training. Many respondents reported never having been taught a general approach to acid-fast bacilli interpretation. There is substantial variation in practice patterns involving all aspects of ordering, histologic examination, and reporting of acid-fast bacilli stains. Future efforts to standardize the interpretation of acid-fast bacilli stains can potentially improve the diagnosis of mycobacterial disease. PMID- 22542128 TI - Immunoexpression status and prognostic value of mammalian target of rapamycin and hypoxia-induced pathway members in papillary cell renal cell carcinomas. AB - Dysregulation of the mammalian target of rapamycin and hypoxia-induced pathways has been consistently identified in clear cell renal cell carcinomas. However, experience with non-clear cell renal cell carcinoma subtypes is scant. In this study, we evaluated the immunohistochemical expression of upstream (PTEN and phosphorylated AKT) and downstream (phosphorylated S6 and 4EBP1) effectors of the mammalian target of rapamycin pathway, as well as related cell-cycle proteins (p27 and c-MYC), and a member of the hypoxia-induced pathway (HIF-1alpha) in 54 patients with papillary renal cell carcinoma treated by nephrectomy. PTEN was lower in tumor than in normal kidney, and loss of PTEN expression was found in 48% of the patients. In tumor tissues, phosphorylated S6, 4EBP1, and HIF-1alpha were higher than in normal kidney. Conversely, scores of p27 were lower in tumor than in normal kidney. Finally, scores of c-MYC and phosphorylated AKT were similar in tumor and in normal kidney. Overall mortality and cancer-specific mortality were 24% and 11%, respectively. Tumor progression was observed in 17% of the patients. None of the tested biomarkers predicted cancer-specific mortality or tumor progression. As expected, patients with high T-stage tumors had higher hazard ratios for cancer-specific mortality (hazard ratio, 6.9) and tumor progression (hazard ratio, 6.7). Patients with higher Fuhrman grades also had higher risks for cancer-specific mortality (hazard ratio, 11.4) and tumor progression (hazard ratio, 4.5). In summary, our study provides evidence of dysregulation of the mammalian target of rapamycin and hypoxia-induced pathways in papillary renal cell carcinoma. Immunohistochemistry for members of the mammalian target of rapamycin pathway and for HIF-1alpha lacked prognostic significance in our cohort. PMID- 22542130 TI - Impact of salinity and pH on the UVC/H2O2 treatment of reverse osmosis concentrate produced from municipal wastewater reclamation. AB - While reverse osmosis (RO) technology is playing an increasingly important role in the reclamation of municipal wastewater, safe disposal of the resulting RO concentrate (ROC), which can have high levels of effluent organic pollutants, remains a challenge to the water industry. The potential of UVC/H(2)O(2) treatment for degrading the organic pollutants and increasing their biodegradability has been demonstrated in several studies, and in this work the impact of the water quality variables pH, salinity and initial organic concentration on the UVC/H(2)O(2) (3 mM) treatment of a municipal ROC was investigated. The reduction in chemical oxygen demand and dissolved organic carbon was markedly faster and greater under acidic conditions, and the treatment performance was apparently not affected by salinity as increasing the ROC salinity 4-fold had only minimal impact on organics reduction. The biodegradability of the ROC (as indicated by biodegradable dissolved organic carbon (BDOC) level) was at least doubled after 2 h UVC/H(2)O(2) treatment under various reaction conditions. However, the production of biodegradable intermediates was limited after 30 min treatment, which was associated with the depletion of the conjugated compounds. Overall, more than 80% of the DOC was removed after 2 h UVC/3 mM H(2)O(2) treatment followed by biological treatment (BDOC test) for the ROC at pH 4-8.5 and electrical conductivity up to 11.16 mS/cm. However, shorter UV irradiation time gave markedly higher energy efficiency (e.g., EE/O 50 kWh/m(3) at 30 min (63% DOC removal) cf. 112 kWh/m(3) at 2 h). No toxicity was detected for the treated ROC using Microtox((r)) tests. Although the trihalomethane formation potential increased after the UVC/H(2)O(2) treatment, it was reduced to below that of the raw ROC after the biological treatment. PMID- 22542131 TI - Effects of increase modes of shear force on granule disruption in upflow anaerobic reactors. AB - Sludge washout is listed among the top practical problems of the high rate upflow anaerobic reactors. This study investigated quantitatively two sludge washout processes operated under different hydrodynamic shear increase modes with the intervals of 1 and 10 days respectively. The results reveal that the sludge washout accompanying with large-scale granule disruption could lead to performance failure with heavy sludge loss ratio of about 46.1% at sludge loss rate about 0.35 gVSS L(-1) d(-1) during the process with shear increase interval of 1 day, while the highest sludge loss rate was only 0.12 gVSS L(-1) d(-1) during the process with 10-day interval. The intensified shear conditions could weaken the granules through inhibiting the extracellular polymers production and bioactivity. As consequences, an outbreak of large-scale granule disruption would raise and then significantly accelerate the sludge washout. Since long interval could provide the granules the opportunity to recover from these negative effects to some extent, the shear increase strategy of long interval over 10 days is favorably recommended to operate full-scale reactors during the start-up and shock load periods. The pioneer use of the micro particle image velocimetry in this study offers the possibility to discover the real hydrodynamic conditions around granules at microscale for the first time and reveals that the shear force exerts directly on the granular surface as a mechanical disruption force and big granules undergo high disruption force. The granule disruption is a result of the competition between the granule and the ambient hydrodynamic shear conditions rather than a process with shear force as a sole dominant factor. These could facilitate the understanding of the complicated interactions between the hydrodynamics and reactor performance and favor then a better control of the full scale reactors. PMID- 22542132 TI - Reactivity of neonicotinoid insecticides with carbonate radicals. AB - The reaction of three chloronicotinoid insecticides, namely Imidacloprid (IMD), Thiacloprid (THIA) and Acetamiprid (ACT), with carbonate radicals (CO.3-) was investigated. The second order rate constants (4 +/- 1) * 106, (2.8 +/- 0.5) * 105, and (1.5 +/- 1) * 105 M-1 s-1 were determined for IMD, THIA and ACT, respectively. The absorption spectra of the organic intermediates formed after CO.3- attack to IMD is in line with those reported for alpha-aminoalkyl radicals. A reaction mechanism involving an initial charge transfer from the amidine nitrogen of the insecticides to CO.3- is proposed and further supported by the identified reaction products. The pyridine moiety of the insecticides remains unaffected until nicotinic acid is formed. CO.3- radical reactivity towards IMD, ACT, and THIA is low compared to that of HO* radicals, excited triplet states, and 1O2, and is therefore little effective in depleting neonicotinoid insecticides. PMID- 22542133 TI - Evaluating dissolved organic carbon-water partitioning using polyparameter linear free energy relationships: Implications for the fate of disinfection by-products. AB - The partitioning of micropollutants to dissolved organic carbon (DOC) can influence their toxicity, degradation, and transport in aquatic systems. In this study carbon-normalized DOC-water partition coefficients (K(DOC-w)) were measured for a range of non-polar and polar compounds with Suwannee River fulvic acid (FA) using headspace and solid-phase microextraction (SPME) methods. The studied chemicals were selected to represent a range of properties including van der Waal forces, cavity formation and hydrogen bonding interactions. The K(DOC-w) values were used to calibrate a polyparameter linear free energy relationship (pp-LFER). The difference between experimental and pp-LFER calculated K(DOC-w) values was generally less than 0.3 log units, indicating that the calibrated pp-LFER could provide a good indication of micropollutant interaction with FA, though statistical analysis suggested that more data would improve the predictive capacity of the model. A pp-LFER was also calibrated for Aldrich humic acid (HA) using K(DOC-w) values collected from the literature. Both experimental and pp LFER calculated K(DOC-w) values for Aldrich HA were around one order of magnitude greater than Suwannee River FA. This difference can be explained by the higher cavity formation energy in Suwannee River FA. Experimental and pp-LFER calculated K(DOC-w) values were compared for halogenated alkanes and alkenes, including trihalomethane disinfection by-products, with good agreement between the two approaches. Experimental and calculated values show that DOC-water partitioning is generally low; indicating that sorption to DOC is not an important fate process for these chemicals in the environment. PMID- 22542134 TI - Development of prototype bandage lapper for constant tension bandaging required for effective medical-clinical treatments. AB - Application of the bandaging materials is a skilled task and required considerable practice to perform it correctly. The variation in bandaging pressure is introduced due to different tensions applied by different persons during lapping. So, a handy mechanical bandage lapper is developed. This helps in keeping lapping tension uniform and adjustable irrespective of the bandager. Its proficiency is checked by bandaging two persons with different fore-arm circumferential measures. Bandaging is done at three different limb positions with and without the use of bandage lapper up to three layers by the same bandager. Three different lapping tensions viz; 0.40 kgf, 0.45 kgf and 0.50 kgf are set up for bandage lapper to study their impact on bandage pressure. Pneumatic bandage pressure mapper is developed for the measurement of bandage pressure. Seven trials separated by different time intervals are conducted for each variable. This has prevented record of consistency of bandage pressure measure by chance. Crepe bandage, normally employed for the management of Oedema in clinical treatment is used throughout the study. Higher coefficient of variations up to 15% in pressure values are found when bandaging done without the lapper. However, identical pressure, coefficient of variation less than 0.3% for all except 0.8% for bandaging done at 0.45 kgf for second person at position 1, is mapped when bandaging done with the lapper by the same bandager. PMID- 22542135 TI - Determining the optimal inner air cell pressure for the effective reduction of interface pressure. AB - Alternating-pressure air mattresses can reduce interface pressure and prevent pressure ulcer development. However, bottoming out sometimes occurs, resulting in an increase in interface pressure. Therefore, optimal settings should be determined based on interface pressures and inner air cell pressures. The purpose of this study was to investigate the most effective inner air cell pressure to reduce interface pressure without causing bottoming out. A new alternating air mattress was used, which comprised three layers: a base layer, fitting (F) layer, and alternating layer. The alternating layer comprises inflated (I) cells and deflating (D) cells. The study participants were 13 healthy volunteers over 18 years of age, each of whom adopted supine position on the mattress. The pressures in the D cells were gradually deflated under different I cell and F layer pressure settings. We measured peak sacral pressure and inner air cell pressure to obtain the bottoming out cut-off values by using receiver-operating characteristic (ROC) curves. We then investigated the effectiveness of different settings to reduce the peak sacral pressures. A number of test conditions were evaluated. Results indicated that the D cell pressure cut-off points were 1.26 kPa and 1.21 kPa, for phases 1 (F = 4 kPa, I = 4 kPa) and 4 (F = 1 kPa, I = 4 kPa), respectively. These settings significantly reduced the interface pressure (P < 0.001, P = 0.026, respectively). Our results suggest that appropriate configuration of inner air cell pressure could reduce interface pressure without causing bottoming out. PMID- 22542136 TI - HDL-like discs for assaying membrane proteins in drug discovery. AB - To broaden the use of the recombinant high-density lipoprotein (rHDL) approach to the characterization of lead compounds, we investigated the pharmacology of the human beta-2-adrenoceptor in nanolipid bilayers (rHDL) with a broad set of beta adrenoceptor antagonists. To that end, we developed a homogeneous copper-chelate scintillation proximity binding assay (SPA) in order to compare receptor-ligand binding affinities before and after reconstitution into rHDLs. Our results clearly show that the beta-2-adrenoceptor reconstituted in rHDLs display the same pharmacology as that in cell membranes and that rHDLs can be used not only to measure affinities for a range of ligands but also to study binding kinetics. PMID- 22542137 TI - Drying characteristics and equilibrium moisture content of steam-treated Douglas fir (Pseudotsuga menziesii L.). AB - Douglas fir (Pseudotsuga menziesii L.) particles were exposed to high pressure saturated steam (200 and 220 degrees C for 5 and 10 min) to improve the durability and hydrophobicity of pellets produced from them. Depending on treatment severity, the moisture content of the particles increased from 10% to 36% (wet basis). Douglas fir particles steam-treated at 220 degrees C for 10 min had the fastest drying rate of 0.014 min(-1). The equilibrium moisture content (EMC) of steam-treated samples decreased with increasing steam temperature and treatment time. The Giggnheim-Anderson-deBoer (GAB) equilibrium model gave a good fit with the equilibrium data with R(2) = 0.99. The adsorption rate of untreated pellets exposed to humid air (30 degrees C, 90% RH) for 72 h was 0.0152 min(-1) while that of steam-treated pellets ranged from 0.0125 to 0.0135 min(-1) without a clear trend with steam treatment severity. These findings are critical to develop durable and less hygroscopic pellets. PMID- 22542138 TI - Enhanced dewaterability of sewage sludge in the presence of Fe(II)-activated persulfate oxidation. AB - The potential benefits of Fe(II)-activated persulfate oxidation on sludge dewatering and its mechanisms were investigated in this study. Capillary suction time (CST) was used to evaluate sludge dewaterability. Both extracellular polymeric substances (EPS) and viscosity were determined in an attempt to explain the observed changes in sludge dewaterability. The optimal conditions to give preferable dewaterability characteristics were found to be persulfate (S(2)O(8)(2 )) 1.2 mmol/gVSS, Fe(II) 1.5 mmol/gVSS, and pH 3.0-8.5, which demonstrated a very high CST reduction efficiency (88.8% reduction within 1 min). It was further observed that both soluble EPS and viscosity played relatively negative roles in sludge dewatering, whereas no correlation was established between sludge dewaterability and bound EPS. Three-dimensional excitation-emission matrix (EEM) fluorescence spectra also revealed that soluble EPS of sludge were degraded and sludge flocs were ruptured by persulfate oxidation, which caused the release of water in the intracellular pace and subsequent improvement of its dewaterability. PMID- 22542139 TI - Understanding obstructive sleep apnea in children with CHARGE syndrome. AB - OBJECTIVE: CHARGE syndrome occurs in approximately 1 in 8500 live births and is diagnosed clinically by combinations of major characteristics: choanal atresia, coloboma, characteristic ears, cranial nerve abnormalities and distinct temporal bone anomalies. More than 50% of children with CHARGE syndrome experience sleep disturbances, with obstructive sleep apnea being one diagnosis. Objectives of this study were to develop a better understanding of the prevalence, symptomatology and treatments of sleep apnea in CHARGE syndrome. Secondary aims were to determine the usefulness of questionnaires examining obstructive sleep apnea in a CHARGE syndrome population. METHODS: Parents of 51 children with CHARGE syndrome (aged 0-14 years) were recruited between May 2010 and July 2011. Genetic testing and/or clinical criteria confirmed diagnosis of CHARGE syndrome. Questionnaires completed by parents included one covering CHARGE characteristics and three previously validated questionnaires: the Brouilette Score Questionnaire, the Pediatric Sleep Questionnaire and the OSA-18 Quality of Life Questionnaire. SPSS 19.0 was used for statistical calculations. RESULTS: Previous diagnosis of obstructive sleep apnea was present in 65% of the study population. Treatments included continuous positive airway pressure, tonsillectomy and/or adenoidectomy, and tracheostomy. Brouilette scores identified the presence of obstructive sleep apnea in the CHARGE syndrome population studied and indicated statistically significant (p=<0.001) improvements following treatment, which were comparable to the general population. Only the subscales of snoring and daytime sleepiness were useful in identifying obstructive sleep apnea using the Pediatric Sleep Questionnaire. The OSA-18 Questionnaire indicated that residual symptoms affecting quality of life may be present in the CHARGE syndrome population after treatment for obstructive sleep apnea. CONCLUSIONS: Obstructive sleep apnea appears to be prevalent in children with CHARGE syndrome. All conventional treatments for obstructive sleep apnea reduce symptomatology. Brouilette scores are useful in identifying obstructive sleep apnea in the CHARGE syndrome population. The Pediatric Sleep Questionnaire could be useful once modified. The OSA-18 Questionnaire would be most useful as a means to measure quality of life gains following treatment. PMID- 22542140 TI - Peak oxygen uptake during cardiopulmonary exercise testing determines response to cardiac resynchronization therapy. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) is an established treatment modality for advanced heart failure (HF) but 20-30% of patients treated with CRT do not experience clinical improvement. Hence, in this study we aimed to investigate whether baseline cardiopulmonary exercise testing (CPX) can help improve the prediction of a positive functional CRT response. METHODS: This prospective observational study included 76 HF patients undergoing elective CRT implantation and clinical CPX and echocardiographic assessment were performed at baseline, 6, and 12 months. RESULTS: Peak VO2 increased from 11.0+/-2.5 ml/min/kg to 12.0+/-4.1 ml/min/kg and 12.2+/-3.5 ml/min/kg at 6 and 12 months after CRT, respectively. The number of patients classified as "CRT-responders" (Delta peak VO2>=1 ml/kg/min) was 33 (46%) and 36 (52%) at 6 and 12 months after CRT, respectively. Patients with baseline peak VO2<40% of predicted (lowest tertile) demonstrated a 68% and 69% response rate at 6 and 12 months, respectively, as compared to a 35% and 42% response rate among patients with baseline peak VO2>=40% of predicted (p=0.01 and p=0.02, respectively). In multivariate analysis patients with baseline peak VO2<40% of predicted had an adjusted odds ratio of 4.4 (95% CI 1.6-12.5; p<0.01) and 3.1 (95% CI 1.1-8.8; p=0.03) for positive CRT response at 6 and 12 months, respectively. CONCLUSIONS: Treatment with CRT improves exercise capacity but this increase is most substantial among patients with a lower baseline peak VO2 (% of predicted). Baseline CPX can, therefore, be utilized to identify patients more likely to exhibit a functional improvement after CRT. PMID- 22542141 TI - Recurrent implantation failure: current update and clinical approach to an ongoing challenge. AB - A better understanding of the mechanisms responsible for implantation may improve our ability to treat RIF and improve IVF results in general. This issue's Views and Reviews aims to summarize the current knowledge on mechanisms involved in recurrent implantation failure and presents a clinical approach and potential treatments to overcome the problem. PMID- 22542142 TI - Defective endometrial receptivity. AB - The endometrium is one of the most fascinating tissues in the human body. Its sole purpose is to enable implantation of an embryo during a relatively short window of opportunity in the menstrual cycle. It is becoming clear that overcoming the current bottleneck in improvements to assisted reproductive techniques will require a closer look at the interface between uterus and embryo. Indeed, embryo implantation requires a cross talk with a receptive endometrium. Using sonography, hysteroscopy and endometrial biopsy we can learn about anatomical and functional markers of endometrial receptivity. This article reviews the factors which might cause defective endometrial receptivity. These include uterine polyps, septa, leiomyomata and adhesions. The effect of thin endometrium, endometriosis and hydrosalpinx is also described. Finally contemporary investigation of molecular markers of endometrial receptivity is described. Improving embryo implantation by a closer look inside the uterus is the key to increasing pregnancy rates in IVF. PMID- 22542143 TI - A good meta-analysis is hard to find. PMID- 22542145 TI - Single port laparoscopy. AB - OBJECTIVE: To demonstrate the abdominal wall anatomy necessary to perform a single port laparoscopic procedure. Single port laparoscopic (SPL) surgery has reduced the number of sites required to perform laparoscopic surgery. However, the incision at the umbilicus is larger than conventional laparoscopic surgery. DESIGN: Video presentation of clinical article. The video uses animation and surgical cases to demonstrate the relevant abdominal wall anatomy to establish surgical access for a single site or single port laparoscopy. RESULT(S): This video demonstrates the regional anatomy pertinent to the anterior abdominal wall, specifically of the umbilicus. The umbilicus is a focal point of fusion of the anterior abdominal wall muscles that allows entry into the peritoneal cavity. For this procedure there are 2 incisions possible, a small midline intra-umbilical one and an omega incision. The video demonstrates each technique. Introduction of a port into this single incision is demonstrated with 2 different trocar systems. These trocar systems show how the limitations of using a single site may be reduced. CONCLUSION(S): The abdominal wall anatomy is unique at the umbilicus and allows optimal placement of a single trocar to allow laparoscopic surgery. Video is available at http://fertstertforum.com/2012974caravalho/. PMID- 22542144 TI - Chromosome transfer in mature oocytes. AB - OBJECTIVE: To demonstrate step-by-step micromanipulation procedures required for transfer of spindle-chromosomal complexes between mature oocytes. DESIGN: Video presentation of reproductive biology study. SETTING: In vitro fertilization and embryo manipulation laboratory. ANIMAL(S): Rhesus (Macaca mulatta) primates. INTERVENTION(S): Transplantation of the genetic material between mammalian oocytes offers many opportunities to study various aspects of nuclear-cytoplasmic interactions during oogenesis, fertilization and embryo development. We demonstrate the feasibility of isolation and transfer of chromosomes between mature metaphase II (MII) primate oocyte. After fertilization, manipulated oocytes were capable of producing healthy offspring or embryonic stem cells. MAIN OUTCOME MEASURE(S): In this video, we show micromanipulation procedures required for isolation and transfer of spindle-chromosomal complexes between rhesus MII oocytes. In brief, the spindle is visualized using a polarized microscope and extracted into a membrane enclosed karyoplast. Karyoplasts are then reintroduced into an enucleated recipient oocyte (cytoplast, derived from an another female) by karyoplast-cytoplast membrane fusion. RESULT(S): Newly reconstructed oocytes consist of nuclear genetic material from one female and cytoplasmic components, including mitochondria and mitochondrial DNA from another. CONCLUSION(S): This video demonstrates the protocol developed for primate oocytes that successfully allowed of isolation and transfer of chromosomes between mature metaphase II (MII) oocytes. Potential clinical applications include mitochondrial gene replacement therapy to prevent transmission of mtDNA mutations and treatment of infertility caused by cytoplasmic defects in oocytes. Video is available at http://fertstertforum.com/2012974tachibana/. PMID- 22542146 TI - Anatomopathological and immunohistochemical study of explanted cryopreserved arteries. AB - BACKGROUND: The aim of the study was to analyze the mechanism of deterioration of implanted arteries. METHODS: Eleven patients were included. Samples of vascular segments obtained from multiorgan donors and samples of the same vascular segments after explantation in the recipient were analyzed. Blood group, time of cold and warm ischemia, cause of death, time spent in the intensive care unit, time of storage of the cryopreserved grafts, and anatomopathological and immunohistochemical studies were analyzed using the preimplant samples obtained from the multiorgan donor. For samples obtained from the recipient, blood group, duration for which the tissue from the donor has been implanted, reason for graft explantation, and anatomopathological and immunohistochemical studies were analyzed. RESULTS: Histopathologically, the main finding has been the substitution of the muscular cap of the arterial wall by an intense fibrosis, in most of the cases, of a symmetrical nature. Besides this degeneration of myocytes, there is marked perivascular fibrosis and fibrointimal thickening also exists. The T lymphocytes suggest the importance of the immunological mechanism in the distortion of the architecture of the arteries. The atherosclerosis plays a less relevant role. CONCLUSIONS: Evidence of immune-mediated injury was found, and this mechanism seems to be responsible for the degenerative process in cryopreserved homografts. PMID- 22542148 TI - Aspirin: the balance between benefits and harms. Preface. PMID- 22542147 TI - Nitric oxide increases susceptibility of Toll-like receptor-activated macrophages to spreading Listeria monocytogenes. AB - Toll-like receptor (TLR) stimulation activates macrophages to resist intracellular pathogens. Yet, the intracellular bacterium Listeria monocytogenes (Lm) causes lethal infections in spite of innate immune cell activation. Lm uses direct cell-cell spread to disseminate within its host. Here, we have shown that TLR-activated macrophages killed cell-free Lm but failed to prevent infection by spreading Lm. Instead, TLR signals increased the efficiency of Lm spread from "donor" to "recipient" macrophages. This enhancement required nitric oxide (NO) production by nitric oxide synthase-2 (NOS2). NO increased Lm escape from secondary vacuoles in recipient cells and delayed maturation of phagosomes containing membrane-like particles that mimic Lm-containing pseudopods. NO also promoted Lm spread during systemic in vivo infection, as shown by the fact that inhibition of NOS2 with 1400W reduced spread-dependent Lm burdens in mouse livers. These findings reveal a mechanism by which pathogens capable of cell-cell spread can avoid the consequences of innate immune cell activation by TLR stimuli. PMID- 22542149 TI - Efficacy and gastrointestinal risk of aspirin used for the treatment of pain and cold. AB - AIMS: To analyse major sources of evidence-based information on the efficacy and gastrointestinal tolerability of aspirin, used short-term, in over-the-counter (OTC) doses, to relieve acute pain and cold symptoms, including associated feverishness. METHODS: Evidence was largely collected from published meta analyses and systematic reviews that focused on randomised, controlled, double blind clinical trials, in which aspirin was compared to placebo and, in some cases also, to active comparators such as OTC doses of paracetamol or ibuprofen. RESULTS: Across a large number of comparisons, aspirin was superior to placebo in treating pain, cold or fever. Efficacy was essentially similar to that of comparators used in equivalent doses. There was no serious GI adverse event attributed to ASA in any study, but mild-to-moderate dyspepsia in small percentages of cases was commonly reported. CONCLUSION: OTC aspirin is safe and effective. Safety concerns should not limit brief use to relieve acute pain, cold or fever. PMID- 22542150 TI - Role of ASA in the primary and secondary prevention of cardiovascular events. AB - Cardiovascular disease, which includes coronary heart disease, cerebrovascular disease and peripheral artery disease, is the leading cause of death in developed countries. Evidence from basic research, clinical investigations, observational epidemiologic studies and randomized clinical trials has provided strong support for the benefits of aspirin in decreasing the risk of cardiovascular events in a wide range of pathologies in secondary prevention. Data in primary prevention have far more uncertainties. An overview for the evidence supporting the efficacy of aspirin in primary and secondary prevention of cardiovascular disease is discussed, including the relative and absolute benefit and the risks of side effects. Finally, future developments in the field directed towards individualized treatment strategies and novel antiplatelet agents are examined. PMID- 22542151 TI - Risk factors for gastrointestinal bleeding associated with low-dose aspirin. AB - Low-dose aspirin use is associated with an increased risk for gastrointestinal ulceration and bleeding. At-risk low-dose aspirin users are therefore recommended to take proton-pump inhibitors. However, it is poorly understood which aspirin users are at risk to develop such complications. It is assumed that the known risk factors for NSAID-induced upper gastrointestinal events also apply to low dose aspirin users. The conventional risk factors for upper gastrointestinal complications associated with aspirin therapy include: (1) a history of peptic ulcer disease or gastrointestinal bleeding, (2) older age, (3) concomitant use of NSAIDs, including coxibs, (4) concomitant use of anticoagulants or other platelet aggregation inhibitors, (5) the presence of severe co-morbidities, and (6) high aspirin dose. In patients with a history of peptic ulcer disease, Helicobacter pylori infection should be assessed and treated. This review focuses on the evidence for upper gastrointestinal risk factors in aspirin users. PMID- 22542152 TI - Gastrointestinal lesions and complications of low-dose aspirin in the gastrointestinal tract. AB - Low dose aspirin (ASA) use has been associated with a wide range of adverse side effects in the upper gastrointestinal (GI) tract, which range from troublesome symptoms without mucosal lesions to more serious toxicity, including ulcers, GI bleeding, perforation and even death. Upper GI symptoms in low dose ASA users are common but often careless or misinterpreted and they are not always related to the presence of mucosal injury. Usually, low dose ASA related ulcers are reasonably small and asymptomatic, and probably heal over a period of weeks to a few months. But, the real clinical problem occurs when the ulcer results in a GI complication (mostly bleeding). The estimated average excess risk of symptomatic or complicated ulcer related to low dose ASA is five cases per 1000 ASA users per year. Death is the worst outcome of GI complications in low dose ASA users, but data about this aspect are scarce. Current evidence indicates that low dose ASA can damage the lower GI tract also, but the real size of the problem is still unknown. PMID- 22542153 TI - Prevention of damage induced by aspirin in the GI tract. AB - Low-dose aspirin (325 mg or less) alone and in combination with other antiplatelet agents is widely used for the management of cardiovascular disease. Although the risk with low-dose aspirin alone is less than Nonsteroidal anti inflammatory drugs (NSAIDs), given widespread use, aspirin related toxicity has become a substantial health care problem due to acute and chronic GI bleeding. A variety of strategies are currently available to minimize the risk of developing upper GI side effects of aspirin. Agents that have efficacy include oral prostaglandin analogues, H2 receptor antagonists and proton pump inhibitors. PPIs appear to be the most effective strategy, with the least side effects and the convenience of once daily dosing. The substitution of another antiplatelet agent such as clopidogrel for aspirin alone does not appear to provide a safer alternative to low-dose aspirin for patients at GI risk. Small bowel injury can occur with aspirin and can be assessed with capsule endoscopy; however, no strategy is known to reduce this potential toxicity in clinical practice. PMID- 22542154 TI - Interaction of Helicobacter pylori infection and low-dose aspirin in the upper gastrointestinal tract: implications for clinical practice. AB - Low-dose aspirin has been shown to increase the risk of upper gastrointestinal tract injury. Risk factors in upper gastrointestinal complications in low-dose aspirin users are less well defined than in other NSAID users, and there are enough intrinsic differences in the two agents to discuss them separately. In particularly, the role of Helicobacter pylori and the benefit of its eradication in decreasing the risk of upper gastrointestinal tract injury in low-dose ASA users remains controversial. Various consensus groups have recommended H. pylori testing and eradication in low-dose ASA users with a prior history of peptic ulcer or ulcer bleeding. The basis of this recommendation is derived from a limited, albeit expanding evidence on the role of H. pylori in upper gastrointestinal tract injury in low-dose ASA users and on the effectiveness of H. pylori eradication in reducing the risk of complications such as rebleeding in high-risk patients. PMID- 22542155 TI - Balancing the risk and benefits of low-dose aspirin in clinical practice. AB - Antiplatelet agents are widely used in primary and secondary prevention of cardiovascular events. The scientific evidence has provided strong support for the benefits of aspirin in decreasing the risk of cardiovascular events in a wide range of pathologies. The relatively rare occurrence of major bleeding complications should not be underestimated, mainly due to its high morbi mortality. The assessment of both gastrointestinal risk and cardiovascular benefits of low-dose aspirin for any individual patient may be difficult in clinical practice. In this review, we summarize the evidence supporting the efficacy of aspirin and the risks of side effects due to hemorrhagic complications. This article proposes a unifying framework for application to help the clinician in the decision making process of individuals who have different risk of cardiovascular and bleeding events with different examples. Finally, new developments in the field directed towards individualized risk assessment strategies are described. PMID- 22542156 TI - Aspirin and the prevention of colorectal cancer. AB - A large body of evidence from basic science, epidemiologic observations and population-based studies demonstrates that aspirin, as well as other non steroidal anti-inflammatory drugs, has a chemopreventive effect on several cancer types and, more specifically, in CRC. This protective effect includes prevention of adenoma recurrence and reduction of CRC incidence and mortality. Although the protective effect appears to depend on the dose and the drug, the most important factor is the duration of exposure. However, the lowest effective dose, treatment duration, specific target populations, and effects on survival have not been defined yet. More important, data on the risk-benefit profile for cancer prevention are insufficient and, accordingly, no definitive recommendation can be made at present. In this article, besides reviewing current knowledge of the mechanisms involved in aspirin-based CRC chemoprevention, we will be focused on randomized controlled studies assessing its efficacy in high-, moderate- and average-risk populations. PMID- 22542157 TI - Aspirin and NSAIDs; benefits and harms for the gut. AB - Despite modern advances in cancer research, screening and treatment options, gastrointestinal tumours remain a leading cause of death worldwide. Both oesophageal and colorectal malignancies carry high rates of morbidity and mortality, presenting a challenge to clinicians in search of effective management strategies. In recent years, the increasing burden of disease has led to a paradigm shift in our approach from treatment to prevention. Among several agents postulated as having a chemopreventive effect on the gastrointestinal tract, aspirin has been most widely studied and has gained universal acknowledgement. There is an expanding evidence base for aspirin as a key mediator in the prevention of dysplastic change in Barrett's oesophagus and colorectal adenomas. Its cardioprotective effects also impact positively on the patient population in question, many of whom have ischaemic vascular disease. The major side effects of aspirin have been well-characterised and may cause significant morbidity and mortality in their own right. Complications such as peptic ulceration, upper gastrointestinal bleeding and haemorrhagic stroke pose serious threats to the routine administration of aspirin and hence a balance between the risks and benefits must be struck if chemoprevention is to be effective on a large scale. In this review, we address the current evidence base for aspirin use in gastrointestinal oncology, as well as several key questions surrounding its safety, cost effectiveness and optimal dose. PMID- 22542158 TI - Analysis of serum microRNAs (miR-26a-2*, miR-191, miR-337-3p and miR-378) as potential biomarkers in renal cell carcinoma. AB - INTRODUCTION: Emerging evidence suggest that microRNAs could serve as non invasive biomarker for cancer patients. Our study was designed to analyze circulating serum microRNAs in patients with renal cell carcinoma (RCC). MATERIALS AND METHODS: Serum RNA was isolated from patients with clear cell RCC (ccRCC) and non-malignant disease; an artificial microRNA (cel-miR-39) was spiked in prior the isolation procedure to control isolation efficiency. The levels of miR-26a-2*, miR-191, miR-337-3p and miR-378 in serum were determined using quantitative real-time PCR; the microRNA levels were normalized to cel-miR-39. RESULTS: First, miR-26a-2*, miR-191, miR-337-3p and miR-378 were quantified in serum of each 25 patients with ccRCC and non-malignant disease. The level of miR 378 was significantly increased in ccRCC patients, and thus chosen for validation. The analysis of miR-378 in the validation cohort with 117 RCC patients and 123 control subjects did not confirm a different level of miR-378. Also, miR-378 was not correlated to pT-stage, lymph node/distant metastasis, vascular invasion and Fuhrman grade. CONCLUSIONS: The analysis of circulating serum levels of miR-26a-2*, miR-191, miR-337-3p and miR-378 is unlikely to provide helpful diagnostic/prognostic information in RCC patients. PMID- 22542159 TI - Mesenchymal-stem-cell-induced immunoregulation involves FAS-ligand-/FAS-mediated T cell apoptosis. AB - Systemic infusion of bone marrow mesenchymal stem cells (BMMSCs) yields therapeutic benefit for a variety of autoimmune diseases, but the underlying mechanisms are poorly understood. Here we show that in mice systemic infusion of BMMSCs induced transient T cell apoptosis via the FAS ligand (FASL)-dependent FAS pathway and could ameliorate disease phenotypes in fibrillin-1 mutated systemic sclerosis (SS) and dextran-sulfate-sodium-induced experimental colitis. FASL(-/-) BMMSCs did not induce T cell apoptosis in recipients, and could not ameliorate SS and colitis. Mechanistic analysis revealed that FAS-regulated monocyte chemotactic protein 1 (MCP-1) secretion by BMMSCs recruited T cells for FASL mediated apoptosis. The apoptotic T cells subsequently triggered macrophages to produce high levels of TGFbeta, which in turn led to the upregulation of CD4(+)CD25(+)Foxp3(+) regulatory T cells and, ultimately, immune tolerance. These data therefore demonstrate a previously unrecognized mechanism underlying BMMSC based immunotherapy involving coupling via FAS/FASL to induce T cell apoptosis. PMID- 22542161 TI - Is there a future for electrophysical agents in musculoskeletal physiotherapy? PMID- 22542162 TI - Is human papilloma virus associated with salivary gland neoplasms? An in situ hybridization study. AB - OBJECTIVE: HPV can infect cells of epithelial origin and is closely associated with carcinomas. Studies investigating its presence in salivary gland neoplasms are few and conflicting. METHODS: Detection of HPV types 16 & 18 was done on 34 formalin-fixed, paraffin-embedded archival material of different salivary gland neoplasms using Digene HPV types 16 & 18 probe using in situ hybridization technique. RESULTS: Eight of neoplastic salivary gland specimens were positively infected by HPV types 16 & 18. Seven of them were benign (4 Warthin's tumour, 2 pleomorphic adenoma and one myoepithelioma), in addition to one malignant specimen (lymphoma). Correlation was found between the incidence of HPV infection and histological differentiation of salivary gland neoplasms. CONCLUSIONS: An association exists between HPV infections and salivary gland neoplasms. However, given the sparse pattern of reactive cells, it cannot be confirmed that this virus is implicated in the aetiology of this group of tumours. PMID- 22542160 TI - Background mutations in parental cells account for most of the genetic heterogeneity of induced pluripotent stem cells. AB - To assess the genetic consequences of induced pluripotent stem cell (iPSC) reprogramming, we sequenced the genomes of ten murine iPSC clones derived from three independent reprogramming experiments, and compared them to their parental cell genomes. We detected hundreds of single nucleotide variants (SNVs) in every clone, with an average of 11 in coding regions. In two experiments, all SNVs were unique for each clone and did not cluster in pathways, but in the third, all four iPSC clones contained 157 shared genetic variants, which could also be detected in rare cells (<1 in 500) within the parental MEF pool. These data suggest that most of the genetic variation in iPSC clones is not caused by reprogramming per se, but is rather a consequence of cloning individual cells, which "captures" their mutational history. These findings have implications for the development and therapeutic use of cells that are reprogrammed by any method. PMID- 22542163 TI - Amplification and up-regulation of microRNA-30b in oral squamous cell cancers. AB - OBJECTIVES: MicroRNAs (miRNAs) are negative regulators of protein coding genes which are frequently deregulated in mammary cancers. Over-expression of microRNA 30b (hsa-miR-30b) is implicated in tumour invasion and immunosuppression during metastasis. The chromosome locus of MIR30B gene, 8q24, is frequently amplified in oral squamous cell cancers (OSCCs). In the present study, we aimed to investigate the copy number variations as well as expression levels of MIR30B gene in OSCCs and analyse their correlation with tumour stage. DESIGN: Quantitative real-time PCR was performed to examine the copy number of MIR-30B gene as well as hsa-miR 30b expression in 107 OSCC samples with matched adjacent normal tissues. Proportional odds regression and two-way repeated measurement ANOVA were used to analyse the association between copy number variations (CNVs) and hsa-miR-30b expression. RESULTS: Copy number gains of MIR-30B gene were detected in a relatively large percentage of the OSCC samples (27.1%, 29 out of 107) and were correlated with tumour stages (p<0.001). MIR30B gene amplification also showed a close correlation with hsa-miR-30b over-expression in OSCCs (p<0.001). On the other hand, enhanced miR-30b expression was also detected in a group of OSCC samples with unaltered copy number of MIR30B gene. CONCLUSIONS: Copy number increase of MIR30B is frequent in advanced OSCC and is correlated with hsa-miR 30b over-expression. Sporadic OSCCs can exhibit different mechanisms of MIR30B regulation. PMID- 22542164 TI - Reducing lifetime cardiovascular risk. PMID- 22542165 TI - Femoral replacement for salvage of periprosthetic fracture around a total hip replacement. AB - A total of 20 patients with a mean age of 72 (range: 36-91) were managed with replacement of the proximal (15) or total (5) femur for salvage of a periprosthetic femoral fracture with bone loss. A mean 12.5 years had elapsed between primary total hip replacement and surgery and the mean follow-up was 48 months (range: 12-116 months). Clinical outcome was assessed using the Toronto Extremity Salvage Score (mean: 68, range: 32-98) and Short Form 36 (SF-36; mean Physical Component Score (PCS): 53, range: 44-62; mean Mental Component Score (MCS): 51, range: 41-64). No prostheses were radiologically loose. There were six major complications; three patients suffered a postoperative dislocation; two patients had persistent deep infection (present preoperatively); and one patient suffered a fracture of their femur distal to the femoral stem of a proximal femoral replacement. Endoprosthetic replacement of the femur is a reasonable salvage option for patients with periprosthetic fracture and bone loss, with good clinical results. It allows immediate weight bearing and does not rely on bony union for success. PMID- 22542166 TI - Deep infection after hip fracture surgery: predictors of early mortality. AB - INTRODUCTION: This study analysed the predictors of mortality in patients who are diagnosed with deep infection following hip fracture surgery. METHODS: Data were prospectively collected for 3 years from all patients undergoing hip fracture surgery and who had developed a subsequent deep infection. Infection was defined as positive microbiology culture from deep tissue or fluid samples. Demographic data, treatment, complications and subsequent surgeries were analysed. Potential predisposing factors including chronic medical co-morbidities, American Society of Anesthesiologists (ASA) grade, alcohol excess and smoking were assessed. The main outcome measures were 30-day and 1-year mortality. RESULTS: There were 2718 consecutive operations performed for a fracture of the proximal femur over a 3 year period. Forty-three (1.6%) patients had a deep postoperative infection diagnosed on fluid and/or tissue sampling. The mean age was 73 years (25-94) and 65% were female. Of the 43 patients who developed deep infection, the primary procedure in 25 (58%) patients was reduction and internal fixation, with 18 (42%) undergoing hemi-arthroplasty. The most common causative organism was Staphylococcus epidermidis (n=13, 30%), with methicillin-resistant Staphylococcus aureus (MRSA) accounting for 23% (n=10). The 30-day mortality was significantly higher than that of patients with no deep infection (19% vs. 6.5%; p=0.004). On univariate analysis, increasing age, dementia and diabetes were predictive of both 30-day and 1-year mortality (all p<0.05). S. aureus (sensitive or resistant) was approaching significance at 1 year (p=0.065). On multivariate analysis, dementia and diabetes were independent predictors of 30-day mortality, with dementia and S. aureus predictive at 1 year. CONCLUSIONS: The 30-day mortality rate in patients diagnosed with deep infection following hip fracture surgery is higher than those without infection. Dementia, diabetes and S. aureus infection are independent predictors of mortality following deep infection. PMID- 22542167 TI - The extended flexor carpi radialis approach for partially healed malaligned fractures of the distal radius. AB - PURPOSE: The aim of the study is to evaluate the safety and utility of the extended flexor carpi radialis (FCR) exposure and volar locking plate fixation for partially healed malaligned fractures of distal radius. MATERIALS AND METHODS: Thirty-five patients with a partially healed malaligned fracture of the distal radius had realignment of the fracture using an extended FCR approach (release of the insertion of the brachioradialis and dorsal periosteum) and volar locked plate and screw fixation. RESULTS: Retrospective review an average of 20 months after the index operation patients identified an average wrist extension of 68 degrees , flexion of 64 degrees , pronation of 84 degrees and supination of 85 degrees . Radial inclination, volar tilt and ulnar variance significantly improved compared to preoperative radiographs. All fractures healed, and there were no infections, implant loosening or breakage or tendon ruptures. CONCLUSIONS: This study demonstrated that the extended FCR approach is safe and effective as a treatment method for nascent malunions of the distal radius. PMID- 22542168 TI - Judet osteoperiosteal decortication for treatment of non-union: the Cornwall experience. AB - BACKGROUND: The treatment of non union can be challenging with a variety of surgical options available to achieve bone consolidation. Robert Judet first described a method of osteo-periosteal decortication in 1963. He stated that by elevating cortical chips that remain attached to the periosteum and overlying soft tissues surrounding the site of non-union, combined with mechanical support, the bone consolidated. Despite excellent results presented in 2008 of 99% union rates with a mean delay of 8 months, the technique has not yet become popularised. We aim to show that Judet's method of decortication can achieve good results in the management of failure of union in a hospital other than Judet's. METHODS: Retrospective analysis was performed from December 2002 to December 2008 of 40 cases in 39 patients of osteoperiosteal decortication for fracture non union. Concurrent stabilisation was with internal fixation only. All procedures were performed by one surgeon (MN) using the Judet technique after learning the technique in the originators hospital. A preoperative non union scoring system was also used to assess its use in predicting persistent non-union. RESULTS: Union was successfully achieved in 36 of the 39 surviving cases (92.3%) after a median delay of 8 months (range 3-47, SD 9.2) Twenty-six patients (65%) achieved union following the decortication procedure without subsequent operations. Factors such as open fracture and smoking did not have a statistically significant effect on union. The mean number of procedures following decortication was 0.68 (range 0-4). Metalwork failure occurred in 11 cases (28%), the majority in femoral decortications (n=9, 82%). The femur was the site of all persistent non unions in the series. Three patients had superficial infections and two had deep infections. The pre-operative non union scoring system (0-100) means were noticeably worse for the persistent non union group 42.0 (20-46) compared with the union group 31.0 (range 4-52). CONCLUSIONS: Osteoperiosteal decortication remains a highly effective surgical technique in the management of failed fracture union. The non union scoring system is a reliable predictor of persistent non union after this type of surgery. CLINICAL RELEVANCE: Relevant to general trauma orthopaedic surgeon and specialist orthopaedic surgeons with an interest in fracture non-union. PMID- 22542169 TI - Variations and asymmetries in regional brain surface in the genus Homo. AB - Paleoneurology is an important field of research within human evolution studies. Variations in size and shape of an endocast help to differentiate among fossil hominin species whereas endocranial asymmetries are related to behavior and cognitive function. Here we analyse variations of the surface of the frontal, parieto-temporal and occipital lobes among different species of Homo, including 39 fossil hominins, ten fossil anatomically modern Homo sapiens and 100 endocasts of extant modern humans. We also test for the possible asymmetries of these features in a large sample of modern humans and observe individual particularities in the fossil specimens. This study contributes important new information about the brain evolution in the genus Homo. Our results show that the general pattern of surface asymmetry for the different regional brain surfaces in fossil species of Homo does not seem to be different from the pattern described in a large sample of anatomically modern H. sapiens, i.e., the right hemisphere has a larger surface than the left, as do the right frontal, the right parieto-temporal and the left occipital lobes compared with the contra-lateral side. It also appears that Asian Homo erectus specimens are discriminated from all other samples of Homo, including African and Georgian specimens that are also sometimes included in that taxon. The Asian fossils show a significantly smaller relative size of the parietal and temporal lobes. Neandertals and anatomically modern H. sapiens, who share the largest endocranial volume of all hominins, show differences when considering the relative contribution of the frontal, parieto temporal and occipital lobes. These results illustrate an original variation in the pattern of brain organization in hominins independent of variations in total size. The globularization of the brain and the enlargement of the parietal lobes could be considered derived features observed uniquely in anatomically modern H. sapiens. PMID- 22542170 TI - Loss of heterozygosity of the Mutated in Colorectal Cancer gene is not associated with promoter methylation in non-small cell lung cancer. AB - 'Mutated in Colorectal Cancer' (MCC) is emerging as a multifunctional protein that affects several cellular processes and pathways. Although the MCC gene is rarely mutated in colorectal cancer, it is frequently silenced through promoter methylation. Previous studies have reported loss of heterozygosity (LOH) of the closely linked MCC and APC loci in both colorectal and lung cancers. APC promoter methylation is a marker of poor survival in non-small cell lung cancer (NSCLC). However, MCC methylation has not been previously studied in lung cancer. Therefore, we wanted to determine if MCC is silenced through promoter methylation in lung cancer and whether this methylation is associated with LOH of the MCC locus or methylation of the APC gene. Three polymorphic markers for the APC/MCC locus were analysed for LOH in 64 NSCLC specimens and matching normal tissues. Promoter methylation of both genes was determined using methylation specific PCR in primary tumours. LOH of the three markers was found in 41-49% of the specimens. LOH within the MCC locus was less common in adenocarcinoma (ADC) (29%) than in squamous cell carcinoma (SCC) (72%; P=0.006) or large cell carcinoma (LCC) (75%; P=0.014). However, this LOH was not accompanied by MCC promoter methylation, which was found in only two cancers (3%). In contrast, 39% of the specimens showed APC methylation, which was more common in ADC (58%) than in SCC (13%). Western blotting revealed that MCC was expressed in a subset of lung tissue specimens but there was marked variation between patients rather than between cancer and matching non-cancer tissue specimens. In conclusion, we have shown that promoter methylation of the APC gene does not extend to the neighbouring MCC gene in lung cancer, but LOH is found at both loci. The variable levels of MCC expression were not associated with promoter methylation and may be regulated through other cellular mechanisms. PMID- 22542171 TI - Use of mutation specific antibodies to detect EGFR status in small biopsy and cytology specimens of lung adenocarcinoma. AB - BACKGROUND: EGFR mutation status is the best predictor of response to tyrosine kinase inhibitors (TKIS) in primary lung adenocarcinoma. Approximately 70% of lung cancers are diagnosed in advanced stages where small biopsies and cytological specimens are the only source of material for both diagnosis and mutation testing. Specific antibodies that can detect mutant EGFR protein were evaluated for the detection of EGFR mutation by immunohistochemistry (IHC) in cytology and small biopsy specimens. METHODS: Assessment of EGFR mutation status was performed by using antibodies specific to the two major forms of mutant EGFR, exon 21 L858R and exon 19 deletion (15bp). The study was performed in 145 lung adenocarcinomas, including cytology material, core biopsy, and decalcified bone biopsy. Stains were scored as negative (0), 1+ (weak and focal), 2+ (moderate intensity and focal), and 3+ (strong and diffuse). The result of the IHC stains was correlated with mutations status determined by standard molecular methods. RESULTS: Validation using clinical material showed deletions in exon 19 were detected in 35% and L858R mutation in 17.6% of all cases by standard molecular methods. A cutoff value of 2+ was used as positive by IHC. No wild type cases were immunoreactive. The positive predictive value (PPV) and specificity for both antibodies was 100%. The antibodies performed well in cytology, core biopsies and decalcified bone biopsies. CONCLUSION: Immunostaining to detect specific mutant EGFR shows a good correlation with mutation analysis and can be used as a screening method to identify patients for TKI therapy. IHC methodology is potentially useful when molecular analysis is not available and for use in small biopsies when material is too scant for molecular tests. Importantly mutation specific antibodies are useful in determining EGFR status in tissues obtained from bone biopsy as decalcification processes used in molecular based studies often result in DNA degradation hindering mutation detection. PMID- 22542172 TI - Angiolymphatic invasion exerts a strong impact on surgical outcomes for stage I lung adenocarcinoma, but not non-adenocarcinoma. AB - Angiolymphatic invasion (ALI), representing lymphatic invasion (Ly) and intratumoral vascular invasion (V), is considered to be a useful prognostic factor for pathological stage I non-small cell lung carcinoma (NSCLC). However, the types of tumor for which prognoses are most influenced by ALI positivity have not previously been discussed, nor has the question of whether these findings should influence postoperative therapeutic decision-making after complete resection. The present study investigated 195 cases of stage I NSCLC treated by potentially curative surgical resection of the primary tumor and systematic lymphadenectomy. ALI-positive (ALI(+)) results were found in 31.8% of tumors, and 5.1% exhibited both Ly(+) and V(+). Five-year recurrence-free survival was significantly lower in ALI(+) cases (50.6%) than in ALI(-) cases (85.9%; p<0.0001, log-rank test). In particular, 5-year recurrence-free survival rate was only 10.0% for Ly(+)V(+) cases. ALI(+) correlated with high age, male sex, tumor size (>2.0 cm), elevated preoperative serum carcinoembryonic antigen level (>=5.0 ng/mL), high maximum standard uptake value (SUVmax) on (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) (>=5.0), pleural invasion, and histological classification of non-adenocarcinoma (ADC). According to histopathological subset analyses, ALI(+) was associated with shorter recurrence free survival than ALI(-) only among ADC patients (p<0.0001, log-rank test), and not among non-ADC patients (p=0.7710). High preoperative serum CEA level, high SUVmax on FDG-PET, pleural invasion, Ly(+), and V(+) were significant risk factors for recurrence in univariate Cox survival analysis among stage I ADC patients. Importantly, Ly(+) and V(+) were identified as independent risk factors for recurrence by multivariate analysis. Histopathological detection of ALI as a risk factor for recurrence should be considered for inclusion in the staging criteria and as additional information for determining postoperative adjuvant treatment of stage I NSCLC, particularly among ADC patients, but not among non ADC patients. PMID- 22542173 TI - Crucial first steps: the transcriptional control of neuron delamination. AB - A crucial event in the birth of a neuron is the detachment of its apical process from the neuroepithelium. In this issue of Neuron, Rousso et al. (2012) show that repression of N-cadherin by Foxp transcription factors disrupts apical adherens junctions and triggers neurogenesis. PMID- 22542174 TI - The CAP-Gly of p150: one domain, two diseases, and a function at the end. AB - In this issue of Neuron, work from Moughamian and Holzbaur (2012) and Lloyd et al. (2012) reveals a role for p150 in initiation of retrograde transport at synaptic terminals. These studies also suggest how mutations of p150's CAP-Gly domain lead to both Perry syndrome and HMN7B disease. PMID- 22542175 TI - Synapses let loose for a change: inhibitory synapse pruning throughout experience dependent cortical plasticity. AB - In this issue of Neuron, Chen et al. (2012) and van Versendaal et al. (2012) used fluorescently tagged gephyrin to track inhibitory synapses in the mouse visual cortex in vivo. Their studies show that visual experience-dependent plasticity is associated with clustered and location-specific pruning of inhibitory synapses. PMID- 22542176 TI - A taste of what to expect: top-down modulation of neural coding in rodent gustatory cortex. AB - A central aspect of sensory perception is the anticipation of forthcoming stimuli, allowing for a faster and more accurate assessment of the surrounding environment. A new study by Samuelsen et al. (2012) in this issue of Neuron highlights the neural mechanisms underlying the expectation of an imminent taste. PMID- 22542177 TI - Neuroscience in the public sphere. AB - The media are increasingly fascinated by neuroscience. Here, we consider how neuroscientific discoveries are thematically represented in the popular press and the implications this has for society. In communicating research, neuroscientists should be sensitive to the social consequences neuroscientific information may have once it enters the public sphere. PMID- 22542179 TI - Timing to perfection: the biology of central and peripheral circadian clocks. AB - The mammalian circadian system, which is comprised of multiple cellular clocks located in the organs and tissues, orchestrates their regulation in a hierarchical manner throughout the 24 hr of the day. At the top of the hierarchy are the suprachiasmatic nuclei, which synchronize subordinate organ and tissue clocks using electrical, endocrine, and metabolic signaling pathways that impact the molecular mechanisms of cellular clocks. The interplay between the central neural and peripheral tissue clocks is not fully understood and remains a major challenge in determining how neurological and metabolic homeostasis is achieved across the sleep-wake cycle. Disturbances in the communication between the plethora of body clocks can desynchronize the circadian system, which is believed to contribute to the development of diseases such as obesity and neuropsychiatric disorders. This review will highlight the relationship between clocks and metabolism, and describe how cues such as light, food, and reward mediate entrainment of the circadian system. PMID- 22542178 TI - On the perception of probable things: neural substrates of associative memory, imagery, and perception. AB - Perception is influenced both by the immediate pattern of sensory inputs and by memories acquired through prior experiences with the world. Throughout much of its illustrious history, however, study of the cellular basis of perception has focused on neuronal structures and events that underlie the detection and discrimination of sensory stimuli. Relatively little attention has been paid to the means by which memories interact with incoming sensory signals. Building upon recent neurophysiological/behavioral studies of the cortical substrates of visual associative memory, I propose a specific functional process by which stored information about the world supplements sensory inputs to yield neuronal signals that can account for visual perceptual experience. This perspective represents a significant shift in the way we think about the cellular bases of perception. PMID- 22542180 TI - Complementary chimeric isoforms reveal Dscam1 binding specificity in vivo. AB - Dscam1 potentially encodes 19,008 ectodomains of a cell recognition molecule of the immunoglobulin (Ig) superfamily through alternative splicing. Each ectodomain, comprising a unique combination of three variable (Ig) domains, exhibits isoform-specific homophilic binding in vitro. Although we have proposed that the ability of Dscam1 isoforms to distinguish between one another is crucial for neural circuit assembly, via a process called self-avoidance, whether recognition specificity is essential in vivo has not been addressed. Here we tackle this issue by assessing the function of Dscam1 isoforms with altered binding specificities. We generated pairs of chimeric isoforms that bind to each other (heterophilic) but not to themselves (homophilic). These isoforms failed to support self-avoidance or did so poorly. By contrast, coexpression of complementary isoforms within the same neuron restored self-avoidance. These data establish that recognition between Dscam1 isoforms on neurites of the same cell provides the molecular basis for self-avoidance. PMID- 22542181 TI - gamma-protocadherins control cortical dendrite arborization by regulating the activity of a FAK/PKC/MARCKS signaling pathway. AB - The 22 gamma-protocadherins (gamma-Pcdhs) potentially specify thousands of distinct homophilic adhesive interactions in the brain. Neonatal lethality of mice lacking the Pcdh-gamma gene cluster has, however, precluded analysis of many brain regions. Here, we use a conditional Pcdh-gamma allele to restrict mutation to the cerebral cortex and find that, in contrast to other central nervous system phenotypes, loss of gamma-Pcdhs in cortical neurons does not affect their survival or result in reduced synaptic density. Instead, mutant cortical neurons exhibit severely reduced dendritic arborization. Mutant cortices have aberrantly high levels of protein kinase C (PKC) activity and of phosphorylated (inactive) myristoylated alanine-rich C-kinase substrate, a PKC target that promotes arborization. Dendrite complexity can be rescued in Pcdh-gamma mutant neurons by inhibiting PKC, its upstream activator phospholipase C, or the gamma-Pcdh binding partner focal adhesion kinase. Our results reveal a distinct role for the gamma Pcdhs in cortical development and identify a signaling pathway through which they play this role. PMID- 22542182 TI - Regulation of presynaptic neurotransmission by macroautophagy. AB - mTOR is a regulator of cell growth and survival, protein synthesis-dependent synaptic plasticity, and autophagic degradation of cellular components. When triggered by mTOR inactivation, macroautophagy degrades long-lived proteins and organelles via sequestration into autophagic vacuoles. mTOR further regulates synaptic plasticity, and neurodegeneration occurs when macroautophagy is deficient. It is nevertheless unknown whether macroautophagy modulates presynaptic function. We find that the mTOR inhibitor rapamycin induces formation of autophagic vacuoles in prejunctional dopaminergic axons with associated decreased axonal profile volumes, synaptic vesicle numbers, and evoked dopamine release. Evoked dopamine secretion was enhanced and recovery was accelerated in transgenic mice in which macroautophagy deficiency was restricted to dopaminergic neurons; rapamycin failed to decrease evoked dopamine release in the striatum of these mice. Macroautophagy that follows mTOR inhibition in presynaptic terminals, therefore, rapidly alters presynaptic structure and neurotransmission. PMID- 22542183 TI - De novo gene disruptions in children on the autistic spectrum. AB - Exome sequencing of 343 families, each with a single child on the autism spectrum and at least one unaffected sibling, reveal de novo small indels and point substitutions, which come mostly from the paternal line in an age-dependent manner. We do not see significantly greater numbers of de novo missense mutations in affected versus unaffected children, but gene-disrupting mutations (nonsense, splice site, and frame shifts) are twice as frequent, 59 to 28. Based on this differential and the number of recurrent and total targets of gene disruption found in our and similar studies, we estimate between 350 and 400 autism susceptibility genes. Many of the disrupted genes in these studies are associated with the fragile X protein, FMRP, reinforcing links between autism and synaptic plasticity. We find FMRP-associated genes are under greater purifying selection than the remainder of genes and suggest they are especially dosage-sensitive targets of cognitive disorders. PMID- 22542184 TI - Mutant PrP suppresses glutamatergic neurotransmission in cerebellar granule neurons by impairing membrane delivery of VGCC alpha(2)delta-1 Subunit. AB - How mutant prion protein (PrP) leads to neurological dysfunction in genetic prion diseases is unknown. Tg(PG14) mice synthesize a misfolded mutant PrP which is partially retained in the neuronal endoplasmic reticulum (ER). As these mice age, they develop ataxia and massive degeneration of cerebellar granule neurons (CGNs). Here, we report that motor behavioral deficits in Tg(PG14) mice emerge before neurodegeneration and are associated with defective glutamate exocytosis from granule neurons due to impaired calcium dynamics. We found that mutant PrP interacts with the voltage-gated calcium channel alpha(2)delta-1 subunit, which promotes the anterograde trafficking of the channel. Owing to ER retention of mutant PrP, alpha(2)delta-1 accumulates intracellularly, impairing delivery of the channel complex to the cell surface. Thus, mutant PrP disrupts cerebellar glutamatergic neurotransmission by reducing the number of functional channels in CGNs. These results link intracellular PrP retention to synaptic dysfunction, indicating new modalities of neurotoxicity and potential therapeutic strategies. PMID- 22542186 TI - Dynactin is required for transport initiation from the distal axon. AB - Dynactin is a required cofactor for the minus-end-directed microtubule motor cytoplasmic dynein. Mutations within the highly conserved CAP-Gly domain of dynactin cause neurodegenerative disease. Here, we show that the CAP-Gly domain is necessary to enrich dynactin at the distal end of primary neurons. While the CAP-Gly domain is not required for sustained transport along the axon, we find that the distal accumulation facilitates the efficient initiation of retrograde vesicular transport from the neurite tip. Neurodegenerative disease mutations in the CAP-Gly domain prevent the distal enrichment of dynactin thereby inhibiting the initiation of retrograde transport. Thus, we propose a model in which distal dynactin is a key mediator in promoting the interaction among the microtubule, dynein motor, and cargo for the efficient initiation of transport. Mutations in the CAP-Gly domain disrupt the formation of the motor-cargo complex, highlighting the specific defects in axonal transport that may lead to neurodegeneration. PMID- 22542185 TI - Foxp-mediated suppression of N-cadherin regulates neuroepithelial character and progenitor maintenance in the CNS. AB - Neuroepithelial attachments at adherens junctions are essential for the self renewal of neural stem and progenitor cells and the polarized organization of the developing central nervous system. The balance between stem cell maintenance and differentiation depends on the precise assembly and disassembly of these adhesive contacts, but the gene regulatory mechanisms orchestrating this process are not known. Here, we demonstrate that two Forkhead transcription factors, Foxp2 and Foxp4, are progressively expressed upon neural differentiation in the spinal cord. Elevated expression of either Foxp represses the expression of a key component of adherens junctions, N-cadherin, and promotes the detachment of differentiating neurons from the neuroepithelium. Conversely, inactivation of Foxp2 and Foxp4 function in both chick and mouse results in a spectrum of neural tube defects associated with neuroepithelial disorganization and enhanced progenitor maintenance. Together, these data reveal a Foxp-based transcriptional mechanism that regulates the integrity and cytoarchitecture of neuroepithelial progenitors. PMID- 22542187 TI - The p150(Glued) CAP-Gly domain regulates initiation of retrograde transport at synaptic termini. AB - p150(Glued) is the major subunit of dynactin, a complex that functions with dynein in minus-end-directed microtubule transport. Mutations within the p150(Glued) CAP-Gly microtubule-binding domain cause neurodegenerative diseases through an unclear mechanism. A p150(Glued) motor neuron degenerative disease associated mutation introduced into the Drosophila Glued locus generates a partial loss-of-function allele (Gl(G38S)) with impaired neurotransmitter release and adult-onset locomotor dysfunction. Disruption of the p150(Glued) CAP-Gly domain in neurons causes a specific disruption of vesicle trafficking at terminal boutons (TBs), the distal-most ends of synapses. Gl(G38S) larvae accumulate endosomes along with dynein and kinesin motor proteins within swollen TBs, and genetic analyses show that kinesin and p150(Glued) function cooperatively at TBs to coordinate transport. Therefore, the p150(Glued) CAP-Gly domain regulates dynein-mediated retrograde transport at synaptic termini, and this function of dynactin is disrupted by a mutation that causes motor neuron disease. PMID- 22542189 TI - Elimination of inhibitory synapses is a major component of adult ocular dominance plasticity. AB - During development, cortical plasticity is associated with the rearrangement of excitatory connections. While these connections become more stable with age, plasticity can still be induced in the adult cortex. Here we provide evidence that structural plasticity of inhibitory synapses onto pyramidal neurons is a major component of plasticity in the adult neocortex. In vivo two-photon imaging was used to monitor the formation and elimination of fluorescently labeled inhibitory structures on pyramidal neurons. We find that ocular dominance plasticity in the adult visual cortex is associated with rapid inhibitory synapse loss, especially of those present on dendritic spines. This occurs not only with monocular deprivation but also with subsequent restoration of binocular vision. We propose that in the adult visual cortex the experience-induced loss of inhibition may effectively strengthen specific visual inputs with limited need for rearranging the excitatory circuitry. PMID- 22542188 TI - Clustered dynamics of inhibitory synapses and dendritic spines in the adult neocortex. AB - A key feature of the mammalian brain is its capacity to adapt in response to experience, in part by remodeling of synaptic connections between neurons. Excitatory synapse rearrangements have been monitored in vivo by observation of dendritic spine dynamics, but lack of a vital marker for inhibitory synapses has precluded their observation. Here, we simultaneously monitor in vivo inhibitory synapse and dendritic spine dynamics across the entire dendritic arbor of pyramidal neurons in the adult mammalian cortex using large-volume, high resolution dual-color two-photon microscopy. We find that inhibitory synapses on dendritic shafts and spines differ in their distribution across the arbor and in their remodeling kinetics during normal and altered sensory experience. Further, we find inhibitory synapse and dendritic spine remodeling to be spatially clustered and that clustering is influenced by sensory input. Our findings provide in vivo evidence for local coordination of inhibitory and excitatory synaptic rearrangements. PMID- 22542190 TI - GABAergic inhibition regulates developmental synapse elimination in the cerebellum. AB - Functional neural circuit formation during development involves massive elimination of redundant synapses. In the cerebellum, one-to-one connection from excitatory climbing fiber (CF) to Purkinje cell (PC) is established by elimination of early-formed surplus CFs. This process depends on glutamatergic excitatory inputs, but contribution of GABAergic transmission remains unclear. Here, we demonstrate impaired CF synapse elimination in mouse models with diminished GABAergic transmission by mutation of a single allele for the GABA synthesizing enzyme GAD67, by conditional deletion of GAD67 from PCs and GABAergic interneurons or by pharmacological inhibition of cerebellar GAD activity. The impaired CF synapse elimination was rescued by enhancing GABA(A) receptor sensitivity in the cerebellum by locally applied diazepam. Our electrophysiological and Ca2+ imaging data suggest that GABA(A) receptor-mediated inhibition onto the PC soma from molecular layer interneurons influences CF induced Ca2+ transients in the soma and regulates CF synapse elimination from postnatal day 10 (P10) to around P16. PMID- 22542191 TI - Distinct cortical circuit mechanisms for complex forelimb movement and motor map topography. AB - Cortical motor maps are the basis of voluntary movement, but they have proven difficult to understand in the context of their underlying neuronal circuits. We applied light-based motor mapping of Channelrhodopsin-2 mice to reveal a functional subdivision of the forelimb motor cortex based on the direction of movement evoked by brief (10 ms) pulses. Prolonged trains of electrical or optogenetic stimulation (100-500 ms) targeted to anterior or posterior subregions of motor cortex evoked reproducible complex movements of the forelimb to distinct positions in space. Blocking excitatory cortical synaptic transmission did not abolish basic motor map topography, but the site-specific expression of complex movements was lost. Our data suggest that the topography of movement maps arises from their segregated output projections, whereas complex movements evoked by prolonged stimulation require intracortical synaptic transmission. PMID- 22542193 TI - Finger-loop inhibitors of the HCV NS5b polymerase. Part 1: Discovery and optimization of novel 1,6- and 2,6-macrocyclic indole series. AB - Novel conformationaly constrained 1,6- and 2,6-macrocyclic HCV NS5b polymerase inhibitors, in which either the nitrogen or the phenyl ring in the C2 position of the central indole core is tethered to an acylsulfamide acid bioisostere, have been designed and tested for their anti-HCV potency. This transformational route toward non-zwitterionic finger loop-directed inhibitors led to the discovery of derivatives with improved cell potency and pharmacokinetic profile. PMID- 22542195 TI - Cerebro-cerebellar functional connectivity profile of an epilepsy patient with periventricular nodular heterotopia. AB - Periventricular nodular heterotopia (PNH) is a rare malformation of cortical development often associated with drug resistant focal onset epilepsy. The link between nodules and neocortex have been demonstrated with depth electrodes investigations showing that seizures may arise from both structures. In the last years fMRI resting-state (fMRI-RS) have received a surge in interest due to its capability to track non-invasively physiological and pathological relevant differences in brain network organization. We performed a cerebro-cerebellar voxel-wise and region-of-interest resting state fMRI (RS-fMRI) functional connectivity analysis in a seizure-free epilepsy patient with a PNH in the right temporal horn. Our finding confirms a spontaneous synchronization between PNH and its surrounding cortex, specifically in the inferior temporal, fusiform and occipital gyrus. We also found a significant connectivity with bilateral cerebellum, more intense and widespread on the PNH cerebellar contralateral lobule. RS-fMRI confirmed its potential as a promising tool for non-invasive mapping of cortical and subcortical brain functional organization. PMID- 22542194 TI - Discovery of a series of 2-(1H-pyrazol-1-yl)pyridines as ALK5 inhibitors with potential utility in the prevention of dermal scarring. AB - A series of 2-(1H-pyrazol-1-yl)pyridines are described as inhibitors of ALK5 (TGFbeta receptor I kinase). Modeling compounds in the ALK5 kinase domain enabled some optimization of potency via substitutions on the pyrazole core. One of these compounds PF-03671148 gave a dose dependent reduction in TGFbeta induced fibrotic gene expression in human fibroblasts. A similar reduction in fibrotic gene expression was observed when PF-03671148 was applied topically in a rat wound repair model. Thus these compounds have potential utility for the prevention of dermal scarring. PMID- 22542192 TI - Effects of cue-triggered expectation on cortical processing of taste. AB - Animals are not passive spectators of the sensory world in which they live. In natural conditions they often sense objects on the bases of expectations initiated by predictive cues. Expectation profoundly modulates neural activity by altering the background state of cortical networks and modulating sensory processing. The link between these two effects is not known. Here, we studied how cue-triggered expectation of stimulus availability influences processing of sensory stimuli in the gustatory cortex (GC). We found that expected tastants were coded more rapidly than unexpected stimuli. The faster onset of sensory coding related to anticipatory priming of GC by associative auditory cues. Simultaneous recordings and pharmacological manipulations of GC and basolateral amygdala revealed the role of top-down inputs in mediating the effects of anticipatory cues. Altogether, these data provide a model for how cue-triggered expectation changes the state of sensory cortices to achieve rapid processing of natural stimuli. PMID- 22542196 TI - Serum magnesium and sudden unexpected death in epilepsy: a curious clinical sign or a necessity of life. PMID- 22542197 TI - Epilepsy surgery can help many more adult patients with intractable seizures. AB - PURPOSE: To quantify underreferral for epilepsy surgery in The Netherlands, and reveal its causes. METHODS: Cross-sectional sample of medical files of epilepsy patients from eight general hospitals and two tertiary care epilepsy centers. We selected patients, not seizure free despite 3 or more anti-epileptic drugs. Medical records were judged by an expert panel whether referral should have been done according to published Dutch guidelines. The treating neurologists were confronted with the panel's judgement. KEY FINDINGS: In a sample of 1424 patients, 69 had been referred; another 265 were intractable and not referred; 139 of these 265 patients should have been according to the panel. In 89 of 139 patients, the neurologist gave additional arguments for not referring, mainly the physician's estimate of (low) seizure burden or the patient's psychological condition. In 66 of 89 cases, this could not convince the panel. Attitudes were similar in secondary and tertiary treatment centers. Multivariable data analysis showed independent predictors of incorrectly, versus correctly, not referred patients. SIGNIFICANCE: Substantial underreferral exists in The Netherlands, withholding refractory patients seizure freedom. Adherence to existing guidelines, better prioritizing of surgical work-up, and unprejudiced discussion of surgical treatment with the patient, could lead to 2-2.5 times more referrals. PMID- 22542198 TI - Investigation of prevalence, clinical characteristics and management of epilepsy in Yueyang city of China by a door-to-door survey. AB - BACKGROUND: The aim of this study was to establish the prevalence rate, types and causes of epilepsy, and information on treatment gap of epilepsy in Yueyang city, and to evaluate the diagnosis and treatment status of these patients. METHODS: A door-to-door epidemiological survey on epilepsy was conducted by random cluster sampling among the urban and rural populations of Yueyang city, Hunan province, China. The screening questionnaire for epilepsy used in this study was adapted from the WHO and ICBERG standard screening questionnaires. All peoples diagnosed with epilepsy or suspected to be epileptic during screening were rechecked by neurologists. Clinical and treatment data were collected from patients with definitive diagnosis. RESULTS: A total of 32059 peoples were screened. 143 peoples were diagnosed with epilepsy. Lifetime prevalence rate was 4.50/00 and 1 year active prevalence rate was 2.80/00. Prevalence rates were higher in male and rural areas. Secondary generalized tonic-clonic seizure prevailed over other seizure types in frequency. 93.4% of the patients with active epilepsy had treatment gaps without receiving standard and regular antiepileptic drugs before the survey. CONCLUSIONS: The prevalence rate of epilepsy in Yueyang is lower than in other areas of China and Asia. The large amount of patients with treatment gaps indicates an urgent need for a rational intervention strategy. PMID- 22542199 TI - Changes in weight and co-morbidities among adolescents undergoing bariatric surgery: 1-year results from the Bariatric Outcomes Longitudinal Database. AB - BACKGROUND: Bariatric surgery is 1 of the few effective treatments of morbid obesity. However, the weight loss and other health-related outcomes for this procedure in large, diverse adolescent patient populations have not been well characterized. Our objective was to analyze the prospective Bariatric Outcomes Longitudinal Database (BOLD) to determine the weight loss and health related outcomes in adolescents. The BOLD data are collected from 423 surgeons at 360 facilities in the United States. METHODS: The main outcome measures included the anthropometric and co-morbidity status at baseline (n = 890) and at 3 (n = 786), 6 (n = 541), and 12 (n = 259) months after surgery. Adolescents (75% female; 68% non-Hispanic white, 14% Hispanic, 11% non-Hispanic black, and 6% other) aged 11 to 19 years were included in the present analyses. RESULTS: The overall 1-year mean weight loss for those who underwent gastric bypass surgery was more than twice that of those who underwent adjustable gastric band surgery (48.6 versus 20 kg, P < .001). Similar results were found for all other anthropometric changes and comparisons within 1 year between surgery types (P < .001). In general, the gastric bypass patients reported more improvement than the adjustable gastric band patients in co-morbidities at 1 year after surgery. A total of 45 readmissions occurred among gastric bypass patients and 10 among adjustable gastric band patients, with 29 and 8 reoperations required, respectively. CONCLUSIONS: The weight loss at 3, 6, and 12 months after surgery is approximately double in adolescent males and females who underwent gastric bypass surgery versus those who underwent adjustable gastric band surgery. Bariatric surgery can safely and substantially reduce weight and related co-morbidities in morbidly obese adolescents for >=1 year. PMID- 22542200 TI - Identification of noncalcified plaque in young persons with diabetes: an opportunity for early primary prevention of coronary artery disease identified with low-dose coronary computed tomographic angiography. AB - PURPOSE: Coronary computed tomographic angiography (CTA) is a valuable tool for assessing coronary artery disease (CAD). Although statin use is widely recommended for persons with diabetes older than age 40, little is known about the presence and severity of CAD in younger patients with diabetes mellitus (DM). We evaluated coronary artery calcium (CAC) and coronary CTA in young persons with both DM1 and DM2 in an attempt to detect the earliest objective evidence of arteriosclerosis eligible for primary prevention. METHODS AND MATERIALS: We prospectively enrolled 40 persons with DM (25 type 1 and 15 type 2) between the ages of 19 and 35 presenting with diabetes for 5 years or longer. All patients underwent coronary CTA and CAC scans to evaluate for early atherosclerotic disease. Each plaque in the coronary artery was classified as noncalcified or calcified-mixed. We also evaluated all segments with stenosis, dividing them into mild (<50%), moderate (50-70%), and severe (>70%). RESULTS: The average age of the DM1 subjects were 26 +/- 4 (SD) years and 30 +/- 4 years for DM2 patients (P < .01), with duration of diabetes of 8 +/- 5 years and average HbA1c% of 8.7 +/- 1.6 (norm = 4.6-6.2). Abnormal scans were present in 57.5%, noncalcified in 35% and calcified-mixed plaque in 22.5%. Persons with DM2 had a higher prevalence of positive coronary CTA scans than DM1: 80% versus 44% (P < .03) and more positive CAC scores 53% versus 4%, (P < .01). The total segment score of 2.1 +/- 3.4 (P < .01) and total plaque score 1.9 +/- 2.8 (P < .01) were highly correlated to each other. Plaque was almost uniformly absent below age 25, and became increasingly common in individuals over the age of 25 years for both groups. The average radiation exposure was 2.5 +/- 1.3 mSv. CONCLUSION: Our study verifies that early CAD can be diagnosed with coronary CTA and minimal radiation exposure in young adults with DM. A negative CAC score was not sufficient to exclude early CAD as we observed a preponderance of noncalcified plaque in this cohort. Coronary CTA in young DM patients older than age 25 may provide earlier identification of disease than does a CAC because only noncalcified plaque is frequently present. Coronary CTA provides an opportunity to consider initiation of earlier primary CAD prevention rather than waiting for the age of 40 as currently recommended by the American Diabetes Association guidelines. PMID- 22542201 TI - Perfluoroalkyl chemicals in vacuum cleaner dust from 39 Wisconsin homes. AB - Perfluoroalkyl chemicals (PFCs) have been used as surfactants and stain repellants in a variety of consumer products for more than 50years and there is growing concern regarding their persistence and toxicity. Human exposure to these chemicals is essentially universal in North America and researchers have linked them to a variety of health problems ranging from higher rates of cancer, to developmental and reproductive problems, and higher cholesterol levels. Major exposure pathways are food and water ingestion, dust ingestion via hand to mouth transfer. In an effort to assess residential exposure, the Wisconsin Department of Health Services tested vacuum cleaner contents from thirty-nine homes for 16 perflouroalkyl chemicals. PFOS, PFOA, PFHxS, PFHpA and PFNA were found in all of the vacuum dust samples and dust from eight homes contained all 16 PFCs included in our analysis. The most commonly detected compounds were perfluorooctanesulfonate (PFOS), perfluorohexanesulfonate (PFHxS) and perfluorooctanoic acid (PFOA) which together made up 70% of the total PFC residues in dust from these homes. Summed PFC concentrations in these dust samples ranged from 70 to 2513ng/g (median 280ng/g). Our investigation suggests that these chemicals may be ubiquitous contaminants in US homes. PMID- 22542202 TI - Immunotoxicity in ascidians: antifouling compounds alternative to organotins: III -the case of copper(I) and Irgarol 1051. AB - After the widespread ban of TBT, due to its severe impact on coastal biocoenoses, mainly related to its immunosuppressive effects on both invertebrates and vertebrates, alternative biocides such as Cu(I) salts and the triazine Irgarol 1051, the latter previously used in agriculture as a herbicide, have been massively introduced in combined formulations for antifouling paints against a wide spectrum of fouling organisms. Using short-term (60 min) haemocyte cultures of the colonial ascidian Botryllus schlosseri exposed to various sublethal concentrations of copper(I) chloride (LC(50)=281 MUM, i.e., 17.8 mg Cu L(-1)) and Irgarol 1051 (LC(50)>500 MUM, i.e., >127 mg L(-1)), we evaluated their immunotoxic effects through a series of cytochemical assays previously used for organotin compounds. Both compounds can induce dose-dependent immunosuppression, acting on different cellular targets and altering many activities of immunocytes but, unlike TBT, did not have significant effects on cell morphology. Generally, Cu(I) appeared to be more toxic than Irgarol 1051: it significantly (p<0.05) inhibited yeast phagocytosis at 0.1 MUM (~10 MUg L(-1)), and affected calcium homeostasis and mitochondrial cytochrome-c oxidase activity at 0.01 MUM (~1 MUg L(-1)). Both substances were able to change membrane permeability, induce apoptosis from concentrations of 0.1 MUM (~10 MUg L(-1)) and 200 MUM (~50 mg L( 1)) for Cu(I) and Irgarol 1051, respectively, and alter the activity of hydrolases. Both Cu(I) and Irgarol 1051 inhibited the activity of phenoloxidase, but did not show any interactive effect when co-present in the exposure medium, suggesting different mechanisms of action. PMID- 22542203 TI - Development of the automated cleanup system for the analysis of PCDDs, PCDFs and DL-PCBs. AB - A new automated cleanup system for the analysis of dioxins (PCDDs, PCDFs and DL PCBs) has been developed. It was controlled by PLC through the touch-panel. This automated cleanup system can simultaneously treat six samples in 2h, using only about 30 mL of solvent. In this study, the recovery rates of the internal standard added as cleanup spiked were between 70% and 120% in the fly ash sample. The RSDs (relative standard deviations) were below 15%. The shortest analysis time from cleanup to calculation of concentration was approximately 6h. Moreover, this automated cleanup system eliminates personal error in sample preparation and training time for the analyst, and improves the accuracy of the experiment. Additionally, this automated cleanup system allowed rapid analysis and less consumption of organic solvent. PMID- 22542204 TI - Age does not impact risk for urethroplasty complications after tubularized incised plate repair of hypospadias in prepubertal boys. AB - OBJECTIVE: Patients often present before or after the recommended age of 6-18 months for hypospadias repair. Reports indicate complications may increase when repair is delayed past 6-12 months of age. We questioned if age was an independent risk for urethroplasty complications (UC). METHODS: A prospectively maintained database of consecutive patients undergoing tubularized incised plate (TIP) repair was queried for age at surgery, primary or reoperative TIP, meatal location, glansplasty suture, and learning curve. The presence of UC (fistula, dehiscence, stricture, meatal stenosis) was analyzed with logistic regression. RESULTS: TIP repairs were performed for 669 consecutive prepubertal patients aged 3-144 months (mean 17.1, SD 22.5). Original meatal location was distal in 540 (80.7%), midshaft in 50 (7.5%), and proximal in 79 (11.8%). Reoperative TIP occurred in 73 (10.9%). UC occurred in 77 (11.5%). Reoperative TIP (OR 3.07, 95% CI 1.54-6.13) and meatal location (OR 1.79, 95% CI 1.34-2.40) were the only independent risk factors for UC. Neither younger nor older age increased risk for UC. CONCLUSIONS: Our data from consecutive TIP repairs in prepubertal children indicate age at surgery does not increase odds of UC. Surgery can be performed any time after 3 months (in full-term, healthy boys) without raising the rate of UC. PMID- 22542205 TI - Influence of discontinuing feeding degradable cosubstrate on the performance of a fluidized bed bioreactor treating a mixture of trichlorophenol and phenol. AB - The purpose of our research was to evaluate the effect of eliminating supplementation of sucrose to the reactor influent on the performance of a lab scale partially-aerated methanogenic fluidized bed bioreactor (PAM-FBBR). Two operational stages were distinguished: in the first stage the influent contained a mixture of 120/30/1000 mg/L of 2,4,6-trichlorophenol/phenol/COD-sucrose (TCP/Phe/COD-sucrose); in the second stage only the xenobiotic concentrations were the same 120/30 mg/L of TCP/Phe whereas sucrose addition was discontinued. Removal efficiencies of TCP, Phe, and COD were very high and close for both stages; i.e., eta(TCP): 99.9 and 99.9%; eta(Phe): 99.9 and 99.9%; eta(COD) = 96.46 and 97.48% for stage 1 and stage 2, respectively. Traces of 2,4,6 dichlorophenol (0.05 mg/L) and 4-chlorophenol (0.07-0.26 mg/L) were found during the first 15 days of operation of the second stage, probably due to the adaptation to no co-substrate conditions. Net increase of chloride anion Cl(-) in effluent ranged between 59.5 and 61.5 mg Cl(-)/L that was very close to the maximum theoretical concentration of 62.8 mg Cl(-)/L. PCR-DGGE analysis revealed a richness decrease of eubacterial domain posterior to sucrose elimination from the influent whereas archaeal richness remained almost the same. However, the bioreactor performance was not negatively affected by discontinuing the addition of co-substrate sucrose. Our results indicate that the application of PAM-FBBR to the treatment of groundwaters polluted with chlorophenols and characterized by the lack of easily degradable co-substrates, is a promising alternative for on site bioremediation. PMID- 22542206 TI - Axonotmesis of the sciatic nerve. PMID- 22542207 TI - Benefit of the Vittel criteria to determine the need for whole body scanning in a severe trauma patient. AB - OBJECTIVE: To evaluate the use of the Vittel criteria in addition to a clinical examination to determine the need for a whole body scan (WBS) in a severe trauma patient. MATERIALS AND METHODS: Between December 2008 and November 2009, 339 severe trauma patients with at least one Vittel criterion were prospectively evaluated with a WBS. The following data were collected: the Vittel criteria present, circumstances of the accident, traumatic injury on the WBS, and irradiation. The original intent to prescribe a computed tomography (CT) scan (whole body or a targeted region), based solely on clinical signs, was specified. RESULTS: Injuries were diagnosed in 55.75% of the WBS (n=189). The most common Vittel criteria were "global assessment" (n=266), "thrown, run over" (n=116), and "ejected from vehicle" (n=94). The multivariate analysis used the following as independent criteria for predicting severe traumatic injury on the WBS: Glasgow score less than 13, penetrating trauma, and colloid resuscitation greater than 11. Based solely on clinical factors, 164 patients would not have had any scan or (only) a targeted scan. In that case, 15% of the severe injuries would have been missed. CONCLUSION: Using the Vittel criteria to determine the need for a WBS in a severe trauma patient makes it possible to find serious injuries not suspected on the clinical examination, but at the cost of an increased number of normal scans. PMID- 22542208 TI - Cirrhotic and malignant ascites: differential CT diagnosis. AB - OBJECTIVES: To assess the diagnostic accuracy of the different computed tomography (CT) signs for differentiating between malignant and cirrhotic ascites. MATERIALS AND METHODS: We performed a retrospective study of 102 CT scans in adults, distributed into two groups based on the cirrhotic or malignant etiology of their ascites. The CT signs studied were ascites volume and relative distribution between the greater peritoneal cavity (GPC) and the omental bursa (OB), the density of the ascites, the thickness of the gallbladder wall, the thickness of the parietal peritoneum and its degree of enhancement, and tethered bowel sign. RESULTS: The CT signs associated with malignant ascites were: presence of fluid in the omental bursa (P=0.003), thickening of the peritoneum its degree of enhancement (P=0.005), increased density of the ascites (P=0.01), and loss of mobility of bowel loops in the ascites (P=0.001). There was no difference in gallbladder wall thickness between the two groups. CONCLUSION: The CT scan can play a role in diagnosing malignant ascites. We confirm the usefulness of the indirect signs composed of distribution of ascites fluid, thickening and enhancement of the parietal peritoneum, and loss of mobility of the bowel loops in the ascites. PMID- 22542209 TI - The contribution of MRI to the diagnosis of traumatic tears of the anterior cruciate ligament. AB - When faced with a clinical suspicion of knee ligament injury, MRI nowadays has a central role in the diagnostic strategy. In particular, it is essential for assessing the cruciate ligaments and any associated meniscal tears. The objective of this review is to present the various direct and indirect MRI signs of tearing of the anterior cruciate ligament (ACL) and then describe the lesions associated with it. The anatomical and clinical aspects are also discussed so that the contribution of MRI to the diagnosis and therapeutic management of an ACL tear can be better understood. PMID- 22542210 TI - Focal dependent pleural thickening at MDCT: pleural lesion or functional abnormality? AB - PURPOSE: To describe the characteristics of reversible focal pleural thickenings (PTs) mimicking real plaques, that firstly suggest asbestos exposure or pleural metastasis; to propose an imaging strategy and propose an explanation for their mechanism of formation. PATIENTS AND METHODS: Retrospective review of data from 19 patients with PTs fitting the description of pleural plaques at chest computed tomography (CT) and presenting modifications (clearance or appearance) of at least one PT at an additional chest examination in prone position. RESULTS: A total of 152 PTs were recorded on the first chest CT examinations with a range of two to 19 pleural opacities per patient. All PTs had a posterior distribution in the lower lobes. On the additional acquisitions, 144 PTs disappeared. Seventeen patients presented complete regression of PTs and two patients presented persistence of eight PTs. CONCLUSION: Additional low dose acquisition in prone position should be performed in all patients presenting with focal PT in a dependent and basal location. This may allow to exclude a pleural plaque in case of asbestos exposure but also a pleural metastasis in oncologic patients. These reversible dependent PTs could be related to physiological focal accumulation of lymphatic fluid in subpleural area. PMID- 22542211 TI - Functional morphology and anatomy of cervical vertebrae in Nacholapithecus kerioi, a middle Miocene hominoid from Kenya. AB - This paper describes the morphology of cervical vertebrae in Nacholapithecus kerioi, a middle Miocene primate species excavated from Nachola, Kenya in 1999 2002. The cervical vertebrae in Nacholapithecus are larger than those of Papio cynocephalus. They are more robust relative to more caudal vertebral bones. Since Nacholapithecus had large forelimbs, it is assumed that strong cervical vertebrae would have been required to resist muscle reaction forces during locomotion. On the other hand, the vertebral foramen of the lower cervical vertebrae in Nacholapithecus is almost the same size as or smaller than that of P. cynocephalus. Atlas specimens of Nacholapithecus resemble those of extant great apes with regard to the superior articular facet, and they have an anterior tubercle trait intermediate between that of extant apes and other primate species. Nacholapithecus has a relatively short and thick dens on the axis, similar to those of extant great apes and the axis body shape is intermediate between that of extant apes and other primates. Moreover, an intermediate trait between extant great apes and other primate species has been indicated with regard to the angle between the prezygapophyseal articular facets of the axis in Nacholapithecus. Although the atlas of Nacholapithecus is inferred as having a primitive morphology (i.e., possessing a lateral bridge), the shape of the atlas and axis leads to speculation that locomotion or posture in Nacholapithecus involved more orthograde behavior similar to that of extant apes, and, in so far as cervical vertebral morphology is concerned, it is thought that Nacholapithecus was incipiently specialized toward the characteristics of extant hominoids. PMID- 22542212 TI - Influence of the distal femoral resection angle on the principal stresses in ceramic total knee components. AB - PURPOSE: A certain failure mode using a newly developed cemented ceramic femoral component in total knee replacement was observed in clinical application, i.e. fracture of the femoral component during intraoperative impaction. This may be caused by unintentional deflection of the saw blades during cutting with consecutive higher resection angle of the distal femur than desired, leading to bending of the femoral component during implantation. A finite-element-analysis was carried out to simulate implantation of the femoral component and to evaluate the influence of distal femur preparation on implant stress. SCOPE: We developed and validated a numerical model of the ceramic femoral component including a contact formulation which allowed calculating the principal stresses of the implant during implantation onto the resected femur. The analysis considered different anterior and posterior resection angles with a total of 17 variations. By increasing the femoral resection angle in the finite-element-model it could be shown that a deviation of three degrees from the intended resection angle can cause critical stress amounts during implantation. CONCLUSIONS: When implanting the ceramic component in total knee arthroplasty, the femoral resection angles should be prepared very precisely, in particular anterior saw blade deflection has to be avoided. The implant manufacturer increased implant safety through an additional resection template. Moreover, the impaction of the ceramic femoral component during cementing was not further recommended by using a hammer. PMID- 22542213 TI - Outcome of obstetric fistula repair after 10-day versus 14-day Foley catheterization. AB - OBJECTIVE: To compare outcome between 10-day and 14-day bladder drainage after obstetric fistula repair. METHODS: In a randomized prospective study at Hamlin Fistula Center, Bahir Dar, Ethiopia, patients presenting with obstetric vesicovaginal fistula between 2007 and 2010 were randomized to undergo 10-day (group 1) or 14-day (group 2) postoperative catheterization. Fistulas were categorized via Goh classification. The inclusion criteria were any type of vesicovaginal fistula except circumferential or recurrent. RESULTS: In total, 189 women were enrolled: 107 in group 1, and 82 in group 2. The groups were similar in age, parity, duration of labor, and time from injury to surgical repair. There was no significant difference in fistula stage according to the Goh classification (urethral length, P=0.3; fistula size, P=0.9; and vaginal scarring, P=0.3). There were 3 fistula breakdowns in group 1, and 6 in group 2. The difference in cure was not significant (P=0.15, confidence interval -0.009 to 0.1). There was no significant difference in non-fistula-related incontinence or urinary retention after repair. CONCLUSION: The outcome of postoperative catheterization for 10 days was not inferior to that for 14 days. A similar treatment outcome with a shorter duration of catheterization will have a significant impact on reducing infection and cost. PMID- 22542214 TI - Women's experience of menopause in rural communities in Orlu, Eastern Nigeria. AB - OBJECTIVE: To document women's experience of menopause in rural communities in Orlu, Eastern Nigeria, and to compare this with urban centers in Nigeria and worldwide. METHODS: A total of 349 women who had not menstruated for at least 12 months were included in a questionnaire-based study. The questionnaire included questions on sociodemographic characteristics, age at menarche and menopause, attitude to menopause, and knowledge and use of hormone replacement therapy. Questionnaires were administered in 13 communities by medical students during the Annual Convention of Christian Women in August 2009. RESULTS: The mean age at menopause of the women was 47 +/- 4.2 years. Menopausal symptoms were prevalent, and bone and joint pain were the most prevalent symptoms. Knowledge and use of hormone replacement therapy were poor. Most of the women considered the menopause to be beneficial. CONCLUSION: Age at menopause and associated postmenopausal symptoms were similar to those seen in urban centers in Nigeria, but age at menopause was lower than in studies of white women. Despite the apparent positive attitude of Nigerian women to menopause, a program of information and education, and use of hormone replacement therapy will improve quality of life for women in Eastern Nigeria. PMID- 22542215 TI - Training Zambian traditional birth attendants to reduce neonatal mortality in the Lufwanyama Neonatal Survival Project (LUNESP). AB - OBJECTIVE: To provide relevant details on how interventions in the Lufwanyama Neonatal Survival Project (LUNESP) were developed and how Zambian traditional birth attendants (TBAs) were trained to perform them. METHODS: The study tested 2 interventions: a simplified version of the American Academy of Pediatrics' neonatal resuscitation protocol (NRP); and antibiotics with facilitated referral (AFR). RESULTS: Key elements that enabled the positive study result were: focusing on common and correctible causes of mortality; selecting a study population with high unmet public health need; early community mobilization to build awareness and support; emphasizing simplicity in the intervention technology and algorithms; using a traditional training approach appropriate to students with low literacy rates; requiring TBAs to demonstrate their competence before completing each workshop; and minimizing attrition of skills by retraining and reassessing the TBAs regularly throughout the study. CONCLUSION: An effective NRP training model was created that is suitable for community-based neonatal interventions, in research or programmatic settings, and by practitioners with limited obstetric skills and low rates of literacy. Clinicaltrials.gov NCT00518856. PMID- 22542216 TI - The mucosal immune system of the respiratory tract. AB - Most viruses use host mucosal surfaces as their initial portals of infection. The respiratory tract has the body's second-largest mucosal surface area after the digestive tract. An understanding of the unique nature of the mucosal immune system of respiratory organs is therefore extremely important for the development of new-generation vaccines and novel methods of preventing and treating respiratory infectious diseases, including viral infections. PMID- 22542218 TI - A direct comparison of spine rotational stiffness and dynamic spine stability during repetitive lifting tasks. AB - Stability of the spinal column is critical to bear loads, allow movement, and at the same time avoid injury and pain. However, there has been a debate in recent years as to how best to define and quantify spine stability, with the outcome being that different methods are used without a clear understanding of how they relate to one another. Therefore, the goal of the present study was to directly compare lumbar spine rotational stiffness, calculated with an EMG-driven biomechanical model, to local dynamic spine stability calculated using Lyapunov analyses of kinematic data, during a series of continuous dynamic lifting challenges. Twelve healthy male subjects performed 30 repetitive lifts under three varying load and three varying rate conditions. With an increase in the load lifted (constant rate) there was a significant increase in mean, maximum, and minimum spine rotational stiffness (p<0.001) and a significant increase in local dynamic stability (p<0.05); both stability measures were moderately to strongly related to one another (r=-0.55 to -0.71). With an increase in lifting rate (constant load), there was also a significant increase in mean and maximum spine rotational stiffness (p<0.01); however, there was a non-significant decrease in the minimum rotational stiffness and a non-significant decrease in local dynamic stability (p>0.05). Weak linear relationships were found for the varying rate conditions (r=-0.02 to -0.27). The results suggest that spine rotational stiffness and local dynamic stability are closely related to one another, as they provided similar information when movement rate was controlled. However, based on the results from the changing lifting rate conditions, it is evident that both models provide unique information and that future research is required to completely understand the relationship between the two models. Using both techniques concurrently may provide the best information regarding the true effects of (in) stability under different loading and movement scenarios, and in comparing healthy and clinical populations. PMID- 22542217 TI - Ten-year stability of remission in private alcohol and drug outpatient treatment: non-problem users versus abstainers. AB - BACKGROUND: This study examined stability of remission in patients who were abstainers and non-problem users at 1-year after entering private, outpatient alcohol and drug treatment. We examined: (a) How does risk of relapse change over time? (b) What was the risk of relapse for non-problem users versus abstainers? (c) What individual, treatment, and extra-treatment characteristics predicted time to relapse, and did these differ by non-problem use versus abstinence? METHODS: The sample consisted of 684 adults in remission (i.e., abstainers or non problem users) 1 year following treatment intake. Participants were interviewed at intake, and 1, 5, 7, 9, and 11 years after intake. We used discrete-time survival analysis to examine when relapse is most likely to occur and predictors of relapse. RESULTS: Relapse was most likely at 5-year, and least likely at 11 year follow-up. Non-problem users had twice the odds of relapse compared to abstainers. Younger individuals and those with fewer 12-step meetings and shorter index treatment had higher odds of relapse than others. We found no significant interactions between non-problem use and the other covariates suggesting that significant predictors of outcome did not differ for non-problem users. CONCLUSIONS: Non-problem use is not an optimal 1-year outcome for those in an abstinence-oriented, heterogeneous substance use treatment program. Future research should examine whether these results are found in harm reduction treatment and self-help models, or in those with less severe problems. Results suggest treatment retention and 12-step participation are prognostic markers of long-term positive outcomes for those achieving remission at 1 year. PMID- 22542219 TI - Residual force enhancement following eccentric induced muscle damage. AB - During lengthening of an activated skeletal muscle, the force maintained following the stretch is greater than the isometric force at the same muscle length. This is termed residual force enhancement (RFE), but it is unknown how muscle damage following repeated eccentric contractions affects RFE. Using the dorsiflexors, we hypothesised muscle damage will impair the force generating sarcomeric structures leading to a reduction in RFE. Following reference maximal voluntary isometric contractions (MVC) in 8 young men (26.5+/-2.8y) a stretch was performed at 30 degrees /s over a 30 degrees ankle excursion ending at the same muscle length as the reference MVCs (30 degrees plantar flexion). Surface electromyography (EMG) of the tibialis anterior and soleus muscles was recorded during all tasks. The damage protocol involved 4 sets of 25 isokinetic (30 degrees /s) lengthening contractions. The same measures were collected at baseline and immediately post lengthening contractions, and for up to 10min recovery. Following the lengthening contraction task, there was a 30.3+/-6.4% decrease in eccentric torque (P<0.05) and 36.2+/-9.7% decrease in MVC (P<0.05) compared to baseline. Voluntary activation using twitch interpolation and RMS EMG amplitude of the tibialis anterior remained near maximal without increased coactivation for MVC. Contrary to our hypothesis, RFE increased (~100-250%) following muscle damage (P<0.05). It appears stretch provided a mechanical strategy for enhanced muscle function compared to isometric actions succeeding damage. Thus, active force of cross-bridges is decreased because of impaired excitation-contraction coupling but force generated during stretch remains intact because force contribution from stretched sarcomeric structures is less impaired. PMID- 22542221 TI - Dynamic material properties of the pregnant human uterus. AB - Given that automobile crashes are the largest single cause of death for pregnant females, scientists are developing advanced computer models of pregnant occupants. The purpose of this study is to quantify the dynamic material properties of the human uterus in order to increase the biofidelity of these models. A total of 19 dynamic tension tests were performed on pregnant human uterus tissues taken from six separate donors. The tissues were collected during full term Cesarean style deliveries and tested within 36 h of surgery. The tissues were processed into uniform coupon sections and tested at 1.5 strains/s using linear motors. Local stress and strain were determined from load data and optical markers using high speed video. The experiments resulted in a non-linear stress versus strain curves with an overall average peak failure true strain of 0.32+/-0.112 and a corresponding peak failure true stress of 656.3+/-483.9 kPa. These are the first data available for the dynamic response of pregnant human uterus tissues, and it is anticipated they will increase the accuracy of future pregnant female computational models. PMID- 22542220 TI - Strain-induced damage reduces echo intensity changes in tendon during loading. AB - Tendon functionality is related to its mechanical properties. Tendon damage leads to a reduction in mechanical strength and altered biomechanical behavior, and therefore leads to compromised ability to carry out normal functions such as joint movement and stabilization. Damage can also accumulate in the tissue and lead to failure. A noninvasive method with which to measure such damage potentially could quantify structural compromise from tendon injury and track improvement over time. In this study, tendon mechanics are measured before and after damage is induced by "overstretch" (strain exceeding the elastic limit of the tissue) using a traditional mechanical test system while ultrasonic echo intensity (average gray scale brightness in a B-mode image) is recorded using clinical ultrasound. The diffuse damage caused by overstretch lowered the stress at a given strain in the tissue and decreased viscoelastic response. Overstretch also lowered echo intensity changes during stress relaxation and cyclic testing. As the input strain during overstretch increased, stress levels and echo intensity changes decreased. Also, viscoelastic parameters and time-dependent echo intensity changes were reduced. PMID- 22542222 TI - Precision of GE Lunar iDXA for the measurement of total and regional body composition in nonobese adults. AB - Dual-energy X-ray absorptiometry (DXA) is a well-accepted technique for measuring body composition. Knowledge of measurement precision is critical for monitoring of changes in bone mineral content (BMC), and fat and lean masses. The purpose of this study was to characterize in vivo precision of total body and regional body composition parameters using the GE Lunar iDXA (GE Healthcare Lunar, Madison, WI) system in a sample of nonobese subjects. We also evaluated the difference between expert and automatic region-of-interest (ROI) analysis on body composition precision. To this end, 2 total body scans were performed on each subject with repositioning between scans. Total body precision for BMC, fat and lean mass were 0.5%, 1.0%, and 0.5% coefficient of variation (CV), respectively. Regional body composition precision error was less than 2.5% CV for all regions except arms. Precision error was higher for the arms (CV: BMC 1.5%; fat mass 2.8%; lean mass 1.6%), likely owing to the placement of arms relative to torso leading to differences in ROI. There was a significant correlation between auto ROI and expert ROI (r>0.99). Small, but statistically significant differences were found between auto and manual ROI. Differences were small in total body, leg, trunk, and android and gynoid regions (0.004-2.8%), but larger in arm region (3.0-6.3%). Total body and regional precision for iDXA are small and it is suggested that iDXA may be useful for monitoring changes in body composition during longitudinal trials. PMID- 22542223 TI - Comparison of cortical bone measurements between pQCT and HR-pQCT. AB - The primary purpose of this study was to determine the accuracy of tibial cortical thickness measurements derived from peripheral quantitative computed tomography (pQCT) with analysis based on the circular ring model, using high resolution peripheral quantitative computed tomography (HR-pQCT) (isotopic voxel size of 82 MUm) as a gold standard. The secondary objective was to evaluate whether the accuracy of the pQCT-based estimates of cortical thickness (CTh), cortical area (CoA), cortical density (CDen), and total area (TotA) improve with alterations of voxel size from the standard 0.5-0.2mm. Fifteen dry tibia specimens were immersed in saline in a sealed cylinder and scanned 22.5mm from the distal tibia plateau using pQCT and HR-pQCT. pQCT yielded higher values for CTh and CDen and lower values for CoA. The differences between imaging techniques increased as the average CTh increased. No systematic bias was observed for CDen, CoA, and TotA. Similar differences were found between pQCT with voxel size 0.2mm and HR-pQCT. Significant correlations were observed for CTh (R=0.97, p <= 0.0001), CDen (R=0.99, p <= 0.0001), CoA (R=0.98, p <= 0.0001), and TotA (R=1.0, p <= 0.0001) when pQCT- and HR-pQCT-derived values were compared irrespective of which voxel size was used. Measurement variability between the imaging techniques was evident. Future studies aimed at examining cortical structure with pQCT should note that there are differences between the 2 techniques. PMID- 22542224 TI - The role of distal third radius dual energy X-ray absorptiometry (DXA) and central DXA in evaluating for osteopenia and osteoporosis in men receiving androgen deprivation therapy for prostate cancer. AB - The authors assessed the use of distal third radius dual energy X-ray absorptiometry (DXA) concomitantly with central (hip and lumbar spine) DXA to identify men with osteopenia or osteoporosis receiving androgen deprivation therapy (ADT) for prostate cancer. Initial classification with central DXA demonstrated 60 (17%) normal, 187 (55%) osteopenic, and 96 (28%) osteoporotic patients. Sixteen of 60 (27%) normal patients were reclassified as osteopenic (14) or osteoporotic (2), and 20 of 187 (11%) osteopenic patients were reclassified as osteoporotic with the combination of central DXA plus distal third radius DXA. The difference in reclassification was statistically significant. The addition of distal third radius to central DXA scanning in men with bone loss associated with ADT identifies a statistically significant number of men being reclassified as having osteopenia or osteoporosis. Combined central and distal third radius DXA scanning should be considered routine in the evaluation of all men suspected of bone loss associated with ADT. This has specific significant clinical relevance because of the large number of men with nonevaluable central DXA studies. Fracture risk prediction and treatment recommendations based on this reclassification will need to be determined by follow-up studies. PMID- 22542225 TI - Estimations of historical atmospheric mercury concentrations from mercury refining and present-day soil concentrations of total mercury in Huancavelica, Peru. AB - Detailed Spanish records of cinnabar mining and mercury production during the colonial period in Huancavelica, Peru were examined to estimate historical health risks to the community from exposure to elemental mercury (Hg) vapor resulting from cinnabar refining operations. Between 1564 and 1810, nearly 17,000 metric tons of Hg were released to the atmosphere in Huancavelica from Hg production. AERMOD was used with estimated emissions and source characteristics to approximate historic atmospheric concentrations of mercury vapor. Modeled 1-hour and long-term concentrations were compared with present-day inhalation reference values for elemental Hg. Estimated 1-hour maximum concentrations for the entire community exceeded present-day occupational inhalation reference values, while some areas closest to the smelters exceeded present-day emergency response guideline levels. Estimated long-term maximum concentrations for the entire community exceeded the EPA Reference Concentration (RfC) by a factor of 30 to 100, with areas closest to the smelters exceeding the RfC by a factor of 300 to 1000. Based on the estimated historical concentrations of Hg vapor in the community, the study also measured the extent of present-day contamination throughout the community through soil sampling and analysis. Total Hg in soils sampled from 20 locations ranged from 1.75 to 698 mg/kg and three adobe brick samples ranging from 47.4 to 284 mg/kg, consistent with other sites of mercury mining and use. The results of the soil sampling indicate that the present-day population of Huancavelica is exposed to levels of mercury from legacy contamination which is currently among the highest worldwide, consequently placing them at potential risk of adverse health outcomes. PMID- 22542226 TI - Formation and transmission of Staphylococcus aureus (including MRSA) aerosols carrying antibiotic-resistant genes in a poultry farming environment. AB - There is a rather limited understanding concerning the antibiotic-resistance of the airborne S. aureus and the transmission of the antibiotic-resistant genes it carries Therefore, we isolated 149 S. aureus strains from the samples collected from the feces, the indoor air and the outdoor air of 6 chicken farms, and performed the research on them with 15 types of antibiotics and the REP-PCR trace identification. The 100% homologous strains were selected to conduct the research on the carrying and transmission status of the antibiotic-resistant genes. The results revealed that 5.37% strains (8/149) were resistant to methicillins (MRSA), and 94% strains (140/149) were resistant to compound sulfamethoxazole, etc. In addition, these strains displayed a resistance to multiple antibiotics (4, 5 or 6 types) and there were also 3 strains resistant to 9 antibiotics. It should be noted that the antibiotic-resistance of some strains isolated from the feces, the indoor and outdoor air was basically the same, and the strains with the same REP-PCR trace identification result carried the same type of antibiotic resistant genes. The results showed that airborne transmission not only causes the spread of epidemic diseases but also exerts threats to the public health of a community. PMID- 22542228 TI - Mercury amalgam exposure: assessment of risks in US after the year 2000. PMID- 22542227 TI - Differential exposure of the urban population to vehicular air pollution in Hong Kong. AB - This study aims to characterize the spatial variations in, and examine the influence of socio-economic class on, the exposure of urban population of Hong Kong to air pollution from vehicular sources. Hong Kong provides a unique and interesting case for an in-depth study of environmental inequality because of its dense environment and housing provision mechanism through which about half of the population is accommodated in public housing estates provided by the government. To estimate the exposure of the urban population to vehicular air pollution, the IMMIS(net) air dispersion model developed for city-wide air quality assessment was used. The annual mean concentrations of CO, NO(x), SO(2) and PM(10) were estimated for various assessment points of 275 public and 295 private building groups. The results show more pronounced inequality among residents living in private than in public housing estates. Elderly people and those of lower socio economic status were found to be exposed to relatively higher levels of vehicular air pollution compared with groups of higher socio-economic status. However, when all the residents in Hong Kong were pooled together for analysis, no distinct class-biased patterns were found. This could be ascribed to the housing provision mechanism, in which less well-off people are accommodated in public housing estates where the air quality is relatively better. This study highlights the importance of government intervention in housing provision, through which the deprived groups in Hong Kong are inadvertently more protected from air pollution exposure. PMID- 22542229 TI - Landfill CH4 oxidation by mineralized refuse: effects of NH4(+)-N incubation, water content and temperature. AB - Mineralized refuse, excavated from a municipal solid waste (MSW) landfill that had been closed for more than 10 years, was incubated in livestock wastewater for 150 d to accumulate ammonia-oxidizing bacteria and also co-oxidize methane (CH(4)). The extent of CH(4) oxidation and carbon dioxide (CO(2)) emissions from the incubated mineralized refuse (IMR) were investigated to assess its applicability as a bio-cover material at landfill sites for minimizing total greenhouse gas emission equivalents. From the initial 200 mg nitrogen (N) kg(-1) incubated for 120 h, the nitrate-N content produced in the IMR was twice (P<0.05) that of the untreated original mineralized refuse (OMR) and 3.81 (P<0.05) times that of soil. For an initial CH(4) concentration of approximately 10% by volume in the headspace, CH(4) consumption and net emission of CO(2) from the soil, IMR and OMR all agreed well with first-order and zero-order kinetics models for a 120 h incubation (R(2)=0.667 and R(2)=0.995, respectively). Similar to N turnover, the rate of consumption of CH(4) by the mineralized refuse was some 50.0% higher than for soil (P<0.05). Based on the net rate of CO(2) generation, the CH(4) oxidation rate by IMR was 14.2% (P>0.05) greater than for OMR and 56.1% (P>0.05) higher than for soil. Variation of water content and temperature produced substantially higher CH(4) consumption rates by IMR than by either OMR or soil. After treatment by livestock wastewater, the CH(4) oxidation capacity of mineralized refuse was moderately improved, due to the enhancement of CH(4) adsorption by retained suspended solids and the subsequent co-oxidation by the accumulated ammonia-oxidizing bacteria. By correlation analysis for the three experimental materials, CH(4) oxidation rate was significantly correlated with specific surface area and organic matter content (P<0.05), and was positively correlated with CO(2) generation, NH(4)(+)N nitrification and NO(3)(-)N generation rate (P>0.05). PMID- 22542230 TI - Critical evaluation of soil contamination assessment methods for trace metals. AB - Correctly distinguishing between natural and anthropogenic trace metal contents in soils is crucial for assessing soil contamination. A series of assessment methods is critically outlined. All methods rely on assumptions of reference values for natural content. According to the adopted reference values, which are based on various statistical and geochemical procedures, there is a considerable range and discrepancy in the assessed soil contamination results as shown by the five methods applied to three weakly contaminated sites. This is a serious indication of their high methodological specificity and bias. No method with off site reference values could identify any soil contamination in the investigated trace metals (Pb, Cu, Zn, Cd, Ni), while the specific and sensitive on-site reference methods did so for some sites. Soil profile balances are considered to produce the most plausible site-specific results, provided the numerous assumptions are realistic and the required data reliable. This highlights the dilemma between model and data uncertainty. Data uncertainty, however, is a neglected issue in soil contamination assessment so far. And the model uncertainty depends much on the site-specific realistic assumptions of pristine natural trace metal contents. Hence, the appropriate assessment of soil contamination is a subtle optimization exercise of model versus data uncertainty and specification versus generalization. There is no general and accurate reference method and soil contamination assessment is still rather fuzzy, with negative implications for the reliability of subsequent risk assessments. PMID- 22542231 TI - Connection between El Nino-Southern Oscillation events and river nitrate concentrations in a Mediterranean river. AB - The causes of interannual nitrate variability in rivers remain uncertain, but extreme climatic events have been suggested as drivers of large nitrate inputs to rivers. Based on a 24-year data set (1983-2006), we suggest that El Nino-Southern Oscillation (ENSO) can affect nitrate behavior in a seasonal extra-tropical stream, the Llobregat (NE Iberian Peninsula), located thousands of kilometers away from the ENSO oscillating system via atmospheric teleconnections. Two commonly used indices, the Southern Oscillation Index (SOI) and the self calibrating-Palmer Drought Severity Index (scPDSI) showed highly significant correlations with nitrate concentrations, which recurrently increased during La Nina phases, coinciding with severe droughts. PMID- 22542232 TI - Embryotoxicity of mixtures of weathered crude oil collected from the Gulf of Mexico and Corexit 9500 in mallard ducks (Anas platyrhynchos). AB - Dispersants are applied to marine crude oil spills to enhance microbial degradation and reduce impacts of crude oils on ecosystems. In summer 2010, the dispersant Corexit 9500 was applied to crude oil in the Gulf of Mexico. The co occurrence of the Deepwater Horizon oil spill with nesting efforts of birds in the Gulf region may have resulted in exposure of adult birds, and subsequently bird eggs, to combinations of crude oil and Corexit 9500. The objective of this study was to examine the embryotoxicity of 50:1 and 10:1 mixtures of weathered crude oil collected from the Gulf of Mexico and Corexit 9500 applied to mallard duck eggs. Combinations of weathered crude oil and Corexit 9500 were applied to eggshells of mallard ducks via paintbrush in varying masses ranging from 0.1 to 59.9 mg and 0.1 to 44.9 mg for 50:1 and 10:1 mixtures, respectively. Conservatively derived median lethal applications for 50:1 and 10:1 mixtures of weathered crude oil and Corexit 9500 were 21.3+/-4.9 mg/egg (321.8 MUg/g egg) and 33.1+/-11.8 mg/egg (517.0 MUg/g egg), respectively. Spleen mass of hatchlings exposed to the 50:1 mixture was the only physiological measure significantly different from controls of both mixtures. Results indicated that decreasing ratios of dispersant relative to weathered crude oil decreased toxicity to mallard embryos. In comparison to treatments of eggs with weathered crude oil alone, toxicity increased when the oil to dispersant ratio was 50:1, but decreased with the mixture that contained more dispersant (10:1). PMID- 22542233 TI - Loss of epiphytic diversity along a latitudinal gradient in southern Europe. AB - Latitudinal gradients that involve macroclimatic changes can affect the diversity of several groups of plants and animals. Here we examined the effect of a latitudinal gradient on epiphytic communities on a single host species (Fagus sylvatica) to test the core-periphery theory. The latitudinal span considered, covering two biogeographic regions, is associated with major changes in rainfall during the dry season. Because bryophytes and lichens are poikilohydric, we hypothesized that their species richness and composition might vary at different latitudes. We also speculated how epiphytic communities may respond to future climate change. The present study was carried out in Spain, and three latitudes that cover the distributional range of F. sylvatica were selected. The presence/absence and coverage of epiphytic lichens and bryophytes were identified on 540 trees (180 in each zone). We found consistent south to north change in the total richness and in the richness of bryophytes and of lichens separately, all of which tend to increase at higher latitudes due to the presence of several hygrophytic species. Epiphytic composition also differed significantly among the three latitudes, and the similarity decreased when the latitudinal span was greater. In addition, high species turnover was driven by the increased rainfall at higher latitudes. We conclude that epiphytic communities have a similar pattern to the predictors of the core-periphery theory from populations, and they suffer a great impoverishment in species richness at lower latitudes, coincident with the southern boundary of the F. sylvatica distribution. PMID- 22542234 TI - Eco-innovation of a wooden childhood furniture set: an example of environmental solutions in the wood sector. AB - The environmental profile of a set of wood furniture was carried out to define the best design criteria for its eco-design. A baby cot convertible into a bed, a study desk and a bedside table were the objects of study. Two quantitative and qualitative environmental approaches were combined in order to propose improvement alternatives: Life Cycle Assessment (LCA) and Design for Environment (DfE). In the first case Life Cycle Assessment (LCA) was applied to identify the hot spots in the product system. As a next step, LCA information was used in eco briefing to determine several improvement alternatives. A wood products company located in Catalonia (NE Spain) was assessed in detail, dividing the process into three stages: assembly, finishing and packaging. Ten impact categories were considered in the LCA study: abiotic depletion, acidification, eutrophication, global warming, ozone layer depletion, human toxicity, fresh water aquatic ecotoxicity, marine aquatic ecotoxicity, terrestrial ecotoxicity and photochemical oxidant formation. Two processes can be considered the key environmental factors: the production of the wooden boards and electricity, with contributions of 45-68% and 14-33% respectively depending on the impact categories. Subsequently, several improvement alternatives were proposed in the eco-design process (DfE) to achieve reductions in a short-medium period of time in the environmental impact. These eco-design strategies could reduce the environmental profile of the setup by 14%. The correct methodological adaptation of the concept of eco-briefing, as a tool for communication among environmental technicians and designers, the simplification of the analytical tool used and the LCA, could facilitate the environmental analysis of a product. The results obtained provide information that can help the furniture sector to improve their environmental performance. PMID- 22542235 TI - Assessment of pollution impact on biological activity and structure of seabed bacterial communities in the Port of Livorno (Italy). AB - The main objective of this study was to assess the impact of pollution on seabed bacterial diversity, structure and activity in the Port of Livorno. Samples of seabed sediments taken from five selected sites within the port were subjected to chemical analyses, enzymatic activity detection, bacterial count and biomolecular analysis. Five different statistics were used to correlate the level of contamination with the detected biological indicators. The results showed that the port is mainly contaminated by variable levels of petroleum hydrocarbons and heavy metals, which affect the structure and activity of the bacterial population. Irrespective of pollution levels, the bacterial diversity did not diverge significantly among the assessed sites and samples, and no dominance was observed. The type of impact of hydrocarbons and heavy metals was controversial, thus enforcing the supposition that the structure of the bacterial community is mainly driven by the levels of nutrients. The combined use of chemical and biological essays resulted in an in-depth observation and analysis of the existing links between pollution macro-indicators and biological response of seabed bacterial communities. PMID- 22542236 TI - Interactions between dissolved natural organic matter and adsorbed DNA and their effect on natural transformation of Azotobacter vinelandii. AB - To better understand gene transfer in the soil environment, the interactions between dissolved natural organic matter (NOM) and chromosomal or plasmid DNA adsorbed to silica surfaces were investigated. The rates of NOM adsorption onto silica surfaces coated with DNA were measured by quartz crystal microbalance (QCM) and showed a positive correlation with carboxylate group density for both soil and aquatic NOM in solutions containing either 1mM Ca(2+) or Mg(2+). Increasing total dissolved organic carbon (DOC) concentrations of the NOM solution also resulted in an increase in the adsorption rates, likely due to divalent cation complexation with NOM carboxylate groups and the phosphate backbones of the DNA. The results from Fourier transform infrared spectroscopy (FTIR) for dissolved DNA and DNA adsorbed on silica beads also suggest that adsorption may result from divalent cation complexation with the DNA's phosphate backbone. The interactions, between DNA and NOM, however, did not influence natural transformation of Azotobacter vinelandii by DNA. These results suggest that DNA adsorbed to NOM-coated silica or otherwise complexed with NOM remains available for natural transformation in the environment. PMID- 22542237 TI - Embryonic toxicity changes of organic nanomaterials in the presence of natural organic matter. AB - When elucidating the potential fate and bioavailability of nanomaterials (NMs) in an aquatic system, it is important to consider the interactions between NMs and natural organic matter (NOM). The present study compared the toxicities of carbon based NMs, with disparate physicochemical properties, on Japanese medaka (Oryzias latipes) embryos after the addition of NOM. The measured embryonic toxicity parameters were mortality, malformation and hatching delay. Various physicochemical properties of water suspended fullerenes (nC(60)) and multi walled carbon nanotubes (MWNTs) were modulated by organic exchange (Tol/nC(60)), stirring over time (Aqu/nC(60)) and acid treatment (f-MWNTs) followed by characterization. Tol/nC(60) produced relatively more hydrophobic surfaces and exhibited smaller closed spherical agglomerates than Aqu/nC(60). Acid-treated f MWNTs displayed functionalized hydrophilic surfaces compared to raw MWNTs (r MWNTs). The resultant embryonic toxicities, in the absence of NOM, were ranked in the order: f-MWNTs>Tol/nC(60)>Aqu/nC(60). As the NOM concentrations were increased, no changes in embryonic toxicities were observed on exposure of Aqu/nC(60) and r-MWNTs; whereas, the toxicities were reduced on exposure to Tol/nC(60) and f-MWNTs, due to a disappearance of hydrophobic primary spherical aggregates and partial coating, respectively. These data suggest that in the presence of NOM, the morphological differences of NMs, as well as their physicochemical properties, play a significant role in their reactions and subsequent medaka embryonic nanotoxicity. PMID- 22542238 TI - Environmental impact of toxic elements in red mud studied by fractionation and speciation procedures. AB - Aluminum (Al) is mostly produced from bauxite ore, which contains up to 70% of Al(2)O(3) (alumina). Before alumina is refined to aluminum metal, it is purified by hot alkaline extraction. As a waste by-product red mud is formed. Due to its high alkalinity and large quantities, it represents a severe disposal problem. In Kidricevo (Slovenia), red mud was washed with water before disposal, and after drying, covered with soil. In Ajka (Hungary), the red mud slurry was collected directly in a containment structure, which burst caused a major accident in October 2010. In the present work the environmental impact of toxic elements in red mud from Kidricevo and Ajka were evaluated by applying a sequential extraction procedure and speciation analysis. The predominant red mud fraction was the insoluble residue; nevertheless, environmental concern was focused on the highly mobile water-soluble fraction of Al and Cr. Al in the water-soluble Ajka mud fraction was present exclusively in form of toxic [Al(OH)(4)](-), while Cr existed in its toxic hexavalent form. Comparative assessment to red mud from Kidricevo (Slovenia) with a lower alkalinity (pH 9) with that from Ajka demonstrated significantly lower Al solubility and the presence of only trace amounts of Cr(VI), confirming that disposal of neutralized mud is environmentally much more acceptable and carries a smaller risk of ecological accidents. Since during the Ajka accident huge amounts of biologically available Al and moderate Cr(VI) concentrations were released into the terrestrial and aquatic environments, monitoring of Al and Cr(VI) set free during remedial actions at the contaminated site is essential. Particular care should be taken to minimize the risk of release of soluble Al species and Cr(VI) into water supplies and surface waters. PMID- 22542239 TI - Linear and nonlinear modeling approaches for urban air quality prediction. AB - In this study, linear and nonlinear modeling was performed to predict the urban air quality of the Lucknow city (India). Partial least squares regression (PLSR), multivariate polynomial regression (MPR), and artificial neural network (ANN) approach-based models were constructed to predict the respirable suspended particulate matter (RSPM), SO(2), and NO(2) in the air using the meteorological (air temperature, relative humidity, wind speed) and air quality monitoring data (SPM, NO(2), SO(2)) of five years (2005-2009). Three different ANN models, viz. multilayer perceptron network (MLPN), radial-basis function network (RBFN), and generalized regression neural network (GRNN) were developed. All the five different models were compared for their generalization and prediction abilities using statistical criteria parameters, viz. correlation coefficient (R), standard error of prediction (SEP), mean absolute error (MAE), root mean squared error (RMSE), bias, accuracy factor (A(f)), and Nash-Sutcliffe coefficient of efficiency (E(f)). Nonlinear models (MPR, ANNs) performed relatively better than the linear PLSR models, whereas, performance of the ANN models was better than the low-order nonlinear MPR models. Although, performance of all the three ANN models were comparable, the GRNN over performed the other two variants. The optimal GRNN models for RSPM, NO(2), and SO(2) yielded high correlation (between measured and model predicted values) of 0.933, 0.893, and 0.885; 0.833, 0.602, and 0.596; and 0.932, 0.768 and 0.729, respectively for the training, validation and test sets. The sensitivity analysis performed to evaluate the importance of the input variables in optimal GRNN revealed that SO(2) was the most influencing parameter in RSPM model, whereas, SPM was the most important input variable in other two models. The ANN models may be useful tools in the air quality predictions. PMID- 22542240 TI - Health risk assessment of lead for children in tinfoil manufacturing and e-waste recycling areas of Zhejiang Province, China. AB - Tinfoil manufacturing and electronic waste (e-waste) recycling remain rudimentary processes in Zhejing Province, China, which could account for elevated blood lead levels (BLLs) and health impacts on children. We assessed the potential health risks of lead in tinfoil manufacturing and e-waste recycling areas. 329 children in total aged 11-12 who lived in a tinfoil manufacturing area (Lanxi), an e-waste recycling area (Luqiao) and a reference area (Chun'an) were studied. Lead levels in children's blood were determined by inductively coupled plasma mass spectrometer (ICP-MS). Blood urea nitrogen (BUN), serum creatinine, serum calcium, delta-Aminolaevulinic acid (delta-ALA) and intelligence quotient (IQ) were also measured. Geometric mean of BLLs in Lanxi, Luqiao and Chun'an were 8.11 MUg/dL, 6.97 MUg/dL, and 2.78 MUg/dL respectively, with 35.1%, 38.9% and 0% of children who had BLLs above 10 MUg/dL. The BLLs in exposed areas were much higher than those in the control area. Lanxi children had higher creatinine and calcium than Chun'an children, and Luqiao children had higher delta-ALA and lower calcium than Chun'an children. No significant differences of IQ were observed between Lanxi, Luqiao and Chun'an, however a negative relationship between BLLs and IQ was shown for the study children. The results indicated that lead pollution from e-waste recycling and tinfoil processing appears to be a potential serious threat to children's health. PMID- 22542241 TI - Correlation between anatomic foot and ankle movement measured with MRI and with a motion analysis system. AB - Several studies have attempted to measure how well external markers track internal bone movement using pins drilled into the foot, but this is too invasive for the pediatric population. This study investigated how well a six segment foot model (6SFM) using external markers was able to measure bone movement in the foot compared to MRI measurements. The foot was moved into different positions using a plastic foot jig and measurements were taken with both systems. The aims were to: (1) Look at the correlation between movement tracked with an Electronic Motion Tracking System (EMTS) and by measurements derived from MRI images, specifically the principal intercept angles (PIAs) which are the angles of intersection between principal axes of inertia of bone volumes. (2) To see how well external motion measured by the 6SFM could predict PIAs. Four bone pairs had their movement tracked: Tibia-Calcaneus, Calcaneus-Cuboid, Navicular-1st Metatarsal, and 1st Metatarsal-Hallux. The results showed moderate correlation between measured PIAs and those predicted at the Tibia-Calcaneus, Navicular-1st Metatarsal, and 1st Metatarsal-Hallux joints. Moderate to high correlation was found between the PIA and movement in a single anatomic plane for all four joints at several positions. The 6SFM using the EMTS allows reliable tracking of 3D rotations in the pediatric foot, except at the Calcaneus-Cuboid joint. PMID- 22542242 TI - Crouched posture maximizes ground reaction forces generated by muscles. AB - Crouch gait decreases walking efficiency due to the increased knee and hip flexion during the stance phase of gait. Crouch gait is generally considered to be disadvantageous for children with cerebral palsy; however, a crouched posture may allow biomechanical advantages that lead some children to adopt a crouch gait. To investigate one possible advantage of crouch gait, a musculoskeletal model created in OpenSim was placed in 15 different postures from upright to severe crouch during initial, middle, and final stance of the gait cycle for a total of 45 different postures. A series of optimizations was performed for each posture to maximize transverse plane ground reaction forces in the eight compass directions by modifying muscle forces acting on the model. We compared the force profile areas across all postures. Larger force profile areas were allowed by postures from mild crouch (for initial stance) to crouch (for final stance). The overall ability to generate larger ground reaction force profiles represents a mechanical advantage of a crouched posture. This increase in muscle capacity while in a crouched posture may allow a patient to generate new movements to compensate for impairments associated with cerebral palsy, such as motor control deficits. PMID- 22542244 TI - Interpreting treatment trials in schizophrenia patients: lessons learned from EUFEST. AB - There are various procedures to account for missing values in clinical trials. Mixed Model and Last Observation Carried Forward (LOCF) analyses are commonly employed methods. We compared the two methods by reanalysing Positive and Negative Syndrome Scale (PANSS) scores from the European First Episode in Schizophrenia Trial (EUFEST). While the predefined Mixed Model analysis detected no differences between PANSS total score changes in first episode patients treated with haloperidol, amisulpride, quetiapine, olanzapine or ziprasidone over the course of a one year treatment trial, a LOCF analysis revealed significant differences in favor of the new generation antipsychotics over haloperidol. Implications for clinical trial design and the interpretation of such studies are discussed. PMID- 22542243 TI - Medial temporal lobe structure and cognition in individuals with schizophrenia and in their non-psychotic siblings. AB - Medial temporal lobe (MTL) structures play a central role in episodic memory. Prior studies suggest that individuals with schizophrenia have deficits in episodic memory as well as structural abnormalities of the medial temporal lobe (MTL). While correlations have been reported between MTL volume loss and episodic memory deficits in such individuals, it is not clear whether such correlations reflect the influence of the disease state or of underlying genetic influences that might contribute to risk. We used high resolution magnetic resonance imaging and probabilistic algorithms for image analysis to determine whether MTL structure, episodic memory performance and the relationship between the two differed among groups of 47 healthy control subjects, 50 control siblings, 39 schizophrenia subjects, and 33 siblings of schizophrenia subjects. High dimensional large deformation brain mapping was used to obtain volume measures of the hippocampus. Cortical distance mapping was used to obtain volume and thickness measures of the parahippocampal gyrus (PHG) and its substructures: the entorhinal cortex (ERC), the perirhinal cortex (PRC), and the parahippocampal cortex (PHC). Neuropsychological data was used to establish an episodic memory domain score for each subject. Both schizophrenia subjects and their siblings displayed abnormalities in episodic memory performance. Siblings of individuals with schizophrenia, and to a lesser extent, individuals with schizophrenia themselves, displayed abnormalities in measures of MTL structure (volume loss or cortical thinning) as compared to control groups. Further, we observed correlations between structural measures and memory performance in both schizophrenia subjects and their siblings, but not in their respective control groups. These findings suggest that disease-specific genetic factors present in both patients and their relatives may be responsible for correlated abnormalities of MTL structure and memory impairment. The observed attenuated effect of such factors on MTL structure in individuals with schizophrenia may be due to non genetic influences related to the development and progression of the disease on global brain structure and cognitive processing. PMID- 22542245 TI - Exposure to morphine affects the expression of endocannabinoid receptors and immune functions. AB - Compared with control rats, rats under morphine exposure exhibited cannabinoid receptor 2 (CB2-R) upregulation in the spleen and periphery blood mononuclear cells (PBMCs). IgG and IgM values in the plasma were also altered. In morphine abusers, cannabinoid receptors were upregulated in the PBMCs, and the expression of IL-4 mRNA in the PBMCs as well as the IgG and IgM values in the plasma were higher compared with those in healthy people. The expression of cannabinoid receptor 1 and CB2-R in culture cells was directly affected by morphine treatment. These findings indicate that the alteration in cannabinoid receptor expression could be disturbed by morphine exposure, and it may be involved in abnormal immune function. PMID- 22542246 TI - Sensitive time-windows for susceptibility in neurodevelopmental disorders. AB - Many neurodevelopmental disorders (NDDs) are characterized by age-dependent symptom onset and regression, particularly during early postnatal periods of life. The neurobiological mechanisms preceding and underlying these developmental cognitive and behavioral impairments are, however, not clearly understood. Recent evidence using animal models for monogenic NDDs demonstrates the existence of time-regulated windows of neuronal and synaptic impairments. We propose that these developmentally-dependent impairments can be unified into a key concept: namely, time-restricted windows for impaired synaptic phenotypes exist in NDDs, akin to critical periods during normal sensory development in the brain. Existence of sensitive time-windows has significant implications for our understanding of early brain development underlying NDDs and may indicate vulnerable periods when the brain is more susceptible to current therapeutic treatments. PMID- 22542247 TI - A novel Sec14 phospholipid transfer protein from Nicotiana benthamiana is up regulated in response to Ralstonia solanacearum infection, pathogen associated molecular patterns and effector molecules and involved in plant immunity. AB - To elucidate the molecular mechanisms of plant immune responses, we isolated genes whose expression was regulated by inoculation with Ralstonia solanacearum. Here, we report the characterization of Nicotiana benthamiana belonging to the SEC14-gene superfamily designated as Nicotiana benthamiana SEC14 (NbSEC14). NbSEC14 rescued growth defects and impaired invertase secretion associated with the yeast sec14p temperature-sensitive mutant, while recombinant NbSec14 protein had phospholipids transfer activity. NbSEC14 expression was up-regulated in N. benthamiana leaves after inoculation with virulent or avirulent R. solanacearum. Expression of NbSEC14 was induced by treatment with chitin, flg22, and by Agrobacterium-mediated transient expression of INF1 elicitin, AvrA from R. solanacearum, and co-expression of the capsid protein from Tobacco mild green mosaic virus with its cognate resistance L1 protein. NbSEC14-silenced plants showed accelerated growth of both the virulent and avirulent R. solanacearum as well as acceleration of disease development. This study may provide useful information for the further analysis of the function of plant Sec14 protein homologs in the regulation of plant immune responses. PMID- 22542248 TI - Computer-assisted preoperative simulation for screw fixation of fractures of the condylar head. PMID- 22542249 TI - Relationship between columnar cell changes and low-grade carcinoma in situ of the breast--a cytogenetic study. AB - Columnar cell lesions of the breast include columnar cell changes without atypia and columnar cell changes with atypia. The latter frequently coexist and share molecular changes with low-grade carcinoma in situ and invasive carcinoma, suggesting that columnar cell changes may be precursors to progression of low grade advanced lesions. In this study, we assessed chromosomal aberrations at 16q, hallmark for low-grade lesions, in columnar cell changes with or without atypia and their adjacent carcinoma in situ by fluorescent in situ hybridization using 3 region-specific probes spanning the entire chromosomal arm. The results were correlated with the histomorphological features of the corresponding lesions. Forty-four percent of low-grade carcinoma in situ and 31% of high-grade carcinoma in situ were associated with columnar cell changes with atypia, suggesting a link between columnar cell changes with atypia and low-grade carcinoma in situ. For the genetic aberrations, heterozygous deletion of 16q was present in 56% of low-grade carcinoma in situ but only in 19% of high-grade carcinoma in situ. Conversely, aneuploidy was found mostly in high-grade carcinoma in situ (88%). Twenty percent of columnar cell changes with atypia but none of the columnar cell changes without atypia showed heterozygous deletion of 16q. Interestingly, the same changes in 16q were observed in the columnar cell changes and their associated low-grade carcinoma in situ lesions. These findings demonstrated a genetic commonality between columnar cell changes with atypia and low-grade carcinoma in situ and substantiated the precursor role of columnar cell changes with atypia for low-grade carcinoma in situ but not high-grade carcinoma in situ of the breast. PMID- 22542250 TI - Treatment of newly diagnosed advanced stage Hodgkin lymphoma. AB - ABVD continues to be the standard of care for patients with advanced stage Hodgkin Lymphoma (HL) although escalated BEACOPP has improved survival in one randomized controlled trial (RCT). More intensive regimens have higher rates of acute and late toxicities and this poses significant issues for patients. Consolidation strategies such as radiation or autologous stem cell transplantation (ASCT) have not demonstrated an improvement in overall survival in RCTs. Novel technology and therapeutics are leading us to investigate new questions. Interim FDG-PET scanning is now being tested in prospective studies. Small, typically retrospective trials suggest that interim PET scans are independent markers of outcome and current trials are piloting the use of PET adapted therapy. Targeted therapeutics have been evaluated in the relapsed and refractory setting and now show promising single agent activity. Agents including brentuximab vedotin (a conjugated anti-CD30 monoclonal antibody) and the histone deacetylase inhibitor panabinostat have reported encouraging single agent activity and a large study of brentuximab vedotin maintenance post ASCT is underway. Combination and maintenance trials are planned or ongoing in the primary treatment setting that will hopefully improve on the treatment standards of the past decade. This review will discuss the current standard of care in advanced stage HL, summarize some of the current data regarding interim FDG-PET scans and will conclude with some issues related to the development of new agents that are likely to be involved in the future standard of therapy. PMID- 22542251 TI - Evaluating drug therapy decision making in patients with epilepsy. PMID- 22542252 TI - Concept building: applying rigor to conceptualize phenomena for nursing research. PMID- 22542253 TI - Participant action research with bedside nurses to identify NANDA-International, Nursing Interventions Classification, and Nursing Outcomes Classification categories for hospitalized persons with diabetes. AB - Experienced bedside nurses identified 14 nursing diagnoses, 78 interventions, and 76 health outcomes for hospitalized persons with diabetes. Using these terms, the nursing department revised the standards of care and the electronic health record. Nurses' engagement in generating knowledge translated to increased interest in research. This methodology is recommended for other agencies. PMID- 22542254 TI - Exploration of a methodology aimed at exploring the characteristics of teenage dating violence and preliminary findings. AB - PURPOSE: The aim of this study was to explore a novel approach toward investigating violence in adolescent dating relationships by administering a reflective survey to female college students. RESEARCH HYPOTHESIS: Results from the Danger Assessment (DA) tool and the Abuse Assessment Screen (AAS) will be highly correlated with concepts from the Theory of Female Adolescents' Safety as Determined by the Dynamics of the Circle (TFASDC). DESIGN: A descriptive cross sectional survey of 188 female college students was conducted. SETTING: This study was carried out in a Northeastern academic university and health center. MAIN RESEARCH VARIABLES AND MEASUREMENT: Main research variables and measurement included the AAS, the DA, and concepts from the TFASDC. FINDINGS: One in three participants reported dating violence on the DA; and one in five, on the AAS. Nine percent of the sample reported forced sex on the DA. Concepts from the TFASDC correlated to dating violence include the following: low scores on group belonging, increased number of sex and/or dating partners, dating an older boy, and time in relationship. CONCLUSION: The TFASDC holds promise for use as both a risk- and a strength-based assessment in teenagers, with the ultimate goal of fostering the development of healthy relationships. PMID- 22542255 TI - Simultaneous indoor and outdoor on-line hourly monitoring of atmospheric volatile organic compounds in an urban building. The role of inside and outside sources. AB - Indoor air quality (IAQ) has become a very important issue in recent years. As in developed countries people spend more than 90% of their time indoors, besides outdoor pollution assessment, the indoor one is also required. IAQ is not only affected by indoor sources linked to indoor activities, outdoor sources such as road or street traffic and industrial and commercial activities have their role too. Volatile organic compounds (VOCs) frequently show higher indoor mixing ratios with respect to the outdoor ones, and monitoring is required to report their indoor mixing ratios. Many studies have reported average indoor VOCs' mixing ratios in different environments, but their temporal variability has not been well documented. The main objective of this work was to simultaneously measure VOCs' indoor and outdoor mixing ratios with high time-resolution in order to assess the effect of sources inside and outside the building upon indoor mixing ratios of individual VOCs. Simultaneous hourly, continuous, and on-line measurements of C(2)-C(11) VOCs were performed inside and outside the School of Engineering of Bilbao (ETSI) building, located in the city center of Bilbao, an urban area in Northern Spain. The analysis of simultaneous data allowed the classification of VOCs based on their main sources. Some VOCs were mainly emitted by indoor sources (1-pentene, 2-methylpentane, n-hexane, methylcyclopentane, benzene, 1-heptene+2,2,4-trimethylbenzene, and tetrachloroethylene) or by outdoor sources (n-heptane, C(8) alkanes except trimethylpentanes and C(9) aromatics). Other VOCs, such as toluene, were emitted by both indoor and outdoor sources. The isoprene indoor pattern indicated that its main indoor source could be the air exhaled by people occupying the building. Some halocarbons, such as trichloroethylene, tetrachloroethylene, and carbon tetrachloride may be generated from the use inside the building of chlorine bleach containing products. PMID- 22542256 TI - Impacts of the phenylpyrazole insecticide fipronil on larval fish: time-series gene transcription responses in fathead minnow (Pimephales promelas) following short-term exposure. AB - The utilization of molecular endpoints in ecotoxicology can provide rapid and valuable information on immediate organismal responses to chemical stressors and is increasingly used for mechanistic interpretation of effects at higher levels of biological organization. This study contributes knowledge on the sublethal effects of a commonly used insecticide, the phenylpyrazole fipronil, on larval fathead minnow (Pimephales promelas), utilizing a quantitative transcriptomic approach. Immediately after 24h of exposure to fipronil concentrations of >=31 MUg.L(-1), highly significant changes in gene transcription were observed for aspartoacylase, metallothionein, glucocorticoid receptor, cytochrome P450 3A126 and vitellogenin. Different mechanisms of toxicity were apparent over the course of the experiment, with short-term responses indicating neurotoxic effects. After 6 days of recovery, endocrine effects were observed with vitellogenin being up regulated 90-fold at 61 MUg.L(-1) fipronil. Principal component analysis demonstrated a significant increase in gene transcription changes over time and during the recovery period. In conclusion, multiple mechanisms of action were observed in response to fipronil exposure, and unknown delayed effects would have been missed if transcriptomic responses had only been measured at a single time point. These challenges can be overcome by the inclusion of multiple endpoints and delayed effects in experimental designs. PMID- 22542257 TI - Selenium fractionation and speciation in agriculture soils and accumulation in corn (Zea mays L.) under field conditions in Shaanxi Province, China. AB - Upland and paddy soils, as well as corn samples, were collected in the selenosis area of Naore Village, Ziyang County, Shaanxi Province, China. A five-step sequential extraction procedure was used for selenium (Se) fractionation, including soluble Se, exchangeable Se and carbonate-bound Se, iron and manganese oxide-bound Se, organic matter-bound Se, and the residual Se fraction. Species of soluble Se in upland soils included Se(-2), Se(4+), and Se(6+). The results showed that soluble Se and exchangeable Se fractions accounted for less than 1% of the total Se in the upland soil, but approximately 16.1% in the paddy soil. Concentrations of residual Se were lower than those of iron and manganese oxide bound Se and organic matter-bound Se in both upland and paddy soils. Iron- and manganese oxide-bound Se was the dominant fractions in upland soil, whereas organic matter-bound Se abounded in paddy soil. Concentrations (mg kg(-1)) of Se in the corn samples ranged from 0.05 to 14.5 in seed, 0.31 to 12.3in root, 0.09 to 9.15 in stalk, and 0.16 to 36.15 in leaf. Path analysis indicated that soluble Se(6+) significantly (P<0.05) affected Se accumulation in corn tissues directly, whereas the organic matter-bound Se had a significant (P<0.05) indirect effect. In conclusion, corn did not readily absorb a major portion of soil Se. However, organic matter-bound Se was an important fraction and source of plant Se in agricultural soil. PMID- 22542258 TI - Ultrasonography for diagnosing carpal tunnel syndrome: a meta-analysis of diagnostic test accuracy. AB - Ultrasonography is widely used to diagnose carpal tunnel syndrome (CTS), a common peripheral neuropathy, but the reported diagnostic accuracy varies. This meta analysis focused on the diagnostic test accuracy of ultrasonography for diagnosing CTS. Structured searches of PubMed for 1990-2010 were done and the data were extracted and meta-analyzed by pooling estimates of sensitivity, specificity, likelihood ratios and diagnostic odds ratios. Diagnostic performance was also judged by using a summary receiver operating characteristic curve. Twenty-eight trials involving 3995 wrists were included. A greater cross sectional area (CSA) of the median nerve at the carpal tunnel inlet (CSA-I) and a greater flattening ratio at the level of the hamate were seen in CTS wrists than in control wrists. A CSA-I >=9 mm(2) is the best single diagnostic criterion, with a diagnostic odds ratio of 40.4 (sensitivity 87.3%, specificity 83.3%). PMID- 22542259 TI - Quantitative ultrasound bone measurements in pre-pubertal children with type 1 diabetes. AB - This case-control study aimed to assess bone status in children with type 1 diabetes mellitus (T1DM). Fifty-seven pre-pubertal patients (37 boys, aged 7.9 +/ 2.5 years, T1DM duration 3.1 +/- 1.6 years) and 171 age-matched healthy controls (111 boys) were studied. Quantitative ultrasound (QUS) was used to measure amplitude dependent speed of sound (Ad-SoS) at hand phalanges (expressed as standard deviation score [SDS]). Anthropometric and disease-related data (including mean HbA(1c) from whole T1DM duration [T], last year [Y], examination day [D]) were collected. Mean Ad-SoS SDS in patients -0.13 +/- 1.32 (95% confidence interval [CI] -0.48, 0.22) was similar to that of controls. Subgroups discriminated according to HbA(1c) D, Y and T (cut-off 7.0%) did not differ regarding analyzed parameters. In patients, Ad-SoS SDS was comparable for both genders. Multivariable stepwise regression analysis showed significant negative influence of diabetes duration on Ad-SoS SDS. QUS findings in pre-pubertal children with T1DM do not differ from those in healthy children. Disease duration seems to affect negatively Ad-SoS SDS. However, independent prospective studies are needed to elucidate the true associations. PMID- 22542260 TI - Tumor and non-tumor liver angiogenesis is traced and evaluated by hepatic arterial ultrasound in murine models. AB - We studied the relationships between hepatic and mesenteric mean blood-flow velocities (mBFVs) measured by ultrasound imaging and (1) downstream tumor angiogenesis during liver metastasis induced by spleen injection of LS174 human colon cells overexpressing the antiangiogenic Netrin4 (LS174-NT4) or not (LS174 WT) and (2) downstream normal angiogenesis during hepatic regeneration after 50% hepatectomy. Liver volume and mBFVs were measured before and after surgery, at day 30 in the first model and at days 2, 7 and 16 in the second model. LS174-NT-4 vs. LS174-WT mice presented fewer metastases (25% vs. 90%, p < 0.001) and decreased hepatic mBFVs (16.5 +/- 0.8 vs. 21.8 +/- 1.4 cm s(-1), p < 0.01), without difference in mesenteric mBFVs. After partial hepatectomy, hepatic and mesenteric mBFVs increased at day 7, from 12.4 +/- 1.7 and 11.8 +/- 2.6 to 19.1 +/- 1.8 and 17.5 +/- 2.4 cm s(-1), respectively, (p < 0.01) then returned to baseline as liver volume. Duplex Doppler ultrasonography reliably assesses normal or tumor angiogenesis and may provide follow-up functional evaluation. PMID- 22542261 TI - In vitro sonothrombolysis of human blood clots with BR38 microbubbles. AB - Microbubble-mediated sonothrombolysis is a promising approach for ischemic stroke treatment. The aim of this in vitro study was to evaluate a new microbubble (MB) formulation (BR38) for sonothrombolysis and to investigate the involved mechanisms. Human whole-blood clots were exposed to different combinations of recombinant tissue plasminogen activator (rtPA), ultrasound (US) and MB. Ultrasound at 1.6 MHz was used at 150, 300, 600 and 1000 kPa (peak-negative pressure). Thrombolysis efficacy was assessed by measuring clot diameter changes during 60-min US exposure. The rate of clot diameter loss (RDL) in MUm/min was determined and clot lysis profiles were analyzed. The most efficient clot lysis (5.9 MUm/min) was obtained at acoustic pressures of 600 and 1000 kPa in combination with MB and a low concentration of rtPA (0.3 MUg/mL). This is comparable with the rate obtained with rtPA at 3 MUg/mL alone (6.6 MUm/min, p > 0.05). Clot lysis profiles were shown to be related to US beam profiles and microbubble cavitation. PMID- 22542262 TI - High diagnostic accuracy and interobserver reliability of real-time elastography in the evaluation of thyroid nodules. AB - Elastography is a new diagnostic tool in the evaluation of thyroid nodules. Aim of the study was to evaluate the accuracy and reliability of elastography in discriminating thyroid lesions and the interobserver variability. One hundred thirty-two nodules in 115 patients selected for thyroid surgery underwent conventional ultrasound and elastographic evaluation. Elastography score was divided in four categories (totally elastic nodule, mainly elastic, mainly rigid and totally rigid) according to signal distribution. Three independent operators conducted the study. Final histology showed 92 benign nodules and 40 malignant. On elastography, 77/92 benign nodules were classified as score 1 or 2 and 34/40 malignant nodules as score 3 or 4 (sensitivity 85%, specificity 83.7%, positive predictive value [PPV] 69.3%, negative predictive value [NPV] 92.7%). Rate of concordance between operators was good (K test: 0.64, p < 0.0001). Simple to use, with good interobserver agreement, elastography has all the requisites to become an important complement of conventional US examination in the near future. PMID- 22542264 TI - Splitting of the P3 component during dual-task processing in a patient with posterior callosal section. AB - When two concurrent sensorimotor tasks have to be performed at a short time interval, the second response is generally delayed at a central decision stage. However, in patients who have undergone full or partial transection of forebrain fibers connecting the two hemispheres (split-brain), independent structures subserving all processing stages should reside in each disconnected hemisphere, thus predicting parallel processing of dual tasks. Surprisingly, this prediction is usually not verified behaviorally. We reasoned that brain imaging with high density recordings of event-related potentials (ERPs) could clarify the extent and limits of parallel processing in callosal patients. We studied a patient (AC) with posterior callosal section in a lateralized number-comparison task. Behaviorally, the split-brain patient showed robust dual-task interference, superficially similar to the psychological refractory period (PRP) effect in the control group of 14 healthy subjects, but significantly different in important aspects such as slowing of response times in the first task. Analysis of ERPs revealed that the parietal P3 component became split into distinct contralateral components in the patient, and was dramatically reduced for targets in his left visual field. In contrast to the control group, P3 latencies showed minimal to nonexistent postponement related to dual-task processing in the patient. In summary, our findings suggest that the left and right hemisphere networks normally involved in a single distributed "global neuronal workspace" that underlies the generation of the P3 component and serial processing, became strongly decoupled after a posterior callosal lesion. PMID- 22542265 TI - Development, content validity, and piloting of an instrument designed to measure managers' attitude toward workplace breastfeeding support. AB - Manager attitude is influential in female employees' perceptions of workplace breastfeeding support. Currently, no instrument is available to assess manager attitude toward supporting women who wish to combine breastfeeding with work. We developed and piloted an instrument to measure manager attitudes toward workplace breastfeeding support entitled the "Managers' Attitude Toward Breastfeeding Support Questionnaire," an instrument that measures four constructs using 60 items that are rated agree/disagree on a 4-point Likert rating scale. We established the content validity of the Managers' Attitude Toward Breastfeeding Support Questionnaire measures through expert content review (n=22), expert assessment of item fit (n=11), and cognitive interviews (n=8). Data were collected from a purposive sample of 185 front-line managers who had experience supervising female employees, and responses were scaled using the Multidimensional Random Coefficients Multinomial Logit Model. Dimensionality analyses supported the proposed four-construct model. Reliability ranged from 0.75 to 0.86, and correlations between the constructs were moderately strong (0.47 to 0.71). Four items in two constructs exhibited model-to-data misfit and/or a low score-measure correlation. One item was revised and the other three items were retained in the Managers' Attitude Toward Breastfeeding Support Questionnaire. Findings of this study suggest that the Managers' Attitude Toward Breastfeeding Support Questionnaire measures are reliable and valid indicators of manager attitude toward workplace breastfeeding support, and future research should be conducted to establish external validity. The Managers' Attitude Toward Breastfeeding Support Questionnaire could be used to collect data in a standardized manner within and across companies to measure and compare manager attitudes toward supporting breastfeeding. Organizations can subsequently develop targeted strategies to improve support for breastfeeding employees through efforts influencing managerial attitude. PMID- 22542263 TI - Quantitative ultrasound criteria for risk stratification in clinical practice: a comparative assessment. AB - This study aimed to compare two different classifications of the risk of fracture/osteoporosis (OP) based on quantitative ultrasound (QUS). Analyses were based on data from the Epidemiological Study on the Prevalence of Osteoporosis, a cross-sectional study conducted in 2000 aimed at assessing the risk of OP in a representative sample of the Italian population. Subjects were classified into 5 groups considering the cross-classification found in previous studies; logistic regression models were defined separately for women and men to study the fracture risk attributable to groups defined by the cross-classification, adjusting for traditional risk factors. Eight-thousand six-hundred eighty-one subjects were considered in the analyses. Logistic regression models revealed that the two classifications seem to be able to identify a common core of individuals at low and at high risk of fractures, and the importance of a multidimensional assessment in older patients to evaluate clinical risk factors together with a simple, inexpensive, radiation-free device such as QUS. PMID- 22542266 TI - The association between nurse-administered midazolam following cardiac surgery and incident delirium: an observational study. AB - BACKGROUND: Post-operative delirium after cardiac surgery is an adverse event that affects patients' recovery and complicates the delivery of nursing care. Numerous risk factors for delirium are uncontrollable; however, nurses' pro re nata drug administration of sedatives may be a controllable risk factor. OBJECTIVES: This study examined the relationship between nurses' pro re nata administration of midazolam hydrochloride to cardiac surgery patients and the development of post-operative delirium. DESIGN: Observational study. SETTING: Cardiac surgery intensive care and nursing units of a tertiary care center in Vancouver, Canada. PARTICIPANTS: 122 male and female patients requiring non emergent surgery for coronary artery disease or valvular heart disease who did not have pre-existing cognitive impairment, severe hearing or visual impairment, substance misuse, alcohol intake exceeding 7 drinks per week, or renal impairment requiring hemodialysis. METHODS: Patients were assessed for delirium, on three occasions, with the Confusion Assessment Method for the Intensive Care Unit (CAM ICU) during the first 72 h after surgery and through reviews of physicians' notes. Risk factor and midazolam dosage data were collected from medical records. RESULTS: 77.9% of the patients in this sample received midazolam hydrochloride post-operatively. The prevalence of delirium ranged from 37.7% to 44.3%. Almost all of the dosages of midazolam (85-87%) were given before the first indication of delirium; that is, most of the patients had received their entire dosage before the first signs of delirium were detected. Bivariate analysis with logistic regression models revealed that for every additional milligram of midazolam administered, the patients were 7-8% more likely to develop delirium. Multivariate logistic regression models demonstrated that the magnitude of the association between midazolam dosage and delirium was not confounded by established risk factors including age and peripheral vascular disease. CONCLUSION: Nurses play an important role in the prediction, assessment and prevention of post-operative delirium. Sedatives should be administered with caution because they increase a patient's risk of developing delirium. Nurses' decisions regarding sedation administration must be informed by empirical knowledge, accurate assessment data and clear rationale with consideration of how these actions may contribute to the development of delirium. PMID- 22542267 TI - The association between malnutrition and oral health status in elderly in long term care facilities: a systematic review. AB - OBJECTIVES: Malnutrition is a common problem in the elderly. It is not clear if oral health is associated to malnutrition in this population. The aim of this systematic review is to determine whether an association exists between oral health and malnutrition in the elderly in a long-term care facility. DESIGN: Systematic review. DATA SOURCE: Medline, Cochrane and Cinahl were systematically searched for to identify articles published between January 1985 and May 2011. Reference lists were checked for additional publications. REVIEW METHODS: Publications were included if they explored the association between oral health status and malnutrition. As no consensus about terminology was found, a sensitive filter was developed. The methodological quality of the studies was assessed. Two independent reviewers performed all methodological steps. RESULTS: Sixteen studies met the criteria for inclusion. Eleven studies used a multivariate approach; nine of these found an association between oral health status and malnutrition. Four studies found a relationship between masticatory problems and malnutrition. Five studies found an association between malnutrition and dental condition, number of oral problems, tongue alteration, problems with saliva flow, and candidiasis. Overall, the methodological quality of the studies was medium. CONCLUSIONS: Tentative evidence indicates an independent association between oral health status and malnutrition in the elderly residing in a long-term care facility. Caution is needed for the interpretation of these results because of the absence of a gold standard to define and assess malnutrition and oral health status and the presence of methodological limitations throughout the studies. PMID- 22542268 TI - Effect of temperature and relative humidity on ultraviolet (UV 254) inactivation of airborne porcine respiratory and reproductive syndrome virus. AB - The objective of this research was to estimate the effects of temperature and relative humidity on the inactivation of airborne porcine reproductive and respiratory syndrome (PRRS) virus by ultraviolet light (UV(254)). Aerosols of PRRS virus were exposed to one of four doses of UV(254) under nine combinations of temperature (n=3) and relative humidity (n=3). Inactivation constants (k), defined as the absolute value of the slope of the linear relationship between the survival fraction of the microbial population and the UV(254) exposure dose, were estimated using the random coefficient model. The associated UV(254) half-life dose for each combination of environmental factors was determined as (log(10)2/k) and expressed as UV(254) mJ per unit volume. The effects of UV(254) dose, temperature, and relative humidity were all statistically significant, as were the interactions between UV(254) dose * temperature and UV(254) dose * relative humidity. PRRS virus was more susceptible to ultraviolet as temperature decreased; most susceptible to ultraviolet inactivation at relative humidity between 25% and 79%, less susceptible at relative humidity <= 24%, and least susceptible at >= 80% relative humidity. The current study allows for calculating the dose of UV(254) required to inactivate airborne PRRS virus under various laboratory and field conditions using the inactivation constants and UV(254) half life doses reported therein. PMID- 22542269 TI - The majority of atypical cpb2 genes in Clostridium perfringens isolates of different domestic animal origin are expressed. AB - This study examined the prevalence and expression of the "consensus" and the "atypical"cpb2 genes in Clostridium perfringens isolates from cattle, chickens, dogs, goats, horses, pigs and sheep using polymerase chain reaction (PCR), sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by Western blotting. Almost all porcine isolates (12/14) carried and expressed the consensus form of cpb2 but, when present in 108 non-porcine isolates, the gene was usually the atypical form (40 atypical versus 9 consensus). Western blotting showed expression in 30 of 40 (75%) atypical cpb2-positive isolates, considerably more frequently than reported previously. CPB2 was expressed by almost all (20/21) the consensus cpb2-positive isolates, regardless of source. PMID- 22542270 TI - Evaluation of two herd-level diagnostic tests for Streptococcus agalactiae using a latent class approach. AB - Streptococcus agalactiae mastitis persists as a significant economic problem for the dairy industry in many countries. In Denmark, the annual surveillance programme for this mastitis pathogen initially based only on bacteriological culture of bulk tank milk (BTM) samples, has recently incorporated the use of the real-time PathoProof Mastitis PCR assay with the goal of improving detection of infected herds. The objective of our study was to estimate the herd sensitivity (Se) and specificity (Sp) of both tests of BTM samples using latent class models in a Bayesian analysis while evaluating the effect of herd-level covariates on the Se and Sp of the tests. BTM samples were collected from all 4258 Danish dairy herds in 2009 and screened for the presence of S. agalactiae using both tests. The highest Se of PCR was realized at a cycle threshold (Ct) cut-off value of 40. At this cut-off, the Se of the PCR was significantly higher (95.2; 95% posterior credibility interval [PCI] [88.2; 99.8]) than that of bacteriological culture (68.0; 95% PCI [55.1; 90.0]). However, culture had higher Sp (99.7; 95% PCI [99.3; 100.0]) compared to PCR (98.8; 95% PCI [97.2; 99.9]). The accuracy of the tests was unaffected by the herd-level covariates. We propose that screenings of BTM samples for S. agalactiae be based on the PCR assay with Ct readings of <40 considered as positive. However, for higher Ct values, confirmation of PCR test positive herds by bacteriological culture is advisable especially when the between-herd prevalence of S. agalactiae is low. PMID- 22542271 TI - A pantropic canine coronavirus genetically related to the prototype isolate CB/05. AB - We report the genetic and biological characterisation of a novel pantropic canine coronavirus (CCoV), strain 450/07, which caused the death of a 60-day-old miniature pinscher. At the genetic level, this virus was strictly related to the prototype strain CB/05, but displayed some unique features. After experimental infection with the new pantropic isolate, most inoculated dogs showed diarrhoea and acute lymphopenia. Gross lesions and histological changes were mainly evident in the gut and lymphoid tissues, although some animals showed remarkable changed also in parenchymatous organs. The viral RNA was detected in the faeces and/or internal organs of most pups. These findings seem to indicate that strain 450/07 is able to spread to internal organs (mainly lymphoid tissues), causing lymphopenia but inducing a mild disease. PMID- 22542273 TI - Evaluation of right ventricular systolic function after mitral valve repair: a two-dimensional Doppler, speckle-tracking, and three-dimensional echocardiographic study. AB - BACKGROUND: Conventional indices of right ventricular (RV) function are known to be reduced after cardiac surgery, as a consequence of geometric rather than functional alterations. New techniques, such as three-dimensional (3D) transthoracic and two-dimensional speckle-tracking echocardiography, may be useful in postsurgical RV assessment. The aim of this study was to compare indices of RV function obtained using different echocardiographic modalities, before and after surgery. METHODS: Forty-two patients were screened the day before and 6 months after mitral valve repair. Twenty healthy patients were also enrolled as controls. Tricuspid annular plane systolic excursion and peak systolic velocity were calculated from Doppler tissue imaging. Longitudinal and radial strain values were obtained from speckle-tracking echocardiography. RV ejection fraction was calculated from 3D transthoracic echocardiographic RV volumes, and similarly, fractional area change was computed from RV areas. RESULTS: Tricuspid annular plane systolic excursion (25 +/- 4 vs 17 +/- 3 mm), peak systolic velocity (17 +/- 4 vs 12 +/- 2 cm/sec), and fractional area change (43 +/- 8% vs 39 +/- 7%) significantly decreased after surgery (P < .01), while 3D RV ejection fraction was preserved (59 +/- 7% vs 59 +/- 6%). Speckle-tracking echocardiographic results were dependent on the considered direction, with preserved radial but decreased longitudinal strain values. All postoperative two dimensional longitudinal indices were smaller than in controls. Preoperative parameters were not significantly correlated with RV functional changes. CONCLUSIONS: Although 3D ejection fraction was preserved after surgery, in agreement with the lack of evidence of RV dysfunction, two-dimensional indices showed a functional loss in the longitudinal direction. Fractional area change, as a combination of radial and longitudinal properties, was slightly decreased. Speckle-tracking echocardiography could constitute a useful approach to relate local and space-dependent changes to the global RV function. PMID- 22542272 TI - Abnormal cardiac strain in children and young adults with HIV acquired in early life. AB - BACKGROUND: Traditional measures of cardiac function are now often normal in adolescents and young adults treated with antiretroviral therapy for human immunodeficiency virus (HIV) infection. There is, however, evidence of myocardial abnormalities in adults with HIV. Cardiac strain analysis may detect impairment in cardiac function that may be missed by conventional measurements in this population. METHODS: This was a retrospective study in which echocardiograms of HIV-infected subjects (n = 28) aged 7 to 29 years who participate in a natural history study of HIV acquired early in life were analyzed and compared with matched controls. Standard echocardiographic measures, along with speckle tracking-derived strain and strain rate, were assessed. RESULTS: Among the HIV infected subjects, the median CD4 count was 667 cells/mm(3), and the mean duration of antiretroviral therapy was 14.6 years. Ejection fractions and fractional shortening were normal. There were no significant differences in measures of systolic or diastolic function between the groups. The HIV-infected group had borderline increased left ventricular mass indices. Global longitudinal and circumferential strain and strain rate, as well as global radial strain rate, were significantly impaired in the HIV-infected group compared with controls. There were no associations identified between left ventricular mass index or strain indices and current CD4 count, CD4 nadir, HIV viral load, or duration of antiretroviral therapy. CONCLUSIONS: HIV-infected participants demonstrated impaired strain and strain rate despite having normal systolic function and ejection fractions. Strain and strain rate may prove to be prognostic factors for long-term myocardial dysfunction. Therefore, asymptomatic children and young adults with long-standing HIV infection may benefit from these more sensitive measures. PMID- 22542274 TI - Is a shorter atrioventricular septal length an intermediate phenotype in the spectrum of nonsyndromic atrioventricular septal defects? AB - BACKGROUND: Atrioventricular septal defects (AVSDs) account for 7% of all congenital cardiovascular malformations. The atrioventricular septum (AVS) is the portion of the septal tissue that separates the right atrium from the left ventricle; deficiency of the AVS contributes to the AVSD phenotype. A study of case and control families was performed to identify whether an intermediate phenotype consisting of a shortened AVS existed in relatives of children with AVSDs. METHODS: AVS length (AVSL) was measured on the echocardiograms of clinically unaffected parents and siblings from families that were identified through children with nonsyndromic AVSDs and in families with no histories of congenital heart disease. RESULTS: No significant differences were seen between case and control family members in terms of gender, age, weight, and height. AVSLs were significantly shorter in case parents compared with control parents. Similar findings were noted within the sibling groups. There was significant evidence for two-component distributions in the case parent, case sibling, and control sibling groups after standardizing AVSL for age and body surface area. Heritability of AVSL standardized for age and body surface area was 0.82 and 0.71 in nonsyndromic case and control families, respectively. CONCLUSIONS: Evidence for two-component distributions from the analysis of AVSL standardized for age and body surface area for case parents and case siblings suggests the presence of an intermediate phenotype for nonsyndromic AVSD. The high heritability in the control families suggests that there may be polygenic involvement in the determination of AVSL. Broadening the definition of AVSD to include those with shortened AVSL may increase the power of genetic association and mapping studies to identify susceptibility genes for AVSD. PMID- 22542275 TI - Accuracy and interobserver concordance of echocardiographic assessment of right ventricular size and systolic function: a quality control exercise. AB - BACKGROUND: Accurate assessment of right ventricular (RV) size (RVS) and RV systolic function (RVSF) is vital in the management of various conditions, but their assessment is challenging using echocardiography. The aim of this study was to determine the accuracy and interobserver concordance of qualitative and quantitative RV echocardiography. METHODS: Fifteen readers evaluated RV function in 12 patients (360 readings) who underwent echocardiography and cardiac magnetic resonance for RV assessment. Readers qualitatively estimated RVS and RVSF as normal, mild, moderate, or severe and then reassessed quantitatively by adding RV dimensions, fractional area change, S', tricuspid annular plane systolic excursion, and RV index of myocardial performance. Cardiac magnetic resonance was used as the reference standard for grading RVS and RVSF. RESULTS: Quantitative measurements increased accuracy and interreader agreement compared to qualitative assessment alone, especially in normal categories. Readers' accuracy for diagnosing normal and severe RVS increased from 38% to 78% (P = .001) and from 70% to 97% (P = .018), and readers' accuracy for diagnosing normal and mild RVSF increased from 52% to 84% (P < .001) and from 36% to 56% (P = .001). Interreader agreement for classification of the subjects as normal or abnormal improved from a kappa value of 0.40 to 0.77 (fair to good agreement) for RVS and from 0.43 to 0.66 (moderate to good agreement) for RVSF. CONCLUSIONS: Visual estimation of RVS and RVSF is inaccurate and has wide interobserver variability. Quantitation improves accuracy and reliability, especially in distinction of normal and abnormal. The reliability of mild and moderate grades remains inadequate, and further guidance is needed for the classification of abnormal categories. PMID- 22542277 TI - Treatment of chronic gouty arthritis: it is not just about urate-lowering therapy. AB - OBJECTIVES: The management of gouty arthritis is focused on treating pain and inflammation associated with acute flares and preventing further acute flares and urate crystal deposition. A challenge associated with the successful management of gouty arthritis is an increased risk of acute flares during the first months after initiation of urate-lowering therapy (ULT). This increase in flare frequency can occur regardless of the choice of ULT and is linked to suboptimal patient adherence to ULT. Current treatment recommendations for the use of prophylaxis are limited. There are no definitive recommendations as to which agents should be used or for how long therapy is beneficial after starting ULT. This article aims to improve awareness of the importance of gouty arthritis flare prophylaxis when initiating ULT and to summarize current recommendations and clinical findings related to the efficacy and safety of currently available and investigational new therapies. METHODS: This review discusses the pathophysiology of acute gouty arthritis flares during initiation of ULT and examines the literature on the use of anti-inflammatory prophylaxis for reduction of these flares. RESULTS: It has recently become clear that, even when the patient is asymptomatic, chronic inflammation is often present in patients with chronic gouty arthritis. Chronic anti-inflammatory therapy should therefore be added to chronic ULT. Prophylaxis with colchicine as well as with nonsteroidal anti inflammatory drugs (NSAIDs) during ULT initiation can reduce the incidence and severity of gouty arthritis flares substantially; however, safety concerns associated with colchicine and NSAIDs may limit their use. CONCLUSION: When colchicine and NSAIDs are contraindicated or poorly tolerated, rilonacept and canakinumab, interleukin-1 inhibitors in trials, may prove to be useful alternatives for flare prevention. (Of note, although both inhibit the IL-1beta pathway, rilonacept also binds to IL-1alpha and IL-1RA, in contrast to canakinumab, which binds selectively to IL-1beta.). PMID- 22542278 TI - Development of leprosy in a patient with rheumatoid arthritis during treatment with etanercept: a case report. AB - BACKGROUND: Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder. There is a clear association between some disease-modifying drugs used to treat RA and infection. The introduction of the anti-tumor necrosis factor (TNF) therapies has improved the outcome of severe RA. The TNF-antagonism may increase susceptibility to granulomatous pathogens such as Mycobacterium tuberculosis, Listeria monocytogenes, and Histoplasma capsulatum. METHODS: We report the case of a 37-year-old woman with RA receiving an anti-TNF agent, who developed a rash on her back and both legs, which was finally diagnosed as tuberculoid leprosy. RESULTS: This is the first case of leprosy due to anti-TNF therapy reported in Europe. CONCLUSIONS: Clinicians should be aware of this and other types of atypical and serious infections that patients may suffer from when treated with anti-TNF agents. PMID- 22542279 TI - Potential immunologic targets for treating fibrosis in systemic sclerosis: a review focused on leukocytes and cytokines. AB - OBJECTIVES: Systemic sclerosis (SSc) is a connective tissue disease characterized by tissue fibrosis. Although the pathogenesis remains unclear, a variety of cells contribute to the fibrotic process via interactions with each other and production of various cytokines. Recent literature related to the immunologic pathogenesis and future strategies for treating the fibrosis of SSc are discussed and, especially, this literature-based review that includes the authors' perspective, focused on leukocytes and cytokines. METHODS: A PubMed search for articles published between January 2005 and January 2012 was conducted using the following keywords: systemic sclerosis, leukocyte, cytokine, growth factor, and chemokine. The reference lists of identified articles were searched for further articles. RESULTS: Targeting profibrogenic cytokines, including transforming growth factor-beta, is still a very active area of research in SSc and most cellular studies have focused on the roles of fibroblasts in SSc. However, a growing number of recent studies indicate a role for B cells in the development of SSc and other autoimmune diseases such as systemic lupus erythematosus. Therefore, B-cell-targeted therapies, including currently available monoclonal antibodies against CD19, CD20, CD22, and B-cell-activating factor, belonging to the tumor necrosis factor family represent possible treatment options. Furthermore, the modulation of T-cell costimulatory molecules such as a recombinant fusion protein of cytotoxic T-lymphocyte antigen-4 may be as effective in SSc as it is in treating other autoimmune diseases. Approaches to antagonize interleukin (IL)-1, IL-6, or IL-17A signaling may also be attractive. CONCLUSIONS: This review describes recent advances in the treatment of fibrosis in SSc patients focused on immunologic strategies, such as leukocyte- or cytokine targeted therapies. PMID- 22542281 TI - Contribution of holins to protein trafficking: secretion, leakage or lysis? PMID- 22542280 TI - Coronary computed tomography angiography during arrhythmia: Radiation dose reduction with prospectively ECG-triggered axial and retrospectively ECG-gated helical 128-slice dual-source CT. AB - BACKGROUND: Arrhythmia during coronary computed tomography angiography (coronary CTA) acquisition increases the risk of nondiagnostic segments and high radiation exposure. An advanced arrhythmia rejection algorithm for prospectively electrocardiogram (ECG)-triggered axial scans using dual-source CT (DSCT) examinations has recently been reported. OBJECTIVE: We compared image quality and effective dose at DSCT examinations using prospectively ECG-triggered axial scanning with advanced arrhythmia rejection software (PT-AAR) versus retrospectively ECG-gated helical scanning with tube-current modulation (RG-TCM) during arrhythmia. METHODS: This was a retrospective case-control study of 90 patients (43 PT-AAR, 47 RG-TCM) with arrhythmia (defined as heart rate variability [HRV] > 10 beats/min during data acquisition) referred for physician supervised coronary CTA between April 2010 and September 2011. A subset of 22 cases matched for body mass index, HR, HRV, and other scan parameters was identified. Subjective image quality (4-point scale) and effective dose (dose length product method) were compared. RESULTS: PT-AAR was associated with lower effective dose than RG-TCM (4.1 vs 12.6 mSv entire cohort and 4.3 vs 9.1 mSv matched controls; both P < 0.01). Image quality scores were excellent in both groups (3.9 PT-AAR vs 3.6 RG-TCM) and nondiagnostic segment rates were low (0.1% vs 0.6%). Significantly higher image quality scores were found with PT-AAR in the entire cohort (P < 0.05), and in matched controls with high HRV > 28 beats/min (P < 0.05). CONCLUSIONS: In patients with variable heart rates, prospectively ECG triggered axial DSCT with arrhythmia rejection algorithm is feasible and can decrease radiation exposure by ~50% versus retrospectively ECG-gated helical DSCT, with preserved image quality. PMID- 22542276 TI - Magnetic resonance imaging of subchondral bone marrow lesions in association with osteoarthritis. AB - OBJECTIVES: This nonsystematic literature review provides an overview of magnetic resonance imaging (MRI) of subchondral bone marrow lesions (BMLs) in association with osteoarthritis (OA), with particular attention to the selection of MRI sequences and semiquantitative scoring systems, characteristic morphology, and differential diagnosis. Histologic basis, natural history, and clinical significance are also briefly discussed. METHODS: PubMed was searched for articles published up to 2011, using the keywords bone marrow lesion, osteoarthritis, magnetic resonance imaging, bone marrow edema, histology, pain, and subchondral. RESULTS: BMLs in association with OA correspond to fibrosis, necrosis, edema, and bleeding of fatty marrow as well as abnormal trabeculae on histopathology. Lesions may fluctuate in size within a short time and are associated with the progression of articular cartilage loss and fluctuation of pain in knee OA. The characteristic subchondral edema-like signal intensity of BMLs should be assessed using T2-weighted, proton density-weighted, intermediate weighted fat-suppressed fast spin echo or short tau inversion recovery. Several semiquantitative scoring systems are available to characterize and grade the severity of BMLs. Quantitative approaches have also been introduced. Differential diagnoses of degenerative BMLs include a variety of traumatic or nontraumatic pathologies that may appear similar to OA-related BMLs on MRI. CONCLUSIONS: Subchondral BMLs are a common imaging feature of OA with clinical significance and typical signal alteration patterns, which can be assessed and graded by semiquantitative scoring systems using sensitive MRI sequences. PMID- 22542282 TI - Discovery of novel indane derivatives as liver-selective thyroid hormone receptor beta (TRbeta) agonists for the treatment of dyslipidemia. AB - Thyromimetics that specifically target TRbeta have been shown to reduce plasma cholesterol levels and avoid atherosclerosis through the promotion of reverse cholesterol transport in an animal model. We designed novel thyromimetics with high receptor (TRbeta) and organ (liver) selectivity based on the structure of eprotirome (3) and molecular modeling. We found that indane derivatives are potent and dual-selective thyromimetics expected to avoid hypothyroidism in some tissues as well as heart toxicity. KTA-439 (29), a representative indane derivative, showed the same high human TRbeta selectivity in a binding assay as 3 and higher liver selectivity than 3 in a cholesterol-fed rat model. PMID- 22542284 TI - Nature and onset of communication disorder in pediatrics with HIV. AB - American Speech-Language Association (ASHA) and the International Association of Physicians in AIDS Care (IAPAC) reported that speech-language and hearing disorders that occur as a direct or indirect consequence of HIV-infection are so common. However there has been little research into the nature and onset of such communication disorders in children living with HIV. Therefore the purpose of the study is to understand about the nature and onset of audiological and speech language disorders of a group of children with HIV for the better management. In methodology 67 children (4-16 years, mean: 11.06) with HIV infection took part in the study. Otoscopic examination, Pure-tone and Impedance audiometry, REELS, SECS, PAT, FDA and BUFFALO-III was used to assess. In result, 22/67 individuals had hearing loss, 17/67 had swallowing disorder, 21/67 individuals had voice problems. Language development was delayed in 21/67 of the individuals at the pragmatic and syntactic level and 7/67 had the deviant language. There was negative correlation (r=-0.932) between the duration of HIV infection and degree of severity of communication disorders in the participants. PMID- 22542283 TI - Lipophilic amines as potent inhibitors of N-acylethanolamine-hydrolyzing acid amidase. AB - N-Acylethanolamines (NAEs) including N-arachidonoylethanolamine (anandamide) and N-palmitoylethanolamine are endogenous lipid mediators. These molecules are degraded to the corresponding fatty acids and ethanolamine by fatty acid amide hydrolase (FAAH) or NAE-hydrolyzing acid amidase (NAAA). Lipophilic amines, especially pentadecylamine (2c) and tridecyl 2-aminoacetate (11b), were found to exhibit potent NAAA inhibitory activities (IC(50)=5.7 and 11.8MUM), with much weaker effects on FAAH. These simple structures would provide a scaffold for further improvement in NAAA inhibitory activity. PMID- 22542285 TI - Stentless endoscopic transnasal repair of bilateral choanal atresia starting with resection of vomer. AB - OBJECTIVES: To assess the results of a transnasal endoscopic repair of congenital choanal atresia beginning by resection of the posterior portion of the vomer and ending by no stent. METHODS: Seven patients with bilateral congenital choanal atresia aged ranging from 3 to 15 days were operated upon between June 2009 and September 2011. This transnasal endoscopic approach allowed resection of the posterior portion of the vomer first then the atretic plates and part of the medial pterygoid plate if needed leaving no stent. Postoperative control included office fiberoptic nasal endoscopy. RESULTS: Adequate functional nasal breathing was maintained in all patients during follow up of 11 to 23 months. Apart from one case that complicated by palatal defect, no any other complications were detected. CONCLUSION: The described technique was proved to be very effective, allowing fast recovery, and one step surgery with early discharge from hospital using neither stents nor nasal packing. Good patency with no reduction in functional quality was also observed. PMID- 22542287 TI - Simultaneous separations of cations and anions by capillary electrophoresis with contactless conductivity detection employing a sequential injection analysis manifold for flexible manipulation of sample plugs. AB - Different schemes for simultaneous separations of both cations and anions were implemented in capillary electrophoresis employing a sequential injection analysis manifold for flexible manipulation of the background electrolyte and samples. The utilization of contactless conductivity allowed sensitive detection in narrow capillaries of 10 MUm internal diameter, which in turn enabled the use of hydrodynamic pumping without significant penalty in dispersion otherwise caused by the laminar nature of the flow. This allowed to position sample plugs at a desired place along the entire length of the capillary prior to electrophoretic separation or to carry out concurrent pumping during the separation itself for optimization of resolution. Also implemented was dual single-end injection, the injection of two sample plugs from one end of the capillary, and the small size of the contactless conductivity detector allowed the concurrent use of two cells at different points along the capillary for added flexibility. Equally considered was the effect of the pH-value of the background electrolyte as this strongly influences the electroosmotic flow, which also has bearing on the protocol to be used. For dual single-end injection reproducibilities in separation time of about 1-3% were obtained and the peak areas could be reproduced to within about 3-5% (both standard deviations). The detection limits for inorganic ions were all about 1 MUM. PMID- 22542286 TI - Determination of saturated-hydrocarbon contamination in baby foods by using on line liquid-gas chromatography and off-line liquid chromatography-comprehensive gas chromatography combined with mass spectrometry. AB - The present contribution describes an investigation directed towards the use of a rapid heart-cutting multidimensional LC-GC-FID method for the analysis of mineral oil saturated hydrocarbons (MOSH), contained in different types of homogenized solid baby food (fish, meat and fruit products). The fish and meat products all contained vegetable oil (sunflower), potentially an important source of mineral oil contamination. Sixteen commercial baby food samples were subjected to analysis, with various degrees of MOSH contamination (from 0.3mg/kg to circa 14 mg/kg) found. Hence, MOSH contamination was found not only in the meat and fish products, but also in the fruit ones. A fruit-based baby food was lab-made, using the ingredients reported on the commercial product, and was found to be contaminated. The single ingredients were then subjected to LC-GC analysis, with corn starch and sugar found to be the source of contamination. For confirmation of the analytical findings, three of the sixteen samples were analyzed in two separate laboratories, using two distinct LC-GC methods, based on different interfaces. The results were confirmed, in qualitative terms, by collecting the LC fractions, relative to some of the food samples, and subjecting them to comprehensive two-dimensional GC-quadrupole mass spectrometry. Thus, mass spectral data were attained for the saturated hydrocarbons. PMID- 22542288 TI - Enantioseparation of omeprazole--effect of different packing particle size on productivity. AB - Enantiomeric separation of omeprazole has been extensively studied regarding both product analysis and preparation using several different chiral stationary phases. In this study, the preparative chiral separation of omeprazole is optimized for productivity using three different columns packed with amylose tris (3,5-dimethyl phenyl carbamate) coated macroporous silica (5, 10 and 25 MUm) with a maximum allowed pressure drop ranging from 50 to 400 bar. This pressure range both covers low pressure process systems (50-100 bar) and investigates the potential for allowing higher pressure limits in preparative applications in a future. The process optimization clearly show that the larger 25 MUm packing material show higher productivity at low pressure drops whereas with increasing pressure drops the smaller packing materials have substantially higher productivity. Interestingly, at all pressure drops, the smaller packing material result in lower solvent consumption (L solvent/kg product); the higher the accepted pressure drop, the larger the gain in reduced solvent consumption. The experimental adsorption isotherms were not identical for the different packing material sizes; therefore all calculations were recalculated and reevaluated assuming identical adsorption isotherms (with the 10 MUm isotherm as reference) which confirmed the trends regarding productivity and solvent consumption. PMID- 22542289 TI - Full evaporation dynamic headspace and gas chromatography-mass spectrometry for uniform enrichment of odor compounds in aqueous samples. AB - A method for analysis of a wide range of odor compounds in aqueous samples at sub ng mL-1 to MUg mL-1 levels was developed by full evaporation dynamic headspace (FEDHS) and gas chromatography-mass spectrometry (GC-MS). Compared to conventional DHS and headspace solid phase microextraction (HS-SPME), FEDHS provides more uniform enrichment over the entire polarity range for odor compounds in aqueous samples. FEDHS at 80 degrees C using 3 L of purge gas allows complete vaporization of 100 MUL of an aqueous sample, and trapping and drying it in an adsorbent packed tube, while providing high recoveries (85-103%) of the 18 model odor compounds (water solubility at 25 degrees C: log0.54-5.65 mg L-1, vapor pressure at 25 degrees C: 0.011-3.2 mm Hg) and leaving most of the low volatile matrix behind. The FEDHS-GC-MS method showed good linearity (r2>0.9909) and high sensitivity (limit of detection: 0.21-5.2 ng mL-1) for the model compounds even with the scan mode in the conventional MS. The feasibility and benefit of the method was demonstrated with analyses of key odor compounds including hydrophilic and less volatile characteristics in beverages (whiskey and green tea). In a single malt whiskey sample, phenolic compounds including vanillin could be determined in the range of 0.92-5.1 MUg mL-1 (RSD<7.4%, n=6). For a Japanese green tea sample, 48 compounds including 19 potent odorants were positively identified from only 100 MUL of sample. Heat-induced artifact formation for potent odorants was also examined and the proposed method does not affect the additional formation of thermally generated compounds. Eighteen compounds including 12 potent odorants (e.g. coumarin, furaneol, indole, maltol, and pyrazine congeners) were determined in the range of 0.21-110 ng mL-1 (RSD<10%, n=6). PMID- 22542290 TI - Association of a novel complement factor H mutation with severe crescentic and necrotizing glomerulonephritis. AB - Severe crescentic and necrotizing glomerulonephritis typically is associated with anti-glomerular basement membrane or antineutrophil cytoplasmic antibodies. In this report, we describe a 23-year-old man with severe crescentic and necrotizing glomerulonephritis. Both anti-glomerular basement membrane and antineutrophil cytoplasmic antibody titers were negative. Kidney biopsy showed bright C3 staining in the mesangium and along capillary walls and no staining for immunoglobulins. Electron microscopy showed waxy deposits (many mesangial; few intramembranous or subendothelial), prompting evaluation of the alternative pathway of complement. Alternative pathway evaluation showed a novel mutation in short consensus repeat (SCR) 19 of complement factor H. In addition, the patient carried complement factor H and C3 risk alleles. Prompt treatment with intravenous steroids followed by oral steroids resulted in symptom alleviation and improved kidney function. This case shows what is to our knowledge a unique and previously unpublished cause of severe crescentic and necrotizing glomerulonephritis. Furthermore, the case demonstrates an expanding spectrum of complement-mediated glomerulonephritis and shows that crescentic and necrotizing glomerulonephritis with solely complement deposits should be evaluated for abnormalities in the alternative pathway of complement. PMID- 22542291 TI - Immune monitoring of kidney allografts. AB - Current strategies for posttransplant monitoring of kidney transplants consist of measuring serial serum creatinine levels, clinical follow-up, and in some programs, protocol biopsies. These strategies may be insufficient to predict acute rejection in kidney transplants, which remains the major factor affecting long-term transplant outcomes. Immune monitoring may conceptually be divided into strategies for detecting humoral rejection (eg, donor-specific antibody) or cellular rejection. Cellular rejection markers may be separated further into those related to cytotoxic T lymphocytes (granzyme A/B, perforin, Fas ligand, and serpin B9), regulatory T cells (FOXP3), and CD4 T cells (the chemokines CXCL9, CXCL10, CXCL11, CCL2, and fractalkine, as well as TIM-3). Finally, transcriptomic changes and renal tubular injury markers also may be useful for detecting early inflammatory changes post-kidney transplant. Ultimately, novel strategies for monitoring the immune status of the kidney transplant may lead to early therapeutic intervention and improved kidney transplant outcomes. PMID- 22542293 TI - Nicotine dependence among clients receiving publicly funded substance abuse treatment. AB - BACKGROUND: Smoking and nicotine dependence (ND) are prevalent among substance abusers but little is known about characteristics of ND in this population. This information would help identify those most in need of smoking cessation programs. This study evaluated the associations of socio-demographic, tobacco- and substance use-related, and health/mental health factors to ND in adults receiving publicly funded substance abuse treatment in Tennessee. METHODS: All Tennessee residents who received federal block grant-funded substance abuse treatment during July-December, 2004 were invited to participate in a 6 month post-intake telephone follow-up interview. Socio-demographic characteristics, perceived health and mental health, tobacco use history and patterns, and ND, assessed by the Fagerstrom Test of Nicotine Dependence (FTND), were obtained at follow-up. Alcohol and illicit drug use and smoking status prior to treatment were assessed at intake. This paper analyzes data for 855 clients who were current cigarette smokers at both intake and follow-up. RESULTS: Sixty three percent of smokers were ND (FTND score >= 4). Correlates of ND included older age, poorer self-rated overall health, earlier age of onset of cigarette smoking and substance abuse, fewer smoking quit attempts in past year, single substance use (alcohol or illicit drug, vs. multiple substances) at intake, use of opiates/narcotics and sedatives, and past month self-reported depression. CONCLUSION: ND was highly prevalent and correlated with specific types and patterns of substance abuse and depression. These results suggest that intensive smoking cessation interventions, involving behavioral support, pharmacotherapy, and mood management, are needed to effectively assist this population. PMID- 22542294 TI - Carcinogenic polycyclic aromatic hydrocarbons in umbilical cord blood of human neonates from Guiyu, China. AB - Unregulated electronic-waste recycling results in serious environmental pollution of polycyclic aromatic hydrocarbons (PAHs) in Guiyu, China. We evaluated the body burden of seven carcinogenic PAHs and potential health risks for neonates. Umbilical cord blood (UCB) samples were collected from Guiyu (n=103), and the control area of Chaonan (n=80), China. PAHs in UCB were determined by gas chromatography/mass spectrometry. The median ?7c-PAH concentration was 108.05 ppb in UCB samples from Guiyu, vs. 79.36 ppb in samples from Chaonan. Residence in Guiyu and longer cooking time of food during the gestation period were significant factors contributing to the ?7c-PAH level. Benzo[a]anthracene (BaA), chrysene (Chr), and benzo[a]pyrene (BaP) were found to correlate with reduced neonatal height and gestational age. Infants experiencing adverse birth outcomes, on the whole, displayed higher BaA, Chr, and BaP levels compared to those with normal outcomes. We conclude that maternal PAH exposure results in fetal accumulation of toxic PAHs, and that such prenatal exposure correlates with adverse effects on neonatal health. PMID- 22542295 TI - Can the joint effect of ternary mixtures be predicted from binary mixture toxicity results? AB - The joint effect of the majority of chemical mixtures can be predicted using the reference model of Concentration Addition (CA). It becomes a challenge, however, when the mixtures include chemicals that synergise or antagonise the effect of each other. In this study we examine if the deviation from CA of seven ternary mixtures of interacting chemicals can be predicted from knowledge of the binary mixture responses involved. We hypothesise that the strongest interactions will take place in the binary mixtures and that the size of the ternary mixture response can be predicted from knowledge of the binary interactions. The hypotheses were tested using a stepwise modelling approach of incorporating the information held in binary mixtures into a ternary mixture model, and comparing the model predictions with observed ternary mixture toxicity data derived from studies of interacting chemical mixtures on the floating plant Lemna minor and the bacteria Vibrio fischeri. The results showed that for both the antagonistic and the synergistic ternary mixtures the ternary model predictions were superior to the conventional CA reference model and provided robust estimations of the size of the experimentally derived ternary mixture toxicity effects. PMID- 22542296 TI - Microbiological quality indicators in waters of dairy farms: detection of pathogens by PCR in real time. AB - When contaminated water is used to wash the udders of dairy cattle and milking utensils, raw milk may become contaminated with pathogens. Washing with high quality water is essential to reduce the microbial contamination of milk. Furthermore, the wastewater generated in dairy herds also contains high populations of pathogens, antibiotics and nutrients that more often are thrown into the water bodies without any treatment. In this work, both supply water and wastewater from 20 dairy farms from Antioquia, Colombia was monitored for 10months to determine the presence of pathogenic microorganisms. Both Cryptosporidium and Fasciola were determined by the Polymerase Chain Reaction (PCR) technique in real time. The results showed that the supply water used for drinking and activities involving the herd, has high populations of Fasciola hepatica and Cryptosporidium parvum, with percentages of about 53.7% and 64.75% respectively. Additionally high populations of Pseudomonas aeruginosa, Shigella, Salmonella, total coliforms and Escherichia coli were found in both types of water, with values around 9.4*10(7), 2.1*10(7), 1.8*10(7), 1.9*10(10) and 1.5*10(10) UFC/100 ml respectively for the wastewater and 3.1*10(4), 1.9*10(4), 7.3*10(3), 1.2*10(5) and 6.2*10(3) UFC/100 ml for the supply water. PMID- 22542292 TI - RECQ1 plays a distinct role in cellular response to oxidative DNA damage. AB - RECQ1 is the most abundant RecQ homolog in humans but its functions have remained mostly elusive. Biochemically, RECQ1 displays distinct substrate specificities from WRN and BLM, indicating that these RecQ helicases likely perform non overlapping functions. Our earlier work demonstrated that RECQ1-deficient cells display spontaneous genomic instability. We have obtained key evidence suggesting a unique role of RECQ1 in repair of oxidative DNA damage. We show that similar to WRN, RECQ1 associates with PARP-1 in nuclear extracts and exhibits direct protein interaction in vitro. Deficiency in WRN or BLM helicases have been shown to result in reduced homologous recombination and hyperactivation of PARP under basal condition. However, RECQ1-deficiency did not lead to PARP activation in undamaged cells and nor did it result in reduction in homologous recombination repair. In stark contrast to what is seen in WRN-deficiency, RECQ1-deficient cells hyperactivate PARP in a specific response to H2O2treatment. RECQ1-deficient cells are more sensitive to oxidative DNA damage and exposure to oxidative stress results in a rapid and reversible recruitment of RECQ1 to chromatin. Chromatin localization of RECQ1 precedes WRN helicase, which has been shown to function in oxidative DNA damage repair. However, oxidative DNA damage-induced chromatin recruitment of these RecQ helicases is independent of PARP activity. As other RecQ helicases are known to interact with PARP-1, this study provides a paradigm to delineate specialized and redundant functions of RecQ homologs in repair of oxidative DNA damage. PMID- 22542297 TI - Fast changes in chemical composition and size distribution of fine particles during the near-field transport of industrial plumes. AB - Aerosol sampling was performed inside the chimneys and in the close environment of a FeMn alloys manufacturing plant. The number size distributions show a higher abundance of ultrafine aerosols (10-100 nm) inside the plume than upwind of the plant, indicating the emissions of nanoparticles by the industrial process. Individual analysis of particles collected inside the plume shows a high proportion of metal bearing particles (Mn-/Fe-) consisting essentially of internally mixed aluminosilicate and metallic compounds. These particles evolve rapidly (in a few minutes) after emission by adsorption of VOC gas and sulfuric acid emitted by the plant but also by agglomeration with pre-existing particles. At the moment, municipalities require a monitoring of industrial emissions inside the chimneys from manufacturers. However those measures are insufficient to report such rapid changes in chemical composition and thus to evaluate the real impact of industrial plumes in the close environment of plants (when those particles leave the industrial site). Consequently, environmental authorities will have to consider such fast evolutions and then to adapt future regulations on air pollution sources. PMID- 22542298 TI - Coadsorption of Cu and sulfamethoxazole on hydroxylized and graphitized carbon nanotubes. AB - Because of their various functional groups, antibiotics may complex with heavy metals and thus the environmental behaviors of both antibiotics and heavy metals may be altered. Noticing the experimental flaws of the previous studies, this study used Cu(2+) and sulfamethoxazole (SMX) as model sorbates and carbon nanotubes (CNTs) as model sorbents to investigate the coadsorption of Cu and SMX. Combining the results of binary interaction experiments, we concluded that Cu and SMX preferentially occupy different types of CNT sorption sites at pHs 1.0 and 3.5, showing no apparent sorption change with the presence of coadsorbates. However, at pH 6.5, ternary complexes of Cu-SMX-CNTs and SMX-Cu-CNTs may be formed depending on Cu(2+) concentrations. XPS data provided further support for the adsorption of both Cu and SMX on CNTs. These results indicated that the environmental behavior of antibiotics should be evaluated with careful consideration of the rule of metal ions. PMID- 22542299 TI - Nitrogen and phosphorus use efficiencies and losses in the food chain in China at regional scales in 1980 and 2005. AB - Crop and animal production in China has increased significantly during the last decades, but at the cost of large increases in nitrogen (N) and phosphorus (P) losses, which contribute to ecosystem degradation and human health effects. This information is largely based on scattered field experiments, surveys and national statistics. As a consequence, there is as yet no comprehensive understanding of the changes in N and P cycling and losses at regional and national scales. Here, we present the results of an integrated assessment of the N and P use efficiencies (NUE and PUE) and N and P losses in the chain of crop and animal production, food processing and retail, and food consumption at regional scale in 1980 and 2005, using a uniform approach and databases. Our results show that the N and P costs of food production-consumption almost doubled between 1980 and 2005, but with large regional variation. The NUE and PUE of crop production decreased dramatically, while NUE and PUE in animal production increased. Interestingly, NUE and PUE of the food processing sector decreased from about 75% to 50%. Intake of N and P per capita increased, but again with large regional variation. Losses of N and P from agriculture to atmosphere and water bodies increased in most regions, especially in the east and south of the country. Highest losses were estimated for the Beijing and Tianjin metropolitan regions (North China), Pearl River Delta (South China) and Yangzi River Delta (East China). In conclusion, the changes and regional variations in NUE and PUE in the food chain of China are large and complex. Changes occurred in the whole crop and animal production, food processing and consumption chain, and were largest in the most populous areas between 1980 and 2005. PMID- 22542300 TI - Dissolved organic carbon (DOC) concentrations in UK soils and the influence of soil, vegetation type and seasonality. AB - Given the lack of studies which measured dissolved organic carbon (DOC) over long periods, especially in non-forest habitat, the aim of this study was to expand the existing datasets with data of mainly non-forest sites that were representative of the major soil and habitat types in the UK. A further aim was to predict DOC concentrations from a number of biotic and abiotic explanatory variables such as rainfall, temperature, vegetation type and soil type in a multivariate way. Pore water was sampled using Rhizon or Prenart samplers at two to three week intervals for 1 year. DOC, pH, organic carbon, carbon/nitrogen (C:N) ratios of soils and slope were measured and data on vegetation, soil type, temperature and precipitation were obtained. The majority of the variation in DOC concentrations between the UK sites could be explained by simple empirical models that included annual precipitation, and soil C:N ratio with precipitation being negatively related to DOC concentrations and C:N ratio being positively related to DOC concentrations. Our study adds significantly to the data reporting DOC concentrations in soils, especially in grasslands, heathlands and moorlands. Broad climatic and site factors have been identified as key factors influencing DOC concentrations. PMID- 22542301 TI - Evaluation of fungal- and photo-degradation as potential treatments for the removal of sunscreens BP3 and BP1. AB - Photodecomposition might be regarded as one of the most important abiotic factors affecting the fate of UV absorbing compounds in the environment and photocatalysis has been suggested as an effective method to degrade organic pollutants. However, UV filters transformation appears to be a complex process, barely addressed to date. The white rot fungus Trametes versicolor is considered as a promising alternative to conventional aerobic bacterial degradation, as it is able to metabolise a wide range of xenobiotics. This study focused on both degradation processes of two widely used UV filters, benzophenone-3 (BP3) and benzophenone-1 (BP1). Fungal treatment resulted in the degradation of more than 99% for both sunscreens in less than 24 h, whereas photodegradation was very inefficient, especially for BP3, which remained unaltered upon 24 h of simulated sunlight irradiation. Analysis of metabolic compounds generated showed BP1 as a minor by-product of BP3 degradation by T. versicolor while the main intermediate metabolites were glycoconjugate derivatives. BP1 and BP3 showed a weak, but significant estrogenic activity (EC50 values of 0.058 mg/L and 12.5 mg/L, respectively) when tested by recombinant yeast assay (RYA), being BP1 200-folds more estrogenic than BP3. Estrogenic activity was eliminated during T. versicolor degradation of both compounds, showing that none of the resulting metabolites possessed significant estrogenic activity at the concentrations produced. These results demonstrate the suitability of this method to degrade both sunscreen agents and to eliminate estrogenic activity. PMID- 22542302 TI - Use of micro-PIXE to determine spatial distributions of copper in Brassica carinata plants exposed to CuSO4 or CuEDDS. AB - A better understanding of the mechanisms that govern copper (Cu) uptake, distribution and tolerance in Brassica carinata plants in the presence of chelators is needed before significant progress in chelate-assisted Cu phytoextraction can be made. The aims of this study were therefore to characterise (S,S)-N,N'-ethylenediamine disuccinic acid (EDDS)-assisted Cu uptake, and to compare the spatial distribution patterns of Cu in the roots and leaves of B. carinata plants. The plants were treated with 30 MUM or 150 MUM CuSO(4) or CuEDDS in hydroponic solution. Quantitative Cu distribution maps and concentration profiles across root and leaf cross-sections of the desorbed plants were obtained by micro-proton induced X-ray emission. In roots, the 30 MUM treatments with both CuSO(4) and CuEDDS resulted in higher Cu concentrations in epidermal/cortical regions. At 150 MUM CuSO(4), Cu was mainly accumulated in root vascular bundles, whereas with 150 MUM CuEDDS, Cu was detected in endodermis and the adjacent inner cortical cell layer. Under all treatments, except with a H(+) ATP-ase inhibitor, the Cu in leaves was localised mainly in vascular tissues. The incubation of plants with 150 MUM CuEDDS enhanced metal translocation to shoots, in comparison to the corresponding CuSO(4) treatment. Inhibition of H(+)-ATPase activity resulted in reduced Cu accumulation in 30 MUM CuEDDS-treated roots and 150 MUM CuEDDS-treated leaves, and induced changes in Cu distribution in the leaves. This indicates that active mechanisms are involved in retaining Cu in the leaf vascular tissues, which prevent its transport to photosynthetically active tissues. The physiological significance of EDDS-assisted Cu uptake is discussed. PMID- 22542303 TI - Annual variability in the radiocarbon age and source of dissolved CO2 in a peatland stream. AB - Radiocarbon dating has the capacity to significantly improve our understanding of the aquatic carbon cycle. In this study we used a new passive sampler to measure the radiocarbon ((14)C) and stable carbon (delta(13)C) isotopic composition of dissolved CO(2) for the first time in a peatland stream throughout a complete year (May 2010-June 2011). The in-stream sampling system collected time integrated samples of CO(2) continuously over approximately 1 month periods. The rate of CO(2) trapping was proportional to independently measured streamwater CO(2) concentrations, demonstrating that passive samplers can be used to estimate the time-averaged dissolved CO(2) concentration of streamwater. While there was little variation and no clear trend in delta(13)CO(2) values (suggesting a consistent CO(2) source), we found a clear temporal pattern in the (14)C concentration of dissolved CO(2). The (14)C age of CO(2) varied from 707+/-35 to 1210+/-39 years BP, with the youngest CO(2) in the autumn and oldest in spring/early summer. Mean stream discharge and (14)C content of dissolved CO(2) were positively correlated. We suggest that the observed pattern in the (14)C content of dissolved CO(2) reflects changes in its origin, with older carbon derived from deeper parts of the peat profile contributing proportionally more gaseous carbon during periods of low stream flow. PMID- 22542305 TI - Are benzodiazepines effective for alcohol withdrawal? PMID- 22542306 TI - Patients with rib fractures do not develop delayed pneumonia: a prospective, multicenter cohort study of minor thoracic injury. AB - STUDY OBJECTIVE: Patients admitted to emergency departments (EDs) for minor thoracic injuries are possibly at risk of delayed pneumonia. We aimed to evaluate the incidence of delayed pneumonia post-minor thoracic injury and the associated risk factors. METHODS: A prospective, multicenter cohort study was conducted in 4 Canadian EDs, from November 2006 to November 2010. All consecutive patients aged 16 years and older with minor thoracic injury who were discharged from the ED were screened for eligibility. Uniform clinical and radiologic evaluations were performed on the initial ED visit and were repeated at weeks 1 and 2. Relative risk analyses quantified incidence with comparison by age, sex, smoking status, alcohol intoxication, pulmonary comorbidity, ability to cough atelectasis, pain level, and number of rib fractures. RESULTS: Of the 1,057 participants recruited, 347 (32.8%) had at least 1 rib fracture, 87 (8.2%) had asthma, and 36 (3.4%) had chronic obstructive pulmonary disease. Only 6 patients (0.6%; 95% confidence interval 0.24% to 1.17%) developed pneumonia during the follow-up period. The relative risk for patients with preexistent pulmonary disease and radiologically proven rib fractures was 8.6 (P=.045; 95% confidence interval 1.05 to 70.9). Sex, smoking habit, initial atelectasis, ability to cough, and alcohol intoxication were not significantly associated with delayed pneumonia. CONCLUSION: This prospective cohort study of nonhospitalized patients with minor thoracic injuries revealed a low incidence of delayed pneumonia. Nonetheless, our results support tailored follow-up for asthmatic or chronic obstructive pulmonary disease patients with rib fracture. PMID- 22542304 TI - Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) as predictors of incident CKD stage 3: the Atherosclerosis Risk in Communities (ARIC) Study. AB - BACKGROUND: Identifying individuals at risk of chronic kidney disease (CKD) is critical for timely treatment initiation to slow progression of the disease. Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) are known biomarkers of acute kidney injury, but it is unknown whether these markers are associated with incident CKD stage 3 in the general population. STUDY DESIGN: Matched case-control study. SETTING & PARTICIPANTS: African American and white participants from the Atherosclerosis Risk in Communities (ARIC) Study who at baseline had an estimated glomerular filtration rate (eGFR) >=60 mL/min/1.73 m(2) and urinary albumin-creatinine ratio <=30 mg/g. 143 controls were matched for age, sex, and race to 143 cases of incident CKD stage 3 after 8.6 years of follow-up. PREDICTORS: Quartile of NGAL and KIM-1. OUTCOMES & MEASUREMENTS: Incident CKD stage 3 (eGFR <60 mL/min/1.73 m(2) at follow-up and a decrease in eGFR from baseline to follow-up >=25%). RESULTS: Both NGAL (P = 0.05) and KIM-1 levels (P < 0.001) were correlated positively with baseline urinary albumin-creatinine ratio; neither was associated with baseline eGFR. Participants with NGAL concentrations in the fourth quartile had more than 2-fold higher odds (adjusted OR, 2.11; 95% CI, 0.96-4.64) of incident CKD stage 3 compared with participants in the first quartile after multivariable adjustment (P-trend = 0.03). Adjustment for urinary creatinine and albumin levels resulted in a nonsignificant association (highest quartile adjusted OR, 1.52; 95% CI, 0.64 3.58; P = 0.2). No significant association between KIM-1 level and incident CKD was observed in crude or adjusted models. LIMITATIONS: The relatively small sample size of the study limits precision and power to detect weak associations. CONCLUSIONS: Higher NGAL, but not KIM-1, levels were associated with incident CKD stage 3. Adjustment for urinary creatinine and albumin concentration attenuated this association. Additional studies are needed to confirm these findings and assess the utility of urinary NGAL as a marker of CKD risk. PMID- 22542307 TI - Simulating various levels of clinical challenge in the assessment of clinical procedure competence. AB - STUDY OBJECTIVE: Immersive simulation is increasingly used for competency assessment of emergency physicians. This group's concept of hybrid simulation (HS) (combining simulated patients and part-task trainers (a simulator that simulates a limited component of a clinical procedure) to create a multimodal clinical context) requires clinicians to integrate technical and nontechnical skills in a holistic clinical performance for assessment. It also offers the potential to provide authentic simulation of a given clinical procedure across multiple levels of challenge. The aims of this study are to systematically design and validate 2 patient-focused HS scenarios (each combining a simulated patient with a part-task simulator) for assessment of the management of a commonly encountered problem in an emergency department (ED) at different levels of clinical challenge, and to explore the effect of level of challenge of the HS scenario on physicians' performance. METHODS: A simple (HS1) and a complex (HS2) HS scenario (based on the management of a patient with a traumatic skin laceration within the ED) was developed according to expert opinion through cognitive task analysis. Interns and emergency medicine residents (stratified into expert and novice groups according to experience) were recruited to participate in both scenarios. Participants were randomized to perform either the HS1 or HS2 scenario first. Participants completed a questionnaire for face validity (realism of simulation) and content validity (comprehensiveness of simulation). Performances were assessed by 2 independent raters using validated rating tools modified to the needs of this study: the Modified Objective Structured Assessment of Technical Skills-Task Specific Checklist, the Objective Structured Assessment of Technical Skills-Global Rating Score, and the Direct Observation of Procedural Skills. RESULTS: Ten novice and 10 expert clinicians completed both scenarios. Mean face and content validity ratings were high for both HS1 (mean 4.4 [SD 0.52] and 4.2 [SD 0.48], respectively) and HS2 scenarios (mean 4.5 [SD 0.35] and 4.3 [SD 0.43], respectively). In HS1, no difference was found between experts' and novices' Modified Objective Structured Assessment of Technical Skills-Task Specific Checklist, Objective Structured Assessment of Technical Skills-Global Rating Score, and Direct Observation of Procedural Skills ratings. Experts performed significantly better than novices in HS2 in terms of the 3 tools' ratings. Novices' Modified Objective Structured Assessment of Technical Skills-Task Specific Checklist and Direct Observation of Procedural Skills ratings were significantly worse in HS2 compared with HS1, but no difference was found with the Objective Structured Assessment of Technical Skills Global Rating Score. No statistical difference was found in experts' Modified Objective Structured Assessment of Technical Skills-Task Specific Checklist, Objective Structured Assessment of Technical Skills-Global Rating Score, and Direct Observation of Procedural Skills ratings between HS2 and HS1 scenarios. CONCLUSION: Recreating clinical challenge is an important consideration in the design of simulation-based assessment of procedural skills of clinicians. In this study, we have demonstrated a systematic approach to developing HS scenarios, which may be able to recreate various levels of clinical challenge for purpose of assessment of procedural skills. PMID- 22542308 TI - Does the use of recombinant factor VIIA reduce morbidity or mortality in nonhemophiliac patients? PMID- 22542309 TI - Comparative effectiveness of care coordination interventions in the emergency department: a systematic review. AB - STUDY OBJECTIVE: To conduct a systematic review on the effectiveness of emergency department (ED)-based care coordination interventions. METHODS: We reviewed any randomized controlled trial or quasi-experimental study indexed in MEDLINE, CINAHL, Web of Science, Cochrane, or Scopus that evaluated the effectiveness of ED-based care coordination interventions. To be included, interventions had to incorporate information from previous visits, provide educational services on continuing care, provide post-ED treatment plans, or transfer information to continuing care providers. Studies had to quantify information transfer or report ED revisits, hospitalizations, or follow-up rates. Randomized controlled trial quality was assessed with the Jadad score. RESULTS: Of 23 included articles, 14 were randomized controlled trials and 9 were quasi-experimental studies. Randomized controlled trial quality ranged from 2 to 3 on a 5-point scale. The majority of the studies (17) were conducted at a single center. Of nineteen studies that developed post-ED plans, 12 were effective in improving follow-up rates or reducing repeated ED visits. Four studies found paradoxically higher ED visit rates. Of 4 that used educational services for continuing care, 2 were effective. Of the 2 evaluating information transfer, 1 was effective. One study assessed incorporating information from other sites and found higher rates of information transfer, but utilization was not studied. CONCLUSION: The majority of ED-based care coordination interventions focus on interfacing with outpatient providers, and about two thirds have been effective in increasing follow-up rates or reducing repeated ED utilization. Other types of interventions have shown similar effectiveness, but fewer have been studied. PMID- 22542310 TI - Head computed tomography use in the emergency department for mild traumatic brain injury: integrating evidence into practice for the resident physician. PMID- 22542311 TI - Emergency department patients' preferences for technology-based behavioral interventions. AB - STUDY OBJECTIVE: To assess emergency department (ED) patients' preferences for technology-based behavioral interventions, and the demographic factors associated with these preferences. METHODS: A cross-sectional survey of a random sample of urban ED patients (>=13 years) from a representative sample of shifts, with oversampling of adolescents/young adults (aged 13 to 24 years). Participants self administered the survey about baseline technology use, concerns about technology based interventions, and preferred intervention format for 7 behavioral health topics. We performed descriptive statistics and multivariate logistic regression (controlling for demographics and then additionally for baseline technology use) to identify factors differentially associated with technology preference for each behavioral topic. RESULTS: Of patients presenting during research assistant shifts, 1,429 (~59%) were screened and 664 (68.2% of eligible) consented to participate. Mean age was 31 years (SD 0.69); 54.5% were female, 64.1% were white, 23.2% were Hispanic, and 46.6% reported low income. Baseline use of computers (91.2%), Internet (70.7%), social networking (66.9%), mobile phones (95.0%), and text messaging (73.8%) was high. Participants reported interest in receiving interventions on each behavioral topic. Ninety percent preferred a technology-based intervention for at least 1 topic. Patients expressed greatest concerns about Internet (51.5%) and social networking (57.6%), particularly about confidentiality. Adjusting for sex, race, ethnicity, and income, younger age associated with preference for technology-based interventions for unintentional injuries (odds ratio 0.63 for technology preference if adult versus youth; 95% confidence interval 0.45 to 0.89) and peer violence (odds ratio 0.63 if adult; 95% confidence interval 0.43 to 0.92). Additionally adjusting for baseline technology usage, only baseline usage was associated with preference for technology-based interventions. CONCLUSION: ED patients reported high baseline technology use, high interest in behavioral health interventions, and varying preferences for technology-based interventions. Future studies should address actual feasibility and acceptability of technology-based interventions in a more generalized population and ways to alleviate concerns about these interventions. PMID- 22542313 TI - Position-controlled marker formation by helium ion microscope for aligning a TEM tomographic tilt series. AB - We formed nano-dots using a helium ion microscope (HIM) equipped with a gas injection system. Because of position controllability, the nano-dot markers could be placed efficiently on a specimen using the HIM. The sizes of the dots were controlled by changing the beam radiation time. We tried for the first time to form dots on a rod-shaped specimen to use them as markers for aligning a transmission electron microscope tomographic tilt series before reconstructing 3D images. PMID- 22542314 TI - Introduction. PMID- 22542315 TI - Biomarkers: an overview for oncology nurses. AB - OBJECTIVES: To provide an overview of the basic principles of biomarker use in clinical oncology practice and discuss the range of biomarker forms (from genes to constitutional characteristics), biomarker functions (both disease- and drug related), modalities (protein expression patterns to patient history), the criteria for biomarker validation, and the integral role of bioinformatics. DATA SOURCES: Published nursing and medical literature. CONCLUSION: The premise of nursing assessment is the same as that of biomarker use - biological variables that appear at one level of biological organization (eg, molecule, organelle, cell, tissue, organ, and organism) correspond to processes or events occurring at other levels of biologic organization. The advent of genomic technologies has logarithmically increased the volume of biomarkers, which are expected to provide new insights that improve patient care. IMPLICATIONS FOR NURSING PRACTICE: Nurses and patients will benefit greatly from the incorporation of molecular biomarkers into patient care. Nurses will be able to better assess (and anticipate) patient needs with the new insights that are available in the post-genomic, personalized medicine era of health care. Although the rapid rate of technological changes and new discoveries will require continuing concerted educational efforts, the improved quality of patient care will be rewarded by better outcomes. PMID- 22542316 TI - Oncology biomarkers: discovery, validation, and clinical use. AB - OBJECTIVES: To discuss the discovery, validation, and clinical use of multiple types of biomarkers. DATA SOURCES: Medical literature and published guidelines. CONCLUSION: Formal validation of biomarkers should include both retrospective analyses of well-characterized samples as well as a prospective clinical trial in which the biomarker is tested for its ability to predict the presence of disease or the efficacy of a cancer therapy. IMPLICATIONS FOR NURSING PRACTICE: Biomarker development is complicated, with very few biomarker discoveries leading to clinically useful tests. Nurses should understand how a biomarker was developed, including the sensitivity and specificity before applying new biomarkers in the clinical setting. PMID- 22542317 TI - Biomarkers as surrogate endpoints in cancer trials. AB - OBJECTIVES: To define and discuss surrogate endpoint biomarkers, which are used in therapeutic trials as a substitute for the clinically meaningful "true" endpoint; and hence, may be used in answering cancer prevention questions in clinical trials evaluating drug/nutrient interventions for a number of common cancer sites. DATA SOURCES: Literature, research articles. CONCLUSION: Surrogate endpoint biomarkers offer greater efficiency in clinical studies because they may allow for the generation of useful results from studies that are of shorter duration using smaller numbers of study participants in clinical trials for treatment and prevention of cancer. IMPLICATION FOR NURSING PRACTICE: Continual changes in the science of cancer diagnosis and prevention demand rigorous scientific knowledge of the professional nurse to optimize the outcome of cancer prevention drug/agent development and the delivery of evidence-based care. PMID- 22542318 TI - Biomarkers as molecular targets of drug interventions. AB - OBJECTIVES: To present an overview of biomarkers used in a multiplicity of roles, including as targets of therapeutic intervention for several organ sites. DATA SOURCES: Journal articles and book chapters from medical and nursing literature, and internet resources. CONCLUSION: A single molecular marker may function in a variety of roles (ie, markers of risk, diagnostics, prognostics, intermediate endpoints). In some instances the molecule can also function as a target of therapeutic intervention. IMPLICATIONS FOR NURSING PRACTICE: Nursing implications include a better understanding of the nature of biomarkers and the multiplicity of their applications, especially with regard to therapeutic targets. PMID- 22542319 TI - The role of biomarkers in cancer clinical trials. AB - OBJECTIVES: To review strategies to incorporate biomarkers into screening studies, and prevention and therapeutic clinical trials. DATA SOURCES: Published research articles. CONCLUSION: The incorporation of biomarkers into cancer clinical trials has been an important advancement in the last two decades of cancer research and has been critical to increasing our understanding of cancer across the spectrum from early lesions to frank cancers. While the incorporation of biomarkers into studies may increase the significance of the results, they also increase cost and a burden on research subjects. IMPLICATIONS FOR NURSING PRACTICE: It is important for nurses to have an understanding of both the science and the implications of the biomarkers. PMID- 22542320 TI - Genetic biomarkers of cancer risk. AB - OBJECTIVES: To provide a review of genetic biomarkers of cancer risk and associated clinical implications. DATA SOURCES: Published literature, evidence based guidelines. CONCLUSION: Identification of the genetic variation associated with cancer risk enables the health care provider to stratify an individual's risk and personalize their cancer risk management. This may lead to a decreased cancer incidence in high-risk populations, but at a minimum, will provide the opportunity for early diagnosis that may decrease cancer morbidity and mortality. IMPLICATIONS FOR NURSING PRACTICE: Nursing implications include assessment for cancer risk, initiate referrals indicated, and delivering ongoing education and support for cancer risk management plans. PMID- 22542322 TI - Supportive care in lung cancer: clinical update. AB - OBJECTIVES: To present a clinical update regarding common distressing lung cancer symptoms and provide an update on management interventions. DATA SOURCES: Journal articles, systematic reviews. CONCLUSION: Goals of treatment of the patient with lung cancer must include management of the high symptom burden that often accompanies the disease. IMPLICATIONS FOR NURSING PRACTICE: Early assessment and management of symptoms improves quality of life. Nurses play a key role in implementing and monitoring these interventions. PMID- 22542321 TI - Biomarkers: symptoms, survivorship, and quality of life. AB - OBJECTIVES: To review the evidence on a number of biomarkers that show potential clinical utility in the prediction of and treatment responsiveness for the four most common symptoms associated with cancer and its treatment (ie, pain, fatigue, sleep disturbance, depression). DATA SOURCES: Review and synthesis of review articles and data-based publications. CONCLUSION: A growing body of evidence suggests that sensitive and specific biomarkers will be available to assist clinicians with the assessment and management of symptoms. IMPLICATIONS FOR NURSING PRACTICE: Nurses will play a critical role in educating patients about their risk for specific symptoms based on an evaluation of specific biomarkers. Nurses will be involved in using biomarker data to titrate medications based on patient's responses to symptom management interventions. PMID- 22542323 TI - Primate enamel evinces long period biological timing and regulation of life history. AB - The factor(s) regulating the combination of traits that define the overall life history matrix of mammalian species, comprising attributes such as brain and body weight, age at sexual maturity, lifespan and others, remains a complete mystery. The principal objectives of the present research are (1) to provide evidence for a key variable effecting life history integration and (2) to provide a model for how one would go about investigating the metabolic mechanisms responsible for this rhythm. We suggest here that a biological rhythm with a period greater than the circadian rhythm is responsible for observed variation in primate life history. Evidence for this rhythm derives from studies of tooth enamel formation. Enamel contains an enigmatic periodicity in its microstructure called the striae of Retzius, which develops at species specific intervals in units of whole days. We refer to this enamel rhythm as the repeat interval (RI). For primates, we identify statistically significant relationships between RI and all common life history traits. Importantly, RI also correlates with basal and specific metabolic rates. With the exception of estrous cyclicity, all relationships share a dependence upon body mass. This dependence on body mass informs us that some aspect of metabolism is responsible for periodic energy allocations at RI timescales, regulating cell proliferation rates and growth, thus controlling the pace, patterning, and co-variation of life history traits. Estrous cyclicity relates to the long period rhythm in a body mass-independent manner. The mass dependency and -independency of life history relationships with RI periodicity align with hypothalamic-mediated neurosecretory anterior and posterior pituitary outputs. We term this period the Havers-Halberg Oscillation (HHO), in reference to Clopton Havers, a 17th Century hard tissue anatomist, and Franz Halberg, a long-time explorer of long-period rhythms. We propose a mathematical model that may help elucidate the underlying physiological mechanism responsible for the HHO. PMID- 22542324 TI - Ordered mesoporous carbon nanoparticles with well-controlled morphologies from sphere to rod via a soft-template route. AB - A facile soft-template method is used to synthesize highly ordered mesoporous carbon nanoparticles (MCNs) with well-controlled morphology from spherical to rod like structures. Low-molecular-weight phenolic resol is used as carbon-yielding component and triblock copolymer Pluronic F127 as pore-forming component. The morphology of nanoparticles could be tuned by well controlling the concentration of F127. The results show that rod-shaped and worm-like mesoporous carbon nanoparticles can be obtained when the concentration of F127 is set at ~12 wt.% and 9 wt.%, respectively. The spherical nanoparticles are obtained when the concentration is reduced to 6 wt.%, and their size can be adjusted by further decreasing the F127 concentration. Moreover, the highly ordered mesostructure can be readily turned from 2D hexagonal (p6m) to 3D caged cubic (Im 3m) along with the tuning of morphologies from rod-shaped to spherical. The as-obtained MCNs exhibit large surface area (~1385 m(2)/g), high pore volume (~0.919 cm(3)/g), highly ordered mesostructure, and continuous electron transport framework. Hence, the obtained mesoporous carbon materials show excellent capacitance (~142 F/g at loading current density of 0.5A/g) in the application of supercapacitors. PMID- 22542325 TI - Overexpression of methionine adenosyltransferase II alpha (MAT2A) in gastric cancer and induction of cell cycle arrest and apoptosis in SGC-7901 cells by shRNA-mediated silencing of MAT2A gene. AB - The aim of this study was to clarify the methionine adenosyltransferase II alpha (MAT2A) expression pattern and to explore its potential role in gastric cancer. Quantitative real-time PCR was performed to examine MAT2A mRNA expression in 20 cases of gastric cancer tissues and corresponding non-tumor tissue samples. Immunohistochemistry was conducted to detect MAT2A protein expression in 91 gastric cancer tissues. Moreover, the stable cell lines transfected with the small hairpin RNA (shRNA) targeting MAT2A mRNA plasmids were established and the biological characteristics of these cells were examined. The expression levels of MAT2A mRNA in gastric cancer tissues were significantly higher than those in corresponding non-tumor tissues. High-level MAT2A expression was observed in 40.7% (37 of 91 cases), and correlated with tumor classification (P=0.012), lymph node metastasis (P=0.001) and poor tumor differentiation (P=0.011) of gastric cancer patients. Additionally, the MAT2A expression level was significantly decreased in the transfected cells with MAT2A specific shRNA expression plasmid pGCsi-H1-792. The stable transfected cancer cells exhibited a decrease in growth ability and an increase in the incidence of spontaneous apoptosis and the percentage of the G1 phase. Our data suggest that MAT2A plays an important role in gastric cancer development and progression. PMID- 22542326 TI - An endoscopic 3D scanner based on structured light. AB - We present a new endoscopic 3D scanning system based on Single Shot Structured Light. The proposed design makes it possible to build an extremely small scanner. The sensor head contains a catadioptric camera and a pattern projection unit. The paper describes the working principle and calibration procedure of the sensor. The prototype sensor head has a diameter of only 3.6mm and a length of 14mm. It is mounted on a flexible shaft. The scanner is designed for tubular cavities and has a cylindrical working volume of about 30mm length and 30mm diameter. It acquires 3D video at 30 frames per second and typically generates approximately 5000 3D points per frame. By design, the resolution varies over the working volume, but is generally better than 200MUm. A prototype scanner has been built and is evaluated in experiments with phantoms and biological samples. The recorded average error on a known test object was 92MUm. PMID- 22542327 TI - Fast versus slow onset of depressive episodes: a clinical criterion for subtyping patients with major depression. AB - PURPOSE: The speed of onset of depressive episodes is a clinical aspect of affective disorders that has not been sufficiently investigated. Thus, we aimed to explore whether patients with fast onset of the full-blown depressive symptomatology (<=7 days) differ from those with slow onset (>7 days) with regard to demographic and clinical aspects. SUBJECTS AND METHODS: Data were obtained within an observational study conducted in outpatients with major depression who were treated with duloxetine (30-120 mg/day). Onset of depression (without any preceding critical life event) was fast in 416 (less than one week) and slower in 2220 patients. RESULTS: Compared to patients with slow onset, those with fast onset of depression had more suicide attempts in the previous 12 months (2.7% versus 1.3%, P=0.046) and less somatic comorbidity (61.7% versus 74.1%, P<0.0001). In addition, they were slightly younger at onset of depression (mean+/ SD 40.2+/-14.6 versus 42.8+/-14.2 years, P<0.001) and used analgesics at baseline significantly less frequently (22.8% versus 33.4%, P<0.0001). DISCUSSION AND CONCLUSION: The speed of onset of depression has to be regarded as a relevant clinical characteristic in patients with unipolar depression. PMID- 22542328 TI - Treatment patterns and costs in patients with generalised anxiety disorder: one year retrospective analysis of data from national registers in Sweden. AB - PURPOSE: To investigate medication use, direct healthcare costs and comorbidities in patients with generalised anxiety disorder (GAD) within specialised care in Sweden 2006-2007. METHODS: A retrospective study was conducted using data from the National Patient Register and the Swedish Prescribed Drug Register. All patients with a primary GAD (ICD-10) diagnosis in 2006 were followed for 12 months to study medication use and health care consumption. Resource use was evaluated from the number of hospitalisation episodes, number of visits to outpatient care and medication dispensed. Costs were calculated by multiplying the number of visits and hospitalisation episodes with the corresponding unit costs. Descriptive statistics were used for all analyses. RESULTS: Three thousand seven hundred and one patients with a primary GAD diagnosis were included in the study. Thirty-four percent of the patients (n=1246) had at least one secondary comorbid diagnosis. SSRIs/SNRIs were the most commonly dispensed medications, followed by benzodiazepine-anxiolytics, hypnotics and antihistamines. The mean number of treatment days for all medications prescribed and dispensed was highest (1144 days) for elderly women aged 65 years or more (treatment days per patient could exceed 365 days due to multiple concomitant medication use). Elderly patients were frequently prescribed benzodiazepine-anxiolytics (n=92/117 men [79%]; n=238/284 women [84%]) and hypnotics (n=70 men [60%]; n=178 women [63%]) compared to the overall study population (n=612/1303 men [47%] and n=935/2398 women [39%], respectively). GAD-related direct costs accounted for 96% of all direct costs. Mean number of hospitalisation days and corresponding costs were high (19 days; SEK 92,156; n=358 [9.7%]) in relation to medication (SEK 5520; n=3352 [91%]) and outpatient costs (SEK 7698; n=3461 [94%]). CONCLUSIONS: The high rate of polypharmacy, significant psychiatric comorbidity and widespread use of benzodiazepine-anxiolytics and medications not indicated for GAD suggest that the disease burden is high. Total direct costs associated with the disease were high but still likely to be underestimated. PMID- 22542329 TI - The use of mental health services by adolescent smokers: a nationwide Israeli study. AB - In this study, we aimed to evaluate the utilization of mental health services by adolescent smokers, the presence of untreated mental disorders in this young population and the associated emotional and behavioral difficulties. We performed a nationwide survey study of an Israeli representative sample of 906 adolescents and their mothers. Mental disorders were assessed using the Development and Well Being Assessment (DAWBA) Inventory. Emotional and behavioral difficulties were evaluated using the Strengths and Difficulties Questionnaire (SDQ). Mental health services use and smoking habits were evaluated by relevant questionnaires. Adolescent smokers were using significantly more mental health services than non smokers (79% vs. 63%, respectively, P<0.001), independently of their mental health status or ethnic group. Adolescent smokers also reported more emotional and behavioral difficulties in most areas (P<0.001), which are consistent with their mothers' reports, except in the area of peer relationships. The treatment gap for the smoking adolescents was 53% compared to 69% in the non-smokers (P<0.001). This is the first study characterizing the use of mental health services and the related emotional and behavioral difficulties in a nationally representative sample of adolescents. The findings of a wide treatment gap and the rates of the associated emotional and behavioral difficulties are highly relevant to the psychiatric assessment and national treatment plans of adolescent smokers. PMID- 22542330 TI - Neuronal correlates of appetite regulation in patients with schizophrenia: is there a basis for future appetite dysfunction? AB - BACKGROUND: Given the undesired metabolic side effects of atypical antipsychotic medication it is important to understand the neuronal basis related to processing of appetite regulation in patients affected by schizophrenia. METHODS: Here we used functional magnetic resonance imaging (fMRI) to assess brain activity in response to food cues and neutral stimuli in twenty patients with schizophrenia and eleven healthy individuals. In addition to clinical and dietary habits assessments, we collected, in patients, measurements of fasting glucose, ghrelin, leptin, insulin, prolactin and lipids blood concentration and we correlated the cerebral activity with clinical and metabolic measures. RESULTS: Both groups engaged a common neuronal network while processing food cues, which included the left insula, primary sensorimotor areas, and inferior temporal and parietal cortices. Cerebral responses to appetitive stimuli in thalamus, parahippocampus and middle frontal gyri were specific only to schizophrenic patients, with parahippocampal activity related to hunger state and increasing linearly over time. Antipsychotic medication dosage correlated positively with a cognitive measure reflecting food cravings, whereas the severity of the disease correlated negatively with a cognitive measure indicating dietary restraint in eating habits. These cognitive variables correlated, in turn, with parahippocampal and thalamic neuronal activities, respectively. CONCLUSIONS: We identified a specific neural substrate underlying cognitive processing of appetitive stimuli in schizophrenia, which may contribute to appetite dysfunction via perturbations in processing of homeostatic signals in relation to external stimuli. Our results also suggest that both antipsychotic medication and the disease severity per se could amplify these effects, via different mechanisms and neuronal networks. PMID- 22542331 TI - Osteoplasty flap technique for repair of latent (30-year) post-traumatic frontal sinus mucocele: case report and review of the literature. AB - Mucoceles are benign, slow-growing lesions defined as mucus-filled pseudocystic formations. Paranasal mucoceles predominantly affect the frontal sinus (60% to 65%), followed in frequency by the ethmoidal (20% to 30%), maxillary (10%), and sphenoid (2% to 3%) sinuses. Mucoceles usually arise because of sinus ostium obstruction, preceded by infection, fibrosis, inflammation, trauma, surgery or tumors such as osteomas. Mucoceles arising from the frontal sinus present with a variety of clinical signs, including decreased visual acuity, visual field abnormalities, proptosis, ptosis, periorbital swelling, displacement of the globe, restricted ocular movements, and choroidal folds. We describe a case of orbital involvement from a mucocele of the frontal sinus 30 years after the initial trauma, with a review of the published data concerning the etiology, diagnosis, and treatment planning. PMID- 22542332 TI - Does a pulsed mode offer advantages over a continuous wave mode for excisional biopsies performed using a carbon dioxide laser? AB - PURPOSE: Animal studies of excisional biopsies have shown less thermal damage when a carbon dioxide (CO(2)) laser (10.6 MUm) is used in a char-free (CF) mode than in a continuous-wave (CW) mode. The authors' aim was to evaluate and compare clinical and histopathologic findings of excisional biopsies performed with CW and CF CO(2) laser (10.6 MUm) modes. MATERIALS AND METHODS: This prospective randomized controlled clinical trial included 60 patients with similar fibrous hyperplasias of the buccal plane willing to undergo excisional CO(2) laser biopsy. Patients were randomly allocated to the CW (5 W) or CF (140 Hz, 400 MUs, 33 mJ) group. Duration of surgery, intra- and postoperative complications, and the width (micrometers) of the histopathologic collateral thermal damage zone were registered as primary outcome variables. Secondary outcome variables were pain (patients filled in a visual analog scale [VAS]) and analgesic intake (recorded by patients). RESULTS: The study group consisted of 36 women and 24 men with a median age of 50.5 years. Median durations of surgery were 74.5 seconds in the CW group and 83.5 seconds in the CF group. Intraoperative venous bleeding occurred in 16.7% of patients in the CW group and in 13.3% of patients in the CF group. Median areas of histopathologic collateral damage zones were similar in the CW group (166.5 MUm) and the CF group (162.5 MUm). There was no statistically significant difference between the VAS values of the 2 groups. Analgesic intake was recorded by 16.7% of patients in the CW group and by 6.7% of patients in the CF group (P = .23, not significant). No statistically significant correlation was found between areas of thermal damage zones and postoperative VAS scores. CONCLUSIONS: In contrast to previous animal studies, no significant difference was found in the widths of thermal damage zones between the CW and CF groups. The VAS values and analgesic intake were low in the 2 groups. The 2 CO(2) laser modes are appropriate for the excision of intraoral mucosal lesions. A safety border of at least 1 mm is recommended regardless of the laser mode used. PMID- 22542333 TI - Ameloblastic fibrosarcoma of the mandible: treatment, long-term follow-up, and subsequent reconstruction of a case. PMID- 22542334 TI - Effect of different methods for decontaminating tooth enamel after contact with blood before bonding orthodontic buttons. AB - PURPOSE: To evaluate the best method for decontaminating tooth enamel contaminated by contact with blood before bonding orthodontic buttons. MATERIALS AND METHODS: The labial surfaces of 195 bovine incisors initially received prophylaxis, followed by 37% phosphoric acid etching, adhesive application, and light polymerization. After this, the labial surfaces of all teeth were contaminated with blood. The teeth were then randomly divided into 13 groups (n = 15), comprising the control group (treated according to the manufacturer's recommendations) and 12 experimental groups treated by the following decontamination methods: group 1, no decontamination; group 2, washing with distilled water; group 3, washing with physiologic solution; group 4, jets of air; group 5, gauze; group 6, cotton wool; group 7, distilled water plus jets of air; group 8, distilled water plus gauze; group 9, distilled water plus cotton wool; group 10, physiologic solution plus jets of air; group 11, physiologic solution plus gauze; and group 12, physiologic solution plus cotton wool. RESULTS: No statistical differences were shown between the control group and groups 4, 7, 10, and 11 (P > .05). The lowest bond strength values were shown in group 1, in which no decontamination was performed, and groups 6 and 12, which were decontaminated with cotton wool and physiologic solution plus cotton wool, respectively. CONCLUSIONS: The best method of decontaminating enamel contaminated with blood is washing with physiologic solution, followed by drying with jets of air and gauze or drying with jets of air only. PMID- 22542335 TI - Global doctor opinion versus a patient questionnaire for the outcome assessment of treated temporomandibular disorder patients. AB - PURPOSE: Accurately assessing treatment outcomes has become increasingly important for maintaining hospital privileges. When these assessments are based on the judgment of the treating doctor, there is often an inherent positive bias. As a result, there has been increased interest in using patient-based assessments. The purpose of this study was to compare doctor's and patient's assessments of the outcomes of treatment in a series of patients with various temporomandibular disorders (TMDs). MATERIALS AND METHODS: Fifty-two consecutive TMD patients were initially given a questionnaire designed to evaluate their pain, problems eating and sleeping, the occurrence of headache and earache, the presence of temporomandibular joint pain and/or jaw stiffness in the morning, and interference with daily activity. The patients then filled out the same questionnaire at each post-treatment visit, and the findings were compared with the baseline information. At each visit, the treating doctor also recorded a global evaluation of the patient's progress as excellent, good, fair, or poor. RESULTS: Comparison of the doctor's global evaluation with the patient's evaluation based on the questionnaire showed a discrepancy in 44% of the cases. When there was a discrepancy, the doctor scored the improvement better than the patient 54.5% of the time and worse than the patient 45.5% of the time. CONCLUSIONS: The results of this study confirm the unreliability of using a global opinion by the treating doctor for outcome assessment in patients with various TMDs. PMID- 22542336 TI - Juvenile mandibular chronic osteomyelitis: 3 cases and a literature review. PMID- 22542337 TI - Diagnosable and non-diagnosable causes of death by postmortem computed tomography: a review of 339 forensic cases. AB - Postmortem computed tomography (PMCT) is often used to diagnose causes of death, especially in nations with a low autopsy rate. To identify the causes of death that can and cannot be determined by PMCT, imaging findings were reviewed in 339 consecutive forensic autopsy cases. Causes of death could be determined based on PMCT findings alone in 7% of these cases, based on suggestive PMCT findings with additional information in 54%, and could not be determined by PMCT in 38%. PMCT screening may be useful for establishment of some causes of death, including traumatic intracranial hematoma, endogenous intracranial hemorrhage, and some cases of cardiac rupture. Suggestive findings from PMCT in other cases, such as those involving subarachnoid hemorrhage or pericardial hematoma, can lead to misdiagnosis and may be a pitfall of PMCT screening. Causes of death including some cases of cervical cord injuries, asphyxiation, burn, drug intoxication, acute myocardial infarction, and pulmonary thromboembolism cannot be diagnosed using PMCT. PMID- 22542338 TI - Invited commentary. PMID- 22542339 TI - Higher mortality in patients hospitalized for acute aortic rupture or dissection during weekends. AB - BACKGROUND: The management of acute aortic aneurysm rupture or dissection (AARD) requires specific medical expertise, diagnostic techniques, and therapeutic options, not always available in all hospitals through the entire week. The aim of our study was to evaluate whether an association exists between weekday (WD) or weekend (WE) admission and mortality for patients with ARRD. METHODS: Based on the database of routinely collected hospital admissions of the region of Emilia Romagna (RER) of Italy, we examined the discharge sheets of all patients with AARD (January 1999 to December 2009). The risk of in-hospital death was calculated for admissions on the WE compared with the admissions during a WD. RESULTS: The analysis considered 4559 events in 4461 patients. AARD admissions were most frequent on Monday (14.7%) and Friday (14.8%) and less frequent on Saturday (12.6%). The percentage of events admitted on Sunday/holiday was 15.0%, whereas the distribution of death rate with respect to day of admission was significantly different (chi(2) = 23.472; P < .001) with the highest frequency peak on Sunday/holiday (17.4%) and the lowest on Tuesday (12.9%). WE admissions were associated with significantly higher in-hospital mortality (43.4%) than WD admissions (36.9%, P < .001). Multivariate regression analysis showed that WE admission was an independent risk factor for increased in-hospital mortality odds ratio 1.318; 95% confidence interval, 1.144-1.517; P < .001). CONCLUSIONS: Our findings show that hospitalization for AARD on WE is associated with a significantly higher mortality rate than hospitalization on WD. Further studies are needed to investigate whether ensuring optimal diagnostic and therapeutic approaches during the entire week might improve the overall survival of patients with ARRD. PMID- 22542340 TI - Invited commentary. PMID- 22542341 TI - Invited commentary. PMID- 22542342 TI - Invited commentary. PMID- 22542343 TI - Invited commentary. PMID- 22542344 TI - Class I obesity is paradoxically associated with decreased risk of postoperative stroke after carotid endarterectomy. AB - INTRODUCTION: Although obesity is a risk factor for vascular disease, previous studies have shown an obesity paradox with decreased mortality in obese patients undergoing vascular surgery. This study examined the relationship between body mass index (BMI) and outcomes after carotid endarterectomy (CEA). METHODS: The 2005-2009 American College of Surgeons National Surgical Quality Improvement Program database was queried to evaluate 30-day outcomes after isolated CEA across National Institutes of Health-defined obesity classes. chi(2) analysis was used to assess the unadjusted relationship of BMI category to postoperative outcomes. The independent association of BMI with morbidity and mortality was assessed with multivariable logistic regression, adjusting for preoperative and operative characteristics. RESULTS: In the cohort of 23,652 CEA, 1.8% of patients were underweight (BMI <18.5), 26.6% were normal weight (BMI 18.5-24.9), 39.4% were overweight (BMI 25.0-29.9), 21.1% were class I obese (BMI 30.0-34.9), 7.5% were class II obese (BMI 35.0-39.9), and 3.5% were class III obese (BMI >= 40). The overall stroke and mortality rates were 1.4% and 0.6%, respectively. On univariable analysis, there were U-shaped relationships between death (P = .017) and stroke (P = .029), with the lowest incidence in overweight and class I obese patients. The incidence of surgical site infection (SSI) (P = .021) increased incrementally with increasing BMI. On multivariable analysis, class I obesity was the only variable associated with decreased risk of stroke (odds ratio [OR], 0.51; 95% confidence interval [CI], 0.31-0.83; P = .007). Independent risk factors for stroke were previous transient ischemic attack (OR, 1.97; P = .006), American Society of Anesthesiologists class 4 to 5 (OR, 1.62; P = .010), surgery performed by a nonvascular surgeon (OR, 1.85; P = .015), and hemiplegia (OR, 1.97; P = .018). There was also a trend, although not statistically significant, toward decreased mortality risk associated with class I obesity (OR, 0.53; 95% CI, .26-1.08; P = .080). Class II obesity was associated with an increased risk of SSI compared with normal weight (OR, 2.21; 95% CI, 1.01-4.82; P = .047). BMI category was not associated with the risk of myocardial infarction. CONCLUSIONS: An obesity paradox exists for stroke and mortality after CEA; for stroke, but not mortality, this protective association was independent of patient demographics and comorbidities. Obesity is not a contraindication to CEA, and surgeons may safely undertake CEA in obese patients when indicated. PMID- 22542345 TI - Thoracic outlet syndrome caused by pseudoarticulation of a cervical rib with the scalene tubercle of the first rib. PMID- 22542346 TI - Preaortic left primitive iliac vein. PMID- 22542348 TI - Invited commentary. PMID- 22542347 TI - Comparison of the five 2011 guidelines for the treatment of carotid stenosis. AB - In 2011, five independent, international guideline committees reported their recommendations for the management of symptomatic and asymptomatic carotid artery stenosis. These included the American College of Cardiology/American Heart Association, the Society for Vascular Surgery, the European Society of Cardiology, the Australasian, and the UK National Institute of Health and Clinical Excellence. As the recommendations of these five guideline committees were based on the same published literature, it would be expected that they are similar, at least to a large extent. Surprisingly, there were considerable differences between the five guidelines regarding the management of both symptomatic and asymptomatic carotid patients. The differences in the recommendations between the five Guideline Committees are analyzed and discussed. PMID- 22542349 TI - The Society for Vascular Surgery Vascular Quality Initiative. AB - The Society for Vascular Surgery (SVS) Vascular Quality Initiative (VQI) is designed to improve the quality, safety, effectiveness, and cost of vascular health care. It uses the structure of a Patient Safety Organization to permit collection of patient-identified information but protect benchmarked comparisons from legal discovery. The SVS VQI is uniquely organized as a distributed network of regional quality groups to facilitate local translation of registry data into practice change while maintaining the power of a national registry. Detailed data specific to each commonly performed open and endovascular procedure are collected, both in-hospital and at >= 1 year of follow-up. Quality measures are reported to physicians and hospitals, which allow anonymous risk-adjusted benchmarking within regions or nationally. All specialties that perform vascular procedures are included, and international participation is encouraged. This review describes the current status of the SVS VQI. PMID- 22542351 TI - Regarding "Trends in the national outcomes and costs for claudication and limb threatening ischemia: angioplasty vs bypass graft". PMID- 22542352 TI - Regarding "A comparison of covered vs bare expandable stents for the treatment of aortoiliac occlusive disease". PMID- 22542354 TI - Determination of 237Np in environmental and nuclear samples: a review of the analytical method. AB - A number of analytical methods has been developed and used for the determination of neptunium in environmental and nuclear fuel samples using alpha, ICP-MS spectrometry, and other analytical techniques. This review summarizes and discusses development of the radiochemical procedures for separation of neptunium (Np), since the beginning of the nuclear industry, followed by a more detailed discussion on recent trends in the separation of neptunium. This article also highlights the progress in analytical methods and issues associated with the determination of neptunium in environmental samples. PMID- 22542355 TI - Measures of small-fiber neuropathy in HIV infection. AB - INTRODUCTION: Noninvasive methods are needed to detect distal sensory polyneuropathy in HIV-infected persons on antiretroviral therapy (ART). METHODS: Quantitative sudomotor axon reflex test (QSART) and Utah Early Neuropathy Scale (UENS), small-fiber sensitive measures, were assessed in subjects with and without clinical neuropathy. Pain was assessed by visual analog scale (VAS). RESULTS: Twenty-two subjects had symptoms and signs of neuropathy, 19 had neither, and all were receiving ART. Median sweat volume (MUL) was lower at all testing sites in those with neuropathy compared to those without (p<0.01 for all). UENS and VAS (mm) were higher in neuropathy subjects (p<0.05 for each). Lower sweat volume at all sites correlated with higher pin UENS subscore, total UENS, and VAS (p<0.05 for all). In multivariable analyses adjusting for age, CD4+ T cells, sex, and use of "d-drug" ART, QSART and UENS remained associated (p=0.003). CONCLUSION: QSART and UENS have not been previously studied in this patient population and may identify small-fiber neuropathy in HIV-infected, ART treated persons. PMID- 22542357 TI - A study on voiding pattern of newborns with hypoxic ischemic encephalopathy. AB - OBJECTIVE: To investigate the difference of voiding pattern between newborns with and those without hypoxic ischemic encephalopathy (HIE). METHODS: Forty hospitalized newborns aged 4-21 days were included in this study. Twenty-one were preterm newborns with HIE, and the remaining 19 preterm newborns were without HIE. The voided volume, postvoid residual (PVR) volume, consciousness at voiding, voiding time, voiding frequency, and quantity of intake milk and liquid within 4 hours from 8 am-12 pm were recorded. The liquid intake was the same in both groups according to standard protocol. The diaper weight difference before and after voiding was defined as voided volume. The PVR volume was determined by ultrasound. The state of consciousness at voiding was monitored by electroencephalography. RESULTS: Voided volume and rate of consciousness at voiding was significant lower in newborns with HIE compared with the control group ([10.8 +/- 6.5 mL, 16.3 +/- 17.1%] vs [14.1 +/- 7.1 mL, 57.1 +/- 21.0%], P <.05, respectively), whereas PVR volume and voiding frequency were significant higher ([1.6 +/- 1.0 mL, 4.0 +/- 1.1 times] vs [1.2 +/- 0.9 mL, 3.2 +/- 0.9 times] per 4 hours, P <.05, respectively). CONCLUSION: The differences in voiding pattern supported the concept that the higher centers of the central nervous system were involved in the control of voiding. HIE had a significant effect on voiding pattern of preterm newborn. PMID- 22542356 TI - Effects of concomitant surgeries during midurethral slings (MUS) on postoperative complications, voiding dysfunction, continence outcomes, and urodynamic variables. AB - OBJECTIVE: To determine whether concomitant surgeries affected outcomes in a randomized trial comparing retropubic midurethral sling (MUS) vs transobturator MUS. METHODS: Subjects (n = 597) were stratified into 4 groups based on type of concomitant surgeries: group I had anterior/apical with or without posterior repairs (n = 79, 13%); group II had posterior repairs or perineorrhaphy only (n = 38, 6%); group III had nonprolapse procedures (n = 34, 6%); and group IV had no concomitant surgeries (n = 446, 75%). Complication rates, voiding dysfunction, objective and subjective surgical failure rates, and changes in urodynamic values (postop minus preop) were assessed and compared in these 4 groups. RESULTS: There were no differences in complications, voiding dysfunction, and subjective failure outcomes between these 4 groups. Group I had lower odds ratio of objective surgical failure compared with group IV (OR 0.38, 95% CI 0.18-0.81, P = .05). The OR of failure of all patients undergoing concomitant surgeries (groups I-III) was lower than group IV (OR 0.57, 95% CI 0.35-0.95, P = .03). The change in Pdet@Qmax (from pressure-flow) was significantly higher in group III vs IV (P = .01). The change in Q(max.) (from uroflowmetry) was significantly less in groups I and II vs group IV (P = .046 and .04, respectively). CONCLUSION: Concomitant surgeries did not increase complications. Subjects who underwent certain concomitant surgeries had lower failure rates than those undergoing slings only. These data support safety and efficacy of performing concomitant surgery at the time of MUS. PMID- 22542358 TI - Sarcoidosis of the ureter. AB - We report a rare case of sarcoidosis of the ureter in a 65-year-old Japanese man. Left nephroureterectomy and regional lymph node dissection were performed under the clinical diagnosis of transitional cell carcinoma of the left ureter with lymph node metastasis. Microscopically, noncaseous epithelioid granuloma with large Langerhans cells was noted in the ureter and dissected lymph nodes. Pulmonary lesions were not found on computed tomography. The final diagnosis was sarcoidosis of the ureter. Although sarcoidosis is rare in the genitourinary tract, it should be considered in the differential diagnosis of urologic conditions. PMID- 22542359 TI - Pluralism of viewpoints as the antidote to intellectual conflict of interest in guidelines. PMID- 22542360 TI - Rebutal of anon's critique: in fact randomization is the limiting probability distribution for imbalance with minimization. PMID- 22542361 TI - Histology of the bone-cement interface in retrieved Oxford unicompartmental knee replacements. AB - INTRODUCTION: Radiolucent lines (RLL) are commonly seen at the cement-bone interface of knee replacements, yet are poorly understood. Although thin RLL are not associated with implant loosening or poor patient outcome there is still concern that they indicate sub-optimal fixation. The primary study aim is to characterise the histology at the cement-tibia interface in Oxford unicompartmental knee replacement (UKR). The second aim is to assess whether a correlation exists between the presence of a RLL and the type of tissue that predominates at the interface. METHODS: The radiology and histology of retrieved specimens of the interface from around firmly fixed tibial trays in ten patients undergoing revision between 1 and 19 years after Oxford UKR were studied. RESULTS: Pre-revision radiographs showed the presence of both full and partial RLL. On contact radiographs of 5mm thick sections of the interface the total percentage of radiolucency ranged from 0 to 90% between patients. There was no consistent pattern for the distribution of radiolucency. Histological assessment demonstrated that under every tibial component there were areas where there was direct contact and interdigitation between bone and cement. The amount of direct bone-cement contact was between 19% and 95% of the tibial tray surface area. The remaining tissue was mainly fibrocartilage but there was also fibrous tissue. The presence of radiolucency was strongly inversely correlated with the percentage of cement-bone contact. CONCLUSION: This study demonstrates that even with partial or complete RLL seen on radiographs there is still cement-bone contact, thus indicating that there is stable fixation. PMID- 22542362 TI - Eculizumab therapy results in rapid and sustained decreases in markers of thrombin generation and inflammation in patients with PNH independent of its effects on hemolysis and microparticle formation. AB - Paroxysmal Nocturnal Hemoglobinuria (PNH) is a clonal bone marrow disorder which results in the loss of glycosylphosphatidyl inositol (GPI) anchors from cell membranes. As a consequence, membrane inhibitors of complement are lost rendering the cells more susceptible to complement mediated destruction. This results in hemolysis, leukopenia, thrombocytopenia and thrombophilia. Eculizumab, a monoclonal antibody to complement protein 5, has been approved for the treatment of PNH and is associated with a significant reduction in hemolysis, thromboembolic events and fatigue. We prospectively studied the effect of Eculizumab therapy on plasma markers of thrombin generation (D-Dimers, TAT), inflammation (IL-6), soluble P-selectin (sP-selectin), antigenic (TFMP) and functional (fTFMP) tissue factor bearing microparticles and total plasma microparticle ex vivo factor Xa generation (MPFXa) in eleven Eculizumab naive PNH patients. Blood sampling occurred day 1, prior to Eculizumab treatment, then on days 8,15,22,29, 43, 90. Our results demonstrate a statistically significant reduction in D-Dimer, TAT, IL-6, sP-selectin, and TFMP during the induction phase of treatment (day 1-29) which was sustained during the maintenance treatment (day 29-90). Although the serum LDH levels decreased rapidly, there was no correlation between the change in LDH and the markers of thrombin generation and inflammation. Although there was a statistically significant decrease in TFMP, this decrease did not correlate with changes in markers of thrombin generation or inflammation. Ex vivo MPFXa generation did not decrease with Eculizumab treatment suggesting continued microparticle formation despite inhibition of hemolysis. Ex vivo total microparticle FXa generation was found to have an inverse correlation with markers of thrombin generation, suggesting that in PNH patients in vivo thrombin generation occurs by a pathway independent of hemolysis and microparticle generation. PMID- 22542363 TI - Prothrombin time, activated partial thromboplastin time and dilute Russell's Viper Venom times are not shorter in patients with the prothrombin G20210A mutation, and dilute Russell's Viper Venom time may be longer. AB - INTRODUCTION: Prothrombin G20210A (PT20210) carriers have increased prothrombin levels and increased risk for venous thrombosis. We hypothesized PT20210 carriers would have decreased PT, aPTT, and dRVVT clotting times. METHODS: We reviewed 1186 thrombotic risk panels that included PT, aPTT, dRVVT, and PT20210 genotype with potential confounding variables, excluding samples consistent with anticoagulant therapy or lupus anticoagulant presence. We examined relationships of PT20210 with PT, aPTT, and dRVVT correcting for covariates using multivariate regression. We confirmed associations in 1876 separate panel results and a group of homozygotes for PT20210 and used general linear models to determine if associated tests predict PT20210 status. RESULTS: Neither PT, aPTT, nor dRVVT was shorter in PT20210 carriers. Contrary to our hypothesis, PT20210 was significantly associated with higher dRVVT (p=0.001), but not PT or aPTT. dRVVT differences were significant in a replicate sample p=0.035 and an additional sample of PT20210 homozygotes (p=0.02). Of all variables available, only dRVVT predicted PT20210 carrier status (p=0.0008, AUC=0.64). CONCLUSIONS: We observed an association between longer dRVVT and the prothrombin G20210A mutation in a retrospective observational study. These findings merit further study in large well-characterized clinical cohorts and laboratory research experiments. PMID- 22542364 TI - Thrombus components in cardioembolic and atherothrombotic strokes. PMID- 22542365 TI - Efficacy and bleeding risk of antithrombin supplementation in septic disseminated intravascular coagulation: a prospective multicenter survey. AB - INTRODUCTION: Although supplementation with antithrombin (AT) concentrates has been widely accepted for the treatment of disseminated intravascular coagulation (DIC) in Japan, the effects and adverse effects have not been investigated. MATERIALS AND METHODS: We conducted a nonrandomized multi-institutional survey. A total of 729 septic DIC patients with AT activity levels of 70% or lower, who had undergone AT substitution at either 1500 IU/day or 3000 IU/day for consecutive 3 days were analyzed. Of these, 650 and 79 patients had received 1500 IU/day (AT1500 group) and 3000 IU/day (AT3000 group), respectively. RESULTS: Bleeding events were observed in 6.52% of patients (severe bleeding, 1.71%). A significant decrease in initial AT level (below 50%) was observed in 69.6% of patients in AT3000 group and 48.2% in AT1500 group, and this difference was significant (P<0.01). A logistic-regression analysis conducted using age, gender, body weight, initial AT activity, and supplemented AT dose, revealed that higher initial AT activity (odds ratio (OR), 1.032; P<0.001), AT dose of 3000 IU/day (OR, 1.912; P=0.026), and age (OR, 0.985; P=0.023) were significant factors for improved survival. CONCLUSION: The risk of severe bleeding is less than 2%, and concomitant administration of heparin did not increase the risk. The survival in AT1500 group was 65.2%, while that in AT3000 group was 74.7%. PMID- 22542366 TI - Effects of the etonogestrel-releasing contraceptive implant inserted immediately postpartum on maternal hemostasis: a randomized controlled trial. AB - INTRODUCTION: The puerperium is the period of highest risk for thrombosis during a woman's reproductive life and it is an important time for initiating an effective contraceptive method in order to increase intergestational interval. Thus, the objective of the present study was to evaluated the effects of the etonogestrel (ENG)-releasing contraceptive implant inserted immediately postpartum on maternal hemostasis markers during the first six weeks of delivery. MATERIALS AND METHODS: Forty healthy women aged 18 to 35 years-old were randomized to receive either the ENG-releasing implant 24-48 h after delivery (implant group; n=20) or nothing (control group) until the sixth postpartum week. Blood samples were collected at 24-48 h and at 6 weeks after delivery, and hemostatic variables, including fibrinogen, coagulation factors, protein C, free protein S, antithrombin, alpha2-antiplasmin, plasminogen activator inhibitor 1, thrombin-antithrombin complex (TAT), prothrombin fragment (PF)1+2, and D-dimers, as well as normalized activated protein C sensitivity ratio (nAPCsr), thrombin time, activated partial thromboplastin time, and prothrombin time were evaluated. RESULTS: Insertion of the ENG-releasing contraceptive implant did not change the physiological reduction in overall coagulation (TAT and PF1+2) and fibrinolysis (D-dimer) markers, or nAPCsr. Reductions in factors II, VII, X and fibrinogen and increases in factor V were greater in the control than in the implant group. Clotting factors remained within normal limits throughout the study. CONCLUSION: The ENG-releasing contraceptive implant inserted immediately postpartum did not have negative effects on physiological variations of the hemostatic system during the first 6 weeks postpartum. PMID- 22542367 TI - [Predictive factors of mortality of the burnt persons: study on 221 adults hospitalized between 2004 and 2009]. AB - The objective of the present study is the evaluation of the predictive factors of mortality to a troop of Moroccan grown-up serious burnt persons. Variables analyzed in the study are: the age, the sex, the localization of the burn, the degree of burn, indicates Total Body Surface Area (TBSA), indicate Unit of Standard Burn (UBS) and the indication of leases, sepsis and the medical histories (tobacco, diabetes). Factors associated significantly to a mortality raised at the burned patients were the female genital organ, the localization of the burn at the level of the head, the sepsis, one TBSA greater or equal to 20%, an UBS greater or equal to 200 and an indication of leases greater or equal to 75. Other factors such as the age, the degree of burn and the histories did not show a significant difference. An evaluation and a good knowledge of factors associated to a high risk of death allow an adequate coverage of this category of patients. PMID- 22542368 TI - [Keloid scars on black skin: myth or reality]. AB - The keloid scar is a thick skin or the cornea of man, due to excessive accumulation of type I collagen in the dermis. Morbidity of the keloid is high, given the frequent recurrences and unpredictable. African blacks and Asians are most affected. The purpose of this study was to analyze the results of treatment of 149 cases of keloids and discuss the reality of keloids in the dark. PATIENTS AND METHODS: From 1990 to 2011, 98 patients were supported for 149 keloid tumors. RESULTS: Seventy-eight adults (79.6%) and 20 children (20.4%) were received. Sixty-four women (65.3%) and 34 men (34.7%) were supported, including 94 blacks (96%) and four redheads (4%). The average age was 25 years with extremes of 2 years and 54 years. The trauma was the dominant etiology in 63.1% of cases. The infection, burns and surgery were implicated in 16.8%, respectively, 15% and 4.7% of cases. The cephalic end, was the seat of choice for keloids, with 84 cases or 56.4%. The ear has been the preferred unit in 38 cases, or 25.5%. The body, legs and genital area were the site of keloids, respectively, in 22.8%, 17.5%) and 3.3% of cases. Keloidal field was found in 24.5% of our cases. The reasons for consultation were the disgrace aesthetics (56.4%), pain (65%), households suppurative intrakeloidal (44.9%), functional impairment (40.8%), and the psychological impact minor (15.3%) and no major suicide attempt (66.3%). Two surgical techniques were used: total excision (TE), with total skin graft immediate or deferred, or not expanded, and intrakeloid excision (IKE) with suture surgery was associated with intra-lesional steroids. Many complications have favored the occurrence of early or late recurrence in 100% of our cases. CONCLUSION: The keloid is not a homogenous biological entity. Its prevalence is higher among black and yellow, and lowest among whites. The research results are still being evaluated. The best prevention is to avoid the scar itself. PMID- 22542369 TI - Development and validation of a standardized tool for reporting retinal findings in abusive head trauma. AB - PURPOSE: To develop and validate a robust standardized reporting tool for describing retinal findings in children examined for suspected abusive head trauma. DESIGN: A prospective interobserver and intraobserver agreement study. METHOD: An evidence-based assessment pro forma was developed, recording hemorrhages (location, layer, severity) and additional features. Eight consultant pediatric ophthalmologists and 7 ophthalmology residents assessed a series of 105 high-quality RetCam images of 21 eyes from abusive head trauma cases with varying degrees of retinal hemorrhage and associated findings. The pediatric ophthalmologists performed a repeat assessment of the randomized images. The images were observed simultaneously with standardized display settings. Interobserver and intraobserver agreement was assessed using free-marginal multirater kappa, intraclass correlation coefficients, and concordance coefficients. RESULTS: Almost-perfect interobserver agreement was observed for residents and pediatric ophthalmologists recording the presence and number of fundus hemorrhages (intraclass correlation coefficients 0.91 and 0.87, respectively) and the location of hemorrhages (concordance coefficients 0.86 and 0.85, respectively). Substantial agreement was observed by both groups regarding size of hemorrhage (concordance coefficients 0.73 and 0.76), moderate agreement for hemorrhage morphology (concordance coefficients 0.53 and 0.52), and other findings (concordance coefficients 0.48 and 0.59). Intraobserver agreement for pediatric ophthalmologists varied by question, ranging from substantial to perfect for the presence, number, location, size, and morphology of fundus hemorrhage. CONCLUSION: We have developed and validated a standardized clinical reporting tool for ophthalmic findings in suspected abusive head trauma, which has excellent interobserver and intraobserver agreement among consultant specialists and residents. We suggest that its use will improve standardized clinical reporting of such cases. PMID- 22542370 TI - [Preliminary study of fetal head engagement diagnosis by transperineal ultrasound before operative vaginal delivery]. AB - OBJECTIVES: Estimate the predictive value of perineum-fetal head distance obtained by transperineal ultrasound on results of an operative vaginal delivery. PATIENTS AND METHOD: A prospective preliminary monocentric study has been conducted on 28 patients between the 18th of April and the 31st of July 2011. Three successive perineum-fetal head distance have been measured before realization of an operative vaginal delivery. RESULTS: With caesarian section deliveries, average distances were higher than with successful operative vaginal deliveries but this result was not significant (49.3mm vs 39.7 mm; P=NS). Ultrasound measured distance was significantly correlated to the time of application of the instrument (r=0.45, P=0.0165). Beyond 50mm, the relative risk of caesarian was 10.5 (IC [0.76-145.36]). The measures were corresponding, with an average time of realization of 29.9 seconds. The transvaginal examination compared to ultrasound showed a discordance of 3.6% for the diagnosis of engagement and of 25% for the descent of fetal head. CONCLUSION: A larger study is necessary to confirm this result and to recommend the realization of a transperineal ultrasound before an operative vaginal delivery in cases of doubt about engagement after the transvaginal examination. PMID- 22542371 TI - [Periconceptional toxoplasmic seroconversion: about 79 cases]. AB - OBJECTIVE: Toxoplasmosis is a cosmopolitan zoonose led by an intracellular protozoon, Toxoplasma gondii. Severe fetal consequences can be encountered in case of infection during pregnancy. Since 1978, a specific screening program has been implemented in France during pregnancy. The purpose of our study is to evaluate the fetal consequences of a maternal contamination during the periconceptional period. MATERIAL AND METHODS: We retrospectively analyzed, over a 10-year period, the outcome of all the pregnancies with a suspicion of periconceptional seroconversion. Periconceptional seroconversion was defined as infection occurring during the two months prior to or following the assumed date of the conception. The obstetric care, the fetal ultrasound scan and the neonatal features were all closely looked at. RESULTS: Seventy-nine patients (81 fetus) showed evidence of the diagnosis criteria of periconceptional infection. Three cases (3.8%) of congenital infection were observed: two late miscarriages (at 15 weeks and 24 weeks) and one case of an alive child with infraclinic toxoplasmosis. CONCLUSION: In our study, the rate of congenital toxoplasmosis (3.8%) in the event of a periconceptional infection is slightly above the rate previously described in the literature (0.6 to 3.3%). The rate of miscarriage is also high: 66% in case of congenital infection. A regular ultrasound follow-up until the end of the pregnancy is necessary to ensure the best care available. The decision whether to carry out an amniocentesis is discussed in that case. PMID- 22542373 TI - A novel 3D shape context method based strain analysis on a rat stomach model. AB - The stomach has the ability to change its geometry and volume during digestion. Thus, the stomach shape changes dynamically due to changes in contents and due to pressure from adjacent organs. Full-field strain analysis is therefore important for accurate estimation of the true deformation in this highly non-homogeneous, anisotropic organ. The aim of this study is to introduce a modified non-rigid image registration based 3D shape context method combined with a full-field strain analysis method to describe a distension-induced 3D gastric deformation. The geometry of a normal rat stomach at distension pressures from 0.05 kPa to 0.8 kPa were obtained by ultrasonic scanning. The full-field strain distribution of the 3D gastric model between the reference state and the distended state were computed on the basis of the improved 3D shape context method and full-field strain analysis method. The registered surface showed a good agreement with the real deformed surface for all distension states. However, the errors increased with the distension pressure due to increasing dissimilarity between the deformed and the reference surface. The strain distributions on the stomach surface were non-uniform with the largest deformation in the non-glandular part and the greater and lesser curvature when the pressure was higher than 0.2 kPa. The wall stiffness of the non-glandular part was softer than that of the glandular part. The modelling analysis method which is closely allied with the non-rigid image registration and strain analysis provides a kinematically possible deformation mode of the gastric wall. This method can be potentially used for clinical data estimating the kinematical properties of the human visceral organs in health and disease. PMID- 22542372 TI - [Robotic surgery in gynecologic oncology: Retrospective and comparative study with laparotomy and laparoscopy]. AB - OBJECTIVES: To compare robot-assisted laparoscopy with conventional laparoscopy and laparotomy in gynecologic oncology. PATIENTS AND METHODS: This is a monocentric retrospective study enrolling 92 patients who underwent a standard or radical hysterectomy (with parametrectomy) with or without pelvic lymphadenectomy between January 2008 and December 2010. All patients were diagnosed for a cervical or endometrial cancer. Laparotomy was performed for 33 patients, conventional laparoscopy for 20 patients, and robot-assisted laparoscopy for 39 patients. The main parameter was the length of hospital stay in the three groups. RESULTS: Length of hospital stay significantly decreased in the robotic group in comparison with the laparotomic group (median 5 and 8 days respectively, P<0.0001), but no differences were found between the robotic and laparoscopic groups (P=0.77). Intraoperative blood loss was lower in the robotic group. Intraoperative complications and lymph nodes removed were equal in the three groups. Regarding the data recorded, there were no significant differences between conventional and robotic laparoscopy. Hysterectomies performed after pelvic radiation, which were all made by laparotomy before the robot's arrival, were all performed with robotic laparoscopy since its arrival. CONCLUSION: Robotic surgery allows a reduced length of hospital stay and a lower blood loss in comparison with laparotomy, without any worse oncologic results. Robotic surgery changed our practice, especially hysterectomy after pelvic radiation, performed by laparotomy before. PMID- 22542374 TI - 18F-Fluorodeoxyglucose positron emission tomography in evaluating treatment response to imatinib or other drugs in gastrointestinal stromal tumors: a systematic review. AB - OBJECTIVE: To systematically review the role of (18)F-fluorodeoxyglucose ((18)F FDG) positron emission tomography (PET) in evaluating treatment response to imatinib or other drugs in gastrointestinal stromal tumors (GIST). METHODS: A comprehensive literature search of published studies through February 2011 in PubMed/MEDLINE and EMBASE databases was performed. RESULTS: We identified 19 studies including 628 patients with GIST. Main findings of included studies are presented. CONCLUSIONS: (18)F-FDG PET has a significant value in assessing treatment response to imatinib or other drugs in GIST patients. (18)F-FDG PET allows an early assessment of treatment response and is a strong predictor of clinical outcome. PMID- 22542375 TI - First description of MR mammographic findings in the tumor bed after intraoperative radiotherapy (IORT) of breast cancer. AB - The aim was to investigate changes in the tumor bed on magnetic resonance mammography (MRM) after intraoperative radiotherapy (IORT) and whether they would limit the diagnostic value of posttherapeutic MRM. We retrospectively investigated 36 patients undergoing MRM after IORT (median interval 2.8 years, range 0.4-7.1). Wound cavities with fat necrosis were common after IORT (81%). They were associated with persisting contrast enhancement, i.e., enhancement was mostly seen irrespective of the posttherapeutic interval. It normally presented as rim enhancement and did not cause any diagnostic uncertainty if viewed together with other tissue characteristics. We do not expect a limited diagnostic value of MRM after IORT. PMID- 22542376 TI - Impact of COPD exacerbation on cerebral blood flow. AB - We aimed to investigate the impact of chronic obstructive pulmonary disease (COPD) exacerbation on cerebral blood flow (CBF). In 21 COPD patients - in both exacerbation and stable phases -Doppler ultrasonographies of internal carotid artery (ICA) and vertebral artery (VA) were performed. There were significant differences in total, anterior and posterior CBF, ICA and VA flow volumes in exacerbated COPD compared to stable COPD. Total CBF was correlated with cross sectional areas of left and right ICA, whereas independent predictor of total CBF was cross-sectional area of right ICA. Increased CBF might indicate cerebral autoregulation-mediated vasodilatation to overcome COPD exacerbation induced hypoxia. PMID- 22542377 TI - Percutaneous treatment of blunt hepatic and splenic trauma under contrast enhanced ultrasound guidance. AB - The objective of this study was to evaluate the clinical application of hemostatic percutaneous therapy of liver and spleen trauma under contrast enhanced ultrasound (CEUS) guidance. A total of 83 patients with 88 traumatic organ lesions were included in this study. Liver or spleen lesions were treated by percutaneous injection of haemocoagulase atrox and alpha-cyanoacrylate under CEUS guidance. The results showed that one treatment was sufficient to successfully control hemorrhaging in 86 of 88 traumatic organ lesions. In 2 of 88 traumas, a second percutaneous hemostatic treatment was necessary. Percutaneous treatment of blunt hemorrhagic trauma under CEUS guidance is a feasible and safe adjunct to observation in the nonoperative management. PMID- 22542378 TI - Human patellar cartilage: echo planar diffusion-weighted MR imaging findings at 3.0 T. AB - PURPOSE: To explore the findings of diffusion-weighted imaging (DWI) and the diffusion characteristics on patellar cartilage in healthy adults. MATERIALS AND METHODS: Thirty healthy subjects were studied on SIEMENS 3.0-T Trio Tim magnetic resonance (MR) scanner. The apparent diffusion coefficient (ADC) values of the patellar cartilage were measured in different areas. RESULTS: The patellar cartilage demonstrated homogeneously high signal intensity on the images of DWI and maps of ADC. The ADC values displayed a spatial dependency, approximately (1.17 +/- 0.31)*10(-3) mm(2)/s of the entire cartilage. CONCLUSIONS: Diffusion weighted MR imaging may display articular cartilage structure. There is a consistent pattern of spatial variation of the ADC values. PMID- 22542379 TI - Sonographic evaluation of bone fractures: a reliable alternative in clinical practice? AB - OBJECTIVE: The objective was to compare the diagnostic accuracy of conventional radiography and ultrasonography (US) for the diagnosis of suspected bone fractures. METHOD: Eighty-six patients were assessed using conventional radiography and US on the affected bone district. RESULTS: Radiographic and sonographic findings were concordant in 93% of cases. In one case, US suggested a fracture not seen on radiographic assessment. Ultrasonography showed a sensitivity of 0.94 and a specificity of 0.92. CONCLUSION: In clinical practice, US could become the first diagnostic approach. PMID- 22542380 TI - Malignant peripheral nerve sheath tumor in spine: imaging manifestations. AB - Malignant peripheral nerve sheath tumor (MPNST) is a relatively rare soft tissue malignant tumor. Most of reports currently are pathological articles and clinical case reports and most of them are MPNST in the thorax, abdomen or extremities. Imaging report of spinal MPNST is very rare, and MPNST is easy to be misdiagnosed. In this study, we explored the computed tomography and magnetic resonance imaging manifestations of MPNST that occurred in the spine and to improve the preoperative diagnostic accuracy of MPNST. PMID- 22542381 TI - Aortic arch vessel anomalies associated with persistent trigeminal artery. AB - Developmental anomalies of the aortic arch vessels and persistent trigeminal artery that is the most common of the four anomalous carotid-basilar anastomoses are repeatedly reported in the literature as separate entities. Herein we report a previously undescribed variant including the coexistence of persistent trigeminal artery, truncus bicaroticus and direct origin of left vertebral artery from aortic arch. PMID- 22542382 TI - Tracheal diverticula in infants: a report of three cases. AB - Tracheal diverticulum is a paratracheal air cyst in connection with the trachea. It may be congenital or acquired. Congenital tracheal diverticula in infants are rare. Imaging techniques such as high-resolution computed tomography and three dimensional reconstruction of the airway are useful for diagnosis. Here we report three cases with congenital tracheal diverticula, which were diagnosed by imaging techniques. PMID- 22542383 TI - Radioiodine (131I) accumulation in bronchogenic cyst in the setting of thyroid carcinoma remission. AB - A 76-year-old woman had (131)I accumulation within the mediastinum in the setting of thyroid carcinoma remission. Extensive diagnostic imaging including computed tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasound, bronchoscopy, and subsequently a needle aspiration biopsy revealed that the mass was a bronchogenic cyst. Five-year clinical and laboratory follow-up showed that the patient was free from thyroid carcinoma recurrence. PMID- 22542384 TI - Thoracolithiasis: a case report. AB - We present a rare case of incidentally found mobile thoracolithiasis in a 76-year old cirrhotic patient on serial computed tomography scans performed before and after transarterial chemoembolization for hepatocellular carcinoma. Mobility and calcification are the important clue to diagnosing this benign condition and avoiding unnecessary surgery. PMID- 22542385 TI - Beyond routine abdominal CT in the ER: a patient with indeterminate recurrent abdominal pain benefits from CT enterography. AB - We report the case of a 52-year-old female with multiple medical complaints and extensive prior clinical and imaging workup who presented to the emergency department with weakness and recurrent episodes of abdominal pain. She had had multiple inconclusive routine computed tomographic (CT) examinations. A 7-mm small bowel tumor was diagnosed on CT enterography and subsequently confirmed to be a carcinoid tumor of the ileum by enteroscopy and at surgery. The diagnosis was suggested prospectively utilizing CT enterography performed in the emergency radiology suite. PMID- 22542386 TI - Inferior vena cava filter presenting as chronic low back pain. AB - Our purpose is to report a rare complication of an inferior vena cava (IVC) filter with vertebral bone penetration, interval fracture, subsequent endovascular management and outcome. We report a case of an IVC filter embedded within the second lumbar vertebral body and in which one of the primary struts fractured, which presented as chronic low back pain. The filter was retrieved percutaneously approximately 2 years after placement. A fractured small strut remained within the vertebral bone; patient's pain resolved. Symptomatic filter in situ should be retrieved even when fractured. PMID- 22542387 TI - Malignant fibrous histiocytoma arising from a hydronephrotic kidney: a case report and review of the literature. AB - Primary malignant fibrous histiocytoma (MFH) is extremely rare, and MFH arising from a hydronephrotic kidney has not been reported. When MFH originates from a long-standing hydronephrotic kidney, the imaging findings can include nearly invisible renal parenchyma and atrophy of the ureter and renal artery, in addition to the findings attributable to the MFH, and the MFH with hydronephrosis may be confused with a cystic renal cell carcinoma. PMID- 22542388 TI - Pelvic solitary fibrous tumor originally diagnosed as prostatic in origin. AB - A 71-year-old man was referred to our hospital because of intermittent urine stream and postmicturition dribbling. Magnetic resonance imaging (MRI) results suggested the mass to be a malignant mesenchymal tumor arising from the left lobe of the prostate, on the basis of the presence of a beak sign. Radical prostatectomy and partial rectal excision with subsequent colostomy were performed. Contrary to preoperative MRI, no prostate involvement was found on histologic examination. Histopathologic and immunohistochemical findings showed typical characteristics of solitary fibrous tumors. The patient's postoperative course was uneventful. He showed no signs of recurrence and metastasis at 2-year follow-up. PMID- 22542389 TI - Corticospinal excitability in patients with anoxic, traumatic, and non-traumatic diffuse brain injury. AB - BACKGROUND: Transcranial magnetic stimulation (TMS) have been frequently used to explore changes in motor cortex excitability in stroke and traumatic brain injury, while the extent of motor cortex reorganization in patients with diffuse non-traumatic brain injury remains largely unknown. OBJECTIVE/HYPOTHESIS: It was hypothesized that the motor cortex excitability would be decreased and would correlate to the severity of brain injury and level of functioning in patients with anoxic, traumatic, and non-traumatic diffuse brain injury. METHODS: TMS was applied to primary motor cortices of 19 patients with brain injury (5 traumatic and 14 non-traumatic causes; on average four months after insult), and 9 healthy controls. The test parameters included resting motor threshold (RMT), short intracortical inhibition (SICI), intracortical facilitation (ICF), and short latency afferent inhibition (SAI). Excitability parameters were correlated to the severity of brain injury measured with Glasgow Coma Scale and the level of functioning assessed using the Ranchos Los Amigos Levels of Cognitive Functioning Assessment Scale and Functional Independence Measure. RESULTS: The patient group revealed a significantly decreased SICI and SAI compared to healthy controls with the amount of SICI correlated significantly to the severity of brain injury. Other electrophysiological parameters did not differ between the groups and did not exhibit any significant relationship with clinical functional scores. CONCLUSIONS: The present study demonstrated the impairment of the cortical inhibitory circuits in patients with brain injury of traumatic and non-traumatic aetiology. Moreover, the significant correlation was found between the amount of SICI and the severity of brain injury. PMID- 22542391 TI - The distribution of Mycobacterium bovis infection in naturally infected badgers. AB - Populations of Eurasian badgers (Meles meles) with tuberculosis (Mycobacterium bovis infection) are a significant reservoir of infection for cattle in Ireland and the United Kingdom. In this study the distribution of infection, histological lesions and gross lesions was determined in a sample of 132 culled badgers from naturally-infected wild populations. Badgers were culled when an epidemiological investigation following a tuberculosis breakdown in a cattle herd implicated badgers as the probable source of infection. The definition of tuberculosis infection was based on the isolation of M. bovis from tissues or clinical samples. An accurate diagnosis of infection was achieved by culturing a wide range of lymph nodes (LN) and organ tissues (mean 32.1) and clinical samples (faeces and urine) from each badger. Infection was detected in 57/132 badgers (43.2%). Histological lesions consistent with tuberculosis were seen in 39/57 (68.4%) culture-positive and 7/75 (9.3%) culture-negative animals. Gross lesions were seen in only 30/57 (52.6%) infected badgers, leaving a high proportion (47.4%) of infected animals with latent infection (no grossly visible lesions). The most frequently infected tissues were the lungs and axillary LN, followed by the deep cervical LN, parotid LN and tracheobronchial LN. The data support the hypotheses that in badgers there are only two significant routes of infection, namely, the lower respiratory tract and bite wounds, and that badgers are very susceptible to infection but resistant to the development and progression of the disease. At all levels of disease severity, infection was found in widely dispersed anatomical locations suggesting that there is early dissemination of infection in the period preceding the development of active immunity. PMID- 22542390 TI - The quantification of vitamin D receptors in coronary arteries and their association with atherosclerosis. AB - OBJECTIVE: The activated vitamin D receptor (VDR) may have an important role in vascular health. The objective of this study was to determine whether there is an association between the expression of VDRs in coronary arteries and the extent of diet-induced atherosclerosis. METHODS: Utilizing a cohort of 39 postmenopausal female cynomolgus monkeys with varying stages of atherosclerosis, histologic sections of the left anterior descending artery (LAD) were analyzed for plaque cross-sectional area, plaque thickness, and VDR quantity using immunohistochemical H-score analysis. The quantities of VDRs were analyzed as a continuous variable and were divided at the median intimal H-score into high vs. low groupings. RESULTS: In the LAD, a significant negative correlation was observed between the quantity of VDR and plaque size (both cross-sectional area [p<0.001] and plaque thickness [p<0.001]). Monkeys in the low VDR group had a significantly greater cross-sectional plaque area (1.2mm(2)) and greater plaque thickness (0.3mm) than those in the high VDR group (0.4mm(2), p=0.005; 0.1mm, p=0.003, respectively). CONCLUSIONS: Lower concentrations of VDRs in a main coronary artery were associated with greater atherosclerotic plaque size in postmenopausal female monkeys. Given that coronary artery atherosclerosis is a major cause of coronary heart disease in postmenopausal women, further research to ascertain the relationship between VDRs and atherosclerosis is warranted. PMID- 22542393 TI - Changes in glucose-6-phosphate dehydrogenase activity in Indian desert malaria vector Anopheles stephensi during aging. AB - Malaria parasite requires a specific time to replicate and disseminate in the mosquito's body before transmission to naive hosts can occur. Vector control has a proven record in the prevention and control of malaria. The evaluation of vector control strategies requires accurate methods of predicting mosquito age. Anopheles stephensi is the principal malaria vector of the desert part of India. The objective of this study was to correlate the age of laboratory reared and field collected adults of An. stephensi with the glucose-6-phosphate dehydrogenase (g6pd) activity. The measurement of g6pd activity was carried out in a UV-vis spectrophotometer. The g6pd activity in the males and females An. stephensi was inversely proportional to their age. A significant correlation of the g6pd activity was recorded between the field collected and laboratory reared mosquitoes. The g6pd activity in the males An. stephensi was found to be significantly higher than the females. The finding of the present study is useful for the prediction of the age of males and females An. stephensi. PMID- 22542392 TI - Synthesis and evaluation of 18F labeled alanine derivatives as potential tumor imaging agents. AB - INTRODUCTION: This paper reports the synthesis and labeling of (18)F alanine derivatives. We also investigate their biological characteristics as potential tumor imaging agents mediated by alanine-serine-cysteine preferring (ASC) transporter system. METHODS: Three new (18)F alanine derivatives were prepared from corresponding tosylate-precursors through a two-step labeling reaction. In vitro uptake studies to evaluate and to compare these three analogs were carried out in 9L glioma and PC-3 prostate cancer cell lines. Potential transport mechanisms, protein incorporation and stability of 3-(1-[(18)F]fluoromethyl)-L alanine (L-[(18)F]FMA) were investigated in 9L glioma cells. Its biodistribution was determined in a rat-bearing 9L tumor model. PET imaging studies were performed on rat bearing 9L glioma tumors and transgenic mouse carrying spontaneous generated M/tomND tumor (mammary gland adenocarcinoma). RESULTS: New (18)F alanine derivatives were prepared with 7%-34% uncorrected radiochemical yields, excellent enantiomeric purity (>99%) and good radiochemical purity (>99%). In vitro uptake of the L-[(18)F]FMA in 9L glioma and PC-3 prostate cancer cells was higher than that observed for the other two alanine derivatives and [(18)F]FDG in the first 1h. Inhibition of cell uptake studies suggested that L [(18)F]FMA uptake in 9L glioma was predominantly via transport system ASC. After entering into cells, L-[(18)F]FMA remained stable and was not incorporated into protein within 2h. In vivo biodistribution studies demonstrated that L-[(18)F]FMA had relatively high uptake in liver and kidney. Tumor uptake was fast, reaching a maximum within 30 min. The tumor-to-muscle, tumor-to-blood and tumor-to-brain ratios at 60 min post injection were 2.2, 1.9 and 3.0, respectively. In PET imaging studies, tumors were visualized with L-[(18)F]FMA in both 9L rat and transgenic mouse. CONCLUSION: L-[(18)F]FMA showed promising properties as a PET imaging agent for up-regulated ASC transporter associated with tumor proliferation. PMID- 22542394 TI - Coexistence of insulin resistance and increased glucose tolerance in pregnant rats: a physiological mechanism for glucose maintenance. AB - AIM: The contribution of insulin resistance (IR) and glucose tolerance to the maintenance of blood glucose levels in non diabetic pregnant Wistar rats (PWR) was investigated. MAIN METHODS: PWR were submitted to conventional insulin tolerance test (ITT) and glucose tolerance test (GTT) using blood sample collected 0, 10 and 60 min after intraperitoneal insulin (1 U/kg) or oral (gavage) glucose (1g/kg) administration. Moreover, ITT, GTT and the kinetics of glucose concentration changes in the fed and fasted states were evaluated with a real-time continuous glucose monitoring system (RT-CGMS) technique. Furthermore, the contribution of the liver glucose production was investigated. KEY FINDINGS: Conventional ITT and GTT at 0, 7, 14 and 20 days of pregnancy revealed increased IR and glucose tolerance after 20 days of pregnancy. Thus, this period of pregnancy was used to investigate the kinetics of glucose changes with the RT CGMS technique. PWR (day 20) exhibited a lower (p<0.05) glucose concentration in the fed state. In addition, we observed IR and increased glucose tolerance in the fed state (PWR-day 20 vs. day 0). Furthermore, our data from glycogenolysis and gluconeogenesis suggested that the liver glucose production did not contribute to these changes in insulin sensitivity and/or glucose tolerance during late pregnancy. SIGNIFICANCE: In contrast to the general view that IR is a pathological process associated with gestational diabetes, a certain degree of IR may represent an important physiological mechanism for blood glucose maintenance during fasting. PMID- 22542395 TI - Vanillin and isovanillin: comparative vibrational spectroscopic studies, conformational stability and NLO properties by density functional theory calculations. AB - This study is a comparative analysis of FT-IR and FT-Raman spectra of vanillin (3 methoxy-4-hydroxybenzaldehyde) and isovanillin (3-hydroxy-4-methoxybenzaldehyde). The molecular structure, vibrational wavenumbers, infrared intensities, Raman scattering activities were calculated for both molecules using the B3LYP density functional theory (DFT) with the standard 6-311++G(**) basis set. The computed values of frequencies are scaled using multiple scaling factors to yield good coherence with the observed values. The calculated harmonic vibrational frequencies are compared with experimental FT-IR and FT-Raman spectra. The geometrical parameters and total energies of vanillin and isovanillin were obtained for all the eight conformers (a-h) from DFT/B3LYP method with 6 311++G(**) basis set. The computational results identified the most stable conformer of vanillin and isovanillin as in the "a" form. Non-linear properties such as electric dipole moment (MU), polarizability (alpha), and hyperpolarizability (beta) values of the investigated molecules have been computed using B3LYP quantum chemical calculation. The calculated HOMO and LUMO energies show that charge transfer occurs within the molecules. PMID- 22542396 TI - Patterns of disability, care needs, and quality of life of people with Parkinson's disease in a general population sample. AB - OBJECTIVE: To quantify patterns of disability, care needs, and quality of life in a national community-dwelling sample of people with Parkinson's disease (PD) in Canada. METHODS: Data from Statistics Canada's Participation and Activity Limitations Survey was used in the analysis. This survey is a post-censual survey that collected data from 28,630 household residents with reported activity limitations in the 2006 Canadian census. Frequencies of specific impairments and care needs as well as mean quality of life ratings were estimated. These estimates were adjusted for age and sex using linear regression modeling. Sampling weights were used to adjust for design effects, ensuring that the estimates were representative of the national population. RESULTS: The estimated prevalence of PD was 0.1% (100 per 100,000 people), consistent with previous estimates. People with PD reported a significantly elevated prevalence of mobility (88.5%), communication (47.9%), pain (68.6%), memory (26.2%) and seeing (47.7%) limitations relative to those with disabilities of other origins. Significantly more people with PD required help with instrumental activities of daily living and activities of daily living. Health related quality of life, measured by the health utility index, was significantly lower in people with PD (mean value 0.46) compared to disabled people without PD (mean value 0.70). CONCLUSIONS: People living in the community with PD have a significant burden of disability. Health related quality of life is also quite poor in people with PD compared to other disabled populations. This study helps to quantify the significant care needs of people with PD. PMID- 22542397 TI - Progressive ataxia and palatal tremor--two cases with an unusual clinical presentation and course. PMID- 22542398 TI - Determination of 17 macrolide antibiotics and avermectins residues in meat with accelerated solvent extraction by liquid chromatography-tandem mass spectrometry. AB - A method has been developed for simultaneous determination of 17 kinds of macrolide antibiotics and avermectins residues in animal origin foods. Samples were extracted with acetonitrile-methanol using accelerated solvent extraction (ASE) instrument. Parameters such as extraction temperature and pressure were investigated by a fractional factorial design (FFD) and the selected extraction (60 degrees C, 1500 psi for 10 min in two cycles) was most effective. High correlation coefficients (r > 0.999) of 17 macrolide antibiotics and avermectins were obtained within their respective linear ranges (2-400 MUg/kg) using roxithromycin as internal standard. The recoveries of them were above 75% at different spiked levels in various samples. Using ASE the method was featured as short extraction times, reduction use of extraction solvent, high extraction yields, with high level of automation. PMID- 22542399 TI - A rapid GC-MS method for quantification of positional and geometric isomers of fatty acid methyl esters. AB - So far the most frequently used method for fatty acid (FA) analysis is GC coupled to flame ionization detector (FID). However, GC-FID does not allow profiling of FA synthesis and metabolism using stable isotopes. Here we present a rapid and sensitive GC-MS method for determination of fatty acid methyl esters (FAMEs). Fatty acid methylation was carried out by transesterification with acetyl chloride and methanol. FAME separation applies a short and polar cyano-column resulting in an analysis time of 17.2min. Separation was achieved for positional and geometrical (cis/trans) isomers with chain lengths between C8 and C28. Partial overlap of FAMEs (e.g. for C20:2 (n-6) and C21:0) could be resolved using selected ion monitoring (SIM). The precisions for human plasma samples were better than 10% coefficient of variation (CV) except for very low abundant FAs and LODs were in the low femtomol range on column. The developed GC-MS method also allows quantification of conjugated FAs such as conjugated linoleic acid (CLA) isomers because lowering the derivatization temperature from 95 degrees C to room temperature prevented cis to trans double bond isomerization. Finally, profiling of fatty acid synthesis and metabolism was exemplified with stable isotope labeling of macrophages using fatty acid precursors or deuterated fatty acids. In summary, we present a fast and robust GC-MS method for fatty acid profiling of positional and geometrical isomers including CLAs as well as very long chain fatty acids (VLCFAs). The method is suitable for both clinical studies and basic research including application of stable isotope compounds. PMID- 22542400 TI - A shorter and more specific oral sensitization-based experimental model of food allergy in mice. AB - Cow's milk protein allergy (CMPA) is one of the most prevalent human food-borne allergies, particularly in children. Experimental animal models have become critical tools with which to perform research on new therapeutic approaches and on the molecular mechanisms involved. However, oral food allergen sensitization in mice requires several weeks and is usually associated with unspecific immune responses. To overcome these inconveniences, we have developed a new food allergy model that takes only two weeks while retaining the main characters of allergic response to food antigens. The new model is characterized by oral sensitization of weaned Balb/c mice with 5 doses of purified cow's milk protein (CMP) plus cholera toxin (CT) for only two weeks and posterior challenge with an intraperitoneal administration of the allergen at the end of the sensitization period. In parallel, we studied a conventional protocol that lasts for seven weeks, and also the non-specific effects exerted by CT in both protocols. The shorter protocol achieves a similar clinical score as the original food allergy model without macroscopically affecting gut morphology or physiology. Moreover, the shorter protocol caused an increased IL-4 production and a more selective antigen-specific IgG1 response. Finally, the extended CT administration during the sensitization period of the conventional protocol is responsible for the exacerbated immune response observed in that model. Therefore, the new model presented here allows a reduction not only in experimental time but also in the number of animals required per experiment while maintaining the features of conventional allergy models. We propose that the new protocol reported will contribute to advancing allergy research. PMID- 22542402 TI - Introduction to the issue regarding research regarding age related macular degeneration. PMID- 22542401 TI - Optimisation of the quantification of glutamine synthetase and myelin basic protein in cerebrospinal fluid by a combined acidification and neutralisation protocol. AB - The measurement of proteins in cerebrospinal fluid (CSF) by enzyme-linked immunosorbent assays (ELISAs) is becoming increasingly important in the diagnosis of many neurodegenerative diseases such as Alzheimer's Disease. However, detection of proteins in these immunoassays can be hampered by confounding factors either present in the sample matrix or inherent to the protein of interest. These confounding factors may, for example, include protein aggregation or binding to other proteins resulting in epitope masking. Furthermore, the pH of CSF may vary considerably amongst different samples which may limit standardisation of CSF analysis. Pre-treatment of CSF to liberate epitopes or optimise conditions for antibody binding may enhance protein detection. In the current study we investigated whether CSF acidification followed by neutralisation (in short: AFBN) or neutralisation alone prior to measurement might improve the detection of a panel of brain-specific proteins. We demonstrate that the AFBN pre-treatment protocol for CSF significantly enhances the measurement of glutamine synthetase (GS) and myelin basic protein (MBP) in CSF but does not affect detection of glial fibrillary protein (GFAP), amyloid beta 42 (Abeta42), total tau (t-tau) or phosphorylated tau (p-tau). Neutralisation alone did not improve detection of any of the proteins tested. Based on our results, we suggest including the AFBN protocol in the evaluation of new biomarker development protocols to avoid confounders such as CSF pH or epitope-masking of the target protein. PMID- 22542403 TI - [Nicotine, a killing faker]. PMID- 22542404 TI - [Helping the "hard-core" smokers]. AB - Smoking cessation specialists are frequently confronted with smokers who have great difficulty in stopping smoking, and who are either motivated to stop or are forced to stop for health, economic or statutory reasons. These smokers are composed of a mixed population but they have in common a heavy dependence on tobacco and a significant level of cigarette consumption. They are exposed to serious morbidity induced by their uncontrollable smoking. Other factors unfavourable to the attempt to stop smoking are often present: anxiety-depressive disorders, socioeconomic difficulties or the use of psychoactive substances. They constitute a priority target for smoking cessation clinics, which must optimise and diversify proposals to improve their interventions. This review describes these highly dependent smokers unable to stop, and suggests medical treatments and therapeutic combinations to assist the practitioners trying to help the "hard core" smokers. PMID- 22542405 TI - [Tests for evaluating tobacco dependence]. AB - The primary reason why there is such a heavy burden of tobacco smoking induced illness and death is dependence on nicotine which makes it difficult for smokers to quit. For clinical or research purposes, the degree of dependence, the intensity of the withdrawal syndrome and/or craving have been evaluated by different scales. This review provides a list of questionnaires that are used in smoking cessation. It pays particular attention to the validated and translated resources that are available in French. Research should be conducted in order to provide French speaking smoking cessation specialists with all the relevant scales allowing better evaluation of tobacco dependence. PMID- 22542406 TI - [Endobronchial ultrasound (EBUS): the state of the art]. AB - Endobronchial ultrasound (EBUS) is a technique which allows the endoscopist to sample mediastinal and/or hilar lymph nodes for complete staging of thoracic malignancy without recourse to surgery. Originally developed at the beginning of the 21st century, EBUS has become a well developed practice within France in recent years. As the technique requires high tech, expensive and fragile equipment, it has been important to develop an approach that is appropriate for the specific features and constraints of the French health system, including access to anaesthesia, imaging modalities and costing. The first centers to adopt EBUS had to adapt quickly and develop their own practices for its use. Training seminars were carried out in order to pass on this experience. After the passage of several years, it seems helpful to give a progress report on this technique through the stages of its development, taking account of the specificities of the French system and thus to transmit this accumulated experience. In this article, the authors review the literature concerning all the essential aspects needed to apply this technique under the best conditions in the French health system. PMID- 22542407 TI - [HIV-related pulmonary arterial hypertension]. AB - Pulmonary arterial hypertension (PAH) is a rare but potentially fatal complication of human immunodeficiency virus (HIV). It may occur in HIV-1 or 2 infection, irrespective of the route of transmission or the degree of immunosuppression. The improved survival of patients infected with HIV in the era of highly active antiretroviral therapy (HAART) justifies systematic screening for PAH according to an algorithm in patients with unexplained dyspnea. In all cases, right heart catheterization must be performed to establish the definitive diagnosis of pulmonary hypertension. The prevalence of PAH is about 0.5% in patients with HIV infection. A beneficial effect of HAART on the course of HIV related PAH has not been clearly established. In contrast, PAH-specific therapies such as epoprostenol and bosentan have been demonstrated to be efficacious for short- and long-term outcomes in this context. Notably, some patients pulmonary hemodynamics and functional class normalized or near normalized with these treatments. Other PAH-specific therapies remain to be evaluated. The advent of HAART associated with the development of PAH-specific therapies has improved the prognosis of patients HIV-related PAH, with a survival rate of about 70% at 3 years. PMID- 22542408 TI - [Clinical exercise testing and the Fick equation: strategic thinking for optimizing diagnosis]. AB - This article examines the expected exercise-induced changes in the components of the oxygen transport system as described by the Fick equation with a view to enable a critical analysis of a standard incremental exercise test to identify normal and abnormal patterns of responses and generate hypotheses as to potential physiological and/or pathophysiological causes. The text reviews basic physiological principals and provides useful reminders of standard equations that serve to integrate circulatory, respiratory and skeletal muscle functions. More specifically, the article provides a conceptual and quantitative framework linking the exercise-induced increase in whole body oxygen uptake to central circulatory and peripheral circulatory factors with the view to establish the normalcy of response. Thus, the article reviews the exercise response to cardiac output determinants and provides qualitative and quantitative perspective bases for making assumptions on the peripheral circulatory factors and oxygen use. Finally, the article demonstrates the usefulness of exercise testing as an effective integrative physiological approach to develop clinical reasoning or verify pathophysiological outcomes. PMID- 22542409 TI - [Exposition markers: mineralogical analysis in the sputum and the bronchoalveolar lavage--asbestos bodies--uncoated fibres]. AB - The aim of mineralogical analysis of lung tissue, bronchoalveolar lavage (BAL) and sputum is to characterize individuals' exposure to asbestos fibres by identifying markers of this; asbestos bodies (AB) and uncoated fibres. The techniques of mineralogical analysis, habitually used to identify AB and uncoated fibres, are respectively optical microscopy (OM) and analytical electronic microscopy (EM). Correlations between levels of retention of AB in lung tissue, BAL and sputum have been established and validated threshold values indicating a high probability of significant exposure exist. These results must be interpreted in the context of clinical and occupational information. Mineralogical analysis is not suitable for use in routine medical screening but it can be considered when a source of exposure is not evident from the questionnaire since a positive analysis of BAL or of sputum is highly specific and thus useful to confirm an important retention of asbestos in the lung, which justifies medical follow-up. A negative result does not exclude previous significant asbestos exposure (frequent false negatives occur especially in sputum and biopersistence of chrysotile is lower than for amphiboles). Thus it can be a complementary tool for the assessment of asbestos exposure but its use imposes conditions for the collection and handling of samples. PMID- 22542410 TI - [Follow-up of subjects occupationally exposed to asbestos: MRI and PET scans]. AB - MRI and PET scans are not normally used for screening and follow-up of patients following occupational exposure to asbestos. These examinations usually complement the investigation of a parenchymal mass, an effusion or pleural thickening. PET and MRI have an excellent ability to define a parenchymal lesion as malignant (cancer versus rounded atelectasis) or a pleural lesion (mesothelioma versus plaque). MRI distinguishes perfectly the involvement of sub pleural fat by bronchial carcinoma or mesothelioma. MRI, taking account of its lack of irradiation, could be regarded as suitable for potentially repeated examinations following initial screeing by CT scan. A comparative study of multidetector scanner versus MRI, including diffusion MRI could be, nevertheless, interesting. PET cannot be proposed for the follow up or for screening on account of the irradiation induced and the difficulty of access. Pleural plaques do not take up FDG. There is no specific study of asbestos related fibrosis and there is discordance between studies of other types of pulmonary fibrosis. PMID- 22542411 TI - [COPD: a disease with systemic inflammation]. AB - COPD is considered today as an inflammatory disease of the lungs and bronchi, often associated with circulating inflammatory markers and non-respiratory co morbidities. C-reactive protein is a good example of a circulating biomarker in this disease. Recent studies have shown that it is particularly associated with some phenotypes of COPD, that it is linked with cardiovascular and other co morbidities, and that it has genetic determinants. In view of reports in the recent literature treatments aimed at decreasing systemic inflammation in COPD, in particular the use of statins, are discussed. Treatment of COPD should no longer be limited to relief of bronchial obstruction, but should, in the future, address the systemic inflammation that characterizes this disease. PMID- 22542412 TI - [COPD and lung cancer: epidemiological and biological links]. AB - Lung cancer and chronic obstructive lung disease (COPD) are two common fatal diseases. Apart from their common link to tobacco, these two diseases are usually considered to be the result of separate distinct mechanisms. In the past 15 years, numerous studies have produced arguments in favour of a relationship between these two pathologies that goes beyond a simple addition of risk factors. At the epidemiological level, there are data that demonstrate an increased incidence of bronchial carcinoma in patients with COPD. The links between these two pathologies are still unexplained but there are numerous arguments supporting a common physiopathology. Common genetic and epigenetic abnormalities, mechanical factors and signalisation pathways have been quoted. COPD and lung cancer appear to be two diseases possessing a genetic basis that creates a predisposition to environmental or toxic assaults, resulting in a different clinical manifestation in each disease. Consequently, improvements in the management of these two diseases will involve a more intensive investigation of their physiopathology, and require a closer collaboration between research centres and clinical units. PMID- 22542413 TI - [Chronic obstructive pulmonary disease: an autoimmune disease?]. AB - Chronic obstructive pulmonary disease (COPD) is an important cause of morbidity and mortality characterized by irreversible airflow limitation involving a reduced caliber of distal airways (less than 2mm) and alveolar destruction. Exposure to tobacco is a major risk factor for COPD, but all smokers do not develop the disease. In addition, there is continued progression of the disease several years after cessation of the exposure. To explain these phenomena, factors involving innate immunity including the release of neutrophil elastase, macrophage metalloproteases, in combination with pro-apoptotic factors, involved in the worsening of the lesions of emphysema and fibrosis of small airways have been described for many years. More recently, it has been proposed at an advanced stage of the disease that an autoimmune reaction directed mainly at elastin could participate to the pathogenesis of the disease. We here review the immunological processes and currently available data on autoimmunity in COPD. PMID- 22542414 TI - [Extrapulmonary tuberculosis]. AB - Extrapulmonary tuberculosis represents an increasing proportion of all cases of tuberculosis reaching 20 to 40% according to published reports. Extrapulmonary TB is found in a higher proportion of women, black people and immunosuppressed individuals. A significant proportion of cases have a normal chest X-Ray at the time of diagnosis. The most frequent clinical presentations are lymphadenitis, pleuritis and osteoarticular TB. Peritoneal, urogenital or meningeal tuberculosis are less frequent, and their diagnosis is often difficult due to the often wide differential diagnosis and the low sensitivity of diagnostic tests including cultures and genetic amplification tests. The key clinical elements are reported and for each form the diagnostic yield of available tests. International therapeutic recommendations and practical issues are reviewed according to clinical presentation. PMID- 22542415 TI - [Treatment of latent tuberculosis infection]. AB - Latent tuberculosis infection is a key stage in the natural history of tuberculosis, and provides an important period where strategies to prevent the development of disease may be implemented. The treatment of latent tuberculosis infection is well described in many national guidelines. In this review, we attempt to help pneumonologists to implement these guidelines accurately and appropriately, prescribing preventive treatment when the benefit-risk ratio is optimal, providing treatment most safely, performing therapeutic education and incorporating preventive treatment into the full array of measures against tuberculosis. PMID- 22542416 TI - [Congenital lung malformations: natural history and pathophysiological mechanisms]. AB - INTRODUCTION: Congenital lung lesions comprise a broad spectrum of various malformations including congenital cystic adenomatoid malformation (CCAM), bronchopulmonary sequestration (BPS), congenital lobar emphysema, bronchial atresia and bronchogenic cyst. This review aims at the description of their natural history, and of the underlying pathophysiological mechanisms. STATE OF THE ART: Congenital lung lesions are frequently diagnosed antenatally and many remain asymptomatic after birth. In the absence of antenatal identification, they are usually revealed by the occurrence of infection. In some cases, spontaneous resolution of the malformation can occur. Different pathogenic hypotheses are discussed for the origin of these abnormalities, and common processes appear likely to all of these malformations. Factors involved in the process of branching seem to play a particularly important role. PERSPECTIVES: Prospective follow-up of operated and unoperated children would complete our knowledge about the natural history of these lesions. The contribution of experimental models has led to advances in the understanding of pathogenic mechanisms. Further studies are needed to identify the factors initiating the malformative process. PMID- 22542417 TI - [Management of acute asthma]. AB - INTRODUCTION: All patients with asthma are at risk of exacerbations. Mortality is often associated with failure to identify patients at risk and/or to appreciate the severity of acute episode, resulting in inadequate initial treatment, delay in referring to emergency care and inappropriate hospitalization rates, including delayed transfer to intensive care units. This review focuses on the management of acute severe and near fatal asthma. STATE OF ART: Lung mechanics and cardiopulmonary interactions associated with airflow obstruction explain the physical presentation and severity criteria for exacerbations. The past and recent medical history, the initial evaluation of severity and the assessment of response to treatment direct the in-hospital management: emergency department visit, transfer to ward or intensive care unit. In any cases, the goals of therapy are summarized as oxygenation, repetitive inhalations of bronchodilators and early administration of systemic corticosteroids. Mechanical ventilation is required in a few patients with near fatal attacks resulting in asphyxia or progressive exhaustion despite maximal therapy. Controlled hypoventilation with permissive hypercapnia is the best strategy to avoid barotrauma. The role of adjunctive therapies, mainly halogenated agents and heliox, is discussed. PERSPECTIVES AND CONCLUSION: During the last decade, asthma related mortality has decreased in France (<1000/year). The majority of deaths occur at home or during transport to the hospital but some deaths occur suddenly. Most deaths could be preventable if one adopts the approach that every exacerbation is potentially fatal. This practice should be more vigorously included in patient and general practitioner educational programs. PMID- 22542418 TI - Hydrogen sulfide prevents formaldehyde-induced neurotoxicity to PC12 cells by attenuation of mitochondrial dysfunction and pro-apoptotic potential. AB - Hydrogen sulfide (H(2)S) has been shown to act as a neuroprotectant and antioxidant. Numerous studies have demonstrated that exposure to formaldehyde (FA) causes neuronal damage and that oxidative stress is one of the most critical effects of FA exposure. Accumulation of FA is involved in the pathogenesis of Alzheimer's disease (AD). The aim of present study is to explore the inhibitory effects of H(2)S on FA-induced cytotoxicity and apoptosis and the molecular mechanisms underlying in PC12 cells. We show that sodium hydrosulfide (NaHS), a H(2)S donor, protects PC12 cells against FA-mediated cytotoxicity and apoptosis and that NaHS preserves the function of mitochondria by preventing FA-induced loss of mitochondrial membrane potential and release of cytochrome c in PC12 cells. Furthermore, NaHS blocks FA-exerted accumulation of intracellular reactive oxygen species (ROS), down-regulation of Bcl-2 expression, and up-regulation of Bax expression. These results indicate that H(2)S protects neuronal cells against neurotoxicity of FA by preserving mitochondrial function through attenuation of ROS accumulation, up-regulation of Bcl-2 level, and down-regulation of Bax expression. Our study suggests a promising future of H(2)S-based preventions and therapies for neuronal damage after FA exposure. PMID- 22542419 TI - Brain, physiological and behavioral modulation induced by immune stimulation in honeybees (Apis mellifera): a potential mediator of social immunity? AB - Social removal is often an adaptive response for preventing the entry and spread of parasitic infection between kin members of a group. Social isolation via removal or the switching of social tasks has also been observed in insect societies; however, the underlying mechanisms are unclear. We tested in honeybees the role of the immune system in physiological and behavioral modulation. Forager bees are often located in the outer area of the colony, and thus have reduced contacts with individuals of high importance, who are located in the inner area of the colony (e.g. queen and brood). We thus expected that an immune challenge would induce a forager profile. This was confirmed by measuring brain (foraging and malvolio gene expression), physiological (hypopharyngeal glands size) and behavioral (queen attendance) parameters of nurse/forager profiles after a treatment with an immune-activator (lipopolysaccharides). Our results support the idea that the interplay between the brain and immune system may be an important regulatory factor of social immunity in insects. PMID- 22542420 TI - The opposite effect of a 5-HT1B receptor agonist on 5-HT synthesis, as well as its resistant counterpart, in an animal model of depression. AB - Flinders Sensitive Line (FSL) rat is as an animal model of depression with altered parameters of the serotonergic (5-HT) system function (5-HT synthesis rates, tissue concentrations, release, receptor density and affinity), as well as an altered sensitivity of these parameters to different 5-HT based antidepressants. The effects of acute and chronic treatments with the 5-HT(1B) agonist, CP-94253 on 5-HT synthesis, in the FSL rats and the Flinders Resistant Line (FRL) controls were measured using alpha-[(14)C]methyl-L-tryptophan (alpha MTrp) autoradiography. CP-94253 (5mg/kg), or an adequate volume of saline, was injected i.p. as a single dose in the acute experiment or delivered via the subcutaneously implanted osmotic minipump (5 mg/kg/day for 14 days) in the chronic experiment. The acute treatment with CP-94253 significantly decreased the 5-HT synthesis in both the FRL and FSL rats, with a more widespread effect in the FRL rats. Chronic treatment with CP-94253 significantly decreased 5-HT synthesis in the FRL rats, while 5-HT synthesis in the FSL rats was significantly increased throughout the brain. In both the acute and chronic experiment, the FRL rats had higher brain 5-HT synthesis rates, relative to the FSL rats. The shift in the direction of the treatment effect from acute to chronic, using the 5-HT(1B) agonist, CP-94253, on 5-HT synthesis in the FSL model of depression, with an opposite effect on the control FRL rats, suggests the differential adaptation of the 5-HT system in the FSL and FRL rats to chronic stimulation of 5-HT(1B) receptors. PMID- 22542421 TI - Evaluation of patient-reported quality-of-life outcomes after renal surgery. AB - OBJECTIVE: To assess the feasibility of 2 patient-reported health-related quality of life (HRQOL) instruments, Convalescence and Recovery Evaluation (CARE), and SF 12, as tools for evaluating HRQOL outcome consequences after renal surgery, and to determine which domains of these HRQOL instruments are most sensitive to HRQOL outcome effects of renal surgery. METHODS: Patients completed CARE and SF-12 preoperatively (baseline) and at 2, 4, 12, and 24 weeks after surgery. Clinical data, patient response rate, HRQOL changes over time, and likelihood of patient return to baseline HRQOL were evaluated. RESULTS: Seventy-one patients were enrolled. Sixty patients completed the baseline and at least 1 follow-up set of questionnaires. The CARE pain, gastrointestinal (GI), and activity domain scores and the SF-12 physical composite score (PCS) were sensitive to changes in HRQOL (all P<.05), whereas other domain subscores of these instruments did not change from presurgical baseline to postsurgical follow-up. Postsurgical HRQOL effects detected by the CARE pain, GI, and activity domains, and SF-12 PCS were most evident at 2 weeks (all P<.001). The CARE composite score demonstrated that 74% and 50% of patients returned to within 90% of baseline 4 weeks after radical and partial nephrectomy, respectively. CONCLUSION: Evaluation of patient-reported HRQOL outcomes after renal surgery is feasible; our findings suggest that the activity, pain, and GI domains of CARE and PCS subscores of the SF-12 are sensitive measures of HRQOL outcome consequences of renal surgery and represent appropriate measures of either care quality or comparative effectiveness analyses of robotic, laparoscopic, and open renal surgery. PMID- 22542422 TI - Combined laparoscopic and percutaneous management of calcified renal hydatid cyst -a novel nephroscope- and lithotripter-assisted technique. AB - OBJECTIVE: To describe the novel technique of percutaneous nephroscope-assisted renal hydatid cyst evacuation and lithotripter-assisted division of the cyst wall for combined laparoscopic and percutaneous management. METHODS: A calcified hydatid cyst of the kidney is a rare entity and needs special techniques for total laparoscopic management. A 45-year-old woman was treated successfully for a calcified renal hydatid cyst using the transperitoneal laparoscopic technique. A chlorhexidine gluconate and cetrimide mixture was used as the scolicidal solution to sterilize the cyst. The endocyst and daughter cysts were removed completely under vision, after placement of a single 26F nephroscope through a 10-mm port in the cyst, with grasper and lithotripter suction, using chlorhexidine-cetrimide mixture irrigation. Laparoscopic suction did not work well for the viscous contents. The calcified cyst wall did not yield to electrocautery or piecemeal fragmentation, until weakened by division and fragmentation using the pneumatic lithotripter. Partial cyst wall exicision/marsupialisation was complemented with omentoplasty. RESULTS: No intraoperative or early postoperative complications occurred. The patient recovered well with little pain and was discharged early. This technique, in which the principles of percutaneous nephrolithotomy were applied for a special problem, is the first of its type. CONCLUSION: Calcified renal hydatid cyst evacuation using the novel nephroscope-assisted retrieval of contents and lithotripter-assisted division of the calcified wall is a safe and feasible technique for total minimally invasive management. PMID- 22542423 TI - Barriers to fertility preservation in male adolescents with cancer: it's time for a multidisciplinary approach that includes urologists. PMID- 22542424 TI - Urolithiasis with penile erection: a rare presentation. AB - Urinary stones are rarely seen in the urethra and are usually encountered in men with urethral stricture or infection. We describe a unique case of giant impacted stones in a 20-year-old man with unreal penile erection. PMID- 22542425 TI - Neisseria gonorrhoeae triggers the PGE2/IL-23 pathway and promotes IL-17 production by human memory T cells. AB - PGE2 is a potent modulator of the T helper (Th)17 immune response that plays a critical role in the host defense against bacterial, fungal and viral infections. We recently showed high serum levels of interleukin (IL)-17 in patients with gonococcal infection and we hypothesized that Neisseria gonorrhoeae could exploit a PGE2 mediated mechanism to promote IL-17 production. Here we show that N. gonorrhoeae induces human dendritic cell (DC) maturation, secretion of prostaglandin E2 and proinflammatory cytokines, including the pro-Th17 cytokine IL-23. Blocking PGE2 endogenous synthesis selectively reduces IL-23 production by DC in response to gonococcal stimulation, confirming recent data on PGE2/IL-23 crosstalk. N. gonorrhoeae stimulated DC induce a robust IL-17 production by memory CD4(+) T cells and this function correlates with PGE2 production. Our findings delineate a previously unknown role for PGE2 in the immune response to N. gonorrhoeae, suggesting its contribute via Th17 cell expansion. PMID- 22542426 TI - [Systemic candidiasis in medical intensive care unit: analysis of risk factors and the contribution of colonization index]. AB - OBJECTIVES: Description of the epidemiological and clinical characteristics of the patients introducing risk factors of invasive candidiasis. Analysis of risk factors for candidiasis invasive and evaluation of the contribution of colonization index (CI) in the diagnosis of the systematic candidiasis in medical intensive care. PATIENTS AND METHODS: Prospective observational study (October 2007 to October 2009). The selected patients present risk factors of system IC candidiasis with an infectious syndrome or clinical signs suggestive of Candida infection and hospitalized more than 48 hours in medical intensive care unit. Pittet's colonization index was calculated at admission and then once a week added to a blood culture. Patients were classified according to level of evidence of Candida infection and the degree of colonization (CI<0.5, CI >= 0.5). RESULTS: The study included 100 patients. Mean age of our patients was 55.8 +/- 18.2 years with male prevalence. Neurological disease was the most frequent pathology in admission (48%). The most common risk factors were broad-spectrum antibiotics and foreign material. In the various mycology IC specimens, Candida albicans was the most frequent, followed by C. tropicalis, then C. glabrata. The CI was greater than or equal to 0.5 at 53% of the patients, and less than 0.5 in 47% of the cases. Among the patients, 15% developed an invasive candidiasis. In multivariate analysis, the corticosteroid therapy was associated with a high colonisation (IC >= 0.5) and neutropenia with a high risk of systemic candidiasis. The positive predictive value of CI was 26%. The negative predictive value was 98%, the sensitivity and specificity was 93% and 48% respectively. CONCLUSION: CI has the advantage to provide a quantified data of the patient's situation in relation to the colonization. But, it isn't helpful with patients having an invasive candidiasis in medical intensive care unit. PMID- 22542427 TI - [Cutaneous leishmaniasis in the military hospital Moulay Ismail of Meknes (Morocco): about 49 cases diagnosed between 2005 and 2011]. AB - An increase in the number of cases of cutaneous leishmaniasis has been observed, in recent years, in Morocco. We tried, through a series of 49 cases collected from the dermatology department at the military hospital Moulay Ismail of Meknes, to clarify the epidemiological, clinical and evolutionary aspects of the reported cases. We recorded for each patient: age, sex, geographic origin and the period before consultation. We have also noted the number of lesions, their location, and their clinical aspects. Finally, we recorded results of direct examination in search of the parasite, treatment and post treatment evolution. The sex ratio was 11. The average age was 35.6 years. The average period of consultation was 3.8 months. Eighty-six percent of cases (n=42) were from the region extending from south to south-east of the atlas. The average number of lesions per patient was 4.46 (from 1 to 40). Thirty-seven percent of cases (n=18) had single lesions and 63% (n=31) multiple lesions. There was a polymorphism of clinical aspects of lesions with predominant of ulcerative crusting aspects observed in 55.1% of cases (n=27). Face localization was observed in 20.4% of cases (n=10). Ninety-two percent of cases (n=45) had involvement of the upper limbs and/or lower. Direct examination was positive in 65% of cases (n=32). The treatment was based on meglumine antimoniate associated in three quarters of cases with cryotherapy using liquid nitrogen. The outcome was favorable for all patients. We observed an increase in the number of cases in 2011 and especially those with multiple lesions followed by a decline in 2011. PMID- 22542428 TI - [Molecular diagnosis of Gaucher disease in Tunisia]. AB - Gaucher disease is a lysosomal storage disorder caused by a deficiency of the enzyme acid beta-glucosidase. In order to determine the mutation spectrum in Tunisia, we performed recurrent mutation screening in 30 Tunisian patients with Gaucher disease. Screening of recurrent mutation by PCR/RFLP and direct sequencing had shown that N370S was the most frequent mutation (22/50 mutant alleles, 44%), followed by L444P mutation, which is found in 16% (8/50 mutant alleles). The recombinant allele (RecNciI) represented 14%. Our findings revealed that the genotype N370S/RecNciI was mosst frequent in patients with childhood onset and it was associated with severe visceral involvement. The screening of these three mutations provided a simple tool for molecular diagnosis of Gaucher disease in Tunisian patients and allowed also genetic counselling for their family members. PMID- 22542429 TI - [Host inflammatory and anti-inflammatory response during sepsis]. AB - Sepsis still remains the major complication for patients admitted in intensive care units (ICU), and is responsible for numerous deaths. ICU patients admitted after sepsis, hemorrhagic shock, severe trauma, severe burns or major surgery show a systemic inflammatory response syndrome (SIRS). This syndrome is characterized by an exacerbation of inflammation, with increased levels of pro- (IL-1beta, TNFalpha, IL-6, IL-8) as well as anti-inflammatory (IL-10, IL-1Ra, TGFbeta) cytokines into their bloodstream. During sepsis, the bacteria release microbial motifs such as peptidoglycan, lipopolysaccharide (LPS) and DNA that initiate the inflammatory response, and are involved in the onset of multiple organ failure. The same microbial motifs can also be found in patients with a SIRS of non-infectious origin, following the translocation of bacteria from their digestive tract. This translocation is certainly contributing to the difficulty of discriminating between septic and SIRS patients using biological markers. Furthermore, the host response is accompanied by an alteration of the ex vivo response of circulating leukocytes, particularly monocytes. This hyporesponsiveness to LPS is associated with a decreased activation of the transcription factor NF-kappaB (required for the expression of pro-inflammatory cytokines) and an increased expression of negative regulators of the NF-kappaB pathway. However, the leukocyte hyporesponsiveness is not a global phenomenon, it depends on the type of patient, on the receptor-activator pair, on the timing, and on the cytokine. PMID- 22542430 TI - AAOS rotator cuff clinical practice guideline misses the mark. PMID- 22542431 TI - Assessing and reporting anchor performance. PMID- 22542433 TI - The Development and validation of a self-administered quality-of-life outcome measure for young, active patients with symptomatic hip disease: the International Hip Outcome Tool (iHOT-33). AB - PURPOSE: The purpose of this study was to develop a self-administered evaluative tool to measure health-related quality of life in young, active patients with hip disorders. METHODS: This outcome measure was developed for active patients (aged 18 to 60 years, Tegner activity level >= 4) presenting with a variety of symptomatic hip conditions. This multicenter study recruited patients from international hip arthroscopy and arthroplasty surgeon practices. The outcome was created using a process of item generation (51 patients), item reduction (150 patients), and pretesting (31 patients). The questionnaire was tested for test retest reliability (123 patients); face, content, and construct validity (51 patients); and responsiveness over a 6-month period in post-arthroscopy patients (27 patients). RESULTS: Initially, 146 items were identified. This number was reduced to 60 through item reduction, and the items were categorized into 4 domains: (1) symptoms and functional limitations; (2) sports and recreational physical activities; (3) job-related concerns; and (4) social, emotional, and lifestyle concerns. The items were then formatted using a visual analog scale. Test-retest reliability showed Pearson correlations greater than 0.80 for 33 of the 60 questions. The intraclass correlation statistic was 0.78, and the Cronbach alpha was .99. Face validity and content validity were ensured during development, and construct validity was shown with a correlation of 0.81 to the Non-Arthritic Hip Score. Responsiveness was shown with a paired t test (P <= .01), effect size of 2.0, standardized response mean of 1.7, responsiveness ratio of 6.7, and minimal clinically important difference of 6 points. CONCLUSIONS: We have developed a new quality-of-life patient-reported outcome measure, the 33 item International Hip Outcome Tool (iHOT-33). This questionnaire uses a visual analog scale response format designed for computer self-administration by young, active patients with hip pathology. Its development has followed the most rigorous methodology involving a very large number of patients. The iHOT-33 has been shown to be reliable; shows face, content, and construct validity; and is highly responsive to clinical change. In our opinion the iHOT-33 can be used as a primary outcome measure for prospective patient evaluation and randomized clinical trials. PMID- 22542434 TI - A short version of the International Hip Outcome Tool (iHOT-12) for use in routine clinical practice. AB - PURPOSE: The purpose of this study was to develop and validate a shorter version of the 33-item International Hip Outcome Tool (iHOT-33) that could be easily used in routine clinical practice to measure both health-related quality of life and changes after treatment in young, active patients with hip disorders. METHODS: A development dataset (104 patients) was explored with forward-selection linear regression analysis to choose a reduced item set for the new scale. This was tested in a validation dataset (1,833 patients) and responsiveness subset (80 patients) to measure agreement between the shorter and longer versions and to test the sensitivity of the shorter instrument to change after treatment. RESULTS: Twelve items were chosen for a short version of the International Hip Outcome Tool (iHOT-12). The iHOT-12 showed excellent agreement with the long version (iHOT-33). It captured 95.9% (95% confidence interval, 95.0% to 96.8%) of the variation of the iHOT-33 and showed equivalent sensitivity to change with a standardized effect size of 0.98 (95% confidence interval, 0.67 to 1.28). CONCLUSIONS: A short version of the International Hip Outcome Tool (iHOT-12) has been developed. It has very similar characteristics to the original rigorously validated 33-item questionnaire, losing very little information despite being only one-third the length. It is valid, reliable, and responsive to change. We suggest that it be used for initial assessment and postoperative follow-up in routine clinical practice. PMID- 22542435 TI - Failure of biceps tenodesis with interference screw fixation. AB - Tenodesis is a common surgical procedure used to treat pain caused by inflammation or instability of the long head of the biceps tendon. Many studies have evaluated different forms of fixation and their biomechanical characteristics, but few have discussed clinical complications or failures as a result of these techniques. The purpose of this article is to report a case series of 3 patients with failures after undergoing arthroscopic biceps tenodesis with an interference screw. PMID- 22542436 TI - The presence of viral subpopulations in an infectious bronchitis virus vaccine with differing pathogenicity--a preliminary study. AB - There are currently four commercially available vaccines in Australia to protect chickens against infectious bronchitis virus (IBV). Predominantly, IBV causes clinical signs associated with respiratory or kidney disease, which subsequently cause an increase in mortality rate. Three of the current vaccines belong to the same subgroup (subgroup 1), however, the VicS vaccine has been reported to cause an increased vaccinal reaction compared to the other subgroup 1 vaccines. Molecular anomalies detected in VicS suggested the presence of two major subspecies, VicS-v and VicS-del, present in the commercial preparation of VicS. The most notable anomaly is the absence of a 40 bp sequence in the 3'UTR of VicS del. In this investigation, the two subspecies were isolated and shown to grow independently and to similar titres in embryonated chicken eggs. An in vivo investigation involved 5 groups of 20 chickens each and found that VicS-del grew to a significantly lesser extent in the chicken tissues collected than did VicS v. The group inoculated with an even ratio of the isolated subspecies scored the most severe clinical signs, with the longest duration. These results indicate the potential for a cooperative, instead of an expected competitive, relationship between VicS-v and VicS-del to infect a host, which is reminiscent of RNA viral quasi-species. PMID- 22542437 TI - MCAD deficiency in Denmark. AB - Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common defect of fatty acid oxidation. Many countries have introduced newborn screening for MCADD, because characteristic acylcarnitines can easily be identified in filter paper blood spot samples by tandem mass spectrometry (MS/MS), because MCADD is a frequent disease, and because of the success of early treatment initiated before clinical symptoms have emerged. In Denmark we have screened 519,350 newborns for MCADD by MS/MS and identified 58 affected babies. The diagnosis of MCADD was confirmed in all 58 newborns by mutation analysis. This gives an incidence of MCADD detected by newborn screening in Denmark of 1/8954. In sharp contrast to this we found that the incidence of clinically presenting MCADD in Denmark in the 10 year period preceding introduction of MS/MS-based screening was only 1 in 39,691. This means that four times more newborns with MCADD are detected by screening than what is expected based on the number of children presenting clinically in an unscreened population. The mutation spectrum in the newborns detected by screening is different from that observed in clinically presenting patients with a much lower proportion of newborns being homozygous for the prevalent disease-causing c.985A>G mutation. A significant number of the newborns have genotypes with mutations that have not been observed in patients detected clinically. Some of these mutations, like c.199T>C and c.127G>A, are always associated with a milder biochemical phenotype and may cause a milder form of MCADD with a relatively low risk of disease manifestation, thereby explaining part of the discrepancy between the frequency of clinically manifested MCADD and the frequency of MCADD determined by screening. In addition, our data suggest that some of this discrepancy can be explained by a reduced penetrance of the c.985A>G mutation, with perhaps only 50% of c.985A>G homozygotes presenting with disease manifestations. Interestingly, we also report that the observed number of newborns identified by screening who are homozygous for the c.985A>G mutation is twice that predicted from the estimated carrier frequency. We therefore redetermined the carrier frequency in a new sample of 1946 blood spots using a new assay, but this only confirmed that the c.985A>G carrier frequency in Denmark is approximately 1/105. We conclude that MCADD is much more frequent than expected, has a reduced penetrance and that rapid genotyping using the initial blood spot sample is important for correct diagnosis and counseling. PMID- 22542438 TI - PKA-mediated eNOS phosphorylation in the protection of ischemic preconditioning against no-reflow. AB - OBJECTIVE: To investigate whether ischemic preconditioning (IP) can reduce myocardial no-reflow by activating endothelial (e-) nitric oxide synthase (NOS) via the protein kinase A (PKA) pathway. METHODS AND RESULTS: In a 90-min ischemia and 3-h reperfusion model, minipigs were assigned into sham, ischemia-reperfusion (IR), IR+IP, IR+IP+L-NNA (an eNOS inhibitor, 10mg.kg(-1)), IR+IP+H-89 (a PKA inhibitor, 1.0MUg.kg(-1).min(-1)), IR+L-NNA, and IR+H-89 groups. IP pretreatment improved cardiac function and coronary blood flow, decreased the activities of creatine kinase by 36.6% after 90 min of ischemia and by 32.8% after 3 h of reperfusion (P<0.05), reduced the no-reflow areas from 49.9% to 11.0% (P<0.01), and attenuated the infarct size from 78.2% to 35.4% (P<0.01). IP stimulated myocardial PKA activities and the expression of PKA and Ser(133) phosphorylated (p-) cAMP response element-binding protein (CREB) in the reflow and no-reflow myocardium, and enhanced the activities of constitutive NOS and the phosphorylation of eNOS at Ser(1179) and Ser(635) in the no-reflow myocardium. IP suppressed the expression of tumor necrosis factor-alpha and P-selectin, and attenuated cardiomyocytes apoptosis by regulating the expression of Bcl-2 and caspase-3 in the reflow and no-reflow myocardium. The eNOS inhibitor L-NNA completely canceled these beneficial effects of IP without any influence on PKA activity, whereas the PKA inhibitor H-89 partially blocked the IP cardioprotective effects and eNOS phosphorylation at the same time. CONCLUSION: IP attenuates myocardial no-reflow and infarction after ischemia and reperfusion by activating the phosphorylation of eNOS at Ser(1179) and Ser(635) in a partly PKA-dependent manner. PMID- 22542439 TI - Baseline EEG theta/beta ratio and punishment sensitivity as biomarkers for feedback-related negativity (FRN) and risk-taking. AB - OBJECTIVE: Feedback-related negativity (FRN) is associated with reinforcement learning and punishment sensitivity. Furthermore, reinforcement learning proficiency can be predicted from pre-task baseline EEG theta/beta ratio. In this study it was examined whether there was a relation between baseline theta/beta ratio in rest and FRN amplitude during a gambling task, and if such a correlation would be related to theta activity or to beta activity. METHODS: Baseline EEG and a self-report measure of punishment sensitivity (BIS) were obtained from 52 healthy volunteers. FRN was recorded during a gambling task. RESULTS: FRN amplitude was negatively correlated with theta/beta ratio in high BIS individuals. Furthermore, source localization indicated that baseline theta activity generated in the anterior cingulate cortex (ACC) accounted for this correlation. For low BIS individuals no correlation was found. CONCLUSIONS: An association between high baseline theta/beta ratio with low amplitude FRN and high risk-taking can be found in individuals who score sufficiently high on the BIS scale. This relationship is carried mostly by baseline theta activity, but not by beta activity. SIGNIFICANCE: This link between baseline brain activity, self-report measures and feedback processing may contribute to further understanding the biological basis of conditions that are accompanied by abnormal theta/beta ratio and reward processing, such as attention deficit hyper activity disorder (ADHD). PMID- 22542440 TI - Exploring the role of peer density in the self-reported oral health outcomes of older adults: a kernel density based approach. AB - Previous research has documented that oral health is inextricably linked with overall health and is an important component of successful aging. Additionally, peer social interactions are known to improve older adults' general well-being by increasing social opportunities and knowledge of local resources. This study examines the relationship between peer density of participants aged 50 and older in the ElderSmile program and self-reported oral health in northern Manhattan. Results from logistic regression models found that higher peer kernel density estimation values are associated with better self-reported oral health. This reinforces the need for place-based health interventions, and provides new evidence of the importance of peer communities for older adults. PMID- 22542441 TI - Crime, fear of crime, environment, and mental health and wellbeing: mapping review of theories and causal pathways. AB - This paper presents the findings from a review of the theoretical and empirical literature on the links between crime and fear of crime, the social and built environment, and health and wellbeing. A pragmatic approach was employed, with iterative stages of searching and synthesis. This produced a holistic causal framework of pathways to guide future research. The framework emphasises that crime and fear of crime may have substantial impacts on wellbeing, but the pathways are often highly indirect, mediated by environmental factors, difficult to disentangle and not always in the expected direction. The built environment, for example, may affect health via its impacts on health behaviours; via its effects on crime and fear of crime; or via the social environment. The framework also helps to identify unexpected factors which may affect intervention success, such as the risk of adverse effects from crime prevention interventions as a result of raising awareness of crime. PMID- 22542442 TI - Preparation of porous polymer monoliths featuring enhanced surface coverage with gold nanoparticles. AB - A new approach to the preparation of porous polymer monoliths with enhanced coverage of pore surface with gold nanoparticles has been developed. First, a generic poly(glycidyl methacrylate-co-ethylene dimethacrylate) monolith was reacted with cystamine followed by the cleavage of its disulfide bonds with tris(2-carboxylethyl)phosphine, which liberated the desired thiol groups. Dispersions of gold nanoparticles with sizes varying from 5 to 40 nm were then pumped through the functionalized monoliths. The materials were then analyzed using both energy dispersive X-ray spectroscopy and thermogravimetric analysis. We found that the quantity of attached gold was dependent on the size of nanoparticles, with the maximum attachment of more than 60 wt% being achieved with 40 nm nanoparticles. Scanning electron micrographs of the cross sections of all the monoliths revealed the formation of a non-aggregated, homogenous monolayer of nanoparticles. The surface of the bound gold was functionalized with 1-octanethiol and 1-octadecanethiol, and these monolithic columns were used successfully for the separations of proteins in reversed phase mode. The best separations were obtained using monoliths modified with 15, 20, and 30 nm nanoparticles since these sizes produced the most dense coverage of pore surface with gold. PMID- 22542443 TI - The oncology drug elesclomol selectively transports copper to the mitochondria to induce oxidative stress in cancer cells. AB - Elesclomol is an investigational drug that exerts potent anticancer activity through the elevation of reactive oxygen species (ROS) levels and is currently under clinical evaluation as a novel anticancer therapeutic. Here we report the first description of selective mitochondrial ROS induction by elesclomol in cancer cells based on the unique physicochemical properties of the compound. Elesclomol preferentially chelates copper (Cu) outside of cells and enters as elesclomol-Cu(II). The elesclomol-Cu(II) complex then rapidly and selectively transports the copper to mitochondria. In this organelle Cu(II) is reduced to Cu(I), followed by subsequent ROS generation. Upon dissociation from the complex, elesclomol is effluxed from cells and repeats shuttling elesclomol-Cu complexes from the extracellular to the intracellular compartments, leading to continued copper accumulation within mitochondria. An optimal range of redox potentials exhibited by copper chelates of elesclomol and its analogs correlated with the elevation of mitochondrial Cu(I) levels and cytotoxic activity, suggesting that redox reduction of the copper triggers mitochondrial ROS induction. Importantly the mitochondrial selectivity exhibited by elesclomol is a distinct characteristic of the compound that is not shared by other chelators, including disulfiram. Together these findings highlight a unique mechanism of action with important implications for cancer therapy. PMID- 22542444 TI - Regulation of adipose tissue energy availability through blood flow control in the metabolic syndrome. AB - Maintenance of blood flow rate is a critical factor for tissue oxygen and substrate supply. The potentially large mass of adipose tissue deeply influences the body distribution of blood flow. This is due to increased peripheral resistance in obesity and the role of this tissue as the ultimate destination of unused excess of dietary energy. However, adipose tissue cannot grow indefinitely, and the tissue must defend itself against the avalanche of nutrients provoking inordinate growth and inflammation. In the obese, large adipose tissue masses show lower blood flow, limiting the access of excess circulating substrates. Blood flow restriction is achieved by vasoconstriction, despite increased production of nitric oxide, the vasodilatation effects of which are overridden by catecholamines (and probably also by angiotensin II and endothelin). Decreased blood flow reduces the availability of oxygen, provoking massive glycolysis (hyperglycemic conditions), which results in the production of lactate, exported to the liver for processing. However, this produces local acidosis, which elicits the rapid dissociation of oxyhemoglobin, freeing bursts of oxygen in localized zones of the tissue. The excess of oxygen (and of nitric oxide) induces the production of reactive oxygen species, which deeply affect the endothelial, blood, and adipose cells, inducing oxidative and nitrosative damage and eliciting an increased immune response, which translates into inflammation. The result of the defense mechanism for adipose tissue, localized vasoconstriction, may thus help develop a more generalized pathologic response within the metabolic syndrome parameters, extending its effects to the whole body. PMID- 22542446 TI - H2O2 signals via iron induction of VL30 retrotransposition correlated with cytotoxicity. AB - The impact of oxidative stress on mobilization of endogenous retroviruses and their effects on cell fate is unknown. We investigated the action of H2O2 on retrotransposition of an EGFP-tagged mouse LTR-retrotransposon, VL30, in an NIH3T3 cell-retrotransposition assay. H2O2 treatment of assay cells caused specific retrotranspositions documented by UV microscopy and PCR analysis. Flow cytometric analysis revealed an unusually high dose- and time-dependent retrotransposition frequency induced, ~420,000-fold at 40 MUM H2O2 compared to the natural frequency, which was reduced by ectopic expression of catalase. Remarkably, H2O2 moderately induced the RNA expression of retrotransposon B2 without affecting the basal expression of VL30s and L1 and significantly induced the expression of various endogenous reverse transcriptase genes. Further, whereas treatment with 50 MUM FeCl2 alone was ineffective, cotreatment with 10 MUM H2O2 and 50 MUM FeCl2 caused a 6-fold higher retrotransposition induction than H2O2 alone, which was associated with cytotoxicity. H2O2- or H2O2/FeCl2 induced retrotransposition was significantly reduced by the iron chelator DFO or the antioxidant NAC, respectively. Furthermore, both H2O2-induced retrotransposition and associated cytotoxicity were inhibited after pretreatment of cells with DFO or the reverse transcriptase inhibitors efavirenz and etravirine. Our data show for the first time that H2O2, acting via iron, is a potent stimulus of retrotransposition contributing to oxidative stress-induced cell damage. PMID- 22542447 TI - Oxidative stress-related biomarkers in autism: systematic review and meta analyses. AB - Autism spectrum disorders (ASDs) are rarely diagnosed in children younger than 2 years, because diagnosis is based entirely on behavioral tests. Oxidative damage may play a central role in this pathogenesis, together with the interconnected transmethylation cycle and transsulfuration pathway. In an attempt to clarify and quantify the relationship between oxidative stress-related blood biomarkers and ASDs, a systematic literature review was carried out. For each identified study, mean biomarker levels were compared in cases and controls providing a point estimate, the mean ratio, for each biomarker. After meta-analysis, the ASD patients showed decreased blood levels of reduced glutathione (27%), glutathione peroxidase (18%), methionine (13%), and cysteine (14%) and increased concentrations of oxidized glutathione (45%) relative to controls, whereas superoxide dismutase, homocysteine, and cystathionine showed no association with ASDs. For the C677T allele in the methylene tetrahydrofolate reductase gene (MTHFR), homozygous mutant subjects (TT) showed a meta-OR of 2.26 (95% CI 1.30 3.91) of being affected by ASD with respect to the homozygous nonmutant (CC). Case-control studies on blood levels of vitamins suggest a lack of association (folic acid and vitamin B12) or rare association (vitamins A, B6, C, D, E). Sparse results were available for other biomarkers (ceruloplasmin, catalase, cysteinylglycine, thiobarbituric acid-reactive substances, nitric oxide) and for polymorphisms in other genes. Existing evidence is heterogeneous and many studies are limited by small sample size and effects. In conclusion, existing evidence suggests a role for glutathione metabolism, the transmethylation cycle, and the transsulfuration pathway, although these findings should be interpreted with caution, and larger, more standardized studies are warranted. PMID- 22542448 TI - Pralatrexate is an effective treatment for relapsed or refractory transformed mycosis fungoides: a subgroup efficacy analysis from the PROPEL study. AB - Transformed mycosis fungoides (tMF) is an aggressive disease with a median survival of 12-24 months. In this retrospective analysis of 12 patients with tMF, treatment with pralatrexate resulted in an objective response of 25% per independent central review and 58% per investigator assessment. Pralatrexate was well tolerated, with no toxicity-related discontinuations, which makes this an additional option for tMF treatment. BACKGROUND: Transformed mycosis fungoides (tMF) is an aggressive disease, with poor prognosis and a median survival of 24 months. PATIENTS AND METHODS: In the Pralatrexate in Patients With Relapsed or Refractory Peripheral T-cell Lymphoma (PROPEL) study, 12 patients with tMF were treated with a median of 10 pralatrexate doses (starting dose of 30 mg/m(2)) administered weekly for 6 weeks in a 7-week cycle. The median number of prior systemic therapies was 3. RESULTS: This retrospective analysis showed that the objective response rate in this subgroup was 25% (n = 3) per independent central review and 58% (n = 7) per investigator assessment, with this discrepancy likely attributed to challenges with photodocumentation of cutaneous lesions. The median duration of response and the median progression-free survival were 2.2 and 1.7 months, respectively, per central review, whereas median duration of response was 4.4 months, and median progression-free survival was 5.3 months per investigator assessment. Median survival was 13 months. Grade 1-3 mucositis was reported in 7 (58%) patients. Grade 4 adverse events were fatigue (n = 1) and thrombocytopenia (n = 1). Pralatrexate was well tolerated, with no toxicity-related discontinuations. CONCLUSIONS: Based on these results, pralatrexate may be a treatment option for patients with relapsed or refractory tMF. PMID- 22542449 TI - Clinical binding properties, internalization kinetics, and clinicopathologic activity of brentuximab vedotin: an antibody-drug conjugate for CD30-positive lymphoid neoplasms. PMID- 22542445 TI - The effects of chromium(VI) on the thioredoxin system: implications for redox regulation. AB - Hexavalent chromium [Cr(VI)] compounds are highly redox active and have long been recognized as potent cytotoxins and carcinogens. The intracellular reduction of Cr(VI) generates reactive Cr intermediates, which are themselves strong oxidants, as well as superoxide, hydrogen peroxide, and hydroxyl radical. These probably contribute to the oxidative damage and effects on redox-sensitive transcription factors that have been reported. However, the identification of events that initiate these signaling changes has been elusive. More recent studies show that Cr(VI) causes irreversible inhibition of thioredoxin reductase (TrxR) and oxidation of thioredoxin (Trx) and peroxiredoxin (Prx). Mitochondrial Trx2/Prx3 are more sensitive to Cr(VI) treatment than cytosolic Trx1/Prx1, although both compartments show thiol oxidation with higher doses or longer treatments. Thiol redox proteomics demonstrate that Trx2, Prx3, and Trx1 are among the most sensitive proteins in cells to Cr(VI) treatment. Their oxidation could therefore represent initiating events that have widespread implications for protein thiol redox control and for multiple aspects of redox signaling. This review summarizes the effects of Cr(VI) on the TrxR/Trx system and how these events could influence a number of downstream redox signaling systems that are influenced by Cr(VI) exposure. Some of the signaling events discussed include the activation of apoptosis signal regulating kinase and MAP kinases (p38 and JNK) and the modulation of a number of redox-sensitive transcription factors including AP-1, NF-kappaB, p53, and Nrf2. PMID- 22542450 TI - The ST2 pathway is involved in acute pancreatitis: a translational study in humans and mice. AB - Acute pancreatitis (AP) is an inflammatory disease in which the regulatory pathways are not clearly elucidated. Activation of interleukin 1beta (IL-1beta) and immunomodulation via MyD88, the first signaling molecule in the ST2 pathway, seem to be involved. Because IL-33, the ST2 ligand, is an IL-1 family member and acts as an alarmin, we explored the ST2 pathway in human and mouse AP. Soluble ST2 was assayed by enzyme-linked immunosorbent assay (ELISA) in plasma of 44 patients admitted for AP. The levels of soluble ST2 increased early during AP and correlated with parameters of severity. Under two different experimental models of AP (ie, choline-deficient-ethionine-supplemented diet and cerulein injections), ST2-deficient mice (Il1rl1(-/-)) presented with more severe disease than wild-type mice, with increased activation of mast cells. In vitro, Il1rl1(-/ ) bone-marrow-derived mast cells exhibited exacerbated degranulation, compared with the wild type. Flow cytometry identified mast cells as the main peritoneal population expressing ST2. Using immunohistochemistry and ELISA, we showed constitutive expression of IL-33 in murine pancreas and its release during experimental AP. Correlated with AP severity, increased soluble ST2 levels evoke involvement of the ST2 pathway in human AP. Furthermore, our experimental data suggest a protective role for ST2 during AP, highlighting the potential regulatory role of mast cells and the possibility of the ST2 pathway as a new therapeutic target in AP. PMID- 22542451 TI - Normalizing the metabolic phenotype after myocardial infarction: impact of subchronic high fat feeding. AB - The normal heart relies primarily on the oxidation of fatty acids (FA) for ATP production, whereas during heart failure (HF) glucose utilization increases, implying pathological changes to cardiac energy metabolism. Despite the noted lipotoxic effects of elevating FA, our work has demonstrated a cardioprotective effect of a high fat diet (SAT) when fed after myocardial infarction (MI), as compared to normal chow (NC) fed cohorts. This data has suggested a mechanistic link to energy metabolism. The goal of this study was to determine the impact of SAT on the metabolic phenotype of the heart after MI. Male Wistar rats underwent coronary ligation surgery (MI) and were evaluated after 8 weeks of SAT. Induction of MI was verified by echocardiography. LV function assessed by in vivo hemodynamic measurements revealed improvements in the MI-SAT group as compared to MI-NC. Perfused working hearts revealed a decrease in cardiac work in MI-NC that was improved in MI-SAT. Glucose oxidation was increased and FA oxidation decreased in MI-NC compared to shams suggesting an alteration in the metabolic profile that was ameliorated by SAT. (31)P NMR analysis of Langendorff perfused hearts revealed no differences in PCr:ATP indicating no overt energy deficit in MI groups. Phospho-PDH and PDK(4) were increased in MI-SAT, consistent with a shift towards fatty acid oxidation (FAO). Overall, these results support the hypothesis that SAT post-infarction promotes a normal metabolic phenotype that may serve a cardioprotective role in the injured heart. PMID- 22542452 TI - Effects of menopause on blood manganese levels in women: analysis of 2008-2009 Korean National Health and Nutrition Examination Survey data. AB - INTRODUCTION: We present data from the Korean National Health and Nutrition Examination Survey 2008-2009 on the association between blood manganese (Mn) levels and menopausal status in women. METHODS: The present analysis was restricted to female participants who completed the health examination survey, including blood Mn measurements (n=1826). Menopausal status was categorized into pre- and post-menopausal. Multivariable linear regression analyses were performed to determine whether menopausal status or serum ferritin were significant predictors of blood Mn level and to investigate whether menopausal status modifies the association between blood Mn and serum ferritin after adjusting for covariates. RESULTS: The geometric means (GMs) of blood Mn in the low and low normal serum ferritin groups were significantly higher than the GM of blood Mn in the normal group. The GM of blood Mn in premenopausal women was significantly higher than in postmenopausal women Multivariable linear regression analyses showed that both serum ferritin and menopausal status were predictors of blood Mn, after adjusting for various covariates, and menopausal status acted as a modifier of the effect of ferritin on blood Mn levels. Blood Mn levels were 11.0% and 22.7% lower in premenopausal women when serum ferritin increased from 10 MUg/dL to 60 and 100 MUg/dL, respectively, but the decrease in blood Mn based on the increase in serum ferritin was minimal in postmenopausal women. DISCUSSION: To our knowledge, this is the first report that menopausal status was a predictor of blood Mn level after adjusting for serum ferritin. In conclusion, the present study showed that both serum ferritin and menopausal status were predictors of blood Mn, after adjusting for various covariates, and menopausal status acted as a modifier of the effect of ferritin on blood Mn levels. PMID- 22542453 TI - Sex and rearing condition modify the effects of perinatal lead exposure on learning and memory. AB - Developmental lead (Pb) exposure is associated with cognitive impairments in humans and rodents alike. In particular, impaired spatial learning and memory, as assessed using the Morris water maze (MWM), has been noted in developmentally Pb exposed rats. Although sex and rearing environment can influence MWM performance in normal animals, the interactions of sex and rearing environment on the impact of developmental Pb exposure on hippocampal-dependent processes has not been well characterized. The present study examined the effects of perinatal exposure (i.e., gestation through weaning) to different levels of Pb (250, 750 and 1500 ppm Pb acetate in food) in males and females raised in a non-enriched environment (standard cage with 3 animals and no toys) or an enriched environment (large cage containing a variety of toys that were changed twice weekly). Testing in the MWM began at postnatal day 55. Behavioral outcomes were influenced by sex and rearing environment, with complex interactions with Pb exposure. In non-Pb exposed control animals, beneficial effects of environmental enrichment on spatial learning and memory were observed in males and females, with greater effects in females. Pb exposure in females mitigated at least some of the benefits of enrichment on learning, particularly at the lowest and highest exposure levels. In males, enrichment conferred a modest learning advantage and for the most part, Pb exposure did not affect this. However, in males with the highest Pb exposure, enrichment did help to overcome detrimental effects of Pb on learning. In females, any potential benefit to reference memory contributed by enrichment was muted by exposure to Pb and for the most part, this was not reproduced in males. Thus, there are complex interactions between sex, environment, and Pb exposure on spatial learning and memory. Environmental manipulation is a potential risk modifier of developmental Pb exposure and interacts with other factors including sex and amount of Pb exposure to affect the functional influences of Pb on the brain. PMID- 22542454 TI - Nitric oxide modulates bacterial biofilm formation through a multicomponent cyclic-di-GMP signaling network. AB - Nitric oxide (NO) signaling in vertebrates is well characterized and involves the heme-nitric oxide/oxygen-binding (H-NOX) domain of soluble guanylate cyclase as a selective NO sensor. In contrast, little is known about the biological role or signaling output of bacterial H-NOX proteins. Here, we describe a molecular pathway for H-NOX signaling in Shewanella oneidensis. NO stimulates biofilm formation by controlling the levels of the bacterial secondary messenger cyclic diguanosine monophosphate (c-di-GMP). Phosphotransfer profiling was used to map the connectivity of a multicomponent signaling network that involves integration from two histidine kinases and branching to three response regulators. A feed forward loop between response regulators with phosphodiesterase domains and phosphorylation-mediated activation intricately regulated c-di-GMP levels. Phenotypic characterization established a link between NO signaling and biofilm formation. Cellular adhesion may provide a protection mechanism for bacteria against reactive and damaging NO. These results are broadly applicable to H-NOX mediated NO signaling in bacteria. PMID- 22542456 TI - MEN1 and pituitary adenomas. AB - MEN1 gene mutations predispose carriers to pituitary tumors. Molecular pathways involved in the development of these tumors seem different to what is known in sporadic tumors. Clinical studies showed that all types of adenomas can be found with a predominance of prolactinoma and macroadenoma compared to a control population. These MEN1 tumors seem more aggressive, invasive and resistant to treatment requiring a very careful long-life follow-up. Occurrence of these tumors can be described in the pediatric population and it can be the first and only manifestation of MEN1 for some years asking the question of the systematic screening for MEN1 gene mutation in pediatric population with pituitary adenoma. PMID- 22542455 TI - USP22 antagonizes p53 transcriptional activation by deubiquitinating Sirt1 to suppress cell apoptosis and is required for mouse embryonic development. AB - The NAD-dependent histone deacetylase Sirt1 antagonizes p53 transcriptional activity to regulate cell-cycle progression and apoptosis. We have identified a ubiquitin-specific peptidase, USP22, one of the 11 death-from-cancer signature genes that are critical in controlling cell growth and death, as a positive regulator of Sirt1. USP22 interacts with and stabilizes Sirt1 by removing polyubiquitin chains conjugated onto Sirt1. The USP22-mediated stabilization of Sirt1 leads to decreasing levels of p53 acetylation and suppression of p53 mediated functions. In contrast, depletion of endogenous USP22 by RNA interference destabilizes Sirt1, inhibits Sirt1-mediated deacetylation of p53 and elevates p53-dependent apoptosis. Genetic deletion of the usp22 gene results in Sirt1 instability, elevated p53 transcriptional activity and early embryonic lethality in mice. Our study elucidates a molecular mechanism in suppression of cell apoptosis by stabilizing Sirt1 in response to DNA damage and reveals a critical physiological function of USP22 in mouse embryonic development. PMID- 22542457 TI - The process of applying for gastroenterology fellowship. PMID- 22542458 TI - Impulsivity, risk taking, and timing. AB - This study examined the relations among measures of impulsivity and timing. Impulsivity was assessed using delay and probability discounting, and self-report impulsivity (as measured by the Barratt Impulsiveness Scale; BIS-11). Timing was assessed using temporal perception as measured on a temporal bisection task and time perspective (as measured by the Zimbardo Time Perspective Inventory). One hundred and forty three college students completed these measures in a computer laboratory. The degree of delay discounting was positively correlated with the mean and range of the temporal bisection procedure. The degree of delay and probability discounting were also positively correlated. Self-reported motor impulsiveness on the BIS-11 was positively correlated with present hedonism and negatively correlated with future orientation on the ZTPI. Self-reported non planning on the BIS-11 was positively correlated with fatalism on the ZTPI. These results show that people who overestimate the passage of time (perceive time as passing more quickly) hold less value in delayed rewards. They also confirm previous results regarding the relation between delay and probability discounting, as well as highlight similarities in self-report measures of impulsivity and time perspective. PMID- 22542459 TI - Strain differences in a high response-cost daily time-place learning task. AB - Previous research has shown that rats, unlike birds, do not readily demonstrate daily time-place learning (TPL). It has been suggested, however, that rats are more successful at these tasks if the response cost (RC) is increased. Widman et al. (2000) found that female Sprague Dawley (SD) rats learned a daily TPL task in which they were required to climb different towers depending on the time of day to find a food reward. Using a similar apparatus, we found that male SD rats learned the task, while male Long Evans rats did not. While all rats quickly learned to restrict the majority of their searching to the two towers that provided food, only the SD rats learned to go to the correct location at the correct time of day. Thus, there appears to be a strain difference in the effectiveness of a high RC task to promote learning. Tests of the timing strategies used revealed individual differences with one rat using a circadian strategy and another using an ordinal strategy. Post criterion decrements in performance did not allow sufficient testing to determine the timing strategies of the remaining rats. Possible interactions between strain, response cost, species typical behaviors and dependent measures are discussed. PMID- 22542460 TI - P3a from white noise. AB - P3a and P3b event-related brain potentials (ERPs) were elicited with an auditory three-stimulus (target, distracter, and standard) discrimination task in which subjects responded only to the target. Distracter stimuli consisted of white noise or novel sounds with stimulus characteristics perceptually matched. Target/standard discrimination difficulty was manipulated by varying target/standard pitch differences to produce relatively easy, medium, and hard tasks. Error rate and response time increased with increases in task difficulty. P3a was larger for the white noise compared to novel sounds, maximum over the central/parietal recording sites, and did not differ in size across difficulty levels. P3b was unaffected by distracter type, decreased as task difficulty increased, and maximum over the parietal recording sites. The findings indicate that P3a from white noise is robust and should be useful for applied studies as it removes stimulus novelty variability. Theoretical perspectives are discussed. PMID- 22542461 TI - Parametric response mapping of CT images provides early detection of local bone loss in a rat model of osteoporosis. AB - Loss of bone mass due to disease, such as osteoporosis and metastatic cancer to the bone, is a leading cause of orthopedic complications and hospitalization. Onset of bone loss resulting from disease increases the risk of incurring fractures and subsequent pain, increasing medical expenses while reducing quality of life. Although current standard CT-based protocols provide adequate prognostic information for assessing bone loss, many of the techniques for evaluating CT scans rely on measures based on whole-bone summary statistics. This reduces the sensitivity at identifying local regions of bone resorption, as well as formation. In this study, we evaluate the effectiveness of a voxel-based image post-processing technique, called the Parametric Response Map (PRM), for identifying local changes in bone mass in weight-bearing bones on CT scans using an established animal model of osteoporosis. Serial CT scans were evaluated weekly using PRM subsequent to ovariectomy or sham surgeries over the period of one month. For comparison, bone volume fraction and mineral density measurements were acquired and found to significantly differ between groups starting 3 weeks post-surgery. High resolution ex vivo measurements acquired four weeks post surgery validated the extent of bone loss in the surgical groups. In contrast to standard methodologies for assessing bone loss, PRM results were capable of identifying local decreases in bone mineral by week 2, which were found to be significant between groups. This study concludes that PRM is able to detect changes in bone mineral with higher sensitivity and spatial differentiation than conventional techniques for evaluating CT scans, which may aid in clinical decision making for patients suffering from bone loss. PMID- 22542462 TI - Acute depression of left ventricular function after one-time alcohol consumption. PMID- 22542463 TI - A significant association between physical restraint and the development of venous thromboembolism in psychiatric patients. PMID- 22542465 TI - The first 90 days following release from jail: findings from the Recovery Management Checkups for Women Offenders (RMCWO) experiment. AB - OBJECTIVES: (1) To examine the impact of monthly Recovery Management Checkups (RMC) vs. control in the first 90 days post-release from jail on receipt of community-based substance abuse treatment, and (2) To explore the impact of RMC, treatment, and abstinence on HIV risk behaviors and recidivism. METHODS: Of the 480 women randomized, 100% completed the intake and release interviews, and over 90% completed the 30-, 60-, and 90-day post-release interviews. Of the 915 times women assigned to RMC were interviewed (at release, 30, 69 and 90 days post release), 885 (97%) times they attended linkage meetings, 429 (47%) times they were identified as in need of substance abuse treatment, 271 (30%) times they agreed to go to treatment, 149 (16%) times they showed to the treatment intake, and 48 (5%) times they stayed in treatment at least two weeks. RESULTS: During the 90 days following release from jail, women in the RMC condition (vs. control) were significantly more likely to return to treatment sooner and to participate in substance abuse treatment. Women who received any treatment were significantly more likely than those who did not to be abstinent from any alcohol or other drugs. Those who were abstinent were significantly more likely to avoid HIV risk behaviors and recidivism. CONCLUSIONS: These results demonstrate the feasibility of conducting monthly Recovery Management Checkups with women offenders post release and provide support for the effectiveness of using RMC to successfully link women offenders to treatment. PMID- 22542464 TI - Common and specific liability to addiction: approaches to association studies of opioid addiction. AB - BACKGROUND: Opioid addiction, whether to opiates such as heroin and morphine, and/or to non-medical use of opioids, is a major problem worldwide. Although drug induced and environmental factors are essential for the liability to develop opioid addiction, the genetic background of an individual is now known also to play a substantial role. METHODS: The overall goal of this article is to address the common and specific liabilities to addiction in the context of approaches to studies of one addiction, opioid addiction. Literature on identifying genetic variants that may play a role in the development of opioid addiction was reviewed. RESULTS: A substantial number of genetic variants have been reported to be associated with opioid addiction. No single variant has been found in any of the reported GWAS studies with a substantial effect size on the liability to develop heroin addiction. It appears that there is a complex interaction of a large number of variants, some rare, some common, which interact with the environment and in response to specific drugs of abuse to increase the liability of developing opioid addiction. CONCLUSIONS: In spite of the inherent difficulties in obtaining large well-phenotyped cohorts for genetic studies, new findings have been reported that are being used to develop testable hypotheses into the biological basis of opioid addiction. PMID- 22542466 TI - Importance of hospital versus surgeon volume in predicting outcomes for gastric bypass procedures. AB - BACKGROUND: A relationship between surgical volume and improved surgical outcomes has been described in gastric bypass patients but the relative importance of surgeon versus hospital volume is unknown. Our objective was to examine whether in-hospital and 30-day mortality are determined more by surgeon volume or hospital volume or whether each has an independent effect. A retrospective cohort study was performed of all hospitals in Pennsylvania providing gastric bypass surgery from 1999 to 2003. METHODS: Data from the Pennsylvania Health Care Cost Containment Council included 14,714 gastric bypass procedures in patients aged >18 years. In-hospital and 30-day mortality were stratified by hospital volume categories (high [>=300], medium [125-299], and low [<125]) and surgeon volume categories (high [>=50] and low [<50]). Multivariate analyses were performed using logistic regression analysis to control for patient demographics and severity. RESULTS: High-volume surgeons at high-volume hospitals had the lowest in-hospital mortality rates of all categories (.12%) and low-volume surgeons at low-volume hospitals had the poorest outcomes (.57%). The same trend was observed for 30-day mortality (.30% versus .98%). After controlling for other covariates, high-volume surgeons at high-volume hospitals also had significantly lower odds of both in-hospital (odds ratio 20, P = .002) and 30-day mortality (odds ratio .30, P = .001). This relationship held true even after excluding surgeons who only performed procedures within a single year. CONCLUSION: In Pennsylvania, both higher surgeon and hospital volume were associated with better outcomes for bariatric surgical procedures. Although a high-surgeon volume correlated with lowered mortality, we also found that high-volume hospitals demonstrated improved outcomes, highlighting the importance of factors other than surgical expertise in determining the outcomes. PMID- 22542467 TI - Cardiac H11 kinase/Hsp22 stimulates oxidative phosphorylation and modulates mitochondrial reactive oxygen species production: Involvement of a nitric oxide dependent mechanism. AB - H11 kinase/Hsp22 (Hsp22), a small heat shock protein upregulated by ischemia/reperfusion, provides cardioprotection equal to ischemic preconditioning (IPC) through a nitric oxide (NO)-dependent mechanism. A main target of NO mediated preconditioning is the mitochondria, where NO reduces O2 consumption and reactive oxygen species (ROS) production during ischemia. Therefore, we tested the hypothesis that Hsp22 overexpression modulates mitochondrial function through an NO-sensitive mechanism. In cardiac mitochondria isolated from transgenic (TG) mice with cardiac-specific overexpression of Hsp22, mitochondrial basal, ADP dependent, and uncoupled O2 consumption was increased in the presence of either glucidic or lipidic substrates. This was associated with a decrease in the maximal capabilities of complexes I and III to generate superoxide anion in combination with an inhibition of superoxide anion production by the reverse electron flow. NO synthase expression and NO production were increased in mitochondria from TG mice. Hsp22-induced increase in O2 consumption was abolished either by pretreatment of TG mice with the NO synthase inhibitor L-N(G) nitroarginine methyl ester (L-NAME) or in isolated mitochondria by the NO scavenger phenyltetramethylimidazoline-1-oxyl-3-oxide. L-NAME pretreatment also restored the reverse electron flow. After anoxia, mitochondria from TG mice showed a reduction in both oxidative phosphorylation and H2O2 production, an effect partially reversed by L-NAME. Taken together, these results demonstrate that Hsp22 overexpression increases the capacity of mitochondria to produce NO, which stimulates oxidative phosphorylation in normoxia and decreases oxidative phosphorylation and reactive oxygen species production after anoxia. Such characteristics replicate those conferred by IPC, thereby placing Hsp22 as a potential tool for prophylactic protection of mitochondrial function during ischemia. PMID- 22542468 TI - Ubiquinone-10 in gold-immobilized lipid membrane structures acts as a sensor for acetylcholine and other tetraalkylammonium cations. AB - It is reported that the reduction of ubiquinone incorporated into supported lipid bilayers and into immobilized liposome layers on gold electrodes is kinetically and thermodynamically enhanced by the presence of acetylcholine and tetrabutylammonium (TBA(+)) in solution. The reduction peak and the mid-peak potentials of the redox reactions, determined by cyclic voltammetry, are displaced towards more positive potentials by approximately 500 and 250mV, respectively, in the case of TBA(+); and by approximately 750 and 530mV, respectively, in the case of acetylcholine. The intensity of the signal varies with the cation concentration, allowing for quantitative determinations in the millimolar range. It is proposed that the enhanced reduction of ubiquinone arises from the formation of tetraalkylammonium cation-ubiquinone radical anion ion pairs. Electrochemical quartz crystal microbalance with dissipation monitoring (EQCM-D) measurements confirmed that the potential shift and the intensity of the redox signal are coupled with the adsorption of the tetraalkylammonium cations on the lipid membrane. The Langmuir adsorption equilibrium constant (K) of TBA(+) on lipid membranes at physiological pH is determined. In supported lipid bilayers K=440.7+/-160M(-1), while in an immobilized liposome layer K=35.53+/-3.53M(-1). PMID- 22542469 TI - Electrochemistry of raloxifene on glassy carbon electrode and its determination in pharmaceutical formulations and human plasma. AB - The electrochemical behavior of raloxifene (RLX) on the surface of a glassy carbon electrode (GCE) has been studied by cyclic voltammetry (CV). The CV studies were performed in various supporting electrolytes, wide range of potential scan rates, and pHs. The results showed an adsorption-controlled and quasi-reversible process for the electrochemical reaction of RLX, and a probable redox mechanism was suggested. Under the optimum conditions, differential pulse voltammetry (DPV) was applied for quantitative determination of the RLX in pharmaceutical formulations. The DPV measurements showed that the anodic peak current of the RLX was linear to its concentration in the range of 0.2-50.0MUM with a detection limit of 0.0750MUM, relative standard deviation (RSD %) below 3.0%, and a good sensitivity. The proposed method was successfully applied for determination of the RLX in pharmaceutical and human plasma samples with a good selectivity and suitable recovery. PMID- 22542471 TI - Outsourcing drug discovery to India and China: from surviving to thriving. AB - Global pharmaceutical companies face an increasingly harsh environment for their primary business of selling medicines. They have to contend with a spiraling decline in the productivity of their R&D programs that is guaranteed to severely diminish their growth prospects. Outsourcing of drug discovery activities to low cost locations is a growing response to this crisis. However, the upsides to outsourcing are capped by the failure of global pharmaceutical companies to take advantage of the full range of possibilities that this model provides. Companies that radically rethink and transform the way they conduct R&D, such as seeking the benefits of low-cost locations in India and China will be the ones that thrive in this environment. In this article we present our views on how the outsourcing model in drug discovery should go beyond increasing the efficiency of existing drug discovery processes to a fundamental rethink and re-engineering of these processes. PMID- 22542470 TI - Genome-wide association study of antibody response to smallpox vaccine. AB - We performed a genome-wide association study (GWAS) of antibody levels in a multi ethnic group of 1071 healthy smallpox vaccine recipients. In Caucasians, the most prominent association was found with promoter SNP rs10489759 in the LOC647132 pseudogene on chromosome 1 (p=7.77*10(-8)). In African-Americans, we identified eight genetic loci at p<5*10(-7). The SNP association with the lowest p-value (rs10508727, p=1.05*10(-10)) was in the Mohawk homeobox (MKX) gene on chromosome 10. Other candidate genes included LOC388460, GPR158, ZHX2, SPIRE1, GREM2, CSMD1, and RUNX1. In Hispanics, the top six associations between genetic variants and antibody levels had p-values less than 5*10(-7), with p=1.78*10(-10) for the strongest statistical association (promoter SNP rs12256830 in the PCDH15 gene). In addition, SNP rs4748153 in the immune response gene PRKCQ (protein kinase C, theta) was significantly associated with neutralizing antibody levels (p=2.51*10( 8)). Additional SNP associations in Hispanics (p<=3.40*10(-7)) were mapped to the KIF6/LOC100131899, CYP2C9, and ANKLE2/GOLGA3 genes. This study has identified candidate SNPs that may be important in regulating humoral immunity to smallpox vaccination. Replication studies, as well as studies elucidating the functional consequences of contributing genes and polymorphisms, are underway. PMID- 22542472 TI - The biological standard of living and mortality in Central Italy at the beginning of the 19th century. AB - The biological standard of living in Central Italy at the beginning of the 19th century is analyzed using newly collected data on the height of recruits in the army of the Papal States. The results reveal a decline in height for the cohorts born under French rule (1796-1815). Although this trend was common to many parts of Europe, the estimated magnitude of the decline suggests a worsening of the biological standard of living of the working classes in the Papal States even relative to that of other countries. Despite the differences in the economic systems within the Papal States, no significant geographical variation in height has been found: even the most dynamic and advanced regions experienced a dramatic height decline. Mortality also increased during the period under consideration. PMID- 22542473 TI - 'Mind genomics': the experimental, inductive science of the ordinary, and its application to aspects of food and feeding. AB - The paper introduces the empirical science of 'mind genomics', whose objective is to understand the dimensions of ordinary, everyday experience, identify mind-set segments of people who value different aspects of that everyday experience, and then assign a new person to a mind-set by a statistically appropriate procedure. By studying different experiences using experimental design of ideas, 'mind genomics' constructs an empirical, inductive science of perception and experience, layer by layer. The ultimate objective of 'mind genomics' is a large scale science of experience created using induction, with the science based upon emergent commonalities across many different types of daily experience. The particular topic investigated in the paper is the experience of healthful snacks, what makes a person 'want' them, and the dollar value of different sensory aspects of the healthful snack. PMID- 22542474 TI - Function of blood monocytes among patients with orofacial infections. AB - Few data are available on the significance of the integrity of the innate immune system among patients with orofacial infections. This was assessed in the present study. Peripheral blood mononuclear cells (PBMCs) were isolated from 23 patients with orofacial infections before surgical debridement and from 12 healthy volunteers. PBMCs were stimulated with bacterial endotoxin (LPS) and with Pam3Cys. Concentrations of interleukin (IL)-1beta, IL-6 and tumor necrosis factor alpha (TNFalpha) were estimated in supernatants by an enzyme immunoassay. Concentrations of estimated cytokines released from PBMCs of healthy volunteers and of patients did not differ. Intensity of cytokine release after stimulation was related with the time until complete resolution of the infection (p: 0.046). It is concluded that adequate functions of blood monocytes are associated with favorable outcome after surgery for orofacial abscesses. It seems, however, that impairment of monocyte function predisposes to infection persistence. PMID- 22542475 TI - StCT2, a new antibacterial peptide characterized from the venom of the scorpion Scorpiops tibetanus. AB - Bacterial infection poses an increasing threat to global public health and new types of antibacterial agents are urgently needed to respond to the threat. Scorpion venom contains series of bioactive peptides, among which antibacterial peptide is an important part. Herein, a new antimicrobial peptide StCT2 was characterized from the venomous gland cDNA library of the Scorpiops tibetanus. The full-length cDNA of StCT2 is 369 nucleotides encoding the precursor that contains a putative 24 residues signal peptide, a presumed 14 residues mature peptide, and a putative 37 residues acidic propeptide at the C-terminus. The minimal inhibition concentrations (MICs) of StCT2 for Staphylococcus aureus were 6.25-25MUg/ml, including antibiotic-resistant strains such as methicillin resistant S. aureus (MRSA). StCT2 was further found to show high in vivo antimicrobial activity by an S. aureus infection mouse model. StCT2 exerted its antimicrobial activity via a rapid bactericidal mechanism. Taken together, these results demonstrate the efficacy and general mechanism of StCT2 antimicrobial action and the therapeutic potential of StCT2 as a new antimicrobial peptide. PMID- 22542477 TI - A structural model of emotions of cognitive dissonances. AB - Cognitive dissonance is the stress that comes from holding two conflicting thoughts simultaneously in the mind, usually arising when people are asked to choose between two detrimental or two beneficial options. In view of the well established role of emotions in decision making, here we investigate whether the conventional structural models used to represent the relationships among basic emotions, such as the Circumplex model of affect, can describe the emotions of cognitive dissonance as well. We presented a questionnaire to 34 anonymous participants, where each question described a decision to be made among two conflicting motivations and asked the participants to rate analogically the pleasantness and the intensity of the experienced emotion. We found that the results were compatible with the predictions of the Circumplex model for basic emotions. PMID- 22542476 TI - Emerging roles for TNIP1 in regulating post-receptor signaling. AB - A vast number of cellular processes and signaling pathways are regulated by various receptors, ranging from transmembrane to nuclear receptors. These receptor-mediated processes are modulated by a diverse set of regulatory proteins. TNFalpha-induced protein 3-interacting protein 1 is such a protein that inhibits both transduction by transmembrane receptors, such as TNFalpha-receptor, EGF-R, and TLR, and nuclear receptors' PPAR and RAR activity. These receptors play key roles in regulating inflammation and inflammatory diseases. A growing number of references have implicated TNIP1 through GWAS and expression studies in chronic inflammatory diseases such as psoriasis and rheumatoid arthritis, although TNIP1s exact role has yet been determined. In this review, we aim to integrate the current knowledge of TNIP1s functions with the diseases in which it has been associated to potentially elucidate the role this regulator has in promoting or alleviating these inflammatory diseases. PMID- 22542478 TI - Surface adsorption and vesicle formation of dilauroylphosphatidylcholine in room temperature ionic liquids. AB - Surface chemical properties of a phospholipid, dilauroylphosphatidylcholine (DLPC), in two ionic liquids (ILs), 1-butyl-3-methylimidazolium tetrafluoroborate (bmimBF(4)) and hexafluorophosphate (bmimPF(6)), were investigated by means of surface tension, dynamic light-scattering, and freeze-fracture transmission electron microscopy. It was found that DLPC shows finite solubility in the ILs and spontaneously forms vesicles with size distribution around 400 nm in diameter above the critical vesicular concentration (CVC) of 0.040 wt.% (in bmimBF(4)) and approx. 0.08 wt.% (in bmimPF(6)). Other than the CVC value, anion specificity of the ILs was also seen in the temperature effect on the vesicular aggregation; that is, a temperature-induced reversible aggregation was observed in bmimPF(6), but not in bmimBF(4). The differences in the vesicular stability against the temperature-induced aggregation could be attributed to differences in the interaction between anion species of the ILs and zwitterionic phosphatidylcholine head groups. The apparent molecular area occupied by DLPC at the air/solution interface was estimated to be 0.37 nm(2) in bmimBF(4) and 0.20 nm(2) in bmimPF(6) by applying the Gibbs adsorption equation. These values are much smaller than the molecular area of 0.69 nm(2) reported for the hydrated DLPC bilayer of lamellar liquid-crystalline phase. This result is not consistent with the traditional Gibbs adsorption model, but can be interpreted in terms of a picture for the surface adsorption of soluble amphiphiles proposed by Moroi et al. Differential scanning calorimetric study is also reported regarding the phase transition behavior of DLPC bilayer solvated by the ILs. PMID- 22542479 TI - Nano-gel containing thermo-responsive microspheres with fast response rate owing to hierarchical phase-transition mechanism. AB - A new strategy is developed in this study to achieve thermo-responsive microspheres with fast response rates by designing a hierarchical phase transition mechanism. The proposed thermo-responsive microspheres are composed of poly(N-isopropylacrylamide-co-acrylic acid) (PNA) microsphere matrixes and embedded poly(N-isopropylacrylamide) (PNIPAM) nano-gels, which have different volume phase-transition temperatures (VPTTs). The VPTT of PNIPAM nano-gels (VPTT(1)) is lower than that of PNA microsphere matrixes (VPTT(2)). Upon heating up, the temperature increases across the VPTT(1) first and then the VPTT(2), as a result the PNIPAM nano-gels shrink earlier than the PNA microsphere matrixes. Upon cooling-down, the temperature decreases across the VPTT(2) first and then the VPTT(1), as a result the PNA microsphere matrixes swell earlier than the PNIPAM nano-gels. Consequently, large amounts of voids and channels form around the nano-gels inside the microsphere matrixes when the temperature changes across the range between VPTT(1) and VPTT(2), which are beneficial to the enhancement of water transport rate inside the microsphere matrixes. The experimental results show that, compared with normal homogeneous PNA (N-PNA) microspheres, the nano gel containing PNA (C-PNA) microspheres exhibit remarkably fast response rate due to the hierarchical phase-transition mechanism attributed to different VPTT values of the embedded nano-gels and the microsphere matrixes. PMID- 22542480 TI - A high activity photocatalyst of hierarchical 3D flowerlike ZnO microspheres: synthesis, characterization and catalytic activity. AB - In this study, three-dimensional (3D) hierarchical flowerlike ZnO microspheres have been hydrothermally synthesized by means of two surfactants at 100 degrees C and characterized by XRD, SEM, TEM, TG, FT-IR and UV-Vis spectroscopies. The results show that the 3D flowerlike ZnO microspheres are composed of 2D nanosheets. A possible formation mechanism is proposed: 0D Zn(5)(CO(3))(2)(OH)(6) colloids tend to form 2D nanosheets with the aid of sodium dodecyl sulfonic, and then, these nanosheets can assemble to 3D flowerlike microspheres by means of two surfactants of sodium dodecyl sulfonic and PEG 600. The flowerlike ZnO has low bandgap energy and exhibits high catalytic activity for photocatalytic degradation of Rhodamin B, which is attributed to its unique morphology and uniform hierarchical structure that significantly facilitates the diffusion and mass transportation of organic molecules and oxygen species in the degradation reaction. PMID- 22542481 TI - Heterostructured mesoporous In2O3/Ta2O5 composite photocatalysts for hydrogen evolution: impacts of In2O3 content and calcination temperature. AB - The crystallinity, textural characteristics, optical absorption properties, as well as the photocatalytic hydrogen production activities of three-dimensional interconnected mesoporous In(2)O(3)/Ta(2)O(5) composites were investigated as functions of In(2)O(3) content (x) and calcination temperature (T). The results show that the incorporation of In(2)O(3) endows intimate heterostructured junctions in the composites and significantly improves the thermal stability of mesopores. With increasing x, the as-prepared composites possess similar textural properties and continuously increased light absorbencies, but a maximum heterojunction area, and thus, the optimal value for the average hydrogen evolution rate ( Q(H(2))) as well as the special surface hydrogen evolution rate ( Q(H(2),S)) at x=20%. For the 20% In(2)O(3)/Ta(2)O(5) composites prepared at different T, the special surface area decreases and the pore size enlarges with increasing T from 450 to 650 degrees C. An obvious collapse of mesopores accompanying with remarkable crystallization occurs at 750 degrees C. The highest [Formula: see text] occurs on the sample calcined at 550 degrees C, while the optimal Q(H(2),S) appears at 750 degrees C. This suggests that good charge carrier separation and transport properties, rapid mass transfer of reactants and gases desorption are as important as large surface area and high crystallinity for the photocatalysts. PMID- 22542482 TI - Tako-tsubo cardiomyopathy with apical variant complicated by cardiac tamponade and mid-ventricular variant presentation during a delayed recurrence. PMID- 22542484 TI - Brugada electrocardiogram pattern induced by cannabis. PMID- 22542487 TI - Characterization of bifunctional sphingolipid Delta4-desaturases/C4-hydroxylases of trypanosomatids by liquid chromatography-electrospray tandem mass spectrometry. AB - Six genes encoding putative sphingolipid desaturases have been identified in trypanosomatid genomes: one in Trypanosoma brucei (TbSLdes protein), one in Trypanosoma cruzi (TcSLdes) and four in Leishmania major (LmSLdes1-4), tandemly arrayed on chromosome 26. The six amino acid sequences showed the three characteristic histidine boxes, with a long spacer between the first and second box, as in fungal desaturases and bifunctional desaturases/hydroxylases, to which they are phylogenetically related. We functionally characterized the trypanosomatid enzymes by their expression in Saccharomyces cerevisiae sur2Delta mutant, which lacks C4-hydroxylase activity. The sphingoid base profile (dinitrophenyl derivatives) of each yeast mutant transformed with each one of the different parasite genes was analyzed by HPLC, using a sur2Delta mutant expressing the Schyzosaccharomyces pombe sphingolipid desaturase (SpSLdes) as positive control. TbSLdes was capable of desaturating endogenous sphingolipids at levels comparable to those found in SpSLdes. By contrast, L. major and T. cruzi enzymes showed either no or negligible activities. Using the HPLC system coupled to electrospray tandem quadrupole/time of flight mass spectrometry we were able to detect significant levels of desaturated and hydroxylated sphingoid bases in extracts of all transformed yeast mutants, except for those transformed with the empty vector. These results indicate that S. pombe, T. brucei, T. cruzi and L. major enzymes are all bifunctional. Using the same methodology, desaturated and hydroxylated sphingoid bases were detected in T. cruzi epimastigotes and L. major promastigote cells, as described previously, and in T. brucei procyclic and bloodstream forms for the first time. PMID- 22542486 TI - A single-cloning-step procedure for the generation of RNAi plasmids producing long stem-loop RNA. AB - RNA interference (RNAi), used as a tool, has revolutionized the studies of gene function. Long stem-loop dsRNA has been proven the most effective trigger for down-regulating target transcripts in RNAi-positive trypanosomatid parasites. Here we describe a protocol for constructing plasmids that produce long stem loops by using a single cloning step. Inverted repeats are first obtained by self ligation of PCR products that contain a randomized segment at one of their ends and then inserted in a plasmid vector. The random sequences create the loop (or "stuffer") of the hairpin. This methodology was tested in Leishmania (Viannia) braziliensis to constitutively knock down the mRNAs for the well-studied paraflagellar rod protein 1 and 2 (PFR1 and PFR2) genes and revealed that mRNA cleavage products are unusually stable in these parasites. The protocol is suitable for any plasmid (for constitutive or inducible expression) and for any organism in which long stem-loops can be used to elicit RNAi. PMID- 22542488 TI - The topological structure and function of Echinococcus granulosus lactate dehydrogenase, a tegumental transmembrane protein. AB - Lactate dehydrogenase (LDH), a terminal glycolytic enzyme, is generally considered as a cytosolic protein. We cloned lactate dehydrogenase from Echinococcus granulosus (EgLDH) and predicted it may be a membrane protein with two transmembrane regions through bioinformatics analysis. Intact worm immunofluorescence with antibodies prepared against linear B cell epitopes predicted in the region inside or outside of the membrane demonstrated that EgLDH spans the tegumental membrane twice, with the N terminal and C terminal all outside, just consistent with the putative topological structure. Then, the enzymatic characteristics and kinetic parameters of recombinant EgLDH were surveyed and the results suggested that EgLDH is responsible for catalyzing the reduction of pyruvic acid into lactic acid under physiological conditions. The enzymatic activity of the recombinant protein was inhibited by antibodies directed against the intact protein or against epitopes that contain key residues in the catalytic center or substrate binding sites. EgLDH is a potential target for drugs and vaccines against E. granulosus. PMID- 22542489 TI - Training mode-dependent changes in motor performance in neck pain. AB - OBJECTIVE: To determine whether changes in motor performance after a course of exercise in patients with mechanical neck pain (MNP) were dependent on the primary behavioral demand of the exercise performed. DESIGN: Randomized controlled trial. SETTING: University laboratory. PARTICIPANTS: Volunteers (N=60; 35 women, 25 men; mean age, 37.9y) with chronic MNP participated in the study. INTERVENTION: Exercise targeted to improve cervical motor performance including endurance training (ETr; n=20), coordination training (CTr; n=20), and active mobility training (n=20). MAIN OUTCOME MEASURES: Changes in the cervical motor performance domains of strength, endurance, coordination, and active mobility were evaluated immediately after the 10-week training program, and at a 26-week follow-up. RESULTS: Between-group comparisons revealed significantly greater gains in endurance (P<.02) by the ETr group, and significantly greater gains in coordination (P<.01) by the CTr group. All 3 groups had improvement in pain (P<.01) and disability (P<.01). CONCLUSIONS: Changes in motor performance in individuals with MNP in response to an exercise program were dependent on the specific mode of exercise performed, with minimal improvement in other domains of motor performance. PMID- 22542491 TI - Two lymph nodes draining the mouse liver are the preferential site of DC migration and T cell activation. AB - BACKGROUND & AIMS: Lymph nodes (LNs) play a critical role in host defence against pathogens. In rodents, lymphatic anatomy and drainage have been characterized for many different organs. Surprisingly, the LNs draining the mouse liver have not been clearly identified. This knowledge is of central importance to allow accurate characterization of immune responses to pathogens infecting the liver. It is also important for exploring immune responses in hepatic tumour models, and mechanisms underlying the relative tolerogenic properties of the liver. In this study, we used both anatomical and immunological approaches to identify the LN(s) draining the mouse liver. METHODS: Evans Blue and purified dendritic cells were directly injected into the hepatic parenchyma. RESULTS: Using Evans Blue, we identified three LNs adjacent to the liver that stained with the dye within the first 5 min, which we termed portal, coeliac, and first mesenteric LNs. We also provide evidence that dendritic cells (DCs) injected under the liver capsule preferentially migrate to the coeliac and portal nodes, leading to local activation of antigen-specific naive CD8 and CD4 T cells, suggesting this is a route of lymphatic drainage from the liver. Consistent with this result, cell associated antigen injected under the liver capsule was also cross-presented to CD8 T cells in these nodes. CONCLUSIONS: These results suggest for the first time that the coeliac and portal nodes are the main LNs draining the liver, and that DCs exiting the liver can elicit primary T cell activation within these lymph nodes; first mesenteric nodes play a secondary role. We propose this nomenclature to be used as common designations for the observed structures. PMID- 22542490 TI - Mouse organic solute transporter alpha deficiency alters FGF15 expression and bile acid metabolism. AB - BACKGROUND & AIMS: Blocking intestinal bile acid (BA) absorption by inhibiting or inactivating the apical sodium-dependent BA transporter (Asbt) classically induces hepatic BA synthesis. In contrast, blocking intestinal BA absorption by inactivating the basolateral BA transporter, organic solute transporter alpha beta (Ostalpha-Ostbeta) is associated with an altered homeostatic response and decreased hepatic BA synthesis. The aim of this study was to determine the mechanisms underlying this phenotype, including the role of the farnesoid X receptor (FXR) and fibroblast growth factor 15 (FGF15). METHODS: BA and cholesterol metabolism, intestinal phenotype, expression of genes important for BA metabolism, and intestinal FGF15 expression were examined in wild type, Ostalpha(-/-), Fxr(-/-), and Ostalpha(-/-)Fxr(-/-) mice. RESULTS: Inactivation of Ostalpha was associated with decreases in hepatic cholesterol 7alpha-hydroxylase (Cyp7a1) expression, BA pool size, and intestinal cholesterol absorption. Ostalpha(-/-) mice exhibited significant small intestinal changes, including altered ileal villus morphology, and increases in intestinal length and mass. Total ileal FGF15 expression was elevated almost 20-fold in Ostalpha(-/-) mice as a result of increased villus epithelial cell number and ileocyte FGF15 protein expression. Ostalpha(-/-)Fxr(-/-) mice exhibited decreased ileal FGF15 expression, restoration of intestinal cholesterol absorption, and increases in hepatic Cyp7a1 expression, fecal BA excretion, and BA pool size. FXR deficiency did not reverse the intestinal morphological changes or compensatory decrease for ileal Asbt expression in Ostalpha(-/-) mice. CONCLUSIONS: These results indicate that signaling via FXR is required for the paradoxical repression of hepatic BA synthesis but not the complex intestinal adaptive changes in Ostalpha(-/-) mice. PMID- 22542492 TI - Modulation of antipsychotic-induced extrapyramidal side effects by medications for mood disorders. AB - Antipsychotic drugs are widely used not only for schizophrenia, but also for mood disorders such as bipolar disorder and depression. To evaluate the interactions between antipsychotics and drugs for mood disorders in modulating extrapyramidal side effects (EPS), we examined the effects of antidepressants and mood stabilizing drugs on haloperidol (HAL)-induced bradykinesia and catalepsy in mice and rats. The selective serotonin reuptake inhibitors (SSRIs), fluoxetine and paroxetine, and the tricyclic antidepressant (TCA) clomipramine, which showed no EPS by themselves, significantly potentiated HAL-induced bradykinesia and catalepsy in a dose-dependent manner. In contrast, the noradrenergic and specific serotonergic antidepressant (NaSSA) mirtazapine failed to augment, but rather attenuated HAL-induced bradykinesia and catalepsy. Mianserin also tended to reduce the EPS induction. In addition, neither treatment with lithium, sodium valproate nor carbamazepine potentiated HAL-induced EPS. Furthermore, treatment of animals with ritanserin (5-HT2A/2C antagonist), ondansetron (5-HT3 antagonist), and SB-258585 (5-HT6 antagonist) significantly antagonized the EPS augmentation by fluoxetine. Intrastriatal injection of ritanserin or SB-258585, but not ondansetron, also attenuated the EPS induction. The present study suggests that NaSSAs are superior to SSRIs or TCAs in combined therapy for mood disorders with antipsychotics in terms of EPS induction. In addition, 5-HT2A/2C, 5-HT3 and 5-HT6 receptors seem to be responsible for the augmentation of antipsychotic-induced EPS by serotonin reuptake inhibitors. PMID- 22542494 TI - Epigenetic variants and biomarkers for colon cancer. PMID- 22542495 TI - Study on the physiology of diapause, cold hardiness and supercooling point of overwintering pupae of the pistachio fruit hull borer, Arimania comaroffi. AB - The pistachio fruit hull borer, Arimania comaroffi (Ragonot) (Lepidoptera: Pyralidae), is a key pest of pistachio orchards in Iran. This pest passes the winter as diapausing pupae. In this study, some physiological changes in relation to environmental temperature were investigated in field collected pupae. The relationship between supercooling point, cold hardiness and physiological changes of a wild population of this pest was also investigated. The glycogen content decreased with decrease in environmental temperature. Decrease in glycogen content was proportional to increase in total body sugar, trehalose, myo-inositol and sorbitol contents. In January with mean ambient temperature of 5.4 degrees C, glycogen (5 mg/g fresh body weight) content was at the lowest level whereas total body sugar (10.3 mg/g fresh body weight), trehalose (8.6 mg/g fresh body weight), myo-inositol (5.3 mg/g fresh body weight) and sorbitol (2.6 mg/g fresh body weight) were at the highest levels. Total body sugar, trehalose, myo-inositol and sorbitol contents increased as mean temperature decreased from 22.7 degrees C in October to 5.4 degrees C in January. Total body lipid decreased during overwintering and reached to the lowest level at the end of March. Supercooling points were decreased from October to January and reached to the lowest level ( 16 degrees C) in January with minimum ambient temperature of -10 degrees C. Survival at low temperature after 24 h was also greatest in January with 72% survival at -10 degrees C, 39% survival at -15 degrees C and 0% survival at -20 degrees C. Increase in temperature from February onward, was proportional with increase in supercooling points and decrease in survival rate. Regardless of sampling date, all pupae died after 24 h at -20 degrees C, whereas none pupae died after 24 h at -5 degrees C. This indicates that this insect is freeze intolerant. PMID- 22542493 TI - Role of Cripto-1 during epithelial-to-mesenchymal transition in development and cancer. AB - Epithelial-to-mesenchymal transition (EMT) is a critical multistep process that converts epithelial cells to more motile and invasive mesenchymal cells, contributing to body patterning and morphogenesis during embryonic development. In addition, both epithelial plasticity and increased motility and invasiveness are essential for the branching morphogenesis that occurs during development of the mammary gland and during tumor formation, allowing cancer cells to escape from the primary tumor. Cripto-1, a member of the epidermal growth factor-Cripto 1/FRL-1/Cryptic (EGF/CFC) gene family, together with the transforming growth factor (TGF)-beta family ligand Nodal, regulates both cell movement and EMT during embryonic development. During postnatal development, Cripto-1 regulates the branching morphogenesis of the mouse mammary gland and enhances both the invasive and migratory properties of mammary epithelial cells in vitro. Furthermore, transgenic mouse models have shown that Cripto-1 promotes the formation of mammary tumors that display properties of EMT, including the down regulation of the cell surface adherens junctional protein E-cadherin and the up regulation of mesenchymal markers, such as vimentin, N-cadherin, and Snail. Interestingly, Cripto-1 is enriched in a subpopulation of embryonal, melanoma, prostate, and pancreatic cancer cells that possess stem-like characteristics. Therefore, Cripto-1 may play a role during developmental EMT, and it may also be involved in the reprogramming of differentiated tumor cells into cancer stem cells through the induction of an EMT program. PMID- 22542497 TI - Quality of life outcomes for residents and quality ratings of care homes: is there a relationship? AB - BACKGROUND: quality ratings of care homes are used by decision makers in the absence of direct information about outcomes. However, there is little evidence about the relationship between regulators' ratings of homes and residents' quality of life outcomes. OBJECTIVES: to capture social care-related quality of life (SCRQoL) outcomes for residents and investigate the relationship between outcomes and regulator quality ratings of homes. METHODS: data were collected for 366 residents of 83 English care homes for older people inspected during 2008. Outcomes were measured using the Adult Social Care Outcomes Toolkit (ASCOT). Multivariate multilevel modelling was used to investigate the relationship between quality of life outcomes and star ratings of homes, controlling for resident and home characteristics. RESULTS: care homes were delivering substantial gains in SCRQoL, but were more successful in delivering 'basic' (e.g. personal cleanliness) than higher-order domains (e.g. social participation). Outcomes were associated with quality ratings of residential homes but not of nursing homes. CONCLUSIONS: the approach to providing quality ratings by the regulator in England is currently under review. Future quality indicators need to demonstrate their relationship with quality of life outcomes if they are to be a reliable guide to commissioners and private individuals purchasing care. PMID- 22542496 TI - Childhood milk consumption is associated with better physical performance in old age. AB - BACKGROUND: studies have shown that milk and dairy consumption in adulthood have beneficial effects on health. METHODS: we examined the impact of childhood and adult diet on physical performance at age 63-86 years. The Boyd Orr cohort (n = 405) is a 65-year prospective study of children who took part in a 1930's survey; the Caerphilly Prospective Study (CaPS; n = 1,195) provides data from mid-life to old age. We hypothesised that higher intakes of childhood and adult milk, calcium, protein, fat and energy would be associated with a better performance. RESULTS: in fully adjusted models, a standard deviation (SD) increase in natural log-transformed childhood milk intake was associated with 5% faster walking times from the get-up and go test in Boyd Orr (95% CI: 1 to 9) and 25% lower odds of poor balance (OR: 0.75; 0.55 to 1.02). Childhood calcium intake was positively associated with walking times (4% faster per SD; 0 to 8) and a higher protein intake was associated with lower odds of poor balance (OR: 0.71; 0.54 to 0.92). In adulthood, protein intake was positively associated with walking times (2% faster per SD; 1 to 3; Boyd Orr and CaPS pooled data). CONCLUSION: this is the first study to show positive associations of childhood milk intake with physical performance in old age. PMID- 22542498 TI - Effects of common beverage colorants on color stability of dental composite resins: the utility of a thermocycling stain challenge model in vitro. AB - OBJECTIVES: To study the color stability of dental composite resins using a thermocycling stain challenge model accounting for the complex effects of oral environment and tooth brushing. METHODS: Composite resin discs were made from Filtek Supreme Ultra (FiltekSU), TPH3 and Renamel, and subjected to thermocycling challenges in warm coffee (55 degrees C/pH 5.2) and a cold tea and fruit juice mixtures (5 degrees C/pH 3.6) for a total of 1000 cycles with 30 seconds dwell time in each solution per cycle. Color was assessed in the CIELAB color space using a Crystaleye dental spectrophotometer before and after thermocycling, and after brushing vigorously for 3 min. The thermocycling stain challenge was repeated for a second 1000 cycles and the discs were brushed again. Color changes were compared among the 3 groups using Kruskal-Wallis test. RESULTS: All 3 groups showed statistically significant color changes after stain challenge, with DeltaE* as 5.74 for FiltekSU, 3.21 for TPH3 and 2.52 for Renamel. Color change was more significant in FiltekSU than in TPH3 and Renamel (p<0.05). After brushing, color recovered mostly to its original CIELAB values in TPH3 and Renamel but less so in FiltekSU. The second round of thermocycling stain challenge resulted in color changes in FiltekSU that largely could not be removed by vigorous brushing. CONCLUSIONS: Color stability of FiltekSU is inferior to that of TPH3 and Renamel. The thermocycling stain challenge model can potentially differentiate surface staining that can be removed by brushing from true discoloration of the material that is refractory to oral hygiene procedures. PMID- 22542499 TI - A study to determine the added value of 740 screening panoramic radiographs compared to intraoral radiography in the management of adult (>18 years) dentate patients in a primary care setting. AB - OBJECTIVES: To measure the added value of panoramic radiography in new dentate patients attending for routine treatment. METHODS: Thirty-seven general dental practitioners using panoramic radiographs routinely were recruited. Twenty dentate patients were identified prospectively by each participating dentist if they were new to the practice, attending for an examination and requesting any treatment deemed necessary. A panoramic radiograph was taken with appropriate intraoral radiographs in line with national guidelines. Each dentist completed a radiological report for the panoramic radiograph only and these 20 reports were forwarded to the researchers along with the 20 panoramic radiographs, their accompanying bitewing and periapical radiographs and twenty completed clinical assessment sheets. RESULTS: 740 panoramic, 1418 bitewing and 325 periapical radiographs were assessed by the researchers. Only 32 panoramic films provided any additional diagnostic value when compared to intraoral films when guidelines had been observed resulting from the poor technical and processing quality of the accompanying intraoral films. Assessment of the number of caries and periapical lesions and the degree of periodontal bone loss from the intraoral films provided a greater diagnostic yield at the p<0.001 level of significance. The research found that dentists underestimated the number of caries lesions present and level of periodontal bone loss when compared to the researchers but overestimated the presence of periapical pathology, at the level of significance at p<0.001. CONCLUSIONS: The study found that there was no support for the use of panoramic radiographs in routine screening as there was no net diagnostic benefit to the patient. PMID- 22542500 TI - Internal adaptation, marginal accuracy and microleakage of a pressable versus a machinable ceramic laminate veneers. AB - OBJECTIVES: The aim of this study was to evaluate the internal adaptation and marginal properties of ceramic laminate veneers fabricated using pressable and machinable CAD/CAM techniques. MATERIALS AND METHODS: 40 ceramic laminate veneers were fabricated by either milling ceramic blocks using a CAD/CAM system (group 1 n=20) or press-on veneering using lost wax technique (group 2 n=20). The veneers were acid etched using hydrofluoric acid, silanated, and cemented on their corresponding prepared teeth. All specimens were stored under water (37 degrees C) for 60 days, then received thermocycling (15,000 cycles between 5 and 55 degrees C and dwell time of 90 s) followed by cyclic loading (100,000 cycles between 50 and 100 N) before immersion in basic fuchsine dye for 24 h. Half of the specimens in each group were sectioned in labio-lingual direction and the rest were horizontally sectioned using precision cutting machine (n=10). Dye penetration, internal cement film thickness, and vertical and horizontal marginal gaps at the incisal and cervical regions were measured (alpha=0.05). RESULTS: Pressable ceramic veneers demonstrated significantly lower (F=8.916, P<0.005) vertical and horizontal marginal gaps at the cervical and incisal margins and lower cement film thickness (F=50.921, P<0.001) compared to machinable ceramic veneers. The inferior marginal properties of machinable ceramic veneers were associated with significantly higher microleakage values. CONCLUSIONS: Pressable ceramic laminate veneers produced higher marginal adaptation, homogenous and thinner cement film thickness, and improved resistance to microleakage compared to machinable ceramic veneers. CLINICAL SIGNIFICANCE: The manufacturing process influences internal and marginal fit of ceramic veneers. Therefore, dentist and laboratory technicians should choose a manufacturing process with careful consideration. PMID- 22542501 TI - Comparative determinations of non SHBG-bound serum testosterone, using ammonium sulfate precipitation, Concanavalin A binding or calculation in men. AB - BACKGROUND: Testosterone (T) circulates tightly bound to sex hormone-binding globulin (SHBG) and weakly to albumin. Non-SHBG-bound T is considered as the bioavailable T (BT) and was recommended for the evaluation of androgen disorders. Two methods, BT calculating from T, SHBG and albumin or BT measurement using ammonium sulfate precipitation of [SHBG-T] complex have been widely used. Using SHBG separation with Concanavalin-A (ConA) was recently proposed as a more specific method. The aim of this work was to compare these three methods in male patients. METHODS: Serum samples of 131 consecutive untreated men (15-81 years) referred for suspicion of hypogonadism were collected. Total T was measured by GC MS, SHBG by immunoradiometric assay. Level of BT was assayed using ammonium sulfate precipitation, ConA separation and calculated using the Issam web calculator. RESULTS: Only few differences were found between ammonium sulfate or ConA BT measurements. However, we found much higher serum calculated BT than assayed BT with an increasing bias when BT levels increased. CONCLUSIONS: Measurement of BT using ConA separation could be recommended. The results are equivalent to those obtained using ammonium sulfate precipitation. This method eliminates the possible non specific albumin precipitation that can occur with ammonium sulfate when the assay conditions are not rigorously controlled. PMID- 22542502 TI - Synthesis of 2-[11C]methoxy-3,17beta-O,O-bis(sulfamoyl)estradiol as a new potential PET agent for imaging of steroid sulfatase (STS) in cancers. AB - Steroid sulfatase (STS) catalyzes the hydrolysis of steroid sulfates to estrones, the main source of estrogens in tumors. Carbonic anhydrase II (CAII) is highly expressed in red blood cells through a coordination of the monoanionic form of the sulfamate moiety to the zinc atom in the enzyme active site, and CAII is highly expressed in several tumors. 2-Methoxy-3,17beta-O,O bis(sulfamoyl)estradiol (5) is a dual-function STS-CAII inhibitor inhibited STS with 39 nM IC(50) value selectively over CAII with 379 nM IC(50) value. This compound exhibited potent antiproferative activity with mean graph midpoint value of 87 nM in the NCI 60-cell-line panel, and antiangiogenic in vitro and in vivo activity in an early-stage Lewis lung model as well. The compound has been recently developed as a multitargeted anticancer agent. Both STS and CAII are over-expressed in cancers and have become attractive targets for cancer treatment and molecular imaging of cancer. Here we report the first design and synthesis of 2-[(11)C]methoxy-3,17beta-O,O-bis(sulfamoyl)estradiol ([(11)C]5) as a new potential imaging agent for biomedical imaging technique positron emission tomography (PET) to image STS in cancers. The authentic standard 5 was synthesized from 17beta-estradiol by published procedures in 5 steps with 40% overall chemical yield. The precursor 2-hydroxy-3,17beta-O,O bis(sulfamoyl)estradiol (14a) for radiolabeling was synthesized from 17beta estradiol in 10 steps with 5% overall chemical yield. The target tracer [(11)C]5 was prepared from the precursor 14a with [(11)C]CH(3)OTf through O [(11)C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) purification in 40-50% radiochemical yields based on [(11)C]CO(2) and decay corrected to end of bombardment (EOB), with 370-740 GBq/MUmol specific activity at EOB. PMID- 22542503 TI - Synthesis and bioassay of a boron-dipyrromethene derivative of estradiol for fluorescence imaging in vivo. AB - C7alpha-substituted estradiols bind to estrogen receptors in cell nuclei, yet these derivatives remain little used in bioimaging. Here, we describe a fluorescent derivative of estradiol (E2) with a boron-dipyrromethene (BODIPY) moiety attached to C7alpha, synthesized by olefin metathesis reaction of 7alpha allylestradiol and 9-decenyl-BODIPY. In ovariectomized rats and non ovariectomized mice, E2-BODIPY promoted the growth of uterine tissue similar to the effect of estradiol. Twenty-four hours after subcutaneous injection of E2 BODIPY in non-ovariectomized mice, we observed fluorescence of E2-BODIPY in the nuclei of uterine epithelial cells. Our findings suggest that fluorescence microscopy can localize this derivative in E2-responsive cells during normal development and tumorigenesis in vivo. PMID- 22542504 TI - Estrogen receptor beta dependent attenuation of cytokine-induced cyclooxygenase-2 by androgens in human brain vascular smooth muscle cells and rat mesenteric arteries. AB - Androgens may provide protective effects in the vasculature under pathophysiological conditions. Our past studies have shown that dihydrotestosterone (DHT) decreases expression of cyclooxygenase-2 (COX-2) during cytokine, endotoxin, or hypoxic stimulation in human vascular smooth muscle cells, in an androgen receptor (AR)-independent fashion. Classically DHT is regarded as a pure AR agonist; however, it can be endogenously metabolized to 5alpha-androstane-3beta, 17beta-diol (3beta-diol), which has recently been shown to be a selective estrogen receptor (ERbeta) agonist. Therefore, we hypothesized that DHT's anti-inflammatory properties following cytokine stimulation are mediated through ERbeta. Using primary human brain vascular smooth muscle cells (HBVSMC), we tested whether DHT's effect on IL-1beta induced COX-2 expression was mediated via AR or ERbeta. The metabolism of DHT to 3beta-diol is a viable pathway in HBVSMC since mRNA for enzymes necessary for the synthesis and metabolism of 3beta-diol [3alpha-hydroxysteroid dehydrogenase (HSD), 3beta-HSD, 17beta-HSD, CYP7B1] was detected. In addition, the expression of AR, ERalpha, and ERbeta mRNA was detected. When applied to HBVSMC, DHT (10nM; 18 h) attenuated IL 1beta-induced increases in COX-2 protein expression. The AR antagonist bicalutamide did not block DHT's ability to reduce COX-2. Both the non-selective estrogen receptor antagonist ICI 182,780 (1 MUM) and the selective ERbeta antagonist PHTPP (1 MUM) inhibited the effect of DHT, suggesting that DHT actions are ERbeta-mediated. In HBVSMC and in rat mesenteric arteries, 3beta-diol, similar to DHT, reduced cytokine-induced COX-2 levels. In conclusion, DHT appears to be protective against the progression of vascular inflammation through metabolism to 3beta-diol and activation of ERbeta. PMID- 22542505 TI - [Clinical practice guidelines for assessment and treatment of transsexualism. SEEN Identity and Sexual Differentiation Group (GIDSEEN)]. AB - Transsexual patients can only be diagnosed and treated at functional gender identity Units with provision of high quality care, development of clinical practice guidelines, and interdisciplinary working groups. The therapeutic process has three mainstays: initial psychological diagnostic evaluation and psychotherapy, endocrinological evaluation and hormone therapy, and sex reassignment surgery. Cross-sex hormone therapy is essential for the anatomical and psychological transition process in duly selected patients. Hormones help optimize real-life sex identity, improve quality of life, and limit psychiatric co-morbidities often associated to lack of treatment. Development of this clinical practice guideline addresses the need for implementing a coordinated action protocol for comprehensive health care for transgender people in the National Health System. PMID- 22542506 TI - RNA interference targeting cytosolic NADP(+)-dependent isocitrate dehydrogenase exerts anti-obesity effect in vitro and in vivo. AB - A metabolic abnormality in lipid biosynthesis is frequently associated with obesity and hyperlipidemia. Nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) is an essential reducing equivalent for numerous enzymes required in fat and cholesterol biosynthesis. Cytosolic NADP(+)-dependent isocitrate dehydrogenase (IDPc) has been proposed as a key enzyme for supplying cytosolic NADPH. We report here that knockdown of IDPc expression by Ribonucleic acid (RNA) interference (RNAi) inhibited adipocyte differentiation and lipogenesis in 3T3-L1 preadipocytes and mice. Attenuated IDPc expression by IDPc small interfering RNA (siRNA) resulted in a reduction of differentiation and triglyceride level and adipogenic protein expression as well as suppression of glucose uptake in cultured adipocytes. In addition, the attenuation of Nox activity and Reactive oxygen species (ROS) generation accompanied with knockdown of IDPc was associated with inhibition of adipogenesis and lipogenesis. The loss of body weight and the reduction of triglyceride level were also observed in diet-induced obese mice transduced with IDPc short-hairpin (shRNA). Taken together, the inhibiting effect of RNAi targeting IDPc on adipogenesis and lipid biosynthesis is considered to be of therapeutic value in the treatment and prevention of obesity and obesity associated metabolic syndrome. PMID- 22542508 TI - Sequencing and analysis of four BAC clones containing innate immune genes from the Zhikong scallop (Chlamys farreri). AB - The sequencing of BAC clones (~100 kb) can reveal some characteristics of a genome that are challenging to obtain based on short sequences. Additionally, although the immune genes of the Zhikong scallop (Chlamys farreri) have been studied widely, few analyses have been conducted at the DNA level. In this study, four C. farreri BAC clones containing innate immune genes, including hsp70, l gbp (lipopolysaccharide and beta-1,3-glucan binding protein), serine protease and a gene with an immunoglobulin-like domain, were sequenced and analyzed both to explore the genomic characteristics of C. farreri based on long DNA sequences and to promote the study of C. farreri immune genes at the DNA level. The total length of the four BACs was 389.98 kb. A total of 34 genes were predicted in these sequences, and several features of protein-coding regions in the C. farreri genome were inferred based on this information. Two LGBP genes were located close together in a 22-kb region in one BAC clone, indicating the physical linkage of some immune genes in C. farreri. A cluster of membrane transport genes was also observed; these genes might play important roles in eliminating toxins in C. farreri, which lives as a filter feeder. Further analysis showed 15.43% of the BAC sequence was repetitive. Tandem repeats were the most abundant repeat type, followed by transposable elements. A total of 31 SSRs were predicted in the four BACs. An IS10 family transposon was identified, and a suspected regulatory non coding RNA gene for this transposon (RNA-OUT) was observed to overlap with it complementarily. This work will promote future studies on the genomics, immune system and non-coding regions of C. farreri. PMID- 22542509 TI - Individual differences in smoking-related cue reactivity in smokers: an eye tracking and fMRI study. AB - Measures of cue reactivity provide a means of studying and understanding addictive behavior. We wanted to examine the relationship between different cue reactivity measures, such as attentional bias and subjective craving, and functional brain responses toward smoking-related cues in smokers. We used eye tracking measurements, a questionnaire for smoking urges-brief and functional magnetic resonance imaging to assess the responses to smoking-related and neutral visual cues from 25 male smokers after 36 h of smoking abstinence. Regression analyses were conducted to determine the correlation between cue-evoked brain responses and the attentional bias to smoking-related cues. The eye gaze dwell time percentage was longer in response to smoking-related cues than neutral cues, indicating significant differences in attentional bias towards smoking-related cues. The attentional bias to smoking-related cues correlated with subjective craving ratings (r=0.660, p<0.001). The dorsolateral prefrontal cortex, the putamen, the posterior cingulate cortex and the primary motor cortex were associated with the attentional bias to smoking-related cues, whereas the orbitofrontal cortex, the insula and the superior temporal gyrus were associated with smoking-related cue-induced craving and smoking urges. These results suggest that attentional mechanisms in combination with motivational and reward-related mechanisms play a role in smoking-related cue reactivity. We confirmed a positive correlation between different smoking-related cue reactivities, such as attentional bias and subjective craving, and functional brain responses in various individuals. Further studies in this field might contribute to a better individualized understanding of addictive behavior. PMID- 22542507 TI - Tracking fetal development through molecular analysis of maternal biofluids. AB - Current monitoring of fetal development includes fetal ultrasonography, chorionic villus sampling or amniocentesis for chromosome analysis, and maternal serum biochemical screening for analytes associated with aneuploidy and open neural tube defects. Over the last 15 years, significant advances in noninvasive prenatal diagnosis (NIPD) via cell-free fetal (cff) nucleic acids in maternal plasma have resulted in the ability to determine fetal sex, RhD genotype, and aneuploidy. Cff nucleic acids in the maternal circulation originate primarily from the placenta. This contrasts with cff nucleic acids in amniotic fluid, which derive from the fetus, and are present in significantly higher concentrations than in maternal blood. The fetal origin of cff nucleic acids in the amniotic fluid permits the acquisition of real-time information about fetal development and gene expression. This review seeks to provide a comprehensive summary of the molecular analysis of cff nucleic acids in maternal biofluids to elucidate mechanisms of fetal development, physiology, and pathology. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure. PMID- 22542510 TI - Sex, rebellion and decadence: the scandalous evolutionary history of the human Y chromosome. AB - It can be argued that the Y chromosome brings some of the spirit of rock&roll to our genome. Equal parts degenerate and sex-driven, the Y has boldly rebelled against sexual recombination, one of the sacred pillars of evolution. In evolutionary terms this chromosome also seems to have adopted another of rock&roll's mottos: living fast. Yet, it appears to have refused to die young. In this manuscript the Y chromosome will be analyzed from the intersection between structural, evolutionary and functional biology. Such integrative approach will present the Y as a highly specialized product of a series of remarkable evolutionary processes. These led to the establishment of a sex-specific genomic niche that is maintained by a complex balance between selective pressure and the genetic diversity introduced by intrachromosomal recombination. Central to this equilibrium is the "polish or perish" dilemma faced by the male-specific Y genes: either they are polished by the acquisition of male-related functions or they perish via the accumulation of inactivating mutations. Thus, understanding to what extent the idiosyncrasies of Y recombination may impact this chromosome's role in sex determination and male germline functions should be regarded as essential for added clinical insight into several male infertility phenotypes. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure. PMID- 22542511 TI - Development of diet-induced insulin resistance in adult Drosophila melanogaster. AB - The fruit fly Drosophila melanogaster is increasingly utilized as an alternative to costly rodent models to study human diseases. Fly models exist for a wide variety of human conditions, such as Alzheimer's and Parkinson's Disease, or cardiac function. Advantages of the fly system are its rapid generation time and its low cost. However, the greatest strength of the fly system are the powerful genetic tools that allow for rapid dissection of molecular disease mechanisms. Here, we describe the diet-dependent development of metabolic phenotypes in adult fruit flies. Depending on the specific type of nutrient, as well as its relative quantity in the diet, flies show weight gain and changes in the levels of storage macromolecules. Furthermore, the activity of insulin-signaling in the major metabolic organ of the fly, the fat body, decreases upon overfeeding. This decrease in insulin-signaling activity in overfed flies is moreover observed when flies are challenged with an acute food stimulus, suggesting that overfeeding leads to insulin resistance. Similar changes were observed in aging flies, with the development of the insulin resistance-like phenotype beginning at early middle ages. Taken together, these data demonstrate that imbalanced diet disrupts metabolic homeostasis in adult D. melanogaster and promotes insulin-resistant phenotypes. Therefore, the fly system may be a useful alternative tool in the investigation of molecular mechanisms of insulin resistance and the development of pharmacologic treatment options. PMID- 22542512 TI - Herpes simplex type 1 activates glycolysis through engagement of the enzyme 6 phosphofructo-1-kinase (PFK-1). AB - Viruses such as HIV, HCV, Mayaro and HCMV affect cellular metabolic pathways, including glycolysis. Although some studies have suggested that the inhibition of glycolysis affects HSV-1 replication and that HSV-1-infected eyes have increased lactate production, the mechanisms by which HSV-1 induces glycolysis have never been investigated in detail. In this study, we observed an increase in glucose uptake, lactate efflux and ATP content in HSV-1-infected cells. HSV-1 triggered a MOI-dependent increase in the activity of phosphofructokinase-1 (PFK-1), a key rate-limiting enzyme of the glycolytic pathway. After HSV-1 infection, we observed increased PFK-1 expression, which increased PFK-1 total activity, and the phosphorylation of this enzyme at serine residues. HSV-1-induced glycolysis was associated with increased ATP content, and these events were critical for viral replication. In summary, our results suggest that HSV-1 triggers glycolysis through a different mechanism than other herpesviruses, such as HCMV. Thus, this study contributes to a better understanding of HSV-1 pathogenesis and provides insights into novel targets for antiviral therapy. HIGHLIGHTS: ?HSV-1 activates glycolysis by PFK-1 activation. ?In HSV-1-infected cells PFK-1 synthesis is up regulated and phosphorylated at serine residues. ?PFK-1 knockdown impairs HSV-1 replication. ?HSV-1-mediated glycolysis activation increases ATP content. PMID- 22542513 TI - On-fiber furan formation from volatile precursors: a critical example of artefact formation during Solid-Phase Microextraction. AB - For the analysis of furan, a possible carcinogen formed during thermal treatment of food, Solid-Phase Microextraction (SPME) is a preferred and validated sampling method. However, when volatile furan precursors are adsorbed on the carboxen/PDMS fiber, additional amounts of furan can be formed on the fiber during thermal desorption, as shown here for 2-butenal and furfural. No significant increase in furan amounts was found upon heating the furan precursor 2-butenal, indicating that the furan amounts formed during precursor heating experiments are negligible as compared to the additional amounts of furan formed during fiber desorption. This artefactual furan formation increased with increasing desorption time, but especially with increasing desorption temperature. Although this effect was most pronounced on the Carboxen/PDMS SPME-fiber, it was also noted on two other SPME fibers tested (PDMS and DVB/Carboxen/PDMS). The general impact on furan data from food and model systems in literature will depend on the amounts of volatile precursors present, but will probably remain limited. However, considering the importance of this worldwide food contaminant, special care has to be taken during SPME-analysis of furan. Especially when performing precursor studies, static headspace sampling should preferably be applied for furan analysis. PMID- 22542514 TI - Determination of four immunosuppressive drugs in whole blood using MEPS and LC MS/MS allowing automated sample work-up and analysis. AB - In treatment with immunosuppressive drugs, monitoring of blood drug concentration is needed. The aim of this work was to explore micro extraction by packed sorbent (MEPS) as a possible on-line sample preparation method in combination with liquid chromatography-tandem mass spectrometry (LC-MS/MS) for quantification of cyclosporine, everolimus, sirolimus and tacrolimus in whole blood. An automated on-line MEPS system connected with a LC-MS/MS instrument was set up. A C8 sorbent was used for the MEPS extraction. Subsequent analysis was performed with a gradient LC system. The adduct ions [M+NH4]+ of the analytes were monitored in SRM mode for quantification. Ascomycin and cyclosporine D were used as internal standards. The chromatographic run time 2.5 min and the quantification ranges were 3-1500 ng/mL (r2 >= 0.999, n=6) for cyclosporine and 0.5-50 ng/mL for everolimus, sirolimus and tacrolimus (r2 >= 0.998, 0.994 and 0.993, respectively, n=6). Precision and accuracy were documented at three levels. Accuracy results were between 102% and 109% with precision between 2% and 13% and carry over <0.02%. Matrix effects were characterized and found to be below 20%. The quantifications obtained were in agreement with a reference LC-MS/MS method based on protein precipitation, and results obtained from external proficiency test samples compared with the mean of all other LC-mass spectrometry methods showed good agreement. This method provides an accurate, precise and automated procedure that can be applied for therapeutic drug monitoring of immunosuppressive drugs in clinical laboratories equipped with LC-MS/MS. PMID- 22542515 TI - Hybrid trans-apical device closure of left ventricular pseudoaneurysm under trans oesophageal echocardiographic guidance. AB - Left ventricular pseudo aneurysm (LVPA) results from contained left ventricular free wall rupture following either myocardial infarction or cardiac surgery. Untreated LVPA carries approximately 30-45% risk of rupture in the first year. Conventional treatment for LVPA is surgery which carries a mortality of about 20%. Interventional closure of LVPA has been reported from trans-arterial and trans-apical routes. Here we report successful hybrid closure of a LVPA under trans-oesophageal echocardiogram (TEE) guidance. PMID- 22542516 TI - Congeneric bio-adhesive mussel foot proteins designed by modified prolines revealed a chiral bias in unnatural translation. AB - Chiral bias in the unnatural translation and 'sticky' mussel proteins. The residue-specific in vivo incorporation of hydroxylated amino acids as well as other synthetic analogs, such as fluoroprolines, emerges as the method of choice for recombinant synthesis of Pro-rich mussel adhesive protein congeners. Chemical diversifications introduced in this way provide a general route towards bio adhesive congeners endowed with properties not developed by natural evolution. Most importantly, we have found that the co-translational incorporation of (4R)-, and (4S)-hyroxylated and fluorinated analogs into mussel proteins presented a chiral bias: the expressed protein was only detectable in samples incubated with analogs with (4R)-substituents. Possible relationship of these stereochemical preferences for (4R)-stereoisomers in the translation to intracellular tRNA concentrations, ribosomal editing and proofreading or structural effects such as preorganization remains to be addressed in future studies. These studies will generally provide a mechanistic framework for the flexibility of the translational machinery and establish the boundaries of the unnatural translation. PMID- 22542517 TI - KBTBD13 interacts with Cullin 3 to form a functional ubiquitin ligase. AB - Autosomal dominant mutations in BTB and Kelch domain containing 13 protein (KBTBD13) are associated with a new type of Nemaline Myopathy (NEM). NEM is a genetically heterogeneous group of muscle disorders. Mutations causing phenotypically distinct NEM variants have previously been identified in components of muscle thin filament. KBTBD13 is a muscle specific protein composed of an N terminal BTB domain and a C terminal Kelch-repeat domain. The function of this newly identified protein in muscle remained unknown. In this study, we show that KBTBD13 interacts with Cullin 3 (Cul3) and the BTB domain mediates this interaction. Using ubiquitination assays, we determined that KBTBD13 participates in the formation of a Cul3 based RING ubiquitin ligase (Cul3-RL) capable of ubiquitin conjugation. Confocal microscopy of transiently expressed KBTBD13 revealed its co-localization with ubiquitin. Taken together, our results demonstrate that KBTBD13 is a putative substrate adaptor for Cul3-RL that functions as a muscle specific ubiquitin ligase, and thereby implicate the ubiquitin proteasome pathway in the pathogenesis of KBTBD13-associated NEM. PMID- 22542518 TI - Validation of differential gene expression in muscle engineered from rat groin adipose tissue by quantitative real-time PCR. AB - Quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR) is a highly sensitive tool that can be used for accurate and reliable gene expression analysis; however, a critical factor for creating reliable data in relative quantification is the normalization of the expression data of the genes of interest. In this study, we demonstrate the important process of validating four muscle-specific genes (myosin, desmin, MEF2D and ADAM12) and 10 common potential reference genes (beta-2-microglobulin, RPL32, RPL17, alpha-tubulin, CYC, ET1A, beta-actin, HSPCB, SDHA and GAPDH) in engineered muscle tissues. Tissue samples were generated out of rat groin adipose tissues by myogenic induction in a perfusion bioreactor for 7, 21 and 49 days. Results of analyzed muscle-specific genes suggested that the gene expression pattern corresponding to myogenic induction observed in adequately treated rat adipose tissue was time dependent, making the length of time in culture in myogenic medium an important factor. Our data suggest that the reference genes were expressed variably in the different samples. During engineered muscle development, beta-2-microglobulin, RPL32 and RPL17 were the most stably expressed genes. The commonly used reference genes beta-actin and GAPDH appeared to be too unstable for normalization of qRT PCR expression in engineered muscle tissue. The use of beta-2-microglobulin, RPL32 and RPL17 as internal standards may improve the accuracy of gene expression studies aimed at muscle tissue engineering under the proposed settings. PMID- 22542519 TI - Diabetic foot osteomyelitis: bone markers and treatment outcomes. AB - AIMS: Novel bone turnover markers could help with the diagnosis and monitoring of osteomyelitis patients. We compared levels of two bone turnover markers, serum amino-terminal telopeptides (NTx) and bone alkaline phosphatase (BAP), in diabetic patients with and without osteomyelitis. METHODS: Matched case-control study was conducted with diabetic patients with and without osteomyelitis. Cases not undergoing immediate amputation were followed with repeat measurements after osteomyelitis treatment and for outcome determination. RESULTS: Analysis included 54 subjects, 27 cases and 27 controls. Median BAP levels were similar between cases and controls at enrollment (p=.55) as were median NTx levels (p=.43). Cases with follow-up data (n=18) had similar bone marker levels at enrollment and 6 weeks. No significant differences in BAP or NTx levels at enrollment or follow-up were seen between cases with poor versus favorable outcomes. CONCLUSIONS: No differences in NTx or BAP levels were seen between cases and controls. Cases with follow-up data had similar levels at enrollment and 6 weeks. Lack of difference may be due to small sample size, small areas of bone involved in foot osteomyelitis, or limitations of these specific markers. More research is needed. PMID- 22542520 TI - Enhanced analysis of bacteria susceptibility in connected biofilms. AB - A common method for visualizing bacterial biofilms is through confocal laser scanning microscopy images. Current software packages separate connected-biofilm bacteria from unconnected bacteria, such as planktonic or dispersed bacteria, but do not save both image sequences, making interpretation of the two bacterial populations difficult. Thus we report the development of an algorithm to save separate image sequences and enable qualitative and quantitative evaluation of each bacterial population. To improve bacterial viability assessment using a membrane integrity dye, a colocalization algorithm was also developed. This assigns colocalized pixels to the dead bacteria population, rather than to both the live and dead bacteria groups. Visually, this makes it clearer to distinguish a green live bacteria pixel from a yellow colocalized dead bacteria pixel. This algorithm also aids in the quantification of viability for connected-biofilm bacteria and unconnected bacteria to investigate susceptibility of each population to antimicrobials. The utility of these algorithms was demonstrated with Pseudomonas aeruginosa biofilms treated with ciprofloxacin hydrochloride. Results from this study indicate that quantification with colocalization adjustment can prevent underestimation of dead bacteria. These improvements in image processing will enable researchers to visually differentiate connected biofilm and unconnected bacteria in a single image and to quantify these populations independently for viability without double counting the colocalized image pixels. PMID- 22542521 TI - An improved medium for growing Staphylococcus aureus biofilm. AB - A medium (Brain Heart Infusion plus 10% human plasma) was developed, tested, and validated for growing Staphylococcus aureus biofilm in vitro. With this medium, S. aureus forms reproducible and robust biofilms in flow chambers under controlled shear flow and with increased viability recovery in static well plates. PMID- 22542522 TI - Polysialylation of the neural cell adhesion molecule: interfering with polysialylation and migration in neuroblastoma cells. AB - Polysialic acid represents a unique posttranslational modification of the neural cell adhesion molecule (NCAM). It is built as a homopolymer of up to 150 molecules of alpha 2-8-linked sialic acids on N-glycans of the fifth immunoglobulin-like domain of NCAM. Besides its role in cell migration and axonal growth during development, polysialic acids are closely related to tumor malignancy as they are linked to the malignant potential of several tumors, such as undifferentiated neuroblastoma. Polysialic acid expression is significantly more frequent in high-grade tumors than in low-grade tumors. It is synthesized in the Golgi apparatus by the activity of two closely related enzymes, the polysialyltransferases ST8SiaII and ST8SiaIV. Interestingly, polysialylation of tumors is not equally synthesized by both polysialyltransferases. It has been shown that especially the ST8SiaII gene is not expressed in some normal tissue, but is strongly expressed in tumor tissue. Here we summarize some knowledge on the role of polysialic acid in cell migration and tumor progression and present novel evidence that interfering with polysialylation using unnatural sialic acid precursors decreases the migration of neuroblastoma cells. PMID- 22542523 TI - Mustelidae are natural hosts of Staphylococcus delphini group A. AB - According to the current taxonomy, the Staphylococcus intermedius group (SIG) comprises of at least three distinct species. While S. intermedius and S. pseudintermedius are associated with specific hosts (pigeons and dogs, respectively), the natural host of S. delphini remains unclear. We analysed 158 SIG isolates from less studied animal species belonging to the order Carnivora, including mink (n=118), fox (n=33), badger (n=6) and ferret (n=1). Species identification was performed by nuc PCR in combination with sodA sequence analysis and pta PCR restriction fragment length polymorphism (RFLP). The results showed a consistent association between host and bacterial species. All isolates from minks, ferret and badgers belonged to S. delphini group A, whereas all fox isolates except one were identified as S. pseudintermedius. The remaining fox isolate belonged to S. delphini group A. The results indicate that Mustelidae such as minks, ferrets and badgers are natural hosts of S. delphini group A. This is in contrast with Canidae, which are primarily colonized and infected with S. pseudintermedius. These findings suggest that coagulase-positive staphylococcal species may have evolved and diverged through host adaptation. PMID- 22542524 TI - In vitro evaluation of Lactobacillus crispatus K313 and K243: high-adhesion activity and anti-inflammatory effect on Salmonella braenderup infected intestinal epithelial cell. AB - Currently, there is an increasing interest in the use of probiotics as an alternative strategy to antimicrobial compounds. In this study, two high adhesive strains Lactobacillus crispatus K313 adhering to HT-29 cells as well as Lb. crispatus K243 adhering to collagen type IV were isolated from chicken intestines. SDS-PAGE analysis revealed the presence of the potential S-proteins SlpA and SlpB in Lb. crispatus K243 and K313. SlpA and SlpB, rich in hydrophobic amino acids, were proved to be involved in adhering to collagen type IV and HT-29 cells, respectively, based on the LiCl treatment assay. After removal of S proteins, the viability and tolerance of the two Lb. crispatus strains to simulated gastric and small intestinal juice were reduced, indicating the protective role of S-proteins against the hostile environments. Lb. crispatus K313 exhibited the stronger autoaggregation ability and inhibitive activity against Salmonella braenderup H9812 adhesion to HT-29 cells than the strain K243. To elucidate the inhibitive mechanism, cultured epithelial cells were exposed with Lb. crispatus strains, and followed by a challenge with S. braenderup H9812. The pro-inflammatory signaling factors (IL-8, CXCL1 and CCL20) from HT-29 were detected by real-time PCR technology. The results showed that both of Lb. crispatus strains down-regulated the transcription level of those pro inflammatory genes induced by S. braenderup H9812 by 36.2-58.8%. ELISA analysis was further confirmed that Lb. crispatus K243 and K313 inhibited the IL-8 secretion triggered by S. braenderup H9812 by 32.8% and 47.0%, indicating that the two isolates could attenuate the pro-inflammatory signaling induced by S. braenderup H9812, and have the potential application in clinical practice to prevent diarrhea. PMID- 22542525 TI - On the possible amyloid origin of protein folds. AB - The diversity of protein folds is derived from the diversity of the underlying proteome. Such diversity must have originated from a so-called common ancestor: a hypothetical fold whose identity will, in all likelihood, never be known. Nonetheless, hypotheses exist to explain the evolution of protein folds. When formulating such hypotheses as done here, the entire repertoire of polypeptide structure, from well-defined tertiary structures and molten globule states to intrinsically disordered proteins and oligomeric aggregates, is worth considering. It is the aim of this short essay to discuss the hypothesis that one type of protein aggregate-the cross-beta-sheet motif-was the first functional protein fold, that is, the common ancestor fold. Support for this hypothesis comes from the observations that (i) short peptides with simple amino acid sequences are able to form the cross-beta-sheet structure, (ii) amyloids can be very stable under harsh conditions, (iii) amyloids can self-assemble in complex mixtures, (iv) amyloids have many potent activities that are attributable to the inherent repetitiveness of the structure, and (v) the proteomes of modern organisms appear to have evolved away from the more amyloidogenic sequences of older organisms, suggesting that amyloids were more ubiquitous earlier in the evolution of modern protein folds. PMID- 22542526 TI - Early steps in oxidation-induced SOD1 misfolding: implications for non-amyloid protein aggregation in familial ALS. AB - Among the diseases of protein misfolding, amyotrophic lateral sclerosis (ALS) is unusual in that the proteinaceous neuronal inclusions that are the hallmark of the disease have neither the classic fibrillar appearance of amyloid by transmission electron microscopy nor the affinity for the dye Congo red that is a defining feature of amyloid. Mutations in the Cu, Zn superoxide dismutase (SOD1) cause the largest subset of inherited ALS cases. The mechanism by which this highly stable enzyme misfolds to form non-amyloid aggregates is currently poorly understood, as are the stresses that initiate misfolding. The oxidative damage hypothesis proposes that SOD1's normal free radical scavenger role puts it at risk of oxidative damage and that it is this damage that triggers the misfolding primed by mutation. Here, we present evidence that hydrogen peroxide treatment, which generates free radical species at the SOD1 active site, causes oxidative damage to active-site histidine residues, leading to major structural changes and non-amyloid aggregation similar to that seen in ALS. Time-resolved measurements of release of bound metal ligands, exposure of hydrophobic surface area, and alterations in the SOD1 proton NMR spectrum have allowed us to model the early structural changes occurring as SOD1 misfolds, prior to aggregation. ALS-causing SOD1 mutations apparently alter this pathway by increasing exposure of buried epitopes in misfolded species populated at endpoint. We have identified a well populated early misfolding intermediate that could serve as a target for therapies designed to block downstream misfolding and aggregation events and thereby treat SOD1-associated ALS. PMID- 22542527 TI - Nucleobindin 1 caps human islet amyloid polypeptide protofibrils to prevent amyloid fibril formation. AB - Many human diseases are associated with amyloid fibril deposition, including type 2 diabetes mellitus where human islet amyloid polypeptide (hIAPP) forms fibrils in the pancreas. We report here that engineered, soluble forms of the human Ca(2+)-binding protein nucleobindin 1 (NUCB1) prevent hIAPP fibril formation and disaggregate preexisting hIAPP fibrils. Scanning transmission electron microscopy (STEM) and atomic force microscopy indicate that NUCB1 binds to and stabilizes heterogeneous prefibrillar hIAPP species. The NUCB1-stabilized prefibrillar species were isolated by size-exclusion chromatography and analyzed by STEM, dynamic light scattering, and multi-angle light scattering. The stabilized prefibrillar species show a size range of 2-6 million Da and have other similarities to hIAPP protofibrils, but they do not progress to become mature fibrils. The effects of NUCB1 are absent in the presence of Ca(2+). We postulate that the engineered forms of NUCB1 prevent hIAPP fibril formation by a mechanism where protofibril-like species are "capped" to prevent further fibril assembly and maturation. This mode of action appears to be different from other protein based inhibitors, suggesting that NUCB1 may offer a new approach to inhibiting amyloid formation and disaggregating amyloid fibrils. PMID- 22542528 TI - Combination of the human prolyl isomerase FKBP12 with unrelated chaperone domains leads to chimeric folding enzymes with high activity. AB - Folding enzymes often use distinct domains for the binding of substrate proteins ("chaperone domains") and for the catalysis of slow folding reactions such as disulfide formation or prolyl isomerization. The human prolyl isomerase FKBP12 is a small single-domain protein without a chaperone domain. Its very low folding activity could previously be increased by inserting the chaperone domain from the homolog SlyD (sensitive-to-lysis protein D) of Escherichia coli. We now inserted three unrelated chaperone domains into human FKBP12: the apical domain of the chaperonin GroEL from E. coli, the chaperone domain of protein disulfide isomerase from yeast, or the chaperone domain of SurA from the periplasm of E. coli. All three conveyed FKBP12 with a high affinity for unfolded proteins and increased its folding activity. Substrate binding and release of the chimeric folding enzymes were found to be very fast. This allows rapid substrate transfer from the chaperone domain to the catalytic domain and ensures efficient rebinding of protein chains that were unable to complete folding. The advantage of having separate sites, first for generic protein binding and then for specific catalysis, explains why our construction of the artificial folding enzymes with foreign chaperone domains was successful. PMID- 22542529 TI - Kinetic studies of the folding of heterodimeric monellin: evidence for switching between alternative parallel pathways. AB - Determining whether or not a protein uses multiple pathways to fold is an important goal in protein folding studies. When multiple pathways are present, defined by transition states that differ in their compactness and structure but not significantly in energy, they may manifest themselves by causing the dependence on denaturant concentration of the logarithm of the observed rate constant of folding to have an upward curvature. In this study, the folding mechanism of heterodimeric monellin [double-chain monellin (dcMN)] has been studied over a range of protein and guanidine hydrochloride (GdnHCl) concentrations, using the intrinsic tryptophan fluorescence of the protein as the probe for the folding reaction. Refolding is shown to occur in multiple kinetic phases. In the first stage of refolding, which is silent to any change in intrinsic fluorescence, the two chains of monellin bind to one another to form an encounter complex. Interrupted folding experiments show that the initial encounter complex folds to native dcMN via two folding routes. A productive folding intermediate population is identified on one route but not on both of these routes. Two intermediate subpopulations appear to form in a fast kinetic phase, and native dcMN forms in a slow kinetic phase. The chevron arms for both the fast and slow phases of refolding are shown to have upward curvatures, suggesting that at least two pathways each defined by a different intermediate are operational during these kinetic phases of structure formation. Refolding switches from one pathway to the other as the GdnHCl concentration is increased. PMID- 22542530 TI - Comparison of the efficacy and safety of statin and statin/ezetimibe therapy after coronary stent implantation in patients with stable angina. AB - Little is known about the efficacy and safety of intensive lowering of low density lipoprotein cholesterol (LDL-C) with statin/ezetimibe therapy after coronary stent implantation in patients with stable angina. Fifty patients with stable angina were randomly divided into an atorvastatin (10 mg/day) (A) group and an atorvastatin (10 mg/day)/ezetimibe (10 mg/day) (A+E) group after stent implantation. Follow-up coronary angiography was performed at 6-9 months after stenting. The A and A+E groups showed significant reductions in LDL-C. The levels of LDL-C in the A+E group were significantly lower than those in the A group at follow-up, whereas there were no differences in major adverse cardiac events, in stent restenosis, or in-stent % diameter stenosis (DS) between the groups. Only the A+E group showed a significant decrease in the levels of highly sensitive C reactive protein. In a sub-analysis, %DS in the non-target vessel significantly decreased in both groups. Moreover, Delta%DS (Delta=the value at baseline minus that at follow-up) in the A+E group was more closely associated with LDL-C levels at follow-up than that in the A group. There were no significant differences in adverse effects between the A and A+E groups. In conclusion, although statin/ezetimibe therapy was effective and safe for intensive lipid-lowering in patients with stable angina after successful coronary stent implantation, improvement in clinical outcomes with the combination therapy remains unclear. PMID- 22542531 TI - Cancer chemotherapy: a critical analysis of its 60 years of history. AB - Chemotherapy has already proven widely effective in the treatment of cancer, occupying a prominent place in the current therapeutic arsenal. However, in recent years, there has been a plateau in the evolution of the clinical results obtained with this modality treatment. In some cases, the limitations of chemotherapy observed during the early days still apply. These facts forced us to do a thorough analysis of what happened in the past 60years. We have observed that each major advance obtained in this field was based on empirical clinical observations. We thus believe that the current results of old or new agents can only be improved by understanding the natural history of each specific cancer subtype at the clinical level and by overcoming the physiological barriers involved in chemotherapy failure. This strategy will surely allow us to enlarge the list of curable cancers by chemotherapy. PMID- 22542532 TI - Crystalloid resuscitation in hemorrhagic shock. PMID- 22542533 TI - Direction of threat attention bias predicts treatment outcome in anxious children receiving cognitive-behavioural therapy. AB - BACKGROUND: A bias to selectively direct attention to threat stimuli is a cognitive characteristic of anxiety disorders. Recent studies indicate that individual differences in pre-treatment threat attention bias predict treatment outcomes from cognitive-behavioural therapy (CBT) in anxious individuals. However, there have been inconsistent findings regarding whether attention bias towards threat predicts better or poorer treatment outcome. METHOD: This longitudinal study examined treatment outcomes in 35 clinically-anxious children following a 10-week, group-based CBT program, as a function of whether children showed a pre-treatment attention bias towards or away from threat stimuli. The effect of CBT on attention bias was also assessed. RESULTS: Both groups showed significant improvement after receiving CBT. However, anxious children with a pre treatment attention bias towards threat showed greater reductions not only in anxiety symptom severity, but also in the likelihood of meeting diagnostic criteria for anxiety disorders at post-treatment assessment, in comparison with anxious children who showed a pre-treatment attention bias away from threat. Children who had a pre-treatment bias away from threat showed a reduction in this bias over the course of CBT. CONCLUSIONS: Findings suggest that pre-existing differences in the direction of attention towards versus away from threat could have important implications for the treatment of anxious children. PMID- 22542534 TI - Overgeneral autobiographical memory recollection in Iranian combat veterans with posttraumatic stress disorder. AB - This study examined the recollection of autobiographical material in memory among Iranian military veterans with and without posttraumatic stress disorder (PTSD), and healthy non-trauma-exposed control subjects. Participants completed the Autobiographical Memory Test, Autobiographical Memory Interview (counterbalanced), Impact of Event Scale-Revised, Beck Depression Inventory-II, Wechsler Memory Scale-III and Wechsler Adult Intelligence Scale-Revised. The PTSD group generated fewer specific episodic and semantic details of autobiographical memory compared to the non-PTSD and control groups. Working memory did not significantly moderate the relationship between PTSD diagnosis and reduced autobiographical memory specificity but did moderate the relationship between PTSD diagnosis and semantic recall; semantic memory recall was not significantly related to working memory ability for those with PTSD but was related to working memory ability for trauma survivors without PTSD. While the data provide some support for the expectation that higher working memory ability is associated with an increased ability to retrieve specific memories (i.e. semantic memory recall in those without PTSD), the findings are also consistent with the view that for those with PTSD the demands on working memory required for affect regulation cancel out this influence of working memory in augmenting access to specific memories. PMID- 22542536 TI - Lidocaine time- and dose-dependently demethylates deoxyribonucleic acid in breast cancer cell lines in vitro. AB - BACKGROUND: Anaesthetic management of cancer surgery may influence tumour recurrence. The modulation of gene expression by methylation of deoxyribonucleic acid (DNA) (epigenetics) is increasingly recognized as a major hallmark of cancer. Next to direct effects of local anaesthetics upon tumour cells, the ester type local anaesthetic, procaine, has been shown to affect methylation status in several tumour cell lines, promoting the reactivation of tumour suppressor genes. We sought to determine whether the prototype amide-type local anaesthetic, lidocaine, influences the survival and epigenetic status of oestrogen receptor (ER)-positive and -negative breast cancer cell lines in vitro. METHODS: Breast cancer cell lines BT-20 (ER-negative) and MCF-7 (ER-positive) were incubated with lidocaine and procaine as the reference substance. We performed cell count and determined apoptosis using TUNEL stain. Further, we assessed global methylation status, and methylation of three known tumour suppressor genes (RASSF1A, MYOD1, and GSTP1) using the MethyLight assay and real-time quantitative polymerase chain reaction, respectively. RESULTS: Baseline methylation was 100-fold higher in BT 20 cells. Here, we observed a dose-dependent decrease in DNA methylation in response to lidocaine (1, 0.01, and 0.01 mM) after 72 h (P<0.001, <0.001, and 0.004, respectively). The corresponding changes were smaller in MCF-7 cells. Global methylation status was profoundly influenced, but the methylation and mRNA expression status of three tumour suppressor genes was unchanged. CONCLUSIONS: Our findings suggest that demethylating tumour-suppressive effects of anaesthetic interventions may only be detectable in specific types of cancer due to differential methylation profiles. In conclusion, at clinically relevant concentrations, lidocaine demethylates DNA of breast cancer cell lines in vitro. PMID- 22542535 TI - Greater emotional arousal predicts poorer long-term memory of communication skills in couples. AB - Many studies have examined the importance of learning skills in behaviorally based couple interventions but none have examined predictors of long-term memory for skills. Associations between emotional arousal and long-term recall of communication skills delivered to couples during a behaviorally based relationship distress prevention program were examined in a sample of 49 German couples. Fundamental frequency (f(0)), a vocal measure of encoded emotional arousal, was measured during pre-treatment couple conflict. Higher levels of f(0) were linked to fewer skills remembered 11 years after completing the program, and women remembered more skills than men. Implications of results for behaviorally based couple interventions are discussed. PMID- 22542537 TI - Modulation of thiopental-induced vascular relaxation and contraction by perivascular adipose tissue and endothelium. AB - BACKGROUND: Thiopental induces relaxation of vascular smooth muscle cells through its direct and/or indirect vasodilator effects. The perivascular adipose tissue (PVAT) and the endothelium are known to attenuate vascular contraction, and we have recently reported that PVAT potentiates the relaxation effect of propofol through endothelium-dependent and -independent mechanisms. Here, we studied the mechanisms of thiopental-induced vascular responses in relation to the involvement of PVAT and endothelium. METHODS: Thoracic aortic rings from male Wistar rats were prepared with or without PVAT (PVAT+ and PVAT-) and with an intact endothelium (E+) or with the endothelium removed (E-) for functional studies. The contraction and relaxation responses of these vessels to thiopental in the presence of agonists and various receptor antagonists and channel blockers were studied. RESULTS: In vessels pre-contracted with phenylephrine or KCl, thiopental-induced relaxation was highest in vessels denuded of both PVAT and the endothelium. PVAT attenuated the relaxation response to thiopental, and this attenuation effect was reduced by both angiotensin II (Ang II) type 1 receptor antagonists CV-11974 (2-n-butyl-4-choloro-5-hydroxymethyl-1-[2'-(1H-tetrazol-5 yl)biphenyl-methyl]-imidazole) or losartan and the angiotensin-converting enzyme inhibitor enalaprilat. Thiopental at high concentration (3 * 10(-3) M) caused a contraction through an endothelin-dependent mechanism. CONCLUSIONS: Thiopental induced relaxation in rat aorta through an endothelium-independent pathway and the presence of PVAT, endothelium, or both attenuated this relaxation response through Ang II-dependent and endothelin-dependent mechanisms, respectively. PMID- 22542539 TI - Prolonged survival and milder impairment of motor function in the SOD1 ALS mouse model devoid of fibroblast growth factor 2. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective motoneuron loss in brain and spinal cord. Mutations in the superoxide dismutase (SOD) 1 gene account for 10-20% of familial ALS patients. The ALS-mouse model over-expressing a mutant human SOD1 (G93A) gene closely mimics human ALS disease. The cause for the selective death of motoneurons is still unclear, but among several pathomechanisms discussed, loss of neurotrophic factors is one possibility. Basic fibroblast growth factor 2 (FGF 2) plays a prominent role in the motor system. In order to evaluate a role of FGF 2 in ALS pathogenesis, double mouse mutants transgenic for the human SOD1 mutation and lacking the endogenous FGF-2 gene were generated. Both heterozygous and homozygous FGF-2 deficient mutant SOD1 mice showed a significant delay in disease onset and less impaired motor performance in comparison to mutant SOD1 mice with normal FGF-2 levels. Survival of the double mouse mutants was significantly prolonged for two weeks. Motoneuron numbers were significantly higher in the double mutants and astrocytosis was diminished at disease endstage. While one would initially have expected that FGF-2 deficiency deteriorates the phenotype of mutant SOD1 animals, our results revealed a protective effect of FGF 2 reduction. In search of the underlying mechanisms, we could show up-regulation of other neurotrophic factors with proven protective effects in the ALS mouse model, ciliary neurotrophic factor (CNTF) and glial derived neurotrophic factor (GDNF) in muscle and spinal cord tissue of double mutant animals. PMID- 22542538 TI - Caveolae and propofol effects on airway smooth muscle. AB - BACKGROUND: The i.v. anaesthetic propofol produces bronchodilatation. Airway relaxation involves reduced intracellular Ca(2+) ([Ca(2+)](i)) in airway smooth muscle (ASM) and lipid rafts (caveolae), and constitutional caveolin proteins regulate [Ca(2+)](i). We postulated that propofol-induced bronchodilatation involves caveolar disruption. METHODS: Caveolar fractions of human ASM cells were tested for propofol content. [Ca(2+)](i) responses of ASM cells loaded with fura 2 were performed in the presence of 10 uM histamine with and without clinically relevant concentrations of propofol (10 and 30 MUM and intralipid control). Effects on sarcoplasmic reticulum (SR) Ca(2+) release were evaluated in zero extracellular Ca(2+) using the blockers Xestospongin C and ryanodine. Store operated Ca(2+) entry (SOCE) after SR depletion was evaluated using established techniques. The role of caveolin-1 in the effect of propofol was tested using small interference RNA (siRNA) suppression. Changes in intracellular signalling cascades relevant to [Ca(2+)](i) and force regulation were also evaluated. RESULTS: Propofol was present in ASM caveolar fractions in substantial concentrations. Exposure to 10 or 30 uM propofol form decreased [Ca(2+)](i) peak (but not plateau) responses to histamine by ~40%, an effect persistent in zero extracellular Ca(2+). Propofol effects were absent in caveolin-1 siRNA transfected cells. Inhibition of ryanodine receptors prevented propofol effects on [Ca(2+)](i), while propofol blunted [Ca(2+)](i) responses to caffeine. Propofol reduced SOCE, an effect also prevented by caveolin-1 siRNA. Propofol effects were associated with decreased caveolin-1 expression and extracellular signal-regulated kinase phosphorylation. CONCLUSIONS: These novel data suggest a role for caveolae (specifically caveolin-1) in propofol-induced bronchodilatation. Due to its lipid nature, propofol may transiently disrupt caveolar regulation, thus altering ASM [Ca(2+)](i). PMID- 22542541 TI - Gender gaps in life expectancy: generalized trends and negative associations with development indices in OECD countries. AB - BACKGROUND: Life expectancy (LE) is a major marker of individual survival. It also serves as a guide to highlight both the progress and the gaps in total social and societal health. Comparative LE in concert with measures of gender specific experience, indices of empowerment and societal happiness and development offer a comparative tool to examine trends and similarities of societal progress as seen through the lens of cross-national experience. METHODS: To determine the gender gaps in LE (GGLE) trends, we performed a longitudinal analysis, covering a period of 49 years (1960-2008). To examine the association of GGLE with development indices, we used the 2007 GGLE data, the newest happiness data mostly drawn from 2006; the 2006 Human Development Index (HDI) data and the 2006 Gender Empowerment Measure (GEM) data. RESULTS: It revealed that most of the Organization for Economic Co-operation and Development (OECD) countries had a GGLE trend that occurred in an inverted U-curve fashion. We divided them into three subgroups based on the peak years of respective GGLE. The earlier the peak year, the happier the countries, the higher the HDI and the smaller the current GGLE are. Association analysis indicates that Happiness, HDI and GEM are all negatively associated with GGLE. CONCLUSION: This pattern suggests that GGLE undergoes three phases of growth, peak and stability and decline. Japan will soon be seeing its GGLE gradually shrinking in the foreseeable future. The continuing increases in Happiness, HDI and GEM are associated with a decrease in GGLE, which should be carefully taken into consideration. PMID- 22542540 TI - Tracking of overweight from mid-adolescence into adulthood: consistent patterns across socio-economic groups. AB - Socially differentiated tracking of health and health behaviours may contribute to health inequalities in adulthood. The modifying effect of socio-economic position on the tracking of overweight from mid-adolescence (age 15 years) into adulthood (age 27 years) was assessed in a randomly sampled Danish cohort (n = 561). The tracking was studied by prediction analyses conducted by logistic regression analyses. Strong tracking patterns were found to be independent of socio-economic background. PMID- 22542542 TI - A cross-national comparative study of metabolic syndrome among non-diabetic Dutch and English ethnic groups. AB - BACKGROUND: Evidence suggests a higher prevalence of type 2 diabetes (T2D) in The Netherlands than in England, although generalized obesity prevalence is substantially lower in The Netherlands. Metabolic syndrome (MS) is more strongly associated with the risk of progression to T2D than generalized obesity. Therefore examining MS may help to better understand the differences in T2D between the two countries. We assessed whether the Dutch and English differences in T2D prevalence reflect similar differences in MS in Whites, South-Asian Indians and African-Caribbeans living in these two countries. METHODS: Secondary analyses of population-based studies of 3010 participants aged 35-60 years. Metabolic syndrome was defined according to the International Diabetes Federation criteria. Prevalence ratios (PRs) were estimated using regression models. RESULTS: In general, the Dutch ethnic groups had a higher prevalence of MS than their English counterparts. Adjusted PRs were 1.37[95% confidence interval (CI)1.03-1.82] and 1.52 (1.06-2.19) in White-Dutch men and women compared to White-English men and women; 2.20 (1.14-4.26) and 1.46 (0.96-2.24) in Dutch African-Caribbean men and women compared to English-African-Caribbean men and women and 0.97 (0.74-1.27) and 1.42 (1.00-2.03) in Dutch-Indian men and women compared with their English-Indian peers, respectively. Similar patterns were also observed for some MS components, e.g. raised fasting glucose in men and central obesity in women. CONCLUSION: The comparatively high prevalence of MS among Dutch ethnic groups may contribute to their high prevalence of T2D. The high levels of some MS components, e.g. raised fasting glucose in men and central obesity in women add to the high prevalence of MS in Dutch ethnic groups. PMID- 22542550 TI - Progesterone receptor and SRC-1 participate in the regulation of VEGF, EGFR and Cyclin D1 expression in human astrocytoma cell lines. AB - Astrocytomas are the most common primary brain tumors in humans. It has been reported that vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), cyclin D1 and progesterone receptor (PR) expression levels are elevated in patients with high-grade astrocytomas. Progesterone (P) regulates astrocytomas growth through its interaction with PR, which recruits coregulatory proteins such as steroid receptor coactivator-1 (SRC-1) that are required for efficient transcriptional activation. The regulation of VEGF, EGFR and cyclin D1 expression by P in human astrocytoma cells is not known. We studied the role of PR and SRC-1 in the expression of VEGF, EGFR and cyclin D1 mediated by P in human astrocytoma cell lines grade III (U373) and IV (D54). P significantly increased VEGF and EGFR mRNA expression after 12h of treatment in D54 cells that was reflected at protein level 24h after treatment. This effect was blocked by the PR antagonist, RU 486. In U373 cells cyclin D1 mRNA and protein expression was induced by P after 6 and 8h of treatment, respectively, and this effect was blocked with RU 486. Transfection with short hairpin RNA targeting coactivator SRC-1 significantly reduced VEGF expression after 24h of treatment. Collectively, our results indicate that P regulates VEGF and EGFR expression in D54 cells and cyclin D1 expression in U373 through PR, and that SRC-1 participates in the regulation of VEGF expression. PMID- 22542551 TI - Association of brain-derived neurotrophic factor and tyrosine kinase B receptor in pregnancy. AB - Abnormal brain development in a compromised prenatal and/or early postnatal environment is thought to be a risk factor for several neurobehavioural disorders. However, the mechanisms underlying these are not well understood. We have earlier reported reduced placental docosahexaenoic acid (DHA) levels in preterm deliveries. We have hypothesized that increased oxidative stress and reduced DHA levels may lead to changes in the circulating levels of maternal and cord brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase B (TrkB) levels. A total number of 96 women delivering preterm and 95 women delivering at term were recruited. Plasma BDNF levels were measured in both mother and cord blood plasma using the BDNF Immuno Assay kit. Placental TrkB levels were analysed using sandwich enzyme-linked immunosorbent assay (ELISA). Maternal plasma BDNF levels and placental TrkB levels were higher (p<0.05) while cord plasma BDNF levels were lower (p<0.01) in women delivering preterm as compared to term. There was a negative association between levels of placental TrkB and DHA (p=0.034). A negative association between maternal plasma BDNF levels and placental weight (p=0.001) was observed while a positive association was seen between cord plasma BDNF levels and gestation (p=0.025). The reduction in cord BDNF levels may have implications for altered neurodevelopment in childhood and later life. Studies need to be undertaken to follow up children born preterm for risk of neurobehavioural disorders like attention deficit hyperactivity disorder (ADHD) to understand the effect of altered BDNF at birth on neurodevelopment. PMID- 22542553 TI - Antigenotoxic effect of acute, subacute and chronic treatments with Amazonian camu-camu (Myrciaria dubia) juice on mice blood cells. AB - Myrciaria dubia, a plant native to the Amazon region, stands out as a fruit rich in vitamin C and other metabolites with nutritional potential. We evaluated the antioxidant, genotoxic and antigenotoxic potential of M. dubia juice on blood cells of mice after acute, subacute and chronic treatments. Flavonoids and vitamin C present in the fruit of M. dubia were quantified. In vitro antioxidant activity was evaluated by DPPH assay. Blood samples were collected for analysis after treatment, and the alkaline comet assay was used to analyze the genotoxic and antigenotoxic activity (ex vivo analysis using H(2)O(2)). The amount of vitamin C per 100mL of M. dubia was 52.5mg. DPPH assay showed an antioxidant potential of the fruit. No M. dubia concentration tested exerted any genotoxic effect on mice blood cells. In the ex vivo test, the juice demonstrated antigenotoxic effect, and acute treatment produced the most significant results. After the treatments, there was no evidence of toxicity or death. In conclusion, our data show that M. dubia juice has antigenotoxic and antioxidant activities, though with no genotoxicity for blood cells. Nevertheless, more in-depth studies should be conducted to assess the safety of this fruit for human consumption. PMID- 22542552 TI - Piperine inhibits PMA-induced cyclooxygenase-2 expression through downregulating NF-kappaB, C/EBP and AP-1 signaling pathways in murine macrophages. AB - Piperine is a major component of black (Piper nigrum Linn) and long (Piper longum Linn) peppers, and is widely used as a traditional food and medicine. It also exhibits a variety of biological activities, which include antioxidant, anti tumor and anti-pyretic properties. In the present study, we investigated the inhibitory effects of piperine on phorbol 12-myristate 13-acetate (PMA)-induced cyclooxygenase-2 (COX-2) gene expression and analyzed the molecular mechanism of its activity in murine RAW 264.7 macrophages. Piperine dose-dependently decreased PMA-induced COX-2 expression and PGE(2) production, as well as COX-2 promoter driven luciferase activity. Transient transfections utilizing COX-2 promoter deletion constructs and COX-2 promoter constructs, in which specific enhancer elements were mutagenized, revealed that the nuclear factor-kappaB (NF-kappaB), CCAAT/enhancer binding protein (C/EBP) and activator protein-1 (AP-1), were the predominant contributors to the effects of piperine. In addition, piperine inhibited PMA-induced NF-kappaB, C/EBP and c-Jun nuclear translocation. Furthermore, piperine significantly inhibited PMA-induced activation of the Akt and ERK. These findings demonstrate that piperine effectively attenuates COX-2 production, and provide further insight into the signal transduction pathways involved in the anti-inflammatory effects of piperine. PMID- 22542554 TI - Protective effect of a novel antioxidative peptide purified from a marine Chlorella ellipsoidea protein against free radical-induced oxidative stress. AB - Protein derived the marine Chlorella ellipsoidea was hydrolyzed using different proteases (papain, trypsin, pepsin and alpha-chymotrypsin) for production of antioxidative peptide, and the antioxidant activities of their hydrolysates were investigated using free radical scavenging assay by electron spin resonance spin trapping technique. Among the hydrolysates, the peptic hydrolysate exhibited the highest antioxidant activity compared to other hydrolysates. To identify antioxidant peptide, the peptic hydrolysate was purified using consecutive chromatographic methods, and the antioxidant peptide was identified to be Leu-Asn Gly-Asp-Val-Trp (702.2 Da) by Q-TOF ESI mass spectroscopy. The antioxidant peptide scavenged peroxyl, DPPH and hydroxyl radicals at the IC(50) values of 0.02, 0.92 and 1.42 mM, respectively. The purified peptide enhanced cell viability against AAPH-induced cytotoxicity on normal cells. Furthermore, the purified peptide reduced the proportion of apoptotic and necrotic cells induced by AAPH, as demonstrated by decreased sub-G(1) hypodiploid cells and decreased apoptotic body formation by flow cytometry. PMID- 22542555 TI - MEHP-induced oxidative DNA damage and apoptosis in HepG2 cells correlates with p53-mediated mitochondria-dependent signaling pathway. AB - In the present study, the effects of MEHP on human hepatocellular liver carcinoma HepG2 cells were investigated. The results showed that MEHP-induced oxidative DNA damage in the treatment groups (>= 25.00 MUM) at 24h after treatment and in the 100.00 MUM treatment group at 36 h after treatment (p < 0.05 or p < 0.01). At 36 h after treatment, MEHP at higher concentrations (>= 25.00 MUM) resulted in a decrease in ATP level, and an increase in the protein levels of cytochrome c and Smac/DIABLO in the cytosol as well as the percentage of apoptotic cells. The activation of caspase-9 and -3 and the expression of the selected apoptosis related proteins, p53, PUMA, NOXA, Bax and Bcl-2 were also induced. Furthermore, vitamin C, a scavenger of reactive oxygen species, attenuated MEHP-induced apoptosis. These findings indicated that MEHP induced oxidative DNA damage and apoptosis in HepG2 cells, and p53 and its downstream proteins were involved in mitochondria- and caspase-mediated apoptosis induced by MEHP. PMID- 22542556 TI - Beneficial effects of gamma-aminobutyric acid on right ventricular pressure and pulmonary vascular remodeling in experimental pulmonary hypertension. AB - AIMS: It has been reported that activation of the sympathetic nervous system and increase in plasma norepinephrine (NE) levels are observed in patients with pulmonary hypertension (PH). gamma-Aminobutyric acid (GABA) is one of the major inhibitory neurotransmitters in the central nervous system and suppresses peripheral sympathetic neurotransmission. This study investigated whether chronic treatment with GABA prevents the development of monocrotaline (MCT)-induced PH. To elucidate the relationship between the development of PH and sympathetic nerve activity, hemodynamic parameters, cardiac functions, and plasma NE concentrations as well as cardiac endothelin-1 (ET-1) contents of MCT-induced PH rats were evaluated with or without GABA treatment. MAIN METHODS: Rats were injected with MCT (60 mg/kg) or saline subcutaneously and these rats were randomly divided into GABA (500 mg/kg/day for 4 weeks)- or vehicle-treated groups, respectively. KEY FINDING: MCT-treated rats had higher right ventricular systolic pressures, right ventricle-to-left ventricle plus septum weight ratios, pulmonary arterial medial thickening, and plasma NE levels than those of saline-injected rats. MCT-induced alternations were significantly attenuated by treatment with GABA. In MCT-induced PH rats with or without GABA treatment, plasma NE levels were positively correlated with right ventricular systolic pressure. Right ventricular endothelin 1 (ET-1) contents were increased by MCT injection, but these increments were not affected by treatment with GABA. SIGNIFICANCE: These results suggest that plasma NE levels play an important role in the development of MCT-induced PH in rats and that GABA exerts a preventive effect against MCT-induced PH by suppressing the sympathetic nervous system but not the cardiac ET-1 system. PMID- 22542562 TI - Radioiodinated dechloro-4-iodofenofibrate: a hydrophobic model drug for molecular imaging studies. AB - Radiolabeling is a valuable option for tracking drug molecules in biodistribution experiments. In the development of innovative drug delivery systems the influence of the pharmaceutical formulation on the drugs' pharmacokinetics has to be investigated. The hypolipidemic agent fenofibrate is an ideal model drug for testing the performance of drug delivery systems designed for poorly soluble compounds. Herein, we report a de novo synthesis of a fenofibrate derivative, dechloro-4-iodofenofibrate, as well as its conversion into its radioiodinated derivatives containing (125)I or (131)I. The enzymatic stability of the radiolabeled compounds synthesized was determined in vitro. A scintigraphic imaging study supplemented by biodistribution experiments and analysis of excreted metabolites revealed the stability required for in vivo applications and its similarity to fenofibrate. Therefore a convenient method is presented to synthesize radioiodinated derivatives of fenofibrate. These tracers show excellent in vitro and in vivo properties to study the behavior of lipophilic drugs. PMID- 22542563 TI - Memory aging and brain maintenance. AB - Episodic memory and working memory decline with advancing age. Nevertheless, large-scale population-based studies document well-preserved memory functioning in some older individuals. The influential 'reserve' notion holds that individual differences in brain characteristics or in the manner people process tasks allow some individuals to cope better than others with brain pathology and hence show preserved memory performance. Here, we discuss a complementary concept, that of brain maintenance (or relative lack of brain pathology), and argue that it constitutes the primary determinant of successful memory aging. We discuss evidence for brain maintenance at different levels: cellular, neurochemical, gray and white-matter integrity, and systems-level activation patterns. Various genetic and lifestyle factors support brain maintenance in aging and interventions may be designed to promote maintenance of brain structure and function in late life. PMID- 22542564 TI - Predicting prostate biopsy outcome: prostate health index (phi) and prostate cancer antigen 3 (PCA3) are useful biomarkers. AB - Indication for prostate biopsy is presently mainly based on prostate-specific antigen (PSA) serum levels and digital-rectal examination (DRE). In view of the unsatisfactory accuracy of these two diagnostic exams, research has focused on novel markers to improve pre-biopsy prostate cancer detection, such as phi and PCA3. The purpose of this prospective study was to assess the diagnostic accuracy of phi and PCA3 for prostate cancer using biopsy as gold standard. Phi index (Beckman coulter immunoassay), PCA3 score (Progensa PCA3 assay) and other established biomarkers (tPSA, fPSA and %fPSA) were assessed before a 18-core prostate biopsy in a group of 251 subjects at their first biopsy. Values of %p2PSA and phi were significantly higher in patients with PCa compared with PCa negative group (p<0.001) and also compared with high grade prostatic intraepithelial neoplasia (HGPIN) (p<0.001). PCA3 score values were significantly higher in PCa compared with PCa-negative subjects (p<0.001) and in HGPIN vs PCa negative patients (p<0.001). ROC curve analysis showed that %p2PSA, phi and PCA3 are predictive of malignancy. In conclusion, %p2PSA, phi and PCA3 may predict a diagnosis of PCa in men undergoing their first prostate biopsy. PCA3 score is more useful in discriminating between HGPIN and non-cancer. PMID- 22542566 TI - Screening for toxicity and resistance to paralytic shellfish toxin of shore crabs inhabiting at Leizhou peninsula, China. AB - The situation of the environment contaminated by paralytic shellfish toxin (PST) in Leizhou peninsula, China, has attracted more attention since seafood poisoning occurred occasionally. In this study, we examined the toxicities of shore crab Leptodius exaratus, Thalamita crenata and Metopograpsus latifrons by mouse assay, resistance to PST by lethal test injection with PST, and discussed the toxicity neutralization of their hemolymph. The results showed 12% of shore crabs possessed toxicity of 4.3-4.4 MU/g. The 100% lethal dose of PST for M. latifrons was about 2 times of those for the other two crab species. The hemolymphs of the crabs were all able to neutralize PST and tetrodotoxin (TTX) toxicity in different extent. The above results indicate shore crabs at this area are exposed to an environment potentially contaminated with PST and/or TTX, and the toxicity neutralizing efficacy of their hemolymph directly affects their resistance to the toxins. PMID- 22542565 TI - Multi-center analytical performance evaluation of the Access Hybritech(r) p2PSA immunoassay. AB - BACKGROUND: Total PSA assays measure both complexed and non-complexed forms of PSA while free PSA assays only measure non-complexed forms. Free PSA is a mixture of isoforms including immature PSA (proPSA) with retained portions of the leader sequence (e.g. [-7], [-4], and [-2]proPSA) and nicked forms (BPSA). ProPSA isoforms in male sera have been associated with prostate cancer. This study characterized the analytical performance of a chemiluminescent immunoassay for [ 2]proPSA. METHODS: The Access Hybritech p2PSA assay is a sandwich immunoassay using an anti-[-2]proPSA monoclonal antibody attached to paramagnetic beads and an anti-PSA monoclonal antibody conjugated to alkaline phosphatase calibrated with recombinant [-2]proPSA. Analytical studies including sensitivity (CLSI EP17 A) and imprecision (CLSI EP5-A2) were performed. RESULTS: The Access Hybritech p2PSA assay for [-2]proPSA had a dynamic range of 0.5 to 5000 pg/ml. The total CV of the assay was <7% for [-2]proPSA concentrations between 20 and 1000 pg/ml. The LOB was 0.50 pg/ml, LOD 0.69 pg/ml, and LOQ 3.23 pg/ml (20% CV). There was no hook effect up to 15,000 pg/ml. There was a <5% difference between calibrator and reagent lots and no interference from normal serum constituents. CONCLUSIONS: The Access Hybritech p2PSA assay is a robust immunoassay for the measurement of serum [-2]proPSA. PMID- 22542567 TI - Dynamic approaches of mixed species biofilm formation using modern technologies. AB - Bacteria and diatoms exist in sessile communities and develop as biofilm on all surfaces in aqueous environments. The interaction between these microorganisms in biofilm was investigated with a bacterial genus Pseudoalteromonas sp. (strain 3J6) and two benthic diatoms Amphora coffeaeformis and Cylindrotheca closterium. Each biofilm was grown for 22 days. Images from the confocal microscopy show a difference of adhesion between Pseudoalteromonas 3J6 and diatoms. Indeed, a stronger adhesion is found with C. closterium suggesting cohabitation between Pseudoalteromonas 3J6 and C. closterium compared at an adaptation for bacteria and A. coffeaeformis. The cellular attachment and the growth evolution in biofilm formation depend on each species of diatoms in the biofilm. Behaviour of microalgae in presence of bacteria demonstrates the complexity of the marine biofilm. PMID- 22542568 TI - Long-term high-fat diet links the regulation of the insulin-sensitizing fibroblast growth factor-21 and visfatin. AB - High-fat diet (HFD) is associated with insulin resistance, hyperinsulinemia, elevated plasma free fatty acid (FFA), and increased risk for atherosclerotic vascular disease. However, the mechanisms underlying the HFD-induced insulin resistance have not been fully clarified. The aim of present study is to evaluate the effects of long-term HFD on the regulation of the insulin-sensitizing fibroblast growth factor-21 (FGF-21) and visfatin in ApoE(-/-) mice. A total of twenty male ApoE(-/-) mice were randomly divided into normal chow diet (NC) or HFD (HF) group for 16 weeks. Euglycemic-hyperinsulinemic clamp was performed to evaluate insulin sensitivity in this animal model. Both mRNA and protein contents of FGF-21 and visfatin were assayed by Quantitative real-time PCR and Western blot. Long-term HFD resulted in the marked abnormality of glucose and lipid metabolism as well as a large decrease in whole-body insulin sensitivity. Accompanied by abnormal glucose-lipid metabolism and aggravated insulin resistance, FGF-21, beta-klotho, FGFR1, FGFR3 and FGFR4 mRNA expressions were markedly up-regulated, whereas visfatin mRNA expression was markedly down regulated in liver and/or adipose tissue of HFD-fed mice. In addition, Western blotting also revealed both up-regulation of the FGF-21 protein and down regulation of visfatin protein in liver, adipose tissue and plasma of HFD-fed mice. Both FGF-21 and visfatin expression and secretion are regulated by a potent regulator, long-term HFD. And these adipokines are associated with glucose-lipid metabolism and insulin resistance. PMID- 22542569 TI - Risk factors for hyperammonemia associated with valproic acid therapy in adult epilepsy patients. AB - Hyperammonemia is one of the side effects of treatment with valproic acid (VPA), but the risk factors and mechanisms involved remain obscure. This study analyzed the risk factors for hyperammonemia associated with VPA therapy in adult epilepsy patients. A retrospective analysis of 2724 Japanese patients (1217 males and 1507 females aged from 16 to 76years) treated with VPA between January 2006 and December 2010 were analyzed. The ammonia level increased markedly in a VPA dose dependent manner, and was significantly elevated in patients who also used hepatic enzyme inducers such as phenytoin (PHT), phenobarbital (PB), carbamazepine (CBZ), and combinations of these drugs. When a blood ammonia level exceeding 200MUg/dl was defined as hyperammonemia, the risk factors for hyperammonemia according to multiple regression analysis were a VPA dose >20mg/kg/day (odds ratio (OR): 4.1; 95% confidence interval (CI): 1.6-10.8) and concomitant use of PHT (OR: 11.0; 95% CI: 3.1-38.7), concomitant PB (OR: 4.3; 95% CI: 1.0-17.9), concomitant CBZ (OR: 2.8; 95% CI: 0.6-11.9), and concomitant topiramate (OR: 2.8; 95% CI: 1.2-6.5). Regimens containing multiple inducers were associated with an increased risk of hyperammonemia. Identification of risk factors for hyperammonemia associated with VPA therapy can help to minimize side effects during its clinical use. PMID- 22542570 TI - Resting motor threshold in idiopathic generalized epilepsies: a systematic review with meta-analysis. AB - Resting motor threshold (rMT) assessed by means of Transcranial Magnetic Stimulation (TMS) is thought to reflect trans-synaptic excitability of cortico spinal neurons. TMS studies reporting rMT in idiopathic generalized epilepsies (IGEs) yielded discrepant results, so that it is difficult to draw a definitive conclusion on cortico-spinal excitability in IGEs by simple summation of previous results regarding this measure. Our purpose was to carry out a systematic review and a meta-analysis of studies evaluating rMT values obtained during single-pulse TMS in patients with IGEs. Controlled studies measuring rMT by single-pulse TMS in drug-naive patients older than 12 years affected by IGEs were systematically reviewed. rMT values were assessed calculating mean difference and odds ratio with 95% confidence intervals (CI). Fourteen trials (265 epileptic patients and 424 controls) were included. Patients with juvenile myoclonic epilepsy (JME) have a statistically significant lower rMT compared with controls (mean difference: 6.78; 95% CI -10.55 to -3.00); when considering all subtypes of IGEs and IGEs other than JME no statistically significant differences were found. Overall considered, the results are indicative of a cortico-spinal hyper-excitability in JME, providing not enough evidence for motor hyper-excitability in other subtypes of IGE. The considerable variability across studies probably reflects the presence of relevant clinical and methodological heterogeneity, and higher temporal variability among rMT measurements over time, related to unstable cortical excitability in these patients. PMID- 22542571 TI - Social isolation stress down-regulates cortical early growth response 1 (Egr-1) expression in mice. AB - Social isolation stress induces behavioral disturbances such as aggression, cognitive impairments, and deficits in prepulse inhibition in mice. Social isolation mice have, therefore, been studied as an animal model of neuropsychiatric disorders such as schizophrenia. Recently, the decrease in early growth response (Egr) gene expression levels were reported in the post-mortem brains of schizophrenia patients. In this study, we investigate the effects of social isolation stress on the expression levels of Egr mRNA and protein in the frontal cortex. Social isolation stress exposure significantly down-regulated the expression of Egr-1 protein and Egr-1 gene transcript in nucleus of cortical neurons in a manner dependent on a social isolation period. This stress had no effect on the expression level of Egr-1 in the striatum or the expression levels of other Egr family members (Egr-2, -3, and -4) in the frontal cortex. These results suggest that the decrease in Egr-1 expression in the frontal cortex may be involved in social isolation stress-induced behavioral abnormalities. PMID- 22542572 TI - On the definition, nomenclature and classification of water channel proteins (aquaporins and relatives). AB - A water channel protein (WCP) or a water channel can be defined as a transmembrane protein that has a specific three-dimensional structure with a pore that provides a pathway for water permeation across biological membranes. The pore is formed by two highly conserved regions in the amino acid sequence, called NPA boxes (or motifs) with three amino acid residues (asparagine-proline-alanine, NPA) and several surrounding amino acids. The NPA boxes have been called the "signature" sequence of WCPs. WCPs are a family of proteins belonging to the Membrane Intrinsic Proteins (MIPs) superfamily. In addition, in the MIP superfamily (with more than 1000 members) there are also proteins with no channel activity. The WCP family include three subfamilies: aquaporins, aquaglyceroporins and S-aquaporins. (1) The aquaporins (AQPs) are water selective or specific water channels, also named by various authors as "orthodox", "ordinary", "conventional", "classical", "pure", "normal", or "sensu strictu" aquaporins); (2) The aquaglyceroporins are permeable to water, but also to other small uncharged molecules, in particular glycerol; this family includes the glycerol facilitators, abbreviated as GlpFs, from glycerol permease facilitators. The "signature" sequence for aquaglyceroporins is the aspartic acid residue (D) in the second NPA box. (3) The third subfamily of WCPs have little conserved amino acid sequences around the NPA boxes, unclassifiable to the first two subfamilies. I recommend to use always for this subfamily the name S-aquaporins. They are also named "superaquaporins", "aquaporins with unusual (or deviated) NPA boxes", "subcellular aquaporins", or "sip-like aquaporins". I also recommend to use always the spelling aquaporin (not aquaporine), and, for various AQPs, the abbreviation AQP followed immediately by the number, (e.g. AQP1), with no space or--which might create confusions with "minus". PMID- 22542573 TI - WITHDRAWN: Complement dysregulation in AMD: RPE-Bruch's membrane-choroid. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1016/j.mam.2012.03.011. The duplicate article has therefore been withdrawn. PMID- 22542574 TI - Protein-oxidized phospholipid interactions in cellular signaling for cell death: from biophysics to clinical correlations. AB - Oxidative stress is associated with several major ailments. However, it is only recently that the developments in our molecular level understanding of the consequences of oxidative stress in modifying the chemical structures of biomolecules, lipids in particular, are beginning to open new emerging insights into the significance of oxidative stress in providing mechanistic insights into the etiologies of these diseases. In this brief review we will first discuss the role of lipid oxidation in controlling the membrane binding of cytochrome c, a key protein in the control of apoptosis. We then present an overview of the impact of oxidized phospholipids on the biophysical properties of lipid bilayers and continue to discuss, how these altered properties can account for the observed enhancement of formation of intermediate state oligomers by cytotoxic amyloid forming peptides associated with pathological conditions as well as host defense peptides of innate immunity. In the third part, we will discuss how the targeting of oxidized phospholipids by i) pathology associated peptides and ii) host defense peptides can readily explain the observed clinical correlations associating Alzheimer's and Parkinson's diseases with increased risk for type 2 diabetes and age-related macular degeneration, and the apparent protective effect of Alzheimer's and Parkinson's diseases from some cancers, as well as the inverse, apparent protection by cancer from Alzheimer's and Parkinson's diseases. This article is part of a Special Issue entitled: Oxidized phospholipids-Their properties and interactions with proteins. PMID- 22542575 TI - Efficient activation of thioglycosides with N-(p-methylphenylthio)-epsilon caprolactam-TMSOTf. AB - N-(p-Methylphenylthio)-epsilon-caprolactam (1) in combination with trimethylsilyl trifluoromethanesulfonate (TMSOTf) provides an efficient thiophilic promoter system, capable of activating different thioglycosides. Both 'armed' and 'disarmed' thioglycosyl donors were activated for glycosidic bond formation. Notably, this reagent combination works well in reactivity-based one-pot oligosaccharide assembly strategy. PMID- 22542576 TI - Synthesis and characterization of a paramagnetic sialic acid conjugate as probe for magnetic resonance applications. AB - Magnetic Resonance Imaging (MRI) using paramagnetic systems as contrast agents is receiving increased attention as diagnostic tool in the clinic. At the same time, NMR of paramagnetic systems can also be applied in biochemical fields; for example, the use of Paramagnetic Relaxation Enhancement (PRE) allows structure refinement and the analysis of transient dynamic processes involved in macromolecular complex formation. Herein we report the synthesis and computational characterization of a new DOTA-like sialic acid conjugate, which can be used both in MRI and PRE applications when coordinated to a suitable paramagnetic metal. PMID- 22542577 TI - How can we reduce hepatic veno-occlusive disease-related deaths after allogeneic stem cell transplantation? AB - Hepatic veno-occlusive disease (VOD) is a common and potentially devastating complication of hematopoietic stem cell transplantation. Confirmative diagnosis of this disorder can prove difficult early post hematopoietic stem cell transplantation, as a broad differential diagnosis exists and no definitive diagnostic test is available. Incidence of VOD has decreased in recent years, with especially dramatic declines in severe and fatal VOD. This improvement is attributed to less toxic and reduced-intensity conditioning regimens, and more appropriate patient selection. When severe VOD does occur, current treatments have been largely ineffective. Prevention remains the primary tool in the clinician's arsenal for managing VOD. Our institution pursues aggressive preventative measures for VOD, including appropriate conditioning regimen selection, avoiding hepatotoxic drugs, early prophylactic use of ursodiol, and aggressive fluid management. With appropriate management steps, we believe the incidence of VOD and related deaths can be further decreased. PMID- 22542578 TI - Low expression of asparagine synthetase in lymphoid blasts precludes its role in sensitivity to L-asparaginase. AB - Childhood acute lymphoblastic leukemia (ALL) is treated with combined chemotherapy, including L-asparaginase (L-asp). Recent studies question the traditional view that the level of asparagine synthetase (ASNS), an enzyme producing the intracellular asparagine, correlates with the response to L-asp treatment. However, the importance of ASNS in response to L-asp has neither been confirmed nor refuted so far. In this study, we wanted to elucidate the effect of ASNS expression level on the sensitivity of ALL cells to L-asp treatment. We used four ALL cell lines (NALM-6, RS4;11, REH, and UOCB6) and 30 diagnostic bone marrow samples of ALL patients to study the relationship between ASNS expression and sensitivity to L-asp using MTS proliferation assay. RNA interference was used to study the effect of a range of ASNS levels on the response to L-asp treatment. Using a cell line model with a gradually knocked-down ASNS gene, we defined a cutoff level below which ASNS gene expression does not correlate with sensitivity to L-asp. Importantly, ASNS gene expression in patients' ALL blasts is below this level. We confirmed that there was no correlation between ASNS gene expression and sensitivity to L-asp in ALL blasts. In addition, we show that cells with low ASNS expression level do not respond to asparagine deprivation by upregulation of ASNS gene expression. In conclusion, the ASNS expression level does not predict sensitivity to L-asp in leukemic blasts. Moreover, cell lines with high basal expression of ASNS cannot serve as a valid model for studies on the relationship between the ASNS and L-asp cytotoxic effect. PMID- 22542579 TI - Laparoscopic para-aortic lymphadenectomy in endometrial cancer patient with left sided inferior vena cava. PMID- 22542580 TI - FDG PET/CT in staging of advanced epithelial ovarian cancer: frequency of supradiaphragmatic lymph node metastasis challenges the traditional pattern of disease spread. AB - OBJECTIVE: Epithelial ovarian cancer (EOC) spreads intra-abdominally and to the retroperitoneal lymph nodes. A greater number of distant metastases are revealed by (18)F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) compared to conventional imaging methods. We aimed to investigate the presence and anatomic distribution of supradiaphragmatic lymph node metastasis (LNM) detected with pretreatment FDG PET/CT. METHODS: Thirty women with advanced stage (IIC-IV) EOC were scanned with whole body contrast enhanced FDG PET/CT prior to surgery/neoadjuvant chemotherapy. We performed PET/CT analysis qualitatively and quantitatively. Additionally, contrast-enhanced CT was analyzed blinded to PET/CT scan. Intra-abdominal dissemination was verified by surgery and histopathology. Metabolically active lymph nodes were biopsied when possible. The clinical characteristics of patients with and without supradiaphragmatic LNM were compared. RESULTS: In 20/30 patients (67%) FDG PET/CT detected supradiaphragmatic LNM in one or more locations, whereas conventional CT found LNM in 10 patients (33%). Fourteen patients had parasternal, 14 cardiophrenic, 8 other mediastinal, 6 axillar, and 1 subclavian LNM. Microscopy of all four biopsied lymph nodes (three axillar and one subclavian) confirmed metastatic dissemination. The patients with supradiaphragmatic LNM had significantly more ascites (p<0.01), higher CA 125 levels, and more frequent subdiaphragmal carcinomatosis (p<0.03) compared to patients without supradiaphragmatic LNM in preoperative FDG PET/CT. CONCLUSIONS: A significant number of patients with advanced EOC showed supradiaphragmatic LNM in pre treatment PET/CT. Our findings suggest that the route of EOC cells from the peritoneal cavity to the lymphatic system permeates the diaphragm mainly to the cardiophrenic and continues to parasternal lymph nodes. PMID- 22542581 TI - Enhancing follicular growth as a prerequisite for GnRH treatment of true anestrum in buffalo. AB - A total of 140 true anestrous buffalo were divided on the basis of receiving short-term (20 days) nutritional supplementation (N, n=80) or not (WN, n=60). The animals in N group were subdivided into NQ (n=40) where the quantity of the offered diet was increased by 20% and NF (n=40) where the offered diet was supplemented by 3% of dry protected fat. Buffaloes in either NQ or NF were equally allotted on the following treatment regimens: Insulin/GnRH (NQi or NFi, n=10 for each); rbST/GnRH (NQr or NFr, n=10 for each); GnRH alone treated (NQG or NFG, n=10 for each) and saline-treated control (NQc or NFc, n=10 for each). Insulin-treated subgroups (NQi or NFi) received s/c injection of insulin at a dose of 0.25 I.U./kg on Days 21, 22 and 23 while rbST-treated subgroups (NQr or NFr) received single IM injection of rbST (500 mg Sometribove) on Day 21. GnRH was injected at a dose of 0.020 mg buserelin (5 ml Receptal((r))) on Day 24 in all subgroups except NQCand NFC where Day 1 was the first day of the short-term nutritional improvement. Buffalo in the WN (n=60) were equally allotted on the same treatment regimens applied in the first group insulin/GnRH (WNi, n=15), rbST/GnRH (WNr, n=15); GnRH alone treated (WNG, n=15) and saline-treated control (WNC, n=15). Ultrasonic scanning of ovaries was conducted on Day 24 to measure largest follicle diameter (LFD). The results showed increases (P<0.05) in the LFD following nutritional supplementation with insulin or rbST. The recorded EIRs for GnRH pre-treated with nutritional improvement - metabolic hormones combinations (9/10 and 8/10 for NQi and NFi or 8/10 for NQr) were greater (P<0.05) than those pre-treated with either metabolic hormone alone (7/15 for WNi and/or WNr) or nutritional improvement alone (6/10 for NQG and/or NFG) and control as well. The greatest CR was recorded in the NQi group. It could be concluded that pre-GnRH nutritional improvement plus administration of insulin or rbST increases LFD in true anestrous buffalo having LFD<8.5 mm thereby increasing their fertility response to GnRH in terms of EIRs and CRs. PMID- 22542582 TI - Positivity rates and performances of immunochemical faecal occult blood tests at different cut-off levels within a colorectal cancer screening programme. AB - BACKGROUND: Immunochemical faecal occult blood tests have greater sensitivity for colorectal cancer screening than guaiac-based tests; however the number of positive tests required is still under discussion. METHODS: A direct comparison of Hemoccult II with two immunochemical quantitative tests (OC-Sensor and FOB Gold) using a 2-sample strategy was performed in over 30,000 patients undergoing colorectal cancer screening in France. RESULTS: Positivity ratio between immunochemical tests and Hemoccult II varied between 2.2 (OC-Sensor) and 2.4 (FOB Gold) for the lowest cut-off value and 1.5-1.4 for the highest cut-off value. The positive predictive value for colorectal cancer was similar for immunochemical tests and Hemoccult II, and significantly higher for immunochemical tests for advanced adenomas. The detection rate of both colorectal cancer and advanced adenomas was higher with immunochemical tests than with Hemoccult II. With the 2 sample strategy and the lowest cut-off value the detection rate of colorectal cancer almost doubled and for advanced adenomas quadrupled. CONCLUSION: For colorectal cancer screening with immunochemical faecal occult blood tests, an acceptable strategy would be 2-day sampling with at least one positive test at a cut-off between 150 and 200 ng/mL (OC-Sensor) and 176 and 234 ng/mL (FOB-Gold). Data on the ease of test interpretation and cost-effectiveness now necessary to make definitive choices. PMID- 22542583 TI - Paeonol from Hippocampus kuda Bleeler suppressed the neuro-inflammatory responses in vitro via NF-kappaB and MAPK signaling pathways. AB - Inflammation has recently been implicated as a critical mechanism responsible for neurodegenerative diseases. In this study, paeonol (1-(2-hydroxy-4 methoxyphenyl)ethanone) isolated from the sea horse Hippocampus kuda Bleeler was studied as an agent to suppress LPS induced activation of BV-2 microglial and RAW264.7 macrophage cells. The results obtained showed that paeonol significantly suppressed LPS induced release of pro-inflammatory products such as nitric oxide (NO), prostaglandin E2 (PGE(2)), and cytokines; tumor necrosis factor-alpha (TNF alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6). Furthermore, the compound down regulated the protein and gene expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-alpha, IL-1beta and IL-6 in both cell lines. Molecular signaling pathway studies showed that paeonol inhibited the translocation of nuclear factor-kappaB (NF-kappaB) p65 and p50 subunits to the nucleus by blocking IKKalpha/beta (IkappaB kinase alpha/beta) mediated degradation of IkappaBalpha. Moreover, it suppressed the phosphorylation of mitogen activated protein kinase (MAPK) pathway molecules; c-Jun N-terminal kinases (JNK) and p38 in both cell lines. Collectively these results indicate that paeonol blocked the LPS stimulated inflammatory responses in BV-2 and RAW264.7 cells via modulating MAPK and NF-kappaB signaling pathways. Therefore, paeonol could be a promising candidate to be used in neuro-inflammatory therapy. PMID- 22542584 TI - Optimisation of culture conditions for differentiation of C17.2 neural stem cells to be used for in vitro toxicity tests. AB - Here we present a multipotent neuronal progenitor cell line for toxicity testing as an alternative to primary cultures of mixed cell types from brain tissue. The v-myc immortalised C17.2 cell line, originally cloned from mouse cerebellar neural stem cells, were maintained as monolayer in cell culture dishes in DMEM supplemented with fetal calf serum, horse serum and antibiotics. Different media and exposure scenarios were used to induce differentiation. The optimal condition which generated mixed cultures of neurons and astrocytes included serum-free DMEM:F12 medium with N2 supplements, brain-derived neurotrophic factor and nerve growth factor. The medium was changed every 3rd or 4th day to fresh N2 medium with supplements. After 7 days, the culture contained two different morphological cell types, assumed to be neurons and glia cells. The presence of astrocytes and neurons in the culture was confirmed by RT-PCR and Western blot analyses, indicating increased mRNA and protein levels of the specific biomarkers glial fibrillary acidic protein (GFAP) and betaIII-tubulin, respectively. Concomitantly, the expression of the neural progenitor cell marker nestin was down-regulated. PMID- 22542585 TI - In vitro skin corrosion: Human skin model test - A validation study. AB - The present article is an attempt to validate the in vitro skin corrosion human skin model test as per the OECD test guidelines 431 as an alternative method for in vivo skin corrosion/irritation test. All over India, in vivo skin corrosion/irritation test is commonly used, rather than in vitro skin corrosion models. Hence, the present study was under taken with EpiSkinTM, SNC, Lyon, France to validate this in vitro model. Various corrosive and non corrosive chemicals with their known skin corrosive property were used to validate the study as specified under the guideline (OECD 431). The results obtained in this study were in accordance with the corrosive properties of the respective chemicals. PMID- 22542586 TI - Structure-activity characterization of sulfide:quinone oxidoreductase variants. AB - Sulfide:quinone oxidoreductase (SQR) is a peripheral membrane protein that catalyzes the oxidation of sulfide species to elemental sulfur. The enzymatic reaction proceeds in two steps. The electrons from sulfides are transferred first to the enzyme cofactor, FAD, which, in turn, passes them onto the quinone pool in the membrane. Several wild-type SQR structures have been reported recently. However, the enzymatic mechanism of SQR has not been fully delineated. In order to understand the role of the catalytically essential residues in the enzymatic mechanism of SQR we produced a number of variants of the conserved residues in the catalytic site including the cysteine triad of SQR from the acidophilic, chemolithotrophic bacterium Acidithiobacillus ferrooxidans. These were structurally characterized and their activities for each reaction step were determined. In addition, the crystal structures of the wild-type SQR with sodium selenide and gold(I) cyanide have been determined. Previously we proposed a mechanism for the reduction of sulfides to elemental sulfur involving nucleophilic attack of Cys356 on C(4A) atom of FAD. Here we also consider an alternative anionic radical mechanism by direct electron transfer from Cys356 to the isoalloxazine ring of FAD. PMID- 22542587 TI - Yeast-based production and purification of HIS-tagged human ATAD3A, A specific target of S100B. AB - ATAD3 is a mitochondrial integral inner membrane ATPase with unknown function. ATAD3 is absent in yeast and protozoan and present in all pluricellular eucaryotes where its expression is essential for development. To date, bacterial based expression of full-length ATAD3 has been unsuccessful because of very high levels of endogenous degradation. Based on Saccharomyces cerevisiae as a heterogeneous expression system, we engineered a high copy strain expressing human ATAD3A-Myc-HIS at a relative high level (2.5mg/l of yeast culture) without significantly affecting yeast growth. Most of the expressed human ATAD3A-Myc-HIS co-purified with the yeast mitochondrial fraction thus suggesting that targeting to this organelle is preserved in yeast. Like the endogenous protein in human cells, ATAD3A-Myc-HIS expressed in yeast is found resistant to extraction with salt and certain detergents, suggesting membrane insertion. Sarkosyl, C13-DAO, C12-DAO and ONMG efficiently solubilized ATAD3A-Myc-HIS from yeast extracts, but these soluble species did not bind to agarose-nickel matrix. By contrast, urea denaturated ATAD3A-Myc-HIS bound to agarose-nickel beads and could be renatured and eluted to obtain highly pure ATAD3A-Myc-HIS. As the native protein in vivo, this recombinant, renatured species specifically bound in vitro to S100B and S100A1 in Far-Western assays. PMID- 22542588 TI - Optimization and efficient purification of recombinant Omp28 protein of Brucella melitensis using Triton X-100 and beta-mercaptoethanol. AB - The high level expression of recombinant proteins in Escherichia coli often leads to the formation of inclusion bodies that contain most of the expressed protein held together by non-covalent forces. The inclusion bodies are usually solubilized using strong denaturing agents like urea and guanidium hydrochloride. In this study recombinant Omp28 (rOmp28) protein of Brucella melitensis was expressed in two different vector systems and further efficient purification of the protein was done by modification in buffers to improve the yield and purity. Different concentrations of Triton X-100 and beta-mercaptoethanol were optimized for the solubilization of inclusion bodies. The lysis buffer with 8M urea alone was not sufficient to solubilize the inclusion bodies. It was found that the use of 1% Triton X-100 and 20mM beta-mercaptoethanol in lysis and wash buffers used at different purification steps under denaturing conditions increased the yield of purified rOmp28 protein. The final yield of purified protein obtained with modified purification protocol under denaturing conditions was 151 and 90mg/l of the culture or 11.8 and 9.37mg/g of wet weight of cells in pQE30UA and pET28a(+) vector respectively. Thus modified purification protocol yielded more than threefold increase of protein in pQE30UA as compared with purification by conventional methods. PMID- 22542589 TI - Co-expression of protein phosphatases in insect cells affects phosphorylation status and expression levels of proteins. AB - The activity of kinases is regulated by phosphorylation on Ser, Thr or Tyr residues within the activation loop. The ability to produce these enzymes recombinantly with a specific phosphorylation status is essential in order to understand structure and function. In this paper we describe a screening approach to co-express different phosphatases together with a kinase in the baculovirus expression system. This enabled the testing of different phosphatases as well as different levels of both phosphatase and kinase by varying the multiplicity of infection (MOI) of the different baculoviruses. This approach translated well to a larger scale. An unexpected observation was that co-expression of the phosphatase could have profound effects on expression levels even of heterologous target proteins that would not be a substrate for the phosphatase. This was most apparent with lambda phosphatase, an enzyme that removes phosphorylation from Ser and Thr residues, where expression was almost completely abolished for all proteins, even at modest MOIs. The effect of lambda phosphatase was observed irrespective of whether co-expression was from two separate baculoviruses or from two genes on the same vector. The effect was shown to be due, in part at least, to a decrease in transcription. PMID- 22542590 TI - Influence of pH on the speciation of copper(II) in reactions with the green tea polyphenols, epigallocatechin gallate and gallic acid. AB - Changes in speciation of copper(II) in reactions with epigallocatechin gallate (EGCG) and gallic acid (GA) as a function of pH have been investigated by multifrequency (X- and S-band) EPR spectroscopy in the fluid and frozen states. The EPR spectra show the formation of three distinct mononuclear species with each of the polyphenols, and these are interpreted in terms of one mono- and two bis-complexes. However, di- or polymeric complexes dominate the Cu(II) speciation in the pH range 4-8, and it is only at alkaline pH values that these mononuclear complexes make appreciable contributions to the metal speciation. Each mononuclear complex displays linewidth anisotropy in fluid solution as a consequence of incomplete averaging of the spin Hamiltonian parameters through molecular motion. Rotational correlation times for the individual complexes have been estimated by analysing the lineshape anisotropy of the fluid solution spectra using parameters determined by simulation of the rigid limit spectra. These show that the molecular masses increase with increasing pH, indicating either coordination of increasing numbers of polyphenol molecules as ligands to the copper or the increasing involvement of polyphenol dimers as ligands in the copper coordination sphere. PMID- 22542591 TI - In vitro anti-leishmania evaluation of nickel complexes with a triazolopyrimidine derivative against Leishmania infantum and Leishmania braziliensis. AB - Studies on the anti-proliferative activity in vitro of seven ternary nickel (II) complexes with a triazolopyrimidine derivative and different aliphatic or aromatic amines as auxiliary ligands against promastigote and amastigote forms of Leishmania infantum and Leishmania braziliensis have been carried out. These compounds are not toxic for the host cells and two of them are effective at lower concentrations than the reference drug used in the present study (Glucantime). In general, the in vitro growth rate of Leishmania spp. was reduced, its capacity to infect cells was negatively affected and the multiplication of the amastigotes decreased. Ultrastructural analysis and metabolism excretion studies were executed in order to propose a possible mechanism for the action of the assayed compounds. Our results show that the potential mechanism is at the level of organelles membranes, either by direct action on the microtubules or by their disorganization, leading to vacuolization, degradation and ultimately cell death. PMID- 22542592 TI - Mixed metal copper(II)-nickel(II) and copper(II)-zinc(II) complexes of multihistidine peptide fragments of human prion protein. AB - Mixed metal copper(II)-nickel(II) and copper(II)-zinc(II) complexes of four peptide fragments of human prion protein have been studied by potentiometric, UV vis and circular dichroism spectroscopic techniques. One peptide contained three histidyl residues: HuPrP(84-114) with H85 inside and H96, H111 outside the octarepeat domain. The other three peptides contained two histidyl residues; H96 and H111 for HuPrP(91-115) and HuPrP(84-114)H85A while HuPrP(84-114)H96A contained the histidyl residues at positions 85 and 111. It was found that both histidines of the latter peptides can simultaneously bind copper(II) and nickel(II) ions and dinuclear mixed metal complexes can exist in slightly alkaline solution. One molecule of the peptide with three histidyl residues can bind two copper(II) and one nickel(II) ions. H85 and H111 were identified as the major copper(II) and H96 as the preferred nickel(II) binding sites in mixed metal species. The studies on the zinc(II)-PrP peptide binary systems revealed that zinc(II) ions can coordinate to the 31-mer PrP peptide fragments in the form of macrochelates with two or three coordinated imidazol-nitrogens but the low stability of these complexes cannot prevent the hydrolysis of the metal ion in slightly alkaline solution. These data provide further support for the outstanding affinity of copper(II) ions towards the peptide fragments of prion protein but the binding of nickel(II) can significantly modify the distribution of copper(II) among the available metal binding sites. PMID- 22542593 TI - The use of a ditopic Gd(III) paramagnetic probe for investigating alpha bungarotoxin surface accessibility. AB - Protein surface accessibility is a critical parameter which drives all intermolecular interaction processes. In this respect a big deal of information has been derived by analyzing paramagnetic perturbation profiles obtained from NMR protein spectra, particularly in the case that the effects due to different soluble paramagnets can be compared. Here Gd(2)L7, a neutral ditopic paramagnetic NMR probe, has been characterized in terms of structure and relaxivity and its paramagnetic perturbations on alpha-bungarotoxin CalphaH signals in ((1))H ((13))C HSQC (heteronuclear single quantum coherence) spectra have been analyzed. Then, these signal attenuations have been compared with the ones previously obtained in the presence of GdDTPA-BMA (gadolinium(III) diethylenetriamine N,N,N',N'",N"-pentaacetate-bis(methylamide)). In spite of the different molecular size and shape, for the two probes a common pathway of approach to the alpha bungarotoxin surface can be observed with an equally enhanced access of both GdDTPA-BMA and Gd(2)L7 toward the protein surface side where residues involved in the receptor binding are located. The different residence times of the water molecule directly coordinated by the Gd(III) ion measured for the two paramagnets account for the reduced broadening of water signal in the presence of the ditopic probe at equivalent gadolinium concentration. These features make Gd(2)L7 a very suitable probe for investigating protein surface accessibility of complex protein systems. PMID- 22542594 TI - Cadmium coordination to the zinc binding domains of the non-classical zinc finger protein Tristetraprolin affects RNA binding selectivity. AB - Tristetraprolin [(TTP), also known as NUP475 and TIS11] is a non-classical zinc finger protein that regulates inflammatory response via a protein-RNA interaction. Specifically, TTP recognizes AU-rich RNA sequences located on the 3' untranslated region of messenger RNA associated with cytokines. Recently, TTP was shown to be upregulated when cells were exposed to cadmium. Other types of zinc finger proteins have been shown to bind Cd(II), thus the Cd(II) binding properties of TTP were pursued. Metal binding titrations using Co(II) as a spectroscopic probe for Cd(II) were performed. Cd(II) was found to coordinate to the two Cys(3)His structural zinc sites of TTP (TTP-2D) with an upper-limit dissociation constant, K(d), of 3.5+/-0.1 nM. Upon reconstitution of TTP-2D with Cd(II), the protein recognized target RNA, UUUAUUUAUUU, with a dissociation constant, K(d), of 2.4+/-0.2 nM. The Cd(II)TTP-2D/RNA binding event was more sensitive to base mutations than the Zn(II)TTP-2D/RNA binding event. A single base mutation within the UUUAUUUAUUU oligomer decreased the Cd(II)TTP-2D binding affinity 50-fold and a double mutation decreased the affinity 1000-2000 fold. In comparison, only 2-fold and 15-25 fold changes for Zn(II)TTP-2D binding to the identical RNA sequences are measured. PMID- 22542595 TI - The environmental stressor ultraviolet B radiation inhibits murine antitumor immunity through its ability to generate platelet-activating factor agonists. AB - Ubiquitous pro-oxidative stressor ultraviolet B radiation (UVB) to human or mouse skin generates platelet-activating factor (PAF) and novel oxidatively modified glycerophosphocholines (Ox-GPCs) with PAF-receptor (PAF-R) agonistic activity. These lipids mediate systemic immunosuppression in a process involving IL-10. The current studies sought to determine the functional significance of UVB-mediated systemic immunosuppression in an established model of murine melanoma. We show that UVB irradiation augments B16F10 tumor growth and is dependent on host, but not melanoma cell; PAF-R-expression as UVB or the PAF-R agonist, carbamoyl PAF (CPAF), both promote B16F10 tumor growth in wild-type (WT) mice, independent of whether B16F10 cells express PAF-Rs, but do not augment tumor growth in Pafr -/- mice. UVB-mediated augmentation of experimental murine tumor growth was inhibited with antioxidants, demonstrating the importance of Ox-GPC PAF-R agonists produced non-enzymatically. Host immune cells are required as CPAF-induced augmentation of tumor growth which is not seen in immunodeficient NOD SCID mice. Finally, depleting antibodies against IL-10 in WT mice or depletion of CD25-positive cells in FoxP3(EGFP) transgenic mice block UVB and/or CPAF-induced tumor growth supporting a requirement for IL-10 and Tregs in this process. These findings indicate that UVB-generated Ox-GPCs with PAF-R agonistic activity enhance experimental murine melanoma tumor growth through targeting host immune cells, most notably Tregs, to mediate systemic immunosuppression. PMID- 22542596 TI - Directional transport and active retention of Dpp/BMP create wing vein patterns in Drosophila. AB - The bone morphogenetic protein (BMP) family ligand decapentaplegic (Dpp) plays critical roles in wing vein development during pupal stages in Drosophila. However, how the diffusible Dpp specifies elaborate wing vein patterns remains unknown. Here, we visualized Dpp distribution in the pupal wing and found that it tightly reflects the wing vein patterns. We show that Dpp is directionally transported from the longitudinal veins (LVs) into the posterior crossvein (PCV) primordial region by the extracellular BMP-binding proteins, short gastrulation (Sog) and crossveinless (Cv). Another BMP-type ligand, glass bottom boat (Gbb), also moves into the PCV region and is required for Dpp distribution, presumably as a Dpp-Gbb heterodimer. In contrast, we found that most of the Dpp is actively retained in the LVs by the BMP type I receptor thickveins (Tkv) and a positive feedback mechanism. We provide evidence that the directionality of Dpp transport is manifested by sog transcription that prepatterns the PCV position in a Dpp signal-independent manner. Taken together, our data suggest that spatial distribution of Dpp is tightly regulated at the extracellular level by combination of long-range facilitated transport toward the PCV and short-range signaling by active retention in the LVs, thereby allowing diffusible ligands to form elaborate wing vein patterns. PMID- 22542597 TI - The CSF-1 receptor ligands IL-34 and CSF-1 exhibit distinct developmental brain expression patterns and regulate neural progenitor cell maintenance and maturation. AB - The CSF-1 receptor (CSF-1R) regulates CNS microglial development. However, the localization and developmental roles of this receptor and its ligands, IL-34 and CSF-1, in the brain are poorly understood. Here we show that compared to wild type mice, CSF-1R-deficient (Csf1r-/-) mice have smaller brains of greater mass. They further exhibit an expansion of lateral ventricle size, an atrophy of the olfactory bulb and a failure of midline crossing of callosal axons. In brain, IL 34 exhibited a broader regional expression than CSF-1, mostly without overlap. Expression of IL-34, CSF-1 and the CSF-1R were maximal during early postnatal development. However, in contrast to the expression of its ligands, CSF-1R expression was very low in adult brain. Postnatal neocortical expression showed that CSF-1 was expressed in layer VI, whereas IL-34 was expressed in the meninges and layers II-V. The broader expression of IL-34 is consistent with its previously implicated role in microglial development. The differential expression of CSF-1R ligands, with respect to CSF-1R expression, could reflect their CSF-1R independent signaling. Csf1r-/- mice displayed increased proliferation and apoptosis of neocortical progenitors and reduced differentiation of specific excitatory neuronal subtypes. Indeed, addition of CSF-1 or IL-34 to microglia free, CSF-1R-expressing dorsal forebrain clonal cultures, suppressed progenitor self-renewal and enhanced neuronal differentiation. Consistent with a neural developmental role for the CSF-1R, ablation of the Csf1r gene in Nestin-positive neural progenitors led to a smaller brain size, an expanded neural progenitor pool and elevated cellular apoptosis in cortical forebrain. Thus our results also indicate novel roles for the CSF-1R in the regulation of corticogenesis. PMID- 22542598 TI - Semaphorin3d mediates Cx43-dependent phenotypes during fin regeneration. AB - Gap junctions are proteinaceous channels that reside at the plasma membrane and permit the exchange of ions, metabolites, and second messengers between neighboring cells. Connexin proteins are the subunits of gap junction channels. Mutations in zebrafish cx43 cause the short fin (sof(b123)) phenotype which is characterized by short fins due to defects in length of the bony fin rays. Previous findings from our lab demonstrate that Cx43 is required for both cell proliferation and joint formation during fin regeneration. Here we demonstrate that semaphorin3d (sema3d) functions downstream of Cx43. Semas are secreted signaling molecules that have been implicated in diverse cellular functions such as axon guidance, cell migration, cell proliferation, and gene expression. We suggest that Sema3d mediates the Cx43-dependent functions on cell proliferation and joint formation. Using both in situ hybridization and quantitative RT-PCR, we validated that sema3d expression depends on Cx43 activity. Next, we found that knockdown of Sema3d recapitulates all of the sof(b123) and cx43-knockdown phenotypes, providing functional evidence that Sema3d acts downstream of Cx43. To identify the potential Sema3d receptor(s), we evaluated gene expression of neuropilins and plexins. Of these, nrp2a, plxna1, and plxna3 are expressed in the regenerating fin. Morpholino-mediated knockdown of plxna1 did not cause cx43 specific defects, suggesting that PlexinA1 does not function in this pathway. In contrast, morpholino-mediated knockdown of nrp2a caused fin overgrowth and increased cell proliferation, but did not influence joint formation. Moreover, morpholino-mediated knockdown of plxna3 caused short segments, influencing joint formation, but did not alter cell proliferation. Together, our findings reveal that Sema3d functions in a common molecular pathway with Cx43. Furthermore, functional evaluation of putative Sema3d receptors suggests that Cx43-dependent cell proliferation and joint formation utilize independent membrane-bound receptors to mediate downstream cellular phenotypes. PMID- 22542599 TI - A network of PUF proteins and Ras signaling promote mRNA repression and oogenesis in C. elegans. AB - Cell differentiation requires integration of gene expression controls with dynamic changes in cell morphology, function, and control. Post-transcriptional mRNA regulation and signaling systems are important to this process but their mechanisms and connections are unclear. During C. elegans oogenesis, we find that two groups of PUF RNA binding proteins (RNABPs), PUF-3/11 and PUF-5/6/7, control different specific aspects of oocyte formation. PUF-3/11 limits oocyte growth, while PUF-5/6/7 promotes oocyte organization and formation. These two PUF groups repress mRNA translation through overlapping but distinct sets of 3' untranslated regions (3'UTRs). Several PUF-dependent mRNAs encode other mRNA regulators suggesting both PUF groups control developmental patterning of mRNA regulation circuits. Furthermore, we find that the Ras-MapKinase/ERK pathway functions with PUF-5/6/7 to repress specific mRNAs and control oocyte organization and growth. These results suggest that diversification of PUF proteins and their integration with Ras-MAPK signaling modulates oocyte differentiation. Together with other studies, these findings suggest positive and negative interactions between the Ras-MAPK system and PUF RNA-binding proteins likely occur at multiple levels. Changes in these interactions over time can influence spatiotemporal patterning of tissue development. PMID- 22542601 TI - Developmental role of dpp in the gastropod shell plate and co-option of the dpp signaling pathway in the evolution of the operculum. AB - The operculum is a novel structure in gastropod molluscs. Because the operculum shows notable similarities to the shell plate, we asked whether there were an evolutionary link between these two secretory organs. We found that some of the genes involved in shell-field development are expressed in the operculum, such as dpp and grainyhead, whereas engrailed and Hox1 are not. Specific knockdown of dpp by injection of double-stranded RNA (dsRNA) resulted in malformation of the shell plate. The shell plate was smaller due to failure of activation of cell proliferation in the shell-field margin. The expressions of grainyhead and chitin synthase 1 in the shell field margin were suppressed by dpp-dsRNA. However, matrix secretion was not completely abolished, and the expressions of ferritin, engrailed or Hox1 were not affected by dpp-dsRNA, indicating that dpp is partly involved in the developmental pathway for shell matrix secretion. We also present evidence that dpp performs a key role in operculum development. Indeed, dpp-dsRNA impaired matrix secretion in the operculum as well as expression of grainyhead. Based on these observations that dpp is important for development of both the shell plate and operculum, we conclude that co-option of dpp to the posterior part of the foot contributed to the innovation of the operculum in gastropods. PMID- 22542600 TI - Developmental changes in expression, subcellular distribution, and function of Drosophila N-cadherin, guided by a cell-intrinsic program during neuronal differentiation. AB - Cell adhesion molecules (CAMs) perform numerous functions during neural development. An individual CAM can play different roles during each stage of neuronal differentiation; however, little is known about how such functional switching is accomplished. Here we show that Drosophila N-cadherin (CadN) is required at multiple developmental stages within the same neuronal population and that its sub-cellular expression pattern changes between the different stages. During development of mushroom body neurons and motoneurons, CadN is expressed at high levels on growing axons, whereas expression becomes downregulated and restricted to synaptic sites in mature neurons. Phenotypic analysis of CadN mutants reveals that developing axons require CadN for axon guidance and fasciculation, whereas mature neurons for terminal growth and receptor clustering. Furthermore, we demonstrate that CadN downregulation can be achieved in cultured neurons without synaptic contact with other cells. Neuronal silencing experiments using Kir(2.1) indicate that neuronal excitability is also dispensable for CadN downregulation in vivo. Interestingly, downregulation of CadN can be prematurely induced by ectopic expression of a nonselective cation channel, dTRPA1, in developing neurons. Together, we suggest that switching of CadN expression during neuronal differentiation involves regulated cation influx within neurons. PMID- 22542602 TI - Fate map of the dental mesenchyme: dynamic development of the dental papilla and follicle. AB - At the bud stage of tooth development the neural crest derived mesenchyme condenses around the dental epithelium. As the tooth germ develops and proceeds to the cap stage, the epithelial cervical loops grow and appear to wrap around the condensed mesenchyme, enclosing the cells of the forming dental papilla. We have fate mapped the dental mesenchyme, using in vitro tissue culture combined with vital cell labelling and tissue grafting, and show that the dental mesenchyme is a much more dynamic population then previously suggested. At the bud stage the mesenchymal cells adjacent to the tip of the bud form both the dental papilla and dental follicle. At the early cap stage a small population of highly proliferative mesenchymal cells in close proximity to the inner dental epithelium and primary enamel knot provide the major contribution to the dental papilla. These cells are located between the cervical loops, within a region we have called the body of the enamel organ, and proliferate in concert with the epithelium to create the dental papilla. The condensed dental mesenchymal cells that are not located between the body of the enamel organ, and therefore are at a distance from the primary enamel knot, contribute to the dental follicle, and also the apical part of the papilla, where the roots will ultimately develop. Some cells in the presumptive dental papilla at the cap stage contribute to the follicle at the bell stage, indicating that the dental papilla and dental follicle are still not defined populations at this stage. These lineage-tracing experiments highlight the difficulty of targeting the papilla and presumptive odontoblasts at early stages of tooth development. We show that at the cap stage, cells destined to form the follicle are still competent to form dental papilla specific cell types, such as odontoblasts, and produce dentin, if placed in contact with the inner dental epithelium. Cell fate of the dental mesenchyme at this stage is therefore determined by the epithelium. PMID- 22542603 TI - Public health actions to improve palliative care in Germany: results of a three round Delphi study. AB - BACKGROUND: In previous studies, key targets for public health initiatives to improve palliative care in Germany were defined. The aim of this study was the identification and prioritisation of actions to achieve these targets. METHODS: A three-round Delphi study with 107 stakeholders acting on the meso and macrolevel of the healthcare system was undertaken. First round: proposing actions for each of the key targets; second round: assessment of the actions regarding their relevance; third round: ranking of the actions. RESULTS: 37 actions were generated (first round) of which 14 actions were rated as relevant (second round). In the third round, the action ranked highest was "close collaboration between specialist palliative care services, general practitioners and community nursing services", followed by "Implementing specialist palliative care in the community consequently" and "Strengthening generalist palliative care through training and education of general practitioners and nursing services". CONCLUSIONS: The range and the ranking of the actions provide an empirical basis to improve palliative care in Germany on different levels of policy, education and clinical practice. A focus should be on strengthening the collaboration between primary health care providers and specialist palliative care services. PMID- 22542604 TI - Fighting 'personhood' initiatives in the United States. AB - 'Personhood' initiatives filed in many states within the United States threaten to impose potentially significant restrictions on infertility treatment, embryo disposition, pre-natal care, abortion, contraception, and stem-cell research, all through attempts to redefine a 'person' or 'human being' as existing from the moment of fertilization or conception, and endowed with the full legal and Constitutional rights of personhood. Virginia's recent, unsuccessful attempt to pass such legislation provides both a dramatic example of these efforts and valuable lessons in the fight against them by infertility advocates and others. Arguments over loss of infertility treatment seemed more persuasive to legislatures than did restrictions on abortion or stem cell research. Indeed, persuading legislators or voters that they could be 'pro-life' and still anti personhood initiatives was a key strategy, and consumer efforts and media attention were instrumental. The most central lessons, however, may be the degree of intensity and coordinated strategy to shift public perception that lie behind these numerous state efforts, regardless of whether the actual initiatives are won or lost. PMID- 22542605 TI - Nutritional therapy versus 6-mercaptopurine as maintenance therapy in patients with Crohn's disease. AB - BACKGROUND: 6-Mercaptopurine is often used as maintenance therapy in patients with Crohn's disease. However, toxicities like myelosuppression limit its clinical benefit. AIMS: To evaluate the efficacy of elemental diet versus 6 mercaptopurine as maintenance therapy in Crohn's disease. METHODS: Ninety-five eligible patients with Crohn's disease activity index <=150 were randomly assigned to: 6-mercaptopurine (0.5-1.5mg/kg/day, n=30); Elental as an elemental diet (>=900 kcal/day, n=32); none (control, n=33). In the three groups, patients were and remained on 5-aminosalicylic acid (2250-3000 mg/day). Patients were observed for 2 years and the rate of relapse (Crohn's disease activity index >=200) was monitored. RESULTS: At 24 months, the fractions of patients who had maintained remission were 60%, 46.9% and 27.2% for 6-mercaptopurine, Elental and the control groups, respectively. Log-rank test showed better efficacy for 6 mercaptopurine (P=0.0041) and Elental (P=0.0348) versus control. No significant difference was found between 6-mercaptopurine and Elental. Further, in the 6 mercaptopurine group, 2 patients experienced liver injury and one developed alopecia. CONCLUSIONS: This 24 months comparison study showed that Elental as maintenance therapy in Crohn's disease patients was as effective as 6 mercaptopurine. Elental should be useful for long-term maintenance therapy in Crohn's disease. This is the first comparison study evaluating nutritional therapy versus 6-mercaptopurine. PMID- 22542606 TI - Clinical evaluation of the Oculus Keratograph. AB - AIM: To determine the validity and reliability of the measurement of corneal curvature and non-invasive tear break-up time (NITBUT) measures using the Oculus Keratograph. METHOD: One hundred eyes of 100 patients had their corneal curvature assessed with the Keratograph and the Nidek ARKT TonorefII. NITBUT was then measured objectively with the Keratograph with Tear Film Scan software and subjectively with the Keeler Tearscope. The Keratograph measurements of corneal curvature and NITBUT were repeated to test reliability. The ocular sensitivity disease index questionnaire was completed to quantify ocular comfort. RESULTS: The Keratograph consistently measured significantly flatter corneal curvatures than the ARKT (MSE difference: +1.83 +/- 0.44D), but was repeatable (p > 0.05). Keratograph NITBUT measurements were significantly lower than observation using the Tearscope (by 12.35 +/- 7.45 s; p < 0.001) and decreased on subsequent measurement (by -1.64 +/- 6.03 s; p < 0.01). The Keratograph measures the first time the tears break up anywhere on the cornea with 63% of subjects having NITBUTs <5 s and a further 22% having readings between 5 and 10 s. The Tearscope results were found to correlate better with the patients symptoms (r = -0.32) compared to the Keratograph (r = -0.19). CONCLUSIONS: The Keratograph requires a calibration off-set to be comparable to other keratometry devices. Its current software detects very early tear film changes, recording significantly lower NITBUT values than conventional subjective assessment. Adjustments to instrumentation software have the potential to enhance the value of Keratograph objective measures in clinical practice. PMID- 22542607 TI - Degenerative myelopathy associated with a missense mutation in the superoxide dismutase 1 (SOD1) gene progresses to peripheral neuropathy in Pembroke Welsh corgis and boxers. AB - Canine degenerative myelopathy (DM) is an adult-onset, fatal neurodegenerative disease with many similarities to an upper-motor-neuron-onset form of human amyotrophic lateral sclerosis (ALS), that results from mutations in the superoxide dismutase (SOD1) gene. DM occurs in many dog breeds, including the Pembroke Welsh Corgi and Boxer. The initial upper motor neuron degeneration produces spastic paraparesis and affected dogs develop general proprioceptive ataxia in the pelvic limbs. Dog owners usually elect euthanasia when their dog becomes paraplegic. When euthanasia is delayed, lower motor neuron signs including ascending tetraparesis, flaccid paralysis and widespread muscle atrophy emerge. For this study, muscle and peripheral nerve specimens were evaluated at varying disease stages from DM-affected Pembroke Welsh Corgis and Boxers that were homozygous for the SOD1 mutation and had spinal cord histopathology consistent with DM. Comparisons were made with age- and breed-matched control dogs. Here we provide evidence that Pembroke Welsh Corgis and Boxers with chronic DM develop muscle atrophy consistent with denervation, peripheral nerve pathology consistent with an axonopathy, and to a lesser degree demyelination. Canine DM has been proposed as a potential spontaneous animal disease model of human ALS. The results of this study provide further support that canine DM recapitulates one form of the corresponding human disorder and should serve as a valuable animal model to develop therapeutic strategies. PMID- 22542608 TI - Coenzyme Q10 deficiency in patients with Parkinson's disease. AB - Reactive oxygen species (ROS) are well known to contribute to the pathophysiology of Parkinson's disease (PD). Clinical trials of antioxidants are currently underway in PD patients, however, antioxidant research has been hindered by a lack of peripheral biomarkers. METHODS: Twenty-two patients with PD elected to have a novel antioxidant assessment (Functional Intracellular Assay (FIA), SpectraCell Lab, Houston, TX) performed between 2004 and 2008. Each PD case was compared to four age- and gender-matched controls (n=88) in four separate, random iterations using laboratory data submitted during the same time period. Logistic regression was used to determine the odds of functional deficiency in antioxidant nutrients (i.e., glutathione, coenzyme Q10, selenium, vitamin E and alpha-lipoic acid) by case-control status. The proportion of cases with functional deficiency was also compared to that for controls by chi(2) test. RESULTS: Compared to cases, PD patients had a significantly greater odds of deficiency in coenzyme Q10 status (OR: 4.7-5.4; 95% CI: 1.5-17.7; P=0.003-0.009) based on FIA results, but not of vitamin E, selenium, lipoic acid, or glutathione (all P>0.05). The proportion of cases with coenzyme Q10 deficiency was also significantly greater in cases than in controls (32-36% vs. 8-9%; P=0.0012-0.006). CONCLUSIONS: Deficiency of coenzyme Q10 assessed via FIA should be explored as a potential peripheral biomarker of antioxidant status in PD. PMID- 22542609 TI - Adult and umbilical cord blood-derived platelet-rich plasma for mesenchymal stem cell proliferation, chemotaxis, and cryo-preservation. AB - Platelet-rich plasma (PRP) was prepared from human adult peripheral blood and from human umbilical cord (uc) blood and the properties were compared in a series of in vitro bioassays. Quantification of growth factors in PRP and platelet-poor plasma (PPP) fractions revealed increased levels of mitogenic growth factors PDGF AB, PDGF-BB, and FGF-2, the angiogenic agent VEGF and the chemokine RANTES in ucPRP compared to adult PRP (aPRP) and PPP. To compare the ability of the various PRP products to stimulate proliferation of human bone marrow (BM), rat BM and compact bone (CB)-derived mesenchymal stem cells (MSC), cells were cultured in serum-free media for 4 and 7 days with varying concentrations of PRP, PPP, or combinations of recombinant mitogens. It was found that while all forms of PRP and PPP were more mitogenic than fetal bovine serum, ucPRP resulted in significantly higher proliferation by 7 days than adult PRP and PPP. We observed that addition of as little as 0.1% ucPRP caused greater proliferation of MSC effects than the most potent combination of recombinant growth factors tested, namely PDGF-AB + PDGF-BB + FGF-2, each at 10 ng/mL. Similarly, in chemotaxis assays, ucPRP showed greater potency than adult PRP, PPP from either source, or indeed than combinations of either recombinant growth factors (PDGF, FGF, and TGF beta1) or chemokines previously shown to stimulate chemotactic migration of MSC. Lastly, we successfully demonstrated that PRP and PPP represented a viable alternative to FBS containing media for the cryo-preservation of MSC from human and rat BM. PMID- 22542610 TI - Developing an antibody-binding protein cage as a molecular recognition drug modular nanoplatform. AB - We genetically introduced the Fc-binding peptide (FcBP) into the loop of a self assembled protein cage, ferritin, constituting four-fold symmetry at the surface to use it as a modular delivery nanoplatform. FcBP-presenting ferritin (FcBP ferritin) formed very stable non-covalent complexes with both human and rabbit IgGs through the simple molecular recognition between the Fc region of the antibodies and the Fc-binding peptide clusters inserted onto the surface of FcBP ferritin. This approach realized orientation-controlled display of antibodies on the surfaces of the protein cages simply by mixing without any complicated chemical conjugation. Using trastuzumab, a human anti-HER2 antibody used to treat patients with breast cancer, and a rabbit antibody to folate receptor, along with fluorescently labeled FcBP-ferritin, we demonstrated the specific binding of these complexes to breast cancer cells and folate receptor over-expressing cells, respectively, by fluorescent cell imaging. FcBP-ferritin may be potentially used as modular nanoplatforms for active targeted delivery vehicles or molecular imaging probes with a series of antibodies on demand. PMID- 22542611 TI - Chemotherapy for gastric cancer by finely tailoring anti-Her2 anchored dual targeting immunomicelles. AB - Micelles with high in vivo serum stability and intratumor accumulation post intravenous (i.v.) injection are highly desired for promoting chemotherapy. Herein, we finely synthesized and tailored well-defined anti-Her2 antibody Fab fragment conjugated immunomicelles (FCIMs), which showed interesting dual targeting function. The thermosensitive poly(N-isopropylacrylamide-co-N,N dimethylacrylamide)(118) (PID(118)) shell with volume phase transition temperature (VPTT: 39 degrees C) and the anchored anti-Her2 Fab moiety contributed to the passive and active targeting, respectively. The doxorubicin (DOX) loading capacity of such FCIMs was successfully increased about 2 times by physically enhanced hydrophobicity of inner reservoir without structural deformation. The cellular uptake and intracellular accumulation of DOX by temperature regulated passive and antibody navigated active targeting was 4 times of Doxil. The cytotoxicity assay against Her2 overexpression gastric cancer cells (N87s) showed that the IC50 of the FCIMs was ~ 9 times lower than that of Doxil under cooperatively targeting by Fab at T > VPTT. FCIMs showed high serum stability by increasing the corona PID(118) chain density (S(corona)/N(agg)). In vivo tissue distribution was evaluated in Balb/c nude mice bearing gastric cancer. As observed by the IVIS((r)) imaging system, the intratumor accumulation of such finely tailored FCIMs system was obviously promoted 24 h post i.v. administration. Due to the high stability and super-targeting, the in vivo xenografted gastric tumor growth was significantly inhibited with relative tumor volume <2 which was much smaller than ~ 5 of the control. Consequently, such finely tailored FCIMs with anti-Her2 active and temperature regulated passive dual tumor-targeting function show high potent in chemotherapy. PMID- 22542612 TI - Pre-emptive analgesia by nerve stimulator guided pudendal nerve block for posterior colpoperineorrhaphy. AB - OBJECTIVE: To assess the effect of pre-emptive analgesia by bilateral nerve stimulator-guided pudendal nerve block (PNB) on pain intensity and consumption of analgesics following posterior colpoperineorrhaphy. STUDY DESIGN: Prospective randomized observer-blinded study. The study included 130 patients who were scheduled to undergo posterior colpoperineorrhaphy under general anesthesia (GA). They were invited to enroll in the study during the period from October 2009 to August 2011 at TAIBA Hospital in Kuwait. Patients were randomly allocated to two groups of 65 patients each: GA alone or GA combined with pre-emptive nerve stimulator-guided PNB with 10 mL of 0.25% bupivacaine in each side. The primary outcome measures were VAS pain scores and postoperative analgesic consumption. RESULTS: Postoperative average VAS pain scores, IM pethidine consumption and IV paracetamol consumption during the first 24 h; were highly significantly lower in the PNB group compared to the GA alone group. This technique was also associated with a significantly higher overall patient satisfaction compared to GA alone, without obvious side effects. CONCLUSION: Pre-emptive analgesia by bilateral nerve stimulator-guided PNB is a simple and useful technique that when combined with GA was found to substantially reduce postoperative pain and consumption of analgesics during the first 24 h postoperatively, and shorten the time to return to normal activities compared to GA alone for patients undergoing posterior colpoperineorrhaphy. The use of PNB was also associated with a high overall patient satisfaction. Thus, the results of the present study may recommend the use of nerve stimulator-guided PNB in posterior colpoperineorrhaphy patients. PMID- 22542613 TI - Heterogeneity of endothelial cell phenotype within and amongst conduit vessels of the swine vasculature. AB - The purpose of this study was to investigate the extent of endothelial cell phenotypic heterogeneity throughout the swine vasculature, with a focus on the conduit vessels of the arterial and venous circulations. We tested the hypothesis that atheroprone arteries exhibit higher expression of markers of inflammation and oxidative stress than do veins and atheroresistant arteries. The study sample included tissues from 79 castrated, male swine. Immediately after the animals were killed, endothelial cells were mechanically scraped from isolated segments of the thoracic and abdominal aorta, carotid, brachial, femoral and renal arteries, and the vein regionally associated with each of these vessels, as well as the internal mammary and right coronary arteries. Cells were also taken from two regions of the aortic arch contrasted by atheroprone versus atherosusceptible haemodynamics. Endothelial cell phenotype was assessed by either immunoblotting or quantitative real-time PCR for a host of both pro- and anti-atherogenic markers (e.g. endothelial nitric oxide synthase, p67phox, cyclo-oxygenase-1 and superoxide dismutase 1). Marked heterogeneity across the vasculature was observed in the expression of both pro- and anti-atherogenic markers, at both the protein and transcriptional levels. In particular, the coronary vascular endothelium expressed higher levels of the oxidative stress marker p67phox (P < 0.05 versus other arteries). In addition, differential expression of endothelial nitric oxide synthase and KLF4 was evident between atheroprone and atherosusceptible regions of the aorta, while expression of endothelial nitric oxide synthase, KLF2, KLF4 and cyclo-oxygenase-1 was lower in both areas of the aortic arch compared with the internal mammary artery. Conduit arteries typically expressed higher levels of both pro- and anti-atherogenic markers relative to their associated veins. We show, for the first time, that endothelial cell phenotype is variable within vessels, across six major vascular territories, and between the arterial and venous circulations. Importantly, even straight vessel segments from systemic conduit arteries (e.g. brachial and carotid arteries) exhibited regional phenotypic heterogeneity; a finding not expected on the basis of local haemodynamic forces alone. PMID- 22542614 TI - Decreased beta-cell insulin secretory function in aged rats due to impaired Ca(2+) handling. AB - Ageing is associated with an increased impairment in glucose homeostasis and an increased incidence of type 2 diabetes. In this study, we evaluated beta-cell function and its implications for glucose homeostasis in 24-month-old female Wistar rats. Aged rats showed lower plasma glucose levels in the fed and fasting states compared with control rats. In addition, insulinaemia in the fed state was reduced in the older rats. Insulin receptor beta (IRbeta) expression was lower in the livers of the aged animals, whereas IRbeta and Akt(1/2/3) protein expressions were higher in the muscles. These effects may contribute to the normal glucose tolerance observed in older rodents. Isolated islets from aged rats secreted less insulin in response to 8.3 and 16.7 mm glucose. Accordingly, this group presented a lower [Ca(2+)](i) in the presence of glucose and a depolarizing stimulus (30 mm K(+)). In addition, islets from aged rats showed reduced insulin secretion in response to 100 MUm carbachol (CCh), 10 nm phorbol 12-myristate 13-acetate and 10 MUm forskolin. The expressions of protein kinase C, protein kinase A and exocytotic proteins, such as syntaxin 1 and synaptosomal-associated protein 25 kDa (SNAP-25), were similar in islets from aged and control rats. In conclusion, our evidence suggests that the increased incidence of type 2 diabetes with age may be due to a progressive decline in beta-cell secretory capacity due to disruption of Ca(2+) handling. Furthermore, the expression of proteins of the insulin transduction cascade showed an adaptive profile, with a compensatory increase in IRbeta and Akt(1/2/3) in gastrocnemius muscles, which may maintain normal glucose homeostasis in 24-month-old rats. PMID- 22542615 TI - Antibodies to retroviruses in recent onset psychosis and multi-episode schizophrenia. AB - BACKGROUND: Immunological abnormalities involving the upregulation of endogenous retroviruses have been associated with schizophrenia in small studies. METHODS: Blood samples from 666 individuals (163 with recent onset psychosis, 268 with multi-episode schizophrenia, and 235 controls) were assayed for IgG antibodies to murine leukemia virus (MuLV), Mason-Pfizer monkey virus (MPMV), and feline immunodeficiency virus (FIV) by enzyme immunoassay utilizing whole virus and viral components. Antibody levels in the psychiatric groups were compared to controls by multivariate linear regression. Odds ratios associated with increased antibody levels were calculated based on values >= 75th percentile of the controls. Samples were also tested for antibodies to viral proteins by Western blotting and for DNA from infectious retroviruses by real time PCR. Homology between the target virus and the prototype human genome was determined using sequence analysis methods. RESULTS: Compared with controls, individuals with recent onset of psychosis had increased levels of antibodies to MPMV and MuLV (both p<.001 adjusted for covariates), and increased antibody levels for defined portions of the MPMV and MuLV gag, pol and env proteins. The specificity of these antibodies was confirmed by Western blotting. Individuals with multi-episode schizophrenia did not show elevated antibody levels to any of the retroviruses measured. Infectious retroviruses were not detected in the blood of any participants. Homology analyses indicated that there are multiple regions of the human genome homologous with MPMV and MuLV proteins, the highest being with the MuLV gag protein. CONCLUSIONS: Antibodies to retroviral proteins are elevated in individuals with recent onset psychosis but not in individuals with multi-episode schizophrenia. The immunopathological consequences of this antibody response should be the subject of additional studies. PMID- 22542616 TI - Augmented gamma band auditory steady-state responses: support for NMDA hypofunction in schizophrenia. AB - Individuals with schizophrenia (SZ) have deviations in auditory perception perhaps attributable to altered neural oscillatory response properties in thalamo cortical and/or local cortico-cortical circuits. Previous EEG studies of auditory steady-state responses (aSSRs; a measure of sustained neuronal entrainment to repetitive stimulation) in SZ have indicated attenuated gamma range (~40 Hz) neural entrainment. Stimuli in most such studies have been relatively brief (500 1000 ms) trains of 1 ms clicks or amplitude modulated pure tones (1000 Hz) with short, fixed interstimulus intervals (200-1000 ms). The current study used extended (1500 ms), more aurally dense broadband stimuli (500-4000 Hz noise; previously demonstrated to elicit larger aSSRs) with longer, variable interstimulus intervals (2700-3300 ms). Dense array EEG (256 sensor) was collected while 17 SZ and 16 healthy subjects passively listed to stimuli modulated at 15 different frequencies spanning beta and gamma ranges (16-44 Hz in 2 Hz steps). Results indicate that SZ have augmented aSSRs that were most extreme in the gamma range. Results also constructively replicate previous findings of attenuated low frequency auditory evoked responses (2-8 Hz) in SZ. These findings (i) highlight differential characteristics of low versus high frequency and induced versus entrained oscillatory auditory responses in both SZ and healthy stimulus processing, (ii) provide support for an NMDA-receptor hypofunction-based pharmacological model of SZ, and (iii) report a novel pattern of aSSR abnormalities suggesting that gamma band neural entrainment deviations among SZ may be more complex than previously supposed, including possibly being substantially influenced by physical stimulus properties. PMID- 22542617 TI - QT-RR hysteresis is caused by differential autonomic states during exercise and recovery. AB - QT-RR hysteresis is characterized by longer QT intervals at a given RR interval while heart rates are increasing during exercise and shorter QT intervals at the same RR interval while heart rates are decreasing during recovery. It has been attributed to a lagging QT response to different directional changes in RR interval during exercise and recovery. Twenty control subjects (8 males, age 51 +/- 6 yr), 16 subjects with type 2 diabetes (12 males, age 56 +/- 8 yr), 71 subjects with coronary artery disease (CAD) and preserved left ventricular ejection fraction (LVEF) (>=50%) (51 males, age 59 +/- 12 yr), and 17 CAD subjects with depressed LVEF (<50%) (13 males, age 57 +/- 10 yr) underwent two 16 min exercise tests followed by recovery. In session 2, parasympathetic blockade with atropine (0.04 mg/kg) was achieved at end exercise. QT-RR hysteresis was quantified as: 1) the area bounded by the QT-RR relationships for exercise and recovery in the range of the minimum RR interval at peak exercise to the minimum RR interval + 100 ms and 2) the difference in QT interval duration between exercise and recovery at the minimum RR interval achieved during peak exercise plus 50 ms (DeltaQT). The effect of parasympathetic blockade was assessed by substituting the QT-RR relationship after parasympathetic blockade. QT-RR hysteresis was positive in all groups at baseline and reversed by parasympathetic blockade (P < 0.01). We conclude that QT-RR hysteresis is not caused by different directional changes in RR interval during exercise and recovery. Instead, it is predominantly mediated by differential autonomic nervous system effects as the heart rate increases during exercise vs. as it decreases during recovery. PMID- 22542618 TI - Pregnancy reduces RhoA/Rho kinase and protein kinase C signaling pathways downstream of thromboxane receptor activation in the rat uterine artery. AB - During pregnancy, reduced vascular responses to constrictors contribute to decreased uterine and total vascular resistance. Thromboxane A(2) (TxA(2)) is a potent vasoconstrictor that exerts its actions via diverse signaling pathways, and its biosynthesis increases in preeclampsia. In this study, we hypothesized that maternal vascular responses to TxA(2) will be attenuated via Rho kinase, PKC, p38 MAPK, and ERK1/2 signaling pathways. Isolated ring segments of uterine and small mesenteric arteries from late pregnant (19-21 days) and virgin rats were suspended in a myograph, and isometric force was measured. Pregnancy did not affect uterine and mesenteric artery responses to the TxA(2) analog U-46619 (10( 9)-10(-5) M), but transduction signals associated with these contractions were different between pregnant and nonpregnant rats. Inhibition of Rho kinase (10(-6) M Y-27632) reduced sensitivity to U-46619 in virgin uterine vessels but did not inhibit these contractions in pregnant uterine arteries and had no effect on mesenteric vessels. Treatment of arterial segments with a PKC inhibitor (10(-6) M bisindolylmaleimide I) reduced U-46619-induced contractions in virgin uterine and mesenteric arteries and in pregnant mesenteric arteries. Pregnant uterine arteries, however, were unresponsive to PKC inhibition. Inhibition of ERK1/2 (10( 5) M PD-98059) and p38 MAPK (10(-5) M SB-203580) reduced U46619-induced contractions in nonpregnant vessels and in pregnant uterine and mesenteric vessels. These data suggest that normal pregnancy does not affect uterine and mesenteric contractile responses to TxA(2) but reduces the contribution of Rho kinase and PKC signaling pathways to these contractions in the uterine vasculature. In contrast, the role of ERK1/2 and p38 MAPK in U-46619-induced uterine contractions remains unchanged with pregnancy. TxA(2)-associated transduction signals and its regulators might present potential targets for the development of new treatments for preeclampsia and other pregnancy-associated vascular diseases. PMID- 22542619 TI - Lack of effect of ovarian cycle and oral contraceptives on baroreceptor and nonbaroreceptor control of sympathetic nerve activity in healthy women. AB - Endogenous and exogenous female hormones regulate sympathetic nerve activity (SNA) in animal models, but their impact in humans is controversial. The purpose of this study is to investigate the effects of the ovarian cycle and oral contraceptive pills (OCPs) on SNA. We hypothesized that the effects of endogenous hormones were baroreflex (BR)-mediated and that these cyclical changes in BR control were blunted by OCPs. Furthermore, we hypothesized that the nocturnal fall in blood pressure (BP) ("dipping"), which is sympathetically mediated, also varied with the ovarian cycle. In 23 healthy females (13 OCP users, 10 age matched, no OCPs), SNA was recorded (microneurography) at rest, during BR activation/deactivation, and cold pressor test (CPT) during low and high hormonal phases. Furthermore, 24-h BP monitoring was performed during low and high hormonal phases. SNA was lower during the low vs. high hormone phase in non-OCP users (17.3 +/- 2.4 vs. 25.4 +/- 3.2 bursts/min, P < 0.001) but was not different between phases in OCP users [15.5 +/- 1.7 vs. 16.6 +/- 2.0 bursts/min, P = not significant (NS)]. BR control of SNA was not different during the hormone phases in either group [SNA (total activity/min) mean slope %change from baseline, no OCP users, low vs. high hormone phase 35.4 +/- 6.2 vs. 29.6 +/- 3.4%, P = NS and OCP users, low vs. high hormone phase 35.7 +/- 3.9 vs. 33.5 +/- 3.5%, P = NS]. SNA activation during CPT was not impacted by hormonal phase or OCP use. Finally, nondipping was not different between OCP users and nonusers, although there was a trend for nondipping to occur more frequently in the OCP users. SNA varies during the ovarian cycle in women in the absence of OCPs. This modulation cannot be attributed to cyclical changes in the BR sensitivity. PMID- 22542621 TI - Cardiomyocyte-restricted inhibition of G protein-coupled receptor kinase-3 attenuates cardiac dysfunction after chronic pressure overload. AB - Transgenic mice with cardiac-specific expression of a peptide inhibitor of G protein-coupled receptor kinase (GRK)3 [transgenic COOH-terminal GRK3 (GRK3ct) mice] display myocardial hypercontractility without hypertrophy and enhanced alpha(1)-adrenergic receptor signaling. A role for GRK3 in the pathogenesis of heart failure (HF) has not been investigated, but inhibition of its isozyme, GRK2, has been beneficial in several HF models. Here, we tested whether inhibition of GRK3 modulated evolving cardiac hypertrophy and dysfunction after pressure overload. Weight-matched male GRK3ct transgenic and nontransgenic littermate control (NLC) mice subjected to chronic pressure overload by abdominal aortic banding (AB) were compared with sham-operated (SH) mice. At 6 wk after AB, a significant increase of cardiac mass consistent with induction of hypertrophy was found, but no differences between GRK3ct-AB and NLC-AB mice were discerned. Simultaneous left ventricular (LV) pressure-volume analysis of electrically paced, ex vivo perfused working hearts revealed substantially reduced systolic and diastolic function in NLC-AB mice (n = 7), which was completely preserved in GRK3ct-AB mice (n = 7). An additional cohort was subjected to in vivo cardiac catheterization and LV pressure-volume analysis at 12 wk after AB. NLC-AB mice (n = 11) displayed elevated end-diastolic pressure (8.5 +/- 3.1 vs. 2.9 +/- 1.2 mmHg, P < 0.05), reduced cardiac output (3,448 +/- 323 vs. 4,488 +/- 342 MUl/min, P < 0.05), and reduced dP/dt(max) and dP/dt(min) (both P < 0.05) compared with GRK3ct-AB mice (n = 16), corroborating the preserved cardiac structure and function observed in GRK3ct-AB hearts assessed ex vivo. Increased cardiac mass and myocardial mRNA expression of beta-myosin heavy chain confirmed the similar induction of cardiac hypertrophy in both AB groups, but only NLC-AB hearts displayed significantly elevated mRNA levels of brain natriuretic peptide and myocardial collagen contents as well as reduced beta(1)-adrenergic receptor responsiveness to isoproterenol, indicating increased LV wall stress and the transition to HF. Inhibition of cardiac GRK3 in mice does not alter the hypertrophic response but attenuates cardiac dysfunction and HF after chronic pressure overload. PMID- 22542623 TI - Deficient Rab11 activity underlies glucose hypometabolism in primary neurons of Huntington's disease mice. AB - Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. Positron emission tomography studies have revealed a decline in glucose metabolism in the brain of patients with HD by a mechanism that has not been established. We examined glucose utilization in embryonic primary cortical neurons of wild-type (WT) and HD knock-in mice, which have 140 CAG repeats inserted in the endogenous mouse huntingtin gene (HD(140Q/140Q)). Primary HD(140Q/140Q) cortical neurons took up significantly less glucose than did WT neurons. Expression of permanently inactive and permanently active forms of Rab11 correspondingly altered glucose uptake in WT neurons, suggesting that normal activity of Rab11 is needed for neuronal uptake of glucose. It is known that Rab11 activity is diminished in HD(140Q/140Q) neurons. Expression of dominant active Rab11 to enhance the activity of Rab11 normalized glucose uptake in HD(140Q/140Q) neurons. These results suggest that deficient activity of Rab11 is a novel mechanism for glucose hypometabolism in HD. PMID- 22542622 TI - Inefficient replication reduces RecA-mediated repair of UV-damaged plasmids introduced into competent Escherichia coli. AB - Transformation of Escherichia coli with purified plasmids containing DNA damage is frequently used as a tool to characterize repair pathways that operate on chromosomes. In this study, we used an assay that allowed us to quantify plasmid survival and to compare how efficiently various repair pathways operate on plasmid DNA introduced into cells relative to their efficiency on chromosomal DNA. We observed distinct differences between the mechanisms operating on the transforming plasmid DNA and the chromosome. An average of one UV-induced lesion was sufficient to inactivate ColE1-based plasmids introduced into nucleotide excision repair mutants, suggesting an essential role for repair on newly introduced plasmid DNA. By contrast, the absence of RecA, RecF, RecBC, RecG, or RuvAB had a minimal effect on the survival of the transforming plasmid DNA containing UV-induced damage. Neither the presence of an endogenous homologous plasmid nor the induction of the SOS response enhanced the survival of transforming plasmids. Using two-dimensional agarose-gel analysis, both replication- and RecA-dependent structures that were observed on established, endogenous plasmids following UV-irradiation, failed to form on UV-irradiated plasmids introduced into E. coli. We interpret these observations to suggest that the lack of RecA-mediated survival is likely to be due to inefficient replication that occurs when plasmids are initially introduced into cells, rather than to the plasmid's size, the absence of homologous sequences, or levels of recA expression. PMID- 22542625 TI - A protein switch with tunable steepness reconstructed in Escherichia coli cells with eukaryotic signaling proteins. AB - An important goal of synthetic biology is to construct reaction circuits with artificial responses by assembling modulated biological elements into living cells. While many such attempts have been based upon the cellular transcriptional apparatus, the use of the post-translational machinery remains relatively rare. Here we report the reconstruction in Escherichia coli of a protein-based artificial module based upon elements of a eukaryotic cell signaling pathway. The module shows a switch-like ultrasensitive response, using the opposing functions of a protein kinase and a phosphatase. The switch is acutely responsive to the kinase:phosphatase ratio, and can be modulated as a function of the expression level of the substrate. We can theoretically predict the response of this module and can control its steepness based on these predictions. Future work will demonstrate the potential of this controllable protein-based switch to be incorporated into artificial circuits. PMID- 22542624 TI - Positive regulation of additional sex comb-like 1 gene expression by the pluripotency factor SOX2. AB - Additional sex comb-like 1 (ASXL1) has been suggested to be an enhancer of trithorax and polycomb proteins, and functions as a dual co-regulator of retinoid acid (RA) signaling. However, the mechanism by which ASXL1 gene expression is regulated remains unresolved. Concomitant downregulation of both SOX2 and ASXL1 during the RA-induced differentiation of P19 cells prompted us to investigate the role of SOX2 in the regulation of ASXL1. Knockdown of SOX2 in SOX2-rich NT2 cells resulted in the reduction of ASXL1 expression, whereas SOX2 overexpression in SOX2-deficient H1299 cells increased ASXL1 expression. Using a cloned ASXL1 luciferase reporter, we demonstrated that SOX2 directly transactivates the ASXL1 promoter. Serial deletion and mutation studies mapped the SOX2 response element region in the ASXL1 promoter to -1600 to -1400 bp. We showed by chromatin immunoprecipitation assay that SOX2 directly binds to the ASXL1 promoter region. Finally, formation of embryonic bodies by ASXL1-depleted murine E14TG2a embryonic stem cells was significantly impaired, similar to SOX2-knockdown cells. From these results, we suggest that ASXL1 may be a direct target of SOX2 and may play a role in maintaining the pluripotency of stem cells. PMID- 22542626 TI - Tellurite-exposed Escherichia coli exhibits increased intracellular alpha ketoglutarate. AB - The tellurium oxyanion tellurite is toxic to most organisms because of its ability to generate oxidative stress. However, the detailed mechanism(s) how this toxicant interferes with cellular processes have yet to be fully understood. As part of our effort to decipher the molecular interactions of tellurite with living systems, we have evaluated the global metabolism of alpha-ketoglutarate a known antioxidant in Escherichia coli. Tellurite-exposed cells displayed reduced activity of the KG dehydrogenase complex (KGDHc), resulting in increased intracellular KG content. This complex's reduced activity seems to be due to decreased transcription in the stressed cells of sucA, a gene that encodes the E1 component of KGDHc. Furthermore, it was demonstrated that the increase in total reactive oxygen species and superoxide observed upon tellurite exposure was more evident in wild type cells than in E. coli with impaired KGDHc activity. These results indicate that KG may be playing a pivotal role in combating tellurite mediated oxidative damage. PMID- 22542627 TI - Lysine-specific demethylase 1 (LSD1) and histone deacetylase 1 (HDAC1) synergistically repress proinflammatory cytokines and classical complement pathway components. AB - Histone modifying enzymes confer epigenetic marks, directing the changes in gene expression required for diverse cellular processes. Lysine-specific demethylase 1 (LSD1) functions as a transcriptional coregulator by demethylating histone H3 on lysine 4 and lysine 9. Analyzing transcriptomes on microarrays, we identified genes which represent inflammatory-related targets of LSD1. We demonstrate a repressive role of LSD1 in proinflammatory cytokine expression such as IL1alpha, IL1beta, IL6 and IL8 and classical complement components. Consistently, LSD1 occupies and regulates the promoter of these genes. In addition, we demonstrate that HDAC1 and LSD1 synergistically regulate these inflammatory-related genes. Our data reveal a novel role for LSD1 in suppressing immune responses. PMID- 22542620 TI - A finer tuning of G-protein signaling through regulated control of RGS proteins. AB - Regulators of G-protein signaling (RGS) proteins are GTPase-activating proteins (GAP) for various Galpha subunits of heterotrimeric G proteins. Through this mechanism, RGS proteins regulate the magnitude and duration of G-protein-coupled receptor signaling and are often referred to as fine tuners of G-protein signaling. Increasing evidence suggests that RGS proteins themselves are regulated through multiple mechanisms, which may provide an even finer tuning of G-protein signaling and crosstalk between G-protein-coupled receptors and other signaling pathways. This review summarizes the current data on the control of RGS function through regulated expression, intracellular localization, and covalent modification of RGS proteins, as related to cell function and the pathogenesis of diseases. PMID- 22542628 TI - Activity and diversity of haloalkaliphilic methanogens in Central Asian soda lakes. AB - Methanogens are of biotechnological interest because of their importance in biogas production. Here we investigate the suitability of sediments from Central Asian soda lakes as inoculum for high pH methane-producing bioreactors. Methane production in these sediments was modest (up to 2.5 MUmol mL sediment), with methanol and hydrogen as the preferred substrates. The responsible methanogenic community was characterized based on mcrA gene sequences. McrA gene sequences so far specific to these habitats indicated the presence of two clusters within the orders Methanobacteriales and Methanomicrobiales, one apparently including representatives of the genus Methanocalculus and another distantly related to the genus Methanobacterium. PMID- 22542629 TI - Escape of leukemia blasts from HLA-specific CTL pressure in a recipient of HLA one locus-mismatched bone marrow transplantation. AB - A case of leukemia escape from an HLA-specific cytotoxic T lymphocyte (CTL) response in a recipient of bone marrow transplantation is presented. Only the expression of HLA-B51, which was a mismatched HLA locus in the graft-versus-host direction, was down-regulated in post-transplant leukemia blasts compared with that in pre-transplant blasts. All CTL clones, that were isolated from the recipient's blood when acute graft-versus-host disease developed, recognized the mismatched B(*)51:01 molecule in a peptide-dependent manner. The pre-transplant leukemia blasts were lysed by CTL clones, whereas the post-transplant leukemia blasts were not lysed by any CTL clones. The IFN-gamma ELISPOT assay revealed that B(*)51:01-reactive T lymphocytes accounted for the majority of the total alloreactive T lymphocytes in the blood just before leukemia relapse. These data suggest that immune escape of leukemia blasts from CTL pressure toward a certain HLA molecule can lead to clinical relapse after bone marrow transplantation. PMID- 22542630 TI - Influence of protic ionic liquids on the structure and stability of succinylated Con A. AB - We report the synthesis of a series of ionic liquids (ILs) from various ions having different kosmotropicity including dihydrogen phosphate (H(2)PO(4)(-)), hydrogen sulfate (HSO(4)(-)) and acetate (CH(3)COO(-)) as anions and chaotropic cation such as trialkylammonium cation. To characterize the biomolecular interactions of ILs with protein, we have explored the stability of succinylated Con A (S Con A) in the presence of these aqueous ILs, which are varied combinations of kosmotropic anion with chaotropic cation such as triethylammonium dihydrogen phosphate [(CH(3)CH(2))(3)NH][H(2)PO(4)] (TEAP), trimethylammonium acetate [(CH(3))(3)NH][CH(3)COO] (TMAA), trimethylammonium dihydrogen phosphate [(CH(3))(3)NH][H(2)PO(4)] (TMAP) and trimethylammonium hydrogen sulfate [(CH(3))(3)NH][HSO(4)] (TMAS). Circular dichroism (CD) and fluorescence experiments have been used to characterize the stability of S Con A by ILs. Our data distinctly demonstrate that the long alkyl chain IL TEAP is a strong stabilizer for S Con A. Further, our experimental results reveal that TEAP is an effective refolding enhancer for S Con A from a thermally denatured protein structure. PMID- 22542631 TI - Oxidatively generated complex DNA damage: tandem and clustered lesions. AB - There is an increasing interest for oxidatively generated complex lesions that are potentially more detrimental than single oxidized nucleobases. In this survey, the recently available information on the formation and processing of several classes of complex DNA damage formed upon one radical hit including mostly hydroxyl radical and one-electron oxidants is critically reviewed. The modifications include tandem base lesions, DNA-protein cross-links and intrastrand (purine 5',8-cyclonucleosides, adjacent base cross-links) and interstrand cross-links. Information is also provided on clustered lesions produced essentially by exposure of cells to ionizing radiation and high energetic heavy ions through the involvement of multiple radical events that induce several lesions DNA in a close spatial vicinity. These consist mainly of double strand breaks (DSBs) and non-DSB clustered lesions that are referred as to oxidatively generated clustered DNA lesions (OCDLs). PMID- 22542633 TI - Influence of variation in semiflexed knee positioning during image acquisition on separate quantitative radiographic parameters of osteoarthritis, measured by Knee Images Digital Analysis. AB - OBJECTIVE: The clinical application of quantitative measurement of separate radiographic parameters of knee osteoarthritis (OA) might be hampered by a lack of reproducible semiflexed joint positioning during acquisition of radiographs. The influence of systematic variations in knee positioning on measurement of separate quantitative radiographic parameters was studied. METHODS: Five components of knee position during radiographic acquisition (beam height, lower and upper leg extension, internal rotation, and lateral shift) were systematically varied within a clinically relevant range, using three cadaver legs. The influence of these variations on the measurement of the separate quantitative radiographic parameters by Knee Images Digital Analysis (KIDA) was evaluated. Significant changes were validated in vivo. Changes were compared with differences during 2-year follow-up in a radiographic progression cohort of early OA. RESULTS: Systematic variation in upper and lower leg extension induced changes in the measurement of joint space width (JSW). Lower leg extension also influenced osteophyte area and eminence height measurement. Also bone density measurement was influenced by variation in all five position components. Variations were of clinical relevance compared with 2-year differences in knees with radiographic progression, and were confirmed in vivo. CONCLUSIONS: Variations in semiflexed knee positioning, which are considered to occur easily during image acquisition in trials and clinical practice despite standardization, are of significant influence on the quantitative measurement of most separate radiographic parameters of OA using KIDA. The additional value of quantitative measurement might improve significantly by better standardization during radiographic acquisition; with radiography still being the gold standard for structure-modification in OA. PMID- 22542632 TI - Cartilage repair of the ankle: first results of T2 mapping at 7.0 T after microfracture and matrix associated autologous cartilage transplantation. AB - BACKGROUND: Both microfracture (MFX) and matrix associated autologous cartilage transplantation (MACT) are currently used to treat cartilage defects of the talus. T2 mapping of the ankle at 7 T has the potential to assess the collagen fibril network organization of the native hyaline cartilage and of the repair tissue (RT). This study provides first results regarding the properties of cartilage RT after MFX (mean follow-up: 113.8 months) and MACT (65.4 months). METHODS: A multi-echo spin-echo sequence was used at 7 T to assess T2 maps in 10 volunteer cases, and in 10 cases after MFX and MACT each. Proton weighted morphological images and clinical data were used to ensure comparable baseline criteria. RESULTS: A significant zonal variation of T2 was found in the volunteers. T2 of the superficial and the deep layer was 39.3 +/- 5.9 ms and 21.1 +/- 3.1 ms (zonal T2 index calculated by superficial T2/deep T2: 1.87 +/- 0.2, P < 0.001). In MFX, T2 of the reference cartilage was 37.4 +/- 5.0 ms and 25.3 +/- 3.5 ms (1.51 +/- 0.3, P < 0.001). In the RT, T2 was 43.4 +/- 10.5 ms and 36.3 +/- 7.7 ms (1.20 +/- 0.2, P = 0.009). In MACT, T2 of the reference cartilage was 39.0 +/- 9.1 ms and 27.1 +/- 6.6 ms (1.45 +/- 0.2, P < 0.001). In the RT, T2 was 44.6 +/- 10.4 ms and 38.6 +/- 7.3 ms (1.15 +/- 0.1, P = 0.003). The zonal RT T2 variation differed significantly from the reference cartilage in both techniques (MFX: P = 0.004, MACT: P = 0.001). CONCLUSION: T2 mapping at 7 T allows for the quantitative assessment of the collagen network organization of the talus. MACT and MFX yielded RT with comparable T2 properties. PMID- 22542634 TI - "I bet they aren't that perfect in reality:" Appearance ideals viewed from the perspective of adolescents with a positive body image. AB - In this qualitative study, we examined the topic of appearance ideals from the perspective of 14-year-old adolescents (N=29) with a positive body image. A thematic analysis revealed that the adolescents with a positive body image were very critical against current ideals, describing them as unnatural and unrealistic, and criticizing media for only showing those consistent with the ideals and having underlying intentions with doing so. Instead, the adolescents defined beauty widely and flexibly, stressed the importance of looking like 'oneself', and conveyed the idea of personality as outplaying looks. The perception of beauty as subjective was also prominent. These results may be helpful when forming preventions targeting those at risk for developing negative body image, adding support for preventions based on media literacy and feminist theories. Additionally, we stress the significance of providing adolescents with alternative ways of thinking about ideals, beauty, and attractiveness. PMID- 22542635 TI - [Health related quality of life in type 1 diabetes mellitus]. AB - INTRODUCTION: The daily impact of DM1 treatment on the psychological aspects of patients, scientifically proven, and the need for preventive and educational approaches in the care processes of this chronic disease, leads to consider the importance of studying the health-related quality of life (HRQOL) during the childhood and adolescence stages. OBJECTIVES: a) To assess the dimensions of HRQoL most affected by the disease, and b) to determine its variation as a function of the school year, sex and number of years from diagnosis. MATERIAL AND METHOD: An applied-descriptive study was used. The sample consisted of 126 patients from 6 to 18 years with type 1 diabetes, controlled in four public hospitals in Extremadura. The questionnaire measuring HRQoL is the Spanish version of EQ-5D-Y. RESULTS: The most affected dimension for the total sample is anxiety/depression, with a significant difference in the adolescent group (P=.004). CONCLUSIONS: It is necessary to consider the HRQOL assessment should be considered in adolescence, with special attention to the psychological aspects in the proposed treatment and design of educational interventions. PMID- 22542636 TI - Manipulations of cognitive strategies and intergroup relationships reduce the racial bias in empathic neural responses. AB - Social relationships affect empathy in humans such that empathic neural responses to perceived pain were stronger to racial in-group members than to racial out group members. Why does the racial bias in empathy (RBE) occur and how can we reduce it? We hypothesized that perceiving an other-race person as a symbol of a racial group, rather than as an individual, decreases references to his/her personal situation and weakens empathy for that person. This hypothesis predicts that individuating other-race persons by increasing attention to each individual's feelings or enclosing other-race individuals within one's own social group can reduce the RBE by increasing empathic neural responses to other-race individuals. In Experiment 1, we recorded event related brain potentials from Chinese adults as they made race judgments on Asian and Caucasian faces with pain or neutral expressions. We identified the RBE by showing that, relative to neutral expressions, pain expressions increased neural responses at 128-188 ms after stimulus onset over the frontal/central brain regions, and this effect was evident for same-race faces but not for other-race faces. Experiments 2 and 3 found that paying attention to observed individual's feelings of pain and including other-race individuals in one's own team for competitions respectively eliminated the RBE by increasing neural responses to pain expressions in other race faces. Our results indicate that the RBE is not inevitable and that manipulations of both cognitive strategies and intergroup relationships can decrease RBE-related brain activity. PMID- 22542637 TI - Twenty years of functional MRI: the science and the stories. AB - Since its inception over twenty years ago, the field of functional magnetic resonance imaging (fMRI) has grown in usage, sophistication, range of applications, and impact. After twenty years, it's useful to briefly look back as well as forward - to size up just how far we have come and speculate just how far we may go. This is an introduction to the special issue of "Twenty years of fMRI: the science and the stories." The one-hundred and three papers in this special issue highlight the major methodological developments and controversies of fMRI from a first person perspective over the past twenty years. The growth of this field is not just fascinating from a science and technology perspective, but also from a human perspective. Most who were fortunate enough to be part of this effort at the beginning, as well as those who jumped in along the way have their fair share of interesting stories consisting of top rate science as well as intense thought and effort, good or bad fortune, and some claim to a contribution. These stories are in the following papers, written by the current leaders in the field and the innovators throughout the twenty year history. The categories, designed to cover every aspect of the emergence and development of fMRI, include: pre-fMRI; the first BOLD brain activation results; developments in pulse sequences, imaging methods, and hardware for fMRI; methodological developments, issues, and mechanisms; new paradigm designs; education; and the future. Within this issue, we have a collage of overlapping, complementary, yet sometimes contradictory accounts of what happened during the breathtakingly diverse and intense development of this still growing field over the past twenty years. PMID- 22542639 TI - Effect of the surface charge of artificial model membranes on the aggregation of amyloid beta-peptide. AB - The neurotoxicity effect of the beta-amyloid (Abeta) peptide, the primary constituent of senile plaques in Alzheimer's disease, occurs through interactions with neuronal membranes. Here, we attempt to clarify the mechanisms and consequences of the interaction of Abeta with lipid membranes. We have used liposomes as a model of biological membrane, and have devoted particular attention to the bilayer charge effect. Our results show that insertion and surface association of peptide with membrane, increased in a membrane charge dependent manner, lead to a reduction of Abeta soluble species, lag time elongation and an increase in the inter-molecular beta-sheet ratio of amyloid fibrils. In addition, our findings suggest that the fine balance between peptide insertion and surface association modulates Abeta aggregation, influencing the amyloid fibrils concentration as well as their morphology. PMID- 22542638 TI - An automatic MEG low-frequency source imaging approach for detecting injuries in mild and moderate TBI patients with blast and non-blast causes. AB - Traumatic brain injury (TBI) is a leading cause of sustained impairment in military and civilian populations. However, mild (and some moderate) TBI can be difficult to diagnose because the injuries are often not detectable on conventional MRI or CT. Injured brain tissues in TBI patients generate abnormal low-frequency magnetic activity (ALFMA, peaked at 1-4 Hz) that can be measured and localized by magnetoencephalography (MEG). We developed a new automated MEG low-frequency source imaging method and applied this method in 45 mild TBI (23 from combat-related blasts, and 22 from non-blast causes) and 10 moderate TBI patients (non-blast causes). Seventeen of the patients with mild TBI from blasts had tertiary injuries resulting from the blast. The results show our method detected abnormalities at the rates of 87% for the mild TBI group (blast-induced plus non-blast causes) and 100% for the moderate group. Among the mild TBI patients, the rates of abnormalities were 96% and 77% for the blast and non-blast TBI groups, respectively. The spatial characteristics of abnormal slow-wave generation measured by Z scores in the mild blast TBI group significantly correlated with those in non-blast mild TBI group. Among 96 cortical regions, the likelihood of abnormal slow-wave generation was less in the mild TBI patients with blast than in the mild non-blast TBI patients, suggesting possible protective effects due to the military helmet and armor. Finally, the number of cortical regions that generated abnormal slow-waves correlated significantly with the total post-concussive symptom scores in TBI patients. This study provides a foundation for using MEG low-frequency source imaging to support the clinical diagnosis of TBI. PMID- 22542640 TI - Crystal structure of dihydroorotate dehydrogenase from Leishmania major. AB - Dihydroorotate dehydrogenase (DHODH) is the fourth enzyme in the de novo pyrimidine biosynthetic pathway and has been exploited as the target for therapy against proliferative and parasitic diseases. In this study, we report the crystal structures of DHODH from Leishmania major, the species of Leishmania associated with zoonotic cutaneous leishmaniasis, in its apo form and in complex with orotate and fumarate molecules. Both orotate and fumarate were found to bind to the same active site and exploit similar interactions, consistent with a ping pong mechanism described for class 1A DHODHs. Analysis of LmDHODH structures reveals that rearrangements in the conformation of the catalytic loop have direct influence on the dimeric interface. This is the first structural evidence of a relationship between the dimeric form and the catalytic mechanism. According to our analysis, the high sequence and structural similarity observed among trypanosomatid DHODH suggest that a single strategy of structure-based inhibitor design can be used to validate DHODH as a druggable target against multiple neglected tropical diseases such as Leishmaniasis, Sleeping sickness and Chagas' diseases. PMID- 22542641 TI - The genome biology of phytoplasma: modulators of plants and insects. AB - Phytoplasmas are bacterial pathogens of plants that are transmitted by insects. These bacteria uniquely multiply intracellularly in both plants (Plantae) and insects (Animalia). Similarly to bacterial endosymbionts, phytoplasmas have reduced genomes with limited metabolic capabilities. Nonetheless, the chromosomes of many phytoplasmas are rich in repeated DNA consisting of mobile elements. Phytoplasmas produce an arsenal of effectors most of which are encoded on these mobile elements and on plasmids. These effectors target conserved plant transcription factors resulting in witches' broom and leafy flower symptoms and suppression of plant defense to insect vectors that transmit the phytoplasmas. Future studies of these fascinating microbes will generate a wealth of new knowledge about forces that shape genomes and microbial interactions with multicellular hosts. PMID- 22542642 TI - Adipogenic constituents from the bark of Larix laricina du Roi (K. Koch; Pinaceae), an important medicinal plant used traditionally by the Cree of Eeyou Istchee (Quebec, Canada) for the treatment of type 2 diabetes symptoms. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Diabetes is a growing epidemic worldwide, especially among indigenous populations. Larix laricina was identified through an ethnobotanical survey as a traditional medicine used by Healers and Elders of the Cree of Eeyou Istchee of northern Quebec to treat symptoms of diabetes and subsequent in vitro screening confirmed its potential. MATERIALS AND METHODS: We used a bioassay-guided fractionation approach to isolate the active principles responsible for the adipogenic activity of the organic extract (80% EtOH) of the bark of Larix laricina. Post-confluent 3T3-L1 cells were differentiated in the presence or absence of the crude extract, fractions or isolates of Larix laricina for 7 days, then triglycerides content was measured using AdipoRed reagent. RESULTS: We identified a new cycloartane triterpene (compound 1), which strongly enhanced adipogenesis in 3T3-L1 cells with an EC(50) of 7.7 MUM. It is responsible for two thirds of the activity of the active fraction of Larix laricina. The structure of compound 1 was established on the basis of spectroscopic methods (IR, HREIMS, 1D and 2D NMR) as 23-oxo-3alpha hydroxycycloart-24-en-26-oic acid. We also identified several known compounds, including three labdane-type diterpenes (compounds 2-4), two tetrahydrofuran-type lignans (compounds 5-6), three stilbenes (compounds 7-9), and taxifolin (compound 10). Compound 2 (13-epitorulosol) also potentiated adipogenesis (EC(50) 8.2 MUM) and this is the first report of a biological activity for this compound. CONCLUSIONS: This is the first report of putative antidiabetic principles isolated from Larix laricina, therefore increasing the interest in medicinal plants from the Cree pharmacopeia. PMID- 22542643 TI - Labisia pumila protects the bone of estrogen-deficient rat model: a histomorphometric study. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Labisia pumila var. alata (LP) is a phytoestrogenic herb with potential as an alternative to Estrogen Replacement Therapy (ERT) in the treatment of postmenopausal osteoporosis. LP has been reported to produce similar effects to ERT on the bone markers, but could not match ERT in terms of maintaining the bone calcium in postmenopausal osteoporosis rat model. This study aimed to examine in detail the effects of LP on the bone of postmenopausal osteoporosis rat model using bone histomorphometry. MATERIALS AND METHODS: Thirty two female rats were randomly divided into groups of: Sham operated (Sham), ovariectomized control (OVXC), ovariectomized with Labisia pumila var. alata (LP) and ovariectomized with ERT (Premarin(r)) (ERT). The LP and ERT were administered through the route of oral gavage daily at the dose of 17.5 mg/kg and 64.5 MUg/kg respectively. Following 2 months of treatment, rats were euthanized and the left femurs were dissected out and prepared for bone histomorphometry. RESULTS: Histomorphometric analysis revealed osteoporotic changes for the ovariectomized rats. Supplementation of LP to ovariectomized rats could prevent these osteoporotic changes, as effective as ERT. CONCLUSION: This confirmed that LP has potential as an alternative to ERT for prevention of postmenopausal osteoporosis. PMID- 22542644 TI - A novel assay detecting recall response to Mycobacterium tuberculosis: Comparison with existing assays. AB - A strategy to reduce the burden of active TB is isoniazid preventive therapy for latent TB infection (LTBI). However, current assays used to diagnose LTBI all have limitations. In these proof of concept studies, we compared the agreement of a novel flow cytometry assay detecting CD25/CD134 co-expression with QuantiFERON TB Gold In-Tube (QFN-GIT) and Tuberculin skin test (TST) in the detection of recall immune response to TB. The CD25/CD134 assay, QFN-GIT and TST were performed on 74 participants referred for TB screening in Sydney and on 50 participants with advanced HIV infection (CD4 <= 350 * 10(6) cells/L) in Bangkok. The agreement between CD25/CD134 assay and QFN-GIT was 93.2% (Kappa 0.631 95% CI 0.336-0.926) in Sydney and 90% (Kappa 0.747 95% CI 0.541-0.954) in Bangkok. Discordant results occurred around the cut off of both tests. The agreement between CD25/CD134 assay and TST was 73.6% (Kappa 0.206 95% CI 0.004-0.409) in Sydney and 84% (Kappa 0.551 95% CI 0.296-0.806) in Bangkok. The CD25/CD134 assay showed good agreement with QFN-GIT in detecting recall response to TB both in well and less resourced setting as well as in persons with advanced HIV infection. Further study into the performance of this assay is thus warranted. PMID- 22542645 TI - Randomization to standard and concise informed consent forms: development of evidence-based consent practices. AB - BACKGROUND: Consent to participate in research is an important component of the conduct of ethical clinical trials. Current consent practices are largely policy driven. This study was conducted to assess comprehension of study information and satisfaction with the consent form between subjects randomized to concise or to standard informed consent forms as one approach to developing evidence-based consent practices. METHODS: Participants (N=111) who enrolled into two Phase I investigational influenza vaccine protocols (VRC 306 and VRC 307) at the NIH Clinical Center were randomized to one of two IRB-approved consents; either a standard or concise form. Concise consents had an average of 63% fewer words. All other aspects of the consent process were the same. Questionnaires about the study and the consent process were completed at enrollment and at the last visit in both studies. RESULTS: Subjects using concise consent forms scored as well as those using standard length consents in measures of comprehension (7 versus 7, p=0.79 and 20 versus 21, p=0.13), however, the trend was for the concise consent group to report feeling better informed. Both groups thought the length and detail of the consent form were appropriate. CONCLUSIONS: Randomization of study subjects to different length IRB-approved consent forms as one method for developing evidence-based consent practices, resulted in no differences in study comprehension or satisfaction with the consent form. A concise consent form may be used ethically in the context of a consent process conducted by well-trained staff with opportunities for discussion and education throughout the study. PMID- 22542646 TI - A new type of Kazal proteinase inhibitor related to shrimp Penaeus (Litopenaeus) vannamei immunity. AB - A clone encoding a four-Kazal domain-containing protein was isolated from the hemostats of a Penaeus vannamei cDNA library. The full-length cDNA sequence is 975 bp in length and encodes a 24.4 kDa protein (228 residues). Four Kazal domains, each 43-46 residues in length, were detected in the deduced primary structure. The first, third and fourth domains have the CPLREELPVC, CPAVYDPVC and CPLYVDPVC motifs, respectively, suggesting that they are able to inhibit chymotrypsin and elastase. The mRNA levels of the Kazal protein were modified after the injection of Vibrio alginolyticus, indicating the probable role of this protein in the immune response. All these characteristics are similar to previously reported shrimp Kazal, however, based on both domain architecture and expression profile following Vibrio stimulation, this protein represents a new type of Kazal inhibitor associated with shrimp immunity. PMID- 22542647 TI - Automatic segmentation of polyps in colonoscopic narrow-band imaging data. AB - Colorectal cancer is the third most common type of cancer worldwide. However, this disease can be prevented by detection and removal of precursor adenomatous polyps during optical colonoscopy (OC). During OC, the endoscopist looks for colon polyps. While hyperplastic polyps are benign lesions, adenomatous polyps are likely to become cancerous. Hence, it is a common practice to remove all identified polyps and send them to subsequent histological analysis. But removal of hyperplastic polyps poses unnecessary risk to patients and incurs unnecessary costs for histological analysis. In this paper, we develop the first part of a novel optical biopsy application based on narrow-band imaging (NBI). A barrier to an automatic system is that polyp classification algorithms require manual segmentations of the polyps, so we automatically segment polyps in colonoscopic NBI data. We propose an algorithm, Shape-UCM, which is an extension of the gPb OWT-UCM algorithm, a state-of-the-art algorithm for boundary detection and segmentation. Shape-UCM solves the intrinsic scale selection problem of gPb-OWT UCM by including prior knowledge about the shape of the polyps. Shape-UCM outperforms previous methods with a specificity of 92%, a sensitivity of 71%, and an accuracy of 88% for automatic segmentation of a test set of 87 images. PMID- 22542648 TI - Surface Laplacian of central scalp electrical signals is insensitive to muscle contamination. AB - The objective of this paper was to investigate the effects of surface Laplacian processing on gross and persistent electromyographic (EMG) contamination of electroencephalographic (EEG) signals in electrical scalp recordings. We made scalp recordings during passive and active tasks, on awake subjects in the absence and in the presence of complete neuromuscular blockade. Three scalp surface Laplacian estimators were compared to left ear and common average reference (CAR). Contamination was quantified by comparing power after paralysis (brain signal, B) with power before paralysis (brain plus muscle signal, B+M). Brain:Muscle (B:M) ratios for the methods were calculated using B and differences in power after paralysis to represent muscle (M). There were very small power differences after paralysis up to 600 Hz using surface Laplacian transforms (B:M > 6 above 30 Hz in central scalp leads). Scalp surface Laplacian transforms reduce muscle power in central and pericentral leads to less than one sixth of the brain signal, two to three times better signal detection than CAR. Scalp surface Laplacian transformations provide robust estimates for detecting high frequency (gamma) activity, for assessing electrophysiological correlates of disease, and also for providing a measure of brain electrical activity for use as a standard in the development of brain/muscle signal separation methods. PMID- 22542649 TI - Graph-based optimization algorithm and software on kidney exchanges. AB - Kidney transplantation is typically the most effective treatment for patients with end-stage renal disease. However, the supply of kidneys is far short of the fast-growing demand. Kidney paired donation (KPD) programs provide an innovative approach for increasing the number of available kidneys. In a KPD program, willing but incompatible donor-candidate pairs may exchange donor organs to achieve mutual benefit. Recently, research on exchanges initiated by altruistic donors (ADs) has attracted great attention because the resultant organ exchange mechanisms offer advantages that increase the effectiveness of KPD programs. Currently, most KPD programs focus on rule-based strategies of prioritizing kidney donation. In this paper, we consider and compare two graph-based organ allocation algorithms to optimize an outcome-based strategy defined by the overall expected utility of kidney exchanges in a KPD program with both incompatible pairs and ADs. We develop an interactive software-based decision support system to model, monitor, and visualize a conceptual KPD program, which aims to assist clinicians in the evaluation of different kidney allocation strategies. Using this system, we demonstrate empirically that an outcome-based strategy for kidney exchanges leads to improvement in both the quantity and quality of kidney transplantation through comprehensive simulation experiments. PMID- 22542650 TI - MEMS capacitive accelerometer-based middle ear microphone. AB - The design, implementation, and characterization of a microelectromechanical systems (MEMS) capacitive accelerometer-based middle ear microphone are presented in this paper. The microphone is intended for middle ear hearing aids as well as future fully implantable cochlear prosthesis. Human temporal bones acoustic response characterization results are used to derive the accelerometer design requirements. The prototype accelerometer is fabricated in a commercial silicon on-insulator (SOI) MEMS process. The sensor occupies a sensing area of 1 mm * 1 mm with a chip area of 2 mm * 2.4 mm and is interfaced with a custom-designed low noise electronic IC chip over a flexible substrate. The packaged sensor unit occupies an area of 2.5 mm * 6.2 mm with a weight of 25 mg. The sensor unit attached to umbo can detect a sound pressure level (SPL) of 60 dB at 500 Hz, 35 dB at 2 kHz, and 57 dB at 8 kHz. An improved sound detection limit of 34-dB SPL at 150 Hz and 24-dB SPL at 500 Hz can be expected by employing start-of-the-art MEMS fabrication technology, which results in an articulation index of approximately 0.76. Further micro/nanofabrication technology advancement is needed to enhance the microphone sensitivity for improved understanding of normal conversational speech. PMID- 22542651 TI - Heart rate variability moderates the association between attachment avoidance and self-concept reorganization following marital separation. AB - Despite substantial evidence indicating that relationships shape people's self concept, relatively little is known about how people reorganize their sense of self when relationships end and whether this varies as a function of people's beliefs about relationships. In this report, we examine the prospective association between self-report adult attachment style and self-concept recovery among 89 adults following a recent marital separation. People high in attachment avoidance are characterized by the tendency to deactivate (i.e., suppress) painful attachment-related thoughts and feelings, and, following Fagundes, Diamond, and Allen (2012), we hypothesized that highly avoidant people would show better or worse self-concept outcomes depending on their ability to successfully regulate their emotional experience during a divorce-related mental recall task. We operationalized self-regulation using respiratory sinus arrhythmia (RSA) and found that highly avoidant people who showed RSA increases across our divorce related mental activation task (DMAT) evidenced improvements in their self concept over three months. In contrast, highly avoidant adults who showed RSA decreases during the DMAT showed no improvement (or a worsening) in their self concept disruptions over the subsequent three months. These results suggest that RSA, an index of heart rate variability, may provide a window into self regulation that has the potential to shed new light on why some people cope well or poorly following the loss of a relationship. Discussion centers on the potential mechanisms of action that explain why some people are able to successfully deactivate attachment-related thoughts and feelings whereas other people are not. PMID- 22542653 TI - Self versus maternal reports of emotional and behavioral difficulties in suicidal and non-suicidal adolescents: an Israeli nationwide survey. AB - There is relatively little research addressing parent-adolescent agreement as regards to reporting on adolescent suicidal behavior in general and their behavioral and emotional difficulties in particular. The objective of this study was to compare maternal and adolescents' reports on behavioral and emotional difficulties among adolescents with and without suicidal behavior. This nationally-representative sample included 906 adolescents and their mothers. The mothers and adolescents were interviewed and evaluated separately using the Development and Well-Being Assessment Inventory (DAWBA) and the Strengths and Difficulties Questionnaire (SDQ). Self-rated SDQ scores of the suicidal adolescents were significantly higher in all SDQ problem scales compared to the non-suicidal participants. In contrast, maternal-rated SDQ assessments failed to discriminate between these groups, except the Hyperactivity scale. We demonstrated that mothers of suicidal adolescents in the community hardly recognize the emotional and behavioral difficulties of their offsprings. CONCLUSION: The mental examination of the adolescent patient should be maintained as the central and most reliable source of information regarding the suicidal adolescent. Mental health services planning of national suicide prevention programs should take into account these poor mother-adolescent agreement findings. PMID- 22542652 TI - Insight in schizophrenia-course and predictors during the acute treatment phase of patients suffering from a schizophrenia spectrum disorder. AB - BACKGROUND: To analyse insight of illness during the course of inpatient treatment, and to identify influencing factors and predictors of insight. METHODS: Insight into illness was examined in 399 patients using the item G12 of the Positive and Negative Syndrome Scale ("lack of insight and judgement"). Ratings of the PANSS, HAMD, UKU, GAF, SOFAS, SWN-K and Kemp's compliance scale were performed and examined regarding their potential association with insight. The item G12 was kept as an ordinal variable to compare insight between subgroups of patients. RESULTS: Almost 70% of patients had deficits in their insight into illness at admission. A significant improvement of impairments of insight during the treatment (p<0.0001) was observed. At admission more severe positive and negative symptoms, worse functioning and worse adherence were significantly associated with poorer insight. Less depressive symptoms (p=0.0004), less suicidality (p=0.0218), suffering from multiple illness-episodes (p<0.0001) and worse adherence (p=0.0012) at admission were identified to be significant predictors of poor insight at discharge. CONCLUSION: The revealed predictors might function as treatment targets in order to improve insight and with it outcome of schizophrenia. PMID- 22542654 TI - Synthetic biotinylated peptide compounds derived from Asp-hemolysin: novel potent inhibitors of platelet-activating factor. AB - Platelet-activating factor (PAF: 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine), a potent inflammatory mediator, is implicated in many inflammatory diseases and may possibly serve as a direct target for anti-inflammatory drugs. We have previously reported that Asp-hemolysin-related synthetic peptides (P4-P29) inhibit the bioactivities of oxidized low-density lipoprotein (ox-LDL) containing PAF-like lipids by direct binding to ox-LDL, which plays a key role in the atherosclerotic inflammatory process. In this study, we investigated whether these peptides inhibit the bioactivities of PAF by binding to PAF and its metabolite/precursor lyso-PAF. In in vitro experiments, P21, one of the peptides, bound to both PAF and lyso-PAF in a dose-dependent manner and markedly inhibited PAF-induced apoptosis in human umbilical vein endothelial cells. Moreover, in in vivo experiments, P4 and P21, particularly their N-terminally biotinylated peptide compounds (BP4 and BP21), inhibited PAF-induced rat paw oedema dose dependently and markedly, and showed sufficient inhibition of the oedema even at doses 150-300 times less than the doses of PAF antagonists. These results provide evidence that direct binding of N-terminally biotinylated peptide compounds derived from Asp-hemolysin to PAF and lyso-PAF leads to a dramatic inhibition of the bioactivities of PAF, both in vitro and in vivo, and strongly suggesting that these compounds may be useful as a novel type of anti-inflammatory drug for the treatment of several inflammatory diseases caused by PAF. PMID- 22542655 TI - Involvement of glutamate, oxidative stress and inducible nitric oxide synthase in the convulsant activity of ciprofloxacin in mice. AB - This study investigated the potential convulsive activity of ciprofloxacin in mice and the possible mechanism(s) of this activity. Intraperitoneal (i.p.) administration of ciprofloxacin into mice resulted in convulsive seizures in a dose-dependent manner. The clonic median convulsant dose (CD(50)) of ciprofloxacin in mice was increased by pretreatment with dizocilpine, alpha lipoic acid or aminoguanidine, not changed by pretreatment with 7-nitroindazole and decreased by pretreatment with L-arginine and fenbufen. The increase in nitric oxide (NO) production and malondialdehyde (MDA) level as well as the decrease in intracellular reduced glutathione (GSH) level and glutathione peroxidase (GSH-Px) activity induced by the estimated clonic CD(50) of ciprofloxacin in mice brain was inhibited by pretreatment with dizocilpine, alpha lipoic acid or aminoguanidine. These biochemical alterations were not changed by pretreatment with 7-nitroindazole but enhanced by pretreatment with L-arginine. The elevation induced by the clonic CD(50) of ciprofloxacin in brain glutamate level was not changed by pretreatment with MK-801, alpha-lipoic acid, aminoguanidine or L-arginine. Combined treatment of mice with fenbufen and ciprofloxacin produced elevation of brain NO production and glutamate and MDA levels as well as inhibition of brain intracellular GSH level and GSH-Px activity. In addition, i.p. administration of the clonic CD(50) of ciprofloxacin produced an increase in inducible but not in neuronal NO synthase mRNA and protein expressions in mice brain. These results suggest that elevation of brain glutamate levels with consequent oxidative stress and increase in the expression and activity of brain inducible NO synthase may play a pivotal role in ciprofloxacin-induced convulsive seizures. PMID- 22542656 TI - A novel glycine transporter-1 (GlyT1) inhibitor, ASP2535 (4-[3-isopropyl-5-(6 phenyl-3-pyridyl)-4H-1,2,4-triazol-4-yl]-2,1,3-benzoxadiazole), improves cognition in animal models of cognitive impairment in schizophrenia and Alzheimer's disease. AB - Hypofunction of brain N-methyl-d-aspartate (NMDA) receptors has been implicated in psychiatric disorders such as schizophrenia and Alzheimer's disease. Inhibition of glycine transporter-1 (GlyT1) is expected to increase glycine, a co agonist of the NMDA receptor and, consequently, to facilitate NMDA receptor function. We have identified ASP2535 (4-[3-isopropyl-5-(6-phenyl-3-pyridyl)-4H 1,2,4-triazol-4-yl]-2,1,3-benzoxadiazole) as a novel GlyT1 inhibitor, and here describe our in vitro and in vivo characterization of this compound. ASP2535 potently inhibited rat GlyT1 (IC(50)=92 nM) with 50-fold selectivity over rat glycine transporter-2 (GlyT2). It showed minimal affinity for many other receptors except for MU-opioid receptors (IC(50)=1.83 MUM). Oral administration of ASP2535 dose-dependently inhibited ex vivo [(3)H]-glycine uptake in mouse cortical homogenate, suggesting good brain permeability. This profile was confirmed by pharmacokinetic analysis. We then evaluated the effect of ASP2535 on animal models of cognitive impairment in schizophrenia and Alzheimer's disease. Working memory deficit in MK-801-treated mice and visual learning deficit in neonatally phencyclidine (PCP)-treated mice were both attenuated by ASP2535 (0.3 3mg/kg, p.o. and 0.3-1mg/kg, p.o., respectively). ASP2535 (1-3mg/kg, p.o.) also improved the PCP-induced deficit in prepulse inhibition in rats. Moreover, the working memory deficit in scopolamine-treated mice and the spatial learning deficit in aged rats were both attenuated by ASP2535 (0.1-3mg/kg, p.o. and 0.1mg/kg, p.o., respectively). These studies provide compelling evidence that ASP2535 is a novel and centrally-active GlyT1 inhibitor that can improve cognitive impairment in animal models of schizophrenia and Alzheimer's disease, suggesting that ASP2535 may satisfy currently unmet medical needs for the treatment of these diseases. PMID- 22542657 TI - A possible participation of transient receptor potential vanilloid type 1 channels in the antidepressant effect of fluoxetine. AB - The present study investigated the influence of transient receptor vanilloid type 1 (TRPV1) channel agonist (capsaicin) and antagonist (capsazepine) either alone or in combination with traditional antidepressant drug, fluoxetine; or a serotonin hydroxylase inhibitor, para-chlorophenylalanine; or a glutamate N methyl-D-aspartate (NMDA) receptor agonist, NMDA on the forced swim test and tail suspension test using male Swiss mice. Results revealed that intracerebroventricular injections of capsaicin (200 and 300 MUg/mouse) and capsazepine (100 and 200 MUg/mouse) reduced the immobility time, exhibiting antidepressant-like activity that was comparable to the effects of fluoxetine (2.5-10 MUg/mouse) in both the tests. However, in the presence of inactive dose (10 MUg/mouse) of capsazepine, capsaicin (300 MUg/mouse) had no influence on the indices of both tests, signifying that the effects are TRPV1-mediated. Further, the antidepressant-like effects of both the TRPV1 ligands were neutralized in mice-pretreated with NMDA (0.1 MUg/mouse), suggestive of the fact that decreased glutamatergic transmission might contribute to the antidepressant-like activity. In addition, co-administration of sub-threshold dose of capsazepine (10 MUg/mouse) and fluoxetine (1.75 MUg/mouse) produced a synergistic effect in both the tests. In contrast, inactive doses of capsaicin (10 and 100 MUg/mouse) partially abolished the antidepressant effect of fluoxetine (10 MUg/mouse), while its effect was potentiated by active dose of capsaicin (200 MUg/mouse). Moreover, pretreatment of mice with para-chlorophenylalanine (300 mg/kg/day * 3 days, i.p.) attenuated the effects of capsaicin and capsazepine, demonstrating a probable interplay between serotonin and TRPV1, at least in parts. Thus, our data indicate a possible role of TRPV1 in depressive-like symptoms. PMID- 22542658 TI - Effect of rosiglitazone on the expression of cardiac adiponectin receptors and NADPH oxidase in type 2 diabetic rats. AB - This study investigated the effect of rosiglitazone on the expression of cardiac adiponectin receptors and NADPH oxidase in type 2 diabetic rats. Thirty-six male Wistar rats were randomly divided into control (C, n=10), diabetic (D, n=13) and diabetic treated with rosiglitazone (DT, n=13). Type 2 diabetes was induced by high-fat and high-sugar diet and intraperitoneal injection of a low dose of streptozotocin (STZ). Eleven rats in diabetic untreated group and twelve rats in diabetic treated group were successfully induced to be diabetes. After induction of diabetes, rosiglitazone (3mg/kg/day) was administrated to diabetic treated rats by gavage for 12 weeks. Twelve weeks later, the heart function was detected. Plasma and myocardial adiponectin levels were detected by enzyme linked immunosorbent assay (ELISA). The cardiac mRNA expression of adiponectin receptors 1 and 2, and monocyte chemoattractant protein-1 (MCP-1) was assayed by reverse transcript-polymerase chain reaction (RT-PCR). The cardiac mRNA expression of p22phox and NOX4 was assayed by real-time fluorescence quantitative PCR. The cardiac protein expression of phosphor-AMPK-alpha (Thr172) and glucose transporter 4 (GLUT4) was determined by Western blotting. The protein expression of adiponectin receptors 1 and 2, and connective tissue growth factor (CTGF)were determined by immunohistochemistrial staining. The ratio of heart weight to body weight was significantly increased in diabetic rats compared to control. Heart function, plasma and myocardial adiponectin levels, the protein and mRNA expression of myocardial adiponectin receptors 1 and 2, myocardial phosphorylation of AMPK-alpha (Thr172) and the protein expression of myocardial GLUT4 were significantly decreased in diabetic rats compared to control (P<0.05). The expression of myocardial p22phox, Nox4, MCP-1 and CTGF was significantly increased in diabetic rats compared to control (P<0.05). Rosiglitazone treatment significantly attenuated the increased ratio of heart weight to body weight, and the increased expression of myocardial p22phox, Nox4, MCP-1 and CTGF in diabetic rats (P<0.05). Heart function, plasma and myocardial adiponectin levels, the expression of myocardial adiponectin receptors 1 and 2 and GLUT4, and myocardial phosphorylation of AMPK-alpha (Thr172) were significantly decreased in diabetic treated with rosiglitazone compared to diabetic untreated (P<0.05). These results suggest that the protective effects of rosiglitazone on diabetic rat hearts may be attributable to the increased myocardial adiponectin and its receptors and the decreased myocardial NADPH oxidase. PMID- 22542660 TI - Acute phorbol ester treatment inhibits thapsigargin-induced cell death in porcine aortic smooth muscle cells. AB - We have previously shown that, in porcine aortic smooth muscle cells, endoplasmic reticulum (ER) stressor thapsigargin simultaneously activate the mitochondrial caspase-dependent death cascade and an extracellular signal-regulated kinase (ERK)-dependent pathway, which inhibits the caspase-independent death pathway. Our aim in the present study was to examine the effect of the phorbol ester phorbol 12-myristate 13-acetate (PMA) on these processes. We found that thapsigargin induced autophagy, which led to cell death. Treatment of cells with PMA for 5min, which activates protein kinase C (PKC), partially inhibited thapsigargin-induced cell death, whereas PMA treatment for 24h, which downregulates PKC, did not. This protection after short PMA treatment was not due to inhibition of the thapsigargin-induced cytosolic calcium concentration increase, mitochondrial permeability transition pore (PTP) opening, or caspase-3 activation, but coincided with increased ERK phosphorylation and decreased autophagosome formation and the decreased autophagosome formation was prevented by the ERK kinase inhibitor PD98059. Thus, under conditions of ER stress caused by thapsigargin-induced disturbance of calcium homeostasis, PKC activation induced ERK phosphorylation, which inhibited autophagic, but not apoptotic, cell death. After acute PMA treatment, protection against thapsigargin-induced cell death was enhanced by the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp(O Me) fluoromethyl ketone or the PTP blocker cyclosporin A, but decreased by PD98059 or the PKC inhibitor Go6983. Taken together, these results suggest that PKC activation alleviates ER stress and that this is attributable to enhanced ERK phosphorylation, which inhibits autophagic, but not apoptotic, cell death. PMID- 22542659 TI - Evidence for constitutively-active adenosine receptors at mammalian motor nerve endings. AB - A study was made to determine if constitutively active adenosine receptors are present at mouse motor nerve endings. In preparations blocked by low Ca(2+)/high Mg(2+) solution, 8-cyclopentyl-1,3,dipropylxanthine (CPX, 10-100 nM), which has been reported to be both an A(1) adenosine receptor antagonist and inverse agonist, produced a dose-dependent increase in the number of acetylcholine quanta released by a nerve impulse. Adenosine deaminase, which degrades ambient adenosine into its inactive congener, inosine, failed to alter the response to 100 nM CPX. 8-Cyclopentyltheophylline (CPT, 3 MUM), a competitive inhibitor at A(1) adenosine receptors, prevented the increase in acetylcholine release produced by CPX. At normal levels of acetylcholine release, neither adenosine deaminase nor CPX affected acetylcholine release at low frequencies of nerve stimulation in (+)-tubocurarine blocked preparations. The results suggest that a proportion of the acetylcholine release process is controlled by constitutively active adenosine receptors at murine motor nerve endings, providing the first evidence for constitutive activity of G-protein-coupled receptors that modulate the function of mammalian nerve endings. PMID- 22542661 TI - Endothelial nitric oxide synthase impairment is restored by clofibrate treatment in an animal model of hypertension. AB - Adequate production of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS) requires eNOS coupling promoted by tetrahydrobiopterin (BH(4)). Under pathological conditions such as hypertension, BH(4) is diminished, avoiding eNOS coupling. When eNOS is "uncoupled", it yields a superoxide anion instead of NO. Peroxisome proliferator activated receptors (NR1C) are a family of nuclear receptors activated by ligand. Clofibrate, a member of a hypolipidemic class of drugs, acts by activating the alpha isoform of NR1C. To determine the participation of NR1C1 activation in BH(4) and dihydrobiopterin (BH(2)) metabolism and its implications on eNOS coupling in hypertension, we performed aortic coarctation (AoCo) at inter-renal level on male Wistar rats in order to have a hypertensive model. Rats were divided into the following groups: Sham+vehicle (Sham-V); AoCo+vehicle (AoCo-V); Sham+clofibrate (Sham-C), and AoCo+clofibrate (AoCo-C). Clofibrate (7 days) increased eNOS coupling in the AoCo C group compared with AoCo-V. Clofibrate also recovered the BH(4):BH(2) ratio in control values and prevented the rise in superoxide anion production, lipoperoxidation, and reactive oxygen species production. In addition, clofibrate increased GTP cyclohydrolase-1 (GTPCH-1) protein expression, which is related with BH(4) recovered production. NR1C1 stimulation re-establishes eNOS coupling, apparently through recovering the BH(4):BH(2) equilibrium and diminishing oxidative stress. Both can contribute to high blood pressure attenuation in hypertension secondary to AoCo. PMID- 22542662 TI - The anti-ulcer agent, irsogladine, increases insulin secretion by MIN6 cells. AB - Insulin secretion by pancreatic islets is a multicellular process. In addition to other essential systems, gap junctions are an important component of cell-to-cell communication in pancreatic islets. It is well known that dysfunction of gap junctions causes inappropriate insulin secretion. The anti-ulcer agent, irsogladine, increases gap junctions in some cell types. To examine the effect of irsogladine on insulin secretion, we investigated insulin secretion by MIN6 cells treated with or without irsogladine. The expression of connexin 36 proteins and intracellular cAMP levels were also determined using immunoblotting and ELISA assays, respectively. Irsogladine had no effect on insulin secretion under 5.6mM glucose conditions. However, under 16.7 mM glucose conditions, irsogladine (1.0 * 10(-5)M) induced a 1.7 +/- 0.20 fold increase in insulin secretion compared to the control (P<0.05). This effect of irsogladine on insulin secretion was inhibited by the addition of the gap junction inhibitor 18-beta-glycyrrhetinic acid. Irsogladine treatment increased the protein level of connexin 36 in the plasma membrane fraction. The intracellular cAMP level in MIN6 cells was significantly, but mildly, increased by irsogladine treatment. Furthermore, Rp cAMP and H89 inhibited the effects of irsogladine on insulin secretion under high glucose conditions. Irsogladine increases insulin secretion under high glucose conditions. The up-regulation of gap junction channels and the increased level of intracellular cAMP induced by irsogladine treatment suggest that these phenomena are involved in irsogladine-induced increased insulin secretion. PMID- 22542663 TI - Tubular network formation by adriamycin-resistant MCF-7 breast cancer cells is closely linked to MMP-9 and VEGFR-2/VEGFR-3 over-expressions. AB - We have previously demonstrated that matrix metalloproteinase-9 (MMP-9) is critical for breast cancer cell migration and is necessary but not sufficient for tubular network formation. Given the important angiogenic activity of vascular endothelial growth factor (VEGF), we investigate here its possible contribution in tubular network formation and its link with MMP-9. Exposure of resistant epithelial breast cancer cells (rMCF-7) to Avastin, a VEGF neutralising antibody, suppresses tubular network formation but not cell migration. However, their exposure to MMP-9 inhibitor markedly decreases both parameters. Besides, the addition of exogenous VEGF or MMP-9 alone or in combination to sensitive parental cells (sMCF-7) or rMCF-7 cells enhances tubular network formation by rMCF-7 cells but not by sMCF-7 cells. The evaluation of the expression levels of VEGF receptor (VEGFR) subtypes shows that sMCF-7 cells express only small quantities of VEGFR-2 and VEGFR-3 compared with rMCF-7 cells that express strong quantities. However, treatment of sMCF-7 cells by phorbol 12-myristate 13-acetate (PMA), a PKC activator, induces both tubular network formation and VEGFR-2/VEGFR-3 over expressions. Interestingly, exposure of rMCF-7 cells or PMA-treated sMCF-7 cells to the specific inhibitors of VEGFR-2 and VEGFR-3 reduces markedly the tubular network formation. Together, our results demonstrate that the proteolytic enzyme MMP-9 promotes rMCF-7 cell migration and, consequently, tubular network formation through VEGFR-2/ VEGFR-3 activation. Understanding of mechanisms involved in vasculogenic mimicry and cell migration related to MMP-9 and VEGF may open new opportunities to improve cancer therapy. PMID- 22542664 TI - Neuroprotective effect of the aminoestrogen prolame against impairment of learning and memory skills in rats injected with amyloid-beta-25-35 into the hippocampus. AB - Alzheimer's disease (AD) is a neurodegenerative disorder caused by the deposition of the amyloid-beta peptide (Abeta) in senile plaques and cerebral vasculature. Its neurotoxic mechanisms are associated with the generation of oxidative stress and reactive astrogliosis that cause neuronal death and memory impairment. Estrogens reduce the rate of Azheimer's disease because of their antioxidant activity. Prolame (N-(3-hydroxy-1,3,5(10)-estratrien-17beta-yl)-3 hydroxypropylamine) is an aminoestrogen with estrogenic and antithrombotic effects. In our study we evaluated the role of prolame on Abeta(25-35)-caused oxidative stress, reactive astrogliosis, and impairment of spatial memory(.) The Abeta(25-35) (100 MUM/MUl) or vehicle was injected into the CA1 subfield of the hippocampus of the rat. The subcutaneous injection of prolame (400 MUl, 50 nM) or sesame oil (400 MUl) started 1 day before the Abeta(25-35) injection and was continued for another 29 days. The results showed a significant impairment of spatial memory evident 30 days after the Abeta(25-35) injection. The prolame treatment significantly reduced spatial-memory impairment and decreased lipid peroxidation, reactive oxygen species, and reactive gliosis. It also restored the eNOS and nNOS expression to normal levels. In conclusion the aminoestrogen prolame should be considered as an alternative in the treatment of Alzheimer's disease. PMID- 22542665 TI - Identifying FMRI model violations with Lagrange multiplier tests. AB - The standard modeling framework in functional magnetic resonance imaging (fMRI) is predicated on assumptions of linearity, time invariance and stationarity. These assumptions are rarely checked because doing so requires specialized software, although failure to do so can lead to bias and mistaken inference. Identifying model violations is an essential but largely neglected step in standard fMRI data analysis. Using Lagrange multiplier testing methods we have developed simple and efficient procedures for detecting model violations such as nonlinearity, nonstationarity and validity of the common double gamma specification for hemodynamic response. These procedures are computationally cheap and can easily be added to a conventional analysis. The test statistic is calculated at each voxel and displayed as a spatial anomaly map which shows regions where a model is violated. The methodology is illustrated with a large number of real data examples. PMID- 22542666 TI - Low-dose X-ray CT reconstruction via dictionary learning. AB - Although diagnostic medical imaging provides enormous benefits in the early detection and accuracy diagnosis of various diseases, there are growing concerns on the potential side effect of radiation induced genetic, cancerous and other diseases. How to reduce radiation dose while maintaining the diagnostic performance is a major challenge in the computed tomography (CT) field. Inspired by the compressive sensing theory, the sparse constraint in terms of total variation (TV) minimization has already led to promising results for low-dose CT reconstruction. Compared to the discrete gradient transform used in the TV method, dictionary learning is proven to be an effective way for sparse representation. On the other hand, it is important to consider the statistical property of projection data in the low-dose CT case. Recently, we have developed a dictionary learning based approach for low-dose X-ray CT. In this paper, we present this method in detail and evaluate it in experiments. In our method, the sparse constraint in terms of a redundant dictionary is incorporated into an objective function in a statistical iterative reconstruction framework. The dictionary can be either predetermined before an image reconstruction task or adaptively defined during the reconstruction process. An alternating minimization scheme is developed to minimize the objective function. Our approach is evaluated with low-dose X-ray projections collected in animal and human CT studies, and the improvement associated with dictionary learning is quantified relative to filtered backprojection and TV-based reconstructions. The results show that the proposed approach might produce better images with lower noise and more detailed structural features in our selected cases. However, there is no proof that this is true for all kinds of structures. PMID- 22542667 TI - HCV NS4B induces apoptosis through the mitochondrial death pathway. AB - The hepatitis C virus (HCV) NS4B protein is known to induce the formation of a membranous web that is thought to be the site of viral RNA replication. However, the exact functions of NS4B remain poorly characterized. In this study, we found that NS4B induced apoptosis in 293T cells and Huh7 cells, as confirmed by Hoechst staining, DNA fragmentation, and annexin V/PI assays. Furthermore, protein immunoblot analysis demonstrated that NS4B triggered the cleavage of caspase 3, caspase 7, and poly(ADP-ribose) polymerase (PARP). Further studies revealed that NS4B induced the activation of caspase 9, the reduction of mitochondrial membrane potential and the release of cytochrome c from the mitochondria. However, NS4B expression did not trigger XBP1 mRNA splicing and increase the expression of binding immunoglobulin protein (BiP, or GRP78) and C/EBP homologous protein (CHOP), which serves as the indicators of ER stress. Taken together, our results suggest that HCV NS4B induces apoptosis through the mitochondrial death pathway. PMID- 22542668 TI - Inhibitory effects of dietary flavonoids on purified hepatic NADH-cytochrome b5 reductase: structure-activity relationships. AB - The structure-activity relationships of flavonoids with regard to their inhibitory effects on NADH-cytochrome b5 reductase (E.C. 1.6.2.2), a clinically and toxicologically important enzyme, are not known. In the present study, the inhibitory effects of fourteen selected flavonoids of variable structure on the activity of purified bovine liver cytochrome b5 reductase, which shares a high degree of homology with the human counterpart, were investigated and the relationship between structure and inhibition was examined. Of all the compounds tested, the flavone luteolin was the most potent in inhibiting b5 reductase with an IC50 value of 0.11 MUM, whereas naringenin, naringin and chrysin were inactive within the concentration range tested. Most of the remaining flavonoids (morin, quercetin, quercitrin, myricetin, luteolin-7-O-glucoside, (-)-epicatechin, and (+)-catechin) produced a considerable inhibition of enzyme activity with IC50 values ranging from 0.81 to 4.5 MUM except apigenin (36 MUM), rutin (57 MUM) and (+)-taxifolin (IC50 not determined). The magnitude of inhibition was found to be closely related to the chemical structures of flavonoids. Analysis of structure activity data revealed that flavonoids containing two hydroxyl groups in ring B and a carbonyl group at C-4 in combination with a double bond between C-2 and C-3 produced a much stronger inhibition, whereas substitution of a hydroxyl group at C-3 was associated with a less inhibitory effect. The physiologically relevant IC50 values for most of the flavonoids tested regarding b5 reductase inhibition indicate a potential for significant flavonoid-drug and/or flavonoid-xenobiotic interactions which may have important therapeutic and toxicological outcomes for certain drugs and/or xenobiotics. PMID- 22542669 TI - Polychlorinated biphenyls and their different level metabolites as inhibitors of glutathione S-transferase isoenzymes. AB - Research on the effects of polychlorinated biphenyl (PCB) toxicity tends to focus on commercial PCB congeners and parent PCBs themselves. However, studies have suggested that PCB metabolites may be more interesting than the parent compounds because of their high reactivity. As a key metabolic enzyme, glutathione S transferases (GSTs) are responsible for detoxification by catalyzing the conjugation reaction of glutathione (GSH) to xenobiotics. Inhibition of GST activity indicates reduced detoxification ability. We investigated the inhibition of chicken liver GSTs by parent PCBs and their metabolites and observed dose dependent inhibition in vitro; inhibitory efficiency declined in the order GSH conjugate > mono-hydroxyl ~ quinone ~ hydroquinone > parent PCB. Structure inhibitory activity relationship studies indicated that with the inhibitory activity greatly increases with the number of GSH moieties or chlorine substituents on the quinone ring. However, no significant linear relationship was observed for chlorine pattern changes on the phenyl ring. The reversibility of PCB metabolite inhibition of GSTs is discussed. PCB mono-hydroxyl, hydroquinone and quinone forms showed irreversible inhibition of GSTs, which suggests a mechanism involving covalent binding to cysteine residues in the GST active site. PCB glutathionyl conjugates showed reversible GST inhibition, implying non covalent binding. Furthermore, reactive oxygen species did not significantly affect GST activity. PMID- 22542670 TI - Perioperative betamethasone treatment reduces signs of bladder dysfunction in a rat model for neurapraxia in female urogenital surgery. AB - BACKGROUND: Information on autonomic neurapraxia in female urogenital surgery is scarce, and a model to study it is not available. OBJECTIVE: To develop a model to study the impact of autonomic neurapraxia on bladder function in female rats, as well as to assess the effects of corticosteroid therapy on the recovery of bladder function in this model. DESIGN, SETTING, AND PARTICIPANTS: Female Sprague Dawley rats were subjected to bilateral pelvic nerve crush (PNC) and perioperatively treated with betamethasone or vehicle. Bladder function and morphology of bladder tissue were evaluated and compared with sham-operated rats. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Western blot, immunohistochemistry, organ bath experiments, and cystometry. RESULTS AND LIMITATIONS: Sham-operated rats exhibited regular micturitions without nonvoiding contractions (NVCs). Crush of all nerve branches of the pelvic plexus or PNC resulted in overflow incontinence and/or NVCs. Betamethasone treatment improved recovery of regular micturitions (87.5% compared with 27% for vehicle; p<0.05), reduced lowest bladder pressure (8 +/- 2 cm H(2)O compared with 21 +/- 5 cm H(2)O for vehicle; p<0.05), and reduced the amplitude of NVCs but had no effect on NVC frequency in PNC rats. Compared with vehicle, betamethasone-treated PNC rats had less CD68 (a macrophage marker) in the pelvic plexus and bladder tissue. Isolated bladder from betamethasone-treated PNC rats exhibited better nerve-induced contractions, contained more cholinergic and sensory nerves, and expressed lower amounts of collagen III than bladder tissue from vehicle-treated rats. CONCLUSIONS: PNC causes autonomic neurapraxia and functional and morphologic changes of isolated bladder tissue that can be recorded as bladder dysfunction during awake cystometry in female rats. Perioperative systemic betamethasone treatment reduced macrophage contents of the pelvic plexus and bladder, partially counteracted changes in the bladder tissue, and had protective effects on micturition function. PMID- 22542672 TI - Dopamine, serotonin and impulsivity. AB - Impulsive people have a strong urge to act without thinking. It is sometimes regarded as a positive trait but rash impulsiveness is also widely present in clinical disorders such as attention deficit hyperactivity disorder (ADHD), drug dependence, mania, and antisocial behaviour. Contemporary research has begun to make major inroads into unravelling the brain mechanisms underlying impulsive behaviour with a prominent focus on the limbic cortico-striatal systems. With this progress has come the understanding that impulsivity is a multi-faceted behavioural trait involving neurally and psychologically diverse elements. We discuss the significance of this heterogeneity for clinical disorders expressing impulsive behaviour and the pivotal contribution made by the brain dopamine and serotonin systems in the aetiology and treatment of behavioural syndromes expressing impulsive symptoms. PMID- 22542671 TI - Manganese induces p21 expression in PC12 cells at the transcriptional level. AB - Manganese is a common environmental and occupational pollutant. Excessive intake of manganese can cause toxicity known as manganism. Recently it has been demonstrated that unusual expression of cell cycle proteins and aberrant cell cycle progression in the central nervous system are involved in the pathogenesis of neurodegenerative diseases. The present studies were initiated to investigate whether p21 are induced after manganese exposure and its potential effects in vitro, with particular attention being given to understand the underlying regulatory mechanism of p21 induction by manganese in this process. We found that manganese induced DAergic cells injury and upregulation of p21 levels in nigrostriatal regions. Treatment of the PC12 cells with manganese resulted in a time- and concentration-dependent loss of cell viability. Analysis of cell cycle profile indicated that manganese blocked cell cycle progression by arresting the cell cycle at G2/M phase. Moreover, manganese treatment resulted in an increase in the mRNA and protein levels of p21, but did not have the same effect on other related factors. Silencing p21 by RNA interference showed a marked reversal of both G2/M arrest and the decrease in cell viability induced by manganese. Manganese did not stabilize the p21 protein and mRNA, and caused a marked increase in p21 mRNA levels together with an increase in its promoter activity, indicating a transcriptional mechanism. Overall, the in vivo and in vitro data suggest that exposure to manganese can increase p21 levels. An altered cell cycle status of PC12 cells can be induced by manganese through p21 up-regulation, and the induction of p21 occurs at the transcriptional level via promoter activation and mRNA induction. PMID- 22542673 TI - Stressor exposure of male and female juvenile mice influences later responses to stressors: modulation of GABAA receptor subunit mRNA expression. AB - Stressors encountered during the juvenile period may have persistent effects on later behavioral and neurochemical functioning and may influence later responses to stressors. In the current investigation, we evaluated the influence of stressor exposure applied during the juvenile period (26-28 days of age) on anxiety-related behavior, plasma corticosterone and on GABA(A) alpha2, alpha3, alpha5 and gamma2 mRNA expression within the prefrontal cortex (PFC) and amygdala measured during adulthood. These changes were monitored in the absence of a further challenge, as well as in response to either a social or a non-social psychogenic stressor administered during adulthood. Exposure to an acute adult stressor elicited anxiety in females and was still more pronounced among females that had also experienced the juvenile stressor. Among males, arousal and impulsivity predominated so that anxiety responses were less notable. Furthermore, experiencing the stressor as a juvenile influenced adult GABA(A) subunit expression, as did the adult stressor experience. These changes were differentially expressed in males and females. Moreover, these subunit variations were further moderated among mice that stressed as juveniles and were again exposed to an adult stressor. Interestingly, under conditions in which the juvenile stressor increased the expression of a particular subunit, exposure to a further stressor in adulthood resulted in the gamma-aminobutyric acid (GABA) subunit variations being attenuated in both sexes. The current results suggest that juvenile and adult stressor experiences elicit variations of GABA(A) receptor subunit expression that are region-specific as well as sexually dimorphic. Stressful events during the juvenile period may have pronounced proactive effects on anxiety-related behaviors, but linking these to specific GABA(A) subunits is made difficult by the diversity of GABA changes that are evident as well as the dimorphic nature of these variations. Nevertheless, these GABA(A) sex-specific subunit variations may be tied to the differences in anxiety in males and females. PMID- 22542675 TI - Stress during development alters dendritic morphology in the nucleus accumbens and prefrontal cortex. AB - The long-term effects of stress during development have been well characterized. However, the effects of developmental stress on the underlying neurological mechanisms related to the reward system are not well understood. The present report studied the long term effects of stress during development on the structural plasticity in the cortical and subcortical regions. Rats exposed to stress during embryonic development (prenatal stress; PS) or soon after birth (maternal separation; MS) were studied for structural alteration at the neuronal level in the nucleus accumbens (NAc), orbital frontal cortex (OFC), and medial prefrontal cortex (mPFC). The findings show that stress during development increased dendritic branching, length, and spine density in the NAc, and subregions of the PFC. PS experience increased dendritic branching and length in the mPFC apical and basilar dendrites. In contrast, a PS-associated decrease in dendritic branching and length was observed in the basilar branches of the OFC. MS resulted in an increase in dendritic growth and spine density in the subregions of the PFC. The effect of PS on neuroanatomy was more robust than MS despite the shorter duration and intensity. The altered dendritic growth and spine density associated with stress during development could have potential impact on NAc and PFC related behaviors. PMID- 22542676 TI - Dendritic structure varies as a function of eccentricity in V1: a quantitative study of NADPH diaphorase neurons in the diurnal South American rodent agouti, Dasyprocta prymnolopha. AB - The cerebral cortex is often described as a composite of repeated units or columns, integrating the same basic circuit. The 'ice-cube' model of cortical organization, and 'canonical' circuit, born from insights into functional architecture, still require systematic comparative data. Here we probed the anatomy of an individual neuronal type within V1 to determine whether or not its dendritic trees are consistent with the 'ice-cube' model and theories of canonical circuits. In a previous report we studied the morphometric variability of NADPH-diaphorase (NADPH-d) neurons in the rat auditory, visual and somatosensory primary cortical areas. Our results suggested that the nitrergic cortical circuitry of primary sensory areas are differentially specialized, probably reflecting peculiarities of both habit and behavior of the species. In the present report we specifically quantified the dendritic trees of NADPH-d type I neurons as a function of eccentricity within V1. Individual neurons were reconstructed in 3D, and the size, branching and space-filling of their dendritic trees were correlated with their location within the visuotopic map. We found that NADPH-d neurons became progressively smaller and less branched with progression from the central visual representation to the intermediate and peripheral visual representation. This finding suggests that aspects of cortical circuitry may vary across the cortical mantle to a greater extent that envisaged as natural variation among columns in the 'ice-cube' model. The systematic variation in neuronal structure as a function of eccentricity warrants further investigation to probe the general applicability of columnar models of cortical organization and canonical circuits. PMID- 22542674 TI - Distinct roles of neuroligin-1 and SynCAM1 in synapse formation and function in primary hippocampal neuronal cultures. AB - Neuroligins are a family of cell adhesion molecules critical in establishing proper central nervous system connectivity; disruption of neuroligin signaling in vivo precipitates a broad range of cognitive deficits. Despite considerable recent progress, the specific synaptic function of neuroligin-1 (NL1) remains unclear. A current model proposes that NL1 acts exclusively to mature pre existent synaptic connections in an activity-dependent manner. A second element of this activity-dependent maturation model is that an alternate molecule acts upstream of NL1 to initiate synaptic connections. SynCAM1 (SC1) is hypothesized to function in this capacity, though several uncertainties remain regarding SC1 function. Using overexpression and chronic pharmacological blockade of synaptic activity, we now demonstrate that NL1 is capable of robustly recruiting synapsin positive terminals independent of synaptic maturation and activity in 2-week old primary hippocampal neuronal cultures. We further report that neither SC1 overexpression nor knockdown of endogenous SC1 impacts synapsin punctum densities, suggesting that SC1 is not a limiting factor of synapse initiation in maturing hippocampal neurons in vitro. Consistent with these findings, we observed profoundly greater recruitment of synapsin-positive presynaptic terminals by NL1 than SC1 in a mixed-culture assay of artificial synaptogenesis between primary neurons and heterologous cells. Collectively, our results contend multiple aspects of the proposed model of NL1 and SC1 function and motivate an alternative model whereby SC1 may mature synaptic connections forged by NL1. Supporting this model, we present evidence that combined NL1 and SC1 overexpression triggers excitotoxic neurodegeneration through SC1 signaling at synaptic connections initiated by NL1. PMID- 22542677 TI - The role of mu-opioid receptor signaling in the dorsolateral periaqueductal gray on conditional and unconditional responding to threatening and aversive stimuli. AB - Here we examined how mu-opioid receptor signaling in the periaqueductal gray (PAG) mediates conditional and unconditional responses to aversive stimuli. The mu-opioid agonist morphine (MOR) and/or the partially mu-selective antagonist naltrexone (NAL) were infused into dorsolateral PAG (dlPAG) during a fear conditioning task, in which rats were trained to fear an auditory conditional stimulus (CS) by pairing it with a unilateral eyelid shock unconditional stimulus (US). During drug-free test sessions, the CS elicited movement suppression responses (indicative of freezing) from trained rats that had not recently encountered the US. In trained rats that had recently encountered the US, the CS elicited flight behavior characterized by turning in the direction away from the eyelid where US delivery was anticipated. Infusions of MOR (30 nmol/side) into dlPAG prior to the test session did not impair CS-evoked movement suppression, but did impair CS-evoked turning behaviors. MOR infusions also reduced baseline motor movement, but US-evoked reflex movements remained largely intact. NAL was infused at two dosages, denoted 1x (26 nmol/side) and 10x (260 nmol/side). Infusions of NAL into dlPAG did not affect CS- or US-evoked behavioral responses at the 1x dosage, but impaired CS-evoked movement suppression at the 10x dosage, both in the presence and absence of MOR. When rats were co-infused with MOR and NAL, MOR-induced effects were not reversed by either dosage of NAL, and some measures of MOR-induced movement suppression were enhanced by NAL at the 1x dosage. Based on these findings, we conclude that mu-opioid receptors in dlPAG may selectively regulate descending supraspinal motor pathways that drive active movement behaviors, and that interactions between MOR and NAL in dlPAG may be more complex than simple competition for binding at the mu receptor. PMID- 22542678 TI - Sustained expression of brain-derived neurotrophic factor is required for maintenance of dendritic spines and normal behavior. AB - Brain-derived neurotrophic factor (BDNF) plays important roles in the development, maintenance, and plasticity of the mammalian forebrain. These functions include regulation of neuronal maturation and survival, axonal and dendritic arborization, synaptic efficacy, and modulation of complex behaviors including depression and spatial learning. Although analysis of mutant mice has helped establish essential developmental functions for BDNF, its requirement in the adult is less well documented. We have studied late-onset forebrain-specific BDNF knockout (CaMK-BDNF(KO)) mice, in which BDNF is lost primarily from the cortex and hippocampus in early adulthood, well after BDNF expression has begun in these structures. We found that although CaMK-BDNF(KO) mice grew at a normal rate and can survive more than a year, they had smaller brains than wild-type siblings. The CaMK-BDNF(KO) mice had generally normal behavior in tests for ataxia and anxiety, but displayed reduced spatial learning ability in the Morris water task and increased depression in the Porsolt swim test. These behavioral deficits were very similar to those we previously described in an early-onset forebrain-specific BDNF knockout. To identify an anatomical correlate of the abnormal behavior, we quantified dendritic spines in cortical neurons. The spine density of CaMK-BDNF(KO) mice was normal at P35, but by P84, there was a 30% reduction in spine density. The strong similarities we find between early- and late-onset BDNF knockouts suggest that BDNF signaling is required continuously in the CNS for the maintenance of some forebrain circuitry also affected by developmental BDNF depletion. PMID- 22542680 TI - An age-related axon terminal pathology around the first olfactory relay that involves amyloidogenic protein overexpression without plaque formation. AB - The glomeruli are the first synaptic relay on the olfactory pathway and play a basic role in smell perception. Glomerular degeneration occurs in humans with age and in Alzheimer's disease (AD). The glomeruli heavily express beta-amyloid precursor protein (APP), beta-secretase (BACE1) and gamma-secretase complex. However, extracellular beta-amyloid peptide (Abeta) deposition occurs fairly rarely at this location in postmortem pathological studies. We sought to explore age-related glomerular changes that might link to alteration in amyloidogenic proteins and/or plaque pathogenesis in transgenic models of AD and humans. Focally increased BACE1 immunoreactivity (IR) in the glomerular layer was identified in several transgenic models, and characterized systematically in transgenic mice harboring five familiar AD-related mutations (5XFAD). These elements were co-labeled with antibodies against APP N-terminal (22C11) and Abeta N-terminal (3D6, 6E10) and mid-sequence (4G8). They were not co-labeled with two Abeta C-terminal antibodies (Ter40, Ter42), nor associated with extracellular amyloidosis. These profiles were further characterized to be most likely abnormal olfactory nerve terminals. Reduced glomerular area was detected in 6-12-month-old 5XFAD mice relative to non-transgenic controls, and in aged humans relative to young/adult controls, more robust in AD than aged subjects without cerebral amyloid and tau pathologies. The results suggest that olfactory nerve terminals may undergo age-related dystrophic and degenerative changes in AD model mice and humans, which are associated with increased labeling for amyloidogenic proteins but not local extracellular Abeta deposition. The identified axon terminal pathology might affect neuronal signal transmission and integration at the first olfactory synaptic relay. PMID- 22542681 TI - Shp1, a regulator of protein phosphatase 1 Glc7, has important roles in cell morphogenesis, cell cycle progression and DNA damage response in Candida albicans. AB - In yeast, the type 1 protein phosphatase (PP1) catalytic subunit Glc7 is involved in the regulation of multiple cellular processes and thought to achieve specificity through association with different regulatory subunits. Here, we report that the Glc7 regulator Shp1 plays important roles in cell morphogenesis, cell cycle progression and DNA damage response in Candida albicans. SHP1 deletion caused the formation of rod-shaped yeast cells with slow growth. Flow cytometry analysis revealed that shp1Delta cells showed a prolonged G(2)/M phase, which was rescued by deleting the spindle-checkpoint gene MAD2. Furthermore, shp1Delta cells were hypersensitive to heat and genotoxic stresses. Interestingly, depletion of Glc7 caused defects similar to the shp1Delta mutant such as arrest at G(2)/M transition; and the GLC7/glc7Delta heterozygous mutant exhibited increased sensitivity to genotoxic stresses, consistent with the recent finding that Saccharomyces cerevisiae Glc7 has a role in DNA damage response. We also show that Shp1 is required for the nuclear accumulation of Glc7, suggesting that Shp1 executes its cellular function partly by regulating Glc7 localization. PMID- 22542679 TI - Lesioning noradrenergic neurons of the locus coeruleus in C57Bl/6 mice with unilateral 6-hydroxydopamine injection, to assess molecular, electrophysiological and biochemical changes in noradrenergic signaling. AB - The locus coeruleus (LC) is the major loci of noradrenergic innervation to the forebrain. Due to the extensive central nervous system innervation of the LC noradrenergic system, a reduction in the number of LC neurons could result in significant changes in noradrenergic function in many forebrain regions. LC noradrenergic neurons were lesioned in adult male C57Bl/6 mice with the unilateral administration of 6-hydroxydopamine (6OHDA) (vehicle on the alternate side). Noradrenergic markers were measured 3 weeks later to determine the consequence of LC loss in the forebrain. Direct administration of 6OHDA into the LC results in the specific reduction of noradrenergic neurons in the LC (as measured by electrophysiology, immunoreactivity and in situ hybridization), the lateral tegmental neurons and dopaminergic neurons in the substantia nigra (SN) and ventral tegmental region were unaffected. The loss of LC noradrenergic neurons did not result in compensatory changes in the expression of mRNA for norepinephrine (NE)-synthesizing enzymes. The loss of LC noradrenergic neurons is associated with reduced NE tissue concentration and NE transporter (NET) binding sites in the frontal cortex and hippocampus, as well as other forebrain regions such as the amygdala and SN. Adrenoreceptor (AR) binding sites (alpha(1)- and alpha(2)-AR) were not significantly affected on the 6OHDA-treated side compared to the vehicle-treated side, although there is a reduction of AR binding sites on both the vehicle- and 6OHDA-treated side in specific forebrain regions. These studies indicate that unilateral stereotaxic injection of 6OHDA into mice reduces noradrenergic LC neurons and reduces noradrenergic innervation to many forebrain regions, including the contralateral side. PMID- 22542682 TI - Functional and mechanistic exploration of an adult neurogenesis-promoting small molecule. AB - Adult neurogenesis occurs throughout life in the mammalian hippocampus and is essential for memory and mood control. There is significant interest in identifying ways to promote neurogenesis and ensure maintenance of these hippocampal functions. Previous work with a synthetic small molecule, isoxazole 9 (Isx-9), highlighted its neuronal-differentiating properties in vitro. However, the ability of Isx-9 to drive neurogenesis in vivo or improve hippocampal function was unknown. Here we show that Isx-9 promotes neurogenesis in vivo, enhancing the proliferation and differentiation of hippocampal subgranular zone (SGZ) neuroblasts, and the dendritic arborization of adult-generated dentate gyrus neurons. Isx-9 also improves hippocampal function, enhancing memory in the Morris water maze. Notably, Isx-9 enhances neurogenesis and memory without detectable increases in cellular or animal activity or vascularization. Molecular exploration of Isx-9-induced regulation of neurogenesis (via FACS and microarray of SGZ stem and progenitor cells) suggested the involvement of the myocyte enhancer family of proteins (Mef2). Indeed, transgenic-mediated inducible knockout of all brain-enriched Mef2 isoforms (Mef2a/c/d) specifically from neural stem cells and their progeny confirmed Mef2's requirement for Isx-9-induced increase in hippocampal neurogenesis. Thus, Isx-9 enhances hippocampal neurogenesis and memory in vivo, and its effects are reliant on Mef2, revealing a novel cell-intrinsic molecular pathway regulating adult neurogenesis. PMID- 22542684 TI - Robust multiperson detection and tracking for mobile service and social robots. AB - This paper proposes an efficient system which integrates multiple vision models for robust multiperson detection and tracking for mobile service and social robots in public environments. The core technique is a novel maximum likelihood (ML)-based algorithm which combines the multimodel detections in mean-shift tracking. First, a likelihood probability which integrates detections and similarity to local appearance is defined. Then, an expectation-maximization (EM) like mean-shift algorithm is derived under the ML framework. In each iteration, the E-step estimates the associations to the detections, and the M-step locates the new position according to the ML criterion. To be robust to the complex crowded scenarios for multiperson tracking, an improved sequential strategy to perform the mean-shift tracking is proposed. Under this strategy, human objects are tracked sequentially according to their priority order. To balance the efficiency and robustness for real-time performance, at each stage, the first two objects from the list of the priority order are tested, and the one with the higher score is selected. The proposed method has been successfully implemented on real-world service and social robots. The vision system integrates stereo based and histograms-of-oriented-gradients-based human detections, occlusion reasoning, and sequential mean-shift tracking. Various examples to show the advantages and robustness of the proposed system for multiperson tracking from mobile robots are presented. Quantitative evaluations on the performance of multiperson tracking are also performed. Experimental results indicate that significant improvements have been achieved by using the proposed method. PMID- 22542685 TI - Osteopontin increases the proliferation of neural progenitor cells. AB - We examined the role of osteopontin in the proliferation of neural progenitor cells in vitro. Osteopontin increased the proliferation of neural progenitor cells in the presence of FGF2 as measured by cell proliferation assay and bromodeoxy uridine incorporation studies. In addition, immunoblot analysis demonstrated an increase in the phosphorylation of retinoblastoma protein with a concurrent increase in the content of phospho-Akt and cyclin D1. These results indicate that osteopontin can upregulate the content of phospho-Akt, cyclin D1 and phospho-Rb to subsequently enhance the proliferation of neural progenitor cells in the presence of FGF2. PMID- 22542683 TI - Microfibrous substrate geometry as a critical trigger for organization, self renewal, and differentiation of human embryonic stem cells within synthetic 3 dimensional microenvironments. AB - Substrates used to culture human embryonic stem cells (hESCs) are typically 2 dimensional (2-D) in nature, with limited ability to recapitulate in vivo-like 3 dimensional (3-D) microenvironments. We examined critical determinants of hESC self-renewal in poly-d-lysine-pretreated synthetic polymer-based substrates with variable microgeometries, including planar 2-D films, macroporous 3-D sponges, and microfibrous 3-D fiber mats. Completely synthetic 2-D substrates and 3-D macroporous scaffolds failed to retain hESCs or support self-renewal or differentiation. However, synthetic microfibrous geometries made from electrospun polymer fibers were found to promote cell adhesion, viability, proliferation, self-renewal, and directed differentiation of hESCs in the absence of any exogenous matrix proteins. Mechanistic studies of hESC adhesion within microfibrous scaffolds indicated that enhanced cell confinement in such geometries increased cell-cell contacts and altered colony organization. Moreover, the microfibrous scaffolds also induced hESCs to deposit and organize extracellular matrix proteins like laminin such that the distribution of laminin was more closely associated with the cells than the Matrigel treatment, where the laminin remained associated with the coated fibers. The production of and binding to laminin was critical for formation of viable hESC colonies on synthetic fibrous scaffolds. Thus, synthetic substrates with specific 3-D microgeometries can support hESC colony formation, self-renewal, and directed differentiation to multiple lineages while obviating the stringent needs for complex, exogenous matrices. Similar scaffolds could serve as tools for developmental biology studies in 3-D and for stem cell differentiation in situ and transplantation using defined humanized conditions. PMID- 22542686 TI - Novel synthesis of silver nanoparticles using 2,3,5,6-tetrakis-(morpholinomethyl) hydroquinone as reducing agent. AB - 2,3,5,6-Tetrakis-(morpholinomethyl) hydroquinone (TMMH) was used as a reducing agent to synthesize spherical shaped silver nanoparticles in water-ethanol medium without using any stabilizing and capping agents. The reducing agent TMMH is prepared by Mannich-type reaction method and (1)H NMR, (13)C NMR and FT-IR spectroscopy techniques were used to characterize the compound (TMMH). The nature of bonding, structural and optical properties of the final product were analyzed using different techniques such as UV-Vis spectroscopy, X-ray diffraction (XRD), scanning electron microscopy (SEM) and Fourier-transform infrared spectroscopy (FTIR). The interaction between silver and reducing agent was confirmed by using FTIR analysis. The final product obtained showed higher crystallinity with cubic structure and an average crystalline size of about 20 nm. The results revealed that it is possible to synthesize crystalline Ag nanoparticles using organic compound as reducing agent. PMID- 22542687 TI - Structural investigation of aroylhydrazones in dimethylsulphoxide/water mixtures. AB - Molecular structures of aroylhydrazones derived from salicylaldehyde, o-vanilin and nicotinic acid hydrazide in DMSO and DMSO/H(2)O mixtures have been studied by NMR, UV-Vis, ATR and Raman spectroscopy. The addition of water to the system did not induce the tautomeric conversion of the existing form constituted of the ketoamino hydrazide part and the enolimino aldehyde part, but it was involved in the formation of hydrated molecules. Vibrational spectra (ATR and Raman) clearly indicated hydrogen bonding of the studied hydrazones through the carbonyl, amino and hydroxyl groups with water molecules. Increasing the water content conversion from E to Z isomer was not observed. PMID- 22542688 TI - In situ approach induced growth of highly monodispersed Ag nanoparticles within free standing PVA/PVP films. AB - Ag nanoparticles supported within polyvinyl alcohol (PVA)/polyvinyl pyrrolidone (PVP) films have been successfully synthesized using novel in situ method. PVA and PVP acted as stabilizer and polyol reductant, respectively. The successful incorporation of silver nanoparticles in PVA/PVP matrix was confirmed by UV-Vis spectroscopy, X-ray diffraction (XRD), transmission electron microscope (TEM) and Fourier transform infrared (FTIR) spectroscopy. It was found that PVA/PVP stabilized silver nanocomposite film revealed the presence of well-dispersed and spherical silver nanoparticles with an average diameter of 30 nm, while the particle sizes were reduced as the PVP percentage increased. A possible formation mechanism of Ag nanoparticles is also proposed in this article. PMID- 22542689 TI - Raman imaging spectroscopic characterization of modified poly(dimethylsiloxane) for micro total analysis systems applications. AB - Methacryloxypropyl-modified poly(dimethylsiloxane) rubbers were obtained from poly(dimethylsiloxane), PDMS, and methacryloxypropyltrimethoxysilane, MPTMS, by polycondensation reactions. The modified rubbers, prepared with 20 and 30% (v/v) of MPTMS, were used as substrates for microchannel fabrication by the CO(2) laser ablation technique. Raman imaging spectroscopy was used for the surface characterization, showing the homogeneity of the rubbery material, with uniform distribution of the crosslinking centers. Under the experimental conditions used, damage to the rubber from the CO(2) laser radiation used for the channel engraving was not observed. Correlation maps of the surface were obtained in order to spatially evaluate the modification inside and outside the channels. The correlations between the methacryloxypropyl-modified poly(dimethylsiloxane) rubbers and MPTMS (spectral range of 1800-1550 cm(-1)) and PDMS (spectral range of 820-670 cm(-1)) precursors were higher than 0.95 and 0.99, respectively. In addition, Raman imaging spectroscopy allows monitoring the topography of the fabricated microchannel. PMID- 22542690 TI - Determinism and probability in the development of the cell theory. AB - A return to Claude Bernard's original use of the concept of 'determinism' displays the fact that natural laws were presumed to rule over all natural processes. In a more restricted sense, the term boiled down to a mere presupposition of constant determinant causes for those processes, leaving aside any particular ontological principle, even stochastic. The history of the cell theory until around 1900 was dominated by a twofold conception of determinant causes. Along a reductionist trend, cells' structures and processes were supposed to be accounted for through their analysis into detailed partial mechanisms. But a more holistic approach tended to subsume those analytic means and the mechanism involved under a program of global functional determinations. When mitotic and meiotic sequences in nuclear replication were being unveiled and that neo Mendelian genetics was being grafted onto cytology and embryology, a conception of strict determinism at the nuclear level, principally represented by Wilhelm Roux and August Weismann, would seem to rule unilaterally over the mosaic interpretation of the cleavage of blastomeres. But, as shown by E.B. Wilson, in developmental processes there occur contingent outcomes of cell division which observations and experiments reveal. This induces the need to admit 'epigenetic' determinants and relativize the presumed 'preformation' of thedevelopmental phases by making room for an emergent order which the accidental circumstances of gene replication would trigger on. PMID- 22542691 TI - Adding complexity to the complex: new insights into the phylogeny, diversification and origin of parthenogenesis in the Aporrectodea caliginosa species complex (Oligochaeta, Lumbricidae). AB - The importance of the Aporrectodea caliginosa species complex lies in the great abundance and wide distribution of the species which exist within it. For more than a century, chaos has surrounded this complex; morphological criteria has failed to solve the taxonomic status of these species. This present body of work aims to study the phylogeny of this complex by increasing the number of samples used in previous molecular works and by including morphologically-similar species that were never studied using molecular tools (A. giardi, Nicodrilus monticola, N. carochensis and N. tetramammalis). Two basal clades were obtained: one formed by A. caliginosa and A. tuberculata and the other by the rest of the species. This second clade was divided into two more: one with Eurosiberian and another with Mediterranean forms. A. caliginosa and A. longa were divided into two paraphyletic groups. Both A. giardi and A. nocturna showed characteristics consistent with monophyletic groups. Each of the two recovered lineages of A. trapezoides were phylogenetically related to different sexual species. While lineage I of A. trapezoides was monophyletic, lineage II resulted to be paraphyletic, as well as the three Nicodrilus 'species'. The diversification of the complex occurred during the Late Miocene-Early Pliocene (6.92-11.09 Mya). The parthenogenetic forms within the Mediterranean clade would have diversified before the ones in the Eurosiberian clade (3.13-4.64 Mya and 1.05-3.48 Mya, respectively), thus implying the existence not only of at least two different moments in which parthenogenesis arose within this complex of species, but also of two different and independent evolutionary lines. Neither the 4* rule nor the GMYC method for species delimitation were successful for distinguishing taxonomically-distinct species. PMID- 22542692 TI - Fish discards management: pollution levels and best available removal techniques. AB - Fish discards and by-catch issues are highly topical subjects that are permanently under a social focus. Two main approaches are being considered to address this discard problem: reducing the by-catch and increasing by-catch utilization. Interest in increased by-catch valorization may arise from a greater demand for fish products, such as the development of new markets for previously discarded species, the use of low-value specimens for aquaculture or the creation of value-added fish products for the food, pharmaceutical or cosmetic industries. However, contaminants present in fish discards may be transferred to their valorized products, leading to possible long-term bioaccumulation and subsequent adverse health effects. In this valorization framework, the aim is to promote responsible and sustainable management of marine resources. The pollutant levels in catches from European fisheries and the best available decontamination techniques for marine valorized discards/by-products are compiled and analyzed in this work. PMID- 22542693 TI - A neosphincter for continent urinary catheterizable channels made from rectus abdominal muscle (Yachia principle): preliminary clinical experience in children. AB - PURPOSE: We investigated continence outcomes for patients undergoing primary or redo reconstruction of a urinary catheterizable reservoir involving the Yachia technique of intersecting two rectus abdominis strips over the outlet channel. MATERIALS AND METHODS: A retrospective evaluation of 22 consecutive patients operated from March 2009 to August 2010 was performed, consisting of 16 primary reconstructions (Macedo catheterizable ileal reservoirs) and 6 rescue cases for leaking stomas. Our data comprised 18 spina bifida patients, 1 sacral agenesis, 1 posterior urethral valves and 1 genitourinary tuberculosis. Mean age at surgery was 8.5 years (3-21 years). We evaluated continence at 3, 6, 12 months, and at the last follow-up based on data from urinary charts. RESULTS: Mean follow-up was 21.1 months (12-29 months). Overall continence was 100% for the primary cases and 66% for the redos (2/6 failed). Three patients had initial difficulty in performing clean intermittent catheterization but this resolved with time and experience. CONCLUSION: Using Yachia's technique has improved the continence rate of our catheterizable reservoirs and was partially successful for suprafascial revision of incontinent conduits. PMID- 22542694 TI - Multichannel ECG data compression based on multiscale principal component analysis. AB - In this paper, multiscale principal component analysis (MSPCA) is proposed for multichannel electrocardiogram (MECG) data compression. In wavelet domain, principal components analysis (PCA) of multiscale multivariate matrices of multichannel signals helps reduce dimension and remove redundant information present in signals. The selection of principal components (PCs) is based on average fractional energy contribution of eigenvalue in a data matrix. Multichannel compression is implemented using uniform quantizer and entropy coding of PCA coefficients. The compressed signal quality is evaluated quantitatively using percentage root mean square difference (PRD), and wavelet energy-based diagnostic distortion (WEDD) measures. Using dataset from CSE multilead measurement library, multichannel compression ratio of 5.98:1 is found with PRD value 2.09% and the lowest WEDD value of 4.19%. Based on, gold standard subjective quality measure, the lowest mean opinion score error value of 5.56% is found. PMID- 22542695 TI - Effect of lipoteichoic acid on IL-2 and IL-5 release from T lymphocytes in asthma and COPD. AB - Susceptibility to infections with gram-positive bacteria, which are an important trigger of exacerbations, is increased in COPD and asthma. Unraveling the underlying mechanisms may help developing therapeutic strategies to reduce exacerbation rates. The aim of this study was to evaluate the effects of lipoteichoic acid (LTA), a danger signal from gram-positive bacteria, on T cell cytokines related to bacterial infection defense in COPD and asthma. T cell populations within peripheral blood mononuclear cells (PBMCs) were ex-vivo activated towards T(H)2/T(C)2 subtypes and subsequently stimulated with LTA. IL-2 and IL-5 concentrations in cell culture supernatants were measured by ELISA comparative between non-smokers (NS), current smokers without airflow limitation (S), smokers with moderate to severe COPD and mild to moderate asthmatics (A) (each n=10). IL-2 and IL-5 baseline levels were without differences between the cohorts. After T cell activation, IL-2 and IL-5 releases were increased in all cohorts, however, for IL-2 this increase was significantly higher in S and by trend in COPD compared to the other groups. LTA time-dependently suppressed IL-2 release in NS, S and COPD but not in A. LTA reduced IL-5 release in COPD and A but not in NS and S. Summarized, LTA reduces T(H)2/T(C)2 cytokines indicating immunosuppressive effects, which are dysregulated in COPD and asthma. This implies a misguided response to gram-positive bacterial infections, which might help to explain the increased susceptibility to bacterial infections in COPD and asthma. PMID- 22542697 TI - Contours of time: topographic construals of past, present, and future in the Yupno valley of Papua New Guinea. AB - Time, an everyday yet fundamentally abstract domain, is conceptualized in terms of space throughout the world's cultures. Linguists and psychologists have presented evidence of a widespread pattern in which deictic time-past, present, and future-is construed along the front/back axis, a construal that is linear and ego-based. To investigate the universality of this pattern, we studied the construal of deictic time among the Yupno, an indigenous group from the mountains of Papua New Guinea, whose language makes extensive use of allocentric topographic (uphill/downhill) terms for describing spatial relations. We measured the pointing direction of Yupno speakers' gestures-produced naturally and without prompting-as they explained common expressions related to the past, present, and future. Results show that the Yupno spontaneously construe deictic time spatially in terms of allocentric topography: the past is construed as downhill, the present as co-located with the speaker, and the future as uphill. Moreover, the Yupno construal is not linear, but exhibits a particular geometry that appears to reflect the local terrain. The findings shed light on how, our universal human embodiment notwithstanding, linguistic, cultural, and environmental pressures come to shape abstract concepts. PMID- 22542696 TI - Omega-3 fatty acids in anti-inflammation (pro-resolution) and GPCRs. AB - Omega-3 fatty acids, such as, DHA and EPA, have well established beneficial effects on human health, but their action mechanisms remain unknown. Recent pharmacological studies have suggested several molecular targets for the anti inflammatory effects of omega-3 fatty acids, namely, nuclear receptor PPARgamma and the G protein-coupled receptor GPR120. Furthermore, the conversions of omega 3 fatty acids to anti-inflammatory and pro-resolving resolvins and protectins and the identifications of putative target GPCRs, ChemR23, BLT1, ALX/FPR2, and GPR32, have drawn great attention. In addition, the pharmacology of omega-3 fatty acids is now under scrutiny. However, questions remain to be answered regarding the in vivo effects of omega-3 fatty acids at the molecular level. In this review, anti inflammatory effects of omega-3 fatty acids are discussed from the viewpoint of molecular pharmacology, particularly with respect to the above-mentioned GPCRs. PMID- 22542698 TI - Parent or community: where do 20-month-olds exposed to two accents acquire their representation of words? AB - The recognition of familiar words was evaluated in 20-month-old children raised in a rhotic accent environment to parents that had either rhotic or non-rhotic accents. Using an Intermodal Preferential Looking task children were presented with familiar objects (e.g. 'bird') named in their rhotic or non-rhotic form. Children were only able to identify familiar words pronounced in a rhotic accent, irrespective of their parents' accent. This suggests that it is the local community rather than parental input that determines accent preference in the early stages of acquisition. Consequences for the architecture of the early lexicon and for models of word learning are discussed. PMID- 22542699 TI - In vivo evaluation of an oral drug delivery system for peptides based on S protected thiolated chitosan. AB - The aim of the present study was the development and evaluation in vitro as well as in vivo of an oral delivery system based on a novel type of thiolated chitosan, so-called S-protected thiolated chitosan, for the peptide drug antide. The sulfhydryl ligand thioglycolic acid (TGA) was covalently attached to chitosan (CS) in the first step of modification. In the second step, these thiol groups of thiolated chitosan were protected by disulfide bond formation with the thiolated aromatic residue 6-mercaptonicotinamide (6-MNA). Absorptive transport studies of antide were evaluated ex vivo using rat intestinal mucosa. Matrix tablets of each polymer sample were prepared and their effect on the absorption of antide evaluated in vivo in male Sprague-Dawley rats. In addition, tablets were examined in terms of their disintegration, swelling and drug release behavior. The resulting S-protected thiomer (TGA-MNA) exhibited 840MUmol of covalently linked 6 MNA per gram thiomer. Based on the implementation of this hydrophobic ligand on the thiolated backbone, the disintegration behavior was reduced greatly and a controlled release of the peptide could be achieved. Furthermore, permeation studies with TGA-MNA on rat intestine revealed a 4.5-fold enhanced absorptive transport of the peptide in comparison to antide in solution. Additional in vivo studies confirmed the potential of this novel conjugate. Oral administration of antide in solution led to only very small detectable quantities in plasma with an absolute and relative bioavailability (BA) of 0.003 and 0.03%, only. In contrast, with antide incorporated in TGA-MNA matrix tablets an absolute and relative BA of 1.4 and 10.9% could be reached, resulting in a 421-fold increased area under the plasma concentration time curve (AUC) compared to the antide solution. According to these results, S-protected thiolated chitosan as oral drug delivery system might be a valuable tool for improving the bioavailability of peptides. PMID- 22542700 TI - Design, production and optimization of solid lipid microparticles (SLM) by a coaxial microfluidic device. AB - This paper describes a method for the production of lipid microparticles (SLM) based on microfluidics using a newly designed modular device constituted of three main parts: a temperature control, a co-flow dripping element and a congealing element. The presented data demonstrated that the microfluidic approach resulted in the production of SLM with narrow size distribution and optimal morphological characteristics in term of sphericity, surface smoothness and absence of defects (i.e. partial coalescence or irregular shape). The optimization of SLM production was performed by screening the effect of different experimental parameters and device configurations by a classical intuitive approach COST (Changing One Separate factor a Time). This process allowed selecting the proper value for a number of parameters including, (i) the congealing element geometry, (ii) the presence and concentration of a stabilizer, (iii) the temperature of water and oil phases and (iv) the water and oil flow rates. In addition, the interplay between oil phase and water phase flow rates, in controlling the size and morphology of SLM, was investigated by a statistical "Design of the Experiments" approach (DoE). The combined use of COST and DoE studies allowed the production of optimized SLM for the encapsulation of dye/drugs. The obtained results demonstrated that the guest molecules did not affect the general characteristics of SLM, confirming the robustness of the microfluidic procedure in view of the production of SLM for biopharmaceutical and biotech protocols. PMID- 22542701 TI - Neuroimaging differences between older adults with maintained versus declining cognition over a 10-year period. AB - BACKGROUND: Maintaining cognitive function protects older adults from developing functional decline. This study aims to identify the neuroimaging correlates of maintenance of higher global cognition as measured by the Modified Mini Mental State Test (3 MS) score. METHODS: Repeated 3 MS measures from 1997-98 through 2006-07 and magnetic resonance imaging with diffusion tensor in 2006-07 were obtained in a biracial cohort of 258 adults free from dementia (mean age 82.9 years, 56% women, 42% blacks). Participants were classified as having shown either maintenance (3 MS slope>0) or decline (3 MS slope<1 SD below the mean) of cognition using linear mixed models. Measures of interest were white matter hyperintensity volume (WMHv) from total brain, volume of the gray matter (GMv) and microstructure (mean diffusivity, MD) for total brain and for brain areas known to be related to memory and executive control function: medial temporal area (hippocampus, parahippocampus and entorhinal cortex), cingulate cortex, dorsolateral prefrontal and posterior parietal cortex. RESULTS: Differences between cognitive maintainers (n=153) and non-maintainers (n=107) were significant for GMv of the medial temporal area (35.8%, p=0.004) and lower MD of the cingulate cortex (37.9%, p=0.008), but not for other neuroimaging markers. In multivariable regression models adjusted for age, race, WMHv and GMV from the total brain and vascular conditions, each standard deviation of GMv of the medial temporal area and each standard deviation of MD of the cingulate cortex were associated with a nearly 4 times greater probability (odds ratio [standard deviation]: 3.80 [1.16, 12.44]) and a 34% lower probability (0.66, [0.46, 0.97]) of maintaining cognitive function, respectively. In these models neither WMHv nor GMv from total brain were significantly associated with probability of maintaining cognitive function. CONCLUSIONS: Preserving the volume of the medial temporal area and the microstructure of the cingulate cortex may contribute to maintaining cognitive function late in life. PMID- 22542703 TI - Intercostal neuroma as a source of pain after aesthetic and reconstructive breast implant surgery. AB - The development of persistent post-operative pain after implant placement for aesthetic or reconstructive breast surgery can lead to significant patient morbidity. Although there are many etiologies for post-operative pain, the diagnosis of an intercostal neuroma is important as this can be treated surgically. We describe three cases of an intercostal neuroma in patients with breast implants. A Tinel's sign can be elicited along the lateral chest wall and a local anesthetic block temporarily alleviates this pain. Surgical management with identification and clipping of the intercostal neuroma and burying into the underlying muscle significantly decreases post-operative pain long term. In patients with persistent pain after breast implant placement, plastic surgeons must be aware of this treatable cause of pain. PMID- 22542704 TI - Impact of QRS duration of frequent premature ventricular complexes on the development of cardiomyopathy. AB - BACKGROUND: Patients with frequent premature ventricular complexes (PVCs) are at risk of developing reversible PVC-induced cardiomyopathy (rPVC-CMP). Not all determinants of rPVC-CMP are known. OBJECTIVE: To assess the impact of the QRS duration of PVCs on the development of rPVC-CMP. METHODS: In a consecutive series of 294 patients with frequent idiopathic PVCs referred for PVC ablation, the width of the PVC-QRS complex was assessed. The QRS width was correlated with the presence of rPVC-CMP. RESULTS: The PVC-QRS width was significantly greater in patients with rPVC-CMP than in patients without rPVC-CMP (164 +/- 20 ms vs 149 +/ 17 ms; P < .0001). The site of origin of the PVC had an impact on the PVC-QRS width, with epicardial PVCs having the broadest QRS complexes. Patients with PVCs originating from the right ventricular outflow tract or the fascicles had the narrowest QRS complexes. After adjusting for PVC burden, symptom duration, and PVC site of origin, PVC-QRS width and an epicardial PVC origin were independently associated with rPVC-CMP. Based on receiver operator characteristics analysis, a QRS duration of >150 ms best differentiated patients with and without rPVC-CMP (area under the curve 0.66; sensitivity 80%; specificity 52%). The PVC burden for developing rPVC-CMP is significantly lower in patients with a PVC-QRS width of >=150 ms than in patients with a narrower PVC-QRS complex (22% +/- 13% vs 28% +/- 12%; P < .0001). CONCLUSION: Broader PVCs and an epicardial PVC origin are associated with the development of rPVC-CMP independent of the PVC burden. PMID- 22542705 TI - Expression and prognostic significance of centromere protein A in human lung adenocarcinoma. AB - BACKGROUND: Centromere protein A (CENP-A), one of the fundamental components of the human active kinetochore, is frequently upregulated in many cancers and plays important roles in cell cycle regulation, cell survival, and genetic stability. The aim of the present study was to explore the expression and prognostic significance of CENP-A in lung adenocarcinoma. EXPERIMENTAL DESIGN: The expression of CENP-A was detected in 20 fresh human lung adenocarcinoma specimens and corresponding non-tumorous lung tissues by real-time polymerase chain reaction (RT-PCR) and Western blotting analysis. Using immunohistochemistry, we analyzed CENP-A protein expression in additional 309 lung adenocarcinomas. The clinicopathological and prognostic significance of CENP-A expression was analyzed. RESULTS: RT-PCR and Western blotting analysis revealed an enhanced expression of CENP-A in lung adenocarcinomas relative to adjacent non-tumorous lung tissues at both transcriptional and translational levels. Immunohistochemistry showed that 146 of 309 lung adenocarcinomas (47.3%) had high expression of CENP-A. CENP-A overexpression was significantly correlated with pathological grade (P=0.009), pT status (P=0.017), pN status (P=0.002), pleural invasion (P=0.013), high Ki-67 expression (P=0.003), and P53 positivity (P=0.001). Patients with high CENP-A expression had shorter overall survival time compared with those with low CENP-A expression. Multivariate analysis identified CENP-A as an independent prognostic factor for lung adenocarcinoma. CONCLUSION: Our results demonstrate that elevated CENP-A expression is closely associated with lung adenocarcinoma progression and has an independent prognostic value in predicting overall survival for patients with lung adenocarcinoma. PMID- 22542706 TI - Impact of non-small cell lung cancer histology on survival predicted from the graded prognostic assessment for patients with brain metastases. AB - INTRODUCTION: The Graded Prognostic Assessment (GPA) provides prognostic classification for patients with brain metastases (BM), based on Radiation Therapy Oncology Group (RTOG) data. Recent evidence suggests differential response and outcomes to chemotherapy for different non-small cell lung cancer (NSCLC) histologies. Using a large BM patient database, we assessed the impact of histologic subtypes on survival stratified by the GPA. METHODS: From an IRB approved database, we analyzed 780 patients with NSCLC BM treated from 1982 to 2004. GPA classification variables included age, KPS, number of BM, and presence of extracranial disease. Histology was identified for each patient. Median survival time (MST) based on GPA class and histology were calculated using Kaplan Meier analysis. The log rank test was used to determine statistical differences. RESULTS: MST, in months, by histology were: adenocarcinoma (AC) 6.2 (n=464), large cell (LC) 4.1 (n=98), squamous (SQ) 4.2 (n=108) (p=0.0549). For GPA 3.5 4.0, MSTs did not differ significantly by histology. Differences in MST by histology were noted for GPA 3.0 (p=0.04), GPA 1.5-2.5 (p=0.01), and GPA 0-1.0 (p=0.02). For all patients with brain metastases BM from NSCLC, MSTs by GPA score were: GPA 3.5-4.0, 12.6; GPA 3.0, 10.2; GPA 1.5-2.5, 5.8; and GPA 0-1.0, 2.7. CONCLUSIONS: Adenocarcinoma showed a statistically significant higher MST than other histologies of NSCLC for patients with GPA 0-3.0. Using histology as a prognostic factor for BM from NSCLC warrants further investigation. Our cohort of NSCLC BM patients validates the GPA, with MST comparable to that of published data. PMID- 22542702 TI - Morphogenetic fields in embryogenesis, regeneration, and cancer: non-local control of complex patterning. AB - Establishment of shape during embryonic development, and the maintenance of shape against injury or tumorigenesis, requires constant coordination of cell behaviors toward the patterning needs of the host organism. Molecular cell biology and genetics have made great strides in understanding the mechanisms that regulate cell function. However, generalized rational control of shape is still largely beyond our current capabilities. Significant instructive signals function at long range to provide positional information and other cues to regulate organism-wide systems properties like anatomical polarity and size control. Is complex morphogenesis best understood as the emergent property of local cell interactions, or as the outcome of a computational process that is guided by a physically encoded map or template of the final goal state? Here I review recent data and molecular mechanisms relevant to morphogenetic fields: large-scale systems of physical properties that have been proposed to store patterning information during embryogenesis, regenerative repair, and cancer suppression that ultimately controls anatomy. Placing special emphasis on the role of endogenous bioelectric signals as an important component of the morphogenetic field, I speculate on novel approaches for the computational modeling and control of these fields with applications to synthetic biology, regenerative medicine, and evolutionary developmental biology. PMID- 22542707 TI - Social inequalities and gender differences in the experience of alcohol-related problems. AB - AIMS: To examine the influence of country-level characteristics and individual socio-economic status (SES) on individual alcohol-related consequences. METHODS: Data from 42,655 men and women collected by cross-sectional surveys in 25 countries of the Gender, Alcohol and Culture: An International Study study were used. The individual SES was measured by the highest attained educational level. Alcohol-related consequences were defined as the self-report of at least one internal or one external consequence in the last year. The relationship between individuals' education and alcohol-related consequences was examined by meta analysis. In a second step, the individual level data and country data were combined in multilevel models. As country-level indicators, we used the purchasing power parity of the gross national income (GNI), the Gini coefficient and the Gender Gap Index. RESULTS: Lower educated men and women were more likely to report consequences than higher educated men and women even after controlling for drinking patterns. For men, this relation was significant for both internal and external problems. For women, it was only significant for external problems. The GNI was significantly associated with reporting external consequences for men such that in lower income countries men were more likely to report social problems. CONCLUSION: The fact that problems accrue more quickly for lower educated persons even if they drink in the same manner can be linked to the social or environmental dimension surrounding problems. That is, those of fewer resources are less protected from the experience of a problem or the impact of a stressful life event. PMID- 22542708 TI - Drinking concordance and relationship satisfaction in New Zealand couples. AB - AIMS: The aim of the study was to examine alcohol consumption patterns in New Zealand couples and the associations of these patterns with time spent drinking together and the level of satisfaction with the relationship. METHODS: Cross sectional survey of a nationally representative sample of New Zealand residents aged 18-70 on the combined electoral roll in 2007. Using reports of the respondents' own drinking patterns and their reports of their partners' drinking, couples were classified as concordant, mildly discordant or discordant for both their drinking frequency and quantity of alcohol consumed per typical drinking occasion. The level of concordance was compared by demographic characteristics and relationship type. Ordinal logistic regression models were used to examine the associations between levels of concordance and both time spent drinking as a couple and level of happiness in the relationship (both reported by the respondent). RESULTS: The largest proportion of couples was classified as concordant for both frequency and quantity of alcohol consumed per typical drinking occasion regardless of the relationship type. For both drinking frequency and quantity per occasion, couples identified as discordant or mildly discordant were less likely to report having spent a large amount of time drinking with their partner (odds ratio 0.2-0.5). Reported level of happiness with the relationship was also associated with the degree of concordance of both drinking frequency and quantity. CONCLUSION: These findings suggest that drinking frequency and quantity of alcohol consumed per typical drinking occasion are concordant in most intimate partnerships and that discordance in either is associated with a lower level of happiness within the relationship. PMID- 22542709 TI - A randomised trial of granulocyte-macrophage colony-stimulating factor for neonatal sepsis: outcomes at 2 years. AB - OBJECTIVE: The authors performed a randomised trial in very preterm small-for gestational age (SGA) babies to determine if prophylaxis with granulocyte macrophage colony-stimulating factor (GM-CSF) improves outcomes (the PROGRAMS trial). Despite increased neutrophil counts following GM-CSF, the authors reported no significant difference in neonatal sepsis-free survival. PATIENTS AND METHODS: 280 babies born <31 weeks of gestation and SGA were entered into the trial. Outcome was determined at 2 years to determine neurodevelopmental and general health outcomes, including economic costs. RESULTS: The authors found no significant differences in health outcomes or health and social care costs between the trial groups. In the GM-CSF arm, 87 of 134 (65%) babies survived to 2 years without severe disability compared with 87 of 131 (66%) controls (RR: 1.0, 95% CI 0.8 to 1.2). Marginally, more children receiving GM-CSF were reported to have cough (RR 1.7, 95% CI 1.1 to 2.6) and had signs of chronic respiratory disease (Harrison's sulcus; RR 2.0, 95% CI 1.0 to 3.9) though this was not reflected in bronchodilator use or need for hospitalisation for respiratory disease. Overall, the rate of neurologic abnormality (7%-9%) was similar but mean overall developmental scores were lower than expected for gestational age. CONCLUSIONS: The administration of GM-CSF to very preterm SGA babies is not associated with improved or more adverse outcomes at 2 years of age. The apparent excess of developmental impairment in the entire PROGRAMS cohort, without corresponding increase in neurological abnormality, may represent diffuse brain injury attributable to intrauterine growth restriction. PMID- 22542710 TI - Phase I study of the tolerability and pharmacokinetics of palifermin in children undergoing allogeneic hematopoietic stem cell transplantation. AB - The maximum tolerated dose of palifermin, a keratinocyte growth factor, in children is not known, and its pharmacokinetics in this population has not been well studied. This is a phase I study of palifermin was designed to evaluate its tolerability at doses of 40, 60, and 90 MUg/kg/day in children age 2-18 years of age, receiving a myeloablative preparative regimen for allogeneic hematopoietic stem cell transplantation (HSCT). In each cohort, palifermin was given for 3 consecutive days before the preparative regimen and for 3 days after the stem cell infusion. Twelve patients were enrolled. Palifermin 90 MUg/kg/day was tolerated in 6 patients without dose-limiting toxicity. All patients had at least 1 adverse event, mostly National Cancer Institute grade 1 or 2 severity. Skin rash, grade 2 or lower, was the most common adverse event, seen in 67% of patients. Only 3 patients (25%) had mucositis. The area under the concentration time curve increased proportionally to the dose, and approximately 97% of palifermin exposure occurred in the first 24 hours after administration. Palifermin clearance increased linearly with body weight, supporting dosing by body weight. The mean clearance was 1893 mL/hour/kg, and it did not change significantly between administration of the first and last doses (P = .80). The mean elimination half-life was 4.6 hours. Our data show that palifermin was tolerated at a dose of 90 MUg/kg/day, and exhibits linear pharmacokinetics in children undergoing allogeneic HSCT. PMID- 22542711 TI - Tissue expression of TGF-beta1 in uterine cervical samples from HIV/AIDS patients. AB - Case-control study based on the immunohistochemistry for TGF-beta1 evaluation of cervical samples obtained from two groups of women: CIN/HIV- and CIN/HIV+. Eleven women infected with HIV and with a histopathological diagnosis of CIN were included. The control group consisted of 12 patients with CIN. Cervical tissue samples obtained from all patients were submitted to histopathology and semiquantitative analysis of immunostaining for TGF-beta1 protein. In addition, the peripheral CD4+ cell count and viral load were evaluated in HIV + patients. Tissue expression of the cytokine was higher in the CIN/HIV+ group compared to control (p = 0.0023). In addition, higher TGF-beta1 expression was observed in higher grade cervical lesions in the two groups. There was a trend toward a direct correlation between peripheral CD4+ T cell count and tissue TGF-beta1, and toward an inverse correlation between viral load and cytokine expression. Thus, TGF-beta1 was more marked in situations in which cervical lesions are known to present a more aggressive behavior, suggesting that this cytokine is involved in the pathogenesis of tumor growth in these lesions. Tissue expression of TGF-beta1 is increased in cervical samples from HIV-infected women with CIN. PMID- 22542712 TI - CARD-024, a vitamin D analog, attenuates the pro-fibrotic response to substrate stiffness in colonic myofibroblasts. AB - Intestinal fibrosis is one of the major complications of Crohn's disease (CD) for which there are no effective pharmacological therapies. Vitamin D deficiency is common in CD, though it is not known whether this is a contributing factor to fibrosis, or simply a consequence of the disease itself. In CD, fibrosis is mediated mainly by activated intestinal myofibroblasts during remodeling of extracellular matrix in response to wound healing. We investigated the effects of CARD-024 (1-alpha-hydroxyvitamin D5), a vitamin D analog with minimal hypercalcemic effects, on the pro-fibrotic response of intestinal myofibroblasts to two fibrogenic stimuli: TGFbeta stimulation and culture on a physiologically stiff matrix. TGFbeta stimulated a fibrogenic phenotype in Ccd-18co colonic myofibroblasts, characterized by an increase in actin stress fibers and mature focal adhesions, and increased alphaSMA protein expression, while CARD-024 repressed alphaSMA protein expression in a dose-dependent manner. Culture of colonic myofibroblasts on physiological high stiffness substrates induced morphological changes with increased actin stress fibers and focal adhesion staining, induction of alphaSMA protein expression, FAK phosphorylation, induction of fibrogenic genes, and repression of COX-2 and IL-1beta. CARD-024 treatment repressed the stiffness-induced morphological features including stellate cell morphology and the maturation of focal adhesions. CARD-024 repressed the stiffness-mediated induction of alphaSMA protein expression, FAK phosphorylation, and MLCK and ET-1 gene expression. In addition, CARD-024 partially stimulated members of the COX-2/IL-1beta inflammatory pathway. In summary, CARD-024 attenuated the pro-fibrotic response of colonic myofibroblasts to high matrix stiffness, suggesting that vitamin D analogs such as CARD-024 may ameliorate intestinal fibrosis. PMID- 22542713 TI - Intracellular Ca2+ waves, afterdepolarizations, and triggered arrhythmias. PMID- 22542714 TI - Decreased fibrocyte number is associated with atherosclerotic plaque instability in man. AB - AIMS: Plaque rupture partly results from inadequate collagen synthesis due to lower smooth muscle cell numbers in fibrous caps. Fibrocytes are bone-marrow derived circulating mesenchymal progenitors and have recently been identified in fibrous caps. This study hypothesized that reduced fibrocyte numbers would be associated with plaque instability. METHODS AND RESULTS: Patients with acute myocardial infarction (MI) (n = 22), stable angina (SA) (n = 20), or healthy controls (n = 22) were recruited. Circulating fibrocytes (CD45(+)/CD34(+)/collagen I(+)) were measured by flow cytometry. Peripheral blood mononuclear cells (PBMCs) were isolated from blood and cultured for 2 weeks, and fibrocytes were quantified by morphology (spindle-shaped) and flow cytometry (CD45(+)/collagen I(+)). Another set of PBMCs was stimulated with macrophage colony-stimulating factor (M-CSF) for 72 h and the expression of several macrophage markers was measured by flow cytometry. Acute MI patients had decreased circulating fibrocyte numbers compared with healthy controls or SA patients. Following 2 weeks' culture, both the number of spindle-shaped fibrocytes counted under the microscope and the percentage of fibrocytes of the remaining adherent cells in culture measured by flow cytometry were reduced in acute MI patients. Expression of macrophage markers CD68, CD36, and EMR in M-CSF stimulated PBMCs was enhanced in acute MI patients compared with the other two groups. SA patients with previous MI had decreased circulating fibrocyte numbers and a lower yield of fibrocytes from PBMCs than those without previous MI. CONCLUSIONS: This is the first report of decreased fibrocyte numbers in patients with MI. Reduced fibrocytes and preferential differentiation of PBMCs into macrophages may contribute to plaque instability. PMID- 22542716 TI - The influence of emotional intensity on facial emotion recognition in disordered eating. AB - Significant facial emotion recognition (FER) deficits have been observed in participants exhibiting high levels of eating psychopathology. The current study aimed to determine if the pattern of FER deficits is influenced by intensity of facial emotion and to establish if eating psychopathology is associated with a specific pattern of emotion recognition errors that is independent of other psychopathological or personality factors. Eighty females, 40 high and 40 low scorers on the Eating Disorders Inventory (EDI) were presented with a series of faces, each featuring one of five emotional expressions at one of four intensities, and were asked to identify the emotion portrayed. Results revealed that, in comparison to Low EDI scorers, high scorers correctly recognised significantly fewer expressions, particularly of fear and anger. There was also a trend for this deficit to be more evident for subtle displays of emotion (50% intensity). Deficits in anger recognition were related specifically to scores on the body dissatisfaction subscale of the EDI. Error analyses revealed that, in comparison to Low EDI scorers, high scorers made significantly more and fear-as anger errors. Also, a tendency to label anger expressions as sadness was related to body dissatisfaction. Current findings confirm FER deficits in subclinical eating psychopathology and extend these findings to subtle expressions of emotion. Furthermore, this is the first study to establish that these deficits are related to a specific pattern of recognition errors. Impaired FER could disrupt normal social functioning and might represent a risk factor for the development of more severe psychopathology. PMID- 22542717 TI - How physicians document outpatient visit notes in an electronic health record. AB - BACKGROUND: Clinical documentation, an essential process within electronic health records (EHRs), takes a significant amount of clinician time. How best to optimize documentation methods to deliver effective care remains unclear. OBJECTIVE: We evaluated whether EHR visit note documentation method was influenced by physician or practice characteristics, and the association of physician satisfaction with an EHR notes module. MEASUREMENTS: We surveyed primary care physicians (PCPs) and specialists, and used EHR and provider data to perform a multinomial logistic regression of visit notes from 2008. We measured physician documentation method use and satisfaction with an EHR notes module and determined the relationship between method and physician and practice characteristics. RESULTS: Of 1088 physicians, 85% used a single method to document the majority of their visits. PCPs predominantly documented using templates (60%) compared to 34% of specialists, while 38% of specialists predominantly dictated. Physicians affiliated with academic medical centers (OR 1.96, CI (1.23, 3.12)), based at a hospital (OR 1.57, 95% CI (1.04, 2.36)) and using the EHR for longer (OR 1.13, 95% CI (1.03, 1.25)) were more likely to dictate than use templates. Most physicians of 383 survey responders were satisfied with the EHR notes module, regardless of their preferred documentation method. CONCLUSIONS: Physicians predominantly utilized a single method of visit note documentation and were satisfied with their approach, but the approaches they chose varied. Demographic characteristics were associated with preferred documentation method. Further research should focus on why variation exists, and the quality of the documentation resulting from different methods used. PMID- 22542715 TI - Regulation and physiological roles of the calpain system in muscular disorders. AB - Calpains, a family of Ca(2+)-dependent cytosolic cysteine proteases, can modulate their substrates' structure and function through limited proteolytic activity. In the human genome, there are 15 calpain genes. The most-studied calpains, referred to as conventional calpains, are ubiquitous. While genetic studies in mice have improved our understanding about the conventional calpains' physiological functions, especially those essential for mammalian life as in embryogenesis, many reports have pointed to overactivated conventional calpains as an exacerbating factor in pathophysiological conditions such as cardiovascular diseases and muscular dystrophies. For treatment of these diseases, calpain inhibitors have always been considered as drug targets. Recent studies have introduced another aspect of calpains that calpain activity is required to protect the heart and skeletal muscle against stress. This review summarizes the functions and regulation of calpains, focusing on the relevance of calpains to cardiovascular disease. PMID- 22542719 TI - Bone morphogenetic protein-2 will be a novel biochemical marker in urinary tract infections and stone formation. AB - OBJECTIVES: To investigate the role of bone morphogenetic protein-2 (BMP-2) in patients with urinary tract infection (UTI) and renal stone in relation to Tamm Horsfall protein (THP) and osteopontin (OPN). DESIGN AND METHODS: ELISA kits were used to determine these markers in serum and urinary samples of 20 patients with UTI, 15 with renal stone and 10 controls. RESULTS: BMP-2 significantly increased in serum of patients who had UTI (P=0.05) and renal stone (P=0.01). In the case of UTI, serum BMP-2 at cutoff 44 pg/mL had sensitivity and specificity (92%, 80%), while cystatin C at cutoff 525 ng/mL showed sensitivity and specificity (85%, 91%). THP is a good predictor of renal diseases (P<0.001) by regression analysis. It is also the most sensitive urinary marker for UTI with sensitivity and specificity (94%, 75%) at cutoff 305 ng/mL. CONCLUSION: Combination of serum BMP-2 and cystatin C are more sensitive and accurate for early diagnosis of renal infection and damage. PMID- 22542718 TI - Association of hsp70-2 (+1267A/G), hsp70-hom (+2437T/C), HMOX-1 (number of GT repeats) and TNF-alpha (+489G/A) polymorphisms with COPD in Croatian population. AB - OBJECTIVE: To test for possible association of hsp70-2 (+1267A/G), hsp70-hom (+2437T/C), HMOX-1 (number of GT repeats) and TNF-alpha (+489G/A) polymorphisms with chronic obstructive pulmonary disease (COPD) in Croatian population. METHODS: Genotyping of DNA isolated from whole blood of 130 COPD patients (as defined by spirometry) and 95 healthy controls was performed. Fragment size analysis upon restriction enzyme digestion and/or sequencing was used for genotype/allele definition. Significance of findings was tested using chi(2) test. RESULTS: hsp70-2 (+1267A/G) polymorphism was significantly associated with COPD. Results of genotyping analysis indicated that a genotype carrying G allele was preferentially associated with COPD; odds ratio (OR)=1.50, 95% confidence interval (CI)=1.00-2.24 and P=0.061. OR for the GG genotype was 3.47 with CI=1.26 9.56 and P=0.04. No association for hsp70-hom (+2437T/C), TNF-alpha (+489G/A) and HMOX-1 (number of GT repeats) polymorphisms were found. In addition, comparison of genotype frequencies among different stages of disease severity (GOLD II-IV) revealed no discrimination for any of the tested polymorphisms. CONCLUSION: This study is supporting the association of hsp70-2 (+1267A/G) polymorphism and COPD. Higher frequency of G allele and GG genotype in Croatian COPD patients was observed. There was no evidence for the association of hsp70-hom (+2437T/C), TNF alpha (+489G/A) SNPs and HMOX-1 (number of GT repeats) polymorphism with COPD. Allele and genotype frequencies for all of the tested polymorphisms show no association with disease severity (GOLD II-IV). PMID- 22542720 TI - [Clostridium difficile reactive arthritis in a 7-year-old child]. AB - Clostridium difficile reactive arthritis is a rare disease; only 5 pediatric cases have been reported in the literature. Its diagnosis is challenging. It manifests as asymmetric aseptic poly- or oligoarthritis, contemporary to infectious colitis, usually after a period of antibiotic therapy. We report a new case in a 7-year-old boy who presented with unusual polyarthritis affecting 12 joints 1 month after antibiotic therapy with amoxicillin-clavulanate. Punctures of both hip joints proved sterile but significantly improved symptoms. Diarrheic stool cultures during hospitalization provided the diagnosis. Antibiotic therapy using metronidazole completely resolved pain and joint swelling within a week. After 1 year of follow-up, there has been no recurrence. We present a review of the literature on this disease and underline the advantages of joint aspiration in this condition with the dual aim of not missing septic arthritis and effectively relieving pain. PMID- 22542721 TI - [Advantages and difficulties of an erythrocytapheresis program for sickle-cell patients: a pediatric experience]. AB - Transfusion programs are sometimes necessary to take care of severe sickle-cell patients. Treatment of cerebrovascular disease in sickle-cell disease is the most common indication. Periodic automated red blood cell exchange (erythrocytapheresis) is an alternative treatment. Sixteen patients less than 20 years old have been treated with chronic erythrocytapheresis since 2004 in the pediatric hematology and oncology department of the University Hospital of Rouen, 10 patients for cerebrovascular disease (1 was on secondary prevention and 9 were on primary prevention), 5 patients for pain crisis recurrence, and the last one for mild psychocognitive deficit disorder. This treatment was unsuccessful for 4 patients, 3 on primary prevention and 1 treated for pain crisis recurrence. These failures were caused by alloimmunization for 2 patients and venous access problems for 2 patients. For the other 12 patients, 5 of the 6 patients on primary prevention showed clear improvement (normalization of transcranial Doppler ultrasound or improvement on magnetic resonance angiography), the patient on secondary prevention had stability on cerebral MRI after 2 years of treatment, the 5 patients with pain crisis recurrence had good improvement, and psychocognitive abilities improved for the last patient. One hundred and ninety nine erythroexchange sessions were performed for the 9 patients treated over a period of 10 to 30 months. Erythrocytapheresis sessions ran on average less than 1.5h. Three patients showed high ferritin levels at the beginning of erythroexchange, which normalized 2 to 10 months later. All patients reported better quality of life. Periodic erythroexchanges are an effective treatment for complicated sickle-cell anemia and iron overload. It requires human, material, and financial support, but not as much as simple transfusion or manual erythroexchange. Practical experience shows problems of venous access because of coagulation when sampling. PMID- 22542722 TI - [Orbital bone infarction in a child with homozygous sickle cell disease]. AB - Vaso-occlusive crises are the most common complication of sickle cell disease. Orbital bone infarction is an unusual manifestation of sickling disorders. It is suspected in patients with acute painful periorbital swelling. Orbital compression syndrome with possible optic nerve injury is a rare but serious complication; therefore, this diagnosis should be considered. Orbital infarction can be difficult to distinguish from osteomyelitis or skin infections. Imaging can be helpful in differentiating infection from infarction. We report a case of orbital bone infarction in a 14-year-old boy with sickle cell disease. Under medical treatment, the clinical course resolved with no sequelae. PMID- 22542723 TI - [Adolescence and type 1 diabetes: self-care and glycemic control]. AB - INTRODUCTION: Type 1 diabetes is one of the most frequent chronic diseases in children and adolescents. Self-care support is a crucial aspect of the medical care provided to adolescent patients with type 1 diabetes. In the perspective of health promotion, which seeks to empower people to become the actors of their own health, self-care may be operationalized in three dimensions: psychosocial life, general health, and disease. We looked at the process of autonomization in adolescents 13-15 years of age, and hypothesized that their level of glycemic control (HbA1c) would be related to their perceived level of self-care. PATIENTS AND METHODS: We conducted an exploratory study through 32 in-depth interviews with adolescents aged 13-15 years. The data collected was analyzed quantitatively and qualitatively, based on the annual mean HbA1c level. RESULTS: Significantly higher scores of perceived self-care were associated with levels of HbA1c <= 7.5% (P=0.038). Overall, adolescents with good glycemic control reported greater autonomy and complexity in self-care behaviors in all three dimensions of self care. Moreover, our results show that adolescents with poor glycemic control tend to restrict the definition of self-care to its medical dimension and to exclude the psychosocial dimension. CONCLUSION: Our study confirms the hypothesis of a relation between HbA1c and the self-reported level of self-care in adolescents with type 1 diabetes. Moreover, it emphasizes the need to better respond to the young patients' psychosocial needs, in order to improve the long-term follow-up of adolescents with type 1 diabetes. PMID- 22542725 TI - The CPEB-family of proteins, translational control in senescence and cancer. AB - Cytoplasmic elongation of the poly(A) tail was originally identified as a mechanism to activate maternal mRNAs, stored as silent transcripts with short poly(A) tails, during meiotic progression. A family of RNA-binding proteins named CPEBs, which recruit the translational repression or cytoplasmic polyadenylation machineries to their target mRNAs, directly mediates cytoplasmic polyadenylation. Recent years have witnessed an explosion of studies showing that CPEBs are not only expressed in a variety of somatic tissues, but have essential functions controlling gene expression in time and space in the adult organism. These "new" functions of the CPEBs include regulating the balance between senescence and proliferation and its pathological manifestation, tumor development. In this review, we summarize current knowledge on the functions of the CPEB-family of proteins in the regulation of cell proliferation, their target mRNAs and the mechanism controlling their activities. PMID- 22542724 TI - Leptin replacement therapy does not improve the abnormal lipid kinetics of hypoleptinemic patients with HIV-associated lipodystrophy syndrome. AB - Patients with HIV-associated dyslipidemic lipodystrophy (HADL) have characteristic lipid kinetic defects: accelerated lipolysis, blunted fat oxidation and increased hepatic fatty acid reesterification. HADL patients with lipoatrophy also have leptin deficiency. Small or non-randomized studies have suggested that leptin replacement improves glucose metabolism in HADL, with very limited data regarding its effects on the lipid kinetic abnormalities. We performed a randomized, double-blind, placebo-controlled, dose-escalating (0.02 mg/kg/d for two months; 0.04 mg/kg/d for a further two months) study of the effects of metreleptin on lipid kinetics in 17 adults with HADL, hypertriglyceridemia and hypoleptinemia. Rates of lipolysis, intra-adipocyte and intrahepatic reesterification and fatty acid oxidation were measured using infusions of (13)C(1)-palmitate and (2)H(5)-glycerol, and indirect calorimetry. Fasting lipid profiles and glucose and insulin responses to oral glucose challenge were also measured. Metreleptin treatment induced significant, dose dependent increases in fasting plasma leptin levels. There was no significant change in total lipolysis, net lipolysis, adipocyte or hepatic re-esterification or fatty acid oxidation, or in fasting triglyceride or HDL-C concentrations, with metreleptin treatment. Metreleptin decreased fasting non-HDL-C levels (P<.01) and area-under-the-curve for glucose (P<.05). In hypoleptinemic HADL patients, treatment with metreleptin at 0.02 or 0.04 mg/kg/d does not improve abnormal fasting lipid kinetics, or triglyceride or HDL-C levels. Metreleptin does, however, improve glycemia and non-HDL-C in these patients. These results suggest a dissociation between leptin's effects on glucose metabolism compared to those on lipid kinetics in HADL. PMID- 22542726 TI - Clinical manifestations of human immunodeficiency virus-induced uveitis. AB - PURPOSE: To describe the clinical manifestations of patients with human immunodeficiency virus (HIV)-induced uveitis in Thailand. DESIGN: Prospective cohort study of 6 patients with HIV-induced uveitis. PARTICIPANTS: Six patients (8 eyes) with HIV-induced uveitis who had an extremely high intraocular: plasma HIV-1 RNA ratio. METHODS: The clinical manifestations and laboratory findings are reported of 6 consecutive patients with HIV-induced uveitis who had an extremely high intraocular-to-plasma HIV-1 RNA ratio and were diagnosed between July 2009 and May 2011. MAIN OUTCOME MEASURES: Clinical manifestations and laboratory findings. RESULTS: Human immunodeficiency virus-induced uveitis was diagnosed in 4 men and 2 women with an average age of 41 years at presentation. None of the patients were receiving highly active anti-retroviral therapy (HAART) or had clinical or laboratory evidence, or both, of opportunistic infections. The mean plasma load was 218 688 copies/ml (median, 137 500 copies/ml; range, 24 900-540 000 copies/ml), and the mean intraocular HIV load was 20 937 755 copies/ml (median, 7 499 000 copies/ml; range, 2 460 000-89 800 000 copies/ml). The average CD4 cell count was 192 cells/MUl (median, 248 cells/MUl; range, 5-342 cells/MUl). All the patients had decreased vision, and none had conjunctival hyperemia. The anatomic location of uveitis was anterior in all patients, and associated vitreitis was present in 4 patients; none exhibited retinal lesions or scars. Anterior segment inflammation and keratic precipitates were observed in all patients, and none responded to topical corticosteroid therapy. After the administration of HAART, the intraocular inflammation disappeared entirely within several weeks in all of the patients and the intraocular and plasma HIV loads decreased. CONCLUSIONS: Human immunodeficiency virus-induced uveitis should be suspected in HAART-naive, HIV-positive patients or in those in whom this treatment fails and who have anterior uveitis without any retinal lesions and exhibit no response to topical corticosteroids. The concurrent determination of HIV load in the intraocular fluids and plasma may clarify the cause of HIV associated uveitis. PMID- 22542727 TI - Impaired non-speech auditory processing at a pre-reading age is a risk-factor for dyslexia but not a predictor: an ERP study. AB - Impaired auditory sensitivity to amplitude rise time (ART) has been suggested to be a primary deficit in developmental dyslexia. The present study investigates whether impaired ART-sensitivity at a pre-reading age precedes and predicts later emerging reading problems in a sample of Dutch children. An oddball paradigm, with a deviant that differed from the standard stimulus in ART, was administered to 41-month-old children (30 genetically at-risk for developmental dyslexia and 14 controls) with concurrent EEG measurement. A second deviant that differed from the standard stimulus in frequency served as a control deviant. Grade two reading scores were used to divide the at-risks in a typical-reading and a dyslexic subgroup. We found that both ART- and frequency processing were related to later reading skill. We however also found that irrespective of reading level, the at risks in general showed impaired basic auditory processing when compared to controls and that it was impossible to discriminate between the at-risk groups on basis of both auditory measures. A relatively higher quality of early expressive syntactic skills in the typical-reading at-risk group might indicate a protective factor against negative effects of impaired auditory processing on reading development. Based on these results we argue that ART- and frequency-processing measures, although they are related to reading skill, lack the power to be considered single-cause predictors of developmental dyslexia. More likely, they are genetically driven risk factors that may add to cumulative effects on processes that are critical for learning to read. PMID- 22542728 TI - Esophageal gastrointestinal stromal tumor: report of 7 patients. AB - PURPOSE: To evaluate imaging features of esophageal gastrointestinal stromal tumors (GIST) with clinical and histopathologic correlation and imaging follow up. MATERIALS AND METHODS: In this institutional review board-approved, Health Insurance Portability and Accountability Act-compliant retrospective study, 14 patients with pathologically proven esophageal GIST seen from January 2001 to October 2011, 7 patients (4 women; mean age 70 years, range 56-87 years) who had imaging of primary tumor and follow-up imaging at our institution were included. Imaging studies were evaluated by 3 radiologists in consensus. Location, size and imaging features of primary tumor and metastases, if any, were recorded, and correlated with pathologic (histopathologic subtype, presence of necrosis, mitotic rate, immunohistochemical profile) and clinical (treatment-related changes, distant spread and outcome) parameters. RESULTS: Of 7 tumors, 5 were located in the lower esophagus and 2 in mid-esophagus. Four were intraluminal, 2 were exophytic, and 1 was intramural. All 7 patients underwent computed tomography (CT); tumors appeared as well-circumscribed, hypoattenuating masses showing mild enhancement, with mean size of 5.7 * 4.2 cm. Necrosis and calcification were seen in 1 tumor each. Five patients underwent fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT. GISTs were FDG avid with mean standardized uptake value (SUV)[max] of 9.5 (4.5-12.3). All tumors were positive for KIT (7/7) and CD34 (6/6). Distant metastases to liver and pleura were seen in 1 patient. On imatinib treatment, the tumors responded with decreased attenuation values and unchanged size on CT, and decreased SUV[max] of primary tumor and metastases on FDG-PET/CT. CONCLUSION: Esophageal GISTs are well circumscribed, FDG-avid, hypoattenuating masses that can metastasize to liver and pleura, and respond to imatinib treatment with decreased attenuation value on CT and decreased SUV[max] on FDG-PET/CT. PMID- 22542730 TI - Odontogenic skin sinus: a commonly overlooked skin presentation. AB - Facial skin lesions present routinely to clinic and are largely dermatological in origin. Odontogenic infections are an unusual cause of facial lesion and are well described in the dental literature; however they are regularly overlooked and mismanaged, often to considerable aesthetic detriment. We present such a case and highlight important avoidable pitfalls. PMID- 22542729 TI - Asymmetric implants for breast asymmetry. AB - The indications, advantages, and disadvantages of round and anatomical implants have previously been described. The principles of biodimensional implant selection have been developed by several authors, where the objective choice of breast prosthesis for augmentation is based on the patient's breast tissues. This process has largely been applied to anatomical implant selection. We report a case of breast asymmetry, where we have applied the same concepts in the selection of implants based on tissue dimension. This resulted in an anatomical implant being used to augment the left breast, and a round implant on the right. To our knowledge a round implant and an anatomical implant have not previously been employed in the same patient to correct breast asymmetry. This resulted in excellent postoperative symmetry. PMID- 22542731 TI - Orthopedic applications of silicon nitride ceramics. AB - Silicon nitride (Si(3)N(4)) is a ceramic material developed for industrial applications that demand high strength and fracture resistance under extreme operating conditions. Recently, Si(3)N(4) has been used as an orthopedic biomaterial, to promote bone fusion in spinal surgery and to develop bearings that can improve the wear and longevity of prosthetic hip and knee joints. Si(3)N(4) has been implanted in human patients for over 3 years now, and clinical trials with Si(3)N(4) femoral heads in prosthetic hip replacement are contemplated. This review will provide background information and data relating to Si(3)N(4) ceramics that will be of interest to engineering and medical professionals. PMID- 22542732 TI - Assessment of CA1 injury after global ischemia using supervised 2D analyses of nuclear pyknosis. AB - Selective neuronal vulnerability is a common theme in both acute and chronic diseases affecting the nervous system. This phenomenon is particularly conspicuous after global cerebral ischemia wherein CA1 pyramidal neurons undergo delayed death while surrounding hippocampal regions are relatively spared. While injury in this model can be easily demonstrated using either histological or immunological stains, current methods used to assess the cellular injury present in these biological images lack the precision required to adequately compare treatment effects. To address this shortcoming, we devised a supervised work-flow that can be used to quantify ischemia-induced nuclear condensation using microscopic images. And while we demonstrate the utility of this technique using models of ischemic brain injury, the approach can be readily applied to other paradigms in which programmed cell death is a major component. PMID- 22542733 TI - Prevalence of bicycle helmet use by users of public bikeshare programs. AB - STUDY OBJECTIVE: Public bikeshare programs are becoming increasingly common in the United States and around the world. These programs make bicycles accessible for hourly rental to the general public. We seek to describe the prevalence of helmet use among adult users of bikeshare programs and users of personal bicycles in 2 cities with recently introduced bikeshare programs (Boston, MA, and Washington, DC). METHODS: We performed a prospective observational study of adult bicyclists in Boston, MA, and Washington, DC. Trained observers collected data during various times of the day and days of the week. Observers recorded the sex of the bicycle operator, type of bicycle, and helmet use. All bicycles that passed a single stationary location in any direction for a period of between 30 and 90 minutes were recorded. RESULTS: There were 43 observation periods in 2 cities at 36 locations; 3,073 bicyclists were observed. There were 562 (18.3%; 95% confidence interval [CI] 16.4% to 20.3%) bicyclists riding shared bicycles. Overall, 54.5% of riders were unhelmeted (95% CI 52.7% to 56.3%), although helmet use varied significantly with sex, day of use, and type of bicycle. Bikeshare users were unhelmeted at a higher rate compared with users of personal bicycles (80.8% versus 48.6%; 95% CI 77.3% to 83.8% versus 46.7% to 50.6%). Logistic regression, controlling for type of bicycle, sex, day of week, and city, demonstrated that bikeshare users had higher odds of riding unhelmeted (odds ratio [OR] 4.4; 95% CI 3.5 to 5.5). Men had higher odds of riding unhelmeted (OR 1.6; 95% CI 1.4 to 1.9), as did weekend riders (OR 1.3; 95% CI 1.1 to 1.6). CONCLUSION: Use of bicycle helmets by users of public bikeshare programs is low. As these programs become more popular and prevalent, efforts to increase helmet use among users should increase. PMID- 22542734 TI - Association between repeated intubation attempts and adverse events in emergency departments: an analysis of a multicenter prospective observational study. AB - STUDY OBJECTIVE: Although repeated intubation attempts are believed to contribute to patient morbidity, only limited data characterize the association between the number of emergency department (ED) laryngoscopic attempts and adverse events. We seek to determine whether multiple ED intubation attempts are associated with an increased risk of adverse events. METHODS: We conducted an analysis of a multicenter prospective registry of 11 Japanese EDs between April 2010 and September 2011. All patients undergoing emergency intubation with direct laryngoscopy as the initial device were included. The primary exposure was multiple intubation attempts, defined as intubation efforts requiring greater than or equal to 3 laryngoscopies. The primary outcome measure was the occurrence of intubation-related adverse events in the ED, including cardiac arrest, dysrhythmia, hypotension, hypoxemia, unrecognized esophageal intubation, regurgitation, airway trauma, dental or lip trauma, and mainstem bronchus intubation. RESULTS: Of 2,616 patients, 280 (11%) required greater than or equal to 3 intubation attempts. Compared with patients requiring 2 or fewer intubation attempts, patients undergoing multiple attempts exhibited a higher adverse event rate (35% versus 9%). After adjusting for age, sex, principal indication, method, medication, and operator characteristics, intubations requiring multiple attempts were associated with an increased odds of adverse events (odds ratio 4.5; 95% confidence interval 3.4 to 6.1). CONCLUSION: In this large Japanese multicenter study of ED patients undergoing intubation, we found that multiple intubation attempts were independently associated with increased adverse events. PMID- 22542735 TI - Subcellular differences in handling Cu excess in three freshwater fish species contributes greatly to their differences in sensitivity to Cu. AB - Since changes in metal distribution among tissues and subcellular fractions can provide insights in metal toxicity and tolerance, we investigated this partitioning of Cu in gill and liver tissue of rainbow trout (Oncorhynchus mykiss), common carp (Cyprinus carpio) and gibel carp (Carassius auratus gibelio). These fish species are known to differ in their sensitivity to Cu exposure with gibel carp being the most tolerant and rainbow trout the most sensitive. After an exposure to 50 MUg/l (0.79 MUM) Cu for 24h, 3 days, 1 week and 1 month, gills and liver of control and exposed fish were submitted to a differential centrifugation procedure. Interestingly, there was a difference in accumulated Cu in the three fish species, even in control fishes. Where the liver of rainbow trout showed extremely high Cu concentrations under control conditions, the amount of Cu accumulated in their gills was much less than in common and gibel carp. At the subcellular level, the gills of rainbow trout appeared to distribute the additional Cu exclusively in the biologically active metal pool (BAM; contains heat-denaturable fraction and organelle fraction). A similar response could be seen in gill tissue of common carp, although the percentage of Cu in the BAM of common carp was lower compared to rainbow trout. Gill tissue of gibel carp accumulated more Cu in the biologically inactive metal pool (BIM compared to BAM; contains heat-stable fraction and metal-rich granule fraction). The liver of rainbow trout seemed much more adequate in handling the excess Cu (compared to its gills), since the storage of Cu in the BIM increased. Furthermore, the high % of Cu in the metal-rich granule fraction and heat-stable fraction in the liver of common carp and especially gibel carp together with the better Cu handling in gill tissue, pointed out the ability of the carp species to minimize the disadvantages related to Cu stress. The differences in Cu distribution at the subcellular level of gills and liver of these fish species strongly reflects their capacity to handle Cu excess and is one of the greatest contributors to their difference in sensitivity to Cu. PMID- 22542736 TI - Characterization of a bystander effect induced by the endocrine-disrupting chemical 6-propyl-2-thiouracil in zebrafish embryos. AB - This study was conducted to evaluate possible bystander effects induced by the model chemical 6-propyl-2-thiouracil (PTU) on melanin synthesis. Zebrafish (Danio rerio) embryos were treated with PTU by either microinjection exposure, via waterborne exposure or indirectly through bystander exposure. Melanin content, related mRNA and protein expression were examined at the end of exposure (36 h post-fertilization). Direct exposure to PTU decreased the melanin content, up regulated mRNA expressions of oculocutaneous albinism type 2 (OCA2), tyrosinase (TYR), dopachrometautomerase (DCT), tyrosinase-related protein 1 (TYRP1) and silver (SILV), and increased the protein expressions of TYR and SILV. Bystander exposure also up-regulated mRNA and protein expressions of TYR and SILV but increased melanin contents. Correlation analysis demonstrated that mRNA expressions of OCA2, TYR, DCT, TYRP1, SILV and protein expressions of TYR and SILV in bystander exposure groups were positively correlated with corresponding expressions in microinjection exposure groups. The results might have environmental implications and highlight the need to consider the bystander effects when assessing potential risks of endocrine-disrupting chemicals. PMID- 22542737 TI - Long-term effects of a binary mixture of perfluorooctane sulfonate (PFOS) and bisphenol A (BPA) in zebrafish (Danio rerio). AB - Previous in vitro studies have reported the potential of perfluorooctane sulfonate (PFOS) to increase the toxicity of other compounds. Given the complex nature of mixtures of environmental pollutants in aquatic systems together with the persistent and bioaccumulative properties of PFOS, this study aimed at evaluating the long-term effects and toxicity-increasing behavior of PFOS in vivo using the zebrafish (Danio rerio). Fish were maintained in flow-through conditions and exposed to single and binary mixtures of PFOS and the endocrine disruptor bisphenol A (BPA) at nominal concentrations of 0.6, 100 and 300 MUg/L and 10, 200 and 400 MUg/L, respectively. F1 and F2 generations were evaluated from 0 to 180 days post-fertilization (dpf) and F3 generation was evaluated from 0 to 14 dpf. Survival was documented in all generations, whereas growth, fecundity, fertilization rate, histological alterations (in liver, thyroid and gonads) and vitellogenin (Vtg) induction in males were evaluated for F1 and F2 generations. Data for growth were collected at 30, 90 and 180 dpf and data for histological evaluations and Vtg induction were analyzed at 90 and 180 dpf. No significant effects on survival were seen in the F1 generation in any treatment following 180 d exposure; however, in the F2 generation, 300 MUg/L PFOS both alone and in combination with BPA (10, 200 and 400 MUg/L) induced 100% mortality within 14 dpf. PFOS (0.6 and 300 MUg/L) did not increase the Vtg-inducing potential of BPA (10, 200 and 400 MUg/L) in a binary mixture. In contrast, binary mixtures with 300 MUg/L PFOS suppressed the Vtg levels in F1 males at 90 dpf when compared to single BPA exposures. Whereas the lowest tested PFOS concentration (0.6 MUg/L) showed an estrogenic potential in terms of significant Vtg induction, Vtg levels were generally found to decrease with increasing PFOS-exposure in both F1 and F2 generations. In F1 generation, BPA-exposure was found to increase Vtg levels in a concentration-dependent manner. Histological analyses of F1 and F2 fish revealed hepatocellular vacuolization, predominantly in males, following PFOS-exposure both alone and in combination with BPA. Hepatotoxicity by PFOS might explain the suppressed Vtg response seen in PFOS-exposed F1 and F2 males. PFOS-exposed fish also showed granulomas, mainly in the liver. Given previous reports of the immunosuppressive potential of PFOS, the granulomas could be a consequence of a PFOS-induced reduction of the immune response potential. In conclusion, the hypothesis that the presence of PFOS increases the endocrine potential of BPA could not be confirmed in zebrafish. Adverse effects on liver structure and survival were only seen at concentrations well above ecologically relevant concentrations; however, the decline in survival rates following PFOS exposure seen over generations again documents the importance of long-term studies for the investigation of persistent environmental pollutants. PMID- 22542738 TI - Immunotoxicology of non-functionalized engineered nanoparticles in aquatic organisms with special emphasis on fish--review of current knowledge, gap identification, and call for further research. AB - The rapid increase in use of nanotechnology products is increasing the presence of metal, metal-oxide and carbon-based nanoparticles in the aquatic environment. These non-functionalized engineered nanoparticles can interact with the immune system of fish and invertebrates, and tip the ecological balance of population sustainability. Most nanoparticle types present in the aquatic environment, such as titanium dioxide, do not exhibit or have very low direct toxicity, but instead display silent or concealed sub-lethal effects on the immune system with serious implications. There is a gap in current available information regarding the immunotoxic potential of engineered nanoparticles toward aquatic organisms. Therefore, there is a critical need to provide the first comprehensive review of the effects of engineered non-functionalized nanoparticles on the immune system of aquatic animals, address the major gaps in current existing information, and recommend the future focus of research. This manuscript identifies cell mediated immunity and the phagocytic cells as the primary target of nanoparticle immunotoxicity. The immunotoxicity is primarily govern by lysosomal destabilization, frustrated phagocytosis, and change in function of the phagocytic cells, which decrease the ability of animals to defend themselves against pathogens and infectious diseases. Humoral immune system is a lesser target of direct immunotoxicity, but plays a critical role in dissemination of the nanoparticles through the body and their presentation to the phagocytic cells. The external innate immunity and the acquired immunity have not been connected with overly important and direct immunotoxic effects, but instead a big gap in current targeted research has been acknowledged. PMID- 22542739 TI - Co-localization of hippocampal cholinergic neurostimulating peptide precursor with collapsin response mediator protein-2 at presynaptic terminals in hippocampus. AB - Hippocampal cholinergic neurostimulating peptide (HCNP) induces the synthesis of acetylcholine in medial septal nucleus in vitro and in vivo. HCNP precursor protein (HCNP-pp) is a multifunctional protein that participates in a number of signaling pathways, including MAPK/extracellular signal and G-protein-coupled receptor kinase 2. We recently demonstrated that the amount of collapsin response mediator protein-2 (CRMP-2) is increased in hippocampus of HCNP-pp transgenic mice. To clarify the interaction between HCNP/HCNP-pp and CRMP-2 and its role in synaptic function, we investigated whether HCNP-pp is localized to the synapse and if it affects protein expression. Here, we demonstrate that HCNP-pp co localizes with CRMP-2 at presynaptic terminals. Furthermore, HCNP-pp overexpression increases synaptophysin levels. These findings suggest that HCNP pp, in association with CRMP-2, plays an important role in presynaptic function in the hippocampus. PMID- 22542741 TI - Aminoacyl-tRNA synthetase-interacting multifunctional protein-1 (AIMP1): the member of a molecular hub with unexpected functions, including CD4 T cell homeostasis. PMID- 22542740 TI - The effects of chronic copper exposure on the amyloid protein metabolisim associated genes' expression in chronic cerebral hypoperfused rats. AB - The pathogens of Alzheimer's disease (AD) are still unclear, while accumulating evidences have indicated that both genetic and environmental factors are involved in the pathogenesis of AD. Recent studies suggest that AD is primarily a vascular disorder and copper (Cu) may play an important role in AD pathology. However, the consequences of chronic Cu exposure at the presence of other AD risk factors remain to be clarified. To investigate the effects of chronic Cu intake on cerebral hypoperfusion-induced AD pathology, Sprague-Dawley rats suffered bilateral common carotid artery occlusion (2VO) were administrated with 250 ppm copper-containing water or not. Morris water maze test showed that Cu exposure for 3 months exacerbated cognitive impairment induced by 2VO. Elevated amyloid precursor protein (APP) and beta-site APP-cleaving enzyme 1 (BACE1) expression in mRNA and protein levels were also observed in brain of Cu-exposed rats suffered 2VO. In contrast, these Cu-exacerbated changes were ameliorated after Cu was withdrawn from drinking water. In summary, our findings demonstrate that chronic Cu exposure might exacerbate AD pathology in 2VO rats. PMID- 22542742 TI - SAR110894, a potent histamine H3-receptor antagonist, displays procognitive effects in rodents. AB - SAR110894 is a novel histamine H3-R ligand, displaying high and selective affinity for human, rat or mouse H3-Rs. SAR110894 is a potent H3-R antagonist at native receptors, reversing R-alpha-methylhistamine-induced inhibition of electrical field stimulation contraction in the guinea-pig ileum. Additionally, SAR110894 inhibited constitutive GTPgammaS binding at human H3-Rs demonstrating inverse agonist properties. In behavioral models addressing certain aspects of cognitive impairment associated with schizophrenia (CIAS) and attention deficit/hyperactivity disorder (ADHD), SAR110894 improved memory performances in several variants of the object recognition task in mice (0.3-3 mg/kg, p.o.) or rats (0.3-1 mg/kg, p.o.). Moreover, SAR110894 (1 mg/kg, p.o.) reversed a deficit in working memory in the Y-maze test, following an acute low dose of phencyclidine (PCP) (0.5 mg/kg, i.p.) in mice sensitized by repeated treatment with a high dose of PCP (10 mg/kg, i.p.). In the latent inhibition (LI) model, SAR110894 potentiated LI in saline-treated rats (1 and 3 mg/kg, i.p.) and reversed abnormally persistent LI induced by neonatal nitric oxide synthase (NOS) inhibition in rodents (0.3-3 mg/kg, i.p.). In a social novelty discrimination task in rats, SAR110894 attenuated selective attention deficit induced by neonatal PCP treatment (3 and 10 mg/kg, p.o.) or a parametric modification of the procedure (3 and 10 mg/kg, p.o.). SAR110894 showed efficacy in several animal models related to the cognitive deficits in Alzheimer's disease (AD). It prevented the occurrence of episodic memory deficit induced by scopolamine in rats (0.01-10 mg/kg, p.o.) or by the central infusion of the toxic amyloid fragment beta25-35 in the object recognition test in mice (1 and 3 mg/kg, p.o.). Altogether, these findings suggest that SAR110894 may be of therapeutic interest for the treatment of the cognitive symptoms of AD, schizophrenia and certain aspects of ADHD. PMID- 22542743 TI - White and pink--emulating nature and beyond. PMID- 22542744 TI - Development of polarization dental imaging modality and evaluation of its clinical feasibility. AB - OBJECTIVES: In the evaluation of tooth color, the specular reflection caused by roughness or saliva on the tooth surface may cause artefacts in image analysis. In this study, a polarization dental imaging modality (PDIM) was developed to obtain cross-polarized images and, therefore, to address the problem of specular reflection. Its clinical validity was evaluated by performing 3 studies of shade tab selection for implant, plaque distribution detection, and evaluation of tooth whitening. METHODS: In vivo human tooth and shade guide color images were obtained, and the minimum color difference between them was calculated for the best color matching shade tab selection. A dental plaque disclosing agent was used to differentiate plaque regions on teeth, and plaque distribution was detected by applying the K-means algorithm. In vivo human teeth were treated with a commercial tooth whitening gel, and tooth whitening was quantitatively evaluated using the PDIM images. RESULTS: The PDIM produced repeatable glare-free tooth color images by effectively removing the specular reflection from the tooth surface. The cross-polarized tooth images were successfully utilized for shade guide selection, plaque detection, and tooth whitening by minimizing artefacts in the quantitative image analysis. The PDIM could simultaneously provide both qualitative and quantitative assessment of the tooth condition in clinical diagnosis. CONCLUSIONS: The clinical feasibility of the PDIM was successfully verified in 3 clinical studies by showing its clinical efficacy as a new imaging modality. PMID- 22542745 TI - Ageing of silorane-based and methacrylate-based composite resins: effects on translucency. AB - OBJECTIVES: Verify if media and time of storage affect the translucency of a silorane-based composite (Filtek P90) compared to two methacrylate-based composites (Z350 and ROK), and compare two methods of translucency evaluation. METHODS: Specimens were divided into two groups (n=7) according to the storage media (deionized water or red wine). With a spectrophotometer (SP60) in reflectance mode, the CIE L*a*b* parameters and opacity percentage readings were conducted at baseline, 24h, 30 days, and 180 days. Data were analyzed using two way repeated measures ANOVA and Tukey (p<0.05). Pearson correlation measured the relationship between translucency parameter and opacity percentage. RESULTS: When stored in water, P90 showed an increase, whereas Z350 decreased in translucency. ROK did not exhibit any tendency over time. When stored in wine, the translucency of all materials decreased. A negative relationship was found between translucency parameter and opacity percentage. When stored in water, the a* values for P90 decreased, whereas Z350 and ROK showed values increasing over time. When stored in wine, the L* parameter tended to decrease over time, an effect that was less intense for P90. Moreover, the b* parameter for P90 decreased, whereas methacrylate-based composites increased over time. CONCLUSIONS: P90 was more stable in red wine than the other materials and became more translucent in water whether metacrilate-based materials became more opaque. Both media as well as storage time affected the translucency of the materials tested. Translucency could be measured with both methods tested. CLINICAL SIGNIFICANCE: Silorane-based composites seemed to be more stable than methacrylate-based composites in red wine and became more translucent over time in water, which was different than methacrylate-based composites. More studies are needed to clarify silorane-based composites performance. PMID- 22542746 TI - Adult mice maintained on a high-fat diet exhibit object location memory deficits and reduced hippocampal SIRT1 gene expression. AB - Mounting evidence has established that diet-induced obesity (DIO) is associated with deficits in hippocampus-dependent memory. The bulk of research studies dealing with this topic have utilized rats fed a high-fat diet as an experimental model. To date, there has been a paucity of research studies that have established whether the memory deficits exhibited in DIO rats can be recapitulated in mice. Moreover, the majority of experiments that have evaluated memory performance in rodent models of DIO have utilized memory tests that are essentially aversive in nature (i.e., Morris water maze). The current study sought to fill an empirical void by determining if mice maintained on a high-fat diet exhibit deficits in two non-aversive memory paradigms: novel object recognition (NOR) and object location memory (OLM). Here we report that mice fed a high-fat diet over 23 weeks exhibit intact NOR, albeit a marked impairment in hippocampus-dependent OLM. We also determined the existence of corresponding aberrations in gene expression within the hippocampus of DIO mice. DIO mice exhibited significant reductions in both SIRT1 and PP1 mRNA within the hippocampus. Our data suggest that mice maintained on a high-fat diet present with impaired hippocampus-dependent spatial memory and a corresponding alteration in the expression of genes that have been implicated in memory consolidation. PMID- 22542747 TI - Small bowel pancreatitis. PMID- 22542748 TI - Ability of rabeprazole to prevent gastric mucosal damage from clopidogrel and low doses of aspirin depends on CYP2C19 genotype. AB - BACKGROUND & AIMS: Low doses of aspirin can injure the gastric mucosa. It is not clear whether other drugs such as the antiplatelet agent clopidogrel also cause gastric mucosal injury or exacerbate aspirin-induced injury, or whether proton pump inhibitors prevent damage. METHODS: Twenty Japanese subjects with different CYP2C19 genotypes were randomly assigned to groups that were given a low dose of aspirin (100 mg; A), clopidogrel (75 mg; C), low dose of aspirin and clopidogrel (AC), or low dose of aspirin in combination with clopidogrel and rabeprazole (10 mg; ACR) once daily for 7 days. Subjects underwent gastroduodenoscopy and platelet tests on days 3 and 7; gastric mucosal damage was assessed by using the modified Lanza score (MLS). We performed 24-hour intragastric pH monitoring on day 7 of each regimen. We also analyzed the effects of the AC regimen on 30 patients with different CYP2C19 genotypes. RESULTS: Subjects in groups A, C, and AC had significantly higher levels of gastric mucosal damage on days 3 and 7, compared with baseline. The median MLS for the AC group was similar to that of the A group. Helicobacter pylori-negative subjects in the ACR group with different CYP2C19 genotypes had significant differences in MLS, intragastric pH, and platelet function. Gastric mucosal injury was inhibited equally among H pylori-positive subjects in the ACR group. Rabeprazole did not appear to affect platelet function or intragastric pH in subjects given clopidogrel. CONCLUSIONS: Clopidogrel and low doses of aspirin cause a similar degree of gastric mucosal damage. Rabeprazole prevented this damage without reducing the antiplatelet function of clopidogrel. However, its prophylactic effect varies with CYP2C19 genotype in H pylori-negative subjects. PMID- 22542749 TI - Ethnic and sex disparities in colorectal neoplasia among Hispanic patients undergoing screening colonoscopy. AB - BACKGROUND & AIMS: Colorectal cancer (CRC) has a high prevalence among the US Hispanic population. In Puerto Rico, CRC is the third leading cause of cancer death in men and the second in women. There are limited published data on the prevalence of colorectal neoplasia (CRN) among the US Hispanic population. We determined the prevalence of CRN (colorectal adenomas and cancer) among asymptomatic, Hispanic subjects who were screened in Puerto Rico and evaluated risk factors associated with CRN. METHODS: We performed a retrospective review of the medical, endoscopic, and pathology records of individuals who underwent first time screening colonoscopies at an ambulatory gastroenterology practice from January 1, 2008, to December 1, 2009. The prevalence of CRN (overall and advanced), documented by colonoscopy and pathology reports, was calculated for the complete cohort and by sex. RESULTS: Of the 745 Hispanic individuals who underwent screening colonoscopies during the study period, the prevalence for overall CRN was 25.1% and for advanced CRN (>= 1 cm and/or with advanced histology) was 4.0%. The prevalence of CRN was higher for men than women (32.0% vs 20.6%; P = .001; odds ratio, 1.92; 95% confidence interval, 1.4-2.6). CRN was more frequently located in the proximal colon (67.7% proximal vs 32.3% distal). A family history of CRC was associated with advanced CRN (odds ratio, 2.73; 95% confidence interval, 1.10-6.79). CONCLUSIONS: CRN was more common among Hispanic men than women and increased with age. CRNs among Hispanic individuals were predominantly located in the proximal colon. These findings indicate that there are ethnic and sex disparities in patterns of CRN that might be related to genomic admixture and have important implications for screening algorithms for Hispanic individuals. PMID- 22542750 TI - Biochemical characterization of a novel cycloisomaltooligosaccharide glucanotransferase from Paenibacillus sp. 598K. AB - Cycloisomaltooligosaccharide glucanotransferase (CITase; EC 2.4.1.248), a member of the glycoside hydrolase family 66 (GH66), catalyzes the intramolecular transglucosylation of dextran to produce cycloisomaltooligosaccharides (CIs; cyclodextrans) of varying lengths. Eight CI-producing bacteria have been found; however, CITase from Bacillus circulans T-3040 (CITase-T3040) is the only CI producing enzyme that has been characterized to date. In this study, we report the gene cloning, enzyme characterization, and analysis of essential Asp and Glu residues of a novel CITase from Paenibacillus sp. 598K (CITase-598K). The cit genes from T-3040 and 598K strains were expressed recombinantly, and the properties of Escherichia coli recombinant enzymes were compared. The two CITases exhibited high primary amino acid sequence identity (67%). The major product of CITase-598K was cycloisomaltoheptaose (CI-7), whereas that of CITase-T3040 was cycloisomaltooctaose (CI-8). Some of the properties of CITase-598K are more favorable for practical use compared with CITase-T3040, i.e., the thermal stability for CITase-598K (<=50 degrees C) was 10 degrees C higher than that for CITase-T3040 (<=40 degrees C); the k(cat)/K(M) value of CITase-598K was approximately two times higher (32.2s(-1)mM(-1)) than that of CITase-T3040 (17.8s(-1)mM(-1)). Isomaltotetraose was the smallest substrate for both CITases. When isomaltoheptaose or smaller substrates were used, a lag time was observed before the intramolecular transglucosylation reaction began. As substrate length increased, the lag time shortened. Catalytically important residues of CITase 598K were predicted to be Asp144, Asp269, and Glu341. These findings will serve as a basis for understanding the reaction mechanism and substrate recognition of GH66 enzymes. PMID- 22542751 TI - Is protein methylation in the human lens a result of non-enzymatic methylation by S-adenosylmethionine? AB - Since crystallins in the human lens do not turnover, they are susceptible to modification by reactive molecules over time. Methylation is a major post translational lens modification, however the source of the methyl group is not known and the extent of modification across all crystallins has yet to be determined. Sites of methylation in human lens proteins were determined using HPLC/mass spectrometry following digestion with trypsin. The overall extent of protein methylation increased with age, and there was little difference in the extent of modification between soluble and insoluble crystallins. Several different cysteine and histidine residues in crystallins from adult lenses were found to be methylated with one cysteine (Cys 110 in gammaD crystallin) at a level approaching 70%, however, methylation of crystallins was not detected in fetal or newborn lenses. S-adenosylmethionine (SAM) was quantified at significant (10-50 MUM) levels in lenses, and in model experiments SAM reacted readily with N alpha-tBoc-cysteine and N-alpha-tBoc-histidine, as well as betaA3-crystallin. The pattern of lens protein methylation seen in the human lens was consistent with non-enzymatic alkylation. The in vitro data shows that SAM can act directly to methylate lens proteins and SAM was present in significant concentrations in human lens. Thus, non-enzymatic methylation of crystallins by SAM offers a possible explanation for this major human lens modification. PMID- 22542752 TI - Differential control of H-reflex amplitude in different weight-bearing conditions in young and elderly subjects. AB - OBJECTIVE: This study measured the modulation of conditioned (femoral nerve, paired-stimuli) and unconditioned soleus H-reflexes in young and elderly subjects when changing weight-bearing (WB) requirements and body position. METHODS: Conditioned and unconditioned H-reflexes were examined in 14 elderly subjects and 11 young subjects during six different WB conditions: (1) lying supine with no WB, (2) supine position inclined by 30 degrees with 50% WB, (3) standing with 50%, (4) 75%, (5) 100% and (6) 125% WB. RESULTS: The elderly subjects had consistently higher background soleus EMG activity across the WB conditions compared to the young. Femoral nerve conditioning caused facilitation of the H reflex that changed across WB conditions in the young subjects, but not in the elderly subjects. Finally, elderly subjects had less depression with paired stimulation (PRD) across WB conditions, which was not observed in the young subjects. CONCLUSIONS: The elderly may have more direct activation of motoneurons from descending pathways, coupled with less segmental spinal control of inhibitory interneurons, as evidenced by the increased background soleus activity, H/M-max ratios and the lack of modulatory control observed when conditioning the H-reflex. SIGNIFICANCE: There was an age-specific response from descending and segmental pathways during conditions that involved either different WB requirements or changes in body position. PMID- 22542753 TI - Co-cultures of enterocytes and hepatocytes for retinoid transport and metabolism. AB - Dietary retinoid bioavailability involves the interplay of the intestine (transport and metabolism) and the liver (secondary metabolism). To reproduce these processes in vitro, differentiated human intestinal Caco-2/TC7 cells were co-cultured with two hepatocyte cell lines. Murine 3A cells and the more highly differentiated human HepaRG hepatocytes were both shown to respond to beta carotene (BC) and retinol (ROH) treatment by secreting Retinol Binding Protein 4 (RBP4). In co-culture experiments, Caco-2/TC7 were differentiated on filter inserts and transferred for the time of the experiment to culture wells containing confluent 3A or differentiated HepaRG cells. Functionality of the co cultures was assayed using as endpoints the retinol-dependent secretion of RBP4 and the retinoic acid-dependent induction of CYP26A1 in hepatocytes. BC and ROH added to intestinal Caco-2/TC7 induced a reduction in intracellular RBP4 levels in the underlying hepatocytes and its secretion into the medium. HepaRG hepatocytes were also shown to up-regulate the expression of CYP26A1 mRNA in response to retinoid treatment. This in vitro model represents a useful tool to analyze the absorption and metabolism of retinoids and could be further developed to investigate other dietary compounds and molecules of pharmacological interest. PMID- 22542754 TI - Cell death induced by the Alternaria mycotoxin Alternariol. AB - Mycotoxins are unavoidable contaminants of most foods and feeds, and some are known to be detrimental to human health. It is thus worthwhile to understand how cells of the intestinal system, one of the primary targets of these toxins, respond to their toxic effects. In this study, human colon carcinoma cells were used to elucidate the cell death mode and the pathways triggered by Alternariol (AOH), the most important mycotoxin produced by Alternaria species, which are the most common mycoflora infecting small grain cereals worldwide. Treatment of cells with AOH resulted in a loss of cell viability by inducing apoptosis. AOH-induced apoptosis was mediated through a mitochondria-dependent pathway, characterized by a p53 activation, an opening of the mitochondrial permeability transition pore (PTP), a loss of mitochondrial transmembrane potential (DeltaPsim), a downstream generation of O(2)(*-) and caspase 9 and 3 activation. Besides, deficiency of the pro-apoptotic protein Bax partially protected cells against AOH-induced mitochondrial alterations. In addition, experiments performed on purified mitochondria indicated that AOH does not directly target this organelle to induce cell death. Our results demonstrate for the first time that AOH-induced cytotoxicity is mediated by activation of the mitochondrial pathway of apoptosis in human colon carcinoma cells. PMID- 22542755 TI - Hypochlorous acid-induced heme damage of hemoglobin and its inhibition by flavonoids. AB - Hypochlorous acid (HOCl), produced by activated neutrophils, is highly reactive oxidizing and chlorinating agent of biologically relevant molecules. Hemoglobin (Hb), present in large amounts inside red blood cells, is the main target for HOCl in these cells. In this work heme damage of hemoglobin induced by hypochlorous acid in the absence and presence of some popular dietary flavonoids, catechin, epigallocatechin gallate and quercetin has been studied by stopped-flow spectrophotometry. Hypochlorous acid, being in a large molar excess to hemoglobin, initiates modifications of the heme group of oxy- as well as of methemoglobin, which eventually leads to heme damage. Flavonoids present at concentrations comparable with that of hemoglobin inhibit these processes. The kinetics of the reactions of the investigated flavonoids with HOCl has been also studied and the rate constants of the order of 10(5)M(-1)s(-1) have been found. It is concluded that under conditions used in this study the inhibition of Hb heme damage by flavonoids results from the competition of these compounds with hemoglobin towards HOCl and/or from the formation of Hb-flavonoid complex in which heme group is more resistant against HOCl-induced damage. PMID- 22542756 TI - Isatin-3-N4-benzilthiosemicarbazone, a non-toxic thiosemicarbazone derivative, protects and reactivates rat and human cholinesterases inhibited by methamidophos in vitro and in silico. AB - Organophosphates (OPs), which are widely used as pesticides, are acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The inactivation of AChE results in the accumulation of acetylcholine at cholinergic receptor sites, causing a cholinergic crisis that can lead to death. The classical treatment for OP poisoning is administration of oximes, but these compounds are ineffective in some cases. Here we determined whether the new compound isatin-3-N(4)-benzilthiosemicarbazone (IBTC), which in our previous study proved to be an antioxidant and antiatherogenic molecule, could protect and reactivate AChE and BChE. Toxicity of IBTC after subcutaneous injection in mice was measured using assays for oxidized diclorofluoresceine (DCF), thiobarbituric acid reactive substances (TBARS), non-protein thiol (NPSH) levels, and catalase (CAT), sodium potassium (Na(+)/K(+)) ATPase, delta-aminolevulinic acid dehydratase (ALA-D), and glutathione peroxidases (GPx) enzyme activities. The cytotoxicity was evaluated and the enzymatic activity of cholinesterase was measured in human blood samples. Molecular docking was used to predict the mechanism of IBTC interactions with the AChE active site. We found that IBTC did not increase the amount of DCF-RS or TBARS, did not reduce NPSH levels, and did not increase CAT, (Na(+)/K(+)) ATPase, ALA-D, or GPx activities. IBTC protected and reactivated both AChE and BChE activities. Molecular docking predicted that IBTC is positioned at the peripheral anionic site and in the acyl binding pocket of AChE and can interact with methamidophos, releasing the enzyme's active site. Our results suggest that IBTC, besides being an antioxidant and a promising antiatherogenic agent, is a non-toxic molecule for methamidophos poisoning treatment. PMID- 22542757 TI - The effect of a novel tobacco process on the in vitro cytotoxicity and genotoxicity of cigarette smoke particulate matter. AB - Some of the toxic effects of smoking have been attributed to the combustion of nitrogenous protein in tobacco. The effects of a treatment which reduces tobacco's protein nitrogen level, on the in vitro cytotoxicity and genotoxicity of cigarette smoke particulate matter (PM), were measured. PMs were tested in the Neutral Red Uptake (NRU) test; the Salmonella mutagenicity assay (SAL); the mouse lymphoma mammalian cell mutation assay (MLA) and the in vitro micronucleus test (IVMNT). PMs from all of the cigarettes were cytotoxic and genotoxic. PM obtained from smoking treated tobacco, showed a small, consistent and statistically significant reduced mutagenicity (revertants/MUg) in TA98 with post-mitochondrial supernatant (S9). No consistent quantitative or qualitative differences were detected in the other tests. The data are discussed in relation to published information on smoke chemistry obtained from cigarettes made of tobacco treated using this technique. The observations confirm that the method did not give rise to any new qualitative or quantitative cytotoxic or genotoxic effects, and may have reduced PM's bacterial mutagenicity in TA98 with S9. Further toxicity testing is warranted, to investigate the effects of the tobacco treatment in more detail and add to the data already obtained. PMID- 22542758 TI - 3-Thiomethyl-5,6-(dimethoxyphenyl)-1,2,4-triazine improves neurite outgrowth and modulates MAPK phosphorylation and HSPs expression in H2O2-exposed PC12 cells. AB - Neurite outgrowth is an important aspect of neuronal plasticity and regeneration after neuronal injury. In this study we aimed to investigate the possible effect of 3-thiomethyl-5,6-dimethoxyphenyl-1,2,4-triazine (TDMT) on H(2)O(2)-induced impairment of neurite outgrowth. We found that TDMT could improve neurite outgrowth and neurite complexity in H(2)O(2)-exposed PC12 cells. Moreover, we found elevated levels of Hsp-70 and suppressed level of Hsp-90 in TDMT-treated cells in the presence of H(2)O(2). As another important signaling pathways that play role in neuritogenesis, as well as apoptosis, we measured the level of phosphorylated and total MAPKs proteins, JNK, ERK and p38 MAPK. We found that TDMT inhibits oxidative stress-induced phosphorylation of MAPKs. Since HSPs and MAPKs are both involved in coping with environmental changes, it will not be surprising if they can modify or augment each other's activity. Neuroprotective effect of this compound could represent a promising approach for treatment of neurodegenerative diseases. PMID- 22542759 TI - Diesel exhaust particles impair platelet response to collagen and are associated with GPIbalpha shedding. AB - OBJECTIVE: Air pollution with fine particulates (PM(10) and PM(2.5)) is associated with an increased incidence of cardiovascular events. The proposed mechanisms include indirect proinflammatory and procoagulant reactions involving activation of pulmonary macrophages, endothelial cells and the TNF/TF pathway, or direct procoagulant effects. Our laboratory has observed a reduction of the platelet responsiveness to collagen after exposure to diesel exhaust particles (DEP). HYPOTHESIS: DEP directly interfere with platelet-collagen interactions by selectively inducing the shedding of platelet signaling receptors via metalloproteinases, which would represent a novel mechanism for DEP action on platelets. METHODS: Citrated blood from healthy volunteers was exposed to highly standardized DEP at concentrations of 0.1, 2.5 and 5.0MUg/ml or ultrafine carbon black (ufCB, 0.1MUg/ml) and the plasmatic and platelet response was analysed. The closure times with the PFA-100 device and the platelet aggregation in response to a variety of agonists were monitored. Interleukins (IL)-1beta and IL-8 levels were determined by ELISA and soluble P-selectin by the Luminex bead assay. Thrombin activity was measured as the endogenous thrombin potential (ETP) by fluorescence spectrometry. Soluble GPVI and GPIbalpha (glycocalicin) ectodomain fragments were measured by ELISA. ADAMTS13 activity was determined by a FRETS based assay and plasmin activity with Spectrozyme PL. RESULTS: Aggregation assays where platelets were treated with low dose DEP or ultrafine carbon black (ufCB) revealed a significantly increased response to low doses of collagen (p<0.05, n=5). At higher doses, however, collagen induced aggregation was suppressed by DEP treatment: at 2.5MUg/ml, the inhibition was 34+/-12% (p<0.01, n=10). Aggregations with cross-linked collagen related peptide (CRPxl), convulxin and with the monoclonal antibody 9O12.2 (all known to specifically bind to and activate GPVI) were also diminished. Ristocetin, arachidonic acid and ADP responses were normal at all DEP concentrations. No cleavage of GPVI ectodomain was detected (soluble GPVI 27.8+/-3 vs. 28+/-4MUg/ml mean+/-SEM, n=10); however increased plasma glycocalicin (GPIbalpha ectodomain) was detected upon diesel exposure (2.58+/-0.11 vs. 2.28+/-0.03MUg/ml p<0.01, n=10). ADAMTS13 and plasmin activity remained unaffected by DEP under the conditions tested. Platelets were not activated by either DEP or ufCB as soluble P-selectin was insensitive to these. CONCLUSIONS: DEP specifically and directly interferes with platelet collagen interactions. The functional consequences are biphasic and include enhance platelet aggregation at lower DEP concentrations and inhibition at a higher dose. Our data indicate that this interaction does not involve P-selectin or GPVI shedding. It is however associated with an increase in GPIb cleavage. PMID- 22542760 TI - A large-scale RNAi screen identifies functional classes of genes shaping synaptic development and maintenance. AB - Neuronal circuit development and function require proper synapse formation and maintenance. Genetic screens are one powerful method to identify the mechanisms shaping synaptic development and stability. However, genes with essential roles in non-neural tissues may be missed in traditional loss-of-function screens. In an effort to circumvent this limitation, we used neuron-specific RNAi knock down in Drosophila and assayed the formation, growth, and maintenance of the neuromuscular junction (NMJ). We examined 1970 Drosophila genes, each of which has a conserved ortholog in mammalian genomes. Knock down of 158 genes in post mitotic neurons led to abnormalities in the neuromuscular system, including misapposition of active zone components opposite postsynaptic glutamate receptors, synaptic terminal overgrowth and undergrowth, abnormal accumulation of synaptic material within the axon, and retraction of synaptic terminals from their postsynaptic targets. Bioinformatics analysis demonstrates that genes with overlapping annotated function are enriched within the hits for each phenotype, suggesting that the shared biological function is important for that aspect of synaptic development. For example, genes for proteasome subunits and mitotic spindle organizers are enriched among the genes whose knock down leads to defects in synaptic apposition and NMJ stability. Such genes play essential roles in all cells, however the use of tissue- and temporally-restricted RNAi indicates that the proteasome and mitotic spindle organizers participate in discrete aspects of synaptic development. In addition to identifying functional classes of genes shaping synaptic development, this screen also identifies candidate genes whose role at the synapse can be validated by traditional loss-of-function analysis. We present one such example, the dynein-interacting protein NudE, and demonstrate that it is required for proper axonal transport and synaptic maintenance. Thus, this screen has identified both functional classes of genes as well as individual candidate genes that are critical for synaptic development and will be a useful resource for subsequent mechanistic analysis of synapse formation and maintenance. PMID- 22542761 TI - Synergistic actions of insulin-sensitive and Sirt1-mediated pathways in the differentiation of mouse embryonic stem cells to osteoblast. AB - Murine embryonic stem cells (mESCs) have the potential to differentiate into almost any type of cell, and hence, represent a useful biological resource for tissue engineering. The differentiation of mESCs into osteoblasts in vitro is usually dampened by simultaneous differentiation of adipocytes. Insulin exerts a profound effect on bone development through increased differentiation of osteoblasts and concurrent formation of adipocytes. Comparatively, Sirt1, which plays a crucial role in osteoblast differentiation, has been reported to down regulate adipocyte formation during osteoblast differentiation. This study analyzed the combined effects of insulin and Sirt1 on the differentiation of osteoblasts. Osteoblast differentiation was quantified by estimating the accumulation of mineralized matrix and expression of osteogenic genes. The present data show that the simultaneous action of the insulin and Sirt1-mediated pathways increased the efficiency of osteoblast differentiation. When the cells were tested for ALP activity and Alizarin red staining, there was a respective increase of ~180% and ~166% (P<0.05) compared to the control. Furthermore, the mRNA expression patterns of osteoprotegerin, osterix, runx2, and osteopontin were increased by 3.6, 2.3, 1.8, and 1.7-fold, respectively, with a concomitant decrease in the mRNA expression levels of adipocyte marker genes. Interestingly, blocking the effects of both Sirt1 and insulin resulted in decreased osteoblastogenesis (60%) and subsequent increased adipocyte differentiation (195%) (P<0.05). Moreover, immunoblotting analysis demonstrated that this activation was via an Akt-dependent pathway. In conclusion, the present data suggests an enhanced process of osteoblast differentiation that can be exploited further to improve mESC differentiation. PMID- 22542764 TI - Role of intravenous cloxacillin for inpatient infections. AB - One of the issues of antibiotic treatment is to warrant its optimal effectiveness while minimizing the risk for emergence of resistance. The time above minimal inhibiting concentration (MIC) (T>MIC) is the best predictive pharmacological parameter of effectiveness for antibiotics with time-dependent activity, such as cloxacillin. Cloxacillin is the first line antibiotic in a great number of clinical situations generated by methicillin sensitive staphylococci, because of its intrinsic properties: bactericidal effect, tissue distribution and safety. The most recent anti-staphylococcal agents do not improve treatment of MSSA infections compared to penicillin M and especially cloxacillin. Cloxacillin has a narrow microbiological spectrum. This ecological feature is in line with the recommendation to use antibiotics with the narrowest spectrum to reduce the pressure of selection. The consensus is to have T>MIC for at least 40% of the dosing interval and is achieved by infusing 2g of cloxacillin per day (T>MIC=50%) or four infusions of 3g per day (T>MIC=42%) in adults. PMID- 22542762 TI - Dynamic evaluation of anterior dental alignment in a sample of 8- to 11-year-old children. AB - OBJECTIVE: To describe perceptions related to different anterior dental alignments in a sample of 106 children aged between 8- and 11-years-old. MATERIALS AND METHODS: We employed dynamic media (videos) showing a smile in four different arrangements (ideal incisal occlusion - N, median diastema - D, incisal crowding - A, protruding incisors - P), with and without general contextual attractiveness. RESULTS: The perception is the same both for the whole face and for the frontal smile alone and there are no significant differences between the answers from male and female interviews. Smiles with normal alignment gain higher scores for esthetics and are associated with more positive qualities. In contrast, smiles with proclined and crowded teeth obtain lower scores. CONCLUSIONS: Analysis of the results showed that there are no significant differences between perceptions, sensations and judgments related to smiles presented either as part of the whole face or in only the lower facial third: general facial attractiveness does not influence evaluations of the smile. The study confirms the general tendency to award higher scores to smiles with normal alignment. PMID- 22542765 TI - Maternal-fetal surgery for structural malformations. AB - Although most prenatally diagnosed correctable anatomic abnormalities are best addressed by surgical interventions after birth, the outcomes of a small number of severe structural malformations with predicted fetal demise or devastating sequelae postnatally may be improved by correction before birth. Consideration of maternal-fetal surgical intervention is restricted to those anatomic malformations that interfere with normal organ development and which, if alleviated, may permit normal development to proceed. Advances in prenatal diagnosis and technical innovations in the surgical approach to the fetus have resulted in an increase in the successful clinical application of fetal intervention over the past 3 decades. The purpose of this review is to describe the current status of maternal-fetal surgery, with a focus on the congenital anomalies most commonly treated by intervention before birth, and to highlight the key areas for further research in this evolving surgical specialty. PMID- 22542767 TI - Law, ethics and clinical judgment in end-of-life decisions--how do Norwegian doctors think? AB - AIM: According to Norwegian law, an autonomous patient has the right to refuse life-prolonging treatment. If the patient is not defined as dying, however, health personnel are obliged to instigate life-saving treatment in an emergency situation even against the patient's wishes. The purpose of this study was to investigate how doctors' attitudes and knowledge agree with these legal provisions, and how the statutory provision on emergency situations influences the principle of patient autonomy for severely ill, but not dying, patients. METHOD: A strategic sample of 1175 Norwegian doctors who are specialists in internal medicine, paediatrics, surgery, neurology and neurosurgery received a mail questionnaire about decisions on end-of-life care in hypothetical scenarios. The case presented concerns a 45-year-old autonomous patient diagnosed with end stage ALS who declines ventilatory treatment. Recipients were randomly selected from the membership roster of the Norwegian Medical Association. 640 (54.5%) responded; of these, 406 had experience with end-of-life decisions. RESULTS: 56.1% (221/394) stated that ALS patients in such situations can always refuse life-prolonging treatment, and 42.4% (167/394) were of the opinion that the patient can normally refuse life-prolonging treatment. 1.5% (6/394) stated that the patient cannot refuse life-prolonging treatment. CONCLUSIONS: The answers indicate that the respondents include patients' refusal in an overall clinical judgement, and interpret patients' right to decline life-saving treatment in different ways. This may reflect the complex legal situation in Norway regarding patient autonomy with respect to the right of severely ill, but not dying, patients' right to decline acute life-saving treatment. PMID- 22542768 TI - Analysis of intraosseous samples using point of care technology--an experimental study in the anaesthetised pig. AB - BACKGROUND: Intraosseous access is an essential method in emergency medicine when other forms of vascular access are unavailable and there is an urgent need for fluid or drug therapy. A number of publications have discussed the suitability of using intraosseous access for laboratory testing. We aimed to further evaluate this issue and to study the accuracy and precision of intraosseous measurements. METHODS: Five healthy, anaesthetised pigs were instrumented with bilateral tibial intraosseous cannulae and an arterial catheter. Samples were collected hourly for 6h and analysed for blood gases, acid base status, haemoglobin and electrolytes using an I-Stat point of care analyser. RESULTS: There was no clinically relevant difference between results from left and right intraosseous sites. The variability of the intraosseous sample values, measured as the coefficient of variance (CV), was maximally 11%, and smaller than for the arterial sample values for all variables except SO2. For most variables, there seems to be some degree of systematic difference between intraosseous and arterial results. However, the direction of this difference seems to be predictable. CONCLUSION: Based on our findings in this animal model, cartridge based point of care instruments appear suitable for the analysis of intraosseous samples. The agreement between intraosseous and arterial analysis seems to be good enough for the method to be clinically useful. The precision, quantified in terms of CV, is at least as good for intraosseous as for arterial analysis. There is no clinically important difference between samples from left and right tibia, indicating a good reproducibility. PMID- 22542769 TI - Electromyography variables during the golf swing: a literature review. AB - The aim of the study was to review systematically the literature available on electromyographic (EMG) variables of the golf swing. From the 19 studies found, a high variety of EMG methodologies were reported. With respect to EMG intensity, the right erector spinae seems to be highly activated, especially during the acceleration phase, whereas the oblique abdominal muscles showed moderate to low levels of activation. The pectoralis major, subscapularis and latissimus dorsi muscles of both sides showed their peak activity during the acceleration phase. High muscle activity was found in the forearm muscles, especially in the wrist flexor muscles demonstrating activity levels above the maximal voluntary contraction. In the lower limb higher muscle activity of the trail side was found. There is no consensus on the influence of the golf club used on the neuromuscular patterns described. Furthermore, there is a lack of studies on average golf players, since most studies were executed on professional or low handicap golfers. Further EMG studies are needed, especially on lower limb muscles, to describe golf swing muscle activation patterns and to evaluate timing parameters to characterize neuromuscular patterns responsible for an efficient movement with lowest risk for injury. PMID- 22542770 TI - Biomechanics--review of approaches for performance training in spinal manipulation. AB - Motor skills development is an inherent part of clinical training in health disciplines. The conscious use of educational theory to ground learning is receiving increasing attention across health care education. There are three distinct, yet overlapping, stages of motor skill learning; the cognitive, the integrative or associative, and the autonomous; in which a contextual framework for learning content may be structured. The learning is associated with a mapping of changes within the central nervous system by the interactive mechanisms of adaptation, use-dependent plasticity and operant reinforcement. Successful skill learning requires a sufficient amount of practice and the implementation of relevant feedback strategies in the form of knowledge of performance (KP) or knowledge of results (KR). There is a natural maturation of skills that may be accelerated by feedback. Several factors contribute to stronger skills development. "Mixture-of-experts" models systematically sequence tasks into logical blocks of theory, practice and student reflection on performance. Feedback should involve both KP and KR that compares performance to a tangible standard. Rehearsals should balance use of simulators and volunteer simulated patients to provide the full range of safe and effective learning opportunities prior to students accepting a role as care givers to the public in any clinical setting. PMID- 22542766 TI - Coordination of cell growth and division by the ubiquitin-proteasome system. AB - The coupling of cellular growth and division is crucial for a cell to make an accurate copy of itself. Regulated protein degradation by the ubiquitin proteasome system (UPS) plays an important role in the coordination of these two processes. Many ubiquitin ligases, in particular the Skp1-Cullin-F-box (SCF) family and the Anaphase-Promoting Complex (APC), couple growth and division by targeting cell cycle and metabolic regulators for degradation. However, many regulatory proteins are targeted by multiple ubiquitin ligases. As a result, we are only just beginning to understand the complexities of the proteolytic regulatory network that connects cell growth and the cell cycle. PMID- 22542771 TI - Exenatide prevents high-glucose-induced damage of retinal ganglion cells through a mitochondrial mechanism. AB - Exenatide (exendin-4 analogue) is widely used in clinics and shows a neuroprotective effect. The main objectives of the present study were to prove that retinal ganglion cells (RGC-5) express GLP-1R, to ascertain whether exenatide prevents a high-glucose-induced RGC-5 impairment, to determine the appropriate concentration of exenatide to protect RGC-5 cells, and to explore the neuroprotective mechanisms of exenatide. Immunofluorescence and Western blot analyses demonstrated that RGC-5 cells express GLP-1R. We incubated RGC-5 cells with 25 mM glucose prior to incubation with either 25 mM glucose, 55 mM glucose (high), high glucose plus exenatide or high glucose plus a GLP-1R antagonist. The survival rates of the cells were measured by CCK-8, and cellular injury was detected by electron microscopy. There were statistical differences between the high-glucose group and the control group (P<0.05). Exenatide improved the survival rate of the cells and suppressed changes in the mitochondrial morphology. The optimum concentration of exenatide to protect the RGC-5 cells from high-glucose-induced RGC injury was 0.5 MUg/ml, and this protective effect could be inhibited by exendin (9-39). To further study the mechanism underlying the beneficial effects of exenatide, the expression levels of cytochrome c, Bcl 2, Bax and caspase-3 were analysed by Western blot. The present study showed that treatment with exenatide significantly inhibited cytochrome c release and decreased the intracellular expression levels of Bax and caspase-3, whereas Bcl-2 was increased (P<0.05). These results suggested that GLP-1R activation can inhibit the cellular damage that is induced by high glucose. A mitochondrial mechanism might play a key role in the protective effect of exenatide on the RGC 5 cells, and exenatide might be beneficial for patients with diabetic retinopathy. PMID- 22542772 TI - siRNA knock down of glutamate dehydrogenase in astrocytes affects glutamate metabolism leading to extensive accumulation of the neuroactive amino acids glutamate and aspartate. AB - Glutamate is the most abundant excitatory neurotransmitter in the brain and astrocytes are key players in sustaining glutamate homeostasis. Astrocytes take up the predominant part of glutamate after neurotransmission and metabolism of glutamate is necessary for a continuous efficient removal of glutamate from the synaptic area. Glutamate may either be amidated by glutamine synthetase or oxidatively metabolized in the mitochondria, the latter being at least to some extent initiated by oxidative deamination by glutamate dehydrogenase (GDH). To explore the particular importance of GDH for astrocyte metabolism we have knocked down GDH in cultured cortical astrocytes employing small interfering RNA (siRNA) achieving a reduction of the enzyme activity by approximately 44%. The astrocytes were incubated for 2h in medium containing either 1.0mM [(15)NH(4)(+)] or 100 MUM [(15)N]glutamate. For those exposed to [(15)N]glutamate an additional 100 MUM was added after 1h. Metabolic mapping was performed from isotope incorporation measured by mass spectrometry into relevant amino acids of cell extracts and media. The contents of the amino acids were measured by HPLC. The (15)N incorporation from [(15)NH(4)(+)] into glutamate, aspartate and alanine was decreased in astrocytes exhibiting reduced GDH activity. However, the reduced GDH activity had no effect on the cellular contents of these amino acids. This supports existing in vivo and in vitro studies that GDH is predominantly working in the direction of oxidative deamination and not reductive amination. In contrast, when exposing the astrocytes to [(15)N]glutamate, the reduced GDH activity led to an increased (15)N incorporation into glutamate, aspartate and alanine and a large increase in the content of glutamate and aspartate. Surprisingly, this accumulation of glutamate and net-synthesis of aspartate were not reflected in any alterations in either the glutamine content or labeling, but a slight increase in mono labeling of glutamine in the medium. We suggest that this extensive net-synthesis of aspartate due to lack of GDH activity is occurring via the concerted action of AAT and the part of TCA cycle operating from alpha-ketoglutarate to oxaloacetate, i.e. the truncated TCA cycle. PMID- 22542773 TI - The levels of renin-angiotensin related components are modified in the hippocampus of rats submitted to pilocarpine model of epilepsy. AB - We previously showed that patients with temporal lobe epilepsy (TLE) present an increased expression of angiotensin II (AngII) AT1 and AT2 receptors in the hippocampus, supporting the idea of an upregulation of renin-angiotensin system (RAS) in this disease. This study aimed to verify the relationship between the RAS and TLE during epileptogenesis. Levels of the peptides angiotensin I (AngI), angiotensin II (AngII) and angiotensin 1-7 (Ang 1-7), were detected by HPLC assay. Angiotensin AT1 and AT2 receptors, Mas mRNA receptors and angiotensin converting enzyme (ACE), tonin and neutral endopeptidase (NEP) mRNA were also quantified at the hippocampus of Wistar rats by real time PCR, during acute (n=10), silent (n=10) and chronic (n=10) phases of pilocarpine-induced epilepsy. We observed an increased peptide level of Ang1-7 into acute and silent phases, decreasing importantly (p<=0.05) in the chronic phase, suggesting that AngI may be converted into Ang 1-7 by NEP, which is present in high levels in these periods. Our results also showed increased peptide level of AngII in the chronic phase of this model. In contraposition, the ACE expression is reduced in all periods. These data suggest that angiotensinogen or AngI may be cleaved to AngII by tonin, which showed increased expression in all phases. We found changes in AT1, AT2 and Mas mRNA receptors levels suggesting that Ang1-7 could act at Mas receptor during the silent period. Herein, we demonstrated for the first time, changes in angiotensin-related peptides, their receptors as well as the releasing enzymes in the hippocampus of rats during pilocarpine-induced epilepsy. PMID- 22542775 TI - Enhanced photodegradation of pentachlorophenol by single and mixed cationic and nonionic surfactants. AB - The photocatalytic degradation of pentachlorophenol (PCP) using a TiO(2) catalyst in a surfactant-containing system was investigated. PCP abatement by photocatalysis was significantly enhanced by the addition of cationic and nonionic surfactants, both single and mixed, at appropriate concentrations. The enhanced photodegradation can be mainly attributed to the formation of admicelles on the TiO(2) surface. This phenomenon can lead to the incorporation of more PCP, thereby providing TiO(2) with remarkably higher capture rates for target pollutants. Hence, PCP was rendered easily available to photo-yielded oxidative radicals on the catalyst surface. Notably, mixed cationic-nonionic surfactants yielded much higher photodegradation efficiencies than the corresponding single surfactants, indicating the existence of a synergistic effect in the complex system. The adsorption behavior of PCP on TiO(2) in the surfactant solutions was investigated to elucidate this synergism. Fourier-transform infrared (FTIR) spectroscopy was adopted to gain insight into the structural changes induced by the surfactants and a better understanding of the surfactant-assisted photocatalytic degradation mechanism was obtained. PMID- 22542774 TI - Biodegradation of di-n-butyl phthalate by an isolated Gordonia sp. strain QH-11: Genetic identification and degradation kinetics. AB - Di-n-butyl phthalate (DBP) is one of the most widely used phthalic acid esters (PAEs), which have shown increasing environmental concerns worldwide. A bacterial strain designated as QH-11, was isolated from activated sludge and found to be capable of utilizing DBP as carbon and energy sources for growth. 16S rRNA and gyrb gene sequence analysis revealed that strain QH-11 was most closely related to Gordonia sp. Kinetics studies of DBP degradation by the strain QH-11 revealed that DBP depletion curves fit with the modified Gompertz model (R(2)>0.98). Meanwhile, substrate utilization tests showed that strain QH-11 could utilize other common PAEs and also the main intermediate product phthalic acid (PA). A gene encoding the large subunit of the phthalate dioxygenase, which is responsible for PA degradation, was successfully detected in strain QH-11. Furthermore, the results of reverse transcription quantitative PCR demonstrate that mRNA expression level of phthalate dioxygenase increased significantly after strain QH-11 was induced by DBP and PA. PMID- 22542776 TI - Occurrence of THM and NDMA precursors in a watershed: Effect of seasons and anthropogenic pollution. AB - In pristine watersheds, natural organic matter is the main source of disinfection by-product (DBP) precursors. However, the presence of point or non-point pollution sources in watersheds may lead to increased levels of DBP precursors which in turn form DBPs in the drinking water treatment plant upon chlorination or chloramination. In this study, water samples were collected from a lake used to obtain drinking water for Istanbul as well as its tributaries to investigate the presence of the precursors of two disinfection by-products, trihalomethanes (THM) and N-nitrosodimethylamine (NDMA). In addition, the effect of seasons and the possible relationships between these precursors and water quality parameters were evaluated. The concentrations of THM and NDMA precursors measured as total THM formation potential (TTHMFP) and NDMA formation potential (NDMAFP) ranged between 126 and 1523MUg/L THM and <2 and 1648ng/L NDMA, respectively. Such wide ranges imply that some of the tributaries are affected by anthropogenic pollution sources, which is also supported by high DOC, Cl(-) and NH(3) concentrations. No significant correlation was found between the water quality parameters and DBP formation potential, except for a weak correlation between NDMAFP and DOC concentrations. The effect of the sampling location was more pronounced than the seasonal variation due to anthropogenic pollution in some tributaries and no significant correlation was obtained between the seasons and water quality parameters. PMID- 22542777 TI - Impact of metals in surface matrices from formal and informal electronic-waste recycling around Metro Manila, the Philippines, and intra-Asian comparison. AB - We report concentrations, enrichment factors, and hazard indicators of 11 metals (Ag, As, Cd, Co, Cu, Fe, In, Mn, Ni, Pb, and Zn) in soil and dust surface matrices from formal and informal electronic waste (e-waste) recycling sites around Metro Manila, the Philippines, referring to soil guidelines and previous data from various e-waste recycling sites in Asia. Surface dust from e-waste recycling sites had higher levels of metal contamination than surface soil. Comparison of formal and informal e-waste recycling sites (hereafter, "formal" and "informal") revealed differences in specific contaminants. Formal dust contained a mixture of serious pollutant metals (Ni, Cu, Pb, and Zn) and Cd (polluted modestly), quite high enrichment metals (Ag and In), and crust-derived metals (As, Co, Fe, and Mn). For informal soil, concentration levels of specific metals (Cd, Co, Cu, Mn, Ni, Pb, and Zn) were similar among Asian recycling sites. Formal dust had significantly higher hazardous risk than the other matrices (p<0.005), excluding informal dust (p=0.059, almost significant difference). Thus, workers exposed to formal dust should protect themselves from hazardous toxic metals (Pb and Cu). There is also a high health risk for children ingesting surface matrices from informal e-waste recycling sites. PMID- 22542778 TI - Biotransformation and detoxification of inorganic arsenic in a marine juvenile fish Terapon jarbua after waterborne and dietborne exposure. AB - Arsenic (As) is a major hazardous metalloid in many aquatic environments. This study quantified the biotransformation of two inorganic As species [As(III) and As(V)] in a marine juvenile grunt Terapon jarbua following waterborne and dietborne exposures for 10d. The fish were fed As contaminated artificial diets at nominal concentrations of 50, 150, and 500MUg As(III) and As(V)/g (dry weight), and their transformation and growth responses were compared to those exposed to 100MUg/L waterborne As(III) and As(V). Within the 10d exposure period, waterborne and dietborne inorganic As exposure had no significant effect on the fish growth performance. The bioaccumulation of As was very low and not proportional to the inorganic As exposure concentration. We demonstrated that both inorganic As(III) and As(V) in the dietborne and waterborne phases were rapidly biotransformed to the less toxic arsenobetaine (AsB, 89-97%). After exposure to inorganic As, T. jarbua developed correspondingly detoxified strategies, such as the reduction of As(V) to As(III) followed by methylation to less toxic organic forms, as well as the synthesis of metal-binding proteins such as metallothionein-like proteins. This study elucidated that As(III) and As(V) had little potential toxicity on marine fish. PMID- 22542779 TI - Cr(VI) retention and transport through Fe(III)-coated natural zeolite. AB - Cr(VI) is a group A chemical based on the weight of evidence of carcinogenicity. Its transport and retention in soils and groundwater have been studied extensively. Zeolite is a major component in deposits originated from volcanic ash and tuff after alteration. In this study, zeolite aggregates with the particle size of 1.4-2.4mm were preloaded with Fe(III). The influence of present Fe(III) on Cr(VI) retention by and transport through zeolite was studied under batch and column experiments. The added Fe(III) resulted in an enhanced Cr(VI) retention by the zeolite with a capacity of 82mg/kg. The Cr(VI) adsorption on Fe(III)-zeolite followed a pseudo-second order kinetically and the Freundlich adsorption isotherm thermodynamically. Fitting the column experimental data to HYDRUS-1D resulted in a retardation factor of 3 in comparison to 5 calculated from batch tests at an initial Cr(VI) concentration of 3mg/L. The results from this study showed that enhanced adsorption and retention of Cr(VI) may happen in soils derived from volcanic ash and tuff that contains significant amounts of zeolite with extensive Fe(III) coating. PMID- 22542782 TI - Changes in glycosaminoglycans and proteoglycans of normal breast and fibroadenoma during the menstrual cycle. AB - BACKGROUND: Fibroadenoma is the most common breast tumor in young women, and its growth and metabolism may be under hormonal control. In the present paper we described the proteoglycan (PG) composition and synthesis rate of normal breast and fibroadenoma during the menstrual cycle. METHODS: Samples of fibroadenoma and adjacent normal breast tissue were obtained at surgery. PGs were characterized by agarose gel electrophoresis and enzymatic degradation with glycosaminoglycan (GAG) lyases, and immunolocalized by confocal microscopy. To assess the synthesis rate, PGs were metabolic labeled by 35S-sulfate. RESULTS: The concentration of PGs in normal breast was higher during the secretory phase. Fibroadenoma contained and synthesized more PGs than their paired controls, but the PG concentrations varied less with the menstrual cycle and, in contrast to normal tissue, peaked in the proliferative phase. The main mammary GAGs are heparan sulfate (HS, 71%-74%) and dermatan sulfate (DS, 26%-29%). The concentrations of both increased in fibroadenoma, but DS increased more, becoming 35%-37% of total. The DS chains contained more beta-d-glucuronic acid (IdoUA/GlcUA ratios were >10 in normal breast and 2-7 in fibroadenoma). The 35S-sulfate incorporation rate revealed that the in vitro synthesis rate of DS was higher than HS. Decorin was present in both tissues, while versican was found only in fibroadenoma. CONCLUSIONS: In normal breast, the PG concentration varied with the menstrual cycle. It was increased in fibroadenoma, especially DS. GENERAL SIGNIFICANCE: PGs are increased in fibroadenoma, but their concentrations may be less sensitive to hormonal control. PMID- 22542781 TI - Structural and biochemical studies of the open state of Lys48-linked diubiquitin. AB - Ubiquitin (Ub) is a small protein highly conserved among eukaryotes and involved in practically all aspects of eukaryotic cell biology. Polymeric chains assembled from covalently-linked Ub monomers function as molecular signals in the regulation of a host of cellular processes. Our previous studies have shown that the predominant state of Lys48-linked di- and tetra-Ub chains at near physiological conditions is a closed conformation, in which the Ub-Ub interface is formed by the hydrophobic surface residues of the adjacent Ub units. Because these very residues are involved in (poly)Ub interactions with the majority of Ub binding proteins, their sequestration at the Ub-Ub interface renders the closed conformation of polyUb binding incompetent. Thus the existence of open conformation(s) and the interdomain motions opening and closing the Ub-Ub interface is critical for the recognition of Lys48-linked polyUb by its receptors. Knowledge of the conformational properties of a polyUb signal is essential for our understanding of its specific recognition by various Ub receptors. Despite their functional importance, open states of Lys48-linked chains are poorly characterized. Here we report a crystal structure of the open state of Lys48-linked di-Ub. Moreover, using NMR, we examined interactions of the open state of this chain (at pH4.5) with a Lys48-linkage-selective receptor, the UBA2 domain of a shuttle protein hHR23a. Our results show that di-Ub binds UBA2 in the same mode and with comparable affinity as the closed state. Our data suggest a mechanism for polyUb signal recognition, whereby Ub-binding proteins select specific conformations out of the available ensemble of polyUb chain conformations. This article is part of a Special Issue entitled: Ubiquitin Drug Discovery and Diagnostics. PMID- 22542784 TI - Polycyclic aromatic hydrocarbons in upstream riverine runoff of the Pearl River Delta, China: an assessment of regional input sources. AB - Water samples collected from upstream tributaries of the Pearl River Delta (PRD) and from locations within the PRD (South China) were analyzed for 27 polycyclic aromatic hydrocarbons (PAHs). Average concentrations (aqueous plus particulate) of total 27 PAHs (Sigma(27)PAH), 16 priority PAHs designated by the United States Environmental Protection Agency (USEPA) except naphthalene (Sigma(15)PAH), and the seven carcinogenic PAHs (Sigma(7)PAH) classified by the USEPA were 260 +/- 410, 130 +/- 310, and 15 +/- 12 ng/L, respectively. Riverine PAHs were predominantly generated from coal and vegetation combustion, coke production, vehicle exhausts, and petroleum residues, accounting for 28%, 25%, 22% and 21%, respectively, on average. Upstream riverine fluxes of Sigma(27)PAH and Sigma(15)PAH amounted to 38.9 and 12.9 tons/year, respectively. The net contributions of Sigma(27)PAH and Sigma(15)PAH from sources within the PRD were estimated at 21.4 and 21.0 tons/year, respectively. PMID- 22542785 TI - High bacterial biodiversity increases degradation performance of hydrocarbons during bioremediation of contaminated harbor marine sediments. AB - We investigated changes of bacterial abundance and biodiversity during bioremediation experiments carried out on oxic and anoxic marine harbor sediments contaminated with hydrocarbons. Oxic sediments, supplied with inorganic nutrients, were incubated in aerobic conditions at 20 degrees C and 35 degrees C for 30 days, whereas anoxic sediments, amended with organic substrates, were incubated in anaerobic conditions at the same temperatures for 60 days. Results reported here indicate that temperature exerted the main effect on bacterial abundance, diversity and assemblage composition. At higher temperature bacterial diversity and evenness increased significantly in aerobic conditions, whilst decreased in anaerobic conditions. In both aerobic and anaerobic conditions, biodegradation efficiencies of hydrocarbons were significantly and positively related with bacterial richness and evenness. Overall results presented here suggest that bioremediation strategies, which can sustain high levels of bacterial diversity rather than the selection of specific taxa, may significantly increase the efficiency of hydrocarbon degradation in contaminated marine sediments. PMID- 22542780 TI - Understanding age-related macular degeneration (AMD): relationships between the photoreceptor/retinal pigment epithelium/Bruch's membrane/choriocapillaris complex. AB - There is a mutualistic symbiotic relationship between the components of the photoreceptor/retinal pigment epithelium (RPE)/Bruch's membrane (BrMb)/choriocapillaris (CC) complex that is lost in AMD. Which component in the photoreceptor/RPE/BrMb/CC complex is affected first appears to depend on the type of AMD. In atrophic AMD (~85-90% of cases), it appears that large confluent drusen formation and hyperpigmentation (presumably dysfunction in RPE) are the initial insult and the resorption of these drusen and loss of RPE (hypopigmentation) can be predictive for progression of geographic atrophy (GA). The death and dysfunction of photoreceptors and CC appear to be secondary events to loss in RPE. In neovascular AMD (~10-15% of cases), the loss of choroidal vasculature may be the initial insult to the complex. Loss of CC with an intact RPE monolayer in wet AMD has been observed. This may be due to reduction in blood supply because of large vessel stenosis. Furthermore, the environment of the CC, basement membrane and intercapillary septa, is a proinflammatory milieu with accumulation of complement components as well as proinflammatory molecules like CRP during AMD. In this toxic milieu, CC die or become dysfunction making adjacent RPE hypoxic. These hypoxic cells then produce angiogenic substances like VEGF that stimulate growth of new vessels from CC, resulting in choroidal neovascularization (CNV). The loss of CC might also be a stimulus for drusen formation since the disposal system for retinal debris and exocytosed material from RPE would be limited. Ultimately, the photoreceptors die of lack of nutrients, leakage of serum components from the neovascularization, and scar formation. Therefore, the mutualistic symbiotic relationship within the photoreceptor/RPE/BrMb/CC complex is lost in both forms of AMD. Loss of this functionally integrated relationship results in death and dysfunction of all of the components in the complex. PMID- 22542786 TI - Isolated epicardial ultrarapid activity. PMID- 22542783 TI - Globoside promotes activation of ERK by interaction with the epidermal growth factor receptor. AB - BACKGROUND: Globoside (Gb4), a globo-series glycosphingolipid (GSL), has been characterized as a stage-specific embryonic antigen (SSEA), and is highly expressed during embryogenesis as well as in cancer tissues. However, the functional role and molecular mechanism of Gb4 are so far unknown. METHODS: GSLs were preferentially inhibited by treatment with D-threo-1-ethylenedioxyphenyl-2 palmitoylamino-3-pyrrolidino-1-propanol (EtDO-P4), a nanomolar inhibitor of GSL synthesis, in two carcinoma cell lines, HCT116 and MCF7. The effect of EtDO-P4 was examined by MTT assay, FACS, wound assay, western blotting, and RTK array analysis. The functional role of Gb4 was determined by the exogenous addition of various GSLs, and an assay utilizing GSL-coated latex beads. RESULTS: Both cell lines contained higher levels of neutral GSLs than of sialic acid-containing GSLs. Gb4 was one of the major neutral GSLs. The depletion of total GSLs caused significant reduction of cell proliferation, but had less effect on cell apoptosis or motility. EtDO-P4 treatment also suppressed activation of the epidermal growth factor receptor (EGFR)-induced ERK pathway and various receptor tyrosine kinases (RTKs). The reduced activation of ERK was restored by the exogenous addition of Gb4, but not by the addition of gangliosides (GM1, GM2, GM3, and GD1a). The GSL-coated bead assay indicated that Gb4 forms a complex with EGFR, but not with other RTKs. Taken together, Gb4 promotes activation of EGFR induced ERK signaling through direct interaction with EGFR. GENERAL SIGNIFICANCE: A globo-series GSL, Gb4, promotes EGFR-induced MAPK signaling, resulting in cancer cell proliferation. These findings suggest a possible application of Gb4 in cancer diagnostics and drug targeting. PMID- 22542787 TI - Associations between Pittsburgh Sleep Quality Index factors and health outcomes in women with posttraumatic stress disorder. AB - OBJECTIVE: The Pittsburgh Sleep Quality Index (PSQI) is a widely used measure of subjective sleep disturbance in clinical populations, including individuals with posttraumatic stress disorder (PTSD). Although the severity of sleep disturbance is generally represented by a global symptom score, recent factor analytic studies suggest that the PSQI is better characterized by a two- or three-factor model than a one-factor model. This study examined the replicability of two- and three-factor models of the PSQI, as well as the relationship between PSQI factors and health outcomes, in a female sample with PTSD. METHODS: The PSQI was administered to 319 women with PTSD related to sexual or physical assault. Confirmatory factor analyses tested the relative fit of one-, two-, and three factor solutions. Bivariate correlations were performed to examine the shared variance between PSQI sleep factors and measures of PTSD, depression, anger, and physical symptoms. RESULTS: Confirmatory factor analyses supported a three-factor model with Sleep Efficiency, Perceived Sleep Quality, and Daily Disturbances as separate indices of sleep quality. The severity of symptoms represented by the PSQI factors was positively associated with the severity of PTSD, depression, and physical symptoms. However, these health outcomes correlated as much or more with the global PSQI score as with PSQI factor scores. CONCLUSIONS: These results support the multidimensional structure of the PSQI. Despite this, the global PSQI score has as much or more explanatory power as individual PSQI factors in predicting health outcomes. PMID- 22542788 TI - Algorithms for using an activity-based accelerometer for identification of infant sleep-wake states during nap studies. AB - OBJECTIVE: To determine the accuracy of using different algorithms on the output from an Actical accelerometer, a device normally used to measure physical activity, to distinguish sleep from wake states. METHODS: Thirty-one infants aged 10-22 weeks wore the accelerometer on the shin for a daytime nap recording in tandem with polysomnography. Sleep-wake epochs were identified using four computations/algorithms: the zero-threshold computation, two common algorithms used for wrist-based devices (Sadeh and Cole), and a new algorithm developed for this study (count-scaled). Accuracy was examined in direct epoch comparison with polysomnography using 15-, 30- and 60-s sampling epochs. RESULTS: Overall agreements (accuracy) for sleep-wake states were >80% for all computations. The count-scaled algorithm sampling 15-s epochs gave the highest accuracy, with sensitivity (sleep agreement) at 86% and specificity (awake agreement) at 85%. Other computations yielded higher sensitivity at the expense of specificity. Another way to assess the accuracy of identification of sleep-wake states was to compare sleep parameter outputs. All computations and sampling epochs were significantly correlated with total sleep time (r=0.76-0.88), sleep latency (r=0.70-0.93), sleep efficiency (r=0.76-0.87), and wake time after sleep onset (r=0.41-0.53). The number of awakenings after sleep onset was overestimated by accelerometry. CONCLUSIONS: The Actical accelerometer, designed to measure physical activity, can reliably identify sleep in infants during napping, with the count-scaled algorithm showing some advantages over other methods for accurate identification of sleep-wake epochs. PMID- 22542789 TI - Effect of different ultrasound contrast materials and temperatures on patient comfort during intrauterine and tubal assessment for infertility. AB - Hysterosalpingo-contrast sonography (HyCoSy) is safe and easy to perform outpatient method in the evaluation of female infertility. During this procedure a certain level of discomfort and pain are experienced by patients. On the basis of reducing avoidable pain inductors the aim of this study was to compare pain sensation due to different warmth of applied contrasts (sterile saline and Echovist((r))). Prospective and randomized study was performed on patients requiring tubal and uterine assessment during standard infertility work up. One group of patients was examined using both contrasts at room temperature and the other group using preheated contrasts at body temperature. Pain experience of the procedure was rated by patients for each contrast by numerical scale (0-10) immediately after the procedure. There was significant statistical difference between pain scores during application of two contrasts in each group; Echovist induces significantly less pain in comparison to sterile saline at the same temperature (P=0.002, 0.001). Between two groups there is also statistically significant difference in pain during introduction of the same contrast at different temperature (P<0.001). The most tolerable for the patient is body temperature of the applied contrasts although their structure and concentrations can be another factor associated with tolerability of the procedure. PMID- 22542790 TI - [Description of characteristics, therapy and outcome of patients older than 75 years presenting with severe renal insufficiency (eGFR below 20 mL/min/1.73 m(2): pilot study]. AB - In France, the incidence of dialysis patients is increasing in people over 75 years and represents 40% of incident patients. In these elderly patients with many comorbidities, the benefit of dialysis in terms of survival and quality of life remains controversial. Using data from REIN, determinants of early mortality were identified and a prognostic score was provided. This approach must now be adapted to elderly with end stage renal failure (ESRF) not on dialysis for which we have little data on their clinical characteristics, therapeutic projects and outcome. We report the results of a pilot study and the prospective study protocol that resulted. In four French nephrology department, 76 patients were studied with a mean age of 83 +/- 5 years, with a MDRD estimated GFR (abbreviated MDRD) of 16 +/- 4 mL/min/1.73 m(2). These patients were different from the population on dialysis recorded in REIN. This pilot study has shown the feasibility of a prospective study on a larger scale, which aims to build a valuable tool for decision making in elderly patients with ESRF not yet on dialysis. PMID- 22542791 TI - Suppressive effects of a pyrazole derivative of curcumin on airway inflammation and remodeling. AB - To advance the control of airway epithelial cell function and asthma, we investigated the effects of a new curcumin derivative, CNB001, which possesses improved pharmacological properties. Normal human bronchial epithelial (NHBE) cells were stimulated with synthetic double-stranded RNA, Poly(I:C). CNB001 significantly suppressed IL-6, TNF-alpha, and GM-CSF production by NHBE cells, and did so more effectively than did curcumin or dexamethasone (DEX). CNB001 significantly inhibited the decrease of E-cadherin mRNA expression and increase of vimentin mRNA expression observed in NHBE cells induced by a combination of TGF-beta1 and TNF-alpha, which are markers of airway remodeling. In NHBE cells stimulated by TGF-beta1, CNB001 significantly downregulated the level of active serine peptidase inhibitor clade E member (SERPINE) 1, which is also reported to be related to airway remodeling. Whereas DEX alone significantly increased the active SERPINE1 level, the combination of DEX and CNB001 significantly suppressed active SERPINE1. In addition, CNB001 significantly suppressed neutrophil infiltration, IL-6, TNF-alpha, IL-13 and active SERPINE1 production in bronchoalveolar lavage fluid of the murine asthma model, which was not observed in the case of DEX. In conclusion, the curcumin derivative, CNB001, is a promising candidate to treat asthma associated with neutrophilic airway inflammation and remodeling. PMID- 22542792 TI - Mutations in the mitochondrial ATPase6 gene are frequent in human osteosarcoma. AB - To explore the polymorphisms and mutations of mitochondrial ATPase6 gene in Chinese patients with osteosarcoma and their possible association with carcinogenesis, direct DNA sequencing method was used to detect the variants of the mitochondrial ATPase6 gene in 39 patients with osteosarcoma. We found mutations of the mitochondrial ATPase6 gene in 24/39 (61.5%) of the tested osteosarcoma samples, and identified 27 variant sites in ATPase6 coding regions. We did not detect any new polymorphisms in osteosarcoma, nor was there any association between variants and the three histopathological subtypes. These data demonstrated that mtDNA mutations within the ATPase6 gene are a frequent event in Chinese patients with osteosarcoma. PMID- 22542793 TI - Involvement of AMPK and MAPK signaling during the progression of experimental autoimmune myocarditis in rats and its blockade using a novel antioxidant. AB - There are various reports suggesting the role of angiotensin (Ang) receptor blockers, Ang converting enzyme inhibitors, calcium channel blockers, diuretics and antioxidants against the progression of experimental autoimmune myocarditis (EAM) to dilated cardiomyopathy (DCM). Most of them were reported to be effective during this adverse cardiac remodeling. Recently much attention has been paid to studying the involvement of AMP-activated protein kinase (AMPK) and mitogen activated protein kinase (MAPK) in various cardiovascular ailments. AMPK acts as a master sensor of cellular energy balance via maintenance of lipid and glucose metabolism. Evidences also suggest the relation between AMPK and oxidative stress during physiological and pathological myocardial cellular function. Since, it is of interest to identify the roles of AMPK and MAPK during the progression of EAM to DCM and also the effect of edaravone, a novel free radical scavenger, against its progression. For this, we have carried out western blotting, histopathological staining and immunohistochemical analyses to measure the myocardial expressions of AMPK signaling and oxidative stress related parameters in normal and vehicle or edaravone-treated EAM rats, respectively. We identified the myocardial levels of phospho Akt and phosphoinositide 3-kinase, which are the upstream proteins of AMPK and MAPK activation and both were up-regulated in the vehicle-treated rats, whereas candesartan treatment significantly reversed these changes. We have also measured the myocardial levels of p-AMPKalpha, different isoforms of protein kinase C and MAPK signaling proteins. All of these protein levels were significantly elevated in the hearts of DCM rats whereas edaravone treatment significantly reversed these changes. In viewing these results, we can suggest that along with MAPK, AMPK signaling also plays a crucial role in the progression of EAM and it can be effectively blocked by the treatment with a novel antioxidant, edaravone. PMID- 22542794 TI - Rapid measurement of 8-oxo-7,8-dihydro-2'-deoxyguanosine in human biological matrices using ultra-high-performance liquid chromatography-tandem mass spectrometry. AB - Interaction of reactive oxygen species with DNA results in a variety of modifications, including 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), which has been extensively studied as a biomarker of oxidative stress. Oxidative stress is implicated in a number of pathophysiological processes relevant to obstetrics and gynecology; however, there is a lack of understanding as to the precise role of oxidative stress in these processes. We aimed to develop a rapid, validated assay for the accurate quantification of 8-oxodG in human urine using solid-phase extraction and ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) and then investigate the levels of 8-oxodG in several fluids of interest to obstetrics and gynecology. Using UHPLC-MS/MS, 8-oxodG eluted after 3.94 min with an RSD for 15 injections of 0.07%. The method was linear between 0.95 and 95 nmol/L with LOD and LOQ of 5 and 25 fmol on-column, respectively. Accuracy and precision were 98.7-101.0 and <10%, respectively, over three concentrations of 8-oxodG. Recovery from urine was 88% with intra- and interday variations of 4.0 and 10.2%, respectively. LOQ from urine was 0.9 pmol/ml. Rank order from the greatest to lowest 8-oxodG concentration was urine>seminal plasma>amniotic fluid>plasma>serum>peritoneal fluid, and it was not detected in saliva. Urine concentrations normalized to creatinine (n=15) ranged between 0.55 and 1.95 pmol/MUmol creatinine. We describe, for the first time, 8 oxodG concentrations in human seminal plasma, peritoneal fluid, amniotic fluid, and breast milk, as well as in urine, plasma, and serum, using a rapid UHPLC MS/MS method that will further facilitate biomonitoring of oxidative stress. PMID- 22542795 TI - Coprisin-induced antifungal effects in Candida albicans correlate with apoptotic mechanisms. AB - Coprisin is a 43-mer defensin-like peptide from the dung beetle, Copris tripartitus. Here, we investigated the induction of apoptosis by coprisin in Candida albicans cells. Coprisin exerted antifungal and fungicidal activity without any hemolytic effect. Confocal microscopy indicated that coprisin accumulated in the nucleus of cells. The membrane studies, 1,6-diphenyl-1,3,5 hexatriene, calcein-leakage, and giant unilamellar vesicle assays, confirmed that coprisin did not disrupt the fungal plasma membrane at all. Moreover, the activity of coprisin was energy- and salt-dependent. Next, we investigated whether coprisin induced apoptosis in C. albicans. Annexin V-FITC staining and TUNEL assay showed that coprisin was involved with both the early and the late stages of apoptosis. Coprisin also increased the intracellular reactive oxygen species level, and hydroxyl radicals were included at high levels among the species. The effect of thiourea as a hydroxyl radical scavenger further confirmed the existence of the hydroxyl radicals. Furthermore, coprisin induced mitochondrial membrane potential dysfunction, cytochrome c release, and activation of metacaspases. In summary, this study suggests that coprisin could be a model molecule for a large family of novel antimicrobial peptides possessing apoptotic activity. PMID- 22542796 TI - Induction of lung glutathione and glutamylcysteine ligase by 1,4 phenylenebis(methylene)selenocyanate and its glutathione conjugate: role of nuclear factor-erythroid 2-related factor 2. AB - The synthetic organoselenium agent 1,4-phenylenebis(methylene)selenocyanate (p XSC) and its glutathione (GSH) conjugate (p-XSeSG) are potent chemopreventive agents in several preclinical models. p-XSC is also an effective inducer of GSH in mouse lung. Our objectives were to test the hypothesis that GSH induction by p XSC occurs through upregulation of the rate-limiting GSH biosynthetic enzyme glutamylcysteine ligase (GCL), through activation of antioxidant response elements (AREs) in GCL genes via activation of nuclear factor-erythroid 2-related factor 2 (Nrf2). p-XSC feeding (10 ppm Se) increased GSH (230%) and upregulated the catalytic subunit of GCL (GCLc) (55%), extracellular-related kinase (220%), and nuclear Nrf2 (610%) in lung but not liver after 14 days in the rat (P<0.05). Similarly, p-XSeSG feeding (10 ppm) induced lung GCLc (88%) and GSH (200%) (P<0.05), whereas the naturally occurring selenomethionine had no effect. Both p XSC and p-XSeSG activated a luciferase reporter in HepG2 ARE-reporter cells up to threefold for p-XSC and greater than or equal to fivefold for p-XSeSG. Luciferase activation by p-XSeSG was associated with enhanced levels of GSH, GCLc, and nuclear Nrf2, which were significantly reduced by co-incubation with short interfering RNA targeting Nrf2. The dependence of GCL induction on Nrf2 was confirmed in Nrf2-deficient mouse embryonic fibroblasts, in which p-XSeSG induced GCL subunits in wild-type but not in Nrf2-deficient cells (P<0.05). These results indicate that p-XSC may act through the Nrf2 pathway in vivo and that p-XSeSG is the putative metabolite responsible for such activation, thus offering p-XSeSG as a less toxic, yet highly efficacious, inducer of GSH. PMID- 22542798 TI - Unexpected uptake of gadoxetic acid in a hepatic metastasis from T-cell lymphoma. AB - We report a case of unexpected heterogeneous uptake of gadoxetic acid into a hepatic metastasis in a patient with T-cell lymphoblastic lymphoma that also lacked hypermetabolic characteristics on positron emission (PET)/computed tomography (CT) with [(18)F]fluorodeoxyglucose (FDG). Therefore, in cases of heterogeneous uptake of gadoxetic acid, infiltrative lesions must be considered. PMID- 22542797 TI - Ascorbate stimulates endothelial nitric oxide synthase enzyme activity by rapid modulation of its phosphorylation status. AB - Long-term exposure to ascorbate is known to enhance endothelial nitric oxide synthase (eNOS) activity by stabilizing the eNOS cofactor tetrahydrobiopterin (BH4). We investigated acute effects of ascorbate on eNOS function in primary (HUVEC) and immortalized human endothelial cells (EA.hy926), aiming to provide a molecular explanation for the rapid vasodilatation seen in vivo upon administration of ascorbate. Enzymatic activity of eNOS and intracellular BH4 levels were assessed by means of an arginine-citrulline conversion assay and HPLC analysis, respectively. Over a period of 4h, ascorbate steadily increased eNOS activity, although endothelial BH4 levels remained unchanged compared to untreated control cells. Immunoblot analyses revealed that as early as 5 min after treatment ascorbate dose-dependently increased phosphorylation at eNOS Ser1177 and concomitantly decreased phosphorylation at eNOS-Thr495, a phosphorylation pattern indicative of increased eNOS activity. By employing pharmacological inhibitors, siRNA-mediated knockdown approaches, and overexpression of the catalytic subunit of protein phosphatase 2A (PP2A), we show that this effect was at least partly owing to reduction of PP2A activity and subsequent activation of AMP-activated kinase. In this report, we unravel a novel mechanism for how ascorbate rapidly activates eNOS independent of its effects on BH4 stabilization. PMID- 22542799 TI - Controversy over misinterpretation of EEG with subsequent misdiagnosis of epilepsy. PMID- 22542800 TI - Effects of age and splenectomy on heavy infection of Angiostrongylus cantonensis in rats. AB - This study was designed to determine the effects of age and the role of spleen in rats with heavy Angiostrongylus cantonensis infection. Young rats (8 weeks) infected with 100 larvae were found to have significantly higher worm recovery rate (75.0+/-6.6%) than the adult (6 months) (55.7+/-1.5%) and the aging ones (13 months) (57.6+/-4.0%). Moreover, the recovery rate in adult rats with 400 larvae (33.6+/-10.67%) was significantly lower than those with 100 larvae (55.7+/-1.53%) or 200 larvae (53.3+/-5.4%). The splenectomized young rats with 100 larvae had a significantly higher recovery rate (84.3+/-2.5%) than the intact (75.0+/-6.6%) or sham splenectomized ones (74.4+/-3.8%). Although titers of antibody against A. cantonensis increased with time, those against young adults were significantly higher before week 4 whereas those against adult worms become significantly higher since week 4. Titers in the splenectomized rats were also found to be significantly lower than those in the intact ones. These finding indicate that young rats are more susceptible to A. cantonensis. Crowding effect may occur in rats with heavy infections. The effects of splenectomy on the host are independent of the intensity of infection. PMID- 22542801 TI - Plasmodium berghei: influence of infection on the oxidant and antioxidants levels in pregnant BALB/c mice. AB - Malarial infection during pregnancy has been associated with maternal anemia and death, abortion, still-birth and is a major cause of low birth weight, an important risk factor for infant morbidity and mortality in endemic areas. The present study was designed to delineate the oxidative stress in various organs (liver, spleen, kidney, brain and placenta) of pregnant Plasmodium berghei infected BALB/c mice. It was observed that pregnant-infected mice had higher parasitaemia than nonpregnant-infected mice. Most notably, levels of malondialdehyde (MDA), a measure of lipid peroxidation, reduced glutathione (GSH) and superoxide dismutase (SOD) levels were significantly higher in the liver, spleen, kidney and brain of pregnant-infected mice compared with pregnant mice. Although MDA levels were significantly higher, GSH and SOD levels remained unaltered in the placenta of pregnant-infected mice compared with pregnant mice. Furthermore, catalase activity was significantly lower in all the organs of pregnant-infected mice compared with pregnant mice. Histopathological observations in the organs clearly show the cellular and morphological alterations that may be occurring due to increased lipid peroxidation. Taken together, the data suggest that the increased severity of malarial infection during pregnancy may be due to accentuated oxidative stress. PMID- 22542802 TI - Effects of percutaneous needle liver biopsy on dairy cow behaviour. AB - In cattle, percutaneous needle liver biopsy is used for scientific examination of liver metabolism. The impact of the biopsy procedure is, however, poorly investigated. Our aim was to examine the behaviour of dairy cows during and after liver biopsy. Data were collected from 18 dry cows. Percutaneous needle liver biopsies (after administration of local anaesthesia (2% Procaine)) and blood samples were taken during restraining. During the control treatment, animals were restrained and blood sampled. During the biopsy procedure, cows showed increased restlessness (P=0.008), frequency of head shaking (P=0.016), and decreased rumination (P=0.064). After biopsies, tail pressing (P=0.016) and time spent perching (P=0.058) increased. Time spent upright (P=0.10) and number of leg movements (P=0.033) increased during the night as compared to controls. Thus, liver biopsy induced behavioural changes for up to 19 h--and particularly for behaviour previously associated with pain. Even though the exact welfare impact of percutaneous needle liver biopsies in cows is not known, and the magnitude of the behavioural changes was limited, pain always has negative effects on animal welfare. Therefore, if the present biopsy procedure--involving several biopsy passes--is to be used, improvement of the anaesthetic protocol as well as the inclusion of analgesics should be considered. PMID- 22542803 TI - PCV2 induces apoptosis and modulates calcium homeostasis in piglet lymphocytes in vitro. AB - This study investigated the process of PCV2-induced apoptosis and the effect of PCV2 inoculation on calcium homeostasis in piglet lymphocytes in vitro. PCV2 inoculated lymphocytes exhibited chromatin condensation, chromatin segregation, the appearance of membrane-enclosed apoptotic bodies, and DNA fragmentation. Moreover, the proportion of apoptotic cells increased significantly in PCV2 inoculated lymphocytes compared with controls. These results demonstrate that PCV2 induces lymphocyte apoptosis. Some evidence suggests that an alteration in the intracellular free Ca2+ concentration ([Ca2+]i) could cause apoptosis. We measured elevated [Ca2+]i in PCV2-inoculated lymphocytes for 12 or 24 h compared with controls. Our results support that PCV2-induced apoptosis may be relative to [Ca2+]i. In addition, calmodulin (CaM) was increased in PCV2-inoculated lymphocytes for 12 h compared with controls. The amount of CaM-dependent protein kinase II (CaMKII) did not change with PCV2 inoculation. We infer that the increased [Ca2+]i can bind CaM protein, but functions independently of CaMKII. Inositol 1,4,5-trisphosphate receptor (IP3R)-1 mRNA expression increased with PCV2 inoculation, whereas plasma Ca2+-ATP4 mRNA expression decreased. A decreased Ca2+-ATP4 level may inhibit Ca2+ efflux, and the increased IP3R-1 may trigger Ca2+ release from the endoplasmic reticulum. Both of these changes may contribute to increased [Ca2+]i. PMID- 22542804 TI - Direct lexical control of eye movements in reading: evidence from a survival analysis of fixation durations. AB - Participants' eye movements were monitored in an experiment that manipulated the frequency of target words (high vs. low) as well as their availability for parafoveal processing during fixations on the pre-target word (valid vs. invalid preview). The influence of the word-frequency by preview validity manipulation on the distributions of first fixation duration was examined by using ex-Gaussian fitting as well as a novel survival analysis technique which provided precise estimates of the timing of the first discernible influence of word frequency on first fixation duration. Using this technique, we found a significant influence of word frequency on fixation duration in normal reading (valid preview) as early as 145ms from the start of fixation. We also demonstrated an equally rapid non lexical influence on first fixation duration as a function of initial landing position (location) on target words. The time-course of frequency effects, but not location effects was strongly influenced by preview validity, demonstrating the crucial role of parafoveal processing in enabling direct lexical control of reading fixation times. Implications for models of eye-movement control are discussed. PMID- 22542805 TI - Blockade of SOX4 mediated DNA repair by SPARC enhances radioresponse in medulloblastoma. AB - SPARC is a matricellular glycoprotein and a putative radioresistance-reversal gene. We therefore explored the possibility of SPARC expression on medulloblastoma radiosensitivity in vitro and in vivo. The combined treatment of the SPARC and irradiation resulted in increased cell death when compared to cells treated with irradiation alone in vitro and in vivo. SPARC expression prior to irradiation suppressed checkpoints-1,-2 and p53 phosphorylation and DNA repair gene XRCC1. We also demonstrate that SPARC expression suppressed irradiation induced SOX-4 mediated DNA repair. These results provide evidence of the anti tumor effect of combining SPARC with irradiation as a new therapeutic strategy for the treatment of medulloblastoma. PMID- 22542806 TI - Decreased carbonyl reductase 1 expression promotes malignant behaviours by induction of epithelial mesenchymal transition and its clinical significance. AB - Human carbonyl reductase 1 (CBR1) is an enzyme that catalyse the reduction of many compounds by using NADPH-dependent oxydoreductase activity. Although CBR1 is known to regulate the tumour progression, the molecular mechanisms of CBR1 in cancer progression and the clinical significance of CBR1 status remain unclear. Here, we investigated the molecular mechanisms by which CBR1 affects cancer cell behaviour in vitro and the clinical significance of CBR1 using immunohistochemical analyses in endometrial cancer. Here, the role of CBR1 in cancer cell invasion and metastasis, and its molecular mechanisms were investigated by transfection of sense and antisense CBR1 cDNAs into a human endometrial adenocarcinoma cell line. The relationship between CBR1 expression analysed by immunohistochemistry and prognosis such as progression free survival (PFS) and overall survival (OS) was examined in endometrial cancer tissues from FIGO stage I-IV (n=109). Suppression of CBR1 by antisense CBR1 cDNA increased cancer cell invasion, and suppressed E-cadherin expression and capacity for cellular aggregation. In contrast, over-expression of CBR1 by sense CBR1 cDNA increased E-cadherin expression and capacity for cellular aggregation, and suppressed cancer cell invasion. The expression of transcriptional suppressors of E-cadherin, Snail and ZEB1, were increased by CBR1 suppression, but suppressed by CBR1 over-expression. Immunohistochemical analyses showed that decreased CBR1 expression is significantly related with poor PFS and OS compared with strong CBR1 expression. In multivariate analyses, decreased CBR1 expression was an independent prognostic factor for PFS and OS. CBR1 regulates cancer cell invasion in endometrial adenocarcinomas by regulating the epithelial mesenchymal transition. A decreased CBR1 expression can be a useful marker of an unfavourable clinical outcome in patients with endometrial cancer. PMID- 22542807 TI - Statins and cancer: current and future prospects. AB - Statins are inhibitors of 3-hydroxy-methylglutaryl (HMG) CoA reductase. They exhibit effects beyond cholesterol reduction, including anticancer activity. This review presents the effects of statins in vitro and their possible molecular anticancer mechanisms and critically discusses the data regarding the role of statins in cancer prevention. Finally, this review focuses on the use of statins combined with other chemotherapeutics to increase the effectiveness of cancer treatments. Despite rare and inconclusive clinical data, the preclinical results strongly suggest that such combined treatment could be a promising new strategy for the treatment of certain tumor types. PMID- 22542808 TI - Autophagy in tumorigenesis and cancer therapy: Dr. Jekyll or Mr. Hyde? AB - Autophagy is an evolutionarily conserved mechanism for intracellular substance degradation, responsible for the recycling of metabolic substances and the maintenance of intracellular stability. It has early been demonstrated to play a significant role in tumorigenesis, but whether it acts as a promoter or a suppressor during tumorigenesis seems to be context-specific. Moreover, autophagy is also implicated in promoting chemoresistance of cancer cells so as to attenuate therapeutic efficacy of chemotherapy. On the contrary, other reports highlight a tumor-killing role of autophagy during cancer treatment. Herein, this review aims to revisit the key features of autophagy, summarize the seemingly contradictory roles of autophagy during both tumorigenesis and cancer chemotherapy, and evaluate the feasibility of altering the level of cellular autophagy as part of cancer adjuvant treatment. PMID- 22542809 TI - Cathepsin D inhibits oxidative stress-induced cell death via activation of autophagy in cancer cells. AB - Cathepsin D (CatD), a lysosomal aspartic protease, plays an essential role in tumor progression and apoptosis. However, the function of CatD in cell death is not yet fully understood. In this study, we identified CatD as one of up regulated proteins in human malignant glioblastoma M059J cells that lack the catalytic subunit of DNA-PK compared with its isogenic M059K cells with normal DNA-PK activity. M059J cells were relatively more resistant to genotoxic stress than M059K cells. Overexpression of wild-type CatD but not catalytically inactive mutant CatD (D295N) inhibited H(2)O(2)-induced cell death in HeLa cells. Furthermore, knockdown of CatD expression abolished anti-apoptotic effect by CatD in the presence of H(2)O(2). Interestingly, high expression of CatD in HeLa cells significantly activated autophagy: increase of acidic autophagic vacuoles, LC3-II formation, and GFP-LC3 puncta. These results suggest that CatD can function as an anti-apoptotic mediator by inducing autophagy under cellular stress. In conclusion, inhibition of autophagy could be a novel strategy for the adjuvant chemotherapy of CatD-expressing cancers. PMID- 22542810 TI - Up-regulation of endogenous PML induced by a combination of interferon-beta and temozolomide enhances p73/YAP-mediated apoptosis in glioblastoma. AB - Interferon-beta (IFN-beta) is reported to augment anti-tumor effects by temozolomide in glioblastoma via down-regulation of MGMT. Promyelocytic leukemia (PML), a gene induced by IFN-beta, is a tumor suppressor. Here, we report for the first time that in combination therapy, an IFN-beta-induced increase in endogenous PML contributes to anti-tumor effects in p53 wild- and mutant glioma cells in a xenograft mice model. The increased PML promoted the accumulation of p73, a structural and functional homolog of p53, to fuse the coactivator Yes associated-protein in the PML nuclear bodies. The adjuvant therapy targeted at PML may be a promising therapeutic strategy for glioblastoma. PMID- 22542811 TI - Responses of brown adipose tissue to diet-induced obesity, exercise, dietary restriction and ephedrine treatment. AB - Drug-induced weight loss in humans has been associated with undesirable side effects not present in weight loss from lifestyle interventions (caloric restriction or exercise). To investigate the mechanistic differences of weight loss by drug-induced and lifestyle interventions, we examined the gene expression (mRNA) in brown adipose tissue (BAT) and conducted histopathologic assessments in diet-induced obese (DIO) mice given ephedrine (18 mg/kg/day orally), treadmill exercise (10 m/min, 1-h/day), and dietary restriction (DR: 26% dietary restriction) for 7 days. Exercise and DR mice lost more body weight than controls and both ephedrine and exercise reduced percent body fat. All treatments reduced BAT and liver lipid accumulation (i.e., cytoplasmic lipids in brown adipocytes and hepatocytes) and increased oxygen consumption (VO2 ml/kg/h) compared with controls. Mitochondrial biogenesis/function-related genes (TFAM, NRF1 and GABPA) were up-regulated in the BAT of all groups. UCP-1 was up-regulated in exercise and ephedrine groups, whereas MFSD2A was up-regulated in ephedrine and DR groups. PGC-1alpha up-regulation was observed in exercise and DR groups but not in ephedrine group. In all experimental groups, except for ephedrine, fatty acid transport and metabolism genes were up-regulated, but the magnitude of change was higher in the DR group. PRKAA1 was up-regulated in all groups but not significantly in the ephedrine group. ADRbeta3 was slightly up-regulated in the DR group only, whereas ESRRA remained unchanged in all groups. Although our data suggest a common pathway of BAT activation elicited by ephedrine treatment, exercise or DR, mRNA changes were indicative of additional nutrient-sensing pathways in exercise and DR. PMID- 22542812 TI - Clinical decision support with automated text processing for cervical cancer screening. AB - OBJECTIVE: To develop a computerized clinical decision support system (CDSS) for cervical cancer screening that can interpret free-text Papanicolaou (Pap) reports. MATERIALS AND METHODS: The CDSS was constituted by two rulebases: the free-text rulebase for interpreting Pap reports and a guideline rulebase. The free-text rulebase was developed by analyzing a corpus of 49 293 Pap reports. The guideline rulebase was constructed using national cervical cancer screening guidelines. The CDSS accesses the electronic medical record (EMR) system to generate patient-specific recommendations. For evaluation, the screening recommendations made by the CDSS for 74 patients were reviewed by a physician. RESULTS AND DISCUSSION: Evaluation revealed that the CDSS outputs the optimal screening recommendations for 73 out of 74 test patients and it identified two cases for gynecology referral that were missed by the physician. The CDSS aided the physician to amend recommendations in six cases. The failure case was because human papillomavirus (HPV) testing was sometimes performed separately from the Pap test and these results were reported by a laboratory system that was not queried by the CDSS. Subsequently, the CDSS was upgraded to look up the HPV results missed earlier and it generated the optimal recommendations for all 74 test cases. LIMITATIONS: Single institution and single expert study. CONCLUSION: An accurate CDSS system could be constructed for cervical cancer screening given the standardized reporting of Pap tests and the availability of explicit guidelines. Overall, the study demonstrates that free text in the EMR can be effectively utilized through natural language processing to develop clinical decision support tools. PMID- 22542813 TI - Using EHRs to integrate research with patient care: promises and challenges. AB - Clinical research is the foundation for advancing the practice of medicine. However, the lack of seamless integration between clinical research and patient care workflow impedes recruitment efficiency, escalates research costs, and hence threatens the entire clinical research enterprise. Increased use of electronic health records (EHRs) holds promise for facilitating this integration but must surmount regulatory obstacles. Among the unintended consequences of current research oversight are barriers to accessing patient information for prescreening and recruitment, coordinating scheduling of clinical and research visits, and reconciling information about clinical and research drugs. We conclude that the EHR alone cannot overcome barriers in conducting clinical trials and comparative effectiveness research. Patient privacy and human subject protection policies should be clarified at the local level to exploit optimally the full potential of EHRs, while continuing to ensure participant safety. Increased alignment of policies that regulate the clinical and research use of EHRs could help fulfill the vision of more efficiently obtaining clinical research evidence to improve human health. PMID- 22542814 TI - Reproductive and metabolic responses of desert adapted common spiny male mice (Acomys cahirinus) to vasopressin treatment. AB - Sufficient amounts of water and food are important cues for reproduction in an unpredictable environment. We previously demonstrated that increased osmolarity levels, or exogenous vasopressin (VP) treatment halt reproduction of desert adapted golden spiny mice Acomys russatus. In this research we studied gonad regulation by VP and food restriction (FR) in desert adapted common spiny mouse (A. cahirinus) males, kept under two different photoperiod regimes-short (SD 8L:16D) and long (LD-16L:8D) days. Mice were treated with VP, FR, and VP+FR for three weeks. Response was assessed from changes in relative testis mass, serum testosterone levels and mRNA receptor gene expression of VP, aldosterone and leptin in treated groups, compared with their controls. SD-acclimation increased testosterone levels, VP treatment decreased expression of aldosterone mRNA receptor in the testes of SD-acclimated males. FR under SD-conditions resulted in testosterone decrease and elevation of VP- receptor gene expression in testes. Aldosterone receptor mRNA expression was also detected in WAT. These results support the idea that water and food availability in the habitat may be used as signals for activating the reproductive system through direct effects of VP, aldosterone and leptin on the testes or through WAT by indirect effects. PMID- 22542815 TI - Intradermally administered TLR4 agonist GLA-SE enhances the capacity of human skin DCs to activate T cells and promotes emigration of Langerhans cells. AB - The natural TLR4 agonist lipopolysaccharide (LPS) has notable adjuvant activity. However, it is not useful as a vaccine adjuvant due to its toxicity. Glucopyranosyl lipid A (GLA) is a synthetic derivative of the lipid A tail of LPS with limited cytotoxicity, but strong potential to induce immune responses in mice, guinea pigs, non-human primates, and humans. In this study we determined how this synthetic TLR4 agonist affects the function of different subsets of human skin dendritic cells (DCs). The effect of GLA in an aqueous formulation (GLA-AF) or in an oil-in-water emulsion (GLA-SE) was compared to that of LPS and TLR3 agonist poly(I:C) using a human skin explant model with intradermal injections for the administration of the agonists. Intradermal injection of GLA SE or LPS, but not GLA-AF, enhanced the emigration of CD1a(high)/langerin(+) Langerhans cells (LCs), but not dermal DCs (DDCs). LCs and CD14(-) DDCs exhibited an enhanced mature phenotype following intradermal administration of either of the two GLA formulations tested, similar to DCs that emigrated from LPS-injected skin. However, only injection of GLA-SE resulted in a significant increase in the production of the wide range of cytokines that is observed with LPS. Moreover, DCs that emigrated from GLA-SE-injected skin induced stronger CD4(+) T-cell activation, as indicated by a more pronounced T-cell proliferation, than DCs from skin injected with GLA-AF or LPS. Altogether, our data show that GLA-SE has a notable potency to stimulate the function of skin DCs, indicating that GLA-SE may be a good candidate as adjuvant for vaccines administered via the intradermal route. PMID- 22542816 TI - Physicochemically stable cholera toxin B subunit pentamer created by peripheral molecular constraints imposed by de novo-introduced intersubunit disulfide crosslinks. AB - We attempted to generate a physicochemically stable cholera toxin B subunit (CTB) by de novo-introduction of intersubunit disulfide bonds between adjacent subunits. Genes encoding double mutant CTB (dmCTB) encompassing a pair of amino acids to be replaced with cysteine residues either at the N-terminal (T1C/T92C, Q3C/T47C), C-terminal (F25C/N103C, Y76C/N103C), or at the internal alpha-helix region (L77C/T78C), were engineered. One mutant with the N-terminal constraint [dmCTB(T1C/T92C)], expressed as pentamer retained monosialoganglioside G(M1) (GM1) binding affinity, and exhibited robust thermostability. However, when the mutant CTB was heat-treated in the presence of a reducing agent, the thermostable phenotype was abolished, indicating the observed phenotype is due to the introduction of intersubunit disulfide bonds. The mutant CTB also exhibited a strong acid stability at a pH as low as 1.2, as well as stability against incubation with sodium dodecyl sulfate at concentrations as high as 10%. Furthermore, intranasal administration of the mutant CTB to mice induced CTB specific serum IgG even after heat treatment, while the wildtype CTB failed to show such heat-resistant mucosal immunogenicity. This study demonstrated that an enterotoxin B subunit could be transformed into a physicochemically stable pentamer by the de novo-introduction of peripherally arranged intersubunit disulfide crosslinks, which may prove to be a useful strategy for the development of molecularly stable enterotoxin B subunit-based vaccines and delivery molecules. PMID- 22542817 TI - Correlates of 2009 H1N1 influenza vaccination among day care-aged children, Miami Dade County. AB - BACKGROUND: The aim of this study was to assess factors influencing 2009 H1N1 influenza vaccination among a demographically diverse group of day care-aged children. Day care children were chosen because they were an initial target group for vaccination and are at higher risk of influenza infection than children cared for at home. METHODS: A cross-sectional study was conducted from March to May 2010 among parents of day care aged children in 13 day care facilities in Miami Dade County. Data was collected by an anonymous self-administered two-page 20 question survey which consisted of demographic variables and information regarding 2009 H1N1 influenza vaccine knowledge, attitude and acceptance. Data was analyzed using SAS to conduct both bivariate and multivariate analyses. RESULTS: There were 773 participants in the study. The response rate ranged from 42% to 72.2% among day care centers. A total of 172 parents (22.3%) and 225 (29.1%) children had received the 2009 H1N1 influenza vaccine. Non-Hispanic White and Black parents were more likely to vaccinate their children than Hispanic and Haitian parents. Primary reasons for non-vaccination included vaccine safety (36.7%) and side effects (27.1%). Among parents who spoke with a health care professional, 274 (61.4%) stated the health care professional recommended the vaccine. CONCLUSION: Misperceptions about influenza vaccination among parents created a barrier to 2009 H1N1 influenza vaccination. Parents who got the vaccine, who believed the vaccine was safe and whose children had a chronic condition were more likely to immunize their children. Clear, reliable and consistent vaccine information to the public and health care providers and initiatives targeting minority groups may increase vaccination coverage among this population. PMID- 22542818 TI - Pneumococcal polysaccharide 23-valent vaccine: long-term persistence of circulating antibody and immunogenicity and safety after revaccination in adults. AB - Since publication of a 1997 review of the immunogenicity and safety data for pneumococcal polysaccharide vaccines (PPSVs), dozens of additional studies have been published, involving larger cohorts, longer observation periods, and more specific assays. Additionally, a 13-valent pneumococcal conjugate vaccine (PCV) has been licensed for adults. This paper reviews adult studies assessing antibody persistence for >= 3 years after pneumococcal vaccination, and adult studies of immunogenicity and safety after revaccination. This review emphasizes the currently registered PPSV23 formulations containing 25-MUg polysaccharide per serotype, for which far more long-term data are available. Broadly, IgG and functional antibody levels after PPSV23 in adults persist above concentrations in unvaccinated adults for at least 5-10 years in most studies. The few exceptions involve populations of non-ambulatory adults or those with confounding host factor issues. Revaccination with PPSV23 5-10 years after a previous dose consistently and substantially increases both IgG and functional antibody levels. There is an inverse association between circulating antibody level just before primary or revaccination and subsequent antibody increase. Although injection site reactions (e.g., pain, swelling, redness) were reported more commonly after PPSV23 revaccination than after primary vaccination in most studies, these reactions typically resolved within 5 days. We interpret the contemporary literature as supporting pneumococcal revaccination as a means to sustain anti pneumococcal antibodies at levels greater than among unvaccinated adults. PPSV23 is a broad-spectrum public-health tool to help prevent serious pneumococcal diseases across the adult lifespan. PMID- 22542819 TI - Body mass index, coronary artery calcification, and kidney function decline in stage 3 to 5 chronic kidney disease patients. AB - OBJECTIVE: To determine whether body mass index (BMI) and coronary artery calcification (CAC) are risk factors for kidney function decline in predialysis chronic kidney disease (CKD) patients. DESIGN: Prospective cohort study of 125 stage 3 to 5 predialysis CKD patients. SUBJECTS AND SETTING: CKD patients receiving care in Kingston, Ontario, Canada. METHODS: BMI, CAC, and kidney function were measured at baseline. CAC was measured by multislice computed tomography scan. Kidney function was determined by the 4-variable reexpressed Modification of Diet in Renal Disease Study equation. At study end, kidney function decline among patients was compared according to baseline BMI and CAC. MAIN OUTCOME: Kidney function decline was defined as a 1-year decline in estimated glomerular filtration rate (eGFR) of >= 5%. RESULTS: Individuals with a decline in eGFR of >= 5% at 1 year had higher baseline BMI (33.5 +/- 8.3 vs. 28.4 +/- 4.9 kg/m(2); P = .0001) and higher baseline median CAC scores (239 vs. 25 Agatston units; P = .01) compared with subjects without such a decline. BMI (r = 0.35; P < .0001) and logarithmically transformed CAC score (r = 0.22; P = .01) correlated with an eGFR decline of >= 5%. Both crude and adjusted logistic regression analyses showed escalating CAC (with CAC reported in quintiles and CAC score = 0 Agatston unit as the reference group) was associated with an increased risk of eGFR decline of >= 5%. CONCLUSIONS: CAC and BMI were associated with kidney function decline over 1 year. The risk of kidney function decline was greater in those with increasing burden of CAC, which remained robust in the adjusted analysis accounting for the risk factors for CKD progression. Larger studies will be required for independent validation of the associations of BMI, CAC, and kidney function decline, and to investigate whether obesity and CAC treatment strategies are efficacious in attenuating kidney function decline in predialysis CKD patients. PMID- 22542820 TI - Surface modification of PAMAM dendrimer improves its biocompatibility. AB - Modification of dendrimer surface groups is one of the methods available to obtain compounds characterized by reduced toxicity. This article reports results of preliminary biocompatibility studies of a modified polyamidoamine dendrimer of the fourth generation. Reaction with dimethyl itaconate resulted in transformation of surface amine groups into pyrrolidone derivatives. Interaction of the modified dendrimer with human serum albumin (HSA) was analyzed. The influence of the dendrimer on mouse neuroblastoma cell line viability and its hemolytic properties were also investigated. The binding constant between analyzed dendrimer and HSA was found to be equal to 1.2 * 10(5) +/- 0.2 * 10(5) M(-1). Small changes in HSA secondary structure were observed. The analyzed dendrimer revealed minor toxic activity, as diminishment in cell viability was observed only for dendrimer concentrations higher than 2 mg/mL. Moreover, under the applied experimental conditions, no hemolytic activity was observed. Those observations point to the potential of the analyzed compound for further studies toward its applicability in nanomedicine. PMID- 22542821 TI - Enhancement of cell permeabilization apoptosis-inducing activity of selenium nanoparticles by ATP surface decoration. AB - A simple method for preparation of adenosine triphosphate (ATP) surface functionalized selenium nanoparticles (SeNPs@ATP) with enhanced cell permeabilization and anticancer activity has been demonstrated in the study reported in this article. Spherical SeNPs were decorated with ATP by strong adsorption through an Se-N bond, leading to the highly stable structure of the conjugates. ATP surface decoration significantly enhanced the cellular uptake and anticancer activity of SeNPs. Induction of apoptosis in HepG2 human hepatocellular carcinoma cells by SeNPs@ATP was evidenced by accumulation of the sub-G1 cell population, phosphatidylserine exposure, DNA fragmentation, PARP cleavage and caspase activation. Further studies found that SeNPs@ATP treatment triggered the depletion of mitochondrial membrane potential and reactive oxygen species (ROS) overproduction. Our results demonstrate that the use of ATP as a surface decorator of SeNPs is a novel strategy to achieve anticancer synergy. SeNPs@ATP may be a candidate for further evaluation as a chemotherapeutic agent for human cancers. FROM THE CLINICAL EDITOR: In this paper, adenosine triphosphate (ATP) surface-functionalized selenium nanoparticles are discussed as cell-penetrating anticancer agents. Conjugates are stable and ATP functionalization greatly enhances the apoptosis induction properties of the selenium nanoparticles in HepG2 human hepatocellular carcinoma cells. PMID- 22542822 TI - Nanoparticles induce platelet activation in vitro through stimulation of canonical signalling pathways. AB - Nanomaterials are attracting growing interest for their potential use in several applications as nanomedicine; therefore, the analysis of their potential toxic effects on various cellular models, including circulating blood cells, is mandatory. This study aimed to investigate the effect of three unrelated nanomaterials, namely nanoscale silica, multiwalled carbon nanotubes, and carbon black, on platelet activation and aggregation. We found that these nanomaterials stimulate some of the typical biochemical pathways involved in canonical platelet activation, such as the stimulation of phospholipase C and Rap1b, resulting in the integrin alpha(IIb)beta3-mediated platelet aggregation, through a mechanism largely dependent on the release of the extracellular second messengers ADP and thromboxane A2. Importantly, we found that doses of nanoparticles unable to trigger appreciable responses can synergize with subthreshold amounts of physiological agonists to mediate platelet aggregation, indicating that even small amounts of nanomaterials in the bloodstream might contribute to the development of thrombosis. FROM THE CLINICAL EDITOR: In this study, nanosized particles of three virtually unrelated materials (silica, multi-walled carbon nanotubes and carbon black) were investigated regarding their effects on platelet activation and aggregation. All were found to stimulate some of the typical biochemical pathways involved in canonical platelet activation, and were found to have synergistic effects with physiologic platelet activator agonists. PMID- 22542823 TI - Evaluation of SERS labeling of CD20 on CLL cells using optical microscopy and fluorescence flow cytometry. AB - Immunophenotyping of lymphoproliferative disorders depends on the effective measurement of cell surface markers. The inherent light-scattering properties of plasmonic nanoparticles (NPs) combined with recent developments in NP design may confer significant advantages over traditional fluorescence probes. We report and evaluate the use of surface-enhanced Raman scattering (SERS) gold NPs (AuNPs) conjugated to therapeutic rituximab antibodies for selective targeting of CD20 molecules. SERS AuNPs were prepared by adsorbing a Raman-active dye onto the surface of 60 nm spherical AuNPs, coating the particles with 5 kDa polyethylene glycol, and conjugating rituximab to functional groups on polyethylene glycol. The effective targeting of CD20 on chronic lymphocytic leukemia cells by rituximab-conjugated SERS AuNPs was evaluated by dark-field imaging, Raman spectroscopy, and flow cytometry with both competitive binding and fluorescence detection procedures. Evidence of CD20 clustering within approximately 100 nm was observed. FROM THE CLINICAL EDITOR: This study discusses the use of surface enhancement Raman scattering (SERS)-based plasmonic gold nanoparticles, which can be used for cell specific labeling. In this example rituximab, a commercially available CD20 humanized monoclonal antibody is used. Dark field imaging, Raman spectroscopy and flow cytometry was utilized to demonstrate the sensitive labeling capability of these gold nanoparticle based hybrid nanodevices. PMID- 22542824 TI - Interaction of inorganic nanoparticles with the skin barrier: current status and critical review. AB - Integration of nanotechnology with biology leads to various advantages in applied pharmaceutical and medical sciences. In that regard, the behavior of nanoparticles (NPs) in relation to the skin, an important biological barrier, has been the target of several recent studies. Yet the potential ability of NPs to penetrate into the underlying viable tissue lies at the center of debate. This review briefly highlights the current applications of inorganic NPs, then discusses the current status of their skin penetration in view of the vast variation among the experimental setups in use. Determinants of particle penetration, adopted approaches for enhanced penetration, the underlying mechanism, as well as qualitative and quantitative analysis of NPs present in the skin are also within the scope of this review article. We emphasize analyzing the data generated from experiments on human skin, the "gold standard" for assessment of in vitro skin penetration. Based on this, we include some recommendations for future research. FROM THE CLINICAL EDITOR: Transdermal application of inorganic nanoparticle-based medications is of growing interest in nanomedicine research. This critical review discusses the knowns and the unknowns of this field, providing insightful recommendations for future research. PMID- 22542825 TI - Human serum albumin-coated lipid nanoparticles for delivery of siRNA to breast cancer. AB - Human serum albumin (HSA)-coated lipid nanoparticles (HSA-LNPs) loaded with phrGFP-targeted siRNA (HSA-LNPs-siRNA) were prepared and evaluated for gene downregulation effect in phrGFP-transfected breast cancer cells and the corresponding xenograft tumor model. HSA-LNPs-siRNA were successfully prepared with a particle size of 79.5+/-5.5 nm. In phrGFP-transfected MCF-7 cells, HSA LNPs-siRNA significantly decreased cell fluorescence even in the presence of fetal bovine serum (FBS). Moreover, cell fluorescence and phrGFP mRNA expression were significantly downregulated by HSA-LNPs-siRNA in phrGFP-transfected MCF-7, MDA-MB-231, and SK-BR-3 cells in comparison with control or HSA-LNPs-siRNA (scrambled). In phrGFP-transfected MCF-7 xenograft tumor model, tumor fluorescence was significantly decreased after three IV administrations of HSA LNPs-siRNA at a dose of 3 mg/kg in comparison with siRNA alone. HSA-LNPs-siRNA demonstrated a superior pharmacokinetic profile in comparison with siRNA at a dose of 1mg/kg. These results show that the novel nonviral carrier, HSA-LNPs, may be used for the delivery of siRNA to breast cancer cells. FROM THE CLINICAL EDITOR: Targeted delivery of siRNA to cancer cells may be a viable anti-cancer strategy with low toxicity. In this study the novel nonviral carrier, human serum albumin-coated lipid nanoparticles (HSA-LNP) were demonstrated as an efficient delivery agent of siRNA to breast cancer cells. PMID- 22542826 TI - Development of an ultrasonic slurry sampling method for the determination of Cu and Mn in antibiotic tablets by electrothermal atomic absorption spectrometry. AB - A new method is described for simple, efficient and rapid determination of Cu and Mn in tablets of antibiotics (ciprofloxacin and cephalexin) by electrothermal atomic absorption spectrometry (ETAAS) using slurry sampling. In order to optimize the procedure, several variables that could affect the performance of the method were investigated. In the best conditions, the tablets could be analyzed by introducing into the graphite tube 20 MUl of a slurry prepared with approximately 90-100mg of the sample and 2 ml of a solution containing 5% m/v of Triton X-114 and 2.8 M of HNO(3). Before the introduction, the slurries were sonicated for 15 min at 40% of amplitude (130 W maximum power) with an ultrasonic probe. The developed method was applied in the determination of Cu and Mn in four samples, and the results were compared with those obtained by focused microwave acid digestion with aqua regia (1:3 mixture of HNO(3):HCl). There was no statistical difference between the obtained values at 95% confidence level when a paired Student t-test was applied. PMID- 22542828 TI - A cholecystohepatic shunt pathway: does the gallbladder protect the liver? PMID- 22542829 TI - Treatment of eosinophilic esophagitis: diet, drugs, or dilation? PMID- 22542830 TI - Can dietary fish intake prevent liver cancer? PMID- 22542831 TI - Self-renewal of tumor-initiating cells: what's new about hepatocellular carcinoma? PMID- 22542832 TI - A submucosal tumor in the cecum. Appendiceal mucocele mimicking a submucosal tumor. PMID- 22542833 TI - Severity of acute pancreatitis: impact of local and systemic complications. PMID- 22542834 TI - Presentation of the Julius M. Friedenwald Medal to Emmet B. Keeffe, MD. PMID- 22542835 TI - Iron deficiency after non-small cell lung cancer. Ileal polypoid angiodysplasia. PMID- 22542837 TI - Gene dose of apolipoprotein E and age-related hearing loss. AB - Next to outer hair cell dysfunction, age-related hearing loss may be explained by apolipoprotein E (APOE) genotype. In the Leiden 85-plus Study, a population-based study, the participants were 85 years old. We measured hearing loss by pure-tone audiometry in 435 participants in relation to APOE. Results demonstrated that those with the APOE-epsilon4/epsilon4 genotype had the highest levels of hearing loss (n = 6; 56.1 dB), those with the APOE-epsilon3/epsilon4 or epsilon2/epsilon4 genotype (n = 89) had intermediate levels of hearing loss (51.0 dB), and those without the APOE-epsilon4 allele (n = 340) had the lowest levels of hearing loss (48.9 dB), p for trend = 0.02. Eighty percent of participants had hearing loss of 35 dB and more, that is, hearing impairment. The APOE-epsilon4 allele was associated with a 2.0-fold increased risk of hearing impairment (confidence interval [CI 95%], 1.0-4.0), compared with those without the APOE-epsilon4 allele. The risk for hearing impairment in subjects with the APOE-epsilon4 allele remained similar after adjustment for cardiovascular disease, stroke, and cognitive impairment. Our results suggest that the APOE-epsilon4 allele contributes to age-related hearing loss. PMID- 22542836 TI - Effects of aging on neural connectivity underlying selective memory for emotional scenes. AB - Older adults show age-related reductions in memory for neutral items within complex visual scenes, but just like young adults, older adults exhibit a memory advantage for emotional items within scenes compared with the background scene information. The present study examined young and older adults' encoding-stage effective connectivity for selective memory of emotional items versus memory for both the emotional item and its background. In a functional magnetic resonance imaging (fMRI) study, participants viewed scenes containing either positive or negative items within neutral backgrounds. Outside the scanner, participants completed a memory test for items and backgrounds. Irrespective of scene content being emotionally positive or negative, older adults had stronger positive connections among frontal regions and from frontal regions to medial temporal lobe structures than did young adults, especially when items and backgrounds were subsequently remembered. These results suggest there are differences between young and older adults' connectivity accompanying the encoding of emotional scenes. Older adults may require more frontal connectivity to encode all elements of a scene rather than just encoding the emotional item. PMID- 22542838 TI - Distribution of natural radionuclide concentrations in sediment samples in Didim and Izmir Bay (Aegean Sea-Turkey). AB - Natural and artificial radionuclide pollutants of the marine environment have been recognized as a serious environmental concern. The natural radioactivity activity concentrations of (226)Ra, (238)U, (232)Th and (40)K were measured by gamma spectrometry in sediment samples collected from two different areas in Aegean Sea Turkish Coast. There is no information about radioactivity level in the study areas sediments so far. The results showed that the concentrations of activity in the sediment samples are 9 +/- 0.6 Bq kg(-1)-12 +/- 0.7 Bq kg(-1), 7 +/- 0.4 Bq kg(-1)-16 +/- 1.0 Bq kg(-1), 6 +/- 0.3 Bq kg(-1)-16 +/- 1.0 Bq kg(-1) and 250 +/- 13 Bq kg(-1)-665 +/- 33 Bq kg(-1) for (226)Ra, (238)U, (232)Th and (40)K, respectively. In general, the distribution of activity concentrations along the coast of the Aegean Sea area were in the same order as international levels. PMID- 22542839 TI - LTB4 is a signal-relay molecule during neutrophil chemotaxis. AB - Neutrophil recruitment to inflammation sites purportedly depends on sequential waves of chemoattractants. Current models propose that leukotriene B(4) (LTB(4)), a secondary chemoattractant secreted by neutrophils in response to primary chemoattractants such as formyl peptides, is important in initiating the inflammation process. In this study we demonstrate that LTB(4) plays a central role in neutrophil activation and migration to formyl peptides. We show that LTB(4) production dramatically amplifies formyl peptide-mediated neutrophil polarization and chemotaxis by regulating specific signaling pathways acting upstream of actin polymerization and MyoII phosphorylation. Importantly, by analyzing the migration of neutrophils isolated from wild-type mice and mice lacking the formyl peptide receptor 1, we demonstrate that LTB(4) acts as a signal to relay information from cell to cell over long distances. Together, our findings imply that LTB(4) is a signal-relay molecule that exquisitely regulates neutrophil chemotaxis to formyl peptides, which are produced at the core of inflammation sites. PMID- 22542841 TI - Biofilm formation by Pseudomonas aeruginosa in solid murine tumors - a novel model system. AB - The ability of opportunistic bacterial pathogens to grow in biofilms is decisive in the pathogenesis of chronic infectious diseases. Growth within biofilms does not only protect the bacteria against the host immune system but also from the killing by antimicrobial agents. Here, we introduce a mouse model in which intravenously administered planktonic Pseudomonas aeruginosa bacteria are enriched in transplantable subcutaneous mouse tumors. Electron microscopy images provide evidence that such bacteria reside in the tumor tissue within biofilm structures. Immunohistology furthermore demonstrated that infection of the tumor tissue elicits a host response characterized by strong neutrophilic influx. Interestingly, the biofilm defective PA14 pqsA transposon mutant formed less biofilm in vivo and was more susceptible to clearance by intravenous ciprofloxacin treatment as compared to the wild-type control. In conclusion, we have established an experimentally tractable model that may serve to identify novel bacterial and host factors important for in vivo biofilm formation and to re-evaluate bactericidal and anti-biofilm effects of currently used and novel antibacterial compounds. PMID- 22542842 TI - Neural activation underlying cognitive control in the context of neutral and affectively charged pictures in children. AB - The neural correlates of cognitive control for typically developing 9-year-old children were examined using dense-array ERPs and estimates of cortical activation (LORETA) during a go/no-go task with two conditions: a neutral picture condition and an affectively charged picture condition. Activation was estimated for the entire cortex after which data were exported for four regions of interests (ROIs): ventrolateral prefrontal cortex (VLPFC), dorsal anterior cingulate cortex (dACC), dorsolateral prefrontal cortex (DLPFC), and orbitofrontal/ventromedial prefrontal cortex (OFC/VMPFC). Results revealed faster reaction times, greater N2 activation, and greater prefrontal activation for the affectively charged picture condition than the neutral picture condition. The findings are discussed in reference to the impact of affective stimuli on recruitment of specific brain regions involved in cognitive control. PMID- 22542840 TI - A dual role for UVRAG in maintaining chromosomal stability independent of autophagy. AB - Autophagy defects have recently been associated with chromosomal instability, a hallmark of human cancer. However, the functional specificity and mechanism of action of autophagy-related factors in genome stability remain elusive. Here we report that UVRAG, an autophagic tumor suppressor, plays a dual role in chromosomal stability, surprisingly independent of autophagy. We establish that UVRAG promotes DNA double-strand-break repair by directly binding and activating DNA-PK in nonhomologous end joining. Disruption of UVRAG increases genetic instability and sensitivity of cells to irradiation. Furthermore, UVRAG was also found to be localized at centrosomes and physically associated with CEP63, an integral component of centrosomes. Disruption of the association of UVRAG with centrosomes causes centrosome instability and aneuploidy. UVRAG thus represents an autophagy-related molecular factor that also has a convergent role in patrolling both the structural integrity and proper segregation of chromosomes, which may confer autophagy-independent tumor suppressor activity. PMID- 22542843 TI - The brain's hemispheres and controlled search of the lexicon: evidence from fixated words and pseudowords. AB - Difference between the brain's hemispheres in efficiency of intentional search of the mental lexicon with phonological, orthographic, and semantic strategies was investigated. Letter strings for lexical decision were presented at fixation, with a lateralized distractor to the LVF or RVF. Word results revealed that both hemispheres were capable of using each of the three strategies, but the right hemisphere had better baseline processing of orthography and was better at processing semantics. Pseudoword results supported the right hemisphere advantage for orthography and showed a left hemisphere advantage for phonology and assessment of possible semantic relationships. Taken together, the data support the idea that the right hemisphere uses orthography to make efficient decisions about novelty of an item, while the left engages in grapheme-to-phoneme conversion to test hypotheses about unfamiliar items. The convergence of data with previous research reveals that the procedure, as well as analyses of pseudowords, inform laterality research. PMID- 22542844 TI - Decreased functional brain activation in Friedreich ataxia using the Simon effect task. AB - The present study applied the Simon effect task to examine the pattern of functional brain reorganization in individuals with Friedreich ataxia (FRDA), using functional magnetic resonance imaging (fMRI). Thirteen individuals with FRDA and 14 age and sex matched controls participated, and were required to respond to either congruent or incongruent arrow stimuli, presented either to the left or right of a screen, via laterally-located button press responses. Although the Simon effect (incongruent minus congruent stimuli) showed common regions of activation in both groups, including the superior and middle prefrontal cortices, insulae, superior and inferior parietal lobules (LPs, LPi), occipital cortex and cerebellum, there was reduced functional activation across a range of brain regions (cortical, subcortical and cerebellar) in individuals with FRDA. The greater Simon effect behaviourally in individuals with FRDA, compared with controls, together with concomitant reductions in functional brain activation and reduced functional connectivity between cortical and sub-cortical regions, implies a likely disruption of cortico-cerebellar loops and ineffective engagement of cognitive/attention regions required for response suppression. PMID- 22542845 TI - Connective tissue growth factor causes glaucoma by modifying the actin cytoskeleton of the trabecular meshwork. AB - The most critical risk factor for optic nerve damage in cases of primary open angle glaucoma (POAG) is an increased intraocular pressure (IOP) caused by a resistance to aqueous humor outflow in the trabecular meshwork (TM). The molecular pathogenesis of this increase in outflow resistance in POAG has not yet been identified, but it may involve transforming growth factor TGF-beta2, which is found in higher amounts in the aqueous humor of patients with POAG. Connective tissue growth factor (CTGF) is a TGF-beta2 target gene with high constitutive TM expression. In this study, we show that either adenoviral-mediated or transgenic CTGF overexpression in the mouse eye increases IOP and leads to optic nerve damage. CTGF induces TM fibronectin and alpha-SMA in animals, whereas actin stress fibers and contractility are both induced in cultured TM cells. Depletion of CTGF by RNA interference leads to a marked attenuation of the actin cytoskeleton. Rho kinase inhibitors cause a reversible decline in the IOP of CTGF overexpressing mice to levels seen in control littermates. Overall, the effects of CTGF on IOP appear to be caused by a modification of the TM actin cytoskeleton. CTGF-overexpressing mice provide a model that mimics the essential functional and structural aspects of POAG and offer a molecular mechanism to explain the increase of its most critical risk factor. PMID- 22542846 TI - Laser scanning-based tissue autofluorescence/fluorescence imaging (LS-TAFI), a new technique for analysis of microanatomy in whole-mount tissues. AB - Intact organ structure is essential in maintaining tissue specificity and cellular differentiation. Small physiological or genetic variations lead to changes in microanatomy that, if persistent, could have functional consequences and may easily be masked by the heterogeneity of tissue anatomy. Current imaging techniques rely on histological, two-dimensional sections requiring sample manipulation that are essentially two dimensional. We have developed a method for three-dimensional imaging of whole-mount, unsectioned mammalian tissues to elucidate subtle and detailed micro- and macroanatomies in adult organs and embryos. We analyzed intact or dissected organ whole mounts with laser scanning based tissue autofluorescence/fluorescence imaging (LS-TAFI). We obtained clear visualization of microstructures within murine mammary glands and mammary tumors and other organs without the use of immunostaining and without probes or fluorescent reporter genes. Combining autofluorescence with reflected light signals from chromophore-stained tissues allowed identification of individual cells within three-dimensional structures of whole-mounted organs. This technique could be useful for rapid diagnosis of human clinical samples and possibly the effect of subtle variations such as low dose radiation. PMID- 22542847 TI - Spontaneous formation of tumorigenic hybrids between breast cancer and multipotent stromal cells is a source of tumor heterogeneity. AB - Breast cancer progression involves cancer cell heterogeneity, with generation of invasive/metastatic breast cancer cells within populations of nonmetastatic cells of the primary tumor. Sequential genetic mutations, epithelial-to-mesenchymal transition, interaction with local stroma, and formation of hybrids between cancer cells and normal bone marrow-derived cells have been advocated as tumor progression mechanisms. We report herein the spontaneous in vitro formation of heterotypic hybrids between human bone marrow-derived multipotent stromal cells (MSCs) and two different breast carcinoma cell lines, MDA-MB-231 (MDA) and MA11. Hybrids showed predominantly mesenchymal morphological characteristics, mixed gene expression profiles, and increased DNA ploidy. Both MA11 and MDA hybrids were tumorigenic in immunodeficient mice, and some MDA hybrids had an increased metastatic capacity. Both in culture and as xenografts, hybrids underwent DNA ploidy reduction and morphological reversal to breast carcinoma-like morphological characteristics, while maintaining a mixed breast cancer mesenchymal expression profile. Analysis of coding single-nucleotide polymorphisms by RNA sequencing revealed genetic contributions from both parental partners to hybrid tumors and metastasis. Because MSCs migrate and localize to breast carcinoma, our findings indicate that formation of MSC-breast cancer cell hybrids is a potential mechanism of the generation of invasive/metastatic breast cancer cells. Our findings reconcile the fusion theory of cancer progression with the common observation that breast cancer metastases are generally aneuploid, but not tetraploid, and are histopathologically similar to the primary neoplasm. PMID- 22542849 TI - Effect of linkage between vWA and D12S391 in kinship analysis. AB - Ideally for use in forensic analyses, genetic markers on the same chromosome should be more than 50 Mb in physical distance to ensure full recombination and thus independent inheritance. The forensic community has given attention to two STR markers, D12S391 and vWA, that are 6.3 megabases (Mb) apart on chromosome 12. Recent studies have shown no significant linkage disequilibrium between vWA and D12S391 in U.S. and worldwide populations, although genetic linkage has been identified. It is important to evaluate the impact of linkage effects on kinship analysis. In this study, we aimed to determine a more precise measurement of the recombination frequency between vWA and D12S391 based on a larger number of informative meiosis than has been studied previously. We estimated the recombination frequency (theta) to 0.089 (95% CI 0.044-0.158). Using pedigrees simulated under specific kinship scenarios where recombination was expected to affect the likelihood ratio (LR), we evaluated the impact on LR values of including or ignoring linkage between vWA and D12S391. For all pedigree scenarios considered, on average, LR values ignoring linkage were slightly underestimated than when linkage was considered. However, in the incest scenario considered, LR values could be overestimated up to 25-30 times when linkage was ignored. We demonstrate that the effect of ignoring linkage in the likelihood ratio calculation can be considerable. These results suggest that linkage should be considered during kinship analysis when vWA and D12S391 are tested for pedigrees where a recombination could impact the LR value. PMID- 22542850 TI - Development of a genomic site for gene integration and expression in Enterococcus faecalis. AB - Enterococcus faecalis, a gram-positive opportunistic pathogen, has become one of the leading causes of nosocomial infections. Normally a resident of the gastrointestinal tract, extensive use of antibiotics has resulted in the rise of E. faecalis strains that are resistant to multiple antibiotics. This, compounded with the ability to easily exchange antibiotic determinants with other bacteria, has made certain E. faecalis infections difficult to treat medically. The genetic toolbox for the study of E. faecalis has expanded greatly in recent years, but has lacked methodology to stably introduce a gene in single copy in a non disruptive manner for complementation or expression of non-native genes. In this study, we identified a specific site in the genome of E. faecalis OG1RF that can serve as an expression site for a gene of interest. This site is well conserved in most of the sequenced E. faecalis genomes. A vector has also been developed to integrate genes into this site by allelic exchange. Using this system, we complemented an in-frame deletion in eutV, demonstrating that the mutation does not cause polar effects. We also generated an E. faecalis OG1RF strain that stably expresses the green fluorescent protein and is comparable to the parent strain in terms of in vitro growth and pathogenicity in C. elegans and mice. Another major advantage of this new methodology is the ability to express integrated genes without the need for maintaining antibiotic selection, making this an ideal tool for functional studies of genes in infection models and co culture systems. PMID- 22542848 TI - Differential regulation and predictive potential of MacroH2A1 isoforms in colon cancer. AB - Histone variant macroH2A1 has two splice isoforms, macroH2A1.1 and macroH2A1.2, with tissue- and cell-specific expression patterns. Although macroH2A1.1 is mainly found in differentiated, nonproliferative tissues, macroH2A1.2 is more generally expressed, including in tissues with ongoing cell proliferation. Consistently, studies in breast and lung cancer have demonstrated a strong correlation between macroH2A1.1 levels and proliferation, which is not the case for macroH2A1.2. This is the first study to assess the differential regulation and predictive potential of macroH2A1 isoforms in colon cancer. We found that macroH2A1.1 mRNA was down-regulated in primary colorectal cancer samples compared to matched normal colon tissue, whereas macroH2A1.2 was up-regulated. At the protein level, down-regulation of macroH2A1.1 correlated significantly with patient outcome (P = 0.0012), and loss of macroH2A1.1 was associated with a worse outcome. Over the course of Caco-2 cell differentiation, macroH2A1.1 was up regulated at both the RNA and protein levels, whereas macroH2A1.2 was slightly down-regulated at the RNA level and stable at the protein level. These changes were accompanied by an antiproliferative phenotype exhibiting features of cellular senescence. Loss of macroH2A1.1 in vitro was characterized by a phenotype associated with cell growth and metastasis. These data demonstrate that macroH2A1 isoforms are differentially regulated in colon cancer, reflecting the degree of cellular differentiation. Notably, macroH2A1.1 expression predicts survival in colon cancer, thus identifying macroH2A1.1 as a novel colon cancer biomarker. PMID- 22542853 TI - A differential behavior of alpha-amylase, in terms of catalytic activity and thermal stability, in response to higher concentration CaCl2. AB - A differential relationship was observed between thermal stability and catalytic activity of alpha-amylase in the presence of different concentrations of CaCl(2). The enzyme displays optimum catalytic activity in the presence of 1.0-2.0 mM CaCl(2). Further addition of CaCl(2) leads to inhibition of the enzyme, however, at the same time the enzyme gains an additional resistance against thermal denaturation. It was evident that the enzyme is thermodynamically more stable (compared to the active enzyme) in the presence of inhibitory concentration of CaCl(2). For example, the thermal transition temperature (T(m)) of optimally active alpha-amylase was found to be 64+/-1 degrees C, whereas, for the less active enzyme (in the presence 10 mM CaCl(2)) the value was determined to be 71+/ 1 degrees C. Similarly, the activation energy of thermal inactivation (Ea) was found to be 228+/-12 kJ/mol and 291+/-15 kJ/mol for the optimally active enzyme and the enzyme in the presence of 10 mM CaCl(2), respectively. Biophysical analysis of different states of the enzymes in response to variable calcium level indicates no significant change in the secondary structure in response to different concentration of CaCl(2), however the less active but thermodynamically stable enzyme (in the presence of higher concentration of CaCl(2)) was shown to have relatively more compact structure. The results suggest that the enzyme has separate catalytic and structure stabilizing domains and they significantly vary in their functional attributes in response to calcium level. PMID- 22542852 TI - Production and in vitro antioxidant activity of exopolysaccharide by a mutant, Cordyceps militaris SU5-08. AB - Cordyceps militaris SU5-08 was derived from an initial strain (C. militaris SU5) by ultraviolet mutagenesis of protoplasts, and the extraction parameters for C. militaris SU5-08 exopolysaccharide (EPS) produced during submerged culture were optimized. The extraction rate of EPS was 1919.16+/-165.27 mg/l, which was 120.38+/-11.36% higher than that of C. militaris SU5. The in vitro scavenging effects of EPS of C. militaris SU5-08 on hydroxyl, superoxide anion and 1,1 diphenyl-2-picrylhydrazyl (DPPH) radicals at a dosage of 5 g/l were 63.64+/ 3.52%, 75.27+/-5.16%, and 6.46+/-5.03%, respectively. The reducing power of EPS of C. militaris SU5-08 was 0.21+/-0.01. The results suggest that the EPS of C. militaris SU5-08 can be used as a potential antioxidant which enhances adaptive immune responses. PMID- 22542851 TI - Raft coalescence and FcgammaRIIA activation upon sphingomyelin clustering induced by lysenin. AB - Activation of immunoreceptor FcgammaRIIA by cross-linking with antibodies is accompanied by coalescence of sphingolipid/cholesterol-rich membrane rafts leading to the formation of signaling platforms of the receptor. In this report we examined whether clustering of the raft lipid sphingomyelin can reciprocally induce partition of FcgammaRIIA to rafts. To induce sphingomyelin clustering, cells were exposed to non-lytic concentrations of GST-lysenin which specifically recognizes sphingomyelin. The lysenin/sphingomyelin complexes formed microscale assemblies composed of GST-lysenin oligomers engaging sphingomyelin of rafts. Upon sphingomyelin clustering, non-cross-linked FcgammaRIIA associated with raft derived detergent-resistant membrane fractions as revealed by density gradient centrifugation. Pretreatment of cells with GST-lysenin also increased the size of detergent-insoluble molecular complexes of activated FcgammaRIIA. Sphingomyelin clustering triggered tyrosine phosphorylation of the receptor and its accompanying proteins, Cbl and NTAL, in the absence of receptor ligands and enhanced phosphorylation of these proteins in the ligand presence. These data indicate that clustering of plasma membrane sphingomyelin induces coalescence of rafts and triggers signaling events analogous to those caused by FcgammaRIIA activation. PMID- 22542855 TI - The 'complexities' of life and death: death receptor signalling platforms. AB - Cell death is critical to the normal functioning of multi-cellular organisms, playing a central role in development, immunity, inflammation, and cancer progression. Two cell death mechanisms, apoptosis and necroptosis, are dependent on the formation of distinct multi-protein complexes including the DISC, Apoptosome, Piddosome and Necrosome following the induction of cell death by specific stimuli. The role of several of these key multi-protein signalling platforms, namely the DISC, TNFR1 complex I/II, the Necrosome and Ripoptosome, in mediating these pathways will be discussed, as well as the open questions and potential therapeutic benefits of understanding their underlying mechanisms. PMID- 22542854 TI - A new investigation for some steroidal derivatives as anti-Alzheimer agents. AB - We herein report the anti-Alzheimer activity of some synthesized heterocyclic pyrimidine and thiopyrimidine derivatives fused with steroidal structure. Twenty one of these compounds were synthesized and conveniently screened for their anti Alzheimer activities using of Flurbiprofen as the reference drug. Some of these compounds were demonstrated to exhibit remarkable activity and their beta-amyloid (Abeta) lowering results as IC(50) values reported. PMID- 22542857 TI - Toxicity mitigation and solidification of municipal solid waste incinerator fly ash using alkaline activated coal ash. AB - Municipal solid waste (MSW) incineration is a common and effective practice to reduce the volume of solid waste in urban areas. However, the byproduct of this process is a fly ash (IFA), which contains large quantities of toxic contaminants. The purpose of this research study was to analyze the chemical, physical and mechanical behaviors resulting from the gradual introduction of IFA to an alkaline activated coal fly ash (CFA) matrix, as a mean of stabilizing the incinerator ash for use in industrial construction applications, where human exposure potential is limited. IFA and CFA were analyzed via X-ray fluorescence (XRF), X-ray diffraction (XRD) and Inductive coupled plasma (ICP) to obtain a full chemical analysis of the samples, its crystallographic characteristics and a detailed count of the eight heavy metals contemplated in US Title 40 of the Code of Federal Regulations (40 CFR). The particle size distribution of IFA and CFA was also recorded. EPA's Toxicity Characteristic Leaching Procedure (TCLP) was followed to monitor the leachability of the contaminants before and after the activation. Also images obtained via Scanning Electron Microscopy (SEM), before and after the activation, are presented. Concrete made from IFA, CFA and IFA-CFA mixes was subjected to a full mechanical characterization; tests include compressive strength, flexural strength, elastic modulus, Poisson's ratio and setting time. The leachable heavy metal contents (except for Se) were below the maximum allowable limits and in many cases even below the reporting limit. The leachable Chromium was reduced from 0.153 down to 0.0045 mg/L, Arsenic from 0.256 down to 0.132 mg/L, Selenium from 1.05 down to 0.29 mg/L, Silver from 0.011 down to .001 mg/L, Barium from 2.06 down to 0.314 mg/L and Mercury from 0.007 down to 0.001 mg/L. Although the leachable Cd exhibited an increase from 0.49 up to 0.805 mg/L and Pd from 0.002 up to 0.029 mg/L, these were well below the maximum limits of 1.00 and 5.00 mg/L, respectively. PMID- 22542856 TI - Astral microtubule asymmetry provides directional cues for spindle positioning in budding yeast. AB - Cortical force generators play a central role in the orientation and positioning of the mitotic spindle. In higher eukaryotes, asymmetrically localized cortical polarity determinants recruit or activate such force generators, which, through interactions with astral microtubules, position the mitotic spindle at the future site of cytokinesis. Recent studies in budding yeast have shown that, rather than the cell cortex, the astral microtubules themselves may provide polarity cues that are needed for asymmetric pulling on the mitotic spindle. Such asymmetry has been shown to be required for proper spindle positioning, and consequently faithful and accurate chromosome segregation. In this review, we highlight results that have shed light on spindle orientation in this classical model of asymmetric cell division, and review findings that may shed light on similar processes in higher eukaryotes. PMID- 22542858 TI - Cathode ray tube (CRT) recycling: current capabilities in China and research progress. AB - It is estimated that approximately 6,000,000 scrap TVs and 10,000,000 personal computers are generated each year in China. Cathode ray tubes (CRTs) from these machines consist of 85% glass (65% panel, 30% funnel and 5% neck glass). The leaded glass (funnel-24%, neck-30%) may seriously pollute the environment if it is not properly disposed of. In this paper, the past, current and future status of CRT dismantling technologies as well as the CRT glass recycling situation in China are presented and discussed. Recycling technology for waste CRTs in China is still immature. While the conventional CRT dismantling technologies have disadvantages from both economic and environmental viewpoints, some of the new and emerging treatments such as automatic optical sorting facilities that have been applied in developed countries offer advantages, and therefore should be transferred to China in the next few years to solve the CRT pre-processing problem. Meanwhile, because the demand for CRT glass closed-loop recycling is extremely limited, the authorities should take effective measures to improve CRT glass recycling rates and to facilitate a match to local conditions. Moreover, we also provide a broad review of the research developments in recycling techniques for CRT cullet. The challenge for the future is to transfer these environmentally friendly and energy-saving technologies into practice. PMID- 22542859 TI - Fossil and biogenic CO2 from waste incineration based on a yearlong radiocarbon study. AB - We describe the first long-term implementation of the radiocarbon (14C) method to study the share of biogenic (%Bio C) and fossil (%Fos C) carbon in combustion CO2. At five Swiss incinerators, a total of 24 three-week measurement campaigns were performed over 1 year. Temporally averaged bag samples were analyzed for 14CO2 by accelerator mass spectrometry. Significant differences between the plants in the share of fossil CO2 were observed, with annual mean values from 43.4 +/- 3.9% to 54.5 +/- 3.1%. Variations can be explained by the waste composition of the respective plant. Based on our dataset, an average value of 48 +/- 4%Fos C was determined for waste incineration in Switzerland. No clear annual trend in %Fos C was observed for four of the monitored incinerators, while one incinerator showed considerable variations, which are likely due to the separation and temporary storage of bulky goods. PMID- 22542860 TI - Novel anticoagulants for non-valvular atrial fibrillation. AB - Non-valvular atrial fibrillation is a major cause of strokes in patients of all ages. Warfarin has been the mainstay anticoagulant for stroke prevention for many years. Warfarin use is limited by frequent monitoring and drug interactions. New oral anticoagulants have been investigated in recent large randomised trials: direct thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban and apixaban). These new anticoagulants do not require regular monitoring. Dabigatran and rivaroxaban have been shown to be non-inferior, whilst apixaban has been shown to be superior to warfarin in terms of stroke and systemic embolism. There are practical issues of cost, lack of availability on the Pharmaceutical Benefits Scheme currently, and a lack of reversal agents. These new oral anticoagulants may revolutionise anticoagulation for stroke prevention in non-valvular atrial fibrillation. PMID- 22542861 TI - Implantable devices and magnetic resonance imaging. AB - The indications for cardiovascular implantable electronic devices (CIEDs) are ever expanding, seemingly in parallel to the similar widespread increase in the use of magnetic resonance imaging (MRI), where there are clear advantages of imaging with no ionizing radiation and superior tissue contrast. However, CIEDs have traditionally been considered an absolute contraindication to MRI, posing a major limitation to investigating various pathologies after implantation of such devices. In the last decade the traditional paradigm of avoiding MRI in patients with CIEDs has been challenged with studies demonstrating relative safety at 1.5T under certain circumstances. Now with the recent approval of 'MR conditional' devices, it is becoming increasingly apparent that CIEDs should no longer be considered an absolute contraindication to MRI. PMID- 22542862 TI - Hypersensitivity to 35% carbon dioxide in patients with adult separation anxiety disorder. AB - BACKGROUND: Adults with panic disorder (PD) and children with separation anxiety disorder (CSAD) show higher reactivity to CO(2). Our hypothesis was patients with adult separation anxiety disorder (ASAD) would show similar hypersensitivity to CO(2). In the present study, we determined whether sensitivity to CO(2) was enhanced in adult patients with separation anxiety disorder with no history of panic attacks. METHODS: Patients with PD (n=38), adult separation anxiety disorder (ASAD) patients with no history of panic attacks (n=31), and healthy subjects (n=40) underwent a 35% CO(2) inhalation challenge procedure. Baseline and post-inhalation anxiety were assessed with the Acute Panic Inventory, Visual Analog Scale, and Anxiety Sensitivity Index-3 (ASI-3). RESULTS: As hypothesized the rate of CO(2)-induced panic attacks was significantly greater in PD and ASAD patient groups (55.3% and 51.6% respectively) than healthy comparison group (17.5%). Nine (69.2%) of 13 patients in PD group who have ASAD concurrent with PD had a CO(2)-induced panic attack. ASI-3 total scores were not different between PD and ASAD groups and both were significantly higher than controls. However, anxiety sensitivity did not predict the occurrence of panic attacks. LIMITATIONS: The researchers were not blind to the diagnosis and there was no placebo arm for comparison. Besides, parameters of respiratory physiology were not evaluated. CONCLUSION: ASAD was associated with CO(2) hypersensitivity quite similar to PD. This finding partly unfolds the complex relationship of 'CSAD, PD, and CO(2) hypersensitivity' and indicates that CO(2) hypersensitivity and separation anxiety extend together beyond childhood. PMID- 22542863 TI - Abnormalities of emotional awareness and perception in patients with obsessive compulsive disorder. AB - BACKGROUND: Emotional awareness deficit may play a critical role in the production and maintenance of obsessive-compulsive symptoms and social dysfunction in patients with obsessive-compulsive disorder (OCD). The aim of this study was to investigate characteristics of emotional awareness such as empathy and alexithymia in OCD patients. In addition, we examined whether impaired emotional awareness measured by self-assessment questionnaires was associated with emotional facial recognition ability in OCD patients. METHODS: Study participants included 107 patients with OCD and 130 healthy age- and sex-matched volunteers. The Interpersonal Reactivity Index (IRI) and Toronto Alexithymia Scale-20 were applied as measures of empathy and alexithymia. A subset of 56 patients with OCD additionally performed the emotional perception task of face expression. RESULTS: Patients with OCD scored significantly lower for perspective taking, and significantly higher for personal distress of IRI, and significantly higher for alexithymia compared to normal controls. Impaired emotional awareness such as lower perspective taking and fantasy seeking had a perception bias towards disgust in response to ambiguous facial expressions in OCD patients. LIMITATIONS: The OCD group consisted of patients in different stages of the illness and with different degrees of severity. CONCLUSIONS: OCD involves the impairment of emotional awareness and perception and it may relate to social dysfunction and to impairments in the ability to shift naturally from obsessive thoughts to other thoughts in response to social situations in patients with OCD. PMID- 22542864 TI - Common perinatal mental disorders and alcohol dependence in men in northern Viet Nam. AB - BACKGROUND: To establish the prevalence and correlates of the perinatal common mental disorders of depression and anxiety (PCMD) and alcohol dependence (AD) in men in northern Viet Nam. METHODS: A cross-sectional study of men whose wives were >28weeks pregnant or mothers of newborns recruited from randomly-selected rural and urban communes. Data sources were Structured Clinical Interviews for DSM IV; CAGE assessment of alcohol use and study-specific questionnaires. Odds ratios and 95% CIs were calculated by multiple logistic regressions. RESULTS: Overall, 231/360 eligible men were recruited, of whom 17.7% [95% CI, 12.8-22.7] were diagnosed with a PCMD; 33.8% [95% CI, 27.9-40.1] with AD (CAGE score>=2) and 6.9% [95% CI, 4.3-11.0] with co-morbid PCMD and AD. PCMD were associated with experiences of coincidental life adversity, intimate partner violence, age>30; an unwelcome pregnancy and primiparity. AD was more common among men with low education, living in the poorest households and in unskilled work. CONCLUSIONS: Common mental disorders and AD are prevalent, but currently unrecognised among men in northern Viet Nam whose wives are pregnant or have recently given birth. PMID- 22542865 TI - Multimodality imaging in amyloidosis. AB - Amyloidosis comprises a rare spectrum of protein deposition diseases that diffusely or focally affect any organ. Amyloid's variable clinical presentation and nonspecific disease course often cause it to evade early diagnosis. This pictorial essay aims to familiarize radiologists with the pathophysiology of amyloidosis, to describe the basic classifications of amyloidosis, and to use multimodality imaging to illustrate its varied appearance throughout the body. This review highlights the diagnostic challenge of interpreting radiographic studies in patients with hematologic malignancies and concurrent amyloidosis. Radiologists should consider amyloid in chronically ill patients or patients with hematologic malignancies who have unusual/unexpected imaging findings. PMID- 22542866 TI - [Polyvalent medical day hospital and patients with chronic multiple conditions]. PMID- 22542867 TI - Population genetic investigation of eight X-chromosomal short tandem repeat loci from a northeast German sample. PMID- 22542868 TI - Association of genetic polymorphisms with personality profile in individuals without psychiatric disorders. AB - OBJECTIVE: Population-based twin studies demonstrate that approximately 40-50% of the variability in personality dimensions results from genetic factors. This study assessed selected polymorphisms in the COMT Val158Met, MAOA 3'VNTR, 5HTTLPR, 102T/C 5-HT2A, DAT 3'VNTR and DRD2 exon 8 genes and evaluated their association with personality profiles, anxiety levels, and depressiveness in healthy subjects. METHODS: This study included 406 unrelated (mean age 38.51 years), mentally and somatically healthy Caucasian subjects of Polish origin. The prevalence of the gene variants mentioned above and their association with personality profiles, anxiety levels, and depressiveness was assessed using the Temperament and Character Inventory, NEO Five-Factor Inventory, Spielberger's State-Trait Anxiety Inventory and Beck's Depression Inventory. RESULTS: The effects of the 5HTTLPR gene on the s/s genotype and empathy (C2) were lowest in the entire group. The effects of gender, age and the HT2A gene for the T/T genotype and attachment (RD3) were highest in women. The effects of gender, age and the DAT gene on the 9/9 DAT genotype, compassion (C4) and cooperativeness (C) were lowest in women. The effects of gender, age and the COMT gene on the Met/Met genotype and neuroticism (NEU) NEO-FFI were also lowest in women. CONCLUSIONS: Our results suggest considerable influence of individual genes on the formation of personality traits. PMID- 22542869 TI - The anxiolytic-like effect of an essential oil derived from Spiranthera odoratissima A. St. Hil. leaves and its major component, beta-caryophyllene, in male mice. AB - Spiranthera odoratissima A. St. Hil. (manaca) is used in folk medicine to treat renal and hepatic diseases, stomachache, headaches and rheumatism. A central nervous system (CNS) depressant effect of the hexane fraction from the ethanolic extract of this plant has been described. beta-caryophyllene, the main component of this essential oil, is a sesquiterpene compound with anti-inflammatory properties that has been found in essential oils derived from several medicinal plants. This work is aimed to evaluate the pharmacological activity of the essential oil obtained from S. odoratissima leaves (EO) and its major component on the murine CNS; we aimed to evaluate a possible anxiolytic-like effect and the underlying mechanisms involved. In an open field test, EO (500 mg/kg) and beta caryophyllene (50, 100 and 200 mg/kg) increased the crossing frequency (P<0.05) and, EO (250 and 500 mg/kg) and beta-caryophyllene (200 mg/kg) increased the time spent in the center (P<0.05) without altering total crossings of the open field. EO and beta-caryophyllene did not alter the number of falls in the rota-rod test (P>0.05). In the pentobarbital-induced sleep test, EO (500 mg/kg) and beta caryophyllene (200 and 400 mg/kg) decreased the latency to sleep (P<0.05), and EO (125, 250 and 500 mg/kg) (P<0.001) and beta-caryophyllene (200 and 400 mg/kg) (P<0.05 and P<0.001) increased the sleep time. In anxiety tests, EO (500 mg/kg) and beta-caryophyllene (100 and 200 mg/kg) increased head-dipping behavior (P<0.05) in the hole-board test, entries (P<0.05) into and time spent (P<0.05) on the open arms of the elevated plus maze (EPM), and number of transitions (P<0.05) and time spent in the light compartment (P<0.05) of a light-dark box (LDB). We further investigated the mechanism of action underlying the anxiolytic-like effect of EO and beta-caryophyllene by pre-treating animals with antagonists of benzodiazepine (flumazenil) and 5-HT(1A) (NAN-190) receptors prior to evaluation using EPM and LDB. The anxiolytic-like effects of EO were significantly reduced by pre-treatment with NAN-190 (P<0.05) but not flumazenil (P>0.05). The anxiolytic-like effects of beta-caryophyllene were not blocked by either NAN-190 or flumazenil (P>0.05). In conclusion, these results suggest that the essential oil derived from S. odoratissima produces an anxiolytic-like effect without altering motor performance and that this effect is mediated by 5-HT(1A) but not via benzodiazepine receptors. In addition, the major component, beta caryophyllene, also has an anxiolytic-like effect that may contribute to the effects of EO, but this effect does not seem to be mediated via 5-HT(1A) or benzodiazepine receptors. PMID- 22542871 TI - Effects of minocycline on endogenous neural stem cells after experimental stroke. AB - Minocycline has been reported to reduce infarct size after focal cerebral ischemia, due to an attenuation of microglia activation and prevention of secondary damage from stroke-induced neuroinflammation. We here investigated the effects of minocycline on endogenous neural stem cells (NSCs) in vitro and in a rat stroke model. Primary cultures of fetal rat NSCs were exposed to minocycline to characterize its effects on cell survival and proliferation. To assess these effects in vivo, permanent cerebral ischemia was induced in adult rats, treated systemically with minocycline or placebo. Imaging 7 days after ischemia comprised (i) Magnetic Resonance Imaging (MRI), assessing the extent of infarcts, (ii) Positron Emission Tomography (PET) with [(11)C]PK11195, characterizing neuroinflammation, and (iii) PET with 3'-deoxy-3'-[(18)F]fluoro-L-thymidine ([(18)F]FLT), detecting proliferating endogenous NSCs. Immunohistochemistry was used to verify ischemic damage and characterize cellular inflammatory and repair processes in more detail. In vitro, specific concentrations of minocycline significantly increased NSC numbers without increasing their proliferation, indicating a positive effect of minocycline on NSC survival. In vivo, endogenous NSC activation in the subventricular zone (SVZ) measured by [(18)F]FLT PET correlated well with infarct volumes. Similar to in vitro findings, minocycline led to a specific increase in endogenous NSC activity in both the SVZ as well as the hippocampus. [(11)C]PK11195 PET detected neuroinflammation in the infarct core as well as in peri-infarct regions, with both its extent and location independent of the infarct size. The data did not reveal an effect of minocycline on stroke-induced neuroinflammation. We show that multimodal PET imaging can be used to characterize and quantify complex cellular processes occurring after stroke, as well as their modulation by therapeutic agents. We found minocycline, previously implied in attenuating microglial activation, to have positive effects on endogenous NSC survival. These findings hold promise for the development of novel treatments in stroke therapy. PMID- 22542872 TI - First trial reactions and habituation rates over successive balance perturbations in Parkinson's disease. AB - BACKGROUND: Balance control in Parkinson's disease is often studied using dynamic posturography, typically with serial identical balance perturbations. Because subjects can learn from the first trial, the magnitude of balance reactions rapidly habituates during subsequent trials. Changes in this habituation rate might yield a clinically useful marker. We studied balance reactions in Parkinson's disease using posturography, specifically focusing on the responses to the first, fully unpractised balance disturbance, and on the subsequent habituation rates. METHODS: Eight Parkinson patients and eight age- and gender matched controls received eight consecutive toe-up rotations of a support surface. Balance reactions were measured with a motion analysis system and converted to centre of mass displacements (primary outcome). RESULTS: Mean centre of mass displacement during the first trial was 51% greater in patients than controls (P=0.019), due to excessive trunk flexion and greater ankle plantar flexion. However, habituated trials were comparable in both groups. Patients also habituated slower: controls were fully habituated at trial 2, whereas habituation in patients required up to five trials (P=0.004). The number of near-falls during the first trial was significantly correlated with centre of mass displacement during the first trial and with habituation rate. CONCLUSIONS: Higher first trial reactions and a slow habituation rate discriminated Parkinson's patients from controls, but habituated trials did not. Further work should demonstrate whether this also applies to clinical balance tests, such as the pull test, and whether repeated delivery of such tests offers better diagnostic value for evaluating fall risks in parkinsonian patients. PMID- 22542870 TI - Acetaminophen differentially enhances social behavior and cortical cannabinoid levels in inbred mice. AB - Supratherapeutic doses of the analgesic acetaminophen (paracetomol) are reported to promote social behavior in Swiss mice. However, we hypothesized that it might not promote sociability in other strains due to cannabinoid CB(1) receptor mediated inhibition of serotonin (5-HT) transmission in the frontal cortex. We examined the effects of acetaminophen on social and repetitive behaviors in comparison to a cannabinoid agonist, WIN 55,212-2, in two strains of socially deficient mice, BTBR and 129S1/SvImJ (129S). Acetaminophen (100mg/kg) enhanced social interactions in BTBR, and social novelty preference and marble burying in 129S at serum levels of >=70 ng/ml. Following acetaminophen injection or sociability testing, anandamide (AEA) increased in BTBR frontal cortex, while behavior testing increased 2-arachidonyl glycerol (2-AG) levels in 129S frontal cortex. In contrast, WIN 55,212-2 (0.1mg/kg) did not enhance sociability. Further, we expected CB(1)-deficient (+/-) mice to be less social than wild-type, but instead found similar sociability. Given strain differences in endocannabinoid response to acetaminophen, we compared cortical CB(1) and 5 HT(1A) receptor density and function relative to sociable C57BL/6 mice. CB(1) receptor saturation binding (Bmax=958+/-117 fmol/mg protein), and affinity for [(3)H] CP55,940 (K(D)=3+/-0.8 nM) was similar in frontal cortex among strains. CP55,940-stimulated [(35)S] GTPgammaS binding in cingulate cortex was 136+/-12, 156+/-22, and 75+/-9% above basal in BTBR, 129S and C57BL/6 mice. The acetaminophen metabolite para-aminophenol (1 MUM) failed to stimulate [(35)S] GTPgammaS binding. Hence, it appears that other indirect actions of acetaminophen, including 5-HT receptor agonism, may underlie its sociability promoting properties outweighing any CB(1) mediated suppression by locally elevated endocannabinoids in these mice. PMID- 22542873 TI - Activation of alpha1-adrenoceptors enhances glutamate release onto ventral tegmental area dopamine cells. AB - The ventral tegmental area (VTA) plays an important role in reward and motivational processes that facilitate the development of drug addiction. Glutamatergic inputs into the VTA contribute to dopamine (DA) neuronal activation related to reward and response-initiating effects in drug abuse. Previous investigations indicate that alpha1-adrenoreceptors (alpha1-ARs) are primarily localized at presynaptic elements in the ventral midbrain. Studies from several brain regions have shown that presynaptic alpha1-AR activation enhances glutamate release. Therefore, we hypothesized that glutamate released onto VTA-DA neurons is modulated by pre-synaptic alpha1-AR. Recordings were obtained from putative VTA-DA cells of male Sprague-Dawley rats (28-50 days postnatal) using voltage clamp techniques. Phenylephrine (10 MUM) and methoxamine (80MUM), both alpha1-AR agonists, increased AMPA receptor-mediated excitatory postsynaptic currents' (EPSCs) amplitude evoked by electrical stimulation of afferent fibers (p<0.05). This effect was blocked by the alpha1-AR antagonist prazosin (1 MUM). Phenylephrine decreased the paired-pulse ratio (PPR) and increased spontaneous EPSCs' frequencies but not their amplitudes suggesting a presynaptic locus of action. No changes in miniature EPSCs (0.5MUM, tetrodotoxin [TTX]) were observed after phenylephrine's application which suggests that alpha1-AR effect was action potential dependent. Normal extra- and intracellular Ca(2+) concentration seems necessary for the alpha1-AR effect since phenylephrine in low Ca(2+) artificial cerebrospinal fluid (ACSF) and depletion of intracellular Ca(2+) stores with thapsigargin (10 MUM) failed to increase the AMPA EPSCs' amplitude. Chelerythrine (1MUM, protein kinase C (PKC) inhibitor) but not Rp-cAMPS (11 MUM, PKA inhibitor) blocked the alpha1-AR activation effect on AMPA EPSCs, indicating that a PKC intracellular pathway is required. These results demonstrated that presynaptic alpha1-AR activation modulates glutamatergic inputs that affect VTA-DA neuronal excitability. alpha1-AR action might be heterosynaptically localized at glutamatergic fibers terminating onto VTA-DA neurons. It is suggested that drug induced changes in alpha1-AR could be part of the neuroadaptations occurring in the mesocorticolimbic circuitry during the addiction process. PMID- 22542875 TI - [Comments on the editorial article "Managing perioperative neuromuscular block. Facial muscle monitoring may lead to faulty clinical decisions"]. PMID- 22542874 TI - Long-lasting transcriptional refractoriness triggered by a single exposure to 1 methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder whose etiology is thought to have environmental (toxin) and genetic contributions. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine (MPTP) induces pathological features of PD including loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and striatal dopamine (DA) depletion. We previously described the striatal transcriptional response following acute MPTP administration in MPTP-sensitive C57BL/6J mice. We identified three distinct phases: early (5h), intermediate (24h) and late (72h) and reported that the intermediate and late responses were absent in MPTP-resistant Swiss-Webster (SWR) mice. Here we show that C57BL/6J mice pre-treated with a single 40 mg/kg dose of MPTP and treated 9 days later with 4*20 mg/kg MPTP, display a striatal transcriptional response similar to that of MPTP-resistant SWR mice, i.e. a robust acute response but no intermediate or late response. Transcriptional refractoriness is dependent upon the dose of the priming challenge with as little as 10mg/kg MPTP being effective and can persist for more than 28 days. Priming of SWR mice has no effect on their response to subsequent challenge with MPTP. We also report that paraquat, another free radical producer, also elicits striatal transcriptional alterations but these are largely distinct from those triggered by MPTP. Paraquat-induced changes are also refractory to priming with paraquat. However neither paraquat nor MPTP elicits cross-attenuation. Thus exposure to specific toxins triggers distinct transcriptional responses in striatum that are influenced by prior exposure to the same toxin. The prolonged refractory period described here for MPTP could explain at the molecular level the reported discrepancies between different MPTP administration regimens and may have implications for our understanding of the relationship between environmental toxin exposure and PD. PMID- 22542876 TI - [Influence of femoral catheter stimulation intensity on post-surgical analgesia after total knee replacement]. AB - INTRODUCTION: Stimulating catheters allow the catheter point to be positioned near the nerve, thus reducing the amount of local anaesthetic required for a successful block. There is currently a debate on what is the stimulation intensity required to provide adequate analgesia, although it does seem that if it is obtained with 1mAmp or less the block is more effective. The objective of the study was to demonstrate whether different neurostimulation intensities with the stimulating catheter at femoral nerve level, had an influence on the adequacy of post-surgical analgesia during the 48h after total knee arthroplasty. MATERIAL AND METHODS: A comparative, prospective and randomised study was conducted on patients subjected to total knee replacement. After surgery with subarachnoid anaesthesia, a continuous femoral block was performed with a stimulating catheter at a neurostimulation intensity 0.2 and 0.5mAmp in Group 1, between 0.6 and 1mAmp in Group 2, equal or higher than 1.1mAmp in Group 3, and in Group 4 the catheter was introduced between 3-5cm without looking for a motor response. A dose of 0.2% ropivacaine 0.4mL/kg and an infusion at 5mL/h, with boluses of 10mL/30min, was administered via the catheter. Sciatic nerve block was also performed on all patients with 20ml of 0.5% ropivacaine. The patient demographics were recorded, as well as, post-surgical analgesia details, sensory and motor block in each area, boluses requested, rescue analgesia, and undesirable effects at 8, 16, 24, 36 and 48h. RESULTS: A total of 124 patients were included, 32 in Group 1 (25.8%), 21 in Group 2 (16.9%), 31 in Group 3 (25%), and 40 in group 4 (32.3%). The 4 groups were homogeneous as regards age, height, weight and ASA. There were no statistically significant differences found in the post-operative pain, except during movement in the femoral area at 36 hours (p=.032). There were also no statistically significant differences found in the sensory block in the femoral area at 48 hours (p=.019) and in the femoral cutaneous nerve block at 8 hours (p=.049) or at 24 hours (p=.045). As regards motor block, differences were only found in the obturator nerve at 24 hours (p=.016). There were no differences in rescue analgesia, patient controlled analgesia (PCA) boluses requested or administered, except that the number of boluses requested at 16 hours was less in Group 3 (p=.049). There were also no significant differences in undesirable effects or in the level of satisfaction of the patients between the four groups. CONCLUSIONS: In our study, no influence was found on the level of analgesia provided after knee replacement surgery with the neurostimulation intensity to which the neuromuscular system involved responded when a stimulating catheter is inserted at femoral level. PMID- 22542877 TI - [Endocarditis due to Candida glabrata on a prosthetic valve]. PMID- 22542878 TI - [Listeria monocytogenes and Herpes simplex type 1, associated in a meningoencephalitis episode in an immunodepressed patient]. PMID- 22542879 TI - [Spanish Society of Anaesthesia (SEDAR) guidelines for pre-anaesthesia checking procedures]. AB - We present this document as a guide to preparing a specific institutional pre anaesthesia checklist, as recommended in the Helsinki declaration on patient safety in anaesthesiology. Also, the recently recommended WHO "safe surgery check list" includes a check-list for anaesthesia. A working group was established in accordance with the charter of the Spanish Society of Anaesthesiology and Resuscitation (Sociedad Espanola de Anestesiologia y Reanimacion [SEDAR]). The new patient safety culture introduced into medicine, and the recommendations of European anaesthesia societies has led us to design and update protocols in order to improve results in this important part of our speciality. We have prepared these recommendations or guidelines using, as examples, updates of pre anaesthesia check-lists by other American (ASA), British, or Canadian societies of anaesthesia. With that aim, we enlisted the help of anaesthesia ventilator experts and the participation and advice of experienced anaesthesiologists from all parts of Spain. After various corrections and modifications, the document was available at www.sedar.es, so that any anaesthesiologist could propose any correction, or give their opinion. Finally, these guidelines have been approved by the SEDAR Board of Directors, before it was sent for publication in this journal. The aims of this document are to provide: a guideline applicable to all anaesthesia machines, a descriptive pre-anaesthesia check-list that include everything necessary for the anaesthesia procedure, and a resumed check-list to be available in all the anaesthesia machines or other equivalent, but prepared for each institution, which should include anaesthetic equipment and drugs. So, in order to ensure the aims and requirements of the European Board of Anaesthesiology, the European Society of Anaesthesiology, and the WHO are met, each institution should have a protocol for checking equipment and drugs. These guidelines are applicable to any anaesthesia equipment, enabling every institution to develop their own checking protocols, adapted to their anaesthesia machines and their procedures. With the consent of the SEDAR, this group will collaborate with anaesthesia machines providers in order to develop specific checklists for each of their models that will be available at www.sedar.es. PMID- 22542880 TI - [Comments on the article "Postdural puncture headache in obstetrics"]. PMID- 22542881 TI - [Comments on the article "Estimation of the intraoperative ejection fraction: comparison between the Simpson and the Doppler tissue method"]. PMID- 22542882 TI - [Detection of a cerebral ischaemia episode during surgery by monitoring the brain tissue oxygen pressure]. AB - The detection and treatment of cerebral ischaemia and tissue hypoxia for the prevention of secondary injury are the basic objectives during anaesthesia for neurosurgical procedures. The monitoring of the tissue oxygen pressure is direct and can enable potentially harmful situations to be detected in real time. Although it was initially used in neurocritical patients, its use has extended to surgical patients. We present the case of a patient subjected to surgical resection of a dural arteriovenous fistula in which the brain tissue oxygen pressure around the area of the lesion was monitored. The finding of an episode of cerebral tissue hypoxia during closure of the craniotomy determined the treatment of the patient. We highlight the possible use of this neuromonitoring for the rapid detection of regional cerebral hypoxia events in the peri-operative period of vascular neurosurgery, procedures that have a significant risk of, mainly ischaemic, hypoxia episodes. PMID- 22542883 TI - Administration of docosahexaenoic acid before birth and until aging decreases kainate-induced seizures in adult zebrafish. AB - Docosahexaeonic acid (DHA) is the final compound in the omega-3 polyunsaturated fatty acids (PUFA) synthetic pathway and the most abundant PUFA found in the brain. DHA plays an essential role in the development of the brain, and the intakes in pregnancy and early life affect growth and cognitive performance later in childhood. Recently, it has been proposed that dietary intake of DHA could be a non-pharmacological interventional strategy for the treatment of seizures in humans. However, to date, the experimental approaches to study the antiepileptic effect of DHA have been exclusively restricted to rodent models during short-to medium periods of treatment. The purpose of the present study was to test the chronic anticonvulsivant effects of DHA supplementation in zebrafish from the pre spawning stage to aging, taking advantage of our recently described kainate induced seizure model using this animal. To that end, two groups of adult female zebrafish were fed with standard or 200mg/kg DHA-enriched diets during 1 month previous to the spawning, and offspring subdivided in two categories, and subsequently fed with standard or DHA diets, generating 4 groups of animals that were aged until 20 months. Afterward, KA was intraperitoneally administered and epileptic score determined. All the DHA-enriched groups presented antiepileptic effects compared to the control group, showing that DHA presents an anticonvulsant potential. Among the studied groups, zebrafish fed with DHA from the pre-spawning stage to aging presented the best antiepileptic profile. These results show a neuroprotective benefit in zebrafish fed with DHA-enriched diet before birth and during the whole life. PMID- 22542884 TI - Cues to solution, restructuring patterns, and reports of insight in creative problem solving. AB - While the subjective experience of insight during problem solving is a common occurrence, an understanding of the processes leading to solution remains relatively uncertain. The goal of this study was to investigate the restructuring patterns underlying solution of a creative problem, and how providing cues to solution may alter the process. Results show that both providing cues to solution and analyzing problem solving performance on an aggregate level may result in restructuring patterns that appear incremental. Analysis of performance on an individual level provides evidence for insight-like solution patterns. However, no evidence is found for a relationship between an individual's restructuring pattern and their subjective experience of insight during problem solving. PMID- 22542885 TI - A review of the application of anodization for the fabrication of nanotubes on metal implant surfaces. AB - Metal implants are the best choice for the long-term replacement of hard tissue, such as hip and knee joints, because of their excellent mechanical properties. Titanium and its alloys, due to their self-organized oxide layer, which protects the surface from corrosion and prevents ion release, are widely accepted as biocompatible metal implants. Surface modification is essential for the promotion of the osseointegration of these biomaterials. Nanotubes fabricated on the surface of metal implants by anodization are receiving ever-increasing attention for surface modification. This paper provides an overview of the employment of anodization for nanotubes fabricated on the surface of titanium, titanium alloys and titanium alloying metals such as niobium, tantalum and zirconium metal implants. This work explains anodic oxidation and the manner by which nanotubes form on the surface of the metals. It then assesses this topical research to indicate how changes in anodizing conditions influence nanotube characteristics such as tube diameters and nanotube-layer thickness. PMID- 22542886 TI - Performance of electrospun poly(epsilon-caprolactone) fiber meshes used with mineral trioxide aggregates in a pulp capping procedure. AB - Living dental pulp tissue exposed to the oral environment should be protected with an appropriate pulp capping material to support the dentinogenesis potential of the pulp cells. Mineral trioxide aggregate (MTA) is the material of choice for the treatment of pulp. However, due to cytotoxicity during the initial setting phase of MTA, a new material is required that can act as a barrier to direct contact but facilitate the favorable effect of MTA. This study examined the feasibility of using electrospun poly(epsilon-caprolactone) fiber (PCL-F) meshes in the MTA-based pulp capping procedures. An experimental pulp capping was performed on the premolars of beagle dogs, and the efficacy of the PCL-F meshes was evaluated after 8 weeks. PCL-F/MTA formed a dentin bridge that was approximately fourfold thicker than that formed by the MTA. Columnar polarized odontoblast-like cells with long processes and tubular dentin-like matrices were observed beneath the dentin bridge in the PCL-F/MTA. The cells were also intensely immunostained for dentin sialoprotein. In cell cultures, PCL-F/MTA reduced cell death to ~8% of that in the MTA group. The proliferation of the cells cultured on PCL-F/MTA was much greater than that of cells cultured on MTA. Furthermore, PCL-F/MTA promoted the differentiation of MDPC23 cells to odontoblast-like cells and biomineralization, as confirmed by the expression of alkaline phosphatase and dentin sialophosphoprotein, and by the deposition of calcium. Based on these histologic findings and the cell responses observed in this study, PCL-F may be used efficiently in the MTA-based dental pulp therapy. PMID- 22542887 TI - [Posterior reversible encephalopathy syndrome (pres) in sepsis]. PMID- 22542889 TI - Evaluation of diazepam-molecularly imprinted microspheres for the separation of diazepam and its main metabolite from body fluid samples. AB - Molecularly imprinted microspheres (MIMs) for the drug diazepam and its main metabolite (nordiazepam) were prepared and used to separate the two species from urine and serum samples via molecularly imprinted solid-phase extraction. The specific binding capacity for diazepam was determined to be 1.97 mg/g, resulting in an imprinting factor of 5.8. The MIMs exhibit highly selective binding affinity for tricyclic benzodiazepines. Water-acetonitrile-acetone mixtures were used as the washing solvent and resulted in complete baseline separation, with a recovery of >87% for diazepam and of 88% for nordiazepam. The limits of detection are 21.5 and 24.5 ng/mL, respectively. PMID- 22542888 TI - The key role of transforming growth factor-beta receptor I and 15-lipoxygenase in hypoxia-induced proliferation of pulmonary artery smooth muscle cells. AB - Our laboratory has proved that 15-hydroxyeicosatetraenoic acid, a product of arachidonic acid catalyzed by 15-lipoxygenase (15-LO), plays a pivotal role in hypoxic pulmonary arterial hypertension. However, the mechanisms of how hypoxia regulates 15-LO expression are still unclear. As the formation of endogenous transforming growth factor-beta1 (TGF-beta1), implicated in pulmonary arterial hypertension pathogenesis, was promoted by hypoxia, we suspect whether hypoxia induced the expression of 15-LO is via the TGF-beta1 pathway. We found that treatment of pulmonary artery smooth muscle cells with TGF-beta1 significantly increased the expression of 15-LO and levels of 15-hydroxyeicosatetraenoic acid, product of 15-LO, which were inhibited by transforming growth factor-beta receptor I (TGFbetaRI) inhibitor, SD-208 and siRNA targeted to knockdown rat TGFbetaRI. Moreover, our results showed that TGF-beta1 regulated the cell cycle progression and made more cells from the G(0)/G(1) phase to the G(2)/M+S phase and enhanced the microtubule formation in cell nucleus. Additionally, we found that the 15-LO pathway was involved in TGFbeta-1-mediated cell viability, DNA synthesis and the cell cycle progression. Our data provide novel evidence that hypoxia induced 15-LO expression is through TGF-beta1, and 15-LO pathway plays a critical role in TGFbetaRI mediated the proliferation of pulmonary artery smooth muscle cells induced by hypoxia. Thus, new strategies aimed at combined blockade of TGFbetaRI as well as 15-LO may yield optimal therapeutic benefits. PMID- 22542890 TI - Analysis of polysorbate 80 and its related compounds by RP-HPLC with ELSD and MS detection. AB - The chemical composition of polysorbate 80 strongly influences the physicochemical properties and performance of many products. Consequently, a reliable characterization of polysorbate 80 is crucial for many applications. However, the exact composition of these chemical mixtures cannot be determined by colorimetry, hydrolysis, size-exclusion chromatography, nuclear magnetic resonance or mass spectrometry (MS). Meanwhile, due to the strong retention of higher esters on the reversed-phase (RP) column, the published high-performance liquid chromatography (HPLC) methods suffered from inadequate elution. In the present paper, an HPLC-evaporative light scattering detection (ELSD) and an HPLC electrospray ionization (ESI)-MS method were developed and validated for the separation and identification of the chemical composition of polysorbate 80. A full separation of the entire composition was achieved in 45 min. In the HPLC-ESI MS spectra, each class of the compound in polysorbate 80 was directly confirmed and identified by [M + NH(4)](+) and [M + 2NH(4)](2+) ions. The number of polyoxyethylene groups and their distribution within the molecule were determined, in addition to the dehydration and esterification degree of sorbitol. Analysis showed that polysorbate 80 contained different proportions of components (polyoxyethylene sorbitan, polyoxyethylene isosorbide, polyoxyethylene sorbitan monooleate-dioesters-trioleates-tetraoleates and polyoxyethylene isosorbide monoester-dioesters). It was concluded that HPLC-ESI-MS is a useful tool for establishing the compositional profile of polysorbate 80. PMID- 22542891 TI - Simultaneous determination of malachite green, crystal violet, methylene blue and the metabolite residues in aquatic products by ultra-performance liquid chromatography with electrospray ionization tandem mass spectrometry. AB - This work describes solid-phase extraction-ultra-performance liquid chromatography with electrospray ionization tandem spectrometry for determination of malachite green and metabolite leucomalachite green, crystal violet and metabolite leucocrystal violet, methylene blue and metabolites including azure A, azure B and azure C in aquatic products. Samples were extracted with acetonitrile and ammonium acetate buffer and purified by liquid extraction with dichloromethane, and then on MCAX solid-phase extraction cartridges. Then the extract was evaporated at 45 degrees C by nitrogen blow. The residue was dissolved and separated by an Acquity BEH C18 column. The mobile phase was acetonitrile (A) and 5 mmol/L of ammonium acetate containing 0.1% formic acid (B). Analytes were confirmed and quantified using a tandem mass spectrometry system in multiple reaction mode with triple quadrupole analyzer using positive polarity mode. The limits of detection of malachite green, leucomalachite green, crystal violet and leucocrystal violet were 0.15 ug/kg, the limits of quantification were 0.50 ug/kg, and the average recoveries were more than 75% with spiked residues from 0.5 to 10 ug/kg. The relative standard deviations were less than 13%. The limits of detection of methylene blue, azure A, azure B and azure C were 0.3 ug/kg, the limits of quantification were 1.0 ug/kg, the average recoveries were more than 70% with spiked residues from 1.0 to 10 ug/kg and the relative standard deviations were less than 15%. The method has the merits of simplicity, sensitivity and rapidity, and can be used for simultaneous determination of the analytes in aquatic products. PMID- 22542892 TI - Neonatal electroencephalography shows low sensitivity to anesthesia. AB - This study examined EEG under clinical anesthesia in neonates and infants, to clarify how growth affects EEG during anesthesia. Subjects comprised 62 neonates and infants. Patients were divided into four groups according to age: Group 1 (neonates), <1 month; Group 2, 1-2 months; Group 3, 3-5 months; and Group 4, 6 months to 2 years. Anesthesia was maintained with sevoflurane and fentanyl and/or caudal block. At four points of sevoflurane concentration (0.5%, 1%, 1.5%, and 2%), 90% spectral edge frequency (SEF90), burst suppression ratio (BSR), relative beta ratio (RBR) and approximate entropy (ApEn) were analyzed. In Group 4, SEF90, BSR, RBR and ApEn changes were dependent on the concentration of anesthesia, along with changes in sevoflurane concentration from 0.5% to 2% (from 14.3 (2.7) [mean (SD)] Hz to 8.2 (3.8) Hz, from 0.0 to 0.32 (0.36), from -1.58 (0.14) to 1.10 (0.15), and from 0.56 (0.25) to 0.24 (0.25) respectively; p<0.05 each). Conversely, these processed EEG parameters in Group 1 showed little anesthesia dependent change under sevoflurane concentrations between 0.5% and 2% (SEF90: 7.3 (1.2) Hz vs. 7.7 (2.1) Hz; BSR: 0.51 (0.20) vs. 0.62 (0.29); RBR: -1.00 (0.17) vs. -1.03 (0.27); ApEn: 0.32 (0.18) vs. 0.25 (0.14), respectively). The unique EEG features of neonates during anesthesia rapidly change to the usual anesthesia dependent patterns seen in older children, with a boundary of 3-5 months old. In infants younger than 6 months old, neural network regulation reflected in EEG by anesthesia is weak. PMID- 22542893 TI - Voxel-based morphometric gray matter correlates of daytime sleepiness. AB - Sleep disorders such as narcolepsy, obstructive sleep apnea, and chronic insomnia have been associated with reduced gray matter volume of the ventromedial prefrontal cortex (VMPFC). Functional neuroimaging and behavioral data also implicate this region as important in sleep-related problems and the ability to resist the impairing effects of sleep loss on cognition. However, no study has linked gray matter volume within this region to normal self-reported levels of daytime sleepiness. We therefore hypothesized that reduced gray matter volume within the VMPFC would be related to greater self-reported levels of general daytime sleepiness, as assessed by the Epworth Sleepiness Scale (ESS) in a sample of 36 healthy non-clinical participants. Using voxel-based morphometry, scores of the ESS were correlated with gray matter volume, after controlling for age, gender, and whole brain volume. Daytime sleepiness correlated negatively with gray matter volume in a cluster of voxels within the left gyrus rectus and medial orbitofrontal cortex. Findings converge with prior evidence to suggest that the VMPFC and medial orbitofrontal cortex may play a particularly important role in sleep-wake related phenomena including sleep disorders and trait-like individual differences in vulnerability to the impairing effects of sleep deprivation on neurobehavioral performance, and also in normal variations in self-reported daytime sleepiness. PMID- 22542894 TI - Detection of KPC-2 and qnrS1 in clinical isolates of Morganella morganii from China. AB - Seven carbapenem-nonsusceptible Morganella morganii isolates, which have similar antibiotic susceptibility profiles, were isolated over a 5-month period. MICs of imipenem, meropenem, and ertapenem were 8, 1, and 0.25 to 0.5 MUg/mL, respectively. Pulsed-field gel electrophoresis indicated that 6 isolates were indistinguishable or closely related. Carbapenem resistance can be transferred from M. morganii to Escherichia coli by conjugation. All M. morganii isolates and E. coli transconjugants produced KPC-2 and carried the qnrS1 gene. Production of KPC-2 mainly contributed to the carbapenem resistance in M. morganii. KPC-2 producing M. morganii clonally spread in a hospital in China. PMID- 22542895 TI - Effects of oral bisphosphonate therapy on serum calcium in elderly veterans with poor kidney function. AB - BACKGROUND: Limited data exist on the use of bisphosphonates in patients with poor kidney function due to a contraindication derived from inadequate experience among patients with kidney failure, accounting for as much as 25% of nonprescribing when otherwise appropriate. OBJECTIVES: To determine whether bisphosphonate use in patients with decreased renal function, as outlined in the package insert (estimated creatinine clearance [eCrCl] <35 mL/min), would result in higher rates of hypocalcemia, as suggested in previous studies. METHODS: This was a retrospective cohort study of elderly veterans 65 years of age and older at the Veterans Affairs North Texas Health Care System in Dallas, Texas. We identified 3089 patients who started oral bisphosphonate therapy between August 1, 2003 and July 12, 2010. Of the 252 patients meeting the inclusion criteria, 25 and 227 patients had an eCrCl <35 mL/min and eCrCl >=35 mL/min, respectively. Analyses of changes in serum calcium from baseline to the 1-year study end point were performed within and between each renal function group. RESULTS: Among the veterans with an eCrCl <35 mL/min and eCrCl >=35 mL/min, there were decreases in median serum calcium levels from baseline to study end point from 9.8 mg/dL (interquartile range [IQR], 9.4-10.2 mg/dL) to 9.3 mg/dL (IQR, 9.0-10.0 mg/dL; P = 0.028) and 9.6 mg/dL (IQR, 9.3-9.9 mg/dL) to 9.4 mg/dL (IQR, 9.1-9.8 mg/dL; P < 0.001), respectively. However, there was no difference in Deltacalcium: -0.2 mg/dL (IQR, 0-0.6 mg/dL) and 0.2 mg/dL (IQR, -0.2 to 0.5 mg/dL; P = 0.547), respectively. CONCLUSIONS: This exploratory assessment may suggest that, in elderly veterans, the initiation of oral bisphosphonate therapy contributed to a statistically significant decrease in serum calcium levels regardless of baseline renal function; however, the clinical impact of this change does not appear to be significant. Future studies should assess serum calcium in a larger population of patients to confirm the safety of oral bisphosphonates in poor kidney function. PMID- 22542896 TI - Airway epithelial cells--hyperabsorption in CF? AB - Airway epithelial cells transport electrolytes and are central to the disease cystic fibrosis (CF), which is an inherited transport defect affecting smaller airways and a number of other epithelial organs. Clinically, CF is dominated by a chronic lung disease, the main cause of morbidity and mortality. Airway obstruction by thick mucus and chronic infection by Pseudomonas aeruginosa eventually lead to loss of pulmonary function. Loss of function of CFTR Cl(-) channels was found to be the cause for CF. However, intensive research on the detailed mechanism of CF lung disease for more than 25 years produced a bewildering number of hypotheses and an endless discussion whether reduced Cl(-) secretion, primarily located in airway submucosal glands, or dehydration of the airways, driven by a hyperabsorption of Na(+) ions, is the primary cause of the disease. Recent results suggest a fine-tuned regulation of the airway fluid layer, but how significant really are Cl(-) and Na(+) transport? PMID- 22542897 TI - Nutritional status and gene expression along the somatotropic axis in roach (Rutilus rutilus) infected with the tapeworm Ligula intestinalis. AB - The tapeworm Ligula intestinalis inhibits gametogenesis of its fish host, the roach (Rutilus rutilus). We investigated whether L. intestinalis infection makes significant demands on nutritional resources and consequently manipulates the endocrine somatotropic axis of roach. Two groups of naturally infected and uninfected roach were studied: a field group (natural feeding) and a laboratory group (ad libitum food supply). In females, no significant impact of parasitization on storage substrates (glycogen, lipids, and protein) was detected, whereas in males, either lipid content of the liver (field group) or lipid of the muscle and glycogen of the liver (laboratory group) were slightly decreased. Except for the females of the field group, higher mRNA expression of growth hormone (gh) in the pituitary of infected fish was observed. Furthermore, the expression of hypophyseal somatolactin alpha and beta (slalpha, slbeta) was up-regulated in infected females of the field and laboratory group, respectively. In liver and muscle, mRNA expression of insulin-like growth factors (igf1, igf2) and igf receptor (igfr) remained either unchanged or were up-regulated with infection. Parasitization showed inconsistent effects on gh receptor 1 (ghr1) expression in liver and muscle, whereas ghr2 mRNA was mostly not influenced by infection. In general, the expression profile of genes involved in the somatotropic axis as well as the content of storage substances in infected roach did not resemble that of food-deprived fish either under natural or ad libitum feeding. In conclusion, the present study does not indicate starvation of L. intestinalis infected roach, and it is suggested that the inhibition of reproduction attenuated the nutritional demand of parasitization. PMID- 22542898 TI - New myotropic and metabotropic actions of pyrokinins in tenebrionid beetles. AB - Pyrokinins are a large family of insect neuropeptides exhibiting pleiotropic activity, but are predominantly myostimulatory hormones. In this study, four pyrokinins Tenmo-PK-1 (HVVNFTPRLa), Tenmo-PK-2 (SPPFAPRLa), Tenmo-PK-3 (HLSPFSPRLa) and Zopat-PK-1 (LPHYPRLa) from the neuro-endocrine system of two tenebrionid beetles, Tenebrio molitor and Zophobas atratus, were tested in homologous bioassays to evaluate their putative myotropic and glycaemic actions. The four investigated bioassays systems (the heart, oviduct, ejaculatory duct and hindgut) revealed species-specific and organ-specific myotropic actions for the pyrokinins tested. In most bioassays with both beetles, the peptides showed myostimulatory properties with different efficacy. However, the T. molitor heart is not sensitive to Tenmo-PK-1, Tenmo-PK-2 and Tenmo-PK-3, and one of the peptides Tenmo-PK-1, is myoinhibitory on the oviduct. Tenmo-PK-2, which is also present in Z. atratus, exerted an inhibitory effect on the contractions of the heart and ejaculatory duct muscles in this beetle. Such myoinhibitory properties of pyrokinins in insects are shown here for the first time. Only one of the peptides tested, Tenmo-PK-2, stimulated a hyperglycaemic response in the haemolymph of larvae of T. molitor and Z. atratus, and this effect suggests a possible additional metabotropic function of this peptide in beetles. The differences in the myotropic and glycaemic responses to pyrokinins suggest that these peptides modulate contractions of muscles from visceral organs and free sugar levels in the haemolymph of the beetles, through complex and species specific mechanisms. PMID- 22542899 TI - Structural backgrounds for the formation of a catalytically competent complex with NADP(H) during hydride transfer in ferredoxin-NADP(+) reductases. AB - The role of the highly conserved C266 and L268 of pea ferredoxin-NADP(+) reductase (FNR) in formation of the catalytically competent complex of the enzyme with NADP(H) was investigated. Previous studies suggest that the volume of these side-chains, situated facing the side of the C-terminal Y308 catalytic residue not stacking the flavin isoalloxazine ring, may be directly involved in the fine tuning of the catalytic efficiency of the enzyme. Wild-type pea FNR as well as single and double mutants of C266 and L268 residues were analysed by fast transient-kinetic techniques and their midpoint reduction potentials were determined. For the C266A, C266M and C266A/L268A mutants a significant reduction in the overall hydride transfer (HT) rates was observed along with the absence of charge-transfer complex formation. The HT rate constants for NADPH oxidation were lower than those for NADP(+) reduction, reaching a 30-fold decrease in the double mutant. In agreement, these variants exhibited more negative midpoint potentials with respect to the wild-type enzyme. The three-dimensional structures of C266M and L268V variants were solved. The C266M mutant shows a displacement of E306 away from the relevant residue S90 to accommodate the bulky methionine introduced. The overall findings indicate that in FNR the volume of the residue at position 266 is essential to attain the catalytic architecture between the nicotinamide and isoalloxazine rings at the active site and, therefore, for an efficient HT process. In addition, flexibility of the 268-270 loop appears to be critical for FNR to achieve catalytically competent complexes with NADP(H). PMID- 22542900 TI - Impaired protein quality control system underlies mitochondrial dysfunction in skeletal muscle of streptozotocin-induced diabetic rats. AB - Hyperglycaemia-related mitochondrial impairment is suggested as a contributor to skeletal muscle dysfunction. Aiming a better understanding of the molecular mechanisms that underlie mitochondrial dysfunction in type 1 diabetic skeletal muscle, the role of the protein quality control system in mitochondria functionality was studied in intermyofibrillar mitochondria that were isolated from gastrocnemius muscle of streptozotocin (STZ)-induced diabetic rats. Hyperglycaemic rats showed more mitochondria but with lower ATP production ability, which was related with increased carbonylated protein levels and lower mitochondrial proteolytic activity assessed by zymography. LC-MS/MS analysis of the zymogram bands with proteolytic activity allowed the identification of an AAA protease, Lon protease; the metalloproteases PreP, LAP-3 and MIP; and cathepsin D. The content and activity of the Lon protease was lower in the STZ animals, as well as the expression of the m-AAA protease paraplegin, evaluated by western blotting. Data indicated that in muscle from diabetic rats the mitochondrial protein quality control system was compromised, which was evidenced by the decreased activity of AAA proteases, and was accompanied by the accumulation of oxidatively modified proteins, thereby causing adverse effects on mitochondrial functionality. PMID- 22542901 TI - Role of hippocalcin in mediating Abeta toxicity. AB - Alzheimer's disease (AD) is the most common cause of dementia, and amyloid-beta (Abeta) plaques and tau-containing tangles are its histopathological hallmark lesions. These do not occur at random; rather, the neurodegenerative process is stereotyped in that it is initiated in the entorhinal cortex and hippocampal formation. Interestingly, it is the latter brain area where the calcium-sensing enzyme hippocalcin is highly expressed. Because calcium deregulation is a well established pathomechanism in AD, we aimed to address the putative role of hippocalcin in human AD brain and transgenic mouse models. We found that hippocalcin levels are increased in human AD brain and in Abeta plaque-forming APP23 transgenic mice compared to controls. To determine the role of hippocalcin in Abeta toxicity, we treated primary cultures derived from hippocalcin knockout (HC KO) mice with Abeta and found them to be more susceptible to Abeta toxicity than controls. Likewise, treatment with either thapsigargin or ionomycin, both known to deregulate intracellular calcium levels, caused an increased toxicity in hippocampal neurons from HC KO mice compared to wild-type. We found further that mitochondrial complex I activity increased from 3 to 6months in hippocampal mitochondria from wild-type and HC KO mice, but that the latter exhibited a significantly stronger aging phenotype than wild-type. Abeta treatment induced significant toxicity on hippocampal mitochondria from HC KO mice already at 3months of age, while wild-type mitochondria were spared. Our data suggest that hippocalcin has a neuroprotective role in AD, presenting it as a putative biomarker. PMID- 22542902 TI - Development and characterization of microsatellite markers for Berberis thunbergii (Berberidaceae). AB - PREMISE OF THE STUDY: Microsatellite markers were isolated and characterized in Berberis thunbergii, an invasive and ornamental shrub in the eastern United States, to assess genetic diversity among populations and potentially identify horticultural cultivars. METHODS AND RESULTS: A total of 12 loci were identified for the species. Eight of the loci were polymorphic and were screened in 24 individuals from two native (Tochigi and Ibaraki prefectures, Japan) and one invasive (Connecticut, USA) population and 21 horticultural cultivars. The number of alleles per locus ranged from three to seven, and observed heterozygosity ranged from 0.048 to 0.636. CONCLUSIONS: These new markers will provide tools for examining genetic relatedness of B. thunbergii plants in the native and invasive range, including phylogeographic studies and assessment of rapid evolution in the invasive range. These markers may also provide tools for examining hybridization with other related species in the invasive range. PMID- 22542903 TI - Unique expression of a sporophytic character on the gametophytes of notholaenid ferns (Pteridaceae). AB - PREMISE OF THE STUDY: Not all ferns grow in moist, shaded habitats; some lineages thrive in exposed, seasonally dry environments. Notholaenids are a clade of xeric adapted ferns commonly characterized by the presence of a waxy exudate, called farina, on the undersides of their leaves. Although some other lineages of cheilanthoid ferns also have farinose sporophytes, previous studies suggested that notholaenids are unique in also producing farina on their gametophytes. For this reason, consistent farina expression across life cycle phases has been proposed as a potential synapomorphy for the genus Notholaena. Recent phylogenetic studies have shown two species with nonfarinose sporophytes to be nested within Notholaena, with a third nonfarinose species well supported as sister to all other notholaenids. This finding raises the question: are the gametophytes of these three species farinose like those of their close relatives, or are they glabrous, consistent with their sporophytes? METHODS: We sowed spores of a diversity of cheilanthoid ferns onto culture media to observe and document whether their gametophytes produced farina. To place these species within a phylogenetic context, we extracted genomic DNA, then amplified and sequenced three plastid loci. The aligned data were analyzed using maximum likelihood to generate a phylogenetic tree. KEY RESULTS: Here we show that notholaenids lacking sporophytic farina also lack farina in the gametophytic phase, and notholaenids with sporophytic farina always display gametophytic farina (with a single exception). Outgroup taxa never displayed gametophytic farina, regardless of whether they displayed farina on their sporophytes. CONCLUSIONS: Notholaenids are unique among ferns in consistently expressing farina across both phases of the life cycle. PMID- 22542904 TI - Activation of ganglion cells in wild-type and P23H rat retinas with a small subretinal electrode. AB - Electronic retinal prostheses are being developed for people who become blind due to loss of photoreceptors from the disease retinitis pigmentosa. Previously, we reported on the responses of RGCs in the P23H rat (a model of retinitis pigmentosa) and the Sprague-Dawley (SD) rat to stimulation with a 400-MUm diameter electrode (Jensen and Rizzo, 2011). With recent clinical trials now utilizing smaller (50-200 MUm) electrodes, I sought to investigate the electrically evoked responses of RGCs in P23H and SD rat retinas with a smaller (125-MUm diameter) electrode. Here, I report on the electrically evoked spike activity from RGCs that arose from stimulation of the retinal neural network. With biphasic current pulses of 1 ms per phase, the thresholds for activation of SD rat RGCs ranged from 0.52 to 2.8 MUA; thresholds of P23H rat RGCs ranged from 1.2 to 7.8 MUA. Median thresholds of RGCs were 1.4 MUA in SD rats and 2.5 MUA in P23H rats. These thresholds measurements were obtained with the recording electrode placed over the stimulating electrode. I also examined how thresholds of RGCs change as a function of distance (100-500 MUm) from the center of the stimulating electrode. The median threshold currents of RGCs were much higher in P23H rats for all distances. What was striking was that the thresholds for activation of RGCs in P23H rat retinas rose much more rapidly. When the recording electrode was only 100-200 MUm from the center of the stimulating electrode, the median threshold current of P23H rat RGCs rose by 460%. In contrast, the median threshold current of SD rat RGCs increased only 29%. I also investigated the contribution of photoreceptors to the electrically evoked responses of ON-center RGCs in SD rat retinas by examining the change in RGC thresholds when photoreceptor input to ON bipolar cells was blocked with the mGluR6 antagonist CPPG. At 500-600 MUm, CPPG suppressed the light-evoked responses of the RGCs and at the same time increased the amount of current needed to generate an electrically evoked response. Similar to what was observed with SD rat RGCs, CPPG suppressed the light-evoked responses of ON-center P23H rat RGCs. However, the stimulation thresholds were not significantly altered. In conclusion, the data show that the threshold currents for indirect stimulation of both SD and P23H rat RGCs with a 125-MUm diameter electrode are much lower than what we found previously with a 400-MUm diameter electrode. To achieve high resolution vision with a multielectrode array, the spread of activation of RGCs needs to be limited. Our findings indicate that the spread of activation of RGCs is more confined in the degenerate retina. Lastly, my findings indicate that photoreceptors contribute to the lower stimulation thresholds of RGCs in normal, healthy retinas. PMID- 22542905 TI - Corneal myofibroblast biology and pathobiology: generation, persistence, and transparency. AB - Important advances have led to a better understanding of the biology and pathobiology of corneal myofibroblasts and their generation after surgery, injury, infection and disease. Transforming growth factor (TGF) beta, along with platelet-derived growth factor (PDGF) and interleukin (IL)-1, has been shown to regulate myofibroblast development and death in in-vitro and in-situ animal models. The myofibroblast precursor cells regulated by these cytokines include both keratocyte-derived and bone marrow-derived cells. Cytokines that promote and maintain myofibroblasts associated with late haze after photorefractive keratectomy are modulated in part by the epithelial basement membrane functioning as barrier between the epithelium and stroma. Structural and functional defects in the basement membrane likely lead to prolonged elevation of TGFbeta, and perhaps other cytokine, levels in the stroma necessary to promote differentiation of myofibroblasts. Conversely, repair of the epithelial basement membrane likely leads to a decrease in stromal TGFbeta levels and apoptosis of myofibroblasts. Repopulating keratocytes subsequently reorganize the associated fibrotic extracellular matrix deposited in the anterior stroma by the myofibroblasts. Investigations of myofibroblast biology are likely to lead to safer pharmacological modulators of corneal wound healing and transparency. PMID- 22542907 TI - Transcriptomic analysis of placenta affected by antiphospholipid antibodies: following the TRAIL of trophoblast death. AB - Antiphospholipid antibodies, a maternal risk factor for preeclampsia, increase shedding of necrotic trophoblast debris from the placenta, leading to endothelial dysfunction. Using Affymetrix HGU133 Plus 2 microarrays we found changes in the transcriptome of placental explants treated with antiphospholipid antibodies, including mRNAs BCL2L1, MCL1, PDCD2L, FASLG, SEMA6A, PRKCE and TRAIL that are involved in the regulation of apoptosis. Quantitative real-time RT-PCR and immunohistochemistry confirmed a reduction in TRAIL expression in response to antiphospholipid antibodies. These results may help to understand how antiphospholipid antibodies affect trophoblast cell death and how the antibodies could contribute to the pathogenesis of preeclampsia. PMID- 22542908 TI - Impaired fetal thymic growth precedes clinical preeclampsia: a case-control study. AB - In preeclampsia the maternal adaptive immune system undergoes specific changes, which are different from the physiological processes associated with healthy pregnancy. Whether preeclampsia also affects the fetal immune system is difficult to investigate, due to limited access to the fetus. We hypothesized that if preeclampsia affects the fetal adaptive immune system this might be associated with early changes in thymic growth. In this case-control study, 53 preeclamptic and 120 healthy control pregnancies were matched for maternal age, gestational age and smoking. Fetal thymus diameter was measured as the greatest width perpendicular to a line connecting sternum and spine based on ultrasound images taken at 17-21 weeks gestation. Independent of fetal and maternal anthropometric measures, thymuses were found to be smaller in preeclamptic pregnancies than healthy controls (16.2 mm versus 18.3 mm, respectively, mean difference=2.1 mm, 95% CI: 0.8-3.3, p<0.001), and the odds of developing preeclampsia was estimated to be 0.72 (95% CI: 0.60-0.86, p<0.001) lower for each 1 mm increase in thymus diameter. There was no correlation between the onset of preeclampsia and fetal thymus size. This is the first study to suggest that fetal thymus growth is reduced before the clinical onset of preeclampsia and precedes any described fetal anomalies or maternal immunological changes associated with preeclampsia. We propose that the fetal adaptive immune system is either passively affected by maternal processes preceding clinical preeclampsia or is actively involved in initiating preeclampsia in later pregnancy. PMID- 22542909 TI - A retrospective study on IVF outcome in patients with anticardiolipin antibody: effects of methylprednisolone plus low-dose aspirin adjuvant treatment. AB - Patients undergoing in vitro fertilization-embryo transfer have a high prevalence of anticardiolipin antibody (ACA). However, the relationship between ACA and IVF outcome is still controversial. The aim of the present study was to evaluate the potential effect of anticardiolipin antibody on IVF outcome and determine the role of adjuvant treatment in these ACA positive patients. The study included a total of 116 infertile women (116 IVF-ET cycles) positive for ACA, including 56 women pretreated with methylprednisolone plus low-dose aspirin before IVF (treated ACA+ group) and 60 patients without treatment (untreated ACA+ group). In addition, 518 infertile women (518 IVF-ET cycles) negative for ACA were enroled as controls (ACA- group). The results show that ACA+ patients who did not receive any adjuvant treatment showed a significantly lower fertilization rate, less high quality embryos, as well as a markedly lower pregnancy rate and implantation rate than controls. Moreover, ACA+ patients who received methylprednisolone plus aspirin achieved significantly higher fertilization, pregnancy and implantation rates than untreated ACA+ patients (FR 69.0%, PR 46.4% and IR 25.4% vs. FR 60.0%, PR 33.3% and IR 17.9%, respectively). The overall IVF results in the treated ACA+ group were comparable to patients negative for ACA (PR 53.9% and IR 32.3%). Thus, while the presence of ACA exerts a detrimental effect on IVF outcome, ACA+ patients have a better outcome if given methylprednisolone for immunosuppression and low-dose aspirin as an anti-thrombotic agent. PMID- 22542910 TI - Trophoblast debris modulates the expression of immune proteins in macrophages: a key to maternal tolerance of the fetal allograft? AB - Interactions between maternal immune cells and the placenta are of substantial interest since diseases of pregnancy, such as recurrent miscarriage, villitis of unknown etiology and preeclampsia may arise due to inadequate adaptation of the maternal immune system. During normal pregnancy trophoblast debris is shed from the placenta into the maternal blood in large quantities. This trophoblast debris is then rapidly cleared from the maternal circulation. In this study, we exposed trophoblast debris generated from an in vitro placental explant model to peripheral blood-derived macrophages and quantified a variety of molecules that are important in immune responses by ELISA or flow cytometry. Phagocytosis of trophoblast debris resulted in reduced cell-surface expression of MHC-II molecules, the costimulatory molecules (CD80, CD86, CD40 and B7H3), monocyte chemoattractant protein-1 (MCP-1), inter-cellular adhesion molecule 1 (ICAM-1) and IL-8 receptors in macrophages while the expression of programmed death-1 ligand 1 (PD-L1) was upregulated. In addition, phagocytosis of trophoblast debris induced the secretion of the anti-inflammatory cytokines IL-10, IL6 and IL1Ra and decreased the secretion of pro-inflammatory cytokines IL-1beta, IL12p70 and IL-8 by macrophages. Phagocytosis of trophoblast debris also increased macrophage expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO). We have shown that phagocytosis of trophoblast debris from normal placentae alters the phenotype of macrophages such that they are likely to deviate maternal immune responses towards tolerance and away from inflammation. This may be one of the mechanisms that allow the human fetal allograft to survive in direct contact with the maternal immune system. PMID- 22542911 TI - A case of interface keratitis following anterior lamellar keratoplasty. AB - Anterior lamellar keratoplasty (ALK) is indicated in patients with anterior corneal opacities. Benefits over penetrating keratoplasty include quicker visual rehabilitation, less postoperative astigmatism, and preservation of the host endothelium, thus minimizing the chances of graft rejection. A rare complication of lamellar corneal surgery is infectious interface keratitis between the donor and host tissue. We report a case of infectious interface keratitis following automated ALK successfully treated medically and by removal of the ALK disk, eventually having a deep anterior lamellar keratoplasty with good visual recovery. PMID- 22542906 TI - Do initial responses to drugs predict future use or abuse? AB - Individuals vary in their initial reactions to drugs of abuse in ways that may contribute to the likelihood of subsequent drug use. In humans, most drugs of abuse produce positive subjective states such as euphoria and feelings of well being, which may facilitate repeated use. In nonhumans, many drugs initially increase locomotor activity and produce discriminative stimulus effects, both of which have been considered to be models of human stimulant and subjective states. Both humans and nonhumans vary in their sensitivity to early acute drug effects in ways that may predict future use or self-administration, and some of these variations appear to be genetic in origin. However, it is not known exactly how the initial responses to drugs in either humans or nonhumans relate to subsequent use or abuse. In humans, positive effects of drugs facilitate continued use of a drug while negative effects discourage use, and in nonhumans, greater genetic risk for drug intake is predicted by reduced sensitivity to drug aversive effects; but whether these initial responses affect escalation of drug use, and the development of dependence is currently unknown. Although early use of a drug is a necessary step in the progression to abuse and dependence, other variables may be of greater importance in the transition from use to abuse. Alternatively, the same variables that predict initial acute drug effects and early use may significantly contribute to continued use, escalation and dependence. Here we review the existing evidence for relations between initial direct drug effects, early use, and continued use. Ultimately, these relations can only be determined from systematic longitudinal studies with comprehensive assessments from early drug responses to progression of problem drug use. In parallel, additional investigation of initial responses in animal models as predictors of drug use will shed light on the underlying mechanisms. PMID- 22542913 TI - Prevalence of diabetic retinopathy in various ethnic groups: a worldwide perspective. AB - The alarming rise in diabetes prevalence is a global public health and economic problem. Diabetic retinopathy is the most common complication of diabetes and the leading cause of blindness among working-age populations in the Western world. Screening and prompt treatment of diabetic retinopathy are not top priorities in many regions of the world, because the impacts of other causes of preventable blindness remain an issue. Ethnicity is a complex, independent risk factor for diabetic retinopathy. Observations from white populations cannot be extrapolated fully to other ethnic groups. The prevalence of diabetic retinopathy, sight threatening diabetic retinopathy, and clinically significant macular edema are higher in people of South Asian, African, Latin American, and indigenous tribal descent compared to the white population. Although all ethnic groups are susceptible to the established risk factors of diabetic retinopathy-such as length of exposure and severity of hyperglycemia, hypertension, and hyperlipidemia-ethnic-specific risk factors also may influence these rates. Such risk factors may include differential susceptibility to conventional risk factors, insulin resistance, differences in anthropometric measurements, truncal obesity, urbanization, variations in access to healthcare systems, genetic susceptibility, and epigenetics. The rates of nonproliferative diabetic retinopathy appear to be declining in the United States, supporting the observation that better medical management of diabetes and prompt treatment of sight-threatening diabetic retinopathy substantially improve the long-term diabetic retinopathy incidence; studies from other parts of the world are limited and do not mirror this finding, however. We examine the ethnicity and region based prevalence of diabetic retinopathy around the world and highlight the need to reinforce ethnicity-based screening and treatment thresholds in diabetic retinopathy. PMID- 22542912 TI - Herpes simplex epithelial and stromal keratitis: an epidemiologic update. AB - Herpes simplex virus (HSV) is associated with a variety of ocular diseases, including epithelial and stromal keratitis. HSV can cause stromal opacification and is believed to be the leading cause of infectious blindness in the developed world. An improved understanding of the global burden of HSV keratitis, including the incidence of severe vision loss, could have a significant effect on prevention and treatment and place it in perspective among causes of corneal ulceration. We found that the global incidence of HSV keratitis is roughly 1.5 million, including 40,000 new cases of severe monocular visual impairment or blindness each year. We also discuss relevant epidemiologic issues regarding HSV epithelial and stromal disease. PMID- 22542914 TI - Bilateral visual loss: more than meets the eye. AB - A 72-year-old woman presented with acute onset bilateral visual loss. She had no other symptoms or signs, but had a complex past medical history including blood transfusions and immunosuppression. T2-weighted magnetic resonance imaging demonstrated bilateral occipital lobe vasogenic edema, consistent with posterior reversible encephalopathy syndrome (PRES). Her vision improved with conservative management. PMID- 22542915 TI - Pain catastrophizing, threat, and the informational value of mood: task persistence during a painful finger pressing task. AB - Pain catastrophizing has shown to predict avoidance behavior in acute and chronic pain, but the literature is inconsistent. The present study tested the hypothesis that current mood and threat context moderate the relationship between pain catastrophizing and performance duration. Affective-motivational models postulate that negative and positive moods provide information about whether an activity is respectively threatening or safe. Moreover, it has been proposed that stable cognitive schemas about threat influence behavior particularly in threat-relevant contexts. The present study aimed to establish whether pain catastrophizing is related to less or greater performance duration, when participants experience respectively negative or positive moods, particularly in a high threatening pain context. A 2 mood * 2 threat context between-subjects factorial design was applied in 89 healthy participants with pain catastrophizing as covariate and performance duration during a painful finger pressing task as dependent variables. As predicted, higher pain catastrophizing was associated with less performance duration when participants experienced negative moods. The opposite was found when participants experienced positive moods. Moreover, these relationships were most pronounced in a high threatening pain context. This study suggests that the relationship between pain catastrophizing and performance duration during painful activities is moderated by situational factors such as current mood and threat context. PMID- 22542917 TI - [Current management of nonvariceal upper gastrointestinal bleeding in Spain]. AB - BACKGROUND: Mortality related to nonvariceal upper gastrointestinal bleeding (NVUGIB) has not changed. More information is needed to improve the management of this entity. The aims of this study were: a) to determine the characteristics of bleeding episodes, b) to describe the clinical approaches routinely used in NVUGIB, and c) to identify adverse outcomes related to endoscopic or medical treatments in Spain. METHODS: The European survey of nonvariceal upper GI bleeding (ENERGiB) was an observational, retrospective cohort study on NVUGIB with endoscopic evaluation carried out across Europe. The present study focused on Spanish patients in the ENERGiB study. The patients were managed according to routine care. The mean and standard deviation were calculated for quantitative variables and absolute and relative frequencies were calculated for categorical variables. RESULTS: Patients (n=403) were mostly men (71%), with a mean age of 65 years, and co-morbidities (62.5%). Most of the patients were managed by gastroenterologists (57.1%) or internal medicine teams (25.1%). A proton pump inhibitor was used empirically in 80% before endoscopy. Bleeding persistence occurred in 6.4% and recurrence in 6.7%. The mortality rate at 30 days was 3.5%. CONCLUSIONS: This study contributes to the characterization of Spanish patients and NVUGIB episodes in a real clinical setting and identifies the routine management of this entity, which is in line with the standards proposed by recent clinical practice guidelines. A notable finding was that age and the number of comorbidities in NVUGIB patients were increasing. These factors could explain the persistent mortality rate, despite the evident advances in the management of this entity. PMID- 22542918 TI - An unusual presentation of congenital adrenocortical carcinoma: a case report and review of the literature. AB - We describe a case of congenital non-functional adrenocortical carcinoma in a male infant who presented with recurrent pneumonia, paraparesis and sclerotic skeletal metastasis. To the best of our knowledge such presentation has never been reported. PMID- 22542919 TI - Molecular analysis of the genus Asparagus based on matK sequences and its application to identify A. racemosus, a medicinally phytoestrogenic species. AB - The plant Asparagus racemosus is one of the most widely used sources of phytoestrogens because of its high content of the steroidal saponins, shatavarins I-IV, in roots. The dry root of A. racemosus, known as "Rak-Sam-Sip" in Thai, is one of the most popular herbal medicines, used as an anti-inflammatory, an aphrodisiac and a galactagogue. Recently, the interest in plant-derived estrogens has increased tremendously, making A. racemosus particularly important and a possible target for fraudulent labeling. However, the identification of A. racemosus is generally difficult due to its similar morphology to other Asparagus spp. Thus, accurate authentication of A. racemosus is essential. In this study, 1557-bp nucleotide sequences of the maturase K (matK) gene of eight Asparagus taxa were analyzed. A phylogenetic relationship based on the matK gene was also constructed. Ten polymorphic sites of nucleotide substitutions were found within the matK sequences. A. racemosus showed different nucleotide substitutions to the other species. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis of the matK gene was developed to discriminate A. racemosus from others. Only the 650-bp PCR product from A. racemosus could be digested with BssKI into two fragments of 397 and 253-bp while the products of other species remained undigested. Ten commercially crude drugs were analyzed and revealed that eight samples were derived from A. racemosus while two samples of that were not. Thus, the PCR-RFLP analysis of matK gene was shown to be an effective method for authentication of the medicinally phytoestrogenic species, A. racemosus. PMID- 22542920 TI - TPMT status determination: the simplest is the most effective? PMID- 22542922 TI - Alkaloid and flavonoid rich fractions of fenugreek seeds (Trigonella foenum graecum L.) with antinociceptive and anti-inflammatory effects. AB - The seeds of fenugreek (Trigonella foenum-graecum L.) have medicinal uses as hypoglycemic, antinociceptive and anti-inflammatory agents. We aimed to evaluate the antinociceptive and anti-inflammatory effects of the major fractions of fenugreek seeds. The methanolic extract of the plant seeds was partitioned using a liquid-liquid extraction procedure to give six major fractions. Following phytochemical screening of isolated fractions, the total extract and each fraction were evaluated for their antinociception and anti-inflammatory effects using formalin and carrageenan-induced paw edema tests respectively. The methanolic extract exhibited both antinociceptive and anti-inflammatory effects at a dose of 100mg/kg. Among the tested fractions, alkaline chloroform fraction (AKC), which was alkaloid positive in screening tests, showed the most anti nociceptive effect in a dose-dependent manner. AKC fraction was as effective as morphine (5mg/kg) in this regard. Both aqueous and acidified chloroform fractions (ACC) could significantly inhibit paw edema at a different dose. The latter fraction dose-dependently inhibited carrageenan-induced paw edema. The results of phytochemical screening tests confirmed the presence of flavonoids in both ACC and aqueous fractions. It can be concluded that the alkaloid and flavonoid content of fenugreek seeds can be responsible for antinociception and anti inflammatory effects of the plant respectively. PMID- 22542923 TI - The impact of globalisation on the distribution of Echinococcus multilocularis. AB - In the past three decades, Echinococcus multilocularis, the cause of human alveolar echinococcosis, has been reported in several new countries both in definitive hosts (canids) as well as in people. Unless treated, infection with this cestode in people is fatal. In previously endemic countries throughout the Northern Hemisphere, geographic ranges and human and animal prevalence levels seem to be increasing. Anthropogenic influences, including increased globalisation of animals and animal products, and altered human/animal interfaces are thought to play a vital role in the global emergence of this pathogenic cestode. Molecular epidemiological techniques are a useful tool for detecting and tracing introductions, and differentiating these from range expansions. PMID- 22542924 TI - Ochronosis in a murine model of alkaptonuria is synonymous to that in the human condition. AB - OBJECTIVE: Alkaptonuria (AKU) is a rare genetic disease which results in severe early onset osteoarthropathy. It has recently been shown that the subchondral interface is of key significance in disease pathogenesis. Human surgical tissues are often beyond this initial stage and there is no published murine model of pathogenesis, to study the natural history of the disease. The murine genotype exists but it has been reported not to demonstrate ochronotic osteoarthropathy consistent with the human disease. Recent anecdotal evidence of macroscopic renal ochronosis in a mouse model of tyrosinaemia led us to perform histological analysis of tissues of these mice that are known to be affected in human AKU. DESIGN: The homogentisate 1,2-dioxygenase Hgd(+/)(-)Fah(-)(/)(-) mouse can model either hereditary tyrosinaemia type I (HT1) or AKU depending on selection conditions. Mice having undergone Hgd reversion were sacrificed at various time points, and their tissues taken for histological analysis. Sections were stained with haematoxylin eosin (H&E) and Schmorl's reagent. RESULTS: Early time point observations at 8 months showed no sign of macroscopic ochronosis of tissues. Macroscopic examination at 13 months revealed ochronosis of the kidneys. Microscopic analysis of the kidneys revealed large pigmented nodules displaying distinct ochre colouration. Close microscopic examination of the distal femur and proximal fibula at the subchondral junctions revealed the presence of numerous pigmented chondrocytes. CONCLUSIONS: Here we present the first data showing ochronosis of tissues in a murine model of AKU. These preliminary histological observations provide a stimulus for further studies into the natural history of the disease to provide a greater understanding of this class of arthropathy. PMID- 22542925 TI - Label-free detection of kanamycin based on the aptamer-functionalized conducting polymer/gold nanocomposite. AB - Highly sensitive label-free detection of kanamycin is achieved with an aptamer sensor based on a conducting polymer/gold self-assembled nanocomposite. The sensor probe is fabricated by covalently immobilizing an in vitro selected DNA aptamer for kanamycin onto gold nanoparticle (AuNP)-comprised conducting polymer, poly-[2, 5-di-(2-thienyl)-1H-pyrrole-1-(p-benzoic acid)] (poly-DPB). The self assembling of DPB on AuNP is investigated by TEM and UV-vis spectroscopy and the modification of the aptamer sensor is characterized using XPS and electrochemical impedance spectroscopy. The probe is applied to detect kanamycin by using voltammetric techniques. The sensor shows a pair of redox peaks around 0.26/ 0.08 V (vs. Ag/AgCl) for kanamycin captured by the aptamer-immobilized probe. The parameters that can affect the response, such as aptamer concentration, incubation time, temperature, and pH are optimized. The calibration plot shows a linear range from 0.05 MUM to 9.0 MUM kanamycin with a detection limit of 9.4+/ 0.4 nM. The proposed aptamer sensor is examined with a real sample. PMID- 22542926 TI - An aptamer based resonance light scattering assay of prostate specific antigen. AB - Prostate specific antigen (PSA) is a valuable tumor marker for prostate cancer screening. In this work, a novel and sensitive resonance light scattering (RLS) spectral assay of PSA was proposed based on PSA aptamer modified gold nanoparticles (AuNPs). The sulfhydryl modified single-strand aptamer could interact with AuNPs, which made the AuNPs stable in high concentration of salt. In pH 7.0 BR buffer solution, the highly selective combination of PSA and AuNPs labeling aptamer resulted in the aggregation of AuNPs which showed high RLS intensity. Under the optimal conditions, the magnitude of enhanced RLS intensity (DeltaI(RLS)) was proportional to the concentration of PSA in the range from 0.13 to 110 ng/mL, with a detection limit (LOD, 3sigma) of 0.032 ng/mL. This developed RLS assay as well as a commercially available enzyme-linked immunosorbent assay (ELISA) kit was successfully applied to the detection of PSA in 15 serum samples, and an excellent correlation of the levels of PSA measured was obtained. This is the first report of the aptamer based RLS assay for PSA and it is also a significant application of instrumental analysis technique. PMID- 22542928 TI - Commentary on: Combat-related gunshot wounds in the United States military: 2000 2009. AB - Gunshot wounds are an important cause of both morbidity and mortality within the military. With the deployment of the United States military into a two theater campaign over the past decade, the role of gunshot wounds in military personnel has come to the forefront. Gunshot wounds are often used and glamourized in popular culture. They are also fascinating to clinicians due to the difficulty in assessing such patients for injuries and treatment options.(1) Gunshot wounds also provide an opportunity to develop certain aspects of trauma management.(2) Walker et al. provide a coherent analysis of gunshot wounds to US military personnel during this period.(3). PMID- 22542927 TI - Monitoring of proteolytic enzyme activity using phase transition-based peptide arrays. AB - We have developed an assay using peptide arrays based on phase transition from the glass substrate to the liquid for monitoring quantitative protease activity in real-time. Peptide arrays were fabricated using a bifunctional cross-linker, N [gamma-maleimidobutyryloxy] sulfosuccinimide ester, and a substrate peptide containing two functional groups, cysteine and tetramethyl-6-carboxyrhodamine (TAMRA) on the C- and N-terminus, respectively. The phase transition-based peptide arrays were characterized by analyzing the substrate peptide cleaved from the solid substrate by matrix metalloproteinase-3 (MMP-3). We successfully used this assay to determine the quantitative proteolytic activity of MMP-3 in a dose dependent manner. In addition, parameters including Michaelis constant (K(m)), maximum rate of enzymatic reaction (V(max)), and half maximal inhibitory concentration (IC(50)) were determined by analyzing the concentrations of substrate peptide cleaved by MMP-3. Therefore, this new assay has potential for the quantitative analysis of enzyme kinetics of protease and informs research developments in drug discovery utilizing kinetic studies. PMID- 22542929 TI - A high fidelity model for single-incision laparoscopic cholecystectomy. AB - Single-incision laparoscopic surgery (SILS) is a safe approach for cholecystectomy, with the potential to minimise the iatrogenic trauma sustained from the operation. However, a number of reports show SILS to be technically challenging and as such there is expected to be a significant learning curve for expert surgeons adopting the new technique, as well as for junior surgical trainees. There are inherent risks to patient safety associated with practicing and developing new skills in a real-life theatre environment. However, thus far, there have been no realistic SILS training models available. We tested the feasibility of conducting SILS cholecystectomies on a cadaveric porcine model with standard operating equipment, which may provide a platform to facilitate safe training and assessment protocols. In this paper we provide an account of the training model technique, and review the literature surrounding SILS training and performance evaluation. PMID- 22542930 TI - Modelling the effects of water-point closure and fencing removal: a GIS approach. AB - Artificial water-points in the form of troughs or ground tanks are used to augment natural water supplies within rangelands in many parts of the world. Access to such water-points leads to the development of a distinct ecological sub system, the piosphere, where trampling and grazing impact modify the vegetation. This study aims to consolidate existing information in a GIS based model to investigate grazing patterns within the landscape. The model focuses on the closure of water-points and removal of fences on Nanya Station, New South Wales, Australia. We found that the manipulation of water-points and fences in one management intervention may change grazing activity in a way different to that which would be experienced if each had been modified separately. Such effects are further modified by the spatial distribution of the water-points and the underlying vegetation. PMID- 22542932 TI - Magnetic particle-linked anti hCG beta antibody for immunoassay of human chorionic gonadotropin (hCG), potential application to early pregnancy diagnosis. AB - The objective of this study was to develop a magnetic particle-linked monoclonal antibody to hCG beta for immunosorbent assay of human chorionic gonadotropin (hCG) with improved detection sensitivity. Monoclonal antibody against hCG beta was found to be optimally cross-linked to the superparamagnetic particles (SPIO) using EDC and NHS as cross-linking reagents. This superparamagnetic particle linked monoclonal antibody was able to concentrate hCG from a tested solution for further ELISA assay using horse radish peroxidase-labeled monoclonal antibody against hCG beta. This hybrid technique had greatly decreased the detection limit to 0.1 mIU/mL, making an early detection of pregnancy possible. With an improved sensitivity and simple operation, the magnetic particle-linked anti hCG beta antibody for immunoassay of human chorionic gonadotropin (hCG) has a great potential to supersede the traditional ELISA for pregnancy diagnosis. PMID- 22542931 TI - Interference of thrombin in immunological assays for hirudin specific antibodies. AB - Recombinant hirudins (desirudin, lepirudin) are direct thrombin inhibitors administered as anticoagulants for heparin-induced thrombocytopenia (HIT) and venous thromboembolism (VTE) prophylaxis. Although these small polypeptides are widely used, concern exists over reports of antigenicity. In the largest study of r-hirudin immunogenicity to-date, we evaluated the prevalence, quantity and specificity of IgG immune responses to desirudin (15 mg SC q12h for as long as clinically required) in 245 surgical and medically-ill subjects enrolled in DESIRABLE, a multicenter, open-label, clinical trial of hospitalized patients requiring VTE prophylaxis. Sera obtained before and 30 days after desirudin administration were analyzed for IgG anti-desirudin by immunoenzymetric assay using immobilized desirudin to bind desirudin-reactive antibody and peroxidase conjugated monoclonal-anti-human IgG Fc to detect bound IgG antibody. Of 245 study subjects, 19 (7.7%) were antibody "responders" (>2-fold increase in IgG antibody levels with >50% inhibition by desirudin 30 days post-treatment). There were no differences between responders and non-responders in incidence of clinical outcomes or bleeding-related adverse events. Forty-six patients had detectable desirudin-reactive IgG antibody prior to treatment, with no significant increase in antibody levels after exposure and no increase in clinical events. The origin of pre-existing hirudin-reactive IgG antibody requires further investigation involving suspected anti-thrombin-thrombin interactions. These results indicate a low potential for immunogenicity, with <8% of patients developing IgG antibodies after desirudin administration for VTE prophylaxis. In contrast to reports on lepirudin, production of anti-hirudin antibodies to desirudin has no apparent effect on clinical events. PMID- 22542933 TI - Influence of manufacturing processes on in vitro properties of the probiotic strain Lactobacillus rhamnosus Lcr35(r). AB - Probiotics are administered as complex manufactured products and yet most studies on probiotic bacterial strains have been performed with native culture strains. Little is known about the influence of industrial processes on the properties of the microorganisms. In this study, we comparatively assessed the characteristics of the probiotic bacterial strain Lactobacillus rhamnosus (Lcr35((r))) together with four of its commercial formulations, including three intestinal formulas (BACILOR with Lcr Restituo((r)) packet and capsule and FLOREA Lcr Lenio((r))) and one vaginal formula (GYNOPHILUS Lcr Regenerans((r))). Lcr35((r)) grown from the intestinal formulas displayed increased resistance to acidic pH and bile stress, especially FLOREA (Lcr Lenio((r))), which showed a 4.5log higher number of viable bacteria compared to the results obtained with the control native Lcr35((r)) strain. Adhesion to intestinal cells was significantly higher with Lcr Restituo((r)) packet and Lcr Restituo((r)) capsule vs Lcr35((r)). Bacteria from the vaginal formulation GYNOPHILUS had increased ability to metabolize glycogen thereby increasing lactic acid production. In vitro growth inhibition of the pathogen Candida albicans was significantly higher with bacteria from the vaginal formulation (4.5 log difference) and in the presence of vaginal epithelial cells than with the native strain. Our results show that the manufacturing process influences strain properties and should therefore be adapted according to the strain and the therapeutic indication. PMID- 22542934 TI - Functional analysis of three type-2 DGAT homologue genes for triacylglycerol production in the green microalga Chlamydomonas reinhardtii. AB - Photosynthetic organisms like plants and algae can use sunlight to produce lipids as important metabolic compounds. Plant-derived triacylglycerols (TAGs) are valuable for human and animal nutrition because of their high energy content and are becoming increasingly important for the production of renewable biofuels. Acyl-CoA:diacylglycerol acyltransferases (DGATs) have been demonstrated to play an important role in the accumulation of TAG compounds in higher plants. DGAT homologue genes have been identified in the genome of the green alga Chlamydomonas reinhardtii, however their function in vivo is still unknown. In this work, the three most promising type-2 DGAT candidate genes potentially involved in TAG lipid accumulation (CrDGAT2a, b and c) were investigated by constructing overexpression strains. For each of the genes, three strains were identified which showed enhanced mRNA levels of between 1.7 and 29.1 times that of the wild type (wt). Total lipid contents, neutral lipids and fatty acid profiles were determined and showed that an enhanced mRNA expression level of the investigated DGAT genes did not boost the intracellular TAG accumulation or resulted in alterations of the fatty acid profiles compared to wild type during standard growth condition or during nitrogen or sulfur stress conditions. We conclude that biotechnological efforts to enhance cellular TAG amount in microalgae need further insights into the complex network of lipid biosynthesis to identify potential bottlenecks of neutral lipid production. PMID- 22542935 TI - Improvement in the bioreactor specific productivity by coupling continuous reactor with repeated fed-batch reactor for acetone-butanol-ethanol production. AB - In comparison to the different fermentation modes for the production of acetone, butanol and ethanol (ABE) researched to date, the continuous fermentation is the most economically favored. Continuous fermentation with two or more reactor cascade is reported to be the most efficient as it results in a more stable solvent production process. In this work, it is shown that a continuous (first stage) reactor coupled to a repeated fed-batch (second stage) is superior to batch and fed-batch fermentations, including two-stage continuous fermentation. This is due to the efficient catalyst use, reported through the specific product rate and rapid glucose consumption rate. High solvents are produced at 19.4 g(ABE) l-1, with volumetric productivities of 0.92 g(butanol) l-1 h-1 and 1.47 g(ABE) l -1 h-1. The bioreactor specific productivities of 0.62 and 0.39 g g 1(cdw) h-1 obtained show a high catalyst activity. This new process mode has not been reported before in the development of ABE fermentation and it shows great potential and superiority to the existing fermentation methods. PMID- 22542937 TI - Negative regulation of Odd-skipped related 2 by TGF-beta achieves the induction of cellular migration and the arrest of cell cycle. AB - The transcription factor Odd-skipped related 2 (Osr2) functions in craniofacial and limb developments in mammals. We previously found that Osr2 gene expression is regulated by intracellular transcription factors such as Runx2, and C/EBP, whereas it remains unclear if extracellular factors would functionally regulate the Osr2 expression. In this study, we showed that TGF-beta down-regulated the Osr2 expression, which is involved in regulation of cellular migration and cell cycle. Furthermore, the down-regulation was found to be mediated by Smad3/Smad4 and p38/ATF2 signaling molecules. The Osr2 promoter was shown to possess Smad3/4 binding element and ATF2 binding element between -647 and -64 of promoter. TGF beta induced cellular migration in C3H10T1/2 cells and arrested cell cycle at G1 phase in NMuMG-Fucci cells. In contrast, the Osr2 reduced the migration and also stimulated the cell-cycle progression. These results suggest that Osr2 is involved in TGF-beta regulating cell migration and cell cycle via a Smad3-ATF2 transcriptional complex mediating pathway. PMID- 22542936 TI - Intranasal exposure to manganese disrupts neurotransmitter release from glutamatergic synapses in the central nervous system in vivo. AB - Chronic exposure to aerosolized manganese induces a neurological disorder that includes extrapyramidal motor symptoms and cognitive impairment. Inhaled manganese can bypass the blood-brain barrier and reach the central nervous system by transport down the olfactory nerve to the brain's olfactory bulb. However, the mechanism by which Mn disrupts neural function remains unclear. Here we used optical imaging techniques to visualize exocytosis in olfactory nerve terminals in vivo in the mouse olfactory bulb. Acute Mn exposure via intranasal instillation of 2-200 MUg MnCl(2) solution caused a dose-dependent reduction in odorant-evoked neurotransmitter release, with significant effects at as little as 2 MUg MnCl(2) and a 90% reduction compared to vehicle controls with a 200 MUg exposure. This reduction was also observed in response to direct electrical stimulation of the olfactory nerve layer in the olfactory bulb, demonstrating that Mn's action is occurring centrally, not peripherally. This is the first direct evidence that Mn intoxication can disrupt neurotransmitter release, and is consistent with previous work suggesting that chronic Mn exposure limits amphetamine-induced dopamine increases in the basal ganglia despite normal levels of dopamine synthesis (Guilarte et al., J Neurochem 2008). The commonality of Mn's action between glutamatergic neurons in the olfactory bulb and dopaminergic neurons in the basal ganglia suggests that a disruption of neurotransmitter release may be a general consequence wherever Mn accumulates in the brain and could underlie its pleiotropic effects. PMID- 22542938 TI - Delivery of cationic polymer-siRNA nanoparticles for gene therapies in neural regeneration. AB - The therapeutic applications of neural stem cells (NSCs) have potential to promote recovery in many obstinate diseases in central nervous system. Regulation of certain gene expressions using siRNA may have significant influence on the fate of NSC. To achieve the optimum gene silencing effect of siRNA, non-viral vector polyethylene glycol-polyethyleneimine (PEG-PEI) was investigated in the delivery of siRNA to NSCs. The characteristics of PEG-PEI/siRNA polyplexes were detected by scanning electron microscopy (SEM). The effects of nanoparticles on cell viability were measured via CCK-8 assay. In addition, the transfection efficiency was evaluated by fluorescence microscope and flow cytometry, and real time PCR and Western Blot were employed to detect the gene inhibition effect of siRNA delivered by PEG-PEI. The SEM micrographs showed that PEG-PEI could condense siRNA to form diffuse and spherical nanoparticles. The cytotoxicity of PEG-PEI/siRNA nanocomplexes (N/P=15) was significantly lower when compared with that of Lipofectamine 2000/siRNA (P<0.05). Moreover, the highest transfection efficiency of PEG-PEI/siRNA nanoparticles was obtained at an N/P ratio of 15, which was better than that achieved in the transfection using Lipofectamine 2000 (P<0.05). Finally, the gene knockdown effect of PEG-PEI/siRNA nanoparticles was verified at the levels of mRNA and protein. These results suggest that PEG-PEI may potentially be used as a siRNA delivery vector for neural regeneration therapy. PMID- 22542939 TI - Effect of PANDER in betaTC6-cell lipoapoptosis and the protective role of exendin 4. AB - Chronic exposure to high concentrations of saturated fatty acids, such as palmitic acid (PA), leads to apoptosis of pancreatic beta-cells through the activation of the c-Jun N-terminal kinase (JNK) signaling pathway. This study of beta-cell lipoapoptosis was designed to investigate the roles of pancreatic derived factor (PANDER), a pro-apoptosis cytokine-like peptide, and exendin-4, a long-acting agonist of the hormone glucagon-like peptide-1 (GLP-1) receptor and anti-apoptosis factor. The glucose-sensitive mouse beta-pancreatic cell line, betaTC6, was used to investigate the mechanisms of PA-induced apoptosis. Twenty four hours of PA exposure led to increased PANDER expression in a dose- and time dependent manner, and significantly increased phosphorylation of JNK. Treatment with the JNK-specific inhibitor SP600125 reduced the PA-induced PANDER expression. After the 24h of PA exposure, cells also underwent marked apoptosis and showed increased activation of the apoptosis protease, caspase-3. The small interfering (si)RNA-mediated silencing of PANDER gene expression significantly reduced both of these effects. When PA-treated betaTC6 cells were exposed to exogenous exendin-4, JNK activation was inhibited, PANDER expression was decreased, and the numbers of apoptotic cells were reduced. Collectively, these results demonstrated that the JNK-mediated signaling mechanism of PA-induced beta cell apoptosis involves up-regulated expression of PANDER and activation of caspase-3. Exendin-4 may protect against lipoapoptosis by interfering with the JNK-PANDER pathway. PMID- 22542940 TI - Proteomic analysis reveals a protective role for DJ-1 during 6-hydroxydopamine induced cell death. AB - Loss-of-function mutations in the DJ-1/PARK7 gene are responsible for early-onset autosomal-recessive Parkinson's disease. DJ-1 is implicated in the protection of neurons from oxidative stress by scavenging hydrogen peroxide and regulating the transcriptional activity of multiple pathways. Here, we attempted to identify the protein profiles modulated by DJ-1 in MN9D dopaminergic neurons following 6 hydroxydopamine (6-OHDA) treatment. We found that reactive oxygen species (ROS) levels increased in DJ-1-deficient cells that were either untreated or subjected to 6-OHDA treatment. The incidence of apoptosis after 6-OHDA treatment was increased in DJ-1 knockdown cells. Using these cells, we then performed two dimensional gel electrophoresis in conjunction with mass spectrometry to assess changes in protein profiles before and after 6-OHDA treatment. Several protein spots were positively or negatively altered in DJ-1-deficient cells with or without 6-OHDA. Among the altered proteins, immunoblot analysis confirmed an increase in galectin-7 and a decrease in peroxiredoxin-6 in DJ-1 knockdown cells. Moreover, transcriptional levels of putative p53 target proteins, including selenophosphate synthetase 1 and glycogen phosphorylase, were increased in the DJ 1 knockdown cells. Taken together, our data suggest that increases in pro apoptotic proteins and decreases in anti-apoptotic proteins render DJ-1 knockdown cells more susceptible to oxidative stress. PMID- 22542941 TI - Cloning and characterization of human Golgi phosphoprotein 2 gene (GOLPH2/GP73/GOLM1) promoter. AB - Human Golgi phosphoprotein 2 gene (also known as GOLPH2, GP73 or GOLM1) encodes an epithelial-specific Golgi membrane protein which can be induced by virus infection. It is also overexpressed in a number of tumors and is currently considered as an early diagnosis marker for hepatocellular carcinoma. However, little is known about how GOLPH2 is dysregulated in these disease conditions and the functional implications of its overexpression. The aim of this study is to investigate human GOLPH2 regulation mechanisms. We cloned a 2599 bp promoter fragment of GOLPH2 and found it maintained epithelial specificity. By deletion analysis, a repressive region (-864 to -734 bp), a positive regulatory region ( 734 to -421 bp) and a core promoter region (-421 to -79 bp) were identified. Sequence analysis revealed that GOLPH2 core promoter was devoid of canonical TATA element and classified as a TATA-less promoter. Adenoviral early region 1A (E1A) was able to activate GOLPH2 and the CtBP interaction domain of E1A was sufficient but not required for activation. A GC-box motif (-89 to -83 bp) in GOLPH2 core promoter region partly mediated E1A transactivation. These results delineated regulatory regions and functional element in GOLPH2 promoter, elucidated adenoviral E1A stimulation mechanisms and provided insight into GOLPH2 functions. PMID- 22542942 TI - Nociceptin is upregulated by FSH signaling in Sertoli cells in murine testes. AB - In postnatal testes, follicle-stimulating hormone (FSH) acts on somatic Sertoli cells to activate gene expression directly via an intracellular signaling pathway composed of cAMP, cAMP-dependent protein kinase (PKA), and cAMP-response element binding protein (CREB), and promotes germ cell development indirectly. Yet, the paracrine factors mediating the FSH effects to germ cells remained elusive. Here we show that nociceptin, known as a neuropeptide, is upregulated by FSH through cAMP/PKA/CREB pathway in Sertoli cells in murine testes. Chromatin immunoprecipitation from Sertoli cells shows that CREB phosphorylated at Ser133 associates with prepronociceptin gene encoding nociceptin. Analyses with Sertoli cells and testes demonstrates that both prepronociceptin mRNA and the nociceptin peptide are induced after FSH signaling is activated. In addition, the nociceptin peptide is induced in testes after 9days post partum following FSH surge. Thus, our findings may identify nociceptin as a novel paracrine mediator of the FSH effects in the regulation of spermatogenesis. PMID- 22542943 TI - Biphasic effect of danazol on human vascular endothelial cell permeability and f actin cytoskeleton dynamics. AB - Breakdown of endothelial barrier function is a hallmark event across a variety of pathologies such as inflammation, cancer, and diabetes. It has also been appreciated that steroid hormones impart direct biological activity on endothelial cells at many levels. The purpose of this investigation was to explore the effect of the androgen-like steroid, danazol, on endothelial cell barrier function in vitro. Primary human endothelial cells exposed to 0.01-50 MUM danazol were evaluated for changes in permeability. We found that danazol altered endothelial permeability in a biphasic manner in which nanomolar concentrations enhance barrier function while micromolar concentrations are detrimental. Monitoring of trans-endothelial electrical resistance demonstrated that these barrier enhancing effects were rapid (within 5 min) and lasted for over 24h. Analysis of intracellular f-actin organization showed that barrier enhancement also correlated with the formation of a submembranous cortical actin ring. Conversely, at higher danazol concentrations, contractile cell phenotypes were observed, represented by stress fiber formation. Competitive binding studies performed using steroid hormone receptor antagonists proved that this activity is the result of androgen and estrogen receptor ligation. These findings suggest that low dose danazol may provide a therapeutic window for diseases involving vascular leakage. PMID- 22542944 TI - SKLB70326, a novel small-molecule inhibitor of cell-cycle progression, induces G0/G1 phase arrest and apoptosis in human hepatic carcinoma cells. AB - We previously reported the potential of a novel small molecule 3-amino-6-(3 methoxyphenyl)thieno[2.3-b]pyridine-2-carboxamide (SKLB70326) as an anticancer agent. In the present study, we investigated the anticancer effects and possible mechanisms of SKLB70326 in vitro. We found that SKLB70326 treatment significantly inhibited human hepatic carcinoma cell proliferation in vitro, and the HepG2 cell line was the most sensitive to its treatment. The inhibition of cell proliferation correlated with G(0)/G(1) phase arrest, which was followed by apoptotic cell death. The SKLB70326-mediated cell-cycle arrest was associated with the downregulation of cyclin-dependent kinase (CDK) 2, CDK4 and CDK6 but not cyclin D1 or cyclin E. The phosphorylation of the retinoblastoma protein (Rb) was also observed. SKLB70326 treatment induced apoptotic cell death via the activation of PARP, caspase-3, caspase-9 and Bax as well as the downregulation of Bcl-2. The expression levels of p53 and p21 were also induced by SKLB70326 treatment. Moreover, SKLB70326 treatment was well tolerated. In conclusion, SKLB70326, a novel cell-cycle inhibitor, notably inhibits HepG2 cell proliferation through the induction of G(0)/G(1) phase arrest and subsequent apoptosis. Its potential as a candidate anticancer agent warrants further investigation. PMID- 22542945 TI - CNTF-mediated preactivation of astrocytes attenuates neuronal damage and epileptiform activity in experimental epilepsy. AB - Activated astrocytes display a broad spectrum of properties, ranging from neuroprotection to active contribution to demise of neural tissue. To investigate if activation of astrocytes by a single, defined stimulus enhances neuroprotective properties, we tested whether injection of ciliary neurotrophic factor (CNTF) can ameliorate epilepsy-related brain damage. Intrahippocampal CNTF injection in mice induced a rapid (within 2 days) and persistent (3 weeks) activation of astrocytes reflected by strong upregulation of glial fibrillary acidic protein (GFAP) mRNA synthesis and GFAP immunoreactivity. Moreover, CNTF signaling via phosphorylation and nuclear translocation of STAT3 (signal transducer and activator of transcription 3) was specifically activated in GFAP positive astrocytes. CNTF-mediated activation of astrocytes 2 days prior to an epileptogenic intrahippocampal injection of kainate (KA) resulted in strongly reduced cell death in the hilus and CA3 region of the hippocampus, revealed by Fluoro-Jade B staining. Granule cell dispersion, the pathological widening of the granule cell layer, was also significantly reduced 16 days after KA injection. Importantly, intrahippocampal in vivo recordings 3 weeks after KA injection showed that the occurrence of high frequency oscillations (fast ripples, FR), a surrogate marker for epileptic activity, was significantly reduced in CNTF+KA injected mice as compared to KA-injected animals. However, when CNTF was applied in the chronic epileptic phase at 3 weeks after KA injection, no reduction of FR activity was observed. In summary, our results indicate that the activation of astrocytes prior to an excitotoxic injury effectively reduces neuronal damage and the severity of epileptiform activity, whereas activation in the chronic phase is no longer protective. PMID- 22542946 TI - Extensive respiratory plasticity after cervical spinal cord injury in rats: axonal sprouting and rerouting of ventrolateral bulbospinal pathways. AB - Spinal cord injury (SCI) causes an interruption of descending motor and autonomic nervous tracts. However, a partial injury, and particularly a unilateral section, is generally followed by spontaneous locomotor and respiratory recovery. Although locomotor functional recovery has been correlated to spontaneous anatomical plasticity of the corticospinal tract, the remodeling of the bulbospinal tract that sustains respiratory improvement is unknown and has therefore been investigated here after chronic lateral cervical injury in rats (90 days post lesion by comparison to 7 days post-lesion). We show that chronic lateral C2 SCI leads both to a decreased thickness of the ipsilateral ventrolateral funiculus at sus and sub-lesional levels and to an opposite effect on the contralateral side. At C1 level, the number of ventrolateral bulbospinal fibers, stained with anterograde tracer was reduced within the ipsilateral ventrolateral funiculi while collateral arborization toward the gray matter and growth associated protein-43 levels was increased. At C2 lesional level, fibers rerouting toward the gray matter were also identified for 5% of the axotomized axon terminals. Despite these chronic sprouting processes respiratory bulbospinal projections to ipsilateral phrenic nucleus remained poor (less than 10% compared to non-injured conditions). Retrograde labeling of projections onto the phrenic nucleus revealed, after chronic injury, an increased recruitment of C1 propriospinal interneurons which moreover received more contacts from bulbospinal collaterals. This chronic remodeling was correlated with chronic diaphragm recovery under conditions of respiratory stress. Thus, despite extensive axonal loss and absence of direct phrenic reinnervation by bulbospinal respiratory neurons, sprouting processes toward cervical propriospinal neurons may contribute to the observed partial respiratory recovery. PMID- 22542947 TI - Novel aspirin-triggered neuroprotectin D1 attenuates cerebral ischemic injury after experimental stroke. AB - Acute ischemic stroke triggers complex neurovascular, neuroinflammatory and synaptic alterations. Aspirin and docosahexaenoic acid (DHA), an omega-3 essential fatty acid family member, have beneficial effects on cerebrovascular diseases. DHA is the precursor of neuroprotectin D1 (NPD1), which downregulates apoptosis and, in turn, promotes cell survival. Here we have tested the effect of aspirin plus DHA administration and discovered the synthesis of aspirin-triggered NPD1 (AT-NPD1) in the brain. Then we performed the total chemical synthesis of this molecule and tested in the setting of 2h middle cerebral artery occlusion (MCAo) in Sprague-Dawley rats. Neurological status was evaluated at 24h, 48 h, 72 h, and 7 days. At 3h post-stroke onset, an intravenous administration of 333 MUg/kg of AT-NPD1 sodium salt (AT-NPD1-SS) or methyl-ester (AT-NPD1-ME) or vehicle (saline) as treatment was given. On day 7, ex vivo magnetic resonance imaging (MRI) of the brains was conducted on 11.7 T MRI. T2WI, 3D volumes, and apparent diffusion coefficient (ADC) maps were generated. In addition, infarct volumes and number of GFAP (reactive astrocytes), ED-1 (activated microglia/macrophages) and SMI-71-positive vessels were counted in the cortex and striatum at the level of the central lesion. All animals showed similar values for rectal and cranial temperatures, arterial blood gases, and plasma glucose during and after MCAo. Treatment with both AT-NPD1-SS and AT-NPD1-ME significantly improved neurological scores compared to saline treatment at 24h, 48 h, 72 h and 7 days. Total lesion volumes computed from T2WI images were significantly reduced by both AT-NPD1-SS and AT-NPD1-ME treatment in the cortex (by 44% and 81%), striatum (by 61% and 77%) and total infarct (by 48% and 78%, respectively). Brain edema, computed from T2WI in the cortex (penumbra) and striatum (core), was elevated in the saline group. In contrast, both AT-NPD1 decreased water content in the striatum on day 7. 3D volumes, computed from T2WI, were dramatically reduced with both AT-NPD1 and the lesion was mostly localized in the subcortical areas. Treatment with both AT-NPD1-SS and AT-NPD1-ME significantly reduced cortical (by 76% and 96%), subcortical (by 61% and 70%) and total (69% and 84%, respectively) infarct volumes as defined by histopathology. In conclusion, a novel biosynthetic pathway that leads to the formation of AT NPD1 mediator in the brain was discovered. In addition, administration of synthetic AT-NPD1, in either its sodium salt or as the methyl ester, was able to attenuate cerebral ischemic injury which leads to a novel approach for pharmaceutical intervention and clinical translation. PMID- 22542948 TI - Ontogeny of Lafora bodies and neurocytoskeleton changes in Laforin-deficient mice. AB - Lafora disease (LD) is an autosomal recessive, always fatal progressive myoclonus epilepsy with rapid cognitive and neurologic deterioration. One of the pathological hallmarks of LD is the presence of cytoplasmic PAS+polyglucosan inclusions called Lafora bodies (LBs). Current clinical and neuropathological views consider LBs to be the cause of neurological derangement of patients. A systematic study of the ontogeny and structural features of the LBs has not been done in the past. Therefore, we undertook a detailed microscopic analysis of the neuropile of a Laforin-deficient (epm2a-/-) mouse model. Wild type and epm2a-/- mice were sacrificed at different ages and their encephalon processed for light microscopy. Luxol-fast-blue, PAS, Bielschowski techniques, as well as immunocytochemistry (TUNEL, Caspase-3, Apaf-1, Cytochrome-C and Neurofilament L antibodies) were used. Young null mice (11 days old) showed necrotic neuronal death in the absence of LBs. Both cell death and LBs showed a progressive increment in size and number with age. Type I LBs emerged at two weeks of age and were distributed in somata and neurites. Type II LBs appeared around the second month of age and always showed a complex architecture and restricted to neuronal somata. Their number was considerably less than type I LBs. Bielschowski method showed neurofibrillary degeneration and senile-like plaques. These changes were more prominent in the hippocampus and ventral pons. Neurofibrillary tangles were already present in 11 days-old experimental animals, whereas senile-like plaques appeared around the third to fourth month of life. The encephalon of null mice was not uniformly affected: Diencephalic structures were spared, whereas cerebral cortex, basal ganglia, pons, hippocampus and cerebellum were notoriously affected. This uneven distribution was present even within the same structure, i.e., hippocampal sectors. Of special relevance, was the observation of the presence of immunoreactivity to neurofilament L on the external rim of type II LBs. Perhaps, type II LB is not the end point of a metabolic abnormality. Instead, we suggest that type II LB is a highly specialized structural and functional entity that emerges as a neuronal response to major carbohydrate metabolism impairment. Early necrotic cell death, neurocytoskeleton derangement, different structural and probably functional profiles for both forms of LBs, a potential relationship between the external rim of the LB type II and the cytoskeleton and an uneven distribution of these abnormalities indicate that LD is both a complex neurodegenerative disease and a glycogen metabolism disorder. Our findings are critical for future studies on disease mechanisms and therapies for LD. Interestingly, the neurodegenerative changes observed in this LD model can also be useful for understanding the process of dementia. PMID- 22542950 TI - Swallowing dysfunction in head and neck cancer patients treated by radiotherapy: review and recommendations of the supportive task group of the Italian Association of Radiation Oncology. AB - PURPOSE: Dysphagia is a debilitating complication in head and neck cancer patients (HNCPs) that may cause a high mortality rate for aspiration pneumonia. The aims of this paper were to summarize the normal swallowing mechanism focusing on its anatomo-physiology, to review the relevant literature in order to identify the main causes of dysphagia in HNCPs and to develop recommendations to be adopted for radiation oncology patients. The chemotherapy and surgery considerations on this topic were reported in recommendations only when they were supposed to increase the adverse effects of radiotherapy on dysphagia. MATERIALS AND METHODS: The review of literature was focused on studies reporting dysphagia as a pre-treatment evaluation and as cancer and cancer therapy related side effects, respectively. Relevant literature through the primary literature search and by articles identified in references was considered. The members of the group discussed the results and elaborated recommendations according to the Oxford CRBM levels of evidence and recommendations. The recommendations were revised by external Radiation Oncology, Ear Nose and Throat (ENT), Medical Oncology and Speech Language Pathology (SLP) experts. RESULTS: Recommendations on pre treatment assessment and on patients submitted to radiotherapy were given. The effects of concurrent therapies (i.e. surgery or chemotherapy) were taken into account. CONCLUSIONS: In HNCPs treatment, disease control has to be considered in tandem with functional impact on swallowing function. SLPs should be included in a multidisciplinary approach to head and neck cancer. PMID- 22542949 TI - Androgen metabolism and JAK/STAT pathway genes and prostate cancer risk. AB - BACKGROUND: Prostate cancer (PC) is the most frequently diagnosed solid tumor in U.S. men. Genome-wide association studies (GWAS) have identified over 40 risk associated single nucleotide polymorphisms (SNPs), including variants in androgen pathway genes (e.g., KLK3 and AR). Androgens are important in PC and genes involved in this pathway are therefore candidates for conferring susceptibility to PC. METHODS: In this hypothesis-testing study, we evaluated PC risk in association with SNPs in 22 candidate genes involved in androgen metabolism or interactions with the androgen receptor (AR). A total of 187 SNPs were genotyped in 1458 cases and 1351 age-matched controls from a population-based study. PC risk was estimated using adjusted unconditional logistic regression and multinomial regression models. RESULTS: Single SNP analyses showed evidence (p < 0.05) for associations with 14 SNPs in 9 genes: NKX3.1, HSD17B3, AKR1C3, SULT2A1, CYP17A1, KLK3, JAK2, NCOA4 and STAT3. The most significant result was observed for rs2253502 in HSD17B3 (odds ratio, OR = 0.57, 95% CI: 0.39-0.84). In addition, five SNPs in four genes (CYP17A1, HSD17B4, NCOA4, and SULT2A1) were associated with more aggressive disease (p < 0.01). CONCLUSIONS: Our results replicate previously reported associations for SNPs in CYP17A1, HSD17B3, ARK1C3, NKX3.1, NCOA4 and KLK3. In addition, novel associations were observed for SNPs in JAK2, HSD17B4, and SULT2A1. These results will require replication in larger studies. PMID- 22542951 TI - Development and piloting of a mother and child intervention to promote resilience in young children of HIV-infected mothers in South Africa. AB - This paper describes the process of developing a parallel intervention for HIV positive mothers and their young children (6-10 years) with a view to strengthening the relationship between them. Strong mother-child relationships can contribute to enhanced psychological resilience in children. The intervention was developed through action research, involving a situation analysis based on focus group discussions; intervention planning, piloting the intervention and a formative evaluation of the intervention. Participants supplied feedback regarding the value of the intervention in mother-child relationships. The findings obtained from the formative evaluation were used to refine the intervention. Two parallel programmes for mothers and children (15 sessions each) were followed by 10 joint sessions. The intervention for mothers focused on maternal mental health and the strengthening of their capacity to protect and care for their young children. The intervention for children addressed the development of their self-esteem, interpersonal relationships and survival skills. The formative evaluation provided evidence of good participation, support and group cohesion. Qualitative feedback indicated that the activities stimulated mother-child interaction. A similar intervention can easily be applied elsewhere using the detailed manual. The insights gained and lessons learnt related to mother and child interaction within an HIV-context that emerged from this research, can be valuable in other settings, both in Sub-Saharan Africa and elsewhere. PMID- 22542952 TI - Interaction effect between the BDNF Val66Met polymorphism and parental rearing for interpersonal sensitivity in healthy subjects. AB - Interpersonal sensitivity is defined as undue and excessive awareness of, and sensitivity to, the behaviour and feelings of others and is one of the vulnerable factors to depression. In a twin study, it was suggested that this personality trait was characterised by both genetic and environmental factors. In the present study, we examined the effects of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and parental rearing on interpersonal sensitivity in 725 healthy Japanese subjects. Assessment of interpersonal sensitivity was performed by the Japanese version of the Interpersonal Sensitivity Measure (IPSM). Perceived parental rearing was assessed by the Parental Bonding Instrument (PBI), which consists of the care and protection factors. The BDNF polymorphism was detected by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. There was no main effect of the BDNF genotype on the IPSM score, while the PBI factors except maternal care had significant main effect on the IPSM score. There was significant interaction effect between the BDNF genotype and maternal care of the PBI on the IPSM score. Post-hoc analysis of simple slopes showed that the negative relationship between the IPSM score and maternal care was strongest and significant in the Met/Met genotype group, intermediate in the Val/Met genotype group and weakest in the Val/Val genotype group. The present study suggests that the interaction between the BDNF Val66Met polymorphism and parental rearing, especially maternal care, influences interpersonal sensitivity in healthy subjects. PMID- 22542953 TI - Loudness dependence of auditory evoked potentials in patients with borderline personality disorder--impact of psychopathology. AB - Alterations of the central serotonergic system are considered to be involved in the pathophysiology of borderline personality disorder (BPD). The loudness dependence of the N1/P2 component of auditory evoked potentials (LD) has been shown to indirectly reflect central serotonergic activity. The aim of this study was to investigate LD in patients with BPD compared to healthy controls, and to evaluate the association between LD and psychopathology such as anxiety, anger or impulsiveness. Female patients with BPD were included and compared to age- and sex-matched healthy subjects. Self-rating instruments, such as the State-Trait Anxiety Inventory (STAI), State-Trait Anger Expression Inventory (STAXI), and the Barratt Impulsiveness Scale (BIS) were used to assess clinical scores of anxiety, anger, and impulsiveness. Evoked potentials were recorded following the application of acoustic stimuli with increasing intensities; the LD was analysed using dipole source analysis. The mean LD was significantly higher in patients with BPD compared to controls. In the entire sample there were significant positive correlations of LD with state anxiety scores and STAXI subscores. The data contribute to the knowledge of neurophysiological alterations in patients with BPD, supporting the hypothesis of serotonergic dysregulation in the pathophysiology of the disorder. The significant clinical correlations suggest monoaminergic modulations of psychopathology on the symptom level. PMID- 22542954 TI - Involvement of microglial RhoA/Rho-kinase pathway activation in the dopaminergic neuron death. Role of angiotensin via angiotensin type 1 receptors. AB - It has recently been shown that the dopaminergic cell loss induced by neurotoxins is enhanced by brain angiotensin II (AII) via type 1 receptors (AT1). However, the mechanisms involved in the dopaminergic degeneration and the brain inflammatory effects of AII have not been clarified. The RhoA-Rho-Kinase (ROCK) pathway may play a critical role in the inflammatory and oxidative effects of AII. In the substantia nigra of mice, administration of the dopaminergic neurotoxin MPTP induced an increase in the expression of RhoA and ROCK II mRNA levels and ROCK activity, which were inhibited by AT1 receptor deletion (i.e., in AT1a null mice treated with MPTP). Administration of the ROCK inhibitor Y-27632 or AT1 deletion induced a significant decrease in MPTP-induced microglial activation and dopaminergic cell death. In rat primary mesencephalic cultures treated with MPP(+), the increase in dopaminergic cell loss induced by AII administration was also inhibited by treatment with Y27632. Intense expression of ROCK II was observed in the microglial cells in the substantia nigra of mice treated with MPTP, and the major role of the microglial ROCK was confirmed by comparing mesencephalic cultures with and without microglia. Activation of the RhoA/ROCK pathway is involved in the MPTP-induced dopaminergic degeneration, and in the enhancing effect of AII/AT1 activation on the microglial response and dopaminergic degeneration. ROCK inhibitors and AT1 receptor antagonists may provide new neuroprotective strategies against the progression of Parkinson's disease. PMID- 22542956 TI - Transference effects of prior non-contingent reinforcement on the acquisition of temporal control on fixed-interval schedules. AB - In two experiments we examined the influence of response and time factors on the speed of acquisition of temporal control on FI schedules. In Experiment 1, prior exposure to FT accelerated the development of temporal control on FI schedules of the same temporal value. It was also found that the slower acquisition on FI with prior RT was similar to that of rats with prior standard training. In Experiment 2, prior exposure to FT accelerated the development of temporal control on a FI schedule with a threefold increase in temporal value. Additionally, it was found that with prior FI 30s training, acquisition of temporal control on FI 90s was even faster than with prior FT 30s. Measures of head-entries into the feeder along the experiments indicated that temporal control was already developed during the periodic but not during the non-periodic histories and that this control transferred to lever press during FI testing phase. PMID- 22542957 TI - Evaluation of rate-dependency and internal clock effects of D-amphetamine. AB - The impact of two doses of d-amphetamine on rats' peak-interval performance was evaluated at two different points of training: with minimum training, 20 sessions, and with extended training, 120 sessions. At both points of training, none of the doses changed the location of the peak time; however, both doses caused a significant increase in the standard deviation of the response distribution during peak trials. Both results are incompatible with some previous empirical results, and with timing accounts that assume that dopamine modulates the pacemaker rate, but are compatible with a rate-dependent effect. PMID- 22542955 TI - Are ambient ultrafine, accumulation mode, and fine particles associated with adverse cardiac responses in patients undergoing cardiac rehabilitation? AB - BACKGROUND: Mechanisms underlying previously reported air pollution and cardiovascular (CV) morbidity associations remain poorly understood. OBJECTIVES: We examined associations between markers of pathways thought to underlie these air pollution and CV associations and ambient particle concentrations in postinfarction patients. METHODS: We studied 76 patients, from June 2006 to November 2009, who participated in a 10-week cardiac rehabilitation program following a recent (within 3 months) myocardial infarction or unstable angina. Ambient ultrafine particle (UFP; 10-100 nm), accumulation mode particle (AMP; 100 500 nm), and fine particle concentrations (PM2.5; <= 2.5 MUm in aerodynamic diameter) were monitored continuously. Continuous Holter electrocardiogram (ECG) recordings were made before and during supervised, graded, twice weekly, exercise sessions. A venous blood sample was collected and blood pressure was measured before sessions. RESULTS: Using mixed effects models, we observed adverse changes in rMSSD [square root of the mean of the sum of the squared differences between adjacent normal-to-normal (NN) intervals], SDNN (standard deviation of all NN beat intervals), TpTe (time from peak to end of T-wave), heart rate turbulence, systolic and diastolic blood pressures, C-reactive protein, and fibrinogen associated with interquartile range increases in UFP, AMP, and PM2.5 at 1 or more lag times within the previous 5 days. Exposures were not associated with MeanNN, heart-rate-corrected QT interval duration (QTc), deceleration capacity, and white blood cell count was not associated with UFP, AMP, and PM2.5 at any lag time. CONCLUSIONS: In cardiac rehabilitation patients, particles were associated with subclinical decreases in parasympathetic modulation, prolongation of late repolarization duration, increased blood pressure, and systemic inflammation. It is possible that such changes could increase the risk of CV events in this susceptible population. PMID- 22542958 TI - Design, synthesis and biological evaluation of a novel series of 1,3,4-oxadiazole bearing N-methyl-4-(trifluoromethyl)phenyl pyrazole moiety as cytotoxic agents. AB - On account of the reported anticancer activity of pyrazoles and oxadiazoles, we have designed and synthesized a novel combinatorial library of S-substituted 1,3,4-oxadiazole bearing N-methyl-4-(trifluoromethyl)phenyl pyrazole moiety and tested for in-vitro cytotoxic activity by MTT assay. Amongst the tested compounds, the compound 5e was the most promising anticancer agent with IC(50) value of 15.54 MUM in MCF-7 cells, compared to Doxorubicin as standard drug. The newly synthesized compounds were characterized by NOE, IR, (1)H NMR, (13)C NMR and LC-MS analysis. PMID- 22542959 TI - Potential effects of lignan-enriched flaxseed powder on bodyweight, visceral fat, lipid profile, and blood pressure in rats. AB - The potential effects of secoisolariciresinol diglucoside lignan-enriched flaxseed powder (LEFP) on bodyweight, visceral fat, lipid profile, adipokines, and blood pressure were investigated using rats, divided into four groups (n=8); a normal control diet (NC), a normal control diet with 0.02% LEFP (NCL), a high fat and high-fructose diet (HFD), or a high-fat and high-fructose diet with 0.02% LEFP (HFDL). Liver, heart, kidney, adipose tissues, and blood were collected following 12-weeks on the diets. The average body weight of the HFD group was significantly higher than those of the NC, NCL, and the HFDL groups (P<0.05). Also, the average weights of kidneys from the HFD and HFDL groups was higher than those of the NC and NCL groups (P<0.05), although not significantly different in the weights of livers and hearts. The visceral fat weight was significantly higher in rats in the HFD group, but notably reduced in the HFDL fed rats (P<0.05). Accordingly, plasma leptin increased significantly in rats fed the HFD diet, higher than rats fed the HFDL diet. Also, the rats in the HFDL group showed improved lipid profile, compared to the rats in the HFD group (P<0.05). Furthermore, a significant reduction in blood pressure was observed in the rats of the HFDL group compared to the HFD group (P<0.05). These data suggest that the LEFP supplementation may provide beneficial effects such as the reduction of bodyweight and fat accumulation, the lipid profile improvement, and blood pressure control. PMID- 22542961 TI - Uses of cell free fetal DNA in maternal circulation. AB - For over a decade, researchers have focused their attention on the development of non-invasive prenatal diagnosis tests based on cell-free fetal DNA circulating in maternal blood. With the possibility of earlier and safer testing, non-invasive prenatal diagnosis has the potential to bring many positive benefits to prenatal diagnosis. Non-invasive prenatal diagnosis for fetal sex determination for women who are carriers of sex-linked conditions is now firmly established in clinical practice. Other non-invasive prenatal diagnosis-based tests are set to follow, as future applications, such as the detection of single-gene disorders and chromosomal abnormalities, are now well within reach. Here, we review recent developments in non-invasive prenatal diagnosis for genetic conditions and chromosomal abnormalities, and provide an overview of research into ethical concerns, social issues and stakeholder view points. PMID- 22542962 TI - Melanosis ilei. PMID- 22542960 TI - Assessing the effect of Measurement-Based Care depression treatment on HIV medication adherence and health outcomes: rationale and design of the SLAM DUNC Study. AB - Depression affects 20-30% of people living with HIV/AIDS (PLWHA) in the U.S. and predicts greater sexual risk behaviors, lower antiretroviral (ARV) medication adherence, and worse clinical outcomes. Yet little experimental evidence addresses the critical clinical question of whether depression treatment improves ARV adherence and clinical outcomes in PLWHA with depression. The Strategies to Link Antidepressant and Antiretroviral Management at Duke, UAB, and UNC (SLAM DUNC) Study is a randomized clinical effectiveness trial funded by the National Institute for Mental Health. The objective of SLAM DUNC is to test whether a depression treatment program integrated into routine HIV clinical care affects ARV adherence. PLWHA with depression (n=390) are randomized to enhanced usual care or a depression treatment model called Measurement-Based Care (MBC). MBC deploys a clinically supervised Depression Care Manager (DCM) to provide evidence based antidepressant treatment recommendations to a non-psychiatric prescribing provider, guided by systematic and ongoing measures of depressive symptoms and side effects. MBC has limited time requirements and the DCM role can be effectively filled by a range of personnel given appropriate training and supervision, enhancing replicability. In SLAM DUNC, MBC is integrated into HIV care to support HIV providers in antidepressant prescription and management. The primary endpoint is ARV adherence measured by unannounced telephone-based pill counts at 6 months with follow-up to 12 months and secondary endpoints including viral load, health care utilization, and depressive severity. Important outcomes of this study will be evidence of the effectiveness of MBC in treating depression in PLWHA and improving HIV-related outcomes. PMID- 22542963 TI - Multiple barriers to nonhomologous DNA end joining during meiosis in Drosophila. AB - Repair of meiotic double-strand breaks (DSBs) uses the homolog and recombination to yield crossovers while alternative pathways such as nonhomologous end joining (NHEJ) are suppressed. Our results indicate that NHEJ is blocked at two steps of DSB repair during meiotic prophase: first by the activity of the MCM-like protein MEI-218, which is required for crossover formation, and, second, by Rad51-related proteins SPN-B (XRCC3) and SPN-D (RAD51C), which physically interact and promote homologous recombination (HR). We further show that the MCM-like proteins also promote the activity of the DSB repair checkpoint pathway, indicating an early requirement for these proteins in DSB processing. We propose that when a meiotic DSB is formed in the absence of both MEI-218 and SPN-B or SPN-D, a DSB substrate is generated that can enter the NHEJ repair pathway. Indeed, due to its high error rate, multiple barriers may have evolved to prevent NHEJ activity during meiosis. PMID- 22542964 TI - Establishment of new mutations in changing environments. AB - Understanding adaptation in changing environments is an important topic in evolutionary genetics, especially in the light of climatic and environmental change. In this work, we study one of the most fundamental aspects of the genetics of adaptation in changing environments: the establishment of new beneficial mutations. We use the framework of time-dependent branching processes to derive simple approximations for the establishment probability of new mutations assuming that temporal changes in the offspring distribution are small. This approach allows us to generalize Haldane's classic result for the fixation probability in a constant environment to arbitrary patterns of temporal change in selection coefficients. Under weak selection, the only aspect of temporal variation that enters the probability of establishment is a weighted average of selection coefficients. These weights quantify how much earlier generations contribute to determining the establishment probability compared to later generations. We apply our results to several biologically interesting cases such as selection coefficients that change in consistent, periodic, and random ways and to changing population sizes. Comparison with exact results shows that the approximation is very accurate. PMID- 22542965 TI - Remarkably simple sequence requirement of the M-factor pheromone of Schizosaccharomyces pombe. AB - The mating reaction is triggered by specific pheromones in a wide variety of organisms. Small peptides are used as mating pheromones in yeasts and fungi. In the fission yeast Schizosaccharomyces pombe, M-factor is a C terminally farnesylated nonapeptide secreted from M-cells, and its counterpart, P-factor, is a simple peptide composed of 23 amino acids. The primary structure requirements for the biological activity of pheromone peptides remain to be elucidated. Here, we conducted comprehensive substitution of each of the amino acids in M-factor peptide and inspected the mating ability of these missense mutants. Thirty-five sterile mutants were found among an array of 152 mutants with single amino acid substitutions. Mapping of the mutation sites clearly indicated that the sterile mutants were associated exclusively with four amino acid residues (VPYM) in the carboxyl-terminal half. In contrast, the substitution of four amino-terminal residues (YTPK) with any amino acid had no or only a slightly deleterious effect on mating. Furthermore, deletion of the three N-terminal residues caused no sterility, although truncation of a fourth residue had a marked effect. We conclude that a farnesylated hexapeptide (KVPYMC(Far)-OCH(3)) is the minimal M factor that retains pheromone activity. At least 15 nonfunctional peptides were found to be secreted, suggesting that these mutant M-factor peptides are no longer recognized by the cognate receptor. PMID- 22542966 TI - Temporal variation in selection accelerates mutational decay by Muller's ratchet. AB - Asexual species accumulate deleterious mutations through an irreversible process known as Muller's ratchet. Attempts to quantify the rate of the ratchet have ignored the role of temporal environmental heterogeneity even though it is common in nature and has the potential to affect overall ratchet rate. Here we examine Muller's ratchet in the context of conditional neutrality (i.e., mutations that are deleterious in some environmental conditions but neutral in others) as well as more subtle changes in the strength (but not sign) of selection. We find that temporal variation increases the rate of the ratchet (mutation accumulation) and the rate of fitness decline over that of populations experiencing constant selection of equivalent average strength. Temporal autocorrelation magnifies the effects of temporal heterogeneity and can allow the ratchet to operate at large population sizes in which it would be halted under constant selection. Classic studies of Muller's ratchet show that the rate of fitness decline is maximized when selection is of a low but intermediate strength. This relationship changes quantitatively with all forms of temporal heterogeneity studied and changes qualitatively when there is temporal autocorrelation in selection. In particular, the rate of fitness decline can increase indefinitely with the strength of selection with some forms of temporal heterogeneity. Our finding that temporal autocorrelation in selection dramatically increases ratchet rate and rate of fitness decline may help to explain the paucity of asexual taxa. PMID- 22542967 TI - A regulatory module controlling pharyngeal development and function in Caenorhabditis elegans. AB - In Caenorhabditis elegans, the differentiation and morphogenesis of the foregut are controlled by several transcriptional regulators and cell signaling events, and by PHA-1, an essential cytoplasmic protein of unknown function. Previously we have shown that LIN-35 and UBC-18-ARI-1 contribute to the regulation of pha-1 and pharyngeal development through the Zn-finger protein SUP-35/ZTF-21. Here we characterize SUP-37/ZTF-12 as an additional component of the PHA-1 network regulating pharyngeal development. SUP-37 is encoded by four distinct splice isoforms, which contain up to seven C2H2 Zn-finger domains, and is localized to the nucleus, suggesting a role in transcription. Similar to sup-35, sup-37 loss of-function mutations can suppress both LOF mutations in pha-1 as well as synthetic-lethal double mutants, including lin-35; ubc-18, which are defective in pharyngeal development. Genetic, molecular, and expression data further indicate that SUP-37 and SUP-35 may act at a common step to control pharyngeal morphogenesis, in part through the transcriptional regulation of pha-1. Moreover, we find that SUP-35 and SUP-37 effect pharyngeal development through a mechanism that can genetically bypass the requirement for pha-1 activity. Unlike SUP-35, SUP-37 expression is not regulated by either the LIN-35 or UBC-18-ARI-1 pathways. In addition, SUP-37 carries out two essential functions that are distinct from its role in regulating pharyngeal development with SUP-35. SUP-37 is required within a subset of pharyngeal muscle cells to facilitate coordinated rhythmic pumping and in the somatic gonad to promote ovulation. These latter observations suggest that SUP-37 may be required for the orchestrated contraction of muscle cells within several tissues. PMID- 22542968 TI - Disentangling the roles of history and local selection in shaping clinal variation of allele frequencies and gene expression in Norway spruce (Picea abies). AB - Understanding the genetic basis of local adaptation is challenging due to the subtle balance among conflicting evolutionary forces that are involved in its establishment and maintenance. One system with which to tease apart these difficulties is clines in adaptive characters. Here we analyzed genetic and phenotypic variation in bud set, a highly heritable and adaptive trait, among 18 populations of Norway spruce (Picea abies), arrayed along a latitudinal gradient ranging from 47 degrees N to 68 degrees N. We confirmed that variation in bud set is strongly clinal, using a subset of five populations. Genotypes for 137 single nucleotide polymorphisms (SNPs) chosen from 18 candidate genes putatively affecting bud set and 308 control SNPs chosen from 264 random genes were analyzed for patterns of genetic structure and correlation to environment. Population genetic structure was low (F(ST) = 0.05), but latitudinal patterns were apparent among Scandinavian populations. Hence, part of the observed clinal variation should be attributable to population demography. Conditional on patterns of genetic structure, there was enrichment of SNPs within candidate genes for correlations with latitude. Twenty-nine SNPs were also outliers with respect to F(ST). The enrichment for clinal variation at SNPs within candidate genes (i.e., SNPs in PaGI, PaPhyP, PaPhyN, PaPRR7, and PaFTL2) indicated that local selection in the 18 populations, and/or selection in the ancestral populations from which they were recently derived, shaped the observed cline. Validation of these genes using expression studies also revealed that PaFTL2 expression is significantly associated with latitude, thereby confirming the central role played by this gene in the control of phenology in plants. PMID- 22542969 TI - Chromatin modulation at the FLO11 promoter of Saccharomyces cerevisiae by HDAC and Swi/Snf complexes. AB - Cell adhesion and biofilm formation are critical processes in the pathogenicity of fungi and are mediated through a family of adhesin proteins conserved throughout yeasts and fungi. In Saccharomyces cerevisiae, Flo11 is the main adhesin involved in cell adhesion and biofilm formation, making the study of its function and regulation in this nonpathogenic budding yeast highly relevant. The S. cerevisiae FLO11 gene is driven by a TATA-box-containing promoter that is regulated through one of the longest regulatory upstream regions (3 kb) in yeast. We reported recently that two chromatin cofactor complexes, the Rpd3L deacetylase and the Swi/Snf chromatin-remodeling complexes, contribute significantly to the regulation of FLO11. Here, we analyze directly how these complexes impact on FLO11 promoter chromatin structure and dissect further the interplay between histone deacetylases, chromatin remodeling, and the transcriptional repressor Sfl1. We show that the regulation of chromatin structure represents an important layer of control in the highly complex regulation of the FLO11 promoter. PMID- 22542971 TI - Megabase-scale inversion polymorphism in the wild ancestor of maize. AB - Chromosomal inversions are thought to play a special role in local adaptation, through dramatic suppression of recombination, which favors the maintenance of locally adapted alleles. However, relatively few inversions have been characterized in population genomic data. On the basis of single-nucleotide polymorphism (SNP) genotyping across a large panel of Zea mays, we have identified an ~50-Mb region on the short arm of chromosome 1 where patterns of polymorphism are highly consistent with a polymorphic paracentric inversion that captures >700 genes. Comparison to other taxa in Zea and Tripsacum suggests that the derived, inverted state is present only in the wild Z. mays subspecies parviglumis and mexicana and is completely absent in domesticated maize. Patterns of polymorphism suggest that the inversion is ancient and geographically widespread in parviglumis. Cytological screens find little evidence for inversion loops, suggesting that inversion heterozygotes may suffer few crossover-induced fitness consequences. The inversion polymorphism shows evidence of adaptive evolution, including a strong altitudinal cline, a statistical association with environmental variables and phenotypic traits, and a skewed haplotype frequency spectrum for inverted alleles. PMID- 22542972 TI - The limits to parapatric speciation: Dobzhansky-Muller incompatibilities in a continent-island model. AB - How much gene flow is needed to inhibit speciation by the accumulation of Dobzhansky-Muller incompatibilities (DMIs) in a structured population? Here, we derive these limits in a classical migration-selection model with two haploid or diploid loci and unidirectional gene flow from a continent to an island. We discuss the dependence of the maximum gene-flow rate on ecological factors (exogeneous selection), genetic factors (epistasis, recombination), and the evolutionary history. Extensive analytical and numerical results show the following: (1) The maximum rate of gene flow is limited by exogeneous selection. In particular, maintenance of neutral DMIs is impossible with gene flow. (2) There are two distinct mechanisms that drive DMI evolution in parapatry, selection against immigrants in a heterogeneous environment and selection against hybrids due to the incompatibility. (3) Depending on the mechanism, opposite predictions result concerning the genetic architecture that maximizes the rate of gene flow a DMI can sustain. Selection against immigrants favors evolution of tightly linked DMIs of arbitrary strength, whereas selection against hybrids promotes the evolution of strong unlinked DMIs. In diploids, the fitness of the double heterozygotes is the decisive factor to predict the pattern of DMI stability. PMID- 22542970 TI - A network of genes antagonistic to the LIN-35 retinoblastoma protein of Caenorhabditis elegans. AB - The Caenorhabditis elegans pRb ortholog, LIN-35, functions in a wide range of cellular and developmental processes. This includes a role of LIN-35 in nutrient utilization by the intestine, which it carries out redundantly with SLR-2, a zinc finger protein. This and other redundant functions of LIN-35 were identified in genetic screens for mutations that display synthetic phenotypes in conjunction with loss of lin-35. To explore the intestinal role of LIN-35, we conducted a genome-wide RNA-interference-feeding screen for suppressors of lin-35; slr-2 early larval arrest. Of the 26 suppressors identified, 17 fall into three functional classes: (1) ribosome biogenesis genes, (2) mitochondrial prohibitins, and (3) chromatin regulators. Further characterization indicates that different categories of suppressors act through distinct molecular mechanisms. We also tested lin-35; slr-2 suppressors, as well as suppressors of the synthetic multivulval phenotype, to determine the spectrum of lin-35-synthetic phenotypes that could be suppressed following inhibition of these genes. We identified 19 genes, most of which are evolutionarily conserved, that can suppress multiple unrelated lin-35-synthetic phenotypes. Our study reveals a network of genes broadly antagonistic to LIN-35 as well as genes specific to the role of LIN-35 in intestinal and vulval development. Suppressors of multiple lin-35 phenotypes may be candidate targets for anticancer therapies. Moreover, screening for suppressors of phenotypically distinct synthetic interactions, which share a common altered gene, may prove to be a novel and effective approach for identifying genes whose activities are most directly relevant to the core functions of the shared gene. PMID- 22542973 TI - Approaches for enhanced phytoextraction of heavy metals. AB - The contamination of the environment with toxic metals has become a worldwide problem. Metal toxicity affects crop yields, soil biomass and fertility. Soils polluted with heavy metals pose a serious health hazard to humans as well as plants and animals, and often requires soil remediation practices. Phytoextraction refers to the uptake of contaminants from soil or water by plant roots and their translocation to any harvestable plant part. Phytoextraction has the potential to remove contaminants and promote long-term cleanup of soil or wastewater. The success of phytoextraction as a potential environmental cleanup technology depends on factors like metal availability for uptake, as well as plants ability to absorb and accumulate metals in aerial parts. Efforts are ongoing to understand the genetics and biochemistry of metal uptake, transport and storage in hyperaccumulator plants so as to be able to develop transgenic plants with improved phytoremediation capability. Many plant species are being investigated to determine their usefulness for phytoextraction, especially high biomass crops. The present review aims to give an updated version of information available with respect to metal tolerance and accumulation mechanisms in plants, as well as on the environmental and genetic factors affecting heavy metal uptake. The genetic tools of classical breeding and genetic engineering have opened the door to creation of 'remediation' cultivars. An overview is presented on the possible strategies for developing novel genotypes with increased metal accumulation and tolerance to toxicity. PMID- 22542974 TI - Infusion of calcium and magnesium for oxaliplatin-induced sensory neurotoxicity in colorectal cancer: a systematic review and meta-analysis. AB - BACKGROUND: It is hypothesised that infusion of calcium and magnesium (Ca/Mg) can reduce the occurrence of oxaliplatin-related sensory neurotoxicity. However, more recent data have drawn a controversial picture concerning this topic. METHODS: A comprehensive literature search was performed using Medline, Embase, Cochrane Library and Google Scholar database up to 1st August 2011. Keywords for the search were: calcium, magnesium and oxaliplatin. The odd ratio (OR) for neurotoxicity and relative risk (RR) for tumour response rate were calculated. RESULTS: Seven studies (four randomised controlled trials (RCTs) and three cohorts) including a total of 1238 participants met our criteria. Meta-analysis of three RCT studies that reported in National Cancer Institute-Common Toxicity Criteria (NCE-CTC) showed that OR for neurotoxicity of Grade ~2 was not significant (OR 0.47; 95%confidence interval (CI) 0.22-1.00, P homogeneity = .729). The OR was also not significant in All Grades (OR 3.15, 0.32-31.35, P homogeneity = .952) and Grade 3 subgroup (OR 1.64, 0.30-9.00, P homogeneity = .656). No statistically significant difference was observed in RR for tumour response rate. (RR = 0.91, 0.78-1.06, P homogeneity = .33) CONCLUSIONS: This meta analysis does not support the hypothesis that infusion of Ca/Mg reduces the occurrence of neurotoxicity in oxaliplatin-treated patients with colorectal cancer measuring with NCE-CTC criteria. On the other hand, our results support the hypothesis that administrations of Ca/Mg do not impair the efficacy of oxaliplatin-based chemotherapy. However, large-scale randomised, controlled clinical trials will be required to confirm these hypotheses. PMID- 22542975 TI - Bovine herpesvirus-1 VP8 interacts with DNA damage binding protein-1 (DDB1) and is monoubiquitinated during infection. AB - VP8 is the most abundant tegument protein of bovine herpesvirus-1 (BHV-1). In the present study DNA damage binding protein 1 (DDB1) was identified as interacting partner of VP8. MALDI-TOF mass spectroscopy analysis of proteins co immunoprecipitated with VP8 identified DDB1 as a protein interacting with VP8. The interaction between VP8 and DDB1 was confirmed based on co immunoprecipitation and co-localization in both VP8-transfected and BHV-1 infected cells. DDB1 was distributed both in the nucleus and the cytoplasm with some nuclear speckles prior to BHV-1 infection, became perinuclear by 4h and was predominantly nuclear at 5h post infection, where it co-localized with VP8. In contrast, in cells infected with a U(L)47 deletion mutant DDB1 remained cytoplasmic throughout the course of infection. This suggests that VP8 mediates nuclear re-localization of DDB1. Finally, VP8 was shown to be monoubiquitinated both in VP8-transfected and BHV-1-infected cells. These data suggest that BHV-1 VP8 interacts with DDB1-CUL4 E3 ubiquitin ligase, which correlates to monoubiquitination of this viral protein. PMID- 22542976 TI - Silicon determination in human ventricular whole blood: a possible marker of drowning. AB - This article presents the first results demonstrating that total silicon trace concentration in human ventricular whole blood may be used as a further marker in the diagnosis of drowning. The difference in silicon content between the left and right ventricles was significantly higher for drowning cases than that from individuals who had not drowned. These findings were in full agreement with autoptic responses, supporting silicon as a marker of freshwater drowning. The procedure entails an alkaline microwave-assisted digestion using tetramethylammonium hydroxide (TMAH) in the presence of H(2)O(2) followed by dynamic reaction cell inductively coupled plasma mass spectrometry (DRC-ICP-MS) detection, whose accuracy was obtained for Seronorm whole blood reference material. Satisfactory recoveries (91-98%) were gained on whole ventricular blood, with a silicon content lower than the method detection limit (MDL), spiked at 5 to 7MUgg(-1) with materials consistent with drowning media constituents, that is, freshwater plankton (CRM [certified reference material] 414), silicon dioxide, diatomaceous earth powder, and a silicon standard solution. Good within lab reproducibility (4-10%) and sensitivity (MDL=0.46MUgg(-1)) were achieved as well. The procedure was applied to blood samples from 18 different real cases of death. PMID- 22542977 TI - Determination of three major catecholamines in human urine by capillary zone electrophoresis with chemiluminescence detection. AB - A sensitive simple method is presented for the determination of three major catecholamines in human urine by capillary electrophoresis (CE) with on-line chemiluminescence (CL) detection. This was also the first time that the luminol Ag(III) complex CL system was used for CE detection. This method was based on the enhancing effect of epinephrine (EP), norepinephrine (NE), and dopamine (DA) on the CL reaction between luminol and the Ag(III) complex in alkaline solution. The separations and determinations were performed with an electrophoretic buffer consisting of 20.0mM sodium borate and 1.0mM luminol. Under optimized conditions, the three catecholamines were baseline separated and detected in less than 8 min. Detection limits of 7.9 * 10(-8)M, 1.0 * 10(-7)M, and 6.9 * 10(-8)M were observed for EP, NE, and DA, respectively. Relative standard deviation (RSD) values for the peak height were 4.7% to 5.4% (n = 5). Our proposed method was applied to the determinations of the catecholamines in urine samples from 12 healthy individuals and 26 pheochromocytoma patients. Our results suggest that this method might be useful to monitor the catecholamine levels in routine screening and to diagnose pheochromocytoma. PMID- 22542978 TI - Rapid affinity measurement of protein-protein interactions in a microfluidic platform. AB - A rapid screening method has been developed to determine binding affinities for protein-ligand interactions using the Gyrolab workstation, a commercial microfluidic platform developed to accurately and precisely quantify proteins in solution. This method was particularly suited for assessing the high-affinity interactions that have become typical of therapeutic antibody-antigen systems. Five different commercially available antibodies that bind digoxin and a digoxin bovine serum albumin (BSA) conjugate with high affinity were rigorously evaluated by this method and by the more conventional kinetic exclusion assay (KinExA) method. Binding parameter values obtained using Gyrolab were similar to those recovered from KinExA. However, the total experimental time for 20 binding affinity titrations, with each titration covering 12 data points in duplicate, took approximately 4h by the Gyrolab method, which reduced the experimental duration by more than 10-fold when compared with the KinExA method. This rapid binding analysis method has significant applications in the screening and affinity ranking selection of antibodies from a very large pool of candidates spanning a wide range of binding affinities from the low pM to MUM range. PMID- 22542980 TI - Are firms' voluntary environmental management activities beneficial for the environment and business? An empirical study focusing on Japanese manufacturing firms. AB - In this paper, to clarify whether a firm's voluntary approach to environmental protection is beneficial for both the environment and business, we analyze whether a firm's voluntary implementation of an environmental management system (EMS) simultaneously reduces its environmental impacts and improves its productivity. Using data on Japanese manufacturing firms for 2002-2008, we find empirical support for the view that the implementation of an EMS simultaneously reduces environmental impacts and improves productivity, and that a reduction in environmental impacts also improves productivity. However, in the context of this relationship, the direct effect of implementing an EMS on productivity is conditional. If various other activities designed to improve productivity implemented in response to market discipline are also taken into account, the effect of implementing an EMS is hidden by the effects of these activities. This implies that voluntary environmental management activities are merely a minor component of these activities. Therefore, the relationship between the implementation of an EMS and productivity improvement is not strong, although implementing an EMS indirectly improves productivity by reducing environmental impacts. PMID- 22542979 TI - Phenylalanine 368 of multidrug resistance-associated protein 4 (MRP4/ABCC4) plays a crucial role in substrate-specific transport activity. AB - Multidrug resistance-associated protein 4 (MRP4) is a membrane transporter that mediates the cellular efflux of a wide range of anionic drugs and endogenous molecules. MRP4 transport can influence the pharmacokinetics of drugs and their metabolites, therefore more knowledge about the molecular determinants important for its transport function would be of relevance. Here, we substituted amino acids Phe(368), Trp(995), and Arg(998) with conservative or non-conservative residues, and determined the effect on transport of the model substrates estradiol 17-beta-d-glucuronide (E(2)17betaG), cyclic guanosine monophosphate (cGMP), methotrexate (MTX), and folic acid into membrane vesicles isolated from baculovirus transduced HEK293 cells overexpressing the mutant MRP4 proteins. This revealed that all Arg(998) mutations appeared to be deleterious, whereas the effect of a Phe(368) or Trp(995) replacement was dependent on the amino acid introduced and the substrate studied. Substitution of Phe(368) with Trp (F368W) induced a gain-of-function of E(2)17betaG transport and a loss-of-function of MTX transport, which could not be attributed to an altered substrate binding. Moreover, we did not observe any modification in ATP or ADP handling for F368W. These results, in combination with docking of substrates in a homology model of MRP4 in the inward- and outward-facing conformation, suggest that Phe(368) and Trp(995) do not play an important role in the initial binding of substrates. They, however, might interact with the substrates during rearrangement of helixes for substrate translocation, funneling the substrates to the exit site in the outward-facing conformation. PMID- 22542981 TI - Recovery and safer disposal of phosphate coating sludge by solidification/stabilization. AB - Solidification/stabilization (S/S) of automotive phosphate coating sludge (PS) containing potentially toxic heavy metals was studied. The hazardous characteristics of this waste were assessed according to both Turkish and U.S. Environmental Protection Agency (EPA) regulations for hazardous solid waste. Unconfined compressive strength (UCS) and leaching behavior tests of the solidified/stabilized product were performed. Solidification studies were conducted using Portland cement (PC) as the binder. UCS was found to decrease with increasing waste content. It was found that recovery of the waste for construction applications was possible when the waste content of the mortar was 20% and below, but solidification for safe disposal was achieved only when higher waste concentrations were added. Cu, Cr, Ni, Pb and Zn were found to be significantly immobilized by the solidification/stabilization process. Ni and Zn, which were present at particularly high concentrations (2.281 and 135.318 g/kg respectively) in the PS, had highest the retention levels (94.87% and 98.74%, respectively) in the PC mortars. The organic contaminants and heavy metals present in PS were determined to be immobilized by the S/S process in accordance with the BS 6920 standard. Thus, the potential for hazardous PS waste to adversely impact human health and the environment was effectively eliminated by the S/S procedure. We conclude that S/S-treated PS is safe for disposal in landfills, while recovery of S/S-treated PS constituents remains possible. PMID- 22542982 TI - Flexible operation of the Cap-and-Trade System for the air pollutants in the Seoul Metropolitan area. AB - To improve the air quality in the Seoul Metropolitan area (SMA), the Korean government has implemented special measures in the 1990s. As part of these measures, the Cap-and-Trade System (CATS) was introduced and executed in July 1, 2007 for the oxides of nitrogen (NOx) and sulfur (SOx) to provide added flexibility for large sources to meet the required emission reductions. However, the trade via the SMA CATS for the air pollutants has not been active because of the limited buyers and sellers within the system as well as limited tradable species. For more flexible operation of the SMA CATS, following strategies have been suggested and their merits are discussed; (1) to link the SMA CATS with the Korea Voluntary Emission Reduction (KVER) program which is a program to manage greenhouse gases (GHGs), and (2) to extend the system, such as extension of the tradable species, participants, and introducing a project-based certification mechanism for pollutants reduction. PMID- 22542983 TI - Efficacy of tranexamic acid on blood loss after primary cementless total hip replacement with rivaroxaban thromboprophylaxis: A case-control study in 70 patients. AB - INTRODUCTION: Perioperative blood loss is a frequent cause of complications in total hip replacement (THR). The present prospective study assessed the efficacy of tranexamic acid (Exacyl((r))) in reducing blood loss in primary THR associated to rivaroxaban (Xarelto((r))) thromboprophylaxis. HYPOTHESIS: Tranexamic acid associated to rivaroxaban reduces blood loss. MATERIAL AND METHOD: A prospective case-control study included 70 primary cementless THRs performed by a single surgeon on a standardized technique, between September 2009 and September 2010. Thirty-seven patients received perioperative tranexamic acid; all patients received rivaroxaban thromboprophylaxis. RESULTS: There was no significant difference between the two groups in terms of peroperative blood-loss volume or rates of thromboembolic or ischemic events or hematoma. Postoperative blood loss, D0-5 differential hemoglobinemia and real blood loss (in mL 100% hematocrit) were significantly lower in the tranexamic acid group. No transfusions were required in the tranexamic acid group, versus four in the control group. DISCUSSION: Tranexamic acid associated to direct anti-Xa (antithrombin-independent) oral anticoagulants was effective in reducing postoperative blood loss, improving hemoglobinemia at 5 days and reducing transfusion rates. The results also confirmed the efficacy of and tolerance for rivaroxaban thromboprophylaxis in primary THR, with no clinical thrombotic events induced by the association of tranexamic acid with rivaroxaban. CONCLUSIONS: Tranexamic acid is a simple means of reducing postoperative blood loss in THR, without increased risk of thromboembolism when associated to rivaroxaban thromboprophylaxis. LEVEL OF EVIDENCE: Level III prospective case-control study. PMID- 22542984 TI - The role of pro- and anti-inflammatory cytokines in the pathogenesis of spontaneous canine CNS diseases. AB - Dogs are comparatively frequently affected by various spontaneously occurring inflammatory and degenerative central nervous system (CNS) conditions, and immunopathological processes are a hallmark of the associated neuropathology. Due to the low regenerative capacity of the CNS a sophisticated understanding of the underlying molecular basis for disease initiation, progression and remission in canine CNS diseases represents a prerequisite for the development of novel therapeutical approaches. In addition, as many spontaneous canine CNS diseases share striking similarities with their human counterpart, knowledge about the immune pathogenesis may in part be translated for a better understanding of certain human diseases. In addition to cytokine-driven differentiation of peripheral leukocytes including different subsets of T cells recent research suggests a pivotal role of these mediators also in phenotype polarization of resident glial cells. Cytokines thus represent the key mediators of the local and systemic immune response in CNS diseases and their orchestration significantly decides on either lesion progression or remission. The aim of the present review is to summarize the growing number of data focusing on the molecular basis of the immune response during spontaneous canine CNS diseases and to detail the effect of cytokines on the immune pathogenesis of selected idiopathic, infectious, and traumatic canine CNS diseases. Steroid-responsive meningitis arteritis (SRMA) represents a unique idiopathic disease of leptomeningeal blood vessels characterized by excessive IgA secretion into the cerebrospinal fluid. Recent reports have given sophisticated insights into the cytokine-driven, immune mediated pathogenesis of SRMA that is characterized by a biased T helper 2 cell response. Canine distemper associated leukoencephalitis represents an important spontaneously occurring disease that allows investigations on the basic pathogenesis of immune-mediated myelin loss. It is characterized by an early virus-induced up-regulation of pro-inflammatory cytokines with chronic bystander immune-mediated demyelinating processes. Lastly, canine spinal cord injury (SCI) shares many similarities with the human counterpart and most commonly results from intervertebral disk disease. The knowledge of its pathogenesis is largely restricted to experimental studies in rodents, and the impact of immune processes that accompany secondary injury is discussed controversially. Recent investigations on canine SCI highlight the pivotal role of pro-inflammatory cytokine expression that is paralleled by a dominating reaction of microglia/macrophages potentially indicating a polarization of these immune cells into a neurotoxic and harmful phenotype. This report will review the role of cytokines in the immune processes of the mentioned representative canine CNS diseases and highlight the importance of cytokine/cytokine interaction as a useful therapeutic target in canine CNS diseases. PMID- 22542985 TI - Lower levels of cannabinoid 1 receptor mRNA in female eating disorder patients: association with wrist cutting as impulsive self-injurious behavior. AB - The cannabinoid 1 (CB 1) receptor as the primary mediator of the endocannabinoid (EC) system was found to play a role in eating disorders (EDs), depression, anxiety, and suicidal behavior. The CB 1 receptor is assumed to play a crucial role in the central reward circuitry with impact on body weight and personality traits like novelty-seeking behavior. In a previous study we found higher levels of CB 1 receptor mRNA in patients with anorexia nervosa (AN) and bulimia nervosa (BN) compared to healthy control women (HCW). The aim of the present study was to investigate the possible influence of the EC and the CB 1 receptor system on wrist cutting as self-injurious behavior (SIB) in women with EDs (n=43; AN: n=20; BN: n=23). Nine ED patients with repetitive wrist cutting (AN, n=4; BN, n=5) were compared to 34 ED patients without wrist cutting and 26 HCW. Levels of CB 1 receptor mRNA were determined in peripheral blood samples using quantitative real time PCR. ED patients with self-injurious wrist cutting exhibited significantly lower CB 1 receptor mRNA levels compared with ED patients without wrist cutting and HCW. No significant differences were found between ED patients without a history of wrist cutting and HCW. Furthermore, a negative association was detected between CB 1 receptor mRNA levels and Beck Depression Inventory (BDI) scores. To our knowledge, this is the first study reporting a down-regulation of CB 1 receptor mRNA in patients with EDs and wrist cutting as SIB. Due to the small sample size, our results should be regarded as preliminary and further studies are warranted to reveal the underlying mechanisms. PMID- 22542986 TI - Difficulties experienced by nurses in older patient care and their attitudes toward the older patients. AB - BACKGROUND: There is little known about nurses' attitudes toward older people in Turkish society, particularly within centers providing care to older patients. OBJECTIVE: This research was conducted to determine nurses' attitudes toward older patient care and the difficulties they experience. DESIGN: A descriptive research design was used. SETTINGS: The research population comprised 282 nurses working in the clinics of public hospitals in central Erzurum that mostly accommodate older patients. METHODS: Participants completed questionnaires regarding descriptive characteristics, the type of difficulties they experienced in older patient care, and the Turkish version of Kogan's Attitudes Toward Old People Scale. Data were evaluated by using percentage, Kruskal-Wallis variance analysis, t test and Mann-Whitney U test. RESULTS: The study revealed that nurses experienced difficulties due to the inadequacy of physical conditions and technical equipment in hospitals; administrative problems; communication problems; and insufficient knowledge, skills and experience in older patient care. The nurses' overall attitude toward the older people was found to be positive (98.83 +/- 11.19). CONCLUSIONS: The difficulties experienced by nurses in this sample resulted from the lack of technically equipped hospitals or clinics for older patients and the inadequacy of nurses' gerontology education. Despite these factors, the nurses' attitude toward older people was positive. PMID- 22542987 TI - Occurrence and genotype of Giardia cysts isolated from faecal samples of children and dogs and from drinking water samples in an aboriginal area of central Taiwan. AB - To investigate some aspects of Giardia infection, we performed a cross-sectional study on schoolchildren from an aboriginal area of Nantou County in central Taiwan. Faecal samples from 209 participants and samples of dog faeces and of water from mountain springs found in the area were collected. The participants also filled a questionnaire pertaining to demographic data. Giardia duodenalis was detected in eight of the 209 participants, and all positive isolates belonged to assemblage A. In addition, assemblage A isolates were obtained from four of the 22 water samples, and assemblage C or D isolates were obtained from four of the 42 canine faecal samples. Our results suggest that the risk of Giardia transmission is greater from waterborne than canine transmission in this study area. PMID- 22542988 TI - Oocyst shedding in cats vaccinated by the nasal and rectal routes with crude rhoptry proteins of Toxoplasma gondii. AB - During this study, cats were immunized by the intranasal and rectal routes with crude rhoptry proteins of Toxoplasma gondii admixed with Quil-A. Twenty-five domestic short hair cats divided into five groups (n=5) were used during this evaluation: G1 and G3 cats received 200 MUg of the rhoptry proteins with Quil-A (20 MUg) by the intranasal and rectal routes, respectively; G2 and G4 cats received bovine serum albumin (BSA, 200 MUg/dose) with Quil-A (20 MUg); and G5 animals served as unvaccinated controls. All treatments were performed at days 0, 21, 42, and 63. The challenge was done with 800 cysts of the ME49 of T. gondii strain at day 70 (challenge day). The serum IgG, IgM, IgA, and fecal IgA antibody levels were evaluated by using the indirect enzyme-linked immunosorbent assay (ELISA). Some animals produced antibody levels beyond cut-off; however, two animals from G1 (OD(mean)=0.308, OD(cut-off)=0.200) and three from G3 (OD(mean)=0.254) demonstrated IgG levels on being challenged, with similar results occurring in two cats from G1 to IgM (OD(mean)=0.279, OD(cut-off)=0.200). Fecal IgA levels were detected in all G1 cats (OD(mean)=0.330, OD(cut off)=0.065), and in one cat from G3 (OD(mean)=0.167). The serum and fecal humoral immune responses did not correlate with oocyst shedding. Oocyst shedding varied from 98.4% (G1), 87.5% (G2), 53.0% (G3), to 58% (G4), and was lower than that of G5 cats. The prepatent period of cats vaccinated intranasally (G1) was reduced from 6-9.6 to 2.8 days, suggesting protection of environmental contamination, considering cats as the primary source of contamination. The intranasally and rectally administered rhoptry vaccines were able to partially protect cats against T. gondii cysts on being challenged; however, the intranasal method of vaccination yielded better results relative to the rectal route. PMID- 22542989 TI - Peritoneal cytokines and adhesion formation in endometriosis: an inverse association with vascular endothelial growth factor concentration. AB - OBJECTIVE: To evaluate inflammatory/angiogenic cytokines-interleukin-1beta (IL 1beta), IL-6, IL-8, IL-12, interferon-gamma (IFN-gamma), tumor necrosis factor (TNF), and vascular endothelial growth factor A (VEGF-A)-in the peritoneal fluid of patients with endometriosis in relation to the occurrence and severity of pelvic adhesions and in control women without pelvic pathology. DESIGN: Case control study. SETTING: University research institution and hospital. PATIENT(S): Sixty-five women with laparoscopically and histopathologically confirmed endometriosis, including 40 women with pelvic adhesions, and 37 control women without pelvic pathology. INTERVENTION(S): Peritoneal fluid aspirated during routine diagnostic laparoscopic examination. MAIN OUTCOME MEASURE(S): Cytokines evaluated in the peritoneal fluid via specific enzyme-linked immunosorbent assays. RESULT(S): Endometriosis and the revised American Fertility Society score of this disease were associated with statistically significantly increased levels of peritoneal IL-6 and IL-8 whereas the incidence and score of endometriosis related pelvic adhesions were negatively associated with increased levels of VEGF A. Notably, the concentration of VEGF-A predicted adhesion development and severity after adjustment for endometriosis severity. The adhesion score also correlated with increased levels of IL-6; however, after adjustment for endometriosis severity, the effect of this cytokine was no longer statistically significant. CONCLUSION(S): Increased levels of VEGF-A may be associated with a decreased rate of pelvic adhesion formation in the course of endometriosis. PMID- 22542990 TI - Uterus transplantation: animal research and human possibilities. AB - Uterus transplantation research has been conducted toward its introduction in the human as a treatment of absolute uterine-factor infertility, which is considered to be the last frontier to conquer for infertility research. In this review we describe the patient populations that may benefit from uterus transplantation. The animal research on uterus transplantation conducted during the past two decades is summarized, and we describe our views regarding a future research based human attempt. PMID- 22542991 TI - Flavor is in the brain. AB - Flavor is perhaps the most multi-modal of all of our sensory experiences. Here flavor is defined as a perception that includes gustatory, oral-somatosensory, and retronasal olfactory signals that arise from the mouth as foods and beverages are consumed. Although the sights, sounds and smells of foods that occur just before, or in the absence of eating, can impact flavor perception, it is argued that these sensory signals exert their influence by creating expectations based upon prior associations. The primary aim of the paper is to review anatomical and neurophysiological data towards an understanding of how the core sensory signals combine in the central nervous system of humans. Based upon the extant literature it is proposed that taste, oral-somatosensory and olfactory inputs are first integrated in the anterior ventral insula. The core flavor percept is then conveyed to upstream regions in the brainstem and thalamus, as well as downstream regions in the amygdala, orbitofrontal cortex and anterior cingulate cortex to produce the rich flavorful experiences that guide our feeding behavior. PMID- 22542992 TI - Preparation and in vitro evaluation of an ultrasound-triggered drug delivery system: 10-hydroxycamptothecin loaded PLA microbubbles. AB - 10-Hydroxycamptothecin (HCPT) loaded PLA microbubbles, used as an ultrasound triggered drug delivery system, were fabricated by a double emulsion-solvent evaporation method. The obtained microbubbles were characterized by scanning electron microscope (SEM), transmission electron microscope (TEM), X-ray diffraction (XRD), differential scanning calorimetry (DSC) and confocal laser scanning microscope (CLSM). In addition, the effect of diagnostic ultrasound exposure on BEL-7402 cells combined with HCPT-loaded PLA microbubbles was evaluated using cytotoxicity assay, CLSM and flow cytometry (FCM). It was found that the HCPT-loaded PLA microbubbles showed smooth surface and spherical shape, and the drug was amorphously dispersed within the shell and the drug loading content reached up to 1.69%. Nearly 20% of HCPT was released upon exposure to diagnostic ultrasound at frequency of 3.5MHz for 10min. Moreover, HCPT fluorescence in the cells treated only with the HCPT-loaded PLA microbubbles was discernible, but less intense, while those treated with the microbubbles in conjunction with ultrasound exposure was evident and intense, indicating an increased cellular uptake of HCPT by ultrasound exposure. Cytotoxicity test on BEL-7402 cells indicated that the HCPT-loaded PLA microbubbles combined with ultrasound exposure were more cytotoxic than the microbubbles alone. The results suggest that the combination of drug loaded PLA microbubbles and diagnostic ultrasound exposure exhibit an effective intracellular drug uptake by tumor cells, indicating their great potential for antitumor therapy. PMID- 22542994 TI - A novel myotropic peptide from the skin secretions of the tree frog, Polypedates pingbianensis. AB - A novel myotropic peptide, polypedatein, was purified and characterized from the skin secretions of the tree frog, Polypedates pingbianensis. Its primary structure, TLLCKYFAIC, was determined by Edman degradation and mass spectrometry. Polypedatein was subjected to bioassays including myotropic, antimicrobial, and serine protease inhibitory activities, which are related with many amphibian skin bioactive peptides. It was found to elicit concentration-dependent contractile effects on isolated rat ileum. cDNA clones encoding the precursor of polypedatein were isolated by screening a skin cDNA library of P. pingbianensis and then sequenced. The amino acid sequence deduced from the cDNA sequences matches well with the result from Edman degradation. BLAST search revealed that the sequence of polypedatein did not show similarity to known protein or peptide sequences. Especially, polypedatein does not contain conserved structural motifs of other amphibian myotropic peptides, such as bradykinins, bombesins, cholecystokinin (CCK), and tachykinins, indicating that polypedatein belongs to a novel amphibian myotropic peptide family. The signal peptide of the precursor encoding polypedatein shows significant sequence identity to that of other amphibian skin defensive peptides, such as antimicrobial peptides, bradykinins, lectins, and serine protease inhibitors, suggesting that polypedatein belongs to a novel amphibian myotropic peptide family. Polypedatein is also the first bioactive peptide from the genus of the frog, Polypedates. PMID- 22542995 TI - Differences in faecal bacteria populations and faecal bacteria metabolism in healthy adults and celiac disease patients. AB - Differences in the intestinal microbiota between children and adults with celiac disease (CD) have been reported; however, differences between healthy adults and adults with CD have not been clearly demonstrated. The aim of this study was to evaluate the differences in the intestinal microbiota between adults with CD and healthy individuals. Microbial communities in faecal samples were evaluated by PCR-denaturing gradient gel electrophoresis (DGGE) and gas-liquid chromatography of short chain fatty acids (SCFAs). The study group included 10 untreated CD patients, 11 treated CD patients and 11 healthy adults (in normal gluten diet and in GFD). UPGMA clustered the dominant microbial communities of healthy individuals together and separated them from the dominant microbial communities of the untreated CD patients. Most of the dominant microbial communities of the treated CD patients clustered together with those of healthy adults. The treated CD patients showed a reduction in the diversity of Lactobacillus and Bifidobacterium species. The presence of Bifidobacterium bifidum was significantly higher in untreated CD patients than healthy adults. There was a significant difference between untreated CD patients and healthy adults, as well as between treated CD patients and healthy adults, regarding acetic acid, propionic acid, butyric acid, and total SCFAs. IN CONCLUSION: healthy adults have a different faecal microbiota from that of untreated CD patients. A portion of the treated CD patients displayed a restored "normal" microbiota. The treated CD patients significantly reduce the Lactobacillus and Bifidobacterium diversity. Healthy adults have a different faecal SCFAs content from that of CD patients. PMID- 22542996 TI - Putative recombination signature and significance of insertion/deletion events in the RNA-dependent RNA polymerase coding region of sugarcane yellow leaf virus. AB - The 5898 nucleotide single-strand RNA genome of Sugarcane yellow leaf virus (SCYLV) contains one long open reading frame, which is translated into a 120.6 kDa polyprotein. The sequences of SCYLV isolates from the two SCYLV-susceptible cultivars from Hawaii had a deletion of 48-51 nt in ORF1. SCYLV from 12 sugarcane hybrid cultivars from different origins were tested by RT-PCR using a specific set of primers, to investigate the genome segment for this deletion. Only three cultivars were found not to have the deletion (H87-4319, JA-605 and CP52-43), while SCYLV from nine cultivars (H73-6110, H87-4094, H78-7750, GT54-9, G84-47, H78-4153, H65-7052, C1051-73, Ph-8013) along with aphid (Melanaphis sacchari), which fed on SCYLV-infected H73-6110, contained a deletion of about 50 nt. The deleted sequence was located in the overlap frameshift of ORF1 and ORF2. Thus, ORFs 1 and 2 of SCYLV are translated via ribosomal frameshift and yield the 120.6 kDa viral replicase. ORF1 plays most likely a role in the replication and is a source of large variability among the virus population. To identify possible recombination events located in the RdRp domain of the Hawaiian isolates, two programs were used: RDP v.4.3 and RECCO. It is noteworthy that according both methods Haw73-6110 was found as a potential recombinant. On the other hand, opposed to the RDP package, RECCO revealed that Haw87-4094 isolate was also a recombinant whereas Haw87-4319 was not. PMID- 22542993 TI - Quantitative fMRI and oxidative neuroenergetics. AB - The discovery of functional magnetic resonance imaging (fMRI) has greatly impacted neuroscience. The blood oxygenation level-dependent (BOLD) signal, using deoxyhemoglobin as an endogenous paramagnetic contrast agent, exposes regions of interest in task-based and resting-state paradigms. However the BOLD contrast is at best a partial measure of neuronal activity, because the functional maps obtained by differencing or correlations ignore the total neuronal activity in the baseline state. Here we describe how studies of brain energy metabolism at Yale, especially with (13)C magnetic resonance spectroscopy and related techniques, contributed to development of quantitative functional brain imaging with fMRI by providing a reliable measurement of baseline energy. This narrative takes us on a journey, from molecules to mind, with illuminating insights about neuronal-glial activities in relation to energy demand of synaptic activity. These results, along with key contributions from laboratories worldwide, comprise the energetic basis for quantitative interpretation of fMRI data. PMID- 22542997 TI - A novel endoribonuclease from the marine sponge Tethya aurantium specific to 2',5'-phosphodiester bonds. AB - In the marine sponge Tethya aurantium a novel endoribonuclease was found which specifically catalyzed the degradation of 2',5'-phosphodiester linkages and was therefore named endo-2',5'-ribonuclease. This enzymatic reaction yielded 2',3' cyclic phosphate and 5'-OH products similarly to the 3'-5' bond cleavage in RNA, catalyzed by metal-independent ribonucleases. The partially purified enzyme preparation was used for its biochemical characterization. The enzyme did not require the presence of metal ions for its activity. The novel nuclease exhibited a preference for 5'-phosphorylated 2',5'-oligoadenylates, but 2'-5' linkage in 5' triphosphorylated hetero-oligomers or homo-dimers comprising guanylate or uridylate residues instead of adenylate was cleaved as well. The enzyme was also able to catalyze the degradation of 5'-unphosphorylated 2',5'-oligoadenylates, except for 2',5'-diadenylate, which were weaker substrates for the enzyme than the respective 5'-triphosphorylated forms. The observed substrate specificity may refer to the specific role of the enzyme in the degradation of natural 2',5' oligoadenylates (2-5A) that function in the interferon-induced mammalian 2-5A system as allosteric regulators of ribonuclease L. They are produced by 2-5A synthetases (OAS) that are also present in sponges, the most ancient phylum of Metazoa. We suggest that the newly discovered endoribonuclease found in the marine sponge T. aurantium could be a representative of the group of 2',5' specific ribonucleases that primarily control the cellular levels of 2',5' oligoadenylates. PMID- 22542998 TI - Magnetic source imaging in non-lesional neocortical epilepsy: additional value and comparison with ICEEG. AB - OBJECTIVE: To investigate the utility of magnetic source imaging (MSI) for localizing the epileptogenic zone (EZ) and predicting epilepsy surgery outcome in non-lesional neocortical focal epilepsy (NLNE) patients. METHODS: Data from 18 consecutive patients with NLNE who underwent presurgical evaluation including intracranial electroencephalography (ICEEG) and MSI were studied. Follow-up after epilepsy surgery was >=24 months. Intracranial electroencephalography and MSI results were classified using a sublobar classification. RESULTS: Sublobar ICEEG focus was completely resected in 15 patients; seizure-free rate was 60%. Eight patients showed sublobar-concordant ICEEG/MSI results and complete resection of both regions; seizure-free rate was 87.5%. Seizure-free rate in cases not matching these criteria was only 30% (p=0.013). CONCLUSIONS: Magnetoencephalography is a useful tool to localize the EZ and determine the site of surgical resection in NLNE patients. When sublobar concordance with ICEEG is observed, MSI increases the predictive value for a seizure-free epilepsy surgery outcome in these patients. PMID- 22542999 TI - Sutton's law in epilepsy: because that is where the lesion is. AB - Successful epilepsy surgery requires unambiguous identification of the epileptogenic zone. This determination may be a challenge when the pre-surgical evaluation yields conflicting data. We evaluated an adult patient with a right insular mass, but a seizure semiology, interictal EEG, and ictal EEG, suggesting left temporal lobe epilepsy. Resection of the mass, a ganglioglioma, resulted in seizure freedom and disappearance of interictal left temporal lobe epileptiform discharges. This case illustrates the principle that in localization-related epilepsy, the money is usually in the mass. PMID- 22543000 TI - Breast cancer genetic counseling after diagnosis but before treatment: a pilot study on treatment consequences and psychological impact. AB - OBJECTIVE: Female breast cancer patients carrying a BRCA1/2-mutation have an increased risk of second primary breast and ovarian tumors. Little is known about the psychological impact and treatment consequences of rapid genetic counseling and testing offered between breast cancer diagnosis and surgery. METHODS: Female breast cancer patients, who had received rapid genetic counseling (and optional testing) (RGC(T)) at The Netherlands Cancer Institute between 2004 and 2008, received a questionnaire in 2009. RESULTS: BRCA-mutations were found in 10 of the 26 participants. Six mutation-carriers (60%) had an immediate bilateral mastectomy, compared with 25% of those without a mutation. Five patients (19%) reported having frequent worries about cancer recurrence; none indicated that such worries impaired daily functioning. Six patients had clinically relevant levels of breast cancer-specific distress at the time of assessment. CONCLUSION: These results suggest that RGC(T) in high-risk breast cancer patients may influence surgical treatment, without causing long-term psychosocial distress in the majority. PRACTICE IMPLICATIONS: These results are important, since rapid genetic counseling and testing are expected to be offered to newly diagnosed breast cancer patients with increasing frequency in order to inform these women and their surgeons about the possible familial/hereditary nature of their disease before deciding on treatment. PMID- 22543001 TI - Development of PRIDe: a tool to assess physicians' preference of role in clinical decision making. AB - OBJECTIVE: To develop and evaluate items for inclusion in PRIDe (Preferred Role in Decision Making), a new tool to assess changes of role preference among professionals exposed to training in shared decision making (SDM). METHODS: This study was part of a pilot trial to evaluate the effectiveness of SDM training on the doctors' prescription of antibiotics for acute respiratory infections. Thirty nine family physicians were randomized to immediate exposure to training or to delayed exposure. Potential items for PRIDe and a questionnaire about physicians' intention to engage in SDM were administered at baseline and at follow-up. RESULTS: Following analysis, we retained five items that captured a change in physicians' preference. The items' scores were pooled and the resulting tool showed limited internal consistency (Cronbach's alpha = 0.41) but significant test-retest reliability (immediate group: P = 0.03; delayed group: P = 0.008) and acceptable discriminant validity, with patients involved in decision making more actively after training than before (Fisher's test, P = .02). CONCLUSION: This initial step to develop an evaluation tool to assess changes in doctors' preference of role in decision making following SDM training shows promising results. The next step is to develop more clinical vignettes followed by questions inspired from this analysis. PRACTICE IMPLICATIONS: The PRIDe instrument can be used in the assessment of health professionals' attitude towards shared decision making after training in shared decision making. Additional research is needed to evaluate its validity before it can be recommended for use. PMID- 22543002 TI - A research strategy to discover the environmental causes of autism and neurodevelopmental disabilities. PMID- 22543003 TI - Bone marrow-derived cells from the footprint infiltrate into the repaired rotator cuff. AB - BACKGROUND: Cells from the bone marrow are considered important during the rotator cuff repair process, but the kinetics of bone marrow-derived cells in this process is unknown. PURPOSE: To analyze the kinetics of bone marrow cells during the rotator cuff repair process, to review whether or not they are histologically involved in rotator cuff healing, and to analyze the biomechanics of the repaired tissues. METHODS: Bone marrow chimeric rats that express green fluorescent protein (GFP) only in bone marrow- and circulation-derived cells were created. Bilateral supraspinatus tendons were separated from the greater tuberosity of the humeral head to produce a rotator cuff transection model. Drilling into the bone marrow was performed in the greater tuberosity of the right humerus and the supraspinatus tendon was repaired (drilling group), while the supraspinatus tendon was repaired on the left shoulder without drilling (control group). We examined the histology of the rotator cuff, the ultimate force-to-failure, and the proportion of GFP-positive cells in the repaired rotator cuff at 2, 4 and 8 weeks after surgery. RESULTS: Mesenchymal cells were observed in the repaired rotator cuff at 2 weeks in both groups. There were more GFP-positive cells in the drilling group than the control group at 2, 4 and 8 weeks. The ultimate force-to-failure was significantly higher in the drilling group than the control group at 4 and 8 weeks. CONCLUSION: Bone marrow-derived cells passed through holes drilled in the humerus footprint, infiltrated the repaired rotator cuff and contributed to postsurgical rotator cuff healing. PMID- 22543004 TI - EST-based identification of immune-relevant genes from spleen of Indian catfish, Clarias batrachus (Linnaeus, 1758). AB - A normalized cDNA library from spleen of Indian catfish, Clarias batrachus, was constructed with a redundancy factor of 2.29. A total of 2045 clones from the library were single-pass sequenced, which generated 1937 high quality ESTs with an average read length of approximately 700 bp. Based on sequence similarities, 65 ESTs were found to be associated with immune functions, which were mainly associated with response to stress, response to chemical stimulus, cellular response to stimulus, response to external stimulus, immune response and regulation of response to stimulus. The immune-relevant gene for CD141, thrombomodulin, has been identified in Teleosts for the first time. Six EST-SSRs and three SNPs were found associated with eight immune-relevant genes. These markers associated with important immune genes would be useful for the identification of trait associated alleles for marker-assisted selection. The identification of the putative immune-related genes provides a meaningful framework to understand the Indian catfish immune system and defense mechanisms. PMID- 22543005 TI - Folate-PEG-superparamagnetic iron oxide nanoparticles for lung cancer imaging. AB - While superparamagnetic iron oxide nanoparticles (SPIONs) have been widely used in biomedical applications, rapid blood clearance, instability and active targeting of the SPIONs limit their availability for clinical trials. This work was aimed at developing stable and lung cancer targeted SPIONs. For this purpose firstly folic acid (FA)-conjugated poly(ethylene glycol) (FA-PEG) was synthesized, and FA-PEG-SPIONs were subsequently prepared by the reaction of FA PEG with aminosilane-immobilized SPIONs. FA-PEG-SPIONs were labeled with Cy5.5 for optical imaging. The intracellular uptake of FA-PEG-SPIONs-Cy5.5 was evaluated in KB cells and lung cancer model mice to confirm active targeting. The sizes of the FA-PEG-SPIONs were little changed after up to 8 weeks at 4 degrees C, suggestive of very stable particle sizes. The results of fluorescent flow cytometry and confocal laser scanning microscopy suggest that the intracellular uptake of FA-PEG-SPIONs-Cy5.5 was greatly inhibited by pre-treatment with free folic acid, indicative of receptor-mediated endocytosis. Stronger optical imaging was observed in the lung cancer model mice for FA-PEG-SPIONs-Cy5.5 than PEG SPIONs-Cy5.5 6 and 24 h post-injection through the tail vein, due to receptor mediated endocytosis. PMID- 22543006 TI - Comparative study of osteogenic potential of a composite scaffold incorporating either endogenous bone morphogenetic protein-2 or exogenous phytomolecule icaritin: an in vitro efficacy study. AB - A local delivery system with sustained and efficient release of therapeutic agents from an appropriate carrier is desirable for orthopedic applications. Novel composite scaffolds made of poly (lactic-co-glycolic acid) with tricalcium phosphate (PLGA/TCP) were fabricated by an advanced low-temperature rapid prototyping technique, which incorporated either endogenous bone morphogenetic protein-2 (BMP-2) (PLGA/TCP/BMP-2) or phytomolecule icaritin (ICT) (PLGA/TCP/ICT) at low, middle and high doses. PLGA/TCP served as control. In vitro degradation, osteogenesis and release tests showed statistical differences among PLGA/TCP/ICT, PLGA/TCP and PLGA/TCP/BMP-2 groups, where PLGA/TCP/ICT had the desired slow release of bioactive icaritin in a dose-dependent manner, whereas there was almost no BMP-2 release from the PLGA/TCP/BMP-2 scaffolds. PLGA/TCP/ICT significantly increased more ALP activity, upregulated mRNA expression of osteogenic genes and enhanced calcium deposition and mineralization in rabbit bone marrow stem cells cultured on scaffolds compared with the other two groups. These results indicate the desired degradation rate, osteogenic capability and release property in PLGA/TCP/ICT composite scaffold, as icaritin preserved its bioactivity and structure after incorporation, while PLGA/TCP/BMP-2 did not show an initially expected osteogenic potential, owing to loss of the original bioactivity of BMP-2 during its incorporation and fabrication procedure. The results suggest that PLGA/TCP composite scaffolds incorporating osteogenic ICT might be a promising approach for bone tissue bioengineering and regeneration. PMID- 22543007 TI - Cross sectional and longitudinal surveys of canine enteric coronavirus infection in kennelled dogs: a molecular marker for biosecurity. AB - Previous studies have suggested that kennelled dogs are more likely to test positive for CECoV than household pets. Here we describe both cross sectional and longitudinal studies in two rescue kennels and two boarding kennels, together with molecular diagnostics, to provide a new insight into the epidemiology of CECoV. Prevalence of CECoV in the cross sectional studies tended to be higher in the rescue kennels (13.8% and 33.3%) than the boarding kennels (5.3% and 13.5%). In each kennel, type I CECoV was more prevalent than type 2 CECoV. The mean quantity of type I detected was equivalent to 6.3 * 10(8)gc/gm (range=5 * 10(6), 8.5 * 10(11)), compared to 1.3 * 10(8)gc/gm (range = 3 * 10(6), 2.4 * 10(10)) for type II. In one rescue shelter where dogs were followed longitudinally, infection was significantly associated with accommodation block as well as the length of stay (increased risk of CECoV per week in residence of * 1.9). Of those animals sampled on two or more occasions, none tested positive on arrival, and 54.5% later shed CECoV, suggesting that infection may have been acquired within the kennel. Shedding patterns and sequence analysis suggested both types I and II CECoV were maintained in this population by a combination of introductions into the shelter and within-shelter transmission. The findings suggest that some kennel environments may be important in maintaining CECoV infection in the population. We also propose that the diversity of viruses like CECoV in these populations may provide a novel surrogate marker for the success of biosecurity. PMID- 22543011 TI - Maternal deprivation in the middle of a stress hyporesponsive period decreases hippocampal calcineurin expression and causes abnormal social and cognitive behaviours in adult male Wistar rats: relevance to negative symptoms of schizophrenia. AB - Adverse experiences in early life profoundly influence the developing nervous, endocrine, and immune systems, and also affect human behaviour during adult life and are considered in the pathogenesis of psychiatric disorders. Numerous studies have provided evidence that maternal deprivation in the middle of a stress hyporesponsive period (SHRP) causes multiple behavioural and physiological abnormalities that mimic positive symptoms of schizophrenia in humans. To investigate the neurochemical characteristics of maternal deprivation in the middle of the SHRP in the context of a possible animal model of the symptoms of schizophrenia, we examined calcineurin expression in the hippocampus of maternally deprived rats. To investigate other behavioural characteristics, we behaviourally phenotyped the rats by applying a comprehensive behavioural test battery. The results indicate that maternal deprivation in the middle of the SHRP has no effects on general health, neurological reflexes, sensory function, or motor function, but does have sex-specific effects on a type of anxiety-related behaviour in the open field test and male-specific effects on hippocampal calcineurin expression, social behaviour, and objective memory function. An interpretation of our results and previous studies in the context of the neurodevelopmental hypothesis of schizophrenia suggests that maternal deprivation in the middle of the SHRP in rats models some positive and negative aspects of schizophrenia. The findings regarding the sex-specific effects of maternal deprivation in the middle of the SHRP may become a strong tool for investigating sex differences in the pathogenesis and pathology of schizophrenia in humans. PMID- 22543008 TI - TcBat a bat-exclusive lineage of Trypanosoma cruzi in the Panama Canal Zone, with comments on its classification and the use of the 18S rRNA gene for lineage identification. AB - We report TcBat, a recently described genetic lineage of Trypanosoma cruzi, in fruit-eating bats Artibeus from Panama. Infections were common (11.6% prevalence), but no other T. cruzi cruzi genotypes were detected. Phylogenetic analyses show an unambiguous association with Brazilian TcBat, but raise questions about the phylogenetic placement of this genotype using the 18S rRNA gene alone. However, analyses with three concatenated genes (18S rRNA, cytb, and H2B) moderately support TcBat as sister to the discrete typing unit (DTU) TcI. We demonstrate that short fragments (>500 bp) of the 18S rRNA gene are useful for identification of DTUs of T. cruzi, and provide reliable phylogenetic signal as long as they are analyzed within a matrix with reference taxa containing additional informative genes. TcBat forms a very distinctive monophyletic group that may be recognized as an additional DTU within T. cruzi cruzi. PMID- 22543012 TI - In situ forming implants - an attractive formulation principle for parenteral depot formulations. AB - In the area of parenteral controlled release formulations, in situ forming implants (ISFI) are attractive alternatives to preformed implants and microparticles. ISFI avoid the use of large needles or microsurgery and they can be manufactured in simple steps with a low requirement of equipment and processes. They are injected as low viscous solutions and transform in the body to a gel or solid depot. Different triggers can be used to stimulate this transformation: (1) in situ cross-linking, (2) in situ solidifying organogels, and (3) in situ phase separation. The review discusses the principles and the pros and cons of each strategy. It also gives examples of clinically used products or systems which are currently in clinical trials. Although the principle of ISFI is so attractive, key issues remain to be solved. They include (i) variability of the implant shape and structure, (ii) avoidance of burst release during implant formation, and (iii) toxicity issues. Unfortunately, until now our knowledge concerning the detailed processes of the implant formation is still very limited. This is due to the fact that the processes of implant formation and degradation, drug release and tissue response are complex, heterogeneous, interconnected and not easy to follow, especially in vivo. Despite this statement, many efforts are made in industry and academia to improve current approaches. New materials and approaches enter the preclinical and clinical phases and one can be sure, that ISFI will gain further clinical importance within the next years. PMID- 22543013 TI - Hydrotropic magnetic micelles for combined magnetic resonance imaging and cancer therapy. AB - Polymeric nanoparticles, capable of encapsulating imaging agents and therapeutic drugs, have significant advantages for simultaneous diagnosis and therapy. Nonetheless, improvements in the loading contents of the active agents are needed to achieve enhanced imaging and effective therapeutic outcomes. Aiming to make these improvements, a hydrotropic micelle (HM) was explored to encapsulate superparamagnetic iron oxide nanoparticles (SPIONs) as the magnetic resonance (MR) imaging agent and paclitaxel (PTX) as the hydrophobic anticancer drug. Owing to its hydrotropic inner core with hydrophobic nature, HM could effectively encapsulate both of PTX and SPION via the simple dialysis method. The hydrodynamic size of HM increased from 68 to 178nm after physical encapsulation of SPION and PTX. Transmission electron microscopy analysis of HM bearing SPION and PTX (HM-SPION-PTX) revealed a spherical morphology with SPION clusters in the micelle cores. The micelles released PTX in a sustained manner. The bare HM and HM-SPION showed no toxicity to SCC7 cells, whereas HM-PTX and HM-SPION-PTX showed dose-dependent cytotoxicity that was lower than free PTX. HM-SPION-PTX exhibited 8.1-fold higher T(2) relaxivity than HM-SPION, implying potential of HM-SPION-PTX as the contrast agent for MR imaging. When systemically administered to tumor bearing mice, HM-SPION-PTX was effectively accumulated at the tumor site, allowing its detection using MR imaging and effective therapy. Overall, these results suggested that HM-SPION-PTX is a promising candidate for combined diagnosis and treatment of cancer. PMID- 22543014 TI - Anti-fibrotic cardio protective efficacy of aminoguanidine against streptozotocin induced cardiac fibrosis and high glucose induced collagen up regulation in cardiac fibroblasts. AB - This study mainly focuses on cardio protective anti-fibrotic activity of aminoguanidine against streptozotocin induced cardiac fibrosis and high glucose induced collagen accumulation in cardiac fibroblasts. Dysregulation of matrix metalloproteinase especially 2 and 9 were considered to be responsible for the abnormal collagen deposition, which resulting improper cardiac contractile function in diabetic mice. Mice received a single dose of streptozotocin (100 mg/kg) through tail vein to induce diabetes. Normal and diabetic mice received aminoguanidine orally (100 mg/kg/day) throughout the study period of 8 weeks. Cardiac fibroblasts cultured and exposed to high glucose, aminoguanidine and both for 48 h. Collagen quantitatively estimated in both in vivo and in vitro models. Altered structural changes were studied using the Masson tri-chrome staining, TEM images of cardiac sections. Increased collagen and metalloproteinase activities were confirmed using gelatin zymography, western blotting and gene expression studies. The exact mechanism responsible for high glucose induced collagen up regulation in diabetic heart was incompletely understood. From this above in vivo and in vitro results, we conclude that, the cardio protective anti fibrotic activity of amino guanidine was mainly attributed by exhibiting the inhibitory efficacy against streptozotocin and high glucose induced collagen accumulation probably by inhibiting high glucose altered metalloproteinase-2 and -9 activities. PMID- 22543015 TI - Kinetics and molecular docking studies of kaempferol and its prenylated derivatives as aldose reductase inhibitors. AB - Aldose reductase inhibitors (ARIs) suppressing the hyperglycemia-induced polyol pathway have been provided as potential therapeutic candidates in the treatment and prevention of diabetic complications. Based upon structure-activity relationships of desmethylanhydroicaritin (1) and sophoflavescenol (2) as promising ARIs, 3,4'-dihydroxy flavonols with a prenyl or lavandulyl group at the C-8 position and a hydroxyl or methoxy group at the C-5 position are important for aldose reductase (AR) inhibition. In order to prove the above results, a combination of computational prediction and enzyme kinetics has begun to emerge as an effective screening technique for the potential. In the present study, we predicted the 3D structure of AR in rat and human using a docking algorithm to simulate binding between AR and prenylated flavonoids (1 and 2) and kaempferol (3) and scrutinized the reversible inhibition of AR by these ARIs. Docking simulation results of 1-3 demonstrated negative binding energies (Autodock 4.0= 9.11 to -7.64 kcal/mol; Fred 2.0=-79.54 to -51.84 kcal/mol) and an additional hydrogen bond through Phe122 and Trp219, in addition to the previously proposed interaction of AR and phenolics through Trp20, Tyr48, His110, and Trp111 residues, indicating that the presence of 8-prenyl and 5-methyl groups might potentiate tighter binding to the active site of the enzyme and more effective AR inhibitors. Moreover, types of AR inhibition were different depending on the presence or absence of the 8-prenyl group, in that 1 and 2 are mixed inhibitors with respective Ki values of 0.69 MUM and 0.94 MUM, while 3 showed noncompetitive inhibition with a Ki value of 4.65 MUM. The present study suggests that an effective strategy for screening potential ARIs could be established by predicting 3D structural conformation of prenylated flavonoids and the orientation within the enzyme as well as by simultaneously determining the mode of enzyme inhibition. PMID- 22543016 TI - Exploring employment in consultation reports of patients with neuromuscular diseases. AB - OBJECTIVES: To explore consultation reports for patient and employment characteristics and recommendations on employment regarding patients with neuromuscular diseases (NMDs). DESIGN: Retrospective study of multidisciplinary reports. SETTING: An outpatient neuromuscular clinic at a university hospital. PARTICIPANTS: Reports (N=102) of patients with NMDs. INTERVENTIONS: Based on one off consultations by occupational therapists, physical therapists, and speech therapists and a multidisciplinary meeting, recommendations were developed regarding therapy content and volume in primary care or rehabilitation settings. MAIN OUTCOME MEASURES: A checklist has been developed to examine employment characteristics. A general questionnaire has been used including demographic variables and data on employment. RESULTS: Of the 102 reports available, 86 were included for analysis. Sixty-nine reports contained information on employment. Thirty-seven patients (43%) with NMD were employed, most in white-collar or moderately strenuous jobs. Of the 37 employed patients, 28 (76%) worked using adaptations. Thirty-two (87%) had employment problems; of these, 15 (40%) needed improvement in 1 or more environmental factors. Twenty patients (54%) needed advice regarding participation in employment, of whom 19 were referred to primary care or rehabilitation settings for treatment to enhance employment participation. CONCLUSIONS: Eighty percent of the included consultation reports contained information on employment. Less than half the patients with NMD were employed, most in office-related jobs, using some kind of adaptations. Nineteen of 20 patients who agreed to recommendations regarding therapy were adequately referred by occupational therapists and physical therapists for treatment of employment problems. PMID- 22543017 TI - Pulmonary function and expiratory flow limitation in acute cervical spinal cord injury. AB - OBJECTIVE: To identify the nature of the changes of respiratory mechanics in patients with middle cervical spinal cord injury (SCI) and their correlation with posture. DESIGN: Clinical trial. SETTING: Acute SCI unit. PARTICIPANTS: Patients with SCI (N=34) at C4-5 level studied within 6 months of injury. INTERVENTIONS: Patients were assessed by the negative expiratory pressure test, maximal static respiratory pressure test, and standard spirometry. MAIN OUTCOME MEASURES: The following respiratory variables were recorded in both the semirecumbent and supine positions: (1) tidal expiratory flow limitation (TEFL); (2) airway resistances; (3) mouth occlusion pressure developed 0.1 seconds after occluded inspiration at functional residual capacity (P(0.1)); (4) maximal static inspiratory pressure (MIP) and maximal static expiratory pressure (MEP); and (5) spirometric data. RESULTS: TEFL was detected in 32% of the patients in the supine position and in 9% in the semirecumbent position. Airway resistances and P(0.1) were much higher compared with normative values, while MIP and MEP were markedly reduced. The ratio of forced expiratory volume in 1 second to forced vital capacity was less than 70%, while the other spirometric data were reduced up to 30% of predicted values. CONCLUSIONS: Patients with middle cervical SCI can develop TEFL. The presence of TEFL, associated with increased airway resistance, could increase the work of breathing in the presence of a reduced capacity of the respiratory muscles to respond to the increased load. The semirecumbent position and the use of continuous positive airway pressure can be helpful to (1) reduce the extent of TEFL and avoid the opening/closure of the small airways; (2) decrease airway resistance; and (3) maintain the expiratory flow as high as possible, which aids in the removal of secretions. PMID- 22543018 TI - CsNAM-like protein encodes a nuclear localized protein and responds to varied cues in tea [Camellia sinensis (L.) O. Kuntze]. AB - Abiotic stress possesses serious threat to plant distribution and production. In response to stress, plants induce the expression of many genes that function to protect the cellular machinery from stress-induced damages. These genes are largely regulated by specific transcription factors (TFs). NAC family proteins are plant specific TFs implicated in diverse processes including development, and biotic and abiotic stress responses. The present work described (i) cloning of CsNAM-like protein gene from a tree crop tea [Camellia sinensis (L.) O. Kuntze], (ii) its cellular localization, and (iii) regulation of the gene by external cues. The gene had an open reading frame of 873 base pairs encoding 291 amino acids with calculated molecular weight of 33.4 kDa and an isoelectric point (pI) of 6.72. Expression characterization showed the gene to be induced by drought, osmoticum, salt, heat and hydrogen peroxide. During the period of active growth, CsNAM-like protein showed ubiquitous expression in all the tissues analyzed, with higher level of transcripts in stem, flower bud and mature leaf as compared to the root, young leaf and fruit. The common response of CsNAM-like protein to various cues suggests its important role in imparting tolerance against abiotic stress. PMID- 22543019 TI - Isolation of cDNA from Jacaratia mexicana encoding a mexicain-like cysteine protease gene. AB - Cysteine proteases (CPs) from the C1 family, which are similar to papain, can be found in animals and plants, as well as some viruses and prokaryotes. These enzymes have diverse physiological functions and are thus very attractive for science and industry. Jacaratia mexicana, a member of the Caricaceae plant family, contains several CPs, the principal being mexicain, found to favorably compete against papain for many industrial applications due to its high stability and specific activity. In this study, leaves of J. mexicana were used to isolate a CP-coding gene, similar to those that code for mexicain and chymomexicain. By using rapid amplification of cDNA ends (RACE) as well as oligonucleotide design from papain-like conserved amino acids (aa), a sequence of 1404 bp consisting of a 5' terminal untranslated region (UTR) of 153 bp, a 3' terminal UTR of 131 bp, with a polyadenylation (poly(A)) signal sequence and a poly(A) tail, and an open reading frame (ORF) of 1046 bp, was obtained by overlapping three partial sequences. Two full-length cDNA sequences that encode for mexicain-like proteases were cloned from mRNA (JmCP4 and JmCP5). JmCP4 is predicted to have an ORF of 1044 bp, which codifies for polypeptides that have a 26 aa signal peptide region, a 108 aa propeptide region and a mature enzyme of 214 aa. A 969 bp fragment (JmCP5) encodes for a partial sequence of a CP gene, without the signal peptide region but with a full-length propeptide region. The sequence analysis showed that this protease presented a high similarity to other plant CPs from J. mexicana, Vasconcellea cundinamarcensis, Vasconcellea stipulata, and Carica papaya, among others, mainly at the conserved catalytic site. Obtaining the sequence of this CP gene from J. mexicana provides an alternative for production in a standard system and could be an initial step towards the commercialization of this enzyme. PMID- 22543020 TI - Accord insertion in the 5' flanking region of CYP6G1 confers nicotine resistance in Drosophila melanogaster. AB - What has driven the sweep of the Accord retrotransposon insertion allele of CYP6G1 in the natural populations of Drosophila melanogaster is unknown. Previous studies on the DDT selection hypothesis produced conflicting data. To reexamine the DDT selection hypothesis and search for alternative explanations, we conducted a series of correlation and genetic linkage experiments with eight D. melanogaster natural populations collected from California (CM1, CM2, CM3, and CM7) and Africa (AM2, AM3, AM4, AM7). Diagnostic PCR showed that CM1, CM2, CM7, and AM3 have the Accord insertion in the CYP6G1 locus, whereas the other four strains do not. RT-PCR analysis exhibits a 100% correlation between Accord insertion and CYP6G1 overexpression. However, among the four strains with Accord mediated CYP6G1 overexpression only CM1 and CM7 are resistant to DDT, and the other two strains (CM2 and AM3), like the four Accord-free strains, are susceptible to DDT. By contrast, all the four strains with Accord-mediated CYP6G1 overexpression are resistant to nicotine, a plant allelochemical. Genetic crosses between DDT resistant and susceptible Accord-insertion strains, as well as crosses between Accord-insertion and Accord-free strains demonstrated that Accord insertion and CYP6G1 overexpression are genetically linked to nicotine resistance rather than DDT resistance. These results suggest that naturally-occurring allelochemicals such as nicotine are the initial driving force for the worldwide prevalence of the Accord insertion allele of CYP6G1 in D. melanogaster natural populations. PMID- 22543021 TI - Editorial commentary: A rare event: a measles outbreak in a population with high 2-dose measles vaccine coverage. PMID- 22543022 TI - All-cause gastroenteritis and rotavirus-coded hospitalizations among US children, 2000-2009. AB - BACKGROUND: Rotavirus vaccine was recommended for US infants in 2006. We estimated baseline prevaccine burden and monitored postvaccine trends in gastroenteritis-coded and rotavirus-coded hospitalizations among US children. METHODS: We analyzed data from the State Inpatient Databases (SID) for 29-44 US states over a 10-year period (2000-2009) to calculate gastroenteritis and rotavirus-coded hospitalization rates by age group, sex, and region, among children <5 years of age. By extrapolating observed pre- and postvaccine gastroenteritis hospitalization rates to the US population <5 years and based on the 2009 cost of a diarrhea hospitalization, we estimated national reductions in diarrhea hospitalizations and associated treatment costs. RESULTS: The prevaccine (2000-2006) annual average gastroenteritis-coded hospitalization rate among children <5 years of age was 74 per 10,000 (annual range, 71-82 per 10,000), and declined to 51 and 50 per 10,000 in 2008 and 2009, respectively (P < .001). The prevaccine (2000-2006) annual average rotavirus-coded hospitalization rate among children <5 years of age was 15 per 10,000 (annual range, 13-18 per 10,000), and declined to 5 and 6 per 10,000 in 2008 and 2009, respectively (P < .001). The decreases in rotavirus-coded hospitalization rates in 2008 and 2009 compared with rates in prevaccine years were observed among all age groups and US regions. Nationally, during 2008 and 2009 combined, we estimated a reduction of approximately 77,000 diarrhea hospitalizations and approximately $242 million in hospital costs. CONCLUSIONS: Since implementation of the US rotavirus vaccination program, a marked reduction in diarrhea hospitalizations and related hospital charges has occurred among US children. PMID- 22543023 TI - Higher risk of measles when the first dose of a 2-dose schedule of measles vaccine is given at 12-14 months versus 15 months of age. AB - BACKGROUND: In 2011, >750 cases of measles were reported in Quebec, Canada, where a routine 2-dose measles immunization schedule, in which measles vaccine is given at 12 and 18 months of age, had been in effect since 1996. Effectiveness of this schedule was assessed during a high school outbreak. METHODS: Cases were identified by passive followed by active surveillance. Classical cases met the national surveillance definition; attenuated cases showed clinical signs and high measles-specific immunoglobulin G but did not fulfill all classical criteria. Immunization status was ascertained from written records, and vaccine effectiveness (VE) was calculated as 1 - [(risk of measles in vaccinated individuals)/(risk in unvaccinated individuals)] * 100%. RESULTS: Among 1306 students, 110 measles cases were identified; 98 were classical cases, and 12 were attenuated cases. The attack rates among unvaccinated and fully vaccinated students were 82% and 4.8%, respectively. The VE among 2-dose recipients was 95.5% against classical and 94.2% against all (classical + attenuated) measles. Among 2-dose recipients, attack rates with first immunization at 12 and >=15 months of age were 5.8% and 2.0%, respectively, with corresponding VE values of 93.0% and 97.5%. The risk of measles in 2-dose recipients was significantly (3-4 fold) higher when vaccine was first administered at 12 months of age, compared with >=15 months of age (P = .04). CONCLUSIONS: Despite compliance with the recommended 2-dose measles immunization schedule, 6% of high school students were susceptible during this outbreak. Residual susceptibility was 2-4-fold higher among 2-dose recipients who had received the first dose of vaccine prior to 15 months of age. If confirmed in other settings, these results suggest that administration of the first dose of measles vaccine before 15 months of age may not be optimal for measles elimination efforts. PMID- 22543024 TI - Reduced influenza antiviral treatment among children and adults hospitalized with laboratory-confirmed influenza infection in the year after the 2009 pandemic. AB - Influenza antiviral treatment is recommended for all persons hospitalized with influenza virus infection. During the 2010-2011 influenza season, antiviral treatment of children and adults hospitalized with laboratory-confirmed influenza declined significantly compared with treatment during the 2009 pandemic (children, 56% vs 77%; adults, 77% vs 82%; both P < .01). PMID- 22543025 TI - Presence of terminal N-acetylgalactosaminebeta1-4N-acetylglucosamine residues on O-linked oligosaccharides from gastric MUC5AC: involvement in Helicobacter pylori colonization? AB - Isolation of MUC5AC mucins from the gastric mucosa from two secretor individuals (one from normal mucosa from a patient with gastric cancer and one from a control) showed different abilities to bind and induce the proliferation of the Helicobacter pylori strain J99. Analysis of the released O-linked oligosaccharides by LC-MS from these individuals showed a very heterogeneous mixture of species from the cancer patient containing both neutral and sialylated structures, whereas the normal sample showed dominating neutral blood group H terminating structures as well as neutral structures containing the di-N acetyllactosamine (lacdiNAc) unit GalNAcbeta1-4GlcNAcbeta1- on the C-6 branch of the reducing end GalNAc. The linkage configuration of these epitopes were determined using C-4-specific fragmentation for the GalNAcbeta1-4GlcNAcbeta1- glycosidic linkage, comparison of the MS(3) fragmentation with standards for linkage configuration and N-acetylhexosamine type as well as exoglycosidase treatment. It was also shown that the lacdiNAc epitope is present in both human and porcine gastric mucins, indicating that this is an epitope preserved between species. We hypothesize that the termination on gastric MUC5AC with lacdiNAc is in competition with complex glycosylation such as the Le(b) and H type 1 as well as complex sialylated structures. These are epitopes known to bind the H. pylori BabA and SabA adhesins. PMID- 22543026 TI - Kinase inhibitory potencies and in vitro antiproliferative activities of N-10 substituted pyrrolo[2,3-a]carbazole derivatives. AB - Development of potent and selective Pim kinase inhibitors has recently emerged as an important field for the design of new anti-cancer drugs. We report the synthesis of new N-10-substituted pyrrolo[2,3-a]carbazole derivatives and their evaluation as Pim kinase inhibitors. Moreover, in vitro antiproliferative activity of these compounds was evaluated toward a human fibroblast primary culture and three human solid cancer cell lines (PA1, PC3 and DU145). Compounds 3, 7 and 10 showed inhibitory potencies toward Pim-1 and Pim-3 in the nanomolar range. Additionally, dimethylamino analog 10 also demonstrated interesting sub micromolar antiproliferative activities toward the cell lines tested. PMID- 22543027 TI - Vascular barrier protective effects of eckol and its derivatives. AB - In this Letter, we first investigated the barrier protective effects of eckol and its derivatives against pro-inflammatory responses in human umbilical vein endothelial cells (HUVECs) and in mice. Data showed that eckol (1) and dieckol (2) inhibited lipopolysaccharide (LPS)-mediated barrier disruption and transendothelial migration of leukocytes to human endothelial cells. Eckol (1) also suppressed acetic acid induced-hyperpermeability and carboxymethylcellulose induced leukocytes migration in vivo. Interestingly, the barrier protective effects of dieckol (2) were better than those of eckol (1) and hydroxyl groups in dieckol (2) positively regulate protective effects. PMID- 22543028 TI - Design and synthesis of new tetrahydroquinolines derivatives as CETP inhibitors. AB - This letter describes the discovery and SAR optimization of tetrazoyl tetrahydroquinoline derivatives as potent CETP inhibitors. Compound 6m exhibited robust HDL-c increase in hCETP/hApoA1 double transgenic model and favorable pharmacokinetic properties. PMID- 22543029 TI - Synthesis of norlignans and in vitro inhibitory activity of antigen-induced degranulation. AB - The synthesis and biological evaluation of a series of novel norlignans are described. Norlignans were evaluated for their inhibitory activity on the release of beta-hexosaminidase, a marker of degranulation, from RBL-2H3 cells induced by the IgE-antigen complex. The results showed that norlignans 4c and 4e potently inhibited degranulation, with IC(50) values of 18.3 and 17.9 MUM, respectively. PMID- 22543030 TI - Fluorometric detection of adenine in target DNA by exciplex formation with fluorescent 8-arylethynylated deoxyguanosine. AB - We demonstrated an intriguing method to discriminate adenine by incident appearance of an intense new emission via exciplex formation in hybridization of target DNA with newly designed fluorescent 8-arylethynylated deoxyguanosine derivatives. We described the synthesis of such highly electron donating fluorescent guanosine derivatives and their incorporation into DNA oligomers which may be used for the structural study and the fluorometric analysis of nucleic acids. PMID- 22543032 TI - 3-Monoglucuronyl-glycyrrhretinic acid is a substrate of organic anion transporters expressed in tubular epithelial cells and plays important roles in licorice-induced pseudoaldosteronism by inhibiting 11beta-hydroxysteroid dehydrogenase 2. AB - Licorice (glycyrrhiza root) has been used as a herbal medicine worldwide with its main active constituent being glycyrrhizin (GL). Licorice sometimes causes adverse effects such as inducing pseudoaldosteronism by inhibiting type 2 11beta hydroxysteroid dehydrogenase (11beta-HSD2) caused by glycyrrhetinic acid (GA), a major metabolite of GL. In this study we compared the inhibitory effects of GA, GL, and 3-monoglucuronyl-glycyrrhetinic acid (3MGA), another metabolite of GL, on 11beta-HSD2 activity by using microsomes and rat kidney tissue slices. GA, 3MGA, and GL inhibited 11beta-HSD2 in rat kidney microsomes, with IC(50) values of 0.32, 0.26, and 2.2 MUM, respectively. However, the inhibitory activity of these compounds was reduced markedly, in the slices, in a medium containing 5% bovine serum albumin. Assays using human embryonic kidney 293 cells with transient transformation in transporter genes showed that 3MGA is a substrate of human organic anion transporter (OAT) 1, human OAT3, and human organic anion transporting peptide 4C1, whereas GA is not. When GA (100 mg/kg/day) was administered orally for 16 days to Eisai hyperbilirubinemic rats, plasma concentrations and urinary excretion of 3MGA were significantly higher, whereas the activity of 11beta-HSD2 in kidney microsomes was significantly lower compared with Sprague Dawley rats. These results suggest that 3MGA is actively transported into tubules through OATs, resulting in the inhibition of 11beta-HSD2. Because the plasma level of 3MGA depends on the function of hepatic transporters, monitoring 3MGA levels in plasma or urine may be useful for preventing pseudoaldosteronism when licorice or GL is prescribed to patients. PMID- 22543033 TI - Relationship between HLA-DP gene polymorphisms and clearance of chronic hepatitis B virus infections: case-control study and meta-analysis. AB - Hepatitis B virus (HBV) infection is a serious public health problem worldwide. Two common genetic variants (rs3077 and rs9277535) of human leukocyte antigen DP (HLA-DP) have been reported to be associated with persistent HBV infection in populations of Japan and Thailand. To confirm whether the association can be replicated in Chinese populations, an independent case-control study were conducted, and two polymorphisms (rs3077 and rs9277535) were genotyped using the TaqMan SNP genotyping assay in 282 persistent chronic HBV carriers and 64 spontaneously HBV recovered carriers. To provide a more definitive conclusion, a meta-analysis combining and summarizing five studies was performed by random effects model using the DerSimonian and Laird's method. By using logistic regression analysis with adjustment for covariates, including age, sex, and alcohol consumption, the results of our independent case-control study showed that the minor allele's homozygote (AA genotype) of rs3077 and rs9277535 was significantly associated with decreasing risk/protection of HBV persistent chronic infection (for rs3077: P=0.0017, OR=0.29, 95% CI=0.13-0.62; for rs9277535, P=0.0004, OR=0.26, 95% CI=0.12-0.54). The results of meta-analysis pooling all eligible studies also showed that rs3077-A and rs9277535-A alleles were associated with an increased clearance rate to HBV infection (rs3077: OR=0.57, 95% CI=0.44-0.75; rs9277535: OR=0.56, 95% CI=0.47-0.63). These results further confirmed the strong influence of HLA-DP gene variants on risk of spontaneous HBV clearance from persistent HBV infection. Both A alleles of HLA-DP SNP rs3077 and rs9277535 showed strong protective effects for spontaneous HBV clearance from persistent HBV infection in the Han Chinese population. PMID- 22543031 TI - Targeting phosphoinositide 3-kinase gamma in airway smooth muscle cells to suppress interleukin-13-induced mouse airway hyperresponsiveness. AB - We recently reported that phosphoinositide 3-kinase gamma (PI3Kgamma) directly regulates airway smooth muscle (ASM) contraction by modulating Ca(2+) oscillations. Because ASM contraction plays a critical role in airway hyperresponsiveness (AHR) of asthma, the aim of the present study was to determine whether targeting PI3Kgamma in ASM cells could suppress AHR in vitro and in vivo. Intranasal administration into mice of interleukin-13 (IL-13; 10 MUg per mouse), a key pathophysiologic cytokine in asthma, induced AHR after 48 h, as assessed by invasive tracheostomy. Intranasal administration of a broad-spectrum PI3K inhibitor or a PI3Kgamma-specific inhibitor 1 h before AHR assessment attenuated IL-13 effects. Airway responsiveness to bronchoconstrictor agonists was also examined in precision-cut mouse lung slices pretreated without or with IL-13 for 24 h. Acetylcholine and serotonin dose-response curves indicated that IL-13-treated lung slices had a 40 to 50% larger maximal airway constriction compared with controls. Furthermore, acetylcholine induced a larger initial Ca(2+) transient and increased Ca(2+) oscillations in IL-13-treated primary mouse ASM cells compared with control cells, correlating with increased cell contraction. As expected, PI3Kgamma inhibitor treatment attenuated IL-13 augmented airway contractility of lung slices and ASM cell contraction. In both control and IL-13-treated ASM cells, small interfering RNA-mediated knockdown of PI3Kgamma by 70% only reduced the initial Ca(2+) transient by 20 to 30% but markedly attenuated Ca(2+) oscillations and contractility of ASM cells by 50 to 60%. This report is the first to demonstrate that PI3Kgamma in ASM cells is important for IL-13-induced AHR and that acute treatment with a PI3Kgamma inhibitor can ameliorate AHR in a murine model of asthma. PMID- 22543034 TI - Personality mediators of psychopathy and substance dependence in male offenders. AB - Psychopathy and substance dependence (SUD) is highly prevalent in incarcerated populations and tends to co-occur in the same individuals. The factors underlying this relationship are not clearly understood. The primary purpose of this study was to investigate whether two personality models mediate the relationship between psychopathy and substance misuse in male offenders. Ninety-two inmates in provincial correctional centers in New Brunswick completed questionnaires, including the Sensitivity to Reward Sensitivity to Punishment Questionnaire to measure behavioral activation and behavioral inhibition, the Substance Use Risk Profile Scale to measure anxiety sensitivity, introversion/hopelessness, sensation seeking and impulsivity, and the Psychopathic Personality Inventory Revised to assess psychopathy levels. Results revealed that high impulsivity indirectly mediated the relationship between psychopathy and stimulant dependence. In addition, low anxiety sensitivity indirectly mediated the relationship between psychopathy and opioid dependence. Finally, impulsivity indirectly and inconsistently mediated the relationship between psychopathy and alcohol dependence. These results suggest that individuals with psychopathic traits are at increased risk of misusing certain drugs due to underlying personality-based differences. PMID- 22543035 TI - Disparities in activity level and nutrition between patients with chronic hepatitis C and blood donors. AB - OBJECTIVE: To compare physical activity levels and dietary choices of patients who have chronic hepatitis C (CHC) with those of blood donors (BDs). DESIGN: A prospective survey. SETTING: A liver disease treatment center and a blood donor center from a nonprofit health system. PATIENTS: A total of 149 subjects (93 with CHC and 56 BDs) participated. Subjects were 18 years or older and agreed to participate; those with CHC had no evidence of cirrhosis. METHODS: All subjects provided basic clinical information and completed a nutrition survey, which contained questions about dietary choices and their frequency, and the Human Activity Profile, which measured maximum effort (Maximum Activity Score; MAS) and daily activity (Adjusted Activity Score; AAS). MAIN OUTCOMES MEASUREMENTS: MAS and AAS scales and 13 indices on the nutrition survey. Independent samples t tests, Pearson correlations, and multiple stepwise regression analyses were performed. RESULTS: No significant differences were found between BDs and patients with CHC in terms of age, gender, race, body mass index, hyperlipidemia, hypertension, or diabetes mellitus. Mean body mass index was 27.5, 17.8% had hyperlipidemia, and 9.6% had diabetes. BDs reported significantly more exercise per week (mean: patients with CHC = 193.6 minutes/week and BDs = 280.4 minutes/week; P = .039) and had a significantly greater MAS (mean: patients with CHC = 77.2 and BDs = 87.4, P = .0001) and AAS (mean: patients with CHC = 72.58 and BDs = 83.8, P = .0001). Stepwise multiple regression analysis proposed 2 models predicting AAS: the presence of CHC (R = .445; R(2) = .198; adjusted R(2) = .184); and the presence of CHC and presence of hypertension (R = .537; R(2) = .289; adjusted R(2) = .263). BDs consumed significantly more alcohol and starchy foods than did patients with CHC (P = .0001 and P = .031, respectively), which may be explained by the compliance of patients with CHC to their hepatologist's recommendations regarding the minimization of alcohol consumption. CONCLUSIONS: Persons with CHC participate in less activity and less vigorous physical activity than do BDs and consume less starch and alcohol. These data about activity level and dietary intake in patients with CHC are novel; few data on these topics have been published previously. Low level of activity adds a substantial risk to this overweight CHC population, many of whom have multiple components of metabolic syndrome. PMID- 22543036 TI - Adverse events associated with fluoroscopically guided sacroiliac joint injections. AB - OBJECTIVE: To describe the type, incidence, and factors that contribute to adverse events associated with fluoroscopically guided intra-articular sacroiliac joint injections (IASIJ). DESIGN: A retrospective cohort study. SETTING: Tertiary, academic, outpatient physical medicine and rehabilitation interventional spine clinic. PARTICIPANTS: English-speaking adults aged 18-90 years who underwent fluoroscopically guided IASIJ injections between March 8, 2004, and April 19, 2007. INTERVENTIONS: After IASIJ injections, 3 senior researchers recorded the presence and types of adverse events. The relationship of adverse events with age, gender, fluoroscopy time, vital signs, and trainee presence was analyzed with the Fisher exact or the Wilcoxon rank sum 2-sided tests. MAIN OUTCOME MEASURES: The frequency of immediate (during or immediately after the procedure) or delayed (within 24-72 hours after the procedure) adverse events. RESULTS: A total of 162 patients (133 women) underwent 191 procedures. The range of subject age was from 20 to 90 years (15.8 years, standard deviation [SD]). The range (SD) of the preprocedure 11-point Likert Pain Scale was from 1.0 to 10.0 (2.0) and for the postprocedure 11-point Likert Pain Scale was from 0.0 to 9.0 (2.5). Trainees were involved in 57% of the procedures. Reported immediate adverse events were vasovagal reaction (2.1% [n = 4]) and steroid-clogged needle (0.5% [n = 1]). Follow-up data were available for 132 of 191 procedures (69%). There were 32 adverse events reported at a mean follow-up interval of 2 days, of which, the most frequent adverse events were injection-site soreness (12.9% [n = 17]), pain exacerbation (5.3% [n = 7]), and facial flushing and/or sweating (2.3% [n = 3]). Delayed adverse events decreased with older age (P = .0029). The patients who underwent bilateral procedures experienced more delayed adverse events than the patients who underwent unilateral procedures (P = .024). CONCLUSIONS: Fluoroscopically guided IASIJ injection is associated with minimal adverse effects. The most common immediate adverse event was vasovagal reaction, and the most common delayed adverse event was injection-site soreness. Younger age is significantly related to reported delayed adverse events. PMID- 22543037 TI - Reliability and repeatability of the Hoffmann sign. AB - OBJECTIVE: To determine the inter-rater, intrarater, and intrasubject reliability of the Hoffmann sign. DESIGN: Observational, cross-sectional study. SETTING: Veterans Affairs medical center. PATIENTS: Fifty-two consenting subjects without amputation of the first through third fingers, fixed finger contractures, relapsing remitting multiple sclerosis, or any acute central neurological illness or injury within the past 3 months requiring hospital admission were recruited from inpatients and outpatients in the Spinal Cord Injury and Physical Medicine and Rehabilitation services. INTERVENTIONS: The Hoffmann sign was elicited by 1 primary and 3 secondary investigators who used a standardized technique. The Hoffmann sign was considered positive if any reflexive flexion of the distal phalanx of the thumb or any of the fingers was present. In the first session, the primary and one secondary examiner performed 2 trials on both hands of each subject. Each investigator pair repeated the procedure in a second session. MAIN OUTCOME MEASURES: Cohen's kappa coefficient was calculated to determine (1) inter rater reliability, calculated per investigator pair per hand, for the first trial of a session; (2) intrarater reliability, calculated between the 2 trials of each session per investigator; and (3) intrasubject reliability, calculated per hand of each subject between the first trials of the 2 sessions. RESULTS: Inter-rater kappa was 0.65 (188 pairs), intrarater kappa was 0.89 (384 pairs), and intrasubject kappa was 0.73 (178 pairs). All kappa values were obtained with P < .01. CONCLUSIONS: The Hoffmann sign has substantial inter-rater and intrasubject reliability, in addition to outstanding intrarater reliability, when tested with the use of a standardized technique. PMID- 22543038 TI - The effects of concussion legislation one year later--what have we learned: a descriptive pilot survey of youth soccer player associates. AB - OBJECTIVE: To assess the knowledge of youth soccer athletes' parents, coaches, and soccer officials regarding concussion and return-to-play guidelines contained in the Lystedt Law in Washington State. DESIGN: Survey study. SETTING: Surveys were distributed via the youth soccer association monthly electronic newsletter in September and October 2010. Links to the survey also were provided via the Washington Youth Soccer Facebook page and Twitter feed. PARTICIPANTS: Respondents were 18 years or older and were associated with Washington Youth Soccer. MAIN OUTCOME MEASURES: The percentage of correct responses to questions regarding the identification and management of concussion symptoms and return to play guidelines as outlined in the Lystedt Law. RESULTS: A total of 391 adults responded; 63% were exclusively parents, 20% were coaches, and 17% were noncoaches (eg, club officers, referees, or volunteers). A total of 96% knew that concussions were a type of traumatic brain injury, 93% identified concussions as serious, and 93% knew that loss of consciousness is not universal. From the responses, 98% identified neurological manifestations of concussions, 90% chose to delay return to play in the presence of neurological symptoms, 85% were aware of the Lystedt Law, and only 73% knew that players must receive written clearance to return to play. A total of 88% were aware that a parent or legal guardian was not allowed to clear an athlete to return to play if a trained professional was not available. Survey respondents were less sure of soccer association guidelines for reporting medical clearance to club officials. CONCLUSIONS: These data suggest that, although general knowledge of parents, coaches, and referees in youth soccer in Washington State is high, gaps in knowledge and practice regarding the prevention of concussion in youth soccer athletes still exist. PMID- 22543040 TI - Innate recognition of malarial parasites by mammalian hosts. AB - Innate immunity plays a central role in combating infections. However, the importance of innate immune sensors in detecting intracellular parasites, such as Plasmodium spp., has only recently emerged as a central topic in the field of host-pathogen interactions. Genetic dissection of innate immune pathways has uncovered a complex relationship between the host innate immune system and Plasmodium blood-stage parasites. In fact, recognition molecules of the innate immune system, such as toll-like receptors, might not only be implicated in host defense but also in the pathogenesis of the disease. Whether Plasmodium liver stage parasites are recognised and controlled by the host innate immune system remains to be discovered. In this review we discuss recent findings on how the host innate immune system may sense and fight the different forms of Plasmodium and how the latter may have evolved mechanisms to escape host detection and/or to manipulate the defensive reaction of the host. PMID- 22543039 TI - Plasmodium subtilisin-like protease 1 (SUB1): insights into the active-site structure, specificity and function of a pan-malaria drug target. AB - Release of the malaria merozoite from its host erythrocyte (egress) and invasion of a fresh cell are crucial steps in the life cycle of the malaria pathogen. Subtilisin-like protease 1 (SUB1) is a parasite serine protease implicated in both processes. In the most dangerous human malarial species, Plasmodium falciparum, SUB1 has previously been shown to have several parasite-derived substrates, proteolytic cleavage of which is important both for egress and maturation of the merozoite surface to enable invasion. Here we have used molecular modelling, existing knowledge of SUB1 substrates, and recombinant expression and characterisation of additional Plasmodium SUB1 orthologues, to examine the active site architecture and substrate specificity of P. falciparum SUB1 and its orthologues from the two other major human malaria pathogens Plasmodium vivax and Plasmodium knowlesi, as well as from the rodent malaria species, Plasmodium berghei. Our results reveal a number of unusual features of the SUB1 substrate binding cleft, including a requirement to interact with both prime and non-prime side residues of the substrate recognition motif. Cleavage of conserved parasite substrates is mediated by SUB1 in all parasite species examined, and the importance of this is supported by evidence for species specific co-evolution of protease and substrates. Two peptidyl alpha-ketoamides based on an authentic PfSUB1 substrate inhibit all SUB1 orthologues examined, with inhibitory potency enhanced by the presence of a carboxyl moiety designed to introduce prime side interactions with the protease. Our findings demonstrate that it should be possible to develop 'pan-reactive' drug-like compounds that inhibit SUB1 in all three major human malaria pathogens, enabling production of broad-spectrum antimalarial drugs targeting SUB1. PMID- 22543041 TI - In vivo temperature controlled ultrasound-mediated intracellular delivery of cell impermeable compounds. AB - Many chemotherapeutic drugs are characterized by high systemic toxicity and/or suffer from limited bioavailability. Thermosensitive liposomes (TSLs) encapsulating drugs in their aqueous lumen are promising activatable nanocarriers for ultrasound (US)-mediated drug delivery in response to mild hyperthermia. On the other hand, US is known to locally break biological barriers and as a consequence enable internalization of molecules. In this work, a two-step protocol for intracellular delivery of cell-impermeable molecules comprising of US-induced permeabilization followed by temperature-controlled release of the model drug from thermosensitive liposomes has been developed. TSLs containing TO PRO-3, a cell-impermeable molecule that displays a significant increase in fluorescence upon binding to nucleic acids thus serving as a 'sensor' for internalization have been prepared and characterized in detail. US-mediated permeabilization followed by temperature-controlled release was applied to tumor bearing mice following i.v. injection of TSLs and microbubbles. The efficacy of this approach was evaluated by in vivo fluorescence imaging followed by histological analysis. A 2.4-fold increase of fluorescence signal was observed and intracellular delivery of TO-PRO-3 was confirmed by a characteristic nuclear staining. These results demonstrate the feasibility of novel drug delivery system to tumors comprising of local cell permeabilization by US followed by in situ release of the payload from thermosensitive liposomes. Possible applications include local and controlled intracellular delivery of molecules with otherwise limited bioavailability. PMID- 22543042 TI - Controlled release of bone morphogenetic protein (BMP)-2 from nanocomplex incorporated on hydroxyapatite-formed titanium surface. AB - Both osteoconductivity and osteoinductivity are equally very important aspects in a new bone formation and ultimately for bone regeneration. The purpose of this study was to create an environment, not only osteoconductive but also osteoinductive on titanium (Ti) surface. To do this bone morphogenetic protein-2 (BMP-2) nanocomplex (NC) was fabricated by using an ionic interaction between BMP 2 and chondroitin sulfate (CS). Meanwhile, Ti was chemically treated, then subjected to soaking in simulated body fluid (SBF), naming the sample Ti(C) hydroxyapatite (HA). Once the BMP-2 NC was precipitated on the Ti(C)-HA surface, along with the addition of calcium/phosphate solution, the final product was formed as Ti(C)-HA-BMP-2. The size of NC was ranged from 150 to 250nm and the amount of CS was influential in determining both NC size and zeta potential. From the SEM observation, Ti surface was found nicely covered with the crystallized apatite layer that was identified using FTIR and NMR. The immobilized BMP-2 was released in a moderate rate for 4 weeks, without an initial burst of BMP-2. When mouse osteoblast cells were seeded on different Ti substrates, cell proliferation was faster in the Ti(C)-HA-BMP-2 group, as compared to other groups. The gene expression of bone-specific markers, osteocalcin and type I collagen, was significantly upregulated with the use of BMP-2 NC. The same result was witnessed in the measurement of alkaline phosphatase activity, in which the difference was statistically significant. This study demonstrated that the delivery system of BMP-2 NC was effective in holding BMP-2 on the apatite-coated Ti surface and that the Ti surface could be modified into the environment osteoinductive as well as osteoconductive. PMID- 22543043 TI - Procedural pain and oxidative stress in premature neonates. AB - Preterm neonates exposed to painful procedures in the neonatal intensive care unit exhibit increased pain scores and alterations in oxygenation and heart rate. It is unclear whether these physiological responses increase the risk of oxidative stress. Using a prospective study design, we examined the relationship between a tissue-damaging procedure (TDP; tape removal during discontinuation of an indwelling central arterial or venous catheter) and oxidative stress in 80 preterm neonates. Oxidative stress was quantified by measuring uric acid (UA) and malondialdehyde (MDA) concentration in plasma before and after neonates (n = 38) experienced a TDP compared to those not experiencing any TDP (control group, n = 42). Pain was measured before and during the TDP using the Premature Infant Pain Profile (PIPP). We found that pain scores were higher in the TDP group compared to the control group (median scores, 11 and 5, respectively; P < .001). UA significantly decreased over time in control neonates but remained stable in TDP neonates (132.76 to 123.23 MUM versus 140.50 to 138.9 MUM; P = .002). MDA levels decreased over time in control neonates but increased in TDP neonates (2.07 to 1.81 MUM versus 2.07 to 2.21 MUM, P = .01). We found significant positive correlations between PIPP scores and MDA. Our data suggest a significant relationship between procedural pain and oxidative stress in preterm neonates. PERSPECTIVE: This article presents data describing a significant relationship between physiological markers of neonatal pain and oxidative stress. The method described in this paper can potentially be used to assess the direct cellular effects of procedural pain as well the effectiveness of interventions performed to decrease pain. PMID- 22543044 TI - Changes in pain and other symptoms in patients with painful multiple myeloma related vertebral fracture treated with kyphoplasty or vertebroplasty. AB - Patients with painful vertebral compression fractures produced by multiple myeloma (MM) often experience reduction in pain after spinal augmentation with kyphoplasty or vertebroplasty. Previous studies have shown pain reduction and improvement in functional status after augmentation, but no studies have examined the effect of augmentation on other cancer-related symptoms. We hypothesized that reduction in pain severity would be significantly associated with improvement in other reported symptoms. We retrospectively studied 79 patients who rated pain and symptom severity both before and after kyphoplasty or vertebroplasty. Pain was significantly reduced after spinal augmentation (1.3 on a 0 to 10 scale; effect size [ES] = .59; P < .001), as were anxiety (1.3; ES = .47), drowsiness (1.3; ES = .39), fatigue (1.1; ES = .32), depression (.7; ES = .28), and difficulty thinking clearly (.7; ES = .26) (all P < .05). Greater reduction in pain was associated with a greater number of symptoms being reduced. Interestingly, insomnia worsened regardless of any amount of improvement in pain. Because appropriate symptom control contributes to the overall well-being of cancer patients, future studies of pain reduction procedures should include measures of other symptoms to fully characterize the potential benefit of treating pain. PERSPECTIVE: Appropriate symptom control contributes to overall well-being for cancer patients. This study demonstrated that pain reduction after spinal augmentation with vertebroplasty or kyphoplasty was positively associated with reduction in other patient-reported cancer-related symptoms. Future studies of these augmentation procedures should measure multiple symptoms, in addition to pain and functional status. PMID- 22543045 TI - Estimating efficacy and drug ED50's using von Frey thresholds: impact of weber's law and log transformation. AB - The use of von Frey filaments, originally developed by Maximilian von Frey, has become the cornerstone for assaying mechanical sensitivity in animal models and is widely used for human assessment. While there are certain limitations associated with their use that make comparisons between studies not straightforward at times, such as stimulus duration and testing frequency, von Frey filaments provide a good measurement of mechanosensation. Here we describe the application of von Frey filaments to testing in animal models, specifically with respect to determining changes in sensory thresholds in a pain state using the Dixon up-down method. In a literature survey, we found that up to 75% of reports using this method analyze the data with parametric statistical analysis and of those that used nonparametric analysis, none took into account that mechanical sensation is perceived on a logarithmic scale (Weber's Law) when calculating efficacy. Here we outline a more rigorous analysis for calculating efficacy and ED(50)'s from von Frey data that incorporates Weber's Law. We show that this analysis makes statistical and biological sense and provide a specific example of how this change affects data analysis that brings results from animal models more in line with clinical observations. PERSPECTIVE: This focus article argues that analyzing von Frey paw withdrawal threshold data obtained by using the Dixon up-down method without considering Weber's Law is inappropriate. An analysis method that incorporates how mechanical sensation is perceived and how its application brings results from animal models more in line with clinical data is presented. PMID- 22543046 TI - Deep brain stimulation and spinal cord stimulation for vegetative state and minimally conscious state. AB - OBJECTIVE: On the basis of the findings of the electrophysiological evaluation of vegetative state (VS) and minimally conscious state (MCS), the effect of deep brain stimulation (DBS) was examined according to long-term follow-up results. The results of spinal cord stimulation (SCS) on MCS was also examined and compared with that of DBS. METHODS: One hundred seven patients in VS and 21 patients in MCS were evaluated neurologically and electrophysiologically over 3 months after the onset of brain injury. Among the 107 VS patients, 21 were treated by DBS. Among the 21 MCS patients, 5 were treated by DBS and 10 by SCS. RESULTS: Eight of the 21 patients recovered from VS and were able to follow verbal instructions. These eight patients showed desynchronization on continuous electroencephalographic frequency analysis. The Vth wave of the auditory brainstem response and N20 of somatosensory evoked potential were recorded even with a prolonged latency, and pain-related P250 was recorded with an amplitude of more than 7 MUV. In addition, DBS and SCS induced a marked functional recovery in MCS patients who satisfied the electrophysiological inclusion criteria. CONCLUSION: DBS for VS and MCS patients and SCS for MCS patients may be useful, when the candidates are selected on the basis of the electrophysiological inclusion criteria. Only 16 (14.9%) of the 107 VS patients and 15 (71.4%) of the 21 MCS patients satisfied the electrophysiological inclusion criteria. PMID- 22543047 TI - Strengths and limits of risk stratification models in vascular surgery. PMID- 22543048 TI - Tegobuvir (GS-9190) potency against HCV chimeric replicons derived from consensus NS5B sequences from genotypes 2b, 3a, 4a, 5a, and 6a. AB - With the exception of nucleoside analogs, few direct acting antivirals in clinical development are active across the six major hepatitis C virus genotypes. We report novel consensus sequence chimeras for genotypes 2b, 3a, 4a, 5a, and 6a NS5B and show variable susceptibilities over a panel of NS5B inhibitors. Tegobuvir (GS-9190) had EC(50)s of <16 nM against genotype 1 and >100 nM for other genotypes tested here. An NS5B F445C mutation engineered into the GT3a, 4a, and 6a chimeric replicons lowered the tegobuvir EC(50) to levels comparable to those for genotype 1a, but did not considerably alter the EC(50) of site 2 or nucleoside analog inhibitors. These data support the use of HCV chimeras in profiling direct acting antivirals across genotypes and specifically determines the impact of the C445F NS5B polymorphism on tegobuvir potency against genotypes 3a, 4a, and 6a. PMID- 22543049 TI - Release of the herpes simplex virus 1 protease by self cleavage is required for proper conformation of the portal vertex. AB - We identify an NLS within herpes simplex virus scaffold proteins that is required for optimal nuclear import of these proteins into infected or uninfected nuclei, and is sufficient to mediate nuclear import of GFP. A virus lacking this NLS replicated to titers reduced by 1000-fold, but was able to make capsids containing both scaffold and portal proteins suggesting that other functions can complement the NLS in infected cells. We also show that Vp22a, the major scaffold protein, is sufficient to mediate the incorporation of portal protein into capsids, whereas proper portal immunoreactivity in the capsid requires the larger scaffold protein pU(L)26. Finally, capsid angularization in infected cells did not require the HSV-1 protease unless full length pU(L)26 was expressed. These data suggest that the HSV-1 portal undergoes conformational changes during capsid maturation, and reveal that full length pU(L)26 is required for this conformational change. PMID- 22543050 TI - Actin coats and rings promote regulated exocytosis. AB - It is well known that actin can associate with intracellular membranes to drive endocytosis and the rocketing motion of bacteria, virions and some organelles and to regulate synaptic vesicle plasticity. Actin also has been extensively reported to be involved at several steps of exocytosis; however, it has typically been described as functioning either within the actin cortex or by providing actin tracks for organelle transport. Increasingly, actin filament coats or rings have been directly localized on the surface of the exocytic organelle. Here, we suggest a common mechanism for actin-based regulation of large secretory granules whereby organelle-associated actomyosin II contraction either directly expels secretory content or stabilizes the exocytosing organelle. PMID- 22543051 TI - Diverse ubiquitin signaling in NF-kappaB activation. AB - Nuclear factor-kappa B (NF-kappaB) is a transcription factor involved in a wide variety of phenomena including inflammation, immune responses, and cell survival. Abnormal activation of NF-kappaB occurs in many pathological conditions, such as allergic and auto-inflammatory diseases and malignancies. As a result, the signal induced NF-kappaB activation pathway has been extensively studied and revealed to be regulated by ubiquitination. Several types of polyubiquitin chains exist and the type of chain seems to impact how ubiquitinated proteins are regulated. Recently, different types of polyubiquitin chains, including linear (M1) and K11 chains, have been implicated in NF-kappaB activation. This review discusses existing evidence of the differential roles played by various ubiquitin chains, particularly K63, M1, and K11 chains, in NF-kappaB activation. PMID- 22543052 TI - The role of the IRE1 pathway in PBDE-47-induced toxicity in human neuroblastoma SH-SY5Y cells in vitro. AB - Polybrominated diphenyl ethers (PBDEs) are widely used as flame retardants. As one of the dominant congeners, 2,2', 4,4'-tetrabromodiphenyl ether (PBDE-47) has been shown to be neurotoxic to neuronal cells although the mechanisms remain unclear. To test whether PBDE-47's toxicity was related to endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), human neuroblastoma cells (SH-SY5Y cells) were treated with different concentrations of PBDE-47. Reactive oxygen species (ROS), apoptosis and the expressions of the inositol-requiring enzyme 1 (IRE1) pathway-related molecules were detected. PBDE-47 exposure increased ROS production and activated the UPR by increasing the expressions of glucose-regulated protein 78 (GRP78), IRE1, X-box-binding protein-1 (XBP1), phosphorylation of c-jun N-terminal kinase (JNK) and GADD153/C/EBP homologous protein (CHOP) genes in SH-SY5Y cells. The apoptotic rate increased with the remarkable up-regulation of the Bax/Bcl-2 ratio after IRE1 knockdown, demonstrating the anti-apoptotic role of IRE1. Furthermore, the expressions of CHOP, XBP1 and JNK were down-regulated indicating that IRE1 may activate these key molecules related to apoptosis. PBDE-47 exposure can increase ROS production and activate the IRE1 pathway of the UPR in SH-SY5Y cells contributing to its toxicity. The IRE1 pathway may have both protective and proapoptotic effects on SH-SY5Y cells. PMID- 22543053 TI - The development of a novel dry powder inhaler. AB - A novel active and multi-dose dry powder inhaler (DPI) was developed and evaluated to deliver a small quantity (100-500 MUg) of pure drug without any excipient. This dry powder inhaler utilized two compressed air flows to dispense and deliver drug powder: the primary flow aerosolizes the drug powder from its pocket and the secondary flow further disperses the aerosol. In vitro tests by Anderson Cascade Impactor (ACI) indicated that the fine particle fraction (FPF) (<4.7 MUm) of drug delivery could reach over a range of 50-70% (w/w). Emitted dose tests showed that delivery efficiency was above 85% and its relative standard deviation (RSD) was under 10%. Confocal microscopy was used to confirm the deposition of fluorescently labeled spray-dried powder in rabbit lungs. Also, a chromatographic method was used to quantify drug deposition. The results of animal tests showed that 57% of aerosol deposited in the rabbit lung and 24% deposited in its trachea. All the results implied that this novel active dry powder inhaler could efficiently deliver a small quantity of fine drug particles into the lung with quite high fine particle fraction. PMID- 22543054 TI - Prenatal bisphenol a exposure and child behavior in an inner-city cohort. AB - BACKGROUND: Experimental laboratory evidence suggests that bisphenol A (BPA), an endocrine disruptor, is a neurodevelopmental toxicant. However, there have been limited and inconclusive results with respect to sex-specific BPA effects on child behavior. OBJECTIVE: We examined the association between prenatal BPA exposure and child behavior, adjusting for postnatal BPA exposure and hypothesizing sex-specific effects. METHODS: We followed African-American and Dominican women and their children from pregnancy to child's age 5 years, collecting spot urine samples from the mothers during pregnancy (34 weeks on average) and from children between 3 and 4 years of age to estimate BPA exposure. We assessed child behavior between 3 and 5 years of age using the Child Behavior Checklist (CBCL) and used generalized linear models to test the association between BPA exposure and child behavior, adjusting for potential confounders. RESULTS: The analysis was conducted on 198 children (87 boys and 111 girls). Among boys, high prenatal BPA exposure (highest quartile vs. the lowest three quartiles) was associated with significantly higher CBCL scores (more problems) on Emotionally Reactive [1.62 times greater; 95% confidence interval (CI): 1.13, 2.32] and Aggressive Behavior syndromes (1.29 times greater; 95% CI: 1.09, 1.53). Among girls, higher exposure was associated with lower scores on all syndromes, reaching statistical significance for Anxious/Depressed (0.75 times as high; 95% CI: 0.57, 0.99) and Aggressive Behavior (0.82 times as high; 95% CI: 0.70, 0.97). CONCLUSION: These results suggest that prenatal exposure to BPA may affect child behavior, and differently among boys and girls. PMID- 22543055 TI - Multiple independent origins of mitochondrial control region duplications in the order Psittaciformes. AB - Mitochondrial genomes are generally thought to be under selection for compactness, due to their small size, consistent gene content, and a lack of introns or intergenic spacers. As more animal mitochondrial genomes are fully sequenced, rearrangements and partial duplications are being identified with increasing frequency, particularly in birds (Class Aves). In this study, we investigate the evolutionary history of mitochondrial control region states within the avian order Psittaciformes (parrots and cockatoos). To this aim, we reconstructed a comprehensive multi-locus phylogeny of parrots, used PCR of three diagnostic fragments to classify the mitochondrial control region state as single or duplicated, and mapped these states onto the phylogeny. We further sequenced 44 selected species to validate these inferences of control region state. Ancestral state reconstruction using a range of weighting schemes identified six independent origins of mitochondrial control region duplications within Psittaciformes. Analysis of sequence data showed that varying levels of mitochondrial gene and tRNA homology and degradation were present within a given clade exhibiting duplications. Levels of divergence between control regions within an individual varied from 0-10.9% with the differences occurring mainly between 51 and 225 nucleotides 3' of the goose hairpin in domain I. Further investigations into the fates of duplicated mitochondrial genes, the potential costs and benefits of having a second control region, and the complex relationship between evolutionary rates, selection, and time since duplication are needed to fully explain these patterns in the mitochondrial genome. PMID- 22543057 TI - Biospecimen reporting for improved study quality (BRISQ). PMID- 22543056 TI - Capacity of capsazepinoids to relax human small airways and inhibit TLR3-induced TSLP and IFNbeta production in diseased bronchial epithelial cells. AB - Thymic stromal lymphopoietin (TSLP), an immunomodulating potentially disease inducing cytokine, is overproduced in TLR3-stimulated bronchial epithelial cells from asthmatic donors whereas production of antiviral IFNbeta is deficient. It is of therapeutic interest that capsazepine inhibits epithelial TSLP and relaxes human small airways with similar potencies. However, it is not known if other capsazepine-like compounds share such dual actions. This study explores epithelial anti-TSLP and anti-IFNbeta effects of capsazepine and novel capsazepine-like bronchorelaxants. We used primary bronchial epithelial cells from asthmatic and chronic obstructive pulmonary disease (COPD) donors, and human small airways dissected from surgically removed lungs. Seven novel capsazepinoids were about 10 times, and one compound (RES187) >30 times, more potent than capsazepine as relaxants of LTD(4)-contracted small airways. TLR3-induced TSLP, TNFalpha, CXCL8, and IFNbeta mRNA and protein levels were dose-dependently and non-selectively inhibited by capsazepine, equally in cells from asthmatic and COPD donors. The novel compounds, except RES187, reduced TSLP and IFNbeta but none are more potent than capsazepine. Only capsazepine consistently inhibited TNFalpha and CXCL8 production and attenuated TLR3-induced epithelial NF-kappaB signalling. Hence, the present compounds did not separate between inhibition of TLR3-induced epithelial TSLP and IFNbeta, but all compounds, except capsazepine, did separate between the bronchorelaxant and the epithelial immune effects. We conclude that similar mechanisms may be involved in capsazepine-like inhibition of TLR3-induced epithelial TSLP and IFNbeta and that these are distinct from mechanisms involved in relaxation of small airways by these compounds. PMID- 22543058 TI - Examination of an antecedent communication intervention to reduce tangibly maintained challenging behavior: a controlled analog analysis. AB - We examined the influence of an antecedent communication intervention on challenging behavior for three students with developmental disorders. Students were taught to request tangible items that were identified as reinforcers for challenging behavior in a prior functional analysis. Individual participant multielement and reversal designs were used to compare the effects of the antecedent communication intervention versus a no antecedent communication intervention condition. Immediately following the antecedent manipulations students were exposed to the tangible condition of the functional analysis. Results indicate that the antecedent communication intervention reduced challenging behavior in the subsequent tangible test condition for all three students. The importance of examining antecedent interventions to treat challenging behavior from a function analytic perspective is discussed. PMID- 22543059 TI - The Motor-Proficiency-Test for children between 4 and 6 years of age (MOT 4-6): an investigation of its suitability in Greece. AB - Given the negative influence of motor difficulties on people's quality of life their early identification seems to be crucial and consequently the information provided by a sound assessment tool is of great importance. The aim of this study was to examine the suitability of the MOT 4-6 (Zimmer & Volkamer, 1987) for use with preschoolers in Greece. Seven hundred and seventy-eight Greek children aged 48-71 months participated in the study. The two-way ANOVA used on total MOT performance revealed significant differences among the age groups formed in preschool age within Greeks, while boys' and girls' scores were quite similar. From the comparisons of Greeks' scores with the German standardization sample's ones, statistically significant differences were found in two age groups. However according to the Cohen's d effect size they were not of great importance. The distribution of Greeks' scores according to the test cut-offs, revealed that the MOT can differentiate all levels of performance, although a slight deviation from the distribution of Germans' scores was noticed. Finally, both the test-retest reliability and internal consistency of the test were found to be excellent. The MOT 4-6 seems to be a valuable motor assessment tool for Greek preschoolers. Regarding its norms, despite the minor differences that were noticed between the motor development of Greek and German preschoolers, their adjustment was thought to be unnecessary. Instead of lowering the norms, efforts for preventing the motor performance decline should be enhanced. PMID- 22543060 TI - Serum proteomic signature of human chagasic patients for the identification of novel potential protein biomarkers of disease. AB - Chagas disease is initiated upon infection by Trypanosoma cruzi. Among the health consequences is a decline in heart function, and the pathophysiological mechanisms underlying this manifestation are not well understood. To explore the possible mechanisms, we employed IgY LC10 affinity chromatography in conjunction with ProteomeLab PF2D and two-dimensional gel electrophoresis to resolve the proteome signature of high and low abundance serum proteins in chagasic patients. MALDI-TOF MS/MS analysis yielded 80 and 14 differentially expressed proteins associated with cardiomyopathy of chagasic and other etiologies, respectively. The extent of oxidative stress-induced carbonyl modifications of the differentially expressed proteins (n = 26) was increased and coupled with a depression of antioxidant proteins. Functional annotation of the top networks developed by ingenuity pathway analysis of proteome database identified dysregulation of inflammation/acute phase response signaling and lipid metabolism relevant to production of prostaglandins and arachidonic acid in chagasic patients. Overlay of the major networks identified prothrombin and plasminogen at a nodal position with connectivity to proteome signature indicative of heart disease (i.e., thrombosis, angiogenesis, vasodilatation of blood vessels or the aorta, and increased permeability of blood vessel and endothelial tubes), and inflammatory responses (e.g., platelet aggregation, complement activation, and phagocyte activation and migration). The detection of cardiac proteins (myosin light chain 2 and myosin heavy chain 11) and increased levels of vinculin and plasminogen provided a comprehensive set of biomarkers of cardiac muscle injury and development of clinical Chagas disease in human patients. These results provide an impetus for biomarker validation in large cohorts of clinically characterized chagasic patients. PMID- 22543061 TI - Quantitative proteomics targeting classes of motif-containing peptides using immunoaffinity-based mass spectrometry. AB - The development of high-performance technology platforms for generating detailed protein expression profiles, or protein atlases, is essential. Recently, we presented a novel platform that we termed global proteome survey, where we combined the best features of affinity proteomics and mass spectrometry, to probe any proteome in a species independent manner while still using a limited set of antibodies. We used so called context-independent-motif-specific antibodies, directed against short amino acid motifs. This enabled enrichment of motif containing peptides from a digested proteome, which then were detected and identified by mass spectrometry. In this study, we have demonstrated the quantitative capability, reproducibility, sensitivity, and coverage of the global proteome survey technology by targeting stable isotope labeling with amino acids in cell culture-labeled yeast cultures cultivated in glucose or ethanol. The data showed that a wide range of motif-containing peptides (proteins) could be detected, identified, and quantified in a highly reproducible manner. On average, each of six different motif-specific antibodies was found to target about 75 different motif-containing proteins. Furthermore, peptides originating from proteins spanning in abundance from over a million down to less than 50 copies per cell, could be targeted. It is worth noting that a significant set of peptides previously not reported in the PeptideAtlas database was among the profiled targets. The quantitative data corroborated well with the corresponding data generated after conventional strong cation exchange fractionation of the same samples. Finally, several differentially expressed proteins, with both known and unknown functions, many relevant for the central carbon metabolism, could be detected in the glucose- versus ethanol-cultivated yeast. Taken together, the study demonstrated the potential of our immunoaffinity-based mass spectrometry platform for reproducible quantitative proteomics targeting classes of motif containing peptides. PMID- 22543062 TI - The protective of hydrogen on stress-induced gastric ulceration. AB - Stress ulceration frequently occurs as a result of major stressful events and hydroxyl radical (?OH) is one of the major causative factors for it. Recently, it has been proved that hydrogen, a potent selectively ?OH scavenger, can effectively protect animals against ROS-induced tissue damage. In like manner, we hypothesize that hydrogen may have a protective effect against stress ulceration. Gastric ulceration was induced by the method of cold restraint stress. Rats in the hydrogen treatment group received hydrogen-rich saline (10 mL/kg body weight) 5 min before the stress. At 6h post-stress, gastric corpus mucosa was harvested for the measurement of malondialdehyde, protein carbonyl, 8-hydroxy desoxyguanosine, glutathione, superoxide dismutase, myeloperoxidase, TNF-alpha, IL-1beta and cytokine-induced neutrophils chemoattractant-1. In addition, western blotting was used to determine the expression of p38 MAPK, P-p38 MAPK, P-JNk, JNK, Bcl-xl, Bax and cleaved caspase-3. Nuclear translocation of NF-kappaB was assessed by electrophoretic mobility shift assay. Gastric mucosa structure and mucosal epithelial cells apoptosis were measured at 12h post-stress. Our present study showed that hydrogen treatment lessened the stress-induced lipid peroxidation, protein carbonyl and DNA oxidant and improved tissue antioxidant potential. In addition, hydrogen mitigated inflammatory response and neutrophils infiltration with suppressing the activity of P-p38 MAPK, P-JNk and NF-kappaB. Importantly, hydrogen ameliorated gastric mucosa damage with preventing cell apoptosis. Furthermore, the up-regulation of cleaved caspase-3, Bax and down regulation of Bcl-xl expression were blocked by hydrogen treatment. In conclusion, hydrogen treatment effectively ameliorated stress-associated gastric mucosa damage via its anti-oxidant, anti-inflammatory and anti-apoptotic effects. PMID- 22543063 TI - There is no association between the circadian clock gene HPER3 and cognitive dysfunction after noncardiac surgery. AB - BACKGROUND: The specific clock-gene PERIOD3 is important with regard to circadian rhythmicity, sleep homeostasis, and cognitive function. The allele PER3(5/5) has been associated with worse cognitive performance in response to sleep deprivation. We hypothesized that patients with the PER3(5/5) genotype would have an increased risk of postoperative cognitive dysfunction (POCD) 1 week after noncardiac surgery. METHODS: Blood samples were analyzed from 93 patients with POCD and 186 patients without POCD from a completed multicenter study. The study population comprised patients ages 40 years and older undergoing noncardiac surgery who were tested preoperatively and 1 week after surgery with a neuropsychological test battery comprising 7 subtests. PER3 genotypes were determined by polymerase chain reaction analysis of DNA from blood samples (Clinicaltrials.gov identifier NCT01088100). RESULTS: The frequencies of the 3 genotypes were 11.8% (32 patients) PER3(5/5), 41.7% (113 patients) PER3(4/5), and 46.5% (126 patients) PER3(4/4). No significant difference was found in the distribution of the 3 genotypes according to POCD at 1 week (P = 0.68). Twelve percent (6% to 21%) of the patients with POCD and 12% (7% to 17%) of the patients without POCD had the PER3(5/5) genotype. The difference of the incidence of POCD/ POCD for the PER3(5/5) genotype was 1% (-7% to 10%). A significantly higher Z score was found in patients having the PER3(4/4) in 1 of the neuropsychological tests (error score of the Concept Shifting Test) (Bonferroni corrected P = 0.042). CONCLUSION: No significant association was found between the clock-gene PER3(5/5) genotype and POCD at 1 week after noncardiac surgery. If PER3(5/5) does worsen cognitive performance, the incidence is <10% of patients. PMID- 22543064 TI - Detection of tidal recruitment/overdistension in lung-healthy mechanically ventilated patients under general anesthesia. AB - BACKGROUND: The volume-dependent single compartment model (VDSCM) has been applied for identification of overdistension in mechanically ventilated patients with acute lung injury. In this observational study we evaluated the use of the VDSCM to identify tidal recruitment/overdistension induced by tidal volume (Vt) and positive end-expiratory pressure (PEEP) in lung-healthy anesthetized subjects. METHODS: Fifteen patients (ASA physical status I-II) undergoing general anesthesia for elective plastic breast reconstruction surgery were mechanically ventilated in volume-controlled ventilation (VCV), with Vt of 8 mL*kg(-1) and PEEP of 0 cm H(2)O. With these settings, ventilatory mode was randomly adjusted in VCV or pressure-controlled ventilation (PCV) and PEEP was sequentially increased from 0 to 5 and 10 cm H(2)O, 5 min per step. Thereafter, PEEP was decreased to 0 cm H(2)O, Vt increased to 10 mL*kg(-1) and, keeping minute ventilation constant, PEEP was similarly increased to 5 and 10 cm H(2)O. Airway pressure and flow were continuously recorded and fitted to the VDSCM with or without considering flow-dependencies. A "distension index" (%E(2)) derived from the VDSCM was used to assess Vt and PEEP-induced recruitment/overdistension. Positive and negative values of %E(2) suggest tidal overdistension or tidal recruitment, respectively. In addition, the linear respiratory system elastance was calculated. Comparisons among variables at each PEEP value, Vt setting, ventilatory mode, and regression model considering or not considering flow dependencies were performed with the Wilcoxon-sign rank test for paired samples (P < 0.05). Multiple comparisons were corrected with the Bonferroni method. The relative change in the estimated noisy variance was used as an index of the goodness of fit of the models. RESULTS: VDSCM including the flow-dependent parameter significantly improved estimated noisy variance in almost all experimental conditions (11.2 to 71.4, smallest of the lower and highest of the upper 95% confidence intervals). No differences in %E(2) were observed between VCV and PCV, at comparable Vt and PEEP levels, when flow-dependencies were included in the regression model. The negligence of the flow-dependent parameter systematically led to an underestimation of %E(2) in PCV compared to VCV mode (all P < 0.02). At a given Vt, %E(2) was negative at a PEEP of 0 cm H(2)O and significantly increased with PEEP, being almost 0 at a PEEP of 5 cm H(2)O. At a given level of PEEP, %E(2) significantly increased with Vt. CONCLUSIONS: The distension index %E(2), derived from the VDSCM considering flow-dependencies, seems able to identify tidal recruitment/overdistension induced by Vt and PEEP independent of flow waveform in healthy lung-anesthetized patients. PMID- 22543065 TI - Carboetomidate inhibits alpha4/beta2 neuronal nicotinic acetylcholine receptors at concentrations affecting animals. AB - BACKGROUND: Carboetomidate is an etomidate derivative that produces hypnosis without inhibiting adrenal corticosteroid synthesis. Similar to etomidate, carboetomidate modulates gamma-aminobutyric acid type A receptors, but its effects on other ion channel targets of general anesthetics are unknown. METHODS: We compared etomidate and carboetomidate effects on human N-methyl-d-aspartate receptors or neuronal nicotinic acetylcholine receptors (nnAChRs) expressed in Xenopus oocytes, using 2-microelectrode voltage clamp electrophysiology. RESULTS: Etomidate did not affect either type of receptor at clinically relevant concentrations, whereas carboetomidate concentrations near 50% effective concentration for anesthesia significantly inhibited nnAChRs. CONCLUSIONS: Compared with etomidate, carboetomidate's higher hydrophobicity is associated with greater inhibition of nnAChRs. PMID- 22543066 TI - A scoring system to predict unplanned intubation in patients having undergone major surgical procedures. AB - BACKGROUND: Unplanned tracheal intubation after surgery has been associated with high mortality. Few studies have examined the risk factors for this complication. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (NSQIP) is a multicenter, prospective, outcome-oriented database for patients having undergone major surgical procedures. Using the NSQIP data for the years 2005 to 2007 (n = 231,548) and Cox proportional hazards modeling, we identified risk factors and used them to derive a scoring system to stratify patients' risk of having an unplanned intubation outcome. NSQIP data for the year 2008 (n = 176,031) were then used to validate the scoring system. RESULTS: The variables most predictive of unplanned intubation were patient age (0-4 points), ASA physical status (0-7 points), the presence of preoperative sepsis (3 points), and total operative time (0-4 points). The Unplanned Intubation Risk Index based on the adjusted hazard ratios for these variables, ranging from 0 (lowest risk) to 18 (highest risk), had a 79% accuracy in distinguishing patients requiring unplanned intubation from those not requiring it (area under the receiver operating characteristic curve 0.79, 95% confidence interval 0.79-0.80). When the scoring system was applied to the validation cohort data, its discriminative performance remained virtually unchanged (area under the receiver operating characteristic curve 0.79, 95% confidence interval 0.79-0.80). CONCLUSIONS: A scoring system based on clinical risk factors was able to accurately predict unplanned intubation after surgery. Further investigation is needed to assess the utility of the Unplanned Intubation Risk Index in reducing the incidence of unplanned intubation through improved risk stratification and management in perioperative care. PMID- 22543068 TI - Using time-frequency analysis of the photoplethysmographic waveform to detect the withdrawal of 900 mL of blood. AB - BACKGROUND: We designed this study to determine if 900 mL of blood withdrawal during spontaneous breathing in healthy volunteers could be detected by examining the time-varying spectral amplitude of the photoplethysmographic (PPG) waveform in the heart rate frequency band and/or in the breathing rate frequency band before significant changes occurred in heart rate or arterial blood pressure. We also identified the best PPG probe site for early detection of blood volume loss by testing ear, finger, and forehead sites. METHODS: Eight subjects had 900 mL of blood withdrawn followed by reinfusion of 900 mL of blood. Physiological monitoring included PPG waveforms from ear, finger, and forehead probe sites, standard electrocardiogram, and standard blood pressure cuff measurements. The time-varying amplitude sequences in the heart rate frequency band and breathing rate frequency band present in the PPG waveform were extracted from high resolution time-frequency spectra. These amplitudes were used as a parameter for blood loss detection. RESULTS: Heart rate and arterial blood pressure did not significantly change during the protocol. Using time-frequency analysis of the PPG waveform from ear, finger, and forehead probe sites, the amplitude signal extracted at the frequency corresponding to the heart rate significantly decreased when 900 mL of blood was withdrawn, relative to baseline (all P < 0.05); for the ear, the corresponding signal decreased when only 300 mL of blood was withdrawn. The mean percent decrease in the amplitude of the heart rate component at 900 mL blood loss relative to baseline was 45.2% (38.2%), 42.0% (29.2%), and 42.3% (30.5%) for ear, finger, and forehead probe sites, respectively, with the lower 95% confidence limit shown in parentheses. After 900 mL blood reinfusion, the amplitude signal at the heart rate frequency showed a recovery towards baseline. There was a clear separation of amplitude values at the heart rate frequency between baseline and 900 mL blood withdrawal. Specificity and sensitivity were both found to be 87.5% with 95% confidence intervals (47.4%, 99.7%) for ear PPG signals for a chosen threshold value that was optimized to separate the 2 clusters of amplitude values (baseline and blood loss) at the heart rate frequency. Meanwhile, no significant changes in the spectral amplitude in the frequency band corresponding to respiration were found. CONCLUSION: A time-frequency spectral method detected blood loss in spontaneously breathing subjects before the onset of significant changes in heart rate or blood pressure. Spectral amplitudes at the heart rate frequency band were found to significantly decrease during blood loss in spontaneously breathing subjects, whereas those at the breathing rate frequency band did not significantly change. This technique may serve as a valuable tool in intraoperative and trauma settings to detect and monitor hemorrhage. PMID- 22543067 TI - Can we make postoperative patient handovers safer? A systematic review of the literature. AB - Postoperative patient handovers are fraught with technical and communication errors and may negatively impact patient safety. We systematically reviewed the literature on handover of care from the operating room to postanesthesia or intensive care units and summarized process and communication recommendations based on these findings. From >500 papers, we identified 31 dealing with postoperative handovers. Twenty-four included recommendations for structuring the handover process or information transfer. Several recommendations were broadly supported, including (1) standardize processes (e.g., through the use of checklists and protocols); (2) complete urgent clinical tasks before the information transfer; (3) allow only patient-specific discussions during verbal handovers; (4) require that all relevant team members be present; and (5) provide training in team skills and communication. Only 4 of the studies developed an intervention and formally assessed its impact on different process measures. All 4 interventions improved metrics of effectiveness, efficiency, and perceived teamwork. Most of the papers were cross-sectional studies that identified barriers to safe, effective postoperative handovers including the incomplete transfer of information and other communication issues, inconsistent or incomplete teams, absent or inefficient execution of clinical tasks, and poor standardization. An association between poor-quality handovers and adverse events was also demonstrated. More innovative research is needed to define optimal patient handovers and to determine the effect of handover quality on patient outcomes. PMID- 22543069 TI - Femoral nerve block with selective tibial nerve block provides effective analgesia without foot drop after total knee arthroplasty: a prospective, randomized, observer-blinded study. AB - BACKGROUND: Sciatic nerve block when combined with femoral nerve block for total knee arthroplasty may provide superior analgesia but can produce footdrop, which may mask surgically induced peroneal nerve injury. In this prospective, randomized, observer-blinded study, we evaluated whether performing a selective tibial nerve block in the popliteal fossa would avoid complete peroneal motor block. METHODS: Eighty patients scheduled for primary total knee arthroplasty were randomized to receive either a tibial nerve block in the popliteal fossa or a sciatic nerve block proximal to its bifurcation in combination with femoral nerve block as part of a multimodal analgesia regimen. Local anesthetic solution of sufficient volume to encircle the target nerve was administered for the block, up to a maximum of 20 mL. General anesthesia was administered for surgery. After emergence from anesthesia, in the recovery room, the presence or absence of peroneal sensory and motor block was noted. Pain scores and opioid consumption were recorded for 24 hours after surgery. RESULTS: The tibial nerve block and sciatic nerve block were performed 1.7 cm (99% CI, 1.3 to 2.1) and 9.4 cm (99% CI, 8.3 to 10.5) proximal to the popliteal crease, respectively (99% CI for difference between means: 6.4 to 9.0; P < 0.001). A lower volume of ropivacaine 0.5% was used for the tibial nerve block, 8.7 mL (99% CI, 7.9 to 9.4) versus 15.2 mL (99% CI, 14.9 to 15.5), respectively (99% CI for difference between means, 5.6 to 7.3; P < 0.001). No patient receiving a tibial nerve block developed complete peroneal motor block compared to 82.5% of patients with sciatic nerve block (P < 0.001). There were no significant differences in the pain scores and opioid consumption between the groups. CONCLUSIONS: Tibial nerve block performed in the popliteal fossa in close proximity to the popliteal crease avoided complete peroneal motor block and provided similar postoperative analgesia compared to sciatic nerve block when combined with femoral nerve block for patients undergoing total knee arthroplasty. PMID- 22543070 TI - Tool perception suppresses 10-12Hz MU rhythm of EEG over the somatosensory area. AB - The perception of tools vs. other objects has been shown to activate the premotor (BA6) and somatosensory cortex (BA3), which neurally represent object affordance related to tool manipulability (Proverbio et al., 2011). The earliest tool/non tool discrimination is represented by increased anterior negativity (210-270ms) in response to tools. In this study, we analyzed MU desynchronization with wavelet analysis based on EEG recordings in response to 300 familiar objects vs. tools in 11 participants. The results showed an early 140-175ms MU desynchronization over centro-parietal sites at approximately 10-12Hz during tool perception. The surface scalp distribution of MU power is compatible with neural generators located in the somatosensory cortex, but no source analysis was performed. These results support the hypothesis that there is a temporal and functional relationship between the rapid and transient MU suppression over the centro/parietal area and the successive increase in time-locked post-synaptic potentials (ERPs) in regions processing tool motor affordance. PMID- 22543071 TI - Antipsychotic drugs: pro-cancer or anti-cancer? A systematic review. AB - INTRODUCTION: Important data was recently published on the potential genotoxic or carcinogenic effects of antipsychotics, as well as on their cytotoxic properties on cancer cells, that must be considered by psychiatrists in the benefit/risk ratio of their prescriptions. AIM OF THE STUDY: To answer whether or not antipsychotics, as a class or only some specific molecules, may influence cancer risk among treated patients. METHODS ELIGIBILITY CRITERIA: All studies (in vitro, animal studies and human studies) concerning effects of antipsychotic drugs on cancer development were included. The search paradigm [neoplasms AND (antipsychotic agents OR neuroleptic OR phenothiazine)] was applied to Medline (1966-present) and Web of Science (1975-present). RESULTS: Ninety-three studies were included in the qualitative synthesis. Results can be summarized as follows: (1) patients with schizophrenia may be less likely to develop cancer than the general population, (2) antipsychotics as a class cannot be considered at the moment as at risk for cancer, even if some antipsychotics have shown carcinogenic properties among rodents, (3) phenothiazines seem to have antiproliferative properties that may be useful in multidrug augmentation strategies in various cancer treatments, but their bad tolerance may decrease usage amongst non psychotic patients, and (4) clozapine appears to have a separate status given that this molecule shows antiproliferative effects implied in agranulocytosis as well as a potential increased risk for leukemia. CONCLUSION: Benefit/risk ratio regarding cancer risk is in favor of treating patients with schizophrenia with antipsychotic drugs. The practicing clinician should be reassuring on the subject of cancer risk due to antipsychotic drugs. PMID- 22543072 TI - Increased membrane turnover in the brain in cutaneous anthrax without central nervous system disorder: a magnetic resonance spectroscopy study. AB - Cutaneous anthrax, caused by Bacillus anthracis contacting the skin, is the most common form of human anthrax. Recent studies implicate the presence of additional, possibly toxin-related subtle changes, even in patients without neurological or radiological findings. In this study, the presence of subtle changes in cutaneous anthrax was investigated at the metabolite level using magnetic resonance spectroscopy. Study subjects were consisted of 10 patients with cutaneous anthrax without co-morbid disease and/or neurological findings, and 13 healthy controls. There were no statistical differences in age and gender between two groups. The diagnosis of cutaneous anthrax was based on medical history, presence of a typical cutaneous lesion, large gram positive bacilli on gram staining and/or positive culture for B. anthracis from cutaneous samples. Brain magnetic resonance imaging examination consisted of conventional imaging and single-voxel magnetic resonance spectroscopy. Magnetic resonance spectroscopy was performed by using point-resolved spectroscopy sequence (TR: 2000ms, TE: 136ms, 128 averages). Voxels of 20mm*20mm*20mm were placed in normal-appearing parietal white matter to detect metabolite levels. Cerebral metabolite peaks were measured in normal appearing parietal white matter. N-acetyl aspartate/creatine and choline/creatine ratios were calculated using standard analytical procedures. Patients and controls were not statistically different regarding parietal white matter N-acetyl aspartate/creatine ratios (p=0.902), a finding that implicates the conservation of neuronal and axonal integrity and neuronal functions. However, choline/creatine ratios were significantly higher in patient groups (p=0.001), a finding implicating an increased membrane turnover. In conclusion, these two findings point to a possibly anthrax toxins-related subtle inflammatory reaction of the central nervous system at the cellular level. PMID- 22543073 TI - An in-silico strategy to explore neuroprotection by quercetin in cerebral ischemia: a novel hypothesis based on inhibition of matrix metalloproteinase (MMPs) and acid sensing ion channel 1a (ASIC1a). AB - Cerebral ischemia are caused by acute interruption of the brain arterial blood supply, typically by a thrombus or embolus, leading to neuronal insult and the remainder damage are caused by blood vessel rupture, leading to hemorrhage. Acidosis and matrix metalloproteinase activation are the central and prominent metabolic feature of ischemic brain. The combined inhibition of MMPs and ASIC1a channels can offer a new therapeutic approach in cerebral stroke management. Moreover, the combined inhibition of MMPs and ASIC1a with flavonoids remains unknown against neuroprotection in animal models of cerebral ischemia. Flavonoids are believed to act as health-promoting substances and some of them have antioxidant and anti-inflammatory properties. Therefore, the target of the present study was in-silico evaluation of the neuroprotective efficacy of quercetin in rat model of focal cerebral ischemia/reperfusion (I/R) injury and efforts were made to analyze its inhibitory effects on MMPs activation and ASIC1a channels mediated downstream survival/damage mechanisms. Thus on the basis of our in-silico studies we hypothesize that quercetin can be a neuroprotective agent in rat model of focal cerebral ischemia/reperfusion (I/R) injury due to its inhibitory effects on MMPs activation and ASIC1a channels mediated downstream survival/damage mechanisms. PMID- 22543074 TI - CREG mediated adventitial fibroblast phenotype modulation: a possible therapeutic target for proliferative vascular disease. AB - Proliferative vascular diseases, of which neointimal formation is a key pathological feature, cause significant morbidity and mortality worldwide. Adventitia is the outermost connective tissue that surrounds an artery. In recent years, accumulating data indicate that adventitial fibroblasts participate in the formation of neointimal lesions. Our previous studies have demonstrated that cellular repressor of E1A-stimulated genes (CREG) plays critical roles in reducing neointimal hyperplasia by promoting vascular smooth muscle cell (VSMC) differentiation and grow arrest and inhibiting migration. Hence, it is plausible that genetical modification with CREG gene in adventitial fibroblasts might inhibit angiotensin II-induced transdifferentiation to myofibroblasts, proliferation and migration, as well as adventitial thickening, finally decreasing neointimal formation. Possible mechanisms may include CREG direct attenuation of reactive oxygen species derived from reduced cathepsin-dependent activation of NADPH oxidase and indirect suppression of the downstream of NADPH oxidase including ERK1/2, JNK and p38 MAPK pathways in adventitial fibroblasts. Therefore, CREG may be a potential therapeutic target for proliferative vascular diseases. PMID- 22543076 TI - Hypothesis about brilliant lights by bioluminescent photons in near death experiences. AB - In near death experiences (NDEs), seeing a brilliant light may arise in the recovery period following cardiac arrest, but the subjects can think that these experiences had happened during the actual period itself. Here we hypothesize a biophysical explanation about the encounter with a brilliant light in NDEs. Accordingly, meeting brilliant light in NDEs is due to the reperfusion that induces unregulated overproduction of free radicals and excited biomolecules among them in numerous parts in the visual system. Unregulated free radicals and excited species can produce a transient increase of bioluminescent photons in different areas of the visual system. If this excess of bioluminescent photon emission exceeds a threshold, they can appear as (phosphene) lights in our mind. In other words, seeing a brilliant light in NDEs may due to bioluminescent photons simultaneously generated in the recovery phase of numerous areas of the visual system and the brain interprets these intrinsic bioluminescent photons as if they were originated from the external visual world. Although our biophysical explanation about brilliant light phenomenon in NDEs can be promising, we do not reject further potential notions. PMID- 22543075 TI - Fast-spiking interneurons and gamma oscillations may be involved in the antidepressant effects of ketamine. AB - Accumulating lines of evidence have indicated that a non-selective N-methyl-d aspartate (NMDA) receptor antagonist ketamine exerts fast and robust antidepressant effects via stimulating glutamate transmission and activating the glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Moreover, NMDA receptor antagonist has the ability to reduce the activity of fast-spiking (FS) interneurons which results in the disinhibition of pyramidal neurons and increases the glutamate transmission. We therefore hypothesize that FS interneurons may play an important role in the antidepressant effects of ketamine. Quantification of FS interneurons function via analyzing gamma oscillations may guide the antidepressant therapy of ketamine in clinical practice. PMID- 22543077 TI - Is premature ejaculation an impulse control disorder? AB - Premature ejaculation (PE) is defined as persistent or recurrent ejaculation with minimal sexual stimulation that occurs before the participant wishes to ejaculate and is associated with marked distress or interpersonal difficulty. Impulse control disorders (ICDs) are grouped as a heterogeneous cluster of disorders linked by a "failure to resist" impulses to engage in harmful, disturbing or distressing behaviours. I hypothesise that premature ejaculation is an impulse control disorder. ICDs share features with PE aspects of impaired control, rapid responses to stimuli and hypersensitivity. These disorders often occur with subjective and social distress for patients. In addition to these features, the neurotransmitter systems have been similarly implicated in ICDs and PE. The same treatment options further support a relationship between ICDs and PE. The behaviours likely exist on a spectrum. PMID- 22543078 TI - Dysbiosis of Gut Microbiota (DOGMA)--a novel theory for the development of Polycystic Ovarian Syndrome. AB - Polycystic Ovarian Syndrome (PCOS) is the most common cause for menstrual disturbance and impaired ovulation, effecting one in twenty women of reproductive age. As the majority of women with PCOS are either overweight or obese, a dietary or adipose tissue related trigger for the development of the syndrome is quite possible. It has now well established that PCOS is characterised by a chronic state of inflammation and insulin resistance, but the precise underlying triggers for these two key biochemical disturbances is presently unknown. In this paper we present support for a microbiological hypothesis for the development of PCOS. This novel paradigm in PCOS aetiology suggests that disturbances in bowel bacterial flora ("Dysbiosis of Gut Microbiota") brought about by a poor diet creates an increase in gut mucosal permeability, with a resultant increase in the passage of lipopolysaccaride (LPS) from Gram negative colonic bacteria into the systemic circulation. The resultant activation of the immune system interferes with insulin receptor function, driving up serum insulin levels, which in turn increases the ovaries production of androgens and interferes with normal follicle development. Thus, the Dysbiosis of Gut Microbiota (DOGMA) theory of PCOS can account for all three components of the syndrome-anovulation/menstrual irregularity, hyper-androgenism (acne, hirsutism) and the development of multiple small ovarian cysts. PMID- 22543079 TI - The schizoictal syndrome. AB - There are several common denominators of schizophrenia and epilepsy including models of pathogenesis as well as their clinical occurrence mainly referring to schizophrenia-like syndrome in epilepsy or similar clinical entities [1]. Up to now it has not been emphasized that a process of synchronization or desynchronization of neuronal cell structures within the context of neuronal plasticity might be a plausible pathogenetic mechanism of epilepsy as well as schizophrenia. Clinical as well as therapeutical implications of this hypothesis on the basis of scientific evidence are discussed. PMID- 22543080 TI - Stability analysis of some delay differential inequalities with small time delays and its applications. AB - In this paper, we discuss the asymptotic stability of the trajectories governed by the scalar delay differential inequalities: D+x(t)<= a(t)x(t)+b(t)sup(0<=s<=tau)x(t-s). Here, the requirements on a(t) and b(t) are more relaxed than those in previous works. For example, a(t), b(t), and a(t)-b(t) are not necessarily nonnegative. We prove that when tau is small, the asymptotic stability of x(t) can be obtained if the time average of a(t)-b(t) on some fixed length T is lower bounded by some positive delta. And we explicitly give the upper bound of tau. We also give two applications of the theoretical results. First, we consider self synchronization in Hopfield networks with time varying connections. Then we investigate consensus in networks with time varying topologies and arbitrary coupling weights. In both applications, we extend some of our previous works where time delays are not considered. At last, two numerical examples with simulations are provided to illustrate the effectiveness of the theoretical results. PMID- 22543081 TI - Dobutamine "stress" test and latent cardiac susceptibility to inhaled diesel exhaust in normal and hypertensive rats. AB - BACKGROUND: Exercise "stress" testing is a screening tool used to determine the amount of stress for which the heart can compensate before developing abnormal rhythm or ischemia, particularly in susceptible persons. Although this approach has been used to assess risk in humans exposed to air pollution, it has never been applied to rodent studies. OBJECTIVE: We hypothesized that a single exposure to diesel exhaust (DE) would increase the risk of adverse cardiac events such as arrhythmia and myocardial ischemia in rats undergoing a dobutamine challenge test, which can be used to mimic exercise-like stress. METHODS: Wistar-Kyoto normotensive (WKY) and spontaneously hypertensive (SH) rats implanted with radiotelemeters and a chronic intravenous catheter were whole-body exposed to 150 MUg/m3 DE for 4 hr. Increasing doses of dobutamine, a beta1-adrenergic agonist, were administered to conscious unrestrained rats 24 hr later to elicit the cardiac response observed during exercise while heart rate (HR) and electrocardiogram (ECG) were monitored. RESULTS: A single exposure to DE potentiated the HR response of WKY and SH rats during dobutamine challenge and prevented HR recovery at rest. During peak challenge, DE-exposed SH rats had lower overall HR variability when compared with controls, in addition to transient ST depression. All DE-exposed animals also had increased arrhythmias. CONCLUSIONS: These results are the first evidence that rats exhibit stress induced cardiac dysrhythmia and ischemia sensitivity comparable to humans after a single exposure to a toxic air pollutant, particularly when in the presence of underlying cardiovascular disease. Thus, exposure to low concentrations of air pollution can impair the heart's ability to respond to stress and increase the risk of subsequent triggered dysfunction. PMID- 22543082 TI - Cisplatin-induced acute renal failure in mice is mediated by chymase-activated angiotensin-aldosterone system and interleukin-18. AB - Mechanism(s) of cisplatin-induced acute renal failure, as manifested by increases in blood urea nitrogen and creatinine, was evaluated in relation to production and activation of endogenous mediator(s) in mice. In interleukin (IL)-18 deficient (IL-18KO) mice, cisplatin failed to induce acute renal failure. Administration of recombinant IL-18 prior to cisplatin restored acute renal failure in IL-18KO mice. Accumulation of cisplatin in the kidney was not different in IL-18KO and wild-type (WT) mice, but, clearance of cisplatin was more rapid in IL-18KO mice than in WT mice. Cisplatin increased serum levels of aldosterone and angiotensin II in WT mice, but only angiotensin II levels in IL 18 KO mice. Administration of IL-18 augmented plasma levels of aldosterone and angiotensin II in WT mice. Eplerenone, an aldosterone receptor blocker, TY-51469, a chymase inhibitor and PD123319, a selective angiotensin II type 2 (AT2) receptor antagonist, but not benazepril, an angiotensin-converting enzyme inhibitor, and candesartan, a selective angiotensin II type 1 (AT1) receptor antagonist improved acute renal failure caused by cisplatin, confirming involvement of IL-18, aldosterone and angiotensin II in cisplatin-induced, chymase-dependent acute renal failure in mice. These results show that IL-18, aldosterone and angiotensin II synergistically act to prolong the accumulation of cisplatin in the kidney, leading to acute renal failure. Combined therapy with inhibitors for chymase and aldosterone receptors or AT2 receptors might reduce acute renal failure induced by cisplatin. PMID- 22543083 TI - Stephanthraniline A inhibits the proliferation and activation of T cells in vitro and in vivo. AB - Stephanthraniline A (STA) isolated from the stems of Stephanotis mucronata (Blanco) Merr. was evaluated for their suppression on T cells' immune responses in vitro and in vivo. In vivo, oral administration of STA significantly inhibited T cell-mediated delayed-type hypersensitivity (DTH) response. In vitro, STA has inhibitory effects on T cell proliferation induced by CD3/CD28 cross-linking or Con A; additionally, CD4(+) T cells are more sensitive to this inhibition than CD8(+) T cells. STA also suppressed the production of cytokines (IL-2, IFN-gamma, IL-4 and IL-17) and mRNA expression of the genes associated with T cell activation, proliferation and differentiation. Our data indicate that STA inhibits the proliferation of T cells by inducing cell cycle arrest but not inducing apoptosis. The inhibitory mechanism of STA on T cells was correlated with the gene change related to multi-signal transduction pathways. Furthermore, we also provided lines of evidence that STA, distinct from glucocorticoids, did not activate the glucocorticoid receptor. These findings would be beneficial for further understanding the therapeutic effects of S. mucronata in the treatment of autoimmune diseases. It also suggested the potential of the natural steroid STA as the effective candidate compounds for use in the treatment of inflammatory and autoimmune diseases. PMID- 22543084 TI - Candesartan, an angiotensin II type 1 receptor antagonist, inhibits pathological retinal neovascularization by downregulating VEGF receptor-2 expression. AB - Several studies have examined the anti-angiogenic effects of angiotensin II type 1 (AT(1)) receptor antagonists; however, the mechanisms underlying these effects are currently unclear. In the present study, we examined the efficacy and the mechanism of candesartan, an AT(1) receptor antagonist, in suppressing pathological retinal neovascularization. We used an in vivo murine oxygen-induced retinopathy (OIR) model and also studied the in vitro proliferation and migration of human retinal microvascular endothelial cells (HRMECs) induced by vascular endothelial growth factor (VEGF)-A. The regulation of angiogenesis-associated genes such as hypoxia-inducible factor (HIF-1alpha), VEGF-A, VEGF receptor-1, and VEGF receptor-2 was evaluated with real-time RT-PCR in the OIR model. In the OIR model, candesartan suppressed the pathological neovascularization in a dose dependent manner, but did not prevent the physiological angiogenesis. However, candesartan did not inhibit VEGF-A-induced proliferation or migration in HRMECs in the in vitro study. When administered interperitoneally in the OIR model, candesartan reduced the upregulation of VEGF receptor-2 in the retina, but had no effects in the other angiogenesis-related genes, such as HIF-1alpha, VEGF-A, and VEGF receptor-1. These findings indicate that candesartan inhibited the retinal pathological neovascularization, at least in part, by suppressing the expression of VEGF receptor-2, independent of VEGF signaling cascade. Therefore, candesartan may be a useful therapeutic target for the inhibition of retinal neovascularization that has a low risk of serious side effects. PMID- 22543085 TI - Involvement of 5-HT7 receptors in the pathogenesis of temporal lobe epilepsy. AB - The 5-hydroxytryptamine 7 (5-HT(7)) receptor is the most recently classified member of the serotonin receptor family. The localization of 5-HT(7) receptors and the biological activity of its ligands have suggested that 5-HT(7) receptors might be involved in the pathogenesis of epilepsy. In the present study, we investigated the correlation between temporal lobe epilepsy and 5-HT(7) receptors using pilocarpine-induced rat models of temporal lobe epilepsy and surgical samples of temporal neocortex from intractable epilepsy patients. An analysis of electroencephalogram (EEG) and behavioral changes before and after the treatment of SB269970 hydrochloride (a selective 5-HT(7) receptor antagonist, 10 mg/kg, i.p.) and AS19 (a selective 5-HT(7) receptor agonist, 10 mg/kg, s.c.) demonstrated that in epileptic rats the activation of 5-HT(7) receptors could increase the number of seizures, which could be reduced by a 5-HT(7) receptor antagonist. Moreover, the expression of 5-HT(7) receptors was higher in the epilepsy group compared with the nonepileptic group in both rat and human brain tissues. The present results suggested that 5-HT(7) receptors participate in the pathogenesis of temporal lobe epilepsy, and a 5-HT(7) receptor antagonist may be used as a therapeutic alternative for temporal lobe epilepsy. PMID- 22543086 TI - Neutrophil recruitment is inhibited by nicotinamide in experimental pleurisy in mice. AB - Several emerging lines of evidence support an anti-inflammatory role for nicotinamide and other vitamin B components. However, the mechanisms underlying their activity remain unclear. In the present study, we investigated the ability of nicotinamide to inhibit both neutrophil recruitment in IL-8-, LTB(4)- or carrageenan-induced pleurisy in mice and the rolling and adherence of neutrophils. Nicotinamide inhibited IL-8-, LTB(4)- and carrageenan-induced neutrophil migration, KC production and carrageenan-induced neutrophil rolling and adherence. We propose that the effects of nicotinamide in inhibiting neutrophil recruitment in carrageenan-induced pleurisy may be due to the ability of nicotinamide to inhibit the action of IL-8 and LTB(4), decrease KC production, and inhibit early events that regulate leukocyte migration from blood vessels into tissue. PMID- 22543088 TI - Age-related changes in the use of regular patterns for auditory scene analysis. AB - A recent approach to auditory processing suggests a close relationship of regularity processing in auditory sensory memory (ASM) and stream segregation, such that within-stream regularities can be used to stabilize stream segregation. The present study investigates age-related changes in how regular patterns are used for auditory scene analysis (ASA), when the stream containing the regularity is attended or unattended. In order to accomplish an intensity level deviant detection task, participants had to segregate the task-relevant pure tone sequence from an irrelevant distractor pure tone sequence, which randomly varied in level. In three conditions a simple spectro-temporal regularity ("Isochronous"), a more complex spectro-temporal regularity ("Rhythmic"), or no regularity ("Random") was embedded in either the attended target sequence (Experiment 1), or the unattended distractor sequence (Experiment 2). When the sequence containing the regularity was attended, older participants showed a similar increase of performance to younger adults in the conditions with regular patterns ("Isochronous" and "Rhythmic") compared to the "Random" condition. In contrast, when the sequence containing the regularity was unattended, older adults showed a specific performance decline compared to younger adults in the "Isochronous" condition. Results suggest a link between impaired automatic processing of regularities in ASM, and age-related deficits in the use of regular patterns for ASA. PMID- 22543087 TI - Atoh1 expression and function during auditory hair cell regeneration in post hatch chickens. AB - Loss of hair cells in humans leads to irreversible hearing deficits, since auditory hair cells are not replaced. In contrast, hair cells are regenerated in the auditory epithelium of mature birds after damage by non-sensory supporting cells that transdifferentiate into hair cells by mitotic and/or non-mitotic mechanisms. Factors controlling these processes are poorly understood. The basic helix-loop-helix transcription factor ATOH1 is both necessary and sufficient for developmental hair cell differentiation, but it is unclear if it plays the same role in the mitotic and non-mitotic pathways in hair cell regeneration. We examined Atoh1 expression and function during hair cell regeneration in chickens. Atoh1 transcripts were increased in many supporting cells in the damaged auditory epithelium shortly after ototoxin administration and later became restricted to differentiating hair cells. Fate-mapping in vitro using an Atoh1 enhancer reporter demonstrated that only 56% of the supporting cells that spontaneously upregulate Atoh1 enhancer activity after damage acquired the hair cell fate. Inhibition of notch signaling using a gamma secretase antagonist stimulated an increase in Atoh1 reporter activity and induced a higher proportion of supporting cells with Atoh1 activity (73%) to differentiate as hair cells. Forced overexpression of Atoh1 in supporting cells triggered 66% of them to acquire the hair cell fate and nearly tripled their likelihood of cell cycle entry. These findings demonstrate that Atoh1 is broadly upregulated in supporting cells after damage, but a substantial proportion of supporting cells with Atoh1 activation fails to acquire hair cell features, in part due to gamma secretase-dependent activities. PMID- 22543089 TI - A long-term high-fat diet increases oxidative stress, mitochondrial damage and apoptosis in the inner ear of D-galactose-induced aging rats. AB - In humans, chronic dyslipidemia associated with elevated triglycerides may reduce auditory function. However, there is little evidence available in the literature concerning the effects of a long-term high-fat diet (HFD) on the inner ears of animals. The purpose of this study was to investigate the effect of 12 month-HFD on the inner ear of Sprague-Dawley rats and on the D-galactose (D-gal)-induced aging process in the inner ear. We found that 12 month-HFD markedly elevated the auditory brainstem response (ABR) threshold in the high-frequency region. The HFD significantly increased the generation of reactive oxygen species (ROS) and the expressions of NADPH oxidase (NOX) and the uncoupling proteins (UCP). Furthermore, an elevated accumulation of the mitochondrial DNA (mtDNA) common deletion (CD) and mitochondrial ultrastructural changes in the inner ear suggested that there was mitochondrial damage in response to the excessive fat intake. The expression level of cleaved caspase-3 and the number of terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick end-labelling (TUNEL)-positive cells in the inner ear were increased by the HFD. The effects of D-gal on the inner ears were similar with 12 month-HFD. We found that rats receiving both the HFD and D-gal exhibited a greater shift in the ABR threshold, larger increases in the expression levels of NOX, UCP and cleaved caspase-3 and an increased number of TUNEL-positive cells in the inner ear. The present study demonstrated that HFD may induce oxidative stress, mitochondrial damage and apoptosis in the inner ear, and it provided evidence regarding the link between HFD and an increased risk of age-related hearing loss. PMID- 22543090 TI - A comparison of the effects of isoflurane and ketamine anesthesia on auditory brainstem response (ABR) thresholds in rats. AB - The auditory brainstem response (ABR) is an acoustically evoked potential commonly used to determine hearing sensitivity in laboratory animals. Both isoflurane and ketamine/xylazine anesthesia are commonly used to immobilize animals during ABR procedures. Hearing threshold determination is often the primary interest. Although a number of studies have examined the effect of different anesthetics on evoked potential waveforms and growth functions, none have directly compared their effect on ABR hearing threshold estimates. The present study used a within-subject comparison and typical threshold criteria, to examine the effect of isoflurane and ketamine/xylazine on ABR thresholds for clicks and pure-tone stimuli extending from 8 to 32 kHz. At comparable physiological doses, hearing thresholds obtained with isoflurane (1.7% in O(2)) were on average elevated across a broad frequency range by greater than 27 dB compared to ketamine/xylazine (ketamine HCl, 50mg/kg; xylazine, 9 mg/kg). This highly significant threshold effect (F(1,6) = 158.3403, p = 3.51 * 10(-22)) demonstrates a substantial difference between general anesthetics on auditory brainstem sensitivity. Potential mechanisms and implications for ABR threshold determination under anesthesia are discussed. PMID- 22543091 TI - Design and synthesis of cleavable biotinylated dideoxynucleotides for DNA sequencing by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. AB - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS)-based methods have been widely explored for DNA sequencing. We report here the design, synthesis, and evaluation of a novel set of chemically cleavable biotinylated dideoxynucleotides, ddNTPs-N3-biotin, for the DNA polymerase extension reaction and its application in DNA sequencing by mass spectrometry (MS). These nucleotide analogs have a biotin moiety attached to the 5 position of the pyrimidines (C and U) or the 7 position of the purines (A and G) via a chemically cleavable azido-based linker, with different length linker arms serving as mass tags that contribute to large mass differences among the nucleotides. We demonstrate that these modified nucleotides are efficiently incorporated by DNA polymerase, and the DNA strand bearing biotinylated nucleotides is captured by streptavidin-coated beads and efficiently released using tris(2-carboxyethyl)phosphine in aqueous solution, which is compatible with DNA and downstream procedures. We performed Sanger sequencing reactions using these nucleotides to generate DNA fragments for MALDI-TOF MS analysis. Both synthetic DNA and polymerase chain reaction (PCR) products were accurately decoded, and a read length of approximately 37 bases was achieved using these nucleotides in MS sequencing. PMID- 22543092 TI - The use of a synthetic DNA-antibody complex as external reference for chromatin immunoprecipitation. AB - Chromatin immunoprecipitation (ChIP) is an analytical method used to investigate the interactions between proteins and DNA in vivo. ChIP is often used as a quantitative tool, and proper quantification relies on the use of adequate references for data normalization. However, many ChIP experiments involve analyses of samples that have been submitted to experimental treatments with unknown effects, and this precludes the choice of suitable internal references. We have developed a normalization method based on the use of a synthetic DNA antibody complex that can be used as an external reference instead. A fixed amount of this synthetic DNA-antibody complex is spiked into the chromatin extract at the beginning of the ChIP experiment. The DNA-antibody complex is isolated together with the sample of interest, and the amounts of synthetic DNA recovered in each tube are measured at the end of the process. The yield of synthetic DNA recovery in each sample is then used to normalize the results obtained with the antibodies of interest. Using this approach, we could compensate for losses of material, reduce the variability between ChIP replicates, and increase the accuracy and statistical resolution of the data. PMID- 22543093 TI - Spatiotemporal variability during gait initiation in Parkinson's disease. AB - During gait initiation (GI), consistency of foot placement while stepping is important in making successful transitions from a state of stable static posture to an unstable state of dynamic locomotion. In populations characterized by gait dysfunction and postural instability, such as persons with Parkinson's disease (PD), the ability to generate a consistent stepping pattern during GI may be essential in the prevention of falls. However, little is known about GI variability in persons with PD as compared to their healthy elderly peers. Therefore, this study investigated spatiotemporal variability during the first two steps of GI in 46 persons with idiopathic PD and 49 healthy age-matched adults. Stepping characteristics, including the length, width, and time of the first two steps of GI as well as their coefficients of variation (CV) were compared between groups. Persons with PD initiated gait with significantly shorter steps (swing step length=.463 vs. .537 m, stance step length=.970 vs. 1.10 m) and higher variability in step length (swing step CV=8.82 vs. 5.45, stance step CV=6.76 vs. 3.61). Persons with PD also showed significantly higher variability in the time of the swing step (swing step CV=10.0 vs. 7.4). GI variability did not differ significantly between disease stages in persons with PD. Because greater variability in these measures during gait is related to an increased risk of falls, we propose that higher GI variability may play a considerable role in falls frequently observed during transitions from quiet standing in PD. PMID- 22543094 TI - Nucleus of the solitary tract chemical stimulation induces extracellular norepinephrine release in the lateral and basolateral amygdala. AB - The NTS catecholaminergic neurons, activated by a variety of afferent stimuli, are ideally situated to coordinate afferent signaling to multiple brain regions. In particular, there is evidence that systemic epinephrine injections induce a significant increase of norepinephrine (NE) in the amygdala during enhanced memory, which can be disrupted by NTS chemical blockade or interruption of vagal afferents. The present experiment was conducted to obtain information about the levels of NE release induced by activation of the whole NTS, which projects to the lateral and basolateral amygdala. Therefore, we compared NE levels before and after general stimulation of the NTS and the amygdala in anesthetized rats, without any behavioral or vagal stimulation, to find out the degree of noradrenergic activation modulated by the NTS through all its projections to the lateral and basolateral amygdala, as well as the degree of noradrenergic activation which may occur locally in the amygdala through rapid and general activation of this structure. PMID- 22543095 TI - New therapeutic aspect for carvedilol: antifibrotic effects of carvedilol in chronic carbon tetrachloride-induced liver damage. AB - Portal hypertension is a common complication of chronic liver diseases associated with liver fibrosis and cirrhosis. At present, beta-blockers such as carvedilol remain the medical treatment of choice for protection against variceal bleeding and other complications. Since carvedilol has powerful antioxidant properties we assessed the potential antifibrotic effects of carvedilol and the underlying mechanisms that may add further benefits for its clinical usefulness using a chronic model of carbon tetrachloride (CCl4)-induced hepatotoxicity. Two weeks after CCl4 induction of chronic hepatotoxicity, rats were co-treated with carvedilol (10mg/kg, orally) daily for 6weeks. It was found that treatment of animals with carvedilol significantly counteracted the changes in liver function and histopathological lesions induced by CCl4. Also, carvedilol significantly counteracted lipid peroxidation, GSH depletion, and reduction in antioxidant enzyme activities; glutathione-S-transferase and catalase that was induced by CCl4. In addition, carvedilol ameliorated the inflammation induced by CCl4 as indicated by reducing the serum level of acute phase protein marker; alpha-2 macroglobulin and the liver expression of nuclear factor-kappa B (NF-kappaB). Finally, carvedilol significantly reduced liver fibrosis markers including hydroxyproline, collagen accumulation, and the expression of the hepatic stellate cell (HSC) activation marker; alpha smooth muscle actin. In conclusion, the present study provides evidences for the promising antifibrotic effects of carvedilol that can be explained by amelioration of oxidative stress through mainly, replenishment of GSH, restoration of antioxidant enzyme activities and reduction of lipid peroxides as well as amelioration of inflammation and fibrosis by decreasing collagen accumulation, acute phase protein level, NF-kappaB expression and finally HSC activation. PMID- 22543096 TI - [Experience on the use of sugammadex in a French university hospital]. PMID- 22543097 TI - [Pulmonary hypertension and femoral neck fracture: interest of continuous spinal anaesthesia]. AB - Anaesthetic management of patients with pulmonary hypertension is challenging and alternatives to general anaesthesia are encouraged. We report anaesthetic management of two patients with pulmonary hypertension admitted for femoral neck fracture. In order to reduce the risk of right-sided heart failure and systemic hypotension, it was decided to operate the patients under continuous spinal anaesthesia. Anaesthesia was induced with excellent hemodynamic tolerance. Quality and extension of the block was correct and allowed surgery. No postoperative complication was observed. These cases suggest that continuous spinal anaesthesia may be considered for the management of patients with pulmonary hypertension undergoing femoral neck fracture surgery. PMID- 22543098 TI - Physician obligation to provide care during disasters: should physicians have been required to go to Fukushima? AB - On 11 March 2011, Japan experienced a major disaster brought about by a 9.0 magnitude earthquake and a massive tsunami that followed. This disaster caused extensive damage to the Fukushima Daiichi nuclear power plant with the release of a large amount of radiation, leading to a crisis level 7 on the International Atomic Energy Agency scale. In this report, we discuss the obligations of physicians to provide care during the initial weeks after the disaster. We appeal to the obligation of general beneficence and argue that physicians should go to disaster zones only if there is no significant risk, cost or burden associated with doing so. We conclude that physicians were not obligated to go to Fukushima given the high risk of radiation exposure and physical and psychological harm. However, we must acknowledge that there were serious epistemic difficulties in accurately assessing the risks or benefits of travelling to Fukushima at the time. The discussion that follows is highly pertinent to all countries that rely on nuclear energy. PMID- 22543100 TI - Molecular cloning and characterization of leucine aminopeptidase from Fasciola gigantica. AB - M17 leucine aminopeptidase (LAP) is one of a family of metalloexopeptidases, of which short peptide fragments are cleaved from the N-terminals. In this study, the full length of cDNA encoding Fasciola gigantica LAP (FgLAP) was cloned from adult parasites. The amino acid sequences of FgLAP showed a high degree of identity (98%) with that from Fasciola hepatica and a low degree of identities (11% and 9%) with those from cattle and human. Phylogenetic analysis revealed that the FgLAP was closely related and grouped with F. hepatica LAP (FhLAP). Northern analysis showed that FgLAP transcriptional products have 1800 base pairs. Analysis by RNA in situ hybridization indicated that LAP gene was expressed in the cecal epithelial cells of adult parasites. A polyclonal antibody to a recombinant FgLAP (rFgLAP) detected the native LAP protein in various developmental stages of the parasite. In a functional test, this rFgLAP displayed aminolytic activity using a fluorogenic Leu-MCA substrate, and was significantly inhibited by bestatin. Its maximum activity was at pH 8.0 and enhanced by Mn(2+) ions. Localization of LAP proteins by immunohistochemistry and immunofluorescence techniques indicated that the enzyme was distributed in the apical cytoplasm of cecal epithelial cells. Because of its important metabolic role and fairly exposed position, FgLAP is a potential drug target and a possible vaccine candidate against fasciolosis. PMID- 22543099 TI - Plasmodium falciparum SSB tetramer wraps single-stranded DNA with similar topology but opposite polarity to E. coli SSB. AB - Single-stranded DNA binding (SSB) proteins play central roles in genome maintenance in all organisms. Plasmodium falciparum, the causative agent of malaria, encodes an SSB protein that localizes to the apicoplast and likely functions in the replication and maintenance of its genome. P. falciparum SSB (Pf SSB) shares a high degree of sequence homology with bacterial SSB proteins but differs in the composition of its C-terminus, which interacts with more than a dozen other proteins in Escherichia coli SSB (Ec-SSB). Using sedimentation methods, we show that Pf-SSB forms a stable homo-tetramer alone and when bound to single-stranded DNA (ssDNA). We also present a crystal structure at 2.1 A resolution of the Pf-SSB tetramer bound to two (dT)(35) molecules. The Pf-SSB tetramer is structurally similar to the Ec-SSB tetramer, and ssDNA wraps completely around the tetramer with a "baseball seam" topology that is similar to Ec-SSB in its "65 binding mode". However, the polarity of the ssDNA wrapping around Pf-SSB is opposite to that observed for Ec-SSB. The interactions between the bases in the DNA and the amino acid side chains also differ from those observed in the Ec-SSB-DNA structure, suggesting that other differences may exist in the DNA binding properties of these structurally similar proteins. PMID- 22543101 TI - The mouse as a model organism in aging research: usefulness, pitfalls and possibilities. AB - The mouse has become the favorite mammalian model. Among the many reasons for this privileged position of mice is their genetic proximity to humans, the possibilities of genetically manipulating their genomes and the availability of many tools, mutants and inbred strains. Also in the field of aging, mice have become very robust and reliable research tools. Since laboratory mice have a life expectancy of only a few years, genetic approaches and other strategies for intervening in aging can be tested by examining their effects on life span and aging parameters during the relatively short period of, for example, a PhD project. Moreover, experiments on mice with an extended life span as well as on mice demonstrating signs of (segmental) premature aging, together with genetic mapping strategies, have provided novel insights into the fundamental processes that drive aging. Finally, the results of studies on caloric restriction and pharmacological anti-aging treatments in mice have a high degree of relevance to humans. In this paper, we review a number of recent genetic mapping studies that have yielded novel insights into the aging process. We discuss the value of the mouse as a model for testing interventions in aging, such as caloric restriction, and we critically discuss mouse strains with an extended or a shortened life span as models of aging. PMID- 22543102 TI - The expression of NR2B subunit of NMDA receptor in the suprachiasmatic nucleus of Wistar rats and its role in glutamate-induced CREB and ERK1/2 phosphorylation. AB - Most behavioral and physiological processes in living organisms exhibit periodic circadian rhythmicity. In mammals, these rhythms are coordinated by the circadian clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. In order to precisely synchronize free-running circadian oscillations to the 24h solar cycle, signals from the external environment, primarily the light/dark cycle, must reach the circadian clock within the SCN. A light pulse elevates intracellular Ca(2+) levels, and activates signaling cascades, leading to transcriptional activation of the clock genes mPer1 and mPer2 via phosphorylation of extracellular-signal-regulated kinases 1/2 (ERK1/2) and cyclic AMP-responsive element binding protein (CREB). Glutamate is the primary excitatory transmitter in retinal terminals in the SCN, and NMDA receptors (NMDAR) are the principal glutamate receptors that mediate the effect of light on resetting the circadian clock. Here we show the circadian rhythm in mRNA expression and protein level of the NMDAR 2B subunit (NR2B) in the SCN, with a peak at night. Also, we demonstrate ifenprodil inhibition of glutamate-induced phosphorylation of CREB (pCREB) and ERK1/2 (pERK1/2), and support thus the evidence for NR2B role in activation of signaling cascade involved in photic resetting of the circadian clock. PMID- 22543104 TI - The influence of a smoking ban on the profitability of Belgian restaurants. AB - OBJECTIVE: To examine whether the nationwide smoking ban, imposed in 2007, had an impact on the profitability of Belgian restaurants. DATA AND METHODS: Objective financial reporting data on 1613 restaurants were analysed with return on assets as the outcome measure. The data were collected from the Belfirst database and cover the period 2004-2009. To assess the impact of the smoking ban, a differences-in-differences estimation method was used, with bars serving as the control group. The regression model was estimated, while controlling for firm specific characteristics and unobserved firm-level heterogeneity. RESULTS: The variable of interest is the interaction between the smoking ban dummy and the dummy for the treatment group. The coefficient of this variable is insignificant. CONCLUSION: The adoption of the nationwide smoking ban did not affect the profitability of Belgian restaurants. PMID- 22543103 TI - Effect of glutamate and riluzole on manganese-induced apoptotic cell signaling in neuronally differentiated mouse P19 Cells. AB - Excess exposure to Mn causes a neurological disorder known as manganism which is similar to dystonic movements associated with Parkinson's disease. Manganism is largely restricted to occupations in which high atmospheric levels are prevalent which include Mn miners, welders and those employed in the ferroalloy processing or related industrial settings. T1 weighted MRI images reveal that Mn is deposited to the greatest extent in the globus pallidus, an area of the brain that is presumed to be responsible for the major CNS associated symptoms. Neurons within the globus pallidus receive glutamatergic input from the subthalamic nuclei which has been suggested to be involved in the toxic actions of Mn. The neurotoxic actions of Mn and glutamate are similar in that they both affect calcium accumulation in the mitochondria leading to apoptotic cell death. In this paper, we demonstrate that the combination of Mn and glutamate potentiates toxicity of neuronally differentiated P19 cells over that observed with either agent alone. Apoptotic signals ROS, caspase 3 and JNK were increased in an additive fashion when the two neurotoxins were combined. The anti-glutamatergic drug, riluzole, was shown to attenuate these apoptotic signals and prevent P19 cell death. Results of this study confirm, for the first time, that Mn toxicity is potentiated in the presence of glutamate and that riluzole is an effective antioxidant which protects against both Mn and glutamate toxicity. PMID- 22543105 TI - Detecting adaptive evolution and functional divergence in aminocyclopropane-1 carboxylate synthase (ACS) gene family. AB - Ethylene is an essential plant gaseous hormone that controls many aspects of plant growth and development, especially the fruit ripening. It is important to know how this hormone is synthesized and how its production is regulated to understand the roles of ethylene in plant development. The aminocyclopropane-1 carboxylate synthase (ACS) gene is a rate-limiting enzyme in the ethylene biosynthesis pathway, which is encoded by a highly divergent multi-gene family in plant species. Although many ACS genes have been cloned from a wide variety of plant species previously, their origin and evolutionary process are still not clear. In this study, we conducted a phylogenetic analysis based on an updated dataset including 107 members of plant ACS genes and eight ACS-like genes from animal as well as six AATase genes. The motifs were identified and the positive selection and functional divergence in the ACS gene family were detected. The results obtained from these analyses are consistent with previous division of the ACS gene family in angiosperm, i.e., three distinct clades, and show that the duplications of three subclades (I, II and III) ACS genes have occurred after the divergence of gymnosperm and angiosperm. We conclude that the ACS genes could have experienced three times significant positive selection as they underwent expansion in land plants and gain the full-scale ethylene biosynthesis and regulatory functions, and all plant ACS genes originated from plant-ACS-like genes which come from AATase genes. PMID- 22543106 TI - Responses of Arabidopsis thaliana plant lines differing in hydroxylation of aliphatic glucosinolate side chains to feeding of a generalist and specialist caterpillar. AB - Plants contain variable chemical compositions which play a role in direct defense against phytophagous insects. Glucosinolates (GSs) are the predominant secondary metabolites and defense compounds in brassicaceous species. As a consequence of co-evolution between adapted crucifer-feeding specialists and their associated host-plants, specific plant-insect interactions have developed in a divergent manner from non-adapted generalists. Therefore, generalist and specialist insects may provoke different insect-inducible plant responses. Here, we have investigated the specific biochemical and molecular plant responses of Arabidopsis thaliana (L.) induced by the generalist Spodoptera exigua (Hubner) and the specialist Pieris brassicae L. To get more detailed information about herbivore-mediated-specific plant responses in different chemotypes within one species, we used multiple plant lines with either the non-hydroxylated 3 methylsulfinylpropyl GS or the hydroxylated 3-hydroxypropyl GS in a comparable genetic background. Caterpillar feeding induced a stronger GS accumulation in the 3-hydroxypropyl GS chemotype than the 3-methylsulfinylpropyl GS chemotype, considering the overall insect-mediated changes in aliphatic and indole GS levels in all lines. Herbivory by the generalist S. exigua and the specialist P. brassicae had similar effects on biochemical and transcriptional response pattern. Contrary to the paradigm that specialists may minimize the induction of chemical defenses, we observed a higher elicitation of GSs by the specialist species. The accumulation of especially 1-methoxy-indol-3-ylmethyl GS and the induced gene transcripts by the two species point to an insect-mediated activation of the jasmonic acid signaling pathway in the plant lines. PMID- 22543107 TI - Salt tolerance traits increase the invasive success of Acacia longifolia in Portuguese coastal dunes. AB - Salt tolerance of two co-occurring legumes in coastal areas of Portugal, a native species--Ulex europaeus, and an invasive species--Acacia longifolia, was evaluated in relation to plant growth, ion content and antioxidant enzyme activities. Plants were submitted to four concentrations of NaCl (0, 50, 100 and 200 mM) for three months, under controlled conditions. The results showed that NaCl affects the growth of both species in different ways. Salt stress significantly reduced the plant height and the dry weight in Acacia longifolia whereas in U. europaeus the effect was not significant. Under salt stress, the root:shoot ratio (W(R):W(S)) and root mass ratio (W(R):W(RS)) increased as a result of increasing salinity in A. longifolia but the same was not observed in U. europaeus. In addition, salt stress caused a significant accumulation of Na+, especially in U. europaeus, and a decrease in K+ content and K+/Na+ ratio. The activities of antioxidant enzymes were higher in A. longifolia compared to U. europaeus. In A. longifolia, catalase (CAT, EC 1.11.1.6) and glutathione reductase (GR, EC 1.6.4.2.) activities increased significantly, while ascorbate peroxidase (APX, EC 1.11.1.11) and peroxidase (POX, EC 1.11.1.7) activities remained unchanged in comparison with the control. In U. europaeus, NaCl concentration significantly reduced APX activity but did not significantly affect CAT, GR and POX activities. Our results suggest that the invasive species copes better with salinity stress in part due to a higher rates of CAT and GR activities and a higher K+/Na+ ratio, which may represent an additional advantage when competing with native species in co-occurring salty habitats. PMID- 22543108 TI - Novel genetic mutations specific for intraductal papillary neoplasm of the pancreas. PMID- 22543109 TI - An unusual diaphragmatic hernia. Parahiatal hernia. . PMID- 22543110 TI - An unusual cause of lower gastrointestinal bleeding in Crohn's disease. Malignant infiltration with Epstein-Barr virus-positive diffuse large B-cell non-Hodgkin's lymphoma. PMID- 22543111 TI - A man with colon cancer and tonsil swelling. Tonsillar metastasis from colon cancer. PMID- 22543112 TI - Upper GI bleeding in a post-liver transplant patient. Hepatic artery pseudoaneurysm. PMID- 22543113 TI - First detection of taste buds in a chimaeroid fish (Chondrichthyes: Holocephali) and their Galphai-like immunoreactivity. AB - The mucosa covering the tongue of the Chimaera monstrosa has been investigated with histological and immunohistochemical methods allowing to describe, for the first time, gustatory structures (taste buds) in this subclass of cartilaginous fish. G-protein-alpha-subunit-inhibitory-like (Galphai-like) immunoreactivity has been detected in the taste buds of C. monstrosa, as described in other vertebrates. In order to gain confidence on the antiserum used, able to recognize three Galphai proteins in mammals, alignments of the antigenic sequence in mammals and other vertebrates were performed. The data were used for a research of putative genes in the genome of the holocephalan Callorhinchus milii, to date the only cartilaginous fish with a sequenced genome; the highlighted sequences could suggest the presence of all three genes (gnai1, gnai2 and gnai3) in holocephalans. The sequences of the predicted proteins present a high identity with the mammalian proteins. PMID- 22543114 TI - DRD4 VNTR polymorphism and age at onset of severe mental illnesses. AB - A large number of studies has investigated the hypothesis that DRD4 48 bp variable number of tandem repeat (VNTR) polymorphism is involved in the etiology of schizophrenia and bipolar disorder. However, the results are inconsistent likely due to genetic and phenotypic heterogeneity. Age at onset (AAO) is considered an important alternate phenotype for genetic investigations of psychiatric disorders. In the present study, the DRD4 VNTR 7 repeat allele (7R) was examined in 477 patients with major psychoses. Age at onset was defined as the age of first psychotic episode for schizophrenia and the age at appearance of first clinically recognized symptoms for the bipolar sample. Our results showed an interaction between sex and DRD4 genotypes among schizophrenia patients (n=203, beta=.213, p=.017). On comparing AAO between carriers and non-carriers of the 7R, we observed that females with 7R present had later onset (p=.021). The effect was not observed for males. In the sample with bipolar disorder, we observed significant association between DRD4 7R-genotype and AAO (n=274, beta= .148, p=.012). No interaction was observed between sex and genotypic groups of the bipolar sample. The 7R was associated with early onset of the bipolar illness (p=.028). In summary, our results suggest that the 7R is associated with AAO in both schizophrenia and bipolar disorders. The effect was observed across both sexes in bipolar disorder, but specifically in females for schizophrenia. PMID- 22543115 TI - Cultured meat from stem cells: challenges and prospects. AB - As one of the alternatives for livestock meat production, in vitro culturing of meat is currently studied. The generation of bio-artificial muscles from satellite cells has been ongoing for about 15 years, but has never been used for generation of meat, while it already is a great source of animal protein. In order to serve as a credible alternative to livestock meat, lab or factory grown meat should be efficiently produced and should mimic meat in all of its physical sensations, such as visual appearance, smell, texture and of course, taste. This is a formidable challenge even though all the technologies to create skeletal muscle and fat tissue have been developed and tested. The efficient culture of meat will primarily depend on culture conditions such as the source of medium and its composition. Protein synthesis by cultured skeletal muscle cells should further be maximized by finding the optimal combination of biochemical and physical conditions for the cells. Many of these variables are known, but their interactions are numerous and need to be mapped. This involves a systematic, if not systems, approach. Given the urgency of the problems that the meat industry is facing, this endeavor is worth undertaking. As an additional benefit, culturing meat may provide opportunities for production of novel and healthier products. PMID- 22543116 TI - High-dose-rate brachytherapy for prostate cancer in a previously radiated patient with polyethylene glycol hydrogel spacing to reduce rectal dose: case report and review of the literature. AB - PURPOSE: To describe the use of a temporary spacer to reduce rectal dose prior to prostate radiation in a man with prior pelvic radiotherapy and review the relevant literature. METHODS AND MATERIALS: A healthy 57-year-old man presented with high-risk prostate cancer (Gleason score of 8, prostate-specific antigen level [PSA] 12.6 ng/mL, T3a by magnetic resonance imaging [MRI]), only 2.5 years after a low anterior resection followed by pelvic chemo-radiotherapy to 50.4 Gy for a locally advanced rectal cancer. Due to the prior radiation, he was not felt to be a candidate for surgery or external beam radiation, so he chose long-term androgen deprivation therapy (ADT) plus high-dose-rate brachytherapy to 36 Gy in 6 fractions. To reduce the radiation dose to the anterior rectal wall, 10 mL of a polyethylene glycol hydrogel spacer was injected between the prostate and rectum and created between 1.4 and 1.5 cm of separation along the length of the prostate. RESULTS: Two randomized trials demonstrating that local therapy plus ADT improves overall survival compared to ADT alone provided the rationale for additional prostate radiotherapy in this otherwise healthy patient. Salvage brachytherapy is associated with a 3.4% rate of rectal fistula among the 251 cases reported in the literature from 2000-2007, with rates as high as 12% in one series. The spacer allowed the rectal dose constraint goals to be easily met. CONCLUSIONS: Injecting an absorbable polyethylene glycol hydrogel to separate the prostate and rectum appears to be associated with decreased maximum and mean rectal doses, and may have particular utility in previously irradiated patients. PMID- 22543117 TI - Seed migration in prostate brachytherapy depends on experience and technique. AB - PURPOSE: To determine seed loss and pulmonary migration rate over time in permanent seed prostate brachytherapy. METHODS AND MATERIALS: We analyzed the first 495 patients treated in our department. All patients were treated with loose (125)I seeds with automated seed delivery system and real-time intraoperative planning. Pelvic fluoroscopic imaging was done 30 days after the implant. Patients were divided into five groups of 100 patients according to the order they were treated, and groups were compared using chi(2) test and one-way analysis of variance. RESULTS: A total of 22.8% of patients lost at least one seed. The highest percentage of patients losing any number of seeds was in the first 100. Thirty-eight percent lost at least one seed. This number decreased gradually and was only 9% in Patients 400-499. The mean total seed loss rate (number of seeds lost/number seeds implanted) changed significantly over time (p<0.001). There was a continuous significant (p<0.001) decline after the first 100 patients (1.25% for the first 100 patients) followed by a rise in Patients 300-399, followed by another decline (0.21% for the last 100 patients). The seed loss rate to the thorax changed significantly over time (p=0.009). It rose after an initial rate of 0.25-0.42% in Patients 200-299 and 300-399 and declined later to a rate of 0.21% in the last 100 patients. CONCLUSIONS: We found a learning curve for seed migration. Avoiding implanting seeds outside of the capsule and modern transrectal ultrasound imaging can help decrease migration. PMID- 22543118 TI - Abnormalities of the testes and semen parameters in clinical varicocele. AB - OBJECTIVE: To investigate the abnormal changes in the testes and semen parameters in patients with varicose veins and analyze the possible relationship between clinical varicocele and infertility. METHODS: We retrospectively reviewed the records of 172 male patients consulting for varicocele in our hospital since 2003. All these patients were examined for the size of the testes with scrotal ultrasound. The semen samples of the patients with varicocele except for 5 under the age of 17 years were collected and analyzed, using the data of semen analyses of 163 healthy young male volunteers (aged 18-29 years) as control. RESULTS: All the 172 patients had left-sided varicose veins. Sixty-three patients were found to have bilateral varicocele, and in most of them, the clinical grades of the left-sided varicose veins were higher than those of the right-sided ones. The mean volume of the left testis of the patients was 10.99?3.71 ml, significantly smaller than that of the right one (11.86?4.05 ml, P<0.01). The physiochemical indices of the patients, including the voiding volume, semen pH, liquefaction time and sperm concentration, were normal or similar with those of the healthy volunteers (P>0.05). Almost all the patients sperm motility and viability were significantly lower than those of the healthy volunteers (P<0.05). In addition, no significant difference was found in the sperm density, motility or viability between the patients with unilateral and bilateral varicocele (P>0.05). CONCLUSION: Varicocele may decrease the testicular volume. Both unilateral and bilateral varicocele may have an effect on the bilateral testes to cause possible functional impairment of the testes manifested by decreased sperm motility and viability. PMID- 22543119 TI - [Developmental expression and cellular distribution of metabotropic glutamate receptor 5 in the frontal cortex of human fetus]. AB - OBJECTIVE: To investigate the expression of metabotropic glutamate receptor 5 (mGluR5) and its cellular distribution in the frontal cortex, ventricular zone (VZ) and subventricular zone (SVZ) in human fetuses. METHODS: According to the gestational age, the collected fetuses were divided into 4 groups, namely 9-11 weeks, 14-16 weeks, 22-24 weeks and 32-36 weeks. Brain tissue blocks including the frontal lobe or VZ/SVZ were prepared into slices, and the expression pattern and cellular distribution of mGluR5 in the frontal cortex and VZ/SVZ were observed by immunohistochemistry or immunofluorescence. RESULTS: mGluR5 immunoreactivity was present in the cell membrane in the frontal cortex, VZ and SVZ from the 9th to 36th weeks and the immunoreactivity in the marginal zone (MZ) and cortical plate (CP) was markedly stronger than that in VZ and SVZ. The cells expressing mGluR5 included neural stem/progenitor cells in the VZ and SVZ, immature neurons in the VZ and MZ, and numerous mature neurons in the CP. CONCLUSION: mGluR5 is expressed by a variety of cells such as neural stem cells in the frontal cortex, VZ and SVZ in human fetus, suggesting a role of mGluR5 in the development of human cerebral cortex. PMID- 22543120 TI - [Motor function evaluation in rats receiving umbilical cord mesenchymal stromal cell transplantation for traumatic brain injury using CatWalk automated gait analysis system]. AB - OBJECTIVE: To assess the effect of CatWalk automated gait analysis system for evaluation of motor function of rats with traumatic brain injury (TBI) after umbilical cord mesenchymal stromal cell (UC-MSC) treatment. METHODS: Eighteen Wistar rats were randomized equally into normal control group, TBI ? saline group, and TBI ? UC-MSCs group. The rats in the latter two groups were subjected to weight-drop impact to induce TBI followed by injection UC-MSCs or saline into the lesion 7 days after TBI. The neurological function was assessed using CatWalk system and modified neurological severity scores (mNSS) before and 3 days after TBI and 7 days after UC-MSC transplantation. The rats were sacrificed 14 days after the cell transplantation and the brain sections were stained for immunohistochemical analyses. RESULTS: Three days after TBI, mNSS test showed moderate injury of the rats. Seven days after the cell transplantation, the rats showed significant motor function improvement and CatWalk analysis indicated partial recovery of the gait parameters of the 4 limbs compared to the rats with saline treatment. Histological analyses showed that DiO-labeled UC-MSCs were present in the lesion boundary and expressed glial fibrillary acidic protein and beta-tubulin III. CONCLUSION: UC-MSC transplantation can promote functional improvement of the brain after TBI in rats. Compared with mNSS test, CatWalk analysis is more sensitive and objective for assessing neurological function and also provides more detailed information on specific gait parameters. PMID- 22543121 TI - [Effect of RNA interference on small heat shock protein Sjp40 of Schistosoma japonicum]. AB - OBJECTIVE: To study the effect of RNA interference (RNAi) on small heat shock protein (sHSP) Sjp40 of Schistosoma japonicum and its synergistic effect on the expression of SjHSP60, SjHSP70, and SjHSP90 mRNA, and observe the mRNA expression levels of Sjp40, SjHSP60, SjHSP70, and SjHSP90 in different stages of S.japonicum. METHODS: Double-stranded RNA (dsRNA) of Sjp40 (dsSjp40) and a control dsRNA of green fluorescent protein (dsGFP) were generated by in vitro transcription and transfected into adult worm by immersing the worm in dsRNA solution. The total RNA and proteins were isolated simultaneously from the adult worms using TRIzol reagent 7 days after transfection. The expression levels of Sjp40, SjHSP60, SjHSP70, and SjHSP90 mRNA and the expression level of Sjp40 protein were determined by quantitative real-time PCR (qPCR) and Western blotting, respectively. The mRNA expression of HSPs of S. japonicum in different stages was evaluated by qPCR. RESULTS: Compared with those in the control worms transfected with dsGFP, Sjp40 mRNA level was decreased by 80% in the worms transfected with dsSjp40, and the level of Sjp40 protein showed also a significant decrease. The mRNA expression levels of SjHSP60, SjHSP70, and SjHSP90 did not show an obvious synergism after Sjp40 RNAi. The expression profiles of Sjp40, SjHSP60, SjHSP70, and SjHSP90 showed significant differences in different stages of S. japonicum, and the expression level of Sjp40 mRNA in the egg stage was much higher than that of other HSP genes. CONCLUSION: dsSjp40-RNAi can induce effective suppression of Sjp40 gene expression at both mRNA and protein levels, but no obvious synergism occurs in the mRNA expressions of SjHSP60, SjHSP70, and SjHSP90. PMID- 22543122 TI - [Effect of clopidogrel combined with calcium-channel blocker on coronary artery disease in elderly patients: a propensity score-based retrospective cohort study]. AB - OBJECTIVE: To compare the effects of clopidogrel combined with dihydropyridine calcium-channel blockers (CCBs) or non-dihydropyridine CCBs on coronary artery disease (CAD) in elderly patients. METHODS: The study cohort was defined as all patients >=60 years old hospitalized for CAD with the prescription of clopidogrel between January 2001 and February 2011. The primary endpoint was death of all causes, and the secondary endpoints were nonfatal myocardial infarction (MI), hospitalization for unstable angina, stroke, transient ischemic attack, or repeat revascularization (PCI or coronary artery bypass graft). RESULTS: A total of 1021 patients were enrolled, among whom 402 patients were prescribed with clopidogrel and 619 with clopidogrel combined with CCB (dihydropyridine in 547 and non dihydropyridine in 72). In clopidogrel group and clopidogrel with CCB group, the incidence density of death was 50.55 per thousand and 42.02 per thousand, respectively. The crude RR was 0.83 (95%CI: 0.55-1.26), and the multivariable adjusted RR was 0.47 (95%CI: 0.14-1.6), showing no statistical significance in the rate of deaths of call causes between the two groups (P>0.05); the incidence density of composite thromboembolic events showed no significant difference between the two groups, either (P>0.05). After weighting of the propensity score, the patients with clopidogrel coadministered with non-dihydropyridine CCB showed a significant increase in composite thromboembolic events than those taking dihydropyridine CCB, with a SMRW-adjusted OR of 1.97 (95%: 1.2-3.23, P=0.007). No significant difference was observed in death or composite thromboembolic events between Pgp-inhibiting CCBs and non-Pgp-inhibiting CCBs. CONCLUSION: Compared with clopidogrel without CCB, clopidogrel with CCB does not increase the mortality or composite thromboembolic events in elderly CAD patients, but clopidogrel combined with non-dihydropyridine CCB is associated with significantly increased composite thromboembolic events in comparison with dihydropyridine CCB. PMID- 22543124 TI - [Effect of omeprazole on gene expression profile of human umbilical vein endothelial cell line and bioinformatics analysis]. AB - OBJECTIVE: To characterize the effect of omeprazole on the spectrum of gene expression in the cultured human umbilical vein endothelial cell (HUVEC) line (EA.hy926), and explore the underlying molecular mechanism. METHODS: Affymetrix U133 plus2.0 oligonucleotide microarray was used to detect the alteration in the gene expression profiles induced by 1*10(-5) mol/L omeprazole in HUVECs. Real time PCR was employed to verify the results of selected differentially expressed genes, and Western blotting was performed to test the expression levels of the related proteins. RESULTS: A total of 282 genes were found to show at least 1.5 fold changes in EA.hy926 cells after treatment with omeprazole for 48 h, including 236 up-regulated and 46 down-regulated ones. These genes were involved in the regulation of transcription, inflammatory response, immune response, cell adherence, anti-apoptosis, and signal transduction. CONCLUSION: Omeprazole modulates the function of endothelial cells by regulating the gene expression profiles of multiple pathways. PMID- 22543123 TI - [Effect of rapamycin on high glucose-induced autophagy impairment, oxidative stress and premature senescence in rat mesangial cells in vitro]. AB - OBJECTIVE: To investigate the effects of rapamycin and 3-methyladenine on autophagy impairment, oxidative stress and premature senescence induced by high glucose in primarily cultured rat mesangial cells. METHODS: Rat glomerular mesangial cells (GMCs) were isolated and cultured in normal glucose, high glucose, high glucose with 3-methyladenine (3-MA), or high glucose with rapamycin. At 24 h, 72 h and 10 days of culture, the cells were examined for expression levels of autophagy markers LC3 and p62/SQSTM1, malondialdehyde (MDA) and protein carbonyl, beta-galactosidase (SA-beta-gal) activity and heterochromatin foci (SAHF). RESULTS: Compared with those of normal cell culture, the cells exposed to high glucose for 72 h and 10 days showed down-regulated LC3 expression, up-regulated p62/SQSTM1 expression, elevated MDA and protein carbonyl levels, and increased SAHF formation and percentage of SA-beta-gal-positive cells. These changes were reversed in GMCs exposed to high glucose and rapamycin for 72 h and 10 days, but exacerbated in cells incubated with 3-MA. CONCLUSION: High glucose can suppress autophagic function of rat GMCs to result in oxidative damage and cell senescence. Rapamycin can attenuate autophagy impairment, oxidative damage and senescence induced by high glucose, whereas 3-MA can further aggravate high glucose-induced cell injuries in rat GMCs. PMID- 22543125 TI - [Analysis of larval excretory-secretory antigen and its immunodiagnosis of Angiostrongyliasis cantonensis infection]. AB - OBJECTIVE: To analyze the diagnostic value of larval excretory-secretory antigen in Angiostrongylus cantonensis (LESA) infection. METHODS: A.cantonensis larvae harvested from mice brain were cultured in vitro. The LESA and the adult worm antigens of A.cantonensis (AWA) were collected and analyzed using SDS-PAGE and Western blotting. Two ELISA systems were established using the two antigens (LESA ELISA and AWA-ELISA) to detect the serum spectra from different sources. RESULTS: SDS-PAGE and Western blotting displayed fewer protein and antigen bands for LESA than for the adult antigen. Two distinct bands of LESA (with relative molecular masses of 40 000 and 26 000) showed reactivity with the sera from patients with A. cantonensis infection. The serum levels of IgG and IgM antibodies to LESA increased at the beginning of infection in mice, reaching the peak on day 5 after infection and decreased on day 10. Compared with AWA-ELISA, LESA-ELISA showed a lower seropositive ratio in suspected patients with A.cantonensis, with also a lower cross-positive ratio in patients with schistosomiasis and clonorchis sinensis. CONCLUSION: LESA possesses fewer antigen reaction bands than AWA. Although with a slightly lower positive ratio than AWA, LESA has a higher specificity for detecting serum antibodies in suspected cases of A.cantonensis infection, and therefore shows a potential for the diagnosis of angiostrongyliasis especially in the early stage and in current infection. PMID- 22543126 TI - [Pathological findings of axonal injury in a rat model of experimental allergic encephalomyelitis]. AB - OBJECTIVE: To observe the pathological changes of axonal injury in a rat model of experimental allergic encephalomyelitis (EAE). METHODS: With HE, luxol fast blue and Bielschowsky staining, the expression of APP, MBP, SMI-32 and MBP in the brain and spinal cord of EAE rats using double-labeling indirect immunofluorescence. RESULTS: Extensive cuffing lesions of inflammatory cell infiltrations were found in the brain and spinal cord of the rats, accompanied by multiple lesions of demyelination, axonal disarrangement with vesicular loss. SMI 32 staining identified numerous nonphosphorylated neurofilament, indicating the presence of axonal injury. Axonal oval bodies formed by APP accumulation were found in the white matters of the spinal cord 14 days after EAE, suggesting that neuraxial damage occurred in the early stage of EAE which was not synchronous with myelin loss. CONCLUSION: Different levels of inflammation occur in different stages of EAE, and inflammatory cell infiltration is the most obvious at the peak of EAE. Axonal injury occurs in the early stage of EAE and progresses over the entire disease course. PMID- 22543127 TI - [u-opioid receptors in the central nucleus of the amygdala modulate sucrose solution intake in rats]. AB - OBJECTIVE: To explore the role of u-opioid receptors (MOR) in the central nucleus of the amygdala (CeA) in modulating sucrose solution intake in rats. METHODS: Sprague-Dawley rats received intra-CeA injection of MOR agonist DAMGO or saline, and then underwent two bottle choice test between sucrose solution and distilled water. After intake of sucrose solution or distilled water, activated neurons in the CeA were labeled and identified with MOR/Fos-double labeling immunohistochemistry. RESULTS: Compared with saline injection, intra-CeA injection of DAMGO significantly increased sucrose solution intake in rats over a 3-h period. Sucrose solution intake induced significantly more c-Fos and MOR/Fos double-labeled neurons in the CeA than distilled water intake. CONCLUSIONS: The CeA participates in modulation of sucrose intake in rats, and MOR may partly mediate this mechanism. PMID- 22543128 TI - [Quantitative characterization of vortex flow in patients with early myocardial ischemia by echocardiography using vector flow mapping]. AB - OBJECTIVE: To quantitatively characterize vortex flow in patients with early myocardial ischemia by echocardiography using vector flow mapping (VFM) and explore a new diagnostic index of early myocardial ischemia. METHODS: This study was conducted among 105 patients with suspected angina pectoris, who were free of a previous cardiac history with a normal ejection fraction. Patients without significant coronary artery stenoses constituted the control group (n=49) and those with significant coronary artery stenoses (n=56) constituted the early myocardial ischemia group. All the patients underwent conventional ultrasonic inspection and VFM. The velocity vector and vorticity were estimated by VFM. The vortex parameters including vortex flow, radius, diameter, area and vortex relative strength index were measured. RESULTS: No significant differences were found in the vortex parameters including the vortex flow, radius, diameter or area between the two groups (P>0.05), but vortex relative strength index was significantly lower in early myocardial ischemia group (23.68?11.66 vs 20.20?6.29, P<0.05). CONCLUSION: VFM is feasible for quantitative evaluation of left ventricular vorticity in healthy individuals and patients with early myocardial ischemia, and the vortex relative strength index may serve as a novel index for the diagnosis of early myocardial ischemia. PMID- 22543129 TI - [Role of PDGF-A/PDGFR-alpha in proliferation and transdifferentiation of fibroblasts from skin lesions of patients with systemic sclerosis]. AB - OBJECTIVE: To study the role of platelet-derived growth factor A (PDGF-A)/PDGF receptor-alpha (PDGFR-alpha) signaling pathway in the proliferation and transdifferentiation of fibroblasts (FB) into myofibroblasts (MFB) in the skin lesions of patients with systemic sclerosis (SSc). METHODS: The primary FBs isolated from the skin lesions of SSc patients and normal adult skin cultured in vitro were examined for alpha-smooth muscle actin (alpha-SMA) using immunocytochemistry. The FBs were incubated with different concentrations of PDGF AA and the changes in their proliferative activity were quantified with MTT assay. RT-PCR was used to determine the effects of transforming growth factor beta(1) (TGF-beta(1)) and PDGF-AA, either alone or in combination, on the expression levels of PDGFR-alpha and alpha-SMA mRNA in the FBs. RESULTS: Although the FBs of the two groups were morphologically similar, only FBs from the skin lesion showed positive staining for alpha-SMA. Below the saturated concentration of PDGF, the FBs in the two groups both proliferated in a dose-dependent manner (P<0.05), but the FBs from the SSc lesions always showed a significantly higher proliferative activity (P<0.05). PDGF-AA and TGF-beta(1), alone or in combination, up-regulated the expression level of PDGFR-alpha and alpha-SMA mRNA in the FBs from SSc lesions; similar results were obtained in the control FBs, except that TGF-beta(1) alone did not influence PDGFR-alpha mRNA expression. PDGFR-alpha and alpha-SMA mRNA always showed higher expressions in FBs in SSc lesions than in the control FBs with the same treatments (P<0.05). The expression levels of PDGFR-alpha and alpha-SMA mRNA increased in the order of untreated, PDGF-AA, TGF-beta(1) and PDGF-AA plus TGF-beta(1) groups and showed a strong positive correlation between them (r=0.925, P<0.05). CONCLUSION: The FBs from the skin lesions of SSc patients have a distinct feature of transdifferentiation into MFB. Over-expression of PDGFR-alpha on the surface of FBs from SSc lesions can bind more PDGF-AA ligands to increase cell proliferation and promote transdifferentiation to MFB, and TGF-beta(1) further enhances this effect . PMID- 22543130 TI - [Prokaryotic expression, purification and antigenicity identification of mouse prostate stem cell antigen]. AB - OBJECTIVE: To amplify mouse prostate stem cell antigen (mPSCA) gene and construct a recombinant plasmid to obtain mPSCA protein and identify its antigenicity. METHODS: The gene of mPSCA was amplified by RT-PCR from mouse prostate cancer cell line RM-1 with the signal peptide sequence removed. The PCR product was cloned into pET-42a prokaryotic expression vector to construct the recombinant plasmid pET-42a-mPSCA, which was transformed into BL21 (DE3) for mPSCA expression. The fusion protein was purified and identified by SDS-PAGE and Western blotting. The antigenicity of the purified protein was characterized by ELISA. RESULTS: The mPSCA gene was obtained with an identical sequence to that retrieved in GenBank. The prokaryotic expression vector for mPSCA was successfully constructed as confirmed by enzyme digestion and DNA sequencing. Both Western blotting and ELISA demonstrated the antigenicity of the purified mPSCA protein. CONCLUSION: The purified mPSCA obtained possesses good antigenicity, which will facilitate further study of immunotherapy for prostate cancer targeting PSCA. PMID- 22543131 TI - [Construction of eukaryotic expression vectors for different domains of the extracellular region of RAGE and their expression in prostate cancer cells]. AB - OBJECTIVE: To construct eukaryotic expression vectors for different domains (V and VC1) of the extracellular region of the receptor of advanced glycation end products (RAGE) and investigate the roles of these domains in prostate cancer. METHODS: The coding sequence of V and VC1 domains was amplified from the plasmid pcDNA3-HA-RAGE by PCR and cloned into the pcDNA3-HA vector following routine procedures. After identification by PCR and sequencing, the vectors including V and VC1 domains were transfected into PC-3 cells. Western blotting and immunofluorescence were used to detect the expression and distribution of the expressed products in transfected PC-3 cells. RESULTS: The expression vectors containing V and VC1 domains of RAGE were successfully constructed as confirmed by PCR and DNA sequence analysis. The V and VC1 domains of RAGE were highly expressed and showed a cytoplasmic distribution in transfected PC-3 cells. CONCLUSION: The constructed eukaryotic expression vectors for V and VC1 domains of RAGE can be efficiently expressed in prostate cancer cells. PMID- 22543132 TI - [Mutation analysis of STK11 gene coding region for 20 Chinese patients with Peutz Jeghers syndrome]. AB - OBJECTIVE: To analyze the sequence of STK11 gene coding region in 20 patients with Peutz-Jeghers syndrome and identify the point mutations in STK11 gene associated with the occurrence of the disease. METHODS: Blood samples were collected from 20 inpatients with Peutz-Jeghers syndrome treated in our center between January 2009 and October 2010. The sequence of STK11 gene coding region was analyzed using PCR and DNA sequencing and compared with the normal sequence of STK11 gene. RESULTS: Of the 20 patients with Peutz-Jeghers syndrome, 14 showed STK11 gene mutations in the coding region, including 1 patient having two mutations and 13 patients with a single mutation site. In one case, sequence analysis of the STK11 gene identified a novel type of STK11 germline mutation, in which the cytosine (C)460 was substituted by guanine (G) in exon 3 to result in a new amino acid at codon 154. Four patients from 2 families were found to have a common mutation. The remaining 6 patients were not found to have mutations in STK11 gene coding region. CONCLUSION: Mutations of STK11 gene is a major cause of Peutz-Jeghers syndrome. The missense mutation of 460 C->G in exon 3 of STK11 gene is a novel mutation associated with Peutz-Jeghers syndrome. PMID- 22543133 TI - [Construction of tissue-engineered skin flap in vitro]. AB - OBJECTIVE: To construct a tissue-engineered skin flap using composite skin and adipose tissue constructed by adipose-derived stem cells(ASCs). METHODS: Human ASCs isolated from adipose tissue were cultured and identified for their adipogenic, osteogenic and chondrogenic differentiation potentials. ASCs were then mixed with collagen gel for adipogenic induction and observed 15 days later with inverted microscope, oil-red O staining and HE staining. To construct the composite skin, keratinocytes and fibroblasts were isolated from human foreskin. The fibroblasts were mixed with collagen gel and cultured for 5 days, and keratinocytes were seeded on the gel for 4 days before transfer of the culture to air-liquid interface for culture for another 10 days. The adipose tissue and composite skin were then assembled according to the structure of normal skin and cultured for 3 days with HE staining observation. RESULTS: The cultured ASCs were capable of adipogenic, osteogenic and chondrogenic differentiation, and adipogenic induction of the ASCs-gel complex for 15 days resulted in adipogenic differentiation of the ASCs in gel. The assembled tissue-engineered skin consisted of 3 layers, including a suprabasal layer formed by the stratified and differentiated keratinocytes, the middle layer and sublayer containing numerous cells, and a underlying sublayer formed by the adipogenic ASCs. CONCLUSION: Tissue-engineered skin flap can be constructed by assembling composite skin and adipose derived from cultured keratinocytes, fibroblasts, and ASCs. PMID- 22543134 TI - [Effects of task probability on context processing: spatiotemporal analysis of event-related potential]. AB - OBJECTIVE: To investigate the effects of task probability on context processing using AX-type continuous performance test (AX-CPT) and event-related potential (ERP). METHODS: We set 3 groups of complementary probabilities (AX/AY: 0.55/0.15, 0.35/0.35, and 0.15/0.55) for AX task and AY task and kept the probability 0.15 for both BX and BY tasks. Eighteen subjects were asked to press the button only when the go-probe (X: green "<<<" or ">>>") followed the go-cue (A: blue "ooo") and withdraw response when the go-probe or a nogo-probe (Y: red "<<<" or ">>>") followed the nogo-cue (B: blue "xxx"). RESULTS: As the task probability increased, the reaction time of AX task was shortened and the rate of false alarm of BX task increased significantly. The probability effects of ERP revealed by statistical parametric mapping occurred in many regions during both cue and probe stages: cue A in the parietal central (300-350 ms) and the left occipital area (450-500 ms); cue B in the right frontal pole (350-500 ms) and the left frontal pole (750-950 ms); AX probe in the right frontoparietal area (200-250 ms), the left frontal pole, the right dorsal prefrontal and bilateral parietal region (300 400 ms), and the bilateral occipital area and parietal region (400-650 ms); AY probe in the fronto-central area (350-500 ms) - the P3 effect; BX probe in the right temporal and the left occipital areas (300-350 ms); BY probe in the left temporal area (150-250 ms). CONCLUSION: The task probability not only influences both the encoding of go-cue and expectancy of nogo-cue but also modulates the neural assemblies of probe processing differentially. PMID- 22543135 TI - [Study of the sonographic functions in targeted high-intensity focused ultrasound using nanoscale bubbles]. AB - OBJECTIVE: To improve the detection sensitivity of coagulative necrosis caused by high intensity focused ultrasound (HIFU) exposure. METHODS: Sixty rabbits bearing VX2 breast neoplasms at the second bilateral breast were divided randomly into 3 groups (n=20) for targeted HIFU exposure at 90, 120, or 150 W for 3 s. With the right breast neoplasms as the control, the left ones were irradiated following nanoscale bubble injection. The ultrasonograms generated before and immediately after the exposure were analyzed for changes in the gray scale values and for computation of the related functions in the target area. The accuracy and sensitivity of gray evaluation and analysis of the related functions were compared in the detection of coagulative necrosis. RESULTS: Analysis of the related functions of the 120 samples showed an significantly higher accuracy (83.3%) than gray scale-based evaluation (68.3%) in detecting the coagulative necrosis (P<0.05). Under the same irradiation conditions, the mean values of the related function was significantly lower in microbubble group than in the control group (P<0.05). CONCLUSION: Analysis of the related functions of the ultrasonographic data can be used to evaluate the coagulative necrosis in the target exposure area following HIFU with a greater sensitivity and accuracy than gray-scale evaluation. PMID- 22543136 TI - [Differences in fecal Bifidobacterium species between patients with type 2 diabetes and healthy individuals]. AB - OBJECTIVE: To determine the changes in fecal Bifidobacterium species in patients with type 2 diabetes in comparison with healthy individuals. METHODS: The bacterial DNA were extracted from the fecal samples from 50 type 2 diabetic patients and 30 healthy individuals. Real-time quantitative PCR was employed to determine the copy numbers of the bacteria in the fecal samples using 16S rRNA targeted genus- and species-specific PCR primers for a selected group of fecal Bifidobacterium species including total Bifidobacterium, B.longum, B.breve, B.adolescent, and B. infantis. RESULTS: The diabetic group had significantly lower copy numbers of total Bifidobacterium and B.adolescent compared to the healthy individuals (P<0.05). CONCLUSION: Type 2 diabetic patients have a lowered number of Bifidobacterium species in the gut microflora. PMID- 22543137 TI - [Primary intestinal non-Hodgkin's lymphoma: a retrospective study of 85 cases]. AB - OBJECTIVE: To review the clinical characteristics and treatment outcomes of primary intestinal non-Hodgkin's lymphomas (PINHL) and analyze the differences between T-cell and B-cell lymphomas. METHODS: The characteristics of PINHL patients treated in our hospital between January 2003 and December 2010 were reviewed for their clinical manifestations, diagnosis, endoscopic findings, treatments and outcomes. RESULTS: Eighty-five cases of PINHL meeting the Dawson's criteria were identified. The median age of the patients at the time of diagnosis was 52 years and the male: female ratio was 3.05:1; 58 cases (68.2%) had B lineage and 27 cases (31.8%) had T-cell lineage lymphomas. Compared to those with B-cell lymphoma, patients with T-cell lymphomas showed a younger age of disease onset (32 vs 56 years, P<0.01) and presented with a greater incidence of such symptoms as fever, hematochezia, diarrhea and night sweats (P<0.05); T-cell lymphoma showed more multifocal and ulcerative/ulcero-infiltrative lesions under endoscope with a longer diagnosis time (4 vs 2 months, P<0.01) and a greater likeliness of misdiagnosis (16/27 vs 12/58, P<0.01) and poor prognosis. Extranodal NK/T-cell lymphoma was the most common type of T-cell lymphomas. CONCLUSION: In our cases, T-cell lymphoma appeared to be more common than B-cell lymphoma with a younger onset age, more difficult diagnosis, a greater likeliness of misdiagnosis, poorer prognosis and more extranodal NK/T-cell lymphoma. PMID- 22543138 TI - [Non-functioning pituitary carcinoma: report of two cases and review of literature]. AB - OBJECTIVE: Pituitary carcinoma is extremely rare. We report two cases of non functioning pituitary carcinoma treated in our hospital. The two female patients, aged 39 and 40 years, were diagnosed by CT and MRI and postoperative pathological examination. The tumor was surgically resected followed by stereotactic radiotherapy. Despite of the treatments, both of the patients showed tumor recurrence and died at 1 and 2 months after discharge. The diagnosis of this disease relies on a combined evaluation of the clinical, radiological, cytological, immunohistochemical features. Due to the highly malignant nature and poor prognosis of this disease, early surgical intervention and systemic evaluation of the patients' condition are imperative. Currently more effective therapeutic approaches are needed to control the tumor progression. PMID- 22543139 TI - [Pseudomonas aeruginosa vaccine inhibits the proliferation of human nasopharyngeal cancer cells in vitro]. AB - OBJECTIVE: To investigate the inhibitory effects of Pseudomonas aeruginosa vaccine (PA-MSHA) on the proliferation of human nasopharyngeal cancer cells and explore the possible mechanism. METHODS: MTT assay was used to determine the cell growth of human nasopharyngeal cancer cell line 5-8F and 6-10B in vitro treated with the vaccine. The cell cycle distribution of the cells was detected by flow cytometry, and the expression levels of apoptosis and cycle-related proteins were evaluated by Western blotting. RESULTS: PA-MSHA treatment significantly suppressed the proliferation of 5-8F and 6-10B cells in a time- and concentration dependent manner compared with the control group (P<0.05). The cells with PA-MSHA treatment exhibited a decreased percentage of cells entering S phase and a corresponding increase in G(1) phase cells in FACS analysis. The expression of cyclin D(1), CDK4, and CDK6 was significantly up-regulated, Bax protein up regulated, and the anti-apoptosis protein Bcl-2 down-regulated in PA-MSHA-treated cells. CONCLUSION: PA-MSHA can suppress the proliferation of nasopharyngeal carcinoma cell in vitro by affecting the cell cycle and promoting cell apoptosis. PMID- 22543140 TI - [Effects of tumor necrosis factor-alpha on nutritional status and proteolysis of respiratory muscles in rats with chronic obstructive pulmonary disease]. AB - OBJECTIVE: To investigate the effect of tumor necrosis factor-alpha (TNF-alpha) on nutritional status and proteolysis of respiratory muscle in a rat model of chronic obstructive pulmonary disease (COPD). METHODS: Ninety healthy male adult Wistar rats were randomly divided into model group (A) and normal control group (B). COPD malnutrition rat models were established by cigarettes smoke and nutrient limitation and divided into normal nutrition COPD group (A(1)), malnutrition COPD group (A(2)), and malnutrition COPD intervention group (A(3)). In group A(3), the rats received intravenous injection of TNF-alpha mAb (0.1 mg/kg). TNF-alpha levels in the serum and respiratory muscle homogenates were measured using enzyme-linked immunosorbent assay (ELISA), and plasma levels of glucose, albumin, and triglyceride were measured with an automatic biochemistry analyzer. High-performance liquid chromatography was used to measure the contents of 3-methylhistidine and tyrosine in the respiratory muscle homogenates. RESULTS: The serum TNF-alpha level and plasma levels of glucose and triglyceride were significantly higher but the plasma albumin level was significantly lower in group A(2) than in groups B, A(1), and A(3) (P<0.01). The contents of 3-MH and Tyr in the respiratory muscle homogenates were significantly higher in group A(2) than in the other 3 groups (P<0.01, P<0.01). TNF-alpha in the respiratory muscle showed a strong positive correlation to 3-MH and Tyr. CONCLUSION: TNF-alpha is one of the causes of increased proteolysis of the respiratory muscle. PMID- 22543141 TI - [Experimental study of the anti-inflammatory and analgesic effects of diethyl 1,3 dicyclohexyl- 1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate]. AB - OBJECTIVE: To study the anti-inflammatory and analgesic activities of diethyl 1,3 dicyclohexyl-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (ZL-5010) in vivo and in vitro. METHODS: The analgesic effect of ZL-5010 was evaluated by acetic acid induced writhing response in mice, and the anti-inflammatory effects was assessed in mice with xylene-induced ear edema and in rats with carrageenan-induced paw edema. Mouse peritoneal exudate cells activated by bacterial lipopolysaccharides (LPS) were used to evaluate the anti-inflammatory effect of ZL-5010 in vitro. The levels of interleukin-1beta (IL -1beta) and tumor necrosis factor-alpha (TNF alpha) in the cell culture supernatant were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: At the doses of 0.25 and 0.5 mmol/kg, ZL 5010 administered by gavage once daily for 3 days significantly reduced acetic acid-induced writhing frequency and suppressed xylene-induced ear edema in mice, and alleviated paw edema induced by carrageenan in rats (P<0.05). The agent also inhibited the production of the pro-inflammatory cytokines IL-1beta and TNF-alpha by LPS-induced mouse peritoneal exudate cells in vitro, with the statistically significant minimum effective concentrations of 10 and 20 umol/L, respectively (P<0.05). CONCLUSION: ZL-5010 administered by gavage has anti-inflammatory and analgesic effects in mice and rats, and in mouse peritoneal exudate cell cultures, the agent also inhibits the production of the pro-inflammatory cytokines IL-1beta and TNF-alpha. PMID- 22543142 TI - [Risk factors of postoperative intravesical recurrence of transitional cell carcinoma of the ureter]. AB - OBJECTIVE: To define the clinicopathological risk factors of intravesical recurrence of primary transitional cell carcinoma of the ureter after surgical intervention. METHODS: Patients with primary carcinoma of the ureter treated between January 2000 and December 2010 were retrospectively analyzed. The intravesical recurrence-free survival rate was calculated using Kaplan-Meier method. Multivariate analysis was conducted with Cox's regression. RESULTS: A total of 104 patients were enrolled, who were followed up for a median of 46 months (13-89 months). Thirty-nine of the patients showed postoperative intravesical recurrence. Urine exfoliative cytology (P=0.000), number of tumors (P=0.006), tumor grade (P=0.039) and co-existence of bladder tumor (P=0.014) were found to independently influence the postoperative intravesical recurrence. Patients with more risk factors had poorer intravesical recurrence-free survival. CONCLUSION: Urine exfoliative cytology, number of tumors, tumor grade and co existence of bladder tumor are independent risk factors for postoperative intravesical recurrence of primary transitional cell carcinoma of the ureter. Close follow-up and rigorous treatment are essential for patients with high risk factors. PMID- 22543143 TI - [Effects of Wulongdan on expression of pineal clock genes in rats with chronic cerebral ischemia]. AB - OBJECTIVE: To explore the changes in the expression of pineal clock genes in rats with chronic cerebral ischemia and evaluate the effect of intervention with Wulongdan, a traditional Chinese medicinal preparation, on these changes. METHODS: Male SD rats were randomly divided into sham-operated group, chronic cerebral ischemia model group, and treatment group. In the latter two groups, chronic cerebral ischemia was induced by permanent ligation of the bilateral carotid arteries, and in the treatment group, Wulongdan was administered intragastrically on a daily basis for 3 weeks after the operation. Real-time quantitative RT-PCR was employed to examine the changes in the pineal expressions of Clock, Bmal1, and Per1 mRNA after the treatment. RESULTS: In the model group, the expression levels of Clock and Per1 mRNA were significantly lowered compared to those in the sham-operated group (P<0.01, P<0.05), but Bmal1 mRNA expression showed no significant changes (P>0.05). Wulongdan treatment caused a significant increase in pineal lock mRNA expression compared to the model group (P<0.01), and significantly reduced pineal Bmal1 expression as compared to the sham-operated group (P<0.05). No significant difference was found in Per1 mRNA expression between the treatment group and the model group. CONCLUSIONS: The changes in the expressions of the pineal clock genes in rats with chronic cerebral ischemia suggest the association between chronic cerebral ischemia and sleep disorders. Wulongdan can mitigate sleep disorders caused by chronic cerebral ischemia. PMID- 22543144 TI - [Tumor necrosis factor-alpha enhances radiosensitivity of A549 cells]. AB - OBJECTIVE: To assess the effects of tumor necrosis factor-alpha (TNF-alpha) in enhancing the radiosensitivity of lung cancer cells in vitro. METHODS: A549 cells were exposed to gamma-ray with or without TNF-alpha treatment. MTT assay was used to evaluate the cell viability, and flow cytometry was performed to assess the cell apoptosis. Western blotting was used to observe the expression of caspase-3 protein in the exposed cells. RESULTS: Compared with the exposed cells without TNF-alpha treatment, the cells treated with TNF-alpha showed significantly suppressed cell proliferation, increased the cell apoptosis, altered cell cycle, and increased caspase-3 protein expression after gamma-ray exposure. CONCLUSION: TNF-alpha can enhance the radiosensitivity of A549 cells to increase the efficiency of radiotherapy with gamma-ray irradiation. PMID- 22543145 TI - [Effects of mustard seed on 2, 4-dinitrofluorobenzene-induced allergic contact dermatitis in BALB/c mice]. AB - OBJECTIVE: To investigate the therapeutic effect of mustard seed on allergic contact dermatitis (ACD) in mice and explore the mechanism. METHODS: Eighteen BALB/c mice were randomly divided into normal control group, model group and mustard seed group. The mice in the normal control group and model group were fed with normal chow, and those in mustard seed group were given 5% mustard seed mixed in the chow. Three weeks later, ACD was induced on the ear using 2, 4 dinitrofluorobenzene. After 24 h, the swelling of the ear was examined, and the rats were sacrificed to collect the ear tissue ears and blood for histopathological and immunohistochemical examinations, RT-PCR and enzyme-linked immunosorbent assay. RESULTS: In mice with ACD, feeding with mustard seeds significantly lessened the ear swelling, improved the tissue histopathology, lowered the number of infiltrating Langerhans cells, and reduced the expressions of IL-1beta, TNF-alpha and IL-6 mRNA in the ear, but did not cause significant changes in serum levels of IL-4, IFN-gamma and IL-17. CONCLUSION: Mustard seed inhibits ACD in mice possibly by suppressing the expressions of IL-1beta, TNF alpha and IL-6 mRNA and inhibiting Langerhans cell migration in the epidermis. PMID- 22543146 TI - [Lipogranuloma of the lung: a case report]. AB - OBJECTIVE: Lipogranuloma is a rare benign disease accompanied by a reactive inflammatory process related to exogenous or endogenous lipids. We report a case of lipogranuloma of the lung mimicking pulmonary neoplastic disease in a 57-year old woman, who presented with the symptom of coughing for a month. The diagnosis of lung cancer was considered for the CT finding of a mass in right lower lobe. The patient underwent subsequent operation, and pathological examination of the surgical specimen revealed a stromal lesion consisting of lipid vacuoles with foreign body type giant cells and scattered lymphocytes. The final diagnosis of lipogranuloma of the lung was established. Clinicians should be aware of lipogranuloma in the lung, which can be easily confused with lung tumors or other benign diseases. A careful differential diagnosis is necessary. PMID- 22543147 TI - [Effect of 1,25-dihydroxyvitamin D(3) combined with 5-fluorouracil on IGFBP-3 expression in human esophageal carcinoma 109 cell xenograft in nude mice]. AB - OBJECTIVE: To investigate the effect of 1,25-dihydroxyvitamin D(3) and 5 fluorouracil, either alone or in combination, on the expression of IGFBP-3 in human esophageal carcinoma 109 cell xenograft in nude mice. METHODS: In vitro cultured esophageal carcinoma Eca-109 cells were inoculated subcutaneously in BALB/c mice. The tumor-bearing mice were randomly divided into control group (A), 1,25-dihydroxyvitamin D(3) group (B), 5-fluorouracil group (C), and 1,25 dihydroxyvitamin D(3) plus 5-fluorouracil group (D). 1,25-dihydroxyvitamin D(3) and 5-fluorouracil were administered at the doses of 2.5 ug/kg and 25 mg/kg via intraperitoneal injections, respectively, and the mice in the control group received saline injection only. The tumor growth was observed and the expression of IGFBP-3 in the tumor xenograft was detected using immunohistochemistry. An automatic biochemistry analyzer was used to determine serum calcium levels, and Von Kossa staining was utilized for observation of calcium deposition in the kidneys. RESULTS: Compared with that in group A, the xenograft in groups B, C, and D all showed a lowered growth rate with a smaller tumor volume, and presented with stronger IGFBP-3 positivity and significantly higher levels of IGFBP-3 protein expression (P<0.05). In group D, the protein expression of IGFBP-3 was significantly increased compared with that in groups B and C (P<0.05). Compared with that in group A, serum calcium level was slightly increased in groups B, C, and D, , but no obvious calcium deposition was found in the kidney tissue sections. CONCLUSION: Both 1,25-dihydroxyvitamin D(3) and 5-fluorouracil can inhibit the growth of the tumor xenograft in nude mice, and their combination is more effective. This effect is probably associated with increased protein expression of IGFBP-3 in the xenograft tumor. No calcium deposition occurs in the kidney tissue of the tumor-bearing mice. PMID- 22543148 TI - [Insulinotropic action of hippocampal cholinergic neurostimulating peptide mediated by activated type 3 muscarinic receptor in INS-1 cells]. AB - OBJECTIVE: [corrected] To characterize the insulinotropic action of hippocampal cholinergic neurostimulating peptide (HCNP) and analyze the role of type 3 muscarinic receptor (M(3)R) pathway in the action of HCNP. METHODS: INS-1 cells were incubated in routine RPMI 1640 medium (control group), RPMI 1640 supplemented with 50 pg/ml synthetic HCNP (HCNP group), or HCNP-containing medium with the addition of PMA 18 h prior to insulin release assay. The insulin levels in the medium was measured using radioimmunoassay following stimulation with different concentrations of glucose. Real-time quantitative PCR was used for detecting the gene expression of HCNP-pp, choline acetyltransferase (ChAT) and M(3)R in HCNP group and control group. RESULTS: After stimulation with different concentrations of glucose (5.6 and 16.7 mmol/L), HCNP group showed significantly higher insulin levels than the control and HCNP+ PMA groups. Compared with those in the control group, the mRNA levels of HCNP-pp, ChAT, and M(3)R were all lowered in HCNP group. CONCLUSION: HCNP can promote insulin release in INS-1 cells by increasing ChAT activity and activating M(3)R, and this effect is inhibited by PMA. PMID- 22543149 TI - [Effect of schizandrin B on H(2)O(2)-induced apoptosis of human hepatocytes in vitro: role of Fas pathway]. AB - OBJECTIVE: To investigate the role of Fas pathway in H(2)O(2)-induced apoptosis of L02 human hepatocytes and the effect of schisandrin B on Fas pathway. METHODS: Real-time quantitative PCR was used to detect the expressions of FAS, fas associated death domain protein (FADD) and caspase-8 mRNA in L02 cells exposed to H(2)O(2). Flow cytometry was employed to assess the cell apoptosis. ELISA, Western blotting and spectrophotometric assay were performed to determine the expressions of FAS protein, FADD protein and caspase-8 activity. RESULTS: Within the dose range of 5-15 mol/L, schisandrin B dose-dependently inhibited FAS and FADD expressions and caspase-8 activation. CONCLUSION: Schisandrin B can partially inhibit H(2)O(2)-induced L02 cell apoptosis possibly by affecting the FAS-FADD-caspase-8 pathway. PMID- 22543150 TI - [Video-assisted thoracoscopic removal of esophageal leiomyomas with intraoperative tumor location by endoscopy]. AB - OBJECTIVE: To summarize our experience with video-assisted thoracoscopic (VATS) removal of esophageal leiomyoma located with endoscopy during operation. METHODS: Between January 2006 and December 2010, 55 patients with esophageal leiomyoma underwent VATS enucleation. The surgical procedure was similar to that of open thoracotomy with intraoperative endoscopic location of the tumor and examination of the mucosal integrity especially for tumors less than 1 cm in diameter. RESULTS: Of the 55 patients undergoing VATS tumor removal, 54 patients completed the procedures smoothly, and 1 patient experienced ventricular fibrillation during the operation to require an open thoracotomy. Endoscopy was used in 38 patients during the operation. VATS enucleation differed significantly from open thoracotomy in the volume of bleeding, postoperative fasting days and postoperative hospital stay (P<0.05). The symptoms were completely relieved after the operation without postoperative complications. The patients were followed up for 8 to 59 months (mean 23.0 months) and no recurrence was found. CONCLUSION: VATS removal of esophageal leiomyomas is minimally invasive, safe and effective and can serve as the primary option for surgical removal of esophageal leiomyomas. PMID- 22543152 TI - [Interrupted aortic arch in a 42-year-old man]. AB - Interrupted aortic arch is a rare congenital vascular malformation associated with a high mortality rate in infancy, and is therefore very unusual in adults. We report a case of interrupted aortic arch in a 42-year-old male hypertensive patient who was found to have a disruption of aorta continuity distal to the left subclavian artery with massive collateral circulation into the descending aorta by computed tomography angiography. The patient was discharged after the blood pressure was controlled by antihypertensive therapy. This case suggests the necessity of careful auscultation for young patients with hypertension. Once murmur in the chest and back is heard, computed tomography angiography should be performed at once to avoid missed diagnosis and misdiagnosis. PMID- 22543151 TI - [Effects of entecavir on serum HBV DNA load and transformer growth factor-beta(1) in patients with chronic hepatitis B]. AB - OBJECTIVE: To investigate the changes in serum hepatitis B viral load (HBV DNA) and transformer growth factor-beta(1)(TGF-beta1) in patients with chronic hepatitis B after entecavir treatment and evaluates the therapeutic effect of entecavir. METHODS: Sixty-three patients with chronic hepatitis B were randomly assigned into entecavir group (n=33) and control group (n=30). The entecavir group consisted of 9 mild, 17 moderate, and 7 severe cases, all treated with oral entecavir (0.5 mg daily) and general hepatoprotective drugs; the control group, consisting of 13 mild, 12 moderate and 5 severe cases, was treated with the hepatoprotective drugs only. Serum HBV DNA and TGF-beta(1)were determined before and at 3 and 6 months during the treatment. RESULTS: Entecavir treatment reduced serum HBV DNA load in all the cases in entecavir group, and the difference was statistically significant between the levels measured at 3 and 6 months (P<0.05). The treatment also resulted in decreased serum TGF-beta(1)levels in moderate and severe cases, and the severe cases showed a significant TGF-beta(1)reduction after a 6-month treatment (P<0.05). CONCLUSION: Entecavir can lower serum HBV DNA load levels in patients with chronic hepatitis B. Entecavir is also effective to reduce serum TGF-beta(1)levels in moderate and severe cases, especially in the latter. PMID- 22543153 TI - [Susceptibility of Aedes albopictus and Culex pipiens quinquefasciatus to infection with bat Japanese encephalitis virus isolates]. AB - OBJECTIVE: To evaluate the susceptibility of Aedes albopictus and Culex pipiens quinquefasciatus to oral infection with bat Japanese encephalitis virus isolates (GD1 and HN2 strains). METHODS: Aedes albopictus and Culex pipiens quinquefasciatus were infected orally by GD1 and HN2 strains of bat Japanese encephalitis virus. TaqMan real-time PCR was used to detect the virus and monitor the changes in the viral loads in Aedes albopictus and Culex pipiens quinquefasciatus at a 2-day interval, starting from 4 days till 20 days after the infection. RESULTS: The infected Aedes albopictus and Culex pipiens quinquefasciatus were found positive for the Japanese encephalitis virus from day 4 to day 20. Both Aedes albopictus and Culex pipiens quinquefasciatus were susceptible to infection by GD1 and HN2 strains, but the latter showed a greater susceptibility. The HN2 strain virus appeared to have a greater virulence than the GD1 strain. CONCLUSION: Aedes albopictus and Culex pipiens quinquefasciatus can carry GD1 and HN2 strains of bat Japanese encephalitis virus isolates. PMID- 22543154 TI - Emergence of SHV-12 extended spectrum beta-lactamase among clinical isolates of Enterobacter cloacae in Tunisia. AB - A collection of seven multidrug-resistant clinical isolates of Enterobacter cloacae with reduced susceptibility to ceftazidime and cefepime recovered from 2009 to 2010 at the University Hospital of Mahdia, Tunisia, was analysed. PCR analysis and sequencing demonstrated that all study isolates harbored SHV-12 beta lactamase that was transferred by conjugation. Characterization of the regions surrounding the bla(SHV-12) showed that this gene was flanked by two IS26 elements. pulsed-field gel electrophoresis (PFGE) revealed differents profiles indicating that the study isolates were not clonally related. Diffusion of E. cloacae producing SHV-12 ESBL in our hospital is the consequence of disseminations of plasmids harboring the SHV-12 gene. PMID- 22543155 TI - An unusual finding during bowel cancer screening colonoscopy. PMID- 22543156 TI - Adipokines from local fat cells shape the macrophage compartment of the creeping fat in Crohn's disease. AB - OBJECTIVE: The creeping fat in Crohn's disease (CD) is infiltrated by macrophages; local adipokine levels are increased. This study aimed to link these observations to define a role for macrophages in the pathology of human CD. METHODS: Human peripheral blood CD14 cells were polarised in vitro into M1 and M2 macrophages. The effects on adipokine receptors, phenotypic surface markers, cytokines and chemokines were assessed after treatment with leptin and adiponectin. Immunohistochemistry visualised macrophage subtypes in samples of mesenteric fat tissue from patients with CD. The chemotactic potential of secreted macrophage products was determined by T cell migration and chemokine production in vitro. RESULTS: Although both adipokines altered the phenotype and function of M1 and M2 macrophages, M2 macrophages were more susceptible. M1 responded to leptin by increased cytokine production, but the stronger effect was seen in M2 macrophages with high expression of interleukin (IL)-10, IL-6 and tumour necrosis factor alpha. Adiponectin exerted similar effects and led to upregulated mannose receptor expression by M2 macrophages. Large macrophage numbers within the mesenteric fat tissue of patients with CD comprise a unique infiltration predominantly of M2 macrophages, leading to an IL-10-rich environment. While leptin increased the potency of both subtypes to attract CD3 T cells, adiponectin only affected M2 macrophages. CONCLUSION: The adipocyte dependent microenvironment within the creeping fat of patients with CD modulates the local macrophage compartment to a preference for the M2 subtype. The findings in this study with human cells suggest a protective role for the mesenteric fat in CD in terms of an enveloping barrier with the potential to limit intestinal inflammation. PMID- 22543157 TI - Next generation exome sequencing of paediatric inflammatory bowel disease patients identifies rare and novel variants in candidate genes. AB - BACKGROUND: Multiple genes have been implicated by association studies in altering inflammatory bowel disease (IBD) predisposition. Paediatric patients often manifest more extensive disease and a particularly severe disease course. It is likely that genetic predisposition plays a more substantial role in this group. OBJECTIVE: To identify the spectrum of rare and novel variation in known IBD susceptibility genes using exome sequencing analysis in eight individual cases of childhood onset severe disease. DESIGN: DNA samples from the eight patients underwent targeted exome capture and sequencing. Data were processed through an analytical pipeline to align sequence reads, conduct quality checks, and identify and annotate variants where patient sequence differed from the reference sequence. For each patient, the entire complement of rare variation within strongly associated candidate genes was catalogued. RESULTS: Across the panel of 169 known IBD susceptibility genes, approximately 300 variants in 104 genes were found. Excluding splicing and HLA-class variants, 58 variants across 39 of these genes were classified as rare, with an alternative allele frequency of <5%, of which 17 were novel. Only two patients with early onset Crohn's disease exhibited rare deleterious variations within NOD2: the previously described R702W variant was the sole NOD2 variant in one patient, while the second patient also carried the L1007 frameshift insertion. Both patients harboured other potentially damaging mutations in the GSDMB, ERAP2 and SEC16A genes. The two patients severely affected with ulcerative colitis exhibited a distinct profile: both carried potentially detrimental variation in the BACH2 and IL10 genes not seen in other patients. CONCLUSION: For each of the eight individuals studied, all non-synonymous, truncating and frameshift mutations across all known IBD genes were identified. A unique profile of rare and potentially damaging variants was evident for each patient with this complex disease. PMID- 22543159 TI - The natural history of Crohn's disease: who holds the crystal ball? PMID- 22543158 TI - Metronomic oral topotecan prolongs survival and reduces liver metastasis in improved preclinical orthotopic and adjuvant therapy colon cancer models. AB - OBJECTIVE: Advanced and recurrent diseases are the major causes of death in colon cancer. No standard preclinical model addresses advanced disease and spontaneous metastasis after orthotopic tumour growth. In this study, the authors report the establishment of such standardised orthotopic mouse models of colon cancer and their use in evaluating metronomic topotecan alone or in combination with standard chemotherapy. DESIGN: Human colon cancer cell lines, transfected with human chorionic gonadotropin and luciferase, were injected orthotopically into the caecal wall of severe combined immunodeficient mice, intrasplenically or subcutaneously. For adjuvant therapy, caecal resections were performed 3-5 weeks after tumour cell injection. Chemotherapy drugs tested included uracil/tegafur, folinic acid, oxaliplatin, topotecan, pazopanib and various combinations. RESULTS: Subcutaneous tumours showed exaggerated sensitivity to treatment by delayed tumour growth (p=0.002) and increased survival (p=0.0064), but no metastatic spread. Intrasplenic cell injection resulted in rapid and extensive but artefactual metastasis without treatment effect. Intracaecal cell injection with tumour take rates of 87.5-100% showed spontaneous metastases at clinically relevant rates. Metronomic topotecan significantly polonged survival and reduced metastasis. In the adjuvant setting, metronomic maintenance therapy (after FOLFOX like induction) prolonged survival compared with vehicle controls (p=0.0003), control followed by topotecan (p=0.0161) or FOLFOX-like therapy (p=0.0003). CONCLUSION: The refined orthotopic implantation technique proved to be a clinically relevant model for metastasis and therapy studies. Furthermore, metronomic therapy with oral topotecan may be promising to consider for clinical trials of metastatic colon cancer and long-term adjuvant maintenance therapy of colon cancer. PMID- 22543160 TI - RNAs in Epstein-Barr virions control early steps of infection. AB - Herpesviruses are dsDNA viruses, but their virions may additionally contain RNAs that can be transduced to recipient cells. The biological functions of herpes virion RNA species are unknown. Here we address this issue for EBV, a widespread human herpesvirus with oncogenic potential. We show that EBV-derived particles that include virions, virus-like particles, and subviral vesicles contain viral mRNAs, microRNAs, and other noncoding RNAs. Viral RNAs were transduced during infection and deployed immediate functions that enhanced EBV's capacity to transform primary B cells. Among these transduced viral RNAs, BZLF1 transcripts transactivated viral promoters triggering the prelatent phase of EBV infection, noncoding EBV-encoded RNA transcripts induced cellular cytokine synthesis, and BNLF2a mRNA led to immune evasion that prevented T-cell responses to newly infected B cells. Hence, transduced viral RNAs govern critical processes immediately after infection of B cells with EBV and likely play important roles in herpesviral infection in general. PMID- 22543161 TI - Transcription factor Olig2 defines subpopulations of retinal progenitor cells biased toward specific cell fates. AB - Previous lineage analyses have shown that retinal progenitor cells (RPCs) are multipotent throughout development, and expression-profiling studies have shown a great deal of molecular heterogeneity among RPCs. To determine if the molecular heterogeneity predicts that an RPC will produce particular types of progeny, clonal lineage analysis was used to investigate the progeny of a subset of RPCs, those that express the basic helix-loop-helix transcription factor, Olig2. The embryonic Olig2(+) RPCs underwent terminal divisions, producing small clones with primarily two of the five cell types being made by the pool of RPCs at that time. The later, postnatal Olig2(+) RPCs also made terminal divisions, which were biased toward production of rod photoreceptors and amacrine cell interneurons. These data indicate that the multipotent progenitor pool is made up of distinctive types of RPCs, which have biases toward producing subsets of retinal neurons in a terminal division, with the types of neurons produced varying over time. This strategy is similar to that of the developing Drosophila melanogaster ventral nerve cord, with the Olig2(+) cells behaving as ganglion mother cells. PMID- 22543162 TI - Naturally improving insulin resistance with amorfrutins. PMID- 22543163 TI - Estimating the sources of global sea level rise with data assimilation techniques. AB - A rapidly melting ice sheet produces a distinctive geometry, or fingerprint, of sea level (SL) change. Thus, a network of SL observations may, in principle, be used to infer sources of meltwater flux. We outline a formalism, based on a modified Kalman smoother, for using tide gauge observations to estimate the individual sources of global SL change. We also report on a series of detection experiments based on synthetic SL data that explore the feasibility of extracting source information from SL records. The Kalman smoother technique iteratively calculates the maximum-likelihood estimate of Greenland ice sheet (GIS) and West Antarctic ice sheet (WAIS) melt at each time step, and it accommodates data gaps while also permitting the estimation of nonlinear trends. Our synthetic tests indicate that when all tide gauge records are used in the analysis, it should be possible to estimate GIS and WAIS melt rates greater than ~0.3 and ~0.4 mm of equivalent eustatic sea level rise per year, respectively. We have also implemented a multimodel Kalman filter that allows us to account rigorously for additional contributions to SL changes and their associated uncertainty. The multimodel filter uses 72 glacial isostatic adjustment models and 3 ocean dynamic models to estimate the most likely models for these processes given the synthetic observations. We conclude that our modified Kalman smoother procedure provides a powerful method for inferring melt rates in a warming world. PMID- 22543165 TI - A double commutant theorem for Murray-von Neumann algebras. AB - Murray-von Neumann algebras are algebras of operators affiliated with finite von Neumann algebras. In this article, we study commutativity and affiliation of self adjoint operators (possibly unbounded). We show that a maximal abelian self adjoint subalgebra A of the Murray-von Neumann algebra A(f)(R) associated with a finite von Neumann algebra R is the Murray-von Neumann algebra A(f)(A(0)), where A(0) is a maximal abelian self-adjoint subalgebra of R and, in addition, A(0) is A Pi R. We also prove that the Murray-von Neumann algebra A(f)(C) with C the center of R is the center of the Murray-von Neumann algebra A(f)(R). Von Neumann's celebrated double commutant theorem characterizes von Neumann algebras R as those for which R'' = R, where R', the commutant of R, is the set of bounded operators on the Hilbert space that commute with all operators in R. At the end of this article, we present a double commutant theorem for Murray-von Neumann algebras. PMID- 22543164 TI - Formation of a long-lived electron-transfer state in mesoporous silica-alumina composites enhances photocatalytic oxygenation reactivity. AB - A simple donor-acceptor linked dyad, 9-mesityl-10-methylacridinium ion (Acr(+) Mes) was incorporated into nanosized mesoporous silica-alumina to form a composite, which in acetonitrile is highly dispersed. In this medium, upon visible light irradiation, the formation of an extremely long-lived electron transfer state (Acr(*)-Mes(*+)) was confirmed by EPR and laser flash photolysis spectroscopic methods. The composite of Acr(+)-Mes-incorporated mesoporous silica alumina with an added copper complex [(tmpa)Cu(II)] (ClO(4)(-))2 (tmpa = tris(2 pyridylmethyl)amine) acts as an efficient and robust photocatalyst for the selective oxygenation of p-xylene by molecular oxygen to produce p-tolualdehyde and hydrogen peroxide. Thus, incorporation of Acr(+)-Mes into nanosized mesoporous silica-alumina combined with an O(2)-reduction catalyst ([(tmpa)Cu(II)](2+)) provides a promising method in the development of efficient and robust organic photocatalysts for substrate oxygenation by dioxygen, the ultimate environmentally benign oxidant. PMID- 22543166 TI - Anti-atherosclerotic action of Ger-Gen-Chyn-Lian-Tang and AMPK-dependent lipid lowering effect in hepatocytes. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The Ger-Gen-Chyn-Lian-Tang (GGCLT), an officially standardized mixture of Chinese herbal medicines, consists of Puerariae Radix, Scutellariae Radix, Coptidis Rhizoma and Glycyrrhizae Radix in a ratio of 8:3:3:2. In this study, we evaluated the benefits of GGCLT in atherosclerotic progression. METHODS: The major constituents of GGCLT were analyzed by HPLC. ApoE /- mice taken 0.15% cholesterol diet were orally given vehicle or GGCLT (2 g/kg/day) for 12 weeks. Serum levels of lipid and glucose were analyzed, and atherosclerosis was examined by histological analyses. Cultures of vascular smooth muscle cells, hepatocytes and bone marrow-derived macrophages were used to investigate the action mechanisms of GGCLT. RESULTS: Our quantitation results indicated that GGCLT contains puerarin, daidzin, daidzein, baicalin, baicalein, wogonin, palmatine, coptisine, berberine and glycyrrhizin. GGCLT decreased serum levels of total cholesterol and LDL, but not TG and HDL in ApoE-/- mice. In parallel, GGCLT treatment reduced atherosclerotic lesions and collagen expression in atheroma plaques. In vascular smooth muscle cells, GGCLT could reduce cell migration, but failed to affect cell viability and proliferation. In hepatocytes, GGCLT can reduce lipid accumulation, and this action was accompanied by the activation of AMPK, upregulation of PPARs, and downregulation of FAS. Pharmacological approach indicated that the latter two events contributing to the anti-lipogenesis is resulting from AMPK pathway, and the lipid lowering effect of GGCLT in hepatocytes is mediated by AMPK and PPARalpha pathways. Meanwhile, two of the major components of GGCLT, berberine and puerarin, also activated AMPK and decreased lipid accumulation in hepatocytes with berberine of higher efficacy. Besides in hepatocytes, AMPK signaling was also activated by GGCLT in vascular smooth muscle cells and macrophages. CONCLUSIONS: These results demonstrate the anti-atherosclerotic action of Chinese medicine mixture GGCLT in ApoE-/- atherosclerotic mouse model. Mechanistic study suggests that activation of AMPK and PPARalpha in hepatocytes leading to a decrease of lipid formation contributes to the beneficial action of GGCLT in atherosclerosis treatment. PMID- 22543167 TI - Food- and gender-dependent pharmacokinetics of paeoniflorin after oral administration with Samul-tang in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Samul-tang (Si-Wu-tang in Chinese, Shimotsu-to in Japanese), widely used in eastern Asia, is composed of Angelica gigas (Angelicae Gigantis Radix), Cnidium officinale (Cnidii Rhizoma), Paeonia lactiflora (Paeonia Radix) and Rehmannia glutinosa (Rehmanniae Radix Preparata). Paeoniflorin, one of active components in Samul-tang has anti-platelet, anti-inflammation, anti-cancer and neuroprotective properties. However, there is no information about the effects of gender and food intake on the pharmacokinetics of paeoniflorin till now. AIM OF THE STUDY: This study was conducted to investigate whether food and gender could influence pharmacokinetic profiles of paeoniflorin after oral administration of Samul-tang. MATERIALS AND METHODS: Male and female rats were administered with a single oral dose of Samul-tang equivalent to 80 mg/kg of paeoniflorin. Plasma concentrations of paeoniflorin were measured by high performance liquid chromatography. The statistical differences of each group were evaluated using the analysis of variance (ANOVA) or Student t-test. RESULTS: The pharmacokinetic parameters of paeoniflorin were not significant different by gender difference. However, the maximum plasma concentration (C(max), 0.47+/-0.29 MUg/mL versus 1.10+/-0.35 MUg/mL), area under the concentration-time curve (AUC(0 >infinity), 1.41+/-0.89 h . MUg/mL versus 3.12+/-1.61 h . MUg/mL) and relative bioavailability (F(rel)=2.21) of fed rats were significantly increased in comparison with those of fasted rats (P<0.05). CONCLUSION: Taken together, food intake can affect both the rate and extent of absorption of paeoniflorin when Samul-tang was administered orally. Furthermore, this study demonstrates a readily preparative HPLC method in the research of traditional herbal medicine. PMID- 22543168 TI - Sanguis Draconis resin stimulates osteoblast alkaline phosphatase activity and mineralization in MC3T3-E1 cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Sanguis Draconis (SD), "Dragon's Blood", is a resin that is obtained from Daemonorops draco (Palmae). Used in traditional medicine, it has shown activity in the prevention of osteoporosis as well as promoting the healing of bone fractures. MATERIALS AND METHODS: In this study, the effects of Sanguis Dranonis ethanol extract on beta-glycerolphosphate and ascorbic acid induced differentiation using mouse calvaria origin MC3T3-E1 osteoblastic cells was examined. We looked at osteoblast differentiation, proliferation, and mineralization by measuring alkaline phosphatase (ALP) and specific bone marker activities. Osteoblast-like MC3T3-E1 cells were cultured in various concentrations of SD ethanol extract (0.005-1mg/mL) during the osteoblast differentiation period (1, 5, 15, and 25 days). RESULTS: As measured by 3-[4,5 dimethylthiazol-2-y]-2,5-diphenyltetrazolium bromide assay, SD extracts increased cell proliferation as compared to control. The most pronounced effect was observed at the concentration range between 0.01 and 0.1 mg/mL (P<0.01). This SD stimulatory effect for cell proliferation was observed during the whole osteogenic period. Cellular (synthesized) ALP activity was increased during 15 days of culture, and was confirmed by the staining of ALP activity on cell matrix layers for matrix calcification. SD stimulatory effect for cell mineralization we observed in 14 and 21 days. Elevated mRNA or protein levels of bone morphogenetic protein-2(BMP 2), the differentiation marker osteocalcin, osteopontin, collgen I, and a master osteogenic transcription factor, Runx2, were observed in SD-treated cells. CONCLUSIONS: These results suggest that SD may increase osteogenic effect by stimulating cell ALP activity and affect the BMP signaling pathway cascades in osteoblastic cells, then promotes osteoblast differentiation, mineralization, and bone formation. PMID- 22543169 TI - Evaluation of antimicrobial activity of ethanol extract and compounds isolated from Trichodesma indicum (Linn.) R. Br. root. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The roots are reportedly used to treat diarrhoea, dysentery, leprosy, skin diseases and fever. AIM OF STUDY: The aim of present study was to investigate the in vitro antimicrobial potential of ethanol extract of Trichdesma indicum root, and its purified compounds and to validate scientifically its use in traditional medicine. MATERIAL AND METHODS: The root of Trichdesma indicum was extracted with ethanol and subjected to chromatographic separation for isolation of phytochemical compounds. Structures of isolated compounds were elucidated by spectroscopic methods. The antimicrobial activities of the ethanol extract of T. indicum and isolated compounds were primarily evaluated by a disc diffusion test. The anti-microbial efficacy of the ethanol extract or isolated compounds was then assessed in vitro by determining minimal inhibition concentration (MIC) and minimal bactericidal or fungicidal concentration (MBC/MFC). RESULTS: n-Decanyl laurate (1), n-tetradecanyl laurate (2), n-nonacosanyl palmitate (3), stigmast-5-en-3beta-ol-21(24)-olide (4), n pentacos-9-one (5), n-dotriacont-9-one-13-ene (6), stigmast-5-en-3beta-ol-23-one (7) and lanast-5-en-3beta-D-glucopyranosyl-21 (24)-olide (8) were isolated from ethanol extract of T.indicum. The ethanol extract and isolated compounds (1-8) showed varying degrees of antimicrobial activities. The ethanol extract exhibited potent growth inhibitory activity against S. aureus, B. subtilis and C. albicans with an MIC value of 19.2 MUg/ml. Among all the isolated compounds, lanast-5-en 3beta-D-glucopyranosyl-21 (24)-olide (8) displayed strongest antibacterial activity against S. aureus with MIC value of 2.4 MUg/ml. CONCLUSIONS: The results of present study provide ground basis for the potential use of the ethanol extract Trichodesma indicum root as well as the some of the isolated compounds in the treatment of infections associated with the studied microorganisms. PMID- 22543170 TI - Pharmacological basis for the medicinal use of muskmelon base (Pedicellus Melo.) for abdominal distention and constipation. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Muskmelon base (Pedicellus Melo.) has a long history (Ming Dynasty) as a Chinese traditional medicine. According to traditional use, it was prepared as rectal suppositories for treating abdominal distention and constipation. The present study was carried out on the pharmacological basis for the medicinal use of muskmelon base. AIM OF THE STUDY: The objective of this study was to determine the pharmacological basis for the medicinal use of the ethanol extract from muskmelon base (EMB) for abdominal distention and constipation. MATERIALS AND METHODS: In this study, we report the gastrointestinal prokinetic action of EMB following single rectal or large intestinal administration. Laxative activity, gastric emptying and small intestinal transit tests were examined in ICR mice. SD rats were used to determine changes in large intestinal transit and contractile effects of the proximal colon in vivo. Guinea pigs were used to evaluate the contractile effects of the proximal colon and the possible mechanism or mechanisms on proximal colon activity ex vivo. Moreover, the acute toxicity of EMB was evaluated. RESULTS: In the in vivo experiments, the acute toxicity test showed that the maximum tolerated dose (MTD) of EMB was 400 mg/kg. A laxative effect was observed in mice at different dosages (6.5, 13 and 26 mg/kg). EMB showed a dose-dependent acceleration of gastric emptying (13 and 26 mg/kg). It also promoted both small intestinal (6.5, 13 and 26 mg/kg) and large intestinal (4, 8 and 16 mg/kg) transit activity. In the SD rat model, single rectal administration of EMB (8 and 16 mg/kg) showed a significant increase in both the frequency and amplitude of proximal colon smooth muscle contractility. These increases in amplitude and frequency peaked 30-60 min after EMB administration and corresponded with the results of the laxative activity test. The ex vivo experiments showed that varying doses of EMB (11.5, 23 and 46 mg/kg) had a direct prokinetic effect that was sensitive to atropine. CONCLUSIONS: Our results show that EMB is a low dosage, fast acting drug with a large therapeutic window (4-400 mg/kg) and shows significant gastrointestinal prokinetic action after single rectal or large intestinal administration. This gastrointestinal prokinetic effect was stronger in the intestines than in the stomach. This effect was sensitive to atropine, suggesting that EMB acts mainly through cholinergic mechanisms. PMID- 22543171 TI - Combined treatment with a traditional Chinese medicine, Hachimi-jio-gan (Ba-Wei Di-Huang-Wan) and alendronate improves bone microstructure in ovariectomized rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Hachimi-jio-gan is one of the most common recipes in traditional Chinese, Japanese and Korean medicines and has been used for preventing and treating various diseases associated with aging, including osteoporosis. AIM OF THE STUDY: The present study was performed to examine the combined effects of a traditional Chinese medicine, Hachimi-jio-gan (HJG) and antiresorptive agent, alendronate (ALN) on ovariectomy-induced bone loss in rats. MATERIALS AND METHODS: Six-month-old female Sprague-Dawley rats were underwent ovariectomy (OVX) or sham operation. Eight weeks later, the OVX rats were treated either with HJG or ALN alone or in combination of both. The skeletal response was evaluated using micro-computed tomography (micro-CT), image analysis software, and biochemical markers. RESULTS: This study demonstrated that treatment with HJG or ALN alone increased trabecular bone volume and bone mineral density (BMD), and partially improved bone microstructure of the proximal tibia and vertebra in OVX rats. Treatment with ALN to OVX rats resulted in significant reduction in both bone resorption and bone formation. Treatment with HJG to OVX rats inhibited bone resorption, with no marked effects on bone formation. Combined treatment of HJG and ALN significantly improved trabecular bone mass and bone microstructure, compared with either agent alone. CONCLUSIONS: We conclude that the combined treatment with HJG and ALN has beneficial effects on trabecular bone mass, improving the structural properties of both tibia and vertebra in OVX rats. PMID- 22543172 TI - Hepatoprotective and antioxidant effects of Myelophil on restraint stress-induced liver injury in BALB/c mice. AB - ETHNOPHARMACOLOGIC RELEVANCE: Myelophil, an ethanol extract of Astragali Radix and Salviae Radix, has been used for patients with chronic fatigue-associated disorders in traditional Oriental clinics. AIM OF THE STUDY: This study aimed to evaluate the pharmacologic effects of Myelophil using a restraint stress-induced liver injury model and to explore the mechanisms underlying these effects. MATERIALS AND METHODS: Distilled water or Myelophil (50 mg/kg, 100 mg/kg, or 200 mg/kg) was orally administered to 6-week-old BALB/c male mice once daily for 5 day. The mice were subjected to restraint stress for 6h, and serum levels of aspartate and alanine aminotransferases (AST and ALT, respectively), total reactive oxygen species, and total antioxidant capacity were determined. Hepatic tissue levels of lipid peroxidation, antioxidant activity (as represented by superoxide dismutase, catalase, and glutathione reductase activity), and interleukin-1 were also measured. RESULTS: Restraint stress induced severe oxidative stress and hepatic injury, as evidenced by marked elevation of serum ALT and AST levels, increased levels of reactive oxygen species and lipid peroxidation activity, and depletion of antioxidant enzyme activities. Myelophil pretreatment significantly attenuated not only the elevation of serum ALT and AST but also the increase in reactive oxygen species and lipid peroxidation. It also restored a significant fraction of the catalase, glutathione reductase, and peroxidase activity in liver tissues. Myelophil pretreatment also partially normalized the levels of interleukin-1beta gene and protein expression. CONCLUSIONS: These results suggest that Myelophil has potent protective effects against restraint stress-induced liver injury via antioxidant activities, and have relevance to the clinical applications of Myelophil in field of traditional herbal medicine. PMID- 22543173 TI - Effects of Schisandra chinensis Baillon (Schizandraceae) on lipopolysaccharide induced lung inflammation in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Schisandra chinensis Baillon (Sc), an anti inflammatory herb that has been used in traditional Chinese medicine for thousands of years, is frequently used to treat upper respiratory tract infections. AIM OF THE STUDY: This study was conducted to evaluate the ability of a water extract of Sc to prevent airway inflammation both in vitro and in vivo. MATERIALS AND METHODS: Human lung alveolar epithelial-derived A549 cells were stimulated with to interleukin-1beta, tumor necrosis factor-alpha, and interferon gamma (IL-1beta, TNF-alpha, and INF-gamma; cytokine mixture; CM) and treated with Sc extracts. They were then evaluated using nitric oxide (NO), IL-8 and monocyte chemotactic protein-1 (MCP-1) secretions. In the in vivo study, BALB/c mice were challenged with lipopolysaccharide (LPS) to induce acute airway inflammation. After this challenge, the mice were treated with Sc extracts (10, 50 and 100mg/kg) by oral administration, and inflammatory cells in the bronchoalveolar lavage (BAL) fluid were counted. IL-6 and TNF-alpha secretions were measured using an enzyme-linked immunosorbent assay. Lung tissues of the LPS treated mice were prepared and stained with hematoxylin and eosin (HE) for histological examination. RESULTS: In the A549 cells, Sc extracts dose-dependently and significantly inhibited CM-induced NO production and reduced IL-8 and MCP-1 secretions. Sc extracts efficiently suppressed neutrophil and macrophage infiltrations of lung tissues and increased IL-6 and TNF-alpha levels in BAL fluid in LPS-instilled BALB/c mice. In addition, Sc extracts treatment inhibited pathologic progress in the lung tissues, as confirmed by H&E staining. These findings indicate that Sc extracts could be potentially useful for the treatment of acute lung inflammation and acute lung injury. PMID- 22543174 TI - Antinociceptive effectiveness of triterpenes from rosemary in visceral nociception. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Rosemary is a species used worldwide as a common spice, but also in folk medicine for their therapeutic properties against abdominal pain. The rationale of this study was to examine the involvement of triterpenes and to compare their effectiveness in the antinociceptive effect of an ethanol extract of Rosmarinus officinalis L. (Lamiaceae). MATERIAL AND METHODS: Fractionation and HPLC analyses allowed the identification of a mixture of micromeric (121 mg/g), oleanolic (64 mg/g) and ursolic (83 mg/g) acids as partial antinociceptive responsible in an ethyl acetate fraction of R. officinalis by using the acetic acid-induced abdominal constrictions model in mice. RESULTS: These triterpenes individually evaluated produced a significant and dose-dependent antinociceptive response with similar potency as follows: ED50=1.1 mg/kg (0.9-1.3 mg/kg), 2.1 mg/kg (1.6-2.6 mg/kg) and 1.6 mg/kg (1.1-2.1 mg/kg), respectively, by using the intraperitoneal (i.p.) route of administration in mice. Their maximal antinociceptive efficacy resembled that produced by ketorolac (10 mg/kg, i.p.), a common clinic analgesic. CONCLUSION: Our results provide evidence that these triterpenes participate in the antinociceptive activity of R. officinalis. In addition, each individual triterpene showed a similar potency to that observed with ketorolac, a non-steroidal anti inflammatory drug, in this experimental model. PMID- 22543175 TI - Polyprenols from Taxus chinensis var. mairei prevent the development of CCl4 induced liver fibrosis in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The aim of this study was to investigate the anti fibrotic effects and the possible underlying mechanisms of taxus polyprenols (TPs) isolated from the needles of Taxus chinensis var. mairei. MATERIALS AND METHODS: The animals were randomly divided into normal control with vehicles only (olive oil), rat model given CCl4 only, CCl4+low TPs (48 mg/kg), CCl4+medium TPs (120 mg/kg), CCl4+high TPs (300 mg/kg), and CCl4+Polyene phosphatidylcholine (PP, 120 mg/kg). The rat model of liver fibrosis was induced by subcutaneous injection of 40% (v/v) of CCl4 diluted in olive oil (3 mL/kg body weight) twice per week for 8 weeks. Liver histopathological study was performed. Aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) and albumin (ALB) of the serum were determined for evaluating the liver function. In order to reveal the possible mechanisms of the anti-fibrotic effects, oxidative stress level, hepatic collagen metabolism, and hepatic stellate cells (HSCs) activation were investigated. Furthermore, the mRNA expression of the fibrotic-related factors was measured by the quantitative real-time RT-PCR. RESULTS: TPs successfully attenuated liver injury induced by CCl4 shown by histopathological sections of livers and improved liver function as indicated by decreased ALT, AST and ALP levels and increased ALB levels in serum of the rats. TPs significantly increased the hepatic Cu/Zn SOD and GSH-Px activities along with GSH content while a remarkable decrease in MDA content. Both immunohistochemical staining and mRNA expression levels of alpha-SMA indicated a profound suppression of HSCs activation. Furthermore, it significantly inhibited the mRNA expression of the pro-fibrotic cytokines Col alpha1(I), Col alpha1(SH), MMP-2, TIMP-1, TIMP-2, PDGF beta, TGF-beta1, CTGF and TNF-alpha and restored the hepatoprotective factor HGF. CONCLUSION: These results suggest that the protective effects of TPs in chronic CCl4-induced liver fibrosis might be related with the reduction of oxidative damage, the inhibition of HSCs activation, the down-regulation of pro-fibrogenic stimuli and the protection of hepatocytes. PMID- 22543176 TI - Vasodilatory effects of ethanol extract of Radix Paeoniae Rubra and its mechanism of action in the rat aorta. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Radix Paeoniae Rubra (RPR) is an important traditional Chinese medicine (TCM) commonly used in clinic for a long history in China. RPR is the radix of either Paeonia lactiflora Pall. or Paeonia veitchii Lynch. RPR has a wide variety of pharmacological actions such as anti-thrombus, anti-coagulation, and anti-atherosclerotic properties, protecting heart and liver. However, the mechanisms involved are to be defined. AIM OF THE STUDY: The aim of the present study was to define the effect of Paeonia lactiflora Pall. extracts on vascular tension and responsible mechanisms in rat thoracic aortic rings. MATERIALS AND METHODS: Ethanol extract of Paeonia lactiflora Pall. (EPL) was examined for their vascular relaxant effects in isolated phenylephrine precontracted rat thoracic aorta. RESULTS: EPL induced relaxation of the phenylephrine-precontracted aortic rings in a concentration-dependent manner. Vascular relaxation induced by EPL was significantly inhibited by removal of the endothelium or pretreatment of the rings with N(G)-nitro-L-arginine methylester (L-NAME) or 1H-[1,2,4]-oxadiazolo-[4,3-alpha]-quinoxalin-1-one (ODQ). Extracellular Ca2+ depletion or diltiazem significantly attenuated EPL-induced vasorelaxation. Modulators of the store-operated Ca2+ entry (SOCE), thapsigargin, 2-aminoethyl diphenylborinate and Gd3+, and an inhibitor of Akt, wortmannin, markedly attenuated the EPL-induced vasorelaxation. Further, the EPL-induced vasorelaxation was significantly attenuated by pretreatment with tetraethylammonium, a non-selective K(Ca) channels blocker, or glibenclamide, an ATP-sensitive K+ channels inhibitor, respectively. Inhibition of cyclooxygenases with indomethacin, and adrenergic and muscarinic receptors blockade had no effects on the EPL-induced vasorelaxation. CONCLUSIONS: The present study suggests that EPL relaxes vascular smooth muscle via endothelium-dependent and Akt- and SOCE-eNOS-cGMP-mediated pathways through activation of both K(Ca) and K(ATP) channels and inhibition of L-type Ca2+ channels. PMID- 22543177 TI - Regulation of signaling molecules associated with insulin action, insulin secretion and pancreatic beta-cell mass in the hypoglycemic effects of Korean red ginseng in Goto-Kakizaki rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Korean red ginseng (KRG) has long history as herbal remedy for antidiabetic effect. AIM OF THE STUDY: To study molecular mechanisms by which KRG ameliorates diabetes mellitus, we investigated whether the supplementation with the aqueous extract of KRG as a dietary admixture (1%, w/w) regulates the expressions of signaling molecules that are associated with insulin action, insulin secretion and pancreatic beta-cell mass in spontaneously diabetic Goto-Kakizaki (GK) rats. METHODS: An aqueous extract of KRG was supplemented for the estimated dosage to be 0.2 g/kg rat/day beginning at 5 weeks of age for 12 weeks in male GK rats. Plasma glucose levels were measured every 4 weeks. The expressions of signaling molecules that are associated with insulin action, insulin secretion and beta-cell mass in tissues were determined by Western blotting. RESULTS: The 12-week supplementation with KRG significantly (P<0.05) decreased blood glucose compared to control. It up-regulated the expression of glucose transporter (GLUT) 4 in adipose tissue, and down-regulated the expression of protein tyrosine phosphatases (PTP)-1B in adipose tissue and skeletal muscle. It also up-regulated the expression of insulin and down regulated the expression of uncoupling protein (UCP) 2, Bax and poly (ADP-ribose) polymerase (PARP) in pancreas. CONCLUSIONS: These results suggest that GLUT4, PTP 1B, insulin, UCP2, Bax and PARP may be the primary targets of KRG that result in increase in insulin action and in insulin secretion, and decrease in beta-cell mass, and that cause the normalization in glucose homeostasis. PMID- 22543179 TI - Epigenetic variation in plant responses to defence hormones. AB - BACKGROUND AND AIMS: There is currently much speculation about the role of epigenetic variation as a determinant of heritable variation in ecologically important plant traits. However, we still know very little about the phenotypic consequences of epigenetic variation, in particular with regard to more complex traits related to biotic interactions. METHODS: Here, a test was carried out to determine whether variation in DNA methylation alone can cause heritable variation in plant growth responses to jasmonic acid and salicylic acid, two key hormones involved in induction of plant defences against herbivores and pathogens. In order to be able to ascribe phenotypic differences to epigenetic variation, the hormone responses were studied of epigenetic recombinant inbred lines (epiRILs) of Arabidopsis thaliana - lines that are highly variable at the level of DNA methylation but nearly identical at the level of DNA sequence. KEY RESULTS: Significant heritable variation was found among epiRILs both in the means of phenotypic traits, including growth rate, and in the degree to which these responded to treatment with jasmonic acid and salicylic acid. Moreover, there was a positive epigenetic correlation between the responses of different epiRILs to the two hormones, suggesting that plant responses to herbivore and pathogen attack may have a similar molecular epigenetic basis. CONCLUSIONS: This study demonstrates that epigenetic variation alone can cause heritable variation in, and thus potentially microevolution of, plant responses to defence hormones. This suggests that part of the variation of plant defences observed in natural populations may be due to underlying epigenetic, rather than entirely genetic, variation. PMID- 22543178 TI - Trait divergence and indirect interactions allow facilitation of congeneric species. AB - BACKGROUND: Plant facilitation occurs when the presence of a plant (i.e. a nurse plant) modifies the environment, making it more favourable for the establishment and survival of other species (i.e. facilitated plants), which can germinate and grow nearby. Facilitative associations can be maintained or turned into competition as the facilitated seedling grows. According to the competition relatedness hypothesis that suggests that closely related species tend to compete more, facilitation turns into competition between phylogenetically close species. However, some examples of facilitation between congeneric species, which are supposed to be closely related species, have been found in nature. SCOPE: In this work, some examples of congeneric facilitation and subsequent coexistence are reviewed and an attempt is made to explain those exceptions to the competition relatedness hypothesis. CONCLUSIONS: Two mechanisms are proposed that can switch the facilitation-competition balance: trait divergence and indirect interactions. When traits have diverged within the genus, the niche overlap is reduced and competition relaxed, thus allowing the coexistence of congeneric species. The presence of third interplayers (mycorrhizal fungi, seed dispersers, pollinators or pathogens) participating in the interaction between plants can alleviate the competition or enhance the reproduction and allow the coexistence of species that could not coexist in their absence. PMID- 22543180 TI - Periprosthetic joint infection diagnosis: a complete understanding of white blood cell count and differential. AB - Recent research has raised doubts regarding the utility of serum white blood cell count (WBC) for diagnosis of periprosthetic joint infection (PJI). As synovial WBC and neutrophil (PMN) percentage have been adopted as accurate markers of PJI, this study investigated the correlation of WBC in serum versus joint fluid and diagnostic value of all WBC levels for failed arthroplasty patients. 153 patients (73 PJI) undergoing revision knee arthroplasty were identified. Weak correlations between joint fluid and serum for WBC (R = 0.19), PMN count (R = 0.31), and lymphocyte count (R = -0.22) were observed. Diagnostic accuracy of PMN (93%) and WBC (93%) synovial count relative to serum was similar to synovial WBC (93%) and PMN% (95%) alone. Serum WBC analysis does little to improve the accurate diagnosis of PJI. PMID- 22543181 TI - Is bigger really bigger? Differential responses to temperature in measures of body size of the mosquito, Aedes albopictus. AB - When confronted with variation in temperature, most ectotherms conform to a growth rule that "hotter is smaller". This phenomenon can have important implications on population dynamics, interactions with other species, and adaptation to new environments for arthropods. However, the impact of other environmental factors and genetics may affect that general rule. Furthermore, most studies measure a single body part, and do not examine how temperature and other factors alter the allometric relationship between measurements of growth. In this study, we test the hypothesis that temperature and nutrition, while strongly affecting growth, do not change the allometric relationship between body mass and wing length in the mosquito Aedes albopictus. We tested this hypothesis by growing larval mosquitoes from two populations at five temperatures with three food levels. Contrary to our hypothesis, we find that temperature has a profound effect on allometry, with higher temperatures resulting in mosquitoes with shorter wings and greater body mass, and that the effects of temperature are dependent upon available food and population origin. We therefore reject our hypothesis and propose several testable mechanisms that will provide greater insight into the relationship between temperature, food, and measures of growth. PMID- 22543182 TI - Simultaneous stressors: interactive effects of an immune challenge and dietary toxin can be detrimental to honeybees. AB - Recent large-scale mortality of honeybee colonies is believed to be caused by multiple interactions between diseases, parasites, pesticide exposure, and other stress factors. To test whether a dual challenge has an additive effect in reducing survival, we experimentally stimulated the immune system of caged Apis mellifera scutellata workers from six colonies by injecting saline or Escherichia coli lipopolysaccharides (LPS), and additionally fed them the alkaloid nicotine (0 MUM, 3 MUM and 300 MUM in 0.63 M sucrose). Workers did not increase their sucrose intake to compensate for the immune system activation, and those injected with E. coli LPS decreased their intake on the highest nicotine concentration. In the single challenges, injection and high nicotine doses negatively affected survival. All injected worker groups showed reduced survival. Without nicotine, survival of the saline and E. coli LPS worker groups was similar, but survival of E. coli LPS-challenged workers dropped below that of the saline groups when additionally challenged by nicotine, with bees dying earlier at higher nicotine concentrations. In the dual challenge of saline injection and dietary nicotine, a reduced effect on survival was observed, with lower mortality than expected from the summed mortalities due to the single challenges. However, additive and synergistic effects on survival were observed in workers simultaneously challenged by E. coli LPS and nicotine, indicating that interactive effects of simultaneous pathogen exposure and dietary toxin are detrimental to honeybee fitness. PMID- 22543183 TI - "Muscle to meat" molecular events and technological transformations: the proteomics insight. AB - Cellular death is characterized by a complex pattern of molecular events that depend on cell type. Specifically, muscle cells first undergo rigor mortis due to ATP depletion, and later, on the time scale of days, muscle fiber degradation due to proteolytic enzyme activity. In the present review, we will refer to proteomic investigations on the post-mortem evolution of the protein patterns of animal muscle cells. These studies, carried out with the application of either bottom-up or top-down methods, are relevant for understanding the biochemical reactions that i) convert muscle to meat, ii) are associated with meat aging and iii) impact on meat tenderness, a feature of significant commercial value. We also report on the proteomic investigations that have been made to analyze the transformation of meat in industrial processes. These studies are primarily aimed at identifying protein patterns and/or individual proteins diagnostic of the quality of the final product. PMID- 22543184 TI - Mass spectrometry and animal science: protein identification strategies and particularities of farm animal species. AB - Proteomic approaches are gaining increasing importance in the context of all fields of animal and veterinary sciences, including physiology, productive characterization, and disease/parasite tolerance, among others. Proteomic studies mainly aim the proteome characterization of a certain organ, tissue, cell type or organism, either in a specific condition or comparing protein differential expression within two or more selected situations. Due to the high complexity of samples, usually total protein extracts, proteomics relies heavily on separation procedures, being 2D-electrophoresis and HPLC the most common, as well as on protein identification using mass spectrometry (MS) based methodologies. Despite the increasing importance of MS in the context of animal and veterinary science studies, the usefulness of such tools is still poorly perceived by the animal science community. This is primarily due to the limited knowledge on mass spectrometry by animal scientists. Additionally, confidence and success in protein identification is hindered by the lack of information in public databases for most of farm animal species and their pathogens, with the exception of cattle (Bos taurus), pig (Sus scrofa) and chicken (Gallus gallus). In this article, we will briefly summarize the main methodologies available for protein identification using mass spectrometry providing a case study of specific applications in the field of animal science. We will also address the difficulties inherent to protein identification using MS, with particular reference to experiments using animal species poorly described in public databases. Additionally, we will suggest strategies to increase the rate of successful identifications when working with farm animal species. PMID- 22543185 TI - Tyrosine-dependent capture of CAP-Gly domain-containing proteins in complex mixture by EB1 C-terminal peptidic probes. AB - Microtubule dynamics is regulated by an array of microtubule associated proteins of which the microtubule plus-end tracking proteins (+TIPs) are prominent examples. +TIPs form dynamic interaction networks at growing microtubule ends in an EB1-dependent manner. The interaction between the C-terminal domain of EB1 and the CAP-Gly domains of the +TIP CLIP-170 depends on the last tyrosine residue of EB1. In the present study, we generated peptidic probes corresponding to the C terminal tail of EB1 to affinity-capture binding partners from cell lysates. Using an MS-based approach, we showed that the last 15 amino-acid residues of EB1, either free or immobilized on beads, bound recombinant CAP-Gly domains of CLIP-170. We further demonstrate that this binding was prevented when the C terminal tyrosine of EB1 was absent in the peptidic probes. Western blotting in combination with a label-free quantitative proteomic analysis revealed that the peptidic probe harboring the C-terminal tyrosine of EB1 effectively pulled-down proteins with CAP-Gly domains from endothelial cell extracts. Additional proteins known to interact directly or indirectly with EB1 and the microtubule cytoskeleton were also identified. Our peptidic probes represent valuable tools to detect changes induced in EB1-dependent +TIP networks by external cues such as growth factors and small molecules. PMID- 22543186 TI - Toxins in mussels (Mytilus galloprovincialis) associated with diarrhetic shellfish poisoning episodes in China. AB - More than 200 people in China suffered illness with symptoms of diarrhetic shellfish poisoning (DSP) following consumption of mussels (Mytilus galloprovincialis). The event occurred in the cities of Ningbo and Ningde near the East China Sea in May, 2011. LC-MS/MS analysis showed that high concentrations of okadaic acid, dinophysistoxin-1, and their acyl esters were responsible for the incidents. The total concentration was more than 40 times the EU regulatory limit of 160 MUg OA eq./kg. Pectentoxin-2 and its seco-acids were also present in the mussels. Additionally, yessotoxins were found to be responsible for positive mouse bioassay results on scallop (Patinopecten yessoensis) and oyster (Crassostrea talienwhanensis) samples collected from the North Yellow Sea in June, 2010. This work shows that high levels of lipophilic toxins can accumulate in shellfish from the Chinese coast and it emphasises that adequate chemical analytical methodologies are needed for monitoring purposes. Further research is required to broaden the knowledge on the occurrence of lipophilic toxins in Chinese shellfish. PMID- 22543187 TI - Spider-venom peptides that target voltage-gated sodium channels: pharmacological tools and potential therapeutic leads. AB - Voltage-gated sodium (Na(V)) channels play a central role in the propagation of action potentials in excitable cells in both humans and insects. Many venomous animals have therefore evolved toxins that modulate the activity of Na(V) channels in order to subdue their prey and deter predators. Spider venoms in particular are rich in Na(V) channel modulators, with one-third of all known ion channel toxins from spider venoms acting on Na(V) channels. Here we review the landscape of spider-venom peptides that have so far been described to target vertebrate or invertebrate Na(V) channels. These peptides fall into 12 distinct families based on their primary structure and cysteine scaffold. Some of these peptides have become useful pharmacological tools, while others have potential as therapeutic leads because they target specific Na(V) channel subtypes that are considered to be important analgesic targets. Spider venoms are conservatively predicted to contain more than 10 million bioactive peptides and so far only 0.01% of this diversity been characterised. Thus, it is likely that future research will reveal additional structural classes of spider-venom peptides that target Na(V) channels. PMID- 22543188 TI - First draft of the genomic organization of a PIII-SVMP gene. AB - The evolutionary pathway of highly toxic proteins expressed in snake venom glands from proteins without toxic function and expressed in non-parotid tissues remains poorly understood. Here we examine gene structure of a representative of a venom protein with an ADAMs metalloproteinase evolutionary origin. The structure of the 15,652 bp Echis ocellatus pre-pro EOC00089-like PIII-SVMP gene was assembled from PCR-amplified sequences of overlapping genomic fragments. The gene comprises 12 exons interrupted by 11 introns. In a homology model of the EOC00089-like protein, the insertion of introns interrupting coding regions lie just after or between secondary structure elements. Long interspersed nuclear retroelements (LINE) L2/CR1 and RTE/Bov-B, short interspersed nuclear retroelements SINE/Sauria, and a hobo-activator DNA (Charlie, hAT) transposon were identified within introns 1, 3, 7 and 8. Pairwise amino acid sequence comparisons between EOC00089-like PIII-SVMP and its closest orthologs, ADAM28, from a mammal, Homo sapiens, and the lizard, Anolis carolinensis, showed that the ORFs of these three proteins share 42%/59%, 49%/69%, and 48%/65% (identity/similarity), respectively. The protein-coding positions interrupted by each of the 11 introns of the Echis PIII-SVMP gene are entirely conserved in the A. carolinensis and human ADAM28 genes. However, the lizard and the human ADAM28 genes contain 5 introns not present in the E. ocellatus gene. Furthermore, Echis and Anolis introns exhibit quantitatively and qualitatively distinctions in their inserted retroelements. These findings identify introns as possible key elements in the recruitment and amplification process of SVMPs into the venom gland of extant snakes. Ongoing reptile genome sequencing projects may shed light on this intriguing aspect of the emergence and evolution of venom toxin genes. Furthermore, the organization of the PIII-SVMP reported here provides a genomic explanation for the emergence of dimeric disintegrin subunits encoded by short messengers. PMID- 22543190 TI - Recombinant human leptin attenuates stress axis activity in common carp (Cyprinus carpio L.). AB - Proper functioning of the endocrine stress axis requires communication between the stress axis and other regulatory mechanisms. We here describe an intimate interplay between the stress axis and recombinant human leptin (rhLeptin) in a teleostean fish, the common carp Cyprinus carpio. Restraint stress (by netting up to 96h) increased plasma cortisol but did not affect hepatic leptin expression. Perifusion of pituitary glands or head kidneys with rhLeptin revealed direct effects of rhLeptin on both tissues. RhLeptin suppresses basal and CRF-induced ACTH-secretion in a rapid and concentration-dependent manner. The rhLeptin effect persisted for over an hour after administration had been terminated. RhLeptin decreases basal interrenal cortisol secretion in vitro, and by doing so attenuates ACTH-stimulated cortisol production; rhLeptin does not affect interrenal ACTH-sensitivity. Our findings show that the endocrine stress axis activity and leptin are inseparably linked in a teleostean fish, a notion relevant to further our insights in the evolution of leptin physiology in vertebrates. PMID- 22543189 TI - Bidirectional attack on the actin cytoskeleton. Bacterial protein toxins causing polymerization or depolymerization of actin. AB - The actin cytoskeleton is one of the major targets of bacterial protein toxins. The family of binary actin-ADP-ribosylating toxins, including Clostridium difficile transferase CDT, Clostridium perfringens iota toxin and Clostridium botulinum C2 toxin, modifies arginine-177 of actin. Thereby actin polymerization is blocked. By contrast, actin polymerization is facilitated by the tripartite Photorhabdus luminescens toxin complex including TccC3, which modifies actin at threonine-148. The review discusses both toxin families in respect to recent findings. PMID- 22543192 TI - Stress or no stress: mineralocorticoid receptors in the forebrain regulate behavioral adaptation. AB - Corticosteroid effects on cognitive abilities during behavioral adaptation to stress are mediated by two types of receptors. While the glucocorticoid receptor (GR) is mainly involved in the consolidation of memory, the mineralocorticoid receptor (MR) mediates appraisal and initial responses to novelty. Recent findings in humans and mice suggest that under stress, the MR might be involved in the use of different learning strategies. Here, we used male mice lacking the MR in the forebrain (MR(CaMKCre)), which were subjected to 5-10 min acute restraint stress, followed 30 min later by training trials on the circular hole board. Mice had to locate an exit hole using extra- and intra-maze cues. We assessed performance and the use of spatial and stimulus-response strategies. Non stressed MR(CaMKCre) mice showed delayed learning as compared to control littermates. Prior stress impaired performance in controls, but did not further deteriorate learning in MR(CaMKCre) mice. When stressed, 20-30% of both MR(CaMKCre) and control mice switched from a spatial to a stimulus-response strategy, which rescued performance in MR(CaMKCre) mice. Furthermore, MR(CaMKCre) mice showed increased GR mRNA expression in all CA areas of the hippocampus and an altered basal and stress-induced corticosterone secretion, which supports their role in the modulation of neuroendocrine activity. In conclusion, our data provide evidence for the critical role of MR in the fast formation of spatial memory. In the absence of forebrain MR spatial learning performance was under basal circumstances impaired, while after stress further deterioration of performance was rescued by switching behavior increasingly to a stimulus-response strategy. PMID- 22543191 TI - Prostaglandin (F and E, 2- and 3-series) production and cyclooxygenase (COX-2) gene expression of wild and cultured broodstock of Senegalese sole (Solea senegalensis). AB - Prostaglandin levels in different tissues and cyclooxygenase (COX-2) gene expression were compared between wild and cultured Senegalese sole (Solea senegalensis) broodstock in which a significantly different fatty acid profile, particularly lower tissue levels of arachidonic acid (ARA, 20:4n-6) and higher levels of eicosapentaenoic acid (EPA, 20:5n-3) in the cultured fish compared to wild had already been described. This is the first report of the COX-2 mRNA expression in Senegalese sole. Cyclooxygenase (COX-2) mRNA expression and prostaglandin (2- and 3-series) levels were determined in tissues from 32 broodstock fish, 16 (8 males and 8 females) from each origin wild and cultured (G1). Transcripts of COX-2 were highly expressed in gills, sperm-duct (s-duct), testis, oviduct and spleen compared to liver, kidney and muscle. Differences in COX-2 transcripts expression were found in response to the origin of the fish and expression was significantly higher in s-duct and gills from wild fish compared to cultured. Wild fish showed significantly higher levels of total 2-series PGs and lower levels of 3-series compared to cultured fish. The significance of the lower COX-2 expression and lower PG 2-series production in some of the tissues of cultured fish was discussed in relation to the previously described differences in fatty acid profile (lower tissue levels of ARA and higher levels of EPA and EPA/ARA ratio in cultured fish) and the reproductive failure to spawn viable eggs from G1 cultured Senegalese sole compared to successful spawning from captive wild broodstock. PMID- 22543193 TI - Roles of hippocampal GABA(A) and muscarinic receptors in consolidation of context memory and context-shock association in contextual fear conditioning: a double dissociation study. AB - Contextual fear conditioning involves forming a context representation and associating it to a shock, both of which involved the dorsal hippocampus (DH) according to our recent findings. This study tested further whether the two processes may rely on different neurotransmitter systems in the DH. Male Wistar rats with cannula implanted into the DH were subjected to a two-phase training paradigm of contextual fear conditioning to separate context learning from context-shock association in two consecutive days. Immediately after each training phase, different groups of rats received bilateral intra-DH infusion of the GABA(A) agonist muscimol, 5HT(1A) agonist 8-OH-DPAT, NMDA antagonist APV or muscarinic antagonist scopolamine at various doses. On the third day, freezing behavior was tested in the conditioning context. Results showed that intra-DH infusion of muscimol impaired conditioned freezing only if it was given after context learning. In contrast, scopolamine impaired conditioned freezing only if it was given after context-shock training. Posttraining infusion of 8-OH-DPAT or APV had no effect on conditioned freezing when the drug was given at either phase. These results showed double dissociation for the hippocampal GABAergic and cholinergic systems in memory consolidation of contextual fear conditioning: forming context memory required deactivation of the GABA(A) receptors, while forming context-shock memory involved activation of the muscarinic receptors. PMID- 22543194 TI - Conformation and activity of lysozyme on binding to two types of gold nanorods: a comparative study. AB - The unique morphology of anisotropic rod-shaped gold nanostructures has offered new prospects for biomedical and biosensing applications. This study investigates the interaction of two types of rod-shaped nanostructures, gold nanorods and gold nanorices with lysozyme as a model protein, comparing the probable structural, activity and kinetic stability alterations. Circular dichroism spectropolarimeter revealed that lysozyme retains high fraction of its native conformation in the presence of both nanostructures, with a slight increase in the helical and beta content. Upon the protein adsorption on both types of nanorods, kinetic studies showed maintenance of enzymatic activity, together with increase in the enzymatic affinity and kinetic stability at high temperature. Comparatively, gold nanorice induced better effect on the activity and stability of enzyme than that of gold nanorod. This study might open new insight into potential applications of gold nanorods as nanocarriers for genes and drugs; provided that the toxicological aspect of cationic surfactant-coated nanostructure is taken into consideration. PMID- 22543196 TI - The pathophysiological consequences of thyroid hormone transporter deficiencies: Insights from mouse models. AB - BACKGROUND: As a prerequisite for thyroid hormone (TH) metabolism and action TH has to be transported into cells where TH deiodinases and receptors are located. The trans-membrane passage of TH is facilitated by TH transporters of which the monocarboxylate transporter MCT8 has been most intensively studied. Inactivating mutations in the gene encoding MCT8 are associated with a severe form of psychomotor retardation and abnormal serum TH levels (Allan-Herndon-Dudley syndrome). In order to define the underlying pathogenic mechanisms, Mct8 knockout mice have been generated and intensively studied. Most surprisingly, Mct8 ko mice do not show any neurological symptoms but fully replicate the abnormal serum thyroid state. SCOPE OF REVIEW: We will summarize the findings of these mouse studies that shed light on various aspects of Mct8 deficiency and unambiguously demonstrated the pivotal role of Mct8 in mediating TH transport in various tissues. These studies have also revealed the presence of the complex interplay between different pathogenic mechanisms that contribute to the generation of the abnormal TH serum profile. MAJOR CONCLUSIONS: Most importantly, studies of Mct8 ko mice indicated the presence of additional TH transporters that act in concert with Mct8. Interesting candidates for such a function are the L-type amino acid transporters Lat1 and Lat2 as well as the organic anion transporting polypeptide Oatp1c1. GENERAL SIGNIFICANCE: Overall, the analysis of Mct8 deficient mice has greatly expanded our knowledge about the (patho-) physiological function of this transporter and established a sound basis for the characterization of additional TH transporter candidates. This article is part of a Special Issue entitled Thyroid hormone signalling. PMID- 22543195 TI - Modulation of the carotid body sensory discharge by NO: an up-dated hypothesis. AB - The carotid body (CB) is a peripheral chemoreceptor organ that initiates compensatory reflex responses so as to maintain gas homeostasis. Stimuli such as low oxygen (hypoxia) and high CO(2)/H(+) (acid hypercapnia) cause an increase in 'afferent' sensory discharge that is relayed via the carotid sinus nerve (CSN) to the brainstem, resulting in corrective changes in ventilation. A parallel autonomic pathway has been recognized for >40 years as the source of 'efferent' inhibition of the CB sensory discharge and, more recently, nitric oxide (NO) has been identified as the key mediator. This review will examine our current understanding of the role of nNOS-positive autonomic neurons, embedded in 'paraganglia' within the glossopharyngeal (GPN) and CSN nerves, in mediating efferent CB chemoreceptor inhibition. We highlight recent data linking the actions of hypoxia, ACh and ATP to NO synthesis/release from GPN neurons. Finally, we consider the novel hypothesis that pannexin-1 channels present in GPN neurons may play a role in NO signaling during hypoxia. PMID- 22543197 TI - Thermostable direct hemolysin diminishes tyrosine phosphorylation of epidermal growth factor receptor through protein kinase C dependent mechanism. AB - BACKGROUND: Adequate evidence mounts to the fact that several bacteria and their toxins have protective or curative roles in colorectal cancers. Thermostable direct hemolysin (TDH), produced by Vibrio parahaemolyticus, down regulates cell proliferation in colon carcinoma cell lines. TDH induces Ca2+ influx from an extracellular environment accompanied by protein kinase C phosphorylation. Activated protein kinase C inhibits the tyrosine kinase activity of epidermal growth factor receptor (EGFR), the rational target of anti-colorectal cancer therapy. METHODS: Immunoblotting analyses were performed to ascertain protein kinase C activation, EGFR status, EGFR phosphorylation and mitogen activated protein kinase (MAPK) activity. Flow cytometry analysis and ELISA reconfirmed tyrosine phosphorylation of EGFR and ERK activations, respectively. PKC-alpha siRNA knockdown was done to corroborate the involvement of PKC-alpha in the undertaken study. RESULTS: Our study showed the translocation of PKC-alpha from cytosol to the membrane fraction in colon carcinoma cell lines on incubation with TDH. The EGFR tyrosine kinase activity exhibited a down regulation on TDH treatment which involved PKC-alpha, as confirmed by siRNA knockdown. Also ERK phosphorylation occurred on PKC-alpha activation. CONCLUSION: TDH activated PKC alpha down regulates EGFR tyrosine kinase activity by MEK dependent mechanism involving MAPK. GENERAL SIGNIFICANCE: In this study we have seen that TDH has an implication in EGFR based therapeutic approach in colorectal cancer via PKC mediated mechanism. PMID- 22543198 TI - Treatment of leaking gastrojejunostomy after gastric bypass surgery with special emphasis on stenting. AB - BACKGROUND: Gastric bypass is one of the most common operations for morbid obesity. One of the most feared complications is a leak, most commonly encountered in the gastrojejunal anastomosis (GJA), leading to significant morbidity and increased costs. Our objective was to evaluate the effectiveness of stenting leaks in the GJA. The setting was a university hospital in Stockholm, Sweden. METHODS: We performed a retrospective analysis of all gastric bypasses from January 2001 to August 2011, with special reference to the treatment of leaks in the GJA. RESULTS: A postoperative leak in the GJA occurred in 69 of 2214 patients. The risk was greater with open surgery and revisional surgery. The risk was also greater with age >50 years but not with a body mass index >50 kg/m(2). There was no mortality. In the later part of the series, stents were used, with a stent time of 2 weeks. The migration rate was 23%, and need for restenting was 20%. CONCLUSION: It is safe and advantageous to use stents in the treatment of leaks at the GJA. Patients can be on oral nutrition and oral medication, reducing the need for in-hospital care. PMID- 22543200 TI - Surgical margins and the risk of local-regional recurrence after mastectomy without radiation therapy. AB - PURPOSE: Although positive surgical margins are generally associated with a higher risk of local-regional recurrence (LRR) for most solid tumors, their significance after mastectomy remains unclear. We sought to clarify the influence of the mastectomy margin on the risk of LRR. METHODS AND MATERIALS: The retrospective cohort consisted of 397 women who underwent mastectomy and no radiation for newly diagnosed invasive breast cancer from 1998-2005. Time to isolated LRR and time to distant metastasis (DM) were evaluated by use of cumulative-incidence analysis and competing-risks regression analysis. DM was considered a competing event for analysis of isolated LRR. RESULTS: The median follow-up was 6.7 years (range, 0.5-12.8 years). The superficial margin was positive in 41 patients (10%) and close (<=2 mm) in 56 (14%). The deep margin was positive in 23 patients (6%) and close in 34 (9%). The 5-year LRR and DM rates for all patients were 2.4% (95% confidence interval, 0.9-4.0) and 3.5% (95% confidence interval, 1.6-5.3) respectively. Fourteen patients had an LRR. Margin status was significantly associated with time to isolated LRR (P=.04); patients with positive margins had a 5-year LRR of 6.2%, whereas patients with close margins and negative margins had 5-year LRRs of 1.5% and 1.9%, respectively. On univariate analysis, positive margins, positive nodes, lymphovascular invasion, grade 3 histology, and triple-negative subtype were associated with significantly higher rates of LRR. When these factors were included in a multivariate analysis, only positive margins and triple-negative subtype were associated with the risk of LRR. CONCLUSIONS: Patients with positive mastectomy margins had a significantly higher rate of LRR than those with a close or negative margin. However, the absolute risk of LRR in patients with a positive surgical margin in this series was low, and therefore the benefit of postmastectomy radiation in this population with otherwise favorable features is likely to be small. PMID- 22543199 TI - Planning hybrid intensity modulated radiation therapy for whole-breast irradiation. AB - PURPOSE: To test tangential and not-tangential hybrid intensity modulated radiation therapy (IMRT) for whole-breast irradiation. METHODS AND MATERIALS: Seventy-eight (36 right-, 42 left-) breast patients were randomly selected. Hybrid IMRT was performed by direct aperture optimization. A semiautomated method for planning hybrid IMRT was implemented using Pinnacle scripts. A plan optimization volume (POV), defined as the portion of the planning target volume covered by the open beams, was used as the target objective during inverse planning. Treatment goals were to prescribe a minimum dose of 47.5 Gy to greater than 90% of the POV and to minimize the POV and/or normal tissue receiving a dose greater than 107%. When treatment goals were not achieved by using a 4-field technique (2 conventional open plus 2 IMRT tangents), a 6-field technique was applied, adding 2 non tangential (anterior-oblique) IMRT beams. RESULTS: Using scripts, manual procedures were minimized (choice of optimal beam angle, setting monitor units for open tangentials, and POV definition). Treatment goals were achieved by using the 4-field technique in 61 of 78 (78%) patients. The 6-field technique was applied in the remaining 17 of 78 (22%) patients, allowing for significantly better achievement of goals, at the expense of an increase of low dose (~5 Gy) distribution in the contralateral tissue, heart, and lungs but with no significant increase of higher doses (~20 Gy) in heart and lungs. The mean monitor unit contribution to IMRT beams was significantly greater (18.7% vs 9.9%) in the group of patients who required 6-field procedure. CONCLUSIONS: Because hybrid IMRT can be performed semiautomatically, it can be planned for a large number of patients with little impact on human or departmental resources, promoting it as the standard practice for whole-breast irradiation. PMID- 22543201 TI - Accelerated partial breast irradiation using only intraoperative electron radiation therapy in early stage breast cancer. AB - BACKGROUND: We report the results of a single-institution, phase II trial of accelerated partial breast irradiation (APBI) using a single dose of intraoperative electron radiation therapy (IOERT) in patients with low-risk early stage breast cancer. METHODS AND MATERIALS: A cohort of 226 patients with low risk, early stage breast cancer were treated with local excision and axillary management (sentinel node biopsy with or without axillary node dissection). After the surgeon temporarily reapproximated the excision cavity, a dose of 21 Gy using IOERT was delivered to the tumor bed, with a margin of 2 cm laterally. RESULTS: With a mean follow-up of 46 months (range, 28-63 months), only 1 case of local recurrence was reported. The observed toxicity was considered acceptable. CONCLUSIONS: APBI using a single dose of IOERT can be delivered safely in women with early, low-risk breast cancer in carefully selected patients. A longer follow-up is needed to ascertain its efficacy compared to that of the current standard treatment of whole-breast irradiation. PMID- 22543202 TI - The role of vaginal brachytherapy in the treatment of surgical stage I papillary serous or clear cell endometrial cancer. AB - OBJECTIVES: The optimal adjuvant therapy for International Federation of Gynecology and Obstetrics (FIGO) stage I papillary serous (UPSC) or clear cell (CC) endometrial cancer is unknown. We report on the largest single-institution experience using adjuvant high-dose-rate vaginal brachytherapy (VBT) for surgically staged women with FIGO stage I UPSC or CC endometrial cancer. METHODS AND MATERIALS: From 1998-2011, 103 women with FIGO 2009 stage I UPSC (n=74), CC (n=21), or mixed UPSC/CC (n=8) endometrial cancer underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy followed by adjuvant high-dose rate VBT. Nearly all patients (n=98, 95%) also underwent extended lymph node dissection of pelvic and paraortic lymph nodes. All VBT was performed with a vaginal cylinder, treating to a dose of 2100 cGy in 3 fractions. Thirty-five patients (34%) also received adjuvant chemotherapy. RESULTS: At a median follow up time of 36 months (range, 1-146 months), 2 patients had experienced vaginal recurrence, and the 5-year Kaplan Meier estimate of vaginal recurrence was 3%. The rates of isolated pelvic recurrence, locoregional recurrence (vaginal+pelvic), and extrapelvic recurrence (including intraabdominal) were similarly low, with 5-year Kaplan-Meier estimates of 4%, 7%, and 10%, respectively. The estimated 5-year overall survival was 84%. On univariate analysis, delivery of chemotherapy did not affect recurrence or survival. CONCLUSIONS: VBT is effective at preventing vaginal relapse in women with surgical stage I UPSC or CC endometrial cancer. In this cohort of patients who underwent comprehensive surgical staging, the risk of isolated pelvic or extrapelvic relapse was low, implying that more extensive adjuvant radiation therapy is likely unnecessary. PMID- 22543203 TI - A prospective pathologic study to define the clinical target volume for partial breast radiation therapy in women with early breast cancer. AB - PURPOSE: To determine an appropriate clinical target volume for partial breast radiation therapy (PBRT) based on the spatial distribution of residual invasive and in situ carcinoma after wide local excision (WLE) for early breast cancer or ductal carcinoma in situ (DCIS). METHODS AND MATERIALS: We performed a prospective pathologic study of women potentially eligible for PBRT who had re excision and/or completion mastectomy after WLE for early breast cancer or DCIS. A pathologic assessment protocol was used to determine the maximum radial extension (MRE) of residual carcinoma from the margin of the initial surgical cavity. Women were stratified by the closest initial radial margin width: negative (>1 mm), close (>0 mm and <= 1 mm), or involved. RESULTS: The study population was composed of 133 women with a median age of 59 years (range, 27-82 years) and the following stage groups: 0 (13.5%), I (40.6%), II (38.3%), and III (7.5%). The histologic subtypes of the primary tumor were invasive ductal carcinoma (74.4%), invasive lobular carcinoma (12.0%), and DCIS alone (13.5%). Residual carcinoma was present in the re-excision and completion mastectomy specimens in 55.4%, 14.3%, and 7.2% of women with an involved, close, and negative margin, respectively. In the 77 women with a noninvolved radial margin, the MRE of residual disease, if present, was <= 10 mm in 97.4% (95% confidence interval 91.6-99.5) of cases. Larger MRE measurements were significantly associated with an involved margin (P<.001), tumor size >30 mm (P=.03), premenopausal status (P=.03), and negative progesterone receptor status (P=.05). CONCLUSIONS: A clinical target volume margin of 10 mm would encompass microscopic residual disease in >90% of women potentially eligible for PBRT after WLE with noninvolved resection margins. PMID- 22543204 TI - A novel risk stratification to predict local-regional failures in urothelial carcinoma of the bladder after radical cystectomy. AB - PURPOSE: Local-regional failures (LF) following radical cystectomy (RC) plus pelvic lymph node dissection (PLND) with or without chemotherapy for invasive urothelial bladder carcinoma are more common than previously reported. Adjuvant radiation therapy (RT) could reduce LF but currently has no defined role because of previously reported morbidity. Modern techniques with improved normal tissue sparing have rekindled interest in RT. We assessed the risk of LF and determined those factors that predict recurrence to facilitate patient selection for future adjuvant RT trials. METHODS AND MATERIALS: From 1990-2008, 442 patients with urothelial bladder carcinoma at the University of Pennsylvania were prospectively followed after RC plus PLND with or without chemotherapy with routine pelvic computed tomography (CT) or magnetic resonance imaging (MRI). One hundred thirty (29%) patients received chemotherapy. LF was any pelvic failure detected before or within 3 months of distant failure. Competing risk analyses identified factors predicting increased LF risk. RESULTS: On univariate analysis, pathologic stage>=pT3, <10 nodes removed, positive margins, positive nodes, hydronephrosis, lymphovascular invasion, and mixed histology significantly predicted LF; node density was marginally predictive, but use of chemotherapy, number of positive nodes, type of surgical diversion, age, gender, race, smoking history, and body mass index were not. On multivariate analysis, only stage>=pT3 and <10 nodes removed were significant independent LF predictors with hazard ratios of 3.17 and 2.37, respectively (P<.01). Analysis identified 3 patient subgroups with significantly different LF risks: low-risk (<=pT2), intermediate-risk (>=pT3 and >=10 nodes removed), and high-risk (>=pT3 and <10 nodes) with 5-year LF rates of 8%, 23%, and 42%, respectively (P<.01). CONCLUSIONS: This series using routine CT and MRI surveillance to detect LF confirms that such failures are relatively common in cases of locally advanced disease and provides a rubric based on pathological stage and number of nodes removed that stratifies patients into 3 groups with significantly different LF risks to simplify patient selection for future adjuvant radiation therapy trials. PMID- 22543206 TI - Radiation therapy oncology group protocol 02-29: a phase II trial of neoadjuvant therapy with concurrent chemotherapy and full-dose radiation therapy followed by surgical resection and consolidative therapy for locally advanced non-small cell carcinoma of the lung. AB - PURPOSE: To evaluate mediastinal nodal clearance (MNC) rates after induction chemotherapy and concurrent, full-dose radiation therapy (RT) in a phase II trimodality trial (Radiation Therapy Oncology Group protocol 0229). PATIENTS AND METHODS: Patients (n=57) with stage III non-small cell lung cancer (pathologically proven N2 or N3) were eligible. Induction chemotherapy consisted of weekly carboplatin (AUC = 2.0) and paclitaxel 50 mg/m(2). Concurrent RT was prescribed, with 50.4 Gy to the mediastinum and primary tumor and a boost of 10.8 Gy to all gross disease. The mediastinum was pathologically reassessed after completion of chemoradiation. The primary endpoint of the study was MNC, with secondary endpoints of 2-year overall survival and postoperative morbidity/mortality. RESULTS: The grade 3/4 toxicities included hematologic 35%, gastrointestinal 14%, and pulmonary 23%. Forty-three patients (75%) were evaluable for the primary endpoint. Twenty-seven patients achieved the primary endpoint of MNC (63%). Thirty-seven patients underwent resection. There was a 14% incidence of grade 3 postoperative pulmonary complications and 1 30-day, postoperative grade 5 toxicity (3%). With a median follow-up of 24 months for all patients, the 2-year overall survival rate was 54%, and the 2-year progression free survival rate was 33%. The 2-year overall survival rate was 75% for those who achieved nodal clearance, 52% for those with residual nodal disease, and 23% for those who were not evaluable for the primary endpoint (P=.0002). CONCLUSIONS: This multi-institutional trial confirms the ability of neoadjuvant concurrent chemoradiation with full-dose RT to sterilize known mediastinal nodal disease. PMID- 22543205 TI - Impact of gemcitabine chemotherapy and 3-dimensional conformal radiation therapy/5-fluorouracil on quality of life of patients managed for pancreatic cancer. AB - PURPOSE: To report quality of life (QOL) results for patients receiving chemoradiation therapy for pancreatic cancer. METHODS AND MATERIALS: Eligible patients (n=41 locally advanced, n=22 postsurgery) entered the B9E-AY-S168 study and received 1 cycle of induction gemcitabine (1000 mg/m2 weekly *3 with 1-week break) followed by 3-dimensional conformal radiation therapy (RT) (54 Gy locally advanced and 45 Gy postsurgery) and concomitant continuous-infusion 5 fluorouracil (5FU) (200 mg/m2/d throughout RT). After 4 weeks, patients received an additional 3 cycles of consolidation gemcitabine chemotherapy. Patients completed the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-PAN26 questionnaires at baseline, before RT/5FU, at end of RT/5FU, before consolidation gemcitabine, and at treatment completion. RESULTS: The patterns of change in global QOL scores differed between groups. In the locally advanced group global QOL scores were +13, +8, +3, and +1 compared with baseline before RT/5FU (P=.008), at end of RT/5FU, before consolidation gemcitabine, and at treatment completion, respectively. In the postsurgery group, global QOL scores were -3, +4, +15, and +17 compared with baseline at the same time points, with a significant improvement in global QOL before consolidation gemcitabine (P=.03). No significant declines in global QOL were reported by either cohort. CONCLUSIONS: This study demonstrates that global QOL and associated function and symptom profiles for pancreatic chemoradiation therapy differ between locally advanced and postsurgery patients, likely owing to differences in underlying disease status. For both groups, the treatment protocol was well tolerated and did not have a negative impact on patients' global QOL. PMID- 22543207 TI - Adjuvant radiation therapy and survival for pure tubular breast carcinoma- experience from the SEER database. AB - PURPOSE: Pure tubular carcinoma of the breast (PTCB) represents a distinct subtype of invasive ductal carcinoma (IDC) that is generally thought to be associated with better prognosis than even low-grade IDC. There has been controversy as to the role of adjuvant radiation therapy (RT) in this population. We hypothesized that adjuvant RT would demonstrate a survival improvement. METHODS AND MATERIALS: We queried the Surveillance, Epidemiology and End Results database for the years 1992-2007 to identify patients with pure tubular carcinomas of the breast. Patient demographics, tumor characteristics, and surgical and RT treatments were collected. Survival analysis was performed using the Kaplan-Meier method for univariate comparisons and Cox proportional hazards modeling for multivariate comparisons, stratifying on the basis of age with a cutoff age of 65. RESULTS: A total of 6465 patients were identified: 3624 (56.1%) patients underwent lumpectomy with RT (LUMP+RT), 1525 (23.6%) patients underwent lumpectomy alone (LUMP), 1266 (19.6%) patients received mastectomy alone (MAST), and 50 (0.8%) patients underwent mastectomy with RT (MAST+RT). When we compared the LUMP+RT and LUMP groups directly, those receiving adjuvant RT tended to be younger and were less likely to be hormone receptor-positive. Overall survival was 95% for LUMP+RT and 90% for LUMP patients at 5 years. For those 65 or younger, the absolute overall survival benefit of LUMP+RT over LUMP was 1% at 5 years and 3% at 10 years. On stratified multivariate analysis, adjuvant RT remained a significant predictor in both age groups (P=.003 in age <= 65 and P=.04 in age >65 patients). Other significant unfavorable factors were older age and higher T stage (age >65 only). CONCLUSIONS: Since sufficiently powered large scale clinical trials are unlikely, we would recommend that adjuvant radiation be considered in PTCB patients age 65 or younger, although consideration of the small absolute survival benefit is important. Adjuvant radiation can be omitted for patients older than 65. PMID- 22543208 TI - Hematological toxicity after robotic stereotactic body radiosurgery for treatment of metastatic gynecologic malignancies. AB - PURPOSE: To evaluate hematological toxicity after robotic stereotactic body radiosurgery (SBRT) for treatment of women with metastatic abdominopelvic gynecologic malignancies. METHODS AND MATERIALS: A total of 61 women with stage IV gynecologic malignancies treated with abdominopelvic SBRT were analyzed after ablative radiation (2400 cGy/3 divided consecutive daily doses) delivered by a robotic-armed Cyberknife SBRT system. Abdominopelvic bone marrow was identified using computed tomography-guided contouring. Fatigue and hematologic toxicities were graded by retrospective assignment of common toxicity criteria for adverse events (version 4.0). Bone marrow volume receiving 1000 cGy (V10) was tested for association with post-therapy (median 32 days [25%-75% quartile, 28-45 days]) white- or red-cell counts, hemoglobin levels, and platelet counts as marrow toxicity surrogates. RESULTS: In all, 61 women undergoing abdominopelvic SBRT had a median bone marrow V10 of 2% (25%-75% quartile: 0%-8%). Fifty-seven (93%) of 61 women had received at least 1 pre-SBRT marrow-taxing chemotherapy regimen for metastatic disease. Bone marrow V10 did not associate with hematological adverse events. In all, 15 grade 2 (25%) and 2 grade 3 (3%) fatigue symptoms were self reported among the 61 women within the first 10 days post-therapy, with fatigue resolved spontaneously in all 17 women by 30 days post-therapy. Neutropenia was not observed. Three (5%) women had a grade 1 drop in hemoglobin level to <10.0 g/dL. Single grade 1, 2, and 3 thrombocytopenias were documented in 3 women. CONCLUSIONS: Abdominopelvic SBRT provided ablative radiation dose to cancer targets without increased bone marrow toxicity. Abdominopelvic SBRT for metastatic gynecologic malignancies warrants further study. PMID- 22543209 TI - Hypofractionated whole-breast radiation therapy: does breast size matter? AB - PURPOSE: To evaluate the effects of breast size on dose-volume histogram parameters and clinical toxicity in whole-breast hypofractionated radiation therapy using intensity modulated radiation therapy (IMRT). MATERIALS AND METHODS: In this retrospective study, all patients undergoing breast-conserving therapy between 2005 and 2009 were screened, and qualifying consecutive patients were included in 1 of 2 cohorts: large-breasted patients (chest wall separation>25 cm or planning target volume [PTV]>1500 cm3) (n=97) and small breasted patients (chest wall separation<25 cm and PTV<1500 cm3) (n=32). All patients were treated prone or supine with hypofractionated IMRT to the whole breast (42.4 Gy in 16 fractions) followed by a boost dose (9.6 Gy in 4 fractions). Dosimetric and clinical toxicity data were collected and analyzed using the R statistical package (version 2.12). RESULTS: The mean PTV V95 (percentage of volume receiving>=95% of prescribed dose) was 90.18% and the mean V105 percentage of volume receiving>=105% of prescribed dose was 3.55% with no dose greater than 107%. PTV dose was independent of breast size, whereas heart dose and maximum point dose to skin correlated with increasing breast size. Lung dose was markedly decreased in prone compared with supine treatments. Radiation Therapy Oncology Group grade 0, 1, and 2 skin toxicities were noted acutely in 6%, 69%, and 25% of patients, respectively, and at later follow-up (>3 months) in 43%, 57%, and 0% of patients, respectively. Large breast size contributed to increased acute grade 2 toxicity (28% vs 12%, P=.008). CONCLUSIONS: Adequate PTV coverage with acceptable hot spots and excellent sparing of organs at risk was achieved by use of IMRT regardless of treatment position and breast size. Although increasing breast size leads to increased heart dose and maximum skin dose, heart dose remained within our institutional constraints and the incidence of overall skin toxicity was comparable to that reported in the literature. Taken together, these data suggest that hypofractionated radiation therapy using IMRT is a viable and appropriate therapeutic modality in large-breasted patients. PMID- 22543210 TI - Recovery from radiation-induced bone marrow damage by HSP25 through Tie2 signaling. AB - PURPOSE: Whole-body radiation therapy can cause severe injury to the hematopoietic system, and therefore it is necessary to identify a novel strategy for overcoming this injury. METHODS AND MATERIALS: Mice were irradiated with 4.5 Gy after heat shock protein 25 (HSP25) gene transfer using an adenoviral vector. Then, peripheral blood cell counts, histopathological analysis, and Western blotting on bone marrow (BM) cells were performed. The interaction of HSP25 with Tie2 was investigated with mouse OP9 and human BM-derived mesenchymal stem cells to determine the mechanism of HSP25 in the hematopoietic system. RESULTS: HSP25 transfer increased BM regeneration and reduced apoptosis following whole-body exposure to ionizing radiation (IR). The decrease in Tie2 protein expression that followed irradiation of the BM was blocked by HSP25 transfer, and Tie2-positive cells were more abundant among the BM cells of HSP25-transferred mice, even after IR exposure. Following systemic RNA interference of Tie2 before IR, HSP25 mediated radioprotective effects were partially blocked in both mice and cell line systems. Stability of Tie2 was increased by HSP25, a response mediated by the interaction of HSP25 with Tie2. IR-induced tyrosine phosphorylation of Tie2 was augmented by HSP25 overexpression; downstream events in the Tie2 signaling pathway, including phosphorylation of AKT and EKR1/2, were also activated. CONCLUSIONS: HSP25 protects against radiation-induced BM damage by interacting with and stabilizing Tie2. This may be a novel strategy for HSP25-mediated radioprotection in BM. PMID- 22543211 TI - A phase II study of intensity modulated radiation therapy to the pelvis for postoperative patients with endometrial carcinoma: radiation therapy oncology group trial 0418. AB - PURPOSE: To determine the feasibility of pelvic intensity modulated radiation therapy (IMRT) for patients with endometrial cancer in a multi-institutional setting and to determine whether this treatment is associated with fewer short term bowel adverse events than standard radiation therapy. METHODS: Patients with adenocarcinoma of the endometrium treated with pelvic radiation therapy alone were eligible. Guidelines for target definition and delineation, dose prescription, and dose-volume constraints for the targets and critical normal structures were detailed in the study protocol and a web-based atlas. RESULTS: Fifty-eight patients were accrued by 25 institutions; 43 were eligible for analysis. Forty-two patients (98%) had an acceptable IMRT plan; 1 had an unacceptable variation from the prescribed dose to the nodal planning target volume. The proportions of cases in which doses to critical normal structures exceeded protocol criteria were as follows: bladder, 67%; rectum, 76%; bowel, 17%; and femoral heads, 33%. Twelve patients (28%) developed grade >=2 short-term bowel adverse events. CONCLUSIONS: Pelvic IMRT for endometrial cancer is feasible across multiple institutions with use of a detailed protocol and centralized quality assurance (QA). For future trials, contouring of vaginal and nodal tissue will need continued monitoring with good QA and better definitions will be needed for organs at risk. PMID- 22543212 TI - Thermochemoradiation therapy using superselective intra-arterial infusion via superficial temporal and occipital arteries for oral cancer with N3 cervical lymph node metastases. AB - PURPOSE: To evaluate the therapeutic results and histopathological effects of treatment with thermochemoradiation therapy using superselective intra-arterial infusion via the superficial temporal and occipital arteries for N3 cervical lymph node metastases of advanced oral cancer. METHODS AND MATERIALS: Between April 2005 and September 2010, 9 patients with N3 cervical lymph node metastases of oral squamous cell carcinoma underwent thermochemoradiation therapy using superselective intra-arterial infusion with docetaxel (DOC) and cisplatin (CDDP). Treatment consisted of hyperthermia (2-8 sessions), superselective intra-arterial infusions (DOC, total 40-60 mg/m(2); CDDP, total 100-150 mg/m(2)) and daily concurrent radiation therapy (total, 40-60 Gy) for 4-6 weeks. RESULTS: Six of 9 patients underwent neck dissection 5-8 weeks after treatment. In four of these 6 patients, all metastatic lymph nodes, including those at N3, were grade 3 (non viable tumor cells present) or grade 4 (no tumor cells present) tumors, as classified by the system by Shimosato et al (Shimosato et al Jpn J Clin Oncol 1971;1:19-35). In 2 of these 6 patients, the metastatic lymph nodes were grade 2b (destruction of tumor structures with a small amount of residual viable tumor cells). The other 3 patients did not undergo neck dissection due to distant metastasis after completion of thermochemoradiation therapy (n=2) and refusal (n=1). The patient who refused neck dissection underwent biopsy of the N3 lymph node and primary sites and showed grade 3 cancer. During follow-up, 5 patients were alive without disease, and 4 patients died due to pulmonary metastasis (n=3) and noncancer-related causes (n=1). Five-year survival and locoregional control rates were 51% and 88%, respectively. CONCLUSIONS: Thermochemoradiation therapy using intra-arterial infusion provided good histopathologic effects and locoregional control rates in patients with N3 metastatic lymph nodes. However, patients with N3 metastatic lymph nodes experienced a high rate of distant metastases. PMID- 22543213 TI - Prone accelerated partial breast irradiation after breast-conserving surgery: compliance to the dosimetry requirements of RTOG-0413. AB - PURPOSE: The dosimetric results from our institution's trials of prone accelerated partial breast irradiation are compared with the dosimetric requirements of RTOG-0413. METHODS AND MATERIALS: Trial 1 and Trial 2 are 2 consecutive trials of prone-accelerated partial breast irradiation. Eligible for both trials were stage I breast cancer patients with negative margins after breast-conserving surgery. The planning target tumor volume (PTV) was created by extending the surgical cavity 2.0 cm for Trial 1 and 1.5 cm for Trial 2, respectively. Contralateral breast, heart, lungs, and thyroid were contoured. Thirty Gray was delivered in five daily fractions of 6 Gy by a three-dimensional conformal radiation therapy technique in Trial 1 and were by image-guided radiation therapy/intensity-modulated radiation therapy in Trial 2. Dosimetric results from the trials are reported and compared with RTOG 0413 requirements. RESULTS: One hundred forty-six consecutive plans were analyzed: 67 left and 79 right breast cancers. The plans from the trials complied with the required>90% of prescribed dose covering 90% of PTV_EVAL (=generated from the PTV by cropping 0.5 cm from the skin edge and excluding the chest wall): V90% was 98.1+/-3.0% (with V100% and V95%, 89.4+/-12.8%, 96.4+/-5.1%, respectively). No significant difference between laterality was found (Student's t test). The dose constraints criteria of the RTOG-0413 protocol for ipsilateral and contralateral lung (V30<15% and Dmax<3%), heart (V5<40%), and thyroid (Dmax<3%) were satisfied because the plans showed an average V5% of 0.6% (range, 0-13.4) for heart, an average V30% of 0.6% (range, 0-9.1%) for ipsilateral lung, and <2% maximum dose to the thyroid. However, our partial breast irradiation plans demonstrated a higher dose to contralateral breast than that defined by RTOG constraints, with a median value of maximum doses of 4.1% (1.2 Gy), possibly as a result of contouring differences. CONCLUSIONS: Our technique for prone accelerated partial breast irradiation generally satisfied RTOG-0413 requirements. PMID- 22543214 TI - Cone beam computed tomography number errors and consequences for radiotherapy planning: an investigation of correction methods. AB - PURPOSE: The potential of keV cone beam computed tomography (CBCT) for guiding adaptive replanning is well-known. There are impediments to this, one being CBCT number accuracy. The purpose of this study was to investigate CBCT number correction methods and the affect of residual inaccuracies on dose deposition. Four different correction strategies were applied to the same patient data to compare performance and the sophistication of correction-method needed for acceptable dose errors. METHODS AND MATERIALS: Planning CT and CBCT reconstructions were used for 12 patients (6 brain, 3 prostate, and 3 bladder cancer patients). All patients were treated using Elekta linear accelerators and XVI imaging systems. Two of the CBCT number correction methods investigated were based on an algorithm previously proposed by the authors but only previously applied to phantoms. Two further methods, based on an approach previously suggested in the research literature, were also examined. Dose calculations were performed using scans of a "worst" subset of patients using the Pinnacle3 version 9.0 treatment planning system and the patients' clinical plans. RESULTS: All mean errors in CBCT number were <50 HU, and all correction methods performed well or adequately in dose calculations. The worst single dose discrepancy identified for any of the examined methods or patients was 3.0%. Mean errors in the doses to treatment volumes or organs at risk were negatively correlated with the mean error in CT number. That is, a mean CT number that was too large, averaged over the entire CBCT volume, implied an underdosing in a volume-of-interest and vice versa. CONCLUSIONS: Results suggest that (1) the correction of CBCT numbers to within a mean error of 50 HU in the scan volume provides acceptable discrepancies in dose (<3%) and (2) this is achievable with even quite unsophisticated correction methods. PMID- 22543215 TI - A phase I/II trial of intensity modulated radiation (IMRT) dose escalation with concurrent fixed-dose rate gemcitabine (FDR-G) in patients with unresectable pancreatic cancer. AB - PURPOSE: Local failure in unresectable pancreatic cancer may contribute to death. We hypothesized that intensification of local therapy would improve local control and survival. The objectives were to determine the maximum tolerated radiation dose delivered by intensity modulated radiation with fixed-dose rate gemcitabine (FDR-G), freedom from local progression (FFLP), and overall survival (OS). METHODS AND MATERIALS: Eligibility included pathologic confirmation of adenocarcinoma, radiographically unresectable, performance status of 0-2, absolute neutrophil count of >= 1,500/mm(3), platelets >= 100,000/mm(3), creatinine <2 mg/dL, bilirubin <3 mg/dL, and alanine aminotransferase/aspartate aminotransferase <= 2.5 * upper limit of normal. FDR-G (1000 mg/m(2)/100 min intravenously) was given on days -22 and -15, 1, 8, 22, and 29. Intensity modulated radiation started on day 1. Dose levels were escalated from 50-60 Gy in 25 fractions. Dose-limiting toxicity was defined as gastrointestinal toxicity grade (G) >= 3, neutropenic fever, or deterioration in performance status to >= 3 between day 1 and 126. Dose level was assigned using TITE-CRM (Time-to-Event Continual Reassessment Method) with the target dose-limiting toxicity (DLT) rate set to 0.25. RESULTS: Fifty patients were accrued. DLTs were observed in 11 patients: G3/4 anorexia, nausea, vomiting, and/or dehydration (7); duodenal bleed (3); duodenal perforation (1). The recommended dose is 55 Gy, producing a probability of DLT of 0.24. The 2-year FFLP is 59% (95% confidence interval [CI]: 32-79). Median and 2-year overall survival are 14.8 months (95% CI: 12.6-22.2) and 30% (95% CI 17-45). Twelve patients underwent resection (10 R0, 2 R1) and survived a median of 32 months. CONCLUSIONS: High-dose radiation therapy with concurrent FDR-G can be delivered safely. The encouraging efficacy data suggest that outcome may be improved in unresectable patients through intensification of local therapy. PMID- 22543216 TI - Predicting radiation pneumonitis after stereotactic ablative radiation therapy in patients previously treated with conventional thoracic radiation therapy. AB - PURPOSE: To determine the incidence of and risk factors for radiation pneumonitis (RP) after stereotactic ablative radiation therapy (SABR) to the lung in patients who had previously undergone conventional thoracic radiation therapy. METHODS AND MATERIALS: Seventy-two patients who had previously received conventionally fractionated radiation therapy to the thorax were treated with SABR (50 Gy in 4 fractions) for recurrent disease or secondary parenchymal lung cancer (T<4 cm, N0, M0, or Mx). Severe (grade>=3) RP and potential predictive factors were analyzed by univariate and multivariate logistic regression analyses. A scoring system was established to predict the risk of RP. RESULTS: At a median follow-up time of 16 months after SABR (range, 4-56 months), 15 patients had severe RP (14 [18.9%] grade 3 and 1 [1.4%] grade 5) and 1 patient (1.4%) had a local recurrence. In univariate analyses, Eastern Cooperative Oncology Group performance status (ECOG PS) before SABR, forced expiratory volume in 1 second (FEV1), and previous planning target volume (PTV) location were associated with the incidence of severe RP. The V10 and mean lung dose (MLD) of the previous plan and the V10-V40 and MLD of the composite plan were also related to RP. Multivariate analysis revealed that ECOG PS scores of 2-3 before SABR (P=.009), FEV1<=65% before SABR (P=.012), V20>=30% of the composite plan (P=.021), and an initial PTV in the bilateral mediastinum (P=.025) were all associated with RP. CONCLUSIONS: We found that severe RP was relatively common, occurring in 20.8% of patients, and could be predicted by an ECOG PS score of 2-3, an FEV1<=65%, a previous PTV spanning the bilateral mediastinum, and V20>=30% on composite (previous RT+SABR) plans. Prospective studies are needed to validate these predictors and the scoring system on which they are based. PMID- 22543217 TI - Adaptive/nonadaptive proton radiation planning and outcomes in a phase II trial for locally advanced non-small cell lung cancer. AB - PURPOSE: To analyze dosimetric variables and outcomes after adaptive replanning of radiation therapy during concurrent high-dose protons and chemotherapy for locally advanced non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Nine of 44 patients with stage III NSCLC in a prospective phase II trial of concurrent paclitaxel/carboplatin with proton radiation [74 Gy(RBE) in 37 fractions] had modifications to their original treatment plans after re-evaluation revealed changes that would compromise coverage of the target volume or violate dose constraints; plans for the other 35 patients were not changed. We compared patients with adaptive plans with those with nonadaptive plans in terms of dosimetry and outcomes. RESULTS: At a median follow-up of 21.2 months (median overall survival, 29.6 months), no differences were found in local, regional, or distant failure or overall survival between groups. Adaptive planning was used more often for large tumors that shrank to a greater extent (median, 107.1 cm(3) adaptive and 86.4 cm(3) nonadaptive; median changes in volume, 25.3% adaptive and 1.2% nonadaptive; P<.01). The median number of fractions delivered using adaptive planning was 13 (range, 4-22). Adaptive planning generally improved sparing of the esophagus (median absolute decrease in V(70), 1.8%; range, 0%-22.9%) and spinal cord (median absolute change in maximum dose, 3.7 Gy; range, 0-13.8 Gy). Without adaptive replanning, target coverage would have been compromised in 2 cases (57% and 82% coverage without adaptation vs 100% for both with adaptation); neither patient experienced local failure. Radiation-related grade 3 toxicity rates were similar between groups. CONCLUSIONS: Adaptive planning can reduce normal tissue doses and prevent target misses, particularly for patients with large tumors that shrink substantially during therapy. Adaptive plans seem to have acceptable toxicity and achieve similar local, regional, and distant control and overall survival, even in patients with larger tumors, vs nonadaptive plans. PMID- 22543218 TI - Evidence suggesting that ghrelin O-acyl transferase inhibitor acts at the hypothalamus to inhibit hypothalamo-pituitary-adrenocortical axis function in the rat. AB - Production of n-octanoyl-modified ghrelin (GHREL), an active form of the peptide requires prohormone processing protease and GHREL O-acyltransferase (GOAT), as well as n-octanoic acid. Recently a selective GOAT antagonist (GO-CoA-Tat) was invented and this tool was used to study the possible role of endogenous GHREL in regulating HPA axis function in the rat. Administration of GOAT inhibitor (GOATi) resulted in a notable decrease in plasma ACTH, aldosterone and corticosterone concentrations at min 60 of experiment. Octanoic acid (OA) administration had no effect on levels of studied hormones. Plasma levels of unacylated and acylated GHREL remained unchanged for 60min after either GOATi or OA administration. Under experimental conditions applied, no significant changes were observed in the levels of GOAT mRNA in hypothalamus, pituitary, adrenal and stomach fundus. After GOATi injection hypothalamic CRH mRNA levels were elevated at 30 min and pituitary POMC mRNA levels at 60 min. Both GOATi and OA lowered basal, but not K(+)-stimulated CRH release by hypothalamic explants and had no effect on basal or CRH-stimulated ACTH release by pituitary slices. Neither GOATi nor OA affected corticosterone secretion by freshly isolated or cultured rat adrenocortical cells. Thus, results of our study suggest that in the rat endogenous GHREL exerts tonic stimulating effect on hypothalamic CRH release. This effect could be demonstrated by administering rats with selected inhibitor of ghrelin O acyltransferase, the enzyme responsible for GHREL acylation, a process which is absolutely required for both GHSR-1a binding and its central endocrine activities. PMID- 22543219 TI - [Management of post partum haemorrhage]. AB - Primary post partum haemorrhage is the most common form of major obstetric haemorrhage. The traditional definition of primary post partum haemorrhage is the loss of 500 ml or more of blood from the genital tract within 24 hours of the birth of a baby. Post partum haemorrhage can be minor (500-1000 ml) or major (more than 1000 ml). Major could be divided to moderate (1000-2000 ml) or severe (more than 2000 ml). The recommendations in this article apply to women experiencing primary post partum haemorrhage of 500 ml or more. Secondary post partum haemorrhage is defined as abnormal or excessive bleeding from the birth canal between 24 hours and 12 weeks postnatally. The main causes of the secondary form are: inflammations (endometritis), placental tissue retention, inadequate involution of the uterus and malignancy. Because of its importance as a leading cause of maternal morbidity and mortality, obstetric haemorrhage must be considered as a priority topic. According to the tragic and dramatic outcomes of this morbidity, and to the fact that most cases of post partum haemorrhage have no identifiable risk factors, the practical obstetricians should be aware of the accurate diagnosis and management of this illness. PMID- 22543220 TI - [A(H1N1)v cases of the 2009/2010 and 2010/2011 influenza seasons in the Medical and Health Sciences Centre of Debrecen University]. AB - The swine-origin new influenza variant A(H1N1) emerged in 2009 and changed the epidemiology of the 2009/2010 influenza season globally and at national level. AIMS: The aim of the authors was to analyse the cases of two influenza seasons. METHODS: The Medical and Health Sciences Centre of Debrecen University has 1690 beds with 85 000 patients admitted per year. The diagnosis of influenza was conducted using real-time polymerase chain reaction in the microbiological laboratories of the University and the National Epidemiological Centre, according to the recommendation of the World Health Organization. RESULTS: The incidence of influenza was not higher than that observed in the previous season, but two high risk patient groups were identified: pregnant women and patients with immunodeficiency (oncohematological and organ transplant patients). The influenza vaccine, which is free for high-risk groups and health care workers in Hungary, appeared to be effective for prevention, because in the 2010/2011 influenza season none of the 58 patients who were administered the vaccination developed influenza. CONCLUSION: It is an important task to protect oncohematological and organ transplant patients. PMID- 22543221 TI - [Midterm outcome after rotator cuff reconstruction]. AB - Rotator cuff tear is a common degenerative shoulder disorder that often requires surgical treatment. However, the correlation between the size of the tear and the functional results is somewhat controversial, which generates inconsistency among orthopaedic surgeons about the indications for and methods of rotator cuff reconstruction. AIMS: The aim of the authors was to evaluate the midterm functional outcome after rotator cuff reconstruction and the possible connection between the results and the surgical technique or the postoperative ultrasound examination. In addition, recently published corresponding studies are also reviewed by the authors. METHODS: Twenty-seven patients with full thickness rotator cuff tear were enrolled into the study who were treated either by arthroscopic (14 patients) or by open repair (13 patients) technique. Functional results were assessed using clinical tests. Ultrasound examination was also performed. RESULTS: The average postoperative Constant Score was 73, the average DASH (Disabilities of the arm, shoulder and hand score) was 14. The Constant scores averaged 80 for the arthroscopic and 70 for the open group. Ultrasound examination showed partial or full thickness retear of the cuff in 40% of the cases. CONCLUSION: More than 70% of the patients had excellent or good results two years after the reconstruction. The change in the acromiohumeral distance or partial retear failed to affect the results significantly, but full thickness tear had an effect on them. PMID- 22543222 TI - [Change of the political system and epidemiologic transition in Hungary]. AB - A new epidemiological stage has begun in Hungary as a result of the implosion of state-socialism. It has made the transition to market economy and open society possible. The emerging economic and social system has created the basis for terminating the chronic qualitative epidemiological crisis and for the renewal of the epidemiological development. The new political and socio-economic system has had a decisive impact on the decrease in mortality and consequently to the increase in life expectancy in the countries east of the River Elbe. Besides the spread of health conscious behaviour, the efficacy of new medications and invasive medical interventions just as much as the network of emergency centres have contributed to the favourable changes. The most characteristic feature of the new epidemiological stage is that it delays the progression of chronic diseases and postpones the time of death. In a large extent the successful prevention, treatment and care of diseases of the circulatory system are mainly responsible for increasing the life expectancy at birth. Paradoxically, whereas life expectancy has increased in the country on the whole, social inequality has also increased. PMID- 22543224 TI - Clinical spectrum, risk factors and outcome of immune reconstitution inflammatory syndrome in patients with tuberculosis-HIV coinfection. AB - BACKGROUND: Here, we aimed to determine the clinical spectrum, predictors and outcomes of paradoxical tuberculosis-immune reconstitution inflammatory syndrome (TB-IRIS) in a resource-limited setting. METHODS: In a prospective cohort, we studied 254 patients with tuberculosis and HIV coinfection commencing antiretroviral therapy (ART). We identified patients with TB-IRIS using the International Network for Studies Against HIV-Associated IRIS (INSHI) case definition. Risk factors and clinical outcomes of TB-IRIS were determined and reported. RESULTS: A total of 53 (21%) patients developed TB-IRIS a median of 2 weeks (IQR 12-22 days) after starting ART. The majority of the patients (70%) with TB-IRIS had extrapulmonary manifestations of TB-IRIS. In a multiple logistic regression model, baseline haemoglobin <100 g/l (OR 2.23 [95% CI 1.08-4.60]; P=0.031) and baseline CD4(+) T-cell count <50 cells/MUl (OR 4.13 [95% CI 1.80 9.51]; P=0.001) were significant predictors of IRIS. Seven additional patients fulfilled all INSHI criteria of TB-IRIS but had the episode of TB-IRIS later than 3 months after ART start. CONCLUSIONS: TB-IRIS was a frequent reason for clinical deterioration among patients with TB commencing ART but was not a primary contributor to mortality. Patients with advanced CD4 depletion and anaemia were at increased risk of TB-IRIS. Some patients developed late-onset TB-IRIS and/or a recurrent TB-IRIS episode. PMID- 22543225 TI - Prevention of tetanus during the First World War. AB - The emergence of tetanus in wounded soldiers during the first months of the First World War (WWI) resulted from combat on richly manured fields in Belgium and Northern France, the use of modern explosives that produced deep tissue wounds and the intimate contact between the soldier and the soil upon which he fought. In response, routine prophylactic injections with anti-tetanus serum were given to wounded soldiers removed from the firing line. Subsequently, a steep fall in the incidence of tetanus was observed on both sides of the conflict. Because of fatal serum anaphylaxis associated with administration of serum at a time when purification methods still needed to be improved, it must be presumed that tens to hundreds of men might have died as a result of the routine administration of anti-tetanus serum during WWI. Yet anti-tetanus serum undoubtedly prevented life threatening tetanus among several hundred thousands of wounded men, making it one of the most successful preventive interventions in wartime medicine. After the abrupt fall in tetanus incidence in 1914 due to introduction of anti-tetanus serum, the incidence of the disease tended to become even lower as the war went on. This was probably due to earlier and more thorough surgical treatment, consisting of opening, cleaning, excision and drainage of wounds as early as possible. In this overview, recent battlefield findings from the Meuse-Argonne offensive in 1918 are used to illustrate common practices employed in the prevention of tetanus during WWI. PMID- 22543226 TI - Neuropathology in patients with multiple surgeries for medically intractable epilepsy. AB - Outcomes following surgery for chronic epilepsy are generally good; however, seizures persist/recur following initial surgery in some patients. We hypothesize that in patients who require multiple surgeries for intractable epilepsy, an identifiable pathologic substrate can be found in the subsequent surgical specimen, which accounts for the recurrent seizures. We retrospectively studied 102 patients (56 females) with medically intractable epilepsy who have had at least 2 surgeries more than 60 days apart from 1990-2010. Patient age at time of 1st surgery ranged from 3 months-60 years (mean 18.1 years). Mean duration of seizures prior to 1st surgery was 9.7 years. Time between the 1st and 2nd surgeries ranged from 0.28-15.3 years (mean 4.3 years). The most common pathologies at initial resection included focal cortical dysplasia (45%), tumor (19%), hippocampal sclerosis (16%), and non-specific changes (13%); 10% of patients had multiple significant pathologies. Of the 89 patients that had a significant initial surgical finding, 74 (83.1%) had a significant pathology at 2nd surgery; the same pathology was identified in 49 (66.2%) of these cases. The most commonly identified pathologies at 2nd surgery included remote infarcts (likely postoperative) (N=51) and focal cortical dysplasia (N=29). Three out of the 13 patients with initially non-specific findings had a significant finding at 2nd surgery, excluding postoperative infarct. Follow-up after last surgery ranged from 0.5-190 months (mean 48 months); 83% of patients were on anti-convulsive medication and 57% were seizure-free at last known follow-up. In the majority of cases of recurrent epilepsy with at least 2 surgeries (84%), pathologic findings accounting for seizures were found at the 2nd surgery. In most cases with significant initial pathology, a similar pathology was present at 2nd surgery (55%). Post-operative contusional damage may account for persistent seizures following initial surgery in a subset of patients. PMID- 22543228 TI - Faster response of NO2 sensing in graphene-WO3 nanocomposites. AB - Graphene-based nanocomposites have proven to be very promising materials for gas sensing applications. In this paper, we present a general approach for the preparation of graphene-WO(3) nanocomposites. Graphene-WO(3) nanocomposite thin layer sensors were prepared by drop coating the dispersed solution onto the alumina substrate. These nanocomposites were used for the detection of NO(2) for the first time. TEM micrographs revealed that WO(3) nanoparticles were well distributed on graphene nanosheets. Three different compositions (0.2, 0.5 and 0.1 wt%) of graphene with WO(3) were used for the gas sensing measurements. It was observed that the sensor response to NO(2) increased nearly three times in the case of graphene-WO(3) nanocomposite layer as compared to a pure WO(3) layer at room temperature. The best response of the graphene-WO(3) nanocomposite was obtained at 250 degrees C. PMID- 22543227 TI - Socioeconomic status over the life-course and adult bone mineral density: the Midlife in the U.S. Study. AB - PURPOSE: Adult bone mass depends on acquisition in childhood and decline in adulthood, and may be influenced by socioeconomic conditions over the entire life course. METHODS: We examined associations of bone mineral density (BMD) in adulthood with life course socioeconomic status in 729 participants in the Midlife in the United States Biomarker Project, adjusting for age, menopausal transition stage, race, gender, body weight, smoking, physical activity in several life stages, and research site. Primary predictors were a) childhood socioeconomic advantage score (including parental education, self-rated financial status relative to others, not being on welfare), b) adult education level (no college vs. some college vs. college graduate), and c) adult current financial advantage score (including family-adjusted poverty to income ratio, self-assessed current financial situation, having enough money to meet needs, ease in paying bills). RESULTS: Mean age was 56.9 (range 34-85) years. After adjustment for covariates, childhood socioeconomic advantage and adult education level were positively associated with lumbar spine BMD: 0.27 standard deviations (SD) higher at 90th compared to 10th percentile of childhood advantage score (P=0.009), and 0.24 SD higher in college graduates compared to participants without college education (P=0.01). Adult current financial advantage was not associated with lumbar spine BMD. None of the three socioeconomic indicators was significantly associated with femoral neck BMD. CONCLUSIONS: Childhood socioeconomic advantage and adult education level were associated with higher adult lumbar spine BMD. Current financial advantage was not associated with BMD. Childhood socioeconomic factors may influence acquisition of lumbar BMD. PMID- 22543229 TI - Spontaneous rupture of a pancreatic acinar cell carcinoma presenting as an acute abdomen. AB - INTRODUCTION: Pancreatic acinar cell carcinoma is a rare malignant pancreatic neoplasm. To the best of our knowledge, there has been no report on spontaneous rupture of acinar cell carcinoma. PRESENTATION OF CASE: A 39-year-old Azari male presented with a history of sudden onset, acute epigastric pain of 12-h duration. Eight hours later the patient's general condition rapidly deteriorated, blood pressure was decreased to 90/70mm/Hg and heart rate was increased to 120beat/min. Emergent abdominal computed tomography scan showed a well-defined hypo-dense, necrotic mass, measured 12cm*12cm that was originating from the uncinate process of pancreas with marked free peritoneal fluid and extensive haziness of retroperitoneal and mesenteric fat compatible with marked bleeding. Emergent abdominal operation was performed and histopathology revealed acinar cell carcinoma of the pancreas. DISCUSSION: Pancreatic acinar cell carcinoma (ACC) usually presents with abdominal pain, nausea and vomiting. To best of our knowledge, no report has been made of spontaneous rupture of ACC. CONCLUSION: Pancreatic carcinoma may present as acute abdomen due to rupture of underlying neoplasm. PMID- 22543230 TI - Adrenocortical carcinoma extending into the inferior vena cava in a patient with right kidney agenesis: Surgical approach and review of literature. AB - INTRODUCTION: Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis and the association with tumor thrombus into the inferior vena cava (IVC) is not common. The best treatment is represented by radical surgery. PRESENTATION OF CASE: We describe a case of a large ACC of the left adrenal gland extending into the IVC through the left renal vein in a young patient with agenesis of the right kidney and signs of acute renal failure. A midline laparotomy was performed, subsequently extended by a left thoracophrenotomy through the 7th intercostal space in order to control the proximal surface of the mass and the thoracic aorta. The tumor was completely excised preserving the kidney, and thrombectomy was performed by a cavotomy with a temporary caval clamping, without cardiopulmonary by-pass (CPB). DISCUSSION: We discuss surgical approaches reported in literature in case of ACC with intracaval extension. The tumor must be completely resected and the thrombectomy can be performed by different approaches: cavotomy with direct suture, partial resection of caval wall without reconstruction, resection of vena cava with graft reconstruction. These procedures could require a CPB, with an increased mortality. In our case we preserved the kidney and a thrombectomy without CPB was performed. CONCLUSION: Intracaval extension of ACC does not represent a contraindication to surgery. The best treatment of intracaval thrombus should be the cavotomy with direct suture. The CPB is not always required. In presence of renal agenesis, the preservation of the kidney is mandatory. PMID- 22543231 TI - Inflammatory pseudotumour secondary to spilled intra-abdominal gallstones. AB - INTRODUCTION: Spillage of calculi in the abdomen is frequent during Laparoscopic Cholecystectomy (LC). Though uncommon, these stones may lead to early or late complications. We describe a rare case of spilled gallstone presenting four years after the index procedure, with a mass in the parietal wall mimicking a neoplastic lesion. PRESENTATION OF CASE: A 50 year old male presented with a mass in the right upper quadrant for the past 2 years. His past surgical history included a LC done four years ago. Intraoperative procedural details of the surgery were not available. A Computed Tomography (CT) scan showed an extrahepatic mass in the subdiaphragmatic space extending onto the soft tissues of the parietal wall. He underwent laparoscopic piecemeal excision of this organized mass. His post operative period was uneventful and he was pain-free on follow up. DISCUSSION: Gallbladder perforation can occur due to excessive traction during retraction or during dissection from the liver bed. It can also occur during extraction from the abdomen. Infected bile, pigment gallstones, male gender, advanced age, perihepatic location of spilled gallstones, more than 15 gallstones and an average size greater than 1.5cm have been identified as risk factors for complications. Definitive treatment is surgery with excision of the organized inflammatory mass and extraction of gallstones to avoid future recurrence. CONCLUSION: Spilled gallstones can be a diagnostic challenge and can cause significant morbidity to the patient. Clear documentation of spillage and explanation to the patient is of utmost importance, as this will enable prompt recognition and treatment of any complications. Prevention of spillage is the best policy. PMID- 22543232 TI - A rare case of giant coronary artery aneurysm in the context of multiple arterial aneurysms. AB - INTRODUCTION: Whilst the incidence of CAA has been reported as up to 5%, giant CAA (>2cm) is rare. PRESENTATION OF CASE: We present a rare case of 3cm*4cm giant coronary artery aneurysm (CAA) in the context of aorto-iliac aneurysmal disease, treated by staged open surgical repair. DISCUSSION: Abdominal aortic aneurysm (AAA) and CAA share risk factors and aetiological mechanisms, therefore should be considered, particularly when CAA is diagnosed in the first instance. CONCLUSIONS: Surgical intervention for diagnosed giant CAA appears to be the treatment of choice in the reported literature, with the order of intervention when AAA co-exists remaining a point for debate. PMID- 22543233 TI - Hypnotic effects and GABAergic mechanism of licorice (Glycyrrhiza glabra) ethanol extract and its major flavonoid constituent glabrol. AB - Licorice (Glycyrrhiza glabra, GG) is one of the most frequently used herbal medicines worldwide, and its various biological activities have been widely studied. GG is reported to have neurological properties such as antidepressant, anxiolytic, and anticonvulsant effects. However, its hypnotic effects and the mechanism of GG and its active compounds have not yet been demonstrated. In this study, GG ethanol extract (GGE) dose-dependently potentiated pentobarbital induced sleep and increased the amount of non-rapid eye movement sleep in mice without decreasing delta activity. The hypnotic effect of GGE was completely inhibited by flumazenil, which is a well-known gamma-aminobutyric acid type A benzodiazepine (GABA(A)-BZD) receptor antagonist, similar to other GABA(A)-BZD receptor agonists (e.g., diazepam and zolpidem). The major flavonoid glabrol was isolated from the flavonoid-rich fraction of GGE; it inhibited [(3)H] flumazenil binding to the GABA(A)-BZD receptors in rat cerebral cortex membrane with a binding affinity (K(i)) of 1.63 MUM. The molecular structure and pharmacophore model of glabrol and liquiritigenin indicate that the isoprenyl groups of glabrol may play a key role in binding to GABA(A)-BZD receptors. Glabrol increased sleep duration and decreased sleep latency in a dose-dependent manner (5, 10, 25, and 50mg/kg); its hypnotic effect was also blocked by flumazenil. The results imply that GGE and its flavonoid glabrol induce sleep via a positive allosteric modulation of GABA(A)-BZD receptors. PMID- 22543235 TI - WITHDRAWN: Maternal cortisol and cord brain derived neurotrophic factor in preterm pregnancy: implications for fetal neurodevelopment. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 22543234 TI - Synthesis of chalcone-amidobenzothiazole conjugates as antimitotic and apoptotic inducing agents. AB - A series of chalcone-amidobenzothiazole conjugates (9a-k and 10a,b) have been synthesized and evaluated for their anticancer activity. All these compounds exhibited potent activity and the IC(50) of two potential compounds (9a and 9f) against different cancer cell lines are in the range of 0.85-3.3 MUM. Flow cytometric analysis revealed that these compounds induced cell cycle arrest at G2/M phase in A549 cell line leading to caspase-3 dependent apoptotic cell death. The tubulin polymerization assay (IC(50) of 9a is 3.5 MUM and 9f is 5.2 MUM) and immuofluorescence analysis showed that these compounds effectively inhibit microtubule assembly at both molecular and cellular levels in A549 cells. Further, Annexin staining also suggested that these compounds induced cell death by apoptosis. Moreover, docking experiments have shown that they interact and bind efficiently with tubulin protein. Overall, the current study demonstrates that the synthesis of chalcone-amidobenzothiazole conjugates as promising anticancer agents with potent G2/M arrest and apoptotic-inducing activities via targeting tubulin. PMID- 22543236 TI - WITHDRAWN: BMP signaling and neurogenesis of developing spinal cord. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 22543237 TI - Generating bispecific human IgG1 and IgG2 antibodies from any antibody pair. AB - Bispecific antibodies and antibody fragments are a new class of therapeutics increasingly utilized in the clinic for T cell recruitment (catumaxomab anti EpCAM/CD3 and blinatumomab anti-CD19/CD3), increase in the selectivity of targeting, or simultaneous modulation of multiple cellular pathways. While the clinical potential for certain bispecific antibody formats is clear, progress has been hindered because they are often difficult to manufacture, may suffer from suboptimal pharmacokinetic properties, and may be limited due to potential immunogenicity issues. Current state-of-the-art human IgG-like bispecific technologies require co-expression of two heavy chains with a single light chain, use crossover domains to segregate light chains, or utilize scFv (single-chain fragment variable)-Fc fusion. We have engineered both human IgG1 and IgG2 subtypes, with minimal point mutations, to form full-length bispecific human antibodies with high efficiency and in high purity. In our system, the two antibodies of interest can be expressed and purified separately, mixed together under appropriate redox conditions, resulting in a formation of a stable bispecific antibody with high yields. With this approach, it is not necessary to generate new antibodies that share a common light chain, therefore allowing the immediate use of an existing antibody regardless of whether it has been generated via standard hybridoma or display methods. We demonstrate the generality of the approach and show that these bispecific antibodies have properties similar to those of wild-type IgGs, and we further demonstrate the utility of the technology with an example of a CD3/CD20 bispecific antibody that effectively depletes B cells in vitro and in vivo. PMID- 22543238 TI - Plasmodium falciparum SSB tetramer binds single-stranded DNA only in a fully wrapped mode. AB - The tetrameric Escherichia coli single-stranded DNA (ssDNA) binding protein (Ec SSB) functions in DNA metabolism by binding to ssDNA and interacting directly with numerous DNA repair and replication proteins. Ec-SSB tetramers can bind ssDNA in multiple DNA binding modes that differ in the extent of ssDNA wrapping. Here, we show that the structurally similar SSB protein from the malarial parasite Plasmodium falciparum (Pf-SSB) also binds tightly to ssDNA but does not display the same number of ssDNA binding modes as Ec-SSB, binding ssDNA exclusively in fully wrapped complexes with site sizes of 52-65 nt/tetramer. Pf SSB does not transition to the more cooperative (SSB)(35) DNA binding mode observed for Ec-SSB. Consistent with this, Pf-SSB tetramers also do not display the dramatic intra-tetramer negative cooperativity for binding of a second (dT)(35) molecule that is evident in Ec-SSB. These findings highlight variations in the DNA binding properties of these two highly conserved homotetrameric SSB proteins, and these differences might be tailored to suit their specific functions in the cell. PMID- 22543239 TI - Transient structure and SH3 interaction sites in an intrinsically disordered fragment of the hepatitis C virus protein NS5A. AB - Understanding the molecular mechanisms involved in virus replication and particle assembly is of primary fundamental and biomedical importance. Intrinsic conformational disorder plays a prominent role in viral proteins and their interaction with other viral and host cell proteins via transiently populated structural elements. Here, we report on the results of an investigation of an intrinsically disordered 188-residue fragment of the hepatitis C virus non structural protein 5A (NS5A), which contains a classical poly-proline Src homology 3 (SH3) binding motif, using sensitivity- and resolution-optimized multidimensional NMR methods, complemented by small-angle X-ray scattering data. Our study provides detailed atomic-resolution information on transient local and long-range structure, as well as fast time scale dynamics in this NS5A fragment. In addition, we could characterize two distinct interaction modes with the SH3 domain of Bin1 (bridging integrator protein 1), a pro-apoptotic tumor suppressor. Despite being largely disordered, the protein contains three regions that transiently adopt alpha-helical structures, partly stabilized by long-range tertiary interactions. Two of these transient alpha-helices form a noncanonical SH3-binding motif, which allows low-affinity SH3 binding. Our results contribute to a better understanding of the role of the NS5A protein during hepatitis C virus infection. The present work also highlights the power of NMR spectroscopy to characterize multiple binding events including short-lived transient interactions between globular and highly disordered proteins. PMID- 22543240 TI - The structure of the Sec13/31 COPII cage bound to Sec23. AB - Structural studies have revealed some of the organizing principles and mechanisms involved in the assembly of the COPII coat including the location of the Sec23/24 adapter layer. Previous studies, however, were unable to unambiguously determine the positions of Sec23 and Sec24 in the coat. Here, we have determined a cryogenic electron microscopic structure of Sec13/31 together with Sec23. Electron tomography revealed that the binding of Sec23 induces Sec13/31 to form a variety of different geometries including a cuboctahedron, as was previously characterized for Sec13/31 alone. Single-particle reconstruction of the Sec13/31 23 cuboctahedra revealed that the binding of Sec23 induces a conformational change in Sec13/31, resulting in a more extended conformation. Docking Sec23 crystal structures into the electron microscopy map suggested that Sec24 projects its cargo binding surface out into the large open faces of the coat. These results have implications for the mechanisms by which COPII transports large cargos, cargos with large intracellular domains, and for tethering complexes that must project out of the coat in order to interact with their binding partners. Furthermore, Sec23 binds Sec13/31 at two unique sites in the coat, which suggests that each site may have unique roles in the mechanisms of COPII vesiculation. PMID- 22543241 TI - The closed and compact domain organization of the 70-kDa human cytochrome P450 reductase in its oxidized state as revealed by NMR. AB - The NADPH cytochrome P450 reductase (CPR), a diflavin enzyme, catalyzes the electron transfer (ET) from NADPH to the substrate P450. The crystal structures of mammalian and yeast CPRs show a compact organization for the two domains containing FMN (flavin mononucleotide) and FAD (flavin adenine dinucleotide), with a short interflavin distance consistent with fast ET from the NADPH-reduced FAD to the second flavin FMN. This conformation, referred as "closed", contrasts with the alternative opened or extended domain arrangements recently described for partially reduced or mutant CPR. Internal domain flexibility in this enzyme is indeed necessary to account for the apparently conflicting requirements of having FMN flavin accessible to both the FAD and the substrate P450 at the same interface. However, how interdomain dynamics influence internal and external ETs in CPR is still largely unknown. Here, we used NMR techniques to explore the global, domain-specific and residue-specific structural and dynamic properties of the nucleotide-free human CPR in solution in its oxidized state. Based on the backbone resonance assignment of this 70-kDa protein, we collected residue specific (15)N relaxation and (1)H-(15)N residual dipolar couplings. Surprisingly and in contrast with previous studies, the analysis of these NMR data revealed that the CPR exists in a unique and predominant conformation that highly resembles the closed conformation observed in the crystalline state. Based on our findings and the previous observations of conformational equilibria of the CPR in partially reduced states, we propose that the large-scale conformational transitions of the CPR during the catalytic cycle are tightly controlled to ensure optimal electron delivery. PMID- 22543242 TI - An extremely rare small bowel lesion associated with refractory ascites. Idiopathic myointimal hyperplasia of mesenteric veins of the small bowel associated with appendiceal mucocoele and pseudomyxoma peritonei. PMID- 22543243 TI - Early and late mortality in hospitalised patients with raised cardiac troponin T. AB - AIMS: Cardiac troponins are measured in acute coronary syndrome (ACS) and other conditions. The authors investigate the prognostic significance of cardiac troponin T (TnT) test and comorbid medical conditions. METHODS: Consecutive patients admitted to the Aintree University Hospital, Liverpool, between 2 January 2004 and 29 February 2004 who had TnT measurement were included. Patients were separated into normal (<0.01 MUg/l) or raised TnT levels (>= 0.01 MUg/l), and further categorised into: (1) normal TnT with unstable angina; (2) normal TnT with non-ACS; (3) raised TnT with ACS; and (4) raised TnT with non-ACS. Cox regression was used to identify prognostic variables, and logrank test to compare 7-year survival. RESULTS: Of 1021 patients, 313 had raised TnT (195 ACS, 118 non ACS) and 708 normal TnT (80 ACS, 628 non-ACS). Age (HR 1.06; 95% CI 1.05 to 1.07), congestive cardiac failure (HR 1.37; 95% CI 1.11 to 1.69), cerebrovascular disease (HR 1.37; 95% CI 1.10 to 1.71), chronic obstructive airway disease (HR 1.44; 95% CI 1.19 to 1.75), liver disease (HR 4.16; 95% CI 2.37 to 7.31), renal disease (HR 1.83; 95% CI 1.27 to 2.64), tumour (HR 1.39; 95% CI 1.07 to 1.79), lymphoma (HR 4.81; 95% CI 2.07 to 11.16), metastatic cancer (HR 3.55; 95% CI 2.32 to 5.45) and a higher Charlson's comorbidity score (HR 1.20, 95% CI 1.13 to 1.26) were adverse predictors. Both raised TnT with ACS (HR 1.92, 95% CI 1.54 to 2.39) and raised TnT with non-ACS (HR 2.37, 95% CI 1.87 to 3.00) were associated with worse survival. Raised TnT with non-ACS had a worse survival than raised TnT with ACS (p=0.001). CONCLUSION: Hospitalised patients with raised TnT levels from any cause predicted a higher mortality than normal TnT, with worst survival in those without an obvious ACS. PMID- 22543244 TI - Gut microbiota: methodological aspects to describe taxonomy and functionality. AB - The human gut is populated by a rich and diverse microbiota that has been described as a human metabolic organ. Its composition has an impact on the health status of the host and could be the target or effector of dietary health effects. The advent of high-throughput sequencing technologies and their integration with advanced analysis methods enables the development of new approaches to characterize the gut microbiota composition and initiates the understanding of its functionality. These technological aspects are not necessarily the limiting factor to successfully identify biological correlations between gut microbiota, diet and health status, as there are other very important aspects. The aim of this article is to address the gut microbiota characterization methodologies, highlight some advantages and challenges, and give our opinion on how critical the sampling and the study design are. PMID- 22543245 TI - Bacterial co-infection with H1N1 infection in patients admitted with community acquired pneumonia. AB - BACKGROUND: Bacterial co-infection is an important contributor to morbidity and mortality during influenza pandemics .We investigated the incidence, risk factors and outcome of patients with influenza A H1N1 pneumonia and bacterial co infection. METHODS: Prospective observational study of consecutive hospitalized patients with influenza A H1N1 virus and community-acquired pneumonia (CAP). We compared cases with and without bacterial co-infection. RESULTS: The incidence of influenza A H1N1 infection in CAP during the pandemic period was 19% (n, 667). We studied 128 patients; 42(33%) had bacterial co-infection. The most frequently isolated bacterial pathogens were Streptococcus pneumoniae (26, 62%) and Pseudomonas aeruginosa (6, 14%). Predictors for bacterial co-infection were chronic obstructive pulmonary disease (COPD) and increase of platelets count. The hospital mortality was 9%. Factors associated with mortality were age >= 65 years, presence of septic shock and the need for mechanical ventilation. Although patients with bacterial co-infection presented with higher Pneumonia Severity Index risk class, hospital mortality was similar to patients without bacterial co infection (7% vs. 11%, respectively, p = 0.54). CONCLUSION: Bacterial co infection was frequent in influenza A H1N1 pneumonia, with COPD and increased platelet count as the main predictors. Although associated with higher severe scales at admission, bacterial co-infection did not influence mortality of these patients. PMID- 22543246 TI - Linear and non-linear relationships between bioconcentration and hydrophobicity: theoretical consideration. AB - A non-linear relationship (e.g. Gaussian-type) between measured bioconcentration factor (BCF) and octanol/water partition coefficient (K(OW)) was noted many years ago. Many studies have focused on the cause of the breakdown in the log BCF/log K(OW) curve for highly hydrophobic chemicals with log K(OW)>6. However, there has been little investigation on the theoretical background of this feature for highly hydrophilic chemicals. In this paper, the cause of linear and non-linear relationships between log BCF and log K(OW) has been investigated on the basis of the partitioning-based mechanism for classified non-ionic and ionisable compounds. For highly hydrophilic compounds, lipid tissue in fish is not the major storage site of chemicals. Uptake from other tissues/organs plays a much more important role than the lipid content, leading to a variation of measured log BCF around 0.5. For hydrophobic chemicals with 0.56. The main reason for this is attributed to the reduced bioavailability of chemicals in water. A linear solvation energy relationship shows that the bioconcentration increases with increasing molecular size by increasing the dispersion interactions between the chemical and lipid content. Bioconcentration decreases with increasing the basicity of hydrophobic compounds by increasing the H-bonding of chemicals with water. Principal component analysis shows that the octanol/water system is the closest system, but not an ideal surrogate, to describe the bioconcentration for hydrophobic compounds as compared with other solvent/water partition systems. PMID- 22543247 TI - Selective estrogen receptor modulation in pancreatic beta-cells and the prevention of type 2 diabetes. AB - We recently showed that the female hormone 17beta-estradiol (E2) protects against beta-cell failure in rodent models of type 2 diabetes (T2D) by suppressing islet fatty acids and glycerolipids synthesis, thus preventing lipotoxic beta-cell failure. E2 anti-lipogenic actions were recapitulated by pharmacological activation of the estrogen receptor (ER)alpha, ERbeta and the G-protein coupled ER (GPER) in cultured rodent and human beta-cells. In vivo, in mouse islets, ERalpha activation inhibited beta-cell lipogenesis by suppressing fatty acid synthase expression (and activity) via an extranuclear, estrogen response element (ERE)-independent pathway requiring the signal transducer and activator of transcription 3. Here, we show that in INS-1 insulin-secreting cells, the selective ER modulator (SERM), Raloxifene, behaves both as ER antagonist with regard to nuclear ERE-dependent actions and as an ER agonist with regard to suppressing triglyceride accumulation. This additional finding opens the perspective that SERMs harboring ER agonistic activity in beta-cells could have application in postmenopausal prevention of T2D. Additional studies using novel generation SERMs are needed to address this issue. PMID- 22543248 TI - Treatment of the ventricular tachycardia with engraftment of pluripotent stem cells-derived cardiomyocytes. PMID- 22543249 TI - Reduction in sensitivity to radial optic-flow congruent with ego-motion. AB - Visual motion, such as radial optic flow, is an important cue for perceiving direction during ego-motion. Several previous studies have reported that the perceived speed of a radial optic flow is underestimated when the represented ego motion direction between radial optic flow and non-visual (such as vestibular or/and proprioceptive) information is congruent. In the present study, we examined whether sensitivity to different types of optic flow (radial vs. laminar) interacts with vestibular input in different ways by using another method: instead of estimating the perceived speed of the visual motion pattern, we measured motion-coherence thresholds. The results indicated that when the heading direction was represented by a radial optic-flow pattern, the radial optic-flow sensitivity was significantly lower under the condition where the visual and vestibular sensory input were congruent with the ego-motion direction than under the condition where the visuo-vestibular input and ego-motion were incongruent. These results indicated that radial optic-flow sensitivity was decreased by the congruent vestibular input during the ego-motion event. On the other hand, when the direction of ego-motion was represented by a laminar optic flow, the results were different from those observed with radial optic flows. These data suggest that vestibular input has some effect on optic-flow sensitivity but that the magnitude of the effect of vestibular input may differ between distinct flow patterns such as radial and laminar optic flows. PMID- 22543250 TI - The stress and strain states of the posterior annulus under flexion. AB - STUDY DESIGN: Experimental measurement of bovine caudal annulus fibrosus (AF) biaxial stress-strain states for unloaded motion segments and those loaded in flexion combined with axial compression. OBJECTIVE: To measure AF biaxial stress strain states for motion segments free of external loads and those loaded in flexion combined with axial compression. SUMMARY OF BACKGROUND DATA: In vitro, cyclically loaded flexion is associated with the complete rupture of the AF in acute cases. However, currently little is known about the tissue-level stress and strain states in this damaging load configuration. METHODS: Surface strains of the posterior annulus were measured, during loading of intact bovine caudal motion segments in flexion combined with axial compression, using the unloaded motion segment as a reference. Planar annulus specimens were excised from the motion segments, and the measured strains from the unloaded and flexed intact discs were applied to the excised specimens in a planar biaxial stress-strain device to determine the stress state in each condition. The annulus strain state of the flexed disc was input into a previously developed nonlinear strain energy function with additive terms that directly represent the structural features of the AF. RESULTS: The AF posterior surface strain for motion segments in flexion combined with compression was -0.1087 (circumferential) and 0.1051 (axial) on average. This strain state corresponded to average biaxial stresses in the annulus of 0.046 MPa (circumferential) and 0.224 MPa (axial). The planar AF specimens contracted after sectioning, resulting in small negative strains. In the absence of external loads on a motion segment, the annulus was approximately in a state of equibiaxial tensile stress. The theoretical analysis indicated that collagen crosslinks store a greater portion of the strain energy than the matrix or collagen fibers. CONCLUSION: In flexion combined with compression, the posterior AF stress state is biaxial and is much larger in the axial direction in bovine caudal discs. PMID- 22543252 TI - Detection of modern spinal implants by airport metal detectors. AB - STUDY DESIGN: Prospective cohort observational study. OBJECTIVE: To determine the detection rates of modern spinal implants by post-9/11 airport metal detectors. SUMMARY OF BACKGROUND DATA: There are few data on the detection rates of modern spinal implants and few that examine the effects of body mass, construct complexity, or implant density. METHODS: Implants were tested ex vivo and in vivo using standard arch way metal detectors (AMDs) and handheld metal detectors (HHMDs) in use at the majority of European airports.A volunteer carried individual spinal implants both individually and in various combinations of increasing mass in clothing pockets into the AMD. The same instrumentation was bench tested using HHMD at a distance of 5 cm. Forty patients with modern spinal implants were tested: lumbar disc replacement (8), cervical disc replacement (1), posterior deformity instrumentation (17), anterior deformity instrumentation (2), anterior reconstruction (2), PLIF (6), interspinous distraction device (1), anterior cervical plate (2), and anterior lumbar interbody fusion with cage (1) all implants were titanium unless indicated. Mean metal mass was 98 g (range, 6 222 g). Subject ages ranged from 13 to 65 years and the mean body mass index was 25 kg/m (range, 15-32). RESULTS: Ex vivo, the AMD did not detect any instrumentation individually or in combination up to a titanium mass of 215 g. The HHMD detected all instrumentation at a distance of 5 cm, with the minimum mass being 2 g. No implants were detected in patients by the AMD.The HHMD did not detect any anterior lumbar or thoracic surgical implants. It detected anterior cervical implants. The HHMD detected all posterior surgical implants. There was no significant relationship between detection rate, body mass index, total metal mass, and metal density/segment. CONCLUSION: AMDs do not detect modern spinal implants. HHMDs detect all modern posterior spinal implants; this has implications for patient documentation. PMID- 22543251 TI - Part 1: Dual-tuned proton/sodium magnetic resonance imaging of the lumbar spine in a rabbit model. AB - STUDY DESIGN: Development of a dual-tuned proton/sodium radiofrequency (RF) coil for magnetic resonance imaging (MRI) of the rabbit spine and quantification of sodium concentration in intervertebral discs. OBJECTIVE: To develop the dual tuned proton/sodium MRI of rabbit lumbar spine to investigate proteoglycan matrix content and intervertebral disc degeneration (IDD). SUMMARY OF BACKGROUND DATA: IDD is a common chronic condition that may lead to back pain, limited activity, and disability. Early-stage IDD involves the loss of proteoglycan matrix and water content in the disc. Sodium MRI is a promising noninvasive technique for quantitative measurement of proteoglycan changes associated with IDD. The combined structural (proton) and biochemical (sodium) MRI facilitates the investigation of morphological and molecular changes associated with degeneration of discs. METHODS: Multichannel dual-tuned proton/sodium transceiver RF coil of the rabbit spine was developed and optimized at 3T human scanner-8 channels allocated for the sodium coil and 4 channels for the proton coil. High-resolution anatomy proton images of the discs were acquired using turbo spin echo and dual echo steady state sequence. Sodium concentration of the discs was quantified from sodium magnetic resonance (MR) images that were calibrated for signal attenuation because of RF field inhomogeneity, sodium MR relaxation times, and disc thickness. Twelve rabbits (~1-yr old, female, 5.2 +/- 0.4 kg) were used for measuring disc sodium concentration. RESULTS: High-resolution in vivo proton and sodium MR images of rabbit discs (<=2-mm thickness) were successfully obtained using an in-house dual-tuned proton/sodium RF coil at 3T. The total acquisition time for each set of images was approximately 40 minutes. Sodium concentration of normal rabbit lumbar discs was measured at 269.7 +/- 6.3 mM, and this measurement was highly reproducible, with 5.3% of coefficient of variation. CONCLUSION: Sodium concentrations of rabbit lumbar discs were reliably measured using our newly developed dual-tuned multichannel proton/sodium RF coil at 3T. PMID- 22543254 TI - Inappropriate metformin prescribing in elderly type 2 diabetes mellitus (T2DM) patients. AB - PURPOSE: Metformin is the most commonly prescribed anti-diabetic medication. However, it is often used despite the presence of contraindications and in unlicensed indications. The main aim of this study was to evaluate the frequency of metformin use before hospitalization in spite of contraindications in patients with type 2 diabetes mellitus (T2DM) and to evaluate the prevalence of metformin associated side effects. MATERIAL/METHODS: 558 hospitalized patients (mean age = 66.65 +/- 12.73 years) with poorly controlled T2DM were enrolled. Detailed medical history including the duration of T2DM, duration of hypoglycemic agents usage prior to hospitalization and possible metformin-associated side effects was recorded. Patients were subjected to a thorough physical examination and indispensable biochemical and diagnostic research panel was performed to establish the degree of heart failure, sufficiency of the respiratory system and kidney function. RESULTS: 335 out of 558 patients were treated before hospitalization with metformin alone or in combination with other hypoglycemic agents, mostly sulfonylureas. Contraindications to metformin were found in 275 patients and despite this 120 of them were using this medication in an average dose of 1793.91 +/- 701.61 mg. However, none of them reported any serious adverse effects and no significant pH changes were observed. Only three patients reported moderate dyspepsia. CONCLUSIONS: The results of this study indicate a relatively good tolerability of metformin by patients with the traditional contraindications to this drug. These findings support other authors' suggestion that indications and contraindications to metformin should be re-evaluated. PMID- 22543253 TI - Cervical spine trauma in diffuse idiopathic skeletal hyperostosis: injury characteristics and outcome with surgical treatment. AB - STUDY DESIGN: Retrospective study of a consecutive series of operatively managed patients with cervical fractures with diffuse idiopathic skeletal hyperostosis (DISH) presenting to 3 institutions over an 8 year period. OBJECTIVE: Assess demographics, fracture characteristics, outcome and complications in patients managed surgically. SUMMARY OF BACKGROUND DATA: Cervical spine injuries related to DISH represent a difficult subgroup of trauma patients to treat. This subset is fraught with potential complications related to the injury of the ankylosed spine, high rate of co-morbidities, and older demographics. The data in the literature on treatment, outcomes and complications is largely comprised of case reports and small case series. METHODS: All patients with cervical fractures in the setting of DISH between January 2001 and December 2008 were reviewed retrospectively. Charts and radiographs were reviewed assessing demographics, injury characteristics and short-term outcomes. Statistical analysis was performed analyzing the impact of distinct parameters on the incidence of medical and surgical complications. RESULTS: Thirty-three patients with age 73.8 +/- 11 years were identified. DISH-affected segments numbered 5.5 +/- 2.1. Injury severity as assessed by the Subaxial-Injury-Classification scoring-system (SLIC) averaged 7.2 +/- 1.4 points. 7 patients (20.6%) were ASIA-A on admission, 4 (11.8%) ASIA-B, 4 (11.8%) ASIA-C, 10 (29.4%) ASIA-D, and 7 (20.6%) ASIA-E. All but 2 patients (6%) had medical co-morbidities. Inpatient stay was 26.6 +/- 23.4 days. 16 patients (47%) had anterior, 12 patients (35.3%) had posterior, and 5 patients (14.7%) had combined anterior-posterior instrumented fusion. 25 patients (73.5%) had medical/surgical complications. 20 patients (58.8%) suffered serious pulmonary complications not related to the neurologic injury (p < 0.05). Nine patients (26.5%) had died. Seven patients (20.6%) showed improved ASIA-scores, 18 patients (52.9%) had no improvement and 2 patients (5.9%) deteriorated. CONCLUSION: The current findings pinpoint the potential for medical and surgical complications in this high risk subgroup. Surgeons should be aware of the unique aspects associated with treatment of these injuries. PMID- 22543255 TI - A real time PCR based approach for the quantitative detection of FUS-CHOP fusion transcripts in human liposarcoma. AB - PURPOSE: Histology still forms the backbone for the diagnosis of the myxoid and round cell subtypes of liposarcoma but the molecular identification of the different transcript variants remains a challenge, due, in part, to the complexity of multiple overlapping exons that they share between them. This study was conducted to develop and evaluate a more sensitive platform than existing semi-quantitative approaches for detecting FUS-CHOP transcripts. MATERIALS AND METHODS: In the present investigation we describe a novel approach using real time PCR to identify and differentiate the fusion transcripts formed in the t(12; 16)(q13; p11) chromosomal translocation. This method is founded on the basis of transcript individualized primers and probes, which were designed to detect specifically the different variants in both frozen and FFPE tissues. RESULTS: Our results show that the method is highly specific, sensitive, and superior to the widely used nested PCR approach, and is accurately able to differentiate the most common variants, as well as quantify copy numbers. Primer amplification and probe detection of FUS-CHOP from genomic DNA of human, mouse, cocker spaniel and chicken sources all resulted in completely negative results indicating this technique is specific for human RNA derived transcripts. CONCLUSION: This new method offers an additional tool in the investigation of liposarcoma that may impact considerably on missed diagnosis and it's accompanying clinical ramifications. PMID- 22543256 TI - Minimal inhibitory concentration (MIC) of caspofungin and itraconazole inhibiting growth of Candida strains calculated from the linear regression equation. AB - PURPOSE: The aim of the study was to compare the susceptibility of Candida species to caspofungin and itraconazole. MATERIAL AND METHODS: 118 strains of Candida species were used in the study: 8 pattern strains and 110 strains isolated from different ontocenoses. The susceptibility of fungi strains to drugs was determined by diffusion in agar gel. The minimal inhibitory concentration (MIC) was calculated from the linear regression equation with the use of the method by Kadlubowski. RESULTS: The MIC value for caspofungin for the pattern strains ranged from 0.321 mg/L to 0.552 mg/L and for itraconazole from 0.019 mg/L to 0.11 mg/L. All the analyzed strains isolated from patients exhibited susceptibility to caspofungin; 5 strains of Candida albicans (8.06%) proved to be resistant to itraconazole. The MIC values for caspofungin ranged from 0.114 mg/L to 1.26 mg/L and for itraconazole from 0.012 mg/L to 16.1 mg/L. CONCLUSIONS: 1. All the studied pattern strains are susceptible to the examined drugs; all those isolated from patients show susceptibility to caspofungin; some Candida albicans strains (8.06%) are resistant to itraconazole. 2. The mean MIC values calculated from the activity curves are 0.426 mg/L for caspofungin and 1.0245 mg/L for itraconazole. 3. The mean MIC values calculated for caspofungin are lower than for itraconazole in the case of Candida albicans, C. glabrata and C. tropicalis. Having compared the influence of the drugs on C. famata, C. lusitaniae, C. parapsilosis and C. ciferri we proved there are statistically significant differences (0.0046>p<0.044). PMID- 22543258 TI - Mobility changes in individuals with dysvascular amputation from the presurgical period to 12 months postamputation. AB - OBJECTIVES: To describe changes in ambulation among individuals with lower extremity amputation secondary to peripheral artery disease and/or diabetes prior to surgery through 12 months after surgery. To compare differences in ambulation by amputation level and to examine risk factors for change in ambulation over time. DESIGN: Prospective cohort study. SETTING: Two Veterans Affairs medical centers, 1 university hospital, and a level I trauma center. PARTICIPANTS: Patients with peripheral artery disease or diabetes (N=239) undergoing a first unilateral major amputation were screened for participation between September 2005 and December 2008. Among these, 57% (n=136) met study criteria, and of these, 64% (n=87) participated. INTERVENTIONS: Standard of care at each facility. MAIN OUTCOME MEASURES: Ambulatory function measured using the Locomotor Capability Index-5. RESULTS: Seventy-five of the 87 (86%) subjects enrolled finished their 12-month follow-up interview. Ambulatory mobility declined during the period immediately prior to surgery (premorbid) and remained low at 6 weeks postsurgery. On average, ambulation improved after surgery but did not return to premorbid levels. In the final multivariate model, age and history of lower extremity arterial reconstruction were significantly associated with a poorer ambulatory trajectory over time, while other factors, such as amputation level, prior alcohol use, and length of disability prior to amputation, were not. CONCLUSIONS: The findings highlight the importance of considering premorbid ambulatory function. Informing providers and patients about the trajectory and time course of changes in ambulation can enhance patient education, patient expectations, and treatment planning. PMID- 22543259 TI - A cross-sectional assessment of stroke rehabilitation in Nebraska hospitals. AB - OBJECTIVE: To assess the structure and process of stroke rehabilitation in Nebraska hospitals. DESIGN: Cross-sectional mail survey using the Dillman tailored-design method of administration. SETTING: Hospitals in Nebraska. PARTICIPANTS: Approximately 77% of the 84 Nebraska hospitals that provide stroke rehabilitation are critical access hospitals (CAHs) that are limited to 25 beds. Our study sample of hospitals (N=53) included the 19 hospitals licensed for 47 to 689 beds (non-CAHs) and a stratified random sample of 34 of the 65 CAHs. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Self-reported stroke rehabilitation team structure and processes, purposes of and barriers to the use of evidence-based standardized assessments, specific assessments used, and access to specialized stroke rehabilitation services and community resources. RESULTS: Thirty-six (68%) of the 53 hospitals responded to the survey. Approximately 61% of the hospitals used an organized team to provide stroke rehabilitation; 8% of the hospitals-all non-CAHs-had a team dedicated to stroke rehabilitation. After adjusting for hospital size, having an organized team was significantly associated with the use of standardized assessments to improve communication, measure progress and outcomes, evaluate effectiveness of practice, and compare patient outcomes across conditions. Access to specialized stroke rehabilitation professionals and services was significantly greater in non-CAHs. CONCLUSIONS: Hospital size and the presence of a team are determinants of the structure and process of stroke rehabilitation in Nebraska hospitals. Further research is needed to determine (1) whether team structure is a determinant of stroke rehabilitation outcomes across the continuum of care settings, (2) the needs of rural stroke survivors, and (3) whether technology can facilitate the use of stroke rehabilitation standardized assessments by rural health care professionals. PMID- 22543257 TI - Sleep disturbance, cytokines, and fatigue in women with ovarian cancer. AB - Pro-inflammatory cytokines, such as interleukin-6 (IL-6), have been implicated in the underlying processes contributing to sleep regulation and fatigue. Despite evidence for sleep difficulties, fatigue, and elevations in IL-6 among women with ovarian cancer, the association between these symptoms and IL-6 has not been investigated. To address this knowledge gap, we examined relationships between sleep disturbance, fatigue, and plasma IL-6 in 136 women with ovarian cancer prior to surgery. These relationships were also examined in 63 of these women who were disease-free and not receiving chemotherapy one year post-diagnosis. At both time-points, higher levels of IL-6 were significantly associated with sleep disturbances (p<0.05), controlling for potentially confounding biological and psychosocial covariates. Higher IL-6 was significantly associated with fatigue prior to surgery (p<0.05); however, when sleep disturbance was included in the model, the relationship was no longer significant. IL-6 was not significantly associated with fatigue at one year. Changes in sleep over time were significantly associated with percent change in IL-6 from pre-surgery to one year, adjusting for covariates (p<0.05). These findings support a direct association of IL-6 with sleep disturbances in this population, whereas the relationship between IL-6 and fatigue prior to surgery may be mediated by poor sleep. As this study is the first to examine cytokine contributions to sleep and fatigue in ovarian cancer, further research is warranted to clarify the role of biological correlates of sleep and fatigue in this population. PMID- 22543260 TI - "It's no big deal": adolescents with congenital heart disease. AB - Improved survival rates for congenital heart disease (CHD) have increasing numbers requiring lifelong specialized health care. In this interpretive description, interview data were analyzed to understand how adolescents with CHD describe everyday life and relate to questions about quality of life. Most viewed themselves as normal, their CHD something that they situated into the foreground or background of their lives as it suited their needs. They spoke of quality-of life issues in a concrete manner focusing on physical activity limitations and their need to fit in. These findings can direct interventions for adolescents with CHD for transition to adulthood. PMID- 22543261 TI - Nurses' uniform color and feelings/emotions in school-aged children receiving health care. AB - Children may fear nurses wearing white uniforms. When emotions and uniform color were studied in 233 children, many positive emotions were most often associated with blue, bold pink-patterned, or yellow-patterned tops (all p <= .002). Negative emotions were not associated with uniform top colors (all p < .001). However, after excluding "uniform color does not matter," 8 negative emotions were most often associated with white uniform color (p < .001-.04), and 2 others were most often associated with the yellow-patterned top. Bold pink-patterned and solid blue uniform tops were preferred. In conclusion, children's emotions were associated with nurse uniform color. PMID- 22543262 TI - Spin dynamics and spin noise in the presence of randomly varying spin-orbit interaction in a semiconductor quantum wire. AB - Using ensemble Monte Carlo simulation, we have studied hot carrier spin dynamics and spin noise in a multi-subband GaAs quantum wire in the presence of a randomly varying Rashba spin-orbit interaction. The random variation reduces the carrier ensemble's spin dephasing time due to the D'yakonov-Perel' mechanism, but otherwise makes no qualitative difference to the temporal spin relaxation characteristics. However, it makes a qualitative difference to the spatial spin relaxation characteristics which change from monotonic and smooth to non monotonic and chaotic because of a complex interplay between carriers in different subbands. As far as spin fluctuation and spin noise are concerned, the random variation has no major effect except that the low-frequency noise power spectral density increases slightly when the magnitude of the Rashba spin-orbit interaction field is varied randomly while holding the direction constant. PMID- 22543264 TI - Dimensions of attention impairment and negative symptoms in schizophrenia: a multidimensional approach using the conners continuous performance test in a Spanish population. AB - OBJECTIVES: The aim of this study was to assess the specific features of attention impairment in patients with schizophrenia and the correlation between those features and the patients' clinical status. METHODS: We administered the Conners Continuous Performance Test (CPT-II), with cognitive and clinical scales, to 40 Spanish inpatients with schizophrenia and 40 healthy controls, and used a cross-sectional design to compare the groups' performances. We identified correlations between the measures and used multiple regression analyses to develop models showing how attention impairment contributed to clinical status. RESULTS: The patients with schizophrenia showed significantly poorer performance than controls in 5 CPT-II measures that were related to focused attention. We also found that CPT-II measures primarily linked to focused attention had a significant association with negative symptoms. These CPT-II measures predicted 37% of the variability in negative symptoms in the regression model. We observed a more modest relationship among CPT-II measures of disorganized thought symptoms, global functioning, and general cognitive performance. CONCLUSIONS: Attention impairment in schizophrenia primarily involves difficulty in focusing attention, mainly related to negative symptoms. By contrast, sustained attention and vigilance seem to be affected only as a secondary consequence of the impairment to focusing attention. PMID- 22543263 TI - Interleukin-25 induces type 2 cytokine production in a steroid-resistant interleukin-17RB+ myeloid population that exacerbates asthmatic pathology. AB - Interleukin-25 (IL-25) is a cytokine associated with allergy and asthma that functions to promote type 2 immune responses at mucosal epithelial surfaces and serves to protect against helminth parasitic infections in the intestinal tract. This study identifies the IL-25 receptor, IL-17RB, as a key mediator of both innate and adaptive pulmonary type 2 immune responses. Allergen exposure upregulated IL-25 and induced type 2 cytokine production in a previously undescribed granulocytic population, termed type 2 myeloid (T2M) cells. Il17rb(-/ ) mice showed reduced lung pathology after chronic allergen exposure and decreased type 2 cytokine production in T2M cells and CD4(+) T lymphocytes. Airway instillation of IL-25 induced IL-4 and IL-13 production in T2M cells, demonstrating their importance in eliciting T cell-independent inflammation. The adoptive transfer of T2M cells reconstituted IL-25-mediated responses in Il17rb( /-) mice. High-dose dexamethasone treatment did not reduce the IL-25-induced T2M pulmonary response. Finally, a similar IL-4- and IL-13-producing granulocytic population was identified in peripheral blood of human subjects with asthma. These data establish IL-25 and its receptor IL-17RB as targets for innate and adaptive immune responses in chronic allergic airway disease and identify T2M cells as a new steroid-resistant cell population. PMID- 22543265 TI - Stability analysis and thermal motion of optically trapped nanowires. AB - We investigate the stability and thermal motion of optically trapped nanowires, with aspect ratios in the range 10-100. A simple analytical model is used to determine qualitative features of the system, assuming that the nanowire is weakly scattering and the incident beam is paraxial. As expected, the model predicts that the nanowire will align with the beam axis. In this configuration the translational stiffness coefficients of the trap approach their limiting values for long nanowires like O(L(-3)), where L is the nanowire length, the limit for the stiffness parallel to the beam axis being zero. The rotational stiffness coefficients vary more slowly, according to O(L(-1)). Also, it is predicted that defocusing decreases the translational stiffness perpendicular to the beam, while increasing rotational stiffness. These findings are reinforced by comparison with rigorous electromagnetic calculations which additionally reveal the effects of radiation pressure and finite scattering. A strong polarization effect is observed in the numerical simulations and coupled translational and rotational motions arise which influence the trap stability. The use of nanowire traps for force sensing is discusse. PMID- 22543266 TI - Fast and sensitive dye-sensor based on fluorescein/reduced graphene oxide complex. AB - We report on a fast, sensitive, label-free, and general dye-sensor platform for synthetic organic dyes detection by competitive adsorption on reduced graphene oxide (rGO) against a fluorescent dye (FD). Fluorescein (Fl) as fluorescence indicator and a cationic dye methylene blue (MB) as model analyte were employed to investigate the analytical feature of this assay platform. An anionic dye sunset yellow FCF (SY) was chosen as a comparison analyte to test the generality of this strategy. Results show that rGO can bind Fl and quench the fluorescence by fluorescence resonance energy transfer (FRET), while MB can displace Fl quickly from the Fl/rGO complex by competitive adsorption, inducing the fluorescence recovery which provides a quantitative readout for MB. Besides, this design was simply based on the competitive adsorption of rGO between dye and FD, and can be generally applied to other dyes for label-free detection. The fluorescence enhancement efficiency (FEE) is proportional to the dye concentration over the range of 7.60-420.00 ng mL(-1) MB and 7.28-400.25 ng mL( 1) SY, respectively. The linear regression equations were calculated as FEE(MB) = 0.0192c(MB)- 0.3103 for MB and FEE(SY) = 0.0142 c(SY)- 0.0427 for SY, with the detection limits of 1.03 and 1.15 ng mL(-1), respectively. The MB in waste water and SY in an orange-flavored sports drink sample were assayed with satisfactory results. PMID- 22543268 TI - Towards an epidemiology of the known unknowns in cryptogenic stroke. PMID- 22543269 TI - Cost-effectiveness of transcatheter aortic valve replacement: overoptimistic study results and a call for publication of complete trial results. PMID- 22543270 TI - Effects of couple interactions and relationship quality on plasma oxytocin and cardiovascular reactivity: empirical findings and methodological considerations. AB - Cardiovascular reactivity is a potential mechanism underlying associations of close relationship quality with cardiovascular disease. Two models describe oxytocin as another mechanism. The "calm and connect" model posits an association between positive relationship experiences and oxytocin levels and responses, whereas the "tend and befriend" model emphasizes the effects of negative relationship experiences in evoking oxytocin release. In this study of 180 younger couples, relationship quality had a small, marginally significant inverse association with plasma oxytocin levels, and neither positive nor negative couple interactions evoked change in plasma oxytocin. Negative couple interactions evoked significant cardiovascular reactivity, especially among women. Hence, in the largest study of these issues to date, there was little support for key tenets of the "calm and connect" model, and only very modest support for the "tend and befriend" model. However, findings were consistent with the view that CVR contributes to the effects of relationship difficulties on health. PMID- 22543271 TI - The HMG-box transcription factor Sox4b is required for pituitary expression of gata2a and specification of thyrotrope and gonadotrope cells in zebrafish. AB - The pituitary is a complex gland comprising different cell types each secreting specific hormones. The extensive network of signaling molecules and transcription factors required for determination and terminal differentiation of specific cell types is still not fully understood. The SRY-like HMG-box (SOX) transcription factor Sox4 plays important roles in many developmental processes and has two homologs in zebrafish, Sox4a and Sox4b. We show that the sox4b gene is expressed in the pituitary anlagen starting at 24 h after fertilization (hpf) and later in the entire head region including the pituitary. At 48 hpf, sox4b mRNA colocalizes with that for TSH (tshbeta), glycoprotein subunit alpha (gsualpha), and the Zn finger transcription factor Gata2a. Loss of Sox4b function, using morpholino knockdown or expression of a dominant-negative Sox4 mutant, leads to a drastic decrease in tshbeta and gsualpha expression and reduced levels of gh, whereas other anterior pituitary gland markers including prl, slbeta, pomc, and lim3 are not affected. Sox4b is also required for expression of gata2a in the pituitary. Knockdown of gata2a leads to decreased tshbeta and gsualpha expression at 48 hpf, similar to sox4b morphants. Injection of gata2a mRNA into sox4b morphants rescued tshbeta and gsualpha expression in thyrotrope cells. Finally, sox4b or gata2a knockdown causes a significant decrease of gonadotropin expression (lhbeta and fshbeta) at 4 d after fertilization. In summary, our results indicate that Sox4b is expressed in zebrafish during pituitary development and plays a crucial role in the differentiation of thyrotrope and gonadotrope cells through induction of gata2a expression in the developing pituitary. PMID- 22543273 TI - What makes the cell differentiate? AB - In the present paper, I propose a hypothesis whereby the necessity to maintain the permanent energy-dissipating metabolic flux represents the primary force that determines the eukaryotic cell's choice to grow, divide and/or differentiate. This view is based on the universal structure and the strict redox neutrality of the core metabolic network. I propose that the direct substrate level coupling between metabolism and gene expression through epigenetic mechanisms provides a mechanistic explanation of how this control is implemented. PMID- 22543274 TI - Scientific progress specific to biology: an epistemological overview. AB - Progresses in leading edge life sciences are undeniable, but there is more to it: from an epistemological perspective, they rest on a paradox vitalizing the very project of biology. Making our understanding of organic functioning all the more objective, life sciences yet exploit a paradigm which structurally rules out any opportunity to explain why biological phenomena are explainable the way we claim they are. As such a blind spot is constitutive of the disciplinary boundaries that condition and permit objective modelling, evolutions in scientists' mode of thought (i.e. paradigm shifts) may require at crucial points some interaction with epistemologists or historians of sciences. The model case of ontophylogenesis thus shows not only how such cooperation can be useful (both in normal science and in transitional contexts), but mostly why it plays a role in helping biology to get out of its intrinsic paradox. The most innovative feature of ontophylogenesis would thus be the following: to give account for the mode of intelligibility it chose by explaining it - in a truly Darwinian manner -in the core of the theory. Though this epistemic move definitely confirms biology to be an autonomous science as long as it faces its constitutive paradox, the methodological detour such realization implied would go through occasional interplay with "exclusively reflexive approaches" - that is to say, humanities. PMID- 22543272 TI - Gene-specific patterns of coregulator requirements by estrogen receptor-alpha in breast cancer cells. AB - Progesterone receptor (PgR) controls the menstrual cycle, pregnancy, embryonic development, and homeostasis, and it plays important roles in breast cancer development and progression. However, the requirement of coregulators for estrogen-induced expression of the PgR gene has not been fully explored. Here we used RNA interference to demonstrate dramatic differences in requirements of 10 different coregulators for estrogen-regulated expression of six different genes, including PgR and the well-studied TFF1 (or pS2) gene in MCF-7 breast cancer cells. Full estrogen-induced expression of TFF1 required all ten coregulators, but PgR induction required only four of the 10 coregulators. Chromatin immunoprecipitation studies demonstrated several mechanisms responsible for the differential coregulator requirements. Actin-binding coregulator Flightless-I, required for TFF1 expression and recruited to that gene by estrogen receptor alpha (ERalpha), is not required for PgR expression and not recruited to that gene. Protein acetyltransferase tat-interactive protein 60 and ATP-dependent chromatin remodeler Brahma Related Gene 1 are recruited to both genes but are required only for TFF1 expression. Histone methyltransferase G9a is recruited to both genes and required for estrogen-induced expression of TFF1 but negatively regulates estrogen-induced expression of PgR. In contrast, histone methyltransferase myeloid/lymphoid or mixed-lineage leukemia 1 (MLL1), pioneer factor Forkhead box A1, and p160 coregulator steroid receptor coactivator-3 are required for expression of and are recruited to both genes. Depletion of MLL1 decreased ERalpha binding to the PgR and TFF1 genes. In contrast, depletion of G9a enhanced ERalpha binding to the PgR gene but had no effect on ERalpha binding to the TFF1 gene. These studies suggest that differential promoter architecture is responsible for promoter-specific mechanisms of gene regulation. PMID- 22543275 TI - Whole and particle-free diesel exhausts differentially affect cardiac electrophysiology, blood pressure, and autonomic balance in heart failure-prone rats. AB - Epidemiological studies strongly link short-term exposures to vehicular traffic and particulate matter (PM) air pollution with adverse cardiovascular (CV) events, especially in those with preexisting CV disease. Diesel engine exhaust is a key contributor to urban ambient PM and gaseous pollutants. To determine the role of gaseous and particulate components in diesel exhaust (DE) cardiotoxicity, we examined the effects of a 4-h inhalation of whole DE (wDE) (target PM concentration: 500 ug/m(3)) or particle-free filtered DE (fDE) on CV physiology and a range of markers of cardiopulmonary injury in hypertensive heart failure prone rats. Arterial blood pressure (BP), electrocardiography, and heart rate variability (HRV), an index of autonomic balance, were monitored. Both fDE and wDE decreased BP and prolonged PR interval during exposure, with more effects from fDE, which additionally increased HRV triangular index and decreased T-wave amplitude. fDE increased QTc interval immediately after exposure, increased atrioventricular (AV) block Mobitz II arrhythmias shortly thereafter, and increased serum high-density lipoprotein 1 day later. wDE increased BP and decreased HRV root mean square of successive differences immediately postexposure. fDE and wDE decreased heart rate during the 4th hour of postexposure. Thus, DE gases slowed AV conduction and ventricular repolarization, decreased BP, increased HRV, and subsequently provoked arrhythmias, collectively suggesting parasympathetic activation; conversely, brief BP and HRV changes after exposure to particle-containing DE indicated a transient sympathetic excitation. Our findings suggest that whole- and particle-free DE differentially alter CV and autonomic physiology and may potentially increase risk through divergent pathways. PMID- 22543276 TI - A comprehensive statistical analysis of predicting in vivo hazard using high throughput in vitro screening. AB - Over the past 5 years, increased attention has been focused on using high throughput in vitro screening for identifying chemical hazards and prioritizing chemicals for additional in vivo testing. The U.S. Environmental Protection Agency's ToxCast program has generated a significant amount of high-throughput screening data allowing a broad-based assessment of the utility of these assays for predicting in vivo responses. In this study, a comprehensive cross-validation model comparison was performed to evaluate the predictive performance of the more than 600 in vitro assays from the ToxCast phase I screening effort across 60 in vivo endpoints using 84 different statistical classification methods. The predictive performance of the in vitro assays was compared and combined with that from chemical structure descriptors. With the exception of chronic in vivo cholinesterase inhibition, the overall predictive power of both the in vitro assays and the chemical descriptors was relatively low. The predictive power of the in vitro assays was not significantly different from that of the chemical descriptors and aggregating the assays based on genes reduced predictive performance. Prefiltering the in vitro assay data outside the cross-validation loop, as done in some previous studies, significantly biased estimates of model performance. The results suggest that the current ToxCast phase I assays and chemicals have limited applicability for predicting in vivo chemical hazards using standard statistical classification methods. However, if viewed as a survey of potential molecular initiating events and interpreted as risk factors for toxicity, the assays may still be useful for chemical prioritization. PMID- 22543277 TI - Synchronized activity of organic cation transporter 3 (Oct3/Slc22a3) and multidrug and toxin extrusion 1 (Mate1/Slc47a1) transporter in transplacental passage of MPP+ in rat. AB - The aim of the present study was to investigate the expression, localization, and function of organic cation transporter 3 (Oct3, Slc22a3) and multidrug and toxin extrusion protein 1 (Mate1, Slc47a1) in the rat placenta. Using qRT-PCR and Western blotting techniques, we demonstrated abundant Oct3 and Mate1 mRNA and protein expression achieving significantly higher levels than those in the maternal kidney (positive control). Immunohistochemical visualization revealed preferential localization of Oct3 on the basolateral, i.e., fetus facing side of the placenta, whereas Mate1 positivity was located in the labyrinth area predominantly on the apical, i.e., maternal side of the placenta. To investigate the role of these transporters in the transplacental pharmacokinetics, the in situ method of dually perfused rat term placenta was employed in open- and closed circuit arrangements; 1-methyl-4-phenylpyridinium (MPP(+)) was used as a model substrate of both Oct3 and Mate1. We provide evidence that Oct3 and Mate1 cause considerable asymmetry between maternal-to-fetal and fetal-to-maternal transport of MPP(+) in favor of fetomaternal direction. Using closed-circuit experimental setup, we further describe the capacity of Oct3 and Mate1 to transport their substrate from fetus to mother even against a concentration gradient. We conclude that Oct3, in a concentration-dependent manner, takes up MPP(+) from the fetal circulation into the placenta, whereas Mate1, on the other side of the barrier, is responsible for MPP(+) efflux from placenta to the maternal circulation. These two transport proteins, thus, form an efficient transplacental eliminatory pathway and play an important role in fetal protection and detoxication. PMID- 22543278 TI - Persistent DNA damage measured by comet assay of Sprague Dawley rat lung cells after five days of inhalation exposure and 1 month post-exposure to dispersed multi-wall carbon nanotubes (MWCNTs) generated by new MWCNT aerosol generation system. AB - Carbon nanotubes (CNTs) have specific physico-chemical properties that are useful for the electronics, automotive, and construction industries. Yet, despite their many advantages, there is a current lack of available information on the human health and environmental hazards of CNTs. For this reason, the current study investigated the inhalation toxicity potential of multiwall CNTs (MWCNTs). Eight week-old rats were divided into four groups (10 rats in each group), the fresh air control (0mg/m(3)), low-concentration group (0.16mg/m(3)), middle concentration group (0.34mg/m(3)), and high-concentration group (0.94mg/m(3)), and the whole body was exposed to MWCNTs for 5 days (6h/day). Lung cells were then isolated from five rats in each group on day 0 and 1 month after the 5-day exposure, respectively. The MWCNTs were generated by a newly designed generation system, and the MWCNT concentrations in the exposure chambers monitored in accordance with National Institute for Occupational Safety and Health (NIOSH) 0500 using a membrane filter. The MWCNTs were also sampled for an elemental carbon concentration analysis using a glass filter. The animals exhibited no significant body weight changes, abnormal clinical signs, or mortality during the experiment. A single-cell gel electrophoresis assay (Comet assay) was conducted to determine the DNA damage in lung cells obtained from the right lung. As a result, the Olive tail moments were 23.00+/-1.76, 30.39+/-1.96, 22.96+/-1.26, and 33.98+/-2.21 for the control, low-, middle-, and high-concentration groups, respectively, on day 0 postexposure. Meanwhile, 1 month postexposure, the Olive tail moments were 25.00+/-2.71, 28.39+/-3.55, 22.56+/-1.36, and 31.97+/-3.16 for the control, low-, middle-, and high-concentration groups, respectively. Thus, the MWCNTs caused a statistically significant increase in lung DNA damage at high concentration (0.94mg/m(3)) when compared with the negative control group on day 0 and 1 month postexposure. PMID- 22543279 TI - A swallowed dental prosthesis causing duodenal obstruction in a patient with schizophrenia: Description of a new technique. AB - INTRODUCTION: Foreign body ingestion has been a fundamental subject in the area of emergency surgery. The problem is encountered across all age groups; however, it is more common in the pediatric age group. Foreign body ingestion is rare in adults and usually occurs accidentally or in those with psychiatric problems, behavioral disorders, emotional disturbance, mental retardation, or impaired judgment caused by alcohol use. PRESENTATION OF CASE: A 33-year-old Caucasian man with chronic schizophrenia was admitted to the emergency department with signs of upper gastrointestinal discomfort as a result of ingestion of a lower dental prosthesis. An abdominal X-ray showed the swallowed dental prosthesis in front of the vertebral column. A technique comprising gastrotomy and duodenal kocherization was used to remove the dental prosthesis; the prosthesis could not be removed endoscopically due to its fixed position on the duodenal wall. DISCUSSION: Surgery of the duodenum is difficult and carries high mortality and morbidity. Therefore, endoscopy should be the first choice for patients in whom a foreign object is demonstrated to be fixed in the duodenum. In cases where endoscopic extraction fails, surgery should be considered. During surgery, foreign bodies should be removed, paying meticulous attention not to harm the integrity of the duodenum. CONCLUSION: The technique presented in this study was performed successfully without any injury to the duodenum. PMID- 22543280 TI - GRP78 induced by estrogen plays a role in the chemosensitivity of endometrial cancer. AB - OBJECTIVE: Molecular chaperone 78 kDa glucose-regulated protein (GRP78) is a residential protein in the endoplasmic reticulum (ER) that is induced by an unfolded-protein response triggered under many kinds of stress against a cell. GRP78 is also known to act as an anti-apoptotic factor by protecting ER-stress induced cell death. In this study, we examined the significance of GRP78 expression in endometrial cancer. METHODS: Tissue samples obtained from patients with a diagnosis of enodometrial cancer were subjected to immunohistochemistry and RT-PCR to determine protein and mRNA expression levels of GRP78 and estrogen receptor alpha. We used Western blot and RT-PCR to examine whether estrogen induced GRP78 expression in cancer cell lines. Western blots and MTT assays of GRP78 siRNA transfected Ishikawa and HHUA cells were used to demonstrate whether GRP78 is involved in chemoresistence. RESULTS: GRP78 was highly expressed in well and moderately differentiated endometrial carcinoma. Estrogen induced GRP78 expression, which was correlated with cell viability and resistance to paclitaxel and cisplatin. Western blot analysis indicated that active caspase-3 and the 85 kDa protein poly (ADP-ribose) polymerase (PARP) were increased by incubation with either paclitaxel or cisplatin, suggesting that the apoptotic pathway was involved in cancer-drug-induced cell death. CONCLUSIONS: These results may open up a novel therapeutic strategy for endometrial cancer: namely, the targeting of GRP78 to sensitize the tumor cell to chemotherapy. PMID- 22543281 TI - The development of a peptide SRM-based tandem mass spectrometry assay for prenatal screening of Down syndrome. AB - Two new biomarkers, serum amyloid-P (SAP) and plasma C1-inhibitor protein are elevated in the maternal circulation of mothers carrying Down syndrome foetuses. Much emphasis of late? has been put on the lack of translational tests being developed following the identification of new biomarkers. We have created a single-reaction-monitoring (SRM) tandem mass spectrometry-based assay for the quantitation of these biomarkers and compared these results with an in-house developed immunofluorescence-based technique (IF). This MS-based assay is a rapid 5 min test and a simple "one pot reaction," requiring only 5MUl of plasma. To evaluate the potential of SRM-based quantitation in a clinical setting, SAP and C1-inhibitor were quantitated in 38 normal and Down syndrome affected pregnancies. Plasma SAP levels in the Down's group were significantly raised at 10-14 weeks (p<0.0015) and 14-20 weeks (p<0.0001). Plasma C1-inhibitor levels were also observed significantly elevated in the Down's group (10-14 weeks, p<0.0193, 14-20 weeks, p<0.0001). Analysis using the IF technique did not show any significant elevation of plasma SAP levels or C1-inhibitor levels. This rapid and sensitive assay demonstrates the potential of multiplexed tandem MS-based quantitation of proteins in chemical pathology labs and in a more cost-effective, accurate manner than conventionally used antibody methods. PMID- 22543282 TI - Proteomic analysis reveals oxidative stress response as the main adaptative physiological mechanism in cows under different production systems. AB - Three groups of cows representing three ranges of welfare in the production system were included in the study: two groups of Bruna dels Pirineus beef cattle maintained under different management systems (good and semiferal conditions) and a group of Alberes cows, a breed that lives in the mountains (hardest conditions). In order to identify new stress/welfare biomarkers, serum from Bruna cows living in both environments was subjected to DIGE labelling, two-dimensional electrophoresis and MALDI-MS or ion trap MS. Identification was achieved for 15 proteins, which mainly belonged to three biological functions, the oxidative stress pathway (glutathione peroxidase (GPx) and paraoxonase (PON-1)), the acute phase protein family (Heremans Schmid glycoprotein alpha2 (alpha2-HSG)) and the complement system. Biological validation included the Alberes breed. GPx and PON 1 were validated by an enzymatic assay and found to be higher and lower, respectively, in cows living in hard conditions. alpha2-HSG was validated by ELISA and found to be reduced in hard conditions. Other biomarkers of the redox status were also altered by living conditions: protein carbonyl content, superoxide dismutase (SOD) and glutathione reductase (GR). Our results show that changes in the redox system are the main adaptation of cows living in challenging environmental conditions. PMID- 22543283 TI - Pig proteomics: a review of a species in the crossroad between biomedical and food sciences. AB - The pig (Sus scrofa) is one of the most important animal species used for meat production worldwide, playing a fundamental role in numerous cultures from Southern Europe to the Pacific Islands. Additionally, it is broadly used as an experimental animal for several purposes, from physiological studies to drug testing and surgical training. Proteomics studies have covered both physiological and biomedical application studies of pig to a much greater extent than for any other farm animal. Despite this fact, no review seems to be available on the application of proteomics to production aspects in pig. The aim of this article is to provide a review on such applications of proteomics to the pig species. The article is divided in three parts. The first is dedicated to productive characterization and includes aspects related to reproduction and meat science. The second concerns the management of health and disease in production. Finally, the third part concerns the use of the pig as a model organism in biomedical research. PMID- 22543284 TI - Embryo-fetal distribution of a biopharmaceutical IgG2 during rat organogenesis. AB - Embryo-fetal biodistribution of a maternally administered humanized IgG2 in rats was evaluated by enzyme-linked immunosorbent assay in dose response and time course studies. Fetal and maternal plasma IgG2 levels increased with dose from 10 to 300mg/kg but fetal:maternal ratio decreased with increasing dose. Plasma IgG2 levels decreased in fetal rat with increasing time post-dose but more slowly than maternal levels. This difference in post-dose kinetics resulted in an increased fetal:maternal ratio with increasing days since last dose. Lastly, IgG2 in embryo fetal tissue was detected at very low levels on gestation day (GD) 10-12 and levels increased over 100-fold by GD 17. The profile of increasing IgG2 levels as gestation progressed continued in extra-embryonic fluid (GD 12-19) until the end of gestation in fetal plasma (GD 19-21). Based on the current study, there is a potential for direct effects on rat embryo-fetal development following maternal administration of a biopharmaceutical IgG2. PMID- 22543285 TI - Abstracts of the 47th Annual Congress of the Canadian Neurological Sciences Federation, June 5-8, 2012, Ottawa, Ontario, Canada. PMID- 22543286 TI - Notes from the Editor-in-Chief. PMID- 22543287 TI - Let's all go to the PROM: the case for routine patient-reported outcome measurement in Canadian healthcare. AB - Overall life expectancy in Canada is among the highest in the world and research evidence suggests that the healthcare system is part of the reason for this. However, patient waits, low international rankings and continued expenditure growth all provide a buttress against complacency. There can be little doubt that improvement can and must happen. Improvement depends on information, and more specifically information about outcomes of care. Without sound analysis of what works in the real world when applied to real patients, we have not done our jobs as stewards of the healthcare system. Current outcomes information in Canada is limited and tends to focus on measures of failure (e.g., hospital readmissions) rather than measures of success (e.g., improvement in functioning). Patient reported outcome measures (PROMs) must become part of regular data collection in the healthcare system. The importance of this is even more pronounced given that healthcare is now dominated by chronic conditions that need to be managed over long periods of time. We offer three recommendations for action: that we begin immediately to collect PROMs in elective surgery; that we start small-scale and coordinated experiments on the implementation of PROMs in care for chronic conditions; and that we convene a pan-Canadian working group to help coordinate and organize these activities. We recognize the challenges these issues raise, but our contention is that there are even greater challenges in continuing on as we are. PMID- 22543288 TI - Realizing the PROMise of PROMs. AB - McGrail and colleagues have made a strong case for embedding PROMs into the everyday healthcare system. This commentary focuses on translating their argument into policy and practice. PROMs can no longer be considered a "nice to have"; they are core elements of a patient-centred, quality-oriented healthcare system. Putting PROMs at the centre of the health information agenda signals a major shift in the orientation of the system. Their development should be mandatory, and they should be used to support quality improvement, accountability, and clinical practice redesign, particularly in primary care. PMID- 22543289 TI - The road to improving patient-reported outcomes: measures or healthcare reform? AB - Some argue that the way to improve the current health system is to ask patients about their experiences and perceptions of whether specific interventions (e.g., surgery) achieve expected health outcomes. Others argue that the way to improve health outcomes is to reform the system, particularly for those patients who suffer from complex chronic diseases and symptoms that do not fall neatly into a clinical pathway. I argue that patient reported outcome measures based on our current healthcare delivery system are necessary but not sufficient to improve patient outcomes. Ongoing dialogue, leadership and action are urgently needed to achieve a preferred future where our silo/sector/disciplinary based health system is reformed into an integrated person-centred system. PMID- 22543290 TI - PROMs: a critical step, but only one of many. AB - Bringing the patient perspective into healthcare is now widely recognized as a somewhat-urgent need, and patient-reported outcome measures (PROMs) are an excellent example of attempts to do more of this. In this commentary, the author puts PROMs into a broader perspective and then speaks more specifically about this particular initiative. The question addressed is, how well can PROMs increase patients' participation in their care? PMID- 22543291 TI - Role for PROMs data to support quality improvement across the healthcare system: an informed exchange with senior health system leaders. AB - The Institute for Healthcare Improvement's Triple Aim (initiated in 2007) and several high-level Canadian studies have made general calls to improve health system performance. Managers and administrators have been urged to tackle the challenges of quality improvement and cost control. In the lead essay, McGrail et al. point to patient-reported outcome measures (PROMs) as something worth doing, and this has been welcomed as an appropriate response to long-standing calls for action. A recent gathering of senior health system leaders explored the prospect of routinely collecting PROMs data to drive quality improvement. The symposium, Measures of Health Outcomes to Improve Performance, Value and Productivity, was held in Victoria, British Columbia, on December 9, 2010. The symposium delegates considered the challenges and issues involved in moving forward with PROMs, looking closely at the potential for enhancing the quality of data resources available for managing our healthcare system. Senior leaders and administrators from the publicly funded healthcare systems of British Columbia and western and northern Canada participated in a frank discussion of challenges and requirements for moving forward with a PROMs initiative. PMID- 22543292 TI - Can routine collection of patient reported outcome data actually improve person centered health? AB - McGrail et al. have provided an important overview of an argument for the routine collection of patient-reported outcome measures (PROM) data as a critical step toward the improvement of population health in the Canadian healthcare system. In this commentary, the authors argue that equal attention must be paid to knowledge translation in the implementation of routine collection of PROM data to ensure a high quality-clinical response if population health is to be improved. They also argue that, based on their experience in cancer, the complexity of the implementation of PROM data, particularly in chronic diseases, cannot be underestimated. Finally, the authors emphasize the need for standardization in the selection of core PROMs data for routine collection that builds on global efforts to advance the person-centredness of healthcare services and reflects the broad physical, emotional and social domains of health that will be important to capture in chronic disease. PMID- 22543293 TI - Getting ready for patient-reported outcomes measures (PROMs) in clinical practice. AB - Patient-reported outcome measures (PROMs) include reports and ratings provided by patients or their proxies about their health, functioning, health behaviours and quality of care. PROMs reflect the patient perspective and increase the comprehensiveness of outcome measurement in clinical research. There is growing interest in using PROMs in clinical practice: for screening, monitoring and improving communication at the individual level; and to aid in decision-making, monitor populations and assess quality in the aggregate. For use in clinical practice, the authors draw an analogy to getting to the prom (a North American graduation dance). Whom to go with? They recommend seeking a group of partners and developing methods and standards with national and international groups. The authors advocate for incentives to encourage broad participation. What to wear? They suggest selecting existing, well-tested PROMs and highlight the ability of dynamic questionnaires to provide tailored assessments. How to get there? The authors recommend web-based formatting of measures and results, using their system, PatientViewpoint, as an example. How to get the most out of the experience? They discuss the variety of applications of PROMs data and recommend providing clinicians with actions that they can take to mitigate problems in non clinical domains. PMID- 22543295 TI - Estimating incidence rates with misclassified disease status: a likelihood-based approach, with application to hepatitis C virus. AB - BACKGROUND: In epidemiologic research, incidence is often estimated from data arising from an imperfect diagnostic test performed at unequally spaced intervals over time. METHODS: We developed a likelihood-based method to estimate incidence when disease status is measured imperfectly and assays are performed at multiple unequally spaced visits. We assumed conditional independence, no remission, known constant levels of sensitivity and specificity, and constant incidence rates over time. The method performance was evaluated by examining its bias, accuracy (i.e., mean squared error (MSE)), and coverage probability in a simulation study of 4000 datasets, and then we applied the proposed method to a study of hepatitis C virus (HCV) infection in a cohort of pregnant women in the period 1997-2006. RESULTS: The simulation revealed that our method has minimal bias and low MSE, as well as good coverage probability of the resulting confidence intervals. In the application to HCV study, the standard incidence rate estimate which ignores the imperfections of the diagnostic test (number of events/person-years), was 13.7 new HCV cases per 1000 person-years (95% confidence interval 10.1, 17.4). The adjusted incidence estimates (obtained using our proposed method) ranged from 0.4 cases per 1000 person-years (when sensitivity and specificity were assumed to both be 95%) to 13.7 cases per 1000 person-years (when sensitivity and specificity were both 100%). The magnitude of difference between standard and adjusted estimates varied depending on specificity and sensitivity assumptions. Specificity had the greatest impact on the magnitude of bias. CONCLUSIONS: Scientists should be aware of the impact of misclassification on incidence estimates. Appropriate study design, proper selection of the diagnostic test, and adjustment for misclassification probabilities in the analysis is necessary to obtain the most accurate incidence estimates. PMID- 22543296 TI - The effect of acrylamide and nitric oxide donors on human mesenchymal progenitor cells. AB - We have examined the effects of nitric oxide donors and acrylamide on mesenchymal progenitor cell (hMPC) viability, programmed cell death (PCD) and differentiation. Acrylamide was examined at 0.5mM and 1.5mM concentrations, NOC 18 at 10MUM and SNP at 100MUM. Cell viability was assayed with MTS, PCD was determined by phosphatidylserine, caspase-9 and -3/7 and mitochondrial membrane potential assays, and osteogenic cell differentiation was evaluated by alkaline phosphatase activity (ALP) and mRNA levels for collagen type I, bone sialoprotein, ostepontin and osteocalcin. Serum-free hMPC cultures treated with 1.5mM acrylamide and SNP for 72h demonstrated reduced viability. PCD analyses revealed that SNP stimulated cells to necrosis in reactive species-dependent manner. Acrylamide (1.5mM) led to apoptosis independent of reactive species. Acrylamide and SNP reduced ALP activity and collagen type I mRNA levels but mRNA levels for bone sialoprotein and osteopontin increased in SNP treated cells and remained unchanged in acrylamide. Acrylamide had no effect on guanylate cyclase and cGMP osteogenic signaling pathway. The study suggests that acrylamide might impair bone development and remodeling upon acute or prolonged intoxication with this compound of mesenchymal cells. PMID- 22543297 TI - Kinetic modeling of beta-chloroprene metabolism: Probabilistic in vitro-in vivo extrapolation of metabolism in the lung, liver and kidneys of mice, rats and humans. AB - beta-Chloroprene (chloroprene) is carcinogenic in inhalation bioassays with B6C3F1 mice and Fischer rats, but the potential effects in humans have not been adequately characterized. In order to provide a better basis for evaluating chloroprene exposures and potential effects in humans, we have explored species and tissue differences in chloroprene metabolism. This study implemented an in vitro-in vivo extrapolation (IVIVE) approach to parameterize a physiologically based pharmacokinetic (PBPK) model for chloroprene and evaluate the influence of species and gender differences in metabolism on target tissue dosimetry. Chloroprene metabolism was determined in vitro using liver, lung and kidney microsomes from male or female mice, rats, and humans. A two compartment PK model was used to estimate metabolism parameters for chloroprene in an in vitro closed vial system, which were then extrapolated to the whole body PBPK model. Two different strategies were used to estimate parameters for the oxidative metabolism of chloroprene: a deterministic point-estimation using the Nelder-Mead nonlinear optimization algorithm and probabilistic Bayesian analysis using the Markov Chain Monte Carlo technique. Target tissue dosimetry (average amount of chloroprene metabolized in lung per day) was simulated with the PBPK model using the in vitro-based metabolism parameters. The model-predicted target tissue dosimetry, as a surrogate for a risk estimate, was similar between the two approaches; however, the latter approach provided a measure of uncertainty in the metabolism parameters and the opportunity to evaluate the impact of that uncertainty on predicted risk estimates. PMID- 22543298 TI - Lung monitoring at the bedside in mechanically ventilated patients. AB - PURPOSE OF REVIEW: It has become clear that mechanical ventilation itself can cause damage to the lung in critically ill patients, also known as ventilator induced lung injury (VILI). Insight into the mechanisms of VILI has learned that a compromise must be found between positive end-expiratory pressure (PEEP) induced alveolar recruitment and prevention of hyperinflation. Therefore, there is a need for clinicians to optimize the PEEP settings for the individual patient at the bedside. In this review, we will discuss several lung-monitoring techniques to improve patient ventilator settings. RECENT FINDINGS: Recently, new monitoring tools like electrical impedance tomography (EIT), vibration response imaging, respiratory inductive plethysmography and functional residual capacity (FRC) have been (re-)introduced in our ICU. Nowadays, FRC can be measured without the use of tracer gases and without disconnection from the ventilator. EIT is another noninvasive bedside monitoring tool that provides regional ventilation distribution images and can be used for qualitative and quantitative assessment of regional change in ventilation after a ventilator change. These new noninvasive techniques are discussed and seem promising to help clinicians to improve their ventilator settings in the individual patient at the bedside. SUMMARY: In conclusion, both FRC and EIT are promising clinical monitoring systems but clinical studies are needed to prove whether these monitors help the clinician toward effective and better ventilator management. PMID- 22543299 TI - Atomically controlled electrochemical nucleation at superionic solid electrolyte surfaces. AB - Electrochemical equilibrium and the transfer of mass and charge through interfaces at the atomic scale are of fundamental importance for the microscopic understanding of elementary physicochemical processes. Approaching atomic dimensions, phase instabilities and instrumentation limits restrict the resolution. Here we show an ultimate lateral, mass and charge resolution during electrochemical Ag phase formation at the surface of RbAg(4)I(5) superionic conductor thin films. We found that a small amount of electron donors in the solid electrolyte enables scanning tunnelling microscope measurements and atomically resolved imaging. We demonstrate that Ag critical nucleus formation is rate limiting. The Gibbs energy of this process takes discrete values and the number of atoms of the critical nucleus remains constant over a large range of applied potentials. Our approach is crucial to elucidate the mechanism of atomic switches and highlights the possibility of extending this method to a variety of other electrochemical systems. PMID- 22543300 TI - A red metallic oxide photocatalyst. AB - Light absorption across the bandgap in semiconductors is exploited in many important applications such as photovoltaics, light emitting diodes and photocatalytic conversion. Metals differ from semiconductors in that there is no energy gap separating occupied and unoccupied levels; however, it is still possible to excite electrons between bands. This is evidenced by materials with metallic properties that are also strongly coloured. An important question is whether such coloured metals could be used in light harvesting or similar applications. The high conductivity of a metal would preclude sufficient electric field being available to separate photocarriers; however, the high carrier mobility in a metal might also facilitate kinetic charge separation. Here we clearly demonstrate for the first time the use of a red metallic oxide, Sr(1 x)NbO(3) as an effective photocatalyst. The material has been used under visible light to photocatalyse the oxidation of methylene blue and both the oxidation and reduction of water assisted by appropriate sacrificial elements. PMID- 22543301 TI - P2-type Na(x)[Fe(1/2)Mn(1/2)]O2 made from earth-abundant elements for rechargeable Na batteries. AB - Rechargeable lithium batteries have risen to prominence as key devices for green and sustainable energy development. Electric vehicles, which are not equipped with an internal combustion engine, have been launched in the market. Manganese- and iron-based positive-electrode materials, such as LiMn(2)O(4) and LiFePO(4), are used in large-scale batteries for electric vehicles. Manganese and iron are abundant elements in the Earth's crust, but lithium is not. In contrast to lithium, sodium is an attractive charge carrier on the basis of elemental abundance. Recently, some layered materials, where sodium can be electrochemically and reversibly extracted/inserted, have been reported. However, their reversible capacity is typically limited to 100 mAh g(-1). Herein, we report a new electrode material, P2-Na(2/3)[Fe(1/2)Mn(1/2)]O(2), that delivers 190 mAh g(-1) of reversible capacity in the sodium cells with the electrochemically active Fe(3+)/Fe(4+) redox. These results will contribute to the development of rechargeable batteries from the earth-abundant elements operable at room temperature. PMID- 22543302 TI - Re-entrant melting as a design principle for DNA-coated colloids. AB - Colloids functionalized with DNA hold great promise as building blocks for complex self-assembling structures. However, the practical use of DNA-coated colloids (DNACCs) has been limited by the narrowness of the temperature window where the target structures are both thermodynamically stable and kinetically accessible. Here we propose a strategy to design DNACCs, whereby the colloidal suspensions crystallize on cooling and then melt on further cooling. In a phase diagram with such a re-entrant melting, kinetic trapping of the system in non target structures should be strongly suppressed. We present model calculations and simulations that show that real DNA sequences exist that should bestow this unusual phase behaviour on suitably functionalized colloidal suspensions. We present our results for binary systems, but the concepts that we develop apply to multicomponent systems and should therefore open the way towards the design of truly complex self-assembling colloidal structures. PMID- 22543303 TI - Children's recognition of advertisements on television and on Web pages. AB - In this paper we consider the issue of advertising to children. Advertising to children raises a number of concerns, in particular the effects of food advertising on children's eating habits. We point out that virtually all the research into children's understanding of advertising has focused on traditional television advertisements, but much marketing aimed at children is now via the Internet and little is known about children's awareness of advertising on the Web. One important component of understanding advertisements is the ability to distinguish advertisements from other messages, and we suggest that young children's ability to recognise advertisements on a Web page is far behind their ability to recognise advertisements on television. PMID- 22543304 TI - Genetics and epigenetics of Alzheimer's disease. AB - Alzheimer's disease (AD) is a highly prevalent condition that predominantly affects older adults. AD is a complex multifactorial disorder with a number of genetic, epigenetic and environmental factors which ultimately lead to premature neuronal death. Predictive and susceptibility genes play a role in AD. Early onset familial AD is a rare autosomal dominant disorder. Genome-wide association studies have identified many potential susceptibility genes for late-onset AD, but the clinical relevance of many of these susceptibility genes is unclear. The genetic variation by susceptibility genes plays a crucial role in determining the risk of late-onset AD, as well as the onset of the disease, the course of the AD and the therapeutic response of patients to conventional drugs for AD. The newer understanding of the epigenetics in AD has also been highlighted. Recent advances in genetics, epigenetics and pharmacogenetics of AD pose new challenges to the future management of AD. PMID- 22543305 TI - Pulmonary alveolar proteinosis treatment by whole-lung lavage. PMID- 22543306 TI - Planar Dirac electrons in magnetic quantum dots. AB - In this paper, we explore the size- and mass-dependent energy spectra and the electronic correlation of two- and three-electron graphene magnetic quantum dots. It is found that only the magnetic dots with large size can well confine the electrons. For large graphene magnetic dots with massless (ultra-relativity) electrons, the energy level structures of two Dirac electrons and even the ground state spin and angular momentum of three electrons are quite different from those of the usual semiconductor quantum dots. Also we reveal that such differences are not due to the magnetic confinement but originate from the character of the Coulomb interaction of two-component electronic wavefunctions in graphene. We reveal that the increase of the mass leads to both the crossover of the energy spectrum structures from the ultra-relativity to non-relativity ones and the increasing of the crystallization. The results are helpful for the understanding of the mass and size effects and may be useful in controlling the few-electron states in graphene-based nanodevices. PMID- 22543307 TI - Deca-heterosubstituted corannulenes. AB - The Cu(I)-catalyzed Ullmann condensation reaction between aliphatic alcohols and sym-pentachlorocorannulene provides a convenient entry to 1,3,5,7,9 pentaalkoxycorannulenes. The latter are easily converted to novel deca heterosubstituted derivatives, such as 1,3,5,7,9-penta-X-2,4,6,8,10-penta-Y corannulenes by electrophilic aromatic substitution. PMID- 22543308 TI - Logic gates for multiplexed analysis of Hg2+ and Ag+. AB - The design of devices with multiple functions, simple handling procedures and sufficient sensitivity has drawn great interests in the field of analysis. Metal nucleotide based pairs, such as T-Hg(2+)-T and C-Ag(+)-C complexes accompanied by SYBR Green I (SG), are used to selectively bind duplex-strand DNA by observing a bright fluorescence signal in this work, thus yielding a simple method for the rapid detection of Hg(2+) and Ag(+) without a complex labeling process. Based on this principle, 'OR' and 'AND' logic gates for the multiplexed analysis of Hg(2+) and Ag(+) were developed, and their practical application for the detection of Hg(2+) and Ag(+) in drinking water was reported. PMID- 22543309 TI - Subnanometric stabilization of plasmon-enhanced optical microscopy. AB - We have demonstrated subnanometric stabilization of tip-enhanced optical microscopy under ambient condition. Time-dependent thermal drift of a plasmonic metallic tip was optically sensed at subnanometer scale, and was compensated in real-time. In addition, mechanically induced displacement of the tip, which usually occurs when the amount of tip-applied force varies, was also compensated in situ. The stabilization of tip-enhanced optical microscopy enables us to perform long-time and robust measurement without any degradation of optical signal, resulting in true nanometric optical imaging with high reproducibility and high precision. The technique presented is applicable for AFM-based nanoindentation with subnanometric precision. PMID- 22543310 TI - A novel reporter system for bacterial and mammalian cells based on the non ribosomal peptide indigoidine. AB - The biosynthesis of non-ribosomal peptides, many of which have pharmaceutical activities, is an evolutionary privilege of microorganisms. Capitalizing on the universal set of the Streptomyces lavendulae non-ribosomal peptide synthase BpsA and the Streptomyces verticillus 4'-phosphopantetheinyl transferase Svp, we have engineered Escherichia coli as well as mammalian cells, including human stem cells, to produce the blue 3,3'-bipyridyl pigment keto-indigoidine and the reduced colorless but fluorescent leuco-isoform. Detailed characterization of a tailored substrate-free chromogenic assay and FACS analysis showed that indigoidine's blue color and fluorescence could be reliably profiled in bacteria and mammalian cells using standard multiwell-compatible detection equipment. Besides serving as an inexpensive, reliable, versatile and easy-to-assay cross kingdom reporter system, the potential of having mammalian cells produce non ribosomal peptides, preferably ones with biopharmaceutical activities, may provide novel treatment opportunities in future gene- and cell-based therapies. PMID- 22543311 TI - Double fire tachycardia. PMID- 22543312 TI - The antimony(III)-bridged heteropolyanion sandwich dimers [Sb(II3(A-alpha XW9O34)2]11- (X = SiIV, GeIV and C-shaped double-sandwich [SbIII6O2(PW6O26)(A alpha-PW9O34)2]15-. AB - Interaction of potassium antimony(iii) tartrate hydrate K(2)(SbC(4)H(2)O(6))(2).3H(2)O with the trilacunary Keggin derivatives [A-alpha XW(9)O(34)](10-) (X = Si(IV), Ge(IV)) and [A-alpha-PW(9)O(34)](9-) in aqueous acidic medium (pH 4.8) resulted in three novel polyanions, [Sb(3)(A-alpha XW(9)O(34))(2)](11-) (X = Si(IV) (1), Ge(IV) (2)) and [Sb(6)O(2)(A-PW(6)O(26))(A alpha-PW(9)O(34))(2)](15-) (3), which were isolated as the hydrated potassium salts K(11)[Sb(3)(A-alpha-XW(9)O(34))(2)].31H(2)O (X = Si(IV) (K-1), Ge(IV) (K 2)) and the mixed potassium-sodium salt K(14)Na[Sb(6)O(2)(A-PW(6)O(26))(A-alpha PW(9)O(34))(2)].61H(2)O (KNa-3) salts, respectively, and characterized by single crystal X-ray diffraction, IR spectroscopy, as well as elemental and thermogravimetric analyses. The Sb(III)-containing polyanions 1-3 possess unique structural features, as they represent the first examples of sandwich-type POMs with trigonal-pyramidal Sb(III)O(3) linkers. The stability of 1-3 in aqueous media was investigated by multinuclear ((183)W, (31)P) NMR and UV-Vis spectroscopy. PMID- 22543313 TI - Water induced protonation of amine-terminated micelles for direct syntheses of ZnO quantum dots and their cytotoxicity towards cancer. AB - This work designs a new strategy for the direct synthesis of different zinc oxide (ZnO) nanostructures at low temperatures. Micelles of dodecylamine (DDA) assembled in an ethanol-water system have been explored as a template to direct the growth of the ZnO nanostructures. The key species for the formation of the ZnO nanostructures, OH(-), can be provided by the water-induced protonation of DDA. The pH of the reaction micro-environment can be regulated by changing the input amount of water and DDA. By controlling the reaction temperature and pH, various ZnO nanostructures, i.e. quantum dots with green or yellow-green emissions, have been prepared. The relationship of the optical properties and the synthetic conditions has been further discussed. This strategy realizes the convenient preparation of ZnO QDs, indicating the potential prospects in the nanotechnology field for their low-cost synthesis. Meanwhile, the cellular toxicity study of ZnO nanoparticles toward cancer cells, including leukemia K562 and K562/A02 cells as well as HepG2 cells, indicates a selective cytotoxic effect of ZnO QDs against a broad range of human cancer cell lines. PMID- 22543314 TI - Quadrivalent meningococcal conjugated vaccine: a routine or selective vaccine in Europe? PMID- 22543315 TI - ADLs and PRMDs. AB - The article by Lamontagne and Belanger in this issue of the journal describes the development of a questionnaire concerning performance-related musculoskeletal disorders (PRMDs) in musicians. It is well designed and deserves careful reading by clinicians and researchers alike. The authors are very clear in stating that their focus was strictly on musculoskeletal problems that are the result of playing an instrument. This is a perfectly reasonable approach to take in the development of a questionnaire that will be used for research purposes. It's often best to start out doing research with a relatively narrow definition of the problem, gain a solid understanding of that particular system, and then broaden the question. PMID- 22543316 TI - Effects of supplemental training on fitness and aesthetic competence parameters in contemporary dance: a randomised controlled trial. AB - Within aesthetic sports such as figure skating and rhythmic gymnastics, physical fitness has been shown to have positive benefits on performance outcomes. Presently the link between physical fitness and aesthetic contemporary dance performance has not been demonstrated within an intervention study. In this study, 24 females engaged in contemporary dance (age 27 +/- 5.9 yrs; height 165.3 +/- 4.8 cm; weight 59.2 +/- 7.6 kg) were recruited and randomly assigned to either an exercise (n = 12) or a control group (n = 12). Three dancers withdrew during the study. The intervention group completed a 6-week conditioning programme comprising two 1-hr sessions of circuit and vibration training per week. The circuit training focused on local muscular endurance and aerobic conditioning and vibration training protocol concentrated on power. Repeated measures ANOVA revealed significant increases for the conditioning group in lower body muscular power (11%), upper body muscular endurance (22%), aerobic fitness (11%), and aesthetic competence (12%) (p < 0.05). The control group reported decreases in all the fitness parameters with the exception of aerobic fitness as well as a decrease in aesthetic competence (7%). A 6-week circuit and vibration training programme, which supplemented normal dance commitments, revealed significant increases in selected fitness components and a concomitant increase in aesthetic competence in contemporary professional and student dancers. PMID- 22543317 TI - Physical and mental health of different types of orchestra musicians compared to other professions. AB - OBEJECTS: This study examined the physical and mental health of orchestra musicians of different types of orchestras compared to a reference sample of the general population and of two other professions. METHODS: Professional musicians (n = 429) from nine opera and/or concert orchestras were surveyed with the Short Form-12 general health questionnaire (SF-12). Data were compared with a reference sample (n = 2805) with a sample of physicians (n = 549) and aircraft manufacturers (n = 822). RESULTS: Compared to the reference sample and the two other professional groups, the musicians had a higher physical health score: 53.07 (SD 5.89) vs 49.03 (SD 9.35) reference, 51.26 (SD 7.53) physicians, and 49.31 (SD 7.99) aircraft manufacturers. The musicians' mental health score was lower compared to the reference sample but did not differ from the other professional groups: 48.33 (SD 9.52) for musicians vs 52.24 (SD 8.10) reference, 48.26 (SD 10.06) physicians, and 48.54 (SD 9.59) aircraft manufacturers. Physical health but not mental health decreased with age in all groups. In physical and mental health, women scored lower than men. There was no significant difference in physical and mental health scores between musicians of concert and opera orchestras. Age and gender accounted for 3.6% of the variance of the physical health score, but none of the demographic characteristics or orchestral roles and functions was predictive for mental health scores. CONCLUSIONS: Musicians report better physical but poorer mental health than the general population, but they did not differ in mental health scores from physicians or aircraft manufacturers. PMID- 22543318 TI - Livelihood vs. life: the occupational well-being of women musician survivors of breast cancer. AB - The Life and Livelihood Study was designed to describe and understand the experience of women musicians treated for breast cancer. This report focuses on Phase I of the study, a web-based survey that examined subjects' physical symptoms and side effects following breast cancer treatment. Subjects were recruited nationally, using advertisements in musicians' publications and presentations at national meetings. Subjects were asked about specific side effects or symptoms they had experienced, their severity and duration, and the effects of symptoms on their capacity to make music. Subjects were also asked what aspect of their breast cancer treatment they associated with each symptom and were invited to provide comments. A total of 321 individuals logged on: 100 met all inclusion criteria. Of these, 90 completed the entire survey. Commonly reported symptoms included fatigue (70%), problems with cognition (53%), limitations in upper body movement (51%), and pain (45%). Many reported that their symptoms were of moderate or greater intensity, and that they persisted for >12 months or were ongoing. The survey documented that many subjects experienced diminished capacity to function as musicians, especially due to pain, limitations in upper body and extremity movement, numbness in the chest and/or arms, contracture/fibrosis, and shortness of breath. These findings are consistent with emerging studies that describe long-term effects of breast cancer treatments. In planning for breast cancer treatment, rehabilitation and survivorship, consideration should be given to how treatment is likely to affect fitness for ongoing professional work. PMID- 22543319 TI - Monitoring stage fright outside the laboratory: an example in a professional musician using wearable sensors. AB - We implemented and tested a wearable sensor system to measure patterns of stress responses in a professional musician under public performance conditions. Using this sensor system, we monitored the cellist's heart activity, the motion of multiple body parts, and their gradual changes during three repeated performances of a skill-demanding piece in front of a professional audience. From the cellist and her teachers, we collected stage fright self-reports and performance ratings that were related to our sensor data analysis results. Concomitant to changes in body motion and heart rate, the cellist perceived a reduction in stage fright. Performance quality was objectively improved, as technical playing errors decreased throughout repeated renditions. In particular, from performance 1 to 3, the wearable sensors measured a significant increase in the cellist's bowing motion dynamics of approximately 6% and a decrease in heart rate. Bowing motion showed a marginal correlation to the observed heart rate patterns during playing. The wearable system did not interfere with the cellist's performance, thereby allowing investigation of stress responses during natural public performances. PMID- 22543320 TI - Noise exposure levels for musicians during rehearsal and performance times. AB - OBJECTIVES: The purpose of this study was to determine daily noise doses and 8 hour time weighted averages for rock band musicians, crew members, and spectators during a typical rehearsal and performance using both Occupational Safety and Health Administration (OSHA) and National Institute of Occupational Safety and Health (NIOSH) measurement criteria. DESIGN: Personal noise dosimetry was completed on five members of a rock band during one 2-hr rehearsal and one 4-hr performance. Time-weighted averages (TWA) and daily dose values were calculated using both OSHA and NIOSH criteria and compared to industry guidelines for enrollment in hearing conservation programs and the use of hearing protection devices. RESULTS: TWA values ranged from 84.3 to 90.4 dBA (OSHA) and from 90.0 to 96.4 dBA (NIOSH) during the rehearsal. The same values ranged from 91.0 to 99.7 dBA (OSHA) and 94.0 to 102.8 dBA (NIOSH) for the performance. During the rehearsal, daily noise doses ranged from 45.54% to 106.7% (OSHA) and from 317.74% to 1396.07% (NIOSH). During the performance, doses ranged from 114.66% to 382.49% (OSHA) and from 793.31% to 5970.15% (NIOSH). CONCLUSIONS: The musicians in this study were exposed to dangerously high levels of noise and should be enrolled in a hearing conservation programs. Hearing protection devices should be worn, especially during performances. The OSHA measurement criteria yielded values significantly more conservative than those produced by NIOSH criteria. Audiologists should counsel musician-patients about the hazards of excessive noise (music) exposure and how to protect their hearing. PMID- 22543321 TI - Development and validation of a questionnaire on musculoskeletal pain in musicians. AB - Musculoskeletal pain is known to be prevalent among musicians. Unfortunately, there are a lack of standard measures to quantify perceived pain in this population. The principal objective of the present study was to develop a self reported questionnaire targeting musculoskeletal pain that is specific to musical activity. The Musculoskeletal Pain Questionnaire for Musicians (MPQM) is composed of 10 items investigating diverse areas related to musculoskeletal pain, divided into three components: a set of items related to disability associated with pain (4 items, component 1), a second one related to pain intensity (4 items, component 2), and a third one related to the frequency and duration of pain episodes (2 items, component 3). Thirty-one professional musicians, from the province of Quebec (Canada), entered the study and answered to the MPQM. Data collected from the MPQM was submitted to a principal component analysis. It found that results from the 10 items of the questionnaire were structured around three factors: pain-related disability (32.71% of variance), pain intensity (25.42% of variance), and frequency and duration of pain (18.2% of variance). Convergent validity was also tested, and an adequate correlation was obtained between the MPQM and the Chronic Pain Grade Questionnaire (r = 0.65, p = <0.01). Internal consistency for the whole instrument was measured and supported by a Cronbach's alpha of 0.768. Because the MPQM shows adequate psychometric characteristics, it is believed that it could be helpful in research on the correlates of musculoskeletal pain in musicians. PMID- 22543323 TI - Increment of fatigue, depression, and stage fright during the first year of high level education in music students. AB - In a recent Letter to the Editor, Grant and Pilz propose the hypothesis of a contribution of very low serum 25-hydroxyvitamin D levels to provoke Wolfgang Amadeus Mozart's death. Mozart died on the 5th of December, 1791, aged 35, probably due to an infection which, very likely, had low vitamin D levels as an important risk factor. According to Grant and Pilz, the lack of vitamin D is to be attributed, in the case of Mozart's, to insufficient exposure to sunlight, because he "did much of his composing at night, so would have slept during much of the day." Historical evidence, however, disproves the nocturnal habits of the Austrian composer. PMID- 22543322 TI - Increment of fatigue, depression, and stage fright during the first year of high level education in music students. AB - BACKGROUND: Public opinion associates music performance with pleasure, relaxation, and entertainment. Nevertheless, several studies have shown that professional musicians and music students are often affected by work-related burdens. These are closely related to stress and anxiety. OBJECTIVE: Scrutinizing specific health strains and work attitudes of music students during their freshman year of high-level education. METHODS: One hundred five students in three Swiss music universities were part of a longitudinal study using standardized assessment questionnaires. Before and after their first study year, some custom-made questionnaires designed to fit the particular work environment of musicians were used together with the already validated inquiry instruments. RESULTS: Fatigue, depression, and stage fright increased significantly. CONCLUSIONS: Our results indicate more study is needed and attempts should be made to minimize the stress level, improve the students' ability to cope with stress, and otherwise reduce their risk for injury. This appears particularly important considering the long-term negative effects of stressors on individuals' health as revealed by modern research. PMID- 22543324 TI - Healthcare systems in Canada. Foreword. PMID- 22543325 TI - How long can we enjoy B-player status? PMID- 22543326 TI - Chartbook: shining a light on the quality of healthcare in Canada: what can be learned to catalyze improvements in healthcare quality? AB - This paper provides a reflection on the findings of Canada's first-ever chartbook on the quality of healthcare in Canada. Quality of Healthcare in Canada: A Chartbook was published in 2010 by the Canadian Health Services Research Foundation in partnership with the Canadian Institute for Health Information and the Canadian Patient Safety Institute, and with support from Statistics Canada. This paper, by the chartbook authors (Sutherland and Leatherman) and colleagues (Law, Verma and Petersen), presents selected key findings and lessons from the chartbook and aims to serve as a catalyst for ideas and discussion in the papers that follow. The chartbook identified a lack of common language and indicators on quality across Canada's provinces and territories, underscoring the need to create and coordinate core measures. The Canadian chartbook and this issue of Healthcare Papers provide an update on the existing quality measures and the state of healthcare quality in Canada, and create the opportunity for jurisdictions to learn from one another and to contemplate the steps required to improve quality across the country. PMID- 22543327 TI - Can a book of charts catalyze improvements in quality? Views of a healthcare alchemist. AB - This commentary reviews international evidence about the impact of public reporting on better care and outcomes, outlines conditions under which publicly available performance information can become a potent catalyst to precipitate improvements in quality and the optimal conditions in healthcare systems to ensure that such a catalyst results in a desirable reaction. PMID- 22543328 TI - Measuring and reporting on quality of care and patient safety in Canada: focusing on what matters. AB - Quality of Healthcare in Canada: A Chartbook is a comprehensive, useful reference that organizes the multiple measures it contains around a well-established framework. It documents Canada's performance relative to several comparator countries and over time on a large number of indicators of care quality. However, the chartbook does not identify where the gaps are in the measurement of quality of care and patient safety, and it is limited in its ability to represent the measurement required to monitor current and upcoming policy initiatives in the field of healthcare quality. Further, it fails to represent fully the perspective of the patient or to incorporate the progress made in measuring patient-centred quality of care. The authors propose four ways forward for strengthening the measurement of healthcare quality and patient safety in Canada: (1) the standardized collection of patient-reported outcome measures; (2) a focus on the standardized measurement of patient safety across the country at micro-, meso- and macro-levels; (3) the measurement of multiple morbidities and of the quality of care provided to patients with multiple chronic conditions; and (4) a design of measurement systems in ways that reflect the perspectives of patients and citizens. PMID- 22543329 TI - Quality of healthcare in Canada: potential for a pan-Canadian measurement standard. AB - Saskatchewan has embarked on a journey to transform the quality of its healthcare. Through our experiences, we have learned many lessons that could be useful to the development of a pan-Canadian system of measurement aimed at bettering care. However, measurement in isolation is insufficient to achieve improved healthcare. The system needs to be linked to a common improvement agenda. Creating a systematic approach to improvement is only possible through developing the capacities of leaders and front-line staff, by alignment through a common purpose, by focusing on value from the perspective of the customer and by creating measures backed by best practice that are transparent and accountable. PMID- 22543330 TI - Incentives required to drive change. AB - The authors of "Chartbook: Shining a Light on the Quality of Healthcare in Canada," focus on building a Canadian healthcare performance baseline, highlighting opportunities to improve the system and then raising policy questions. This is a thoughtful approach to gaining awareness of the relative performance across the Canadian healthcare system. In essence, it is necessary to first establish a felt need, identify areas to improve and then ensure the system will implement the necessary changes to improve. The authors build a reasonable case for why improvements are necessary, and they identify key barriers that must be removed to actually realize improvements and offer a wide range of policy recommendations. However, not all of these recommendations are focused on the key point of ensuring that there are incentives in place to drive participants to implement changes. PMID- 22543332 TI - High pressure luminescence spectra of CaMoO4:Pr3+. AB - Steady state and time resolved luminescence measurements of CaMoO(4) doped with Pr(3+) as a function of hydrostatic pressure in the 1-175 kbar range are presented. It has been observed that with increasing pressure the spectral features shift towards lower energies, the decay times of both (3)P(0) and (1)D(2) emitting levels become shorter and the intensity of the (3)P(0) emission decreases to complete quenching at about 110 kbar, whereas that of the (1)D(2) emission increases in the 0-100 kbar range and then rapidly decreases when the pressure exceeds 127 kbar. A variation of the structure of the spectral manifolds indicates that a pressure induced phase transition of the host lattice occurs in the 80-100 kbar range. The quenching of the luminescence and the shortening of the decay times have been accounted for by means of a model that takes into account the role played by a praseodymium trapped exciton in the excited state dynamics of the investigated material. PMID- 22543333 TI - Clinical labeling and imaging of transplanted CD133+/CD34+ stem cells in patients with ischemic heart disease. AB - The application of somatic stem cells has been shown to support the recovery of the myocardium in end-stage heart failure. A novel method for the intraoperative isolation and labeling of bone marrow-derived stem cells was established. After induction of general anesthesia, up to 400 mL of bone marrow were harvested from the posterior iliac crest and processed in the operating room under good manufacturing practice conditions by means of the automated cell-selection device Clini-MACS (Miltenyi Biotec). We subsequently injected autologous CD133+ and CD34+ stem cells in a predefined pattern around the laser channels in patients undergoing coronary artery bypass surgery and transmyocardial laser procedures. Intraoperative isolation and labeling is an effective cell-separation tool for the future, considering that novel cell markers can be promising new candidates for cell therapy. PMID- 22543334 TI - Quality of life after children undergo a radical arterial switch operation at an older age. AB - OBJECTIVE: The goal of the study was to evaluate the quality of life of children after the older corrective arterial switch operation (ASO) by means of the Pediatric Quality of Life Inventory (PedsQL), version 4.0. METHODS: The records of 86 patients who had complete transposition of the great arteries plus a nonrestrictive ventricular septal defect, or a Taussig-Bing anomaly, and severe pulmonary arterial hypertension, and who underwent a corrective ASO at an older age (>6 months) between May 2000 and October 2008 were reviewed retrospectively. Eighty survivors were followed up, and the health-related quality of life of the survivors was evaluated with the PedsQL, version 4.0. RESULTS: There were 6 hospital deaths. The mean (SD) follow-up interval was 3.5 +/- 2.3 years, and the mean age at last visit was 7.0 +/- 1.2 years. Two late deaths occurred, and 8 patients were lost to follow-up. Patients who underwent a corrective ASO at an older age showed acceptable scores for all scales, and they were all comparable with those of a healthy population. CONCLUSIONS: Our data suggest that the quality of life of children who undergo a corrective ASO at an older age (>6 months) is acceptable, compared with that of healthy children in China. PMID- 22543335 TI - Metastasizing primary atrial leiomyosarcoma causing a functional high-grade mitral stenosis. AB - We report the case of a 43-year-old man who presented with a primary cardiac leiomyosarcoma and multiple metastases. Despite the severely poor prognosis, cardiac surgery was performed as part of a multidisciplinary palliative approach, which paved the way for further chemotherapy and radiation therapy. PMID- 22543336 TI - Surgical strategy in patients with atrial septal defect and severe pulmonary hypertension. AB - The aim of the study was to review our experience with atrial septal defect (ASD) closure with a fenestrated patch in patients with severe pulmonary hypertension. Between July 2004 and February 2009, 16 patients with isolated ASD underwent closure with a fenestrated patch. All patients had a secundum type ASD and severe pulmonary hypertension. Patients ranged in age from 6 to 57 years (mean +/- SD, 34.9 +/- 13.5 years). The follow-up period was 9 to 59 months (mean, 34.5 +/- 13.1 months). The ranges of preoperative systolic and pulmonary arterial pressures were 63 to 119 mm Hg (mean, 83.8 +/- 13.9 mm Hg) and 37 to 77 mm Hg (mean, 51.1 +/- 10.1 mm Hg). The ranges of preoperative values for the ratio of the pulmonary flow to the systemic flow and for pulmonary arterial resistance were 1.1 to 2.7 (mean, 1.95 +/- 0.5) and 3.9 to 16.7 Wood units (mean, 9.8 +/- 2.9 Wood units), respectively. There was no early or late mortality. Tricuspid annuloplasty was performed in 14 patients (87.5%). The peak tricuspid regurgitation gradient and the ratio of the systolic pulmonary artery pressure to the systemic arterial pressure were decreased in all patients. The New York Heart Association class and the grade of tricuspid regurgitation were improved in 13 patients (81.2%) and 15 patients (93.7%), respectively. ASD closure in patients with severe pulmonary hypertension can be performed safely if we create fenestration. Tricuspid annuloplasty and a Cox maze procedure may improve the clinical result. Close observation and follow-up will be needed to validate the long-term benefits. PMID- 22543337 TI - Ligation of a fistula between the left main coronary artery and both the pulmonary artery and the right ventricle. AB - The frequency of coronary artery fistula among all coronary angiography patients is 0.1% to 0.2%; however, involvement of both the pulmonary artery and the right ventricle is a rare clinical entity. A 53-year-old man patient was admitted to our clinic with rarely occurring chest pain, palpitations, and dyspnea. A coronary angiogram showed a fistula between the left main coronary artery and both the pulmonary artery and the right ventricle. We performed a ligation of this fistula without cardiopulmonary bypass. Aorta and right ventricle sutures were made, and the proximal and distal portions of the fistula were obliterated with 5-0 Prolene sutures and previously prepared Teflon felt. The patient recovered and was discharged without any complications. The surgical indications for coronary artery fistulas are symptomatic disease, an aneurysmic coronary artery, signs of heart failure, and ischemia. The surgical options in such cases- depending on whether the fistula is complicated or not--are simple ligation or transarterial ligation under cardiopulmonary bypass. PMID- 22543338 TI - Review of a 13-year single-center experience with minimally invasive direct coronary artery bypass as the primary surgical treatment of coronary artery disease. AB - BACKGROUND AND AIM OF THE STUDY: In this study, we review our experience with 1768 minimally invasive direct coronary artery bypass (MIDCAB) operations. The focus is on long-term outcome with more than 10 years of follow-up. METHODS: All patients undergoing standard MIDCAB between 1996 and 2009 were included. For all 1768 patients, pre-, intra-, and postoperative data could be completed. Long-term follow-up information about health status, major adverse cardiac and cerebrovascular events (MACCE), and freedom from angina was collected annually via questionnaire or personal contact. Five-year follow-up is available for 1313 patients, and 10-year-follow-up is available for 748 patients. A multivariate Cox regression analysis was performed to determine risk factors for long-term outcome. RESULTS: Mean age was 63.4 +/- 10.8 years, mean ejection fraction was 60.0% +/- 14.2%, and perioperative mortality risk calculated by logistic EuroSCORE was 3.8 +/- 6.2%. In 31 patients (1.75%) intraoperative conversion to sternotomy was necessary. Early postoperative mortality was 0.8% (15 patients); 0.4% (7 patients) had a perioperative stroke. Seven hundred twelve patients received routine postoperative angiogram, showing 95.5% early graft patency. Short-term target vessel reintervention was needed in 59 patients (3.3%) (11 percutaneous transluminal coronary angioplasty (PTCA)/stent, 48 re-operation). Kaplan-Meyer analysis revealed a 5-year survival rate of 88.3% (95% confidence interval [CI], 86.6% to 89.9%) and a 10-year-survival rate of 76.6% (95% CI, 73.5% to 78.7%). The freedom from MACCE and angina after 5 and 10 years was 85.3% (95% CI, 83.5% to 87.1%) and 70.9% (95% CI, 68.1% to 73.7%), respectively. CONCLUSIONS: MIDCAB is a safe operation with low postoperative mortality and morbidity. With excellent short-term and long-term results, it is a very good alternative compared to both percutaneous coronary intervention (PCI) and conventional surgery. PMID- 22543340 TI - Computerized tomography may underestimate the patency of internal thoracic artery composite grafts. AB - BACKGROUND: Multidetector-row computerized tomography (MDCT) has been regarded as useful for noninvasive assessment of the bypass grafts after coronary artery bypass grafting (CABG), but there have been few reports validating its accuracy in assessment of composite arterial graft patency. METHODS: In 108 patients who underwent CABG with a Y-composite graft made of bilateral internal thoracic arteries (ITAs), early postoperative (mean interval, 4.9 months) MDCT findings were compared with the findings of subsequent conventional coronary angiography (19 patients, mean 4.7 months after initial MDCT) or later MDCT (89 patients, mean 31.0 months after surgery). A total of 248 grafts with 409 distal anastomoses (mean 3.8/patient) were assessed. RESULTS: In the early MDCT, the left ITA was patent in 94.4%. The right ITA with multiple sequential anastomoses was completely patent in 73.8% and partially patent in 21.4%. Discrepancy of findings between early computed tomography (CT) and later imaging studies was found in 18 patients (16.7%). Fourteen (42.4%, 4 left and 10 right ITAs) among the 33 initially nonvisualized grafts showed improved patency in later MDCT or conventional angiogram. The positive predictive value of the early MDCT for ITA composite graft occlusion was calculated at 57.6% or lower, whereas the negative predictive value was 97.8% or higher. CONCLUSIONS: For a composite graft made of bilateral ITAs, especially for those with multiple sequential anastomoses, MDCT may reflect only the functional patency and underestimate the actual anatomic patency. PMID- 22543339 TI - Primary coronary artery bypass surgery in the presence of decreasing preoperative renal function: effect on short-term outcomes. AB - BACKGROUND: This study evaluated the impact of decreasing renal function on short term outcomes in patients undergoing primary coronary artery bypass grafting (CABG). METHODS: The study period was from February 1999 to February 2009. Data on 4050 patients undergoing primary CABG were prospectively collected and analyzed retrospectively. The study population was divided into 3 groups: the CABG:N group, patients with preoperative serum creatinine levels <2 mg/dL (n = 3947); the CABG:RF group, patients with preoperative creatinine levels >2 mg/dL (n = 87); and the CABG:D group, patients on dialysis (n = 16). RESULTS: The significant differences between the groups (CABG:D > CABG:RF > CABG:N) in short term outcomes were with respect to blood product use (P < .001), postoperative acute myocardial infarction (P < .001), pulmonary complications (P .001), infection (P < .001), and death (P < .001). The risk of short-term death (30 days) in the CABG:D group (4/16, 25%) was 25 times greater than that in the CABG:N group (38/3947, 0.96%). CONCLUSION: CABG in the presence of renal failure is associated with significant morbidity and mortality. PMID- 22543341 TI - Surgery for type B dissection using a short-stented elephant trunk procedure. AB - BACKGROUND: Stent grafting is a very important treatment for type B dissection. Some patients are unsuitable for endograft repair because of inadequate proximal and/or distal fixation zones. We reviewed our experience of proximal descending thoracic replacement combined with short-stented elephant trunk implantation for type B dissection for patients without adequate fixation zones for endografts. METHODS: Twenty-one patients with type B dissection (10 acute, 11 chronic) underwent this procedure between August 2003 and December 2007. After replacement of the proximal descending thoracic aorta, a short-stented elephant trunk was implanted into the residual descending thoracic aorta. The residual false lumen was evaluated post-operatively using computed tomography (CT) scans. RESULTS: There were no in-hospital deaths. One death was observed during a mean follow-up of 69 +/- 15 months. One patient with preoperative shock suffered paraparesis but recovered postoperatively. One patient had paraplegia and was lost to follow-up. Cerebral hemorrhage was observed in 1 patient, but he recovered. Thrombus obliteration of the false lumen around the stented elephant trunk was observed in 19 patients (95%) and at the diaphragmatic level in 17 patients (85%) during follow-up. CONCLUSION: Replacement of the proximal descending thoracic aorta combined with short-stented elephant trunk implantation was a suitable alternative for type B dissection for patients without adequate fixation zones for endografts (particularly for young subjects). This procedure allowed enlargement of the true lumen, re-establishment of the true lumen, induction of thrombosis of the false lumen, and shrinkage of the aorta. Injury to the spinal cord, however, was an intractable problem. PMID- 22543342 TI - The use of posterior pericardiotomy technique to prevent postoperative pericardial effusion in cardiac surgery. AB - AIM: The goal was to determine the effectiveness of the posterior pericardiotomy technique in preventing the development of early and late pericardial effusions (PEs) and to determine the role of anxiety level for the detection of late pericardial tamponade (PT). MATERIALS AND METHODS: We divided 100 patients randomly into 2 groups, the posterior pericardiotomy group (n = 50) and the control group (n = 50). All patients undergoing coronary artery bypass grafting surgery (CABG), valvular heart surgery, or combined valvular and CABG surgeries were included. The posterior pericardiotomy technique was performed in the first group of 50 patients. Evaluations completed preoperatively, postoperatively on day 1, before discharge, and on postoperative days 5 and 30 included electrocardiographic study, chest radiography, echocardiographic study, and evaluation of the patient's anxiety level. Postoperative causes of morbidity and durations of intensive care unit and hospital stays were recorded. RESULTS: The 2 groups were not significantly different with respect to demographic and operative data (P > .05). Echocardiography evaluations revealed no significant differences between the groups preoperatively; however, before discharge the control group had a significantly higher number of patients with moderate, large, and very large PEs compared with the pericardiotomy group (P < .01). There were 6 cases of late PT in the control group, whereas there were none in the pericardiotomy group (P < .05). Before discharge and on postoperative day 15, the patients in the pericardiotomy group showed significant improvement in anxiety levels (P = .03 and .004, respectively). No differences in postoperative complications were observed between the 2 groups. CONCLUSION: Pericardiotomy is a simple, safe, and effective method for reducing the incidence of PE and late PT after cardiac surgery. It also has the potential to provide a better quality of life. PMID- 22543343 TI - Modified reposition of the JOTEC prosthesis in the frozen elephant trunk procedure. AB - We describe a procedure in which we inserted a modified JOTEC graft following a known complication in the case of a 78-year-old male patient who underwent surgery with the frozen elephant trunk technique for an acute Stanford type A aortic dissection. PMID- 22543344 TI - Nitroglycerin and sodium nitroprusside: potential contributors to postoperative bleeding? AB - Postoperative bleeding is common in patients undergoing cardiac surgery with cardiopulmonary bypass. Most cases of severe postoperative bleeding not due to incomplete surgical hemostasis are related to acquired transient platelet dysfunction mediated by platelet activation during contact with the synthetic surfaces of the cardiopulmonary bypass equipment. Antihypertensive agents nitroglycerin and sodium nitroprusside have been shown to have platelet inhibitory properties, yet the clinical consequence in terms of postoperative bleeding has been little studied. Knowing that cardiopulmonary bypass causes platelet dysfunction, it is prudent for physicians to be aware of the additional platelet inhibition caused by these commonly used antihypertensive agents. PMID- 22543345 TI - Clinical and pathologic comparison of simple left-to-right shunt congenital heart disease and transposition of the great arteries with ventricular septal defect. AB - BACKGROUND: This study aimed to compare clinical and pathologic data for selected patients with congenital heart disease (CHD) and severe pulmonary hypertension (PH) treated with a diagnostic-treatment-and-repair strategy and to compare results for patients with pulmonary vascular disease (PVD) with simple left-to right shunt CHD with patients with transposition of the great arteries (TGA) and ventricular septal defect (VSD). METHODS: Group I comprised 38 patients with simple left-to-right shunt CHD and severe PH; group II included 11 older patients with TGA with VSD and severe PH; and group III comprised 6 autopsy cases of individuals with a normal circulation. The nature of the pulmonary arteries was determined by the Heath-Edwards classification system. All specimens were quantitatively analyzed. RESULTS: Group I showed 31 patients with a change to grade I, 3 patients were grade II, 3 patients were grade III, and only 1 patient was grade IV. Group II showed 7 patients with a change to grade I, 2 patients were grade II, 1 patient was grade III, and only 1 patient was grade IV. The media wall thickness percentage (%MT), the media wall area percentage (%MS), and arteriole density were significantly higher in groups I and II than in group III. %MS was significantly higher in group II than in group I; no significant differences in %MT and arteriole density could be found between groups I and II. CONCLUSIONS: The PVD in these selected patients with CHD and severe PH who were cared for with a diagnostic-treatment-and-repair strategy is generally reversible, and the changes in PVD in the patients with TGA and VSD were similar to those in the patients with simple left-to-right shunt CHD. PMID- 22543346 TI - The use of the glucocorticoid receptor antagonist mifepristone in Cushing's syndrome. AB - PURPOSE OF REVIEW: Mifepristone is the first and only available glucocorticoid receptor antagonist. Cushing's syndrome is a rare disease, responsible for increased morbidity and mortality. The treatment of Cushing's syndrome is far from perfect. The aim of this review is to better define the merits and pitfalls of mifepristone in treating Cushing's syndrome, and try to determine its potential roles in the treatment of hypercortisolism. RECENT FINDINGS: Only case reports or series based on a low number of patients had been reported in the literature. A recent retrospective European Study based on about 20 patients with Cushing's syndrome gave more precise data about mifepristone. Coupled with the 20 previously reported patients in various studies, these results determine the profile of patients who could benefit from mifepristone. SUMMARY: High clinical efficacy of mifepristone is counterbalanced by the lack of available biological monitoring data during treatment, and the risk of worsening of hypokalemia and blood pressure levels. However, its rapid efficacy and the fact that the drug uses a mechanism that is different from all currently available treatment should make mifepristone a valuable treatment in particular cases of uncontrolled hypercortisolism despite classical methods. PMID- 22543347 TI - Update on the diagnosis and management of hypophysitis. AB - PURPOSE OF REVIEW: To discuss the multiple forms of hypophysitis, the various methods of classification, the recent findings in pituitary autoimmunity and novel methods of treating resistant or recurrent hypophysitis. (January 2010 December 2011). RECENT FINDINGS: Multiple novel presentations of hypophysitis have been described including cytotoxic T-lymphocyte antigen-4 antibody-related hypophysitis, an adverse event associated with a novel treatment for cancer, Food and Drug Administration approved for use in the treatment of metastatic melanoma. A rare, but newly described entity of immunoglobulin G4 related plasmacytic hypophysitis has been described and reviewed. Multiple investigations addressing the role of autoimmunity in the diagnosis and pathogenesis of hypophysitis have been reported with positive antipituitary antibodies found in patients with autoimmune hypophysitis, other autoimmune diseases, and nonimmune-related pituitary diseases. Several case series and case reports present new associations with concomitant diseases and novel therapy for cases requiring treatment when standard therapy fails or is contraindicated. SUMMARY: Hypophysitis is a rare disease with multiple subtypes. The description of hypophysitis related to cytotoxic T-lymphocyte antigen-4 antibody treatment is one of the first descriptions of hypophysitis triggered by medication. As the use of this novel treatment for cancer increases, so must our awareness of immune-related adverse effects and their treatment. Pituitary autoimmunity is a challenging field with multiple discoveries reported to help further our understanding of the disease and assist in diagnosis. Insufficient sensitivity and specificity of the currently reported methods prevents recommending measurement of antipituitary antibodies as standard of care in the diagnosis of hypophysitis. The treatment of hypophysitis remains controversial with recommendations ranging from hormonal replacement to newly described therapies such as azathioprine and radiation. PMID- 22543348 TI - A simple, versatile method for GFP-based super-resolution microscopy via nanobodies. AB - We developed a method to use any GFP-tagged construct in single-molecule super resolution microscopy. By targeting GFP with small, high-affinity antibodies coupled to organic dyes, we achieved nanometer spatial resolution and minimal linkage error when analyzing microtubules, living neurons and yeast cells. We show that in combination with libraries encoding GFP-tagged proteins, virtually any known protein can immediately be used in super-resolution microscopy and that simplified labeling schemes allow high-throughput super-resolution imaging. PMID- 22543349 TI - An optimized two-finger archive for ZFN-mediated gene targeting. AB - The widespread use of zinc-finger nucleases (ZFNs) for genome engineering is hampered by the fact that only a subset of sequences can be efficiently recognized using published finger archives. We describe a set of validated two finger modules that complement existing finger archives and expand the range of ZFN-accessible sequences threefold. Using this archive, we introduced lesions at 9 of 11 target sites in the zebrafish genome. PMID- 22543350 TI - A new locus affects cell motility, cellulose binding, and degradation by Cytophaga hutchinsonii. AB - Cytophaga hutchinsonii is a Gram-negative gliding bacterium, which can rapidly degrade crystalline cellulose via a novel strategy without any recognizable processive cellulases. Its mechanism of cellulose binding and degradation is still a mystery. In this study, the mutagenesis of C. hutchinsonii with the mariner-based transposon HimarEm3 and gene complementation with the oriC-based plasmid carrying the antibiotic resistance gene cfxA or tetQ were reported for the first time to provide valuable tools for mutagenesis and genetic manipulation of the bacterium. Mutant A-4 with a transposon mutation in gene CHU_0134, which encodes a putative thiol-disulfide isomerase exhibits defects in cell motility and cellulose degradation. The cellulose binding ability of A-4 was only half of that of the wild-type strain, while the endo-cellulase activity of the cell-free supernatants and on the intact cell surface of A-4 decreased by 40%. Sodium dodecyl sulfate polyacrylamide gel electrophoresis of proteins binding to cellulose in the outer membrane showed that most of them were significantly decreased or disappeared in A-4 including some Gld proteins and hypothetical proteins, indicating that these proteins might play an important role in cell motility and cellulose binding and degradation by the bacterium. PMID- 22543351 TI - The microbiology of metalworking fluids. AB - Metalworking fluids (MWFs) are complex mixtures of chemicals and are indispensable materials in industry. They are used as cooling and lubricating agents in different machining process such as grinding, milling, and cutting. The quality of MWFs is affected by physical, chemical, and microbial contaminates. In particular, MWFs are highly vulnerable to microbial contamination, which may act both as potential pathogens and deteriorgens. Microbial contamination is of major concern due to potential health hazards such as skin dermatitis and hypersensitivity pneumonitis. The contaminated MWFs can exhibit high degrees of microbial loading, ranging from 10(4) to 10(10) colony-forming units (CFU)/ml. Wide varieties of microorganisms are reported to colonize MWFs. Traditional culturing techniques are not only laborious and time consuming but also underestimate the actual distribution of the microorganisms present in the contaminated MWFs. Therefore, rapid molecular methods such as real-time PCR and fluorescent in situ hybridization are implemented to monitor the microbial load. In industry, biocides are presently used to control microbial contamination. However, it has its own disadvantages and therefore, in recent years, alternative methods such as UV irradiation were evaluated to reduce microbial contamination in MWFs. Microbes inhabiting the MWF are also capable of forming biofilm which is detrimental to the MWF system. Biofilm is resistant to common disinfectant methods, and thus further research and development is required to effectively control its formation within MWF systems. This review is intended to discuss the overall microbiological aspects of MWF. PMID- 22543352 TI - gamma-Heptalactone is an endogenously produced quorum-sensing molecule regulating growth and secondary metabolite production by Aspergillus nidulans. AB - Microbes monitor their population density through a mechanism termed quorum sensing. It is believed that quorum-sensing molecules diffuse from the microbial cells and circulate in the surrounding environment as a function of cell density. When these molecules reach a threshold concentration, the gene expression of the entire population is altered in a coordinated manner. This work provides evidence that Aspergillus nidulans produces at least one small diffusible molecule during its growth cycle which accumulates at high cell density and alters the organism's behaviour. When added to low-density cell cultures, ethyl acetate extracts from stationary phase culture supernatants of A. nidulans resulted in the abolition of the lag phase, induced an earlier deceleration phase with 16.3 % decrease in the final cell dry weight and resulted in a 37.8 % increase in the expression of ipnA::lacZ reporter gene construct, which was used as a marker for penicillin production compared to non-treated controls. The bioactive molecule present in the stationary phase extract was purified to homogeneity and was identified by liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy to be gamma-heptalactone. This study provides the first evidence that A. nidulans produces gamma-heptalactone at a high cell density and it can alter the organism's behaviour at a low cell density. gamma-Heptalactone hence acts as a quorum-sensing molecule in the producing strain. PMID- 22543354 TI - New insights into activation and substrate recognition of polyhydroxyalkanoate synthase from Ralstonia eutropha. AB - The polyhydroxyalkanoate synthase of Ralstonia eutropha (PhaC(Re)) shows a lag time for the start of its polymerization reaction, which complicates kinetic analysis of PhaC(Re). In this study, we found that the lag can be virtually eliminated by addition of 50 mg/L TritonX-100 detergent into the reaction mixture, as well as addition of 2.5 g/L Hecameg detergent as previously reported by Gerngross and Martin (Proc Natl Sci USA 92: 6279-6283, 1995). TritonX-100 is an effective lag eliminator working at much lower concentration than Hecameg. Kinetic analysis of PhaC(Re) was conducted in the presence of TritonX-100, and PhaC(Re) obeyed Michaelis-Menten kinetics for (R)-3-hydroxybutyryl-CoA substrate. In inhibitory assays using various compounds such as adenosine derivatives and CoA derivatives, CoA free acid showed competitive inhibition but other compounds including 3'-dephospho CoA had no inhibitory effect. Furthermore, PhaC(Re) showed a considerably reduced reaction rate for 3'-dephospho (R)-3-hydroxybutyryl CoA substrate and did not follow typical Michaelis-Menten kinetics. These results suggest that the 3'-phosphate group of CoA plays a critical role in substrate recognition by PhaC(Re). PMID- 22543353 TI - A marine-derived Streptomyces sp. MS449 produces high yield of actinomycin X2 and actinomycin D with potent anti-tuberculosis activity. AB - In the course of our screening program for anti-Mycobacterium bovis bacillus Calmette-Guerin (BCG) and anti-Mycobacterium tuberculosis H37Rv (MTB H37Rv) agents from our marine natural product library, a newly isolated actinomycete strain, designated as MS449, was picked out for further investigation. The strain MS449, isolated from a sediment sample collected from South China Sea, produced actinomycin X(2) and actinomycin D in substantial quantities, which showed strong inhibition of BCG and MTB H37Rv. The structures of actinomycins were elucidated by nuclear magnetic resonance and mass spectrometric analysis. The strain MS449 was taxonomically characterized on the basis of morphological and phenotypic characteristics, genotypic data, and phylogenetic analysis. The 16S rRNA gene sequence of the strain was determined and a database search indicated that the strain was closely associated with the type strain of Streptomyces avermitilis (99.7 % 16S rRNA gene similarity). S. avermitilis has not been previously reported to produce actinomycins. The marine-derived strain of Streptomyces sp. MS449 produced notably higher quantities of actinomycin X(2) (1.92 mg/ml) and actinomycin D (1.77 mg/ml) than previously reported actinomycins producing strains. Thus, MS449 was considered of great potential as a new industrial producing strain of actinomycin X(2) and actinomycin D. PMID- 22543355 TI - Construction of an electrochemical sensor based on the electrodeposition of Au-Pt nanoparticles mixtures on multi-walled carbon nanotubes film for voltammetric determination of cefotaxime. AB - Mixtures of gold-platinum nanoparticles (Au-PtNPs) are fabricated consecutively on a multi-walled carbon nanotubes (MWNT) coated glassy carbon electrode (GCE) by the electrodeposition method. The surface morphology and nature of the hybrid film (Au-PtNPs/MWCNT) deposited on glassy carbon electrodes is characterized by scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS), X ray diffraction (XRD), electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV) techniques. The modified electrode is used as a new and sensitive electrochemical sensor for the voltammetric determination of cefotaxime (CFX). The electrochemical behavior of CFX is investigated on the surface of the modified electrode using linear sweep voltammetry (LSV). The results of voltammetric studies exhibited a considerable improvement in the oxidation peak current of CFX compared to glassy carbon electrodes individually coated with MWCNT or Au-PtNPs. Under the optimized conditions, the modified electrode showed a wide linear dynamic range of 0.004-10.0 MUM with a detection limit of 1.0 nM for the voltammetric determination of CFX. The modified electrode was successfully applied for the accurate determination of trace amounts of CFX in pharmaceutical and clinical preparations. PMID- 22543356 TI - Model-guided ligation strategy for optimal assembly of DNA libraries. AB - DNA ligation is essential to many molecular biology manipulations, but this reaction is often carried out by following generic guidelines or by trial and error. Maximizing the desired ligation product is especially important in DNA library construction for directed evolution experiments since library diversity is directly affected by ligation efficiency. Here, we suggest that display vectors that rely on Type IIP restriction sites for cloning should be redesigned to utilize Type IIS restriction sites instead because ligation yield is significantly improved: we observed up to 15- and 2.6-fold increases in desired products for circular and linear ligation reactions, respectively. To guide ligation optimization more rationally, we developed an easily parameterized thermodynamic model that predicts product distributions based on input DNA concentrations and free energies of the ligation events. We applied this model to study ligation reactions using a ribosome display vector redesigned with Type IIS restriction sites (pRDV2). We computationally predicted and experimentally validated the relative abundance of various products in three-piece linear ligations as well as the extent of transformation from vector-insert circular ligations. Based on our results, we provide general insights into ligation and we outline guidelines for optimizing this reaction for both in vivo and in vitro display methodologies. PMID- 22543359 TI - Dynamic stability of fcc crystals under isotropic loading from first principles. AB - Lattice dynamics and stability of four fcc crystals (Al, Ir, Pt and Au) under isotropic (hydrostatic) tensile loading are studied from first principles using the linear response method and the harmonic approximation. The results reveal that, contrary to former expectations, strengths of all the studied crystals are limited by instabilities related to soft phonons with finite or vanishing wavevectors. The critical strains associated with such instabilities are remarkably lower than those related to the volumetric instability. On the other hand, the corresponding reduction of the tensile strength is by 20% at the most. An analysis of elastic stability conditions is also performed and the results obtained by means of both approaches are compared. PMID- 22543358 TI - The (pro)renin receptor. A decade of research: what have we learned? AB - The discovery of a (pro)renin receptor ((P)RR) in 2002 provided a long-sought explanation for tissue renin-angiotensin system (RAS) activity and a function for circulating prorenin, the inactive precursor of renin, in end-organ damage. Binding of renin and prorenin (referred to as (pro)renin) to the (P)RR increases angiotensin I formation and induces intracellular signalling, resulting in the production of profibrotic factors. However, the (pro)renin concentrations required for intracellular signalling in vitro are several orders of magnitude above (patho)physiological plasma levels. Moreover, the phenotype of prorenin overexpressing animals could be completely attributed to angiotensin generation, possibly even without the need for a receptor. The efficacy of the only available putative (pro)renin receptor blocker handle region peptide remains doubtful, leading to inconclusive results. The fact that, in contrast to other RAS components, (P)RR knock-outs, even tissue-specific, are lethal, points to an important, (pro)renin-independent, function of the (P)RR. Indeed, recent research has highlighted ancillary functions of the (P)RR as an essential accessory protein of the vacuolar-type H(+)-ATPase (V-ATPase), and in this role, it acts as an intermediate in Wnt signalling independent of (pro)renin. In conclusion, (pro)renin-dependent signalling is unlikely in non-(pro)renin synthesizing organs, and the (P)RR role in V-ATPase integrity and Wnt signalling may explain some, if not all of the phenotypes previously associated with (pro)renin-(P)RR interaction. PMID- 22543357 TI - The second sodium pump: from the function to the gene. AB - Transepithelial Na(+) transport is mediated by passive Na(+) entry across the luminal membrane and exit through the basolateral membrane by two active mechanisms: the Na(+)/K(+) pump and the second sodium pump. These processes are associated with the ouabain-sensitive Na(+)/K(+)-ATPase and the ouabain insensitive, furosemide-inhibitable Na(+)-ATPase, respectively. Over the last 40 years, the second sodium pump has not been successfully associated with any particular membrane protein. Recently, however, purification and cloning of intestinal alpha-subunit of the Na(+)-ATPase from guinea pig allowed us to define it as a unique biochemical and molecular entity. The Na(+)- and Na(+)/K(+)-ATPase genes are at the same locus, atp1a1, but have independent promoters and some different exons. Herein, we spotlight the functional characteristics of the second sodium pump, and the associated Na(+)-ATPase, in the context of its role in transepithelial transport and its response to a variety of physiological and pathophysiological conditions. Identification of the Na(+)-ATPase gene (atna) allowed us, using a bioinformatics approach, to explore the tertiary structure of the protein in relation to other P-type ATPases and to predict regulatory sites in the promoter region. Potential regulatory sites linked to inflammation and cellular stress were identified in the atna gene. In addition, a human atna ortholog was recognized. Finally, experimental data obtained using spontaneously hypertensive rats suggest that the Na(+)-ATPase could play a role in the pathogenesis of essential hypertension. Thus, the participation of the second sodium pump in transepithelial Na(+) transport and cellular Na(+) homeostasis leads us to reconsider its role in health and disease. PMID- 22543360 TI - Analysis of cutaneous and internal gill gas exchange morphology in early larval amphibians, Pseudophryne bibronii and Crinia georgiana. AB - This study uses stereological techniques to examine body, internal gill and cardiovascular morphology of two larval amphibians, Pseudophryne bibronii and Crinia georgiana, to evaluate the roles of diffusive and convective gas exchange. Gosner stage 27 specimens were prepared for light microscopy and six parallel sections of equal distance taken through the body as well as a further six through the heart and internal gills. Body, internal gill and heart volume as well as body and internal gill surface areas were determined. The harmonic mean distance across the internal gills was also measured and used to estimate oxygen diffusive conductance, DO2. The species were of similar body size and surface area, but the heart and internal gills were larger in P. bibronii, which may represent precursors for greater growth of the species beyond stage 27. The much larger surface area of the skin compared to the internal gills in both species suggests it is the main site for gas exchange, with the gills supplementing oxygen uptake. The sparse cutaneous capillary network suggests diffusion is the main oxygen transport mechanism across the skin and directly into deeper tissues. A numerical model that simplifies larval shape, and has an internal (axial vessels) and external oxygen source, confirms that diffusion is able to maintain tissue oxygen with limited convective input. PMID- 22543361 TI - Environment-friendly biomimetic synthesis of TiO2 nanomaterials for photocatalytic application. AB - We have demonstrated an environment-friendly biomimetic synthesis method for the preparation of TiO(2) nanomaterials with different crystal phases and morphologies. This is the first time that it has been found that the crystal phase of TiO(2) can be controlled just by using different biotemplates, and cannot be changed by calcination up to 750 degrees C. In our experiment, anatase TiO(2) was obtained by using yeast and albumen templates, while rutile TiO(2) was formed by using dandelion pollen as the template. PMID- 22543363 TI - Concept and development of a discharge alert filter for abnormal laboratory values coupled with computerized provider order entry: a tool for quality improvement and hospital risk management. AB - PURPOSE: To develop a clinical decision support system activated at the time of discharge to reduce potentially inappropriate discharges from unidentified or unaddressed abnormal laboratory values. METHODS: We identified 106 laboratory tests for possible inclusion in the discharge alert filter. We selected 7 labs as widely available, commonly obtained, and associated with high risk for potential morbidity or mortality within abnormal ranges. We identified trigger thresholds at levels that would capture significant laboratory abnormalities while avoiding excessive flag generation because of laboratory results that minimally deviate outside the normal reference range. RESULTS: We selected sodium (>155 or <125 mmol/L), potassium (<2.5 or >6 mEq/dL) phosphorous (<1.6 mg/dL), magnesium (<1.2 mg/dL), creatinine greater than 1.1 with a rise of 20% or more between the 2 most recent results, white blood cell count (>11,000 cells/mm with a rise of 20% or more between the 2 most recent results), and international normalized ratio greater than 4. CONCLUSIONS: A discharge alert filter that reliably and effectively identifies patients that may be discharged in unsafe situations because of unaddressed critical laboratory values can improve patient safety at discharge and potentially reduce the incidence of costly litigation. Further research is needed to validate whether the proposed discharge alert filter is effective at improving patient safety at discharge. PMID- 22543362 TI - Safety in the home healthcare sector: development of a new household safety checklist. AB - OBJECTIVES: Unsafe household conditions could adversely affect safety and quality in home health care. However, risk identification tools and procedures that can be readily implemented in this setting are lacking. To address this need, we developed and tested a new household safety checklist and accompanying training program. METHODS: A 50-item, photo-illustrated, multi-hazard checklist was designed as a tool to enable home healthcare paraprofessionals (HHCPs) to conduct visual safety inspections in patients' homes. The checklist focused on hazards presenting the greatest threat to the safety of seniors. A convenience sample of 57 HHCPs was recruited to participate in a 1-hour training program, followed by pilot testing of the checklist in their patients' households. Checklist data from 116 patient homes were summarized using descriptive statistics. Qualitative feedback on the inspection process was provided by HHCPs participating in a focus group. RESULTS: Pretesting and posttesting determined that the training program was effective; participating HHCPs' ability to identify household hazards significantly improved after training (P<0.001). Using the checklist, HHCPs were able to identify unsafe conditions, including fire safety deficiencies, fall hazards, unsanitary conditions, and problems with medication management. Home healthcare paraprofessionals reported that the checklist was easy to use and that inspections were well accepted by patients. Inspections took roughly 20 minutes to conduct. CONCLUSIONS: Home healthcare paraprofessionals can be effectively trained to identify commonplace household hazards. Using this checklist as a guide, visual household inspections were easily performed by trained HHCPS. Additional studies are needed to evaluate the reliability of the checklist and to determine if hazard identification leads to interventions that improve performance outcomes. PMID- 22543364 TI - Semi-supervised classification of patient safety event reports. AB - OBJECTIVES: The Veterans Health Administration patient safety reporting system receives more than 100,000 reports annually. The information contained in these reports is primarily in the form of natural language text. Improving the ability to efficiently mine these patient safety reports for information is the objective of a proposed semi-supervised method. METHODS: A semi-supervised classification method leverages information from both labeled and unlabeled reports to predict categories for the unlabeled reports. RESULTS: Two different scenarios involving a semi-supervised learning process are examined, and both demonstrate good predictive results. CONCLUSIONS: The semi-supervised method shows much promise in assisting researchers and analysts toward accurately and more quickly separating reports of varying and often overlapping topics. The method is able to use the "stories" provided in patient safety reports to extend existing patient safety taxonomies beyond their static design. PMID- 22543365 TI - Speeding up tandem mass spectral identification using indexes. AB - MOTIVATION: Tandem mass spectrometry (MS/MS) has been routinely used in proteomics studies. Post-translational modification (PTM) identification is a challenging problem in tandem mass spectral analysis. RESULTS: In this article, we define two scoring functions for identifying peptides/proteins with PTMs from MS/MS spectra: match scores and diagonal scores, as well as two spectral identification problems based on the two scores. We propose several index-based algorithms for the two problems. Both theoretical and experimental analyses show that the index-based algorithms significantly improve on speed when compared with existing algorithms. PMID- 22543366 TI - DAVID-WS: a stateful web service to facilitate gene/protein list analysis. AB - SUMMARY: The database for annotation, visualization and integrated discovery (DAVID), which can be freely accessed at http://david.abcc.ncifcrf.gov/, is a web based online bioinformatics resource that aims to provide tools for the functional interpretation of large lists of genes/proteins. It has been used by researchers from more than 5000 institutes worldwide, with a daily submission rate of ~1200 gene lists from ~400 unique researchers, and has been cited by more than 6000 scientific publications. However, the current web interface does not support programmatic access to DAVID, and the uniform resource locator (URL) based application programming interface (API) has a limit on URL size and is stateless in nature as it uses URL request and response messages to communicate with the server, without keeping any state-related details. DAVID-WS (web service) has been developed to automate user tasks by providing stateful web services to access DAVID programmatically without the need for human interactions. AVAILABILITY: The web service and sample clients (written in Java, Perl, Python and Matlab) are made freely available under the DAVID License at http://david.abcc.ncifcrf.gov/content.jsp?file=WS.html. PMID- 22543367 TI - Geneious Basic: an integrated and extendable desktop software platform for the organization and analysis of sequence data. AB - The two main functions of bioinformatics are the organization and analysis of biological data using computational resources. Geneious Basic has been designed to be an easy-to-use and flexible desktop software application framework for the organization and analysis of biological data, with a focus on molecular sequences and related data types. It integrates numerous industry-standard discovery analysis tools, with interactive visualizations to generate publication-ready images. One key contribution to researchers in the life sciences is the Geneious public application programming interface (API) that affords the ability to leverage the existing framework of the Geneious Basic software platform for virtually unlimited extension and customization. The result is an increase in the speed and quality of development of computation tools for the life sciences, due to the functionality and graphical user interface available to the developer through the public API. Geneious Basic represents an ideal platform for the bioinformatics community to leverage existing components and to integrate their own specific requirements for the discovery, analysis and visualization of biological data. AVAILABILITY AND IMPLEMENTATION: Binaries and public API freely available for download at http://www.geneious.com/basic, implemented in Java and supported on Linux, Apple OSX and MS Windows. The software is also available from the Bio-Linux package repository at http://nebc.nerc.ac.uk/news/geneiousonbl. PMID- 22543368 TI - easyFRAP: an interactive, easy-to-use tool for qualitative and quantitative analysis of FRAP data. AB - SUMMARY: We present easyFRAP, a versatile tool that assists quantitative and qualitative analysis of fluorescence recovery after photobleaching (FRAP) data. The user can handle simultaneously large data sets of raw data, visualize fluorescence recovery curves, exclude low quality data, perform data normalization, extract quantitative parameters, perform batch analysis and save the resulting data and figures for further use. Our tool is implemented as a single-screen Graphical User Interface (GUI) and is highly interactive, as it permits parameterization and visual data quality assessment at various points during the analysis. AVAILABILITY: easyFRAP is free software, available under the General Public License (GPL). Executable and source files, supplementary material and sample data sets can be downloaded at: ccl.med.upatras.gr/easyfrap.html. PMID- 22543369 TI - Optimal simultaneous superpositioning of multiple structures with missing data. AB - MOTIVATION: Superpositioning is an essential technique in structural biology that facilitates the comparison and analysis of conformational differences among topologically similar structures. Performing a superposition requires a one-to one correspondence, or alignment, of the point sets in the different structures. However, in practice, some points are usually 'missing' from several structures, for example, when the alignment contains gaps. Current superposition methods deal with missing data simply by superpositioning a subset of points that are shared among all the structures. This practice is inefficient, as it ignores important data, and it fails to satisfy the common least-squares criterion. In the extreme, disregarding missing positions prohibits the calculation of a superposition altogether. RESULTS: Here, we present a general solution for determining an optimal superposition when some of the data are missing. We use the expectation maximization algorithm, a classic statistical technique for dealing with incomplete data, to find both maximum-likelihood solutions and the optimal least squares solution as a special case. AVAILABILITY AND IMPLEMENTATION: The methods presented here are implemented in THESEUS 2.0, a program for superpositioning macromolecular structures. ANSI C source code and selected compiled binaries for various computing platforms are freely available under the GNU open source license from http://www.theseus3d.org. CONTACT: dtheobald@brandeis.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22543370 TI - Fast, accurate error-correction of amplicon pyrosequences using Acacia. PMID- 22543371 TI - 'Self-healing' dyes: intramolecular stabilization of organic fluorophores. PMID- 22543373 TI - Enhanced photostability of cyanine fluorophores across the visible spectrum. PMID- 22543375 TI - Reprogramming in suspension. PMID- 22543376 TI - Hitting the sweet spot. PMID- 22543377 TI - Close encounters: integrating nanopores and CMOS amplifiers for single-molecule detection. PMID- 22543378 TI - Toward objective evaluation of proteomic algorithms. PMID- 22543380 TI - Old roots and new growth. PMID- 22543381 TI - Definition of sexual minority raises concerns for reader. PMID- 22543383 TI - Evidence-based practice for obtaining blood specimens from a central venous access device. PMID- 22543384 TI - Management of dyspnea in a patient with lung cancer. PMID- 22543385 TI - Physical activity and the risk of breast cancer recurrence: a literature review. AB - PURPOSE/OBJECTIVES: To examine the association between physical activity and breast cancer mortality and recurrence, and to provide an overview of factors related to physical activity behavior in women with breast cancer. DATA SOURCES: An extensive review of the epidemiologic literature on the effect of physical activity on breast cancer recurrence and mortality was conducted using PubMed up to December 2010, involving the following key words: physical activity, exercise, breast cancer, breast cancer recurrence, and breast cancer mortality. DATA SYNTHESIS: For breast cancer recurrence and breast cancer-related mortality, studies were included if physical activity served as the independent variable and a measure of association was reported. To examine determinants of physical activity, studies were included if a hypothesized factor served as the independent variable and a measure of association was reported. CONCLUSIONS: Of the six studies that examined the influence of physical activity on breast cancer mortality, four (67%) reported a protective effect (i.e., inverse association), two examined the influence of physical activity on breast cancer recurrence and reported a nonsignificant risk reduction. Few studies have examined factors that influence physical activity behavior in women with breast cancer, and findings suggest that psychosocial factors play an important role in influencing the activity patterns of breast cancer survivors. Future longitudinal studies are needed to confirm those findings. IMPLICATIONS FOR NURSING: To prevent breast cancer recurrence and breast cancer-related mortality, nurses should encourage breast cancer survivors to engage in regular exercise. PMID- 22543386 TI - Fatigue in breast cancer survivors: the impact of a mind-body medicine intervention. AB - PURPOSE/OBJECTIVES: To evaluate a mind-body medicine (MBM) program for its impact on persistent fatigue following breast cancer treatment. DESIGN: Quasiexperimental. SETTING: An urban community hospital and a health department in a semirural county, both in Maryland. SAMPLE: 68 breast cancer survivors who were at least six months postadjuvant chemotherapy and/or radiation therapy and had a baseline fatigue score of 50 or lower per the vitality subscale of the SF 36(r) Health Survey. METHODS: A 10-week group-based MBM program for breast cancer survivors with persistent fatigue was evaluated using a pretest/post-test study design. MAIN RESEARCH VARIABLES: Sustained change in fatigue severity as measured by the Piper Fatigue Scale (PFS), SF-36 vitality subscale, and 10 cm visual analog scale (VAS). FINDINGS: Participants were 2.6 years post-treatment, with a mean age of 56.8 years. Overall, fatigue scores improved by 40%. The mean PFS improved from a score of 6 (SD = 1.6) at baseline to 4.2 (SD = 2) at the end of the program (p < 0.001), with additional improvement at two months and sustained at six months (X = 3.6, SD = 2, p < 0.001). Results from the SF-36 and VAS also showed significant improvement in fatigue (p < 0.001). CONCLUSIONS: The findings support the use of a holistic MBM intervention to reduce persistent fatigue in breast cancer survivors. Results should be confirmed with a randomized clinical trial. IMPLICATIONS FOR NURSING: Nurses and other healthcare team members can effectively impact persistent fatigue in breast cancer survivors through the use of a multipronged MBM program. PMID- 22543388 TI - African Americans with a family history of colorectal cancer: barriers and facilitators to screening. AB - PURPOSE/OBJECTIVES: To explore barriers and facilitators of screening for colorectal cancer (CRC), as well as suggestions for improving screening among African Americans with first-degree relatives with CRC. RESEARCH APPROACH: A qualitative, descriptive approach involving focus groups. SETTING: A community healthcare clinic in Baltimore, MD. PARTICIPANTS: 14 African American men and women aged 40 or older with at least one first-degree family member affected by CRC. METHODOLOGIC APPROACH: In-depth focus groups were conducted until thematic saturation was achieved. Thematic analysis and data reduction were conducted using ATLAS.ti, version 5.0. MAIN RESEARCH VARIABLES: CRC screening barriers and facilitators. FINDINGS: The participants were mostly male, insured, and had a parent with CRC. Commonly reported barriers to CRC screening included fear of serious illness, mistrust of the medical establishment, potential screening discomfort, lack of information on CRC risk factors, lack of healthcare access, absence of symptoms, no knowledge of CRC screening benefits, community reticence about cancer, and CRC myths. Facilitating factors for CRC screening included a belief of personal risk for CRC, physician recommendations, and acknowledgment of age as a risk factor. Suggestions to increase screening rates included distribution of culturally appropriate and community-based efforts (e.g., mobile units, church-based interventions). Participants also suggested ways to increase motivation and provide social support for screening patients. CONCLUSIONS: Additional research is needed to identify and test effective screening approaches for this underserved group at increased risk for CRC. Study results suggest that cancer risk and screening education, coupled with screening opportunities in the community, may yield increased screening rates. INTERPRETATION: Lack of knowledge about CRC and CRC screening exists in the study population. Promoting screening across generations, developing and disseminating culturally appropriate educational materials within the community, and encouraging older individuals to screen to take care of their family may be appropriate interventions. PMID- 22543387 TI - Predicting fear of breast cancer recurrence and self-efficacy in survivors by age at diagnosis. AB - PURPOSE/OBJECTIVES: To determine the effect that age at diagnosis has on fear of breast cancer recurrence and to identify the predictors of fear of recurrence using self-efficacy as a mediator. DESIGN: Cross-sectional survey. SETTING: Two university cancer centers and one cooperative group in the midwestern United States. SAMPLE: 1,128 long-term survivors. METHODS: Survivors were eligible if they were aged 18-45 years (younger group) or 55-70 years (older group) at cancer diagnosis, had received chemotherapy, and were three to eight years postdiagnosis. Fear of recurrence was compared between younger and older groups. Multiple regression analyses were used to test variables' prediction of fear of recurrence and breast cancer survivor self-efficacy, as well as breast cancer survivor self-efficacy mediation effects. MAIN RESEARCH VARIABLES: Fear of recurrence, breast cancer survivor self-efficacy, and age at diagnosis. FINDINGS: Survivors diagnosed at a younger age had significantly higher fear of recurrence, as well as health, role, womanhood, death, and parenting worries. Perceived risk of recurrence, trait anxiety, and breast cancer reminders explained significant variance in fear of recurrence and breast cancer survivor self-efficacy. Breast cancer survivor self-efficacy partially mediated the effects of variables on fear of recurrence. CONCLUSIONS: The findings suggest that breast cancer survivor self efficacy may have a protective effect for survivors who are younger at diagnosis and have higher perceived risk of recurrence, higher trait anxiety, and more breast cancer reminders. Oncology nurses already use the skills required to support self-efficacy. Additional research is needed to define and test breast cancer survivor self-efficacy interventions. IMPLICATIONS FOR NURSING: Oncology nurses are in a key role to assess fear of recurrence and provide self-efficacy interventions to reduce it in breast cancer survivors. Strategies to efficiently address fear of recurrence to reduce psychological distress in survivorship follow-up care are warranted. PMID- 22543389 TI - Breast cancer survivors' perception of survivorship. AB - PURPOSE/OBJECTIVES: To explore (a) how women who were diagnosed with breast cancer (BC) defined themselves as survivors and when this occurred, and (b) the types of benefits they derived from their experiences. RESEARCH APPROACH: An exploratory, qualitative approach. PARTICIPANTS: 112 women who had BC (response rate = 70%). SETTING: Participants were recruited from two cancer survivor organizations in a northeastern U.S. city. METHODOLOGIC APPROACH: Responses to open-ended questions in telephone interviews were examined by age at diagnosis using thematic analysis. Chi squares were used to conduct analyses by age (younger than 51 years; aged 51 years or older). MAIN RESEARCH VARIABLES: Meaning of survivorship, defining moment, benefits derived from surviving from breast cancer. FINDINGS: Participants' perceptions of survivorship included two main components, a defining moment and the meaning attached to being a survivor. Becoming a survivor is an active process, except in the case of those participants who realized they were survivors when informed by a third party. Meanings differed by age at diagnosis. Most participants listed at least one benefit from surviving cancer. CONCLUSIONS: The definitions of survivorship and benefits outlined here suggest that many positive aspects of the survivorship experience exist that may inform future interventions' designs. IMPLICATIONS FOR PRACTICE: Providers should acknowledge the strength survivors show in the process of meaning-making and finding benefits in their adverse experiences. The use of expressive and supportive interventions may hold promise for women facing difficulties in coping with their diagnosis. PMID- 22543393 TI - Identifying family members who are likely to perceive benefits from providing care to a person with a primary malignant brain tumor. AB - PURPOSE/OBJECTIVES: To identify changes in positive aspects of care (PAC) from the time of diagnosis to four months following the diagnosis in family caregivers of care recipients with primary malignant brain tumors. DESIGN: Longitudinal. SETTING: Dyads were recruited from neurosurgery clinics in Pittsburgh, PA, at the time of care recipients' diagnosis with a primary malignant brain tumor. A second data collection took place four months following the diagnosis. SAMPLE: 89 caregiver and care recipient dyads. METHODS: Paired t tests were used to examine change in PAC, univariate analyses were used to determine predictors of PAC at four months, Mann-Whitney U tests and t tests were used to examine associations between categorical predictor variables and PAC at four months, and univariate linear regressions were used to examine associations between continuous predictors and PAC at four months. MAIN RESEARCH VARIABLES: The impact of sociodemographic factors, caregiver-perceived social support, mastery, neuroticism, and marital satisfaction on PAC. FINDINGS: Caregivers' PAC scores during the first four months following diagnosis appeared to remain stable over time. Significant differences were found between the care recipient reasoning domain group at diagnosis and PAC score. Care recipients who scored below average were associated with caregivers with higher PAC scores. Caregiver PAC at four months following diagnosis was significantly predicted by care recipient reasoning and caregiver social support. CONCLUSIONS: PAC scores appear to remain stable over time, although levels of PAC may be related to care recipients' level of functioning. Future research should focus on the development of interventions for caregivers who report low levels of PAC at the time of diagnosis in an attempt to help these individuals identify PAC in their caregiving situation. IMPLICATIONS FOR NURSING: Findings have clinical and research implications. Clinicians may be able to better identify caregivers who are at risk for negative outcomes by understanding the risks faced by caregivers of patients with milder symptoms in addition to those caring for more profoundly affected care recipients. PMID- 22543394 TI - The experience of patients with cancer who develop venous thromboembolism: an exploratory study. AB - PURPOSE/OBJECTIVES: To better understand the experience of venous thromboembolism (VTE) from the points of view of patients with cancer during various stages of the cancer experience. RESEARCH APPROACH: Qualitative, descriptive. SETTING: Various inpatient and outpatient units of a large urban university-affiliated hospital in Montreal, Quebec, Canada. PARTICIPANTS: Purposive sample of 10 participants who were anticipating, had recently undergone, or were currently undergoing cancer treatment and who had received a VTE diagnosis within the past year. METHODOLOGIC APPROACH: Semistructured interviews were transcribed verbatim. Thematic analysis of data revealed themes contributing to understanding the lived experience of VTE during cancer care. MAIN RESEARCH VARIABLES: The experience of patients with cancer who develop VTE. FINDINGS: Patients' initial reaction to VTE included VTE as a life-threat, past experience with VTE, and VTE as the "cherry on the sundae" in light of other cancer-related health issues. Patients' coping with VTE also included three themes: VTE being overshadowed by unresolved cancer related concerns, VTE as a setback in cancer care, and attitudes about VTE treatment. CONCLUSIONS: This study contributes new insight into the experience of patients with cancer who develop VTE. The most salient finding was that patients having no prior VTE knowledge experienced VTE as more challenging. Future studies comparing experiences with VTE across the various stages of cancer care are needed. INTERPRETATION: Study findings suggest that patient education about VTE would be useful for the initial reaction and subsequent coping phases of VTE, thus representing an important target area for nursing intervention. PMID- 22543395 TI - Chemotherapy-related cognitive change: a principle-based concept analysis. AB - PURPOSE/OBJECTIVES: To present the results of a principle-based concept analysis of cognitive change in patients with cancer following chemotherapy treatment. DATA SOURCES: 86 English-language articles retrieved through OVID, PubMed, CINAHL(r), and Web of Knowledge searches through June 2010. No time limits were imposed. DATA SYNTHESIS: Analysis was based on the philosophical principles: epistemologic, pragmatic, linguistic, and logical. Conceptual components were identified and a theoretical definition of chemotherapy-related cognitive change emerged; the term was not clearly defined or well differentiated in the scientific literature. Implicit meanings are found in patients' subjective accounts, descriptions of the cognitive domains studied, and the choice of neuropsychological assessment instruments. Antecedents relative to chemotherapy related cognitive change include disease and treatment factors. Moderators may include anxiety, depression, and fatigue. Consequences or outcomes of the experience of chemotherapy-related cognitive change include adjustment to illness, impact on quality of life, and potential for emotional distress. CONCLUSIONS: The principle-based concept analysis generated conceptual insights about chemotherapy-related cognitive change that are based on sound scientific evidence. The product of this method of analysis is a theoretical definition that reflects the state of the science. IMPLICATIONS FOR NURSING: When the impact of cognitive change following chemotherapy is better understood, meaningful and timely interventions can be developed to improve quality of life for cancer survivors. PMID- 22543396 TI - Perspectives on coping among patients with head and neck cancer receiving radiation. AB - PURPOSE/OBJECTIVES: To describe coping among patients with laryngeal and oropharyngeal cancer during definitive radiation with or without chemotherapy. RESEARCH APPROACH: Qualitative content analysis conducted within a larger study. SETTING: Two radiation oncology outpatient clinics in Baltimore, MD. PARTICIPANTS: 21 patients with oropharyngeal or laryngeal cancer. METHODOLOGIC APPROACH: Interviews with open-ended questions were conducted during treatment. Questions covered topics such as coping during treatment, treatment-related issues, and resources. MAIN RESEARCH VARIABLES: Coping, treatment, and coping resources. FINDINGS: Patients' self-assessments suggested they were coping or that coping was rough or upsetting. Issues that required coping varied over four time points. Physical side effects were problematic during and one month after treatment completion. Patients used coping to manage the uncertainties of physical and psychological aspects of their experience. Family and friend support was a common coping strategy used by patients, with the intensity of side effects corresponding with the support provided across time points. CONCLUSIONS: Findings confirm previous research, but also provide new information about ways in which patients with head and neck cancer cope with their illness experience. Emergent themes provide insight into patients' feelings, issues, and assistance received with coping. INTERPRETATION: Patients with head and neck cancer need education on the amount and severity of side effects and should be appraised of potential difficulties with scheduling, driving, and other logistic issues. Patients also should be informed of helpful types of support and coping strategies. Additional research is needed to expand the findings related to patients' coping with treatment and to explore the experiences of family and friends who provide social support. PMID- 22543397 TI - Reclaiming life on one's own terms: a grounded theory study of the process of breast cancer survivorship. AB - PURPOSE/OBJECTIVES: To develop a substantive theory of the process of breast cancer survivorship. RESEARCH APPROACH: Grounded theory. SETTING: A LISTSERV announcement posted on the SHARE Web site and purposeful recruitment of women known to be diagnosed and treated for breast cancer. PARTICIPANTS: 15 women diagnosed with early-stage breast cancer. METHODOLOGIC APPROACH: Constant comparative analysis. MAIN RESEARCH VARIABLES: Breast cancer survivorship. FINDINGS: The core variable identified was Reclaiming Life on One's Own Terms. The perceptions and experiences of the participants revealed overall that the diagnosis of breast cancer was a turning point in life and the stimulus for change. That was followed by the recognition of breast cancer as now being a part of life, leading to the necessity of learning to live with breast cancer, and finally, creating a new life after breast cancer. Participants revealed that breast cancer survivorship is a process marked and shaped by time, the perception of support, and coming to terms with the trauma of a cancer diagnosis and the aftermath of treatment. The process of survivorship continues by assuming an active role in self-healing, gaining a new perspective and reconciling paradoxes, creating a new mindset and moving to a new normal, developing a new way of being in the world on one's own terms, and experiencing growth through adversity beyond survivorship. CONCLUSIONS: The process of survivorship for women with breast cancer is an evolutionary journey with short- and long-term challenges. INTERPRETATION: This study shows the development of an empirically testable theory of survivorship that describes and predicts women's experiences following breast cancer treatment from the initial phase of recovery and beyond. The theory also informs interventions that not only reduce negative outcomes, but promote ongoing healing, adjustment, and resilience over time. PMID- 22543399 TI - Malglycemia and cancer: introduction to a conceptual model. AB - PURPOSE/OBJECTIVES: To introduce a conceptual model detailing the physiologic contributions of malglycemia to cancer formation and increased morbidity and mortality. DATA SOURCES: A literature search was conducted using the PubMed, CINAHL(r), and Cochrane databases, as well as Surveillance, Epidemiology and End Results (SEER) cancer statistics. DATA SYNTHESIS: Multiple complex factors are associated with malignancy formation, proliferation, and outcomes for each individual. The authors present a model, termed the Malglycemia Orbit Model, that is analogous to an atom, centered on a core of individual factors, and surrounded by "orbits" containing cancer and related factors. Highlighted in this model is the role of malglycemia. CONCLUSIONS: Cancer formation and sequelae involve numerous multifaceted factors. One factor not well described or understood within the context of malignancies is glycemic status, most notably how malglycemia impacts cancer formation and risks for adverse outcomes. The atomic-structured malglycemia model describes this process. IMPLICATIONS FOR NURSING: Among the many uncontrollable factors that contribute to cancer formation and adverse outcomes, malglycemia is one that is modifiable. Nurses are in a prime position to conduct research to enhance understanding and ultimately improve protocols for better glycemic control and, in effect, better outcomes for individuals with cancer. PMID- 22543398 TI - Hope in patients with cancer transitioning to survivorship: the mid-life directions workshop as a supportive intervention. AB - PURPOSE/OBJECTIVES: To describe the Mid-Life Directions workshop as an intervention to support hope and quality of life in midlife cancer survivors. DATA SOURCES: Published articles and books. DATA SYNTHESIS: The Mid-Life Directions workshop assists survivors to integrate the cancer experience through conscious awareness and choice, and transition to survivorship with an increased level of adaptation. Quality of life and hope are enhanced through new information and skills allowing participants to direct their lives into a preferred future. CONCLUSIONS: The midlife cancer survivor is challenged to face the fear of recurrence, death, and the crisis of meaning in a developmentally appropriate way. The task of midlife is to navigate the tension of generativity versus stagnation for care to emerge as the predominant strength. The Mid-Life Directions workshop provides the cancer survivor the opportunity to reevaluate goals, reprioritize values, and find one's own answers to these challenges to adapt to life as a cancer survivor. IMPLICATIONS FOR NURSING: This clinically relevant intervention merits formal study. Facilitator preparation, mode of delivery, and other elements for possible research are discussed. PMID- 22543379 TI - The 1000 Genomes Project: data management and community access. AB - The 1000 Genomes Project was launched as one of the largest distributed data collection and analysis projects ever undertaken in biology. In addition to the primary scientific goals of creating both a deep catalog of human genetic variation and extensive methods to accurately discover and characterize variation using new sequencing technologies, the project makes all of its data publicly available. Members of the project data coordination center have developed and deployed several tools to enable widespread data access. PMID- 22543400 TI - Exploring the role of community health workers in providing cancer navigation: perceptions of African American older adults. AB - PURPOSE/OBJECTIVES: To obtain experiential data regarding African American older adult survivors' perceptions of and recommendations on the role of community health workers (CHWs) in providing a cancer navigation intervention. RESEARCH APPROACH: Focus groups. SETTING: Rural Virginia and urban Maryland. PARTICIPANTS: 48 African American solid-tumor cancer survivors, aged 65 years or older, with Medicare insurance. METHODOLOGIC APPROACH: Analysis was accomplished through a reflexive process of transcript review, categorization, and interpretation. FINDINGS: Themes and accompanying categories identified were uneasiness surrounding the CHW role (disconnect between identified support needs and CHW role, essential CHW characteristics, and potential application of CHWs), recommendations to adequately address cancer needs (coordinating cancer treatment and unmet needs during cancer), and the importance of individualized interventions. Participants provided specific recommendations regarding the role of the CHW and how to develop supportive interventions. CONCLUSIONS: Study participants had surprisingly limited prior exposure to the CHW role. However, they stated that, in certain circumstances, CHWs could effectively assist older adult African Americans undergoing cancer diagnosis or treatment. INTERPRETATION: Study findings can be helpful to researchers and to healthcare providers engaged in assisting older African Americans during cancer diagnosis and treatment. The results lay a foundation for developing culturally appropriate interventions to assist this at-risk population. PMID- 22543401 TI - Factors influencing oncology nurses' use of hazardous drug safe-handling precautions. AB - PURPOSE/OBJECTIVES: To examine relationships among factors affecting nurses' use of hazardous drug (HD) safe-handling precautions, identify factors that promote or interfere with HD precaution use, and determine managers' perspectives on the use of HD safe-handling precautions. DESIGN: Cross-sectional, mixed methods; mailed survey to nurses who handle chemotherapy and telephone interviews with managers. SETTING: Mailed invitation to oncology centers across the United States. SAMPLE: 165 nurses who reported handling chemotherapy and 20 managers of nurses handling chemotherapy. METHODS: Instruments measured the use of HD precautions and individual and organizational factors believed to influence precaution use. Data analysis included descriptive statistics and hierarchical regression. Manager interview data were analyzed using content analysis. MAIN RESEARCH VARIABLES: Chemotherapy exposure knowledge, self-efficacy, perceived barriers, perceived risk, interpersonal influences, and workplace safety climate. FINDINGS: Nurses were well educated, experienced, and certified in oncology nursing. The majority worked in outpatient settings and administered chemotherapy to an average of 6.8 patients per day. Exposure knowledge, self-efficacy for using personal protective equipment, and perceived risk of harm from HD exposure were high; total precaution use was low. Nurse characteristics did not predict HD precaution use. Fewer barriers, better workplace safety climate, and fewer patients per day were independent predictors of higher HD precaution use. HD handling policies were present, but many did not reflect current recommendations. Few managers formally monitored nurses' HD precaution use. CONCLUSIONS: Circumstances in the workplace interfere with nurses' use of HD precautions. IMPLICATIONS FOR NURSING: Interventions should include fostering a positive workplace safety climate, reducing barriers, and providing appropriate nurse patient ratios. PMID- 22543402 TI - How women with advanced cancer pray: a report from two focus groups. AB - PURPOSE/OBJECTIVES: To explore the meaning, function, and focus of prayer for patients with advanced cancer, and to identify the effects of prayer on their coping. RESEARCH APPROACH: Qualitative, descriptive design using focus groups. SETTING: Three cancer centers that are part of a university-affiliated comprehensive cancer network in the northeastern United States. PARTICIPANTS: 13 adult, female outpatients receiving active treatment for ovarian or lung cancer. METHODOLOGIC APPROACH: Two semistructured, focus group interviews were conducted. Audiotapes were transcribed verbatim. Data were coded and analyzed using standard content analysis procedures. MAIN RESEARCH VARIABLES: Prayer and coping. FINDINGS: Four themes emerged: finding one's own way, renewed appreciation for life, provision of strength and courage, and gaining a stronger spiritual connection. In addition, praying for others, conversational prayer, petitionary prayer, ritual prayer, and thanksgiving prayer were used most often by participants to cope. CONCLUSIONS: The findings support prayer as a positive coping mechanism for women with advanced ovarian or lung cancer. INTERPRETATION: The study provides knowledge about prayer as a source of spiritual and psychological support. Oncology nurses should consider the use of prayer for patients coping with advanced cancer. PMID- 22543403 TI - Progress in artificial metallonucleases. AB - The development of synthetic agents able to hydrolytically cleave DNA with high efficiency and selectivity is still a fascinating challenge. Over the years, many examples have been reported reproducing part of the behaviour of the corresponding natural enzymes. Eventually, even the possibility to apply such systems to the manipulation of DNA of higher organisms has been demonstrated. However, efficiency of enzymes is still unrivalled. This feature article discusses the progress reported toward the realization of synthetic nucleases with particular attention to the comprehension of the reaction mechanisms and to the strategies that need to be addressed to obtain more efficient systems. PMID- 22543405 TI - Current world literature. PMID- 22543404 TI - Autoinflammatory grey matter lesions in humans: cortical encephalitis, clinical disorders, experimental models. AB - PURPOSE OF REVIEW: In recent years, evidence has accumulated that grey matter abnormalities are common in many inflammatory central nervous system (CNS) disorders, such as multiple sclerosis (MS), which is by far the most frequent autoimmune-mediated CNS disease. RECENT FINDINGS: A recent study described comprehensively the pathology of grey matter lesions in early MS. In this study, cortical demyelination together with inflammation was frequently observed in early MS cases. This study and others serve as a basis for a model of the development of cortical MS lesions in which several consecutive events may be involved. After the activation of T cells, which may open the blood-brain barrier, the humoral immune system may mediate the inflammatory process. The inflammation may become chronic through the involvement of activated glial cells and the persistence of immune cells in the meninges.Apart from MS, other grey matter CNS disorders exist in which antibodies against neuronal structures contribute to pathophysiological events such as in limbic encephalitis. Humoral and adaptive immunity mediates the pathophysiology of Rasmussen encephalitis. SUMMARY: This review focuses on the difference between inflammatory grey matter and white matter lesions. New insights into inflammatory grey matter lesions in MS and other CNS inflammatory processes such as limbic encephalitis are discussed. PMID- 22543407 TI - Trichlorosilyl triflate-mediated enantioselective directed cross-aldol reaction between ketones using a chiral phosphine oxide as an organocatalyst. AB - Trichlorosilyl triflate-promoted directed cross-aldol reaction between ketones in the presence of a chiral phosphine oxide as an organocatalyst is described. This is the first enantioselective cross-aldol reaction between simple ketones with good enantioselectivity. PMID- 22543408 TI - Structural and dynamical aspects of alkylammonium salts of a silicodecatungstate as heterogeneous epoxidation catalysts. AB - The structural and dynamical aspects of alkylammonium salts of a silicodecatungstate [(CH(3))(4)N](4)[gamma-SiW(10)O(34)(H(2)O)(2)] [C1], [(n C(3)H(7))(4)N](4)[gamma-SiW(10)O(34)(H(2)O)(2)] [C3], [(n-C(4)H(9))(4)N](4)[gamma SiW(10)O(34)(H(2)O)(2)] [C4], and [(n-C(5)H(11))(4)N](4)[gamma SiW(10)O(34)(H(2)O)(2)] [C5] were investigated. The results of sorption isotherms, XRD analyses, and solid-state NMR spectroscopy show that facile sorption of solvent molecules, flexibility of structures, and high mobility of alkylammonium cations are crucial to the uniform distribution of reactant and oxidant molecules throughout the bulk solid, which are related to the high catalytic activities for epoxidation of alkenes. PMID- 22543409 TI - A hyphenated optical trap capillary electrophoresis laser induced native fluorescence system for single-cell chemical analysis. AB - Single-cell measurements allow a unique glimpse into cell-to-cell heterogeneity; even small changes in selected cells can have a profound impact on an organism's physiology. Here an integrated approach to single-cell chemical sampling and assay are described. Capillary electrophoresis (CE) with laser-induced native fluorescence (LINF) has the sensitivity to characterize natively fluorescent indoles and catechols within individual cells. While the separation and detection approaches are well established, the sampling and injection of individually selected cells requires new approaches. We describe an optimized system that interfaces a single-beam optical trap with CE and multichannel LINF detection. A cell is localized within the trap and then the capillary inlet is positioned near the cell using a computer-controlled micromanipulator. Hydrodynamic injection allows cell lysis to occur within the capillary inlet, followed by the CE separation and LINF detection. The use of multiple emission wavelengths allows improved analyte identification based on differences in analyte fluorescence emission profiles and migration time. The system enables injections of individual rat pinealocytes and quantification of their endogenous indoles, including serotonin, N-acetyl-serotonin, 5-hydroxyindole-3-acetic acid, tryptophol and others. The amounts detected in individual cells incubated in 5-hydroxytryptophan ranged from 10(-14) mol to 10(-16) mol, an order of magnitude higher than observed in untreated pinealocytes. PMID- 22543410 TI - Solution-processed, nanostructured hybrid solar cells with broad spectral sensitivity and stability. AB - Hybrid organic-inorganic solar cells, as an alternative to all-organic solar cells, have received significant attention for their potential advantages in combining the solution-processability and versatility of organic materials with high charge mobility and environmental stability of inorganic semiconductors. Here we report efficient and air-stable hybrid organic-inorganic solar cells with broad spectral sensitivity based on a low-gap polymer poly[2,6-(4,4-bis-(2 ethylhexyl)-4H-cyclopenta[2,1-b;3,4-b']-dithiophene)-alt-4,7-(2,1,3 benzothiadiazole)] (PCPDTBT) and spherical CdSe nanoparticles. The solvents used for depositing the hybrid PCPDTBT:CdSe active layer were shown to strongly influence the film morphology, and subsequently the photovoltaic performance of the resulted solar cells. Appropriate post-deposition annealing of the hybrid film was also shown to improve the solar cell efficiency. The inclusion of a thin ZnO nanoparticle layer between the active layer and the metal cathode leads to a significant increase in device efficiency especially at long wavelengths, due to a combination of optical and electronic effects including more optimal light absorption in the active layer and elimination of unwanted hole leakage into the cathode. Overall, maximum power conversion efficiencies up to 3.7 +/- 0.2% and spectral sensitivity extending above 800 nm were achieved in such PCPDTBT:CdSe nanosphere hybrid solar cells. Furthermore, the devices with a ZnO nanoparticle layer retained ~70% of the original efficiency after storage under ambient laboratory conditions for over 60 days without any encapsulation. PMID- 22543411 TI - Comparative evaluation of a novel measurement tool to assess lumbar spine posture and range of motion. AB - PURPOSE: The diagnosis of low back pain pathology is generally based upon invasive image-based assessment of structural pathology, but is limited in methods to evaluate function. The accurate and robust measurement of dynamic function may assist in the diagnosis and monitoring of therapy success. Epionics SPINE is an advanced strain-gauge measurement technology, based on the two sensor strips SpineDMS system, which allows the non-invasive assessment of lumbar and thoraco-lumbar motion for periods of up to 24 h. The aim of this study was to examine the reliability of Epionics SPINE and to collect and compare normative data for the characterisation of spinal motion in healthy subjects. Furthermore, the identification of parameters that influence lumbar range of motion (RoM) was targeted. METHODS: Spinal shape was measured using Epionics SPINE in 30 asymptomatic volunteers during upright standing, as well as maximum flexion and extension, to check intra-rater reliability. Furthermore, back shape was assessed throughout repeated maximum flexion and extension movements in 429 asymptomatic volunteers in order to collect normative data of the lordosis angle and RoM in different gender and age classes. RESULTS: The lordosis angle during standing in the healthy collective measured with Epionics SPINE was 32.4 degrees +/- 9.7 degrees . Relative to this standing position, the average maximum flexion angle was 50.8 degrees +/- 10.9 degrees and the average extension angle 25.0 degrees +/- 11.5 degrees . Comparisons with X-ray and Spinal Mouse data demonstrated good agreement in static positions. Age played a larger role than gender in influencing lumbar posture and RoM. CONCLUSIONS: The Epionics SPINE system allows the practical and reliable dynamic assessment of lumbar spine shape and RoM, and may therefore provide a clinical solution for the evaluation of lower back pain as well as therapy monitoring. PMID- 22543412 TI - Comparing effects of kyphoplasty, vertebroplasty, and non-surgical management in a systematic review of randomized and non-randomized controlled studies. AB - PURPOSE: To determine if differences in safety or efficacy exist between balloon kyphoplasty (BKP), vertebroplasty (VP) and non-surgical management (NSM) for the treatment of osteoporotic vertebral compression fractures (VCFs). METHODS: As of February 1, 2011, a PubMed search (key words: kyphoplasty, vertebroplasty) resulted in 1,587 articles out of which 27 met basic selection criteria (prospective multiple-arm studies with cohorts of >= 20 patients). This systematic review adheres to preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. RESULTS: Pain reduction in both BKP (-5.07/10 points, P < 0.01) and VP (-4.55/10, P < 0.01) was superior to that for NSM ( 2.17/10), while no difference was found between BKP/VP (P = 0.35). Subsequent fractures occurred more frequently in the NSM group (22 %) compared with VP (11 %, P = 0.04) and BKP (11 %, P = 0.01). BKP resulted in greater kyphosis reduction than VP (4.8o vs. 1.7 degrees , P < 0.01). Quality of life (QOL) improvement showed superiority of BKP over VP (P = 0.04), along with a trend for disability improvement (P = 0.08). Cement extravasation was less frequent in the BKP (P = 0.01). Surgical intervention within the first 7 weeks yielded greater pain reduction than VCFs treated later. CONCLUSIONS: BKP/VP provided greater pain relief and fewer subsequent fractures than NSM in osteoporotic VCFs. BKP is marginally favored over VP in disability improvement, and significantly favored in QOL improvement. BKP had a lower risk of cement extravasation and resulted in greater kyphosis correction. Despite this analysis being restricted to Level I and II studies, significant heterogeneity suggests that the current literature is delivering inconsistent messages and further trials are needed to delineate confounding variables. PMID- 22543414 TI - A shared response of thaumatin like protein, chitinase, and late embryogenesis abundant protein3 to environmental stresses in tea [Camellia sinensis (L.) O. Kuntze]. AB - Drought poses a significant threat to tree plants including tea [Camellia sinensis (L.) O. Kuntze] that yields a popular beverage "tea." Consequence of drought is heat and salt stress, for which data on molecular response in tree species are not available. The present work analyzed drought-responsive subtracted cDNA libraries of tea to identify drought-responsive genes. Temporal and spatial gene expression suggested the involvement of chaperones as one of the major mechanisms to protect the plant against drought-related damages. A common response of thaumatin like protein, chitinase, and late embryogenesis abundant protein3 across four stresses suggests these to be useful targets to generate "drought stress proof" tea. PMID- 22543413 TI - Resistive straight leg raise test, resistive forward bend test and heel compression test: novel techniques in identifying secondary gain motives in low back pain cases. AB - PURPOSE: 'Low back pain' (LBP) is a prevalent condition with a majority showing no specific organic pathology. Distinguishing 'secondary gain motives (SGM)' from organic causes is imperative in clinical practice. We describe here, three new tests-resistive straight leg raise test (rSLRT), resistive forward bend test (rFBT) and heel compression test (HCT) to help differentiate patients with 'SGM' from those without. We conducted a prospective study to validate the above tests in predicting non-organic causes as a reason for LBP. METHODS: 200 patients presenting with low back pain at the senior author's outpatient orthopaedic clinic from Jan 2009 to Nov 2010 were studied. Patients were separated into two groups-'SGM group' (n = 100) and 'non-SGM group' (n = 100). 'SGM group' patients had a history of work-related accidents, road traffic accidents or assault, with a background of ongoing litigation issues or compensation benefits. rSLRT, rFBT, HCT, Schober's test and Waddell's five signs were performed on them. Statistical analysis was done to identify correlations between test results, MRI findings and 'SGM' status. RESULTS: Statistically significant differences were observed between the SGM and non-SGM group (p < 0.0005) for all tests studied. In predicting SGM status, rSLRT showed highest specificity (0.94) and highest positive predictive value (0.925) while HCT showed the highest negative predictive value (0.859). Positive rSLRT was found to be strongly correlated with >=3 positive Waddell's signs. SGM patients with positive rSLRT tended to show resistance <=45 degrees . CONCLUSIONS: rSLRT, rFBT and HCT (NK triad) are highly practical tests which strongly predict SGM status in patients. PMID- 22543416 TI - Historical and Cultural Influences on HIV Prevention in Swaziland. AB - Most who work in international development recognize the importance of implementing locally driven, grassroots initiatives for achieving positive outcomes. Yet, when it comes to HIV prevention strategies in Swaziland, there is a lack of understanding for the cultural and historical influences that determine group and individual behaviour. As a result, prevention efforts have failed to have a major impact on the world's highest prevalence rate of HIV. Greater understanding and observance of historical influences, local norms and beliefs, and the ongoing processes of adaptation must be incorporated into all efforts if any HIV prevention strategies are to be effective. PMID- 22543417 TI - Breastfeeding in Cambodia: mother knowledge, attitudes and practices. AB - PURPOSE: To conduct a knowledge, attitudes and practices study of breastfeeding in the province of Krong Kep, Cambodia. METHODS: Mothers' breastfeeding knowledge, attitudes and practices were evaluated using a structured questionnaire. The questionnaire was administered in Khmer to women with at least one child less than 60 months of age. Women meeting the eligibility requirements (N = 141) answered questions regarding their infant feeding practices, including initiation and duration of breastfeeding. FINDINGS: In Cambodia, the decision to breastfeed is rooted in a history of poverty. Twenty-five percent of women sampled initiated breastfeeding within the first hour post-delivery. In total, 82% of women initiated breastfeeding within the first 24 hours post-delivery, and 53% of women breastfed exclusively for exactly the recommended 6 months' duration. Nine women who reported exclusive breastfeeding for 6 months did not initiate breastfeeding within the first 24 hours post-delivery, likely because of the cultural practice of "roasting." Professional breastfeeding support programs do not exist in Krong Kep, Cambodia. PMID- 22543418 TI - A qualitative inquiry into the application of verbal autopsy for a mortality surveillance system in a rural community of southern India. AB - The aim of this investigation was to identify operational and ethical issues encountered in the application of verbal autopsy (VA) in a rural community in south India. A qualitative study involving semi-structured interviews was conducted with 183 bereaved caregivers in rural Andhra Pradesh, India. Simple descriptive analysis was undertaken. Only 16% of adult deaths and 27% of child deaths occurred in healthcare settings. Healthcare utilization for the terminal illness was reported in two thirds of medical (non-injury) causes of death. Supporting medical evidence was available in <10% of cases to supplement the interpretation of verbal autopsies. About 14% of bereaved caregivers refused to give written consent but provided oral consent. Additional ethical concerns included inability to ensure privacy in 15% of interviews and unsolicited information from unauthorized neighbours in 5% of cases. Such methodological, logistical and ethical issues operate to impact on the quality of VAs. Consideration of these issues would strengthen ongoing efforts in the harmonization of VA procedures. PMID- 22543420 TI - Cognitive interventions to reduce diagnostic error: a narrative review. AB - BACKGROUND: Errors in clinical reasoning occur in most cases in which the diagnosis is missed, delayed or wrong. The goal of this review was to identify interventions that might reduce the likelihood of these cognitive errors. DESIGN: We searched PubMed and other medical and non-medical databases and identified additional literature through references from the initial data set and suggestions from subject matter experts. Articles were included if they either suggested a possible intervention or formally evaluated an intervention and excluded if they focused solely on improving diagnostic tests or provider satisfaction. RESULTS: We identified 141 articles for full review, 42 reporting tested interventions to reduce the likelihood of cognitive errors, 100 containing suggestions, and one article with both suggested and tested interventions. Articles were classified into three categories: (1) Interventions to improve knowledge and experience, such as simulation-based training, improved feedback and education focused on a single disease; (2) Interventions to improve clinical reasoning and decision-making skills, such as reflective practice and active metacognitive review; and (3) Interventions that provide cognitive 'help' that included use of electronic records and integrated decision support, informaticians and facilitating access to information, second opinions and specialists. CONCLUSIONS: We identified a wide range of possible approaches to reduce cognitive errors in diagnosis. Not all the suggestions have been tested, and of those that have, the evaluations typically involved trainees in artificial settings, making it difficult to extrapolate the results to actual practice. Future progress in this area will require methodological refinements in outcome evaluation and rigorously evaluating interventions already suggested, many of which are well conceptualised and widely endorsed. PMID- 22543421 TI - A novel strain of Brevibacillus laterosporus produces chitinases that contribute to its biocontrol potential. AB - A novel strain exhibiting entomopathogenic and chitinolytic activity was isolated from mangrove marsh soil in India. The isolate was identified as Brevibacillus laterosporus by phenotypic characterization and 16S rRNA sequencing and designated Lak1210. When grown in the presence of colloidal chitin as the sole carbon source, the isolate produced extracellular chitinases. Chitinase activity was inhibited by allosamidin indicating that the enzymes belong to the family 18 chitinases. The chitinases were purified by ammonium sulfate precipitation followed by chitin affinity chromatography yielding chitinases and chitinase fragments with 90, 75, 70, 55, 45, and 25 kDa masses. Mass spectrometric analyses of tryptic fragments showed that these fragments belong to two distinct chitinases that are almost identical to two putative chitinases, a 89.6-kDa four domain chitodextrinase and a 69.4-kDa two-domain enzyme called ChiA1, that are encoded on the recently sequenced genome of B. laterosporus LMG15441. The chitinase mixture showed two pH optima, at 6.0 and 8.0, and an optimum temperature of 70 degrees C. The enzymes exhibited antifungal activity against the phytopathogenic fungus Fusarium equiseti. Insect toxicity bioassays with larvae of diamondback moths (Plutella xylostella), showed that addition of chitinases reduced the time to reach 50 % mortality upon infection with non induced B. laterosporus from 3.3 to 2.1 days. This study provides evidence for the presence of inducible, extracellular chitinolytic enzymes in B. laterosporus that contribute to the strain's antifungal activity and insecticidal activity. PMID- 22543422 TI - Correlation lengths, porosity and water adsorption in TiO2 thin films prepared by glancing angle deposition. AB - This paper reports a thorough microstructural characterization of glancing angle deposited (GLAD) TiO(2) thin films. Atomic force microscopy (afm), grazing incidence small-angle x-ray scattering (GISAXS) and water adsorption isotherms have been used to determine the evolution of porosity and the existence of some correlation distances between the nanocolumns constituting the basic elements of the film's nanostructure. It is found that the deposition angle and, to a lesser extent, the film thickness are the most important parameters controlling properties of the thin film. The importance of porosity and some critical dimensions encountered in the investigated GLAD thin films is highlighted in relation to the analysis of their optical properties when utilized as antireflective coatings or as hosts and templates for the development of new composite materials. PMID- 22543423 TI - Cellular and molecular processes leading to embryo formation in sponges: evidences for high conservation of processes throughout animal evolution. AB - The emergence of multicellularity is regarded as one of the major evolutionary events of life. This transition unicellularity/pluricellularity was acquired independently several times (King 2004). The acquisition of multicellularity implies the emergence of cellular cohesion and means of communication, as well as molecular mechanisms enabling the control of morphogenesis and body plan patterning. Some of these molecular tools seem to have predated the acquisition of multicellularity while others are regarded as the acquisition of specific lineages. Morphogenesis consists in the spatial migration of cells or cell layers during embryonic development, metamorphosis, asexual reproduction, growth, and regeneration, resulting in the formation and patterning of a body. In this paper, our aim is to review what is currently known concerning basal metazoans--sponges' morphogenesis from the tissular, cellular, and molecular points of view--and what remains to elucidate. Our review attempts to show that morphogenetic processes found in sponges are as diverse and complex as those found in other animals. In true epithelial sponges (Homoscleromorpha), as well as in others, we find similar cell/layer movements, cellular shape changes involved in major morphogenetic processes such as embryogenesis or larval metamorphosis. Thus, sponges can provide information enabling us to better understand early animal evolution at the molecular level but also at the cell/cell layer level. Indeed, comparison of molecular tools will only be of value if accompanied by functional data and expression studies during morphogenetic processes. PMID- 22543424 TI - Transpulmonary thermodilution measurements are not affected by continuous veno venous hemofiltration at high blood pump flow. AB - PURPOSE: To assess whether continuous veno-venous hemofiltration (CVVH) with high blood pump flow alters the measurements of cardiac index (CI), global end diastolic volume indexed (GEDVI), and extravascular lung water indexed (EVLWI) performed by transpulmonary thermodilution. METHODS: Sixty-nine patients were included if they were monitored by a PiCCO2 device and received CVVH through a femoral (n = 62) or an internal jugular (n = 7) dialysis catheter. The blood pump flow was set at 250 mL/min (n = 31) or 350 mL/min (n = 38) and the filtration flow at 6,000 mL/h. A first set of data was collected with a first transpulmonary thermodilution (TD(on)). The blood pump was stopped and the continuous CI derived from pulse contour analysis was recorded (PC(off)). A second data set (TD(off)) was collected before and a last one (TD(on-last)) after restarting the blood pump. RESULTS: [Formula: see text], [Formula: see text], [Formula: see text] , and [Formula: see text] were not significantly different in patients with a femoral dialysis catheter (3.49 +/- 0.96, 3.51 +/- 0.96, 3.51 +/- 0.99, and 3.44 +/- 1.00 L min(-1) m(-2), respectively). This was observed with a blood pump flow at 350 mL/min and at 250 mL/min. In these patients with a femoral dialysis catheter, GEDVI did not significantly change when the blood pump was stopped. EVLWI significantly decreased when the blood pump was stopped but to a non clinically relevant extent (-0.3 +/- 0.8 mL/kg). No significant changes in CI, GEDVI, and EVLWI were observed in patients with an internal jugular dialysis catheter over the study period. CONCLUSIONS: CVVH with a high blood flow pump does not alter the transpulmonary thermodilution measurements of CI, GEDVI, and EVLWI. PMID- 22543425 TI - Outcomes in children with refractory pneumonia supported with extracorporeal membrane oxygenation. AB - PURPOSE: To review the use of extracorporeal membrane oxygenation (ECMO) in severe paediatric pneumonia and evaluate factors that may affect efficacy of this treatment. METHODS: Retrospective study of the ECMO database of a tertiary paediatric intensive care unit and chart review of all patients who were managed with ECMO during their treatment for severe pneumonia over a 23-year period. The main outcome measures were survival to hospital discharge, and ICU and hospital length of stay. We compared the groups of culture-positive versus culture negative pneumonia, venoarterial (VA) versus venovenous (VV) ECMO, community- versus hospital-acquired cases, and cases before and after 2005. RESULTS: Fifty patients had 52 cases of pneumonia managed with ECMO. Community-acquired cases were sicker with higher oxygenation index (41.5 +/- 20.5 versus 26.8 +/- 17.8; p = 0.031) and higher inotrope score [20 (5-37.5) versus 7.5 (0-18.8); p = 0.07]. Use of VA compared with VV ECMO was associated with higher inotrope scores [20 (10-50) versus 5 (0-20); p = 0.012]. There was a trend towards improved survival in the VV ECMO group (82.4 versus 62.9 %; p = 0.15). Since 2005, patients have been older [4.7 (1-8) versus 1.25 (0.15-2.8) years; p = 0.008] and survival has improved (88.2 versus 60.0 %; p = 0.039). CONCLUSIONS: Survival in children with pneumonia requiring ECMO has improved over time and is now 90 % in the modern era. Risk factors for death include performing a circuit change [odds ratio (OR) 5.0; 95 % confidence interval (CI) 1.02-24.41; p = 0.047] and use of continuous renal replacement therapy (OR 4.2; 95 % CI 1.13-15.59; p = 0.032). PMID- 22543426 TI - Red, green and blue lasing enabled by single-exciton gain in colloidal quantum dot films. AB - Colloidal quantum dots exhibit efficient photoluminescence with widely tunable bandgaps as a result of quantum confinement effects. Such quantum dots are emerging as an appealing complement to epitaxial semiconductor laser materials, which are ubiquitous and technologically mature, but unable to cover the full visible spectrum (red, green and blue; RGB). However, the requirement for high colloidal-quantum-dot packing density, and losses due to non-radiative multiexcitonic Auger recombination, have hindered the development of lasers based on colloidal quantum dots. Here, we engineer CdSe/ZnCdS core/shell colloidal quantum dots with aromatic ligands, which form densely packed films exhibiting optical gain across the visible spectrum with less than one exciton per colloidal quantum dot on average. This single-exciton gain allows the films to reach the threshold of amplified spontaneous emission at very low optical pump energy densities of 90 uJ cm(-2), more than one order of magnitude better than previously reported values. We leverage the low-threshold gain of these nanocomposite films to produce the first colloidal-quantum-dot vertical-cavity surface-emitting lasers (CQD-VCSEL). Our results represent a significant step towards full-colour single-material lasers. PMID- 22543427 TI - Nanoelectromechanical contact switches. AB - Nanoelectromechanical (NEM) switches are similar to conventional semiconductor switches in that they can be used as relays, transistors, logic devices and sensors. However, the operating principles of NEM switches and semiconductor switches are fundamentally different. These differences give NEM switches an advantage over semiconductor switches in some applications--for example, NEM switches perform much better in extreme environments--but semiconductor switches benefit from a much superior manufacturing infrastructure. Here we review the potential of NEM-switch technologies to complement or selectively replace conventional complementary metal-oxide semiconductor technology, and identify the challenges involved in the large-scale manufacture of a representative set of NEM based devices. PMID- 22543428 TI - Neurostimulation therapies for primary headache disorders: present and future. AB - PURPOSE OF REVIEW: Most pharmacological treatments of primary headache disorders are partially effective and have cumbersome side effects. Therapies with better efficacy and tolerance are needed. Neurostimulation techniques may have this potential. This is an attempt to summarize the latest clinical trial results published in the field. RECENT FINDINGS: Hypothalamic deep brain stimulation is effective in drug-resistant chronic cluster headache (drCCH) but not riskless. Recent anatomical MRI studies indicate that the effective stimulation sites are rather widespread. Occipital nerve stimulation (ONS) seems to be effective in up to 76% of drCCH patients and its benefit long-lasting. A minority of patients are able to abandon preventive drugs. Its mechanism of action appears nonspecific. In chronic migraine, randomized controlled trials of ONS showed recently encouraging results, but long-term studies are missing. An ongoing sham-controlled trial suggests sphenopalatine ganglion neurostimulation (SPGS) efficacy in drCCH acute treatment, but possibly also in preventive therapy. Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) modulate cortical excitability and connectivity. TMS could prevent headache when applied over the occipital cortex during the migraine aura. Repetitive TMS and tDCS have provided mixed results in a few small studies and warrant further trials. SUMMARY: Neurostimulation therapies inaugurate a new era in headache management and offer a promising alternative to medications. Future studies are necessary to provide evidence-based efficacy data, knowledge on their mode of action and information about their pharmaco-economic advantages. PMID- 22543429 TI - Mitochondrial changes within axons in multiple sclerosis: an update. AB - PURPOSE OF REVIEW: Here, we discuss the recent developments in axonal mitochondrial response to demyelination and remyelination in multiple sclerosis (MS), and following experimental demyelination as well as myelination. RECENT FINDINGS: There is a gathering body of evidence implicating an energy-deficient state in the pathogenesis of MS, and mitochondrial defects have been the subject of a number of previous reviews. In myelinated axons within the central nervous system, over 90% of mitochondria are located within juxtaparanodal and internodal axoplasm. The electrogenic machinery, mitochondria and myelin form a triad that is disrupted in MS. The axonal mitochondrial content increases following demyelination and persists despite the residual inflammatory reaction subsiding to levels seen in control cases. The changes in axonal mitochondrial content following demyelination in MS and experimental demyelination in vivo and in vitro do not return to the levels in nondemyelinated and myelinated axons following remyelination. SUMMARY: Understanding the mechanisms of axonal mitochondrial response to a disturbance in myelin and determining if certain aspects of the axonal mitochondrial response to demyelinated and remyelinated axons are beneficial may identify potential therapeutic targets for the progressive forms of MS. PMID- 22543430 TI - The use of harmonic scalpel in spinal surgery with contraindication to the use of monopolar electrocautery: a case report in a 14-year-old girl with a primary generalized dystonia and a 100 degrees thoracic scoliosis. PMID- 22543431 TI - Pediatric meningiomas in The Netherlands 1974-2010: a descriptive epidemiological case study. AB - OBJECTIVE: The purpose of this study was to review the epidemiology and the clinical, radiological, pathological, and follow-up data of all surgically treated pediatric meningiomas during the last 35 years in The Netherlands. METHODS: Patients were identified in the Pathological and Anatomical Nationwide Computerized Archive database, the nationwide network and registry of histopathology and cytopathology in The Netherlands. Pediatric patients of 18 years or younger at first operation in 1974-2009 with the diagnosis meningioma were included. Clinical records, follow-up data, radiological findings, operative reports, and pathological examinations were reviewed. RESULTS: In total, 72 patients (39 boys) were identified. The incidence of operated meningiomas in the Dutch pediatric population is 1:1,767,715 children per year. Median age at diagnosis was 13 years (range 0-18 years). Raised intracranial pressure and seizures were the most frequent signs at presentation. Thirteen (18 %) patients had neurofibromatosis type 2 (NF2). Fifty-three (74 %) patients had a meningioma World Health Organization grade I. Total resection was achieved in 35 of 64 patients. Fifteen patients received radiotherapy postoperatively. Mean follow-up was 4.8 years (range 0-27.8 years). Three patients died as a direct result of their meningioma within 3 years. Four patients with NF2 died as a result of multiple tumors. Nineteen patients had disease progression, requiring additional treatment. CONCLUSION: Meningiomas are extremely rare in the pediatric population; 25 % of all described meningiomas show biological aggressive behavior in terms of disease progression, requiring additional treatment. The 5-year survival is 83.9 %, suggesting that the biological behavior of pediatric menigiomas is more aggressive than that of its adult counterparts. PMID- 22543432 TI - Cavum septum pellucidum cyst in children: a case-based update. AB - BACKGROUND: Cavum septum pellucidum (CSP) cysts are rare lesions which are frequently asymptomatic. Some clinical findings may be associated with CSP cysts, such as headache and other symptoms of increased intracranial pressure, neurological deficit, and mental status changes. There is still controversy in the management of symptomatic cases, especially in children. The main difficulty is to establish a correlation between symptoms and the cyst. When indicated, the treatment is essentially surgical, and the ideal operative technique is also a matter of debate. CASE REPORT: We present a case of a 14-year-old boy with a symptomatic CSP cyst who was successfully treated by neuronavigation-assisted neuroendoscopy with a bilateral fenestration. A literature review is provided with regard to clinical presentation, treatment, and outcome in children. CONCLUSION: The treatment is considered whenever there is an association of a CSP cyst on imaging studies and symptoms attributable to the obstruction of the cerebrospinal fluid flow or direct compression of surrounding structures by the cyst. Endoscopic fenestration is a less invasive and highly effective technique, and is currently the treatment of choice for such lesions in children. PMID- 22543434 TI - Endoscopic fenestration of cavum velum interpositum cysts: a case study of two symptomatic patients. AB - INTRODUCTION: Cavum velum interpositum (CVI) is commonly an incidental asymptomatic finding on imaging studies. Encystment can occur and, in most situations, is also asymptomatic. Clinical symptoms occurring in patients with CVI cysts have been reported infrequently with the result that the relationship of these symptoms and the cyst are usually unclear. This report contributes to the knowledge base of symptoms that can occur in patients with CVI and the response of symptoms to effective treatment. PATIENTS AND METHODS: We report the clinical outcomes of a 3-year-old male patient and a 13-year-old female patient with symptoms and CVI cysts on imaging who were treated successfully with endoscopic fenestration. RESULTS: The developmental delay and occasional headache present in the 3-year-old male patient resolved after endoscopic fenestration; however, the 13-year-old patient who had neuropsychiatric symptoms did not improve. CONCLUSIONS: Our cases add to the literature describing the response to cyst treatment in symptomatic patients harboring CVI cysts. Symptoms due to CSF pathway obstruction may respond to cyst fenestration, while the response of symptoms in patents who do not have clear CSF circulation disorders is less predictable. PMID- 22543433 TI - Langerhans' cell histiocytosis in the pediatric spine: therapeutic dynamic change of spinal deformity. PMID- 22543435 TI - Anomalous pancreaticobiliary junction. PMID- 22543436 TI - Clinical significance of eosinophilia and chronic inflammatory infiltrate in children's rectal biopsies. AB - AIMS: The aim of the present study was to determine the clinical significance of an incidental finding of eosinophilia (EOS) and chronic inflammatory infiltrate (CINF) in rectal biopsies of children investigated for suspected Hirschsprung disease (HSCR). METHODS: A retrospective study (2000-2010) of children incidentally found to have EOS and CINF was performed. HSCR cases were excluded. Presence of gastrointestinal (GI) symptoms and nutritional status (weight-for-age z score) were investigated and compared with a matched cohort with normal biopsy. RESULTS: Of 364 children undergoing rectal biopsy for suspected HSCR, 109 had confirmed HSCR, whereas 255 children had normal ganglia. Forty-four of 255 (17%) children had EOS and/or CINF incidentally reported and are the subject of the present study. In 13 of 44 (29%) children, the biopsy was performed neonatally. At follow-up (4.6 months [1-22]), 21 (48%) had food and/or milk allergy, 30 (68%) had constipation and/or other GI symptoms. There was no change in weight-for-age z score (P = 0.85) at follow-up and 8 (20%) had failure to thrive. Only 10 of 44 (P = 0.0001 vs patients with EOS and/or CINF) children with normal biopsy had persistent constipation at follow-up (9.7 months [0.5-84.7]) and 1 patient had atopy. Patients with normal biopsy exhibited an increase in weight-for-age z score at follow-up (P = 0.003) and only 3 patients (7%) had failure to thrive. CONCLUSIONS: EOS and CINF are found in 17% of children who had rectal biopsies negative for HSCR. Half of these children will need further medical input for the presence of persisting GI symptoms, food/milk allergy and failure to thrive, and the possibility to develop inflammatory bowel disease later in life. PMID- 22543438 TI - Guest editorial: toward a systemic approach to the global health workforce. PMID- 22543437 TI - Analysis of ehealth search perspectives among female college students in the health professions using Q methodology. AB - BACKGROUND: The current "Millennial Generation" of college students majoring in the health professions has unprecedented access to the Internet. Although some research has been initiated among medical professionals to investigate the cognitive basis for health information searches on the Internet, little is known about Internet search practices among health and medical professional students. OBJECTIVE: To systematically identify health professional college student perspectives of personal eHealth search practices. METHODS: Q methodology was used to examine subjective perspectives regarding personal eHealth search practices among allied health students majoring in a health education degree program. Thirteen (n = 13) undergraduate students were interviewed about their attitudes and experiences conducting eHealth searches. From the interviews, 36 statements were used in a structured ranking task to identify clusters and determine which specific perceptions of eHealth search practices discriminated students into different groups. Scores on an objective measure of eHealth literacy were used to help categorize participant perspectives. RESULTS: Q technique factor analysis of the rankings identified 3 clusters of respondents with differing views on eHealth searches that generally coincided with participants' objective eHealth literacy scores. The proficient resourceful students (pattern/structure coefficient range 0.56-0.80) described themselves as using multiple resources to obtain eHealth information, as opposed to simply relying on Internet search engines. The intermediate reluctant students (pattern/structure coefficient range 0.75-0.90) reported engaging only Internet search engines to locate eHealth information, citing undeveloped evaluation skills when considering sources of information located on the Internet. Both groups of advanced students reported not knowing how to use Boolean operators to conduct Internet health searches. The basic hubristic students (pattern/structure coefficient range 0.54-0.76) described themselves as independent procrastinators when searching for eHealth information. Interestingly, basic hubristic students represented the only cluster of participants to describe themselves as (1) having received instruction on using the Internet to conduct eHealth searches, and (2) possessing relative confidence when completing a search task. CONCLUSIONS: Subjective perspectives of eHealth search practices differed among students possessing different levels of eHealth literacy. These multiple perspectives present both challenges and opportunities for empowering college students in the health professions to use the Internet to obtain and appraise evidence-based health information using the Internet. PMID- 22543439 TI - The Global Health Initiative and the health workforce. AB - The United States Government (USG) strategy for global health is embodied in the Global Health Initiative (GHI), announced by President Obama in 2009. The GHI addresses the array of US global health programs and concerns. There is laudable recognition of the health workforce crisis as a major barrier to achieving the Millennium Development Goals and the USG's global health goals. Significant funding is provided to train health workers and conduct other activities that may be seen as addressing the health workforce crisis. Unfortunately, the USG approach to the health workforce is not guided by a coherent strategy. In sharp contrast to its approach to more traditional, disease-specific programs, the GHI fails to articulate objectives, technical approach, metrics, organization, staffing or resource allocation with regard to the health workforce. The result is a series of projects unguided by any framework. The article outlines a health workforce strategy for the GHI. It proposes objectives, a technical approach, key indicators of progress, structural reforms and resource requirements. PMID- 22543440 TI - Reducing maternal mortality in Senegal: using GIS to identify priority regions for the expansion of human resources for health. AB - In 2005, Senegal had an estimated maternal mortality ratio of 980 deaths per 100,000 live births, well above the global average of 400. The concentration of health workers has been shown to be associated with improved health outcomes, including maternal mortality. To explore this relationship, this paper uses geographic information systems (GIS) to examine the regional distribution of human resources for health and related maternal health indicators in Senegal. Results show that a regional imbalance in the distribution of health personnel and health indicators exists in Senegal. This disparity may contribute to the disproportionate burden of disease experienced in the eastern part of the country. Based on a spatial analysis, a priority index is used to identify regions to target for the recruitment and training of midwives. GIS is an appropriate and practical tool for governments and other agencies to use in identifying regional disparities and for priority setting. PMID- 22543441 TI - Making non-discrimination and equal opportunity a reality in Kenya's health provider education system: results of a gender analysis. AB - IntraHealth International's USAID-funded Capacity Kenya project conducted a performance needs assessment of the Kenya health provider education system in 2010. Various stakeholders shared their understandings of the role played by gender and identified opportunities to improve gender equality in health provider education. Findings suggest that occupational segregation, sexual harassment and discrimination based on pregnancy and family responsibilities present problems, especially for female students and faculty. To grow and sustain its workforce over the long term, Kenyan human resource leaders and managers must act to eliminate gender-based obstacles by implementing existing non-discrimination and equal opportunity policies and laws to increase the entry, retention and productivity of students and faculty. Families and communities must support girls' schooling and defer early marriage. All this will result in a fuller pool of students, faculty and matriculated health workers and, ultimately, a more robust health workforce to meet Kenya's health challenges. PMID- 22543442 TI - Will they stay or will they go? Putting theory into practice to guide effective workforce retention mechanisms. AB - Policy makers in healthcare in all countries are faced with challenges of designing and implementing strategies that will achieve three major and essential goals: produce enough health workers for a cost-effective skills mix to deliver high-quality care; attract trained health workers into the workforce; and deploy health workers where they are most needed and keep them there. Yet these apparently straightforward strategies are seldom wholly successful, and there is little clear evidence to guide the frustrated policy maker. This paper explores the reasons why it may be so difficult to come up with strategies that guarantee success and looks at what we do know about attracting, retaining and motivating health workers to get them and keep them working productively where they are most needed. PMID- 22543443 TI - Acute pancreatitis in pediatrics: a systematic review of the literature. AB - OBJECTIVE: To describe the main epidemiological, clinical, diagnostic and treatment aspects of children with acute pancreatitis. SOURCES: Systematic review of MEDLINE and SciELO databases in the last 5 years on acute pancreatitis in children, as well as consultation of relevant references on the texts obtained. SUMMARY OF THE FINDINGS: Cases of acute pancreatitis in children have received growing attention in recent years, and an increase in the number of cases has been reported in several studies. The main etiologies in children involve biliary disease, drug-induced pancreatitis, recurrent hereditary pancreatitis and trauma, and up to 30% of cases have no defined etiology. The diagnosis is based on the combination of clinical and laboratory aspects with the increase of acinar enzymes and radiologic tests. Initial support treatment, with proper volume replacement and correction of the metabolic disturbances, besides specific nutritional therapy, are the fundamental points in the handling of acute conditions. Long term complications are unusual, and mortality rates are inferior to the rates for the adult population. CONCLUSION: The early diagnosis and the appropriate handling can contribute to a better outcome for the child with pancreatitis and to prevent the immediate and late complications related to the disease. More studies are required to better explain aspects related to the clinical and radiological diagnosis of pancreatitis in children, as well as aspects related to the nutritional therapy for this age group. PMID- 22543444 TI - Decompressive craniectomy for encephalitis with brain herniation: case report and review of the literature. AB - BACKGROUND: Decompressive craniectomy (DC) has been sporadically used in cases of infectious encephalitis with brain herniation. Like for other indications of DC, evidence is lacking regarding the beneficial or detrimental effects for this pathology. METHODS: We reviewed all the cases of viral and bacterial encephalitis treated with decompressive craniectomy reported in the literature. We also present one case from our institution. These data were analyzed to determine the relation between clinical and epidemiological variables and outcome in surgically treated patients. RESULTS: Of 48 patients, 39 (81.25 %) had a favorable functional recovery and 9 (18.75 %) had a negative course. Only two patients (4 %) died after surgical treatment. A statistically significant association was found between diagnosis (viral and bacterial encephalitis) and outcome (GOS) in surgically treated patients. Viral encephalitis, usually caused by herpes simplex virus (HSV), has a more favorable outcome (92.3 % with GOS 4 or 5) than bacterial encephalitis (56.2 % with GOS 4 or 5). CONCLUSIONS: Based on this literature review, we consider that, due to the specific characteristics of infectious encephalitis, especially in case of viral infection, decompressive craniectomy is probably an effective treatment when brain stem compression threatens the course of the disease. In patients with viral encephalitis, better prognosis can be expected when surgical decompression is used than when only medical treatment is provided. PMID- 22543445 TI - Rh2O3 versus IrO2: relativistic effects and the stability of Ir4+. AB - Despite the wide-ranging applications of binary Rh and Ir oxides, their stability and trends in Rh and Ir oxidation states are not fully understood. Using first principles electronic structure calculations, we demonstrate that the origin of the categorical stability of Ir(4+) is the relativistic contraction of the 6s orbital and, consequently, an expansion of 5d orbitals. Relativistic effects significantly stabilize Ir(4+)-containing metallic rutile IrO(2) over a wide range of O chemical potentials, despite the choice that Ir has of forming semiconducting corundum Ir(2)O(3). In contrast, Rh is found to display a wider stability range for corundum Rh(2)O(3) with Rh(3+) and a greater propensity for multiple oxidation states. PMID- 22543446 TI - Cluster-tic syndrome as the initial manifestation of multiple sclerosis. AB - We report the case of a patient diagnosed as having cluster-tic syndrome as the initial manifestation of multiple sclerosis (MS). The patient's headache bouts improved after treatment with antiepileptic drugs, steroids, and beta-interferon. Magnetic resonance imaging (MRI) scans showed a pontine demyelinating lesion involving the area of the trigeminal root inlet and main sensory nucleus. Neurophysiological studies correlated well with MRI lesions. The association between cluster-tic syndrome and MS is an exception, and the mechanism of the pain is still unknown; therefore, this case might suggest a pathophysiological relationship between the trigeminal main sensory nucleus and cluster-tic syndrome. PMID- 22543447 TI - Triggered release in lipid bilayer-capped mesoporous silica nanoparticles containing SPION using an alternating magnetic field. AB - We report here the on-command cargo controlled delivery using an alternating magnetic field (AMF) from magnetic silica mesoporous supports capped with a lipid bilayer. PMID- 22543448 TI - Detection of DNA based on fluorescence resonance energy transfer of polyelectrolyte-protected CdTe quantum dots as energy donors. AB - The approach for DNA detection was established by using a fluorescence resonance energy transfer (FRET) system, in which the energy donor was poly diallyldimethylammonium chloride-protected quantum dots and the energy receptor was ethidium bromide (EB) inserting into the double stranded DNA. The concentration of the probe DNA, EB and NaCl was optimized. Under the optimized conditions, the FRET system has a stable signal and good reproducibility. The linear range is 7.7-61.6 nM with the correlation coefficient of 0.998 and the limit of detection is 7.7 nM. This method is simple and sensitive, and makes the label-free DNA detection come true. PMID- 22543449 TI - Ligand symmetry-equivalence on thiolate protected gold nanoclusters determined by NMR spectroscopy. AB - The Au(144)(SR)(60) nanocluster has been a subject of structural conjecture since its initial description over a decade ago as a 29 kDa compound, yet a decisive empirical structure is elusive. Herein we show that (1)H NMR spectroscopy can provide a detailed view of ligand-layer equivalence for thiolate protected gold nanoclusters. We show that Au(25)(SR)(18), Au(38)(SR)(24) and Au(102)(SR)(44) nanoclusters have (1)H NMR spectra where the number of distinct chemical environments for the R-groups is equivalent to the number of symmetry environments of the sulfur headgroups, which anchor each ligand. We also show that the Au(144)(SR)(60)(1)H NMR spectrum is consistent with a previously published DFT-derived structural model for Au(144)(SR)(60). We suggest that this analysis may be extended to other structurally obscure nanoclusters, such as a ~59 kDa compound for which we observe up to four symmetry environments. PMID- 22543450 TI - Surface-enhanced Raman spectroscopy using gold-coated horizontally aligned carbon nanotubes. AB - Gold-coated horizontally aligned carbon nanotube (Au-HA-CNT) substrates were fabricated for surface-enhanced Raman spectroscopy (SERS). The Au-HA-CNT substrates, which are granular in nature, are easy-to-prepare with large SERS active area. Enhancement factors (EFs) of ~10(7) were achieved using the Au-HA CNTs as substrates for rhodamine 6G (R6G) molecules. Maximum enhancement was found when the polarization direction (E-field) of the incident laser beam was parallel to the aligned direction of the HA-CNTs. Simulations using the finite difference time-domain (FDTD) method were carried out for the granular Au-HA-CNT samples. Enhancement mechanisms and determination of EFs were analyzed. Biological samples, including (13)C- and deuterium (D)-labeled fatty acids and Coccomyxa sp. c-169 microalgae cells, were also measured using this SERS substrate. The limits of detection (LODs) of D- and (13)C-labeled fatty acids on the SERS substrate were measured to be around 10 nM and 20 nM, respectively. Significantly enhanced Raman signals from the microalgae cells were acquired using the SERS substrate. PMID- 22543451 TI - Specific adsorption of tungstate by cell surface display of the newly designed ModE mutant. AB - By cell surface display of ModE protein that is a transcriptional regulator of operons involved in the molybdenum metabolism in Escherichia coli, we have constructed a molybdate-binding yeast (Nishitani et al., Appl Microbiol Biotechnol 86:641-648, 2010). In this study, the binding specificity of the molybdate-binding domain of the ModE protein displayed on yeast cell surface was improved by substituting the amino acids involved in oxyanion binding with other amino acids. Although the displayed S126T, R128E, and T163S mutant proteins adsorbed neither molybdate nor tungstate, the displayed ModE mutant protein (T163Y) abolished only molybdate adsorption, exhibiting the specific adsorption of tungstate. The specificity of the displayed ModE mutant protein (T163Y) for tungstate was increased by approximately 9.31-fold compared to the displayed wild type ModE protein at pH 5.4. Therefore, the strategy of protein design and its cell surface display is effective for the molecular breeding of bioadsorbents with metal-specific adsorption ability based on a single species of microorganism without isolation from nature. PMID- 22543452 TI - Molinate biodegradation in soils: natural attenuation versus bioaugmentation. AB - The aims of the present study were to assess the potential of natural attenuation or bioaugmentation to reduce soil molinate contamination in paddy field soils and the impact of these bioremediation strategies on the composition of soil indigenous microbiota. A molinate mineralizing culture (mixed culture DC) was used as inoculum in the bioaugmentation assays. Significantly higher removal of molinate was observed in bioaugmentation than in natural attenuation microcosms (63 and 39 %, respectively) after 42 days of incubation at 22 degrees C. In the bioaugmentation assays, the impact of Gulosibacter molinativorax ON4(T) on molinate depletion was observed since the gene encoding the enzyme responsible for the initial molinate breakdown (harboured by that actinobacterium) was only detected in inoculated microcosms. Nevertheless, the exogenous mixed culture DC did not overgrow as the heterotrophic counts of the bioaugmentation microcosms were not significantly different from those of natural attenuation and controls. Moreover, the actinobacterial clone libraries generated from the bioaugmentation microcosms did not include any 16S rRNA gene sequences with significant similarity to that of G. molinativorax ON4(T). The multivariate analysis of the 16S rRNA DGGE patterns of the soil microcosm suggested that the activity of mixed culture DC did not affect the soil bacterial community structure since the DGGE patterns of the bioaugmentation microcosms clustered with those of natural attenuation and controls. Although both bioremediation approaches removed molinate without indigenous microbiota perturbation, the results suggested that bioaugmentation with mixed culture DC was more effective to treat soils contaminated with molinate. PMID- 22543453 TI - Smooth muscle actin expression in primary bone tumours. AB - Alpha isoform of smooth muscle actin (SMA) expression has been reported in giant cell tumour of bone (GCTB) and other benign and malignant bone tumours, but the pattern of SMA expression and the precise nature of SMA-expressing cells in these lesions is uncertain. We determined by immunohistochemistry the expression of SMA and other muscle and vascular markers in normal bone, GCTB and a wide range of primary benign and malignant bone tumours. Cultured stromal cells of GCTB, chondroblastoma (CB), and aneurysmal bone cyst (ABC) were also analysed for SMA expression. SMA was only noted in blood vessels in normal bone. SMA was expressed by mononuclear stromal cells (MSC) cultured from GCTB, ABC and CB. SMA was strongly and diffusely expressed by MSC in non-ossifying fibroma, fibrous dysplasia, and "brown tumour" of hyperparathyroidism. SMA expression was also noted in GCTB, ABC, CB, chondromyxoid fibroma, malignant fibrous histiocytoma of bone and osteosarcoma. Little or no SMA was noted in Langerhans cell histiocytosis, simple bone cyst, Ewing's sarcoma, osteoblastoma, osteoid osteoma, enchondroma, osteochondroma, chondrosarcoma, myeloma, lymphoma, chordoma and adamantinoma. Our findings show that there is differential SMA expression in primary bone tumours and that identifying the presence or absence of SMA is useful in the differential diagnosis of these lesions. The nature of SMA expressing cells in bone tumours is uncertain but they are negative for desmin and caldesmon and could represent either myofibroblasts or perivascular cells, such as pericytes. PMID- 22543454 TI - Control of peptide assembly through directional interactions. AB - We demonstrate the self-assembly of tripeptide amphiphiles into spherical hollow capsules from linear nanoribbons via control of the molecular packing. We achieved a transition of arrangement from anisotropic to isotropic by an elaborate design of the molecular architecture. PMID- 22543455 TI - Innovation and value-driven engineering. AB - Emerging strategies to simultaneously catalyse rewardable innovation in the field of medical devices and reduce health-care costs could also be applicable in drug development. PMID- 22543456 TI - Anti-NGF painkillers back on track? PMID- 22543457 TI - Oncology trials gear up for high-throughput sequencing. PMID- 22543459 TI - Trial watch: Genetic association studies link interleukin-6 receptor to coronary heart disease. PMID- 22543460 TI - Deal watch: Alcon invests in first non-surgical therapy for common eye disorder. PMID- 22543461 TI - Ivacaftor. PMID- 22543462 TI - Neurodegenerative disease: The stress of misfolding. PMID- 22543463 TI - Cancer genomics: Constructing a 'cancerpaedia'. PMID- 22543468 TI - Finding the sweet spot: the role of nature and nurture in medicinal chemistry. AB - Given its position at the heart of small-molecule drug discovery, medicinal chemistry has an important role in tackling the well-known productivity challenges in pharmaceutical research and development. In recent years, extensive analyses of successful and failed discovery compounds and drug candidates have improved our understanding of the role of physicochemical properties in drug attrition. Based on the clarified challenges in finding the 'sweet spot' in medicinal chemistry programmes, we suggest that this goal can be achieved through a combination of first identifying chemical starting points with appropriate 'nature' and then rigorously 'nurturing' them during lead optimization. Here, we discuss scientific, strategic, organizational and cultural considerations for medicinal chemistry practices, with the aim of promoting more effective use of what is already known, as well as a wider appreciation of the risks of pursuing suboptimal compounds. PMID- 22543470 TI - Three-dimensional in vivo motion analysis of normal knees employing transepicondylar axis as an evaluation parameter. AB - PURPOSE: The transepicondylar axis (TEA) has been used as a flexion axis of the knee and a reference of the rotational alignment of the femoral component. However, no study has showed dynamic normal knee kinematics employing TEA as the evaluation parameter throughout the full range of motion in vivo. The purpose of this study was to analyze dynamic kinematics of the normal knee through the full range of motion via the 3-dimensional to 2-dimensional registration technique employing TEA as the evaluation parameter. METHODS: Dynamic motion of the right knee was analyzed in 20 healthy volunteers (10 female, 10 male; mean age 37.2 years). Knee motion was observed as subjects squatted from standing with knee fully extended to maximum flexion. The following parameters were determined: (1) Anteroposterior translations of the medial and lateral ends of the TEA; and (2) changes in the angle of the TEA on the tibial axial plane (rotation angle). RESULTS: The medial end of the TEA demonstrated anterior translation (3.6 +/- 3.0 mm) from full extension to 30 degrees flexion and demonstrated posterior translation (18.1 +/- 3.7 mm) after 30 degrees , while the lateral end of the TEA demonstrated consistent posterior translation (31.1 +/- 7.3 mm) throughout knee flexion. All subjects exhibited femoral external rotation (16.9 +/- 6.2 degrees ) relative to the tibia throughout knee flexion. CONCLUSION: Compared to previously used parameters, the TEA showed bicondylar posterior translation from early flexion phase. These results provide control data for dynamic kinematic analyses of pathologic knees in the future and will be useful in the design of total knee prostheses. PMID- 22543471 TI - Changing sagittal plane body position during single-leg landings influences the risk of non-contact anterior cruciate ligament injury. AB - PURPOSE: To examine the effects of different sagittal plane body positions during single-leg landings on biomechanics and muscle activation parameters associated with risk for anterior cruciate ligament (ACL) injury. METHODS: Twenty participants performed single-leg drop landings onto a force plate using the following landing styles: self-selected, leaning forward (LFL) and upright (URL). Lower extremity and trunk 3D biomechanics and lower extremity muscle activities were recorded using motion analysis and surface electromyography, respectively. Differences in landing styles were examined using 2-way Repeated-measures ANOVAs (sex * landing conditions) followed by Bonferroni pairwise comparisons. RESULTS: Participants demonstrated greater peak vertical ground reaction force, greater peak knee extensor moment, lesser plantar flexion, lesser or no hip extensor moments, and lesser medial and lateral gastrocnemius and lateral quadriceps muscle activations during URL than during LFL. These modifications of lower extremity biomechanics across landing conditions were similar between men and women. CONCLUSIONS: Leaning forward while landing appears to protect the ACL by increasing the shock absorption capacity and knee flexion angles and decreasing anterior shear force due to the knee joint compression force and quadriceps muscle activation. Conversely, landing upright appears to be ACL harmful by increasing the post-impact force of landing and quadriceps muscle activity while decreasing knee flexion angles, all of which lead to a greater tibial anterior shear force and ACL loading. ACL injury prevention programmes should include exercise regimens to improve sagittal plane body position control during landing motions. PMID- 22543469 TI - Bench to bedside: elucidation of the OPG-RANK-RANKL pathway and the development of denosumab. AB - Bone is a complex tissue that provides mechanical support for muscles and joints, protection for vital organs, a mineral reservoir that is essential for calcium homeostasis, and the environment and niches required for haematopoiesis. The regulation of bone mass in mammals is governed by a complex interplay between bone-forming cells termed osteoblasts and bone-resorbing cells termed osteoclasts, and is guided physiologically by a diverse set of hormones, cytokines and growth factors. The balance between these processes changes over time, causing an elevated risk of fractures with age. Osteoclasts may also be activated in the cancer setting, leading to bone pain, fracture, spinal cord compression and other significant morbidities. This Review chronicles the events that led to an increased understanding of bone resorption, the elucidation of the signalling pathway mediated by osteoprotegerin, receptor activator of NF-kappaB (RANK) and RANK ligand (RANKL) and its role in osteoclast biology, as well as the evolution of recombinant RANKL antagonists, which culminated in the development of the therapeutic RANKL-targeted antibody denosumab. PMID- 22543472 TI - Remnant volume of anterior cruciate ligament correlates preoperative patients' status and postoperative outcome. AB - PURPOSE: A cohort study was conducted to evaluate the correlation of anterior cruciate ligament (ACL) remnant volume with preoperative status and postoperative outcome of the patients after a remnant-preserving double-bundle (DB) ACL reconstruction. METHODS: Eighty-eight patients of 105 unilateral DB anatomic ACL reconstructions performed between 2006 and 2008 were followed up for 24 months or more. They were evaluated with regard to preoperative knee laxity data under anaesthesia. Postoperative outcome was evaluated based on knee extension and flexion strength, manual laxity tests, KT measurements, etc. Overall knee condition and sports performance were evaluated with Lysholm knee score and subjective rating scale. Overall correlation of the remnant volume with the preoperative and postoperative evaluation was assessed. Then, the patients were divided into three subgroups based on the remnant volume (remnant volume: <= 30, 35-55 and <= 60 %). The evaluation was performed and analysed statistically among the three subgroups. RESULTS: Generally, preoperative laxity tests showed a weak correlation with the ACL remnant volume. Postoperative knee stability also indicated a weak correlation with the ACL remnant volume. Statistical analyses revealed that there were significant differences among the three groups regarding age at surgery, preoperative period, number of giving-way and preoperative KT measurements. Postoperatively, there were significant differences in Lachman test, KT measurements, Lysholm knee scale, subjective and sports performance recovery scores. As the clinical relevance, the study suggests that the remnant volume will be important as a background of preoperative condition and a predictor of operative outcome for each patient and that a remnant preserving surgery may not be simply better than a non-preserving technique with regard to subjective evaluation and sports performance recovery. CONCLUSION: The preoperative condition of patients with ACL injury was different depending upon the remnant volume. The remnant volume was also weakly correlated with the postoperative outcome regarding objective stability and subjective recovery. PMID- 22543473 TI - Pediatric bilateral spontaneous pneumothoraces in monozygotic twins. AB - Primary spontaneous pneumothorax from subpleural bleb disease is an uncommon occurrence in pediatric patients. This is a rare case of monozygotic twins presenting at alternating intervals with a single-sided spontaneous pneumothorax, only to have it surgically corrected, and to present later with a subsequent contralateral pneumothorax. A review of familial spontaneous pneumothoraces occurring in children was queried for congenital or genetic syndromes. We concluded that a vast majority of pneumothoraces in children, like adults, are not spontaneous and not familial linked. While they are rare, some congenital syndromes have been identified. The HLA haplotype A2 B40, the gene encoding folliculin, Alph-1-antitrypsin, Marfan's syndrome, Ehlers-Danlos syndrome and Birt-Hogg-Dube syndrome have all been associated with familial spontaneous pneumothoraces. Physicians need to counsel family members to ensure appropriate observation and expedited treatment is not delayed. PMID- 22543475 TI - Ten challenges in improving quality in healthcare: lessons from the Health Foundation's programme evaluations and relevant literature. AB - BACKGROUND: Formal evaluations of programmes are an important source of learning about the challenges faced in improving quality in healthcare and how they can be addressed. The authors aimed to integrate lessons from evaluations of the Health Foundation's improvement programmes with relevant literature. METHODS: The authors analysed evaluation reports relating to five Health Foundation improvement programmes using a form of 'best fit' synthesis, where a pre-existing framework was used for initial coding and then updated in response to the emerging analysis. A rapid narrative review of relevant literature was also undertaken. RESULTS: The authors identified ten key challenges: convincing people that there is a problem that is relevant to them; convincing them that the solution chosen is the right one; getting data collection and monitoring systems right; excess ambitions and 'projectness'; organisational cultures, capacities and contexts; tribalism and lack of staff engagement; leadership; incentivising participation and 'hard edges'; securing sustainability; and risk of unintended consequences. The authors identified a range of tactics that may be used to respond to these challenges. DISCUSSION: Securing improvement may be hard and slow and faces many challenges. Formal evaluations assist in recognising the nature of these challenges and help in addressing them. PMID- 22543474 TI - Current management of paediatric urolithiasis. AB - We aimed to review a current management of paediatric nephrolithiasis. The current literature, including our own experience on the treatment of paediatric nephrolithiasis was reviewed by MEDLINE/PubMed search. We have used in our search following keywords: urolithiasis, nephrolithiasis, paediatrics, surgical treatment, conservative management, ESWL, ureteroscopy, and open renal surgery. The search was limited to the English language literature during the period of time from 1990 to 2011. All papers were reviewed independently by all co-authors and only the manuscripts directly related to the reviewed subjects were included into the current review. Due to the high incidence of predisposing factors for urolithiasis in children and high stone recurrence rates, every child with urinary stone should be given a complete metabolic evaluation. Most stones in children can be managed by ESWL and endoscopic techniques. Paediatric stone disease is an important clinical problem in paediatric urology practice. Because of its recurrent nature, every effort should be made to discover the underlying metabolic abnormality so that it can be treated appropriately. Obtaining a stone free state with interventional management and close follow-up are of utmost importance. PMID- 22543476 TI - Life strategies in intra-annual dynamics of wood formation: example of three conifer species in a temperate forest in north-east France. AB - We investigated whether timing and rate of growth are related to the life strategies and fitness of three conifer species. Intra-annual dynamics of wood formation, shoot elongation and needle phenology were monitored over 3 years in five Norway spruces (Picea abies (L.) Karst.), five Scots pines (Pinus sylvestris L.) and five silver firs (Abies alba Mill.) grown intermixed. For the three species, the growing season (delimited by cambial activity onset and cessation) lasted about 4 months, while the whole process of wood formation lasted 5-6 months. Needle unfolding and shoot elongation followed the onset of cambial activity and lasted only one-third of the season. Pines exhibited an 'extensive strategy' of cambial activity, with long durations but low growth rates, while firs and spruces adopted an 'intensive strategy' with shorter durations but higher growth rates. We estimated that about 75% of the annual radial increment variability was attributable to the rate of cell production, and only 25% to its duration. Cambial activity rates culminated at the same time for the three species, whereas shoot elongation reached its maximal rate earlier in pines. Results show that species-specific life strategies are recognizable through functional traits of intra-annual growth dynamics. The opposition between Scots pine extensive strategy and silver fir and Norway spruce intensive strategy supports the theory that pioneer species are greater resource expenders and develop riskier life strategies to capture resources, while shade-tolerant species utilize resources more efficiently and develop safer life strategies. Despite different strategies, synchronicity of the maximal rates of cambial activity suggests a strong functional convergence between co-existing conifer species, resulting in head-on competition for resources. PMID- 22543477 TI - Improving sap flux density measurements by correctly determining thermal diffusivity, differentiating between bound and unbound water. AB - Several heat-based sap flow methods, such as the heat field deformation method and the heat ratio method, include the thermal diffusivity D of the sapwood as a crucial parameter. Despite its importance, little attention has been paid to determine D in a plant physiological context. Therefore, D is mostly set as a constant, calculated during zero flow conditions or from a method of mixtures, taking into account wood density and moisture content. In this latter method, however, the meaning of the moisture content is misinterpreted, making it theoretically incorrect for D calculations in sapwood. A correction to this method, which includes the correct application of the moisture content, is proposed. This correction was tested for European and American beech and Eucalyptus caliginosa Blakely & McKie. Depending on the dry wood density and moisture content, the original approach over- or underestimates D and, hence, sap flux density by 10% and more. PMID- 22543478 TI - Stand-level patterns of carbon fluxes and partitioning in a Eucalyptus grandis plantation across a gradient of productivity, in Sao Paulo State, Brazil. AB - Wood production represents a large but variable fraction of gross primary production (GPP) in highly productive Eucalyptus plantations. Assessing patterns of carbon (C) partitioning (C flux as a fraction of GPP) between above- and belowground components is essential to understand mechanisms driving the C budget of these plantations. Better knowledge of fluxes and partitioning to woody and non-woody tissues in response to site characteristics and resource availability could provide opportunities to increase forest productivity. Our study aimed at investigating how C allocation varied within one apparently homogeneous 90 ha stand of Eucalyptus grandis (W. Hill ex Maiden) in Southeastern Brazil. We assessed annual above-ground net primary production (ANPP: stem, leaf, and branch production) and total belowground C flux (TBCF: the sum of root production and respiration and mycorrhizal production and respiration), GPP (computed as the sum of ANPP, TBCF and estimated aboveground respiration) on 12 plots representing the gradient of productivity found within the stand. The spatial heterogeneity of topography and associated soil attributes across the stand likely explained this fertility gradient. Component fluxes of GPP and C partitioning were found to vary among plots. Stem NPP ranged from 554 g C m(-2) year(-1) on the plot with lowest GPP to 923 g C m(-2) year(-1) on the plot with highest GPP. Total belowground carbon flux ranged from 497 to 1235 g C m(-2) year(-1) and showed no relationship with ANPP or GPP. Carbon partitioning to stem NPP increased from 0.19 to 0.23, showing a positive trend of increase with GPP (R(2) = 0.29, P = 0.07). Variations in stem wood production across the gradient of productivity observed at our experimental site were a result of the variability in C partitioning to different forest system components. PMID- 22543479 TI - Application of the femtosecond laser LASIK microkeratome in eye banking. AB - PURPOSE OF REVIEW: To review the literature for recent advancements in the femtosecond laser technology with regard to its applications in corneal transplantation and eye banking. RECENT FINDINGS: Advancements in corneal surgery have encouraged the use of disease-specific corneal subcomponents, utilized in procedures such as anterior-lamellar keratoplasty and endothelial keratoplasty, instead of traditional transplant procedures to minimize adverse effects of penetrating keratoplasty. Femtosecond laser microkeratomes can precisely create flaps for such transplant procedures, achieve better wound stability, and promote healing by shaped wound configurations. Laser microkeratomes have been compared to traditional mechanical microkeratomes for keratoplasty procedures from various aspects and are superior in some aspects and offer unique capabilities. SUMMARY: Femtosecond laser applications in eye banking include preparation of donor and recipient corneas for use in penetrating keratoplasty, anterior-lamellar keratoplasty, and endothelial keratoplasty. Advantages of femtosecond laser microkeratomes include higher precision of the cut, ability to achieve thinner flaps, and wound configurations that allow greater wound stability, shorter recovery time, and less postoperative pain. However, cost and availability at the eye-bank level may hinder widespread and immediate application. PMID- 22543480 TI - Gene therapy for corneal dystrophies and disease, where are we? AB - PURPOSE OF REVIEW: We assess the studies on vector systems for delivery of transgenes to the cornea that have been published over the last year and summarize new work on the identification of specific transgenes for corneal diseases. RECENT FINDINGS: Adeno-associated viral vectors are increasingly being successfully applied to the cornea, although transgene expression requires corneal epithelial debridement or intrastromal injection of the vector. Gene delivery platforms based on nanoparticles of chitosan or gold also show promise. Overexpression of vasoinhibin-1 or decorin, or siRNA-mediated blockade of the cannabinoid receptor CB1, can all reduce corneal neovascularization. Overexpression of decorin or matrix metalloproteinase 14 can reduce corneal fibrosis and haze, whereas overexpression of c-Met accelerates the epithelial wound healing. Induction of corneal endothelial cell replication by overexpression of E2F2, p16 or p21 can maintain or even increase corneal endothelial cell density in eye bank corneas. Overexpression of the antiapoptotic transgenes Bcl-xL or p35 significantly enhances corneal endothelial cell survival and reduces apoptosis in stored human corneas. SUMMARY: Despite a wealth of information on the methods for the delivery of nucleic acids to the human cornea and ever-increasing information on the transgenes with substantial therapeutic potential, gene therapy for corneal disorders has yet to reach the clinic. PMID- 22543481 TI - Nerve growth factor therapy for corneal disease. AB - PURPOSE OF REVIEW: To review the experimental and clinical data on the effects of nerve growth factor (NGF) in corneal physiopathology and to discuss the future development of NGF therapy for corneal diseases. RECENT FINDINGS: NGF plays a key role in the modulation of immune reaction, trophic support, healing of ocular surface, corneal sensitivity and tear film function. These properties of NGF make this neurotrophin a potential therapeutic agent for several corneal diseases. In this review, experimental evidence of the mechanisms of action of NGF on the ocular surface and clinical data on topical NGF use are described and discussed. This review includes the studies performed on corneal diseases such as neurotrophic keratitis, peripheral ulcerative keratopathy, dry eye and corneal surgery. Moreover, experimental studies that extended the NGF action on herpes virus corneal infection and ocular surface stem cell differentiation and proliferation are also reviewed. SUMMARY: Since the first clinical use of topical NGF therapy in patients with neurotrophic keratitis, the ocular surface healing and immune-modulating actions of NGF have been extensively studied and demonstrated in the past two decades, opening new perspectives for its use in clinical practice in patients with infective and noninfective diseases of the ocular surface. PMID- 22543482 TI - The nurse education imperative. PMID- 22543483 TI - Efficacy and safety of pharmacological options for rate control in atrial fibrillation. PMID- 22543485 TI - Radiology nursing staff use the HWE assessment tool to improve the work environment. PMID- 22543486 TI - Nursing mortality and morbidity and journal club cycles: paving the way for nursing autonomy, patient safety, and evidence-based practice. AB - The ability to perform professional scrutiny is a required component of autonomous practice, and the ability to use science to guide care delivery is a hallmark of professional practice. The cardiovascular intensive care unit staff initiated a forum for peer review to encourage the use of the best available evidence to guide system and practice changes. A focus group was formed, resulting in development and implementation of a specific process for regular cycles of nursing mortality and morbidity (M & M) conferences, a journal club, and interdisciplinary educational sessions in staff meetings. After performing several cycles, the team observed interdisciplinary practice changes that improved patient care delivery. Thus, cycles of nursing M & M conferences, a journal club, and educational sessions can help support patient safety, enhance professional autonomy, and foster evidence-based interdisciplinary practice in the cardiovascular intensive care setting. PMID- 22543487 TI - APN plan improves outcome for pregnant patient with congenital heart disease. AB - Advanced practice nurses work in many roles to support delivery of safe patient care. Eighty-five percent of children born with congenital heart disease (CHD) live to adulthood. The pregnant adult with CHD presents challenges for nursing across many care-delivery systems. Progression of care delivery across these systems requires innovative planning and organization. This article describes the plan developed by advanced practice nurses in a CHD clinic and in inpatient coronary care and obstetric units to support a pregnant patient with CHD. The plan focused on collaboration and communication among interdisciplinary teams. The goal was to address multidisciplinary communication, leadership, and staff education. The result was a successful high-risk delivery with organized education and patient care across systems. PMID- 22543488 TI - The challenge of caring for critically ill neuroscience patients. PMID- 22543489 TI - Controversies in acute stroke treatment. AB - The evidence base supporting the management of patients with acute stroke is evolving at a rapid rate, as new methods that aim to reduce disability and death from stroke are explored. Intravenous tissue plasminogen activator remains the only treatment shown in numerous studies to reduce disability 3 months after stroke with no increase in the risk of death and a relatively minor rate of symptomatic intracerebral hemorrhage complications. Despite these findings, health care providers have been slow to adopt this evidence-based treatment, which results in many patients experiencing disability caused by stroke. Numerous controversies exist related to the management of patients with acute stroke, including the use of tissue plasminogen activator, positioning and early mobility, blood pressure lowering in acute intracerebral hemorrhage, and even the use of innovative advanced practice nurse-led stroke treatment teams, with varying amounts of evidence available to provide direction. This article explores controversies associated with both approved and evolving treatments for ischemic and hemorrhagic stroke and makes recommendations for practice on the basis of the body of existing evidence, with an aim to improve the delivery of acute stroke treatment. PMID- 22543491 TI - Unresolved issues in the management of aneurysmal subarachnoid hemorrhage. AB - A cerebral aneurysm is an outpouching of a weakened arterial wall, usually at a bifurcation of one of the larger vessels of the Circle of Willis. When the outpouching ruptures, arterial pressure forces blood into the subarachnoid space. The annual incidence of aneurysmal subarachnoid hemorrhage is 8 to 10 per 100 000 in the United States. The outcome varies for this patient population. New management strategies have emerged; some practices are evidence based, whereas others are based on anecdotal experiences. This variation has resulted in a number of unresolved issues in caring for patients with an aneurysmal subarachnoid hemorrhage. This article discusses some of these unresolved issues, including the use of medications such as nimodipine, antifibrinolytics, statins, and magnesium; coiling or clipping for aneurysm securement; and the prevention and treatment of potential complications. Critical care nurses must conduct detailed assessments and provide complex care to optimize patient outcomes. PMID- 22543492 TI - Controversies in the management of adults with severe traumatic brain injury. AB - Despite progress in the management of adults with severe traumatic brain injury, several controversies persist. Among the unresolved issues of greatest concern to neurocritical care clinicians and scientists are the following: (1) the best use of technological advances and the data obtained from multimodality monitoring; (2) the use of mannitol and hypertonic saline in the management of increased intracranial pressure; (3) the use of decompressive craniectomy and barbiturate coma in refractory increased intracranial pressure; (4) therapeutic hypothermia as a neuroprotectant; (5) anemia and the role of blood transfusion; and (6) venous thromboembolism prophylaxis in severe traumatic brain injury. Each of these strategies for managing severe traumatic brain injury, including the postulated mechanism(s) of action and beneficial effects of each intervention, adverse effects, the state of the science, and critical care nursing implications, is discussed. PMID- 22543493 TI - Fever management in patients with brain injury. AB - Elevated temperature in patients with brain injury has been linked to increased hospital and intensive care unit lengths of stay, increased morbidity, greater disability, and higher mortality. The prevailing medical opinion is that maintaining normothermia in patients with acute brain injury is beneficial. However, little evidence exists to support this recommendation. Nurses are responsible for diagnosing and treating fever, but evidence-based guidelines that would govern fever management for these patients do not exist. This article discusses what evidence is available to support the management of fever in patients with brain injury and in what areas evidence is lacking. PMID- 22543494 TI - Research evidence and beyond. PMID- 22543495 TI - Preventive ethics in the intensive care unit. PMID- 22543496 TI - Brugada syndrome. PMID- 22543497 TI - Silencing of PCDH10 in hepatocellular carcinoma via de novo DNA methylation independent of HBV infection or HBX expression. AB - PCDH10 is a key tumor suppressive gene for nasopharyngeal, esophageal, and other carcinomas with frequent methylation. In this study, we investigated the potential epigenetic modification of the PCDH10 gene by hepatitis B virus * protein (HBx), a pivotal factor in the progression of HBV replication and potential carcinogenesis. PCDH10 expression was found to be down-regulated in 9/13 (69.2 %) of hepatocellular carcinoma (HCC) cell lines. Decreased PCDH10 expression was correlated with the methylation status of the PCDH10 promoter. Treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (Aza) was sufficient to restore PCDH10 mRNA expression by suppressing PCDH10 promoter methylation in HepG2 cells. Treatment with Trichostatin A alone had no significant effect on PCDH10 expression but enhanced the effect of Aza. PCDH10 methylation was further detected in 76 % (38 of 50) of HCC tissues compared with 40 % (20 of 50) of paired adjacent tissues, with no methylation detected in normal human liver tissues. There were significant correlations between methylation status of PCDH10 and tumor size, serum AFP levels, metastasis or TNM staging (P < 0.05). Moreover, PCDH10 promoter methylation status was not associated with HBV infection in our panel of 50 primary HCC tumors, and transfection with HBX could not alter the status of PCDH10 promoter methylation. Collectively, these observations suggested that the expression of PCDH10 was silenced in HCC via de novo DNA methylation independent of HBV infection or HBX expression, and PCDH10 might form a potentially useful therapeutic target for HCC. PMID- 22543498 TI - A novel CDH1 germline missense mutation in a sporadic gastric cancer patient in north-east of Italy. AB - It is well documented that germline mutations in the E-cadherin (CDH1) gene are linked to hereditary diffuse gastric cancer (HDGC). Despite the known molecular genetic causes, most gastric cancers are sporadic and poorly investigated for susceptibility genes. We report the finding of a novel germline missense mutation in exon 6, c. 820 G > A (p.G274S) in one sporadic gastric cancer patient. This new variant does not affect cryptic splicing of CDH1 as demonstrated by molecular assay. Immunohistochemical analysis shows a mixed pattern of E-cadherin staining (membranous and cytoplasmic) in the intestinal component, while in the diffuse counterpart, the membranous staining was prevalent and a reduced membranous expression of beta-catenin was observed. In vitro assays suggest that the mutant G274S does not affect the E-cadherin protein function, its expression pattern or subcellular localization. This new variant is present in EC2 extracellular domain of the protein (p.G120S in mature protein). The molecular modelling shows that this point mutation is not dramatic for local structure. However, p.S120 is located on the surface of the protein close to the functional calcium sites and in the region of interaction with EC1 domain of another E-cadherin molecule involved in the formation of the intercellular junction. Moreover, p.S120 residue could be involved in posttranslational modifications, such as phosphorylation or glycosylation, with possible effects on stability and integrity of adhesive properties of E-cadherin. In conclusion, the pathogenicity of this mutation is unlikely; probably we found a new germline CDH1 missense mutation with potential impact, however, of uncertain significance. PMID- 22543499 TI - Truncated branch and bound achieves efficient constraint-based genetic design. AB - MOTIVATION: Computer-aided genetic design is a promising approach to a core problem of metabolic engineering-that of identifying genetic manipulation strategies that result in engineered strains with favorable product accumulation. This approach has proved to be effective for organisms including Escherichia coli and Saccharomyces cerevisiae, allowing for rapid, rational design of engineered strains. Finding optimal genetic manipulation strategies, however, is a complex computational problem in which running time grows exponentially with the number of manipulations (i.e. knockouts, knock-ins or regulation changes) in the strategy. Thus, computer-aided gene identification has to date been limited in the complexity or optimality of the strategies it finds or in the size and level of detail of the metabolic networks under consideration. RESULTS: Here, we present an efficient computational solution to the gene identification problem. Our approach significantly outperforms previous approaches--in seconds or minutes, we find strategies that previously required running times of days or more. AVAILABILITY AND IMPLEMENTATION: GDBB is implemented using MATLAB and is freely available for non-profit use at http://crab.rutgers.edu/~dslun/gdbb. PMID- 22543500 TI - Statistical analysis of glycosylation profiles to compare tissue type and inflammatory disease state. AB - MOTIVATION: Glycosylation is one of the most important post-translational modifications of proteins and explains some aspects of the diversification of higher organisms not explained by template-driven synthesis. For glycomics to mature as much as genomics and proteomics, the necessary tools need to be developed and tested. Liquid chromatography-mass spectrometry is one of the gold standards for oligosaccharide analysis and leads to large amounts of data, not easily interpreted manually. We present a study on the testing and validation of statistical analysis tools to aid the structural elucidation of these analyses as well as using the results to answer biologically relevant questions. RESULTS: We show the usefulness of data reduction and statistical analysis in the interpretation of complex glycosylation data. The reduction does not result in the loss of importance of the glycosylation information as shown by comparison of control and disease samples in two tissue types. PMID- 22543501 TI - Purification and partial characterization of glyceraldehyde-3-phosphate dehydrogenase from the ciliate Tetrahymena thermophila. AB - In the present study, we purified the glycolytic enzyme glyceraldehyde-3 phosphate dehydrogenase (GAPDH) which is involved in cellular energy production and has important housekeeping functions, from the ciliate Tetrahymena thermophila using a three-step procedure. The enzyme was purified ~68 folds by ammonium sulfate precipitation, followed by two steps of column chromatography (DEAE-cellulose and Mono-S). The purified enzyme is a homotetramer with a molecular weight of ~120 kDa. Isoelectric focusing analysis showed the presence of only one basic GAPDH isoform with an isoelectric point of 8.8. Western blot analysis showed a single 32-kDa band corresponding to the enzyme subunit using a monospecific polyclonal antibody against the T. thermophila GAPDH. The maximum of enzyme activity occurred at pH 8.0 and at 30-35 degrees C. The apparent K(m) values for both NAD(+) and D-glyceraldehyde-3-phosphate were 0.102 +/- 0.012 and 0.360 +/- 0.018 mM, respectively. The maximal velocity (V(max)) was 39.40 +/- 2.95 U/mg. The T. thermophila GAPDH is inhibited by oxidative and nitrosative stress reagents. PMID- 22543502 TI - Reactivity of phosphonodithioato-dppt Ni(II) mixed ligand complexes with halogens: first example of a metal-coordinating tribromide anion. AB - The first example of a metal complex containing a tribromide anion is presented and characterised by X-ray diffraction. Hybrid DFT calculations were used to investigate the nature of the bond in coordinating trihalides and the differences with the corresponding mono-halide complexes. PMID- 22543503 TI - Kinetic study of oxygen adsorption over nanosized Au/gamma-Al2O3 supported catalysts under selective CO oxidation conditions. AB - O2 adsorption is a key process for further understanding the mechanism of selective CO oxidation (SCO) on gold catalysts. Rate constants related to the elementary steps of O2 adsorption, desorption and surface bonding, as well as the respective activation energies, over a nanosized Au/gamma-Al2O3 catalyst, were determined by Reversed-Flow Inverse Gas Chromatography (RF-IGC). The present study, carried-out in a wide temperature range (50-300 degrees C), both in excess as well as in the absence of H2, resulted in mechanistic insights and kinetic as well as energetic comparisons, on the sorption processes of SCO reactants. In the absence of H2, the rate of O2 binding, over Au/gamma-Al2O3, drastically changes with rising temperature, indicating possible O2 dissociation at elevated temperatures. H2 facilitates stronger O2 bonding at higher temperatures, while low temperature binding remains practically unaffected. The lower energy barriers observed, under H2 rich conditions, can be correlated to O2 dissociation after hydrogenation. Although, H2 enhances both selective CO reactant's desorption, O2 desorption is more favored than that of CO, in agreement with the well-known mild bonding of SCO reactant's at lower temperatures. The experimentally observed drastic change in the strength of CO and O2 binding is consistent both with well-known high activity of SCO at ambient temperatures, as well as with the loss of selectivity at higher temperatures. PMID- 22543504 TI - Gossypol exhibits a strong influence towards UDP-glucuronosyltransferase (UGT) 1A1, 1A9 and 2B7-mediated metabolism of xenobiotics and endogenous substances. AB - Gossypol, the polyphenolic constituent isolated from cottonseeds, has been used as a male antifertility drug for a long time, and has been demonstrated to exhibit excellent anti-tumor activity towards multiple cancer types. The toxic effects of gossypol limit its clinical utilization, and enzyme inhibition is an important facet of this. In the present study, in vitro human liver microsomal incubation system supplemented with UDPGA was used to investigate the inhibition of gossypol towards UGT1A1, 1A9 and 2B7-mediated metabolism of xenobiotics and endogenous substances. Estradiol, the probe substrate of UGT1A1, was selected as representative endogenous substance. Propofol (a probe substrate of UGT1A9) and 3'-azido-3'-deoxythimidine (AZT, a probe substrate of UGT2B7) were employed as representative xenobiotics. The results showed that gossypol noncompetitively inhibits UGT-mediated estradiol-3-glucuronidation and propofol O-glucuronidation, and the inhibition kinetic parameters (K(i)) were calculated to be 34.2 and 16.4 MUM, respectively. Gossypol was demonstrated to exhibit competitive inhibition towards UGT-mediated AZT glucuronidation, and the inhibition kinetic parameter (K(i)) was determined to be 14.0 MUM. All these results indicated that gossypol might induce metabolic disorders of endogenous substances and alteration of metabolic behaviour of co-administered xenobiotics through inhibition of UGTs' activity. PMID- 22543505 TI - Microbial enhance of chitosan production by Rhizopus arrhizus using agroindustrial substrates. AB - This study investigated the potential of Rhizopus arrhizus UCP 402 for producing chitosan using corn steep liquor and honey as agroindustrial nitrogen and carbon sources. A complete factorial design was used to assess the improved biomass and chitosan production. The results were evaluated using Pareto charts (Statistica 7.0 software). The chitosan obtained was characterized by X-ray diffraction. The cristallinity index (I(C)), and infrared spectroscopy (FTIR) were used to evaluate the degree of deacetylation (DD %). The morphological aspects of the R. arrhizus were evaluated by measuring the diameter of the colonies by light microscopy. The results obtained showed higher biomass and chitosan yields (20.61 g/L and 29.3 mg/g), respectively, in the selected assays. The characterization of the macromolecular arrangement of chitosan showed a crystallinity index compatible with the literature, and the infrared peaks confirmed a degree of 86%. The experimental data obtained suggest that adding honey to corn steep liquor is a promising way to improve microbiological chitosan production. PMID- 22543506 TI - The IMPACT prognosis calculator used in patients with severe traumatic brain injury treated with an ICP-targeted therapy. AB - BACKGROUND: The prognosis of severe traumatic brain injury (sTBI) is important. The International Mission on Prognosis in Traumatic Brain Injury (IMPACT) study group has developed a prediction calculator for the outcome of patients with sTBI, and this has been made available on the World Wide Web. We have studied the use of the IMPACT calculator on sTBI patients treated with an ICP-targeted therapy based on the Lund concept. METHOD: The individual clinical data of patients in a prospective sTBI protocol-driven trial of the treatment of sTBI using the Lund concept were entered into the prognosis calculator, and the individual prognosis for each patient was calculated and compared with the actual outcome at 6 months. FINDINGS: The use of the IMPACT calculator led to an overestimation of mortality and of an unfavourable outcome. Compared with the IMPACT database, the absolute risk reduction (ARR) for mortality was 13.6 %. There is a statistically significant probability for the prediction of mortality and unfavourable outcome. A ROC curve analysis shows an area under the curve (AUC) in the Core model for mortality of 0.744 and of unfavourable outcome of 0.731, in the Extended model of 0.751 and 0.721 respectively, and in the Lab model of 0.779 and 0.810 respectively. CONCLUSIONS: The IMPACT prognosis calculator should be used with caution for the prediction of outcome for an individual patient with sTBI treated with an ICP-targeted therapy based on the Lund concept. We conclude that we have to initiate treatment in all patients with blunt sTBI and an initial cerebral perfusion pressure (CPP)>=10 mmHg [corrected]. It seems that the outcome in sTBI patients treated in this fashion is better than would have been expected from the IMPACT prognosis. PMID- 22543507 TI - Multicentric intracranial epidermoid or epi/dermoid cysts? PMID- 22543508 TI - An aptazyme-based molecular device that converts a small-molecule input into an RNA output. AB - We describe the construction of an aptazyme-based molecular device that converts, through a cascade of reactions, a small-molecule input into output RNA strands. This device is applicable as an interface between a small molecule and a molecular system that accepts only nucleic acid input. PMID- 22543509 TI - Lesions of the anterior thalamic nuclei and intralaminar thalamic nuclei: place and visual discrimination learning in the water maze. AB - Medial thalamic damage produces memory deficits in humans (e.g., Korsakoff's syndrome) and experimental animals. Both the anterior thalamic nuclei (ATN) and rostral intralaminar plus adjacent lateral thalamic nuclei (ILN/LT) have been implicated. Based on the differences in their main connections with other neural structures, we tested the prediction that ATN lesions would selectively impair acquisition of spatial location discrimination, reflecting a hippocampal system deficit, whereas ILN/LT lesions would impair acquisition of visual pattern discrimination, reflecting a striatal system deficit. Half the rats were first trained in a spatial task in a water maze before switching to a visual task in the same maze, while the remainder were tested with the reverse order of tasks. Compared with sham-operated controls, (1) rats with ATN lesions showed impaired place learning, but normal visual discrimination learning, (2) rats with ILN/LT lesions showed no deficit on either task. Rats with ATN lesions were also hyperactive when their home cage was placed in a novel room and remained more active than ILN/LT or SHAM rats for the subsequent 21 h, especially during the nocturnal phase. These findings confirmed the influence of ATN lesions on spatial learning, but failed to support the view that ILN/LT lesions disrupt striatal dependent memory. PMID- 22543510 TI - Surgical management of pediatric Graves' disease: an effective definitive treatment. AB - PURPOSE: The optimal treatment for pediatric Graves' disease (GD) is controversial. Antithyroid drugs are often used initially, but they are associated with a high failure rate. Therefore alternative therapies have become important. In the present study, we analyze our institution's experience regarding the safety and efficacy of thyroid surgery among pediatric patients with GD. METHODS: This is a retrospective chart review of 27 pediatric patients (age <= 18 years) with GD who underwent thyroid surgery between 1991 and 2009 at a single academic Institution. We recorded preoperative, intraoperative, and short-term postoperative data. RESULTS: All 27 patients were initially treated with thionamides. The high rate of hyperthyroidism relapse after discontinuation of medical treatment, age < 5 years, adverse reaction to medical therapy, severe ophthalmopathy, and patient preference justified the final decision to proceed with surgery as definitive therapy. All patients underwent total thyroidectomy. We had no mortality; surgical complications were rare: 4 (14.8 %) cases of transient hypocalcemia, 1 (3.7 %) of permanent hypocalcemia, 3 (11.1 %) of transient RLN neuropraxia, and 2 (7 %) of keloid scar. No bleeding, permanent RLN palsy or relapse hyperthyroidism were reported. CONCLUSIONS: Surgical therapy for pediatric GD performed by experienced thyroid surgeons is a safe, definitive and cost-effective treatment. PMID- 22543511 TI - Is partial colectomy the operation of choice in pediatric Clostridium difficile colitis? AB - PURPOSE: This study examined the national trends in incidence and surgical management of pediatric Clostridium difficle colitis (CDC) hospitalizations. METHODS: This was a cross-sectional Nationwide Inpatient Sample (NIS) analysis of pediatric CDC from 2000 to 2008. Data analysis included patient demographics, procedures, length of stay (LOS), total hospital charges (THC), and in-hospital mortality. RESULTS: During the 9-year study period, the total number of CDC hospitalizations per year increased almost twofold, from 2,513 in 2000 to 4,817 in 2008. The rate per 100,000 discharges followed a similar trend, increasing from 38.08 in 2000 to 72.57 in 2008. Abdominal colectomy was performed in 0.35 %, with partial colectomy performed more often than total colectomy. Mortality, mean LOS, and mean THC were not statistically different between partial versus total colectomy. Children with ulcerative colitis were more likely to undergo total colectomy, (OR 35.700, CI 11.025-115.98, P < 0.001). Infants under the age of 1 year were less likely to undergo total colectomy (OR 0.568, 0.477-0.677, P < 0.001). CONCLUSION: Pediatric hospitalizations for CDC are on the rise. Partial colectomy is performed more often than total colectomy without statistical compromise of mortality, length of stay, and total hospital charges. Further studies are needed to determine the standard surgical management of pediatric CDC. PMID- 22543512 TI - Quantification of Cry1Ab in genetically modified maize leaves by liquid chromatography multiple reaction monitoring tandem mass spectrometry using 18O stable isotope dilution. AB - Cry1Ab is one of the most common Bacillus thuringiensis (Bt) proteins in genetically modified crops, which exhibits strong resistance against insect pests. In the present study, a sensitive and precise liquid chromatography stable isotope dilution multiple reaction monitoring tandem mass spectrometry (LC-SID MRM-MS) assay was developed and validated to quantify the amount of Cry1Ab expression in transgenic maize leaves. The measurement of protein was converted to measurement of unique peptides to Cry1Ab protein. Two peptides unique to Cry1Ab were synthesized and labeled in H(2)(18)O to generate (18)O stable isotope peptides as internal standards. The validated method obtained superior specificity and good linearity. And the inter- and intra-day precision and accuracy for all samples were satisfactory. The results demonstrated Cry1Ab protein was 31.7 +/- 4.1 MUg g(-1) dry weight in Bt-176 transgenic maize leaves. It proved that the novel LC-SID-MRM-MS method was sensitive and selective to quantify Cry1Ab in the crude extract without time-consuming pre-separation or purification procedures. PMID- 22543513 TI - Phase separation in a lattice model of a superconductor with pair hopping. AB - We have studied the extended Hubbard model with pair hopping in the atomic limit for arbitrary electron density and chemical potential. The Hamiltonian considered consists of (i) the effective on-site interaction U and (ii) the intersite charge exchange interactions I, determining the hopping of electron pairs between nearest-neighbour sites. The model can be treated as a simple effective model of a superconductor with very short coherence length in which electrons are localized and only electron pairs have a possibility of transferring. The phase diagrams and thermodynamic properties of this model have been determined within the variational approach, which treats the on-site interaction term exactly and the intersite interactions within the mean-field approximation. We have also obtained rigorous results for a linear chain (d = 1) in the ground state. Moreover, at T = 0 some results derived within the random phase approximation (and the spin-wave approximation) for d = 2 and 3 lattices and within the low density expansions for d = 3 lattices are presented. Our investigation of the general case (as a function of the electron concentration n and as a function of the chemical potential MU) shows that, depending on the values of interaction parameters, the system can exhibit not only the homogeneous phases, superconducting (SS) and nonordered (NO), but also the phase separated states (PS: SS-NO). The system considered exhibits interesting multicritical behaviour including tricritical points. PMID- 22543514 TI - Flexion and extension laxity after medial, mobile-bearing unicompartmental knee arthroplasty: a comparison between a spacer- and a tension-guided technique. AB - PURPOSE: In a mobile-bearing unicompartmental knee arthroplasty (UKA), stability is of utmost importance to promote knee function and to prevent dislocation of the insert. Gap balancing can be guided by the use of spacers or a tensioner. The goal of this study is to compare laxity of a tension-guided implantation technique versus a spacer-guided technique for medial UKA with a mobile bearing. Also clinical function was compared between the groups. METHODS: The tension guided UKA system (BalanSysTM, Mathys Ltd, Bettlach, Switzerland) was compared with a retrospective group with a spacer-guided system (Oxford, Biomet Ltd, Bridgend, UK). A total of 30 tension-guided medial UKAs were implanted and compared with 35 spacer-guided medial prostheses. In both groups, valgus laxity was measured at least 4 months postoperatively in extension and 70 degrees flexion using stress radiographs. Knee Society Scores (KSS) were obtained at the 6-month follow-up. RESULTS: Valgus laxity in flexion was significantly higher in the tension-guided group compared with the spacer-guided group: 3.9 degrees (SD 1.8 degrees ) versus 2.4 degrees (SD 1.2 degrees ), respectively, P < 0.001). In extension, valgus laxity was significantly different: 1.8 degrees (SD 1.0 degrees ) in the tension-guided group compared with 2.7 degrees (SD 0.9 degrees ) in the spacer-guided group (P < 0.001). There was no significant difference between the KSS for the two groups (n.s.). CONCLUSIONS: The tensor-guided system resulted in significantly more valgus laxity in flexion compared with the spacer guided system. However, in extension, the situation was reversed: the tension guided system resulted in less valgus laxity than the spacer-guided system. Clinically, there were no differences between the groups. The valgus laxity found with the spacer-guided system better approximates the valgus laxity values of the healthy elderly. PMID- 22543515 TI - Comparison between Nintendo Wii Fit and conventional rehabilitation on functional performance outcomes after hamstring anterior cruciate ligament reconstruction: prospective, randomized, controlled, double-blind clinical trial. AB - PURPOSE: The aim of this prospective, randomized, controlled, double-blind clinical trial was to compare the outcomes, including knee strength, balance, coordination, proprioception and response time, of Nintendo Wii Fit with those of conventional rehabilitation on the subjects with anterior cruciate ligament reconstruction. METHODS: Thirty volunteer subjects were enrolled in either Wii Fit (n = 15; mean age, 29 +/- 7 years) or conventional rehabilitation (n = 15; mean age, 29 +/- 6 years) programmes from the first week up to 12th weeks of the operation. Endoscopic reconstruction of a completely ruptured ACL was performed by using graft harvested from hamstrings. Each subject underwent an individual therapeutic programme. Functional examinations included the measurements of the balance using modified star excursion balance test, coordination, proprioception and response time using functional squat system and strength of flexor and extensor muscles of the involved and uninvolved leg using an isokinetic machine. RESULTS: There was no significant difference between Wii Fit and conventional group in terms of isokinetic knee strength at 12th week, and dynamic balance, and functional squat tests including coordination, proprioception and response time at first, 8th and 12th weeks of the rehabilitation. CONCLUSION: Two different 12 week-physiotherapy programmes following ACL reconstruction have the same affect on muscle strength, dynamic balance and functional performance values in both groups. We considered that the practice of Wii Fit activities like conventional rehabilitation could also address physical therapy goals, which included improving visual-perceptual processing, coordination, proprioception and functional mobility. PMID- 22543516 TI - Quantifying the dielectric constant of thick insulators by electrostatic force microscopy: effects of the microscopic parts of the probe. AB - We present a systematic analysis of the effects that the microscopic parts of electrostatic force microscopy probes (the cone and cantilever) have on the electrostatic interaction between the tip apex and thick insulating substrates (thickness > 100 MUm). We discuss how these effects can influence the measurement and quantification of the local dielectric constant of the substrates. We propose and experimentally validate a general methodology that takes into account the influence of the cone and the cantilever, thus enabling us to obtain very accurate values of the dielectric constants of thick insulators. PMID- 22543517 TI - Vertically building Zn2SnO4 nanowire arrays on stainless steel mesh toward fabrication of large-area, flexible dye-sensitized solar cells. AB - Zn(2)SnO(4) nanowire arrays were for the first time grown onto a stainless steel mesh (SSM) in a binary ethylenediamine (En)/water solvent system using a solvothermal route. The morphology evolution following this reaction was carefully followed to understand the formation mechanism. The SSM-supported Zn(2)SnO(4) nanowire was utilized as a photoanode for fabrication of large-area (10 cm * 5 cm size as a typical sample), flexible dye-sensitized solar cells (DSSCs). The synthesized Zn(2)SnO(4) nanowires exhibit great bendability and flexibility, proving potential advantage over other metal oxide nanowires such as TiO(2), ZnO, and SnO(2) for application in flexible solar cells. Relative to the analogous Zn(2)SnO(4) nanoparticle-based flexible DSSCs, the nanowire geometry proves to enhance solar energy conversion efficiency through enhancement of electron transport. The bendable nature of the DSSCs without obvious degradation of efficiency and facile scale up gives the as-made flexible solar cell device potential for practical application. PMID- 22543518 TI - Characteristics of endophthalmitis in patients with the Boston keratoprosthesis. PMID- 22543520 TI - Monitoring of pediatric patients with malignant hematological diseases after allogeneic HSCT: Serbian experience. AB - We describe the implementation of short tandem repeats-polymerase chain reaction (STR-PCR) chimerism analyses coupled with reverse transcription PCR detection of recurrent translocations characteristic for childhood leukemia in monitoring of patients after allogeneic hematopoietic stem cell transplantation in Serbia and the first clinical results thereof. Chimerism and minimal residual disease were regularly analyzed from blood and marrow samples of 26 pediatric patients taken after stem cell transplantation with a median follow-up of 17.6 months. Our results demonstrate that STR-based chimerism monitoring is sufficient in establishing the origin of engrafted cells after transplantation and in detecting graft rejection, but more specific and more sensitive method is necessary for identifying patients with threatening leukemia relapse. PMID- 22543521 TI - Clinical and needle autopsy correlation evaluation in a tertiary care teaching hospital: a prospective study of 50 cases from the emergency department. AB - With gradual fall in autopsy all over the world in recent years, the present study aimed to assess the accuracy of clinical diagnosis and efficacy of needle autopsy from the emergency department. Fifty deceased patients, who died in the emergency department during a period of 1 year, were subjected to needle autopsy of the major viscera, using spring-loaded automated biopsy gun, and the findings were correlated with clinical diagnosis. The deceased patients were in the age range of 12 to 80 years (mean [SD], 50.48 [18.41] years). The tissues yielded from various organs were as follows: lungs, 90%; liver, 82%; kidney, 48%; heart, 28%; spleen, 22%; and pancreas, 18%. Before death, 86 clinical diagnoses were recorded, of which 21 (24%) (eg, metabolic encephalopathy, cardiac arrhythmia, diabetic ketoacidosis) were impossible to verify on needle autopsy. A total of 48 new diagnoses, missed by physicians, were revealed by needle autopsy. The most frequently missed diagnoses were liver fatty change (19 patients) and pneumonitis (11 patients). Other frequently missed diagnoses were chronic hepatitis (3 patients) and cancer (2 patients: 1 lung squamous cell carcinoma and 1 lung adenocarcinoma). Major diagnostic errors (Goldman classes I and II) were noted in 16 (32%) of 50 cases. Needle autopsy can be a better alternative in the absence of conventional autopsy. PMID- 22543522 TI - Traumatic thrombosis of internal carotid artery sustained by transfer of kinetic energy. AB - A 31-year-old male patient with a fatal thrombosis of the internal carotid artery caused by gun shot injury was presented in this case report. The patient was referred to the hospital with a diffuse edema on his left cheek. On otolaryngologic examination, there was a bullet entrance hole at the left mandibular corpus. No exit hole could be found. The finding from his axial computed tomography of neck and paranasal sinuses was normal. On neurological examination, a dense right hemiparesis was observed. In his cerebral angiogram, left common carotid artery was totally obliterated. Diffuse ischemia was observed in the left cerebral hemisphere. Despite intensive interventions, the patient died 4 days after the accident. In the autopsy, a large thrombosis was obtained in the left common carotid artery. This case emphasizes a fatal kinetic energy effect in vascular structures. It is stressed that a gun shot injury could be fatal with its indirect kinetic energy effects at subacute phase. PMID- 22543519 TI - Trypanosomal immune evasion, chronicity and transmission: an elegant balancing act. AB - During their life cycle, trypanosomes must overcome conflicting demands to ensure their survival and transmission. First, they must evade immunity without overwhelming the host. Second, they must generate and maintain transmission stages at sufficient levels to allow passage into their tsetse vector. Finally, they must rapidly commit to onward development when they enter the tsetse fly. On the basis of recent quantification and modelling of Trypanosoma brucei infection dynamics, we propose that the interplay between immune evasion and development achieves both infection chronicity and transmissibility. Moreover, we suggest that a novel form of bistable regulation ensures developmental commitment on entry into the tsetse fly midgut. PMID- 22543523 TI - Carbon monoxide-related deaths in Greece: a 23-year survey. AB - Carbon monoxide (CO) is the cause of more than one half of the fatal poisonings throughout the world. The aim of this study was to assess the characteristics of nonfire CO-related deaths in Greece, as they were recorded at the Department of Forensic Medicine and Toxicology, School of Medicine, University of Athens. This retrospective study concerned the toxicological records of all fatal cases of CO poisoning received by the Department of Forensic Medicine and Toxicology during the period 1987 to 2009. The records were reviewed and compiled according to the official coroner's verdict as to the manner of poisoning (accident or suicide), as well as according to the sex and the nationality of the victims. The registered victims were 176 (131 males, 45 females). Of CO deaths, 97.2% were accidental, and 2.8% were suicides, through automobile exhaust. Among the decedents, 32 victims were immigrants (30 males, 2 females). The average annual death rate for males was nearly 31/2 times higher than that for females. This increase suggests a need for preventive strategies targeting not only high-risk population, such as homeless or immigrants, but also the general population. Preventive messages in many languages through the media about potential sources of CO exposure are recommended. Precautions should also be taken during periods of low temperatures. PMID- 22543524 TI - Structural changes of corn stover lignin during acid pretreatment. AB - In this study, raw corn stover was subjected to dilute acid pretreatments over a range of severities under conditions similar to those identified by the National Renewable Energy Laboratory (NREL) in their techno-economic analysis of biochemical conversion of corn stover to ethanol. The pretreated corn stover then underwent enzymatic hydrolysis with yields above 70 % at moderate enzyme loading conditions. The enzyme exhausted lignin residues were characterized by 31P NMR spectroscopy and functional moieties quantified and correlated to enzymatic hydrolysis yields. Results from this study indicated that both xylan solubilization and lignin degradation are important for improving the enzyme accessibility and digestibility of dilute acid pretreated corn stover. At lower pretreatment temperatures, there is a good correlation between xylan solubilization and cellulose accessibility. At higher pretreatment temperatures, lignin degradation correlated better with cellulose accessibility, represented by the increase in phenolic groups. During acid pretreatment, the ratio of syringyl/guaiacyl functional groups also gradually changed from less than 1 to greater than 1 with the increase in pretreatment temperature. This implies that more syringyl units are released from lignin depolymerization of aryl ether linkages than guaiacyl units. The condensed phenolic units are also correlated with the increase in pretreatment temperature up to 180 degrees C, beyond which point condensation reactions may overtake the hydrolysis of aryl ether linkages as the dominant reactions of lignin, thus leading to decreased cellulose accessibility. PMID- 22543525 TI - Structural variety of zinc and copper complexes based on a 2,3-disubstituted 1,2,3,4-tetrahydroquinazoline ligand. AB - The ring-chain tautomerism of 2-(3-tosyl-1,2,3,4-tetrahydroquinazolin-2 yl)quinolin-8-ol (H(2)L(ring)) has been exploited to produce mononuclear complexes or, alternatively, dinuclear complexes, as desired, by varying the stoichiometry of the ligand. Cu(2+) and Zn(2+) stabilise the ring tautomeric form of the ligand in their mononuclear complexes M(HL(ring))(2). The structural characterisation of Zn(HL(ring))(2).2MeOH.0.5H(2)O shows O,N-donor behaviour of the ring tautomer. The 1,2,3,4-tetrahydroquinazoline undergoes a ring-opening reaction upon formation of phenoxo-bridged dinuclear complexes M(2)(L(chain))(2) in which the chain tautomer is acting as O,N,N,N-donor. The crystal structure of Cu(2)(L(amide))(L(quinazoline))(MeOH).2MeOH evidenced the sensitivity of H(2)L(ring) to the copper-mediated aerobic oxidation, which results in two derivatives of the ligand, a quinazoline and an amide. The quinazoline ligand is acting as monoanionic and mononucleating through its O,N,N binding site, while the amide ligand behaves as a trianionic and binucleating through its O,N,N,N and O,O binding sites in Cu(2)(L(amide))(L(quinazoline))(MeOH).2MeOH. PMID- 22543526 TI - Design of chiral sulfoxide-Schiff base hybrids and their application in Cu catalyzed asymmetric Henry reactions. AB - A new class of chiral sulfoxide-Schiff base ligands has been developed by the rational combination of two privileged chiral backbones. These sulfoxide-Schiff base ligands were found to be highly efficient for Cu-catalyzed asymmetric Henry reactions (up to 98% yield and 96% ee). PMID- 22543527 TI - Congenital cystic adenomatoid malformation: clinical features, pathological concepts and management in 172 cases. AB - OBJECTIVE: Congenital cystic adenomatoid malformation (CCAM) is the most common surgically resected pulmonary malformation in children. This retrospective study was undertaken to present the experience of 172 CCAM cases in a pediatric hospital. METHODS: Published series with a small number of patients reports details of lesions, progress and management. As this study addresses clinical characteristics, progress and surgical procedures in 172 children with CCAM diagnosis, the population includes cases treated and followed up in a pediatric hospital throughout 25 years (1986-2011). RESULTS: Mean age at diagnosis was 48 months (r = 0.03-213), 52% (n = 90) were male. The most common presenting symptoms were respiratory distress in children under 6 months of age (40%) and recurrent pneumonia in older ones (75%; p = 0.001). Lobectomy was the procedure of choice in the majority. All histological types were found: 1 (70%), 2 (24%), 4 (4%), and 0 and 3 (n = 1). A mixed pattern was observed in nine patients. Associated anomalies were found in 47% of children. The most frequent was sequestration (71%), mostly present in CCAM type 2 (p = 0.001). Severe anomalies were mostly related to type 2 (p = 0.008). A pleuropulmonary blastoma and a bronchioloalveolar carcinoma were also observed. Mortality was 5% (n = 9). Risk factors for mortality were respiratory failure (OR = 25.7 [95%CI 3.2-221]; p = 0.03), sepsis (OR = 9.9 [95%CI 8.2-12]; p = 0.002), respiratory assistance requirements (OR = 9.5 [95%CI 2.3-37]; p = 0.04), and severe associated comorbidities (OR = 3.3 [95%CI 1.2-22]; p = 0.008). CONCLUSIONS: Related anomalies were observed in almost half of the population. Due to the possibility of recurrent infection or development of malignancies, surgical resection should be considered when CCAM is diagnosed. Surgical outcome is favorable with manageable complications. PMID- 22543528 TI - Intratumoral delivery of CpG-conjugated anti-MUC1 antibody enhances NK cell anti tumor activity. AB - Monoclonal antibodies (mAbs) against tumor-associated antigens are useful anticancer agents. Antibody-dependent cellular cytotoxicity (ADCC) is one of the major mechanisms responsible for initiating natural killer cell (NK)-mediated killing of tumors. However, the regulation of ADCC via NK cells is poorly understood. We have investigated the cytolytic activity of NK cells against pancreatic cancer cells that were coated with an antibody directed against the human tumor antigen, Mucin-1 designated HMFG-2, either alone or conjugated to CpG oligodeoxynucleotide (CpG ODN). Conjugated antibodies were tested for their ability to elicit ADCC in vitro and in vivo against pancreatic cancer cells. NK cells cultured in the presence of immobilized CpG ODN, HMFG-2 Ab, or CpG ODN conjugated HMFG-2 Ab were able to up-regulate perforin similarly. Interestingly, a significant higher ADCC was observed when CpG ODN-conjugated HMFG-2-coated tumor cells were co-cultured with NK cells compared to unconjugated HMFG-2 Ab or CpG ODN alone. Moreover, MyD88-deficient NK cells can perform ADCC in vitro. Furthermore, intratumoral injections of CpG ODN-conjugated HMFG-2 induced a significant reduction in tumor burden in vivo in an established model of pancreatic tumor in nude mice compared to CpG ODN or the HMFG-2 alone. Depletion of macrophages or NK cells before treatment confirmed that both cells were required for the anti-tumor response in vivo. Results also suggest that CpG ODN and HMFG-2 Ab could be sensed by NK cells on the mAb-coated tumor cells triggering enhanced ADCC in vitro and in vivo. PMID- 22543529 TI - A 12-year-old girl with absent radial pulse: arterial thoracic outlet syndrome with subclavian artery aneurysm and thrombosis of the brachial artery. AB - Brachial arterial occlusion is rare in children and adolescents. Once a traumatic cause is excluded, the differential diagnosis consists of a variety of rare conditions. We report the case of a 12-year-old girl whose presenting symptoms- an absent radial pulse and Raynaud's phenomenon of the right hand--could be easily mistaken for a vasculitis. She was found to have arterial thoracic outlet syndrome with right subclavian artery compression and aneurysm formation caused by an anomalous first rib and consecutive thromboembolic occlusion of the brachial artery. The diagnosis and differential diagnosis of this condition are reviewed. PMID- 22543531 TI - Magnetic field enhanced cell uptake efficiency of magnetic silica mesoporous nanoparticles. AB - The advantages of using magnetic mesoporous silica nanoparticles (M-MSNs) in biomedical applications have been widely recognized. However, poor uptake efficiency may hinder the potential of M-MSNs in many applications, such as cell tracking, drug delivery, fluorescence and magnetic resonance imaging. An external magnetic field may improve the cellular uptake efficiency. In this paper, we evaluated the effect of a magnetic field on the uptake of M-MSNs. We found that the internalization of M-MSNs by A549 cancer cells could be accelerated and enhanced by a magnetic field. An endocytosis study indicated that M-MSNs were internalized by A549 cells mainly through an energy-dependent pathway, namely clathrin-induced endocytosis. Transmission electron microscopy showed that M-MSNs were trafficked into lysosomes. With the help of a magnetic field, anticancer drug-loaded M-MSNs induced elevated cancer cell growth inhibition. PMID- 22543530 TI - Circadian rhythms in obsessive-compulsive disorder. AB - The etiopathology and neurobiology of obsessive-compulsive disorder (OCD) are not fully understood. As for altered circadian rhythms associated with OCD, hormonal dysregulation and a delayed sleep phase have come into the focus of research. The novel antidepressant agomelatine is able to resynchronize circadian rhythms and the augmentative administration of this compound has been shown to be of benefit in some OCD patients who are refractory to common forms of pharmacotherapy. Adjunctive chronotherapy might also enhance the outcome in treatment-refractory OCD. The present review summarises the findings regarding circadian abnormalities in OCD. PMID- 22543532 TI - Strain effect on the diffusion of interstitial Mn in GaAs. AB - The influence of external strain on the diffusion barriers of interstitial Mn in GaAs is studied using the first-principles calculations within the density functional theory. The diffusion barrier changes with strain in different manners: linear on the tensile strain and nonlinear on compressive strain, in contrast to the linear behavior of the continuum elastic model. The discrepancy between the continuum elastic model and the results of the first-principles method is attributed to the energy-level crossing caused by strain. Moreover, we find that the external strain can not only effectively change the diffusion barrier (even to zero, at certain strain), but also the position of saddle points along the migration path. Our finding provides an alternative way to reduce the population of interstitial Mn in GaAs, thus correspondingly to increase the Curie temperature of this system. PMID- 22543533 TI - Management of ankylosing spondylitis: what is known; what is not known? PMID- 22543534 TI - Imaging and clinical measurements. AB - A variety of clinical and imaging parameters have been well validated and standardized for assessment in patients with spondyloarthritis during longitudinal follow-up in clinical practice and research. Outstanding questions were identified by the working group and include further assessment of the most appropriate method for assessment of disease activity and what cutoff is appropriate before access to advanced and costly biologic agents. The Ankylosing Spondylitis Disease Activity Score instrument may have advantages over the Bath Ankylosing Spondylitis Disease Activity Index, but this requires further study. A Bath Ankylosing Spondylitis Disease Activity Index cutoff of 4 has never been validated and also requires further evaluation. It is unclear what constitutes expert opinion for the purposes of defining disease activity. In particular, the role of magnetic resonance imaging requires further investigation. PMID- 22543535 TI - Treatment of ankylosing spondylitis: a critical appraisal of nonsteroidal anti inflammatory drugs and corticosteroids. AB - Treatment of ankylosing spondylitis and related disorders has been revolutionized by the advent of biological therapy, especially tumor necrosis factor-alpha inhibitors. Nonsteroidal anti-inflammatory drugs, however, remain the first line of treatment. Evidence has accumulated that nonsteroidal anti-inflammatory drug therapy of ankylosing spondylitis and related disorders is effective in controlling several of the clinical manifestations seen in these disorders, particularly pain, physical function and perhaps progressive spinal fusion. What needs to be proven, however, is the long-term safety profile of these drugs. PMID- 22543536 TI - Physical therapy and surgery. AB - Physical therapy and orthopedic surgery are important components in the treatment of ankylosing spondylitis (AS). Supervised physical therapy is more effective than individual or unsupervised exercise in improving symptoms, but controlled trials suggest that combined inpatient and outpatient therapy provides the greatest improvement. Recommendations for exercise are universal, but the best types and sequence of therapies are not known. Total hip replacement is the surgery most commonly performed for AS, with good long-term implant survival. Heterotopic ossification may occur no more frequently after hip replacement in patients with AS than in patients with other diseases. Corrective spinal surgery is rarely performed and requires specialized centers and experienced surgeons. PMID- 22543537 TI - Critical appraisal of the guidelines for the management of ankylosing spondylitis: disease-modifying antirheumatic drugs. AB - Surprisingly, little data are available for the use of disease-modifying antirheumatic drugs in ankylosing spondylitis. Sulfasalazine has been the best studied. Efficacy data for individual agents (including pamidronate) and combinations of agents are detailed in this review. Intriguingly, these agents continue to be used with some frequency, even in the absence of efficacy data. To answer these questions, additional systematic studies of these agents in ankylosing spondylitis are needed and will likely need to be done by interested collaborative groups such as SPARTAN. PMID- 22543538 TI - The "knowns" and "unknowns" of biologic therapy in ankylosing spondylitis. AB - Since the first biologic agent was tested in the treatment of ankylosing spondylitis (AS), the ability of these therapies to dramatically improve the clinical symptoms and signs of the disease was very evident. Over the past decade, 4 tumor necrosis factor-alpha inhibitors have been approved by the Food and Drug Administration for the treatment of AS. Published data include randomized controlled trials, registries and observational studies. Guidelines have also been developed for the use of biologics in AS. Although a lot is known about the use of biologics in the AS, several "unknowns" remain. Whether these agents can alter the natural history of AS if started very early in the course or whether they can prevent extra-articular manifestations are among the important unanswered questions. Most of the data summarized in this review relate to tumor necrosis factor-alpha inhibitors, and other biologic agents that have been studied are included, as well. This review also summarizes what questions remain about the use of biologics in AS and what type of studies will be required to answer them. PMID- 22543539 TI - Management of comorbidities in ankylosing spondylitis. AB - The major comorbidities of ankylosing spondylitis include uveitis, bowel inflammation, psoriasis and heart disease. The pathogenic mechanism to account for the coexistence of comorbidities remains largely unknown. In some instances, the comorbidity has a major impact on the choice of therapy. PMID- 22543540 TI - Juvenile spondyloarthritis treatment recommendations. AB - No specific recommendations for the treatment of juvenile spondyloarthritis have been established. Important differences exist in how spondyloarthritis begins and progresses in children and adults, supporting the need for pediatric-specific recommendations. Recently published recommendations for the treatment of juvenile arthritis consider children with sacroiliitis in a separate group and allow for more accelerated institution of a tumor necrosis factor inhibitor depending on disease activity and prognostic factors that derive primarily from studies of other forms of juvenile arthritis. There is a need to develop measures of disease activity and prognosis specific for juvenile spondyloarthritis that reflect spinal disease, as well as other major clinical features, such as enthesitis, before significant progress can be made in this area. PMID- 22543541 TI - Economic considerations of the treatment of ankylosing spondylitis. AB - Ankylosing spondylitis (AS) is associated with both significant direct and indirect costs, which vary by country, and have generally increased dramatically since the introduction of anti-tumor necrosis factor therapy. The cost effectiveness of biologic agents is controversial, although cost-effectiveness studies need to consider the potential impact of anti-tumor necrosis factor treatments on work ability. Alternatives to reduce costs associated with biologics have been examined, including on-demand dosing and lower dose alternatives. Other treatment measures, such as total hip arthroplasty and physical therapy, are also effective in reducing pain and improving function in patients with AS, although the optimal type or combination of physical therapy treatment modalities, the optimal frequency and duration of treatment and whether therapy is equally effective in stable disease and uncontrolled AS need to be determined. No studies have examined differences in patient outcomes based on subspecialty care. Establishing an evidence base for these questions would help inform policy decisions to design the most cost-effective measures to treat AS. PMID- 22543542 TI - Breast cancer incidence in Mongolia. AB - PURPOSE: Data on international variation in breast cancer incidence may help to identify additional risk factors. Substantially lower breast cancer rates in Asia than in North America and Western Europe are established, but differences within Asia have been largely ignored despite heterogeneity in lifestyles and environments. Mongolia's breast cancer experience is of interest because of its shared genetics but vastly different diet compared with other parts of Asia. METHODS: Age-standardized breast cancer incidence and mortality rates obtained from the International Association of Cancer Registries are presented for several Asian countries. Mongolian incidence rates obtained from its cancer registry describe incidence within the country. RESULTS: Breast cancer incidence in Mongolia (age standardized 8.0/100,000) is almost a third of rates in China (21.6/100,000), and over five times that of Japan (42.7/100,000) and Russia (43.2/100,000). Rates within Mongolia appear to have increased slightly over the last decade and are higher in urban than rural areas (annual percentage increase of age-standardized rates from 1998 to 2005 was 3.60 and 2.57 %, respectively). The increase in breast cancer incidence with age plateaus at menopause, as in other Asian populations. CONCLUSIONS: Mongolia's low breast cancer incidence is of particular interest because of their unusual diet (primarily red meat and dairy) compared with other Asian countries. More intensive study of potential dietary, reproductive and lifestyle factors in Mongolia with comparison to other Asian populations may provide more clarity in what drives the international breast cancer rate differences. PMID- 22543543 TI - Sun exposure and risk of lymphoid neoplasms in Singapore. AB - BACKGROUND: Epidemiologic studies have reported an inverse association between sun exposure and non-Hodgkin lymphoma (NHL), but these have been almost exclusively conducted in Western populations residing in temperate locations. We evaluated the association between personal outdoor sun exposure and risk of malignant lymphomas in Singapore. METHODS: A hospital-based case-control study of 541 incident cases of lymphoid neoplasms and 830 controls were recruited during 2004-2008. Participants were interviewed regarding recreational or occupational outdoor activities during childhood and in adulthood. Basic demographics and potential confounders were also collected. Odds ratios (OR) and 95 % confidence intervals (CI) were calculated using unconditional logistic regression analysis. RESULTS: Compared with individuals who did not have regular sun exposure, a lower risk of NHL was observed for those who reported regular exposure on non-school days during childhood [OR, 0.62; 95 % CI, 0.46-0.83] and non-working days in adulthood [OR, 0.70; 95 % CI, 0.51-0.97]. The protective effect was more evident among women. CONCLUSION: Our findings support an inverse relationship between intermittent sun exposure and the risk of NHL. These findings are consistent with the growing evidence from various countries, but further studies, especially prospective studies, are needed in Asian populations. PMID- 22543544 TI - Adverse cardiorespiratory events following primary vaccination of very low birth weight infants. AB - OBJECTIVE: To examine the relationship between primary vaccination of preterm infants and prevalence ratios of associated factors for unwanted cardiorespiratory events, following the recommendation of the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices for immunization of preterm infants at 2 months of chronological age. METHODS: Two year retrospective study of very low birth weight infants receiving their primary vaccination. Major cardiorespiratory events, such as apnea, bradycardia, SpO(2) desaturation, and minor adverse events, such as temperature instability, poor handling and local reactions, were recorded. Prevalence ratio with 95% confidence interval for associated factors between infants with and without cardiorespiratory events was calculated. RESULTS: Eighty neonates were studied (median [range] birth weight 970 g [428-1,490]), gestational age of 27.4 weeks (23.3-33). Adverse reactions occurred in 35 (44%): minor events in 19 (24%) patients, major events in 28 (35%). Infants with major events had significantly lower gestational age (p = 0.008) and a higher incidence of bronchopulmonary dysplasia (71% vs. 48%; p < 0.05). In very low birth weight infants with major events, O(2) desaturations before vaccination were 3.40 (1.41-8.23) times higher and treatment with methylxanthines for apnea and bradycardia syndrome was 8.05 (2.50-25.89) times higher compared to infants without major events. CONCLUSION: Major cardiorespiratory events occurred in over 1/3 of all very low birth weight infants after vaccination. Associated factors were low gestational age, bronchopulmonary dysplasia, methylxanthine treatment, and persisting O(2) desaturations before vaccination. Primary vaccination of very low birth weight infants should be performed under continuous monitoring of vital parameters. PMID- 22543545 TI - Variation of distances from mid-urethra to the obturator foramen: an MRI study. AB - INTRODUCTION AND HYPOTHESIS: To estimate distances from the mid-urethra to the obturator foramina and to explore correlations between pelvic dimensions and body height. METHODS: This is a secondary analysis of a parent case-control study on the mechanisms of stress urinary incontinence. We measured pelvic dimensions on magnetic resonance images of women with (cases, n = 50) and without (controls, n = 50) stress urinary incontinence. RESULTS: The mean distance from mid-urethra to the obturator membrane among cases is 31.8 mm (left) and 32.1 mm (right), with a range from 25.9 to 42.0 mm. There were no significant differences in these distances when comparing left with right, or cases with controls. Weak correlation was found between the urethra-to-obturator foramina distances and heights only in the case subjects. CONCLUSION: There is high variability in the distance from mid-urethra to the obturator foramina. Height should not be used as a predictor of dimensions in the lesser pelvis. PMID- 22543546 TI - Does neuromuscular blockade affect the assessment of pelvic organ prolapse? AB - INTRODUCTION AND HYPOTHESIS: The purpose of this study was to determine if anesthesia with neuromuscular blockade alters the Pelvic Organ Prolapse Quantification (POP-Q) examination. METHODS: A prospective, multi-center trial was conducted of women undergoing pelvic surgery. A POP-Q examination performed pre-operatively was compared with an examination performed intra-operatively under neuromuscular blockade. For the latter examination, an Allis clamp was used to apply gentle traction until the point being examined did not undergo further descent. International Continence Society (ICS) stages and individual POP-Q points were compared using a paired sample t test. A sample size of 32 provided 80% power to detect a clinically significant difference between office and operating room measurements (Sample Power, SPSS, 1997). RESULTS: Of 153 women, 76% received general endotracheal anesthesia and 21% laryngeal mask airway. With an increase of 3 cm, the apical compartment was significantly more prolapsed in the operating room (OR; p < 0.05); however, a comparison of the mean values demonstrated a larger change in means for all points except total vaginal length. When separated into anterior, apical, and posterior compartments, the ICS stages were systematically different in the OR than in the office for all stages (p < 0.0005). CONCLUSIONS: Neuromuscular blockade leads to significantly greater increases in POP-Q examination measurements compared with the office measurements, and this increase is most pronounced apically. PMID- 22543547 TI - Associations between subjective overactive bladder symptoms and objective parameters on bladder diary and filling cystometry. AB - INTRODUCTION AND HYPOTHESIS: A study was conducted to assess associations between different overactive bladder (OAB) symptoms and their outcomes on bladder diary and filling cystometry parameters. METHODS: We performed a retrospective cohort study in database of 6,876 Urinary Distress Inventories, 3,185 bladder diaries and 2,153 filling cystometries from women referred to our urogynecological center between 2003 and 2009. Women were dichotomized into two groups. Group I: those women without symptoms, and those with symptoms that were not bothersome. Group II: women with bothersome symptoms. Data obtained from bladder diaries were: daytime urinary frequency, nocturnal frequency, minimum voided volume, maximum voided volume, average voided volume, and incontinence episodes. From filling cystometries, volumes at first desire to void, normal desire to void, strong desire to void and maximum cystometric capacity, were extracted. Univariate and multiple linear regression analysis were performed to determine associations between OAB symptoms and bladder diary and filling cystometry measurements. RESULTS: After multivariate analysis the objective daytime frequency was most strongly associated with the frequency symptom (beta 0.27, p < 0.05), night time frequency with the nocturia symptom (beta 0.40, p < 0.05) and the number of incontinence episodes with the urge incontinence symptom (beta 0.37, p < 0.05). Both frequency and nocturia symptoms were significantly associated with bladder diary and cystometry filling volumes, and their effect size was the same. The urgency symptom proved to be poorly associated with objective parameters. CONCLUSIONS: In contrast to the frequency and nocturia symptom, the urgency symptom is poorly associated with objective parameters on bladder diary and filling cystometry. Therefore, the current practice of using frequency and incontinence episodes in outcome research of OAB trials is justified. PMID- 22543548 TI - Accuracy of assessing Pelvic Organ Prolapse Quantification points using dynamic 2D transperineal ultrasound in women with pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: We determined the relationship between clinical assessment of female pelvic organ prolapse (POP) using the validated Pelvic Organ Prolapse Quantification (POP-Q) and dynamic 2D transperineal ultrasound (TPUS). METHODS: Women attending the urogynecology clinics between July and October 2009 were recruited. Prolapse was assessed using the POP-Q. Points Ba, Bp and C (anterior, posterior and middle compartments, respectively) were measured. TPUS was performed at maximum Valsalva by another clinician. As the TPUS probe compresses the prolapse that extends beyond the hymen, these women were excluded. A reference line was drawn parallel to the inferoposterior margin of the pubic symphysis, perpendicular to which the leading edge of descent was measured. The offset measured from the curved array of the probe to the reference line was added to the prolapse quantification on ultrasound (US) scan to make it objectively comparable with the POP-Q reference of the hymen. Points Ba, Bp and C on POP-Q were then compared with points of maximum descent achieved on TPUS. RESULTS: One hundred and fifty-eight women had a POP-Q and TPUS; 20 scans (12.6 %) were not analysable, and 41 women had prolapse beyond the hymen. Ninety-seven women were thus analysed. The correlation between 2D TPUS (with/without the addition of the offset) and POP-Q was statistically significant (p value <0.0001) for all three compartments. The proportion of correct predictions was 59.6 %, 61.5 % and 32.6 % for bladder, bowel and middle-compartment prolapse, respectively. CONCLUSION: These findings suggest that the accuracy of pelvic floor US staging is limited and that clinical assessment remains the gold standard. PMID- 22543549 TI - Magnetic resonance imaging of abdominal versus vaginal prolapse surgery with mesh. AB - INTRODUCTION AND HYPOTHESIS: We compared two surgical approaches in patients with symptomatic prolapse of the vaginal apex with normal controls by analyzing pelvic landmark relationships measured using magnetic resonance imaging (MRI) before and after surgery. METHODS: In this prospective multicenter pilot study involving 16 participants, nulliparous controls (n = 6) were compared with ten parous (3.0 +/- 1.0) women with uterine apical prolapse equal to or greater than stage 2. Group A (n = 5) underwent abdominal sacral colpopexy with monofilament polypropylene mesh and group B (n = 5) with vaginal mesh kit repair (Total ProLift). Subtotal hysterectomy was performed in all group A and no group B women. All patients underwent preoperative and 3-month postoperative Pelvic Organ Prolapse Quantification (POP-Q) and dynamic MRI. Comparison of MRI pelvic angles and distances was performed and analyzed by Mann-Whitney rank sum test and chi-square test. RESULTS: Vaginal apical support is similar at 3 months for abdominal sacral colpopexy (ASCP) and ProLift by POP-Q examination and MRI analysis. In both treatment groups, the postoperative POP-Q point C and MRI parameters were similar to nulliparous controls at 3 months. CONCLUSIONS: Anatomic outcomes for ASCP compared with ProLift were similar at 3 months in terms of vaginal apical support by POP-Q and MRI analysis. Continued comparative analysis of postoperative support with objective imaging seems warranted. PMID- 22543550 TI - Comments on Jha et al.: Incontinence during intercourse: myths unravelled. PMID- 22543552 TI - Laparoscopic resection for sigmoid and rectosigmoid colon cancer performed by trainees: impact on short-term outcomes and selection of suitable patients. AB - PURPOSE: This study aimed (1) to evaluate the impact of clinical factors, particularly operation by trainees, on the short-term outcomes of laparoscopic resection for sigmoid and rectosigmoid cancer, and (2) to determine patients suitable for operation by trainees. METHODS: From a prospectively maintained single-institution database, we identified 133 patients who underwent laparoscopic resection for sigmoid or rectosigmoid cancer between 2007 and 2010. Gender, age, body mass index (BMI), previous abdominal surgery, tumor location, tumor size, tumor stage, extent of lymph node dissection, and primary surgeon were evaluated using univariate and multivariate analyses to determine the predictive significance of these variables on surgical outcomes including operative time, blood loss, complication, postoperative stay, and retrieved lymph nodes. RESULTS: Multivariate analysis showed that location of the tumor in the rectosigmoid (p < 0.001), higher BMI (p < 0.001), operation by trainees (p < 0.001), male gender (p = 0.002), and greater tumor depth (p = 0.011) were independently predictive of longer operative time. Larger tumor size (p = 0.025) and higher BMI (p = 0.040) were independently predictive of greater blood loss. Larger tumor size was also related to longer postoperative stay (p = 0.001) and a greater number of retrieved lymph nodes (p = 0.001). CONCLUSIONS: This study identified operation by trainees as an independent risk factor for longer operative time but with no negative impact on any of the other outcomes. Female patients with a low BMI, sigmoid cancer, shallow tumor depth, and/or small tumor are suitable for operation by trainees. PMID- 22543553 TI - The size of cytoplasmic lipid droplets varies between tumour cell lines of the nervous system: a 1H NMR spectroscopy study. AB - OBJECT: Cytoplasmic lipid droplets (LDs) are dynamic cellular organelles; their accumulation is associated with several cellular processes, such as cell proliferation, apoptosis and necrosis. (1)H Nuclear Magnetic Resonance (NMR) spectroscopy detects resonances from lipids present in cytoplasmic (LDs); an understanding of the relationship between LD characteristics and NMR lipid signals is important. MATERIALS AND METHODS: In this study, five nervous system cancer cell lines were investigated. Nile red staining was used to measure the diameter of LDs. High-resolution magic angle spinning NMR (HR-MAS) was performed on harvested cell pellets to quantify the patterns of lipid signals. RESULTS: LDs were present in all five cell lines with different morphology. An average LD diameter of approximately 0.2 MUm was found in all cell types. Diameter of the largest LDs varied across the cell lines. The intensity of NMR lipid signals varied greatly between cell types, and a good correlation was found between total volume of LDs and the proton NMR lipid signal intensity at 0.9 and 1.3 ppm. CONCLUSION: The correlation implied that little NMR signal is detected from LDs of diameters less than approximately 0.34 MUm, most likely due to restriction of rotational motion of the lipids. PMID- 22543555 TI - Neurocognitive rehabilitative approach effectiveness after anterior cruciate ligament reconstruction with patellar tendon. A randomized controlled trial. AB - BACKGROUND: A proper knee rehabilitation after a surgical reconstruction of the anterior cruciate ligament (ACL) should start immediately after the injury and it should be focused on recovery of symmetry, proprioception, swelling reduction, gait training, hyperextension exercises, and even mental preparation. AIM: Aim of this study was to test a neurocognitive rehabilitative approach based on proprioceptive exercises and proper motor strategy choices, compared with conventional rehabilitation, assessing baropodometric, gait and clinical changes. DESIGN: Randomized controlled trial. SETTING: Ambulatory University Centre. POPULATION: Fourteen subjects (27.9+/-5.2 years) underwent to a surgical reconstruction of ACL were divided into the two groups. METHODS: The subjects were randomly assigned into a group who received a specific neurocognitive and perceptive rehabilitation treatment (TG), and into a control group who received the common physical therapy (CG). The following outcome measures were assessed pre-intervention, one, three and six months later: static and dynamic baropodometry, Visual Analog Scale for pain, Short Form SF-36, Range of Motion, trophism of thigh region, edema, Manual Muscle Test, magneto-resonance imaging assessment. RESULTS: Lower impairment was observed in TG in respect of CG in terms of load asymmetry during static baropodometry (from 7% to 3% vs. from 10% to 7%, interaction time per treatment: P=0.037), less wide steps during gait (effect size=1.05 vs. 0.38 for CG), swelling (treatment effect: P=0.012). A significantly higher improvement (from 35% to 100%) in terms of SF-36 was recorded only in TG for physical activity (P=0.027). CG showed a quite higher walking speed (treatment effect: P=0.049). CONCLUSION: Even if further studies are needed on larger samples, the obtained results showed that a neurocognitive rehabilitative approach could be an effective treatment after ACL-reconstruction: in TG we observed a more rapid load symmetrization, the reduction of step width and a more rapid resolution of edema. CLINICAL REHABILITATION IMPACT: Posture, gait, clinical features and quality of life could benefit from a neurocognitive rehabilitation after ACL surgical reconstruction. PMID- 22543556 TI - EJPRM systematic continuous update on Cochrane reviews in rehabilitation: news from December 2011 to February 2012. AB - AIM: In order to present to our readers the best available evidence in the field of Rehabilitation, we continuously perform systematic reviews of the articles regularly published in the Cochrane Library, being these considered the most reliable instruments of synthesis, reliable because based on a strict methodology. Moreover, according to the aim of the Cochrane Collaboration, in order to diffuse sound data, we invited Cochrane authors to republish their articles in the EJPRM. The aim of the present paper is to systematically review all the new rehabilitation papers published from December 2011 up to February 2012 from the Cochrane Library in order to provide to physicians involved in the field a summary of the best evidence nowadays available. METHODS: The authors systematically searched all the new papers of rehabilitative interest from the 5th of December 2011 to the 27th of February 2012 in the Cochrane Library. The retrieved papers have been then divided in subgroups on the base of the topic and the Cochrane Groups. RESULTS: The number of included papers was 5, 4 new reviews and 2 updates reviews. A synthesis of abstracts is presented. CONCLUSION: The field of rehabilitation, being cross-sectional to the whole Medicine, can be of interest for many specialty. This was documented by the large number of Cochrane Group publishing reviews of Rehabilitative interest. Reviewing periodically the Cochrane reviews is a good way to remain up to date and to find solid bases for everyday clinical practice. PMID- 22543557 TI - Use of the robot assisted gait therapy in rehabilitation of patients with stroke and spinal cord injury. AB - Difficulty in walking is a major feature of neurological disease, and loss of mobility is the activity of daily living on which patients place the greatest value. The impact on patients is enormous, with negative ramifications on their participation in social, vocational, and recreational activities. In current clinical practice the gait restoration with robotic device is an integral part of rehabilitation program. Robot therapy involves the use of a robot exoskeleton device or end-effector device to help the patient retrain motor coordination by performing well-focused and carefully directed repetitive practice. The exoskeleton, as an assistive device, is also an external structural mechanism with joints and links corresponding to those of the human body. These robots use joint trajectories of the entire gait cycle and offer a uniform (more or less) stiff control along this trajectory. In this field the new powered exoskeleton ReWalk (Argo Medical Technologies Ltd) was developed to have an alternative mobility solution to the wheelchair and rehabilitation treatment for individuals with severe walking impairments, enabling them to stand, walk, ascend/descent stairs and more. The end-effector-based robot is a device with footplates placed on a double crank and rocker gear system. Alternatives to powered exoskeletons are devices that use movable footplates to which the patient's feet are attached. All devices include some form of body weight support. Prominent goals in the field include: developing implementable technologies that can be easily used by patients, therapists, and clinicians; enhancing the efficacy of clinician's therapies and increasing the ease of activities in the daily lives of patients. PMID- 22543558 TI - Applicability of a new robotic walking aid in a patient with cerebral palsy. Case report. AB - BACKGROUND: Gait training with the help of assistive technological devices is an innovative field of research in neurological rehabilitation. Most of the available gait training devices do not allow free movement in the environment, which would be the most suitable natural and motivating condition for training children with neurological gait impairment. AIM: To evaluate the potential applicability of a new robotic walking aid as a tool for gait training in non ambulatory children with Cerebral Palsy. DESIGN: Single case study SETTING: Outpatient regimen POPULATION: A 11-years-old child unable to stand and walk independently as a result of spastic tetraplegic cerebral palsy (CP). METHODS: The experimental device was a newly actuated version of a dynamic combined walking and standing aid (NF-Walker(r)) available in the market which was modified by means of two pneumatic artificial muscles driven by a foot-switch inserted in the shoes. The child was tested at baseline (while maintaining the standing position aided by the non-actuated NF-Walker(r)) and in the experimental condition (while using the actuated robotic aid). The outcome measures were: 2 minute walking test, 10-metre walking test, respiratory and heart parameters, energy cost of locomotion. RESULTS: At baseline, the child was unable to perform any autonomous form of locomotion. When assisted by the actuated aid (i.e. during the experimental condition), the child was successful in moving around in his environment. His performance was 19.63 m in the 2-minute walking test and 64 s in the 10-metre walking test. Respiratory and heart parameters were higher than healthy age-matched children both at baseline and in the experimental condition. The energy cost of gait, which was not valuable in the baseline condition, was significantly higher than normality during the experimental condition. CONCLUSION: The new robotic walking aid may help children suffering from CP with severe impairment of gait to move around in their environment. CLINICAL REHABILITATION IMPACT: This new robotic walking device may have a potential impact in stimulating the development and in training of gait in children with neurological gait impairment. Future studies are warranted in order to test this hypothesis. PMID- 22543562 TI - Co-linear, double-uranyl coordination by an expanded Schiff-base polypyrrole macrocycle. AB - Expansion of a Schiff-base polypyrrolic macrocycle allows the formation of a binuclear uranyl complex with co-linear uranyl ions and a very short oxo-oxo distance. PMID- 22543561 TI - Time delay between diagnosis and arthroscopic lavage in septic arthritis. Does it matter? AB - PURPOSE: Septic arthritis is a life-threatening emergency with high mortality of up to 11 %. We investigated if delay of arthroscopic lavage of infected major joints would have a bearing on the mortality and morbidity such as admission to an intensive care unit (ICU). METHODS: We retrospectively reviewed patients presenting with septic arthritis to two regional hospitals over a period of seven years from 1 January 2005 to 31 December 2011. We divided our sample of 82 patients into four groups based on the time delay between clinical diagnosis and arthroscopic lavage ranging from less than six hours to more than 24 hours. RESULTS: We determined that 35.4 % of patients had prosthetic joints. Knee joints were predominantly involved (74.4 %). Staphylococcus aureus was the most commonly isolated pathogen (41.5 %). There were ten (12.2 %) deaths and the same number of admissions to an ICU. Our study revealed there was no statistical significance between the time delay and mortality (P = 0.25) or ICU admission (P = 0.74) or the number of washouts (P = 0.08) in all four groups. CONCLUSIONS: Up to 48 hours delayed arthroscopic lavage for septic arthritis does not increase the risk of mortality. Further prospective large sample studies are recommended to investigate this and the risk of long-term morbidity. PMID- 22543563 TI - Characterization of the incidence and risk factors for the development of lumbar radiculopathy. AB - STUDY DESIGN: Epidemiological study of a prospectively collected database. OBJECTIVES: This investigation sought to evaluate the incidence of symptomatic lumbar radiculopathy, and identify risk factors for its development, among individuals serving in the United States military over a 10-year period. SUMMARY OF BACKGROUND DATA: Risk factors for the development of lumbar radiculopathy are poorly understood and the incidence of this disorder has not been characterized earlier for a young, high-demand population. METHODS: The Defense Medical Epidemiology Database was queried for the years 2000 to 2009 using the International Classification of Diseases ninth revision code for lumbar radiculopathy (724.4). Overall incidence was determined and multivariate Poisson regression analysis was carried out to identify the influence of risk factors such as age, sex, race, military rank, and branch of service on the development of this condition. RESULTS: In this population, the overall incidence of lumbar radiculopathy was 4.86 per 1000 person-years. Multivariate Poisson regression analysis showed that female sex, white race, senior positions within the rank structure, and service in the Army, Navy, or Air Force increased the risk of developing lumbar radiculopathy. Servicemembers of 30 years and older were found to have >3 times the risk of developing lumbar radiculopathy when compared with individuals <20. CONCLUSIONS: The incidence of lumbar radiculopathy in this young, racially diverse, and physically active population is higher than many other degenerative conditions. In this study female sex and white race increased the risk of developing lumbar radiculopathy. However, increasing age seems to be one of the most significant independent factors for developing this disorder. LEVEL OF EVIDENCE: Level II, prognostic study. PMID- 22543564 TI - A polyoxometalate-based Pd(II)-coordinated ionic solid catalyst for heterogeneous aerobic oxidation of benzene to biphenyl. AB - An ionic solid catalyst by pairing Keggin polyoxometalate-anions with Pd(II) coordinated nitrile-tethered ionic liquid cations was synthesized, characterized, and tested for aerobic oxidation of benzene to biphenyl. A unique heterogeneous intramolecular electron transfer mechanism is proposed to understand its high activity. PMID- 22543565 TI - High-speed atomic force microscopy in slow motion--understanding cantilever behaviour at high scan velocities. AB - Using scanning laser Doppler vibrometer we have identified sources of noise in contact mode high-speed atomic force microscope images and the cantilever dynamics that cause them. By analysing reconstructed animations of the entire cantilever passing over various surfaces, we identified higher eigenmode oscillations along the cantilever as the cause of the image artefacts. We demonstrate that these can be removed by monitoring the displacement rather than deflection of the tip of the cantilever. We compare deflection and displacement detection methods whilst imaging a calibration grid at high speed and show the significant advantage of imaging using displacement. PMID- 22543566 TI - Hereditary angioedema (HAE) in children and adolescents--a consensus on therapeutic strategies. AB - Hereditary angioedema due to C1 inhibitor (C1 esterase inhibitor) deficiency (types I and II HAE-C1-INH) is a rare disease that usually presents during childhood or adolescence with intermittent episodes of potentially life threatening angioedema. Diagnosis as early as possible is important to avoid ineffective therapies and to properly treat swelling attacks. At a consensus meeting in June 2011, pediatricians and dermatologists from Germany, Austria, and Switzerland reviewed the currently available literature, including published international consensus recommendations for HAE therapy across all age groups. Published recommendations cannot be unconditionally adopted for pediatric patients in German-speaking countries given the current approval status of HAE drugs. This article provides an overview and discusses drugs available for HAE therapy, their approval status, and study results obtained in adult and pediatric patients. Recommendations for developing appropriate treatment strategies in the management of HAE in pediatric patients in German-speaking countries are provided.Conclusion Currently, plasma-derived C1 inhibitor concentrate is considered the best available option for the treatment of acute HAE-C1-INH attacks in pediatric patients in German-speaking countries, as well as for short term and long-term prophylaxis. PMID- 22543567 TI - Silent slipped capital femoral epiphysis in overweight and obese children and adolescents. AB - Abnormal loading of the hip in obese children may lead to anatomic alterations and an increased prevalence of slipped capital femoral epiphysis (SCFE). The aims of this study were to examine the hip motion in obese children and adolescents and to estimate the prevalence of SCFE in a subgroup of patients characterized by pathological clinical examination and/or pain in the knee or hip joint. A total of 411 individuals (196 males), mean age 14.5 +/- 2.5 years (7.8-20.4), mean BMI of 32.9 +/- 5.6 kg/m(2) (20.3-51.5, z score +2.65) who were consecutively admitted for an inpatient weight loss program were included in the study. Twenty six percent of the patients had load-dependent and 11.7 % had load-independent pain in the knee joint. A total of 9.3 % had load-dependent and 4.7 % had load independent pain in the hip joint. Two patients (0.5 %) underwent surgical treatment of SCFE prior to entry. A total of 18.2 % of the patients showed a reduced range of motion for hip flexion (<90 degrees ) and 18.5 % a pathological decreased internal rotation (<10 degrees ). Radiological evaluation of the hips in the clinically conspicuous subgroup (n = 54) revealed an abnormal head-neck ratio as a sign of prior silent slipped capital femoral epiphysis in 11 patients (20.4 % of the 54 patients, 2.7 % of total cohort). In conclusion, these data show a high prevalence of SCFE-like tilt deformities in a selected group of severely obese children. Mild deformation of the epiphysis at young age might be a major predisposing factor for the development of hip osteoarthritis in obese adults. PMID- 22543568 TI - A Bayesian latent group analysis for detecting poor effort in the assessment of malingering. AB - Despite their theoretical appeal, Bayesian methods for the assessment of poor effort and malingering are still rarely used in neuropsychological research and clinical diagnosis. In this article, we outline a novel and easy-to-use Bayesian latent group analysis of malingering whose goal is to identify participants displaying poor effort when tested. Our Bayesian approach also quantifies the confidence with which each participant is classified and estimates the base rates of malingering from the observed data. We implement our Bayesian approach and compare its utility in effort assessment to that of the classic below-chance criterion of symptom validity testing (SVT). In two experiments, we evaluate the accuracy of both a Bayesian latent group analysis and the below-chance criterion of SVT in recovering the membership of participants assigned to the malingering group. Experiment 1 uses a simulation research design, whereas Experiment 2 involves the differentiation of patients with a history of stroke from coached malingerers. In both experiments, sensitivity levels are high for the Bayesian method, but low for the below-chance criterion of SVT. Additionally, the Bayesian approach proves to be resistant to possible effects of coaching. We conclude that Bayesian latent group methods complement existing methods in making more informed choices about malingering. PMID- 22543569 TI - The efficiency and accuracy of the Test of Memory Malingering trial 1, errors on the first 10 items of the test of memory malingering, and five embedded measures in predicting invalid test performance. AB - The current study attempted to improve upon the efficiency and accuracy of one of the most frequently administered measures of test validity, the Test of Memory Malingering (TOMM) by utilizing two short forms (TOMM trial 1 or TOMM1; and errors on the first 10 items of TOMM1 or TOMMe10). In addition, we cross validated the accuracy of five embedded measures frequently used in malingering research. TOMM1 and TOMMe10 were highly accurate in predicting test validity (area under the curve [AUC]=92% and 87%, respectively; TOMM1<=40 and TOMMe10>=1; sensitivities>70% and specificities>90%). A logistic regression of five embedded measures showed better accuracy compared with any individual embedded measure alone or in combination (AUC=87%). TOMM1 and TOMMe10 provide evidence of greater sensitivity to invalid test performance compared with the standard TOMM administration and the use of regression improved the accuracy of the five embedded cognitive measures. PMID- 22543570 TI - Analysis of electrical and mechanical left atrial properties in patients with persistent atrial fibrillation. AB - The study of left atrial (LA) mechanical function during atrial fibrillation (AFib) can provide valuable information, particularly if such profiling is related to the cavity electrical substrate and conveys prognostic information. To assess if there is any relation between LA mechanical and electrical asynchrony and if such evaluation can be of interest in stratifying AFib patients. 50 patients with persistent AFib who underwent electrical cardioversion (CV) were evaluated with pre-CV atrial electrograms (AEGs). Electrical asynchrony was classified according to Wells' patterns of AEGs, ranging from most organized (I) to most dispersed (III) one. LA mechanical asynchrony was addressed by transthoracic 2D-speckle-tracking echo and quantified according to time-to-peak standard deviation (TP-SD) of wall strains and their peak values (PS) before CV, after 24 h, at 1 month. Pre-CV a linear, inverse relation between TP-SD and PS (p < 0.001) and a direct linear relation between TP-SD and Wells' classes (p = 0.04) were observed. With sinus rhythm TP-SD decreased (p = 0.023) and PS increased (p < 0.001), suggesting improved LA mechanical milieu. A multivariate analysis, testing the effects of baseline variables in predicting post-CV recurrence of AFib, revealed that amount of TP-SD variation pre/24 h post-CV was the only independent predictor at 6 months (p = 0.046). Speckle tracking-derived LA parameters can describe LA wall forces during AFib, categorizing the asynchronous mechanistic profile of AFib that correlates with the degree of the dispersed LA electrical activity. The amount of changes in LA mechanical asynchrony pre/post CV seems to have prognostic relevance in predicting SR maintenance. PMID- 22543571 TI - Critical cerebral oxygen desaturation: how should we define baseline saturation? PMID- 22543572 TI - The disconnected epidural catheter: a survey of current practice in Scotland. PMID- 22543573 TI - Pharmacology in the very young: anaesthetic implications. AB - Anaesthesia dosing in infants (0-2 years) should be based on pharmacokinetic pharmacodynamic considerations and adverse effects profiles. Disease processes and treatments in this group are distinct from those in adults. Absorption, distribution and clearance change dramatically during this period because of maturation of anatomical and physiological processes as well as behavioural changes. Pharmacogenomic expression also matures in this period. Population-based and physiological-based pharmacokinetic modelling has improved the understanding of maturation and subsequent dose approximation. Postmenstrual, rather than postnatal, age is a reasonable measure for maturation. There remains a need for clinically applicable tools to assess pharmacodynamics which can provide response feedback; this has been achieved for neuromuscular monitoring, but not yet fully for depth of anaesthesia, sedation or pain. Morbidity and mortality associated with paediatric anaesthesia have historically been highest in this age group and continue to be so. Some of this morbidity was attributable to a poor understanding of developmental pharmacology; this facet continues to plague the specialty. PMID- 22543574 TI - Amino-terminal pro-brain natriuretic peptide as a predictor of outcome in patients admitted to intensive care. A prospective observational study. AB - CONTEXT: Amino-terminal pro-brain-type natriuretic peptide is known to predict outcome in patients with heart failure, but its role in an intensive care setting is not yet fully established. OBJECTIVE: To assess the incidence of elevated amino-terminal pro-brain natriuretic peptide (NT-pro-BNP) on admission to intensive care and its relation to death in the ICU and within 30 days. DESIGN: Prospective, observational cohort study. SETTING: A mixed non-cardiothoracic tertiary ICU in Sweden. PATIENTS AND MAIN OUTCOME MEASURES: NT-pro-BNP was collected from 481 consecutive patients on admission to intensive care, in addition to data on patient characteristics and outcome. A receiver-operating characteristic curve was used to identify a discriminatory level of significance, a stepwise logistic regression analysis to correct for other clinical factors and a Kaplan-Meier analysis to assess survival. The correlation between Simplified Acute Physiology Score (SAPS) 3, Sequential Organ Failure Assessment score (SOFA) and NT-pro-BNP was analysed using Spearman's correlation test. Quartiles of NT pro-BNP elevation were compared for baseline data and outcome using a logistic regression model. RESULTS: An NT-pro-BNP more than 1380 ng -l on admission was an independent predictor of death in the ICU and within 30 days [odds ratio (OR) 2.6; 95% confidence interval (CI), 1.5 to 4.4] and was present in 44% of patients. Thirty-three percent of patients with NT-pro-BNP more than 1380 ng -1, and 14.6% of patients below that threshold died within 30 days (log rank P=0.005). NT-pro-BNP correlated moderately with SAPS 3 and with SOFA on admission (Spearman's rho 0.5552 and 0.5129, respectively). In quartiles of NT-pro-BNP elevation on admission, severity of illness and mortality increased significantly (30-day mortality 36.1%; OR 3.9; 95% CI, 2.0 to 7.3 in the quartile with the highest values, vs. 12.8% in the lowest quartile). CONCLUSION: We conclude that NT-pro-BNP is commonly elevated on admission to intensive care, that it increases with severity of illness and that it is an independent predictor of mortality. PMID- 22543575 TI - What's in a name? What constitutes the clinical diagnosis of osteoporosis? AB - Osteoporosis is a skeletal disorder in which reductions in bone strength predispose to an increased risk for fractures. Currently, the diagnosis is officially made based exclusively on bone mineral density T-scores that are <= 2.5 at the spine or hip. Limiting the clinical diagnosis of osteoporosis solely to a T-score-based criterion, which is the official convention in the USA, creates uncertainty about the use of the term osteoporosis to diagnose older women and men who have T-scores >-2.5, but either have already sustained low trauma fractures or are recognized as having high fracture risk based on absolute fracture risk calculations from FRAX or other algorithms. A failure to diagnose such patients as having osteoporosis may be one component of the well-documented underdiagnosis and undertreatment of this disease which limits our ability to reduce the burden of fractures worldwide. There is a need to expand the criteria for making a clinical diagnosis and to codify these changes in order to help patients, physicians, policy makers, and payers better understand who has this disease and the elevated risk for fracture that it represents. PMID- 22543576 TI - Hip fracture patients in India have vitamin D deficiency and secondary hyperparathyroidism. AB - SUMMARY: This study evaluated the parameters of bone mineral homeostasis including 25(OH)D and PTH in 90 Indian patients with hip fracture and 90 controls. Hypovitaminosis D, secondary hyperparathyroidism, and biochemical osteomalacia was present in 77, 69, and 50 % patients, respectively, significantly higher compared to controls. Vitamin D deficiency is an important risk factor for hip fracture. INTRODUCTION: The prevalence of vitamin D deficiency is not well known in hip fracture patients from India. Therefore, the present study was conducted to evaluate the parameters of bone mineral homeostasis including 25(OH)D and intact PTH in hip fracture from North India. METHODS: Ninety consecutive patients with hip fracture and similar number of age- and sex-matched controls were enrolled in the study. The fasting venous samples were analyzed for 25-hydroxyvitamin D (25-OHD), intact parathyroid hormone (PTH), alkaline phosphatase (ALP), calcium, and phosphorus. Vitamin D deficiency was defined as serum 25-OHD of <20 ng/dl. RESULTS: The mean age of hip fracture subjects was 65.9 +/- 12.6 which was comparable in men and women. Majority of study subjects were women (70 women and 20 men). The serum 25(OH)D and calcium levels were significantly lower, whereas the intact PTH and ALP levels were significantly higher in patients compared to controls. There was significant negative correlation between serum 25(OH)D and PTH. In the hip fracture group, 76.7 % of the subjects had vitamin D deficiency, and 68.9 % had secondary hyperparathyroidism. In the control group, vitamin D deficiency and elevated PTH levels were seen in 32.3 and 42.2 %, respectively. CONCLUSION: About three fourths of hip fracture patients have vitamin D deficiency, and two thirds have secondary hyperparathyroidism. Therefore, the serum 25-OHD level may be a useful index for the assessment of risk of hip fracture in India. PMID- 22543577 TI - Health-related predictors of falls and fractures in women over 40. AB - SUMMARY: A longitudinal study of women aged 40-80 predicted single falls from a previous fall history and deficient vestibular integration. Multiple falls were predicted by a fall history, low activity levels, more medical conditions and deficient vestibular integration. Low bone mineral density, more medical conditions and fall history predicted fractures. INTRODUCTION: The purpose of this study was to identify potentially modifiable health-related factors predicting falls and fractures, focussing on women over 40. METHODS: Four hundred and forty-nine women aged 40-80 years from the Longitudinal Assessment of Women study participated. Demographic information (age, BMI, medications, medical conditions and activity level), balance assessments (including timed up & go and modified clinical test for sensory interaction of balance) and measurements of bone mineral density and body composition were collected in 2001; fall and fracture data were gathered in 2003, 2005, 2007, 2008 and 2010 to determine incidence. RESULTS: Multinomial logistic regression revealed that single falls could be predicted by a history of previous falls (OR 3.08) and being unsteady in bipedal stance on foam with eyes closed (OR 1.99). Multiple falls were predicted by a history of falls at baseline (OR 4.69), low levels of activity (OR 2.17), greater number of medical conditions (OR 1.12) and being unsteady in bipedal stance on foam with eyes closed (OR 4.21). Low bone mineral density (OR 3.13), greater number of medical conditions (OR 1.32) and a history of falls (OR 3.04) were predictive of fractures. CONCLUSIONS: Poor health, decreased balance, and inactivity are predictive of falls and low bone mineral density, low activity level and poor health predictive fractures. Results suggest failing the balance test bipedal stance on foam with eyes closed in the presence of low activity and poor health is a valid quick screening tool for detecting potential fallers for referral for in-depth balance assessment and intervention. PMID- 22543578 TI - The intracellular controlled release from bioresponsive mesoporous silica with folate as both targeting and capping agent. AB - A smart mesoporous silica nanocarrier with intracellular controlled release is fabricated, with folic acid as dual-functional targeting and capping agent. The folate not only improves the efficiency of the nanocarrier internalized by the cancer cells, but also blocks the pores of the mesoporous silica to eliminate premature leakage of the drug. With disulfide bonds as linkers to attach the dual functional folate within the surface of mesoporous silica, the controlled release can be triggered in the presence of reductant dithiothreitol (DTT) or glutathione (GSH). The cellular internalization via folate-receptor-mediated endocytosis and the intracellular controlled release of highly toxic anticancer drug DOX were demonstrated with an in vitro HeLa cell culture, indicating an efficient cancer targeted drug delivery. PMID- 22543579 TI - Irreversible metamagnetic transition and magnetic memory in small-bandwidth manganite Pr(1-x)Ca(x)MnO3 (x = 0.0-0.5). AB - The present paper reports detailed structural and magnetic characterization of the low-bandwidth manganite Pr(1-x)Ca(x)MnO(3) (with x = 0.0-0.5) (PCMO) polycrystalline samples. With increasing Ca content, reduction of the unit cell volume and improvement in perovskite structure symmetry was observed at room temperature. Magnetic characterization shows the signature of coexisting AFM-FM ordering and spin-glass phase at the low doping range (x = 0.0-0.2) while increased hole doping (x = 0.3-0.5) leads to charge ordering, training effect and an irreversible metamagnetic phenomenon. The large irreversible metamagnetism in the CO phase of PCMO and the corresponding spin memory effect is a direct consequence of hysteretic first-order phase transition arising from the weakening of the CO state under the external magnetic field and trapping of the spins due to a strong pinning potential in the material. PMID- 22543580 TI - Putting the "ecology" into environmental flows: ecological dynamics and demographic modelling. AB - There have been significant diversions of water from rivers and streams around the world; natural flow regimes have been perturbed by dams, barriers and excessive extractions. Many aspects of the ecological 'health' of riverine systems have declined due to changes in water flows, which has stimulated the development of thinking about the maintenance and restoration of these systems, which we refer to as environmental flow methodologies (EFMs). Most existing EFMs cannot deliver information on the population viability of species because they: (1) use habitat suitability as a proxy for population status; (2) use historical time series (usually of short duration) to forecast future conditions and flow sequences; (3) cannot, or do not, handle extreme flow events associated with climate variability; and (4) assume process stationarity for flow sequences, which means the past sequences are treated as good indicators of the future. These assumptions undermine the capacity of EFMs to properly represent risks associated with different flow management options; assumption (4) is untenable given most climate-change predictions. We discuss these concerns and advocate the use of demographic modelling as a more appropriate tool for linking population dynamics to flow regime change. A 'meta-species' approach to demographic modelling is discussed as a useful step from habitat based models towards modelling strategies grounded in ecological theory when limited data are available on flow-demographic relationships. Data requirements of demographic models will undoubtedly expose gaps in existing knowledge, but, in so doing, will strengthen future efforts to link changes in river flows with their ecological consequences. PMID- 22543581 TI - Accidental bait: do deceased fish increase freshwater turtle bycatch in commercial fyke nets? AB - Bycatch of turtles in passive inland fyke net fisheries has been poorly studied, yet bycatch is an important conservation issue given the decline in many freshwater turtle populations. Delayed maturity and low natural adult mortality make turtles particularly susceptible to population declines when faced with additional anthropogenic adult mortality such as bycatch. When turtles are captured in fyke nets, the prolonged submergence can lead to stress and subsequent drowning. Fish die within infrequently checked passive fishing nets and dead fish are a potential food source for many freshwater turtles. Dead fish could thus act as attractants and increase turtle captures in fishing nets. We investigated the attraction of turtles to decomposing fish within fyke nets in eastern Ontario. We set fyke nets with either 1 kg of one-day or five-day decomposed fish, or no decomposed fish in the cod-end of the net. Decomposing fish did not alter the capture rate of turtles or fish, nor did it alter the species composition of the catch. Thus, reducing fish mortality in nets using shorter soak times is unlikely to alter turtle bycatch rates since turtles were not attracted by the dead fish. Interestingly, turtle bycatch rates increased as water temperatures did. Water temperature also influences turtle mortality by affecting the duration turtles can remain submerged. We thus suggest that submerged nets to either not be set or have reduced soak times in warm water conditions (e.g., >20 degrees C) as turtles tend to be captured more frequently and cannot withstand prolonged submergence. PMID- 22543583 TI - Tumor-derived macrophage migration inhibitory factor promotes an autocrine loop that enhances renal cell carcinoma. AB - The macrophage migration inhibitory factor (MIF) is a hypoxia regulated gene that has a variety of tumorigenic functions. In clear cell renal carcinoma (CCRC), hypoxic signaling is constitutively active because of the frequent loss of function of the von Hippel-Lindau tumor suppressor protein. We therefore sought to assess the expression of MIF in CCRC and its biological functions. We stained tumor tissue microarrays comprising sections of 128 CCRC tumors and found MIF to be moderately or highly expressed in >98%. MIF expression was further found to be dramatically elevated in blood plasma of individuals with CCRC compared with healthy controls, suggesting that measurement of MIF levels in the blood may have utility as a diagnostic marker in CCRC. At a functional level, MIF has been reported to engage the CD74 and CD44 receptors and induce signal transduction. In CCRC cell lines, depletion of MIF, CD74 or CD44 by small hairpin RNA led to a significant reduction in growth rate, and clonogenic survival, coinciding with the degree of knockdown. Interruption of the MIF pathway also decreased tumorigenic potential. Biochemically, we found that in CCRC cells MIF signaling leads to activation of the mitogen-activated protein kinase pathway and to Src phosphorylation, which is critical for regulation of p27. Together, our studies establish MIF as a protumorigenic signaling molecule that functions in an autocrine fashion to promote renal cell carcinoma and may be useful as a minimally invasive marker of disease status. PMID- 22543582 TI - Glucocorticoids and histone deacetylase inhibitors cooperate to block the invasiveness of basal-like breast cancer cells through novel mechanisms. AB - Aggressive cancers often express E-cadherin in cytoplasmic vesicles rather than on the plasma membrane and this may contribute to the invasive phenotype of these tumors. Therapeutic strategies are not currently available that restore the anti invasive function of E-cadherin in cancers. MDA-MB-231 cells are a frequently used model of invasive triple-negative breast cancer, and these cells express low levels of E-cadherin that is mislocalized to cytoplasmic vesicles. MDA-MB-231 cell lines stably expressing wild-type E-cadherin or E-cadherin fused to glutathione S-transferase or green fluorescent protein were used as experimental systems to probe the mechanisms responsible for cytoplasmic E-cadherin localization in invasive cancers. Although E-cadherin expression partly reduced cell invasion in vitro, E-cadherin was largely localized to the cytoplasm and did not block the invasiveness of the corresponding orthotopic xenograft tumors. Further studies indicated that the glucocorticoid dexamethasone and the highly potent class I histone deacetylase (HDAC) inhibitor largazole cooperated to induce E-cadherin localization to the plasma membrane in triple-negative breast cancers, and to suppress cellular invasion in vitro. Dexamethasone blocked the production of the cleaved form of the CDCP1 (that is, CUB domain-containing protein 1) protein (cCDCP1) previously implicated in the pro-invasive activities of CDCP1 by upregulating the serine protease inhibitor plasminogen activator inhibitor-1. E-cadherin preferentially associated with cCDCP1 compared with the full-length form. In contrast, largazole did not influence CDCP1 cleavage, but increased the association of E-cadherin with gamma-catenin. This effect on E cadherin/gamma-catenin complexes was shared with the nonisoform selective HDAC inhibitors trichostatin A (TSA) and vorinostat (suberoylanilide hydroxamic acid, SAHA), although largazole upregulated endogenous E-cadherin levels more strongly than TSA. These results demonstrate that glucocorticoids and HDAC inhibitors, both of which are currently in clinical use, cooperate to suppress the invasiveness of breast cancer cells through novel, complementary mechanisms that converge on E-cadherin. PMID- 22543584 TI - Endoplasmic reticulum protein 29 regulates epithelial cell integrity during the mesenchymal-epithelial transition in breast cancer cells. AB - The epithelial-mesenchymal transition (EMT) correlates with disruption of cell cell adhesion, loss of cell polarity and development of epithelial cell malignancy. Identifying novel molecules that inhibit EMT has profound potential for developing mechanism-based therapeutics. We previously demonstrated that the endoplasmic reticulum protein 29 (ERp29) is a novel factor that can drive mesenchymal-epithelial transition (MET) and induce cell growth arrest in MDA-MB 231 cells. Here, we show that ERp29 is an important molecule in establishing epithelial cell integrity during the MET. We demonstrate that ERp29 regulates MET in a cell context-dependent manner. ERp29 overexpression induced a complete MET in mesenchymal MDA-MB-231 cells through downregulating the expression of transcriptional repressors (for example, Slug, Snai1, ZEB2 and Twist) of E cadherin. In contrast, overexpression of ERp29 induces incomplete MET in basal like BT549 cells in which the expression of EMT-related markers (for example, vimentin; cytokeratin 19 (CK19) and E-cadherin) and the transcriptional repressors of E-cadherin were not altered. However, ERp29 overexpression in both cell-types resulted in loss of filamentous stress fibers, formation of cortical actin and restoration of an epithelial phenotype. Mechanistic studies revealed that overexpression of ERp29 in both cell-types upregulated the expression of TJ proteins (zonula-occludens-1 (ZO-1) and occludin) and the core apical-basal polarity proteins (Par3 and Scribble) at the membrane to enhance cell-cell contact and cell polarization. Knockdown of ERp29 in the epithelial MCF-7 cells decreased the expression of these proteins, leading to the disruption of cell cell adhesion. Taken together, ERp29 is a novel molecule that regulates MET and epithelial cell integrity in breast cancer cells. PMID- 22543587 TI - The ubiquitin ligase CHIP regulates c-Myc stability and transcriptional activity. AB - c-Myc is a proto-oncogenic transcription factor and its rapid turnover mediated by the ubiquitin-proteasome system is critical for maintaining normal cellular homeostasis. Multiple ubiquitin ligases have been assigned for c-Myc regulation till date. However, the available data suggest for the possible existence of additional E3 ligase(s). Here, we report a new E3 ligase for c-Myc, the carboxyl terminus of Hsc70-interacting protein or CHIP, which is a chaperone-associated Ubox-containing E3 ligase. In this report, we show that CHIP interacts and ubiquitinates c-Myc, thus targeting it for proteasome-mediated degradation. Overexpression of CHIP could accelerate the turnover rate of c-Myc protein. Conversely, knockdown of CHIP by RNAi stabilizes endogenous c-Myc. The interaction between CHIP and c-Myc depends on the N-terminally located tetratricopeptide repeats of CHIP, which has been implicated as a chaperone binding motif. Inhibition of Hsp90 chaperone activity by 17-N-allylamino-17 demethoxygeldanamycin reduces c-Myc protein level. We found that the association between CHIP and c-Myc is dependent on the chaperones; particularly Hsp70. CHIP antagonizes the transcriptional activity of c-Myc and decreases the abundance of the transcripts of its target genes. Overall, CHIP-knockdown increases malignant behavior of C6 glioma cells. To the best of our knowledge, this is the first report of c-Myc being regulated by a bona-fide chaperone-associated E3 ligase in HEK293 as well as glioma cells. Because CHIP has been reported earlier to be negatively regulating Akt1, BCR-ABL and hTERT, and now c-Myc, the present study may strengthen the view that CHIP acts as a tumor suppressor. PMID- 22543586 TI - Depletion of the receptor for advanced glycation end products (RAGE) sensitizes towards apoptosis via p53 and p73 posttranslational regulation. AB - The receptor for advanced glycation endproduct (RAGE) is involved in diabetic complications and chronic inflammation, conditions known to affect the sensitivity towards apoptosis. Here, we studied the effect of genetically depleting RAGE on the susceptibility towards apoptosis. In murine osteoblastic cells, RAGE knockout increased both spontaneous and induced apoptosis. Decreased levels of B-cell lymphoma 2 protein and increased intrinsic apoptosis were observed in Rage(-/-) cells. Furthermore, loss of RAGE increased expression of the death receptor CD95 (Fas, Apo-1), CD95-dependent caspase activation and extrinsic apoptosis, whereas NF-kB-p65 nuclear translocation was diminished. Importantly, depletion of RAGE reduced the ubiquitination and degradation of p53 and p73 and increased their nuclear translocation. The increase of p53 and p73 transactivational activity was essential for the RAGE-dependent regulation of apoptosis, because knockdown of p53 and p73 significantly decreased apoptosis in RAGE-deficient but not in RAGE-expressing cells. Thus, the RAGE-mediated posttranslational regulation of p53 and p73 orchestrates a sequence of events culminating in control of intrinsic and extrinsic apoptosis signaling pathways. PMID- 22543585 TI - Rescue of glandular dysmorphogenesis in PTEN-deficient colorectal cancer epithelium by PPARgamma-targeted therapy. AB - Disruption of glandular architecture associates with poor clinical outcome in high-grade colorectal cancer (CRC). Phosphatase and tensin homolog deleted on chromosome ten (PTEN) regulates morphogenic growth of benign MDCK (Madin Darby Canine Kidney) cells through effects on the Rho-like GTPase cdc42 (cell division cycle 42). This study investigates PTEN-dependent morphogenesis in a CRC model. Stable short hairpin RNA knockdown of PTEN in Caco-2 cells influenced expression or localization of cdc42 guanine nucleotide exchange factors and inhibited cdc42 activation. Parental Caco-2 cells formed regular hollow gland-like structures (glands) with a single central lumen, in three-dimensional (3D) cultures. Conversely, PTEN-deficient Caco-2 ShPTEN cells formed irregular glands with multiple abnormal lumens as well as intra- and/or intercellular vacuoles evocative of the high-grade CRC phenotype. Effects of targeted treatment were investigated. Phosphatidinylinositol 3-kinase (PI3K) modulating treatment did not affect gland morphogenesis but did influence gland number, gland size and/or cell size within glands. As PTEN may be regulated by the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma), cultures were treated with the PPARgamma ligand rosiglitazone. This treatment enhanced PTEN expression, cdc42 activation and rescued dysmorphogenesis by restoring single lumen formation in Caco-2 ShPTEN glands. Rosiglitazone effects on cdc42 activation and Caco-2 ShPTEN gland development were attenuated by cotreatment with GW9662, a PPARgamma antagonist. Taken together, these studies show PTEN-cdc42 regulation of lumen formation in a 3D model of human CRC glandular morphogenesis. Treatment by the PPARgamma ligand rosiglitazone, but not PI3K modulators, rescued colorectal glandular dysmorphogenesis of PTEN deficiency. PMID- 22543588 TI - IGFBP-3 methylation-derived deficiency mediates the resistance to cisplatin through the activation of the IGFIR/Akt pathway in non-small cell lung cancer. AB - Although many cancers initially respond to cisplatin (CDDP)-based chemotherapy, resistance frequently develops. Insulin-like growth factor-binding protein-3 (IGFBP-3) silencing by promoter methylation is involved in the CDDP-acquired resistance process in non-small cell lung cancer (NSCLC) patients. Our purpose is to design a translational-based profile to predict resistance in NSCLC by studying the role of IGFBP-3 in the phosphatidyl inositol 3-kinase (PI3K) signaling pathway. We have first examined the relationship between IGFBP-3 expression regulated by promoter methylation and activation of the epidermal growth factor receptor (EGFR), insulin-like growth factor-I receptor (IGFIR) and PI3K/AKT pathways in 10 human cancer cell lines and 25 NSCLC patients with known IGFBP-3 methylation status and response to CDDP. Then, to provide a helpful tool that enables clinicians to identify patients with a potential response to CDDP, we have calculated the association between our diagnostic test and the true outcome of analyzed samples in terms of cisplatin IC50; the inhibitory concentration that kills 50% of the cell population. Our results suggest that loss of IGFBP-3 expression by promoter methylation in tumor cells treated with CDDP may activate the PI3K/AKT pathway through the specific derepression of IGFIR signaling, inducing resistance to CDDP. This study also provides a predictive test for clinical practice with an accuracy and precision of 0.84 and 0.9, respectively, (P=0.0062). We present a biomarker test that could provide clinicians with a robust tool with which to decide on the use of CDDP, improving patient clinical outcomes. PMID- 22543589 TI - Adsorption of the antiepileptic carbamazepine onto agricultural soils. AB - Carbamazepine is an antiepileptic pharmaceutical which is commonly found in environmental matrices. It passes through wastewater treatment plants (WWTPs) almost completely unaffected and has been found to be highly persistent in the environment. The application of sludge in agricultural fields and the use of WWTP effluents for irrigation constitute a potential source of soil contamination. Consequently, the assessment of the interaction between carbamazepine and soils is of crucial importance to understand its fate in the environment. To monitor the sorption behavior of carbamazepine onto agricultural soils, batch equilibrium experiments were performed using soils subjected to distinct long-term fertilizations. In order to follow the adsorption experiments, an UV spectral deconvolution methodology was applied and the results compared with those from micellar electrokinetic chromatography. The results obtained by both methods did not present significant statistical differences at 95% confidence level. Therefore, it was proven that, in the context of adsorption studies, UV spectral deconvolution is a valid alternative to common chromatographic methods, with the major advantage of being a simple and fast procedure. The adsorption of carbamazepine onto the selected soils was satisfactorily described by the Freundlich model. The obtained Freundlich parameters (K(F)) (between 1.79 +/- 0.07 and 4.8 +/- 0.2 mg kg(-1) (mg L(-1))(-N)) indicate that the adsorption behavior of carbamazepine is dependent on the soil fertilization. Also, it is not extensively sorbed, indicating that carbamazepine present in soils can be a potential source of contamination of surface and ground waters through run-off and infiltration. PMID- 22543590 TI - Supported Au nanoparticles as efficient catalysts for aerobic homocoupling of phenylboronic acid. AB - Au nanoparticles with small sizes (1-4 nm) were effectively formed on Mg-Al mixed oxides (Au/MAO), which showed superior catalytic performances and good recyclability in aerobic homocoupling of phenylboronic acid. PMID- 22543591 TI - Penicillium pneumonia in a patient with newly diagnosed Franklin disease. AB - Franklin disease, or gamma heavy-chain disease, in patients with autoimmune disorders is a challenge for clinicians to diagnose due to its rarity, and recurrent infection is one of its characteristics. Within the spectrum of infections in Franklin disease patients, various fungi should always be considered. In this study, the authors describe a 57-year-old non-human immunodeficiency virus-infected systemic lupus erythematosus patient later diagnosed with Franklin disease and then developed Penicillium pneumonia. Because of the unexpected combination of Franklin disease and Penicillium infection in a non-human immunodeficiency virus-infected patient, the diagnosis of common hospital-acquired pneumonia was initially made. The laboratory examinations and cultures helped confirm the correct diagnosis of Franklin disease and Penicillium pneumonia. This is the first report of Penicillium sp. infection in a patient with Franklin disease, and it emphasizes the importance of proper preparation for biopsy, complete hematologic investigation, culture preparation and early antifungal coverage to improve the outcome. PMID- 22543592 TI - Hemorrhages from cerebral amyloid angiopathy. PMID- 22543593 TI - The impact of a family history of type 2 diabetes on insulin secretion and insulin sensitivity in individuals with varying glucose tolerance. AB - INTRODUCTION: This study was performed to investigate the impact of a family history of type 2 diabetes (T2DM) on insulin resistance and beta-cell dysfunction in populations with varying glucose tolerance. METHODS: Among the total of 142 participants, 73 subjects with no family history of T2DM (FH-) included 42 with normal glucose tolerance (NGT/FH-) and 31 with impaired glucose tolerance (IGT/FH ); and 69 first-degree relatives of patients with T2DM (FH+) included 36 with NGT (NGT/FH+) and 33 with IGT (IGT/FH+). Insulin resistance was evaluated by Insulin Sensitivity Index (ISI) based on the euglycemic hyperinsulinemic clamp. Islet beta-cell function was assessed by disposition index (DI) for the acute insulin response to glucose (AIRg) using intravenous glucose tolerance test. Metabolic data were compared between groups after adjustment for age, sex, body mass index and waist-to-hip ratio. RESULTS: The NGT/FH+ group showed lower level of ISI (P = 0.023) than the NGT/FH- group, whereas no difference was found in AIRg or DI between these 2 subgroups. In the FH- individuals, both ISI and DI of the IGT/FH- group decreased compared with the NGT/FH- group (both P < 0.05). In the FH+ individuals, no difference was found in ISI between the IGT/FH+ and NGT/FH+ groups, whereas the IGT/FH+ group had a lower level of AIRg and DI than the NGT/FH+ group (both P < 0.0001). CONCLUSIONS: This study showed that the pathophysiological changes were different between individuals with and without a family history of T2DM during the glucose tolerance aggravation. PMID- 22543594 TI - Ritonavir and epidural triamcinolone as a cause of iatrogenic Cushing's syndrome. AB - Ritonavir is a protease inhibitor (PI) frequently prescribed with highly active antiretroviral therapy. It functions to boost the effectiveness of other PIs as a result of blocking their breakdown by the cytochrome P450 (3A4) pathway. Through this same mechanism, ritonavir has been shown to cause iatrogenic Cushing's syndrome (ICS) in patients using inhaled fluticasone. In addition, a small number of recent cases suggest that ritonavir may also cause this disorder by prolonging the duration of injected corticosteroids, such as triamcinolone. This case report presents a human immunodeficiency virus (HIV) patient taking ritonavir with ICS and secondary adrenal insufficiency, presumably due to systemic absorption and decreased metabolism of an epidural triamcinolone injection. To the authors knowledge, there have only been 4 previously reported cases describing ritonavir potentiating ICS after receiving a corticosteroid epidural. This provides further proof that caution should be taken with nonparenteral use of triamcinolone in HIV patients on PIs. PMID- 22543595 TI - Acute epiglottitis due to Serratia marcescens in an immunocompetent adult. AB - Acute epiglottitis (AE) is inflammation of the epiglottis and contiguous tissues, which carries a potential for complete airway obstruction. With routine pediatric immunization for Hemophilus influenzae serotype b, epiglottitis is now more prevalent in adults, with a shift in the causative organisms and a change in the natural history of this disease. Over the past 5 decades, Serratia marcescens has gone from being recognized as a harmless saprophyte to an important opportunistic human pathogen. It is known to be associated with outbreaks of nosocomial infections, but it is an uncommon cause of serious invasive infections in patients presenting from the community. The authors present a fatal case of AE caused by S marcescens in a previously immunocompetent 58-year-old woman, which was complicated by fasciitis, myositis and bacteremia. To the authors' knowledge, till date, only 3 cases of AE by S marcescens have been reported, all in immunocompromised patients. PMID- 22543596 TI - Nature's bypass. PMID- 22543597 TI - First molecular detection of Leishmania major within naturally infected Phlebotomus salehi from a zoonotic cutaneous leishmaniasis focus in southern Iran. AB - Human cutaneous leishmaniasis (CL) is a major notifiable public health problem in many parts of Iran. It is often caused by the zooflagellate parasite Leishmania major which is mainly transmitted by the bites of female phlebotomine sandflies belonging to the genus Phlebotomus (Diptera: Psychodidae). The annual incidence of CL in Fars province, southern Iran, was about 108-144 in 2007. The leishmanial infections of wild sandflies that may act as vectors were thus investigated at an endemic focus in this province. In all 330 female Phlebotomus sandflies were screened for the detection of Leishmania-specific kinetoplast DNA (kDNA) by polymerase chain reaction (PCR) methods. A two stage nested PCR protocol was used to establish the identity of Leishmania major species in naturally infected sandflies. The L. major kDNA was detected in 18 (5.5%) individual sandflies which belonged to four different Phlebotomus species (Phlebotomus papatasi, Phlebotomus salehi, Phlebotomus sergenti and P. major group). For the first time, one naturally infected P. salehi specimen contained the kDNA of the protozoan parasite, L. major, with a main band of 560 base pairs identified using the nested PCR method. It seems most likely therefore that P. salehi is potentially a rare sylvatic vector of L. major parasites in parts of this province. This is the first combined morphological and molecular studies of P. salehi in Iran. PMID- 22543598 TI - Malathion extraction from larvae of Chrysomya megacephala (Fabricius) (Diptera: Calliphoridae) for determining death due to malathion. AB - The use of Chrysomya megacephala larvae for detecting malathion for diagnosing the cause of death was investigated. This could prove useful when the visceral organs have become liquefied during decomposition and therefore cannot be sampled. A field experiment was conducted in which C. megacephala were allowed to colonise naturally the corpses of rabbits that had died of malathion poisoning. The concentration of malathion increased gradually during the larval stages of C. megacephala reaching the maximum concentration in the third instar larvae. The concentration of malathion declined during prepupal stage and reached its lowest level among tenerals. The average malathion concentrations in C. megacephala growing in poisoned rabbit corpses left in a sunlit habitat were significantly higher (p<0.05) than those growing on poisoned rabbits left in a shaded habitat. The concentrations of malathion in the different stages of development of C. megacephala were moderately correlated (r = 0.51-0.69) with the administered doses as well as with those estimated in visceral organs. Thus, it would not be reliable to suggest the formulation of mathematical algorithms for relating the concentration of malathion found in the different stages of development of C. megacephala with those found in the visceral organs. However, in the context of forensic investigation, the qualitative detection of malathion in C. megacephala may prove useful in diagnosing the cause of death, since malathion is a common cause of accidental and suicidal deaths. PMID- 22543599 TI - Cases of hydatidosis in patients referred to Governmental hospitals for cyst removal in Sana'a City, Republic of Yemen. AB - Hydatidosis is a parasitic infestation caused by Echinococcus granulosus. This disease is endemic in many countries including Yemen. The present review article aims to have a glimpse at the present status of hydatidosis in Yemen. This is the first descriptive study, investigating recorded cases of hydatidosis from the five main governmental hospitals in the capital Sana'a city, over a longer period starting from 2001 and ending in 2008. A total of 796 medical records of patients referred to the five main governmental hospitals in Sana'a city for cyst removal, were studied. Of these cases 482 were females and 314 were males. Their mean age was 30.0 +/- 16.9 years. Information regarding the location of the cyst in the body, age, sex and residence of each patient was recorded. A higher infection rate was found in females than males (60.6% and 39.4%, respectively). Single organ involvement was observed in 98.6% cases, among which, the most frequent localizations were the liver (60.8%) followed by the lung (24.7%). Cases of hydatidosis appeared to increase during the period 2001-2008, with the lowest number (n=26) and the highest number (n=140) recorded in 2001 and 2007, respectively. We conclude that the risk of hydatidosis is still high in Yemen, where street or stray dogs move freely down town and the population should be aware about the role of dogs in the transmission of this disease. Hospital records provide a useful indication of infection expressed as annual rate of hospital cases. Finally, the collaboration of Public Health Authorities, the Veterinary Medical Authorities and the Environmental Affairs Authorities is a must to control this disease. PMID- 22543600 TI - Surgical management of morbidity due to lymphatic filariasis: the usefulness of a standardized international clinical classification of hydroceles. AB - The objective of this work is to evaluate the usefulness of a standardized clinical classification of hydroceles in lymphatic filariasis endemic countries to guide their surgical management. 64 patients with hydroceles were operated in 2009-2010, in Level II hospitals (WHO classification), during two visits to Fiji, by the same mobile surgical team. The number of hydroceles treated was 83. We developed and evaluated a much needed clinical classification of hydroceles based on four criteria: Type (uni/bilateral); Side (left/right); Stage of enlargement of the scrotum rated from I to VI; Grade of burial of the penis rated from 0 to 4. It lead to the conclusion that 1) A Stage I or II hydrocele, associated with Grade 0 or 1 penis burial could be considered a "Simple Hydrocele". The surgical treatment is simple with no anticipated early complication. WHO Level II of health care structure seems adapted. 2) A Stage III or IV hydrocele associated with Grade 2, 3 or 4 penis burial could be considered a "Complicated Hydrocele". The operation is longer, more complicated and the possibility of occurrence of complications seems greater. A level III health care facility would be more adapted under the normal functioning of the health system. We conclude that a standardized clinical classification of hydroceles based on the Stage of enlargement of the scrotum and the Grade of burial of the penis appears to be a useful tool to guide the decision about the level of care and the surgical technique required. We use the same classification for penoscrotal lymphoedema. A decision tree is presented for the management of hydroceles in lymphatic filariasis endemic countries which could usefully complement the "Algorithm for management of scrotal swelling" proposed by WHO in 2002. An international classification system of hydroceles would also allow standardization and facilitate study design and comparisons of their results. PMID- 22543601 TI - Study of the malariogenic potential of Eastern Spain. AB - Recent autochtonous malaria cases which occurred in Spain, France, Greece or Italy have shown the need to delve into the knowledge of potential influence of tropical diseases in Southern Europe. The malariogenic potential of a formerly endemic area of Spain was analyzed in present manuscript according to the epidemiological parameters of receptivity, infectivity and vulnerability. During a five years period (2005-2009) comprehensive larval surveys of anophelines and continuous analysis of imported malaria cases were conducted in a study region of about 23 260 km2. The next seven potential malaria vectors were collected: Anopheles algeriensis, Anopheles atroparvus, Anopheles claviger, Anopheles maculipennis, Anopheles marteri, Anopheles petragnani and Anopheles plumbeus. The entomological results conclude that malaria receptivity is still high in different rural and hinterland regions where it is possible to find high densities of An. atroparvus. Moreover An. algeriensis was also commonly found breeding in irrigation channels surrounding urban areas. Although receptivity is relevant in much of the study area, fortunately the vulnerability of the territory is very low. In conclusion, despite our data together with current socio-economic and sanitary conditions of Spain indicate a relatively low malariogenic potential, we must maintain the entomological and epidemiological vigilance in order to prevent the potential appearance of indigenous malaria cases. Therefore, the present Spanish situation can be described as what malariologists of the first half of the last century would have called "anophelism without malaria." PMID- 22543602 TI - The utility of mitochondrial DNA fragments for genetic identification of forensically important sarcophagid flies (Diptera: Sarcophagidae) in China. AB - Species-diagnostic anatomical characters of fleshflies are not known for most immature stages or even adults, and an existing key may be incomplete or difucult for nonspecialists to use. The use of sarcophagids for PMI estimations has been greatly hampered by their highly similar morphological characters. DNA-based method can be used as a supplemental means of morphological method in identification of forensically important sarcophagid flies. However, relying solely on single DNA fragment for delimiting species is considered to be unreliable, especially when the fragment was small. Sequence data of selected regions of the cytochrome oxidase subunit two (COII) and 16S ribosomal RNA (16S rRNA) genes of the most important Chinese fleshfly taxa associated with cadavers are presented, which can be instrumental for implementation of the Chinese Sarcophagidae database. Phylogenetic analysis of the sequenced segments showed that all sarcophagid specimens were properly assigned into five species, which indicated the possibility of separation congeneric species with the short fragments. PMID- 22543603 TI - In vitro evaluation of acaricidal activity of fipronil against Haemaphysalis bispinosa based on adult immersion test. AB - Fipronil is a phenylpyrazole family insecticide which mainly affects the nervous system of insects. In the present study, the in vitro acaricidal effects of the compound against the widely prevalent multihost tick, Haemaphysalis bispinosa was assessed. The lowest concentration at which complete adult tick mortality was observed was at 25 ppm while complete absence of egg mass observed at 10 ppm. Hundred per cent inhibition of fecundity was observed at 1 ppm while complete blocking of hatching of the laid ova was observed even at 500 ppb. PMID- 22543604 TI - Comparative seroprevalences of bovine trypanosomiasis and anaplasmosis in five states of Malaysia. AB - A comparative seroprevalence study on bovine trypanosomiasis and anaplasmosis was conducted. Sera of adult cattle and buffaloes of different breeds from farms from five different states in Malaysia were collected and tested for the presence of Trypanosoma evansi antibodies by CATT and Anaplasma marginale antibodies by c-ELISA. Of the 116 samples, 14.7% tested positive for bovine trypanosomiasis and 77.6% for bovine anaplasmosis. PMID- 22543606 TI - Eimeria infection in camels (Camelus dromedarius) in Yazd province, central Iran. AB - This study was carried out during the winter of 2008 to the summer 2010 to determine the rate of infection of Eimeria spp. in dromedary camels in Yazd province, Iran at that period. A total of 305 faecal samples were taken per recta from live and slaughtered, apparently healthy camels 9 months to 23 years old. Using saturated zinc sulfate solution floatation technique, samples were prepared and investigated microscopically to detect Eimeria spp. oocysts. Results revealed that the overall frequency of infection in samples was 9.51%. Identified species were Eimeria cameli (47.5%), Eimeria dromedarii (42.5%) and Eimeria bactriani (10%). The rate of infection was higher in the winter season, and in camels aged 5 to 10 years old. Statistical analysis showed that there is a significant difference between infection rate and season, but no effect by age or sex on eimeriosis was found. Since most of the positive cases in our study were adult, our findings suggest that older camels may play an important role in spreading infection as asymptomatic oocyst shedders. PMID- 22543605 TI - Contamination of faecal coliforms in ice cubes sampled from food outlets in Kubang Kerian, Kelantan. AB - The use of ice cubes in beverages is common among patrons of food outlets in Malaysia although its safety for human consumption remains unclear. Hence, this study was designed to determine the presence of faecal coliforms and several useful water physicochemical parameters viz. free residual chlorine concentration, turbidity and pH in ice cubes from 30 randomly selected food outlets in Kubang Kerian, Kelantan. Faecal coliforms were found in ice cubes in 16 (53%) food outlets ranging between 1 CFU/100mL to >50 CFU/ 100mL, while in the remaining 14 (47%) food outlets, in samples of tap water as well as in commercially bottled drinking water, faecal coliforms were not detected. The highest faecal coliform counts of >50 CFU/100mL were observed in 3 (10%) food outlets followed by 11-50 CFU/100mL and 1-10 CFU/100mL in 7 (23%) and 6 (20%) food outlets, respectively. All samples recorded low free residual chlorine concentration (<0.10mg/L) with the pH ranging between 5.5 and 7.3 and turbidity between 0.14-1.76 NTU. Since contamination by faecal coliforms was not detected in 47% of the samples, tap water and commercially bottled drinking water, it was concluded that (1) contamination by faecal coliforms may occur due to improper handling of ice cubes at the food outlets or (2) they may not be the water sources used for making ice cubes. Since low free residual chlorine concentrations were observed (<0.10mg/ L) in all samples as well as in both tap water and commercially bottled drinking water, with the pH ranged between 5.5 7.3, ineffective disinfection of water source as a contributing factor to such high counts of faecal coliforms in ice cubes also could not be ruled out. Therefore, a periodical, yet comprehensive check on the food outlets, including that of ice cube is crucial in ensuring better food and water for human consumption. PMID- 22543608 TI - Notes on black flies (Diptera: Simuliidae) from North-East India: new records of five species from Arunachal Pradesh and taxonomic reviews of two species from Assam. AB - In recent surveys of black flies in Arunachal Pradesh, North-East India, five species are newly recorded from Arunachal Pradesh: Simulium (Montisimulium) nemorivagum Datta, 1973, Simulium (Gomphostilbia) darjeelingense Datta, 1973, Simulium (Gomphostilbia) decuplum Takaoka & Davies, 1995, Simulium (Simulium) barnesi Takaoka & Suzuki, 1984 and Simulium (Simulium) pradyai Takaoka & Somboon, 2008, of which the latter three species also represent new records from India. Taxonomic reviews of two species of black flies reported from Assam show that Simulium (Gomphostilbia) unum Datta, 1975 is a junior synonym of Simulium (Gomphostilbia) darjeelingense, and the larva of Simulium (Gomphostilbia) sp. nr. varicorne Edwards is identifiable as Simulium (Gomphostilbia) parahiyangum Takaoka & Sigit, 1992. PMID- 22543607 TI - A novel cost-effective medium for the production of Bacillus thuringiensis subsp. israelensis for mosquito control. AB - Bacillus thuringiensis subsp. israelensis (Bti) has been used for mosquito control programmes the world-wide. Indeed, the large-scale production of Bti for mosquito control is very expensive due to the high cost of its culture. In the present study, we attempted to widen the scope in developing cost-effective culture medium for Bti production, based on the raw materials available on the biosphere, including coconut cake powder, CCP (Cocos nucifera), neem cake powder, NCP (Azadirachta indica) and groundnut cake powder, GCP (Arachis hypogea). Among these raw materials, the biomass production of Bti, sporulation and toxin synthesizing from 'CCP' in combination with mineral salt (MnCl(2)) was comfortably satisfactory. Bioassays with mosquito species (Culex quinquefasciatus, Anopheles stephensi and Aedes aegypti) and field trials were also satisfactory. The present investigation suggests that coconut cake-based culture medium can be used as an alternative for industrial production of Bti in mosquito-control programme. Therefore, the study is very important from the point of effective production of Bti from cost-effective culture medium for the control of mosquito vectors. PMID- 22543609 TI - Effects of vitamin E administration on Plasmodium berghei induced pathological changes and oxidative stress in mice. AB - The effects of daily intraperitoneal doses of 1000 i.u/kg body weight of vitamin E on the course of Plasmodium berghei NK 65 infection and the parasite-induced anemia as well as alterations in the relative weight of some selected organs and antioxidant status in mice were investigated. The number of parasitized red cells were not initially affected by the vitamin administration but were persistently lowered after 11th day post infection to the termination of the experiment. The P. berghei infection was found to induce anemia, significantly (P<0.05) increased the relative weight of liver, spleen and kidney but significantly decreased (P<0.05) the relative brain weight. However, all the parasite-induced changes in these parameters were significantly (P<0.05) ameliorated by the vitamin administration. Furthermore, malonydialdehyde concentration in the serum, liver and brain of infected animals was significantly (P<0.05) increased whereas superoxide dismutase and catalase activities were significantly (P<0.05) decreased by the infection. But vitamin E administration was found to, a significant degree (P<0.05), reversed the disease-induced alterations in these oxidative stress markers. It was concluded that vitamin E at the dose and route used prevented P. berghei induced anemia as well as alterations in relative organ weight and antioxidant status in mice. PMID- 22543610 TI - An occurrence of Synthesiomyia nudiseta (Wulp) (Diptera: Muscidae) from a human corpse in a high-rise building in Malaysia: a case report. AB - This is the first report of Synthesiomyia nudiseta (Wulp) (Diptera: Muscidae) on a human corpse discovered in a high-rise building in Malaysia. On 5 March 2008, a decomposing body of an adult female was found on the top floor of a thirteen story building in Kuala Lumpur, Malaysia. Her body was colonized by S. nudiseta larvae, which were normally associated with corpses found indoors at ground level. The post-mortem interval (PMI) was estimated at approximately 5 to 9 days. This case is significant as it demonstrates that this species can locate a dead body even in a high-rise building. Further findings of fly distribution especially in high-rise buildings should be reported to assist entomologists in PMI analysis. PMID- 22543611 TI - Spatial pattern of 2009 dengue distribution in Kuala Lumpur using GIS application. AB - In the last few years in Malaysia, dengue fever has increased dramatically and has caused huge public health concerns. The present study aimed to establish a spatial distribution of dengue cases in the city of Kuala Lumpur using a combination of Geographic Information System (GIS) and spatial statistical tools. Collation of data from 1,618 dengue cases in 2009 was obtained from Kuala Lumpur City Hall (DBKL). These data were processed and then converted into GIS format. Information on the average monthly rainfall was also used to correlate with the distribution pattern of dengue cases. To asses the spatial distribution of dengue cases, Average Nearest Neighbor (ANN) Analysis was applied together with spatial analysis with the ESRI ArcGIS V9.3 programme. Results indicated that the distribution of dengue cases in Kuala Lumpur for the year 2009 was spatially clustered with R value less than 1 (R = 0.42; z-scores = - 4.47; p < 0.001). Nevertheless, when this pattern was further analyzed according to month by each zone within Kuala Lumpur, two distinct patterns were observed which include a clustered pattern (R value < 1) between April to June and a dispersed pattern (R value > 1) between August and November. In addition, the mean monthly rainfall has not influenced the distribution pattern of the dengue cases. Implementation of control measures is more difficult for dispersed pattern compared to clustered pattern. From this study, it was found that distribution pattern of dengue cases in Kuala Lumpur in 2009 was spatially distributed (dispersed or clustered) rather than cases occurring randomly. It was proven that by using GIS and spatial statistic tools, we can determine the spatial distribution between dengue and population. Utilization of GIS tools is vital in assisting health agencies, epidemiologist, public health officer, town planner and relevant authorities in developing efficient control measures and contingency programmes to effectively combat dengue fever. PMID- 22543612 TI - Modelling the effect of temperature change on the extrinsic incubation period and reproductive number of Plasmodium falciparum in Malaysia. AB - According to the report of the Intergovernmental Panel on Climate Change (IPCC), Malaysia will experience an increase of 3-5 degrees C in the future. As the development of the malaria parasite, Plasmodium falciparum, is sensitive to temperature, we investigated, using computer models, the effect of increase of 3o and 5oC on the possible changes in the epidemiology of malaria transmission of P. falciparum in Malaysia. Four environmentally different locations were selected: Kuala Lumpur (KL), Cameron Highlands (CH), Kota Kinabalu (KK) and Kinabalu Park (KP). The extrinsic incubation period (EIP) was estimated using hourly temperatures and the mean daily temperatures. The EIP values estimated using the mean daily temperature were lower than those computed from hourly temperatures in warmer areas (KL, KK), but higher in the cooler areas (CH, KP). The computer simulations also indicated that the EIP will be decreased if the temperature was raised by 3o or 5oC, with the effect more pronounced for the greater temperature increase, and for the cooler places. The vector cohort that is still alive at a time to transmit malaria (s(EIP)) also increased when the temperature was raised, with the increase more pronounced in the cooler areas. This study indicates an increase in temperature will have more significant effect in shortening the EIP in a cooler place (eg CH, KP), resulting in a greater s(EIP), and consequently increasing the transmission intensity and malaria risk. A temperature increase arising from the global climate change will likely affect the epidemiology of malaria in Malaysia, especially in the cooler areas. PMID- 22543614 TI - The effects of herbal essential oils on the oviposition-deterrent and ovicidal activities of Aedes aegypti (Linn.), Anopheles dirus (Peyton and Harrison) and Culex quinquefasciatus (Say). AB - The effect of oviposition-deterrent and ovicidal of seven essential oils were evaluated towards three mosquito vectors, Aedes aegypti, Anopheles dirus and Culex quinquefasciatus. The oviposition activity index (OAI) values of six essential oils namely Cananga odorata, Cymbopogon citratus, Cymbopogon nardus, Eucalyptus citriodora, Ocimum basilicum and Syzygium aromaticum indicated that there were more deterrent than the control whereas Citrus sinensis oil acted as oviposition attractant. At higher concentration (10%) of Ca. odorata (ylang ylang flowers) showed high percent effective repellency (ER) against oviposition at 99.4% to Ae. aegypti, 97.1% to An. dirus and 100% to Cx. quinquefasciatus, respectively. The results showed that mean numbers of eggs were lower in treated than in untreated water. In addition, there was an inverse relationship between essential oil concentrations and ovicidal activity. As the concentration of essential oil increased from 1%, 5% and up to 10% conc., the hatching rate decreased. The essential oil of Ca. odorata at 10% conc. gave minimum egg hatch of 10.4% (for Ae. aegypti), 0.8% (for An. dirus) and 1.1% (for Cx. quinquefasciatus) respectively. These results clearly revealed that the essential oil of Ca. odorata served as a potential oviposition-deterrent and ovicidal activity against Ae. aegypti, An. dirus and Cx. quinquefasciatus. PMID- 22543613 TI - Recombinant proteins from new constructs of SAG1 and GRA7 sequences and their usefulness to detect acute toxoplasmosis. AB - In this study we have cloned unreported gene fragments of Toxoplasma gondii GRA7 and SAG1 and expressed the corresponding recombinant proteins, followed by evaluation of their usefulness for the serological diagnosis of toxoplasmosis. Both recombinant proteins were expressed efficiently in insoluble form, purified by single step Ni-NTA affinity chromatography and their antigenicity to detect toxoplasma specific IgG antibodies were determined by immunoblotting. A total of 60 serum samples from three groups of individuals based on their anti-toxoplasma antibody profiles were tested, namely (I) IgM+, IgG+ (n=20), (II) IgM-, IgG+ (n=20) and (III) IgM-, IgG- (n=20). Both recombinant proteins exhibited high sensitivity (100%) with sera from Group I. rGRA7 and rSAG1 reacted 40% and 80% respectively with Group II sera. The specificity of the recombinant proteins based on reactivities with Group III sera were 100% and 80% with rGRA7 and rSAG1 respectively. Thus rGRA7 was found to be better at discriminating probable acute from chronic phases of toxoplasmosis, and it also showed higher specificity. PMID- 22543615 TI - Seroprevalence of anti-Toxoplasma gondii IgG antibody in patients with schizophrenia. AB - Schizophrenia is a pervasive neuropsychiatric disease of unknown cause. Previous studies have reported that toxoplasmosis may be a possible cause of schizophrenia. To ascertain possible relationship between Toxoplasma gondii and schizophrenia, a cross sectional study, employing an enzyme-linked immunosorbent assay (ELISA) was performed to study the seroprevalence of anti-T. gondii IgG antibody in schizophrenic patients. Furthermore, demographic data analysis from schizophrenic patients were analysed to associate toxoplasmosis with schizophrenia. A total of 288 serum samples from schizophrenic patients (n=144) and psychiatrically healthy volunteers (n=144) were recruited in this study. Interestingly, a significant result in the serointensity rate of anti-T. gondii IgG antibody (> 60 IU/mL) in schizophrenic patients (61.1%) was demonstrated as compared to psychiatrically healthy volunteers (40.8%) (X2 = 4.236, p < 0.050). However, there was no significant difference between the seropositivity rate of anti-T. gondii IgG antibody between the two groups. Analysis from demographic data revealed that the seropositivity rate of anti-T. gondii IgG antibody in schizophrenic patients was significantly associated with age group of more than 40 years old (p=0.007) and between ethnic (p=0.046). Nevertheless, no significant association between seropositivity rate of anti-T. gondii IgG antibody with gender (p=0.897), duration of illness (p=0.344) and family history of schizophrenia (p=0.282) in these patients. Thus, this finding is essential as a preliminary data in Malaysia to establish the association between T. gondii and schizophrenia. PMID- 22543616 TI - Enzymatic profiling of clinical and environmental isolates of Burkholderia pseudomallei. AB - Melioidosis has been recognized as an important cause of sepsis in the tropics. The disease caused by an environmental saprophyte Burkholderia pseudomallei, affects mostly adults with underlying immunocompromised conditions. In this study, the enzymatic profiles of 91 clinical and 9 environmental isolates of B. pseudomallei were evaluated using the APIZYM system, in addition to assessment of protease, phospholipase C and sialidase activities using agar plate methods and other assays. The activity of 10 enzymes - alkaline phosphatase, esterase, esterase lipase, lipase, leucine arylamidase, valine arylamidase, cystine arylamidase, acid phosphatase, naphthol-AS-BI-phosphohydrolase and N-acetyl beta-glucosaminidase were detected in >75% of the clinical isolates. The majority of B. pseudomallei isolates in this study exhibited protease and phospholipase activities. No sialidase activity was detected. Five Burkholderia thailandensis isolates had similar APIZYM profiles as B. pseudomallei clinical isolates except for the lower detection rate for N-acetyl-beta-glucosaminidase. The subtle differences in the number of enzymes secreted and the levels of enzymatic activities of phenotypically identical clinical and environmental strains of B. pseudomallei give weight to the fact that the causative agent of melioidodis originates from the environment. PMID- 22543617 TI - A novel mosquito feeding system for routine blood-feeding of Aedes aegypti and Aedes albopictus. AB - A novel mosquito feeding system for routine blood-feeding of Aedes aegypti and Aedes albopictus was developed and evaluated. The system consisted of a collagen membrane casing filled with specific pathogen free (SPF) mini-pig blood, which is warmed by a simple in-house designed heating device. Blood feeding rate, fecundity, survival rate and hatchability of Ae. aegypti and Ae. albopictus colonies maintained by the feeding system were compared with those raised by conventional guinea pig feeding method. Aedes aegypti, displayed a significant difference in the feeding rate when offered blood meal using the membrane feeding (85.3%) and the guinea pig feeding (96.2%) methods (P=0.012). Though the feeding rate was reduced, the level was acceptable for maintenance of laboratory colonies. There was no significant difference in the fecundity (P=0.556), survival rate (P=0.715), and hatchability (P=0.932) between the two methods. For Ae. albopictus, the two feeding methods yielded no significant difference for the three parameters (fecundity, survival rate and hatchability=0.887, 0.580 and 0.564, respectively). Hence, we conclude that this simple collagen based membrane blood feeding system can be used for routine colonization of laboratory strains of Ae. aegypti and Ae. albopictus. PMID- 22543618 TI - Nasal myiasis due to Lucilia sericata (Meigen, 1826) from Iran: a case report. AB - Although not very common, human myiasis occurs more in developing tropical countries. A variety of dipterans cause nasal myiasis including the family Caliphoridae. In this report a case of nasal myiasis due to Lucilia sericata is reported for the first time, in a 74-year old patient from Mazandaran Heart Centre, North of Iran. The patient was originally admitted to the Mazandaran Heart Centre due to cardiac arrest and cerebral ischemia with diminishing consciousness. Because of the emergence of large number of maggots from his left nostril and the suspicion of infectious diseases, he was referred to the ICU of the Razi Infectious Diseases Hospital the next day. The larvae were identified as L. sericata. The conditions of the patient were medicated and the myiasis was treated by washing with 2% solution of xylocaine and oral administration of 2 mg tablets of ivermectin. PMID- 22543619 TI - Domiciliary cockroaches found in restaurants in five zones of Kuala Lumpur Federal Territory, peninsular Malaysia. AB - The following domiciliary cockroaches were collected from restaurants in five zones of Kuala Lumpur Federal Territory, Malaysia using 1L glass beaker traps baited with ground mouse-pellets: Periplaneta americana (Linnaeus) (n = 820), Periplaneta brunnea Burmeister (n = 46), Blattella germanica (Linnaeus) (n = 12504), Supella longipalpa (Fabricius) (n = 321), Symploce pallens Stephens (n = 29) and Neostylopyga rhombifolia (Stoll) (n = 5). The following bacteria were isolated from 10 cockroach specimens: Enterobacter cloacae, Klebsiella pneumoniae ssp. pneumoniae, Klebsiella pneumoniae ssp. rhinoscleromatis and Serratia liquefaciens from 5 B. germanica; Acinetobacter calcoaceticus var. anitratus, Citrobacter diversus/amalonaticus, Escherichia vulneris and K.p. pneumoniae from 3 P. brunnea; and Citrobacter freundii, Enterobacter agglomerans 4, Escherichia adecarboxylate, E. vulneris, K. p. pneumonia, K. p. rhinoscleromatis and Proteus vulgeris from 2 P. americana. PMID- 22543620 TI - Low prevalence of Dirofilaria immitis in dogs in Johor Bahru, Malaysia as a reflection of vector availability? AB - This study was conducted to investigate the low prevalence of Dirofilaria immitis in dogs in Johor Bahru as reported by veterinary practitioners, using wet blood mount, Knott's Concentration Test and two heartworm antigen test kits (IDEXX Canine SNAP(r) 4Dx and RapiGEN(r)). This study also compared the two test kits used and determined the microfilaria species. Blood were collected from 100 owned dogs and 50 stray dogs in Johor Bahru via cephalic venipuncture. A thick blood smear was done and examined for samples that were positive for microfilaria species identification. The overall prevalence of D. immitis in dogs in Johor Bahru was 1.33% (2/150) and the microfilaria identified was D. immitis. The prevalence of heartworm in owned and stray dogs in this study was 1% and 2% respectively. With only one false negative result from RapiGEN(r) test kit, comparing the sensitivity between the two test kits could not be achieved. The low prevalence of D. immitis found in this study confirmed anecdotal evidence that prevalence of dirofilariasis is indeed low in Johor Bahru. Additionally, we speculate that dirofilariasis in dogs might be considered as an indicator of vector availability. PMID- 22543621 TI - Duration of detection of anti-BmR1 IgG4 antibodies after mass-drug administration (MDA) in Sarawak, Malaysia. AB - The detection rates of brugian filariasis in three regions of Sarawak namely Central, North and South after three courses of mass drug administration (MDA) from year 2004 to 2006 was investigated. A recombinant BmR1 antigen-based IgG4 detection test, named Brugia Rapid and night blood smear for microfilaria (mf) detection were used. All three regions recorded a sharp fall in mf positive rates after a year post-MDA. Meanwhile Brugia Rapid positive rates declined more gradually to 3.8% and 5.6% of the pre-MDA levels in the Central and North regions, respectively. This study showed that in filariasis endemic areas in Sarawak, anti-filarial IgG4 antibodies to BmR1, as detected by the Brugia Rapid test, were positive for one to two years after mf disappearance. PMID- 22543622 TI - Larval aggregation on a burned human remain. AB - A burned human remain was found outdoor (5o 27' N, 100o 16' E) in Penang Island. The deceased was last seen alive on 23 April 2010 at 2230 h and was found burned on 24 April 2010 at 1920 h. Larval aggregation of second instar Chrysomya megacephala was observed on the chest of the deceased. PMID- 22543623 TI - A moderate weight reduction through dietary intervention decreases hepatic fat content in patients with non-alcoholic fatty liver disease (NAFLD): a pilot study. AB - PURPOSE: As a diet rich in fructose and an impaired intestinal barrier function have been proposed to be risk factors for the development of non-alcoholic fatty liver disease (NAFLD), the aim of the present pilot study was to determine whether a dietary intervention focusing on a reduction of fructose intake (-50 % in comparison with baseline) has a beneficial effect on liver status. METHODS: A total of 15 patients with NAFLD were enrolled in the study of which 10 finished the study. Fructose and total nutrient intake were assessed using a diet history. At baseline and after 6 months liver status and markers of intestinal barrier function as well as plasminogen activator inhibitor (PAI-) 1 concentration were determined in plasma. RESULTS: Hepatic lipid content and transaminases in plasma as well as body mass index and some parameters of glucose metabolism (e.g., fasting plasma insulin) were significantly lower at the end of the intervention when compared to baseline. Whereas the dietary intervention had no effect on the prevalence of bacterial overgrowth, orocecal transit time and the intestinal permeability or blood ethanol levels endotoxin and PAI-1 concentration in plasma were significantly lower at the end of 6 months intervention period than at baseline. CONCLUSIONS: Taken together, our results indicate that a dietary intervention focusing only on one dietary parameter like fructose may help to decrease intrahepatic fat content of NAFLD patients. PMID- 22543624 TI - Increased hepatic de novo lipogenesis and mitochondrial efficiency in a model of obesity induced by diets rich in fructose. AB - PURPOSE: To assess hepatic de novo lipogenesis and mitochondrial energetics as well as whole-body energy homeostasis in sedentary rats fed a fructose-rich diet. METHODS: Male rats of 90 days of age were fed a high-fructose or control diet for 8 weeks. Body composition, energy balance, oxygen consumption, carbon dioxide production, non-protein respiratory quotient, de novo lipogenesis and insulin resistance were measured. Determination of specific activity of hepatic enzymes of de novo lipogenesis, mitochondrial mass, oxidative capacity and degree of coupling, together with parameters of oxidative stress and antioxidant defence, was also carried out. RESULTS: Body energy and lipid content as well as plasma insulin and non-esterified fatty acids were significantly higher in fructose-fed than in control rats. Significantly higher rates of net de novo lipogenesis and activities of hepatic lipogenic enzymes fatty acid synthase and stearoyl CoA desaturase-1 were found in fructose-fed rats compared to controls. Mitochondrial protein mass and degree of coupling were significantly higher in fructose-fed rats compared to controls. Hepatic mitochondria showed oxidative damage, both in the lipid and in the protein component, together with decreased activity of antioxidant defence. CONCLUSION: Liver mitochondrial compartment is highly affected by fructose feeding. The increased mitochondrial efficiency allows liver cells to burn less substrates to produce ATP for de novo lipogenesis and gluconeogenesis. In addition, increased lipogenesis gives rise to whole body and ectopic lipid deposition, and higher mitochondrial coupling causes mitochondrial oxidative stress. PMID- 22543625 TI - Functional state of CD4+ and CD8+ T lymphocytes and their role in the slow progression of HIV infection in pediatric patients. AB - OBJECTIVE: To evaluate simultaneously the functional state of CD4+ and CD8+ T lymphocytes from Venezuelan HIV-1-infected pediatric patients. METHODS: Children were assigned to subgroups of rapid progressors (RPs) and slow progressors (SPs), based on clinical features. To determine the degree of CD4+ and CD8+ T-lymphocyte functionality, flow cytometry techniques were used, and diverse parameters of the functionality of these cells were characterized by ex vivo tests, such as expression of CD95/Fas and CD127, and frequency of apoptosis. In addition, we determined, in cultured peripheral blood mononuclear cells, HIV-specific proliferation and the production of interleukin-10 (IL-10), tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma), besides measuring intracellular IFN-gamma in CD4+ T cells. RESULTS: Our results indicate that several molecular and cellular mechanisms of CD4+ and CD8+ T lymphocytes are deteriorated in RPs in comparison with SPs and controls. Indeed, both types of T lymphocytes from RPs exhibited an increased expression of CD95/Fas (p < 0.01), a significantly reduced expression of CD127 (p < 0.01), and an augmented frequency of apoptosis (p < 0.01). Furthermore, T cells from these patients displayed a diminished capacity of mitogen proliferation (p < 0.05), a reduced percentage of IFN-gamma producing CD4+ T lymphocytes (p < 0.05), and a smaller capacity of IL 10, TNF-alpha and IFN-gamma production (p < 0.01) in comparison with SP and control patients. CONCLUSION: Our findings indicate that the decline of the normal T lymphocyte molecular and cellular responses is related to a rapid progression and a decreased resistance to HIV-1 infection in children. PMID- 22543626 TI - Infections of cardiac implantable electronic devices: a retrospective multicenter observational study. AB - Infections of cardiac implantable electronic devices (CIED) can cause significant morbidity, mortality, and financial burden. Although staphylococcal organisms account for most infections of these cardiac devices, approximately 20% of all CIED-related infections are caused by non-Staphylococcus species. Herein we describe and compare the demographics, clinical presentation, and outcomes of Staphylococcus aureus and non-staphylococcal infections of CIED.We performed a retrospective, multicenter, observational study of patients from 4 academic hospitals in Houston between 2002 and 2009. All 80 identified non-staphylococcal CIED-related infections were matched, at a 1:1 ratio, to S. aureus infections.Although the demographics and general comorbidities in the 2 study groups were relatively similar, the S. aureus group had a higher proportion of patients with coronary artery disease, diabetes mellitus, and end-stage renal disease. Additionally, 81% of S. aureus compared with only 48.5% of the non staphylococcal CIED-related infections were health care-associated (p < 0.001). Furthermore, when compared to non-staphylococcal infections, the S. aureus group had more indwelling intravascular foreign material (p < 0.001), more rapid clinical progression (p < 0.001), and overall worse clinical presentation (p < 0.001). However, after stratifying by clinical presentation, the mortality rates in the 2 groups were similar (p = 0.45).Since approximately one-fifth of all CIED related infections are caused by non-staphylococcal organisms, and untimely antibiotic treatment can result in serious complications, it may be prudent to broaden empiric antimicrobial therapy to cover both Gram-positive and -negative bacteria, until the causative organism is identified. PMID- 22543627 TI - Familial Mediterranean fever: risk factors, causes of death, and prognosis in the colchicine era. AB - We assessed the risk factors and causes of death in patients with familial Mediterranean fever (FMF) in an era when colchicine is the standard therapy for all patients.This study included all FMF patients who had presented to any of the internal medicine, rheumatology, or nephrology clinics at Dokuz Eylul University Hospital between 1992 and 2009. Of the 650 patients with FMF identified, 587 (90.3%) had either a face-to-face (n = 380) or telephone (n = 193) interview, or were confirmed as deceased. A structured questionnaire was used to obtain socioeconomic and demographic data, presenting and cumulative clinical features, and disease severity scores.During the follow-up period mortality was analyzed by calculating age- and sex-standardized mortality ratio (SMR) according to the mortality statistics of the Turkish population. Factors predictive of mortality were evaluated using Kaplan-Meier and Cox proportional hazard models. Sixty-three (9.7%) patients whose initial demographic and major clinical characteristics were similar to the rest of the group could not be contacted during the study period.Most (94.2%) patients were on colchicine at the time of the study. Thirty seven (6.3%) patients had biopsy-verified amyloidosis, and 44 (7.5%) had renal disease. During a median follow-up of 6 years, 14 patients (9 women) died, and amyloidosis and its related complications were the leading causes of death in 7 patients. Univariate analysis revealed that increasing age, coronary heart disease, hypertension, renal disease, and amyloidosis were associated with mortality. However, Cox regression analysis showed amyloidosis as the only significant predictor of mortality (p < 0.001). The overall patient survival rate was not significantly different from the age- and sex-matched Turkish general population (SMR, 1.48; 95% confidence interval, 0.817-2.49).Our findings suggest that although the survival of FMF patients in the colchicine era is comparable to that of the general population, renal involvement still predicts mortality. PMID- 22543628 TI - Infective endocarditis at autopsy: a review of pathologic manifestations and clinical correlates. AB - The frequency of autopsies appears to be declining, and the usefulness has been challenged. We reviewed cases of autopsied active infective endocarditis (IE) during 2 periods based on the availability of high-tech 2-dimensional echocardiograms: Period 1 (P1) included 40 cases studied from 1970 to 1985, and Period 2 (P2) included 28 cases seen from 1986 to 2008--that is, before and after the introduction of echocardiograms in our institution. We conducted the study to reassess the pathology of IE and to determine how frequently diagnosis is not made during life.The age of patients increased 10 years on average between the 2 periods, and comorbidities were significantly more frequent in P2. While the frequency of rheumatic valve disease and prosthetic valve endocarditis (PVE) decreased, degenerative valve disease increased. Isolated mitral or aortic valve IE was most common. Right-sided IE was observed in patients with Staphylococcus aureus bacteremia from infected venous lines. In most cases IE involved only the cusps of cardiac valves. "Virulent" microorganisms caused ulcerations, rupture, and perforation of the cusps and necrosis of chordae tendiniae and perivalvular apparatus. In PVE the lesions were located behind the site of attachment, and vegetations were seen on the sewing ring in both metallic and biologic prostheses. Infection spread to adjacent structures and myocardium with ring abscess observed in 88% of cases. Prosthetic detachment causing valve regurgitation was associated with abscesses in 76% of cases; these patients developed persistent sepsis and severe cardiac failure. Obstruction occurred in patients with PVE of the mitral valve. Acute purulent pericarditis was observed in 22% of cases, mainly in patients with aortic valve IE and myocardial abscesses.Gross infarcts were seen in 63% of cases but were asymptomatic in most instances. The spleen, kidneys, and mesentery were the sites most frequently involved. Myocardial infarctions were found in less than 10% of cases. Abscesses were also frequently found and were a common source of persistent fever and bacteremia. Glomerulonephritis was more common in the first period. Brain pathology consisted of ischemic and hemorrhagic infarcts and abscesses. Cerebral bleeding was more frequent in patients with PVE on anticoagulant therapy. Neutrophilic meningitis was observed in S. aureus IE.Diagnosis of IE was not made during life in 14 (35%) cases during P1 and 12 (42.8%) cases in P2. Overall, diagnosis was missed until autopsy in 38.2% of cases. IE was hospital acquired in 28 instances. While a clinical diagnosis was made in all but 4 cases of early onset PVE (23.5%), the diagnosis was not made during life in 22 of 51 patients with native-valve IE (43.1%). Of these 22 patients, IE was hospital acquired in 11 (50%). The absence of fever, cardiac murmurs, and many of the typical stigmata of endocarditis may have led to the diagnosis being overlooked clinically.Brain bleeding, cardiac failure and less frequently acute myocardial infarct were the most common causes of death.IE continues to be missed frequently until autopsy. Postmortem examination is an important tool for evaluating the quality of care, and for guiding teaching and research related to cardiovascular infections. PMID- 22543629 TI - Late-onset sarcoidosis: a comparative study. AB - Sarcoidosis is not rare in patients aged more than 65 years, but studies of elderly patients with sarcoidosis are scarce. We analyzed the characteristics and outcomes of patients in a French teaching hospital with late-onset sarcoidosis, defined as sarcoidosis diagnosed in patients aged 65 years or older, and compared them with those of younger patients with sarcoidosis. From 2002 to 2006, 30 patients were identified as having late-onset sarcoidosis and were compared to 70 patients randomly selected aged younger than 65 years. We compared clinical characteristics, laboratory data at diagnosis, severity, therapy, and outcome. The female to male ratio was higher in the late-onset sarcoidosis group than in the younger group (5:1 vs. 1:1, respectively; p = 0.003). Asthenia (30% vs. 10%; p = 0.012), uveitis (33.3 vs. 8.6%; p = 0.002), and specific skin lesions (36.7% vs. 15.7%; p = 0.002) occurred more frequently in patients with late-onset sarcoidosis than in younger patients. On the contrary, asymptomatic chest radiograph abnormalities (p = 0.031) and erythema nodosum (p = 0.016) were not reported in the group of elderly patients. The 2 groups were similar with regard to race, other organ systems involved, pulmonary function, radiographic stage, laboratory values, and severity. The proportion of patients with accessory salivary glands (p = 0.002) and skin (p = 0.023) biopsies was more often contributory to the diagnosis in the late-onset group.After a mean follow-up of 50 months, 1 death related to pulmonary mycetoma and 2 others unrelated to sarcoidosis occurred in the late-onset sarcoidosis group. The 5-year survival rate was 93.3% in the late-onset group compared with 100% in the young-onset group (p = 0.03), while overall mortality was not significantly different. The 2 groups were similar with regard to oral corticosteroid therapy and immunosuppressive use, although steroid-related adverse events were more common in the elderly group.In conclusion, we found certain clinical and diagnostic peculiarities in patients with late-onset sarcoidosis. Asthenia, uveitis, and specific cutaneous lesions were more frequent in this group, whereas erythema nodosum and disclosure on a routine chest roentgenogram were not observed. Biopsy of the minor salivary glands appears to be particularly pertinent for the diagnosis. Evolution and therapeutic management were not different in the 2 groups. However, the patients aged more than 65 years had more side effects related to the corticosteroid therapy. PMID- 22543630 TI - A flow cytometry-based dopamine transporter binding assay using antagonist conjugated quantum dots. AB - Here we present the development and validation of a flow cytometry-based dopamine transporter (DAT) binding assay that uses antagonist-conjugated quantum dots (QDs). We anticipate that our QD-based assay is of immediate value to the high throughput screening of novel DAT modulators. PMID- 22543631 TI - Risk differences between children and adults in road traffic injuries: a descriptive study from a tertiary-care hospital in a low-income country. AB - OBJECTIVE: Our study attempted to describe the differences in circumstances, risk groups, and severity of road traffic injuries (RTIs) among injured children (1-15 years) and adults (>=16 years) coming to the tertiary-care hospital, Karachi, Pakistan. METHODS: Past medical records from June 2006 to May 2007 of injured patients coming to the Emergency Department of the Aga Khan University Hospital, Karachi were reviewed. Data were recorded regarding the basic epidemiological features, hospital stay, body parts that are injured, and severity of injuries. RESULTS: Of 411 RTI patients, males outnumbered females by a ratio of 4 : 1 accounting for 81% (n = 333) of injured. Among pedestrians (82; 20%), females were injured more than males (38 vs. 16%; P < 0.01). When compared with adults, injured children were mostly pedestrians (18 vs. 36%; P = 0.01) and presented with severe Glasgow Coma Scale (GCS) (9 vs. 18%; P = 0.02). Among adults, most RTIs were caused by two wheelers crashing with four wheelers (16 vs. 19%; P = 0.01). Motor vehicle occupants (adjusted odds ratio: 3.04; 95% confidence interval: 1.382-6.668) were more likely to have severe GCS (GCS < 8) even after adjusting for injury severity. CONCLUSION: The study may assist local authorities in Karachi to prioritize interventions to address common injuries among those who are at a high risk for RTIs. Further quantitative and qualitative studies are needed to assess the factors leading to RTIs among pedestrians in Karachi. PMID- 22543632 TI - The role of the emergency department in detecting high-risk cocaine users. PMID- 22543633 TI - First record of a mosquito iridescent virus in Culex pipiens L. (Diptera: Culicidae). AB - The mosquito iridescent viruses (MIVs) are large icosahedral DNA viruses that replicate and assemble in the cytoplasm of the host. Paracrystalline arrangements of virions that accumulate in the cytoplasm produce an iridescent color that is symptomatic of acute infections. In August 2010, we found larvae of Culex pipiens with these symptoms in suburban ditches around the city of La Plata, Argentina. Electron microscope studies, DNA sequencing, and phylogenetic analysis of the major capsid protein confirmed this as the first record of an MIV in C. Pipiens. PMID- 22543634 TI - A novel maize-infecting mastrevirus from La Reunion Island. AB - Despite extensive sampling, only one virus belonging to the genus Mastrevirus of the family Geminiviridae, maize streak virus (MSV), has until now been detected in maize with maize streak disease (MSD) symptoms. Here, we report for the first time a second, highly divergent, mastrevirus isolated from two maize plants displaying characteristic MSD-like symptoms, sampled on the South-west Indian Ocean Island, La Reunion. The two isolates shared <57 % genome-wide identity with all other known mastreviruses. We propose calling the new species Maize streak Reunion virus. PMID- 22543635 TI - Sequencing and analysis of the complete genome of Rana grylio virus (RGV). AB - Infection with Rana grylio virus (RGV), an iridovirus isolated in China in 1995, resulted in a high mortality rate in frogs. The complete genome sequence of RGV was determined and analyzed. The genomic DNA was 105,791 bp long, with 106 open reading frames (ORFs). Dot plot analysis showed that the gene order of RGV shared colinearity with three completely sequenced ranaviruses. A phylogenetic tree was constructed based on concatenated sequences of iridovirus 26 core-gene-encoded proteins, and the result showed high bootstrap support for RGV being a member of the genus Ranavirus and that iridoviruses of other genera also clustered closely. A microRNA (miRNA) prediction revealed that RGV could encode 18 mature miRNAs, many of which were located near genes associated with virus replication. Thirty three repeated sequences were found in the RGV genome. These results provide insight into the genetic nature of RGV and are useful for laboratory diagnosis for vertebrate iridoviruses. PMID- 22543636 TI - Isolation of Newcastle disease virus from a non-avian host (sheep) and its implications. AB - Newcastle disease virus (NDV) is an avian virus that has not been isolated from naturally infected non-avian and non-human hosts except for one report in which it was isolated from cattle in 1952. We report here for the first time the isolation and identification of NDV from sheep and suggest that this virus be included in the screening of viruses from non-avian hosts. PMID- 22543637 TI - Quantification of electron-phonon scattering for determination of temperature variations at high spatial resolution in the transmission electron microscope. AB - This work investigates the quantification of electron-phonon thermal diffuse scattering (TDS) for detection of temperature variations with nanometer spatial resolution in transmission electron microscopy (TEM). Observations of TDS intensity for (100) single crystal Si and Ge show interdependences of temperature and sample thickness which can be understood through the angular distributions of electron-phonon scattering as a function of temperature. The temperature sensitivity of the integrated TDS intensity can be of the order of 10(-3) K(-1) for Si and Ge. This shows that measurement of the TDS intensity in the TEM is a promising means for nanoscale temperature measurement; our measurements to date have demonstrated that temperature changes as small as 5 K are detectable. PMID- 22543638 TI - The best people I know. PMID- 22543641 TI - Feeding tube placement. PMID- 22543642 TI - Feeding tube placement. PMID- 22543643 TI - Feeding tube placement. PMID- 22543644 TI - Vaccinating cancer patients. PMID- 22543645 TI - Attitudes toward piercings and tattoos. PMID- 22543646 TI - RN population care coordinators. PMID- 22543652 TI - Long work hours for nurses. PMID- 22543660 TI - Competence in CPR. PMID- 22543661 TI - Key ideas in nursing's first century. AB - OVERVIEW: This article identifies some of the major ideas underpinning modern American nursing in its first 100 years, and postulates that distinct periods in nursing's early formal development were dominated by a particular theme or set of ideas. The themes, which were largely determined by social priorities, scientific advances, and national emergencies, overlapped, enriched each other, and provided an impetus for nursing to evolve into the highly skilled profession it has become. PMID- 22543662 TI - The coronary care unit turns 50. PMID- 22543668 TI - Obesity: a new risk factor for cardiac syndrome X? Editorial to: "Obesity, inflammation and brachial artery flow-mediated dilatation: therapeutic targets in patients with microvascular angina (cardiac syndrome X)" by P. Ong et al. PMID- 22543669 TI - Statins counter the effects of hyperlipidemia on iNKT cells: Editorial to: "Statin-induced immunomodulation alters peripheral invariant natural killer T cell prevalence in hyperlipidemic patients" by E. Nakou et al. PMID- 22543670 TI - Neutron diffraction and electrical transport studies on the incommensurate magnetic phase transition in holmium at high pressures. AB - Neutron diffraction and electrical transport measurements have been made on the heavy rare earth metal holmium at high pressures and low temperatures in order to elucidate its transition from a paramagnetic (PM) to a helical antiferromagnetic (AFM) ordered phase as a function of pressure. The electrical resistance measurements show a change in the resistance slope as the temperature is lowered through the antiferromagnetic Neel temperature. The temperature of this antiferromagnetic transition decreases from approximately 122 K at ambient pressure at a rate of -4.9 K GPa(-1) up to a pressure of 9 GPa, whereupon the PM to-AFM transition vanishes for higher pressures. Neutron diffraction measurements as a function of pressure at 89 and 110 K confirm the incommensurate nature of the phase transition associated with the antiferromagnetic ordering of the magnetic moments in a helical arrangement and that the ordering occurs at similar pressures as determined from the resistance results for these temperatures. PMID- 22543672 TI - Influence of domestic violence on the association between malnutrition and low cognitive development. AB - OBJECTIVES: To investigate the size and direction of the association between malnutrition and low cognitive performance and to evaluate the effect of domestic violence on this association. METHODS: This cross-sectional study enrolled students of both sexes, aged 7 to 14 years old, attending public elementary schools. The Raven's Progressive Matrices Test was used to measure cognitive development, the Revised Conflict Tactics Scales (CTS2), to measure domestic violence, and the body mass index (BMI) for age and sex, to define anthropometric indices. Socioeconomic data and information about food intake were also collected. Malnutrition was defined as BMI < 3rd percentile. Cognitive deficit was defined when the results of Raven's test were <= 25th percentile. Family violence was defined as a positive answer in at least one item about severe physical violence in the last 12 months. The size of the associations of interest was expressed as prevalence ratio (PR) and 95% confidence interval (95%CI). RESULTS: Below-average intellectual development was found for 63.3% of the participants. Malnutrition was identified in 9.5%. Malnutrition had a negative effect on cognitive performance (adjusted prevalence ratio [aPR] = 1.60, 95% CI = 1.01 - 2.52; p = 0.042) when adjusted for the association between exposure to domestic violence and age. CONCLUSION: The association between malnutrition and below-average intellectual development found in this study was affected by domestic violence, which must be taken into account when addressing the problem. PMID- 22543671 TI - Cannabinol and cannabidiol exert opposing effects on rat feeding patterns. AB - RATIONALE: Increased food consumption following ?(9)-tetrahydrocannabinol-induced cannabinoid type 1 receptor agonism is well documented. However, possible non ?(9)-tetrahydrocannabinol phytocannabinoid-induced feeding effects have yet to be fully investigated. Therefore, we have assessed the effects of the individual phytocannabinoids, cannabigerol, cannabidiol and cannabinol, upon feeding behaviors. METHODS: Adult male rats were treated (p.o.) with cannabigerol, cannabidiol, cannabinol or cannabinol plus the CB(1)R antagonist, SR141716A. Prior to treatment, rats were satiated and food intake recorded following drug administration. Data were analyzed for hourly intake and meal microstructure. RESULTS: Cannabinol induced a CB(1)R-mediated increase in appetitive behaviors via significant reductions in the latency to feed and increases in consummatory behaviors via increases in meal 1 size and duration. Cannabinol also significantly increased the intake during hour 1 and total chow consumed during the test. Conversely, cannabidiol significantly reduced total chow consumption over the test period. Cannabigerol administration induced no changes to feeding behavior. CONCLUSION: This is the first time cannabinol has been shown to increase feeding. Therefore, cannabinol could, in the future, provide an alternative to the currently used and psychotropic ?(9)-tetrahydrocannabinol based medicines since cannabinol is currently considered to be non-psychotropic. Furthermore, cannabidiol reduced food intake in line with some existing reports, supporting the need for further mechanistic and behavioral work examining possible anti-obesity effects of cannabidiol. PMID- 22543673 TI - Predictive value of ABCB1 polymorphisms G2677T/A, C3435T, and their haplotype in small cell lung cancer patients treated with chemotherapy. AB - PURPOSE: Multiple drug resistance limits the efficacy of numerous cytotoxic drugs used in the treatment of small cell lung cancer (SCLC). The drug efflux protein ATP-binding cassette transporter B1 (ABCB1) has an important role in this process, and its gene variability may affect chemotherapy outcomes. PATIENTS AND METHODS: This study aimed to evaluate the associations between ABCB1 polymorphisms G2677T/A, C3435T, and their haplotype with progression-free survival (PFS) and overall survival (OS) in 177 SCLC patients treated with cisplatin-etoposide or cyclophosphamide-epirubicin-vincristine chemotherapy. To determine the ABCB1 genotype, allelic specific TaqMan((r)) probes were used in a RT-PCR . RESULTS: Patients carrying the G2677T/A TT + TA + AA genotypes (24 %) or the C3435T CT + TT genotypes (72 %) or the 2677T/A-3435T haplotype (40 %) had a longer PFS (Cox regression, P = 0.052, 0.037 and 0.037, respectively); these associations persisted also in multivariate analyses (Cox regression, P = 0.028, 0.037 and 0.030, respectively). Moreover, patients with the C3435T CT + TT genotypes had a longer OS both in univariate and multivariate analysis (Cox regression, P = 0.022 and 0.028, respectively). A trend toward longer OS was noted for the 2677T/A-3435T haplotype (Cox regression, P = 0.051), but its independent value was not confirmed (Cox regression, P = 0.071). CONCLUSIONS: Our study reported a possible predictive value of ABCB1 polymorphisms G2677T/A, C3435T, and their haplotype for longer PFS and OS in Caucasian SCLC patients treated with chemotherapy. However, to be implemented into routine clinical practice, ABCB1 polymorphisms require further validation. PMID- 22543674 TI - Using growth mixture modeling to identify heterosexual men who reduce their frequency of unprotected sex following a behavioral intervention. AB - Using growth mixture modeling, two 12-month trajectories of unprotected sex were identified in 210 heterosexual men (76 % African American, M(age) = 33.2 years) attending a sexual risk reduction intervention. Risk Reducers (46 %) reported fewer acts of unprotected sex following intervention, whereas Risk Maintainers (54 %) reported continuously high levels of unprotected sex. These groups did not differ with respect to demographic characteristics or intervention type. However, Risk Maintainers were more likely than Risk Reducers to report lifetime sex work, forced sex in the past year, and alcohol use before sex at baseline. They had higher levels of peak alcohol use, poorer condom skills, and scored lower on stage of change for condom use at baseline. Risk Maintainers were also more likely to have steady partners at baseline and less likely to change partner status following intervention. Understanding factors distinguishing these groups can contribute to the development of targeted Risk Reduction interventions. PMID- 22543675 TI - Toll-like receptor 7 stimulation by imiquimod induces macrophage autophagy and inflammation in atherosclerotic plaques. AB - Atherosclerotic plaques tend to rupture as a consequence of a weakened fibrous cap, particularly in the shoulder regions where most macrophages reside. Macrophages express Toll-like receptors to recognize pathogens and eliminate intracellular pathogens by inducing autophagy. Because Toll-like receptor 7 (TLR7) is thought to be expressed in macrophages but not in smooth muscle cells (SMCs), we investigated whether induction of macrophage autophagic death by TLR7 ligand imiquimod can affect the composition of atherosclerotic plaques in favor of their stability. Immunohistochemical staining of human carotid plaques as well as Western blotting of cultured macrophages and SMCs confirmed that TLR7 was expressed in macrophages, but not in SMCs. In vitro experiments showed that only TLR7 expressing cells underwent imiquimod-induced cell death, which was characterized by autophagosome formation. Imiquimod-treated macrophages activated nuclear factor-kappaB (NF-kappaB) and released pro-inflammatory cytokines and chemokines. This effect was inhibited by the glucocorticoid dexamethasone. Imiquimod-induced cytokine release was significantly decreased in autophagy deficient macrophages because these cells died by necrosis at an accelerated pace. Local in vivo administration of imiquimod to established atherosclerotic lesions in rabbit carotid arteries induced macrophage autophagy without induction of cell death, and triggered cytokine production, upregulation of vascular adhesion molecule-1, infiltration of T-lymphocytes, accumulation of macrophages and enlargement of plaque area. Treatment with dexamethasone suppressed these pro inflammatory effects in vivo. SMCs and endothelial cells in imiquimod-treated plaques were not affected. In conclusion, imiquimod induces macrophage autophagy in atherosclerotic plaques, but stimulates plaque progression through cytokine release and enhanced infiltration of inflammatory cells. PMID- 22543676 TI - Inherited susceptibility for aggressive prostate cancer. AB - Whether or not there is inherited basis for prostate cancer aggressiveness is not clear, but advances in DNA analysis should provide an answer to this question in the very near future. PMID- 22543677 TI - Reduction in sperm aneuploidy levels in severe oligoasthenoteratospermic patients after medical therapy: a preliminary report. AB - The objective of this study was to investigate whether medical therapy can reduce sperm aneuploidy levels and improve the results of intracytoplasmic sperm injection (ICSI) in patients with severe idiopathic oligoasthenoteratospermia (OAT). Thirty-three infertile couples requiring ICSI because of severe idiopathic OAT after at least one unsuccessful ICSI cycle were considered. Semen parameters (concentration, motility and morphology), the percentage of aneuploid sperm and the results of ICSI (the number of oocytes fertilized, embryos transferred, biochemical pregnancies, clinical pregnancies and live births) were compared before and after a 3-month course of treatment with L-carnitine 1 g given twice per day+acetyl-L-carnitine 500 mg given twice per day+one 30-mg cinnoxicam tablet every 4 days. Aneuploidy was assessed using fluorescent in situ hybridisation (FISH) performed on chromosomes X, Y, 13, 15, 16, 17, 18, 21 and 22. The results showed that 22 of the 33 patients had a reduced frequency of aneuploid sperm and improved sperm morphology after treatment (group 1), and 11 showed no change (group 2). The numbers of biochemical pregnancies, clinical pregnancies and live births were significantly higher in group 1 than in group 2. No significant difference was found between the groups regarding the numbers of oocytes fertilized and embryos transferred. The side effects were negligible. The numbers of ICSI pregnancies and live births in severe idiopathic OAT patients improved with a course of L-carnitine, acetyl-L-carnitine and cinnoxicam. PMID- 22543679 TI - Effects of morphology on the micro-compression response of carbon nanotube forests. AB - This study reports the mechanical response of distinct carbon nanotube (CNT) morphologies as revealed by flat punch in situ nanoindentation in a scanning electron microscope. We find that the location of incipient deformation varies significantly by changing the CNT growth parameters. The initial buckles formed close to the growth substrate in 70 and 190 MUm tall CNT forests grown with low pressure chemical vapor deposition (LPCVD) and moved to ~100 MUm above the growth substrate when the height increased to 280 MUm. Change of the recipe from LPCVD to CVD at pressures near atmospheric changed the location of the initial buckling event from the bottom half to the top half of the CNT forest. Plasma pretreatment of the catalyst also resulted in a unique CNT forest morphology in which deformation started by bending and buckling of the CNT tips. We find that the vertical gradients in CNT morphology dictate the location of incipient buckling. These new insights are critical in the design of CNT forests for a variety of applications where mechanical contact is important. PMID- 22543678 TI - Meyerson's phenomenon in a patient affected by high-risk melanoma under treatment with interferon-alpha. PMID- 22543680 TI - Compliance with wetland mitigation standards in the upper peninsula of Michigan, USA. AB - The United States has lost about half its wetland acreage since European settlement, and the effectiveness of current wetland mitigation policies is often questioned. In most states, federal wetland laws are overseen by the U.S. Army Corps of Engineers, but Michigan administers these laws through the state's Department of Environmental Quality (MDEQ). Our research provides insight into the effectiveness of the state's implementation of these laws. We examined wetland mitigation permit files issued in Michigan's Upper Peninsula between 2003 and 2006 to assess compliance with key MDEQ policies. Forty-six percent of files were out of compliance with monitoring report requirements, and forty-nine percent lacked required conservation easement documents. We also conducted site assessments of select compensatory wetland projects to determine compliance with MDEQ invasive plant species performance standards. Fifty-five percent were out of compliance. We found no relationship between invasive species noncompliance and past site monitoring, age of mitigation site, or proximity to roads. However, we found wetland restoration projects far more likely to be compliant with performance standards than wetland creation projects. We suggest policy changes and agency actions that could increase compliance with wetland restoration and mitigation goals. PMID- 22543682 TI - Sunlight-induced effective heterogeneous photocatalytic decomposition of aqueous organic pollutants to CO2 assisted by a CO2 sorbent, amine-containing mesoporous silica. AB - Photocatalytic mineralization of aqueous formic acid and phenol on pure TiO(2) under sunlight irradiation was substantially accelerated to give a reliable photocatalytic efficiency by conducting the reactions in the presence of a CO(2) sorbent, amine-containing SBA-15, placed in the gas phase of the reactor. PMID- 22543681 TI - Preparation, characterization, and surface immobilization of native vesicles obtained by mechanical extrusion of mammalian cells. AB - Native vesicles or "reduced protocells" derived by mechanical extrusion concentrate selected plasma membrane components, while downsizing complexities of whole cells. We illustrate this technique, characterize the physical-chemical properties of these reduced configurations of whole cells, and demonstrate their surface immobilization and patternability. This simple detergent-free vesicularized membrane preparation should prove useful in fundamental studies of cellular membranes, and may provide a means to engineer therapeutic cells and enable high-throughput devices containing near-native, functional proteolipidic assemblies. PMID- 22543683 TI - Current antiplatelet options for NSTE-ACS patients. AB - Non-ST elevation (NSTE) myocardial infarction and unstable angina are the most common clinical presentations of acute coronary syndrome (ACS). Platelet activation is central to the pathogenesis of NSTE-ACS and consensus guidelines that advocate early revascularization supported by intensive antiplatelet therapy. This review examines the drugs used concurrently with aspirin as dual antiplatelet therapy in the NSTE-ACS setting. Clopidogrel represented an important therapeutic advance. However, variations in platelet response and a relatively slow onset of action compromise outcomes with clopidogrel. Evidence reviewed in this article shows that in NSTE-ACS patients, ticagrelor and prasugrel are more effective than clopidogrel and are relatively well tolerated, with an acceptable and manageable bleeding risk. The literature suggests several differences between ticagrelor and prasugrel that should allow clinicians to better tailor treatment to the patient. Head-to-head comparisons are now needed to compare directly the risks and benefits of ticagrelor and prasugrel in NSTE ACS. Further studies also need to address other outstanding issues such as the benefits and risks of prasugrel pre-treatment and to stratify efficacy and tolerability according to diabetes mellitus (DM) and other co-morbidities. In the meantime, the issues discussed in this review should enhance clinicians' ability to optimize and individualize NSTE-ACS treatment, thereby further reducing the morbidity and mortality associated with this common cardiovascular condition. PMID- 22543684 TI - Gastric bypass surgery as an intervention for obese patients with hemochromatosis. PMID- 22543685 TI - Toxic epidermal necrolysis and Stevens-Johnson syndrome in South Africa: a 3-year prospective study. AB - BACKGROUND: Toxic Epidermal Necrolysis (TEN) and Stevens-Johnson syndrome (SJS) remain feared medication-related reactions. HIV infection and tuberculosis predispose to drug eruptions, yet there is a paucity of data on TEN/SJS in populations with high prevalences of both diseases. AIM: The aim of this prospective observational study was to describe the features and outcomes of patients admitted with TEN/SJS at a large academic hospital in South Africa. We aimed to identify poor prognostic indicators and to validate the use of the TEN specific severity-of-illness score (SCORTEN) in this population. METHODS: All patients admitted with TEN/SJS over a 3-year period were enrolled. Disease severity was graded according to percentage skin involved and SCORTEN. Co-morbid diagnoses, clinical features, investigations, complications and outcomes were noted. RESULTS: 75 patients (39.9 +/- 10.6 years, 16 males, 59 HIV positive) were classified as TEN (n = 42), TEN/SJS overlap (n = 11) and SJS (n = 22). Twenty four percent died, most from refractory septic shock. Non-survivors had a higher mean SCORTEN on Days 1 and 3 (1.89 vs. 1.04, P = 0.006 and 2.27 vs. 0.90, P < 0.001). A SCORTEN >=2 on Days 1 and 3 predicted non-survival (OR = 2.94, P = 0.047; OR = 7.45, P < 0.001). Other predictors of non-survival included HIV infection (OR = 6.01, P = 0.058), HIV-tuberculosis co-infection (OR = 8.5, P < 0.001), >=40% skin involvement (OR = 20.27, P < 0.001), anaemia (OR = 4.68, P = 0.005), hypoalbuminemia (OR = 8.5, P = 0.001) and severe sepsis (OR = 71.09, P < 0.001). CONCLUSION: Most patients with TEN/SJS were HIV positive and female. We validated the use of SCORTEN and identified several prognostic indicators, most significant being HIV-tuberculosis co-infection, >=40% skin involvement and severe sepsis. PMID- 22543686 TI - Influence of peers and friends on overweight/obese youths' physical activity. AB - This review offers a theoretical framework to account for the effects of peers on youths' physical activity. Our research indicates the following: 1) that the youth are more physically active in the presence of friends and peers than in the presence of family members or when alone, 2) peers and friends increase overweight/obese youths' motivation to be physically active, 3) peers' weight status does not moderate the effect of peers on youths' physical activity, and 4) experiencing negative peer interaction, such as ostracism, decreases physical activity in youth. We propose that the consideration of the peer social context as a contributor to physical (in)activity and maintenance of overweight status may further our understanding of physical and behavioral health trajectories and improve prevention and intervention efforts. PMID- 22543687 TI - The role of ribosylated-BSA in regulating PC12 cell viability. AB - Glycation, one of the post-translational modifications, is known to influence protein structure and biological function. Advanced glycation end products (AGEs) have been shown to cause pathologies of diabetes. Glycation levels in patients with Alzheimer's disease (AD) are higher than in normal people. However, whether the glycation of susceptible proteins is a triggering event for cell damage or simply a result remains to be elucidated. In this study, we demonstrated that ribose-conjugated BSA (Rib-BSA) directly induces PC12 cell death in a dose- and time-dependent manner. The IC(50) is 4.6 MUM. Unlike glucose-incubated BSA, Rib BSA rapidly forms cytotoxic AGEs. PC12 is vulnerable to Rib-BSA. However, fructose can induce AGE formation, although no effect on cell survival was observed. This effect of Rib-BSA is reversed by pretreatment of pioglitazone and rosiglitazone, which belongs to thiazolidinediones (TZDs) and are peroxisome proliferator-activated receptor (PPAR-gamma) ligands. Moreover, Rib-BSA upregulates inducible nitric oxide synthase (iNOS), cycloxygenase 2 (COX-2) expression, and p-38 phosphorylation and leaves extracellular regulated protein1/2 (ERK1/2) phosphorylation unchanged. The Rib-BSA-induced signaling changes are blocked by rosiglitazone and confirmed by PPAR-gamma small interfering RNA transfection. The reduction of cell survival by Rib-BSA is blocked by the iNOS inhibitor and p38 inhibitor. No effect on cell survival was observed using the COX-2 inhibitor. Consequently, these results show that Rib-BSA directly inducing PC12 cell death is a triggering event and TZDs protect PC12 cell from Rib-BSA damage. Signaling molecules, such as PPAR-gamma, P38, and iNOS, are involved in Rib-BSA-mediated cytotoxicity. PMID- 22543688 TI - Eduard Strasburger (1844-1912): founder of modern plant cell biology. AB - Eduard Strasburger, director of the Botany Institute and the Botanical Garden at the University of Bonn from 1881 to 1912, was one of the most admirable scientists in the field of plant biology, not just as the founder of modern plant cell biology but in addition as an excellent teacher who strongly believed in "education through science." He contributed to plant cell biology by discovering the discrete stages of karyokinesis and cytokinesis in algae and higher plants, describing cytoplasmic streaming in different systems, and reporting on the growth of the pollen tube into the embryo sac and guidance of the tube by synergides. Strasburger raised many problems which are hot spots in recent plant cell biology, e.g., structure and function of the plasmodesmata in relation to phloem loading (Strasburger cells) and signaling, mechanisms of cell plate formation, vesicle trafficking as a basis for most important developmental processes, and signaling related to fertilization. PMID- 22543689 TI - Jan Evangelista Purkyne/Purkinje (1787-1869) and the establishment of cellular physiology--Wroclaw/Breslau as a central European cradle for a new science. AB - Being a professor of physiology in Wroclaw/Breslau till the half of nineteenth century, Jan Evangelista Purkyne/Purkinje made, along with his students, many crucial discoveries combining original experimental approaches with new advanced microscopy and histology techniques. Here, he established first Institute of Physiology worldwide and created a framework for the new science of cellular physiology. With his work, he not only substantially contributed to the establishment of cellular and protoplasmic concepts in biology but represented a rare type of Central European scholar by bridging communities separated by ethnicity and language. PMID- 22543691 TI - Current induced surface diffusion on a single-crystalline silver nanowire. AB - Scanning tunnelling microscopy was used to study the morphological changes of the surface of a single-crystalline silver nanowire caused by a lateral electron current. At current densities of about 1.5 * 10(7) A cm(-2), surface atoms are extracted from step edges, resulting in the motion of surface steps, islands and holes with a thickness or depth of one monolayer. Upon current reversal the direction of the material transport can be altered. The findings are interpreted in terms of the wind force. PMID- 22543690 TI - The relevance of compartmentation for cysteine synthesis in phototrophic organisms. AB - In the vascular plant Arabidopsis thaliana, synthesis of cysteine and its precursors O-acetylserine and sulfide is distributed between the cytosol, chloroplasts, and mitochondria. This compartmentation contributes to regulation of cysteine synthesis. In contrast to Arabidopsis, cysteine synthesis is exclusively restricted to chloroplasts in the unicellular green alga Chlamydomonas reinhardtii. Thus, the question arises, whether specification of compartmentation was driven by multicellularity and specified organs and tissues. The moss Physcomitrella patens colonizes land but is still characterized by a simple morphology compared to vascular plants. It was therefore used as model organism to study evolution of compartmented cysteine synthesis. The presence of O-acetylserine(thiol)lyase (OAS-TL) proteins, which catalyze the final step of cysteine synthesis, in different compartments was applied as criterion. Purification and characterization of native OAS-TL proteins demonstrated the presence of five OAS-TL protein species encoded by two genes in Physcomitrella. At least one of the gene products is dual targeted to plastids and cytosol, as shown by combination of GFP fusion localization studies, purification of chloroplasts, and identification of N termini from native proteins. The bulk of OAS-TL protein is targeted to plastids, whereas there is no evidence for a mitochondrial OAS-TL isoform and only a minor part of OAS-TL protein is localized in the cytosol. This demonstrates that subcellular diversification of cysteine synthesis is already initialized in Physcomitrella but appears to gain relevance later during evolution of vascular plants. PMID- 22543692 TI - Thermo-magnetic history effects in the giant magnetostriction across the first order transition and minor hysteresis loops modeling in Fe0.955Ni0.045Rh alloy. AB - Results of temperature- and magnetic field-dependent strain measurements across the first-order antiferromagnetic to ferromagnetic phase transition in Fe(0.955)Ni(0.045)Rh are presented. Distinct thermal and magnetic field hystereses are observed in the measured strain across the phase transition. The minor hysteresis loops inside the hysteretic regime across the temperature-driven transition are modeled using the Preisach model of hysteresis. The applicability of the Preisach model to explain the general features of minor hysteresis loops is discussed for a disorder influenced first-order transition. The minor hysteresis loops show the property of retaining the memory of the starting or end point of the temperature cycle followed within the hysteretic region. A larger temperature excursion within the hysteretic region wipes out the memory of a smaller temperature cycle which contains one of the extrema of the larger cycle. The end-point memory and the wiping-out property of the minor hysteresis loops can be described quite well within the Preisach model, irrespective of the temperature history followed to reach a particular starting point. Thermo magnetic history effects across the magnetic field-induced transition are explained, which will enable the choice of the starting point of an experimental cycle in the field-temperature phase space so as to achieve the desired functionality. Our results highlight the necessity to understand the influence of disorder on a first-order phase transition so as to achieve a repeatable performance of materials whose functionalities are based on such a transition. PMID- 22543693 TI - Artificial sweeteners--a recently recognized class of emerging environmental contaminants: a review. AB - An overview is given of existing trace analytical methods for the determination of seven popular artificial sweeteners [acesulfame (ACE), aspartame, cyclamate (CYC), neotame, neohesperidine dihydrochalcone, saccharin (SAC), and sucralose (SUC)] from aqueous environmental samples. Liquid chromatography-electrospray ionization tandem mass spectrometry and liquid chromatography-electrospray ionization high-resolution mass spectrometry are the methods most widely applied, either directly or after solid-phase extraction. Limits of detection and limits of quantification down to the low nanogram per liter range can be achieved. ACE, CYC, SAC, and SUC were detected in wastewater treatment plants in high microgram per liter concentrations. Per capita loads of individual sweeteners can vary within a wide range depending on their use in different countries. Whereas CYC and SAC are usually degraded by more than 90% during wastewater treatment, ACE and SUC pass through wastewater treatment plants mainly unchanged. This suggests their use as virtually perfect markers for the study of the impact of wastewater on source waters and drinking waters. In finished water of drinking water treatment plants using surface-water-influenced source water, ACE and SUC were detected in concentrations up to 7 and 2.4 MUg/L, respectively. ACE was identified as a precursor of oxidation byproducts during ozonation, resulting in an aldehyde intermediate and acetic acid. Although the concentrations of ACE and SUC are among the highest measured for anthropogenic trace pollutants found in surface water, groundwater, and drinking water, the levels are at least three orders of magnitude lower than organoleptic threshold values. However, ecotoxicology studies are scarce and have focused on SUC. Thus, further research is needed both on identification of transformation products and on the ecotoxicological impact of artificial sweeteners and their transformation products. PMID- 22543694 TI - Hydrophilic properties as a new contribution for computer-aided identification of short peptides in complex mixtures. AB - A new method to predict elementary amino acid (AA) composition of peptides (molar mass <1,000 g/mol) is described. This procedure is based on a computer-aided method using three combined analyses-reversed phase liquid chromatography (RPLC), hydrophilic interaction chromatography (HILIC) and capillary electrophoresis coupled with mass spectrometry-and using a software calculating all possible amino acid combinations from the mass of any given peptide. The complementarity between HILIC and RPLC was demonstrated. Peptide retention prediction in HILIC was successfully modelled, and the achieved prediction accuracy was as high as r2=0.97. This mathematical model, based on amino acid retention contributions and peptide length, provided the information about peptide hydrophilicity that was not redundant with its hydrophobicity. Correlations between respectively the hydrophobicity coefficients and RPLC retention time, hydrophilicity and HILIC retention time, and electrophoretic mobility and migration time were used for ranking all potential AA combinations corresponding to the given mass. The essential contribution of HILIC in this identification strategy and the need to combine the three models to significantly increase identification capabilities were both shown. Applied to an 18-standard peptide mixture, the identification procedure enabled the actual AA combination determination of the 14 di- to pentapeptides, in addition to an over 98 % reduction of possible combination numbers for the four hexapeptides. This procedure was then applied to the identification of 24 unknown peptides in a rapeseed protein hydrolysate. The effective AA composition was found for ten peptides, whereas for the 14 other peptides, the number of possible combinations was reduced by over 95 % thanks to the association of the three analyses. Finally, as a result of the information provided by the analytical techniques about peptides present in the mixture, the proposed method could become a highly valuable tool to recover bioactive peptides from undefined protein hydrolysates. PMID- 22543695 TI - Characteristics of the spin-trapping reaction of a free radical derived from AAPH: further development of the ORAC-ESR assay. AB - The characteristics of the spin-trapping reaction in the oxygen radical absorbance capacity (ORAC)-electron spin resonance (ESR) assay were examined, focusing on the kind of spin traps. 2,2-Azobis(2-amidinopropane) dihydrochloride (AAPH) was used as a free radical initiator. The spin adducts of the AAPH-derived free radical were assigned as those of the alkoxyl radical, RO. (R=H(2)N(HN)C C(CH(3))(2)). Among the spin traps tested, 5,5-dimethyl-1-pyrroline N-oxide (DMPO), 5,5-dimethyl-4-phenyl-1-pyrroline N-oxide (4PDMPO), 5-(2,2-dimethyl-1,3 propoxycyclophosphoryl)-5-methyl-1-pyrroline N-oxide (CYPMPO), and 5 diethoxyphosphoryl-5-methyl-1-pyrroline N-oxide (DEPMPO) were applicable to the ORAC-ESR assay. Optimal formation of spin-trapped radical adduct was observed with 1 mM AAPH, 10 mM spin trap, and 5 s UV irradiation. The calibration curve (the Stern-Volmer's plot) for each spin trap showed good linearity, and their slopes, k (SB)/k (ST), were estimated to be 87.7+/-2.3, 267+/-15, 228+/-9, and 213+/-16 for DMPO, 4PDMPO, CYPMPO, and DEPMPO, respectively. Though the k (SB)/k (ST) values for selected biosubstances varied with various spin traps, their ratios to Trolox (the relative ORAC values) were almost the same for all spin traps tested. The ORAC-ESR assay also had a very good reproducibility. The ORAC ESR assay was conducted under stoichiometric experimental conditions. The present results demonstrate the superiority of the ORAC-ESR assay. PMID- 22543696 TI - Development of antibody-labelled superparamagnetic nanoparticles for the visualisation of benzo[a]pyrene in porous media with magnetic resonance imaging. AB - Biogeochemical interfaces in soil are dynamic in the spatial and temporal domain and require advanced visualisation and quantification tools to link in vitro experiments with natural systems. This study presents the development, characterization and application of functional nanoparticles coated with monoclonal antibodies to visualise the distribution of benzo[a]pyrene in porous media using magnetic resonance imaging. The labelled particles are 450 nm in diameter and interact with benzo[a]pyrene covalently bound to silanized silica gel. They did not bind to benzo[a]pyrene adsorbed to plain silica gel. Although unspecific filtration was low, washing steps are required for visualisation. The ability to visualise benzo[a]pyrene is inversely correlated to the heterogeneity of the soil materials. There are access restrictions to narrow pore spaces which allow the visualisation of only those pathways which are also accessible to bacteria and hydrocolloids. The production of the particles is applicable to other antibodies which extends the range of potential target contaminants. PMID- 22543697 TI - Prenatal diagnosis of dilated cavum vergae with three-dimensional transvaginal ultrasound. PMID- 22543698 TI - Use of progestogens in pregnant and infertile patients. AB - Progesterone is an essential hormone in the occurence and maintenance of pregnancy. Natural or synthetic progestogens are commonly used in pregnant patients or patients undergoing infertility treatments for various indications. Most frequently put indications for the use of progestogens in these patient populations are the prevention of spontaneous preterm birth, the prevention of pregnancy loss in pregnancies with an unexplained recurrent pregnancy loss and in patients with threatened abortion. It is also used in pregnant women undergoing nonobstetric surgery, for infertility or recurrent pregnancy loss that is thought to be due to luteal phase defect or as a luteal support in stimulated IVF cycles. We aimed to review the current evidence for the use of progestogens in each of these settings. PMID- 22543699 TI - Is thrombophilia a risk factor for placenta-mediated pregnancy complications? AB - PURPOSE: To determine if thrombophilia is a risk factor for placenta-mediated pregnancy complications (PMPC) (i.e., preeclampsia, intrauterine growth restriction (IUGR), placental abruption, intrauterine fetal death and recurrent pregnancy loss). METHODS: A 5-year retrospective cohort study. Ongoing pregnancies in women with an antecedent PMPC with thrombophilia were compared with the pregnancies in similar women without thrombophilia. The main outcome measures were mean birth weight deviations, corrected for gestational age, and recurrence of PMPC. Low-molecular-weight heparin (LMWH) was employed for thromboprophylaxis only. Mann-Whitney's, Fisher's and Chi-square tests were employed for comparison. RESULTS: PMPC recurred in 10/43 (23 %) in the thrombophilia group and in 7/41 (17 %) in the non-thrombophilia group, P < 0.059. The mean birth weight deviations were not significantly different either: -7.2 versus -3.0 %, respectively. LMWH, as could be expected, was used more often in thrombophilia patients (39/43 vs. 10/41, P < 0.001). CONCLUSION: Thrombophilia does hardly increase the risk of IUGR/PMPC or if so, it can be prevented by LMWH. PMID- 22543700 TI - Parasitological examination for presence of hookworms (Uncinaria spp.) in northern elephant seals (Mirounga angustirostris) at Ano Nuevo State Reserve, California (2012). AB - Northern elephant seals (Mirounga angustirostris Gill, 1866), inhabiting rookeries on the mainland of Ano Nuevo State Reserve in central California, were investigated in 2012 for presence of hookworms (Uncinaria spp.). Material collected and examined for hookworms included: blubber (n = 15), stomach and intestines (n = 21) from dead pups; feces from the rectum of weaned pups (n = 23); sand containing apparent feces in areas of weaned pups (n = 28) and sand without apparent feces in areas of weaned pups (n = 54); milk from females (n =23) at 5 days and about 23 to 26 days postpartum; and placenta from one female. Evidence of hookworm presence was not detected in any of the samples examined. Possible reasons why hookworms were not found in northern elephant seals on the mainland of Ano Nuevo State Reserve are discussed. PMID- 22543701 TI - Influence of the curvature of deformed graphene nanoribbons on their electronic and adsorptive properties: theoretical investigation based on the analysis of the local stress field for an atomic grid. AB - Electronic and adsorptive properties of deformed graphene are investigated in the current work. Armchair and zigzag nanoribbons are the subject of the study. The axial compression was a deforming load. A calculation method for the local stress field was developed. This method was based on the quantum model of the finite graphene nanoribbon and empirical calculation method of the single atom energy. The stress field of the deformed ribbon was calculated by means of the suggested methodology. The effects of the atomic grid curvature on the adsorptive capacity of graphene and the hydrogenation process was investigated by means of the developed method. The prediction of the appearance of defects on covalent C-C bond breakdown is also performed. PMID- 22543702 TI - Biphasic regulation of P-glycoprotein function and expression by NO donors in Caco-2 cells. AB - AIM: To investigate the effects of nitric oxide (NO) donors on the function and expression of P-glycoprotein (P-gp) in Caco-2 cells. METHODS: Caco-2 cells were exposed to NO donors for designated times. P-gp function and expression were assessed using Rhodamine123 uptake assay and Western blotting, respectively. Intracellular reactive oxygen species (iROS) and intracellular reactive nitrogen species (iRNS) levels were measured using ROS and RNS assay kits, respectively. RESULTS: Exposure of Caco-2 cells to 0.1 or 2 mmol/L of sodium nitroprusside (SNP) affected the function and expression of P-gp in concentration- and time dependent manners. A short-term (4 h) exposure reduced P-gp function and expression accompanied with significantly increased levels of iROS and iRNS. In contrast, a long-term (24 h) exposure stimulated the P-gp function and expression. The stimulatory effects of 2 mmol/L SNP was less profound as compared to those caused by 0.1 mmol/L SNP. The other NO donors SIN-1 and SNAP showed similar effects. Neither the NO scavenger PTIO (2 mmol/L) nor soluble guanylate cyclase inhibitor ODQ (50 MUmol/L) reversed the SNP-induced alteration of P-gp function. On the other hand, free radical scavengers ascorbate, glutathione and uric acid (2 mmol/L for each), PKC inhibitor chelerythrine (5 MUmol/L), PI3K/Akt inhibitor wortmannin (1 MUmol/L) and p38 MAPK inhibitor SB203580 (10 MUmol/L) reversed the upregulation of P-gp function by the long-term exposure to SNP, but these agents had no effect on the impaired P-gp function following the short-term exposure to SNP. CONCLUSION: NO donors time-dependently regulate P-gp function and expression in Caco-2 cells: short-term exposure impairs P-gp function and expression, whereas long-term exposure stimulates P-gp function and expression. The regulation occurs via a NO-independent mechanism. PMID- 22543703 TI - beta-Asarone protects PC12 cells against OGD/R-induced injury via attenuating Beclin-1-dependent autophagy. AB - AIM: To explore the effects of beta-asarone from Acorus Tatarinowii Schott on autophagy in an ischemic stroke model of PC12 cells. METHODS: The ischemic stroke model of PC12 cells was made by OGD/R (2 h oxygen-glucose deprivation followed by 24 h reperfusion). Drug administration was started 1 h before OGD and last for 3 h. Then the cells were incubated in the drug-free and full culture medium under normoxic conditions for 24 h. After the treatments, Beclin-1, intracellular free calcium concentration ([Ca(2+)](i)) and mitochondrial membrane potential (MMP) were analyzed using flow cytometry. Cell viability was measured using MTT assay. Cell morphology was studied under inverted phase contrast microscope, and autophagosomes were observed under transmission electron microscope. RESULTS: Pretreatment with beta-asarone (20, 30, or 45 MUg/mL) or the calcium channel antagonist nimodipine (10 MUmol/L) significantly increased the cell viability and MMP, and decreased Beclin-1 expression and [Ca(2+)](i) in OGD/R-treated PC12 cells. Under inverted phase contrast microscope, pretreatment with beta-asarone or nimodipine dramatically increase the number of cells and improved the cellular morphology. Autophagosomes were found in OGD/R-treated PC12 cells as well as in drug plus OGD/R-treated PC12 cells. CONCLUSION: beta-Asarone protects PC12 cells against OGD/R-induced injury partly due to attenuating Beclin-1-dependent autophagy caused by decreasing [Ca(2+)](i) and increasing MMP. PMID- 22543704 TI - Preclinical assessment of the distribution, metabolism, and excretion of S propargyl-cysteine, a novel H2S donor, in Sprague-Dawley rats. AB - AIM: To study the distribution, metabolism and excretion of S-propargyl-cysteine (SPRC), a novel hydrogen sulfide (H2S) donor, after oral administration in rats. METHODS: Adult Sprague-Dawley rats were used. The tissue distribution of [(35)S] SPRC-derived radioactivity was measured using a liquid scintillation counter. The plasma protein binding of SPRC was examined using 96-well equilibrium dialysis. The excretion of SPRC in urine, bile and feces was analyzed using the LC-MS/MS method. The major metabolites in rat biomatrices were identified using MRM information-dependent, acquisition-enhanced product ion (MRM-IDA-EPI) scans on API 4000QTrap system. RESULTS: After oral administration of [(35)S]-SPRC at a dose of 75 mg/kg, [(35)S] SPRC-derived radioactivity displayed broad biological distribution in various tissues of rats, including its target organs (heart and brain) with the highest in kidney. On the other hand, the binding of SPRC to human, rat and dog plasma protein was low. Only 2.18% +/- 0.61% and 0.77% +/- 0.61% of the total SPRC administered was excreted unchanged in the bile and urine. However, neither intact SPRC nor its metabolites were detected in rat feces. The major metabolic pathway in vivo (rat bile, urine, and plasma) was N acetylation. CONCLUSION: The preliminary results suggest that SPRC possesses acceptable pharmacokinetic properties in rats. PMID- 22543705 TI - Protective effects of tiopronin against high fat diet-induced non-alcoholic steatohepatitis in rats. AB - AIM: To study the protective effects of tiopronin against high fat diet-induced non-alcoholic steatohepatitis in rats. METHODS: Male Sprague-Dawley rats were given a high-fat diet for 10 weeks. The rats were administered tiopronin (20 mg/kg) or a positive control drug ursodeoxycholic acid (UDCA, 15 mg/kg) via gavage daily from week 5 to week 10. After the rats were sacrificed, serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), free fatty acids (FFA), high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C), and liver homogenate FFA, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) were measured using commercial analysis kits. The expression levels of CYP2E1 mRNA and protein were determined using RT-PCR and immunoblot assays, respectively. RESULTS: Tiopronin significantly lowered both the serum ALT and AST levels, while only the serum ALT level was lowered by UDCA. Tiopronin significantly decreased the serum and liver levels of TG, TC and FFA as well as the serum LDL-C level, and increased the serum HDL-C level, while UDCA decreased the serum and liver TC levels as well as the serum LDL-C level, but did not change the serum levels of TG, FFA and HDL-C. Tiopronin apparently ameliorated the hepatocyte degeneration and the infiltration of inflammatory cells in the livers, but UDCA did not affect the pathological features of the livers. Both tiopronin and UDCA ameliorated the mitochondrial abnormality in the livers. The benefits of tiopronin were associated with increased SOD and GSH-Px activities, and with decreased MDA activity and CYP2E1 expression in the livers. CONCLUSION: Tiopronin exerts protective effects against non-alcoholic steatohepatitis in rats, which may be associated with its antioxidant properties and regulation of lipid metabolism. PMID- 22543706 TI - E-cadherin promotes proliferation of human ovarian cancer cells in vitro via activating MEK/ERK pathway. AB - AIM: E-cadherin is unusually highly expressed in most ovarian cancers. This study was designed to investigate the roles of E-cadherin in the carcinogenesis and progression of ovarian cancers. METHODS: Human ovarian adenocarcinoma cell line SKOV-3 was examined. E-cadherin gene CDH1 in SKOV-3 cells was knocked down via RNA interference (RNAi), and the resultant variation of biological behavior was observed using CCK-8 and colony formation experiment. E-cadherin-mediated Ca(2+) dependent cell-cell adhesion was used to study the mechanisms underlying the effects of E-cadherin on the proliferation and survival of SKOV-3 cells. The expression levels of E-cadherin, extracellular signal-related kinase (ERK), phosphorylated ERK (P-ERK) were measured using Western blot assays. RESULTS: Transfection with CDH1-siRNA for 24-96 h significantly suppressed the growth and proliferation of SKOV-3 cells. E-cadherin-mediated calcium-dependent cell-cell adhesion of SKOV-3 cells resulted in a rapid increase of P-ERK, but did not modify the expression of ERK protein. The phosphorylation of ERK in the cells was blocked by pretreatment with the MEK1 specific inhibitor PD98059 (50 MUmol/L), but not by the PI3K inhibitor wortmannin (1 MUmol/L) or PKA inhibitor H89 (10 MUmol/L). CONCLUSION: E-cadherin may function as a tumor proliferation enhancer via activating the MEK/ERK pathway in development of ovarian epithelial cancers. PMID- 22543707 TI - The regulation of N-terminal Huntingtin (Htt552) accumulation by Beclin1. AB - AIM: Huntingtin protein (Htt) was a neuropathological hallmark in human Huntington's Disease. The study aimed to investigate whether the macroautophagy regulator, Beclin1, was involved in the degradation of Htt. METHODS: PC12 cells and primary cultured brain neurons of rats were examined. pDC316 adenovirus shuttle plasmid was used to mediate the expression of wild-type Htt-18Q-552 or mutant Htt-100Q-552 in PC12 cells. The expression of the autophagy-related proteins LC3 II and Beclin1, as well as the lysosome-associated enzymes Cathepsin B and L was evaluated using Western blotting. The locations of Beclin1 and Htt were observed with immunofluorescence and confocal microscope. RESULTS: Htt552 expression increased the expression of LC3 II, Beclin1, cathepsin B and L in autophagy/lysosomal degradation pathway. Treatment with the autophagy inhibitor 3 MA or the proteasome inhibitors lactacystin and MG-132 increased Htt552 levels in PC12 cells infected with Ad-Htt-18Q-552 or Ad-Htt-100Q-552. The proteasome inhibitor caused a higher accumulation of Htt552-18Q than Htt552-100Q, and the autophagy inhibitor resulted in a higher accumulation of Htt552-100Q than Htt552 18Q. Similar results were observed in primary cultured neurons infected with adenovirus. In Htt552-expressing cells, Beclin1 was redistributed from the nucleus to the cytoplasm. Htt siRNA prevented Beclin1 redistribution in starvation conditions. Blockade of Beclin1 nuclear export by leptomycin B or Beclin1 deficiency caused by RNA interference induced the formation of mHtt552 aggregates. CONCLUSION: Beclin1 regulates the accumulation of Htt via macroautophagy. PMID- 22543709 TI - Surgical menopause: still confused after all these years. PMID- 22543708 TI - Hedgehog signaling pathway mediates invasion and metastasis of hepatocellular carcinoma via ERK pathway. AB - AIM: To investigate the role of Hedgehog (Hh) signaling pathway in the invasion and metastasis of human hepatocellular carcinoma (HCC). METHODS: Eighty six HCC tissues samples and HCC cell line Bel-7402 were examined. The protein expression of sonic hedgehog (Shh), nuclear glioma-associated oncogene-1 (Gli1), MMP-9 and p ERK1/2 in HCC was analyzed using immunohistochemistry and Western blot analysis. Boyden chamber assay and wound-healing assay were used to quantify the invasion and metastasis of Bel-7402 cells. RESULTS: In 86 HCC tissue samples, the positive ratio of Shh and nucleus Gli1 was 67.44% (58/86) and 60.47% (52/86), respectively; the expression of nucleus Gli1 was correlated with the tumor pathological grade (P=0.034), and with the ability of the tumor to invade and metastasize (P=0.001); the expression of nucleus Gli1 was also correlated with p ERK1/2 (P=0.031) and with MMP-9 (P=0.034). Neither Shh, nor nucleus Gli1 was observed in normal liver tissue. KAAD-cyclopamine (KAAD-cyc), a specific inhibitor of the Hh pathway, at the concentrations of 1 and 4 MUmol/L inhibited the invasion and migration of Bel-7402 cells and decreased the expression of Gli1 in nucleus and MMP-9, p-ERK1/2 proteins in Bel-7402 cells. On the other hand, Shh, a ligand of the Hh pathway, at the concentration of 0.5 MUg/mL produced opposite effects. The MAPK pathway inhibitors U0126 and PD98059 at the concentrations of 5 and 10 MUmol/L inhibited invasion and metastasis of Bel-7402 cells induced by Shh, and decreased the expression of p-ERK1/2 and MMP-9. However, U0126 and PD98059 had no effect on the expression of Gli1. CONCLUSION: Hh signaling pathway mediates invasion and metastasis of human HCC by up regulating the protein expression of MMP-9 via ERK pathway. PMID- 22543710 TI - Room temperature self-healing power of silicone elastomers having silver nanoparticles as crosslinkers. AB - Thiol-functionalised silicone-oils were crosslinked with silver nanoparticles to give mechanically consistent elastomers with high self-healing power. The materials were broken into small pieces and put together in intimate contact for 24 hours at room temperature, observing a complete macroscopic healing and a quantitative recovery of compression-stress and strain. PMID- 22543712 TI - Metabolomic study of plasma of patients with abdominal aortic aneurysm. AB - Abdominal aortic aneurysm (AAA) is an important health problem, both because of AAA rupture and death and because of increased cardiovascular mortality. Identification of new biomarkers of AAA may suggest novel pathological mechanisms and targets for new medical treatments to slow AAA progression. Metabolic changes in AAA patients were mainly related to carbohydrate and lipid metabolism and many of these changes can be associated with a situation of insulin resistance (which can be related to metabolic syndrome) together with altered amino acid metabolism. For the first time, metabolites that can be associated with differential metabolism by the gut microflora of AAA patients have also been found. Moreover, aminomalonic acid in plasma has been shown to be the metabolite with the biggest difference between patients suffering from large aneurysm (>5 cm) and controls. PMID- 22543713 TI - Analysis of carbon and nitrogen co-metabolism in yeast by ultrahigh-resolution mass spectrometry applying 13C- and 15N-labeled substrates simultaneously. AB - Alternative metabolic pathways inside a cell can be deduced using stable isotopically labeled substrates. One prerequisite is accurate measurement of the labeling pattern of targeted metabolites. Experiments are generally limited to the use of single-element isotopes, mainly (13)C. Here, we demonstrate the application of direct infusion nanospray, ultrahigh-resolution Fourier transform ion cyclotron resonance-mass spectrometry (FTICR-MS) for metabolic studies using differently labeled elemental isotopes simultaneously--i.e., (13)C and (15)N--in amino acids of a total protein hydrolysate. The optimized strategy for the analysis of metabolism by a hybrid linear ion trap-FTICR-MS comprises the collection of multiple adjacent selected ion monitoring scans. By limiting both the width of the mass range and the number of ions entering the ICR cell with automated gain control, sensitive measurements of isotopologue distribution were possible without compromising mass accuracy and isotope intensity mapping. The required mass-resolving power of more than 60,000 is only achievable on a routine basis by FTICR and Orbitrap mass spectrometers. Evaluation of the method was carried out by comparison of the experimental data to the natural isotope abundances of selected amino acids and by comparison to GC/MS results obtained from a labeling experiment with (13)C-labeled glucose. The developed method was used to shed light on the complexity of the yeast Saccharomyces cerevisiae carbon nitrogen co-metabolism by administering both (13)C-labeled glucose and (15)N labeled alanine. The results indicate that not only glutamate but also alanine acts as an amino donor during alanine and valine synthesis. Metabolic studies using FTICR-MS can exploit new possibilities by the use of multiple-labeled elemental isotopes. PMID- 22543711 TI - Resolving brain regions using nanostructure initiator mass spectrometry imaging of phospholipids. AB - In a variety of neurological diseases, pathological progression is cell type and region specific. Previous reports suggest that mass spectrometry imaging has the potential to differentiate between brain regions enriched in specific cell types. Here, we utilized a matrix-free surface mass spectrometry approach, nanostructure initiator mass spectrometry (NIMS), to show that spatial distributions of multiple lipids can be used as a 'fingerprint' to discriminate between neuronal- and glial- enriched brain regions. In addition, glial cells from different brain regions can be distinguished based on unique lipid profiles. NIMS images were generated from sagittal brain sections and were matched with immunostained serial sections to define glial cell enriched areas. Tandem mass spectrometry (LC-MS/MS QTOF) on whole brain extracts was used to identify 18 phospholipids. Multivariate statistical analysis (Nonnegative Matrix Factorization) enhanced differentiation of brain regions and cell populations compared to single ion imaging methods. This analysis resolved brain regions that are difficult to distinguish using conventional stains but are known to have distinct physiological functions. This method accurately distinguished the frontal (or somatomotor) and dorsal (or retrosplenial) regions of the cortex from each other and from the pons region. PMID- 22543714 TI - In vivo skin leptin modulation after 14 MeV neutron irradiation: a molecular and FT-IR spectroscopic study. AB - This paper discusses gene expression changes in the skin of mice treated by monoenergetic 14 MeV neutron irradiation and the possibility of monitoring the resultant lipid depletion (cross-validated by functional genomic analysis) as a marker of radiation exposure by high-resolution FT-IR (Fourier transform infrared) imaging spectroscopy. The irradiation was performed at the ENEA Frascati Neutron Generator (FNG), which is specifically dedicated to biological samples. FNG is a linear electrostatic accelerator that produces up to 1.0 * 10(11) 14-MeV neutrons per second via the D-T nuclear reaction. The functional genomic approach was applied to four animals for each experimental condition (unirradiated, 0.2 Gy irradiation, or 1 Gy irradiation) 6 hours or 24 hours after exposure. Coregulation of a subclass of keratin and keratin-associated protein genes that are physically clustered in the mouse genome and functionally related to skin and hair follicle proliferation and differentiation was observed. Most of these genes are transiently upregulated at 6 h after the delivery of the lower dose delivered, and drastically downregulated at 24 h after the delivery of the dose of 1 Gy. In contrast, the gene coding for the leptin protein was consistently upregulated upon irradiation with both doses. Leptin is a key protein that regulates lipid accumulation in tissues, and its absence provokes obesity. The tissue analysis was performed by monitoring the accumulation and the distribution of skin lipids using FT-IR imaging spectroscopy. The overall picture indicates the differential modulation of key genes during epidermis homeostasis that leads to the activation of a self-renewal process at low doses of irradiation. PMID- 22543715 TI - Laser ablation ICP-MS for quantitative biomedical applications. AB - LA-ICP-MS allows precise, relatively fast, and spatially resolved measurements of elements and isotope ratios at trace and ultratrace concentration levels with minimal sample preparation. Over the past few years this technique has undergone rapid development, and it has been increasingly applied in many different fields, including biological and medical research. The analysis of essential, toxic, and therapeutic metals, metalloids, and nonmetals in biomedical tissues is a key task in the life sciences today, and LA-ICP-MS has proven to be an excellent complement to the organic MS techniques that are much more commonly employed in the biomedical field. In order to provide an appraisal of the fast progress that is occurring in this field, this review critically describes new developments for LA-ICP-MS as well as the most important applications of LA-ICP-MS, with particular emphasis placed on the quantitative imaging of elements in biological tissues, the analysis of heteroatom-tagged proteins after their separation and purification by gel electrophoresis, and the analysis of proteins that do not naturally have ICP-MS-detectable elements in their structures, thus necessitating the use of labelling strategies. PMID- 22543716 TI - Lateral-flow immunoassays for mycotoxins and phycotoxins: a review. AB - Natural toxin (for example mycotoxin and phycotoxin) contamination of food is of safety and economic concern, so much effort is devoted to the development of screening methods which enable the toxins to be continuously and widely monitored in food and feed. More generally speaking, rapid and non-instrumental assays for detection of a variety of food contaminants are generating ever-increasing scientific and technological interest because they enable high-throughput, economical, on-site monitoring of such contaminants. Among rapid methods for first-level screening of food contaminants, lateral-flow immunoassay (LFIA), also named immunochromatographic assay or immune-gold colloid immunoassay, has recently attracted scientific and industrial interest because of its attractive property of enabling very rapid, one-step, in-situ analysis. This review focuses on new aspects of the development and optimization of lateral-flow devices for mycotoxin and phycotoxin detection, including strategies for management of matrix interference and, particularly, for investigation of the improvements achieved by signal-enhancing strategies or by application of non-gold nanoparticle signal reporters. PMID- 22543717 TI - Benefits of postpartum vitamin A supplementation. PMID- 22543718 TI - A business model for managing system change through strategic financing and performance indicators: a case study. AB - This article describes how a system of care operated by a county government agency used a fiscal crisis as the opportunity to reform its children's system. A cross-system response to the crisis is outlined that includes a system of care framework coupled with a business model, inter-departmental collaboration and leadership, the use of strategic reinvestment strategies, and a quality improvement system that focuses on key indicators. Implementation of the system change is described with a specific focus on cross-system entry points, financing strategies that re-allocate funds from deep-end programs to community-based services, and management oversight through the use of performance indicators to monitor and support effectiveness. This article examines the results of the system change, including the diversion of youth from system penetration, the reduction in residential treatment bed days, the re-allocation of these savings to community-based services, and the outcomes of children who were diverted from residential care and served in the community. The article offers a number of recommendations for other communities contemplating system change. PMID- 22543719 TI - Sustaining and expanding systems of care to provide mental health services for children, youth and families across America. AB - The Substance Abuse and Mental Health Services Administration has been instrumental in supporting the development and implementation of systems of care to provide services to children and youth with serious mental health conditions and their families. Since 1993, 173 grants have been awarded to communities in all 50 states, Puerto Rico, Guam, the District of Columbia, and 21 American Indian/Alaska Native communities. The system of care principles of creating comprehensive, individualized services, family-driven and youth-guided care and cultural and linguistic competence, supported by a well-trained and competent workforce, have been successful in transforming the field of children's mental health and facilitating the integration of child-serving systems. This approach has achieved positive outcomes at the child and family, practice and system levels, and numerous articles have been published using data collected from system of care communities, demonstrating the effectiveness of this framework. This article will describe lessons learned from implementing the system of care approach, and will discuss the importance of expanding and sustaining systems of care across the country. PMID- 22543720 TI - Impact of anemia on surgical outcomes: innovative interventions in resource-poor settings. AB - BACKGROUND: The aim of this work was to study the impact of anemia on surgical outcomes and the impact of instituting appropriate workup and treatment of anemia on surgical outcomes. METHODS: We conducted a case-control retrospective chart review of all hernia repair, hydrocele repair, and hysterectomy cases at the SEARCH Hospital in Gadchiroli, India, from January 2008 to April 2010, and included 340 male and 112 female surgical patients. We also performed a prospective assessment of the impact of the institution of appropriate workup and treatment of anemia on the surgical outcomes for all hernia repair, hydrocele repair, and hysterectomy cases at SEARCH from May 2010 to May 2011 and included 138 male and 76 female surgical patients. RESULTS: The retrospective arm of the study included 340 males and 112 females with a median age of 39 and 41 years, respectively. The mean hemoglobin values were 12.50 (range = 8.8-15.4) for men and 10.39 (range = 5.2-14.8) for women. Patients with anemia had (1) increased incidence of spinal headache after inguinal hernia repair (p = 0.0266) and (2) increased incidence of fever after total hysterectomy (p = 0.0070). There was no statistically significant correlation between anemia and other outcomes (all p > 0.05). The prospective arm of the study included 138 males and 76 females with a median age of 35 and 40, respectively. The mean hemoglobin values were 11.8 (range = 6.4-14.8) for men and 10.6 (range = 6.9-12.8) for women. There was no statistically significant correlation between anemia and any surgical outcomes (p > 0.05). The incidence of complications in both the retrospective and the prospective arm was compared according to increasing severity of anemia across genders. Overall, there was no statistically significant increase in complication rates with increasing severity of anemia (p > 0.05). CONCLUSIONS: In the retrospective arm of this study, anemia was associated with increased incidence of spinal headache and fever. In the prospective arm of this study, there was no statistically significant correlation between anemia and any surgical outcome. The incidence of complications did not increase with the severity of anemia in either arm of the study. Further investigation is needed into the optimal management and treatment of anemia prior to surgery in resource-poor settings. PMID- 22543721 TI - Lack of uniformity in levels of evidence and recommendation grades in surgical oncology guidelines. PMID- 22543722 TI - Leech infestation in children through body orifices: experience in a hospital in Bangladesh. AB - INTRODUCTION: Bangladesh harbors many leeches in its vast wetlands. Leeches have a tendency to enter through body orifices with potentially life-threatening consequences. Literature search revealed inadequate description of clinical manifestations and treatment of leech infestations in children. We describe our experience with leech infestations in children. METHODS: Between January 1, 2004 and December 31, 2010, 17 cases of leech infestation through body orifices in children were managed. This is a retrospective study on age, sex, route of leech entry, investigation and treatment, and outcome. RESULTS: Age ranged from 4.5 to 11 years (mean 6.4 +/- 1.8) and females accounted for more than 70 %. The orifices of leech entry include urethra, vagina, and rectum. Leeches could be found in eight cases. Two boys with leeches in the urinary bladder needed suprapubic removal. Leeches were retrieved from the vagina under general anesthesia in three cases, and on three occasions leeches came out from the vagina after normal saline instillation. In nine cases with different routes of entry where leech was not found, instillation of normal saline was sufficient to stop bleeding. Fifteen cases presented with bleeding and transfusion was required in five cases with Hb% <7 gm/dl. CONCLUSIONS: Leech infestation through lower body orifices is common in children of rural Bangladesh. Prompt diagnosis is of paramount importance, and application of normal saline is effective in most cases. Sometimes surgical intervention is required. PMID- 22543723 TI - Diagnosing appendicitis at different time points in children with right lower quadrant pain: comparison between pediatric appendicitis score and the Alvarado score. PMID- 22543724 TI - Comparative proteome analysis of drought-sensitive and drought-tolerant rapeseed roots and their hybrid F1 line under drought stress. AB - Rapeseed (Brassica napus L.), which is the third leading source of vegetable oil, is sensitive to drought stress during the early vegetative growth stage. To investigate the initial response of rapeseed to drought stress, changes in the protein expression profiles of drought-sensitive (RGS-003) and drought-tolerant lines (SLM-003), and their F1 hybrid, were analyzed using a proteomics approach. Seven-day-old rapeseed seedlings were treated with drought stress by restricting water for 7 days, and proteins were extracted from roots and separated by two dimensional polyacrylamide gel electrophoresis. In the sensitive rapeseed line, 35 protein spots were differentially expressed under drought stress, and proteins related to metabolism, energy, disease/defense, and transport were decreased. In the tolerant line, 32 protein spots were differentially expressed under drought stress, and proteins involved in metabolism, disease/defense, and transport were increased, while energy-related proteins were decreased. Six protein spots in F1 hybrid were common among expressed proteins in the drought-sensitive and tolerant lines. Notably, tubulin beta-2 and heat shock protein 70 were decreased in the drought-sensitive line and hybrid F1 plants, while jasmonate-inducible protein and 20S proteasome subunit PAF1 were increased in the F1 hybrids and drought-tolerant line. These results indicate that (1) V-type H(+) ATPase, plasma membrane associated cation-binding protein, HSP 90, and elongation factor EF-2 have a role in the drought tolerance of rapeseed; (2) The decreased levels of heat shock protein 70 and tubulin beta-2 in the drought-sensitive and hybrid F1 lines might explain the reduced growth of these lines in drought conditions. PMID- 22543726 TI - Trends in mortality by labour market position around retirement ages in three European countries with different welfare regimes. AB - OBJECTIVES: In the face of economic downturn and increasing life expectancy, many industrial nations are adopting a policy of postponing the retirement age. However, questions still remain around the consequence of working longer into old age. We examine mortality by work status around retirement ages in countries with different welfare regimes; Finland (social democratic), Turin (Italy; conservative), and England and Wales (liberal). METHODS: Death rates and rate ratios (RRs) (reference rates = 'in-work'), 1970 s-2000 s, were estimated for those aged 45-64 years using the England and Wales longitudinal study, Turin longitudinal study, and the Finnish linked register study. RESULTS: Mortality of the not-in-work was consistently higher than the in-work. Death rates for the not in-work were lowest in Turin and highest in Finland. Rate ratios were smallest in Turin (RR men 1972-76 1.73; 2002-06 1.63; women 1.22; 1.68) and largest in Finland (RR men 1991-95 3.03; 2001-05 3.80; women 3.62; 4.11). Unlike RRs for men, RRs for women increased in every country (greatest in Finland). CONCLUSIONS: These findings signal that overall, employment in later life is associated with lower mortality, regardless of welfare regime. PMID- 22543725 TI - Regulation of leucine catabolism by metabolic fuels in mammary epithelial cells. AB - Lactation is associated with elevated catabolism of branched-chain amino acids (BCAA) in mammary glands to produce glutamate, glutamine, alanine, aspartate, and asparagine. This study determined effects of metabolic fuels on the catabolism of leucine (a representative BCAA) in bovine mammary epithelial cells. Cells were incubated at 37 degrees C for 2 h in Krebs buffer containing 0.5 mM L-leucine and either L-[1-(14)C]leucine or L-[U-(14)C]leucine. The medium also contained 0 5 mM D-glucose, 0-2 mM L-glutamine, 0-4 mM DL-beta-hydroxybutyrate, or 0-2 mM oleic acid. Rates of leucine decarboxylation were 60 % lower, but rates of alpha ketoisocaproate production were 34 % higher, in the presence of 2 mM glucose than in its absence. All variables of leucine catabolism did not differ between 2 and 5 mM glucose or between 0 and 4 mM DL-beta-hydroxybutyrate. Compared with 0-0.25 mM glutamine, 0.5 and 2 mM L-glutamine reduced leucine transport, transamination, and decarboxylation. In contrast, increasing the concentration of oleic acid from 0 to 2 mM dose-dependently stimulated leucine transamination, decarboxylation, and oxidation of carbons 2-6. Oleic acid also enhanced the abundance of cytosolic BCAA transaminase, while reducing the phosphorylated level (inactive state) of the E1alpha subunit of the mitochondrial branched-chain alpha-ketoacid dehydrogenase complex. Thus, hypoglycemia or ketosis in early lactation does not likely affect BCAA metabolism in mammary epithelial cells. Increasing circulating levels of BCAA and oleic acid may have great potential to increase the syntheses of glutamate, glutamine, aspartate, alanine, and asparagine by lactating mammary glands, thereby leading to enhanced production of milk for suckling neonates. PMID- 22543727 TI - A label-free fluorescent molecular beacon based on DNA-templated silver nanoclusters for detection of adenosine and adenosine deaminase. AB - A simple and reliable fluorescent molecular beacon is developed utilizing DNA templated silver nanoclusters as a signal indicator and adenosine triphosphate (ATP) and adenosine deaminase as mechanical activators. PMID- 22543728 TI - Stress-induced domain dynamics and phase transitions in epitaxially grown VO2 nanowires. AB - We demonstrate that surface stresses in epitaxially grown VO2 nanowires (NWs) have a strong effect on the appearance and stability of intermediate insulating M2 phases, as well as the spatial distribution of insulating and metallic domains during structural phase transitions. During the transition from an insulating M1 phase to a metallic R phase, the coexistence of insulating M1 and M2 phases with the absence of a metallic R phase was observed at atmospheric pressure. In addition, we show that, for a VO2 NW without the presence of an epitaxial interface, surface stresses dominantly lead to spatially inhomogeneous phase transitions between insulating and metallic phases. In contrast, for a VO2 NW with the presence of an epitaxial interface, the strong epitaxial interface interaction leads to additional stresses resulting in uniformly alternating insulating and metallic domains along the NW length. PMID- 22543729 TI - Changes needed? PMID- 22543730 TI - Jupiter Scleral Lenses: the UC Davis Eye Center experience. AB - PURPOSE: The aim of this study was to evaluate both the indications for and results of fitting the Jupiter Scleral Lens in patients with corneal abnormalities. METHOD: This was a retrospective case review of 63 patients (107 eyes) fitted with scleral lenses between October 2009 and March 2011 at the UC Davis Eye Center. RESULTS: Sixty-three percent of 107 eyes were in patients with keratoconus. Other conditions included high postkeratoplasty astigmatism and corneal scarring. The improvement in best-corrected visual acuity compared with previous contact lens or glasses correction was a mean gain of 3.5 Snellen lines (SD=2.6). Seventy-eight percent of patients found the scleral lenses to be comfortable or comfortable. Twenty-five eyes discontinued the wear after at least 3 months. CONCLUSIONS: Jupiter Scleral lenses are a good alternative for patients with corneal abnormalities and for those who failed other types of lens rehabilitation. Seventy-seven percent of eyes fit with Jupiter Scleral Lenses were still wearing after a follow-up of 3 months. PMID- 22543731 TI - Clinical significance of tear menisci in dry eye. AB - PURPOSE: To determine the relationships among tear menisci variables and clinical tests used in the diagnosis of dry eye patients. METHODS: Dry eye patients (n=50; age, 35.2 years) and healthy subjects (n=48; age, 33.3 years) were recruited. Upper and lower tear menisci were imaged noninvasively by optical coherence tomography (OCT) immediately after normal and delayed blinking in both eyes. Tear meniscus heights, areas, and radius of curvatures were obtained by custom software. Tear film break-up time was measured by fluorescein (fluorescein film tear break-up time, FTBUT) and tearscope (noninvasive tear film break-up time), ocular surface vital staining was evaluated with fluorescein (FS), and secretion was measured by Schirmer I test without and with anesthesia. RESULTS: In dry eye patients, all lower tear meniscus variables during normal blinking were correlated with all clinical tests except Schirmer I test without anesthesia. Upper tear meniscus variables were correlated with FTBUT and Schirmer I test with anesthesia. During delayed blinking, upper and lower tear menisci variables were correlated with Schirmer I test without anesthesia and FS; however, there were no correlations between menisci variables and FTBUT or Schirmer I test with anesthesia. In healthy subjects, only lower meniscus variables were correlated with Schirmer I test with anesthesia during normal blinking. During delayed blinking, the lower meniscus variables were correlated with only the Schirmer I test without anesthesia. CONCLUSIONS: Lower tear menisci were correlated more strongly with the clinical tests than were upper menisci. The tear menisci were associated with the basic tear secretion during normal blinking. Delayed blinking may affect reflex tearing levels. PMID- 22543732 TI - Development of methicillin-resistant Staphylococcus aureus keratitis in a dry eye patient with a therapeutic contact lens. AB - PURPOSE: The aim was to report a case of methicillin-resistant Staphylococcus aureus (MRSA) keratitis possibly associated with the use of a silicone hydrogel soft contact lens in a patient with dry eye. METHODS: This is a case report. RESULTS: A 61-year-old woman who wore a silicone hydrogel lens as therapy for filamentary keratitis with severe dry eye presented with pain and redness in her left eye. She developed severe keratitis with ulceration and hypopyon. The MRSA grew in the culture, and intensive systemic and topical antibiotics resolved the corneal keratitis. CONCLUSIONS: The MRSA may cause infectious keratitis associated with silicone hydrogel contact lens therapy. PMID- 22543733 TI - Risk factors for neurological complications and sequelae in childhood acute bacterial meningitis. PMID- 22543734 TI - Chiral proton catalysis of secondary nitroalkane additions to azomethine: synthesis of a potent GlyT1 inhibitor. AB - The first enantioselective synthesis of a potent GlyT1 inhibitor is described. A 3-nitroazetidine donor is used in an enantioselective aza-Henry reaction catalyzed by a bis(amidine)-triflic acid salt organocatalyst, delivering the key intermediate with 92% ee. This adduct is reductively denitrated and converted to the target through a short sequence, thereby allowing assignment of the absolute configuration of the more potent enantiomer. PMID- 22543735 TI - Exercise speeds cutaneous wound healing in high-fat diet-induced obese mice. AB - PURPOSE: Obesity has been shown to impair cutaneous wound healing, which is associated with increased wound inflammation. Exercise is known to decrease obesity-associated inflammation and has been shown to speed cutaneous wound healing in aged mice. Therefore, we investigated whether treadmill exercise could speed cutaneous wound healing in obese, high-fat diet-fed mice. METHODS: We fed female C57Bl/6J mice a high-fat diet (45% calories from fat) for 16 wk to induce a state of obesity and insulin resistance. Mice then ran on a treadmill for 3 d before excisional wounding. On day 4, mice were wounded 1 h after exercise. Mice then exercised for 5 d after wounding, and healing was assessed by photoplanimetry for 10 d. RESULTS: As described previously, obesity impaired wound healing, with significantly larger wound sizes measured from days 3 to day 10 after wounding (P < 0.05). Exercise did not improve healing in lean mice fed a normal chow diet. However, wound size was significantly smaller in exercised obese mice compared with their lean counterparts (P < 0.05 at day 1, day 4, and day 5 after wound). Surprisingly, we were unable to detect any differences in gene or protein expression of proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha or the anti-inflammatory cytokine interleukin-10 in the wounds. Likewise, there were no differences in gene expression of chemokines monocyte chemoattractant protein-1 and keratinocyte chemoattractant or of growth factor platelet-derived growth factor in wounds of exercise and sedentary mice. CONCLUSION: This suggests an effect of exercise independent of alterations in inflammation. Future work should focus on early events after wounding, including exercise effects on hemostasis and myofibroblast function. PMID- 22543736 TI - Cardiorespiratory fitness, fatness, and blood pressure associations in Nigerian youth. AB - PURPOSE: This study aimed to examine the independent associations of cardiorespiratory fitness (CRF) and body fatness with resting blood pressure (BP) in children (9-11 yr) and adolescents (12-15 yr) in Benue State of Nigeria. METHODS: A total of 3243 children (n = 1017) and adolescents (n = 2226) were evaluated for aerobic fitness, body fatness, resting preexercise BP and recovery BP at minutes 1, 5, and 10 after a progressive aerobic cardiovascular endurance run test. Regression models, controlling for age and recovery BP at 1, 5, and 10 min after the progressive aerobic cardiovascular endurance run, determined the associations of independent variables with the dependent variables. RESULTS: Fatness and fitness were independent predictors of resting BP among participants, and the relationship of fatness with BP was more robust in adolescents than in children. In all cases, the relationships were stronger in boys than in girls. Combined fitness and fatness in predicting BP was modest (R(2) = 1%-3%) after controlling for age and postexercise BP. Postexercise BP was a major determinant of resting BP in both groups (R(2) = 23%-93%). In adolescents, fatter boys had 1.9 times likelihood of systolic HTN compared with leaner peers. Systolic and diastolic BP scores varied by fit-fat groups, the fit-low-fat group demonstrated the most favorable BP profiles, whereas the unfit-high-fat group showed the most adverse profiles. CONCLUSIONS: Irrespective of fatness, participants with higher CRF had more favorable BP profiles compared with their fat-unfit peers. PMID- 22543737 TI - Repolarization perturbation and hypomagnesemia after extreme exercise. AB - PURPOSE: Strenuous exercise induces significant increases in inflammatory and cardiac biomarkers and transient dysfunction of the left ventricle. It is still unclear whether the electrophysiological correlate of these alterations can also be observed in ECG recordings, which indicate increased vulnerability for arrhythmias. METHODS: ECG parameters were measured and compared with inflammatory and electrolyte statuses in 198 healthy men (42 +/- 9 yr) 1 wk before (baseline) and at 0, 24, and 72 h after participating in a marathon. RESULTS: HR-corrected QT interval (QTc) duration increased significantly immediately after the race (442.4 +/- 23.0 ms) compared with baseline (415.3 +/- 22.5 ms, P < 0.001) and returned to baseline values within 72 h (415.8 +/- 24.7 ms). Other indices of ventricular repolarization (Sagie-Framingham-corrected QTcF, T(peak)-Tend (T(pe)) duration, T(pe)/QT ratio) showed similar results.Compared with baseline, significant decreases in serum concentrations of magnesium and potassium were shown immediately after the race (median (interquartile range): [Mg(2+)] = 0.85 (0.79-0.92) vs 0.77 (0.70-0.82) mmol . L(-1), P < 0.001; [K+] = 4.27 (4.02-4.58) vs 4.14 (3.81-4.57) mmol . L(-1), P < 0.05). Interleukin 6 values were significantly augmented immediately after the race compared with baseline (interleukin 6 = 2.08 (1.96-2.20) vs 30.56 (19.83-43.63) ng . L, P < 0.001) and returned to baseline values within 72 h.Significant associations were not observed between ECG alterations and inflammatory or electrolyte concentrations (all P > 0.05). CONCLUSIONS: Cardiac repolarization was significantly altered immediately after a marathon, coincident with hypomagnesemia and hypokalemia. Inflammatory and electrolyte statuses returned to baseline values within 72 h. The current data do not support that ECG alterations after marathon running represent an increased risk for arrhythmic events. However, further investigation is warranted to describe these relationships in more detail. PMID- 22543738 TI - Physical activity levels and patterns of 19-month-old children. AB - PURPOSE: It is a commonly held perception that most young children are naturally active and meet physical activity recommendations. However, there is no scientific evidence available on which to confirm or refute such perceptions. The purpose of this study was to describe the physical activity levels and patterns of Australian toddlers. METHODS: Physical activity and demographic data of two hundred ninety-five 19-month-old children from the Melbourne InFANT Program were measured using accelerometers and parent surveys. Validated cut points of 192 1672 and >1672 counts per minute were used to determine time spent in light- (LPA) and moderate-to-vigorous- (MVPA) intensity physical activity, respectively. To be included in the analysis, children were required to have four valid days of accelerometer data to provide an acceptable (>0.70) reliability estimate of LPA and MVPA. Physical activity data for different periods of the day were examined. RESULTS: On average, toddlers engaged in 184 min of LPA and 47 min of MVPA daily, and 90.5% met the current Australian physical activity recommendations for 0- to 5-yr-olds (180 min of LPA/MVPA per day). Physical activity levels during mid morning and mid afternoon were higher than those during other periods. Physical activity patterns for boys and girls were similar, although boys engaged in more physical activity during the morning hours than girls did. CONCLUSIONS: Most children meet the physical activity recommendations, although the majority of activity undertaken in the study was of light intensity. Boys were more active than girls were in the morning hours, but there were no differences between sexes over the entire day. Certain periods of the day may hold more promise for intervention implementation than others do. PMID- 22543739 TI - Effects of dehydration during cycling on skeletal muscle metabolism in females. AB - INTRODUCTION: This study investigated the effects of progressive dehydration on the time course of changes to whole body substrate oxidation and skeletal muscle metabolism during 120 min of cycling in hydrated females. METHODS: Subjects (n = 9) cycled for 120 min at approximately 65% VO(2peak) on two occasions: with no fluid (DEH) and with fluid (HYD) replacement to match sweat losses. Venous blood samples were taken at rest and every 20 min and muscle biopsies taken at 0, 60, and 120 min of exercise. RESULTS: DEH subjects lost 0.9% body mass from 0 to 60 min and 1.1% from 60 to 120 min (2.0% total). HR and core temperature (Tc) were significantly greater from 30 to 120 min, plasma volume (Pvol) loss from 40 to 120 min, and RPE from 60 to 120 min in the DEH trial. There were no differences in VO(2) or sweat loss between trials. RER (HYD, 0.85 +/- 0.01, vs. DEH, 0.87 +/- 0.01) and total CHO oxidation (175 +/- 17 vs. 191 +/- 17 g) were higher in the DEH trial. Blood (La) was significantly higher in the DEH trial, with no change in plasma free fatty acid and epinephrine concentrations. Muscle glycogenolysis was 31% greater in the DEH trial (252 +/- 49 vs. 330 +/- 33 mmol.kg(-1) dry muscle), and muscle (La) was also higher at 60 min. CONCLUSION: Progressive dehydration significantly increased HR, Tc, RPE, Pvol loss, whole body CHO oxidation, and muscle glycogenolysis, and these changes were already apparent in the first hour of exercise when body mass losses were <= 1%. The increased muscle glycogenolysis with DEH appeared to be due to increased core and muscle temperature, secondary to less efficient movement of heat from the core to the periphery. PMID- 22543740 TI - Acute exercise modulates BDNF and pro-BDNF protein content in immune cells. AB - PURPOSE: Although several studies have shown that immune cells stimulated by in vitro stress are capable to produce neurotrophins, there is still no evidence whether physiological stress, such as exercise, can modulate the in vivo levels of brain-derived neurotrophic factor (BDNF) in peripheral blood mononuclear cells (PBMCs). METHODS: This work investigated whether acute exercise modulates the expression of BDNF, pro-BDNF, and p75(NTR) in the PBMCs of 10 healthy young men who performed a cycling incremental test to exhaustion (MAX) or exercised at individual anaerobic threshold (IAT). The PBMC expression of stress response proteins and the level of circulating BDNF, vascular endothelial growth growth factor, platelet-derived growth factor subunit B, basic fibroblast growth factor pro-inflammatory, and anti-inflammatory cytokines were analyzed as well. RESULTS: A major finding is that both sessions of acute exercise regulated the content of BDNF isoforms within PBMCs in a manner related to the physiological stress exerted. Although the pro-BDNF increased after both MAX and IAT protocols, BDNF showed a kinetics dependent on exercise type: MAX induced a 54% protein increase immediately after exercise, followed by a significant drop 60 min after its conclusion (38% lower than the baseline). Differently, in the IAT, BDNF increased significantly up to 75% from the baseline throughout the recovery phase. All physiological parameters, as well as the p75(NTR) receptor and the stress inducible proteins, were also differently regulated by the two exercise conditions. CONCLUSIONS: These data supported the hypothesis that PBMCs might produce and secrete BDNF isoforms, as well as modulate the proteins p75(NTR) , Bcl-xL, hsp90, hsp27, and alphaB-crystallin, as part of the physiological stress response induced by acute exercise, offering a novel example of bidirectional interaction between nervous and immune systems. PMID- 22543741 TI - Vigorous-intensity leisure-time physical activity and risk of major chronic disease in men. AB - PURPOSE: Although studies have shown health benefits for moderate-intensity physical activity, there is limited evidence to support beneficial effects for high amounts of vigorous activity among middle-age and older men. The objective of this study was to examine the relationship between vigorous-intensity physical activity, compared with moderate-intensity activity, and risk of major chronic disease in men. METHODS: We prospectively examined the associations between vigorous- and moderate-intensity physical activity and risk of major chronic disease among 44,551 men age 40-75 yr in 1986. Leisure-time physical activity was assessed biennially by questionnaire. During 22 yr of follow-up, we documented 14,162 incident cases of major chronic disease, including 4769 cardiovascular events, 6449 cancer events, and 2944 deaths from other causes. RESULTS: The HR of major chronic disease comparing >= 21 to 0 MET.h.wk(-1) of exercise was 0.86 (95% confidence interval (CI), 0.81-0.91) for vigorous-intensity activity and 0.85 (95% CI, 0.80-0.90) for moderate activity. For cardiovascular disease (CVD), the corresponding HRs were 0.78 (95% CI, 0.70-0.86) and 0.80 (95% CI, 0.72-0.88), respectively. When examined separately, running, tennis, and brisk walking were inversely associated with CVD risk. Furthermore, more vigorous activity was associated with lower disease risk; the HR comparing >70 to 0 MET.h.wk(-1) of vigorous-intensity exercise was 0.79 (95% CI, 0.68-0.92; P < 0.0001 for trend) for major chronic disease and 0.73 (95% CI, 0.56-0.96; P < 0.0001 for trend) for CVD. CONCLUSIONS: Vigorous- and moderate-intensity physical activities were associated with lower risk of major chronic disease and CVD. Increasing amounts of vigorous activity remained inversely associated with disease risk, even among men in the highest categories of exercise. PMID- 22543742 TI - Maximal physiological parameters during partial body-weight support treadmill testing. AB - PURPOSE: This study investigated maximal cardiometabolic response while running in a lower body positive pressure treadmill (antigravity treadmill (AG)), which reduces body weight (BW) and impact. The AG is used in rehabilitation of injuries but could have potential for high-speed running, if workload is maximally elevated. METHODS: Fourteen trained (nine male) runners (age 27 +/- 5 yr; 10-km personal best, 38.1 +/- 1.1 min) completed a treadmill incremental test (CON) to measure aerobic capacity and heart rate (VO(2max) and HR(max)). They completed four identical tests (48 h apart, randomized order) on the AG at BW of 100%, 95%, 90%, and 85% (AG100 to AG85). Stride length and rate were measured at peak velocities (V(peak)). RESULTS: VO(2max) (mL.kg(-1).min(-1)) was similar across all conditions (men: CON = 66.6 (3.0), AG100 = 65.6 (3.8), AG95 = 65.0 (5.4), AG90 = 65.6 (4.5), and AG85 = 65.0 (4.8); women: CON = 63.0 (4.6), AG100 = 61.4 (4.3), AG95 = 60.7 (4.8), AG90 = 61.4 (3.3), and AG85 = 62.8 (3.9)). Similar results were found for HR(max), except for AG85 in men and AG100 and AG90 in women, which were lower than CON. V(peak) (km.h(-1)) in men was 19.7 (0.9) in CON, which was lower than every other condition: AG100 = 21.0 (1.9) (P < 0.05), AG95 = 21.4 (1.8) (P < 0.01), AG90 = 22.3 (2.1) (P < 0.01), and AG85 = 22.6 (1.6) (P < 0.001). In women, V(peak) (km.h(-1)) was similar between CON (17.8 (1.1) ) and AG100 (19.3 (1.0)) but higher at AG95 = 19.5 (0.4) (P < 0.05), AG90 = 19.5 (0.8) (P < 0.05), and AG85 = 21.2 (0.9) (P < 0.01). CONCLUSIONS: The AG can be used at maximal exercise intensities at BW of 85% to 95%, reaching faster running speeds than normally feasible. The AG could be used for overspeed running programs at the highest metabolic response levels. PMID- 22543743 TI - Reduced surround inhibition in musicians. AB - To investigate whether surround inhibition (SI) in the motor system is altered in professional musicians, we performed a transcranial magnetic stimulation (TMS) study in 10 professional musicians and 15 age-matched healthy non-musicians. TMS was set to be triggered by self-initiated flexion of the index finger at different intervals ranging from 3 to 1,000 ms. Average motor evoked potential (MEP) amplitudes obtained from self-triggered TMS were normalized to average MEPs of the control TMS at rest and expressed as a percentage. Normalized MEP amplitudes of the abductor digiti minimi (ADM) muscles were compared between the musicians and non-musicians with the primary analysis being the intervals between 3 and 80 ms (during the movement). A mixed-design ANOVA revealed a significant difference in normalized ADM MEPs during the index finger flexion between groups, with less SI in the musicians. This study demonstrated that the functional operation of SI is less strong in musicians than non-musicians, perhaps due to practice of movement synergies involving both muscles. Reduced SI, however, could lead susceptible musicians to be prone to develop task-specific dystonia. PMID- 22543744 TI - Simple route to (NH4)(x)WO3 nanorods for near infrared absorption. AB - Described here is how to synthesize one-dimensional ammonium tungsten bronze ((NH(4))(x)WO(3)) by a facile solvothermal approach in which ethylene glycol and acetic acid were employed as solvents and ammonium paratungstate was used as a starting material, as well as how to develop the near infrared absorption properties of (NH(4))(x)WO(3) nanorods for application as a solar light control filter. The as-obtained product was characterized by field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), thermogravimetry (TG), atomic force microscope (AFM) and UV-Vis-NIR spectra. The SEM and TEM images clearly revealed that the obtained sample possessed rod/fiber-like morphologies with diameters around 120 nm. As determined by UV-Vis-NIR optical measurement, the thin film consisted of (NH(4))(x)WO(3) nanoparticles, which can selectively transmit most visible lights, but strongly absorb the near-infrared (NIR) lights and ultraviolet rays. These interesting optical properties make the (NH(4))(x)WO(3) nanorods suitable for the solar control windows. PMID- 22543745 TI - Evaluation of BM cytomorphology after allo-SCT in patients with AML. AB - Estimation of relapse risk in AML after allo-SCT is critical. The negative impact of increased blast count post transplant is widely accepted. Here, we studied cellularity and dysplasia in BM cytomorphology on days 30 and 100 in 112 AML patients who achieved haematological CR after SCT. Overall cellularity on day 30 was normal in 45.3%, reduced in 37.3% and increased in 17.3% of samples (day 100: normal: 54.8%; reduced: 38.7%; and increased: 6.5%). Dysplasia in >=10% of cells was frequent on day 30 (granulopoiesis: 25.0% of samples; erythropoiesis: 34.6%; and megakaryopoiesis: 47.7%) and also on day 100. Relapses were less frequent in patients with normal BM cellularity on day 30 (7/34; 20.6%) when compared with reduced (9/28; 32.1%) or increased cellularity (10/13; 76.9%; P = 0.001). Estimated 2-year OS was 59.0% for patients with normal overall cellularity, followed by patients with increased (44.0%) and reduced cellularity (31.4%, P = 0.009). In contrast, cellularity at day 100 and dysplasia at days 30 and 100 did not correlate with outcome measures. Thus, in the cohort studied, BM cellularity represents a prognostic parameter for the post-transplant period in AML patients. Dysplasia seems to be an unspecific phenomenon in the cohort analysed. PMID- 22543746 TI - The EBMT activity survey: 1990-2010. AB - A total of 654 centers from 48 countries were contacted for the 2010 survey. In all, 634 centers reported a total of 33 362 hematopoietic SCT (HSCT) with 30 012 patients receiving their first transplant (12 276 allogeneic (41%) and 17 736 autologous (59%)). Main indications were leukemias: 9355 (31%; 93% allogeneic), lymphoid neoplasias specifically Non Hodgkin's lymphoma, Hodgkin's lymphoma and plasma cell disorders: 17 362 (58%; 12% allogeneic), solid tumors: 1585 (5%; 6% allogeneic) and non-malignant disorders: 1609 (6%; 88% allogeneic). There were more unrelated donors than HLA-identical sibling donors (53% versus 41%); the proportion of peripheral blood as stem cell source was 99% for autologous and 71% for allogeneic HSCT. Cord blood was primarily used in allogeneic transplants (6% of total) with three autologous cord blood HSCT being reported. The number of transplants has increased by 19% since 2005 (allogeneic 37% and autologous 9%) and continued to increase by about 1100 HSCT per year since 2000. Patterns of increase were distinct and different. The data show the development of transplantation in Europe since 1990, with the number of patients receiving a HSCT increasing from 4200 to over 30 000 annually. The most impressive trend seen is the steady increase of unrelated donor transplantation, in parallel to the availability of unrelated donors through donor registries. PMID- 22543747 TI - The use of different diagnostic tools for Babesia and Theileria parasites in cattle in Menofia, Egypt. AB - Bovine piroplasmosis is caused by tick-borne hemoprotozoans of the genera Babesia and Theileria and is the most prevalent in tropical and subtropical countries, causing a major economic impact worldwide. In the current study, a total of 405 cattle of different ages, sexes, and breeds were randomly sampled for surveying and diagnosis of babesiosis and theileriosis using three methods: direct microscopy (blood smears), indirect fluorescent antibody test (IFAT) and polymerase chain reaction (PCR). Giemsa-stained blood smears revealed that, out of 405 examined cattle, 33 (8.15 %) were infected with Babesia sp. and 65 (16.05 %) with Theileria sp. (total number of infected cattle was 98). Mixed infection was seen in 11 (2.72 %) animals. Moreover, application of the three diagnostic assays on 158 randomly sampled cattle indicated that 17 (10.76 %) and 33 (20.89 %) were positive for Babesia and Theileria spp. by the direct smear technique, 25 (15.82 %) and 33 (20.89 %) by IFAT (fluorescence was greenish yellow for Babesia and yellowish for Theileria), and 20 (12.66 %) and 38 (24.05 %) by PCR. Using primers specific for Babesia and Theileria spp., we found that diagnostic bands appeared at ~350 and ~370 bp, respectively indicating the presence of these piroplasms. Statistically, there was a non-significant difference of the positivity in response to the three techniques; thus, any of these methods can be described as useful for diagnosing blood parasites in both domesticated animals and birds. On the basis of the obtained results, it could be concluded that direct microscopy can be used in acute infections, whereas IFAT and PCR are useful in chronicity. PMID- 22543748 TI - Cohnella plantaginis sp. nov., a novel nitrogen-fixing species isolated from plantain rhizosphere soil. AB - A novel bacterium capable of fixing nitrogen was isolated from plantain rhizosphere soil in China. The isolate, designated YN-83(T), is Gram-positive, aerobic, motile and rod-shaped (0.4-0.6 MUm * 1.9-2.6 MUm). Phylogenetic analysis based on the 16S rRNA gene sequence revealed that strain YN-83(T) was a member of the genus Cohnella. High similarity of 16S rRNA gene sequence was found between YN-83(T) and Cohnella ginsengisoli DSM18997(T) (97.99%), whereas the similarity was below 96.0% between YN-83(T) and the other Cohnella species. DNA-DNA relatedness between strain YN-83(T) and C. ginsengisoli DSM18997(T) was 27.4 +/- 6.2%. The DNA G+C content of strain YN-83(T) was 59.3 mol%. The predominant isoprenoid quinone was MK-7 and the major fatty acids were anteiso-C(15:0) (44.3%), iso-C(15:0) (11.3%), iso-C(16:0) (18.6%) and C(16:0) (7.7%). The polar lipids of strain YN-83(T) consist of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, lyso- phosphatidylglycerol, phosphatidylinositol and phosphatidylinositol mannosides. On the basis of phenotypic and chemotaxonomic properties, 16S rRNA gene sequence, G+C content and DNA-DNA hybridization, strain YN-83(T) represents a novel species of the genus Cohnella, for which the name Cohnella plantaginis sp. nov. (type strain YN-83(T) = DSM 25424(T) = CGMCC 1.12047(T)) is proposed. PMID- 22543749 TI - Sediminihabitans luteus gen. nov., sp. nov., a new member of the family Cellulomonadaceae isolated from sea sediment. AB - Two novel Gram-positive actinobacteria, designated H97-3(T) and H83-5, were isolated from marine sediment samples and their taxonomic positions were investigated by a polyphasic approach. Both strains formed vegetative hyphae in the early phase of growth but the hyphae eventually fragmented into coccoid cells. The peptidoglycan type was found to be A4alpha. The predominant menaquinone was MK-9(H(4)), and the major fatty acids were anteiso-C(15:0), anteiso-C(17:0) and C(16:0). The DNA G+C content was 74.0-74.9 mol %. 16S rRNA gene sequencing analysis revealed that strains H97-3(T) and H83-5 represented novel members of the family Cellulomonadaceae. Their nearest phylogenetic neighbours were the members of the genus Oerskovia, with a similarity of 98.3 98.4 %. However, strains H97-3(T) and H83-5 were distinguishable from the members of the genus Oerskovia and the other genera of the family Cellulomonadaceae in terms of chemotaxonomic characteristics and phylogenetic relationship. The result of the DNA-DNA hybridization indicated that strains H97-3(T) and H83-5 belonged to the same species. Therefore, strains H97-3(T) and H83-5 represent a novel genus and species of the family Cellulomonadaceae, for which the name Sediminihabitans luteus gen. nov., sp. nov. is proposed. The type strain of S. lutes is H97-3(T) (=NBRC 108568(T) = DSM 25478(T)). PMID- 22543750 TI - Two piperazic acid-containing cyclic hexapeptides from Streptomyces alboflavus 313. AB - Two novel cyclic hexapeptides, designated NW-G10 (1) and NW-G11 (2), were isolated from the fermentation broth of Streptomyces alboflavus 313. Their relative structures were elucidated on the basis of extensive spectroscopic analysis, and the absolute configurations of several constituent amino acids were determined by Marfey's method. NW-G10 (1) and NW-G11 (2) exhibited significant activity against Gram-positive bacteria, such as Bacillus cereus, Bacillus subtilis and Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA), but they are not active against gram negatives. PMID- 22543751 TI - Enhanced leishmanicidal activity of cryptopeptide chimeras from the active N1 domain of bovine lactoferrin. AB - Two antimicrobial cryptopeptides from the N1 domain of bovine lactoferrin, lactoferricin (LFcin17-30) and lactoferrampin (LFampin265-284), together with a hybrid version (LFchimera), were tested against the protozoan parasite Leishmania. All peptides were leishmanicidal against Leishmania donovani promastigotes, and LFchimera showed a significantly higher activity over its two composing moieties. Besides, it was the only peptide active on Leishmania pifanoi axenic amastigotes, already showing activity below 10 MUM. To investigate their leishmanicidal mechanism, promastigote membrane permeabilization was assessed by decrease of free ATP levels in living parasites, entrance of the vital dye SYTOX Green (MW = 600 Da) and confocal and transmission electron microscopy. The peptides induced plasma membrane permeabilization and bioenergetic collapse of the parasites. To further clarify the structural traits underlying the increased leishmanicidal activity of LFchimera, the activity of several analogues was assessed. Results revealed that the high activity of these hybrid peptides seems to be related to the order and sequence orientation of the two cryptopeptide moieties, rather than to their particular linkage through an additional lysine, as in the initial LFchimera. The incorporation of both antimicrobial cryptopeptide motifs into a single linear sequence facilitates chemical synthesis and should help in the potential clinical application of these optimized analogues. PMID- 22543752 TI - Antenatal corticosteroids for fetal lung maturation in threatened preterm delivery: indications and administration. AB - INTRODUCTION: Antenatal maternal administration of corticosteroids has been shown to reduce morbidity and mortality rates in preterm delivery. Threatened spontaneous or medically indicated preterm delivery for maternal or fetal indications between 24 and 34 weeks of gestation with unknown fetal lung maturity status are indications for antenatal corticosteroid administration. Recent studies have challenged current practice of antenatal glucocorticoid use. The goal of this expert letter is to provide recommendations based for the clinical use of antenatal glucocorticoids based on the current evidence from published studies. METHODS: The published literature (PubMed search), as well as the recommendations of other national societies, has been searched and taken into consideration for these recommendations. RESULTS/CONCLUSIONS: The standard regimen of antenatal corticosteroids involves a single course of 2 * 12 mg betamethasone administered intramuscularly within 24 h. The administration of corticosteroids usually is performed between 24 and 34 weeks gestation. However, under particular circumstances it may be beneficial even at 23 weeks and at 35-36 weeks of gestation. The evidence to date is clearly against the routine administration of multiple antenatal steroid courses. In special clinical situations, a second course of betamethasone ("rescue course") may be justifiable. Tocolysis during administration of steroids is not routinely indicated in the absence of contractions, cervical shortening or rupture of membranes. PMID- 22543753 TI - Human unrestricted somatic stem cells: how far from clinics? PMID- 22543754 TI - Baroreflex sensitivity controller by intra-aortic pump: a potential benefit for heart recovery. AB - Left ventricular assist devices are increasingly used for long-term support in heart failure patients. To promote heart recovery, finding an optimum operating point of the pump that is appropriate for the heart function, and state of the circulatory system is important. Therefore, the baroreflex sensitivity (BRS), which reflect the state of heart function, is used as a control variable. To find the optimum point automatically, an extremum search algorithm (ESA) is designed to find the mean arterial pressure (MAP) that is corresponding to the maximum value of BRS. Then, a MAP controller based on model-free adaptive controller (MFAC) is designed to maintain the measured MAP tracking the desired one. A mathematical model of the cardiovascular system is used to verify the feasibility of the control strategy in the presence of left ventricular (LV) failure, physically active, and a recovery of cardiac function. The simulation shows that the ESA can find the maximum value of BRS automatically. When the peripheral resistance is reduced for simulating a slight physical active, the rotational speed of the pump is automatically increased (6,800 rpm vs. 8,000 rpm). When E(max) is increased from 0.6 to 1.8 mm Hg/ml to mimic a heart recovery, the speed is decreased from 8000 to 7200 rpm, which may avoid the damage of LV contractility. As a key feature, the proposed control strategy finds the optimum operating point of the pump without the need to set reference value of control variable. This feature is benefit for heart recovery. PMID- 22543755 TI - Predicted oxygenation efficacy of a thoracic artificial lung. AB - A thoracic artificial lung (TAL) provides respiratory support for lung disease. How well a TAL improves blood oxygenation for a specific pathology depends on how the TAL is attached to the pulmonary circulation: in series with the natural lungs (NLs), in parallel, or in a hybrid series/parallel combination. A computational model, including hemodynamic and O(2) and CO(2) exchange components, predicts TAL effects on blood flow rates and gas transport in pulmonary disease states modeled by elevated pulmonary vascular resistance (PVR) or reduced oxygen diffusivity in the NLs. In most cases, parallel and series TAL attachment provide comparable, maximal oxygenation. Series, with passage of total cardiac output (CO) through the NLs, is preferred for its filtration of emboli. Hybrid TAL attachment is more complicated, requiring a third graft, yet oxygenates less well than parallel and series. With extreme elevations of PVR, as in primary pulmonary hypertension, parallel TAL attachment provides an oxygenating shunt around the high resistance of the NLs, thus unloading the right ventricle, normalizing CO, and maximizing oxygenation. PMID- 22543756 TI - Portal application of human unrestricted somatic stem cells to support hepatic regeneration after portal embolization and tumor surgery. AB - Insufficient liver remnant volume still precludes patients with potentially resectable tumors from curative surgery. Clinically, it has been demonstrated that transplanted adult stem cells promote liver regeneration. However, the mechanisms of the observed functional improvements are unknown. The aim of our study was to evaluate the impact of transplanted human multipotent cord blood derived unrestricted somatic stem cells (USSC) on liver regeneration and identify the underlying mechanisms in an ovine model. We performed partial embolization of the right liver lobe and grafted USSC in the portal venous system of the left liver lobe. After 4 weeks, livers were explanted and analyzed for differentiation of USSC into hepatocytes by histopathologic examination and for fusion of USSC with recipient hepatocytes by single-cell polymerase chain reaction. The studies revealed that transplanted USSC differentiate into hepatocytes and produce human albumin. No ovine DNA was found in the hepatocytes with a human phenotype. Transplantation of USSC enhances the number of viable hepatocytes in liver disease by differentiation and opens new therapeutic perspectives. PMID- 22543757 TI - Scaffold-based transplantation of vascular endothelial growth factor overexpressing stem cells leads to neovascularization in ischemic myocardium but did not show a functional regenerative effect. AB - The transplantation of skeletal myoblasts (SkM) might improve cardiac function after myocardial infarction via paracrine action. We used scaffold-based cell transfer by using vascular endothelial growth factor (VEGF)-overexpressing myoblasts. Skeletal myoblasts were isolated and expanded from newborn Lewis rats. Cells were transfected with pCINeo-VEGF(121) and seeded on polyurethane (PU) scaffolds. The seeded scaffolds were epicardially implanted in rats 2 weeks after myocardial infarction (group: PU-VEGF-SkM). Before this intervention and 6 weeks later, pressure/volume loops were analyzed followed by histology. Additional study groups (n = 10 per group) were injected with VEGF-overexpressing myoblasts (Inj-VEGF-SkM) or unmodified myoblasts (Inj-SkM) or underwent a sham operation. Overexpression of VEGF was verified in vitro. The transplantation of growth factor producing myoblast-seeded scaffolds resulted in enhanced angiogenesis of ischemically damaged myocardium in vivo. However, the infarction size was not reduced. In group Inj-SkM, hemodynamics remained unchanged. Systolic function as measured by dP/dt(max) was not significantly altered in PU-VEGF-SkM (preinterventionally 2,156 +/- 1,222 mmHg vs. postinterventionally 2,134 +/- 850 mmHg). Other systolic function and diastolic function parameters as measured by dP/dt(min), tau, and pressure half-time were not restored in groups PU-VEGF-SkM and Inj-VEGF-SkM either. Transplantation of VEGF-overexpressing skeletal myoblasts leads to neovascularization in infarcted hearts. No functional myocardial recovery was observed. Scaffold-based transfer of genetically-modified cells remains a useful tool to study paracrine stem cell action. PMID- 22543758 TI - Printed two-dimensional photonic crystals for single-step label-free biosensing of insulin under wet conditions. AB - Two-dimensional photonic crystals (2D-PCs) fabricated on a cyclo-olefin polymer (COP) film using a printable photonics technology based on nano-imprint lithography (NIL) were used for label-free biosensing of insulin under wet conditions. In general, 2D-PC-based biosensing involves a complicated dry-up procedure after biosensing reactions on the 2D-PCs to obtain a high sensitivity through the large difference in refractive index. Therefore, it can be difficult to achieve simple operation involving single-step analysis. Performance of the biosensing under wet conditions would simplify the operational procedure. For label-free biosensing of insulin under wet conditions, the Fresnel reflection intensity change was used instead of the wavelength shift, which is the commonly used sensing signal. By detecting changes in refractive index caused by specific interactions between the antigen and antibody as the Fresnel reflection intensity changes, physiologically important concentrations of insulin could be detected, even under wet conditions. These results suggest that low-cost printed 2D-PCs offer great potential for single-step label-free biosensing through the introduction of a sample solution. PMID- 22543760 TI - An unusual intraventricular interthalamic vein: two anatomical case reports. AB - Neurosurgeons use ventricular veins during an endoscopic third ventriculocisternostomy as landmark to progress in ventricles. In the current literature, there is lack of detailed intraventricular venous anatomy. Majority of those papers treats Monro's foramen venous variations. There are no data of third ventricle venous anatomy and variations in the literature. We reported two cases of unusual interthalamic vein that we need to spare during endoscopy. PMID- 22543761 TI - SN-38 loaded polymeric micelles to enhance cancer therapy. AB - 7-Ethyl-10-hydroxycamptothecin (SN-38) loaded poly(ethylene glycol)-block poly(propylene glycol)-block-poly(ethylene glycol) (Pluronic F-108) and poly(ethylene glycol)-block-poly(epsilon-caprolactone) (PEG-b-PCL) nanoparticles were successfully prepared by a modified film hydration method and characterized by scanning electric microscopy (SEM), transmission electron microscopy (TEM), atomic force microscopy (AFM) and dynamic light scattering (DLS). Satisfactory drug loading of 20.73 +/- 0.66% and a high encapsulation efficiency of 83.83 +/- 1.32% were achieved. The SN-38 nanoparticles (SN-38 NPs) can completely disperse into a phosphate buffered saline (PBS) medium to produce a clear aqueous suspension that remains stable for up to three days. Total drug releases were 67.91% and 91.09% after 24 h in a PBS or fetal bovine serum (FBS) medium. Half maximal inhibitory concentration (IC(50)) tests of SN-38 and SN-38 NPs on A549 lung cells produced results of 200.0 +/- 14.9 ng ml(-1) and 80.0 +/- 4.6 ng ml( 1), respectively. Similarly, IC(50) tests of SN-38 and SN-38 NPs on MCF-7 breast cells yielded results of 16.0 +/- 0.7 ng ml(-1) and 8.0 +/- 0.5 ng ml(-1), respectively. These in vitro IC(50) studies show significant (p < 0.01) enhancement of the SN-38 NP drug efficiency in killing cancer cells in comparison to the free drug SN-38 control. All the materials used for this nanoformulation are approved by the US FDA, with the virtue of extremely low toxicity to normal cells. PMID- 22543762 TI - The role of investigator indifference in research. PMID- 22543763 TI - Patients' understanding of pelvic floor disorders: what women want to know. AB - OBJECTIVE: To assess the effect of initial visit with a specialist on disease understanding in women with pelvic floor disorders. METHODS: Women with referrals or chief complaints suggestive of urinary incontinence or pelvic organ prolapse were recruited from an academic urology clinic. The patients completed a Test of Functional Health Literacy in Adults and scripted interview sessions before and after a physician encounter. Physician's treatment plans were standardized based on diagnosis and were explained using models. Interview transcripts were analyzed using qualitative grounded theory methodology. RESULTS: Twenty women with pelvic floor disorders (urinary incontinence or pelvic organ prolapse) were recruited and enrolled in this pilot study. The mean age was 60.5 years (range, 31-87 years) and most of the women were white, with a college degree or beyond. Test of Functional Health Literacy in Adults scores indicated adequate to high levels of health literacy. Preliminary themes before and after the physician encounter were extracted from interviews, and 2 main concepts emerged. First, after the initial physician's visit, knowledge of their diagnosis and the ability to treat their symptoms relieved the patients' concerns related to misunderstandings of the severity of their disease, Second, the patients tended to focus on treatment and had difficulty grasping certain diagnostic terms. This resulted in good understanding of treatment plans despite an inconsistent understanding of diagnosis. CONCLUSION: Our findings demonstrated a significant effect of the initial physician's visit on the patients' understanding of their pelvic floor disorder. Despite the variation in diagnostic recall after the physician encounter, the patients had a good understanding of treatment plans. This served to increase perceived control and adequately relieve patients' fears. PMID- 22543764 TI - The effect of preoperative checklists on final histology and rates of hysterectomy for benign conditions. AB - OBJECTIVES: Our null hypothesis was that the introduction of preoperative hysterectomy checklists for fibroids, dysfunctional uterine bleeding (DUB), and chronic pelvic pain (CPP) would not affect the rate of hysterectomy or the proportion of cases with nonconfirmable final pathology. STUDY DESIGN: Using a prospective 6-month cohort, we compared the rate of hysterectomy (using ambulatory current procedural terminology codes for all eligible patients) and the preoperative diagnoses to final histologic diagnoses, to a baseline 6-month retrospective cohort. We also sought to determine the proportion of completed preoperative checklists among eligible cases. RESULTS: Checklist implementation was associated with a significant decrease in the hysterectomy rate for DUB: 25 (15.2%) of 165 fell to 12 (6.5%) of 185 (P = 0.014): for CPP: 11 (10.9%) of 101 to 3 (2.9%) of 105 (P = 0.044), as well as for the combined total rate: 86 (25.2%) of 341 to 52 (15.2%) of 342 (P = 0.002). There was a 50% decrease in nonconfirmable pathology for all cases: 21 of 86 at baseline compared to 6 of 52 after intervention (P = 0.049). CONCLUSION: In this 6-month pilot analysis, the use of preoperative hysterectomy checklists for 3 common nonmalignant conditions (fibroids, DUB, and CPP) was associated with a statistically significant decrease in hysterectomy rates and overall nonconfirmable pathology. PMID- 22543765 TI - Estrogen affects the glycosaminoglycan layer of the murine bladder. AB - OBJECTIVES: Urinary tract infections (UTIs), commonly caused by uropathogenic Escherichia coli (UPEC), confer significant morbidity among postmenopausal women. Glycosaminoglycans (GAGs) comprise the first line of defense at the bladder's luminal surface. Our objective was to use a murine model of menopause to determine whether estrogen status affects the GAG layer in response to UPEC infection. METHODS: Adult female mice underwent sham surgery (SHAM, n = 18) or oophorectomy (OVX, n = 66) to establish a murine model of menopause. A subset of oophorectomized mice underwent hormone therapy (HT, n = 33) with 17beta estradiol. Mice were inoculated with UPEC and killed at various time points; bladders were collected and GAG layer thickness was assessed in multiple bladder sections. Sixteen measurements were made per bladder. A repeated-measures 2-way analysis of variance was performed to determine the effect of time after infection and hormonal condition on GAG thickness. We also investigated the molecular underpinnings of GAG biosynthesis in response to alterations in estrogen status and infection. RESULTS: We did not observe significant difference of GAG thickness among the 3 hormonal conditions; however, the time course of GAG thickness was significantly different (P < 0.05). The OVX mice demonstrated significantly greater thickness at 72 hours after infection (P = 0.0001), and this effect was shifted earlier (24 hours after infection) on the addition of HT (P = 0.001). At 2 to 4 weeks after infection, GAG thickness among all cohorts was not significantly different from baseline. In addition, quantitative reverse transcription-polymerase chain reaction analysis revealed that GAG biosynthesis is altered by estrogen status at basal level and on infection. CONCLUSIONS: The GAG layer is dynamically altered during the course of UTI. Our data show that HT positively regulates GAG layer thickness over time, as well as the composition of the GAGs. In addition, the GAG sulfation status can be influenced by estrogen levels in response to UPEC infection. The protective effects of the GAG layer in UTI may represent pharmacologic targets for the treatment and prevention of postmenopausal UTI. PMID- 22543766 TI - Perioperative bowel habits of women undergoing gynecologic surgery: a pilot study. AB - OBJECTIVES: To describe perioperative bowel habits of women undergoing gynecologic surgery. METHODS: This prospective cohort study included women undergoing gynecologic surgery. Before surgery, participants completed the Bristol Stool Form Scale (BSFS), a validated instrument describing stool characteristics consistent with transit categories: slow (BSFS 1-2), normal (BSFS 3-5), and fast (BSFS 6-7). For 2 weeks after surgery, the participants recorded daily medications and bowel movements (BM), and completed BSFS. The chi(2) test, the Fisher exact test, analysis of variance, t tests, and ordinal regression were used. RESULTS: Preoperatively, most (70%) of 340 women had normal stool transit, with 15% having slow transit and 7% having fast transit. Complete postoperative data were available for 170 (50%). Mean +/- SD time to first postoperative BM was 2.8 +/- 1.4 days with transit classification: 48% normal, 32% slow, and 20% fast. CONCLUSIONS: Most women had normal stool transit both preoperatively and postoperatively. Time to first BM was longer after open surgery by approximately 3 days. PMID- 22543767 TI - Short-term outcomes of robotic versus conventional laparoscopic sacral colpopexy. AB - OBJECTIVE: This study aimed to compare operative times and short-term outcomes between robotic and laparoscopic sacral colpopexy. METHODS: A retrospective cohort study using a convenience sample was performed comparing patients who underwent robotic and laparoscopic sacral colpopexy during a 4-year period. Operative time, blood loss, perioperative complications, and objective cure of prolapse at 3 months were compared. RESULTS: Robotic procedures in 65 women and laparoscopic sacral colpopexy procedures in 23 women were performed. Median preoperative prolapse was stage 3 for both groups. There was no statistically significant difference in the median operative time between the robotic and laparoscopic groups, although this did not include robot setup time and did include concurrent procedures that differed significantly between groups (334 vs 325 minutes, P = 0.30). Estimated blood loss was lower in the robotic group (50 vs 100 mL, P = 0.003). Median hospital stay was 1 day in both groups (P = 0.23). There were no differences in overall objective cure rates between robotic and laparoscopic groups at 3 months of follow-up (87.1% vs 91.3%, P = 0.72). Perioperative complications, including visceral injury and mesh erosion, did not differ significantly between these groups. CONCLUSIONS: Robotic and laparoscopic sacral colpopexy had similar operative times, short-term anatomic cure rates, perioperative complications, and length of hospital stay. PMID- 22543768 TI - The ureter as a landmark for robotic sacrocolpopexy. AB - OBJECTIVE: The objective of this study was to report on the location of the ureters in relation to the sacral promontory at the level of the pelvic brim. METHODS: Female patients undergoing indicated computed tomographic (CT) urograms were selected for this study. Charts and images from a defined 3-year study period were reviewed. The GE Centricity software was used to evaluate multiplanar CT views and measure the distance from the bilateral ureters to the midpoint of the distal sacral promontory for each subject. RESULTS: Sixty-three women underwent CT urography during the study period. Of these, 38 met the criteria for inclusion. Among these, the left ureter was 35.9 +/- 4.9 mm lateral to the midsacral promontory. The right ureter was 29.7 +/- 6.2 mm lateral to the sacral promontory. CONCLUSIONS: On average, the sacral promontory is located 29.7 mm medial to the right ureter at the level of the pelvic brim. This represents a landmark that may prove clinically useful, along with other visual cues, in choosing the proper location for careful dissection toward the anterior longitudinal ligament during robotic sacrocolpopexy. PMID- 22543769 TI - Perineal body length among different racial groups in the first stage of labor. AB - OBJECTIVE: Anatomic differences among racial groups may contribute to observed differences in the occurrence of severe perineal lacerations at the time of vaginal delivery. The purpose of this study was to identify differences in perineal body length between racial groups. METHODS: Perineal body length was measured in primigravid women aged 18 to 45 years who were admitted in labor. Women were classified into 1 of 6 racial groups: White, Filipino, Japanese, Chinese, Native Hawaiian, or Micronesian. The primary outcome, perineal body length, was compared using analysis of variance. RESULTS: A total of 200 women were recruited. There were no significant differences in perineal body length (P = 0.42) and severe perineal lacerations (P = 0.82) between the different racial groups. The mean (SD) perineal body length of women who had a severe laceration was 3.9 (0.5) versus 3.9 (0.6) cm in women who did not have a severe laceration (P= 0.98). CONCLUSION: Perineal body length does not seem to differ among the different racial groups studied and therefore an unlikely cause of racial variation in rates of severe perineal lacerations. PMID- 22543770 TI - Radiologic images of retrograde ureterography before and after release of bilateral sacrospinous ligament fixation sutures. AB - Ureteral injury or compromise can occur after pelvic floor reconstruction for prolapse. Therefore, it is routine to perform intraoperative urethrocystoscopy at end of the operative case to confirm ureteral patency. We show retrograde ureterogram before and after release of fixation sutures from bilateral sacrospinous ligament fixation performed for stage III vaginal prolapse. The fluoroscopic images presented are intended to help pelvic surgeons visualize what could occur during sacrospinous ligament fixation. Furthermore, this case report illustrates how angulation of the distal ureter, without complete obstruction, may result in renal compromise. PMID- 22543771 TI - Comparison of urodynamic volume measurements using room and body temperature saline: a double-blinded randomized crossover study design. AB - INTRODUCTION: Urodynamic studies, routinely performed in women with lower urinary tract symptoms, have a large impact on clinical decision making. Unfortunately, these studies are insensitive in reproducing idiopathic detrusor overactivity (IDO). We set out to examine whether serial cystometry with different distending fluid temperatures could better reproduce symptoms. METHODS: Eighty-six women were enrolled in a double-blinded, randomized, crossover study. Two cystometries were performed in series, starting with either body temperature fluid (BTF) or room temperature fluid (RTF) and then repeating cystometry with the other temperature fluid. Primary outcomes included first sensation, first urge, and maximum cystometric capacity. Secondary outcomes included subjective sensation of bladder discomfort and the incidence of IDO. RESULTS: In aggregate, the temperature of the fluid did not affect volumes of bladder sensation. There were no differences in self-reported bladder irritation or IDO between the different temperature fluids. There was a significant carryover effect with BTF. BTF administered first reached sensory thresholds at lower volumes than when it was administered second after RTF. Room temperature fluid cystometry showed no statistical difference in volume between first fill and second fill. Idiopathic detrusor overactivity contractions were seen in 9% of studies and were not affected by period or temperature. CONCLUSIONS: These data suggest that BTF and RTF independently do not affect bladder sensory thresholds. The periodicity in combination with varying fluid temperature is of greater impact. This study documents that changes in temperature of the distending fluid from BTF to RTF or vice versa likely do not provoke IDO contractions. PMID- 22543773 TI - Use of suprapubic tube to assess voiding function after synthetic midurethral slings. AB - INTRODUCTION: Up to 50% of patients are unable to void immediately after midurethral sling (MUS) procedures. The objective of this study was to present our case series of use of suprapubic tube (SPT) to assess voiding function after MUS procedures. METHODS: This was a retrospective cohort study of patients who underwent MUS procedures along with insertion of SPT between January 2007 and August 2010. RESULTS: A total of 123 patients were identified. Among the patients who met criteria for SPT removal within 4 weeks, the mean number of days of SPT use was 6 (4.6) days. One major complication involved a urinoma after SPT removal. CONCLUSION: The use of SPT after MUS procedures is practical. In our cohort of patients, it took up to 1 week for voiding function to return to normal. PMID- 22543772 TI - Treatment for urinary tract infection after midurethral sling: a retrospective study comparing patients who receive short-term postoperative catheterization and patients who pass a void trial on the day of surgery. AB - INTRODUCTION: This is a retrospective cohort study comparing the risk of treatment for postoperative urinary tract infection (UTI) in patients who receive short-term postoperative catheterization versus those who pass a void trial on the day of surgery after midurethral sling with or without concomitant pelvic surgery. MATERIALS AND METHODS: We compared two cohorts to determine our primary outcome: treatment for UTI, culture proven or empiric, within three weeks after surgery. RESULTS: 138 patients, were included in the study of which 80 (58%) received postoperative catheterization. The baseline characteristics of the catheterized and noncatheterized groups were similar except that the catheterized group had a lower mean body mass index (28 +/- 5 vs 30 +/- 5 kg/m(2); P = 0.01), were more likely to have undergone concomitant pelvic surgery (51% vs 20%; P < 0.01), had higher estimated blood loss (92 +/- 87 vs 47 +/- 49 mL; P < 0.01), and had longer operative times (108 +/- 75 vs 62 +/- 47 min; P < 0.01). Overall, 19.6% of the patients received treatment for UTI. Patients in the catheterized group were more likely to receive treatment for UTI (24/80 [30%] catheterized vs 3/58 [5%] noncatheterized; P < 0.01). This significant difference in treatment for UTI persisted when examining patients who underwent midurethral sling only without concomitant pelvic surgery (6/29 [20.7%] catheterized vs 1/38 [2.6%] noncatheterized; P = 0.04). In a logistic regression model adjusting for age, body mass index, concomitant surgery, and postoperative catheterization, only postoperative catheterization remained significantly associated with treatment for UTI (OR, 6.6; 95% confidence interval, 1.8-24.5; P < 0.01). CONCLUSIONS: Treatment for postoperative UTI is significantly higher in patients who receive short-term postoperative catheterization after midurethral sling with or without concomitant pelvic surgery. PMID- 22543774 TI - Necrotizing postsurgical infection complicating midurethral sling procedure with unrecognized cystotomy. AB - A 39-year-old woman with stress urinary incontinence underwent a retropubic midurethral sling procedure. On postoperative day 1, she presented with persistent abdominal pain and fever. A computed tomographic scan showed subcutaneous lower abdominal wall edema and gas above the fascia suggesting a necrotizing soft tissue infection. She was surgically debrided twice, which included removal of the mesh sling on postoperative day 4. Cystoscopy suggested unrecognized bladder perforation had occurred during the initial procedure, and record rerevealed untreated bacteriuria before sling placement. The patient required wound vacuum therapy and a later secondary wound closure procedure. Six months after the initial surgery, she was reevaluated for stress urinary incontinence and underwent a transobturator midurethral sling procedure with resolution of these symptoms. Necrotizing postsurgical infection is a rarely described complication of midurethral slings. Treatment for this potentially life threatening complication includes aggressive surgical debridement, administration of broad-spectrum antibiotic, removal of infected implants, and supportive therapy. Unrecognized bladder injury and preoperative bacteriuria are discussed as potential risk factors for postsling necrotizing infection. PMID- 22543775 TI - Unusual findings on cystoscopy in a patient with detrusor overactivity. AB - BACKGROUND: Chronic lithium ingestion has been shown to cause polyuria and polydipsia in 20% to 40% of patients, secondary to diabetes insipidus. However, it has not been reported to cause lithium deposition in the bladder. CASE: A 77 year-old woman presented to our clinic with complaints of urinary incontinence, urinary urgency, and nocturnal enuresis for the past 3 to 4 years. She denied polydipsia. Her medical history was significant for bipolar disorder for which she had been on lithium therapy for more than 10 years. Metallic deposition was noted in the suburothelium of a urethral biopsy by gross inspection. CONCLUSION: Suburothelial deposition of metal may act as a bladder irritant and account for this patient's overactive bladder symptoms. PMID- 22543776 TI - Postpartum vaginal agglutination: a case report. AB - BACKGROUND: Vaginal agglutination after spontaneous vaginal delivery has not been previously described in the medical literature. CASE: A healthy 35-year-old Gravida 2 Para 2002 had a normal, spontaneous vaginal delivery. At her 8-week postpartum visit, a speculum could not be inserted into her vagina secondary to significant foreshortening. She was breastfeeding at the time. She ultimately underwent scar tissue takedown in the operating room, with subsequent vaginal estrogen and dilator use. CONCLUSIONS: Postpartum vaginal agglutination after spontaneous delivery is rare, and this case highlights an interesting complication of vaginal delivery in a hypoestrogenic state. PMID- 22543777 TI - Laparoscopic repair of vesicouterine fistula. AB - BACKGROUND: Vesicouterine fistulae are the least common type of urogenital fistulae found in women and are often the result of inadvertent bladder injury at the time of cesarean delivery. Few case reports exist on the management and repair of these fistulae. CASE: A 41-year-old woman with a history of three cesarean deliveries with persistent urinary incontinence who underwent laparoscopic repair of a vesicouterine fistula. CONCLUSION: Whereas in the past, these fistulae were predominantly repaired via a transvaginal or abdominal approach, vesicouterine fistulae can be successfully repaired endoscopically. PMID- 22543809 TI - Selective colorimetric sensing of Co(II) in aqueous media with a spiropyran-amide dipicolylamine linkage under UV irradiation. AB - A spiropyran-amide-dipicolylamine linkage behaves as a colorimetric receptor for selective Co(2+) sensing in aqueous media under UV irradiation. This is promoted by strong coordination of Co(2+) with amide oxygens of the receptors and efficient photoisomerization of the spiropyran moieties. PMID- 22543811 TI - Prominent activation of the bilateral inferior parietal lobule of literate compared with illiterate subjects during Chinese logographic processing. AB - Chinese is a logographic language system that differs from alphabetic languages, and some of the neurocognitive mechanisms underlying Chinese logographic reading also differ from those underlying alphabetic word reading. However, whether education level effects the neural activation associated with logographic processing of Chinese is still unknown. In the present study, 11 Chinese illiterate and 11 literate (age-matched) subjects participated in an event related fMRI experiment with Chinese character discrimination (CD) and figure discrimination (FD) tasks. All subjects were asked to view the character or figure pairs and discriminate whether the characters or figures of each stimuli pair were the same or not using response keys. Both literate and illiterate subjects activated a widely distributed cerebral network, including the bilateral inferior, middle and superior frontal gyri, superior temporal gyrus and parietal lobe, in the CD task. Finally, we directly compared the activations of literate subjects with illiterate subjects. The results suggest that the bilateral parts of the angular gyrus and supramarginal gyrus are more active for literate than illiterate subjects in the CD task. We found no significant group difference in the FD task. Therefore, the present results may indicate that education level effects the neural activation associated with the logographic processing of Chinese. PMID- 22543813 TI - Acute physical activity on cognitive function: a heart rate variability examination. AB - The purpose of this study was to examine the relationship of physical activity and cognitive function (as determined by reaction time and the trail-making test) in active versus non-active participants. Participants were divided into one of four groups: active experimental, active control, non-active experimental and non active control. All groups completed a complex cognitive task (the trail-making test) as well as a set of reaction time tasks both before and after the experimental session. The experimental groups completed a 30-min exercise session while the control groups monitored the physical activity of the experimental group. In addition to the measures of cognitive function, heart rate variability was recorded during the pre- and post-tests. There was significant cognitive performance improvement in tasks with a higher cognitive and perceptual component. Heart rate variability data indicated that a moderate level of arousal based on sympathetic nervous system activity post exercise was associated with an increase in cognitive performance. The findings are discussed in light of the inverted-U hypothesis. PMID- 22543812 TI - Three TERT genes in Nicotiana tabacum. AB - Telomerase is essential for proper functioning of telomeres in eukaryotes. We cloned and characterised genes for the protein subunit of telomerase (TERT) in the allotetraploid Nicotiana tabacum (tobacco) and its diploid progenitor species Nicotiana sylvestris and Nicotiana tomentosiformis with the aim of determining if allopolyploidy (hybridisation and genome duplication) influences TERT activity and divergence. Two of the three sequence variants present in the tobacco genome (NtTERT-C/s and NtTERT-D) revealed similarity to two sequence variants found in N. sylvestris and another variant (NtTERT-C/t) was similar to TERT of N. tomentosiformis. Variants of N. sylvestris origin showed less similarity to each other (80.5 % in the genomic region; 90.1 % in the coding sequence) than that between the NtTERT-C/s and NtTERT-C/t variants (93.6 and 97.2 %, respectively). The NtTERT-D variant was truncated at the 5' end, and indels indicated that it was a pseudogene. All tobacco variants were transcribed and alternatively spliced sequences were detected. Analysis of gene arrangements uncovered a novel exon in the N-terminal domain of TERT variants, a feature that is likely to be commonly found in Solanaceae species. In addition, species-specific duplications were observed within exon 5. The putative function, copy number and evolutionary origin of these NtTERT sequence variants are discussed. PMID- 22543814 TI - Preference reversals and effects of D-amphetamine on delay discounting in rats. AB - Impulsive choice is correlated with behavioral problems such as attention deficit/hyperactivity disorder and substance abuse. Effects of stimulant drug administration on impulsive choice are not consistent and may depend on baseline differences in impulsive choice. A within-session delay-discounting procedure in which choice was between one food pellet delivered immediately (impulsive choice) and three food pellets delivered after increasing delays (self-controlled choice) was used to determine effects of adding and subtracting delays common to both reinforcers on impulsive choice in male Sprague-Dawley rats (n=8). Delay discounting was observed and impulsive choice was quantified using area under the curve (AUC). Adding delays common to both reinforcers decreased impulsive choice and subtracting delays common to both reinforcers increased impulsive choice. Before administration of D-amphetamine (0.03-1.80 mg/kg, intraperitoneally), subjects were rank ordered into a low-AUC or a high-AUC group. Select doses of D amphetamine decreased impulsive choice for subjects in the low-AUC group but not for subjects in the high-AUC group. These results indicate that impulsive choice can be altered by changing the delay common to both reinforcers and suggest that effects of D-amphetamine may depend, in part, on baseline differences in impulsive choice. PMID- 22543815 TI - Preparation of carboxyl group-modified palladium nanoparticles in an aqueous solution and their conjugation with DNA. AB - The use of nanomaterials in biomolecular labeling and their corresponding detection has been attracting much attention, recently. There are currently very few studies on palladium nanoparticles (Pd NPs) due to their lack of appropriate surface functionalities for conjugation with DNA. In this paper, we thus firstly present an approach to prepare carboxyl group-modified Pd NPs (with an average size of 6 nm) by the use of 11-mercaptoundecanoic acid (MUDA) as a stabilizer in the aqueous solution. The effect of the various reducing reaction conditions on the morphology of the Pd NPs was investigated. The particles were further characterized by TEM, UV-vis, FT-IR and XPS techniques. DNA was finally covalently conjugated to the surface of the Pd NPs through the activation of the carboxyl group, which was confirmed by agarose gel electrophoresis and fluorescence analysis. The resulting Pd NPs-DNA conjugates show high single base pair mismatch discrimination capabilities. This work therefore sets a good foundation for further applications of Pd NPs in bio-analytical research. PMID- 22543816 TI - Multiple histone deacetylases are recruited by corepressor Sin3 and contribute to gene repression mediated by Opi1 regulator of phospholipid biosynthesis in the yeast Saccharomyces cerevisiae. AB - Yeast genes of phospholipid biosynthesis are negatively regulated by repressor protein Opi1 when precursor molecules inositol and choline (IC) are available. Opi1-triggered gene repression is mediated by recruitment of the Sin3 corepressor complex. In this study, we systematically investigated the regulatory contribution of subunits of Sin3 complexes and identified Pho23 as important for IC-dependent gene repression. Two non-overlapping regions within Pho23 mediate its direct interaction with Sin3. Previous work has shown that Sin3 recruits the histone deacetylase (HDAC) Rpd3 to execute gene repression. While deletion of SIN3 strongly alleviates gene repression by IC, an rpd3 null mutant shows almost normal regulation. We thus hypothesized that various HDACs may contribute to Sin3 mediated repression of IC-regulated genes. Indeed, a triple mutant lacking HDACs, Rpd3, Hda1 and Hos1, could phenocopy a sin3 single mutant. We show that these proteins are able to contact Sin3 in vitro and in vivo and mapped three distinct HDAC interaction domains, designated HID1, HID2 and HID3. HID3, which is identical to the previously described structural motif PAH4 (paired amphipathic helix), can bind all HDACs tested. Chromatin immunoprecipitation studies finally confirmed that Hda1 and Hos1 are recruited to promoters of phospholipid biosynthetic genes INO1 and CHO2. PMID- 22543818 TI - Analytical miniaturization and nanotechnologies. PMID- 22543817 TI - [Severe bacterial infection: increased mortality in elderly women with low body weight taking drugs prolonging the QTc interval]. AB - AIMS: Women have a higher risk of acquired long QT syndrome which could be of vital importance in severe bacterial infections when macrolides or fluoroquinolones are administered. This study evaluated whether age, drugs prolonging the QTc interval and body weight were additional influencing factors on mortality in the critically ill with respect to gender. METHODS: In an exploratory investigation 204 intensive care unit (ICU) patients (78 f, 126 m, 61.1+/-16.1 years) with severe bacterial infections were studied (mortality probability model II(0) 49.1+/-28%). Antibiotic therapy was carried out following standard guidelines. In 65.2% of patients potentially QTc prolonging drugs were administered for >=48 h. Body weight was ascertained on ICU admission. RESULTS: By comparable severity of illness and comparable effect of antibiotic therapy, age, QTc prolonging drugs and less body weight showed significant effects on survival in women (p<0.001, 0.008 and 0.009, respectively). For women mortality increased with age >=60 years (p=0.01). The division between survival versus non survival was intensified by addition of QTc prolonging medication and body weight. As such a best risk assessment in women was achieved if age, QTc prolonging therapy and less body weight were combined (p<0.001). In a direct comparison to men, women with at least two of these factors had a significantly poorer outcome (OR 2.37; 95% CI 1.13-4.98; p=0.022). CONCLUSIONS: Age, QTc prolonging drugs and lower body weight can additionally increase mortality in critically ill women. If negative outcome is attributed to a higher dosage, an adjustment for body weight must be carried out. Until now it should be considered whether it would be better to replace QTc prolonging antibiotics in routinely performed drug alternation in elderly lean women. PMID- 22543819 TI - Identification and characterization of anti-osteoclastogenic peptides derived from the cytoplasmic tail of receptor activator of nuclear factor kappa B. AB - Pathological bone resorption by osteoclasts is primarily treated with bisphosphonates. Because the administration of bisphosphonates is associated with a risk for multiple adverse symptoms, a precise understanding of the mechanisms underlying osteoclastogenesis is required to develop drugs with minimal side effects. Osteoclastogenesis depends on receptor activator of nuclear factor kappa B (RANK) signaling mediated by TRAF6. We previously identified a highly conserved domain in the cytoplasmic tail of RANK (HCR), which did not share any significant homology with other proteins and was essential for osteoclastogenesis. HCR acts as a platform for the formation of Gab2- and Vav3-containing signal complexes, and ectopic expression of the HCR peptide inhibits osteoclastogenesis. Here, we uncover the mechanisms of HCR peptide-mediated inhibition of osteoclastogenesis. Expression of either the amino- or carboxyl-terminal half of the HCR peptide (N- or C-peptide) independently inhibited RANK signaling prior to cell-cell fusion. In contrast, expression of the GY-peptide, which is a part of the C-peptide, did not significantly affect prefusion RANK signaling, but did inhibit cell-cell fusion to prevent formation of multinucleated mature osteoclasts. Moreover, Gab2, which is involved in RANK signaling by binding TRAF6, bound the C-peptide but not the N-peptide, suggesting that the C- and the N-peptides sequester TRAF6 in a Gab2-dependent and Gab2-independent manner, respectively. In contrast, the GY peptide did not bind Gab2 but could bind Vav3, which mediates signaling for cell cell fusion. Collectively, we propose that the HCR peptide inhibits osteoclastogenesis through two modes of action-inhibition of (1) prefusion RANK signaling and (2) cell-cell fusion by blocking TRAF6- and Vav3-mediated signaling, respectively. PMID- 22543822 TI - The effect of fluorination of zinc oxide nanoparticles on evaluation of their biodistribution after oral administration. AB - Monitoring of the behavior of metal nanoparticles in the body following exposure is very important for investigation of the physiological fates and safety of these nanoparticles. In this study, we investigated the behavior and accumulation of nano-scaled ZnO (20 nm) and submicro-scaled ZnO (100 nm) particles in organic tissues after oral administration using PET imaging. Both types of ZnO nanoparticle (20 or 100 nm) were labeled with the radionuclide (18)F in high yield via 'click reaction'. (18)F labeling on the ZnO nanoparticles was maintained stably in simulated gastric fluid (pH 1.2) for 7 h. PET images indicated that (18)F and (18)F-ethoxy azide showed radioactivity in the bone and bladder 3 h after oral administration, whereas radioactivity for (18)F-labeled ZnO nanoparticles was seen only in the gastrointestinal (GI) tract. At 5 h post administration, biodistribution studies demonstrate that (18)F accumulated in the bone (10.19 +/- 1.1%ID g(-1)) and (18)F-ethoxy azide showed radioactivity in the bone (7.55 +/- 0.6%ID g(-1)), liver, and brain (0.94 +/- 0.3%ID g(-1)). Unlike (18)F and (18)F-ethoxy azide, (18)F-labeled ZnO nanoparticles showed radioactivity in the lung, liver and kidney including the GI tract. Submicro scaled (18)F-labeled ZnO nanoparticles (100 nm) showed stronger radioactivity in the liver and kidney compared to nano-scaled (18)F-labeled ZnO nanoparticles (20 nm). In conclusion, PET imaging has the potential to monitor and evaluate the behavior of ZnO nanoparticles absorbed in organic tissues following oral exposures. PMID- 22543820 TI - Menin and bone metabolism. AB - Menin, a product of the MEN1 gene, is related to the ontogeny of several cancers such as MEN1 and sporadic endocrine tumors, although it is considered to be a tumor suppressor. Many proteins interact with menin, and it is involved in various biological functions in several tissues. Menin plays some physiological and pathological roles related to transforming growth factor-beta (TGF-beta) signaling pathway in the parathyroid, and it is implicated in the tumorigenesis of parathyroid tumors. In bone, the bone phenotype was observed in some menin deleted mice. Menin is considered to support BMP-2- and Runx2-induced differentiation of mesenchymal cells into osteoblasts by interacting with Smad1/5, Runx2, beta-catenin and LEF-1, although it has different effects on osteoblasts at later differentiation stages through TGF-beta-Smad3 and AP-1 pathways. Further research is expected to shed more light on the role of menin in bone. PMID- 22543823 TI - Specific surface modification of the acetylene-linked glycolipid vesicle by click chemistry. AB - A novel glycolipid with a terminal acetylene was synthesized and used to prepare unilamellar vesicles. Using these vesicles, a convenient method was developed for the specific modification of the vesicle surface using the photoresponsive copper complex [Cu(OH(2))(cage)] as the catalyst for a click reaction. PMID- 22543821 TI - Effect of ibuprofen on proliferation, differentiation, antigenic expression, and phagocytic capacity of osteoblasts. AB - Ibuprofen is a nonselective nonsteroidal antiinflammatory drug commonly prescribed for acute postsurgical and posttraumatic pain. However, little known is about the effect of this drug on osteoblasts. In this study, we aimed to investigate the effect of ibuprofen on cell proliferation, differentiation, antigenic profile, and phagocytic activity, in a human MG-63 osteosarcoma cell line, as a model of osteoblasts. Flow cytometry was used to study proliferation, antigenic profile, and phagocytic activity, and radioimmunoassay was used to determine osteocalcin synthesis as a cell differentiation marker. Our results showed that therapeutic doses of ibuprofen (5 and 25 MUM) did not modify cell proliferation and osteocalcin synthesis in the MG-63 cellular line. However, treatment with a higher dose (25 MUM) increased the expression of antigens CD21, CD44, CD80, CD86, and HLA-DR and decreased phagocytic activity. The results indicate that a therapeutic dose of ibuprofen has no adverse effects on growth of the osteoblast-like cells. Treatment with ibuprofen alone may produce some cell activation, which would explain the increase in expression of membrane markers and decrease in phagocytic capacity. PMID- 22543825 TI - Health information technology vendor selection strategies and total factor productivity. AB - OBJECTIVE: The aim of this study was to compare health information technology (HIT) adoption strategies' relative performance on hospital-level productivity measures. DATA SOURCES: The American Hospital Association's Annual Survey and Healthcare Information and Management Systems Society Analytics for fiscal years 2002 through 2007 were used for this study. STUDY DESIGN: A two-stage approach is employed. First, a Malmquist model is specified to calculate hospital-level productivity measures. A logistic regression model is then estimated to compare the three HIT adoption strategies' relative performance on the newly constructed productivity measures. PRINCIPAL FINDINGS: The HIT vendor selection strategy impacts the amount of technological change required of an organization but does not appear to have either a positive or adverse impact on technical efficiency or total factor productivity. CONCLUSIONS: The higher levels in technological change experienced by hospitals using the best of breed and best of suite HIT vendor selection strategies may have a more direct impact on the organization early on in the process. However, these gains did not appear to translate into either increased technical efficiency or total factor productivity during the period studied. Over a longer period, one HIT vendor selection strategy may yet prove to be more effective at improving efficiency and productivity. PMID- 22543824 TI - The effects of nurse staffing on hospital financial performance: competitive versus less competitive markets. AB - BACKGROUND: Hospitals facing financial uncertainty have sought to reduce nurse staffing as a way to increase profitability. However, nurse staffing has been found to be important in terms of quality of patient care and nursing-related outcomes. Nurse staffing can provide a competitive advantage to hospitals and as a result of better financial performance, particularly in more competitive markets. PURPOSE: In this study, we build on the Resource-Based View of the Firm to determine the effect of nurse staffing on total profit margin in more competitive and less competitive hospital markets in Florida. METHODOLOGY/APPROACH: By combining a Florida statewide nursing survey with the American Hospital Association Annual Survey and the Area Resource File, three separate multivariate linear regression models were conducted to determine the effect of nurse staffing on financial performance while accounting for market competitiveness. The analysis was limited to acute care hospitals. FINDINGS: Nurse staffing levels had a positive association with financial performance (beta = 3.3, p = .02) in competitive hospital markets, but no significant association was found in less competitive hospital markets. PRACTICE IMPLICATIONS: Hospitals in more competitive hospital markets should reconsider reducing nursing staff, as these cost-cutting measures may be inefficient and negatively affect financial performance. PMID- 22543826 TI - Which health-related quality of life aspects are important to patients with chronic myeloid leukemia receiving targeted therapies and to health care professionals? GIMEMA and EORTC Quality of Life Group. AB - The objective of this study was to investigate the health-related quality of life (HRQOL) aspects valued the most by patients with chronic myeloid leukemia (CML) receiving targeted therapies (TT), and to compare their perception with that of health-care professionals' (HCPs). Semi-structured interviews were conducted with 137 CML patients receiving TT from five different countries. An additional sample of 99 CML patients, completing an online interview, was considered for supportive analyses. A sample of 59 HCPs from 12 countries also participated in the study. Patients and HCPs were asked to rate and rank the importance of a predefined list of 74 HRQOL aspects of potential relevance for CML patients. Patients and HCPs agreed that the following five aspects are most important: fatigue, muscle cramps, swelling, worries, and uncertainty about health condition in the future, and importance of social support in coping with the disease. However, the difference in rankings between the two groups was substantial with respect to other HRQOL aspects investigated. Patients valued some issues related to symptoms much higher than HCPs, thus suggesting that a better symptom management could be the crucial aspects to improve HRQOL of CML patients. PMID- 22543827 TI - Ophthalmologic outcomes after chemotherapy and/or radiotherapy in non conjunctival ocular adnexal MALT lymphoma. AB - In the present study, we evaluated the ophthalmologic outcomes of 24 patients who received chemotherapy and/or radiotherapy for the treatment of non-conjunctival ocular adnexal mucosa-associated lymphoid tissue-type (MALT) lymphoma. Ophthalmologic outcomes were assessed in patients who received chemotherapy and/or radiotherapy from March 2004 until May 2010. Outcomes were determined according to common symptoms following chemotherapy and/or radiotherapy, which consisted of decreased visual acuity, dry eye symptoms, retinopathy, optic neuropathy, increased intraocular pressure, and blepharitis. Nine patients received chemotherapy alone, eight patients received radiotherapy alone, and seven patients received chemotherapy with additional radiotherapy (chemoradiation therapy). Patients treated by chemotherapy alone showed better ophthalmologic outcome scores (mean score, 1.56) than those treated by radiation alone or chemoradiation therapy (mean score, 4.01). In conclusion, the treatment of ocular adnexal lymphoma including radiotherapy showed poor ophthalmologic outcomes due to radiation-induced complications. Recently, many new treatment options have emerged, such as immunotherapy or radioimmunotherapy. In the future study, to select a better treatment modality with fewer complications, well-designed prospective trials with ophthalmologic outcomes are needed. PMID- 22543828 TI - POEMS syndrome treated with melphalan high-dose therapy and autologous blood stem cell transplantation: a single-institution experience. AB - The acronym POEMS syndrome stands for a rare multi-system disorder, comprised of polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes. Here, we present a single-center report of a series of five POEMS patients treated with melphalan high-dose therapy (HDT) with subsequent autologous blood stem cell transplantation (ABSCT). After a median follow-up of 52 months from time of diagnosis (range, 15-192) and a median follow-up of 18 months after ABSCT (range, 11-120), all patients were alive. Overall, no severe transplantation-associated complications such as engraftment syndrome or peri- or post-transplant death were noted. In two cases, HDT followed by ABSCT resulted in a complete hematologic response; in the additional three cases, partial responses (PR) were achieved including one very good hematologic PR. Only one patient with initial PR developed progressive disease nearly 2.5 years after transplantation. Consequently, a second HDT with ABSCT was successfully applied resulting in clinical improvement and hematologic PR. In line with previous single-center reports, melphalan HDT followed by ABSCT proved to be a first-line treatment option with tolerable side effects in severely affected POEMS patients with progressing symptoms. PMID- 22543829 TI - Mechanisms of defective erythropoiesis and anemia in pediatric acute lymphoblastic leukemia (ALL). AB - Anemia frequently accompanies the diagnosis of acute lymphoblastic leukemia (ALL) in children and is considered to be one of the most common clinical complications of the disease. In addition, a low hemoglobin (Hb) level is often responsible for fatigue and other associated symptoms that cause a decline in the quality of life of these children. Traditionally, a number of contributing factors such as overcrowding of the marrow, coexisting infections, and nutritional deficits have been used to explain this phenomenon. However, recent advances in in vivo modeling and real-time ultrastructural analytical techniques have enabled researchers to examine leukemic bone marrow (BM) microenvironment more closely and helped to build mechanistic models of this process. Importantly, data from these studies show that in the majority of cases, the required stem cell populations and the erythropoietic growth mechanisms remain intact in leukemia. In this report, we aim to review the current state of knowledge regarding the cellular and molecular mechanisms implicated in the altered erythropoiesis at the time of diagnosis of leukemia. We propose that further understanding of the mechanisms of anemia in leukemia may help to manage some of its clinical consequences more effectively as well as to yield key insight into the process of leukemogenesis itself. PMID- 22543830 TI - Philadelphia-negative acute promyelocytic leukemia in a patient with chronic myeloid leukemia in complete cytogenetic response after treatment with tyrosine kinase inhibitor. PMID- 22543832 TI - Dectin-1 isoforms contribute to distinct Th1/Th17 cell activation in mucosal candidiasis. AB - The recognition of beta-glucans by dectin-1 has been shown to mediate cell activation, cytokine production and a variety of antifungal responses. Here, we report that the functional activity of dectin-1 in mucosal immunity to Candida albicans is influenced by the genetic background of the host. Dectin-1 was required for the proper control of gastrointestinal and vaginal candidiasis in C57BL/6, but not BALB/c mice; in fact, the latter showed increased resistance in the absence of dectin-1. The susceptibility of dectin-1-deficient C57BL/6 mice to infection was associated with defects in IL-17A and aryl hydrocarbon receptor dependent IL-22 production and in adaptive Th1 responses. In contrast, the resistance of dectin-1-deficient BALB/c mice was associated with increased IL-17A and IL-22 production and the skewing towards Th1/Treg immune responses that provide immunological memory. Disparate canonical/noncanonical NF-kappaB signaling pathways downstream of dectin-1 were activated in the two different mouse strains. Thus, the net activity of dectin-1 in antifungal mucosal immunity is dependent on the host's genetic background, which affects both the innate cytokine production and the adaptive Th1/Th17 cell activation upon dectin-1 signaling. PMID- 22543834 TI - British Society of Antimicrobial Chemotherapy (BSAC) guidelines for the diagnosis and treatment of endocarditis: what the cardiologist needs to know. PMID- 22543835 TI - Acute coronary syndrome in pregnancy: time to act. PMID- 22543833 TI - Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus. AB - Elevated expression of heat shock protein 90 (HSP90) has been found in kidneys and serum of systemic lupus erythematosus (SLE) patients and MRL/Mp Fas(lpr)/Fas(lpr) (MRL/lpr) autoimmune mice. We investigated if inhibition of HSP90 would reduce disease in MRL/lpr mice. In vitro, pretreatment of mesangial cells with HSP90 inhibitor Geldanamycin prior to immune-stimulation showed reduced expression of IL-6, IL-12 and NO. In vivo, we found HSP90 expression was elevated in MRL/lpr kidneys when compared to C57BL/6 mice and MRL/lpr mice treated with HSP90 inhibitor 17-DMAG. MRL/lpr mice treated with 17-DMAG showed decreased proteinuria and reduced serum anti-dsDNA antibody production. Glomerulonephritis and glomerular IgG and C3 were not significantly affected by administration of 17-DMAG in MRL/lpr. 17-DMAG increased CD8(+) T cells, reduced double-negative T cells, decreased the CD4/CD8 ratio and reduced follicular B cells. These studies suggest that HSP90 may play a role in regulating T-cell differentiation and activation and that HSP90 inhibition may reduce inflammation in lupus. PMID- 22543836 TI - Osteoprotegerin and outcomes in acute coronary syndromes--when the culprit is not the plaque. PMID- 22543837 TI - Perioperative myocardial necrosis in patients at high cardiovascular risk undergoing elective non-cardiac surgery. AB - OBJECTIVE: Cardiovascular complications are important causes of morbidity and mortality in elective non-cardiac surgery. Although difficult to diagnose, perioperative myocardial infarction (MI) remains prognostically important. High sensitivity troponin T (hs-TnT) assays allow detection of very minor damage to cardiac muscle. These assays are yet to be fully evaluated in the perioperative setting. Our aim was to determine the incidence and predictors of myocardial necrosis in patients at high cardiovascular risk undergoing elective non-cardiac surgery using hs-TnT. DESIGN: Prospective observational cohort study. PATIENTS: 352 consecutive patients undergoing elective major non-cardiac surgery prescribed antiplatelet therapy for primary or secondary cardiovascular event prevention. MAIN OUTCOME MEASURE: The incidence of elevated preoperative hs-TnT (>=14 ng/litre), hs-TnT-defined perioperative myocardial necrosis (>= 14ng/litre and 50% increase from preoperative level), and perioperative MI were determined in relation to patient and surgical factors. RESULTS: Preoperative hs-TnT was elevated in 31% and postoperative myocardial necrosis occurred in 22% of patients. Predictors of elevated baseline hs-TnT included age (OR 1.10, p<0.001), male gender (OR 2.91, p<0.001), diabetes requiring insulin therapy (OR 4.85, p=0.004) and chronic kidney disease (OR 3.60, p<0.001). Independent predictors of perioperative myocardial necrosis were age (OR 1.07, p<0.001), intraoperative hypotension (OR 3.67, p=0.001) and orthopaedic surgery (OR 2.46, p=0.005). Only 2% of patients suffered clinically apparent MI. Elevated preoperative hs-TnT did not predict perioperative myocardial necrosis or MI. CONCLUSIONS: Perioperative myocardial damage occurs frequently in patients undergoing elective non-cardiac surgery, although the majority of events are clinically undetected. Age and intraoperative hypotension are independent predictors of myocardial necrosis in this setting. PMID- 22543838 TI - Determinants and trajectory of phobic anxiety in patients living with an implantable cardioverter defibrillator. AB - OBJECTIVE: The implantable cardioverter defibrillator (ICD) is the gold standard therapy to prevent life-threatening arrhythmias. Phobic anxiety predicts ventricular arrhythmia in coronary heart disease patients, but little is known about phobic anxiety in ICD patients. This study aimed to identify determinants and the course of phobic anxiety in ICD patients. PATIENTS: 140 outpatients living with an ICD (mean age 56+/-14 years, 66% men). MAIN OUTCOME MEASURES: Phobic anxiety was assessed with the Symptom Checklist-90 Revised at a mean of 27+/-21 months (range 3-109) post-ICD placement (baseline) and after an average follow-up of 41+/-18 months (range 10-82). Multivariate linear regression models considered sociodemographic factors, clinical variables and psychological scales as potential determinants of phobic anxiety scores. RESULTS: ICD patients reported more than 10-fold higher levels of phobic anxiety than a previous representative population survey (2.6+/-3.4 vs 0.2+/-0.4). Greater age (p=0.003), previous shock experience (p=0.007), depressed mood (p<0.001) and hypochondriasis (p=0.005) were associated with higher phobic anxiety scores at baseline. Multimorbidity (p=0.030) and higher baseline phobic anxiety (p<0.001) determined greater phobic anxiety at follow-up. Younger age (p=0.029) and an elevated number of non-cardiac diseases (p=0.019) were both associated with an increase in phobic anxiety scores from baseline to follow-up. More patients had high phobic anxiety levels (score >4) at follow-up compared with baseline (31% vs 24%; p=0.048). CONCLUSIONS: Phobic anxiety was comparably high and persisted over time in ICD patients. Modifiable determinants of phobic anxiety were identified, which may inform tailored interventions to improve ICD patients' distress and perhaps also prognosis. PMID- 22543839 TI - Left atrial minimum volume and reservoir function as correlates of left ventricular diastolic function: impact of left ventricular systolic function. AB - OBJECTIVE: Left atrial (LA) maximum volume (LAV(max)) is an indicator of left ventricular (LV) diastolic function. However, LAV(max) is also influenced by systolic events, whereas the LA minimum volume (LAV(min)) is directly exposed to LV pressure. The authors hypothesised that LAV(min) may be a better correlate of LV diastolic function than LAV(max). DESIGN: Cross-sectional. SETTING: University hospital. PATIENTS: 357 participants from a community-based cohort study. METHODS: LA volumes and reservoir function, measured as total LA emptying volume (LAEV) and LA emptying fraction (LAEF), were assessed by real-time three dimensional echocardiography. LV diastolic function was assessed by trans-mitral early (E) and late (A) Doppler velocities and mitral early diastolic velocity by tissue-Doppler (e'). LV systolic function was assessed by LV ejection fraction (LVEF) and global longitudinal strain (GLS) by speckle-tracking. RESULTS: LAV(min) significantly increased with worsening diastolic dysfunction (p<0.001), whereas the increase in LAV(max) was less pronounced (p=0.07). LAEV and LAEF decreased with worsening diastolic dysfunction (both p<0.001). In linear regressions, LAV(min) and LAV(max) were significant predictors of E/e', with higher parameter estimates for LAV(min). In multivariate models, LAV(min) resulted strongly associated with E/e' (beta=0.45, p<0.001), whereas LAV(max) was not (beta=-0.16, p=0.08). LA reservoir function was better associated with GLS than LVEF. In multivariate analyses, GLS was significantly associated with LAV(max) (beta=-0.15, p=0.002), LAEV (beta=-0.37, p<0.001) and LAEF (beta=-0.28, p<0.001) but not with LAV(min). CONCLUSIONS: LAV(min) is a better correlate of LV diastolic function than LAV(max). The impact of LV longitudinal systolic function on LA reservoir function might explain the weaker relation between LAV(max) and LV diastolic function. PMID- 22543840 TI - Management of chronic total occlusion by percutaneous coronary intervention. PMID- 22543843 TI - A new type of silica-coated Gd2(CO3)3:Tb nanoparticle as a bifunctional agent for magnetic resonance imaging and fluorescent imaging. AB - We report a new type of dual modal nanoprobe to combine optical and magnetic resonance bioimaging. A simple reverse microemulsion method and coating process was introduced to synthesize silica-coated Gd(2)(CO(3))(3):Tb nanoparticles, and the particles, with an average diameter of 16 nm, can be dispersed in water. As in vitro cell imaging of the nanoprobe shows, the nanoprobe accomplishes delivery to gastric SGC7901 cancer cells successfully in a short time, as well as NCI-H460 lung cancer cells. Furthermore, it presents no evidence of cell toxicity or adverse affect on kidney cell growth under high dose, which makes the nanoprobe's optical bioimaging modality available. The possibility of using the nanoprobe for magnetic resonance imaging is also demonstrated, and the nanoprobe displays a clear T(1)-weighted effect and could potentially serve as a bimodal T(1)-positive contrast agent. Therefore, the new nanoprobe formed from carbonate nanoprobe doped with rare earth ions provides the dual modality of optical and magnetic resonance imaging. PMID- 22543841 TI - Epidemiology of substance use disorders. AB - Epidemiological studies of substance use and substance use disorders (SUDs) have provided an abundance of data on the patterns of substance use in nationally representative samples across the world (Degenhardt et al. in PLoS Med 5(7):e141, 2008; Johnston et al. in Monitoring the future national survey results on drug use, 1975-2010, vol I, secondary school students. Institute for Social Research, Ann Arbor, MI, 2011; SAMHSA in Results from the 2010 national survey on drug use and health: summary of national findings, vol NSDUH, series H-41, HHS Publication No. (SMA) 11-4658. Substance Abuse and Mental Health Services Administration, Rockville, 2011). This paper presents a summary of the goals, methods, and recent findings on the epidemiology of substance use and disorders in the general population of adults and adolescents and describes the methods and findings on the genetic epidemiology of drug use disorders. The high 12-month prevalence rates of substance dependence in US adults (about 12 % for alcohol and 2-3 % for illicit drugs) approximate those of other mental disorders as well as chronic physical disorders with major public health impact. New findings from the nationally representative samples of US youth reveal that the lifetime prevalence of alcohol use disorders is approximately 8 % and illicit drug use disorders is 2 3 % (Merikangas et al. in J Am Acad Child Adolesc Psychiatry 49(10):980-989, 2010; Swendsen et al. in Arch Gen Psychiatry 69(4):390-398, 2012; SAMHSA in Results from the 2010 national survey on drug use and health: summary of national findings, vol NSDUH, Series H-41, HHS Publication No. (SMA) 11-4658. Substance Abuse and Mental Health Services Administration, Rockville, 2011). The striking increase in prevalence rates from ages 13 to 18 highlight adolescence as the key period of development of SUDs. The application of genetic epidemiological studies has consistently demonstrated that genetic factors have a major influence on progression of substance use to dependence, whereas environmental factors unique to the individual play an important role in exposure and initial use of substances. Identification of specific susceptibility genes and environmental factors that influence exposure and progression of drug use may enhance our ability to prevent and treat SUDs. PMID- 22543845 TI - Long-term risk of cholangitis in patients with metal stents for malignant biliary obstruction. AB - BACKGROUND: Patients with malignant biliary obstruction are commonly living longer than previously due to improved oncologic therapies, often exceeding expected times of self-expanding metal stent patency. AIMS: The purpose of this study was to assess the long-term risk and impact of cholangitis in these patients. METHODS: Retrospective review of electronic medical records at an academic medical center. RESULTS: One hundred and one patients had a self expanding metal stent placed for malignant biliary obstruction. The median survival after SEMS was 214 days. Of these patients, 22 % developed at least one episode of cholangitis requiring inpatient admission, 20 % (9/45) of patients were hospitalized for cholangitis at 6 months, 40 % (8/20) at 1 year, and 75 % (3/4) at 2 years. All of the (8/8) patients receiving chemotherapy prior to hospitalization for cholangitis experienced delays in subsequent chemotherapy. Follow-up of 36 episodes of cholangitis revealed a 14 % 30-day mortality. CONCLUSIONS: Cholangitis develops commonly in long-term survivors with self expanding metal stents for malignant biliary obstruction, and is associated with delays in chemotherapy and a 14 % 30-day mortality. PMID- 22543844 TI - Vitamin C, gastritis, and gastric disease: a historical review and update. AB - The discovery of Helicobacter pylori as the cause of gastritis and peptic ulcers ushered in the modern era of research into gastritis and into acid-peptic diseases and rekindled interest in the role of ascorbic acid in the pathophysiology and treatment of gastritis and peptic ulcer disease. Here, we review historic and modern studies on ascorbic acid and gastric diseases with an emphasis on H. pylori gastritis and its sequelae. The relationship of ascorbic acid and gastritis and peptic ulcer and its complications was extensively studied during the 1930s through the 1950s. Much of this extensive literature has been effectively "lost." Ascorbic acid deficiency was associated with all forms of gastritis (e.g., autoimmune, chemical, and infectious) due in varying degrees to insufficient intake, increased metabolic requirements, and destruction within the GI tract. Importantly, gastritis-associated abnormalities in gastric ascorbic acid metabolism are reversed by H. pylori-eradication and potentially worsened by proton pump inhibitor therapy. Diets rich in naturally occurring ascorbic acid are associated with protection of the gastric corpus from atrophy and a reduction in the incidence of gastric cancer possibly through the ability of ascorbic acid to reduce oxidative damage to the gastric mucosa by scavenging carcinogenic N nitroso compounds and free radicals and attenuating the H. pylori-induced inflammatory cascade. Ascorbic acid supplementation was possibly associated with a decreased incidence of bleeding from peptic ulcer disease. Pharmacologic doses of ascorbic acid also may improve the effectiveness of H. pylori-eradication therapy. Occasionally, looking back can help plot the way forward. PMID- 22543846 TI - Late-life depression as a risk factor for mild cognitive impairment or Alzheimer's disease in 30 US Alzheimer's disease centers. AB - Identification of potentially modifiable risk factors for cognitive deterioration is important. We conducted a prospective study of 5,607 subjects with normal cognition and 2,500 subjects with mild cognitive impairment (MCI) at 30 Alzheimer's Disease Centers in the Unites States between 2005 and 2011. Cox regression was used to determine whether depression predicted transition from normal to MCI, or MCI to Alzheimer's disease (AD). Over an average of 3.3 visits, 15% of normal subjects transitioned to MCI (62/1000 per year), while 38% of MCI subjects transitioned to AD (146/1000 per year). At baseline, 22% of participants had recent (within the last two years) depression defined by clinician judgment; 9% and 17% were depressed using the Geriatric Depression Scale (GDS score >=5) and the Neuropsychiatric Inventory Questionnaire (NPI-Q), respectively. At baseline, depressed subjects performed significantly worse on cognitive tests. Those always depressed throughout follow-up had an increased risk for progression from normal to MCI (RR = 2.35; 95% CI 1.93-3.08) versus never depressed. Normal subjects, identified as depressed at first visit but subsequently improved, were found to have lower risk of progression (RR 1.40 (1.01-1.95)). The 'always depressed' had only a modest increased risk of progression from MCI to AD (RR = 1.21 (1.00-1.46). Results were similar using time-dependent variables for depression or when defining depression via the GDS or NPI-Q. We found no effect of earlier depression (>2 years past). The effect of recent depression did not differ by antidepressant treatment, APOE4 allele status, or type of MCI. In conclusion, late-life depression is a strong risk factor for normal subjects progressing to MCI. PMID- 22543847 TI - Differential expression of interneuron populations and correlation with amyloid beta deposition in the olfactory cortex of an AbetaPP/PS1 transgenic mouse model of Alzheimer's disease. AB - Impaired olfaction is an early symptom of Alzheimer's disease (AD). Neuroanatomical changes underlying this deficit in the olfactory system are largely unknown. Cell neurodegeneration is known to involve, among others, somatostatin (SST)- and calcium-binding protein-positive cells. We report here quantitative analysis of temporal changes in the distribution of interneuron cell populations in the olfactory cortex of an AbetaPP/PS1 double-transgenic mouse model of AD and its correlation with amyloid-beta pathology. To investigate early stages of pathology, the piriform and lateral entorhinal cortices were analyzed in groups of homozygous AbetaPP/PS1 and control animals at 2, 4, 6, and 8 months of age. There was a significant increase in brain levels of aggregated amyloid beta peptide with age, accompanied by an early and marked fall in numbers of SST- and calretinin-positive interneurons; a later and less pronounced decrease in levels of calbindin- and parvalbumin-positive cells was also observed. In addition, double-labeling experiments indicated high levels of co-localization of SST-positive cells with amyloid-beta expression in olfactory areas. These observations argue that SST-positive cells are vulnerable to amyloid-beta neuropathy in the olfactory cortex during the early stages of AD. These data may cast light on the neural basis of hyposmia associated with this disorder and on the mechanisms of cell vulnerability to neurodegeneration. PMID- 22543848 TI - Dietary intakes of vitamin E, vitamin C, and beta-carotene and risk of Alzheimer's disease: a meta-analysis. AB - In view of the vital role of oxidative stress in the pathogenesis of Alzheimer's disease (AD), the potential of antioxidant supplements to prevent AD have gained much interest, while there are conflicting results on this topic in recent years. The purpose of the present study is to comprehensively evaluate the association between dietary intakes, instead of supplements, of the most common three antioxidants (vitamin E, vitamin C, and beta-carotene) and the risk of AD on the basis of the meta-analysis studies published up to October 2011 in Medline and Scopus databases. In total, seven articles were included in the meta-analysis. According to the pooled relative risk [(95% CI) 0.76 (0.67-0.84) for vitamin E, 0.83 (0.72-0.94) for vitamin C, and 0.88 (0.73-1.03) for beta-carotene], dietary intakes of the three antioxidants can lower the risk of AD, with vitamin E exhibiting the most pronounced protective effects. The findings will be of significance to the prevention and interventional treatment of AD. PMID- 22543849 TI - Apathy and depression in mild Alzheimer's disease: a cross-sectional study using diagnostic criteria. AB - Apathy and depression are the most frequent neuropsychiatric symptoms in Alzheimer's disease (AD). In a cross-sectional observational study of 734 subjects with probable mild AD, we evaluated the prevalence of apathy and depression. After the use of specific diagnostic criteria, we tested the interaction between the two syndromes and their relation with specific comorbidities, and different functional outcomes. Depression was diagnosed using the diagnostic criteria for depression in AD, and apathy with the diagnostic criteria for apathy in neuropsychiatric disorders. According to the specific diagnostic criteria, depression had a 47.9% prevalence, while apathy prevalence was 41.6%. Apathy and depression were associated in 32.4% of patients (n = 225). 9.4% (n = 65) had only apathy, 15.4% (n = 107) had only depression, and 42.9% had no apathy and no depression (n = 298). The three most frequent depressive symptoms were fatigue or loss of energy (59.4%), decreased positive affect or pleasure in response to social contacts and activities (46.2%), and psychomotor agitation or retardation (36.9%). Concerning apathy, loss of goal-directed cognition was the most frequently altered (63.6%), followed by loss of goal directed action (60.6%) and loss of goal-directed emotion (43.8%). Patients with both apathy and depression more frequently required a resource allowance for dependency. Neurological comorbidities were more frequent in the "apathy and depression" and "depression alone" groups (p < 0.001). Apathy and depression overlap considerably, and this might be explained by the presence of some non specific symptoms in both diagnostic criteria. The need for social support is higher when a patient fulfills the two diagnostic criteria. PMID- 22543851 TI - Gintonin, a ginseng-derived lysophosphatidic acid receptor ligand, attenuates Alzheimer's disease-related neuropathies: involvement of non-amyloidogenic processing. AB - Ginseng extracts show cognition-enhancing effects in Alzheimer's disease (AD) patients. However, little is known about the active components and molecular mechanisms of how ginseng exerts its effects. Recently, we isolated a novel lysophosphatidic acid (LPA) receptor-activating ligand from ginseng, gintonin. AD is caused by amyloid-beta protein (Abeta) accumulation. Abeta is derived from amyloid-beta protein precursors (AbetaPPs) through the amyloidogenic pathway. In contrast, non-amyloidogenic pathways produce beneficial, soluble AbetaPPalpha (sAbetaPPalpha). Here, we describe our investigations of the effect of gintonin on sAbetaPPalpha release, Abeta formation, Swedish-AbetaPP transfection-mediated neurotoxicity in SH-SY5Y neuroblastoma cells, and Abeta-induced neuropathy in mice. Gintonin promoted sAbetaPPalpha release in a concentration- and time dependent manner. Gintonin action was also blocked by the Ca2+ chelator BAPTA, alpha-secretase inhibitor TAPI-2, and protein-trafficking inhibitor brefeldin. Gintonin decreased Abeta1-42 release and attenuated Abeta1-40-induced cytotoxicity in SH-SY5Y cells. Gintonin also rescued Abeta1-40-induced cognitive dysfunction in mice. Moreover, in a transgenic mouse AD model, long-term oral administration of gintonin attenuated amyloid plaque deposition as well as short- and long-term memory impairment. In the present study, we demonstrated that gintonin mediated the promotion of non-amyloidogenic processing to stimulate sAbetaPPalpha release to restore brain function in mice with AD. Gintonin could be a useful agent for AD prevention or therapy. PMID- 22543850 TI - Elevated plasma MCP-1 concentration following traumatic brain injury as a potential "predisposition" factor associated with an increased risk for subsequent development of Alzheimer's disease. AB - We explored whether changes in the expression profile of peripheral blood plasma proteins may provide a clinical, readily accessible "window" into the brain, reflecting molecular alterations following traumatic brain injury (TBI) that might contribute to TBI complications. We recruited fourteen TBI and ten control civilian participants for the study, and also analyzed banked plasma specimens from 20 veterans with TBI and 20 control cases. Using antibody arrays and ELISA assays, we explored differentially-regulated protein species in the plasma of TBI compared to healthy controls from the two independent cohorts. We found three protein biomarker species, monocyte chemotactic protein-1 (MCP-1), insulin-like growth factor-binding protein-3, and epidermal growth factor receptor, that are differentially regulated in plasma specimens of the TBI cases. A three-biomarker panel using all three proteins provides the best potential criterion for separating TBI and control cases. Plasma MCP-1 contents are correlated with the severity of TBI and the index of compromised axonal fiber integrity in the frontal cortex. Based on these findings, we evaluated postmortem brain specimens from 7 mild cognitive impairment (MCI) and 7 neurologically normal cases. We found elevated MCP-1 expression in the frontal cortex of MCI cases that are at high risk for developing Alzheimer's disease. Our findings suggest that additional application of the three-biomarker panel to current diagnostic criteria may lead to improved TBI detection and more sensitive outcome measures for clinical trials. Induction of MCP-1 in response to TBI might be a potential predisposing factor that may increase the risk for development of Alzheimer's disease. PMID- 22543852 TI - Handling macromolecule signals in the quantification of the neurochemical profile. AB - In vivo localized proton magnetic resonance spectroscopy (1H MRS) became a powerful and unique technique to non-invasively investigate brain metabolism of rodents and humans. The main goal of 1H MRS is the reliable quantification of concentrations of metabolites (neurochemical profile) in a well-defined region of the brain. The availability of very high magnetic field strengths combined with the possibility of acquiring spectra at very short echo time have dramatically increased the number of constituents of the neurochemical profile. The quantification of spectra measured at short echo times is complicated by the presence of macromolecule signals of particular importance at high magnetic fields. An error in the macromolecule estimation can lead to substantial errors in the obtained neurochemical profile. The purpose of the present review is to overview methods of high field 1H MRS with a focus on the metabolite quantification, in particular in handling signals of macromolecules. Three main approaches of handling signals of macromolecules are described, namely mathematical estimation of macromolecules, measurement of macromolecules in vivo, and direct acquisition of the in vivo spectrum without the contribution of macromolecules. PMID- 22543854 TI - Effect of low-intensity pulsed ultrasound stimulation on gap healing in a rabbit osteotomy model evaluated by quantitative micro-computed tomography-based cross sectional moment of inertia. AB - BACKGROUND: It has been previously demonstrated that low-intensity pulsed ultrasound stimulation (LIPUS) enhances formation of the medullary canal and cortex in a gap-healing model of the tibia in rabbits, shortens the time required for remodeling, and enhances mineralization of the callus. In the current study, the mechanical integrity of these models was confirmed. In order to do this, the cross-sectional moment of inertia (CSMI) obtained from quantitative micro computed tomography scans was calculated, and a comparison was made with a four point bending test. METHODS: This parameter can be analyzed in any direction, and three directions were selected in order to adopt an XYZ coordinate (X and Y for bending; Z for torsion). RESULTS: The present results demonstrated that LIPUS improved earlier restoration of bending stiffness at the healing site. In addition, LIPUS was effective not only in the ultrasound-irradiated plane, but also in the other two planes. CONCLUSIONS: CSMI may provide the structural as well as compositional determinants to assess fracture healing and would be very useful to replace the mechanical testing. PMID- 22543856 TI - An orthogonal comparison of the proteome of human embryonic stem cells with that of human induced pluripotent stem cells of different genetic background. AB - Induced pluripotent stem cells (iPSCs) provide an invaluable resource for drug or toxicology screening, medical research and patient-specific cell therapy. However, the potential applications of iPSCs are largely dependent on the degree of similarity between iPSCs and embryonic stem cells (ESCs). In the present study, we analyzed the proteome of human ESCs and hiPSCs with different genetic background. We carried out an orthogonal contrast analysis of the proteome pattern of two human ESC lines (Royan H5 and Royan H6) and two hiPSC lines from a normal individual, three hiPSC lines from a normal individual with Bombay blood group phenotype, and two hiPSC lines from a patient with tyrosinemia. Forty-nine protein spots showed statistically significant differences between two human ESC lines and seven human iPSCs. Mass spectrometry analysis resulted in the identification of 48 proteins belonging to different biological processes, including cytoskeleton organization, energy and metabolic processes, protein synthesis and processing, signal transduction, cell growth and proliferation, cellular trafficking, transcription, calcium binding and immune response. Our results showed that hESCs and hiPSCs had subtle differences at the proteome level thus warranting more detailed and systematic examinations of these cells. PMID- 22543853 TI - Adiposity and cognitive decline: underlying mechanisms. AB - Level of adiposity is linked to manifest dementia and Alzheimer's disease in epidemiological studies. Overweight and obesity in mid- and late-life may increase risk for dementia, whereas decline in body weight or body mass index and underweight in years preceding and at the time of a dementia diagnosis may also relate to dementia. The role of adiposity during the period of cognitive decline is, as yet, not understood; however, some hypotheses relating adipose tissue to brain can be drawn. This review focuses on potential, varied mechanisms whereby adipose tissue may influence or interact with the brain and/or dementia risk during the dynamic period of life characterized by both body weight and cognitive decline. These mechanisms relate to: a) adipose tissue location and cell types, b) body composition, c) endocrine adipose, and d) the interplay among adipose, brain structure and function, and genes. This review will illustrate that adipose tissue is a quintessential, multifunctional tissue of the human body. PMID- 22543857 TI - Selective PI3K inhibition by BKM120 and BEZ235 alone or in combination with chemotherapy in wild-type and mutated human gastrointestinal cancer cell lines. AB - PURPOSE: New targeted agents like antibodies or small molecules against tyrosine and lipid kinases clearly expand the standard therapy options in oncology. However, tumour resistance is still a challenge, often induced by mutations in growth-related signalling cascades. Twenty and ten percentage of all patients with colorectal and gastric cancers, respectively, carry phosphatidyl-3-kinase (PI3K) mutations and do not respond to receptor-blocking therapies. Recently, selective kinase inhibitors have been generated, which block the PI3K signalling pathway in tumour cells. So far, their therapeutic role for the treatment of mutated versus wild-type human gastrointestinal cancers has not been clarified in detail. METHODS: To define the inhibitory and pro-apoptotic effects of the two PI3K inhibitors BEZ235 and BKM120 in three human colon cancer (HT-29, HCT-116 and DLD-1) and three gastric cancer (NCI-n87, AGS and MKN-45), cell lines with different PIK3CA gene mutation status were used. Firstly, viability, apoptosis and caspase assays were performed during incubation with either the inhibitors alone or combined with different cytotoxic agents. Secondly, the molecular consequences for the cell cycle and signalling pathways were analysed by defining the protein levels by FACS and Western blot analysis. RESULTS: Both the PI3K inhibitors BEZ235 and BKM120 induced a clear concentration-dependent reduction in cell viability and an increase in apoptotic cell death, with the mutated cells being more sensitive to treatment. However, single-agent BEZ235 caused a G1 arrest in tumour cells, whilst BKM120 induced a G2 shift in a half of the gastrointestinal cancer cell lines. There was a clear downregulation in the protein levels of the PI3K-AKT pathway at the concentrations of 100 nM for both agents and for BEZ235 the additional inhibition of the mTOR pathway. Furthermore, BEZ235 caused synergistic induction of apoptosis when combined with irinotecan in colon cancer cell lines. Human gastric cancer cells were less sensitive to both BEZ235 and BKM120. CONCLUSIONS: BEZ235 and BKM120 induced pro-apoptotic effects in all cell lines and especially with an increased response in the PI3KCA mutated cells. Our data support the clinical development of these PI3K inhibitors for patients with wild-type or mutated colon cancers. PMID- 22543858 TI - An acid-promoted novel skeletal rearrangement initiated by intramolecular ipso Friedel-Crafts-type addition to 3-alkylidene indolenium cations. AB - An acid-promoted novel skeletal rearrangement is described. Using trifluoroacetic acid as the acid promoter, an intramolecular ipso-Friedel-Crafts-type addition of phenols to 3-alkylidene indolenium cations, formation of iminium cations through rearomatization of the spirocyclohexadienone units, and intramolecular Pictet Spengler reaction proceeded sequentially, producing tricyclic indole derivatives. PMID- 22543859 TI - A general solid phase method for the synthesis of sequence independent peptidyl fluoromethyl ketones. AB - We present here a new, general, solid phase strategy for the synthesis of sequence independent peptidyl-fluoromethyl ketones using standard Fmoc peptide chemistry. Our method is based on the synthesis of bifunctional linkers which allows the incorporation of amino acid fluoromethyl ketone unit at the C-terminal end of peptide sequences. Application of this approach for the synthesis of activity based probes for SENPs is also described. PMID- 22543860 TI - The topic of fertility presentation for young patients with cervical cancer. PMID- 22543861 TI - Letter to the editor on "Preoperative bowel preparation in gynecologic oncology: a review of practice and an impetus to change" by Wells et al, Int J Gyn Cancer 2011; 21(6):1135-1142. PMID- 22543862 TI - Identification of differentially expressed microRNAs in endometrial cancer cells after progesterone treatment. AB - INTRODUCTION: The main methods of treatment of endometrial carcinoma are hysterectomy and bilateral oophorectomy with lymphadenectomy. However, another option for hormonal treatment of endometrial carcinoma, the use of progesterone in young patients to preserve childbearing capacity, has been reported, and a high remission rate has been described in well-selected stage I, grade 1 endometrial cancer. Although it is intriguing that hormonal therapy alone can treat endometrial carcinoma without surgery or cytotoxic chemotherapy, the molecular basis for the effects of progesterone on endometrial carcinoma is not clearly known. MicroRNAs (miRNAs) are a class of naturally occurring small, noncoding RNA molecules that control cellular function and are known to function as both tumor suppressors and oncogenes. Thus, in the present study, changes in the miRNA profile of endometrial carcinoma cells on progesterone treatment were studied. METHOD: To elucidate the mechanism of hormonal treatment in endometrial carcinoma cells, we studied the changes in miRNA expression in endometrial carcinoma cells on treatment with progesterone using the Hec1A endometrial carcinoma cell line as a model system. Hec1A cells were treated with medroxyprogesterone acetate, and total RNA was extracted. The changes in the miRNA profile after progesterone treatment were determined using a microarray containing 868 miRNAs. RESULTS: Of 868 miRNAs, the expression levels of miR-625*, -21, -142-5p, and 146b-5p were increased by more than 400%, whereas the expression levels of miR-633, -29c, -29*, and -193b were decreased by 50%. To validate the array results, quantitative real-time polymerase chain reactions were performed. CONCLUSIONS: MiRNA expression was modulated by progesterone treatment in endometrial carcinoma cells, implying a possible critical role of miRNAs in regulating posttranscriptional gene expression on progesterone treatment. Further studies are required to clarify the mechanism involved in the hormonal treatment of endometrial carcinoma. PMID- 22543863 TI - Exploring purine N7 interactions via atomic mutagenesis: the group I ribozyme as a case study. AB - Atomic mutagenesis has emerged as a powerful tool to unravel specific interactions in complex RNA molecules. An early extensive study of analogs of the exogenous guanosine nucleophile in group I intron self-splicing by Bass and Cech demonstrated structure-function relationships analogous to those seen for protein ligands and provided strong evidence for a well-formed substrate binding site made of RNA. Subsequent functional and structural studies have confirmed these interacting sites and extended our understanding of them, with one notable exception. Whereas 7-methyl guanosine did not affect reactivity in the original study, a subsequent study revealed a deleterious effect of the seemingly more conservative 7-deaza substitution. Here we investigate this paradox, studying these and other analogs with the more thoroughly characterized ribozyme derived from the Tetrahymena group I intron. We found that the 7-deaza substitution lowers binding by ~20-fold, relative to the cognate exogenous guanosine nucleophile, whereas binding and reaction with 7-methyl and 8-aza-7-deaza substitutions have no effect. These and additional results suggest that there is no functionally important contact between the N7 atom of the exogenous guanosine and the ribozyme. Rather, they are consistent with indirect effects introduced by the N7 substitution on stacking interactions and/or solvation that are important for binding. The set of analogs used herein should be valuable in deciphering nucleic acid interactions and how they change through reaction cycles for other RNAs and RNA/protein complexes. PMID- 22543864 TI - Identification of the human PMR1 mRNA endonuclease as an alternatively processed product of the gene for peroxidasin-like protein. AB - The PMR1 endonuclease was discovered in Xenopus liver and identified as a member of the large and diverse peroxidase gene family. The peroxidase genes arose from multiple duplication and rearrangement events, and their high degree of sequence similarity confounded attempts to identify human PMR1. The functioning of PMR1 in mRNA decay depends on the phosphorylation of a tyrosine in the C-terminal polysome targeting domain by c-Src. The sequences of regions that are required for c-Src binding and phosphorylation of Xenopus PMR1 were used to inform a bioinformatics search that identified two related genes as potential candidates for human PMR1: peroxidasin homolog (PXDN) and peroxidasin homolog-like (PXDNL) protein. Although each of these genes is predicted to encode a large, multidomain membrane-bound peroxidase, alternative splicing of PXDNL pre-mRNA yields a transcript whose predicted product is a 57-kDa protein with 42% sequence identity to Xenopus PMR1. Results presented here confirm the existence of the predicted 57 kDa protein, show this is the only form of PXDNL detected in any of the human cell lines examined, and confirm its identity as human PMR1. Like the Xenopus protein, human PMR1 binds to c-Src, is tyrosine phosphorylated, sediments on polysomes, and catalyzes the selective decay of a PMR1 substrate mRNA. Importantly, the expression of human PMR1 stimulates cell motility in a manner similar to that of the Xenopus PMR1 expressed in human cells, thus providing definitive evidence linking endonuclease decay to the regulation of cell motility. PMID- 22543865 TI - Identification of eRF1 residues that play critical and complementary roles in stop codon recognition. AB - The initiation and elongation stages of translation are directed by codon anticodon interactions. In contrast, a release factor protein mediates stop codon recognition prior to polypeptide chain release. Previous studies have identified specific regions of eukaryotic release factor one (eRF1) that are important for decoding each stop codon. The cavity model for eukaryotic stop codon recognition suggests that three binding pockets/cavities located on the surface of eRF1's domain one are key elements in stop codon recognition. Thus, the model predicts that amino acid changes in or near these cavities should influence termination in a stop codon-dependent manner. Previous studies have suggested that the TASNIKS and YCF motifs within eRF1 domain one play important roles in stop codon recognition. These motifs are highly conserved in standard code organisms that use UAA, UAG, and UGA as stop codons, but are more divergent in variant code organisms that have reassigned a subset of stop codons to sense codons. In the current study, we separately introduced TASNIKS and YCF motifs from six variant code organisms into eRF1 of Saccharomyces cerevisiae to determine their effect on stop codon recognition in vivo. We also examined the consequences of additional changes at residues located between the TASNIKS and YCF motifs. Overall, our results indicate that changes near cavities two and three frequently mediated significant effects on stop codon selectivity. In particular, changes in the YCF motif, rather than the TASNIKS motif, correlated most consistently with variant code stop codon selectivity. PMID- 22543866 TI - ePAT: a simple method to tag adenylated RNA to measure poly(A)-tail length and other 3' RACE applications. AB - The addition of a poly(A)-tail to the 3' termini of RNA molecules influences stability, nuclear export, and efficiency of translation. In the cytoplasm, dynamic changes in the length of the poly(A)-tail have long been recognized as reflective of the switch between translational silence and activation. Thus, measurement of the poly(A)-tail associated with any given mRNA at steady-state can serve as a surrogate readout of its translation-state. Here, we describe a simple new method to 3'-tag adenylated RNA in total RNA samples using the intrinsic property of Escherichia coli DNA polymerase I to extend an RNA primer using a DNA template. This tag can serve as an anchor for cDNA synthesis and subsequent gene-specific PCR to assess poly(A)-tail length. We call this method extension Poly(A) Test (ePAT). The ePAT approach is as efficient as traditional Ligation-Mediated Poly(A) Test (LM-PAT) assays, avoids problems of internal priming associated with oligo-dT-based methods, and allows for the accurate analysis of both the poly(A)-tail length and alternate 3' UTR usage in 3' RACE applications. PMID- 22543867 TI - Basis for ligand discrimination between ON and OFF state riboswitch conformations: the case of the SAM-I riboswitch. AB - Riboswitches are RNA elements that bind to effector ligands and control gene expression. Most consist of two domains. S-Adenosyl Methionine (SAM) binds the aptamer domain of the SAM-I riboswitch and induces conformational changes in the expression domain to form an intrinsic terminator (transcription OFF state). Without SAM the riboswitch forms the transcription ON state, allowing read through transcription. The mechanistic link between the SAM/aptamer recognition event and subsequent secondary structure rearrangement by the riboswitch is unclear. We probed for those structural features of the Bacillus subtilis yitJ SAM-I riboswitch responsible for discrimination between the ON and OFF states by SAM. We designed SAM-I riboswitch RNA segments forming "hybrid" structures of the ON and OFF states. The choice of segment constrains the formation of a partial P1 helix, characteristic of the OFF state, together with a partial antiterminator (AT) helix, characteristic of the ON state. For most choices of P1 vs. AT helix lengths, SAM binds with micromolar affinity according to equilibrium dialysis. Mutational analysis and in-line probing confirm that the mode of SAM binding by hybrid structures is similar to that of the aptamer. Altogether, binding measurements and in-line probing are consistent with the hypothesis that when SAM is present, stacking interactions with the AT helix stabilize a partially formed P1 helix in the hybrids. Molecular modeling indicates that continuous stacking between the P1 and the AT helices is plausible with SAM bound. Our findings raise the possibility that conformational intermediates may play a role in ligand induced aptamer folding. PMID- 22543868 TI - Gene expression of pluripotency determinants is conserved between mammalian and planarian stem cells. AB - Freshwater planaria possess extreme regeneration capabilities mediated by abundant, pluripotent stem cells (neoblasts) in adult animals. Although planaria emerged as an attractive in vivo model system for stem cell biology, gene expression in neoblasts has not been profiled comprehensively and it is unknown how molecular mechanisms for pluripotency in neoblasts relate to those in mammalian embryonic stem cells (ESCs). We purified neoblasts and quantified mRNA and protein expression by sequencing and shotgun proteomics. We identified ~4000 genes specifically expressed in neoblasts, including all ~30 known neoblast markers. Genes important for pluripotency in ESCs, including regulators as well as targets of OCT4, were well conserved and upregulated in neoblasts. We found conserved expression of epigenetic regulators and demonstrated their requirement for planarian regeneration by knockdown experiments. Post-transcriptional regulatory genes characteristic for germ cells were also enriched in neoblasts, suggesting the existence of a common ancestral state of germ cells and ESCs. We conclude that molecular determinants of pluripotency are conserved throughout evolution and that planaria are an informative model system for human stem cell biology. PMID- 22543869 TI - Reshaping of global gene expression networks and sex-biased gene expression by integration of a young gene. AB - New genes originate frequently across diverse taxa. Given that genetic networks are typically comprised of robust, co-evolved interactions, the emergence of new genes raises an intriguing question: how do new genes interact with pre-existing genes? Here, we show that a recently originated gene rapidly evolved new gene networks and impacted sex-biased gene expression in Drosophila. This 4-6 million year-old factor, named Zeus for its role in male fecundity, originated through retroposition of a highly conserved housekeeping gene, Caf40. Zeus acquired male reproductive organ expression patterns and phenotypes. Comparative expression profiling of mutants and closely related species revealed that Zeus has recruited a new set of downstream genes, and shaped the evolution of gene expression in germline. Comparative ChIP-chip revealed that the genomic binding profile of Zeus diverged rapidly from Caf40. These data demonstrate, for the first time, how a new gene quickly evolved novel networks governing essential biological processes at the genomic level. PMID- 22543870 TI - The inner membrane histidine kinase EnvZ senses osmolality via helix-coil transitions in the cytoplasm. AB - Two-component systems mediate bacterial signal transduction, employing a membrane sensor kinase and a cytoplasmic response regulator (RR). Environmental sensing is typically coupled to gene regulation. Understanding how input stimuli activate kinase autophosphorylation remains obscure. The EnvZ/OmpR system regulates expression of outer membrane proteins in response to osmotic stress. To identify EnvZ conformational changes associated with osmosensing, we used HDXMS to probe the effects of osmolytes (NaCl, sucrose) on the cytoplasmic domain of EnvZ (EnvZ(c)). Increasing osmolality decreased deuterium exchange localized to the four-helix bundle containing the autophosphorylation site (His(243)). EnvZ(c) exists as an ensemble of multiple conformations and osmolytes favoured increased helicity. High osmolality increased autophosphorylation of His(243), suggesting that these two events are linked. In-vivo analysis showed that the cytoplasmic domain of EnvZ was sufficient for osmosensing, transmembrane domains were not required. Our results challenge existing claims of robustness in EnvZ/OmpR and support a model where osmolytes promote intrahelical H-bonding enhancing helix stabilization, increasing autophosphorylation and downstream signalling. The model provides a conserved mechanism for signalling proteins that respond to diverse physical and mechanical stimuli. PMID- 22543871 TI - Novel sequence variations in the CER1 gene are strongly associated with low bone mineral density and risk of osteoporotic fracture in postmenopausal women. AB - Osteoporosis is a common skeletal disease characterized by a combination of low bone mass and increased fragility. In this case-control study, we investigated the possible association of two novel candidate genes, CER1 and TOB1, with bone mineral density (BMD) and fragility risk in 300 postmenopausal women of Hellenic origin. The entire CER1 and TOB1 gene sequences were amplified and resequenced to assess whether there is a correlation between these genes and BMD. We identified 26 variants in both genes. Statistical analysis did not reveal any correlation between TOB1 and osteoporosis. However, CER1 genetic analysis indicated that five polymorphisms, c.194C>G, c.507+506G>T, c.508-182A>G, c.531A>G, and c.*121T>C, were correlated, with a mean T score <=-2.2. In particular, the greater number of vertebral fractures was found in patients with osteoporosis carrying the G allele of c.531A>G SNP (p = 0.015). When multiple logistic regression analysis was performed, only the c.507+506G>T polymorphism was independently associated with hip fractures or the presence of any fracture (OR = 6.95, p = 0.016, and OR = 5.33, p < 0.001, respectively). These results suggest that CER1 gene variations play a significant role in determining BMD and vertebral or hip fractures, which might be helpful in clinical practice to identify patients with increased fracture risk. PMID- 22543873 TI - Impact of thermoelectric phenomena on phase-change memory performance metrics and scaling. AB - The coupled transport of heat and electrical current, or thermoelectric phenomena, can strongly influence the temperature distribution and figures of merit for phase-change memory (PCM). This paper simulates PCM devices with careful attention to thermoelectric transport and the resulting impact on programming current during the reset operation. The electrothermal simulations consider Thomson heating within the phase-change material and Peltier heating at the electrode interface. Using representative values for the Thomson and Seebeck coefficients extracted from our past measurements of these properties, we predict a cell temperature increase of 44% and a decrease in the programming current of 16%. Scaling arguments indicate that the impact of thermoelectric phenomena becomes greater with smaller dimensions due to enhanced thermal confinement. This work estimates the scaling of this reduction in programming current as electrode contact areas are reduced down to 10 nm * 10 nm. Precise understanding of thermoelectric phenomena and their impact on device performance is a critical part of PCM design strategies. PMID- 22543874 TI - Are young adults following the dietary guidelines for Americans? AB - An analysis of lifestyle choices of Midwestern young adults suggests that this sector does not heed evidence-based guidelines for reducing risk of chronic diseases, which are the most common, costly, and preventable of all health problems. Nurse practitioners who consistently promote the guidelines may improve long-term health in this subpopulation. PMID- 22543875 TI - Rivaroxaban for thromboprophylaxis after hip or knee replacement surgery. PMID- 22543872 TI - Mouse models of SMA: tools for disease characterization and therapeutic development. AB - Mouse models of human disease are an important tool for studying disease mechanism and manifestation in a way that is physiologically relevant. Spinal muscular atrophy (SMA) is a neurodegenerative disease that is caused by deletion or mutation of the survival motor neuron gene (SMN1). The SMA disease is present in a spectrum of disease severities ranging from infant mortality, in the most severe cases, to minor motor impairment, in the mildest cases. The variability of disease severity inversely correlates with the copy number, and thus expression of a second, partially functional survival motor neuron gene, SMN2. Correspondingly, a plethora of mouse models has been developed to mimic these different types of SMA. These models express a range of SMN protein levels and extensively cover the severe and mild types of SMA, with neurological and physiological manifestation of disease supporting the relevance of these models. The SMA models provide a strong background for studying SMA and have already shown to be useful in pre-clinical therapeutic studies. The purpose of this review is to succinctly summarize the genetic and disease characteristic of the SMA mouse models and to highlight their use for therapeutic testing. PMID- 22543876 TI - Ketoacidosis in patients with type 2 diabetes. PMID- 22543877 TI - Using hCG testing in pregnancy and beyond. PMID- 22543878 TI - Venous ultrasound of the lower extremities. PMID- 22543881 TI - Uncomplicated UTIs in women. AB - Empirical diagnosis and treatment of lower urinary tract infection (UTI) in women is the most common clinical approach due to the urgency of symptoms and cost. This study examines the importance of recognizing common symptoms and accurately diagnosing UTIs in the primary care setting. PMID- 22543882 TI - Strategies for success as a clinical preceptor. AB - An integral part of an advanced practice nursing student's education is to partner with a clinical preceptor. Developing strategies to balance busy clinical practice and preceptor responsibilities can foster a positive mentoring experience. PMID- 22543884 TI - Radiation-induced oesophagitis in lung cancer patients. Is susceptibility for neutropenia a risk factor? AB - BACKGROUND: Radiation-induced oesophagitis is a major side effect of concurrent chemotherapy and radiotherapy. A strong association between neutropenia and oesophagitis was previously shown, but external validation and further elucidation of the possible mechanisms are lacking. METHODS AND PATIENTS: A total of 119 patients were included at two institutions. The concurrent group comprised 34 SCLC patients treated with concurrent carboplatin and etoposide, and concurrent chest irradiation, and 36 NSCLC patients with concurrent cisplatin and etoposide, and concurrent radiotherapy, while the sequential group comprised 49 NSCLC patients received sequential cisplatin and gemcitabine, and radiotherapy. RESULTS: Severe neutropenia was very frequent during concurrent chemoradiation (grade: 4 41.4%) and during induction chemotherapy in sequentially treated patients (grade 4: 30.6%), but not during radiotherapy (only 4% grade 1). In the concurrent group, the odds ratios of grade 3 oesophagitis vs. neutropenia were the following: grade 2 vs. grade 0/1: 5.60 (95% CI 1.55-20.26), p = 0.009; grade 3 vs. grade 0/1: 10.40 (95% CI 3.19-33.95); p = 0.0001; grade 4 vs. grade 0/1: 12.60 (95% CI 4.36-36.43); p < 0.00001. There was no correlation between the occurrence of neutropenia during induction chemotherapy and acute oesophagitis during or after radiotherapy alone. In the univariate analysis, total radiation dose (p < 0.001), overall treatment time of radiotherapy (p < 0.001), mean oesophageal dose (p = 0.038) and neutropenia (p < 0.001) were significantly associated with the development of oesophagitis. In a multivariate analysis, only neutropenia remained significant (p = 0.023). CONCLUSION: We confirm that neutropenia is independently correlated with oesophagitis in concurrent chemoradiation, but that the susceptibility for chemotherapy-induced neutropenia is not associated with radiation-induced oesophagitis. Further studies focusing on the underlying mechanisms are thus warranted. PMID- 22543885 TI - The association of genetic variants with hepatic steatosis in patients with genotype 1 chronic hepatitis C infection. AB - BACKGROUND: Single-nucleotide polymorphisms (SNPs) in the IL28B and PNPLA3 gene regions have been associated with hepatic steatosis in genotype 1 (G1) chronic HCV infection but their clinical impacts remain to be determined. AIM: We sought to validate these associations and to explore their impact on treatment response to peginterferon and ribavirin therapy. METHODS: A total of 972 G1 HCV-infected Caucasian patients were genotyped for the SNPs rs12979860 (IL28B) and rs2896019 (PNPLA3). Multivariable analysis tested IL28B and PNPLA3 for association with the presence of any steatosis (>0 %); clinically significant steatosis (>5 %); steatosis severity (grade 0-3/4); and the interacting associations of the SNPs and hepatic steatosis to sustained viral response (SVR). RESULTS: IL28B and PNPLA3 polymorphisms were associated with the presence of any steatosis (rs12979860, p = 1.87 * 10(-7); rs2896019, p = 7.56 * 10(-4)); clinically significant steatosis (rs12979860, p = 1.82 * 10(-3); rs2896019, p = 1.27 * 10( 4)); and steatosis severity (rs12979860, p = 2.05 * 10(-8); rs2896019, p = 2.62 * 10(-6)). Obesity, hypertriglyceridemia, hyperglycemia, liver fibrosis, and liver inflammation were all independently associated with worse steatosis. Hepatic steatosis was associated with lower SVR, and this effect was attenuated by IL28B. PNPLA3 had no independent association with SVR. CONCLUSIONS: IL28B and PNPLA3 are associated with hepatic steatosis prevalence and severity in Caucasians with G1 HCV, suggesting differing potential genetic risk pathways to steatosis. IL28B attenuates the association between steatosis and SVR. Remediable metabolic risk factors remain important, independently of these polymorphisms, and remain key therapeutic goals to achieve better outcomes for patients with HCV-associated hepatic steatosis. PMID- 22543886 TI - Tenofovir disoproxil fumarate for prevention of vertical transmission of hepatitis B virus infection by highly viremic pregnant women: a case series. AB - BACKGROUND: Despite appropriate immunoprophylaxis, up to 10 % of infants born to highly viremic hepatitis B virus (HBV-DNA >= 7 log IU/mL) mothers are infected with HBV. Use of TDF to prevent vertical transmission (VT) by such mothers has not been evaluated. PURPOSE: To evaluate the efficacy and safety of TDF in preventing VT from highly viremic HBV-infected mothers. METHODS: Data were collected retrospectively from HBV mono-infected, hepatitis B e antigen (HBeAg) positive, pregnant women between 6/2008 and 11/2010. Cases enrolled were HBV mono infected mothers who received TDF (300 mg orally once a day) in the third trimester. Those with pregnancy complications or an abnormal fetus on sonography were excluded from use of TDF. All infants received hepatitis B immunoglobulin and vaccination at birth and subsequently. RESULTS: Eleven Asian mothers received TDF at the median gestational age of 29 (28-32) weeks and the median duration of TDF use before delivery was 10 (7-12) weeks. A significant reduction in serum HBV DNA was achieved at delivery compared with baseline (mean 5.25 +/- 1.79 vs. 8.87 +/- 0.45 log(10) copies/mL, respectively; p < 0.01). Three had serum ALT levels more than 1.5 times the upper limit of normal and two of these normalized before delivery. The 11 infants were born with no obstetric complication or birth defects. Five infants were breastfed. All infants were hepatitis B surface antigen negative 28-36 weeks after birth. CONCLUSION: Our preliminary data suggest that TDF use in the third trimester is safe, and effectively prevents VT of HBV from high viremic HBeAg-positive mothers. PMID- 22543887 TI - Pediatric idiopathic transverse myelitis presenting as an anterior cord syndrome: a case report. AB - OBJECTIVES: Describe the case of an Anterior Cord Syndrome secondary to transverse myelitis. ANTERIOR CORD SYNDROME: Anterior Cord syndrome (ACS) is characterized by a lesion that affects the anterior two thirds of the spinal cord while preserving the posterior columns. TRANSVERSE MYELITIS: Transverse myelitis (TM) is an inflammatory disorder with a heterogeneous pathogenesis affecting the spinal cord at one or more segments, resulting in motor, sensory, and autonomic dysfunction in the absence of a preexisting neurological disease or spinal cord compression. TREATMENT: The patient was treated with methylprednisolone, IV Antibiotics, acyclovir, and inpatient rehabilitation. REHABILITATION: The patient significantly improved her function throughout inpatient rehabilitation and was discharged after achieving modified independent level with ambulation and all activities of daily living. The patient also gained independence with an intermittent catheterization program and a nightly bowel program, which included suppository and digital stimulation. CONCLUSIONS: This case illustrates the first documented pediatric patient with a unique case of Anterior Cord Syndrome caused by idiopathic transverse myelitis. PMID- 22543888 TI - StepWatch stride counting: accuracy, precision, and prediction of energy expenditure in children. AB - INTRODUCTION: Accuracy and precision of the StepWatch (SW) was tested in typically developing youth (TDY) with the prediction of oxygen consumption derived from stride counts. METHODS: Ten TDY (5 boys, 5 girls) with an average age 14.1 years (SD=2.2) enrolled. Participants underwent treadmill cardiopulmonary exercise testing (CPET) wearing two SW devices at 1, 2, 3, and 4 miles per hour (mph). RESULTS: Average sign-corrected disagreement for strides counted between the 2 monitors was 0.4 (0.52), 0.2 (0.42), 0.1 (0.32), and 0.1 (0.32) for 1, 2, 3, and 4 mph, respectively. The ratio of SW counts to observed manual counts averaged 100.03% with ICC=0.995. Oxygen consumption equations were derived from resting and walking VO(2), age, gender, and stride counts. CONCLUSIONS: Excellent accuracy and precision was documented for treadmill walking speeds up to 4 mph while VO(2) per number of strides taken appears to decrease with age and is lower in girls. PMID- 22543890 TI - A preliminary evaluation of the PEDI-CAT Mobility item bank for children using walking aids and wheelchairs. AB - OBJECTIVE: To examine the discriminant validity and scoring patterns of the PEDI CAT Mobility item bank for children who use a walking aid or wheelchair. METHODS: Parents whose children use a walking aid (n=35) or a wheelchair (n=31) completed the full PEDI-CAT Mobility item bank (105 items including 13 walking aid and 14 wheelchair items) on-line. An independent sample t-test was used to examine mean scores between the groups. Point spread and placement of the scores along the overall 20-80 test scale and response patterns for the 27 mobility device items were analyzed descriptively. RESULTS: Mean scaled scores were significantly different (p < 0.001) for the two groups. Mean score for the Wheelchair Group (38.37, SD=7.09) was lower than the Walking Aid Group (46.97, SD=5.10). The Walking Aid Group started and ended higher on the 20 to 80 scale metric than the Wheelchair Group. No floor or ceiling effects were seen for the scoring of the 27 items specifying use of a mobility device. CONCLUSION: The %scores of the PEDI CAT Mobility domain could differentiate the functional mobility status between known groups of children who use a walking aid or wheelchair and provides specific items to measure functional mobility with use of a mobility device. PMID- 22543889 TI - Effects on motor development of kicking and stepping exercise in preterm infants with periventricular brain injury: a pilot study. AB - BACKGROUND: Preterm infants with periventricular brain injury (PBI) have a high incidence of atypical development and leg movements. OBJECTIVE: Determine whether kicking and treadmill stepping intervention beginning at 2 months corrected age (CA) in children with PBI improves motor function at 12 months CA when compared with control subjects. METHOD: In a multi-center pilot study for a controlled clinical trial, sixteen infants with PBI were randomly assigned to home exercise consisting of kicking and treadmill stepping or a no-training control condition. Development was assessed at 2, 4, 6, 10, and 12 months CA with the Alberta Infant Motor Scale (AIMS). At 12 months children were classified as normal, delayed, or with cerebral palsy (CP). RESULTS: At 12 months CA 3 of 7 (43%) of the exercise group children walked alone or with one hand held versus 1 of 9 (11%) in the control group (p=0.262), but no significant differences in AIMS scores were found at any age. Half of the subjects had CP or delay; the outcomes of these infants were not improved by exercise. Compliance with the home program was lower than requested and may have affected results. CONCLUSION: Although not statistically significant with a small sample size, self-produced kicking and treadmill exercise may lower age at walking in infants with normal development following PBI, but improvements of the protocol to increase and document compliance are needed before a larger study is implemented. PMID- 22543891 TI - Functional capacity evaluation of patients with mucopolysaccharidosis. AB - INTRODUCTION: The mucopolysaccharidoses (MPS) are rare genetic disorders caused by a deficiency in lysosomal enzymes that affect the catabolism of glycosaminoglycans and cause their accumulation, resulting in a multisystemic clinical picture. Their clinical manifestations result in limited ability to perform daily life tasks. OBJECTIVES: To evaluate functional capacity and joint range of motion (ROM) in patients with MPS followed at the reference center for lysosomal disorders at Hospital de Clinicas de Porto Alegre, Brazil. METHODS: This was a prospective longitudinal study with a convenience sample. The Pediatric Evaluation of Disability Inventory (PEDI) and the Functional Independence Measure (FIM) were used to evaluate functionality and goniometry was used to evaluate ROM at three times (baseline, 6 months, and 12 months after study inclusion). An exploratory analysis was done of the effect of enzyme replacement therapy (ERT) in both variables; thus, patients were divided into Group 1 (patients without ERT), Group 2 (patients on ERT before and after study inclusion), and Group 3 (patients who started ERT after study inclusion). RESULTS: 21 patients were included: 7 in Group 1 (MPS II: 3, MPS III-B: 2, MPS IV A: 2), 6 in Group 2 (MPS I: 3; MPS VI: 3), and 8 in Group 3 (MPS I: 3, MPS II: 4, MPS VI: 1). A limitation in the mobility of all joints studied was found especially in MPS I, II, and VI. Functionality compromise was also frequent (PEDI=5/7 patients; MIF=9/14 patients), even in individuals with preserved cognition. No correlation was found between the findings of goniometry and the PEDI domains (self-care, mobility, social function). ERT did not seem to significantly change the parameters analyzed. DISCUSSION/CONCLUSION: The compromise of joint mobility and functionality seems to be common in MPS I, II, III-B, IV-A, and VI. This finding is in line with the fact that, although these types of MPS are caused by different genetic defects, they share metabolic routes and physiopathogenic processes and present similar clinical manifestations. The preservation of functionality is an increasing challenge in the treatment of MPS patients, and maintenance of occupational performance should be defined as an objective to be reached by therapies used. Further studies with a greater sample size are necessary in order to verify the effect of ERT in these variables. PMID- 22543892 TI - Physical therapy and rehabilitation issues for patients supported with extracorporeal membrane oxygenation. AB - Extracorporeal Membrane Oxygenation (ECMO) is widely used to support patients who have failed conventional therapies for cardio-respiratory failure. Patient immobility during management of critical illness and ECMO support can result in physical impairment that can lead to prolonged hospitalization and poor functional outcomes for ECMO survivors. Although little information regarding the role of physical therapy in improving functional outcomes for ECMO patients is available, early intervention with physical therapy may decrease duration of hospitalization and improve functional outcomes for patients supported with ECMO. PMID- 22543893 TI - Access to augmentative and alternative communication: new technologies and clinical decision-making. AB - Children with severe physical impairments require a variety of access options to augmentative and alternative communication (AAC) and computer technology. Access technologies have continued to develop, allowing children with severe motor control impairments greater independence and access to communication. This article will highlight new advances in access technology, including eye and head tracking, scanning, and access to mainstream technology, as well as discuss future advances. Considerations for clinical decision-making and implementation of these technologies will be presented along with case illustrations. PMID- 22543895 TI - Disinfection effect of dental impression tray adhesives. AB - OBJECTIVES: Iatrogenic infections are serious problems in dental offices. Impression tray adhesives are delivered in glass containers with a fixed brush attached inside the cap. Using the brush for application of the impression tray adhesive on a contaminated impression tray or prostheses, pathogen transmission by replacing the cap with the brush is possible. MATERIALS AND METHODS: Bacterial strains (patient strains and in vitro strains) were supervaccinated on Columbia agar. The bacterial solution was diluted with TSB and aerobically grown, and starting concentration was 1 * 10(7) cfu/ml. The stock solution was placed on Columbia agar. Alginate, polyether, and silicon impression tray adhesives were applied to the center of the particular blood agar plates and incubated for 48 h. The expansion of the inhibition zone assays were measured using a microscope. RESULTS: Twenty-one different bacterial strains were selected in the saliva samples of 20 patients. The growth inhibition for alginate impression tray adhesive was 1.1 % (+/-0.3) of the patient strains. The overgrowth of polyether impression tray adhesive was 30.6 % (+/-9.3) and for silicon impression tray adhesive 11.8 % (+/-5.0). In in vitro strains, alginate impression tray adhesive performed an inhibition of 0.7 % (+/-0.3). The overgrowth of polyether impression tray adhesive was 7.0 % (+/-1.6) and for silicon impression tray adhesive was 6.5 % (+/-1.3). CONCLUSIONS: Using the fixed brush for application of the impression tray adhesive on multiple patients, a cross-contamination cannot be ruled out. CLINICAL RELEVANCE: An application of the impression tray adhesive with a pipette and a single-use brush would eliminate the contamination. PMID- 22543896 TI - The prevalence of root resorption of maxillary incisors caused by impacted maxillary canines. AB - OBJECTIVES: The aim of this study was to evaluate the prevalence of root resorption of maxillary incisors caused by impacted maxillary canines using low dose dental computed tomography and to gain additional knowledge of the underlying aetiology and the progression of root resorption. MATERIALS AND METHODS: A total of 440 patients (mean age, 24.7 years) with 557 impacted maxillary canines were examined regarding their location and the occurrence of root resorption of maxillary incisors. RESULTS: The frequency of root resorption was 2 % of central and 7.7 % of lateral maxillary incisors. The location of the 557 impacted canines within the dental arch was palatal in 67.5 %, buccal in 15.4 % and central in 17.1 %. No significant differences could be shown with respect to the width and the shape of the dental follicle of the impacted maxillary canines and the presence of root resorption of incisors. The presence of root resorption of central (p < 0.0001) and lateral (p < 0.023) maxillary incisors was significantly correlated with an existing contact relationship of the impacted maxillary canines. CONCLUSIONS: Our investigation confirms the theory of prior reports comprising a much larger patient population, hypothesising that the dental follicle of impacted maxillary canines does not cause resorption of adjacent maxillary incisors per se. CLINICAL RELEVANCE: Root resorption of maxillary incisors is correlated with effects of contact of the impacted maxillary canines, and these findings should be considered in treatment planning. Our findings are consistent with other reports and may develop new treatment approaches for the treatment of this sequela. PMID- 22543901 TI - Harnessing regulatory T cells for therapeutic purposes. AB - Lai and colleagues demonstrate that pretreatment with N,N-dimethylsphingosine (DMS), a naturally occurring sphingosine derivative, provides renoprotection in ischemia/reperfusion injury. This DMS-induced renoprotection was abolished by the administration of agents that suppress regulatory T cells (Tregs) or by anti-CTLA 4 or anti-CD45 monoclonal antibodies, suggesting that Tregs played a critical role. The finding that Tregs are recruited to the kidney via DMS points to the exciting potential of new approaches to harnessing Tregs for therapeutic purposes. PMID- 22543897 TI - Metabolic effects of the iodothyronine functional analogue TRC150094 on the liver and skeletal muscle of high-fat diet fed overweight rats: an integrated proteomic study. AB - A novel functional iodothyronine analogue, TRC150094, which has a much lower potency toward thyroid hormone receptor (alpha1/beta1) activation than triiodothyronine, has been shown to be effective at reducing adiposity in rats simultaneously receiving a high-fat diet (HFD). Here, by combining metabolic, functional and proteomic analysis, we studied how the hepatic and skeletal muscle phenotypes might respond to TRC150094 treatment in HFD-fed overweight rats. Drug treatment increased both the liver and skeletal muscle mitochondrial oxidative capacities without altering mitochondrial efficiency. Coherently, in terms of individual respiratory in-gel activity, blue-native analysis revealed an increased activity of complex V in the liver and of complexes II and V in tibialis muscle in TCR150094-treated animals. Subsequently, the identification of differentially expressed proteins and the analysis of their interrelations gave an integrated view of the phenotypic/metabolic adaptations occurring in the liver and muscle proteomes during drug treatment. TRC150094 significantly altered the expression of several proteins involved in key liver metabolic pathways, including amino acid and nitrogen metabolism, and fructose and mannose metabolism. The canonical pathways most strongly influenced by TRC150094 in tibialis muscle included glycolysis and gluconeogenesis, amino acid, fructose and mannose metabolism, and cell signaling. The phenotypic/metabolic influence of TRC150094 on the liver and skeletal muscle of HFD-fed overweight rats suggests the potential clinical application of this iodothyronine analogue in ameliorating metabolic risk parameters altered by diet regimens. PMID- 22543902 TI - Renal vitamin D receptor expression and vitamin D renoprotection. AB - Therapy to enhance the renoprotective actions of vitamin D receptor (VDR) activation should safely overcome the distinct VDR content along the nephron to effectively control renal calcium reabsorption, control renal klotho levels for the phosphaturic actions of FGF23, and inhibit proteinuria and the activation of the renin-angiotensin system. PMID- 22543903 TI - Programmed anti-inflammatory macrophages protect against AKI and promote repair through trophic actions. AB - Because pharmacological interventions for the treatment of acute kidney injury (AKI) have remained ineffective, cell-based therapies have been developed. Marrow stromal cells have been found to be safe and potentially effective in study subjects. Jung et al. demonstrate that macrophages made to overexpress anti inflammatory interleukin-10 protect rats with AKI through iron-mediated upregulation of lipocalin-2 and its receptors, eliciting both anti-inflammatory and proliferative responses. These data further advance our understanding of cell based therapies for AKI. PMID- 22543904 TI - Chloride and the measurement of acid transport. PMID- 22543906 TI - Serum-soluble urokinase receptor concentration in primary FSGS. PMID- 22543907 TI - The contribution of chronic kidney disease to the global burden of major noncommunicable diseases. PMID- 22543908 TI - Intra-glomerular metastases. PMID- 22543910 TI - International Conference on Ovarian Cancer Screening: 29th-30th November 2011, Royal College of Physicians, London. Foreword. PMID- 22543911 TI - Inherited risk of ovarian cancer and the implications for screening. AB - Epithelial ovarian cancer is a disease normally diagnosed at late stages, when survival rates are particularly poor. Diagnostic screening strategies are currently ineffective at detecting diseases at the earliest most treatable stages. This is confounded by the relative rarity of the disease. Stratifying the population according to genetic, lifestyle, and/or epidemiological risk factors could improve early-stage screening approaches by enriching the population for individuals at greatest disease risk. If lifetime risks are substantial, surgical interventions such as laparoscopic salpingo-oophorectomy could be offered to women to eliminate altogether their risks of primary cancer of the ovary. There have been significant recent advances in characterizing genetic risk factors for a multitude of cancers, including ovarian cancer. This research has been driven by technological advances that enable very high throughput DNA scanning approaches in tens of thousands of subjects. This article summarizes the progress in identifying genetic alleles for ovarian cancer in the population and the implications for clinical intervention strategies based on identifying the proportion of the population at greatest risk of disease. PMID- 22543912 TI - The potential for risk stratification in the management of ovarian cancer risk. AB - Invasive epithelial ovarian cancer (EOC) is the most fatal malignancy of the female reproductive tract, causing more deaths than all other gynecologic cancers combined. Most cases are diagnosed at an advanced stage, and 5-year survival with EOC is less than 50%. Screening for EOC in the general population has not been found to be effective, with the recently reported results from the Prostate, Lung, Colorectal and Ovarian trial showing that there was no shift in the stage at diagnosis among the screen-detected cases and no reduction in mortality. Targeting screening at those at highest risk may prove to be more effective. An alternative approach to risk management is prophylactic surgery, which may be a useful option for women in the highest risk groups. In this article, I will summarize the current state of knowledge about ovarian cancer genetics and discuss how this knowledge may be used to target primary or secondary prevention in ovarian cancer. PMID- 22543913 TI - The UKCTOCS experience--reasons for hope? AB - There has been concern about current ovarian cancer screening strategies after the publication showing a lack of benefit from screening in the ovarian part of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. The ongoing United Kingdom Collaborative Trial of Ovarian Cancer Screening involves 202,638 low-risk postmenopausal women. The performance characteristics on prevalence screen in sensitivity, specificity, and stage distribution have been encouraging. Screening differs from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial in the use of algorithms to interpret CA125 and ultrasound imaging and well-defined, centrally coordinated management of screen-detected abnormalities with protocols for intervention based on screening findings. There is a possibility that these essential differences may be sufficient to alter the natural history of ovarian cancer and ultimately lead to demonstration of a mortality benefit from screening when the trial reports in 2014/2015. PMID- 22543914 TI - An overview of current diagnosis and treatment in ovarian cancer. PMID- 22543915 TI - Ovarian cancer screening--what women want. AB - BACKGROUND: The attitude of women with regard to the threat of ovarian cancer and toward screening for this disease is undefined. OBJECTIVE: To examine the 30-day moving results of a poll presented to women with a brief instructional component about ovarian cancer. METHODS: A poll was incorporated into the information page (http://ovarianscreening.info) used for recruitment of women into the University of Kentucky Ovarian Screening Research Program. Instructional information on ovarian cancer was included in the poll. The information page has received 26,055 unique visits, with 89.6% originating in the United States. Poll tabulation changes daily to cover the most current 30-day moving window. RESULTS: The current window (December 19, 2011) of poll results included views from 748 respondents. Ninety-seven percent of the respondents felt that ovarian cancer was a concern or threat to them. Only approximately 3% of women who felt that they were without risk factors and did not have any symptoms responded that they either did not want to participate in screening or were undecided, whereas only 2 women (<1%) with risk factors answered similarly. Ninety-one percent of the responders replied that their health insurance should pay $150 or more for screening, whereas 64% replied that they would pay $150 or more if their insurance would not. Only 1% replied that they would not want or need ovarian screening no matter what the cost, whereas 78% felt ovarian screening cost should be in line with other screening tests and be part of the standard of care. CONCLUSIONS: Women in the United States indicate in the ongoing poll that they are concerned about ovarian cancer and want screening to the extent that they express a willingness to pay for it from their own resources. PMID- 22543916 TI - Ovarian cancer screening: development of the risk of ovarian cancer algorithm (ROCA) and ROCA screening trials. AB - Ovarian cancer is most often detected in late stage when prognosis is poor; in contrast, prognosis is excellent when detection occurs in early stage. Early detection with regular biomarker tests may reduce disease-specific mortality. Two screening trials with annual CA125 greater than 35 U/mL demonstrated promise. Before undertaking larger trials, statistical analyses of serial CA125 levels showed each woman has her own baseline level; and in ovarian cancer cases, CA125 rose rapidly from her baseline after a change point. Improved early detection of ovarian cancer may result if each woman were tested for the presence of a change point CA125 profile. Using the serial CA125 from the completed trials, a statistical method was developed to measure the probability a change-point had occurred. Subsequent screening trials implemented the risk of ovarian cancer algorithm (ROCA) in which screening decisions are made based on the risk of having a change point. Development of ROCA is described, and ROCA trials are listed. PMID- 22543917 TI - Ovarian cancer screening in the high-risk population--the UK Familial Ovarian Cancer Screening Study (UKFOCSS). PMID- 22543918 TI - BRCA, the oviduct, and the space and time continuum of pelvic serous carcinogenesis. AB - In recent years, the distal oviduct has emerged as a critical organ in the pathogenesis of pelvic ("ovarian") serous cancer. Studies have uncovered early serous tubal intraepithelial carcinomas in approximately 8% of asymptomatic women with germline BRCA1 or BRCA2 mutations, linked serous tubal intraepithelial carcinomas to one half of serous cancers irrespective of genetic risk, and described a precursor lesion in the distal tube with early alterations in p53 function (the p53 signature). This work has established a linear serous carcinogenic sequence in a single focus within the fimbria. In addition, a more broadly distributed array of gene alterations has been discovered in the oviduct, manifested as secretory (or stem) cell outgrowths that are increased in frequency as a function of older age and serous cancer status. These "surrogate precursors" expand the existing model beyond the fimbria, implying that the molecular events leading to serous cancer are distributed over space and time. The potential promise of these discoveries is "targeted prevention" by discovering of multiple pathways integral to carcinogenesis and successfully preventing malignancy by interrupting one or a few of these pathways. PMID- 22543919 TI - The quest for ovarian cancer screening biomarkers: are we on the right road? AB - Recent discoveries in the field of biomarkers for screening and early detection of ovarian cancer (OC) identified current needs for biomarkers capable of recognizing preclinical disease. The suggested approaches are (1) development of highly analytically sensitive CA 125 assays capable of detecting CA 125 released from small cancerous and preneoplastic lesions; (2) identification of biomarkers effective in CA 125-negative cases; and (3) performing biomarker discovery in samples obtained from patients with prophylactic bilateral salpingo-oophorectomy with pathologically confirmed preneoplastic lesions, or in appropriate animal models of ovarian cancer. PMID- 22543920 TI - Systematic, evidence-based discovery of biomarkers at the National Cancer Institute. PMID- 22543922 TI - Characterizing ovarian pathology: refining the performance of ultrasonography. PMID- 22543921 TI - Differential diagnosis of a pelvic mass: improved algorithms and novel biomarkers. AB - More than 200,000 women undergo exploratory surgery for a pelvic mass in the United States each year and 13%-21% of pelvic lesions are found to be malignant. Individual reports and meta-analysis indicate better outcomes when cancer surgery is performed by gynecologic oncologists. Despite the advantages provided by more thorough staging and cytoreductive surgery, only 30%-50% of women with ovarian cancer are referred to surgeons with specialized training in the United States. Imaging, menopausal status and biomarkers can aid in distinguishing malignant from benign pelvic masses to inform decisions regarding appropriate referral. The risk of malignancy index (RMI) uses ultrasound, menopausal status and CA125 and has been utilized in the United Kingdom for two decades, providing sensitivity that has ranged from 71%-88% and specificity it from 97%-74% for identifying patients with malignant disease. Criteria have been established by the Society of Gynecology Oncology and American College of Obstetrics and Gynecology for referral to a gynecologic oncologist, but these have lower sensitivity and specificity than the RMI. Recently, two new algorithms have been developed to identify women at sufficiently high risk to prompt referral to a specialized surgeon. The OVA1 multivariate index incorporates imaging, menopausal status, CA125 and four other proteomic biomarkers. Use of OVA1 provides 85%-96% sensitivity at 28%-40% specificity depending upon menopausal status. The negative predictive value for women judged to be at low risk is 94%-96%. The risk of malignancy algorithm (ROMA) includes CA125, human epididymal protein 4 and menopausal status, but not imaging results. The ROMA has yielded 93%-94% sensitivity at 75% specificity with a negative predictive value of 93%-98%. In a direct comparison, ROMA has achieved greater sensitivity (94%) than the RMI (75%) at 75% specificity. OVA1 has not been compared directly to ROMA, but is likely to be as sensitive, but substantially less specific. Both algorithms have high negative predictive values 94%-98%. Although a difference in specificity should not affect patient outcomes, it could affect distribution of medical resources. PMID- 22543923 TI - Information recovery in molecular biology: causal modelling of regulated promoter switching experiments. AB - The recovery of information from indirect measurements takes different forms depending on the sophistication with which the process being researched can be modelled mathematically. The forms range from (1) the historical and classical inverse problems regularization situation where explicit models which guaranteed existence and uniqueness have been formulated, through (2) situations where model formulation is performed implicitly as a calibration-and-prediction ansatz, to (3) the exploratory (biology) situation where the underlying mechanism is unknown and constraining information about its dynamics is being sought through appropriate experimentation. Each represents a different aspect of the solution of inverse problems. It is the nature of the exploratory form that is discussed in this paper. The focus is the causal modelling of regulated promoter switching experiments performed to understand the dynamics of the genetic control of various biological developmental processes such as vernalization in plants; in particular, regulated promoter switching experiments used to examine the relationship between FLC transcription activity and the associated histone H3 lysine 27 trimethylation at a vernalization-responsive gene in plants. Using a causal representation with Kohlrausch function fading memory, it is shown how such modelling can be used to quantitatively assess the closeness of the linking of one biological process with another, and, in particular, to conclude that the dynamics of FLC transcription and associated H3K27me3 activity are closely linked biologically. PMID- 22543924 TI - Degree of molecular self-sorting in multicomponent systems. AB - Self-sorting represents the spontaneous and high fidelity self and/or non-self recognition of two or more related components within a complex mixture. While the effective management of self-sorting principles perceptibly requires some key expertise in molecular programming, at a higher stage of operation it is of supreme interest to guide the process to increasingly higher degrees of self sorting. In this article, we present the emerging principles of how to guide several components toward formation of self-sorted multicomponent architectures. To provide further guidance in denominating such systems, we suggest to utilise a systematic classification as well as a formula to evaluate their degree of self sorting (M). PMID- 22543925 TI - Pathogenesis of Paget disease of bone. AB - Paget disease of bone (PDB) is a common disease characterized by focal areas of increased and disorganized bone turnover. Some patients are asymptomatic, whereas others develop complications such as pain, osteoarthritis, fracture, deformity, deafness, and nerve compression syndromes. PDB is primarily caused by dysregulation of osteoclast differentiation and function, and there is increasing evidence that this is due, in part, to genetic factors. One of the most important predisposing genes is SQSTM1, which harbors mutations that cause osteoclast activation in 5-20 % of PDB patients. Seven additional susceptibility loci for PDB have been identified by genomewide association studies on chromosomes 1p13, 7q33, 8q22, 10p13, 14q32, 15q24, and 18q21. Although the causal variants remain to be discovered, three of these loci contain CSF1, TNFRSF11A, and TM7SF4, genes that are known to play a critical role in osteoclast differentiation and function. Environmental factors are also important in the pathogenesis of PDB, as reflected by the fact that in many countries the disease has become less common and less severe over recent years. The most widely studied environmental trigger is paramyxovirus infection, but attempts to detect viral transcripts in tissues from patients with PDB have yielded mixed results. Although our understanding of the pathophysiology of PDB has advanced tremendously over the past 10 years, many questions remain unanswered, such as the mechanisms responsible for the focal nature of the disease and the recent changes in prevalence and severity. PMID- 22543926 TI - Serum 25 hydroxy-vitamin D does not exhibit an acute phase reaction after acute myocardial infarction. AB - BACKGROUND: There is growing epidemiological evidence linking serum 25 hydroxy vitamin D (25(OH)D) concentrations to outcome in cardiovascular and other diseases. We have studied patients with acute myocardial infarction (AMI) to determine if they exhibit an acute phase reaction affecting 25(OH)D. METHODS: Patients (n=32) with first AMI who had been treated with primary percutaneous coronary intervention within 12 h of symptom onset had venous blood samples taken two days, one week, one month and three months after presentation. Samples were analysed for troponin I, C-reactive protein (CRP) and 25(OH)D. RESULTS: All patients had significant rises in troponin confirming the myocardial damage and CRP, both of which resolved by 28 days. In contrast, 25(OH)D remained unchanged throughout the 90-day observation period with a median concentration of 46 nmol/L. CONCLUSION: Serum 25(OH)D does not change after AMI and is likely to be a reliable marker of vitamin D status in patients with cardiovascular disease. PMID- 22543927 TI - Isobutanol production in engineered Saccharomyces cerevisiae by overexpression of 2-ketoisovalerate decarboxylase and valine biosynthetic enzymes. AB - Engineering of Saccharomyces cerevisiae to produce advanced biofuels such as isobutanol has received much attention because this yeast has a natural capacity to produce higher alcohols. In this study, construction of isobutanol production systems was attempted by overexpression of effective 2-keto acid decarboxylase (KDC) and combinatorial overexpression of valine biosynthetic enzymes in S. cerevisiae D452-2. Among the six putative KDC enzymes from various microorganisms, 2-ketoisovalerate decarboxylase (Kivd) from L. lactis subsp. lactis KACC 13877 was identified as the most suitable KDC for isobutanol production in the yeast. Isobutanol production by the engineered S. cerevisiae was assessed in micro-aerobic batch fermentations using glucose as a sole carbon source. 93 mg/L isobutanol was produced in the Kivd overexpressing strain, which corresponds to a fourfold improvement as compared with the control strain. Isobutanol production was further enhanced to 151 mg/L by additional overexpression of acetolactate synthase (Ilv2p), acetohydroxyacid reductoisomerase (Ilv5p), and dihydroxyacid dehydratase (Ilv3p) in the cytosol. PMID- 22543928 TI - A CRITICAL STUDY ON THE INTERACTIONS OF HESPERITIN WITH HUMAN HEMOGLOBIN: FLUORESCENCE SPECTROSCOPIC AND MOLECULAR MODELING APPROACH. AB - Hesperitin, a ubiquitous bioactive flavonoid abundant in citrus fruits is known to possess antioxidant, anti-carcinogenic, hypolipidemic, vasoprotective and other important therapeutic properties. Here we have explored the interactions of hesperitin with normal human hemoglobin (HbA), using steady state and time resolved fluorescence spectroscopy, far UV circular dicroism (CD) spectroscopy, combined with molecular modeling computations. Specific interaction of the flavonoid with HbA is confirmed from flavonoid-induced static quenching which is evident from steady state fluorescence as well as lifetime data. Both temperature dependent fluorescence measurements and molecular docking studies reveal that apart from hydrogen bonding and van der Waals interactions, electrostatic interactions also play crucial role in hesperitin-HbA interactions. Furthermore, electrostatic surface potential calculations indicate that the hesperitin binding site in HbA is intensely positive due to the presence of several lysine and histidine residues. PMID- 22543929 TI - [Congratulations to Professor Dr. med. Dr. h.c. mult. Otto Braun-Falco on the occasion of his 90th birthday]. PMID- 22543930 TI - [Prof. Dr. Otto Braun-Falco: Editor of Der Hautarzt and many medical textbooks]. PMID- 22543931 TI - [To Professor Dr. Otto Braun-Falco: An expression of appreciation and recognition from the Internal League of Dermatologic Societies (ILDS)]. PMID- 22543932 TI - [Congratulations from the DDG]. PMID- 22543934 TI - My life-long friend Otto Braun-Falco (OBF) will celebrate his 90th birthday. PMID- 22543933 TI - Congratulations. PMID- 22543935 TI - [Congratulations from the Austrian Society for Dermatology and Venereology (OGDV)]. PMID- 22543936 TI - [To Prof. Dr. Dr. h.c. mult. Otto Braun-Falco: Birthday wishes and expression of appreciation from the Swiss Society for Dermatology and Venereology (SGDV)]. PMID- 22543937 TI - [The ADF congratulates Prof. Otto Braun-Falco!]. PMID- 22543938 TI - [Otto Braun-Falco: our constant companion in daily practice]. PMID- 22543939 TI - [Greetings from the German Society for Dermatosurgery]. PMID- 22543940 TI - [Prof. Dr. h.c. mult Otto Braun-Falco and Hungarian dermatology]. PMID- 22543941 TI - [Congratulations from Prague]. PMID- 22543942 TI - [History of the textbook]. AB - The textbook "Dermatologie und Venerologie" originated with the 1st (1961) and 2nd (1969) German editions by Keining and Braun-Falco from the Departments of Dermatology at the Universities of Mainz and Marburg. The 3rd German edition was written by Braun-Falco, Plewig and Wolff (1984). The three authors became editors with the 4th German edition. Until now three English and several other foreign editions appeared. New editors are now Plewig, Burgdorf, Landthaler, Ruzicka and Hertl. Not only in German speaking countries but also in many other parts of the world the textbook is frequently used by students, residents, and dermatologists. With this retrospective view, the story of the revised editions of the book and its distribution is told. PMID- 22543943 TI - [The Otto-Braun-Falco-Stipendium: A German-Polish success story]. PMID- 22543944 TI - [Otto Braun-Falco Alumni Lecture: an illustrious occasion]. PMID- 22543945 TI - [The age of Gutenberg is over: a consideration of medical education--past, present and future]. AB - Education is the basis for reliable medical care and medical progress. Our medical knowledge has increased more in the past 50 years than in the 500 years before. The spatial and human resource capacity of our universities cannot cope with the existing academic structures and needs. Part of the problem can be solved by "blended learning", that is a combination of traditional teaching methods (frontal lectures, courses, bedside teaching) with supplementary web based e-learning. In addition to conveying a sound basic knowledge, the ability to cope with modern media and prepare for lifelong learning must also be taught. Out of the large number of e-learning platforms for undergraduate students offered in the internet, we present the program DOIT (Dermatology Online with Interactive Technology; http://www.swisdom.org) and the program Dermokrates (http://www.Dermokrates.com) of the German, Austrian and Swiss Dermatological Societies for postgraduate Continuing Medical Education (CME). The biggest obstacle in the implementation of new developments is the stubborn adherence to traditional structures. PMID- 22543946 TI - [The role of molecular genetics in dermatologic diagnosis]. AB - Modern molecular techniques have tremendously expanded our knowledge about the biologic processes in healthy individuals as well as our understanding about the pathologic events in an increasing number of dermatological diseases. These technologies initially came from basic molecular biology and genetic research but have become firmly anchored in clinical diagnosis approaches. Included in this group are immunohistochemistry (IHC), polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH), chromogen in situ hybridization (CISH), comparative genomic hybridization (CGH), and microarray technology. IHC and PCR already belong to the armamentarium for routine daily diagnostics due to their high degree of standardization and reproducibility, ease of use and relatively low costs. Others like FISH and CISH are currently employed for specific indications in a growing number of larger laboratories, whereas CGH and microarray technology still remain in the hands of a few highly specialized laboratories. These new ancillary methods will help to improve diagnostic accuracy particularly in cases in which conventional histopathology is ambiguous. In addition, they will provide new and important information concerning the prognosis, progression and response rate to therapies in several particular malignant diseases. PMID- 22543948 TI - [New developments in laser therapy]. AB - Based on the theory of stimulated emission of radiation that was proposed by Albert Einstein in 1916, the first lasers were developed in the 1960s. The first clinical use of laser technology in a German university took place in 1978 in the Department of Dermatology of the Ludwig-Maximilian-University in Munich under the guidance of the former director, Prof. Dr. med. Dr. h.c. mult. Otto Braun-Falco. In the following years, laser technology developed rapidly. Today laser technology is a widely used interdisciplinary therapeutic procedure that has deep clinical and scientific roots in dermatology. There are many conditions in both classic and aesthetic dermatology that are routinely - and sometimes exclusively treated with lasers. Here we review recent developments in laser medicine. There seems to be a trend to combination procedures. To enhance efficacy, different laser systems are together or lasers are combined with specific topical medications. PMID- 22543947 TI - [A decade of biologics in dermatology]. AB - Basic research on psoriasis has identified a number of molecular targets which can be of therapeutic interest. While the first two biologics--alefacept and efalizumab--were developed primarily for dermatologists, other agents like cytokine antagonists (TNFalpha antagonists) were introduced primarily by other medical fields. Knowledge has provided new impulses for research, so that today many therapeutic strategies are being developed, not exclusively limited to biologics. Others branches of dermatology also have benefitted greatly from biologics like ipilimumab or omalizumab. PMID- 22543949 TI - [New advances in atopic dermatitis]. AB - Atopic Dermatitis (AD) is one of the most frequent chronic skin diseases. AD is characterized by a complex, heterogeneous pathogenesis. In this review, we highlight some selected aspects of the pathophysiology of AD, which have gained much attention during recent years. These aspects profoundly changed our view of the pathogenesis of AD and will have impact on its management. PMID- 22543950 TI - [The German network for systemic sclerosis (DNSS): current data on diagnostics and therapy]. AB - An essential prerequisite for progress in understanding the pathophysiology and the clinical treatment of rare diseases is the national cooperation of specialized centers. The German network for systemic sclerosis (DNSS) is such an interdisciplinary union of hospitals and research centers with a special interest in systemic sclerosis (SSc). A core activity is the patient register of the DNSS which includes over 3,100 patients. It is one of largest national registers of SSc patients worldwide and comprises prospective data on diagnostics as well as primarily therapy of the patients. The register has now proven to be an extremely successful basis for clinical research and basic studies within the framework of international cooperation. The most important results of the cooperation and the register will be presented in this article. PMID- 22543951 TI - [Delayed appearance of symptoms in immediate hypersensitivity: type I sensitization to galactose-alpha-1,3-galactose]. AB - Delayed immediate-type allergy to innards and red meat can be mediated by IgE antibodies to galactose-alpha-1, 3-galactose (alpha-Gal). Apart from humans and Old World apes, alpha-Gal is ubiquitously expressed in glycoproteins and glycolipids. Thus, as alpha-Gal is immunogenic for humans, they can be easily sensitized even through a tick bite. Anti-alpha-Gal IgG represents approximately 1% of total IgG; IgE antibodies to alpha-Gal are comparably rare. However, in these patients, consuming red meat and especially innards can lead to the development of immediate type reactions such as urticaria. Cetuximab is a humanized IgG1 antibody containing murine alpha-Gal. Therefore, allergic reactions may occur with its first administration. PMID- 22543952 TI - Stakeholder perspectives on the use of positron emission tomography in phase III oncology trials in the UK. AB - AIM: To identify factors that influence the use of PET in phase III oncology trials in the UK by evaluating stakeholder perspectives. METHODS: A wide range of UK PET research stakeholders with a potential interest in the use of PET in phase III trials were identified and invited to participate. These UK PET research stakeholders were consulted using a semistructured questionnaire on their personal experience with and involvement in PET research, the role of PET in phase III oncology clinical trials and on the promotion of UK PET research and unmet clinical needs in oncology. Responses were analysed quantitatively and by qualitative content analysis of free-text responses. RESULTS: A total of 118 responses were received from a wide range of stakeholders representing several professional groups and working environments. Of these respondents, 49 (42%) were using PET in their research. There was the general perception that using PET in clinical research is beneficial in oncology. The two major barriers identified were poor availability of PET and perceived difficulties in funding of excess treatment costs (75% of respondents). Other factors included limited coverage of PET in training, uncertainty about developing imaging protocols or the status of tracers other than 18F-fluorodeoxyglucose, and low awareness of the role of PET in patient selection for therapeutic trials. Patient concerns about radiation were not perceived as a research barrier. CONCLUSION: Interventions that improve the availability and funding pathways for PET research scans and that increase researcher awareness could help promote the use of PET for phase III oncology trials in the UK. PMID- 22543955 TI - Graphene nanoring as a tunable source of polarized electrons. AB - We propose a novel spin filter based on a graphene nanoring fabricated above a ferromagnetic strip. The exchange interaction between the magnetic moments of the ions in the ferromagnet and the electron spin splits the electronic states, and gives rise to spin polarization of the conductance and the total electric current. We demonstrate that both the current and its polarization can be controlled by a side-gate voltage. This opens the possibility to use the proposed device as a tunable source of polarized electrons. PMID- 22543956 TI - More than just tails: intrinsic disorder in histone proteins. AB - Many biologically active proteins are disordered as a whole, or contain long disordered regions. These intrinsically disordered proteins/regions are very common in nature, abundantly found in all organisms, where they carry out important biological functions. The functions of these proteins complement the functional repertoire of "normal" ordered proteins, and many protein functional classes are heavily dependent on intrinsic disorder. Among these disorder-centric functions are interactions with nucleic acids and protein complex assembly. In this study, we present the results of comprehensive bioinformatics analyses of the abundance and roles of intrinsic disorder in 2007 histones from 746 species. We show that all the members of the histone family are intrinsically disordered proteins. Furthermore, intrinsic disorder is not only abundant in histones, but is absolutely necessary for various histone functions, starting from heterodimerization to formation of higher order oligomers, to interactions with DNA and other proteins, and to posttranslational modifications. PMID- 22543957 TI - Observational, hypothesis-driven and genomics research strategies for analyzing inherited differences in responses to infectious diseases. AB - The first phase of research on genetic factors influencing susceptibility to infectious diseases was observational and descriptive. It began with the identification of children and adults with selective and non-selective immunodeficiencies. The types of infections to which these patients are susceptible provided evidence for the roles of T-cells, B-cells, leukocytes, and complement in controlling infectious diseases. Later the biochemical bases for these deficiencies were characterized. For example, an abnormal tyrosine kinase is associated with X-linked agammaglobulinemia, and lack of adenosine deaminase results in severe combined immunodeficiency. The second strategy for analyzing inherited resistance to disease was hypothesis-driven. Observations on the distribution of the sickle-cell gene suggested that heterozygotes might be resistant to P. falciparum malaria. That proposal has been confirmed repeatedly. Persons heterozygous for other hemoglobin mutations and those with glucose-6 phosphate dehydrogenase deficiency also have some degree of resistance to malaria. The third, modern phase of research on susceptibility to infectious diseases is genomic. This powerful approach facilitated characterization of the mutations responsible for most of the above-mentioned defects. Moreover, genomics strategies make analyses of susceptibility to infections possible even when these are under multifactorial genetic control, as exemplified by malaria. This is likely to be true for most infectious diseases, so the genomic approach is an important way forward. PMID- 22543958 TI - Effects of 1,1,1-trichloroethane on enzymatic activity and bacterial community in anaerobic microcosm form sequencing batch reactors. AB - 1,1,1-Trichloroethane (TCA), a major organic and groundwater contaminant, has very strong toxic effects on humans, plants and microorganisms. Effects of TCA on enzymatic activity and microbial diversity were investigated in the anaerobic sequencing batch reactor (ASBR) under methanogenic, nitrate-reducing, sulfate reducing and benzene/toluene degrading conditions. The activities of three enzymes (lactate dehydrogenase, phosphatase and protease) were significantly decreased in the presence of 5 mg/L TCA. Within these three affected enzymes, phosphatase activity may serve as a noteworthy marker of bacterial toxicity. The activity of phosphatase was 0.2 U/L in methanogenic conditions with 5 mg/L TCA, which was 99% lower than the controls, and the enzyme activity was 18.6 U/L in methanogenic conditions with 1 mg/L TCA, which was 7% lower than the controls. DGGE profiles showed that TCA altered the bacterial community distribution and diversity obviously during the 21 day of TCA exposure. The enzyme activities decreased second lowest but TCA degrading strains Clostridium sp. DhR-2/LM-G01, Bacterial clone DCE25 and Bacterial clone DPHB06 were enriched in the methanogenic ASBR amended TCA. PMID- 22543959 TI - Zebrafish (Danio rerio) life-cycle exposure to chronic low doses of ethinylestradiol modulates p53 gene transcription within the gonads, but not NER pathways. AB - Parental full life-cycle exposure to ethinylestradiol (EE2) significantly affects embryo development and survival. One of the possible mechanisms of action of EE2 may involve the impairment of an organism's ability to repair DNA damage. DNA repair mechanisms have sophistically evolved to overcome DNA damaging hazards that threaten the integrity of the genome. In the present study, changes in the transcription levels of key genes involved in two of the most thoroughly studied DNA repair systems in mammals were evaluated in adult zebrafish (Danio rerio) gonad upon full life-cycle exposure to chronic environmentally low levels of EE2 (i.e., 0.5, 1 and 2 ng/L EE2). Real time PCR was used to analyse the expression levels of nucleotide excision repair genes (NER) as well as the tumor suppressor p53 and downstream selected effectors, i.e., p21 (cyclin-dependent kinase inhibitor), GADD45alpha (growth arrest and DNA damage induced 45, alpha), bax (bcl2-associated X protein) and p53 key regulator MDM2 (murine double minute 2 protein). NER genes transcription levels in gonads did not differ significantly among treatments. In contrast, the number of transcripts of p53 gene was significantly increased in male gonads at all EE2 exposure concentrations and in females at 1 ng/L EE2. Despite the increase in p53 transcripts, transcription levels of p21, GADD45alpha and bax genes were not affected upon EE2 treatment, whereas MDM2 gene expression significantly increased in females at the intermediate EE2 dose (1 ng/L). Overall, the present study indicate that chronic low levels of EE2 significantly modulates the transcription of p53, a key gene involved in DNA repair, particularly in male zebrafish gonads, which supports the hypothesis of an impact of EE2 in male gonad DNA repair pathways. PMID- 22543960 TI - Biodiversity and structure of spider communities along a metal pollution gradient. AB - The objective of the study was to determine whether long-term metal pollution affects communities of epigeal spiders (Aranea), studied at three taxonomic levels: species, genera, and families. Biodiversity was defined by three indices: the Hierarchical Richness Index (HRI), Margalef index (D(M)) and Pielou evenness index (J). In different ways the indices describe taxa richness and the distribution of individuals among taxa. The dominance pattern of the communities was described with four measures: number of dominant species at a site, percentage of dominant species at a site, average dominant species abundance at a site, and the share of the most numerous species (Alopecosa cuneata) at a site. Spiders were collected along a metal pollution gradient in southern Poland, extending ca. 33 km from zinc and lead smelter to an uncontaminated area. The zinc concentration in soil was used as the pollution index.The study revealed a significant effect of metal pollution on spider biodiversity as described by HRI for species (p = 0.039), genera (p = 0.0041) and families (p = 0.0147), and by D(M) for genera (p = 0.0259) and families (p = 0.0028). HRI correlated negatively with pollution level, while D(M) correlated positively. This means that although broadly described HRI diversity decreased with increasing pollution level, species richness increased with increasing contamination. Mesophilic meadows were generally richer. Pielou (J) did not show any significant correlations. There were a few evidences for the intermediate disturbance hypothesis: certain indices reached their highest values at moderate pollution levels rather than at the cleanest or most polluted sites. PMID- 22543961 TI - Tourette syndrome in youth with and without obsessive compulsive disorder and attention deficit hyperactivity disorder. AB - Chronic tic disorders (TD) are consistently found to have high rates of comorbidity with obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD). The purpose of this study is to compare the severity of TD only to TD with comorbid OCD or ADHD based on severity of tics, measures of psychopathology and additional comorbid diagnoses. Baseline data from 158 youth with a chronic TD who participated in two longitudinal studies were examined. Fifty-three percent (N = 85) of the youth also met criteria for a diagnosis of OCD, 38.6 % (n = 61) met criteria for ADHD and 24.1 % (N = 38) met criteria for both. Measures of interest addressed severity of tics, symptoms of anxiety, depression, ADHD, psychosocial stress, global functioning and the presence of comorbid diagnoses. Youth with comorbid TD and OCD were characterized by more severe tics, increased levels of depressive and anxious symptoms, heightened psychosocial stress and poorer global functioning. Youth with comorbid TD and ADHD did not differ from those with TD alone on measures of tic severity, but experienced greater psychosocial stress and poorer global functioning. Subjects with comorbid TD and OCD had more internalizing disorders than those without OCD, while those with comorbid ADHD were more likely to meet criteria for oppositional defiant disorder. TD with OCD is a more severe subtype of TD than TD without OCD. TD with ADHD is associated with higher psychosocial stress and more externalizing behaviors. Further research is needed into the underlying relationships between these closely associated conditions. PMID- 22543962 TI - Risk factors for problem behavior in adolescents of parents with a chronic medical condition. AB - A wide array of risk factors for problem behavior in adolescents with chronically ill parents emerges from the literature. This study aims to identify those factors with the highest impact on internalizing problem behavior (anxious, depressed and withdrawn behavior, and somatic complaints) and externalizing problem behavior (aggressive and rule-breaking behavior) as measured by the Youth Self-Report (YSR). The YSR was filled in by 160 adolescents (mean age = 15.1 years) from 100 families (102 chronically ill parents and 83 healthy spouses). Linear mixed model analyses were used, enabling separation of variance attributable to individual factors and variance attributable to family membership (i.e., family cluster effect). Predictors were child, parent, illness-related and family characteristics. The results showed that almost half of the variance in internalizing problem scores was explained by family membership, while externalizing problems were mainly explained by individual factors. Roughly 60 % of the variance in internalizing problems was predicted by illness duration, adolescents' feeling of isolation, daily hassles affecting personal life and alienation from the mother. Approximately a third of the variance in externalizing problems was predicted by adolescents' male gender, daily hassles concerning ill parents and alienation from both parents. In conclusion, the variance in adolescent problem behavior is largely accounted for by family membership, children's daily hassles and parent-child attachment. To prevent marginalization of adolescents with a chronically ill parent, it is important to be alert for signs of problem behavior and foster the peer and family support system. PMID- 22543963 TI - Expansion of bone marrow neutrophils following G-CSF administration in mice results in osteolineage cell apoptosis and mobilization of hematopoietic stem and progenitor cells. AB - Proliferation and differentiation of hematopoietic stem/progenitor cells (HSPC) within bone marrow (BM) niches are regulated by adhesion molecules and cytokines produced by mesenchymal stem/progenitor cells (MPC) and osteoblasts (OB). HSPCs that egresses to peripheral blood are widely used for transplant and granulocyte colony stimulating factor (G-CSF) is used clinically to induce mobilization. The mechanisms, through which G-CSF regulates HSPC trafficking, however, are not completely understood. Herein we show that G-CSF-driven neutrophil expansion alters the BM niche that leads to HSPC mobilization. Alcam(-)Sca-1(+)MPC and Alcam(+)Sca-1(-) OB are reduced coincident with mobilization, which correlates inversely with BM neutrophil expansion. In mice made neutropenic by the neutrophil-specific anti-Ly6G antibody, G-CSF-mediated reduction in MPC and OB is attenuated and mobilization reduced without an effect on monocytes/macrophages. Neutrophils, expanded in response to G-CSF-induced MPC and OB apoptosis leading to reduced production of BM HSPC retention factors, including stromal cell derived factor-1, stem cell factor and vascular cell adhesion molecule-1. Blockade of neutrophil reactive oxygen species attenuates G-CSF-mediated MPC and OB apoptosis. These data show that the expansion of BM neutrophils by G-CSF contributes to the transient degradation of retention mechanisms within the BM niche, facilitating enhanced HSPC egress/mobilization. PMID- 22543965 TI - Liver transplantation: impaired biliary excretion of gadoxate is associated with an inferior 1-year retransplantation-free survival. AB - OBJECTIVES: The aim of this study was to evaluate gadoxate-enhanced magnetic resonance imaging (MRI) in liver transplant recipients with regard to graft function and mortality at 1 year from imaging. MATERIAL AND METHODS: This was a retrospective, proof-of-concept study of gadoxate-enhanced 3-T MRI in 51 patients with orthotopic liver transplantation. Relative liver enhancement was calculated as the ratio between the signal intensities in unenhanced and gadoxate-enhanced T1-weighted gradient echo sequences with fat saturation. Impaired excretion was defined as the absence of gadoxate visualization in the common bile duct 20 minutes after intravenous injection. RESULTS: Of the 51 liver transplant recipients, 31 patients showed a normal hepatobiliary excretion of gadoxate after 20 minutes (group A), whereas 20 patients showed an impaired excretion (group B). Group B had significantly higher serum levels of bilirubin (P < 0.001), aspartate aminotransferase (P = 0.003), and alkaline phosphatase (P = 0.007), and a higher median Model for End-Stage Liver Disease score (P < 0.001). Within one-year of MRI, 55% of group B died (n = 7) or had to undergo retransplantation (n = 4), whereas all patients in group A survived without retransplantation (P < 0.001). The relative liver enhancement 20 minutes after gadoxate injection was directly related to serum levels of cholinesterase (P < 0.001) and inversely related to the serum levels of bilirubin (P = 0.0098), aspartate-aminotransferase (P = 0.007), and the Model for End-Stage Liver Disease score (P < 0.001). The relative liver enhancement 20 minutes after contrast injection was directly related to the probability of 1-year retransplantation-free survival in proportional hazard regression analysis (P = 0.005). CONCLUSION: Gadoxate-enhanced MRI may be a helpful noninvasive prognostic biomarker for chronic rejection and increased risk for 1-year mortality or retransplantation. PMID- 22543966 TI - MP2RAGE multiple sclerosis magnetic resonance imaging at 3 T. AB - OBJECTIVES: Lesion detection and characterization in multiple sclerosis (MS) are an essential part of its clinical diagnosis and an important research field. In this pilot study, we applied the recently introduced two inversion-contrast magnetization-prepared rapid gradient echo sequence (MP2RAGE) to patients with early-stage MS. MATERIALS AND METHODS: The MP2RAGE is a 3-dimensional (3D) magnetization-prepared rapid gradient echo derivative providing homogeneous T1 weighting and simultaneous T1 mapping. The MP2RAGE performance was compared with that of 2 clinical routine sequences (2D fluid-attenuated inversion recovery [FLAIR] and 3D magnetization-prepared rapid gradient echo [MP-RAGE]) and 2 state of-the art clinical research sequences (the 3D FLAIR-SPACE [sampling perfection with application-optimized contrasts by using different flip-angle evolutions], a fluid-attenuated variable flip-angle fast spin echo technique, and the 3D double inversion recovery SPACE). A cohort of 10 early-stage female MS patients (age, 31.6 +/- 4.7 years; disease duration, 3.8 +/- 1.9 years; median expanded disability status scale score, 1.75) and 10 age- and gender-matched controls were enrolled after approval of the local institutional review board was obtained. Multiple sclerosis lesions were identified and assigned to brain locations and tissue types by two experienced physicians in all 5 contrasts. Subsequently, lesions were manually delineated for comparison and statistical analysis of lesion count, volume and quantitative measures. RESULTS AND CONCLUSIONS: The results show that the 3D T1-weighted high-resolution MP2RAGE contrast provides a sensitive means for MS lesion assessment. The additional quantitative T1 relaxation time maps obtained with the MP2RAGE provide further potential diagnostic and prognostic information that could help (a) to better discriminate lesion subtypes and (b) to stage and predict the activity and the evolution of MS. Results also indicate that the T2-weighted double-inversion recovery and FLAIR-SPACE contrasts are attractive complements to the MP2RAGE for lesion detection. PMID- 22543967 TI - Diagnostic accuracy of dynamic computed tomographic angiographic of the lower leg in patients with critical limb ischemia. AB - OBJECTIVE: The purpose of this study was to assess the diagnostic accuracy of dynamic computed tomographic angiography (dyn-CTA) in patients with critical lower leg ischemia. MATERIALS AND METHODS: A population of 29 patients with known peripheral arterial occlusive disease (Fontaine stage III or IV) was examined with a combined CTA protocol consisting of a standard CTA (s-CTA) of the lower leg runoff from the diaphragm to the toes and dyn-CTA of the calves (scan range, 48 cm; 8 phases; 3.5 seconds per phase, 100 kV; 120 mAs; contrast volume, 50 mL; flow rate, 5.0 mL/s). Digital subtraction angiography was performed on all patients and served as a reference standard. For each of seven lower leg artery segments, arterial contrast and diagnostic confidence for stenosis assessment (3 point scale) were tested for s-CTA and dyn-CTA. Similarly, stenoses of calf segments were classified on a 3-point scale separately for s-CTA and dyn-CTA and were compared with digital subtraction angiography to assess diagnostic accuracy. RESULTS: Compared with s-CTA, dyn-CTA resulted in significantly higher arterial contrast enhancement (68% vs 46% optimal contrast; P < 0.01) and higher diagnostic confidence (64% vs 48% fully confident, respectively, P < 0.05). Dyn CTA had a slightly higher sensitivity for the detection of significant stenosis (98.0% vs 96.6%), and for the detection of occlusion (95.4% vs 94.4%). Specificity for dyn-CTA was higher than for s-CTA, both for detection of stenosis (97.1% vs 92.2%) and especially for the detection of vessel occlusions (99.3% vs 94.4%; P < 0.05). CONCLUSIONS: Compared with s-CTA, dyn-CTA provides improved arterial contrast enhancement, higher diagnostic confidence, and increased diagnostic accuracy for the detection of stenoses and occlusions in peripheral arterial occlusive disease patients. PMID- 22543968 TI - Mapping of proton relaxation near superparamagnetic iron oxide particle-loaded polymer threads for magnetic susceptibility difference quantification. AB - OBJECTIVES: Conventional radiological methods, including magnetic resonance imaging (MRI), fail to visualize polymeric surgical mesh implants because of small thread dimensions and material characteristics. For MRI delineation of such meshes, superparamagnetic iron oxide particles (SPIOs) are integrated in the mesh polymer. Usually, if SPIOs are used as an intravenous contrast agent, they increase the R1 and R2 of adjacent protons. It can be assumed that embedding SPIOs in polymers alters their molecular dynamics. The aim of this study was to investigate the influence of SPIO integration in polymer on the relaxation of adjacent protons. MATERIALS AND METHODS: Polymer threads were placed in an agarose phantom. At 1.5 T, R1, R2, and R2* maps were calculated from multi inversion-recovery spin echo, multi-spin echo, and multi-gradient echo images, respectively. The threads were aligned parallel or orthogonal to B(0). RESULTS: No impact of SPIO on proton R1 and R2 was observed. R2* was increased by the SPIO loaded threads. R1 and R2 amplitude maps showed a magnetic susceptibility difference of 0.97 ppm/(mg SPIO/g polymer) around SPIO-loaded threads. CONCLUSIONS: In contrast to SPIO in aqueous solutions, polymer-embedded SPIO do not affect proton R1 and R2. However, embedded SPIO generate strong local static magnetic field gradients. Thus, SPIO integration is suitable to control the magnetic susceptibility of polymer threads. This can be exploited to visualize implanted polymer-based meshes in MRI using R2* susceptible sequences. Because no impact on R1 and R2 of adjacent protons by SPIO embedded in mesh threads was observed, structures adjacent to implanted meshes will be observable in R1 and R2 maps. PMID- 22543969 TI - Hepatic fat quantification: a prospective comparison of magnetic resonance spectroscopy and analysis methods for chemical-shift gradient echo magnetic resonance imaging with histologic assessment as the reference standard. AB - OBJECTIVE: The aims of this study were to assess the confounding effects of hepatic iron deposition, inflammation, and fibrosis on hepatic steatosis (HS) evaluation by magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) and to assess the accuracies of MRI and MRS for HS evaluation, using histology as the reference standard. MATERIALS AND METHODS: In this institutional review board-approved prospective study, 56 patients gave informed consents and underwent chemical-shift MRI and MRS of the liver on a 1.5-T magnetic resonance scanner. To estimate MRI fat fraction (FF), 4 analysis methods were used (dual-echo, triple-echo, multiecho, and multi-interference), and MRS FF was calculated with T2 correction. Degrees of HS, iron deposition, inflammation, and fibrosis were analyzed in liver resection (n = 37) and biopsy (n = 19) specimens. The confounding effects of histology on fat quantification were assessed by multiple linear regression analysis. Using the histologic degree of HS as the reference standard, the accuracies of each method in estimating HS and diagnosing an HS of 5% or greater were determined by linear regression and receiver operating characteristic analyses. RESULTS: Iron deposition significantly confounded estimations of FF by the dual-echo (P < 0.001) and triple-echo (P = 0.033) methods, whereas no histologic feature confounded the multiecho and multi-interference methods or MRS. The MRS (r = 0.95) showed the strongest correlation with histologic degree of HS, followed by the multiecho (r = 0.92), multi-interference (r = 0.91), triple-echo (r = 0.90), and dual-echo (r = 0.85) methods. For diagnosing HS, the areas under the curve tended to be higher for MRS (0.96) and the multiecho (0.95), multi-interference (0.95), and triple echo (0.95) methods than for the dual-echo method (0.88) (P >= 0.13). CONCLUSION: The multiecho and multi-interference MRI methods and MRS can accurately quantify hepatic fat, with coexisting histologic abnormalities having no confounding effects. PMID- 22543970 TI - Magnetic resonance perfusion of the myocardium: semiquantitative and quantitative evaluation in comparison with coronary angiography and fractional flow reserve. AB - PURPOSE: The aim of this study was to investigate if a quantitative evaluation of a magnetic resonance (MR) perfusion examination of the myocardium can achieve a comparable diagnostic accuracy as a semiquantitative evaluation. METHODS: A total of 31 patients with suspected coronary artery disease underwent MR imaging and conventional coronary angiography. Stenoses with a diameter reduction between 50% and 75% were evaluated by an intracoronary pressure wire examination (fractional flow reserve) for assessment of their hemodynamic relevance. A 0.05 mmol/kg contrast material bolus (gadopentetate dimeglumine) was applied during adenosine induced stress (140 MUg/kg/min) and at rest with a flow rate of 5 mL/s. Signal intensity time curves of the first-pass MR perfusion images, acquired at rest and under adenosine stress with a Saturation Recovery-turbo Fast Low Angle Shot Magnetic Resonance Imaging sequence, were analyzed by Argus Dynamic Signal Analysis (Siemens Healthcare, Erlangen, Germany). For the semiquantitative evaluation, the upslope value of a linear fit from the foot point to the signal maximum was calculated for 18 segments (signal intensity units per second). For the quantitative evaluation, a model-independent deconvolution was used to calculate coronary blood flow (MBF in mL/100 g/min). For each segment for the stress and rest examination, upslope value and MBF were determined. In addition, the ratio of the stress and rest value for each segment was determined (myocardial perfusion reserve index [MPRI]). The mean value of the 2 segments with the lowest value was calculated for each patient. Coronary artery stenosis greater than 75% or greater than 50% with positive fractional flow reserve less than 0.75 was considered as hemodynamically relevant. Receiver-operator-curves were calculated. RESULTS: The values of the area under the ROC curves were 0.74, 0.66, and 0.92 for the US(Stress), US(Rest), and US(MPRI) evaluations (semiquantitative evaluation). The values for the MBF(Stress), MBF(Rest), and MBF(MPRI) evaluations (quantitative evaluation) were 0.92, 0.68, and 0.84, respectively. Comparing US(MPRI) and MBF(Stress), identical values and no significant difference were found for the area under the ROC curves. CONCLUSION: A quantitative evaluation using a model-free deconvolution provides identical diagnostic performance when only a stress examination is used, much similar to a semiquantitative evaluation, if both stress and rest examinations are used. PMID- 22543971 TI - Magnetic resonance evaluation of renal artery stenosis in a swine model: performance of low-dose gadobutrol versus gadoterate meglumine in comparison with digital subtraction intra-arterial catheter angiography. AB - PURPOSE: The aim of this study was to compare low-dose imaging with gadobutrol and gadoterate meglumine (Gd-DOTA) for evaluation of renal artery stenosis with 3 T magnetic resonance angiography (MRA) in a swine model. METHOD AND MATERIALS: A total of 12 experimental animals were evaluated using equivalently dosed gadobutrol and Gd-DOTA for time-resolved and static imaging. For time-resolved imaging, the time-resolved imaging with stochastic trajectories (TWIST) technique (temporal footprint, 4.4 seconds) was used; a dose of 1 mL of gadobutrol was injected at 2 mL/s and a dose of 2 mL of Gd-DOTA was injected at both 2 and 4 mL/s. For a separate static acquisition, doses were doubled. The static scans were used for stenosis gradation and the time-resolved scans for comparison of enhancement dynamics, signal-to-noise ratio (SNR), and qualitative assessments. RESULTS: The average magnitude of difference in the stenosis measurements with static gadobutrol scans relative to digital subtraction intra-arterial catheter angiography (mean [SD], 7.4% [5.6%]) was less than with both the 2 mL/s (10.6% [6.2%]) and 4 mL/s (11.5% [7.8%]) Gd-DOTA MRA protocols. On time-resolved scans, peak signal-to-noise ratio was greatest with the gadobutrol protocol (P < 0.05), and the gadobutrol TWIST scan was preferred to the TWIST Gd-DOTA scan in terms of image quality and stenosis visualization in every case for every reader. CONCLUSION: Low-dose gadobutrol (~0.05 mmoL/kg) contrast-enhanced MRA results in improved accuracy of renal artery stenosis assessments relative to equivalently dosed Gd-DOTA at 3 T. PMID- 22543972 TI - Small rare recurrent deletions and reciprocal duplications in 2q21.1, including brain-specific ARHGEF4 and GPR148. AB - We have identified a rare small (~450 kb unique sequence) recurrent deletion in a previously linked attention-deficit hyperactivity disorder (ADHD) locus at 2q21.1 in five unrelated families with developmental delay (DD)/intellectual disability (ID), ADHD, epilepsy and other neurobehavioral abnormalities from 17 035 samples referred for clinical chromosomal microarray analysis. Additionally, a DECIPHER (http://decipher.sanger.ac.uk) patient 2311 was found to have the same deletion and presented with aggressive behavior. The deletion was not found in either six control groups consisting of 13 999 healthy individuals or in the DGV database. We have also identified reciprocal duplications in five unrelated families with autism, developmental delay (DD), seizures and ADHD. This genomic region is flanked by large, complex low-copy repeats (LCRs) with directly oriented subunits of ~109 kb in size that have 97.7% DNA sequence identity. We sequenced the deletion breakpoints within the directly oriented paralogous subunits of the flanking LCR clusters, demonstrating non-allelic homologous recombination as a mechanism of formation. The rearranged segment harbors five genes: GPR148, FAM123C, ARHGEF4, FAM168B and PLEKHB2. Expression of ARHGEF4 (Rho guanine nucleotide exchange factor 4) is restricted to the brain and may regulate the actin cytoskeletal network, cell morphology and migration, and neuronal function. GPR148 encodes a G-protein-coupled receptor protein expressed in the brain and testes. We suggest that small rare recurrent deletion of 2q21.1 is pathogenic for DD/ID, ADHD, epilepsy and other neurobehavioral abnormalities and, because of its small size, low frequency and more severe phenotype might have been missed in other previous genome-wide screening studies using single-nucleotide polymorphism analyses. PMID- 22543973 TI - Reticulon-like-1, the Drosophila orthologue of the hereditary spastic paraplegia gene reticulon 2, is required for organization of endoplasmic reticulum and of distal motor axons. AB - Several causative genes for hereditary spastic paraplegia encode proteins with intramembrane hairpin loops that contribute to the curvature of the endoplasmic reticulum (ER), but the relevance of this function to axonal degeneration is not understood. One of these genes is reticulon2. In contrast to mammals, Drosophila has only one widely expressed reticulon orthologue, Rtnl1, and we therefore used Drosophila to test its importance for ER organization and axonal function. Rtnl1 distribution overlapped with that of the ER, but in contrast to the rough ER, was enriched in axons. The loss of Rtnl1 led to the expansion of the rough or sheet ER in larval epidermis and elevated levels of ER stress. It also caused abnormalities specifically within distal portions of longer motor axons and in their presynaptic terminals, including disruption of the smooth ER (SER), the microtubule cytoskeleton and mitochondria. In contrast, proximal axon portions appeared unaffected. Our results provide direct evidence for reticulon function in the organization of the SER in distal longer axons, and support a model in which spastic paraplegia can be caused by impairment of axonal the SER. Our data provide a route to further understanding of both the role of the SER in axons and the pathological consequences of the impairment of this compartment. PMID- 22543974 TI - Regulatory variation in a TBX5 enhancer leads to isolated congenital heart disease. AB - Recent studies have identified the genetic underpinnings of a growing number of diseases through targeted exome sequencing. However, this strategy ignores the large component of the genome that does not code for proteins, but is nonetheless biologically functional. To address the possible involvement of regulatory variation in congenital heart diseases (CHDs), we searched for regulatory mutations impacting the activity of TBX5, a dosage-dependent transcription factor with well-defined roles in the heart and limb development that has been associated with the Holt-Oram syndrome (heart-hand syndrome), a condition that affects 1/100 000 newborns. Using a combination of genomics, bioinformatics and mouse genetic engineering, we scanned ~700 kb of the TBX5 locus in search of cis regulatory elements. We uncovered three enhancers that collectively recapitulate the endogenous expression pattern of TBX5 in the developing heart. We re sequenced these enhancer elements in a cohort of non-syndromic patients with isolated atrial and/or ventricular septal defects, the predominant cardiac defects of the Holt-Oram syndrome, and identified a patient with a homozygous mutation in an enhancer ~90 kb downstream of TBX5. Notably, we demonstrate that this single-base-pair mutation abrogates the ability of the enhancer to drive expression within the heart in vivo using both mouse and zebrafish transgenic models. Given the population-wide frequency of this variant, we estimate that 1/100 000 individuals would be homozygous for this variant, highlighting that a significant number of CHD associated with TBX5 dysfunction might arise from non coding mutations in TBX5 heart enhancers, effectively decoupling the heart and hand phenotypes of the Holt-Oram syndrome. PMID- 22543975 TI - Evaluation of copy number variations reveals novel candidate genes in autism spectrum disorder-associated pathways. AB - Autism spectrum disorders (ASDs) are highly heritable, yet relatively few associated genetic loci have been replicated. Copy number variations (CNVs) have been implicated in autism; however, the majority of loci contribute to <1% of the disease population. Therefore, independent studies are important to refine associated CNV regions and discover novel susceptibility genes. In this study, a genome-wide SNP array was utilized for CNV detection by two distinct algorithms in a European ancestry case-control data set. We identify a significantly higher burden in the number and size of deletions, and disrupting more genes in ASD cases. Moreover, 18 deletions larger than 1 Mb were detected exclusively in cases, implicating novel regions at 2q22.1, 3p26.3, 4q12 and 14q23. Case-specific CNVs provided further evidence for pathways previously implicated in ASDs, revealing new candidate genes within the GABAergic signaling and neural development pathways. These include DBI, an allosteric binder of GABA receptors, GABARAPL1, the GABA receptor-associated protein, and SLC6A11, a postsynaptic GABA transporter. We also identified CNVs in COBL, deletions of which cause defects in neuronal cytoskeleton morphogenesis in model vertebrates, and DNER, a neuron specific Notch ligand required for cerebellar development. Moreover, we found evidence of genetic overlap between ASDs and other neurodevelopmental and neuropsychiatric diseases. These genes include glutamate receptors (GRID1, GRIK2 and GRIK4), synaptic regulators (NRXN3, SLC6A8 and SYN3), transcription factor (ZNF804A) and RNA-binding protein FMR1. Taken together, these CNVs may be a few of the missing pieces of ASD heritability and lead to discovering novel etiological mechanisms. PMID- 22543978 TI - Using social network analysis for assessing mental health and social services inter-organisational collaboration: findings in deprived areas in Brussels and London. AB - Fragmentation in mental health and social care delivery should be addressed at the system level. A Social Network Analysis was carried out on relations between services in order to assess Leutz's levels of care integration: linkage, coordination, and full integration. Findings for deprived areas in Brussels and London show that linkage across clusters of services is weak in both networks. However, the integration of care relies on the level of linkage in London, while in Brussels it is more dependent on central services playing brokerage roles. The method offers a useful and complementary basis for evaluating the integration of care. PMID- 22543977 TI - Duramycin exhibits antiproliferative properties and induces apoptosis in tumour cells. AB - Duramycin is a polypeptide that binds specifically to phosphatidylethanolamine (PE) on cell surfaces with high affinity, and has been shown to disrupt tumour cell surface-based coagulation and exhibit weak antimicrobial activity. The aim of the present study was to characterize the effect of duramycin on tumour cell proliferation and viability. Duramycin was used to detect phosphatidylethanolamine expression on cell lines by flow cytometry. Cells were cultured in the presence of duramycin and proliferation and cell viability assessed. Electron microscopy and confocal microscopy were utilized to investigate cell membrane structure after duramycin treatment. Pancreatic tumour cells were shown to express phosphatidylethanolamine on their cell surfaces by specific labelling with duramycin. Phosphatidylethanolamine expression was generally increased in apoptotic cells and more so in necrotic cells. Cells cultured in the presence of duramycin showed increasing levels of apoptosis and ultimately necrosis with increasing duramycin concentrations, and cell proliferation was reduced in a duramycin dose-dependent manner between 0.125 and 12.5 MUmol/l. Tissue factor expression was also reduced when cells were cultured in the presence of duramycin. Cells imaged by electron microscopy were fragile, suggesting that membrane integrity was compromised by duramycin, although no obvious differences in membrane structure were observed by live cell confocal imaging. Duramycin induced apoptosis and exhibited antiproliferative and anticoagulant effects on pancreatic tumour cells, most probably by disrupting cell membrane structure and/or function. PMID- 22543976 TI - OCRL localizes to the primary cilium: a new role for cilia in Lowe syndrome. AB - Oculocerebral renal syndrome of Lowe (OCRL or Lowe syndrome), a severe X-linked congenital disorder characterized by congenital cataracts and glaucoma, mental retardation and kidney dysfunction, is caused by mutations in the OCRL gene. OCRL is a phosphoinositide 5-phosphatase that interacts with small GTPases and is involved in intracellular trafficking. Despite extensive studies, it is unclear how OCRL mutations result in a myriad of phenotypes found in Lowe syndrome. Our results show that OCRL localizes to the primary cilium of retinal pigment epithelial cells, fibroblasts and kidney tubular cells. Lowe syndrome-associated mutations in OCRL result in shortened cilia and this phenotype can be rescued by the introduction of wild-type OCRL; in vivo, knockdown of ocrl in zebrafish embryos results in defective cilia formation in Kupffer vesicles and cilia dependent phenotypes. Cumulatively, our data provide evidence for a role of OCRL in cilia maintenance and suggest the involvement of ciliary dysfunction in the manifestation of Lowe syndrome. PMID- 22543979 TI - Postmortem distribution of tapentadol and N-desmethyltapentadol. AB - Postmortem distribution concentrations of the pain medication tapentadol and its metabolite N-desmethyltapentadol are reported. Tapentadol (Nucynta(r)) is a synthetic mu-opioid receptor agonist that also has norepinephrine reuptake inhibitor action. The laboratory received two cases. Case 1: a 19-year-old, morbidly obese male with sudden unexpected death. Toxicology results revealed tapentadol (femoral blood: 0.77 mg/L, liver: 1.65 mg/kg), N-desmethyltapentadol (femoral blood: 0.07 mg/L, liver: 0.19 mg/kg), diazepam (femoral blood: 0.04 mg/L), nordiazepam (femoral blood: 0.06 mg/L) and amiodarone (femoral blood: 5.30 mg/L). Case 2: a 60-year-old female who died from complications following hip replacement. Only tapentadol (femoral blood: 0.26 mg/L, liver: 0.52 mg/kg) was found in the toxicology results. Quantitative results of tapentadol/N desmethyltapentadol were achieved using liquid chromatography-tandem mass spectrometry in multiple reactions monitoring mode. This is the first known distribution study of tapentadol and N-desmethyltapentadol values in postmortem cases. PMID- 22543980 TI - VCD to determine absolute configuration of natural product molecules: secolignans from Peperomia blanda. AB - The absolute configuration and solution-state conformers of three peperomin-type secolignans isolated from Peperomia blanda (Piperaceae) are unambiguously determined by using vibrational circular dichroism (VCD) spectroscopy associated with density functional theory (DFT) calculations. Advantages of VCD over the electronic form of CD for the analysis of diastereomers are also discussed. This work extends our growing knowledge about secondary metabolites within the Piperaceae family species while providing a definitive and straightforward method to assess the absolute stereochemistry of secolignans. PMID- 22543981 TI - Pharmacogenetics and healthcare outcomes in patients with chronic heart failure. AB - PURPOSE: To test for associations between genetic polymorphisms of adrenergic receptors (AR) and other candidate genes and healthcare utilization in heart failure patients, taking into account other important factors, such as medication adherence. METHODS: One year-hospital utilization data were collected from 140 participants with heart failure, aged 50 years or older. Medication adherence was measured. Hospitalization and emergency department (ED) visits due to heart failure were used as healthcare outcomes. The genotypes of polymorphisms in six genes were determined: alpha(2C)-AR (ADRA2C), beta1-AR (ADRB1), beta2-AR (ADRB2), endothelial nitric oxide synthase (eNOS), angiotensin converting enzyme (ACE), and CYP4A11. Haplotypes for ADRB1 and ADRB2 were estimated. The genotype effects on healthcare outcomes were examined using log-linear regression models. RESULTS: Compared to ADRB1 Arg389 carriers, homozygous Gly389Gly carriers experienced fewer ED visits [incidence rate ratio (IRR) 0.07, 95 % confidence interval (CI) 0.01-0.54, P = 0.022]. Compared to ADRB2 homozygous Gly16Gly carriers, Arg16Gly carriers had fewer ED visits (IRR 0.23, 95 % CI 0.09-0.59, P = 0.006). Polymorphisms in ADRB1 as well as those in ADRB2 were in linkage disequilibrium, with three defining haplotypes, respectively. For ADRB2, the risk of hospitalizations and ED visits were relatively lower in Arg16/Gln27 carriers but relatively higher in homozygous Gly16/Gln27 carriers (P < 0.05). Compared to eNOS 894TT homozygous variants, 894GG and 894GT carriers had notably fewer ED visits (IRR 0.05, 95 % CI 0.01-0.25, P = 0.0013 and IRR 0.10, 95 % CI 0.02-0.42, P = 0.006, respectively). The other polymorphisms showed no association with healthcare outcomes. CONCLUSIONS: After controlling for demographics, functional status, and treatment adherence, polymorphisms in ADRB1, ADRB2 and eNOS are associated with healthcare outcomes in heart failure patients. PMID- 22543983 TI - Coherent molecular resonances in quantum dot-metallic nanoparticle systems: coherent self-renormalization and structural effects. AB - It is known that surface-plasmon resonances of metallic nanoparticles can significantly enhance the field experienced by semiconductor quantum dots. In this paper we show that, when quantum dots are in the vicinity of metallic nanoparticles and interact with coherent light sources (laser fields), coherent exciton-plasmon coupling (quantum coherence effects) can increase the amount of the plasmonic field enhancement significantly. We also study how the coherent molecular resonances generated by such a coupling process are influenced by the self-renormalization of the plasmonic fields and the structural parameters of the systems, particularly the size and shape of the metallic nanoparticle. The renormalization process happens via mutual impacts of the radiative decay rate of excitons and the coherent exciton-plasmon coupling on each other. Our results highlight the conditions where the molecular resonances become very sharp, offering optical switching processes with high extinction ratio and wide ranging device applications. PMID- 22543982 TI - Hsp90 interaction with Cdc2 and Plo1 kinases contributes to actomyosin ring condensation in fission yeast. AB - In Schizosaccharomyces pombe, cytokinesis occurs by ordered recruitment of actomyosin components at the division site, followed by lateral condensation to produce a ring-like structure early in anaphase, which eventually matures and contracts at the end of mitosis. We found that in temperature-sensitive hsp90-w1 mutant cells, encoding an Hsp90 mutant protein, ring components were recruited to form a cortical network at the division site, but this network failed to condense into a compact ring, suggesting a role for Hsp90 in this particular step. hsp90 w1 mutant shows strong genetic interaction with specific mutant alleles of the fission yeast cdc2, such as cdc2-33. Interestingly, actomyosin ring defects in hsp90-w1 cdc2-33 mutant cells resembled that of hsp90-w1 single mutant at restrictive temperature. Noteworthy, similar genetic interaction was found with a mutant allele of polo-like kinase, plo1-ts4, suggesting that Hsp90 collaborates with Cdc2 and Plo1 cell cycle kinases to condense medial ring components. In vitro analyses suggested that Cdc2 and Plo1 physically interact with Hsp90. Association of Cdc2 to Hsp90 was ATP independent, while Plo1 binds to this chaperone in an ATP-dependent manner, indicating that these two kinases interact with different Hsp90 complexes. Overall, our analyses of hsp90-w1 reveal a possible role for this chaperone in medial ring condensation in association with Cdc2 and Plo1 kinases. PMID- 22543984 TI - Legionella pneumophila found in windscreen washer fluid without added screenwash. PMID- 22543985 TI - Health Promotion Practice expands focus on global health promotion. PMID- 22543986 TI - Going global: building a foundation for global health promotion research to practice. AB - Global health promotion is now becoming an integral part of foreign policy of many countries. Health Promotion Practice has always kept pace with changes in the field of health education and promotion. The Society for Public Health Education Board of Trustees and the Editorial Board of Health Promotion Practice are pleased to announce the launch of a new department, "Global Health Promotion." This introductory commentary for the new Global Health Promotion Department of Health Promotion Practice defines global health and the new challenges for health education and health promotion. The "ecology" of global health promotion is presented as a framework to initiate dialog and discussion. Global health domains and competencies are discussed as future directions. In this commentary, we also present our vision and mission for the department as we strive for linkages between research, practice, policy, and population health promotion through cross-cultural collaboration. A call for general and departmental submissions-in the form of original research papers, case studies, symposium reports, interviews, and other forms of interprofessional communication is included to bridge research and practice in global health promotion. PMID- 22543988 TI - Adjunct teaching: part-time professorial possibilities, provisions, and provisos. PMID- 22543989 TI - Effective global health promotion achievements, tools, and strategies used in the Americas over the past decade. AB - There have been numerous international commitments made by governments from around the world to promote health and prevent illness and disease. As globalization increases our interdependence with both positive and negative effects, the World Health Organization and the Pan American Health Organization (its Regional Office for the Americas), have responded to ever increasing mandates from their member countries by developing responses to support governments in promoting health and incorporating upstream approaches into their policies, programs and activities. This article highlights some of the most important of these political declarations that have direct impact on health education and promotion ranging from the Alma Ata Declaration on Primary Health Care in 1978 to the Rio Declaration on the Social Determinants of Health in 2011. Additionally, emphasis is placed on identifying and providing examples of the application of specific tools, strategies and approaches to facilitate fulfillment of these mandates; ones that should be useful for health education and promotion practitioners everywhere. It closes by raising some of the challenges that health education and promotion will face in the future given the current trends in the world today. PMID- 22543990 TI - Views from a small Pacific island: prospects for tobacco control on Niue. AB - BACKGROUND AND AIMS: Tobacco smoking is a significant public health issue in Niue, a small Western Pacific nation where 31% of males and 16% of females smoke, and smoking initiation is still occurring at high levels among young people. There is evidence of political support for stronger tobacco control measures in Niue with ratification of the Framework Convention on Tobacco Control in 2005 and the Niue Tobacco Control Bill 2007 currently in discussion. However, more information is needed about how best to implement tobacco control measures in Niue. The aim of this research was to identify key contextual factors for progressing effective tobacco control in Niue. METHODS: Twelve in-depth interviews were conducted with health, tobacco control, and public health professionals selected purposively from both Niue and New Zealand. A semistructured interview format was used and a qualitative thematic analysis undertaken to explore common and divergent viewpoints. RESULTS: Significant progress in tobacco control is feasible in Niue, but outside technical assistance will be needed as there is very limited capacity to undertake all that needs to be done. Key steps will include developing a comprehensive tobacco control plan that will adopt a health promotion paradigm. This will include the building of strong cross-sectoral political support and community engagement to ensure local contextual knowledge guides the development of interventions. Capacity building throughout will be vital. CONCLUSION: A comprehensive health promotion approach that draws on outside technical assistance for support and capacity when needed is recommended to advance tobacco control in Niue. PMID- 22543991 TI - Bibliography-editors' selection of current world literature. PMID- 22543992 TI - Damage control strategy for the management of perforated diverticulitis with generalized peritonitis: laparoscopic lavage and drainage vs. laparoscopic Hartmann's procedure. AB - BACKGROUND: This study was designed to compare laparoscopic peritoneal lavage and drainage (LLD) with laparoscopic Hartmann's procedure (LHP) in the management of perforated diverticulitis and to investigate a safer and more effective laparoscopic method for managing acute perforated diverticulitis with generalized peritonitis. METHODS: A consecutive series of patients who underwent emergent LHP or LLD for perforated diverticulitis were identified from a prospectively designed database. All procedure-related information was collected and analyzed. P < 5 % was considered statistically significant in this study. RESULTS: A total of 88 patients underwent emergent laparoscopic procedures (47 LLD and 41 LHP) between 1995 and 2010 for acute perforated diverticulitis. Diagnostic laparoscopy classified 74 (84.1 %) patients as Hinchey III or IV perforated diverticulitis. OT for LHP was 182 +/- 54.7 min, and EBL was 210 +/- 170.5 ml. Six LHP (14.6 %) were converted to open Hartmann's for various reasons. Moreover the rates of LHP associated postoperative mortality and morbidity were 2.4 and 17.1 %, respectively. For LLD, the operating time was 99.7 +/- 39.8 min, and blood loss was 34.4 +/- 21.2 ml. Three patients (6.4 %) were reoperated for the worsening of septic symptoms during post-LLD course. Moreover, the patients with LHP had significantly longer hospital stay than the ones with LLD did (16.3 +/- 10.1 vs. 6.7 +/- 2.2 days, P < 0.01). In the long-term follow-up, the rate of colostomy closure for LHP is 72.2 %, and 21 of 47 patients who underwent LLD had elective sigmoidectomy for the source control with the rate of 44.7 %. CONCLUSIONS: Both LHP and LLD can be performed safely and effectively for managing severe diverticulitis with generalized peritonitis. Compared with LHP, LLD does not remove the pathogenic source; however, the clinical application of this damage control operation to our patients showed significantly better short- and long term clinical outcomes for managing perforated diverticulitis with various Hinchey classifications. PMID- 22543993 TI - Endoscopic balloon dilatation for benign fibrotic strictures after curative nonsurgical treatment for esophageal cancer. AB - BACKGROUND: Endoscopic balloon dilatation (EBD) is performed to treat strictures after esophagectomy. However, little is known about using EBD for benign strictures that occur after nonsurgical treatments for esophageal cancer such as chemoradiotherapy (CRT) or endoscopic mucosal resection (EMR). The aim of this study was to evaluate the safety and efficacy of EBD for benign strictures after nonsurgical treatment compared with those after surgery. METHODS: We identified 823 patients with esophageal cancer who completed definitive treatments between 2004 and 2007. Of these patients, 122 were enrolled in our study, including 60 who had surgery and 62 who did not have surgery (32 CRT, 30 EMR). The indication criteria for EBD were complaint of dysphagia and the inability to pass a conventional endoscope due to benign stricture. We retrospectively analyzed the safety and efficacy of EBD, and the measured outcomes were treatment success rate, time to treatment success, and refractory stricture rate. RESULTS: Perforation occurred in 3 (0.3 %) of 1,077 EBD sessions, with no bleeding. Efficacy was evaluated in 110 of the 122 patients. While the treatment success rate was over 90 % in both the surgery and the nonsurgery group, there was a significant difference in the median time to treatment success between both groups (2.3 vs. 5.6 months, p = 0.02: log-rank test). There was a significant difference in the median time to treatment success between CRT and surgery groups (7.0 months, p = 0.01), with no significant difference in the EMR group (4.4 months, p = 0.85). A significant difference in the refractory stricture rate was evident between the nonsurgery group (75 %) and the surgery group (45 %, p < 0.01). CONCLUSION: EBD for stricture after nonsurgical treatment of esophageal cancer was safe and effective. However, patients with benign strictures after nonsurgical treatment required significantly longer time to recover from dysphasia compared to those after surgery. PMID- 22543995 TI - Feasibility of transanal minimally invasive surgery for mid-rectal lesions. AB - BACKGROUND: Transanal minimally invasive surgery (TAMIS) has emerged as an alternative to transanal endoscopic microsurgery. We assessed the feasibility of TAMIS for lesions located in the mid rectum. METHODS: From July 2010 to October 2011, 16 consecutive patients with rectal pathology underwent TAMIS. After a single-incision laparoscopic surgery port was introduced into the anal canal, pneumorectum was established with a laparoscopic device, followed by transanal excision with conventional laparoscopic instruments, including graspers, monopolar electrocautery, and needle drivers. Clinicopathological findings, surgical procedure results, and perioperative outcomes were determined prospectively. RESULTS: Of the 16 patients, 11 had rectal cancers (3 T1 lesions and 8 after preoperative chemoradiotherapy), 4 had neuroendocrine tumors, and 1 had a mucocele. The median length of the lesions from anal verge was 7.5 cm (range 4-10 cm). All procedures were completed laparoscopically without conversion to conventional transanal approach. The median operating time was 86 min (range 33-160 min), and the median estimated blood loss was 15 ml (range 0 150 ml) with no patient requiring intraoperative transfusions. There was no surgical morbidity or mortality, but one patient died during follow-up due to synchronous advanced gastric cancer. The median postoperative hospital stay was 3 days (range 2-6 days). CONCLUSIONS: TAMIS seems to be a feasible and safe treatment option for lesions located in the mid rectum. PMID- 22543994 TI - Marginal ulcer after Roux-en-Y gastric bypass: what have we really learned? AB - BACKGROUND: The definition of marginal ulcer after Roux-en-Y gastric bypass (RYGB) is widely debated. This study reviewed findings of upper endoscopy in symptomatic patients at a quaternary bariatric referral center. Further investigation included symptom constellation, potential etiologies, and efficacy of treatment for patients found to have marginal ulcer. METHODS: Patients presenting for upper gastrointestinal endoscopy after Roux-en-Y gastric bypass were included in this study. An institutional review board-approved database was queried for the period 1 June 2010 to 31 August 2011. Subgroup analysis was performed for patients with marginal ulcer. Statistical analysis was performed using PASW version 18 for Windows. RESULTS: During the study period, 455 upper gastrointestinal endoscopies were performed for 328 consecutive symptomatic patients. Marginal ulcer, found in 112 patients (34 %), was diagnosed for 59 of the patients (53 %) within 12 months after surgery and for 53 of the patients (47 %) more than 12 months after surgery. In patients found to have marginal ulcer, the most common presenting symptoms were pain, dysphagia, nausea, and vomiting. All the patients with marginal ulcer underwent acid suppression and cytoprotective therapy. Using uni- and multivariate analyses for healing, nonhealing, and healing with recurrence, tobacco use was found to be the solitary significant risk factor for recurrence (p = 0.01). CONCLUSION: Patients with pain or dysphagia after gastric bypass warrant upper endoscopy given the high yield for abnormalities. Although the risk factors for the development of marginal ulcer remain multifactorial, a thorough investigation for potential etiologies including tobacco, alcohol, and nonsteroidal antiinflammatory drug (NSAID) usage should be determined and eliminated. The presence of multiple risk factors may pose a higher challenge in ulcer resolution, leading to increased recurrence. In the current series, prior or current tobacco use remained the sole independent risk factor for ulcer persistence. PMID- 22543998 TI - Nematode-induced low-grade chronic inflammation of the iris. AB - PURPOSE: There are thousands of parasitic nematode species that have been identified. Many have been documented to invade the eye and periorbital tissues. Whether adult or larvae, alive or dead, they can result in a wide range of ocular and systemic manifestations. Classification of the nematode can be helpful in the treatment planning for these patients. CASE REPORT: A 60-year-old Hispanic male presented without complaints. During routine examination, the presence of peripheral anterior synechiae, posterior synechiae, and focal cataract were linked to an immobile, partly degenerated 2 to 3 mm long coiled nematode in the anterior chamber. CONCLUSION: Results from DNA analysis were most consistent with a member of the Trichostrongylus or Metastrongylus genera, or a new nematode species. PMID- 22543997 TI - Exacerbations in idiopathic pulmonary fibrosis triggered by pulmonary and nonpulmonary surgery: a case series and comprehensive review of the literature. AB - BACKGROUND: Acute exacerbations (AE) of idiopathic pulmonary fibrosis (IPF) are well recognized in the progression of this uniformly fatal disease. Surgical lung biopsy and lung resection may initiate these acute events leading to a rapid deterioration and permanent decline in lung function. Our aim is to discuss the role of pulmonary and nonpulmonary surgery as a precipitating factor and to review the literature on the nature, course, and outcomes of acute exacerbations in the context of surgical interventions. METHODS: This study consisted of a retrospective case series of patients at the Johns Hopkins Hospital who experienced acute exacerbation following a surgical procedure. Patients included in the case series suffered from aggravation of dyspnea within 1 month after surgical intervention, with new infiltrates on imaging. There was no other more likely cause after diagnostic evaluation. A comprehensive review of the current literature pertaining to AEs of IPF in the context of a surgical intervention was performed. RESULTS: In a series of four patients from Johns Hopkins Hospital with AE in IPF, two of three patients who underwent video-assisted thoracoscopic surgery (VATS) lung biopsy had a fatal outcome. The fourth patient survived an AE after a total knee replacement but had a fatal outcome after a subsequent coronary artery bypass graft surgery. We found no report in the literature of AE in an IPF patient who underwent nonpulmonary surgery. CONCLUSIONS: Acute exacerbations of IPF can occur postoperatively after both pulmonary and nonpulmonary surgery and are associated with a high mortality rate. As a next step, a prospective multicenter clinical study of patients with IPF undergoing both pulmonary and nonpulmonary surgeries would allow the identification of perioperative risk factors in the development of AE of IPF. PMID- 22543999 TI - Repeatability of internal aberrometry with a new simultaneous capture aberrometer/corneal topographer. AB - PURPOSE: To compare repeatability of internal eye aberrations derived from aberrometry and corneal topography (CT) measured simultaneously by the Innovative Visual Systems Discovery, against time displaced but same instrument measurement (Nidek OPD-Scan 3), and time displaced different instrument measurement (Medmont E300 and Imagine Eyes irx3). METHODS: Three aberrometry and CT measurements were captured with each instrument, except for the OPD-Scan 3 where three aberrometry scans were followed by a single CT. Measurements were repeated across 2 days. Corneal surface Zernike coefficients were derived from CT and subtracted from aberrometry to establish internal aberration coefficients. For the OPD-Scan 3, internal Zernike coefficients were derived by the instrument's software. Repeatability for second-order root mean square (RMS), spherical aberration, coma RMS, trefoil RMS, and the refraction components M, J0, and J45 were assessed using intraclass correlation coefficient (ICC). RESULTS: Intrasession repeatability was similar between the Discovery and E300/irx3, with the E300/irx3 slightly more repeatable for second-order RMS. Across days, the Discovery was most repeatable for second-order RMS (ICC 0.98) followed by the E300/irx3 (ICC 0.96) and OPD-Scan 3 (ICC 0.88). All instruments were less repeatable for higher order aberrations with only the Discovery moderately repeatable for spherical aberration and trefoil RMS (both ICC >= 0.75). The Discovery was highly repeatable for all derived refractive components (ICC >= 0.96). The E300/irx3 was highly repeatable for M (ICC 0.98) and moderately repeatable for J0 (ICC 0.89). The OPD-Scan 3 was highly repeatable for the M component (ICC 0.98) but not repeatable for the cylindrical components. CONCLUSIONS: The Discovery was highly repeatable for second-order RMS and derived refractive components. The lower repeatability for internal higher order aberrations measured with all instruments suggests caution in their use until further work is carried out to investigate sources of error and to develop methods to improve repeatability. PMID- 22544000 TI - A cross-sectional analysis of U.S. contact lens user demographics. AB - PURPOSE: Large population studies carried out in the United States, while addressing refractive error prevalence, have published little addressing the modes of refractive correction. As such, there are little data in the biomedical literature concerning the characteristics of the contact lens wearing population in the United States. The purpose of this project was to develop estimates of the demographic characteristics of a cross section of contact lens wearers in the United States based on those who wore contact lenses on the day of their National Health and Nutrition Examination Survey (NHANES) examination. METHODS: The NHANES is a nationally representative sample of the U.S. population. As part of NHANES, the type of refractive correction used is collected during a mobile medical clinic examination along with demographic variables. Data files from the 2005 2006 and 2007-2008 NHANES were obtained from the National Center for Health Statistics. Demographic characteristics of the U.S. population using contacts during the medical clinic examination were derived. Associations between demographic variables and contact lens use were explored in age-stratified univariate and multivariate analyses taking into account the complex sampling frame. RESULTS: In univariate analysis, age (p < 0.001) and the availability of health insurance (p = 0.007) have negative associations with contact lens use, while female gender (p < 0.001), higher socioeconomic status (p < 0.001), and higher educational attainment (p < 0.001) are associated with increased contact lens use. In multivariate analysis, age (p < 0.001), socioeconomic status (p < 0.001), the interaction of age with gender (p < 0.001), and the interaction of socioeconomic status with education (p = 0.002) are associated with contact lens use. CONCLUSIONS: Four demographic variables, age, socioeconomic status, age gender interaction, and socioeconomic status-education interaction, defined those likely to be using contact lens on any given day in the United States. Together, these four variables identify almost 9 of 10 contact lens users. PMID- 22544001 TI - Predictors of adequate correction following vision screening failure. AB - PURPOSE: To determine whether compliance with referral 1 year after vision screening failure was associated with care model, demographic, or ocular factors. METHODS: Data were analyzed from 798 children in the Collaborative Longitudinal Evaluation of Ethnicity and Refractive Error Study with habitual logMAR visual acuity (VA) >=0.26 (20/40 + 2 or worse) in either eye due to uncorrected or undercorrected refractive error and who returned the following year. The parents of 492 children failing in TX and CA were sent letters indicating the need for a complete vision examination (screening model), while 306 children seen primarily in AZ and AL received a free complete examination and eyeglasses if needed (complete care model). Presenting to follow-up with adequate correction (logMAR <0.26) in each eye was considered compliant. Logistic regression models for compliance were fit to assess whether care model, ethnicity, sex, age, uncorrected logMAR in the better eye, or parental income, education, or myopia were predictors. RESULTS: Overall compliance was 28%. Age [p = 0.01, odds ratio (OR) = 1.12] and uncorrected logMAR (p < 0.001, OR = 1.13) were associated with compliance but care model, ethnicity, and sex were not. Among the 447 children for whom data on parental factors were available, 27% were compliant. In this model, age, ethnicity, sex, parental income, parental education, and parental myopia were not associated with compliance, but uncorrected logMAR (p = 0.005; OR = 1.13) was predictive. An interaction between unaided VA and care model predicted improved compliance with poorer unaided VA in the complete care model. CONCLUSIONS: Expensive complete care screening programs may not improve compliance over typical notification and referral screening protocols in school aged children, unless unaided VA is worse than the common 20/40 referral criteria. Unaided VA had less impact on predicted compliance in the screening only protocol. PMID- 22544002 TI - The impact of severity of parental myopia on myopia in Chinese children. AB - PURPOSE: To assess the impact of severity of parental myopia on myopia in Chinese children. METHODS: Children aged 12 to 15 years were identified from a population based sample in Guangzhou. Children's myopia was defined as a spherical equivalent refraction of <=0.5 D based on cycloplegic (1% cyclopentolate) autorefraction. Using a questionnaire reported by the parents, the parental myopia was confirmed and the severity of myopia on the right eyes was classified into mild (<3.0 D myopia), moderate (3.0 to 6.0 D myopia), and high (>6.0 D myopia) myopia. RESULTS: Information was available for 1567 children aged 12 to 15 years. Analysis was restricted to children with no myopia in one parent and no, mild, moderate, or high myopia in the other. The prevalence of myopia in children was 53.5, 65.1, 76.3, and 80.6% when the severity of myopia in the second parent was no, mild, moderate, and high, and the prevalence of high myopia (spherical equivalent >6.0 D myopia) in children was 1.4, 2.9, 8.5, and 16.1% in the corresponding groups of parental myopia severity. Of the children with high myopia, 45.3% had parents with no reported myopia. CONCLUSIONS: More severe myopia in one parent results in an increased risk of myopia in the children. However, most highly myopic children did not have a highly myopic parent and also half did not have any reported parental myopia. This suggests that while genetic factors contribute to the development of more severe myopia, environmental factors also contribute to high myopia in children in Guangzhou. PMID- 22544003 TI - [Problematic bacteria in intensive care units : STAR-ICU Trial (Strategies to Reduce Transmission of Antimicrobial Resistant Bacteria in Intensive Care Units)]. PMID- 22544004 TI - Open-label treatment with olanzapine for patients with borderline personality disorder. AB - This report presents efficacy and safety outcomes for patients with borderline personality disorder (BPD) treated with olanzapine for up to 24 weeks. In 2 concurrent studies, patients received open-label olanzapine for 12 weeks after 12 weeks of double-blind olanzapine or placebo. Open-label dosing started at 2.5 or 5 mg/d and could be increased up to 20 mg/d (study 1) or 15 mg/d (study 2). The primary efficacy measure was open-label baseline-to-endpoint change in Zanarini Rating Scale for BPD (ZAN-BPD) total score. Of 472 patients who completed the double-blind acute phase, 444 entered and 320 (72.1%) completed 12 weeks of open label extension treatment. Mean ZAN-BPD total scores at the start of the acute phase were approximately 17, indicating moderate symptom severity. Mean ZAN-BPD total scores ranged from 7.8 to 10.5 at the start of the open-label treatment and decreased to 5.7 to 6.5, indicating mild symptom severity, by the end of the open label treatment. Patients taking placebo during the acute phase showed increases in weight, prolactin level, and other laboratory values during open-label olanzapine treatment similar in magnitude to increases seen in olanzapine-treated patients during the acute phase. Patients proceeding from olanzapine during the acute phase to open-label olanzapine showed smaller changes in weight and laboratory values. In conclusion, these results suggest that continued therapy with olanzapine may sustain and build upon improvements seen with acute olanzapine treatment of patients with BPD. However, no medication is currently approved for treatment of BPD, and physicians should carefully weigh potential benefits and risks of antipsychotic treatment in this population. PMID- 22544005 TI - Dysregulation of adipocytokines related to second-generation antipsychotics in normal fasting glucose patients with schizophrenia. AB - OBJECTIVE: The underlying mechanism for second-generation antipsychotic (SGA) related glucose-lipid metabolic dysfunction is not fully understood. Recent studies have suggested a possible impact of SGAs on endocrine regulation, especially on adipocytokines. We examined the effect of each SGA on various adipocytokines in normal fasting glucose (NFG) subjects. METHOD: The study population comprised 113 Japanese inpatients with schizophrenia who were treated with olanzapine, risperidone, or quetiapine, and 123 healthy control (CONT) volunteers. All of the subjects were diagnosed with NFG. Plasma concentration of adiponectin, leptin, tumor necrosis factor alpha, total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were compared between the SGA and CONT groups. RESULTS: Second generation antipsychotic subjects had significantly higher leptin levels in comparison to the CONT subjects. The plasma concentration of adiponectin, total cholesterol, and high-density lipoprotein cholesterol in the SGA subjects were significantly lower than those in the CONT subjects. There were no significant differences in tumor necrosis factor alpha, triglyceride, and low-density lipoprotein cholesterol levels between the 2 groups. In a stepwise multiple regression analysis, olanzapine was found to be a factor that contributed to decreased adiponectin levels, and the CONT subjects were detected to be a factor associated with lower leptin levels. CONCLUSIONS: The present study indicates the possibility that the administration of SGAs may affect adipocytokines in the NFG stage, excluding the impaired fasting glucose group, which is in the transition stage into diabetes mellitus. PMID- 22544006 TI - Prevalence of concomitant oral antipsychotic drug use among patients treated with long-acting, intramuscular, antipsychotic medications. AB - OBJECTIVE: Long-acting injectable (LAI) antipsychotic drugs are viewed as monotherapeutic alternatives to oral medications to promote medication adherence, but there have been no descriptive studies of concomitant use of oral and LAI medications. METHODS: A list of all patients receiving services from the Connecticut Mental Health Center from July 1, 2009, to June 30, 2010, was obtained from center administrative records, and those carrying an initial intake diagnosis of schizophrenia or schizoaffective disorder were identified. All team leaders were approached, and all clinicians were asked to identify patients on their case load prescribed LAIs during the time interval above. Also, all internal and external pharmacy orders were reviewed. Concomitancy was defined as simultaneous oral and LAI antipsychotic use at any time from July 1, 2009, to June 30, 2010. Data were culled from the medical records using a form (available on request) that recorded current LAI antipsychotic, reasons for LAI use, length of time on LAI, monthly dosage, and all concomitant oral antipsychotics, antidepressants, and anxiolytic agents. RESULTS: Among 124 patients on LAI medications, 57 (46%) received concomitant oral and LAI antipsychotics: 27 (47%) were prescribed LAI haloperidol, 19 (33%) LAI fluphenazine, and 11 (19%) risperidone microspheres. Logistic regression showed greater use of oral antipsychotic for both Hispanic ethnicity (odds ratio, 3.8; 95% confidence interval, 1.3-10.8) and alcohol abuse/dependence (odds ratio, 6.5; 95% confidence interval, 1.3-31.9), with no significant differences on other variables. There were no significant differences between LAI agents in rates of use of concomitant oral antipsychotic, anticholinergic, sedative/hypnotic, or mood stabilizer. Patients were more likely to be prescribed concomitant oral preparations of their LAI agent than another oral antipsychotic. Higher dosing of LAI treatments was associated with a significantly greater likelihood of use of oral psychotropics and anticholinergics. CONCLUSIONS: Almost one half of patients prescribed LAI antipsychotics receive oral antipsychotics and other oral psychotropics. This challenges the notion that LAIs are used as monotherapy in real-world settings. Concomitant oral and LAI antipsychotic prescriptions may represent a common practice of polypharmacy that merits further investigation. PMID- 22544007 TI - Do local meteorological conditions influence skin irritation caused by transdermal rivastigmine? A retroprospective, pilot study. AB - OBJECTIVE: This retrospective study aimed to evaluate the incidence of transdermal rivastigmine treatment withdrawal secondary to adverse skin reactions among the patients from our Memory Clinic. In addition, we tested whether climatic conditions might have an influence on skin irritations leading to eventual treatment disruption. METHODS: We performed a retrospective review of patients from the Brugmann University Hospital Memory Clinic having started transdermal rivastigmine between June 2008 and December 2010. Local meteorological data were provided by the Royal Meteorological Institute of Belgium. RESULTS: A total of 26.9% of the patients experienced adverse skin reactions at the rivastigmine application site, leading to treatment discontinuation in 19.2% of the cases. Rivastigmine cutaneous tolerability was not found to be related to demographic parameters, Mini Mental Status Examination score, or type of dementia. High temperature and low air humidity during the first month of treatment were found to be associated with a higher incidence of skin reactions and secondary treatment disruption. CONCLUSIONS: Transdermal rivastigmine induced a higher incidence of cutaneous adverse events than previously reported in a prospective clinical trial. Moreover, it seems that meteorological conditions favoring skin perspiration (high temperature and low air humidity) during the first month of treatment might have an influence on transdermal rivastigmine skin tolerability. PMID- 22544008 TI - From disordered eating to addiction: the "food drug" in bulimia nervosa. AB - The high prevalence of substance abuse in individuals with bulimia nervosa (BN) and the pervasive symptom substitution in many types of drug addiction suggest that a number of substances--including food--can impair an individual's self control, even in the presence of negative consequences. Nonetheless, the neurobiological similarities between BN and drug addiction are not clearly established. This review explores how the specific eating patterns seen in BN (binge eating and purging, with intermittent dietary restriction) are particularly addictive and differentiate BN from other eating disorders and obesity. A number of peripheral and central biological aberrations seen in BN may result in altered reward sensitivity in these individuals, particularly through effects on the dopaminergic system. Neurobiological findings support the notion that BN is an addictive disorder, which has treatment implications for therapy and pharmacological manipulations. PMID- 22544009 TI - Modulation of central serotonin affects emotional information processing in impulsive aggressive personality disorder. AB - BACKGROUND: The mechanistic model whereby serotonin affects impulsive aggression is not completely understood. The purpose of this study was to test the hypothesis that depletion of serotonin reserves by tryptophan depletion affects emotional information processing in susceptible individuals. METHODS: The effect of tryptophan (vs placebo) depletion on processing of Ekman emotional faces was compared in impulsive aggressive personality disordered, male and female adults with normal controls. All subjects were free of psychotropic medications, medically healthy, nondepressed, and substance free. Additionally, subjective mood state and vital signs were monitored. RESULTS: For emotion recognition, a significant interaction of Aggression * Drug * Sex (F(1, 31) = 7.687, P = 0.009) was found, with male normal controls but not impulsive aggressive males showing increased recognition of fear. For intensity ratings of emotional faces, a significant interaction was discovered of Drug * Group * Sex (F(1, 31) = 5.924, P = 0.021), with follow-up tests revealing that males with intermittent explosive disorder tended to increase intensity ratings of angry faces after tryptophan depletion. Additionally, tryptophan depletion was associated with increased heart rate in all subjects, and increased intensity of the subjective emotional state of "anger" in impulsive aggressive subjects. CONCLUSIONS: Individuals with clinically relevant levels of impulsive aggression may be susceptible to effects of serotonergic depletion on emotional information processing, showing a tendency to exaggerate their impression of the intensity of angry expressions and to report an angry mood state after tryptophan depletion. This may reflect heightened sensitivity to the effects of serotonergic dysregulation, and suggests that what underlies impulsive aggression is either supersensitivity to serotonergic disturbances or susceptibility to fluctuations in central serotonergic availability. PMID- 22544010 TI - Different impacts of aquaporin 4 and MAOA allele variation among olanzapine, risperidone, and paliperidone in schizophrenia. AB - Apoptosis has been considered to be involved in schizophrenia. Water channels are modulated just before apoptosis. In the aquaporin family, aquaporin 4 (AQP-4) is most highly expressed in the brain and is supposed to play an important role in a neuronal environment. In this clinical study, we investigated the relationship between the AQP-4 polymorphism and drug response in schizophrenia under the control of the MAOA (monoamine oxidase A) promoter gene. We recruited 91 patients with schizophrenia, and they were randomized to receive olanzapine (n = 44), risperidone (n = 23), or paliperidone (n = 24). Genotyping of AQP-4 and MAOA polymorphisms was done in all patients. Patients with the AQP-4 non-C polymorphism needed a higher dosage of olanzapine for treatment (z = 4.163, P = 0.041), and patients with a short form of the MAOA polymorphism needed a higher dosage of risperidone for treatment (z = 5.124, P = 0.024). Patients who smoked cigarettes needed a higher dosage of olanzapine for treatment (z = 4.905, P = 0.027), but cigarette smoking did not affect the dosage of paliperidone. The AQP 4 polymorphism may have an effect in influencing the dosage of olanzapine. However, the roles of AQP-4 polymorphisms in the blood-brain barrier and different neuroprotective effects need further exploration in future studies. PMID- 22544012 TI - Behavioral adverse effects of antiepileptic drugs in epilepsy. AB - Patient tolerability is a significant limiting factor in the treatment of epilepsy and adverse effect profiles often determine drug retention rates. A full appreciation of the behavioral effects of a wide range of antiepileptic drugs (AEDs) is therefore essential to make informed treatment decisions. In this timely review, we highlight key alterations in mood, emotional experience, and other behavioral/psychiatric features, which can exert a crucial impact on patients' quality of life and well-being. With a view to prescribing both in general and in relation to more specific clinical characteristics, the evidence reviewed indicates that the incidence and characteristics of behavioral effects may be related to age, epilepsy type, the presence of learning disability, and previous psychiatric history. Medication parameters including dosage, titration rate, efficacy in controlling seizures, and concurrent AEDs can also contribute to the occurrence of behavioral effects. However, there are a number of limitations in drawing conclusions from the available literature. These include variation in study design, treatment group, and assessment tools that lead to difficulties comparing findings across studies, and problems with the consistency of available information relating to the study methodology. Future longitudinal studies assessing the impact of tolerance or developmental change on behavioral effects and specific studies comparing the effects of commonly prescribed agents across subgroups of patients with epilepsy will make an informative contribution to the available literature. A valuable outcome of further research may be the development of specific instruments that are sensitive to the behavioral effects associated with particular AEDs. PMID- 22544011 TI - Antidepressant agents and suicide death among US Department of Veterans Affairs patients in depression treatment. AB - BACKGROUND: Studies report mixed findings regarding antidepressant agents and suicide risks, and few examine suicide deaths. Studies using observational data can accrue the large sample sizes needed to examine suicide death, but selection biases must be addressed. We assessed associations between suicide death and treatment with the 7 most commonly used antidepressants in a national sample of Department of Veterans Affairs patients in depression treatment. Multiple analytic strategies were used to address potential selection biases. METHODS: We identified Department of Veterans Affairs patients with depression diagnoses and new antidepressant starts between April 1, 1999, and September 30, 2004 (N = 502,179). Conventional Cox regression models, Cox models with inverse probability of treatment weighting, propensity-stratified Cox models, marginal structural models (MSM), and instrumental variable analyses were used to examine relationships between suicide and exposure to bupropion, citalopram, fluoxetine, mirtazapine, paroxetine, sertraline, and venlafaxine. RESULTS: Crude suicide rates varied from 88 to 247 per 100,000 person-years across antidepressant agents. In multiple Cox models and MSMs, sertraline and fluoxetine had lower risks for suicide death than paroxetine. Bupropion had lower risks than several antidepressants in Cox models but not MSMs. Instrumental variable analyses did not find significant differences across antidepressants. DISCUSSION: Most antidepressants did not differ in their risk for suicide death. However, across several analytic approaches, although not instrumental variable analyses, fluoxetine and sertraline had lower risks of suicide death than paroxetine. These findings are congruent with the Food and Drug Administration meta-analysis of randomized controlled trials reporting lower risks for "suicidality" for sertraline and a trend toward lower risks with fluoxetine than for other antidepressants. Nevertheless, divergence in findings by analytic approach suggests caution when interpreting results. PMID- 22544013 TI - A naturalistic study of intramuscular haloperidol versus intramuscular olanzapine for the management of acute agitation. AB - OBJECTIVE: Published research on agitation is limited by the difficulty in generalizing findings from trials using moderately agitated, carefully selected patients treated with single agents. More specifically, there are few comparative studies examining common intramuscular (IM) regimens (ie, haloperidol with or without benzodiazepines) with IM atypical antipsychotics. Therefore, we conducted a retrospective chart review to compare IM olanzapine and haloperidol in a "real world" population with agitation. METHOD: We performed a retrospective evaluation of charts from 146 consecutive emergency department patients who received either IM haloperidol or IM olanzapine for agitation. We used a clinically oriented proxy marker of efficacy--the necessity for additional medication intervention for agitation (AMI)--as our primary outcome measure. RESULTS: Additional medication intervention for agitation was required by 43% (13/30) patients when haloperidol was given alone and by 18% (13/72) when haloperidol was given with a benzodiazepine. In the case of olanzapine, AMI was required by 29% (6/21) of patients receiving olanzapine alone and by 18% (2/11) of patients given olanzapine plus a benzodiazepine. A significant percentage of patients had clinical characteristics (nonpsychiatric triage complaint, drug/alcohol use, severe agitation) that differ from more selective samples. CONCLUSIONS: Overall, these finding suggest that in a naturalistic emergency department setting, haloperidol monotherapy is less effective--at least in requiring AMI--than olanzapine with or without a benzodiazepine or haloperidol plus a benzodiazepine. Moreover, these later 3 regimens seemed comparable. Prospective studies examining the treatment of real-world agitation, including head-to-head comparisons of the haloperidol-benzodiazepine combination with newer IM antipsychotics, are needed. PMID- 22544014 TI - Selective serotonin reuptake inhibitors and the risk of acute pancreatitis: a Swedish population-based case-control study. AB - Case reports have indicated an increased risk of acute pancreatitis during use of selective serotonin reuptake inhibitors (SSRIs), an association not found in a few epidemiological studies. We studied the use of SSRI in relation to risk of acute pancreatitis in a population-based case-control study of people aged 40 to 84 years between 2006 and 2008 in Sweden. The Patient Register was used to identify 6161 cases of first-episode acute pancreatitis. The Register of the Total Population was used to randomly select 61,637 control subjects from the general population using frequency-based density sampling, matched for age, sex, and calendar year. Use of SSRI was defined as "current," "recent," "past," or "former" if the drug had been dispensed 1 to 114 days, 115 to 180 days, 181 to 365 days, or 1 to 3.5 years before a given index date, respectively. Logistic regression with adjustment for potential confounding factors was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs). The OR for acute pancreatitis, adjusted for matching variables, was increased among present users of SSRI (OR, 1.5; 95% CI, 1.4-1.7). After adjusting for diseases or medications related to alcohol overconsumption, tobacco smoking, diabetes, ischemic heart disease, obesity, and severe pain together with educational level and marital status, the corresponding OR was 1.1 (95% CI, 1.0-1.3). After adjusting for the number of distinct medications, a proxy for comorbidity, the corresponding OR was 1.0 (95% CI, 0.9-1.1). The OR for antidepressant use other than SSRI showed a similar pattern. In conclusion, no increased risk of acute pancreatitis remained among users of SSRI after adjusting for confounding factors. PMID- 22544015 TI - Short-term exposure to antidepressant drugs and risk of acute angle-closure glaucoma among older adults. AB - Acute angle-closure glaucoma (AACG) is an ocular emergency that may be precipitated by certain types of medications. Antidepressant drugs can affect a number of neurotransmitters, which are involved in the regulation of the iris, which may precipitate AACG. We used a case-crossover study design to investigate the association between recent exposure to antidepressant drugs and AACG. We identified patients with AACG among adults aged 66 years or older between 1998 and 2010 in Ontario using linked population-based administrative databases. We identified intermittent users of antidepressant medications through prescription drug claims in the year preceding AACG. We determined antidepressant exposure in the period immediately before AACG and compared it with antidepressant exposure in 2 earlier control periods. We used conditional logistic regression to determine the odds ratio for antidepressant exposure in the hazard period compared with the control periods. A total of 6470 patients with AACG occurred during the study period. The mean age of the patients was 74.3 years, and 66% were female. Overall, 5.6% of individuals were intermittent users of antidepressant drugs in the year preceding AACG. The odds ratio for any antidepressant exposure in the period immediately preceding AACG was 1.62 (95% confidence interval, 1.16-2.26). An increased risk of AACG was also observed in several subgroups. We conclude that recent exposure to antidepressant drugs is associated with an increased risk of AACG. Clinicians should remain vigilant for the development of this uncommon but potentially serious adverse event after initiating antidepressant therapy. PMID- 22544016 TI - Escitalopram for treatment of night eating syndrome: a 12-week, randomized, placebo-controlled trial. AB - The primary objective of this study was to examine the short-term effects of escitalopram on symptoms of night eating syndrome (NES) in a randomized controlled clinical trial. A total of 40 patients with NES were randomly assigned to double-blind treatment with escitalopram 20 mg (n = 20) or placebo (n = 20) for 12 weeks. Escitalopram was started at 10 mg/d with a dosage increase to 20 mg/d after 4 weeks; placebo dosing was identical. The primary end point was a mean change in total score of the Night Eating Questionnaire (NEQ). At 12 weeks, mean (SE) change in NEQ total score was -13.0 (1.6) and -10.6 (2.2) in the escitalopram and placebo groups, respectively (F(1,37) = 2.5, P = 0.124). There was a marginal interaction effect between response to escitalopram and race (F(1,34) = 4.0, P = 0.052), with a favorable effect for white patients (F(1,20) = 6.0, P = 0.024) but not for black patients (F(1,13) = 0.6, P = 0.453). Seven patients in the escitalopram group, compared with 6 patients in the placebo group, showed a 50% NEQ score reduction (P = 0.736). Sixteen patients in the escitalopram group and 12 patients in the placebo group no longer met NES criteria (P = 0.168). Twelve patients in the escitalopram group were classified as responders according to the Clinical Global Impression Improvement scale compared with 7 patients in the placebo group (P = 0.113). No significant between group differences were found for weight, mood ratings, or adverse events. We conclude that escitalopram treatment for 12 weeks was not superior to placebo in reducing NES symptoms as measured by the NEQ. PMID- 22544017 TI - Adverse events in healthy subjects exposed to single and multiple doses of LY2140023 monohydrate: pooled results from 10 phase 1 studies. AB - Ten phase 1 studies of LY2140023 monohydrate (LY2140023), an mGlu2/3 receptor agonist, in healthy male and female subjects were pooled to evaluate the adverse event profile. These studies included both single-dose (5-200 mg) and multiple dose (20-160 mg 2 times a day) treatment groups. The percentage of subjects reporting treatment-emergent adverse events (TEAEs) were assessed in placebo and LY2140023 dose groups: 5 to 20, 40, 60 to 80, and more than 80 mg (120-200 mg). The severity and duration of TEAEs were also determined. Electroencephalograms were performed in 1 study to detect if there were any prodromal signs of convulsions or seizures. Subjects who received either placebo or LY2140023 and participated in the single-dose (n = 159) and multiple-dose (n = 102) treatment groups were included in these analyses. No clear trends for increased TEAE incidence occurred with higher doses of LY2140023 in both the single-dose and multiple-dose treatment groups. The TEAEs with the highest incidence were gastrointestinal and nervous system events. No serious adverse events occurred in any of the 10 studies, and most TEAEs were mild in severity and transient in nature. There were no clinically significant changes in electroencephalograms in subjects receiving LY2140023 (n = 26). LY2140023 was generally well tolerated in healthy subjects. PMID- 22544018 TI - Randomized trials published in Chinese or Western journals: comparative empirical analysis. AB - A major concern to the inclusion in systematic reviews of studies originating in China and published in Chinese journals refers to the quality of study reporting. In this systematic survey of randomized trials, we compared the characteristics of studies published in Chinese journals with those of studies published in Western journals. We included 69 studies comparing citalopram with other antidepressant drugs in the treatment of major depression. Of these, 37 (54%) were published in Chinese journals. The standard of reporting was generally poor in both Western and Chinese studies. In some Chinese studies, the generation of the randomization sequence raised concern about their experimental nature, and in almost all included studies, the concealment of allocation was not properly described. Blinding was seldom adopted in Chinese studies, and the risk of sponsorship bias was uncertain because Chinese studies did not report any financial support. In most Western studies, outcome data were selectively and incompletely reported. Pooling together all trials revealed that citalopram was similarly effective in comparison with all other antidepressant drugs both in Western studies (standardized mean difference, -0.04; 95% confidence interval, 0.15 to 0.06) and in Chinese studies (standardized mean difference, -0.08, 95% confidence interval, -0.18 to 0.02). Randomized controlled trials published in Chinese journals represent most of the studies included in this review. This suggests that omitting to search biomedical databases originating from China would systematically exclude a relevant proportion of randomized trials published in Chinese journals, with a risk of random error or bias. The increasing inclusion of Chinese studies in systematic reviews reinforces the need to check the quality of randomized trials that are meta-analyzed. PMID- 22544019 TI - Adverse effects of second-generation antipsychotics in children and adolescents: a Bayesian meta-analysis. AB - In adults, second-generation antipsychotics (SGAs) have a low frequency of extrapyramidal syndrome (EPS) and a moderate frequency of metabolic adverse effects. Here we aimed to assess short-term adverse effects of SGAs in children and adolescents. We searched for relevant studies in MEDLINE and EMBASE (1996 2010), Food and Drug Administration and European Medicines Agency clinical trial registries, and reference lists of review articles. We found 41 were short-term (3-12 weeks) controlled studies that evaluated SGA adverse effects in youths. Using Bayesian meta-analysis, we analyzed odds ratios (ORs) or mean average effects. Numbers of arms (subjects) in the 41 trials were aripiprazole, 10 (n = 671); olanzapine, 14 (n = 413); quetiapine, 10 (n = 446); risperidone, 25 (n = 1040); ziprasidone, 4 (n = 228); clozapine, 5 (n = 79); and placebo/untreated, 23 (n = 1138), totaling 93 arms (4015 patients). Clozapine was assessed only for weight gain and somnolence. Compared with placebo, significant treatment-related increases were observed for weight gain with olanzapine (mean +/- SD = 3.99 +/- 0.42 kg; 95% credible interval, 3.17-4.84 kg), clozapine (2.38 +/- 1.13 kg; 95% credible interval, 0.19-4.62 kg), risperidone (2.02 +/- 0.32 kg; 95% credible interval, 1.39-2.66 kg), quetiapine (1.74 +/- 0.38 kg; 95% credible interval, 0.99-2.5 kg), and aripiprazole (0.89 +/- 0.32 kg; 95% credible interval, 0.26 1.51 kg); glucose levels with risperidone (3.7 +/- 1.36 mg/dL; 95% credible interval, 1.08-6.42 mg/dL) and olanzapine (2.09 +/- 1.08 mg/dL; 95% credible interval, 0.13-4.32 mg/dL); cholesterol levels with quetiapine (10.77 +/- 2.14 mg/dL; 95% credible interval, 6.6-14.95 mg/dL) and olanzapine (4.46 +/- 1.65 mg/dL; 95% credible interval, 1.24-7.73 mg/dL); triglyceride levels with olanzapine (20.18 +/- 5.26 mg/dL; 95% credible interval, 9.85-30.53 mg/dL) and quetiapine (19.5 +/- 3.92 mg/dL; 95% credible interval, 11.84-27.17 mg/dL); hyperprolactinemia with risperidone (OR, 38.63; 95% credible interval, 8.62 125.6), olanzapine (OR, 15.6; 95% credible interval, 4.39-41.1), and ziprasidone (OR, 9.35; 95% credible interval, 1.24-37.03); and EPS with ziprasidone (OR, 20.56; 95% credible interval, 3.53-68.94), olanzapine (OR, 6.36; 95% credible interval, 2.43-13.84), aripiprazole (OR, 3.79; 95% credible interval, 2.17-6.17), and risperidone (OR, 3.71; 95% credible interval, 2.18-6.02). All SGAs increased the risk of somnolence/sedation. We conclude that short-term metabolic effects and EPS are frequent in children treated with SGAs. Second-generation antipsychotics have distinct profiles of secondary effects, which should be considered in making treatment decisions. PMID- 22544020 TI - Is psychiatry ignoring suicide? The case for clozapine. PMID- 22544021 TI - Full-length RecE enhances linear-linear homologous recombination and facilitates direct cloning for bioprospecting. AB - Functional analysis of genome sequences requires methods for cloning DNA of interest. However, existing methods, such as library cloning and screening, are too demanding or inefficient for high-throughput application to the wealth of genomic data being delivered by massively parallel sequencing. Here we describe direct DNA cloning based on the discovery that the full-length Rac prophage protein RecE and its partner RecT mediate highly efficient linear-linear homologous recombination mechanistically distinct from conventional recombineering mediated by Redalphabeta from lambda phage or truncated versions of RecET. We directly cloned all ten megasynthetase gene clusters (each 10-52 kb in length) from Photorhabdus luminescens into expression vectors and expressed two of them in a heterologous host to identify the metabolites luminmycin A and luminmide A/B. We also directly cloned cDNAs and exactly defined segments from bacterial artificial chromosomes. Direct cloning with full-length RecE expands the DNA engineering toolbox and will facilitate bioprospecting for natural products. PMID- 22544023 TI - [Chronic hepatitis C and insulin resistance]. AB - Insulin resistance is frequently associated with chronic liver disease, and the interaction between hepatitis C virus (HCV) infection and insulin resistance is a major public health issue, bound to increase in the near term. Because of their potential synergism on liver disease severity, a better understanding of the clinical consequences of the relationship between HCV infection and insulin resistance is needed. This translates into accelerated liver disease progression, reduced response to anti-viral agents and, in susceptible individuals, increased risk of developing type 2 diabetes. HCV may also cause hepatic steatosis, especially in patients infected with genotype 3, although the clinical impact of viral steatosis is debated. Little is known regarding the effect of anti-diabetic agents on HCV infection, and a possible association between use of exogenous insulin or a sulfonylurea agents and the development of hepatocellular carcinoma has recently been reported. Thus, modified lifestyle and pharmacological modalities are urgently warranted in chronic hepatitis C with metabolic alterations. PMID- 22544022 TI - Absolute quantification of somatic DNA alterations in human cancer. AB - We describe a computational method that infers tumor purity and malignant cell ploidy directly from analysis of somatic DNA alterations. The method, named ABSOLUTE, can detect subclonal heterogeneity and somatic homozygosity, and it can calculate statistical sensitivity for detection of specific aberrations. We used ABSOLUTE to analyze exome sequencing data from 214 ovarian carcinoma tumor-normal pairs. This analysis identified both pervasive subclonal somatic point-mutations and a small subset of predominantly clonal and homozygous mutations, which were overrepresented in the tumor suppressor genes TP53 and NF1 and in a candidate tumor suppressor gene CDK12. We also used ABSOLUTE to infer absolute allelic copy number profiles from 3,155 diverse cancer specimens, revealing that genome doubling events are common in human cancer, likely occur in cells that are already aneuploid, and influence pathways of tumor progression (for example, with recessive inactivation of NF1 being less common after genome doubling). ABSOLUTE will facilitate the design of clinical sequencing studies and studies of cancer genome evolution and intra-tumor heterogeneity. PMID- 22544024 TI - [Association between dyspepsia and upper endoscopic findings]. AB - BACKGROUND/AIMS: We aimed to estimate the proportion of significant endoscopic findings and their association with dyspeptic symptoms and to evaluate the predictors for significant endoscopic findings. METHODS: Total of 3,872 subjects (58.3% men, mean age 43.6+/-9.3 years) who had undergone endoscopy were enrolled at the health promotion center. Each subject completed validated questionnaires, including data on gastrointestinal symptoms, socio-demographic history and medical history. Significant endoscopic findings were included peptic ulcer disease, reflux esophagitis, gastric cancer, Barrett's esophagus and gastro duodenal erosions. Multiple logistic regression models were used to assess the predictors for significant endoscopic findings. RESULTS: The proportion of significant endoscopic findings was 39.1%. There was no significant difference of endoscopic findings between the dyspepsia and asymptomatic group (41.0% vs. 37.4%, p>0.05). There was no difference of the incidence of reflux esophagitis or peptic ulcer between subjects with and without dyspepsia. Peptic ulcer was more frequently present in subjects with reflux symptoms than asymptomatic subjects (12.3% vs. 9.0%, p=0.03). Male gender (odds ratio [OR], 3.91; 95% confidence interval [CI], 3.18-4.81) increased the risk for having endoscopic abnormality and having symptoms of functional dyspepsia according to Rome III criteria (OR, 0.75; 95% CI, 0.57-0.97) significantly decreased this risk. CONCLUSIONS: About 40% of subjects with dyspepsia had abnormal endoscopic findings, and the dyspepsia symptoms may not predict the significant endoscopic findings. Diagnostic criteria of functional dyspepsia by Rome III may be useful to predict not having significant upper endoscopic findings. PMID- 22544025 TI - [Comparison of treatments in patients with inoperable stage IV advanced esophageal cancer]. AB - BACKGROUND/AIMS: The aim of this study was to compare palliative treatments such as chemotherapy, chemoradiotherapy or radiotherapy with best supportive care in patients with inoperable advanced esophageal cancer. METHODS: A total of 67 patients with inoperable advanced esophageal cancer visiting Kosin University Gospel Hospital between January 2000 and July 2010 were included in a retrospective analysis. Patients were categorized as having palliative treatment or best supportive care to compare their prognosis. RESULTS: The median survival was 6.4 months in 67 patients. There was significant difference in median survival between the palliative and best supportive treatment (9.8 months vs. 4.5 months, p=0.01). The patients who underwent palliative treatment had superior 1 year and 3-year overall survival rate than those with best supportive treatment (27%, 10% vs. 5%, 5%, respectively). The 1-year and 3-year overall survival rate of palliative treatment was 18% (1-year overall survival rate) in chemotherapy, 33% (1-year overall survival rate) in radiotherapy, 45% and 9% in concurrent chemoradiotherapy, and 20% and 20% in sequential chemoradiotherapy, respectively. CONCLUSIONS: These results may suggest that palliative treatments are more effective than best supportive care. Further prospective studies are still needed to elucidate beneficial effect of palliative treatments on inoperable advanced esophageal cancer. PMID- 22544026 TI - [Clinicopathologic characteristics of patients who underwent curative additional gastrectomy after endoscopic submucosal dissection for early gastric cancer or adenoma]. AB - BACKGROUND/AIMS: Endoscopic submucosal dissection (ESD) has been widely performed. However, procedure related-complications and the risk of tumor recurrence are limitations. We analyzed the clinicopathological characteristics of patients who underwent curative additional gastrectomy (gastrectomy) after ESD. METHODS: The clinical characteristics of cases underwent gastrectomy after ESD were retrospectively analyzed. RESULTS: Between January 2002 and August 2010, 1,512 cases underwent ESD for early gastric cancer (n=511) or adenoma (n=1,001). Thirty-two cases (2.1%) underwent gastrectomy after ESD. Thirty cases (2.0%) were EGC and 2 cases (0.1%) were adenoma. Extended indication, larger tumor size and piecemeal resection were risk factors for gastrectomy after ESD. According to the causes of gastrectomy, 13 cases underwent gastrectomy due to complications (40.6%; bleeding in 9, perforation in 4), and 19 cases based on pathological results (incomplete resection in 13, lymphatic invasion in 6). In cases with incomplete resection, the rate of residual tumor and lymph node metastasis after gastrectomy was 69.2% (75% lateral margin, 60% deep and 75% both) and 7.7%, respectively. Three (50%) of the 6 cases with lymphatic invasion had lymph node metatstasis. CONCLUSIONS: The causes of gastrectomy after ESD were the procedure related complications, the incomplete resection and lymphatic invasion. For complete and curative ESD, endoscopists should try to minimize complications and determine the depth of invasion accurately before ESD. PMID- 22544027 TI - Etiology, clinical features, and endoscopic management of hemobilia: a retrospective analysis of 37 cases. AB - BACKGROUND/AIMS: Hemobilia is a rare cause of upper gastrointestinal bleeding. Endoscopic retrograde cholangiopancreaticography (ERCP) is considered to be an excellent diagnostic and treatment modality. Thirty-seven cases of hemobilia with different underlying pathologies were analyzed to illustrate clinical features and to evaluate the role of endoscopic management. METHODS: A total of 37 patients (26 men and 11 women; mean age, 66.2+/-15.3 years) who were confirmed to have hemobilia by ERCP in a single center from 2000 to 2010 were reviewed retrospectively. Patients with iatrogenic causes of hemobilia were excluded in this study. RESULTS: The causes of hemobilia were hepatocellular carcinoma in 14, bile duct and gallbladder malignancies in 12, common bile duct stones with cholangitis in 4, acute cholecystitis in 4, and pancreatic cancer in 2 patients. The clinical features of hemobilia were jaundice (89.2%), abdominal pain (78.4%), and melena (13.5%). The cholangiographic findings of hemobilia were amorphous filling defects in 15, tubular filling defects in 6, and cast-like filling defects in 6 patients. Endoscopic management included endoscopic nasobiliary drainage in 26 patients and endoscopic retrograde biliary drainage in 7 patients. Biliary obstruction caused by hemobilia was successfully treated with endoscopic biliary drainages in most cases. CONCLUSIONS: The most common non-iatrogenic causes of hemobilia were hepatobiliary malignancies, and the majority of patients presented with jaundice and abdominal pain. Endoscopic biliary drainage is recommended as the initial management to control biliary obstruction. PMID- 22544028 TI - [A case of cytomegalovirus colitis with endoscopic finding resembling Crohn's disease]. AB - Cytomegalovirus (CMV) colitis is common among immunocompromised patients, and often diagnosed by pathologic confirmation because it is associated with a diverse spectrum of clinical and endoscopic features. However, Crohn's disease has no definitive diagnostic criteria, but longitudinal ulcers and cobble stone appearance are accepted as typical endoscopic features of Crohn's disease. An 83 year-old male with a history of radiotherapy for hypopharyngeal cancer visited our hospital with a complaint of melena for 1 week. His colonoscopic exam showed multiple longitudinal ulcers along the entire colon. Most of the ulcers were longer than 4 cm, these endoscopic findings were suspected as typical endoscopic features of Crohn's disease. Pathologic reports revealed multiple inclusion bodies with CMV on immunohistochemistry. He was finally diagnosed as having CMV colitis, and received a 3 week-course of intravenous ganciclovir. A colonoscopic follow-up showed complete healing of the multiple longitudinal ulcers, and he is doing well now without further treatment. PMID- 22544029 TI - [Adrenal metastasis from hepatocellular carcinoma without intrahepatic recurrence after hepatic resection]. AB - Although the adrenal gland is a common site of metastasis from hepatocellular carcinoma (HCC), adrenal metastases are rarely seen in clinical practice because of its lower metastatic potential compared to the other malignancies. Adrenal metastases usually were detected at the time of diagnosis of primary HCC or simultaneously with intrahepatic recurrence after curative management of HCC. It is very rare that only metastatic HCC is detected without evidence of intrahepatic recurrence. Hereby, we report two cases of adrenal metastasis from HCC without intrahepatic recurrence after hepatic resection. PMID- 22544030 TI - [A case of sustained cholestasis caused by acute A viral hepatitis in Dubin Johnson syndrome]. AB - Dubin-Johnson syndrome is a rare clinical entity. It shows intermittent symptoms such as chronic or intermittent jaundice, abdominal pain, weakness, nausea, vomiting, anorexia and diarrhea. Symptoms are precipitated or aggravated by pregnancy, alcoholism, surgical procedures and intercurrent disease. Chronic idiopathic jaundice is typical of Dubin-Johnson syndrome and its prognosis is good. We describe a case of prolonged cholestasis for more than 10 months caused by acute A viral hepatitis in a patient with Dubin-Johnson syndrome. It is a first report of cholestasis complicated by acute A viral hepatitis in a patient with Dubin-Johnson syndrome. PMID- 22544031 TI - [Spontaneous regression of sclerosing mesenteritis presenting as a huge mass]. AB - Sclerosing mesenteritis is a rare benign disease originated from the mesenteries. It can be related to autoimmune disease, vasculitis, ischemia, infection, trauma and operation, but most of cases are idiopathic. The overall prognosis of sclerosing mesenteritis is usually good with benign, course. However, no consensus of treatment has yet been established. We report a case of spontaneous partial regression of sclerosing mesenteritis presented as a huge mass and diagnosed by finding of contrast enhanced abdominal computed tomography and percutaneous ultrasonography guided needle biopsy. PMID- 22544033 TI - Editorial: Molecular Endocrinology articles in the spotlight for May 2012. PMID- 22544035 TI - Community and school mental health professionals' knowledge and use of evidence based substance use prevention programs. AB - Youth with learning and behavioral problems are at elevated risk for substance use during adolescence. Although evidence-based substance use prevention and screening practices are described in the literature, the extent with which these are provided to these youth is unclear. Mental health professionals in schools and community mental health centers are in an ideal position to conduct substance use screening and prevention practices since they have frequent contact with this high risk group. In order to determine whether these mental health professionals were using evidence based substance use screening and prevention programs with these youth, we analyzed 345 completed surveys from mental health professionals in schools and community clinics throughout a mid-Atlantic state. Results indicated that a large portion of the respondents were unfamiliar with evidence based practices and they were infrequently used. Implications for the division of labor at schools and community mental health centers are discussed in relation to time allotment and priority for these procedures. PMID- 22544036 TI - Cell density-dependent shift in activity of iron regulatory protein 1 (IRP 1)/cytosolic (c-)aconitase. AB - Iron regulatory protein 1 (IRP-1) is a bifunctional protein involved in iron homeostasis and metabolism. In one state, it binds to specific sequences in the mRNA's of several proteins involved in iron and energy metabolism, thereby influencing their expression post-transcriptionally. In another state it contains a [4Fe-4S] iron-sulfur cofactor and displays aconitase activity in the cytosol. We have shown that this protein binds and hydrolyzes ATP, with kinetic and thermodynamic equilibrium constants that predict saturation with ATP, favouring a non-RNA-binding form at normal cellular ATP levels, and thus pointing to additional function(s) of the protein. Here we show for the first time that the RNA-binding and aconitase forms of IRP-1 can undergo interconversion dependent on the density of cells growing in culture. Thus, in high density confluent cultures, compared with low density, actively proliferating cultures, cytosolic aconitase activity is increased whereas RNA binding activity is diminished. This is accompanied by a decrease in transferrin receptor expression in confluent cells, possibly due to loss of the transcript-stabilizing activity of bound IRP 1. In high density HepG2 cultures, cytosolic glutamate and the ratio of reduced to-oxidized glutathione were increased. We propose that increased cytosolic aconitase activity in confluent cultures may divert cytosolic citrate away from the fatty acid/membrane synthetic pathways required by dividing cells, into a glutamate-dependent maintenance of cellular macromolecular synthesis. In addition, this may confer additional protection from oxidative stress due to down regulation of iron acquisition from transferrin and increased glutamate for glutathione synthesis. PMID- 22544037 TI - Risk factors for gout developed from hyperuricemia in China: a five-year prospective cohort study. AB - The aim of the study was to investigate the factors that promote the development of gout in Chinese patients with hyperuricemia. Chinese cohort with 659 patients with hyperuricemia who had no history of gout at base line had been followed up for 5 years. The baseline data of the general states (gender, age, occupation and education level), lifestyle and behavior (smoking, drinking, and diet), the major chronic diseases (diabetes and hypertension), family history and gout attacks, physical examination (height, weight and blood pressure), and blood parameters (creatinine, urea nitrogen, triglycerides, total cholesterol and high-density lipoprotein cholesterol) were recorded before the follow-up. Over the five-year period, 75 hyperuricemia patients developed gout. In the logistic regression model, shrimp intake and shell intake were the risk factors (P = 0.038 and P < 0.001, respectively) and, combined with diabetes, also served as risk factor for gout developed from hyperuricemia, with relative risk (RR) of 2.571 (95 % confidence interval (95 % CI), 1.110-5.953), and females served as protective factors of gout, with RR of 0.113 (95 % CI, 0.041-0.312, referred to male). We identified that shrimp intake and shell intake, combined with diabetes, were the independent risk factors, and females served as protective factors of gout in those suffering from hyperuricemia in coast regions of Shandong province, China. PMID- 22544038 TI - Enhanced binding strength between metal nanoclusters and carbon nanotubes with an atomic nickel defect. AB - Using spin-polarized density functional theory calculations, we study binding properties of small metal nanoclusters (Cu(13) and Al(13)) onto carbon nanotubes (CNTs). On defect-free CNTs, the binding affinity with the Cu or Al cluster is very weak. When various defects such as vacancies, substitutional nickel defects, and nickel adatoms are introduced in CNTs to increase the binding strength, the binding energies of the metal nanoclusters increase substantially irrespective of types of defects. The effect of the Ni adatom is especially noticeable. Our results propose a method for improving the wettability of metal-CNT complex composites. PMID- 22544039 TI - Impact of eutrophication on the occurrence of Trichodesmium in the Cochin backwaters, the largest estuary along the west coast of India. AB - Phytoplankton studies in early 1970s have shown the annual dominance of diatoms and a seasonal abundance of Trichodesmium in the lower reaches of the Cochin backwaters (CBW) and adjacent coastal Arabian Sea during the pre-summer monsoon period (February to May). Surprisingly, more recent literature shows a complete absence of Trichodesmium in the CBW after 1975 even though their seasonal occurrence in the adjacent coastal Arabian Sea continued without much change. In order to understand this important ecological feature, we analyzed the long-term water quality data (1965-2005) from the lower reaches of the CBW. The analyses have shown that salinity did not undergo any major change in the lower reaches over the years and values remained >30 throughout the period. In contrast, a tremendous increase was well marked in levels of nitrate (NO(3)) and phosphate (PO(4)) in the CBW after 1975 (av. 15 and 3.5 MUM, respectively) compared with the period before (av. 2 and 0.9 MUM, respectively). Monthly time series data collected in 2004-2005 period from the lower reaches of the CBW and coastal Arabian Sea have clearly shown that the physical characteristics like salinity, temperature, water column stability, and transparency in both regions are very similar during the pre-summer monsoon period. In contrast, the nutrient level in the CBW is several folds higher (NO(3), 8(;) PO(4), 4; SiO(4), 10; and NH(4), 19 MUM) than the adjacent coastal Arabian Sea (NO(3), 0.7; PO(4), 0.5; SiO(4), 0.9; and NH(4), 0.6 MUM). The historic and fresh time series data evidences a close coupling between enriched levels of nutrients and the absence of Trichodesmium in the Cochin backwaters. PMID- 22544040 TI - Distribution of polycyclic aromatic hydrocarbons (PAHs) and sterols in termite nest, soil, and sediment from Great Kwa River, SE Nigeria. AB - Costal sediment samples from Great Kwa River as well as adjoining termite nest and soil samples were analyzed for quantitative determination of polycyclic aromatic hydrocarbons (PAHs) and sterols using gas chromatography-mass spectrometry (GC-MS) in order to access the possibility of transport of biologically produced PAHs/sterols from termite nest to the sediments. The total PAH concentrations (sum of parent and alkyl) for the sediments ranged between 131.96 and 139.35 ng/g dry weight (dw) while those for the nest and soil samples were in the range 9.51-9.71 and 71.85-77.26 ng/g dw, respectively. These levels of PAHs in sediments were relatively low compared to other urban/industrial Asian and American countries. No evidence of the usual biologically produced PAHs was found, thus reducing the likelihood of transport of these compounds from the nest to the sediments. The absence of parent and alkyl PAHs in central compartment of the nest may reflect the selective fern leaves feeding pattern of the dominant termite species prevalent in the vicinity of the study site. Utilization of six selected PAH ratios such as Fla/(Fla + Pyr) (0.4-0.5), Ant/(Ant + Phe) (0.25 0.90), BaA/(BaA + Chrys) (0.45-0.61), MP/P (0.05-6.81), 1,7/(1,7 + 2,6)-DMP (0.61 0.95), and LPAH/HPAH ( 2.80-3.80) allows discrimination of PAH sources for the samples to be made with a mixed source dominance observed. Examination of sterol distributions in the samples shows relatively high abundance of cholest-5-en 3beta-ol in central compartment of the nest, considered here as a consequence of metabolic conversion of phyto-/fungi sterols in the tissues of the termite species. The relatively reduced levels of stanol compounds in central compartment of the nest may be associated with their utilization by the termites for growth and development. PMID- 22544041 TI - Positively charged silver nanoparticles and their effect on surface-enhanced Raman scattering of dye-labelled oligonucleotides. AB - Improved positively charged nanoparticles are described to provide a simplified SERS substrate for DNA detection. Complete flocculation of the nanoparticles is prevented due to the controlled analyte induced aggregation. This provides a stable aggregation state which significantly extends the analysis window simplifying DNA detection by SERS. PMID- 22544042 TI - Kinetics and mechanism of the racemic addition of trimethylsilyl cyanide to aldehydes catalysed by Lewis bases. AB - The mechanism by which four Lewis bases, triethylamine, tetrabutylammonium thiocyanate, tetrabutylammonium azide and tetrabutylammonium cyanide, catalyse the addition of trimethylsilyl cyanide to aldehydes is studied by a combination of kinetic and spectroscopic methods. The reactions can exhibit first or second order kinetics corresponding to three different reaction mechanisms. Spectroscopic evidence for the formation of hypervalent silicon species is obtained for reaction between all of the tetrabutylammonium salts and trimethylsilyl cyanide. The reactions are accelerated by the presence of water in the reaction mixture, an effect which is due to a change in the reaction mechanism from Lewis to Bronsted base catalysis. Tetrabutylammonium thiocyanate is shown to be an excellent catalyst for the synthesis of cyanohydrin trimethylsilyl ethers on a preparative scale. PMID- 22544043 TI - Pelvic tuberculosis mimicking advanced ovarian malignancy. AB - We sought to identify the characteristic features of pelvic tuberculosis (TB) in women with symptoms and sonogaphic findings which were otherwise consistent with an ovarian malignancy. This study is a retrospective analysis of 138 women who underwent an operation and had a preoperative diagnosis of ovarian malignancy at the Government Medical College Hospital, Chandigarh, from January 2004 to January 2008. Among these 138 women, seven cases (5.7%) of pelvic TB were identified. Abdominal pain and distension were the most common presenting symptoms. All patients had a pelvic mass, six had ascites (85%) and five had a fever (71%). The mean cancer antigen (CA) 125 level was 295 IU (13-529). Pelvic TB can present with symptoms and signs which mimic ovarian malignancy. Therefore, a high-index of clinical suspicion should be maintained when treating patients in countries with a high prevalence of TB. PMID- 22544044 TI - Maternal mortality in northern Nigeria: findings of a health and demographic surveillance system in Zamfara State, Nigeria. AB - The aim of this study was to estimate: (1) the lifetime risk (LTR) of maternal death; and (2) the maternal mortality ratio (MMR) in the Zamfara State of northern Nigeria. Data from the Nahuche Health and Demographic Surveillance System were utilized using the 'sisterhood method' for estimating maternal mortality. Female respondents (15-49 years) from six districts in the surveillance area were interviewed, creating a retrospective cohort of their sisters who had reached the reproductive age of 15 years. Based on population and fertility estimates, we calculated the LTR of maternal death and the MMR. A total of 17,087 respondents reported 38,761 maternal sisters of whom 3592 had died and of whom 1261 were maternal-related deaths. This corresponded to an LTR of maternal death of 8% (referring to a period of about 10.5 years prior to the survey) and an MMR of 1049 deaths per 100,000 live births (95% confidence interval, 1021-1136). The study provides documented evidence of high maternal mortality in the study area and the state as a whole. Thus, there is a need to improve the health system with an emphasis on interventions that will accelerate reduction in MMR such as the availability of skilled birth attendants and emergency obstetric care, promotion of facility delivery and antenatal care attendance. This can be achieved through a holistic approach and is critical in order to accelerate progress in meeting the Millennium Development Goal of maternal mortality reduction. PMID- 22544045 TI - Intravital high-frequency ultrasonography to evaluate cardiovascular and uteroplacental blood flow in mouse pregnancy. AB - OBJECTIVE: The objective of this study is to define the ultrasonographic changes in the cardiovascular and uteroplacental circulation of normal pregnant mice compared to non-pregnant mice using high-frequency, high-resolution ultrasonography. METHODS: Ten to twelve-week-old CD-1 mice (six non-pregnant and six pregnant animals) were used for all experiments. Vevo(r) 2100 (VisualSonics) was used to evaluate the cardiovascular and uteroplacental circulation physiology. Cardiac echocardiogram and uterine artery Doppler studies were performed on all animals. Pregnant animals were evaluated on embryonic day seven (E7), thirteen (E13) and eighteen (E18). Fetal heart rate and umbilical artery Doppler flows were obtained on pregnant animals. Three-dimensional ultrasonography imaging was utilized for quantification of placental volumes. All data are presented as median {10(th)-90(th) percentiles}. RESULTS: In pregnant mice on E7 compared to non-pregnant mice, there was an increase in cardiac output (p=0.008), stroke volume (p=0.002), ejection fraction, (p=0.02) and fractional shortening (p=0.02). The maternal heart rate increased throughout gestation (p= 0.009). During pregnancy, a gestational sac was clearly visible on E7. Between E13 and E18, the fetal size and fetal heart rate increased (p=0.001) and the umbilical artery peak systolic velocity increased (p <0.001). Minimal diastolic blood flow was observed in the umbilical artery on E13, which increased slightly on day E18 (p=0.01). There was also no change in the uterine artery resistance index between non-pregnant and pregnant mice. The placental volume increased between E13 and E18 (p=0.03). CONCLUSION: Several changes noted in cardiovascular and uteroplacental systems occurring during normal murine pregnancy have striking similarities to humans and can be accurately measured using newer ultrasonographic techniques. Further studies are needed to evaluate changes in these vascular beds in mouse models of diseases such as preeclampsia and intrauterine growth restriction. PMID- 22544046 TI - A randomized, double-blind, placebo-controlled trial of cyproheptadine for appetite stimulation in cystic fibrosis. AB - OBJECTIVE: To determine whether the administration of cyproheptadine was able to induce weight gain in patients with cystic fibrosis. METHODS: We performed a double-blind, placebo-controlled trial in two centers in Brazil. Twenty-five patients with cystic fibrosis between 5 and 18 years completed the study. Patients were randomized into two groups, to receive either cyproheptadine 4 mg three times per day for 12 weeks or placebo. All data were collected at the beginning and at the end of the study period and included weight, height and spirometry. RESULTS: Average weight gain was 0.67 kg in the placebo group and 1.61 kg in the cyproheptadine group (p = 0.036). Body mass index (BMI) decreased 0.07 kg/m(2); in the placebo group and increased 0.46 kg/m(2); in the intervention group (p = 0.027). The change in BMI for age (z score) was -0.19 in the placebo group and +0.20 in the cyproheptadine group (p = 0.003). BMI z score decreased 0.19 in the placebo group and increased 0.2 in the cyproheptadine group (p = 0.003). Changes in pulmonary function were not statistically different. CONCLUSION: Use of cyproheptadine in cystic fibrosis patients was well tolerated, showing a significant weight gain and a significant increase in BMI after 12 weeks. A clinically relevant effect size for weight/age (z score) and body mass index for age (z score) was found. Such findings suggest that the prescription of cyproheptadine can be an alternative approach for patients who need nutritional support for a short period of time. PMID- 22544047 TI - Linking stomatal sensitivity and whole-tree hydraulic architecture. PMID- 22544048 TI - Light-mediated K(leaf) induction and contribution of both the PIP1s and PIP2s aquaporins in five tree species: walnut (Juglans regia) case study. AB - Understanding the response of leaf hydraulic conductance (K(leaf)) to light is a challenge in elucidating plant-water relationships. Recent data have shown that the effect of light on K(leaf) is not systematically related to aquaporin regulation, leading to conflicting conclusions. Here we investigated the relationship between light, K(leaf), and aquaporin transcript levels in five tree species (Juglans regia L., Fagus sylvatica L., Quercus robur L., Salix alba L. and Populus tremula L.) grown in the same environmental conditions, but differing in their K(leaf) responses to light. Moreover, the K(leaf) was measured by two independent methods (high-pressure flow metre (HPFM) and evaporative flux method (EFM)) in the most (J. regia) and least (S. alba) responsive species and the transcript levels of aquaporins were analyzed in perfused and unperfused leaves. Here, we found that the light-induced K(leaf) value was closely related to stronger expression of both the PIP1 and PIP2 aquaporin genes in walnut (J. regia), but to stimulation of PIP1 aquaporins alone in F. sylvatica and Q. robur. In walnut, all newly identified aquaporins were found to be upregulated in the light and downregulated in the dark, further supporting the relationship between the light-mediated induction of K(leaf) and aquaporin expression in walnut. We also demonstrated that the K(leaf) response to light was quality-dependent, K(leaf) being 60% lower in the absence of blue light. This decrease in K(leaf) was correlated with strong downregulation of three PIP2 aquaporins and of all the PIP1 aquaporins tested. These data support a relationship between light-mediated K(leaf) regulation and the abundance of aquaporin transcripts in the walnut tree. PMID- 22544049 TI - Kinetic analysis of gill (Na+,K+)-ATPase activity in selected ontogenetic stages of the Amazon River shrimp, Macrobrachium amazonicum (Decapoda, Palaemonidae): interactions at ATP- and cation-binding sites. AB - We investigated modulation by ATP, Mg2+, Na+, K+ and NH4+ and inhibition by ouabain of (Na+,K+)-ATPase activity in microsomal homogenates of whole zoeae I and decapodid III (formerly zoea IX) and whole-body and gill homogenates of juvenile and adult Amazon River shrimps, Macrobrachium amazonicum. (Na+,K+) ATPase-specific activity was increased twofold in decapodid III compared to zoea I, juveniles and adults, suggesting an important role in this ontogenetic stage. The apparent affinity for ATP (K(M) = 0.09 +/- 0.01 mmol L-1) of the decapodid III (Na+,K+)-ATPase, about twofold greater than the other stages, further highlights this relevance. Modulation of (Na+,K+-ATPase activity by K+ also revealed a threefold greater affinity for K+ (K0.5 = 0.91 +/- 0.04 mmol L-1) in decapodid III than in other stages; NH4+ had no modulatory effect. The affinity for Na+ (K0.5 = 13.2 +/- 0.6 mmol L-1) of zoea I (Na+,K+)-ATPase was fourfold less than other stages. Modulation by Na+, Mg2+ and NH4+ obeyed cooperative kinetics, while K+ modulation exhibited Michaelis-Menten behavior. Rates of maximal Mg2+ stimulation of ouabain-insensitive ATPase activity differed in each ontogenetic stage, suggesting that Mg2+-stimulated ATPases other than (Na+,K+) ATPase are present. Ouabain inhibition suggests that, among the various ATPase activities present in the different stages, Na+-ATPase may be involved in the ontogeny of osmoregulation in larval M. amazonicum. The NH4+-stimulated, ouabain insensitive ATPase activity seen in zoea I and decapodid III may reflect a stage specific means of ammonia excretion since functional gills are absent in the early larval stages. PMID- 22544050 TI - Transmission of meropenem in breast milk. AB - A case is presented of a breast-feeding mother receiving meropenem treatment for a postpartum urinary tract infection caused by extended-spectrum beta-lactamase producing Escherichia coli. Five milk samples were collected in a 48-hour period during meropenem therapy. The average and maximum meropenem concentrations in milk were 0.48 and 0.64 ug/mL, respectively. Based on the maximum concentration, the calculated infant daily exposure from breast milk was 97 ug/kg/d, and the infant weight-adjusted percentage of maternal dosage was 0.18%. There were no dermatologic or gastrointestinal side effects noted in the breastfed infant. Meropenem appears to be acceptable to use during breast-feeding. PMID- 22544051 TI - Survival benefit of early infant antiretroviral therapy is compromised when diagnosis is delayed. AB - Late presentation is common among African HIV-1-infected infants. Incidence and correlates of mortality were examined in 99 infants with HIV-1 diagnosis by 5 months of age. Twelve-month survival was 66.8% (95% confidence interval: 55.9 75.6%). World Health Organization stage 3 or 4, underweight, wasting, microcephaly, low hemoglobin, pneumonia and gastroenteritis predicted mortality. Early HIV-1 diagnosis with antiretroviral therapy before symptomatic disease is critical for infant survival. PMID- 22544052 TI - Benzathine penicillin G: a documentably important antibiotic in need of a tune up? PMID- 22544053 TI - Comparison of the severity and outcome of invasive pneumococcal infections in children and adults. AB - In a population-based observational study of 285 patients with positive blood culture for pneumococci, we found that the course and outcome of invasive pneumococcal infections differ considerably between adults and children. None of the children died, whereas the infection was fatal for 15% (35/229) of the adults (P<0.001). The differences are only partly explained by the underlying conditions. PMID- 22544055 TI - Discovery of novel protein partners of the transcription factor FOXL2 provides insights into its physiopathological roles. AB - FOXL2 transcription factor is responsible for the Blepharophimosis Ptosis Epicantus inversus Syndrome (BPES), a genetic disease involving craniofacial malformations often associated with ovarian failure. Recently, a somatic FOXL2 mutation (p.C134W) has been reported in >95% of adult-type granulosa cell tumors. Here, we have identified 10 novel FOXL2 partners by yeast-two-hybrid screening and co-immunoprecipitation. Most BPES-inducing mutated FOXL2 proteins display aggregation in cultured cells. Here, we show that two of the partners (NR2C1 and GMEB1) can be sequestered in such aggregates. This co-aggregation can contribute to the pathogenesis of FOXL2 mutations. We have also measured the effects of FOXL2 interactants on the transcriptional regulation of a series of target promoters. Some of the partners (CXXC4, CXXC5, BANF1) were able to repress FOXL2 activity indistinctively of the promoter. Interestingly, CREM-tau2alpha, which acted as a repressor on most promoters, increased wild-type (WT) FOXL2 activity on two promoters (PTGS2 and CYP19A1), but was unable to increase the activity of the oncogenic mutant p.C134W. Conversely, GMEB1, which also acted as a repressor on most promoters and increased WT FOXL2 activity on the Per2 promoter, increased to a greater extent the activity of the p.C134W variant. Interestingly, partners with intrinsic pro-apoptotic effect were able to increase apoptosis induction by WT FOXL2, but not by the p.C134W mutant, whereas partners with an anti-apoptotic effect decreased apoptosis induction by both FOXL2 versions. Altogether, these results suggest that the p.C134W mutated form fails to integrate signals through protein-protein interactions to regulate target promoter subsets and in particular to induce cell death. PMID- 22544057 TI - Neuropsychological testing and concussions: a reasoned approach. PMID- 22544056 TI - Enhanced J-protein interaction and compromised protein stability of mtHsp70 variants lead to mitochondrial dysfunction in Parkinson's disease. AB - Parkinson's disease (PD) is the second most prevalent progressive neurological disorder commonly associated with impaired mitochondrial function in dopaminergic neurons. Although familial PD is multifactorial in nature, a recent genetic screen involving PD patients identified two mitochondrial Hsp70 variants (P509S and R126W) that are suggested in PD pathogenesis. However, molecular mechanisms underlying how mtHsp70 PD variants are centrally involved in PD progression is totally elusive. In this article, we provide mechanistic insights into the mitochondrial dysfunction associated with human mtHsp70 PD variants. Biochemically, the R126W variant showed severely compromised protein stability and was found highly susceptible to aggregation at physiological conditions. Strikingly, on the other hand, the P509S variant exhibits significantly enhanced interaction with J-protein cochaperones involved in folding and import machinery, thus altering the overall regulation of chaperone-mediated folding cycle and protein homeostasis. To assess the impact of mtHsp70 PD mutations at the cellular level, we developed yeast as a model system by making analogous mutations in Ssc1 ortholog. Interestingly, PD mutations in yeast (R103W and P486S) exhibit multiple in vivo phenotypes, which are associated with 'mitochondrial dysfunction', including compromised growth, impairment in protein translocation, reduced functional mitochondrial mass, mitochondrial DNA loss, respiratory incompetency and increased susceptibility to oxidative stress. In addition to that, R103W protein is prone to aggregate in vivo due to reduced stability, whereas P486S showed enhanced interaction with J-proteins, thus remarkably recapitulating the cellular defects that are observed in human PD variants. Taken together, our findings provide evidence in favor of direct involvement of mtHsp70 as a susceptibility factor in PD. PMID- 22544058 TI - Comparison of 2-dimensional measurement techniques for predicting knee angle and moment during a drop vertical jump. AB - OBJECTIVE: To determine the association of 2-dimensional (2D) video-based techniques and 3-dimensional (3D) motion analysis to assess potential knee injury risk factors during jump landing. DESIGN: Observational study. SETTING: Research laboratory. PARTICIPANTS: Thirty-six female athletes in cutting and pivoting sports. ASSESSMENT OF RISK FACTORS: : Athletes performed a drop vertical jump during which movement was recorded with a motion analysis system and a digital video camera positioned in the frontal plane. MAIN OUTCOME MEASURES: The 2D variables were the frontal plane projection angle (FPPA), the angle formed between thigh and leg, and the knee-to-ankle separation ratio, the distance between knee joints divided by the distance between ankles. The 3D variables were knee abduction angle and external abduction moment. All variables were assessed at peak knee flexion. Linear regression assessed the relationship between the 2D and 3D variables. In addition, intraclass correlation coefficients (ICC) determined rater reliability for the 2D variables and compared the 2D measurements made from digital video with the same measurements from the motion analysis. RESULTS: : The knee-to-ankle separation ratio accounted for a higher variance of 3D knee abduction angle (r = 0.350) and knee abduction moment (r = 0.394) when compared with the FPPA (r = 0.145, 0.254). The digital video measures had favorable rater reliability (ICC, 0.89-0.94) and were comparable with the motion analysis system (ICC, >= 0.92). CONCLUSIONS: When compared with the FPPA, the knee-to-ankle separation ratio had better association with previously cited knee injury risk factors in female athletes. The 2D measures have adequate consistency and validity to merit further clinical consideration in jump landing assessments. PMID- 22544059 TI - An Australian case of surfer's myelopathy. AB - Surfer's myelopathy is a rare, nontraumatic spinal cord injury that typically occurs in beginner surfers. The condition was first described in 2004 by Thompson et al and usually presents in thin young men. We present a 19-year-old man who developed lower back pain, profound bilateral lower limb paraparesis, and hyperesthesia during his first learn to surf class. The event was not associated with trauma. Subsequent magnetic resonance imaging demonstrated features consistent with spinal cord ischemia. The motor recovery due to surfer's myelopathy is variable; our case remained a paraplegic with a T10 sensory level. PMID- 22544060 TI - Exercise training to prevent anterior knee pain in military recruits. PMID- 22544061 TI - When do mild traumatic brain injuries occur in community rugby? PMID- 22544062 TI - Do Ibuprofen or glucosamine in addition to resistance exercise training improve muscle strength in patients with knee osteoarthritis? PMID- 22544063 TI - Purposeful exercise, including bicycle transportation, improves health. PMID- 22544064 TI - Renal size and sonographic involution of multicystic dysplastic kidney. PMID- 22544065 TI - Patchwork organization of the yeast plasma membrane into numerous coexisting domains. AB - The plasma membrane is made up of lipids and proteins, and serves as an active interface between the cell and its environment. Many plasma-membrane proteins are laterally segregated in the plane of the membrane, but the underlying mechanisms remain controversial. Here we investigate the distribution and dynamics of a representative set of plasma-membrane-associated proteins in yeast cells. These proteins were distributed non-homogeneously in patterns ranging from distinct patches to nearly continuous networks, and these patterns were in turn strongly influenced by the lipid composition of the plasma membrane. Most proteins segregated into distinct domains. However, proteins with similar or identical transmembrane sequences (TMSs) showed a marked tendency to co-localize. Indeed we could predictably relocate proteins by swapping their TMSs. Finally, we found that the domain association of plasma-membrane proteins has an impact on their function. Our results are consistent with self-organization of biological membranes into a patchwork of coexisting domains. PMID- 22544067 TI - Perioperative steroids for peritumoral intracranial edema: a review of mechanisms, efficacy, and side effects. AB - There has been a renewed interest in the recent literature regarding the proposed benefits of systemic steroids in the perioperative period. Among these benefits are the relief of postoperative pain, the decrease in postoperative nausea, and a higher overall multiparameter quality of recovery. Perioperative steroids, however, are not without their potential drawbacks, including decreased immune function, hyperglycemia, and impaired wound healing. The use of perioperative steroids for brain tumor treatment and resection has been a component of therapy for approximately 50 years, owing primarily to their well-described, although poorly understood, effect in minimizing vasogenic peritumoral edema, and therefore intracranial pressure. This review seeks to highlight the history, mechanisms, therapeutic efficacy, and side effects of steroid use for brain tumors in the perioperative period. PMID- 22544066 TI - Anti-apoptotic MCL-1 localizes to the mitochondrial matrix and couples mitochondrial fusion to respiration. AB - MCL-1, an anti-apoptotic BCL-2 family member that is essential for the survival of multiple cell lineages, is also among the most highly amplified genes in cancer. Although MCL-1 is known to oppose cell death, precisely how it functions to promote survival of normal and malignant cells is poorly understood. Here, we report that different forms of MCL-1 reside in distinct mitochondrial locations and exhibit separable functions. On the outer mitochondrial membrane, an MCL-1 isoform acts like other anti-apoptotic BCL-2 molecules to antagonize apoptosis, whereas an amino-terminally truncated isoform of MCL-1 that is imported into the mitochondrial matrix is necessary to facilitate normal mitochondrial fusion, ATP production, membrane potential, respiration, cristae ultrastructure and maintenance of oligomeric ATP synthase. Our results provide insight into how the surprisingly diverse salutary functions of MCL-1 may control the survival of both normal and cancer cells. PMID- 22544068 TI - Boron neutron capture therapy (BNCT) for liver metastasis: therapeutic efficacy in an experimental model. AB - Boron neutron capture therapy (BNCT) was proposed for untreatable colorectal liver metastases. The present study evaluates tumor control and potential radiotoxicity of BNCT in an experimental model of liver metastasis. BDIX rats were inoculated with syngeneic colon cancer cells DHD/K12/TRb. Tumor-bearing animals were divided into three groups: BPA-BNCT, boronophenylalanine (BPA) + neutron irradiation; Beam only, neutron irradiation; Sham, matched manipulation. The total absorbed dose administered with BPA-BNCT was 13 +/- 3 Gy in tumor and 9 +/- 2 Gy in healthy liver. Three weeks post-treatment, the tumor surface area post-treatment/pre-treatment ratio was 0.46 +/- 0.20 for BPA-BNCT, 2.7 +/- 1.8 for Beam only and 4.5 +/- 3.1 for Sham. The pre-treatment tumor nodule mass of 48 +/- 19 mg fell significantly to 19 +/- 16 mg for BPA-BNCT, but rose significantly to 140 +/- 106 mg for Beam only and to 346 +/- 302 mg for Sham. For both end points, the differences between the BPA-BNCT group and each of the other groups were statistically significant (ANOVA). No clinical, macroscopic or histological normal liver radiotoxicity was observed. It is concluded that BPA-BNCT induced a significant remission of experimental colorectal tumor nodules in liver with no contributory liver toxicity. PMID- 22544069 TI - The evolution of evolutionary molecular medicine: genomics are transforming evolutionary biology into a science with new importance for modern medicine. PMID- 22544070 TI - The BTB/POZ-ZF transcription factor dPLZF is involved in Ras/ERK signaling during Drosophila wing development. AB - In Drosophila, broad complex, tramtrack, bric a brac (BTB)/poxvirus and zinc finger (POZ) transcription factors are essential regulators of development. We searched the Drosophila genome for BTB/POZ-ZF domains and discovered an unknown Drosophila gene, dPLZF, which encodes an orthologue of human PLZF. We then characterized the biological function of the dPLZF via genetic interaction analysis. Ectopic expression of dPLZF in the wing induced extra vein formation during wing development in Drosophila. Genetic interactions between dPLZF and Ras or extracellular signal-regulated kinase (ERK) significantly enhanced the formation of vein cells. On the other hand, loss-of-function mutations in dPLZF resulted in a dramatic suppression of the extra and ectopic vein formation induced by elevated Ras/ERK signaling. Moreover, dPLZF activity upregulated the expression of rhomboid (rho) and spitz, which perform crucial functions in vein cell formation in the developing wing. These results indicate that dPLZF is a transcription factor controlled by the Ras/ERK signaling pathway, which is a prominent regulator of vein cell formation during wing development in Drosophila. PMID- 22544071 TI - Analysis of elemental concentration using ICP-AES and pathogen indicator in drinking water of Qasim Abad, District Rawalpindi, Pakistan. AB - The present study was conducted to investigate drinking water quality (groundwater) from water samples taken from Qasim Abad, a locality of approximately 5,000 population, situated between twin cities Rawalpindi and Islamabad in Pakistan. The main sources of drinking water in this area are water bores which are dug upto the depth of 250-280 ft in almost every house. The study consists of the determination of physico-chemical properties, trace metals, heavy metals, rare earth elements and microbiological quality of drinking water. The data showed the variation of the investigated parameters in samples as follows: pH 6.75 to 8.70, electrical conductivity 540 to 855 MUS/cm, total dissolved solids 325.46 to 515.23 ppm and dissolved oxygen 1.50 to 5.64 mg/L which are within the WHO guidelines for drinking water quality. The water samples were analysed for 30 elements (aluminium, iron, magnesium, manganese, silicon, zinc, molybdenum, titanium, chromium, nickel, tungsten, silver, arsenic, boron, barium, beryllium, cadmium, cobalt, copper, gallium, mercury, lanthanum, niobium, neodymium, lead, selenium, samarium, tin, vanadium and zirconium) by using inductively coupled plasma atomic emission spectroscopy. The organic contamination was detected in terms of most probable number (MPN) of faecal coliforms. Overall, elemental levels were lower than the recommended values but three water bores (B-1, B-6, B-7) had higher values of iron (1.6, 2.206, 0.65 ppm), two water bores (B-1, B-6) had higher values of aluminium (0.95, 1.92 ppm), respectively, and molybdenum was higher by 0.01 ppm only in one water bore (B 11). The total number of coliforms present in water samples was found to be within the prescribed limit of the WHO except for 5 out of 11 bore water samples (B-2, B-3, B-4, B-8, B-11), which were found in the range 5-35 MPN/100 mL, a consequence of infiltration of contaminated water (sewage) through cross connection, leakage points and back siphoning. PMID- 22544072 TI - Solid-state dye-sensitized solar cells based on ordered ZnO nanowire arrays. AB - A solid-state dye-sensitized solar cell (DSC) is fabricated by using arrays of 11 12 um long, vertically oriented ZnO nanowires as the anode and CuSCN as the solid hole-transport material. The fabricated DSC yields a remarkably higher photocurrent density (J(SC) = 8 mA cm(-2)) compared to previously reported data for solid-state DSCs based on either one-dimensional nanostructures (J(SC) = 0.34 mA cm(-2)) or nanoporous nanocrystalline structures (J(SC) = 4.5 mA cm(-2)) of ZnO. A power conversion efficiency of 1.7% under an irradiation of AM 1.5 G simulated sunlight is reported. PMID- 22544073 TI - Testing for collective choices in the two-spotted spider mite. AB - Silk is a vector for collective behaviour in many spinning arthropods, including social spiders, social caterpillars, and some spider mites. In this study, the potential for silk-mediated collective choices is evaluated for the two-spotted spider mite Tetranychus urticae. This subsocial mite lives in large colonies on plants, sheltered under a collectively spun silk web. The silk has an attractive and arresting effect. We test whether the silk trails left by the spider mites can give rise to the collective choice of a path. The experiment consists in offering two identical paths to a group of migrating mites. Our results show that the presence of a silk trail influences the mites, but not sufficiently to systematically provoke a collective choice. In order to determine the trail following potential of T. urticae, we parameterise a theoretical trail following model to fit our experiments and those found in the literature. Our prediction is that even after a large number of mites have passed (200), a systematic collective choice of path should not be expected under the tested conditions. Our results, combined with what is known from the literature, allow us to propose a general scenario for the dispersal behaviour of T. urticae. PMID- 22544075 TI - Length matters: C-terminal tails regulate Mdm2-MdmX complexes. PMID- 22544074 TI - Ticks (Ixodida) on humans from central Panama, Panama (2010-2011). AB - From January 2010 to December 2011, a total of 138 cases of ticks feeding on humans were reported from 11 locations in central Panama. Five of these locations were situated in forest environments, three in rural landscapes and three in urban areas. The ticks were submitted to the Gorgas Memorial Institute, where nine species were identified among 65 specimens: Amblyomma cajennense s.l., A. dissimile, A. naponense, A. oblongoguttatum, A. ovale, A. sabanerae, A. tapirellum, Haemaphysalis juxtakochi and Rhipicephalus sanguineus s.l. The remaining 73 specimens consisted of unidentified immature ticks, all belonging to the genus of Amblyomma. Rhipicephalus sanguineus s.l. was the species most frequently associated with humans, particularly in urban environments. In rural landscapes, tick bites were most often caused by A. cajennense s.l., whereas A. tapirellum was the species most often found parasitizing humans in forest environments. These data provide information on the tick species most commonly associated with humans in forested environments, rural areas and cities around the Panama Canal. PMID- 22544076 TI - pRb or its cousins: who controls the family business? PMID- 22544077 TI - Milking the stroma in triple-negative breast cancer. PMID- 22544078 TI - Stress, specificity and the NEDD8 proteome. PMID- 22544080 TI - Asymmetric H-D exchange reactions of fluorinated aromatic ketones. AB - Chiral bicyclic guanidine catalyzes the asymmetric H-D exchange reactions. Up to 30% ee was achieved. DFT calculations were employed to elucidate and explain the origin of the reaction's stereoselectivity. PMID- 22544081 TI - The importance of adding EDTA for the nanopore analysis of proteins. AB - Nanopore analysis is a promising technique for studying the conformation of proteins and protein/protein interactions. Two proteins (bacterial thioredoxin and maltose binding protein) were subjected to nanopore analysis with alpha hemolysin. Two types of events were observed; bumping events with a blockade current less than -40 pA and intercalation events with blockade currents between 40 pA and -100 pA. In potassium phosphate buffer, pH 7.8, both proteins gave intercalation events but the frequency of these events was significantly reduced in TRIS or HEPES buffers especially in the presence of 0.01 mM divalent metal ions. The frequency of events was restored by the addition of EDTA. For maltose binding protein, the frequency of intercalation events was also decreased in the presence of maltose but not lactose to which it does not bind. It is proposed that the events with large blockade currents represent transient intercalation of a loop or end of the protein into the pore and that divalent metal ions inhibit this process. The results demonstrate that the choice of buffer and the effects of metal ion contamination are important considerations in nanopore analysis. PMID- 22544079 TI - Incidence, medical and socio-behavioural predictors of psychiatric events in an 11-year follow-up of HIV-infected patients on antiretroviral therapy. AB - BACKGROUND: Psychiatric disorders are relatively common among HIV-infected patients. However, there are few studies about their potential risk factors. This analysis aimed to measure the incidence of severe psychiatric events (PE) among patients receiving combination antiretroviral therapy (cART) of the French APROCO COPILOTE (ANRS CO8) cohort, and to identify the medical and socio-behavioural correlates of their first episode of depression, suicide or suicide attempt (D/S/SA). METHODS: APROCO-COPILOTE is a cohort of patients started on a protease inhibitor regimen between 1997 and 1999, with prospective medical standardized records and self-administered questionnaires collecting socio-demographic and socio-behavioural data. This analysis included all 11-year follow-up visits for 1,095 patients having completed baseline self-administered questionnaires. A proportional hazard Cox model was used to identify the correlates of a first D/S/SA event. RESULTS: The overall prevalence of severe PE remained low: 50 patients experienced 67 events (incidence rate [95% CI] =1.04 [0.82, 1.32] per 100 person-years). Depression (n=16), suicides (n=5) and suicide attempts (n=14) were the most frequently diagnosed PE (0.54 [0.39, 0.76] per 100 person-years) among 25 patients. Multivariate results showed that unemployment, unstable housing, detectable viral load and smoking more than 20 cigarettes/day were independently associated with D/S/SA. CONCLUSIONS: Although the incidence of severe PE remained relatively low among the patients of APROCO-COPILOTE cohort, this study's results underline a clinically important problem in HIV-infected patients receiving cART. Furthermore, our findings not only emphasize the importance of comprehensive care, especially for socially vulnerable patients, but may also help future studies designed to assess the effectiveness of interventions in reducing the risk of PE during cART. PMID- 22544083 TI - Localized optimized orbitals, coupled cluster theory, and chiroptical response properties. AB - The impact of orbital localization on the efficiency and accuracy of the optimized-orbital coupled cluster model is examined for the prediction of chiroptical properties, in particular optical rotation. The specific rotations of several test cases-(P)-[4]triangulane, (S)-1-phenylethanol, and chiral conformers of 1-fluoropentane, heptane, and nonane-were computed using an approach in which localization is enforced throughout the orbital optimization and subsequent linear response computation. This method provides a robust local-correlation scheme for future production-level implementation. Although the cross-over point between the canonical and localized coupled cluster approach lies at larger molecules than for ground-state energies, the scheme presented should still provide reduced scaling sufficient to investigate much larger molecules than are presently accessible. PMID- 22544082 TI - Dual-age-class population model to assess radiation dose effects on non-human biota populations. AB - In the present paper, a two-age-class group, logistic growth model for generic populations of non-human biota is described in order to assess non-stochastic effects of low linear energy-transfer radiation using three endpoints: repairable radiation damage, impairment of reproductive ability and, at higher radiation dose rates, mortality. This model represents mathematically the exchange between two life stages considering fecundity, growth and mortality. Radiation effects are modeled with a built-in self-recovery pool whereupon individuals can repair themselves. In acute effects mode, the repairing pool becomes depleted due to radiation and the model tends to lethality mode. A base calibration of the model's two free parameters is possible assuming that in acute mode 50% of the individuals die on 30 days when a radiation dose equal to the LD(50/30) is applied during that period. The model, which requires 10 species-dependent life history parameters, was applied to fish and mammals. Its use in the derivation of dose-rate screening values for the protection of non-human biota from the effects of ionizing radiation is demonstrated through several applications. First, results of model testing with radiation effects data for fish populations from the EPIC project show the predictive capability of the model in a practical case. Secondly, the model was further verified with FREDERICA radiation effects data for mice and voles. Then, consolidated predictions for mouse, rabbit, dog and deer were generated for use in a population model comparison made within the IAEA EMRAS II project. Taken together, model predictions suggest that radiation effects are more harmful for larger organisms that generate lower numbers of offspring. For small mammal and fish populations, dose rates that are below 0.02 Gy day(-1) are not fatal; in contrast, for large mammals, chronic exposure at this level is predicted to be harmful. At low exposure rates similar to the ERICA screening dose rate of 2.4 * 10(-4) Gy day(-1), long-term effects on the survivability of populations are negligible, supporting the appropriateness of this value for radiological assessments to wildlife. PMID- 22544084 TI - Involvement of alternative oxidase (AOX) in adventitious rooting of Olea europaea L. microshoots is linked to adaptive phenylpropanoid and lignin metabolism. AB - Alternative oxidase (AOX) has been proposed as a functional marker candidate in a number of events involving cell differentiation, including rooting efficiency in semi-hardwood shoot cuttings of olive (Olea europaea L.). To ascertain the general importance of AOX in olive rooting, the auxin-induced rooting process was studied in an in vitro system for microshoot propagation. Inhibition of AOX by salicylhydroxamic acid (SHAM) significantly reduced rooting efficiency. However, the inhibitor failed to exhibit any effect on the preceding calli stage. This makes the system appropriate for distinguishing dedifferentiation and de novo differentiation during root induction. Metabolite analyses of microshoots showed that total phenolics, total flavonoids and lignin contents were significantly reduced upon SHAM treatment. It was concluded that the influence of alternative respiration on root formation was associated to adaptive phenylpropanoid and lignin metabolism. Transcript profiles of two olive AOX genes (OeAOX1a and OeAOX2) were examined during the process of auxin-induced root induction. Both genes displayed stable transcript accumulation in semi-quantitative RT-PCR analysis during all experimental stages. In contrary, when the reverse primer for OeAOX2 was designed from the 3'-UTR instead of the ORF, differential transcript accumulation was observed suggesting posttranscriptional regulation of OeAOX2 during metabolic acclimation. This result confirms former observations in olive semi-hardwood shoot cuttings on differential OeAOX2 expression during root induction. It further points to the importance of future studies on the functional role of sequence and length polymorphisms in the 3'-UTR of this gene. KEY MESSAGE: The manuscript reports the general importance of AOX in olive adventitious rooting and the association of alternative respiration to adaptive phenylpropanoid and lignin metabolism. PMID- 22544086 TI - Discussion: mammographic changes after fat transfer to the breast compared with changes after breast reduction: a blinded study. PMID- 22544085 TI - Hypothesis: emergence of translation as a result of RNA helicase evolution. AB - The origin of translation and the genetic code is one of the major mysteries of evolution. The advantage of templated protein synthesis could have been achieved only when the translation apparatus had already become very complex. This means that the translation machinery, as we know it today, must have evolved towards some different essential function that subsequently sub-functionalised into templated protein synthesis. The hypothesis presented here proposes that translation originated as the result of evolution of a primordial RNA helicase, which has been essential for preventing dying out of the RNA organism in sterile double-stranded form. This hypothesis emerges because modern ribosome possesses RNA helicase activity that likely dates back to the RNA world. I hypothesise that codon-anticodon interactions of tRNAs with mRNA evolved as a mechanism used by RNA helicase, the predecessor of ribosomes, to melt RNA duplexes. In this scenario, peptide bond formation emerged to drive unidirectional movement of the helicase via a molecular ratchet mechanism powered by Brownian motion. I propose that protein synthesis appeared as a side product of helicase activity. The first templates for protein synthesis were functional RNAs (ribozymes) that were unwound by the helicase, and the first synthesised proteins were of random or non sense sequence. I further suggest that genetic code emerged to avoid this randomness. The initial genetic code thus emerged as an assignment of amino acids to codons according to the sequences of the pre-existing RNAs to take advantage of the side products of RNA helicase function. PMID- 22544087 TI - Predicting mastectomy skin flap necrosis with indocyanine green angiography: the gray area defined. AB - BACKGROUND: Preservation of breast skin during mastectomy has improved the cosmetic results of breast reconstruction. Unfortunately, the incidence of mastectomy skin flap necrosis remains high using conventional evaluation methods; therefore, accurate prediction of flap viability is an important component of postmastectomy reconstruction. METHODS: The authors studied a prospective cohort of women who underwent skin-sparing mastectomy and breast reconstruction over a 2 year period at Emory University. Mastectomy skin flap perfusion was measured intraoperatively using indocyanine green angiography. Once necrosis matured postoperatively, digital images were taken and superimposed over the intraoperative scan. Perfusion percentages were measured in healthy and nonviable skin. RESULTS: One hundred eighteen patients were included, and 14 patients (15 breasts) with postoperative skin necrosis and sufficient image data were analyzed. The average woman's age was 49.7 years (range, 28 to 73 years) and the average body mass index was 27.7 (range, 21.2 to 42.2). Skin with 25 percent or less perfusion (perfusion score, <= 25) was not viable 90 percent of the time, and areas with greater than or equal to 45 percent perfusion survived 98 percent of the time. A 33 percent perfusion score had a positive predictive value of removing nonviable skin of 88 percent and a negative predictive value of removing healthy skin of 16 percent. CONCLUSIONS: Indocyanine green angiography is a useful adjunct to assess mastectomy skin flap viability. A gray zone exists between 25 and 45 percent of maximal skin perfusion in which the ultimate viability remains in question. By designating the cutoff perfusion score of 33 percent, the surgeon can expect to more accurately remove nonviable skin. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, III. PMID- 22544088 TI - The use of acellular dermal matrix in immediate two-stage tissue expander breast reconstruction. AB - BACKGROUND: Acellular dermal matrix is commonly used in implant-based breast reconstruction to allow for quicker tissue expansion with better coverage and definition of the lower pole of the breast. This study was performed to analyze complications associated with its use in immediate two-stage, implant-based breast reconstruction and to subsequently develop guidelines for its use. METHODS: A retrospective analysis of 628 consecutive immediate two-stage tissue expander breast reconstructions at a single institution over a 3-year period was conducted. The reconstructions were divided into two groups: reconstruction with acellular dermal matrix and reconstruction without it. Demographic information, patient characteristics, surface area of acellular dermal matrix, and complications were analyzed and compared. RESULTS: A total of 407 patients underwent 628 immediate two-stage, implant-based breast reconstructions; 442 reconstructions (70.3 percent) used acellular dermal matrix and 186 (29.6 percent) did not. The groups had similar patient characteristics; however, major complications were significantly increased in the acellular dermal matrix group (15.3 versus 5.4 percent; p = 0.001). These complications included infection requiring intravenous antibiotics (8.6 versus 2.7 percent; p = 0.001), flap necrosis requiring excision (6.7 versus 2.7 percent; p = 0.015), and explantation of the tissue expander (7.7 versus 2.7 percent; p = 0.004). CONCLUSIONS: Use of acellular dermal matrix in immediate two-stage, implant-based breast cancer reconstruction is associated with a significant increase in major complications. Therefore, it should only be used in specific patients and in minimal amounts. Indications for its use include single-stage permanent implant reconstruction and inadequate local muscle coverage of the tissue expander. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 22544089 TI - Discussion: the use of acellular dermal matrix in immediate two-stage tissue expander breast reconstruction. PMID- 22544090 TI - Single-stage breast reconstruction with the anterior approach latissimus dorsi flap and permanent implants. AB - BACKGROUND: Traditional latissimus dorsi myocutaneous flap breast reconstruction results in a large wound on the back, difficult inset of flap, and skin color disparity. An anterior approach to harvesting the latissimus dorsi muscle flap reduces morbidity, and with skin-sparing mastectomy, immediate single-stage reconstruction with a permanent implant is provided. METHODS: A retrospective review was performed of patients who underwent skin-sparing mastectomies and immediate reconstruction with the anterior approach latissimus dorsi muscle flap and permanent implant with 6- to 12-month follow-up. All procedures were performed by a single surgeon at three facilities from January of 2008 through December of 2008. Data included the patient's age; body mass index; history of axillary dissection, chemotherapy, or irradiation; occurrence of seroma, flap necrosis, infection, or cellulitis; and the need for further surgery. RESULTS: Fifty-eight reconstructions were performed in 36 patients (bilateral, 22 patients). Major complications included pulmonary embolism in one patient, removal of both implants in one patient because of infection, and removal of one implant because of hematoma. Minor complications included seroma in 40 of 58 procedures (68.9 percent), flap necrosis in seven (12 percent), cellulitis in four (6.8 percent), and a secondary procedure for cosmesis in four (6.8 percent). Seroma formation was more frequent in patients with a body mass index greater than 25 kg/m2, patients aged older than 50 years, and after axillary dissection (p > 0.05). CONCLUSIONS: The anterior approach latissimus dorsi muscle flap with permanent implants provides a single-stage reconstructive option after skin sparing mastectomy. Postoperative morbidity is comparable to that of the traditional latissimus dorsi muscle flap. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 22544091 TI - The influence of sociodemographic factors and hospital characteristics on the method of breast reconstruction, including microsurgery: a U.S. population-based study. AB - BACKGROUND: Microsurgical breast reconstruction has gained popularity because of associations with decreased abdominal morbidity and high satisfaction. Nationwide use of these procedures is unknown. Although many factors can influence the method of breast reconstruction, sociodemographic and hospital characteristics have not been specifically evaluated. The authors studied the importance of microsurgical flaps among the techniques available for breast reconstruction and evaluated the effect of sociodemographic and hospital characteristics on the technique chosen. METHODS: A cross-sectional study of breast reconstructions was performed using the Nationwide Inpatient Sample database for 2008. National estimates of breast reconstructive procedures including microsurgery were obtained. Impact of variables on reconstructive method was analyzed using logistic regression. RESULTS: Among women undergoing breast reconstruction in 2008, implants were the most common procedure (60.5 percent), followed by pedicled flaps (34 percent) and microsurgical flaps (5.5 percent). Multivariable analysis showed that women aged 50 to 59 years, treated at teaching hospitals, with private insurance, or undergoing delayed reconstruction were more likely to have autologous than implant reconstruction. Implant use was associated with young patients, Caucasians, Asians, higher income, and all regions except the Northeast. Analysis of autologous reconstructions showed the likelihood for a microsurgical versus a pedicle flap was greater in teaching hospitals, private insurance carriers, and delayed reconstructions. CONCLUSIONS: Microsurgical techniques are currently used in only a minority of reconstructions. Sociodemographic variables and teaching hospital status influence the method of breast reconstruction. The presence of disparities in care suggests that current decision making for breast reconstruction is not based solely on patient preference or anatomical features. PMID- 22544092 TI - Discussion: the fate of adipocytes after nonvascularized fat grafting: evidence of early death and replacement of adipocytes. PMID- 22544093 TI - Rethinking the blastema. AB - The phenomenon of tissue regeneration has been well documented across many species. Although some possess the capacity to completely restore an entire amputated limb, others are limited to just the distal digit tip. Initiation of limb regeneration has been described to start with the formation of a blastema, the composition of which has long been thought to consist of undifferentiated pluripotent cells derived through the process of dedifferentiation. Competing theories have been proposed, however, including cellular contributions through transdifferentiation and tissue-specific stem cells. Recent studies have now begun to shed light on this controversy, demonstrating tissue resident stem cells to be an evolutionarily conserved measure for limb regeneration. PMID- 22544094 TI - Restoration of the donor after face graft procurement for allotransplantation: report on the technique and outcomes of seven cases. AB - BACKGROUND: After organ retrieval, restoration of the donor is a legal and ethical necessity; this is particularly true in facial transplantation. However, very few data are available regarding this procedure. METHODS: This article reviews the seven facial masks produced during seven consecutive face transplants carried out at Henri Mondor Hospital in Paris, France. The time of production, morphologic outcome, and donor family feedback were recorded. Technical tips and pitfalls are also discussed. RESULTS: Recording an impression of the donor's face with alginate required less than 25 minutes and, in all cases, the production of a resin mask was completed before the surgical harvesting was finished. Although all morphologic results were satisfactory or very satisfactory, the best outcomes were achieved using a total face mask, avoiding color discrepancies. Family feedback was positive, and none of the funeral ceremonies was disturbed by the procedure. CONCLUSIONS: The production of a full-face resin mask is a reliable and reproducible technique. This procedure restores donor integrity and gives a very satisfactory morphologic and aesthetic outcome. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 22544095 TI - Outcome comparison of endoscopic and transpalpebral decompression for treatment of frontal migraine headaches. AB - BACKGROUND: This study was designed to compare the efficacy of the transpalpebral versus endoscopic approach to decompression of the supraorbital and supratrochlear nerves in patients with frontal migraine headaches. METHODS: The medical charts of 253 patients who underwent surgery for frontal migraine headaches were reviewed. These patients underwent either transpalpebral nerve decompression (n = 62) or endoscopic nerve decompression (n = 191). Preoperative and 12-month or greater postoperative migraine frequency, duration, and intensity were analyzed to determine the success of the surgeries. RESULTS: Forty-nine of 62 patients (79 percent) in the transpalpebral nerve decompression group and 170 of 191 patients (89 percent) who underwent endoscopic nerve decompression experienced a successful outcome (at least a 50 percent decrease in migraine frequency, duration, or intensity) after 1 year from surgery. Endoscopic nerve decompression had a significantly higher success rate than transpalpebral nerve decompression (p < 0.05). Thirty-two patients (52 percent) in the transpalpebral nerve decompression group and 128 patients (67 percent) who underwent endoscopic nerve decompression observed elimination of migraine headaches. The elimination rate was significantly higher in the endoscopic nerve decompression group than in the transpalpebral nerve decompression group (p < 0.03). CONCLUSION: Endoscopic nerve decompression was found to be more successful at reducing or eliminating frontal migraine headaches than transpalpebral nerve decompression and should be selected as the first choice whenever it is anatomically feasible. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 22544096 TI - Discussion: outcome comparison of endoscopic and transpalpebral decompression for treatment of frontal migraine headaches. PMID- 22544097 TI - Tissue engineering: revolution and challenge in auricular cartilage reconstruction. AB - External ear reconstruction for congenital deformity such as microtia or following trauma remains one of the greatest challenges for reconstructive plastic surgeons. The problems faced in reconstructing the intricate ear framework are highly complex. A durable, inert material that is resistant to scar contracture is required. To date, no material, autologous or prosthetic, is available that perfectly mimics the shapely elastic cartilage found in the ear. Current procedure involves autologous costal cartilage that is sculpted to create a framework for the overlying soft tissues. However, this is associated with donor-site morbidity, and few surgeons worldwide are skilled in the techniques required to obtain excellent results. Various alloplastic materials have therefore been used as a framework. However, a degree of immunogenicity and infection and extrusion are inevitable, and results are often disappointing. Tissue-engineered cartilage is an alternative approach but, despite significant progress in this area, many problems remain. These need to be addressed before routine clinical application will become possible. The current tissue-engineered options are fragile and inflexible. The next generation of auricular cartilage engineering is promising, with smart materials to enhance cell growth and integration, and the application of stem cells in a clinical setting. More recently, the authors' team designed the world's first entirely synthetic trachea composed of a novel nanocomposite material seeded with the patient's own stem cells. This was successfully transplanted in a patient at the Karolinska Hospital in Sweden and may translate into a tissue-engineered auricle in the future. PMID- 22544098 TI - A multivariate analysis of nasal tip deprojection. AB - BACKGROUND: Projection of the nasal tip is a complex problem that often mandates attention during rhinoplasty. Occasionally, the goal is to decrease tip projection. Most published solutions to this problem involve division or manipulation of the lower lateral cartilages, although objective data on the efficacy of these techniques are limited. This study reviews a series of rhinoplasties and determines which maneuvers had the greatest effect on tip projection. METHODS: One hundred twenty-five consecutive rhinoplasties performed by a single surgeon in a university setting were reviewed. Charts were analyzed for surgical indications and technical steps performed in the operating room. Preoperative and postoperative photographs underwent multivariate analysis to determine changes in nasal projection and which factors contribute to affecting tip projection. RESULTS: Overall revision rate was 3.8 percent. Cartilage splitting techniques were used in only 2.4 percent of cases. Multivariate dummy variable analysis revealed that only dorsal component reduction and caudal trim were associated with significant decreases in tip projection. Alar base resection did not change absolute tip position but did have a marked effect on the position of the alar-cheek junction and thus the overall balance of the nose with regard to length-to-projection ratios and projection proportions. CONCLUSIONS: Cartilage dividing techniques are rarely necessary to reduce projection. Release of the soft-tissue attachments of the lower lateral cartilages and modification of the anterior septum are frequently sufficient to achieve a satisfactory aesthetic endpoint. Alar base resection has a complex interaction with nasal aesthetics with regard to tip projection. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 22544099 TI - The platysma window: an anatomically safe, efficient, and easily reproducible approach to neck contour in the face lift. AB - BACKGROUND: The cornerstone of the face lift is neck contour. The pursuit of reliable and reproducible results has led plastic surgeons to investigate a multitude of different approaches. Unfortunately, addressing neck contour can lead to complications such as injury to the great auricular nerve. The purpose of this study was to describe an efficient, safe, and reproducible technique of improving face lifts: the platysma window. METHODS: The authors use a reference point located one fingerbreadth inferior to the angle of the mandible and one fingerbreadth anterior to the anterior border of the sternocleidomastoid muscle. A two-fingerbreadth incision is made on the muscle to open a small "window," approximately 2 cm of total vertical flap length. Two figure-of-eight 4-0 Mersilene sutures are placed from the window to the mastoid fascia, spanning the great auricular nerve at McKinney's point. RESULTS: The platysma window technique is designed to minimize the complications of neck lifts-especially the risk of injury to the great auricular nerve. Placing the window inferior and anterior to these structures ensures a safe area for executing platysma tightening. This maneuver can augment a myriad of face-lifting techniques. The authors have used the maneuver described in over 200 cases, with consistently repeatable and improved neck contour results. CONCLUSIONS: Patients demand expedient and safe procedures in addition to an excellent cosmetic outcome. Plastic surgeon should try to meet their patients' needs; the authors believe the platysma window can play a role in becoming a useful method available to surgeons when addressing neck contour in face lifting. PMID- 22544100 TI - Teaching plastic surgeons how to be better teachers. AB - The purpose of this article is to introduce plastic surgeons to a theory of adult education. Most surgeons have been hired by their parent institution because of their clinical skills, and rightly so. At the same time, these same surgeons choose or are expected to be involved to varying degrees in the surgical education process with medical students, surgical residents, fellows, and allied health workers. Likewise, busy surgical residents are also expected to teach other residents and students, and yet these two groups of teachers of surgery have little or no training in the theory and practice of adult education. This article has four major sections. The first is a scenario designed to bring to mind a context and set of ideas with which the reader is already familiar. The second provides new information, Kolb's theory of adult learning and Arseneau and Rodenberg's teaching principles, and discusses their implications. The third section is designed to give the reader an opportunity to work with the new knowledge and practice possible applications, and the fourth encourages the reader to use the new knowledge in concrete ways in a real-world environment. PMID- 22544101 TI - Discussion: teaching plastic surgeons how to be better teachers. PMID- 22544102 TI - A guide to interpreting a study of patient-reported outcomes. AB - Outcomes measured from the patient perspective are particularly important in plastic surgery, where many of the treatments are aimed at improving physical function, psychosocial function, and quality of life. Understanding the measurement of patient-reported outcomes is critical to determine the value of the interventions performed, to better inform clinical decision-making, and to guide policy debates. It is critical that physicians understand their patients' individual values when making treatment and policy recommendations based on evidence. This guide outlines the questions that readers should ask when appraising literature using patient-reported outcomes. PMID- 22544103 TI - Are teachers born or do they develop over time? PMID- 22544108 TI - Intraoperative perfusion techniques can accurately predict mastectomy skin flap necrosis in breast reconstruction: results of a prospective trial. AB - BACKGROUND: Intraoperative vascular imaging can assist assessment of mastectomy skin flap perfusion to predict areas of necrosis. No head-to-head study has compared modalities such as laser-assisted indocyanine green dye angiography and fluorescein dye angiography with clinical assessment. METHODS: The authors conducted a prospective clinical trial of tissue expander-implant breast reconstruction with intraoperative evaluation of mastectomy skin flaps by clinical assessment, laser-assisted indocyanine green dye angiography, and fluorescein dye angiography. Intraoperatively predicted regions of necrosis were photographically documented, and clinical assessment guided excision. Postoperative necrosis was directly compared with each prediction. The primary outcome was all-inclusive skin necrosis. RESULTS: Fifty-one tissue expander implant breast reconstructions (32 patients) were completed, with 21 cases of all inclusive necrosis (41.2 percent). Laser-assisted indocyanine green dye angiography and fluorescein dye angiography correctly predicted necrosis in 19 of 21 of cases where clinical judgment had failed. Only six of 21 cases were full thickness necrosis, and five of 21 required an intervention (9.8 percent). Risk factors such as smoking, obesity, and breast weight greater than 1000 g were statistically significant. Laser-assisted indocyanine green dye angiography and fluorescein dye angiography overpredicted areas of necrosis by 72 percent and 88 percent (p = 0.002). Quantitative analysis for laser-assisted indocyanine green dye angiography in necrotic regions showed absolute perfusion units less than 3.7, with 90 percent sensitivity and 100 percent specificity. CONCLUSIONS: Laser assisted indocyanine green dye angiography is a better predictor of mastectomy skin flap necrosis than fluorescein dye angiography and clinical judgment. Both methods overpredict without quantitative analysis. Laser-assisted indocyanine green dye angiography is more specific and correlates better with the criterion standard diagnosis of necrosis. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, I. PMID- 22544109 TI - Immediate breast reconstruction and lymphedema incidence. AB - BACKGROUND: As breast cancer survivorship increases, more women are being affected by treatment sequelae, including lymphedema. The purpose of this study was to evaluate lymphedema incidence among immediate breast reconstruction patients and determine what factors are associated with lymphedema, including reconstruction method. METHODS: The authors reviewed the outcomes of all consecutive patients who underwent immediate postmastectomy breast reconstruction at their institution between 2001 and 2006. Patient, treatment, and outcome characteristics were compared among reconstruction types: expander and implant, latissimus dorsi myocutaneous flap and implant, and autologous flap alone. Regression models were used to determine whether patient and treatment characteristics were associated with lymphedema development. RESULTS: This study included 1117 patients (1499 breasts), with a mean follow-up of 56 months. Axillary interventions (p < 0.001), high numbers of positive lymph nodes (p = 0.004), postoperative radiation therapy (p = 0.007), and body mass index of 25 kg/m or greater (p = 0.010) were strong predictors of increased lymphedema incidence. After excluding prophylactic mastectomy and reconstruction group changes, the authors found that the mean lymphedema incidence was 4.0 percent (of 1013 breasts). Reconstruction type had no significant effect on incidence of or time to lymphedema, and no interaction was found between axillary intervention and reconstruction type (p = 0.799). CONCLUSIONS: The incidence of lymphedema after immediate reconstruction was associated with high body mass index, axillary interventions, and high numbers of positive lymph nodes. The reconstructive method did not appear to affect lymphedema incidence or timing. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 22544110 TI - Cranial particulate bone graft ossifies calvarial defects by osteogenesis. AB - BACKGROUND: Cranial particulate bone graft heals inlay calvarial defects and can be harvested as early as infancy. The purpose of this study was to test the hypothesis that particulate bone promotes ossification primarily by osteogenesis. METHODS: Freshly harvested particulate bone, devitalized particulate bone, and high-speed drilled bone dust from rabbit calvaria were assayed for metabolic activity (resazurin) and viable osteoblasts (alkaline phosphatase). A rabbit cranial defect model was used to test the effect of devitalizing particulate bone on in vivo ossification. A parietal critical-size defect was created and managed in three ways: (1) no implant (n = 6); (2) particulate bone implant (n = 6); and (3) devitalized particulate bone implant (n = 6). Micro-computed tomographic scanning was used to measure ossification 16 weeks later; histology also was studied. RESULTS: Particulate bone contained more viable cells (0.94 percent transmittance per milligram) compared with devitalized particulate bone (0.007 percent) or bone dust (0.21 percent) (p = 0.01). Particulate bone had greater alkaline phosphatase activity (0.13 MUU/MUg) than devitalized particulate bone (0.000) or bone dust (0.06) (p = 0.01). Critical-size defects treated with particulate bone had more ossification (99.7 percent) compared with devitalized particulate bone implants (42.2 percent) (p = 0.01); no difference was found between devitalized particulate bone and the control (40.8 percent) (p = 0.9). CONCLUSIONS: Particulate bone graft contains living cells, including osteoblasts, that are required to heal critical-size cranial defects. These data support the hypothesis that particulate bone promotes ossification primarily by osteogenesis. PMID- 22544112 TI - Validation of a lip fullness scale for assessment of lip augmentation. AB - BACKGROUND: Given the growing use of dermal fillers for cosmetic lip augmentation, a validated instrument with which to measure lip fullness is desirable in the clinic and as an efficacy endpoint in clinical studies. The authors developed and conducted a validation study of a Medicis-developed lip fullness scale. METHODS: The Medicis Lip Fullness Scale consists of separate five point scales for the upper and lower lips, with three photographs exemplifying each grade. Five board-certified dermatologists or plastic surgeons assessed 85 test photographs for each lip on two separate occasions for the first round of validation (photograph versus photograph). Three of the evaluators also graded lip fullness in 39 live subjects, followed 2 weeks later by scoring of the same subjects' photographs for the second round of validation (live versus photographic). RESULTS: Within-observer agreement between the two sequential photographic evaluations was almost perfect (weighted kappa = 0.81). Between observer weighted kappa values ranged from 0.60 to 0.83 for the upper lip and 0.61 to 0.82 for the lower lip. Exact agreement between the live and photographic assessments of the same subjects was 60 percent and 52 percent for upper and lower lips, respectively. CONCLUSIONS: The Medicis Lip Fullness Scale showed high interrater and intrarater reliability in comparisons of test photographs and moderate to substantial reliability in live assessment of patients versus photographs. The Medicis Lip Fullness Scale is suitable for grading lip fullness in clinical trials. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, III. PMID- 22544111 TI - Molecular genetic analysis of TWIST1 and FGFR3 genes in Korean patients with coronal synostosis: identification of three novel TWIST1 mutations. AB - BACKGROUND: Craniosynostosis is very heterogeneous in terms of its causes, presentation, and management. In particular, coronal synostosis evidences a higher tendency to be genetically caused, and TWIST1 and FGFR3 have been identified as major causative genes. The authors analyzed the clinical and molecular characteristics of Korean patients with coronal synostosis in this study. METHODS: Forty-three Korean patients with unicoronal or bicoronal synostosis were included in this study. All samples were first screened for TWIST1 and FGFR3 mutation hot spots, and the negative samples were subsequently screened for FGFR2. The patients' clinical features were analyzed and compared. RESULTS: Seven sequence alterations (six in TWIST1 and one in FGFR3) were identified in 11 patients (25.6 percent). Three novel TWIST1 mutations were detected, and p.P250R was the only mutation in FGFR3. Bicoronal cases evidenced a much higher mutation detection rate (52.9 percent) than unicoronal cases (7.7 percent). In the TWIST1 group, five patients had Saethre-Chotzen syndrome, and one was nonsyndromic. In the FGFR3 group, four patients had Muenke syndrome, and one was nonsyndromic. The majority of associated anomalies, with the exception of psychomotor retardation and Chiari malformation, were detected more frequently in TWIST1 patients than in FGFR3 p.P250R patients. CONCLUSIONS: This study is, to the best of the authors' knowledge, the first to illustrate the frequency and spectrum of mutations in TWIST1 and FGFR3 in Korea. Considering that molecular diagnosis techniques can prove helpful in providing adequate genetic counseling and guidance, genetic screening for TWIST1 and FGFR3 p.P250R in cases of coronal synostosis is recommended. PMID- 22544113 TI - Breast reduction. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Understand the preoperative considerations that must be weighed to appropriately assess operative risk of breast reduction. 2. Have a full understanding of the basic techniques that are available to treat the patient with macromastia. 3. Identify which patients are best suited to a particular technique. 4. Identify common complications associated with breast reduction and understand how to treat them. SUMMARY: Breast reduction remains a basic plastic surgery procedure designed to alleviate upper torso complaints resulting from macromastia. Historically, the inverted-T inferior pedicle procedure was the dominant technique for the treatment of macromastia for 40 years. The past two decades have seen a reexamination of breast reduction technique in an attempt to improve on the results and minimize complications. As a result, a new genre of procedures based on different pedicles and short-scar skin management techniques has been introduced. With these new procedures, the plastic surgeon now has a variety of different techniques that can be offered for reducing the hypertrophic breast. Strategically applying the concepts inherent in these procedures to the correct patient can provide outstanding results with few complications. In this article, the concepts and results of these various procedures are discussed to give the reader a basic understanding of the options available for breast reduction. PMID- 22544114 TI - Oral prednisolone for infantile hemangioma: efficacy and safety using a standardized treatment protocol. PMID- 22544116 TI - The five-step lower blepharoplasty: blending the eyelid-cheek junction. PMID- 22544118 TI - A new carbon dioxide laser combined with cyanoacrylate glue to treat earlobe keloids. PMID- 22544120 TI - The clinical relevance of lower triglyceride and leukocyte levels after liposuction. PMID- 22544122 TI - Introducing the septocutaneous gluteal artery perforator flap: a simplified approach to microsurgical breast reconstruction. PMID- 22544124 TI - Perforator anatomy of the fibula osteocutaneous flap. PMID- 22544126 TI - Facial nerve reconstruction using a thoracodorsal nerve graft after radical parotidectomy. PMID- 22544127 TI - Evidence-based analysis of vein graft interposition in head and neck free flap reconstruction. PMID- 22544128 TI - Reconstruction of total nasal defect including skin, bone, and lining, using a single free radial forearm osteocutaneous perforator flap. PMID- 22544129 TI - A technique to make spreader graft fixation easier. PMID- 22544130 TI - The design and rapid prototyping of surgical guides and bone plates to support iliac free flaps for mandible reconstruction. PMID- 22544131 TI - A novel fibula osteotomy guide for mandibular reconstruction. PMID- 22544132 TI - Reconstruction with an osmotic tissue expander in pediatric patients. PMID- 22544133 TI - The "fish" mastopexy. PMID- 22544134 TI - Evaluation, comparison, and analysis of postoperative injury between submuscular and retroglandular augmentation mammaplasty. PMID- 22544135 TI - Free flap breast reconstruction consent forms should warn against the potential loss of the internal thoracic artery for coronary artery bypass grafting. PMID- 22544136 TI - Recreating the lateral footprint of obese patients in immediate silicone implant breast reconstruction using an elongated teardrop incision. PMID- 22544137 TI - Capsular contracture after breast reconstruction: a modified classification system incorporating the effects of radiation. PMID- 22544138 TI - Brief recommendations for dealing with a new case of anaplastic large T-cell lymphoma. PMID- 22544139 TI - Submuscular breast augmentation with a support pad technique based on gold percentage measurement: stabilizing the implant position and temperature. PMID- 22544140 TI - Successful DIEP flap for breast reconstruction in a patient with prior abdominoplasty. PMID- 22544141 TI - Perforator-supercharged perforator-based propeller flaps. PMID- 22544142 TI - Establishing a perforator flap nomenclature based on anatomical principles. PMID- 22544143 TI - Intraoperative navigation-assisted identification of deep inferior epigastric artery perforators. PMID- 22544144 TI - The end-to-side neurorrhaphy in axillary nerve reconstruction in patients with brachial plexus palsy. PMID- 22544145 TI - Rupture of both the abductor pollicis longus and extensor pollicis brevis tendons after steroid injection for de quervain tenosynovitis. PMID- 22544146 TI - German version of the brief Michigan Hand Outcomes Questionnaire: implications for early quality of life following collagenase injection in dupuytren contracture. PMID- 22544147 TI - Can we save the arm? A 38-year-old man with morbus ollier (enchondromatosis) and secondary chondrosarcoma. PMID- 22544148 TI - Vascularized femur flap for stabilization after combined total sacrectomy and external hemipelvectomy. PMID- 22544149 TI - Low-cost simulation plank for microsurgical success. PMID- 22544150 TI - Elongation through Z-plasty: an experimental study comparing 11 Z-plasty variations on nonbiological tissue. PMID- 22544151 TI - Are smaller plastic surgery residency programs at an Accreditation Council for Graduate Medical Education accreditation disadvantage? PMID- 22544152 TI - Twitter for plastic surgeons. PMID- 22544153 TI - Stability of lidocaine-epinephrine mixtures after multiple accesses. PMID- 22544154 TI - Consensus is the negation of leadership. PMID- 22544155 TI - In defense of eponyms. PMID- 22544156 TI - Workplace psychological harassment in Canadian nurses: a descriptive study. AB - This descriptive study investigated workplace psychological harassment in a sample of 1179 Canadian nurses. Two complementary types of assessment were used: exposure to negative behaviors and perceived victimization. Results revealed that exposure to negative behaviors was associated with certain sociodemographic variables (i.e. job status and the amount of overtime performed weekly), lower psychological health, and poorer functioning at work. Although many nurses reported being exposed to negative behaviors, few perceived these behaviors as psychological harassment per se. However, regardless of perceptions of victimization, exposure to negative behaviors was detrimental to nurses' psychological health and functioning at work. Practical implications are discussed. PMID- 22544157 TI - Existential relatedness in light of eudemonic well-being and religious coping among middle-aged and older cardiac patients. AB - This study examined the prediction of preoperative faith factors for perceived spiritual support, indicating existential relationship as a dimension of eudemonic well-being (EWB), at 30 months after cardiac surgery (N=226). The study capitalized on data from preoperative surveys and the Society of Thoracic Surgeons' National Database. Controlling for demographics, cardiac indices, and mental health, hierarchical regression showed that preoperative prayer coping, subjective religiousness, and internal control were positive predictors of spiritual support. Negative religious coping was a negative predictor. Internal control mediated the role of positive religious coping. Certain faith-based experiences may enhance aspects of EWB, but future research should investigate mechanisms. PMID- 22544158 TI - Balancing motherhood and drug addiction: the transition to parenthood of addicted mothers. AB - This is a study about balancing motherhood and drug addiction, during the transition to parenthood. Few studies have dealt with the parental experience of drug-addicted mothers. The participants included 24 drug-addicted mothers, on methadone, with ages 25-42 and with children 1-32 months of age. Semi-structured interviews were conducted and analyzed according to Grounded Theory. The mothers' main concern was the ambivalence they felt towards pregnancy/motherhood and drug addiction, which was associated with strong feelings of guilt. Confronted with this ambivalence their maternal role becomes merely functional. They focus on providing the basic care to the child, but show little willingness to talk or play. Social support, especially from the partner seems to have a positive role. PMID- 22544159 TI - Enantioselective Friedel-Crafts reactions between phenols and N-tosylaldimines catalyzed by a leucine-derived bifunctional catalyst. AB - Enantioselective Friedel-Crafts reactions between phenols and N-tosylaldimines were developed using a bifunctional catalyst readily prepared from L-leucine. The chiral benzylic amine products were obtained in high yields (up to 96% yield) and good to high enantiomeric excesses (up to 95% ee). PMID- 22544160 TI - Risk communication in deployment-related exposure concerns. AB - OBJECTIVE: Veterans Affairs and Department of Defense health care providers and educators serve as primary channels of communication with veterans but may not understand the importance and benefits of risk communication to inform and empower veterans about actions to take or not take to improve the quality of their health. This article describes the importance of understanding and applying risk communication principles in communicating to veterans about the potential for health concerns/impacts from deployment-related exposures. RESULTS: The principles of risk communication as relevant to clinical encounters are presented, focusing on a review of risk perception factors influencing deployment related exposure concerns. Results show that risk communication can impact how veterans will take in and process information about deployment-related exposures. CONCLUSION: This article illustrates how providers can effectively use risk communication to structure better clinical encounters and communication with veterans. PMID- 22544161 TI - Surveillance for long-term health effects associated with depleted uranium exposure and retained embedded fragments in US veterans. AB - OBJECTIVE: To ensure that all veterans with retained embedded fragments are properly monitored for potential health effects of embedded materials. METHODS: Urine biomonitoring and health surveillance programs were developed to gather information about health risks associated with chemicals released from embedded fragments. RESULTS: Elevated systemic exposure to depleted uranium (DU) that continues to occur in veterans with DU fragments remains a concern, although no clinically significant DU-related health effects have been observed to date. Other metals and local tissue reactions to embedded fragments are also of concern. CONCLUSIONS: Knowledge gained from these programs will help to develop guidelines for surgical removal of tissue-embedded fragments. PMID- 22544162 TI - Exposure estimates for workers in a facility expanding Libby vermiculite: updated values and comparison with original 1980 values. AB - OBJECTIVE: Low cumulative fiber exposure (CFE) has been associated with health effects in a cohort exposed to Libby vermiculite. This study refines the original 1980 exposure estimates and compares the CFE results. METHODS: Cumulative fiber exposure estimates were developed using three times more industrial hygiene measurements and long-term workers' input. New adjustments included vermiculite ore source, seasonal overtime hours, time spent in various tasks, and recollection of historical dustiness. RESULTS: The overall mean (95% confidence interval) CFE (n = 513) in 1980 (0.80 [0.69 to 0.93]) was statistically similar to the overall mean (95% confidence interval) CFE in 2010 (0.74 [0.61 to 0.90]). The mean CFE in the lowest exposure category (<2 fiber-years/cm) decreased from 0.36 to 0.22 fiber-years/cm (P < 0.05). The 2010 CFE estimate extended the upper bound of the range of previous estimates from 28.10 to 106.31 fiber-years/cm. CONCLUSIONS: The range of CFE values was expanded. These estimates may impact the understanding of Libby vermiculite health outcomes. PMID- 22544163 TI - Mesothelioma associated with commercial use of vermiculite containing Libby amphibole. AB - OBJECTIVES: To describe asbestos-related mortality among manufacturing workers who expanded and processed Libby vermiculite that contained amphibole fiber. METHODS: Standardized mortality ratio was calculated for 465 white male workers 31 years after last Libby vermiculite exposure. RESULTS: Two workers died from mesothelioma, resulting in a significantly increased standardized mortality ratio of 10.5 (95% confidence interval, 1.3 to 38.0). These workers were in the upper 10th percentile of cumulative fiber exposure, that is, 43.80 and 47.23 fiber years/cm, respectively. One additional worker with cumulative fiber exposure of 5.73 fiber-years/cm developed mesothelioma but is not deceased. There were no other significantly increased standardized mortality ratios. CONCLUSIONS: Workers expanding and processing Libby vermiculite in a manufacturing setting demonstrated an increased risk for the development of mesothelioma following exposure to the amphibole fiber contained within this vermiculite ore source. PMID- 22544164 TI - Relationship between several markers and presence of metabolic syndrome or components of the metabolic syndrome in Japanese workers. AB - BACKGROUND: The reported associations between metabolic syndrome (MetS) and systemic vascular inflammation/insulin resistance prompted the author to determine the predictive ability of markers for MetS in the occupational field. METHODS: The study was performed in 3460 working men aged 30 to 64 years. The author measured the serum levels of high-sensitivity C-reactive protein and insulin as potential key biomarkers of MetS. RESULTS: Multivariate analysis revealed significant associations between the presence of MetS and the log transformed value of serum insulin and log-transformed value of serum C-reactive protein, with odds ratios of 29.4 (95% confidence interval, 18.0 to 48.2; P < 0.001) and 1.87 (95% confidence interval, 1.47 to 2.38; P < 0.001) of these two markers, respectively, for the presence of MetS. CONCLUSION: Elevated serum levels of insulin were found to be strongly associated with MetS in this cross sectional study. PMID- 22544165 TI - Living my family's story: identifying the lived experience in healthy women at risk for hereditary breast cancer. AB - BACKGROUND: Based on known or suggested genetic risk factors, a growing number of women now live with knowledge of a potential cancer diagnosis that may never occur. Given this, it is important to understand the meaning of living with high risk for hereditary breast cancer. OBJECTIVE: The objective of the study was to explore how women at high risk for hereditary breast cancer (1) form self identity, (2) apply self-care strategies toward risk, and (3) describe the meaning of care through a high-risk breast program. METHODS: Interpretive hermeneutic phenomenology guided the qualitative research method. Women at high risk for hereditary breast cancer were recruited from a high-risk breast program. Open-ended interview questions focused on experiences living as women managing high risk for breast cancer. Consistent with hermeneutic methodology, the principal investigator led a team to analyze the interview transcripts. RESULTS: Twenty women participated in in-depth interviews. Analysis revealed that women describe their own identity based on their family story and grieve over actual and potential familial loss. This experience influences self-care strategies, including seeking care from hereditary breast cancer risk experts for early detection and prevention, as well as maintaining a connection for early treatment "when" diagnosis occurs. CONCLUSIONS: Healthy women living with high risk for hereditary breast cancer are living within the context of their family cancer story, which influences how they define themselves and engage in self-care. IMPLICATIONS FOR PRACTICE: Findings present important practical, research, and policy information regarding health promotion, psychosocial assessment, and support for women living with hereditary breast cancer risk. PMID- 22544166 TI - C1GALT1 polymorphisms are associated with Henoch-Schonlein purpura nephritis. AB - BACKGROUND: Henoch-Schonlein purpura nephritis (HSPN) is the most serious long term complication of Henoch-Schonlein purpura and aberrant galactosylation of IgA1 plays a role in its development. However, the precise role of genetic factors contributing to the abnormal IgA1 galactosylation remains unknown. METHODS: In order to examine the effects of C1GALT1 gene encoding core 1 beta1,3 galactosyltransferase, an important role in the beta1,3 glycosylation of IgA1, on HSPN susceptibility, we conducted a case-control association genetic study in 269 HSP and 61 HSPN in China. Five tagging SNPs, SNP1(-734 C/T), SNP4(-465A/G), SNP6( 330 G/T), SNP7(-292 C/-), and SNP8(1365 G/A) in C1GALT1 were studied using single locus and haplotype-based multilocus analysis. RESULTS: Our results demonstrated that 1365 G allele frequency was significantly higher in HSPN patients than in HSP patients without nephritis (0.459 vs 0.331, p = 0.0008, adjusted p' = 0.004) with an odds ratio (OR) = 1.716, 95%CI 1.151-2.560). The GG genotype of 1,365 G/A was significantly different in HSP without nephritis and HSPN (p = 0.008, adjusted p'' = 0.04). We did not observe statistically significant differences in haplotype frequencies between HSPN and HSP patients. CONCLUSIONS: In conclusion, our study suggested that the 1365 G/A polymorphism of the C1GALT1 gene may contribute to HSPN development. PMID- 22544167 TI - Intramolecular cyclization of alkoxyaminosugars: access to novel glycosidase inhibitor families. AB - We report the synthesis of two novel families of iminosugars as glycosidase inhibitors involving an intramolecular cyclization between an N-alkoxyamino group and a latent aldehyde of a reducing sugar as the key step. Using this methodology we have prepared the hitherto unknown bicyclic polyhydroxylated N-(methoxy, benzyloxy)anhydroazepanes and N-benzyloxy-d-xylonojirimycin; all these novel compounds turned out to be moderate beta-glucosidase inhibitors in a pH-dependent manner. PMID- 22544168 TI - Evolutionary molecular medicine. AB - Evolution has long provided a foundation for population genetics, but some major advances in evolutionary biology from the twentieth century that provide foundations for evolutionary medicine are only now being applied in molecular medicine. They include the need for both proximate and evolutionary explanations, kin selection, evolutionary models for cooperation, competition between alleles, co-evolution, and new strategies for tracing phylogenies and identifying signals of selection. Recent advances in genomics are transforming evolutionary biology in ways that create even more opportunities for progress at its interfaces with genetics, medicine, and public health. This article reviews 15 evolutionary principles and their applications in molecular medicine in hopes that readers will use them and related principles to speed the development of evolutionary molecular medicine. PMID- 22544170 TI - Axially aligned electrically conducting biodegradable nanofibers for neural regeneration. AB - In this study, electrically conducting axially aligned nanofibers have developed to provide both electrical and structural cues. Poly(lactide-co-glycolide) (PLGA) with poly(3-hexylthiophene) (PHT) was electrospun into 2D random (196 +/- 98 nm) and 3D axially aligned nanofibers (200 +/- 80 nm). Electrospun random and aligned PLGA-PHT fibers were characterized for surface morphology, mechanical property, porosity, degradability, and electrical conductivity. The pore size of random PLGA-PHT nanofibers (6.0 +/- 3.3 MUm) were significantly higher than the aligned (1.9 +/- 0.4 MUm) (P < 0.05) and the Young's modulus of aligned scaffold was significantly lower than the random. Aligned nanofibers showed significantly lesser degradation rate and higher electrical conductivity (0.1 * 10(-5) S/cm) than random nanofibers (P < 0.05). Results of in vitro cell studies indicate that aligned PLGA-PHT nanofibers have a significant influence on the adhesion and proliferation of Schwann cells and could be potentially used as scaffold for neural regeneration. PMID- 22544169 TI - Responses of solid organ transplant recipients to the AS03-adjuvanted pandemic influenza vaccine. AB - BACKGROUND: Solid organ transplant (SOT) recipients are a priority group for influenza vaccination and strategies enhancing immunogenicity are needed. METHODS: We determined adverse reactions, changes in biomarkers of graft function and immune responses to two doses of the AS03-adjuvanted influenza A/09/H1N1 vaccine in 216 SOT recipients and in 138 controls after one dose. Antibody responses were measured by haemagglutination inhibition and confirmed by microneutralization. We calculated geometric mean titres (GMT) and seroprotection rates (GMT>=40). RESULTS: Adverse reactions were fewer than in controls and graft function remained unaffected. Seroprotection was achieved by only 70.3% of SOT recipients, with significant differences between groups (lung 43.6%, heart 72.0%, kidney 83.3%, liver 83.3% and pancreas 85%), compared to 87% of controls (P<0.001). The weakest responses (seroprotection 43.5%) were elicited in lung transplant recipients. GMT remained threefold lower (115 versus 340) in SOT recipients than controls. Multivariate analyses identified increasing age, type of transplant and increasing blood levels of mycophenolate as independently associated to weaker responses. In contrast, even high blood levels of calcineurin inhibitors remained without significant influence on vaccine responses. CONCLUSIONS: The squalene-based adjuvanted A/09/H1N1 vaccine was safe in SOT recipients. However, even two doses of this adjuvanted influenza vaccine did not provide adequate protection for lung transplant recipients and those with high mycophenolate blood levels. Additional prophylactic measures should, therefore, be considered for these high-risk groups. PMID- 22544171 TI - Differential patterns of serum concentration and adipose tissue expression of chemerin in obesity: adipose depot specificity and gender dimorphism. AB - Chemerin, a recognized chemoattractant, is expressed in adipose tissue and plays a role in adipocytes differentiation and metabolism. Gender- and adipose tissue specific differences in human chemerin expression have not been well characterized. Therefore, these differences were assessed in the present study. The body mass index (BMI) and the circulating levels of chemerin and other inflammatory, adiposity and insulin resistance markers were assessed in female and male adults of varying degree of obesity. Chemerin mRNA expression was also measured in paired subcutaneous and visceral adipose tissue samples obtained from a subset of the study subjects. Serum chemerin concentrations correlated positively with BMI and serum leptin levels and negatively with high density lipoprotein (HDL)-cholesterol levels. No correlation was found between serum chemerin concentrations and fasting glucose, total cholesterol, low density lipoprotein (LDL)-cholesterol, triglycerides, insulin, C-reactive protein or adiponectin. Similarly, no relation was observed with the homeostasis model assessment for insulin resistance (HOMA-IR) values. Gender- and adipose tissue specific differences were observed in chemerin mRNA expression levels, with expression significantly higher in women than men and in subcutaneous than visceral adipose tissue. Interestingly, we found a significant negative correlation between circulating chemerin levels and chemerin mRNA expression in subcutaneous fat. Among the subjects studied, circulating chemerin levels were associated with obesity markers but not with markers of insulin resistance. At the tissue level, fat depot-specific differential regulation of chemerin mRNA expression might contribute to the distinctive roles of subcutaneous vs. visceral adipose tissue in human obesity. PMID- 22544172 TI - Integrative sediment assessment at Atlantic Spanish harbours by means of chemical and ecotoxicological tools. AB - This study refers to the integrative assessment of sediment quality in three harbour areas at the Spanish Atlantic Coast: Vigo (Northwestern Spain), Bilbao and Pasajes (Northern Spain). At each site, two lines of evidence have been considered: chemical analyses (metal, PAH and PCB concentrations in sediments and ammonia concentration in bioassays) and toxicity tests (Microtox(r), Corophium sp. marine amphipod and Paracentrotus lividus sea urchin larvae). Chemical and ecotoxicological results have been integrated by means of a tabular matrix and a multivariate factorial analysis (FA). Highly toxic samples have been characterised in Vigo and Pasajes harbours while Bilbao samples present toxicity levels ranging from non-toxic to moderately toxic. High toxicity is associated with high levels of contaminants whereas confounding factors (ammonia, organic matter and mud) have been identified to be the main cause of low to moderate toxicity. Based on the obtained results, it can be concluded that deriving potential toxicity of sediments based on comparison with Sediment Quality Guidelines (SQGs) is in agreement to toxicity results in areas presenting high levels of contaminants. However, at lower levels of toxicity (low to moderate), the mismatch between the potential toxicity (SQG approach) and the toxicity measured by bioassays is greater, as the former only accounts for chemical concentrations, without considering the interaction between contaminants and the effect of confounding factors. Contrarily, the multivariate analysis seems to be a robust tool for the integration and interpretation of different lines of evidence in areas affected by different sources of contamination. PMID- 22544173 TI - Misoprostol prior to hysteroscopy in premenopausal and post-menopausal women. A systematic review and meta-analysis. AB - BACKGROUND: Although several randomized controlled trials (RCTs) have examined the effect of misoprostol prior to hysteroscopy for cervical dilatation, no solid conclusion has been reached. We therefore set out to perform a meta-analysis of RCTs. METHODS: We searched MEDLINE, the ISI Web of Science and the Cochrane Library to identify RCTs comparing misoprostol versus placebo or control prior to hysteroscopy. No restrictions on language or time were applied. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated for all dichotomous outcomes, whereas mean differences (MDs) and 95% CIs were calculated for continuous outcomes using the Mantel-Haenszel or DerSimonian-Laird model according to the heterogeneity. RESULTS: Of the initial 141 potentially relevant articles that were retrieved, 21 RCTs involving 1786 patients were included in the meta-analysis. Subgroup analyses were performed according to menopausal status and according to whether diagnostic or operative hysteroscopy was performed. Premenopausal women treated with misoprostol had a significantly lower risk for further cervical dilatation in the diagnostic setting [RR (95% CI): 0.56 (0.34-0.92)] and a significantly lower risk for cervical laceration in the operative setting [RR (95% CI): 0.22 (0.09-0.54)], compared with placebo. In contrast, post-menopausal patients did not experience any clear benefit from misoprostol compared with placebo regarding the need for further cervical dilatation [RR (95% CI): 0.99 (0.76-1.30)] and the cervical laceration rate [RR (95% CI): 1.15 (0.40-3.29)]. In addition, the mean cervical width prior to hysteroscopy was significantly higher in premenopausal women treated with misoprostol compared with placebo [MD (95% CI): 2.47 mm (1.81-3.13)] but did not differ among post-menopausal patients [MD (95% CI): 0.39 mm (-0.42 to 1.21)]. CONCLUSIONS: Misoprostol prior to hysteroscopy appears to facilitate an easier and uncomplicated procedure only in premenopausal women. PMID- 22544174 TI - Synopsis of the hard ticks (Acari: Ixodidae) of Romania with update on host associations and geographical distribution. AB - The current paper is a synoptic review of the distribution and host associations of the 25 species of hard tick fauna (family Ixodidae) in Romania. In addition to a full literature survey, original data is presented, based on eight years of occasional or targeted sample collection. The literature data on geographical distribution was transposed digitally to the decimal degree coordinate system. For each species, an updated distribution map is given together with all historical data and new host associations. Overall, our paper records 58 new tick host associations for Romania: 20 for Ixodes ricinus, 1 for I. apronophorus, 6 for I. arboricola, 2 for I. hexagonus, 9 for I. redikorzevi, 1 for I. trianguliceps, 2 for I. vespertilionis, 2 for Haemaphysalis punctata, 1 for H. sulcata, 2 for H. concinna, 1 for D. marginatus, 4 for Rhipicephalus sanguineus sensu lato, 1 for R. bursa and 6 for Hyalomma marginatum. PMID- 22544183 TI - Are countries using global fund support to implement HIV drug resistance surveillance? A review of funded HIV grants. AB - The Global Fund to Fight AIDS, Tuberculosis and Malaria (Global Fund) is the largest funder of human immunodeficiency virus (HIV) prevention and treatment programs worldwide. Since 2002, the Global Fund has encouraged grant recipients to implement drug resistance surveillance (DRS) as part of treatment programs. We reviewed documentation of 147 grants funded in 2004-2008 (funding rounds 4-8) to assess grantees' use of funds to support HIV DRS. Overall, 94 grants (64%) described HIV DRS as part of the national treatment program. However, only 32 grants (22%) specifically documented DRS as a grant-funded activity. This review provides baseline information suggesting limited use by countries of Global Fund financing to support HIV DRS. Additional assessment is required to evaluate barriers to using Global Fund grants to support DRS. PMID- 22544182 TI - Update on World Health Organization HIV drug resistance prevention and assessment strategy: 2004-2011. AB - The HIV drug resistance (HIVDR) prevention and assessment strategy, developed by the World Health Organization (WHO) in partnership with HIVResNet, includes monitoring of HIVDR early warning indicators, surveys to assess acquired and transmitted HIVDR, and development of an accredited HIVDR genotyping laboratory network to support survey implementation in resource-limited settings. As of June 2011, 52 countries had implemented at least 1 element of the strategy, and 27 laboratories had been accredited. As access to antiretrovirals expands under the WHO/Joint United Nations Programme on HIV/AIDS Treatment 2.0 initiative, it is essential to strengthen HIVDR surveillance efforts in the face of increasing concern about HIVDR emergence and transmission. PMID- 22544184 TI - World Health Organization generic protocol to assess drug-resistant HIV among children <18 months of age and newly diagnosed with HIV in resource-limited countries. AB - Increased use of nonnucleoside reverse transcriptase inhibitors (NNRTIs) in pregnant and breastfeeding women will result in fewer children infected with human immunodeficiency virus (HIV). However, among children infected despite prevention of mother-to-child transmission (PMTCT), a substantial proportion will acquire NNRTI-resistant HIV, potentially compromising response to NNRTI-based antiretroviral therapy (ART). In countries scaling up PMTCT and pediatric ART programs, it is crucial to assess the proportion of young children with drug resistant HIV to improve health outcomes and support national and global decision making on optimal selection of pediatric first-line ART. This article summarizes a new World Health Organization surveillance protocol to assess resistance using remnant dried blood spot specimens from a representative sample of children aged <18 months being tested for early infant diagnosis. PMID- 22544185 TI - Building capacity for the assessment of HIV drug resistance: experiences from the PharmAccess African Studies to Evaluate Resistance network. AB - The PharmAccess African Studies to Evaluate Resistance (PASER) network was established as a collaborative partnership of clinical sites, laboratories, and research groups in 6 African countries; its purpose is to build research and laboratory capacity in support of a coordinated effort to assess population-level acquired and transmitted human immunodeficiency virus type-1 drug resistance (HIVDR), thus contributing to the goals of the World Health Organization Global HIV Drug Resistance Network. PASER disseminates information to medical professionals and policy makers and conducts observational research related to HIVDR. The sustainability of the network is challenged by funding limitations, constraints in human resources, a vulnerable general health infrastructure, and high cost and complexity of molecular diagnostic testing. This report highlights experiences and challenges in the PASER network from 2006 to 2010. PMID- 22544186 TI - Genotyping external quality assurance in the World Health Organization HIV drug resistance laboratory network during 2007-2010. AB - The World Health Organization (WHO) has developed a global laboratory network to support human immunodeficiency virus drug resistance genotyping for public health surveillance in resource-limited countries. Blinded proficiency panels are an essential part of a genotyping quality-assurance program and are used to monitor the reliability of genotyping data in the WHO laboratory network. Laboratories in Europe, North America, Asia, Africa, and the Caribbean have tested panels annually since 2007; 103 of 131 submissions (79%) had >99% nucleotide sequence identity and resistance mutation concordance, compared with consensus. Most errors were associated with mixtures in the test specimen, leading to subjectivity in base-calling or amplification bias. Overall, genotyping assays used by the WHO laboratory network are reliable. PMID- 22544187 TI - Evaluation of in-house genotyping assay performance using dried blood spot specimens in the Global World Health Organization laboratory network. AB - In resource-limited settings, there is increased demand for human immunodeficiency virus type 1 drug resistance testing. Because preservation of plasma specimens is often not feasible in resource-limited settings, use of dried blood spots (DBSs) is being adopted. We used 2 panels of DBSs for genotyping assay validation and proficiency testing in selected laboratories in the World Health Organization laboratory network in 14 countries. An amplification sensitivity of 1000 copies/mL was achieved by 2 laboratories. Reproducibility and accuracy of nucleotide sequence determination and resistance-associated mutation identification from DBSs was similar to that previously determined for plasma. International shipping at ambient temperature had no significant effect on amplification success. These studies indicate that DBS-based genotyping is equally reproducible and reliable, although slightly less sensitive, compared with plasma. PMID- 22544188 TI - HIV drug resistance early warning indicators in cohorts of individuals starting antiretroviral therapy between 2004 and 2009: World Health Organization global report from 50 countries. AB - The World Health Organization developed a set of human immunodeficiency virus drug resistance (HIVDR) early warning indicators (EWIs) to assess antiretroviral therapy clinic and program factors associated with HIVDR. EWIs are monitored by abstracting data routinely recorded in clinical records, and the results enable clinics and program managers to identify problems that should be addressed to minimize preventable emergence of HIVDR in clinic populations. As of June 2011, 50 countries monitored EWIs, covering 131 686 patients initiating antiretroviral treatment between 2004 and 2009 at 2107 clinics. HIVDR prevention is associated with patient care (appropriate prescribing and patient monitoring), patient behavior (adherence), and clinic/program management efforts to reduce treatment interruptions (follow up, retention on first-line ART, procurement and supply management of antiretroviral drugs). EWIs measure these factors and the results have been used to optimize patient and population treatment outcomes. PMID- 22544189 TI - Implementing early-warning indicators of HIV drug resistance in the Caribbean. AB - A key component of the World Health Organization's (WHO's) Global HIV Drug Resistance (HIVDR) prevention and assessment strategy is to monitor HIVDR early warning indicators (EWIs), which provide strategic information for HIVDR containment. The Pan American Health Organization (PAHO)/WHO supported implementation of HIVDR EWI monitoring in 16 Caribbean countries. Results from 15 countries were analyzed by year of patient initiation of antiretroviral therapy for the period 2005-2009. This report demonstrates the need for capacity-building to standardize prescribing practices and to strengthen adherence strategies and antiretroviral drug procurement management systems. PMID- 22544190 TI - Early warning indicators for population-based monitoring of HIV drug resistance in 6 African countries. AB - Human immunodeficiency virus (HIV) RNA testing and HIV drug resistance (HIVDR) testing are not routinely available for therapeutic monitoring of patients receiving antiretroviral therapy (ART) in resource-limited settings. World Health Organization HIVDR early warning indicators (EWIs) assess ART site factors known to favor the emergence of HIVDR. HIV drug resistance EWI monitoring was performed within the PharmAccess African Studies to Evaluate Resistance Monitoring (PASER M) study, comprising 13 ART sites in 6 African countries. Early warning indicator assessment in the PASER network identified vulnerable aspects of ART programs and triggered interventions aimed at minimizing HIVDR emergence. Additionally, data suggest an advantage of medication possession ratio over on-time antiretroviral drug pickup in identifying patients at risk for HIVDR development. PMID- 22544191 TI - Monitoring HIV drug resistance using early warning indicators in China: results from a pilot survey conducted in 2008. AB - Robust programmatic monitoring of factors associated with the emergence of human immunodeficiency virus (HIV) drug resistance is an essential component of antiretroviral therapy (ART) program evaluation and treatment optimization. China piloted World Health Organization HIV drug resistance early warning indicators to assess the feasibility and usefulness of results. Overall, early warning indicator monitoring showed high levels of appropriate ART prescribing, low rates of loss to follow-up 12 months after ART initiation, and high rates of retention of first-line ART at 12 months. On-time drug pick-up, which may signal treatment interruptions, was identified as a challenge. HIV drug resistance early warning indicator monitoring provides a valuable assessment of ART service delivery, and its application will be scaled up throughout China. PMID- 22544192 TI - Experience in piloting HIV drug resistance early warning indicators to improve the antiretroviral program in Papua New Guinea. AB - In 2009, World Health Organization human immunodeficiency virus drug resistance early warning indicator monitoring was piloted at 2 large antiretroviral therapy (ART) clinics in Papua New Guinea: Heduru Clinic in Port Moresby and Tininga Clinic in Mount Hagen. Results demonstrated that both Heduru and Tininga clinics met internationally suggested targets for prescribing appropriate first-line ART regimens in accordance with national ART guidelines, retention on first-line ART at 12 months, and drug supply continuity. However, both clinics failed to achieve suggested targets for rates of loss to follow-up and on-time pill pickup. Reasons for poor clinic performance on loss to follow-up and on-time pill pickup were explored, and appropriate corrective actions were implemented. PMID- 22544193 TI - Combining cohort analysis and monitoring of HIV early-warning indicators of drug resistance to assess antiretroviral therapy services in Vietnam. AB - Antiretroviral therapy (ART) retention and 5 early-warning indicators (EWIs) of HIV drug resistance (HIVDR) were abstracted at 27 adult and 4 pediatric clinics in Vietnam in 2009. Of 4531 adults and 313 children, 81.2% and 84.4% respectively were still on ART at 12 months. More than 90% of the clinics monitored achieved the World Health Organization (WHO) targets for lost-to-follow-up (LTFU), ART prescribing practices, and ARV supply continuity. Only 83.9% of the clinics met the target for first-line ART retention and 79.3% met the target for clinic appointment-keeping. Clinic factors (i.e. number of patients, administrative level, and geographical region) were associated with ART retention and LFTU. Data were useful in guiding public health action to optimize ART services. PMID- 22544194 TI - Monitoring of early warning indicators for HIV drug resistance in antiretroviral therapy clinics in Zimbabwe. AB - Monitoring human immunodeficiency virus drug resistance (HIVDR) early warning indicators (EWIs) can help national antiretroviral treatment (ART) programs to identify clinic factors associated with HIVDR emergence and provide evidence to support national program and clinic-level adjustments, if necessary. World Health Organization-recommended HIVDR EWIs were monitored in Zimbabwe using routinely available data at selected ART clinics between 2007 and 2009. As Zimbabwe's national ART coverage increases, improved ART information systems are required to strengthen routine national ART monitoring and evaluation and facilitate scale-up of HIVDR EWI monitoring. Attention should be paid to minimizing loss to follow up, supporting adherence, and ensuring clinic-level drug supply continuity. PMID- 22544195 TI - Surveillance of transmitted drug-resistant HIV among young pregnant women in Ouagadougou, Burkina Faso. AB - Burkina Faso began rapid antiretroviral therapy (ART) scale-up in 2003 and by December 2009, 26,448 individuals were on treatment. With rapid scale-up of ART, some degree of human immunodeficiency virus transmitted drug resistance (TDR) is inevitable. Following World Health Organization methods, between June 2008 and July 2009, Burkina Faso assessed TDR in primigravid pregnant women aged <25 years attending antenatal care clinics in Ouagadougou, Burkina Faso. TDR was classified as moderate (5%-15%) for both nucleoside reverse-transcriptase inhibitors and nonnucleoside reverse-transcriptase inhibitors. The observed moderate TDR in Ouagadougou is a cause for concern and calls for closer monitoring of Burkina Faso's ART program. PMID- 22544196 TI - Surveys of transmitted HIV drug resistance in 7 geographic Regions in China, 2008 2009. AB - In 2003, antiretroviral therapy became available free of charge in China's public health sector. During 2008 and 2009, 10 surveys to classify transmitted human immunodeficiency virus drug resistance (HIVDR) were conducted in 7 regions in 5 provinces (autonomous regions and municipalities) according to World Health Organization guidance. In 2008, transmitted HIVDR was classified as low (<5%) to nucleoside reverse-transcriptase inhibitors, nonnucleoside reverse-transcriptase inhibitors, and protease inhibitors in 6 surveys performed in 6 regions. In 2009, 3 of 4 surveys showed low rates of transmitted HIVDR to all drug classes, and 1 survey showed moderate (5%-15%) rates of transmitted protease inhibitor resistance. In China, routine surveillance of transmitted HIVDR should continue and be expanded to other regions of the country. PMID- 22544197 TI - Prevalence of transmitted HIV drug resistance among newly diagnosed antiretroviral therapy-naive pregnant women in Lilongwe and Blantyre, Malawi. AB - In 2006, a survey of transmitted human immunodeficiency virus (HIV) drug resistance (TDR) was conducted in Lilongwe, Malawi. The survey followed the World Health Organization method to classify TDR to nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs) among primigravid women aged <25 years. Results of the 2006 survey showed <5% TDR in all drug classes. In 2009, TDR surveys using the same method were repeated in Lilongwe and expanded to Blantyre. Findings show that in Lilongwe TDR to NRTIs and PIs was <5%, whereas TDR to NNRTIs was 5%-15%. In Blantyre, TDR was <5% to all drug classes. Observed moderate TDR in Lilongwe is cause for concern and signals the need for closer monitoring of Malawi's antiretroviral therapy program. PMID- 22544198 TI - Transmitted HIV drug resistance among drug-naive subjects recently infected with HIV in Mexico City: a World Health Organization survey to classify resistance and to field test two alternative patient enrollment methods. AB - In 2004, the World Health Organization performed a survey to assess transmitted drug resistance in Mexico City among drug-naive persons with newly diagnosed human immunodeficiency virus (HIV) infection and likely to be recently infected who were attending 3 voluntary counseling and testing sites. A parallel study comparing 2 alternative methods of enrolling survey participant was conducted in 9 voluntary counseling and testing sites in central Mexico. In study arm 1, subject information, consent and blood specimens were obtained during the HIV diagnostic testing visit. In study arm 2, consent and blood specimens were obtained at the return visit, only from those who were HIV infected. This survey classified nonnucleoside reverse-transcriptase inhibitor and nucleoside reverse transcriptase inhibitor transmitted drug resistance as <5% and 5%-15%, respectively. Arm 2 yielded major advantages in cost and workload, with no evidence of increased sampling bias. PMID- 22544200 TI - Transmitted antiretroviral drug resistance among drug-naive female sex workers with recent infection in Kampala, Uganda. AB - During 2006-2007, transmitted human immunodeficiency virus (HIV) drug resistance (TDR) among drug-naive women with newly diagnosed HIV infection and likely to be recently infected when attending antenatal clinics in Entebbe was found to be <5% with use of the World Health Organization (WHO) survey method. Using the same method, we attempted to classify TDR among women who seroconverted during 2008 2010 and who were identified from a cohort of recently infected sex workers in Kampala, Uganda. TDR mutations were identified using the 2009 WHO TDR mutations list. The WHO survey method could not be used to classify TDR because the necessary sample size was not reached during the survey period. However, a point prevalence estimate of 2.6% (95% confidence interval, 0.07%-13.8%) nonnucleoside reverse-transcriptase inhibitor TDR was determined. PMID- 22544199 TI - Surveillance of transmitted HIV-1 drug resistance in Gauteng and KwaZulu-Natal Provinces, South Africa, 2005-2009. AB - Surveillance of human immunodeficiency virus type 1 transmitted drug resistance (TDR) was conducted among pregnant women in South Africa over a 5-year period after the initiation of a large national antiretroviral treatment program. Analysis of TDR data from 9 surveys conducted between 2005 and 2009 in 2 provinces of South Africa suggests that while TDR remains low (<5%) in Gauteng Province, it may be increasing in KwaZulu-Natal, with the most recent survey showing moderate (5%-15%) levels of resistance to the nonnucleoside reverse transcriptase inhibitor drug class. PMID- 22544201 TI - Surveillance of transmitted HIV drug resistance using matched plasma and dried blood spot specimens from voluntary counseling and testing sites in Ho Chi Minh City, Vietnam, 2007-2008. AB - During 2007-2008, surveillance of transmitted human immunodeficiency virus (HIV) drug resistance (TDR) was performed following World Health Organization guidance among clients with newly diagnosed HIV infection attending voluntary counseling and testing (VCT) sites in Ho Chi Minh City (HCMC), Vietnam. Moderate (5%-15%) TDR to nonnucleoside reverse-transcriptase inhibitors (NNRTIs) was observed among VCT clients aged 18-21 years. Follow-up surveillance of TDR in HCMC and other geographic regions of Vietnam is warranted. Data generated will guide the national HIV drug resistance surveillance strategy and support selection of current and future first-line antiretroviral therapy and HIV prevention programs. PMID- 22544203 TI - A retrospective survey of HIV drug resistance among patients 1 year after initiation of antiretroviral therapy at 4 clinics in Malawi. AB - In 2004, Malawi began scaling up its national antiretroviral therapy (ART) program. Because of limited treatment options, population-level surveillance of acquired human immunodeficiency virus drug resistance (HIVDR) is critical to ensuring long-term treatment success. The World Health Organization target for clinic-level HIVDR prevention at 12 months after ART initiation is >= 70%. In 2007, viral load and HIVDR genotyping was performed in a retrospective cohort of 596 patients at 4 ART clinics. Overall, HIVDR prevention (using viral load <= 400 copies/mL) was 72% (95% confidence interval [CI], 67%-77%; range by site, 60% 83%) and detected HIVDR was 3.4% (95% CI, 1.8%-5.8%; range by site, 2.5%-4.7%). Results demonstrate virological suppression and HIVDR consistent with previous reports from sub-Saharan Africa. High rates of attrition because of loss to follow-up were noted and merit attention. PMID- 22544202 TI - Initial virologic response and HIV drug resistance among HIV-infected individuals initiating first-line antiretroviral therapy at 2 clinics in Chennai and Mumbai, India. AB - Human immunodeficiency virus drug resistance (HIVDR) in cohorts of patients initiating antiretroviral therapy (ART) at clinics in Chennai and Mumbai, India, was assessed following World Health Organization (WHO) guidelines. Twelve months after ART initiation, 75% and 64.6% of participants at the Chennai and Mumbai clinics, respectively, achieved viral load suppression of <1000 copies/mL (HIVDR prevention). HIVDR at initiation of ART (P <.05) and 12-month CD4 cell counts <200 cells/MUL (P <.05) were associated with HIVDR at 12 months. HIVDR prevention exceeded WHO guidelines (>= 70%) at the Chennai clinic but was below the target in Mumbai due to high rates of loss to follow-up. Findings highlight the need for defaulter tracing and scale-up of routine viral load testing to identify patients failing first-line ART. PMID- 22544204 TI - Prevalence of HIV drug resistance before and 1 year after treatment initiation in 4 sites in the Malawi antiretroviral treatment program. AB - Since 2004, the Malawi antiretroviral treatment (ART) program has provided a public health-focused system based on World Health Organization clinical staging, standardized first-line ART regimens, limited laboratory monitoring, and no patient-level monitoring of human immunodeficiency virus drug resistance (HIVDR). The Malawi Ministry of Health conducts periodic evaluations of HIVDR development in prospective cohorts at sentinel clinics. We evaluated viral load suppression, HIVDR, and factors associated with HIVDR in 4 ART sites at 12-15 months after ART initiation. More than 70% of patients initiating ART had viral suppression at 12 months. HIVDR prevalence (6.1%) after 12 months of ART was low and largely associated with baseline HIVDR. Better follow-up, removal of barriers to on-time drug pickups, and adherence education for patients 16-24 years of age may further prevent HIVDR. PMID- 22544205 TI - Surveillance of HIV drug resistance in children receiving antiretroviral therapy: a pilot study of the World Health Organization's generic protocol in Maputo, Mozambique. AB - Between 2007 and 2008, the Mozambique Ministry of Health conducted an assessment of human immunodeficiency virus drug resistance (HIVDR) using World Health Organization (WHO) methods in a cohort of children initiating antiretroviral therapy (ART) at the main pediatric ART referral center in Mozambique. It was shown that prior to ART initiation 5.4% of children had HIVDR that was associated with nevirapine perinatal exposure (P < .001). Twelve months after ART initiation, 77% had viral load suppression (<1000 copies/mL), exceeding the WHO target of >= 70%; 10.3% had HIVDR at 12 months. Baseline HIVDR (P = .04), maternal prevention of mother-to-child transmission (P = .02), and estimated days of missed medication (P = .03) predicted HIVDR at 12 months. As efforts to eliminate pediatric AIDS are intensified, implementation of ritonavir-boosted protease inhibitor regimens in children with prevention of mother-to-child transmission exposure may reduce risk of virological failure in our setting. PMID- 22544206 TI - Virological response and HIV drug resistance 12 months after antiretroviral therapy initiation at 2 clinics in Nigeria. AB - This report describes a pilot study, conducted in Nigeria, of the World Health Organization protocol for monitoring human immunodeficiency virus (HIV) drug resistance (HIVDR) and associated program factors among patients receiving first line antiretroviral therapy (ART). In 2008, 283 HIV-infected patients starting ART were consecutively enrolled at 2 ART clinics in Abuja. Twelve months after ART initiation, 62% were alive and on first-line ART, 3% had died, 1% had transferred out of the program, and 34% were lost to follow-up. Among patients on first-line ART at 12 months, 90% had viral suppression. However, in view of the high loss to follow-up rate (34%), strategies for patient retention and tracking are critical to minimize possible HIVDR and optimize treatment outcomes. PMID- 22544207 TI - A novel 2D -> 3D {Co6PW9}-based framework extended by semi-rigid bis(triazole) ligand. AB - The building blocks {Co(6)PW(9)} converging lacunary polyoxometalates and high nuclear {Co(6)} clusters are further linked by semi-rigid bis(triazole) ligands to construct a 2D -> 3D framework under hydrothermal conditions, [Co(6)(MU(3) OH)(3)(H(2)O)(9)L(PW(9)O(34))] (1) (L = 4,4'-bis(1,2,4-triazol-1 ylmethyl)biphenyl). PMID- 22544209 TI - Spectrum of F9 mutations in Chinese haemophilia B patients: identification of 20 novel mutations. AB - AIMS: Haemophilia B (HB) is an X-linked recessive haemorrhagic disorder caused by F9 mutations. In this study, we performed molecular analysis of 107 Chinese HB patients and analysed the F9 mutation spectrum of Chinese HB patients. METHODS: 107 Chinese HB patients were enrolled in this study. Direct sequencing of the whole F9 or mutation scanning of exon 1 to exon 7 by high resolution melting (HRM) curve analysis combined with direct sequencing of exon 8 was used to identify the mutations in these patients. RESULTS: 78 different F9 mutations were identified in the 107 HB patients. The mutations were composed of 50 missense mutations, 14 nonsense mutations, nine small deletions, three splice site mutations and two small insertions. Forty-three of 78 mutations were located in factor IX (FIX) catalytic domain. Among the 78 mutations, 20 have not been previously reported. CONCLUSIONS: The F9 mutations were heterogenous and the missense mutations were the most prevalent gene defects in Chinese HB patients. PMID- 22544210 TI - Prognostic impact of the cancer stem cell related markers ALDH1 and EZH2 in triple negative and basal-like breast cancers. AB - AIMS: We assessed the expression of ALDH1 and EZH2, cancer stem cell (CSC) related markers, in triple negative and basal-like breast cancers, investigating their association with clinicopathological features and outcome. METHODS: Clinicopathological data were obtained from 140 cases of triple negative breast cancer. A tissue microarray was constructed and immunohistochemistry for ER, PR, HER2, ALDH1, EZH2, CK5, CK14, EGFR, p63, caveolin, and p53 was performed. Tumour cell and stromal expression of ALDH1 were evaluated. Multivariate analysis was conducted, including all significant variables. RESULTS: The majority of triple negative breast cancers were invasive ductal carcinomas of no special type (NST) (116/140). Tumour cells exhibited cytoplasmic expression of ALDH1 in 26 of 140 cases, while stromal expression was detected in 117 of 140 cases. Tumour cell expression did not correlate with any of the parameters. Conversely, stromal expression was associated with better overall survival (p=0.044). Assessment by Cox Regression Model showed a HR of 2.80 (HR = 1/0.357 = 2.80; 95%CI 0.178-0.714; p = 0.004) for breast cancer death when ALDH1 was not found in the stromal compartment of tumours, independent of age, histological type/grade, nodal status, stage, relapse, and expression of basal markers. High EZH2 expression was noted in 120 of 140 triple negative breast cancers and was not associated with other variables. Basal-like cancers comprised 75% (105/140) of triple negative breast cancers. Interestingly, we found association between EZH2 and CK14 expression (p = 0.041). CONCLUSIONS: ALDH1 expression is frequent in tumour associated stromal cells of triple negative breast cancer and is associated with better outcome. Tumour microenvironment should be considered when studying prognostic impact of CSCs in breast cancer. PMID- 22544211 TI - Succinate dehydrogenase (SDH) and mitochondrial driven neoplasia. AB - The genes for the succinate dehydrogenase (SDH) subunits SDHA, SDHB, SDHC and SDHD are encoded in the autosome. The proteins are assembled in the mitochondria to form the mitochondrial complex 2, a key respiratory enzyme which links the Krebs cycle and the electron transport chain. Thirty percent of phaeochromocytoma and paraganglioma (PHEO/PGL) are hereditary and perhaps as many as half of these familial cases are caused by germline mutations of the SDH subunits. Negative immunohistochemical staining for the SDHB subunit identifies PHEO/PGL associated with germline mutation of any of the mitochondrial complex 2 components and can be used to triage formal genetic testing of all PHEO/PGL for SDH mutations. PHEO/PGL associated with SDHA mutation also show negative staining for SDHA as well as SDHB.A unique subgroup of gastrointestinal stromal tumours (GISTs) are driven by mitochondrial complex 2 dysfunction. These SDH deficient GISTs can also be definitively identified by negative staining for SDHB and show distinct clinical and morphological features including frequent onset in childhood and young adulthood, gastric location, a tendency to multifocality, absence of KIT and PDGFRA mutations, a prognosis not predicted by size and mitotic rate and a tendency to indolent behaviour of metastases. Some of these SDH deficient GISTs are driven by classical SDH mutations, but the precise mechanisms of tumourigenesis in many (including those associated with the Carney triad) remain unknown. Germline SDHB mutation is associated with a newly recognised type of renal carcinoma which commonly but not always demonstrates distinctive morphology and can also be recognised by negative staining for SDHB.Immunohistochemistry for SDHB therefore has emerged as a useful tool to recognise these distinct neoplasias driven by mitochondrial complex 2 dysfunction and to triage formal genetic testing for the associated syndromes. PMID- 22544212 TI - Prognostic significance of MGMT gene promoter methylation in differently treated metastatic melanomas. AB - AIMS: The methylation status of the MGMT gene promoter, considered of prognostic significance by enhancing chemosensitivity to alkylating drugs in gliomas and melanomas, was evaluated in a series of primary melanomas and metastases of patients treated with different therapies, to identify any correlation with the patients' outcome or response to different therapeutic regimens. METHODS: Twenty nine primary melanomas and 74 metastases, collected from 52 patients, were assessed for MGMT gene promoter methylation using a standard methylation specific PCR-based method. All materials were formalin fixed and paraffin embedded. RESULTS: One of 29 primary melanomas (3.4%) and 22 of 74 metastases (29.7%) showed MGMT gene promoter methylation. MGMT methylation was more frequent in visceral (17/40, 42.5%) than in cutaneous/lymph node metastases (5/34, 14.7%) (p = 0.019). Both disease free (DFS) and overall survival (OS) were significantly longer in patients with methylated metastases (p = 0.009 and p = 0.007, respectively). No correlations were found among methylation, therapeutic regimens and DFS or OS. CONCLUSIONS: MGMT methylation appears to be a late event in the biological history of melanoma and is more frequently seen in visceral metastases. The MGMT gene promoter methylation in metastatic disease is associated with longer survival, irrespective of therapy. Thus it could be considered a prognostic factor in metastatic melanoma. PMID- 22544213 TI - Sarcomatoid carcinoma involving the renal pelvis and ureter with heterologous osteosarcomatous differentiation. PMID- 22544214 TI - Primary signet-ring cell carcinoma of Meckel's diverticulum: an uncommon cause of abdominal pain. PMID- 22544215 TI - Correct diagnosis of NK and T cell lymphomas. PMID- 22544216 TI - Primary chondroblastic osteogenic sarcoma of the clavicle. PMID- 22544217 TI - Filiform serrated adenoma. PMID- 22544219 TI - Alkali-metal mediated reactivity of a diaminobromoborane: mono- and bis borylation of naphthalene versus boryl lithium or hydroborane formation. AB - Reaction of lithium with PDABBr [PDA = C(6)H(4)-1,2-(NTripp)(2), Tripp = 2,4,6 Pr(i)(3)C(6)H(2)] and naphthalene afforded 2- and 2,6-borylated naphthalenes; conversely, use of high-sodium lithium (0.5% Na) afforded the lithium boryl [(PDAB)Li(THF)(2)]; this work establishes that main group reagents can achieve selective borylations of fused polycyclic aromatics under mild conditions in good yields. PMID- 22544220 TI - Proline sulphonamide-catalysed Yamada-Otani condensation: reaction development, substrate scope and scaffold reactivity. AB - The development of a proline sulphonamide-catalysed method for enantioselective and diastereoselective construction of functionalized cyclohexenones is described. Impact of catalyst structure as well as solvent effects and additives are explored. A significant substrate scope is demonstrated by variation of both the aldehyde and the enone components. Diastereoselective derivatization of the cyclohexenone scaffold illustrates its utility as a building block for chemical synthesis. PMID- 22544221 TI - Modelling drug-related morbidity in Sweden using an expert panel of pharmacists'. AB - BACKGROUND: Drug-related morbidity (DRM) is common and to some extent preventable, and associated with considerable costs in patients attending hospital. In outpatients and in the general public corresponding data are limited, but pharmacists' expert opinion has suggested high rates of DRM also in US ambulatory care. It is unknown if the results are applicable in Sweden today. OBJECTIVE: To estimate the proportions of patients with DRM and preventable DRM and the cost-of-illness (COI) of DRM in Sweden based on pharmacists' expert opinion. SETTING: Swedish healthcare. METHOD: The study applied a conceptual model of DRM based on a decision tree. An expert panel of pharmacists determined the probabilities of therapeutic outcomes of medication therapy. The COI analysis included direct costs from the healthcare perspective. Sensitivity analyses were performed for variations in probabilities and pathway costs. MAIN OUTCOME MEASURE: DRM included new medical problems (adverse drug reactions, drug dependence and intoxications) and therapeutic failures (insufficient effects of medicines and morbidity due to untreated indication). RESULTS: The expert panel estimated that 61 +/- 14 % (mean +/- SD) of all patients attending healthcare suffered from DRM, of which 29 +/- 8 % suffered from new medical problems, 18 +/- 6 % from therapeutic failures, and 15 +/- 7 % from a combination of both. The DRM was considered preventable in 45 +/- 15 % of the patients with DRM. The estimated COI was EUR 997 per patient attending healthcare, corresponding to an annual cost of EUR 6,600 million to the Swedish healthcare system. The COI ranged from EUR 490 to EUR 1,314 when varying the participants' probabilities of DRM and clinical outcomes from the first to the third quartile. Of the pathway costs, the COI was most sensitive to variation in the cost of prolonged hospital stay (COI range EUR 953-1,306). CONCLUSION: According to pharmacists' expert opinion, a large proportion of patients in Sweden experience DRM and preventable DRM, and the estimated COI of DRM is extensive. Since observational studies have not addressed the burden of DRM to the general public, this study adds the pharmacists' perception on DRM. Other healthcare professionals' perceptions on DRM need to be investigated in future studies. PMID- 22544222 TI - Systematic review and mixed treatment comparison: dressings to heal diabetic foot ulcers. AB - AIMS/HYPOTHESIS: Foot ulcers in people with diabetes are a common and serious global health issue. Dressings form a key part of ulcer treatment. Existing systematic reviews are limited by the lack of head-to-head comparisons of alternative dressings in a field where there are several different dressing options. We aimed to determine the relative effects of alternative wound dressings on the healing of diabetic foot ulcers. METHODS: This study was a systematic review involving Bayesian mixed treatment comparison. We included randomised controlled trials evaluating the effects on diabetic foot ulcer healing of one or more wound dressings. There were no restrictions based on language or publication status. RESULTS: Fifteen eligible studies, evaluating nine dressing types, were included. Ten direct treatment comparisons were made. Whilst there was increased healing associated with hydrogel and foam dressings compared with basic wound contact materials, these findings were based on data from small studies at unclear or high risk of bias. The mixed treatment comparison suggested that hydrocolloid-matrix dressings were associated with higher odds of ulcer healing than all other dressing types; there was a high degree of uncertainty around these estimates, which were deemed to be of very low quality. CONCLUSIONS/INTERPRETATION: These findings summarise all available trial evidence regarding the use of dressings to heal diabetic foot ulcers. More expensive dressings may offer no advantages in terms of healing than cheaper basic dressings. In addition, evidence pointing to a difference in favour of 'advanced' dressing types over basic wound contact materials is of low or very low quality. PMID- 22544223 TI - Implementing patient-centred cancer care: using experience-based co-design to improve patient experience in breast and lung cancer services. AB - PURPOSE: The aim of this paper was to briefly describe how the experience-based co-design (EBCD) approach was used to identify and implement improvements in the experiences of breast and lung cancer patients before (1) comparing the issues identified as shaping patient experiences in the different tumour groups and (2) exploring participants' reflections on the value and key characteristics of this approach to improving patient experiences. METHODS: Fieldwork involved 36 filmed narrative patient interviews, 219 h of ethnographic observation, 63 staff interviews and a facilitated co-design change process involving patient and staff interviewees over a 12-month period. Four of the staff and five patients were interviewed about their views on the value of the approach and its key characteristics. The project setting was a large, inner-city cancer centre in England. RESULTS: Patients from both tumour groups generally identified similar issues (or 'touchpoints') that shaped their experience of care, although breast cancer patients identified a need for better information about side effects of treatment and end of treatment whereas lung cancer patients expressed a need for more information post-surgery. Although the issues were broadly similar, the particular improvement priorities patients and staff chose to work on together were tumour specific. Interviewees highlighted four characteristics of the EBCD approach as being key to its successful implementation: patient involvement, patient responsibility and empowerment, a sense of community, and a close connection between their experiences and the subsequent improvement priorities. CONCLUSION: EBCD positions patients as active partners with staff in quality improvement. Breast and lung cancer patients identified similar touchpoints in their experiences, but these were translated into different improvement priorities for each tumour type. This is an important consideration when developing patient-centred cancer services across different tumour types. PMID- 22544224 TI - Utility of peripheral blood cultures in patients with cancer and suspected blood stream infections: a systematic review. AB - PURPOSE: The utility of peripheral blood cultures in patients with cancer and/or hematopoietic stem cell transplantation (HSCT) recipients with central venous lines (CVL) and suspected blood stream infection (BSI) is controversial. Our main objective was to describe the proportion of bacteremia detected only by the peripheral blood (PB) culture in order to define its role in the evaluation of patients in this setting. METHODS: We performed electronic searches of OVID Medline, EMBASE, and the Cochrane Central Register of Controlled Trials for studies of adults or children with cancer and/or HSCT that evaluated concurrent PB and CVL cultures and reported sufficient data to permit calculation of the primary outcome. The proportion of bacteremia identified by site of sample was used as the effect measure. The review was registered in PROSPERO: CRD42011001610. RESULTS: From 149 reviewed articles, 7 were included in the meta analysis. In a total number of 10,370 paired blood cultures, bacteremia was detected in 17 %. Thirteen percent of BSI were only identified by PB, while 28 % of infections were only identified by CVL. CONCLUSIONS: PB cultures identified many episodes of bacteremia not detected in the CVL culture. This finding suggests that PB culture should be considered in the evaluation of patients with cancer and/or HSCT with suspected BSI. PMID- 22544225 TI - Efficacy of microwave versus radiofrequency ablation for treatment of small hepatocellular carcinoma: experimental and clinical studies. AB - OBJECTIVE: To prospectively compare microwave (MW) ablation using a modified internal cooled-shaft antenna with radiofrequency (RF) ablation in in vivo porcine liver and in patients with small hepatocellular carcinoma (sHCC). METHODS: In an animal study, MW and RF ablations using a cooled-shaft antenna or internally cooled electrode were performed in in vivo porcine liver. Coagulation diameters of both ablations were compared. For clinical study, 42 patients with sHCC were treated with MW or RF ablation. Complete ablation (CA) and local tumour progression (LTP) were compared. RESULTS: MW ablation produced significantly larger ablation zones than RF ablation in both porcine liver and sHCC with an ablated volume of 33.3 +/- 15.6 cm(3) vs. 18.9 +/- 9.1 cm(3) and 109.3 +/- 58.3 cm(3) vs. 48.7 +/- 30.5 cm(3), respectively. The CA rate was 95.5 % (21/22) for MW ablation and 95.0 % (19/20) for RF ablation. In a 5.1-month follow-up, the LTP rate was 18.2 % (4/22) in the MW ablation group and 15.0 % (3/20) in the RF ablation group. CONCLUSION: MW ablation using a modified cooled-shaft antenna produces a larger ablation zone than RF ablation, with an efficacy similar to RF ablation in local tumour control. MW ablation is a safe and promising treatment of sHCC. PMID- 22544227 TI - How DRACMA changes clinical decision for the individual patient in CMA therapy. AB - PURPOSE OF REVIEW: To describe the impact of the diagnosis and rationale for action against cow's milk allergy (DRACMA) guidelines on the decision process in the therapy of cow's milk allergy (CMA). RECENT FINDINGS: We report here the experience of a 2-year application of DRACMA worldwide. Variations in the socioeconomic profile of CMA sufferers and their context can modify the application of DRACMA recommendations. As an example, we use the country-by country modifications of the social structure and the modifications of the prices for special formula in Italy. SUMMARY: The DRACMA guidelines were issued to inform formula choice for CMA treatment by integrating patients' underlying values, preferences and remarks into grading of recommendations assessment, development and evaluation (GRADE) recommendations, which serve to facilitate their interpretation. This method allows every pediatrician/allergist to follow the changing variables of formulas (cost, palatability, nutritional value) and tailor their prescription for individual patients accordingly. The art of CMA treatment has always relied on physicians' interpretation and the goal of the DRACMA guidelines is to provide a rationale-based and evidence-based indication for choosing an appropriate formula. PMID- 22544226 TI - HMGB1 gene knockout in mouse embryonic fibroblasts results in reduced telomerase activity and telomere dysfunction. AB - Telomere repeats are added onto chromosome ends by telomerase, consisting of two main core components: a catalytic protein subunit (telomerase reverse trancriptase, TERT), and an RNA subunit (telomerase RNA, TR). Here, we report for the first time evidence that HMGB1 (a chromatin-associated protein in mammals, acting as a DNA chaperone in transcription, replication, recombination, and repair) can modulate cellular activity of mammalian telomerase. Knockout of the HMGB1 gene (HMGB1 KO) in mouse embryonic fibroblasts (MEFs) results in chromosomal abnormalities, enhanced colocalization of gamma-H2AX foci at telomeres, and a moderate shortening of telomere lengths. HMGB1 KO MEFs also exhibit significantly (>5-fold) lower telomerase activity than the wild-type MEFs. Correspondingly, enhanced telomerase activity is observed upon overexpression of HMGB1 in MEFs. HMGB1 physically interacts with both TERT and TR, as well as with active telomerase complex in vitro. However, direct interaction of HMGB1 with telomerase is most likely not accountable for the observed higher telomerase activity in HMGB1-containing cells, as revealed from the inability of purified HMGB1 protein to stimulate telomerase activity in vitro. While no transcriptional silencing of TERT is observed in HMGB1 KO MEFs, levels of TR are diminished (~3-fold), providing possible explanation for the observed lower telomerase activity in HMGB1 KO cells. Interestingly, knockout of the HMGB2 gene elevates telomerase activity (~3-fold) in MEFs, suggesting that the two closely related proteins of the HMGB family, HMGB1 and HMGB2, have opposite effects on telomerase activity in the cell. The ability of HMGB1 to modulate cellular activity of telomerase and to maintain telomere integrity can help to understand some aspects of the protein involvement in chromosome stability and cancer. PMID- 22544228 TI - Current world literature. PMID- 22544230 TI - Emotional memory retrieval. rTMS stimulation on left DLPFC increases the positive memories. AB - A suggestive hypothesis proposed that the lateral prefrontal cortex (LPFC) may be identified as the site of emotion-memory integration, since it was shown to be sensitive to the encoding and retrieval of emotional content. In the present research we explored the role of the dorsolateral prefrontal cortex (DLPFC) in memory retrieval of positive vs. negative emotional stimuli. This effect was analyzed by using an rTMS paradigm that induced a cortical activation of the left DLPFC. Subjects were required to perform a task consisting of two experimental phases: an encoding phase, where some lists composed by positive and negative emotional words were presented to the subjects; a retrieval phase, where the old stimuli and the new stimuli were presented for a recognition performance. The rTMS stimulation was provided during the retrieval phase over the left DLPFC. We found that the rTMS stimulation over this area affects the memory retrieval of positive emotional material, with higher memory efficiency (reduced RTs). This result suggested that left DLPFC activation promotes the memory retrieval of emotional information. Secondly, the valence model of emotional cue processing may explain decreasing of RTs, by pointing out the distinct role the left hemisphere has in positive emotional cue processing. PMID- 22544231 TI - Evidence that naturopathic therapy including Cordyceps sinensis prolongs survival of patients with hepatocellular carcinoma. AB - HYPOTHESIS: Naturopathic treatment will benefit patients with hepatocellular carcinoma (HCC). STUDY DESIGN: Retrospective analysis of case series of HCC patients treated with naturopathic agents. METHODS: HCC was diagnosed by dynamic computed tomography (CT) imaging and alpha-fetoprotein (AFP) or PIVKA II, or by histology. Tumor staging was determined by CT. A modified Childs-Pugh scoring was used to assess liver disease. Patients were treated with orally administered combinations of 12 naturopathic agents. Patients were monitored clinically and by CT tumor imaging, serial tumor markers, and liver function tests. RESULTS: PATIENT CHARACTERISTICS: 101 patients with HCC (67 men and 34 women, age 67.2 +/- 8.8 years) were treated for a median of 13.4 months (range 0.8-100.8). Of these 84% had cirrhosis, 63% had hepatitis C virus, 18% had hepatitis B virus, 1% had both, and 9% had metastatic disease. Median modified Childs-Pugh score was 6 (range 3-13). Barcelona Clinic Liver Cancer tumor stages of 0, A, B, C, and D were found in 36%, 25%, 20%, 14%, and 6%, respectively. Median AFP was 40 (range 0-311,000). Median PIVKA II was 59 (0-378,000). Previous treatment was included none (27%), resection with relapse (20%), transarterial chemoembolization (50%), radiofrequency ablation (28%), percutaneous ethanol injection therapy (15%), chemotherapy (14%). OUTCOMES: Initial treatment was with 2.6 +/- 0.8 agents (range 2-4). Overall, patients were treated with 3.7 +/- 1.2 agents (range 2-7). There was a significant correlation between number of agents administered and survival (P < .0001). Patients treated with >=4 agents survived significantly longer than patients treated with <=3 agents (40.2 vs 6.4 months, P < .0001). This difference could not be attributed to statistically significant differences in severity of liver disease or tumor stage, delay in treatment, previous treatment, concurrent nondrug treatment, or censoring effects. The greatest effect was seen in patients treated with at least 4 agents that included Cordyceps sinensis. This prolonged survival was without toxic side effects and appeared to potentiate the survival benefit of conventional therapy. CONCLUSION: Treatment of HCC with a regimen of >=4 agents prepared from natural products was associated with prolonged survival in a substantial portion of patients. The data provide level II evidence for the efficacy of naturopathic therapy in HCC. PMID- 22544232 TI - Lack of effect of coenzyme q10 on doxorubicin cytotoxicity in breast cancer cell cultures. AB - BACKGROUND/HYPOTHESES: Doxorubicin is a standard adjuvant therapy for early-stage breast cancer, and it significantly improves disease-free and overall survival. However, 3% to 20% of breast cancer patients develop chronic cardiomyopathic changes and congestive heart failure because of doxorubicin therapy. Doxorubicin induced cardiotoxicity is thought to be due to the increased generation of reactive oxygen species within cardiac myocyte mitochondria. Coenzyme Q10 (CoQ10) is a lipid-soluble antioxidant that may protect against mitochondrial reactive oxygen species and thus prevent doxorubicin-induced cardiotoxicity. Despite the potential benefits of CoQ10 in preventing cardiotoxicity, it is not known if CoQ10 diminishes the antineoplastic effects of doxorubicin therapy. STUDY DESIGN: In vitro cell culture experiments. METHODS: Breast cancer cell lines (MDA-MB-468 and BT549) were tested for their ability to uptake exogenous CoQ10 using high performance liquid chromatography. Breast cancer cell lines were then treated with doxorubicin and a range of CoQ10 concentrations to determine the effect of CoQ10 on doxorubicin's cytotoxicity. RESULTS: This study demonstrated that intracellular and mitochondrial CoQ10 concentrations increased substantially as higher exogenous concentrations were administered to breast cancer cells. CoQ10 had no effect on the ability of doxorubicin to induce apoptosis or inhibit growth or colony formation in both the cell lines tested when applied over a wide dose range, which encompassed typical basal plasma levels and plasma levels above those typically achieved by supplemented patients. CONCLUSION: The clinical testing of CoQ10 as a supplement to prevent doxorubicin-induced cardiotoxicity requires confidence that it does not decrease the efficacy of chemotherapy. These results support the hypothesis that CoQ10 does not alter the antineoplastic properties of doxorubicin. Further in vivo studies, as well as combination chemotherapy studies, would be reassuring before a large-scale clinical testing of CoQ10 as a cardioprotective drug. PMID- 22544233 TI - The patient, the physician, and the payor: a multiperspective look at the challenges of treating primary immunodeficiency. PMID- 22544235 TI - Evidence for lack of acquisition of tolerance in Salmonella enterica serovar Typhimurium ATCC 14028 after exposure to subinhibitory amounts of Origanum vulgare L. essential oil and carvacrol. AB - Overnight exposure of Salmonella enterica serovar Typhimurium to sublethal amounts of Origanum vulgare essential oil (OV) and carvacrol (CAR) did not result in direct and cross-bacterial protection. Cells subcultured with increasing amounts of OV or CAR survived up to the MIC of either compound, revealing few significant changes in bacterial susceptibility. PMID- 22544234 TI - Detecting genetic introgression: high levels of intersubspecific recombination found in Xylella fastidiosa in Brazil. AB - Documenting the role of novel mutation versus homologous recombination in bacterial evolution, and especially in the invasion of new hosts, is central to understanding the long-term dynamics of pathogenic bacteria. We used multilocus sequence typing (MLST) to study this issue in Xylella fastidiosa subsp. pauca from Brazil, a bacterium causing citrus variegated chlorosis (CVC) and coffee leaf scorch (CLS). All 55 citrus isolates typed (plus one coffee isolate) defined three similar sequence types (STs) dominated by ST11 (85%), while the remaining 22 coffee isolates defined two STs, mainly ST16 (74%). This low level of variation masked unusually large allelic differences (>1% divergence with no intermediates) at five loci (leuA, petC, malF, cysG, and holC). We developed an introgression test to detect whether these large differences were due to introgression via homologous recombination from another X. fastidiosa subspecies. Using additional sequencing around these loci, we established that the seven randomly chosen MLST targets contained seven regions of introgression totaling 2,172 bp of 4,161 bp (52%), only 409 bp (10%) of which were detected by other recombination tests. This high level of introgression suggests the hypothesis that X. fastidiosa subsp. pauca became pathogenic on citrus and coffee (crops cultivated in Brazil for several hundred years) only recently after it gained genetic variation via intersubspecific recombination, facilitating a switch from native hosts. A candidate donor is the subspecies infecting plum in the region since 1935 (possibly X. fastidiosa subsp. multiplex). This hypothesis predicts that nonrecombinant native X. fastidiosa subsp. pauca (not yet isolated) does not cause disease in citrus or coffee. PMID- 22544236 TI - Involvement of Clostridium botulinum ATCC 3502 sigma factor K in early-stage sporulation. AB - A key survival mechanism of Clostridium botulinum, the notorious neurotoxic food pathogen, is the ability to form heat-resistant spores. While the genetic mechanisms of sporulation are well understood in the model organism Bacillus subtilis, nothing is known about these mechanisms in C. botulinum. Using the ClosTron gene-knockout tool, sigK, encoding late-stage (stage IV) sporulation sigma factor K in B. subtilis, was disrupted in C. botulinum ATCC 3502 to produce two different mutants with distinct insertion sites and orientations. Both mutants were unable to form spores, and their elongated cell morphology suggested that the sporulation pathway was blocked at an early stage. In contrast, sigK complemented mutants sporulated successfully. Quantitative real-time PCR analysis of sigK in the parent strain revealed expression at the late log growth phase in the parent strain. Analysis of spo0A, encoding the sporulation master switch, in the sigK mutant and the parent showed significantly reduced relative levels of spo0A expression in the sigK mutant compared to the parent strain. Similarly, sigF showed significantly lower relative transcription levels in the sigK mutant than the parent strain, suggesting that the sporulation pathway was blocked in the sigK mutant at an early stage. We conclude that sigma(K) is essential for early-stage sporulation in C. botulinum ATCC 3502, rather than being involved in late-stage sporulation, as reported for the sporulation model organism B. subtilis. Understanding the sporulation mechanism of C. botulinum provides keys to control the public health risks that the spores of this dangerous pathogen cause through foods. PMID- 22544237 TI - Lactobacillus casei ferments the N-Acetylglucosamine moiety of fucosyl-alpha-1,3 N-acetylglucosamine and excretes L-fucose. AB - We have previously characterized from Lactobacillus casei BL23 three alpha-L fucosidases, AlfA, AlfB, and AlfC, which hydrolyze in vitro natural fucosyl oligosaccharides. In this work, we have shown that L. casei is able to grow in the presence of fucosyl-alpha-1,3-N-acetylglucosamine (Fuc-alpha-1,3-GlcNAc) as a carbon source. Interestingly, L. casei excretes the L-fucose moiety during growth on Fuc-alpha-1,3-GlcNAc, indicating that only the N-acetylglucosamine moiety is being metabolized. Analysis of the genomic sequence of L. casei BL23 shows that downstream from alfB, which encodes the alpha-L-fucosidase AlfB, a gene, alfR, that encodes a transcriptional regulator is present. Divergently from alfB, three genes, alfEFG, that encode proteins with homology to the enzyme IIAB (EIIAB), EIIC, and EIID components of a mannose-class phosphoenolpyruvate:sugar phosphotransferase system (PTS) are present. Inactivation of either alfB or alfF abolishes the growth of L. casei on Fuc-alpha-1,3-GlcNAc. This proves that AlfB is involved in Fuc-alpha-1,3-GlcNAc metabolism and that the transporter encoded by alfEFG participates in the uptake of this disaccharide. A mutation in the PTS general component enzyme I does not eliminate the utilization of Fuc-alpha-1,3 GlcNAc, suggesting that the transport via the PTS encoded by alfEFG is not coupled to phosphorylation of the disaccharide. Transcriptional analysis with alfR and ccpA mutants shows that the two gene clusters alfBR and alfEFG are regulated by substrate-specific induction mediated by the inactivation of the transcriptional repressor AlfR and by carbon catabolite repression mediated by the catabolite control protein A (CcpA). This work reports for the first time the characterization of the physiological role of an alpha-L-fucosidase in lactic acid bacteria and the utilization of Fuc-alpha-1,3-GlcNAc as a carbon source for bacteria. PMID- 22544238 TI - Polyphyly of gut symbionts in stinkbugs of the family Cydnidae. AB - Symbiotic bacteria associated with midgut crypts of stinkbugs of the family Cydnidae, representing seven species and 13 populations, were investigated. All of the symbionts were species specific, and constituted at least four distinct lineages in the Gammaproteobacteria, indicating multiple evolutionary origins of the gut symbionts among the burrower bugs. PMID- 22544239 TI - High-resolution analysis of gut environment and bacterial microbiota reveals functional compartmentation of the gut in wood-feeding higher termites (Nasutitermes spp.). AB - Higher termites are characterized by a purely prokaryotic gut microbiota and an increased compartmentation of their intestinal tract. In soil-feeding species, each gut compartment has different physicochemical conditions and is colonized by a specific microbial community. Although considerable information has accumulated also for wood-feeding species of the genus Nasutitermes, including cellulase activities and metagenomic data, a comprehensive study linking physicochemical gut conditions with the structure of the microbial communities in the different gut compartments is lacking. In this study, we measured high-resolution profiles of H(2), O(2), pH, and redox potential in the gut of Nasutitermes corniger termites, determined the fermentation products accumulating in the individual gut compartments, and analyzed the bacterial communities in detail by pyrotag sequencing of the V3-V4 region of the 16S rRNA genes. The dilated hindgut paunch (P3 compartment) was the only anoxic gut region, showed the highest density of bacteria, and accumulated H(2) to high partial pressures (up to 12 kPa). Molecular hydrogen is apparently produced by a dense community of Spirochaetes and Fibrobacteres, which also dominate the gut of other Nasutitermes species. All other compartments, such as the alkaline P1 compartment (average pH, 10.0), showed high redox potentials and comprised small but distinct populations characteristic for each gut region. In the crop and the posterior hindgut compartments, the community was even more diverse than in the paunch. Similarities in the communities of the posterior hindgut and crop suggested that proctodeal trophallaxis or coprophagy also occurs in higher termites. The large sampling depths of pyrotag sequencing in combination with the determination of important physicochemical parameters allow cautious conclusions concerning the functions of particular bacterial lineages in the respective gut sections to be drawn. PMID- 22544240 TI - A 50-kilodalton Cry2A peptide is lethal to Bombyx mori and Lymantria dispar. AB - The Cry2Aa3 gene was introduced into asporogenic Bacillus thuringiensis, and the synthesized protoxin killed Bombyx mori and Lymantria dispar larvae. Chymotrypsin hydrolyzed the linkages between 49Tyr/Val50 and 145Lys/Ser146 in the protoxin, and 50- and 58-kDa fragments were generated, respectively. Both peptides killed the larvae of both insects. PMID- 22544241 TI - Phylogenetically related Argentinean and Australian Escherichia coli O157 isolates are distinguished by virulence clades and alternative Shiga toxin 1 and 2 prophages. AB - Shiga toxigenic Escherichia coli O157 is the leading cause of hemolytic uremic syndrome (HUS) worldwide. The frequencies of stx genotypes and the incidences of O157-related illness and HUS vary significantly between Argentina and Australia. Locus-specific polymorphism analysis revealed that lineage I/II (LI/II) E. coli O157 isolates were most prevalent in Argentina (90%) and Australia (88%). Argentinean LI/II isolates were shown to belong to clades 4 (28%) and 8 (72%), while Australian LI/II isolates were identified as clades 6 (15%), 7 (83%), and 8 (2%). Clade 8 was significantly associated with Shiga toxin bacteriophage insertion (SBI) type stx(2) (locus of insertion, argW) in Argentinean isolates (P < 0.0001). In Argentinean LI/II strains, stx(2) is carried by a prophage inserted at argW, whereas in Australian LI/II strains the argW locus is occupied by the novel stx(1) prophage. In both Argentinean and Australian LI/II strains, stx(2c) is almost exclusively carried by a prophage inserted at sbcB. However, alternative q(933)- or q(21)-related alleles were identified in the Australian stx(2c) prophage. Argentinean LI/II isolates were also distinguished from Australian isolates by the presence of the putative virulence determinant ECSP_3286 and the predominance of motile O157:H7 strains. Characteristics common to both Argentinean and Australian LI/II O157 strains included the presence of putative virulence determinants (ECSP_3620, ECSP_0242, ECSP_2687, ECSP_2870, and ECSP_2872) and the predominance of the tir255T allele. These data support further understanding of O157 phylogeny and may foster greater insight into the differential virulence of O157 lineages. PMID- 22544242 TI - Impact of malic enzymes on antibiotic and triacylglycerol production in Streptomyces coelicolor. AB - In this paper, we have characterized two malic enzymes (ME), SCO2951 and SCO5261, from Streptomyces coelicolor and analyzed their role in antibiotic and triacylglycerol (TAG) production. Biochemical studies have demonstrated that Sco2951 and Sco5261 genes encode NAD(+)- and NADP(+)-dependent malic enzymes, respectively. Single or double mutants in the ME-encoding genes show no effect on growth rate compared to the parental M145 strain. However, the single Sco2951 and the double Sco2951 Sco5261 mutants display a strong reduction in the production of the polyketide antibiotic actinorhodin; additionally, the Sco2951 Sco5261 mutant shows a decrease in stored TAGs during exponential growth. The lower production of actinorhodin in the double mutant occurs as a consequence of a decrease in the expression of actII-ORF4, the transcriptional activator of the actinorhodin gene cluster. On the other hand, the reduced TAG accumulation is not due to reduced transcript levels of fatty acid biosynthetic genes nor to changes in the amount of the precursor acetyl coenzyme A (acetyl-CoA). This mutant accumulates intermediates of the tricarboxylic acid (TCA) cycle that could alter the regulation of the actinorhodin biosynthetic pathway, suggesting that MEs are important anaplerotic enzymes that redirect C4 intermediates from the TCA cycle to maintain secondary metabolism and TAG production in Streptomyces. PMID- 22544243 TI - Aspergillus niger DLFCC-90 rhamnoside hydrolase, a new type of flavonoid glycoside hydrolase. AB - A novel rutin-alpha-L-rhamnosidase hydrolyzing alpha-L-rhamnoside of rutin, naringin, and hesperidin was purified and characterized from Aspergillus niger DLFCC-90, and the gene encoding this enzyme, which is highly homologous to the alpha-amylase gene, was cloned and expressed in Pichia pastoris GS115. The novel enzyme was classified in glycoside-hydrolase (GH) family 13. PMID- 22544244 TI - Differential regulation by organic compounds and heavy metals of multiple laccase genes in the aquatic hyphomycete Clavariopsis aquatica. AB - To advance the understanding of the molecular mechanisms controlling microbial activities involved in carbon cycling and mitigation of environmental pollution in freshwaters, the influence of heavy metals and natural as well as xenobiotic organic compounds on laccase gene expression was quantified using quantitative real-time PCR (qRT-PCR) in an exclusively aquatic fungus (the aquatic hyphomycete Clavariopsis aquatica) for the first time. Five putative laccase genes (lcc1 to lcc5) identified in C. aquatica were differentially expressed in response to the fungal growth stage and potential laccase inducers, with certain genes being upregulated by, e.g., the lignocellulose breakdown product vanillic acid, the endocrine disruptor technical nonylphenol, manganese, and zinc. lcc4 is inducible by vanillic acid and most likely encodes an extracellular laccase already excreted during the trophophase of the organism, suggesting a function during fungal substrate colonization. Surprisingly, unlike many laccases of terrestrial fungi, none of the C. aquatica laccase genes was found to be upregulated by copper. However, copper strongly increases extracellular laccase activity in C. aquatica, possibly due to stabilization of the copper-containing catalytic center of the enzyme. Copper was found to half-saturate laccase activity already at about 1.8 MUM, in favor of a fungal adaptation to low copper concentrations of aquatic habitats. PMID- 22544245 TI - Variable within- and between-herd diversity of CTX-M cephalosporinase-bearing Escherichia coli isolates from dairy cattle. AB - bla(CTX-M) beta-lactamases confer resistance to critically important cephalosporin drugs. Recovered from both hospital- and community-acquired infections, bla(CTX-M) was first reported in U.S. livestock in 2010. It has been hypothesized that veterinary use of cephalosporins in livestock populations may lead to the dissemination of beta-lactamase-encoding genes. Therefore, our objectives were to estimate the frequency and distribution of coliform bacteria harboring bla(CTX-M) in the fecal flora of Ohio dairy cattle populations. In addition, we characterized the CTX-M alleles carried by the isolates, their plasmidic contexts, and the genetic diversity of the bacterial isolates themselves. We also evaluated the association between ceftiofur use and the likelihood of recovering cephalosporinase-producing bacteria. Thirty fresh fecal samples and owner-reported ceftiofur use data were collected from each of 25 Ohio dairy farms. Fecal samples (n = 747) yielded 70 bla(CTX-M)-positive Escherichia coli isolates from 5/25 herds, 715 bla(CMY-2) E. coli isolates from 25/25 herds, and 274 Salmonella spp. from 20/25 herds. The within-herd prevalence among bla(CTX-M)-positive herds ranged from 3.3 to 100% of samples. Multiple pulsed field gel electrophoresis (PFGE) patterns, plasmid replicon types, and CTX-M genes were detected. Plasmids with CTX-M-1, -15, and -14 alleles were clonal by restriction fragment length polymorphism (RFLP) within herds, and specific plasmid incompatibility group markers were consistently associated with each bla(CTX-M) allele. PFGE of total bacterial DNA showed similar within-herd clustering, with the exception of one herd, which revealed at least 6 different PFGE signatures. We were unable to detect an association between owner-reported ceftiofur use and the probability of recovering E. coli carrying bla(CTX-M) or bla(CMY-2). PMID- 22544246 TI - Quantification of Tinto River sediment microbial communities: importance of sulfate-reducing bacteria and their role in attenuating acid mine drainage. AB - Tinto River (Huelva, Spain) is a natural acidic rock drainage (ARD) environment produced by the bio-oxidation of metallic sulfides from the Iberian Pyritic Belt. This study quantified the abundance of diverse microbial populations inhabiting ARD-related sediments from two physicochemically contrasting sampling sites (SN and JL dams). Depth profiles of total cell numbers differed greatly between the two sites yet were consistent in decreasing sharply at greater depths. Although catalyzed reporter deposition fluorescence in situ hybridization with domain specific probes showed that Bacteria (>98%) dominated over Archaea (<2%) at both sites, important differences were detected at the class and genus levels, reflecting differences in pH, redox potential, and heavy metal concentrations. At SN, where the pH and redox potential are similar to that of the water column (pH 2.5 and +400 mV), the most abundant organisms were identified as iron-reducing bacteria: Acidithiobacillus spp. and Acidiphilium spp., probably related to the higher iron solubility at low pH. At the JL dam, characterized by a banded sediment with higher pH (4.2 to 6.2), more reducing redox potential (-210 mV to 50 mV), and a lower solubility of iron, members of sulfate-reducing genera Syntrophobacter, Desulfosporosinus, and Desulfurella were dominant. The latter was quantified with a newly designed CARD-FISH probe. In layers where sulfate reducing bacteria were abundant, pH was higher and redox potential and levels of dissolved metals and iron were lower. These results suggest that the attenuation of ARD characteristics is biologically driven by sulfate reducers and the consequent precipitation of metals and iron as sulfides. PMID- 22544248 TI - TatAc, the third TatA subunit of Bacillus subtilis, can form active twin-arginine translocases with the TatCd and TatCy subunits. AB - Two independent twin-arginine translocases (Tat) for protein secretion were previously identified in the Gram-positive bacterium Bacillus subtilis. These consist of the TatAd-TatCd and TatAy-TatCy subunits. The function of a third TatA subunit named TatAc was unknown. Here, we show that TatAc can form active protein translocases with TatCd and TatCy. PMID- 22544247 TI - Implications of microfauna-host interactions for trypanosome transmission dynamics in Glossina fuscipes fuscipes in Uganda. AB - Tsetse flies (Diptera: Glossinidae) are vectors for African trypanosomes (Euglenozoa: kinetoplastida), protozoan parasites that cause African trypanosomiasis in humans (HAT) and nagana in livestock. In addition to trypanosomes, two symbiotic bacteria (Wigglesworthia glossinidia and Sodalis glossinidius) and two parasitic microbes, Wolbachia and a salivary gland hypertrophy virus (SGHV), have been described in tsetse. Here we determined the prevalence of and coinfection dynamics between Wolbachia, trypanosomes, and SGHV in Glossina fuscipes fuscipes in Uganda over a large geographical scale spanning the range of host genetic and spatial diversity. Using a multivariate analysis approach, we uncovered complex coinfection dynamics between the pathogens and statistically significant associations between host genetic groups and pathogen prevalence. It is important to note that these coinfection dynamics and associations with the host were not apparent by univariate analysis. These associations between host genotype and pathogen are particularly evident for Wolbachia and SGHV where host groups are inversely correlated for Wolbachia and SGHV prevalence. On the other hand, trypanosome infection prevalence is more complex and covaries with the presence of the other two pathogens, highlighting the importance of examining multiple pathogens simultaneously before making generalizations about infection and spatial patterns. It is imperative to note that these novel findings would have been missed if we had employed the standard univariate analysis used in previous studies. Our results are discussed in the context of disease epidemiology and vector control. PMID- 22544249 TI - Cloning of a novel arylamidase gene from Paracoccus sp. strain FLN-7 that hydrolyzes amide pesticides. AB - The bacterial isolate Paracoccus sp. strain FLN-7 hydrolyzes amide pesticides such as diflubenzuron, propanil, chlorpropham, and dimethoate through amide bond cleavage. A gene, ampA, encoding a novel arylamidase that catalyzes the amide bond cleavage in the amide pesticides was cloned from the strain. ampA contains a 1,395-bp open reading frame that encodes a 465-amino-acid protein. AmpA was expressed in Escherichia coli BL21 and homogenously purified using Ni nitrilotriacetic acid affinity chromatography. AmpA is a homodimer with an isoelectric point of 5.4. AmpA displays maximum enzymatic activity at 40 degrees C and a pH of between 7.5 and 8.0, and it is very stable at pHs ranging from 5.5 to 10.0 and at temperatures up to 50 degrees C. AmpA efficiently hydrolyzes a variety of secondary amine compounds such as propanil, 4-acetaminophenol, propham, chlorpropham, dimethoate, and omethoate. The most suitable substrate is propanil, with K(m) and k(cat) values of 29.5 MUM and 49.2 s(-1), respectively. The benzoylurea insecticides (diflubenzuron and hexaflumuron) are also hydrolyzed but at low efficiencies. No cofactor is needed for the hydrolysis activity. AmpA shares low identities with reported arylamidases (less than 23%), forms a distinct lineage from closely related arylamidases in the phylogenetic tree, and has different biochemical characteristics and catalytic kinetics with related arylamidases. The results in the present study suggest that AmpA is a good candidate for the study of the mechanism for amide pesticide hydrolysis, genetic engineering of amide herbicide-resistant crops, and bioremediation of amide pesticide-contaminated environments. PMID- 22544250 TI - Expression of the arginine deiminase pathway genes in Lactobacillus sakei is strain dependent and is affected by the environmental pH. AB - The adaptation of Lactobacillus sakei to a meat environment is reflected in its metabolic potential. For instance, the ability to utilize arginine through the arginine deiminase (ADI) pathway, resulting in additional ATP, represents a competitive benefit. In L. sakei CTC 494, the arc operon (arcABCTDR) shows the same gene order and organization as that in L. sakei 23K, the genome sequence of which is known. However, differences in relative gene expression were found, and these seemed to be optimal in different growth phases, namely, the highest relative gene expression level was in the end exponential growth phase in the case of L. sakei CTC 494 and in the mid-exponential growth phase of L. sakei 23K. Also, the environmental pH influenced the relative expression level of the arc operon, as shown for L. sakei CTC 494, with the highest relative expression level occurring at the optimal pH for growth (pH 6.0). Deviations from this optimal pH (pH 5.0 and pH 7.0) resulted in an overall decline of the relative expression level of all genes of the arc operon. Furthermore, a differential relative expression of the individual genes of the arc operon was found, with the highest relative gene expression occurring for the first two genes of the arc operon (arcA and arcB). Finally, it was shown that some L. sakei strains were able to convert agmatine into putrescine, suggesting an operational agmatine deiminase pathway in these strains, a metabolic trait that is undesirable in meat fermentations. This study shows that this metabolic trait is most probably encoded by a previously erroneously annotated second putative arc operon. PMID- 22544251 TI - The wood rot ascomycete Xylaria polymorpha produces a novel GH78 glycoside hydrolase that exhibits alpha-L-rhamnosidase and feruloyl esterase activities and releases hydroxycinnamic acids from lignocelluloses. AB - Soft rot (type II) fungi belonging to the family Xylariaceae are known to substantially degrade hardwood by means of their poorly understood lignocellulolytic system, which comprises various hydrolases, including feruloyl esterases and laccase. In the present study, several members of the Xylariaceae were found to exhibit high feruloyl esterase activity during growth on lignocellulosic materials such as wheat straw (up to 1,675 mU g(-1)) or beech wood (up to 80 mU g(-1)). Following the ester-cleaving activity toward methyl ferulate, a hydrolase of Xylaria polymorpha was produced in solid-state culture on wheat straw and purified by different steps of anion-exchange and size exclusion chromatography to apparent homogeneity (specific activity, 2.2 U mg( 1)). The peptide sequence of the purified protein deduced from the gene sequence and verified by de novo peptide sequencing shows high similarity to putative alpha-L-rhamnosidase sequences belonging to the glycoside hydrolase family 78 (GH78; classified under EC 3.2.1.40). The purified enzyme (98 kDa by SDS-PAGE, 103 kDa by size-exclusion chromatography; pI 3.7) converted diverse glycosides (e.g., alpha-L-rhamnopyranoside and alpha-L-arabinofuranoside) but also natural and synthetic esters (e.g., chlorogenic acid, hydroxycinnamic acid glycoside esters, veratric acid esters, or p-nitrophenyl acetate) and released free hydroxycinnamic acids (ferulic and coumaric acid) from arabinoxylan and milled wheat straw. These catalytic properties strongly suggest that X. polymorpha GH78 is a multifunctional enzyme. It is the first fungal enzyme that combines glycosyl hydrolase with esterase activities and may help this soft rot fungus to degrade lignocelluloses. PMID- 22544252 TI - Recombinogenic properties of Pyrococcus furiosus strain COM1 enable rapid selection of targeted mutants. AB - We recently reported the isolation of a mutant of Pyrococcus furiosus, COM1, that is naturally and efficiently competent for DNA uptake. While we do not know the exact nature of this mutation, the combined transformation and recombination frequencies of this strain allow marker replacement by direct selection using linear DNA. In testing the limits of its recombination efficiency, we discovered that marker replacement was possible with as few as 40 nucleotides of flanking homology to the target region. We utilized this ability to design a strategy for selection of constructed deletions using PCR products with subsequent excision, or "pop-out," of the selected marker. We used this method to construct a "markerless" deletion of the trpAB locus in the GLW101 (COM1 DeltapyrF) background to generate a strain (JFW02) that is a tight tryptophan auxotroph, providing a genetic background with two auxotrophic markers for further strain construction. The utility of trpAB as a selectable marker was demonstrated using prototrophic selection of plasmids and genomic DNA containing the wild-type trpAB alleles. A deletion of radB was also constructed that, surprisingly, had no obvious effect on either recombination or transformation, suggesting that its gene product is not involved in the COM1 phenotype. Attempts to construct a radA deletion mutation were unsuccessful, suggesting that this may be an essential gene. The ease and speed of this procedure will facilitate the construction of strains with multiple genetic changes and allow the construction of mutants with deletions of virtually any nonessential gene. PMID- 22544253 TI - Temperature-dependent survival of hepatitis A virus during storage of contaminated onions. AB - Pre- or postharvest contamination of green onions by hepatitis A virus (HAV) has been linked to large numbers of food-borne illnesses. Understanding HAV survival in onions would assist in projecting the risk of the disease associated with their consumption. This study defined HAV inactivation rates in contaminated green onions contained in air-permeable, moisture-retaining high-density polyethylene packages that were stored at 3, 10, 14, 20, 21, 22, and 23 degrees C. A protocol was established to recover HAV from whole green onions, with 31% as the average recovery by infectivity assay. Viruses in eluates were primarily analyzed by a 6-well plaque assay on FRhK-4 cells. Eight storage trials, including two trials at 3 degrees C, were conducted, with 3 to 7 onion samples per sampling and 4 to 7 samplings per trial. Linear regression correlation (r(2) = 0.80 to 0.98) was observed between HAV survival and storage time for each of the 8 trials, held at specific temperatures. Increases in the storage temperature resulted in greater HAV inactivation rates, e.g., a reduction of 0.033 log PFU/day at 3.4 +/- 0.3 degrees C versus 0.185 log PFU/day at 23.4 +/- 0.7 degrees C. Thus, decimal reduction time (D) values of 30, 14, 11, and 5 days, respectively, were obtained for HAV in onions stored at 3, 10, 14, and 23 degrees C. Further regression analysis determined that 1 degree Celsius increase would increase inactivation of HAV by 0.007 log PFU/day in onions (r(2) = 0.97). The data suggest that natural degradation of HAV in contaminated fresh produce is minimal and that a preventive strategy is critical to produce safety. The results are useful in predicting the risks associated with HAV contamination in fresh produce. PMID- 22544254 TI - Histopathological effects of the Yen-Tc toxin complex from Yersinia entomophaga MH96 (Enterobacteriaceae) on the Costelytra zealandica (Coleoptera: Scarabaeidae) larval midgut. AB - Yersinia entomophaga MH96, which was originally isolated from the New Zealand grass grub, Costelytra zealandica, produces an orally active proteinaceous toxin complex (Yen-Tc), and this toxin is responsible for mortality in a range of insect species, mainly within the Coleoptera and Lepidoptera. The genes encoding Yen-Tc are members of the toxin complex (Tc) family, with orthologs identified in several other bacterial species. As the mechanism of Yen-Tc activity remains unknown, a histopathological examination of C. zealandica larvae was undertaken in conjunction with cultured cells to identify the effects of Yen-Tc and to distinguish the contributions that its individual subunit components make upon intoxication. A progressive series of events that led to the deterioration of the midgut epithelium was observed. Additionally, experiments using a cell culture assay system were carried out to determine the cellular effects of intoxication on cells after topical application and the transient expression of Yen-Tc and its individual components. While observations were broadly consistent with those previously reported for other Tc family members, some differences were noted. In particular, the distinct stepwise disintegration of the midgut shared features associated with both apoptosis and necrotic programmed cell death pathways. Second, we observed, for the first time, a contribution of toxicity from two chitinases associated with the Yen-Tc complex. Our findings were suggestive of the activities encoded within the subunit components of Yen-Tc targeting different sites along putative programmed cell death pathways. Given the observed broad host range for Yen-Tc, these targeted loci are likely to be widely shared among insects. PMID- 22544255 TI - Novel metagenome-derived, cold-adapted alkaline phospholipase with superior lipase activity as an intermediate between phospholipase and lipase. AB - A novel lipolytic enzyme was isolated from a metagenomic library obtained from tidal flat sediments on the Korean west coast. Its putative functional domain, designated MPlaG, showed the highest similarity to phospholipase A from Grimontia hollisae CIP 101886, though it was screened from an emulsified tricaprylin plate. Phylogenetic analysis showed that MPlaG is far from family I.6 lipases, including Staphylococcus hyicus lipase, a unique lipase which can hydrolyze phospholipids, and is more evolutionarily related to the bacterial phospholipase A(1) family. The specific activities of MPlaG against olive oil and phosphatidylcholine were determined to be 2,957 +/- 144 and 1,735 +/- 147 U mg(-1), respectively, which means that MPlaG is a lipid-preferred phospholipase. Among different synthetic esters, triglycerides, and phosphatidylcholine, purified MPlaG exhibited the highest activity toward p-nitrophenyl palmitate (C(16)), tributyrin (C(4)), and 1,2-dihexanoyl-phosphatidylcholine (C(8)). Finally, MPlaG was identified as a phospholipase A(1) with lipase activity by cleavage of the sn-1 position of OPPC, interfacial activity, and triolein hydrolysis. These findings suggest that MPlaG is the first experimentally characterized phospholipase A(1) with lipase activity obtained from a metagenomic library. Our study provides an opportunity to improve our insight into the evolution of lipases and phospholipases. PMID- 22544256 TI - Elevated enterotoxin A expression and formation in Staphylococcus aureus and its association with prophage induction. AB - Staphylococcus aureus strains producing the bacteriophage-encoded staphylococcal enterotoxin A (SEA) were divided into two groups, high- and low-SEA-producing strains, based on the amount of SEA produced. After growth under favorable conditions in batch cultures, 10 of the 21 strains tested produced more than 1,000 ng/ml SEA, and 9 strains produced less than 10 ng/ml SEA; two enterotoxigenic strains, MRSA252 and Newman, produced intermediate levels of SEA (around 450 ng/ml). The differences in the production of SEA were found to be associated with the expression level of sea and whether the strains hosted the sea(1) or sea(2) version. Furthermore, differences in nucleotide sequence in the Siphoviridae phage region showed two clonal lineages of the high-SEA-producing strains. One of these lines was correlated with the capacity for a massive increase in SEA levels by prophage induction as demonstrated using mitomycin C (MC). This was also confirmed by the occurrence of additional sea expression, presumed to be initiated by a latent phage promoter located upstream of the endogenous sea promoter. Remarkably, the SEA level was increased up to 10-fold in some strains due to prophage induction. The low-SEA-producing group and the high SEA-producing subgroup lacking phage-activated sea transcription showed no increase in SEA formation after the addition of MC. This study demonstrates that sea expression in enterotoxigenic strains is correlated with the clonal lineage of sea-carrying phages. The high-SEA-producing group, in particular the prophage inducible sea(1) group, may be more relevant to staphylococcal food poisoning than the low-SEA-producing group, harboring mainly sea(2). PMID- 22544257 TI - No beneficial effects evident for Enterococcus faecium NCIMB 10415 in weaned pigs infected with Salmonella enterica serovar Typhimurium DT104. AB - Salmonella enterica serovar Typhimurium DT 104 is the major pathogen for salmonellosis outbreaks in Europe. We tested if the probiotic bacterium Enterococcus faecium NCIMB 10415 can prevent or alleviate salmonellosis. Therefore, piglets of the German Landrace breed that were treated with E. faecium (n = 16) as a feed additive and untreated controls (n = 16) were challenged with S. Typhimurium 10 days after weaning. The presence of salmonellae in feces and selected organs, as well as the immune response, were investigated. Piglets treated with E. faecium gained less weight than control piglets (P = 0.05). The feeding of E. faecium had no effect on the fecal shedding of salmonellae and resulted in a higher abundance of the pathogen in tonsils of all challenged animals. The specific (anti-Salmonella IgG) and nonspecific (haptoglobin) humoral immune responses as well as the cellular immune response (T helper cells, cytotoxic T cells, regulatory T cells, gammadelta T cells, and B cells) in the lymph nodes, Peyer's patches of different segments of the intestine (jejunal and ileocecal), the ileal papilla, and in the blood were affected in the course of time after infection (P < 0.05) but not by the E. faecium treatment. These results led to the conclusion that E. faecium may not have beneficial effects on the performance of weaned piglets in the case of S. Typhimurium infection. Therefore, we suggest a critical discussion and reconsideration of E. faecium NCIMB 10415 administration as a probiotic for pigs. PMID- 22544258 TI - Synthesis of chiral cyanohydrins by recombinant Escherichia coli cells in a micro aqueous reaction system. AB - Synthesis of chiral cyanohydrins is performed in a monophasic micro-aqueous reaction system using whole recombinant Escherichia coli cells expressing the Arabidopsis thaliana hydroxynitrile lyase (AtHNL). Microscopy studies employing a fusion of AtHNL with a flavin-based fluorescent protein (FbFP) reveal that the cells remain intact in the reaction system. PMID- 22544259 TI - Mining new crystal protein genes from Bacillus thuringiensis on the basis of mixed plasmid-enriched genome sequencing and a computational pipeline. AB - We have designed a high-throughput system for the identification of novel crystal protein genes (cry) from Bacillus thuringiensis strains. The system was developed with two goals: (i) to acquire the mixed plasmid-enriched genomic sequence of B. thuringiensis using next-generation sequencing biotechnology, and (ii) to identify cry genes with a computational pipeline (using BtToxin_scanner). In our pipeline method, we employed three different kinds of well-developed prediction methods, BLAST, hidden Markov model (HMM), and support vector machine (SVM), to predict the presence of Cry toxin genes. The pipeline proved to be fast (average speed, 1.02 Mb/min for proteins and open reading frames [ORFs] and 1.80 Mb/min for nucleotide sequences), sensitive (it detected 40% more protein toxin genes than a keyword extraction method using genomic sequences downloaded from GenBank), and highly specific. Twenty-one strains from our laboratory's collection were selected based on their plasmid pattern and/or crystal morphology. The plasmid-enriched genomic DNA was extracted from these strains and mixed for Illumina sequencing. The sequencing data were de novo assembled, and a total of 113 candidate cry sequences were identified using the computational pipeline. Twenty-seven candidate sequences were selected on the basis of their low level of sequence identity to known cry genes, and eight full-length genes were obtained with PCR. Finally, three new cry-type genes (primary ranks) and five cry holotypes, which were designated cry8Ac1, cry7Ha1, cry21Ca1, cry32Fa1, and cry21Da1 by the B. thuringiensis Toxin Nomenclature Committee, were identified. The system described here is both efficient and cost-effective and can greatly accelerate the discovery of novel cry genes. PMID- 22544260 TI - Genetic and functional characterization of cyclic lipopeptide white-line-inducing principle (WLIP) production by rice rhizosphere isolate Pseudomonas putida RW10S2. AB - The secondary metabolite mediating the GacS-dependent growth-inhibitory effect exerted by the rice rhizosphere isolate Pseudomonas putida RW10S2 on phytopathogenic Xanthomonas species was identified as white-line-inducing principle (WLIP), a member of the viscosin group of cyclic lipononadepsipeptides. WLIP producers are commonly referred to by the taxonomically invalid name "Pseudomonas reactans," based on their capacity to reveal the presence of a nearby colony of Pseudomonas tolaasii by inducing the formation of a visible precipitate ("white line") in agar medium between both colonies. This phenomenon is attributed to the interaction of WLIP with a cyclic lipopeptide of a distinct structural group, the fungitoxic tolaasin, and has found application as a diagnostic tool to identify tolaasin-producing bacteria pathogenic to mushrooms. The genes encoding the WLIP nonribosomal peptide synthetases WlpA, WlpB, and WlpC were identified in two separate genomic clusters (wlpR-wlpA and wlpBC) with an operon organization similar to that of the viscosin, massetolide, and entolysin biosynthetic systems. Expression of wlpR is dependent on gacS, and the encoded regulator of the LuxR family (WlpR) activates transcription of the biosynthetic genes and the linked export genes, which is not controlled by the RW10S2 quorum sensing system PmrR/PmrI. In addition to linking the known phenotypes of white line production and hemolytic activity of a WLIP producer with WLIP biosynthesis, additional properties of ecological relevance conferred by WLIP production were identified, namely, antagonism against Xanthomonas and involvement in swarming and biofilm formation. PMID- 22544261 TI - Involvement of a natural fusion of a cytochrome P450 and a hydrolase in mycophenolic acid biosynthesis. AB - Mycophenolic acid (MPA) is a fungal secondary metabolite and the active component in several immunosuppressive pharmaceuticals. The gene cluster coding for the MPA biosynthetic pathway has recently been discovered in Penicillium brevicompactum, demonstrating that the first step is catalyzed by MpaC, a polyketide synthase producing 5-methylorsellinic acid (5-MOA). However, the biochemical role of the enzymes encoded by the remaining genes in the MPA gene cluster is still unknown. Based on bioinformatic analysis of the MPA gene cluster, we hypothesized that the step following 5-MOA production in the pathway is carried out by a natural fusion enzyme MpaDE, consisting of a cytochrome P450 (MpaD) in the N-terminal region and a hydrolase (MpaE) in the C-terminal region. We verified that the fusion gene is indeed expressed in P. brevicompactum by obtaining full-length sequence of the mpaDE cDNA prepared from the extracted RNA. Heterologous coexpression of mpaC and the fusion gene mpaDE in the MPA-nonproducer Aspergillus nidulans resulted in the production of 5,7-dihydroxy-4-methylphthalide (DHMP), the second intermediate in MPA biosynthesis. Analysis of the strain coexpressing mpaC and the mpaD part of mpaDE shows that the P450 catalyzes hydroxylation of 5-MOA to 4,6-dihydroxy-2 (hydroxymethyl)-3-methylbenzoic acid (DHMB). DHMB is then converted to DHMP, and our results suggest that the hydrolase domain aids this second step by acting as a lactone synthase that catalyzes the ring closure. Overall, the chimeric enzyme MpaDE provides insight into the genetic organization of the MPA biosynthesis pathway. PMID- 22544262 TI - A widespread occurrence of extra open reading frames in plant Ty3/gypsy retrotransposons. AB - Long terminal repeat (LTR) retrotransposons make up substantial parts of most higher plant genomes where they accumulate due to their replicative mode of transposition. Although the transposition is facilitated by proteins encoded within the gag-pol region which is common to all autonomous elements, some LTR retrotransposons were found to potentially carry an additional protein coding capacity represented by extra open reading frames located upstream or downstream of gag-pol. In this study, we performed a comprehensive in silico survey and comparative analysis of these extra open reading frames (ORFs) in the group of Ty3/gypsy LTR retrotransposons as the first step towards our understanding of their origin and function. We found that extra ORFs occur in all three major lineages of plant Ty3/gypsy elements, being the most frequent in the Tat lineage where most (77 %) of identified elements contained extra ORFs. This lineage was also characterized by the highest diversity of extra ORF arrangement (position and orientation) within the elements. On the other hand, all of these ORFs could be classified into only two broad groups based on their mutual similarities or the presence of short conserved motifs in their inferred protein sequences. In the Athila lineage, the extra ORFs were confined to the element 3' regions but they displayed much higher sequence diversity compared to those found in Tat. In the lineage of Chromoviruses the extra ORFs were relatively rare, occurring only in 5' regions of a group of elements present in a single plant family (Poaceae). In all three lineages, most extra ORFs lacked sequence similarities to characterized gene sequences or functional protein domains, except for two Athila like elements with similarities to LOGL4 gene and part of the Chromoviruses extra ORFs that displayed partial similarity to histone H3 gene. Thus, in these cases the extra ORFs most likely originated by transduction or recombination of cellular gene sequences. In addition, the protein domain which is otherwise associated with DNA transposons have been detected in part of the Tat-like extra ORFs, pointing to their origin from an insertion event of a mobile element. PMID- 22544263 TI - Prospective study of HBV reactivation risk in rheumatoid arthritis patients who received conventional disease-modifying antirheumatic drugs. AB - Studies that reported hepatitis B virus (HBV) reactivation in rheumatoid arthritis (RA) patients have caused attention of disease-modifying antirheumatic drug (DMARD)-related HBV reactivation. Most of the studies were focused on HBV reactivation risk of biologic DMARDs; insufficient data are available to identify the exact risk of conventional DMARD (c-DMARD)-related HBV reactivation. This prospective study aimed to investigate the risk of HBV reactivation in HBV infected RA patients who received c-DMARDs. A total of 476 RA patients were screened in this prospective non-randomized, non-controlled study. HBV-infected patients characterized by hepatitis B surface antigen (HBsAg) positive or HBsAg negative/anti-hepatitis B core antigen (anti-HBc) positive were analyzed for HBV DNA, followed with HBV DNA monitoring scheduled every 3 months, serum alanine aminotransferase test at 2-month intervals, or more frequently. Prevalence of HBsAg positive and HBsAg negative/anti-HBc positive was 6.51 and 51.1 %, respectively, among the 476 RA patients. Among 211 patients (23 patients were HBsAg positive and 188 patients were HBsAg negative/anti-HBc positive) who received c-DMARDs without antiviral prophylactic treatment, 4 patients developed HBV reactivation. Both HBsAg positive and HBsAg negative/anti-HBc positive patients have the possibility of developing HBV reactivation. There was no correlation between HBV reactivation and any specific c-DMARD. Glucocorticoid coadministration and negative anti-hepatitis B surface antigen (anti-HBs) at baseline showed correlation with reactivation. In conclusion, it would be rational to initiate antiviral prophylaxis according to risk stratification rather than universal prophylaxis for HBV-infected RA patients. Conventional DMARDs are relatively safe to HBV-infected patients with low reactivation risk (low HBV DNA level, no GCs administration, and anti-HB positive). PMID- 22544264 TI - A selective inhibitor reveals PI3Kgamma dependence of T(H)17 cell differentiation. AB - We devised a high-throughput chemoproteomics method that enabled multiplexed screening of 16,000 compounds against native protein and lipid kinases in cell extracts. Optimization of one chemical series resulted in CZC24832, which is to our knowledge the first selective inhibitor of phosphoinositide 3-kinase gamma (PI3Kgamma) with efficacy in in vitro and in vivo models of inflammation. Extensive target- and cell-based profiling of CZC24832 revealed regulation of interleukin-17-producing T helper cell (T(H)17) differentiation by PI3Kgamma, thus reinforcing selective inhibition of PI3Kgamma as a potential treatment for inflammatory and autoimmune diseases. PMID- 22544265 TI - MexT functions as a redox-responsive regulator modulating disulfide stress resistance in Pseudomonas aeruginosa. AB - MexT is a global LysR transcriptional regulator known to modulate antibiotic resistance and virulence in Pseudomonas aeruginosa. In this study, a novel role for MexT in mediating intrinsic disulfide stress resistance was demonstrated, representing the first identified phenotype associated with inactivation of this regulator in wild-type cells. Disruption of mexT resulted in increased susceptibility to the disulfide stress elicitor diamide [diazenedicarboxylic acid bis(N,N,-di-methylamide)]. This compound is known to elicit a specific stress response via depletion of reduced glutathione and alteration of the cellular redox environment, implicating MexT in redox control. In support of this, MexT regulated targets, including the MexEF-OprN multidrug efflux system, were induced by subinhibitory concentrations of diamide. A mexF insertion mutant also exhibited increased diamide susceptibility, implicating the MexEF-OprN efflux system in MexT-associated disulfide stress resistance. Purified MexT protein was observed to form an oligomeric complex in the presence of oxidized glutathione, with a calculated redox potential of -189 mV. This value far exceeds the thiol disulfide redox potential of the bacterial cytoplasm, ensuring that MexT remains reduced under normal physiological conditions. MexT is activated by mutational disruption of the predicted quinone oxidoreductase encoded by mexS. Alterations in the cellular redox state were observed in a mexS mutant (PA14nfxC), supporting a model whereby the perception of MexS-associated redox signals by MexT leads to the induction of the MexEF-OprN efflux system, which, in turn, may mediate disulfide stress resistance via efflux of electrophilic compounds. PMID- 22544266 TI - The divergent AmoC3 subunit of ammonia monooxygenase functions as part of a stress response system in Nitrosomonas europaea. AB - The ammonia monooxygenase of chemolithotrophic ammonia-oxidizing bacteria (AOB) catalyzes the first step in ammonia oxidation by converting ammonia to hydroxylamine. The monooxygenase of Nitrosomonas europaea is encoded by two nearly identical operon copies (amoCAB(1,2)). Several AOB, including N. europaea, also possess a divergent monocistronic copy of amoC (amoC(3)) of unknown function. Previous work suggested a possible functional role for amoC(3) as part of the sigma(E) stress response regulon during the recovery of N. europaea from extended ammonia starvation, thus indicating its importance during the exit of cells from starvation. We here used global transcription analysis to show that expression of amoC(3) is part of a general poststarvation cellular response system in N. europaea. We also found that amoC(3) is required for an efficient response to some stress conditions, as deleting this gene impaired growth at elevated temperatures and recovery following starvation under high oxygen tensions. Deletion of the sigma(32) global stress response regulator demonstrated that the heat shock regulon plays a significant role in mediating the recovery of N. europaea from starvation. These findings provide the first described phenotype associated with the divergent AmoC(3) subunit which appears to function as a stress-responsive subunit capable of maintaining ammonia oxidation activity under stress conditions. While this study was limited to starvation and heat shock, it is possible that the AmoC(3) subunit may be responsive to other membrane stressors (e.g., solvent or osmotic shocks) that are prevalent in the environments of AOB. PMID- 22544267 TI - Rrp2, a prokaryotic enhancer-like binding protein, is essential for viability of Borrelia burgdorferi. AB - The Lyme disease spirochete, Borrelia burgdorferi, exists in two diverse niches (i.e., an arthropod tick vector and mammalian host) during its enzootic life cycle. To effectively adapt to these unique environments, the bacterium alters the expression of numerous genes, including several major outer surface (lipo)proteins that are required for infection and transmission. An enhancer binding protein (EBP), known as Rrp2, is one identified activator of the RpoN/RpoS alternative sigma factor cascade. Because initial efforts to generate an rrp2 deletion strain were unsuccessful, the role of Rrp2 in the activation of the RpoN/RpoS pathway was first defined using a strain of B. burgdorferi carrying an rrp2 point mutant that was defective in its ability to activate RpoN-dependent transcription. The fact that subsequent attempts to disrupt rrp2 have also been unsuccessful has led investigators to hypothesize that Rrp2 has other undefined functions which are essential for B. burgdorferi survival and independent of its EBP function. We used a lac-based inducible expression system to generate a conditional rrp2 mutant in virulent B. burgdorferi. In this strain, an isopropyl beta-D-thiogalactopyranoside-inducible copy of the rrp2 gene is expressed in trans from a borrelial shuttle vector. We found that the chromosomal copy of rrp2 could be inactivated only when rrp2 was induced, and the maintenance of rrp2 expression was required for the growth of the mutants. In addition, the overexpression of rrp2 is detrimental to B. burgdorferi growth in a manner that is independent of the RpoN/RpoS pathway. These studies provide the first direct evidence that rrp2 is an essential gene in B. burgdorferi. PMID- 22544269 TI - P65 truncation impacts P30 dynamics during Mycoplasma pneumoniae gliding. AB - The cell wall-less prokaryote Mycoplasma pneumoniae is a major cause of community acquired bronchitis and pneumonia in humans. Colonization is mediated largely by a differentiated terminal organelle, which is also the leading end in gliding motility. Cytadherence-associated proteins P30 and P65 appear to traffic concurrently to the distal end of developing terminal organelles. Here, truncation of P65 due to transposon insertion in the corresponding gene resulted in lower gliding velocity, reduced cytadherence, and decreased steady-state levels of several terminal organelle proteins, including P30. Utilizing fluorescent protein fusions, we followed terminal organelle development over time. New P30 foci appeared at nascent terminal organelles in P65 mutants, as in the wild type. However, with forward cell motility, P30 in the P65 mutants appeared to drag toward the trailing cell pole, where it was released, yielding a fluorescent trail to which truncated P65 colocalized. In contrast, P30 was only rarely observed at the trailing end of gliding wild-type cells. Complementation with the recombinant wild-type P65 allele by transposon delivery restored P65 levels and stabilized P30 localization to the terminal organelle. PMID- 22544268 TI - Clostridium difficile MazF toxin exhibits selective, not global, mRNA cleavage. AB - Clostridium difficile is an important, emerging nosocomial pathogen. The transition from harmless colonization to disease is typically preceded by antimicrobial therapy, which alters the balance of the intestinal flora, enabling C. difficile to proliferate in the colon. One of the most perplexing aspects of the C. difficile infectious cycle is its ability to survive antimicrobial therapy and transition from inert colonization to active infection. Toxin-antitoxin (TA) systems have been implicated in facilitating persistence after antibiotic treatment. We identified only one TA system in C. difficile strain 630 (epidemic type X), designated MazE-cd and MazF-cd, a counterpart of the well-characterized Escherichia coli MazEF TA system. This E. coli MazF toxin cleaves mRNA at ACA sequences, leading to global mRNA degradation, growth arrest, and death. Likewise, MazF-cd expression in E. coli or Clostridium perfringens resulted in growth arrest. Primer extension analysis revealed that MazF-cd cleaved RNA at the five-base consensus sequence UACAU, suggesting that the mRNAs susceptible to cleavage comprise a subset of total mRNAs. In agreement, we observed differential cleavage of several mRNAs by MazF-cd in vivo, revealing a direct correlation between the number of cleavage recognition sites within a given transcript and its susceptibility to degradation by MazF-cd. Interestingly, upon detailed statistical analyses of the C. difficile transcriptome, the major C. difficile virulence factor toxin B (TcdB) and CwpV, a cell wall protein involved in aggregation, were predicted to be significantly resistant to MazF-cd cleavage. PMID- 22544270 TI - EbfC (YbaB) is a new type of bacterial nucleoid-associated protein and a global regulator of gene expression in the Lyme disease spirochete. AB - Nearly every known species of Eubacteria encodes a homolog of the Borrelia burgdorferi EbfC DNA-binding protein. We now demonstrate that fluorescently tagged EbfC associates with B. burgdorferi nucleoids in vivo and that chromatin immunoprecipitation (ChIP) of wild-type EbfC showed it to bind in vivo to sites throughout the genome, two hallmarks of nucleoid-associated proteins. Comparative RNA sequencing (RNA-Seq) of a mutant B. burgdorferi strain that overexpresses EbfC indicated that approximately 4.5% of borrelial genes are significantly impacted by EbfC. The ebfC gene was highly expressed in rapidly growing bacteria, but ebfC mRNA was undetectable in stationary phase. Combined with previous data showing that EbfC induces bends in DNA, these results demonstrate that EbfC is a nucleoid-associated protein and lead to the hypothesis that B. burgdorferi utilizes cellular fluctuations in EbfC levels to globally control transcription of numerous genes. The ubiquity of EbfC proteins in Eubacteria suggests that these results apply to a wide range of pathogens and other bacteria. PMID- 22544271 TI - Genetic, biochemical, and molecular characterization of the polypeptide transport associated domain of Escherichia coli BamA. AB - The BamA protein of Escherichia coli plays a central role in the assembly of beta barrel outer membrane proteins (OMPs). The C-terminal domain of BamA folds into an integral outer membrane beta-barrel, and the N terminus forms a periplasmic polypeptide transport-associated (POTRA) domain for OMP reception and assembly. We show here that BamA misfolding, caused by the deletion of the R44 residue from the alpha2 helix of the POTRA 1 domain (DeltaR44), can be overcome by the insertion of alanine 2 residues upstream or downstream from the DeltaR44 site. This highlights the importance of the side chain orientation of the alpha2 helix residues for normal POTRA 1 activity. The DeltaR44-mediated POTRA folding defect and its correction by the insertion of alanine were further demonstrated by using a construct expressing just the soluble POTRA domain. Besides misfolding, the expression of BamA(DeltaR44) from a low-copy-number plasmid confers a severe drug hypersensitivity phenotype. A spontaneous drug-resistant revertant of BamA(DeltaR44) was found to carry an A18S substitution in the alpha1 helix of POTRA 1. In the BamA(DeltaR44, A18S) background, OMP biogenesis improved dramatically, and this correlated with improved BamA folding, BamA-SurA interactions, and LptD (lipopolysaccharide transporter) biogenesis. The presence of the A18S substitution in the wild-type BamA protein did not affect the activity of BamA. The discovery of the A18S substitution in the alpha1 helix of the POTRA 1 domain as a suppressor of the folding defect caused by DeltaR44 underscores the importance of the helix 1 and 2 regions in BamA folding. PMID- 22544272 TI - In vivo and in vitro analyses of regulation of the pheromone-responsive prgQ promoter by the PrgX pheromone receptor protein. AB - Expression of conjugative transfer and virulence functions of the Enterococcus faecalis antibiotic resistance plasmid pCF10 is regulated by the interaction of the pheromone receptor protein PrgX with two DNA binding operator sites (XBS1 and XBS2) upstream from the transcription start site of the prgQ operon (encoding the pCF10 transfer machinery) and by posttranscriptional mechanisms. Occupancy of both binding sites by PrgX dimers results in repression of the prgQ promoter. Structural and genetic studies suggest that the peptide pheromone cCF10 functions by binding to PrgX and altering its oligomerization state, resulting in reduced occupancy of XBSs and increased prgQ transcription. The DNA binding activity of PrgX has additional indirect regulatory effects on prgQ transcript levels related to the position of the convergently transcribed prgX operon. This has complicated interpretation of previous analyses of the control of prgQ expression by PrgX. We report here the results of in vivo and in vitro experiments examining the direct effects of PrgX on transcription from the prgQ promoter, as well as quantitative correlation between the concentrations of XBSs, PrgX protein, and prgQ promoter activity in vivo. The results of electrophoretic mobility shift assays and quantitative analysis of prgQ transcription in vitro and in vivo support the predicted roles of the PrgX DNA binding sites in prgQ transcription regulation. The results also suggest the existence of other factors that impede PrgX repression or enhance its antagonism by cCF10 in vivo. PMID- 22544273 TI - Effects of the ERES pathogenicity region regulator Ralp3 on Streptococcus pyogenes serotype M49 virulence factor expression. AB - Streptococcus pyogenes (group A streptococcus [GAS]) is a highly virulent Gram positive bacterium. For successful infection, GAS expresses many virulence factors, which are clustered together with transcriptional regulators in distinct genomic regions. Ralp3 is a central regulator of the ERES region. In this study, we investigated the role of Ralp3 in GAS M49 pathogenesis. The inactivation of Ralp3 resulted in reduced attachment to and internalization into human keratinocytes. The Deltaralp3 mutant failed to survive in human blood and serum, and the hyaluronic acid capsule was slightly decreased. In addition, the mutant showed a lower binding capacity to human plasminogen, and the SpeB activity was significantly decreased. Complementation of the Deltaralp3 mutant restored the wild-type phenotype. The transcriptome and quantitative reverse transcription-PCR analysis of the serotype M49 GAS strain and its isogenic Deltaralp3 mutant identified 16 genes as upregulated, and 43 genes were found to be downregulated. Among the downregulated genes, there were open reading frames encoding proteins involved in metabolism (e.g., both lac operons and the fru operon), genes encoding lantibiotics (e.g., the putative salivaricin operon), and ORFs encoding virulence factors (such as the whole Mga core regulon and further genes under Mga control). In summary, the ERES region regulator Ralp3 is an important serotype specific transcriptional regulator for virulence and metabolic control. PMID- 22544276 TI - Electroluminescence based on thermally activated delayed fluorescence generated by a spirobifluorene donor-acceptor structure. AB - An organic light emitting diode based on thermally activated delayed fluorescence (TADF) has been produced using a spirobifluorene derivative (Spiro-CN) having the donor-acceptor moieties as an emitter. PMID- 22544274 TI - Escherichia coli DNA polymerase IV (Pol IV), but not Pol II, dynamically switches with a stalled Pol III* replicase. AB - The dnaN159 allele encodes a temperature-sensitive mutant form of the beta sliding clamp (beta159). SOS-induced levels of DNA polymerase IV (Pol IV) confer UV sensitivity upon the dnaN159 strain, while levels of Pol IV ~4-fold higher than those induced by the SOS response severely impede its growth. Here, we used mutations in Pol IV that disrupted specific interactions with the beta clamp to test our hypothesis that these phenotypes were the result of Pol IV gaining inappropriate access to the replication fork via a Pol III*-Pol IV switch relying on both the rim and cleft of the clamp. Our results clearly demonstrate that Pol IV relied on both the clamp rim and cleft interactions for these phenotypes. In contrast to the case for Pol IV, elevated levels of the other Pols, including Pol II, which was expressed at levels ~8-fold higher than the normal SOS-induced levels, failed to impede growth of the dnaN159 strain. These findings suggest that the mechanism used by Pol IV to switch with Pol III* is distinct from those used by the other Pols. Results of experiments utilizing purified components to reconstitute the Pol III*-Pol II switch in vitro indicated that Pol II switched equally well with both a stalled and an actively replicating Pol III* in a manner that was independent of the rim contact required by Pol IV. These results provide compelling support for the Pol III*-Pol IV two-step switch model and demonstrate important mechanistic differences in how Pol IV and Pol II switch with Pol III*. PMID- 22544275 TI - The Entner-Doudoroff pathway is obligatory for gluconate utilization and contributes to the pathogenicity of Vibrio cholerae. AB - The Entner-Doudoroff (ED) pathway has recently been shown to play an important role in sugar catabolism for many organisms although very little information is available on the functionality of this pathway in Vibrio cholerae, the causative agent of cholera. In this study, activation of the genes edd and eda, encoding 6 phosphogluconate dehydratase and 2-keto-3-deoxy-6-phosphogluconate aldolase, was used as a marker of a functional ED pathway in V. cholerae. Transcriptional activation analyses and gene silencing experiments with cells grown in sugar supplemented M9 medium demonstrated that the ED pathway is functional in V. cholerae and is obligatory for gluconate catabolism. Importantly, selective activation of the ED pathway led to concurrent elevation of transcripts of prime virulence genes (ctxA and tcpA) and their regulator (toxT). Further, lowering of these transcript levels and cholera toxin production in vitro by an ED pathway defective mutant (strain N16961 with a Deltaedd mutation [Deltaedd(N16961) strain]) suggested the importance of this pathway in regulating V. cholerae virulence. The in vivo relevance of these data was established as the mutant failed to colonize in suckling mice intestine or to induce fluid accumulation in ligated rabbit ileal loops. Activation of the ED pathway in V. cholerae was shown to inhibit biofilm formation in vitro that could be reversed in the mutant. As further support for these results, comparative transcriptome analysis with cells grown in the presence of glucose or gluconate revealed that a functional ED pathway led to activation of a subset of previously reported in vivo expressed genes. All of these results suggest the importance of the ED pathway in V. cholerae pathogenesis. PMID- 22544277 TI - The nitric oxide donor sodium nitroprusside requires the 18 kDa Translocator Protein to induce cell death. AB - Various studies have shown that several lethal agents induce cell death via the mitochondrial 18 kDa Translocator Protein (TSPO). In this study we tested the possibility that nitric oxide (NO) is the signaling component inducing the TSPO to initiate cell death process. Cell viability assays included Trypan blue uptake, propidium iodide uptake, lactate dehydrogenase release, and DNA fragmentation. These assays showed that application of the specific TSPO ligand PK 11195 reduced these parameters for the lethal effects of the NO donor sodium nitroprusside (SNP) by 41, 27, 40, and 42 %, respectively. TSPO silencing by siRNA also reduced the measured lethal effects of SNP by 50 % for all of these four assays. With 2,3-bis[2-methoxy-4-nitro-5-sulphophenyl]-2H-tetrazolium-5 carboxyanilide (XTT) changes in metabolic activity were detected. PK 11195 and TSPO knockdown fully prevented the reductions in XTT signal otherwise induced by SNP. Collapse of the mitochondrial membrane potential was studied with the aid of JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-benzimidazolylcarbocyanine chloride). PK 11195 and TSPO knockdown reduced, respectively by 36 and 100 %, the incidence of collapse of the mitochondrial membrane potential otherwise induced by SNP. 10-N-Nonyl-Acridine Orange (NAO) was used to detect mitochondrial reactive oxygen species generation due to SNP. PK 11195 and TSPO knockdown reduced this effect of SNP by 65 and 100 %, respectively. SNP did not affect TSPO protein expression and binding characteristics, and also did not cause TSPO S nitrosylation. However, beta-actin and various other proteins (not further defined) were S-nitrosylated. In conclusion, TSPO is required for the lethal and metabolic effects of the NO donor SNP, but TSPO itself is not S-nitrosylated. PMID- 22544278 TI - A reversible SCSC transformation from a blue metamagnetic framework to a pink antiferromagnetic ordering layer exhibiting concomitant solvatochromic and solvatomagnetic effects. AB - A [Co(6)(MU(3)-OH)(4)(datrz)(2)](6+) ribbon-based blue framework with a metamagnetic transition from an antiferromagnetic ordering to a weak spontaneous magnetization state, {[Co(3)(CH(3)OH)(MU(3)-OH)(2)(datrz)(sip)].2.25H(2)O}(n) (1, Hdatrz = 3,5-diamino-1,2,4-triazole, sip(3-) = 3,5-dicarboxybenzenesulfonate), was solvothermally synthesized. 1 exhibits a reversible single-crystal-to-single crystal transformation by solvent exchange to generate a pink antiferromagnetic ordering coordination layer with a similar [Co(6)(MU(3)-OH)(4)(datrz)(2)](6+) ribbon to 1, {[Co(3)(H(2)O)(3)(MU(3)-OH)(2)(datrz)(sip)].2.125H(2)O}(n) (2). Such concomitant solvatochromic and solvatomagnetic effects are scarcely observed and are significantly due to the coexistence of differently distorted metal coordination spheres and the cleavage/generation of the weak coordination bond. PMID- 22544280 TI - Flexible and mechanical strain resistant large area SERS active substrates. AB - We report a cost effective and facile way to synthesize flexible, uniform, and large area surface enhanced Raman scattering (SERS) substrates using an oblique angle deposition (OAD) technique. The flexible SERS substrates consist of 1 MUm long, tilted silver nanocolumnar films deposited on flexible polydimethylsiloxane (PDMS) and polyethylene terephthalate (PET) sheets using OAD. The SERS enhancement activity of these flexible substrates was determined using 10(-5) M trans-1,2-bis(4-pyridyl) ethylene (BPE) Raman probe molecules. The in situ SERS measurements on these flexible substrates under mechanical (tensile/bending) strain conditions were performed. Our results show that flexible SERS substrates can withstand a tensile strain (epsilon) value as high as 30% without losing SERS performance, whereas the similar bending strain decreases the SERS performance by about 13%. A cyclic tensile loading test on flexible PDMS SERS substrates at a pre-specified tensile strain (epsilon) value of 10% shows that the SERS intensity remains almost constant for more than 100 cycles. These disposable and flexible SERS substrates can be integrated with biological substances and offer a novel and practical method to facilitate biosensing applications. PMID- 22544279 TI - Esophageal hematoma after atrial fibrillation ablation: incidence, clinical features, and sequelae of esophageal injury of a different sort. AB - BACKGROUND: Esophageal hematoma recently has been reported as a form of esophageal injury after atrial fibrillation (AF) ablation, attributed to the use of transesophageal echocardiography (TEE). We sought to determine the incidence, clinical features, and sequelae of this form of esophageal injury. METHODS AND RESULTS: This was a prospective series of 1110 AF ablation procedures performed under general anesthesia (GA) over 9 years. TEE was inserted after induction of GA to exclude left atrial appendage thrombus, define cardiac function, and guide transseptal puncture. The procedural incidence of esophageal hematoma was 0.27% (3/1110 procedures, mortality 0%). Odonyphagia, regurgitation, and hoarseness were the predominant symptoms, with an onset within 12 hours. There was absence of fever and neurological symptoms. Chest computed tomography excluded atrio esophageal fistula and was diagnostic of esophageal hematoma localized to either the upper esophagus or extending the length of the mid and lower esophagus; endoscopy confirmed the diagnosis. Management was conservative in all cases comprising of ceasing oral intake and anticoagulation. Long term sequelae included esophageal stricture formation requiring dilatation, persistent esophageal dysmotility (mid esophageal hematoma), and vocal cord paralysis, resulting in hoarse voice (upper esophageal hematoma). CONCLUSIONS: Esophageal hematoma is a rare but important differential diagnosis for esophageal injury after TEE-guided AF ablation under GA, and can result in significant patient morbidity. Key clinical features differentiate presentation of esophageal hematoma from that of an atrio-esophageal fistula. PMID- 22544281 TI - Sym-(CH2X)5-corannulenes: molecular pentapods displaying functional group and bioconjugate appendages. AB - Pentapodal omega-functional derivatives of corannulene have been synthesized from sym-pentachlorocorannulene by iron-catalyzed aryl-alkyl cross coupling reactions. Click chemistry gives access to pentapods with bioconjugate appendages. PMID- 22544282 TI - Integrating role of T antigen, Rb2/p130, CTCF and BORIS in mediating non canonical endoplasmic reticulum-dependent death pathways triggered by chronic ER stress in mouse medulloblastoma. AB - Distinct molecular pathways could be constitutively active in mouse T-Antigen positive and T-Antigen negative medulloblastoma cell lines, contributing to their phenotypic differences as well as to cellular responses, cell cycle progression, cell death and survival. The diversity of these responses may be due, at least in part, to distinct activities of Rb2/p130, CTCF and BORIS proteins in response to an altered network of signaling evoked by the T-Ag presence. Here, we provided evidence supporting a role for the T-Antigen in causing chronic endoplasmic reticulum (ER) stress and aberrant Caspase-12 expression and activation, subsequently driving to both massive cell death, and perhaps selection of cells with a higher malignant phenotype. Furthermore, we observed that the endoplasmic stress, either chronically caused by T-Ag or transiently induced by glucose deprivation, is accompanied by the formation of complexes between the retinoblastoma related protein Rb2/p130 and the chromatin insulator CCCTC-binding factor CTCF, or the CTCF-paralogue BORIS. Our study represents the first evidence supporting a role of the T-Antigen in inducing/maintaining chronic ER-stress, as well as, indicating a role of Rb2/p130, CTCF and BORIS as potential mediators of non-canonical ER-dependent death pathway in mouse medulloblastoma. PMID- 22544283 TI - Photobiology of sea ice algae during initial spring growth in Kangerlussuaq, West Greenland: insights from imaging variable chlorophyll fluorescence of ice cores. AB - We undertook a series of measurements of photophysiological parameters of sea ice algae over 12 days of early spring growth in a West Greenland Fjord, by variable chlorophyll fluorescence imaging. Imaging of the ice-water interface showed the development of ice algae in 0.3-0.4 mm wide brine channels between laminar ice crystals in the lower 4-6 mm of the ice, with a several-fold spatial variation in inferred biomass on cm scales. The maximum quantum yield of photosynthesis, F(v) /F(m), was initially low (~0.1), though this increased rapidly to ~0.5 by day 6. Day 6 also saw the onset of biomass increase, the cessation of ice growth and the time at which brine had reached <50 psu and >-2 degrees C. We interpret this as indicating that the establishment of stable brine channels at close to ambient salinity was required to trigger photosynthetically active populations. Maximum relative electron transport rate (rETR(max)), saturation irradiance (E(k)) and photosynthetic efficiency (alpha) had also stabilised by day 6 at 5-6 relative units, ~30 MUmol photons m-2 s-1 and 0.4-0.5 MUmol photons m-2s-1, respectively. E(k) was consistent with under-ice irradiance, which peaked at a similar value, confirming that daytime irradiance was adequate to facilitate photosynthetic activity throughout the study period. Photosynthetic parameters showed no substantial differences with depth within the ice, nor variation between cores or brine channels suggesting that during this early phase of ice algal growth cells were unaffected by gradients of environmental conditions within the ice. Variable chlorophyll fluorescence imaging offers a tool to determine how this situation may change over time and as brine channels and algal populations evolve. PMID- 22544284 TI - Pediatric noncontiguous spinal injuries: the 15-year experience at a level 1 trauma center. AB - STUDY DESIGN: Retrospective review. OBJECTIVE: To determine the incidence and clinical characteristics of noncontiguous spinal injuries (NCSI) in a pediatric population. The secondary objective is to identify high-risk patients requiring further imaging to rule out NCSI. SUMMARY OF BACKGROUND DATA: NCSI can add significant complexity to the diagnosis, management, and outcome of children. There is very little in the pediatric literature examining the nature, associated risk factors, management, and outcomes of NCSI. METHODS: All children up to 18 years of age with a spinal injury, as defined by International Classification of Diseases, Ninth Revision codes, at one pediatric trauma hospital were included (n = 211). Data for patient demographics, mechanism of injury, spinal levels involved, extent of neurological injury and recovery, associated injuries, medical complications, treatment, and outcome were recorded. RESULTS: Twenty-five (11.8%) of 211 patients had NCSI, with a median age of 13.0 years (interquartile range = 8-15). The most common pattern of injury was a double thoracic noncontiguous injury. Sixteen percent of the cases of NCSI were initially missed, with no clinical deterioration due to missed diagnosis. Associated injuries occurred in 44% of patients with NCSI. Twenty-four percent of patients with multiple NCSI had a neurological injury compared with 9.7% in patients with single-level or contiguous injuries (P = 0.046). CONCLUSION: There is a high incidence of children with multiple NCSI who are more likely to experience neurological injuries compared with patients with single-level or contiguous spinal injuries. Patients with a single-level spinal injury on existing imaging with an associated neurological injury should undergo at least plain films of the entire spine to exclude noncontiguous injuries. In patients without neurological injury and a single spinal fracture, radiography showing at least 4 levels above and below the fracture should be performed. All children with spinal injury should have associated injuries carefully excluded. PMID- 22544286 TI - Selective processes in development: implications for the costs and benefits of phenotypic plasticity. AB - Adaptive phenotypic plasticity, the ability of a genotype to develop a phenotype appropriate to the local environment, allows organisms to cope with environmental variation and has implications for predicting how organisms will respond to rapid, human-induced environmental change. This review focuses on the importance of developmental selection, broadly defined as a developmental process that involves the sampling of a range of phenotypes and feedback from the environment reinforcing high-performing phenotypes. I hypothesize that understanding the degree to which developmental selection underlies plasticity is key to predicting the costs, benefits, and consequences of plasticity. First, I review examples that illustrate that elements of developmental selection are common across the development of many different traits, from physiology and immunity to circulation and behavior. Second, I argue that developmental selection, relative to a fixed strategy or determinate (switch) mechanisms of plasticity, increases the probability that an individual will develop a phenotype best matched to the local environment. However, the exploration and environmental feedback associated with developmental selection is costly in terms of time, energy, and predation risk, resulting in major changes in life history such as increased duration of development and greater investment in individual offspring. Third, I discuss implications of developmental selection as a mechanism of plasticity, from predicting adaptive responses to novel environments to understanding conditions under which genetic assimilation may fuel diversification. Finally, I outline exciting areas of future research, in particular exploring costs of selective processes in the development of traits outside of behavior and modeling developmental selection and evolution in novel environments. PMID- 22544287 TI - Assessing the impacts of phenotypic plasticity on evolution. AB - In the past decade, there has been a resurgent interest in whether and how phenotypic plasticity might impact evolutionary processes. Of fundamental importance is how the environment influences individual phenotypic development while simultaneously selecting among phenotypic variants in a population. Conceptual and theoretical treatments of the evolutionary implications of plasticity are numerous, as are criticisms of the conclusions. As such, the time is ripe for empirical evidence to catch up with theoretical predictions. To this end, I provide a summary of eight hypotheses at the core of this issue, highlighting various approaches by which they can be tested. My goal is to provide practical guidance to those seeking to understand the complex ways by which phenotypic plasticity can influence evolutionary innovation and diversification. PMID- 22544288 TI - Establishing developmental genetics in a self-fertilizing fish (Krytolebias marmoratus). AB - Kryptolebias marmoratus is a synchronous hermaphroditic vertebrate that utilizes an ovotestis for reproduction. This fish develops externally, is easy to maintain, and has about a 100-day life cycle, making it a desirable developmental genetic model organism. Here, we present a pilot zygotic mutant screen utilizing the common chemical mutagen, N-ethyl-N-nitrosourea (ENU) to establish genetics in this model species. Selection of clonal stocks and optimal conditions for mutagenizing this fish are presented and the types and frequencies of zygotic mutants are documented in comparison to other fish models. Kryptolebias marmoratus is an exemplar model organism that will complement future developmental genetic screens in vertebrates. PMID- 22544291 TI - Standardising measurement of tumour vascularity by imaging: recommendations for ultrasound, computed tomography, magnetic resonance imaging and positron emission tomography. AB - This review analyses the need for, and likely impact of, four subsequent papers which discuss the importance of standardisation of ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) when assessing tumour vascularity. This is particularly important when measuring the vascular effects of therapeutic agents in oncological research and practice. As imaging inexorably moves from the subjective interpretative art-form of the past into its modern role as a fully fledged objective scientific discipline, it is incumbent on all radiologists to understand the need for strict adherence to perceived best practice when evaluating lesions as part of trials. Indeed trials may only be funded by pharmaceutical companies and other grant-giving bodies if rigorous adherence to imaging protocols and quality assurance is in place. Key Points * Various imaging methods can now robustly assess tumour vascular support. * US, CT, MRI and PET are increasingly used to assess tumour vascularity. * These techniques have reached technical maturity for use in therapeutic oncological trials. * Consensus guidelines about using these techniques in assessing tumour vascularity are introduced. * Image acquisition protocols and quality assurance must be established for large trials. PMID- 22544290 TI - The quality of supportive care among inpatients dying with advanced cancer. AB - PURPOSE: Managing symptoms and communicating effectively are essential aspects of providing high-quality cancer care, especially among patients with advanced cancer. The purpose of this study is to apply novel quality indicators to measure the quality of supportive care provided to patients with advanced cancer who died in a large university medical center. METHODS: Cancer quality ASSIST is a comprehensive quality indicator (QI) set that includes 92 symptom and care planning indicators, of which we piloted 15 applicable to persons with advanced cancer who died in the hospital setting. We evaluated medical records of all adult terminal hospitalizations with lengths of stay >=3 days at one university medical center between April 2005 and April 2006. RESULTS: Of 496 decedents, 118 had advanced cancer (mean age 60, 54% male). Forty-five percent received chemotherapy or radiation in the month prior to or during admission. During the hospitalization, 56% of the patients spent time in the ICU (median length of stay 8 days), one in five received first-time hemodialysis, and 23% had a ventilator withdrawn anticipating death. The 118 patients triggered 596 quality indicators of which 476 passed (QI level pass rate 80%, range 50-100%). Pain assessment and management were consistently performed; however, other cancer supportive care needed improvement: 26% of patients not receiving cancer therapy who had nausea and vomiting received inadequate follow-up, more than one quarter of patients with dyspnea had this symptom inadequately addressed, and 29% of patients taking long-acting opioids were not prescribed a bowel regimen. Timely discussion of patient preferences upon admission to the ICU or initiation of mechanical ventilation occurred in 64 and 69% of cases, respectively. CONCLUSIONS: This set of quality indicators can evaluate the quality of supportive and end-of-life care provided to inpatients dying with advanced cancer and identify aspects of care that need improvement. PMID- 22544292 TI - Diagnostic performance of whole-body MRI for the detection of persistent or relapsing disease in multiple myeloma after stem cell transplantation. AB - OBJECTIVES: To compare the diagnostic performance of whole-body MRI (WBMRI) with haematological parameters for detecting persistent or relapsing disease in patients with multiple myeloma after stem cell transplantation. METHODS: Sixty six WBMRI acquisitions were performed in 33 patients with multiple myeloma at two time points after stem cell transplantation. Extent of disease and inter-test dynamics of intra- and extramedullary myeloma manifestations were compared (kappa statistics) with Uniform Response Criteria, comprising haematological parameters. RESULTS: Using data from 66 sequential WBMRI acquisitions in 33 patients, 10 patients (30.3 %) were classified as having progressive disease and 23 (69.7 %) as being in remission. Eight (80 %) of the ten patients with progressive disease revealed intramedullary lesions, and two patients (20 %) had intra- and extramedullary lesions. WBMRI and laboratory tests were concordant in 26/33 (78.8 %) patients. We found an agreement of 51.2 %, 95 % confidence interval 19.8 % 82.6 %, between results from WBMRI and haematological parameters. WBMRI had a sensitivity of 63.6 %, specificity of 86.4 %, PPV of 70.0 %, NPV of 82.6 % and accuracy of 78.8 % for detection of remission. CONCLUSIONS: WBMRI allows the detection and exact localisation of intra- and extramedullary myeloma manifestations after stem cell transplantation, but shows only moderate agreement with routinely performed laboratory tests for determination of remission. PMID- 22544293 TI - Axial T2 mapping in intervertebral discs: a new technique for assessment of intervertebral disc degeneration. AB - OBJECTIVES: To demonstrate the potential benefits of biochemical axial T2 mapping of intervertebral discs (IVDs) regarding the detection and grading of early stages of degenerative disc disease using 1.5-Tesla magnetic resonance imaging (MRI) in a clinical setting. METHODS: Ninety-three patients suffering from lumbar spine problems were examined using standard MRI protocols including an axial T2 mapping protocol. All discs were classified morphologically and grouped as "healthy" or "abnormal". Differences between groups were analysed regarding to the specific T2 pattern at different regions of interest (ROIs). RESULTS: Healthy intervertebral discs revealed a distinct cross-sectional T2 value profile: T2 values were significantly lower in the annulus fibrosus compared with the nucleus pulposus (P = 0.01). In abnormal IVDs, T2 values were significantly lower, especially towards the centre of the disc representing the expected decreased water content of the nucleus (P = 0.01). In herniated discs, ROIs within the nucleus pulposus and ROIs covering the annulus fibrosus showed decreased T2 values. CONCLUSIONS: Axial T2 mapping is effective to detect early stages of degenerative disc disease. There is a potential benefit of axial T2 mapping as a diagnostic tool, allowing the quantitative assessment of intervertebral disc degeneration. PMID- 22544294 TI - Percutaneous embolization of persistent low-output enterocutaneous fistulas. AB - OBJECTIVES: To present and retrospectively evaluate the technique of percutaneous embolization of chronic enterocutaneous fistulas (ECFs) using n-butyl-2 cyanoacrylate and Lipiodol under fluoroscopic guidance. METHODS: Six patients with a total of seven post-operative low-output ECFs of the large intestine were treated. After fistulography a hydrophilic guide wire and a catheter were advanced through the ECF into the intestine. After dilation of the bowel with saline and contrast medium, the catheter was withdrawn into the enteric orifice and glue together with Lipiodol was injected while simultaneously pulling the catheter. RESULTS: Complete closure of all seven fistulas was achieved. There were no peri-procedural complications. In one patient 1 month following embolization a low-output enteric discharge was observed, but the ECF spontaneously healed 5 days later. In one patient 18 months after the embolization a new perforation due to diverticulitis close to the embolization site occurred and resection of the sigmoid colon was performed. One patient needed reoperation due to a recurrence of rectal carcinoma. CONCLUSIONS: In our series of patients, the presented technique of percutaneous embolization proved to be efficacious and easy to perform. It may have potential as a first-line treatment of low-output ECFs but a prospective study with a larger series of patients and a longer follow-up is required. PMID- 22544295 TI - High accuracy of mesoscopic epi-fluorescence tomography for non-invasive quantitative volume determination of fluorescent protein-expressing tumours in mice. AB - OBJECTIVES: To compare mesoscopic epi-fluorescence tomography (MEFT) and EPRI illumination reflectance imaging (EPRI) for quantitative tumour size assessment in mice. METHODS: Tumour xenografts of green/red fluorescent protein (GFP/RFP) expressing colon cancer cells were measured using MEFT, EPRI, ultrasound (US) and micro computed tomography (MUCT) at day 14 post-injection (n = 6). Results from MEFT and EPRI were correlated with each other and with US and MUCT (reference methods). Tumour volumes were measured ex vivo by GFP and RFP fluorescence imaging on cryoslices and compared with the in vivo measurements. RESULTS: High correlation and congruency were observed between MEFT, US and MUCT (MEFT/US: GFP: r (2) = 0.96; RFP: r (2) = 0.97, both P < 0.05; MEFT/MUCT: GFP: r (2) = 0.93; RFP: r (2) = 0.90; both P < 0.05). Additionally, in vivo MEFT data were highly correlated and congruent with ex vivo cryoslice imaging results (GFP: r (2) = 0.96; RFP: r (2) = 0.99; both P < 0.05). In comparison, EPRI significantly overestimated tumour volumes (P < 0.05), although there was a significant correlation with US and MUCT (EPRI/US: GFP: r (2) = 0.95; RFP: r (2) = 0.94; both P < 0.05; EPRI/MUCT GFP: r (2) = 0.86; RFP: r (2) = 0.86; both P < 0.05). CONCLUSIONS: Fluorescence distribution reconstruction using MEFT affords highly accurate three-dimensional (3D) tumour volume data showing superior accuracy compared to EPRI. Thus, MEFT is a very suitable technique for quantitatively assessing fluorescence distribution in superficial tumours at high spatial resolution. PMID- 22544296 TI - Prevalence, utilization, and costs of antiepileptic drugs for epilepsy in Germany -a nationwide population-based study in children and adults. AB - Nationwide analyses of drug use can provide a prevalence estimate of the underlying disease and can help in understanding the characteristics of treatment. This study aimed for such analyses regarding the utilization of antiepileptic drugs (AED) for epilepsy in Germany. In 2009, all 4,115,705 AED prescriptions of all German patients with statutory health insurance (70,011,508 persons) were retrospectively analyzed. The IMS((r)) LRx database served as data source, which accesses nationwide pharmacy data centers processing all German prescription data. To establish the age and sex-specific percentage of patients taking AED because of epilepsy, we used a second database, Disease Analyzer((r)), which covered a representative sample of the German population (7.2 million patients) and contained ICD10 codes alongside with prescription data. The period prevalence of patients taking AED because of epilepsy was 9.1/1,000 (children/adolescents: 5.2/1,000; elderly: 12.5/1,000). Of the patients, 83.1 % took at least one of four AED: valproate (29.8 %), carbamazepine (26.4 %), lamotrigine (21.4 %), and levetiracetam (16.9 %). Oxcarbazepine and sultiame were popular with pediatricians. Elderly patients frequently received phenytoin and primidone. More than half of the patients were treated by family physicians; 68 % took AED in monotherapy and 7.9 % received >2 AED (children/adolescents: 12.5 %). The costs for AED prescribed for epilepsy amounted to ?285.1 Mio (median AED costs/patient: ?158/a). The German 2009 prevalence of epileptic patients taking AED was 9.1/1,000. Family physicians cared for the majority of patients. Prevalence and prescribing patterns changed with age. Costs of AED against epilepsy added up to 1 % of total medication costs in Germany. PMID- 22544297 TI - Permanent muscular sodium overload and persistent muscle edema in Duchenne muscular dystrophy: a possible contributor of progressive muscle degeneration. AB - To assess the presence and persistence of muscular edema and increased myoplasmic sodium (Na(+)) concentration in Duchenne muscular dystrophy (DMD). We examined eight DMD patients (mean age 9.5 +/- 5.4 years) and eight volunteers (mean age 9.5 +/- 3.2 years) with 3-tesla proton ((1)H) and (23)Na density-adapted 3D radial MR sequences. Seven DMD patients were re-examined about 7 months later without change of therapy. The eighth DMD patient was re-examined after 5 and 11 months under medication with eplerenone. We quantified muscle edema on STIR images with background noise as reference and fatty degeneration on T1-weighted images using subcutaneous fat as reference. Na(+) was quantified by a muscular tissue Na(+) concentration (TSC) sequence employing a reference containing 51.3 mM Na(+) with 5 % agarose. With an inversion-recovery (IR) sequence, we determined mainly the myoplasmic Na(+). The normalized muscular (23)Na IR signal intensity was higher in DMD than in volunteers (n = 8, 0.75 +/- 0.07 vs. 0.50 +/- 0.05, p < 0.001) and persisted at second measurement (n = 7, 1st 0.75 +/- 0.07, 2nd 0.73 +/- 0.06, p = 0.50). When compared to volunteers (25.6 +/- 2.0 mmol/l), TSC was markedly increased in DMD (38.0 +/- 5.9 mmol/l, p < 0.001) and remained constant (n = 7, 1st 37.9 +/- 6.4 mmol/l, 2nd 37.0 +/- 4.0 mmol/l, p = 0.49). Muscular edema (15.6 +/- 3.5 vs. 6.9 +/- 0.7, p < 0.001) and fat content (0.48 +/ 0.08 vs. 0.38 +/- 0.01, p = 0.003) were elevated in DMD when compared to volunteers. This could also be confirmed during follow-up (n = 7, p = 0.91, p = 0.12). Eplerenone slightly improved muscle strength and reduced muscular sodium and edema. The permanent muscular Na(+) overload in all DMD patients is likely osmotically relevant and responsible for the persisting, mainly intracellular muscle edema that may contribute to the progressive muscle degeneration. PMID- 22544298 TI - The plantar reflex: additional value of stroking the lateral border of the foot to provoke an upgoing toe sign and the influence of experience. AB - The aim of this work was to determine the value of stroking the lateral dorsal border of the foot, in addition to stroking the sole in patients with a suspected pyramidal tract lesion. In addition, we studied the differences in interpretation between neurologists, residents, and medical students. We included subjects who had weakness of at least one leg and in whom a pyramidal tract lesion was suspected. After testing muscle power, tone, reflexes, and foot tapping, a decision on the presence of a pyramidal syndrome had to be made by each observer. After stimulating the sole as well as the lateral border of the foot, observers made a decision about the presence of a pyramidal syndrome again. Twenty-two legs of 18 patients were examined. Testing the plantar reflex (according to both methods) led to a change of opinion on the presence of a pyramidal syndrome in 45 of 69 (65 %) observations. On analysis according to level of experience, a change of opinion occurred in 19 (86 %) observations by medical students, 15 (65 %) by residents, and 11 (46 %) by neurologists. On eight occasions, the change was prompted by stimulation of the lateral border; in five of these cases the examiner (three medical students and two residents) found a new pathological response. Consecutively stroking the sole and the lateral border may be of added value, especially for less-experienced physicians. It seems that more-experienced physicians need fewer tests in the physical examination in order to identify a pyramidal syndrome of the leg. PMID- 22544299 TI - The biopharmaceutical industry in China: history and future perspectives. AB - Biopharmaceuticals reflect the rapid progress achieved in modern biomedical research. This area has also become one of the main criteria for assessing the development level of biotechnology for a particular country. Although it has been only three decades since the first biopharmaceutical, recombinant human insulin, was licensed by the US Food and Drug Administration, the biopharmaceutical industry has become the fastest growing, most dynamic and technology-intensive sector in the biomedical field. Since the licensing of recombinant human interferon alpha1b in 1989, the biopharmaceutical industry in China has gone through initial developments and gradually entered a period of rapid growth. This paper provides an overview of the status and development trends of biopharmaceuticals in China, and compares them with those observed in developed countries. PMID- 22544301 TI - Cor triatriatum sinister versus bowed septum primum in an infant with total anomalous pulmonary venous connection: a difficult imaging distinction. AB - In cor triatriatum sinister, a membrane divides the left atrium into a posterior chamber that receives the pulmonary veins and an anterior chamber that communicates with the mitral valve. With right-side chamber overload, the septum primum can separate from the muscular septum and bow toward the left atrial cavity, leading to a thin membrane within the left atrium and imaging findings that may mimic cor triatriatum. We report the multidetector CT findings of a 3 month-old infant with a supracardiac total anomalous pulmonary venous connection with a bowed septum primum. A description of the imaging findings that distinguish cor triatriatum and bowed septum primum will be discussed. This case demonstrates the usefulness of MDCT in the assessment of supracardiac vascular anomalies and intracardiac anatomy. PMID- 22544302 TI - Barriers and traps: great apes' performance in two functionally equivalent tasks. AB - Tool-using tasks that require subjects to overcome the obstacles to get a reward have been a major component of research investigating causal knowledge in primates. Much of the debate in this research has focused on whether subjects simply use certain stimulus features or instead use more functionally relevant information regarding the effect that certain features may have on a moving reward. Here, we presented two obstacle tasks, a trap platform and a barrier platform, to 22 great apes. Although perceptually similar, these two tasks contain two perceptually different but functionally equivalent obstacles: a trap and a barrier. In a pre-exposure phase, subjects either experienced an obstacle task or a task without any obstacle. In the transfer phase, all subjects were presented with an obstacle task, either the trap platform or the barrier platform. Our results show that those subjects who received an obstacle task prior to the second task performed better than those who first received a non obstacle task. The type of obstacle task that subjects received first did not have any effect on their performance in the transfer phase. We suggest that apes possess some knowledge about the effects that obstacles have on slow-moving unsupported objects. PMID- 22544303 TI - Are temporal features crucial acoustic cues in dog vocal recognition? AB - To investigate the perceptual mechanisms underlying conspecific vocal recognition in canine species, eighteen dogs were presented with playbacks of normal and reversed versions of typical dog vocalizations. Auditory perception was analysed using the head-turn paradigm, a non-invasive technique extensively employed to study hemispheric specializations for processing conspecific vocalizations in primates. The results revealed that dogs usually turn their heads with the right ear leading (left hemisphere activation) in response to the forward version of their typical calls, and with either no bias and the left ear leading (right hemisphere activation) in response to the reversed call versions. Overall, our findings suggest that temporal features are determinant auditory cues for call sound recognition in dogs, and support earlier findings of the role of the left hemisphere in the analyses of intraspecific communication. PMID- 22544304 TI - Sexual infidelity in China: prevalence and gender-specific correlates. AB - The nature of extra-relational sex in societies with rapidly changing sexual mores and widespread commercial sex remains under-explored. The 2006 Sexuality Survey of China provides a national probability survey with data on 3,567 people 18-49 years old who were in a marital (89%) or dating/cohabiting (11%) relationship. In attitudes, extramarital sex was completely unacceptable to 74% of women and 60% of men and either somewhat or completely unacceptable to 95% of women and men. Most (77%) women wanted severe punishment of men's short-term commercial sex and women's jealousy was equally elevated by their primary partner's episodes of commercial and non-commercial sex. Nevertheless, the prevalence of infidelity during the last 12 months was 4.5% (women's non commercial sex), 11.0% (men's non-commercial), and 5.5% (men's commercial), with each percent matching or exceeding the median for other countries. In multivariate equations for non-commercial infidelity, men's infidelity was significantly more responsive to sexual dissatisfaction with his primary partner while women's was more responsive to deficits in love. In commercial sex, men were uninfluenced by primary partner deficits in love, sexual satisfaction or oral sex-pursuing, it would seem, simply a greater variety of sexual partners. In a "trading up" pattern, women partnered with low income men had elevated infidelity. The minority of women reporting early masturbation and premarital sex were just as likely as men with these backgrounds to have elevated infidelity. The Chinese patterns provide ample material for deliberations on gender similarities and differences in extra-relational sex. PMID- 22544305 TI - Love 2.0: a quantitative exploration of sex and relationships in the virtual world Second Life. AB - This study presents the quantitative results of a web-based survey exploring the experiences of those who seek sex and relationships in the virtual world of Second Life. The survey gathered data on demographics, relationships, and sexual behaviors from 235 Second Life residents to compare with U.S. General Social Survey data on Internet users and the general population. The Second Life survey also gathered data on interests in and experiences with a number of sexual practices in both offline and online environments. Comparative analysis found that survey participants were significantly older, more educated, and less religious than a wider group of Internet users, and in certain age groups were far less likely to be married or have children. Motivations for engaging in cybersex were presented. Analysis of interest and experience of different sexual practices supported findings by other researchers that online environments facilitated access, but also indicated that interest in certain sexual practices could differ between offline and online environments. PMID- 22544306 TI - Women's rape fantasies: an empirical evaluation of the major explanations. AB - This study evaluated explanations of rape fantasy in a sample of female undergraduates (N = 355) using a sexual fantasy checklist which included eight types of rape fantasy, participants' detailed descriptions of a rape fantasy they have had, a rape fantasy scenario audio presentation, and measures of personality. Three explanations of rape fantasy were tested: openness to sexual experience, sexual desirability, and sexual blame avoidance. Women who were higher in erotophilia and self-esteem and who had more frequent consensual sexual fantasies and more frequent desirability fantasies, particularly of performing as a stripper, had more frequent rape fantasies. Women who were higher in erotophilia, openness to fantasy, desirability fantasies, and self-esteem reported greater sexual arousal to rape fantasies. Sexual blame avoidance theory was not supported; sexual desirability theory was moderately supported; openness to sexual experience theory received the strongest support. PMID- 22544307 TI - PTPIP51 in protein interactions: regulation and in situ interacting partners. AB - This study investigated the regulation of 14-3-3beta binding to PTPIP51 by the tyrosine phosphorylation status of PTPIP51. The tyrosine 176 residue is phosphorylated by c-Src. Up to now, nothing is known about the impact of such well-established phosphorylation events on the interaction profile of PTPIP51 with its partners of the mitogen-activated protein kinase (MAPK) pathway. In human keratinocytes the PTPIP51 phosphorylation was varied by inhibiting the phosphatase activity, thus enhancing the phosphorylation of PTPIP51. Differential blocking of Src kinase family members (despite c-Src) by PP2 increased the activity of c-Src and the tyrosine phosphorylation of PTPIP51 at position 176, which is the substrate of c-Src kinase. The amount of PTPIP51 interactions with 14-3-3beta, Raf-1, PTP1B and c-Src was evaluated and the resulting data were compared to an untreated control group. The increased phosphorylation level resulted in a sharp drop of the 14-3-3beta/PTPIP51 and 14-3-3beta/Raf-1 interaction. Besides the 14-3-3 interaction of PTPIP51, the interaction with the two MAPK modulators, protein kinase A (PKA) and diacylglycerol kinase alpha (DAGKalpha), are also regulated by the tyrosine phosphorylation status of PTPIP51. Additional immunostaining experiments were done investigating the functional implication on these interactions of the phosphorylation in apoptotic processes. In the pervanadate- and PP2-treated HaCaT cells, higher amounts of apoptotic cells were not detected as compared to the control group. The presented data confirms a tyrosine phosphorylation-dependent interaction of PTPIP51 with 14 3-3beta and Raf-1 in vivo and a tyrosine-dependent interaction profile with DAGKalpha and PKA. The non-interaction of PTPIP51 with 14-3-3 is not sufficient for triggering apoptosis. PMID- 22544308 TI - Decline of the new Swedish variant of Chlamydia trachomatis after introduction of appropriate testing. AB - OBJECTIVE: The longitudinal epidemiological development of the new variant of Chlamydia trachomatis was studied after appropriate testing procedures had been introduced when the strain was detected in 2006. METHODS: The number of cases of the new variant of C trachomatis was followed from 2007 through 2011 from the laboratory records. Testing for C trachomatis is centralised to one laboratory with around 80-85 000 persons being tested annually in a population of 1.1 million. RESULTS: During the 5-year period, 410 973 patients were tested of which 25 723 cases were positive. The proportion of the new variant of all positive cases declined from 30% in 2007 to 6% in 2011. While the number of the new variant of C trachomatis declined, the ordinary wild-type strains remained largely unchanged. CONCLUSIONS: A selective decline of the new variant of C trachomatis has occurred after appropriate laboratory testing was introduced. A new balance point between 5% and 10% for the new variant seems to be gradually approached. PMID- 22544309 TI - Evaluation of PIMA point-of-care CD4 testing in a large UK HIV service. AB - OBJECTIVES: To evaluate the performance and patient acceptability of the PIMA point-of-care (POCT) CD4 test. METHODS: Parallel POCT and laboratory CD4 testing were performed in newly diagnosed HIV patients and those with chronic infection attending routine or emergency clinics. Demographics, clinical status and time taken for CD4 results to be available were recorded. Patient acceptability was assessed using a five-point Likert scale. POCT and laboratory results were compared. RESULTS: 283 patients underwent POCT and laboratory CD4 testing. Paired laboratory and POCT results were available in 269 patients. After excluding 15 patients tested during the lead-in period, the test comparison was based on 254 results. Most patients were asymptomatic, male and white British reflecting this patient cohort. 236 patients were chronically infected and 47 were newly diagnosed HIV positive. The POCT result was available within 30 min (86%). The laboratory and POCT results were strongly correlated, r=0.93 (p<0.001), but were generally lower for the POCT (201/254 (79%): p<0.001). As a percentage of the laboratory count, the median (95% range) POCT was 87% (57%-126%). The difference between the POCT and laboratory result was greater for those patients attending the emergency clinic. The sensitivity and specificity of the POCT, to identify patients with laboratory CD4 below 350, were 95% (95% CI 88% to 98%) and 88% (95% CI 82% to 93%), respectively. 235 (83%) patients completed the questionnaire and the POCT was highly acceptable. CONCLUSIONS: POCT CD4 was highly correlated with laboratory CD4 testing in this cohort, provided immediate results and was highly acceptable to patients. PMID- 22544310 TI - Distinct roles for direct and indirect pathway striatal neurons in reinforcement. AB - Dopamine signaling is implicated in reinforcement learning, but the neural substrates targeted by dopamine are poorly understood. We bypassed dopamine signaling itself and tested how optogenetic activation of dopamine D1 or D2 receptor-expressing striatal projection neurons influenced reinforcement learning in mice. Stimulating D1 receptor-expressing neurons induced persistent reinforcement, whereas stimulating D2 receptor-expressing neurons induced transient punishment, indicating that activation of these circuits is sufficient to modify the probability of performing future actions. PMID- 22544312 TI - Calbindin controls release probability in ventral tegmental area dopamine neurons. AB - Relatively little is known about the molecular control of midbrain dopamine release. Using high-fidelity imaging of pHluorin-tagged vesicular monoamine transporter 2 in dopamine neurons, we found that exocytosis was more loosely coupled to calcium entry than in fast synapses. In ventral tegmental area neurons, this allows exocytosis to be efficiently controlled by a native fast calcium buffer, calbindin-D28k, maintaining a lower vesicular release probability compared with substantia nigra neurons. PMID- 22544311 TI - Adolescent impulsivity phenotypes characterized by distinct brain networks. AB - The impulsive behavior that is often characteristic of adolescence may reflect underlying neurodevelopmental processes. Moreover, impulsivity is a multi dimensional construct, and it is plausible that distinct brain networks contribute to its different cognitive, clinical and behavioral aspects. As these networks have not yet been described, we identified distinct cortical and subcortical networks underlying successful inhibitions and inhibition failures in a large sample (n = 1,896) of 14-year-old adolescents. Different networks were associated with drug use (n = 1,593) and attention-deficit hyperactivity disorder symptoms (n = 342). Hypofunctioning of a specific orbitofrontal cortical network was associated with likelihood of initiating drug use in early adolescence. Right inferior frontal activity was related to the speed of the inhibition process (n = 826) and use of illegal substances and associated with genetic variation in a norepinephrine transporter gene (n = 819). Our results indicate that both neural endophenotypes and genetic variation give rise to the various manifestations of impulsive behavior. PMID- 22544313 TI - Visual neurotransmission in Drosophila requires expression of Fic in glial capitate projections. AB - Fic domains can catalyze the addition of adenosine monophosphate to target proteins. To date, the function of Fic domain proteins in eukaryotic physiology remains unknown. We generated genetic models of the single Drosophila Fic domain containing protein, Fic. Flies lacking Fic were viable and fertile, but blind. Photoreceptor cells depolarized normally following light stimulation, but failed to activate postsynaptic neurons, as indicated by the loss of ON transients in electroretinograms, consistent with a neurotransmission defect. Functional rescue of neurotransmission required expression of enzymatically active Fic on capitate projections of glia cells, but not neurons, supporting a role in the recycling of the visual neurotransmitter histamine. Histamine levels were reduced in the lamina of Fic null flies, and dietary histamine partially restored ON transients. These findings establish a previously unknown regulatory mechanism in visual neurotransmission and provide, to the best of our knowledge, the first evidence for a role of glial capitate projections in neurotransmitter recycling. PMID- 22544314 TI - Endocrine cells in human fetal corpus of stomach: appearance, distribution, and density. AB - BACKGROUND: Since reports on endocrine cells and their kinetics in the corpus of the human stomach are limited, the aim of this study was to examine the appearance, localization, density, and the relationship among the endocrine cell types in the corpus of the human stomach during prenatal and early postnatal development. METHODS: We examined chromogranin A, somatostatin, ghrelin, glucagon, and serotonin expression by immunohistochemistry in 2 embryos, 38 fetuses, and 3 infants in the corpus of human stomach. RESULTS: Chromogranin A secreting endocrine cells were identified in the corpus at week 10 of gestation. Somatostatin cells were present from the 10th week, ghrelin and serotonin cells from the 11th week, and glucagon cells from the 12th week of gestation. Endocrine cells were present individually or clustered within the glandular base and body during the first trimester, and were present separately within the basal and central parts of glands during the second and third trimesters. Somatostatin cells were the most common type of cells (~46 %) during the first trimester, while ghrelin cells were the most numerous during the second trimester (~34 %), and in infants (~28 %). The percentage of glucagon cells was significant only during the first trimester of pregnancy (5.5 %), and the percentage of serotonin cells was only significant just before birth (4.8 %). CONCLUSIONS: These results show, for the first time, that the largest number of endocrine cells are present in the corpus during the first trimester of prenatal development. Also, these results suggest that secretory products of endocrine cells play a role in the regulation of homeostasis, growth, and differentiation, and in human stomach function. PMID- 22544315 TI - Polymorphisms of DNA repair genes in endometrial cancer. AB - Endometrial cancer belongs to the commonest malignancy in females. Its development may be associated with the high exposure of endometrium to exo- and endogenous estrogens. Estrogens produce DNA bulky adducts and oxidative base damages which are removed in nucleotide excision repair (NER) and base excision repair (BER) pathways. The reaction of endometrial cells to DNA damage may be crucial for their susceptibility to cancer transformation. This reaction is executed mainly by DNA repair, which can be modulated by the variability in the genes encoding DNA repair proteins. In this report we genotyped 4 polymorphisms of 3 DNA repair genes in 94 endometrial cancer patients and 114 age-matched cancer-free women using RFLP-PCR. The following polymorphisms were studied: p.Arg194Trp, p.Arg399Gln of the XRCC1 gene, p.Ser326Cys of the hOGG1 gene and p.Lys751Gln of the ERCC2 gene. We found an association between the ERCC2 751Gln variant and endometrial cancer occurrence (OR 3.95; 95 % CI 1.88-8.31). Gene-gene interaction between the ERCC2 751Gln and XRCC1 194Trp variants also increased the risk of endometrial cancer (OR 4.41; 95 % CI 2.01-9.67). The risk in the carriers of the ERCC2 751Gln variant was increased by a positive cancer history in first degree relatives (OR 4.97; 95 % CI 1.98-12.48). The risk of endometrial cancer was not alter by polymorphism p.Ser326Cys of the hOGG1 gene. The 751 Lys/Gln polymorphism of the ERCC2 gene may be linked with endometrial cancer occurrence and its effect can be potentiated by variants of the XRCC1 gene or first degree relatives positive cancer history. PMID- 22544316 TI - Mechanistic aspects of the Hsp90 phosphoregulation. PMID- 22544317 TI - Role of the SMYD3 histone methyltransferase in tumorigenesis: local or global effects? PMID- 22544318 TI - Epigenetic inactivation of the tumor suppressor BIN1 drives proliferation of SNF5 deficient tumors. AB - Emerging evidence demonstrates that subunits of the SWI/SNF chromatin remodeling complex are specifically mutated at high frequency in a variety of human cancer types. SNF5 (SMARCB1/INI1/BAF47), a core subunit of the SWI/SNF complex, is inactivated in the vast majority of rhabdoid tumors (RT), an aggressive type of pediatric cancer. SNF5-deficient cancers are diploid and genomically stable, suggesting that epigenetically based changes in transcription are key drivers of tumor formation caused by SNF5 loss. However, there is limited understanding of the target genes that drive cancer formation following SNF5 loss. Here we performed comparative expression analyses upon three independent SNF5-deficient cancer data sets from both human and mouse and identify downregulation of the BIN1 tumor suppressor as a conserved event in primary SNF5-deficient cancers. We show that SNF5 recruits the SWI/SNF complex to the BIN1 promoter, and that the marked reduction of BIN1 expression in RT correlates with decreased SWI/SNF occupancy. Functionally, we demonstrate that re-expression of BIN1 specifically compromises the proliferation of SNF5-deficient RT cell lines. Identification of BIN1 as a SNF5 target gene reveals a novel tumor suppressive regulatory mechanism whose disruption can drive cancer formation. PMID- 22544319 TI - Checkpoint kinase 1 is essential for meiotic cell cycle regulation in mouse oocytes. AB - Checkpoint kinase 1 (Chk1) plays key roles in all currently defined cell cycle checkpoints, but its functions in mouse oocyte meiosis remain unclear. In this study, we report the expression, localization and functions of Chk1 in mouse oocyte meiosis. Chk1 was expressed from germinal vesicle (GV) to metaphase II (MII) stages and localized to the spindle from pro-metaphase I (pro-MI) to MII stages in mouse oocytes. Chk1 depletion facilitated the G 2/M transition while Chk1 overexpression inhibited the G 2/M transition as indicated by germinal vesicle breakdown (GVBD), through regulation of Cdh1 and Cyclin B1. Chk1 depletion did not affect meiotic cell cycle progression after GVBD, but its overexpression after GVBD activated the spindle assembly checkpoint and prevented homologous chromosome segregation, thus arresting oocytes at pro-MI or metaphase I (MI) stages. These results suggest that Chk1 is indispensable for prophase I arrest and functions in G 2/M checkpoint regulation in meiotic oocytes. Moreover, Chk1 overexpression affects meiotic spindle assembly checkpoint regulation and thus chromosome segregation. PMID- 22544321 TI - Wip1 sensitizes p53-negative tumors to apoptosis by regulating the Bax/Bcl-xL ratio. AB - Wip1 is a stress-response phosphatase that negatively regulates several tumor suppressors, including p53. In a sizeable fraction of tumors, overexpression or amplification of Wip1 compromises p53 functions; inhibition of Wip1 activity is an attractive strategy for improving treatment of these tumors. However, over half of human tumors contain mutations in the p53 gene or have lost both alleles. Recently, we observed that in cancer cells lacking wild type p53, reduction of Wip1 expression was ineffective, whereas, surprisingly, overexpression of Wip1 increased anticancer drug sensitivity. The increased sensitivity resulted from activation of the intrinsic pathway of apoptosis through increased levels of the pro-apoptotic protein Bax and decreased levels of the anti-apoptotic protein Bcl xL. We showed that interaction of Wip1 and the transcription factor RUNX2, specifically through dephosphorylation of RUNX2 phospho-S432, resulted in increased expression of Bax. Interestingly, overexpression of Wip1 increased drug sensitivity only in the p53-negative tumor cells while protecting the wild type p53-containing normal cells from drug-induced collateral injury. Here, we provide evidence that Wip1 overexpression decreases expression of Bcl-xL through negative regulation of NFkappaB activity. Thus, Wip1 overexpression increases the sensitivity of p53-negative cancer cells to anticancer drugs by separately affecting Bax and Bcl-xL protein levels. PMID- 22544322 TI - RUNX3 interactome reveals novel centrosomal targeting of RUNX family of transcription factors. AB - RUNX family proteins are critical regulators of lineage differentiation during development. The high prevalence of RUNX mutation/epigenetic inactivation in human cancer indicates a causative role for dysfunctional RUNX in carcinogenesis. This is supported by well-documented evidence of functional interaction of RUNX with components of major oncogenic or tumor suppressive signaling pathways such as TGFbeta and Wnt. Here, we explore the binding partners of RUNX3 proteins to further define the scope of RUNX3 function. Using a mass spectrometry-based approach, we found that RUNX3 binds to centrosomal protein rootletin. This led us to uncover the presence of RUNX proteins at the centrosome. Our findings suggest a potential function for RUNX3 during mitosis. PMID- 22544320 TI - Expanding applications of chemical genetics in signal transduction. AB - Chemical genetics represents an expanding collection of techniques applied to a variety of signaling processes. These techniques use a combination of chemical reporters and protein engineering to identify targets of a signaling enzyme in a global and non-directed manner without resorting to hypothesis-driven candidate approaches. In the last year, chemical genetics has been applied to a variety of kinases, revealing a much broader spectrum of substrates than had been appreciated. Here, we discuss recent developments in chemical genetics, including insights from our own proteomic screen for substrates of the kinase ERK2. These studies have revealed that many kinases have overlapping substrate specificity, and they often target several proteins in any particular downstream pathway. It remains to be determined whether this configuration exists to provide redundant control, or whether each target contributes a fraction of the total regulatory effect. From a general perspective, chemical genetics is applicable in principle to a broad range of posttranslational modifications (PTMs), most notably methylation and acetylation, although many challenges remain in implementing this approach. Recent developments in chemical reporters and protein engineering suggest that chemical genetics will soon be a powerful tool for mapping signal transduction through these and other PTMs. PMID- 22544323 TI - ZFP36 expression impairs glioblastoma cell lines viability and invasiveness by targeting multiple signal transduction pathways. AB - RNA binding proteins belonging to the TIS11/TTP gene family regulate the stability of multiple targets. Their inactivation or deregulated expression has recently been related to cancer, and it has been suggested that they are capable of displaying tumor suppressor activities. Here we describe three new targets of ZFP36 (PIM-1, PIM-3 and XIAP) and show by different approaches that its ectopic expression is capable of impairing glioblastoma cell lines viability and invasiveness by interfering with different transduction pathways. Moreover, we provide evidence that compounds capable of inducing the expression of TIS11/TTP genes determine a comparable biological effect on the same cell contexts. PMID- 22544324 TI - [32P]ATP inhibits the growth of xenografted tumors in nude mice. AB - The search for new therapeutic agents that are effective against cancer has been difficult and expensive. The activity of anticancer candidate agents against human cancer-derived cell lines in immunocompromised mice is an important tool in this search. Because ATP is a naturally occurring small molecule, its radiolabeled form poses many advantages as a potential anticancer therapeutic agent. We previously found that a single, low-dose intravenous injection of [ ( 32) P]ATP inhibited the growth of xenografted tumors in nude mice for up to several weeks. The current study describes the biodistribution and the results and advantages of multi-dose administration of this potential drug. Future studies should investigate the mechanism involved in the possible use of [ ( 32) P]ATP as a cytotoxic agent that homes naturally to the tumor microenvironment. PMID- 22544325 TI - Tumor suppressor activity of CBX7 in lung carcinogenesis. AB - The generation of knockout mice for the Cbx7 gene validates the tumor suppressor role of CBX7, whose expression is lost in several human malignancies. Indeed, these mice developed liver and lung adenomas and carcinomas. Cyclin E overexpression due to the lack of Cbx7 negative regulation of its expression likely accounts for the phenotype of the Cbx7-KO mice. A similar mechanism is likely involved in human lung carcinogenesis, since cyclin E upregulation associated with the loss of CBX7 expression has been observed in most of the human lung carcinomas analyzed. PMID- 22544326 TI - Calcium sensitivity of alpha-actinin is required for equatorial actin assembly during cytokinesis. AB - The actin cross-linking protein, alpha-actinin, plays a crucial role in mediating furrow ingression during cytokinesis. However, the mechanism by which its dynamics are regulated during this process is poorly understood. Here we have investigated the role of calcium sensitivity of alpha-actinin in the regulation of its dynamics by generating a functional calcium-insensitive mutant (EFM). GFP tagged EFM (EFM-GFP) localized to the equatorial regions during cell division. However, the maximal equatorial accumulation of EFM-GFP was significantly smaller in comparison to alpha-actinin-GFP when it was expressed in normal cells and cells depleted of endogenous alpha-actinin. No apparent defects in cytokinesis were observed in these cells. However, F-actin levels at the equator were significantly reduced in cells expressing EFM-GFP as compared with alpha-actinin GFP at furrow initiation but were recovered during furrow ingression. These results suggest that calcium sensitivity of alpha-actinin is required for its equatorial accumulation that is crucial for the initial equatorial actin assembly but is dispensable for cytokinesis. Equatorial RhoA localization was not affected by EFM-GFP overexpression, suggesting that equatorial actin assembly is predominantly driven by the RhoA-dependent mechanism. Our observations shed new light on the role and regulation of the accumulation of pre-existing actin filaments in equatorial actin assembly during cytokinesis. PMID- 22544328 TI - Ovarian carcinoma tumor-initiating cells have a mesenchymal phenotype. AB - Solid tumors appear to contain a subpopulation of cells (tumor-initiating cells, TICs) that not only drives and sustains tumor growth, but is possibly responsible for recurrence. We isolated, after enzymatic digestion of primary ovarian carcinoma samples, a subpopulation of cells propagating as non-adherent spheres in medium suitable for tumor stem cells. These cells were able to self-renew in vitro, as suggested by PKH-26 staining studies, were tumorigenic and acquired an epithelial morphology when grown in FBS-supplemented medium, losing their tumorigenic potential. Interestingly, the tumorigenic potential of PKH-26 (high) and PKH-26 (neg) -sorted cells was similar. These TIC-enriched cultures showed higher levels of genes involved in stemness than differentiated cells derived from them and were more resistant to the cytotoxic effects of some drugs but equally sensitive to others. The higher level of ABCG2 efflux pump could explain increased resistance to taxol and VP16, and higher levels of genes involved in nucleotide excision repair partially explain the resistance to cisplatin. These cells express mesenchymal markers, and epithelial transition could be induced when cultured in differentiating conditions, with a loss of invasive potential. These data suggest that ovarian cancer is a stem cell disease and should help elucidate the role of these cells in the aggressive phenotype of this tumor and find new therapeutic strategies to reduce resistance to current chemotherapeutic drugs. PMID- 22544327 TI - mTORC1 signaling and regulation of pancreatic beta-cell mass. AB - The capacity of beta cells to expand in response to insulin resistance is a critical factor in the development of type 2 diabetes. Proliferation of beta cells is a major component for these adaptive responses in animal models. The extracellular signals responsible for beta-cell expansion include growth factors, such as insulin, and nutrients, such as glucose and amino acids. AKT activation is one of the important components linking growth signals to the regulation of beta-cell expansion. Downstream of AKT, tuberous sclerosis complex 1 and 2 (TSC1/2) and mechanistic target of rapamycin complex 1 (mTORC1) signaling have emerged as prime candidates in this process, because they integrate signals from growth factors and nutrients. Recent studies demonstrate the importance of mTORC1 signaling in beta cells. This review will discuss recent advances in the understanding of how this pathway regulates beta-cell mass and present data on the role of TSC1 in modulation of beta-cell mass. Herein, we also demonstrate that deletion of Tsc1 in pancreatic beta cells results in improved glucose tolerance, hyperinsulinemia and expansion of beta-cell mass that persists with aging. PMID- 22544330 TI - Sibling rivalry in checkpoint control of cell cycle and DNA damage response. PMID- 22544331 TI - Efficient photocatalytic hydrogen evolution over hydrogenated ZnO nanorod arrays. AB - Hydrogenated ZnO nanorod arrays (NRAs) grown on F-doped SnO(2) (FTO) glass substrates yield a benchmark specific hydrogen production rate of 122,500 MUmol h(-1) g(-1), and exhibit excellent stability and recyclability. PMID- 22544329 TI - The DNA damage checkpoint protein ATM promotes hepatocellular apoptosis and fibrosis in a mouse model of non-alcoholic fatty liver disease. AB - Steatoapoptosis is a hallmark of non-alcoholic fatty liver disease (NAFLD) and is an important factor in liver disease progression. We hypothesized that increased reactive oxygen species resulting from excess dietary fat contribute to liver disease by causing DNA damage and apoptotic cell death, and tested this by investigating the effects of feeding mice high fat or standard diets for 8 weeks. High fat diet feeding resulted in increased hepatic H 2O 2, superoxide production, and expression of oxidative stress response genes, confirming that the high fat diet induced hepatic oxidative stress. High fat diet feeding also increased hepatic steatosis, hepatitis and DNA damage as exemplified by an increase in the percentage of 8-hydroxyguanosine (8-OHG) positive hepatocytes in high fat diet fed mice. Consistent with reports that the DNA damage checkpoint kinase Ataxia Telangiectasia Mutated (ATM) is activated by oxidative stress, ATM phosphorylation was induced in the livers of wild type mice following high fat diet feeding. We therefore examined the effects of high fat diet feeding in Atm deficient mice. The prevalence of apoptosis and expression of the pro-apoptotic factor PUMA were significantly reduced in Atm-deficient mice fed the high fat diet when compared with wild type controls. Furthermore, high fat diet fed Atm ( /-) mice had significantly less hepatic fibrosis than Atm (+/+) or Atm (+/-) mice fed the same diet. Together, these data demonstrate a prominent role for the ATM pathway in the response to hepatic fat accumulation and link ATM activation to fatty liver-induced steatoapoptosis and fibrosis, key features of NAFLD progression. PMID- 22544332 TI - Effects of ultraviolet radiation and nutrients on the structure-function of phytoplankton in a high mountain lake. AB - The combined effect of high solar ultraviolet radiation (UVR) and nutrient supply in a phytoplankton community of a high mountain lake is analyzed in a in situ experiment for 6 days with 2 * 2 factorial design. Interactive UVR * nutrient effects on structural and functional variables (algal biomass, chlorophyll a (chl a), primary production (PP), maximal electron transport rate (ETR(max)), and alkaline phosphatase activity (APA)), as well as stoichiometric ones (sestonic N per cell and N:P ratio) were found. Under non-nutrient enriched conditions, no deleterious effects of UVR on structural variables, PP, photosynthetic efficiency and ETR(max) were observed, whereas only particulate and total APA were affected by UVR. However, percentage excreted organic carbon (%EOC), dissolved APA and sestonic C and P per cell increased under UVR, leading to a decrease in algal C:P and N:P ratios. After nutrient enrichment, chl a, total algal biomass and PP were negatively affected by UVR whereas %EOC, ETR(max) and internal C, P and N content increased. We suggest that the mechanism of algal acclimation to UVR in this high UVR flux ecosystem seems to be related to the increase of internal algal P content mediated by physiological mechanisms to save P and by a stimulatory UVR effect on dissolved extracellular APA. The mechanism involved in the unmasking effect of UVR after nutrient-enrichment may be the result of a greater sensitivity to UVR-induced cell damage, making the negative UVR effects more evident. PMID- 22544333 TI - Association between perceived union connection and upper body musculoskeletal pains among unionized construction apprentices. AB - BACKGROUND: Several studies show varying associations between unionization and workers' health and well-being. This study investigated the association between individual worker's perceived union connection and musculoskeletal pains (MSPs). METHODS: We conducted a cross-sectional survey of 1,757 unionized construction apprentices. Perceived union connection is a psychosocial scale measured by six questions that assessed individual worker's connection to their union (range 10 24) at unionized workplaces. We measured the prevalence of four MSPs (neck, shoulder, arm, and back pain) and difficulty in daily home activities, job activities, and sleeping caused by each of the four MSPs. RESULTS: We found that a one score increase in perceived union connection was associated with 5% decreased odds of reporting neck pain (OR: 0.95, 95% CI: 0.91-1.00) and back pain (OR: 0.95, 95% CI: 0.91-0.99) after adjusting for confounders including self reported ergonomic strain. We also found significant associations between perceived union connection and MSPs causing difficulty in daily activities. For a one score increase in perceived union connection, the odds of reporting back pain causing difficulty in home activities, job activities, and sleeping was 9% (95% CI: 0.87-0.96), 8% (95% CI: 0.88-0.96), and 7% (95% CI: 0.89-0.98) lower, respectively. CONCLUSIONS: Although our findings are limited by the cross sectional nature of the data, these results suggest that workers' perceived union connection can vary even within unionized workplaces, and it may be associated with the prevalence of MSPs and MSPs causing difficulty in daily activities. PMID- 22544334 TI - Electrophysiological and behavioral responses of the bark beetle Dendroctonus rhizophagus to volatiles from host pines and conspecifics. AB - The bark beetle Dendroctonus rhizophagus is endemic to northwestern Mexico where it kills immature pines < 3 m tall. We report the first investigation of the chemical ecology of this pest of forest regeneration. We used GC-EAD to assess olfactory sensitivity of this species to volatile compounds from: resin of a major host, Pinus arizonica; mid/hindguts of single, gallery-initiating females; and mate-paired males within galleries of attacked host trees in the field. Antennae of both sexes responded to monoterpenes alpha-pinene, beta-pinene and 3 carene as well as to the beetle-derived oxygenated monoterpenes fenchyl alcohol, myrtenal, cis-verbenol, trans-verbenol, verbenone, and myrtenol. These monoterpenes were quantified from pre-emerged D. rhizophagus adults forced to attack host tissue in the laboratory, and from individuals dissected from naturally-attacked hosts at different stages of colonization. In both bioassays, myrtenol and trans-verbenol were the most abundant volatiles, and trans-verbenol was the only one produced in significantly greater quantities by females than males in a naturally-colonized host. Two field experiments were performed to evaluate behavioral responses of D. rhizophagus to antennally-active monoterpenes. Results show that 3-carene was significantly attractive either alone or in a ternary (1:1:1) combination with alpha-pinene and beta-pinene, whereas neither alpha-pinene nor beta-pinene alone were attractive. None of the beetle-associated oxygenated monoterpenes enhanced the attractiveness of the ternary mixture of monoterpenes, while verbenone either alone or combined with the other five oxygenated terpenes reduced D. rhizophagus attraction to the ternary mixture. The results suggest that attraction of D. rhizophagus to the host tree P. arizonica is mediated especially by 3-carene. There was no conclusive evidence for an aggregation or sex attractant pheromone. PMID- 22544335 TI - Seasonal changes in Undifilum colonization and swainsonine content of locoweeds. AB - Locoweeds (Astragalus and Oxytropis) are leguminous plants that are toxic due to a symbiotic association with the endophytic fungus Undifilum oxytropis. The fungus produces the alkaloid swainsonine, an alpha-mannosidase-inhibitor that causes serious damage to mammals when consumed. A real-time PCR technique was developed to quantify the colonization extent of Undifilum in locoweeds and to compare it to the swainsonine concentration in the plants. Amplification of the endophyte nuclear ITS region allowed reliable quantification of Undifilum DNA from field plants and in vitro cultures. Swainsonine concentration was highly correlated (rho = 0.972, P < 0.001) with the proportion of Undifilum DNA during the first 4 weeks of in vitro culture growth. Species of Astragalus and Oxytropis were sampled seasonally in New Mexico and Colorado for two years. High swainsonine concentration in plant samples was associated with high levels of endophyte DNA, except in plant reproductive tissues. PMID- 22544336 TI - Transition from core-shell to Janus chemical configuration for bimetallic nanoparticles. AB - In order to determine the possibilities to control the chemical configuration of bimetallic nanoparticles, we have considered CuAg nanoparticles synthesized by a physical route as a model in this study. The synthesis was made by pulsed laser deposition under ultra-high vacuum conditions, via a sequential deposition procedure. We show that the temperature of the substrate and the absolute quantity of Ag in a particle are the main parameters that drive the chemical configuration. To explain the transition from a core-shell configuration to a Janus configuration as a function of Ag quantity, we have conducted density functional theory calculations and atomistic molecular dynamics simulations to investigate the stability of this system. The results are presented together with the experimental observations. PMID- 22544337 TI - Bladder injuries after external trauma: 20 years experience report in a population-based cross-sectional view. AB - OBJECTIVES: Report 20 years experience of bladder injuries after external trauma. METHODS: Gender, age, mechanism/location of damage, associated injuries, systolic blood pressure (SBP), Revised Trauma Score (RTS), Injury Severity Score (ISS), Trauma Injury Severity Score (TRISS), complications, and length of stay (LOS) were analyzed in a prospective collected bladder injuries AAST-OIS grade >= II database (American Association for the Surgery of Trauma Organ Injury Scaling) from 1990 to 2009 in a trauma reference center. RESULTS: Among 2,575 patients experiencing laparotomy for trauma, 111 (4.3 %) presented bladder ruptures grade >= II, being 83.8 % (n = 93) males, mean age 31.5 years old (+/- 11.2). Blunt mechanism accounted for 50.5 % (n = 56)-motor vehicle crashes 47.3 % (n = 26), pedestrians hit by a car (29.1 %). Gunshot wounds represented 87.3 % of penetrating mechanism. The most frequent injury was grade IV (51 patients, 46 %). The mean ISS was 23.8 (+/- 11.2), TRISS 0.90 (+/- 0.24), and RTS 7.26 (+/- 1.48). Severity (AAST-OIS), mechanism (blunt/penetrating), localization of the bladder injury (intra/extraperitoneal, associated), and neither concomitant rectum lesion were related to complications, LOS, or death. Mortality rate was 10.8 %. ISS > 25 (p = 0.0001), SBP <90 mmHg (p = 0.0001), RTS <7.84 (p = 0.0001), and pelvic fracture (p = 0.0011) were highly associated with grim prognosis and death with hazard ratios of 5.46, 2.70, 2.22, and 2.06, respectively. CONCLUSIONS: Trauma scores and pelvic fractures impact survival in bladder trauma. The mortality rate has remained stable for the last two decades. PMID- 22544338 TI - Do pure squamous cell carcinomas and urothelial carcinomas have similar prognosis after radical cystectomy? AB - PURPOSE: The purpose of this study was to evaluate the surgical treatment results of urothelial carcinoma (UC) and pure squamous cell carcinoma of the bladder (SCC). METHODS: The records of 460 patients who have undergone radical cystectomy in our department between the years 1991 and 2011 were analyzed retrospectively, and 364 patients with UC and 60 patients with pure SCC were evaluated. RESULTS: Average ages of the patients with UC and SCC were 61.12 +/- 8.9 and 59.38 +/- 8.6 years, respectively (p = 0.902). UC group had 29 female patients, whereas SCC group had 9 female patients (p = 0.077). The mean follow-up periods were 26.09 +/ 24.75 months for UC group and 22.23 +/- 31.01 months for SCC group (p = 0.805). The incidence of organ-confined, extravesical, lymph node-positive diseases in UC and SCC cases was 48.9 and 32.2, 29.3 and 32.2 %, 21.8 and 35.6 %, respectively (p = 0.028). Five-year disease-specific survival (DSS) rates were 57.5 % in UC and 39.1 % in SCC group (p = 0.011). Five-year DSS rates were 81.2 % in UC and 75.0 % in SCC group in organ-confined disease (p = 0.534) and 28.2 % in UC and 40.9 % in SCC group in extravesical disease (p = 0.845). In lymph node-positive patients, DSS time was 20.9 +/- 2.85 months in UC and 12.8 +/- 2.07 months in SCC patients (p = 0.182). In multivariate analysis, pT stage (HR: 2.221; 95 % CI: 1.695-2.911) and lymph node involvement (HR: 2.863; 95 % CI: 1.819-4.509) were independently associated with DSS (p < 0.001), but histological subtype (HR: 1.423; 95 % CI: 0.798-2.538) was not a statistically significant factor (p = 0.232). CONCLUSIONS: Although pure SCC cases are diagnosed at advanced stages of the disease, UC and pure SCC cases have similar prognosis by stages. Lymph node involvement and stages are the most important prognostic factors after radical cystectomy. PMID- 22544339 TI - Long-term angiogenic activity of free grafts and pedicle flap in a rabbit urethroplasty model. AB - PURPOSE: We studied the late angiogenic activity of free grafts and a pedicle flap in a rabbit urethroplasty model to determine whether angiogenic activity plays a role in late outcomes of urethral reconstruction in rabbits. METHODS: Twenty-eight rabbits were randomly divided into five groups according to the method used to bridge a urethral defect as an onlay patch: Control, simple closure of urethral defect (Group O1); free penile skin graft (FPSG, Group A1); buccal mucosal graft (BuMG, Group B1); bladder mucosal graft (BlMG, Group C1); and pedicle penile skin flap (PPSF, Group D1). Angiogenic activity of the patch on postoperative day 84 was assessed by immunohistochemistry. RESULTS: The angiogenic activity in Groups O1, A1, B1, C1, and D1 was 23.33 +/- 4.92 (means +/ SD), 42.89 +/- 6.52, 55.78 +/- 3.46, 53.61 +/- 6.17, and 24.11 +/- 9.07 vessels per optical field, respectively. There were statistically significant differences (p < .001) between Group O1 and A1 B1, C1, Group A1 and B1, C1, D1, Groups B1 and D1 and Groups C1 and D1, but not between Groups O1 and D1 (p = 1.000) and Groups B1 and C1 (p = .872). The long-term angiogenic activity of all the groups was significantly lower (p < .001) than in the corresponding early groups. CONCLUSIONS: Although the angiogenic activity of all the groups decreased in the late assessment, the buccal mucosal graft continued to exhibit elevated angiogenesis above bladder or skin (free or pedicle) graft. Therefore, buccal mucosal patch graft might be preferable because of its easier harvesting. PMID- 22544340 TI - Prediction of perioperative outcomes following minimally invasive partial nephrectomy: role of the R.E.N.A.L nephrometry score. AB - OBJECTIVES: Objective characterization of renal mass anatomy facilitates treatment selection and prediction of surgical outcomes. We investigated R.E.N.A.L nephrometry score (NS) efficacy in predicting outcomes after minimally invasive nephron-sparing surgery (MINSS). METHODS: A total of 250 patients with 252 renal masses underwent MINSS by a surgeon between January 2003 and July 2011. Preoperative films were available for 181 (72 %) renal masses, which were retrospectively assigned a NS. NS was categorized as low, moderate or high, reflecting tumor complexity. Perioperative outcomes were analyzed by NS category. Outcomes for laparoscopic (LPN) versus robotic (RALPN) partial nephrectomy were compared. Multivariable regression was used to investigate predictors of postoperative complications. RESULTS: Among 181 renal masses, 128 (71 %) were managed by LPN and 53 were (29 %) by RALPN. And 103, 74 and 4 renal lesions were low, medium and high complexity, respectively. For low versus medium versus high NS, respective overall complication rate was 5.8 versus 16.0 versus 50.0 % (p = 0.01); mean warm ischemia time (WIT) was 29 versus 33 versus 39 min (p = 0.02); and transfusion rate was 5/103 (4.8 %) versus 6/74 (8.1 %) versus 1/4 (25 %) (p = 0.20). NS category was significantly associated with overall complication rate (p = 0.04) and Clavien grade III complication rate (p = 0.05). Nearness to the collecting system ("N") was significantly associated with overall complications (p = 0.02) and postoperative hemorrhage (p = 0.02). Postoperative outcomes for LPN versus RALPN were statistically similar across all categories. CONCLUSIONS: R.E.N.A.L NS is predictive of overall complications and WIT during MINSS. Our data also suggest that "N" score may be used as a single predictor of overall complications and postoperative hemorrhage following MINSS. PMID- 22544341 TI - L1CAM from human melanoma carries a novel type of N-glycan with Galbeta1 4Galbeta1- motif. Involvement of N-linked glycans in migratory and invasive behaviour of melanoma cells. AB - Dramatic changes in glycan biosynthesis during oncogenic transformation result in the emergence of marker glycans on the cell surface. We analysed the N-linked glycans of L1CAM from different stages of melanoma progression, using high performance liquid chromatography combined with exoglycosidase sequencing, matrix assisted laser desorption/ionisation time-of-flight mass spectrometry, and lectin probes. L1CAM oligosaccharides are heavily sialylated, mainly digalactosylated, biantennary complex-type structures with galactose beta1-4/3-linked to GlcNAc and with or without fucose alpha1-3/6-linked to GlcNAc. Hybrid, bisected hybrid, bisected triantennary and tetraantennary complex oligosaccharides, and beta1-6 branched complex-type glycans with or without lactosamine extensions are expresses at lower abundance. We found that metastatic L1CAM possesses only alpha2-6-linked sialic acid and the loss of alpha2-3-linked sialic acid in L1CAM is a phenomenon observed during the transition of melanoma cells from VGP to a metastatic stage. Unexpectedly, we found a novel monoantennary complex-type oligosaccharide with a Galbeta1-4Galbeta1- epitope capped with sialic acid residues A1[3]G(4)2S2-3. To our knowledge this is the first report documenting the presence of this oligosaccharide in human cancer. The novel and unique N glycan should be recognised as a new class of human melanoma marker. In functional tests we demonstrated that the presence of cell surface alpha2-3 linked sialic acid facilitates the migratory behaviour and increases the invasiveness of primary melanoma cells, and it enhances the motility of metastatic cells. The presence of cell surface alpha2-6-linked sialic acid enhances the invasive potential of both primary and metastatic melanoma cells. Complex-type oligosaccharides in L1CAM enhance the invasiveness of metastatic melanoma cells. PMID- 22544342 TI - Galectins and their ligands: negative regulators of anti-tumor immunity. AB - Cytotoxic CD8(+) T cells are major players of anti-tumor immune responses, as their functional activity can limit tumor growth and progression. Data show that cytotoxic T cells efficiently control the proliferation of tumor cells through major histocompatibility complex class I-mediated mechanisms; nevertheless, the presence of tumor-infiltrating CD8(+) T cells in lesional tissue does not always correlate with better prognosis and increased survival of cancer patients. Similarly, adoptive transfer of tumor-specific cytotoxic T cells has only shown marginal improvement in life spans of patients with metastatic disease. In this report, we discuss experimental evidence showing that expression of tumor-derived galectins, galectin (Gal)-1, Gal-3 and Gal-9, and concomitant presence of their ligands on the surface of anti-tumor immunocytes directly compromise anti-tumor CD8(+) T cell immune responses and, perhaps, undermine the promise of adoptive CD8(+) T cell immunotherapy. Furthermore, we describe novel strategies designed to counteract Gal-1-, Gal-3- and Gal-9-mediated effects and highlight their targeting potential for creating more effective anti-tumor immune responses. We believe that Gal and their ligands represent an efficacious targeted molecular paradigm that warrants clinical evaluation. PMID- 22544343 TI - Lactobacillus rhamnosus bacteremia: an emerging clinical entity. AB - Lactobacillus spp. are ubiquitous commensals of the normal human flora that are only occasionally found in clinical infections. Their role in human disease is established for infectious endocarditis but is controversial for other infections. We sought to characterize clinically associated Lactobacillus spp. We conducted a retrospective study, which consisted of the screening of Lactobacillus isolates obtained in our laboratory from January 2004 to December 2009. The polymerase chain reaction (PCR) assay was selected as the gold standard method. The isolates were first identified using API Coryne strips, matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), and 16S rRNA gene sequencing. Lactobacillus tuf gene-based identification was used when the 16S rRNA results were inconclusive. Among the 60 strains of Lactobacillus spp. obtained in our laboratory, L. rhamnosus was the most commonly isolated species and was found in blood cultures from 16 patients. Combined with 45 patients reported in the literature, we found that patients presenting with L. rhamnosus bacteremia experienced nosocomial infections associated with both immunosuppression (66 %) and catheters (83 %). PMID- 22544344 TI - Pyrosequencing reveals the complex polymicrobial nature of invasive pyogenic infections: microbial constituents of empyema, liver abscess, and intracerebral abscess. AB - The polymicrobial nature of invasive pyogenic infections may be underestimated by routine culture practices, due to the fastidious nature of many organisms and the loss of viability during transport or from prior antibacterials. Pyrosequencing was performed on brain and liver abscesses and pleural fluid and compared to routine culture data. Forty-seven invasive pyogenic infection samples from 44 patients [6 intracerebral abscess (ICA), 21 pyogenic liver abscess (PLA), and 18 pleural fluid (PF) samples] were assayed. Pyrosequencing identified an etiologic microorganism in 100 % of samples versus 45 % by culture, p <0.01. Pyrosequencing was also more likely than traditional cultures to classify infections as polymicrobial, 91 % versus 17 %, p <0.001. The median number of genera identified by pyrosequencing compared to culture was 1 [interquartile range (IQR) 1-3] versus 0 (IQR 0-1) for ICA, 7 (IQR 1-15) versus 1 (IQR 0-1) for PLA, and 15 (IQR 9-19) versus 0 (IQR 0-1) for PF. Where organisms were cultured, they typically represented the numerically dominant species identified by pyrosequencing. Complex microbial communities are involved in invasive pyogenic infection of the lung, liver, and brain. Defining the polymicrobial nature of invasive pyogenic infections is the first step towards appreciating the clinical and diagnostic implications of these complex communities. PMID- 22544345 TI - Exploring biodiversity in the bacterial community of the Mediterranean phyllosphere and its relationship with airborne bacteria. AB - We studied the structure and diversity of the phyllosphere bacterial community of a Mediterranean ecosystem, in summer, the most stressful season in this environment. To this aim, we selected nine dominant perennial species, namely Arbutus unedo, Cistus incanus, Lavandula stoechas, Myrtus communis, Phillyrea latifolia, Pistacia lentiscus, Quercus coccifera (woody), Calamintha nepeta, and Melissa officinalis (herbaceous). We also examined the extent to which airborne bacteria resemble the epiphytic ones. Genotype composition of the leaf and airborne bacteria was analysed by using denaturing gradient gel electrophoresis profiling of a 16S rDNA gene fragment; 75 bands were cloned and sequenced corresponding to 28 taxa. Of these, two were found both in the air and the phyllosphere, eight only in the air, and the remaining 18 only in the phyllosphere. Only four taxa were found on leaves of all nine plant species. Cluster analysis showed highest similarity for the five evergreen sclerophyllous species. Aromatic plants were not grouped all together: the representatives of Lamiaceae, bearing both glandular and non-glandular trichomes, formed a separate group, whereas the aromatic and evergreen sclerophyllous M. communis was grouped with the other species of the same habit. The epiphytic communities that were the richest in bacterial taxa were those of C. nepeta and M. officinalis (Lamiaceae). Our results highlight the remarkable presence of lactic acid bacteria in the phyllosphere under the harsh conditions of the Mediterranean summer, the profound dissimilarity in the structure of bacterial communities in phyllosphere and air, and the remarkable differences of leaf microbial communities on neighbouring plants subjected to similar microbial inocula; they also point to the importance of the leaf glandular trichome in determining colonization patterns. PMID- 22544346 TI - Composition of methane-oxidizing bacterial communities as a function of nutrient loading in the Florida everglades. AB - Agricultural runoff of phosphorus (P) in the northern Florida Everglades has resulted in several ecosystem level changes, including shifts in the microbial ecology of carbon cycling, with significantly higher methane being produced in the nutrient-enriched soils. Little is, however, known of the structure and activities of methane-oxidizing bacteria (MOB) in these environments. To address this, 0 to 10 cm plant-associated soil cores were collected from nutrient impacted (F1), transition (F4), and unimpacted (U3) areas, sectioned in 2-cm increments, and methane oxidation rates were measured. F1 soils consumed approximately two-fold higher methane than U3 soils; additionally, most probable numbers of methanotrophs were 4-log higher in F1 than U3 soils. Metabolically active MOB containing pmoA sequences were characterized by stable-isotope probing using 10 % (v/v) (13)CH(4). pmoA sequences, encoding the alpha subunit of methane monooxygenase and related to type I methanotrophs, were identified from both impacted and unimpacted soils. Additionally, impacted soils also harbored type II methanotrophs, which have been shown to exhibit preferences for high methane concentrations. Additionally, across all soils, novel pmoA-type sequences were also detected, indicating presence of MOB specific to the Everglades. Multivariate statistical analyses confirmed that eutrophic soils consisted of metabolically distinct MOB community that is likely driven by nutrient enrichment. This study enhances our understanding on the biological fate of methane being produced in productive wetland soils of the Florida Everglades and how nutrient-enrichment affects the composition of methanotroph bacterial communities. PMID- 22544347 TI - Phenolic compounds from mate (Ilex paraguariensis) inhibit adipogenesis in 3T3-L1 preadipocytes. AB - Leaves of Ilex paraguariensis are used to prepare a tea known as mate which is a common beverage in several South American countries. The ethanol extract was fractionated to identify the compounds responsible for the anti-adipogenic activity in 3T3-L1 cells. Extracts of both fresh and dried mate leaves were subjected to column chromatography using molecular permeation to obtain the saponin (20 % yields) and the polyphenol extracts (40 % yields) from the fresh and dried leaves. The phenolic content was determined using high-performance liquid chromatography analysis and the Folin-Ciocalteau method. Also, mate extracts (50 MUg/ml to 1,000 MUg/ml) did not display citotoxicity using MTT. The polyphenol extract from the dried leaves was the most effective (50 MUg/ml) in the inhibition of triglyceride accumulation in 3T3-L1 adipocytes, and rutin (100 MUg/ml) likely accounted for a large portion of this activity. Additionally, mate extracts had a modulatory effect on the expression of genes related to the adipogenesis as PPARgamma2, leptin, TNF-alpha and C/EBPalpha. PMID- 22544348 TI - Pharmacological treatment of unipolar depression. AB - Antidepressants were first developed serendipitously 60 years ago and gave rise to the monoamine hypothesis of depression and antidepressant action which has persisted in various forms ever since. Although we have made huge strides in our understanding of the pharmacology of antidepressants, and in the neuroscience of depression, our current antidepressants have changed little since the original drugs. In this chapter I first review some controversies in the use of antidepressant drugs including whether they actually work, and then go on to describe the current state of our clinical use of antidepressants, looking both at the principles and practice of treatment and reviewing the evidence for efficacy, tolerability and safety in acute and sequenced treatments. I finally briefly consider future directions and the aspiration of developing more effective antidepressants. PMID- 22544350 TI - Distribution of cystinosin-LKG in human tissues. AB - Nephropathic cystinosis is multisystemic progressive disorder caused by mutations of CTNS gene that encodes for the lysosomal cystine co-transporter cystinosin, and for a less abundant isoform termed cystinosin-LKG, which is expressed in not only lysosomes but also other cell compartments. To overcome the absence of high quality antibodies against cystinosin, we have obtained a rabbit antiserum against cystinosin-LKG and have analyzed in human tissues the expression of the two known cystinosin isoforms by RT-PCR, and the expression of cystinosin-LKG by immunohistochemistry. In most tissues, CTNS-LKG represents 5-20 % of CTNS transcripts, with the exception of the testis that expresses both isoforms in equal proportions. Cystinosin-LKG was found to be highly expressed in renal tubular cells, pancreatic islets of Langerhans, Leydig cells of the testis, mucoserous glands of the bronchial wall, melanocytes and keratinocytes. These results are parallel with many features of cystinosis, such as early onset Fanconi syndrome, male infertility, diabetes mellitus and hypopigmentation. Intermediate expression levels were of the LKG isoform observed in the gastro intestinal tract and thyroid glands; low levels of expression were observed in the brain, skeletal and cardiac muscles. PMID- 22544349 TI - Epidermal growth factor modulates claudins and tight junctional functions in ovarian cancer cell lines. AB - Ovarian adenocarcinomas, like human ovarian surface epithelial cells, form functional tight junctions. Tight junction molecules claudin-3 and claudin-4, which are the receptors of Clostridium perfringens enterotoxin (CPE), are abnormally upregulated in epithelial ovarian cancers of all subtypes including, mucinous cystadenocarcinoma and serous cystadenocarcinoma. Clostridium perfringens enterotoxin may be a novel tumor-targeted therapy for ovarian cancers. In epithelial ovarian cancers, overexpression of epidermal growth factor receptor has been observed and the exogenous ligand EGF induces epithelial mesenchymal transition in ovarian surface epithelium. Epidermal growth factor (EGF) signaling modulates expression of claudins with changes of fence and barrier functions in various cell types. However, the regulation of tight junctions by EGF in ovarian cancers remains unclear. In the present study, to investigate the mechanisms of the regulation of tight junctions in ovarian cancers, ovarian cancer cell lines mucinous cystadenocarcinoma (MCAS) and serous cystadenocarcinoma (HUOA) were treated with EGF. Epidermal growth factor downregulated claudin-3 in MCAS and claudin-4 in HUOA by inducing degradation of the proteins with changes in structures and functions of tight junctions via the MEK/ERK or PI3K/Akt signaling pathway. In addition, in HUOA but not MCAS, EGF downregulated the cytotoxic effect of CPE via claudin-4. Thus, there were different mechanisms for regulation of claudins by EGF between subtypes of epithelial ovarian cancer cells in vitro. These results indicate that EGF may affect claudins and tight junctional functions in ovarian cancer cells during cancer progression. PMID- 22544351 TI - Plasmid DNA is internalized from the apical plasma membrane of the salivary gland epithelium in live animals. AB - Non-viral-mediated gene delivery represents an alternative way to express the gene of interest without inducing immune responses or other adverse effects. Understanding the mechanisms by which plasmid DNAs are delivered to the proper target in vivo is a fundamental issue that needs to be addressed in order to design more effective strategies for gene therapy. As a model system, we have used the submandibular salivary glands in live rats and we have recently shown that reporter transgenes can be expressed in different cell populations of the glandular epithelium, depending on the modality of administration of plasmid DNA. Here, by using a combination of immunofluorescence and intravital microscopy, we have explored the relationship between the pattern of transgenes expression and the internalization of plasmid DNA. We found that plasmid DNA is internalized: (1) by all the cells in the salivary gland epithelium, when administered alone, (2) by large ducts, when mixed with empty adenoviral particles, and (3) by acinar cells upon stimulation of compensatory endocytosis. Moreover, we showed that plasmid DNA utilizes different routes of internalization, and evades both the lysosomal degradative pathway and the retrograde pathway towards the Golgi apparatus. This study clearly shows that in vivo approaches have the potential to address fundamental questions on the cellular mechanisms regulating gene delivery. PMID- 22544353 TI - Biological characterization of lead-enhanced exopolysaccharide produced by a lead resistant Enterobacter cloacae strain P2B. AB - A lead resistant bacterial strain isolated from effluent of lead battery manufacturing company of Goa, India has been identified as Enterobacter cloacae strain P2B based on morphological, biochemical characters, FAME profile and 16S rDNA sequence data. This bacterial strain could resist lead nitrate up to 1.6 mM. Significant increase in exopolysaccharide (EPS) production was observed as the production increased from 28 to 108 mg/L dry weight when exposed to 1.6 mM lead nitrate in Tris buffered minimal medium. Fourier-transformed infrared spectroscopy of this EPS revealed presence of several functional groups involved in metal binding viz. carboxyl, hydroxyl and amide groups along with glucuronic acid. Gas chromatography coupled with mass spectrometry analysis of alditol acetate derivatives of acid hydrolysed EPS produced in presence of 1.6 mM lead nitrate demonstrated presence of several neutral sugars such as rhamnose, arabinose, xylose, mannose, galactose and glucose, which contribute to lead binding hydroxyl groups. Scanning electron microscope coupled with energy dispersive X-ray spectrometric analysis of this lead resistant strain exposed to 1.6 mM lead nitrate interestingly revealed mucous EPS surrounding bacterial cells which sequestered 17 % lead (as weight %) extracellularly and protected the bacterial cells from toxic effects of lead. This lead resistant strain also showed multidrug resistance. Thus these results significantly contribute to better understanding of structure, function and environmental application of lead enhanced EPSs produced by bacteria. This lead-enhanced biopolymer can play a very important role in bioremediation of several heavy metals including lead. PMID- 22544352 TI - Impact of restrictive (sleeve gastrectomy) vs hybrid bariatric surgery (Roux-en-Y gastric bypass) on lipid profile. AB - BACKGROUND: Few studies have evaluated the impact of hybrid versus purely restrictive bariatric surgery on lipid profile, with the results being contradictory. The effect of laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass (LRYGB) on lipid profile was compared. METHODS: A nonrandomized prospective cohort study was conducted on severely obese patients undergoing bariatric surgery. Indication for the type of surgical procedure was based on clinical criteria. Patients on lipid-lowering drugs and those that could not be matched for age, sex, and body mass index were excluded. Finally, 51 patients who underwent LSG and 51 undergoing LRYGB completed this study. RESULTS: During the first year post-surgery, no differences in percentage of excess weight loss and triglyceride reduction were found between groups. After LRYGR, low-density lipoprotein (LDL) cholesterol concentrations fell significantly (125.9 +/- 29.3 to 100.3 +/- 26.4 mg/dl, p < 0.001), whereas no significant changes were observed in the LSG group (118.6 +/- 30.7 to 114.6 +/- 33.5 mg/dl, p = 0.220). High-density lipoprotein (HDL) cholesterol increase was significantly greater after LSG (15.4 +/- 13.1 mg/dl) compared with LRYGB (9.4 +/ 14.0 mg/dl, p = 0.032). Factors independently associated with LDL cholesterol reduction were higher baseline total cholesterol and undergoing LRYGB. A greater increase in HDL cholesterol was associated with LSG, older age, and baseline HDL cholesterol. CONCLUSIONS: LRYGB produces an overall improvement in lipid profile, with a clear benefit in all lipid fractions. Although LSG does not alter LDL cholesterol levels, its effect on HDL cholesterol is comparable to or greater than that obtained with malabsorptive techniques. PMID- 22544354 TI - Venous thoracic outlet syndrome caused by a congenital rib malformation. AB - Venous thoracic outlet syndrome (VTOS) represents a rare disorder. Hypertrophy of the anterior scalene musculature is the cause of the compression syndrome in most cases. To our knowledge, we describe the first reported case worldwide of a venous compression syndrome caused by a congenital malformation of the 1st and 2nd ribs. Treatment by transaxillary partial rib resection was necessary and a very good postoperative result was achieved. PMID- 22544355 TI - Second allogeneic transplantation for relapsed acute leukemia after initial allogeneic hematopoietic stem cell transplantation. AB - We retrospectively reviewed the medical records of 45 patients with relapsed acute leukemia after initial allogeneic hematopoietic stem cell transplantation (allo-HSCT). Among 45 patients, a total of 11 patients eventually underwent second allo-HSCT (HSCT-2). Median survival after relapse was 294 days (range, 135 942 days) for HSCT-2. Multivariate analysis showed significantly better survival for recipients of second allo-HSCT than for other patients (hazard ratio, 4.38; 95 % confidence interval, 1.45-13.2; P = 0.009). Although outcomes for patients with relapsed leukemia were generally poor, our results suggest that second HSCT could offer a survival advantage over other conventional salvage strategies. PMID- 22544357 TI - Expert's comment concerning grand rounds case entitled "management of cervical myelopathy due to ossification of posterior longitudinal ligament in a patient with Alstrom syndrome" (by Bronek M. Boszczyk, Rishi Mugesh Kanna and Daniela Gradil). PMID- 22544356 TI - The expression of high mobility group box 1 is associated with lymph node metastasis and poor prognosis in esophageal squamous cell carcinoma. AB - The objective is to explore the expression of high mobility group box 1 (HMGB1) in esophageal squamous cell carcinoma (ESCC) and its relationship with lymph node metastasis and the prognosis of patients as well as possible mechanism. The expression of HMGB1, vascular endothelial growth factor C (VEGF-C) and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1) in ESCC tissues, which were obtained from 72 patients who underwent radical esophagectomy, was detected through immunohistochemistry, firstly. The correlations between HMGB1 and VEGF-C, and micro-lymphatic vessel density (MLD), and lymph node metastasis, and the prognosis of patients, were analyzed by statistic analysis. The plasmid of small interference RNA (siRNA) targeting HMGB1, giving siHMGB1, was transfected into exponentially growing KYSE150 human esophageal squamous cancer cells and the expression of HMGB1 mRNA and protein was observed by Real-time PCR and Western Blot and the expression of VEGF-C was examined by ELISA. HMGB1 expressed highly in the nuclei and cytoplasm of carcinoma cells as well as the extracellular space in ESCC and was associated with lymph node metastasis, MLD, the expression of VEGF-C, TNM stage and the prognosis of patients (P < 0.05 or P < 0.01). In vitro, siHMGB1 inhibited the expression of HMGB1 mRNA and protein and the secretion of VEGF-C in KYSE150 cells. In ESCC, HMGB1 expresses highly and affects the prognosis of patients through regulating the expression of VEGF-C to promote lymphangiogenesis and lymph node metastasis, and HMGB1 might serve as the marker of progression and potential target for anti-lymphangiogenesis therapy. PMID- 22544358 TI - Schmorl's nodes. AB - INTRODUCTION: First described in 1927, a Schmorl's node (SN) is the herniation of nucleus pulposus (NP) through the cartilaginous and bony end plate into the body of the adjacent vertebra. SNs are common findings on imaging, and although most SNs are asymptomatic, some have been shown to become painful lesions. In this manuscript, we review the literature regarding the epidemiology, clinical presentation, pathogenesis, imaging, and management of SNs. MATERIALS AND METHODS: Using databases from the US National Library of Medicine and the National Institutes of Health, relevant articles were identified. RESULTS: While several theories regarding the pathogenesis of SNs have been proposed, an axial load model appears to have the greatest supporting evidence. Symptomatic SNs are thought to be due to the inflammatory response solicited by the herniation of NP into the well-vascularized vertebral body. Management options for symptomatic SNs vary, ranging from medical management to surgical fusion. CONCLUSION: SNs are common lesions that are often asymptomatic. In certain cases, SNs can cause back pain. No consensus on pathogenesis exists. There is no established treatment modality for symptomatic SNs. PMID- 22544359 TI - Loading rate patterns in scoliotic children during gait: the impact of the schoolbag carriage and the importance of its position. AB - PURPOSE: Concerns have been raised regarding the effects of schoolbag carriage on adolescent schoolchildren and particularly those with a pre-existing spinal deformity. The purpose of this study was to determine the effect of school backpack loads in scoliotic and healthy school-age children during walking, in terms of peak vertical ground reaction forces and loading rates. We hypothesized that walking with a loaded backpack would have a greater effect on gait kinetics of scoliotic compared to healthy. METHODS: Eight children with idiopathic scoliosis and eight healthy children were assessed. Kinetic data were collected using two AMTI OR6-7 force-plates, while the subjects walked freely along a 6-m walkway under three walking conditions: (1) without a schoolbag, (2) carrying a schoolbag bilaterally (over both shoulders-symmetrical load) and (3) carrying a schoolbag unilaterally (over each shoulder-asymmetrical load). Kinetic data were collected and four parameters were calculated; peak ground reaction force at the first maximum force peak (F1), time needed to reach F1 (T1), loading rate of F1 (LRF1) and total contact time (T2). RESULTS: We found no significant differences between the scoliotic and healthy children for any of the kinetic variables examined. In addition, the position of the bag did not seem to have any effect on loading rate. CONCLUSIONS: The results of this study indicate that in terms of kinetic parameters during normal gait, the schoolbag load (symmetrical or asymmetrical) does not have a different effect on children with mild adolescent idiopathic scoliosis compared to normal controls. PMID- 22544360 TI - Comparison of cardiac stem cells and mesenchymal stem cells transplantation on the cardiac electrophysiology in rats with myocardial infarction. AB - INTRODUCTION: Whether transplanted cardiac stem cells (CSCs) and mesenchymal stem cells (MSCs) improved ventricular fibrillation threshold (VFT) similarly is still unclear. We sought to compare the effects of the CSC and MSC transplantation on the electrophysiological characteristics and VFT in rats with myocardial infarction (MI). METHODS: MI was induced in 30 male Sprague-Dawley rats. Two weeks later, animals were randomized to receive 5 * 10(6) CSCs labeled with PKH26 in PBS or 5 * 10(6) MSCs labeled with PKH26 in phosphate buffer solution(PBS) or PBS alone injection into the infarcted anterior ventricular free wall. Six weeks after the injection, electrophysiological characteristics and VFT were measured. Labeled CSCs and MSCs were observed in 5 MUm cryostat sections from each heart. RESULTS: Malignant ventricular arrhythmias were significantly (P = 0.0055) less inducible in the CSC group than the MSC group. The VFTs were improved in the CSC group compared with the MSC group. Labeled CSCs and MSCs were identified in the infarct zone and infarct marginal zone. Labeled CSCs expressed Connexin-43, von Willebrand factor, alpha-smooth muscle actin and alpha-sarcomeric actin,while the Labeled MSCs expressed von Willebrand factor, alpha-smooth muscle actin and alpha sarcomeric actin in vivo. CONCLUSIONS: After 6 weeks of cell transplantation, CSCs are superior to MSCs in modulating the electrophysiological abnormality and improving the VFT in rats with MI. CSCs and MSCs express markers that suggest muscle, endothelium and vascular smooth muscle phenotypes in vivo, but MSCs rarely express Connexin-43. PMID- 22544362 TI - Controlled surface trap state photoluminescence from CdS QDs impregnated in poly(methyl methacrylate). AB - A method of microwave (MW) assisted synthesis was employed to prepare cadmium sulfide (CdS) quantum dots (QDs) in dimethylformamide in the presence of poly(methyl methacrylate) (PMMA). The MW irradiation was carried out for a fixed time of 20-30 s and the size of QDs varied from 2.9-5.5 nm. Before each irradiation the solution was cooled down to ambient temperature and the irradiation process was repeated six times. An increase in the intensity and red shift of the characteristic UV-vis absorption peak originating from CdS QDs were observed with repeated MW irradiation, suggesting that the amount of generated CdS QDs increased within the PMMA network and aggregated with repeated MW irradiation. MW irradiation could influence selectively the nucleation and growing rates of PMMA-CdS QDs systems. The broadness and large Stokes shift of the emission from Cd(2+)-rich PMMA-CdS QDs was due to the surface trap state photoluminescence. The recombination of shallow trapped electrons and shallow trapped holes has been considered as the primary source of the surface trap state photoluminescence in Cd(2+)-rich PMMA-CdS QDs. The photoluminescence lifetime was observed to be decreased sharply when the amount of QDs was less, showing the emission decay was dependent on the surface property of PMMA-CdS QDs. The origin of the longer lifetime was due to the involvement of surface trap states and dependent on the amount of CdS QDs present within PMMA and its environment. The effect of the concentration of Cd(2+), S(2-) and PMMA on the generation of CdS QDs within PMMA and the effect of repeated MW irradiation on the optical properties was studied and the results are discussed in this article. PMID- 22544361 TI - Extrinsic purinergic regulation of neural stem/progenitor cells: implications for CNS development and repair. AB - There has been tremendous progress in understanding neural stem cell (NSC) biology, with genetic and cell biological methods identifying sequential gene expression and molecular interactions guiding NSC specification into distinct neuronal and glial populations during development. Data has emerged on the possible exploitation of NSC-based strategies to repair adult diseased brain. However, despite increased information on lineage specific transcription factors, cell-cycle regulators and epigenetic factors involved in the fate and plasticity of NSCs, understanding of extracellular cues driving the behavior of embryonic and adult NSCs is still very limited. Knowledge of factors regulating brain development is crucial in understanding the pathogenetic mechanisms of brain dysfunction. Since injury-activated repair mechanisms in adult brain often recapitulate ontogenetic events, the identification of these players will also reveal novel regenerative strategies. Here, we highlight the purinergic system as a key emerging player in the endogenous control of NSCs. Purinergic signalling molecules (ATP, UTP and adenosine) act with growth factors in regulating the synchronized proliferation, migration, differentiation and death of NSCs during brain and spinal cord development. At early stages of development, transient and time-specific release of ATP is critical for initiating eye formation; once anatomical CNS structures are defined, purinergic molecules participate in calcium-dependent neuron-glia communication controlling NSC behaviour. When development is complete, some purinergic mechanisms are silenced, but can be re activated in adult brain after injury, suggesting a role in regeneration and self repair. Targeting the purinergic system to develop new strategies for neurodevelopmental disorders and neurodegenerative diseases will be also discussed. PMID- 22544363 TI - Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome. AB - We show that haploinsufficiency of KANSL1 is sufficient to cause the 17q21.31 microdeletion syndrome, a multisystem disorder characterized by intellectual disability, hypotonia and distinctive facial features. The KANSL1 protein is an evolutionarily conserved regulator of the chromatin modifier KAT8, which influences gene expression through histone H4 lysine 16 (H4K16) acetylation. RNA sequencing studies in cell lines derived from affected individuals and the presence of learning deficits in Drosophila melanogaster mutants suggest a role for KANSL1 in neuronal processes. PMID- 22544364 TI - A genome-wide association study identifies susceptibility loci for Wilms tumor. AB - Wilms tumor is the most common renal malignancy of childhood. To identify common variants that confer susceptibility to Wilms tumor, we conducted a genome-wide association study in 757 individuals with Wilms tumor (cases) and 1,879 controls. We evaluated ten SNPs in regions significantly associated at P < 5 * 10(-5) in two independent replication series from the UK (769 cases and 2,814 controls) and the United States (719 cases and 1,037 controls). We identified clear significant associations at 2p24 (rs3755132, P = 1.03 * 10(-14); rs807624, P = 1.32 * 10( 14)) and 11q14 (rs790356, P = 4.25 * 10(-15)). Both regions contain genes that are plausibly related to Wilms tumorigenesis. We also identified candidate association signals at 5q14, 22q12 and Xp22. PMID- 22544365 TI - Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration. AB - RNA exosomes are multi-subunit complexes conserved throughout evolution and are emerging as the major cellular machinery for processing, surveillance and turnover of a diverse spectrum of coding and noncoding RNA substrates essential for viability. By exome sequencing, we discovered recessive mutations in EXOSC3 (encoding exosome component 3) in four siblings with infantile spinal motor neuron disease, cerebellar atrophy, progressive microcephaly and profound global developmental delay, consistent with pontocerebellar hypoplasia type 1 (PCH1; MIM 607596). We identified mutations in EXOSC3 in an additional 8 of 12 families with PCH1. Morpholino knockdown of exosc3 in zebrafish embryos caused embryonic maldevelopment, resulting in small brain size and poor motility, reminiscent of human clinical features, and these defects were largely rescued by co-injection with wild-type but not mutant exosc3 mRNA. These findings represent the first example of an RNA exosome core component gene that is responsible for a human disease and further implicate dysregulation of RNA processing in cerebellar and spinal motor neuron maldevelopment and degeneration. PMID- 22544367 TI - Mutations in KANSL1 cause the 17q21.31 microdeletion syndrome phenotype. AB - The chromosome 17q21.31 deletion syndrome is a genomic disorder characterized by highly distinctive facial features, moderate-to-severe intellectual disability, hypotonia and friendly behavior. Here, we show that de novo loss-of-function mutations in KANSL1 (also called KIAA1267) cause a full del(17q21.31) phenotype in two unrelated individuals that lack deletion at 17q21.31. These findings indicate that 17q21.31 deletion syndrome is a monogenic disorder caused by haploinsufficiency of KANSL1. PMID- 22544368 TI - Mice lacking neuropeptide Y show increased sensitivity to cocaine. AB - There is increasing data implicating neuropeptide Y (NPY) in the neurobiology of addiction. This study explored the possible role of NPY in cocaine-induced behavior using NPY knockout mice. The transgenic mice showed a hypersensitive response to cocaine in three animal models of cocaine addiction. Whether this is due to an observed compensatory increase in striatal dopamine transporter binding or an anxiogenic phenotype of the transgenic mice remains to be determined. PMID- 22544369 TI - Genetic counseling for personal genomic testing: optimizing client uptake of post test telephonic counseling services. AB - The field of genetic counseling faces a broad challenge: many potential clients may not be aware of the value and benefit of genetic counseling services, and therefore may not utilize those services. Navigenics is a personal genomic testing company that provides telephonic genetic counseling services for multifactorial diseases and pharmacogenetics. When first offered in 2008, utilization of the Navigenics genetic counseling service was less than expected. To explore the basis for under-utilization and potential mechanisms for increasing uptake, Navigenics initiated a quality improvement study, in which three different methods of engaging clients in the uptake of genetic counseling services were assessed over the course of 1 year. Outcomes showed significant differences in uptake rates between methodologies (7.5%, 24.6%, and 60.1%), yielding an 8-fold increase in service utilization when post-test telephonic outreach to all clients was performed. Further, utilization spanned all risk levels based on client results, evidence that not only clients with high-risk results were motivated to engage in the genetic counseling service. This research indicates that implementing strategies to educate clients about genetic counseling can positively impact client engagement and utilization of available services. PMID- 22544370 TI - Barriers to reforming healthcare: the Italian case. AB - Using the conceptual lenses offered by the ideational and cultural path taken in the health care arena, this article attempts to explain the trajectory of recent major health care reforms in Italy and the reasons for their failure, as well as providing some directions for successful intervention. A diachronic analysis of the relatively under-investigated phenomenon of health care reforms in Italy is carried out, drawing on a systematic review of the Italian and international literature combined with the research work carried out by the Author. For all the three major health reforms examined, a significant gap between the authoritative policy choices taken and the overall implementation, in terms of process and system changes, can be observed, determining a growing distance between the theoretical efficiency and the practical effectiveness of the Italian National Health Service (NHS) as well as its detachment from the social system. The main obstacle to effective reform seems to be the cultural hegemony of the administrative-managerial and the biomedical paradigms, which, by reinforcing one another, yielded infertile ground for renewing in a post-modern sense the Italian NHS. The various Reforms have not been conceived to break such a positivistic monopoly in that they did not promote cultural or educational intervention. In this context, intervention that acts at a cultural level, such as reforming university education for physicians and managers or devising immigration policies to attract adequately acculturated people to the Italian NHS, seems to be the most promising. PMID- 22544366 TI - Meta-analysis identifies six new susceptibility loci for atrial fibrillation. AB - Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 * 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules. PMID- 22544371 TI - Establishing quality review of cardiac and respiratory arrest in a pediatric intensive care unit. AB - Cardiac arrest in children is a rare event; however, the outcomes following resuscitation are universally disappointing. Despite widespread recognition of its importance, there is no standard approach to conducting reviews surrounding critical resuscitation events. A standardized approach to the review of respiratory and cardiac arrests occurring in the pediatric intensive care unit focusing on processes of care and team performance was undertaken at a single pediatric academic medical center. Data collection and quality improvement tools were created, and a formal code review was established. Improvement in code team performance was observed. Clinician documentation improved, and multiple system redesigns were implemented that ultimately resulted in fewer clinician concerns. The rate of successful resuscitation was consistent with current published benchmarks. The development of an interdisciplinary code review process focusing on the procedure of resuscitation can identify critical issues that may impede successful resuscitation. PMID- 22544373 TI - Applying risk adjusted cost-effectiveness (RAC-E) analysis to hospitals: estimating the costs and consequences of variation in clinical practice. AB - Cost-effectiveness analysis is well established for pharmaceuticals and medical technologies but not for evaluating variations in clinical practice. This paper describes a novel methodology--risk adjusted cost-effectiveness (RAC-E)--that facilitates the comparative evaluation of applied clinical practice processes. In this application, risk adjustment is undertaken with a multivariate matching algorithm that balances the baseline characteristics of patients attending different settings (e.g., hospitals). Linked, routinely collected data are used to analyse patient-level costs and outcomes over a 2-year period, as well as to extrapolate costs and survival over patient lifetimes. The study reports the relative cost-effectiveness of alternative forms of clinical practice, including a full representation of the statistical uncertainty around the mean estimates. The methodology is illustrated by a case study that evaluates the relative cost effectiveness of services for patients presenting with acute chest pain across the four main public hospitals in South Australia. The evaluation finds that services provided at two hospitals were dominated, and of the remaining services, the more effective hospital gained life years at a low mean additional cost and had an 80% probability of being the most cost-effective hospital at realistic cost-effectiveness thresholds. Potential determinants of the estimated variation in costs and effects were identified, although more detailed analyses to identify specific areas of variation in clinical practice are required to inform improvements at the less cost-effective institutions. PMID- 22544372 TI - Expression parameters of the metabolic pathway genes pyruvate dehydrogenase kinase-1 (PDK-1) and DJ-1/PARK7 in renal cell carcinoma (RCC). AB - PURPOSE: Metabolic adaptations, such as increases in glucose and energy metabolism, play a pivotal role in the biology of RCC. PDK-1 and DJ-1/PARK7 are thought to control metabolic pathways in cancer. We investigated the expression of PDK-1 and DJ-1/PARK7 in RCC and their prognostic relevance. METHODS: RCC tumor tissue and corresponding normal parenchyma samples were obtained from 91 patients with clear cell RCC. Expression of PDK-1 and DJ-1/PARK7 was determined on the mRNA and protein levels using quantitative RT-PCR and immunohistochemistry. Expression ratios tumor/normal were analyzed for associations with pathological stage and grade (Kruskal-Wallis ANOVA, chi-square test). Potential associations with progression-free and overall survival were analyzed using Cox regression models. RESULTS: PDK-1 mRNA expression was up-regulated as compared to normal tissue (p < 0.001). Differences were observed by tumor stage (p < 0.05) with a trend toward lower expression with increasing stage (p > 0.01). Expression ratio tumor/normal also showed differences by tumor stage with the lowest ratio observed in advanced (pT3) disease. MRNA expression data were confirmed on the protein level with the lowest protein expression in pT3 tumors. PDK-1 expression ratio tumor/normal was inversely associated with outcome after adjustment for stage and grade (HR, 0.54; 95 % CI, 0.31-0.94). No associations observed for DJ 1/PARK7 expression. CONCLUSIONS: PDK is up-regulated in RCC, but down-regulation may be associated with progression toward a metastasizing behavior. Given the role of PDK-1 in the control of glucose metabolism, aerobic glycolysis via up regulation of PDK-1 may be an early event in RCC development, but less relevant for the progression toward an aggressive phenotype. PMID- 22544376 TI - Evaluation of the French version of the 4-item index of the Acne-QoL (AcneQ4fr). AB - BACKGROUND: The 4-item index of the 19-item Acne-Quality of Life (Acne-QoL) has been validated in English (AcneQ4). French translation and linguistic validation of the Acne-QoL have recently been completed (Acne-QoLfr). PURPOSE: This study sought to evaluate reliability and responsivity of the French version of the AcneQ4 (AcneQ4fr). METHODS: Calculation of intraclass correlation coefficients (ICC) and regression modeling was performed to evaluate reliability (comparing Day 0 to Day 2-3 responses) and responsivity (comparing Day 0 to Day 60+ responses). RESULTS: Thirty-four native French-speaking acne subjects in Quebec, Canada (n = 20) and France (n = 14) completed the Acne-QoLfr on 3 occasions over 3 months (Day 0, Day 2-3, and Day 60+). Of 14 completed responses for Day 0 and Day 2-3, ICC for AcneQ4fr was 0.73 (with 95 % confidence interval (0.348, 0.905) and P value 0.001), and mean score difference was 0.85 (range of possible scores for AcneQ4fr: 0-24; P = 0.41). Of 19 completed responses for Day 0 and Day 60+, ICC for Acne-Q4fr was 0.45 (with 95 % confidence interval (0.046, 0.728) and P value 0.015) and mean score difference was 4.14 (P = 0.001). CONCLUSIONS: The abbreviated AcneQ4fr is somewhat reflective of the entire Acne-QoLfr and by its brevity may facilitate psychometric evaluation of francophone acne patients in routine practice. PMID- 22544374 TI - Genomic approaches to study genetic and environmental influences on fish sex determination and differentiation. AB - The embryonic gonad is the only organ that takes two mutually exclusive differentiating pathways and hence gives rise to two different adult organs: testes or ovaries. The recent application of genomic tools including microarrays, next-generation sequencing approaches, and epigenetics can significantly contribute to decipher the molecular mechanisms involved in the processes of sex determination and sex differentiation. However, in fish, these studies are complicated by the fact that these processes depend, perhaps to a larger extent when compared to other vertebrates, on the interplay of genetic and environmental influences. Here, we review the advances made so far, taking into account different experimental approaches, and illustrate some technical complications deriving from the fact that as development progresses it becomes more and more difficult to distinguish whether changes in gene expression or DNA methylation patterns are the cause or the consequence of such developmental events. Finally, we suggest some avenues for further research in both model fish species and fish species facing specific problems within an aquaculture context. PMID- 22544375 TI - Biomass and lipid production of dinoflagellates and raphidophytes in indoor and outdoor photobioreactors. AB - The principal fatty acids from the lipid profiles of two autochthonous dinoflagellates (Alexandrium minutum and Karlodinium veneficum) and one raphidophyte (Heterosigma akashiwo) maintained in bubble column photobioreactors under outdoor culture conditions are described for the first time. The biomass production, lipid content and lipid productivity of these three species were determined and the results compared to those obtained when the strains were cultured indoors. Under the latter condition, the biotic values did not significantly differ among species, whereas under outdoor conditions, differences in both duplication time and fatty acids content were observed. Specifically, A. minutum had higher biomass productivity (0.35 g.L-1 day-1), lipid productivity (80.7 mg lipid.L-1 day-1) and lipid concentration (252 mg lipid.L-1) at harvest time (stationary phase) in outdoor conditions. In all three strains, the growth rate and physiological response to the light and temperature fluctuations of outdoor conditions greatly impacted the production parameters. Nonetheless, the species could be successfully grown in an outdoor photobioreactor and were of sufficient robustness to enable the establishment of long-term cultures yielding consistent biomass and lipid production. PMID- 22544377 TI - U.S. Food and Drug Administration approval: ruxolitinib for the treatment of patients with intermediate and high-risk myelofibrosis. AB - On November 16, 2011, the U.S. Food and Drug Administration (FDA) granted full approval to ruxolitinib, (Jakafi; Incyte Corp.), an inhibitor of the Janus kinases 1 and 2, for the treatment of patients with intermediate- or high-risk myelofibrosis, including primary myelofibrosis, postpolycythemia vera myelofibrosis, and postessential thrombocythemia myelofibrosis. This approval was based on the results of 2 large randomized phase III trials that enrolled patients with intermediate-2 or high-risk myelofibrosis and compared ruxolitinib with placebo (study 1) or best available therapy (study 2). The primary efficacy endpoint was the proportion of patients who experienced a reduction in spleen volume of >= 35% at 24 weeks (study 1) or 48 weeks (study 2). The key secondary endpoint in study 1 was the proportion of patients who experienced a >= 50% improvement from baseline in myelofibrosis total symptom score at 24 weeks. The results of these studies showed that a greater proportion of patients treated with ruxolitinib experienced a >= 35% reduction in spleen volume as compared with those treated with placebo (42% vs. 1%, P < 0.0001) or best available therapy (29% vs. 0%, P < 0.0001). A greater proportion of patients in study 1 experienced a >= 50% reduction in the myelofibrosis total symptom score during treatment with ruxolitinib than with placebo (46% vs. 5%, P < 0.0001). Ruxolitinib treatment was associated with an increased incidence of grades III and IV anemia, thrombocytopenia, and neutropenia. This is the first drug approved for myelofibrosis. PMID- 22544378 TI - Occurrence of insecticide residues in selected crops and natural resources. AB - Pesticide residue monitoring was taken up at Kothapally and Enkepally villages of Ranga Reddy district, Andhra Pradesh in food crops (rice, maize, pigeonpea), vegetables (tomato and brinjal), cotton besides soil and water during 2008-2009 seasons. Of the 80 food crop and cotton samples, only two rice grain samples (3 %) showed beta endosulfan residues and two (3 %) out of 80 soil samples of food crops and cotton showed alpha and beta endosulfan residues. Out of 75 tomato samples, 26 (35 %) were contaminated and 4 % had residues above maximum residue limit (MRLs). Out of the 50 soil samples from tomato fields, 13 (26 %) contained residues. Among the 80 brinjal samples, 46 (56 %) contained residues and 4 % of samples had residues above MRLs. Only 13 % of the soil samples from brinjal fields were contaminated. Water samples found free from residues. In general the incidence of residues was below MRL in food crops. PMID- 22544379 TI - Is specific IgE antibody analysis feasible for the diagnosis of methylenediphenyl diisocyanate-induced occupational asthma? AB - PURPOSE: Early recognition improves the prognosis of isocyanate asthma. A major unanswered question is whether IgE-dependent mechanisms are of diagnostic value? Our objective was to appraise serological methods using various methylenediphenyl diisocyanate (MDI)-albumin conjugates and weigh up the data versus the outcome of standardized comprehensive clinical diagnostics to evaluate the viability of immunological analysis in supportive MDI-asthma diagnosis (OAI). METHODS: Specific IgE (sIgE) and IgG (sIgG) binding was measured with fluorescence enzyme immunoassay in 43 study subjects (using conjugates prepared in-vapor, in-solution and commercial preparations). The differential clinical diagnosis included standardized measurement of pulmonary function, non-specific bronchial hyper responsiveness, specific MDI-prick test (MDI-SPT) and specific inhalation challenge (MDI-SIC). RESULTS: Detailed diagnostic scheme allows the differential OAI and MDI-induced hypersensitivity pneumonitis (PI). The presumed OAI diagnoses were confirmed in 84 % (45 % cases having demonstrable sIgE antibodies) with RR 5.7, P > 0.001, when OAI diagnosis is correlated with MDI-SIC/MDI-SPT (RR 1.28 for MDI-SIC alone); sIgG antibodies were clinically relevant for PI and not for the OA diagnosis. MDI-specific IgE data generated with commercial ImmunoCAP preparations show high correlation with our in-vapor generated MDI conjugates. CONCLUSIONS: Isocyanate-specific IgE antibodies are not always detectable but their presence is strongly predictive of OAI and supportive for the diagnosis. MDI-SPT can be a valuable parameter differentiating OAI and PI. We have confirmed and extended published data showing that isocyanate-albumin conjugates perform better in specific antibody assays when prepared with volatile phase formulations and would like to stress additionally the necessity for further refinements and standardization in clinical diagnostics procedures. PMID- 22544381 TI - A uniform sub-50 nm-sized magnetic/upconversion fluorescent bimodal imaging agent capable of generating singlet oxygen by using a 980 nm laser. AB - Upconverting nanoparticles (UCNPs) with fascinating properties hold great potential as nanotransducers for solving the problems that traditional photodynamic therapy (PDT) has been facing. In this report, by using well selected bifunctional gadolinium (Gd)-ion-doped UCNPs and water-soluble methylene blue (MB) combined with the water-in-oil reverse microemulsion technique, we have succeeded in developing a new kind of UCNP/MB-based PDT drug, NaYF(4):Er/Yb/Gd@SiO(2)(MB), with a particle diameter less than 50 nm. Great efforts have been made to investigate the drug-formation mechanism and provide detailed physical and photochemical characterizations and the potential structure optimization of the as-designed PDT drug. We envision that such a PDT drug will become a potential theranostic nanomedicine for future near-infrared laser triggered photodynamic therapy and simultaneous magnetic/optical bimodal imaging. PMID- 22544380 TI - The fatty acid 8,11-diol synthase of Aspergillus fumigatus is inhibited by imidazole derivatives and unrelated to PpoB. AB - (8R)-Hydroperoxy-(9Z,12Z)-octadecadienoic acid (8-HPODE) is formed by aspergilli as an intermediate in biosynthesis of oxylipins with effects on sporulation. 8 HPODE is transformed by separate diol synthases to (5S,8R)-dihydroxy- and (8R,11S)-dihydroxy-(9Z,12Z)-octadecadienoic acids (5,8- and 8,11-DiHODE). The former is formed by the cytochrome P450 (P450) domain of 5,8-linoleate diol synthase (5,8-LDS or PpoA). Our aim was to characterize the 8,11-diol synthase of Aspergillus fumigatus, which is prominent in many strains. The 8,11-diol synthase was soluble and had a larger molecular size (>100 kDa) than most P450. Miconazole, ketoconazole, and 1-benzylimidazole, classical inhibitors of P450, reduced the biosynthesis of 8,11-DiHODE from 8-HPODE (apparent IC(50) values ~0.8, ~5, and ~0.6 MUM, respectively), but did not inhibit the biosynthesis of 5,8-DiHODE. Analysis of hydroperoxides of regioisomeric C(18) and C(20) fatty acids showed that the 8,11-diol synthase was specific for certain hydroperoxides with R configuration. The suprafacial hydrogen abstraction and oxygen insertion at C-11 of 8-HPODE was associated with a small deuterium kinetic isotope effect ((H) k (cat)/(D) k (cat) ~1.5), consistent with P450-catalyzed oxidation. The genome of A. fumigatus contains over 70 P450 sequences. The reaction mechanism, size, and solubility of 8,11-diol synthase pointed to PpoB, a homologue of 5,8 LDS, as a possible candidate of this activity. Gene deletion of ppoB of A. fumigatus strains AF:?ku80 and J272 did not inhibit biosynthesis of 8,11-DiHODE and recombinant PpoB appeared to lack diol synthase activity. We conclude that 8,11-DiHODE is formed from 8-HPODE by a soluble and substrate-specific 8,11-diol synthase with catalytic characteristics of class III P450. PMID- 22544382 TI - Conformational distributions of N-acetyl-L-cysteine in aqueous solutions: a combined implicit and explicit solvation treatment of VA and VCD spectra. AB - The conformational distributions of N-acetyl-L-cysteine (NALC) in aqueous solutions at several representative pH values are investigated using vibrational absorption (VA), UV/Vis, and vibrational circular dichroism (VCD) spectroscopy, together with DFT and molecular dynamics (MD) simulations. The experimental VA and UV/Vis spectra of NALC in water are obtained under strongly acid, neutral, and strongly basic conditions, as well as the VCD spectrum at pH 7 in D(2)O. Extensive searches are carried out to locate the most stable conformers of the protonated, neutral, deprotonated, and doubly deprotonated NALC species at the B3LYP/6-311++G(d,p) level. The inclusion of the polarizable continuum model (PCM) modifies the geometries and the relative stabilities of the conformers noticeably. The simulated PCM VA spectra show significantly better agreement with the experimental data than the gas-phase ones, thus allowing assignment of the conformational distributions and dominant species under each experimental condition. To further properly account for the discrepancies noted between the experimental and simulated VCD spectra, PCM and the explicit solvent model are utilized. MD simulations are used to aid the modelling of the NALC-(water)(N) clusters. The geometry optimization, harmonic frequency calculations, and VA and VCD intensities are computed for the NALC-(water)(3,4) clusters at the B3LYP/6 311++G(d,p) level without and with the PCM. The inclusion of both explicit and implicit solvation models at the same time provides a decisively better agreement between theory and experiment and therefore conclusive information about the conformational distributions of NALC in water and hydrogen-bonding interactions between NALC and water molecules. PMID- 22544383 TI - The correlation between carotid-femoral pulse wave velocity and composition of the aortic media in CAD patients with or without hypertension. AB - OBJECTIVES: To investigate the influence of hypertension on large artery elasticity and the microstructure of the ascending aortic media in patients with coronary artery disease (CAD), and the association between arterial compliance and composition of the ascending aorta. METHODS: 60 patients with CAD who underwent coronary artery bypass graft surgery were divided into two groups: 30 patients in a hypertension group and 30 patients in a non-hypertension group. Carotid-femoral pulse wave velocity (cfPWV) was measured by an automatic device (Complior, Artech, France). The severity of coronary atherosclerosis was assessed after selective coronary angiography using the Gensini score system. A quantitative study was conducted on ascending aorta specimens by histological and computer image analysis. RESULTS: cfPWV of the hypertension group was higher than that of the non-hypertension group. The relative content of collagen in the ascending aortic media of the hypertension group was higher than that of the non hypertension group, while the relative content of elastin in the ascending aortic media of the hypertension group was lower than that of the non-hypertension group. cfPWV showed a positive correlation with relative contents of collagen in the ascending aorta and a negative correlation with relative contents of elastin in the ascending aorta in the two groups. CONCLUSIONS: Hypertension may raise the contents of collagen and decrease the contents of elastin in the ascending aortic media of patients with CAD, which in turn may decrease the patients' large artery compliance. cfPWV may reflect the quantitative changes of collagen and elastin in the ascending aortic media in CAD patients independently of hypertension. PMID- 22544384 TI - Adolescent and caregiver reports of ADHD symptoms among inner-city youth: agreement, perceived need for treatment, and behavioral correlates. AB - OBJECTIVE: This study investigated adolescent and caregiver reports of ADHD symptoms in a sample of clinically referred inner-city adolescents. METHOD: Participants (N = 168) included youth ages 12-18 (54% male, 98% ethnic minority) and their caregivers who each completed diagnostic interviews of ADHD symptoms and assessments of perceived need for ADHD treatment and correlated behavior problems. RESULTS: Informants showed poor agreement on DSM-IV diagnostic categories and also dimensional scales, Inattention/Disorganization (I/D) and Hyperactivity/Impulsivity (H/I). Both caregiver and adolescent reports of I/D symptoms, but not H/I symptoms, were related to perceived need for ADHD treatment. Caregiver reports were linked to behavioral correlates typically associated with ADHD: I/D symptoms correlated with planning/organization and socioemotional deficits, and H/I symptoms correlated with externalizing and behavior regulation deficits. In contrast, adolescent reports of I/D were related to internalizing and externalizing problems, and their reports of H/I correlated with externalizing only. Few gender effects were found. CONCLUSION: Study results underscore the developmental salience of I/D symptoms and have implications for ADHD diagnosis and treatment planning for adolescents. PMID- 22544385 TI - Navigating adolescence: an epidemiological follow-up of adaptive functioning in girls with childhood ADHD symptoms and conduct disorder. AB - OBJECTIVE: The current study investigated the experience of girls growing up with cognitive and social disorders. METHOD: Eight adolescent girls participated in interviews that were transcribed and analyzed using Interpretative Phenomenological Analysis. RESULTS: Four of the girls had a history of ADHD symptoms and conduct disorder problems (ADHD/CP), four did not. Three master themes emerged within the domain of "Coping Behaviors": seeking social support, bravado, and avoidance. Three master themes emerged within the domain of "Barriers to Adaptive Functioning": lack of support and guidance, poor negotiation of interpersonal conflict, and victimization. Although all participants experienced developmental barriers, the girls with ADHD/CP coped with these barriers in a less effective way. CONCLUSION: The study raises an important developmental concern, the seemingly ineffective coping strategies of ADHD/CP adolescents. PMID- 22544386 TI - Language profiles and mental health problems in children with specific language impairment and children with ADHD. AB - OBJECTIVE: This study aimed to explore whether children with specific language impairment (SLI) and children with ADHD can be differentiated from each other in terms of their language profiles, and also to investigate whether these two clinical groups differ regarding mental health problems. METHOD: A total of 59 children in the age range 6 to 12 years participated in the study. The parents completed the Children's Communication Checklist-Second Edition and the Strengths and Difficulties Questionnaire. RESULTS: Communication impairments were as prominent in the ADHD group as in the SLI group; however, the groups were separable from each other in terms of their language profiles. Furthermore, the ADHD group experienced significantly more mental health problems compared with the SLI group. CONCLUSION: Language should be assessed in children with ADHD and instruments sensitive to ADHD should be included when assessing children with SLI. Mental health should be an area of concern to be addressed in both groups. PMID- 22544387 TI - Symptom dimensions of disruptive behavior disorders in adolescent drivers. AB - OBJECTIVE: Adolescents with disruptive behavior disorder, including ADHD, are more likely to engage in risky driving practices and, consequently, are more likely to be involved in a motor vehicle crash (MVC) than their non-ADHD peers. It is unclear whether symptoms of inattention, hyperactivity/impulsivity, or oppositional defiant disorder (ODD) increase risk of poor driving outcomes. METHOD: A total of 41 participants (16-19 years old) reported their ADHD and ODD symptoms and risky driving practices (errors and violations). History of citations and MVCs were acquired from state records. Relative predictive utility of symptom dimensions was assessed using multiple regressions. RESULTS: Inattention solely predicted driving variables of interest: Greater levels of inattention were predictive of more citations, MVCs, and self-reported errors and violations. CONCLUSION: Findings suggest that symptoms of inattention play a primary role in driving-related problems among adolescents. Implications for future research and practice are discussed. PMID- 22544388 TI - Atomoxetine for treating ADHD symptoms in autism: a systematic review. AB - OBJECTIVE: This study systematically reviews the current literature on the administration of atomoxetine for treating children and adolescents with comorbidity on autism spectrum disorder (ASD) and ADHD. METHOD: PubMed/Medline and Google Scholar databases were electronically searched to find the published trials on atomoxetine and ASD. RESULTS: Six articles reported the clinical trials of atomoxetine for treatment of ADHD symptoms in patients with autism or pervasive development disorders. Only one study that was placebo-controlled crossover pilot trial reported that it is effective. Atomoxetine may be effective in high-functioning patients with autism or patients with low severity. Those with high severity of ASD may be more vulnerable to the adverse effects of atomoxetine. CONCLUSION: There are not enough controlled clinical trials for showing the efficacy of atomoxetine for treatment of ADHD symptoms in autism. Although evidence suggests potential efficacy of atomoxetine, the current evidences are not conclusive. PMID- 22544389 TI - Pentacycloundecane-diol-based HIV-1 protease inhibitors: biological screening, 2D NMR, and molecular simulation studies. AB - Novel compounds incorporating a pentacycloundecane (PCU) diol moiety were designed, synthesized, and evaluated as inhibitors of the wild-type C-South African (C-SA) HIV-1 protease. Seven compounds are reported herein, three of which displayed IC(50) values in the 0.5-0.6 MUM range. The cytotoxicity of PCU cage peptides toward human MT-4 cells appears to be several orders of magnitude less toxic than the current antiviral medications ritonavir and lopinavir. NMR studies based on the observed through-space (1)H,(1)H distances/contacts in the EASY-ROESY spectra of three of the considered PCU peptide inhibitors enabled us to describe their secondary solution structure. Conserved hydrogen bonding interactions were observed between the hydroxy group of the PCU diol inhibitors and the catalytic triad (Asp25, Ile26, Gly27) of HIV protease in docking and molecular dynamics simulations. The biological significance and possible mode of inhibition by PCU-based HIV protease inhibitors discussed herein facilitates a deeper understanding of this family of inhibitors and their potential application to a vast number of alternative diseases related to proteases. PMID- 22544390 TI - Isolation of cell nuclei in microchannels by short-term chemical treatment via two-step carrier medium exchange. AB - Separation/purification of nuclei from cells is a critical process required for medical and biochemical research applications. Here, we report a flow-through microfluidic device for isolating cell nuclei by selectively digesting the cell membrane by using the concept of hydrodynamic filtration (HDF). When a cell suspension is continuously introduced into a microchannel (main channel) possessing multiple side channels, cells flow through the main channel, whereas the carrier medium of the cells is drained through the side channels. Introductions of a cell treatment solution containing a surfactant and a washing buffer enable the two-step exchange of the carrier-medium and the cell treatment by the surfactant for a short span of time. The precise control of the treatment time by changing the flow rate and/or the size of the microchannel enables the selective digestion of cell membranes, resulting in the isolation of cell nuclei after separation from membrane debris and cytoplasmic components according to size. We examined several surfactant molecules and demonstrated that Triton X-100 exhibited high efficiency regarding nucleus isolation for both adherent (HeLa) and nonadherent (JM) cells, with a recovery ratio of ~80 %. In addition, the isolation efficiency was evaluated by western blotting. The presented flow through microfluidic cell-nucleus separator may be a useful tool for general biological applications, because of its simplicity in operation, high reproducibility, and accuracy. PMID- 22544391 TI - Adrenal haemangioblastoma presenting as phaeochromocytoma: a rare manifestation of extraneural hemangioblastoma. AB - PURPOSE: Adrenal haemangioblastoma presenting clinically as pheochromocytoma is a rare manifestation of extraneural haemangioblastoma. We present an unusual case of von Hippel-Lindau (VHL) disease that had adrenal and cerebellar haemangioblastoma with multiple renal cysts, and a review of the literature. METHODS: Unlike the usual manifestations of secondary polycythemia or increased intracranial pressure and hydrocephalus due to cerebellar lesion, this 36-year old male presented with hypertension. Investigations revealed right suprarenal mass with raised urinary catecholamines and serum vanillylmandelic acid (VMA) levels, apparently confirming the clinical diagnosis of phaeochromocytoma. RESULTS: Histopathology of the biopsy specimen showed features of haemangioblastoma, which was confirmed by immunohistochemistry using antibodies to neuron specific enolase and aquaporin-1. Based on this, the patient was screened for possible features of VHL, which revealed cerebellar haemangioblastoma and multiple renal cysts with angiomatous lesion. Postoperative follow-up showed normal levels of catecholamines without any symptoms of phaeochromocytoma. CONCLUSIONS: Adrenal haemangioblastoma is a rare entity with only four cases reported in the literature. Surgical removal is the treatment of choice. However, screening for other possible features of VHL, even in the absence of clinical features, is essential to exclude other potential lesions. PMID- 22544392 TI - TRIM28 prevents autoinflammatory T cell development in vivo. AB - TRIM28 is a component of heterochromatin complexes whose function in the immune system is unknown. By studying mice with conditional T cell-specific deletion of TRIM28 (CKO mice), we found that TRIM28 was phosphorylated after stimulation via the T cell antigen receptor (TCR) and was involved in the global regulation of CD4(+) T cells. The CKO mice had a spontaneous autoimmune phenotype that was due in part to early lymphopenia associated with a defect in the production of interleukin 2 (IL-2) as well as incomplete cell-cycle progression of their T cells. In addition, CKO T cells showed derepression of the cytokine TGF-beta3, which resulted in an altered cytokine balance; this caused the accumulation of autoreactive cells of the T(H)17 subset of helper T cells and of Foxp3(+) T cells. Notably, CKO Foxp3(+) T cells were unable to prevent the autoimmune phenotype in vivo. Our results show critical roles for TRIM28 in both T cell activation and T cell tolerance. PMID- 22544393 TI - Translational control of the activation of transcription factor NF-kappaB and production of type I interferon by phosphorylation of the translation factor eIF4E. AB - Type I interferon is an integral component of the antiviral response, and its production is tightly controlled at the levels of transcription and translation. The eukaryotic translation-initiation factor eIF4E is a rate-limiting factor whose activity is regulated by phosphorylation of Ser209. Here we found that mice and fibroblasts in which eIF4E cannot be phosphorylated were less susceptible to virus infection. More production of type I interferon, resulting from less translation of Nfkbia mRNA (which encodes the inhibitor IkappaBalpha), largely explained this phenotype. The lower abundance of IkappaBalpha resulted in enhanced activity of the transcription factor NF-kappaB, which promoted the production of interferon-beta (IFN-beta). Thus, regulated phosphorylation of eIF4E has a key role in antiviral host defense by selectively controlling the translation of an mRNA that encodes a critical suppressor of the innate antiviral response. PMID- 22544394 TI - Clonal deletion and the fate of autoreactive thymocytes that survive negative selection. AB - Clonal deletion of autoreactive thymocytes is important for self-tolerance, but the intrathymic signals that induce clonal deletion have not been clearly identified. We now report that clonal deletion during negative selection required CD28-mediated costimulation of autoreactive thymocytes at the CD4(+)CD8(lo) intermediate stage of differentiation. Autoreactive thymocytes were prevented from undergoing clonal deletion by either a lack of CD28 costimulation or transgenic overexpression of the antiapoptotic factors Bcl-2 or Mcl-1, with surviving thymocytes differentiating into anergic CD4(-)CD8(-) double-negative thymocytes positive for the T cell antigen receptor alphabeta subtype (TCRalphabeta) that 'preferentially' migrated to the intestine, where they re expressed CD8alpha and were sequestered as CD8alphaalpha(+) intraepithelial lymphocytes (IELs). Our study identifies costimulation by CD28 as the intrathymic signal required for clonal deletion and identifies CD8alphaalpha(+) IELs as the developmental fate of autoreactive thymocytes that survive negative selection. PMID- 22544401 TI - From fish to philosopher. AB - Fifty years ago, your editor had the pleasure of reading From Fish To Philosopher, a book by Homer Smith. An eminent physiologist, he related the story of vertebrate kidney evolution seen through kidney function on different phylogenetic levels and how it facilitates the adaptation of organisms to highly specialized environments. At this juncture, a wary reader may be wondering where in the world this editorial in a journal of allied health is headed. The answer is that the topic of evolution serves as an architectural framework for thinking about many things pertaining to the Journal of Allied Health. PMID- 22544400 TI - Patient selection for mechanical circulatory support. AB - Heart failure continues to be associated with high morbidity and mortality. Over the past decade, left ventricular assist devices have been shown to improve the survival and quality of life. However, it is quite clear that very sick patients do not do as well, and it is therefore imperative to select patients at the proper time. In this article, we review both the indications for considering left ventricular assist device therapy as well as discuss the considerations and therapy that should be done pre-operatively to possibly improve post-insertion outcomes. PMID- 22544402 TI - Viewing health care through a semiotic veil of signs. AB - An old joke goes as follows. A patient is admitted to an emergency room and, while lying there, overhears a conversation about his case by a group of health professionals. One asks, "Should we treat him or should we let him live." Fear of the unknown upon entering the health care arena is an important element in life for many patients. Apart from a sense of anxiety that may result from the appearance of a suspicious lump or stomach pain, patients bring a host of important attributes to the health care setting. Depending on the degree of similarity, or lack thereof, between patients and providers on factors such as age, gender, and race/ethnicity, their interaction might be more of a social collision than a satisfactory encounter. This chapter touches upon certain elements that have the potential to influence the quality of their interaction. PMID- 22544395 TI - TGF-beta and retinoic acid induce the microRNA miR-10a, which targets Bcl-6 and constrains the plasticity of helper T cells. AB - Distinct CD4(+) T cell subsets are critical for host defense and immunoregulation. Although these subsets can act as terminally differentiated lineages, they have been increasingly noted to demonstrated plasticity. MicroRNAs are factors that control T cell stability and plasticity. Here we report that naturally occurring regulatory T cells (T(reg) cells) had high expression of the microRNA miR-10a and that miR-10a was induced by retinoic acid and transforming growth factor-beta (TGF-beta) in inducible T(reg) cells. By simultaneously targeting the transcriptional repressor Bcl-6 and the corepressor Ncor2, miR-10a attenuated the phenotypic conversion of inducible T(reg) cells into follicular helper T cells. We also found that miR-10a limited differentiation into the T(H)17 subset of helper T cells and therefore represents a factor that can fine tune the plasticity and fate of helper T cells. PMID- 22544403 TI - Development, implementation, and short-term effectiveness of an interprofessional education course in a school of health professions. AB - It is accepted that interprofessional education (IPE) has positive benefits for health profession students, including effective communication, increased teamwork skills, and better appreciation for the roles of other health professions. However, the question remains of how to effectively deliver IPE for health professions students in an educational environment. To address this problem, the University of Texas Southwestern School of Health Professions developed an IPE course, Interdisciplinary Development, Education, and Active Learning (IDEAL), incorporating seven disciplines represented within the school. The hypothesis was that a two-semester exposure to the new curriculum and related activities would have a significant positive influence on students' understanding of the elements required for effective communication (e.g., listening and interpersonal skills), teamwork skills, and understanding the roles of other health professions. An assessment of a student's understanding of communication and teamwork skills was administered on the first and last day of the IDEAL course to test the hypothesis and determine if course objectives of improving student's communication and teamwork skills were met. Questions were divided into three focus areas of teamwork, listening, and interpersonal communication. Findings showed a significant (p < 0.016) increase in scores for all three areas, the largest being in teamwork. Also, results from an anonymous, open-ended survey of the overall IDEAL course at the end of the course showed overwhelming consensus regarding the success and effectiveness of the healthcare team grand rounds presentations from which the students learned about other professions and their roles on the healthcare team in a case-based format. PMID- 22544404 TI - Attitudes of faculty and students in medicine and the health professions toward interprofessional education. AB - BACKGROUND: This study evaluated the important relationship between faculty and student attitudes toward interprofessional education using the Interdisciplinary Education Perception Scale (IEPS). METHODS: Medicine, nursing, occupational therapy, pharmacy, and physical therapy faculty (n = 177) completed the IEPS. Students from these disciplines participate in a 2-year, interdisciplinary curriculum in which they were assigned to a team to work with a patient volunteer. Students (n = 496) completed the IEPS at the end of program year one. The IEPS measures four factors: professional competence/autonomy; perceived need for professional cooperation; perception of actual cooperation/resource sharing within and across professions; and understanding the value of other professions. FINDINGS: Overall attitude scores for faculty and students were high, ranging from 3.93 to 4.40 on a 5-point scale. Attitudes on each factor were also high, with the exception of factor 4, "understanding the value of other professions," having the lowest scores, 3.26 to 3.92. CONCLUSION: The positive attitudes among faculty and students and across professions suggest an acceptance of the principles of interprofessional education and a readiness to engage in interprofessional practice. The lower scores on factor 4 indicate the need for additional educational programs focusing on understanding the roles of each profession. PMID- 22544405 TI - Changes in student attitudes toward interprofessional learning and collaboration arising from a case-based educational experience. AB - Working effectively with other disciplines is an important and necessary skill for healthcare practitioners. Academic institutions can provide educational experiences that can begin to foster the prerequisite competencies needed to collaborate successfully with other healthcare professionals. The purpose of this study was to examine changes in attitudes toward learning from and collaborating with other healthcare students and professionals arising from an interprofessional educational (IPE) experience. A total of 123 graduate students from clinical psychology (n = 35), education (n = 17), physical therapy (n = 36), and social work (n = 35) were enrolled in the study and participated in a 6-hour IPE experience designed to improve their understanding of the roles played by other healthcare professionals on teams and to teach the skills necessary to effectively collaborate. Attitudes toward learning from and collaborating with other disciplines were examined prior to and immediately after an IPE experience using the Interdisciplinary Education Preparation Scale (IEPS), the Readiness for Professional Learning Scale (RIPLS), and the Attitudes Toward Healthcare Teams Scales (ATHCTS). A 4 (discipline) 3 2 (pre- vs post-IPE) repeated measures ANOVA was used to investigate between- and within-group differences. Statistical significance was set at p <= 0.05 for all primary analyses, and post hoc differences for any statistically significant ANOVA findings were explored using a Bonferroni procedure. Statistically significant increases in post-IPE scores on the IEPS, RIPLS, and ATHCTS were found, indicating positive changes in attitudes toward learning from and collaborating with graduate students and other healthcare professionals. A well-structured educational experience, consisting of 6 hours of interprofessional interaction, can change student attitudes toward learning from and collaborating with peers in other healthcare disciplines prior to graduation and professional licensure. The current study provides evidence that a relatively short educational intervention implemented prior to graduation can positively change attitudes toward learning and collaboration. PMID- 22544406 TI - Facilitating neurorehabilitation through principles of engagement. AB - A primary goal of neurorehabilitation is to guide recovery of functional skills after injury through evidence-based interventions that operate to manipulate the sensorimotor environment of the client. While choice of intervention is an important decision for clinicians, we contend it is only one part of producing optimal activity-dependent neuroplastic changes. A key variable in the rehabilitation equation is engagement. Applying principles of engagement may yield greater neuroplastic changes and functional outcomes for clients. We review the principles of neuroplasticity and engagement and their potential linkage through concepts of attention and motivation and strategies such as mental practice and enriched environments. Clinical applications and challenges for enhancing engagement during rehabilitation are presented. Engagement strategies, such as building trust and rapport, motivational interviewing, enhancing the client education process, and interventions that empower clients, are reviewed. Well-controlled research is needed to test our theoretical framework and suggested outcomes. Clinicians may enhance engagement by investing time and energy in the growth and development of the therapeutic relationship with clients, as this is paramount to maintaining clients' investment in continuing therapy and also may act as a driver of neuroplastic changes. PMID- 22544407 TI - An impact of an aging society on allied health practice and education. PMID- 22544408 TI - Mentors matter: relationships that increase the number of oral health professionals serving the underserved. AB - Access to oral healthcare is a persistent problem in the United States. One barrier to this multifaceted issue is the shortage of oral healthcare providers who are willing to provide care for underserved populations. Mentoring relationships with oral health professionals is one solution that will increase the number of public oral health professionals. Using narrative inquiry, this interpretive study explored the relationships that public health dental hygienists had with mentors who leveraged their capital to empower those they mentored. The stories of six dental hygienists practicing in public health and four of their mentors were gathered through one or two 60- to 90-minute interviews. Qualitative data analysis was used to untangle and make meaning of their narrations. The findings are reported in the words of dental hygienists and their mentors, wherever possible, to embrace the voice of the participants. The Iroquois legend of The Three Sisters is used as a metaphor to illustrate the mentoring relationship. These mentor relationships, in which there was mutual growth, were built on a symbiotic, natural bond. The dental hygienists recalled relationships with multiple mentors who leveraged their social and political capital to empower and thereby encouraged a career path in public health. PMID- 22544409 TI - Librarians and occupational therapy faculty: a collaboration for teaching evidence-based practice. AB - Students in allied health educational programs learn evidence-based practice (EBP) skills, yet often do not consistently utilize these skills as practitioners. Barriers to implementing EBP include time pressures and lack of skill. This descriptive study explains how librarians can teach information literacy skills and strengthen knowledge of EBP in graduate occupational therapy (OT) students. The goal of the study was to evaluate students' perception of the effectiveness of learning activities about EBP, and librarians' perception of the value of teaching in an OT curriculum. Sixty-three students at the University of Texas Health Science Center at San Antonio read articles and learned didactic information from OT faculty and librarians about EBP. Students researched intervention questions and electronically sent searches to librarians for feedback. Students applied skills by researching an intervention of their choice. Evaluative data were collected from students in 2009 and 2010 and from librarians in 2009. Both groups rated the learning experiences highly. Students felt the learning experiences improved their effectiveness in carrying out EBP. Librarians valued the experience of teaching information literacy to OT students. These results support other studies showing librarians' effectiveness in developing EBP skills in students. Recommendations are given about using journal clubs and secondary literature to ensure the use of EBP at the workplace. PMID- 22544410 TI - Use of a food frequency questionnaire to fulfill the research competency requirement for dietetics students. AB - This article describes a research project developed by the Nutrition Division at Georgia State University (GSU). The project involved students' development of a food frequency questionnaire (FFQ) and satisfied the research competency requirements of the American Dietetic Association's accrediting body. Both Coordinated Program students and Dietetic Interns from a variety of research training backgrounds were trained as a single group on topics related to the research requirements and that would prepare them to develop and use a FFQ. Students completed a literature review on a nutrient or food group of interest and received training on human subject research, subject recruitment, and data analysis with statistical methods. They then developed, administered, and analyzed the results of a FFQ and compared it to a gold standard FFQ. GSU nutrition professors conducted pre- and post-session surveys to gauge whether students gained the research skills they need. Students' evaluation of the assignment strongly suggests that they felt more capable of calculating and interpreting results from survey data after completing the project. The present article provides a framework other nutrition educators can follow. Other allied health educators can consider designing similar research projects that: (a) are uniquely relevant to their professional competency requirements, (b) are feasible for students from a variety of research training backgrounds, and (c) allow students to practice using research tools and skills frequently used in their profession. PMID- 22544411 TI - Standardized patient feedback: making it work across disciplines. AB - In health professions education, feedback can be defined as the sharing of information about a student's performance. The most valuable learning occurs when students receive detailed feedback delivered in a way they can utilize it. In clinical simulations, feedback from a standardized patient (SP) offers a unique perspective. This article presents some of the underlying theory and research on feedback delivery with a particular emphasis on the role of non-verbal communication. We explore what feedback students need from SPs, how to provide feedback effectively as well as common challenges to the process. The authors, working from different health care disciplines, collaborated to develop a training workshop for the college's SPs designed to ensure a consistent approach to SP feedback delivery. We describe this workshop and its outcomes. PMID- 22544412 TI - Online course design for teaching critical thinking. AB - Teaching critical thinking (CT) skills, a goal in higher education, is seldom considered in the primary design of either classroom or online courses, and is even less frequently measured in student learning. In health professional education, CT along with clinical reasoning skills is essential for the development of clinical practitioners. This study, measuring CT skill development in an online theory course, supports using a cyclical course design to build higher level processes in student thinking. Eighty-six Masters of Occupational Therapy students in four sections of an occupation-based theory course were evaluated on elements in the Paul and Elder CT Model throughout the course and surveyed for their perceptions in their ability to think critically at course completion. Results of this study demonstrated that the online theory course design contributed to improving critical thinking skills and student's perceived CT skill development as applicable to their future professional practice. In a focus group, eight students identified four effective course design features that contributed to their CT skill development: highly structured learning, timely feedback from instructor, repetition of assignments, and active engagement with the material. PMID- 22544413 TI - Cross-cultural adaptation, reliability, and validity of the Turkish version of PedsQL 3.0 Arthritis Module: a quality-of-life measure for patients with juvenile idiopathic arthritis in Turkey. AB - PURPOSE: The aim of this study was to describe the cultural adaptation, validity, and reliability of a Turkish version of the pediatric quality-of-life inventory (PedsQL) 3.0 Arthritis Module in a population with juvenile idiopathic arthritis (JIA). METHODS: A total of 169 patients with JIA and their parents were enrolled in the study. The Turkish version of the childhood health assessment questionnaire (CHAQ) was used to evaluate the validity of related domains in the PedsQL 3.0 Arthritis Module. Both the PedsQL 3.0 Arthritis Module and CHAQ were filled out by children over 8 years of age and by the parents of children 2-7 years of age. RESULTS: Internal reliability was poor to excellent (Cronbach's alpha coefficients 0.56-0.84 for self-reporting and 0.63-0.82 for parent reporting), and interobserver reliability varied from good to excellent (intraclass correlation coefficient (ICC) 0.79-0.91 for self-reporting and 0.80 0.88 for parent reporting) for the total scores of the PedsQL 3.0 Arthritis Module. Parent-child concordance for all scores was moderate to excellent (ICC 0.42-0.92). The PedsQL 3.0 Arthritis Module and CHAQ were highly positively correlated, with coefficients from 0.21 to 0.76, indicating concurrent validity. CONCLUSIONS: We demonstrated the reliability and validity of quality-of-life measurement using the Turkish version of the PedsQL 3.0 Arthritis Module in our sociocultural context. The PedsQL 3.0 Arthritis Module can be utilized as a tool for the evaluation of quality of life in patients with JIA aged 2-18 years. PMID- 22544414 TI - Self-efficacy and adherence as mediating factors between personality traits and health-related quality of life. AB - PURPOSE: Personality traits are rather stable dispositions in adulthood, while self-efficacy and adherence may be modified through targeted interventions. Health-related quality of life (HRQL) serves as a vital outcome measure. The present aim was to explore the function of self-efficacy and adherence as mediators for the influencing effect of personality traits on HRQL in people with chronic disease. METHODS: An epidemiological sample of 786 persons completed questionnaires on personality, general self-efficacy, adherence behaviour and HRQL. Data were statistically analysed using descriptive statistics, correlation analyses and path models. RESULTS: Self-efficacy mediated the effect of Extraversion and Conscientiousness on mental HRQL. Neuroticism had a direct effect on both physical and mental HRQL. Adherence partially mediated the effect of both Agreeableness and Conscientiousness on mental HRQL. CONCLUSIONS: The mental HRQL in people scoring low on Extraversion or low on Conscientiousness could be improved by strengthening general self-efficacy. Increasing adherence in people scoring low on Agreeableness or Conscientiousness could improve their mental HRQL, but the improvement was small and may be of lesser clinical relevance. These results argue for personalized interventions intended to positively affect health outcomes in people with chronic disease. PMID- 22544415 TI - Correlations between physician-perceived functional status, patient-perceived health status, and cardiopulmonary exercise results in hypertrophic cardiomyopathy. AB - BACKGROUND: Dyspnea and the resulting functional impairment are a common complication in hypertrophic cardiomyopathy (HCM). The relationship between physician-perceived functional status, patient-perceived health status, and objective exercise test results has not been evaluated in this condition. PURPOSE: To evaluate the correlation between the Kansas City Cardiomyopathy Questionnaire (KCCQ) and (1) physician's perceived (NYHA class) and (2) objective measurement (cardiopulmonary exercise test) of functional capacity in patients with HCM. METHODS: In 24 outpatients with HCM at a single, referral center, the KCCQ instrument was administered and cardiopulmonary exercise testing (CPX) was performed. Severity of symptoms as determined by physician (NYHA classification) and patient (KCCQ instrument) was obtained before exercise test results were known. Pearson correlation was used to assess the independent correlation between KCCQ score and the various exercise parameters; Spearman correlation was used to assess correlation between KCCQ score and NYHA class. RESULTS: KCCQ results demonstrated moderate reductions in all domains, with greatest reduction in quality-of-life domain. CPX testing showed reduction in peak oxygen consumption (mean absolute VO2 20.5 +/- 7.8 ml/kg/min and percent predicted VO2 76.8 +/- 4.1 %). There were negative correlations between NYHA class and all KCCQ components except the self-efficacy score. The strongest correlations were between NYHA class and the overall summary score (r = -0.623, p = 0.001) as well as the physical limitation score (r = -0.604, p = 0.002). Similarly, there were statistically significant positive correlations between the KCCQ components and percent predicted peak VO2. The strongest correlation was between percent predicted peak VO2 and the physical limitation score (r = 0.474, p = 0.019), but there was also correlation between percent predicted peak VO2 and the quality-of life score (r = 0.456, p = 0.025), the functional status score (r = 0.455, p = 0.025), and the clinical summary score (r = 0.444, p = 0.030). CONCLUSIONS: The multiple domains of the KCCQ provide data on patient-perceived health status, which correlate with physician-perceived and objective measurement of functional capacity in HCM. Additional studies are needed to evaluate the sensitivity of the KCCQ to changes in functional capacity over time or in response to therapies for this condition. PMID- 22544416 TI - A descriptive analysis of quality of life using patient-reported measures in major depressive disorder in a naturalistic outpatient setting. AB - PURPOSE: Major depressive disorder (MDD) negatively impacts different aspects of an individual's life leading to grave impairments in quality of life (QOL). We performed a detailed analysis of the interaction between depressive symptom severity, functioning, and QOL in outpatients with MDD in order to better understand QOL impairments in MDD. METHODS: This cross-sectional study was conducted with 319 consecutive outpatients seeking treatment for DSM-IV-diagnosed MDD at an urban hospital-based outpatient clinic from 2005 to 2008 as part of the Cedars-Sinai Psychiatric Treatment Outcome Registry, a prospective cohort study of clinical, functioning, and patient-reported QOL outcomes in psychiatric disorders using a measurement-based care model. This model utilizes the following measures: (a) Depressive symptom severity: Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR); (b) Functioning measures: Global Assessment of Functioning (GAF), Sheehan Disability Scale (SDS), Work and Social Adjustment Scale, and the Endicott Work Productivity Scale; and (c) Quality of Life measure: Quality of Life, Enjoyment, and Satisfaction Questionnaire-Short Form (Q-LES-Q). RESULTS: QOL is significantly impaired in MDD, with a mean Q-LES-Q score for this study population of 39.8 % (SD = 16.9), whereas the community norm average is 78.3 %. Regression modeling suggested that depressive symptom severity, functioning/disability, and age all significantly contributed to QOL. QIDS-SR (measuring depressive symptom severity), GAF, and SDS (measuring functioning/disability) scores accounted for 48.1, 17.4, and 13.3 % (semi-partial correlation values) of the variance in Q-LES-Q, respectively. CONCLUSIONS: Our results show that impairment of QOL increases in a monotonic fashion with depressive symptom severity; however, depression symptom severity only accounted for 48.1 % of the QOL variance in our patient population. Furthermore, QOL is uniquely associated with measures of Functioning. We believe these results demonstrate the need to utilize not only Symptom Severity scales, but also Functioning and Quality of Life measures in MDD assessment, treatment, and research. PMID- 22544417 TI - Depression and anxiety symptoms in bronchiectasis: associations with health related quality of life. AB - BACKGROUND AND PURPOSE: Bronchiectasis causes pulmonary infections and loss of lung function, resulting in chronic respiratory symptoms and worsening health related quality of life. The aims of this study were to measure symptoms of depression and anxiety in a sample of patients with bronchiectasis and evaluate their relationship to health outcomes and health-related quality of life. METHODS: This cross-sectional study included adolescents and adults with bronchiectasis. Patients completed the hospital anxiety and depression scale and the St. George respiratory questionnaire. Health outcome data, including clinical, radiological and spirometric values, were recorded from medical charts. RESULTS: Ninety-three participants with bronchiectasis of any aetiology were recruited: 20 % had elevated depression-related scores and 38 % had elevated anxiety-related scores. Increased symptoms of depression and anxiety were significantly associated with age; anxiety was associated with more frequent exacerbations. Regression analyses indicated that after controlling for demographic (gender and age) and clinical variables (exacerbations frequency, daily sputum, aetiology and spirometry), both depression and anxiety symptoms predicted significantly worse health-related quality of life. In comparison with other predictors, psychological symptoms explained the largest amount of variance in health-related quality of life. CONCLUSIONS: Symptoms of depression and anxiety were significant predictors of health-related quality of life in patients with bronchiectasis, independently of respiratory involvement, gender, age or other variables. PMID- 22544418 TI - Surveillance of colorectal cancer screening in new Mexico hispanics and non Hispanic whites. AB - The incidence of colorectal cancer (CRC) among Hispanics in the state of New Mexico has increased in the past decade while that among whites has declined significantly. Using the 2006 New Mexico Behavioral Risk Factor Surveillance System (BRFSS) survey, we compared CRC screening among Hispanics and whites by gender to examine the influence of demographic, socioeconomic, preventive health, and clinical measures on the utilization of CRC screening. Although we found no ethnic differences in the prevalence of current breast, cervical and cancer screening, Hispanics were less likely to be current with CRC screening than whites. These differences were observed across a range of socioeconomic and other explanatory measures and in both genders. Hispanics also had a higher prevalence of CRC-related risk factors than whites, including inactivity, obesity, and diabetes, and ranked lower for most socioeconomic measures. Adjusting for healthcare coverage, education, and income in logistic regression models eliminated the Hispanic-white differences in CRC screening among men, and substantially reduced but did not eliminate screening differences among women. Innovative methods are needed to reach Hispanics to raise awareness of and participation in CRC screening. Because many CRC risk factors are potentially modifiable, appropriate cultural and linguistic interventions tailored to specific Hispanic subgroups and aimed at promoting CRC screening and reducing CRC risk factors may decrease ethnic disparities in CRC incidence. PMID- 22544421 TI - Left atrial thrombus in patient with coronary-left atrium fistula. AB - We treated a 77-year-old woman diagnosed with severe aortic stenosis, who had undergone catheter ablation for paroxysmal supraventricular tachycardia at the age of 62. Although the patient remained in sinus rhythm, she had been receiving Coumadin with a target INR level of 2.0 since that time. Preoperative coronary angiography revealed a coronary-left atrium (LA) fistula, while computed tomography and echocardiography findings did not detect thrombus formation. Intra operative transesophageal echocardiography revealed a 2-cm solid mass, which unexpectedly appeared during deairing manipulation. Prompt cross-clamping and removal of an LA thrombus with closure of the LA appendage contributed to an uneventful postoperative course. The LA should be explored if a coronary-LA fistula is noted, even in non-mitral cases, especially those with a history of catheter ablation. PMID- 22544420 TI - Effectiveness of participatory training for prevention of musculoskeletal disorders: a randomized controlled trial. AB - PURPOSE: Health and safety training program has been applied to prevent work related musculoskeletal disorders (MSDs) in workplace. We evaluated the effectiveness of participatory training and didactic training programs on MSD prevention among frontline workers in Shenzhen, China. METHODS: The authors randomly assigned 918 workers from intervention factories to receive participatory training (intervention group), and 907 workers from intervention factories and 1,654 workers from control factories to receive didactic training (control_1 group, control_2 group, respectively) from June 1, 2008 to November 30, 2009. Participants were asked to report experience of ache, pain or discomfort in 10 body parts at baseline and 1 year after training. Data were analyzed to compare the MSD prevalence 1 year before and 1 year after training in different groups from 2009 to 2010. RESULTS: The follow-up rate was 61 % (2,120/3,479) at 1 year after training. In the year after training, there were no statistically significant changes in the proportion of workers who reported MSD in any body part. MSD prevalence rates in the intervention group reduced from 16.8 to 9.9 % for lower extremities (chi(2) = 13.102, p < 0.001) and from 12.9 to 8.3 % (chi(2) = 9.433, p = 0.002) for wrist and finger at 1 year after training. However, the rates did not change significantly for upper back, lower back, neck, shoulder and elbow in the intervention group and for all 10 body parts in two control groups. CONCLUSIONS: Overall, the training programs did not seem to prevent the occurrence of MSD among frontline workers. However, participatory training might be effective to reduce MSD in the lower extremities and wrist and finger. PMID- 22544422 TI - Null allele alpha-1 antitrypsin deficiency: case report of the total pleural covering technique for disease-associated pneumothorax. AB - A 44-year-old woman, who had been diagnosed as having null type alpha-1 antitrypsin (AAT) deficiency, was admitted with right recurrent pneumothorax. She had undergone right visceral pleural strengthening and pleural adhesion preventing surgery, the total pleural covering technique (TPC), with oxidized regenerative cellulose (ORC). Three years after the operation, she developed left recurrent pneumothorax and underwent left TPC. AAT deficiency is a rare inherited disease in Japan that causes early-onset emphysema and secondary pneumothorax. In addition, null/null phenotype has the highest risk of emphysema and may require lung transplantation. For future lung transplantation, pleural adhesion should be prevented. However, pleurodesis and surgery for pneumothorax generally cause adhesion. TPC with ORC is a surgical treatment for pneumothorax that is done to strengthen visceral pleura and prevent pleural adhesions. The patient has had no recurrence of pneumothorax 3.5 years after right TPC and 6 months after left TPC. PMID- 22544423 TI - Use of side branch of total arch replacement graft as bypass inflow to prevent visceral ischemia with type B aortic dissection. AB - When operating on patients with type B aortic dissection, the preoperative hemodynamics and malperfusion of visceral organs should be considered. We report a 70-year-old man with dissecting distal arch aneurysm following type B aortic dissection, whose celiac artery arose from a false lumen and who was successfully treated with total arch replacement and ascending graft-celiac artery bypass. PMID- 22544424 TI - Pulmonary artery replacement for pulmonary Takayasu's arteritis. AB - Takayasu's arteritis is a chronic inflammatory disease that affects the pulmonary artery, as well as the aorta and its major branches. A 59-year-old man presented with a 2-month history of progressive exertional dyspnea. Further examination revealed marked wall thickening of the pulmonary trunk and bilateral proximal pulmonary artery, resulting in severe stenoses with high pressure gradient of 60 mmHg. The patient underwent graft replacement of the bilateral pulmonary artery and the pulmonary trunk with a 16-mm ring-supported extended polytetrofluoroethylene graft under extracorporeal circulation. Histopathological findings were consistent with Takayasu's arteritis with pulmonary artery involvement. After the operation, the pressure gradient decreased to 6 mmHg and the patient was free from exertional dyspnea. PMID- 22544425 TI - Transdiaphragmatic intercostal hernia following blunt trauma. AB - We report a rare case of traumatic transdiaphragmatic intercostal hernia (TDIH) in an 85-year-old women who was transported to our hospital by ambulance after blunt trauma caused by the involvement in a motor vehicle accident. Chest and abdominal computed tomography (CT) revealed a left diaphragmatic rupture with a chest wall hernia involving loops of small intestine. An emergency operation was performed and led to a diagnosis of TDIH. Surgery via a thoracoabdominal incision in the left side was performed to reduce the hernia contents, and the diaphragmatic and intercostal defects were reconstructed by direct suture. CT scans were very helpful in detecting TDIH in this case. PMID- 22544426 TI - A case of ascending aortic pseudoaneurysm in a patient with aortic replacement. AB - A 59-year-old man with a history of ascending aorta replacement for an aortic dissection using gelatin-resorcin-formalin glue at age of 50 years presented with paroxysmal nocturnal dyspnea. An echocardiogram showed severe aortic regurgitation associated with aortic root enlargement. Chest computed tomography showed that the ascending aorta was dilated and a pseudoaneurysm was observed around the implanted prosthetic graft. Upon opening the ascending aorta, we found that the posterior wall of the proximal anastomotic portion of the implanted graft was ruptured. After replacement of the aortic root with a composite graft and reconstruction of the orifices of the right and left coronary arteries, total arch replacement by the separated graft technique was performed. The postoperative course was uneventful. PMID- 22544427 TI - Posterior reversible encephalopathy syndrome due to immunosuppressant after living-donor lobar lung transplantation: report of a case. AB - Living-donor lobar lung transplantation was performed in a 10-year-old boy with bronchiolitis obliterans after bone marrow transplantation for recurrent acute myeloid leukemia. He developed posterior reversible encephalopathy syndrome (PRES) due to calcineurin inhibitor (CNI) postoperatively, which was recovered with suspension of CNI. PRES should be considered one of the important morbidity after lung transplantation. PMID- 22544428 TI - Choriocarcinoma of the lung: report of a case. AB - In this report, a 27-year-old woman with a solitary pulmonary nodule is described. Because computed tomography-guided biopsy could not confirm the diagnosis, surgical treatment was performed by video-assisted thoracic surgery. Histological findings showed cytotrophoblasts and syncytiotrophoblasts, suggesting choriocarcinoma. However, there were no abnormal findings on gynecological examination, including ultrasonography, magnetic resonance imaging, and positron-emission tomography. Choriocarcinoma is a malignant neoplasm and can arise after a pregnancy, as a component of germ cell tumors, or in association with a poorly differentiated somatic carcinoma. Our patient, a young female with an antecedent gestation, has no recurrence after surgery. There were tumor emboli in pulmonary arteries and no component of primary lung carcinoma on histological examination. These findings indicate that the lesion was a metastasis of gestational choriocarcinoma. A rare case of a patient with metastatic gestational choriocarcinoma of a solitary pulmonary nodule without any uterine abnormality is presented. PMID- 22544429 TI - The association between nonstandard work and occupational injury in Korea. AB - BACKGROUND: The number of workers who died due to occupational injury in Korea as of 2007 was 1,383. The aim of this study was to identify whether there were any differences in the risk of occupational injury between nonstandard workers (temporary workers and/or subcontract workers) and regular workers. METHODS: 1,576 injured workers, selected from National Health Insurance and National Workers' Compensation Insurance, were interviewed via telephone survey using standardized questionnaires in 2007. The control group was 1,500 workers matched for age, gender, and severity of injury. A multivariate logistic regression model was used to analyze the association between the type of nonstandard work and occupational injury. RESULTS: Nonstandard temporary workers were more likely to be injured than regular workers even if other related factors of occupational injury were statistically adjusted (adjusted odds ratio, OR 2.87, 95% confidence interval 2.37-3.49). CONCLUSIONS: The reason why the risks of nonstandard workers are higher than those of regular workers is that nonstandard workers are placed in poor working conditions. PMID- 22544430 TI - Water-soluble red-emitting distyryl-borondipyrromethene (BODIPY) dyes for biolabeling. AB - A series of water-soluble red-emitting distyryl-borondipyrromethene (BODIPY) dyes were designed and synthesized by using three complementary approaches aimed at introducing water-solubilizing groups on opposite faces of the fluorescent core to reduce or completely suppress self-aggregation. An additional carboxylic acid functional group was introduced at the pseudo-meso position of the BODIPY scaffold for conjugation to amine-containing biomolecules/biopolymers. The optical properties of these dyes were evaluated under simulated physiological conditions (i.e., phosphate-buffered saline (PBS), pH 7.5) or in pure water. The emission wavelength (lambda(max)) of these labels was found in the 640-660 nm range with quantum yields from modest to unprecedentedly high values (4 to 38%). The bioconjugation of these distyryl-BODIPY dyes with bovine serum albumin (BSA) and the monoclonal antibody (mAb) 12A5 was successfully performed under mild aqueous conditions. PMID- 22544431 TI - An economic theory of the fourth hurdle. AB - Third party payers' decision processes for financing health technologies ('fourth hurdle' processes) are subject to intensive descriptive empirical investigation. This paper addresses the need for a theoretical foundation of this research and develops a theoretical framework for analysing fourth hurdle processes from an economics perspective. On the basis of a decision-analytic framework and the theory of agents, fourth hurdle processes are described as sets of institutions to maximize the value derived from finite healthcare resources. Benefits are assumed to arise from the value of better information about and better implementation of the most cost-effective choice. Implementation is improved by decreased information asymmetries and better alignment of incentives. This decreases the effects of ex ante and ex post moral hazard on service provision. Potential indicators of high benefit include high costs associated with wrong decisions and large population sizes affected by the decision. The framework may serve as a basis both for further theoretical work, for example, on the appropriate degree of participation as well as further empirical work, for example, on comparative assessments of fourth hurdle processes. It needs to be complemented by frameworks for analysing fourth hurdle institutions developed by other disciplines such as bioethics or law. PMID- 22544432 TI - Enantioselective copper-aminopyridine-catalyzed aza-Henry reaction with chelating N-(2-pyridyl)sulfonyl imines. AB - This article describes a copper-catalyzed aza-Henry reaction. Copper complexes of camphor-derived aminopyridines catalyze the addition of nitromethane to N-(2 pyridyl)sulfonyl aldimines to give the corresponding beta-nitrosulfonamides with good yields and variable enantiomeric excesses (up to 83%). An example of transformation of these compounds into N-(2-pyridyl)sulfonyl-alpha-amino acids and deprotection of the sulfonamide with Mg-MeOH is provided. PMID- 22544433 TI - Targeted therapies in breast cancer. AB - Targeted therapies have improved cure rates and prolonged survival in metastasised breast cancer. The most important new molecular targets in breast cancer therapy are epidermal growth factor receptor (ErbB) family signalling, DNA repair pathways and angiogenesis. Blocking ErbB2 signalling with anti-ErbB2 antibodies or ErbB2 kinase inhibitors is effective in both the adjuvant and the palliative treatment of ErbB2 positive breast cancer. Poly-ADP-ribose polymerase (PARP) inhibitors lead to synthetic lethality in double strand repair deficient tumours. Anti-VEGF antibodies reduce tumour-induced angiogenesis and prolong progression-free survival in breast cancer. The use of both PARP inhibitors and antiangiogenic therapy is currently hampered by a lack of predictive biomarkers. In contrast, predictive markers are available for ErbB family signalling. This review is intended to give a concise summary of recent developments in the therapy of breast cancer with a focus on new, targeted therapies. PMID- 22544434 TI - Plasma hormones, metabolites, milk production, and cholesterol levels in Murrah buffaloes fed with Asparagus racemosus in transition and postpartum period. AB - Ten dry and pregnant Murrah buffaloes were selected to investigate the effect of Asparagus racemosus feeding on hormones, metabolites, milk yield, and plasma cholesterol levels. The treatment groups of buffaloes were fed with A. racemosus (shatavari) @ 150 g/day/animal during prepartum and @ 300 g/day/animal during the postpartum period. Blood samples collected on -6, -4, -2-week, day of parturition (0), and +2, +4, and +6-week postpartum were analyzed for plasma total cholesterol, triglycerides, HDL, low-density lipoproteins (LDL), prolactin, cortisol, and blood metabolites. Milk samples collected at weekly intervals (+1, +3, +5, and 7 weeks) were analyzed for total milk fat cholesterol. Prepartum plasma cholesterol concentrations were significantly higher in treatment group over the control (P < 0.05). Mean plasma triglycerides, LDL cholesterol, HDL cholesterol, glucose, and nonesterified fatty acid (NEFA) levels varied nonsignificantly between groups. Plasma prolactin and cortisol concentrations were significantly (P < 0.01) more in treatment group than in control group. On day of parturition, plasma prolactin, cortisol, LDL, and plasma total cholesterol were higher (P < 0.01) in treatment group buffaloes in comparison to control group. A. racemosus feeding significantly (P < 0.01) increased plasma prolactin, cortisol (P < 0.01), and milk fat cholesterol (P < 0.05) without affecting total cholesterol, HDL, LDL, glucose, and NEFA concentrations. The buffaloes of treatment group produced more milk (@ 0.526 kg/animal/day) suggesting thereby that A. racemosus is galactopoietic. It was concluded that feeding of A. racemosus increases plasma prolactin and cortisol and decreased plasma total cholesterol and LDL concentration. PMID- 22544435 TI - Genetic trends production and somatic cell count for Jersey cattle in Zimbabwe born from 1994 to 2005. AB - Genetic trends for Jersey dairy cattle in Zimbabwe were estimated. A total of 10,986 lactation records were obtained from Zimbabwe Livestock Identification Trust, with cows calving in the period 1996 to 2008. An ASReml program fitting an animal model was used for the analyses. The animal model that was used included overall mean, herd-year-season, previous calving interval, and days dry as fixed effects while linear and quadratic regression coefficients of age at calving as covariates. Random effects were cow, permanent environmental effects, and residual error. The pedigree file included 1,228 animals born from 1994 to 2005. The traits studied were milk yield, fat yield, protein yield, fat percent, protein percent, and Log(10)SCC. Results indicated that milk yield, fat yield, and protein yield increased genetically (P < 0.0001) on average by 1.420, 0.160, and 0.164 kg per year, respectively. Fat percent, protein percent, and Log(10)SCC declined over the past 12 years (P < 0.0001) at the rate of -0.021, -0.015, and 0.0002 per year, respectively. This was due to the negative correlation between milk composition and milk yield. The results implies that the selection applied in the last decade has achieved genetic progress and that there is genetic variance for continued improvement and for setting up an effective dairy breeding program in Zimbabwean Jersey herds for milk, fat, and protein production. PMID- 22544436 TI - Matching between regional coronary vasodilator capacity and corresponding circumferential strain in individuals with normal and increasing body weight. AB - BACKGROUND: To define the relationship between regional coronary vasodilator capacity and myocardial circumferential strain at rest in normal weight, overweight, and obese individuals with normal global left-ventricular function. METHODS AND RESULTS: Myocardial blood flow at rest and during pharmacologic vasodilation was measured with (13)N-ammonia PET/CT in mL/g/minute in normal weight control (CON, n = 12), overweight (OW, n = 10), and obese individuals (OB, n = 10). In addition, resting myocardial function was evaluated as circumferential strain (?c, %) by MRI. Global myocardial flow reserve (MFR) did not differ significantly between CON and OW (2.98 +/- 0.96 vs 2.70 +/- 0.66, P = .290), whereas it declined significantly in OB (1.98 +/- 1.04, P = .030). Further, global ?c (%) was comparable between CON, OW, and OB (-0.24 +/- 0.03, 0.23 +/- 0.02, and -0.23 +/- 0.04) but it was lowest in OB when normalized to the rate-pressure product (N?c: -0.31 +/- 0.06, -0.32 +/- 0.05, and -0.26 +/- 0.08). When MFR of the three major coronary territories was correlated with corresponding ?c, a positive association was observed in CON (r = 0.36, P = .030), in OW (r = 0.54, P = .002), and also in OB when relating N?c to coronary vascular resistance during pharmacologic vasodilation (r = -0.46, P = .010). CONCLUSIONS: Higher coronary vasodilator capacity is related to corresponding regional circumferential strain at rest in non-obese individuals, while this is also observed for reduced MFR in obesity. PMID- 22544437 TI - Newborn screening programmes in Europe; arguments and efforts regarding harmonization. Part 2. From screening laboratory results to treatment, follow-up and quality assurance. AB - In a survey conducted in 2010/2011 data from the 28 EU member states, four EU candidate states (Croatia, FYROM, Iceland, Turkey), three potential EU candidate states (Bosnia Herzegovina, Montenegro, Serbia), and two EFTA states (Norway and Switzerland) were collected. The status and function of newborn screening (NBS) programmes were investigated from the information to prospective parents and the public via confirmation of a positive screening result up to decisions on treatment. This article summarises the results from screening laboratory findings to start of treatment. In addition we asked about the existence of feedback loops reporting the conclusions of confirmation of screening results to the screening laboratory and communication of long-term outcome to diagnostic units and possibly existing central registries. Parallel to the description of actual practices of where, how and by whom the different steps of the programmes are executed, we also asked for the existence of guidelines or directives regulating the screening programmes, material to support information of parents about diagnoses and treatment and training facilities for professionals involved in the programmes. This survey gives a first comprehensive overview of the steps following a positive screening result in European NBS programmes. The 37 data sets reveal substantial variation of national screening panels, but also a lot of similarities. Analysis across all countries revealed that actual practice is often organised but not regulated by guidelines. Material to inform patients is available more often for explaining treatment (69 %) than explaining the necessity of confirmatory diagnostics (41 %). Training of professionals is rarely regulated by a guideline (2 %), but is offered for paediatricians (40 %) and dieticians (29 %) and only rarely for other professions (e.g. geneticists, clinical nurse specialists, psychologists). Registry-based evaluation of long term outcome is as yet almost nonexistent (3 %). PMID- 22544438 TI - Evaluation of bis-alkylamidoxime O-alkylsulfonates as orally available antimalarials. AB - The main threat to controlling malaria is the emerging multidrug resistance of Plasmodium sp. parasites. Bis-alkylamidines were developed as a potential new chemotherapy that targets plasmodial phospholipid metabolism. Unfortunately, these compounds are not orally available. To solve this absorption issue, we investigated a prodrug strategy based on sulfonate derivatives of alkylamidoximes. A total of 25 sulfonates were synthesized as prodrug candidates of one bis-N-alkylamidine and of six N-substituted bis-C-alkylamidines. Their antimalarial activities were evaluated in vitro against P. falciparum and in vivo against P. vinckei in mice to define structure-activity relationships. Small alkyl substituents on the sulfonate group of both C-alkyl- and N-alkylamidines led to the best oral antimalarial activities; alkylsulfonate derivatives are chemically transformed into the corresponding alkylamidines. PMID- 22544439 TI - Bacterial cell wall constituents induce hepcidin expression in macrophages through MyD88 signaling. AB - Hepcidin is a key regulator of iron recycling by macrophages that is synthesized mainly by hepatocytes but also by macrophages. However, very little is known about the molecular regulation of hepcidin in macrophages. In the present study, we investigated hepcidin regulation in the RAW264.7 macrophage cell line and in murine peritoneal macrophages stimulated with different Toll-like receptor (TLR) ligands. We found that TLR-2 and TLR-4 ligands activated hepcidin expression in RAW264.7 cells and in wild-type murine peritoneal macrophages, but not in murine peritoneal macrophages isolated from TLR2(-/-), TLR-4-deficient or MyD88(-/-) mice. IL-6 production by RAW264.7 cells stimulated with lipopolysaccharide (LPS, TLR4 ligand) was enhanced by high amounts of iron present in the culture medium. We conclude that hepcidin expression in macrophages is regulated mainly through TLR2 and TLR4 receptors via the MyD88-dependent signaling pathway and that autocrine regulation of iron accumulation in macrophages by hepcidin may affect the levels of proinflammatory cytokine production. PMID- 22544440 TI - Effects of hypoxia on cerebral and muscle haemodynamics during knee extensions in healthy subjects. AB - A hypoxic model was used to investigate changes in localized cerebral and muscle haemodynamics during knee extension (KE) in healthy individuals. Thirty-one young healthy volunteers performed one set of KE until failure under hypoxia (14 % O(2)) or normoxia (21 % O(2)) at 50, 75 or 100 % of 1 repetition maximum, in random order, on three occasions. Prefrontal cerebral and vastus lateralis muscle oxygenation and blood volume (Cox, Mox, Cbv and Mbv, respectively) were recorded simultaneously by near-infrared spectroscopy. Hypoxia induced significant declines in Cox [-0.017 +/- 0.016 optical density (OD) units] and Mox (-0.014 +/- 0.026 OD units) and increases in Cbv (0.017 +/- 0.027 OD units) and Mbv (0.016 +/ 0.023 OD units) at rest. Hypoxia significantly reduced total work (TW) performed during KE at each exercise intensity. Cox, Cbv, Mox, and Mbv changes during KE did not differ between normoxia and hypoxia. Correlations between TW done and Cox changes under normoxia (r = 0.04, p = 0.182) and hypoxia (r = 0.05, p = 0.122) were not significant. However, TW was significantly correlated with Mox under both normoxia (R (2) = 0.24, p = 0.000) and hypoxia (R (2) = 0.15, p = 0.004). Since changes in Cox and Mox reflect alterations in the balance between oxygen delivery and extraction in these tissues, which, in the brain, is an index of neuronal activation, we conclude that: (1) limitation of KE performance was mediated peripherally under both normoxia and hypoxia, with no additional effect of hypoxia, and (2) because of the low common variance with Mox additional intramuscular factors likely play a role in limiting KE performance. PMID- 22544441 TI - YWHAE-FAM22 gene fusion in clear cell sarcoma of the kidney. PMID- 22544442 TI - Thermal cleavage of cyclobutane rings in photodimerized coordination-polymeric sheets. AB - Three coordination polymers, [Cd(2)(pvba)(2)(tbdc)(dmf)(2)] (1), [Co(2)(pvba)(2)(tbdc)(dmf)(2)(H(2)O)(2)] (2), and [Ni(2)(pvba)(2)(tbdc)(dmf)(2)(H(2)O)(2)] (3) (H(2)tbdc = 2,3,5,6 tetrabromobenzenedicarboxylic acid, Hpvba = trans-2-(4'-pyridyl)vinylbenzoic acid), were synthesized by solvothermal methods. The solid-state structures of compounds 1 and 2 were determined by X-ray crystallography. In compounds 1 and 2, the bimetallic cores acted as secondary building units that connected the tbdc ligands in one direction and a pair of pvba ligands, which were aligned in a head to-tail parallel manner, in the orthogonal direction to form sheet structures. The C=C bonds in these pvba ligand pairs in all three compounds were well-aligned to undergo quantitative [2+2] cycloaddition reactions in the solid state under UV irradiation, thereby yielding their cyclobutane derivatives. This photochemical reaction appeared to facilitate structural transformations from one 2D structure into another in the solid state. The photoreactive Co(II)- and Ni(II) coordination polymers exhibited a reversible dehydration-rehydration reaction that was accompanied by color changes from pink to purple and green to yellow, respectively, owing to a change in coordination number from six to five. Magnetic studies showed that compound 2 was an antiferromagnet, which displayed a field dependent transition with a critical field (H(c)) of 40 kOe at 2 K; the antiferromagnetic interaction between the Co(2) units was strengthened and weakened by dehydration and UV irradiation, respectively. The cyclobutane ligand in the photodimerized products was cleaved on heating to yield a mixture of trans and cis-isomers of pvba, as monitored by (1)H NMR spectroscopy. The Cd(II) coordination polymer underwent quantitative cleavage of the cyclobutane ring whilst the other two underwent partial cleavage. PMID- 22544443 TI - Fatal occupational injuries among non-governmental employees in Malaysia. AB - BACKGROUND: In Malaysia, surveillance of fatal occupational injuries is fragmented. We therefore analyzed an alternative data source from Malaysia's Social Security organization, the Pertubuhan Keselamatan Sosial (PERKESO). METHODS: We conducted a secondary data analysis of the PERKESO database comprised of 7 million employees from 2002 to 2006. RESULTS: Overall, the average annual incidence was 9.2 fatal occupational injuries per 100,000 workers. During the 5 year period, there was a decrease in the absolute number of fatal injuries by 16% and the incidence by 34%. The transportation sector reported the highest incidence of fatal injuries (35.1/100,000), followed by agriculture (30.5/100,000) and construction (19.3/100,000) sectors. Persons of Indian ethnicity were more likely to sustain fatal injuries compared to other ethnic groups. CONCLUSIONS: Government and industry should develop rigorous strategies to detect hazards in the workplace, especially in sectors that continuously record high injury rates. Targeted interventions emphasizing worker empowerment coupled with systematic monitoring and evaluation is critical to ensure success in prevention and control measures. PMID- 22544444 TI - Air transfer of patients with intraaortic balloon pump support: Swiss experience and recommendations. AB - BACKGROUND AND AIM: Inter-hospital transfers are high-risk operations for critically ill patients dependent on intra-aortic balloon pump (IABP) support. Since September 2008, Swiss Air-Rescue (Rega) has offered such transfers by helicopter. The aim of the present study was to review the first 38 IABP transfers and to promulgate the currently used standard operating procedure (SOP). METHODS: All helicopter transfers of IABP-dependent patients by Swiss Air Rescue (Rega) between September 2008 and October 2010 were retrospectively analysed. Adverse events (e.g., death), vital parameters and respiratory modus during takeover by the Rega crew and discharge at the receiving hospital, as well as patient demographics, aetiology of heart failure and outcome at the receiving hospital were assessed. RESULTS: A total of 38 IABP transfers occurred, 35 of which were carried out to hospitals within Switzerland. No major adverse events were observed during flight. The mean patient age was 64 +/- 11 (mean +/- SD) years. The leading cause for IABP support was ischaemic heart failure (32 patients, 84%). The outcome of 35 patients was available: 30 were discharged home or to another institution, and 5 died at the receiving hospital. CONCLUSIONS: Based on these findings, the helicopter transport, the equipment provided, the crew composition and the predefined process offer a safe concept for these complex transfers. The adherence to standard operating procedures is a precondition to achieve excellent quality of care, facilitating and accelerating the hand-over and comprehensive care of such high-risk patients. PMID- 22544445 TI - Religiosity, depression, and quality of life in Korean patients with breast cancer: a 1-year prospective longitudinal study. AB - OBJECTIVE: To investigate the association among religiosity and depression, anxiety, and quality of life in women with breast cancer. METHOD: The sample consisted of 284 patients with breast cancer who were undergoing surgery. They were assessed with the following instruments at baseline and at 1 year after surgery: the Duke Religious Index (DRI), the Montgomery-Asberg Depression Rating Scale, the Hospital Anxiety Depression Scale, and the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30. Depression was diagnosed with the Mini International Neuropsychiatric Interview. RESULTS: The prevalence of depression at baseline and at 1 year was 22.5% and 16.5%, respectively. The religious groups did not differ significantly with respect to the prevalence of depression or scores on psychiatric measures at either baseline or at 1 year. The prevalence of depression significantly decreased only in the Protestant group, from 30.1% to 15.7%. Scores on the DRI were significantly negatively correlated with scores on all of the anxiety and depression scales at 1 year after surgery in this group. In contrast, scores on the religious activity subscale of the DRI were significantly positively correlated with scores on the Hospital Anxiety Depression Scale at baseline or at 1 year among Catholic participants. The DRI scores of Protestant respondents were significantly positively correlated with scores on the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 at 1 year after surgery. CONCLUSION: Religiosity plays an important role in the emotional state and quality of life of Korean women with breast cancer. However, its clinical meaning may differ according to the type of religious affiliation and the stage of illness. PMID- 22544446 TI - Diarrhea associated with lopinavir/ritonavir-based therapy: results of a meta analysis of 1469 HIV-1-infected participants. AB - BACKGROUND: Antiretroviral therapy is associated with adverse events (AEs). The most frequently reported AE associated with lopinavir/ritonavir (LPV/r) containing regimens is diarrhea. The objective of this meta-analysis is to describe the incidence, prevalence, and duration of diarrhea in individuals taking LPV/r. METHODS: This is a meta-analysis of Abbott-conducted clinical trials. Inclusion criteria included prospective randomized clinical trials with the LPV/r tablet formulation and had AE data (moderate/severe diarrhea) available through 48 weeks of treatment. RESULTS: Three trials (total 1469 participants) met the inclusion criteria. In all, 11.2% of participants reported moderate/severe diarrhea by week 8, with median time to resolution of 7.4 weeks. The overall 48-week incidence of moderate/severe diarrhea was 15.5%. The discontinuation rate due to moderate/severe diarrhea was 1.3%. CONCLUSIONS: Moderate/severe diarrhea occurred in less than 1 in 6 participants taking LPV/r, typically started in the first 8 weeks of treatment and infrequently resulted in premature discontinuation. PMID- 22544447 TI - Polyneuropathy associated with the diffuse infiltrative lymphocytosis syndrome. AB - Diffuse infiltrative lymphocytosis syndrome (DILS) arises in HIV-positive patients secondary to infiltration of lymphocytes into the peripheral tissues and produces the disease's characteristic symptoms-parotid gland enlargement and a sicca syndrome. Many patients, however, first seek medical attention for treatment of the extraglandular manifestations of DILS, most commonly interstitial pneumonitis. In this case report, we describe an atypical presentation of DILS characterized by polyradiculoneuropathy in the absence of parotid gland enlargement or interstitial pneumonitis. Minor salivary gland biopsy of the patient's lip confirmed a chronic inflammatory state with lymphoid aggregates within the minor salivary glands. He was started on prednisone with immediate improvement in his symptoms. This report illustrates for clinicians the diverse extraglandular manifestations of DILS and underscores the importance of considering it in the differential diagnosis of HIV-positive patients with a preserved CD4 count who present with peripheral neuropathy. PMID- 22544448 TI - Hypoxia reduces the effect of photoreceptor bleaching. AB - Hypoxia and light illumination can both decrease oxygen consumption in the photoreceptor layers. The purpose of the present study was to investigate whether the mutual effects of hypoxia and intense illumination to the photoreceptors are additive. The a-wave of flash electroretinogram (fERG) was recorded to indirectly measure the photoreceptors function under given conditions. Six normal healthy subjects, mean age 34.0 +/- 3.8 years, all of whom had high-altitude (>3,000 m) mountain hiking experience, were recruited for the study. Flash a-wave electroretinography was examined under four conditions: (1) normal (D/N); (2) systemic hypoxia induced by inhaling a mixture of O(2) and N(2) gases, which caused oxyhemoglobin saturation (SaO(2)) ~ 80% (D/H); (3) intense light illumination, which resulted in photoreceptor bleaching (B/N); and (4) a combination of conditions b and c (B/H). Thirty light stimuli, each with a 20-ms ON and 1,980-ms OFF cycle, were given and ERG performed to probe the photoreceptor function. The results showed that a-wave at the various conditions did not respond to all stimuli. The average a-wave amplitudes were 91.4 +/- 46.5, 22.8 +/- 42.5, 15.5 +/- 28.9, and 35.2 +/- 41.1 MUV for D/N, D/H, B/N, and B/H, respectively. Nonparametric Friedman test for a-wave amplitude indicated that significant differences occurred in D/N-D/H, D/N-B/N, D/N-B/H, D/H-B/H, and B/N B/H (all p values were <0.001, but D/H-B/N was 0.264). Thus, systemic hypoxia or strong illumination to the retina can cause an absence of the ERG a-wave or change its response, although individual differences were observed. In this study, systemic hypoxia appeared to reduce photoreceptor bleaching, an interesting finding in itself. The mechanisms underlying the disappearance of the ERG a-wave following hypoxia or intense illumination to the photoreceptors seem to differ. PMID- 22544449 TI - Urinary chemokines and anti-inflammatory molecules in renal transplanted patients as potential biomarkers of graft function: a prospective study. AB - PURPOSE: Clinical- and histopathology-based scores are the limited predictors of allograft outcome. Thus, predictors of allograft survival still remain a challenge. This study aimed to evaluate the urinary levels of chemokines and anti inflammatory molecules at 30, 90, and 300 days after renal transplantation and to further correlate these measurements to graft function. METHODS: Glomerular filtration rate (GFR) and urinary levels of MCP-1/CCL2, MIP-1alpha/CCL3, RANTES/CCL5, IL-8/CXCL8, IP-10/CXCL10, interleukin-1 receptor antagonist, soluble tumor necrosis factor receptor-1, and receptor-2 were determined at 30, 90, and 300 days after renal transplantation in 22 patients. Transplanted patients were also divided according to the type of donor (living donor, LD, n = 13 or deceased donor, DD, n = 9). RESULTS: Urinary levels of all molecules, except MIP 1alpha/CCL3, remained unchanged at 30, 90, and 300 days after transplantation in our 22 patients. MIP-1alpha/CCL3 levels significantly reduced from 30 to 300 days and showed a negative correlation with GFR at 30 days. The comparison between LD and DD groups showed similar levels of all markers, except for MCP-1/CCL2, which presented higher values in LD than in DD at 30 days. sTNFR1 and MCP-1/CCL2 significantly reduced from 30 to 300 days in LD group, but only sTNFR2 concentrations at 30 days were negatively correlated with GFR at 300 days. On the other hand, in DD group, IL-1Ra concentrations at 30 and at 90 days were positively correlated with GFR at 300 days. CONCLUSION: Urinary chemokine and anti-inflammatory molecules measurements may be a promising tool in the follow-up of renal transplanted patients. PMID- 22544450 TI - Isolated tarso-conjunctival superior eyelid traumatic laceration. AB - To report a unusual case of an isolated traumatic stellated tarso-conjunctival laceration located in the upper left eyelid without eyelid margin involvement and with normal ocular examination. A 19 year-old male wounded by a bokken (wooden katana) while practicing a sham duel had an isolated eyelid tarso-conjunctival laceration, without any other eyelid layer damage, neither skin nor muscle. Treatment was conservative without suture, by means of compressive occlusion fixing the pieces of broken tarsus in the correct position. The aim of the treatment was to avoid any wrong eyelid position secondary to healing. The eyelid maintained normal structure and movement in the follow-up at 8 months. Tarsal plate rupture is usually combined with other eyelid layer damage, which usually requires suture by layers. If eyelid skin and muscle are intact, we may choose conservative management. PMID- 22544451 TI - Disease self-management needs of adolescents with cancer: perspectives of adolescents with cancer and their parents and healthcare providers. AB - PURPOSE: The ability for adolescents with cancer (AWC) to engage in disease self management may result in improved cancer outcomes and quality-of-life ratings for this group. Despite this, a comprehensive self-management program for this group is yet to be developed. To ensure that self-management programming developed for AWC meets the needs of this group, discussion with key stakeholders (i.e., AWC, parents, and healthcare providers) is required. METHODS: A descriptive qualitative design was used. Adolescents (n = 29) who varied in age (12 to 18 years) and type of cancer, their parents (n = 30) and their healthcare providers (n = 22) were recruited from one large tertiary-care oncology center. Audio-taped semi-structured individual and focus-group interviews were conducted with participants. Transcribed data were organized into categories that reflected emerging themes. RESULTS: Four major themes, which captured the self-management needs of AWC, emerged from the data. These themes were: (1) disease knowledge and cancer care skills, (2) knowledge and skills to support effective transition to adult healthcare, (3) delivery of AWC-accessible healthcare services, and (4) supports for the adolescent with cancer. CONCLUSIONS: In order to provide comprehensive, relevant, and acceptable self-management programs to AWC, the voices of this population, their parents, and healthcare providers should be considered. Findings from this study will be used to develop and evaluate cancer self-management programming for AWC. IMPLICATIONS FOR CANCER SURVIVORS: Self management represents an important avenue for exploration into improving cancer outcomes and quality of life for survivors of cancers during adolescence. PMID- 22544452 TI - Development of an (S)-1-{2-[tris(4-methoxyphenyl)methoxy]ethyl}piperidine-3 carboxylic acid [(S)-SNAP-5114] carba analogue inhibitor for murine gamma aminobutyric acid transporter type 4. AB - A series of GABA uptake inhibitors related to (S)-1-{2-[tris(4 methoxyphenyl)methoxy]ethyl}piperidine-3-carboxylic acid [(S)-SNAP-5114], the most potent mGAT4 inhibitor known so far, were synthesized and biologically evaluated for their inhibitory potency at the four GABA uptake transporters mGAT1 4 stably expressed in HEK-293 cell lines. New analogues were developed with potencies that are similar to or slightly higher than those of current mGAT4 inhibitors, but with distinctly improved chemical stability. (S)-Nipecotic acid derivatives possessing a 2-[1-(4-methoxy-2-methylphenyl)-1,1-bis(4 methoxyphenyl)methoxy]ethyl (DDPM-859) or a 4,4,4-tris(4-methoxyphenyl)but-2-en-1 yl moiety (DDPM-1457) were found to exhibit pIC(50) values of 5.78 and 5.87, respectively. Thus, as mGAT4 inhibitors, these compounds compare well with (S) SNAP-5114 (pIC(50) =5.71), but are far more stable than the latter. Moreover, DDPM-859 displays a more favorable subtype selectivity for mGAT4 versus mGAT3 than does (S)-SNAP-5114. PMID- 22544454 TI - Food groups and risk of prostate cancer: a case-control study in Uruguay. AB - OBJECTIVE: The role of foods and beverages has been studied in detail in order to establish probable risk factors for prostate cancer. METHODS: Data were derived from 326 cases with incident and microscopically confirmed adenocarcinomas of the prostate and 652 controls. Odds ratios and 95 % confidence intervals of prostate cancer were estimated by unconditional multiple logistic regression. RESULTS: We identified the following food items as risk factors: lamb meat, salted meat, whole milk, total eggs, and mate consumption. The highest OR was associated with total eggs (OR, 2.43; 95 % CI, 1.70-3.48), followed by salted meat (OR, 2.65; 95 % CI, 1.36-3.76), mate consumption (OR, 1.96; 95 % CI, 1.17-3.31), and whole milk (OR, 2.01; 95 % CI, 1.26-2.51). CONCLUSIONS: The final model, fitted by stepwise forward method, included total eggs, salted meat, whole milk, and mate consumption, whereas fruits were protective. PMID- 22544453 TI - Early life sun exposure, vitamin D-related gene variants, and risk of non-Hodgkin lymphoma. AB - PURPOSE: It has been hypothesized that vitamin D mediates the inverse relationship between sun exposure and non-Hodgkin lymphoma (NHL) risk reported in several recent studies. We evaluated the association of self-reported sun exposure at ages <13, 13-21, 22-40, and 41+ years and 19 single nucleotide polymorphisms (SNPs) from 4 candidate genes relevant to vitamin D metabolism (RXR, VDR , CYP24A1, CYP27B1) with NHL risk. METHODS: This analysis included 1,009 newly diagnosed NHL cases and 1,233 frequency-matched controls from an ongoing clinic-based study. Odds ratios (OR), 95 % confidence intervals (CI), and tests for trend were estimated using unconditional logistic regression. RESULTS: There was a significant decrease in NHL risk with increased sun exposure at ages 13-21 years (OR(>=15 vs. <=3 h/week) = 0.68; 95 % CI, 0.43-1.08; p(trend) = 0.0025), which attenuated for older ages at exposure. We observed significant main effect associations for 3 SNPs in VDR and 1 SNP in CYP24A1: rs886441 (OR(per allele) = 0.82; 95 % CI, 0.70-0.96; p = 0.016), rs3819545 (OR(per-allele) = 1.24; 95 % CI, 1.10-1.40; p = 0.00043), and rs2239186 (OR(per-allele) = 1.22; 95 % CI, 1.05-1.41; p = 0.0095) for VDR and rs2762939 (OR(per-allele) = 0.85; 95 % CI, 0.75-0.98; p = 0.023) for CYP24A1. Moreover, the effect of sun exposure at age 13 21 years on overall NHL risk appears to be modified by germline variation in VDR (rs4516035; p(interaction) = 0.0066). Exploratory analysis indicated potential heterogeneity of these associations by NHL subtype. CONCLUSION: These results suggest that germline genetic variation in VDR, and therefore the vitamin D pathway, may mediate an association between early life sun exposure and NHL risk. PMID- 22544455 TI - Patterns of cerebral and cerebellar herniation. PMID- 22544456 TI - Unified performance evaluation of health centers with integrated model of data envelopment analysis and bargaining game. AB - This paper introduces a new integrated approach to measure unified efficiency of the healthcare systems. Health centers as an important part of the healthcare systems are considered for evaluation. For this purpose, we define two categories of inputs to measure performance of health centers based on medical human resources and characteristics of spatial information by using geographic information system (GIS). Catching the balance in the spatial distribution of populations and services is one of the main problems in health centers evaluation. On the other hand, data envelopment analysis (DEA) is widely applied for measuring efficiency of the healthcare systems. But, the conventional DEA models may fail to integrated several categories of measures. In this paper, DEA and bargaining game model are integrated for evaluation of health centers. In other words, two categories of measures are used to measure unified efficiency for each health center in the competitive environment. Two models according to constant return to scale (CRS) and variable return to scale (VRS) assumptions are developed. The case study of health centers under supervising of Tehran university of medical sciences (TMUS) is presented to show the abilities of the proposed approach. PMID- 22544457 TI - Transport of a lipophilic ionizable permeant (capric acid) across a lipophilic membrane (silicone polymer membrane) from aqueous buffered solutions in the presence of hydroxypropyl-beta-cyclodextrin. AB - The present study describes a physical model approach applicable to understanding the transport of highly lipophilic, ionizable drugs across a lipophilic membrane between two aqueous compartments in the presence of a cyclodextrin in the aqueous phase. Model predictions were compared with experimental results of capric acid (HA) transport across a silicone polymer membrane in the presence and in the absence of 2-hydroxypropyl-beta-cyclodextrin (HPB) in the aqueous phase over wide ranges of conditions. Key parameters entering into the physical model calculations were the HA-HPB and the A(-)-HPB binding constants, the unionized and ionized free and the complexed HA species diffusion coefficients, the HA pKa, the HA intrinsic silicone polymer membrane permeability coefficient, and the aqueous boundary layer thickness. All of these key parameters were determined from independent or essentially independent experiments. The agreement between the model predictions and the experiments were generally quite good over the entire ranges of the studied independent variables. The results of this study provide an approach that is useful in the mechanistic understanding of how cyclodextrins may enhance the passive absorption of highly lipophilic, low solubility drug molecules in the intestinal tract. PMID- 22544458 TI - Depressive symptomatology among Latina breast cancer survivors. AB - OBJECTIVE: Healthcare professionals are providing care for a growing number of Latinas who are breast cancer survivors (BCS) and at greater risk for distress. This study reports on the prevalence of depressive symptomatology among a cohort of Latina BCS. METHODS: This study reports the outcomes of a population-based sample of 232 Latina BCS recruited via case ascertainment from the California Cancer and hospital registries. RESULTS: Fifty-three percent had elevated depressive symptoms. In the regression model, education, physical functioning, social support, family stress, functional stress, social functioning, and Spanish language preference were significantly associated with depressive symptoms. CONCLUSIONS: Among Latina BCS, the prevalence of depressed mood may be higher than European-Americans and presents a formidable clinical challenge. These findings underscore the need for timely, appropriate assessment of distress and its contributing factors including patients' socio-ecological contexts and family strain to inform effective patient-centered and family-centered psychosocial referrals and intervention strategies to reduce distress and the undue burden of cancer among Latinos. Latino survivors constitute an increasing proportion of patients in community medical practices. Thus, the requisite to perform follow-up cancer care that addresses the needs of the whole person is rapidly emerging in prominence as a component of medical practice. Therefore, primary care providers and oncology and mental health specialists must work collaboratively via the sharing of electronic medical records, survivorship care plans, and consultations to implement the Institute of Medicine and National Comprehensive Cancer Network recommendations by attending to the psychological status of cancer patients to optimize patient outcomes. PMID- 22544459 TI - Clinical significance of increased guanine nucleotide exchange factor Vav3 expression in human gastric cancer. AB - Although gastric cancer is one of the most common malignancies worldwide, little is known on the molecular process of its development and progression. This study investigates the involvement of guanine nucleotide exchange factor Vav3 in tumor progression and in the prognosis of human gastric cancer. The two patient cohorts in this study consisted of 167 gastric cancer cases from 1997 through 2001, documenting pathologic and clinical factors, as well as the clinical outcomes. Immunohistochemistry, reverse transcription PCR, immunoblotting, and immunofluorescence were used to examine Vav3 expression in tumor and nontumor pairs of gastric tissues and gastric cell lines. Small hairpin RNA (shRNA) technology was used to study the effects of Vav3 knockdown on the growth and spread of gastric cancer cells. Finally, xenograph proliferation was used to study the tumor growth. Overexpression of Vav3 was associated with the depth of invasion (P = 0.0004), nodal status (P = 0.0260), distant metastasis (P = 0.0003), stage (P = 0.0002), and vascular invasion (P = 0.0286); and correlated with poor disease-free survival (P < 0.0001). Multivariate Cox regression analysis shows that overexpression of Vav3 is an independent prognostic marker for gastric cancer (P = 0.033). Disrupting the expression of Vav3 using shRNA technology inhibited gastric cancer cell growth, spread, and xenograph proliferation. This study suggests that overexpression of Vav3 can be a useful marker for predicting the outcome of patients with gastric cancer and that Vav3 targeting can represent a potential modality for treating gastric cancer. PMID- 22544460 TI - A cognitive- behavioral therapeutic program for patients with obesity and binge eating disorder: short- and long- term follow-up data of a prospective study. AB - The goal of this study is to investigate the efficacy of a manualized cognitive behavioral therapeutic (CBT) approach for patients with obesity and binge eating disorder (BED) on the short and longer term. A prospective study without a control group consisting of three measurements (a baseline measurement and two follow-up assessments up to 5 years after the start of the CBT treatment) was used. A total of 56 patients with obesity and BED (age = 39.7 +/- 10-9 years; body mass index [BMI] = 38.5 +/- 8.3 kg/m(2)) participated in the study. BMI, number of binges per week, general psychological well-being, mood, attitude toward one's body, and loss of control over the eating behavior were evaluated by means of mixed models. Results indicate that a CBT approach offered 1 day a week during an average 7 months produces benefits on eating behaviors, weight, and psychological parameters that are durable up to 3.5 years post treatment. PMID- 22544461 TI - Assignment of relative configuration of desoxypropionates by 1H NMR spectroscopy: method development, proof of principle by asymmetric total synthesis of xylarinic acid A and applications. AB - The determination of the relative configuration of 1,3-dimethyl-substituted alkyl chains is possible by interpretation of (1)H NMR shift differences. Additionally, assignments are feasible in a variety of deuterated solvents, because the corresponding shift differences are not significantly influenced by the solvent. The trends for Deltadelta values depending on functional groups adjacent to the stereogenic centers are shown. Based on a thorough comparison with literature data, the relative configuration of natural products can be predicted. For this purpose, we derived an empirical rule for the ranges in which Deltadelta values usually occur. Furthermore, we were able to proof the validity of our method by the successful prediction of the relative configuration for the polyketide natural product xylarinic acid A, which was confirmed by the asymmetric total synthesis of its enantiomer. Based on the proposed simple analysis of published (1)H NMR data and the determination of the relevant chemical-shift differences, we predicted the relative configurations of several previously unassigned natural products. PMID- 22544462 TI - Healthcare quality management in Switzerland--a survey among providers. AB - BACKGROUND: In the last decade assessing the quality of healthcare has become increasingly important across the world. Switzerland lacks a detailed overview of how quality management is implemented and of its effects on medical procedures and patients' concerns. This study aimed to examine the systematics of quality management in Switzerland by assessing the providers and collected parameters of current quality initiatives. METHODS: In summer 2011 we contacted all of the medical societies in Switzerland, the Federal Office of Public Health, the Swiss Medical Association (FMH) and the head of Swiss medical insurance providers, to obtain detailed information on current quality initiatives. All quality initiatives featuring standardised parameter assessment were included. RESULTS: Of the current 45 initiatives, 19 were powered by medical societies, five by hospitals, 11 by non-medical societies, two by the government, two by insurance companies or related institutions and six by unspecified institutions. In all, 24 medical registers, five seals of quality, five circles of quality, two self assessment tools, seven superior entities, one checklist and one combined project existed. The cost of treatment was evaluated by four initiatives. A data report was released by 24 quality initiatives. CONCLUSIONS: The wide variety and the large number of 45 recorded quality initiatives provides a promising basis for effective healthcare quality management in Switzerland. However, an independent national supervisory authority should be appointed to provide an effective review of all quality initiatives and their transparency and coordination. PMID- 22544463 TI - Vibrational and electronic circular dichroism monitoring of copper(II) coordination with a chiral ligand. AB - Novel copper(II) coordination compounds with chiral macrocyclic imine ligands derived from R-/S-camphor were asymmetrically synthesized and characterized with the aid of chiroptical spectroscopies. Crystal structures of both enantiomers were determined by single crystal X-ray diffraction analysis. Circular dichroism (CD) spectra were analyzed using a simplified exciton model as well as quantum chemical computations. The absolute configuration of the copper(II) coordination compounds determined from CD was found consistent with the crystal data. The copper(II) complexes were further investigated by vibrational CD (VCD) measurement combined with density functional theory calculation. The complex formation was evidenced by spectral shifts of the characteristic bands in the CD and VCD spectra. PMID- 22544464 TI - The effects of serotonin/norepinephrine reuptake inhibitors and serotonin receptor agonist on morphine analgesia and tolerance in rats. AB - Several studies have demonstrated that serotonergic and noradrenergic systems have important roles in morphine analgesia and tolerance. However, the exact mechanism underlying the development of morphine tolerance is not fully understood. The aim of this study was to investigate the possible role of serotonin/norepinephrine reuptake inhibitors (amitriptyline, venlafaxine) and serotonin receptor (5-HT(1A) and 5-HT(1B/1D)) agonist (dihydroergotamine) in morphine analgesia and tolerance in rats. To constitute morphine tolerance, animals received morphine (50 mg/kg; s.c.) once daily for 3 days. After the last dose of morphine was injected on day 4, morphine tolerance was evaluated. The analgesic effects of amitriptyline (20 mg/kg; i.p.), venlafaxine (20 mg/kg; s.c.), dihydroergotamine (100 MUg/kg; i.v.) and morphine (5 mg/kg) were considered at 15- to 30-min intervals (0, 15, 30, 60, 90, and 120 min) by tail flick and hot-plate analgesia tests. In this study, the data obtained suggested that amitriptyline and venlafaxine significantly increased the analgesic effect of morphine and attenuated the expression of morphine tolerance. However, dihydroergotamine significantly increased the analgesic effect of morphine but did not reduce the expression of morphine tolerance. In conclusion, we determined that co-administration of morphine with amitriptyline and venlafaxine increased the analgesic effects of morphine and attenuated the morphine analgesic tolerance. PMID- 22544465 TI - Computational approaches to understanding dendritic cell responses to influenza virus infection. AB - The evolution of immunology research from measurements of single entities to large-scale data-intensive assays necessitates the integration of experimental work with bioinformatics and computational approaches. The introduction of physics into immunology has led to the study of new phenomena, such as cellular noise, which is likely to prove increasingly important to understand immune system responses. The fusion of "hard science" and biology is also leading to a re-examination of data acquisition, analysis, and statistical validation and is resulting in the development of easy-to-access tools for immunology research. Here, we review some of our models, computational tools, and results related to studies of the innate immune response of human dendritic cells to viral infection. Our project functions on an open model across institutions with electronic record keeping and public sharing of data. Our tools, models, and data can be accessed at http://tsb.mssm.edu/primeportal/ . PMID- 22544466 TI - Comparison of Maddrey Discriminant Function, Child-Pugh Score and Glasgow Alcoholic Hepatitis Score in predicting 28-day mortality on admission in patients with acute hepatitis. AB - BACKGROUND: Acute hepatitis (AH) in patients with chronic alcoholic liver disease is associated with high mortality. It is therefore vital to identify patients at greatest risk of mortality who may benefit from aggressive intervention. The scoring systems used to assess the severity of AH [Maddrey Discriminant Function (mDF), Child-Pugh Score (CPS) and Glasgow Alcoholic Hepatitis Score (GAHS)] have shown to be useful in determining severity and predicting mortality in these patients. AIM: The aim of this study was to compare three scoring systems in predicting 28-day mortality in AH on admission. METHOD AND RESULTS: Case notes of 82 patients with AH were reviewed on admission; mDF, CPS, GAHS were calculated and their outcome recorded on day 28. Thirty-six patients (44%) died within 28 days of admission. There was no difference in the age of patients who survived (51.2 +/- 11 years) and those who died (52.6 +/- 10 years). However, mDF, CPS and GAHS were significantly higher in dead patients (68.7 +/- 56.4, 11.8 +/- 1.3, 8.6 +/- 1.6, respectively) compared to those who survived (36.2 +/- 25.9, 10 +/- 1.6, 7.6 +/- 1.5, respectively) (p < 0.01). Similarly, prothrombin time (PT) was significantly higher in patients who died (23 +/- 2 s) compared to those who survived (17.6 +/- 0.7 s) (p = 0.007). CONCLUSION: There was no difference among three scoring systems in predicting 28-day mortality at the time of admission in patients with AH. In addition, increased PT, gastro-intestinal bleeding and advanced encephalopathy at presentation were associated with high mortality. Furthermore, rise in creatinine from admission increased risk of mortality. PMID- 22544467 TI - Single-step turn-on homogeneous fluorescent immunosensor for rapid, sensitive, and selective detection of proteins. AB - Quick & easy: A simple and positive-readout fluorescent immunosensor was developed based on a quencher composed of a 3 nm gold nanoparticle (GNP) covalently linked to a Fab fragment, which proved to be stable and specific. The method allows for direct and sensitive detection of target antigens in homogeneous solutions in one step without any separation steps. It has been successfully applied to rapidly quantify the amount of secretory immunoglobulin A (sIgA) in human saliva samples. PMID- 22544468 TI - Inadvertent severe acute kidney injury and oxaliplatin. PMID- 22544469 TI - Hepatitis B virus infection and waste collection: prevalence, risk factors, and infection pathway. AB - BACKGROUND: Waste collectors have a potential risk of infectious diseases. The aim of the study was to assess; the prevalence of hepatitis B (HBV), risk factors for infection and possible ways of virus transmission among municipal solid waste workers (MSWWs) in a municipality of central Greece. METHODS: A cross-sectional study was conducted among the employees of a municipality in Central Greece. The prevalence of an HBV infection biological marker (anti-Hbc) and its association with exposure to waste, socio-demographic factors, and history of occupational injuries with sharp objects/needle sticks was examined among 208 employees. RESULTS: The prevalence of HBV infection among the municipal waste collectors was 23%. Logistic regression analysis showed that exposure to waste (OR = 4.05;95%CI = 1.23-13.33) and age (OR = 5.22;95% CI = 1.35-20.1) were independently associated with the anti-Hbc positivity. Moreover, waste collectors who reported occupational injuries with needle sticks were at higher risk of HBV infection (RR = 2.64; 95% CI = 1.01-6.96). CONCLUSIONS: Occupational exposure to waste is a possible risk factor for HBV infection. Occupational injury with sharp instruments could be a means of hepatitis B virus transmission. Immunization of MSWWs and adoption of more safe ways for waste collection could be considered in order to control the risk of HBV infection. PMID- 22544470 TI - Brief report: oxytocin enhances paternal sensitivity to a child with autism: a double-blind within-subject experiment with intranasally administered oxytocin. AB - Oxytocin seems associated with parenting style, and experimental work showed positive effects of intranasally administered oxytocin on parenting style of fathers. Here, the first double-blind, placebo-controlled, within-subject experiment with intranasal oxytocin administration to fathers of children with autism spectrum disorder (ASD) is presented. Fathers with their typically developing toddler (n = 18), and fathers of toddlers diagnosed with ASD (n = 14), were observed in two play sessions of 15 min each with an intervening period of 1 week. In all fathers oxytocin elevated the quality of paternal sensitive play: fathers stimulated their child in a more optimal way, and they showed less hostility which suggests the positive effects of oxytocin on paternal sensitive play irrespective of clinical status of their child. PMID- 22544471 TI - Analysis of exposure-response of CI-945 in patients with epilepsy: application of novel mixed hidden Markov modeling methodology. AB - We propose to describe exposure-response relationship of an antiepileptic agent, using mixed hidden Markov modeling methodology, to reveal additional insights in the mode of the drug action which the novel approach offers. Daily seizure frequency data from six clinical studies including patients who received gabapentin were available for the analysis. In the model, seizure frequencies are governed by underlying unobserved disease activity states. Individual neighbouring states are dependent, like in reality and they exhibit their own dynamics with patients transitioning between low and high disease states, according to a set of transition probabilities. Our methodology enables estimation of unobserved disease dynamics and daily seizure frequencies in all disease states. Additional modes of drug action are achievable: gabapentin may influence both daily seizure frequencies and disease state dynamics. Gabapentin significantly reduced seizure frequencies in both disease activity states; however it did not significatively affect disease dynamics. Mixed hidden Markov modeling is able to mimic dynamics of seizure frequencies very well. It offers novel insights into understanding disease dynamics in epilepsy and gabapentin mode of action. PMID- 22544473 TI - Direct health care costs of laryngeal diseases and disorders. AB - OBJECTIVES/HYPOTHESIS: To estimate the annual direct costs associated with the diagnosis and management of laryngeal disorders. STUDY DESIGN: Retrospective analysis of data from a large, nationally representative, administrative US claims database. METHODS: Patients with a laryngeal disorder based on International Classification of Diseases,Ninth Revision-Clinical Modification codes from January 1, 2004 to December 31, 2008 and who were continuously enrolled for 12 months were included. Data regarding age, gender, geographic location, and type of physician providing the diagnosis were collected. Medical encounter, medication, and procedure costs were determined. Total and mean costs per person for 12 months were determined. RESULTS: Of almost 55 million individuals in the database, 309,300 patients with 12 months follow-up, mean age of 47.3 years (standard deviation: 21.3), and 63.5% female were identified. Acute and chronic laryngitis, nonspecific causes of dysphonia, and benign vocal fold lesions were the most common etiologies. The total annual direct costs ranged between $178,524,552 to $294,827,671, with mean costs per person between $577.18 and $953.21. Pharmacy claims accounted for 20.1% to 33.3%, procedure claims 50.4% to 69.9%, and medical encounter claims 16.3% to 8.6% of overall direct costs. Antireflux medication accounted for roughly 10% and antibiotics 6% of annual direct costs. CONCLUSIONS: This study establishes the economic impact of the assessment and management of patients with laryngeal disorders and permits cost comparisons with other diseases. PMID- 22544474 TI - High-yield diastereoselective synthesis of planar chiral [2]- and [3]rotaxanes constructed from per-ethylated pillar[5]arene and pyridinium derivatives. AB - Planar chiral [2]- and [3]rotaxanes constructed from pillar[5]arenes as wheels and pyridinium derivatives as axles were obtained in high yield using click reactions. The process of rotaxane formation was diastereoselective; the obtained [2]rotaxane was a racemic mixture consisting of (pS, pS, pS, pS, pS) and (pR, pR, pR, pR, pR) forms of the per-ethylated pillar[5]arene (C2) wheel, and other possible types of the [2]rotaxane did not form. Isolation of the enantiopure [2]rotaxanes with one axle through (pS, pS, pS, pS, pS)-C2 or (pR, pR, pR, pR, pR)-C2 wheels was accomplished. Furthermore, pillar[5]arene-based [3]rotaxane was successfully synthesized by attachment of two pseudo [2]rotaxanes onto a bifunctional linker. [3]Rotaxane formed in a 1:2:1 mixture with one axle threaded through two (pS, pS, pS, pS, pS)-C2, one (pS, pS, pS, pS, pS)-C2 and one (pR, pR, pR, pR, pR)-C2 (meso form), or two (pR, pR, pR, pR, pR)-C2 wheels. The [3]rotaxane enantiomers and the meso form were successfully isolated using appropriate chiral HPLC column chromatography. The procedure developed in this study is the starting point for the creation of pillar[5]arene-based interlocked molecules. PMID- 22544472 TI - Approaching the asymptote: obstacles and opportunities for nanomedicine in cardiovascular disease. AB - Over the past decades, tremendous advances have been made in the understanding, diagnosis, and treatment of cardiovascular disease. However, we now face new challenges, including an aging population and increases in metabolic risk factors, that threaten to slow and even reverse these gains. To overcome these new challenges, fundamental insights from the life sciences must be integrated with advances from the physical sciences to develop novel molecular tools to better diagnose, monitor, and treat this complex disease. Nanotechnology has emerged from the intersection of several disciplines and, if combined with our evolving molecular understanding of atherogenesis, has the potential to revolutionize our management of patients at risk for or with existing cardiovascular disease. However, to realize this potential, we must understand the principles governing the interactions between nanomaterials and biological systems. This review explores nanoparticle attributes and how they can be leveraged to develop novel molecular tools for the diagnosis and treatment of cardiovascular disease. PMID- 22544475 TI - Smoking cessation interventions in the pre-admission clinic: assessing two approaches. AB - PURPOSE: Brief intervention (BI) to encourage patients who smoke to quit is effective and should occur at every patient interaction. If smokers receive a motivational interview in addition to BI and are offered pharmacotherapy to treat nicotine withdrawal, cessation rates may be improved. We compared the uptake, implementation, and effectiveness of these two approaches in the delivery of a smoking cessation intervention during assessments in a pre-admission clinic (PAC). METHODS: The study was performed in the PAC at two tertiary care hospitals. At both hospitals, PAC patients were screened for smoking status, and current smokers were offered the opportunity to participate in a cessation program. Those who agreed were asked to consent to participate in an evaluation of program effectiveness that included a telephone interview about smoking status six months after hospital discharge. A cohort design was used to compare cessation outcomes across PACs during a one-year period of patient recruitment. The primary outcome measure was a self-reported continuous quit rate six months following hospitalization. Secondary outcomes included the number of patients willing to participate and the completeness of the delivery of program components. INTERVENTIONS: A BI delivered at one PAC consisted of brief advice and self-help materials, including handing the patient a business card with an available 1-800 Quit line (a telephone smoking cessation help line). The other PAC offered an intensive intervention (II) that included augmenting the BI with an in-hospital and post-discharge motivational interview and access to nicotine replacement therapy (NRT) during admission. RESULTS: At follow-up, we were able to contact 147 of the 288 smokers who agreed to participate in the evaluation of the program, and the self-reported quit rates for the BI and II interventions were 11.4% and 19.5%, respectively. More than 1,200 current smokers were identified and approached at both PACs during the 12-month patient recruitment period, and 60% of those were willing to accept the offered smoking cessation intervention (either BI or II). Implementation of II was uneven, particularly the delivery of the in-hospital motivational interview and prescription of NRT. Uptake of the 1-800 Quit service after discharge was inadequate. CONCLUSION: The PAC is a feasible location to identify smokers and offer a cessation intervention. There are considerable logistical barriers to the development of an II intervention program as described. A program that incorporates elements of BI and II could offer a practical approach to the implementation of a hospital-wide smoking cessation intervention. PMID- 22544476 TI - Safety of intraventricular hemorrhage (IVH) thrombolysis based on CT localization of external ventricular drain (EVD) fenestrations and analysis of EVD tract hemorrhage. AB - BACKGROUND: The purpose of the study is to review the CT findings associated with ventriculostomy placement in regards to the safety of an EVD plus recombinant tissue plasminogen activator (rt-PA) for IVH. METHODS: A retrospective review was conducted for patients receiving intraventricular rt-PA for IVH from January 2004 to September 2009. Safety was assessed by the presence of EVD tract hemorrhage by CT at baseline after EVD placement, worsening hemorrhage after rt-PA, and CSF infection. IVH volumetrics were assessed by the Le Roux score and outcomes by Glasgow Outcome Scale and modified Rankin Scale. RESULTS: Twenty-seven patients received rt-PA for IVH. Median dose was 2 mg (range 0.3-8) and a median of two doses (range 1-17) were given. Worsening EVD catheter tract hemorrhage after rt PA was 46.7 %, with a significantly higher incidence of worsening tract hemorrhage seen with incorrectly placed EVDs (p = 0.04). IVH hematoma burden decreased by a median Le Roux score of 10 (range 3-16) prior to rt-PA to 4 (range 0-16) after rt-PA. There were no central nervous system bacterial infections. CONCLUSION: Intraventricular rt-PA appears to be relatively safe especially when all EVD fenestrations are within the ventricle and reduces IVH burden similar to other studies. We describe a CT-based EVD tract hemorrhage grading scale to evaluate EVD tract hemorrhage before and after thrombolysis, and a bone-window technique to evaluate EVD fenestrations prior to IVH thrombolysis. Further research is needed evaluating these imaging techniques in regard to intraventricular thrombolytic safety and EVD tract hemorrhage. PMID- 22544478 TI - Effective response with bortezomib retreatment in relapsed multiple myeloma--a multicentre retrospective survey in Switzerland. AB - Previous studies have shown that retreatment of relapsed/refractory multiple myeloma (MM) with a second course of bortezomib therapy could be effective in heavily pre-treated patients. In this study, the results of a multicentre, retrospective survey were reported involving patients in Switzerland with MM who responded to initial bortezomib therapy; 43 patients were enrolled and 42 were evaluated for response. The overall response rate (complete response [CR] + near CR [nCR] + partial response [PR]) to bortezomib retreatment was 64.3%, and the clinical benefit rate (CR + nCR + PR + stable disease) for retreatment was 83%. The response rate to bortezomib retreatment in the subgroup with a first treatment-free interval (TFI) >6 months was higher than that in the subgroup with first TFI <=6 months (74.1% vs. 46.7%) and lower in patients who received concomitant dexamethasone with bortezomib retreatment (57.1% vs. 78.6%). The median overall survival (OS) from first diagnosis of MM was 9.3 years, and after retreatment with bortezomib the median OS was 1.7 years. In total, 85.7% of patients who achieved CR or nCR with initial bortezomib treatment achieved CR or nCR with retreatment. Bortezomib as retreatment was well tolerated, and the safety profile was consistent with previous studies of bortezomib in relapsed MM. The most common adverse drug reaction attributed to bortezomib was peripheral neuropathy in 5 patients. In conclusion, bortezomib retreatment was a well tolerated, effective therapeutic option for relapsed MM patients in the Swiss clinical setting who have previously responded to bortezomib, particularly for those who experienced an initial TFI of >6 months. PMID- 22544477 TI - The molecular diversity and evolution of Rice tungro bacilliform virus from Indian perspective. AB - Rice tungro disease is caused by a combination of two viruses: Rice tungro spherical virus and Rice tungro bacilliform virus (RTBV). This study was performed with the objective to decipher the molecular variability and evolution of RTBV isolates present in the tungro-affected states of Indian subcontinent. Phylogenetic analysis based on ORF-I, ORF-II, and ORF-IV sequences showed distinct divergence of Indian RTBV isolates into two groups; one consisted isolates from Hyderabad (Andhra Pradesh), Cuttack (Orissa), and Puducherry and another from West Bengal, Chinsura West Bengal, and Kanyakumari (Tamil Nadu). The results obtained from phylogenetic analysis were further supported with the single nucleotide polymorphisms (SNPs), insertion and deletion (INDELs) and evolutionary distance analysis. In addition, sequence difference count matrix revealed a maximum of 56 (ORF-I), 13 (ORF-II) and 73 (ORF-IV) nucleotides differences among all the Indian RTBV isolates taken in this study. However, at the protein level these differences were not significant as revealed by K (a)/K (s) ratio calculation. Sequence identity at nucleotide and amino acid level was 92-100 % (ORF-I), 96-100 % (ORF-II), 94-100 % (ORF-IV) and 86-100 % (ORF-I), 98 100 % (ORF-II) and 95-100 % (ORF-IV), respectively, among Indian isolates of RTBV. The divergence of RTBV isolates into two independent clusters of Indian and non-Indian was shown with the help of the data obtained from phylogeny, SNPs, and INDELs, evolutionary distance analysis, and conserved motifs analysis. The important role of ORF-I and ORF-IV in RTBV diversification and adaptation to different rice growing regions is also discussed. PMID- 22544479 TI - Absolute configurations of integracins A, B, and 15'-dehydroxy-integracin B. AB - Integracins A (1) and B (2), potent HIV-1 integrase inhibitors, and 15'-dehydroxy integracin B (3) were isolated for the first time from Chinese mangrove plant Sonneratia hainanensis. Their absolute configurations were determined by the Mosher's method and specific rotation analysis of alcohols (6 and 7) obtained from integracin A in two steps and by chemical correlation. Integracin A (1) also exhibited significant cytotoxicity against the tumor cell lines HepG2 and NCI H460 with both 100% inhibitions at 25 ug/ml. PMID- 22544480 TI - Work safety climate and safety practices among immigrant Latino residential construction workers. AB - BACKGROUND: Latino residential construction workers experience high rates of occupational fatality and injury. Work safety climate is an especially important consideration for improving the safety of these immigrant workers. This analysis describes work safety climate among Latino residential construction workers, delineates differences in work safety climate by personal and employment characteristics, and determines associations of work safety climate with specific work safety behaviors. METHODS: Data are from a cross-sectional survey of 119 Latino residential framers, roofers, and general construction workers in western North Carolina; 90 of these participants also provided longitudinal daily diary data for up to 21 days using an Interactive Voice Response (IVR) system. Measures included the Perceived Safety Climate Scale, and daily reports of five individual and five collective safety practices. RESULTS: Work safety climate was mixed among workers, with roofers (19.9) having lower levels than framers (24.3) or general construction workers (24.3). Days reported for several individual (glove related risks, not doing something known to be unsafe) and collective safety practices (attended daily safety meeting, not needing to use damaged equipment, not seeing coworker create an unsafe situation) were positively associated with work safety climate. CONCLUSIONS: Work safety climate predicts subsequent safety behaviors among Latino residential construction workers, with differences by trade being particularly important. Interventions are needed to improve safety training for employers as well as workers. Further research should expand the number of workers and trades involved in analyses of work safety climate. PMID- 22544481 TI - Renewable nitrogen-doped hydrothermal carbons derived from microalgae. AB - Nitrogen-doped carbon materials are synthesized via an effective, sustainable, and green one-step route based on the hydrothermal carbonization of microalgae with high nitrogen content (ca. 11 wt %). The addition of the monosaccharide glucose to the reaction mixture is found to be advantageous, enhancing the fixation of nitrogen in the synthesized carbons, resulting in materials possessing nitrogen content in excess of 7 wt %, and leading to promising reaction yields. Increasing the amount of glucose leads to a higher nitrogen retention in the carbons, which suggests co-condensation of the microalgae and glucose-derived degradation/hydrolysis products via Maillard-type cascade reactions, yielding nitrogen-containing aromatic heterocycles (e.g., pyrroles) as confirmed by several analytical techniques. Increasing the HTC processing temperature leads to a further aromatization of the chemical structure of the HTC carbon and the formation of increasingly more condensed nitrogen-containing functional motifs (i.e., pyridinic and quaternary nitrogen). PMID- 22544482 TI - Intellectual disability, consumerism and identity: to have and have not? AB - Here we consider the consumer society as it currently exists in the UK and examine its relationship and relevance to the population of individuals with intellectual disability. We do this through a reading of the associated literature on theories of shopping and consumption which we then contrast with research evidence as it applies to the lives of people with intellectual disability. By brining together these two perspectives we hope to shine some light on ideas around identity and choice. We then transfer these arguments to the health and social care sector. Here we ask whether an economic model which has been exposed as divisive and exclusionary should be used in the administration of social secutity benefits of the kind accesed by people with a range of disabilities. We conclude that the unchallenged advance of marketisation within health and social care may benefit those who are financially able but for those who are economically disadvantaged the choices offered are illusory at best. PMID- 22544483 TI - Ethical dilemmas in social work practice with disabled people: the use of physical restraint. AB - This article discusses the use of restraint with disabled adults and children and uses a case study of one particular child to explore issues related to the use of restraint, including the consent of the person subjected to restraint, their human rights, and the balancing of these rights with the need to reduce the risk of harm. The case study involves a young woman who requested to be restrained in a particular way and the challenges this posed to the staff caring for her. The article concludes that in many complex situations there is no clearly right approach to take, and each situation involving restraint must be considered on an individual case-by-case basis. PMID- 22544484 TI - Update on echocardiography in the management of infective endocarditis. AB - Echocardiography is the major imaging modality used for the diagnosis of infective endocarditis (IE). It is also useful in detecting the complications of IE which often necessitate surgical intervention and strongly influence patient outcomes. Transesophageal echocardiography (TEE), with proven superiority over transthoracic echocardiography (TTE) for the detection of vegetations and complications such as abscess, should be performed in the vast majority of cases especially when TTE image quality is poor or implanted devices are present. Three dimensional (3D) TEE provides enhanced display of anatomic-spatial relationships allowing more precise delineation of complex pathology, particularly of the mitral valve and annulus. Importantly, echocardiographic findings can be non specific and should always be interpreted in the context of the pre-test probability of IE based on careful clinical assessment. IE remains a challenging disease associated with variable clinical presentations, and high mortality. Whenever IE is suspected, echocardiography should be utilized early for both diagnosis and detection of complications. PMID- 22544485 TI - Editorial: special issue on helium ion microscopy. PMID- 22544486 TI - Imaging and nanofabrication with the helium ion microscope of the Van Leeuwenhoek Laboratory in Delft. AB - Although helium ion microscopy (HIM) was introduced only a few years ago, many new application fields are emerging. The connecting factor between these novel applications is the unique interaction of the primary helium ion beam with the sample material at and just below its surface. In particular, the HIM secondary electron signal stems from an area that is extremely well localized around the point of incidence of the primary beam. This makes the HIM well suited for both high-resolution imaging and high-resolution nanofabrication. Another advantage in nanofabrication is the low ion backscattering fraction, which leads to a weak proximity effect. The subnanometer probe size and the unique beam-materials interactions have opened new areas of research. This review presents a selection of studies conducted on a single instrument. The selection encompasses applications ranging from imaging to nanofabrication and from fundamental academic research to applied industrial developments. PMID- 22544487 TI - Fluorescence quenching method for the determination of carbazochrome sodium sulfonate with aromatic amino acids. AB - In Britton-Robinson (BR) buffer medium (pH 3.3), carbazochrome sodium sulfonate (CSS) can react with some aromatic amino acids such as tryptophan (Trp), tyrosine (Tyr) and phenylalanine (Phe) to form a 1:1 complex by electrostatic attraction, aromatic stacking interaction and Van der Waals' force, resulting in fluorescence quenching of these amino acids. Maximum quenching wavelengths were located at 352 nm (CSS-Trp system), 303 nm (CSS-Tyr system) and 284 nm (CSS-Phe system), respectively. The fluorescence quenching value (DeltaF) was proportional to the concentration of CSS in a certain range. The fluorescence quenching method for the determination of CSS showed high sensitivity, with detection limits of 31.3 ng/mL (CSS-Trp system), 44.6 ng/mL (CSS-Tyr system) and 315.0 ng/mL (CSS-Phe system), respectively. The optimum conditions of the reaction conditions and the effect of coexisting substances were investigated and results showed that the method had good selectivity. The method was successfully applied for the rapid determination of CSS in blood and urine samples. Based on the bimolecular quenching constant Kq , the effect of temperature and Stern-Volmer plots, this study showed that quenching of fluorescence of amino acids by CSS was a static quenching process. PMID- 22544488 TI - A systematic review of research using the diagnostic criteria for cancer-related fatigue. AB - BACKGROUND: Prevalence rates for cancer-related fatigue vary widely depending on how fatigue is defined and assessed. In 1998, formal diagnostic criteria were proposed for a syndrome of cancer-related fatigue. These criteria were intended to facilitate the study of cancer-related fatigue and the development of appropriate interventions to ameliorate fatigue. Although the criteria have been widely cited, to date, there has been no systematic review of research using the criteria that might inform their continued use or revision. METHODS: We conducted a systematic review of the literature reporting results based on use of the diagnostic criteria. Data were analyzed to characterize the reliability and validity of the criteria and to describe the prevalence of cancer-related fatigue. RESULTS: We identified nine eligible studies. The purpose of the majority of the studies was to estimate the prevalence of cancer-related fatigue; there was considerable variability with respect to design and nature of the samples included. Although few studies examined reliability of the criteria, findings reported support their reliability. The validity of the criteria judged relative to established measures of fatigue and related constructs appears to be strong. Prevalence rates for cancer-related fatigue based on the diagnostic criteria vary widely, reflecting a lack of consistency in how the criteria have been applied. CONCLUSIONS: As a comprehensive approach to diagnosing cancer related fatigue, the diagnostic criteria have received relatively scant attention by the clinical research community. Our findings suggest the need for research aimed at revising the criteria, enhancing their usefulness, and promoting their more widespread use. PMID- 22544489 TI - Giant staghorn common bile duct calculus. PMID- 22544490 TI - Supramolecular photochirogenesis with novel cyclic tetrasaccharide: enantiodifferentiating photoisomerization of (Z)-cyclooctene with cyclic nigerosylnigerose-based sensitizers. AB - Isophthalic and terephthalic acid monoesters of cyclic nigerosyl-(1->6)-nigerose (CNN), a cyclic tetrasaccharide composed of four d-glucopyranosyl residues connected by alternating alpha-1,3- and alpha-1,6-linkages, were synthesized as novel chiral supramolecular sensitizers for enantiodifferentiating photoisomerization of (Z)-cyclooctene (1Z) to planar chiral (E)-isomer (1E). Despite the saucer-shaped shallow cavity of CNN that does not immediately guarantee strong ground-state interactions with 1Z, the sensitizer-appended CNNs afforded optically active 1E in such enantiomeric excesses that are much improved than those obtained with an alpha-cyclodextrin analog and comparable with those obtained with a beta-cyclodextrin analog. Interestingly, the enantiomeric excess values obtained were a critical function of temperature and solvent to show an inversion of the product chirality by changing the environmental variants. Nevertheless, all of the differential activation parameters calculated from the temperature-dependent enantiomeric excesses gave an excellent compensatory enthalpy-entropy relationship, indicating an operation of a single enantiodifferentiating mechanism in the present chiral photosensitization with modified CNNs. PMID- 22544491 TI - RNAi-mediated blocking of ezrin reduces migration of ectopic endometrial cells in endometriosis. AB - Ezrin is a member of the ezrin-radixin-moesin (ERM) family of membrane cytoskeletal linkage proteins. It is important for maintenance of cell shape, adhesion, migration and division. The overexpression of ezrin in some tumours is associated with increased cell migration that is mediated by the Rho/ROCK family of small GTPases. To investigate the role of ezrin in the migration of ectopic endometrial cells in endometriosis, we conducted real-time quantitative RT-PCR analysis of the eutopic and ectopic endometrium from women with endometriosis compared with those without the disease. RNAi, wound healing assays and western blot analysis of endometriotic cells were also included in this research. We found significantly higher levels of mRNA expression of ezrin (0.42 versus 0.27, P < 0.05), RhoA (0.99 versus 0.74, P < 0.05), RhoC (0.79 versus 0.43, P < 0.005) and ROCK1 (0.68 versus 0.38, P < 0.005) in the ectopic endometrial cells compared with the eutopic endometrial cells in endometriosis. Blocking ezrin with small interfering RNA reduced the migration of ectopic endometrial cells with decreased expression of RhoA (42.68%), RhoC (58.42%) and ROCK1 (59.88%). Our results indicate that the over-expression of ezrin in endometriosis may play a significant role in the migration of endometrial cells of endometriosis, and the RhoC/Rock pathway may provide a promising treatment target. PMID- 22544492 TI - A guest-dependent approach to retain permanent pores in flexible metal-organic frameworks by cation exchange. AB - Two anionic metal-organic frameworks were successfully prepared based on pre designed flexible multicarboxylate ligands and indium cations. Owing to the flexibility of the bridging organic linkers, which could not themselves sustain the frameworks, both of the frameworks showed thermal instability and shrinkage after removal of guest solvent molecules. Inspired by bamboo, we used a guest dependent approach to tune the permanent porosity of the MOFs. In this approach, several tetraalkyammonium cations of different sizes were introduced into the channels by cation exchange to act as partitions and to support the main frameworks. This approach significantly enhanced the stability of the framework and its permanent porosity. Moreover, the gas-adsorption properties (such as gate sorption, hysteresis, and selectivity) of the MOFs were also modulated by the judicious choice of guest cations. PMID- 22544494 TI - Mapping the knowledge base for maritime health: introduction. PMID- 22544493 TI - Diagnostic and therapeutic challenges in hepatic epithelioid hemangioendothelioma. AB - BACKGROUND: Epithelioid hemangioendothelioma is a very rare, low-grade vascular tumor known to arise in soft tissues and visceral organs. Clinical diagnosis of hepatic epithelioid hemangioendothelioma remains a challenge, and although it is frequently managed with a liver transplant due to its multifocal nature, recurrence is a common complication. METHODS: We review recent advances in the diagnosis of hepatic epithelioid hemangioendothelioma, including major genetic breakthroughs, and discuss efforts to reduce post-liver transplant recurrence of hepatic epithelioid hemangioendothelioma. PMID- 22544495 TI - Mapping the knowledge base for maritime health: 1 historical perspective. AB - There have been major developments in the understanding of disease and its treatment in the last 150 years. The development of the knowledge base on patterns of disease and injury in seafarers and on the effectiveness of intervention to prevent and treat them indicates the sorts of information that were collected and the settings in which it was possible to collect it. They also show how it has been used, as well as the reactions of those in the maritime sector to the collection and analysis of health information and to its use as a means of reducing harm. PMID- 22544496 TI - Mapping the knowledge base for maritime health: 2. a framework for analysis. AB - The knowledge base for maritime health has a number of constant features that have become apparent over the last 150 years. These can be used to structure an analysis of the current state of knowledge and to identify where there is sound evidence about the nature and scale of risks and about the effectiveness of intervention to reduce harm. It can also show where there are deficiencies in knowledge and point to the ways in which these could be remedied. Past events, as discussed in the first article, also indicate the dynamics of the political, economic and human interactions that are central to improving knowledge and to its application to improve the health of seafarers. The sources of useful knowledge about seafarer's health range from single case reports of an unusual disease to long-term studies of common chronic disease incidence. The most accessible events to record are clinically apparent illness, injury, or cause of death, but active investigative studies may look at risks in the environment, personal risk factors, or pre-clinical phases of disease. Comparisons between subsets of a population are needed to look rigorously at health risks or at the effectiveness of intervention. This is best done if information on the at risk population can be used as the basis for deriving the incidence or prevalence of illness and if the populations compared are as similar as possible in every way, except that being studied. Sometimes large studies in onshore populations can provide information that it is not feasible to collect on seafarers. Information on seafarers' health can be collected in several settings: at sea, on arrival in port, during leave periods, or after retirement. For acute illness and for injury a single setting can provide the basis for estimating risks, but for chronic conditions cases arising in several settings have to be included and the at risk population calculated to enable the incidence to be studied. Knowledge about the health of seafarers can be used to improve prevention both by attention to the conditions of living and working at sea and by selection of seafarers who are considered 'fit' for work. It is also important for defining the needs for emergency care at sea and in port. The overall patterns of illness and injury in seafarers and how these compare with other workers are important inputs to regulatory decisions on the measures to be taken to reduce harm from illness and injury. Markers of improved seafarer health can confirm the effectiveness of measures taken with this goal in mind. Reducing the contribution of health-related impairment to accidents and other risks at sea requires knowledge of the effects of such impairments on performance and safety in the routine and emergency tasks of a seafarer. This information can then be used to determine whether someone with an impairment can safely work at sea. PMID- 22544497 TI - Mapping the knowledge base for maritime health: 3 illness and injury in seafarers. AB - Recent studies of illness and injury in seafarers and of disease risk factors have been mapped. There is a good knowledge base on some aspects of health, especially on causes of death. By contrast there are very few studies on aspects of current importance, such as illness at sea, the scope for its prevention, and its treatment and outcome. Results are presented in terms of the settings in which the investigations were conducted: medical fitness examinations at recruitment and periodically, illness and injury at sea, telemedical advice, evacuation and urgent port referrals, repatriations, illness at other times in serving seafarers, health related cessation of work, and illness after cessation of work. Mortality studies were mapped in a similar way, as were population based surveys of health and of risk factors. The scope for valid extrapolation of the results from studies in other populations to seafarers is discussed. A more immediate problem of extrapolation relates to the current knowledge base, which is largely derived from own nationality seafarers of the traditional developed world maritime nations. It is uncertain whether this can be validly extrapolated to seafarers from the major crewing countries, who come from populations with very different patterns of illness. Existing studies mirror the priorities of those who commissioned them, in that many of the most valid ones relate to the overall lifetime risks of seafaring in developed countries. These enable comparisons to be made with other occupational groups. The major concerns of many interest groups in the maritime sector about health are now focused on the risks within a single contract period and how these can most efficiently be minimized. Studies on this are limited in scope, are of uncertain validity, and are often used for operational purposes rather than entering the scientific literature. Gaps in knowledge about health risks over a relatively short timescale in seafarers from the major crewing countries have been identified, and the uncertainties about extrapolating from studies in traditional maritime nations to the majority of the world's seafarers means that a major redirection of effort is needed if maritime health practice is to have a sound knowledge base on illness and injury risks in the future. PMID- 22544498 TI - Mapping the knowledge base for maritime health: 4 safety and performance at sea. AB - There is very little recent investigative work on the contribution of health related impairment and disability to either accident risks or to reduced performance at sea, the only exception being studies on fatigue and parallel data on sleep related incidents. Incidents where health related impairment, other than fatigue, has contributed are very rarely found in reports of maritime accident investigations. This may either indicate the irrelevance of these forms of impairment to accidents or alternatively point to the effectiveness of existing control measures. The main approach to risk reduction is by the application of fitness criteria to seafarers during medical examinations. Where there is a knowledge base it is either, as in the case of vision, a very old one that relates to patterns of visual task that differ markedly from those in modern shipping or, as with hearing, is based on untested assumptions about the levels of impairment that will prevent effective communications at sea. There are practical limitations to the assessment of cognitive functions as these encompass such a wide range of impairments from those associated with fatigue, medication, or substance abuse to those relating to age or to the risks of sudden incapacitation from a pre-existing illness. Physical capability can be assessed but only in limited ways in the course of a medical examination. In the absence of clear evidence of accident risks associated with health-related impairments or disabilities it is unlikely that there will be pressure to update criteria that appear to be providing satisfactory protection. As capability is related to the tasks performed, investigations need to integrate information on ergonomic and organizational aspects with that on health and impairment. Criteria that may select seafarers with health- -related impairment need to be reviewed wherever the task demands in modern shipping have changed, in order to relax or modify them where indicated in order to reduce unjustifiable discrimination. PMID- 22544499 TI - Mapping the knowledge base for maritime health: conclusions. PMID- 22544500 TI - The morbidity of malaria: a strategy for seafarer safety. PMID- 22544501 TI - Varicella at sea: a two-year study on cruise ships. AB - BACKGROUND: Being highly contagious by person-to-person transmission, varicella can easily spread within the multinational population of a cruise ship and into communities ashore. The aim of the study was to report the prevalence of varicella infections in a fleet of cruise ships during a two-year period and to discuss measures to prevent and contain shipboard outbreaks. MATERIAL AND METHODS: All probable varicella cases among passengers and crew on 34 cruise ships were registered for 2 years by the medical facilities onboard. Patients remained isolated until 6 days after rash onset. Susceptible contacts were identified and offered post-exposure prophylaxis. Crew nationality, number of vaccinated contacts, and direct vaccination costs were registered. RESULTS: During two years 187 varicella cases (36 passengers, 151 crew) were registered and 2,685 varicella vaccinations were administered at an estimated direct vaccination cost of US $ 283,832. Of the 34 ships, only 3 reported no cases of varicella. There were 8 clusters ('outbreaks') of >= 5 varicella cases presenting less than 42 days apart, comprising a total of 89 patients. While > 130 nations were represented among the crew, the 151 crew cases came from 26 countries, and 88 (58%) of them came from 5 sub-tropical/tropical countries. CONCLUSIONS: All cruise vessels must expect to encounter varicella cases or outbreaks onboard every few years. Every varicella case can start an outbreak and thus trigger several time-consuming and expensive containment measures, including isolation and mass vaccination of susceptible contacts. Mandatory pre-contract evidence of varicella immunity from all seafarers or from subgroups according to position or nationality might be worth considering. Seafarers known to be immune to varicella should always carry valid documentation while traveling. PMID- 22544502 TI - The challenge and prevention of epidemics: experience from offshore petroleum installations and its extrapolation to ships. AB - The risk of epidemics represents an important challenge in offshore petroleum activities. All personnel are needed for regular operations, and the outbreak of an epidemic will soon affect the operations. The economical consequences can be vast. The risk of an epidemic is raised due to the closeness of living and catering offshore combined with frequent changes of personnel who travel offshore from many nations. The article is based on the experience gained by the author during 22 years as a senior medical officer in a Norwegian oil company. Some endemics and epidemics are described. None of these resulted in the shutdown of production, but they still represented a major challenge to the company and to the medical staff in particular. The transfer value from experience offshore to ships is obvious but there are differences. Risk analysis and quality assurance systems play an important part in the prevention and limitation of epidemics offshore. The infrastructure of the food supply chain as well as education and training of personnel are key elements. Campaigns on different hygiene topics that address all personnel are launched at regular intervals. Contingency plans must be established and be ready for use in case of a threatening epidemic. Identification of the type and source of the infection or food poisoning, isolation of the infected personnel, safe evacuation of patients, and the establishment of other necessary barriers for reduction of spread of infection are necessary to control an outbreak of an epidemic. PMID- 22544503 TI - Loss of health certificates among offshore petroleum workers on the Norwegian Continental Shelf 2002-2010. AB - BACKGROUND: A health certificate is required to work on the offshore petroleum installations of the Norwegian Shelf. Loss of health certificate (loss of licence, LOL) may cause economic problems for the individual worker. A private compensation system (OSO) was established for Norwegian offshore workers in 2002, comprising 8000-11,000 individual members of workers organisations: approximately one third of the population offshore. This study aims at describing the reasons for compensation of offshore workers who have lost their certificates. MATERIALS AND METHODS: Of 595 workers who applied for compensation in the period 2002-2010, 38 declined to participate in the study. Of the remaining 557, 507 were granted and 50 were denied compensation. All medical records held by the scheme concerning the 507 compensated applicants were examined. Health data were systematically extracted, analysed, and compared with general population statistics. RESULTS: Musculoskeletal conditions were the most frequent conditions causing LOL for both sexes (42.5%), followed by psychiatric, neurological, and malignant diseases for women, and cardiovascular (19%), neurological, and psychiatric conditions for men. Musculoskeletal disorders were more prevalent than in the general population, and the prevalence of knee problems was particularly high. Among malignant diseases we found a high proportion of brain tumours and renal cancer. The causes are unknown and warrant further investigation in this population. Among women granted compensation, 78% were catering workers, while 50% of the men were process workers, reflecting the gender distribution in these working groups. CONCLUSIONS: Musculoskeletal conditions were the most frequent cause of application for LOL compensation for both sexes, followed by psychiatric, neurological, and malignant diseases for women, and cardiovascular, neurological, and psychiatric conditions for men. The cause of the higher incidence of musculoskeletal diseases, brain tumours, and renal cancer found in this study compared to the general population warrants further investigation. PMID- 22544504 TI - Assessment of physical, environmental, and cardiac strain in 43 operators (wearing protective equipment) conducting clean-up of heavy oil products. AB - BACKGROUND: The aim of the study was to organise an assessment of the physical strains and environmental exposure to hydrocarbon derivatives in persons involved in shoreline clean-up of heavy oil products, in order to investigate the dangers of oil spill clean-up. MATERIAL AND METHODS: Forty-three healthy volunteers wearing protective equipment cleaning up an artificial shoreline underwent cardiac strain measurements, as well as a study of thermal stress (approximate WBGT index, water loss, measurement of internal body temperature before and after physical activity). A subjective assessment of perceived exertion was correlated to articular strain indicators recorded for the weight of loads lifted, movement frequency, and the range of movement. Environmental exposure was determined by using portable hydrocarbon detectors. RESULTS: For adult subjects in good physical condition, in neutral temperatures, oil spill clean-up is considered non arduous. However, in sedentary, stressed subjects exposed to difficult climatic conditions, cleanup can be considered hard to extremely hard. In terms of environmental exposure, slight traces of toluene appeared once out of a total of 18 analysed samples. CONCLUSIONS: The sample studied was subject to physical articular strains and presented variable cardiac strain; environmental exposure was, on the other hand, slight when involving cleaning up heavy petroleum products. The subjects liable to carry out this activity are more tolerant to the efforts required when they are healthy, fit, young adults, in the non-arduous thermal conditions recorded in this study. PMID- 22544505 TI - Assessment of the European Guide for Risk Prevention in Small Fishing Vessels. Guide applicability in Polish coastal fishing. AB - The European Commission--The Directorate General of Employment, Social Affairs, and Equal Opportunities is going to publish the European Guide for Risk Prevention in Small Fishing Vessels. The legislative basis was the Report COM (2009) 599 on the practical implementation of Health and Safety at Work Directives 93/103/EC (fishing vessels) and 92/29/EEC (medical treatment on board vessels), which recommended the drawing up of a non-binding guide for vessels under 15 m in length. The Guide draft was produced directly by Labour Asociados, SSL, Spain. The organization has asked IIMTM in Gdynia, Poland, to participate in the project of evaluating the draft of the Guide. The testing took place simultaneously and homogenously in other chosen European countries. The results of the assessment are presented below. They indicate some differences and specific challenges faced by fishermen working in small costal boats in the Baltic area. The Guide should take these under consideration. PMID- 22544506 TI - First trimester exposure to ambient air pollution, pregnancy complications and adverse birth outcomes in Allegheny County, PA. AB - Despite numerous studies of air pollution and adverse birth outcomes, few studies have investigated preeclampsia and gestational hypertension, two pregnancy disorders with serious consequences for both mother and infant. Relying on hospital birth records, we conducted a cohort study identifying 34,705 singleton births delivered at Magee-Women's Hospital in Pittsburgh, PA between 1997 and 2002. Particle (<10 MUm-PM10; <2.5 MUm-PM2.5) and ozone (O3) exposure concentrations in the first trimester of pregnancy were estimated using the space time ordinary Kriging interpolation method. We employed multiple logistic regression estimate associations between first trimester exposures and preeclampsia, gestational hypertension, preterm delivery, and small for gestational age (SGA) infants. PM2.5 and O3 exposures were associated with preeclampsia (adjusted OR = 1.15, 95% CI = 0.96-1.39 per 4.0 MUg/m(3) increase in PM2.5; adjusted OR = 1.12, 95% CI = 0.89-1.42 per 16.8 ppb increase in O3), gestational hypertension (for PM2.5 OR = 1.11, 95 % CI = 1.00-1.23; for O3 OR = 1.12, 95 % CI = 0.97-1.29), and preterm delivery (for PM2.5 ORs = 1.10, 95% CI = 1.01-1.20; for O3 ORs = 1.23, 95% CI = 1.01-1.50). Smaller 5-8 % increases in risk were also observed for PM10 with gestational hypertension and SGA, but not preeclampsia. Our data suggest that first trimester exposure to particles, mostly PM2.5, and ozone, may increase the risk of developing preeclampsia and gestational hypertension, as well as preterm delivery and SGA. PMID- 22544508 TI - Neurohospitalists: an emerging subspecialty. AB - Akin to the rapid growth in hospitalist medicine seen in the prior decade, there has been a recent explosion in the need for neurohospitalists. Factors driving this demand include nationally mandated quality and safety measures, the increasing complexity and age of the hospitalized patient, and diminished training in diagnosis and management of neurological illnesses for internal medicine residents. The role of the neurohospitalist is varied and may include not only providing neurological care to hospitalized patients but also serving as a leader in an institution's push to meet quality and safety measures. Close collaboration with intensivists, vascular neurologists, and outpatient neurologists is both a challenge and essential for successful delivery of care both during hospitalization and after discharge. Future challenges facing neurohospitalists include defining its relationship to other fields, instituting a pathway for certification, and conducting research to guide the development of evidence-based practice and quality measures. PMID- 22544507 TI - Molecular therapies for tuberous sclerosis and neurofibromatosis. AB - Neurofibromatosis type 1 (NF1) and tuberous sclerosis complex (TSC) are autosomal dominant genetic disorders that result from dysregulation of the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway. NF1 is caused by mutations in the NF1 gene on chromosome 17q11.2. Its protein product, neurofibromin, functions as a tumor suppressor and ultimately produces constitutive upregulation of mTOR. TSC is caused by mutations in either the TSC1 (chromosome 9q34) or TSC2 (chromosome 16p.13.3) genes. Their protein products, hamartin and tuberin, respectively, form a dimer that acts via the GAP protein Rheb (Ras homolog enhanced in brain) to directly inhibit mTOR, again resulting in upregulation. Specific inhibitors of mTOR are in clinical use, including sirolimus, everolimus, temsirolimus, and deforolimus. Everolimus has been shown to reduce the volume and appearance of subependymal giant cell astrocytomas (SEGA), facial angiofibromas, and renal angiomyolipomas associated with TSC, with a recent FDA approval for SEGA not suitable for surgical resection. This article reviews the use of mTOR inhibitors in these diseases, which have the potential to be a disease-modifying therapy in these and other conditions. PMID- 22544509 TI - Intense photon emission induced by fracture of gamma-irradiated Dy-, Tm-, Sm- and Mn-doped CaSO4 single crystals. AB - When an gamma-irradiated Dy-, Tm-, Sm- or Mn-doped CaSO4 crystal is impulsively deformed, two peaks appear in the ML intensity versus time curve, whereby the first ML peak is found in the deformation region and the second in the post deformation region of the crystals. In this study, intensities Im1 and Im2 corresponding to first and second ML peaks, respectively, increased linearly with an impact velocity v0 of the piston used to deform the crystals, and times tm1 and tm2 corresponding to the first and second ML peaks, respectively, decreased with impact velocity. Total ML intensity initially increased with impact velocity and then reached a saturation value for higher values of impact velocity. ML intensity increased with increasing gamma-doses and size of crystals. Results showed that the electric field produced as a result of charging of newly-created surfaces caused tunneling of electrons to the valence band of the hole-trapping centres. The free holes generated moved in the valence band and their subsequent recombination with electron trapping centres released energy, thereby resulting in excitation of luminescent centres. PMID- 22544510 TI - Atomic multipoles: electrostatic potential fit, local reference axis systems, and conformational dependence. AB - Currently, all standard force fields for biomolecular simulations use point charges to model intermolecular electrostatic interactions. This is a fast and simple approach but has deficiencies when the electrostatic potential (ESP) is compared to that from ab initio methods. Here, we show how atomic multipoles can be rigorously implemented into common biomolecular force fields. For this, a comprehensive set of local reference axis systems is introduced, which represents a universal solution for treating atom-centered multipoles for all small organic molecules and proteins. Furthermore, we introduce a new method for fitting atomic multipole moments to the quantum mechanically derived ESP. This methods yields a 50-90% error reduction compared to both point charges fit to the ESP and multipoles directly calculated from the ab initio electron density. It is shown that it is necessary to directly fit the multipole moments of conformational ensembles to the ESP. Ignoring the conformational dependence or averaging over parameters from different conformations dramatically deteriorates the results obtained with atomic multipole moments, rendering multipoles worse than partial charges. PMID- 22544511 TI - Evaluating a skin cancer education program for the Deaf community. AB - Skin cancer is the most common, preventable, and treatable cancer, so public education has been a priority. Unfortunately, for the Deaf community, most skin cancer information is difficult to access, so tailored approaches are needed. Participants (N=136) were randomly assigned to view either a skin cancer education video in American Sign Language (n=75) or an alternate video (n=61). All participants completed skin cancer knowledge questionnaires at baseline, immediately post-intervention, and 2-month post-intervention. Control group participants could then transfer to the experimental condition, using their 2 month follow-up data as their baseline. Participants who saw the skin cancer video gained significantly more knowledge than control participants, demonstrating the video's effectiveness in increasing skin cancer control knowledge. There was no difference between the original experimental group and the delayed intervention group on knowledge gains. PMID- 22544512 TI - Approaches for the Evaluation of the National Cancer Institute's Summer Curriculum in Cancer Prevention: lessons from the all-Ireland NCI cancer consortium. AB - The NCI Summer Curriculum in Cancer Prevention (SCCP) has provided interdisciplinary training in cancer prevention and control to cancer health-care professionals, including nurses, physicians, and scientists, since 1986. It has trained over 1,200 participants, 256 of them from Ireland and Northern Ireland through two summer courses: a 4-week course on Principles and Practice of Cancer Prevention and Control (PP) and 1-week on Molecular Prevention (MP). This report is our attempt to measure achievements and level of satisfaction among alumni from the island of Ireland upon return to their home institution. A questionnaire was developed to assess this. Our analysis found statistically significant differences in the types of accomplishments reported among respondents of the MP and PP courses as well as statistically significant differences in their level of satisfaction. More data are needed to better explain the differences observed as well as level of resources available to alumni upon their return home. PMID- 22544513 TI - Feasibility and value of PatientViewpoint: a web system for patient-reported outcomes assessment in clinical practice. AB - BACKGROUND: The PatientViewpoint website collects patient-reported outcomes and links them with the electronic health record to aid patient management. This pilot test evaluated PatientViewpoint's use, usefulness, and acceptability to patients and clinicians. METHODS: This was a single-arm prospective study that enrolled breast and prostate cancer patients undergoing treatment and the clinicians who managed them. Patients completed patient-reported outcomes every 2 weeks, and clinicians could access the results for patient visits. Scores that were poor relative to norms or substantially worse than the previous assessment were highlighted. After three on-study visits, we assessed patient and clinician perspectives on PatientViewpoint using close-ended and open-ended questions. RESULTS: Eleven out of 12 eligible clinicians (92%) and 52/76 eligible patients (68%) enrolled. Patients completed a median of 71% of assigned questionnaires; clinicians reported using the information for 79% of patients, most commonly as a source of additional information (51%). At the median, score reports identified three potential issues, of which 1 was discussed during the visit. Patients reported the system was easy to use (92%), useful (70%), aided recall of symptoms/side effects (72%), helped them feel more in control of their care (60%), improved discussions with their provider (49%), and improved care quality (39%). Patients and clinicians desired more information on score interpretation and minor adjustments to site navigation. CONCLUSIONS: These results support the feasibility and value of PatientViewpoint. An ongoing study is using a continuous quality improvement approach to further refine PatientViewpoint. Future studies will evaluate its impact on patient care and outcomes. PMID- 22544514 TI - Protective effects of vasoactive intestinal peptide (VIP) in ischemic retinal degeneration. AB - Vasoactive intestinal peptide (VIP) is a pleiotropic neuropeptide, acting as a neuromodulator and neuroprotective peptide in the CNS after injuries. We have previously described that pituitary adenylate cyclase-activating polypeptide (PACAP), another member of the same peptide family, is retinoprotective in ischemic lesions. The aim of this study was to investigate the protective potential of VIP in bilateral common carotid artery occlusion (BCCAO)-induced ischemic retinal lesion. Two-month-old rats were subjected to BCCAO and treated with intravitreal VIP injection. Their retinas were processed for histology after 2 weeks of survival. We measured the number of the cells/100 MUm of the ganglion cell layer and the thickness of each layer such as the outer nuclear, outer plexiform, inner nuclear, and inner plexiform layers as well as that of the whole retina. We found that treatment with 1,000 pmol VIP, but not 100 pmol VIP, had significant protective effects in BCCAO-injured retina, as shown by the morphometric analysis. Comparing the neuroprotective effects of VIP and PACAP in BCCAO-operated retinas, PACAP was more effective, already protective at 100-pmol doses. Similar to other studies, we found that VIP must be given at least in 10 times more concentration than PACAP to achieve a similar degree of neuroprotection in the retina. PMID- 22544515 TI - Expression of K2P channels in sensory and motor neurons of the autonomic nervous system. AB - Several types of neurons within the central and peripheral somatic nervous system express two-pore-domain potassium (K2P) channels, providing them with resting potassium conductances. We demonstrate that these channels are also expressed in the autonomic nervous system where they might be important modulators of neuronal excitability. We observed strong mRNA expression of members of the TRESK and TREK subfamilies in both the mouse superior cervical ganglion (mSCG) and the mouse nodose ganglion (mNG). Motor mSCG neurons strongly expressed mRNA transcripts for TRESK and TREK-2 subunits, whereas TASK-1 and TASK-2 subunits were only moderately expressed, with only few or very few transcripts for TREK-1 and TRAAK (TRESK ~ TREK-2 > TASK-2 ~ TASK-1 > TREK-1 > TRAAK). Similarly, the TRESK and TREK-1 subunits were the most strongly expressed in sensorial mNG neurons, while TASK-1 and TASK-2 mRNAs were moderately expressed, and fewer TREK-2 and TRAAK transcripts were detected (TRESK ~ TREK-1 > TASK-1 ~ TASK-2 > TREK-2 > TRAAK). Moreover, cell-attached single-channel recordings showed a major contribution of TRESK and TREK-1 channels in mNG. As the level of TRESK mRNA expression was not statistically different between the ganglia analysed, the distinct expression of TREK-1 and TREK-2 subunits was the main difference observed between these structures. Our results strongly suggest that TRESK and TREK channels are important modulators of the sensorial and motor information flowing through the autonomic nervous system, probably exerting a strong influence on vagal reflexes. PMID- 22544516 TI - Vasoactive intestinal peptide enhances striatal plasticity and prevents dopaminergic cell loss in Parkinsonian rats. AB - Destruction of the nigrostriatal dopaminergic pathway by the administration of 6 OHDA generates an animal model of Parkinson's disease. The main characteristic of this progressive neurological disorder is the loss of the dopaminergic neurons located in the substantia nigra pars compacta (SNc). Dopaminergic inputs from the SNc innervate the medium spiny neurons of the striatum and modulate the spontaneous activity of the primary output nuclei of the basal ganglia, globus pallidus interna, and substantia nigra pars reticulata. In our previous studies, we showed that systematically administered vasoactive intestinal peptide (VIP) is effective at reversing motor deficits, decreasing neuronal cell death, and repairing the myelin sheet in parkinsonian rats. In the current study, the effects of VIP on the dendritic morphology of the striatal neurons and the number of dopaminergic neurons in the SNc were examined in 6-OHDA-lesioned rats using Golgi-Cox staining and design-based stereological methods, respectively. Adult Sprague-Dawley rats were separated into sham-operated, bilaterally 6-OHDA lesioned and lesioned + i.p. VIP-injected (25 ng/kg) groups. VIP was first injected 1 h after the intrastriatal 6-OHDA microinjection (every 2 days for 15 days). The 6-OHDA significantly decreased the total number of dopaminergic neurons, branching, and spine density of the medium spiny neurons in the striatum. VIP significantly increased the number of neurons immunostained with tyrosine hydroxylase and the density of spines without altering the branching and the total length of dendrites. In conclusion, VIP might display synaptogenetic activity by enhancing the spine density in the striatum of the parkinsonian rats. PMID- 22544518 TI - Quantitative ultrasound in Spanish children and young adults with cystic fibrosis. AB - We studied the relationship between bone density and cystic fibrosis in Spanish children and young adults. We measured the phalangeal bone amplitude-dependent speed of sound (Ad-SoS) in 35 patients with cystic fibrosis and in 30 healthy controls matched for gender, age, and body mass index (BMI). Participants were subjects with normal levels of 25(OH) Vitamin D. We found no difference in Ad-SoS between patients and controls. The only difference between the groups was that the patients had a significantly higher daily caloric intake than the controls (p < .05) as a result of the patient group's greater intake of fats (p < .05). There was a positive correlation between Ad-SoS and weight (p < .0001), but after adjusting for potential confounding factors such as age, the correlation was lost. The percentage of ideal weight did not differ between the two groups. We conclude that well-nourished CF patients had similar Ad-SoS to controls. PMID- 22544517 TI - Skin viscoelasticity: physiologic mechanisms, measurement issues, and application to nursing science. AB - Skin is the primary interface between health care providers and patients and is assessed clinically to predict physiological stability or instability. The biomechanical properties of human skin, most notably elasticity and viscoelasticity, are critical to its protective function. In this article, the authors describe the physiological basis for skin elasticity and viscoelasticity. The authors discuss the role of viscoelasticity in nursing science and consider avenues for scientific exploration of the skin's biomechanical properties, including applications in pressure ulcer research, injury, and healing. They also discuss the Cutometer(r) as one option for measurement of viscoelasticity in clinical and bench research protocols. PMID- 22544519 TI - Protective effects of rosuvastatin in experimental renal failure rats via improved endothelial function. AB - Rosuvastatin is a statin (3-hydroxy-3-methylglutaryl coenzyme-A [HMG-CoA] reductase inhibitor) that also serves as an endothelial dysfunction salvager in many disease models. Endothelial dysfunction is assumed to play a pivotal role in the process of chronic renal failure. The authors tested rosuvastatin on a rat model of renal failure with hypertension. Renal failure was induced by 5/6 nephrectomy (Nx). Fisher rats were divided into four groups: sham (n = 10), sham + rosuvastatin (n = 10), Nx (n = 9), and Nx + rosuvastatin (n =10). After 4 weeks, the authors determined renal function, lipid profile, and urine albumin excretion, investigated small renal arteries for endothelium function in response to acetylcholine by perfused juxtamedullary nephron technique, and detected intrarenal inflammatory cytokine expression by real-time reverse transcription polymerase chain reaction. 5/6 Nx significantly increased blood urea nitrogen, serum creatinine, and systolic/diastolic blood pressure, and severe albuminuria developed. The deterioration of renal function, hypertension, and albuminuria were almost normalized by rosuvastatin therapy; in addition, rosuvastatin prevented intrarenal inflammatory cytokine expression and the impaired response to acetylcholine of the renal endothelium. Microscopically, rosuvastatin significantly inhibited the development of progressing renal fibrosis, preserved glomerular structure and tubular integrity, and significantly reduced the degree of tubular atrophy and interstitial fibrosis. In conclusion, HMG-CoA reductase inhibitor rosuvastatin can ameliorate markers of endothelium dysfunction and offers a significant protective effect against the development of renal failure caused by 5/6 Nx in rats. Rosuvastatin might, therefore, represent a novel therapeutic agent for chronic kidney disease. PMID- 22544520 TI - PP2A and DUSP6 are involved in sphingosylphosphorylcholine-induced hypopigmentation. AB - Activation of extracellular signal-related kinase (ERK) is involved in decreased melanogenesis by sphingosylphosphorylcholine (SPC). In the present study, we confirmed that SPC activated ERK and that a specific inhibitor of the ERK pathway (PD98059) recovered SPC-induced hypopigmentation. Moreover, we found that SPC significantly reduces protein phosphatase 2A (PP2A) activity in Mel-Ab cells, and that PP2A activator treatment abrogated SPC-induced hypopigmentation. We determined that alpha-melanocyte-stimulating hormone (alpha-MSH) increased the expression of dual-specificity phosphatase 6 (DUSP6), an ERK phosphatase, in a time-dependent manner. In contrast, SPC decreased the level of DUSP6 in Mel-Ab cells. Furthermore, inhibiting DUSP6 increased ERK activation and subsequently augmented the SPC-induced hypopigmenting effects. Taken together, our data suggest that SPC-induced phosphatase inhibition is also responsible for the hypopigmentary effects. PMID- 22544522 TI - Ferromagnetic interactions in a 1D alternating linear chain of pi-stacked 1,3 diphenyl-7-(thien-2-yl)-1,4-dihydro-1,2,4-benzotriazin-4-yl radicals. AB - X-ray studies show that 1,3-diphenyl-7-(thien-2-yl)-1,4-dihydro-1,2,4 benzotriazin-4-yl (6) adopts a distorted, slipped pi-stacked structure of centrosymmetric dimers with alternate short and long interplanar distances (3.48 and 3.52 A). Cyclic voltammograms of 7-(thien-2-yl)benzotriazin-4-yl 6 show two fully reversible waves that correspond to the -1/0 and 0/+1 processes. EPR and DFT studies on radical 6 indicate that the spin density is mainly delocalized over the triazinyl fragment. Magnetic susceptibility measurements show that radical 6 obeys Curie-Weiss behavior in the 5-300 K region with C=0.378 emu K mol(-1) and theta=+4.72 K, which is consistent with ferromagnetic interactions between S=1/2 radicals. Fitting the magnetic susceptibility revealed the behavior is consistent with an alternating ferromagnetic chain (g=2.0071, J(1) =+7.12 cm( 1), J(2) =+1.28 cm(-1)). PMID- 22544521 TI - 2,2'-dipyridyl diselenide is a better antioxidant than other disubstituted diaryl diselenides. AB - The aim of this study was to investigate the in vitro antioxidant activity of 2,2'-dipyridyl diselenide (e) by comparing this effect with m-trifluoromethyl diphenyl diselenide (a), p-fluor-diphenyl diselenide (b), p-chloro-diphenyl diselenide (c), and p-methoxyl-diphenyl diselenide (d) in rat liver homogenate. We also investigated if the mechanisms involved in the antioxidant property of 2,2'-dipyridyl diselenide are the same that of other diselenides. Thiobarbituric acid reactive substances (TBARS) and protein carbonyl (PC) levels were determined in rat liver homogenate, as indicators of antioxidant activity. Dehydroascorbate (DHA) reductase- and glutathione S-transferase (GST)-like activities, 2,2' diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzthiazoline-6 sulfonic acid) (ABTS) radical-scavenging activities and the protection against the oxidation of Fe(2+) were determined to better understand the antioxidant property of compounds. delta-Aminolevulinic dehydratase (delta-ALA-D) activity was also carried out in rat liver homogenates, as a toxicological parameter. Compound e showed the highest potency in reducing TBARS (order of IC(50) values: e < b <= a < d <= c) and PC (order of IC(50) values: e < c <= b <= a < d) levels and lower potency in inhibiting delta-ALA-D activity than other diselenides. Compound e at all concentrations tested had no enzyme-mimetic property, but had radical-scavenging activity (>=5 MUM) and protected against the oxidation of Fe(2+) (50 MUM); while compounds a-d showed GST and DHA-mimetic activities and protected against the oxidation of Fe(2+), but had not radical-scavenging activities. This study indicates that (i) 2,2'-dipyridyl diselenide (e) had better in vitro antioxidant effect than other diselenides and lower inhibitory effect on delta-ALA-D activity, (ii) the presence of pyridine ring is responsible for the best antioxidant effect of this compound, and (iii) 2,2'-dipyridyl diselenide acts by different mechanisms of other diselenides. PMID- 22544524 TI - Borneol administration protects primary rat hepatocytes against exogenous oxidative DNA damage. AB - Experimental evidences suggest that most essential oils possess a wide range of biological and pharmacological activities that may protect tissues against oxidative damage. In this study, we investigated DNA-protective effect of borneol, a component of many essential oils, against oxidative DNA damage induced in primary cultures of rat hepatocytes. Borneol was added to drinking water of Sprague-Dawley rats and DNA resistance against oxidative agents was compared in hepatocytes originated from control and borneol-treated rats. Oxidative stress induced by visible light-excited methylene blue (MB/VL) or 2,3-dimethoxy-1,4 naphthoquionone (DMNQ) resulted in increased levels of DNA lesions measured by the modified single cell gel electrophoresis. Borneol (17 or 34 mg/kg body weight) added to drinking water of rats for 7 days reduced the level of oxidative DNA lesions induced in their hepatocytes by MB/VL or DMNQ. To explain the increased resistance of DNA towards oxidative stress, we measured the base excision repair (BER) capacity in liver cell extracts of control and borneol supplemented rats on DNA substrate of HepG2 cells containing oxidative damage. Our results showed that administration of borneol in drinking water had no effect on incision activity of hepatocytes isolated from supplemented rats. The spectrophotometric assessment of enzymatic antioxidants superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities and the flow cytometric assessment of total intracellular glutathione (iGSH) in primary hepatocytes of borneol-supplemented rats showed no changes in SOD and GPx activities but higher iGSH content particularly in hepatocytes of higher borneol dose (34 mg/kg) supplemented rats in comparison to control animals. Despite the fact that borneol had no effect either on BER of oxidative DNA damage or on the levels of antioxidant enzymes and manifested no reducing power and radicals scavenging activity, it increased significantly the level of non-enzymatic antioxidant iGSH which could reduce the oxidative DNA lesions induced by MB/VL or DMNQ. PMID- 22544523 TI - Variations in peak expiratory flow measurements associated to air pollution and allergic sensitization in children in Sao Paulo, Brazil. AB - BACKGROUND: In the last 20 years, there has been an increase in the incidence of allergic respiratory diseases worldwide and exposure to air pollution has been discussed as one of the factors associated with this increase. The objective of this study was to investigate the effects of air pollution on peak expiratory flow (PEF) and FEV1 in children with and without allergic sensitization. METHODS: Ninety-six children were followed from April to July, 2004 with spirometry measurements. They were tested for allergic sensitization (IgE, skin prick test, eosinophilia) and asked about allergic symptoms. Air pollution, temperature, and relative humidity data were available. RESULTS: Decrements in PEF were observed with previous 24-hr average exposure to air pollution, as well as with 3-10-day average exposure and were associated mainly with PM(10), NO(2), and O(3) in all three categories of allergic sensitization. Even though allergic sensitized children tended to present larger decrements in the PEF measurements they were not statistically different from the non-allergic sensitized. Decrements in FEV1 were observed mainly with previous 24-hr average exposure and 3-day moving average. CONCLUSIONS: Decrements in PEF associated with air pollution were observed in children independent from their allergic sensitization status. Their daily exposure to air pollution can be responsible for a chronic inflammatory process that might impair their lung growth and later their lung function in adulthood. PMID- 22544525 TI - Alterations of the erythrocyte membrane proteome and cytoskeleton network during storage--a possible tool to identify autologous blood transfusion. AB - Mature red blood cells (RBCs) are the end-stage of a development process that starts in the bone marrow and continues to differentiate, through reticulocyte stage, entering into the circulation with a four-month lifespan. While stored, RBCs undergo different changes. The aim of this study was to evaluate changes occurring in RBC membranes during storage that could be used as possible markers to detect the misuse of blood transfusion in sports. Whole blood was collected from two volunteers in blood bags and stored for 42 days at 4 degrees C. At different times (1, 7, 21, and 42 days of storage) whole blood was extracted under sterile conditions and submitted to RBC membrane ghost preparation and further analysis. Proteomic methods were applied using two strategies: protein oriented using 2-DE gels and peptide oriented using isobaric tags for relative and absolute quantitation (iTRAQ). In both approaches, the goal was to compare detectable changes in RBC membrane proteome before and after standard storage at different times. Some of the changes were confirmed with both methodologies employed, while with others only with one of them. Complementarities of the methods in this case showed to be an advantage. Changes were observed in two different protein complexes. In one of them, changes consisted of proteins decreasing, while increasing in the other during storage of RBCs. They are mostly located in cytoskeleton--spectrin beta, band 4.2, ankyrin-1, tropomodulin-1, beta adducin, band 4.9 (dematin), tropomyosin, while some changes were also observed in transmembrane proteins (glycophorin C, aquaporin-1, band 3). PMID- 22544527 TI - Promotion of bone repair by implantation of cryopreserved bone marrow-derived mononuclear cells in a rabbit model of steroid-associated osteonecrosis. AB - OBJECTIVE: Cytotherapy is an insufficient method for promoting bone repair in steroid-associated osteonecrosis (SAON), and this has been attributed to impairment of the bioactivity of bone marrow-derived stem cells (BMSCs) after pulsed administration of steroids. Cryopreserved autologous bone marrow-derived mononuclear cells (BMMNCs), which contain BMSCs, might maintain their bioactivity in vitro. This study sought to investigate the effects of cryopreserved BMMNCs, before steroid administration, on the enhancement of bone repair in an established rabbit model of SAON. METHODS: For in vitro study, bone marrow was harvested 4 weeks before SAON induction from the iliac crests of rabbits (n = 10) to isolate fresh BMMNCs, and the BMMNCs were then cryopreserved for 8 weeks. Both the fresh and the cryopreserved BMMNCs were evaluated for their bioactivity and osteogenic differentiation capacity. In addition, BMMNCs were isolated 2 weeks after SAON induction and subjected to the same evaluations. For in vivo study, cryopreserved BMMNCs were implanted into the bone tunnel during core decompression of the femur (n = 12 rabbits) after the induction of SAON, and tissue regeneration was evaluated by micro-computed tomography and histologic analyses at 12 weeks postoperation. RESULTS: In vitro, there were no significant differences in the bioactivity or ability to undergo osteogenic differentiation between fresh BMMNCs and cryopreserved BMMNCs, but after SAON induction, both features were decreased significantly. In vivo, the bone mineral density, ratio of bone volume to total volume of bone, and volume and diameter of neovascularization within the bone tunnel were significantly higher in the BMMNC treated group compared to the nontreated control group at 12 weeks postoperation. CONCLUSION: Cryopreserved BMMNCs maintained their bioactivity and promoted bone regeneration and neovascularization within the bone tunnel after core decompression in this rabbit model of SAON. PMID- 22544526 TI - Variant alleles of the Wnt antagonist FRZB are determinants of hip shape and modify the relationship between hip shape and osteoarthritis. AB - OBJECTIVE: To test whether single-nucleotide polymorphisms (SNPs) of the FRZB gene are associated with hip shape, and to determine whether FRZB variant alleles affect the relationship between hip shape and radiographic osteoarthritis (OA) of the hip. METHODS: A nested case-control study of Caucasian women, age >=65 years, from the Study of Osteoporotic Fractures cohort was performed. Cases (n = 451) were defined as subjects with radiographic evidence of incident hip OA during followup, while controls (n = 601) were subjects in whom no radiographic hip OA was identified at baseline or followup. Statistical shape modeling (SSM) of the digitized hip radiographs was performed to assess the shape of the proximal femur, using 10 independent modes of shape variation generated by principal components analysis. In addition, center-edge angle and acetabular depth were assessed as geometric measurements of acetabular shape. The association of the rs288326 and rs7775 FRZB variant alleles with hip shape was analyzed using linear regression. The effect of these alleles on the relationship between hip shape and radiographic hip OA was analyzed using a logistic regression model with or without inclusion of interaction terms. RESULTS: The rs288326 and rs7775 alleles were associated with the shape of the proximal femur (SSM mode 2). There was a significant interaction between the rs288326 SNP and proximal femur shape (SSM mode 2) in predicting radiographic hip OA (P for interaction = 0.022). Among subjects with the rs288326 variant allele, there was an increased likelihood of radiographic hip OA in association with increasing quartiles of proximal femur shape mode 2 (for the fourth quartile of mode 2, odds ratio 2.5, 95% confidence interval 1.15, 5.25; P for linear trend = 0.02). CONCLUSION: The rs288326 and rs7775 FRZB SNPs are associated with the shape of the proximal femur. The presence of the rs288326 SNP alters the relationship between proximal femur shape and incident radiographic hip OA. These findings suggest that FRZB may serve an important role in determining hip shape and may modify the relationship between hip shape and OA. PMID- 22544528 TI - Childhood primary angiitis of the central nervous system: identifying disease trajectories and early risk factors for persistently higher disease activity. AB - OBJECTIVE: To compare clinical, laboratory, and imaging characteristics of childhood primary angiitis of the central nervous system (PACNS) subtypes at diagnosis and during followup; to characterize disease activity trajectories in childhood PACNS subtypes; and to identify early risk factors for higher disease activity. METHODS: We performed a single-center cohort study of consecutive children diagnosed as having childhood PACNS. Demographic, clinical, laboratory, and imaging data were collected at diagnosis and during standardized clinic visits. Outcome measures included disease activity measured by physician's global assessment. Descriptive statistics were used to assess characteristics of the study cohort, and longitudinal data were analyzed using linear mixed-effects regression. RESULTS: The study cohort consisted of 45 patients with childhood PACNS; 26 had angiography-negative childhood PACNS and 19 had angiography positive childhood PACNS. There were 24 females, the median age at diagnosis was 9.8 years, and the median followup period was 1.8 years. Patients with angiography-negative childhood PACNS were more likely to be female and to present with seizures, cognitive dysfunction, vision abnormalities, high levels of inflammatory markers, and bilateral findings on magnetic resonance imaging (MRI). Motor deficits and ischemic MRI lesions were more common in angiography-positive disease. Disease activity decreased significantly after treatment in all patients. Distinct trajectories of disease activity over time were identified for both childhood PACNS subtypes. Patients with angiography-negative childhood PACNS had persistently higher disease activity. Seizures at presentation also predicted higher disease activity over time. CONCLUSION: Distinct subtypes of childhood PACNS have unique disease activity trajectories. Patients with angiography negative disease and seizures at presentation experience higher disease activity. Early recognition of this high-risk cohort may enable the treating physician to initiate targeted therapies and prevent long-term brain injury. PMID- 22544530 TI - Foveal avascular zone and foveal pit formation after preterm birth. AB - BACKGROUND: Vascularisation of the macula takes place between 24 and 27 weeks post-conception. Preterm birth may affect the formation of the foveal avascular zone (FAZ) and foveal depression, and displacement of inner retinal layers away from the incipient fovea. OBJECTIVE: To examine whether vascular abnormalities accompany an inner retinal abnormality, and whether they are coincident. METHODS: High-density spectral domain optical coherence tomography volume scans were obtained from 24 preterm children and 34 full-term controls (5-16 years). Matlab programs were used to quantify total retinal thickness, thickness of individual retinal layers and metrics of foveal morphology. Summed voxel projections for the ganglion cell layer-inner nuclear layer were used to identify the FAZ. RESULTS: Preterm children had significantly smaller FAZ diameters than controls (p<0.0001). The foveal pits of preterm children were significantly shallower and less steep (p<0.0001) and total retinal thickness at the fovea was significantly increased (p<0.0001) compared to controls. The ganglion cell layer-inner plexiform layer and outer nuclear layer were significantly (p<=0.0001) thicker in preterm children than in controls. CONCLUSIONS: Preterm birth results in abnormal foveal vascularisation, a failure of the inner retinal neurons to migrate away from the fovea, and an elevated outer nuclear layer ratio. The spatial coincidence of inner retinal and vascular abnormalities in preterm children supports the hypothesis that aspects of foveal development are interdependent. PMID- 22544531 TI - Re: 'Long-term surgical outcomes of porous polyethylene orbital implants: a review of 314 cases'. PMID- 22544532 TI - The changing face of corneal graft rejection. PMID- 22544533 TI - Allogeneic hematopoietic stem cell transplantation in children with sickle cell disease. AB - Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents the only curative treatment for sickle cell disease (SCD), being successful in around 85-90% of patients. Mortality and long-term morbidity (including infertility, gonadal failure, and chronic graft-vs.-host disease) associated with conventional approaches curtail the number of patients who undergo allo-HSCT. Recently, it has been demonstrated that cord blood is as effective as and possibly safer than bone marrow in pediatric patients with SCD. Likewise, transplant strategies based on the use of reduced-intensity regimens and the induction of mixed chimerism have been explored to decrease allo-HSCT short- and long-term complications. PMID- 22544529 TI - Pathophysiology of astroglial purinergic signalling. AB - Astrocytes are fundamental for central nervous system (CNS) physiology and are the fulcrum of neurological diseases. Astroglial cells control development of the nervous system, regulate synaptogenesis, maturation, maintenance and plasticity of synapses and are central for nervous system homeostasis. Astroglial reactions determine progression and outcome of many neuropathologies and are critical for regeneration and remodelling of neural circuits following trauma, stroke, ischaemia or neurodegenerative disorders. They secrete multiple neurotransmitters and neurohormones to communicate with neurones, microglia and the vascular walls of capillaries. Signalling through release of ATP is the most widespread mean of communication between astrocytes and other types of neural cells. ATP serves as a fast excitatory neurotransmitter and has pronounced long-term (trophic) roles in cell proliferation, growth, and development. During pathology, ATP is released from damaged cells and acts both as a cytotoxic factor and a proinflammatory mediator, being a universal "danger" signal. In this review, we summarise contemporary knowledge on the role of purinergic receptors (P2Rs) in a variety of diseases in relation to changes of astrocytic functions and nucleotide signalling. We have focussed on the role of the ionotropic P2X and metabotropic P2YRs working alone or in concert to modify the release of neurotransmitters, to activate signalling cascades and to change the expression levels of ion channels and protein kinases. All these effects are of great importance for the initiation, progression and maintenance of astrogliosis-the conserved and ubiquitous glial defensive reaction to CNS pathologies. We highlighted specific aspects of reactive astrogliosis, especially with respect to the involvement of the P2X(7) and P2Y(1)R subtypes. Reactive astrogliosis exerts both beneficial and detrimental effects in a context-specific manner determined by distinct molecular signalling cascades. Understanding the role of purinergic signalling in astrocytes is critical to identifying new therapeutic principles to treat acute and chronic neurological diseases. PMID- 22544534 TI - Mammalian target of rapamycin (mTOR) inhibition: potential for antiseizure, antiepileptogenic, and epileptostatic therapy. AB - New epilepsy treatments are needed that not only inhibit seizures symptomatically (antiseizure) but also prevent the development of epilepsy (antiepileptogenic). The mammalian target of rapamycin (mTOR) pathway may mediate mechanisms of epileptogenesis and serve as a rational therapeutic target. mTOR inhibitors have antiepileptogenic and antiseizure effects in animal models of the genetic disease, tuberous sclerosis complex. The mTOR pathway is also implicated in epileptogenesis in animal models of acquired epilepsy and infantile spasms, although the effects of mTOR inhibitors are variable depending on the specific conditions and model. Furthermore, beneficial effects on seizures are lost when treatment is withdrawn, suggesting that mTOR inhibitors are "epileptostatic" in only stalling epilepsy progression during treatment. Clinical studies of rapamycin in human epilepsy are limited, but suggest that mTOR inhibitors at least have antiseizure effects in tuberous sclerosis patients. Further studies are needed to assess the full potential of mTOR inhibitors for epilepsy treatment. PMID- 22544535 TI - Therapy in Huntington's disease: where are we? AB - As of 2012, almost 20 years after the discovery of the causative gene, clinical research has yet to find a disease-modifying treatment for Huntington's disease. However, both pharmacologic and nonpharmacologic therapies are available for many of the common symptoms of the disease. Recent studies of gene-positive patients in the prodromal, not clinically diagnosable, stages of the disease, are changing our perception of when the process of neurodegeneration begins. Once disease modifying therapies become available, the approach to the diagnosis of Huntington's disease will likely shift from an examination-based clinical diagnosis, to one that includes a more complex combination of imaging, examination, and biomarker analysis. PMID- 22544537 TI - Distribution of the h-index in radiation oncology conforms to a variation of power law: implications for assessing academic productivity. AB - Leaders of academic institutions evaluate academic productivity when deciding to hire, promote, or award resources. This study examined the distribution of the h index, an assessment of academic standing, among radiation oncologists. The authors collected h-indices for 826 US academic radiation oncologists from a commercial bibliographic database (SCOPUS, Elsevier B.V., NL). Then, logarithmic transformation was performed on h-indices and ranked h-indices, and results were compared to estimates of a power law distribution. The h-index frequency distribution conformed to both the log-linear variation of a power law (r (2) = .99) and the beta distribution with the same fitting exponents as previously described in a power law analysis of the productivity of neurosurgeons. Within radiation oncology, as in neurosurgery, there are exceedingly more faculty with an h-index of 1-2. The distribution fitting the same variation of a power law within two fields suggests applicability to other areas of academia. PMID- 22544536 TI - Understanding the psychosocial issues of African American couples surviving prostate cancer. AB - African Americans are disproportionately affected by prostate cancer, yet less is known about the most salient psychosocial dimensions of quality of life. The purpose of this study was to explore the perceptions of African American prostate cancer survivors and their spouses of psychosocial issues related to quality of life. Twelve African American couples were recruited from a National Cancer Institute Comprehensive Cancer Center registry and a state-based non-profit organization to participate in individual interviews. The study was theoretically based on Ferrell's Quality of Life Conceptual Model. Common themes emerged regarding the psychosocial needs of African American couples. These themes were categorized into behavioral, social, psychological, and spiritual domains. Divergent perspectives were identified between male prostate cancer survivors and their female spouses. This study delineated unmet needs and areas for future in depth investigations into psychosocial issues. The differing perspectives between patients and their spouses highlight the need for couple-centered interventions. PMID- 22544538 TI - Influence of framing and graphic format on comprehension of risk information among American Indian tribal college students. AB - We evaluated methods for presenting risk information by administering six versions of an anonymous survey to 489 American Indian tribal college students. All surveys presented identical numeric information, but framing varied. Half expressed prevention benefits as relative risk reduction, half as absolute risk reduction. One third of surveys used text to describe prevention benefits; one third used text plus bar graph; one third used text plus modified bar graph incorporating a culturally tailored image. The odds ratio (OR) for correct risk interpretation for absolute risk framing vs. relative risk framing was 1.40 (95 % CI = 1.01, 1.93). The OR for correct interpretation of text plus bar graph vs. text only was 2.16 (95 % CI = 1.46, 3.19); OR for text plus culturally tailored bar graph vs. text only was 1.72 (95 % CI = 1.14, 2.60). Risk information including a bar graph was better understood than text-only information; a culturally tailored graph was no more effective than a standard graph. PMID- 22544539 TI - Importance of continuing therapy and maintaining one-month relative dose intensity in sunitinib therapy for metastatic renal cell carcinoma. AB - Sunitinib is a multikinase inhibitor used as first- and second-line treatment of metastatic renal cell carcinoma. However, there are few reports on the necessary doses of sunitinib to get better clinical outcome in general practice with Japanese patients. We examined the relationship between the efficacy and the necessary doses of sunitinib therapy in a multi-institutional retrospective study. A study population of 94 metastatic renal cell carcinoma patients was eligible for this investigation. The most frequent grade 3/4 laboratory adverse events were decreased platelet (31.9 %) and white blood cell (21.3 %) counts. Treatment was discontinued in 18 patients (31.0 %) initially receiving a 50 mg/day dose within only one course, and median 1-month relative dose intensity was 74.3 %. Median progression-free survival time was 2.3 months in patients treated for only one course and 10.8 months in patients treated for more than one course (P < 0.001). Multivariate analysis showed that only one course of treatment and 60 % and less of 1-month relative dose intensity were significantly associated with inferior progression-free survival (P < 0.001 and P = 0.027, respectively). Moreover, modified Memorial Sloan-Kettering Cancer Center poor risk was significantly associated with progression-free survival time. It is difficult for Japanese patients to continue an initial dose of sunitinib therapy without drug withdrawal. Continuing therapy for more than one course and maintaining more than 60 % of 1-month relative dose intensity were very important in the prolongation of progression-free survival time regardless of the initial treatment doses. PMID- 22544541 TI - Molecular structure determination using chiroptical spectroscopy: where we may go wrong? AB - Chiroptical spectroscopy is being widely used for determining the three dimensional molecular structures (i.e., absolute configurations and conformations) of chiral molecules. The general procedure used with any of the chiroptical spectroscopic methods is to analyze the experimental data using corresponding quantum chemical predictions. Such analysis involves multiple steps, including consideration of conformations, solvent effects, electronic transitions, stereoisomers, and experimental artifacts, each of which possesses certain limitations. These limitations, when not recognized or properly taken into account, may lead to incorrect conclusions. This review emphasizes on selected examples that illustrate the potential limitations in utilizing the chiroptical spectroscopic methods. The examples used include hibiscus acid dimethylester, hibiscus acid disodium salt, 3,3'-diphenyl-[2,2'-binaphthalene] 1,1'-diol, tartaric acid esters, and 6,6'-dibromo-[1,1'-binaphthalene]-2,2'-diol. PMID- 22544540 TI - High expression of TIMP-1 in human breast cancer tissues is a predictive of resistance to paclitaxel-based chemotherapy. AB - For breast cancer patients with lymph node metastasis, paclitaxel is the first line chemotherapy drug. Clinical studies showed that some patients with breast cancer were insensitive to paclitaxel, which led to chemotherapy failure. Today, no validated markers exist for the prediction of chemotherapy sensitivity in this patient group. Tissue inhibitor of metalloproteinases-1 (TIMP-1) has been shown to protect against apoptosis. Epidemiological studies have also associated elevated tumor tissue TIMP-1 levels with a poor response to cyclophosphamide/methotrexate/5-fluorouracil and anthracycline-based chemotherapy. Additionally, our previous study proved that TIMP-1 significantly decreased the sensitivity of breast cancer cells to paclitaxel-induced apoptosis by enhancing degradation of cyclin B1. These data imply that TIMP-1 may be a useful predictive biomarker for chemotherapy resistance. In this retrospective study, we investigated the association between expression levels of TIMP-1 protein in the primary tumor and objective response to paclitaxel-based chemotherapy in 99 patients with breast cancer. With Kaplan-Meier survival analysis, the patients with high TIMP-1 levels were found to have significantly worse 5-year DFS (71.1 %) than the patients with low levels (88.5 %; P = 0.020). Similarly, the patients with high TIMP-1 levels had significantly worse 5-year OS (78.9 %) than patients with low levels (96.7 %; P = 0.004). In Cox's univariate and multivariate analyses, TIMP-1 was prognostic for both DFS and OS. Our data showed that elevated tumor tissue TIMP-1 levels were significantly associated with a poor response to paclitaxel-based chemotherapy, and TIMP-1 might be a potential biomarker for predicting response of breast cancer patients to paclitaxel-based chemotherapy. PMID- 22544542 TI - Ultrasound assessment of placental function: the effectiveness of placental biometry in a low-risk population as a predictor of a small for gestational age neonate. AB - OBJECTIVE: The aims of the study were to establish reference ranges for placental length and thickness in a low-risk obstetric population and to assess the likelihood of a small for gestational age (SGA) neonate on the basis of placental length at 18-24 weeks' gestation. METHODS: Placental length and thickness were measured by two sonographers in 520 singleton pregnancies. Uterine artery Doppler studies and a placental morphological assessment were also performed. Placental size was correlated with the birthweight centiles at delivery. RESULTS: A placental length <10th centile between the gestational age of 18 and 24 weeks is a significant factor associated with SGA neonate [odds ratio (OR) = 2.8, 95% CL, 1.1-6.9]. An abnormal uterine artery Doppler is a significant factor for SGA neonate (OR = 3.4, 95% CL, 1.6-7.4). There was a weak relationship between cord insertion <2 cm from the placental margin and an SGA neonate (OR = 1.8, 95% CL, 0.4-8.2). CONCLUSION: We have provided reference ranges for placental length and thickness from 18 to 24 weeks' gestation. A single measurement of placental length incorporated into the anatomy scan may assist in the early detection of a group at risk of delivering an SGA neonate. PMID- 22544543 TI - Malignant mesothelioma incidence among talc miners and millers in New York State. AB - BACKGROUND: There is controversy about the potential for dust from the talc mines and mills of New York State to cause mesothelioma. Honda et al. published a study of mortality among New York talc workers and concluded that it was unlikely that the two deaths from mesothelioma were caused by talc ore dust. However, fibers of tremolite and anthophyllite have been found in the lungs of talc workers and Hull concluded that "New York talc exposure is associated with mesothelioma, and deserves further public health attention." METHODS: Data concerning additional cases of mesothelioma in the cohort have been posted by NIOSH. I used information from the NIOSH website and the Honda report to analyze the incidence of mesothelioma during the years 1990-2007. RESULTS: There were at least five new cases of mesothelioma in the cohort and mesothelioma incidence rates were at least five (1.6-11.7) times the rate in the general population (P < 0.01). CONCLUSIONS: I conclude that: (1) mesothelioma has been diagnosed among members of the cohort at a rate in excess of that in the general population; (2) fibers of tremolite and anthophyllite have been detected in dust and the lungs of talc workers; and (3) these fibers are known causes of mesothelioma. It is prudent, on the balance of probabilities, to conclude that dusts from New York State talc ores are capable of causing mesothelioma in exposed individuals. PMID- 22544545 TI - Explanatory models and mental health treatment: is vodou an obstacle to psychiatric treatment in rural Haiti? AB - Vodou as an explanatory framework for illness has been considered an impediment to biomedical psychiatric treatment in rural Haiti by some scholars and Haitian professionals. According to this perspective, attribution of mental illness to supernatural possession drives individuals to seek care from houngan-s (Vodou priests) and other folk practitioners, rather than physicians, psychologists, or psychiatrists. This study investigates whether explanatory models of mental illness invoking supernatural causation result in care-seeking from folk practitioners and resistance to biomedical treatment. The study comprised 31 semi structured interviews with community leaders, traditional healers, religious leaders, and biomedical providers, 10 focus group discussions with community members, community health workers, health promoters, community leaders, and church members; and four in-depth case studies of individuals exhibiting mental illness symptoms conducted in Haiti's Central Plateau. Respondents invoked multiple explanatory models for mental illness and expressed willingness to receive treatment from both traditional and biomedical practitioners. Folk practitioners expressed a desire to collaborate with biomedical providers and often referred patients to hospitals. At the same time, respondents perceived the biomedical system as largely ineffective for treating mental health problems. Explanatory models rooted in Vodou ethnopsychology were not primary barriers to pursuing psychiatric treatment. Rather, structural factors including scarcity of treatment resources and lack of psychiatric training among health practitioners created the greatest impediments to biomedical care for mental health concerns in rural Haiti. PMID- 22544544 TI - Protein dynamics viewed by hydrogen exchange. AB - To examine the relationship between protein structural dynamics and measurable hydrogen exchange (HX) data, the detailed exchange behavior of most of the backbone amide hydrogens of Staphylococcal nuclease was compared with that of their neighbors, with their structural environment, and with other information. Results show that H-bonded hydrogens are protected from exchange, with HX rate effectively zero, even when they are directly adjacent to solvent. The transition to exchange competence requires a dynamic structural excursion that removes H bond protection and allows exposure to solvent HX catalyst. The detailed data often make clear the nature of the dynamic excursion required. These range from whole molecule unfolding, through smaller cooperative unfolding reactions of secondary structural elements, and down to local fluctuations that involve as little as a single peptide group or side chain or water molecule. The particular motion that dominates the exchange of any hydrogen is the one that allows the fastest HX rate. The motion and the rate it produces are determined by surrounding structure and not by nearness to solvent or the strength of the protecting H-bond itself or its acceptor type (main chain, side chain, structurally bound water). Many of these motions occur over time scales that are appropriate for biochemical function. PMID- 22544546 TI - Certification of steroid carbon isotope ratios in a freeze-dried human urine reference material. AB - An accurate method for the measurement of carbon isotope ratios of steroids in human urine has been developed at the National Measurement Institute, Australia (NMIA) for the certification of a freeze-dried human urine reference material (CRM NMIA MX005). The method measures delta(13)C values by gas chromatography combustion-isotope ratio mass spectrometry (GC-C-IRMS) analysis following hydrolysis, solvent extraction and high performance liquid chromatography (HPLC) purification. Reference delta(13)C values for testosterone metabolites etiocholanolone, androsterone, and endogenous reference compounds (ERCs) 11beta hydroxyandrosterone and pregnanediol were determined, as well as information delta(13)C values for testosterone, epitestosterone, 11-oxoetiocholanolone, and a range of differences (Delta(13)C) between testosterone metabolites and ERCs. The measurement uncertainty was rigorously evaluated with expanded uncertainties for the reference delta(13)C values between 1.1 and 1.6 0/00 at the 95% coverage level. PMID- 22544547 TI - Clinical significance of large rearrangements in BRCA1 and BRCA2. AB - BACKGROUND: Current estimates of the contribution of large rearrangement (LR) mutations in the BRCA1 (breast cancer 1, early onset) and BRCA2 (breast cancer 2, early onset) genes responsible for hereditary breast and ovarian cancer are based on limited studies of relatively homogeneous patient populations. The prevalence of BRCA1/2 LRs was investigated in 48,456 patients with diverse clinical histories and ancestries, referred for clinical molecular testing for suspicion of hereditary breast and ovarian cancer. METHODS: Sanger sequencing analysis was performed for BRCA1/2 and LR testing for deletions and duplications using a quantitative multiplex polymerase chain reaction assay. Prevalence data were analyzed for patients from different risk and ethnic groups between July 2007 and April 2011. Patients were designated as "high-risk" if their clinical history predicted a high prior probability, wherein LR testing was performed automatically in conjunction with sequencing. "Elective" patients did not meet the high-risk criteria, but underwent LR testing as ordered by the referring health care provider. RESULTS: Overall BRCA1/2 mutation prevalence among high risk patients was 23.8% versus 8.2% for the elective group. The mutation profile for high-risk patients was 90.1% sequencing mutations versus 9.9% LRs, and for elective patients, 94.1% sequencing versus 5.9% LRs. This difference may reflect the bias in high-risk patients to carry mutations in BRCA1, which has a higher penetrance and frequency of LRs compared with BRCA2. There were significant differences in the prevalence and types of LRs in patients of different ancestries. LR mutations were significantly more common in Latin American/Caribbean patients. CONCLUSIONS: Comprehensive LR testing in conjunction with full gene sequencing is an appropriate strategy for clinical BRCA1/2 analysis. PMID- 22544548 TI - Triggering of acute myocardial infarction by different means of transportation. AB - BACKGROUND: Prior studies have reported an association between traffic-related air pollution in urban areas and exacerbation of cardiovascular disease. We assess here whether time spent in different modes of transportation can trigger the onset of acute myocardial infarction (AMI). DESIGN: We performed a case crossover study. We interviewed consecutive cases of AMI in the KORA Myocardial Infarction Registry in Augsburg, Southern Germany between February 1999 and December 2003 eliciting data on potential triggers in the four days preceding myocardial infarction onset. RESULTS: A total of 1459 cases with known date and time of AMI symptom onset, who had survived 24 hours after the onset, completed the registry's standard interview on potential triggers of AMI. An association between exposure to traffic and AMI onset 1 hour later was observed (odds ratio: 3.2; 95% confidence interval [CI]: 2.7-3.9, p < 0.001). Using a car was the most common source of traffic exposure; nevertheless, times spent in public transport or on a bicycle were similarly associated with AMI onset 1 hour later. While the highest risk for AMI onset was within 1 hour of exposure to traffic, the elevated risk persisted for up to 6 hours. Women, patients aged 65 years or older, patients not part of the workforce, and those with a history of angina or diabetes exhibited the largest associations between times spent in traffic and AMI onset 1 hour later. CONCLUSION: The data suggest that transient exposure to traffic regardless of the means of transportation may increase the risk of AMI transiently. PMID- 22544549 TI - Understanding effects of global change on water quantity and quality in river basins - the SCARCE project. PMID- 22544550 TI - Assessing and forecasting the impacts of global change on Mediterranean rivers. The SCARCE Consolider project on Iberian basins. AB - INTRODUCTION: The Consolider-Ingenio 2010 project SCARCE, with the full title "Assessing and predicting effects on water quantity and quality in Iberian Rivers caused by global change" aims to examine and predict the relevance of global change on water availability, water quality, and ecosystem services in Mediterranean river basins of the Iberian Peninsula, as well as their socio economic impacts. Starting in December 2009, it brought together a multidisciplinary team of 11 partner Spanish institutions, as well as the active involvement of water authorities, river basin managers, and other relevant agents as stakeholders. METHODS: The study areas are the Llobregat, Ebro, Jucar, and Guadalquivir river basins. These basins have been included in previous studies and projects, the majority of whom considered some of the aspects included in SCARCE but individually. Historical data will be used as a starting point of the project but also to obtain longer time series. The main added value of SCARCE project is the inclusion of scientific disciplines ranging from hydrology, geomorphology, ecology, chemistry, and ecotoxicology, to engineering, modeling, and economy, in an unprecedented effort in the Mediterranean area. The project performs data mining, field, and lab research as well as modeling and upscaling of the findings to apply them to the entire river basin. RESULTS: Scales ranging from the laboratory to river basins are addressed with the potential to help improve river basin management. The project emphasizes, thus, linking basic research and management practices in a single framework. In fact, one of the main objectives of SCARCE is to act as a bridge between the scientific and the management and to transform research results on management keys and tools for improving the River Basin Management Plans. Here, we outline the general structure of the project and the activities conducted within the ten Work Packages of SCARCE. PMID- 22544551 TI - Spatial distribution of illicit drugs in surface waters of the natural park of Pego-Oliva Marsh (Valencia, Spain). AB - BACKGROUND, AIM AND SCOPE: The Pego-Oliva Marsh is the second most important wetland in the Valencian Community (Spain). It is included in the RAMSAR agreement and represents one key point for migratory birds. Emerging contaminants from the human pressure, such as pharmaceuticals, illicit drugs and personal care product, are not included in the list of priority contaminants of the Water Framework Directive yet, and are neither monitored nor controlled. However, pollution of emerging contaminants can threaten the environment and even human health. In order to understand the status of the emerging contamination and recommend future rationalization of countermeasures, the occurrence of illicit drugs was investigated. MATERIAL AND METHODS: Samples were collected at 23 sites from the main irrigation channels and the marsh. Illicit drugs were extracted using solid phase extraction and determined by liquid chromatography tandem mass spectrometry. The method detection limits ranged from 0.01 to 1.54 ng l(-1) and the recoveries from 57% to 120%. RESULTS AND DISCUSSION: 3,4 Methylenedioxymethamphetamine, ketamine, morphine, benzoylecgonine, cocaine, methadone, 6-acetylmorphine and nor-9-carboxy-tetrahydrocannabinol were detected. The mean concentrations were 0.62, 21.33, 1.30, 1.92, 2.25, 0.32, 0.04 and 0.07 ng l(-1), respectively. The highest concentrations were in the north of Pego Oliva Marsh. CONCLUSIONS: The pollution status by illicit drugs of the Pego-Oliva Marsh has been established. However, contamination levels in all the area of the natural park were low compared with those reported in other superficial waters. PMID- 22544552 TI - A concurrent neuro-fuzzy inference system for screening the ecological risk in rivers. AB - PURPOSE: A conceptual model to assess water quality in river basins was developed here. The model was based on ecological risk assessment principles, and incorporated a novel ranking and scoring system, based on self-organizing maps, to account for the likely ecological hazards posed by the presence of chemical substances in freshwater. This approach was used to study the chemical pollution in the Ebro River basin (Spain), whose currently applied environmental indices must be revised in terms of scientific accuracy. METHODS: Ecological hazard indexes for chemical substances were calculated by pattern recognition of persistence, bioaccumulation, and toxicity properties. A fuzzy inference system was proposed to compute ecological risk points (ERP), which are a combination of the ecological hazard to aquatic sensitive organisms and environmental concentrations. By aggregating ERP, changes in water quality over time were estimated. RESULTS: The proposed concurrent neuro-fuzzy model was applied to a comprehensive dataset of the network controlling the levels of dangerous substances, such as metals, pesticides, and polycyclic aromatic hydrocarbons, in the Ebro river basin. The approach was verified by comparison versus biological monitoring. The results showed that water quality in the Ebro river basin is affected by presence of micro-pollutants. CONCLUSIONS: The ERP approach is suitable to analyze overall trends of potential threats to freshwater ecosystems by anticipating the likely impacts from multiple substances, although it does not account for synergies among pollutants. Anyhow, the model produces a convenient indicator to search for pollutant levels of concern. PMID- 22544553 TI - Assessing the effects of tertiary treated wastewater reuse on the presence emerging contaminants in a Mediterranean river (Llobregat, NE Spain). AB - PURPOSE: The Llobregat River, which is characterized by important fluctuations of the flow rates, receives treated waters from WWTPs. During the years 2007 and 2008, the Llobregat River basin suffered from a severe drought which affected the supply of drinking water facilities (DWF) that rely on the exploitation of the river water. The Catalan Water Agency implemented a water reuse experiment with the objective of maintaining the river flow rate at sufficiently high level so as to ensure the supply of raw water to Barcelona's major DWF. METHOD: A total of 103 emerging contaminants belonging to the groups of pharmaceuticals (74), illicit drugs (17) and oestrogens (12) were determined using LC-MS/MS methods in river water samples during the water reuse campaign. The effect of the reclaimed water discharge on the river water quality, in terms of contamination loads and environmental risk (based on the concentration addition mode), is discussed. RESULTS: Fifty-eight pharmaceuticals out of 74 monitored were detected at least in one sample. In river water upstream (site R0) majority of compounds were detected at low nanograms per litre levels, while downstream of discharge of tertiary effluent only few compounds were detected at levels higher than 100 ng L(-1) (i.e. acetaminophen, diclofenac, erythromycin, sulfamethazine), but never exceeding 500 ng L(-1). The total concentration of illicit drugs was found to be very low at both sampling sites (<50 ng L(-1)). No relevant ecotoxicity risks were identified, except for pharmaceuticals vs. algae. CONCLUSIONS: In general, the discharge of reclaimed water in the river influenced perceptibly in terms of concentrations, mass loads and environmental risk, especially for pharmaceuticals and in less extent for illicit drugs. Nevertheless, it was not very significant in any case. PMID- 22544554 TI - Pharmaceuticals on a sewage impacted section of a Mediterranean River (Llobregat River, NE Spain) and their relationship with hydrological conditions. AB - INTRODUCTION: Mediterranean rivers are characterized by a high flow variability, which is strongly influenced by the seasonal rainfall. When water scarcity periods occur, water flow, and dilution capacity of the river is reduced, increasing the potential environmental risk of pollutants. On the other hand, floods contribute to remobilization of pollutants from sediments. Contamination levels in Mediterranean rivers are frequently higher than in other European river basins, including pollution by pharmaceutical residues. Little attention has been paid to the transport behavior of emerging contaminants in surface waters once they are discharged from WWTP into a river. In this context, this work aimed to relate presence and fate of emerging contaminants with hydrological conditions of a typical Mediterranean River (Llobregat, NE Spain). METHODS: River fresh water samples were collected twice a week over a period of 5 weeks at three sampling points. Sixty-six pharmaceutical compounds belonging to different therapeutical classes were analyzed by LC-MS/MS. RESULTS AND DISCUSSION: Positive and negative correlations between the concentrations of the target analytes and hydrological variables like river flow and dissolved organic matter were observed pointing out the relevance of different hydrological phenomena like dilution effects or sediment re-suspension. Sensitivity calculations showed that the majority of compounds were sensitive to flow variations. PMID- 22544555 TI - RO/NF membrane treatment of veterinary pharmaceutical wastewater: comparison of results obtained on a laboratory and a pilot scale. AB - BACKGROUND: Emerging contaminants (ECs) are commonly derived from industrial wastewater, which is often a consequence of an inadequate treatment of the latter. Improperly pretreated pharmaceutical wastewater could cause difficulties in operations of wastewater treatment plants while incomplete elimination of ECs during the processing might result in their appearance in drinking water. METHODS: This paper deals with membrane treatment of pharmaceutical wastewater on a laboratory and a pilot scale as well as with the removal of the following veterinary pharmaceuticals (VPs) (sulfamethoxazole, trimethoprim, ciprofloxacin, dexamethasone, and febantel). RESULTS: The pretreatment of pharmaceutical wastewater by means of coagulation and microfiltration (MF) prevented the irreversible fouling of the fine porous structure of the reverse osmosis (RO) and nanofiltration (NF) membranes which were used in the final stage of wastewater processing. The percentage of the removal of the selected VPs ranges from 94% to almost 100% in the case of NF and RO membranes in both scales. The recovery percentage concerning the pilot scale amounted to 88%. Membrane cleaning was successfully carried out in both scales. CONCLUSIONS: The differences in retention between laboratory and pilot tests are due to different raw wastewater quality and different recovery and hydrodynamic of the two systems. Fouling and concentration polarization were more pronounced in laboratory setup (frame-plate module) than in pilot unit (spiral module). The proposed integrated membrane treatment (coagulation, MF, NF, and RO) can be employed for treatment of wastewater originating from pharmaceutical factory. The obtained permeate can be safely discharged to sewer system or could be reused in manufacturing process. PMID- 22544557 TI - Expression and stability of hypoxia inducible factor 1alpha in osteosarcoma. AB - BACKGROUND: Hypoxia contributes to both physiological and pathological processes and its effects are mainly mediated through the transcription factors hypoxia inducible factor 1alpha and 2alpha (HIF1alpha and HIF2alpha). The purpose of this study was to examine the role of these proteins in osteosarcoma progression. PROCEDURES: We developed a method to isolate primary human osteoblast cell lines. HIF1alpha and HIF2alpha expression were then compared in osteoblast and osteosarcoma cell lines under 21% oxygen (normoxia) and 1% oxygen (hypoxia). We also used hypoxia-responsive element (HRE)-driven reporter constructs in conjunction with siRNAs specific to HIF1alpha or HIF2alpha to determine the contribution of each protein to HRE-mediated transcription. Finally, we measured HIF1alpha expression in primary osteosarcoma tumors by immunohistochemistry. RESULTS: We found that mainly HIF1alpha transcript was significantly higher in osteosarcoma cell lines compared to normal osteoblasts under both normoxia and hypoxia. At the protein level, HIF1alpha was preferentially stabilized in osteosarcoma cell lines under both conditions. HIF1alpha expression was required for the observed increases in HRE activity. Finally, nuclear or nucleocytoplasmic HIF1alpha staining in osteosarcoma cases was associated with high-grade tumors. CONCLUSIONS: These findings point to a role for HIF1alpha in osteosarcoma progression and suggest that the observed differences in HIF1alpha oxygen dependent degradation may play an important pathophysiological role in this disease. Pediatr Blood Cancer 2012; 59: 1215-1222. (c) 2012 Wiley Periodicals, Inc. PMID- 22544558 TI - Nasal septal perforation from bevacizumab: a discussion of outcomes, management, and pharmacovigilance. AB - To date, the published literature describes 18 reports of nasal septal perforation in cancer patients with the administration of bevacizumab. This complication was detected during post-marketing surveillance of bevacizumab. How should patients who develop this complication be managed? This discussion summarizes suggestions for management of bevacizumab-associated nasal septal perforation and, as relevant to healthcare providers, discusses some of the practical aspects of post-marketing pharmacovigilance. PMID- 22544559 TI - Current developments in the management of locally advanced esophageal cancer. AB - Loco-regionally advanced esophageal cancer is a lethal disease with poor outcomes despite aggressive multimodality therapy. The appropriate management of these patients is contentious and no single standard of care has been defined. Literature suggests that preoperative chemoradiotherapy may be superior to preoperative chemotherapy. Recently, several developments have impacted the care of these patients. The 2010 AJCC TNM staging system now recognizes the biologic heterogeneity of the disease and stages adenocarcinoma and squamous cell carcinoma separately. Studies suggest potentially less toxic chemotherapeutic agents including oxaliplatin may be useful in the management of this disease. FDG PET imaging appears to have prognostic value and may predict for pathologic response. In addition, several trials have explored inhibition of the ErbB1 (EGFR) and ErbB2 (Her2) receptors. The monoclonal antibody trastuzumab appears to extend survival for patients with metastatic gastric and gastroesophageal junction adenocarcinoma and is under investigation for use in patients with loco regionally advanced disease. PMID- 22544560 TI - VEGF inhibition, hypertension, and renal toxicity. AB - The use of anti-angiogenic agents as part of the therapeutic armamentarium for advanced stage solid tumors has become the standard of care in several instances, particularly for renal cell carcinoma, non-small cell lung carcinoma, colorectal carcinoma, and gastrointestinal stromal tumors. These agents primarily target vascular endothelial growth factor (VEGF) and/or its receptors, and include bevacizumab, a humanized monoclonal antibody against VEGF, as well as tyrosine kinase inhibitors that target several receptor tyrosine kinases (RTK), including VEGF receptors. These therapies, as a general class of anti-angiogenic medications, have been shown to have common adverse vascular effects attributable directly or indirectly to their anti-VEGF effects, including hypertension, renal vascular injury, often manifested by proteinuria and thrombotic microangiopathy, and congestive heart failure. Knowledge of these common side effects and their underlying mechanisms may allow for more accurate and prompt diagnoses, timely clinical interventions, and the development of rational and standard treatments. These measures may minimize patient morbidity and mortality, not only by the treatment of side effects, but also by minimizing the disruption of treatment of the underlying malignancy, as well as improving patient quality of life. PMID- 22544562 TI - Long-term outcomes of the FRESH START trial: exploring the role of self-efficacy in cancer survivors' maintenance of dietary practices and physical activity. AB - BACKGROUND: This study examined whether changes in self-efficacy explain the effects of a mailed print intervention on long-term dietary practices of breast and prostate cancer survivors. The relationship between change in self-efficacy and long-term physical activity (PA) also was examined. METHODS: Breast and prostate cancer survivors (N = 543) from 39 US states and two Canadian provinces participated in the FRESH START intervention trial. Participants were randomly assigned to receive a 10-month program of mailed print materials on diet and PA available in the public domain or a 10-month program of tailored materials designed to increase fruit and vegetable (F&V) intake, decrease fat intake, and/or increase PA. Changes in self-efficacy for F&V intake and fat restriction were analyzed as potential mediators of the intervention's effects on diet at 2 year follow-up. Because we previously found that change in self-efficacy for PA did not vary by group assignment, the relationship between change in self efficacy and PA at 2-year follow-up was examined across study conditions. RESULTS: Results suggest that change in self-efficacy for fat restriction partially explained the intervention's effect on fat intake (mean indirect effect = -0.28), and change in self-efficacy for F&V consumption partially explained the intervention's effect on daily F&V intake (mean indirect effect = .11). Change in self-efficacy for fat restriction partially accounted for the intervention's impact on overall diet quality among men only (mean indirect effect = 0.60). Finally, change in self-efficacy for PA predicted PA at 2-year follow-up. CONCLUSIONS: Findings suggest that self-efficacy may influence long-term maintenance of healthy lifestyle practices among cancer survivors. PMID- 22544563 TI - Purification, characterization of GH11 endo-beta-1,4-xylanase from thermotolerant Streptomyces sp. SWU10 and overexpression in Pichia pastoris KM71H. AB - We have previously described two forms of an endo-beta-1,4-xylanase (XynSW2A and XynSW2B) synthesized by thermotolerant Streptomyces sp. SWU10. Here, we describe another xylanolytic enzyme, designated XynSW1. The enzyme was purified to homogeneity from 2 L of culture filtrate. Its apparent molecular mass was 24 kDa. The optimal pH and temperature were pH 5.0 and 40 degrees C, respectively. The enzyme was stable in a wide pH ranges (pH 1-11), more than 80 % of initial activity remained at pH 2-11 after 16 h of incubation at 4 degrees C and stable up to 50 degrees C for 1 h. Xylobiose and xylotriose were the major xylooligosaccharides released from oat spelt xylan by the action of XynSW1, indicating of endo-type xylanase. The complete xynSW1 gene contains 1,011 bp in length and encode a polypeptide of 336 with 41 amino acids of signal peptide. The amino acid sequence analysis revealed that it belongs to glycoside hydrolase family 11 (GH11). The mature xynSW1 gene without signal peptide sequence was overexpressed in Pichia pastoris KM71H. The recombinant XynSW1 protein showed higher molecular mass due to the differences in glycosylation levels at the six N glycosylation sites in the amino acid sequence and exhibited better physicochemical properties than those of the native enzyme including higher optimal temperature (60 degrees C), and specific activity, but lower optimal pH (4.0). Because of their stability in a wide pH ranges, both of native and recombinant enzymes of XynSW1, may have potential application in several industries including food, textile, biofuel, and also waste treatment. PMID- 22544561 TI - The potential link between PML NBs and ICP0 in regulating lytic and latent infection of HSV-1. AB - Herpes simplex virus type 1 (HSV-1) is a common human pathogen causing cold sores and even more serious diseases. It can establish a latent stage in sensory ganglia after primary epithelial infections, and reactivate in response to stress or sunlight. Previous studies have demonstrated that viral immediate-early protein ICP0 plays a key role in regulating the balance between lytic and latent infection. Recently, It has been determined that promyelocytic leukemia (PML) nuclear bodies (NBs), small nuclear sub-structures, contribute to the repression of HSV-1 infection in the absence of functional ICP0. In this review, we discuss the fundamentals of the interaction between ICP0 and PML NBs, suggesting a potential link between PML NBs and ICP0 in regulating lytic and latent infection of HSV-1. PMID- 22544564 TI - Horse liver alcohol dehydrogenase: new perspectives for an old enzyme. AB - The EE subunit of horse liver alcohol dehydrogenase (HLADH-EE) has been subcloned in pRSETb vector to generate a fusion His-tag protein. The migration from a multistep purification protocol for this well-known enzyme to a single-step has been successfully achieved. Several adjustments to the traditional purification procedure for His-tag proteins have been made to retain protein activity. A full characterization of the fusion enzyme has been carried out and compared with the native one. The K (m) for EtOH, NAD and NADH in the His-tag version of HLADH are in line with the ones reported in literature for the native enzyme. A shift in optimal pH activity is also observed. The enzyme retains the same stability and quaternary structure as the wild type and can therefore be easily used instead of the native HLADH for biotechnological applications. PMID- 22544565 TI - Prevalence of musculoskeletal disorders and ergonomic assessments of cleaners. AB - BACKGROUND: Professional cleaning has emerged as a new industry in Taiwan in the past few years. However, information about the workload and prevalence of musculoskeletal disorders (MSDs) among these workers is still limited. This study investigated the prevalence of musculoskeletal discomforts and the characteristics of musculoskeletal activities of cleaning workers in Taiwan. METHODS: Face-to-face interviews to collect basic information and to administer the Chinese version of the Standardized Nordic Musculoskeletal Questionnaire were conducted on 180 cleaners. Biaxial electrogoniometers and electromyography were used to characterize the motion and forceful exertion of 56 cleaners during work. RESULTS: Nearly 90% of the participants reported musculoskeletal discomfort in at least one body part due to work. Of the nine body parts examined, hand/wrist (41.7%), shoulder (41.1%), low back (37.8%), and elbow (33.3%) were most frequently reported to exhibit discomfort. Additionally, time pressure as a psychosocial risk factor was found to be associated with discomfort in several body parts. Measurements of electrogoniometry showed that wrists of many cleaners were frequently held in extreme angles of ulnar/radial deviation, leading to an increased risk of developing carpal tunnel syndrome. Motion repetitiveness and force output during mopping and sweeping tasks were considered less influential in developing hand/wrist discomfort. CONCLUSIONS: Cleaners in Taiwan are a high risk group for developing MSDs, and solutions are needed to avoid extreme motion angles of the wrists when performing cleaning tasks. Moreover, both psychosocial stress and the welfare of this group of workers deserve immediate attention from management and the government. PMID- 22544566 TI - Outcome of prenatally detected bilateral higher urinary tract obstruction or megacystis: sex-related study on a series of 709 cases. AB - OBJECTIVE: To compare the sex specific outcome of fetuses with prenatally detected urinary tract dilatation, with the exclusion of pyelectasia. METHOD: Included in the study were 709 cases of major dilatation of the fetal urinary tract, diagnosed at routine ultrasound scan. For each sex group, cases were divided into two subgroups depending on the level of dilatation. Final diagnosis was based on postnatal evaluation or on fetal autopsy. Postnatal renal function was evaluated using serum creatinine at two years of age. RESULTS: Bilateral higher urinary tract dilatation was prenatally observed in 148 (20.8%) and lower urinary tract obstruction or bladder dilatation in 561 (79.1%) of the 709 cases (121 female and 588 male fetuses) (P <0.001). Bladder dilatation was less frequent in female fetuses (62%) than in males (82.6%) (P <0.001). At final diagnosis, associated malformations were observed in 53.7% of female fetuses versus 11% in males (P <0.001). The survival rate was 42.7%. Postnatal renal function, evaluated in 289/303 live infants, was impaired in 29.7% of cases and depended on the level of obstruction, but not on the sex. CONCLUSION: Prenatally detected urinary tract dilatation has a poor prognosis both in male and female fetuses. Associated malformations are observed more frequently in female than in male fetuses. PMID- 22544567 TI - Protein hydrogen exchange: testing current models. AB - To investigate the determinants of protein hydrogen exchange (HX), HX rates of most of the backbone amide hydrogens of Staphylococcal nuclease were measured by NMR methods. A modified analysis was used to improve accuracy for the faster hydrogens. HX rates of both near surface and well buried hydrogens are spread over more than 7 orders of magnitude. These results were compared with previous hypotheses for HX rate determination. Contrary to a common assumption, proximity to the surface of the native protein does not usually produce fast exchange. The slow HX rates for unprotected surface hydrogens are not well explained by local electrostatic field. The ability of buried hydrogens to exchange is not explained by a solvent penetration mechanism. The exchange rates of structurally protected hydrogens are not well predicted by algorithms that depend only on local interactions or only on transient unfolding reactions. These observations identify some of the present difficulties of HX rate prediction and suggest the need for returning to a detailed hydrogen by hydrogen analysis to examine the bases of structure-rate relationships, as described in the companion paper (Skinner et al., Protein Sci 2012;21:996-1005). PMID- 22544568 TI - Cytotoxicity of flowable resin composite on cultured human periodontal ligament cells compared with mineral trioxide aggregate. AB - AIM: To investigate the cytotoxicity of three flowable resin composites that potentially useful as retrograde filling materials, compared with mineral trioxide aggregate (MTA). METHODS: Ten standard cylinder discs were used for each of the tested materials: Tetric Flow, Filtex Flow, Aeliteflo, and MTA, which were prepared under aseptic conditions. Cytotoxicity of eluates from all materials after 1-4 days' immersion in culture medium and direct contact cytotoxicity were evaluated using cultured human periodontal ligament cells (PDLC). The colorimetric (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay and scanning electron microscope of cell morphology (direct contact only) were used. RESULTS: No eluates of set materials demonstrated cytotoxicity at any concentration or elution time. Freshly-mixed MTA was cytotoxic in direct contact, but not set MTA. Freshly-mixed Aeliteflo was also cytotoxic, as was set material up to 2 days' elution. With morphological assessment, some differences were seen among resin composites, but all changes were rated as slight using the International Standard Organization criteria. CONCLUSIONS: Of all of the materials tested, Tetric Flow showed the least cytotoxic effects on PDLC. Further research is needed to determine the clinical usefulness of flowable composites as retrograde filling materials. PMID- 22544569 TI - Synthesis and characterization of the atropisomeric relationships of a substituted N-phenyl-bipyrazole derivative with anti-inflammatory properties. AB - This work describes the atropisomeric relationships of 3-methyl-5-(3-methyl-5 phenyl-1H-pyrazol-1-yl)-1-phenyl-1H-pyrazol-4-amine (2d), which belongs to series 4-aminobipyrazole derivatives designed as anti-inflammatory agents. The (1)H nuclear magnetic resonance spectra obtained in the presence of a chiral lanthanide shift salt associated to chiral high-performance liquid chromatography analysis, X-ray diffraction, and molecular modeling tools confirmed that ortho bis-functionalized bipyrazole 2d exists as a mixture of aR,aS-atropisomers. These results provide useful information to understand the pharmacological profile of this derivative and of other 4-aminobipyrazole analogs. PMID- 22544570 TI - Expression of TopBP1 in hereditary breast cancer. AB - TopBP1 protein displays structural as well as functional similarities to BRCA1 and is involved in DNA replication, DNA damage checkpoint response and transcriptional regulation. Aberrant expression of TopBP1 may lead to genomic instability and can have pathological consequences. In this study we aimed to investigate expression of TopBP1 gene at mRNA and protein level in hereditary breast cancer. Real-time quantitative PCR was performed in 127 breast cancer samples. Expression of TopBP1 mRNA in lobular carcinoma was significantly lower compared with ductal carcinoma (p < 0.05). The level of TopBP1 mRNA appeared to be lower in poorly differentiated (III grade) hereditary breast cancer in comparison with moderately (II grade) and well-differentiated cancer (I grade) (p < 0.05 and p < 0.001 respectively). We analyzed TopBP1 protein expression using immunohistochemistry and Western blot techniques. Expression of TopBP1 protein was found to be significantly increased in poorly differentiated breast cancer (III grade) (p < 0.05). The percentage of samples with cytoplasmic apart from nuclear staining increased with increasing histological grade. There was no significant association between level and intracellular localization of TopBP1 protein in hereditary breast cancer and other clinicopathological parameters such as estrogen and progesterone receptors status, appearance of metastasis in the axillary lymph nodes and type of cancer. Our data suggest that decreased level of TopBP1 mRNA and increased level of TopBP1 protein might be associated with progression of hereditary breast cancer. PMID- 22544571 TI - A novel pathogenic variant of the LDLR gene in the Asian population and its clinical correlation with familial hypercholesterolemia. AB - Familial hypercholesterolemia (FH) is a disease implicated with defects in either, Low density lipoprotein receptor gene (LDLR), Apolipoprotein B-100 gene (APOB), the Proprotein convertase subtilisin/kexin type 9 gene (PCSK9) or other related genes of the lipid metabolism pathway. The general characterization of heterozygous FH is by elevated low-density lipoprotein (LDL) cholesterol and early-onset cardiovascular diseases, while the more severe type, the homozygous FH results in extreme elevated levels of LDL cholesterol and usually death of an affected individual by early twenties. We present here a novel non-synonymous, missense mutation in exon 14 of the LDLR gene in two siblings of the Malay ethnicity discovered during an in-house genetic test. We postulate that their elevated cholesterol is due to this novel mutation and they are positive for homozygous FH. This is the first report of a C711Y mutation in patients with elevated cholesterol in Asia. PMID- 22544572 TI - cDNA cloning and differential expression patterns of ascorbate peroxidase during post-harvest in Brassica rapa L. AB - Ascorbate is an antioxidant and a cofactor of many dioxygenases in plant and animal cell metabolism. A well-recognized enzyme consuming ascorbate is ascorbate peroxidase (APX), which catalyses the reduction of hydrogen peroxide to water with the simultaneous oxidation of ascorbate with a high specificity. The isolation and characterisation of new Apx cDNAs, could provide new insights about the physiological roles and regulation of these enzymes. In this work chloroplastic (Br-chlApx) and cytosolic (Br-cApx) isoform transcripts were isolated by RT-PCR in Brassica rapa and expression changes were analysed by semi quantitative RT-PCR performed in different tissues (layer, stalk and florets) at different days (0, 4 and 14 day). The result showed that BrApx isoforms were differentially expressed and the Br-chlApx, in particular in the layer, had the highest expression level and remained unchanged also after 14 day after harvest. In addition, expression changes were compared with total BrAPX activity and the results showed that the activity decreased in all tissues at 14 day after harvest, independently of transcripts. Finally, additional solutes as the substrate of APX ascorbate and its oxidized form, dehydroascorbate, as well as alpha-tocopherol, the major vitamin E compound that prevents the propagation of lipid peroxidation in thylakoid membranes, were followed. The changes in the BrApx expression, BrAPX activity and metabolites can provide further evidence of the close relationships that exist between antioxidants which compensate for each other and suggest that there are multiple sites of reciprocal control. PMID- 22544573 TI - PTPN22 C1858T and the risk of psoriasis: a meta-analysis. AB - Psoriasis is a chronic autoimmune skin disease with both environmental and genetic risk factors. Previous studies of the association between psoriasis and PTPN22 C1858T (rs2476601), a gain of function variant associated with a stronger inhibitory effect of T-lymphocytes, have produced inconsistent results. The purpose of the current study is to evaluate the association between PTPN22 C1858T and psoriasis using meta-analysis to: (1) have a sufficient sample size for detecting a weak association; and (2) to explore the heterogeneity between studies. A meta-analysis based on random-effects model was performed with ten studies (3,334 psoriasis cases and 5,753 controls) identified from a literature search. A non-significantly positive association between psoriasis and the PTPN22 T1858 was observed [summary allelic odds ratio (OR) = 1.15, 95 % confidence interval (CI): 1.00-1.33] and the association appears stronger among subjects with psoriatic arthritis (summary allelic OR = 1.23, 95 % CI: 1.00-1.52). A null association between PTPN22 T1858 and early-onset psoriasis was observed (summary allelic OR = 1.08, 95 % CI: 0.92-1.28). The current analysis showed a non significantly positive association between psoriasis and the PTPN22 T1858 allele, and the association appeared stronger among subjects with psoriatic arthritis. Future studies of psoriasis should incorporate gene-environment interaction in the analysis and pay attention to the heterogeneity of psoriasis cases and bias associated with population stratification. PMID- 22544574 TI - A search for genetic markers associated with egg production in the ostrich (Struthio camelus). AB - The aim of the current study was to search for genetic markers, microsatellite loci associated with laying performance in ostriches. The material consisted of two groups of ostrich hens characterized by high or low laying performance (over 75 and less than 25 eggs per season, respectively). The investigation covered 30 microsatellite loci characteristic for the ostrich (the CAU group) and led to identification of significant differences in allele and genotype frequencies between the two groups of hens considered. Out of a total of 30 microsatellite loci examined, 28 showed different alleles in relation to analyzed performance groups. In hens of high laying performance (HP group, n = 12), specific alleles occurred in 23 microsatellite loci (40 alleles of 243 identified), while in those of low egg production (LP group, n = 12), they occurred in 22 (51 alleles of 243 identified). The results indicate the usefulness of the microsatellite loci as the potential genetic markers associated with laying performance that can be applied for genetic improvement of ostrich flocks. PMID- 22544575 TI - Variability of mRNA abundance of leukemia inhibitory factor gene (LIF) in porcine ovary, oviduct and uterus tissues. AB - The leukemia inhibitory factor (LIF) gene encodes a pleiotropic cytokine which is produced by the endometrium and plays an important role in implantation and early embryonic development. Because of its function, LIF gene is considered as a candidate gene for litter size in many mammalian species including pig. The aim of present study was to evaluate the expression of LIF gene in the porcine ovary, oviduct and two regions of uterus (corpus uteri, cornu uteri) in prepubertal and pubertal gilts. In order to precise estimation of LIF transcript abundance we evaluated the stability of expression for several candidate housekeeping genes in investigated tissues across different breeds and different stage of oestrus cycle. The geNorm analysis indicated that the most stable reference genes across analyzed tissues were: OAZ1 and RPL27. The analysis conducted separately for each tissue confirmed that the most stable gene was OAZ1 in all tissues expect oviduct (the most stable was RPL27 gene). In prepubertal pigs, the highest level of the LIF expression was obtained in both regions of uterus compare to ovary and oviduct tissues (P < 0.01). A similar trend in LIF expression pattern was observed in follicular phase-the significantly highest transcript level was obtained in cornu uteri, it was about ninefold higher than in ovary (P < 0.05). In luteal stage the highest expression was in corpus uteri. In pig, the high expression in luteal phases suggested that, LIF may be mainly secreted in respond to the increased of progesterone concentration and it can be connected with the preparation of the uterus for implantation. PMID- 22544576 TI - The BARD1 Cys557Ser variant and risk of familial breast cancer in a South American population. AB - Since the discovery of the BRCA1 and BRCA2 genes, much work has been carried out to identify further breast cancer (BC) susceptibility genes. BARD1 (BRCA1 associated ring domain) was originally identified as a BRCA1-interacting protein but has also been described in tumor-suppressive functions independent of BRCA1. Some association studies have suggested that the BARD1 Cys557Ser variant might be associated with increased risk of BC, but others have failed to confirm this finding. To date, this variant has not been analyzed in Spanish or South-American populations. In this study, using a case-control design, we analyzed the C terminal Cys557Ser change in 322 Chilean BC cases with no mutations in BRCA1 or BRCA2 and in 570 controls in order to evaluate its possible association with BC susceptibility. BARD1 Cys557Ser was associated with an increased BC risk (P = 0.04, OR = 3.4 [95 % CI 1.2-10.2]) among cases belonging to families with a strong family history of BC. No difference between single cases affected with age <50 years at diagnosis (n = 117) and controls was observed for carriers of Cys/Ser genotype. It is likely that this variant is not involved in BC risk in this group of women. We also analyzed a possible interaction between BARD1 557Ser/XRCC3 241Met variants considering the role of both genes in the maintenance of genome integrity. The combined genotype Cys/Ser-carrier with the XRCC3 241Met allele was associated with an increased BC risk (P = 0.02, OR = 5.01 [95 % CI 1.36-18.5]) among women belonging to families with at least three BC and/or ovarian cancer cases. Our results suggest that BARD1 557Ser and XRCC3 241Met may play roles in BC risk in women with a strong family history of BC. Nevertheless there is no evidence of an interaction between the two SNPs. These findings should be confirmed by other studies and in other populations. PMID- 22544577 TI - Phytoremediation and phytosensing of chemical contaminant, toluene: identification of the required target genes. AB - As an industrial chemical produced worldwide in high volumes, toluene is commonly detected in ambient air and water. It can combine with oxygen and form compounds that are harmful to humans. In recent years, phytoremediation has been increasingly applied to repair the environmental damage caused by pollutants. However, insufficient knowledge is available regarding the response of plants to toluene. To detect the potential genes in plants that are related to the sensing mechanism and metabolism of toluene, a microarray analysis has been conducted on Arabidopsis thaliana seedlings grown on toluene-containing media. Following the validation of data and the application of appropriate selection criteria, the results show a coordinated induction and suppression of 202 and 67 toluene responsive genes, respectively. Within the functional class "metabolism", the genes encoding detoxification proteins represent the most strongly up-regulated group. These include genes encoding cytochrome P450s, glucosyl transferases, and transporters. Subsequently, the toluene-induced genes of Arabidopsis are analyzed in detail. PMID- 22544578 TI - RNAi assay in primary cells: a new method for gene function analysis in marine bivalve. AB - RNA interference (RNAi) is an effective approach for gene function analysis, which is well developed in mammal cell lines. However, RNAi has rarely been reported in marine bivalve species. To provide support on functional analysis of bivalve genes, for the first time to our knowledge, we conducted RNAi assay on primary cell of clam Meretrix meretrix in this study. Firstly we explored the method of culturing primary cells of M. meretrix to ensure the cells to live at high activity for at least 2 weeks. Ferritin gene was chosen as the target gene and RNAi assay was conducted through soaking the primary cells of M. meretrix digestive gland in medium containing dsRNA of ferritin gene. Realtime PCR, western blot and immunocytochemistry analysis were used to analyze the inhibition of gene expression after RNAi. Results showed the ferritin mRNA was significantly down-regulated by 66.11% after RNAi. Western blot result showed that the expression level of ferritin protein was also depressed post RNAi. The method developed in this study proved to be reliable and effective for RNAi assay on marine bivalve cells. It would be an efficient tool for gene function analysis in marine bivalves and more studies based on primary cells of marine bivalves can be expected. PMID- 22544580 TI - Disappointment at government proposals on dangerous dogs. PMID- 22544579 TI - Phase 2 trial of maintenance bevacizumab alone after bevacizumab plus pemetrexed and carboplatin in advanced, nonsquamous nonsmall cell lung cancer. AB - BACKGROUND: The authors performed a phase 2 study of bevacizumab plus pemetrexed and carboplatin followed by maintenance bevacizumab in patients with advanced, nonsquamous nonsmall cell lung cancer. METHODS: Previously untreated patients with advanced, nonsquamous nonsmall cell lung cancer and an Eastern Cooperative Oncology Group performance status of 0 or 1 received bevacizumab 15 mg/kg, pemetrexed 500 mg/m(2) and carboplatin at an area under the concentration-time curve of 6 intravenously on day 1 every 21 days. Responding or stable patients who completed 6 cycles then received bevacizumab maintenance every 21 days until disease progression. RESULTS: In total, 43 patients (40 who were evaluable for response) were entered on the study. Treatment-related grade 3/4 toxicities were low and included febrile neutropenia (2%), neutropenia (28%), anemia (18%), thrombocytopenia (11%), hypertension (7%), epistaxis (5%), venous thrombosis (8%), dyspnea (7%), rectovaginal fistula (2.3%), infusion reaction (2%), and cerebrovascular event (2%). One patient died from complications of venous thromboembolism and cerebrovascular accident after Cycle 2. Minimal clinically significant toxicity occurred during maintenance bevacizumab. Two complete responses (5%) were observed, and 17 patients (42%) had a partial response. Fifteen patients (38%) displayed disease stability. The overall disease control rate was 85%. At a median follow-up of 15.8 months, the median progression-free survival was 7.1 months (95% confidence interval, 5.9-8.3 months), and the median overall survival was 17.1 months (95% confidence interval, 8.8-25.5 months). CONCLUSIONS: Combined bevacizumab, pemetrexed, and carboplatin followed by maintenance bevacizumab was well tolerated and displayed remarkable activity in patients with previously untreated, advanced, nonsquamous nonsmall cell lung cancer. PMID- 22544582 TI - A canid abroad--analysing the travel patterns of UK dogs. PMID- 22544583 TI - Permission granted for legal challenge to pilot badger cull in England. PMID- 22544584 TI - Historic teaching aid restored. PMID- 22544587 TI - Combined sheep anthelmintic launched. PMID- 22544588 TI - Tackling uterine disease in cattle. PMID- 22544590 TI - Addressing epidemiology (and a haggis) in Glasgow. PMID- 22544591 TI - From small beginnings to 'a shining example'. PMID- 22544592 TI - Neutering: how early is too early? PMID- 22544593 TI - Ethical concerns in research. PMID- 22544594 TI - Encouraging active health planning. PMID- 22544595 TI - Modernising meat inspection. PMID- 22544596 TI - Perfluorinated alginate for cellular encapsulation. AB - Molecules of pentadecafluorooctanoyl chloride (PFC) were grafted onto alginate (Alg) using a linear poly(ethylene glycol) linker and amide bonds. The resulting Alg-PFC material was characterized by proton nuclear magnetic resonance and infrared spectroscopies. The degree of PFC functionalization significantly influenced the physical and chemical properties of Alg-PFC, particularly when the resulting polymer was ionically crosslinked into hydrogels. Alg-PFC hydrogel beads fabricated via Ba(2+) crosslinking were found to match the permeability properties of control alginate beads, except upon swelling over time in culture media. When used to encapsulate MIN6 cells, a beta cell line, Alg-PFC beads demonstrated enhanced cell proliferation over alginate control beads. These results indicate that Alg-PFC hydrogels retain some of the PFC's biological relevant benefits, such as enhancement of mass transport and bioinertness, to enhance cellular viability within alginate three-dimensional hydrogel environments. We envision these functionalized hydrogels to be particularly useful in the encapsulation of cells with a high metabolic demand, such as pancreatic islets. PMID- 22544597 TI - Interlaboratory comparison of a standardized toxicity test using the nematode Caenorhabditis elegans (ISO 10872). AB - A ring test was carried out within the standardization process of ISO 10872 to evaluate the precision of the toxicity test for the nematode Caenorhabditis elegans. Eight different laboratories tested aqueous solutions of the reference substance benzylcetyldimethylammonium chloride as well as native sediments and soils for toxic effects on the growth and reproduction of C. elegans. Validity criteria were met in all laboratories. Average median- and low-effect concentrations were determined to be 15.1 mg L(-1) (EC50) and 8.7 mg L(-1) (EC10) for growth and 7.5 mg L(-1) (EC50) and 3.8 mg L(-1) (EC10) for reproduction of C. elegans, with ECx values showing a high degree of reproducibility (CV(R) : <21% and <11% for EC10 and EC50, respectively) and repeatability (CV(r) : <20% and <7% for EC10 and EC50, respectively). The toxic effects of the sediments and soils revealed by the different laboratories were well related to each samples' degree of chemical contamination. Moreover, the effects showed an acceptable reproducibility (CV(R) : 5-33% and 0-28% for growth and reproduction, respectively) and repeatability (CV(r) : 3-13% and 0-12% for growth and reproduction, respectively). The present study confirms that the toxicity test with C. elegans according to ISO 10872 is a reliable and precise tool to assess the toxicity of aqueous media, freshwater sediments, and soils. PMID- 22544598 TI - Prevention education effects on fundamental memory processes. AB - This study evaluated effects of a key session from a nationally recognized drug abuse prevention program on basic memory processes in 211 high-risk youth in Southern California. In a randomized, between-subject design, the authors manipulated assignment to a Myth and Denial program session and the time of assessment (immediate vs. 1-week delay). The authors examined program decay effects on memory accessibility and judgment errors. Those participants exposed to the program session generated more myths and facts from the program than those in the control group, suggesting that even a single program session influenced students' memory for program information and this was retained at least 1 week and detectable with indirect tests of memory accessibility. However, consistent with basic research perspectives, participants in the program-delayed assessment group erroneously generated more fact-related information from the session to the prompt "It is a myth that_____" than the participants in the program immediate assessment group; that is, they retained more facts as myths. These types of program effects, anticipated by basic memory theory, were not detected with a traditional judgment task in the present sample. The results suggest that basic science approaches offer a novel way of conceptually recasting prevention effects to more completely understand how these effects may operate. Implications for program evaluation and conceptualization are discussed. PMID- 22544599 TI - Distribution of polybrominated diphenyl ethers in Japanese autopsy tissue and body fluid samples. AB - Brominated flame retardants are components of many plastics and are used in products such as cars, textiles, televisions, and personal computers. Human exposure to polybrominated diphenyl ether (PBDE) flame retardants has increased exponentially during the last three decades. Our objective was to measure the body burden and distribution of PBDEs and to determine the concentrations of the predominant PBDE congeners in samples of liver, bile, adipose tissue, and blood obtained from Japanese autopsy cases. Tissues and body fluids obtained from 20 autopsy cases were analyzed. The levels of 25 PBDE congeners, ranging from tri- to hexa-BDEs, were assessed. The geometric means of the sum of the concentrations of PBDE congeners having detection frequencies >50 % (SigmaPBDE) in the blood, liver, bile, and adipose tissue were 2.4, 2.6, 1.4, and 4.3 ng/g lipid, respectively. The most abundant congeners were BDE-47 and BDE-153, followed by BDE-100, BDE-99, and BDE-28+33. These concentrations of PBDE congeners were similar to other reports of human exposure in Japan but were notably lower than concentrations than those reported in the USA. Significant positive correlations were observed between the concentrations of predominant congeners and SigmaPBDE among the samples analyzed. The SigmaPBDE concentration was highest in the adipose tissue, but PBDEs were distributed widely among the tissues and body fluids analyzed. The PBDE levels observed in the present study are similar to those reported in previous studies in Japan and significantly lower than those reported in the USA. PMID- 22544600 TI - Occurrence of priority organic pollutants in Strymon river catchment, Greece: inland, transitional, and coastal waters. AB - Twenty-five sampling stations were selected in order to monitor persistent organic pollutants (polycyclic aromatic hydrocarbons (PAHs), organochlorine (OC) pesticides and total polychlorinated biphenyls (PCBs)) in surface water from Kerkini Lake, the Strymon River, its main tributaries and estuary in N. Aegean Sea during January to July, 2008, according to recent European Union (EU) guidelines. The data were divided among the high (January to April) and the low flow season (May to July). Generally, the values for organic pollutants were within the range reported worldwide for surface water. Elevated PAHs concentrations were observed compared with other places in Greece. Anthracene and benzo(a)pyrene exceeded maximum allowable concentration (MAC) of the relative EU guideline. Also, concentrations above MAC were observed for OCs, gamma-HCH, and a endosulfan. Despite the fact that it is banned since 1972, Aldrin was detected during the monitoring season (from limit of detection (LOD) to 15 ng L(-1)). Total PCB concentrations ranged from LOD to 162 ng L(-1). In addition, the load of organic pollutants was estimated in April (high flow) and June (low flow) in selected sampling stations. According to this estimation, napthalene, anthracene, and fluoranthene (PAHs), total dichlorodiphenyltrichloroethane (DDT), aldrin, and total PCBs had the highest load. Taking into account the relative EU guidelines concerning the pollutants studied, the water quality in the Strymon River catchment could be characterized as poor, which can lead to negative impacts to its biota. PMID- 22544601 TI - Exposure to chemical mixtures in Mexican children: high-risk scenarios. AB - In developing countries, the management of environmental toxicants is inadequate, thus, humans may be exposed to levels higher than normal levels (background levels). Therefore, the aim of this study was to evaluate the exposure level of Mexican children to dichlorodiphenyltrichloroethane (DDT), dichlorodiphenyldichloroethylene (DDE), lead, and polycyclic aromatic hydrocarbons [using 1-hydroxypyrene (1-OHP) as exposure biomarker] and to assess the percentage of children exposed to these four compounds at concentrations higher than normal in each community studied. We performed random sampling in eight communities in Mexico (five communities in Chiapas State and three communities in San Luis Potosi State). DDT and DDE were analyzed by gas chromatography/mass spectrometry, the quantification of lead in blood was performed using atomic absorption spectrophotometry, and 1-OHP analyses were performed using HPLC with a fluorescence detector. Elevated DDT, DDE, and 1-OHP levels were found in children living in the indigenous communities of Chiapas State, while higher blood lead levels were found in two communities in San Luis Potosi. Approximately 30 % of children living in Chiapas were exposed to all four compounds at concentrations above the guidelines for each compound, whereas 48 % of children studied were exposed to all four contaminants at concentrations higher than normal in a community in San Luis Potosi State. As expected, our results showed that in hot spots, children are exposed to levels higher than normal. Therefore, child environmental health programs are urgently needed. PMID- 22544602 TI - Removal of anionic azo dye from aqueous solution via an adsorption photosensitized regeneration process on a TiO2 surface. AB - Textile dye effluents are typically characterized by strong color and recalcitrance, even at very low concentration. The process of enrichment of anionic azo dye on the surface of TiO(2) fibers followed by photosensitization degradation under ambient air conditions was extensively investigated. Adsorption isotherms and zeta potentials were used to describe the "dye/TiO(2) surface" interface, taking into account the effects of pH on the nature and population of the surface groups on the TiO(2) fibers. The extent of the photocatalytic degradation of dye on TiO(2) surface was determined by FTIR. N(2) adsorption isotherms and optical spectra were employed to investigate the effect of photosensitization. The adsorption of dyes on the TiO(2) surface occurs via electrostatic attraction through the formation of single- or multidentate coordinated surface complexes. Almost complete photobleaching of the absorption band at 534 nm is achieved in ~4 h. Dye-sensitized TiO(2) fiber could absorb part of the visible light spectrum (lambda < 600 nm). Interfacial electron transfer can potentially alter the degradation efficiency. The regenerated TiO(2) fiber could be reused for subsequent decolorization without a decline in adsorption efficiency compared with freshly prepared TiO(2) samples, which may be attributed to preservation of the hierarchical pore structure and restoration of the original surface properties. In summary, we propose an efficient "adsorption photoregeneration-reuse" process applying TiO(2) fibers for the degradation of dyes in water. PMID- 22544604 TI - Improvements in the Protein Identifier Cross-Reference service. AB - The Protein Identifier Cross-Reference (PICR) service is a tool that allows users to map protein identifiers, protein sequences and gene identifiers across over 100 different source databases. PICR takes input through an interactive website as well as Representational State Transfer (REST) and Simple Object Access Protocol (SOAP) services. It returns the results as HTML pages, XLS and CSV files. It has been in production since 2007 and has been recently enhanced to add new functionality and increase the number of databases it covers. Protein subsequences can be Basic Local Alignment Search Tool (BLAST) against the UniProt Knowledgebase (UniProtKB) to provide an entry point to the standard PICR mapping algorithm. In addition, gene identifiers from UniProtKB and Ensembl can now be submitted as input or mapped to as output from PICR. We have also implemented a 'best-guess' mapping algorithm for UniProt. In this article, we describe the usefulness of PICR, how these changes have been implemented, and the corresponding additions to the web services. Finally, we explain that the number of source databases covered by PICR has increased from the initial 73 to the current 102. New resources include several new species-specific Ensembl databases as well as the Ensembl Genome ones. PICR can be accessed at http://www.ebi.ac.uk/Tools/picr/. PMID- 22544603 TI - Role of insulin-like growth factor-1 in the regulation of skeletal growth. AB - The importance of the insulin-like growth factor (IGF)-I axis in the regulation of bone size and bone mineral density, two important determinants of bone strength, has been well established from clinical studies involving patients with growth hormone deficiency and IGF-I gene disruption. Data from transgenic animal studies involving disruption and overexpression of components of the IGF-I axis also provide support for a key role for IGF-I in bone metabolism. IGF-I actions in bone are subject to regulation by systemic hormones, local growth factors, as well as mechanical stress. In this review we describe findings from various genetic mouse models that pertain to the role of endocrine and local sources of IGF-I in the regulation of skeletal growth. PMID- 22544605 TI - TFIIS is required for the balanced expression of the genes encoding ribosomal components under transcriptional stress. AB - Transcription factor IIS (TFIIS) stimulates RNA cleavage by RNA polymerase II by allowing backtracked enzymes to resume transcription elongation. Yeast cells do not require TFIIS for viability, unless they suffer severe transcriptional stress due to NTP-depleting drugs like 6-azauracil or mycophenolic acid. In order to broaden our knowledge on the role of TFIIS under transcriptional stress, we carried out a genetic screening for suppressors of TFIIS-lacking cells' sensitivity to 6-azauracil and mycophenolic acid. Five suppressors were identified, four of which were related to the transcriptional regulation of those genes encoding ribosomal components [rRNAs and ribosomal proteins (RP)], including global regulator SFP1. This led us to discover that RNA polymerase II is hypersensitive to the absence of TFIIS under NTP scarcity conditions when transcribing RP genes. The absence of Sfp1 led to a profound alteration of the transcriptional response to NTP-depletion, thus allowing the expression of RP genes to resist these stressful conditions in the absence of TFIIS. We discuss the effect of transcriptional stress on ribosome biogenesis and propose that TFIIS contributes to prevent a transcriptional imbalance between rDNA and RP genes. PMID- 22544606 TI - beta-Catenin recognizes a specific RNA motif in the cyclooxygenase-2 mRNA 3'-UTR and interacts with HuR in colon cancer cells. AB - RNA-binding proteins regulate multiple steps of RNA metabolism through both dynamic and combined binding. In addition to its crucial roles in cell adhesion and Wnt-activated transcription in cancer cells, beta-catenin regulates RNA alternative splicing and stability possibly by binding to target RNA in cells. An RNA aptamer was selected for specific binding to beta-catenin to address RNA recognition by beta-catenin more specifically. Here, we characterized the structural properties of the RNA aptamer as a model and identified a beta-catenin RNA motif. Similar RNA motif was found in cellular RNA, Cyclooxygenase-2 (COX-2) mRNA 3'-untranslated region (3'-UTR). More significantly, the C-terminal domain of beta-catenin interacted with HuR and the Armadillo repeat domain associated with RNA to form the RNA-beta-catenin-HuR complex in vitro and in cells. Furthermore, the tertiary RNA-protein complex was predominantly found in the cytoplasm of colon cancer cells; thus, it might be related to COX-2 protein level and cancer progression. Taken together, the beta-catenin RNA aptamer was valuable for deducing the cellular RNA aptamer and identifying novel and oncogenic RNA protein networks in colon cancer cells. PMID- 22544607 TI - Construction of an immunostimulatory plasmid, pUCpGs10, and research on its immune adjuvant effect. AB - In order to overcome the instability of CpG ODN in vivo, sequence diversity, and individual differences, eleven CpG ODN fragments were meticulously selected and linked to form a Multi-CpG, which were repeatedly inserted into the cloning vector pUC19 for constructing the recombinant plasmid pUCpGs10 containing ten of Multi-CpG. Using the multi-genotype HCV E1 and multi-epitope complex HCV-T as immunogens, and plasmid pUCpGs10 as the immune adjuvant, Balb/c mice were immunized through nasal and subcutaneous immunization. Strong-specific humoral and cellular immune response were induced, which can obviously inhibit the growth of homograft expressing HCV antigen. The immune adjuvant effect of pUCpGs10 closely matched that of Freund's complete adjuvant. The plasmid pUCpGs10 can significantly improve IgA content in serum and different mucosal extract and systematical T-cell response via intranasal immunization. In conclusions, the newly constructed immunostimulatory plasmid pUCpGs10 is able to effectively activate the humoral and cellular immune activity, and possesses activation on mucosal immune response. PMID- 22544608 TI - Expression of hepatic 3beta-hydroxysteroid dehydrogenase and sulfotransferase 2A1 in entire and castrated male pigs. AB - The present study investigated the effect of surgical (SC) and immunological castration on the steroid metabolizing enzymes 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and sulfotransferase 2A1 (SULT2A1) in male pigs. Thirty-two male pigs were divided in four groups; in one group the pigs were SC before the age of 7 days, two groups were injected with Improvac((r)) a vaccine against gonadotropin releasing hormone (immunological castration), while the pigs in the last group remained entire males (EMs). Immunological castration was in one group performed by vaccine injection at ages 11 and 14 weeks, while the other group received injections at ages 17 and 21 weeks. Plasma, adipose and liver tissue were collected at the time of slaughter. Plasma was analyzed for concentrations of testosterone and oestradiol. The adipose tissue was analyzed for the concentration of androstenone, while the liver tissue was analyzed for mRNA and protein expression of 3beta-HSD and SULT2A1. Independent of method, all castrated pigs showed greater mRNA and protein expression of 3beta-HSD and lower levels of all steroids in plasma compared with EMs. Moreover, there was a strong correlation between mRNA and protein expression of 3beta-HSD and steroid levels. The same was not valid for expression of SULT2A1. It is concluded that steroid levels can increase expression of the steroid metabolizing enzyme 3beta-HSD and thereby influence steroid metabolism, e.g. of androstenone. PMID- 22544609 TI - Isolation and analysis of genes mainly expressed in adult mouse heart using subtractive hybridization cDNA library. AB - Subtractive hybridization cDNA library (SHL) is one of the powerful approaches for isolating differentially expressed genes. Using this technique between mouse heart and skeletal muscle (skm) tissues, we aimed to construct a cDNA-library that was specific to heart tissue and to identify the potential candidate genes that might be responsible for the development of cardiac diseases or related pathophysiological conditions. In the first step of the study, we created a cDNA library between mouse heart and skm tissues. The homologies of the randomly selected 215 clones were analyzed and then classified by function. A total of 146 genes were analyzed for their expression profiles in the heart and skm tissues in published mouse microarray dataset. In the second step, we analyzed the expression patterns of the selected genes by Northern blot and RNA in situ hybridization (RISH). In Northern blot analyses, the expression levels of Myl3, Myl2, Mfn2, Dcn, Pdlim4, mt-Co3, mt-Co1, Atpase6 and Tsc22d1 genes were higher in heart than skm. For first time with this study, expression patterns of Pdlim4 and Tsc22d1 genes in mouse heart and skm were shown by RISH. In the last step, 43 genes in this library were identified to have relationships mostly with cardiac diseases and/or related phenotypes. This is the first study reporting differentially expressed genes in healthy mouse heart using SHL technique. This study confirms our hypothesis that tissue-specific genes are most likely to have a disease association, if they possess mutations. PMID- 22544610 TI - The complete mitochondrial genome of Pseudochauhanea macrorchis (Monogenea: Chauhaneidae) revealed a highly repetitive region and a gene rearrangement hot spot in Polyopisthocotylea. AB - The complete mitochondrial genome of Pseudochauhanea macrorchis was determined and compared with other monogenean mitochondrial genomes from GenBank. The circular genome was 15,031 bp in length and encoded 36 genes (12 protein-coding genes, two ribosomal RNAs, and 22 transfer RNAs) typically found in flatworms. Structures of the mitochondrial genome were mostly concordant with that known for Microcotyle sebastis and Polylabris halichoeres, but also contained two noted features-a gene rearrangement hot spot and the highly repetitive region (HRR) in major non-coding region (NCR). The gene rearrangement hot spot located between the cox3 and nad5 genes, including a cluster of tRNA genes, nad6 gene and one major NCR. The HRR seemed to be a unique feature of the polyopisthocotylean mitochondrial genomes. In conclusion, the present study provided new molecular data for future studies of the comparative mitochondrial genomics and also served as a resource of markers for the studies of species populations and monogenean phylogenetics. PMID- 22544611 TI - Core antigen tests for hepatitis C virus: a meta-analysis. AB - Diagnosis and monitoring of hepatitis C virus (HCV) infection relies mainly on the detection of HCV antibodies and HCV RNA. HCV antibody test has a longer window period and is not applicable in the immunosuppressed population. Although HCV RNA test reduces the window period, it is still not widely recommended because of its high cost and requirement of specific equipment. HCV core antigen is another direct virological marker which has been investigated in recent years. HCV core antigen assay is as simple as the HCV antibodies assay and can detect HCV infection only 1 day delay compared to the HCV RNA assay. In order to evaluate the application of HCV core antigen test in HCV diagnosis and management, we performed this meta-analysis. Twenty five articles were finally included in meta-analysis. All statistical analyses were performed with MetaDisc 1.4 and Stata 11.0. The pooled sensitivity of HCV core antigen assay was 0.84 (95 % CI, 0.83-0.85), and the pooled specificity was 0.98 (95 % CI, 0.97-0.98). HCV core antigen assays may not displace HCV RNA assays to be a definitive diagnosis of HCV infection until now. Considering the higher sensitivity (0.926) and specificity (0.991) of subgroup, HCV-cAg detection is a promising method as a confirmatory test for HCV antibody positive, therapy-naive individuals. Explored by meta-regression and subgroup analysis, possible sources of heterogeneity of specificity was found, while the heterogeneity of sensitivity was still significant. PMID- 22544612 TI - Prenasal thickness in first-trimester screening for Down syndrome. PMID- 22544613 TI - X-interface is not the explanation for the slow disassembly of N-cadherin dimers in the apo state. AB - In spite of structural similarities Epithelial- (E-) and Neural- (N-) cadherins are expressed at two types of synapses and differ significantly in dimer disassembly kinetics. Recent studies suggested that the formation of an X-dimer intermediate in E-cadherin is the key requirement for rapid disassembly of the adhesive dimer (Harrison et al., Nat Struct Mol Biol 2010;17:348-357 and Hong et al., J Cell Biol 2011;192:1073-1083). The X-interface in E-cadherin involves three noncovalent interactions, none of which is conserved in N-cadherin. Dimer disassembly is slow at low calcium concentration in N-cadherin, which may be due to the differences in the X-interface residues. To investigate the origin of the slow disassembly kinetics we introduced three point mutations into N-cadherin to provide the opportunity for the formation of X-interface interactions. Spectroscopic studies showed that the triple mutation did not affect the stability or the calcium-binding affinity of the X-enabled N-cadherin mutant. Analytical size exclusion chromatography was used to assay for the effect of the mutation on the rate of dimer disassembly. Contrary to our expectation, the disassembly of dimers of the X-enabled N-cadherin mutant was as slow as seen for wild-type N-cadherin in the apo-state. Thus, the differences in the X-interface residues are not the origin of slow disassembly kinetics of N-cadherin in the apo state. PMID- 22544614 TI - Expression of transforming growth factor-beta1 (TGF-beta1) and E-cadherin in glioma. AB - Gliomas are the most common tumors in the central nervous system. This study aims to investigate the expressions of transforming growth factor-beta1 (TGF-beta1) and epithelial cadherin (E-cadherin) in human brain glioma tissues and the correlation between their expressions with clinical pathological features and clinical significance. The expressions of mRNA or protein of TGF-beta1 and E cadherin were detected by using reverse transcription polymerase chain reaction (RT-PCR) and Western blot in these tissues. Positive rates of the expression of TGF-beta1 and E-cadherin were 62.9 % and 38.6 % in brain tissues of glioma patients. The expressions of mRNA or protein for TGF-beta1 in brain glioma tissues were significantly higher than that in normal brain tissues (p < 0.01). Their expressions in well-differentiated glioma brain tissues were lower than those in poorly differentiated glioma brain tissues (p < 0.01). A negative correlation was found between TGF-beta1 and E-cadherin in brain glioma tissues (r = -0.302, p < 0.011). The cell numbers of C6 glioma through Transwell chambers were decreased significantly (p < 0.01), and the expression of TGF-beta1 was downregulated significantly (p < 0.01). However, the expression of E-cadherin was upregulated significantly (p < 0.01) after transfecting TGF-beta1 siRNA. The expression changes of TGF-beta1 and E-cadherin may be related to the emergence and the development of glioma. Downregulation of TGF-beta1 expression using siRNA can decrease the invasive capability of C6 glioma cells. PMID- 22544615 TI - Chiral recognition of metalaxyl enantiomers by human serum albumin: evidence from molecular modeling and photophysical approach. AB - Metalaxyl is an acylamine fungicide, belonging to the most widely known member of the amide group. This task is aimed to scrutinize binding region and spatial structural change of principal vector human serum albumin (HSA) complex with (R) /(S)-metalaxyl by exploiting molecular modeling, steady-state and time-resolved fluorescence, and circular dichroism (CD) approaches. According to molecular modeling, (R)-metalaxyl is situated within subdomains IIA and IIIA and the affinity of site I with (R)-metalaxyl is greater than site II, whereas (S) metalaxyl is only located at subdomain IIA and the affinity of (S)-metalaxyl with site I is superior compared with that with (R)-metalaxyl. This coincides with the competitive ligand binding, guanidine hydrochloride-induced unfolding of protein, and hydrophobic 8-anilino-1-naphthalenesulfonic acid experiments; the acting forces between (R)-/(S)-metalaxyl and HSA are hydrophobic, pi-pi interactions, and hydrogen bonds, as derived from molecular modeling. Fluorescence emission manifested that the complex of (R)-/(S)-metalaxyl to HSA is the formation of adduct with an affinity of 10(4) M(-1), which corroborates the time-resolved fluorescence that the static type was operated. Furthermore, the changes of far UV CD spectra evidence the polypeptide chain of HSA partially unfolded after conjugation with (R)-/(S)-metalaxyl. Through this work, we envisage that it can offer central clues on the biodistribution, absorption, and bioaccumulation of (R)-/(S)-metalaxyl. PMID- 22544616 TI - Relationship between ventilatory function and age in master athletes and a sedentary reference population. AB - Ageing is accompanied with a decline in respiratory function. It is hypothesised that this may be attenuated by high physical activity levels. We performed spirometry in master athletes (71 women; 84 men; 35-86 years) and sedentary people (39 women; 45 men; 24-82 years), and calculated the predicted lung age (PLA). The negative associations of age with forced expiratory volume in 1 s (FEV1; 34 mL.year(-1)) and other ventilatory parameters were similar in controls and master athletes. FEV1pred was 9 % higher (P < 0.005) and PLA 15 % lower (P = 0.013) in athletes than controls. There were no significant differences between endurance and power athletes and sedentary people in maximal inspiratory and expiratory pressure. Neither age-graded performance nor weekly training hours were significantly related to lung age. Life-long exercise does not appear to attenuate the age-related decrease in ventilatory function. The better respiratory function in master athletes than age-matched sedentary people might be due to self-selection and attrition bias. PMID- 22544618 TI - Gastrointestinal bleeding following intravenous ibandronate administration. AB - PURPOSE: Gastrointestinal (GI) adverse effects have been reported with oral bisphosphonate formulations and are the primary adverse effects influencing their tolerability. New intermittent formulations, including intravenous (IV) ibandronate, may increase compliance and decrease the rate of GI adverse effects. We describe a 67-year-old woman with a 2-day history of hematemesis and melena 1 week after administration of IV ibandronate. SUMMARY: The patient was initially stable but began to develop a small bowel obstruction for which a nasogastric (NG) tube was placed. During placement of the NG tube, the patient vomited and aspirated. Due to continued nausea and vomiting with the NG tube and shortness of breath, the patient was intubated and an orogastric tube was placed. Despite the use of a ventilator, the patient's blood pressure and oxygen saturation began to fall. Even with the use of mechanical ventilation and 3 pressors, her condition deteriorated, she was made DNR/DNI (do not resuscitate or intubate) and subsequently expired. The Naranjo adverse drug reaction score was 2, indicating a possible association between GI bleed and IV ibandronate. The exact mechanism of this is not known. CONCLUSION: Clinicians should be aware of this possible adverse effect and monitor high-risk patients for bleeding when administering IV bisphosphonates. PMID- 22544617 TI - Cardiovascular risk in cognitively preserved elderlies is associated with glucose hypometabolism in the posterior cingulate cortex and precuneus regardless of brain atrophy and apolipoprotein gene variations. AB - Cardiovascular risk factors (CVRF) possibly contribute to the emergence of Alzheimer's disease (AD). Fluorodeoxyglucose-positron emission tomography (FDG PET) has been widely used to demonstrate specific patterns of reduced cerebral metabolic rates of glucose (CMRgl) in subjects with AD and in non-demented carriers of the apolipoprotein epsilon4 (APOE epsilon4) allele, the major genetic risk factor for AD. However, functional neuroimaging studies investigating the impact of CVRF on cerebral metabolism have been scarce to date. The present FDG PET study investigated 59 cognitively preserved elderlies divided into three groups according to their cardiovascular risk based on the Framingham 10-year risk Coronary Heart Disease Risk Profile (low-, medium-, and high-risk) to examine whether different levels of CVRF would be associated with reduced CMRgl, involving the same brain regions affected in early stages of AD. Functional imaging data were corrected for partial volume effects to avoid confounding effects due to regional brain atrophy, and all analyses included the presence of the APOE epsilon4 allele as a confounding covariate. Significant cerebral metabolism reductions were detected in the high-risk group when compared to the low-risk group in the left precuneus and posterior cingulate gyrus. This suggests that findings of brain hypometabolism similar to those seen in subjects with AD can be detected in association with the severity of cardiovascular risk in cognitively preserved individuals. Thus, a greater knowledge about how such factors influence brain functioning in healthy subjects over time may provide important insigths for the future development of strategies aimed at delaying or preventing the vascular-related triggering of pathologic brain changes in the AD. PMID- 22544619 TI - Diabetes care practice patterns of recent pharmacy graduates. AB - PURPOSE: The objective of this project was to determine the amount and type of clinical skills and diabetes education provided by recent pharmacy school graduates. METHODS: Six hundred and one graduates were e-mailed a link to an online survey. Subjects were asked to report how frequently they either educate patients on diabetes self-care activities or perform diabetes-related patient care skills and to rate their ability to do so as poor, fair, good, or excellent. RESULTS: Data from 155 (25.8%) respondents were analyzed. The most commonly reported clinical activity was changing medication, followed by interpreting blood glucose patterns, medication management therapy, and interpreting laboratory results. Subjects reported educating patients more on the signs and symptoms of hypoglycemia, blood glucose monitoring, and diet information relative to other topics. The majority of subjects rated their skills as good or excellent. CONCLUSION: Pharmacists reported the most commonly performed diabetes related clinical skill was changing medication and they most often educate patients about hypoglycemia and blood glucose monitoring. Subjects, who rated themselves poor/fair in these skills, preferred active learning strategies to enhance their ability. PMID- 22544620 TI - Review of survey articles regarding medication therapy management (MTM) services/programs in the United States. AB - OBJECTIVE: To provide a summary of published survey articles regarding the provision of medication therapy management (MTM) services in the United States. METHODS: A literature search was conducted to identify original articles on MTM related surveys conducted in the United States, involving community and outpatient pharmacists, physicians, patients, or pharmacy students and published by the primary researchers who conducted the study. Search engines used included PubMed, Medline, and International Pharmaceutical Abstracts (IPA). If MTM was in the keyword list, mesh heading, title, or abstract, the article was reviewed. References from these articles were searched to determine whether other relevant articles were available. RESULTS: A total of 405 articles were initially reviewed; however, only 32 articles met the study requirements. Of the 32 articles, 17 surveyed community/outpatient pharmacists, 3 surveyed pharmacy students, 4 surveyed physicians, and 8 surveyed patients. The survey periods varied across the different studies, with the earliest survey conducted in 2004 and the most recent survey conducted in 2009. The surveys were conducted via the telephone, US mail, interoffice mail, e-mails, Internet/Web sites, hand-delivered questionnaires, and focus groups. CONCLUSION: Despite the identified barriers to the provision of MTM services, pharmacists reportedly found it professionally rewarding to provide these services. Pharmacists claimed to have adequate clinical knowledge, experience, and access to information required to provide MTM services. Pharmacy students were of the opinion that the provision of MTM services was important to the advancement of the pharmacy profession and in providing patients with a higher level of care. Physicians supported having pharmacists adjust patients' drug therapy and educate patients on general drug information but not in selecting patients' drug therapy. Finally, patients suggested that alternative ways need to be explored in describing and marketing MTM services for it to be appealing to them. PMID- 22544621 TI - Tablet splitting and weight uniformity of half-tablets of 4 medications in pharmacy practice. AB - BACKGROUND: Tablet splitting is a common practice for multiple reasons including cost savings; however, it does not necessarily result in weight-uniform half tablets. OBJECTIVES: To determine weight uniformity of half-tablets resulting from splitting 4 products available in the Jordanian market and investigate the effect of tablet characteristics on weight uniformity of half-tablets. METHODS: Ten random tablets each of warfarin 5 mg, digoxin 0.25 mg, phenobarbital 30 mg, and prednisolone 5 mg were weighed and split by 6 PharmD students using a knife. The resulting half-tablets were weighed and evaluated for weight uniformity. Other relevant physical characteristics of the 4 products were measured. RESULTS: The average tablet hardness of the sampled tablets ranged from 40.3 N to 68.9 N. Digoxin, phenobarbital, and prednisolone half-tablets failed the weight uniformity test; however, warfarin half-tablets passed. Digoxin, warfarin, and phenobarbital tablets had a score line and warfarin tablets had the deepest score line of 0.81 mm. CONCLUSION: Splitting warfarin tablets produces weight-uniform half-tablets that may possibly be attributed to the hardness and the presence of a deep score line. Digoxin, phenobarbital, and prednisolone tablet splitting produces highly weight variable half-tablets. This can be of clinical significance in the case of the narrow therapeutic index medication digoxin. PMID- 22544622 TI - Probable linezolid-induced thrombocytopenia in a patient with vancomycin resistant enterococci. AB - PURPOSE: A probable case of linezolid-induced thrombocytopenia is reported. SUMMARY: A 74-year-old Caucasian male with renal dysfunction was diagnosed with diverticulosis. Patient was prescribed linezolid 600 mg orally twice daily for vancomycin-resistant enterococci abdominal infection that developed secondary to colon resection. Upon initiation of linezolid, platelet count dropped from 248 000 cells/mm(3) on day 1 to 97 000 cells/mm(3) on day 5 of treatment. Linezolid was discontinued and platelet counts improved to pretreatment levels. Application of the Naranjo probability scale indicated a probable association of linezolid therapy and thrombocytopenia. Clinicians should be aware that linezolid has this hematologic side effect and that patients with renal dysfunction are at increased risk. Monitoring platelet count more than once weekly should be advisable in these patients. CONCLUSION: A 74-year-old Caucasian male with renal dysfunction developed a probable case of linezolid-induced thrombocytopenia after receiving the drug for 5 days for treatment of vancomycin-resistant enterococci abdominal infection. PMID- 22544623 TI - A pharmacotherapeutic approach to the management of chronic posttraumatic stress disorder. AB - Due to relatively recent and ongoing world events (eg, terrorist attacks, wars, and natural disasters), there has been a shift in attention from some of the more common psychiatric illnesses to one of the more elusive, namely, posttraumatic stress disorder (PTSD). PTSD is a severe, and often chronic, condition that can lead to significant morbidity and mortality. Although originally a condition seen primarily among war veterans, PTSD is now becoming more prevalent in the general community. PTSD often presents concurrently with other conditions, such as depression, bipolar, anxiety/panic disorders, and alcohol and drug abuse. Because of this, PTSD often goes unrecognized and is underdiagnosed in clinical practice. Thus, an opportunity for pharmacist intervention exists, both in the institution and in the community. With proper education and training, pharmacists can be efficient in screening for signs and symptoms of PTSD, triaging appropriate patients, and can play an integral role in managing the diverse array of drug therapy options for PTSD. PMID- 22544624 TI - When one drug affects 2 patients: a review of medication for the management of nonlabor-related pain, sedation, infection, and hypertension in the hospitalized pregnant patient. AB - One of the most difficult challenges health care providers encounter is drug selection for pregnant patients. Drug selection can be complex as efficacy and maternal side effects must be weighed against potential risk to the embryo or fetus. Verification of an individual drug's fetal safety is limited as most evidence is deduced from epidemiologic, prospective cohort, or case-control studies. Medication selection for the pregnant inpatient is a particularly complex task as the illnesses and conditions that require hospitalization mandate different medications, and the risk versus benefit ratio can vary significantly compared to the outpatient setting. Some degree of acute pain is not uncommon among inpatients. Acetaminophen is generally considered the drug of choice in pregnancy for mild to moderate acute pain, while most opioids are thought to be safe for short-term use to manage moderate to severe pain. Providing sedation is particularly challenging as the few options available for the general population are further limited by either known increased risk of congenital malformations or very limited human pregnancy data. Propofol is the only agent recommended for continuous sedation, which has a Food and Drug Administration classification as a pregnancy category B medication. Treatment of infections in hospitalized patients requires balancing the microbiology profile against the fetal risk. Older antimicrobials proven generally safe include beta-lactams, and those with proven fetal risks include tetracyclines. However, little to no information regarding gestational use is available on the newer antimicrobials that are frequently employed to treat resistant infections more commonly found in the inpatient setting. Management of maternal blood pressure is based on the severity of blood pressure elevations and not the hypertensive classification. Agents generally considered safe to use in hypertensive pregnant patients include methyldopa, labetolol, and hydralazine, while angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, hydrochlorothiazide, and atenolol should be avoided. PMID- 22544625 TI - Model uncertainty in economic impacts of climate change: Bernoulli versus Lotka Volterra dynamics. AB - The dynamic economic behavior in most integrated assessment models linking economic growth to climate change involves a differential equation solved by Jacob Bernoulli in 1695. Using the dynamic integrated climate economy (DICE) model and freezing exogenous variables at initial values, this dynamic is shown to produce implausible projections on a 60-year time frame. If world capital started at US$1, after 60 years the world economy would be indistinguishable from one starting with 10 times the current capitalization. Such behavior points to uncertainty at the level of the fundamental dynamics, and suggests that discussions of discounting, utility, damage functions, and ethics should be conducted within a more general modeling vocabulary. Lotka Volterra dynamics is proposed as an alternative with greater prime facie plausibility. With near universality, economists assume that economic growth will go on forever. Lotka Volterra dynamics alert us to the possibility of collapse. PMID- 22544626 TI - A decade of malignant mesothelioma surveillance in Korea. AB - BACKGROUND: The objectives of this study were to examine trends in mesothelioma incidence over a decade and to identify histories of asbestos exposure among cases in Korea. METHODS: In 2001, The Korea Occupational Safety and Health Agency organized a nationwide cardiopulmonary pathology group and established a malignant mesothelioma surveillance system covering all general hospitals in Korea. Mesothelioma cases were reported to this surveillance system with information about age, gender, location, occupational history, asbestos exposure environment, date of diagnosis, diagnostic method, histopathologic subtype, occurrence site, and other clinical information. Additionally, an epidemiological survey was conducted using a structured verbal questionnaire to allow further evaluation of asbestos exposures. RESULTS: A total of 399 cases of malignant mesothelioma were reported in the last decade, translating to approximately 40 annual cases, and an annual average incidence rate of 0.83 cases per million. Of the 152 patients interviewed by occupational physicians, 56 had occupational asbestos exposure histories (36.8%). Their occupations and industries included construction (19.7%), automobile repair (5.9%), asbestos textile, shipbuilding and repair, refinery work, boiler making, and asbestos cement work. Another 31 patients had environmental asbestos exposure histories. CONCLUSIONS: Surveillance data indicate that malignant mesothelioma incidence in Korea is, thus far, lower than that of other developed countries, and that construction and environmental asbestos exposure were the main identifiable causes of malignant mesothelioma. PMID- 22544627 TI - Tracking chiral polychlorinated biphenyl sources near a hazardous waste incinerator: fresh emissions or weathered revolatilization? AB - The Swan Hills Treatment Centre (SHTC), located in central Alberta, is the primary facility in Canada for incinerating polychlorinated biphenyls (PCBs). Past studies have shown significant contamination by PCBs and other pollutants of the immediate surrounding region. However, it is unclear whether the major source of contamination to the region's atmosphere is historical release incidents or long-term emissions. To answer this question, concentrations of PCBs and enantiomer fractions of several PCB congeners were determined in soil and air, via polyurethane foam passive samplers, over several seasons between 2005 and 2008. Concentrations in both media were highest for samples collected closest to the SHTC, demonstrating a concentration profile typical of a point source. Enantiomer analysis revealed racemic profiles in air for all congeners, while soil was significantly nonracemic for PCB 95, indicating significant microbial degradation of this congener. However, the primary source of this congener, and likely others, in the surrounding atmosphere is recent and continual releases from the SHTC, rather than the release of weathered PCBs previously deposited to local soils. In addition, enantiomer compositions for PCBs 95 and 149 yielded minimum biotransformation half-lives of 25 and 97 years, respectively, suggesting an expected gradual decline in the region's PCB load once fresh inputs cease. PMID- 22544629 TI - Thymic volume in healthy, small for gestational age and growth restricted fetuses. AB - OBJECTIVE: The aim of this study was to verify the hypothesis that a difference in thymic size exists between small for gestational age (SGA) fetuses, likely constitutional, and intrauterine growth restricted (IUGR) fetuses because of placental causes. METHODS: We studied 27 SGA and 36 control fetuses. SGA was defined as fetal abdominal circumference (AC) and birthweight <10th percentile for gestational age. We defined as constitutional SGA those with normal uterine and umbilical artery Doppler flow velocity waveforms (FVW), and as IUGR those with abnormal uterine FVW. IUGR were further divided based on normal or abnormal umbilical FVW. Fetal thymic volume (TV) was acquired by three-dimensional ultrasound and reconstructed with virtual organ computer-aided analysis. To correct for the influence of fetal size on thymic dimension, TV/AC ratio was calculated. RESULTS: Controls presented a higher TV/AC compared with each group of SGA (p < 0.001). TV/AC was significantly lower in IUGR with abnormal umbilical FVW compared with both constitutional SGA (p = 0.01) and IUGR with normal umbilical FVW (p = 0.01). CONCLUSIONS: The differences in TV/AC between constitutional SGA and IUGR with abnormal umbilical FVW suggest that, in the latter, a specific 'trigger' might compromise trophoblastic invasion and thymic development; however, some kind of alteration of the immune system might occur in all SGA fetuses. PMID- 22544628 TI - Vitamin D and bone. AB - All cells comprising the skeleton-chondrocytes, osteoblasts, and osteoclasts contain both the vitamin D receptor and the enzyme CYP27B1 required for producing the active metabolite of vitamin D, 1,25 dihydroxyvitamin D. Direct effects of 25 hydroxyvitamin D and 1,25 dihydroxyvitamin D on these bone cells have been demonstrated. However, the major skeletal manifestations of vitamin D deficiency or mutations in the vitamin D receptor and CYP27B1, namely rickets and osteomalacia, can be corrected by increasing the intestinal absorption of calcium and phosphate, indicating the importance of indirect effects. On the other hand, these dietary manipulations do not reverse defects in osteoblast or osteoclast function that lead to osteopenic bone. This review discusses the relative importance of the direct versus indirect actions of vitamin D on bone, and provides guidelines for the clinical use of vitamin D to prevent/treat bone loss and fractures. PMID- 22544630 TI - Mycobacterium thermoresistibile as a source of thermostable orthologs of Mycobacterium tuberculosis proteins. AB - The genus Mycobacterium comprises major human pathogens such as the causative agent of tuberculosis, Mycobacterium tuberculosis (Mtb), and many environmental species. Tuberculosis claims ~1.5 million lives every year, and drug resistant strains of Mtb are rapidly emerging. To aid the development of new tuberculosis drugs, major efforts are currently under way to determine crystal structures of Mtb drug targets and proteins involved in pathogenicity. However, a major obstacle to obtaining crystal structures is the generation of well-diffracting crystals. Proteins from thermophiles can have better crystallization and diffraction properties than proteins from mesophiles, but their sequences and structures are often divergent. Here, we establish a thermophilic mycobacterial model organism, Mycobacterium thermoresistibile (Mth), for the study of Mtb proteins. Mth tolerates higher temperatures than Mtb or other environmental mycobacteria such as M. smegmatis. Mth proteins are on average more soluble than Mtb proteins, and comparison of the crystal structures of two pairs of orthologous proteins reveals nearly identical folds, indicating that Mth structures provide good surrogates for Mtb structures. This study introduces a thermophile as a source of protein for the study of a closely related human pathogen and marks a new approach to solving challenging mycobacterial protein structures. PMID- 22544631 TI - Lasiodiplodia theobromae keratitis: a case report and review of literature. AB - A case report and review of literature is reported of a rare case of fungal keratitis from eastern India. A 32-year-old woman with a history of vegetative trauma presented with keratitis in left eye. Microbiological examination of corneal scraping showed refractile hyphae with aseptate branching filaments and black pigmented colonies on multiple solid agar medium. Organism was identified from culture using D1/D2 region of LSU (Large Sub Unit: 28S rDNA)-based molecular technique. PCR amplified a band with a sequence that was 100 % homologous with Lasiodiplodia theobromae. The organism was susceptible to amphotericin B and voriconazole and demonstrated resistance to itraconazole and fluconazole. A therapeutic keratoplasty was performed following non-responsiveness to initial topical voriconazole (2 %) therapy. Recurrence in graft was controlled with topical voriconazole and intracameral amphotericin B. However, the graft failed at the end of 3 months. L. theobromae is a rare cause of fungal keratitis. Management of these cases is difficult, often involving surgical procedures. PMID- 22544632 TI - Phospholipase D1 is an important regulator of bFGF-induced neurotrophin-3 expression and neurite outgrowth in H19-7 cells. AB - The purpose of this study was to examine the role of phospholipase D1 (PLD1) in basic fibroblast growth factor (bFGF)-induced neurotrophin-3 (NT-3) expression and neurite outgrowth in H19-7 rat hippocampal neuronal progenitor cells. Overexpression of PLD1 increased bFGF-induced NT-3 expression, and dominant negative-PLD1 or PLD1 siRNA abolished bFGF-induced NT-3 expression and neurite outgrowth. Treatment with bFGF activated the RhoA/Rho-associated kinase (ROCK)/c jun N-terminal kinase (JNK) pathway, and bFGF-induced NT-3 expression was blocked by a dominant-negative RhoA as well as by a specific Rho-kinase inhibitor (Y27632) and a SAPK/JNK inhibitor (SP600125). Furthermore, bFGF-induced JNK activation was also blocked by Y27632. These results indicate that the RhoA/ROCK/JNK pathway acts as an upstream signaling pathway in bFGF-induced NT-3 expression. Also, phosphatidic acid, the product of PLD, increased NT-3 expression. We found that PLD regulated the RhoA/ROCK/JNK pathway, which then led to Elk-1 transactivation. When Elk-1 activity was blocked by Elk-1 siRNA, bFGF induced NT-3 expression and neurite outgrowth decreased. NT-3 overexpression increased neurite outgrowth, indicating that NT-3 is important for neurite outgrowth. Taken together, these results suggest that PLD1 is an important regulator of bFGF-induced NT-3 expression and neurite outgrowth, which are mediated by the RhoA/ROCK/JNK pathway via Elk-1 in H19-7 cells. PMID- 22544635 TI - Socio-economic stakes and perceptions of wetland management in an arid region: a case study from Chott Merouane, Algeria. AB - The objective of our study was to identify how actors from the main socio economic sectors perceive their interactions and impacts on a sensitive wetland in an arid climate, specifically the salt pans of Chott Merouane in Algeria. The results revealed that there are three main economic stakes including agriculture, livestock production and salt mining, each activity providing a great benefit for local and national populations. The local population perceived that the current activities are conducted in such a way that they created conflict between socio economic sectors and caused a threat for long term sustainability of the wetlands. The results highlighted the need to initiate an integrated management approach between the different sectors and to develop a shared vision for the territory. PMID- 22544634 TI - Functional analysis of nonsynonymous single nucleotide polymorphisms in human SLC26A9. AB - Slc26 anion transporters play crucial roles in transepithelial Cl(-) absorption and HCO(3)(-) secretion; Slc26 protein mutations lead to several diseases. Slc26a9 functions as a Cl(-) channel and electrogenic Cl(-)--HCO(3)(-) exchanger, and can interact with cystic fibrosis transmembrane conductance regulator. Slc26a9(-/-) mice have reduced gastric acid secretion, yet no human disease is currently associated with SLC26A9 coding mutations. Therefore, we tested the function of nonsynonymous, coding, single nucleotide polymorphisms (cSNPs) of SLC26A9. Presently, eight cSNPs are NCBI documented: Y70N, T127N, I384T, R575W, P606L, V622L, V744M, and H748R. Using two-electrode voltage-clamp and anion selective electrodes, we measured the biophysical consequences of these cSNPs. Y70N (cytoplasmic N-terminus) displays higher channel activity and enhanced Cl(-) -HCO(3)(-) exchange. T127N (transmembrane) results in smaller halide currents but not for SCN(-). V622L (STAS domain) and V744M (STAS adjacent) decreased plasma membrane expression, which partially accounts for decreased whole cell currents. Nevertheless, V622L transport is reduced to ~50%. SLC26A9 polymorphisms lead to several function modifications (increased activity, decreased activity, altered protein expression), which could lead to a spectrum of pathophysiologies. Thus, knowing an individual's SLC26A9 genetics becomes important for understanding disease potentially caused by SLC26A9 mutations or modifying diseases, for example, cystic fibrosis. Our results also provide a framework to understand SLC26A9 transport modalities and structure-function relationships. PMID- 22544633 TI - Impact of diagnosis and treatment of clinically localized prostate cancer on health-related quality of life for older Americans: a population-based study. AB - BACKGROUND: Few studies have measured longitudinal changes in health-related quality of life (HRQOL) among patients with prostate cancer starting before their cancer diagnosis or have provided simultaneous comparisons with a matched noncancer cohort. In the current study, the authors addressed these gaps by providing unique estimates of the effects of a cancer diagnosis on HRQOL accounting for the confounding effects of ageing and comorbidity. METHODS: Data from the Surveillance, Epidemiology, and End Results registry were linked with Medicare Health Outcomes Survey (MHOS) data. Eligible patients (n = 445) were Medicare beneficiaries aged >=65 years from 1998 to 2003 whose first prostate cancer diagnosis occurred between their baseline and follow-up MHOS. By using propensity score matching, 2225 participants without cancer were identified from the MHOS data. Analysis of covariance models were used to estimate changes in HRQOL as assessed with the Medical Outcomes Study Short Form-36 survey and the activities of daily living scale. RESULTS: Before diagnosis, patients with prostate cancer reported HRQOL similar to that of men without cancer. After diagnosis, men with prostate cancer experienced significant decrements in physical, mental, and social aspects of their lives relative to controls, especially within the first 6 months after diagnosis. For men who were surveyed beyond 1 year after diagnosis, HRQOL was similar to that for controls. However, an increased risk for major depressive disorder was observed among men who received either conservative management or external beam radiation. CONCLUSIONS: The current findings illustrated the time-sensitive nature of decline in HRQOL after a cancer diagnosis and enhanced understanding of the impact of prostate cancer diagnosis and treatment on physical, mental, and social well being among older men. PMID- 22544636 TI - Livelihood security, vulnerability and resilience: a historical analysis of Chibuene, southern Mozambique. AB - A sustainable livelihood framework is used to analyse livelihood security, vulnerability and resilience in the village of Chibuene, Vilanculos, southern Mozambique from a historical and contemporary perspective. Interviews, assessments, archaeology, palaeoecology and written sources are used to address tangible and intangible aspects of livelihood security. The analysis shows that livelihood strategies for building resilience, diversification of resource use, social networks and trade, have long historical continuities. Vulnerability is contingent on historical processes as long-term socio-environmental insecurity and resultant biodiversity loss. These contingencies affect the social capacity to cope with vulnerability in the present. The study concludes that contingency and the extent and strength of social networks should be added as a factor in livelihood assessments. Furthermore, policies for mitigating vulnerability must build on the reality of environmental insecurity, and strengthen local structures that diversify and spread risk. PMID- 22544637 TI - Enantioselective toxicological response of the green alga Scenedesmus obliquus to isocarbophos. AB - Chiral compounds usually behave enantioselectively in phyto-biochemical processes. Isocarbophos (ICP) is a chiral pesticide that is widely used. To evaluate the toxicological response of ICP and its enantiomers to Scenedesmus obliquus, algal growth, total chlorophyll, total soluble protein, and the superoxide anion radicals (O(2)(*-)) were investigated. The microalgae were treated with ICP and its enantiomers at 0.01-10 mg/l for 96 h. The growth of S. obliquus was stimulated at low levels of ICP and its enantiomers (0.01-1 mg/l), but all were inhibited at high concentrations (10 mg/l). The total soluble protein content and total chlorophyll content of the tested green alga S. obliquus gradually increased, depending on the growth of algal cells in the medium. Meanwhile, the content of O(2)(*-) was decreased. Interestingly, the cell number and content of the chlorophylls and protein decreased with increasing levels of concentration, whereas O(2)(*-) increased. Our results indicated that enantioselectivity was observed in the dose-response of ICP and its enantiomers in S. obliquus. The high O(2)(*-) level might lead to the death of S. obliquus. The stimulation of growth suggests a regulatory mechanism that is related to the capability of the algae to adapt to the O(2)(*-). PMID- 22544638 TI - Identification and accumulation of aromatic sensitizers in fish from paper recycling in Japan. AB - Aromatic sensitizers and related compounds (SRCs) originating from thermal recording material as impurities in waste paper have been detected in aquatic environments near cities where the paper industry is flourishing. In the present study, the levels of exposure to such SRCs and the stable isotope ratios (delta(13)C and delta(15)N) in different fish species (Konosirus punctatus, Takifugu niphobles, and Tribolodon hakonensis) were analyzed. These fish species were collected from the vicinity of waste paper recycling plants in Japan. Eleven SRCs were identified in fish muscle at total concentration levels (SigmaSRCs) of 64 to 818 ng/g wet weight (mean 181 ng/L wet wt). The dominant SRCs in the fish samples were 1,1-di(4-methylphenyl)ethane, 1,2-bis(3-methylphenoxy)ethane, and 1,4-dibenzyloxybenzene. Stable isotope ratios showed that, although three species feed on the same trophic level, K. punctatus and T. niphobles live in waters farther offshore than those in which T. hakonensis live. The contributions of various factors to the accumulation were also assessed. The lipid content (r(2) = 0.512, p < 0.001) was found to be the significant factor that influenced accumulation of SRCs in fish. The results also revealed significant positive correlation between the accumulation patterns and SRC components in water (r(2) = 0.512-0.658, all p values <0.05), but they showed negative correlations between the SRCs in fish and log K(OW) values. This suggests that the aqueous route is the predominant route for the accumulation of SRCs in fish. This is the first study on the accumulation of aromatic sensitizers in aquatic biota. PMID- 22544639 TI - The effect of substrate, season, and agroecological zone on mycoflora and aflatoxin contamination of poultry feed from Khyber Pakhtunkhwa, Pakistan. AB - To study the effects of and interactions among feed types, seasons, and agroecological zones on the total fungal viable count and aflatoxins B1 (AFB1), B2 (AFB2), G1 (AFG1), and G2 (AFG2) production in poultry feed, an experiment was conducted using three-factorial design. A total of 216 samples of poultry feed ingredients, viz. maize, wheat, rice, cotton seed meal (CSM), and finished products, that is, starter and finisher broilers' rations, were collected from Peshawar, Swat, and D. I. Khan districts of Khyber Pakhtunkhwa, Pakistan, during the winter, spring, summer, and autumn seasons of the year 2007/2008. Analysis of variance showed that there was a complex interaction among all these factors and that this influenced the total fungal viable count and relative concentrations of the aflatoxins produced. Minimum total culturable fungi (6.43 * 103 CFUs/g) were counted in CSM from D. I. Khan region in winter season while maximum (26.68 * 103 CFUs/g) in starter ration from Peshawar region in summer. Maximum concentrations of AFB1 (191.65 ng/g), AFB2 (86.85 ng/g), and AFG2 (89.90 ng/g) were examined during the summer season whereas the concentration of AFG1 was maximum (167.82 ng/g) in autumn in finisher ration from Peshawar region. Minimum aflatoxins were produced in the winter season across all the three agroecological zones. PMID- 22544640 TI - Complementary medicine in cancer care: adding a therapy dog to the team. AB - Animal-assisted therapy, including visits from certified therapy dogs, offer a valuable and often underutilized resource for addressing unmet needs in cancer patients. Prospective research studies have documented symptomatic benefits for reducing pain, psychological distress, and fatigue in a variety of patient populations, including cancer patients. Utilizing consistent policies minimizes patient risk and infection control concerns associated with animal visits. PMID- 22544641 TI - Environmental and human exposure to soil chlorinated and brominated polycyclic aromatic hydrocarbons in an urbanized region. AB - Nine chlorinated and brominated polycyclic aromatic hydrocarbons (Cl/BrPAHs) and five parent polycyclic aromatic hydrocarbons (PAHs) were measured in urban surface soil and fly ash samples collected from Shenzhen, south China in winter 2010. The concentrations of total Cl/BrPAHs and PAHs in soil ranged from below the reporting limit to 142 ng/g and from 4.34 to 158 ug/g, respectively, and in fly ash they ranged from 17.7 to 19.5 ng/g and 26.1 to 28.3 ug/g, respectively. Concentrations of Cl/BrPAHs and parent PAHs were not significantly correlated with each other in soil or in fly ash, suggesting that Cl/BrPAHs were formed mainly by mechanisms other than direct halogenation of parent PAHs. Estimated mass inventories of 2-BrFlu varied from 68.1 kg in commercial land to 669 kg in countryside land, the highest among all Cl/BrPAHs. Loss fluxes via soil erosion accounted for only small proportions of total soil mass inventories of Cl/BrPAHs. Average daily human intake via soil ingestion decreased with increasing age, with 2-BrFlu as the main contributor. Children of 0 to 8 years old were the most sensitive subgroup (13.7 pg/kg body wt/d for total Cl/BrPAHs), and females were more sensitive than males in the same age group. The mean dioxin-like toxic equivalency quotient (TEQ) concentration of total Cl/BrPAHs (0.008 ng-TEQ/g) was lower in soil than in fly ash (0.06 ng-TEQ/g). Conversely, the mean TEQ concentration of total parent PAHs (2.23 ng-TEQ/g) was higher in soil than in fly ash. PMID- 22544642 TI - Structure-based optimization of designed Armadillo-repeat proteins. AB - The armadillo domain is a right-handed super-helix of repeating units composed of three alpha-helices each. Armadillo repeat proteins (ArmRPs) are frequently involved in protein-protein interactions, and because of their modular recognition of extended peptide regions they can serve as templates for the design of artificial peptide binding scaffolds. On the basis of sequential and structural analyses, different consensus-designed ArmRPs were synthesized and show high thermodynamic stabilities, compared to naturally occurring ArmRPs. We determined the crystal structures of four full-consensus ArmRPs with three or four identical internal repeats and two different designs for the N- and C-caps. The crystal structures were refined at resolutions ranging from 1.80 to 2.50 A for the above mentioned designs. A redesign of our initial caps was required to obtain well diffracting crystals. However, the structures with the redesigned caps caused domain swapping events between the N-caps. To prevent this domain swap, 9 and 6 point mutations were introduced in the N- and C-caps, respectively. Structural and biophysical analysis showed that this subsequent redesign of the N cap prevented domain swapping and improved the thermodynamic stability of the proteins. We systematically investigated the best cap combinations. We conclude that designed ArmRPs with optimized caps are intrinsically stable and well expressed monomeric proteins and that the high-resolution structures provide excellent structural templates for the continuation of the design of sequence specific modular peptide recognition units based on armadillo repeats. PMID- 22544643 TI - Clinicopathologic features, patterns of recurrence, and survival among women with triple-negative breast cancer in the National Comprehensive Cancer Network. AB - BACKGROUND: The objective of this study was to describe clinicopathologic features, patterns of recurrence, and survival according to breast cancer subtype with a focus on triple-negative tumors. METHODS: In total, 15,204 women were evaluated who presented to National Comprehensive Cancer Network centers with stage I through III breast cancer between January 2000 and December 2006. Tumors were classified as positive for estrogen receptor (ER) and/or progesterone receptor (PR) (hormone receptor [HR]-positive) and negative for human epidermal growth factor receptor 2 (HER2); positive for HER2 and any ER or PR status (HER2 positive); or negative for ER, PR, and HER2 (triple-negative). RESULTS: Subtype distribution was triple-negative in 17% of women (n = 2569), HER2-positive in 17% of women (n = 2602), and HR-positive/HER2-negative in 66% of women (n = 10,033). The triple-negative subtype was more frequent in African Americans compared with Caucasians (adjusted odds ratio, 1.98; P < .0001). Premenopausal women, but not postmenopausal women, with high body mass index had an increased likelihood of having the triple-negative subtype (P = .02). Women with triple-negative cancers were less likely to present on the basis of an abnormal screening mammogram (29% vs 48%; P < .0001) and were more likely to present with higher tumor classification, but they were less likely to have lymph node involvement. Relative to HR-positive/HER2-negative tumors, triple-negative tumors were associated with a greater risk of brain or lung metastases; and women with triple negative tumors had worse breast cancer-specific and overall survival, even after adjusting for age, disease stage, race, tumor grade, and receipt of adjuvant chemotherapy (overall survival: adjusted hazard ratio, 2.72; 95% confidence interval, 2.39-3.10; P < .0001). The difference in the risk of death by subtype was most dramatic within the first 2 years after diagnosis (overall survival for 0-2 years: OR, 6.10; 95% confidence interval, 4.81-7.74). CONCLUSIONS: Triple negative tumors were associated with unique risk factors and worse outcomes compared with HR-positive/HER2-negative tumors. PMID- 22544644 TI - Absorption, disposition, metabolic fate and elimination of the anti-epileptic drug lacosamide in humans: mass balance following intravenous and oral administration. AB - The absorption, distribution, metabolism and elimination of the anti-epileptic drug lacosamide were determined in 10 healthy male volunteers following intravenous or oral administration in a single-center, open-label, single-dose trial. Volunteers were randomized to receive either a continuous intravenous infusion of 100 mg (40 MUCi) [14C]-lacosamide administered over 60 min, or a 100 mg (40 MUCi) [14C]-lacosamide dose given as an oral solution. During the infusion, total radioactivity concentrations reached peak levels at 1 h post dose followed by a decline of 71 % within 24 h. More than 97 % of radioactivity was excreted within 168 h; 96.8 % in urine and 0.3 % in feces. Following oral administration, total radioactivity concentrations increased to peak levels within 0.5 h followed by a decline of 65 % within 24 h. Approximately 94.6 % of radioactivity was excreted within 168 h after oral administration, 94.2 % by the kidneys and 0.4% in feces. A comparison of AUC values (po/iv) of unchanged lacosamide indicates a high absolute bioavailability. The metabolic profile was analyzed using pooled urine samples, and following intravenous and oral administration, respectively, a total of 38 and 34 % unchanged lacosamide, 28 and 28 % of the desmethyl metabolite and 19 and 17 % of a polar fraction were measured. Additional metabolites were identified only in small amounts (<3 %). In plasma at maximum concentration, most of the total radioactivity was found as unchanged drug after intravenous and oral dose. The plasma concentration curves of total radioactivity following intravenous and oral administration were similar. PMID- 22544645 TI - The long-term outcome of treated high-risk nonmuscle-invasive bladder cancer: time to change treatment paradigm? AB - BACKGROUND: The treatment of high-risk nonmuscle-invasive bladder cancer (NMIBC) is difficult given its unpredictable natural history and patient comorbidities. Because current case series are mostly limited in size, the authors report the outcomes from a large, single-center series. METHODS: The authors reviewed all patients with primary, high-risk NMIBC at their institution from 1994 to 2010. Outcomes were matched with clinicopathologic data. Patients who had muscle invasion within 6 months or had insufficient follow-up (<6 months) were excluded. Correlations were analyzed using multivariable Cox regression and log-rank analysis (2-sided; P < .05). RESULTS: In total, 712 patients (median age, 73.7 years) were included. Progression to muscle invasion occurred in 110 patients (15.8%; 95% confidence interval [CI], 13%-18.3%) at a median of 17.2 months (interquartile range, 8.9-35.8 months), including 26.5% (95% CI, 22.2%-31.3%) of the 366 patients who had >5 years follow-up. Progression was associated with age (hazard ratio [HR], 1.04; P = .007), dysplastic urothelium (HR, 1.6; P = .003), urothelial cell carcinoma variants (HR, 3.2; P = .001), and recurrence (HR, 18.3; P < .001). Disease-specific mortality occurred in 134 patients (18.8%; 95% CI, 16.1%-21.9%) at a median of 28 months (interquartile range, 15-45 months), including 28.7% (95% CI, 24.5%-33.3%) of those who had 5 years of follow-up. Disease-specific mortality was associated with age (HR, 1.1; P < .001), stage (HR, 1.7; P = .003), dysplasia (HR, 1.3; P = .05), and progression (HR, 5.2; P < .001). Neither progression nor disease-specific mortality were associated with the receipt of bacillus Calmette-Guerin (P > .6). CONCLUSIONS: Within a program of conservative treatment, progression of high-risk NMIBC was associated with a poor prognosis. Surveillance and bacillus Calmette-Guerin were ineffective in altering the natural history of this disease. The authors concluded that the time has come to rethink the paradigm of management of this disease. PMID- 22544646 TI - Women's knowledge, attitudes, and beliefs about Down syndrome: a qualitative research study. AB - Women who are or may become pregnant need up-to-date information about Down syndrome (DS). Asking women about their knowledge, opinions, resources, and information needs on the topic of DS is an important precursor to develop effective strategies for education. We conducted 24 focus groups (N = 111) in two US cities with women who were recently pregnant (who had a child <= 3 years old without DS) and women who planned to have a child in the next year. Groups were further segmented by age and race-ethnicity. Questions explored women's knowledge, attitudes, and beliefs about DS; resources used to obtain information about health and DS; and information needs on the topic of DS. All participants reported having some knowledge of DS: facial features, chromosomal condition, and maternal age as a risk factor. Many participants had misconceptions, including the life expectancy for persons with DS, other maternal and paternal risk factors, and the idea that having a child with DS would disrupt their lives. Participants requested stories to help illustrate what life is like for families with DS. Many Hispanic and African American participants said they only saw or knew of Caucasian persons with DS and requested culturally diverse educational materials about DS. Participants said they would seek information on DS from the Internet and from their health care providers. Results suggest that women need tailored materials that contain clinical information about DS as well as information about living with a child with DS. Published 2012. This article is a U.S. Government work and is in the public domain in the USA. PMID- 22544648 TI - Analysis of chirality by femtosecond laser ionization mass spectrometry. AB - Recent progress in the field of chirality analysis employing laser ionization mass spectrometry is reviewed. Emphasis is given to femtosecond (fs) laser ionization work from the author's group. We begin by reviewing fundamental aspects of determining circular dichroism (CD) in fs-laser ionization mass spectrometry (fs-LIMS) discussing an example from the literature (resonant fs LIMS of 3-methylcyclopentanone). Second, we present new data indicating CD in non resonant fs-LIMS of propylene oxide. PMID- 22544649 TI - Determination of protease subsite preference on SPOT peptide array by fluorescence quenching-based assay. AB - A peptide SPOT array was synthesized on a glass chip and used to determine protease subsite preference. To synthesize a peptide array for positional scanning, the ratio of the isokinetic concentration was determined for every Fmoc amino acid except Cys. Based on this ratio, a peptide array consisting of Dabcyl X-X-P(2)-Arg-X-X-X-Lys(FITC) (X: equimolar mixture of 19 amino acids, P(2): one of 19 amino acids) was synthesized on a chitosan-grafted glass chip. Subsequently, the peptide substrates on the array were hydrolyzed by thrombin to screen for subsite specificity using a fluorescence quenching-based assay. The P(2) subsite specificity of thrombin was screened by the fluorescence images obtained after hydrolysis. Pro at the P(2) subsite showed the highest specificity for thrombin based on both the fluorescence quenching-based assay and the solution phase assay. From these results, we confirmed that our mixture-based peptide SPOT array format on the chitosan-grafted glass chips could be used to determine protease subsite preference. PMID- 22544650 TI - Efficacy of clinically relevant temozolomide dosing schemes in glioblastoma cancer stem cell lines. AB - The effectiveness of temozolomide (TMZ) dosing schemes and the "rechallenge" of recurrent glioblastoma (GBM) with TMZ are controversial. We therefore compared the efficacy of different TMZ dosing schemes against GBM cancer stem cell (CSC) lines in vitro. In O(6)-methyl-guanidine-methyl-transferase (MGMT)-negative CSC lines, all schedules (1 day on/27 days off, 5 days on/23 days off, 7 days on/7 days off, 21 days on/7 days off, continuous low-dose TMZ) depleted clonogenic cells. In TMZ-resistant CSC lines, the 7 days on/7 days off scheme showed higher toxicity as compared with the other schemes. However, clinically feasible concentrations remained ineffective in highly resistant CSC lines. In addition, none of the schedules induced long-term depletion of clonogenic cells even at the highest concentrations (up to 250 MUM). After sublethal TMZ treatment for 5 days, TMZ rechallenge of recovering CSC lines remained effective. Our data advocate CSC lines as in vitro model to address clinical questions. Using this model, our data suggest the effectiveness of TMZ in MGMT-negative CSC lines and support the concept of TMZ rechallenge. The 7 days on/7 days off scheme consistently showed the best activity of all schedules in TMZ-resistant CSC lines. PMID- 22544651 TI - A prospective pilot study of two-session Gamma Knife surgery for large metastatic brain tumors. AB - The purpose of this prospective study is to evaluate the efficacy and limitations of two-session Gamma Knife radiosurgery (GKS) alone for large metastatic brain tumors. Inclusion criteria were as follows: (i) patients with large metastatic brain tumors (volume >15 cm(3) in the supratentorial region or >10 cm(3) in the infratentorial region), and (ii) tumors not causing clinical signs of impending cerebral herniation. Twenty-eight lesions in 27 consecutive patients (18 men and 9 women, age range 32 to 88 years, median age 65 years) were included in this study. The radiosurgical protocol was as follows: 20-30 Gy given in two fractions 3-4 weeks apart. The local tumor control rate and the overall survival rate were calculated by using the Kaplan-Meier method. Median tumor volumes were 17.8 cm(3) at first GKS and 9.7 cm(3) at second GKS. Median follow-up time was 8.9 months. The local control rate was 85 % at 6 months and 61 % at 12 months. The overall survival rate after GKS was 63 % at 6 months and 45 % at 12 months. The 1-year rate of prevention of neurological death was maintained at 78 %. Mean Karnofsky performance status (KPS) improved from 61 [95 % confidence interval (CI), 57-71] at first GKS to 80 (95 % CI, 74-85) at second GKS; the best follow-up mean KPS was 85 (95 % CI, 78-91) (p < 0.001). Local tumor recurrence necessitated craniotomy in two patients and repeat GKS in three patients. Seventeen patients died, and the causes of death were as follows: 3 from local progression, 2 from meningeal carcinomatosis, and 12 from progression of the primary tumor. Delayed symptomatic perilesional edema developed in one patient and eventually resolved with conservative treatment. Two-session GKS for large brain metastases appears to be an effective treatment in terms of both local tumor control and neurological palliation with minimal treatment-related morbidity. These data suggest that two-session GKS could be used as an alternative to surgical resection of large tumors in patients with significant comorbidity and/or at an advanced age. The optimum regimen for dose and fraction schedule remains to be established. PMID- 22544647 TI - Inflammation and alpha-synuclein's prion-like behavior in Parkinson's disease--is there a link? AB - Parkinson's disease patients exhibit progressive spreading of aggregated alpha synuclein in the nervous system. This slow process follows a specific pattern in an inflamed tissue environment. Recent research suggests that prion-like mechanisms contribute to the propagation of alpha-synuclein pathology. Little is known about factors that might affect the prion-like behavior of misfolded alpha synuclein. In this review, we suggest that neuroinflammation plays an important role. We discuss causes of inflammation in the olfactory bulb and gastrointestinal tract and how this may promote the initial misfolding and aggregation of alpha-synuclein, which might set in motion events that lead to Parkinson's disease neuropathology. We propose that neuroinflammation promotes the prion-like behavior of alpha-synuclein and that novel anti-inflammatory therapies targeting this mechanism could slow disease progression. PMID- 22544652 TI - Intracranial capillary hemangioma: extra-axial tumorous lesions closely mimicking meningioma. AB - Capillary hemangiomas are common tumorous lesions of the skin and soft tissue in infants. These lesions often involve internal organs and rarely develop in the intracranial space. Because of their rarity, clinical descriptions of intracranial capillary hemangioma have been anecdotal and have not provided a coherent understanding of these lesions. We report four cases of intracranial capillary hemangioma. Review of these 4 cases and 14 cases reported in the literature was undertaken to assess the influence of age, sex, location, clinical manifestation, treatment, and outcome. A significant difference was observed in age at diagnosis between sexes. The median age for male patients was 4.8 years (range 6 weeks to 20 years), and the median age for female patients was 22.5 years (range 4 months to 44 years). Approximately two-thirds of intracranial capillary hemangioma lesions develop in the vicinity of major venous sinuses, such as the cavernous/sphenoparietal sinus and the transverse sinus/torcular/superior sagittal sinus. This propensity for specific locations appears to be responsible for the symptom manifestation. The majority of the lesions also seem to be extra-axial in imaging and operative findings. Complete surgical resection provided excellent outcome, but incomplete resection led to recurrence. Capillary hemangioma should be considered in the diagnosis of extra axial, contrast-enhancing lesions, especially in children and adolescents. PMID- 22544653 TI - Atypical and anaplastic meningiomas treated with bevacizumab. AB - Atypical and anaplastic (WHO Grades II and III) meningiomas are aggressive tumors, and patients often progress despite surgery and radiation. There is no known effective chemotherapeutic option for these patients. Meningiomas have a high expression of vascular endothelial growth factor receptor (VEGFR). We sought to retrospectively study the activity of bevacizumab, which is an anti-angiogenic agent targeting the VEGF pathway in these tumors. This is a retrospective review of WHO Grade II and III meningiomas treated at four institutions, selecting only those patients who received bevacizumab. We analyzed radiographic response according to standard RANO criteria, progression-free survival (PFS) and overall survival from the initiation of bevacizumab therapy using Kaplan-Meier statistics. We identified 15 patients across four institutions who carried a diagnosis of atypical or anaplastic meningioma and were treated with bevacizumab. Best radiographic response was stable disease. MR perfusion studies showed decreased tumor blood volume in one patient. Three patients developed non-fatal intratumoral hemorrhage. Median PFS was 26 weeks (95 % CI, 10-29 weeks). Six month PFS rate was 43.8 % (95 % CI, 15.7-69.1 %). Bevacizumab was well-tolerated in our patients, and may be considered in patients who have exhausted radiation and surgical options. Prospective studies are required to define the safety and efficacy of bevacizumab in atypical and anaplastic meningiomas. PMID- 22544654 TI - Influence of essential elements on cadmium uptake and toxicity in a unicellular green alga: the protective effect of trace zinc and cobalt concentrations. AB - Within the biotic ligand model (BLM) construct, major cations are considered to be simple competitors for metal binding to uptake sites and may offer some protection against metal-induced toxicity, but the influence of essential trace elements and cell preconditioning to different micronutrient concentrations on metal uptake and toxicity is considered negligible. To test these underlying assumptions, we monitored Cd uptake and toxicity in a green alga (Chlamydomonas reinhardtii) after long-term exposures (60 h) to a range of environmentally realistic free Zn(2+) , Co(2+) , Fe(3+) , Mn(2+) , Ca(2+) , and Cu(2+) concentrations buffered with nitrilotriacetic acid. A 200-fold increase in free [Mn(2+) ] as well as a 100-fold increase in free [Fe(3+) ] did not affect Cd uptake or toxicity, whereas a 50-fold increase in free [Ca(2+) ] effectively offered some protection, as predicted by the BLM. However, a 10-fold increase in free [Cu(2+) ] significantly enhanced Cd toxicity by a factor of approximately 2, whereas a 100-fold increase in free [Zn(2+) ] and [Co(2+) ] from 10(-11) to 10( 9) M significantly decreased Cd uptake and toxicity by more than twofold. These effects did not change with prior algal acclimation to different essential micronutrient concentrations. Low essential trace metal concentrations may strongly affect the uptake and toxicity of Cd in freshwater algae and should be taken into consideration in future developments of the BLM. PMID- 22544655 TI - Definitive radiotherapy for stage I nonsmall cell lung cancer: a population-based study of survival. AB - BACKGROUND: The current study characterizes the overall survival (OS) and cause specific survival (CSS) of patients with stage I nonsmall cell lung cancer (NSCLC) who were treated with radiotherapy alone, and analyzes the variables potentially affecting survival outcomes. METHODS: A total of 8524 patients with stage I NSCLC (according to the sixth edition of the American Joint Committee on Cancer staging manual) who were diagnosed between 1988 and 2008 were retrospectively analyzed using the population-based Surveillance, Epidemiology, and End Results database. Cox regression analysis was used to calculate hazard ratios (HR) from multivariate analyses. RESULTS: The 1-year, 2-year, and 5-year OS rates were 62%, 37%, and 11%, respectively; the corresponding lung cancer CSS survival rates were 68%, 45%, and 20%, respectively. Approximately 77% of deaths were from lung cancer (5292 of 6891 total deaths). Cardiac (n = 477 deaths) and pulmonary (other than lung cancer deaths; n = 475 deaths) deaths accounted for 14% of deaths. From Cox proportional hazards analyses, male sex (HR, 1.2) and squamous cell carcinoma histology (HR, > 1.1) were found to be significantly (P < .0001) adverse prognostic factors for both OS and lung cancer CSS. A more recent calendar year of diagnosis was associated with significantly (P < .0001) improved OS (HR, 0.84 per decade) and lung cancer CSS. This trend was also significant (P < 0.0001) when restricting analyses to those patients with tumors measuring <= 5 cm (n = 5402 patients). T1 classification (vs T2 or T unknown) and smaller tumor size were found to be significantly (P < .0001) favorable factors. CONCLUSIONS: From a population-based registry analysis of patients with stage I NSCLC, significant (albeit modest) improvements in survival in more recent years were appreciated, which likely reflect technologic advances in the diagnosis of, staging of, and radiotherapy for NSCLC. PMID- 22544656 TI - Characterization of a complex rearrangement involving chromosomes 1, 4 and 8 by FISH and array-CGH. AB - Complex chromosomal rearrangements (CCRs) are structural aberrations involving more than two chromosomes with at least three breakpoints. CCRs can be divided into familial and de novo. Balanced CCR are extremely rare in humans and are at high risk of producing unbalanced gametes. Individuals with balanced CCR are usually phenotipically normal but report fertility problems, recurrent miscarriages or congenital anomalies in newborn offsprings as consequence of either meiotic failure or imbalanced chromosomes segregation.We describe the case of an unbalanced CCR involving chromosomes 1, 4 and 8 found in a girl with developmental delay, hexadactilia and microcephaly. The rearrangement, apparently balanced at a standard karyotype analysis and of maternal origin, was demonstrated to be unbalanced by array-CGH and FISH. In conclusion our study underlines the importance of the combined use of a quantitative technique, as array-CGH, to detect criptic segmental aneuploidies, and a qualitative tool, as FISH analysis, to physically map the localization of the chromosome segments involved, in order to realize the exact nature that underlies a chromosomal rearrangement. PMID- 22544657 TI - How to narrow down chromosomal breakpoints in small and large derivative chromosomes--a new probe set. AB - Here a new fluorescence in situ hybridization (FISH-) based probe set is presented and its possible applications are highlighted in 34 exemplary clinical cases. The so-called pericentric-ladder-FISH (PCL-FISH) probe set enables a characterization of chromosomal breakpoints especially in small supernumerary marker chromosomes (sSMC), but can also be applied successfully in large inborn or acquired derivative chromosomes. PCL-FISH was established as 24 different chromosome-specific probe sets and can be used in two- up multicolor-FISH approaches. PCL-FISH enables the determination of a chromosomal breakpoint with a resolution between 1 and ~10 megabasepairs and is based on locus-specific bacterial artificial chromosome (BAC) probes. Results obtained on 29 sSMC cases and five larger derivative chromosomes are presented and discussed. To confirm the reliability of PCL-FISH, eight of the 29 sSMC cases were studied by array comparative genomic hybridization (aCGH); the used sSMC-specific DNA was obtained by glass-needle based microdissection and DOP-PCR-amplification. Overall, PCL FISH leads to a better resolution than most FISH-banding approaches and is a good tool to narrow down chromosomal breakpoints. PMID- 22544658 TI - Changes in smoking prevalence and number of cigarettes smoked per day following the implementation of a comprehensive tobacco control plan in New York City. AB - The New York City (NYC) Health Department has implemented a comprehensive tobacco control plan since 2002, and there was a 27% decline in adult smoking prevalence in NYC from 2002 to 2008. There are conflicting reports in the literature on whether residual smoker populations have a larger or smaller share of "hardcore" smokers. Changes in daily consumption and daily and nondaily smoking prevalence, common components used to define hardcore smokers, were evaluated in the context of the smoking prevalence decline. Using the NYC Community Health Survey, an annual random digit dial, cross-sectional survey that samples approximately 10,000 adults, the prevalence of current heavy daily, light daily, and nondaily smokers among NYC adults was compared between 2002 and 2008. A five-level categorical cigarettes per day (CPD) variable was also used to compare the population of smokers between the 2 years. From 2002 to 2008, significant declines were seen in the prevalence of daily smoking, heavy daily smoking, and nondaily smoking. Among daily smokers, there is also evidence of population declines in all but the lowest smoking category (one to five CPD). The mean CPD among daily smokers declined significantly, from 14.6 to 12.5. After an overall decline in smoking since 2002, the remaining smokers may be less nicotine dependent, based on changes in daily consumption and daily and nondaily smoking prevalence. These findings suggest the need to increase media and cessation efforts targeted towards lighter smokers. PMID- 22544660 TI - Oncologic outcome in surgical management of jugular paraganglioma and factors influencing outcomes. AB - BACKGROUND: The purpose of this study was to identify the factors that may influence the management outcome in patients with jugular paragangliomas. METHODS: The surgical records of 121 cases of jugular paraganglioma (Fisch classifications C and D) were reviewed. RESULTS: The average follow-up was 88 months. Intracranial extension (ICE; Fisch classification De and Di) constitutes 55.4% of the cases. Two cases had a malignant jugular paraganglioma. Complete tumor resection was achieved in 81.8% of the cases, and there was evidence of recurrence in 4.0% from this group. Surgical tumor control was achieved in 96% of cases. Perioperative complications consisted mainly of cerebrospinal fluid leakage in 1.6% of the cases. The lower cranial nerve (CN) was preserved in 63% of the patients mainly in the cases without ICE. CONCLUSION: The infratemporal fossa approach type A allows for complete tumor resection with low perioperative morbidity and recurrence rates. The significant influential factors were the severity of ICE and internal carotid artery involvement. PMID- 22544659 TI - Candidate locus analysis for PHACE syndrome. AB - PHACE syndrome (OMIM #606519) is a neurocutaneous syndrome of unknown etiology and pathogenesis. We report on an individual with PHACE syndrome with a complete deletion of SLC35B4 on 7q33. In order to further analyze this region, SLC35B4 was sequenced for 33 individuals with PHACE syndrome and one parental set. Common polymorphisms with a possible haplotype but no disease causing mutation were identified. Sixteen of 33 samples of the PHACE syndrome patients were also analyzed for copy number variations using high-resolution oligo-comparative genomic hybridization (CGH) microarray. A second individual in this cohort had a 26.5 kb deletion approximately 80 kb upstream of SLC35B4 with partial deletion of the AKR1B1 on 7q33. The deletions observed on 7q33 are not likely the singular cause of PHACE syndrome; however, it is possible that this region provides a genetic susceptibility to phenotypic expression with other confounding genetic or environmental factors. PMID- 22544662 TI - Phospholipid profiling of 57 soybean (Glycine max) varieties by high-performance liquid chromatography-tandem mass spectrometry and principal component analysis to classify Korean soybean germplasm. AB - Phospholipids (PLs) in 57 varieties of soybeans were profiled by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry and principal component analysis (PCA) to discriminate PL-rich soybeans. The PL calibration curves showed linearity with correlation coefficients >0.9964. The recoveries at 5 mg/L spiked level ranged from 72.8 to 86.7% and those at 12.5 mg/L from 78.2 to 85.1%. The repeatability at a 5 mg/L spiked level ranged from 2.5 to 7.0% and those at 12.5 mg/L from 1.2 to 3.9%. The average total PL content in the 57 soybean varieties was about 35.3 mg/kg. The total PL content was the highest in Aodaiz (35, 48.7 +/- 1.4 mg/kg) and the lowest in Poongsannamul (56, 16.0 +/- 0.7 mg/kg). The PCA showed that RS-78sun (42), Gyeongsang #1 (3) and Aodaiz (35) are the most improved varieties of the investigated 57 varieties from the viewpoint of PL content. PMID- 22544661 TI - Assessment of the American Joint Committee on Cancer staging (sixth and seventh editions) for clinically localized prostate cancer treated with external beam radiotherapy and comparison with the National Comprehensive Cancer Network risk stratification method. AB - BACKGROUND: The objective of this study was to compare the prognostic value of the sixth and seventh editions of the American Joint Cancer Committee (AJCC) Cancer Staging Manual and the risk-stratification model of the National Comprehensive Cancer Network (NCCN). METHODS: Two-thousand four hundred twenty nine men who received definitive radiotherapy with or without androgen deprivation therapy (median follow-up, 74 months) were analyzed. RESULTS: There was a migration of stage II patients to stage I with AJCC seventh edition (stage I increased from 1% to 38%, and stage II decreased from 91% to 55%). One pair wise comparison (4%) of Kaplan-Meier estimates of biochemical failure, distant metastasis, prostate cancer-specific survival, and overall survival between stages was statistically significant for the AJCC sixth edition. Conversely, 16 of 24 comparisons (67%) were significant for the AJCC seventh edition. With the NCCN risk-stratification model, 9 of 12 comparisons (75%) were significant. Concordance probability estimate (CPE) and standard error (SE) analysis indicated uniform and significant improvement in the predictive power of the AJCC seventh edition versus the sixth edition for all outcomes. CPE +/- SE values for the AJCC seventh edition versus the sixth edition were 0.51 +/- 0.009 versus 0.59 +/- 0.02, respectively, for biochemical failure; 0.54 +/- 0.02 versus 0.70 +/- 0.05, respectively, for distant metastasis; 0.57 +/- 0.009 versus 0.76 +/- 0.007, respectively, for prostate cancer-specific survival; and 0.52 +/- 0.006 versus 0.57 +/- 0.01, respectively, for overall survival. CPE +/- SE values for the NCCN model were 0.59 +/- 0.02 for biochemical failure, 0.72 +/- 0.05 for distant metastasis, 0.80 +/- 0.01 for prostate cancer-specific survival, and 0.57 +/- 0.01 for overall survival. CONCLUSIONS: The current results indicated that the seventh edition of the AJCC Cancer Staging Manual is a major improvement over the sixth edition, because it distributes patients better among the stages and is more prognostic. However, the NCCN model was superior to the AJCC seventh edition and remains the preferred method for risk-based clinical management of prostate cancer with radiotherapy. PMID- 22544663 TI - Comparative study of three methods for affinity measurements: capillary electrophoresis coupled with UV detection and mass spectrometry, and direct infusion mass spectrometry. AB - We present affinity capillary electrophoresis and mass spectrometry (ACE-MS) as a comprehensive separation technique for label-free solution-based affinity analysis. The application of ACE-MS for measuring affinity constants between eight small molecule drugs [ibuprofen, s-flurbiprofen, diclofenac, phenylbutazone, naproxen, folic acid, resveratrol, and 4,4'-(propane-1,3-diyl) dibenzoic acid] and beta-cyclodextrin is described. We couple on-line ACE with MS to combine the separation and kinetic capability of ACE together with the molecular weight and structural elucidation of MS in one system. To understand the full potential of ACE-MS, we compare it with two other methods: Direct infusion mass spectrometry (DIMS) and ACE with UV detection (ACE-UV). After the evaluation, DIMS provides less reliable equilibrium dissociation constants than separation-based ACE-UV and ACE-MS, and cannot be used solely for the study of noncovalent interactions. ACE-MS determines apparent dissociation constants for all reacting small molecules in a mixture, even in cases when drugs overlap with each other during separation. The ability of ACE-MS to interact, separate, and rapidly scan through m/z can facilitate the simultaneous affinity analysis of multiple interacting pairs, potentially leading to the high-throughput screening of drug candidates. PMID- 22544665 TI - Conformational flexibility and absolute stereochemistry of (3R)-3-hydroxy-4-aryl beta-lactams investigated by chiroptical properties and TD-DFT calculations. AB - The effect of conformational flexibility on the chiroptical properties of a series of synthetic (3R)-3-hydroxy-4-aryl-beta-lactams of known stereochemistry (1-6) was investigated by means of electronic circular dichroism (ECD) measurements and time-dependent density functional theory (TD-DFT) calculations. The application of the beta-lactam sector rules allowed a correct stereochemical characterization of these compounds, with the exception of a thienyl-substituted derivative (cis-). TD-DFT calculations yielded accurate predictions of experimental ECD spectra and [alpha](D) values, allowing us to assign the correct absolute configuration to all the investigated compounds. A detailed analysis of the beta-lactam ring equilibrium geometry on optimized conformers identified regular patterns for the arrangement of atoms around the amide chromophore, confirming the validity of the beta-lactam sector rules. However, relevant variations in theoretical chiroptical properties were found for compounds bearing a heterocyclic substituent at C4 or a phenyl substituent at C3, whose conformers deviate from these regular geometric patterns. This behavior explains the failure of the beta-lactam sector rules in cis-. This study showed the importance of conformational flexibility for the determination of chiroptical properties and highlighted the strengths and weaknesses of the different methods for the stereochemical characterization of chiral molecules in solution. PMID- 22544664 TI - Transporters and channels in cytotoxic astrocyte swelling. AB - Brain edema is a severe clinical complication in a number of pathologies and is a major cause of increased morbidity and death. The swelling of astrocytes caused by a disruption of water and ion homeostasis, is the primary event contributing to the cytotoxic form of brain edema. Astrocyte cytotoxic swelling ultimately leads to transcapillary fluxes of ions and water into the brain parenchyma. This review focuses on the implication of transporters and channels in cytotoxic astrocyte swelling in hyponatremia, ischemia, trauma and hepatic encephalopathy. Emphasis is put on some salient features of the astrocyte physiology, all related to cell swelling, i.e. predominance of aquaporins, control of K(+) homeostasis and ammonia accumulation during the brain ammonia-detoxifying process. PMID- 22544666 TI - A 16-year-old boy with multifocal, painless osseous lesions. PMID- 22544667 TI - Reliability and relationship of radiographic measurements in hallux valgus. AB - BACKGROUND: Although various radiographic measurements have been developed and used for evaluating hallux valgus, not all are universally believed to be necessary and their relationships have not been clearly established. Determining which are related could provide some insight into which might be useful and which would not. QUESTIONS/PURPOSES: We investigated the reliability of eight radiographic measurements used to evaluate hallux valgus, and determined which were correlated and which predicted the hallux valgus angle. METHODS: We determined eight radiographic indices for 732 patients (mean age, 51 years; SD, 17 years; 107 males and 625 females) with hallux valgus: hallux valgus angle, intermetatarsal angle, hallux interphalangeal angle, distal metatarsal articular angle, proximal phalangeal articular angle, simplified metatarsus adductus angle, first metatarsal protrusion distance, and sesamoid rotation angle. Intraobserver and interobserver reliabilities of each radiographic measurement were analyzed on 36 feet from 36 randomly selected patients. Correlations among the radiographic measurements were analyzed. Radiographic measurements predicting hallux valgus angle were evaluated using multiple regression analysis. RESULTS: Hallux valgus angle had the highest reliability, whereas the distal metatarsal articular angle and simplified metatarsus adductus angle had the lowest. Distal metatarsal articular angle, intermetatarsal angle, and sesamoid rotation angle had the highest correlations with hallux valgus angle. Distal metatarsal articular angle correlated with sesamoid rotation angle. The intermetatarsal angle, interphalangeal angle, distal metatarsal articular angle, first metatarsal protrusion distance, sesamoid rotation angle, and metatarsus adductus angle predicted the hallux valgus angle. CONCLUSIONS: We suggest using hallux valgus angle, intermetatarsal angle, interphalangeal angle, sesamoid rotation angle, and first metatarsal protrusion distance considering their reliability and prediction of the deformity. PMID- 22544669 TI - Aquatic toxicity tests with substances that are poorly soluble in water and consequences for environmental risk assessment. AB - Aquatic toxicity tests with substances that are poorly soluble in water have been conducted using different methods, and estimates of toxicity have varied accordingly. The present study illustrates differences in toxicity values resulting from variation in test designs and solution preparation methods, and offers guidance on the best way to conduct these tests. Consequences for environmental risk assessment and classification are also discussed. The present study mainly considers active ingredients of plant protection products, but is also considered relevant to other chemicals. It is recommended that toxicity tests be conducted only up to the saturation limit, dispersants avoided, and solvents used only if necessary to support handling and speed of dissolution. Analytical measurements of exposure concentrations should reflect what organisms are exposed to. If acute toxicity testing at the saturation limit yields no adverse effects, further testing should not normally be required; the toxicity value of the endpoints should be considered as the saturation limit and adverse classification should not be required. Chronic testing, if required, should then be conducted at the practical saturation limit as this is the most realistic worst-case exposure scenario. If no adverse effects occur, the risk should be acceptable because higher aqueous exposure cannot occur. This could be substantiated by testing additional species. Assessment factors on no observed effect concentration (NOEC) values at the saturation limit require careful consideration in the risk assessment to avoid unnecessarily low regulatory acceptable concentrations. PMID- 22544668 TI - Acetabular tilt correlates with acetabular version and coverage in hip dysplasia. AB - BACKGROUND: The rotational position of the acetabulum to the pelvis (acetabular tilt) may influence acetabular version and coverage of the femoral head. To date, the pathologic significance of acetabular tilt in hip dysplasia is unknown. QUESTIONS/PURPOSES: We determined whether acetabular tilt in hip dysplasia is different from that in normal hips and whether this correlates with acetabular version and coverage. METHODS: We measured the acetabular tilt angle on the lateral view of three-dimensional pelvic CT images of 40 patients (72 hips) with hip dysplasia. Forty normal hips from 40 patients were used as controls. The acetabular sector angle was measured as an index for acetabular coverage of the femoral head. RESULTS: The mean acetabular tilt angle was increased in dysplastic hips compared with controls. In dysplastic hips, a posteriorly rotated acetabulum (increased acetabular tilt) was associated with increased acetabular anteversion and with decreased anterior and anterosuperior acetabular coverage. No correlation was found in controls. In dysplastic hips with a posterior acetabular deficiency, the acetabulum was rotated anteriorly (decreased acetabular tilt) compared with hips with anterior and lateral deficiencies. CONCLUSIONS: We observed a correlation between the rotational position of the acetabulum in the pelvis with acetabular version and coverage in hip dysplasia. Our observations confirmed anterior rotation of the acetabular fragment during periacetabular osteotomies is an anatomically reasonable maneuver for hips with anterolateral acetabular deficiencies, while the maneuver can exacerbate posterior coverage and should be avoided in hips with a posterior acetabular deficiency. LEVEL OF EVIDENCE: Level IV, diagnostic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID- 22544670 TI - Average sound speed estimation using speckle analysis of medical ultrasound data. AB - PURPOSE: Most ultrasound imaging systems assume a pre-determined sound propagation speed for imaging. However, a mismatch between assumed and real sound speeds can lead to spatial shift and defocus of ultrasound image, which may limit the applicability of ultrasound imaging. The estimation of real sound speed is important for improving positioning accuracy and focus quality of ultrasound image. METHOD: A novel method using speckle analysis of ultrasound image is proposed for average sound speed estimation. Firstly, dynamic receive beam forming technology is employed to form ultrasound images. These ultrasound images are formed by same pre-beam formed radio frequency data but using different assumed sound speeds. Secondly, an improved speckle analysis method is proposed to evaluate focus quality of these ultrasound images. Thirdly, an iteration strategy is employed to locate the desired sound speed that corresponds to the best focus quality image. RESULTS: For quantitative evaluation, a group of ultrasound data with 20 different structure patterns is simulated. The comparison of estimated and simulated sound speeds shows speed estimation errors to be -0.7 +/- 2.54 m/s and -1.30 +/- 5.15 m/s for ultrasound data obtained by 128- and 64 active individual elements linear arrays, respectively. Furthermore, we validate our method via phantom experiments. The sound speed estimation error is -1.52 +/- 8.81 m/s. CONCLUSION: Quantitative evaluation proves that proposed method can estimate average sound speed accurately using single transducer with single scan. PMID- 22544671 TI - Occipital encephalocele and spinal meningomyelocele in same patient: new theories hold true? PMID- 22544672 TI - Severe persistent thrombocytopenia as a sole manifestation of brucellosis. PMID- 22544673 TI - Youngest survivor of naegleria meningitis. AB - Primary amebic meningoencephalitis (PAME) is a rare condition, usually caused by free living motile amebae. These are universally fatal infections with very few survivors reported till now. The authors report a 25-d-old boy, the youngest survivor of Naegleria meningitis. The child was admitted with a diagnosis of partially treated meningitis. Cerebro-spinal fluid wet mount examination revealed free living motile amebae resembling Naegleria, which was further confirmed by culture. He was treated with amphoterecin B, rifampicin and fluconazole for 4 wk and ventriculoperitoneal shunt for obstructive hydrocephalous. At 8 mo follow up, child has survived with neurological sequlae. PMID- 22544674 TI - Calcified cerebral cryptococcal granuloma. AB - The authors report a 12-mo-old girl with calcified cerebral cryptococcal granuloma. She was admitted with a 6-mo history of seizures. Laboratory examinations showed no abnormal findings. Electroencephalography revealed bilateral slow wave activity, greater in the right occipital region. CT showed an irregular calcified focus with small surrounding low density in the right parieto occipital region. MRI demonstrated mixed signals without edema and visible flow voids. The clinical symptoms mimicked intracranial vascular malformations. The diagnosis of cerebral cryptococcal granuloma was made by histopathology. Partial resection of the lesion with post-operatively antifungal and anticonvulsant therapy offered the satisfactory result. Cerebral cryptococcal granuloma is extremely rare, especially in infants. Calcification is indeed unusual. Cerebral cryptococcal granuloma should be included in the differential diagnosis of intracranial mass with calcification in infants. PMID- 22544675 TI - Metronomic chemotherapy in progressive pediatric malignancies: old drugs in new package. AB - Despite intensive research in the field of cancer, many pediatric cancers are still incurable with current treatment protocols. Repetitive administration of conventional chemotherapy at maximal tolerated dose imposes many side effects that further limits the dosing and therefore decreases the anticancer effects. Usually limited options remain when a malignancy progresses after one or two lines of standard chemotherapy protocol. The goal of an oncologist at this point of time remains mainly palliative with an effort to halt the progression of cancer and improve quality of life. Metronomic chemotherapy is defined as the chronic administration of chemotherapeutic agents at relatively low, minimally toxic doses, and with no prolonged drug-free breaks. It is thought this type of chemotherapy inhibits tumor growth primarily through anti-angiogenic mechanisms, promoting apoptosis and immune- surveillance. PMID- 22544676 TI - Kangaroo Mother Care in reducing pain in preterm neonates on heel prick. AB - OBJECTIVES: To determine the effect of Kangaroo Mother Care (KMC) of small duration of 15 min in decreasing pain in preterm neonates between 32-36 wk 6 d on heel prick by a 26 gauge needle. METHODS: Randomized controlled double masked crossover trial involving 50 neonates, between 32 wk and 36 wk 6 d gestation and weighing less than 2500 g, within 10 d of birth, vitally stable, breathing without assistance or on Continuous positive airway pressure (CPAP), without any clinically evident neurological signs, not having received analgesics/sedatives within last 24 h and not fed within last 30 min and requiring heel pricking were eligible. Outcome measured was the Premature Infant Pain Profile (PIPP). Analysis was done using independent sample t test, with Bonferroni correction applied for comparing individual components of PIPP score. RESULTS: The heart rate, behaviour and facial scores were statistically significant and lower in KMC group. But there was no statistically significant difference in oxygen saturation (SpO(2)). The difference(4.85) in PIPP score was clinically and statistically significant (p < 0.0001). CONCLUSIONS: The findings suggest that short duration KMC (15 min) has stress reducing benefits. Preterm neonates above 32 wk gestational age can benefit from KMC to decrease pain from heel prick procedure. PMID- 22544677 TI - Immunohistochemical detection of intra-neuronal VZV proteins in snap-frozen human ganglia is confounded by antibodies directed against blood group A1-associated antigens. AB - Varicella-zoster virus (VZV) causes chickenpox, establishes latency in trigeminal (TG) and dorsal root ganglia (DRG), and can lead to herpes zoster upon reactivation. The VZV proteome expressed during latency remains ill-defined, and previous studies have shown discordant data on the spectrum and expression pattern of VZV proteins and transcripts in latently infected human ganglia. Recently, Zerboni and colleagues have provided new insight into this discrepancy (Zerboni et al. in J Virol 86:578-583, 2012). They showed that VZV-specific ascites-derived monoclonal antibody (mAb) preparations contain endogenous antibodies directed against blood group A1 proteins, resulting in false-positive intra-neuronal VZV staining in formalin-fixed human DRG. The aim of the present study was to confirm and extend this phenomenon to snap-frozen TG (n=30) and DRG (n=9) specimens of blood group genotyped donors (n=30). The number of immunohistochemically stained neurons was higher with mAb directed to immediate early protein 62 (IE62) compared with IE63. The IE63 mAb-positive neurons always co-stained for IE62 but not vice versa. The mAb staining was confined to distinct large intra-neuronal vacuoles and restricted to A1(POS) donors. Anti-VZV mAb staining in neurons, but not in VZV-infected cell monolayers, was obliterated after mAb adsorption against blood group A1 erythrocytes. The data presented demonstrate that neuronal VZV protein expression detected by ascites-derived mAb in snap-frozen TG and DRG of blood group A1(POS) donors can be misinterpreted due to the presence of endogenous antibodies directed against blood group A1 associated antigens present in ascites-derived VZV-specific mAb preparations. PMID- 22544678 TI - Accumulation and toxicity of metals (copper, zinc, cadmium, and lead) and organic compounds (geraniol and benzo[a]pyrene) in the oribatid mite Oppia nitens. AB - The oribatid mite Oppia nitens has been suggested as a test species for ecotoxicological assessment of contaminated boreal soils. Knowledge of the ecotoxicity of pollutants of different modes of action to this species is necessary to assess its relative sensitivity in comparison with other invertebrates. The toxicity of four metals and two organic chemicals to O. nitens was evaluated over a 28- or 35-d period. Mite survival, reproduction, and tissue accumulation were assessed at the end of the test. Reproduction was a more sensitive endpoint than survival for all of the compounds except geraniol. The reproduction median inhibitory concentration (IC50) values for Cu, Zn, Cd, and Pb were 2,896, 1,562, 137, and 1,678 mg/kg, respectively, whereas those for benzo[a]pyrene and geraniol were greater than 1,600 and 283 mg/kg. The median lethal concentration (LC50) values for Cu, Zn, Cd, and Pb were 3,311, 2,291, 603, and 6,761 mg/kg, respectively, whereas those for benzo[a]pyrene and geraniol were greater than 1,600 and 251 mg/kg. When effects on reproduction are compared with those of other soil invertebrates, O. nitens appears less sensitive to Cu and Zn but within the same order of magnitude of sensitivity as that for Cd and Pb. Despite its lower sensitivity to Cu and Zn, O. nitens is a member of a group underrepresented in ecotoxicological evaluations and should therefore be included in test battery for risk assessment of contaminated boreal and other northern soils. PMID- 22544679 TI - Outcomes of squamous cell cancer of the oral tongue managed at the Princess Margaret Hospital. AB - BACKGROUND: The purpose of this study was to analyze the outcomes and treatment in patients with squamous cell carcinoma (SCC) of the oral tongue, as well as validate previously reported predictors of survival. METHODS: We retrospectively reviewed 259 patients treated with curative intent between 1994 and 2004. Kaplan Meier estimates, log-rank test, and Cox regression models were used for statistical analysis. RESULTS: Two hundred fifty-nine patients were managed with surgery; 67 patients (25%) received adjuvant radiotherapy. Mean follow-up was 60 months. The 5-year local and regional control rates were 78% and 69.4%, respectively. The 5-year overall, disease-specific, and recurrence-free survival rates were 69%, 70.9%, and 53%, respectively. The only significant predictor of both overall survival (OS) and disease-free survival (DFS) on multivariable analysis was pathologic N classification. CONCLUSION: Treatment of early tongue SCC effectively achieves local control and DFS. Nodal disease remains to be 1 of the most important prognostic factors in terms of recurrence and survival. PMID- 22544680 TI - Investigation of the metabolic biotransformation of substance P in liver microsomes by liquid chromatography quadrupole ion trap mass spectrometry. AB - Substance P (SP) belongs to the tachykinin family and plays an essential role in pain transmission and in neurogenic inflammation. It can be detected in the central and peripheral nervous systems. The objectives of this study were to establish SP metabolic stability in liver microsomes in three species (rat, mouse and human), and identify and characterize SP metabolites by LC-MS/MS. Endogenous peptide metabolism is not well documented and this is particularly true for neuropeptides participating in neurogenic inflammation. In vitro, T(1/2) results in pooled liver microsomes were 9.2, 5.6 and 18.6 min for rat, mouse and human liver microsomes, respectively. Five major SP metabolites were identified and quantified, including C-terminal SP fragments SP(3-11) , SP(5-11) , SP(6-11) , SP(8-11) as well as N-terminal fragment SP(1-7) . The results suggest significant differences between species in SP metabolite concentrations. Consequently, the metabolic profile of each species is distinctive and may have a significant impact on biomolecular mechanisms involved in specific pathophysiological changes. PMID- 22544682 TI - Micropatterned antibody-terminated nanocomposites (MANs) fabricated using layer by-layer lift-off (LBL-LO) technique. AB - Patterned functional biomolecular surfaces have been created using a wide range of fabrication methods for applications in cell-based studies, with the most common methods based on photolithography or soft lithography. In this study, a simple fabrication method combining photolithography, layer-by-layer (LbL) self assembly, and photoresist lift-off (LO) was used to create spatially defined nanocomposite micropatterns of antibodies on polyelectrolyte-protein multilayer beds. The two components of the micropatterned surfaces consisted of an anti-CD44 rat monoclonal antibody atop a vitronectin-coated multilayer film and an anti-rat osteopontin (MPIIIB10(1)) anitibody atop a fibronectin-coated multilayer film. The micropatterned antibody-terminated nanocomposites (MANs) were characterized using bright field microscopy, surface profilometry, and atomic force microscopy. The results demonstrate that LbL-LO method can be successfully used to create patterns of proteins and antibodies in precise spatial arrangements. The MAN surfaces can be utilized in many bionanotechnology applications, including patterned cell cocultures or tricultures, cytotoxicity testing, drug screening, and biosensing. In addition, the general fabrication approach used in this study is applicable to other antibodies and other ligands. PMID- 22544681 TI - Completion of the human papillomavirus vaccine series among insured females between 2006 and 2009. AB - BACKGROUND: Completion of the human papillomavirus (HPV) vaccine in a large percentage of young females is an important goal to prevent anogenital cancers associated with HPV. The current study examined whether the percentage of insured women who complete the vaccine series has changed across time, and how provider type and age at initiation affects rates of completion. METHODS: This retrospective cohort study used administrative data from a private insurance company. The study included 271,976 females in whom the HPV vaccine series was initiated and who had been continuously enrolled in their respective insurance plan for 365 days after vaccine initiation. Multivariate logistic regression was used to determine the odds of completing the vaccine series within 365 days after initiation. RESULTS: Females aged 13 years to 18 years, 19 years to 26 years, and >= 27 years were found to be less likely than those ages 9 years to 12 years to complete their HPV vaccine series. Obstetricians/gynecologists were more likely to administer vaccines to completers than pediatricians, whereas clinics, nurses, family care practitioners, and specialists were less likely to administer initial vaccines to completers compared with pediatricians. The results of the current study also found that females aged 9 years to 12 years and 13 years to 18 years had lower odds of completing the HPV vaccine series for each subsequent year compared with those aged 19 years to 26 years and >= 27 years. CONCLUSIONS: Among insured females in the United States, the percentage of females who complete the HPV vaccine series is dropping over time, especially among younger females, who are specifically targeted to receive the vaccine. Physicians need to stress the importance of completing all 3 vaccinations to their patients. PMID- 22544683 TI - Controlled nucleation of lipid nanoparticles. AB - PURPOSE: We describe a nucleation-based method which allows for the generation of monodisperse lipid nanoparticles over a range of diameters. Using a set of novel zwitterionic lipids and inverse phosphocholine lipids with pKas ranging from 2 to 5, we showed how the hydrodynamic diameter of lipid nanoparticles can be systematically manipulated over a 60 nm to 500 nm size range. METHOD: Lipid nanoparticles were prepared by adding an anti-solvent, such as water, to the organic phase containing the lipid components. This led to super-saturation and the spontaneous formation of particles. RESULTS: The growth and final particle size was controlled by the ratio of the components in the ternary system: lipid, organic solvent and aqueous phase. Particles with diameter below 125 nm were formed under conditions where the super-saturation coefficient was between 2.3 and 20. PEG-lipid served as an efficient growth inhibitor except at very high and low lipid concentrations. Encapsulation efficiency of siRNA into lipid nanoparticles was shown to be pH-dependent and requires the protonation of the anionic carboxylate groups of the zwitterionic lipids, emphasizing the importance of electrostatic forces. CONCLUSION: This process enables high encapsulation efficiency of nucleic acids and allows the size of lipid nanoparticles to be controlled. PMID- 22544684 TI - Bio-inspired nanostructured sensor for the detection of ultralow concentrations of explosives. PMID- 22544685 TI - Immunogenicity of Japanese encephalitis virus envelope protein by Hyphantria cunea nuclear polyhedrosis virus vector in guinea pig. AB - Japanese encephalitis virus (JEV) is an important pathogen causing febrile syndrome, encephalitis, and death. Envelop (E) glycoprotein is the major target of inducing neutralizing antibodies and protective immunity in host. In this study, E glycoprotein of JEV was expressed in Spodoptera frugiperd 9 cells as a fusion protein containing a gX signal sequence of pseudorabies virus. This purified HcE recombinant protein was evaluated for their immunogenicity and protective efficacy in guinea pig. The survival rates of guinea pig immunized with HcE protein was significantly increased over that of JE vaccine. This result indicates helpful information for developing a subunit vaccine against JEV. PMID- 22544686 TI - Isolation, screening, and optimization of the fermentation conditions of highly cellulolytic bacteria from the hindgut of Holotrichia parallela larvae (Coleoptera: Scarabaeidae). AB - From the hindgut contents of Holotrichia parallela, 93 cellulolytic bacterial isolates were isolated after enrichment in carboxymethyl cellulose medium. Among these isolates, a novel bacterium, designated HP207, with the highest endoglucanase productivity was selected for further study. This bacterium was identified as Pseudomonas sp. based on the results of the 16S ribosomal DNA analysis, morphological characteristics, and biochemical properties. The production of the endoglucanase was optimized by varying various physical culture conditions using a submerged fermentation method. Under the optimized fermentation conditions, the maximum endoglucanase activity of 1.432 U mL(-1) in bacterial cultures was obtained, higher than those of the most widely studied bacteria and fungi, which are the attractive candidates for the commercial producer of cellulase. And the crude endoglucanase enzyme was also highly thermostable; approximately 55% of the original activity was maintained after pretreatment at 70 degrees C for 1 h. Thus, from the present study, the bacterium can be added up to the database of cellulolytic bacteria. PMID- 22544687 TI - Selective liquefaction of wheat straw in phenol and its fractionation. AB - For the first time, a method of phenol-selective liquefaction is proposed for the fractionation and multilevel conversion of lignocellulose. Through phenol selective liquefaction, lignin and hemicellulose are liquefied, with large amounts of cellulose retained in the unliquefied residues. Using a phenol/straw ratio of 3 and a sulfuric acid concentration of 3%, large amounts of hemicellulose (>=85%) and lignin (>=70%) can be liquefied at 100 degrees C in 30 min, with a high quantity of cellulose (>=80%) retained. Unliquefied residues from selective liquefaction have higher susceptibility for enzymatic attack. Enzymatic hydrolyzation of residues can be as high as 65% in 48 h with 40.7 FPU/g of dry materials, which can then be used to prepare sugar platform intermediates. The liquefied products of wheat straw are then resinified with formaldehyde in the presence of NaOH as a catalyst and synthesized into phenol formaldehyde-type resins reaching up to GB/T 14732-2006 standards. Phenol selective liquefaction, a new technology for the fractionation of lignocellulose, achieves effective fractionation and multilevel conversion of straw components. Hence, it is an important tool to achieve full utilization of biomass and high value-added conversion of lignocellulose. PMID- 22544688 TI - Effect of acid, steam explosion, and size reduction pretreatments on bio-oil production from sweetgum, switchgrass, and corn stover. AB - Bio-oil produced from biomass by fast pyrolysis has the potential to be a valuable substitute for fossil fuels. In a recent work on pinewood, we found that pretreatment alters the structure and chemical composition of biomass, which influence fast pyrolysis. In this study, we evaluated dilute acid, steam explosion, and size reduction pretreatments on sweetgum, switchgrass, and corn stover feedstocks. Bio-oils were produced from untreated and pretreated feedstocks in an auger reactor at 450 degrees C. The bio-oil's physical properties of pH, water content, acid value, density, and viscosity were measured. The chemical characteristics of the bio-oils were determined by gas chromatography-mass spectrometry. The results showed that bio-oil yield and composition were influenced by the pretreatment method and feedstock type. Bio oil yields of 52, 33, and 35 wt% were obtained from medium-sized (0.68-1.532 mm) untreated sweetgum, switchgrass, and corn stover, respectively, which were higher than the yields from other sizes. Bio-oil yields of 56, 46, and 51 wt% were obtained from 1% H(2)SO(4)-treated medium-sized sweetgum, switchgrass, and corn stover, respectively, which were higher than the yields from untreated and steam explosion treatments. PMID- 22544689 TI - Antioxidant effect of Azadirachta indica on high fat diet induced diabetic Charles Foster rats. AB - Oxidative stress plays a major role in the pathogenesis of both types of diabetes mellitus. Excessively high levels of free radicals cause damage to cellular proteins, membrane lipids and nucleic acids, and eventually cell death. The present study was designed to investigate the possible effect of Azadirachta indica leaf extract in high fat diet induced diabetic Charles Foster rats. The increased level of lipidperoxidation and altered levels of enzymatic (superoxide dismutase, glutathione peroxidase and catalase) and non-enzymatic (glutathione) antioxidants were seen in high fructose fed animals. The treatment with A. indica leaf extract significantly normalized the altered levels of lipid peroxidation and antioxidant status at 400 mg/kg b.w. dose. The A. indica leaf extract was also tested for in vitro inhibition of generation of superoxide anion and hydroxyl free radical in both enzymatic and non-enzymatic systems. The A. indica leaf extract was found to inhibit generation of superoxide anion and hydroxyl free radical significantly at 200 MUg/ml concentration. Data of present study demonstrated that the A. indica leaf extract has both antidiabetic and antioxidant properties. PMID- 22544690 TI - Exploring the cause of oseltamivir resistance against mutant H274Y neuraminidase by molecular simulation approach. AB - Oseltamivir (Tamiflu) is the preferred anti-viral drug employed to fight the flu virus in infected individuals. The principal target for this drug is a virus surface glycoprotein, neuraminidase (NA), which facilitates the release of nascent virus and thus spreads infections. Until recently, only a low prevalence of neuraminidase inhibitors (NAIs) resistance (<1%) had been detected in circulating viruses. However, there have been reports of significant numbers of A (H1N1) influenza strains with a H274Y neuraminidase mutation that was highly resistant to the NAI, oseltamivir. In this study, we highlight the effect of point mutation-induced oseltamivir resistance in H1N1 subtype neuraminidases by molecular docking and molecular dynamics simulation approach. Our results suggested that wild-type NA could be more indispensable for the oseltamivir binding, as characterized by minimum number of H-bonds, high flexibility and largest binding affinity than mutant-type NA. This study throws light on the possible effects of drug-resistant mutations on the large functionally important collective motions in biological systems. PMID- 22544691 TI - A study on the stability and enzymatic activity of yeast alcohol dehydrogenase in presence of the self-assembling block copolymer Poloxamer 407. AB - Yeast alcohol dehydrogenase (ADH) is an enzyme widely studied for biotechnological applications due to its involvement in fermentation industry, and various attempts to improve its catalytic properties and its thermal stability have been carried out. In this paper, the influence of a block copolymer (Poloxamer 407) on ADH enzymatic activity and thermal behaviour has been studied in order to get new insights about the use of poloxamers in formulation of sustained release systems for therapeutic proteins. Poloxamer 407 has the ability to form micelles and gel due to its self-assembling and thermoresponsive properties. The effect of the copolymer towards thermal stress and pH changes, which often reduce enzymes activity it has been investigated by means of enzymatic assays and differential scanning calorimetry. Results showed that at pH 9.1 and 7.3, the Poloxamer in the form of unimeric, micellar and gel state is able to effectively preserve the enzyme from thermoinactivation. In addition by calorimetric data Poloxamer 407 has showed an effect in preserving ADH from aggregation at pH 7.3. In conclusion, Poloxamer 407 seems to be very effective in protecting ADH from stress related events, like alkaline inactivation and aggregation. PMID- 22544692 TI - Hemothorax and hematocele: unusual presentations of vitamin K deficiency bleeding disorder. PMID- 22544693 TI - Phenytoin induced DRESS syndrome. PMID- 22544694 TI - HIV genotype resistance testing in antiretroviral (ART) exposed Indian children- a need of the hour. AB - Development of drug resistance in HIV infected children with treatment failure is a major impediment to selection of appropriate therapy. HIV genotype resistance assays predict drug resistance on the basis of mutations in the viral genome. However, their clinical utility, especially in a resource limited setting is still a subject of debate. The authors report two cases in which both the children suffered from treatment failure of various antiretroviral therapy regimes. In both the cases, Genotype Resistance Testing (GRT) prompted a radical change from proposed failure therapy as per existing guidelines. GRT was specifically important for the selection of a new dual Nucleoside reverse transcriptase inhibitors (NRTI) component of failure regimen by identifying TAMS and M184V mutations in the HIV genome. These case reports highlight the importance of GRT in children failing multiple antiretroviral regimes; and emphasizes the need to recognize situations where GRT is absolutely essential to guide appropriate therapy, even in a resource limited setting. PMID- 22544695 TI - Immune thrombocytopenic purpura due to mixed viral infections. AB - An 11-year-old boy presented with epistaxis, petechial hemorrhages, easy bruising, and purpuric rash. He was diagnosed to have immune thrombocytopenic purpura and evidence of concomitant parvovirus B19 and dengue viral infection. PMID- 22544697 TI - Chiral separation of cathinone derivatives used as recreational drugs by HPLC-UV using a CHIRALPAK(r) AS-H column as stationary phase. AB - Cathinone derivatives gained high popularity on the recreational drugs market during the past 10 years. All these compounds are chiral, and the pharmacological potency of the enantiomers of these stimulants is supposed to differ. The goal of this research was to develop a reliable and easy-to-perform high-performance liquid chromatography ultraviolet method for the chiral separation of a set of 24 cathinone derivatives. A commercially available CHIRALPAK(r) AS-H column consisting of amylose tris [(S)-alpha-methylbenzylcarbamate] coated on 5-um silica gel was found to be suitable to resolve a majority of the tested compounds. High-performance liquid chromatography measurements were performed in normal phase mode under isocratic conditions with a mobile phase consisting of hexane, isopropanol, and triethylamine at a flowrate of 1 ml/min. The ratio between hexane and isopropanol was optimized by means of three model substances. Under final conditions with a mobile phase of hexane, isopropanol, and triethylamine (97:3:0.1), 19 out of 24 compounds were successfully resolved into their enantiomers and detected at a wavelength of 254 nm. A correlation between the substituents of the nitrogen atom and the separation results are shown. Furthermore, enantiomer separation results of four cathinone derivatives were compared with the results of their amphetamine analogs. PMID- 22544696 TI - Vitamin D in chronic kidney disease. AB - Vitamin D deficiency is widespread in both the pediatric and adult chronic kidney disease (CKD) population. CKD is characterized by dysregulation of vitamin D and mineral metabolism. Secondary hyperparathyroidism and its management puts patients with CKD at increased cardiovascular risk. Emergence of experimental and some clinical data suggesting beneficial effects of vitamin D on proteinuria, blood pressure, inflammation and cardiovascular outcomes has pushed it to the center stage of CKD research. Pediatric data on vitamin D dysregulation and its consequences are still in its infancy. Ongoing prospective studies such as Chronic Kidney disease in Children (CKiD) and the Cardiovascular Comorbidity in Children with CKD (4 C) should help to delineate the evolution of disturbances in mineral metabolism and its adverse effects on growth, CKD progression and cardiovascular outcomes. PMID- 22544698 TI - Rapid development of exhaustion and down-regulation of eomesodermin limit the antitumor activity of adoptively transferred murine natural killer cells. AB - Natural killer (NK) cells are potent anti-viral and antitumor "first responders" endowed with natural cytotoxicity and cytokine production capabilities. To date, attempts to translate these promising biologic functions through the adoptive transfer of NK cells for the treatment of cancer have been of limited benefit. Here we trace the fate of adoptively transferred murine NK cells and make the surprising observation that NK cells traffic to tumor sites yet fail to control tumor growth or improve survival. This dysfunction is related to a rapid down regulation of activating receptor expression and loss of important effector functions. Loss of interferon (IFN)gamma production occurs early after transfer, whereas loss of cytotoxicity progresses with homeostatic proliferation and tumor exposure. The dysfunctional phenotype is accompanied by down-regulation of the transcription factors Eomesodermin and T-bet, and can be partially reversed by the forced overexpression of Eomesodermin. These results provide the first demonstration of NK-cell exhaustion and suggest that the NK-cell first-response capability is intrinsically limited. Further, novel approaches may be required to circumvent the described dysfunctional phenotype. PMID- 22544699 TI - Prospective study of rabbit antithymocyte globulin and cyclosporine for aplastic anemia from the EBMT Severe Aplastic Anaemia Working Party. AB - Rabbit antithymocyte globulin (rATG; thymoglobulin, Genzyme) in combination with cyclosporine, as first-line immunosuppressive therapy, was evaluated prospectively in a multicenter, European, phase 2 pilot study, in 35 patients with aplastic anemia. Results were compared with 105 age- and disease severity matched patients from the European Blood and Marrow Transplant registry, treated with horse ATG (hATG; lymphoglobulin) and cyclosporine. The primary end point was response at 6 months. At 3 months, no patients had achieved a complete response to rATG. Partial response occurred in 11 (34%). At 6 months, complete response rate was 3% and partial response rate 37%. There were 10 deaths after rATG (28.5%) and 1 after subsequent HSCT. Infections were the main cause of death in 9 of 10 patients. The best response rate was 60% for rATG and 67% for hATG. For rATG, overall survival at 2 years was 68%, compared with 86% for hATG (P = .009). Transplant-free survival was 52% for rATG and 76% for hATG (P = .002). On multivariate analysis, rATG (hazard ratio = 3.9, P = .003) and age more than 37 years (hazard ratio = 4.7, P = .0008) were independent adverse risk factors for survival. This study was registered at www.clinicaltrials.gov as NCT00471848. PMID- 22544700 TI - Identification of early gene expression changes during human Th17 cell differentiation. AB - Th17 cells play an essential role in the pathogenesis of autoimmune and inflammatory diseases. Most of our current understanding on Th17 cell differentiation relies on studies carried out in mice, whereas the molecular mechanisms controlling human Th17 cell differentiation are less well defined. In this study, we identified gene expression changes characterizing early stages of human Th17 cell differentiation through genome-wide gene expression profiling. CD4(+) cells isolated from umbilical cord blood were used to determine detailed kinetics of gene expression after initiation of Th17 differentiation with IL1beta, IL6, and TGFbeta. The differential expression of selected candidate genes was further validated at protein level and analyzed for specificity in initiation of Th17 compared with initiation of other Th subsets, namely Th1, Th2, and iTreg. This first genome-wide profiling of transcriptomics during the induction of human Th17 differentiation provides a starting point for defining gene regulatory networks and identifying new candidates regulating Th17 differentiation in humans. PMID- 22544701 TI - MT1-MMP plays a critical role in hematopoiesis by regulating HIF-mediated chemokine/cytokine gene transcription within niche cells. AB - HSC fate decisions are regulated by cell-intrinsic and cell-extrinsic cues. The latter cues are derived from the BM niche. Membrane-type 1 matrix metalloproteinase (MT1-MMP), which is best known for its proteolytic role in pericellular matrix remodeling, is highly expressed in HSCs and stromal/niche cells. We found that, in MT1-MMP(-/-) mice, in addition to a stem cell defect, the transcription and release of kit ligand (KitL), stromal cell-derived factor-1 (SDF-1/CXCL12), erythropoietin (Epo), and IL-7 was impaired, resulting in a trilineage hematopoietic differentiation block, while addition of exogenous KitL and SDF-1 restored hematopoiesis. Further mechanistic studies revealed that MT1 MMP activates the hypoxia-inducible factor-1 (HIF-1) pathway via factor inhibiting HIF-1 (FIH-1) within niche cells, thereby inducing the transcription of HIF-responsive genes, which induce terminal hematopoietic differentiation. Thus, MT1-MMP in niche cells regulates postnatal hematopoiesis, by modulating hematopoietic HIF-dependent niche factors that are critical for terminal differentiation and migration. PMID- 22544702 TI - IKKalpha-mediated signaling circuitry regulates early B lymphopoiesis during hematopoiesis. AB - Multiple transcription factors regulate B-cell commitment, which is coordinated with myeloid-erythroid lineage differentiation. NF-kappaB has long been speculated to regulate early B-cell development; however, this issue remains controversial. IkappaB kinase-alpha (IKKalpha) is required for splenic B-cell maturation but not for BM B-cell development. In the present study, we unexpectedly found defective BM B-cell development and increased myeloid erythroid lineages in kinase-dead IKKalpha (KA/KA) knock-in mice. Markedly increased cytosolic p100, an NF-kappaB2-inhibitory form, and reduced nuclear NF kappaB p65, RelB, p50, and p52, and IKKalpha were observed in KA/KA splenic and BM B cells. Several B- and myeloid-erythroid-cell regulators, including Pax5, were deregulated in KA/KA BM B cells. Using fetal liver and BM congenic transplantations and deleting IKKalpha from early hematopoietic cells in mice, this defect was identified as being B cell-intrinsic and an early event during hematopoiesis. Reintroducing IKKalpha, Pax5, or combined NF-kappaB molecules promoted B-cell development but repressed myeloid-erythroid cell differentiation in KA/KA BM B cells. The results of the present study demonstrate that IKKalpha regulates B-lineage commitment via combined canonical and noncanonical NF-kappaB transcriptional activities to target Pax5 expression during hematopoiesis. PMID- 22544703 TI - Platelets can enhance vascular permeability. AB - Platelets survey blood vessels, searching for endothelial damage and preventing loss of vascular integrity. However, there are circumstances where vascular permeability increases, suggesting that platelets sometimes fail to fulfill their expected function. Human inflammatory arthritis is associated with tissue edema attributed to enhanced permeability of the synovial microvasculature. Murine studies have suggested that such vascular leak facilitates entry of autoantibodies and may thereby promote joint inflammation. Whereas platelets typically help to promote microvascular integrity, we examined the role of platelets in synovial vascular permeability in murine experimental arthritis. Using an in vivo model of autoimmune arthritis, we confirmed the presence of endothelial gaps in inflamed synovium. Surprisingly, permeability in the inflamed joints was abrogated if the platelets were absent. This effect was mediated by platelet serotonin accumulated via the serotonin transporter and could be antagonized using serotonin-specific reuptake inhibitor antidepressants. As opposed to the conventional role of platelets to microvascular leakage, this demonstration that platelets are capable of amplifying and maintaining permeability adds to the rapidly growing list of unexpected functions for platelets. PMID- 22544704 TI - The long-term effects of military conscription on mortality: estimates from the Vietnam-era draft lottery. AB - Research on the effects of Vietnam military service suggests that Vietnam veterans experienced significantly higher mortality than the civilian population at large. These results, however, may be biased by nonrandom selection into the military if unobserved background differences between veterans and nonveterans affect mortality directly. To generate unbiased estimates of exposure to conscription on mortality, the present study compares the observed proportion of draft-eligible male decedents born 1950-1952 to the (1) expected proportion of draft-eligible male decedents given Vietnam draft-eligibility cutoffs; and (2) observed proportion of draft-eligible decedent women. The results demonstrate no effect of draft exposure on mortality, including for cause-specific death rates. When we examine population subgroups-including splits by race, educational attainment, nativity, and marital status-we find weak evidence for an interaction between education and draft eligibility. This interaction works in the opposite direction of putative education-enhancing, mortality-reducing effects of conscription that have, in the past, led to concern about a potential exclusion restriction violation in instrumental variable (IV) regression models. We suggest that previous research, which has shown that Vietnam-era veterans experienced significantly higher mortality than nonveterans, might be biased by nonrandom selection into the military and should be further investigated. PMID- 22544705 TI - Two-year trends in cancer screening among low socioeconomic status women in an HMO-based high-deductible health plan. AB - BACKGROUND: Cancer screening is often fully covered under high-deductible health plans (HDHP), but low socioeconomic status (SES) women still might forego testing. OBJECTIVE: To determine the impact of switching to a HDHP on breast and cervical cancer screening among women of low SES. DESIGN: Pre-post with comparison group. PARTICIPANTS: Four thousand one hundred and eighty-eight health plan members enrolled for one year before and up to two years after an employer mandated switch from a traditional HMO to an HMO-based HDHP, compared with 9418 propensity score matched controls who remained in HMOs by employer choice. Both groups had low outpatient copayments. High-deductible members had full coverage of mammography and Pap smears, but $500 to $2000 individual deductibles for most other services. HMO members had full coverage of cancer screening and low copayments for other services without any deductible. We stratified analyses by SES. INTERVENTION: Transition to a HDHP. MAIN MEASURES: Annual breast and cervical cancer screening rates; rates of annual preventive outpatient visits. KEY RESULTS: In follow-up years 1 and 2, low SES HDHP members experienced no statistically detectable changes in rates of breast cancer screening (ratio of change, 1.14, 95 % CI, [0.93,1.40] and 1.05, [0.80,1.37], respectively) or preventive visits (difference-in-differences, +1.9 %, [-11.9 %,+17.7 %] and +10.1 %, [-9.4 %,+33.7 %], respectively) relative to HMO counterparts. Similarly, among low SES HDHP members eligible for cervical cancer screening, no significant changes occurred in either screening rates (1.01, [0.86,1.20] and 1.08, [0.86,1.35]) or preventive visits (+0.2 %, [-11.4 %,+13.3 %] and -1.4 %, [ 18.1,+18.6]). Patterns were statistically similar for high SES members. CONCLUSION: During two follow-up years, transition to an HMO-based HDHP with coverage of primary care visits and cancer screening did not lead to differentially lower rates of breast and cervical cancer screening or preventive visits for low SES women. Generalizability is limited to commercially insured women transitioning to HDHPs with low cost-sharing for cancer screening and primary care visits, a common design. PMID- 22544706 TI - Towards characterization of DNA structure under physiological conditions in vivo at the single-molecule level using single-pair FRET. AB - Fluorescence resonance energy transfer (FRET) under in vivo conditions is a well established technique for the evaluation of populations of protein bound/unbound nucleic acid (NA) molecules or NA hybridization kinetics. However, in vivo FRET has not been applied to in vivo quantitative conformational analysis of NA thus far. Here we explored parameters critical for characterization of NA structure using single-pair (sp)FRET in the complex cellular environment of a living Escherichia coli cell. Our measurements showed that the fluorophore properties in the cellular environment differed from those acquired under in vitro conditions. The precision for the interprobe distance determination from FRET efficiency values acquired in vivo was found lower (~ 31%) compared to that acquired in diluted buffers (13%). Our numerical simulations suggest that despite its low precision, the in-cell FRET measurements can be successfully applied to discriminate among various structural models. The main advantage of the in-cell spFRET setup presented here over other established techniques allowing conformational analysis in vivo is that it allows investigation of NA structure in various cell types and in a native cellular environment, which is not disturbed by either introduced bulk NA or by the use of chemical transfectants. PMID- 22544707 TI - SNPnexus: a web server for functional annotation of novel and publicly known genetic variants (2012 update). AB - Broader functional annotation of single nucleotide variations is a valuable mean for prioritizing targets in further disease studies and large-scale genotyping projects. We originally developed SNPnexus to assess the potential significance of known and novel SNPs on the major transcriptome, proteome, regulatory and structural variation models in order to identify the phenotypically important variants. Being committed to providing continuous support to the scientific community, we have substantially improved SNPnexus over time by incorporating a broader range of variations such as insertions/deletions, block substitutions, IUPAC codes submission and region-based analysis, expanding the query size limit, and most importantly including additional categories for the assessment of functional impact. SNPnexus provides a comprehensive set of annotations for genomic variation data by characterizing related functional consequences at the transcriptome/proteome levels of seven major annotation systems with in-depth analysis of potential deleterious effects, inferring physical and cytogenetic mapping, reporting information on HapMap genotype/allele data, finding overlaps with potential regulatory elements, structural variations and conserved elements, and retrieving links with previously reported genetic disease studies. SNPnexus has a user-friendly web interface with an improved query structure, enhanced functional annotation categories and flexible output presentation making it practically useful for biologists. SNPnexus is freely available at http://www.snp nexus.org. PMID- 22544708 TI - A new way of measuring apoptosis by absolute quantitation of inter-nucleosomally fragmented genomic DNA. AB - Several critical events of apoptosis occur in the cell nucleus, including inter nucleosomal DNA fragmentation (apoptotic DNA) and eventual chromatin condensation. The generation of apoptotic DNA has become a biochemical hallmark of apoptosis because it is a late 'point of no return' step in both the extrinsic (cell-death receptor) and intrinsic (mitochondrial) apoptotic pathways. Despite investigators observing apoptotic DNA and understanding its decisive role as a marker of apoptosis for over 20 years, measuring it has proved elusive. We have integrated ligation-mediated PCR and qPCR to design a new way of measuring apoptosis, termed ApoqPCR, which generates an absolute value for the amount (picogram) of apoptotic DNA per cell population. ApoqPCR's advances over current methods include a 1000-fold linear dynamic range yet sensitivity to distinguish subtle low-level changes, measurement with a 3- to 4-log improvement in sample economy, and capacity for archival or longitudinal studies combined with high throughput capability. We demonstrate ApoqPCR's utility in both in vitro and in vivo contexts. Considering the fundamental role apoptosis has in vertebrate and invertebrate health, growth and disease, the reliable measurement of apoptotic nucleic acid by ApoqPCR will be of value in cell biology studies in basic and applied science. PMID- 22544709 TI - The human RecQ helicases BLM and RECQL4 cooperate to preserve genome stability. AB - Bacteria and yeast possess one RecQ helicase homolog whereas humans contain five RecQ helicases, all of which are important in preserving genome stability. Three of these, BLM, WRN and RECQL4, are mutated in human diseases manifesting in premature aging and cancer. We are interested in determining to which extent these RecQ helicases function cooperatively. Here, we report a novel physical and functional interaction between BLM and RECQL4. Both BLM and RECQL4 interact in vivo and in vitro. We have mapped the BLM interacting site to the N-terminus of RECQL4, comprising amino acids 361-478, and the region of BLM encompassing amino acids 1-902 interacts with RECQL4. RECQL4 specifically stimulates BLM helicase activity on DNA fork substrates in vitro. The in vivo interaction between RECQL4 and BLM is enhanced during the S-phase of the cell cycle, and after treatment with ionizing radiation. The retention of RECQL4 at DNA double-strand breaks is shortened in BLM-deficient cells. Further, depletion of RECQL4 in BLM-deficient cells leads to reduced proliferative capacity and an increased frequency of sister chromatid exchanges. Together, our results suggest that BLM and RECQL4 have coordinated activities that promote genome stability. PMID- 22544711 TI - Comparison of pulsed and pseudocontinuous arterial spin-labeling for measuring CO2 -induced cerebrovascular reactivity. AB - PURPOSE: To compare the performance of pulsed and pseudocontinuous arterial spin labeling (PASL and pCASL) methods in measuring CO(2) -induced cerebrovascular reactivity (CVR). MATERIALS AND METHODS: Subjects were scanned using both ASL sequences during a controlled hypercapnia procedure and visual stimulation. CVR was computed as the percent CO(2) -induced increase in cerebral blood flow (Delta%CBF) per mmHg increase in end-tidal PCO(2) . Visually evoked responses were expressed as Delta%CBF. Resting CBF and temporal signal-to-noise ratio were also computed. Regionally averaged values for the different quantities were compared in gray matter (GM) and visual cortex (VC) using t-tests. RESULTS: Both PASL and pCASL yielded comparable respective values for resting CBF (56 +/- 3 and 56 +/- 4 mL/min/100g) and visually evoked responses (75 +/- 5% and 81 +/- 4%). Values of CVR determined using pCASL (GM 4.4 +/- 0.2, VC 8 +/- 1 Delta%CBF/mmHg), however, were significantly higher than those measured using PASL (GM 3.0 +/- 0.6, VC 5 +/- 1 Delta%CBF/mmHg) in both GM and VC. The percentage of GM voxels in which statistically significant hypercapnia responses were detected was also higher for pCASL (27 +/- 5% vs. 16 +/- 3% for PASL). CONCLUSION: pCASL may be less prone to underestimation of CO(2) -induced flow changes due to improved label timing control. PMID- 22544710 TI - Phototoxicity of TiO2 nanoparticles under solar radiation to two aquatic species: Daphnia magna and Japanese medaka. AB - One target of development and application of TiO(2) nanoparticles (nano-TiO(2) ) is photochemical degradation of contaminants and photo-killing of microbes and fouling organisms. However, few ecotoxicological studies have focused on this aspect of nano-TiO(2) , specifically whether this photoreactivity might significantly increase hazard and risk of the materials in the natural environment. In the present study, we evaluated acute phototoxicity of nano TiO(2) under simulated solar radiation (SSR) to two aquatic species-Daphnia magna and Japanese medaka, using 48-h and 96-h assays, respectively. A thorough characterization of the exposure system was performed by measuring particle agglomeration and TiO(2) concentration in suspension in a time-course manner. Sedimentation and loss of bulk concentration of nano-TiO(2) particles occurred at all concentrations above 2 mg/L and was more significant as concentration increased. Phototoxicity of nano-TiO(2) under SSR was enhanced by two to four orders of magnitude as compared to toxicity under ambient laboratory light, with a 48-h median lethal concentration (LC50) of 29.8 ug/L in D. magna and a 96-h LC50 of 2.2 mg/L in medaka. Our results also indicate that these effects are dependent on simultaneous exposure of the organisms to nanoparticles and SSR. This dramatic increase in toxicity of nano-TiO(2) at environmentally realistic levels of SSR indicates the need to incorporate this mode of action into risk assessment for nano-TiO(2) and other photoreactive nanomaterials. PMID- 22544712 TI - Simultaneous determination of sitagliptin and simvastatin in human plasma by LC MS/MS and its application to a human pharmacokinetic study. AB - A simple, rapid and sensitive liquid chromatography-tandem mass spectrometric (LC MS/MS) assay method has been developed and validated for simultaneous quantification of sitagliptin and simvastatin in human plasma. Carbamazepine was used as an internal standard (IS). The analytes and IS were extracted from the human plasma by liquid-liquid extraction technique. The reconstituted samples were chromatographed on an Alltima HP C(18) column using an isocratic solvent mixture [acetonitrile-5 mm ammonium acetate (pH 4.5), 85:15 (v/v)] at a flow rate of 1.0 mL/min. Method validation was performed as per Food and Drug Administration guidelines and the results met the acceptance criteria. The calibration curves obtained were linear (r(2) >= 0.99) over the concentration range of 0.10-501 and 0.05-105 ng/mL for sitagliptin and simvastatin, respectively. The results of the intra- and inter-day precision and accuracy studies were well within the acceptable limits. Both the analytes were found to be stable in a battery of stability studies. The method is precise and sensitive enough for its intended purpose. A run time of 3.0 min for each sample made it possible to analyze more than 300 plasma samples per day. The developed assay was successfully applied to a pharmacokinetic study in human volunteers. PMID- 22544713 TI - Developmental evolution in social insects: regulatory networks from genes to societies. AB - The evolution and development of complex phenotypes in social insect colonies, such as queen-worker dimorphism or division of labor, can, in our opinion, only be fully understood within an expanded mechanistic framework of Developmental Evolution. Conversely, social insects offer a fertile research area in which fundamental questions of Developmental Evolution can be addressed empirically. We review the concept of gene regulatory networks (GRNs) that aims to fully describe the battery of interacting genomic modules that are differentially expressed during the development of individual organisms. We discuss how distinct types of network models have been used to study different levels of biological organization in social insects, from GRNs to social networks. We propose that these hierarchical networks spanning different organizational levels from genes to societies should be integrated and incorporated into full GRN models to elucidate the evolutionary and developmental mechanisms underlying social insect phenotypes. Finally, we discuss prospects and approaches to achieve such an integration. PMID- 22544714 TI - Pattern and density of vascularization in mammalian testes, ovaries, and ovotestes. AB - According to the classical paradigm, the vasculature of the embryonic testis is more dense and complex than that of the ovary, but recent studies based on whole mount detection of Caveolin-1 (CAV1) as an endothelial cell marker, have suggested that the level of ovarian vascularization is higher than previously assumed. However, this new hypothesis has been neither tested using alternative methodology nor investigated in other mammalian species. In this paper, we have studied the vascularization process in the gonads of males and females of two mammalian species, the mouse (Mus musculus) and the Iberian mole (Talpa occidentalis). Our results show that the pattern of testis vascularization is very well conserved among mammals, including both pre- and postnatal stages of development and, at least in the mole, it is conserved irrespectively of whether the testicular tissue is XY or XX. We have shown that CAV1 is present not only in endothelial cells but also in prefollicular oocytes and in an ovarian population of somatic cortical cells. These data clearly establish that: (1) according to the classical hypothesis, the degree of vascularization of the developing ovary is lower than that of the testis, (2) ovarian vascularization is also evolutionarily conserved as it occurs similarly both in moles and in mice, and (3) that the degree of vascular development of the mammalian ovary is age dependent increasing significatively at puberty. The expression of CAV1 in the ovary of most animal taxa, from nematodes to mammals, strongly suggests a role for this gene in the female meiosis. PMID- 22544715 TI - Sex-linked mitochondrial behavior during early embryo development in Ruditapes philippinarum (Bivalvia Veneridae) a species with the Doubly Uniparental Inheritance (DUI) of mitochondria. AB - In most metazoans mitochondria are inherited maternally. However, in some bivalve molluscs, two mitochondrial lineages are present: one transmitted through females (F-type), the other through males (M-type). This unique system is called Doubly Uniparental Inheritance (DUI) of mitochondria. In DUI species, M-type mitochondria have to invade the germ line of male embryos during development, otherwise sperm would transmit F-type mtDNA and DUI would fail. The mechanisms by which sperm mitochondria enter the germ line are still unknown. To address this question, we traced the movement of spermatozoon mitochondria (M-type) in embryos of the DUI species Ruditapes philippinarum by fertilizing eggs with sperm stained with the mitochondrial-specific vital dye MitoTracker Green. As in Mytilus DUI species, in R. philippinarum the distribution of sperm mitochondria follows two different patterns: an aggregated one in which these organelles locate near the first cleavage furrow, and a dispersed one in which sperm mitochondria are scattered. The presence of the two mitochondrial patterns in these taxa, together with their absence in species with Strictly Maternal Inheritance (SMI), confirms that their occurrence is related to DUI. Moreover, a Real-Time qPCR analysis showed that neither M-type nor F-type mitochondria undergo replication boosts in the earliest embryo development. This is the first study on sex-linked mtDNA copy number carried out by qPCR analysis on embryos of a DUI species and the first time the segregation patterns of sperm mitochondria are described in a DUI system other than Mytilus. PMID- 22544716 TI - Expression patterns of runx2, sparc, and bgp during scale regeneration in the goldfish Carassius auratus. AB - Teleost fish scale is a dermal skeleton equipped with a strong regenerative ability. Owing to this regenerative ability, teleost fish scale can be used as a model for the regeneration of the dermal skeleton. However, there is insufficient fundamental knowledge of the regeneration, and this limits the usage of fish scale. In this study, as a first step toward understanding the molecular mechanism of the cellular differentiation during scale regeneration, we cloned the cDNAs for osteoblast-related proteins (Runx2, Sparc, and Bgp) in goldfish, and analyzed their expressions during scale regeneration. The expression profiles of these genes during scale regeneration were similar to those during mammalian osteoblastic differentiation. Specifically, runx2 expression was increased at the earliest time point, followed by sparc expression and then bgp expression. In the earlier stages, these genes were expressed in cells that formed cellular condensations and the flat cells surrounding them in the scale pocket. As the regeneration proceeded, the expressions became restricted to the episquamal, hyposquamal, and marginal scleroblasts and the cells around the marginal area of the regenerating scale. These results strongly suggest that (1) the differentiation mechanism of scleroblasts is similar to that of mammalian osteoblasts and odontoblasts, (2) scleroblast differentiation occurs around the cellular condensations at the early regeneration stage and is restricted to the marginal area of the scale at the later stage, and (3) the differentiation mechanisms are similar between the episquamal scleroblasts that produce the external layer and the hyposquamal scleroblasts that produce the basal plate. PMID- 22544717 TI - A small number of genes underlie male pigmentation traits in Lake Malawi cichlid fishes. AB - Pigmentation patterns are one of the most recognizable forms of phenotypic diversity and an important component of organismal fitness. While much progress has been made in understanding the genes controlling pigmentation in model systems, many questions remain about the genetic basis of pigment traits observed in nature. Lake Malawi cichlid fishes are known for their diversity of male pigmentation patterns, which have been shaped by sexual selection. To begin the process of identifying the genes underlying this diversity, we quantified the number of pigment cells on the body and fins of two species of the genus Metriaclima and their hybrids. We then used the Castle-Wright equation to estimate that differences in individual pigmentation traits between these species are controlled by one to four genes each. Different pigmentation traits are highly correlated in the F(2) , suggesting shared developmental pathways and genetic pleiotropy. Melanophore and xanthophore traits fall on opposite ends of the first principal component axis of the F(2) phenotypes, suggesting a tradeoff during the development of these two pigment cell types. PMID- 22544718 TI - An epigenetic model for pigment patterning based on mechanical and cellular interactions. AB - Pigment patterning in animals generally occurs during early developmental stages and has ecological, physiological, ethological, and evolutionary significance. Despite the relative simplicity of color patterns, their emergence depends upon multilevel complex processes. Thus, theoretical models have become necessary tools to further understand how such patterns emerge. Recent studies have reevaluated the importance of epigenetic, as well as genetic factors in developmental pattern formation. Yet epigenetic phenomena, specially those related to physical constraints that might be involved in the emergence of color patterns, have not been fully studied. In this article, we propose a model of color patterning in which epigenetic aspects such as cell migration, cell-tissue interactions, and physical and mechanical phenomena are central. This model considers that motile cells embedded in a fibrous, viscoelastic matrix-mesenchyme can deform it in such a way that tension tracks are formed. We postulate that these tracks act, in turn, as guides for subsequent cell migration and establishment, generating long-range phenomenological interactions. We aim to describe some general aspects of this developmental phenomenon with a rather simple mathematical model. Then we discuss our model in the context of available experimental and morphological evidence for reptiles, amphibians, and fishes, and compare it with other patterning models. We also put forward novel testable predictions derived from our model, regarding, for instance, the localization of the postulated tension tracks, and we propose new experiments. Finally, we discuss how the proposed mechanism could constitute a dynamic patterning module accounting for pattern formation in many animal lineages. PMID- 22544719 TI - Embryonic development and gene expression of porcine SCNT embryos treated with sodium butyrate. AB - Incomplete epigenetic modification is one of important reasons of inefficient reprogramming of the donor cell nuclei in ooplasm after somatic cell nuclear transfer (SCNT). It may also underlie the observed reduced viability of cloned embryos. Sodium butyrate (NaBu) is a natural histone deacetylase inhibitor that is produced in the intestine. In the current study, we evaluated the effects of NaBu on preimplantation development, histone acetylation, and gene expression in porcine SCNT embryos. Our results showed that the blastocyst rate (24.88 +/- 2.09) of cloned embryos treated with 1.0 mM NaBu for 12 hr after activation was significantly higher (P < 0.05) than that of untreated cloned embryos (13.15 +/- 3.07). In addition, treated embryos displayed a global acetylated histone H3 at lysine 14 profile similar to that of in vitro fertilized (IVF) embryos during preimplantation development. Lower levels of Oct4 and Bcl-2, but higher levels of Hdac1, in SCNT embryos at the two-cell and blastocyst stages were observed, compared with those in the IVF counterparts. The four-cell embryos showed no differences in the levels of these genes among IVF embryos or SCNT embryos treated with or without NaBu; however, the levels of Dnmt3b were significantly different. NaBu-treated SCNT embryos showed similar levels of Oct4, Bcl-2, and Dnmt3b as in IVF blastocysts. These results indicated that NaBu treatment in SCNT embryos alters their histone acetylation pattern to provide beneficial effects on in vitro developmental competence and gene expression. PMID- 22544724 TI - Directional self-assembly of a colloidal metal-organic framework. PMID- 22544723 TI - Atomic structure of the nuclear pore complex targeting domain of a Nup116 homologue from the yeast, Candida glabrata. AB - The nuclear pore complex (NPC), embedded in the nuclear envelope, is a large, dynamic molecular assembly that facilitates exchange of macromolecules between the nucleus and the cytoplasm. The yeast NPC is an eightfold symmetric annular structure composed of ~456 polypeptide chains contributed by ~30 distinct proteins termed nucleoporins. Nup116, identified only in fungi, plays a central role in both protein import and mRNA export through the NPC. Nup116 is a modular protein with N-terminal "FG" repeats containing a Gle2p-binding sequence motif and a NPC targeting domain at its C-terminus. We report the crystal structure of the NPC targeting domain of Candida glabrata Nup116, consisting of residues 882 1034 [CgNup116(882-1034)], at 1.94 A resolution. The X-ray structure of CgNup116(882-1034) is consistent with the molecular envelope determined in solution by small-angle X-ray scattering. Structural similarities of CgNup116(882 1034) with homologous domains from Saccharomyces cerevisiae Nup116, S. cerevisiae Nup145N, and human Nup98 are discussed. PMID- 22544725 TI - Alteration of HLA-F and HLA I antigen expression in the tumor is associated with survival in patients with esophageal squamous cell carcinoma. AB - Alteration of human leukocyte antigen (HLA) expression, such as decreased HLA I (HLA-A, -B and -C) antigens and elevated nonclassical HLA I antigens (HLA-E, -F and -G), was reported to have an unfavorable prognosis in various cancers. In our study, HLA-F expression in 105 primary esophageal squamous cell carcinoma (ESCC) lesions and 62 case-matched adjacent normal tissues, and HLA I antigens among 68 cases were analyzed by immunohistochemistry. Data revealed that HLA-F expression was observed in 58.1% (61/105) of the ESCC lesions and in 54.8% (34/62) of the normal esophageal tissues. Among the 62 case-matched samples, HLA-F expression (lesion vs. normal tissue) was upregulated, unchanged and downregulated in 13 (21.0%), 6 (9.6%) and 43 (69.4%) cases, respectively. Patients with HLA-F positive had a worse survival than those with HLA-F negative (p = 0.040). Patients with upregulated HLA-F expression (lesion vs. normal tissue) had significantly worse survival than those with HLA-F unchanged and downregulated (p = 0.010). Furthermore, decreased HLA I expression was observed in 41.2% (28/68) patients and was with worse prognosis in comparison to those with preserved HLA I expression (p = 0.001). Multivariate analysis using Cox's proportional hazards model revealed that upregulated HLA-F expression (p = 0.026) and downregulated HLA I expression (p = 0.013) could be an independent unfavorable prognostic factor. In conclusion, our study provided the evidence that alteration of HLA I and HLA-F antigen expression was associated with survival in patients with ESCC. PMID- 22544727 TI - Is it really right? When lateralization is misleading: two cases of unusual lateralization of physiological EEG patterns. PMID- 22544726 TI - Recommendations for the treatment of epilepsy in adult patients in general practice in Belgium: an update. AB - In 2008, a group of Belgian epilepsy experts published recommendations for antiepileptic drug (AED) treatment of epilepsies in adults and children. Selection of compounds was based on the registration and reimbursement status in Belgium, the level of evidence for efficacy, common daily practice and the personal views and experiences of the authors. In November 2011 the validity of these recommendations was reviewed by the same group of Belgian epilepsy experts who contributed to the preparation of the original paper. The recommendations made in 2008 for initial monotherapy in paediatric patients were still considered to be valid, except for the first choice treatment for childhood absence epilepsy. This update therefore focuses on the treatment recommendations for initial monotherapy and add-on treatment in adult patients. Several other relevant aspects of treatment with AEDs are addressed, including considerations for optimal combination of AEDs (rational polytherapy), pharmacokinetic properties, pharmacodynamic and pharmacokinetic interaction profile, adverse effects, comorbidity, treatment of elderly patients, AED treatment during pregnancy, and generic substitution of AEDs. PMID- 22544728 TI - Environmental degradation of microbial polyhydroxyalkanoates and oil palm-based composites. AB - This paper investigates the degradation of polyhydroxyalkanoates and its biofiber composites in both soil and lake environment. Time-dependent changes in the weight loss of films were monitored. The rate of degradation of poly(3 hydroxybutyrate) [P(3HB)], poly(3-hydroxybutyrate-co-4-hydroxybutyrate) [P(3HB-co 23 mol% 4HB)] and poly(3-hydroxybutyrate-co-3-hydroxyvalerate-co-4 hydroxybutyrate) [P(3HB-co-9 mol% 3HV-co-19 mol% 4HB)] were investigated. The rate of degradation in the lake is higher compared to that in the soil. The highest rate of degradation in lake environment (15.6% w/w week(-1)) was observed with P(3HB-co-3HV-co-4HB) terpolymer. Additionally, the rate of degradation of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) [P(3HB-co-38 mol% 3HV)] was compared to PHBV biofiber composites containing compatibilizers and empty fruit bunch (EFB). Here, composites with 30% EFB displayed the highest rate of degradation both in the lake (25.6% w/w week(-1)) and soil (15.6% w/w week(-1)) environment. PMID- 22544730 TI - Piezo-semiconductive quasi-1D nanodevices with or without anti-symmetry. AB - The piezopotential in floating, homogeneous, quasi-1D piezo-semiconductive nanostructures under axial stress is an anti-symmetric (i.e., odd) function of force. Here, after introducing piezo-nano-devices with floating electrodes for maximum piezo-potential, we show that breaking the anti-symmetric nature of the piezopotential-force relation, for instance by using conical nanowires, can lead to better nanogenerators, piezotronic and piezophototronic devices. PMID- 22544731 TI - Development and evaluation of TWIST Dixon for dynamic contrast-enhanced (DCE) MRI with improved acquisition efficiency and fat suppression. AB - PURPOSE: To develop a new pulse sequence called time-resolved angiography with stochastic trajectories (TWIST) Dixon for dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). MATERIALS AND METHODS: The method combines dual-echo Dixon to generate separated water and fat images with a k-space view-sharing scheme developed for 3D TWIST. The performance of TWIST Dixon was compared with a volume interpolated breathhold examination (VIBE) sequence paired with spectrally selective adiabatic inversion Recovery (SPAIR) and quick fat-sat (QFS) fat suppression techniques at 3.0T using quantitative measurements of fat-suppression accuracy and signal-to-noise ratio (SNR) efficiency, as well as qualitative breast image evaluations. RESULTS: The water fraction of a uniform phantom was calculated from the following images: 0.66 +/- 0.03 for TWIST Dixon; 0.56 +/- 0.23 for VIBE-SPAIR, and 0.53 +/- 0.14 for VIBE-QFS, while the reference value is 0.70 measured by spectroscopy. For phantoms with contrast (Gd-BOPTA) concentration ranging from 0-6 mM, TWIST Dixon also provides consistently higher SNR efficiency (3.2-18.9) compared with VIBE-SPAIR (2.8-16.8) and VIBE-QFS (2.4 12.5). Breast images acquired with TWIST Dixon at 3.0T show more robust and uniform fat suppression and superior overall image quality compared with VIBE SPAIR. CONCLUSION: The results from phantom and volunteer evaluation suggest that TWIST Dixon outperforms conventional methods in almost every aspect and it is a promising method for DCE-MRI and contrast-enhanced perfusion MRI, especially at higher field strength where fat suppression is challenging. PMID- 22544732 TI - Conjugated polymer and gold nanoparticle co-loaded PLGA nanocomposites with eccentric internal nanostructure for dual-modal targeted cellular imaging. AB - Herein is reported the one-step synthesis of an integrated nanocomposite with eccentrically loaded 5 nm gold nanoparticles (Au NPs) and conjugated polymer of poly[9,9-bis(6'-N,N,N-trimethylammonium)hexyl)fluorenyldivinylene-alt-4,7-(2,1,3, benzothiadiazole) dibromide] (PFVBT). The nanocomposite is generated with surface-functionalized folic acid groups due to the matrix polymer of PLGA PEG(2000) -folate used for encapsulation. The nanocomposite shows far-red fluorescence from PFVBT and scattering signal from Au NPs. Although Au NPs have been widely reported to quench the fluorescence of conjugated polymers, the PFVBT fluorescence is well maintained in the nanocomposite due to the eccentric location of Au NPs. The folic acid groups at the nanocomposite surface favor its cellular uptake by MCF-7 breast cancer cells, which have overexpressed folate receptors on the cell membranes. In conjugation with its low cytotoxicity, the folic-acid-functionalized nanocomposite has been successfully utilized for fluorescence and dark-field dual-modal targeted cellular imaging. PMID- 22544733 TI - A nomogram for individualized estimation of survival among patients with brain metastasis. AB - PURPOSE: An estimated 24%-45% of patients with cancer develop brain metastases. Individualized estimation of survival for patients with brain metastasis could be useful for counseling patients on clinical outcomes and prognosis. METHODS: De identified data for 2367 patients with brain metastasis from 7 Radiation Therapy Oncology Group randomized trials were used to develop and internally validate a prognostic nomogram for estimation of survival among patients with brain metastasis. The prognostic accuracy for survival from 3 statistical approaches (Cox proportional hazards regression, recursive partitioning analysis [RPA], and random survival forests) was calculated using the concordance index. A nomogram for 12-month, 6-month, and median survival was generated using the most parsimonious model. RESULTS: The majority of patients had lung cancer, controlled primary disease, no surgery, Karnofsky performance score (KPS) >= 70, and multiple brain metastases and were in RPA class II or had a Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) score of 1.25-2.5. The overall median survival was 136 days (95% confidence interval, 126-144 days). We built the nomogram using the model that included primary site and histology, status of primary disease, metastatic spread, age, KPS, and number of brain lesions. The potential use of individualized survival estimation is demonstrated by showing the heterogeneous distribution of the individual 12-month survival in each RPA class or DS-GPA score group. CONCLUSION: Our nomogram provides individualized estimates of survival, compared with current RPA and DS-GPA group estimates. This tool could be useful for counseling patients with respect to clinical outcomes and prognosis. PMID- 22544734 TI - Drug-induced cholestatic hepatitis: how late can it occur even after the cessation of the culpable drug? PMID- 22544735 TI - Loss of mammal-specific tectorial membrane component carcinoembryonic antigen cell adhesion molecule 16 (CEACAM16) leads to hearing impairment at low and high frequencies. AB - The vertebrate-restricted carcinoembryonic antigen gene family evolves extremely rapidly. Among their widely expressed members, the mammal-specific, secreted CEACAM16 is exceptionally well conserved and specifically expressed in the inner ear. To elucidate a potential auditory function, we inactivated murine Ceacam16 by homologous recombination. In young Ceacam16(-/-) mice the hearing threshold for frequencies below 10 kHz and above 22 kHz was raised. This hearing impairment progressed with age. A similar phenotype is observed in hearing-impaired members of Family 1070 with non-syndromic autosomal dominant hearing loss (DFNA4) who carry a missense mutation in CEACAM16. CEACAM16 was found in interdental and Deiters cells and was deposited in the tectorial membrane of the cochlea between postnatal days 12 and 15, when hearing starts in mice. In cochlear sections of Ceacam16(-/-) mice tectorial membranes were significantly more often stretched out as compared with wild-type mice where they were mostly contracted and detached from the outer hair cells. Homotypic cell sorting observed after ectopic cell surface expression of the carboxyl-terminal immunoglobulin variable-like N2 domain of CEACAM16 indicated that CEACAM16 can interact in trans. Furthermore, Western blot analyses of CEACAM16 under reducing and non-reducing conditions demonstrated oligomerization via unpaired cysteines. Taken together, CEACAM16 can probably form higher order structures with other tectorial membrane proteins such as alpha-tectorin and beta-tectorin and influences the physical properties of the tectorial membrane. Evolution of CEACAM16 might have been an important step for the specialization of the mammalian cochlea, allowing hearing over an extended frequency range. PMID- 22544736 TI - TGD1, -2, and -3 proteins involved in lipid trafficking form ATP-binding cassette (ABC) transporter with multiple substrate-binding proteins. AB - Members of the ATP-binding cassette (ABC) transporter family are essential proteins in species as diverse as archaea and humans. Their domain architecture has remained relatively fixed across these species, with rare exceptions. Here, we show one exception to be the trigalactosyldiacylglycerol 1, 2, and 3 (TGD1, 2, and -3) putative lipid transporter located at the chloroplast inner envelope membrane. TGD2 was previously shown to be in a complex of >500 kDa. We demonstrate that this complex also contains TGD1 and -3 and is very stable because it cannot be broken down by gentle denaturants to form a "core" complex similar in size to standard ABC transporters. The complex was purified from Pisum sativum (pea) chloroplast envelopes by native gel electrophoresis and examined by mass spectrometry. Identified proteins besides TGD1, -2, or -3 included a potassium efflux antiporter and a TIM17/22/23 family protein, but these were shown to be in separate high molecular mass complexes. Quantification of the complex components explained the size of the complex because 8-12 copies of the substrate-binding protein (TGD2) were found per functional transporter. PMID- 22544737 TI - The dormancy regulator DosR controls ribosome stability in hypoxic mycobacteria. AB - It is thought that during latent infection, Mycobacterium tuberculosis bacilli are retained within granulomas in a low-oxygen environment. The dormancy survival (Dos) regulon, regulated by the response regulator DosR, appears to be essential for hypoxic survival in M. tuberculosis, but it is not known how the regulon promotes survival. Here we report that mycobacteria, in contrast to enteric bacteria, do not form higher-order structures (e.g. ribosomal dimers) upon entry into stasis. Instead, ribosomes are stabilized in the associated form (70S). Using a strategy incorporating microfluidic, proteomic, and ribosomal profiling techniques to elucidate the fate of mycobacterial ribosomes during hypoxic stasis, we show that the dormancy regulator DosR is required for optimal ribosome stabilization. We present evidence that the majority of this effect is mediated by the DosR-regulated protein MSMEG_3935 (a S30AE domain protein), which is associated with the ribosome under hypoxic conditions. A Delta3935 mutant phenocopies the DeltadosR mutant during hypoxia, and complementation of DeltadosR with the MSMEG_3935 gene leads to complete recovery of dosR mutant phenotypes during hypoxia. We suggest that this protein is named ribosome-associated factor under hypoxia (RafH) and that it is the major factor responsible for DosR mediated hypoxic survival in mycobacteria. PMID- 22544738 TI - Control of mesenchymal lineage progression by microRNAs targeting skeletal gene regulators Trps1 and Runx2. AB - Multiple microRNAs (miRNAs) that target the osteogenic Runt-related transcription factor 2 (RUNX2) define an interrelated network of miRNAs that control osteoblastogenesis. We addressed whether these miRNAs have functional targets beyond RUNX2 that coregulate skeletal development. Here, we find that seven RUNX2 targeting miRNAs (miR-23a, miR-30c, miR-34c, miR-133a, miR-135a, miR-205, and miR 217) also regulate the chondrogenic GATA transcription factor tricho-rhino phalangeal syndrome I (TRPS1). Although the efficacy of each miRNA to target RUNX2 or TRPS1 differs in osteoblasts and chondrocytes, each effectively blocks maturation of precommitted osteoblasts and chondrocytes. Furthermore, these miRNAs can redirect mesenchymal stem cells into adipogenic cell fate with concomitant up-regulation of key lineage-specific transcription factors. Thus, a program of multiple miRNAs controls mesenchymal lineage progression by selectively blocking differentiation of osteoblasts and chondrocytes to control skeletal development. PMID- 22544739 TI - Crystal structure of DnaK protein complexed with nucleotide exchange factor GrpE in DnaK chaperone system: insight into intermolecular communication. AB - The conserved, ATP-dependent bacterial DnaK chaperones process client substrates with the aid of the co-chaperones DnaJ and GrpE. However, in the absence of structural information, how these proteins communicate with each other cannot be fully delineated. For the study reported here, we solved the crystal structure of a full-length Geobacillus kaustophilus HTA426 GrpE homodimer in complex with a nearly full-length G. kaustophilus HTA426 DnaK that contains the interdomain linker (acting as a pseudo-substrate), and the N-terminal nucleotide-binding and C-terminal substrate-binding domains at 4.1-A resolution. Each complex contains two DnaKs and two GrpEs, which is a stoichiometry that has not been found before. The long N-terminal GrpE alpha-helices stabilize the linker of DnaK in the complex. Furthermore, interactions between the DnaK substrate-binding domain and the N-terminal disordered region of GrpE may accelerate substrate release from DnaK. These findings provide molecular mechanisms for substrate binding, processing, and release during the Hsp70 chaperone cycle. PMID- 22544740 TI - Constitutive cholesterol-dependent endocytosis of melanocortin-4 receptor (MC4R) is essential to maintain receptor responsiveness to alpha-melanocyte-stimulating hormone (alpha-MSH). AB - Melanocortin-4 receptor (MC4R) is a G-protein-coupled receptor expressed in the hypothalamus where it controls feeding behavior. MC4R cycles constitutively and is internalized at the same rate in the presence or absence of stimulation by the agonist, melanocyte-stimulating hormone (alpha-MSH). This is different from other G-protein-coupled receptors, such as beta(2)-adrenergic receptor (beta(2)AR), which internalizes more rapidly in response to agonist stimulation. Here, it is found that in immortalized neuronal Neuro2A cells expressing exogenous receptors, constitutive endocytosis of MC4R and agonist-dependent internalization of beta(2)AR were equally sensitive to clathrin depletion. Inhibition of MC4R endocytosis by clathrin depletion decreased the number of receptors at the cell surface that were responsive to the agonist, alpha-MSH, by 75%. Mild membrane cholesterol depletion also inhibited constitutive endocytosis of MC4R by ~5-fold, while not affecting recycling of MC4R or agonist-dependent internalization of beta(2)AR. Reduced cholesterol did not change the MC4R dose-response curve to alpha-MSH, but it decreased the amount of cAMP generated per receptor number indicating that a population of MC4R at the cell surface becomes nonfunctional. The loss of MC4R function increased over time (25-50%) and was partially reversed by mutations at putative phosphorylation sites (T312A and S329A). This was reproduced in hypothalamic GT1-7 cells expressing endogenous MC4R. The data indicate that constitutive endocytosis of MC4R is clathrin- and cholesterol dependent. MC4R endocytosis is required to maintain MC4R responsiveness to alpha MSH by constantly eliminating from the plasma membrane a pool of receptors modified at Thr-312 and Ser-329 that have to be cycled to the endosomal compartment to regain function. PMID- 22544741 TI - ADAM15 protein amplifies focal adhesion kinase phosphorylation under genotoxic stress conditions. AB - ADAM15, a disintegrin and metalloproteinase, is capable of counteracting genotoxic stress-induced apoptosis by the suppression of caspase-3 activation. A cell line expressing the membrane-bound ADAM15 without its cytoplasmic tail, however, lost this anti-apoptotic property, suggesting a crucial role of the intracellular domain as a scaffold for recruitment of survival signal-transducing kinases. Accordingly, an enhanced phosphorylation of FAK at Tyr-397, Tyr-576, and Tyr-861 was detected upon genotoxic stress by camptothecin in ADAM15-transfected T/C28a4 cells, but not in transfectants expressing an ADAM15 mutant without the cytoplasmic tail. Accordingly, a specific binding of the cytoplasmic ADAM15 domain to the C terminus of FAK could be shown by mammalian two-hybrid, pulldown, and far Western studies. In cells expressing full-length ADAM15, a concomitant activation of Src at Tyr-416 was detected upon camptothecin exposure. Cells transfected with a chimeric construct consisting of the extracellular IL-2 receptor alpha-chain and the cytoplasmic ADAM15 domain were IL-2-stimulated to prove that the ADAM15 tail can transduce a percepted extracellular signal to enhance FAK and Src phosphorylation. Our studies further demonstrate Src binding to FAK but not a direct Src interaction with ADAM15, suggesting FAK as a critical intracellular adaptor for ADAM15-dependent enhancement of FAK/Src activation. Moreover, the apoptosis induction elicited by specific inhibitors (PP2, FAK 14 inhibitor) of FAK/Src signaling was significantly reduced by ADAM15 expression. The newly uncovered counter-regulatory response to genotoxic stress in a chondrocytic survival pathway is potentially also relevant to apoptosis resistance in neoplastic growth. PMID- 22544742 TI - Acquisition of structure-guiding and structure-forming properties during maturation from the pro-silicatein to the silicatein form. AB - Silicateins are the key enzymes involved in the enzymatic polycondensation of the inorganic scaffold of the skeletal elements of the siliceous sponges, the spicules. The gene encoding pro-silicatein is inserted into the pCold TF vector, comprising the gene for the bacterial trigger factor. This hybrid gene is expressed in Escherichia coli and the synthesized fusion protein is purified. The fusion protein is split into the single proteins with thrombin by cleavage of the linker sequence present between the two proteins. At 23 degrees C, the 87 kDa trigger factor-pro-silicatein fusion protein is cleaved to the 51 kDa trigger factor and the 35 kDa pro-silicatein. The cleavage process proceeds and results in the release of the 23 kDa mature silicatein, a process which very likely proceeds by autocatalysis. Almost in parallel with its formation, the mature enzyme precipitates as pure 23 kDa protein. When the precipitate is dissolved in an urea buffer, the solubilized protein displays its full enzymatic activity which is enhanced multi-fold in the presence of the silicatein interactor silintaphin-1 or of poly(ethylene glycol) (PEG). The biosilica product formed increases its compactness if silicatein is supplemented with silintaphin-1 or PEG. The elastic modulus of the silicatein-mediated biosilica product increases in parallel with the addition of silintaphin-1 and/or PEG from 17 MPa (silicatein) via 61 MPa (silicatein:silintaphin-1) to 101 MPa (silicatein:silintaphin-1 and PEG). These data show that the maturation process from the pro-silicatein state to the mature form is the crucial step during which silicatein acquires its structure-guiding and structure-forming properties. PMID- 22544743 TI - Obstructor-A is required for epithelial extracellular matrix dynamics, exoskeleton function, and tubulogenesis. AB - The epidermis and internal tubular organs, such as gut and lungs, are exposed to a hostile environment. They form an extracellular matrix to provide epithelial integrity and to prevent contact with pathogens and toxins. In arthropods, the cuticle protects, shapes, and enables the functioning of organs. During development, cuticle matrix is shielded from premature degradation; however, underlying molecular mechanisms are poorly understood. Previously, we identified the conserved obstructor multigene-family, which encodes chitin-binding proteins. Here we show that Obstructor-A is required for extracellular matrix dynamics in cuticle forming organs. Loss of obstructor-A causes severe defects during cuticle molting, wound protection, tube expansion and larval growth control. We found that Obstructor-A interacts and forms a core complex with the polysaccharide chitin, the cuticle modifier Knickkopf and the chitin deacetylase Serpentine. Knickkopf protects chitin from chitinase-dependent degradation and deacetylase enzymes ensure extracellular matrix maturation. We provide evidence that Obstructor-A is required to control the presence of Knickkopf and Serpentine in the extracellular matrix. We propose a model suggesting that Obstructor-A coordinates the core complex for extracellular matrix protection from premature degradation. This mechanism enables exoskeletal molting, tube expansion, and epithelial integrity. The evolutionary conservation suggests a common role of Obstructor-A and homologs in coordinating extracellular matrix protection in epithelial tissues of chitinous invertebrates. PMID- 22544744 TI - CtIP protein dimerization is critical for its recruitment to chromosomal DNA double-stranded breaks. AB - CtIP (CtBP-interacting protein) associates with BRCA1 and the Mre11-Rad50-Nbs1 (MRN) complex and plays an essential role in homologous recombination (HR) mediated DNA double-stranded break (DSB) repair. It has been described that CtIP forms dimers in mammalian cells, but the biological significance is not clear. In this study, we identified a conserved motif in the N terminus of CtIP, which is required for dimer formation. We further showed that CtIP mutants impaired in forming dimers are strongly defective in HR, end resection, and activation of the ataxia telangiectasia and Rad3-related pathway, without notable change of CtIP interactions with BRCA1 or Nbs1. In addition to HR, CtIP dimerization is also required for microhomology-mediated end joining. Live cell imaging of enhanced GFP-tagged CtIP demonstrates that the CtIP dimerization mutant fails to be localized to DSBs, whereas placing a heterologous dimerization motif to the dimerization mutant restores CtIP recruitment to DSBs. These studies suggest that CtIP dimer formation is essential for its recruitment to DSBs on chromatin upon DNA damage. Furthermore, DNA damage-induced phosphorylation of CtIP is significantly reduced in the CtIP dimerization mutants. Therefore, in addition to the C-terminal conserved domains critical for CtIP function, the dimerization motif on the N terminus of CtIP is also conserved and essential for its function in DNA damage responses. The severe repair defects of CtIP dimerization mutants are likely due to the failure in localization to chromosomal DSBs upon DNA damage. PMID- 22544745 TI - The MUC1-C oncoprotein binds to the BH3 domain of the pro-apoptotic BAX protein and blocks BAX function. AB - The pro-apoptotic BAX protein contains a BH3 domain that is necessary for its dimerization and for activation of the intrinsic apoptotic pathway. The MUC1 (mucin 1) heterodimeric protein is overexpressed in diverse human carcinomas and blocks apoptosis in the response to stress. In this study, we demonstrate that the oncogenic MUC1-C subunit associates with BAX in human cancer cells. MUC1 C.BAX complexes are detectable in the cytoplasm and mitochondria and are induced by genotoxic and oxidative stress. The association between MUC1-C and BAX is supported by the demonstration that the MUC1-C cytoplasmic domain is sufficient for the interaction with BAX. The results further show that the MUC1-C cytoplasmic domain CQC motif binds directly to the BAX BH3 domain at Cys-62. Consistent with binding to the BAX BH3 domain, MUC1-C blocked BAX dimerization in response to (i) truncated BID in vitro and (ii) treatment of cancer cells with DNA-damaging agents. In concert with these results, MUC1-C attenuated localization of BAX to mitochondria and the release of cytochrome c. These findings indicate that the MUC1-C oncoprotein binds directly to the BAX BH3 domain and thereby blocks BAX function in activating the mitochondrial death pathway. PMID- 22544746 TI - Specific soluble oligomers of amyloid-beta peptide undergo replication and form non-fibrillar aggregates in interfacial environments. AB - Aggregates of amyloid-beta (Abeta) peptides have been implicated in the etiology of Alzheimer disease. Among the different forms of Abeta aggregates, low molecular weight species ranging between ~2- and 50-mers, also called "soluble oligomers," have emerged as the species responsible for early synaptic dysfunction and neuronal loss. Emerging evidence suggests that the neurotoxic oligomers need not be formed along the obligatory nucleation-dependant fibril formation pathway. In our earlier work, we reported the isolation of one such "off-pathway" 12-18-mer species of Abeta42 generated from fatty acids called large fatty acid-derived oligomers (LFAOs) (Kumar, A., Bullard, R. L., Patel, P., Paslay, L. C., Singh, D., Bienkiewicz, E. A., Morgan, S. E., and Rangachari, V. (2011) PLoS One 6, e18759). Here, we report the physiochemical aspects of LFAO monomer interactions as well as LFAO-LFAO associations in the presence of interfaces. We discovered that LFAOs are a replicating strain of oligomers that recruit Abeta42 monomers and quantitatively convert them into LFAO assemblies at the expense of fibrils, a mechanism similar to prion propagation. We also found that in the presence of hexane-buffer or chloroform-buffer interfaces LFAOs are able to associate with themselves to form larger but non-fibrillar aggregates. These results further support the hypothesis that low molecular weight oligomers can be generated via non-fibril formation pathways. Furthermore, the unique replicating property of off-pathway oligomers may hold profound significance for Alzheimer disease pathology. PMID- 22544748 TI - Depletion of p31comet protein promotes sensitivity to antimitotic drugs. AB - Antimitotic spindle poisons are among the most important chemotherapeutic agents available. However, precocious mitotic exit by mitotic slippage limits the cytotoxicity of spindle poisons. The MAD2-binding protein p31(comet) is implicated in silencing the spindle assembly checkpoint after all kinetochores are attached to spindles. In this study, we report that the levels of p31(comet) and MAD2 in different cell lines are closely linked with susceptibility to mitotic slippage. Down-regulation of p31(comet) increased the sensitivity of multiple cancer cell lines to spindle poisons, including nocodazole, vincristine, and Taxol. In the absence of p31(comet), lower concentrations of spindle poisons were required to induce mitotic block. The delay in checkpoint silencing was induced by an accumulation of mitotic checkpoint complexes. The increase in the duration of mitotic block after p31(comet) depletion resulted in a dramatic increase in mitotic cell death upon challenge with spindle poisons. Significantly, cells that are normally prone to mitotic slippage and resistant to spindle disruption-mediated mitotic death were also sensitized after p31(comet) depletion. These results highlight the importance of p31(comet) in checkpoint silencing and its potential as a target for antimitotic therapies. PMID- 22544747 TI - Taurine inhibits K+-Cl- cotransporter KCC2 to regulate embryonic Cl- homeostasis via with-no-lysine (WNK) protein kinase signaling pathway. AB - GABA inhibits mature neurons and conversely excites immature neurons due to lower K(+)-Cl(-) cotransporter 2 (KCC2) expression. We observed that ectopically expressed KCC2 in embryonic cerebral cortices was not active; however, KCC2 functioned in newborns. In vitro studies revealed that taurine increased KCC2 inactivation in a phosphorylation-dependent manner. When Thr-906 and Thr-1007 residues in KCC2 were substituted with Ala (KCC2T906A/T1007A), KCC2 activity was facilitated, and the inhibitory effect of taurine was not observed. Exogenous taurine activated the with-no-lysine protein kinase 1 (WNK1) and downstream STE20/SPS1-related proline/alanine-rich kinase (SPAK)/oxidative stress response 1 (OSR1), and overexpression of active WNK1 resulted in KCC2 inhibition in the absence of taurine. Phosphorylation of SPAK was consistently higher in embryonic brains compared with that of neonatal brains and down-regulated by a taurine transporter inhibitor in vivo. Furthermore, cerebral radial migration was perturbed by a taurine-insensitive form of KCC2, KCC2T906A/T1007A, which may be regulated by WNK-SPAK/OSR1 signaling. Thus, taurine and WNK-SPAK/OSR1 signaling may contribute to embryonic neuronal Cl(-) homeostasis, which is required for normal brain development. PMID- 22544749 TI - Striatal-enriched protein-tyrosine phosphatase (STEP) regulates Pyk2 kinase activity. AB - Proline-rich tyrosine kinase 2 (Pyk2) is a member of the focal adhesion kinase family and is highly expressed in brain and hematopoietic cells. Pyk2 plays diverse functions in cells, including the regulation of cell adhesion, migration, and cytoskeletal reorganization. In the brain, it is involved in the induction of long term potentiation through regulation of N-methyl-d-aspartate receptor trafficking. This occurs through the phosphorylation and activation of Src family tyrosine kinase members, such as Fyn, that phosphorylate GluN2B at Tyr(1472). Phosphorylation at this site leads to exocytosis of GluN1-GluN2B receptors to synaptic membranes. Pyk2 activity is modulated by phosphorylation at several critical tyrosine sites, including Tyr(402). In this study, we report that Pyk2 is a substrate of striatal-enriched protein-tyrosine phosphatase (STEP). STEP binds to and dephosphorylates Pyk2 at Tyr(402). STEP KO mice showed enhanced phosphorylation of Pyk2 at Tyr(402) and of the Pyk2 substrates paxillin and ASAP1. Functional studies indicated that STEP opposes Pyk2 activation after KCl depolarization of cortical slices and blocks Pyk2 translocation to postsynaptic densities, a key step required for Pyk2 activation and function. This is the first study to identify Pyk2 as a substrate for STEP. PMID- 22544750 TI - Mitochondrial DNA variant for complex I reveals a role in diabetic cardiac remodeling. AB - Myocardial remodeling and dysfunction are serious complications of type 2 diabetes mellitus (T2DM). Factors controlling their development are not well established. To specifically address the role of the mitochondrial genome, we developed novel conplastic rat strains, i.e. strains with the same nuclear genome but a different mitochondrial genome. The new animals were named T2DN(mtFHH) and T2DN(mtWistar), where the acronym T2DN denotes their common nuclear genome (type 2 diabetic nephropathy (T2DN) rats) and mtFHH or mtWistar the origin of their mitochondria, Fawn Hooded Hypertensive (FHH) or Wistar rats, respectively. The T2DN(mtFHH) and T2DN(mtWistar) showed a similar progression of diabetes as determined by HbA1c, cholesterol, and triglycerides with normal blood pressure, thus enabling investigation of the specific role of the mitochondrial genome in cardiac function without the confounding effects of obesity or hypertension found in other models of diabetes. Echocardiographic analysis of 12-week-old animals showed no abnormalities, but at 12 months of age the T2DN(mtFHH) showed left ventricular remodeling that was verified by histology. Decreased complex I and complex IV but not complex II activity within the electron transport chain was found only in T2DN(mtFHH), which was not explained by differences in protein content. Decreased cardiac ATP levels in T2DN(mtFHH) were in agreement with a lower ATP synthetic capacity by isolated mitochondria. Together, our data provide experimental evidence that mtDNA sequence variations have an additional role in energetic heart deficiency. The mitochondrial DNA background may explain the increased susceptibility of certain T2DM patients to develop myocardial dysfunction. PMID- 22544751 TI - Membrane-deforming proteins play distinct roles in actin pedestal biogenesis by enterohemorrhagic Escherichia coli. AB - Many bacterial pathogens reorganize the host actin cytoskeleton during the course of infection, including enterohemorrhagic Escherichia coli (EHEC), which utilizes the effector protein EspF(U) to assemble actin filaments within plasma membrane protrusions called pedestals. EspF(U) activates N-WASP, a host actin nucleation promoting factor that is normally auto-inhibited and found in a complex with the actin-binding protein WIP. Under native conditions, this N-WASP/WIP complex is activated by the small GTPase Cdc42 in concert with several different SH3 (Src homology-3) domain-containing proteins. In the current study, we tested whether SH3 domains from the F-BAR (FCH-Bin-Amphiphysin-Rvs) subfamily of membrane deforming proteins are involved in actin pedestal formation. We found that three F-BAR proteins: CIP4, FBP17, and TOCA1 (transducer of Cdc42-dependent actin assembly), play different roles during actin pedestal biogenesis. Whereas CIP4 and FBP17 inhibited actin pedestal assembly, TOCA1 stimulated this process. TOCA1 was recruited to pedestals by its SH3 domain, which bound directly to proline rich sequences within EspF(U). Moreover, EspF(U) and TOCA1 activated the N WASP/WIP complex in an additive fashion in vitro, suggesting that TOCA1 can augment actin assembly within pedestals. These results reveal that EspF(U) acts as a scaffold to recruit multiple actin assembly factors whose functions are normally regulated by Cdc42. PMID- 22544752 TI - Molecular mechanism of telokin-mediated disinhibition of myosin light chain phosphatase and cAMP/cGMP-induced relaxation of gastrointestinal smooth muscle. AB - Phospho-telokin is a target of elevated cyclic nucleotide concentrations that lead to relaxation of gastrointestinal and some vascular smooth muscles (SM). Here, we demonstrate that in telokin-null SM, both Ca(2+)-activated contraction and Ca(2+) sensitization of force induced by a GST-MYPT1(654-880) fragment inhibiting myosin light chain phosphatase were antagonized by the addition of recombinant S13D telokin, without changing the inhibitory phosphorylation status of endogenous MYPT1 (the regulatory subunit of myosin light chain phosphatase) at Thr-696/Thr-853 or activity of Rho kinase. Cyclic nucleotide-induced relaxation of force in telokin-null ileum muscle was reduced but not correlated with a change in MYPT1 phosphorylation. The 40% inhibited activity of phosphorylated MYPT1 in telokin-null ileum homogenates was restored to nonphosphorylated MYPT1 levels by addition of S13D telokin. Using the GST-MYPT1 fragment as a ligand and SM homogenates from WT and telokin KO mice as a source of endogenous proteins, we found that only in the presence of endogenous telokin, thiophospho-GST-MYPT1 co precipitated with phospho-20-kDa myosin regulatory light chain 20 and PP1. Surface plasmon resonance studies showed that S13D telokin bound to full-length phospho-MYPT1. Results of a protein ligation assay also supported interaction of endogenous phosphorylated MYPT1 with telokin in SM cells. We conclude that the mechanism of action of phospho-telokin is not through modulation of the MYPT1 phosphorylation status but rather it contributes to cyclic nucleotide-induced relaxation of SM by interacting with and activating the inhibited full-length phospho-MYPT1/PP1 through facilitating its binding to phosphomyosin and thus accelerating 20-kDa myosin regulatory light chain dephosphorylation. PMID- 22544753 TI - Ubiquitin-specific peptidase 9, X-linked (USP9X) modulates activity of mammalian target of rapamycin (mTOR). AB - The mammalian target of rapamycin (mTOR) is an atypical serine/threonine kinase that responds to extracellular environment to regulate a number of cellular processes. These include cell growth, proliferation, and differentiation. Although both kinase-dependent and -independent functions of mTOR are known to be critical modulators of muscle cell differentiation and regeneration, the signaling mechanisms regulating mTOR activity during differentiation are still unclear. In this study we identify a novel mTOR interacting protein, the ubiquitin-specific protease USP9X, which acts as a negative regulator of mTOR activity and muscle differentiation. USP9X can co-immunoprecipitate mTOR with both Raptor and Rictor, components of mTOR complexes 1 and 2 (mTORC1 and -2), respectively, suggesting that it is present in both mTOR complexes. Knockdown of USP9X leads to increased mTORC1 activity in response to growth factor stimulation. Interestingly, upon initiation of differentiation of C2C12 mouse skeletal myoblasts, knockdown of USP9X increases mTORC2 activity. This increase in mTORC2 activity is accompanied by accelerated differentiation of myoblasts into myotubes. Taken together, our data describe the identification of the deubiquitinase USP9X as a novel mTORC1 and -2 binding partner that negatively regulates mTOR activity and skeletal muscle differentiation. PMID- 22544754 TI - Phosphorylation of CpgA protein enhances both its GTPase activity and its affinity for ribosome and is crucial for Bacillus subtilis growth and morphology. AB - In Bacillus subtilis, the ribosome-associated GTPase CpgA is crucial for growth and proper morphology and was shown to be phosphorylated in vitro by the Ser/Thr protein kinase PrkC. To further understand the function of the Escherichia coli RsgA ortholog, CpgA, we first demonstrated that its GTPase activity is stimulated by its association with the 30 S ribosomal subunit. Then the role of CpgA phosphorylation was analyzed. A single phosphorylated residue, threonine 166, was identified by mass spectrometry. Phosphoablative replacement of this residue in CpgA induces a decrease of both its affinity for the 30 S ribosomal subunit and its GTPase activity, whereas a phosphomimetic replacement has opposite effects. Furthermore, cells expressing a nonphosphorylatable CpgA protein present the morphological and growth defects similar to those of a cpgA-deleted strain. Altogether, our results suggest that CpgA phosphorylation on Thr-166 could modulate its ribosome-induced GTPase activity. Given the role of PrkC in B. subtilis spore germination, we propose that CpgA phosphorylation is a key regulatory process that is essential for B. subtilis development. PMID- 22544755 TI - Partitioning-defective protein 6 (Par-6) activates atypical protein kinase C (aPKC) by pseudosubstrate displacement. AB - Atypical protein kinase C (aPKC) controls cell polarity by modulating substrate cortical localization. Aberrant aPKC activity disrupts polarity, yet the mechanisms that control aPKC remain poorly understood. We used a reconstituted system with purified components and a cultured cell cortical displacement assay to investigate aPKC regulation. We find that aPKC is autoinhibited by two domains within its NH(2)-terminal regulatory half, a pseudosubstrate motif that occupies the kinase active site, and a C1 domain that assists in this process. The Par complex member Par-6, previously thought to inhibit aPKC, is a potent activator of aPKC in our assays. Par-6 and aPKC interact via PB1 domain heterodimerization, and this interaction activates aPKC by displacing the pseudosubstrate, although full activity requires the Par-6 CRIB-PDZ domains. We propose that, along with its previously described roles in controlling aPKC localization, Par-6 allosterically activates aPKC to allow for high spatial and temporal control of substrate phosphorylation and polarization. PMID- 22544756 TI - PDK1 protein phosphorylation at Thr354 by murine protein serine-threonine kinase 38 contributes to negative regulation of PDK1 protein activity. AB - Murine protein serine-threonine kinase 38 (MPK38) is a member of the AMP activated protein kinase-related serine/threonine kinase family, which acts as cellular energy sensors. In this study, MPK38-induced PDK1 phosphorylation was examined to elucidate the biochemical mechanisms underlying phosphorylation dependent regulation of 3-phosphoinositide-dependent protein kinase-1 (PDK1) activity. The results showed that MPK38 interacted with and inhibited PDK1 activity via Thr(354) phosphorylation. MPK38-PDK1 complex formation was mediated by the amino-terminal catalytic kinase domain of MPK38 and the pleckstrin homology domain of PDK1. This activity was dependent on insulin, a PI3K/PDK1 stimulator, as well as various apoptotic stimuli, including TNF-alpha, H(2)O(2), thapsigargin, and ionomycin. MPK38 inhibited PDK1 activity in a kinase-dependent manner and alleviated PDK1-mediated suppression of TGF-beta (or ASK1) signaling, probably via the phosphorylation of PDK1 at Thr(354). In addition, MPK38-mediated inhibition of PDK1 activity was accompanied by the modulation of PDK1 binding to its positive and negative regulators, serine/threonine kinase receptor-associated protein and 14-3-3, respectively. Together, these findings suggest an important role for MPK38-mediated phosphorylation of PDK1 in the negative regulation of PDK1 activity. PMID- 22544757 TI - A novel acetylation cycle of transcription co-activator Yes-associated protein that is downstream of Hippo pathway is triggered in response to SN2 alkylating agents. AB - Yes-associated protein (YAP) is a transcriptional co-activator that acts downstream of the Hippo signaling pathway and regulates multiple cellular processes. Although cytoplasmic retention of YAP is known to be mediated by Hippo pathway-dependent phosphorylation, post-translational modifications that regulate YAP in the nucleus remain unclear. Here we report the discovery of a novel cycle of acetylation/deacetylation of nuclear YAP induced in response to S(N)2 alkylating agents. We show that after treatment of cells with the S(N)2 alkylating agent methyl methanesulfonate, YAP phosphorylation mediated by the Hippo pathway is markedly reduced, leading to nuclear translocation of YAP and its acetylation. This YAP acetylation occurs on specific and highly conserved C terminal lysine residues and is mediated by the nuclear acetyltransferases CBP (CREB binding protein) and p300. Conversely, the nuclear deacetylase SIRT1 is responsible for YAP deacetylation. Intriguingly, we found that YAP acetylation is induced specifically by S(N)2 alkylating agents and not by other DNA-damaging stimuli. These results identify a novel YAP acetylation cycle that occurs in the nucleus downstream of the Hippo pathway. Intriguingly, our findings also indicate that YAP acetylation is involved in responses to a specific type of DNA damage. PMID- 22544758 TI - Optimized inversion-prepared gradient echo imaging. AB - PURPOSE: To implement a method using an extended phase graph (EPG)-based simulation to optimize inversion-prepared gradient echo sequences with respect to signal and contrast within the shortest acquisition time. MATERIALS AND METHODS: A critical issue in rapid gradient-echo imaging is the effect of residual transverse magnetization between consecutive data acquisition windows. Various spoiling schemes have been proposed to mitigate this problem, and while spoiling is often considered to be perfect, imaging can be more truthfully described using the EPG. An EPG-based simulation is used to analyze and predict the image signal and contrast to serve as a basis for sequence optimization. RESULTS: Fourteen biological phantom experiments and five brain imaging experiments on each of five healthy volunteers was performed to validate and verify the accuracy of the EPG based simulation. In addition, two experiments on an in-cranial cadaver brain were performed to show the ability of the proposed method for improving overall image quality. CONCLUSION: From the experiment results, it is demonstrated that optimization of 3D magnetization-prepared rapid gradient-echo imaging sequences can be performed with an EPG-based simulation to manipulate the sequence parameters for generating images with highly specific signal and contrast characteristics for quantitative T1-weighted human brain imaging. PMID- 22544760 TI - Single-molecule FRET reveals the folding dynamics of the human telomerase RNA pseudoknot domain. PMID- 22544759 TI - CD11b(+) Gr1(+) bone marrow cells ameliorate liver fibrosis by producing interleukin-10 in mice. AB - Clinical trials and animal models suggest that infusion of bone marrow cells (BMCs) is effective therapy for liver fibrosis, but the underlying mechanisms are obscure, especially those associated with early effects of BMCs. Here, we analyzed the early impact of BMC infusion and identified the subsets of BMCs showing antifibrotic effects in mice with carbon tetrachloride-induced liver fibrosis. An interaction between BMCs and activated hepatic stellate cells (HSCs) was investigated using an in vitro coculturing system. Within 24 hours, infused BMCs were in close contact with activated HSCs, which was associated with reduced liver fibrosis, enhanced hepatic expression of interleukin (IL)-10, and expanded regulatory T cells but decreased macrophage infiltration in the liver at 24 hours after BMC infusion. In contrast, IL-10-deficient (IL-10(-/-) ) BMCs failed to reproduce these effects in fibrotic livers. Intriguingly, in isolated cells, CD11b(+) Gr1(high) F4/80(-) and CD11b(+) Gr1(+) F4/80(+) BMCs expressed more IL 10 after coculturing with activated HSCs, leading to suppressed expression of collagen and alpha-smooth muscle actin in HSCs. Moreover, these effects were either enhanced or abrogated, respectively, when BMCs were cocultured with IL-6( /-) and retinaldehyde dehydrogenase 1(-/-) HSCs. Similar to murine data, human BMCs expressed more IL-10 after coculturing with human HSC lines (LX-2 or hTERT), and serum IL-10 levels were significantly elevated in patients with liver cirrhosis after autologous BMC infusion. CONCLUSION: Activated HSCs increase IL 10 expression in BMCs (CD11b(+) Gr1(high) F4/80(-) and CD11b(+) Gr1(+) F4/80(+) cells), which in turn ameliorates liver fibrosis. Our findings could enhance the design of BMC therapy for liver fibrosis. PMID- 22544761 TI - Serum insulin-like, growth factor binding protein-related protein 1 (IGFBP-rP1) and endometrial cancer risk in Chinese women. AB - Hyperinsulinemia and the metabolic syndrome confer increased risks of endometrial carcinoma. The roles of insulin, and, insulin-like growth factor-binding proteins (IGFBPs) in the etiology of endometrial carcinoma, remain unclear. We recruited 206 patients with endometrial carcinoma and 350 healthy women to a case-control study of fasting insulin and IGFBP-related protein 1 (IGFBP-rP1) in a Chinese tertiary centre. Patients with endometrial carcinoma had higher insulin concentrations (14.8 +/- 16.7 vs. 8.1 +/- 9.4 MUU/mL; p < 0.001) and lower IGFBP rP1 levels (17.5 +/- 17.2 vs. 22.4 +/- 22.8 MUg/L; p = 0.018) than controls. High insulin and IGFBP-rP1 levels were both positively and negatively associated with endometrial cancer (odds ratio for the highest tertile versus the lowest tertile: insulin: 4.11; 95% CI = 2.61-6.47; IGFBP-rP1: 0.38; 95% CI = 0.24-0.60). Logistic regression analysis confirmed the associations between endometrial carcinoma and fasting insulin or IGFBP-rP1 after adjustments for age, BMI, serum glucose, cholesterol, triglycerides and high-density lipoprotein cholesterol (odds ratio for the highest tertile versus the lowest tertile: insulin: 2.13; 95% CI = 1.30 3.49; IGFBP-rP1: 0.57; 95% CI = 0.34-0.94). Hyperinsulinemia and high IGFBP-rP1 levels confer altered risks for endometrial carcinoma. PMID- 22544762 TI - Modulation of physiological and pathological activities of lysozyme by biological membranes. AB - The molecular details of interactions between lipid membranes and lysozyme (Lz), a small polycationic protein with a wide range of biological activities, have long been the focus of numerous studies. The biological consequences of this process are considered to embrace at least two aspects: i) correlation between antimicrobial and membranotropic properties of this protein, and ii) lipid mediated Lz amyloidogenesis. The mechanisms underlying the lipid-assisted protein fibrillogenesis and membrane disruption exerted by Lz in bacterial cells are believed to be similar. The present investigation was undertaken to gain further insight into Lz-lipid interactions and explore the routes by which Lz exerts its antimicrobial and amyloidogenic actions. Binding and Forster resonance energy transfer studies revealed that upon increasing the content of anionic lipids in lipid vesicles, Lz forms aggregates in a membrane environment. Total internal reflection fluorescence microscopy and pyrene excimerization reaction were employed to study the effect of Lz on the structural and dynamic properties of lipid bilayers. It was found that Lz induces lipid demixing and reduction of bilayer free volume, the magnitude of this effect being much more pronounced for oligomeric protein. PMID- 22544763 TI - Human adipose-derived stem cells for the treatment of intracerebral hemorrhage in rats via femoral intravenous injection. AB - Human adipose-derived stem cells (huADSC) were generated from fat tissue of a 65 year-old male donor. Flow cytometry and reverse transcription polymerase chain reaction (RT-PCR) analyses indicated that the huADSC express neural cell proteins (MAP2, GFAP, nestin and beta-III tubulin), neurotrophic growth factors (BDNF and GDNF), and the chemotactic factor CXCR4 and its corresponding ligand CXCL12. In addition, huADSC expressed the characteristic mesenchymal stem cell (MSC) markers CD29, CD44, CD73, CD90, CD105 and HLA class I. The huADSC were employed, via a right femoral vein injection, to treat rats inflicted with experimental intracerebral hemorrhage (ICH). Behavioral measurement on the experimental animals, seven days after the huADSC therapy, showed a significant functional improvement in the rats with stem cell therapy in comparison with rats of the control group without the stem cell therapy. The injected huADSC were detectable in the brains of the huADSC treated rats as determined by histochemistry analysis, suggesting a role of the infused huADSC in facilitating functional recovery of the experimental animals with ICH induced stroke. PMID- 22544765 TI - Full visible range covering InP/ZnS nanocrystals with high photometric performance and their application to white quantum dot light-emitting diodes. PMID- 22544764 TI - West Nile virus transmission through organ transplantation in north-eastern Italy: a case report and implications for pre-procurement screening. AB - PURPOSE: West Nile virus (WNV) transmission through organ transplantation occurs rarely and screening of organ donors for WNV infection remains controversial. This report describes the case of WNV encephalitis in a kidney recipient and the case of asymptomatic WNV infection in the organ donor, both observed at Treviso Hospital, northeastern Italy. After briefly reviewing the literature, we discuss the implications for WNV screening. METHODS: We reviewed medical, laboratory and epidemiological records at our hospital, and the literature concerning cases of organ-transmitted WNV infections and WNV screening of organ donors in Italy and worldwide. RESULTS: The kidney recipient was the first confirmed case of WNV infection notified in northeastern Italy in 2011, and the first case of WNV infection in a cluster of four transplant recipients who acquired the infection from a common organ donor. The organ donor, whose WNV infection was only retrospectively diagnosed by IgM detection, represents the index case of a WNV outbreak in the Treviso Province. Screening of her blood prior to organ recovery did not show detectable levels of WNV nucleic acid with the use of quantitative real-time polymerase chain reaction. CONCLUSIONS: This report emphasizes that transplant-acquired WNV neuroinvasive disease can be particularly severe. We suggest that pre-procurement screening of organ donors by testing blood with both WNV IgM capture ELISA and a sensitive nucleic acid testing should be adopted during the transmission season in the present Italian epidemiological setting. PMID- 22544766 TI - Rotamer libraries and probabilities of transition between rotamers for the side chains in protein-protein binding. AB - Conformational changes in the side chains are essential for protein-protein binding. Rotameric states and unbound- to-bound conformational changes in the surface residues were systematically studied on a representative set of protein complexes. The side-chain conformations were mapped onto dihedral angles space. The variable threshold algorithm was developed to cluster the dihedral angle distributions and to derive rotamers, defined as the most probable conformation in a cluster. Six rotamer libraries were generated: full surface, surface noninterface, and surface interface-each for bound and unbound states. The libraries were used to calculate the probabilities of the rotamer transitions upon binding. The stability of amino acids was quantified based on the transition maps. The noninterface residues' stability was higher than that of the interface. Long side chains with three or four dihedral angles were less stable than the shorter ones. The transitions between the rotamers at the interface occurred more frequently than on the noninterface surface. Most side chains changed conformation within the same rotamer or moved to an adjacent rotamer. The highest percentage of the transitions was observed primarily between the two most occupied rotamers. The probability of the transition between rotamers increased with the decrease of the rotamer stability. The analysis revealed characteristics of the surface side-chain conformational transitions that can be utilized in flexible docking protocols. PMID- 22544767 TI - Effects of copper-loaded chitosan nanoparticles on intestinal microflora and morphology in weaned piglets. AB - The objective of the present study was to investigate the effects of dietary supplementation with copper-loaded chitosan nanoparticles (CNP-Cu) on growth performance, intestinal microflora, and morphology in weaned piglets. A number of 90 weaned piglets (Duroc * Landrace * Yorkshire), weaned at 21 days with body weight of 7.2 +/- 0.81 kg, were randomly divided into three groups by weight and sex, each treatment including three replicates of ten pigs. The piglets were fed the same basal diet supplemented with 0 (the control group), 100 mg/kg CNP-Cu, and 100 mg/kg chlortetracycline (the positive group). The results showed that 100 mg/kg CNP-Cu significantly increased average daily gain and feed intake and decreased feed/gain ratio and diarrhea rate (P < 0.05). Compared with the control group, the amount of Escherichia coli in duodenum, jejunal, and caecum were significantly decreased by 100 mg/kg CNP-Cu; the number of lactobacillus in jejunal and caecum were increased (P < 0.05), and the amount of bifidobacterium in duodenum and caecum were also increased (P < 0.05). Moreover, the villous height of duodenum, jejunum, and ileum mucosa was significantly increased (P < 0.05), and the crypt depth was significantly decreased (P < 0.05). The results indicated that CNP-Cu is beneficial to growth and intestinal microflora and morphology and could be a potential substitution of chlortetracycline in diets of weaned piglets. PMID- 22544768 TI - High light intensity augments mercury toxicity in cyanobacterium Nostoc muscorum. AB - The present study is aimed at investigating the role of growth irradiance in determining the extent of mercury (Hg) toxicity on various physiological parameters viz. growth, pigment contents, photosynthesis, respiration, (14)CO(2) fixation, photosynthetic electron transport, photorespiration and enzyme activity of cyanobacterium Nostoc muscorum. A general decline was observed in all these parameters with increasing concentration of Hg except for carotenoids content and respiratory activity which exhibited significant enhancement. This effect was more pronounced in high light (130 MUmol photon m(-2) s(-1)) exposed cells as compared to normal (70 MUmol photon m(-2) s(-1)) and low (10 MUmol photon m(-2) s(-1)) light exposed cells. Among the photosynthetic electron transport activities, whole chain was found to be more sensitive than photosystem II (PSII) and photosystem I (PSI). (14)CO(2) fixation was more affected as compared to O(2) evolution when exposed to Hg and different light intensities. Photorespiratory activity, which is an index of protecting organisms from light-induced damage, also showed a similar declining trend. Enzyme assay revealed that among the carboxylating enzymes, activity of RUBISCO was more severely inhibited than PEPCase. Thus, these results suggest that Hg itself was toxic at all tested concentrations and high light intensity augmented its toxicity in N. muscorum inhibiting the growth, pigment contents and photosynthetic activity of the organism. PMID- 22544769 TI - Characterization of hemangioblast in umbilical arteries of mid-gestation mouse embryos. AB - Hemangioblasts are the common precursors of hematopoietic and vascular cells, and are characterized as blast colony-forming cells (BL-CFCs) in vitro. We previously identified BL-CFCs in the mouse aorta-gonads-mesonephros (AGM) region, but not yolk sac, placenta, circulation, or fetal liver. Here, we aim to determine whether BL-CFCs develop in the umbilical arteries (UA) that link the dorsal aorta (sub-region of AGM) and placenta. We find that the UA cells of E11.5 mouse embryos were capable of generating typical blast colonies. On replating, these colonies produced erythroid/myeloid progenitors and B220(+) B lymphocytes in vitro, corroborating their definitive hematopoietic nature. They also generated CD31(+) or endomucin(+) tube-like structures on OP9 stromal cells, showing their endothelial potential. The proximal and distal regions of UA had equal numbers of BL-CFCs. To evaluate whether BL-CFCs can be autonomously maintained or expanded in UA or AGM, in vitro organ culture was performed. Interestingly, the BL-CFC pool in the AGM was significantly amplified, in striking contrast to a decrease in the UA. Taken together, our findings indicate that in addition to the AGM the UA serves as an important, but less supportive, niche for hemangioblast development. PMID- 22544770 TI - Hysteresis-free blue phase liquid-crystal-stabilized by ZnS nanoparticles. PMID- 22544771 TI - Editorial. Crisis in nutrition. PMID- 22544772 TI - An essay on agriculture and population pressure. AB - This is an essay highlighting the fundamental importance of agriculture (historical and present) in the agro-socioeconomic evolution of human societies, from the times of the hunter/gatherers to the modern day. Attention is drawn in the text to the importance of deforestation in relation to micro and macro climate changes, and the vital role of carbon dioxide to plant and animal life. The essay also relates the world's natural resources to the present unsustainable population pressures. PMID- 22544773 TI - The role of docosahexaenoic and the marine food web as determinants of evolution and hominid brain development: the challenge for human sustainability. AB - Life originated on this planet about 3 billion years ago. For the first 2.5 billion years of life there was ample opportunity for DNA modification. Yet there is no evidence of significant change in life forms during that time. It was not until about 600 million years ago, when the oxygen tension rose to a point where air-breathing life forms became thermodynamically possible, that a major change can be abruptly seen in the fossil record. The sudden appearance of the 32 phyla in the Cambrian fossil record was also associated with the appearance of intracellular detail not seen in previous life forms. That detail was provided by cell membranes made with lipids (membrane fats) as structural essentials. Lipids thus played a major, as yet unrecognised, role as determinants in evolution. The compartmentalisation of intracellular, specialist functions as in the nucleus, mitochondria, reticulo-endothelial system and plasma membrane led to cellular specialisation and then speciation. Thus, not only oxygen but also the marine lipids were drivers in the Cambrian explosion. Docosahexaenoic acid (DHA) (all cis-docosa-4,7,10,13,16,19-hexaenoic acid, C22:6omega3 or C22:6, n-3, DHA) is a major feature of marine lipids. It requires six oxygen atoms to insert its six double bonds, so it would not have been abundant before oxidative metabolism became plentiful. DHA provided the membrane backbone for the emergence of new photoreceptors that converted photons into electricity, laying the foundation for the evolution of other signalling systems, the nervous system and the brain. Hence, the omega3 DHA from the marine food web must have played a critical role in human evolution. There is also clear evidence from molecular biology that DHA is a determinant of neuronal migration, neurogenesis and the expression of several genes involved in brain growth and function. That same process was essential to the ultimate cerebral expansion in human evolution. There is now incontrovertible support of this hypothesis from fossil evidence of human evolution taking advantage of the marine food web. Lipids are still modifying the present evolutionary phase of our species; their signature is evident in the changing panorama of non-communicable diseases. The most worrying change in disease pattern is the sharp rise in brain disorders, which, in the European Union, has overtaken the cost of all other burdens of ill health at ?386 billion for the 25 member states at 2004 prices. In 2007, the UK cost was estimated at L77 billion and confirmed in 2010 at L105 billion - greater than heart disease and cancer combined. The rise in mental ill health is now being globalised. The solution to the rising vascular disorders in the last century and now brain disorders in this century lies in a radical reappraisal of the food system, which last century was focussed on protein and calories, with little attention paid to the requirements of the brain - the very organ that was the determinant of human evolution. With the marine fish catch having plateaued 20 years ago and its sustainability now under threat, a critical aspect of this revision is the development of marine agriculture from estuarine, coastal and oceanic resources. Such action is likely to play a key role in future health and intelligence. PMID- 22544774 TI - Further evidence that infantile autism is a chronic psychosis distinguished by a deficient delayed response function affecting the connections between hippocampus and singulum in its center, the SMA and the inhibitory Purkinje cells in cerebellum. AB - Older literature on infantile autism accompanied by mental retardation, focussed on epilepsy, cerebral palsy and microcephaly. Multiple adversity was needed to delay growth sufficiently to pruning of connection between Hippocampus and Singulum in its centre, SMA and inhibitory cells in Cerebellum in the synaptogenesis in infancy. Temporary macrocephaly was observed. Today, macrocephaly dominates the discussion. One single adversity, deficient "brain food", seemingly retards growth sufficiently to cause excess pruning with absent activity in inhibitory Purkinje cells in Cerebellum, the SMA and A DEFICIENT, LACKING DELAYED RESPONSE FUNCTION. The brain needs time to adapt, but the Delayed Response Task is lost. Microcephaly predominates at puberty. We wanted to understand cerebellar reactions more fully. PMID- 22544775 TI - Sudanese women's and neonates' vitamin A status. AB - We have determined and compared the concentration levels of retinol and beta carotene in the plasma of three Sudanese women groups (displaced southern Sudanese women (DSSW), non-displaced southern Sudanese (NDSSW) and northern Sudanese women (NSW)), who were either pregnant or non-pregnant; and in their neonates (cord plasma). Plasma samples were analysed by high-performance liquid chromatography using reversed-phase column and diode-array detectors. The results revealed that retinol and beta-carotene in the plasma of non-pregnant and pregnant women in the three groups were very low compared with studies reported elsewhere. Over 50% of pregnant DSSW and NDSSW had a low concentration of retinol plasma (< 0.70 umol/L), and about 15-20% were deficient (< 0.35 umol/L) according to World Health Organization criteria. Although the average retinol concentration in the plasma of pregnant NSW was > 0.70 umol/L, which suggests sufficiency status, 32% showed lower levels and 10% were deficient. Plasma retinol beta carotene levels in the neonates' cords were also lower than their mothers and in comparison with other studies. These findings are in agreement with previous survey data and clinical reports, which also suggest that vitamin A deficiency is of great concern in the country. We concluded that insufficient intake of food of animal origin and repeated malarial and other parasitic diseases are the most likely causes of vitamin A deficiency. PMID- 22544776 TI - Umami flavour as a means of regulating food intake and improving nutrition and health. AB - Diet and lifestyle have an impact on the burden of ill health and non communicable ailments such as cardiovascular disease (including hypertension), obesity, diabetes, cancer and certain mental illnesses. The consequences of malnutrition and critical unbalances in the diet with regard to sugar, salt and fat are becoming increasingly manifest in the Western world and are also gradually influencing the general health condition for populations in developing countries. In this topical mini-review I highlight the lack of deliciousness and umami (savoury) flavour in prepared meals as a possible reason for poor nutritional management and excess intake of salt, fat and sugar. I argue that a better informed use of the current scientific understanding of umami and its dependence of the synergetic relationship between monosodium glutamate and certain 5'-ribonucleotides and their action on the umami taste receptors will not only provide better-tasting and more flavoursome meals but may also help to regulate food intake, in relation to both overeating and nutritional management of elderly and sick individuals. PMID- 22544777 TI - Darwin's passionate environmentalism or the dangerous fallacy of the 'All sufficiency of natural selection' theory. AB - Following his last edition of the Origin of Species in 1872, Darwin spent much of the rest of his life searching for possible mechanisms, such as the pangenes in the blood, which would communicate information from the environment to the genome. In each of his six editions of the 'Origin', he stated that there were two forces in evolution - natural selection and conditions of existence. Of the two, he claims that the latter is the more powerful. In so doing, he recognized that natural selection could only operate within the bounds of possibility, that is the environment. August Weismann claimed that conditions of existence had no place in evolution. His publication, the 'All-sufficiency of natural selection', was based on mutilation (cutting tails of rodents and watching the next generation grow tails), which has nothing to do with Darwin's concept of conditions of existence. Nonetheless, evolutionary biologists in general followed the line of the 'all sufficiency' theory and ignored Darwin's conditions of existence, which in other words means the environment. Natural selection has a weak predictive power as it is based on random events. However, the conditions of existence have, by contrast, strong predictive powers that can be tested. The environmental views of two of the greatest evolutionists, Lamarck and Darwin, have been consistently ignored by most evolution theorists who came after them, continuing for over 200 years. Looking at the fossil record through the eyes of Darwin's conditions of existence, not to mention the recent changes in height and shape over the last century, it is possible to draw important conclusions about the past and predictions of the future. With new knowledge of epigenetics, it is perhaps time that Darwin's conditions of existence were given a second hearing. PMID- 22544778 TI - Occupational activities and osteoarthritis of the knee. AB - BACKGROUND: The prevalence of knee osteoarthritis (OA) is rising and the search for interventions to mitigate risk is intensifying. This review considers the contribution of occupational activities to disease occurrence and the lessons for prevention. SOURCES: Systematic search in Embase and Medline covering the period 1996 to November 2011. AREAS OF AGREEMENT: Reasonably good evidence exists that physical work activities (especially kneeling, squatting, lifting and climbing) can cause and/or aggravate knee OA. These exposures should be reduced where possible. Obese workers with such exposures are at additional risk of knee OA and should therefore particularly be encouraged to lose weight. AREAS OF UNCERTAINTY/RESEARCH NEED: Workplace interventions and policies to prevent knee OA have seldom been evaluated. Moreover, their implementation can be problematic. However, the need for research to optimize the design of work in relation to knee OA is pressing, given population trends towards extended working life. PMID- 22544779 TI - The older worker with osteoarthritis of the knee. AB - BACKGROUND: Changing demographics mean that many patients with large joint arthritis will work beyond traditional retirement age. This review considers the impact of knee osteoarthritis (OA) on work participation and the relation between work and total knee replacement (TKR). SOURCES: Two systematic searches in Embase and Medline, supplemented by three systematic reviews. AREAS OF AGREEMENT: Probably, although evidence is limited, knee OA considerably impairs participation in work (labour force participation, work attendance and work productivity). AREAS OF UNCERTAINTY/RESEARCH NEED: Little is known about effective interventions (treatments, work changes and policies) to improve vocational participation in patients with knee OA; or how type of work affects long-term clinical outcomes (e.g. pain, function and the need for revision surgery) in patients with TKRs. The need for such research is pressing and opportune, as increasing numbers of patients with knee OA or TKR expect to work on. PMID- 22544780 TI - Umbilical cord blood stem cells: clinical trials in non-hematological disorders. AB - BACKGROUND: Umbilical cord blood (UCB) has become the second most common source of stem cells for cell therapy. The recent boom in stem cell research and public fascination with promises of stem cell-based therapies, fueled by the media, have led researchers to explore the potential of UCB stem cells in therapy for non hematological disorders. SOURCES OF DATA: ClinicalTrials.gov database searched with key words 'cord blood stem cells' on December 28, 2011. AREAS OF AGREEMENT: As a rich source of the most primitive hematopoietic stem cells, UCB has a strong regenerative potential in stem cell-based-therapy for hematological disorders. AREAS OF CONTROVERSY: Potential of UCB stem cells in therapy for non hematological disorders. GROWING POINTS: Increasing number of clinical trials with UCB stem cell-based therapy for a variety of diseases. AREAS TIMELY FOR DEVELOPING RESEARCH: A need for standardization of criteria for selection of UCB units for stem cell-based therapy, outcome measures and long-term follow-up. PMID- 22544781 TI - Rhizobium subbaraonis sp. nov., an endolithic bacterium isolated from beach sand. AB - Two strains (JC85(T) and JC108) of Gram-stain-negative, motile bacteria were isolated from endolithic beach sand samples on an oligotrophic medium. Based on the 16S rRNA gene sequence analysis, both strains were identified as belonging to the genus Rhizobium. Strain JC108 had 16S rRNA gene sequence similarity of 100 % with Rhizobium pusense NRCPB10(T) and formed a cluster with this strain. Strain JC85(T) had 96.9 % 16S rRNA gene sequence similarity and was 18 % related (based on DNA-DNA hybridization) to Rhizobium borbori DN316(T). With other strains of the genus Rhizobium, the 16S rRNA gene sequence similarity was less than 96.3 %. Strain JC85(T) could tolerate up to 3 % salinity, fix N(2), was resistant to ampicillin (10 ug) and was positive for catalase and oxidase. The major fatty acid was C(18 : 1)omega7c (69 %) with minor amounts of C(19 : 0) cyclo omega8c (8.9 %), C(16 : 0) (6.9 %), C(12 : 0) (5.7 %) and C(19 : 1)omega7c/C(19 : 1)omega6c (2.2 %). Polar lipids of strain JC85(T) include two unidentified aminophospholipids (APL1,2), two unidentified phospholipids (PL1,2), phosphatidylcholine and four unidentified lipids (L1-4). Q-10 is the major quinone of strain JC85(T). Based on polyphasic taxonomic analysis, strain JC85(T) represents a novel species for which, the name Rhizobium subbaraonis JC85(T) is proposed. The type strain is JC85(T) ( = DSM 24765(T) = KCTC 23614(T)). PMID- 22544782 TI - Blautia faecis sp. nov., isolated from human faeces. AB - A strictly anoxic, Gram-stain-positive, non-motile Blautia-like bacterium, designated strain M25(T), was isolated from a human faecal sample. Strain M25(T) was negative for both catalase and oxidase activity, utilized carbohydrates as fermentable substrates, produced lactate and acetate as the major end products of glucose fermentation in PYG medium, and had a DNA G+C content of 41.6 mol%. Comparative 16S rRNA gene sequencing showed that strain M25(T) was closely related to Ruminococcus obeum ATCC 29174(T) (96.40 % 16S rRNA gene sequence similarity) and Blautia glucerasea HFTH-1(T) (96.17 %) within the family Lachnospiraceae. Straight-chain saturated and monounsaturated cellular fatty acids were also detected, the majority being C(14 : 0), C(16 : 0) and C(16 : 0) dimethyl acetal acids. Based on the phenotypic, genotypic and phylogenetic characteristics presented in this study, strain M25(T) represents a novel species within the genus Blautia for which the name Blautia faecis sp. nov. is proposed. The type strain is M25(T) ( = KCTC 5980(T) = JCM 17205(T)). PMID- 22544783 TI - Novosphingobium fuchskuhlense sp. nov., isolated from the north-east basin of Lake Grosse Fuchskuhle. AB - A yellow pigmented, gram-negative, rod-shaped bacterium designated FNE08-7(T) was isolated from subsurface water of the north-east basin of the bog lake Grosse Fuchskuhle (Brandenburg, Germany). A first analysis of the nearly full-length 16S rRNA gene sequence analysis including environmental 16S rRNA gene sequences derived from freshwater ecosystems showed that strain FNE08-7(T) is the first cultured representative, to our knowledge, of the freshwater tribe Novo-A2. Further analysis indicates highest 16S rRNA gene sequence similarities to the type strains of Novosphingobium stygium (98.0 %) and Novosphingobium taihuense (97.4 %) and between 94.0 % and 96.9 % sequence similarity to other members of the genus Novosphingobium. Reconstruction of phylogenetic trees showed that strain FNE08-7(T) formed a distinct cluster with the type strains of N. stygium and N. taihuense supported by high bootstrap values. DNA-DNA hybridization of strain FNE08-7(T) with N. stygium SMCC B0712(T) and N. taihuense DSM 17507(T) revealed low similarity values of 18.4 % (reciprocal: 11.4 %) and 23.1 % (reciprocal: 54.2 %), respectively. The predominant fatty acid of the isolate is C(18 : 1)omega7c (56.4 %) and two characteristic 2-hydroxy fatty acids, C(14 : 0) 2-OH (16.5 %) and C(15 : 0) 2-OH (3.3 %) occur. Ubiquinone Q-10 is the major respiratory quinone. The predominant polar lipids are phosphatidylethanolamine, phosphatidylmethylethanolamine, phosphatidylglycerol, sphingoglycolipid, phosphatidylcholine and minor amounts of diphosphatidylglycerol. Spermidine is the predominant polyamine. Characterization by genotypic, chemotaxonomic and phenotypic analysis indicate that strain FNE08-7(T) represents a novel species of the genus Novosphingobium within the Alphaproteobacteria. Therefore, we propose the species Novosphingobium fuchskuhlense sp. nov., with FNE08-7(T) ( = DSM 25065(T) = CCM 7978(T) = CCUG 61508(T)) as the type strain. PMID- 22544784 TI - Sphingobium cupriresistens sp. nov., a copper-resistant bacterium isolated from copper mine soil, and emended description of the genus Sphingobium. AB - A gram-negative, aerobic, copper-resistant bacterium, designated strain CU4(T), was isolated from copper mine soil in Daye, China. Phylogenetic analysis based on 16S rRNA gene sequences showed highest similarity to Sphingobium rhizovicinum CC FH12-1(T) (98.4 %), followed by Sphingobium francense Sp+(T) (97.2 %), Sphingobium japonicum UT26(T) (97.1 %), Sphingobium abikonense NBRC 16140(T) (97.0 %), Sphingobium xenophagum DSM 6383(T) (96.9 %) and Sphingobium yanoikuyae DSM 7462(T) (95.5 %). The major fatty acids (>5 %) were summed feature 7 (C(18 : 1)omega7c, C(18 : 1)omega9t and/or C(18 : 1)omega12t), summed feature 4 (C(16 : 1)omega7c and/or iso-C(15 : 0) 2-OH), C(16 : 0) and C(14 : 0) 2-OH, and the predominant quinone was ubiquinone Q-10. Spermidine was the major polyamine component. The major polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, sphingoglycolipid, phosphatidyldimethylethanolamine and phosphatidylcholine. The genomic DNA G+C content of strain CU4(T) was 64.9 mol%. Comparison of DNA-DNA hybridization, phenotypic and chemotaxonomic characteristics between strain CU4(T) and phylogenetically related strains revealed that the new isolate represents a novel species of the genus Sphingobium, for which the name Sphingobium cupriresistens sp. nov. is proposed. The type strain is CU4(T) ( = KCTC 23865(T) = CCTCC AB 2011146(T)). An emended description of the genus Sphingobium is also proposed. PMID- 22544785 TI - Angustibacter aerolatus sp. nov., isolated from air. AB - A novel actinomycete strain, 7402J-48(T), was isolated from an air sample collected from Jeju island, Republic of Korea. Cells were gram-positive, aerobic, flagellated, short rods. Strain 7402J-48(T) showed highest 16S rRNA gene sequence similarity (98.6 %) with Angustibacter luteus TT07R-79(T), and had relatively low sequence similarities (below 95.1 %) with other members of the family Kineosporiaceae. The cell wall of strain 7402J-48(T) contained alanine, glutamic acid and 2,6-diaminopimelic acid, suggesting A1gamma-type peptidoglycan. The menaquinones were MK-9(H(4)) and MK-8(H(4)). The acyl type of the cell-wall muramic acid was acetyl. Diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, phosphatidylinositol mannoside and an unknown lipid were present. The cellular fatty acid profile comprised a large amount of anteiso-C(15 : 0), moderate amounts of C(16 : 0), summed feature 3 (including C(16 : 1)omega7c and/or C(16 : 1)omega6c), C(17 : 0), iso-C(15 : 0), C(16 : 0) N alcohol and C(17 : 1)omega8c, and small amounts of other fatty acids. The DNA G+C content of strain 7402J-48(T) was 73 mol%. Based on its phenotypic and genotypic characteristics, strain 7402J-48(T) ( = KACC 15527(T) = NBRC 108730(T)) is proposed as the type strain of a novel species, Angustibacter aerolatus sp. nov. An emended description of the genus Angustibacter is provided. PMID- 22544786 TI - Desulfosporosinus burensis sp. nov., a spore-forming, mesophilic, sulfate reducing bacterium isolated from a deep clay environment. AB - A novel anaerobic, gram-positive, spore-forming, curved rod-shaped, mesophilic and sulfate-reducing bacterium was isolated from pore water collected in a borehole at -490 m in Bure (France). This strain, designated BSREI1(T), grew at temperatures between 5 degrees C and 30 degrees C (optimum 25 degrees C) and at a pH between 6 and 8 (optimum 7). It did not require NaCl for growth, but tolerated it up to 1.5 % NaCl. Sulfate, thiosulfate and elemental sulfur were used as terminal electron acceptors. Strain BSREI1(T) used crotonate, formate, lactate, pyruvate, fructose, glycerol and yeast extract as electron donors in the presence of sulfate. The sole quinone was MK-7. The G+C content of the genomic DNA was 43.3 mol%. Strain BSREI1(T) had the type strains of Desulfosporosinus lacus (16S rRNA gene sequence similarity of 96.83 %), Desulfosporosinus meridiei (96.31 %) and Desulfosporosinus hippei (96.16 %) as its closest phylogenetic relatives. On the basis of phylogenetic and physiological properties, strain BSREI1(T) is proposed as a representative of a novel species of the genus Desulfosporosinus, Desulfosporosinus burensis sp. nov.; the type strain is BSREI1(T) ( = DSM 24089(T) = JCM 17380(T)). PMID- 22544787 TI - Bradyrhizobium daqingense sp. nov., isolated from soybean nodules. AB - Thirteen slow-growing rhizobial strains isolated from root nodules of soybean (Glycine max L.) grown in Daqing city in China were classified in the genus Bradyrhizobium based on 16S rRNA gene sequence analysis. Multilocus sequence analysis of IGS, atpD, glnII and recA genes revealed that the isolates represented a novel clade in this genus. DNA-DNA relatedness lower than 42.5 % between the representative strain CCBAU 15774(T) and the type strains of the closely related species Bradyrhizobium liaoningense USDA 3622(T), Bradyrhizobium yuanmingense CCBAU 10071(T) and Bradyrhizobium betae LMG 21987(T), further confirmed that this group represented a novel species. CCBAU 15774(T) shared seven cellular fatty acids with the three above-mentioned species, but the fatty acids 15 : 0 iso and summed feature 5 (18 : 2omega6,9c and/or 18 : 0 anteiso) were unique for this strain. The respiratory quinone in CCBAU 15774(T) was ubiquinone-10 and the cellular polar lipids were phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine, cardiolipin and unknown aminolipid, polar lipid and phospholipid. In addition, some phenotypic features could be used to differentiate the novel group from the related species. On basis of these results, we propose the name Bradyrhizobium daqingense sp. nov., with CCBAU 15774(T) ( = LMG 26137(T) = HAMBI 3184(T) = CGMCC 1.10947(T)) as the type strain. The DNA G+C content of the type strain is 61.2 mol% (T(m)). PMID- 22544788 TI - 'Candidatus Phytoplasma balanitae' associated with witches' broom disease of Balanites triflora. AB - A phytoplasma was identified in naturally infected wild Balanites triflora plants exhibiting typical witches' broom symptoms (Balanites witches' broom: BltWB) in Myanmar. The 16S rRNA gene sequence revealed that BltWB phytoplasma had the highest similarity to that of 'Candidatus Phytoplasma ziziphi' and it was also closely related to that of 'Candidatus Phytoplasma ulmi'. Phylogenetic analysis of the 16S rRNA gene sequences indicated that the BltWB phytoplasma clustered as a discrete subclade with Elm yellows phytoplasmas. RFLP analysis of the 16S rRNA gene including the 16S-23S spacer region differentiated the BltWB phytoplasma from 'Ca. P. ziziphi', 'Ca. P. ulmi' and 'Candidatus Phytoplasma trifolii'. Analysis of additional ribosomal protein (rp) and translocase protein (secY) gene sequences and phylogenetic analysis of BltWB showed that this phytoplasma was clearly distinguished from those of other 'Candidatus Phytoplasma' taxa. Taking into consideration the unique plant host and the restricted geographical occurrence in addition to the 16S rRNA gene sequence similarity, the BltWB phytoplasma is proposed to represent a novel taxon, 'Candidatus Phytoplasma balanitae'. PMID- 22544789 TI - Wickerhamomyces xylosica sp. nov. and Candida phayaonensis sp. nov., two xylose assimilating yeast species from soil. AB - Two strains (NT29(T) and NT31(T)) of xylose-assimilating yeasts were obtained from soils collected in northern Thailand. On the basis of morphological, biochemical, physiological and chemotaxonomic characteristics, and sequence analysis of the D1/D2 domain of the large subunit rRNA gene and the internal transcribed spacer region, the two strains were found to represent two novel ascomycete yeast species. Strain NT29(T) was assigned to the genus Candida belonging to the Pichia clade as a representative of Candida phayaonensis sp. nov.; the type strain is NT29(T) (=BCC 47634(T)=NBRC 108868(T)=CBS 12319(T)). Strain NT31(T) represented a novel Wickerhamomyces species, which was named Wickerhamomyces xylosica sp. nov.; the type strain is NT31(T) (=BCC 47635(T)=NBRC 108869(T)=CBS 12320(T)). PMID- 22544790 TI - Listeria weihenstephanensis sp. nov., isolated from the water plant Lemna trisulca taken from a freshwater pond. AB - The phylogenetic position and phenotypic characteristics of two non-spore-forming bacilli similar to members of the genus Listeria were studied. The gram-reaction positive, slightly motile, facultatively anaerobic strains were isolated from the water plant Lemna trisulca sampled from a freshwater pond in Bavaria, Germany. Although no identification was possible employing the API Listeria test (bioMerieux), 16S rRNA sequence analysis confirmed a close phylogenetic similarity to Listeria rocourtiae DSM 22097(T) (99.0 % sequence similarity) and a more distant relationship to other Listeria species (96.0 % to Listeria monocytogenes DSM 20600(T) and 95.0 % similarity to Listeria grayi DSM 20601(T)). DNA-DNA hybridization analysis between the isolates and Listeria rocourtiae DSM 22097(T) yielded a similarity of 22.5 %. Analysis of partial sequences of sigB, prs, recA and HSP60 were studied and compared with those of other members of the genus Listeria and Brochothrix thermosphacta DSM 20171(T) supporting the relationships indicated by 16S rRNA gene sequences. The studied isolates were non haemolytic and were not associated with cases of human or animal disease. While the results demonstrate that the strains belong to the genus Listeria, phenotypic and genotypic differences from Listeria rocourtiae DSM 22097(T) suggest that the strains represent a novel species for which the name Listeria weihenstephanensis sp. nov. is proposed; the type strain is WS 4560(T) ( = DSM 24698(T) = LMG 26374(T)), with WS 4615 ( = DSM 24699 = LMG 26375) as a second strain of the species. PMID- 22544791 TI - Algoriphagus chungangensis sp. nov., isolated from a tidal flat sediment. AB - A Gram-stain-negative, non-spore-forming, non-motile, strictly aerobic, rod shaped bacterial strain, designated CAU 1002(T), was isolated from a tidal flat sediment and its taxonomic position was investigated using a polyphasic approach. Strain CAU 1002(T) grew optimally at 30 degrees C and pH 7.5. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain CAU 1002(T) formed a distinct lineage within the genus Algoriphagus and was most closely related to Algoriphagus lutimaris KCTC 22630(T) and Algoriphagus halophilus KCTC 12051(T) (97.75 and 97.74 % 16S rRNA gene sequence similarity, respectively). The strain contained MK-7 as the major isoprenoid quinone and iso-C(15 : 0) and C(16 : 1)omega7c and/or iso-C(15 : 0) 2-OH (summed feature 3) as the major fatty acids. The cell-wall peptidoglycan of strain CAU 1002(T) contained meso-diaminopimelic acids. The major whole-cell sugars were glucose, arabinose, sucrose, and ribose. The polar lipid profile was composed of phosphatidylethanolamine, five unidentified aminolipids, one unidentified aminophospholipid, one unidentified phospholipid, one unidentified aminoglycolipid, one unidentified glycolipid and twelve unidentified lipids. The DNA G+C content of strain CAU 1002(T) was 38.0 mol%. On the basis of phylogenetic inference, phenotypic, chemotaxonomic and genotypic data, strain CAU 1002(T) should be classified into the genus Algoriphagus as a member of a novel species, for which the name Algoriphagus chungangensis sp. nov. is proposed. The type strain is CAU 1002(T) ( = KCTC 23759(T) = CCUG 61890(T)). The description of the genus Algoriphagus is emended. PMID- 22544792 TI - Hymenobacter ginsengisoli sp. nov., isolated from soil of a ginseng field. AB - A Gram-stain-negative, non-motile, red bacterium, designated DCY57(T), was isolated from soil of a ginseng field in a mountainous region of Chungnam province in South Korea. Strain DCY57(T) grew with 0-1 % (w/v) NaCl and the optimum temperature for growth was 30 degrees C. Strain DCY57(T) contained MK-7 as the predominant menaquinone. The polyamine was sym-homospermidine. The major fatty acids were C(16:1)omega5c, iso-C(15:0), anteiso-C(15:0) and summed feature 3 (containing C(16:1)omega7c and/or C(16:1)omega6c). The major polar lipids were phosphatidylethanolamine, unknown aminophospholipids, unknown aminolipids and unknown lipids. The DNA G+C content was 58.9 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain DCY57(T) was most closely related to members of the genus Hymenobacter. The isolate exhibited 91.7 % 16S rRNA gene sequence similarity with H. soli PB17(T), 94.5 % with H. flocculans A2-50A(T) and 95.8 % with H. metalli A2-91(T). On the basis of the evidence presented in this study, strain DCY57(T) represents a novel species within the genus Hymenobacter, for which the name Hymenobacter ginsengisoli sp. nov. is proposed. The type strain is DCY57(T) ( = KCTC 23674(T) = JCM 17841(T)). PMID- 22544793 TI - Chryseolinea serpens gen. nov., sp. nov., a member of the phylum Bacteroidetes isolated from soil. AB - An aerobic chemoheterotrophic gliding bacterium, designated RYG(T), was isolated from a soil in Germany. Cells were Gram-stain-negative, thin rods (0.4-0.6 um in width and 2.0-5.5 um in length). Cells multiplied by normal cell division and no resting stages were observed. Colonies were yellow and displayed swarming edges. Gliding motility was observed in wet mounts. Strain RYG(T) grew at pH 5.6-7.7 (optimum pH 6.6-7.0), at 13-37 degrees C (optimum 25-30 degrees C) and with 0 1.0 % NaCl (optimum 0-0.1 %). The isolate was incapable of atmospheric nitrogen fixation and grew on most mono- and disaccharides as well as a few polysaccharides and organic acids. The predominant menaquinone was MK-7, the major cellular fatty acids were C(16 : 1)omega5c and iso-C(15 : 0) and the major intact polar lipids were composed of phosphatidylethanolamine derivatives and two unknown series. The DNA G+C content was 49.9 mol%. Based on 16S rRNA gene sequence analysis, the isolate belonged to the phylum Bacteroidetes, class Cytophagia, order Cytophagales, but was only distantly related to any cultured bacteria. The closest relatives were Ohtaekwangia koreensis 3B-2(T) and Ohtaekwangia kribbensis 10AO(T) (both 93 % 16S rRNA gene sequence similarity). We propose a novel genus and species, Chryseolinea serpens gen. nov., sp. nov.. Strain RYG(T) ( = DSM 24574(T) = ATCC BAA-2075(T)) is the type strain. PMID- 22544794 TI - Arenibacter hampyeongensis sp. nov., a marine bacterium isolated from a tidal flat. AB - A Gram-staining-negative, dark orange, strictly aerobic bacterium, designated strain HP12(T), was isolated from a tidal flat at Hampyeong in South Korea. Cells were moderately halotolerant, catalase- and oxidase-positive, non-motile rods. Growth was observed at 5-35 degrees C (optimum, 25 degrees C), at pH 6.0-8.5 (optimum, pH 7.0-7.5), and in the presence of 1-6 % (w/v) NaCl (optimum, 1-2 %). The major cellular fatty acids were summed feature 3 (C(16 : 1)omega7c and/or iso C(15 : 0) 2-OH), iso-C(17 : 0) 3-OH, C(15 : 0), iso-C(15 : 1) G and iso-C(15 : 0). The polar lipid pattern indicated the presence of phosphatidylethanolamine and two unidentified lipids. The G+C content of the genomic DNA was 37.1 mol% and the predominant respiratory quinone was menaquinone-6. Phylogenetic analysis based on 16S rRNA gene sequences showed that the novel strain formed a tight phyletic lineage with members of the genus Arenibacter and was most closely related to Arenibacter palladensis KMM 3961(T), Arenibacter troitsensis KMM 3674(T) and Arenibacter echinorum KMM 6032(T), with 16S rRNA gene sequence similarities of 98.1 %, 98.0 % and 97.8 %, respectively. However, the DNA-DNA relatedness values between strain HP12(T) and A. palladensis JCM 13509(T), A. troitsensis KCTC 12362(T) and A. echinorum KCTC 22013(T) were only 20.2+/-0.3 %, 22.6+/-0.6 % and 9.1+/-2.6 %, respectively. On the basis of phenotypic and molecular features, strain HP12(T) represents a novel species of the genus Arenibacter, for which the name Arenibacter hampyeongensis sp. nov. is proposed. The type strain is HP12(T) ( = KACC 16193(T) = JCM 17788(T)). PMID- 22544795 TI - Bacteroides reticulotermitis sp. nov., isolated from the gut of a subterranean termite (Reticulitermes speratus). AB - An obligately anaerobic, non-pigmented, non-spore-forming, Gram-staining negative, rod-shaped bacterium, designated strain Rs-03(T), was isolated from the gut of the subterranean termite Reticulitermes speratus. The taxonomic position of the novel strain was determined by following a polyphasic approach. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain Rs 03(T) was a member of the genus Bacteroides and was most closely related to Bacteroides thetaiotaomicron JCM 5827(T) (95.0 % sequence similarity), Bacteroides faecis JCM 16478(T) (94.8 %) and Bacteroides xylanisolvens JCM 15633(T) (94.3 %). The results of hsp60 gene sequence analysis indicated that the novel strain was different from established members of the genus Bacteroides. Strain Rs-03(T) was saccharolytic and produced succinic and acetic acids, with small amounts of propionic acid, as metabolic end products. The major cellular fatty acids of strain Rs-03(T) were anteiso-C(15 : 0), C(18 : 1)omega9c and iso C(17 : 0) 3-OH. The major menaquinones were MK-10 and MK-9 and the genomic DNA G+C content was 44.9 mol%. Based on these data, strain Rs-03(T) represents a novel species in the genus Bacteroides, for which the name Bacteroides reticulotermitis sp. nov. is proposed. The type strain is Rs-03(T) ( = JCM 10512(T) = CCUG 62153(T)). PMID- 22544796 TI - Bizionia hallyeonensis sp. nov., isolated from seawater in an oyster farm. AB - A Gram-staining-negative, non-spore-forming, aerobic, non-flagellated, non gliding, rod-shaped bacterium, designated strain T-y7(T), was isolated from seawater collected in an oyster farm in the South Sea, South Korea, and subjected to a polyphasic study. Strain T-y7(T) grew optimally at 25 degrees C, at pH 7.0 8.0 and in the presence of 2 % (w/v) NaCl. In phylogenetic analyses based on 16S rRNA gene sequences, strain T-y7(T) fell within a clade comprising Bizionia species. It formed a coherent cluster with the type strains of Bizionia algoritergicola, B. argentinensis, B. echini and B. myxarmorum, with which it exhibited 16S rRNA gene sequence similarities of 97.4-98.9 % and mean DNA-DNA relatedness values of 11-27 %. Strain T-y7(T) had MK-6 as its predominant menaquinone and iso-C(15 : 1) G, summed feature 3 (C(16 : 1)omega7c and/or iso C(15 : 0) 2-OH), iso-C(15 : 0) and iso-C(17 : 0) 3-OH as its major fatty acids. The major polar lipids were phosphatidylethanolamine, one unidentified aminolipid and one unidentified lipid. The genomic DNA G+C content was 37.1 mol%. Its phylogenetic and genetic distinctiveness and differential phenotypic properties revealed that strain T-y7(T) does not belong to any established Bizionia species. On the basis of the data presented, strain T-y7(T) is considered to represent a novel species of the genus Bizionia, for which the name Bizionia hallyeonensis sp. nov. is proposed. The type strain is T-y7(T) ( = KCTC 23881(T) = CCUG 62110(T)). PMID- 22544797 TI - Dehalococcoides mccartyi gen. nov., sp. nov., obligately organohalide-respiring anaerobic bacteria relevant to halogen cycling and bioremediation, belong to a novel bacterial class, Dehalococcoidia classis nov., order Dehalococcoidales ord. nov. and family Dehalococcoidaceae fam. nov., within the phylum Chloroflexi. AB - Six obligately anaerobic bacterial isolates (195(T), CBDB1, BAV1, VS, FL2 and GT) with strictly organohalide-respiring metabolisms were obtained from chlorinated solvent-contaminated aquifers, contaminated and uncontaminated river sediments or anoxic digester sludge. Cells were non-motile with a disc-shaped morphology, 0.3 1 um in diameter and 0.1-0.2 um thick, and characteristic indentations on opposite flat sides of the cell. Growth occurred in completely synthetic, reduced medium amended with a haloorganic electron acceptor (mostly chlorinated but also some brominated compounds), hydrogen as electron donor, acetate as carbon source, and vitamins. No other growth-supporting redox couples were identified. Aqueous hydrogen consumption threshold concentrations were <1 nM. Growth ceased when vitamin B(12) was omitted from the medium. Addition of sterile cell-free supernatant of Dehalococcoides-containing enrichment cultures enhanced dechlorination and growth of strains 195 and FL2, suggesting the existence of so far unidentified stimulants. Dechlorination occurred between pH 6.5 and 8.0 and over a temperature range of 15-35 degrees C, with an optimum growth temperature between 25 and 30 degrees C. The major phospholipid fatty acids were 14 : 0 (15.7 mol%), br15 : 0 (6.2 mol%), 16 : 0 (22.7 mol%), 10-methyl 16 : 0 (25.8 mol%) and 18 : 0 (16.6 mol%). Unusual furan fatty acids including 9-(5-pentyl-2 furyl)-nonanoate and 8-(5-hexyl-2-furyl)-octanoate were detected in strains FL2, BAV1 and GT, but not in strains 195(T) and CBDB1. The 16S rRNA gene sequences of the six isolates shared more than 98 % identity, and phylogenetic analysis revealed an affiliation with the phylum Chloroflexi and more than 10 % sequence divergence from other described isolates. The genome sizes and G+C contents ranged from 1.34 to 1.47 Mbp and 47 to 48.9 mol% G+C, respectively. Based on 16S rRNA gene sequence comparisons, genome-wide average nucleotide identity and phenotypic characteristics, the organohalide-respiring isolates represent a new genus and species, for which the name Dehalococcoides mccartyi gen. nov., sp. nov. is proposed. Isolates BAV1 ( = ATCC BAA-2100 = JCM 16839 = KCTC 5957), FL2 ( = ATCC BAA-2098 = DSM 23585 = JCM 16840 = KCTC 5959), GT ( = ATCC BAA-2099 = JCM 16841 = KCTC 5958), CBDB1, 195(T) ( = ATCC BAA-2266(T) = KCTC 15142(T)) and VS are considered strains of Dehalococcoides mccartyi, with strain 195(T) as the type strain. The new class Dehalococcoidia classis nov., order Dehalococcoidales ord. nov. and family Dehalococcoidaceae fam. nov. are described to accommodate the new taxon. PMID- 22544798 TI - Huanghella arctica gen. nov., sp. nov., a bacterium of the family Cytophagaceae isolated from Arctic tundra soil. AB - A novel, strictly aerobic, red-pigmented, gram-reaction-negative bacterium, designated strain R9-9(T), was isolated from tundra soil collected near Ny Alesund, Svalbard Archipelago, Norway (78 degrees N). The novel strain was subjected to a taxonomic study using a polyphasic approach. It grew optimally at 20-22 degrees C and at pH 7.0. Flexirubin-type pigments were absent. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain R9-9(T) represents a distinct phyletic line that reflects a novel generic status within the family Cytophagaceae. The novel strain showed relatively low 16S rRNA gene sequence similarities (<88.0 %) to members of established genera. Strain R9-9(T) contained summed feature 3 (C(16 : 1)omega7c and/or C(16 : 1)omega6c), iso-C(17 : 0) 3-OH, iso-C(15 : 0) and C(16 : 1)omega5c as its major cellular fatty acids, phosphatidylethanolamine as its main polar lipid, and MK-7 as its major respiratory quinone. The genomic DNA G+C content was 56.1 mol%. On the basis of phenotypic, chemotaxonomic and phylogenetic data, strain R9-9(T) is considered to represent a novel species in a new genus in the family Cytophagaceae, for which the name Huanghella arctica gen. nov., sp. nov. is proposed. The type strain is R9-9(T) ( = CCTCC AB 2010418(T) = NRRL B-59750(T)). PMID- 22544799 TI - Psychroserpens damuponensis sp. nov., isolated from seawater. AB - A novel bacterium, designated strain F051-1(T), isolated from a seawater sample collected from the coast at Damupo beach in Pohang, Korea, was investigated in a polyphasic taxonomic study. Cells were yellow-pigmented, strictly aerobic, Gram staining-negative and rod-shaped. The temperature, pH and NaCl ranges for growth were 4-30 degrees C, pH 6.0-9.0 and 1.0-6.0 % (w/v), respectively. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain F051-1(T) belongs to the genus Psychroserpens in the family Flavobacteriaceae. Its closest relatives were Psychroserpens burtonensis ACAM 188(T) (96.8 % 16S rRNA gene sequence similarity) and Psychroserpens mesophilus KOPRI 13649(T) (95.7 %). The major cellular fatty acids were iso-C(15 : 0), iso-C(15 : 1) G and anteiso-C(15 : 0). The polar lipid profile consisted of a mixture of phosphatidylethanolamine, two unidentified aminolipids, one unidentified phospholipid and eight unidentified lipids. The major respiratory quinone was menaquinone-6 and the genomic DNA G+C content of the strain was 33.5 mol%. On the basis of phenotypic, phylogenetic and genotypic data, strain F051-1(T) represents a novel species within the genus Psychroserpens, for which the name Psychroserpens damuponensis sp. nov. is proposed. The type strain is F051-1(T) ( = KCTC 23539(T) = JCM 17632(T)). PMID- 22544800 TI - Sphingobium baderi sp. nov., isolated from a hexachlorocyclohexane dump site. AB - A Gram-stain-negative, rod-shaped and white-coloured bacterial strain, designated LL03(T), was isolated from hexachlorocyclohexane-contaminated soil at Spolana Neratovice, Czech Republic, where lindane was formerly produced. Strain LL03(T) was found to be a degrader of alpha-, gamma- and delta-isomers of hexachlorocyclohexane, although no significant degradation activity was observed for the beta-isomer. A neighbour-joining tree based on 16S rRNA gene sequences showed that strain LL03(T) occupied a distinct phylogenetic position in the Sphingobium cluster, showing the highest similarity with Sphingobium wenxiniae JZ 1(T) (99.2 %). The DNA G+C content of strain LL03(T) was 67.0 mol%. DNA-DNA relatedness values of strain LL03(T) with its close phylogenetic neighbours were below the threshold level of 70 %, supporting its identification as a representative of a novel species of the genus Sphingobium. The predominant respiratory quinone was ubiquinone Q-10. The polar lipid profile of strain LL03(T) also corresponded to those reported for other Sphingobium species (phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylcholine, phosphatidylglycerol, phosphatidylmonomethylethanolamine and sphingoglycolipid), supporting its identification as a member of the genus Sphingobium. Spermidine was identified as the major polyamine. The predominant fatty acids were 16 : 0, summed feature 3 (16 : 1omega7c and/or 16 : 1omega6c), summed feature 8 (18 : 1omega7c and/or 18 : 1omega6c) and 14 : 0 2-OH. The polar lipid pattern, the presence of spermidine and ubiquinone Q-10, the predominance of the cellular fatty acids C(18 : 1)omega7c, C(16 : 0) and C(14 : 0) 2-OH and the G+C content of the genomic DNA supported the affiliation of the strain to the genus Sphingobium. The results obtained after DNA-DNA hybridization, biochemical and physiological tests clearly distinguished it from closely related species of the genus Sphingobium. Therefore, strain LL03(T) represents a novel species of the genus Sphingobium for which the name Sphingobium baderi LL03(T) sp. nov. is proposed; the type strain is LL03(T) ( = CCM 7981(T) = DSM 25433(T)). PMID- 22544801 TI - Novosphingobium barchaimii sp. nov., isolated from hexachlorocyclohexane contaminated soil. AB - A yellow-pigmented bacterial strain, designated LL02(T), was isolated from hexachlorocyclohexane-contaminated soil from Spolana Neratovice, a former Czech producer of lindane. A neighbour-joining tree based on 16S rRNA gene sequences showed that strain LL02(T) occupied a distinct phylogenetic position in the genus Novosphingobium and showed the highest sequence similarity with Novosphingobium resinovorum NCIMB 8767(T) (98.59 %). DNA-DNA relatedness between strain LL02(T) and its closest phylogenetic neighbours was <70 %, which indicated that strain LL02(T) represented a novel species of the genus Novosphingobium. The DNA G+C content of strain LL02(T) was 67.72+/-0 mol%. The major respiratory quinone was ubiquinone Q-10. The polar lipid profile of the isolate corresponded to those reported for other members of the genus Novosphingobium (phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylcholine, phosphatidylglycerol, phosphatidylmonomethylethanolamine and sphingoglycolipids), thus supporting its classification in the genus. Spermidine was the major polyamine. The major fatty acids were summed feature 3 (consisting of C(16 : 1)omega7c and/or C(16 : 1)omega6c; 40.13 %), summed feature 8 (consisting of C(18 : 1)omega7c and/or C(18 : 1)omega6c; 31.09 %) and C(14 : 0) 2-OH (23.16 %). The results obtained from DNA-DNA hybridization and biochemical and physiological tests clearly distinguished the isolate from its closest phylogenetic neighbours. Thus, strain LL02(T) represents a novel species of the genus Novosphingobium, for which the name Novosphingobium barchaimii sp. nov. is proposed. The type strain is LL02(T) ( = CCM 7980(T) = DSM 25411(T)). PMID- 22544802 TI - Endozoicomonas numazuensis sp. nov., a gammaproteobacterium isolated from marine sponges, and emended description of the genus Endozoicomonas Kurahashi and Yokota 2007. AB - Two non-motile, rod-shaped gammaproteobacteria were isolated from marine sponges collected from the coast of Japan at Numazu. The isolates were oxidase- and catalase-positive facultative anaerobes that fermented carbohydrates. They required sodium ions for growth and were slightly halophilic, growing in the presence of 1.0-5.0 % (w/v) NaCl (optimum of 2.0 % NaCl). Under aerobic conditions, the major isoprenoid quinones were ubiquinone-9 and menaquinone-9 and the minor quinones were ubiquinone-8 and menaquinone-8. The major cellular fatty acids were C(18 : 1)omega7c, C(16 : 1)omega7c and C(16 : 0) and the hydroxy acids were C(10 : 0) 3-OH and C(12 : 0) 3-OH. The DNA G+C content was 48.3-48.7 mol%. Phylogenetic analysis of 16S rRNA gene sequences placed the isolates within the radiation of the genus Endozoicomonas in a broad clade of uncultured clones recovered from various marine invertebrates. The isolates exhibited 96.5-96.9 % 16S rRNA gene sequence similarity with Endozoicomonas elysicola MKT110(T) and Endozoicomonas montiporae CL-33(T), with which the isolates formed a monophyletic cluster with 100 % bootstrap support. The phenotypic features (carbohydrate fermentation, quinone system and some major cellular fatty acids) differed from those of members of the genus Endozoicomonas, which are aerobic, produce little or no menaquinone under aerobic conditions and possess different amounts of C(14 : 0) and C(18 : 1)omega7c. Although some phenotypic differences were identified, the isolates should be assigned to the genus Endozoicomonas on the basis of congruity of phylogeny and should be classified as representatives of a novel species, for which the name Endozoicomonas numazuensis sp. nov. is proposed. The type strain is HC50(T) ( = NBRC 108893(T) = DSM 25634(T)). An emended description of the genus Endozoicomonas is presented. PMID- 22544803 TI - Effect of DNA binding on geminate CO recombination kinetics in CO-sensing transcription factor CooA. AB - Carbon monoxide oxidation activator (CooA) proteins are heme-based CO-sensing transcription factors. Here we study the ultrafast dynamics of geminate CO rebinding in two CooA homologues, Rhodospirillum rubrum (RrCooA) and Carboxydothermus hydrogenoformans (ChCooA). The effects of DNA binding and the truncation of the DNA-binding domain on the CO geminate recombination kinetics were specifically investigated. The CO rebinding kinetics in these CooA complexes take place on ultrafast time scales but remain non-exponential over many decades in time. We show that this non-exponential kinetic response is due to a quenched enthalpic barrier distribution resulting from a distribution of heme geometries that is frozen or slowly evolving on the time scale of CO rebinding. We also show that, upon CO binding, the distal pocket of the heme in the CooA proteins relaxes to form a very efficient hydrophobic trap for CO. DNA binding further tightens the narrow distal pocket and slightly weakens the iron-proximal histidine bond. Comparison of the CO rebinding kinetics of RrCooA, truncated RrCooA, and DNA bound RrCooA proteins reveals that the uncomplexed and inherently flexible DNA binding domain adds additional structural heterogeneity to the heme doming coordinate. When CooA forms a complex with DNA, the flexibility of the DNA binding domain decreases, and the distribution of the conformations available in the heme domain becomes restricted. The kinetic studies also offer insights into how the architecture of the heme environment can tune entropic barriers in order to control the geminate recombination of CO in heme proteins, whereas spin selection rules play a minor or non-existent role. PMID- 22544804 TI - Randomized, placebo-controlled trial of tenofovir disoproxil fumarate in adolescents with chronic hepatitis B. AB - Tenofovir disoproxil fumarate (DF) is highly effective for the suppression of hepatitis B virus (HBV) in chronically infected adults. This study evaluated the safety and efficacy of tenofovir DF in adolescents with chronic hepatitis B (CHB). In this double-blind, placebo-controlled trial, adolescents 12 to <18 years of age with CHB were randomized to tenofovir DF 300 mg (n = 52) or placebo (n = 54) once daily for 72 weeks. The primary endpoint was virologic response (HBV DNA <400 copies/mL) at week 72. One hundred six patients were enrolled; 101 patients completed 72 weeks of treatment. At baseline, 91% of patients were hepatitis B e antigen-positive and 85% had prior exposure to HBV therapy. A virologic response was observed in 89% (46/52) of patients who received tenofovir DF and 0% (0/54) of patients who received placebo (P < 0.001). Treatment response was not affected by prior HBV treatment. Furthermore, no resistance to tenofovir DF developed through week 72. Among patients with an alanine aminotransferase (ALT) level greater than the upper limit of normal at baseline, normalization of ALT occurred in 74% of patients receiving tenofovir DF and 31% of patients receiving placebo (P < 0.001). The rate of grade 3/4 adverse events was higher among patients treated with placebo (24%) than patients treated with tenofovir DF (10%). No patients met the safety endpoint of a 6% decrease in spine bone mineral density at week 72. CONCLUSION: Tenofovir DF therapy in HBV-infected adolescents was well tolerated and highly effective at suppressing HBV DNA and normalizing ALT values in both treatment-naive adolescents and those with prior exposure to HBV therapy. PMID- 22544805 TI - An algorithm to identify medical practices common to both the General Practice Research Database and The Health Improvement Network database. AB - PURPOSE: To identify practices common to both the General Practice Research Database and The Health Improvement Network database for purposes of combining the databases for analysis without duplicate records. METHODS: We developed two independent algorithms to identify practices common to the two databases. The first used the total number of patients in the therapy and clinical data sets and the total number of etoricoxib and celecoxib users each year during the study period. The second used the total number of patients stratified by gender and four different categories of birth year. Further checking of potential matched practice pairs identified by the two algorithms was performed by comparing the patient-level medical records by birth year, dates of clinical visits, and diagnosis codes. RESULTS: Three hundred twelve potential matched pairs of practices were found by both algorithms. Fifteen additional potential pairs were matched by only one algorithm: 13 by algorithm 1 (A1) only and 2 by algorithm 2 (A2) only. The examination of the patient-level visit dates and diagnosis codes for the matches revealed that all of the 327 potential pairs of duplicate practices were in fact the same practice in the two databases. CONCLUSIONS: The two algorithms successfully found the practices common to the two different databases without de-identifying the practices. The identification of the common practices allows for combining the two databases without duplicate records to create a larger data set for analysis, with 168 more practices than when using the General Practice Research Database alone, or with 268 more practices than when using The Health Improvement Network alone. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 22544806 TI - Incarceration of (PdO)n and Pd(n) clusters by cage-templated synthesis of hollow silica nanoparticles. PMID- 22544807 TI - A leavening strategy to prepare reduced graphene oxide foams. PMID- 22544808 TI - PRL-Dock: protein-ligand docking based on hydrogen bond matching and probabilistic relaxation labeling. AB - Protein-ligand docking is widely applied to structure-based virtual screening for drug discovery. This article presents a novel docking technique, PRL-Dock, based on hydrogen bond matching and probabilistic relaxation labeling. It deals with multiple hydrogen bonds and can match many acceptors and donors simultaneously. In the matching process, the initial probability of matching an acceptor with a donor is estimated by an efficient scoring function and the compatibility coefficients are assigned according to the coexisting condition of two hydrogen bonds. After hydrogen bond matching, the geometric complementarity of the interacting donor and acceptor sites is taken into account for displacement of the ligand. It is reduced to an optimization problem to calculate the optimal translation and rotation matrixes that minimize the root mean square deviation between two sets of points, which can be solved using the Kabsch algorithm. In addition to the van der Waals interaction, the contribution of intermolecular hydrogen bonds in a complex is included in the scoring function to evaluate the docking quality. A modified Lennard-Jones 12-6 dispersion-repulsion term is used to estimate the van der Waals interaction to make the scoring function fairly "soft" so that ligands are not heavily penalized for small errors in the binding geometry. The calculation of this scoring function is very convenient. The evaluation is carried out on 278 rigid complexes and 93 flexible ones where there is at least one intermolecular hydrogen bond. The experiment results of docking accuracy and prediction of binding affinity demonstrate that the proposed method is highly effective. PMID- 22544809 TI - Design and development of a new micro-beam treatment planning system: effectiveness of algorithms of optimization and dose calculations and potential of micro-beam treatment. AB - A new treatment planning system (TPS) was designed and developed for a new treatment system, which consisted of a micro-beam-enabled linac with robotics and a real-time tracking system. We also evaluated the effectiveness of the implemented algorithms of optimization and dose calculations in the TPS for the new treatment system. In the TPS, the optimization procedure consisted of the pseudo Beam's-Eye-View method for finding the optimized beam directions and the steepest-descent method for determination of beam intensities. We used the superposition-/convolution-based (SC-based) algorithm and Monte Carlo-based (MC based) algorithm to calculate dose distributions using CT image data sets. In the SC-based algorithm, dose density scaling was applied for the calculation of inhomogeneous corrections. The MC-based algorithm was implemented with Geant4 toolkit and a phase-based approach using a network-parallel computing. From the evaluation of the TPS, the system can optimize the direction and intensity of individual beams. The accuracy of the dose calculated by the SC-based algorithm was less than 1% on average with the calculation time of 15 s for one beam. However, the MC-based algorithm needed 72 min for one beam using the phase-based approach, even though the MC-based algorithm with the parallel computing could decrease multiple beam calculations and had 18.4 times faster calculation speed using the parallel computing. The SC-based algorithm could be practically acceptable for the dose calculation in terms of the accuracy and computation time. Additionally, we have found a dosimetric advantage of proton Bragg peak like dose distribution in micro-beam treatment. PMID- 22544810 TI - A general strategy for self-assembly of nanosized building blocks on liquid/liquid interfaces. AB - A family of water/oil interfaces is introduced to provide effective platforms for rapid fabrication of large-area self-assembled nanofilms composed of various nanosized building blocks, including nanoparticles (NPs), nanocubes (NC), nanowires (NWs), and nanosheets, at room temperature. As a general interfacial assembly method, NWs and NPs are co-assembled at the liquid/liquid interface. The as-prepared co-assembled Ag NW and Ag NC films show high surface-enhanced Raman spectroscopy (SERS) intensity, the SERS performance being strongly dependent on the number ratio of the two kinds of nanosized building blocks. The results demonstrate that this interfacial system provides a general method for the assembly of various nanosized building blocks with different shapes and dimensionalities, and thus paves an alternative pathway for further applications of macroscopic assemblies with different functionalities. PMID- 22544811 TI - How many infants likely died in Africa as a result of the 2008-2009 global financial crisis? AB - The human consequences of the recent global financial crisis for the developing world are presumed to be severe, but few studies have quantified them. This letter estimates the human cost of the 2008-2009 global financial crisis in one critical dimension-infant mortality-for countries in sub-Saharan Africa. The analysis pools birth-level data, as reported in female adult retrospective birth histories from all Demographic and Health Surveys collected in sub-Saharan Africa. This results in a data set of 639,000 births to 264,000 women in 30 countries. We use regression models with flexible controls for temporal trends to assess an infant's likelihood of death as a function of fluctuations in national income. We then calculate the expected number of excess deaths by combining these estimates with growth shortfalls as a result of the crisis. The results suggest 28,000-50,000 excess infant deaths in sub-Saharan Africa in the crisis-affected year of 2009. Notably, most of these additional deaths were concentrated among girls. Policies that protect the income of poor households and that maintain critical health services during times of economic contraction may reduce the expected increase in mortality. Interventions targeted at female infants and young girls can be particularly beneficial. PMID- 22544813 TI - Synthesis and characterization of an isolable base-stabilized silacycloprop-1 ylidene. AB - Strained but stable: An isolable silacycloprop-1-ylidene stabilized by intramolecular complexation with an iminophosphorus ylide fragment was successfully synthesized and fully characterized. The formation of this small highly strained cyclic silylene involves an unprecedented Si(IV)->Si(II) rearrangement under very mild conditions. PMID- 22544814 TI - Design of a voltage-controlled magnetic random access memory based on anisotropic magnetoresistance in a single magnetic layer. AB - A simple and fully gate-voltage-controlled magnetic random access memory is designed based on anisotropic magnetoresistance. This multiferroic memory device consists of just a single magnetic film grown on a ferroelectric layer with bistable in-plane anisotropic ferroelastic or piezo strains induced by out-of plane voltages. It can simultaneously achieve ultrahigh storage density, ultralow energy consumption, and GHz high-speed operation at room temperature. PMID- 22544812 TI - Pericentral activity of alpha-fetoprotein enhancer 3 and glutamine synthetase upstream enhancer in the adult liver are regulated by beta-catenin in mice. AB - We previously showed that mouse alpha-fetoprotein (AFP) enhancer 3 activity is highly restricted to pericentral hepatocytes in the adult liver. Here, using transgenic mice, we show that the upstream enhancer of the rat glutamine synthetase gene is also active, specifically in pericentral regions. Activity of both enhancers is lost in the absence of beta-catenin, a key regulator of zonal gene expression in the adult liver. Both enhancers contain a single, highly conserved T-cell factor/lymphoid enhancer factor binding site that is required for responsiveness to beta-catenin. We also show that endogenous AFP messenger RNA levels in the perinatal liver are lower when beta-catenin is reduced. CONCLUSION: These data identify the first distinct zonally active regulatory regions required for beta-catenin responsiveness in the adult liver, and suggest that postnatal AFP repression and the establishment of zonal regulation are controlled, at least in part, by the same factors. PMID- 22544815 TI - Factors controlling induction of reproduction in algae--review: the text. AB - This review surveys on the influence of different environmental factors like light (intensity, quality, photoperiod), temperature, season, nutrients (inorganic, organic), biotic factors (algal extracellular products, bacterial association, animals grazing), osmotic stress, pH of the medium, wave motion and mechanical shock, pollution, and radiations (UV, X-rays, gamma radiation) on the induction (or inhibition) of algal reproduction like cell division in unicellular algae, and formation of zoospores, aplanospores, akinetes, cysts, antheridia, oogonia, zygospores, etc. PMID- 22544816 TI - Strength: a relevant link to functional performance in the neurodegenerative disease of adrenomyeloneuropathy. AB - BACKGROUND: With progressive abnormalities in leg strength, tone, and sensation, adrenomyeloneuropathy (AMN) is a differential diagnosis for multiple sclerosis and hereditary spastic paraparesis. AMN pathology has been linked to weakness, making it a relevant model to evaluate the relationship between neurodegeneration and disability. Quantifying symptom severity in AMN is essential for treatment development in rehabilitative management. OBJECTIVE: To identify deficits in body functions, activity, and participation of people with AMN and provide a practical framework for evaluating the severity of disability. METHODS: Cohort analysis of 142 participants with AMN. MEASURES: of body functions (leg strength, vibration sensation, range of motion, and spasticity), activity (walk velocity, standing balance, Timed Up and Go, and Sit-to-Stand Time), and participation (6-Minute Walk) are evaluated. Regression analyses identify relationships between the measures. A staging framework (mild, moderate, and severe) reflects the continuum of disability. Finally, an analysis of variance/Kruskal-Wallis was used for between-stage and sex differences among the variables. RESULTS: Strength is the strongest correlate for the 5 measures of activity and participation. Staging based on weakness distinguishes 3 levels of severity along a continuum of disability. Differences between the sexes are more prevalent earlier in the continuum but show equally severe deficits in the last stage. CONCLUSIONS: In AMN, staging based on degrees of weakness provides a practical means to characterize the severity of common deficits in body functions as well as activity and participation at each stage, to direct the evaluation. Such information could help clinicians develop more effective rehabilitative techniques. PMID- 22544817 TI - Exercise to enhance mobility and prevent falls after stroke: the community stroke club randomized trial. AB - BACKGROUND: Exercise interventions can enhance mobility after stroke as well as prevent falls in elderly persons. OBJECTIVE: Investigate whether an exercise intervention can enhance mobility, prevent falls, and increase physical activity among community-dwelling people after stroke. METHOD: A randomized trial with blinding of physical outcome assessment was conducted through local stroke clubs. Both groups, on average 5.9 years poststroke, received exercise classes, advice, and a home program for 12 months. The experimental group (EG) program (n = 76) aimed to improve walking, prevent falls and increase physical activity. The control group (CG) program (n = 75) aimed to improve upper-limb and cognitive functions. The primary outcomes were walking capacity, walking speed measured before and after the intervention, and fall rates monitored monthly. RESULTS: At 12 months, the EG walked 34 m further in 6 minutes (95% confidence interval [CI] = 19-50; P < .001) and 0.07 m/s faster over 10 m (95% CI = 0.01-0.14; P = .03) than the CG. The EG had 129 falls, and the CG had 133. There were no differences in proportion of fallers (relative risk = 1.22; 95% CI = 0.91-1.62; P = .19) or the rate of falls between groups (incidence rate ratio = 0.96; 95% CI = 0.59 1.51; P = .88). CONCLUSION: The experimental intervention delivered through stroke clubs enhanced aspects of mobility but had no effect on falls. PMID- 22544818 TI - Nanostructuring of thermoelectric Mg(2) Si via a nonequilibrium intermediate state. AB - A new route to self-assembled nanocomposite thermoelectric materials is proposed. High-energy mechanical alloying brings materials into a nonequilibrium intermediate state, such as a solid solution with an extended solubility. The large driving force for the transformation to the equilibrium state leads to nanometer-scale microstructure formation, which is ideal for reducing lattice thermal conductivity. PMID- 22544819 TI - Wingspan experience in the treatment of symptomatic intracranial atherosclerotic disease after antithrombotic failure. AB - BACKGROUND AND PURPOSE: Intracranial stenting with the Wingspan system has been used as a revascularization strategy in symptomatic patients with intracranial atherosclerotic disease (ICAD). The latest results of the Stenting versus Aggressive Medical Therapy for Intracranial Artery Stenosis (SAMMPRIS) trial challenge this approach. Our experience in the treatment of symptomatic ICAD with the Wingspan system is reported. MATERIALS AND METHODS: Patients who underwent stenting for symptomatic ICAD were included in the analysis. Demographic data, periprocedural complications, long term radiological and clinical outcomes are reported. RESULTS: 46 lesions were treated in 45 patients. 13 patients (29%) presented with a transient ischemic attack and 32 (71%) with a stroke. 43 patients (95.5%) failed antithrombotic therapy at presentation. One (2%) symptomatic periprocedural (24 h) complication occurred. The 30 day incidence of stroke and vascular death was 6.6%--a fatal hemorrhagic stroke and two non-fatal hemorrhagic strokes. In-stent stenosis (>=50%) was seen in nine (42.8%) lesions, two were symptomatic. CONCLUSIONS: This cohort of patients with symptomatic ICAD who failed antithrombotic medications benefited from angioplasty and stenting with the Wingspan system. PMID- 22544821 TI - Outcome of forced-suction thrombectomy in acute intracranial internal carotid occlusion. AB - OBJECTIVES: Ischemic stroke from acute intracranial distal internal carotid artery (ICA) occlusion usually carries a poor prognosis. Despite the intra arterial revascularization therapies, the results are still unsatisfactory. The aim of this study was to compare the outcomes between two endovascular techniques, the modified Penumbra System (mPS) and mechanical clot disruption (MCD), and to confirm the influence of recanalization on the outcomes. METHODS: In a retrospective review of 39 consecutive cases of acute distal ICA occlusion, the recanalization rates and functional outcomes at 3 months of the two intra arterial techniques during two consecutive periods (May 2006 to February 2009: MCD technique (n=19) vs March 2009 to August 2010: mPS technique (n=20)) were compared. Univariate and multivariate analyses were performed to determine the predictors of a favorable functional outcome. RESULTS: The rate of successful recanalization (Thrombolysis In Cerebral Infarction score 2 or 3) was significantly higher in the mPS group than in the MCD group (85% (17/20) vs 32% (6/19); p=0.001). Favorable outcomes at 3 months (modified Rankin Scale score 0 2) were achieved in 9/20 and 3/19 in the mPS and MCD groups, respectively (45% vs 16%; p=0.048). Binary logistic regression analysis showed that younger age and successful recanalization were independent predictors of a favorable functional outcome. CONCLUSIONS: Forced-suction thrombectomy using the mPS technique may be a viable option for acute distal ICA occlusion and could result in more successful recanalization and a more positive clinical outcome. PMID- 22544820 TI - The stent anchor technique for distal access through a large or giant aneurysm. AB - Large and giant aneurysms pose significant challenges to the endovascular techniques of coil embolization or parent vessel reconstruction. Many large aneurysms are wide-necked with bulbous domes and frequently require stent assisted coiling or flow diversion to reconstruct and preserve flow through the parent artery. Often the wire must be looped in the dome before catheterization of the exiting portion of the parent vessel is possible. In addition, it can be challenging to obtain stable distal purchase of the microcatheter that will allow the loop to be withdrawn from the aneurysm without the entire microcatheter unwinding, resulting in herniation into the aneurysm or proximal vessels. The stent anchor technique, a novel method of obtaining distal purchase that allows straightening of the catheter loop within a large aneurysm for the purposes of stenting for vessel reconstruction across large or giant aneurysms, is presented. This technique may facilitate the use of new stent technologies in the treatment of large aneurysms that have traditionally been exceedingly difficult to treat via an endovascular approach. PMID- 22544822 TI - Marked decrease in coil and stent utilization following introduction of flow diversion technology. AB - BACKGROUND: Flow diversion represents a major paradigm shift in the treatment of unruptured intracranial aneurysms. The potential impact of this technique on coil utilization and adjunctive techniques such as balloon-assisted and stent-assisted coiling is unknown. In this study, the effect of introduction of flow diversion devices on the utilization of coil and adjunctive techniques was assessed. METHODS: A retrospective review was conducted of consecutive patients with unruptured aneurysms treated at our institution comparing two groups: Group 1 (patients treated in the 2-year interval preceding the introduction of the Pipeline Embolization Device (PED) and Group 2 (patients treated during the 2 year interval following introduction in our practice of the PED). RESULTS: Mean aneurysm diameter was 8.7 +/- 6.3 mm in Group 1 and 8.5 +/- 6.1 mm in Group 2 (p=0.79). PED therapy was employed in 38 (21.7%) of 175 aneurysms in Group 2. The proportion of stent-assisted procedures was significantly less in Group 2 than in Group 1 (6.9% vs 14.7%, p=0.04), as was the proportion of patients undergoing parent artery sacrifice (0.6% vs 3.9%, p=0.046). The mean and median number of coils used per aneurysm were 5.4 +/- 3.6 and 5 (range 1-18) for Group 1 and 3.2 +/- 3.2 and 3 (range 0-19) for Group 2 (p <= 0.0001). CONCLUSIONS: Flow diversion represents a disruptive technology. More than one-fifth of unruptured aneurysms at our institution were treated with PED after introduction of this technology, resulting in marked decreases in coil and stent utilization. PMID- 22544823 TI - Hematopoietic chimerism in liver transplantation patients and hematopoietic stem/progenitor cells in adult human liver. AB - Liver transplantation (LT) is a cure for many liver diseases. Blood chimerism of donor origin can develop after LT, which raises the possibility of the existence of hematopoietic stem/progenitor cells (HSPCs) in the liver. We characterized the blood chimerism in a large cohort of 249 LT patients and analyzed putative HSPCs in adult human livers. The overall incidence of chimerism was 6.43%, of which 11.11% was among short-term (1 day to 6 months) and 3.77% was among long-term (6 months to 8 years) LT patients. Hematopoietic Lin(-) CD34(+) CD38(-) CD90(+) populations have been demonstrated to generate long-term lymphomyeloid grafts in transplantations. In human adult livers, we detected Lin(-) CD34(+) CD38(-) CD90(+) populations accounting for 0.03% +/- 0.017% of the total single liver cells and for 0.05% +/- 0.012% of CD45(+) liver cells. Both Lin(-) CD34(+) and Lin(-) CD45(+) liver cells, from extensively perfused human liver grafts, were capable of forming hematopoietic myeloid-lineage and erythroid-lineage methylcellulose colonies. More importantly, Lin(-) CD45(+) or CD45(+) liver cells could be engrafted into hematopoietic cells in an immunodeficient mouse model. These results are the first evidence of the presence of putative HSPC populations in the adult human liver, where the liver is a good ectopic niche. The discovery of the existence of HSPCs in the adult liver have implications for the understanding of extramarrow hematopoiesis, liver regeneration, mechanisms of tolerance in organ transplantation, and de novo cancer recurrence in LT patients. CONCLUSION: The human adult liver contains a small population of HSPCs. In LT patients, there are two types of chimerisms: transient chimerism, resulting from mature leucocytes, and long-term chimerism, derived from putative HSPCs in the liver graft. PMID- 22544824 TI - Computational identification of self-inhibitory peptides from envelope proteins. AB - Fusion process is known to be the initial step of viral infection and hence targeting the entry process is a promising strategy to design antiviral therapy. The self-inhibitory peptides derived from the enveloped (E) proteins function to inhibit the protein-protein interactions in the membrane fusion step mediated by the viral E protein. Thus, they have the potential to be developed into effective antiviral therapy. Herein, we have developed a Monte Carlo-based computational method with the aim to identify and optimize potential peptide hits from the E proteins. The stability of the peptides, which indicates their potential to bind in situ to the E proteins, was evaluated by two different scoring functions, dipolar distance-scaled, finite, ideal-gas reference state and residue-specific all-atom probability discriminatory function. The method was applied to alpha helical Class I HIV-1 gp41, beta-sheet Class II Dengue virus (DENV) type 2 E proteins, as well as Class III Herpes Simplex virus-1 (HSV-1) glycoprotein, a E protein with a mixture of alpha-helix and beta-sheet structural fold. The peptide hits identified are in line with the druggable regions where the self-inhibitory peptide inhibitors for the three classes of viral fusion proteins were derived. Several novel peptides were identified from either the hydrophobic regions or the functionally important regions on Class II DENV-2 E protein and Class III HSV-1 gB. They have potential to disrupt the protein-protein interaction in the fusion process and may serve as starting points for the development of novel inhibitors for viral E proteins. PMID- 22544826 TI - Abstracts of the XIII Symposium of the International Society of Oncology Pharmacy Practitioners. May 9-11, 2012. Melbourne, Australia. PMID- 22544827 TI - Piezotronic effect on the transport properties of GaN nanobelts for active flexible electronics. AB - The transport properties of GaN nanobelts (NBs) are tuned using a piezotronic effect when a compressive/tensile strain is applied on the GaN NB. This is mainly due to a change in Schottky barrier height (SBH). A theoretical model is proposed to explain the observed phenomenon. PMID- 22544828 TI - Targeting 'high-risk' individuals. PMID- 22544829 TI - Traumatic and non-traumatic spinal cord impairment in New Zealand: incidence and characteristics of people admitted to spinal units. AB - This paper estimates the incidence (all ages) of spinal cord neurological impairment (SCI; traumatic and non-traumatic) in New Zealand and describes pre SCI characteristics and early post-SCI outcomes for participants (16-64 years) in this longitudinal study. Demographic and clinical data on all people admitted to New Zealand's two spinal units (mid-2007 to mid-2009) were included for the estimate of incidence. Participants in this longitudinal study were asked at first interview about pre-SCI socio-demographic, health and behavioural characteristics, and about post-SCI symptoms, general health status (EQ-5D) and disability (WHODAS 12-item). Age-adjusted incidence rates (95% CI) for European, Maori, Pacific and 'Other' ethnicities were 29 (24-34), 46 (30-64), 70 (40-100) and 16 (9-22) per million, respectively. Interviews with 118 (73%) participants (16-64 years), occurred 6.5 months post-SCI. Most reported bother with symptoms, and problems with health status and disability. Compared with Europeans, the incidence of SCI is high among Maori and particularly high among Pacific people. Six months after SCI, proximate to discharge from the spinal units, considerable symptomatic, general health and disability burden was borne by people with SCI. PMID- 22544831 TI - Large-scale synthesis of ultra-small-sized silver nanoparticles. PMID- 22544830 TI - Attenuation of blast pressure behind ballistic protective vests. AB - BACKGROUND: Clinical studies increasingly report brain injury and not pulmonary injury following blast exposures, despite the increased frequency of exposure to explosive devices. The goal of this study was to determine the effect of personal body armour use on the potential for primary blast injury and to determine the risk of brain and pulmonary injury following a blast and its impact on the clinical care of patients with a history of blast exposure. METHODS: A shock tube was used to generate blast overpressures on soft ballistic protective vests (NIJ Level-2) and hard protective vests (NIJ Level-4) while overpressure was recorded behind the vest. RESULTS: Both types of vest were found to significantly decrease pulmonary injury risk following a blast for a wide range of conditions. At the highest tested blast overpressure, the soft vest decreased the behind armour overpressure by a factor of 14.2, and the hard vest decreased behind armour overpressure by a factor of 56.8. Addition of body armour increased the 50th percentile pulmonary death tolerance of both vests to higher levels than the 50th percentile for brain injury. CONCLUSIONS: These results suggest that ballistic protective body armour vests, especially hard body armour plates, provide substantial chest protection in primary blasts and explain the increased frequency of head injuries, without the presence of pulmonary injuries, in protected subjects reporting a history of blast exposure. These results suggest increased clinical suspicion for mild to severe brain injury is warranted in persons wearing body armour exposed to a blast with or without pulmonary injury. PMID- 22544832 TI - Multiple annular lesions on the legs. PMID- 22544833 TI - As with tuberculosis, earlier identification and treatment is the way to tackle HIV. PMID- 22544834 TI - Global health research needs to focus on clinical trials to deliver products for patients, says report. PMID- 22544835 TI - Gastroenterologist overturns GMC's "irrational" misconduct ruling. PMID- 22544836 TI - Winter appeal latest: BMJ readers raise almost 34,000 pound for Lifebox. PMID- 22544837 TI - Reach and effectiveness of a community program to reduce smoking among ethnic Turkish residents in Rotterdam, the Netherlands: a quasi-experimental design. AB - INTRODUCTION: Community interventions have been considered promising strategies to reduce smoking prevalence among ethnic minority populations. We assessed the reach and effectiveness of a community program targeted at the Turkish population in Rotterdam, the Netherlands. METHODS: The study had a quasi-experimental design, with 1 pretest and 1 posttest among 18- to 60-year-old Turkish residents in a district in Rotterdam (n = 388 at pretest) and in a comparison area in the city of Utrecht (n = 389 at pretest). The surveys included measures of reach and measures of effectiveness. Logistic regression analysis assessed changes in the outcome measures over time, adjusting for sex, age, and educational level. RESULTS: At posttest, more smokers (62.5%) perceived pros of quitting, and 8.2% had quit. Compared with the comparison group, in the intervention group the changes tended to be greater, but differences were not statistically significant. Of all respondents, 61.2% recognized at least 1 program component, and 23.1% participated in at least 1. CONCLUSIONS: Based on the greater changes in the intervention group (particularly regarding quit rates and pros of smoking), this community intervention can become a promising strategy. To increase potential effectiveness, participation rates need to increase and interventions should last longer and include smoking-cessation support. PMID- 22544839 TI - Panic attack history and anxiety sensitivity in relation to cognitive-based smoking processes among treatment-seeking daily smokers. AB - INTRODUCTION: Empirical research has found that panic attacks are related to increased risk of more severe nicotine withdrawal and poor cessation outcome. Anxiety sensitivity (AS; fear of anxiety and related sensations) has similarly been found to be related to an increased risk of acute nicotine withdrawal and poorer cessation outcome. However, research has yet to examine the relative contributions of panic attacks and AS in terms of cognitive-based smoking processes (e.g., negative reinforcement smoking expectancies, addictive and negative affect-based reduction smoking motives, barriers to cessation, problem symptoms experienced while quitting). METHOD: Participants (n = 242; 57.4% male; M (age) = 38.1) were daily smokers recruited as a part of a larger randomized control trial for smoking cessation. It was hypothesized that both panic attacks and AS would uniquely and independently predict the studied cognitive-based smoking processes. RESULTS: As hypothesized, AS was uniquely and positively associated with all smoking processes after controlling for average number of cigarettes smoked per day, current Axis I diagnosis, and participant sex. However, panic attack history was only significantly related to problem symptoms experienced while quitting smoking. CONCLUSIONS: Although past research has demonstrated significant associations between panic attacks and certain aspects of cigarette smoking (e.g., severity of nicotine withdrawal; lower abstinence rates, and negative affect reduction motives), the present findings suggest that AS may be more relevant to understanding beliefs about and motives for smoking behavior as well as perceptions of cessation-related difficulties. PMID- 22544840 TI - Glutamine prevents apoptosis in intestinal epithelial cells and induces differential protective pathways in heat and oxidant injury models. AB - BACKGROUND: Glutamine (GLN) can decrease mortality and length of hospital stay in the critically ill. GLN protects via enhancing protective heat shock proteins (HSPs) in heat stress (HS). GLN's effect on HSPs in oxidant injury and apoptosis remains to be elucidated. The purpose of this study was to determine if GLN protects via decreasing apoptosis during both heat and oxidative stress. METHODS: IEC-18 cells were treated (15 minutes) with 0 mM GLN (control cells [CTs]) or 8 mM GLN and exposed to either lethal injury (44 degrees C for 50 minutes or 4 mM H(2)O(2) for 30 minutes) or nonlethal injury (43 degrees C for 45 minutes or 600 uM H(2)O(2) for 30 minutes). Survival was determined via MTS assay. Injured groups were normalized to noninjured controls. HSPs and cleaved caspase-3 (CC3), a key mediator for apoptosis, were evaluated via Western blot following a 3-hour recovery. RESULTS: MTS assays showed GLN increased survival 4- to 5-fold (P < .001 vs HS CT or H(2)O(2)). Western blot showed GLN increased all 3 HSPs in HS (P < .001 vs HS CTs) but only HSP32 during oxidant injury (P < .02 vs H(2)O(2) only). GLN decreased CC3 in both injuries (P < .03 vs non-GLN-treated cells). CONCLUSIONS: GLN protects intestinal cells from both heat and oxidant injury. HSP25, 32, and 70 levels increased with GLN during HS, but in oxidant injury, only HSP32 increased, suggesting GLN's mechanism of protection may vary in different models of injury. In both injuries, GLN lowered the expression of CC3, indicating prevention of apoptosis may be a key mechanism by which GLN protects. PMID- 22544842 TI - Correction. PMID- 22544838 TI - From men to mice: CHRNA5/CHRNA3, smoking behavior and disease. AB - INTRODUCTION: The nicotinic acetylcholine receptor (nAChR) gene cluster CHRNA5-A3 B4 on chromosome 15 has been the subject of a considerable body of research over recent years. Two highly correlated single nucleotide polymorphisms (SNPs) within this region--rs16969968 in CHRNA5 and rs1051730 in CHRNA3--have generated particular interest. METHODS: We reviewed the literature relating to SNPs rs16969968 and rs1051730 and smoking-related phenotypes, and clinical and preclinical studies, which shed light on the mechanisms underlying these associations. RESULTS: Following the initial discovery of an association between this locus and smoking behavior, further associations with numerous phenotypes have been subsequently identified, including smoking-related behaviors, diseases, and cognitive phenotypes. Potential mechanisms thought to underlie these have also been described, as well as possible gene * environment interaction effects. CONCLUSIONS: Perhaps counter to the usual route of scientific inquiry, these initial findings, based exclusively on human samples and strengthened by their identification through agnostic genome-wide methods, have led to preclinical research focused on determining the mechanism underlying these associations. Progress has been made using knockout mouse models, highlighting the importance of alpha5 nAChR subunits in regulating nicotine intake, particularly those localized to the habenula-interpeduncular nucleus pathway. Translational research seeking to evaluate the effect of nicotine challenge on brain activation as a function of rs16969968 genotype using neuroimaging technologies is now called for, which may point to new targets for novel smoking cessation therapies. PMID- 22544841 TI - Therapeutic oral sesame oil is ineffectual against monocrotaline-induced sinusoidal obstruction syndrome in rats. AB - BACKGROUND: The chemotherapeutic drug oxaliplatin causes sinusoidal obstruction syndrome (SOS), which is analogous to that of monocrotaline-induced SOS. Sesame oil is a nutrient-rich antioxidant in alternative medicine. It contains phenol, sesamin, sesamol, and sesamolin, all of which contribute to its antioxidant property. The authors investigated the therapeutic effect of oral sesame oil against monocrotaline-induced SOS in rats. METHODS: Male Sprague-Dawley rats were gavaged with monocrotaline (90 mg/kg) to induce SOS. Control rats were treated with saline only at 0 and 24 hours. Sesame oil (0.5, 1, 2, or 4 mL/kg, orally) was given 24 hours after monocrotaline in rats. Blood samples were collected at 24 and 48 hours after monocrotaline was given to assess the level of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Histopathology was also assessed 48 hours after monocrotaline was given. RESULTS: AST and ALT were significantly higher in monocrotaline-treated rats than in control rats. Oral sesame oil did not decrease AST and ALT in monocrotaline-treated rats. In addition, liver pathology revealed that oral sesame oil had no therapeutic effect against SOS. CONCLUSION: Oral sesame oil is therapeutically ineffectual against monocrotaline-induced SOS. PMID- 22544843 TI - Intoxication with a tropenol ester. AB - BACKGROUND: While the effects of medicinal products are investigated in depth before approval, often very little is known about the intermediates occurring during synthesis. The pharmacological properties of these intermediates can differ substantially from those of the end product. AIMS: To describe a work accident involving intoxication with such an intermediate, tropenol ester. CASE REPORT: A healthy 40-year-old chemical-technical operative erroneously used a scrubbing brush that had just been used to clear up tropenol ester, contaminating his work clothes. Presumably, contact was made with his skin when removing his work clothes later. Shortly thereafter, he developed signs of anticholinergic intoxication with mydriasis, dry mouth, abnormal coordination and later sleepiness and seizures. The patient received intensive medical treatment. Two weeks later, the anticholinergic symptoms had subsided. Qualitative analysis of a urine sample showed traces of tropenol ester. The substance is a muscarinic acetylcholine receptor antagonist. CONCLUSIONS: The clinical symptoms and biomonitoring suggest that intoxication with tropenol ester had occurred, which, as a tertiary amine, readily passes through the blood-brain barrier. The protracted course suggests high affinity for the receptor. Appropriate safety precautions must be taken when handling research substances and intermediates of unknown toxicity. PMID- 22544844 TI - Profile: The Kilifi Health and Demographic Surveillance System (KHDSS). AB - The Kilifi Health and Demographic Surveillance System (KHDSS), located on the Indian Ocean coast of Kenya, was established in 2000 as a record of births, pregnancies, migration events and deaths and is maintained by 4-monthly household visits. The study area was selected to capture the majority of patients admitted to Kilifi District Hospital. The KHDSS has 260 000 residents and the hospital admits 4400 paediatric patients and 3400 adult patients per year. At the hospital, morbidity events are linked in real time by a computer search of the population register. Linked surveillance was extended to KHDSS vaccine clinics in 2008. KHDSS data have been used to define the incidence of hospital presentation with childhood infectious diseases (e.g. rotavirus diarrhoea, pneumococcal disease), to test the association between genetic risk factors (e.g. thalassaemia and sickle cell disease) and infectious diseases, to define the community prevalence of chronic diseases (e.g. epilepsy), to evaluate access to health care and to calculate the operational effectiveness of major public health interventions (e.g. conjugate Haemophilus influenzae type b vaccine). Rapport with residents is maintained through an active programme of community engagement. A system of collaborative engagement exists for sharing data on survival, morbidity, socio-economic status and vaccine coverage. PMID- 22544845 TI - Cohort profile: the Fremantle Diabetes Study. PMID- 22544846 TI - Long-term sickness absence due to adjustment disorder. AB - BACKGROUND: Although adjustment disorder is frequently reported in clinical settings, scientific evidence is scarce regarding its impact on sickness absence and the variables associated with sickness absence duration. AIMS: To report sickness absence duration and to identify predictors of long-term sickness absence in patients with adjustment disorder. METHODS: This observational, prospective study included subjects with non-work-related sickness absence (>15 days) after a diagnosis of adjustment disorder. A stepwise logistic regression analysis was conducted to identify the best predictors of long-term sickness absence (>= 6 months). RESULTS: There were 1182 subjects in the final analysis. The median duration of sickness absence due to adjustment disorder was 91 days. Twenty-two per cent of the subjects reported long-term sickness absence. After multivariate analysis, comorbidity (OR = 2.23, 95% CI 1.43-3.49), age (25-34 years old versus <25 years old: OR = 2.78, 95% CI 1.27-6.07; 35-44 years old versus <25 years old: OR = 3.70, 95% CI 1.71-7.99; 45-54 years old versus <25 years old: OR = 3.58, 95% CI 1.60-8.02; >= 55 years old versus <25 years old: OR = 6.35, 95% CI 2.64-15.31) and occupational level (blue collar versus white collar: OR = 1.52, 95% CI 1.10-2.09) remained significantly associated with long term sickness absence. Comorbidity was the strongest predictor. CONCLUSIONS: It is possible to predict long-term sickness absence due to adjustment disorder on the basis of demographic, work-related and clinical information available during the basic assessment of the patient. PMID- 22544847 TI - Quantitative analysis of cellular proliferation and differentiation of the human seminiferous epithelium in vitro. AB - The aim of the present work was to quantitate the temporal and stage-specific effects of follicle-stimulating hormone (FSH) and testosterone on the proliferation and differentiation capacities of the human seminiferous epithelium. Seminiferous tubule fragments were kept in culture for 28 days and 5 bromo-2'-deoxyuridine incorporation was used to determine cell proliferation. Data demonstrated a gradual loss of germ cells during the culture period, no decrease in Sertoli cell numbers, and maintenance of the general architecture of the seminiferous tubules. Both FSH and testosterone increased germ cell survival, spermatogonia proliferation, and germ cell differentiation, especially during the first week of culture. At the end of the first week, differentiation of spermatocytes was observed, especially when 50 IU/L FSH and 1 umol/L testosterone were used. In conclusion, using this methodology, it was possible to quantify germ cell proliferation and differentiation, in a reproducible way, with results compatible with the timing of human spermatogenesis in vivo. PMID- 22544848 TI - Uterine lavage or aspirate: which view of the intrauterine environment? AB - Fluid within the uterine cavity provides the microenvironment for preimplantation blastocyst development and early implantation. Analysis of uterine fluid sampled by aspiration or lavage provides a view of this microenvironment but the similarity or otherwise of the sample components is not known. This study compared proteins in aspirates versus lavage samples taken sequentially from the same women, using surface-enhanced laser desorption/ionization-time of flight mass spectrometry (SELDI-TOF-MS), multiplex cytokine assays, and an activity assay for proprotein convertase 6. Both lavage and aspiration enabled analysis of uterine fluid components, but they provided substantially different protein profiles. Although there were many similarities in overall protein profiles and most specific proteins examined were detected in both fluids, these were neither qualitatively nor quantitatively comparable within each participant. A likely explanation is that lavage samples the entire uterine cavity including washing the endometrial surface (glycocalyx), whereas aspiration sampling is very local. PMID- 22544849 TI - Ghrelin: new insights into female reproductive system-associated disorders and pregnancy. AB - Ghrelin is considered the endogenous ligand of growth hormone secretagogue receptor type 1a, and its modulatory actions have been demonstrated in a large array of endocrine and nonendocrine functions. According to recent studies, ghrelin seems to act at different levels of the reproductive system, exerting predominantly inhibitory effects on mammalian reproduction. It has been shown to influence the reproductive system by regulating hormone secretion from the brain and by acting directly on the gonads to affect tissue development and steroidogenesis. Thus, the endocrine network, which integrates energy balance and fertility, might involve ghrelin. Furthermore, ghrelin levels and actions have been assessed in various female reproductive system disorders. The findings could lead to a better understanding of the pathogenesis of these disorders and, possibly, to more beneficial therapeutic strategies. PMID- 22544850 TI - Successful treatment of methicillin-resistant Staphylococcus epidermidis prosthetic joint infection with telavancin. PMID- 22544851 TI - Comment on: daily 300 mg dose of linezolid for multidrug-resistant and extensively drug-resistant tuberculosis: updated analysis of 51 patients. PMID- 22544852 TI - Perioperative management of peripheral vascular trauma. AB - Peripheral vascular trauma is not uncommon in the civilian setting, and it can be uniquely challenging because of the limited time during which intervention can salvage an ischemic extremity. Injuries can be from a blunt or penetrating mechanism, and these injuries can be isolated or can be in the setting of a complex multisystem trauma. The intent of this review is to discuss the perioperative management of peripheral vascular trauma with an emphasis of predicting, preventing, and managing common postoperative complications. PMID- 22544853 TI - Livestock-associated MRSA ST398 carriage in pig slaughterhouse workers related to quantitative environmental exposure. AB - OBJECTIVES: To assess livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) carriage among workers in pig slaughterhouses and assess associated risk factors, including occupational exposure to LA-MRSA. METHODS: A cross-sectional study in three Dutch pig slaughterhouses was undertaken. Nasal swabs of participants were taken. Nasal swabs and surface wipes, air and glove samples were screened for presence of methicillin-resistant Staphylococcus aureus (MRSA). MRSA was quantitatively determined on gloves and in air samples by culturing and real-time PCR. RESULTS: 11 of 341 (3.2%) participants were identified as nasal MRSA carriers. MRSA-positive workers were predominantly found at the start of the slaughter process. Major risk factors for carriage were working in the lairage and working in the scalding and dehairing area. Most nasal isolates (73%) belonged to the LA-MRSA clone ST398. MRSA ST398-positive environmental samples were found throughout the slaughter process. A clear decrease was seen along the slaughterline in the number of MRSA-positive samples and in the MRSA amount per sample. CONCLUSIONS: This study showed that working in the lairage area or scalding and dehairing area were the major risk factors for MRSA carriage in pig slaughterhouse workers, while the overall prevalence of MRSA carriage is low. Occupational exposure to MRSA decreased along the slaughterline, and the risk of carriage showed a parallel decrease. PMID- 22544854 TI - Impact of organisational change on mental health: a systematic review. AB - Although limited evidence is available, organisational change is often cited as the cause of mental health problems. This paper provides an overview of the current literature regarding the impact of organisational change on mental health. A systematic search in PUBMED, PsychInfo and Web of Knowledge combining MeSH search terms for exposure and outcome. The criterion for inclusion was original data on exposure to organisational change with mental health problems as outcome. Both cross-sectional and longitudinal studies were included. We found in 11 out of 17 studies, an association between organisational change and elevated risk of mental health problems was observed, with a less provident association in the longitudinal studies. Based on the current research, this review cannot provide sufficient evidence of an association between organisational change and elevated risk of mental health problems. More studies of long-term effects are required including relevant analyses of confounders. PMID- 22544855 TI - Log Gaussian Cox processes and spatially aggregated disease incidence data. AB - This article presents a methodology for modeling aggregated disease incidence data with the spatially continuous log-Gaussian Cox process. Statistical models for spatially aggregated disease incidence data usually assign the same relative risk to all individuals in the same reporting region (census areas or postal regions). A further assumption that the relative risks in two regions are independent given their neighbor's risks (the Markov assumption) makes the commonly used Besag-York-Mollie model computationally simple. The continuous model proposed here uses a data augmentation step to sample from the posterior distribution of the exact locations at each step of an Markov chain Monte Carlo algorithm, and models the exact locations with an log-Gaussian Cox process. A simulation study shows the log-Gaussian Cox process model consistently outperforming the Besag-York-Mollie model. The method is illustrated by making inference on the spatial distribution of syphilis risk in North Carolina. The effect of several known social risk factors are estimated, and areas with risk well in excess of that expected given these risk factors are identified. PMID- 22544856 TI - A 54-year-old diabetic man with low serum cholesterol. PMID- 22544857 TI - Commentary. PMID- 22544858 TI - Commentary. PMID- 22544859 TI - A 69-year-old man with long-standing thrombocytopenia. PMID- 22544860 TI - Lab on a stamp: paper-based diagnostic tools. Interview by Molly Webster and Vikram Sheel Kumar. PMID- 22544863 TI - Observation and creativity: Leonardo da Vinci. PMID- 22544866 TI - Review: insufficient evidence available on parent training programmes for ADHD in children. PMID- 22544864 TI - Physical and chemical strategies for therapeutic delivery by using polymeric nanoparticles. AB - A significant challenge that most therapeutic agents face is their inability to be delivered effectively. Nanotechnology offers a solution to allow for safe, high-dose, specific delivery of pharmaceuticals to the target tissue. Nanoparticles composed of biodegradable polymers can be designed and engineered with various layers of complexity to achieve drug targeting that was unimaginable years ago by offering multiple mechanisms to encapsulate and strategically deliver drugs, proteins, nucleic acids, or vaccines while improving their therapeutic index. Targeting of nanoparticles to diseased tissue and cells assumes two strategies: physical and chemical targeting. Physical targeting is a strategy enabled by nanoparticle fabrication techniques. It includes using size, shape, charge, and stiffness among other parameters to influence tissue accumulation, adhesion, and cell uptake. New methods to measure size, shape, and polydispersity will enable this field to grow and more thorough comparisons to be made. Physical targeting can be more economically viable when certain fabrication techniques are used. Chemical targeting can employ molecular recognition units to decorate the surface of particles or molecular units responsive to diseased environments or remote stimuli. In this review, we describe sophisticated nanoparticles designed for tissue-specific chemical targeting that use conjugation chemistry to attach targeting moieties. Furthermore, we describe chemical targeting using stimuli responsive nanoparticles that can respond to changes in pH, heat, and light. PMID- 22544868 TI - Basal segmental auto-transplantation after pneumonectomy for advanced central lung cancer. AB - In patients with central lung cancer that extensively involves the bronchus/pulmonary artery, a double-sleeve lobectomy is often difficult to perform. We describe a case of post-pneumonectomy basal segmental auto transplantation using a lung preservation technique that uses cold low-potassium dextran glucose solution to protect the lung graft from ischaemia-reperfusion injury during the ex situ division of the segmental graft and the pathological investigations for the clearance of the surgical margins. A right basal segmental auto-transplantation procedure was performed in a patient with stage-IIIA squamous cell lung cancer. This technique could allow extensive pulmonary resection while minimizing the loss of pulmonary reserve. PMID- 22544867 TI - Genetic evidence for the reduction of brassinosteroid levels by a BAHD acyltransferase-like protein in Arabidopsis. AB - Brassinosteroids (BRs) are a group of steroidal hormones involved in plant development. Although the BR biosynthesis pathways are well characterized, the BR inactivation process, which contributes to BR homeostasis, is less understood. Here, we show that a member of the BAHD (for benzylalcohol O-acetyltransferase, anthocyanin O-hydroxycinnamoyltransferase, anthranilate N hydroxycinnamoyl/benzoyltransferase, and deacetylvindoline 4-O-acetyltransferase) acyltransferase family may play a role in BR homeostasis in Arabidopsis (Arabidopsis thaliana). We isolated two gain-of-function mutants, brassinosteroid inactivator1-1Dominant (bia1-1D) and bia1-2D, in which a novel BAHD acyltransferase-like protein was transcriptionally activated. Both mutants exhibited dwarfism, reduced male fertility, and deetiolation in darkness, which are typical phenotypes of plants defective in BR biosynthesis. Exogenous BR treatment rescued the phenotypes of the bia1-1D mutant. Endogenous levels of BRs were reduced in the bia1-1D mutant, demonstrating that BIA1 regulates endogenous BR levels. When grown in darkness, the bia1 loss-of-function mutant showed a longer hypocotyl phenotype and was more responsive to exogenous BR treatment than the wild-type plant. BIA1 expression was predominantly observed in the root, where low levels of BRs were detected. These results indicate that the BAHD acyltransferase family member encoded by BIA1 plays a role in controlling BR levels, particularly in the root and hypocotyl in darkness. Taken together, our study provides new insights into a mechanism that maintains BR homeostasis in Arabidopsis, likely via acyl conjugation of BRs. PMID- 22544865 TI - Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application. AB - Aldehyde dehydrogenases (ALDHs) belong to a superfamily of enzymes that play a key role in the metabolism of aldehydes of both endogenous and exogenous derivation. The human ALDH superfamily comprises 19 isozymes that possess important physiological and toxicological functions. The ALDH1A subfamily plays a pivotal role in embryogenesis and development by mediating retinoic acid signaling. ALDH2, as a key enzyme that oxidizes acetaldehyde, is crucial for alcohol metabolism. ALDH1A1 and ALDH3A1 are lens and corneal crystallins, which are essential elements of the cellular defense mechanism against ultraviolet radiation-induced damage in ocular tissues. Many ALDH isozymes are important in oxidizing reactive aldehydes derived from lipid peroxidation and thereby help maintain cellular homeostasis. Increased expression and activity of ALDH isozymes have been reported in various human cancers and are associated with cancer relapse. As a direct consequence of their significant physiological and toxicological roles, inhibitors of the ALDH enzymes have been developed to treat human diseases. This review summarizes known ALDH inhibitors, their mechanisms of action, isozyme selectivity, potency, and clinical uses. The purpose of this review is to 1) establish the current status of pharmacological inhibition of the ALDHs, 2) provide a rationale for the continued development of ALDH isozyme selective inhibitors, and 3) identify the challenges and potential therapeutic rewards associated with the creation of such agents. PMID- 22544869 TI - Carotid-cavernous fistula treatment with ethylene vinyl alcohol (onyx) exclusively through anterior venous approach. AB - The type of venous drainage of a direct carotid-cavernous fistula is an important issue to consider for the endovascular therapeutic decision. In case of an inadequate posterior drainage associated with a good anterior drainage, the facial vein is a useful alternative. The exclusive embolization with ethylene vinyl alcohol (EVOH Onyx), arterial and/or venous via the internal carotid artery (ICA) occlusion has been used successfully, in a few cases until now. Nevertheless, the use of this method through anterior transvenous approach has not been previously described. Presented here is the case of a 13-year-old female patient with left posttraumatic carotid-cavernous fistula, with predominant anterior drainage, as well as carrier of traumatic occlusion of the contralateral ICA. The treatment was by means of a transvenous approach with transient occlusion of the left ICA. PMID- 22544870 TI - Technical factors affecting the accuracy of bedside IVC filter placement using intravascular ultrasound. AB - PURPOSE: To compare the accuracy of inferior vena cava (IVC) filter placement using a bedside technique guided by intravascular ultrasound (IVUS) with a concurrent experience of filter deployment with fluoroscopic venogram imaging. METHODS: From November 2006 to December 2009, 195 consecutive IVC filters were placed to prevent pulmonary embolism in 120 high-risk patients without lower limb deep vein thrombosis (DVT) and 75 patients with DVT and anticoagulation contraindications. Filter insertion techniques included bedside IVUS-guided (n = 97) and fluoroscopic-guided (n = 98) procedures. Before mid-2008, 2 bedside IVUS guided protocols were used evolving from a single-puncture, pullback technique (n = 48), in which the measured distance from the venous access site to the IVC landing zone then allowed a calibrated reinsertion of a 7F delivery sheath and filter deployment. After mid-2008, a single puncture 8F sheath technique (n = 48) using IVUS to position the delivery sheath tip within the IVC landing zone without catheter or sheath measurement or reinsertion was used. Venous access was via the right femoral (84 IVUS and 56 fluoroscopy), left femoral (10 IVUS and 16 fluoroscopy), or right internal jugular vein (3 IVUS and 26 fluoroscopy). The 3 filter insertion techniques were compared for "optimal" IVC placement defined as the filter positioning between L1 and L4 vertebrae with tilt <15 degrees based on postprocedure abdominal x-rays or venography. RESULTS: Filter malposition occurred with 6% (6 of 97) bedside IVUS-guided procedures with no malpositions during fluoroscopic imaging. Malposition was lower with the evolved sheath (4%, 2 of 48) compared with the earlier pullback (8%, 4 of 48) insertion technique (P = .03). The incidence of the filter malposition during IVUS-guided deployment was highest using left femoral access (4 of 10) compared with right femoral (2 of 84) or internal jugular (0 of 3) vein access (P < .01). Filter tilt occurred more after IVUS-guided procedure (10 of 97) than fluoroscopic procedure (3 of 98; P = .05) and was most frequent for left femoral access (5 of 10 IVUS and 1 of 16 fluoroscopy; P < .01) and was not related to filter type (P = .13). CONCLUSION: Our current bedside IVUS-guided IVC filter technique using a single venous puncture and single sheath positioning has improved the placement accuracy. Left femoral venous access should be avoided to minimize the occurrence of filter malpositioning and tilt. PMID- 22544871 TI - Long-term follow-up of intracranial aneurysms treated with endovascular coiling: experience from one institution. AB - BACKGROUND: Our aim was to evaluate the long-term treatment results in patients with intracranial aneurysms treated with endovascular techniques. METHODS: Forty four patients treated due to intracranial aneurysms between 1996 and 2002 were investigated with a time-of-flight sequence magnetic resonance angiography (TOF MRA). RESULTS: Depending on the assessment, 47% to 51% of the treated aneurysms had a residual neck at the last digital subtraction angiography follow-up. There was filling of the aneurysm base (2%) in only 1 patient, whereas the remaining aneurysms were totally occluded. A TOF MRA performed 6 to 14 (mean 9.68) years after the last procedure showed a stable result in 93.9% of the treated aneurysms. There were no de novo aneurysms and previously untreated aneurysms were unchanged in size. CONCLUSION: Our long-term follow-up showed a stable result in previously coiled intracranial aneurysms. PMID- 22544873 TI - Changes in left atrial volume in diabetes mellitus: more than diastolic dysfunction? AB - AIM: To evaluate left atrial (LA) volume and function as assessed by strain and strain rate derived from 2D speckle tracking and their association with diastolic dysfunction (DD) in patients with diabetes mellitus (DM). METHODS AND RESULTS: Seventy three patients with DM were compared with age- and gender-matched normal controls; 30 patients with DM alone were compared to those with hypertension (HT) alone. The maximum LA volume, traditional measures of atrial function, 2D strain and strain rate were analysed. The LA indexed volume (LAVI) was larger in DM group than that in normal controls (38.2 +/- 9.9 vs. 20.5 +/- 4.8 ml/m(2), P< 0.0001), as well as in DM alone compared with hypertensive patients (33.9 +/- 10 vs. 25.7 +/- 8 ml/m(2), P< 0.0001). Global strain was significantly reduced in the DM group compared with that in normal controls (22.5 +/- 8.67 vs. 30.6 +/- 8.27%; P< 0.0001) but was similar with HT. There was a weak correlation between LAVI and global strain with increasing grades of DD (r= 0.439, P< 0.0001 and r= - 0.316, P< 0.0001, respectively) in the diabetic group. However, there was no significant difference in LAVI between these groups. A logistic regression analysis for predictors of LAVI demonstrated that only diabetes was a determinant of LAVI. Patients with diabetes showed a significant reduction in global strain compared with normal controls but no difference with increasing grades of diastolic function. CONCLUSIONS: LA enlargement in DM is independent of associated HT and diastolic function. LA enlargement is associated with LA dysfunction as evaluated by 2D strain. It is likely that a combination of DD and a diabetic atrial myopathy contribute to LA enlargement in patients with DM. PMID- 22544872 TI - Limiting multiple sclerosis related axonopathy by blocking Nogo receptor and CRMP 2 phosphorylation. AB - Multiple sclerosis involves demyelination and axonal degeneration of the central nervous system. The molecular mechanisms of axonal degeneration are relatively unexplored in both multiple sclerosis and its mouse model, experimental autoimmune encephalomyelitis. We previously reported that targeting the axonal growth inhibitor, Nogo-A, may protect against neurodegeneration in experimental autoimmune encephalomyelitis; however, the mechanism by which this occurs is unclear. We now show that the collapsin response mediator protein 2 (CRMP-2), an important tubulin-associated protein that regulates axonal growth, is phosphorylated and hence inhibited during the progression of experimental autoimmune encephalomyelitis in degenerating axons. The phosphorylated form of CRMP-2 (pThr555CRMP-2) is localized to spinal cord neurons and axons in chronic active multiple sclerosis lesions. Specifically, pThr555CRMP-2 is implicated to be Nogo-66 receptor 1 (NgR1)-dependent, since myelin oligodendrocyte glycoprotein (MOG)(35-55)-induced NgR1 knock-out (ngr1(-)(/)(-)) mice display a reduced experimental autoimmune encephalomyelitis disease progression, without a deregulation of ngr1(-)(/)(-) MOG(35-55)-reactive lymphocytes and monocytes. The limitation of axonal degeneration/loss in experimental autoimmune encephalomyelitis-induced ngr1(-)(/)(-) mice is associated with lower levels of pThr555CRMP-2 in the spinal cord and optic nerve during experimental autoimmune encephalomyelitis. Furthermore, transduction of retinal ganglion cells with an adeno-associated viral vector encoding a site-specific mutant T555ACRMP-2 construct, limits optic nerve axonal degeneration occurring at peak stage of experimental autoimmune encephalomyelitis. Therapeutic administration of the anti Nogo(623-640) antibody during the course of experimental autoimmune encephalomyelitis, associated with an improved clinical outcome, is demonstrated to abrogate the protein levels of pThr555CRMP-2 in the spinal cord and improve pathological outcome. We conclude that phosphorylation of CRMP-2 may be downstream of NgR1 activation and play a role in axonal degeneration in experimental autoimmune encephalomyelitis and multiple sclerosis. Blockade of Nogo-A/NgR1 interaction may serve as a viable therapeutic target in multiple sclerosis. PMID- 22544874 TI - Association of abnormal coronary microcirculatory function with impaired response of longitudinal left ventricular function during adenosine stress echocardiography in untreated hypertensive patients. AB - AIMS: Coronary microcirculation is disturbed in hypertensive patients. We investigated the association of coronary flow reserve (CFR) with the response of left ventricular (LV) function as assessed by tissue Doppler imaging (TDI) during adenosine stress echocardiography in never-treated hypertensive patients. METHODS AND RESULTS: We studied 90 hypertensive patients and 30 control subjects, matched for age and sex, by adenosine stress echocardiography. We measured: (i) CFR, E and A Doppler, S', E', A' mitral annulus velocities with TDI, as well as the E'/A' ratio and the E/E' ratio before and during adenosine infusion (ii) the %changes of the measured indices between baseline and adenosine infusion. After adenosine infusion, there was an increase in S', E', and A' in all patients and controls (P < 0.05). Compared with controls and patients with CFR >= 2.5, patients with CFR <2.5 showed a smaller increase in S' (28.6 vs. 30.0 vs. 11.1%, F for interaction = 14.592) and E' (33.3 vs. 33.3 vs.1.5%, F = 28.927) as well as a decrease in E'/A' (9.2 vs. 6.4% vs. -20.0%, F = 5.128) and an increase in E/E' (-6.1 vs. -1.6 vs. 30.5%. F = 12.780) after adenosine infusion (P < 0.05 for all comparisons). CFR was independently related to %changes of TDI parameters (regression coefficient b = 0.576 for S'; b = 0.517 for E'; b = 0.473 for E'/A'; b = -0.520 for E/E', respectively, P < 0.001). By the receiver operating curve, a CFR <2.5 predicted the median changes of all measured TDI markers, with a sensitivity and specificity over 70% (AUC >75%, P < 0.05). CONCLUSION: An abnormal response of the LV longitudinal function during adenosine stress echocardiography is related to impaired CFR in untreated hypertensive patients. PMID- 22544875 TI - Patients' and emergency clinicians' perceptions of improving pre-hospital pain management: a qualitative study. AB - BACKGROUND: The authors aimed to investigate patients' and practitioners' views and experiences of pre-hospital pain management to inform improvements in care and a patient-centred approach to treatment. METHODS: This was a qualitative study involving a single emergency medical system. Data were gathered through focus groups and semi-structured interviews. Participants were purposively sampled from patients transported by ambulance to hospital with a painful condition during the past 6 months, ambulance service and emergency department (ED) clinicians. Interviews were audiotaped, transcribed and thematic analysis was conducted. RESULTS: 55 participants were interviewed: 17 patients, 25 ambulance clinicians and 13 ED clinicians. Key themes included: (1) consider beliefs of patients and staff in pain management; (2) widen pain assessment strategies; (3) optimise non-drug treatment; (4) increase drug treatment options; and (5) enhance communication and coordination along the pre-hospital pain management pathway. Patients and staff expected pain to be relieved in the ambulance; however, refusal of or inadequate analgesia were common. Pain was commonly assessed using a verbal score, but practitioners' views of severity were sometimes discordant with this. Morphine and Entonox were commonly used to treat pain. Reassurance, positioning and immobilisation were used as alternatives to drugs. Pre-hospital pain management could be improved by addressing practitioner and patient barriers, increasing available drugs and developing multi organisational pain management protocols supported by training for staff. CONCLUSIONS: Pain is often poorly managed and undertreated in the pre-hospital environment. The authors' findings may be used to inform guidance, education and policy to improve the pre-hospital pain management pathway. PMID- 22544876 TI - What factors influence emergency department staff attitudes towards using information technology? AB - OBJECTIVES: Information technology (IT) has an important role in the emergency department (ED) functioning, but staff attitudes can influence the way IT is used. Qualitative research into the perceptions of the ED staff has identified a variety of individual, environmental and system factors that may influence attitudes towards using IT. The authors aimed to determine which factors predict attitudes towards using IT and which factors are the most influential. METHODS: Findings from a previous qualitative study were used to develop a self administered questionnaire measuring individual, environmental and system factors, along with staff attitudes towards using IT. The questionnaire was sent to 535 staff working in three English EDs. Simple linear regression was used to examine the relationship between each potential predictor and user attitude, and multiple regression was used to identify the most important predictors. RESULTS: Completed questionnaires were returned by 362/535 participants (68%). The factors with the strongest positive association with staff attitudes towards using IT were the perceived individual impact of technology (r(2)=39%, p<0.001), perceived usefulness (r(2)=7%, p<0.001), perceived ease of use (r(2)=2%, p=0.006), perceived subjective norms (r(2)=1%, p=0.013) and computer experience (r(2)=1%, p=0.034). CONCLUSION: The perceived individual impact of technology is the most important factor in determining ED staff attitude towards using IT. The ED staff are more likely to view using IT systems positively if they can see direct individual benefits arising from their use. PMID- 22544888 TI - Time-of-day-dependent changes in GnRH1 neuronal activities and gonadotropin mRNA expression in a daily spawning fish, medaka. AB - GnRH neurons in the preoptic area and hypothalamus control the secretion of GnRH and form the final common pathway for hypothalamic-pituitary-gonadal axis regulation in vertebrates. Temporal regulation of reproduction by coordinating endogenous physiological conditions and behaviors is important for successful reproduction. Here, we examined the temporal regulation of reproduction by measuring time-of-day-dependent changes in the electrical activity of GnRH1 neurons and in levels of expression of pituitary gonadotropin mRNA using a daily spawning teleost, medaka (Oryzias latipes). First, we performed on-cell patch clamp recordings from GnRH1 neurons that directly project to the pituitary, using gnrh1-green fluorescent protein transgenic medaka. The spontaneous firing activity of GnRH1 neurons showed time-of-day-dependent changes: overall, the firing activity in the afternoon was higher than in the morning. Next, we examined the daily changes in the pituitary gonadotropin transcription level. The expression levels of lhb and fshb mRNA also showed changes related to time of day, peaking during the lights-off period. Finally, we analyzed effects of GnRH on the pituitary. We demonstrated that incubation of isolated pituitary with GnRH increases lhb mRNA transcription several hours after GnRH stimulation, unlike the well-known immediate LH releasing effect of GnRH. From these results, we propose a working hypothesis concerning the temporal regulation of the ovulatory cycle in the brain and pituitary of female medaka. PMID- 22544889 TI - Root repair after contact with mini-implants: systematic review of the literature. AB - This systematic review identified and qualified the current evidence of dental root damage and repair after contact with mini-implants. The electronic databases Cochrane library, Ovid, Scirus, Scopus, and Virtual Health Library were used to search original articles from 1980 to December 2011. The inclusion criteria to select the articles were 1. randomized controlled trials and prospective clinical studies based on trials involving humans, 2. randomized controlled studies in animals, 3. use of mini-implants with a diameter less than 2.5 mm, and 4. root contact evaluation associated with the use of orthodontic mini-implants. Two authors independently reviewed and extracted data from the selected studies and a methodological quality assessment process was used to rank the studies classifying them as low moderate or high quality. The searches retrieved 579 citations. After initial selection, 17 studies were considered eligible and their full texts were assessed. Four of those were excluded because root damage was not evaluated and two were excluded because of overlapping samples. Eleven articles, nine in animals and two in humans, fulfilled the inclusion criteria. From these, two studies were ranked as presenting high methodological quality, eight were judged to be of moderate, and one of low quality. The evidence found suggested that the quality of root repair depends on the amount of damage caused by the mini-implant. When the damage is limited to the cementum or dentin, healing and almost complete and repair of the periodontal structure can occur. Mini-implants that injured the pulp were less likely to result in complete repair of the periodontal tissues. PMID- 22544890 TI - Annual fasting plasma glucose variation increases risk of cancer incidence and mortality in patients with type 2 diabetes: the Taichung Diabetes Study. AB - The study aims to examine whether the annual variations in fasting plasma glucose (FPG) measurements, represented by the coefficient of variation (CV), predict cancer incidence and mortality in the subsequent years independent of traditional risk factors of type 2 diabetic patients. A computerized database of patients with type 2 diabetes of 30 years old and older (n=4805) enrolled in the Diabetes Care Management Program of a medical center before 2006 was analyzed using a time dependent Cox's proportional hazards regression model. The mortality rates for the first, second, and third tertiles of the first annual FPG-CV were 8.64, 12.71, and 30.82 per 1000 person-years respectively. After adjusting for mean FPG, HbA1c, and other risk factors, the annual FPG-CV was independently associated with cancer incidence, cancer mortality, and cancer incidence or mortality, and the corresponding hazard ratios for the third vs first tertile of the annual FPG-CV were 3.03 (1.98, 4.65), 5.04 (2.32, 10.94), and 2.86 (1.91, 4.29) respectively. The annual variation in FPG was a strong predictor of cancer incidence and mortality in type 2 diabetic patients; therefore, glucose variation may be important in the clinical practice of care management and cancer prevention. PMID- 22544891 TI - Concurrent use of indacaterol plus tiotropium in patients with COPD provides superior bronchodilation compared with tiotropium alone: a randomised, double blind comparison. AB - BACKGROUND: Current guidelines recommend treatment with one or more long-acting bronchodilators for patients with moderate or more severe chronic obstructive pulmonary disease (COPD). The authors investigated the approach of dual bronchodilation using indacaterol, a once-daily long-acting beta(2) agonist, and the long-acting muscarinic antagonist tiotropium, compared with tiotropium alone. METHODS: In two identically designed, double-blind, 12-week studies, patients with moderate to severe COPD were randomised to indacaterol 150 MUg once daily or matching placebo. All patients concurrently received open-label tiotropium 18 MUg once daily. The primary outcome was standardised area under the curve of forced expiratory volume in 1 s (FEV(1)) from 5 min to 8 h post dose at week 12. The key secondary outcome was 24 h post-dose ('trough') FEV(1) at week 12. Resting inspiratory capacity (IC) was measured in a subgroup. RESULTS: 1134 and 1142 patients were randomised in studies 1 and 2; 94% and 94% completed. Compared with monotherapy, concurrent therapy increased FEV(1) (area under the curve by 130 and 120 ml, trough by 80 and 70 ml; all p<0.001) and trough IC (by 130 and 100 ml, p<0.01). Cough was more common with indacaterol plus tiotropium (10% and 9%) than with tiotropium alone (4% and 4%). Most cases (~90%) of cough were mild. Other adverse events were similar for the treatment groups. CONCLUSIONS: Compared with tiotropium monotherapy, indacaterol plus tiotropium provided greater bronchodilation and lung deflation (reflected by increased resting IC). Adverse events were similar between treatments apart from mild cough being more common with indacaterol plus tiotropium. These results support COPD guideline recommendations to combine bronchodilators with different mechanisms of action. TRIAL REGISTRATION NUMBERS: NCT00846586 and NCT00877383. PMID- 22544893 TI - Acronyms, pneumothoraces and the impact of international health on the NHS. PMID- 22544892 TI - Effect of mindfulness training on asthma quality of life and lung function: a randomised controlled trial. AB - BACKGROUND: This study evaluated the efficacy of a mindfulness training programme (mindfulness-based stress reduction (MBSR)) in improving asthma-related quality of life and lung function in patients with asthma. METHODS: A randomised controlled trial compared an 8-week MBSR group-based programme (n=42) with an educational control programme (n=41) in adults with mild, moderate or severe persistent asthma recruited at a university hospital outpatient primary care and pulmonary care clinic. Primary outcomes were quality of life (Asthma Quality of Life Questionnaire) and lung function (change from baseline in 2-week average morning peak expiratory flow (PEF)). Secondary outcomes were asthma control assessed by 2007 National Institutes of Health/National Heart Lung and Blood Institute guidelines, and stress (Perceived Stress Scale (PSS)). Follow-up assessments were conducted at 10 weeks, 6 and 12 months. RESULTS: At 12 months MBSR resulted in clinically significant improvements from baseline in quality of life (differential change in Asthma Quality of Life Questionnaire score for MBSR vs control: 0.66 (95% CI 0.30 to 1.03; p<0.001)) but not in lung function (morning PEF, PEF variability and forced expiratory volume in 1 s). MBSR also resulted in clinically significant improvements in perceived stress (differential change in PSS score for MBSR vs control: -4.5 (95% CI -7.1 to -1.9; p=0.001)). There was no significant difference (p=0.301) in percentage of patients in MBSR with well controlled asthma (7.3% at baseline to 19.4%) compared with the control condition (7.5% at baseline to 7.9%). CONCLUSIONS: MBSR produced lasting and clinically significant improvements in asthma-related quality of life and stress in patients with persistent asthma, without improvements in lung function. CLINICAL TRIAL REGISTRATION NUMBER: Asthma and Mindfulness-Based Reduction (MBSR) Identifier: NCT00682669. clinicaltrials.gov. PMID- 22544894 TI - Ventilation heterogeneity in the acinar and conductive zones of the normal ageing lung. AB - RATIONALE: Small airways function studies in lung disease have used three promising multiple breath washout (MBW) derived indices: indices of ventilation heterogeneity in the acinar (S(acin)) and conductive (S(cond)) lung zones, and the lung clearance index (LCI). Since peripheral lung structure is known to change with age, ventilation heterogeneity is expected to be affected too. However, the age dependence of the MBW indices of ventilation heterogeneity in the normal lung is unknown. OBJECTIVES: The authors systematically investigated S(acin), S(cond) or LCI as a function of age, testing also the robustness of these relationships across two laboratories. METHODS: MBW tests were performed by never-smokers (50% men) in the age range 25-65 years, with data gathered across two laboratories (n=120 and n=60). For comparison with the literature, the phase III slopes from classical single breath washout tests were also acquired in one group (n=120). MEASUREMENTS AND MAIN RESULTS: All three MBW indices consistently increased with age, representing a steady worsening of ventilation heterogeneity in the age range 25-65. Age explained 7-16% of the variability in S(acin) and S(cond) and 36% of the variability in LCI. There was a small but significant gender difference only for S(acin). Classical single breath washout phase III slopes also showed age dependencies, with gender effects depending on the normalisation method used. CONCLUSIONS: With respect to the clinical response, age is a small but consistent effect that needs to be factored in when using the MBW indices for the detection of small airways abnormality in disease. PMID- 22544895 TI - Stability of inflammatory phenotypes in asthma. PMID- 22544898 TI - Draft genome sequence of Daldinia eschscholzii isolated from blood culture. AB - Daldinia eschscholzii is an invasive endophyte that is most commonly found in plant tissues rich in secondary metabolites. We report the draft genome sequence of D. eschscholzii isolated from blood culture. The draft genome is 35,494,957 bp in length, with 42,898,665 reads, 61,449 contigs, and a G+C content of 46.8%. The genome was found to contain a high abundance of genes associated with plant cell wall degradation enzymes, mycotoxin production, and antifungal drug resistance. PMID- 22544899 TI - Sequencing of Cladosporium sphaerospermum, a Dematiaceous fungus isolated from blood culture. AB - Cladosporium sphaerospermum is one of the most widely distributed allergens causing serious problems in patients with respiratory tract disease. We report the 26,644,473-bp draft genome sequence and gene annotation of C. sphaerospermum UM843. Analysis of the genome sequence led to the finding of genes associated with C. sphaerospermum's melanin biosynthesis, allergens, and antifungal drug resistance. PMID- 22544896 TI - Worldwide patterns of bronchodilator responsiveness: results from the Burden of Obstructive Lung Disease study. AB - RATIONALE: Criteria for a clinically significant bronchodilator response (BDR) are mainly based on studies in patients with obstructive lung diseases. Little is known about the BDR in healthy general populations, and even less about the worldwide patterns. METHODS: 10 360 adults aged 40 years and older from 14 countries in North America, Europe, Africa and Asia participated in the Burden of Obstructive Lung Disease study. Spirometry was used before and after an inhaled bronchodilator to determine the distribution of the BDR in population-based samples of healthy non-smokers and individuals with airflow obstruction. RESULTS: In 3922 healthy never smokers, the weighted pooled estimate of the 95th percentiles (95% CI) for bronchodilator response were 284 ml (263 to 305) absolute change in forced expiratory volume in 1 s from baseline (DeltaFEV(1)); 12.0% (11.2% to 12.8%) change relative to initial value (%DeltaFEV(1i)); and 10.0% (9.5% to 10.5%) change relative to predicted value (%DeltaFEV(1p)). The corresponding mean changes in forced vital capacity (FVC) were 322 ml (271 to 373) absolute change from baseline (DeltaFVC); 10.5% (8.9% to 12.0%) change relative to initial value (DeltaFVC(i)); and 9.2% (7.9% to 10.5%) change relative to predicted value (DeltaFVC(p)). The proportion who exceeded the above threshold values in the subgroup with spirometrically defined Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2 and higher (FEV(1)/FVC <0.7 and FEV(1)% predicted <80%) were 11.1%, 30.8% and 12.9% respectively for the FEV(1)-based thresholds and 22.6%, 28.6% and 22.1% respectively for the FVC-based thresholds. CONCLUSIONS: The results provide reference values for bronchodilator responses worldwide that confirm guideline estimates for a clinically significant level of BDR in bronchodilator testing. PMID- 22544900 TI - Brain. Editorial. PMID- 22544901 TI - Multi-centre diagnostic classification of individual structural neuroimaging scans from patients with major depressive disorder. AB - Quantitative abnormalities of brain structure in patients with major depressive disorder have been reported at a group level for decades. However, these structural differences appear subtle in comparison with conventional radiologically defined abnormalities, with considerable inter-subject variability. Consequently, it has not been possible to readily identify scans from patients with major depressive disorder at an individual level. Recently, machine learning techniques such as relevance vector machines and support vector machines have been applied to predictive classification of individual scans with variable success. Here we describe a novel hybrid method, which combines machine learning with feature selection and characterization, with the latter aimed at maximizing the accuracy of machine learning prediction. The method was tested using a multi-centre dataset of T(1)-weighted 'structural' scans. A total of 62 patients with major depressive disorder and matched controls were recruited from referred secondary care clinical populations in Aberdeen and Edinburgh, UK. The generalization ability and predictive accuracy of the classifiers was tested using data left out of the training process. High prediction accuracy was achieved (~90%). While feature selection was important for maximizing high predictive accuracy with machine learning, feature characterization contributed only a modest improvement to relevance vector machine-based prediction (~5%). Notably, while the only information provided for training the classifiers was T(1)-weighted scans plus a categorical label (major depressive disorder versus controls), both relevance vector machine and support vector machine 'weighting factors' (used for making predictions) correlated strongly with subjective ratings of illness severity. These results indicate that machine learning techniques have the potential to inform clinical practice and research, as they can make accurate predictions about brain scan data from individual subjects. Furthermore, machine learning weighting factors may reflect an objective biomarker of major depressive disorder illness severity, based on abnormalities of brain structure. PMID- 22544902 TI - Disrupted surface cross-talk between NMDA and Ephrin-B2 receptors in anti-NMDA encephalitis. AB - Autoimmune synaptic encephalitides are recently described human brain diseases leading to psychiatric and neurological syndromes through inappropriate brain autoantibody interactions. The most frequent synaptic autoimmune encephalitis is associated with autoantibodies against extracellular domains of the glutamatergic N-methyl-d-aspartate receptor, with patients developing psychotic and neurological symptoms in an autoantibody titre-dependent manner. Although N methyl-d-aspartate receptors are the primary target of these antibodies, the cellular and molecular pathway(s) that rapidly lead to N-methyl-d-aspartate receptor dysfunction remain poorly understood. In this report, we used a unique combination of high-resolution nanoparticle and bulk live imaging approaches to demonstrate that anti-N-methyl-d-aspartate receptor autoantibodies from patients with encephalitis strongly alter, in a time-dependent manner, the surface content and trafficking of GluN2-NMDA receptor subtypes. Autoantibodies laterally displaced surface GluN2A-NMDA receptors out of synapses and completely blocked synaptic plasticity. This loss of extrasynaptic and synaptic N-methyl-d-aspartate receptor is prevented both in vitro and in vivo, by the activation of EPHB2 receptors. Indeed, the anti-N-methyl-d-aspartate receptor autoantibodies weaken the interaction between the extracellular domains of the N-methyl-d-aspartate and Ephrin-B2 receptors. Together, we demonstrate that the anti-N-methyl-d-aspartate receptor autoantibodies from patients with encephalitis alter the dynamic retention of synaptic N-methyl-d-aspartate receptor through extracellular domain dependent mechanism(s), shedding new light on the pathology of the neurological and psychiatric disorders observed in these patients and opening possible new therapeutic strategies. PMID- 22544904 TI - Titan cells confer protection from phagocytosis in Cryptococcus neoformans infections. AB - The human fungal pathogen Cryptococcus neoformans produces an enlarged "titan" cell morphology when exposed to the host pulmonary environment. Titan cells exhibit traits that promote survival in the host. Previous studies showed that titan cells are not phagocytosed and that increased titan cell production in the lungs results in reduced phagocytosis of cryptococcal cells by host immune cells. Here, the effect of titan cell production on host-pathogen interactions during early stages of pulmonary cryptococcosis was explored. The relationship between titan cell production and phagocytosis was found to be nonlinear; moderate increases in titan cell production resulted in profound decreases in phagocytosis, with significant differences occurring within the first 24 h of the infection. Not only were titan cells themselves protected from phagocytosis, but titan cell formation also conferred protection from phagocytosis to normal-size cryptococcal cells. Large particles introduced into the lungs were not phagocytosed, suggesting the large size of titan cells protects against phagocytosis. The presence of large particles was unable to protect smaller particles from phagocytosis, revealing that titan cell size alone is not sufficient to provide the observed cross-protection of normal-size cryptococcal cells. These data suggest that titan cells play a critical role in establishment of the pulmonary infection by promoting the survival of the entire population of cryptococcal cells. PMID- 22544903 TI - The RAM network in pathogenic fungi. AB - The regulation of Ace2 and morphogenesis (RAM) network is a protein kinase signaling pathway conserved among eukaryotes from yeasts to humans. Among fungi, the RAM network has been most extensively studied in the model yeast Saccharomyces cerevisiae and has been shown to regulate a range of cellular processes, including daughter cell-specific gene expression, cell cycle regulation, cell separation, mating, polarized growth, maintenance of cell wall integrity, and stress signaling. Increasing numbers of recent studies on the role of the RAM network in pathogenic fungal species have revealed that this network also plays an important role in the biology and pathogenesis of these organisms. In addition to providing a brief overview of the RAM network in S. cerevisiae, we summarize recent developments in the understanding of RAM network function in the human fungal pathogens Candida albicans, Candida glabrata, Cryptococcus neoformans, Aspergillus fumigatus, and Pneumocystis spp. PMID- 22544905 TI - N-acetylglucosamine induces white-to-opaque switching and mating in Candida tropicalis, providing new insights into adaptation and fungal sexual evolution. AB - Pathogenic fungi are capable of switching between different phenotypes, each of which has a different biological advantage. In the most prevalent human fungal pathogen, Candida albicans, phenotypic transitions not only improve its adaptation to a continuously changing host microenvironment but also regulate sexual mating. In this report, we show that Candida tropicalis, another important human opportunistic pathogen, undergoes reversible and heritable phenotypic switching, referred to as the "white-opaque" transition. Here we show that N acetylglucosamine (GlcNAc), an inducer of white-to-opaque switching in C. albicans, promotes opaque-cell formation and mating and also inhibits filamentation in a number of natural C. tropicalis strains. Our results suggest that host chemical signals may facilitate this phenotypic switching and mating of C. tropicalis, which had been previously thought to reproduce asexually. Overexpression of the C. tropicalis WOR1 gene in C. albicans induces opaque-cell formation. Additionally, an intermediate phase between white and opaque was observed in C. tropicalis, indicating that the switching could be tristable. PMID- 22544906 TI - Function of Cryptococcus neoformans KAR7 (SEC66) in karyogamy during unisexual and opposite-sex mating. AB - The human basidiomycetous fungal pathogen Cryptococcus neoformans serves as a model fungus to study sexual development and produces infectious propagules, basidiospores, via the sexual cycle. Karyogamy is the process of nuclear fusion and an essential step to complete mating. Therefore, regulation of nuclear fusion is central to understanding sexual development of C. neoformans. However, our knowledge of karyogamy genes was limited. In this study, using a BLAST search with the Saccharomyces cerevisiae KAR genes, we identified five C. neoformans karyogamy gene orthologs: CnKAR2, CnKAR3, CnKAR4, CnKAR7 (or CnSEC66), and CnKAR8. There are no apparent orthologs of the S. cerevisiae genes ScKAR1, ScKAR5, and ScKar9 in C. neoformans. Karyogamy involves the congression of two nuclei followed by nuclear membrane fusion, which results in diploidization. ScKar7 (or ScSec66) is known to be involved in nuclear membrane fusion. In C. neoformans, kar7 mutants display significant defects in hyphal growth and basidiospore chain formation during both a-alpha opposite and alpha-alpha unisexual reproduction. Fluorescent nuclear imaging revealed that during kar7 * kar7 bilateral mutant matings, the nuclei congress but fail to fuse in the basidia. These results demonstrate that the KAR7 gene plays an integral role in both opposite-sex and unisexual mating, indicating that proper control of nuclear dynamics is important. CnKAR2 was found to be essential for viability, and its function in mating is not known. No apparent phenotypes were observed during mating of kar3, kar4, or kar8 mutants, suggesting that the role of these genes may be dispensable for C. neoformans mating, which demonstrates a different evolutionary trajectory for the KAR genes in C. neoformans compared to those in S. cerevisiae. PMID- 22544907 TI - Lysine acetylation is widespread on proteins of diverse function and localization in the protozoan parasite Toxoplasma gondii. AB - While histone proteins are the founding members of lysine acetylation substrates, it is now clear that hundreds of other proteins can be acetylated in multiple compartments of the cell. Our knowledge of the scope of this modification throughout the kingdom of life is beginning to emerge, as proteome-wide lysine acetylation has been documented in prokaryotes, Arabidopsis thaliana, Drosophila melanogaster, and human cells. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify parasite peptides enriched by immunopurification with acetyl-lysine antibody, we produced the first proteome wide analysis of acetylation for a protozoan organism, the opportunistic apicomplexan parasite Toxoplasma gondii. The results show that lysine acetylation is abundant in the actively proliferating tachyzoite form of the parasite, which causes acute toxoplasmosis. Our approach successfully identified known acetylation marks on Toxoplasma histones and alpha-tubulin and detected over 400 novel acetylation sites on a wide variety of additional proteins, including those with roles in transcription, translation, metabolism, and stress responses. Importantly, an extensive set of parasite-specific proteins, including those found in organelles unique to Apicomplexa, is acetylated in the parasite. Our data provide a wealth of new information that improves our understanding of the evolution of this vital regulatory modification while potentially revealing novel therapeutic avenues. We conclude from this study that lysine acetylation was prevalent in the early stages of eukaryotic cell evolution and occurs on proteins involved in a remarkably diverse array of cellular functions, including those that are specific to parasites. PMID- 22544908 TI - Functional analysis of the single Est1/Ebs1 homologue in Kluyveromyces lactis reveals roles in both telomere maintenance and rapamycin resistance. AB - Est1 and Ebs1 in Saccharomyces cerevisiae are paralogous proteins that arose through whole-genome duplication and that serve distinct functions in telomere maintenance and translational regulation. Here we present our functional analysis of the sole Est1/Ebs1 homologue in the related budding yeast Kluyveromyces lactis (named KlEst1). We show that similar to other Est1s, KlEst1 is required for normal telomere maintenance in vivo and full telomerase primer extension activity in vitro. KlEst1 also associates with telomerase RNA (Ter1) and an active telomerase complex in cell extracts. Both the telomere maintenance and the Ter1 association functions of KlEst1 require its N-terminal domain but not its C terminus. Analysis of clusters of point mutations revealed residues in both the N terminal TPR subdomain and the downstream helical subdomain (DSH) that are important for telomere maintenance and Ter1 association. A UV cross-linking assay was used to establish a direct physical interaction between KlEst1 and a putative stem-loop in Ter1, which also requires both the TPR and DSH subdomains. Moreover, similar to S. cerevisiae Ebs1 (ScEbs1) (but not ScEst1), KlEst1 confers rapamycin sensitivity and may be involved in nonsense-mediated decay. Interestingly, unlike telomere regulation, this apparently separate function of KlEst1 requires its C terminal domain. Our findings provide insights on the mechanisms and evolution of Est1/Ebs1 homologues in budding yeast and present an attractive model system for analyzing members of this multifunctional protein family. PMID- 22544909 TI - Divergent targets of Candida albicans biofilm regulator Bcr1 in vitro and in vivo. AB - Candida albicans is a causative agent of oropharyngeal candidiasis (OPC), a biofilm-like infection of the oral mucosa. Biofilm formation depends upon the C. albicans transcription factor Bcr1, and previous studies indicate that Bcr1 is required for OPC in a mouse model of infection. Here we have used a nanoString gene expression measurement platform to elucidate the role of Bcr1 in OPC-related gene expression. We chose for assays a panel of 134 genes that represent a range of morphogenetic and cell cycle functions as well as environmental and stress response pathways. We assayed gene expression in whole infected tongue samples. The results sketch a portrait of C. albicans gene expression in which numerous stress response pathways are activated during OPC. This one set of experiments identifies 64 new genes with significantly altered RNA levels during OPC, thus increasing substantially the number of known genes in this expression class. The bcr1Delta/Delta mutant had a much more limited gene expression defect during OPC infection than previously reported for in vitro growth conditions. Among major functional Bcr1 targets, we observed that ALS3 was Bcr1 dependent in vivo while HWP1 was not. We used null mutants and complemented strains to verify that Bcr1 and Hwp1 are required for OPC infection in this model. The role of Als3 is transient and mild, though significant. Our findings suggest that the versatility of C. albicans as a pathogen may reflect its ability to persist in the face of multiple stresses and underscore that transcriptional circuitry during infection may be distinct from that detailed during in vitro growth. PMID- 22544910 TI - Rationale and design of the health economics evaluation registry for remote follow-up: TARIFF. AB - AIMS: The aims of the study are to develop a cost-minimization analysis from the hospital perspective and a cost-effectiveness analysis from the third payer standpoint, based on direct estimates of costs and QOL associated with remote follow-ups, using Merlin@home and Merlin.net, compared with standard ambulatory follow-ups, in the management of ICD and CRT-D recipients. METHODS AND RESULTS: Remote monitoring systems can replace ambulatory follow-ups, sparing human and economic resources, and increasing patient safety. TARIFF is a prospective, controlled, observational study aimed at measuring the direct and indirect costs and quality of life (QOL) of all participants by a 1-year economic evaluation. A detailed set of hospitalized and ambulatory healthcare costs and losses of productivity that could be directly influenced by the different means of follow ups will be collected. The study consists of two phases, each including 100 patients, to measure the economic resources consumed during the first phase, associated with standard ambulatory follow-ups, vs. the second phase, associated with remote follow-ups. CONCLUSION: Remote monitoring systems enable caregivers to better ensure patient safety and the healthcare to limit costs. TARIFF will allow defining the economic value of remote ICD follow-ups for Italian hospitals, third payers, and patients. The TARIFF study, based on a cost-minimization analysis, directly comparing remote follow-up with standard ambulatory visits, will validate the cost effectiveness of the Merlin.net technology, and define a proper reimbursement schedule applicable for the Italian healthcare system. TRIAL REGISTRATION: NCT01075516. PMID- 22544911 TI - The impact of out-of-pocket payments on prevention and health-related lifestyle: a systematic literature review. AB - BACKGROUND: Out-of-pocket payments can have a large impact on the demand for healthcare. They can be essential not only to decrease unnecessary service use, but also to encourage the use of particular preventive services provided free of charge or at a lower price. Moreover, out-of-pocket payments may increase the costs of unhealthy behaviour and provide incentives for a healthier lifestyle. METHOD: This study systematically reviews empirical evidence on the effects of out-of-pocket payments on the use of preventive services and health-related lifestyle. All possible combinations of three key words 'prevention', 'patient payment' and 'health-related behaviour' were searched in PUBMED, ECONLITH, ECONPAPER and EMBASE. In total, 47 relevant publications were identified. RESULTS: The results suggest that out-of-pocket payments can create a financial barrier and can decrease the use of preventive services and the uptake of preventive medications. A few studies (with contradicting empirical evidence) address the impact of cost sharing and reduced insurance coverage on a healthier lifestyle. CONCLUSION: Although the great diversity of study designs (various indicators of out-of-pocket payments and preventive/health-related behaviour) makes it difficult to offer robust policy recommendations, our findings support calls to reconsider how preventive services should be financed. More research is needed to explore the actual impact of cost sharing on different aspects of health-related lifestyles, as well as to explain the role of other relevant determinants that could impact this relationship. PMID- 22544912 TI - Frequency and effects of meeting health behaviour guidelines among adolescents. AB - BACKGROUND: To assess the relationship between overweight status and the concomitant adherence to physical activity, daily screen time and nutritional guidelines. METHODS: Data were derived from the Swiss Health Behaviour in School aged Children Survey 2006. Participants (n = 8130, 48.7% girls) were divided into two groups: normal weight (n = 7215, 44.8% girls) and overweight (n = 915, 34.8% girls), using self-reported height and weight. Groups were compared on adherence to physical activity, screen time and nutritional guidelines. Bivariate analyses were carried out followed by multivariate analyses using normal-weight individuals as the reference category. RESULTS: Regardless of gender, overweight individuals reported more screen time, less physical activity and less concomitant adherence to guidelines. For boys, the multivariate analysis showed that any amount exceeding screen time recommendations was associated with increased odds of being overweight [>2-4 h: adjusted odds ratio (AOR) = 1.40; >4 6 h: AOR = 1.48; >6 h: AOR = 1.83]. A similar relation was found for any amount below physical activity recommendations (4-6 times a week: AOR = 1.67; 2-3 times a week: AOR = 1.87; once a week or less: AOR = 2.1). For girls, not meeting nutritional guidelines was less likely among overweight individuals (0-2 recommendations: AOR = 0.54). Regardless of weight status, more than half of the adolescents did not comply with any guideline and <2% met all three at the same time. CONCLUSIONS: Meeting current nutritional, physical activity and screen time guidelines should be encouraged with respect to overweight. However, as extremely low rates of concomitant adherence were found regardless of weight status, their achievability is questionable (especially for nutrition), which warrants further research to better adapt them to adolescents. PMID- 22544913 TI - Self-reported TV and computer time do not represent accelerometer-derived total sedentary time in 10 to 12-year-olds. AB - Screen-time activities are often used as proxies for sedentary time. We studied associations of self-reported television (TV), computer and total screen-time with accelerometer-derived total sedentary time in European children (10-12 years). Analyses showed significant positive associations between TV, computer and total screen-time with total sedentary time for the total sample, however, the explained variance was low and stratified analyses only revealed a significant positive association between total screen-time and total sedentary time in boys and between computer time and total sedentary time in Dutch children. This suggests that self-reported TV and computer time do not adequately reflect total sedentary time in schoolchildren. PMID- 22544915 TI - Hypermethylated in cancer 1 (HIC1), a tumor suppressor gene epigenetically deregulated in hyperparathyroid tumors by histone H3 lysine modification. AB - CONTEXT: Primary hyperparathyroidism (pHPT) resulting from parathyroid tumors is a common endocrine disorder with incompletely understood etiology. In renal failure, secondary hyperparathyroidism (sHPT) occurs with multiple tumor development as a result of calcium and vitamin D regulatory disturbance. OBJECTIVE: The aim of the study was to investigate whether HIC1 may act as a tumor suppressor in the parathyroid glands and whether deregulated expression involves epigenetic mechanisms. PATIENTS AND METHODS: Parathyroid tumors from patients with pHPT included single adenomas, multiple tumors from the same patient, and cancer. Hyperplastic parathyroid glands from patients with sHPT and hypercalcemia and normal parathyroid tissue specimens were included in the study. Quantitative RT-PCR, bisulfite pyrosequencing, colony formation assay, chromatin immunoprecipitation, and RNA interference was used. RESULTS: HIC1 was generally underexpressed regardless of the hyperparathyroid disease state including multiple parathyroid tumors from the same patient, and overexpression of HIC1 led to a decrease in clonogenic survival of parathyroid tumor cells. Only the carcinomas showed a high methylation level and reduced HIC1 expression. Cell culture experiments, including use of primary parathyroid tumor cells prepared directly after operation, the general histone methyltransferase inhibitor 3 deazaneplanocin A, chromatin immunoprecipitation, and RNA interference of DNA methyltransferases and EZH2 (enhancer of zeste homolog 2), supported a role of repressive histone H3 modifications (H3K27me2/3) rather than DNA methylation in repression of HIC1. CONCLUSIONS: The results strongly support a growth-regulatory role of HIC1 in the parathyroid glands and suggest that perturbed expression of HIC1 may represent an early event during tumor development. Repressive histone modification H3K27me2/3 is involved in repression of HIC1 expression in hyperparathyroid tumors. PMID- 22544914 TI - Children with NAFLD are more sensitive to the adverse metabolic effects of fructose beverages than children without NAFLD. AB - CONTEXT: Dietary fructose induces unfavorable lipid alterations in animal models and adult studies. Little is known regarding metabolic tolerance of dietary fructose in children. OBJECTIVES: The aim of the study was to evaluate whether dietary fructose alters plasma lipids in children with nonalcoholic fatty liver disease (NAFLD) and in healthy children. DESIGN AND SETTING: We performed a 2-d, crossover feeding study at the Inpatient Clinical Interaction Site of the Atlanta Clinical and Translational Science Institute at Emory University Hospital. PARTICIPANTS AND INTERVENTION: Nine children with NAFLD and 10 matched controls without NAFLD completed the study. We assessed plasma lipid levels over two nonconsecutive, randomly assigned, 24-h periods under isocaloric, isonitrogenous conditions with three macronutrient-balanced, consecutive meals and either: 1) a fructose-sweetened beverage (FB); or 2) a glucose beverage (GB) being consumed with each meal. MAIN OUTCOME MEASURES: Differences in plasma glucose, insulin, triglyceride, apolipoprotein B, high-density lipoprotein cholesterol, and nonesterified free fatty acid levels were assessed using mixed models and 24-h incremental areas under the time-concentration curve. RESULTS: After FB, triglyceride incremental area under the curve was higher vs. after GB both in children with NAFLD (P = 0.011) and those without NAFLD (P = 0.027); however, incremental response to FB was greater in children with NAFLD than those without NAFLD (P = 0.019). For all subjects, high-density lipoprotein cholesterol declined in the postprandial and overnight hours with FB, but not with GB (P = 0.0006). Nonesterified fatty acids were not impacted by sugar but were significantly higher in NAFLD. CONCLUSIONS: The dyslipidemic effect of dietary fructose occurred in both healthy children and those with NAFLD; however, children with NAFLD demonstrated increased sensitivity to the impact of dietary fructose. PMID- 22544916 TI - Transplacental supply of mannose and inositol in uncomplicated pregnancies using stable isotopes. AB - OBJECTIVE: The aim of this study was to determine relative contributions of transplacental flux vs. fetal production for inositol and mannose in normal term pregnancies. STUDY DESIGN: Seven term uncomplicated pregnancies undergoing cesarean section were infused with (13)C- and (2)H-labeled isotopes of glucose, inositol, and mannose until a steady state was achieved. Maternal and fetal concentrations of labeled and unlabeled glucose, mannose, and inositol were measured using gas chromatography/mass spectroscopy. The fetomaternal molar percentage excess ratio was calculated for each glucose, mannose, and inositol. RESULTS: The fetomaternal molar percentage excess ratio of mannose in the fetal artery (F(artery)/M) was 0.99 [97.5% confidence interval (CI), 0.91-1.07] and in the fetal vein (F(vein)/M), 1.02 (97.5% CI, 0.95-1.10). Both were not significantly different from 1.0, consistent with transplacental supply. The fetomaternal ratios for glucose were similar to mannose (fetal artery, 0.95; 97.5% CI, 0.84-1.15; and fetal vein, 0.96; 97.5% CI, 0.85-1.07). The fetomaternal ratio for inositol was significantly less than 1.0 (fetal artery, 0.08; 97.5% CI, 0.05-0.12; fetal vein, 0.12; 97.5% CI, 0.06-0.18), indicating little transplacental flux and significant fetal production. CONCLUSION: In normal term pregnancies, fetal mannose and glucose concentrations are dependent upon maternal transplacental supply. Fetal inositol is not dependent upon transplacental supply. PMID- 22544917 TI - Exenatide alters myocardial glucose transport and uptake depending on insulin resistance and increases myocardial blood flow in patients with type 2 diabetes. AB - CONTEXT: Glucagon-like peptide-1 (GLP-1) and GLP-1 receptor agonists provide beneficial cardiovascular effects by protecting against ischemia and reperfusion injury. Type 2 diabetes mellitus patients have reduced glycolysis in the heart. OBJECTIVE: We hypothesized that cardioprotection by GLP-1 is achieved through increased glucose availability and utilization and aimed to assess the effect of exenatide, a synthetic GLP-1 receptor agonist, on myocardial glucose uptake (MGU), myocardial glucose transport, and myocardial blood flow (MBF). DESIGN AND METHODS: We conducted a randomized, double-blinded, placebo-controlled crossover study in eight male, insulin-naive, type 2 diabetes mellitus patients without coronary artery disease. Positron emission tomography was used to determine the effect of exenatide on MGU and MBF during a pituitary-pancreatic hyperglycemic clamp with (18)F-fluorodeoxyglucose and (13)N-ammonia as tracers. RESULTS: Overall, exenatide did not alter MGU. However, regression analysis revealed that exenatide altered initial clearance of glucose over the membrane of cardiomyocytes and MGU, depending on the level of insulin resistance (P = 0.017 and 0.010, respectively). Exenatide increased MBF from 0.73 +/- 0.094 to 0.85 +/- 0.091 ml/g . min (P = 0.0056). Except for an increase in C-peptide levels, no differences in circulating hormones or metabolites were found. CONCLUSIONS: The action of exenatide as an activator or inhibitor of the glucose transport and glucose uptake in cardiomyocytes is dependent on baseline activity of glucose transport and insulin resistance. Exenatide increases MBF without changing MGU. PMID- 22544918 TI - Construction of an adaptable European transnational ecological deprivation index: the French version. AB - BACKGROUND: Studying social disparities in health implies the ability to measure them accurately, to compare them between different areas or countries and to follow trends over time. This study proposes a method for constructing a French European deprivation index, which will be replicable in several European countries and is related to an individual deprivation indicator constructed from a European survey specifically designed to study deprivation. METHODS AND RESULTS: Using individual data from the European Union Statistics on Income and Living Conditions survey, goods/services indicated by individuals as being fundamental needs, the lack of which reflect deprivation, were selected. From this definition, which is specific to a cultural context, an individual deprivation indicator was constructed by selecting fundamental needs associated both with objective and subjective poverty. Next, the authors selected among variables available both in the European Union Statistics on Income and Living Conditions survey and French national census those best reflecting individual experience of deprivation using multivariate logistic regression. An ecological measure of deprivation was provided for all the smallest French geographical units. Preliminary validation showed a higher association between the French European Deprivation Index (EDI) score and both income and education than the Townsend index, partly ensuring its ability to measure individual socioeconomic status. CONCLUSION: This index, which is specific to a particular cultural and social policy context, could be replicated in 25 other European countries, thereby allowing European comparisons. EDI could also be reproducible over time. EDI could prove to be a relevant tool in evidence-based policy-making for measuring and reducing social disparities in health issues and even outside the medical domain. PMID- 22544919 TI - Does an electrocardiogram add predictive value to the rose angina questionnaire for future coronary heart disease? 10-year follow-up in a Middle East population. AB - BACKGROUND: To evaluate the power of abnormal resting ECG versus Rose Questionnaire angina and its additive value in predicting 10-year coronary heart disease (CHD) risk in an Iranian urban population with high prevalence of CHD. METHODS: There were 5101 subjects >=30 years (2900 women), free of CHD at baseline; they were categorised in to four groups according to their Rose Angina and ECG status for ischaemia as Rose-/ECG-, Rose+/ECG-, Rose-/ECG+ and Rose+/ECG+. HR of CHD was estimated using Cox regression analysis, given Rose /ECG- as the reference. The authors used Akaike information criterion, C-index and integrated discrimination improvement indices to evaluate the prognostic value of ECG when would be added to Rose Questionnaire. RESULTS: During follow up, 387 CHD events (169 women) were observed. Multivariate analysis showed a HR of 2.59 (95% CI 1.71 to 3.91) and 2.26 (1.48 to 3.44) for Rose+/ECG- group in men and women, respectively. These figures for Rose-/ECG+ were 1.36 (0.90 to 2.05) in men and 2.09 (1.40 to 3.12) in women. There was no any interaction between Rose Questionnaire and gender to predict incident CHD, in age-adjusted analysis. Akaike information criterion, C-index and relative integrated discrimination improvement did not show any difference between models including Rose alone and Rose plus ECG to predict CHD events especially in men. CONCLUSIONS: Rose Questionnaire as a simple screening tool is equally important to predict incident CHD in both genders. Adding abnormal ECG to angina did not culminate in higher risk for future CHD events. PMID- 22544920 TI - Dose-response relationships between physical activity, walking and health-related quality of life in mid-age and older women. AB - BACKGROUND: Although physical activity is associated with health-related quality of life (HRQL), the nature of the dose-response relationship remains unclear. OBJECTIVES: To examine the concurrent and prospective dose-response relationships between total physical activity (TPA) and (only) walking with HRQL in two age cohorts of women. METHODS: Participants were 10 698 women born in 1946-1951 and 7646 born in 1921-1926, who completed three mailed surveys for the Australian Longitudinal Study on Women's Health. They reported weekly TPA minutes (sum of walking, moderate and vigorous minutes). HRQL was measured with the Medical Outcomes Study Short-Form 36 Health Status Survey (SF-36). Linear mixed models, adjusted for socio-demographic and health-related variables, were used to examine associations between TPA level (none, very low, low, intermediate, sufficient, high and very high) and SF-36 scores. For women who reported walking as their only physical activity, associations between walking and SF-36 scores were also examined. RESULTS: Curvilinear trends were observed between TPA and walking with SF-36 scores. Concurrently, HRQL scores increased significantly with increasing TPA and walking, in both cohorts, with increases less marked above sufficient activity levels. Prospectively, associations were attenuated although significant and meaningful improvements in physical functioning and vitality were observed across most TPA and walking categories above the low category. CONCLUSION: For women in their 50s-80s without clinical depression, greater amounts of TPA are associated with better current and future HRQL, particularly physical functioning and vitality. Even if walking is their only activity, women, particularly those in their 70s-80s, have better HRQL. PMID- 22544921 TI - Socio-demographic determinants of worsening in frailty among community-dwelling older people in 11 European countries. AB - BACKGROUND: The rapid increase of frail older people worldwide will have a substantial impact on healthcare systems. The frailty process may be delayed or even reversed, which makes it attractive for early interventions. However, little is known about the determinants of frailty state changes. The aim of this study is to compare socio-demographic determinants of worsening in frailty state in 11 European countries. METHODS: Data of 14,424 community-dwelling persons aged >=55 years, enrolled in 2004 in the Survey of Health, Ageing and Retirement in Europe, were analysed. Three frailty states were identified (non-frail, pre-frail and frail) using Fried's criteria, and frailty state changes over a 2-year period were determined. Multinomial regression analyses adjusted for baseline frailty state were conducted to investigate whether sex, age, marital status and level of education determined a worsening in frailty state in the total and country specific European population. RESULTS: Of all individuals, 22.1% worsened, 61.8% showed no change and 16.1% improved in frailty state. Women, those aged >=65 years, and lower educated persons showed an increased risk of worsening in frailty state. In Southern European countries, there was an earlier and larger increase in risk of worsening in frailty state in life, which was more pronounced in women compared with men. CONCLUSIONS: In Europe, persons aged >=65 years, women and lower educated persons are at increased risk of worsening in frailty state. Differences between countries indicate that interventions aimed at delaying the frailty process in Southern European countries should start earlier with more attention towards women. PMID- 22544922 TI - Seven-year hospital and nursing home care use according to age and proximity to death: variations by cause of death and socio-demographic position. AB - BACKGROUND: Provision of hospital and long-term care services for the growing number of older people is a major policy concern. The authors estimate hospital and nursing home care use by age and proximity to death for selected causes and by gender, education and marital status. METHODS: A 40% random sample of the Finnish population aged 65+ years alive at the end of 1997 was followed to death in 1998-2002. Use of hospital and nursing home care was assessed up to 7 years prior to death for those who died and prior to the end of 2002 for survivors. RESULTS: In the 7-year period, before death total average care days were 294 (95% CI 286 to 301) for men and 430 (95% CI 423 to 438) for women. For surviving men and women, the corresponding figures were 89 (95% CI 86 to 92) and 136 (95% CI 130 to 141) days. Use of hospital and particularly nursing home care increased rapidly with age, while proximity to death was more important for hospital care. The married used less care than the non-married. Care use of those dying from dementia was approximately twice that for all causes combined and was substantial for an extended period before death. CONCLUSIONS: The effects of age are more substantial for nursing home than for hospital care use, and both are larger the older the age at death. Care use will be considerably higher among the non married. Increasing longevity coupled with a rising trend of dementia is likely to mean a major shift towards higher nursing home care use in the future. PMID- 22544923 TI - Every unhealthy population is unhealthy in its own way; population risk assessment: common and specific challenges. PMID- 22544924 TI - Ceramide synthase 6 plays a critical role in the development of experimental autoimmune encephalomyelitis. AB - Ceramides are mediators of apoptosis and inflammatory processes. In an animal model of multiple sclerosis (MS), the experimental autoimmune encephalomyelitis (EAE) model, we observed a significant elevation of C(16:0)-Cer in the lumbar spinal cord of EAE mice. This was caused by a transiently increased expression of ceramide synthase (CerS) 6 in monocytes/macrophages and astroglia. Notably, this corresponds to the clinical finding that C(16:0)-Cer levels were increased 1.9 fold in cerebrospinal fluid of MS patients. NO and TNF-alpha secreted by IFN gamma-activated macrophages play an essential role in the development of MS. In murine peritoneal and mouse-derived RAW 264.7 macrophages, IFN-gamma-mediated expression of inducible NO synthase (iNOS)/TNF-alpha and NO/TNF-alpha release depends on upregulation of CerS6/C(16:0)-Cer. Downregulation of CerS6 by RNA interference or endogenous upregulation of C(16:0)-Cer mediated by palmitic acid in RAW 264.7 macrophages led to a significant reduction or increase in NO/TNF alpha release, respectively. EAE/IFN-gamma knockout mice showed a significant delay in disease onset accompanied by a significantly less pronounced increase in CerS6/C(16:0)-Cer, iNOS, and TNF-alpha compared with EAE/wild-type mice. Treatment of EAE mice with l-cycloserine prevented the increase in C(16:0)-Cer and iNOS/TNF-alpha expression and caused a remission of the disease. In conclusion, CerS6 plays a critical role in the onset of MS, most likely by regulating NO and TNF-alpha synthesis. CerS6 may represent a new target for the inhibition of inflammatory processes promoting MS development. PMID- 22544925 TI - Mycobacterium tuberculosis modulates macrophage lipid-sensing nuclear receptors PPARgamma and TR4 for survival. AB - Mycobacterium tuberculosis-macrophage interactions are key to pathogenesis and clearance of these bacteria. Although interactions between M. tuberculosis associated lipids and TLRs, non-TLRs, and opsonic receptors have been investigated, interactions of these lipids and infected macrophage lipid repertoire with lipid-sensing nuclear receptors expressed in macrophages have not been addressed. In this study, we report that M. tuberculosis-macrophage lipids can interact with host peroxisome proliferator-activated receptor gamma and testicular receptor 4 to ensure survival of the pathogen by modulating macrophage function. These two lipid-sensing nuclear receptors create a foamy niche within macrophage by modulating oxidized low-density lipoprotein receptor CD36, phagolysosomal maturation block by induction of IL-10, and a blunted innate response by alternative polarization of the macrophages, which leads to survival of M. tuberculosis. These results also suggest possible heterologous ligands for peroxisome proliferator-activated receptor gamma and testicular receptor 4 and are suggestive of adaptive or coevolution of the host and pathogen. Relative mRNA expression levels of these receptors in PBMCs derived from clinical samples convincingly implicate them in tuberculosis susceptibility. These observations expose a novel paradigm in the pathogenesis of M. tuberculosis amenable for pharmacological modulation. PMID- 22544926 TI - Two preferentially expressed proteins protect vascular endothelial cells from an attack by peptide-specific CTL. AB - Vascular endothelial cells (EC) are an exposed tissue with intimate contact with circulating Ag-specific CTL. Experimental in vitro and clinical data suggested that endothelial cells present a different repertoire of MHC class I-restricted peptides compared with syngeneic leukocytes or epithelial cells. This endothelial specific peptide repertoire might protect EC from CTL-mediated cell death. The HLA-A*02-restricted peptide profile of human EC and syngeneic B lymphoblastoid cells was biochemically analyzed and compared. For EC selective peptides, source protein expression, peptide binding affinity, and peptide-HLA-A*02 turnover were measured. The significance of abundant peptide presentation for target cell recognition by immunodominant CTL was tested by small interfering RNA treatment of EC to knock down the source proteins. High amounts of two peptides, PTRF(56 64) and CD59(106-114), were consistently detected in EC. This predominance of two endothelial peptides was explained by cell type-specific source protein expression that compensated for poor HLA-A*02 binding affinity and short half live of peptide/HLA-A*02 complexes. Knocking down the source proteins containing the abundant endothelial peptide motifs led to a nearly 100-fold increase of surface expression of SMCY(311-319), an immunodominant minor histocompatibility Ag, as detected by cytotoxicity assays using SMCY(311-319)-specific CTL. We conclude that EC express and present preferentially two distinct HLA-A*02 restricted peptides at extraordinary high levels. These abundant self-peptides may protect EC from CTL-mediated lysis by competing for HLA-A*02 binding sites with immunodominant scarcely expressed antigenic peptides. PMID- 22544927 TI - Incorporation of transmembrane hydrophobic mutations in the TCR enhance its surface expression and T cell functional avidity. AB - TCR-gene transfer represents an effective way to redirect the specificity of T lymphocytes for therapeutic purposes. Recent successful clinical trials have underscored the potential of this approach in which efficient expression of the exogenous TCR has been directly linked to the efficacy of T cell activity. It has been also demonstrated that the TCR exhibits a lack of stability associated with the presence of positively charged residues in its transmembrane (TM) region. In this study, we designed an original approach selectively to improve exogenous TCR stability by increasing the hydrophobic nature of the TCRalpha TM region. Incorporation of hydrophobic residues at evolutionarily permissive positions resulted in an enhanced surface expression of the TCR chains, leading to an improved cellular avidity and anti-tumor TCR activity. Furthermore, this strategy was successfully applied to different TCRs, enabling the targeting of human tumors from different histologies. We also show that the combination of these hydrophobic mutations with another TCR-enhancing approach further improved TCR expression and function. Overall, these findings provide information regarding TCR TM composition that can be applied for the improvement of TCR-gene transfer based treatments. PMID- 22544928 TI - Prostaglandin E2 affects T cell responses through modulation of CD46 expression. AB - The ubiquitous protein CD46, a regulator of complement activity, promotes T cell activation and differentiation toward a regulatory Tr1-like phenotype. The CD46 mediated differentiation pathway is defective in several chronic inflammatory diseases, underlying the importance of CD46 in controlling T cell function and the need to understand its regulatory mechanisms. Using an RNA interference-based screening approach in primary T cells, we have identified that two members of the G protein-coupled receptor kinases were involved in regulating CD46 expression at the surface of activated cells. We have investigated the role of PGE(2), which binds to the E-prostanoid family of G protein-coupled receptors through four subtypes of receptors called EP 1-4, in the regulation of CD46 expression and function. Conflicting roles of PGE(2) in T cell functions have been reported, and the reasons for these apparent discrepancies are not well understood. We show that addition of PGE(2) strongly downregulates CD46 expression in activated T cells. Moreover, PGE(2) differentially affects T cell activation, cytokine production, and phenotype depending on the activation signals received by the T cells. This was correlated with a distinct pattern of the PGE(2) receptors expressed, with EP4 being preferentially induced by CD46 activation. Indeed, addition of an EP4 antagonist could reverse the effects observed on cytokine production after CD46 costimulation. These data demonstrate a novel role of the PGE(2)-EP4 axis in CD46 functions, which might at least partly explain the diverse roles of PGE(2) in T cell functions. PMID- 22544930 TI - Cutting edge: in the absence of regulatory T cells, a unique Th cell population expands and leads to a loss of B cell anergy. AB - The absence of regulatory T cells (Tregs) results in significant immune dysregulation that includes autoimmunity. The mechanism(s) by which Tregs suppress autoimmunity remains unclear. We have shown that B cell anergy, a major mechanism of B cell tolerance, is broken in the absence of Tregs. In this study, we identify a unique subpopulation of CD4(+) Th cells that are highly supportive of Ab production and promote loss of B cell anergy. Notably, this novel T cell subset was shown to express the germinal center Ag GL7 and message for the B cell survival factor BAFF, yet failed to express markers of the follicular Th cell lineage. We propose that the absence of Tregs results in the expansion of a unique nonfollicular Th subset of helper CD4(+) T cells that plays a pathogenic role in autoantibody production. PMID- 22544929 TI - IRF5 risk polymorphisms contribute to interindividual variance in pattern recognition receptor-mediated cytokine secretion in human monocyte-derived cells. AB - Monocyte-derived cells display highly variable cytokine secretion upon pattern recognition receptor (PRR) stimulation across individuals; such variability likely affects interindividual inflammatory/autoimmune disease susceptibility. To define mechanisms for this heterogeneity, we examined PRR-induced monocyte derived cell cytokine secretion from a large cohort of healthy individuals. Although cytokine secretion ranged widely among individuals, the magnitude of cytokine induction after individual nucleotide-binding oligomerization domain 2 (Nod2) and TLR2 stimulation (a cohort of 86 individuals) or stimulation of multiple TLRs (a cohort of 77 individuals), either alone or in combination with Nod2, was consistent intraindividually across these stimuli. Nod2 and TLRs signal through IFN regulatory factor 5 (IRF5), and common IRF5 polymorphisms confer risk for autoimmunity. We find that cells from rs2004640 IRF5 risk-associated allele carriers secrete increased cytokines upon individual or synergistic PRR stimulation in a gene dose- and ligand dose-dependent manner in both monocyte derived dendritic cells and monocyte-derived macrophages. IRF5 expression knockdown in IRF5 risk allele carrier cells significantly decreases PRR-induced cytokines. Moreover, we find that IRF5 knockdown profoundly decreases Nod2 mediated MAPK and NF-kappaB pathway activation, whereas the PI3K and mammalian target of rapamycin pathways are not impaired. Finally, the IRF5 rs2004640 polymorphism is a major determinant of the variance (r(2) = 0.53) in Nod2-induced cytokine secretion by monocyte-derived cells from different individuals. We therefore show a profound contribution of a single gene to the variance in interindividual PRR-induced cytokines. The hyperresponsiveness of IRF5 disease associated polymorphisms to a wide spectrum of microbial triggers has broad implications on global immunological responses, host defenses against pathogens, and inflammatory/autoimmune disease susceptibility. PMID- 22544931 TI - Strong impact of CD4+ Foxp3+ regulatory T cells and limited effect of T cell derived IL-10 on pathogen clearance during Plasmodium yoelii infection. AB - It is well established that CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) play a crucial role in the course of different infectious diseases. However, contradictory results have been published regarding to malaria infection. In this study, we report that specific ablation of Foxp3(+) Tregs in Plasmodium yoelii infected DEREG-BALB/c mice leads to an increase in T cell activation accompanied by a significant decrease in parasitemia. To better understand how Foxp3(+) Tregs orchestrate this phenotype, we used microarrays to analyze CD4(+)CD25(+)Foxp3(+) Tregs and CD4(+)CD25(-)Foxp3(-) T cells in the course of P. yoelii infection. Using this approach we identified genes specifically upregulated in CD4(+)CD25(+)Foxp3(+) Tregs in the course of infection, such as G-protein-coupled receptor 83 and Socs2. This analysis also revealed that both CD4(+)CD25(+)Foxp3(+) Tregs and CD4(+)CD25(-)Foxp3(-) T cells upregulate CTLA-4, granzyme B, and, more strikingly, IL-10 during acute blood infection. Therefore, we aimed to define the function of T cell-derived IL-10 in this context by Cre/loxP-mediated selective conditional inactivation of the IL-10 gene in T cells. Unexpectedly, IL-10 ablation in T cells exerts only a minor effect on parasite clearance, even though CD8(+) T cells are more strongly activated, the production of IFN-gamma and TNF-alpha by CD4(+)CD25(-) T cells is increased, and the suppressive activity of CD4(+)CD25(+) Tregs is reduced upon infection. In summary, these results suggest that CD4(+)Foxp3(+) Tregs modulate the course of P. yoelii infection in BALB/c mice. Moreover, CD4(+) T cell-derived IL-10 affects T effector function and Treg activity, but has only a limited direct effect on parasite clearance in this model. PMID- 22544932 TI - Severe impairment of leukocyte recruitment in ppGalNAcT-1-deficient mice. AB - P-selectin glycoprotein ligand-1 plays an important role in leukocyte recruitment. Its binding affinity to selectins is modulated by posttranslational modifications. The polypeptide N-acetylgalactosamine transferase-1 (ppGalNAcT-1) initiates core-type protein O-glycosylation. To address whether the glycosylation of P-selectin glycoprotein ligand-1 by ppGalNAcT-1 is important for leukocyte recruitment in vivo, we investigated leukocyte recruitment in untreated and TNF alpha-treated cremaster muscles comparing ppGalNAcT-1-deficient mice (Galnt1(-/ )) and wild-type mice. In untreated and TNF-alpha-treated Galnt1(-/-) mice, leukocyte rolling, adhesion, and transmigration were significantly reduced, with markedly increased rolling velocity compared with control mice. L-selectin dependent leukocyte rolling was completely abolished in Galnt1(-/-) mice compared with wild-type mice. Thioglycollate-induced peritonitis experiments with chimeric mice revealed that hematopoietic ppGalNAcT-1 is important for leukocyte recruitment. These data show that the loss of ppGalNAcT-1 led to reduced leukocyte rolling and recruitment and increased rolling velocity, suggesting a predominant role for ppGalNAcT-1 in attaching functionally relevant O-linked glycans to selectin ligands. PMID- 22544933 TI - MicroRNA-494 is required for the accumulation and functions of tumor-expanded myeloid-derived suppressor cells via targeting of PTEN. AB - Myeloid-derived suppressor cells (MDSCs) potently suppress the anti-tumor immune responses and also orchestrate the tumor microenvironment that favors tumor angiogenesis and metastasis. The molecular networks regulating the accumulation and functions of tumor-expanded MDSCs are largely unknown. In this study, we identified microRNA-494 (miR-494), whose expression was dramatically induced by tumor-derived factors, as an essential player in regulating the accumulation and activity of MDSCs by targeting of phosphatase and tensin homolog (PTEN) and activation of the Akt pathway. TGF-beta1 was found to be the main tumor-derived factor responsible for the upregulation of miR-494 in MDSCs. Expression of miR 494 not only enhanced CXCR4-mediated MDSC chemotaxis but also altered the intrinsic apoptotic/survival signal by targeting of PTEN, thus contributing to the accumulation of MDSCs in tumor tissues. Consequently, downregulation of PTEN resulted in increased activity of the Akt pathway and the subsequent upregulation of MMPs for facilitation of tumor cell invasion and metastasis. Knockdown of miR 494 significantly reversed the activity of MDSCs and inhibited the tumor growth and metastasis of 4T1 murine breast cancer in vivo. Collectively, our findings reveal that TGF-beta1-induced miR-494 expression in MDSCs plays a critical role in the molecular events governing the accumulation and functions of tumor expanded MDSCs and might be identified as a potential target in cancer therapy. PMID- 22544934 TI - E2A and CBP/p300 act in synergy to promote chromatin accessibility of the immunoglobulin kappa locus. AB - V(D)J recombination of Ig and TCR genes is strictly regulated in a lineage- and stage-specific manner by the accessibility of target gene chromatin to the recombinases RAG1 and RAG2. It has been shown that enforced expression of the basic helix-loop-helix protein, E2A, together with RAG1/2 in a nonlymphoid cell line BOSC23 can induce V(D)J recombination in endogenous Igkappa and TCR loci by increasing chromatin accessibility of target gene segments. In this study, we demonstrate that ectopically expressed E2A proteins in BOSC23 cells have the ability to bind directly to the promoter and recombination signal sequence of Vkappa genes and to recruit histone acetyltransferase CBP/p300. Overexpression of CBP/p300 in conjunction with E2A results in enhancement of E2A-induced histone acetylation, germline transcription, and Igkappa rearrangement. Conversely, knockdown of endogenous CBP/p300 expression by small interfering RNA leads to a decrease in histone acetylation, germline transcription and Igkappa rearrangement. Furthermore, analyses using a mouse pre-B cell line revealed that endogenous E2A proteins also bind to a distinct set of Vkappa genes and regulatory regions in the mouse Igkappa locus and act to increase histone acetylation by recruiting p300, confirming the similar findings observed with BOSC23 cells. These observations indicate that E2A plays critical roles in inducing Igkappa rearrangement by directly binding to and increasing chromatin accessibility at target gene segments. PMID- 22544935 TI - CD13 regulates dendritic cell cross-presentation and T cell responses by inhibiting receptor-mediated antigen uptake. AB - Dendritic cell (DC) Ag cross-presentation is generally associated with immune responses to tumors and viral Ags, and enhancement of this process is a focus of tumor vaccine design. In this study, we found that the myeloid cell surface peptidase CD13 is highly and specifically expressed on the subset of DCs responsible for cross-presentation, the CD8(+) murine splenic DCs. In vivo studies indicated that lack of CD13 significantly enhanced T cell responses to soluble OVA Ag, although development, maturation, and Ag processing and presentation of DCs are normal in CD13KO mice. In vitro studies showed that CD13 regulates receptor-mediated, dynamin-dependent endocytosis of Ags such as OVA and transferrin but not fluid-phase or phagocytic Ag uptake. CD13 and Ag are cointernalized in DCs, but CD13 did not coimmunoprecipitate with Ag receptors, suggesting that CD13 does not control internalization of specific receptors but regulates endocytosis at a more universal level. Mechanistically, we found that phosphorylation of the endocytic regulators p38MAPK and Akt was dysregulated in CD13KO DCs, and blocking of these kinases perturbed CD13-dependent endocytic uptake. Therefore, CD13 is a novel endocytic regulator that may be exploited to enhance Ag uptake and T cell activation to improve the efficacy of tumor-targeted vaccines. PMID- 22544937 TI - TLR9 provokes inflammation in response to fetal DNA: mechanism for fetal loss in preterm birth and preeclampsia. AB - Preterm birth, the major cause of neonatal mortality in developed countries, is associated with intrauterine infections and inflammation, although the exact mechanisms underlying this event are unclear. In this study, we show that circulating fetal DNA, which is elevated in pregnancies complicated by preterm labor or preeclampsia, triggers an inflammatory reaction that results in spontaneous preterm birth. Fetal DNA activates NF-kappaB, shown by IkappaBalpha degradation in human PBMCs resulting in production of proinflammatory IL-6. We show that fetal resorption and preterm birth are rapidly induced in mice after i.p. injection of CpG or fetal DNA (300 MUg/dam) on gestational day 10-14. In contrast, TLR9(-/-) mice were protected from these effects. Furthermore, this effect was blocked by oral administration of the TLR9 inhibitor chloroquine. Our data therefore provide a novel mechanism for preterm birth and preeclampsia, highlighting TLR9 as a potential therapeutic target for these common disorders of pregnancy. PMID- 22544936 TI - CRTH2 is a critical regulator of neutrophil migration and resistance to polymicrobial sepsis. AB - Although arachidonic acid cascade has been shown to be involved in sepsis, little is known about the role of PGD(2) and its newly found receptor, chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), on the septic response. Severe sepsis is associated with the failure of neutrophil migration. To investigate whether CRTH2 influences neutrophil recruitment and the lethality during sepsis, sepsis was induced by cecal ligation and puncture (CLP) surgery in mice. CRTH2 knockout (CRTH2(-/-)) mice were highly resistant to CLP-induced sepsis, which was associated with lower bacterial load and lower production of TNF-alpha, IL-6, and CCL3. IL-10, an anti-inflammatory cytokine, was higher in CRTH2(-/-) mice, blunting CLP-induced lethality in CRTH2(-/-) mice. Neutrophil accumulation in the peritoneum was more pronounced after CLP in CRTH2(-/-) mice, which was associated with higher CXCR2 levels in circulating neutrophils. Furthermore, sepsis caused a decrease in the level of acetylation of histone H3, an activation mark, at the CXCR2 promoter in wild-type neutrophils, suggesting that CXCR2 expression levels are epigenetically regulated. Finally, both pharmacological depletion of neutrophils and inhibition of CXCR2 abrogated the survival benefit in CRTH2(-/-) mice. These results demonstrate that genetic ablation of CRTH2 improved impaired neutrophil migration and survival during severe sepsis, which was mechanistically associated with epigenetic-mediated CXCR2 expression. Thus, CRTH2 is a potential therapeutic target for polymicrobial sepsis. PMID- 22544938 TI - Differential effect of CD69 targeting on bystander and antigen-specific T cell proliferation. AB - In spite of an initially proposed role as a costimulatory molecule for CD69, in vivo studies showed it as a regulator of immune responses and lymphocyte egress. We found constitutive CD69 expression by T cell subsets and pDC. We examined a possible effect of CD69 on T cell proliferation using transfer models and in vitro assays. In mice locally expressing or receiving antigen, anti-CD692.2 treatment did not affect the proliferation of antigen-specific transgenic T cells in ADLN, although we observed the presence of proliferated T cells in non-ADLN and spleen. This was not affected by FTY720 treatment and thus, not contributed by increased egress of proliferated lymphocytes from ADLN. In the absence of antigen, anti-CD69 2.2 treatment induced bystander proliferation of transferred memory phenotype T cells. This proliferation was mediated by IL-2, as it was inhibited by anti-IL-2 or anti-CD25 antibodies in vitro and by anti-CD25 antibodies in vivo. It was also dependent on CD69 expression by donor T cells and recipient cells. CD69 targeting on T cells enhanced IL-2-mediated proliferation and CD25 expression. However, it did not lead to increased early IL-2 production by T cells. No T cell subset was found to be specifically required in the recipient. Instead, CD69 targeting on pDC induced their expression of IL-2 and CD25, and pDC depletion showed that this subset was involved in the proliferation induction. These results indicate that CD69 targeting induces bystander T cell proliferation through pDC IL-2 production and T cell sensitization to IL-2 without affecting antigen-driven T cell proliferation. PMID- 22544940 TI - Direct in vivo evidence of CD4+ T cell requirement for CTL response and memory via pMHC-I targeting and CD40L signaling. AB - CD4(+) T cell help contributes critically to DC-induced CD8(+) CTL immunity. However, precisely how these three cell populations interact and how CD4(+) T cell signals are delivered to CD8(+) T cells in vivo have been unclear. In this study, we developed a novel, two-step approach, wherein CD4(+) T cells and antigen-presenting DCs productively engaged one another in vivo in the absence of cognate CD8(+) T cells, after which, we selectively depleted the previously engaged CD4(+) T cells or DCs before allowing interactions of either population alone with naive CD8(+) T cells. This protocol thus allows us to clearly document the importance of CD4(+) T-licensed DCs and DC-primed CD4(+) T cells in CTL immunity. Here, we provide direct in vivo evidence that primed CD4(+) T cells or licensed DCs can stimulate CTL response and memory, independent of DC-CD4(+) T cell clusters. Our results suggest that primed CD4(+) T cells with acquired pMHC I from DCs represent crucial "immune intermediates" for rapid induction of CTL responses and for functional memory via CD40L signaling. Importantly, intravital, two-photon microscopy elegantly provide unequivocal in vivo evidence for direct CD4-CD8(+) T cell interactions via pMHC-I engagement. This study corroborates the coexistence of direct and indirect mechanisms of T cell help for a CTL response in noninflammatory situations. These data suggest a new "dynamic model of three cell interactions" for CTL immunity derived from stimulation by dissociated, licensed DCs, primed CD4(+) T cells, and DC-CD4(+) T cell clusters and may have significant implications for autoimmunity and vaccine design. PMID- 22544941 TI - New NIH center broadens scope of translational research. PMID- 22544939 TI - Regulation of alveolar macrophage p40phox: hierarchy of activating kinases and their inhibition by PGE2. AB - PGE(2), produced in the lung during infection with microbes such as Klebsiella pneumoniae, inhibits alveolar macrophage (AM) antimicrobial functions by preventing H(2)O(2) production by NADPH oxidase (NADPHox). Activation of the NADPHox complex is poorly understood in AMs, although in neutrophils it is known to be mediated by kinases including PI3K/Akt, protein kinase C (PKC) delta, p21 activated protein kinase (PAK), casein kinase 2 (CK2), and MAPKs. The p40phox cytosolic subunit of NADPHox has been recently recognized to function as a carrier protein for other subunits and a positive regulator of oxidase activation, a role previously considered unique to another subunit, p47phox. The regulation of p40phox remains poorly understood, and the effect of PGE(2) on its activation is completely undefined. We addressed these issues in rat AMs activated with IgG-opsonized K. pneumoniae. The kinetics of kinase activation and the consequences of kinase inhibition and silencing revealed a critical role for a PKCdelta-PAK-class I PI3K/Akt1 cascade in the regulation of p40phox activation upon bacterial challenge in AMs; PKCalpha, ERK, and CK2 were not involved. PGE(2) inhibited the activation of p40phox, and its effects were mediated by protein kinase A type II, were independent of interactions with anchoring proteins, and were directed at the distal class I PI3K/Akt1 activation step. Defining the kinases that control AM p40phox activation and that are the targets for inhibition by PGE(2) provides new insights into immunoregulation in the infected lung. PMID- 22544943 TI - Preserving fertility in cancer patients. PMID- 22544944 TI - Pregnancy after breast cancer appears safe. PMID- 22544945 TI - Prepping omics for the clinic. PMID- 22544946 TI - A clinically silent, but severe, duodenal complication of duodopa infusion. PMID- 22544947 TI - Can regional spreading of amyotrophic lateral sclerosis motor symptoms be explained by prion-like propagation? AB - Progressive accumulation of specific misfolded protein is a defining feature of amyotrophic lateral sclerosis (ALS), similarly seen in Alzheimer disease, Parkinson disease, Huntington disease and Creutzfeldt-Jakob disease. The intercellular transfer of inclusions made of tau, alpha-synuclein and huntingtin has been demonstrated, revealing the existence of mechanisms reminiscent of those by which prions spread through the nervous system. Evidence for such a prion-like propagation mechanism has now spread to the major misfolded proteins, superoxide dismutase 1 (SOD1) and the 43 kDa transactive response DNA binding protein (TDP 43), implicated in ALS. The focus in this review is on what is known about ALS progression in terms of clinical as well as molecular aspects. Furthermore, the concept of 'propagation' is dissected into contiguous and non-contiguous types, and this concept is expanded to the severity of the focal symptom as well as its regional spread which can be explained by cell to cell propagation in the local neuron pool. PMID- 22544948 TI - Doctors' knowledge of preparedness and response to nuclear power plant emergencies. PMID- 22544950 TI - Actin stress fibers--assembly, dynamics and biological roles. AB - Actin filaments assemble into diverse protrusive and contractile structures to provide force for a number of vital cellular processes. Stress fibers are contractile actomyosin bundles found in many cultured non-muscle cells, where they have a central role in cell adhesion and morphogenesis. Focal-adhesion anchored stress fibers also have an important role in mechanotransduction. In animal tissues, stress fibers are especially abundant in endothelial cells, myofibroblasts and epithelial cells. Importantly, recent live-cell imaging studies have provided new information regarding the mechanisms of stress fiber assembly and how their contractility is regulated in cells. In addition, these studies might elucidate the general mechanisms by which contractile actomyosin arrays, including muscle cell myofibrils and cytokinetic contractile ring, can be generated in cells. In this Commentary, we discuss recent findings concerning the physiological roles of stress fibers and the mechanism by which these structures are generated in cells. PMID- 22544952 TI - Reexamining the Factor structure of somatization using the children's somatization inventory (CSI-24) in a community sample. AB - OBJECTIVE: Pediatric somatization studies have used the 35-item Child Somatization Inventory (CSI-35) or psychometrically refined 24-item CSI (CSI-24). Exploratory factor analysis of the CSI-24 has identified a single factor that did not show good model fit in confirmatory factor analysis (CFA). Further evaluation of the CSI-24 factor structure is needed. METHODS: The present study examined alternative factor structures of the CSI-24 in a community sample (N = 233, ages 8-15). RESULTS: The CFA showed good fit for a single CSI-24 factor, better fit for multiple factor models, and best fit for a single, six-item factor. Construct validity for that factor was found in significant correlations with anxiety, depression, functional disability, and quality of life. CONCLUSIONS: Results are consistent with a single somatization factor, but research is needed to verify the factor structure in different, race/ethnic/demographic, and clinical groups. PMID- 22544951 TI - Catalysis leads to posttranslational inactivation of the type 1 deiodinase and alters its conformation. AB - Previously, it was shown that the type 1 deiodinase (D1) is subject to substrate dependent inactivation that is blocked by pretreatment with the inhibitor of D1 catalysis, propylthiouracil (PTU). Using HepG2 cells with endogenous D1 activity, we found that while considerable D1-mediated catalysis of reverse tri iodothyronine (rT(3)) is observed in intact cells, there was a significant loss of D1 activity in sonicates assayed from the same cells in parallel. This rT(3) mediated loss of D1 activity occurs despite no change in D1 mRNA levels and is blocked by PTU treatment, suggesting a requirement for catalysis. Endogenous D1 activity in sonicates was inactivated in a dose-dependent manner in HepG2 cells, with a ~50% decrease after 10 nM rT(3) treatment. Inactivation of D1 was rapid, occurring after only half an hour of rT(3) treatment. D1 expressed in HEK293 cells was inactivated by rT(3) in a similar manner. (75)Se labeling of the D1 selenoprotein indicated that after 4 h rT(3)-mediated inactivation of D1 occurs without a corresponding decrease in D1 protein levels, though rT(3) treatment causes a loss of D1 protein after 8-24 h. Bioluminescence resonance energy transfer studies indicate that rT(3) exposure increases energy transfer between the D1 homodimer subunits, and this was lost when the active site of D1 was mutated to alanine, suggesting that a post-catalytic structural change in the D1 homodimer could cause enzyme inactivation. Thus, both D1 and type 2 deiodinase are subject to catalysis-induced loss of activity although their inactivation occurs via very different mechanisms. PMID- 22544953 TI - Keeping your eyes on the dashboard. PMID- 22544954 TI - Engaging in rapid cycle innovation. PMID- 22544955 TI - Incorporating a continuous quality improvement process into pharmacy accreditation for well-established programs. PMID- 22544956 TI - Junior pharmacy faculty members' perceptions of their exposure to postgraduate training and academic careers during pharmacy school. AB - OBJECTIVE: To determine the perceptions of junior pharmacy faculty members with US doctor of pharmacy (PharmD) degrees regarding their exposure to residency, fellowship, and graduate school training options in pharmacy school. Perceptions of exposure to career options and research were also sought. METHODS: A mixed mode survey instrument was developed and sent to assistant professors at US colleges and schools of pharmacy. RESULTS: Usable responses were received from 735 pharmacy faculty members. Faculty members perceived decreased exposure to and awareness of fellowship and graduate education training as compared to residency training. Awareness of and exposure to academic careers and research-related fields was low from a faculty recruitment perspective. CONCLUSIONS: Ensuring adequate exposure of pharmacy students to career paths and postgraduate training opportunities could increase the number of PharmD graduates who choose academic careers or other pharmacy careers resulting from postgraduate training. PMID- 22544957 TI - Clinical cultural competency and knowledge of health disparities among pharmacy students. AB - OBJECTIVE: To evaluate the level of competency and knowledge about health disparities among third-year doctor of pharmacy (PharmD) students at 2 Florida public colleges of pharmacy and to explore the demographic correlates of these variables. METHODS: A cross-sectional survey study design was used to collect data from participants. RESULTS: The students had low health-disparities knowledge and moderate skills in dealing with sociocultural issues and cross cultural encounters. Speaking a language(s) other than English and having exposure to cultural-competency instruction were the demographic variables found to be most significantly associated with clinical cultural competency and/or knowledge of health disparities. CONCLUSIONS: Clinical cultural competency and health-disparities instruction may not be adequately incorporated into the pharmacy school curricula in the institutions studied. Relevant education and training are necessary to enhance cultural competency among pharmacy students. PMID- 22544958 TI - The effect of various grading scales on student grade point averages. AB - OBJECTIVE: To investigate changes in and the impact of grading scales from 2005 to 2010 and explore pharmacy faculty and student perceptions of whole-letter and plus/minus grading scales on cumulative grade point averages (GPAs) in required courses. METHODS: Grading scales used in 2010 at the University of Cincinnati College of Pharmacy were retrospectively identified and compared to those used in 2005. Mean GPA was calculated using a whole-letter grading scale and a plus/minus grading scale to determine the impact of scales on GPA. Faculty members and students were surveyed regarding their perceptions of plus/minus grading. RESULTS: Nine unique grading scales were used throughout the curriculum, including plus/minus (64%) and whole-letter (21%) grading scales. From 2005 to 2010 there was transition from use of predominantly whole-letter scales to plus/minus grading scales. The type of grading scale used did not affect the mean cumulative GPA. Students preferred use of a plus-only grading scale while faculty members preferred use of a plus/minus grading scale. CONCLUSIONS: The transition from whole-letter grading to plus/minus grading in courses from 2005 to 2010 reflects pharmacy faculty members' perception that plus/minus grading allows for better differentiation between students' performances. PMID- 22544959 TI - An introductory pharmacy practice experience on improving medication adherence. AB - OBJECTIVE: To evaluate the impact of a medication adherence activity on introductory pharmacy practice experience students' perceptions of patient adherence as well as student development of empathy and confidence in patient counseling. DESIGN: Students participated in a personal medication simulation using an automated medication dispenser. Students then identified a patient with nonadherence and provided counseling on use of the dispenser. After 4 to 6 weeks, students interviewed the patient about their experience with the dispenser and assessed changes in adherence. ASSESSMENT: One hundred fifty-three students completed the assignment and 3 surveys instruments. Following the experience, the majority of students agreed or strongly agreed that they developed more empathy for patients with multiple medications and felt confident counseling a patient in the use of a dispenser (92.0% and 88.2%, respectively). Most students (91.4%) reported feeling that their patient education session was successful. CONCLUSION: An introductory pharmacy practice experience involving an automated medication dispenser and patient counseling to improve medication adherence resulted in the development of empathy and improved student confidence. PMID- 22544960 TI - An advanced clinical track within a doctor of pharmacy program. AB - OBJECTIVE: To evaluate the advanced clinical track, a curricular track designed to prepare doctor of pharmacy (PharmD) students for residency training and institutional practice. DESIGN: The advanced clinical track required completion of elective coursework, an additional advanced practice experience, 8 clinical experiences, and a skills checklist, and participation in a clinical skills competition. ASSESSMENT: Thirty-two graduates of the advanced clinical track were surveyed. Of the 23 respondents, 95% of those who pursued residency training were successfully matched with a residency program. Ninety-one percent of respondents felt that the advanced clinical track increased their confidence and 74% felt it was definitely an advantage when applying to a residency program. All participants agreed that the advanced clinical track met their expectations or goals and would recommend it to other students. CONCLUSION: Completion of an advanced clinical track was viewed by PharmD graduates as valuable preparation for residency training and institutional practice and would be recommended to other students. PMID- 22544961 TI - An objective structured clinical examination to assess problem-based learning. AB - OBJECTIVES: To compare pharmacy students' performance on an objective structured clinical examination (OSCE) to their performance on a written examination for the assessment of problem-based learning (PBL); and to determine students' and faculty members' perceptions of OSCEs for PBL evaluations. DESIGN: Four OSCEs were added to the written examination to assess 4 PBL cases in a third-year pharmacotherapy course. OSCE scores were compared to written examination scores. Faculty members evaluated student performance. ASSESSMENT: OSCE performance did not correlate with the written-examination scores. Most students (>= 75%) agreed that OSCEs reflected their learning from PBL and measured knowledge, communication, and clinical skills. A majority of faculty members (>=75%) agreed that OSCEs should be part of PBL assessment. CONCLUSIONS: Addition of an OSCE to written examinations was valued and provided a more comprehensive assessment of the PBL experience. PMID- 22544962 TI - Sharing ideas in experiential education. PMID- 22544963 TI - Portfolio use and practices in US colleges and schools of pharmacy. AB - OBJECTIVES: To identify the prevalence of portfolio use in US pharmacy programs, common components of portfolios, and advantages of and limitations to using portfolios. METHODS: A cross-sectional electronic survey instrument was sent to experiential coordinators at US colleges and schools of pharmacy to collect data on portfolio content, methods, training and resource requirements, and benefits and challenges of portfolio use. RESULTS: Most colleges and schools of pharmacy (61.8%) use portfolios in experiential courses and the majority (67.1%) formally assess them, but there is wide variation regarding content and assessment. The majority of respondents used student portfolios as a formative evaluation primarily in the experiential curriculum. CONCLUSIONS: Although most colleges and schools of pharmacy have a portfolio system in place, few are using them to fulfill accreditation requirements. Colleges and schools need to carefully examine the intended purpose of their portfolio system and follow-through with implementation and maintenance of a system that meets their goals. PMID- 22544964 TI - A comprehensive approach to preceptor development. AB - OBJECTIVE: To assess the impact of a comprehensive preceptor development program. DESIGN: A comprehensive preceptor development program was designed that included live and recorded online programming, a preceptor manual, a preceptor newsletter, live events (local and regional), and one-on-one practice site visits. ASSESSMENT: Over 5,000 evaluations (1,900 pre-implementation and 3,160 post implementation) of preceptor performance were completed by students. Students rated preceptors higher in items related to providing helpful midpoint and final evaluations after program implementation. Over 1,000 Web-based preceptor development activities were completed by preceptors from 2007 to 2011. Preceptors felt activities enhanced their current knowledge, skills, attitudes, and values, and more than 90% felt the core development activities would improve their current practice. CONCLUSION: A comprehensive approach to preceptor development that offered a variety of development and training opportunities received positive evaluations from preceptors and resulted in improved student evaluations of preceptors. A comprehensive development program should be made available to preceptors to foster their continuing professional development. PMID- 22544965 TI - Pharmacy preceptors' views on the value and optimal frequency of quality assurance visits to advanced pharmacy practice experience sites. AB - OBJECTIVE: To determine volunteer preceptors' perceived value and desired frequency of quality assurance visits by experiential education faculty members. METHODS: An electronic survey instrument was sent to 235 volunteer preceptors. RESULTS: A 71.5% response rate was achieved. Nearly 90% of respondents indicated that onsite visits met their needs. Approximately 50% of respondents preferred monthly onsite visits, 17% preferred every other month, and 32% preferred once per year. CONCLUSIONS: A quality assurance program for preceptors and experiential sites that includes onsite visits from experiential education faculty members meets multiple needs of the college and the preceptors. More research is needed to determine the impact of this method of quality assurance on experiential education. PMID- 22544966 TI - Impact of advanced pharmacy practice experience placement changes in colleges and schools of pharmacy. AB - OBJECTIVE: To document the annual number of advanced pharmacy practice experience (APPE) placement changes for students across 5 colleges and schools of pharmacy, identify and compare initiating reasons, and estimate the associated administrative workload. METHODS: Data collection occurred from finalization of the 2008-2009 APPE assignments throughout the last date of the APPE schedule. Internet-based customized tracking forms were used to categorize the initiating reason for the placement change and the administrative time required per change (0 to 120 minutes). RESULTS: APPE placement changes per institution varied from 14% to 53% of total assignments. Reasons for changes were: administrator initiated (20%), student initiated (23%), and site/preceptor initiated (57%) Total administrative time required per change varied across institutions from 3,130 to 22,750 minutes, while the average time per reassignment was 42.5 minutes. CONCLUSION: APPE placements are subject to high instability. Significant differences exist between public and private colleges and schools of pharmacy as to the number and type of APPE reassignments made and associated workload estimates. PMID- 22544967 TI - Further development of pharmacy student-facilitated diabetes management clinics. AB - OBJECTIVE: To further develop and evaluate a diabetes disease state management (DSM) program that provided direct patient care responsibilities to advanced pharmacy practice experience (APPE) students as members of healthcare teams. DESIGN: Nine new clinics and 3 established sites that provide self-care management education to patients with diabetes were established and maintained in rural Colorado pharmacies and supported by students in APPE training for 48 weeks per year. EVALUATION: The 12 clinics provided 120 APPE student placements in 2010 2011. Students' perceptions of their experiences were positive. Patients who completed the student-supported diabetes self-management education program had improvements in blood glucose, blood pressure, and lipid values. CONCLUSIONS: Twelve diabetes DSM clinics provided direct patient care opportunities to APPE students working as part of healthcare teams while expanding healthcare resources in underserved communities in Colorado. PMID- 22544968 TI - Medication therapy management services provided by student pharmacists. AB - OBJECTIVES: To evaluate the impact of student pharmacists delivering medication therapy management (MTM) services during an elective advanced pharmacy practice experience (APPE). METHODS: Student pharmacists provided MTM services at community pharmacy APPE sites, documented their recommendations, and then made follow-up telephone calls to patients to determine the impact of the MTM provided. Students were surveyed about the MTM experience. RESULTS: Forty-seven students provided MTM services to 509 patients over 2 years and identified 704 drug-related problems (average of 1.4 problems per patient). About 53% of patients relayed the recommendations to their physician and 205 (75%) physicians accepted the recommendations. Eighty-eight percent of patients reported feeling better about their medications after receiving MTM services. A majority of the students perceived their provision of MTM services as valuable to their patients. CONCLUSIONS: Providing MTM services to patients in a pharmacy practice setting allowed student pharmacists to apply skills learned in the doctor of pharmacy (PharmD) curriculum. PMID- 22544969 TI - Integration of an introductory pharmacy practice experience with an advanced pharmacy practice experience in adult internal medicine. AB - OBJECTIVE: To describe the development, implementation, and assessment of an internal medicine introductory pharmacy practice experience (IPPE) that was integrated with an existing advanced pharmacy practice experience (APPE) in internal medicine. DESIGN: A structured IPPE was designed for first-, second-, and third-year pharmacy (P1, P2, and P3) students. Activities for the IPPE were based on the established APPE and the individual learner's educational level. ASSESSMENT: Students reported a greater understanding of clinical pharmacists' roles, increased confidence in their clinical skills, and better preparation for APPEs. Peers viewed the approach as innovative and transferable to other practice settings. Participating faculty members provided a greater number of contact hours compared to traditional one-time site visits. CONCLUSIONS: Integrating an IPPE with an existing APPE is an effective and efficient way to provide patient care experiences for students in the P1-P3 years in accordance with accreditation standards. PMID- 22544970 TI - A collaborative approach to improving and expanding an experiential education program. AB - The lessons learned from a collaboration between a faculty of pharmacy and a practice site that involved implementation of an innovative experiential placement model are described, as well as the broader impact of the project on other practice sites, the faculty of pharmacy's experiential education program, and experiential placement capacity. The partnerships and collaborative strategies formed were key to the implementation and evaluation of a pharmacy student clinical teaching unit pilot program and integration of concepts used in the unit into the advanced pharmacy practice experience (APPE) program to enhance capacity and quality. The university-practice partnerships have made it possible to promote the delegation of responsibility and accountability for patient care to students, challenge the anticipated workload burden for preceptors, question the optimal length of an APPE placement, and highlight the value of higher student-to-preceptor ratios that facilitate peer-assisted learning (PAL) and optimize the practice learning experiences for preceptors and students. Collaboration in experiential education between universities and practice sites can provide opportunities to address challenges faced by practitioners and academics alike. PMID- 22544971 TI - Plagiarism among faculty applicants. PMID- 22544972 TI - On the Assessment of Monte Carlo Error in Simulation-Based Statistical Analyses. AB - Statistical experiments, more commonly referred to as Monte Carlo or simulation studies, are used to study the behavior of statistical methods and measures under controlled situations. Whereas recent computing and methodological advances have permitted increased efficiency in the simulation process, known as variance reduction, such experiments remain limited by their finite nature and hence are subject to uncertainty; when a simulation is run more than once, different results are obtained. However, virtually no emphasis has been placed on reporting the uncertainty, referred to here as Monte Carlo error, associated with simulation results in the published literature, or on justifying the number of replications used. These deserve broader consideration. Here we present a series of simple and practical methods for estimating Monte Carlo error as well as determining the number of replications required to achieve a desired level of accuracy. The issues and methods are demonstrated with two simple examples, one evaluating operating characteristics of the maximum likelihood estimator for the parameters in logistic regression and the other in the context of using the bootstrap to obtain 95% confidence intervals. The results suggest that in many settings, Monte Carlo error may be more substantial than traditionally thought. PMID- 22544973 TI - Population Genetics of Aedes albopictus (Diptera: Culicidae) Invading Populations, Using Mitochondrial nicotinamide Adenine Dinucleotide Dehydrogenase Subunit 5 Sequences. AB - Aedes albopictus (Skuse) (Diptera: Culicidae), the Asian tiger mosquito indigenous to Asia, now an invasive species worldwide, is an important vector for several arboviruses. Genetic analysis using the mitochondrial nicotinamide adenine dinucleotide dehydrogenase subunit 5 (ND5) gene was carried out in populations from Cameroon (n = 50), Hawaii (n = 38), Italy (n = 20), the continental United States, Brazil, and its native range. Data for Brazil, the continental United States, and the native range was obtained from Birungi and Munstermann (2002). Direct sequencing was used to identity unique haplotypes. The limited phylogeographic partitioning of haplotypes with low levels of sequence divergence in both Cameroon and Hawaii was consistent with the population structure of Ae. albopictus in the United States and Brazil. Four new haplotypes were identified from the samples from Cameroon and Hawaii, adding to previously described haplotypes. Hawaii shared a haplotype with Cameroon that was unique to these two regions. Hawaii also had higher overall haplotype diversity than seen in previous continental United States, Brazil, or native range populations. Hawaiian, Cameroon, and Italian populations did not share haplotypes with Brazil, which validates the earlier mitochondrial DNA studies indicating a separate introduction of this species into Brazil. PMID- 22544974 TI - Mismatch Discrimination and Efficient Photomodulation with Split 10-23 DNAzymes. AB - DNA enzymes (DNAzymes) that catalyze the degradation of complementary RNA molecules have been investigated for many biochemical and sensing applications. Here, we investigated a 10-23 DNAzyme that has been shown previously to possess cellular activity. We determined that it has very low Mg(2+) ion dependence, with DNAzyme activity observed at [Mg(2+)] = 0.01 mM. This metal ion dependence is much lower than is typical for DNAzymes studied to date, and suggests that DNAzymes may be engineered for many additional biological applications. Recently, we demonstrated that this 10-23 DNAzyme can be divided into two parts, which assemble into an active oligonucleotide complex. We investigated in more detail the functionality of the split 10-23 DNAzyme and found that dividing the 15 nucleotide catalytic loop after the 7(th) or 8(th) base maximized its activity. The split DNAzymes required higher metal ion concentrations ([Mg(2+)] = 5 mM), and as we anticipated due to their lower hybridization activity, the split enzymes had the advantage of being more sensitive to single base mismatches in the DNAzyme-RNA duplex. Finally, we demonstrated facile photomodulation of split DNAzyme activity by incorporating a photocleavable biotin moiety bound to streptavidin. PMID- 22544975 TI - Adolescents' Pregnancy Intentions, Wantedness, and Regret: Cross-Lagged Relations With Mental Health and Harsh Parenting. AB - The authors used cross-lagged analyses to examine the across-time influences on and consequences of adolescents' pregnancy intentions, wantedness, and regret. One hundred pregnant Latina adolescents were studied during pregnancy and at 6 and 12 months postpartum. The results revealed 4 main findings: (a) similar to what has been found in adult women, adolescents' lower prenatal pregnancy intendedness and wantedness predicted initial difficulties in parenting; (b) frequent depression symptoms predicted subsequent lower pregnancy intendedness and wantedness; (c) adolescents' poor mental health and harsh parenting of their child predicted subsequent higher childbearing regret, and (d) high childbearing regret and parenting stress were reciprocally related across time. In addition, adolescents' wantedness of their pregnancy declined prenatally to postbirth, and strong pregnancy intendedness and wantedness were not concurrently related to adolescents' poor prenatal mental health. The findings reveal how adolescents' thoughts and feelings about their pregnancies are influenced by and predictive of their mental health and parenting experiences. PMID- 22544976 TI - Satellite Remote Sensing of Space-Time Plankton Variability in the Bay of Bengal: Connections to Cholera Outbreaks. AB - Cholera bacteria exhibit strong association with coastal plankton. Characterization of space-time variability of chlorophyll, a surrogate for plankton abundance, in Northern Bay of Bengal is an essential first step to develop any methodology for predicting cholera outbreaks in the Bengal Delta region using remote sensing. This study quantifies the space-time distribution of chlorophyll, using data from SeaWiFS, in the Bay of Bengal region using ten years of satellite data. Variability of chlorophyll at daily scale, irrespective of spatial averaging, resembles white noise. At a monthly scale, chlorophyll shows distinct seasonality and chlorophyll values are significantly higher close to the coast than in the offshore regions. At pixel level (9 km) on monthly scale, on the other hand, chlorophyll does not exhibit much persistence in time. With increased spatial averaging, temporal persistence of chlorophyll increases and lag one autocorrelation stabilizes around 0.60 for 1296 km(2) or larger areal averages. In contrast to the offshore regions, spatial analyses of chlorophyll suggest that only coastal region has a stable correlation length of 100 km. Presence (absence) of correlation length in the coastal (offshore) regions, indicate that the two regions may have two separate processes controlling the production a phytoplankton This study puts a lower limit on space-time averaging of satellite measured plankton at 1296 km(2)-monthly scale to establish relationships with cholera incidence in Bengal Delta. PMID- 22544977 TI - Age Effects and Heuristics in Decision Making. AB - Using controlled experiments, we examine how individuals make choices when faced with multiple options. Choice tasks are designed to mimic the selection of health insurance, prescription drug, or retirement savings plans. In our experiment, available options can be objectively ranked allowing us to examine optimal decision making. First, the probability of a person selecting the optimal option declines as the number of options increases, with the decline being more pronounced for older subjects. Second, heuristics differ by age with older subjects relying more on suboptimal decision rules. In a heuristics validation experiment, older subjects make worse decisions than younger subjects. PMID- 22544978 TI - Intergenerational Ties in Context: Grandparents Caring for Grandchildren in China. AB - Guided by theories and empirical research on intergenerational relationships, we examine the phenomenon of grandparents caring for grandchildren in contemporary China. Using a longitudinal dataset (China Health and Nutrition Survey), we document a high level of structural and functional solidarity in grandparent grandchildren relationships. Intergenerational solidarity is indicated by a high rate of coresidence between grandchildren and grandparents, a sizable number of skipped-generation households (no parent present), extensive childcare involvement by non-coresidential grandparents, and a large amount of care provided by coresidential grandparents. Multivariate analysis further suggests that grandparents' childcare load is adaptive to familial needs, as reflected by the characteristics of the household, household members, and work activities of the mothers. PMID- 22544979 TI - Synthesis of Fluoroolefins via Julia-Kocienski Olefination. AB - The Julia-Kocienski olefination provides a versatile platform for the synthesis of fluorovinyl compounds. This review describes our efforts as well as those of others in the synthesis of various fluorinated aryl and heteroaryl sulfones and their utility as olefination reagents for the modular assembly of fluoroalkenes. Where data is available, the influence of the fluorine atom on the reactivity of the olefination reagents and the stereochemical outcome of the olefination are described. PMID- 22544980 TI - Organocatalyzed enantioselective aldol reaction of 1H-pyrrole-2,3-diones. AB - The enantioselective cross aldol reaction of 1-benzyl 4,5-dioxo-2-aryl-4,5 dihydro-1H-pyrrole-3-carboxylates and ketones was studied with proline derivatives or cinchona alkaloid-derived primary amines as the catalysts for the first time. trans-4-Benzoyloxy-L-proline (15) was found to be the best catalyst for acyclic ketones. For cyclohexanone, the best results were achieved with 9 deoxy-9-epi-aminoquinine (18) as the catalyst in the presence of racemic 1,1' binaphthyl-2,2'-diyl hydrogen phosphate (19) as the cocatalyst. Using these protocols, 3-alkyl-3-hydroxy-1H-pyrrol-2(3H)-one derivatives were obtained in excellent yields and good to high ee values (up to 94% ee). PMID- 22544981 TI - Hydrazine-mediated cyclization of Ugi products to synthesize novel 3 hydroxypyrazoles. AB - This report discloses a novel concise synthesis of a series of 3-hydroxypyrazoles 5 via a tandem Ugi/debenzylation /hydrazine-mediated cyclization sequence. Herein, n-butyl isocyanide 4b was utilized as an alternative to classical convertible isocyanides enabling high yielding hydrazine-mediated cyclization. Taken together, a novel class of 3-hydroxypyrazoles 5a-5i was synthesized with potential to be of interest in future library enrichment strategies. PMID- 22544982 TI - Diversity Oriented Synthesis: Concise Entry to Novel Derivatives of Yohimbine and Corynanthe Alkaloids. AB - A novel MCAP-cycloaddition sequence has been applied to the facile synthesis of beta-carboline intermediates to gain rapid access to novel derivatives of yohimbine-like and corynanthe-like compounds that may be easily diversified by cross-coupling reactions and N-derivatizations to generate small compound libraries. PMID- 22544983 TI - A Welfare Measure of "Offset Effects" in Health Insurance. AB - Changing health insurance coverage for one service may affect use of other insured services. When improving coverage for one service reduces use of another, the savings are referred to as "offset effects." For example, costs of better coverage for prescription drugs may be partly "offset" by reductions in hospital costs. Offset effects have welfare implications but it has not been clear how to value these impacts in design of health insurance. We show that plan-paid - rather than total -- spending is the right welfare measure of the offset effect, and go on to develop a "sufficient statistic" for evaluating the welfare effects of change in coverage in the presence of multiple goods. We derive a simple rule for when a coverage improvement increases welfare due to offset effects. PMID- 22544984 TI - ? AB - The chemical pesticide, imidacloprid (IMI) has long-lasting effectiveness against Hemiptera. IMI is commonly used to control the brown planthopper (BPH), Nilaparvata lugens Stal (Hemiptera: Delphacidae). Some chemical pesticides, however, can induce the susceptibility of rice to BPH, which has indirectly led to the resurgence of BPH. The mechanism of the chemical induction of the susceptibility of rice to BPH was not previously understood. Here, a 44 K Agilent Rice Expression Microarray was used to identify changes in gene expression that accompany IMI-induced rice susceptibility to BPH. The results showed that 225 genes were differentially expressed, of which 117 were upregulated, and 108 were downregulated. Gene ontology annotation and pathway analysis revealed that differentially expressed genes were mainly classified into the eight functional groups: oxidation reduction, regulation of cellular process, response to stress, electron carrier activity, metabolic process, transport, signal transducer, and organismal development. The genes encoding plant lipid transfer protein, lignin peroxidase, and flavonol-3-O-methyltransferenase may be important responses to the IMI-induced susceptibility of rice to BPH. The reliability of the microarray data was verified by performing quantitative real-time PCR and the data provide valuable information for further study of the molecular mechanism of IMI-induced susceptibility of rice. PMID- 22544985 TI - Determination of neutralization capacity and stability of a basic methacrylate monomer using NMR. AB - The durability of dental resin depends on the stability of the polymer. The neutralizing capacity of a basic methacrylate monomer and its chemical stability were measured using nuclear magnetic resonance (NMR) spectroscopy. Lactic acid solution was titrated with 2-(dimethylamino)ethylmethacrylate (DMAEMA) or 2 hydroxyethylmethacrylate (HEMA) and its chemical shifts monitored. Addition of DMAEMA alters the chemical shift proportionally to pH neutralization, whereas HEMA has no impact. Chemical shifts were used to quantify both the change in pH and monomer stability. The results demonstrate that neutralization by basic monomer can be achieved and that this can be measured using an NMR assay. PMID- 22544986 TI - Frozen Film and FOSDIC Forms: Restoring the 1960 U.S. Census of Population and Housing. AB - In this article, the authors describe a collaboration of the Minnesota Population Center (MPC), the U.S. Census Bureau, and the National Archives and Records Administration to restore the lost data from the 1960 Census. The data survived on refrigerated microfilm in a cave in Lenexa, Kansas. The MPC is now converting the data to usable form. Once the restored data are processed, the authors intend to develop three new data sources based on the 1960 census. These data will replace the most inadequate sample in the series of public-use census microdata spanning the years from 1850 to 2000, extend the chronological scope of the public census summary files, and provide a powerful new resource for the Census Bureau and its Research Data Centers. PMID- 22544987 TI - Why Do People Use Facebook? AB - The social networking site, Facebook, has gained an enormous amount of popularity. In this article, we review the literature on the factors contributing to Facebook use. We propose a model suggesting that Facebook use is motivated by two primary needs: (1) The need to belong and (2) the need for self-presentation. Demographic and cultural factors contribute to the need to belong, whereas neuroticism, narcissism, shyness, self-esteem and self-worth contribute to the need for self presentation. Areas for future research are discussed. PMID- 22544988 TI - Forms of Spanking and Children's Externalizing Behaviors. AB - Research suggests that corporal punishment is related to higher levels of child externalizing behavior, but there has been controversy regarding whether infrequent, mild spanking predicts child externalizing or whether more severe and frequent forms of corporal punishment account for the link. Mothers rated the frequency with which they spanked and whether they spanked with a hand or object when their child was 6, 7, and 8 years old. Mothers and teachers rated children's externalizing behaviors at each age. Analyses of covariance revealed higher levels of mother-reported externalizing behavior for children who experienced harsh spanking. Structural equation models for children who experienced no spanking or mild spanking only revealed that spanking was related to concurrent and prior, but not subsequent, externalizing. Mild spanking in one year was a risk factor for harsh spanking in the next year. Findings are discussed in the context of efforts to promote children's rights to protection. PMID- 22544990 TI - ON THE CHEMICAL SYNTHESIS OF NEW TOPOLOGICAL STRUCTURES. PMID- 22544989 TI - NEGATIVE AND POSITIVE CAREGIVING EXPERIENCES: A CLOSER LOOK AT THE INTERSECTION OF GENDER AND RELATIOSHIPS. AB - Using data from the 2004 wave of the National Long-Term Care Survey, we examined how negative and positive caregiving experiences differ by caregivers' gender and relationship to care recipients. We further considered how their caregiving experiences are affected by caregivers' demographic characteristics, care recipients' problem behavior and dependency, caregivers' involvement, reciprocal help from care recipients, and social support available for caregivers. We found that female and adult-child caregivers, in general, reported having had more negative experiences than male and spouse caregivers, respectively. Wife caregivers were least likely to report positive experiences. We also found different risk factors for negative and positive caregiving experiences, and these factors varied depending on caregivers' gender and relationship to the care recipient. The findings underscore the heterogeneity of caregiving experiences. To sustain informal care, state and local agencies need to tailor services to wife, husband, daughter, and son caregivers' unique needs. PMID- 22544991 TI - Mixed-Poisson Point Process with Partially-Observed Covariates: Ecological Momentary Assessment of Smoking. AB - Ecological Momentary Assessment is an emerging method of data collection in behavioral research that may be used to capture the times of repeated behavioral events on electronic devices, and information on subjects' psychological states through the electronic administration of questionnaires at times selected from a probability-based design as well as the event times. A method for fitting a mixed Poisson point process model is proposed for the impact of partially-observed, time-varying covariates on the timing of repeated behavioral events. A random frailty is included in the point-process intensity to describe variation among subjects in baseline rates of event occurrence. Covariate coefficients are estimated using estimating equations constructed by replacing the integrated intensity in the Poisson score equations with a design-unbiased estimator. An estimator is also proposed for the variance of the random frailties. Our estimators are robust in the sense that no model assumptions are made regarding the distribution of the time-varying covariates or the distribution of the random effects. However, subject effects are estimated under gamma frailties using an approximate hierarchical likelihood. The proposed approach is illustrated using smoking data. PMID- 22544992 TI - Change point-cure models with application to estimating the change-point effect of age of diagnosis among prostate cancer patients. AB - Previous research on prostate cancer survival trends in the United States National Cancer Institute's Surveillance Epidemiology and End Results database has indicated a potential change-point in the age of diagnosis of prostate cancer around age 50. Identifying a change-point value in prostate cancer survival and cure could have important policy and health care management implications. Statistical analysis of this data has to address two complicating features: (1) change-point models are not smooth functions and so present computational and theoretical difficulties; and (2) models for prostate cancer survival need to account for the fact that many men diagnosed with prostate cancer can be effectively cured of their disease with early treatment. We develop a cure survival model that allows for change-point effects in covariates to investigate a potential change-point in the age of diagnosis of prostate cancer. Our results do not indicate that age under 50 is associated with increased hazard of death from prostate cancer. PMID- 22544993 TI - Effects of working memory load on processing of sounds and meanings of words in aphasia. AB - BACKGROUND: Language performance in aphasia can vary depending on several variables such as stimulus characteristics and task demands. This study focuses on the degree of verbal working memory (WM) load inherent in the language task and how this variable affects language performance by individuals with aphasia. AIMS: The first aim was to identify the effects of increased verbal WM load on the performance of judgments of semantic similarity (synonymy) and phonological similarity (rhyming). The second aim was to determine if any of the following abilities could modulate the verbal WM load effect: semantic or phonological access, semantic or phonological short-term memory (STM) and any of the following executive processing abilities: inhibition, verbal WM updating, and set shifting. METHOD AND PROCEDURES: Thirty-one individuals with aphasia and 11 controls participated in this study. They were administered a synonymy judgment task and a rhyming judgment task under high and low verbal WM load conditions that were compared to each other. In a second set of analyses, multiple regression was used to identify which factors (as noted above) modulated the verbal WM load effect. OUTCOME AND RESULTS: For participants with aphasia, increased verbal WM load significantly reduced accuracy of performance on synonymy and rhyming judgments. Better performance in the low verbal WM load conditions was evident even after correcting for chance. The synonymy task included concrete and abstract word triplets. When these were examined separately, the verbal WM load effect was significant for the abstract words, but not the concrete words. The same pattern was observed in the performance of the control participants. Additionally, the second set of analyses revealed that semantic STM and one executive function, inhibition ability, emerged as the strongest predictors of the verbal WM load effect in these judgment tasks for individuals with aphasia. CONCLUSIONS: The results of this study have important implications for diagnosis and treatment of aphasia. As the roles of verbal STM capacity, executive functions and verbal WM load in language processing are better understood, measurements of these variables can be incorporated into our diagnostic protocols. Moreover, if cognitive abilities such as STM and executive functions support language processing and their impairment adversely affects language function, treating them directly in the context of language tasks should translate into improved language function. PMID- 22544994 TI - Intellectual Property And Other Contractual Issues In Cooperative Research And Development Agreements (CRADAs): Part I. PMID- 22544995 TI - Addiction and "Generation Me:" Narcissistic and Prosocial Behaviors of Adolescents with Substance Dependency Disorder in Comparison to Normative Adolescents. AB - The purpose of this study is to explore narcissistic and prosocial behaviors as reported by adolescents with and without substance dependency disorder (SDD). This study employs a quasi-experimental design using SDD adolescents compared with two normative samples of adolescents. In comparison to normative adolescents, adolescents with SDD were strongly distinguished by overt narcissistic behaviors and less monetary giving. Levels of narcissistic and prosocial behaviors among adolescents with SDD suggest a connection between self centeredness and addiction. Results also suggest volunteerism as a potential option to counter narcissism in substance dependent adolescents. PMID- 22544996 TI - Social Network Visualization in Epidemiology. AB - Epidemiological investigations and interventions are increasingly focusing on social networks. Two aspects of social networks are relevant in this regard: the structure of networks and the function of networks. A better understanding of the processes that determine how networks form and how they operate with respect to the spread of behavior holds promise for improving public health. Visualizing social networks is a key to both research and interventions. Network images supplement statistical analyses and allow the identification of groups of people for targeting, the identification of central and peripheral individuals, and the clarification of the macro-structure of the network in a way that should affect public health interventions. People are inter-connected and so their health is inter-connected. Inter-personal health effects in social networks provide a new foundation for public health. PMID- 22544997 TI - Observers' proficiency at identifying pretense acts based on behavioral cues. AB - Discriminating what is pretense from what is real is a fundamental problem in development. Research has addressed the proficiency with which adults and children discriminate between play fighting and real fighting, and yet none (to our knowledge) has investigated discrimination of other kinds of pretense and real acts. In addition, little is known about what aspects of pretender behavior (as opposed to pretend content) might cue pretense interpretations. In two experiments, 8-20 s clips showing pretense and real snack behaviors were presented to adult and child participants. All participants distinguished between pretense and real behaviors at better than chance level. Furthermore, certain features (specific looking patterns and mistimed behaviors) were most prominent in the videotapes that were most often correctly identified. This provides empirical support for the suggestion that these cues, as opposed to more commonly cited cues, like smiles, might serve as important indicators of pretense for children and adults. PMID- 22544999 TI - The Role of Phonology in Children's Acquisition of the Plural. AB - The correct use of an affix, such as the English plural suffix, may reflect mastery of a morphological process but it may also depend on children's syntactic, semantic and phonological abilities. The present paper reports a set of experiments in support of this latter view, specifically focusing on the importance of the phonological make-up of plural forms for both production and comprehension. In Experiments 1 and 2 plural productions were elicited from eighty two-year-old children for nouns with codas with varying phonological properties. The results provide evidence that production of the plural morpheme is partly governed by the complexity of the coda and its sonority. Experiments 3 and 4 show that these constraints on codas also hold for comprehension as well, suggesting this effect is not simply articulatory, but also impacts the morphophonology of the plural. PMID- 22545000 TI - Assessing Adolescents' Attachment Hierarchies: Differences Across Developmental Periods and Associations With Individual Adaptation. AB - Adolescents' attachment hierarchies were assessed in a sample of 212 high school and 198 college students. The Important People Interview (IPI) differentiated attachment bonds from other supportive or affiliative relationships and indicated that adolescents show a hierarchical ordering of preferences for multiple attachment figures. Differences in the composition and structure of adolescents' attachment hierarchies were found between the early high school (9(th) and 10(th) grades), later high school (11(th) and 12(th) grades), and college samples. In the college sample, romantic partners were placed in higher positions in adolescents' hierarchies, fathers were placed in lower positions, and the structure of adolescents' hierarchies were less differentiated than in the high school samples. Individual differences in the composition of adolescents' hierarchies were associated with adjustment outcomes. Friends' placement in higher positions and fathers' exclusion from or placement in quaternary positions was associated with increased behavior problems. Findings demonstrate that the IPI provides a measure of adolescents' attachment hierarchies that is sensitive to developmental stage and individual differences. PMID- 22544998 TI - Oxidative stress and microglial cells in Parkinson's disease. AB - Significant evidence has now been accumulated that microglial cells play a central role in the degeneration of DA neurons in animal models of PD. The oxidative stress response by microglial cells, most notably the activity of the enzyme NADPH oxidase, appears to play a central role in the pathology of PD. This oxidative stress response occurs in microglia through the activation of the ERK signaling pathway by proinflammatory stimuli, leading to the phosphorylation and translocation of the p47(phox) and p67(phox) cytosolic subunits, the activation of membrane-bound PHOX, and the production of ROS. Therapeutic anti inflammatories which prevent DA neurodegeneration in PD, including anti inflammatory cytokines, morphinan compounds, NADPH oxidase inhibitors, NF-kappaB inhibitors, and beta2-AR agonists, all function to inhibit the activation of the PHOX in microglial cells. These observations suggest a central role for the oxidative stress response in microglial cells as a mediator or regulator of DA neurodegeneration in PD. PMID- 22545001 TI - Designing a Technology Coach: A multidisciplinary team models a system that can alert users of a complex medical device when they make an error. AB - Technology in the home environment has the potential to support older adults in a variety of ways. We took an interdisciplinary approach (human factors/ergonomics and computer science) to develop a technology "coach" that could support older adults in learning to use a medical device. Our system provided a computer vision system to track the use of a blood glucose meter and provide users with feedback if they made an error. This research could support the development of an in-home personal assistant to coach individuals in a variety of tasks necessary for independent living. PMID- 22545002 TI - In vivo clearance of alpha-1 acid glycoprotein is influenced by the extent of its N-linked glycosylation and by its interaction with the vessel wall. AB - Alpha-1 acid glycoprotein (AGP) is a highly glycosylated plasma protein that exerts vasoprotective effects. We hypothesized that AGP's N-linked glycans govern its rate of clearance from the circulation, and followed the disappearance of different forms of radiolabeled human AGP from the plasma of rabbits and mice. Enzymatic deglycosylation of human plasma-derived AGP (pdAGP) by Peptide: N Glycosidase F yielded a mixture of differentially deglycosylated forms (PNGase AGP), while the introduction of five Asn to Gln mutations in recombinant Pichia pastoris-derived AGP (rAGP-N(5)Q) eliminated N-linked glycosylation. PNGase-AGP was cleared from the rabbit circulation 9-fold, and rAGP-N(5)Q, 46-fold more rapidly than pdAGP, primarily via a renal route. Pichia pastoris-derived wild type rAGP differed from pdAGP in expressing mannose-terminated glycans, and, like neuraminidase-treated pdAGP, was more rapidly removed from the rabbit circulation than rAGP-N(5)Q. Systemic hyaluronidase treatment of mice transiently decreased pdAGP clearance. AGP administration to mice reduced vascular binding of hyaluronic acid binding protein in the liver microcirculation and increased its plasma levels. Our results support a critical role of N-linked glycosylation of AGP in regulating its in vivo clearance and an influence of a hyaluronidase sensitive component of the vessel wall on its transendothelial passage. PMID- 22545003 TI - Organization of Estrogen-Associated Circuits in the Mouse Primary Auditory Cortex. AB - Sex steroid hormones influence the perceptual processing of sensory signals in vertebrates. In particular, decades of research have shown that circulating levels of estrogen correlate with hearing function. The mechanisms and sites of action supporting this sensory-neuroendocrine modulation, however, remain unknown. Here we combined a molecular cloning strategy, fluorescence in-situ hybridization and unbiased quantification methods to show that estrogen-producing and -sensitive neurons heavily populate the adult mouse primary auditory cortex (AI). We also show that auditory experience in freely-behaving animals engages estrogen-producing and -sensitive neurons in AI. These estrogen-associated networks are greatly stable, and do not quantitatively change as a result of acute episodes of sensory experience. We further demonstrate the neurochemical identity of estrogen-producing and estrogen-sensitive neurons in AI and show that these cell populations are phenotypically distinct. Our findings provide the first direct demonstration that estrogen-associated circuits are highly prevalent and engaged by sensory experience in the mouse auditory cortex, and suggest that previous correlations between estrogen levels and hearing function may be related to brain-generated hormone production. Finally, our findings suggest that estrogenic modulation may be a central component of the operational framework of central auditory networks. PMID- 22545004 TI - Alkenenitrile Transmissive Olefination: Synthesis of the Putative Lignan "Morinol I" AB - Grignard reagents trigger an addition-elimination with alpha'-hydroxy acrylonitriles to selectively generate Z-alkenenitriles. The modular assembly of Z-alkenenitriles from a Grignard reagent, acrylonitrile, and an aldehyde is ideal for stereoselectively synthesizing alkenes as illustrated in the synthesis of the putative lignan "morinol I." PMID- 22545005 TI - Biomedical Visual Computing: Case Studies and Challenges. AB - Advances in computational geometric modeling, imaging, and simulation let researchers build and test models of increasing complexity, generating unprecedented amounts of data. As recent research in biomedical applications illustrates, visualization will be critical in making this vast amount of data usable; it's also fundamental to understanding models of complex phenomena. PMID- 22545006 TI - Preschooler's Understanding of the Role of Mental States and Action in Pretense. AB - This research investigated 3- to 5-year-old's understanding of the role of intentional states and action in pretense. There are two main perspectives on how children conceptualize pretense. One view is that children understand the mental aspects of pretending (the rich interpretation). The alternative view is that children conceptualize pretense as "acting-like" and do not appreciate that the mind is crucial to pretense (the lean interpretation). The experiments in this article used a novel approach to test these two interpretations. Children were presented with two types of videotaped scenarios. In Experiment 1, children were presented with a scenario in which people wanted to be like something else (e.g., a kangaroo) and either acted like it or did not act like it. Children were asked whether the protagonists were pretending and whether they were thinking about the pretend entity. In Experiment 2, children were presented with the Experiment 1 scenarios and also with a scenario in which a person had the intention to do something else (e.g., look for her keys) but whose actions were similar to those of a pretend entity (e.g., a bear). Children were asked about the pretense, thoughts, and the intentions of the protagonists. Experiment 3 tested for the effect of asking an open-ended versus a forced-choice question on the Experiment 2 tasks. The results of this study suggest that in certain facilitating conditions (e.g., intention information salient, forced-choice question) children have an early understanding of the role of mind in pretense. PMID- 22545007 TI - Intervention based exclusively on stage-matched printed educational materials regarding healthy eating does not result in changes to adolescents' dietary behavior. AB - PURPOSE: To assess the impact of a six-month stage-based intervention on fruit and vegetable intake, regarding perceived benefits and barriers, and self efficacy among adolescents. DESIGN: Randomized treatment-control, pre-post design. SUBJECTS/SETTING: Schools were randomized between control and experimental groups. 860 adolescents from ten public schools in Brasilia, Federal District, Brazil were evaluated at baseline; 771 (81%) completed the study. INTERVENTION: Experimental group received monthly magazines and newsletters aimed at promotion of healthy eating. MEASURES: Self-reported fruit and vegetable intake, stages of change, self-efficacy and decisional balance scores were evaluated at baseline and post-intervention in both groups. ANALYSIS: The effectiveness of the intervention was evaluated using the analysis of covariance model (ANCOVA) and repeated measurement analysis by means of weighted least squares. Comparison between the proportions of adolescents who advanced through the stages during the intervention was performed using the Mantel-Haenszel chi square test. RESULTS: After adjusting for sex and age, study variables showed no modifications through the proposed intervention. There was no statistical difference in participant mobility in the intervention and control groups between the stages of change, throughout the study. CONCLUSION: A nutritional intervention based exclusively on distribution of stage-matched printed educational materials was insufficient to change adolescents' dietary behavior. PMID- 22545008 TI - Exploring marine cyanobacteria for lead compounds of pharmaceutical importance. AB - The Ocean, which is called the "mother of origin of life," is also the source of structurally unique natural products that are mainly accumulated in living organisms. Cyanobacteria are photosynthetic prokaryotes used as food by humans. They are excellent source of vitamins and proteins vital for life. Several of these compounds show pharmacological activities and are helpful for the invention and discovery of bioactive compounds, primarily for deadly diseases like cancer, acquired immunodeficiency syndrome (AIDS), arthritis, and so forth, while other compounds have been developed as analgesics or to treat inflammation, and so forth. They produce a large variety of bioactive compounds, including substances with anticancer and antiviral activity, UV protectants, specific inhibitors of enzymes, and potent hepatotoxins and neurotoxins. Many cyanobacteria produce compounds with potent biological activities. This paper aims to showcase the structural diversity of marine cyanobacterial secondary metabolites with a comprehensive coverage of alkaloids and other applications of cyanobacteria. PMID- 22545009 TI - Changes in structure and histochemistry of glandular trichomes of Thymus quinquecostatus Celak. AB - The types, morphology, distribution, structure, and development process of the glandular trichomes on the leaves of Thymus quinquecostatus Celak had been investigated in this study. Two different types of glandular trichomes were determined in detail, namely, capitate trichomes and peltate ones. Besides, there were distinct differences on morphology, distribution, structure, and development process between the two kinds of trichomes. As the peltate trichome stepping into senium stage, it caved in the epidermis integrally, which was different from the capitate one. The secretion of the capitate trichome contained essential oil, polyphenols, and flavonoids, while, in addition to these three components, the secretion of the peltate one also contained acid polysaccharides. A distinctive difference was also seen in the secretory pathway of the secretion between the two types of trichomes. The secretion of capitate one was extruded through the cuticle of the head cell, but the secretion of the peltate one kept accumulating in the subcuticular space of the head cells until it was released by cuticle rupture. PMID- 22545010 TI - Investigation of dose minimisation protocol for 18F-FDG PET-CT in the management of lymphoma postchemotherapy followup. AB - INTRODUCTION: (18)F-FDG-PET-CT plays an important role in the management of lymphoma postchemotherapy followup. Some centres perform prechemotherapy baseline CT and postchemotherapy PETCT. With a concern of radiation burden, especially in young patients, this study aimed to assess if PETCT radiation dose could be reduced. METHODS: Retrospective analysis of 100 lymphoma patients was performed to record sites of disease on prechemotherapy CT and postchemotherapy PETCT. The potential reduction in radiation and time achieved with PETCT limited to sites of known disease identified on prechemotherapy CT was calculated. RESULTS: No FDG uptake was seen in 72 cases. FDG uptake at known disease sites was seen in 24. Of the remaining 4, one had clinically significant pathology, a rectal adenocarcinoma. PETCT did not reveal any unexpected sites of lymphoma. Limiting PETCT to sites of known disease would have saved a mean radiation dose of 4 mSv (27.3%), with a mean time of 16 minutes. CONCLUSION: Our study suggests that young patients may benefit from reduced radiation by limiting PETCT to sites of known disease with low risk of missing significant pathology. However, in older patients, with increased incidence of asymptomatic synchronous malignancies, whole-body PETCT is advisable unless prechemotherapy PETCT has been performed. PMID- 22545011 TI - A facile synthesis of new 2-amino-4H-pyran-3-carbonitriles by a one-pot reaction of alpha, alpha'-bis(arylidene) cycloalkanones and malononitrile in the presence of K2CO3. AB - A rapid and environmentally friendly method is developed for the synthesis of a series of new substituted 2-amino-4H-pyran-3-carbonitriles through a one-pot condensation of malononitrile and alpha, alpha'-bis(arylidene) cycloalkanones in ethanol by using K(2)CO(3) as a catalyst. Short experimental reaction times, excellent yields, no need to use cumbersome apparatus for purification of the products, and inexpensiveness and commercially availability of the catalyst are the advantages of this method. PMID- 22545012 TI - The design of new adjuvants for mucosal immunity to Neisseria meningitidis B in nasally primed neonatal mice for adult immune response. AB - The aim of this study was to determine the value of detoxified Shiga toxins Stx1 and Stx2 (toxoids of Escherichia coli) as mucosal adjuvants in neonatal mice for immunogenicity against the outer membrane proteins (OMPs) of Neisseria meningitidis B. Mucosal immunization has been shown to be effective for the induction of antigen-specific immune responses in both the systemic and mucosal compartments. Systemic antibody levels (IgG, IgG1, IgG2a, IgG2b, IgM, and IgA) and mucosal IgM and IgA were measured by ELISA using an N. meningitidis as an antigen. In addition, IFN-gamma and IL-6 production were measured after stimulated proliferation of immune cells. Intranasal administration elicited a higher anti-OMP IgA response in both saliva and vaginal fluids. Our results suggest that both Stx1 and Stx2 toxoids are effective mucosal adjuvants for the induction of Ag-specific IgG, IgM, and IgA antibodies. The toxoids significantly enhanced the IgG and IgM response against OMPs with a potency equivalent to CT, with the response being characterized by both IgG1 and IgG2a isotypes, and increased IFN-gamma production. Additionally, bactericidal activity was induced with IgG and IgM antibodies of high avidity. These results support the use of the new toxoids as potent inducing adjuvants that are particularly suitable for mucosal immunization. PMID- 22545013 TI - Percutaneous trigeminal ganglion balloon compression rhizotomy: experience in 27 patients. AB - PURPOSE: Percutaneous ganglion balloon compression (PBC) is a minimally invasive procedure for treatment of trigeminal neuralgia. MATERIALS AND METHODS: Twenty seven (19 female and 8 male) patients, who presented with classical symptoms of trigeminal neuralgia, were included. Age ranged from 34 to 91 years (median 62 years), 33 procedures were performed. Duration of the symptoms ranged from 1 year to 30 years (median 5 years). RESULTS: After the procedure, pain relief was reported in 25 (93%) patients. In two patients, the pain remained the same. The pain free period ranged from 2 to 74 months (median 15 months). A mean duration of analgesia was longer in patients with ideal pear shape of balloon at the time of the procedure compared to nonideal shape (P = 0.01). No major complications occurred in our group of patients. CONCLUSIONS: Percutaneous trigeminal ganglion balloon compression is a safe, simple, and effective method for temporary pain relief in a selective group of trigeminal neuralgia patients. PMID- 22545014 TI - Polymerized-type I collagen downregulates inflammation and improves clinical outcomes in patients with symptomatic knee osteoarthritis following arthroscopic lavage: a randomized, double-blind, and placebo-controlled clinical trial. AB - OBJECTIVES: Polymerized-type I collagen (polymerized collagen) is a downmodulator of inflammation and cartilage regenerator biodrug. AIM: To evaluate the effect of intraarticular injections of polymerized collagen after arthroscopic lavage on inflammation and clinical improvement in patients with knee osteoarthritis (OA). METHODS: Patients (n = 19) were treated with 6 intraarticular injections of 2 mL of polymerized collagen (n = 10) or 2 mL of placebo (n = 9) during 3 months. Followup was 3 months. The primary endpoints included Lequesne index, pain on a visual analogue scale (VAS), WOMAC, analgesic usage, the number of Tregs and proinflammatory/anti-inflammatory cytokine-expressing peripheral cells. Secondary outcomes were Likert score and drug evaluation. Clinical and immunological improvement was determined if the decrease in pain exceeds 20 mm on a VAS, 20% of clinical outcomes, and inflammatory parameters from baseline. Urinary levels of C terminal crosslinking telopeptide of collagen type II (CTXII) and erythrocyte sedimentation rate (ESR) were determined. RESULTS: Polymerized collagen was safe and well tolerated. Patients had a statistically significant improvement (P < 0.05) from baseline versus polymerized collagen and versus placebo at 6 months on Lequesne index, VAS, ESR, Tregs IL-1beta, and IL-10 peripheral-expressing cells. Urinary levels of CTXII were decreased 44% in polymerized collagen versus placebo. No differences were found on incidence of adverse events between groups. CONCLUSION: Polymerized collagen is safe and effective on downregulation of inflammation in patients with knee OA. PMID- 22545015 TI - Early healing events around titanium implant devices with different surface microtopography: a pilot study in an in vivo rabbit model. AB - In the present pilot study, the authors morphologically investigated sandblasted, acid-etched surfaces (SLA) at very early experimental times. The tested devices were titanium plate-like implants with flattened wide lateral sides and jagged narrow sides. Because of these implant shape and placement site, the device gained a firm mechanical stability but the largest portion of the implant surface lacked direct contact with host bone and faced a wide peri-implant space rich in marrow tissue, intentionally created in order to study the interfacial interaction between metal surface and biological microenvironment. The insertion of titanium devices into the proximal tibia elicited a sequence of healing events. Newly formed bone proceeded through an early distance osteogenesis, common to both surfaces, and a delayed contact osteogenesis which seemed to follow different patterns at the two surfaces. In fact, SLA devices showed a more osteoconductive behavior retaining a less dense blood clot, which might be earlier and more easily replaced, and leading to a surface-conditioning layer which promotes osteogenic cell differentiation and appositional new bone deposition at the titanium surface. This model system is expected to provide a starting point for further investigations which clarify the early cellular and biomolecular events occurring at the metal surface. PMID- 22545016 TI - eVITAL: a preliminary taxonomy and electronic toolkit of health-related habits and lifestyle. AB - OBJECTIVES: To create a preliminary taxonomy and related toolkit of health related habits (HrH) following a person-centered approach with a focus on primary care. METHODS: From 2003-2009, a working group (n = 6 physicians) defined the knowledge base, created a framing document, and selected evaluation tools using an iterative process. Multidisciplinary focus groups (n = 29 health professionals) revised the document and evaluation protocol and participated in a feasibility study and review of the model based on a demonstration study with 11 adult volunteers in Antequera, Spain. RESULTS: The preliminary taxonomy contains 6 domains of HrH and 1 domain of additional health descriptors, 3 subdomains, 43 dimensions, and 141 subdimensions. The evaluation tool was completed by the 11 volunteers. The eVITAL toolkit contains history and examination items for 4 levels of engagement: self-assessment, basic primary care, extended primary care, and specialty care. There was positive feedback from the volunteers and experts, but concern about the length of the evaluation. CONCLUSIONS: We present the first taxonomy of HrH, which may aid the development of the new models of care such as the personal contextual factors of the International Classification of Functioning (ICF) and the positive and negative components of the multilevel person-centered integrative diagnosis model. PMID- 22545018 TI - Planting Jatropha curcas on constrained land: emission and effects from land use change. AB - A study was carried out to assess carbon emission and carbon loss caused from land use change (LUC) of converting a wasteland into a Jatropha curcas plantation. The study was conducted for 12 months at a newly established Jatropha curcas plantation in Port Dickson, Malaysia. Assessments of soil carbon dioxide (CO(2)) flux, changes of soil total carbon and plant biomass loss and growth were made on the wasteland and on the established plantation to determine the effects of land preparation (i.e., tilling) and removal of the wasteland's native vegetation. Overall soil CO(2) flux showed no significant difference (P < 0.05) between the two plots while no significant changes (P < 0.05) on soil total carbon at both plots were detected. It took 1.5 years for the growth of Jatropha curcas to recover the biomass carbon stock lost during land conversion. As far as the present study is concerned, converting wasteland to Jatropha curcas showed no adverse effects on the loss of carbon from soil and biomass and did not exacerbate soil respiration. PMID- 22545020 TI - Learning Curves: Making Quality Online Health Information Available at a Fitness Center. AB - Meeting consumer health information needs can be a challenge. Research suggests that women seek health information from a variety of resources, including the Internet. In an effort to make women aware of reliable health information sources, the Louisiana State University Health Sciences Center - Shreveport Medical Library engaged in a partnership with a franchise location of Curves International, Inc. This article will discuss the project, its goals and its challenges. PMID- 22545019 TI - Stand-alone lateral interbody fusion for the treatment of low-grade degenerative spondylolisthesis. AB - The purpose of this paper was to investigate the stand-alone lateral interbody fusion as a minimally invasive option for the treatment of low-grade degenerative spondylolisthesis with a minimum 24-month followup. Prospective nonrandomized observational single-center study. 52 consecutive patients (67.6 +/- 10 y/o; 73.1% female; 27.4 +/- 3.4 BMI) with single-level grade I/II single-level degenerative spondylolisthesis without significant spine instability were included. Fusion procedures were performed as retroperitoneal lateral transpsoas interbody fusions without screw supplementation. The procedures were performed in average 73.2 minutes and with less than 50cc blood loss. VAS and Oswestry scores showed lasting improvements in clinical outcomes (60% and 54.5% change, resp.). The vertebral slippage was reduced in 90.4% of cases from mean values of 15.1% preoperatively to 7.4% at 6-week followup (P < 0.001) and was maintained through 24 months (7.1%, P < 0.001). Segmental lordosis (P < 0.001) and disc height (P < 0.001) were improved in postop evaluations. Cage subsidence occurred in 9/52 cases (17%) and 7/52 cases (13%) spine levels needed revision surgery. At the 24 month evaluation, solid fusion was observed in 86.5% of the levels treated. The minimally invasive lateral approach has been shown to be a safe and reproducible technique to treat low-grade degenerative spondylolisthesis. PMID- 22545017 TI - The role of neurokinin-1 receptor in the microenvironment of inflammation and cancer. AB - The recent years have witnessed an exponential increase in cancer research, leading to a considerable investment in the field. However, with few exceptions, this effort has not yet translated into a better overall prognosis for patients with cancer, and the search for new drug targets continues. After binding to the specific neurokinin-1 (NK-1) receptor, the peptide substance P (SP), which is widely distributed in both the central and peripheral nervous systems, triggers a wide variety of functions. Antagonists against the NK-1 receptor are safe clinical drugs that are known to have anti-inflammatory, analgesic, anxiolytic, antidepressant, and antiemetic effects. Recently, it has become apparent that SP can induce tumor cell proliferation, angiogenesis, and migration via the NK-1 receptor, and that the SP/NK-1 receptor complex is an integral part of the microenvironment of inflammation and cancer. Therefore, the use of NK-1 receptor antagonists as a novel and promising approach for treating patients with cancer is currently under intense investigation. In this paper, we evaluate the recent scientific developments regarding this receptor system, its role in the microenvironment of inflammation and cancer, and its potentials and pitfalls for the usage as part of modern anticancer strategies. PMID- 22545023 TI - osDesign: An R Package for the Analysis, Evaluation, and Design of Two-Phase and Case-Control Studies. AB - The two-phase design has recently received attention in the statistical literature as an extension to the traditional case-control study for settings where a predictor of interest is rare or subject to missclassification. Despite a thorough methodological treatment and the potential for substantial efficiency gains, the two-phase design has not been widely adopted. This may be due, in part, to a lack of general-purpose, readily-available software. The osDesign package for R provides a suite of functions for analyzing data from a two-phase and/or case-control design, as well as evaluating operating characteristics, including bias, efficiency and power. The evaluation is simulation-based, permitting flexible application of the package to a broad range of scientific settings. Using lung cancer mortality data from Ohio, the package is illustrated with a detailed case-study in which two statistical goals are considered: (i) the evaluation of small-sample operating characteristics for two-phase and case control designs and (ii) the planning and design of a future two-phase study. PMID- 22545021 TI - Essential role for miR-196a in brown adipogenesis of white fat progenitor cells. AB - The recent discovery of functional brown adipocytes in adult humans illuminates the potential of these cells in the treatment of obesity and its associated diseases. In rodents, brown adipocyte-like cells are known to be recruited in white adipose tissue (WAT) by cold exposure or beta-adrenergic stimulation, but the molecular machinery underlying this phenomenon is not fully understood. Here, we show that inducible brown adipogenesis is mediated by the microRNA miR-196a. We found that miR-196a suppresses the expression of the white-fat gene Hoxc8 post transcriptionally during the brown adipogenesis of white fat progenitor cells. In mice, miR-196a is induced in the WAT-progenitor cells after cold exposure or beta adrenergic stimulation. The fat-specific forced expression of miR-196a in mice induces the recruitment of brown adipocyte-like cells in WAT. The miR-196a transgenic mice exhibit enhanced energy expenditure and resistance to obesity, indicating the induced brown adipocyte-like cells are metabolically functional. Mechanistically, Hoxc8 targets and represses C/EBPbeta, a master switch of brown fat gene program, in cooperation with histone deacetylase 3 (HDAC3) through the C/EBPbeta 3' regulatory sequence. Thus, miR-196a induces functional brown adipocytes in WAT through the suppression of Hoxc8, which functions as a gatekeeper of the inducible brown adipogenesis. The miR-196a-Hoxc8-C/EBPbeta signaling pathway may be a therapeutic target for inducing brown adipogenesis to combat obesity and type 2 diabetes. PMID- 22545022 TI - Sialyllactose in viral membrane gangliosides is a novel molecular recognition pattern for mature dendritic cell capture of HIV-1. AB - HIV-1 is internalized into mature dendritic cells (mDCs) via an as yet undefined mechanism with subsequent transfer of stored, infectious virus to CD4+ T lymphocytes. Thus, HIV-1 subverts a DC antigen capture mechanism to promote viral spread. Here, we show that gangliosides in the HIV-1 membrane are the key molecules for mDC uptake. HIV-1 virus-like particles and liposomes mimicking the HIV-1 lipid composition were shown to use a common internalization pathway and the same trafficking route within mDCs. Hence, these results demonstrate that gangliosides can act as viral attachment factors, in addition to their well known function as cellular receptors for certain viruses. Furthermore, the sialyllactose molecule present in specific gangliosides was identified as the determinant moiety for mDC HIV-1 uptake. Thus, sialyllactose represents a novel molecular recognition pattern for mDC capture, and may be crucial both for antigen presentation leading to immunity against pathogens and for succumbing to subversion by HIV-1. PMID- 22545025 TI - Where there is no health research: what can be done to fill the global gaps in health research? PMID- 22545026 TI - Does conflict of interest disclosure worsen bias? PMID- 22545027 TI - Convergence of Free Energy Profile of Coumarin in Lipid Bilayer. AB - Atomistic molecular dynamics (MD) simulations of druglike molecules embedded in lipid bilayers are of considerable interest as models for drug penetration and positioning in biological membranes. Here we analyze partitioning of coumarin in dioleoylphosphatidylcholine (DOPC) bilayer, based on both multiple, unbiased 3 MUs MD simulations (total length) and free energy profiles along the bilayer normal calculated by biased MD simulations (~7 MUs in total). The convergences in time of free energy profiles calculated by both umbrella sampling and z constraint techniques are thoroughly analyzed. Two sets of starting structures are also considered, one from unbiased MD simulation and the other from "pulling" coumarin along the bilayer normal. The structures obtained by pulling simulation contain water defects on the lipid bilayer surface, while those acquired from unbiased simulation have no membrane defects. The free energy profiles converge more rapidly when starting frames from unbiased simulations are used. In addition, z-constraint simulation leads to more rapid convergence than umbrella sampling, due to quicker relaxation of membrane defects. Furthermore, we show that the choice of RESP, PRODRG, or Mulliken charges considerably affects the resulting free energy profile of our model drug along the bilayer normal. We recommend using z-constraint biased MD simulations based on starting geometries acquired from unbiased MD simulations for efficient calculation of convergent free energy profiles of druglike molecules along bilayer normals. The calculation of free energy profile should start with an unbiased simulation, though the polar molecules might need a slow pulling afterward. Results obtained with the recommended simulation protocol agree well with available experimental data for two coumarin derivatives. PMID- 22545028 TI - Image Alignment for Multiple Camera High Dynamic Range Microscopy. AB - This paper investigates the problem of image alignment for multiple camera high dynamic range (HDR) imaging. HDR imaging combines information from images taken with different exposure settings. Combining information from multiple cameras requires an alignment process that is robust to the intensity differences in the images. HDR applications that use a limited number of component images require an alignment technique that is robust to large exposure differences. We evaluate the suitability for HDR alignment of three exposure-robust techniques. We conclude that image alignment based on matching feature descriptors extracted from radiant power images from calibrated cameras yields the most accurate and robust solution. We demonstrate the use of this alignment technique in a high dynamic range video microscope that enables live specimen imaging with a greater level of detail than can be captured with a single camera. PMID- 22545024 TI - Induction of labor versus expectant management in women with preterm prelabor rupture of membranes between 34 and 37 weeks: a randomized controlled trial. AB - BACKGROUND: At present, there is insufficient evidence to guide appropriate management of women with preterm prelabor rupture of membranes (PPROM) near term. METHODS AND FINDINGS: We conducted an open-label randomized controlled trial in 60 hospitals in The Netherlands, which included non-laboring women with >24 h of PPROM between 34(+0) and 37(+0) wk of gestation. Participants were randomly allocated in a 1:1 ratio to induction of labor (IoL) or expectant management (EM) using block randomization. The main outcome was neonatal sepsis. Secondary outcomes included mode of delivery, respiratory distress syndrome (RDS), and chorioamnionitis. Patients and caregivers were not blinded to randomization status. We updated a prior meta-analysis on the effect of both interventions on neonatal sepsis, RDS, and cesarean section rate. From 1 January 2007 to 9 September 2009, 776 patients in 60 hospitals were eligible for the study, of which 536 patients were randomized. Four patients were excluded after randomization. We allocated 266 women (268 neonates) to IoL and 266 women (270 neonates) to EM. Neonatal sepsis occurred in seven (2.6%) newborns of women in the IoL group and in 11 (4.1%) neonates in the EM group (relative risk [RR] 0.64; 95% confidence interval [CI] 0.25 to 1.6). RDS was seen in 21 (7.8%, IoL) versus 17 neonates (6.3%, EM) (RR 1.3; 95% CI 0.67 to 2.3), and a cesarean section was performed in 36 (13%, IoL) versus 37 (14%, EM) women (RR 0.98; 95% CI 0.64 to 1.50). The risk for chorioamnionitis was reduced in the IoL group. No serious adverse events were reported. Updating an existing meta-analysis with our trial results (the only eligible trial for the update) indicated RRs of 1.06 (95% CI 0.64 to 1.76) for neonatal sepsis (eight trials, 1,230 neonates) and 1.27 (95% CI 0.98 to 1.65) for cesarean section (eight trials, 1,222 women) for IoL compared with EM. CONCLUSIONS: In women whose pregnancy is complicated by late PPROM, neither our trial nor the updated meta-analysis indicates that IoL substantially improves pregnancy outcomes compared with EM. TRIAL REGISTRATION: Current Controlled Trials ISRCTN29313500 PMID- 22545029 TI - Factors Associated with Choice of Exposure Therapy for PTSD. AB - Exposure therapy, despite its demonstrated efficacy for chronic PTSD, remains underutilized across clinical settings. One suggested cause is that traumatized clients may not prefer exposure treatment. This paper reviews the current literature on factors associated with treatment preference for exposure therapy. Contrary to expectations, exposure-based therapy is not only perceived as a viable therapy but is well regarded among current therapy choices by potential clients. In particular, we highlight the central role of client beliefs about the need to talk about problems, the efficacy of treatment, and perceived need for help as crucial factors potentially impacting preference for exposure therapy. Importantly, fear of exposure treatment does not appear to play a significant role. To increase utilization, clinicians should provide clients information to address factors believed to increase preference for effective treatment. PMID- 22545030 TI - Terra and Aqua: new data for epidemiology and public health. AB - Earth-observing satellites have only recently been exploited for the measurement of environmental variables of relevance to epidemiology and public health. Such work has relied on sensors with spatial, spectral and geometric constraints that have allowed large-area questions associated with the epidemiology of vector borne diseases to be addressed. Moving from pretty maps to pragmatic control tools requires a suite of satellite-derived environmental data of higher fidelity, spatial resolution, spectral depth and at similar temporal resolutions to existing meteorological satellites. Information derived from sensors onboard the next generation of moderate-resolution Earth-observing sensors may provide the key. The MODIS and ASTER sensors onboard the Terra and Aqua platforms provide substantial improvements in spatial resolution, number of spectral channels, choices of bandwidths, radiometric calibration and a much-enhanced set of pre processed and freely available products. These sensors provide an important advance in moderate-resolution remote sensing and the data available to those concerned with improving public health. PMID- 22545033 TI - Acoustic Radiation Force Impulse (ARFI) Imaging: a Review. AB - Acoustic radiation force based elasticity imaging methods are under investigation by many groups. These methods differ from traditional ultrasonic elasticity imaging methods in that they do not require compression of the transducer, and are thus expected to be less operator dependent. Methods have been developed that utilize impulsive (i.e. < 1 ms), harmonic (pulsed), and steady state radiation force excitations. The work discussed herein utilizes impulsive methods, for which two imaging approaches have been pursued: 1) monitoring the tissue response within the radiation force region of excitation (ROE) and generating images of relative differences in tissue stiffness (Acoustic Radiation Force Impulse (ARFI) imaging); and 2) monitoring the speed of shear wave propagation away from the ROE to quantify tissue stiffness (Shear Wave Elasticity Imaging (SWEI)). For these methods, a single ultrasound transducer on a commercial ultrasound system can be used to both generate acoustic radiation force in tissue, and to monitor the tissue displacement response. The response of tissue to this transient excitation is complicated and depends upon tissue geometry, radiation force field geometry, and tissue mechanical and acoustic properties. Higher shear wave speeds and smaller displacements are associated with stiffer tissues, and slower shear wave speeds and larger displacements occur with more compliant tissues. ARFI images have spatial resolution comparable to that of B-mode, often with greater contrast, providing matched, adjunctive information. SWEI images provide quantitative information about the tissue stiffness, typically with lower spatial resolution. A review these methods and examples of clinical applications are presented herein. PMID- 22545032 TI - Relation of Blood Pressure to Cognitive Impairment and Dementia. AB - Over the past decade several studies have assessed the relation of blood pressure with cognitive function and dementia. While some cross-sectional studies have shown an inverse association between blood pressure levels and cognitive performance or dementia, longitudinal studies yielded controversial results. Most studies relating blood pressure levels in mid-life with late-life risk of cognitive decline or dementia reported a harmful effect of higher blood pressure levels on cognitive function. Studies assessing the effect of late-life blood pressure levels reported that low diastolic and very high systolic levels may increase the risk. Observational studies and randomized cinical trials provide limited evidence for a protective effect of antihypertensive therapy. It seems that the older the person and the more advanced the disease process, the less harmful or even inverted the effect of blood pressure elevation on dementia risk. The reason for this may be that blood pressure declines with age-related pathology, such as vessel stiffening, weight loss, and changes in the autonomic regulation of blood flow. PMID- 22545031 TI - GABA Targets for the Treatment of Cognitive Dysfunction in Schizophrenia. AB - Cognitive deficits, including impairments in working memory that have been linked to the prefrontal cortex, are among the most debilitating and difficult to treat features of schizophrenia. Consequently, the identification of potential targets informed by the pathophysiology of the illness is needed to develop novel pharmacological approaches for ameliorating these deficits. Postmortem studies of the prefrontal cortex in schizophrenia subjects have revealed disturbances restricted to a subpopulation of inhibitory neurons that includes chandelier neurons, whose axon terminals synapse on the axon initial segment of pyramidal neurons. Chandelier neurons play an important role in synchronizing pyramidal neuron activity and appear to be a critical component of the prefrontal cortical circuitry that subserves working memory function. Therefore, in this paper we review evidence suggesting that drugs which selectively enhance chandelier neuron mediated inhibition of prefrontal pyramidal neurons may improve working memory dysfunction in schizophrenia. Potential novel targets for such agents include GABA(A) receptors that contain the alpha(2) subunit. In addition, we discuss potential complementary mechanisms for enhancing inhibitory input to pyramidal cell bodies, including drugs with activity at the CB1 receptor of the endocannabinoid system. The development of pathophysiologically-based treatments that selectively remediate disturbances in specific neural circuits underlying working memory may provide an effective approach to improving cognitive deficits in schizophrenia. PMID- 22545034 TI - Acceptance of Nordic snack bars in children aged 8-11 years. AB - BACKGROUND: A health promoting diet is suggested to be tailored to regional circumstances to preserve the cultural diversity in eating habits, as well as contribute to more environmentally friendly eating. It may influence consumer acceptance, however, if the components of the diet differs considerably from their habitual food. OBJECTIVE: This study aimed to investigate whether snack bars composed of Nordic ingredients were accepted by 8-11 year-old Danish (n=134) and Swedish (n=109) children. DESIGN: A seven-point hedonic scale was used to measure the children's acceptance of five snack bars that varied in their composition of whole grains, berries and nuts. A preference rank ordering of the five bars was also performed. RESULTS: The results showed that samples that were rated highest in liking and were most preferred in both countries were a kamut/pumpkin bar and an oat/cranberry bar. The sample with the lowest rating that was also least preferred was a pumpernickel/sea buckthorn bar. Flavour was the most important determinant of overall liking followed by texture, odour and appearance. CONCLUSIONS: Children's acceptances and preferences were highly influenced by the sensory characteristics of the bars, mainly flavour. In agreement with earlier studies, the novel food ingredients seemed to influence children's preferences. The Nordic snack bars may have a potential to be a snack option for Danish and Swedish school children, but repeated exposures to the products are recommended to increase children's acceptance. PMID- 22545035 TI - Nightmare-enacting behavior responding to zonisamide in early Parkinson's disease. AB - Recently, zonisamide (ZNS) has been approved as a new adjunctive therapy for motor complications of Parkinson's disease (PD). More recently, ZNS was reported to be effective for the management of impulse control behavior in PD, suggesting potential effects on non-motor PD symptoms. Dream enactment associated with aggressive, violent behavior can carry a serious risk of injury to patients, as well as to spouses or caretakers. This report describes a patient with PD who had vivid nightmares and dream-enacting behavior that resolved after treatment with ZNS. The present case raises the question whether ZNS might potentially be effective for the management of vivid nightmares or dream-enacting behavior. PMID- 22545036 TI - Cerebral embolism associated with left atrial myxoma that was treated with thrombolytic therapy. AB - We present a case of cerebral embolism associated with a left atrial myxoma that was treated with intravenous thrombolytic therapy. A 79-year-old right-handed man with no history of neurological or psychiatric illnesses was referred to our hospital because of confusion. He had been self-supported in the activity of daily living and could enjoy gardening until just before his admission. He had aphasia, left conjugate deviation, right hemiparesis, and right pathological reflexes. His NIHSS score was 24. Cranial DWI showed hyperintense lesions in the left middle cerebral artery territory, and MRA revealed left middle cerebral artery occlusion. We started treatment with the recombinant tissue plasminogen activator alteplase intravenously 3 h after the onset. However, the therapy was ineffective, and the NIHSS score was 25 on the second day. A transthoracic echocardiogram and heart MRI showed a left atrial myxoma. However, surgery was contraindicated because of the patient's poor general condition. Although intravenous recombinant tissue plasminogen activator is a reasonable treatment for stroke patients, even with a cardiac myxoma, we cannot always expect good effects, especially if the emboli are parts of the tumor itself. In this case, we could not perform an endovascular mechanical embolectomy; however, we speculate that mechanical embolus retrieval in cerebral ischemia might be effective in such cases. PMID- 22545037 TI - Evidence for a Common Founder and Clinical Characteristics of Japanese Families with the MAPT R406W Mutation. AB - BACKGROUND/AIM: Mutations in MAPT cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Patients with the MAPT R406W mutation were reported to show phenotypic heterogeneity in different ethnic backgrounds. We here report the clinical and genetic characteristics of Japanese families with the R406W mutation. METHODS: We examined the clinical and neuroimaging features of 6 patients from three families with the R406W mutation. We determined the genotypes of intragenic MAPT single-nucleotide polymorphisms (SNPs) and the flanking microsatellite markers to search for a common founder. RESULTS: The initial symptom was memory loss with the average age at onset being 54 years. Anterograde amnesia with episodic memory impairment was the predominant phenotype. Behavioral and personality changes or parkinsonism is not a prominent feature. A brain MRI study revealed marked atrophy of the medial temporal lobe. Genetic analysis of SNPs and microsatellite markers revealed that the affected members of the three families share common genotypes. CONCLUSION: The findings of the affected members in this study, which corroborate previously reported findings of European families, suggest that the R406W mutation may represent a phenotype of predominant anterograde amnesia in FTLD-17. Our genetic data suggest that a founder effect may account for some families with the R406W mutation. PMID- 22545038 TI - The chinese (cantonese) montreal cognitive assessment in patients with subcortical ischemic vascular dementia. AB - BACKGROUND: Subcortical ischemic vascular dementia (SIVD) has been proposed as the most frequent subtype of vascular cognitive impairment. The aim of this study was to evaluate the psychometric properties of the Chinese (Cantonese) Montreal Cognitive Assessment (CC-MoCA) in patients with SIVD in the Guangdong Province of China. METHODS: 71 SIVD patients and 60 matched controls were recruited for the CC-MoCA, Mini Mental State Examination and executive clock drawing tasks. Receiver-operating characteristic curve analyses were performed to determine optimal sensitivity and specificity of the CC-MoCA total score in differentiating mild vascular dementia (VaD) patients from moderate VaD patients and controls. RESULTS: The mean CC-MoCA scores of the controls, and mild and moderate VaD patients were 25.2 +/- 3.8, 16.4 +/- 3.7, and 10.0 +/- 5.1, respectively. In our study, the optimal cutoff value for the CC-MoCA to be able to differentiate patients with mild VaD from controls is 21/22, and 13/14 to differentiate mild VaD from moderate VaD. CONCLUSION: The CC-MoCA is a useful cognitive screening instrument in SIVD patients. PMID- 22545040 TI - Lipofuscin hypothesis of Alzheimer's disease. AB - The primary culprit responsible for Alzheimer's disease (AD) remains unknown. Abeta protein has been identified as the main component of amyloid of senile plaques, the hallmark lesion of AD, but it is not definitively established whether the formation of extracellular Abeta deposits is the absolute harbinger of the series of pathological events that hit the brain in the course of sporadic AD. The aim of this paper is to draw attention to a relatively overlooked age related product, lipofuscin, and advance the hypothesis that its release into the extracellular space following the death of neurons may substantially contribute to the formation of senile plaques. The presence of intraneuronal Abeta, similarities between AD and age-related macular degeneration, and the possible explanation of some of the unknown issues in AD suggest that this hypothesis should not be discarded out of hand. PMID- 22545039 TI - Positive FP-CIT SPECT (DaTSCAN) in Clinical Alzheimer's Disease - An Unexpected Finding? AB - Clinically, Alzheimer's disease (AD) is by far the most common cause of dementia. Criteria for the diagnosis of dementia with Lewy bodies (DLB) are highly specific but not at all sensitive, which is reflected by the higher number of DLB cases detected histopathologically at autopsy. Imaging of dopamine transporter with FP CIT SPECT is one possibility to increase sensitivity. Pathological confirmation was also included in the revised consensus criteria for the diagnosis of DLB. However, in the absence of parkinsonism, one of the core features, a clinical diagnosis of AD is more likely. The role of FP-CIT SPECT in DLB diagnosis remains to be clarified. Based on our 3 case reports and a review of the literature, the utility of this imaging method in the differential diagnosis of AD and DLB is highlighted. PMID- 22545041 TI - Two Blood Monocytic Biomarkers (CCL15 and p21) Combined with the Mini-Mental State Examination Discriminate Alzheimer's Disease Patients from Healthy Subjects. AB - BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder. In AD, monocytes migrate across the blood-brain barrier and differentiate into microglia, are linked to inflammatory responses and display age-dependent decreases in telomere lengths. METHODS: Six monocyte-specific chemokines and the (telomere-associated) tumor suppressor proteins p53 and p21 were determined by multiplex immunoassay in plasma and monocyte extracts of patients with AD or mild cognitive impairment, and levels were compared between patients and controls (without cognitive impairment). RESULTS: CCL15 (macrophage inflammatory protein 1delta), CXCL9 (monokine-induced by interferon-gamma) and p21 levels were decreased in monocytes of AD patients compared with controls. CONCLUSION: The combination of monocytic CCL15 and p21 together with the Mini-Mental State Examination enables to differentiate AD patients from controls with high specificity and sensitivity. PMID- 22545042 TI - Frequency of celiac disease in adult patients with typical or atypical malabsorption symptoms in isfahan, iran. AB - Aim. Atypical presentations of celiac disease (CD) have now been shown to be much more common than classical (typical) form. We evaluated the frequency of CD among adult patients with typical or atypical symptoms of CD. Materials and Methods. Patients referred to two outpatient gastroenterology clinics in Isfahan (IRAN) were categorized into those with typical or atypical symptoms of CD. IgA antitissue transglutaminase antibody was assessed and followed by duodenal biopsy. In patients for whom endoscopy was indicated (independent of the serology), duodenal biopsy was taken. Histopathological changes were assessed according to the Marsh classification. Results. During the study period, 151 and 173 patients with typical and atypical symptoms were evaluated (mean age = 32.8 +/- 12.6 and 35.8 +/- 14.8 years, 47.0% and 56.0% female, resp.). Frequency of CD in patients with typical and atypical symptoms was calculated, respectively, as 5.9% (9/151) and 1.25% (3/173) based on positive serology and pathology. The overall frequency was estimated as at least 9.2% (14/151) and 4.0% (7/173) when data of seronegative patients were also considered. Conclusions. CD is more frequent among patients with typical symptoms of malabsorption and these patients should undergo duodenal biopsy, irrespective of the serology. In patients with atypical symptoms, serological tests should be performed followed by endoscopic biopsy, and routine duodenal biopsy is recommended when endoscopic evaluation is indicated because of symptoms. PMID- 22545044 TI - Function of serum complement in drinking water arsenic toxicity. AB - Serum complement function was evaluated in 125 affected subjects suffering from drinking water arsenic toxicity. Their mean duration of exposure was 7.4 +/- 5.3 yrs, and the levels of arsenic in drinking water and urine samples were 216 +/- 211 and 223 +/- 302 MUg/L, respectively. The mean bactericidal activity of complement from the arsenic patients was 92% and that in the unexposed controls was 99% (P < 0.01), but heat-inactivated serum showed slightly elevated activity than in controls. In patients, the mean complement C3 was 1.56 g/L, and C4 was 0.29 g/L compared to 1.68 g/L and 0.25 g/L, respectively, in the controls. The mean IgG in the arsenic patients was 24.3 g/L that was highly significantly elevated (P < 0.001). Arsenic patients showed a significant direct correlation between C3 and bactericidal activity (P = 0.014). Elevated levels of C4 indicated underutilization and possibly impaired activity of the classical complement pathway. We conclude reduced function of serum complement in drinking water arsenic toxicity. PMID- 22545043 TI - Age-related neurodegeneration and memory loss in down syndrome. AB - Down syndrome (DS) is a condition where a complete or segmental chromosome 21 trisomy causes variable intellectual disability, and progressive memory loss and neurodegeneration with age. Many research groups have examined development of the brain in DS individuals, but studies on age-related changes should also be considered, with the increased lifespan observed in DS. DS leads to pathological hallmarks of Alzheimer's disease (AD) by 40 or 50 years of age. Progressive age related memory deficits occurring in both AD and in DS have been connected to degeneration of several neuronal populations, but mechanisms are not fully elucidated. Inflammation and oxidative stress are early events in DS pathology, and focusing on these pathways may lead to development of successful intervention strategies for AD associated with DS. Here we discuss recent findings and potential treatment avenues regarding development of AD neuropathology and memory loss in DS. PMID- 22545046 TI - Metals and disease. PMID- 22545045 TI - Evaluation of genotoxic and cytotoxic effects in human peripheral blood lymphocytes exposed in vitro to neonicotinoid insecticides news. AB - Calypso (thiacloprid), Poncho (clothianidin), Gaucho (imidacloprid), and Jade (imidacloprid) are commercial neonicotinoid insecticides, a new class of agrochemicals in Mexico. However, genotoxic and cytotoxic studies have not been performed. In the present study, human peripheral blood lymphocytes (PBL) were exposed in vitro to different concentrations of the four insecticides. The genotoxic and cytotoxic effects were evaluated using the alkaline comet and trypan blue dye exclusion assays. DNA damage was evaluated using two genotoxicity parameters: tail length and comet frequency. Exposure to 9.5 * 10(-6) to 5.7 * 10(-5) M Jade; 2.8 * 10(-4) to 1.7 * 10(-3) M Gaucho; 0.6 * 10(-1) to 1.4 * 10( 1) M Calypso; 1.2 * 10(-1) to 9.5 * 10(-1) M Poncho for 2 h induced a significant increase DNA damage with a concentration-dependent relationship. Jade was the most genotoxic of the four insecticides studied. Cytotoxicity was observed in cells exposed to 18 * 10(-3) M Jade, 2.0 * 10(-3) M Gaucho, 2.0 * 10(-1) M Calypso, 1.07 M Poncho, and cell death occurred at 30 * 10(-3) M Jade, 3.3 * 10( 3) M Gaucho, 2.8 * 10(-1) M Calypso, and 1.42 M Poncho. This study provides the first report of genotoxic and cytotoxic effects in PBL following in vitro exposure to commercial neonicotinoid insecticides. PMID- 22545047 TI - Update on a Pharmacokinetic-Centric Alternative Tier II Program for MMT-Part I: Program Implementation and Lessons Learned. AB - Concerns have been raised regarding environmental manganese exposure since high exposures have been associated with neurological disorders. The USA Environmental Protection Agency most recent human health risk assessment of inhaled manganese conducted in 1993 identified specific areas of uncertainty regarding manganese pharmacokinetics. This led to the development of a test rule under the USA Clean Air Act that required the generation of pharmacokinetic information on the inorganic manganese combustion products of the organometallic fuel additive methylcyclopentadienyl manganese tricarbonyl (MMT). The Alternative Tier 2 testing program for MMT, described in this paper, has yielded substantial pharmacokinetic data and has enabled the generation of physiologically based pharmacokinetic (PBPK) models for manganese. These models are capable of predicting tissue manganese concentrations across a variety of dose routes, levels, and durations while accounting for factors such as age, gender, and reproductive status, enabling the consideration of tissue dosimetry in future risk assessments. PMID- 22545049 TI - Overexpression of the orotate phosphoribosyl-transferase gene enhances the effect of 5-Fluorouracil in head and neck squamous cell carcinoma in vitro. AB - 5-Fluorouracil (5-FU) is a widely used drug in head and neck squamous cell carcinoma (HNSCC). In the anabolic pathway of 5-FU, the first step in activation of the drug is phosphorylation of 5-FU by orotate phosphoribosyltransferase (OPRT), which directly metabolizes 5-FU to 5-fluorouridine monophosphate (FUMP) in the presence of 5-phosphoribosyl-1-pyrophosphate. To date, OPRT expression in the tumors has been related to the clinical response or survival of cancer patients receiving 5-FU-based chemotherapy. In this study, we examined whether OPRT expression correlates with the chemosensitivity to 5-FU and cell proliferation in HNSCC. We constitutively expressed an OPRT cDNA in an HNSCC cell line. The effects of OPRT expression on in vitro cell growth and 5-FU cytotoxicity were examined. OPRT transfection increases the cytotoxicity of 5-FU without affecting cell proliferation of HNSCC cells in vitro. These results indicate that OPRT expression plays an important role in the sensitivity of HNSCC to 5-FU chemotherapy. PMID- 22545048 TI - Age of 40 years or younger is an independent risk factor for locoregional failure in early breast cancer: a single-institutional analysis in saudi arabia. AB - Background. This study was undertaken to evaluate the impact of prognostic factors on the locoregional failure-free survival of early breast cancer patients. Methods. In this single-institutional study, 213 breast cancer patients were retrospectively analysed. Fifty-five of 213 patients were <=40 years of age at diagnosis. The impact of patient- or treatment-related factors on the locoregional failure-free survival was assessed using the Kaplan-Meier method. The simultaneous impact of factors on the locoregional failure-free survival was assessed using the Cox proportional hazards regression analysis. Results. The median follow-up time of the censored patients was 22 months (mean 28 months, range 3-92 months). On univariate analysis, statistically significant factors for the locoregional failure-free survival were the age (<=40 versus >40 years), T stage (Tis, T0-2 versus T3-4), molecular tumor type (luminal A versus luminal B, Her2neu overexpression, or triple negative), and lymphovascular status (LV0 versus LV1). On multivariate analysis, age and T stage remained statistically significant. Conclusions. Being 40 years or younger has a statistically significant independent adverse impact on the locoregional failure-free survival of patients with early breast cancer. PMID- 22545050 TI - Angiogenesis in Paget's Disease of the Vulva and the Breast: Correlation with Microvessel Density. AB - Our understanding of the pathogenesis of Paget's disease of the vulva and the breast remains limited. Current evidence supports the fact that angiogenesis plays an important role in the pathogenesis of several diseases. Therefore, we sought to define its role, as correlated with microvessel density, in Paget's disease of the vulva and the breast. Microvessels were analysed using anti-von Willebrand factor antibody in 105 cases of Paget's disease of the vulva and the breast comprising 71 cases of Paget's disease of the vulva, including 8 cases with invasive disease, and 34 cases of Paget's disease of the breast. The latter included 12 cases with DCIS, 5 cases with both DCIS and invasive carcinoma, and 6 with carcinoma alone. Eleven cases had no underlying tumour identified. Increased microvessel density was demonstrated in Paget's disease of the breast with DCIS and with carcinoma alone compared to Paget's disease of the breast alone, P < 0.08 and P < 0.013, respectively. There were no significant differences in microvessel density in the vulval cases. Neovascularisation is an important process in the development of Paget's disease of the breast. Other biological and molecular processes are more involved in the pathogenesis of Paget's disease of the vulva. PMID- 22545051 TI - Full-Length Enrich c-DNA Libraries-Clear Cell-Renal Cell Carcinoma. AB - Clear cell renal cell carcinoma (ccRCC), the most common subtype of RCC, is characterized by high metastasis potential and strong resistance to traditional therapies, resulting in a poor five-year survival rate of patients. Several therapies targeted to VEGF pathway for advanced RCC have been developed, however, it still needs to discover new therapeutic targets for treating RCC. Genome-wide gene expression analyses have been broadly used to identify unknown molecular mechanisms of cancer progression. Recently, we applied the oligo-capping method to construct the full-length cDNA libraries of ccRCC and adjacent normal kidney, and analyzed the gene expression profiles by high-throughput sequencing. This paper presents a review for recent findings on therapeutic potential of MYC pathway and nicotinamide N-methyltransferase for the treatment of RCC. PMID- 22545052 TI - Modulation of telomeres in alternative lengthening of telomeres type I like human cells by the expression of werner protein and telomerase. AB - The alternative lengthening of telomeres (ALT) is a recombination-based mechanism of telomere maintenance activated in 5-20% of human cancers. In Saccharomyces cerevisiae, survivors that arise after inactivation of telomerase can be classified as type I or type II ALT. In type I, telomeres have a tandem array structure, with each subunit consisting of a subtelomeric Y' element and short telomere sequence. Telomeres in type II have only long telomere repeats and require Sgs1, the S. cerevisiae RecQ family helicase. We previously described the first human ALT cell line, AG11395, that has a telomere structure similar to type I ALT yeast cells. This cell line lacks the activity of the Werner syndrome protein, a human RecQ helicase. The telomeres in this cell line consist of tandem repeats containing SV40 DNA, including the origin of replication, and telomere sequence. We investigated the role of the SV40 origin of replication and the effects of Werner protein and telomerase on telomere structure and maintenance in AG11395 cells. We report that the expression of Werner protein facilitates the transition in human cells of ALT type I like telomeres to type II like telomeres in some aspects. These findings have implications for the diagnosis and treatment of cancer. PMID- 22545054 TI - Present and Future of EGFR Inhibitors for Head and Neck Squamous Cell Cancer. AB - Although EGFR is expressed at high levels in head and neck squamous cell carcinomas (HNSCCs) and mutations are extremely rare, monotherapy with EGFR inhibitors has shown limited success. The PI3kinase/Akt pathway is responsible for cellular survival, and inhibition of phosphatidylinositol (PI) synthesis has antiproliferative, anti-invasive, and antiangiogenesis effects on HNSCC. Molecular crosstalk has been observed between EGFR and IGF1R signaling through the PI3kinase/Akt pathway in HNSCC, as has molecular crosstalk between the NFkappaB and STAT3 signaling pathways. Therefore, the combination of an EGFR antagonist with an agent that inhibits the activation of both Akt and NFkappaB may overcome resistance to EGFR antagonists in HNSCC. PMID- 22545053 TI - Dual Roles of METCAM in the Progression of Different Cancers. AB - METCAM, an integral membrane cell adhesion molecule (CAM) in the Ig-like gene superfamily, is capable of performing typical functions of CAMs, such as mediating cell-cell and cell-extracellular interactions, crosstalk with intracellular signaling pathways, and modulating social behaviors of cells. METCAM is expressed in about nine normal cells/tissues. Aberrant expression of METCAM has been associated with the progression of several epithelial tumors. Further in vitro and in vivo studies show that METCAM plays a dual role in the progression of different tumors. It can promote the malignant progression of several tumors. On the other hand, it can suppress the malignant progression of other tumors. We suggest that the role of METCAM in the progression of different cancer types may be modulated by different intrinsic factors present in different cancer cells and also in different stromal microenvironment. Many possible mechanisms mediated by this CAM during early tumor development and metastasis are suggested. PMID- 22545055 TI - The Th17/IL-23 Axis and Natural Immunity in Psoriatic Arthritis. AB - Psoriatic arthritis (PsA) is a chronic inflammatory skin disease that causes enthesitis and destructive arthritis and significantly lowers patient quality of life. Recognition of the two target organs (the skin and joints) involved in the immunopathophysiology of PsA helped in elucidating the pathology of various systemic autoimmune diseases targeting multiple organs. Recent advances in immunology and genetics have made it clear that acquired immunity, especially that mediated by the Th17/IL-23 axis, plays an important role in the inflammatory pathology observed in psoriasis and PsA. Additionally, involvement of natural immunity has also been suggested. Microbial infection has been known to trigger psoriasis and PsA. Recent clinical studies using biopharmaceuticals, such as tumor-necrosis-factor- (TNF-) alpha inhibitors and IL-12/23 p40 antibodies, indicate that studies need not be based only on the immunological phenomena observed in PsA pathology since disease pathology can now be verified using human based science. Considering this aspect, this paper discusses the immunopathology of PsA compared to psoriasis (cutaneous) and rheumatoid arthritis in humans and immunopathology of PsA with respect to the Th17/IL-23 axis and microbial infection. PMID- 22545056 TI - Anterior mediastinal mass in a young marijuana smoker: a rare case of small-cell lung cancer. AB - The use of cannabis is embedded within many societies, mostly used by the young and widely perceived to be safe. Increasing concern regarding the potential for cannabis to cause mental health effects has dominated cannabis research, and the potential adverse respiratory effects have received relatively little attention. We report a rare case of 22-year-old man who presented with bilateral neck lymphadenopathy, fatigue, and sore throat without significant medical or family history. The patient had smoked one marijuana joint three times a week for three years but no cigarettes. Chest CT demonstrated a large anterior mediastinal mass compressing the superior vena cava and mediastinal lymphadenopathy. A final diagnosis of small-cell lung cancer was reached. Although rare, a small-cell lung cancer in this patient should alert the physician that cannabis smoking may be a risk factor for lung cancer. PMID- 22545057 TI - Towards Point-of-Care Diagnostic and Staging Tools for Human African Trypanosomiaisis. AB - Human African trypanosomiasis is a debilitating disease prevalent in rural sub Saharan Africa. Control of this disease almost exclusively relies on chemotherapy that should be driven by accurate diagnosis, given the unacceptable toxicity of the few available drugs. Unfortunately, the available diagnostics are characterised by low sensitivities due to the inherent low parasitaemia in natural infections. Demonstration of the trypanosomes in body fluids, which is a prerequisite before treatment, often follows complex algorithms. In this paper, we review the available diagnostics and explore recent advances towards development of novel point-of-care diagnostic tests. PMID- 22545058 TI - Reducing the Impact of Stereotype Threat on Women's Math Performance: Are Two Strategies Better Than One? AB - INTRODUCTION: Two studies examined whether stereotype threat impairs women's math performance and whether concurrent threat reduction strategies can be used to offset this effect. METHOD: In Study 1, collegiate men and women (N = 100) watched a video purporting that males and females performed equally well (gender fair) or males outperformed females (gender differences) on an imminent math test. In Study 2, (N = 44) women viewed the gender differences video, followed by misattribution (cue present, absent) and self-affirmation (present, absent) manipulations, before taking the aforesaid test. RESULTS: In the initial study, women underperformed men on the test after receiving the gender differences video, whereas no gender differences emerged in the gender-fair condition. In Study 2, affirming the self led to better performance than not doing so. Planned contrasts indicated, however, that only women receiving a misattribution cue and self-affirmation opportunity outperformed their counterparts not given these reduction strategies. DISCUSSION: These findings are discussed relative to Stereotype Threat Theory and educational implications are provided. PMID- 22545060 TI - Dexamethasone Resisted Podocyte Injury via Stabilizing TRPC6 Expression and Distribution. AB - TRPC6, a member of the canonical transient receptor potential channel (TRPC) subfamily, is an important cation selective ion channel on podocytes. Podocytes are highly differentiated cells located on the visceral face of glomerular basement membrane and featured by numerous foot processes, on which nephrin, podocin, and TRPC6 locate. Podocytes and the slit diaphragm (SD) between adjacent foot processes form a selective filtration barrier impermeable to proteins. TRPC6 is very critical for normal podocyte function. To investigate the function of TRPC6 in podocytes and its relation to proteinuria in kidney diseases, we over expressed TRPC6 in podocytes by puromycin aminonucleoside (PAN) and observed the changes of foot processes, TRPC6 protein distribution, and mRNA expression. Accordingly, in this study, we further investigated the role of specific signaling mechanisms underlying the prosurvival effects of dexamethasone (DEX) on podocyte repair. Our results showed that podocytes processes of overexpressing TRPC6 were reduced remarkably. These changes could be rescued by DEX via blocking TRPC6 channel. Additionally, our results also showed an improvement in TRPC6 arrangement in the cells and decrease of mRNA expression and protein distribution. From these results, we therefore proposed that overexpression of TRPC6 in podocytes may be one of the fundamental changes relating to the dysfunction of the SD and proteinuria. DEX may be maintained the structure and function integrity of SD by blocking TRPC6 signal pathway and played an important role in mechanisms of anti-proteinuria. PMID- 22545059 TI - Understanding delayed T-cell priming, lung recruitment, and airway luminal T-cell responses in host defense against pulmonary tuberculosis. AB - Mycobacterium tuberculosis (M.tb), the causative bacterium of pulmonary tuberculosis (TB), is a serious global health concern. Central to M.tb effective immune avoidance is its ability to modulate the early innate inflammatory response and prevent the establishment of adaptive T-cell immunity for nearly three weeks. When compared with other intracellular bacterial lung pathogens, such as Legionella pneumophila, or even closely related mycobacterial species such as M. smegmatis, this delay is astonishing. Customarily, the alveolar macrophage (AM) acts as a sentinel, detecting and alerting surrounding cells to the presence of an invader. However, in the case of M.tb, this may be impaired, thus delaying the recruitment of antigen-presenting cells (APCs) to the lung. Upon uptake by APC populations, M.tb is able to subvert and delay the processing of antigen, MHC class II loading, and the priming of effector T cell populations. This delay ultimately results in the deferred recruitment of effector T cells to not only the lung interstitium but also the airway lumen. Therefore, it is of upmost importance to dissect the mechanisms that contribute to the delayed onset of immune responses following M.tb infection. Such knowledge will help design the most effective vaccination strategies against pulmonary TB. PMID- 22545061 TI - Novel neutron sources at the Radiological Research Accelerator Facility. AB - Since the 1960s, the Radiological Research Accelerator Facility (RARAF) has been providing researchers in biology, chemistry and physics with advanced irradiation techniques, using charged particles, photons and neutrons.We are currently developing a unique facility at RARAF, to simulate neutron spectra from an improvised nuclear device (IND), based on calculations of the neutron spectrum at 1.5 km from the epicenter of the Hiroshima atom bomb. This is significantly different from a standard fission spectrum, because the spectrum changes as the neutrons are transported through air, and is dominated by neutron energies between 0.05 and 8 MeV. This facility will be based on a mixed proton/deuteron beam impinging on a thick beryllium target.A second, novel facility under development is our new neutron microbeam. The neutron microbeam will, for the first time, provide a kinematically collimated neutron beam, 10-20 micron in diameter. This facility is based on a Proton Microbeam, impinging on a thin lithium target near the threshold of the (7)Li(p,n)(7)Be reaction. This novel neutron microbeam will enable studies of neutron damage to small targets, such as single cells, individual organs within small animals or microelectronic components. PMID- 22545062 TI - Prediagnosis of obstructive sleep apnea via multiclass MTS. AB - Obstructive sleep apnea (OSA) has become an important public health concern. Polysomnography (PSG) is traditionally considered an established and effective diagnostic tool providing information on the severity of OSA and the degree of sleep fragmentation. However, the numerous steps in the PSG test to diagnose OSA are costly and time consuming. This study aimed to apply the multiclass Mahalanobis-Taguchi system (MMTS) based on anthropometric information and questionnaire data to predict OSA. Implementation results showed that MMTS had an accuracy of 84.38% on the OSA prediction and achieved better performance compared to other approaches such as logistic regression, neural networks, support vector machine, C4.5 decision tree, and rough set. Therefore, MMTS can assist doctors in prediagnosis of OSA before running the PSG test, thereby enabling the more effective use of medical resources. PMID- 22545063 TI - Improved DCT-based nonlocal means filter for MR images denoising. AB - The nonlocal means (NLM) filter has been proven to be an efficient feature preserved denoising method and can be applied to remove noise in the magnetic resonance (MR) images. To suppress noise more efficiently, we present a novel NLM filter based on the discrete cosine transform (DCT). Instead of computing similarity weights using the gray level information directly, the proposed method calculates similarity weights in the DCT subspace of neighborhood. Due to promising characteristics of DCT, such as low data correlation and high energy compaction, the proposed filter is naturally endowed with more accurate estimation of weights thus enhances denoising effectively. The performance of the proposed filter is evaluated qualitatively and quantitatively together with two other NLM filters, namely, the original NLM filter and the unbiased NLM (UNLM) filter. Experimental results demonstrate that the proposed filter achieves better denoising performance in MRI compared to the others. PMID- 22545065 TI - Survival data analysis with time-dependent covariates using generalized additive models. AB - We discuss a flexible method for modeling survival data using penalized smoothing splines when the values of covariates change for the duration of the study. The Cox proportional hazards model has been widely used for the analysis of treatment and prognostic effects with censored survival data. However, a number of theoretical problems with respect to the baseline survival function remain unsolved. We use the generalized additive models (GAMs) with B splines to estimate the survival function and select the optimum smoothing parameters based on a variant multifold cross-validation (CV) method. The methods are compared with the generalized cross-validation (GCV) method using data from a long-term study of patients with primary biliary cirrhosis (PBC). PMID- 22545064 TI - Revealing -1 programmed ribosomal frameshifting mechanisms by single-molecule techniques and computational methods. AB - Programmed ribosomal frameshifting (PRF) serves as an intrinsic translational regulation mechanism employed by some viruses to control the ratio between structural and enzymatic proteins. Most viral mRNAs which use PRF adapt an H-type pseudoknot to stimulate -1 PRF. The relationship between the thermodynamic stability and the frameshifting efficiency of pseudoknots has not been fully understood. Recently, single-molecule force spectroscopy has revealed that the frequency of -1 PRF correlates with the unwinding forces required for disrupting pseudoknots, and that some of the unwinding work dissipates irreversibly due to the torsional restraint of pseudoknots. Complementary to single-molecule techniques, computational modeling provides insights into global motions of the ribosome, whose structural transitions during frameshifting have not yet been elucidated in atomic detail. Taken together, recent advances in biophysical tools may help to develop antiviral therapies that target the ubiquitous -1 PRF mechanism among viruses. PMID- 22545066 TI - Should We Care About Adolescents Who Care for Themselves? What We've Learned and What We Need to Know About Youth in Self-Care. AB - This article provides an overview of existing research on the prevalence and predictors of adolescent self-care and on the consequences associated with it. Self-care, in which the young are left unsupervised during out-of-school hours, is a common experience for millions of American youth, and existing studies suggest that this arrangement may represent a risk for the development of behavior problems. However, the behavior problems associated with self-care depend on both individual and environmental factors and are most likely to develop when self-care (1) occurs out of the home, (2) involves permissive parenting and/or low parental monitoring, (3) takes place in neighborhoods with high levels of crime and disorganization, (4) involves adolescents with preexisting behavioral problems, and (5) represents an intensive and persistent arrangement. Following our survey of current research on self-care, we offer recommendations regarding future research and policy. PMID- 22545067 TI - Educational Neuroscience: New Discoveries from Bilingual Brains, Scientific Brains, and the Educated Mind. PMID- 22545068 TI - Digital Gaming and Pediatric Obesity: At the Intersection of Science and Social Policy. AB - Children and adolescents in developed countries are heavily immersed in digital media, creating an inexpensive, far-reaching marketing opportunity for the food industry and the gaming industry. However, exposure to nonnutritious food and beverage advertisements combined with the use of stationary media create a conflict between entertainment and public health. Using the popular digital gaming platforms advergames (online games that market branded products) and exergames (video games that involves gross motor activity for play) as exemplars, the following article provides an analysis of the negative and positive health impacts of digital gaming as they relate specifically to overweight and obesity outcomes for children and adolescents. Theoretical explanations including the food marketing defense model, persuasion knowledge model, and social cognitive theory are used to explain the influence of gaming on young players' health. Throughout the article, we discuss the role of public policy to encourage the development and use of health-promoting digital games as an innovative, effective tool to combat the pediatric obesity crisis. PMID- 22545069 TI - Promoting exercise in Parkinson's disease through community-based participatory research. AB - Parkinson's disease (PD) is a chronic, progressive, as-of-yet incurable, neurodegenerative condition affecting the nigro-striatal dopaminergic system. Emerging evidence suggests the importance of exercise in improving the trajectory of PD. Yet few people with PD are physically active. One challenge that healthcare professionals face in the 21st century is how to deliver physical activity programs to the population of individuals living with PD. A novel approach to delivering physical activity to people with PD is introduced - termed community-based participatory research (CBPR) - which engages people with PD and patient advocates as co-researchers in the development and implementation of community-based exercise programs. The authors describe the CBPR approach and provide several recent examples of community exercise programs that are steps in the direction of developing the CBPR model. This is followed by a discussion of what a more fully realized CBPR model might look like. Finally, the authors describe some obstacles to conducting CBPR and suggest strategies for overcoming them. It is argued that people with PD are an integral component of delivering the exercise intervention. PMID- 22545070 TI - The juvenile Batten disease protein, CLN3, and its role in regulating anterograde and retrograde post-Golgi trafficking. AB - Loss-of-function mutations in CLN3 are responsible for juvenile-onset neuronal ceroid lipofuscinosis (JNCL), or Batten disease, which is an incurable lysosomal disease that manifests with vision loss, followed by seizures and progressive neurodegeneration, robbing children of motor skills, speech and cognition, and eventually leading to death in the second or third decade of life. Emerging clinical evidence points to JNCL pathology outside of the CNS, including the cardiovascular system. The CLN3 gene encodes an unusual transmembrane protein, CLN3 or battenin, whose elusive function has been the subject of intense study for more than 10 years. Owing to the detailed characterization of a large number of disease models, our knowledge of CLN3 protein function is finally coming into focus. This review will describe the most current understanding of CLN3 structure, function and dysfunction in JNCL. PMID- 22545071 TI - Heart rate recovery does not predict endothelial function in obese women. AB - The purpose of the present study was to examine the relationship between heart rate recovery (HR(REC)) and endothelial function in obese women with the metabolic syndrome. The metabolic syndrome has been associated with increased cardiometabolic risk including endothelial dysfunction. However, measurement of endothelial function via flow-mediated dilation (FMD) requires expensive equipment and qualified medical personnel, and therefore may be impractical in some healthcare settings. Heart rate recovery (HR(REC)) has predictive utility with respect to endothelial function in individuals with suspected coronary artery disease and individuals with the metabolic syndrome also have elevated risk for developing coronary artery disease. Thirty-one obese, sedentary women (age: 47.7+/-11.2 yr, mean+/-SD) who met the International Diabetes Federation criteria for the metabolic syndrome underwent a brachial artery ultrasound to determine FMD and nitroglycerine-mediated dilation (NTG). HR(REC) was assessed during 5 min of active recovery following a standardized VO(2 Peak) treadmill protocol. Results revealed that the %FMD was not correlated to HR(REC) when examined across all participants (r= 0.067, p=0.72). However, this relationship was significant in participants with impaired FMD (n=16, %FMD<6%) (r=0.71, p=0.002). Although HR(REC) may be a significant correlate of FMD in women with the metabolic syndrome and with prevalent endothelial dysfunction, it was not a significant correlate across all women with the metabolic syndrome. The present data do not support the use of HR(REC) as a possible screening tool for endothelial dysfunction in obese women with the metabolic syndrome. PMID- 22545072 TI - Proteolytic Activity Attenuates the Response of Endothelial Cells to Fluid Shear Stress. AB - Recent evidence indicates that several experimental pathophysiological conditions are associated with elevated protease activity in plasma, which impacts endothelial function. We hypothesize that extracellular structures bound to the endothelial cell (EC) membrane may be degraded by proteolytic activity and cause the cells to respond abnormally to physiological shear stress (12 dyn/cm(2)). To test this hypothesis, cultured bovine aortic endothelial cells (BAECs) were exposed to low levels of a serine protease, trypsin. Extracellular mechanosensor densities of the glycocalyx and vascular endothelial growth factor receptor 2 (VEGFR-2) were determined. Metabolic dysfunction was tested by examining insulin receptor and glucose uptake levels. Protease treatment impaired the cells' ability to align in the direction of fluid flow after 12 hours of shear stress; however, cells realigned after an additional 12 hours of shear stress with protease inhibition. Proteases caused reduction in the densities of glycocalyx, VEGFR-2, and insulin receptor in static and shear conditions, except for static VEGFR-2 cells. Under static conditions, protease-treated endothelial cells had reduced glucose uptake compared to untreated controls. Under shear, however, glucose uptake for protease-treated BAECs was greater than untreated controls. In conclusion, protease activity in plasma alters the exofacial membrane components of ECs and may interfere with mechanotransduction. PMID- 22545073 TI - End of the Beginning and Public Health Pharmacogenomics: Knowledge in 'Mode 2' and P5 Medicine. PMID- 22545078 TI - Downregulation of integrin beta4 decreases the ability of airway epithelial cells to present antigens. AB - Airway epithelial cells have been demonstrated to be accessory antigen presentation cells (APC) capable of activating T cells and may play an important role in the development of allergic airway inflammation of asthma. In asthmatic airways, loss of expression of the adhesion molecule integrin beta4 (ITGB4) and an increase in Th2 inflammation bias has been observed in our previous study. Given that ITGB4 is engaged in multiple signaling pathways, we studied whether disruption of ITGB4-mediated cell adhesion may contribute to the adaptive immune response of epithelial cells, including their ability to present antigens, induce the activate and differentiate of T cells. We silenced ITGB4 expression in bronchial epithelial cells with an effective siRNA vector and studied the effects of ITGB4 silencing on the antigen presentation ability of airway epithelial cells. T cell proliferation and cytokine production was investigated after co culturing with ITGB4-silenced epithelial cells. Surface expression of B7 homologs and the major histocompatibility complex (MHC) class II was also detected after ITGB4 was silenced. Our results demonstrated that silencing of ITGB4 resulted in impaired antigen presentation processes and suppressed T cell proliferation. Meanwhile, decrease in Th1 cytokine production and increase in Th17 cytokine production was induced after co-culturing with ITGB4-silenced epithelial cells. Moreover, HLA-DR was decreased and the B7 homologs expression was different after ITGB4 silencing. Overall, this study suggested that downregulation of ITGB4 expression in airway epithelial cells could impair the antigen presentation ability of these cells, which further regulate airway inflammation reaction in allergic asthma. PMID- 22545080 TI - Ophthalmic artery chemosurgery for less advanced intraocular retinoblastoma: five year review. AB - BACKGROUND: Ophthalmic artery chemosurgery (OAC) for retinoblastoma was introduced by us 5 years ago for advanced intraocular retinoblastoma. Because the success was higher than with existing alternatives and systemic side effects limited we have now treated less advanced intraocular retinoblastoma (Reese Ellsworth (RE) I-III and International Classification Retinoblastoma (ICRB) B and C). METHODOLOGY/PRINCIPAL FINDINGS: Retrospective review of 5 year experience in eyes with Reese Ellsworth (Table 1) I (7 eyes), II (6 eyes) or III (6 eyes) and/or International Classification (Table 2) B (19 eyes) and C (11 eyes) treated with OAC (melphalan with or without topotecan) introduced directly into the ophthalmic artery. Patient survival was 100%. Ocular event-free survival was 100% for Reese-Ellsworth Groups I, II and III (and 96% for ICRB B and C) at a median of 16 months follow-up. One ICRB Group C (Reese-Ellsworth Vb) eye could not be treated on the second attempt for technical reasons and was therefore enucleated. No patient required a port and only one patient required transfusion of blood products. The electroretinogram (ERG) was unchanged or improved in 14/19 eyes. CONCLUSIONS/SIGNIFICANCE: Ophthalmic artery chemosurgery for retinoblastoma that was Reese-Ellsworth I, II and III (or International Classification B or C) was associated with high success (100% of treatable eyes were retained) and limited toxicity with results that equal or exceed conventional therapy with less toxicity. PMID- 22545081 TI - Knockdown of amyloid precursor protein in zebrafish causes defects in motor axon outgrowth. AB - Amyloid precursor protein (APP) plays a pivotal role in Alzheimer's disease (AD) pathogenesis, but its normal physiological functions are less clear. Combined deletion of the APP and APP-like protein 2 (APLP2) genes in mice results in post natal lethality, suggesting that APP performs an essential, if redundant, function during embryogenesis. We previously showed that injection of antisense morpholino to reduce APP levels in zebrafish embryos caused convergent-extension defects. Here we report that a reduction in APP levels causes defective axonal outgrowth of facial branchiomotor and spinal motor neurons, which involves disorganized axonal cytoskeletal elements. The defective outgrowth is caused in a cell-autonomous manner and both extracellular and intracellular domains of human APP are required to rescue the defective phenotype. Interestingly, wild-type human APP rescues the defective phenotype but APPswe mutation, which causes familial AD, does not. Our results show that the zebrafish model provides a powerful system to delineate APP functions in vivo and to study the biological effects of APP mutations. PMID- 22545082 TI - Follicle stimulating hormone and anti-Mullerian hormone per oocyte in predicting in vitro fertilization pregnancy in high responders: a cohort study. AB - BACKGROUND: Follicle stimulating hormone (FSH) and Anti-Mullerian hormone (AMH) are utilized to differentiate between good and poor response to controlled ovarian hyperstimulation. Their respective roles in defining functional ovarian reserve remain, however, to be elucidated. To better understand those we investigated AMH and FSH per oocyte retrieved (AMHo and FSHo). METHODOLOGY/PRINCIPAL FINDINGS: Three-hundred and ninety-six women, undergoing first in vitro fertilization cycles, were retrospectively evaluated. Women with oocyte yields >75(th) percentile for their age group were identified as high responders. In a series of logistic regression analyses, AMHo and FSHo levels were then evaluated as predictive factors for pregnancy potential in high responders. Patients presented with a mean age of 38.0+/-5.0 years, mean baseline FSH of 11.8+/-8.7 mIU/mL and mean AMH of 1.6+/-2.1 ng/mL. Those 88 women, who qualified as high responders, showed mean FSH of 9.7+/-6.5 mIU/mL, AMH of 3.1+/ 3.1 ng/mL and oocyte yields of 15.8+/-7.1. Baseline FSH and AMH did not predict pregnancy in high responders. However, a statistically significant association between FSHo and pregnancy was observed in high responders, both after univariate regression (p = 0.02) and when adjusted for age, percentage of usable embryos, and number of embryos transferred (p = 0.03). Rate of useable embryos also significantly affected pregnancy outcome independently of FSHo (p = 0.01). AMHo was also associated with clinical pregnancy chances in high responders (p = 0.03) and remained significant when adjusted for usable embryos and number of embryos transferred (p = 0.04). CONCLUSIONS: AMHo and FSHo are predictive of pregnancy potential in high responders, but likely reflect different responsibilities in recruitment and maturation of growing follicle cohorts. PMID- 22545079 TI - Cost effectiveness analysis of clinically driven versus routine laboratory monitoring of antiretroviral therapy in Uganda and Zimbabwe. AB - BACKGROUND: Despite funding constraints for treatment programmes in Africa, the costs and economic consequences of routine laboratory monitoring for efficacy and toxicity of antiretroviral therapy (ART) have rarely been evaluated. METHODS: Cost-effectiveness analysis was conducted in the DART trial (ISRCTN13968779). Adults in Uganda/Zimbabwe starting ART were randomised to clinically-driven monitoring (CDM) or laboratory and clinical monitoring (LCM); individual patient data on healthcare resource utilisation and outcomes were valued with primary economic costs and utilities. Total costs of first/second-line ART, routine 12 weekly CD4 and biochemistry/haematology tests, additional diagnostic investigations, clinic visits, concomitant medications and hospitalisations were considered from the public healthcare sector perspective. A Markov model was used to extrapolate costs and benefits 20 years beyond the trial. RESULTS: 3316 (1660LCM;1656CDM) symptomatic, immunosuppressed ART-naive adults (median (IQR) age 37 (32,42); CD4 86 (31,139) cells/mm(3)) were followed for median 4.9 years. LCM had a mean 0.112 year (41 days) survival benefit at an additional mean cost of $765 [95%CI:685,845], translating into an adjusted incremental cost of $7386 [3277,dominated] per life-year gained and $7793 [4442,39179] per quality-adjusted life year gained. Routine toxicity tests were prominent cost-drivers and had no benefit. With 12-weekly CD4 monitoring from year 2 on ART, low-cost second-line ART, but without toxicity monitoring, CD4 test costs need to fall below $3.78 to become cost-effective (<3xper-capita GDP, following WHO benchmarks). CD4 monitoring at current costs as undertaken in DART was not cost-effective in the long-term. CONCLUSIONS: There is no rationale for routine toxicity monitoring, which did not affect outcomes and was costly. Even though beneficial, there is little justification for routine 12-weekly CD4 monitoring of ART at current test costs in low-income African countries. CD4 monitoring, restricted to the second year on ART onwards, could be cost-effective with lower cost second-line therapy and development of a cheaper, ideally point-of-care, CD4 test. PMID- 22545083 TI - In-vivo biodistribution and safety of 99mTc-LLP2A-HYNIC in canine non-Hodgkin lymphoma. AB - Theranostic agents are critical for improving the diagnosis and treatment of non Hodgkin Lymphoma (NHL). The peptidomimetic LLP2A is a novel peptide receptor radiotherapy candidate for treating NHL that expresses the activated alpha4beta1 integrin. Tumor-bearing dogs are an excellent model of human NHL with similar clinical characteristics, behavior, and compressed clinical course. Canine in vivo imaging studies will provide valuable biodistribution and affinity information that reflects a diverse clinical population of lymphoma. This may also help to determine potential dose-limiting radiotoxicity to organs in human clinical trials. To validate this construct in a naturally occurring model of NHL, we performed in-vivo molecular targeted imaging and biodistribution in 3 normal dogs and 5 NHL bearing dogs. (99m)Tc-LLP2A-HYNIC-PEG and (99m)Tc-LLP2A HYNIC were successfully synthesized and had very good labeling efficiency and radiochemical purity. (99m)Tc-LLP2A-HYNIC and (99m)Tc-LLP2A-HYNIC-PEG had biodistribution in keeping with their molecular size, with (99m)Tc-LLP2A-HYNIC PEG remaining longer in the circulation, having higher tissue uptake, and having more activity in the liver compared to (99m)Tc-LLP2A-HYNIC. (99m)Tc-LLP2A-HYNIC was mainly eliminated through the kidneys with some residual activity. Radioactivity was reduced to near-background levels at 6 hours after injection. In NHL dogs, tumor showed moderately increased activity over background, with tumor activity in B-cell lymphoma dogs decreasing after chemotherapy. This compound is promising in the development of targeted drug-delivery radiopharmaceuticals and may contribute to translational work in people affected by non-Hodgkin lymphoma. PMID- 22545085 TI - Characterization of multi-functional properties and conformational analysis of MutS2 from Thermotoga maritima MSB8. AB - The MutS2 homologues have received attention because of their unusual activities that differ from those of MutS. In this work, we report on the functional characteristics and conformational diversities of Thermotoga maritima MutS2 (TmMutS2). Various biochemical features of the protein were demonstrated via diverse techniques such as scanning probe microscopy (SPM), ATPase assays, analytical ultracentrifugation, DNA binding assays, size chromatography, and limited proteolytic analysis. Dimeric TmMutS2 showed the temperature-dependent ATPase activity. The non-specific nicking endonuclease activities of TmMutS2 were inactivated in the presence of nonhydrolytic ATP (ADPnP) and enhanced by the addition of TmMutL. In addition, TmMutS2 suppressed the TmRecA-mediated DNA strand exchange reaction in a TmMutL-dependent manner. We also demonstrated that small-angle X-ray scattering (SAXS) analysis of dimeric TmMutS2 exhibited nucleotide- and DNA-dependent conformational transitions. Particularly, TmMutS2 ADPnP showed the most compressed form rather than apo-TmMutS2 and the TmMutS2-ADP complex, in accordance with the results of biochemical assays. In the case of the DNA-binding complexes, the stretched conformation appeared in the TmMutS2-four way junction (FWJ)-DNA complex. Convergences of biochemical- and SAXS analysis provided abundant information for TmMutS2 and clarified ambiguous experimental results. PMID- 22545086 TI - Spatio-temporal differentiation and sociality in spiders. AB - Species that differ in their social system, and thus in traits such as group size and dispersal timing, may differ in their use of resources along spatial, temporal, or dietary dimensions. The role of sociality in creating differences in habitat use is best explored by studying closely related species or socially polymorphic species that differ in their social system, but share a common environment. Here we investigate whether five sympatric Anelosimus spider species that range from nearly solitary to highly social differ in their use of space and in their phenology as a function of their social system. By studying these species in Serra do Japi, Brazil, we find that the more social species, which form larger, longer-lived colonies, tend to live inside the forest, where sturdier, longer lasting vegetation is likely to offer better support for their nests. The less social species, which form single-family groups, in contrast, tend to occur on the forest edge where the vegetation is less robust. Within these two microhabitats, species with longer-lived colonies tend to occupy the potentially more stable positions closer to the core of the plants, while those with smaller and shorter-lived colonies build their nests towards the branch tips. The species further separate in their use of common habitat due to differences in the timing of their reproductive season. These patterns of habitat use suggest that the degree of sociality can enable otherwise similar species to differ from one another in ways that may facilitate their co-occurrence in a shared environment, a possibility that deserves further consideration. PMID- 22545084 TI - Analysis of Tp53 codon 72 polymorphisms, Tp53 mutations, and HPV infection in cutaneous squamous cell carcinomas. AB - BACKGROUND: Non-melanoma skin cancers are one of the most common human malignancies accounting for 2-3% of tumors in the US and represent a significant health burden. Epidemiology studies have implicated Tp53 mutations triggered by UV exposure, and human papilloma virus (HPV) infection to be significant causes of non-melanoma skin cancer. However, the relationship between Tp53 and cutaneous HPV infection is not well understood in skin cancers. In this study we assessed the association of HPV infection and Tp53 polymorphisms and mutations in lesional specimens with squamous cell carcinomas. METHODS: We studied 55 cases of histologically confirmed cutaneous squamous cell carcinoma and 41 controls for the presence of HPV infection and Tp53 genotype (mutations and polymorphism). RESULTS: We found an increased number of Tp53 mutations in the squamous cell carcinoma samples compared with perilesional or control samples. There was increased frequency of homozygous Tp53-72R polymorphism in cases with squamous cell carcinomas, while the Tp53-72P allele (Tp53-72R/P and Tp53-72P/P) was more frequent in normal control samples. Carcinoma samples positive for HPV showed a decreased frequency of Tp53 mutations compared to those without HPV infection. In addition, carcinoma samples with a Tp53-72P allele showed an increased incidence of Tp53 mutations in comparison carcinomas samples homozygous for Tp53-72R. CONCLUSIONS: These studies suggest there are two separate pathways (HPV infection and Tp53 mutation) leading to cutaneous squamous cell carcinomas stratified by the Tp53 codon-72 polymorphism. The presence of a Tp53-72P allele is protective against cutaneous squamous cell carcinoma, and carcinoma specimens with Tp53-72P are more likely to have Tp53 mutations. In contrast Tp53-72R is a significant risk factor for cutaneous squamous cell carcinoma and is frequently associated with HPV infection instead of Tp53 mutations. Heterozygosity for Tp53-72R/P is protective against squamous cell carcinomas, possibly reflecting a requirement for both HPV infection and Tp53 mutations. PMID- 22545087 TI - Cervical screening within HIV care: findings from an HIV-positive cohort in Ukraine. AB - INTRODUCTION: HIV-positive women have an increased risk of invasive cervical cancer but cytologic screening is effective in reducing incidence. Little is known about cervical screening coverage or the prevalence of abnormal cytology among HIV-positive women in Ukraine, which has the most severe HIV epidemic in Europe. METHODS: Poisson regression models were fitted to data from 1120 women enrolled at three sites of the Ukraine Cohort Study of HIV-infected Childbearing Women to investigate factors associated with receiving cervical screening as part of HIV care. All women had been diagnosed as HIV-positive before or during their most recent pregnancy. Prevalence of cervical abnormalities (high/low grade squamous intraepithelial lesions) among women who had been screened was estimated, and associated factors explored. RESULTS: Overall, 30% (337/1120) of women had received a cervical screening test as part of HIV care at study enrolment (median 10 months postpartum), a third (115/334) of whom had been tested >12 months previously. In adjusted analyses, women diagnosed as HIV positive during (vs before) their most recent pregnancy were significantly less likely to have a screening test reported, on adjusting for other potential risk factors (adjusted prevalence ratio (APR) 0.62, 95% CI 0.51-0.75 p<0.01 for 1(st)/2(nd) trimester diagnosis and APR 0.42, 95% CI 0.28-0.63 p<0.01 for 3(rd) trimester/intrapartum diagnosis). Among those with a cervical screening result reported at any time (including follow-up), 21% (68/325) had a finding of cervical abnormality. In adjusted analyses, Herpes simplex virus 2 seropositivity and a recent diagnosis of bacterial vaginosis were associated with an increased risk of abnormal cervical cytology (APR 1.83 95% CI 1.07-3.11 and APR 3.49 95% CI 2.11-5.76 respectively). CONCLUSIONS: In this high risk population, cervical screening coverage as part of HIV care was low and could be improved by an organised cervical screening programme for HIV-positive women. Bacterial vaginosis testing and treatment may reduce vulnerability to cervical abnormalities. PMID- 22545088 TI - A 6 week randomized double-blind placebo-controlled trial of ziprasidone for the acute depressive mixed state. AB - OBJECTIVE: To examine the efficacy of ziprasidone vs. placebo for the depressive mixed state in patients with bipolar disorder type II or major depressive disorder (MDD). METHODS: 73 patients were randomized in a double-blinded, placebo controlled study to ziprasidone (40-160 mg/d) or placebo for 6 weeks. They met DSM-IV criteria for a major depressive episode (MDE), while also meeting 2 or 3 (but not more nor less) DSM-IV manic criteria. They did not meet DSM-IV criteria for a mixed or manic episode. Baseline psychotropic drugs were continued unchanged. The primary endpoint measured was Montgomery-Asberg Depression Rating Scale (MADRS) scores over time. The mean dose of ziprasidone was 129.7+/-45.3 mg/day and 126.1+/-47.1 mg/day for placebo. RESULTS: The primary outcome analysis indicated efficacy of ziprasidone versus placebo (p = 0.0038). Efficacy was more pronounced in type II bipolar disorder than in MDD (p = 0.036). Overall ziprasidone was well tolerated, without notable worsening of weight or extrapyramidal symptoms. CONCLUSIONS: There was a statistically significant benefit with ziprasidone versus placebo in this first RCT of any medication for the provisional diagnostic concept of the depressive mixed state. TRIAL REGISTRATION: Clinicaltrials.gov NCT00490542. PMID- 22545091 TI - Who underreports smoking on birth records: a Monte Carlo predictive model with validation. AB - BACKGROUND: Research has shown that self-reports of smoking during pregnancy may underestimate true prevalence. However, little is known about which populations have higher rates of underreporting. Availability of more accurate measures of smoking during pregnancy could greatly enhance the usefulness of existing studies on the effects of maternal smoking offspring, especially in those populations where underreporting may lead to underestimation of the impact of smoking during pregnancy. METHODS AND FINDINGS: In this paper, we develop a statistical Monte Carlo model to estimate patterns of underreporting of smoking during pregnancy, and apply it to analyze the smoking self-report data from birth certificates in the state of Massachusetts. Our results illustrate non-uniform patterns of underreporting of smoking during pregnancy among different populations. Estimates of likely underreporting of smoking during pregnancy were highest among mothers who were college-educated, married, aged 30 years or older, employed full-time, and planning to breastfeed. The model's findings are validated and compared to an existing underreporting adjustment approach in the Maternal and Infant Smoking Study of East Boston (MISSEB). CONCLUSIONS: The validation results show that when biological assays are not available, the Monte Carlo method proposed can provide a more accurate estimate of the smoking status during pregnancy than self-reports alone. Such methods hold promise for providing a better assessment of the impact of smoking during pregnancy. PMID- 22545089 TI - Novel regulatory mechanisms for generation of the soluble leptin receptor: implications for leptin action. AB - BACKGROUND: The adipokine leptin realizes signal transduction via four different membrane-anchored leptin receptor (Ob-R) isoforms in humans. However, the amount of functionally active Ob-R is affected by constitutive shedding of the extracellular domain via a so far unknown mechanism. The product of the cleavage process the so-called soluble leptin receptor (sOb-R) is the main binding protein for leptin in human blood and modulates its bioavailability. sOb-R levels are differentially regulated in metabolic disorders like type 1 diabetes mellitus or obesity and can, therefore, enhance or reduce leptin sensitivity. METHODOLOGY/PRINCIPAL FINDINGS: To describe mechanisms of Ob-R cleavage and to investigate the functional significance of differential sOb-R levels we established a model of HEK293 cells transiently transfected with different human Ob-R isoforms. Using siRNA knockdown experiments we identified ADAM10 (A Disintegrin And Metalloproteinase 10) as a major protease for constitutive and activated Ob-R cleavage. Additionally, the induction of lipotoxicity and apoptosis led to enhanced shedding shown by increased levels of the soluble leptin receptor (sOb-R) in cell supernatants. Conversely, high leptin concentrations and ER stress reduced sOb-R levels. Decreased amounts of sOb-R due to ER stress were accompanied by impaired leptin signaling and reduced leptin binding. CONCLUSIONS: Lipotoxicity and apoptosis increased Ob-R cleavage via ADAM10-dependent mechanisms. In contrast high leptin levels and ER stress led to reduced sOb-R levels. While increased sOb-R concentrations seem to directly block leptin action, reduced amounts of sOb-R may reflect decreased membrane expression of Ob-R. These findings could explain changes of leptin sensitivity which are associated with variations of serum sOb-R levels in metabolic diseases. PMID- 22545092 TI - Influence of motor planning on distance perception within the peripersonal space. AB - We examined whether movement costs as defined by movement magnitude have an impact on distance perception in near space. In Experiment 1, participants were given a numerical cue regarding the amplitude of a hand movement to be carried out. Before the movement execution, the length of a visual distance had to be judged. These visual distances were judged to be larger, the larger the amplitude of the concurrently prepared hand movement was. In Experiment 2, in which numerical cues were merely memorized without concurrent movement planning, this general increase of distance with cue size was not observed. The results of these experiments indicate that visual perception of near space is specifically affected by the costs of planned hand movements. PMID- 22545090 TI - The EYA tyrosine phosphatase activity is pro-angiogenic and is inhibited by benzbromarone. AB - Eyes Absents (EYA) are multifunctional proteins best known for their role in organogenesis. There is accumulating evidence that overexpression of EYAs in breast and ovarian cancers, and in malignant peripheral nerve sheath tumors, correlates with tumor growth and increased metastasis. The EYA protein is both a transcriptional activator and a tyrosine phosphatase, and the tyrosine phosphatase activity promotes single cell motility of mammary epithelial cells. Since EYAs are expressed in vascular endothelial cells and cell motility is a critical feature of angiogenesis we investigated the role of EYAs in this process. Using RNA interference techniques we show that EYA3 depletion in human umbilical vein endothelial cells inhibits transwell migration as well as Matrigel induced tube formation. To specifically query the role of the EYA tyrosine phosphatase activity we employed a chemical biology approach. Through an experimental screen the uricosuric agents Benzbromarone and Benzarone were found to be potent EYA inhibitors, and Benzarone in particular exhibited selectivity towards EYA versus a representative classical protein tyrosine phosphatase, PTP1B. These compounds inhibit the motility of mammary epithelial cells over expressing EYA2 as well as the motility of endothelial cells. Furthermore, they attenuate tubulogenesis in matrigel and sprouting angiogenesis in the ex vivo aortic ring assay in a dose-dependent fashion. The anti-angiogenic effect of the inhibitors was also demonstrated in vivo, as treatment of zebrafish embryos led to significant and dose-dependent defects in the developing vasculature. Taken together our results demonstrate that the EYA tyrosine phosphatase activity is pro-angiogenic and that Benzbromarone and Benzarone are attractive candidates for repurposing as drugs for the treatment of cancer metastasis, tumor angiogenesis, and vasculopathies. PMID- 22545093 TI - Demersal fish assemblages and spatial diversity patterns in the Arctic-Atlantic transition zone in the Barents Sea. AB - Direct and indirect effects of global warming are expected to be pronounced and fast in the Arctic, impacting terrestrial, freshwater and marine ecosystems. The Barents Sea is a high latitude shelf Sea and a boundary area between arctic and boreal faunas. These faunas are likely to respond differently to changes in climate. In addition, the Barents Sea is highly impacted by fisheries and other human activities. This strong human presence places great demands on scientific investigation and advisory capacity. In order to identify basic community structures against which future climate related or other human induced changes could be evaluated, we analyzed species composition and diversity of demersal fish in the Barents Sea. We found six main assemblages that were separated along depth and temperature gradients. There are indications that climate driven changes have already taken place, since boreal species were found in large parts of the Barents Sea shelf, including also the northern Arctic area. When modelling diversity as a function of depth and temperature, we found that two of the assemblages in the eastern Barents Sea showed lower diversity than expected from their depth and temperature. This is probably caused by low habitat complexity and the distance to the pool of boreal species in the western Barents Sea. In contrast coastal assemblages in south western Barents Sea and along Novaya Zemlya archipelago in the Eastern Barents Sea can be described as diversity "hotspots"; the South-western area had high density of species, abundance and biomass, and here some species have their northern distribution limit, whereas the Novaya Zemlya area has unique fauna of Arctic, coastal demersal fish. (see Information S1 for abstract in Russian). PMID- 22545094 TI - Erythroid-specific transcriptional changes in PBMCs from pulmonary hypertension patients. AB - BACKGROUND: Gene expression profiling of peripheral blood mononuclear cells (PBMCs) is a powerful tool for the identification of surrogate markers involved in disease processes. The hypothesis tested in this study was that chronic exposure of PBMCs to a hypertensive environment in remodeled pulmonary vessels would be reflected by specific transcriptional changes in these cells. METHODOLOGY/PRINCIPAL FINDINGS: The transcript profiles of PBMCs from 30 idiopathic pulmonary arterial hypertension patients (IPAH), 19 patients with systemic sclerosis without pulmonary hypertension (SSc), 42 scleroderma associated pulmonary arterial hypertensio patients (SSc-PAH), and 8 patients with SSc complicated by interstitial lung disease and pulmonary hypertension (SSc-PH ILD) were compared to the gene expression profiles of PBMCs from 41 healthy individuals. Multiple gene expression signatures were identified which could distinguish various disease groups from controls. One of these signatures, specific for erythrocyte maturation, is enriched specifically in patients with PH. This association was validated in multiple published datasets. The erythropoiesis signature was strongly correlated with hemodynamic measures of increasing disease severity in IPAH patients. No significant correlation of the same type was noted for SSc-PAH patients, this despite a clear signature enrichment within this group overall. These findings suggest an association of the erythropoiesis signature in PBMCs from patients with PH with a variable presentation among different subtypes of disease. CONCLUSIONS/SIGNIFICANCE: In PH, the expansion of immature red blood cell precursors may constitute a response to the increasingly hypoxic conditions prevalent in this syndrome. A correlation of this erythrocyte signature with more severe hypertension cases may provide an important biomarker of disease progression. PMID- 22545095 TI - Expression profiling of Cucumis sativus in response to infection by Pseudoperonospora cubensis. AB - The oomycete pathogen, Pseudoperonospora cubensis, is the causal agent of downy mildew on cucurbits, and at present, no effective resistance to this pathogen is available in cultivated cucumber (Cucumis sativus). To better understand the host response to a virulent pathogen, we performed expression profiling throughout a time course of a compatible interaction using whole transcriptome sequencing. As described herein, we were able to detect the expression of 15,286 cucumber genes, of which 14,476 were expressed throughout the infection process from 1 day post inoculation (dpi) to 8 dpi. A large number of genes, 1,612 to 3,286, were differentially expressed in pair-wise comparisons between time points. We observed the rapid induction of key defense related genes, including catalases, chitinases, lipoxygenases, peroxidases, and protease inhibitors within 1 dpi, suggesting detection of the pathogen by the host. Co-expression network analyses revealed transcriptional networks with distinct patterns of expression including down-regulation at 2 dpi of known defense response genes suggesting coordinated suppression of host responses by the pathogen. Comparative analyses of cucumber gene expression patterns with that of orthologous Arabidopsis thaliana genes following challenge with Hyaloperonospora arabidopsidis revealed correlated expression patterns of single copy orthologs suggesting that these two dicot hosts have similar transcriptional responses to related pathogens. In total, the work described herein presents an in-depth analysis of the interplay between host susceptibility and pathogen virulence in an agriculturally important pathosystem. PMID- 22545096 TI - Matrix metalloproteinase-10 is required for lung cancer stem cell maintenance, tumor initiation and metastatic potential. AB - Matrix metalloproteinases (Mmps) stimulate tumor invasion and metastasis by degrading the extracellular matrix. Here we reveal an unexpected role for Mmp10 (stromelysin 2) in the maintenance and tumorigenicity of mouse lung cancer stem like cells (CSC). Mmp10 is highly expressed in oncosphere cultures enriched in CSCs and RNAi-mediated knockdown of Mmp10 leads to a loss of stem cell marker gene expression and inhibition of oncosphere growth, clonal expansion, and transformed growth in vitro. Interestingly, clonal expansion of Mmp10 deficient oncospheres can be restored by addition of exogenous Mmp10 protein to the culture medium, demonstrating a direct role for Mmp10 in the proliferation of these cells. Oncospheres exhibit enhanced tumor-initiating and metastatic activity when injected orthotopically into syngeneic mice, whereas Mmp10-deficient cultures show a severe defect in tumor initiation. Conversely, oncospheres implanted into syngeneic non-transgenic or Mmp10(-/-) mice show no significant difference in tumor initiation, growth or metastasis, demonstrating the importance of Mmp10 produced by cancer cells rather than the tumor microenvironment in lung tumor initiation and maintenance. Analysis of gene expression data from human cancers reveals a strong positive correlation between tumor Mmp10 expression and metastatic behavior in many human tumor types. Thus, Mmp10 is required for maintenance of a highly tumorigenic, cancer-initiating, metastatic stem-like cell population in lung cancer. Our data demonstrate for the first time that Mmp10 is a critical lung cancer stem cell gene and novel therapeutic target for lung cancer stem cells. PMID- 22545097 TI - Co-expression of alpha9beta1 integrin and VEGF-D confers lymphatic metastatic ability to a human breast cancer cell line MDA-MB-468LN. AB - INTRODUCTION AND OBJECTIVES: Lymphatic metastasis is a common occurrence in human breast cancer, mechanisms remaining poorly understood. MDA-MB-468LN (468LN), a variant of the MDA-MB-468GFP (468GFP) human breast cancer cell line, produces extensive lymphatic metastasis in nude mice. 468LN cells differentially express alpha9beta1 integrin, a receptor for lymphangiogenic factors VEGF-C/-D. We explored whether (1) differential production of VEGF-C/-D by 468LN cells provides an autocrine stimulus for cellular motility by interacting with alpha9beta1 and a paracrine stimulus for lymphangiogenesis in vitro as measured with capillary-like tube formation by human lymphatic endothelial cells (HMVEC-dLy); (2) differential expression of alpha9 also promotes cellular motility/invasiveness by interacting with macrophage derived factors; (3) stable knock-down of VEGF-D or alpha9 in 468LN cells abrogates lymphangiogenesis and lymphatic metastasis in vivo in nude mice. RESULTS: A comparison of expression of cyclo-oxygenase (COX)-2 (a VEGF-C/-D inducer), VEGF-C/-D and their receptors revealed little COX-2 expression by either cells. However, 468LN cells showed differential VEGF-D and alpha9beta1 expression, VEGF-D secretion, proliferative, migratory/invasive capacities, latter functions being stimulated further with VEGF-D. The requirement of alpha9beta1 for native and VEGF-D-stimulated proliferation, migration and Erk activation was demonstrated by treating with alpha9beta1 blocking antibody or knock-down of alpha9. An autocrine role of VEGF-D in migration was shown by its impairment by silencing VEGF-D and restoration with VEGF-D. 468LN cells and their soluble products stimulated tube formation, migration/invasiveness of HMVEC-dLy cell in a VEGF-D dependent manner as indicated by the loss of stimulation by silencing VEGF-D in 468LN cells. Furthermore, 468LN cells showed alpha9-dependent stimulation of migration/invasiveness by macrophage products. Finally, capacity for intra-tumoral lymphangiogenesis and lymphatic metastasis in nude mice was completely abrogated by stable knock-down of either VEGF-D or alpha9 in 468LN cells. CONCLUSION: Differential capacity for VEGF-D production and alpha9beta1 integrin expression by 468LN cells jointly contributed to their lymphatic metastatic phenotype. PMID- 22545098 TI - Modulation of the activity of Sp transcription factors by mithramycin analogues as a new strategy for treatment of metastatic prostate cancer. AB - Deregulated activity of transcription factors (TFs) of the Sp/KLF family, like Sp1, Sp3 and Sp4, and consequent over-expression of Sp-regulated genes occur frequently in human cancers. This provides the rationale for development of inhibitors of Sp TFs as cancer therapeutics. Mithramycin A (MTM-A) is a natural polyketide that binds GC-rich DNA sequences, inhibits activity of Sp TFs and exhibits potent antitumor activity in experimental systems. However, clinical use of MTM-A is limited by the severe toxicity of the compound. Here, we studied two MTM-A analogues, which had been generated by genetically engineering of the MTM-A biosynthetic pathway, and evaluated their activity in human prostate cancer in cell cultures and mouse models. The compounds, named MTM-SDK and MTM-SK, were highly effective in vitro inhibiting proliferation of prostate cancer cells and transcription of Sp-regulated genes by blocking binding of Sp proteins to the gene promoters. When administered to mice, both compounds were well tolerated with maximum tolerated doses of MTM-SDK and MTM-SK, respectively, 4- and 32- fold higher than MTM-A. After systemic administration, both compounds were cleared rapidly from the bloodstream but maintained plasma levels well above the active concentrations required in vitro for inhibition of Sp TF activity and cell proliferation. Consistently, MTM-SDK and MTM-SK inhibited transcription of Sp regulated genes in prostate tumor xenografts and exhibited potent antitumor activity in subcutaneous and metastatic tumor xenograft models with no or minimal toxicity. Taken together, these data indicate that MTM-SDK and MTM-SK possess significantly improved pharmacological and toxicological properties compared to MTM-A and represent promising drugs for treatment of advanced prostate cancer. PMID- 22545099 TI - APC/C-mediated degradation of dsRNA-binding protein 4 (DRB4) involved in RNA silencing. AB - BACKGROUND: Selective protein degradation via the ubiquitin-26S proteasome is a major mechanism underlying DNA replication and cell division in all Eukaryotes. In particular, the APC/C (Anaphase Promoting Complex or Cyclosome) is a master ubiquitin protein ligase (E3) that targets regulatory proteins for degradation allowing sister chromatid separation and exit from mitosis. Interestingly, recent work also indicates that the APC/C remains active in differentiated animal and plant cells. However, its role in post-mitotic cells remains elusive and only a few substrates have been characterized. METHODOLOGY/PRINCIPAL FINDINGS: In order to identify novel APC/C substrates, we performed a yeast two-hybrid screen using as the bait Arabidopsis APC10/DOC1, one core subunit of the APC/C, which is required for substrate recruitment. This screen identified DRB4, a double stranded RNA binding protein involved in the biogenesis of different classes of small RNA (sRNA). This protein interaction was further confirmed in vitro and in plant cells. Moreover, APC10 interacts with DRB4 through the second dsRNA binding motif (dsRBD2) of DRB4, which is also required for its homodimerization and binding to its Dicer partner DCL4. We further showed that DRB4 protein accumulates when the proteasome is inactivated and, most importantly, we found that DRB4 stability depends on APC/C activity. Hence, depletion of Arabidopsis APC/C activity by RNAi leads to a strong accumulation of endogenous DRB4, far beyond its normal level of accumulation. However, we could not detect any defects in sRNA production in lines where DRB4 was overexpressed. CONCLUSIONS/SIGNIFICANCE: Our work identified a first plant substrate of the APC/C, which is not a regulator of the cell cycle. Though we cannot exclude that APC/C-dependent degradation of DRB4 has some regulatory roles under specific growth conditions, our work rather points to a housekeeping function of APC/C in maintaining precise cellular-protein concentrations and homeostasis of DRB4. PMID- 22545100 TI - Variation in prices charged to patients for specialty intraocular lenses inserted during universally covered cataract surgery. AB - BACKGROUND: Patients often pay for specialty intraocular lenses (IOLs) for cataract surgery covered by universal insurance. This practice creates the potential for inequitable pricing where the medical service provider is also the retailer. We measured the variation in prices between cataract surgeons for the same IOL and associated testing. METHODS: We telephoned every cataract surgeon in Ontario, Canada, and asked their price for the most common type of specialty IOL as a prospective patient. We measured the total prices quoted and variation between providers. RESULTS: We contacted 404 ophthalmologists. There were 256 that performed cataract surgery but 127 offered the most commonly employed specialty IOL and would provide a price to patients over the telephone. We obtained prices from all 127 ophthalmologists. Prices for the same lens and associated testing varied substantially between ophthalmologists from $358 to $2790 (median $615, interquartile range $528-$915). There was variation in all components of the total out-of-pocket price, including the price for the IOL itself, charges for uninsured eye measurements, and non-specific supplemental fees. CONCLUSION: Although cataract surgery is covered by public health insurance, some ophthalmologists charge much more than others for the same specialty IOL and associated testing. Greater access to price information and better regulatory control could help ensure patients receive fair value for out of-pocket health expenses. PMID- 22545101 TI - RAB-5 controls the cortical organization and dynamics of PAR proteins to maintain C. elegans early embryonic polarity. AB - In all organisms, cell polarity is fundamental for most aspects of cell physiology. In many species and cell types, it is controlled by the evolutionarily conserved PAR-3, PAR-6 and aPKC proteins, which are asymmetrically localized at the cell cortex where they define specific domains. While PAR proteins define the antero-posterior axis of the early C. elegans embryo, the mechanism controlling their asymmetric localization is not fully understood. Here we studied the role of endocytic regulators in embryonic polarization and asymmetric division. We found that depleting the early endosome regulator RAB-5 results in polarity-related phenotypes in the early embryo. Using Total Internal Reflection Fluorescence (TIRF) microscopy, we observed that PAR-6 is localized at the cell cortex in highly dynamic puncta and depleting RAB-5 decreased PAR-6 cortical dynamics during the polarity maintenance phase. Depletion of RAB-5 also increased PAR-6 association with clathrin heavy chain (CHC-1) and this increase depended on the presence of the GTPase dynamin, an upstream regulator of endocytosis. Interestingly, further analysis indicated that loss of RAB-5 leads to a disorganization of the actin cytoskeleton and that this occurs independently of dynamin activity. Our results indicate that RAB-5 promotes C. elegans embryonic polarity in both dynamin-dependent and -independent manners, by controlling PAR-6 localization and cortical dynamics through the regulation of its association with the cell cortex and the organization of the actin cytoskeleton. PMID- 22545102 TI - Germline BAP1 inactivation is preferentially associated with metastatic ocular melanoma and cutaneous-ocular melanoma families. AB - BACKGROUND: BAP1 has been shown to be a target of both somatic alteration in high risk ocular melanomas (OM) and germline inactivation in a few individuals from cancer-prone families. These findings suggest that constitutional BAP1 changes may predispose individuals to metastatic OM and that familial permeation of deleterious alleles could delineate a new cancer syndrome. DESIGN: To characterize BAP1's contribution to melanoma risk, we sequenced BAP1 in a set of 100 patients with OM, including 50 metastatic OM cases and 50 matched non metastatic OM controls, and 200 individuals with cutaneous melanoma (CM) including 7 CM patients from CM-OM families and 193 CM patients from CM-non-OM kindreds. RESULTS: Germline BAP1 mutations were detected in 4/50 patients with metastatic OM and 0/50 cases of non-metastatic OM (8% vs. 0%, p = 0.059). Since 2/4 of the BAP1 carriers reported a family history of CM, we analyzed 200 additional hereditary CM patients and found mutations in 2/7 CM probands from CM OM families and 1/193 probands from CM-non-OM kindreds (29% vs. 0.52%, p = .003). Germline mutations co-segregated with both CM and OM phenotypes and were associated with the presence of unique nevoid melanomas and highly atypical nevoid melanoma-like melanocytic proliferations (NEMMPs). Interestingly, 7/14 germline variants identified to date reside in C-terminus suggesting that the BRCA1 binding domain is important in cancer predisposition. CONCLUSION: Germline BAP1 mutations are associated with a more aggressive OM phenotype and a recurrent phenotypic complex of cutaneous/ocular melanoma, atypical melanocytic proliferations and other internal neoplasms (ie. COMMON syndrome), which could be a useful clinical marker for constitutive BAP1 inactivation. PMID- 22545103 TI - Association analysis of single nucleotide polymorphisms at five loci: comparison between atopic dermatitis and asthma in the Chinese Han population. AB - Atopic diseases, such as atopic dermatitis (AD) and asthma, are closely related to clinical phenotypes with hypersensitivity, and often share some similar genetic and pathogenic bases. Our recent GWAS identified three susceptibility gene/loci FLG (rs11204971 and rs3126085), 5q22.1 (rs10067777, rs7701890, rs13360927 and rs13361382) and 20q13.33 (rs6010620) to AD. The effect of these AD associated polymorphisms in asthma is so far unknown. To investigate whether AD relevant genetic variants is identical to asthma and reveal the differences in genetic factors between AD and asthma in Chinese Han population, seven AD associated single nucleotide polymorphisms (SNPs) as well as 3 other SNPs (rs7936562 and rs7124842 at 11q13.5 and rs4982958 at 14q11.2) from our previous AD GWAS were genotyped in 463 asthma patients and 985 controls using Sequenom MassArray system. We found rs4982958 at 14q11.2 was significantly associated with asthma (P = 3.04*10(-4), OR = 0.73). We also detected one significant risk haplotype GGGA from the 4 SNPs (rs10067777, rs7701890, rs13360927 and rs13361382) at 5q22.1 in AD cases (P(correction) = 3.60*10(-10), OR = 1.26), and the haplotype was suggestive of risk in asthma cases in this study (P = 0.014, P(correction) = 0.084, OR = 1.38). These SNPs (rs11204971, rs3126085, rs7936562, rs712484 and rs6010620) at AD susceptibility genes/loci FLG, 11q13.5 and 20q13.33 were not associated with asthma in this study. Our results further comfirmed that 14q11.2 was an important candidate locus for asthma and demonstrated that 5q22.1 might be shared by AD and asthma in Chinese Han population. PMID- 22545104 TI - Novel small-molecule inhibitors of hepatitis C virus entry block viral spread and promote viral clearance in cell culture. AB - Combinations of direct-acting anti-virals offer the potential to improve the efficacy, tolerability and duration of the current treatment regimen for hepatitis C virus (HCV) infection. Viral entry represents a distinct therapeutic target that has been validated clinically for a number of pathogenic viruses. To discover novel inhibitors of HCV entry, we conducted a high throughput screen of a proprietary small-molecule compound library using HCV pseudoviral particle (HCVpp) technology. We independently discovered and optimized a series of 1,3,5 triazine compounds that are potent, selective and non-cytotoxic inhibitors of HCV entry. Representative compounds fully suppress both cell-free virus and cell-to cell spread of HCV in vitro. We demonstrate, for the first time, that long term treatment of an HCV cell culture with a potent entry inhibitor promotes sustained viral clearance in vitro. We have confirmed that a single amino acid variant, V719G, in the transmembrane domain of E2 is sufficient to confer resistance to multiple compounds from the triazine series. Resistance studies were extended by evaluating both the fusogenic properties and growth kinetics of drug-induced and natural amino acid variants in the HCVpp and HCV cell culture assays. Our results indicate that amino acid variations at position 719 incur a significant fitness penalty. Introduction of I719 into a genotype 1b envelope sequence did not affect HCV entry; however, the overall level of HCV replication was reduced compared to the parental genotype 1b/2a HCV strain. Consistent with these findings, I719 represents a significant fraction of the naturally occurring genotype 1b sequences. Importantly, I719, the most relevant natural polymorphism, did not significantly alter the susceptibility of HCV to the triazine compounds. The preclinical properties of these triazine compounds support further investigation of entry inhibitors as a potential novel therapy for HCV infection. PMID- 22545105 TI - A single nucleotide polymorphism of the neuropeptide B/W receptor-1 gene influences the evaluation of facial expressions. AB - Neuropeptide B/W receptor-1 (NPBWR1) is expressed in discrete brain regions in rodents and humans, with particularly strong expression in the limbic system, including the central nucleus of the amygdala. Recently, Nagata-Kuroiwa et al. reported that Npbwr1(-/-) mice showed changes in social behavior, suggesting that NPBWR1 plays important roles in the emotional responses of social interactions.The human NPBWR1 gene has a single nucleotide polymorphism at nucleotide 404 (404A>T; SNP rs33977775). This polymorphism results in an amino acid change, Y135F. The results of an in vitro experiment demonstrated that this change alters receptor function. We investigated the effect of this variation on emotional responses to stimuli of showing human faces with four categories of emotional expressions (anger, fear, happiness, and neutral). Subjects' emotional levels on seeing these faces were rated on scales of hedonic valence, emotional arousal, and dominance (V-A-D). A significant genotype difference was observed in valence evaluation; the 404AT group perceived facial expressions more pleasantly than did the 404AA group, regardless of the category of facial expression. Statistical analysis of each combination of [V-A-D and facial expression] also showed that the 404AT group tended to feel less submissive to an angry face than did the 404AA group. Thus, a single nucleotide polymorphism of NPBWR1 seems to affect human behavior in a social context. PMID- 22545106 TI - Effects of DHA-rich n-3 fatty acid supplementation on gene expression in blood mononuclear leukocytes: the OmegAD study. AB - BACKGROUND: Dietary fish oil, rich in n-3 fatty acids (n-3 FAs), e.g. docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), regulate inflammatory reactions by various mechanisms, e.g. gene activation. However, the effects of long-term treatment with DHA and EPA in humans, using genome wide techniques, are poorly described. Hence, our aim was to determine the effects of 6 mo of dietary supplementation with an n-3 FA preparation rich in DHA on global gene expression in peripheral blood mononuclear cells. METHODS AND FINDINGS: In the present study, blood samples were obtained from a subgroup of 16 patients originating from the randomized double-blind, placebo-controlled OmegAD study, where 174 Alzheimer disease (AD) patients received daily either 1.7 g of DHA and 0.6 g EPA or placebo for 6 months. In blood samples obtained from 11 patients receiving n-3 FA and five placebo, expressions of approximately 8000 genes were assessed by gene array. Significant changes were confirmed by real-time PCR. At 6 months, the n-3 FAs group displayed significant rises of DHA and EPA plasma concentrations, as well as up- and down-regulation of nine and ten genes, respectively, was noticed. Many of these genes are involved in inflammation regulation and neurodegeneration, e.g. CD63, MAN2A1, CASP4, LOC399491, NAIP, and SORL1 and in ubiqutination processes, e.g. ANAPC5 and UBE2V1. Down-regulations of ANAPC5 and RHOB correlated to increases of plasma DHA and EPA levels. CONCLUSIONS: We suggest that 6 months of dietary n-3 FA supplementation affected expression of genes that might influence inflammatory processes and could be of significance for AD. TRIAL REGISTRATION: ClinicalTrials.gov NCT00211159. PMID- 22545107 TI - Fetal window of vulnerability to airborne polycyclic aromatic hydrocarbons on proportional intrauterine growth restriction. AB - BACKGROUND: Although the entire duration of fetal development is generally considered a highly susceptible period, it is of public health interest to determine a narrower window of heightened vulnerability to polycyclic aromatic hydrocarbons (PAHs) in humans. We posited that exposure to PAHs during the first trimester impairs fetal growth more severely than a similar level of exposure during the subsequent trimesters. METHODS: In a group of healthy, non-smoking pregnant women with no known risks of adverse birth outcomes, personal exposure to eight airborne PAHs was monitored once during the second trimester for the entire cohort (n = 344), and once each trimester within a subset (n = 77). Both air monitoring and self-reported PAH exposure data were used in order to statistically estimate PAH exposure during the entire gestational period for each individual newborn. RESULTS: One natural-log unit increase in prenatal exposure to the eight summed PAHs during the first trimester was associated with the largest decrement in the Fetal Growth Ratio (FGR) (-3%, 95% Confidence Interval (CI), -5 to -0%), birthweight (-105 g, 95% CI, -188 to -22 g), and birth length ( 0.78 cm, 95% CI, -1.30 to -0.26 cm), compared to the unit effects of PAHs during the subsequent trimesters, after accounting for confounders. Furthermore, a unit exposure during the first trimester was associated with the largest elevation in Cephalization Index (head to weight ratio) (3 MUm/g, 95% CI, 1 to 5 MUm/g). PAH exposure was not associated with evidence of asymmetric growth restriction in this cohort. CONCLUSION: PAH exposure appears to exert the greatest adverse effect on fetal growth during the first trimester. The present data support the need for the protection of pregnant women and the embryo/fetus, particularly during the earliest stage of pregnancy. PMID- 22545108 TI - Modeling the impact of integrating HIV and outpatient health services on patient waiting times in an urban health clinic in Zambia. AB - BACKGROUND: Rapid scale up of HIV treatment programs in sub-Saharan Africa has refueled the long-standing health policy debate regarding the merits and drawbacks of vertical and integrated system. Recent pilots of integrating outpatient and HIV services have shown an improvement in some patient outcomes but deterioration in waiting times, which can lead to worse health outcomes in the long run. METHODS: A pilot intervention involving integration of outpatient and HIV services in an urban primary care facility in Lusaka, Zambia was studied. Data on waiting time of patients during two seven-day periods before and six months after the integration were collected using a time and motion study. Statistical tests were conducted to investigate whether the two observation periods differed in operational details such as staffing, patient arrival rates, mix of patients etc. A discrete event simulation model was constructed to facilitate a fair comparison of waiting times before and after integration. The simulation model was also used to develop alternative configurations of integration and to estimate the resulting waiting times. RESULTS: Comparison of raw data showed that waiting times increased by 32% and 36% after integration for OPD and ART patients respectively (p<0.01). Using simulation modeling, we found that a large portion of this increase could be explained by changes in operational conditions before and after integration such as reduced staff availability (p<0.01) and longer breaks between consecutive patients (p<0.05). Controlling for these differences, integration of services, per se, would have resulted in a significant decrease in waiting times for OPD and a moderate decrease for HIV services. CONCLUSIONS: Integrating health services has the potential of reducing waiting times due to more efficient use of resources. However, one needs to ensure that other operational factors such as staff availability are not adversely affected due to integration. PMID- 22545109 TI - Zinc sensing receptor signaling, mediated by GPR39, reduces butyrate-induced cell death in HT29 colonocytes via upregulation of clusterin. AB - Zinc enhances epithelial proliferation, protects the digestive epithelial layer and has profound antiulcerative and antidiarrheal roles in the colon. Despite the clinical significance of this ion, the mechanisms linking zinc to these cellular processes are poorly understood. We have previously identified an extracellular Zn(2+) sensing G-protein coupled receptor (ZnR) that activates Ca(2+) signaling in colonocytes, but its molecular identity as well as its effects on colonocytes' survival remained elusive. Here, we show that Zn(2+), by activation of the ZnR, protects HT29 colonocytes from butyrate induced cell death. Silencing of the G protein coupled receptor GPR39 expression abolished ZnR-dependent Ca(2+) release and Zn(2+)-dependent survival of butyrate-treated colonocytes. Importantly, GPR39 also mediated ZnR-dependent upregulation of Na(+)/H(+) exchange activity as this activity was found in native colon tissue but not in tissue obtained from GPR39 knock-out mice. Although ZnR-dependent upregulation of Na(+)/H(+) exchange reduced the cellular acid load induced by butyrate, it did not rescue HT29 cells from butyrate induced cell death. ZnR/GPR39 activation however, increased the expression of the anti-apoptotic protein clusterin in butyrate-treated cells. Furthermore, silencing of clusterin abolished the Zn(2+)-dependent survival of HT29 cells. Altogether, our results demonstrate that extracellular Zn(2+), acting through ZnR, regulates intracellular pH and clusterin expression thereby enhancing survival of HT29 colonocytes. Moreover, we identify GPR39 as the molecular moiety of ZnR in HT29 and native colonocytes. PMID- 22545110 TI - Heme oxygenase isoforms differ in their subcellular trafficking during hypoxia and are differentially modulated by cytochrome P450 reductase. AB - Heme oxygenase (HO) degrades heme in concert with NADPH cytochrome P450 reductase (CPR) which donates electrons to the reaction. Earlier studies reveal the importance of the hydrophobic carboxy-terminus of HO-1 for anchorage to the endoplasmic reticulum (ER) which facilitates the interaction with CPR. In addition, HO-1 has been shown to undergo regulated intramembrane proteolysis of the carboxy-terminus during hypoxia and subsequent translocation to the nucleus. Translocated nuclear HO-1 was demonstrated to alter binding of transcription factors and to alter gene expression. Little is known about the homologous membrane anchor of the HO-2 isoform. The current work is the first systematic analysis in a eukaryotic system that demonstrates the crucial role of the membrane anchor of HO-2 for localization at the endoplasmic reticulum, oligomerization and interaction with CPR. We show that although the carboxy terminal deletion mutant of HO-2 is found in the nucleus, translocation of HO-2 to the nucleus does not occur under conditions of hypoxia. Thus, we demonstrate that proteolytic regulation and nuclear translocation under hypoxic conditions is specific for HO-1. In addition we show for the first time that CPR prevents this translocation and promotes oligomerization of HO-1. Based on these findings, CPR may modulate gene expression via the amount of nuclear HO-1. This is of particular relevance as CPR is a highly polymorphic gene and deficiency syndromes of CPR have been described in humans. PMID- 22545111 TI - Benzoxazinoids in root exudates of maize attract Pseudomonas putida to the rhizosphere. AB - Benzoxazinoids, such as 2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one (DIMBOA), are secondary metabolites in grasses. In addition to their function in plant defence against pests and diseases above-ground, benzoxazinoids (BXs) have also been implicated in defence below-ground, where they can exert allelochemical or antimicrobial activities. We have studied the impact of BXs on the interaction between maize and Pseudomonas putida KT2440, a competitive coloniser of the maize rhizosphere with plant-beneficial traits. Chromatographic analyses revealed that DIMBOA is the main BX compound in root exudates of maize. In vitro analysis of DIMBOA stability indicated that KT2440 tolerance of DIMBOA is based on metabolism dependent breakdown of this BX compound. Transcriptome analysis of DIMBOA-exposed P. putida identified increased transcription of genes controlling benzoate catabolism and chemotaxis. Chemotaxis assays confirmed motility of P. putida towards DIMBOA. Moreover, colonisation essays in soil with Green Fluorescent Protein (GFP)-expressing P. putida showed that DIMBOA-producing roots of wild type maize attract significantly higher numbers of P. putida cells than roots of the DIMBOA-deficient bx1 mutant. Our results demonstrate a central role for DIMBOA as a below-ground semiochemical for recruitment of plant-beneficial rhizobacteria during the relatively young and vulnerable growth stages of maize. PMID- 22545112 TI - Gene expression analysis implicates a death receptor pathway in schizophrenia pathology. AB - An increase in apoptotic events may underlie neuropathology in schizophrenia. By data-mining approaches, we identified significant expression changes in death receptor signaling pathways in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia, particularly implicating the Tumor Necrosis Factor Superfamily member 6 (FAS) receptor and the Tumor Necrosis Factor [ligand] Superfamily member 13 (TNFSF13) in schizophrenia. We sought to confirm and replicate in an independent tissue collection the noted mRNA changes with quantitative real-time RT-PCR. To test for regional and diagnostic specificity, tissue from orbital frontal cortex (OFC) was examined and a bipolar disorder group included. In schizophrenia, we confirmed and replicated significantly increased expression of TNFSF13 mRNA in the DLPFC. Also, a significantly larger proportion of subjects in the schizophrenia group had elevated FAS receptor expression in the DLPFC relative to unaffected controls. These changes were not observed in the bipolar disorder group. In the OFC, there were no significant differences in TNFSF13 or FAS receptor mRNA expression. Decreases in BH3 interacting domain death agonist (BID) mRNA transcript levels were found in the schizophrenia and bipolar disorder groups affecting both the DLPFC and the OFC. We tested if TNFSF13 mRNA expression correlated with neuronal mRNAs in the DLPFC, and found significant negative correlations with interneuron markers, parvalbumin and somatostatin, and a positive correlation with PPP1R9B (spinophilin), but not DLG4 (PSD-95). The expression of TNFSF13 mRNA in DLPFC correlated negatively with tissue pH, but decreasing pH in cultured cells did not cause increased TNFSF13 mRNA nor did exogenous TNFSF13 decrease pH. We concluded that increased TNFSF13 expression may be one of several cell-death cytokine abnormalities that contribute to the observed brain pathology in schizophrenia, and while increased TNFSF13 may be associated with lower brain pH, the change is not necessarily causally related to brain pH. PMID- 22545113 TI - Reduced expression of inflammatory genes in deceased donor kidneys undergoing pulsatile pump preservation. AB - BACKGROUND: The use of expanded criteria donor kidneys (ECD) had been associated with worse outcomes. Whole gene expression of pre-implantation allograft biopsies from deceased donor kidneys (DDKs) was evaluated to compare the effect of pulsatile pump preservation (PPP) vs. cold storage preservation (CSP) on standard and ECD kidneys. METHODOLOGY/PRINCIPAL FINDINGS: 99 pre-implantation DDK biopsies were studied using gene expression with GeneChips. Kidneys transplant recipients were followed post transplantation for 35.8 months (range = 24-62). The PPP group included 60 biopsies (cold ischemia time (CIT) = 1,367+/-509 minutes) and the CSP group included 39 biopsies (CIT = 1,022+/-485 minutes) (P<0.001). Donor age (42.0+/-14.6 vs. 34.1+/-14.2 years, P = 0.009) and the percentage of ECD kidneys (PPP = 35% vs. CSP = 12.8%, P = 0.012) were significantly different between groups. A two-sample t-test was performed, and probe sets having a P<0.001 were considered significant. Probe set level linear models were fit using cold ischemia time and CSP/PPP as independent variables to determine significant probe sets (P<0.001) between groups after adjusting for cold ischemia time. Thus, 43 significant genes were identified (P<0.001). Over-expression of genes associated with inflammation (CD86, CD209, CLEC4, EGFR2, TFF3, among others) was observed in the CSP group. Cell-to-cell signaling and interaction, and antigen presentation were the most important pathways with genes significantly over-expressed in CSP kidneys. When the analysis was restricted to ECD kidneys, genes involved in inflammation were also differentially up-regulated in ECD kidneys undergoing CSP. However, graft survival at the end of the study was similar between groups (P = 0.2). Moreover, the incidence of delayed graft function was not significant between groups. CONCLUSIONS/SIGNIFICANCE: Inflammation was the most important up regulated pattern associated with pre-implantation biopsies undergoing CSP even when the PPP group has a larger number of ECD kidneys. No significant difference was observed in delayed graft function incidence and graft function post transplantation. These findings support the use of PPP in ECD donor kidneys. PMID- 22545114 TI - Homeodomain-interacting protein kinase (HIPK)-1 is required for splenic B cell homeostasis and optimal T-independent type 2 humoral response. AB - The homeodomain-interacting protein kinase (HIPK) family is comprised of four highly related serine/threonine kinases originally identified as co-repressors for various homeodomain-containing transcription factors. The HIPKs have been shown to be involved in growth regulation and apoptosis, with numerous studies highlighting HIPK regulation of the tumor suppressor p53. In this study, we have discovered a B cell homeostatic defect in HIPK1-deficient (HIPK1(-/-)) mice. Lymphopoietic populations within the thymus and bone marrow of HIPK1(-/-) mice appeared normal based upon FACS analysis; however, the spleen exhibited a reduced number of total B cells with a significant loss of transitional-1 and follicular B cell populations. Interestingly, the marginal zone B cell population was expanded in HIPK1(-/-) mice, yielding an increased frequency of these cells. HIPK1(-/-) B cells exhibited impaired cell division in response to B cell receptor cross-linking in vitro based upon thymidine incorporation or CFSE dilution; however, the addition of CD40L rescued HIPK1(-/-) proliferation to wild type levels. Despite the expanded MZ B cell population in the HIPK1(-/-) mice, the T-independent type 2 humoral response was impaired. These data identify HIPK1 as a novel kinase required for optimal B cell function in mice. PMID- 22545115 TI - In vivo inhibitory effect on the biofilm formation of Candida albicans by liverwort derived riccardin D. AB - Riccardin D, a macrocyclic bisbibenzyl isolated from Chinese liverwort Dumortiera hirsute, has been proved to have inhibitory effect on biofilms formation of Candida albicans in in vitro study. Our present study aims to investigate the in vivo effect and mechanisms of riccardin D against C. albicans biofilms when used alone or in combination with clinical using antifungal agent fluconazole. XTT reduction assay revealed riccardin D had both prophylactic and therapeutic effect against C. albicans biofilms formation in a dose-dependent manner when using a central venous catheter related infective animal model. Scanning electron microscope and laser confocal scanning microscope showed that the morphology of biofilms was altered remarkably after riccardin D treatment, especially hypha growth inhibition. To uncover the underlying molecular mechanisms, quantitative real-time RT-PCR was performed to observe the variation of related genes. The downregulation of hypha-specific genes such as ALS1, ALS3, ECE1, EFG1, HWP1 and CDC35 following riccardin D treatment suggested riccardin D inhibited the Ras cAMP-Efg pathway to retard the hypha formation, then leading to the defect of biofilms maturation. Moreover, riccardin D displayed an increased antifungal activity when administered in combination with fluconazole. Our study provides a potential clinical application to eliminate the biofilms of relevant pathogens. PMID- 22545116 TI - Differential modulation of retinal degeneration by Ccl2 and Cx3cr1 chemokine signalling. AB - Microglia and macrophages are recruited to sites of retinal degeneration where local cytokines and chemokines determine protective or neurotoxic microglia responses. Defining the role of Ccl2-Ccr2 and Cx3cl1-Cx3cr1 signalling for retinal pathology is of particular interest because of its potential role in age related macular degeneration (AMD). Ccl2, Ccr2, and Cx3cr1 signalling defects impair macrophage trafficking, but have, in several conflicting studies, been reported to show different degrees of age-related retinal degeneration. Ccl2/Cx3cr1 double knockout (CCDKO) mice show an early onset retinal degeneration and have been suggested as a model for AMD. In order to understand phenotypic discrepancies in different chemokine knockout lines and to study how defects in Ccl2 and/or Cx3cr1 signalling contribute to the described early onset retinal degeneration, we defined primary and secondary pathological events in CCDKO mice. To control for genetic background variability, we compared the original phenotype with that of single Ccl2, Cx3cr1 and Ccl2/Cx3cr1 double knockout mice obtained from backcrosses of CCDKO with C57Bl/6 mice. We found that the primary pathological event in CCDKO mice develops in the inferior outer nuclear layer independently of light around postnatal day P14. RPE and vascular lesions develop secondarily with increasing penetrance with age and are clinically similar to retinal telangiectasia not to choroidal neovascularisation. Furthermore, we provide evidence that a third autosomal recessive gene causes the degeneration in CCDKO mice and in all affected re-derived lines and subsequently demonstrated co segregation of the naturally occurring RD8 mutation in the Crb1 gene. By comparing CCDKO mice with re-derived CCl2(-/-)/Crb1(Rd8/RD8), Cx3cr1(-/ )/Crb1(Rd8/RD8) and CCl2(-/-)/Cx3cr1(-/-)/Crb1(Rd8/RD8) mice, we observed a differential modulation of the retinal phenotype by genetic background and both chemokine signalling pathways. These findings indicate that CCDKO mice are not a model of AMD, but a model for an inherited retinal degeneration that is differentially modulated by Ccl2-Ccr2 and Cx3cl1-Cx3cr1 chemokine signalling. PMID- 22545117 TI - Costs and cost-effectiveness of training traditional birth attendants to reduce neonatal mortality in the Lufwanyama Neonatal Survival study (LUNESP). AB - BACKGROUND: The Lufwanyama Neonatal Survival Project ("LUNESP") was a cluster randomized, controlled trial that showed that training traditional birth attendants (TBAs) to perform interventions targeting birth asphyxia, hypothermia, and neonatal sepsis reduced all-cause neonatal mortality by 45%. This companion analysis was undertaken to analyze intervention costs and cost-effectiveness, and factors that might improve cost-effectiveness. METHODS AND FINDINGS: We calculated LUNESP's financial and economic costs and the economic cost of implementation for a forecasted ten-year program (2011-2020). In each case, we calculated the incremental cost per death avoided and disability-adjusted life years (DALYs) averted in real 2011 US dollars. The forecasted 10-year program analysis included a base case as well as 'conservative' and 'optimistic' scenarios. Uncertainty was characterized using one-way sensitivity analyses and a multivariate probabilistic sensitivity analysis. The estimated financial and economic costs of LUNESP were $118,574 and $127,756, respectively, or $49,469 and $53,550 per year. Fixed costs accounted for nearly 90% of total costs. For the 10 year program, discounted total and annual program costs were $256,455 and $26,834 respectively; for the base case, optimistic, and conservative scenarios, the estimated cost per death avoided was $1,866, $591, and $3,024, and cost per DALY averted was $74, $24, and $120, respectively. Outcomes were robust to variations in local costs, but sensitive to variations in intervention effect size, number of births attended by TBAs, and the extent of foreign consultants' participation. CONCLUSIONS: Based on established guidelines, the strategy of using trained TBAs to reduce neonatal mortality was 'highly cost effective'. We strongly recommend consideration of this approach for other remote rural populations with limited access to health care. PMID- 22545118 TI - Inflammation-driven reprogramming of CD4+ Foxp3+ regulatory T cells into pathogenic Th1/Th17 T effectors is abrogated by mTOR inhibition in vivo. AB - While natural CD4(+)Foxp3(+) regulatory T (nT(REG)) cells have long been viewed as a stable and distinct lineage that is committed to suppressive functions in vivo, recent evidence supporting this notion remains highly controversial. We sought to determine whether Foxp3 expression and the nT(REG) cell phenotype are stable in vivo and modulated by the inflammatory microenvironment. Here, we show that Foxp3(+) nT(REG) cells from thymic or peripheral lymphoid organs reveal extensive functional plasticity in vivo. We show that nT(REG) cells readily lose Foxp3 expression, destabilizing their phenotype, in turn, enabling them to reprogram into Th1 and Th17 effector cells. nT(REG) cell reprogramming is a characteristic of the entire Foxp3(+) nT(REG) population and the stable Foxp3(NEG) T(REG) cell phenotype is associated with a methylated foxp3 promoter. The extent of nT(REG) cell reprogramming is modulated by the presence of effector T cell-mediated signals, and occurs independently of variation in IL-2 production in vivo. Moreover, the gut microenvironment or parasitic infection favours the reprogramming of Foxp3(+) T(REG) cells into effector T cells and promotes host immunity. IL-17 is predominantly produced by reprogrammed Foxp3(+) nT(REG) cells, and precedes Foxp3 down-regulation, a process accentuated in mesenteric sites. Lastly, mTOR inhibition with the immunosuppressive drug, rapamycin, stabilizes Foxp3 expression in T(REG) cells and strongly inhibits IL-17 but not RORgammat expression in reprogrammed Foxp3(-) T(REG) cells. Overall, inflammatory signals modulate mTOR signalling and influence the stability of the Foxp3(+) nT(REG) cell phenotype. PMID- 22545119 TI - Construction of vascular tissues with macro-porous nano-fibrous scaffolds and smooth muscle cells enriched from differentiated embryonic stem cells. AB - Vascular smooth muscle cells (SMCs) have been broadly used for constructing tissue-engineered blood vessels. However, the availability of mature SMCs from donors or patients is very limited. Derivation of SMCs by differentiating embryonic stem cells (ESCs) has been reported, but not widely utilized in vascular tissue engineering due to low induction efficiency and, hence, low SMC purity. To address these problems, SMCs were enriched from retinoic acid induced mouse ESCs with LacZ genetic labeling under the control of SM22alpha promoter as the positive sorting marker in the present study. The sorted SMCs were characterized and then cultured on three-dimensional macro-porous nano-fibrous scaffolds in vitro or implanted subcutaneously into nude mice after being seeded on the scaffolds. Our data showed that the LacZ staining, which reflected the corresponding SMC marker SM22alpha expression level, was efficient as a positive selection marker to dramatically enrich SMCs and eliminate other cell types. After the sorted cells were seeded into the three-dimensional nano-fibrous scaffolds, continuous retinoic acid treatment further enhanced the SMC marker gene expression level while inhibited pluripotent maker gene expression level during the in vitro culture. Meanwhile, after being implanted subcutaneously into nude mice, the implanted cells maintained the positive LacZ staining within the constructs and no teratoma formation was observed. In conclusion, our results demonstrated the potential of SMCs derived from ESCs as a promising cell source for therapeutic vascular tissue engineering and disease model applications. PMID- 22545120 TI - Segregation of regulatory polymorphisms with effects on the gluteus medius transcriptome in a purebred pig population. AB - BACKGROUND: The main goal of the present study was to analyse the genetic architecture of mRNA expression in muscle, a tissue with an outmost economic importance for pig breeders. Previous studies have used F(2) crosses to detect porcine expression QTL (eQTL), so they contributed with data that mostly represents the between-breed component of eQTL variation. Herewith, we have analysed eQTL segregation in an outbred Duroc population using two groups of animals with divergent fatness profiles. This approach is particularly suitable to analyse the within-breed component of eQTL variation, with a special emphasis on loci involved in lipid metabolism. METHODOLOGY/PRINCIPAL FINDINGS: GeneChip Porcine Genome arrays (Affymetrix) were used to determine the mRNA expression levels of gluteus medius samples from 105 Duroc barrows. A whole-genome eQTL scan was carried out with a panel of 116 microsatellites. Results allowed us to detect 613 genome-wide significant eQTL unevenly distributed across the pig genome. A clear predominance of trans- over cis-eQTL, was observed. Moreover, 11 trans regulatory hotspots affecting the expression levels of four to 16 genes were identified. A Gene Ontology study showed that regulatory polymorphisms affected the expression of muscle development and lipid metabolism genes. A number of positional concordances between eQTL and lipid trait QTL were also found, whereas limited evidence of a linear relationship between muscle fat deposition and mRNA levels of eQTL regulated genes was obtained. CONCLUSIONS/SIGNIFICANCE: Our data provide substantial evidence that there is a remarkable amount of within-breed genetic variation affecting muscle mRNA expression. Most of this variation acts in trans and influences biological processes related with muscle development, lipid deposition and energy balance. The identification of the underlying causal mutations and the ascertainment of their effects on phenotypes would allow gaining a fundamental perspective about how complex traits are built at the molecular level. PMID- 22545121 TI - Dobrava-Belgrade hantavirus from Germany shows receptor usage and innate immunity induction consistent with the pathogenicity of the virus in humans. AB - BACKGROUND: Dobrava-Belgrade virus (DOBV) is a European hantavirus causing hemorrhagic fever with renal syndrome (HFRS) in humans with fatality rates of up to 12%. DOBV-associated clinical cases typically occur also in the northern part of Germany where the virus is carried by the striped field mouse (Apodemus agrarius). However, the causative agent responsible for human illness has not been previously isolated. METHODOLOGY/PRINCIPAL FINDINGS: Here we report on characterization of a novel cell culture isolate from Germany obtained from a lung tissue of "spillover" infected yellow necked mouse (A. flavicollis) trapped near the city of Greifswald. Phylogenetic analyses demonstrated close clustering of the new strain, designated Greifswald/Aa (GRW/Aa) with the nucleotide sequence obtained from a northern German HFRS patient. The virus was effectively blocked by specific antibodies directed against beta3 integrins and Decay Accelerating Factor (DAF) indicating that the virus uses same receptors as the highly pathogenic Hantaan virus (HTNV). In addition, activation of selected innate immunity markers as interferon beta and lambda and antiviral protein MxA after viral infection of A549 cells was investigated and showed that the virus modulates the first-line antiviral response in a similar way as HTNV. CONCLUSIONS/SIGNIFICANCE: In summary, our study reveals novel data on DOBV receptor usage and innate immunity induction in relationship to virus pathogenicity and underlines the potency of German DOBV strains to act as human pathogen. PMID- 22545123 TI - A single long day triggers follicle growth in captive female great tits (Parus major) in winter but does not affect laying dates in the wild in spring. AB - In many forest passerine bird species, rapid climate warming has led to a phenological mismatch between the period of maximum nestlings' food requirements and the period of maximum food availability (seasonal caterpillar biomass peak) due to an insufficient advancement of the birds' laying dates. The initiation of laying is preceded by the development of the gonads, which in birds are regressed outside the breeding season. Increasing day length in late winter and early spring triggers a cascade of hormones which induces gonadal development. Since day length is not altered by climate change, one potential restriction to advancing laying date is the seasonal timing of gonadal development. To assess the importance of gonadal growth for timing of reproduction we experimentally manipulated the timing of gonadal development. We show that the growth of the largest follicle of captive female great tits (Parus major) increased after being exposed to just a single long day in winter (20 hours of light followed by 4 hours darkness). We then photostimulated wild female great tits from two study areas in a field experiment in spring for a single day and determined their laying date. These populations differed in the availability of food allowing us to test if food availability in combination with photostimulation affected egg laying dates. Despite an expected difference in the onset of gonadal growth, laying dates of photostimulated females did not differ from control females in both populations. These results suggest that wild great tits are not restricted in the advancement of their laying date by limited gonadal development. PMID- 22545122 TI - ABC transporters B1, C1 and G2 differentially regulate neuroregeneration in mice. AB - BACKGROUND: ATP-binding cassette (ABC) transporters are essential regulators of organismic homeostasis, and are particularly important in protecting the body from potentially harmful exogenous substances. Recently, an increasing number of in vitro observations have indicated a functional role of ABC transporters in the differentiation and maintenance of stem cells. Therefore, we sought to determine brain-related phenotypic changes in animals lacking the expression of distinct ABC transporters (ABCB1, ABCG2 or ABCC1). METHODOLOGY AND PRINCIPAL FINDINGS: Analyzing adult neurogenesis in ABC transporter-deficient animals in vivo and neuronal stem/progenitor cells in vitro resulted in complex findings. In vivo, the differentiation of neuronal progenitors was hindered in ABC transporter deficient mice (ABCB1(0/0)) as evidenced by lowered numbers of doublecortin(+) ( 36%) and calretinin(+) (-37%) cells. In vitro, we confirmed that this finding is not connected to the functional loss of single neural stem/progenitor cells (NSPCs). Furthermore, assessment of activity, exploratory behavior, and anxiety levels revealed behavioral alterations in ABCB1(0/0) and ABCC1(0/0) mice, whereas ABCG2(0/0) mice were mostly unaffected. CONCLUSION AND SIGNIFICANCE: Our data show that single ABC transporter-deficiency does not necessarily impair neuronal progenitor homeostasis on the single NSPC level, as suggested by previous studies. However, loss of distinct ABC transporters impacts global brain homeostasis with far ranging consequences, leading to impaired neurogenic functions in vivo and even to distinct behavioral phenotypes. In addition to the known role of ABC transporters in proteopathies such as Parkinson's disease and Alzheimer's disease, our data highlight the importance of understanding the general function of ABC transporters for the brain's homeostasis and the regeneration potential. PMID- 22545124 TI - Direct stimulation of adult neural stem/progenitor cells in vitro and neurogenesis in vivo by salvianolic acid B. AB - BACKGROUND: Small molecules have been shown to modulate the neurogenesis processes. In search for new therapeutic drugs, the herbs used in traditional medicines for neurogenesis are promising candidates. METHODOLOGY AND PRINCIPAL FINDINGS: We selected a total of 45 natural compounds from Traditional Chinese herbal medicines which are extensively used in China to treat stroke clinically, and tested their proliferation-inducing activities on neural stem/progenitor cells (NSPCs). The screening results showed that salvianolic acid B (Sal B) displayed marked effects on the induction of proliferation of NSPCs. We further demonstrated that Sal B promoted NSPCs proliferation in dose- and time-dependent manners. To explore the molecular mechanism, PI3K/Akt, MEK/ERK and Notch signaling pathways were investigated. Cell proliferation assay demonstrated that Ly294002 (PI3K/Akt inhibitor), but neither U0126 (ERK inhibitor) nor DAPT (Notch inhibitor) inhibited the Sal B-induced proliferation of cells. Western Blotting results showed that stimulation of NSPCs with Sal B enhanced the phosphorylation of Akt, and Ly294002 abolished this effect, confirming the role of Akt in Sal B mediated proliferation of NSPCs. Rats exposed to transient cerebral ischemia were treated for 4 weeks with Sal B from the 7th day after stroke. BrdU incorporation assay results showed that exposure Sal B could maintain the proliferation of NSPCs after cerebral ischemia. Morris water maze test showed that delayed post ischemic treatment with Sal B improved cognitive impairment after stroke in rats. SIGNIFICANCE: Sal B could maintain the NSPCs self-renew and promote proliferation, which was mediated by PI3K/Akt signal pathway. And delayed post ischemic treatment with Sal B improved cognitive impairment after stroke in rats. These findings suggested that Sal B may act as a potential drug in treatment of brain injury or neurodegenerative diseases. PMID- 22545126 TI - Variable copy number, intra-genomic heterogeneities and lateral transfers of the 16S rRNA gene in Pseudomonas. AB - Even though the 16S rRNA gene is the most commonly used taxonomic marker in microbial ecology, its poor resolution is still not fully understood at the intra genus level. In this work, the number of rRNA gene operons, intra-genomic heterogeneities and lateral transfers were investigated at a fine-scale resolution, throughout the Pseudomonas genus. In addition to nineteen sequenced Pseudomonas strains, we determined the 16S rRNA copy number in four other Pseudomonas strains by Southern hybridization and Pulsed-Field Gel Electrophoresis, and studied the intra-genomic heterogeneities by Denaturing Gradient Gel Electrophoresis and sequencing. Although the variable copy number (from four to seven) seems to be correlated with the evolutionary distance, some close strains in the P. fluorescens lineage showed a different number of 16S rRNA genes, whereas all the strains in the P. aeruginosa lineage displayed the same number of genes (four copies). Further study of the intra-genomic heterogeneities revealed that most of the Pseudomonas strains (15 out of 19 strains) had at least two different 16S rRNA alleles. A great difference (5 or 19 nucleotides, essentially grouped near the V1 hypervariable region) was observed only in two sequenced strains. In one of our strains studied (MFY30 strain), we found a difference of 12 nucleotides (grouped in the V3 hypervariable region) between copies of the 16S rRNA gene. Finally, occurrence of partial lateral transfers of the 16S rRNA gene was further investigated in 1803 full-length sequences of Pseudomonas available in the databases. Remarkably, we found that the two most variable regions (the V1 and V3 hypervariable regions) had probably been laterally transferred from another evolutionary distant Pseudomonas strain for at least 48.3 and 41.6% of the 16S rRNA sequences, respectively. In conclusion, we strongly recommend removing these regions of the 16S rRNA gene during the intra genus diversity studies. PMID- 22545125 TI - MEKK1-MKK4-JNK-AP1 pathway negatively regulates Rgs4 expression in colonic smooth muscle cells. AB - BACKGROUND: Regulator of G-protein Signaling 4 (RGS4) plays an important role in regulating smooth muscle contraction, cardiac development, neural plasticity and psychiatric disorder. However, the underlying regulatory mechanisms remain elusive. Our recent studies have shown that upregulation of Rgs4 by interleukin (IL)-1beta is mediated by the activation of NFkappaB signaling and modulated by extracellular signal-regulated kinases, p38 mitogen-activated protein kinase, and phosphoinositide-3 kinase. Here we investigate the effect of the c-Jun N-terminal kinase (JNK) pathway on Rgs4 expression in rabbit colonic smooth muscle cells. METHODOLOGY/PRINCIPAL FINDINGS: Cultured cells at first passage were treated with or without IL-1beta (10 ng/ml) in the presence or absence of the selective JNK inhibitor (SP600125) or JNK small hairpin RNA (shRNA). The expression levels of Rgs4 mRNA and protein were determined by real-time RT-PCR and Western blot respectively. SP600125 or JNK shRNA increased Rgs4 expression in the absence or presence of IL-1beta stimulation. Overexpression of MEKK1, the key upstream kinase of JNK, inhibited Rgs4 expression, which was reversed by co-expression of JNK shRNA or dominant-negative mutants for MKK4 or JNK. Both constitutive and inducible upregulation of Rgs4 expression by SP600125 was significantly inhibited by pretreatment with the transcription inhibitor, actinomycin D. Dual reporter assay showed that pretreatment with SP600125 sensitized the promoter activity of Rgs4 in response to IL-1beta. Mutation of the AP1-binding site within Rgs4 promoter increased the promoter activity. Western blot analysis confirmed that IL 1beta treatment increased the phosphorylation of JNK, ATF-2 and c-Jun. Gel shift and chromatin immunoprecipitation assays validated that IL-1beta increased the in vitro and ex vivo binding activities of AP1 within rabbit Rgs4 promoter. CONCLUSION/SIGNIFICANCE: Activation of MEKK1-MKK4-JNK-AP1 signal pathway plays a tonic inhibitory role in regulating Rgs4 transcription in rabbit colonic smooth muscle cells. This negative regulation may aid in maintaining the transient level of RGS4 expression. PMID- 22545127 TI - Rab20 regulates phagosome maturation in RAW264 macrophages during Fc gamma receptor-mediated phagocytosis. AB - Rab20, a member of the Rab GTPase family, is known to be involved in membrane trafficking, however its implication in FcgammaR-mediated phagocytosis is unclear. We examined the spatiotemporal localization of Rab20 during phagocytosis of IgG-opsonized erythrocytes (IgG-Es) in RAW264 macrophages. By the live-cell imaging of fluorescent protein-fused Rab20, it was shown that Rab20 was transiently associated with the phagosomal membranes. During the early stage of phagosome formation, Rab20 was not localized on the membranes of phagocytic cups, but was gradually recruited to the newly formed phagosomes. Although Rab20 was colocalized with Rab5 to some extent, the association of Rab20 with the phagosomes persisted even after the loss of Rab5 from the phagosomal membranes. Then, Rab20 was colocalized with Rab7 and Lamp1, late endosomal/lysosomal markers, on the internalized phagosomes. Moreover, our analysis of Rab20 mutant expression revealed that the maturation of phagosomes was significantly delayed in cells expressing the GDP-bound mutant Rab20-T19N. These data suggest that Rab20 is an important component of phagosome and regulates the phagosome maturation during FcgammaR-mediated phagocytosis. PMID- 22545128 TI - Inhibitors of phosphatidylinositol 3'-kinases promote mitotic cell death in HeLa cells. AB - The phosphatidylinositol 3-kinase (PI3K) pathway plays an important role in many biological processes, including cell cycle progression, cell growth, survival, actin rearrangement and migration, and intracellular vesicular transport. However, the involvement of the PI3K pathway in the regulation of mitotic cell death remains unclear. In this study, we treated HeLa cells with the PI3K inhibitors, 3-methyladenine (3-MA, as well as a widely used autophagy inhibitor) and wortmannin to examine their effects on cell fates using live cell imaging. Treatment with 3-MA decreased cell viability in a time- and dose-dependent manner and was associated with caspase-3 activation. Interestingly, 3-MA-induced cell death was not affected by RNA interference-mediated knockdown (KD) of beclin1 (an essential protein for autophagy) in HeLa cells, or by deletion of atg5 (an essential autophagy gene) in mouse embryonic fibroblasts (MEFs). These data indicate that cell death induced by 3-MA occurs independently of its ability to inhibit autophagy. The results from live cell imaging studies showed that the inhibition of PI3Ks increased the occurrence of lagging chromosomes and cell cycle arrest and cell death in prometaphase. Furthermore, PI3K inhibitors promoted nocodazole-induced mitotic cell death and reduced mitotic slippage. Overexpression of Akt (the downstream target of PI3K) antagonized PI3K inhibitor induced mitotic cell death and promoted nocodazole-induced mitotic slippage. These results suggest a novel role for the PI3K pathway in regulating mitotic progression and preventing mitotic cell death and provide justification for the use of PI3K inhibitors in combination with anti-mitotic drugs to combat cancer. PMID- 22545129 TI - The foraging ecology of the mountain long-eared bat Plecotus macrobullaris revealed with DNA mini-barcodes. AB - Molecular analysis of diet overcomes the considerable limitations of traditional techniques for identifying prey remains in bat faeces. We collected faeces from individual Mountain Long-eared Bats Plecotus macrobullaris trapped using mist nets during the summers of 2009 and 2010 in the Pyrenees. We analysed their diet using DNA mini-barcodes to identify prey species. In addition, we inferred some basic features of the bat's foraging ecology that had not yet been addressed. P. macrobullaris fed almost exclusively on moths (97.8%). As prey we detected one dipteran genus (Tipulidae) and 29 moth taxa: 28 were identified at species level (23 Noctuidae, 1 Crambidae, 1 Geometridae, 1 Pyralidae, 1 Sphingidae, 1 Tortricidae), and one at genus level (Rhyacia sp., Noctuidae). Known ecological information about the prey species allowed us to determine that bats had foraged at elevations between 1,500 and 2,500 m amsl (above mean sea level), mostly in subalpine meadows, followed by other open habitats such as orophilous grasslands and alpine meadows. No forest prey species were identified in the diet. As 96.4% of identified prey species were tympanate moths and no evidence of gleaning behaviour was revealed, we suggest P. macrobullaris probably forages by aerial hawking using faint echolocation pulses to avoid detection by hearing moths. As we could identify 87.8% of the analysed sequences (64.1% of the MOTUs, Molecular Operational Taxonomic Units) at species level, we conclude that DNA mini-barcodes are a very useful tool to analyse the diet of moth-specialist bats. PMID- 22545130 TI - M. tuberculosis sliding beta-clamp does not interact directly with the NAD+ dependent DNA ligase. AB - The sliding beta-clamp, an important component of the DNA replication and repair machinery, is drawing increasing attention as a therapeutic target. We report the crystal structure of the M. tuberculosis beta-clamp (Mtbbeta-clamp) to 3.0 A resolution. The protein crystallized in the space group C222(1) with cell dimensions a = 72.7, b = 234.9 & c = 125.1 A respectively. Mtbbeta-clamp is a dimer, and exhibits head-to-tail association similar to other bacterial clamps. Each monomer folds into three domains with similar structures respectively and associates with its dimeric partner through 6 salt-bridges and about 21 polar interactions. Affinity experiments involving a blunt DNA duplex, primed-DNA and nicked DNA respectively show that Mtbbeta-clamp binds specifically to primed DNA about 1.8 times stronger compared to the other two substrates and with an apparent K(d) of 300 nM. In bacteria like E. coli, the beta-clamp is known to interact with subunits of the clamp loader, NAD(+)-dependent DNA ligase (LigA) and other partners. We tested the interactions of the Mtbbeta-clamp with MtbLigA and the gamma-clamp loader subunit through radioactive gel shift assays, size exclusion chromatography, yeast-two hybrid experiments and also functionally. Intriguingly while Mtbbeta-clamp interacts in vitro with the gamma-clamp loader, it does not interact with MtbLigA unlike in bacteria like E. coli where it does. Modeling studies involving earlier peptide complexes reveal that the peptide binding site is largely conserved despite lower sequence identity between bacterial clamps. Overall the results suggest that other as-yet-unidentified factors may mediate interactions between the clamp, LigA and DNA in mycobacteria. PMID- 22545131 TI - TIMP-2 fusion protein with human serum albumin potentiates anti-angiogenesis mediated inhibition of tumor growth by suppressing MMP-2 expression. AB - TIMP-2 protein has been intensively studied as a promising anticancer candidate agent, but the in vivo mechanism underlying its anticancer effect has not been clearly elucidated by previous works. In this study, we investigated the mechanism underlying the anti-tumor effects of a TIMP-2 fusion protein conjugated with human serum albumin (HSA/TIMP-2). Systemic administration of HSA/TIMP-2 effectively inhibited tumor growth at a minimum effective dose of 60 mg/kg. The suppressive effect of HSA/TIMP-2 was accompanied by a marked reduction of in vivo vascularization. The anti-angiogenic activity of HSA/TIMP-2 was directly confirmed by CAM assays. In HSA/TIMP-2-treated tumor tissues, MMP-2 expression was profoundly decreased without a change in MT1-MMP expression of PECAM-1 positive cells. MMP-2 mRNA was also decreased by HSA/TIMP-2 treatment of human umbilical vein endothelial cells. Zymographic analysis showed that HSA/TIMP-2 substantially decreased extracellular pro-MMP-2 activity (94-99% reduction) and moderately decreased active MMP-2 activity (10-24% reduction), suggesting MT1-MMP independent MMP-2 modulation. Furthermore, HSA/TIMP-2 had no effect on in vitro active MMP-2 activity and in vivo MMP-2 activity. These studies show that HSA/TIMP-2 potentiates anti-angiogenic activity by modulating MMP-2 expression, but not MMP-2 activity, to subsequently suppress tumor growth, suggesting an important role for MMP-2 expression rather than MMP-2 activity in anti angiogenesis. PMID- 22545132 TI - Antagonist effect of triptolide on AKT activation by truncated retinoid X receptor-alpha. AB - BACKGROUND: Retinoid X receptor-alpha (RXRalpha) is a key member of the nuclear receptor superfamily. We recently demonstrated that proteolytic cleavage of RXRalpha resulted in production of a truncated product, tRXRalpha, which promotes cancer cell survival by activating phosphatidylinositol-3-OH kinase (PI3K)/AKT pathway. However, how the tRXRalpha-mediated signaling pathway in cancer cells is regulated remains elusive. METHODOLOGY/PRINCIPAL FINDINGS: We screened a natural product library for tRXRalpha targeting leads and identified that triptolide, an active component isolated from traditional Chinese herb Trypterygium wilfordii Hook F, could modulate tRXRalpha-mediated cancer cell survival pathway in vitro and in animals. Our results reveal that triptolide strongly induces cancer cell apoptosis dependent on intracellular tRXRalpha expression levels, demonstrating that tRXRalpha serves as an important intracellular target of triptolide. We show that triptolide selectively induces tRXRalpha degradation and inhibits tRXRalpha dependent AKT activity without affecting the full-length RXRalpha. Interestingly, such effects of triptolide are due to its activation of p38. Although triptolide also activates Erk1/2 and MAPK pathways, the effects of triptolide on tRXRalpha degradation and AKT activity are only reversed by p38 siRNA and p38 inhibitor. In addition, the p38 inhibitor potently inhibits tRXRalpha interaction with p85alpha leading to AKT inactivation. Our results demonstrate an interesting novel signaling interplay between p38 and AKT through tRXRalpha mediation. We finally show that targeting tRXRalpha by triptolide strongly activates TNFalpha death signaling and enhances the anticancer activity of other chemotherapies. CONCLUSIONS/SIGNIFICANCE: Our results identify triptolide as a new xenobiotic regulator of the tRXRalpha-dependent survival pathway and provide new insight into the mechanism by which triptolide acts to induce apoptosis of cancer cells. Triptolide represents one of the most promising therapeutic leads of natural products of traditional Chinese medicine with unfortunate side-effects. Our findings will offer new strategies to develop improved triptolide analogs for cancer therapy. PMID- 22545134 TI - HRS1 acts as a negative regulator of abscisic acid signaling to promote timely germination of Arabidopsis seeds. AB - In this work, we conducted functional analysis of Arabidopsis HRS1 gene in order to provide new insights into the mechanisms governing seed germination. Compared with wild type (WT) control, HRS1 knockout mutant (hrs1-1) exhibited significant germination delays on either normal medium or those supplemented with abscisic acid (ABA) or sodium chloride (NaCl), with the magnitude of the delay being substantially larger on the latter media. The hypersensitivity of hrs1-1 germination to ABA and NaCl required ABI3, ABI4 and ABI5, and was aggravated in the double mutant hrs1-1abi1-2 and triple mutant hrs1-1hab1-1abi1-2, indicating that HRS1 acts as a negative regulator of ABA signaling during seed germination. Consistent with this notion, HRS1 expression was found in the embryo axis, and was regulated both temporally and spatially, during seed germination. Further analysis showed that the delay of hrs1-1 germination under normal conditions was associated with reduction in the elongation of the cells located in the lower hypocotyl (LH) and transition zone (TZ) of embryo axis. Interestingly, the germination rate of hrs1-1 was more severely reduced by the inhibitor of cell elongation, and more significantly decreased by the suppressors of plasmalemma H(+)-ATPase activity, than that of WT control. The plasmalemma H(+)-ATPase activity in the germinating seeds of hrs1-1 was substantially lower than that exhibited by WT control, and fusicoccin, an activator of this pump, corrected the transient germination delay of hrs1-1. Together, our data suggest that HRS1 may be needed for suppressing ABA signaling in germinating embryo axis, which promotes the timely germination of Arabidopsis seeds probably by facilitating the proper function of plasmalemma H(+)-ATPase and the efficient elongation of LH and TZ cells. PMID- 22545133 TI - Development of B cells and erythrocytes is specifically impaired by the drug celastrol in mice. AB - BACKGROUND: Celastrol, an active compound extracted from the root of the Chinese medicine "Thunder of God Vine" (Tripterygium wilfordii), exhibits anticancer, antioxidant and anti-inflammatory activities, and interest in the therapeutic potential of celastrol is increasing. However, described side effects following treatment are significant and require investigation prior to initiating clinical trials. Here, we investigated the effects of celastrol on the adult murine hematopoietic system. METHODOLOGY/PRINCIPAL FINDINGS: Animals were treated daily with celastrol over a four-day period and peripheral blood, bone marrow, spleen, and peritoneal cavity were harvested for cell phenotyping. Treated mice showed specific impairment of the development of B cells and erythrocytes in all tested organs. In bone marrow, these alterations were accompanied by decreases in populations of common lymphoid progenitors (CLP), common myeloid progenitors (CMP) and megakaryocyte-erythrocyte progenitors (MEP). CONCLUSIONS/SIGNIFICANCE: These results indicate that celastrol acts through regulators of adult hematopoiesis and could be used as a modulator of the hematopoietic system. These observations provide valuable information for further assessment prior to clinical trials. PMID- 22545135 TI - Genetic background analysis of protein C deficiency demonstrates a recurrent mutation associated with venous thrombosis in Chinese population. AB - BACKGROUND: Protein C (PC) is one of the most important physiological inhibitors of coagulation proteases. Hereditary PC deficiency causes a predisposition to venous thrombosis (VT). The genetic characteristics of PC deficiency in the Chinese population remain unknown. METHODS: Thirty-four unrelated probands diagnosed with hereditary PC deficiency were investigated. PC activity and antigen levels were measured. Mutation analysis was performed by sequencing the PROC gene. In silico analyses, including PolyPhen-2, SIFT, multiple sequence alignment, splicing prediction, and protein molecular modeling were performed to predict the consequences of each variant identified. One recurrent mutation and its relative risk for thrombosis in relatives were analyzed in 11 families. The recurrent mutation was subsequently detected in a case (VT patients)-control study, and the adjusted odds ratio (OR) for VT risk was calculated by logistic regression analysis. RESULTS: A total of 18 different mutations, including 12 novel variants, were identified. One common mutation, PROC c.565C>T (rs146922325:C>T), was found in 17 of the 34 probands. The family study showed that first-degree relatives bearing this variant had an 8.8-fold (95%CI = 1.1 71.6) increased risk of venous thrombosis. The case-control (1003 vs. 1031) study identified this mutation in 5.88% patients and in 0.87% controls, respectively. The mutant allele conferred a high predisposition to venous thrombosis (adjusted OR = 7.34, 95%CI = 3.61-14.94). The plasma PC activity and antigen levels in heterozygotes were 51.73+/-6.92 U/dl and 75.17+/-4.84 U/dl, respectively. CONCLUSIONS: This is the first study on the genetic background of PC deficiency in the Chinese population. The PROC c.565C>T mutation is the most frequent cause of PC deficiency as well as a prevalent risk factor for VT in Chinese individuals. The inclusion of this variant in routine thrombophilic detection may improve the diagnosis and prevention of venous thrombosis. PMID- 22545136 TI - Heterogeneity of persistence of Salmonella enterica serotype Senftenberg strains could explain the emergence of this serotype in poultry flocks. AB - Salmonella enterica serotype Senftenberg (S. Senftenberg) has recently become more frequent in poultry flocks. Moreover some strains have been implicated in severe clinical cases. To explain the causes of this emergence in farm animals, 134 S. Senftenberg isolates from hatcheries, poultry farms and human clinical cases were analyzed. Persistent and non-persistent strains were identified in chicks. The non-persistent strains disappeared from ceca a few weeks post inoculation. This lack of persistence could be related to the disappearance of this serotype from poultry farms in the past. In contrast, persistent S. Senftenberg strains induced an intestinal asymptomatic carrier state in chicks similar to S. Enteritidis, but a weaker systemic infection than S. Enteritidis in chicks and mice. An in vitro analysis showed that the low infectivity of S. Senftenberg is in part related to its low capacity to invade enterocytes and thus to translocate the intestinal barrier. The higher capacity of persistent than non persistent strains to colonize and persist in the ceca of chickens could explain the increased persistence of S. Senftenberg in poultry flocks. This trait might thus present a human health risk as these bacteria could be present in animals before slaughter and during food processing. PMID- 22545137 TI - mRNA-Seq analysis of the Pseudoperonospora cubensis transcriptome during cucumber (Cucumis sativus L.) infection. AB - Pseudoperonospora cubensis, an oomycete, is the causal agent of cucurbit downy mildew, and is responsible for significant losses on cucurbit crops worldwide. While other oomycete plant pathogens have been extensively studied at the molecular level, Ps. cubensis and the molecular basis of its interaction with cucurbit hosts has not been well examined. Here, we present the first large-scale global gene expression analysis of Ps. cubensis infection of a susceptible Cucumis sativus cultivar, 'Vlaspik', and identification of genes with putative roles in infection, growth, and pathogenicity. Using high throughput whole transcriptome sequencing, we captured differential expression of 2383 Ps. cubensis genes in sporangia and at 1, 2, 3, 4, 6, and 8 days post-inoculation (dpi). Additionally, comparison of Ps. cubensis expression profiles with expression profiles from an infection time course of the oomycete pathogen Phytophthora infestans on Solanum tuberosum revealed similarities in expression patterns of 1,576-6,806 orthologous genes suggesting a substantial degree of overlap in molecular events in virulence between the biotrophic Ps. cubensis and the hemi-biotrophic P. infestans. Co-expression analyses identified distinct modules of Ps. cubensis genes that were representative of early, intermediate, and late infection stages. Collectively, these expression data have advanced our understanding of key molecular and genetic events in the virulence of Ps. cubensis and thus, provides a foundation for identifying mechanism(s) by which to engineer or effect resistance in the host. PMID- 22545138 TI - Novel serial positive enrichment technology enables clinical multiparameter cell sorting. AB - A general obstacle for clinical cell preparations is limited purity, which causes variability in the quality and potency of cell products and might be responsible for negative side effects due to unwanted contaminants. Highly pure populations can be obtained best using positive selection techniques. However, in many cases target cell populations need to be segregated from other cells by combinations of multiple markers, which is still difficult to achieve--especially for clinical cell products. Therefore, we have generated low-affinity antibody-derived Fab fragments, which stain like parental antibodies when multimerized via Strep-tag and Strep-Tactin, but can subsequently be removed entirely from the target cell population. Such reagents can be generated for virtually any antigen and can be used for sequential positive enrichment steps via paramagnetic beads. First protocols for multiparameter enrichment of two clinically relevant cell populations, CD4(high)/CD25(high)/CD45RA(high) 'regulatory T cells' and CD8(high)/CD62L(high)/CD45RA(neg) 'central memory T cells', have been established to determine quality and efficacy parameters of this novel technology, which should have broad applicability for clinical cell sorting as well as basic research. PMID- 22545139 TI - Comparative analysis of the heptahelical transmembrane bundles of G protein coupled receptors. AB - BACKGROUND: G protein-coupled receptors represent a large family of eukaryotic membrane proteins, and are involved in almost all physiological processes in humans. Recent advances in the crystallographic study of these receptors enable a detailed comparative analysis of the commonly shared heptahelical transmembrane bundle. Systematic comparison of the bundles from a variety of receptors is indispensable for understanding not only of the structural diversification optimized for the binding of respective ligands but also of the structural conservation required for the common mechanism of activation accompanying the interaction changes among the seven helices. METHODOLOGY/PRINCIPAL FINDINGS: We have examined the bundles of 94 polypeptide chains from almost all available structures of 11 receptors, which we classified into either inactivated chain or activated chain, based on the type of bound ligand. For the inactivated chains, superposition of 200 residue bundles by secondary structure matching demonstrated that the bound ligands share a laterally limited cavity in the extracellular section of the bundle. Furthermore, a distinct feature was found for helix III of bovine rhodopsin, which might have evolved to lower its activity in the presence of 11-cis-retinal, to a level that other receptors could hardly achieve with any currently available ligands. CONCLUSIONS/SIGNIFICANCE: Systematic analysis described here would be valuable for understanding of the rearrangement of seven helices which depends on the ligand specificity and activation state of the receptors. PMID- 22545140 TI - Tracking invasion histories in the sea: facing complex scenarios using multilocus data. AB - In recent years, new analytical tools have allowed researchers to extract historical information contained in molecular data, which has fundamentally transformed our understanding of processes ruling biological invasions. However, the use of these new analytical tools has been largely restricted to studies of terrestrial organisms despite the growing recognition that the sea contains ecosystems that are amongst the most heavily affected by biological invasions, and that marine invasion histories are often remarkably complex. Here, we studied the routes of invasion and colonisation histories of an invasive marine invertebrate Microcosmus squamiger (Ascidiacea) using microsatellite loci, mitochondrial DNA sequence data and 11 worldwide populations. Discriminant analysis of principal components, clustering methods and approximate bayesian computation (ABC) methods showed that the most likely source of the introduced populations was a single admixture event that involved populations from two genetically differentiated ancestral regions--the western and eastern coasts of Australia. The ABC analyses revealed that colonisation of the introduced range of M. squamiger consisted of a series of non-independent introductions along the coastlines of Africa, North America and Europe. Furthermore, we inferred that the sequence of colonisation across continents was in line with historical taxonomic records--first the Mediterranean Sea and South Africa from an unsampled ancestral population, followed by sequential introductions in California and, more recently, the NE Atlantic Ocean. We revealed the most likely invasion history for world populations of M. squamiger, which is broadly characterized by the presence of multiple ancestral sources and non-independent introductions within the introduced range. The results presented here illustrate the complexity of marine invasion routes and identify a cause-effect relationship between human-mediated transport and the success of widespread marine non-indigenous species, which benefit from stepping-stone invasions and admixture processes involving different sources for the spread and expansion of their range. PMID- 22545141 TI - Residual expression of the reprogramming factors prevents differentiation of iPSC generated from human fibroblasts and cord blood CD34+ progenitors. AB - Human induced pluripotent stem cells (hiPSC) have been generated from different tissues, with the age of the donor, tissue source and specific cell type influencing the reprogramming process. Reprogramming hematopoietic progenitors to hiPSC may provide a very useful cellular system for modelling blood diseases. We report the generation and complete characterization of hiPSCs from human neonatal fibroblasts and cord blood (CB)-derived CD34+ hematopoietic progenitors using a single polycistronic lentiviral vector containing an excisable cassette encoding the four reprogramming factors Oct4, Klf4, Sox2 and c-myc (OKSM). The ectopic expression of OKSM was fully silenced upon reprogramming in some hiPSC clones and was not reactivated upon differentiation, whereas other hiPSC clones failed to silence the transgene expression, independently of the cell type/tissue origin. When hiPSC were induced to differentiate towards hematopoietic and neural lineages those hiPSC which had silenced OKSM ectopic expression displayed good hematopoietic and early neuroectoderm differentiation potential. In contrast, those hiPSC which failed to switch off OKSM expression were unable to differentiate towards either lineage, suggesting that the residual expression of the reprogramming factors functions as a developmental brake impairing hiPSC differentiation. Successful adenovirus-based Cre-mediated excision of the provirus OKSM cassette in CB-derived CD34+ hiPSC with residual transgene expression resulted in transgene-free hiPSC clones with significantly improved differentiation capacity. Overall, our findings confirm that residual expression of reprogramming factors impairs hiPSC differentiation. PMID- 22545142 TI - Development of GPCR modulation of GABAergic transmission in chicken nucleus laminaris neurons. AB - Neurons in the nucleus laminaris (NL) of birds act as coincidence detectors and encode interaural time difference to localize the sound source in the azimuth plane. GABAergic transmission in a number of CNS nuclei including the NL is subject to a dual modulation by presynaptic GABA(B) receptors (GABA(B)Rs) and metabotropic glutamate receptors (mGluRs). Here, using in vitro whole-cell patch clamp recordings from acute brain slices of the chick, we characterized the following important but unknown properties pertaining to such a dual modulation: (1) emergence of functional GABA synapses in NL neurons; (2) the temporal onset of neuromodulation mediated by GABA(B)Rs and mGluRs; and (3) the physiological conditions under which GABA(B)Rs and mGluRs are activated by endogenous transmitters. We found that (1) GABA(A)R-mediated synaptic responses were observed in about half of the neurons at embryonic day 11 (E11); (2) GABA(B)R mediated modulation of the GABAergic transmission was detectable at E11, whereas the modulation by mGluRs did not emerge until E15; and (3) endogenous activity of GABA(B)Rs was induced by both low- (5 or 10 Hz) and high-frequency (200 Hz) stimulation of the GABAergic pathway, whereas endogenous activity of mGluRs was induced by high- (200 Hz) but not low-frequency (5 or 10 Hz) stimulation of the glutamatergic pathway. Furthermore, the endogenous activity of mGluRs was mediated by group II but not group III members. Therefore, autoreceptor-mediated modulation of GABAergic transmission emerges at the same time when the GABA synapses become functional. Heteroreceptor-mediated modulation appears at a later time and is receptor type dependent in vitro. PMID- 22545143 TI - Assessing corpus callosum changes in Alzheimer's disease: comparison between tract-based spatial statistics and atlas-based tractography. AB - Tractography based on Diffusion Tensor Imaging (DTI) represents a valuable tool for investigating brain white matter (WM) microstructure, allowing the computation of damage-related diffusion parameters such as Fractional Anisotropy (FA) in specific WM tracts. This technique appears relevant in the study of pathologies in which brain disconnection plays a major role, such as, for instance, Alzheimer's Disease (AD). Previous DTI studies have reported inconsistent results in defining WM abnormalities in AD and in its prodromal stage (i.e., amnestic Mild Cognitive Impairment; aMCI), especially when investigating the corpus callosum (CC). A reason for these inconsistencies is the use of different processing techniques, which may strongly influence the results. The aim of the current study was to compare a novel atlas-based tractography approach, that sub-divides the CC in eight portions, with Tract-Based Spatial Statistics (TBSS) when used to detect specific patterns of CC FA in AD at different clinical stages. FA data were obtained from 76 subjects (37 with mild AD, 19 with aMCI and 20 elderly healthy controls, HC) and analyzed using both methods. Consistent results were obtained for the two methods, concerning the comparisons AD vs. HC (significantly reduced FA in the whole CC of AD patients) and AD vs. aMCI (significantly reduced FA in the frontal portions of the CC in AD patients), thus identifying a relative preservation of the frontal CC regions in aMCI patients compared to AD. Conversely, the atlas-based method but not the TBSS showed the ability to detect a selective FA change in the CC parietal, left temporal and occipital regions of aMCI patients compared to HC. This finding indicates that an analysis including a higher number of voxels (with no restriction to tract skeletons) may detect characteristic pattern of FA in the CC of patients with preclinical AD, when brain atrophy is still modest. PMID- 22545144 TI - Non-overlapping progesterone receptor cistromes contribute to cell-specific transcriptional outcomes. AB - The transcriptional effects of the ovarian hormone progesterone are pleiotropic, and binding to DNA of the nuclear progesterone receptor (PR), a ligand-activated transcription factor, results in diverse outcomes in a range of target tissues. To determine whether distinct patterns of genomic interaction of PR contribute to the cell specificity of the PR transcriptome, we have compared the genomic binding sites for PR in breast cancer cells and immortalized normal breast cells. PR binding was correlated with transcriptional outcome in both cell lines, with 60% of progestin-regulated genes associated with one or more PR binding regions. There was a remarkably low overlap between the PR cistromes of the two cell lines, and a similarly low overlap in transcriptional targets. A conserved PR binding element was identified in PR binding regions from both cell lines, but there were distinct patterns of enrichment of known cofactor binding motifs, with FOXA1 sites over-represented in breast cancer cell binding regions and NF1 and AP 1 motifs uniquely enriched in the immortalized normal line. Downstream analyses suggested that differential cofactor availability may generate these distinct PR cistromes, indicating that cofactor levels may modulate PR specificity. Taken together these data suggest that cell-specificity of PR binding is determined by the coordinated effects of key binding cofactors. PMID- 22545145 TI - Trappin-2/elafin modulate innate immune responses of human endometrial epithelial cells to PolyI:C. AB - BACKGROUND: Upon viral recognition, innate and adaptive antiviral immune responses are initiated by genital epithelial cells (ECs) to eradicate or contain viral infection. Such responses, however, are often accompanied by inflammation that contributes to acquisition and progression of sexually transmitted infections (STIs). Hence, interventions/factors enhancing antiviral protection while reducing inflammation may prove beneficial in controlling the spread of STIs. Serine antiprotease trappin-2 (Tr) and its cleaved form, elafin (E), are alarm antimicrobials secreted by multiple cells, including genital epithelia. METHODOLOGY AND PRINCIPAL FINDINGS: We investigated whether and how each Tr and E (Tr/E) contribute to antiviral defenses against a synthetic mimic of viral dsRNA, polyinosine-polycytidylic acid (polyI:C) and vesicular stomatitis virus. We show that delivery of a replication-deficient adenovector expressing Tr gene (Ad/Tr) to human endometrial epithelial cells, HEC-1A, resulted in secretion of functional Tr, whereas both Tr/E were detected in response to polyI:C. Moreover, Tr/E were found to significantly reduce viral replication by either acting directly on virus or through enhancing polyI:C-driven antiviral protection. The latter was associated with reduced levels of pro-inflammatory factors IL-8, IL-6, TNFalpha, lowered expression of RIG-I, MDA5 and attenuated NF-kappaB activation. Interestingly, enhanced polyI:C-driven antiviral protection of HEC-Ad/Tr cells was partially mediated through IRF3 activation, but not associated with higher induction of IFNbeta, suggesting multiple antiviral mechanisms of Tr/E and the involvement of alternative factors or pathways. CONCLUSIONS AND SIGNIFICANCE: This is the first evidence of both Tr/E altering viral binding/entry, innate recognition and mounting of antiviral and inflammatory responses in genital ECs that could have significant implications for homeostasis of the female genital tract. PMID- 22545146 TI - Pair-wise regulation of convergence and extension cell movements by four phosphatases via RhoA. AB - Various signaling pathways regulate shaping of the main body axis during early vertebrate development. Here, we focused on the role of protein-tyrosine phosphatase signaling in convergence and extension cell movements. We identified Ptpn20 as a structural paralogue of PTP-BL and both phosphatases were required for normal gastrulation cell movements. Interestingly, knockdowns of PTP-BL and Ptpn20 evoked similar developmental defects as knockdown of RPTPalpha and PTPepsilon. Co-knockdown of RPTPalpha and PTP-BL, but not Ptpn20, had synergistic effects and conversely, PTPepsilon and Ptpn20, but not PTP-BL, cooperated, demonstrating the specificity of our approach. RPTPalpha and PTPepsilon knockdowns were rescued by constitutively active RhoA, whereas PTP-BL and Ptpn20 knockdowns were rescued by dominant negative RhoA. Consistently, RPTPalpha and PTP-BL had opposite effects on RhoA activation, both in a PTP-dependent manner. Downstream of the PTPs, we identified NGEF and Arhgap29, regulating RhoA activation and inactivation, respectively, in convergence and extension cell movements. We propose a model in which two phosphatases activate RhoA and two phosphatases inhibit RhoA, resulting in proper cell polarization and normal convergence and extension cell movements. PMID- 22545147 TI - Regulation of Toll-like receptor 5 gene expression and function on mucosal dendritic cells. AB - Toll-like receptor (TLR) 5 has been shown to maintain intestinal homeostasis and regulate host defense against enterobacterial infection. However, how TLR5 expression is regulated and its function in the intestine have not been fully elucidated. Here we demonstrate that mucosal dendritic cells (DCs), but not splenic DCs, express high levels of TLR5 protein. Alternatively spliced Tlr5 transcripts were identified but it did not explain the selective expression of TLR5 on mucosal DCs. Treatment with various bacterial ligands downregulated BMDC TLR5 expression, while retinoic acid and host stromal cell-derived signals promoted TLR5 expression in a TGF-beta-independent mechanism. Signaling through TLR5 restrained regulatory T (Treg) cell generation, and accordingly, TLR5(-/-) mice displayed increased frequencies of Foxp3(+) Treg cells in the intestinal lamina propria. Our data indicate that bacterial and host factors differentially regulate DC TLR5 expression. TLR5 signaling regulates immune responses towards the microbiota via modulation of the Treg/effector T cell balance. PMID- 22545148 TI - DRB2 is required for microRNA biogenesis in Arabidopsis thaliana. AB - BACKGROUND: The Arabidopsis thaliana (Arabidopsis) DOUBLE-STRANDED RNA BINDING (DRB) protein family consists of five members, DRB1 to DRB5. The biogenesis of two developmentally important small RNA (sRNA) species, the microRNAs (miRNAs) and trans-acting small interfering RNAs (tasiRNAs) by DICER-LIKE (DCL) endonucleases requires the assistance of DRB1 and DRB4 respectively. The importance of miRNA-directed target gene expression in plant development is exemplified by the phenotypic consequence of loss of DRB1 activity (drb1 plants). PRINCIPAL FINDINGS: Here we report that the developmental phenotype of the drb235 triple mutant plant is the result of deregulated miRNA biogenesis in the shoot apical meristem (SAM) region. The expression of DRB2, DRB3 and DRB5 in wild-type seedlings is restricted to the SAM region. Small RNA sequencing of the corresponding tissue of drb235 plants revealed altered miRNA accumulation. Approximately half of the miRNAs detected remained at levels equivalent to those of wild-type plants. However, the accumulation of the remaining miRNAs was either elevated or reduced in the triple mutant. Examination of different single and multiple drb mutants revealed a clear association between the loss of DRB2 activity and altered accumulation for both the elevated and reduced miRNA classes. Furthermore, we show that the constitutive over-expression of DRB2 outside of its wild-type expression domain can compensate for the loss of DRB1 activity in drb1 plants. CONCLUSIONS/SIGNIFICANCE: Our results suggest that in the SAM region, DRB2 is both antagonistic and synergistic to the role of DRB1 in miRNA biogenesis, adding an additional layer of gene regulatory complexity in this developmentally important tissue. PMID- 22545149 TI - Chlamydia pneumoniae-specific IgE is prevalent in asthma and is associated with disease severity. AB - BACKGROUND: Several Chlamydia pneumoniae (Cp) biomarkers have been associated with asthma but Cp-specific IgE (Cp IgE) has not been investigated extensively. Our objective was to investigate Cp IgE in community adult asthma patients. METHODS: (1) Prevalence of Cp IgE (measured by immunoblotting) and Cp DNA (by polymerase chain reaction) in peripheral blood, and biomarker associations with asthma severity. (2) Case-control studies of Cp IgE association with asthma using healthy blood donor (study 1) and non-asthmatic clinic patient (study 2) controls. RESULTS: Of 66 asthma subjects (mean age 40.9 years, range 5-75, 59% male, 45% ever-smokers) 33 (50%) were Cp IgE positive and 16 (24%) were Cp DNA positive (P = 0.001 for association of Cp IgE and DNA). Cp IgE was detected in 21% of mild intermittent asthma v 79% of severe persistent asthma (test for trend over severity categories, P = 0.002). Cp IgE detection was significantly (P = 0.001) associated with asthma when compared to healthy blood donor controls but not when compared to clinic controls. CONCLUSIONS: Half of this sample of community asthma patients had detectable IgE against C. pneumoniae. Cp IgE was strongly and positively associated with asthma severity and with asthma when healthy blood donor controls were used. These results support the inclusion of Cp IgE as a biomarker in future studies of infectious contributions to asthma pathogenesis. PMID- 22545150 TI - Association of BMI category change with TB treatment mortality in HIV-positive smear-negative and extrapulmonary TB patients in Myanmar and Zimbabwe. AB - OBJECTIVE: The HIV epidemic has increased the proportion of patients with smear negative and extrapulmonary tuberculosis (TB) diagnoses, with related higher rates of poor TB treatment outcomes. Unlike in smear-positive pulmonary TB, no interim markers of TB treatment progress are systematically used to identify individuals most at risk of mortality. The objective of this study was to assess the association of body mass index (BMI) change at 1 month (+/-15 days) from TB treatment start with mortality among HIV-positive individuals with smear-negative and extrapulmonary TB. METHODS AND FINDINGS: A retrospective cohort study of adult HIV-positive new TB patients in Medecins Sans Frontieres (MSF) treatment programmes in Myanmar and Zimbabwe was conducted using Cox proportional hazards regression to estimate the association between BMI category change and mortality. A cohort of 1090 TB patients (605 smear-negative and 485 extrapulmonary) was followed during TB treatment with mortality rate of 28.9 per 100 person-years. In multivariable analyses, remaining severely underweight or moving to a lower BMI category increased mortality (adjusted hazard ratio 4.05, 95% confidence interval 2.77-5.91, p<0.001) compared with remaining in the same or moving to a higher BMI category. CONCLUSIONS: We found a strong association between BMI category change during the first month of TB treatment and mortality. BMI category change could be used to identify individuals most at risk of mortality during TB treatment among smear-negative and extrapulmonary patients. PMID- 22545151 TI - Evaluating surveillance strategies for the early detection of low pathogenicity avian influenza infections. AB - In recent years, the early detection of low pathogenicity avian influenza (LPAI) viruses in poultry has become increasingly important, given their potential to mutate into highly pathogenic viruses. However, evaluations of LPAI surveillance have mainly focused on prevalence and not on the ability to act as an early warning system. We used a simulation model based on data from Italian LPAI epidemics in turkeys to evaluate different surveillance strategies in terms of their performance as early warning systems. The strategies differed in terms of sample size, sampling frequency, diagnostic tests, and whether or not active surveillance (i.e., routine laboratory testing of farms) was performed, and were also tested under different epidemiological scenarios. We compared surveillance strategies by simulating within-farm outbreaks. The output measures were the proportion of infected farms that are detected and the farm reproduction number (R(h)). The first one provides an indication of the sensitivity of the surveillance system to detect within-farm infections, whereas R(h) reflects the effectiveness of outbreak detection (i.e., if detection occurs soon enough to bring an epidemic under control). Increasing the sampling frequency was the most effective means of improving the timeliness of detection (i.e., it occurs earlier), whereas increasing the sample size increased the likelihood of detection. Surveillance was only effective in preventing an epidemic if actions were taken within two days of sampling. The strategies were not affected by the quality of the diagnostic test, although performing both serological and virological assays increased the sensitivity of active surveillance. Early detection of LPAI outbreaks in turkeys can be achieved by increasing the sampling frequency for active surveillance, though very frequent sampling may not be sustainable in the long term. We suggest that, when no LPAI virus is circulating yet and there is a low risk of virus introduction, a less frequent sampling approach might be admitted, provided that the surveillance is intensified as soon as the first outbreak is detected. PMID- 22545152 TI - Transcriptome of protoplasts reprogrammed into stem cells in Physcomitrella patens. AB - BACKGROUND: Differentiated plant cells can retain the capacity to be reprogrammed into pluripotent stem cells during regeneration. This capacity is associated with both cell cycle reactivation and acquisition of specific cellular characters. However, the molecular mechanisms underlying the reprogramming of protoplasts into stem cells remain largely unknown. Protoplasts of the moss Physcomitrella patens easily regenerate into protonema and therefore provide an ideal system to explore how differentiated cells can be reprogrammed to produce stem cells. PRINCIPAL FINDINGS: We obtained genome-wide digital gene expression tag profiles within the first three days of P. patens protoplast reprogramming. At four time points during protoplast reprogramming, the transcript levels of 4827 genes changed more than four-fold and their expression correlated with the reprogramming phase. Gene ontology (GO) and pathway enrichment analysis of differentially expressed genes (DEGs) identified a set of significantly enriched GO terms and pathways, most of which were associated with photosynthesis, protein synthesis and stress responses. DEGs were grouped into six clusters that showed specific expression patterns using a K-means clustering algorithm. An investigation of function and expression patterns of genes identified a number of key candidate genes and pathways in early stages of protoplast reprogramming, which provided important clues to reveal the molecular mechanisms responsible for protoplast reprogramming. CONCLUSIONS: We identified genes that show highly dynamic changes in expression during protoplast reprogramming into stem cells in P. patens. These genes are potential targets for further functional characterization and should be valuable for exploration of the mechanisms of stem cell reprogramming. In particular, our data provides evidence that protoplasts of P. patens are an ideal model system for elucidation of the molecular mechanisms underlying differentiated plant cell reprogramming. PMID- 22545153 TI - The hepatitis E virus polyproline region is involved in viral adaptation. AB - Genomes of hepatitis E virus (HEV), rubivirus and cutthroat virus (CTV) contain a region of high proline density and low amino acid (aa) complexity, named the polyproline region (PPR). In HEV genotypes 1, 3 and 4, it is the only region within the non-structural open reading frame (ORF1) with positive selection (4-10 codons with dN/dS>1). This region has the highest density of sites with homoplasy values >0.5. Genotypes 3 and 4 show ~3-fold increase in homoplastic density (HD) in the PPR compared to any other region in ORF1, genotype 1 does not exhibit significant HD (p<0.0001). PPR sequence divergence was found to be 2-fold greater for HEV genotypes 3 and 4 than for genotype 1. The data suggest the PPR plays an important role in host-range adaptation. Although the PPR appears to be hypervariable and homoplastic, it retains as much phylogenetic signal as any other similar sized region in the ORF1, indicating that convergent evolution operates within the major HEV phylogenetic lineages. Analyses of sequence-based secondary structure and the tertiary structure identify PPR as an intrinsically disordered region (IDR), implicating its role in regulation of replication. The identified propensity for the disorder-to-order state transitions indicates the PPR is involved in protein-protein interactions. Furthermore, the PPR of all four HEV genotypes contains seven putative linear binding motifs for ligands involved in the regulation of a wide number of cellular signaling processes. Structure based analysis of possible molecular functions of these motifs showed the PPR is prone to bind a wide variety of ligands. Collectively, these data suggest a role for the PPR in HEV adaptation. Particularly as an IDR, the PPR likely contributes to fine tuning of viral replication through protein-protein interactions and should be considered as a target for development of novel anti-viral drugs. PMID- 22545154 TI - Structure of an enzyme-derived phosphoprotein recognition domain. AB - Membrane Associated Guanylate Kinases (MAGUKs) contain a protein interaction domain (GK(dom)) derived from the enzyme Guanylate Kinase (GK(enz)). Here we show that GK(dom) from the MAGUK Discs large (Dlg) is a phosphoprotein recognition domain, specifically recognizing the phosphorylated form of the mitotic spindle orientation protein Partner of Inscuteable (Pins). We determined the structure of the Dlg-Pins complex to understand the dramatic transition from nucleotide kinase to phosphoprotein recognition domain. The structure reveals that the region of the GK(dom) that once served as the GMP binding domain (GBD) has been co-opted for protein interaction. Pins makes significantly more contact with the GBD than does GMP, but primarily with residues that are conserved between enzyme and domain revealing the versatility of the GBD as a platform for nucleotide and protein interactions. Mutational analysis reveals that the GBD is also used to bind the GK ligand MAP1a, suggesting that this is a common mode of MAGUK complex assembly. The GK(enz) undergoes a dramatic closing reaction upon GMP binding but the protein-bound GK(dom) remains in the 'open' conformation indicating that the dramatic conformational change has been lost in the conversion from nucleotide kinase to phosphoprotein recognition domain. PMID- 22545155 TI - Massive nest-box supplementation boosts fecundity, survival and even immigration without altering mating and reproductive behaviour in a rapidly recovered bird population. AB - Habitat restoration measures may result in artificially high breeding density, for instance when nest-boxes saturate the environment, which can negatively impact species' demography. Potential risks include changes in mating and reproductive behaviour such as increased extra-pair paternity, conspecific brood parasitism, and polygyny. Under particular cicumstances, these mechanisms may disrupt reproduction, with populations dragged into an extinction vortex. With the use of nuclear microsatellite markers, we investigated the occurrence of these potentially negative effects in a recovered population of a rare secondary cavity-nesting farmland bird of Central Europe, the hoopoe (Upupa epops). High intensity farming in the study area has resulted in a total eradication of cavity trees, depriving hoopoes from breeding sites. An intensive nest-box campaign rectified this problem, resulting in a spectacular population recovery within a few years only. There was some concern, however, that the new, high artificially induced breeding density might alter hoopoe mating and reproductive behaviour. As the species underwent a serious demographic bottleneck in the 1970-1990s, we also used the microsatellite markers to reconstitute the demo-genetic history of the population, looking in particular for signs of genetic erosion. We found i) a low occurrence of extra-pair paternity, polygyny and conspecific brood parasitism, ii) a high level of neutral genetic diversity (mean number of alleles and expected heterozygosity per locus: 13.8 and 83%, respectively) and, iii) evidence for genetic connectivity through recent immigration of individuals from well differentiated populations. The recent increase in breeding density did thus not induce so far any noticeable detrimental changes in mating and reproductive behaviour. The demographic bottleneck undergone by the population in the 1970s 1990s was furthermore not accompanied by any significant drop in neutral genetic diversity. Finally, genetic data converged with a concomitant demographic study to evidence that immigration strongly contributed to local population recovery. PMID- 22545156 TI - Distinct effector memory CD4+ T cell signatures in latent Mycobacterium tuberculosis infection, BCG vaccination and clinically resolved tuberculosis. AB - Two billion people worldwide are estimated to be latently infected with Mycobacterium tuberculosis (Mtb) and are at risk for developing active tuberculosis since Mtb can reactivate to cause TB disease in immune-compromised hosts. Individuals with latent Mtb infection (LTBI) and BCG-vaccinated individuals who are uninfected with Mtb, harbor antigen-specific memory CD4(+) T cells. However, the differences between long-lived memory CD4(+) T cells induced by latent Mtb infection (LTBI) versus BCG vaccination are unclear. In this study, we characterized the immune phenotype and functionality of antigen-specific memory CD4(+) T cells in healthy BCG-vaccinated individuals who were either infected (LTBI) or uninfected (BCG) with Mtb. Individuals were classified into LTBI and BCG groups based on IFN-gamma ELISPOT using cell wall antigens and ESAT 6/CFP-10 peptides. We show that LTBI individuals harbored high frequencies of late-stage differentiated (CD45RA(-)CD27(-)) antigen-specific effector memory CD4(+) T cells that expressed PD-1. In contrast, BCG individuals had primarily early-stage (CD45RA(-)CD27(+)) cells with low PD-1 expression. CD27(+) and CD27( ) as well as PD-1(+) and PD-1(-) antigen-specific subsets were polyfunctional, suggesting that loss of CD27 expression and up-regulation of PD-1 did not compromise their capacity to produce IFN-gamma, TNF-alpha and IL-2. PD-1 was preferentially expressed on CD27(-) antigen-specific CD4(+) T cells, indicating that PD-1 is associated with the stage of differentiation. Using statistical models, we determined that CD27 and PD-1 predicted LTBI versus BCG status in healthy individuals and distinguished LTBI individuals from those who had clinically resolved Mtb infection after anti-tuberculosis treatment. This study shows that CD4(+) memory responses induced by latent Mtb infection, BCG vaccination and clinically resolved Mtb infection are immunologically distinct. Our data suggest that differentiation into CD27(-)PD-1(+) subsets in LTBI is driven by Mtb antigenic stimulation in vivo and that CD27 and PD-1 have the potential to improve our ability to evaluate true LTBI status. PMID- 22545157 TI - Viral kinetics suggests a reconciliation of the disparate observations of the modulation of claudin-1 expression on cells exposed to hepatitis C virus. AB - The tight junction protein claudin-1 (CLDN1) is necessary for hepatitis C virus (HCV) entry into target cells. Recent studies have made disparate observations of the modulation of the expression of CLDN1 on cells following infection by HCV. In one study, the mean CLDN1 expression on cells exposed to HCV declined, whereas in another study HCV infected cells showed increased CLDN1 expression compared to uninfected cells. Consequently, the role of HCV in modulating CLDN1 expression, and hence the frequency of cellular superinfection, remains unclear. Here, we present a possible reconciliation of these disparate observations. We hypothesized that viral kinetics and not necessarily HCV-induced receptor modulation underlies these disparate observations. To test this hypothesis, we constructed a mathematical model of viral kinetics in vitro that mimicked the above experiments. Model predictions provided good fits to the observed evolution of the distribution of CLDN1 expression on cells following exposure to HCV. Cells with higher CLDN1 expression were preferentially infected and outgrown by cells with lower CLDN1 expression, resulting in a decline of the mean CLDN1 expression with time. At the same time, because the susceptibility of cells to infection increased with CLDN1 expression, infected cells tended to have higher CLDN1 expression on average than uninfected cells. Our study thus presents an explanation of the disparate observations of CLDN1 expression following HCV infection and points to the importance of considering viral kinetics in future studies of receptor expression on cells exposed to HCV. PMID- 22545158 TI - Nationwide surveillance of influenza during the pandemic (2009-10) and post pandemic (2010-11) periods in Taiwan. AB - INTRODUCTION: Although WHO declared the world moving into the post-pandemic period on August 10, 2010, influenza A(H1N1) 2009 virus continued to circulate globally. Its impact was expected to continue during the 2010-11 influenza season. This study describes the nationwide surveillance findings of the pandemic and post-pandemic influenza periods in Taiwan and assesses the impact of influenza A(H1N1) 2009 during the post-pandemic period. METHODS: The Influenza Laboratory Surveillance Network consisted of 12 contract laboratories for collecting and testing samples with acute respiratory tract infections. Surveillance of emergency room visits and outpatient department visits for influenza-like illness (ILI) were conducted using the Real-Time Outbreak and Disease Surveillance system and the National Health Insurance program data, respectively. Hospitalized cases with severe complications and deaths were reported to the National Notifiable Disease Surveillance System. RESULTS: During the 2009-10 influenza season, pandemic A(H1N1) 2009 was the predominant circulating strain and caused 44 deaths. However, the 2010-11 influenza season began with A(H3N2) being the predominant circulating strain, changing to A(H1N1) 2009 in December 2010. Emergency room and outpatient department ILI surveillance displayed similar trends. By March 31, 2011, there were 1,751 cases of influenza with severe complications; 50.1% reported underlying diseases. Of the reported cases, 128 deaths were associated with influenza. Among these, 93 (72.6%) were influenza A(H1N1) 2009 and 30 (23.4%) A(H3N2). Compared to the pandemic period, during the immediate post-pandemic period, increased number of hospitalizations and deaths were observed, and the patients were consistently older. CONCLUSIONS: Reemergence of influenza A(H1N1) 2009 during the 2010-11 influenza season had an intense activity with age distribution shift. To further mitigate the impact of future influenza epidemics, Taiwan must continue its multifaceted influenza surveillance systems, remain flexible with antiviral use policies, and revise the vaccine policies to include the population most at risk. PMID- 22545159 TI - miR-125b promotes early germ layer specification through Lin28/let-7d and preferential differentiation of mesoderm in human embryonic stem cells. AB - Unlike other essential organs, the heart does not undergo tissue repair following injury. Human embryonic stem cells (hESCs) grow indefinitely in culture while maintaining the ability to differentiate into many tissues of the body. As such, they provide a unique opportunity to explore the mechanisms that control human tissue development, as well as treat diseases characterized by tissue loss, including heart failure. MicroRNAs are small, non-coding RNAs that are known to play critical roles in the regulation of gene expression. We profiled the expression of microRNAs during hESC differentiation into myocardial precursors and cardiomyocytes (CMs), and determined clusters of human microRNAs that are specifically regulated during this process. We determined that miR-125b overexpression results in upregulation of the early cardiac transcription factors, GATA4 and Nkx2-5, and accelerated progression of hESC-derived myocardial precursors to an embryonic CM phenotype. We used an in silico approach to identify Lin28 as a target of miR-125b, and validated this interaction using miR 125b knockdown. Anti-miR-125b inhibitor experiments also showed that miR-125b controls the expression of miRNA let-7d, likely through the negative regulatory effects of Lin28 on let-7. We then determined that miR-125b overexpression inhibits the expression of Nanog and Oct4 and promotes the onset of Brachyury expression, suggesting that miR-125b controls the early events of human CM differentiation by inhibiting hESC pluripotency and promoting mesodermal differentiation. These studies identified miR-125b as an important regulator of hESC differentiation in general, and the development of hESC-derived mesoderm and cardiac muscle in particular. Manipulation of miR-125b-mediated pathways may provide a novel approach to directing the differentiation of hESC-derived CMs for cell therapy applications. PMID- 22545161 TI - A research agenda for helminth diseases of humans: towards control and elimination. AB - Human helminthiases are of considerable public health importance in sub-Saharan Africa, Asia, and Latin America. The acknowledgement of the disease burden due to helminth infections, the availability of donated or affordable drugs that are mostly safe and moderately efficacious, and the implementation of viable mass drug administration (MDA) interventions have prompted the establishment of various large-scale control and elimination programmes. These programmes have benefited from improved epidemiological mapping of the infections, better understanding of the scope and limitations of currently available diagnostics and of the relationship between infection and morbidity, feasibility of community directed or school-based interventions, and advances in the design of monitoring and evaluation (M&E) protocols. Considerable success has been achieved in reducing morbidity or suppressing transmission in a number of settings, whilst challenges remain in many others. Some of the obstacles include the lack of diagnostic tools appropriate to the changing requirements of ongoing interventions and elimination settings; the reliance on a handful of drugs about which not enough is known regarding modes of action, modes of resistance, and optimal dosage singly or in combination; the difficulties in sustaining adequate coverage and compliance in prolonged and/or integrated programmes; an incomplete understanding of the social, behavioural, and environmental determinants of infection; and last, but not least, very little investment in research and development (R&D). The Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to undertake a comprehensive review of recent advances in helminthiases research, identify research gaps, and rank priorities for an R&D agenda for the control and elimination of these infections. This review presents the processes undertaken to identify and rank ten top research priorities; discusses the implications of realising these priorities in terms of their potential for improving global health and achieving the Millennium Development Goals (MDGs); outlines salient research funding needs; and introduces the series of reviews that follow in this PLoS Neglected Tropical Diseases collection, "A Research Agenda for Helminth Diseases of Humans." PMID- 22545160 TI - A research agenda for helminth diseases of humans: basic research and enabling technologies to support control and elimination of helminthiases. AB - Successful and sustainable intervention against human helminthiases depends on optimal utilisation of available control measures and development of new tools and strategies, as well as an understanding of the evolutionary implications of prolonged intervention on parasite populations and those of their hosts and vectors. This will depend largely on updated knowledge of relevant and fundamental parasite biology. There is a need, therefore, to exploit and apply new knowledge and techniques in order to make significant and novel gains in combating helminthiases and supporting the sustainability of current and successful mass drug administration (MDA) programmes. Among the fields of basic research that are likely to yield improved control tools, the Disease Reference Group on Helminth Infections (DRG4) has identified four broad areas that stand out as central to the development of the next generation of helminth control measures: 1) parasite genetics, genomics, and functional genomics; 2) parasite immunology; 3) (vertebrate) host-parasite interactions and immunopathology; and 4) (invertebrate) host-parasite interactions and transmission biology. The DRG4 was established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR). The Group was given the mandate to undertake a comprehensive review of recent advances in helminthiases research in order to identify notable gaps and highlight priority areas. This paper summarises recent advances and discusses challenges in the investigation of the fundamental biology of those helminth parasites under the DRG4 Group's remit according to the identified priorities, and presents a research and development agenda for basic parasite research and enabling technologies that will help support control and elimination efforts against human helminthiases. PMID- 22545162 TI - A research agenda for helminth diseases of humans: modelling for control and elimination. AB - Mathematical modelling of helminth infections has the potential to inform policy and guide research for the control and elimination of human helminthiases. However, this potential, unlike in other parasitic and infectious diseases, has yet to be realised. To place contemporary efforts in a historical context, a summary of the development of mathematical models for helminthiases is presented. These efforts are discussed according to the role that models can play in furthering our understanding of parasite population biology and transmission dynamics, and the effect on such dynamics of control interventions, as well as in enabling estimation of directly unobservable parameters, exploration of transmission breakpoints, and investigation of evolutionary outcomes of control. The Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to review helminthiases research and identify research priorities and gaps. A research and development agenda for helminthiasis modelling is proposed based on identified gaps that need to be addressed for models to become useful decision tools that can support research and control operations effectively. This agenda includes the use of models to estimate the impact of large-scale interventions on infection incidence; the design of sampling protocols for the monitoring and evaluation of integrated control programmes; the modelling of co-infections; the investigation of the dynamical relationship between infection and morbidity indicators; the improvement of analytical methods for the quantification of anthelmintic efficacy and resistance; the determination of programme endpoints; the linking of dynamical helminth models with helminth geostatistical mapping; and the investigation of the impact of climate change on human helminthiases. It is concluded that modelling should be embedded in helminth research, and in the planning, evaluation, and surveillance of interventions from the outset. Modellers should be essential members of interdisciplinary teams, propitiating a continuous dialogue with end users and stakeholders to reflect public health needs in the terrain, discuss the scope and limitations of models, and update biological assumptions and model outputs regularly. It is highlighted that to reach these goals, a collaborative framework must be developed for the collation, annotation, and sharing of databases from large-scale anthelmintic control programmes, and that helminth modellers should join efforts to tackle key questions in helminth epidemiology and control through the sharing of such databases, and by using diverse, yet complementary, modelling approaches. PMID- 22545163 TI - A research agenda for helminth diseases of humans: intervention for control and elimination. AB - Recognising the burden helminth infections impose on human populations, and particularly the poor, major intervention programmes have been launched to control onchocerciasis, lymphatic filariasis, soil-transmitted helminthiases, schistosomiasis, and cysticercosis. The Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to review helminthiases research and identify research priorities and gaps. A summary of current helminth control initiatives is presented and available tools are described. Most of these programmes are highly dependent on mass drug administration (MDA) of anthelmintic drugs (donated or available at low cost) and require annual or biannual treatment of large numbers of at-risk populations, over prolonged periods of time. The continuation of prolonged MDA with a limited number of anthelmintics greatly increases the probability that drug resistance will develop, which would raise serious problems for continuation of control and the achievement of elimination. Most initiatives have focussed on a single type of helminth infection, but recognition of co-endemicity and polyparasitism is leading to more integration of control. An understanding of the implications of control integration for implementation, treatment coverage, combination of pharmaceuticals, and monitoring is needed. To achieve the goals of morbidity reduction or elimination of infection, novel tools need to be developed, including more efficacious drugs, vaccines, and/or antivectorial agents, new diagnostics for infection and assessment of drug efficacy, and markers for possible anthelmintic resistance. In addition, there is a need for the development of new formulations of some existing anthelmintics (e.g., paediatric formulations). To achieve ultimate elimination of helminth parasites, treatments for the above mentioned helminthiases, and for taeniasis and food-borne trematodiases, will need to be integrated with monitoring, education, sanitation, access to health services, and where appropriate, vector control or reduction of the parasite reservoir in alternative hosts. Based on an analysis of current knowledge gaps and identification of priorities, a research and development agenda for intervention tools considered necessary for control and elimination of human helminthiases is presented, and the challenges to be confronted are discussed. PMID- 22545164 TI - A research agenda for helminth diseases of humans: the problem of helminthiases. AB - A disproportionate burden of helminthiases in human populations occurs in marginalised, low-income, and resource-constrained regions of the world, with over 1 billion people in developing areas of sub-Saharan Africa, Asia, and the Americas infected with one or more helminth species. The morbidity caused by such infections imposes a substantial burden of disease, contributing to a vicious circle of infection, poverty, decreased productivity, and inadequate socioeconomic development. Furthermore, helminth infection accentuates the morbidity of malaria and HIV/AIDS, and impairs vaccine efficacy. Polyparasitism is the norm in these populations, and infections tend to be persistent. Hence, there is a great need to reduce morbidity caused by helminth infections. However, major deficiencies exist in diagnostics and interventions, including vector control, drugs, and vaccines. Overcoming these deficiencies is hampered by major gaps in knowledge of helminth biology and transmission dynamics, platforms from which to help develop such tools. The Disease Reference Group on Helminths Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to review helminthiases research and identify research priorities and gaps. In this review, we provide an overview of the forces driving the persistence of helminthiases as a public health problem despite the many control initiatives that have been put in place; identify the main obstacles that impede progress towards their control and elimination; and discuss recent advances, opportunities, and challenges for the understanding of the biology, epidemiology, and control of these infections. The helminth infections that will be discussed include: onchocerciasis, lymphatic filariasis, soil-transmitted helminthiases, schistosomiasis, food-borne trematodiases, and taeniasis/cysticercosis. PMID- 22545165 TI - Community risk factors for ocular Chlamydia infection in Niger: pre-treatment results from a cluster-randomized trachoma trial. AB - BACKGROUND: Trachoma control programs utilize mass azithromycin distributions to treat ocular Chlamydia trachomatis as part of an effort to eliminate this disease world-wide. But it remains unclear what the community-level risk factors are for infection. METHODS: This cluster-randomized, controlled trial entered 48 randomly selected communities in a 2*2 factorial design evaluating the effect of different treatment frequencies and treatment coverage levels. A pretreatment census and examination established the prevalence of risk factors for clinical trachoma and ocular chlamydia infection including years of education of household head, distance to primary water source, presence of household latrine, and facial cleanliness (ocular discharge, nasal discharge, and presence of facial flies). Univariate and multivariate associations were tested using linear regression and Bayes model averaging. FINDINGS: There were a total of 24,536 participants (4,484 children aged 0-5 years) in 6,235 households in the study. Before treatment in May to July 2010, the community-level prevalence of active trachoma (TF or TI utilizing the World Health Organization [WHO] grading system) was 26.0% (95% CI: 21.9% to 30.0%) and the mean community-level prevalence of chlamydia infection by Amplicor PCR was 20.7% (95% CI: 16.5% to 24.9%) in children aged 0-5 years. Univariate analysis showed that nasal discharge (0.29, 95% CI: 0.04 to 0.54; P = 0.03), presence of flies on the face (0.40, 95% CI: 0.17 to 0.64; P = 0.001), and years of formal education completed by the head of household (0.07, 95% CI: 0.07 to 0.13; P = 0.03) were independent risk factors for chlamydia infection. In multivariate analysis, facial flies (0.26, 95% CI: 0.02 to 0.49; P = 0.03) and years of formal education completed by the head of household (0.06, 95% CI: 0.008 to 0.11; P = 0.02) were associated risk factors for ocular chlamydial infection. INTERPRETATION: We have found that the presence of facial flies and years of education of the head of the household are risk factors for chlamydia infection when the analysis is done at the community level. TRIAL REGISTRATION: ClinicalTrials.gov NCT00792922. PMID- 22545167 TI - A research agenda for helminth diseases of humans: health research and capacity building in disease-endemic countries for helminthiases control. AB - Capacity building in health research generally, and helminthiasis research particularly, is pivotal to the implementation of the research and development agenda for the control and elimination of human helminthiases that has been proposed thematically in the preceding reviews of this collection. Since helminth infections affect human populations particularly in marginalised and low-income regions of the world, they belong to the group of poverty-related infectious diseases, and their alleviation through research, policy, and practice is a sine qua non condition for the achievement of the United Nations Millennium Development Goals. Current efforts supporting research capacity building specifically for the control of helminthiases have been devised and funded, almost in their entirety, by international donor agencies, major funding bodies, and academic institutions from the developed world, contributing to the creation of (not always equitable) North-South "partnerships". There is an urgent need to shift this paradigm in disease-endemic countries (DECs) by refocusing political will, and harnessing unshakeable commitment by the countries' governments, towards health research and capacity building policies to ensure long-term investment in combating and sustaining the control and eventual elimination of infectious diseases of poverty. The Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to review helminthiases research and identify research priorities and gaps. This paper discusses the challenges confronting capacity building for parasitic disease research in DECs, describes current capacity building strategies with particular reference to neglected tropical diseases and human helminthiases, and outlines recommendations to redress the balance of alliances and partnerships for health research between the developed countries of the "North" and the developing countries of the "South". We argue that investing in South-South collaborative research policies and capacity is as important as their North-South counterparts and is essential for scaled-up and improved control of helminthic diseases and ultimately for regional elimination. PMID- 22545166 TI - A research agenda for helminth diseases of humans: diagnostics for control and elimination programmes. AB - Diagnostic tools appropriate for undertaking interventions to control helminth infections are key to their success. Many diagnostic tests for helminth infection have unsatisfactory performance characteristics and are not well suited for use in the parasite control programmes that are being increasingly implemented. Although the application of modern laboratory research techniques to improve diagnostics for helminth infection has resulted in some technical advances, uptake has not been uniform. Frequently, pilot or proof of concept studies of promising diagnostic technologies have not been followed by much needed product development, and in many settings diagnosis continues to rely on insensitive and unsatisfactory parasitological or serodiagnostic techniques. In contrast, PCR based xenomonitoring of arthropod vectors, and use of parasite recombinant proteins as reagents for serodiagnostic tests, have resulted in critical advances in the control of specific helminth parasites. The Disease Reference Group on Helminths Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR) was given the mandate to review helminthiases research and identify research priorities and gaps. In this review, the diagnostic technologies relevant to control of helminth infections, either available or in development, are reviewed. Critical gaps are identified and opportunities to improve needed technologies are discussed. PMID- 22545168 TI - A research agenda for helminth diseases of humans: social ecology, environmental determinants, and health systems. AB - In this paper, the Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), with the mandate to review helminthiases research and identify research priorities and gaps, focuses on the environmental, social, behavioural, and political determinants of human helminth infections and outlines a research and development agenda for the socioeconomic and health systems research required for the development of sustainable control programmes. Using Stockols' social-ecological approach, we describe the role of various social (poverty, policy, stigma, culture, and migration) and environmental determinants (the home environment, water resources development, and climate change) in the perpetuation of helminthic diseases, as well as their impact as contextual factors on health promotion interventions through both the regular and community based health systems. We examine these interactions in regard to community participation, intersectoral collaboration, gender, and possibilities for upscaling helminthic disease control and elimination programmes within the context of integrated and interdisciplinary approaches. The research agenda summarises major gaps that need to be addressed. PMID- 22545169 TI - Pathogen-specific epitopes as epidemiological tools for defining the magnitude of Mycobacterium leprae transmission in areas endemic for leprosy. AB - During recent years, comparative genomic analysis has allowed the identification of Mycobacterium leprae-specific genes with potential application for the diagnosis of leprosy. In a previous study, 58 synthetic peptides derived from these sequences were tested for their ability to induce production of IFN-gamma in PBMC from endemic controls (EC) with unknown exposure to M. leprae, household contacts of leprosy patients and patients, indicating the potential of these synthetic peptides for the diagnosis of sub- or preclinical forms of leprosy. In the present study, the patterns of IFN-gamma release of the individuals exposed or non-exposed to M. leprae were compared using an Artificial Neural Network algorithm, and the most promising M. leprae peptides for the identification of exposed people were selected. This subset of M. leprae-specific peptides allowed the differentiation of groups of individuals from sites hyperendemic for leprosy versus those from areas with lower level detection rates. A progressive reduction in the IFN-gamma levels in response to the peptides was seen when contacts of multibacillary (MB) patients were compared to other less exposed groups, suggesting a down modulation of IFN-gamma production with an increase in bacillary load or exposure to M. leprae. The data generated indicate that an IFN gamma assay based on these peptides applied individually or as a pool can be used as a new tool for predicting the magnitude of M. leprae transmission in a given population. PMID- 22545170 TI - Innate immune response to Rift Valley fever virus in goats. AB - Rift Valley fever (RVF), a re-emerging mosquito-borne disease of ruminants and man, was endemic in Africa but spread to Saudi Arabia and Yemen, meaning it could spread even further. Little is known about innate and cell-mediated immunity to RVF virus (RVFV) in ruminants, which is knowledge required for adequate vaccine trials. We therefore studied these aspects in experimentally infected goats. We also compared RVFV grown in an insect cell-line and that grown in a mammalian cell-line for differences in the course of infection. Goats developed viremia one day post infection (DPI), which lasted three to four days and some goats had transient fever coinciding with peak viremia. Up to 4% of peripheral blood mononuclear cells (PBMCs) were positive for RVFV. Monocytes and dendritic cells in PBMCs declined possibly from being directly infected with virus as suggested by in vitro exposure. Infected goats produced serum IFN-gamma, IL-12 and other proinflammatory cytokines but not IFN-alpha. Despite the lack of IFN-alpha, innate immunity via the IL-12 to IFN-gamma circuit possibly contributed to early protection against RVFV since neutralising antibodies were detected after viremia had cleared. The course of infection with insect cell-derived RVFV (IN-RVFV) appeared to be different from mammalian cell-derived RVFV (MAM-RVFV), with the former attaining peak viremia faster, inducing fever and profoundly affecting specific immune cell subpopulations. This indicated possible differences in infections of ruminants acquired from mosquito bites relative to those due to contact with infectious material from other animals. These differences need to be considered when testing RVF vaccines in laboratory settings. PMID- 22545171 TI - Selective inhibitors of protozoan protein N-myristoyltransferases as starting points for tropical disease medicinal chemistry programs. AB - Inhibition of N-myristoyltransferase has been validated pre-clinically as a target for the treatment of fungal and trypanosome infections, using species specific inhibitors. In order to identify inhibitors of protozoan NMTs, we chose to screen a diverse subset of the Pfizer corporate collection against Plasmodium falciparum and Leishmania donovani NMTs. Primary screening hits against either enzyme were tested for selectivity over both human NMT isoforms (Hs1 and Hs2) and for broad-spectrum anti-protozoan activity against the NMT from Trypanosoma brucei. Analysis of the screening results has shown that structure-activity relationships (SAR) for Leishmania NMT are divergent from all other NMTs tested, a finding not predicted by sequence similarity calculations, resulting in the identification of four novel series of Leishmania-selective NMT inhibitors. We found a strong overlap between the SARs for Plasmodium NMT and both human NMTs, suggesting that achieving an appropriate selectivity profile will be more challenging. However, we did discover two novel series with selectivity for Plasmodium NMT over the other NMT orthologues in this study, and an additional two structurally distinct series with selectivity over Leishmania NMT. We believe that release of results from this study into the public domain will accelerate the discovery of NMT inhibitors to treat malaria and leishmaniasis. Our screening initiative is another example of how a tripartite partnership involving pharmaceutical industries, academic institutions and governmental/non governmental organisations such as Medical Research Council and Wellcome Trust can stimulate research for neglected diseases. PMID- 22545173 TI - Deficient regulatory T cell activity and low frequency of IL-17-producing T cells correlate with the extent of cardiomyopathy in human Chagas' disease. AB - BACKGROUND: Myocardium damage during Chagas' disease results from the immunological imbalance between pro- and production of anti-inflammatory cytokines and has been explained based on the Th1-Th2 dichotomy and regulatory T cell activity. Recently, we demonstrated that IL-17 produced during experimental T. cruzi infection regulates Th1 cells differentiation and parasite induced myocarditis. Here, we investigated the role of IL-17 and regulatory T cell during human Chagas' disease. METHODOLOGY/PRINCIPAL FINDINGS: First, we observed CD4(+)IL-17(+) T cells in culture of peripheral blood mononuclear cells (PBMC) from Chagas' disease patients and we evaluated Th1, Th2, Th17 cytokine profile production in the PBMC cells from Chagas' disease patients (cardiomyopathy-free, and with mild, moderate or severe cardiomyopathy) cultured with T. cruzi antigen. Cultures of PBMC from patients with moderate and severe cardiomyopathy produced high levels of TNF-alpha, IFN-gamma and low levels of IL-10, when compared to mild cardiomyopathy or cardiomyopathy-free patients. Flow cytometry analysis showed higher CD4(+)IL-17(+) cells in PBMC cultured from patients without or with mild cardiomyopathy, in comparison to patients with moderate or severe cardiomyopathy. We then analyzed the presence and function of regulatory T cells in all patients. All groups of Chagas' disease patients presented the same frequency of CD4(+)CD25(+) regulatory T cells. However, CD4(+)CD25(+) T cells from patients with mild cardiomyopathy or cardiomyopathy-free showed higher suppressive activity than those with moderate and severe cardiomyopathy. IFN gamma levels during chronic Chagas' disease are inversely correlated to the LVEF (P = 0.007, r = -0.614), while regulatory T cell activity is directly correlated with LVEF (P = 0.022, r = 0.500). CONCLUSION/SIGNIFICANCE: These results indicate that reduced production of the cytokines IL-10 and IL-17 in association with high levels of IFN-gamma and TNF-alpha is correlated with the severity of the Chagas' disease cardiomyopathy, and the immunological imbalance observed may be causally related with deficient suppressor activity of regulatory T cells that controls myocardial inflammation. PMID- 22545172 TI - Regulatory T cells in the pathogenesis and healing of chronic human dermal leishmaniasis caused by Leishmania (Viannia) species. AB - BACKGROUND: The inflammatory response is prominent in the pathogenesis of dermal leishmaniasis. We hypothesized that regulatory T cells (Tregs) may be diminished in chronic dermal leishmaniasis (CDL) and contribute to healing during treatment. METHODOLOGY/PRINCIPAL FINDINGS: The frequency and functional capacity of Tregs were evaluated at diagnosis and following treatment of CDL patients having lesions of >=6 months duration and asymptomatically infected residents of endemic foci. The frequency of CD4(+)CD25(hi) cells expressing Foxp3 or GITR or lacking expression of CD127 in peripheral blood was determined by flow cytometry. The capacity of CD4(+)CD25(+) cells to inhibit Leishmania-specific responses was determined by co-culture with effector CD4(+)CD25(-) cells. The expression of FOXP3, IFNG, IL10 and IDO was determined in lesion and leishmanin skin test site biopsies by qRT-PCR. Although CDL patients presented higher frequency of CD4(+)CD25(hi)Foxp3(+) cells in peripheral blood and higher expression of FOXP3 at leishmanin skin test sites, their CD4(+)CD25(+) cells were significantly less capable of suppressing antigen specific-IFN-gamma secretion by effector cells compared with asymptomatically infected individuals. At the end of treatment, both the frequency of CD4(+)CD25(hi)CD127(-) cells and their capacity to inhibit proliferation and IFN-gamma secretion increased and coincided with healing of cutaneous lesions. IDO was downregulated during healing of lesions and its expression was positively correlated with IFNG but not FOXP3. CONCLUSIONS/SIGNIFICANCE: The disparity between CD25(hi)Foxp3(+) CD4 T cell frequency in peripheral blood, Foxp3 expression at the site of cutaneous responses to leishmanin, and suppressive capacity provides evidence of impaired Treg function in the pathogenesis of CDL. Moreover, the concurrence of increased Leishmania-specific suppressive capacity with induction of a CD25(hi)CD127(-) subset of CD4 T cells during healing supports the participation of Tregs in the resolution of chronic dermal lesions. Treg subsets may therefore be relevant in designing immunotherapeutic strategies for recalcitrant dermal leishmaniasis caused by Leishmania (Viannia) species. PMID- 22545174 TI - A research and development agenda for the control and elimination of human helminthiases. PMID- 22545176 TI - Regulation of lysosomal secretion by cortactin drives fibronectin deposition and cell motility. AB - Directional cellular movement is required for various organismal processes, including immune defense and cancer metastasis. Proper navigation of migrating cells involves responding to a complex set of extracellular cues, including diffusible chemical signals and physical structural information. In tissues, conflicting gradients and signals may require cells to not only respond to the environment but also modulate it for efficient adhesion formation and directional cell motility. Recently, we found that cells endocytose fibronectin (FN) and resecrete it from a late endosomal/lysosomal (LE/Lys) compartment to provide an autocrine extracellular matrix (ECM) substrate for cell motility. Branched actin assembly regulated by cortactin was required for trafficking of FN-containing vesicles from LE/Lys to the cell surface. These findings suggest a model in which migrating cells use lysosomal secretion as a versatile mechanism to modulate the ECM environment, promote adhesion assembly and enhance directional migration. PMID- 22545175 TI - Exposing the Moving Parts of Proteins with NMR Spectroscopy. AB - Nuclear Magnetic Resonance (NMR) spectroscopy is a powerful tool for investigating the dynamics of biomolecules since it provides a description of motion that is comprehensive, site-specific, and relatively non-invasive. In particular, the study of protein dynamics has benefited from sustained methodological advances in NMR that have expanded the scope and time scales of accessible motion. Yet, many of these advances may not be well known to the more general physical chemistry community. Accordingly, this Perspective provides a glimpse of some of the more powerful methods in liquid state NMR that are helping reshape our understanding of functional motions of proteins. PMID- 22545178 TI - Microtubule dynamics in the peripheral nervous system: A matter of balance. AB - The special architecture of neurons in the peripheral nervous system, with axons extending for long distances, represents a major challenge for the intracellular transport system. Two recent studies show that mutations in the small heat shock protein HSPB1, which cause an axonal type of Charcot-Marie-Tooth (CMT) neuropathy, affect microtubule dynamics and impede axonal transport. Intriguingly, while at presymptomatic age the neurons in the mutant HSPB1 mouse show a hyperstable microtubule network, at postsymptomatic age, the microtubule network completely lost its stability as reflected by a marked decrease in tubulin acetylation levels. We here propose a model explaining the role of microtubule stabilization and tubulin acetylation in the pathogenesis of HSPB1 mutations. PMID- 22545177 TI - A novel function of the cell polarity-regulating kinase PAR-1/MARK in dendritic spines. AB - Dendritic spines are postsynaptic structures that receive excitatory synaptic signals from presynaptic terminals in neurons. Because the morphology of spines has been considered to be a crucial factor for the efficiency of synaptic transmission, understanding the mechanisms regulating their morphology is important for neuroscience. Actin filaments and their regulatory proteins are known to actively maintain spine morphology; recent studies have also shown an essential role of microtubules (MTs). Live imaging of the plus-ends of MTs in mature neurons revealed that MTs stochastically enter spines and mediate accumulation of p140Cap, which regulates reorganization of actin filaments. However, the molecular mechanism by which MT dynamics is controlled has remained largely unknown. A cell polarity-regulating serine/threonine kinase, partitioning defective 1 (PAR-1), phosphorylates classical MAPs and inhibits their binding to MTs. Because the interaction of MAPs with MTs can decrease MT dynamic instability, PAR-1 is supposed to activate MT dynamics through its MAP/MT affinity-regulating kinase (MARK) activity, although there is not yet any direct evidence for this. Here, we review recent findings on the localization of PAR-1b in the dendrites of mouse hippocampal neurons, and its novel function in the maintenance of mature spine morphology by regulating MT dynamics. PMID- 22545179 TI - Microfluidics pushes forward microscopy analysis of actin dynamics. AB - Actin filaments, an essential part of the cytoskeleton, drive various cell processes, during which they elongate, disassemble and form different architectures. Over the past 30 years, the study of actin dynamics has relied mainly on bulk solution measurements, which revealed the kinetics and thermodynamics of actin self-assembly at barbed and pointed ends, its control by ATP hydrolysis and its regulation by proteins binding either monomeric actin or filament ends and sides. These measurements provide quantitative information on the averaged behavior of a homogeneous population of filaments. They have been complemented by light microscopy observations of stabilized individual filaments, providing information inaccessible using averaging methods, such as mechanical properties or length distributions. In the past ten years, the improvement of light microscopy techniques has allowed biophysicists to monitor the dynamics of individual actin filaments, thus giving access to the length fluctuations of filaments or the mechanism of processive assembly by formins. Recently, in order to solve some of the problems linked to these observations, such as the need to immobilize filaments on a coverslip, we have used microfluidics as a tool to improve the observation, manipulation and analysis of individual actin filaments. This microfluidic method allowed us to rapidly switch filaments from polymerizing to depolymerizing conditions, and derive the molecular mechanism of ATP hydrolysis on a single filament from the kinetic analysis of its nucleotide dependent disassembly rate. Here, we discuss how this work sets the basis for future experiments on actin dynamics, and briefly outline promising developments of this technique. PMID- 22545180 TI - Modulation of striated muscle contraction by binding of myosin binding protein C to actin. AB - Myosin binding protein C (MyBP-C or C-protein) is a protein of the thick (myosin containing) filaments of striated muscle thought to be involved in the modulation of cardiac contraction in response to beta-adrenergic stimulation. The mechanism of this modulation is unknown, but one possibility is through transient binding of the N-terminal end of MyBP-C to the thin (actin-containing) filaments. While such binding has been demonstrated in vitro, it was not known until recently whether such a link between thick and thin filaments also occurred in vivo. Here we review a recent paper in which electron microscopy (EM) is used to directly demonstrate MyBP-C links between myosin and actin filaments in the intact sarcomere, suggesting a possible physical mechanism for modulating filament sliding. Molecular details of MyBP-C binding to actin have recently been elucidated by EM of isolated filaments: the results suggest that MyBP-C might contribute to the modulation of contraction in part by competing with tropomyosin for binding sites on actin. New results on the structure and dynamics of the MyBP C molecule provide additional insights into the function of this enigmatic molecule. PMID- 22545181 TI - TPM3 and TPM4 gene products segregate to the postsynaptic region of central nervous system synapses. AB - Synaptic function in the central nervous system (CNS) is highly dependent on a dynamic actin cytoskeleton in both the pre- and the postsynaptic compartment. Remodelling of the actin cytoskeleton is controlled by tropomyosins, a family of actin-associated proteins which define distinct actin filament populations. Here we show that TPM3 and TPM4 gene products localize to the postsynaptic region in mouse hippocampal neurons. Furthermore our data confirm previous findings of isoform segregation to the pre- and postsynaptic compartments at CNS synapses. These data provide fundamental insights in the formation of functionally distinct actin filament populations at the pre- and post-synapse. PMID- 22545182 TI - Antibiotic prophylaxis: reasoned choice and not casual use. PMID- 22545183 TI - Evaluation of the efficacy of an hyaluronic acid-based biogel on periodontal clinical parameters. A randomized-controlled clinical pilot study. AB - Hyaluronic acid (HA) is an ubiquitous form of non-sulphated glycosaminoglycan of the extracellular matrix of all mammalian connective tissues. It is mainly present during tissue's formation or during most of initial tissue's repair processess. Cell migration, adhesion and differentiation are only part of several unique biological characteristics of HA which have been under investigation in the past decades. AIM OF THE STUDY: Evaluate the possible positive effect of an esterified form of HA on gingival tissues in mild chronic periodontitis patients, seeking for the reduction of all the periodontal disease clinical parameters PLI (Plaque Index), BOP (Bleeding on Probing), PPD (Probing Pocket Depth), GI (Gingival Index), PAL (Probing Attachment Level). MATERIALS AND METHODS: The study is an open, intra-patient, controlled, single center pilot clinical trial including 19 adult patients with mild chronic periodontitis and shallow pockets (< 4 mm) in at least two different quadrants. One quadrant was treated with HA gel after regular toothbrushing (test), the other without (control). RESULTS: Although oral hygiene itself had a similar positive influence on the improvement of all the clinical indexes for test and control, the treatment with HA gel showed a greater effect almost always statistically significant. BOP in the HA gel treated areas had a decrease of 92.7% and GI of 96.5%, whereas controls 75.8% and 79.0% respectively. The difference of PPD in both areas was statistically significant (p<0.01) in favour of the HA gel treated zone. Also PAL and Pl were reduced more with gel than with oral hygiene alone, although this did not reach a statistical significant difference. CONCLUSION: It appears that an esterified gel form of HA has shown an effect in reducing the gingival inflammation when used as an adjunct to mechanical home plaque control and that it could be successfully used to improve the periodontal clinical indexes. This pilot study will gain substantial scientific significance when both a higher number of patients can be utilized and also by adding any possible further biological information, as with immunocytochemistry and histology. PMID- 22545184 TI - Lactoferrin and oral diseases: current status and perspective in periodontitis. AB - Lactoferrin (Lf), an iron-binding glycoprotein able to chelate two ferric ions per molecule, is a component of human secretions synthesized by exocrine glands and neutrophils in infection/inflammation sites. Lactoferrin in saliva represents an important defence factor against bacterial injuries including those related to Streptococcus mutans and periodontopathic bacteria through its ability to decrease bacterial growth, biofilm development, iron overload, reactive oxygen formation and inflammatory processes.A growing body of research suggests that inflammatory periodontal disease involves a failure of resolution pathways to restore tissue homeostasis. There is an important distinction between anti inflammation and resolution; anti-inflammation is pharmacologic intervention in inflammatory pathways, whereas resolution involves biologic pathways restoring inflammatory homeostasis. An appropriate regulation of pro-inflammatory cytokine synthesis might be useful in reducing periodontal tissue destruction. Recently, the multi-functional IL-6 is emerging as an important factor able to modulate bone, iron and inflammatory homeostasis.Here, we report an overview of Lf functions as well as for the first time Lf anti-inflammatory ability against periodontitis in in vitro model and observational clinical study. In in vitro model, represented by gingival fibroblasts infected with Prevotella intermedia, Lf exerted a potent anti-inflammatory activity. In the observational clinical trial performed through bovine Lf (bLf) topically administered to volunteers suffering from periodontitis, bLf decreased cytokines, including IL-6 in crevicular fluid, edema, bleeding, pocket depth, gingival and plaque index, thus improving clinical attachment levels.Even if other clinical trials are required, these results provide strong evidence for a instead of an therapeutic potential of this multifunctional natural protein. PMID- 22545185 TI - Investigation of complete dental arches of 23 patients aged at least 75 years. AB - Numerous factors help to conserve the dentition of elderly patients, such as healthy food habits, a strong physical constitution, and a good quality of life. The aim of this study was to define a model that takes into account the integration of both the structural and functional aspects of a healthy dentition. Twenty-three patients aged at least 75 years were recruited. The patients were required to possess all of their dentition and have no prosthetic rehabilitations and be asymptomatic for temporomandibular joint disorders. Occlusal characteristics were measured and recorded using the criteria adopted by the US National Health and Nutrition Examination Survey: presence or absence of rotation of the upper arches, trend of the occlusal table, and distribution of occlusal contacts during movements. We believe that the following parameters are predictive of a condition of the dental arches' equilibrium: crowding and disalignment of the teeth, derotated position of the upper arches, absence of the curve of Spee, an occlusal plane trend contrary to spherical theory, and presence of group function on the working side and malocclusion on the nonworking side. We consider that these factors are merely the consequence of correct functioning within the framework of favorable environmental factors. PMID- 22545186 TI - Disabled patients and oral health in Rome, Italy: long-term evaluation of educational initiatives. AB - This study is concerned with the educational intervention layout proposed as a possible answer for the disparities in healthcare services for disabled persons. MATERIAL AND METHODS: The data sampling was performed on individuals in Rome, affected by psychophysical disabilities, living in residential care facilities. Participants were randomly divided into two groups: Study and Control Group, consisting of patients who did or did not participate in the Educational Phase. All the caregivers participated in an educational course. Screening period: September 2008 - March 2009. Examinations were performed using Visible Plaque Index (VPI), Gingival Bleeding Index (GBI) and Microbiological Analysis. RESULTS: The total number of patients utilized for the study was 36 (18 in each group). The final sample amounted to 70% (14/20) in the Study Group and to 75% (15/20) in the Control Group. In both examined groups Oral Hygiene, Gingival Health State and Microbiological Analysis show an overall improvement of the indices, compared with the initial status, mostly at a follow-up after 4 weeks. However, Study Group show a significantly better improvement. Conversely, after 6 months the overall clinical indices worsened again. CONCLUSION: The difference in the significant improvements of the groups, even if only over a short-time evaluation, endorses that the participation of the patients as well as tutors in the educational phase is an effective strategy for the short-term. PMID- 22545187 TI - 3D cephalometric analysis obtained from computed tomography. Review of the literature. AB - INTRODUCTION: The aim of this systematic review is to estimate accuracy and reproducibility of craniometric measurements and reliability of landmarks identified with computed tomography (CT) techniques in 3D cephalometric analysis. METHODS: Computerized and manual searches were conducted up to 2011 for studies that addressed these objectives. The selection criteria were: (1) the use of human specimen; (2) the comparison between 2D and 3D cephalometric analysis; (3) the assessment of accuracy, reproducibility of measurements and reliability of landmark identification with CT images compared with two-dimensional conventional radiographs. The Cochrane Handbook for Systematic Reviews of Interventions was used as the guideline for this article. RESULTS: Twenty-seven articles met the inclusion criteria. Most of them demonstrated high measurements accuracy and reproducibility, and landmarks reliability, but their cephalometric analysis methodology varied widely. CONCLUSION: These differencies among the studies in making measurements don't permit a direct comparison between them. The future developments in the knowledge of these techniques should provide a standardized method to conduct the 3D CT cephalometric analysis. PMID- 22545188 TI - Fused upper central incisors: management of two clinical cases. AB - This paper reports the management of two clinical cases, in which the upper right central incisor was fused with a supernumerary tooth and the upper left central incisor was macrodontic. A radiographic examination revealed that the fused teeth had two separate roots. Hemisectioning of the fused teeth was performed, the supernumerary portion was extracted and the remaining part was reshaped to remove any sharp margins and to achieve a normal morphology. The macrodontic central incisors were not treated. At 12-months post-surgery there were no periodontal problems and no hypersensitivity. Orthodontic treatment was performed to appropriately align the maxillary teeth and to correct the malocclusion. PMID- 22545189 TI - Inter- relationships between orthodontics and posture: basic theories. AB - The first part of the present report deals mainly with the concept of posture - both in static and in dynamic sense - its relationships with equilibrium, weight balance and motion, its phylogenic origin, reasons why any orthodontic professional should be aware of it; moreover, different profile types and their connections with one's own skeletal class are briefly discussed. Two more papers are following on the subject. PMID- 22545190 TI - Multilevel analysis of clinical parameters in chronic periodontitis after root planing/scaling, surgery, and systemic and local antibiotics: 2-year results. AB - AIM: Find the periodontal treatment that best maintained clinical results over time evaluated by changes in pocket depth (PD) and clinical attachment level (CAL). METHODS: 229 patients with chronic periodontitis from USA (n=134) and Sweden (n=95) were randomly assigned to eight groups receiving (1) scaling+root planing (SRP) alone or combined with (2) surgery (SURG)+systemic amoxicillin (AMOX)+systemic metronidazole (MET); (3) SURG+local tetracycline (TET); (4) SURG; (5) AMOX+MET+TET; (6) AMOX+MET; (7) TET; and (8) SURG+AMOX+MET+TET. Antibiotics were given immediately after SRP. Plaque, gingival redness, bleeding on probing, suppuration, PD, and CAL were recorded at baseline and after 3, 6, 12, 18, and 24 months. Treatment effects were evaluated by linear multilevel regression and logistic multilevel regression models. We considered only data from sites with a baseline PD of at least 5 mm of 187 patients completing the study. RESULTS: Surgically treated patients experienced most CAL loss. Adjunctive therapy including SURG was most effective in reducing PD. Combining SURG with AMOX, MET, and TET gave significant clinical benefits. Past and current smoking habits were significant predictors of deeper PD. Only current smoking was a significant predictor of CAL loss. Bleeding, accumulation of plaque, gingival redness, and suppuration were significant predictors of further CAL loss and deeper PD. CONCLUSIONS: Both surgical and non-surgical therapies can be used to arrest chronic periodontitis. SURG+AMOX+MET+TET gave best maintenance of clinical results. PMID- 22545192 TI - Intrinsic noise alters the frequency spectrum of mesoscopic oscillatory chemical reaction systems. AB - Mesoscopic oscillatory reaction systems, for example in cell biology, can exhibit stochastic oscillations in the form of cyclic random walks even if the corresponding macroscopic system does not oscillate. We study how the intrinsic noise from molecular discreteness influences the frequency spectrum of mesoscopic oscillators using as a model system a cascade of coupled Brusselators away from the Hopf bifurcation. The results show that the spectrum of an oscillator depends on the level of noise. In particular, the peak frequency of the oscillator is reduced by increasing noise, and the bandwidth increased. Along a cascade of coupled oscillators, the peak frequency is further reduced with every stage and also the bandwidth is reduced. These effects can help understand the role of noise in chemical oscillators and provide fingerprints for more reliable parameter identification and volume measurement from experimental spectra. PMID- 22545191 TI - New considerations in the design of clinical trials for amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis is a devastating neurodegenerative disease caused by loss of motor neurons. Its pathophysiology remains unknown, but progress has been made in understanding its genetic and biochemical basis. Clinical trialists are working to translate basic science successes into human trials with more efficiency, in the hope of finding successful treatments. In the future, new preclinical models, including patient-derived stem cells may augment transgenic animal models as preclinical tools. Biomarker discovery projects aim to identify markers of disease onset and progression for use in clinical trials. New trial designs are reducing study time, improving efficiency and helping to keep pace with the increasing rate of basic and translational discoveries. Ongoing trials with novel designs are paving the way for amyotrophic lateral sclerosis clinical research. PMID- 22545193 TI - Clues from joint inversion of tsunami and geodetic data of the 2011 Tohoku-oki earthquake. AB - The 2011 Tohoku-oki (Mw 9.1) earthquake is so far the best-observed megathrust rupture, which allowed the collection of unprecedented offshore data. The joint inversion of tsunami waveforms (DART buoys, bottom pressure sensors, coastal wave gauges, and GPS-buoys) and static geodetic data (onshore GPS, seafloor displacements obtained by a GPS/acoustic combination technique), allows us to retrieve the slip distribution on a non-planar fault. We show that the inclusion of near-source data is necessary to image the details of slip pattern (maximum slip ~48 m, up to ~35 m close to the Japan trench), which generated the large and shallow seafloor coseismic deformations and the devastating inundation of the Japanese coast. We investigate the relation between the spatial distribution of previously inferred interseismic coupling and coseismic slip and we highlight the importance of seafloor geodetic measurements to constrain the interseismic coupling, which is one of the key-elements for long-term earthquake and tsunami hazard assessment. PMID- 22545194 TI - A Peptide/MHCII conformer generated in the presence of exchange peptide is substrate for HLA-DM editing. AB - The mechanism of HLA-DM (DM) activity is still unclear. We have shown that DM mediated peptide release from HLA-DR (DR) is dependent on the presence of exchange peptide. However, DM also promotes a small amount of peptide release in the absence of exchange peptide. Here we show that SDS-PAGE separates purified peptide/DR1 complexes (pDR1) into two conformers whose ratio is peptide K(d) dependent. In the absence of exchange peptide, DM only releases peptide from the slower migrating conformer. Addition of exchange peptide converts the DM resistant conformer to the slower migrating conformer, which is DM labile. Thus, exchange peptide generates a conformer of pDR1 which constitutes the intermediate for peptide exchange and the substrate for DM activity. The resolution of the intermediate favors the highest affinity peptide. However, once folded into the DM-resistant conformer, even low affinity peptides can be presented in the absence of free peptide, broadening the repertoire available for presentation. PMID- 22545195 TI - Prognostic significance of melanoma differentiation and trans-differentiation. AB - Cutaneous malignant melanomas share a number of molecular attributes such as limitless replicative potential that define capabilities acquired by most malignancies. Accordingly, much effort has been focused on evaluating and validating protein markers related to these capabilities to function as melanoma prognostic markers. However, a few studies have also highlighted the prognostic value of markers that define melanocytic differentiation and the plasticity of melanoma cells to trans-differentiate along several other cellular pathways. Here, we provide a comprehensive review and evaluation of the prognostic significance of melanocyte-lineage markers such as MITF and melanogenic proteins, as well as markers of vascular epithelial and neuronal differentiation. PMID- 22545197 TI - Gyral window mapping of typical cortical folding using MRI. AB - Using the NIH Pediatric MRI Data Repository for normative developmental studies, white matter depth within the gyri of the frontal, temporal, parietal, and occipital lobes, and of the left and right hemisphere was identified for 312 typically developing children and young adults (168 male and 144 female) between 4 and 23 years of age. There was no significant age difference between male and female groups overall (F(1,867) = 0.0002; p = 0.99) or per-visit (F(2,867) = 2.18; p = 0.86). There was significant dependence of gyral window upon age (F(1,6544) = 115, p < 0.0001), lobe (F(3,6544) = 229, p < 0.0001), hemisphere (F(1,6544) = 5.23, p = 0.022), age*sex (F(1,6544) = 13.8, p = 0.0002), age*lobe (F(3,6544) = 120, p = 0.0001), and age*hemisphere (F(1,6544) = 4.41, p = 0.036). Gyrification increased with age in both males and females in the frontal, temporal and parietal lobes with opposite effects observed in the occipital lobe. Relative gyral depth, as measured in this study, was significantly (p < 0.0001) inversely correlated with gyrification index. Previous studies relate gyral window measurements to the differential expression of short and long corticocortical projections. Our results therefore suggest that the pattern of corticocortical connections is malleable during the first two decades of development. PMID- 22545196 TI - Corpus Callosum Shape Analysis with Application to Dyslexia. AB - Morphometric studies of the corpus callosum suggest its involvement in a number of psychiatric conditions. In the present study we introduce a novel pattern recognition technique that offers a point-by-point shape descriptor of the corpus callosum. The method uses arc lengths of electric field lines in order to avoid discontinuities caused by folding anatomical contours. We tested this technique by comparing the shape of the corpus callosum in a series of dyslexic men (n = 16) and age-matched controls (n = 14). The results indicate a generalized increase in size of the corpus callosum in dyslexia with a concomitant diminution at its rostral and caudal poles. The reported shape analysis and 2D reconstruction provide information of anatomical importance that would otherwise passed unnoticed when analyzing size information alone. PMID- 22545198 TI - Spherical harmonic analysis of cortical complexity in autism and dyslexia. AB - Alterations in gyral form and complexity have been consistently noted in both autism and dyslexia. In this present study, we apply spherical harmonics, an established technique which we have exapted to estimate surface complexity of the brain, in order to identify abnormalities in gyrification between autistics, dyslexics, and controls. On the order of absolute surface complexity, autism exhibits the most extreme phenotype, controls occupy the intermediate ranges, and dyslexics exhibit lesser surface complexity. Here, we synthesize our findings which demarcate these three groups and review how factors controlling neocortical proliferation and neuronal migration may lead to these distinctive phenotypes. PMID- 22545199 TI - Antibody-mediated rejection: pathogenesis, prevention, treatment, and outcomes. AB - Antibody-mediated rejection (AMR) is a major cause of late kidney transplant failure. It is important to have an understanding of human-leukocyte antigen (HLA) typing including well-designed studies to determine anti-MHC-class-I related chain A (MICA) and antibody rejection pathogenesis. This can allow for more specific diagnosis and treatment which may improve long-term graft function. HLA-specific antibody detection prior to transplantation allows one to help determine the risk for AMR while detection of DSA along with a biopsy confirms it. It is now appreciated that biopsy for AMR does not have to include diffuse C4d, but does require a closer look at peritubular capillary microvasculature. Although plasmapheresis (PP) is effective in removing alloantibodies (DSAs) from the circulation, rebound synthesis of alloantibodies can occur. Splenectomy is used in desensitization protocols for ABO incompatible transplants as well as being found to treat AMR refractory to conventional treatment. Also used are agents targeted for plasma cells, B cells, and the complement cascade which are bortezomib rituximab and eculizumab, respectively. PMID- 22545200 TI - Antibody-mediated rejection: an evolving entity in heart transplantation. AB - Antibody-mediated rejection (AMR) is gaining increasing recognition as a major complication after heart transplantation, posing a significant risk for allograft failure, cardiac allograft vasculopathy, and poor survival. AMR results from activation of the humoral immune arm and the production of donor-specific antibodies (DSA) that bind to the cardiac allograft causing myocardial injury predominantly through complement activation. The diagnosis of AMR has evolved from a clinical diagnosis involving allograft dysfunction and the presence of DSA to a primarily pathologic diagnosis based on histopathology and immunopathology. Treatment for AMR is multifaceted, targeting inhibition of the humoral immune system at different levels with emerging agents including proteasome and complement inhibitors showing particular promise. While there have been significant advances in our current understanding of the pathogenesis, diagnosis, and treatment of AMR, further research is required to determine optimal diagnostic tools, therapeutic agents, and timing of treatment. PMID- 22545201 TI - Immunosuppressive Activity of Size-Controlled PEG-PLGA Nanoparticles Containing Encapsulated Cyclosporine A. AB - We encapsulated cyclosporine A (CsA) in poly(ethylene glycol)-b-poly(d,l-lactide co-glycolide) (PEG-PLGA) nanoparticles (NPs) by nanoprecipitation of CsA and PEG PLGA. The resulting CsA/PEG-PLGA-NPs were <100 nm in diameter with a narrow particle size distribution. The NP size could be controlled by tuning the polymer concentration, solvent, or water/solvent ratio during formulation. The PEGylated NPs maintained non-aggregated in salt solution. Solid NPs lyoprotected with bovine serum albumin were prepared for the convenience of storage and transportation. The release kinetics of CsA (55.6% released on Day 1) showed potential for maintaining therapeutic CsA concentrations in vivo. In T-cell assays, both free CsA and CsA/PEG-PLGA-NPs suppressed T-cell proliferation and production of inflammatory cytokines dose dependently. In a mixed lymphocyte reaction assay, the IC(50) values for free CsA and CsA/PEG-PLGA-NPs were found to be 30 and 35 ng/mL, respectively. This nanoparticulate CsA delivery technology constitutes a strong basis for future targeted delivery of immunosuppressive drugs with improved efficiency and potentially reduced toxicity. PMID- 22545202 TI - Analysis of Circulating Haemocytes from Biomphalaria glabrata following Angiostrongylus vasorum Infection Using Flow Cytometry. AB - Angiostrongylus vasorum is an emerging parasite of dogs and related to carnivores that have an indirect life cycle, with a wide range of terrestrial and aquatic gastropods as the obligatory intermediate host. Unfortunately, the relationship between A. vasorum and their snail hosts remains poorly understood. Circulating haemocytes are the main line of cellular defence involved in the destruction of helminths in snails. Aiming to further characterize the haemocyte subsets in Biomphalaria snails, we have performed a flow cytometric analysis of whole haemolymph cellular components using a multiparametric dual colour labelling procedure. Our findings demonstrated that B. glabrata infected with A. vasorum have two major circulating haemocyte subsets, referred to as small and large haemocytes. Differences in the cell proportion occurred over time. The development of better invertebrate infection control strategies would certainly result in the better control of human diseases caused by other species of the genus Angiostrongylus. Such knowledge will assist in the establishment of novel control strategies aimed at parasites that use molluscs as intermediate hosts and clarify new aspects of the parasite-host relationship regarding cell recognition and activation mechanisms, which are also found in the innate response of vertebrates. PMID- 22545205 TI - Studies on acetone powder and purified rhus laccase immobilized on zirconium chloride for oxidation of phenols. AB - Rhus laccase was isolated and purified from acetone powder obtained from the exudates of Chinese lacquer trees (Rhus vernicifera) from the Jianshi region, Hubei province of China. There are two blue bands appearing on CM-sephadex C-50 chromatography column, and each band corresponding to Rhus laccase 1 and 2, the former being the major constituent, and each had an average molecular weight of approximately 110 kDa. The purified and crude Rhus laccases were immobilized on zirconium chloride in ammonium chloride solution, and the kinetic properties of free and immobilized Rhus laccase, such as activity, molecular weight, optimum pH, and thermostability, were examined. In addition, the behaviors on catalytic oxidation of phenols also were conducted. PMID- 22545204 TI - Malignant glaucoma: a review of the modern literature. AB - Malignant glaucoma is a rare form of glaucoma that typically follows surgery in patients with primary angle closure and primary angle-closure glaucoma. In this paper, the clinical features, classification, pathogenesis, and principles of management are discussed. Despite a high prevalence of primary angle closure glaucoma in South-East Asia, the vast majority of cases of malignant glaucoma are reported in White populations. This may reflect differing mechanisms of angle closure in White and Asian patients, which somehow reduces the likelihood of an aberrant relationship developing between the lens, ciliary body, anterior hyaloid, and vitreous structures within the eye. Although the exact underlying pathogenic mechanism remains unclear, the prognosis is good with modern medical, laser, and surgical treatment modalities. PMID- 22545203 TI - Toxoplasma on the brain: understanding host-pathogen interactions in chronic CNS infection. AB - Toxoplasma gondii is a prevalent obligate intracellular parasite which chronically infects more than a third of the world's population. Key to parasite prevalence is its ability to form chronic and nonimmunogenic bradyzoite cysts, which typically form in the brain and muscle cells of infected mammals, including humans. While acute clinical infection typically involves neurological and/or ocular damage, chronic infection has been more recently linked to behavioral changes. Establishment and maintenance of chronic infection involves a balance between the host immunity and parasite evasion of the immune response. Here, we outline the known cellular interplay between Toxoplasma gondii and cells of the central nervous system and review the reported effects of Toxoplasma gondii on behavior and neurological disease. Finally, we review new technologies which will allow us to more fully understand host-pathogen interactions. PMID- 22545206 TI - Parental Influences on Children's Self-Regulation of Energy Intake: Insights from Developmental Literature on Emotion Regulation. AB - The following article examines the role of parents in the development of children's self-regulation of energy intake. Various paths of parental influence are offered based on the literature on parental influences on children's emotion self-regulation. The parental paths include modeling, responses to children's behavior, assistance in helping children self-regulate, and motivating children through rewards and punishments. Additionally, sources of variation in parental influences on regulation are examined, including parenting style, child temperament, and child-parent attachment security. Parallels in the nature of parents' role in socializing children's regulation of emotions and energy intake are examined. Implications for future research are discussed. PMID- 22545207 TI - Laparoscopic gastric sleeve and micronutrients supplementation: our experience. AB - Background. Laparoscopic gastric sleeve (LGS) has been recently introduced as a stand-alone, restrictive bariatric surgery. Theoretically, LGS attenuates micronutrients deficiencies and associated complications that were typically observed following malabsorptive procedures. The aim of this study was to assess some micronutrients and mineral deficiencies in patients undergoing LGS. Methods. In the period between July 2008 and April 2010, 138 obese patients (110 females and 28 males) with mean BMI 44.4 kg/m(2) +/- 6.5, mean age 43.9 +/- 10.9 years were enrolled and underwent LGS. Patients were followed up with routine laboratory tests and anthropometric measurements and assessed for nutritional status, as regards vitamin B12, folic acid, iron, hemoglobin, calcium, and vitamin D, every three months throughout 12 months. Results. 12 months after sleeve, patients did not show iron deficiency and/or anemia; plasma calcium levels were in the normal range without supplementation from the sixth month after the operation. Vitamin B12 and folic acid were adequately supplemented for all the follow-up period. Vitamin D was in suboptimal levels, despite daily multivitamin supplementation. Conclusion. In this study, we showed that LGS is an effective surgery for the management of morbid obesity. An adequate supplementation is important to avoid micronutrients deficiencies and greater weight loss does not require higher dosage of multivitamins. PMID- 22545208 TI - Functional movement is negatively associated with weight status and positively associated with physical activity in british primary school children. AB - Although prior studies have suggested that overweight and obesity in childhood are associated with poorer functional movement performance, no study appears to have examined this issue in a pediatric population. The relations between BMI, ambulatory physical activity and functional movement screen (FMS) performance were compared in 58, 10-11-year-old children. Total FMS score was significantly, negatively correlated with BMI (P = .0001) and positively related to PA (P = .029). Normal weight children scored significantly better for total FMS score compared to children classified as overweight/obese (P = .0001). Mean +/- S.D. of FMS scores were 15.5 +/- 2.2 and 10.6 +/- 2.1 in normal weight and overweight/obese children, respectively. BMI and PA were also significant predictors of functional movement (P = .0001, Adjusted R(2) = .602) with BMI and PA predicting 52.9% and 7.3% of the variance in total FMS score, respectively. The results of this study highlight that ambulatory physical activity and weight status are significant predictors of functional movement in British children. Scientists and practitioners therefore need to consider interventions which develop functional movement skills alongside physical activity and weight management strategies in children in order to reduce the risks of orthopaedic abnormality arising from suboptimal movement patterns in later life. PMID- 22545209 TI - Exercise intensity modulation of hepatic lipid metabolism. AB - Lipid metabolism in the liver is complex and involves the synthesis and secretion of very low density lipoproteins (VLDL), ketone bodies, and high rates of fatty acid oxidation, synthesis, and esterification. Exercise training induces several changes in lipid metabolism in the liver and affects VLDL secretion and fatty acid oxidation. These alterations are even more conspicuous in disease, as in obesity, and cancer cachexia. Our understanding of the mechanisms leading to metabolic adaptations in the liver as induced by exercise training has advanced considerably in the recent years, but much remains to be addressed. More recently, the adoption of high intensity exercise training has been put forward as a means of modulating hepatic metabolism. The purpose of the present paper is to summarise and discuss the merit of such new knowledge. PMID- 22545210 TI - Evaluation of Hepatic Mitochondria and Hematological Parameters in Zidovudine Treated B6C3F(1) Mice. AB - The effects of 12-week exposure to zidovudine (AZT) at 400, 500, and 600 mg/kg/d were examined on expression of 542 mitochondria-related genes and mitochondrial DNA (mtDNA) copy number in the liver of male and female B6C3F(1) mice to understand mitochondrial role in sex-related differences in development of lactic acidosis. Plasma lactate levels and hematologic parameters were also examined. Results indicated increased red blood cell (RBC) count in vehicle-treated controls, whereas a dose-related decline in the RBC count was noted in AZT treated mice compared to the basal levels before treatments began. These decreases were associated with significant dose-related increases in mean corpuscular volume and mean corpuscular hemoglobin levels. This effect was greater in AZT-treated females compared to males. In both sexes, 12-week AZT or vehicle exposure significantly reduced plasma lactate levels compared to the basal levels. Results also showed modest, but significant, changes in the expression of genes associated with apoptosis and lipid metabolism at 600 mg/kg/d AZT. Neither drug nor sex influenced hepatic mtDNA copy number. Altogether, 12 week AZT exposure as high as 600 mg/kg/d did not impair hepatic mitochondria or induce lactic acidosis in B6C3F(1) mice. However, AZT-mediated hematologic toxicity appeared to be greater in females compared to males. PMID- 22545211 TI - Cobalamin and folic Acid status in relation to the etiopathogenesis of pancytopenia in adults at a tertiary care centre in north India. AB - Background. Pancytopenia has multiple etiologies like megaloblastic anemia, aplastic anemia, leukemia, and various infections. We investigated the clinical, etiological and hematological profile including bone marrow morphology of patients with pancytopenia in relation to their vitamin B12 and folic acid status at a tertiary care referral hospital in north India. Methods. A total of 140 consecutive patients with pancytopenia were selected from June 2007 to December 2008. Bone marrow examination and other tests were carried out as warranted, including serum cobalamin and folate assays using liquid chromatography mass spectroscopy (LC MS/MS). Results. The study population consisted of 92 males and 48 females with a mean age of 32.8 years. Megaloblastic anemia 60.7%, aplastic anemia (7.8%), and leukemia (9.2%) were common causes. Infectious causes (16.4% of all cases) included leishmaniasis, HIV-AIDS, malaria and tuberculosis. Severe cobalamin deficiency (B12 < 100 pg/mL) was seen in 81% of all patients including 91.6% of patients with MA. In contrast, only 7.14% of all pancytopenic patients were folate deficient. Folate deficiency (<5 ng/mL) was seen in just 5% MA patients. Combined cobalamin and folate deficiency was seen in 5 patients (3.51%). Conclusion. Cobalamin deficiency was found to be more common in our setting and is largely underdiagnosed in the age of folate supplementation. Infectious diseases like tuberculosis, leishmaniasis, and increasingly HIV are important and treatable causes of pancytopenia. This is in contrast with the developed nations where the bulk of disease is due to malignancy or marrow aplasia. PMID- 22545212 TI - Electrical muscle stimulation: an effective form of exercise and early mobilization to preserve muscle strength in critically ill patients. AB - Purpose. This is a secondary analysis of previously published data to investigate the effects of electrical muscle stimulation (EMS) on strength of various muscle groups in critically ill patients. Methods. One hundred forty-two consecutive patients, with APACHE II score >= 13, were randomly assigned to the EMS or the control group. EMS sessions were applied daily on vastus lateralis, vastus medialis, and peroneus longus of both lower extremities. Various muscle groups were evaluated with the Medical Research Council (MRC) scale for muscle strength. Handgrip strength assessment was also employed. Results. Twenty four patients in the EMS group and 28 patients in the control group were finally evaluated. EMS patients achieved higher MRC scores than controls (P <= 0.05) in wrist flexion, hip flexion, knee extension, and ankle dorsiflexion. Collectively, the EMS group performed higher (P < 0.01) in the legs and overall. Handgrip strength correlated (P <= 0.01) with the upper and lower extremities' muscle strength and the overall MRC scores. Conclusions. EMS has beneficial effects on the strength of critically ill patients mainly affecting muscle groups stimulated, while it may also affect muscle groups not involved presenting itself as a potential effective means of muscle strength preservation and early mobilization in this patient population. PMID- 22545213 TI - Crosstalk between p53 and TGF-beta Signalling. AB - Wild-type p53 and TGF-beta are key tumour suppressors which regulate an array of cellular responses. TGF-beta signals in part via the Smad signal transduction pathway. Wild-type p53 and Smads physically interact and coordinately induce transcription of a number of key tumour suppressive genes. Conversely mutant p53 generally subverts tumour suppressive TGF-beta responses, diminishing transcriptional activation of key TGF-beta target genes. Mutant p53 can also interact with Smads and this enables complex formation with the p53 family member p63 and blocks p63-mediated activation of metastasis suppressing genes to promote tumour progression. p53 and Smad function may also overlap during miRNA biogenesis as they can interact with the same components of the Drosha miRNA processing complex to promote maturation of specific subsets of miRNAs. This paper investigates the crosstalk between p53 and TGF-beta signalling and the potential roles this plays in cancer biology. PMID- 22545214 TI - DNA in 3R: Repair, Replication, and Recombination. PMID- 22545216 TI - Studies on angiotensin-converting enzyme insertion/deletion polymorphism and genotype distributions in Turkish preeclampsia patients. AB - Placental, immune and genetic factors are thought to play an important role in preeclampia (PE)'s pathophysiology. Angiotensin-Converting Enzyme (ACE) plays a vital role in the renin-angiotensin-system (RAS) which regulates blood pressure by converting angiotensin I into a powerfull vasoconstrictor angiotensin II. A deletion polymorphism (D allele) has been reported to be associated with elevated ACE activity. The aim of the this study was to investigate whether there is an association between angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism and PE. In this study, 120 preeclamptic and 116 normotensive Turkish pregnant women were genotyped for ACE I/D polymorphism and the distribution of genotype and allele frequencies of this polymorphism in preeclampsia and controls were evaluated. Codominant, dominant and recessive models were appplied in ACE gene I/D polymorphism. In the codominant model, DD genotype was found significantly more frequent in preeclampsia than controls (P = 0.016). Moreover, in dominant model (DD frequency versus DI+II frequency) there was a significant relation between DD genotype and preeclampsia (P = 0.006). D allele frequency was 64.6% in preeclampsia while it was 56.1% in controls (P = 0.062). In conclusion, there was significant difference in genotype distribution between preeclampsia and controls. PMID- 22545217 TI - Toxic bradycardias in the critically ill poisoned patient. AB - Cardiovascular drugs are a common cause of poisoning, and toxic bradycardias can be refractory to standard ACLS protocols. It is important to consider appropriate antidotes and adjunctive therapies in the care of the poisoned patient in order to maximize outcomes. While rigorous studies are lacking in regards to treatment of toxic bradycardias, there are small studies and case reports to help guide clinicians' choices in caring for the poisoned patient. Antidotes, pressor support, and extracorporeal therapy are some of the treatment options for the care of these patients. It is important to make informed therapeutic decisions with an understanding of the available evidence, and consultation with a toxicologist and/or regional Poison Control Center should be considered early in the course of treatment. PMID- 22545218 TI - Porphyromonas gingivalis Fimbria-Induced Expression of Inflammatory Cytokines and Cyclooxygenase-2 in Mouse Macrophages and Its Inhibition by the Bioactive Compounds Fibronectin and Melatonin. AB - Porphyromonas gingivalis (Pg) fimbriae, in addition to lipopolysaccharide, are involved in the pathogenesis of periodontal disease. At the same time, bioactive compounds such as fibronectin (FN) and melatonin in saliva and gingival crevicular fluid have been reported to exert a preventive effect against periodontitis. Here, we review current knowledge regarding the potent inhibitory effects of FN and melatonin against Pg fimbria-induced induction of proinflammatory cytokines, cyclooxygenase-2 (COX-2) expression, and NF-kappa B activation in mouse macrophages and discuss their possible clinical application for prevention of periodontal diseases induced by oral bacteria. PMID- 22545219 TI - POEMS Syndrome: A Report of 14 Cases and Review of the Literature. AB - POEMS syndrome is a rare paraneoplastic disorder associated with an underlying plasma cell dyscrasia presenting polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes. This study reviewed the clinical characteristics of 14 POEMS patients in Zhongshan hospital. The ratio of male to female was 9 : 5, and the average age was 47.1 years. The clinical manifestations were various, including motorial symptoms (weakness), sensory symptoms (numbness), lymphadenopathy, edema, abdominal distention, and skin hyperpigmentation. Imaging studies and laboratory tests also exhibited hepatomegaly, splenomegaly, thrombocytosis, endocrinopathy, and positive serum immunofixation in most patients. In addition, increased plasma cells in bone marrow and Castleman Disease were found in bone marrow and lymph nodes biopsies. All the eight follow-up patients were treated with alkylator-based combination chemotherapy or corticosteroids and thalidomide, with or without autologous stem cell transplantation. Unfortunately, two patients died three or four years after diagnosis of POEMS syndrome. The others showed response to therapy to some extent, but not completely remission. Currently, treatments for POEMS include radiation to the plasmacytoma, and systemic therapy is indicated. Low-dose alkylators with or without corticosteroids are effective in some patients. However, high-dose chemotherapy with auto-SCT dramatically improved symptoms and outcomes for POEMS patients. PMID- 22545215 TI - The Impact of HIV Coinfection on Cerebral Malaria Pathogenesis. AB - HIV infection is widespread throughout the world and is especially prevalent in sub-Saharan Africa and Asia. Similarly, Plasmodium falciparum, the most common cause of severe malaria, affects large areas of sub-Saharan Africa, the Indian subcontinent, and Southeast Asia. Although initial studies suggested that HIV and malaria had independent impact upon patient outcomes, recent studies have indicated a more significant interaction. Clinical studies have shown that people infected with HIV have more frequent and severe episodes of malaria, and parameters of HIV disease progression worsen in individuals during acute malaria episodes. However, the effect of HIV on development of cerebral malaria, a manifestation of P. falciparum infection that is frequently fatal, has not been characterized. We review clinical and basic science studies pertaining to HIV and malaria coinfection and cerebral malaria in particular in order to highlight the likely role HIV plays in exacerbating cerebral malaria pathogenesis. PMID- 22545220 TI - Normocalcemic versus Hypercalcemic Primary Hyperparathyroidism: More Stone than Bone? AB - Introduction. Normocalcemic primary hyperparathyroidism (NPHPT) is considered a variant of the more frequent form of the disease characterized by normal serum calcium levels with high PTH. The higher prevalence of renal stones in patients with HPTP and the well established association with bone disorders show the importance of studies on how to manage asymptomatic patients. Objective. To compare the clinical and laboratory data between the normocalcemic and mild hypercalcemic forms of PHPT. Methods. We retrospectively evaluated 70 patients with PHPT, 33 normocalcemic and 37 mild hypercalcemic. Results. The frequency of nephrolithiasis was 18.2% in normocalcemic patients and 18.9% in the hypercalcemic ones (P = 0.937). Fifteen percent of normocalcemic patients had a previous history of fractures compared to 10.8% of hypercalcemic patients, although there was no statistically significant difference (P = 0.726). Conclusion. Our data confirms a high prevalence of urolithiasis in normocalcemic primary hyperparathyroidism, but with the preservation of cortical bone. This finding supports the hypothesis that this disease is not an idle condition and needs treatment. PMID- 22545221 TI - Genetic influence of candidate osteoporosis genes in saudi arabian population: a pilot study. AB - Background and Objectives. The purpose of the present study is to find the genes and SNP that influence BMD and postmenopausal Saudi women. Material and Methods. Two-hundred ethnic Saudi Arabian women with a diagnosis of postmenopausal osteoporosis were the subjects of this study. Baseline blood hematology, biochemistry, and bone panel were done. Blood was collected, and three TaqMan-MGB probes were used to analyze SNP variants in ALOX15 (rs7220870), LRP5 (C 25752205 10), and TNFRSF11B (C 11869235 10). Results. The variant of ALOX15 17p13 showed that the BMD of the spine was lower in the AA allele (P value <0.002) and fractures were highest at 50% compared to CC allele. In the TNFRSF11B gene, BMD of the hip and spine was significantly higher in the GG allele and the history of fractures was significantly higher in GG group. With regard to the LRP5 (C 25752205 10) gene, there was no significant difference between allele groups. Conclusion(s). This study shows that the genetic influence of osteoporosis in the Caucasian and Saudi Arabians population is similar. We believe that the same genetic markers that influence osteoporosis in the Caucasian race could be used for further studies in the Saudi Arabian population. PMID- 22545222 TI - Thyroid and pregnancy. PMID- 22545223 TI - Frequency of celiac disease in patients with hypothyroidism. AB - Background. Celiac disease (CD) is closely associated with other autoimmune endocrine disorders, particularly autoimmune thyroid disease. The aim of this study was to find the frequency of celiac disease in patients with hypothyroidism in Guilan province, north of Iran. Methods. A total of 454 consecutive patients with hypothyroidism underwent celiac serological tests antiGliadin antibodies (AGA), antitissue transglutaminase antibodies (IgA-tTG) and antiendomysial antibodies (EMA-IgA). Small intestinal biopsy was performed when any of celiac serological tests was positive. Results. Eleven (2.4%) patients were positive for celiac serology, and two patients with documented villous atrophy were diagnosed with classic CD (0.4%; 95%). Two patients with classic CD had Hashimoto's thyroiditis (HT) (0.6%; 95%). Six (54.5%) of 11 were suffering from overt hypothyroidism and 45.5% from subclinical hypothyroidism. Six (54.5%) had HT, and 45.5% had nonautoimmune hypothyroidism. Conclusions. In this study, prevalence of CD was lower than other studies. Most of the patients with CD were suffering from HT, but there was no significant statistical relation between CD and HT. PMID- 22545224 TI - Determination of RET Sequence Variation in an MEN2 Unaffected Cohort Using Multiple-Sample Pooling and Next-Generation Sequencing. AB - Multisample, nonindexed pooling combined with next-generation sequencing (NGS) was used to discover RET proto-oncogene sequence variation within a cohort known to be unaffected by multiple endocrine neoplasia type 2 (MEN2). DNA samples (113 Caucasians, 23 persons of other ethnicities) were amplified for RET intron 9 to intron 16 and then divided into 5 pools of <30 samples each before library prep and NGS. Two controls were included in this study, a single sample and a pool of 50 samples that had been previously sequenced by the same NGS methods. All 59 variants previously detected in the 50-pool control were present. Of the 61 variants detected in the unaffected cohort, 20 variants were novel changes. Several variants were validated by high-resolution melting analysis and Sanger sequencing, and their allelic frequencies correlated well with those determined by NGS. The results from this unaffected cohort will be added to the RET MEN2 database. PMID- 22545226 TI - Optimization and stabilization of Rho small GTPase proteins for solution NMR studies: The case of Rnd1. AB - Rho GTPases of the Ras superfamily have important roles in regulating the organization of the actin filament system, morphogenesis and migration of cells. Structural details for these proteins are still emerging, and information on their dynamics in solution is much needed to understand the mechanisms underlying their signaling functions. This report reviews conditions for solution NMR studies of Rho GTPases and describes our optimization and stabilization of Rnd1 for such experiments. Rnd1 belongs to the Rnd protein subfamily branch of Rho small GTPases and functions in neurite outgrowth, dendrite development and in axon guidance. However, as we report here, solution NMR studies of this protein are challenging. Multiple methods have been employed to enhance the stability of Rnd1, including by cleavage of an N-terminal His expression tag and by addition of non-hydrolysable GMPPNP (beta: gamma-imidoguanosine 5'-triphosphate) nucleotide. Further stabilization of Rnd1 against aggregation was achieved through a structure informed point mutation while maintaining its conformation and binding affinity for a partner protein. The NMR spectrum of the optimized protein reveals significant improvement in NMR signal dispersion and intensity. This work paves the way for structural and protein-protein/protein-ligand interaction studies of Rnd1 by solution NMR and also provides a guide for optimization and stabilization of other Rho GTPases. PMID- 22545227 TI - Rac GTPase signaling in mechanotransduction during embryonic morphogenesis. AB - How cells sense and respond to mechanical forces is attracting considerable attention. We recently demonstrated that mechanical tension originating from one tissue strongly influences the differentiation and morphogenesis of another tissue during C. elegans embryogenesis (Nature 471:99-103). Specifically, we found that the repeated contractions of muscle cells stimulate a signaling cascade involving the Rac GTPase within the epidermis. This pathway ultimately leads to strengthen hemidesmosome-like junctions and promote embryonic morphogenesis. Our work provides further evidence that mechanical inputs impact on development, much like inputs involving growth factors and morphogens. After briefly outlining the pioneering work that inspired us, I will present the mechanotransduction process underlying the response to tension and the key experiments supporting our conclusions. PMID- 22545225 TI - Revisiting thyroid hormones in schizophrenia. AB - Thyroid hormones are crucial during development and in the adult brain. Of interest, fluctuations in the levels of thyroid hormones at various times during development and throughout life can impact on psychiatric disease manifestation and response to treatment. Here we review research on thyroid function assessment in schizophrenia, relating interrelations between the pituitary-thyroid axis and major neurosignaling systems involved in schizophrenia's pathophysiology. These include the serotonergic, dopaminergic, glutamatergic, and GABAergic networks, as well as myelination and inflammatory processes. The available evidence supports that thyroid hormones deregulation is a common feature in schizophrenia and that the implications of thyroid hormones homeostasis in the fine-tuning of crucial brain networks warrants further research. PMID- 22545228 TI - Atypical RhoV and RhoU GTPases control development of the neural crest. AB - This review addresses the developmental roles of two GTPases of the Rho family, RhoV/Chp and RhoU/Wrch. These two GTPases form a distinct subfamily related to Rac and Cdc42 proteins and were detected in a screen for Rho members that are particularly expressed in the neural crest, an embryonic tissue peculiar to vertebrates. The neural crest represents a physiological model of normal epithelial to mesenchymal transition (EMT), in which epithelial cells at the border of neural and non-neural ectoderm differentiate, lose their intercellular connections and migrate throughout the embryo. We showed that RhoV, transiently induced by the canonical Wnt pathway, is required for the full differentiation of neural crest cells, while RhoU, induced later by the non-canonical Wnt pathway, is necessary for the migration process. These two GTPases, which are highly conserved across vertebrates, are thus tightly functionally linked to Wnt signaling, whose implication in embryonic development and cancer progression is well established. In the light of the recent literature, we discuss how RhoV and RhoU may achieve their physiological functions. PMID- 22545229 TI - Cellular mechanism of bile acid-accelerated hepatocyte polarity. AB - We recently discovered that the major mammalian bile acid, taurocholate, accelerated polarity in primary rat hepatocytes. Taurocholate increased cellular cAMP and signals through an Epac-Rap1-MEK-LKB1-AMPK pathway for its polarity effect. This review discusses possible mechanisms for how taurocholate affects different cell polarity factors, particularly AMPK, and thereby regulates events that generate polarity. These include tight junction formation, apical trafficking, recycling endosome dynamics, and cytoskeleton rearrangement. We also discuss whether the effects of taurocholate are mediated by other LKB1 downstream kinases, such as Par1 and NUAK1. PMID- 22545230 TI - Exploiting the origins of Ras mediated squamous cell carcinoma to develop novel therapeutic interventions. AB - The small GTPase Ras is activated in a high proportion of human cancers. Attempts to clinically block Ras activity through pharmacological means has proven largely ineffective thus far. We employed an inducible mouse model of squamous cell carcinoma (SCC) to study the effect of Ras activation and show that hair follicle stem cells (HFSCs) are a cell of origin for SCC, whereas their more restricted progeny cannot serve as cancer cells of origin and are refractory to Ras activation. We propose that by identifying the unique mechanisms by which HFSCs are mobilized to initiate Ras mediated tumorigenesis, the molecular process behind SCC can be more completely elucidated and context dependent activities for Ras more clearly defined. Here, we summarize our recent results and point to future experiments designed to create novel therapeutics by exploiting the differential sensitivities of various cells within the epidermis to Ras activation. PMID- 22545231 TI - Polarization of migrating cortical neurons by Rap1 and N-cadherin: Revisiting the model for the Reelin signaling pathway. AB - Neuronal migration is essential for the development of the cerebral cortex. Mutations leading to defective migration are associated with numerous brain pathologies. An important challenge in the field is to understand the intrinsic and extrinsic mechanisms that regulate neuronal migration during normal development and in disease. Many small GTPases are expressed in the central nervous system during embryonic development. Recent findings have shown that Rap1 and its downstream partners Ral, Rac and Cdc42 are involved in the maintenance of N-Cadherin at the plasma membrane which is necessary for the correct polarization of migrating neurons. The activation of Rap1 is triggered by Reelin, an extracellular protein known for its role in the organization of the cortex into layers of neurons. In the absence of Reelin, neurons exhibit a broader and irregular pattern of positioning. The prevailing model suggests that Reelin signals to neurons during the last step of their migration, a notion that is inconsistent with new data describing an effect of Reelin on early steps of migration. In regard to these recent findings I suggest a revised model, which I call the "polarity model," that further refines our understanding of the developmental function played by Reelin and its downstream small GTPases. PMID- 22545232 TI - Breaking up is hard to do: RalA, mitochondrial fission and cancer. AB - The small GTPases RalA and RalB are activated downstream of oncogenic Ras. While activation of RalA is critically important for tumor initiation and growth of Ras driven cancers, the highly similar small GTPase RalB is implicated in cell survival and metastasis. This difference in function between these two related proteins maps to the C-terminus, a 30 amino acid region that regulates subcellular localization and contains several potential phosphorylation sites. Here we discuss our recent evidence that phosphorylation by the mitotic kinase Aurora A promotes RalA relocalization to mitochondrial membranes, where it recruits the effector RalBP1 and the large dynamin-related GTPase Drp1 to promote mitochondrial fission. As upregulation of both RalA and Aurora A have been observed in human tumors, and phosphorylation of RalA at the site targeted by Aurora A promotes tumorigenesis, it is possible that regulation of mitochondrial fission is one mechanism by which RalA promotes cancer. PMID- 22545234 TI - Microsporidia: Horizontal gene transfers in vicious parasites. AB - Microsporidia are obligate intracellular parasites whose genomes have been shaped by an extreme lifestyle. Specifically, their obligate intracellular parasitism has resulted in the loss of many genes and biochemical pathways, but these reductive processes have been often offset by the acquisition of several genes by means of horizontal gene transfer (HGT). Until recently, these HGTs were all found to have derived from prokaryotic donors, but a recent study suggests that some species took advantage of this mechanism to acquire one gene from an animal, which they maintained in their genome for metabolic purposes. The gene encodes for a purine nucleoside phosphorylase, and shows a strong phylogenetic signal of arthropod origin. Here, we briefly review our current knowledge of HGTs discovered across microsporidian genomes and discuss the implications of the most recent findings in this research area for understanding the origin and evolution of this highly adapted group of intracellular parasites. A novel gene potentially transferred by means of HGT to one microsporidia is also reported. PMID- 22545233 TI - Impact of Sex and Gonadal Hormones on Cocaine and Food Reinforcement Paradigms. AB - Men and women express sexually dimorphic patterns of cocaine abuse, such that women progress faster from initially trying cocaine to becoming dependent upon the drug and display a greater incidence of relapse. Sex differences in response to cocaine are also seen in the laboratory in both humans and animal models. In this review, animal models of cocaine abuse that have reported sex differences in appetitive reinforcement are discussed. In both human and animal studies, sex differences in the subjective and behavioral effects of cocaine are often related to the female reproductive cycle and ovarian hormones. As a comparison, food reinforcement studies have shown the opposite profile of sex differences and the impact of sex steroids on food intake and response rate. In contrast, limited attention has been given to "choice" models in rodents of either sex, however, our recent studies have indicated a role of sex and estrogen in cocaine choice over food with intact females, and OVX females treated with estrogen, choosing cocaine significantly more than males. Interestingly, estrous cycle phase does not seem to impact cocaine choice as it does response rate in single-reinforcer studies, suggesting that genomic rather than neurosteroid effects of estrogen modulate sex differences in this model. Future studies should more fully explore the impact of sex hormones on concurrent reinforcement and discrete choice models of addiction. PMID- 22545235 TI - HGT turbulence: Confounding phylogenetic influence of duplicative horizontal transfer and differential gene conversion. AB - Horizontal gene transfer (HGT) often leads to phylogenetic incongruence. When "duplicative HGT" introduces a second copy of a pre-existing gene, the two copies may then engage in gene conversion, leading to phylogenetically mosiac genes. When duplicative HGT is followed by differential gene conversion among descendant lineages, as under the DH-DC model, phylogenetic analysis is further complicated. To explore the effects of DH-DC on phylogeny reconstruction, we analyzed two sets of sequences: (1) an augmented set of plant mitochondrial atp1 sequences for which we recently published evidence of DH-DC; and (2) a set of simulated sequences for which we varied the extent of chimerism, the number of chimeric genes and nucleotide substitution rates. We show that the phylogenetic behavior of evolutionarily chimeric genes is highly volatile and depends on both the degree of chimerism and the number of differentially chimeric genes present in the analysis. Furthermore, we show that the presence of chimeric genes in gene trees can spuriously affect the phylogenetic position of purely native sequences, especially by attracting these sequences toward basal positions in trees. We propose the term "HGT turbulence" to describe these complex effects of evolutionarily chimeric genes on phylogenetic results. PMID- 22545236 TI - Curiosities of REPINs and RAYTs. AB - Repetitive extragenic palindromic (REP) sequences are a ubiquitous feature of bacterial genomes. Recent work shows that REPs are remnants of a larger mobile genetic element termed a REPIN. REPINs consists of two REP sequences in inverted orientation separated by a spacer region and are thought to be non-autonomous mobile genetic elements that exploit the transposase encoded by REP-Associated tYrosine Transposases (RAYTs). Complimentarity between the two ends of the REPIN suggests that the element forms hairpin structures in single stranded DNA or RNA. In addition to REPINs, other more complex arrangements of REPs have been identified in bacterial genomes, including the genome of the model organism Pseudomonas fluorescens SBW25. Here, we summarize existing knowledge and present new data concerning REPIN diversity. We also consider factors affecting the evolution of REPIN diversity, the ease with which REPINs might be co-opted by host genomes and the consequences of REPIN activity for the structure of bacterial genomes. PMID- 22545237 TI - What Nematode genomes tell us about the importance of horizontal gene transfers in the evolutionary history of animals. AB - Horizontal gene transfer (HGT), the transmission of a gene from one species to another by means other than direct vertical descent from a common ancestor, has been recognized as an important phenomenon in the evolutionary biology of prokaryotes. In eukaryotes, in contrast, the importance of HGT has long been overlooked and its evolutionary significance has been considered to be mostly negligible. However, a series of genome analyses has now shown that HGT not only do probably occur at a higher frequency than originally thought in eukaryotes but recent examples have also shown that they have been subject to natural selection, thus suggesting a significant role in the evolutionary history of the receiver species. Surprisingly, these examples are not from protists in which integration and fixation of foreign genes intuitively appear relatively straightforward, because there is no clear distinction between the germline and the somatic genome. Instead, these examples are from nematodes, multicellular animals that do have distinct cells and tissues and do possess a separate germline. Hence, the mechanisms of gene transfer appears in this case much more complicated. In this commentary, I will further discuss two recent publications that describe HGT in nematodes, one that highlights the importance of HGT in the emergence of plant parasitism and another one that probably represents the most convincing example of a potential transfer between two different metazoan animals, an insect and a nematode. PMID- 22545238 TI - Role of piRNAs in the Drosophila telomere homeostasis. AB - Drosophila telomeres are maintained as a result of transpositions of specialized telomeric retrotransposons. The abundance of telomeric retroelement transcripts, as well as the frequency of their transpositions onto the chromosome ends, is controlled by a PIWI-interacting RNA (piRNA) pathway. In our recent report, we demonstrate strong evidence of piRNA-mediated transcriptional silencing of telomeric repeats in the Drosophila germline. Telomerase-generated repeats serve as a platform for recruiting specialized DNA-binding proteins which are involved in chromosome end protection and in the telomere length control. No specific proteins are known to bind to heterogeneous long sequences of the Drosophila telomeric retrotransposons. The importance of the piRNA silencing mechanism in the formation of telomeric chromatin along the region of the retrotransposon array will be discussed. We propose that Drosophila telomeric retrotransposon HeT A serves as a template for the piRNA-mediated assembly of the specific protein complex, which is functionally similar to the recruiting of the DNA-binding telomeric proteins by the telomerase-generated repeats. The role of the piRNA pathway components in the assembly of the telomere capping complex was recently unveiled. Taken together, these data elucidate the importance of the piRNA pathway in the Drosophila telomere homeostasis. PMID- 22545239 TI - Is somatic retrotransposition a parasitic or symbiotic phenomenon? AB - The extraordinary evolutionary success of transposable elements (TEs) invites us to question the nature of the co-evolutionary dynamics between TE and host. Although sometimes assumed to be wholly parasitic, TEs have penetrated and spread throughout eukaryotic genomes at a rate unparalleled by other parasites. This near-ubiquity, occurring despite the potentially deleterious effects of insertional mutagenesis, raises the possibility that a counterbalancing benefit exists for the host. Such a benefit may act at the population level to generate genomic diversity within a species and hence greater adaptability under new selective pressures, or at the level of primary gain for the individual. Recent studies have highlighted the occurrence of retrotransposition events in the germline and discovered a surprisingly high rate of mobilization in somatic cells. Here we examine the available evidence for somatic retrotransposition and discuss how this phenomenon may confer a selective advantage upon an individual or species. PMID- 22545240 TI - Bacterial toxin-antitoxin systems: Translation inhibitors everywhere. AB - Toxin-antitoxin (TA) systems are composed of two elements: a toxic protein and an antitoxin which is either an RNA (type I and III) or a protein (type II). Type II systems are abundant in bacterial genomes in which they move via horizontal gene transfer. They are generally composed of two genes organized in an operon, encoding a toxin and a labile antitoxin. When carried by mobile genetic elements, these small modules contribute to their stability by a phenomenon denoted as addiction. Recently, we developed a bioinformatics procedure that, along with experimental validation, allowed the identification of nine novel toxin super families. Here, considering that some toxin super-families exhibit dramatic sequence diversity but similar structure, bioinformatics tools were used to predict tertiary structures of novel toxins. Seven of the nine novel super families did not show any structural homology with known toxins, indicating that combination of sequence similarity and three-dimensional structure prediction allows a consistent classification. Interestingly, the novel super-families are translation inhibitors similar to the majority of known toxins indicating that this activity might have been selected rather than more detrimental traits such as DNA-gyrase inhibitors, which are very toxic for cells. PMID- 22545241 TI - The evolution and consequences of snaR family transposition in primates. AB - The small NF90 associated RNA (snaR) family of small noncoding RNAs (ncRNA) appears to have evolved from retrotransposon ancestors at or soon after pivotal stages in primate evolution. snaRs are thought to be derived from a FLAM C-like (free left Alu monomer) element through multiple short insertion/deletion (indel) and nucleotide (nt) substitution events. Tracing snaR's complex evolutionary history through primate genomes led to the recent discovery of two novel retrotransposons: the Alu/snaR related (ASR) and catarrhine ancestor of snaR (CAS) elements. ASR elements are present in the genomes of Simiiformes, CAS elements are present in Old World Monkeys and apes, and snaRs are restricted to the African Great Apes (Homininae, including human, gorilla, chimpanzee and bonobo). Unlike their ancestors, snaRs have disseminated by multiple rounds of segmental duplication of a larger encompassing element. This process has produced large tandem gene arrays in humans and possibly precipitated the accelerated evolution of snaR. Furthermore, snaR segmental duplication created a new form of chorionic gonadotropin beta subunit (CGbeta) gene, recently classified as Type II CGbeta, which has altered mRNA tissue expression and can generate a novel short peptide. PMID- 22545242 TI - Expression of DNA transposable elements during nervous system development: A discussion about its possible functions. AB - Transposable elements (retrotransposons and DNA transposons) comprise a large proportion of animal genomes, for example 20% in D. melanogaster, 36% in X. tropicalis and 45% in humans. After invading a new genome, the transposable element increases its copy number and subsequently accumulates mutations. These may eventually result in inactive copies. Until recent days transposons have been considered "junk" DNA and no clear function have been assigned for this important amount of information on genomes. PMID- 22545243 TI - Tnt1 retrotransposon tagging of STF in Medicago truncatula reveals tight coordination of metabolic, hormonal and developmental signals during leaf morphogenesis. AB - Tnt1 (transposable element if Nicotiana tabaccum cell type 1) is one of the very few active LTR retrotransposons used for gene tagging in plants. In the model legume Medicago truncatula, Tnt1 has been effectively used as a gene knock-out tool to generate several very useful mutants. stenofolia (stf) is such a mutant identified by Tnt1 insertion in a WUSCHEL-like homeobox transcription factor. STF is required for blade outgrowth, leaf vascular patterning and female reproductive organ development in barrel medic and woodland tobacco. Using transcript profiling and metabolite analysis, we uncovered that mutant leaves are compromised in steady-state levels of multiple phytohormones, sugar metabolites and derivatives including flavonoids and polyamines. In the lam1 mutant (caused by deletion of the STF ortholog in Nicotiana sylvestris), while glucose, fructose, mannose, galactose, myo-inositol and aromatic aminoacids are dramatically reduced, sucrose is comparable to wild-type levels, and glutamine, proline, putrescine, nicotine and sorbitol are highly increased. We demonstrated that both stf and lam1 mutants accumulate reduced levels of free auxin and ABA in their leaves, and ectopic expression of STF in tobacco leads to auxin and cytokinin overproduction phenotypes including formation of tumors on the roots and crown. These data suggest that STF mediated integration of metabolic and hormonal signals are required for lateral organ morphogenesis and elaboration. PMID- 22545244 TI - Goods-thinking vs. tree-thinking: Finding a place for mobile genetic elements. AB - While it has become increasingly clear that the Tree of Life hypothesis has limitations in its ability to describe the evolution of all evolving entities on the planet, there has been a marked reluctance to move away from the tree-based language. Ironically, while modifying the idea of the Tree of Life to the extent that it is only very distantly related to its original descriptions, there has been a very careful attempt to retain the language of tree-thinking. The recent movement away from a tree-thinking language toward a goods-thinking language and perspective is a significant improvement. In this commentary, we describe how goods-thinking can provide better descriptions of evolution, can integrate evolution with environment more closely and can offer an equal place for Mobile Genetic Elements and chromosomal elements in discussions of evolutionary history. PMID- 22545245 TI - Using modeling to help understand vaginal microbicide functionality and create better products. AB - A summary is presented of a range of mathematical models that relate to topical microbicidal molecules, applied vaginally to inhibit HIV transmission. These models contribute to the fundamental understanding of the functioning of those molecules, as introduced in different delivery systems. They also provide computational tools that can be employed in the practical design and evaluation of vaginal microbicide products. Mathematical modeling can be implemented, using stochastic principles, to understand the probability of infection by sexually transmitted HIV virions. This provides a frame of reference for the deterministic models of the various processes that underlie HIV transmission and its inhibition, including: the temporal and spatial history of HIV migration from semen to vaginal epithelial surfaces and thence to the underlying stroma; the time and spatial distribution of microbicidal drugs as delivered by various vehicles (e.g., gels, rings, films, and tablets)-this is central to understanding microbicide product pharmacokinetics; and the time and space history of the drug interactions with HIV directly and with host cells for HIV within the vaginal environment-this informs the understanding of microbicide pharmacodynamics. Models that characterize microbicide functionality and performance should and can interface with both in vitro and in vivo experimental studies. They can serve as a rapidly applied, inexpensive tool, to facilitate microbicide R&D, in advance of more costly and time consuming clinical trials. PMID- 22545246 TI - Oncogenic splicing factor SRSF1 is a critical transcriptional target of MYC. AB - The SR protein splicing factor SRSF1 is a potent proto-oncogene that is frequently upregulated in cancer. Here, we show that SRSF1 is a direct target of the transcription factor oncoprotein MYC. These two oncogenes are significantly coexpressed in lung carcinomas, and MYC knockdown downregulates SRSF1 expression in lung-cancer cell lines. MYC directly activates transcription of SRSF1 through two noncanonical E-boxes in its promoter. The resulting increase in SRSF1 protein is sufficient to modulate alternative splicing of a subset of transcripts. In particular, MYC induction leads to SRSF1-mediated alternative splicing of the signaling kinase MKNK2 and the transcription factor TEAD1. SRSF1 knockdown reduces MYC's oncogenic activity, decreasing proliferation and anchorage independent growth. These results suggest a mechanism for SRSF1 upregulation in tumors with elevated MYC and identify SRSF1 as a critical MYC target that contributes to its oncogenic potential by enabling MYC to regulate the expression of specific protein isoforms through alternative splicing. PMID- 22545248 TI - Initiative in standardized dental education developments in Italy. PMID- 22545247 TI - Regulation of monocyte functional heterogeneity by miR-146a and Relb. AB - Monocytes serve as a central defense system against infection and injury but can also promote pathological inflammatory responses. Considering the evidence that monocytes exist in at least two subsets committed to divergent functions, we investigated whether distinct factors regulate the balance between monocyte subset responses in vivo. We identified a microRNA (miRNA), miR-146a, which is differentially regulated both in mouse (Ly-6C(hi)/Ly-6C(lo)) and human (CD14(hi)/CD14(lo)CD16(+)) monocyte subsets. The single miRNA controlled the amplitude of the Ly-6C(hi) monocyte response during inflammatory challenge whereas it did not affect Ly-6C(lo) cells. miR-146a-mediated regulation was cell intrinsic and depended on Relb, a member of the noncanonical NF-kappaB/Rel family, which we identified as a direct miR-146a target. These observations not only provide mechanistic insights into the molecular events that regulate responses mediated by committed monocyte precursor populations but also identify targets for manipulating Ly-6C(hi) monocyte responses while sparing Ly-6Clo monocyte activity. PMID- 22545249 TI - Clinical performance of conical and electroplated telescopic double crown retained partial dentures: a randomized clinical study. AB - PURPOSE: The aim of this study was to quantify and compare the clinical performance of cast conical double crown-retained removable partial dentures (C RPDs) and electroplated double crown-retained removable partial dentures (EP RPDs). MATERIALS AND METHODS: A total of 60 RPDs were placed in 54 patients. Participants were randomly assigned to two study groups (C-RPD and EP-RPD). Altogether, 217 abutment teeth were provided with double crowns. Patients were reexamined after 6, 12, 24, and 36 months. The main endpoints were the survival times of RPDs and abutment teeth; secondary endpoints included failure of the facing, loss of cementation of primary crowns, and postprosthetic endodontic treatment. Chi-square tests were used to evaluate group differences regarding characteristics of patients and RPDs. Survival differences were investigated using the log-rank test and Cox regression; secondary endpoints were assessed using logistic regression. RESULTS: After 36 months, survival was 100% for C-RPDs and 93.3% for EP-RPDs. Cumulative survival for abutment teeth was 97.3% (C-RPDs) and 96.2% (EP-RPDs). Survival differences between the two study groups did not reach statistical significance. The survival of abutments depended on tooth vitality and position; for example, the hazard of tooth loss was 676% higher for nonvital teeth. No differences were found between study groups regarding facing failure, decementation of primary crowns, or postprosthetic endodontic treatment. CONCLUSIONS: Vitality and position are important to the survival of teeth supporting partial dentures. Longer follow-up and larger patient collectives are needed to evaluate possible differences between cast conical and electroplated telescopic double crown-retained partial dentures. PMID- 22545250 TI - Frictional telescopic crowns in severely reduced dentitions: a 5-year clinical outcome study. AB - Clinical outcomes for frictional telescopic crowns supporting removable prostheses in patients with severely reduced dentitions with one to three remaining teeth per arch have been inadequately documented. Seventy-four patients with severely reduced dentitions received 82 telescopic removable partial dentures that were supported by 173 frictional telescopic crowns. The recorded individual telescopic abutment survival rate over a 60-month period was 80.6%. This observation was significantly influenced by sex and tooth vitality and mobility (Kaplan-Meier). The risk of loss of telescopic crowns was significantly influenced by sex, arch, vitality, and abutment tooth distribution (Cox regression). Telescopic removable partial dentures were proven to be a favorable treatment concept for severely reduced dentitions in the selected group of patients. PMID- 22545251 TI - A randomized, prospective, open-ended clinical trial of zirconia fixed partial dentures on teeth and implants: interim results. AB - PURPOSE: The aim of this randomized controlled clinical trial was to compare the outcomes of zirconia crowns and fixed partial dentures (FPDs) supported by teeth or implants. MATERIALS AND METHODS: Patients were recruited based on inclusion/exclusion criteria, and 59 eligible subjects were assigned randomly to treatment by one of four zirconia systems (Cercon, ZirkonZahn, Lava, and Katana). One hundred seven single-tooth and 160 three- to six-unit FPDs were fabricated on teeth and implants and cemented using composite resin cement. Californian Dental Association (CDA) quality evaluation, Plaque Index, and Gingival Index scores were recorded, and radiographic assessment of the restorations was performed using periapical and panoramic radiographs at baseline and annually up to 4 years. RESULTS: Five failures (1.9%) were recorded. The 4-year Kaplan-Meier survival probabilities of FPDs were higher than those of single-tooth restorations (P = .046). The highest survival probability for crowns was observed for Katana and the lowest for Cercon (P < .05). For FPDs, the survival probabilities of Lava restorations were similar to those of Cercon but lower than those of ZirkonZahn and Katana (P < .05). The 4-year survival probabilities of implant- and tooth-supported crowns were comparable (P = .182). Regarding CDA ratings, the slight marginal discrepancy scores for the Cercon restorations were higher than for the other systems at 1 year (P < .05). In FPDs, 94.5% of Katana FPDs had slight or gross color mismatch scores, and the difference between color and surface ratings among zirconia systems was significant (P < .05). FPDs had better periodontal scores than crowns over the 4-year observation period (P < .05). CONCLUSION: The 4-year interim results of this study suggest that zirconia systems used to fabricate FPDs have predictably high survival rates on teeth and implants and may exhibit differences, particularly in terms of mechanical failures, marginal adaptation, and color matching. PMID- 22545252 TI - Microwave denture disinfection versus nystatin in treating patients with well controlled type 2 diabetes and denture stomatitis: a randomized clinical trial. AB - PURPOSE: The aim of this randomized clinical trial was to compare the effectiveness of microwave denture disinfection and nystatin in the treatment of well-controlled type 2 diabetic patients with denture stomatitis in terms of microbiologic and clinical outcomes. MATERIALS AND METHOD: Diabetic patients wearing maxillary complete dentures with denture stomatitis (n = 40) were divided into two groups: NYS (patients treated with topical nystatin 4 times/day for 14 days) and MW (patients who had their dentures microwaved [650 W for 3 minutes] 3 times/week for 14 days). Mycologic samples were taken from the palates and dentures of the patients for quantification and identification of Candida, and standardized photographs of the palates were taken for clinical analysis. Evaluations were repeated at baseline, the end of treatment (day 14), and throughout follow-up (days 30, 60, and 90). Microbiologic data were evaluated by analysis of variance using a random effects statistical model, Tukey post hoc test, and chi-square test (alpha = .05). Clinical results were analyzed using Mann-Whitney and Fisher exact tests (alpha = .05). RESULTS: Both treatments were considered successful in reducing the clinical signs of denture stomatitis and significantly reduced the values of colony-forming units/mL from the palates and dentures at days 14 and 30. In addition, 40% of treated patients were cured by the end of treatment. No significant differences in the microbiologic and clinical outcomes were revealed between the two groups (P > .05). C albicans was the most predominant species isolated (P < .01), followed by C tropicalis and C glabrata. CONCLUSION: Denture microwave disinfection was as effective as nystatin for the treatment of diabetic patients with denture stomatitis. PMID- 22545253 TI - Digitally designed surgical guides for placing implants in the nasal floor of dentate patients: a series of three cases. AB - PURPOSE: Insight into the bone volume and position of natural teeth is essential when placing implants to retain nasal prostheses. This paper describes a series of three cases in which a new method was applied for implant placement in the nasal floor of dentate patients using digital planning techniques. MATERIALS AND METHODS: With the aid of computer software, digital planning of implants in the nasal floor based on cone beam computed tomography was performed. Next, surgical guides for implant placement were digitally designed and fabricated using rapid prototyping. RESULTS: In all three patients, implants could be placed and nasal prostheses could be manufactured as planned. All anterior teeth remained vital. Analysis of planning and post-implant placement cone beam computed tomography scans revealed high accuracy of implant placement. CONCLUSION: The applied method allows for reliable implant placement in close proximity to the preoperatively planned implant position. PMID- 22545255 TI - Alternative decision-making considerations in prosthodontics. PMID- 22545254 TI - Clinical and radiographic evaluation of patients receiving both tooth- and implant-supported prosthodontic treatment after 5 years of function. AB - PURPOSE: The aim of this research was to assess survival and complication rates of tooth- and implant-supported fixed dental prostheses (FDPs) and single crowns (SCs) after 5 years of function in a specific patient population group who underwent comprehensive prosthetic treatment. MATERIALS AND METHODS: This retrospective study included a convenience sample of 52 patients who met specific inclusion and exclusion criteria and were treated during two specific courses as part of the undergraduate curriculum. The patients' prosthodontic treatment comprised 296 tooth-supported and 37 implant-supported SCs together with 76 tooth supported and 15 implant-supported FDPs. Pre- and posttreatment clinical examinations included screening for biologic and technical complications, probing pocket depth, bleeding on probing (BoP), and plaque control record (PCR) as well as intraoral radiographs. Information was obtained from the patients about dental hygiene and dental visits, treated complications, and patient satisfaction during the observation period. Descriptive statistics were employed. RESULTS: Forty-five patients were followed for a mean observation period of 5.26 +/- 0.47 years. The survival rates were 99.0% for tooth-supported SCs, 98.7% for tooth-supported FDPs, and 100% for implant-supported FDPs and SCs. Loss of vitality was observed in 2.9% of all abutment teeth deemed to be vital initially. Endodontic complications occurred in 5% and root fracture in 2.5% of nonvital abutment teeth. Caries was found in 0.4% of abutments. No framework or implant fractures were observed, but fracture of the veneering ceramic affected 3.8% of FDPs. The mean BoP was 21.5% +/- 9.9%, and the mean PCR was 22.8% +/- 16.5%. A high satisfaction rating was provided by 82.2% of patients. CONCLUSIONS: High survival and relatively few complication rates were observed for all prescribed FDPs over the observation period. PMID- 22545256 TI - Internal and marginal adaptation of pressable and computer-aided design/computer assisted manufacture onlay restorations. AB - The aim of this research was to evaluate internal and marginal adaptation of lithium disilicate partial crowns fabricated using IPS e.max Press and IPS e.max CAD systems. Forty maxillary first molars were divided into two groups. The margins were located above the cementoenamel junction mesially and below it distally. The adaptation of the restoration was evaluated by means of the silicone replica technique. The lowest marginal discrepancy was measured between the preparation margin on the enamel and the IPS e.max Press specimens; the highest discrepancy was observed on the occlusal surface of the IPS e.max CAD specimens. Both systems tested demonstrated acceptable marginal discrepancies in vitro. PMID- 22545257 TI - A retrospective study of the clinical performance of porcelain-fused-to-metal resin-bonded fixed partial dentures. AB - PURPOSE: This study investigated the clinical performance of resin-bonded fixed partial dentures (RBFPDs) using minimally invasive, nonretentive abutment tooth preparation. MATERIALS AND METHODS: Forty-four patients received 56 porcelain fused-to-metal RBFPDs (52 three-unit RBFPDs, 4 four-unit RBFPDs). All RBFPDs were inserted between 1995 and 2010 according to a standardized protocol. Thirty-eight RBFPDs replaced anterior teeth in the maxilla, 18 RBFPDs replaced anterior teeth in the mandible, and 3 RBFPDs replaced premolars (1 maxillary, 2 mandibular). At annual recall appointments, RBFPDs were carefully inspected for technical and biologic failures or complications (eg, debonding, abutment tooth caries). RESULTS: The mean observation period was 76 months, with a minimum of 4 months and a maximum of 198 months. Five RBFPDs debonded. Further complications comprised one instance of porcelain chipping and one caries lesion underneath a loose retainer. One patient was dissatisfied with the esthetic appearance of her RBFPD. The cumulative survival rate with the event "debonding" dropped to 90% after 23 months and then remained constant. Survival rate with the event "any restoration complication" dropped to 84% after 77 months and then remained constant. CONCLUSIONS: With regard to the high patient satisfaction and relatively low incidence of failures and complications, the clinical performance of nonretentive RBFPDs can be considered satisfactory. Hence, within the limitations of this study, the data justify nonretentive RBFPDs as long-term provisional restorations. PMID- 22545258 TI - Grounded theory on factors involved in the decision-making processes of patients treated with implant therapy. AB - PURPOSE: The aims of this research were to describe the process leading to desire for implant treatment, describe how patients missing teeth gained information about implant treatment, identify gatekeeping factors for implant treatment, and note experiences in changes in oral health-related quality of life. MATERIALS AND METHODS: The constant comparative method for a grounded theory was used in collecting and analyzing data. Ten informants participated in the study, all of whom were treated with implant-supported fixed dentures during the past year. RESULTS: The emerging core category was that participants experienced a journey from social stigma to exhilaration. This process ended in the perspective that the participants' new lives with dental implants were very good and meant an end to their social stigma, but gatekeeping factors before treatment, such as cost and dental anxiety, were noted. The dentist's opinion and suggestions were the most decisive part of the decision-making process, and trust in the dentist and dental team was crucial in the decision to undergo treatment and in the overall treatment experience. Great improvement in oral health-related quality of life was noted. CONCLUSION: This qualitative study gives as the core category and main finding the importance of patients' trust and confidence in the dentist and his/her staff in the process of transforming desire for dental implant treatment into demand and also in making it more likely for patients to be satisfied with treatment regardless of complications. PMID- 22545259 TI - Preliminary 2-year report on treatment outcomes for 6-mm-long implants in posterior atrophic mandibles. AB - PURPOSE: The aim of this study was to prospectively evaluate clinical and radiographic outcomes of ultrashort implants (4-mm diameter, 6-mm length) supporting fixed partial dentures in severely atrophic posterior mandibles. MATERIALS AND METHODS: Twenty-five patients with posterior edentulous mandibular spans and 7- to 8-mm residual bone heights above the mandibular canal were enrolled. In total, 61 submerged implants were placed and loaded 5 to 6 months later. Patients were followed for 2 years after prosthesis connection with clinical, radiographic, and resonance frequency analysis (RFA) examinations. RESULTS: Two implants failed in one patient before loading; all other implants showed favorable clinical and radiographic findings throughout the observation period (2-year survival and success rate: 96.8%). Postoperative pain and swelling were negligible. Mean changes in marginal bone levels were stable (0.40 +/- 0.23, 0.51 +/- 0.38, and 0.60 +/- 0.13 mm after 6 months and 1 and 2 years, respectively) and were unaffected by measured crown-to-implant ratios (range: 1.31 to 3.12). Mean RFA values increased significantly from implant placement (67.35 +/- 6.67) to 2 years (72.91 +/- 5.07, P < .0001). Prosthetic complications included two prosthesis decementations, three ceramic veneer chippings, and one prosthesis screw loosening. CONCLUSION: Within the limitations of the short follow-up period, the use of 6-mm-long implants was a predictable treatment method for patients with atrophic posterior mandibles and increased crown-to implant ratios. PMID- 22545260 TI - Restoration of facial symmetry in a patient with bell palsy using a modified maxillary complete denture: a case report. AB - Permanent facial paralysis can be devastating for a patient. Modern society's emphasis on appearance and physical beauty contributes to this problem and often leads to isolation of patients embarrassed by their appearance. Lagophthalmos with ocular exposure, loss of oral competence with resultant drooling, alar collapse with nasal airway obstruction, and difficulties with mastication and speech production are all potential consequences of facial paralysis. Affected patients are confronted with both a cosmetic defect and the functional deficits associated with loss of facial nerve function. In this case history report, a modified maxillary complete denture permitted a patient with Bell palsy to carry on daily activities with minimal facial distortion, pain, speech difficulty, and associated emotional trauma. PMID- 22545261 TI - Zirconia versus metal: a preliminary comparative analysis of ceramic veneer behavior. AB - PURPOSE: Clinical studies have revealed a high rate of fracture for porcelain veneered zirconia-based restorations that varies between 6% and 15% over a 3- to 5-year period. These are high values compared to the 4% fracture rate shown by conventional metal-ceramic restorations over 10 years. To date, little in vitro research has been carried out on the fracture resistance of the new generation of ceramic crowns. The aims of this study were to develop preliminary research on the mechanical failure behavior of three types of porcelain-veneered crowns with zirconia cores when subjected to static compressive loading and to analyze fracture characteristics using scanning electron microscopy (SEM). MATERIALS AND METHODS: Eighty individual full-coverage crowns were studied: 60 crowns with a zirconia core and 20 with a metal core (control). RESULTS: Values obtained in compressive testing were as follows: ZirPress: 1,818.01 N, ZirCAD: 1,773.92 N, Lava: 2,210.95 N, and metal-ceramic (control): 2,310.49 N. SEM analysis revealed that 71.66% of zirconia-based restoration mechanical failures were cohesive, while 100% of mechanical failures for metal-ceramic restorations were adhesive. CONCLUSIONS: The mechanical behavior of the porcelain veneering on a zirconia core is more fragile than that on metal-ceramic crowns, and when load forces exerted on these restorations lead to mechanical failure, this will occur in the interior of the porcelain veneering. PMID- 22545262 TI - A fluorous synthetic receptor that recognizes perfluorooctanoic acid (PFOA) via fluorous interaction obtained by molecular imprinting. AB - A polymeric sorbent selective for perfluorooctanoic acid (PFOA) was synthesized by a molecular imprinting technique using a fluorous monomer and cross-linker, and assessed chromatographically, suggesting that the fluorous imprinted polymer recognizes PFOA via hydrogen bonding and fluorine-fluorine interaction. PMID- 22545263 TI - Disposable polyester-toner electrophoresis microchips for DNA analysis. AB - Microchip electrophoresis has become a powerful tool for DNA separation, offering all of the advantages typically associated with miniaturized techniques: high speed, high resolution, ease of automation, and great versatility for both routine and research applications. Various substrate materials have been used to produce microchips for DNA separations, including conventional (glass, silicon, and quartz) and alternative (polymers) platforms. In this study, we perform DNA separation in a simple and low-cost polyester-toner (PeT)-based electrophoresis microchip. PeT devices were fabricated by a direct-printing process using a 600 dpi-resolution laser printer. DNA separations were performed on PeT chip with channels filled with polymer solutions (0.5% m/v hydroxyethylcellulose or hydroxypropylcellulose) at electric fields ranging from 100 to 300 V cm(-1). Separation of DNA fragments between 100 and 1000 bp, with good correlation of the size of DNA fragments and mobility, was achieved in this system. Although the mobility increased with increasing electric field, separations showed the same profile regardless of the electric field. The system provided good separation efficiency (215,000 plates per m for the 500 bp fragment) and the separation was completed in 4 min for 1000 bp fragment ladder. The cost of a given chip is approximately $0.15 and it takes less than 10 minutes to prepare a single device. PMID- 22545264 TI - "Good looks don't boil the pot": Irish-Newfoundland women as fish(-producing) wives. AB - This article explores the historical understanding of maritime womanhood in Newfoundland by examining women in fishing families along the southern Avalon Peninsula from the late eighteenth to the early twentieth centuries. It does not talk about fishwives in any popular sense of the word, for these women did not market fish; rather, they produced salt fish for market. And while middle-class observers may have perceived them as coarse and bold, within their own families and fishing communities they were seen as essential partners who contributed equally to family economies. Within a sexual division of labor that assigned vital and complementary tasks to both men and women, Newfoundland fish( producing) wives carried out hard physical labor at public sites of production. This contributed significantly to the construction of "woman" as essential worker, which in turn had broader repercussions for their status and authority within fishing communities. The participation of fish(-producing) wives changed significantly from the 1950s onward, as the fishery moved from household production to a modernized, and discursively masculinized, industry. Yet the iconic image of the fish(-producing) wife in traditional household production remains undisrupted in the early twenty-first century. PMID- 22545265 TI - Aboriginal women and Asian men: a maritime history of color in white Australia. AB - In 1901, Broome-a port town on the northwest edge of the Australian continent-was one of the principal and most lucrative industrial pearling centers in the world and entirely dependent on Asian indentured labor. Relations between Asian crews and local Aboriginal people were strong, at a time when the project of White Australia was being pursued with vigorous, often fanatical dedication across the newly federated continent. It was the policing of Aboriginal women, specifically their relations with Asian men, that became the focus of efforts by authorities and missionaries to uphold and defend their commitment to the White Australia policy. This article examines the historical experience of Aboriginal women in the pearling industry of northwest Australia and the story of Asian-Aboriginal cohabitation in the face of oppressive laws and regulations. It then explores the meaning of "color" in contemporary Broome for the descendants of this mixed heritage today. PMID- 22545266 TI - Relations between people, relations about things: gendered investment and the case of the Lake Victoria fishery, Tanzania. AB - Using the example of one of the African fisheries that has been most significantly transformed from family based to commercialized-that on Lake Victoria in Tanzania-this article considers the social nexus of decision making and focuses on analyzing women's place. It is true that women have never been more than a minority in fisheries due to traditional inheritance patterns and new market structures, both of which bypass women in questions of ownership and decision making. We look in vain for fishwives, if this means female fish producers acting with a highly visible degree of economic and social autonomy. There is no vernacular term to identify women who work with fish or those rare women who own fishing vessels. And yet the absence of derogatory representation suggests that there have been few attempts to detract from women who are active in the fishery. Should we thus be aiming at more subtlety in our analytical approaches to fishing relations on Lake Victoria? The article unveils the ways in which women's relations with fishermen are negotiated and how agreements are reached on behalf of their families. It explores for women's empowerment via the customary social relations and management arrangements that exist in these riparian communities. The lake fishery has a basis for development, but its potential for the kind of growth that will have returns for future generations rests on an appreciation of how fisher-wives conceive of, and respond to, the opportunities, constraints and risks of investing in this fishery. PMID- 22545273 TI - Unruly women and invisible workers: the shrimp traders of Mazatlan, Mexico. AB - During the 1980s, a group of women from rural communities in the Mexican state of Sinaloa organized a grassroots social movement in order to gain legal access to the sale of shrimp. The movement reached its peak in 1984, with the formation of a shrimp traders union and the establishment of a shrimp marketplace in the tourist city of Mazatlan. Despite the long trajectory of the movement and the success of the shrimp market, these women and their work have been completely ignored by government agencies in charge of the development and management of the fishing industry. For the most part, one gets to read about the shrimp traders only in tourist-oriented brochures depicting them as a "local attraction," something to be seen while one is touring the city on a private charter bus en route to the Archaeological Museum or to the upscale jewelry shops in the Golden Zone. In this article, I examine how women used their gender and their identity as rural workers to defy the state and its policies, overcome poverty, and take control of the local marketing of shrimp. Another objective of this article is to show why and how women engaged in collective action so they could be legitimized as workers and how gender shaped their individual experiences. PMID- 22545274 TI - Aspirin provides minimal cardiac protection to healthy adults. Risk of serious internal bleeding far outweighs any benefit. PMID- 22545275 TI - Brain-stimulating habits linked to lower Alzheimer's protein levels. Research shows that a lifetime of mentally challenging activities may help delay dementia. PMID- 22545276 TI - Statin use linked to increased risk of diabetes in older women. Risk of type 2 diabetes in postmenopausal women may be up to 48 percent higher than in women who do not use the cholesterol-lowering drugs, but the jury tilts in favor of continuing medication. PMID- 22545277 TI - Exercise aids long-term independence and mobility. Targeted physical activity can prevent disability that leads to loss of mobility--and independence--among seniors. PMID- 22545278 TI - Psoriatic arthritis: biologics seen as new treatment. More aggressive treatment is recommended for psoriatic arthritis, a severe, progressive form of the disease. PMID- 22545279 TI - I've been taking warfarin (Coumadin) for atrial fibrillation. I have to limit my consumption of leafy green vegetables because of the amount of vitamin K they contain. Since vitamin K is important to bone health, are there any substitutes that could provide similar nutrients? PMID- 22545280 TI - My wife has moderate Alzheimer's disease. It's difficult to get her to perform even the simplest task for herself. How can I best deal with her apathy? PMID- 22545281 TI - Lately I've had a decline in my sex drive, feel fatigued and depressed. Would I be a candidate for testosterone therapy? PMID- 22545282 TI - [Gynecologic cancer]. PMID- 22545283 TI - [I. Uterine cervical neoplasms 1. Small cell carcinoma,]. PMID- 22545284 TI - [I. Uterine cervical neoplasms 2. Strategy for treatment of adenocarcinoma in situ of uterine cervix and the role of chemotherapy ]. PMID- 22545285 TI - [II. Endometrial neoplasms 1. Papillary serous carcinoma]. PMID- 22545286 TI - [II. Endometrial neoplasms 2. Clear cell cancer]. PMID- 22545287 TI - [III. Ovarian cancer 1. Ovarian clear cell carcinoma]. PMID- 22545288 TI - [III. Ovarian cancer 2. Treatment strategy for mucinous adenocarcinoma of the ovary]. PMID- 22545289 TI - Tumour immunotherapy--leukocytes take up the fight. AB - The immune system can promote the elimination of tumours, but often immune responses are modulated or suppressed by the tumour microenvironment. In this joint Focus from Nature Reviews Cancer and Nature Reviews Immunology, leading researchers describe our current understanding of the complex interactions that occur between the immune system and tumour cells, and discuss how the power of the immune system can be harnessed by anticancer immunotherapies. PMID- 22545290 TI - Early results of HemiCAP((r)) resurfacing implant. AB - OBJECTIVE: Metallic implants in the first metatarsophalangeal (MTP) joint have been used for many years in the treatment of hallux rigidus (HR). The HemiCAP((r)) prosthesis is the first implant used for resurfacing the metatarsal head in HR treatment. The aim of our study was to evaluate the early results of the HemiCAP((r)) prosthesis for the treatment of HR. METHODS: A total of 27 toes of 25 patients with MTP arthritis of the great toe were treated with an Arthrosurface((r))HemiCAP((r)) resurfacing implant. The average follow-up time was 37.6 (range: 30 to 43) months. All patients were evaluated clinically and radiographically. Postoperative satisfaction and function were scored according to the American Orthopaedic Foot and Ankle Society (AOFAS) score. Pain was assessed with the use of a visual analogue scale (VAS) ranging from 0 to 10, with 0 indicating the absence of pain and 10 describing the worst pain imaginable. RESULTS: Mean preoperative AOFAS score improved from 40.94 (range: 25 to 63) to 85.1 (range: 54 to 98) at the final follow-up (p<0.0001). Preoperative average VAS pain scores improved from 8.30 preoperatively to 2.05 at the final follow-up (p<0.0001). The average MTP joint range of motion (ROM) the improved from 14.36 degrees preoperatively to 54.38 degrees at the final follow-up. No radiologic loosening or osteolysis was observed in patients with HemiCAP((r)) implant. CONCLUSION: The early results of the HemiCAP((r)) implant on the metatarsal head are promising. However, studies over a longer period involving more patients would be beneficial in terms of defining and reviewing the stability of the implant and any innovations in the treatment strategy for HR. PMID- 22545292 TI - Ethnographies of place: a new urban research agenda. PMID- 22545293 TI - Retailing in urban Japan, 1868-1945. PMID- 22545294 TI - Domestic service, privacy and the eighteenth-century metropolitan household. PMID- 22545296 TI - "Ibadan - a model of historical facts": militarism and civic culture in a Yoruba city. PMID- 22545299 TI - Morphological periods, planning and reality: the case of England's inter-war suburbs. PMID- 22545300 TI - The Blitz, civilian morale and the city: mass-observation and working-class culture in Britain, 1940-41. PMID- 22545302 TI - Ukrainian psychology in search of identity and the new dimensions in ethnopsychology. PMID- 22545303 TI - China's urban transformation: patterns and processes of morphological change in Beijing, Shanghai and Guangzhou. PMID- 22545305 TI - Lymphedema: separating fact from fiction. AB - Lymphedema is a feared complication of cancer treatment and one that negatively impacts survivorship. The incidence of breast cancer-related lymphedema ranges from 6% to 70%, but lymphedema may be a common and under-reported morbidity. No standard guidelines for its diagnosis and assessment exist. Although the true etiology of lymphedema remains unknown, radiation, chemotherapy, type of breast surgery, and extent of axillary surgery are commonly cited risk factors. However, the relationship between the number of nodes removed and the risk of lymphedema is not clearly correlated. Clinical trials are focusing on ways to reduce the need for axillary dissection even in the setting of a positive sentinel node, to help minimize axillary morbidity. Risk-reduction practices, including avoidance of skin puncture and blood pressures in the ipsilateral upper extremity, and precautionary behaviors such as wearing compression garments during air travel continue to be advocated by the medical and survivor communities, despite a lack of rigorous evidence supporting their benefit. Emerging data support exercise in at-risk and affected women with lymphedema when started gradually and increased cautiously. PMID- 22545304 TI - Oncology Smartphone applications: perspectives from a researcher/community-based hematologist/oncologist and a physician reviewer of medical apps. PMID- 22545306 TI - Lymphedema prevention and early intervention: a worthy goal. PMID- 22545307 TI - Lymphedema: still a problem without an answer. PMID- 22545308 TI - Oral therapies and food: to eat or not to eat? PMID- 22545309 TI - Semuloparin helps prevent thromboembolic events in patients receiving chemotherapy. PMID- 22545310 TI - FDA grants imatinib (Gleevec) full approval for adjuvant treatment of GIST. PMID- 22545311 TI - Can metastatic colorectal cancer be cured? AB - Significant advances have been made in the treatment of metastatic colorectal cancer (mCRC). Development of the targeted biologic agents and their integration with cytotoxic chemotherapy regimens has led to improvements in clinical efficacy. Despite these gains, the overall impact of these combination regimens in mCRC therapy has been relatively modest. While 2-year survival has improved, substantive gains have yet to be made in 5-year survival. However, a small subset of patients can be cured of their metastatic disease, with prolonged 5- and 10 year overall survival. This select group of patients includes those with metastatic disease limited to the liver or other organ-specific sites, as these patients are able to undergo surgical resection at the time of diagnosis or following conversion therapy with the appropriate integration of chemotherapy. A multimodality team-based approach involving medical oncologists, surgical oncologists, radiologists, and other healthcare providers is absolutely critical for the success of this therapeutic approach. This article reviews the main issues that must be considered from the surgical oncology and medical oncology perspectives, respectively. PMID- 22545312 TI - Metastatic colorectal cancer: a curable disease. PMID- 22545313 TI - Metastatic colorectal cancer: potential for cure? PMID- 22545314 TI - Systemic therapy in renal cell carcinoma: advancing paradigms. AB - The 21st century has seen an explosion in the development of agents for renal cell carcinoma (RCC), a malignancy previously considered refractory to systemic therapy beyond cytokine therapy. At this time, there are six US Food and Drug Administration (FDA)-approved agents available. In addition, there was a recent favorable review by the FDA's Oncologic Drugs Advisory Committee of a next generation vascular endothelial growth factor receptor (VEGFR) inhibitor, axitinib (Inlyta); other agents are in advanced testing. Moreover, while VEGF- and mammalian target of rapamycin (mTOR)-targeted therapies have become the mainstay of RCC treatment, other new molecular targets and therapeutic approaches are being developed. The availability of active agents also brings opportunities for additional clinical maneuvers, such as neoadjuvant and adjuvant therapy, as well as a need for decisions on combinatorial therapeutics in the advanced disease setting. Together, these developments and the issues they raise pose important challenges for oncologists and cancer biologists, given the limited number of patients and resources available for studies and the urgent clinical needs of the patients and families affected by RCC. PMID- 22545315 TI - Renal cancer therapeutics: now what? PMID- 22545316 TI - Metastatic RCC: moving towards a chronic disease. PMID- 22545317 TI - New way to predict prostate cancer severity: size of prostate. PMID- 22545318 TI - Scabies then and now. PMID- 22545320 TI - New findings in delusions of parasitosis. AB - Two new cases are presented with delusions of parasitosis. Both were women, one middle-aged and one elderly, and exhibited classic symptoms of parasites and "strings" in the skin indicative of Morgellons disease. Each had an additional psychiatric disorder: drug addiction to cocaine and senile dementia. They also illustrate the difficulty encountered by the dermatologist in providing adequate therapy because of resistance to psychiatric referral as well as to standard accepted medication. Newer psychotropics, such as risperdal and lexapro, show promise in helping these patients and add to the therapeutic armamentarium of pimozide. PMID- 22545319 TI - Erlotinib-induced scalp perifolliculitis. AB - Erlotinib is a highly specific epidermal growth factor receptor tyrosine kinase inhibitor used to treat various metastatic cancers. The most commonly reported side effects in patients receiving erlotinib are dermatitis and diarrhea. The authors present two cases of erlotinib-induced severe scalp perifolliculitis, which is an adverse reaction that has not been reported to date. Both patients developed pustules and thick yellow-green crusted plaques on the scalp within weeks of starting treatment with erlotinib for metastatic non-small cell lung carcinoma. Skin biopsies revealed a perifollicular accumulation of inflammatory cells, lymphocytes, and neutrophils. Both patients were treated with oral doxycycline and achieved complete resolution within 2 to 3 weeks and no recurrence despite continuing the epidermal growth factor receptor tyrosine kinase inhibitor. This is a unique presentation of an erlotinib-induced skin eruption. PMID- 22545321 TI - Wound care in short-term rehabilitation facilities and long-term care: special needs for a special population. AB - Chronic wounds can pose a challenging diagnostic and treatment dilemma in the older frail adult population. The benefits of short-term rehabilitation and long term care settings are the access to interdisciplinary resources. Rehabilitative specialists, dieticians, and skilled nurses are readily available to meet the patients' needs as they transition to home or remain in a long-term care setting for their higher level of care needs. This article follows 3 cases: a skin tear complicated by venous ulceration, a pressure ulcer with fever, and arterial ulcers in a patient who opts for comfort care. The cases illustrate the higher needs of this population and emphasize the attention that must be paid to respect nursing-time intensiveness, incorporate realistic goals of care for wound healing, and ensure excellent communication with the team members, patients, and family. PMID- 22545322 TI - Cutaneous tuberculosis: a diagnostic dilemma--laboratory inputs. AB - Bacterial cultures are the gold standard for diagnosing cutaneous tuberculosis, but there are limitations, despite the advances embracing the innovative technologies, including interferon yrelease assays, enzyme-linked immunoabsorbant assay, and molecular diagnostics, in addition to conventional skin tests and microscopic pathology. The results and their interpretation of cultures are reviewed for use in day-to-day practice. PMID- 22545323 TI - Sometimes it takes darkness to see the light: pitfalls in the interpretation of cell proliferation markers (Ki-67 and PCNA). AB - The degree of cell proliferation in a tumor is often associated with metastatic risk and mortality. Proliferating cell nuclear antigen (PCNA) and Ki-67 are proliferation markers that can be used to assess malignant potential in cutaneous lesions and pathological cell proliferation in psoriasis. These markers are elevated during periods of cell proliferation; however, they are also upregulated following UV irradiation. This upregulation may be problematic, as many skin lesions are subject to sun exposure in an everyday setting. PMID- 22545324 TI - The lion is NOT sleeping tonight. PMID- 22545325 TI - Actinomycetoma. PMID- 22545326 TI - Malignant melanoma arising within nevus spilus. AB - A 68-year-old Caucasian man presented with a suspicious lesion near the left axilla during a full skin examination that was performed for a presentation for dermatitis. The patient stated that he had the lesion for several decades but that it may have become more raised over the past few months. He did not think much of the changes, however, because it was to him, "just a birthmark." The patient had no personal or family history of melanoma. On examination, the patient had a 4.5-cm by 1.2-cm oval light tan patch studded with multiple hyperpigmented macules regularly distributed within the lesion. In addition, at the lateral aspect of the lesion, the patient had a 0.9-cm irregularly pigmented black papule that was suspicious for melanoma (Figure 1). A deep saucerization biopsy of the lesion was performed, and histopathological examination revealed malignant melanoma, with a Breslow depth of 1.13 mm (Figure 2 and Figure 3). It was recommended that the patient have a wide local excision of the biopsy site and the adjacent remaining portions of the nevus spilus. A sentinel lymph node biopsy and an oncologic evaluation were also performed. The sentinel lymph node biopsies, as well as a computed tomographic scan performed by oncology, showed no evidence of metastatic disease. Since the procedure, the patient has shown no signs of disease recurrence. PMID- 22545328 TI - Necrotic ulcer: a manifestation of leukemia cutis. AB - A 71-year-old man presented to our dermatological clinic with a 3-month history of a wound on his leg. He complained of weakness for the past few months. On his dermatological examination he had a 3x3-cm necrotic ulcer on his left tibia (Figure 1). On physical examination, there was 1 x 1-cm axillary lymphadenopathy. There was no other lymph node enlargement, hepatosplenomegaly, or gingival hypertrophy. Peripheral blood results showed 2.4x103/mm3 leukocytes (normal range 4-11 x 103/mm3) with 66% neutrophils. The hemoglobin value was 10.1 g/dL (13-18 g/dL), and the platelet count was 63x103/mm3 (150-440 x 103/mm3). No blasts were detected in a peripheral blood smear. His lactate dehydrogenase level was 567 U/L (240-480 U/L). All other results of blood chemistry were within normal limits. Punch biopsy of the skin lesion showed ulceration and dense dermal acute and chronic inflammation. There was a superficial and deep perivascular and periadnexal infiltrate of neoplastic cells composed of relatively abundant eosinophilic cytoplasm and large nuclei with blastic chromatin and occasional small nucleoli (Figure 2). Mitotic figures were prominent. Immunohistochemical stains were performed, and the neoplastic cells were CD3, CD20, CD138, and S100 protein negative. Myeloperoxidase and CD68 were positive. The histopathological findings were consistent with leukemic infiltration. Examination of bone marrow biopsy revealed that the blastic cells constituted more than 20% of the bone marrow cellularity. Cytogenetic analysis of bone marrow aspiration with fluorescence in situ hybridization was negative for inversion 16, t(8;21) and t(15;7). Histochemical stains for myeloperoxidase, sudan black, periodic acid Schiff, and alpha naphthyl acetate were also negative. Blastic cells were DR, CD13, CD117, and CD34 positive and CD5, CD7, CD10, CD14, CD19, CD20, CD33, CD41, CD56, CD64, and CD79 negative according to flow cytometry immunophenotyping. Blastic cells were 35% in the bone marrow. Based on the findings of bone marrow examination, the patient was diagnosed as having acute myeloblastic leukeamia (AML) with minimal differentiation (subtype MO) according to French-American British and World Health Organization classification. The examination of abdominal ultrasonography and thorocic and abominal computed tomography revealed no metastases. The patient was treated with chemotherapy that consisted of cytarabin and daunorubicin. After chemotherapy, the lesion regressed. One month after chemotherapy, the patient presented to the hospital with a complaint of fever. He was diagnosed with febrile neutropenia. He died of cardiac failure 12 months after appearance of skin infiltration. PMID- 22545327 TI - Pseudocyst of the auricle: an uncommon entity of the ear. AB - A 48-year-old white man presented with a 2-month history of a lump on his right ear following purported exposure to the cold. The patient denied any history of trauma, rubbing, insect bite, or inflammation at the site. The patient was otherwise healthy and was not taking any medications. The lesion was completely asymptomatic, as the patient denied any pain, tenderness, or change in size since the lesion appeared. Physical examination revealed a 1.1-cm x 1-cm skin-colored, slightly fluctuant, rubbery, nonmobile dermal nodule on the right scaphoid fossa (Figure 1). No erythema, warmth, tenderness, or drainage was noted. A review of systems was noncontributory. A punch biopsy performed at the site of the cyst yielded clear, serous drainage. The cystic lesion was drained completely and decompressed. Histological examination revealed the surface of an intracartilaginous cystic space lined by degenerated cartilage, consistent with a diagnosis of pseudocyst of the auricle (Figure 2 and Figure 3). The lesion, although much smaller than at the time of presentation, persisted at the 3-week follow-up visit. It remained asymptomatic, without pain or irritation. At that time, the patient declined re-excision with bolster dressing. At 7-month follow up, he reported the lesion to be stable. PMID- 22545329 TI - Historical diagnosis & treatment--Syphilis primaria: sclerosis syphilitica et oedema indurativum. The Stereoscopic Skin Clinic. 1910. PMID- 22545330 TI - Inflammatory linear verrucous epidermal nevus with genital involvement. AB - An 18-year-old woman was admitted to our clinic complaining of pruritic lesions on her inguinal and genital areas that had been present since birth. She had previously used topical steroids and a combination of topical steroids and calcipotriol for approximately 6 months; however, the treatment was unsuccessful. Her medical history was unremarkable. On dermatologic examination, mild erythematous, lichenified, and verrucous papules occurring in a linear pattern on the right inguinal area and on the region extending from the right labium majus to the perianal area were noted (Figure). Additionally, an erythematous area with central erosion surrounded by maceration was noted on the intergluteal area. Two separate punch biopsy samples were obtained from the erythematous, lichenified, verrucous, papular lesion on the inguinal area and from the erythematous, eroded, macerated lesion on the intergluteal area. Histopathological examination of both biopsy specimens revealed a thin orthokeratotic layer and scattered parakeratotic layers, as well as papillomatosis and acanthosis of the epidermis with a slight hyperpigmentation of the basal layer. A mild, perivascular, chronic inflammatory cell infiltration was noted in the dermis. Based on the clinical and histopathological findings, the patient was considered to have inflammatory linear verrucous epidermal nevus, and cryotherapy was initiated. At the 2-week follow-up after the first application, it was observed that the itching complaint decreased substantially and the eroded lesions in the intergluteal area were re epithelialized. On clinical follow-up, no improvement was observed in the papular component of the lesion after 4 sessions of cryotherapy. The patient voluntarily discontinued the follow-up after 4 sessions of cryotherapy. PMID- 22545331 TI - Oral frictional hyperkeratosis (morsicatio buccarum): an entity to be considered in the differential diagnosis of white oral mucosal lesions. AB - A 55-year-old man presented with desquamating lesions on his bilateral buccal mucosa intermittently for approximately 3 years. The alteration in texture within his mouth created an uncomfortable sensation and, at times, the lesions spontaneously peeled away requiring him to spit repeatedly. The patient denied any history of trauma, cheek biting, or use of tobacco products. On initial examination, the patient was asymptomatic and the oral mucosa had no abnormal findings, but on repeat examination when symptoms were present, the patient had shaggy white plaques on the bilateral buccal mucosa limited to the line of dental occlusion (Figure 1). The plaques could be easily peeled away from the underlying skin with a cotton swab without any pain, leaving behind normal underlying mucosa. A review of the prior biopsy of the affected mucosa revealed an irregularly hyperplastic epithelium with foci of ballooned epithelial cells within the upper layer, parakeratosis, and bacterial overgrowth (Figure 2). Microscopic examination of fragments of mucosa peeled away from the affected area revealed fragments ofparakeratotic cornified material colonized by numerous bacteria (Figure 3). Results from periodic acid-Schiffstain revealed no fungal elements. The diagnosis of oral frictional hyperkeratosis was established based on the clinical and microscopic findings. It was concluded that the hyperkeratosis was likely caused by bite trauma or grinding of the teeth while the patient was asleep. Triamcinolone 0.1% ointment in Orabase and tretinoin 0.05% gel were ineffective. The patient found that rinsing with hydrogen peroxide solution was most helpful in reducing the lesions. A bite guard was recommended by an oral and maxillofacial surgeon, but the patient has yet to use it. PMID- 22545332 TI - Vesicular palmoplantar pityriasis rosea. AB - A 16-year-old young man presented with intensely itchy erythematous dermatitis on the body for 1 week and vesicular lesions on the palms and soles for 4 to 5 days. Lesions on the palms and soles were accompanied by severe burning and itching. The patient gave a history of sore throat and fever, 1 week prior to the onset of lesions. A general physical examination was normal, and cutaneous examination revealed multiple, well-defined erythematous scaly plaques with collaret scaling on the trunk and extremities (Figure 1). Vesicular lesions were seen on the palms and soles (Figure 2). The differential diagnoses we considered were pityriasis rosea and secondary syphilis. The possibility of dermatophytid, vesicular pityriasis rosea, and pompholyx was limited to the palms and sole lesions. Complete blood cell count was within normal limits. Results from antistreptolysin O titer, potassium hydroxide mount, and venereal disease research laboratory were negative. Skin biopsies were taken from the back and left palm. The biopsy specimen from the back revealed focal spongiosis, lymphocyte exocytosis, vacuolar changes in the basal layer, and perivascular lymphocytic infiltrate in the dermis (Figure 3). The biopsy obtained from the vesicular lesion on the left palm revealed an intraepidermal vesicle with no evidence of acantolytic process (Figure 4). A diagnosis of pityriasis rosea was made and the patient was started on clarithromycin 500 mg once a day for 7 days, along with antihistamines and emollients. The lesions faded dramatically in a very short period, and there was significant involution of almost all of the lesions after 7 days of clarithromycin. During the 6 months of follow-up, no recurrence was observed. PMID- 22545333 TI - Joining forces. PMID- 22545334 TI - The radioimmunoassay: an assay that revolutionized medicine. PMID- 22545335 TI - Evidence-based medicine at the point of care: student utilization and faculty implications. AB - Evidence-based medicine (EBM) practiced at the point-of-care (POC) requires a specific skill set and appropriate resources. In this paper, we report medical student use of EBM resources in a novel simulated clinical exercise. In addition, we discuss three quality EBM resources, most available through the Sanford School of Medicine of The University of South Dakota library system, and we encourage faculty to incorporate these resources in their daily practice and clinical teaching. PMID- 22545336 TI - Beyond a single condition focus: how does comorbidity interfere with clinicians' and patients' disease management? PMID- 22545337 TI - Quality focus: improvement in health care-associated infections. PMID- 22545338 TI - EDs in the Midwest and South activate disaster plans as deadly tornadoes sweep through the region. AB - Hospitals in the Midwest and South activated their disaster plans in early March to deal with a phalanx of powerful tornadoes that leveled several small towns and killed at least two dozen people. Some hospitals had to activate plans for both internal and external disasters as their own facilities were threatened. One small critical-access hospital in West Liberty, KY, sustained significant damage and had to evacuate its patients to another facility. All the hospitals credit their disaster plans and practice drills with helping them to manage the crisis as efficiently as possible. Morgan County ARH Hospital in West Liberty, KY, went for several days without an operational lab or radiology department, but staff kept the ED open for absolute emergencies. Margaret Mary Community Hospital (MMCH) in Batesville, IN, received six tornado victims, but it was prepared for many more. Administrators credit advanced warning of the storms with helping them to prepare effectively, as well as to coordinate their response with other hospitals in the area. As a level 1 trauma center, the University of Louisville Hospital in Louisville, KY, received all the most seriously injured patients in the region, even while the facility itself was under a tornado warning. Staff had to route families away from the glassed-in waiting room to the basement until the tornado warning had passed. At one point during the crisis, there were 90 patients in the hospital's ED even though the department is only equipped with 29 beds. Administrators at Huntsville Hospital in Huntsville, AL, encouraged colleagues to take advantage of smaller-scale emergencies to activate parts of their disaster plans, and to focus disaster preparation drills on their hospital's top hazard vulnerabilities. PMID- 22545339 TI - Take advantage of smaller-scale crises to work your disaster plan. PMID- 22545340 TI - Rapid intake, empowered nursing staff energize no-wait ED model. AB - By empowering front-line staff to come up with some of their own solutions, the ED at Swedish Medical Center in Issaquah, WA, has implemented a no-wait model that eschews traditional triage in favor of a rapid intake process that puts patients in beds immediately and kick-starts the evaluation process. While the approach has proven challenging to implement and maintain, patient satisfaction is greater than 95%. The no-wait model was developed and fine-tuned by the staff at a free-standing ED that preceded the opening of the hospital in Issaquah, WA. Key to the approach is a team-based system that puts all personnel on the same level with no hierarchical structure. In the model, charge nurses are under constant pressure to make sure a room is always available for the next patient, and nursing staff are empowered through protocols and standard order sets to respond to patient needs before physicians complete their assessments. PMID- 22545341 TI - EDs grapple with surging demand from patients with dental problems. AB - Emergency departments across the country are experiencing surging demand from patients who present with toothaches and other dental problems. In a new report, the Pew Center on the States in Washington, DC, reports that ED visits for dental concerns grew by 16% between 2006 and 2009. Analysts say the main contributing factor to this problem is a severe shortage of dentists--particularly dentists willing to accept low reimbursement levels from Medicaid programs. States and EDs are responding to the problem in multiple ways. Emergency department providers report that these patients often keep returning to the ED for dental care even though the most ED providers can generally do for them is provide antibiotics and pain medication, and referral to a list of dentists. Some EDs have had success distributing dental resource sheets with the names of dental providers who are willing to establish payment plans for patients. Also, some EDs utilize patient navigators to help make dental appointments for patients with dental concerns. A number of states are considering laws that would enable mid-level dental providers to provide routine dental care at lower cost. Alaska and Minnesota already allow the practice, although the impact on EDs is not yet clear. State dental associations are fiercely opposed to the practice, and experts acknowledge that no one solution will completely solve the problem. PMID- 22545342 TI - CYP3A genotypes in Bangladeshi tuberculosis patients. AB - The purpose of this study is to investigate the genotype and allelic frequencies of CYP3A in Bangladeshi Tuberculosis (TB) patients which may help for individualized drug dosing and improved therapeutics. Genotyping was done using the extracted genomic DNA from 90 TB patients followed by amplification of target alleles by Polymerase Chain Reaction (PCR). Amplified alleles were then digested by restriction enzymes followed by gel electrophoresis & sequencing to identify the targeted alleles namely CYP3A4*1B, CYP3A4*2, CYP3A4*4, CY3A4*5, CYP3A4*6, CYP3A4*10, CYP3A4*18, and CYP3A5*3. In TB patients, no samples were positive for CYP3A4*2, CYP3A4*4, CYP3A4*5, CYP3A4*6, CYP3A4*10, and CYP3A4*18 alleles. One sample was found to be heterozygous for CYP3A4*1B (1.11%). The wild homozygous (CYP3A5*1/*1) genotype frequency was 7.78%, the heterozygous (CYP3A5*1/*3) frequency was 42.22% and the homozygous mutant (CYP3A5*3/*3) frequency was 50% in Bangladeshi TB patients. The absence of the common polymorphic gene suggests that there will be no impact of CYP3A drug metabolizing enzymes on antituberculosis drugs. PMID- 22545343 TI - A postmortem study on the volume of the human thyroid gland. AB - The present study was designed to find out the difference in volume of the thyroid gland of Bangladeshi people in relation to age and sex and to compare with previous local and foreign studies. It was a Cross-sectional descriptive type of study. The hospital based study was conducted in the Department of Anatomy, Dhaka Medical College, Dhaka, from January to December 2008. The present study was performed on 60 post mortem human thyroid gland (39 of male and 21 of female) collected from unclaimed dead bodies which were in the morgue under examination in the Department of Forensic Medicine, Dhaka Medical College, Dhaka. The samples were divided into three age-groups including group A (10-20 years), group B (21-50 years) & group C (>50 years) and the volume of the thyroid glands were measured by fluid displacement method and recorded. No difference was found in mean volume of the thyroid gland between male and female. However, significant difference was found in between age groups. The volume of the gland was found to increase from early childhood and puberty up to 50 years of age and then decreased. PMID- 22545344 TI - Elevated serum homocysteine level has a positive correlation with serum cardiac troponin I in patients with acute myocardial infarction. AB - The objective of the present study is to find out whether the increased serum homocysteine level is associated with the increased serum troponin I as a surrogate marker of extent of myocardial injury in acute myocardial infarction patients. Elevated homocysteine levels are associated with increased thrombosis. In patients presenting with Acute Coronary Syndrome (ACS), it is not known whether this association is reflected in the degree of myocardial injury. This was a cross sectional study conducted among the patients with acute myocardial infarction in the Department of Cardiology, Dhaka Medical College Hospital during the period of October 2009 to September 2010 and which included 194 consecutive patients with acute myocardial infarction. The mean (+/- SD) serum homocysteine level was 20.2 +/- 14.3 micromol/L with range from 7.4 to 129.1 micromol/L. Mean serum troponin-I level was classified according to normal (<15 micromol/L) and high (> or = 15 micromol/L) levels of serum homocysteine values. The mean serum troponin-I level was 8.9 +/- 8.6 ng/ml in the patients having normal serum homocysteine level and 18.4 +/- 6.5 ng/ml in the patients having high serum homocysteine level. A significant positive correlation (r=0.273; p<0.001) was found between serum troponin-I level with homocysteine level. Patients with moderate hyperhomocysteinemia (> or = 15 micromol/L) was found to be 7.09 times more likely to have increased serum troponin-I (a surrogate marker of extent of myocardial injury). The main observation of the present study was that elevated serum homocysteine level has a positive correlation with serum cardiac troponin-I in patients with acute myocardial infarction. So serum homocysteine is associated with increased extent of myocardial injury as measured by serum cardiac troponin I level, a surrogate marker in patients with acute myocardial infarction. PMID- 22545345 TI - Comparison between prostate volume and intravesical prostatic protrusion in detecting bladder outlet obstruction due to benign prostatic hyperplasia. AB - The objectives of this study were to determine and compare the correlation of intravesical prostatic protrusion (IPP) and prostate volume (PV) with bladder outlet obstruction (BOO). This study was conducted in the department of urology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh, between July 2009 to September 2010. Fifty benign prostatic hyperplasia (BPH) patients were included in the study. Their evaluation consisted of history along with International Prostate Symptoms Score (IPSS), digital rectal examination (DRE), transabdominal ultrasonography to measure prostate volume, intravesical prostatic protrusion & post voidal residual (PVR) urine and pressure-flow studies to detect bladder outflow obstruction (BOO). Statistical analysis included Unpaired 't' test, Chi-square test and Spearman's Rank correlation test. Receiver Operator Characteristic (ROC) curves were used to compare the correlation of PV and IPP with BOO. Mean prostate volume was significantly larger in bladder outlet obstructed patients (P<0.05). Mean IPP was significantly greater in obstructed patients (P<0.001). Area under ROC curve was 0.700 for PV and 0.821 for IPP. Prostate volume & intravesical prostatic protrusion measured through transabdominal ultrasonography are noninvasive and accessible method that significantly correlates with bladder outlet obstruction in patients with benign prostatic hyperplasia and the correlation of IPP is much more stronger than that of prostate volume. PMID- 22545346 TI - Chronic kidney disease specific cardiovascular risk factors among non dialytic patients with chronic kidney disease stage-V--an experience of a specialized hospital. AB - The study was carried out to see prevalence of Chronic Kidney Disease (CKD) specific cardiovascular risk factors and cardiovascular events among patients with Chronic Kidney Disease stage-V (CKD-V) before starting dialysis therapy in the department of Nephrology of National Institute of Kidney Diseases & Urology (NIKDU), Dhaka, Bangladesh. Among CKD specific cardiovascular risk factors, anemia showed the highest prevalence (96.7%) in study population. More than fifty percent of CKD-V patients had both hypocalcaemia and hyperphosphataemia. Calcium Phosphate Product (CaXP) was elevated among 23 percent of the population. C reactive protein, an acute phase protein was positive in 78% of CKD-V patients. Besides, among traditional risk factors, Hypertension and Diabetes Mellitus were present in 83.3% and 23% of the study population respectively. The prevalence of cardiovascular events among CKD-V patients showed that 18.3% had ischemic heart disease, 38% heart failure, 4.7% arrhythmia and 9% left ventricular hypertrophy. Females were significantly prone to develop cardiovascular events than their male counterpart (p=0.028). Diabetes was significantly higher in patients with cardiovascular complications than in patients without cardiovascular complications (p=0.021). PMID- 22545347 TI - A simple biological marker to differentiate the types of Herpes Simplex Viruses in resource-limited settings. AB - Herpes simplex viruses (HSV) multiply readily on the chorioallantoic membrane (CAM) of embryonated hen's egg and produce easily visible foci or pocks on this membrane. In the present study, pocks produced by the two antigenic types of HSV (1 & 2) were compared to evaluate the effectiveness of typing HSV isolates by pock size on CAMs. A total of 57 HSV isolates from both non-genital and genital samples were typed by the pock size produced on the CAMs of fertile hen's eggs. Twenty two HSV isolates yielded visible pocks on CAM, of which 9 (40.9%) produced small pocks, while 13 (59.1%) produced large pocks. All pocks produced on CAM were confirmed by antigenic typing by the Direct Fluorescent Antibody (DFA) method. HSV isolates which produced small pocks were in complete (100%) concordance with HSV type-1, while those producing larger pocks were in full (100%) concordance with HSV type-2. Thus, the pock size on CAM of embryonated fertile hen's egg may be used as a simple and relatively inexpensive biological marker for the differentiation of HSV types 1 & 2. PMID- 22545348 TI - What cannot be measured cannot be done; risk factors for childhood tuberculosis: a case control study. AB - Childhood tuberculosis is one of the major causes of childhood mortality and morbidity though much neglected within our National Tuberculosis Control Program. This case control study was carried out to identify the risk factors for tuberculosis among children. Cases (n=95) and controls (n=94) were selected from Directly Observed Treatment Short Course (DOTS) centers of four upazillas of Dhaka and Gazipur districts. Cases were childhood tuberculosis patient, who were test positive by sputum microscopy from January to May, 2011 and controls were children who visited DOTS laboratory suspecting tuberculosis infection but were sputum negative. Both cases and controls were selected from the sputum examination registers and were traced at home for exposure data. The study showed more girls were infected than boys. Several socio demographic and environmental factors were found to be associated with the development of childhood tuberculosis. Logistic regression model was constructed to find out the important predictors which revealed age, education of the respondents, indoor environment and contact pattern were significantly associated with childhood tuberculosis. Children more than 14 years of age had 6.25 times higher risk of developing childhood tuberculosis; (Odds ratio=6.25; 95% CI for OR=2.00 to 19.55), Children completed primary education had 3.12 times lower risk of developing childhood tuberculosis, (Odds ratio=.32; 95% CI for OR=.10 to 1.00). Those who resided in better in-house environment had 4.35 times lower risk of developing childhood tuberculosis (Odds ratio=.23; 95% CI for OR=.06 to .95) and children came in contact with source tuberculosis cases who were their relatives or neighbors were 5.26 times lower risk of developing childhood tuberculosis than being in contact with family members with TB (Odds ratio=.19; 95% CI for OR=.07 to .49). Contact Screening should be incorporated in National TB program for early detection and effective treatment of tuberculosis. Improvement of indoor environment and ventilation status of the bedroom might reduce the risk of developing childhood tuberculosis. PMID- 22545349 TI - Symptomatic overlap in patients with diarrhea predominant irritable bowel syndrome and microscopic colitis in a sub group of Bangladeshi population. AB - Microscopic Colitis (MC) and diarrhea predominant irritable bowel syndrome (IBS D) has almost similar clinical feature but MC is diagnosed by histologic criteria and IBS is diagnosed by symptom-based criteria. There is ongoing debate about the importance of biopsies from endoscopically normal colonic mucosa in the investigation of patients with IBS-D. Aim of this study was to assess the prevalence of MC in patient with IBS-D and to determine the distribution of MC in the colon. This observational study was conducted in department of Gastroenterology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from January 2008 to December 2009. Patients were evaluated thoroughly & who meet Rome-II criteria with normal routine laboratory tests, were included in the study. Colonoscopy was done and biopsies were taken from the caecum, transverse colon, descending colon, and rectum. Out of total 60 patients, 22 had Lymphocytic Colitis (LC), 28 had nonspecific microscopic colitis (NSMC) and 10 had irritable bowel syndrome noninflamed (IBSNI). The distribution of LC was restricted to proximal colon in 15 patients, in the left colon in 2 patients and diffuses throughout the colon in 5 patients. There is considerable symptom overlap between the patients of IBS-D and patients with microscopic colitis. Without colonoscopic biopsy from multiple sites, possibility of MC cannot be excluded in patients with IBS-D and it can be said that clinical symptom based criteria for irritable bowel syndrome are not sufficient enough to rule out the diagnosis of microscopic colitis. PMID- 22545350 TI - Congenital absence of one tonsil without any other congenital abnormality: a rare presentation. PMID- 22545351 TI - Back pain: an unusual presentation of Castleman's diseases. PMID- 22545352 TI - Constipation--presenting compliant and clinical marker of Parkinson's disease. PMID- 22545353 TI - Purification of an antifungal endochitinase from a potential biocontrol Agent Streptomyces griseus. AB - Streptomyces griseus (MTCC 9723) is a chitinolytic bacterium isolated from prawn cultivated pond soil of Peddapuram Village; East Godavari District was studied in detailed. Chitinase (EC 3.2.1.14) was extracted from the culture filtrate of Streptomyces griseus and purified by ammonium sulfate precipitation, DEAE cellulose ionexchange chromatography, Sephadex G-100 and Sephadex G-200 gel filtration chromatography. The molecular mass of the purified chitinase was estimated to be 34, 32 kDa by SDS gel electrophoresis and confirmed by activity staining with Calcofluor White M2R. Chitinase was optimally active at pH of 6.0 and at 40 degrees C. The enzyme was stable from pH 5-9 and up to 20-50 degrees C. The chitinase exhibited Km and Vmax values of 400 mg and 180 IU mL(-1) for colloidal chitin. Among the metals and inhibitors that were tested, the Hg+, Hg2+ and P-chloromercuribenzoic acid completely inhibited the chitinase activity at 1 mM concentration. The purified chitinase showed high activity on colloidal chitin, chitobiose, and chitooligosaccharide. An in vitro assay proved that the crude chitinase, actively growing cells of S. griseus having antifungal activity against all studied fungal pathogen. This result implies that characteristics of S. griseus producing endochitinase made them suitable for biotechnological purpose such as for degradation of chitin containing waste and it might be a promising biocontrol agent for plant pathogens. PMID- 22545354 TI - Effect of Urtica dioica L. (Urticaceae) on testicular tissue in STZ-induced diabetic rats. AB - Urtica dioica L. (Stinging nettle) has already been known for a long time as a medicinal plant in the world. This histopathological and morphometrical study was conducted to determine the effects of the hydroalcoholic extract of Urtica dioica leaves on testis of streptozotocin-induced diabetic rats. Eighteen male Wistar rats were allocated to equally normal, diabetic and treatment groups. Hyperglycemia was induced by Streptozotocin (80 mg kg(-1)) in animals of diabetic and treatment groups. One week after STZ injection (80 mg kg(-1)), the rats of treatment group received the extract of U. dioica (100 mg/kg/day) IP for 28 days. After 5 weeks of study, all the rats were sacrificed and testes were removed and fixed in bouin and after tissue processing stained with H and E technique. Tubular cell disintegration, sertoli and spermatogonia cell vacuolization and decrease in sperm concentration in seminiferous tubules were seen in diabetic and treatment groups group in comparison with control. External Seminiferous Tubular Diameter (STD) and Seminiferous Epithelial Height (SEH) significantly reduced (p < 0.05) in the diabetic rats compared with controls and these parameters in the treatment group were similar to diabetics animals. This study showed that hydroalcoholic extract of Urtica dioica leaves, after induction of diabetes; has no treatment effect on seminiferous tubules alterations in streptozotocin-induced diabetic rats. PMID- 22545355 TI - Growth and heavy metals accumulation potential of microalgae grown in sewage wastewater and petrochemical effluents. AB - Microalgae exhibit a number of heavy metal uptake process by different metabolism. In this study, the ability of microalgae for removal of heavy metal from wastewater was studied. Growth and biochemical contents of microalgae were determined by spectrophotometer. Heavy metal analysis of wastewater effluents were performed by atomic absorption spectrophotometer before and after treatment at laboratory scale. The growth of Scenedesmus bijuga and Oscillatoria quadripunctulata in sewage wastewater was higher than those grown in synthetic medium. Whereas, the growth of S. bijuga and O. quadripunctulata in sterilized petrochemical effluents was slightly lower than that grown in the standard synthetic medium. The chlorophyll, carotenoid and protein content of S. bijuga and O. quadripunctulata grown in sterilized sewage wastewater were higher than those grown in the standard medium. Similarly S. bijuga and O. quadripunctulata grown in sterilized petrochemical effluents showed lower contents of pigments and protein than those grown in sewage and synthetic medium. Heavy metals copper, cobalt, lead and zinc were removed by 37-50, 20.3-33.3, 34.6-100 and 32.1-100%, respectively from sewage wastewater and petrochemical effluent using Ocillatoria culture. The metal absorption by S. bijuga were (Cu, Co, Pb, Zn) 60-50, 29.6-66, 15.4-25 and 42.9-50%, respectively from sewage and petrochemical effluents. Both species showed high level of heavy metal removal efficiency and metal sorption efficiency of both microalgae depended on the type of biosorbent, the physiological status of the cells, availability of heavy metal, concentration of heavy metal and chemical composition of wastewater. PMID- 22545356 TI - Common carotid intima-media thickness in patients with late rheumatoid arthritis; what is the role of gender? AB - This study aimed to evaluate color Doppler sonographic findings in carotid arteries in RA patients under pharmacological treatments and to compare them with normal population. Forty nine patients with late RA and 48 healthy age and sex matched controls were recruited. The two groups were matched for other known risk factors of atherosclerosis including serum lipid abnormalities, smoking status, diabetes mellitus and hypertension. High resolution B-mode color Doppler ultrasound with a 7 MHZ transducer was used for measuring the Common Carotid Intima-Medial Thickness (CCIMT) in both sides in all subjects. Presence of atherosclerotic plaque was also investigated. The mean left and maximum CCIMT was significantly higher in the case group (0.72 vs. 0.62 mm for the left artery; p < 0.01; 0.72 vs. 0.64 mm for the maximum reading; p = 0.01). No atherosclerotic plaque was found in common carotid arteries. There were 3 (6.1), 7 (14.3) and 9 (18.4%) plaques in left internal carotid artery, right carotid bulb and left carotid bulb in the case group, respectively with no atherosclerotic plaques in the controls (p = 0.24, 0.01 and < 0.001, respectively). Comparing the findings by gender in the case group with the controls, the mentioned significant differences were only between the male patients and the controls. The process of atherosclerosis in RA patients is similar to that in normal population. However, it is apparently accelerated and more advanced in these patients. PMID- 22545357 TI - Comparing the effects of ginger and metoclopramide on the treatment of pregnancy nausea. AB - This study assesses the effects of ginger on nausea and vomiting caused by pregnancy and compares it with metoclopramide medicine. This study was a randomized double-blind controlled trial. Metoclopramide, Ginger and placebo were putted in similar capsules. The medicines were administered three times a day. Then the Rhodes questionnaire was completed and its score were calculated. Data were analyzed by Chi square test, ANOVA and Repeated measurement. The intensity of changes in nausea, vomiting and Rhodes during study were statistically different in two groups of ginger and metoclopramide compared with placebo (p < 0.05), but it was not statistically significant between two groups of ginger and metoclopramide. According to our study, ginger is less effective than metoclopramide in reducing nausea and vomiting but it could be a good alternative for metoclopramide. PMID- 22545358 TI - A review on cardiovascular diseases originated from subclinical hypothyroidism. AB - Thyroid hormones play an important role on the cardiovascular systems and thyroid disorder ultimately have a profound adverse effects on myocardium and vascular functions. There are extensive reports on the role of overt thyroid dysfunction which adversely can modify the cardiovascular metabolism but even at the present of some controversial reports, the subclinical thyroid disorders are able also to manipulate cardiovascular system to some extent. The aim of this study is to review the cardiovascular disorders accompanied with subclinical hypothyroidism. It is concluded that adverse effect of thyroid malfunction on myocardium and vascular organs are through the direct role of thyroid hormone and dyslipidemia on heart muscle cells at nuclear level and vascular system, respectively. It seems many cardiovascular disorders initially would not have been occurred in the first place if the thyroid of affected person had functioned properly, therefore thyroid function tests should be one of a prior laboratory examinations in cardiovascular disorders. PMID- 22545359 TI - Non alcoholic fatty liver disease, insulin resistance, dyslipidemia and atherogenic ratios in epileptic children and adolescents on long term antiepileptic drug therapy. AB - This study explores the occurrence of Non-alcoholic Fatty Liver Disease (NAFLD), Insulin Resistance (IR), dyslipidemia and atherogenic ratios in epileptic children and adolescents receiving Valproic Acid (VPA), Carbamazepine (CBZ) or both (combination therapy) compared to healthy controls. Abdominal Computerized Tomography (CT), measurements of serum fasting insulin, glucose, serum lipids and liver enzymes were performed in VPA (n = 14), CBZ (n = 14) or both (n = 10) treated non-diabetic non-obese epileptic patients compared to healthy controls (n = 10). Abdominal CT demonstrated characteristics of fatty liver disease in 42.8% of VPA, in 21.4% of CBZ, in 60% of combination therapy treated patients and none of the healthy controls. All of them were overweight and 53.3% had IR. In conclusion VPA therapy was associated with increased risk of IR and NAFLD, while CBZ therapy was associated with dyslipidemia and combination therapy was associated with all these risks. PMID- 22545360 TI - Breeding maize for resistance to ear rot caused by Fusarium moniliforme. AB - Maize ear rots are among the most important impediments to increased maize production in Egypt. The present research was conducted to estimate combining abilities, heterosis and correlation coefficients for resistance to ear rot disease in seven corn inbred lines and their 21 crosses under field conditions. Results demonstrated that both additive and non-additive gene actions were responsible for the genetic expression of all characters with the preponderance of non-additive actions for days to 50% silking. The parental line L51 was the best combiner for earliness, low infection severity %, high phenols content, short plants and reasonable grain yield, while L101 was good combiner for low ear rot infection only. The cross: L122 x L84, L122 x L101, L51 x L101, L76 x L36, L76 x L84, L36 x L84, L36 x L81 and L36 x L101 which involved one or both parents with good General Combining Ability (GCA) effects expressed useful significant heterosis and Specific Combining Ability (SCA) effects for low infection severity %, high phenol contents, early silking, tall plants and high grain yield. Phenotypic and genotypic correlation coefficients suggest that selection for resistance to ear rot should identify lines with high yielding ability, early silking, tall plants, high phenols content and chitinase activity. PMID- 22545361 TI - Multivariate analysis of some economic characters in flax. AB - Twenty one parent flax genotypes and twenty F1 hybrids using principal components analysis based on 16 quantitative charismas were used to study the genetic relationship. Analysis of variance exposed high significant differences for all studied charismas among genotypes. High Genotypic Coefficient of Variation (GCV) values were observed with high Phenotypic Coefficient of Variation (PCV) for seed yield/plant, number of capsules/plant, fruiting zone length, main stem diameter and seed index which designated that variation for these characters substantively donates to the total variability moderate to low PCV and GCV were perceived for fiber characters, earliness and growth characters, respectively. Most characters, showed high heritability estimated in broad sense (> 70%) indicated that selection based on these characters would be effective as they are likely to be controlled by additive genes. The first five principal components were significant and accounted 78.2% of a total variance of all characters. The maximal amount of difference is shown in the first PC axis were 25.3%. Stem diameter, seed yield/plant, number of capsules/plant, straw yield/plant, fruiting zone length, number of apical branches and number of seed/capsules were a primary source of variation of the first PC axes and give high coefficients, respectively. While, the biggest coefficient in PC2 were earliness characters, plant height and fiber length. The other rest PC axes deals with seed index, fiber fineness and oil contented. The flax genotypes were plotted according to the first two PC axis. The most earlier parents Gowhar and L6 were separated according to PC2 since this axis deals with earliness characters. PMID- 22545362 TI - Genotoxic and cytotoxic study of Tecoma stans Bignoniaceae. AB - Tecoma stans (Bignoniaceae) is a central and south American tree used for the control of diabetes. This plant is cultivated in Iraq. The dried leaves were soaked in ethanol and water separately for 3 days then filtered and dried. The genotoxic potential of Tecoma stans was studied by in vivo and in vitro system. This study examined the genotoxic activity of aqueous and ethanolic extracts on bone marrow cells from BALB/c mice through evaluation of mitotic index and chromosomal aberrations and cytotoxic effect of the two extracts on Mouse Embryo Fibroblast (MEF) cell line. No alteration in the total number of chromosomal aberrations or the number of cells with chromosomal aberrations observed and percentage of mitotic index at the concentrations tested remained unchanged. The higher concentrations used of the plant extracts had a cytotoxic effect on the MEF cell line. Both extracts had no significant clastogenic effect in vivo but showed cytotoxic effects on mouse embryo in vitro, caution should be exercised in the use of this substance as a medicine. PMID- 22545363 TI - The effect of hydro alcoholic nettle (Urtica dioica) extract on oxidative stress in patients with type 2 diabetes: a randomized double-blind clinical trial. AB - Diabetes type 2 is a metabolic disorder that characterized by hyperglycemia and insulin resistance. Hyperglycemia and impairment of oxidant/antioxidant balance, can increase oxidative stress and increase risk of cardiovascular disease. In the present study, Effects of hydro alcoholic extract of Nettle on oxidative stress in type 2 diabetes were evaluated. Fifty patients (27 men, 23 women) with type 2 diabetes patients were studied. They received 100 mg kg(-1) of nettle extract of body weight hydro alcoholic for 8 weeks. At the baseline and end of 8th weeks of intervention blood levels of oxidative stress markers were measured. Data was analyzed by SPSS version 18, p < 0.05 was considered significant for all variables. After 8 weeks, Total Antioxidant Capacity (TAC) and Superoxidant Dismutase (SOD) showed a significant increase in the intervention group compared to the control group (p < 0.05). The findings showed that the hydro alcoholic extract of nettle has increasing effects on TAC and SOD in patients with type 2 diabetes without no changes in Malondialdehyde (MDA) and Glutathione Peroxides (GPX) after eight weeks intervention. PMID- 22545364 TI - Comparison of topical triamcinolone and oral atorvastatin in treatment of paederus dermatitis Northern Iran. AB - Dermatitis caused by stimulation of beetle paederus, is a common health problem in Northern and some southern parts of Iran. Since by now, traditional medicine and some corticosteroid agents have been used for treatment of dermatitis caused by beetle paederus. Because, there are few researches about classical treatment of the disease at academic level, this study planned to compare the effectiveness of triamcinolone ointment and atorvastatin tablet with placebo in treatment ofpaederus dermatitis in Northern Iran. A randomized double-blind clinical trial was carried out on 30 patients referred to the hospital and clinics at Sari and Neka countries in Northern Iran during 6 months. Patients were randomly divided into two therapeutic equal groups. The first group was triamcinolone ointment twice a day and a placebo atorvastatin tablet daily. The second group was oral atorvastatin one tablet (20 mg) daily and a placebo triamcinolone ointment twice a day. In Seventh day of visits, therapeutic response of the patients in triamcinolone and atorvastatin group were 93.33 and 80%, respectively. No significant differences were found in therapeutic outcome between the two groups (p > 0.05). The results showed both oftriamcinolone ointment and oral atorvastatin had similar effect on paederus dermatitis. Because the paederus dermatitis is a self-limited disease use of topical therapy for treatment of the disease is recommend. PMID- 22545365 TI - Internal fixation on deployment: never, ever, clever? PMID- 22545367 TI - Casualty rates among Danish soldiers in Iraq and Afghanistan. AB - In 2002 - 2009 Danish forces suffered a mortality rate of 0.09% in Iraq and 0.38% in Afghanistan, and a morbidity rate of 0.30% in Iraq and 1.01% in Afghanistan, as a result of weapons effects. In Afghanistan the survival rate is 97.0% for Danish wounded who were alive on arrival at UK R3 Hospital. British data from Afghanistan are compared to the Danish figures and there is no significant difference. We found an increase in injuries and deaths caused by mines/IEDs from 33% in 2006 to 72.7% in 2009 of all weapon effects causes. The more offensive war fighting posture of the Danish forces in Afghanistan has resulted in greater numbers of casualties. The study also indicates that the great majority of fatalities occur almost immediately at the point of injury. Most of the wounded survive, and a large of number of them are only lightly injured with a partial incapacity level of less than five percent. Haemostatic's and active employment of tourniquets, improved first aid training and training of medics, better evacuation methods including optimised in-flight diagnostics and treatment (including blood transfusion) by Medical Emergency Response Teams, Damage Control Surgery as well as access to quicker diagnostic methods have increased survivability. PMID- 22545366 TI - Ethical dilemmas in providing medical care to captured persons on operations. PMID- 22545368 TI - The influence of perceptions and beliefs of civilian physiotherapist working for the Ministry of Defence in their management of back pain: an exploratory study using mixed methods. AB - BACKGROUND: There is a high prevalence of Lower Back Pain (LBP) within military populations. Physiotherapeutic management has a primary role for patient care, but there is a need to establish the most effective management. Civilian physiotherapists provide the majority of clinical provision throughout the Defence Medical Rehabilitation Programme for British Armed Forces personnel. To date no study has been carried out looking at their perceptions and beliefs with regards to management of non-specific LBP and the potential impact this had on the delivery of rehabilitation across Defence. METHODS: This mixed methods exploratory study aimed to explore the potential complexities surrounding the decision making process with regards to management of non-specific LBP using semi structured interviews with 14 MOD civilian physiotherapists. All interviews were transcribed verbatim. The transcribed data was then subjected to a categorical content analysis. RESULTS: The analysis of the interview data revealed four interrelated themes that influence civilian physiotherapists in their management of back pain in military personnel: the military environment, integration of military procedures, physiotherapist treatment approach and communication. DISCUSSION: This paper highlights the value civilian physiotherapists place on experience when managing non-specific LBP. This experience however was gained through 'patient mileage' rather than integration of best evidence into practice. Several problems were identified in patient management including specific types of patients and their expectations and the importance of the right communication between Health Care Professionals, but also with patients. PMID- 22545369 TI - Multinational medical support to operations: challenges, benefits and recommendations for the future. AB - This paper considers the strategic aspects of medical support to military operations as delivered through multi-national collaboration. The military medical services are in essence a people organisation; the purpose of the organisation is primarily to support the people engaged in military operations, and also the people providing healthcare to them. Increasingly, supporting the latter also includes preparation for the ethical dilemmas that they will face. Providing health advice and healthcare on operations is now usually undertaken on a multinational basis, in order to generate sufficient medical capacity to meet the requirement with assets of the appropriate (and NATO mandated) capability. This will be an enduring feature, particularly in light of increasing costs of providing high quality healthcare and the operational and logistic challenges of delivering this capability in adverse environments, and in the context of medical personnel being a limited resource. The key to overcoming the challenges, often the result of the "people issues" such as cultural differences, is to recognise the value that the inherent diversity of multinational healthcare provision brings. The benefit is realised through sharing best practice, and the lessons from challenges met, as well as through burden sharing, and to understand that challenges are most commonly the result of misunderstandings, such as those inherent in language differences. The advice for those bringing a multinational team together includes considering the implications of culture (noting differences in national and military perspectives, and in medical processes such as clinical governance), to ensure effective communication, and to utilise feedback to confirm understanding. It is important not to prejudge or denigrate others. Share information and knowledge, provide positive reinforcement when things go well, and recognise that there will inevitably be challenges and use these as an opportunity to learn. Above all, the personal touch builds a culture within the multinational team that transcends national culture; celebrating success breeds success and thus optimal outcome for patients. PMID- 22545370 TI - Anaesthetic and other treatments of shell shock: World War I and beyond. AB - Post-traumatic stress disorder (PTSD) is an important health risk factor for military personnel deployed in modern warfare. In World War I this condition (then known as shell shock or 'neurasthenia') was such a problem that 'forward psychiatry' was begun by French doctors in 1915. Some British doctors tried general anaesthesia as a treatment (ether and chloroform), while others preferred application of electricity. Four British 'forward psychiatric units' were set up in 1917. Hospitals for shell shocked soldiers were also established in Britain, including (for officers) Craiglockhart War Hospital in Edinburgh; patients diagnosed to have more serious psychiatric conditions were transferred to the Royal Edinburgh Asylum. Towards the end of 1918 anaesthetic and electrical treatments of shell shock were gradually displaced by modified Freudian methods psychodynamic intervention. The efficacy of 'forward psychiatry' was controversial. In 1922 the War Office produced a report on shell shock with recommendations for prevention of war neurosis. However, when World War II broke out in 1939, this seemed to have been ignored. The term 'combat fatigue' was introduced as breakdown rates became alarming, and then the value of pre selection was recognised. At the Maudsley Hospital in London in 1940 barbiturate abreaction was advocated for quick relief from severe anxiety and hysteria, using i.v. anaesthetics: Somnifaine, paraldehyde, Sodium Amytal. 'Pentothal narcosis' and 'narco-analysis' were adopted by British and American military psychiatrists. However, by 1945 medical thinking gradually settled on the same approaches that had seemed to be effective in 1918. The term PTSD was introduced in 1980. In the UK the National Institute for Health and Clinical Excellence (NICE) guidelines for management (2005) recommend trauma-focussed Cognitive Behavioural Therapy and consideration of antidepressants. PMID- 22545371 TI - The pattern of paediatric trauma on operations. AB - OBJECTIVES: Recent military campaigns in Iraq and Afghanistan have resulted in the treatment of children in British Medical facilities. In order to determine how care for children may develop in the future, it is necessary to understand the current situation. The aim of this article is to examine the pattern of paediatric trauma on recent operations in Iraq and Afghanistan. METHODS: Data was requested from the Joint Theatre Trauma Registry, held at the Royal Centre for Defence Medicine in Birmingham, on all trauma calls for patients aged under 16 between the dates 21/3/03 and 31/8/09. Data included age, gender, theatre of operation, injury mechanism and type, trauma scores and destination of the child. RESULTS: 176 children were identified with 16.5% from Iraq and 83.5% from Afghanistan. The overall survival rate was 88.6% with survival rates in Iraq of 89.7% and in Afghanistan of 88.4%. Males accounted for 66.5% of admissions and the commonest age group was age 6-8 years. In 59.1% of total admissions the mechanism of injury was related to explosives. This differed between theatres with explosive injury causing 27.6% of admissions in Iraq and 63.5% in Afghanistan. Injury Severity Scores (ISS) showed equal numbers of minor and severe injuries with fewer moderately injured patients. The median ISS of all data was nine. The median ISS from Iraq was 16 and the median ISS from Afghanistan was nine. CONCLUSIONS: The treatment of children in British medical facilities whilst deployed on operations is likely to continue. An assessment of the injury patterns of paediatric patients on current deployments allows development of training and an understanding of logistic requirements. Data collection will also need to be adapted to meet the needs of paediatric patients. These remain issues that are being addressed by the Defence Medical Services. PMID- 22545372 TI - Anti-malarial chemoprophylaxis following evacuation from Afghanistan. AB - UK forces deployed to Afghanistan between March and November are prescribed anti malarial chemoprophylaxis (AMC). In 2007 an audit showed poor pre-injury AMC compliance and a prescription rate of 50% amongst those casualties evacuated to Role 4. We re-audited the post-deployment AMC prescribing practice for casualties from Afghanistan for the 2008 and half of the 2009 malaria season. Using the Role 4 prescribing information and communication system (PICS), a retrospective AMC search for Proguanil, Chloroquine, Doxycycline, Mefloquine and Malarone was performed on these casualties. Only five out of 305 (1.64%) inpatients were prescribed appropriate post-deployment AMC medication. Awareness of the need to prescribe AMC following evacuation remains poor, and may be improved by recording AMC compliance in field medical records and modifying the PICS software. PMID- 22545373 TI - Effects of an eight week military training program on aerobic indices and psychomotor function. AB - This study assessed the effects of eight weeks of military training on aerobic fitness indices, military skills and neuropsychological function. Thirty five (n = 35) male Irish Defence Forces personnel, divided into training (n = 20) and control (n = 15) subgroups, completed tests of military aptitude (Kim's games, judging distance, fire order, map reading, weapon assembly) and neuropsychological function (Symbol digit modalities test (SDMT), Trail making test, Stroop test and grooved pegboard test) pre- and post-intervention. The repeated measures study design sought to account for any learning effect. Participants also completed a 10km route march, a two mile run and three by 20m shuttle run tests at both time points to quantify changes in fitness variables. The training sub-group significantly (P < 0.001) improved mean 20m shuttle-run distance and consequently estimated VO2 max pre- to post-intervention (49.8 +/- 1.0 vs. 52.4 +/- 0.9 mL x kg x min(-1)). Two mile run time was not significantly improved. Mean %HRmax during the 10km route march was significantly higher in both training (P < 0.001) and control (P < 0.01) sub-groups post-intervention (71 +/- 1 and 83 +/- 1%) compared to pre-intervention (65 +/- 1 and 77 +/- 1%). However, the training sub-group conducted the route march at a significantly faster speed on the second occasion. Military training significantly improved performance in 3/18 neuropsychological test components and 2/12 military skills test components. Training significantly improved ability to estimate both short (error; 36 +/- 6 vs. 12 +/- 1%) and intermediate (error; 72 +/- 12 vs. 11 +/- 3%) distances post-intervention. The training sub-group significantly (P < 0.01) improved SDMT score and mean Trail 1 time pre- to post-intervention (58.0 +/- 2.8 vs. 69.5 +/- 3.4; 18.1 +/- 0.8 vs. 14.4 +/- 0.8s, respectively). In Part 3 of the Stroop test, time mediated a significant (P < 0.05) and selective improvement in the training sub-group (51.3 +/- 3.2 vs. 63.8 +/- 5.4). In conclusion, aerobic fitness and a minority of neuropsychological and military skills tests improved following 8 weeks of military training. PMID- 22545374 TI - Hereditary neuropathy with liability to pressure palsies occurring during military training. AB - Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant peripheral neuropathy characterized by recurrent isolated nerve palsies, which are precipitated by trivial compression and trauma. Although HNPP has been well-described in literature, it often goes unrecognized. We report a case of HNPP occurring during military training to promote recognition and proper management of this entity. PMID- 22545375 TI - Simple posterior elbow dislocation and brachial artery transection. AB - We report the uncommon occurrence of a complete brachial artery transection following simple posterior dislocation of the elbow, successfully managed by cephalic vein interposition grafting. This case together with a review of the literature was conducted with the aim of highlighting important issues regarding the diagnosis, management and prognosis of this rare complication. PMID- 22545376 TI - CBRN response and the future. AB - The Haywood Medical Society met in June 2011 to discuss issues surrounding the preparedness of both civilian and military emergency services to deal with a CBRN threat. PMID- 22545377 TI - Adequacy of existing guidelines for potential Army recruits with pre-existing orthopaedic problems. PMID- 22545378 TI - A mistaken case of intestinal helminth infection due to New Zealand flatworm? PMID- 22545379 TI - The deployed medical director: managing the challenges of a complex trauma system. PMID- 22545381 TI - Medical contribution to the comprehensive approach. PMID- 22545380 TI - The military importance of cystic fibrosis. PMID- 22545382 TI - The short life and times of assistant surgeon Donald E White. PMID- 22545383 TI - Prevalence of risk factors for sensorineural hearing loss in NICU newborns. AB - OBJECTIVES: The aim of this study was to determine the prevalence and significance of traditional risk factors associated with sensorineural hearing loss (SNHL) in a population of 615 neonates who attended the neonatal intensive care unit (NICU) of the University Hospital in Leuven, Belgium between January 2005 and December 2007. METHODOLOGY: Auditory brainstem response (ABR) audiometry using 40 dB stimuli was performed in all 615 neonates. A retrospective medical database analysis was performed to evaluate the influence of 14 predetermined risk factors. The evaluated risk factors were ototoxic medication, hyperbilirubinemia, in utero infections (including CMV, rubella, syphilis, herpes, and toxoplasmosis), craniofacial anomalies, syndromes associated with SNHL, low birth weight (< 1,500 g), low Apgar score, mechanical ventilation lasting for 5 days or longer, bacterial meningitis, family history of hereditary childhood SNHL, endocranial hemorrhage, hypoxic ischemic encephalopathy, convulsions, and sepsis RESULTS: Uni- or bilateral hearing impairment was diagnosed in 25 out of 615 neonates (4.1%). In utero infections (especially CMV), craniofacial anomalies, and syndromes known to include SNHL were significant risk factors. For the remaining risk factors, no significant correlation with SNHL was found. CONCLUSIONS: In this study, only in utero infections (especially CMV), craniofacial anomalies, and syndromes known to include SNHL were significant risk factors associated with SNHL. Adequate management of hyperbilirubinemia and ototoxic drug administration may eliminate some of the major historical risk factors associated with SNHL in NICU neonates. PMID- 22545384 TI - Effectiveness of Ericksonian hypnosis in tinnitus therapy: preliminary results. AB - INTRODUCTION: The present study was performed to evaluate the efficacy of Ericksonian hypnosis in reducing the impact of tinnitus on patients' quality of life. PATIENTS AND METHODS: A controlled prospective longitudinal study was designed. The severity of tinnitus was assessed with Tinnitus Handicap Inventory (THI) before hypnotherapy and then 1 week, 1 month, 3 months, and 6 months after therapy. Health Survey SF-36 was used to assess health-related quality of life before and after hypnotherapy. Thirty-nine patients with severe idiopathic subjective tinnitus were enrolled in the study. RESULTS: The mean SD age of the patients was 44.5 +/- 12.5 years, ranging from 21 to 65 years; 48% were female. Mean THI scores assessed at the beginning and 4 times after commencement of therapy were evaluated. The changes in THI scores were significant. Health Survey SF-36 was assessed separately. The greatest increases were seen in physical role followed by emotional role difficulty. CONCLUSION: The preliminary results of our study demonstrated the effectiveness of Ericksonian hypnosis in the study group. PMID- 22545385 TI - Effect of septoplasty and per-operative antibiotic prophylaxis on nasal flora. AB - OBJECTIVES: Septoplasty is one of the most commonly performed procedures in otolaryngology practice. Prophylactic use of antibiotics is controversial. Disruption of nasal flora may predispose individuals to infection. We investigated the effect of antibiotic prophylaxis and septoplasty on nasal flora. METHODOLOGY: We included 115 consecutive patients who underwent septoplasty because of symptomatic nasal septal deviation. Patients were divided into study and control groups. Study patients received prophylactic parenteral sodium cefazoline twice a day beginning intra-operatively and while the nasal packing remained in the nose for 48 h, and expandable polyvinyl acetate (Merocel) packing covered with antibiotic ointment containing 0.2% nitrofurazone was inserted into each nostril at the end of the operation. Control patients received neither parenteral antibiotic prophylaxis nor antibiotic ointment around the Merocel packs. Both groups received oral prophylactic cefuroxime axetil for 5 d after nasal packing was removed. Nasal flora was determined pre-operatively, post operatively when nasal packing was removed, and 3 mo after surgery. RESULTS: Study patients were compared to control patients at pack removal and 1 mo after surgery The effect of antibiotic use in septoplasty on nasal flora was as follows: Increased isolation rate of gram-positive rods (p = 0.007), decreased methicillin-sensitive coagulase-negative staphylococci (p = 0.002). Pre-operative and post-operative culture results at 3 mo were compared. The effect of septoplasty on nasal flora was as follows: Decreased coagulase-negative staphylococci (p = 0.05), decreased Klebsiella (p < 0.001), decreased gram positive rods (p < 0.001), increased methicillin-sensitive Staphylococcus aureus (p < 0.001). CONCLUSIONS: Septoplasty increases S. aureus colonization and decreases normal flora. Antibiotics do not protect against S. aureus colonization and contribute to a decrease in normal flora. Antibiotics do not seem to confer benefit in terms of flora changes. Studies investigating flora changes with a longer follow-up should be conducted. PMID- 22545386 TI - Another advantage of nasal septal suturing: pulmonary function unaffected. AB - BACKGROUND: Nasal packing (NP) after septoplasty has some negative aspects. The nasal septal suture (NSS) is therefore becoming increasingly preferred. OBJECTIVE: The aim of this study was to analyze the effects of NSS and NP on pulmonary function tests. METHODS: Sixty patients who suffered from nasal blockage resulting from nasal septal deviation and who were otherwise healthy were included. Patients were randomized into two groups, NP or NSS. Pre-operative spirometry was performed for all patients. The NP group received a finger glove packing for two days after septoplasty, whereas no additional dressing was used for the NSS group. Narcotic analgesics were not used for pain relief after septoplasty in either group. Spirometry was performed post-operatively on the third day for all patients and before removal of the NP for the NP group. RESULTS: We observed statistically significant differences between pre-operative and post-operative values of forced vital capacity (FVC; p = 0.008), forced expiratory volume in the first second (FEV1; p = 0.006), and forced expiratory flow ((FEF)25-75%; p = 0.011) in the NP group. In comparison, pre-operative and post-operative values did not differ for FVC, FEV1, FEV1/FVC%, and FEF25-75% in the NSS group. CONCLUSION: NP negatively influenced pulmonary function based on spirometric parameters, while NSS did not. PMID- 22545387 TI - Influence of allergy on clinical, immunological and histological characteristics of nasal polyposis. AB - OBJECTIVES: Although polyps seem to be a manifestation of the chronic inflammation of nasal/paranasal sinuses mucosa in both allergic and non-allergic subjects, the pathogenesis of nasal polyposis remains unknown. The aim of this prospective study was to compare the clinical characteristics of nasal polyposis in non-allergic and allergic patients, to compare the cytokine levels in nasal secretions in atopic and non-atopic nasal polyp patients and to correlate these levels with eosinophil counts in nasal polyp tissue specimens. METHODS: This study included thirty patients with nasal polyposis (13 atopic and 17 non-atopic) requiring surgical treatment. Nasal secretion samples were collected from the nasal cavities of all 30 subjects a few days before the surgical treatment. The levels of tumour necrosis factor-alpha (TNF-alpha), tumour necrosis factor-beta (TNF-beta), interleukin (IL)-1beta, IL-2, IL-12, interferon-gamma (IFN-gamma), IL 4, IL-5, IL-6, IL-10, and IL-8 were measured using the flow cytometric method. Each of the 30 patients was staged clinically according to nasal symptom score, endoscopic score and Lund-Mackay computed tomography (CT) score. All these patients had undergone sinus surgery. Eosinophils were counted in hematoxylin- and eosin-stained sections of all nasal polyp samples. RESULTS: Our results showed that allergy does not modify the symptoms, or the endoscopic and CT findings, of nasal polyposis. We found significantly higher concentrations of IL 4 (p < 0.01), IL-5 (p < 0.05), IL-6 (p < 0.05) and TNF-beta (p < 0.05) in nasal secretions of allergic nasal polyp patients than in non-allergic ones. Eosinophil counts were significantly higher in tissues of atopic patients' polyps than in non-atopic subjects (p < 0.01). No correlation was observed between cytokine levels and eosinophil counts. CONCLUSION: Non-atopic and atopic patients' polyps have different immunological patterns. Our results showed that the presence of Th2 cytokines was a more significant feature in allergic patients with nasal polyposis than in non-allergic patients. PMID- 22545388 TI - Outpatient clinic letters in ENT. Is there any margin of improvement? AB - INTRODUCTION: Outpatient clinic letters are a widely used and effective means of communication between hospital staff and general practitioners. This study audited the letter format used by consultants and specialist registrars (SpRs) at an otolaryngology clinic to assess the readability of different formats. MATERIALS AND METHODS: The two-cycle audit was performed at the Otolaryngology Clinic at Guy's and St Thomas' NHS Foundation Trust in London, England. A readability score (0-4) was assigned to the letters as an indication of how easy it was to extract information from structured or unstructured (paragraph) format letters. RESULTS: In the first cycle, 71.91% of the SpR letters followed a structured format and had an overall mean readability score of 2.87/4; 46.58% of the consultant letters followed a structured format and had an overall mean readability score of 1.25/4. In the second cycle, after the results of the first audit were presented to the participating physicians, 84.72% of the SpR letters followed a structured format and had an overall mean readability score of 3.41/4. Consultants followed a structured format in 52.56% of the letters, which had an overall mean readability score of 2.04/4. CONCLUSIONS: We found that a structured format for outpatient letters was better than unstructured format. This audit helped change the structure and consequently the readability scores of the clinic letters. PMID- 22545389 TI - A possible case of complex regional pain syndrome of the nose? AB - OBJECTIVE: We present a case report of a patient with a putative diagnosis of complex regional pain syndrome of the nose. We would like to bring this disorder to the attention of rhinologists. CASE REPORT: A 53-year-old man presented with a history of extreme, constant, debilitating pain in his nose that started after he underwent several extensive nasal surgeries. Examination revealed atrophic nasal mucous membranes at the nasal septum. No other abnormalities were found. The pain did not diminish despite administration of analgesics and neuropathic pain medications. We propose a diagnosis of complex regional pain syndrome of the nose. CONCLUSION: The large number of nasal surgeries performed worldwide and the far reaching consequences of this debilitating syndrome indicate that it merits further investigation to determine whether it is a distinct disorder that should be recognized as such. PMID- 22545390 TI - Atypical adenolymphoma and glomus caroticum tumour: a rare coincidence. AB - We describe the rare simultaneous appearance of an atypical adenolymphoma with a glomus caroticum tumour on the same side of the neck in a middle-aged man. This case report is the first to describe this coexistence. Due to the atypical, cyst like presentation of the Warthin's tumour, a final diagnosis was made only after surgical resection and histopathological examination. Both the adenolymphoma and glomus caroticum tumour were successfully removed surgically. PMID- 22545391 TI - The simultaneous appearance of a nasal natural killer-cell lymphoma and acute myelogenous leukemia. AB - INTRODUCTION AND AIM: Sinonasal malignant neoplasms are uncommon, with an annual incidence of less than 1/100,000. About 80% of these are squamous cell carcinoma. Adenocarcinoma and adenoid cystic carcinoma are next in frequency. Lymphoma of the nasal cavity, paranasal sinuses and nasopharynx are rare, constituting less than 5% of all extranodal lymphomas. CASE REPORT: A 47-year-old man was referred to our hospital because of severe headache and progressive facial pain. He also complained of right-sided visual acuity. He had a manifest exopthalmia with disturbed eye movements. Nasoscopy showed a large mass with atypical appearance. CT and MRI showed a bilateral ethmoid mass invading the frontal sinuses, the right orbit, the lamina cribrosa and the right frontal cerebral region, and growing posteriorly through the choana. The first biopsies were inconclusive, showing only necrotic cells and purulent inflammation with epithelial elements. A larger biopsy demonstrated a high-grade malignant tumour with necrosis. The differential diagnosis of undifferentiated sinonasal carcinoma, undifferentiated neuro-endocrine tumour or T-cell lymphoma was suggested. In the meantime our patient developed high fever and sudden-onset pancytopenia. Bone marrow punction showed 65% blasts, leading to the diagnosis of AML type M2. He was immediately referred for chemotherapy, but died in intensive care before his first session. The biopsy of the sinonasal mass was diagnosed surprisingly as a natural killer cell lymphoma stage IVB. CONCLUSIONS: Natural killer cell lymphoma is rare in Europe. The simultaneous appearance of a NK-cell lymphoma and acute myelogenous leukemia has, as far as we know, never been described in the English literature before. PMID- 22545392 TI - Huge mastoid congenital cholesteatoma in a 52-year-old patient. AB - Congenital cholesteatoma may arise in various locations within the temporal bone. The rarest site of origin is the mastoid process. We report an unusual case of a 52-year-old man with mastoid congenital cholesteatoma that manifested as a persistent ear discharge. The preoperative suspicion was based on the imaging findings and the patient's history. A simple mastoidectomy was conducted and the cholesteatoma was completely removed while using facial nerve monitoring. Although rare, mastoid congenital cholesteatoma can be considered as an alternative in the differential diagnosis of persistent otorrhea. PMID- 22545393 TI - Successful outcome of cochlear implantation in a patient with superficial siderosis. AB - OBJECTIVE: To present the management of a rare case of progressive bilateral sensorineural hearing loss in a patient with superficial siderosis secondary to a cavernoma. METHOD: A case report and a review of the literature concerning superficial siderosis. RESULTS: The patient benefited significantly from a cochlear implantation. CONCLUSIONS: Careful assessment and adequate counselling is necessary to determine the best approach to hearing rehabilitation in patients with superficial siderosis of the central nervous system. Cochlear implantation in patients with superficial siderosis is controversial due to the retrocochlear origin of the hearing loss and, although the case presented had a successful outcome, the results might deteriorate with time. PMID- 22545394 TI - Self expandable polytetrafluoroethylene stent for carotid blowout syndrome. AB - Carotid blowout syndrome (CBS) is an emergency complication in patients undergoing treatment for head and neck cancers. The classical management of CBS is the ligation of the common carotid artery, because suturing is not be possible due to infection and necrosis of the field. In this case report, we present a patient with CBS, in whom we applied a self-expandable polytetrafluoroethylene (PTFE) stent and observed no morbidity. Endovascular stent is a life-saving technique with minimum morbidity that preserves blood flow to the brain. We believe that this method is preferable to ligation of the artery in CBS. PMID- 22545395 TI - Syphilis is back: presentation of three cases at the ENT department. AB - PROBLEM: Syphilis is a sexually-transmitted disease caused by the spirochete Treponema pallidum, and is transmitted either through sexual contact or vertically across the placenta. Rates of infection were at a low point in the early 1990s. Since then, increasing numbers of new cases of infections have been observed in all Western countries. AIM: Presentation of three patients with syphilis who presented within a short period of time in an ENT outpatient clinic. CONCLUSIONS: One must be aware of the increasing incidence of syphilis, even in head and neck disciplines. Typical symptoms of an early infection are an ulcerous lesion in the mouth, with or without cervical lymphadenopathy. The main therapy is high doses of penicillin G administered intramuscularly. Other simultaneous sexually-transmitted diseases, especially HIV infection, must be excluded. Unnoticed and untreated patients may develop late and life-threatening complications. PMID- 22545396 TI - Efficient preparation of incensole and incensole acetate, and quantification of these bioactive diterpenes in Boswellia papyrifera by a RP-DAD-HPLC method. AB - Incensole and incensole acetate, found in incense, are encouraging potent bioactive diterpenic cembrenoids, inhibiting Nuclear Factor-kappaB activation. Furthermore, incensole acetate elicits psycho-activity in mice by activating the TRPV3 channels in the brain. Starting from crude extracts of the incense species Boswellia papyrifera Hochst., a convenient procedure for the efficient large scale synthesis of incensole and its acetate is presented. Additionally, a reversed-phase, diode-array-detection, high-performance liquid chromatography (RP DAD-HPLC) method for the quantification of incensole and incensole acetate is reported, indicating that these two compounds are typical biomarkers for B. papyrifera. PMID- 22545397 TI - A comparison investigation on the solubilization of betulin and betulinic acid in cyclodextrin derivatives. AB - Betulin (BET) and betulinic acid (BA) are naturally occurring pentacyclic lupane triterpenes, exhibit great promise as bioactive agents for the treatment of many diseases. The poor solubilities of BET and BA in water have limited their applications. In the present work, BET and BA were selected as guest molecules, three hydrophilic gamma-cyclodextrin (CD) thioethers were synthesized and selected as host molecules. beta-, Hydroxypropyl-beta-CD, (HP-beta-CD), gamma-CD and HP-gamma-CD were also investigated as hosts in order to compare the solubilization abilities of these host molecules. The solubilities of BET and BA were estimated from 1H NMR measurements by comparing the relative integral areas of the proton signals between CDs and guests. gamma-CD thioethers 5-7solubilized BET and BA to much higher extends than other host molecules. The obtained maximal solubilities of BET and BA were 5.2 and 4.5 mM, respectively. The topographies of the inclusion compounds were determined by ROESY NMR spectroscopy. PMID- 22545398 TI - Two new antimicrobial metabolites from the endophytic fungus, Seimatosporium sp. AB - Two new acaranoic acids, named seimatoporic acid A and B (1, and 2), together with six known compounds, R-(-)-mellein (3), cis-4-hydroxymellein (4), trans-4 hydroxymellein (5), 4R-hydroxy-5-methylmellein (6), (-)-5-hydroxymethylmellein (7), and ergosterol (8) were isolated from an endophytic fungus, Seimatosporium sp, by a bioassay-guided procedure. The structures of the new compounds have been assigned from analysis of the 1H and 13C NMR spectra, DEPT, and by 2D COSY, HMQC, HMBC and NOESY experiments. A mixture of compounds 1 and 2 showed strong antifungal activity against Botrytis cinerea, Septoria tritici, and Pyricularia oryzae. PMID- 22545399 TI - Simulation of intramolecular hydrogen bond dynamics in manzamine A as a sensitive test for charge distribution quality. AB - Subtle balance of inter- and intramolecular hydrogen bond strength in aqueous solutions often governs the structure and dynamics of molecular species used as potential drugs and in supramolecular applications. In silico molecular dynamics study of water solution of manzamine A has been performed with different atomic charges in order to investigate the influence of charge distribution choice on predicting qualitative and quantitative features of the simulated systems. Various well known charge schemes (MK-ESP, RESP, Mulliken, AMI-BCC, Gasteiger Huckel, Gasteiger-Marsili, MMFF94, and Dynamic Electronegativity Relaxation - DENR) led to qualitatively different pictures of dynamic behavior of the intramolecular hydrogen bond. The reported calculation framework represents a relatively rare case where differences in charge distributions lead to noticeable differences in simulated properties, thus providing a useful test case for force field and charge distribution development, provided high quality experiments are conducted to use as references. PMID- 22545400 TI - A quinoline based bis-urea receptor for anions: a selective receptor for hydrogen sulfate. AB - A dipodal bis-urea receptor has been synthesized from the reaction of 8-amino quinoline and 1,4-phenylene diisocyanate in dichloromethane, and the anion binding ability of the receptor has been studied using fluoride, chloride, bromide, iodide, perchlorate, nitrate, dihydrogen phosphate and hydrogen sulfate by UV-Vis titrations in DMSO. The results show that the receptor binds each of the anions with a 1:1 stoichiometry, showing high affinity and moderate selectivity for hydrogen sulfate among the anions studied. Ab initio calculations based on density functional theory (DFT) suggest that an anion (X(-)) is bonded within the cleft formed by the two arms of the receptor through two NH...X(-) and two aromatic CH...X(-) interactions. The results from solution and theoretical studies suggest that binding is predominantly influenced by hydrogen bonding interactions and the basicity of anions. PMID- 22545401 TI - DNA binding studies of Vinca alkaloids: experimental and computational evidence. AB - Fluorescence studies on the indole alkaloids vinblastine sulfate, vincristine sulfate, vincamine and catharanthine have demonstrated the DNA binding ability of these molecules. The binding mode of these molecules in the minor groove of DNA is non-specific. A new parameter of the purine-pyrimidine base sequence specificty was observed in order to define the non-specific DNA binding of ligands. Catharanthine had shown 'same' pattern of 'Pu-Py' specificity while evaluating its DNA binding profile. The proton resonances of a DNA decamer duplex were assigned. The models of the drug:DNA complexes were analyzed for DNA binding features. The effect of temperature on the DNA binding was also evaluated. PMID- 22545402 TI - Natural flavonoids interact with dinitrobenzene system in aprotic media: an electrochemical probing. AB - Three structurally related natural flavonoids (FlOH), quercetin (Q), rutin (R) and morin (M), were investigated by cyclic voltammetry to probe their interactions with hazardous 1,4-dinitrobenzene (1,4-DNB) using a glassy carbon electrode. Scavenging of 1,4-DNB by FlOH was inferred from a positive shift in reduction potential, decrease in anodic peak current, and irreversible electrochemical behavior of 1,4-DNB on increasing the flavonoid concentration. The homogeneous bi-molecular rate constant (k2) was determined using the Nicholson-Shain equation and found to be higher for the dianion. Morin posed a comparatively higher k2 value for its interaction with the 1,4-DNB electrochemical system owing to its more acidic nature and least intramolecular hydrogen bonding. The cyclic voltammetric (CV) results were further supported by HyperchemPM3 quantum mechanical semi-empirical calculations, which point towards E(r)C(i) interactions between flavonoids and 1,4-DNB. The present investigation is biologically significant in terms of natural flavonoidal scavenging activity toward toxins such as dinitroaromatics. PMID- 22545403 TI - Live cell imaging of a fluorescent gentamicin conjugate. AB - Understanding cellular mechanisms of ototoxic and nephrotoxic drug uptake, intracellular distribution, and molecular trafficking across cellular barrier systems aids the study of potential uptake blockers that preserve sensory and renal function during critical life-saving therapy. Herein we report the design, synthesis characterization and evaluation of a fluorescent conjugate of the aminoglycoside antibiotic gentamicin. Live cell imaging results show the potential utility of this new material. Related gentamicin conjugates studied to date quench in live kindney cells, and have been largely restricted to use in fixed (delipidated) cells. PMID- 22545404 TI - Molecular recognition of carbohydrates: evaluation of the binding properties of pyrazole-based receptors and their comparison with imidazole- and indole-based systems. AB - The aim of the study was to evaluate the potential of pyrazole-based receptors in the complexation of carbohydrates. Representatives of a new series of acyclic pyrazole-based receptors were prepared and their binding properties toward selected mono- and disaccharides evaluated. The results of the binding studies were compared with those obtained for acyclic imidazole- and indole-based receptors. The first binding studies revealed di- vs monosaccharide binding preferences of the new receptors and showed that pyrazole units are useful building blocks for the construction of receptors with interesting binding preferences. PMID- 22545405 TI - Transformations of griseofulvin in strong acidic conditions--crystal structures of 2'-demethylgriseofulvin and dimerized griseofulvin. AB - The structure of griseofulvic acid, C16H15ClO6, at 100 K has orthorhombic (P2(1)2(1)2) symmetry. It is of interest with respect to biological activity. The structure displays intermolecular O-H...O, C-H...O hydrogen bonding as well as week C-H...pi and pi...pi interactions. In strong acidic conditions the griseofulvin undergoes dimerization. The structure of dimerized griseofulvin, C34H32C12O12 x C2H6O x H2O, at 100 K has monoclinic (P2(1)) symmetry. The molecule crystallized as a solvate with one ethanol and one water molecule. The dimeric molecules form intermolecular O-H...O hydrogen bonds to solvents molecules only but they interact via week C-H...O, C-H...pi, C-Cl...pi and pi...pi interactions with other dimerized molecules. PMID- 22545406 TI - Rapid acyl migration between pyrogallyl 1,2- and 1,3-dipivaloates. AB - Pyrogallol and its derivatives are biologically active compounds, and pyrogallol also forms the basis of an increasingly important tetrameric supramolecular scaffold. Pyrogallol[4]arenes are tetrameric macrocycles that form from 1,2,3 trihydroxybenzene and aldehydes under acidic conditions. Pyrogallol was treated with two equivalents of pivaloyl chloride to form pyrogallyl dipivaloate. A mixture of regioisomers was invariably obtained and a rapid equilibrium was observed between the 1,2- and 1,3-diesters in polar solvents. A pure sample of solid pyrogallyl 1,2-dipivaloate was isolated and its crystal structure was obtained. The pure compound was shown to rearrange to mixtures similar to those isolated initially. PMID- 22545407 TI - Toward engineering intra-receptor interactions into bis(crown ethers). AB - A synthetic receptor was designed in which cooperative binding of two crown ether moieties to an alkali metal ion simultaneously causes two hydrophobic substituents not involved in direct host-guest interactions to converge. Hydrophobic interactions between these substituents can be expected to contribute to the overall complex stability. Independent binding studies involving two diastereoisomers of this bis(crown ether), one in which intra-receptor interactions between the substituents are potentially possible and one in which they are not, using isothermal titration calorimetry showed that both isomers bind potassium ions in different solvent mixtures with the same overall affinity. Profound differences were observed for each isomer, however, in the enthalpies and entropies of binding, which are consistent with intra-receptor interactions in one compound. These interactions are counteracted by enthalpy-entropy compensation so that no overall improvement in cation affinity could be observed. PMID- 22545408 TI - Monitoring stepwise proteolytic degradation of peptides by supramolecular domino tandem assays and mass spectrometry for trypsin and leucine aminopeptidase. AB - A label-free optical detection method has been designed that allows direct monitoring of enzymatic peptide digestion in vitro. The method is based on the addition of a reporter pair, composed of the macrocyclic host cucurbit[7]uril (CB7) and the fluorescent dye acridine orange (AO), to detect the proteolytic degradation of peptides. The enzymatic activity of trypsin and leucine aminopeptidase (LAP) was investigated using H-LSRFSWGA-OH as a substrate. The substrate as well as the intermediary and final products (i.e., H-FSWGA-OH and phenylalanine) formed during its enzymatic hydrolysis differ in their binding affinity to the receptor CB7, which results in varying degrees of dye displacement and, therefore, different fluorescence intensities. CB7 showed a relatively weak binding constant of K approximately 10(4) M(-1) with the substrate, a relatively strong binding constant of K > or = 10(6) M(-1) with H FSWGA-OH (which is a final product formed by trypsin digestion and the intermediary product formed during the enzymatic activity of LAP), and a moderate binding constant of K < or = 10(5) M(-1) with phenylalanine. Owing to this differential binding affinity of CB7 with the substrate and the corresponding products, the digestion of a peptide by trypsin was followed as a decrease in fluorescence signal, while the complete degradation of the peptide by LAP was monitored as a decrease and a subsequent increase in fluorescence signal. The k(cat)/K(M) value for trypsin (2.0 x 10(7) min(-1) M(-1)) was derived from the change in fluorescence signal with time. Additionally, the complete degradation of the peptide by LAP was also followed by mass spectrometry. The use of a supramolecular sensing ensemble (macrocyclic host and dye) as a fluorescent reporter pair gives this method the flexibility to adapt for monitoring the stepwise degradation of different biologically relevant peptides by other proteases. PMID- 22545409 TI - Intracellular localization of PNA in human cells upon its introduction by electroporation. AB - Peptide nucleic acid (PNA) is one of the most useful DNA analogs in a wide variety of gene analysis in human cells. In order to exhibit its maximal functions, PNA must be localized to a desired place (e.g., nucleus, cytoplasm and other organelles). Here, we introduced PNAs into HeLa cells by electroporation and examined their localization at various time points. The PNA which binds to the mitochondrial COII gene was initially accumulated in the nucleus, and thereafter mostly transferred to cytoplasm. This time-dependent intracellular localization of PNA is ascribed to the breakdown of the nuclear envelope in the cell division. On the other hand, another PNA that binds to telomere repeat sequence mostly remained in the nucleus, even after the cell division occurred. The retention of this PNA in the nucleus was further enhanced when it was conjugated with Cy3. PMID- 22545410 TI - Fliposomes: pH-controlled release from liposomes containing new trans-2 morpholinocyclohexanol-based amphiphiles that perform a conformational flip and trigger an instant cargo release upon acidification. AB - A new type of pH-sensitive liposome (fliposomes) was designed based on the amphiphiles that are able to perform a pH-triggered conformational flip (flipids). This flip disrupts the liposome membrane and causes rapid release of the liposome cargo, specifically in the areas of increased acidity. The flipids (1-3) are equipped with a trans-2-morpholinocyclohexanol conformational switch, pH-Sensitive fliposomes containing one of these flipids, POPC and PEG-ceramide (molar ratio 50/45/5) were constructed and characterized. These compositions were stable at 4 degrees C and pH 7.4 for several months. Fliposomes loaded with ANTS/DPX demonstrated an unusually quick content release (in a few seconds) at pH below 5.5, which was more efficient in the case of flipid 1 with the shorter linear C12-tails. The pH-titration curve for the fliposome leakage paralleled the curve for the acid-induced conformational flip of 1-3 studied by 1H NMR. A plausible mechanism of the pH-sensitivity starts with an acid-triggered conformational flip of 1, 2 or 3, which changes the molecular size and shape, shortens the lipid tails, and perturbs the liposome membrane resulting in the content leakage. PMID- 22545411 TI - Competition of ester, amide, ether, carbonate, alcohol and epoxide ligands in the dirhodium experiment (chiral discrimination by NMR spectroscopy). AB - Thirty-eight derivatives of 3-hydroxy-2-methylpropanoic acid, each with two different oxygen functionalities, were synthesized and subjected to the standard dirhodium experiment (1H NMR in the presence of an equimolar amount of the chiral dirhodium tetracarboxylate complex Rh*). Their structures represent ester, amide, carbonate, ether, alcohol and/or epoxy groups. Significant selectivity in the binding of those oxygen groups to the complex were determined. From these results, a priority list in binding to a rhodium atom of Rh* was established: epoxides > primary alcohols > ethers > or = esters > or = amides > carbonates > tertiary alcohols. This sequence allows the prediction of the preferred binding site of oxygen-containing groups in polyfunctional compounds, which frequently occur among natural products, and, particularly, in asymmetric synthesis of such compounds. Differentiation of the enantiomers by the dirhodium experiment is easily accomplished due to numerous signal dispersions in nearly all cases. PMID- 22545412 TI - Synthesis of acetylene bridged germanium phthalocyanines. AB - The octaalkyl- or octaalkoxysubstituted phthalocyaninatogermanium dichlorides 10b,d,e and 10a-c were reacted with bisbromomagnesiumacetylene 16 and bisbromomagnesium-p-diethynylbenzene 18, respectively with formation of the corresponding acetylene bridged oligomers 17a-c and 19a-c, respectively. PMID- 22545413 TI - Host-guest chemistry of alkaloids. AB - Binding of alkaloids by different hosts (native and modified cyclodextrins, cucurbiturils, calixarenes, and metal complexes of porphyrin and Salphen-type ligands), as well as receptor properties of alkaloid based hosts are reviewed. With alkaloids as guests, the largest binding constants and most significant spectral changes, in particular strong fluorescence enhancements induced by complexation with isoquinoline alkaloids, are observed with cucurbituril hosts. Cyclodextrins are successfully employed for improvement of solubility and for chiral separation of alkaloids of different types. Receptor properties of native and modified cinchona and bisbenzylisoquinoline alkaloids have attracted considerable attention for development of chiral selectors for analysis and separation. PMID- 22545414 TI - Proanthocyanidins: oligomeric structures with unique biochemical properties and great therapeutic promise. AB - Proanthocyanidins represent a unique class of oligomeric and polymeric secondary metabolites found ubiquitously and in considerable amounts in plants and some algae. These substances exhibit a range of rather surprising physical and chemical properties which, once applied to living organisms, are translated into a multitude of biological activities. The latter include antioxidant properties, cancer chemoprevention, anti-inflammatory and anti-diabetic effects as well as some exceptional, yet highly interesting activities, such as anti-nutritional and antimicrobial activity. Despite the wide range of activities and possible medical/agricultural applications of proanthocyanidins, many questions still remain, including issues related to bioavailability, metabolism and the precise biochemical, extra- and intracellular targets and mode(s) of action of these highly potent materials. Among the various physical and chemical interactions of such substances, strong binding to proteins appears to form the basis of many of their biological activities. Once easy-to-use synthetic methods to produce appropriate quantities of pure proanthocyanidins are available, it will be possible to identify the prime biological targets of these oligomers, study oligomer-protein interactions in more detail and develop possible practical applications in medicine and agriculture. PMID- 22545415 TI - Aurones: interesting natural and synthetic compounds with emerging biological potential. AB - Aurones [2-benzylidenebenzofuran-3(2H)-ones] are either natural or synthetic compounds, belonging to the flavonoid family. They are isomeric to flavones and provide a bright yellow color to the plants in which they occur. Today, a literature survey indicates that the related flavonoids have been studied not only for their physiological properties and effects on Nature, but also for their therapeutic potential. Aurones are recently attracting the interest of an increasing number of research groups, and, since the last review, some interesting advances have been made in understanding the aurones. In this review, we report the recent advances made on the synthetic routes towards aurones. We also highlight their activity in different biological areas, as well as applied genetic plant modifications to produce these colored compounds. Their synthesis, structure-activity relationships and the importance of the substitution pattern will also be mentioned. Finally, some aspects regarding the possible development of aurones will be discussed briefly. PMID- 22545416 TI - Sulfur and sulfur compounds in plant defence. AB - The multiplicity of chemical structures of sulfur containing compounds, influenced in part by the element's several oxidation states, directly results in diverse modes of action for sulfur-containing natural products synthesized as secondary metabolites in plants. Sulfur-containing natural products constitute a formidable wall of defence against a wide range of pathogens and pests. Steady progress in the development of new technologies have advanced research in this area, helping to uncover the role of such important plant defence molecules like endogenously-released elemental sulphur, but also deepening current understanding of other better-studied compounds like the glucosinolates. As studies continue in this area, it is becoming increasingly evident that sulfur and sulfur compounds play far more important roles in plant defence than perhaps previously suspected. PMID- 22545417 TI - The effect of diallyl polysulfanes on cellular signaling cascades. AB - Diallyl polysulfanes, such as diallyl trisulfide and diallyl tetrasulfide, are regarded as a group of potential chemopreventive compounds as they have been proven to be effective inhibitors of cancer cells. These agents have been implicated in signal transductions, including the generation of Reactive Oxygen Species (ROS), Endoplasmic Reticulum (ER) stress, mitogen-activated protein kinase (MAPK) signaling, regulation of cell cycle progression, and induction of apoptosis. Nonetheless, certain aspects of the diallyl polysulfane triggered inhibitory effects on cancer cells are still not clear. Understanding the targeted signaling pathways may help to develop new strategies to treat cancer and other diseases. This review is therefore aimed at addressing the targeting of specific intracellular signal transduction cascades by these diallyl polysulfanes in order to shed some light on possible mechanisms of action of these compounds. PMID- 22545418 TI - Interactions of calix[n]arenes with nucleic acids. AB - DNA interaction with artificial binders is of great interest, especially in light of the broad range of possible biomedical applications. The growing understanding of replication, transcription and translation opened the path for new approaches to target pathological effects at a very early stage. Meanwhile, the competitive binding to nucleic acids by designed molecules, which, for example, block certain sequences for natural binders, such as transcription factors, has become a promising concept in the context of gene therapy. On the other extreme, the transport of nucleic acids over the cell membrane into the nucleus by transfection agents opens the possibility to reprogram protein biosynthesis within host cells. In the past decades several substance classes have been developed for a noncovalent specific DNA binding with predictable biological effects, such as peptide nucleic acids or polyamide ligands. Calixarenes have not received so much attention, although they consist of a compact aromatic core tuneable in size, and allow the introduction of cationic functionalities at their upper and lower rims. Formerly being utilized as receptor moieties due to the possibility of complexating guests in their cavities, calixarenes are now also used as molecular scaffolds for multivalent ligands and are, therefore, suitable tools for cooperative DNA complexation. This review surveys specific supramolecular interactions between calixarene derivatives and nucleic acids, with an emphasis on structural elements in the calixarenes and the biological consequences of their complex formation with DNA strands. PMID- 22545419 TI - A peptide fraction from germinated soybean protein down-regulates PTTG1 and TOP2A mRNA expression, inducing apoptosis in cervical cancer cells. AB - The aim of this study was to evaluate the effect of a peptide fraction, obtained from a germinated soybean protein hydrolysate, on the viability, apoptosis and cancer related gene expression in HeLa cells. Soybean was germinated for 0-6 days and proteins were isolated from the seeds. Protein isolates, without ethanol soluble phytochemicals, were hydrolyzed with digestive enzymes and their effect on growth in HeLa cells was evaluated. The most active hydrolysate was separated by ultrafiltration into five peptide fractions. A >10 kDa fraction was the most active against cancer cells. This fraction down-regulated PTTG1 and TOP2A mRNA expression (two genes considered as therapeutic targets) and induced apoptosis in cancer cells activating the caspase cascade and causing DNA fragmentation. Germinated soy protein isolates could be a bioactive ingredient of functional food. PMID- 22545420 TI - Influence of hesperidin on renal cell surface glycoprotein content, nucleic acids, lysosomal enzymes and macromolecules against 7, 12-dimethylbenz [a] anthracene induced experimental breast carcinoma. AB - Therapeutic substances may reduce the risk of developing cancer by modulating the factors responsible for carcinogenesis. To evaluate these hypotheses, the present study was designed to investigate the modulatory effect of bioflavonoid "Hesperidin" against DMBA induced experimental breast cancer with reference to renal cell surface glycoproteins, nucleic acids, protein content, lipid profile and lysosomal enzymes. The female sprague-dawley rats were orally administered with single dose of 7, 12-DMBA to induce breast cancer and were treated with hesperidin [30 mg/kg/body weight] for a consecutive 45 days. The results revealed that there was a significant elevation in the levels of glycoproteins, nucleic acids, lysosomal enzymes and also significant alterations in macromolecules in renal tissues of cancer bearing animals. Interestingly, the altered levels of these parameters were remarkably reverted back to near normal in hesperidin treatment. The histopathological analysis of liver and kidney tissues were well supported the biochemical alterations and inevitably proves the protective role of hesperidin. It is proposed that, the effect of hesperidin during DMBA induced breast cancer could be due to the intervention strategies of hesperidin in the protein, nucleic acid biosynthesis, membrane stabilizing potentials on lysosomal compartment and inhibitory effect on cell surface glycoproteins and bio-fuel such as lipids. PMID- 22545421 TI - The triterpenoid fraction from Trichosanthes dioica root exhibits antiproliferative activity against Ehrlich ascites carcinoma in albino mice: involvement of possible antioxidant role. AB - The present study assessed the triterpenoid fraction from T dioica root (CETD) for antiproliferative effect and antioxidant influence against Ehrlich ascites carcinoma (EAC) in Swiss albino mice. Twenty-four hours after intraperitoneal inoculation of tumor (EAC) cells in mice, CETD was administered at 2 and 4 mg/ kg body weight daily for 9 consecutive days. On the 10th day, half of the mice were sacrificed for estimation of tumor proliferation, haematological, and hepatic antioxidative parameters viz. lipid peroxidation, reduced glutathione (GSH), glutathione-S-transferase (GST), superoxide dismutase(SOD)and catalase (CAT); the rest were kept alive for assessment of survival parameters. The antiproliferative effect of CETD was assessed by evaluating tumor weight, tumor volume, packed cell volume, viable and non-viable tumor cell counts, mean survival time and percentage increase in life span of EAC-bearing mice. CETD exhibited dose dependent and significant (p < 0.001) decreases in tumor weight, tumor volume, packed cell volume and viable cell count and extended the life span of EAC bearing mice. Hematological profiles were significantly (p < 0.001) normalized in CETD treated mice as compared to EAC control. CETD treatment significantly (p < 0.001) modulated the aforementioned hepatic antioxidative parameters as compared to EAC control. The present study demonstrated that CETD possessed promising antiproliferative efficacy against EAC in mice, plausibly mediated by alleviation of oxidative stress by multiple mechanisms. PMID- 22545422 TI - Chemoprotective effect of Decalepis hamiltonii against cyclophosphamide induced toxicity. AB - Cancer is a hyper-proliferative disorder that involves transformation, dysregulation of apoptosis, Proliferation, invasion, angiogenesis and metastasis. The conventional methods to treat cancer are surgery, radiotherapy and chemotherapy. Chemotherapy, being a major treatment modality used for the control of advanced stages of malignancies and as a prophylactic against possible metastasis, exhibits severe toxic side effects like diarrhea, fatigue, nausea, vomiting etc. Plants have been used for treating various diseases of human beings since time immemorial. In this study, methanolic extract of Decalepis hamiltonii was studied for its chemoprotective and antioxidant activity. Intraperitoneal administration of the extract significantly increased the total WBC count (3166 +/- 202 cells/cm2), bone marrow cellularity (680 +/- 70.1cells/femur), alpha esterase positive cells (641 +/- 26.2 cells/4000 cells), Weights of organs such as a spleen and lungs, in Cyclophosphamide (CTX) treated animals when compared to control. D. hamiltonii administration significantly decreased the levels of Serum glutamate pyruvate transaminase (SGPT), Serum glutamate oxaloacetate transaminase (SGOT), creatinine and urea in serum and increased their levels in liver and kidney. Histopathological analysis of small intestine also suggests that extract could reduce the CTX induced intestinal damage. Analysis of the antioxidant status revealed that treatment with D. hamiltonii could significantly inhibit the free radical generation in vitro. Similarly in vivo studies using D. hamiltonii showed that the extract could significantly decrease the level of SOD in serum of the treated animals compared to control animals. In conclusion the finding of this study suggested that the extract from D. hamiltonii has strong chemo protective effect against CTX induced toxicity. PMID- 22545423 TI - Role of glutathione in cancer pathophysiology and therapeutic interventions. AB - Glutathione (GSH) is an important intracellular antioxidant that instills several vital roles within a cell including maintenance of the redox state, drug detoxification, and cellular protection from damage by free radicals, peroxides and toxins. Molecular alterations in the components of the GSH system in various tumors can lead to increased survival and enhanced tumor drug resistance. Early identification of the importance of intracellular GSH to detoxification reactions has now led to investigating the potential importance that GSH chemistry has on signal transduction, molecular regulation of cellular physiology and regulation of apoptosis pathway. Several therapeutic agents that target this system have been developed and used experimentally and clinically in an attempt to improve cancer chemotherapy. This review highlights different roles played by GSH that finally regulate tumor growth and advances in the use of GSH-based drugs to specifically target this detoxifying system in cancer treatment as a means to increase therapeutic response and decrease chemotherapeutic drug resistance. PMID- 22545424 TI - Comparative effect of lornoxicam and paracetamol in pain relief in endometrial sampling. AB - We conducted a study to compare the analgesic effect of oral lornoxicam and oral paracetamol before endometrial sampling for benign conditions. This prospective, double-blind, randomized study was conducted on sixty women underwent endometrial sampling for benign indications, from November 2010 to April 2011. The patients were divided into two groups (lornoxicam and paracetamol group) and both administered drugs (8 mg oral lornoxicam or 500 mg oral paracetamol) one hour before the procedure. Pain scores, by VAS (Visual analog scale) pain score, were recorded 0, 30 and 60 minutes after the procedure and compared. All patients gave informed consent to the study. Statistical analyses were carried out by using the statistical packages for SPSS 15.0 for Windows (SPSS Inc., Chicago, IL, USA). There was no statistically significant difference between the groups about the demographic parameters (p > 0.05). Lornoxicam group showed lower VAS pain score than the paracetamol group (p < 0.05). A total of thirteen patients took additional analgesic in two groups (p < 0.05). According to the current study, oral lornoxicam is more effective in pain relief than oral paracetamol in patients underwent endometrial sampling. PMID- 22545425 TI - Hesperidin a citrus bioflavonoid modulates hepatic biotransformation enzymes and enhances intrinsic antioxidants in experimental breast cancer rats challenged with 7, 12-dimethylbenz (a) anthracene. AB - DMBA is a major class of potent genotoxic chemical carcinogen present in the environment and it may increase breast cancer risk. Flavonoids have been shown to have interesting biological activities in many experimental investigations. Hesperidin is one of the citrus flavonoid shown to be active against various oxidative stress mediated diseases. The aim of the present study was to investigate the beneficial impact of a natural citrus flavonoglycoside hesperidin against 7, 12-Dimethylbenz [a] anthracene challenged experimental breast carcinogenesis with reference to drug metabolizing enzymes and intrinsic antioxidant status. The female Sprague-Dawley rats were orally administered with single dose of 7, 12-DMBA to induce breast cancer and were treated with hesperidin [30mg/kg/body weight] for a consecutive 45 days. The results revealed that there was a significant reduction in the status of antioxidants levels and also significant alterations in the drug metabolizing enzymes were found in genotoxin DMBA exposed animals. Interestingly these, altered levels were significantly revered back to near normal in hesperidin administered animals via enhancing the intrinsic antioxidant levels and induction in Phase II enzymes and modulation in Phase I enzyme levels. Thus the antigenotoxic activity of hesperidin may be due to the modulatory effect in biotransformation enzymes and excellent antioxidant potentials which paving a way to consider hesperidin against the genotoxin involved oxidative stress mediated diseases. PMID- 22545426 TI - Dental tourism: an opportunity for public health. Interview by Lois K Cohen. PMID- 22545427 TI - Crestal bone loss and the consequences of retained excess cement around dental implants. AB - Crestal bone loss around dental implants has been a subject of discussion in implant dentistry since its inception. Many of the research and design developments related to dental implants have sought to limit the amount of crestal bone loss. While there are a variety of possible causes for crestal bone loss around dental implants, one iatrogenic cause that has become the subject of several articles is retained dental cement. The focus of this article will be to discuss the predisposing factors that can lead to retained cement and clinical strategies to minimize or prevent cement peri-implantitis. Case reports are presented in which retained cement resulted in significant peri-implant inflammation and bone loss around restored dental implants. Strategies for early detection to limit the damage from retained dental cement and cementing techniques are also discussed. PMID- 22545428 TI - Posterior tooth replacement with dental implants in sites augmented with rhBMP-2 at time of extraction--a case series. AB - This case series demonstrates seven molar-site implants placed in six consecutively treated patients. All sites were augmented with rhBMP-2 (1.50 mg/cc)/ACS (recombinant human Bone Morphogenetic Protein-2/Absorbable Collagen Sponge) at extraction to regenerate bone-facilitating implant placement. In four patients, osteotomies were initiated with trephines to evaluate qualitatively for native bone and for the absence of residual ACS. All sites facilitated implant placement after augmentation. All seven implants achieved primary stabilization and were functionally loaded. No implants were lost or developed complications. It can be concluded that augmenting molar extraction sockets with rhBMP-2/ACS can allow standard implant placement in the posterior dentition that is capable of withstanding a functional load. PMID- 22545429 TI - Obliteration of the nasopalatine canal in conjunction with horizontal ridge augmentation. AB - The presence of a wide nasopalatine canal and the lack of an adequate ridge width may affect the correct placement of implants in the central incisor area. This could lead to functional and esthetic problems. This article describes bone grafting of the canal and concurrent ridge augmentation to obtain adequate bone quantity and quality and to allow correct 3-dimensional placement of the implant. The lack of sensorial complications utilizing this technique is also reported here. PMID- 22545430 TI - Systematic analysis of an anterior wear case to fulfill esthetic and functional objectives. AB - It is beneficial to have a system in place for analysis of clinical data collected from a patient's initial examination. This system has four diagnostic categories that enable the clinician to thoroughly assess the clinical findings and establish a comprehensive diagnosis. An optimal treatment plan can be formulated to positively affect the prognosis of the presenting conditions. With the patient's treatment goals in mind, the clinician can determine the minimum amount of dentistry needed to increase long-term prognosis. PMID- 22545431 TI - Randomized controlled trial of 0.454% stannous fluoride dentifrice to treat gingival bleeding. AB - PURPOSE: To evaluate the effects of a highly bioavailable 0.454% stannous fluoride dentifrice on established gingival bleeding over a 3-month period. MATERIALS AND METHODS: A randomized controlled clinical trial was conducted. In total, 100 adults with mild-to-moderate gingivitis and an average of 15 bleeding sites were assigned to either the stannous fluoride or regular control pastes for at-home use. Of these, 99 received study treatment and 97 completed the study. RESULTS: The stannous fluoride group experienced 50% to 74% reductions in bleeding sites relative to baseline or the control, differing significantly (P < 0.001) at all time points. Most subjects in the stannous fluoride group (94%) had measured improvements in bleeding, and nearly one half completed treatment with one or no bleeding sites. CONCLUSION: These study results suggest that incorporation of this 0.454% stannous fluoride dentifrice into daily oral hygiene maybe expected to yield less gingival bleeding at subsequent dental check-ups, and therefore reduce the risk of progressive periodontal disease. PMID- 22545432 TI - Digital radiography: analyzing the benefits. PMID- 22545433 TI - DEXIS digital radiography offers dentists positive imaging experience. PMID- 22545434 TI - Schick offers modular digital radiography technology. PMID- 22545435 TI - Vatech: digital radiography technologies for precise dental diagnostics. PMID- 22545436 TI - Single-shaded direct anterior composite restorations: a simplified technique for enhanced results. PMID- 22545437 TI - [Distribution of psychrophilic microorganisms in terrestrial biotopes of the Antarctic Region]. AB - It is shown that the total number of chemoorganotrophic aerobic microorganisms in the Antarctic Region revealed at 1 degree C and 5 degrees C made from 10(4) up to 10(6) cells/g of plant-soil sample of biotopes: grass Deschampcia antarctica, grass Colobanthus, green mosses, crustose black lichens and a biofilm of accretion on vertical rocks. From 10(6) up to 10(8) cells/g of samples were revealed in the same Antarctic samples at 30 degrees C. At 42 degrees C thermotolerant bacteria were either absent, or their quantity was less than 10(4) cells/g of samples. Thus the fraction (part) of the Antarctic microorganisms, which grow at different temperatures, varied: at 1-5 degrees C their part made from 5 to 15%, and at 30 degrees C--from 10 to 45%. At 15-20 degrees C the growth of both psychrophilic/psychrotolerant, and mesophilic microorganisms was observed. When comparing the results of plating of samples from different climatic zones (the Antarctic Region and Ukraine), it is shown that in the Antarctic biotopes in comparison with biotopes of the zone with temperate climate: (1) the total number of microorganisms is lower, (2) quantity of psychrophilic/psychrotolerant bacteria is higher, (3) quantity of mesophilic microorganisms is less, (4) as a result the part psychrophilic/psychrotolerant microorganisms in the total number of microorganisms is much higher. It is evident, that low temperatures, and also daily cycles of freezing and thawing are factors which limit microbial colonization ofAntarctic biotopes. PMID- 22545438 TI - [Bifidobacterial species composition of digestive tract of people of different age groups]. AB - The quantitative and species composition of bifidoflora of intestinal content of people of different age groups has been studied. It was established that B. longum subsp. infantis, B. bifidum, B. brev, B. longum subsp. longum and B. dentium were the dominant species of intestinal bifidoflora of people of all ages. The dependence of the species composition of intestinal bifidobacteria on the human age was shown. A decrease of species diversity of bifidobacteria in elderly people was observed. PMID- 22545439 TI - [Use of real-time PCR for quantitative assessment of lactic acid bacteria and bifidobacteria in dairy products]. AB - Composition of lactic acid bacteria and bifidobacteria in raw milk and home-made milk products has been analyzed using real-time PCR (quantitative PCR) with genus specific primers to Enterococcus, Lactobacillus and Bifidobacteria. Bacteria belonging to these genera have been revealed in all samples analyzed (milk, sour cream, cottage cheese). It has been shown that the representatives of Enterococcus and Lactobacillus genera dominated in the samples analyzed (10(3) 10(7) genome equivalent/ml (mg)). The largest number of these microorganisms (10(7) genome equivalent/mg) has been detected in cottage cheese. PMID- 22545440 TI - [Synthesis of surfactants acinetobacter calcoaceticus IMV B-7241 and Rhodococcus erythropolis IMV Ac-5070 in the medium with glycerol]. AB - It was established that glycerol, a byproduct of biodiesel production, may be used as substrate for synthesis of surfactants Rhodococcus erythropolis IMV Ac 5017 and Acinetobacter calcoaceticus IMV B-7241. Maximum indices of surfactants synthesis by the strain IMV B-7241 have been fixed, when the medium with glycerol included yeast autolysate and trace elements. It was shown that the surfactants synthesis could be intensified when cultivating A. calcoaceticus IMV B-7241 and R. erythropolis IMV Ac-5017 on the mixture of hexadecane and glycerol in concentration of 0.5-1.0% (in volume). When using inoculate grown on hexadecane, the conditional concentration of the surfactant A.calcoaceticus IMV B-7241 on the mixed substrate was higher by 56-100, and that of R. erythropolis IMVAc-5017 by 260-320 % than on the monosubstrate glycerol. The paper is presented in Russian. PMID- 22545441 TI - [Biological degradation of sticky-gene compositions in different type soils]. AB - The ability of native microbial associations from different types of soils to degrade sticky-gene composition which were created on the EPAA basis have been determined. The ecological safety and harmlessness of sticky-gene composition, its slow degradation by soils microorganisms and providing long-term influence (impact) of preparations introduced on plants protection have been shown. The conditions of gray forest and sod podzol soil are the most favorable for the sticky-gene composition degradation. Sticky-gene composition degradation goes slower in sandy soil conditions. PMID- 22545442 TI - Characteristics of defective phage particles of Pectobacterium carotovorum ZM1. AB - It is shown for the first time that the expression products of defective prophages are typical of defective lysogenic systems of phytopathogenic Pectobacterium carotovorum. It is established that virus-like particles (LP) such as phage capsids are packing bacterial DNA which size is determined by pulse field gel electrophoresis separation. Based on data about capsid structures which are formed by the virulent mutant ZF40/421, there is made a suggestion about the forming mechanism of defective virions of P carotovorum. PMID- 22545443 TI - [Dissociation of Pectobacterium carotovorum subsp. carotovorumrelated to the changes in the cell wall lipopolysaccharide]. AB - It is shown for the first time that population heterogeneity of Pectobacterium carotovorum subsp. carotovorum is applicable to a wide range of strains and therefore is a universal characteristic. Using the method of specific selection with the help of carotovoricins which are identical to the phage tails a set of population dissociants of different types was obtained, due to the fact that S LPS is the part of the cell wall which contains their attachment sites. It was determined that changes in S-lipopolysaccharides lead to the formation of SR-, R forms of P. carotovorum. A suggestion is made that the changes in the surface structures of dissociants have a significant impact on secretion types II and III -the main pathogenicity factor of some bacteria. The results presented are a prerequisite for studying the direction, the reasons for dissociation process and its impact on the pathogenicity of P. carotovorum. PMID- 22545444 TI - Biological characteristic and identification of soybean virus isolated from different Ukraine regions. AB - To examine the presence and level of viral infection, field observations of the soybean crops in the Cherkassy, Vinnitsa and Kyiv regions have been performed. It was established that the diseases in the soybean plants growing in the examined areas have been caused by two major viruses--SMV (Soybean mosaic virus) and BYMV (Bean yellow mosaic virus). The results of field observations have been confirmed using light and electron microscopy and ELISA. PMID- 22545445 TI - [Prebiotic properties of lactite and lactulose under creation of synbiotics of bacillus genus bacteria]. AB - The influence of lactite and lactulose on growth of probiotic strains B. subtilis UKM 5139 and B. subtilis UKM 5140 and conditionally pathogenic microorganisms has been studied. It is shown that the extent of influence of these substances depends on their concentration. Addition of lactite or lactulose in the nutrient medium stimulated growth of probiotic bacilli strains in concentration of 15-20 % and inhibited growth of conditionally pathogenic microorganisms. It specifies the prebiotic properties of the studied disaccharides. It is established that the extent of inhibition of P. vulgaris, S. flexnery, S. enterica abony, E. coli 028 by lactulose was higher in comparison with the extent of their inhibition by lactite, but in turn lactite was more effective in relation to the strains E coli ATCC 25922, C. albicans, S. derby and S. aureus. PMID- 22545446 TI - [Medical support of the Armed Forces of Russia: results of the activities and major tasks for 2012]. AB - The article presents whole range of activity of medical service of the Army and Navy. There were defined main directions and peculiarities of medical supply of the Armed Forces in conditions of forming of a new image. A special attention was paid to questions of combat and mobile readiness of medical armed units and institutes taking into account optimization of structure and quantity of medical service of the AF of RF. The main direction of activity of the medical service is organization of treatment-prophylaxis work for saving of life and health of the staff of Army and Navy. The article informs about stabilization of morbidity by the most popular diseases, about capabilities of medical service of armed unit in a new organization-staff structure, about ways of increasing of effectiveness of activeness of military treatment-prophylaxis institutes. PMID- 22545447 TI - [Contact dermatitis: an approach used by a medical officer]. AB - The article deals with contact dermatitis issues, that are of interest not only for dermatologists and specialists in professional pathology, but as well as for general practitioners. Issues of contact dermatitis classification, pathogenic peculiarities of the disease main forms and their basic causes are discussed. Clinical manifestations of irritative and allergic contact dermatitis are described in detail, aspects of differential diagnostics analysed. A detailed consideration is given to allergic diagnostics of contact dermatitis using application test-systems with the most common contact allergens. Main principles of contact dermatitis treatment are outlined in the article. The necessity of a complex approach to this disease therapy that requires not only external therapy, but the compliance with an appropriate treatment regimen, diet as well as application of a particular system therapy is shown. Recommendations for contact dermatitis prophylaxis are given. PMID- 22545448 TI - [Blasting damage in manmade disasters and terrorist attacks]. AB - In the present case of explosive injuries in peacetime, when suddenly there are usually accidental or intentional explosions methane in mines, tanks with gas or explosives, fuel tanks or gas content, gas tanks, gas pipelines, product pipelines, as well as the explosion of military ordnance--grenades, mines, fuses, shells, and accidentally found child or maliciously used by terrorists. Collected statistical data on manmade disasters in coal mines and explosive injuries in terrorist attacks, the physical parameters of which were able to identify only approximately and type of damage incurred,mostly multiple and combinative combined and presented significant challenges in health care. The reasons and circumstances of the explosion in peacetime, gave a detailed description of the damaging factors, mechanisms, and characteristics arise from injuries suffered in the blast injuries. We describe the pathogenesis of blast injury, basic and clinical manifestations of lesions in the explosions. PMID- 22545449 TI - [Diagnosis and treatment of metabolic syndrome combined with liver toxicity genesis in contract service officers]. AB - In this paper is synthesized current and recent data on the problem of metabolic syndrome (MS) in combination with toxic liver injury (CCI). Statistical parameters of the last 15 years, the dynamics of alimentary-constitutional obesity (ABC) in patients from the officers contracted service of Defense Ministry of Russia are reflected. Two-year experience in the application of modern non-invasive methods of diagnosis of liver fibrosis with a reflection of its dynamics on the background of complex treatment of patients with MS in conjunction with the Chamber on the example of 57 patients is shown. Paid great attention to psychological and emotional adjustment of patients with ABC, given the complex survey design and treatment in violation of motivational and behavioral responses. High clinical efficiency of combination drug therapy of MS and CCI, the diagnostic value of modern non-invasive methods of diagnosis of hepatic fibrosis are reliably performed. Technique of elastography significantly improves the liver clinical evaluation of the effectiveness of the therapy, allows for early detect the presence of the initial degree of hepatic fibrosis, choose the optimal treatment regimen and to evaluate the results dynamically. PMID- 22545450 TI - [Medical and psychological prediction of professional readiness of graduates of military school]. AB - The authors propose a method for assessing the professional readiness of graduates of military educational institution, taking into account academic performance, the results of sociometric surveys, data on the professional fitness and health. The high efficiency of the developed method for predicting successful adaptation of graduates to serve in the armed forces is showed. PMID- 22545451 TI - [The problems of assessment of the high noise impact on the experts of the Air Force]. AB - Air Force specialists are exposed to high intensity noise levels exceeded the maximum permissible levels. Infrasound as a productive factor in accordance with the general technical requirements (OTT) Air Force-86 is not included in the list of standardized factors. The adverse acoustic environment makes the risk of occupational (sensorineural deafness) and professionally-related diseases of the nervous and cardiovascular systems. The system of physical fitness for military service in the Air Force and serving in the Air Force with high-intensity sources of noise, the system of treatment and preventive measures for adverse effects of noise and the procedure for examination of persons with diseases caused by the influence of noise are needed to be reviewed in accordance with the existing state legislative frameworks. PMID- 22545452 TI - [Experience in organization of drug supply for military personnel and military retirees in the United States]. AB - In the U.S. troops and military retirees realize the right to obtain drugs by participating in a nationwide managed care program TRICARE under the routines TRICARE Pharmacy. Militarily, the U.S. health care holding drug based on the Basic Core Formulary and Extended Core Formulary, which are developed by US Department of Defense Pharmacy and Therapeutics Committee. Realization of subprogram TRICARE Pharmacy is performed by Express Scripts. PMID- 22545453 TI - [Military doctors and Community of St. Eugene]. AB - Article focuses on the role of military physicians in the establishment and operation of the Community of St. Eugene in St. Petersburg (1882-1918). Since 1900 the hospital functioned as a community of 3 pavilions, which had 84 regular beds, including 15 free. At various times in outpatient clinics and courses of the Community of St. Eugene worked different professors of Military-medical Academy: ophthalmologist Bellyarminov L.G., physician Manassein V.A., medicolegist Kosorotov D.P. and assistant professors Danillo S.N. and Popov. In the implementation of a "medical project" Community of St. Eugene exceptional role belonged to MD Aleksey Belyaev, a staff member of the Main Military Medical Administration, also chairing the editorial board "Military-medical journal". Role of community in care for the wounded during the Russian-Japanese war and World Wars is significant. Russian Community of fame has been associated with the outbreak in 1898, long-term activities for the production of art publications. PMID- 22545454 TI - [Physician of Obukhov school (90 years of the birth of Alexander Nikolayevich Senenko)]. AB - At the beginning of December 2011 turns the 90th anniversary of a prominent national physician Alexander Nikolayevich Senenko. He was an educatee of the two academies--Military Medical Kirov (graduated with honors in March 1944) and the Naval Medical (VMMA), where he studied at post-graduate at the Department of Faculty Therapy (1950-1953). The results of the scientific work of the department summarized in the monograph of Gogin E.E., Senenko A.N., Tyurin E.I., "Arterial Hypertension" (1978, 1983). Monograph of Senenko A.N. "Heart and focal infection" (1973) has not lost its scientific and practical importance to this day. Shortly before the death (June 1, 1991), Alexander Nikolaevich completed the major work on the role of focal infection in the pathology of internal organs. In all he published over 250 scientific papers, including one textbook, four monographs and several major textbooks. PMID- 22545455 TI - [Volgograd military hospital--70 years]. AB - History of the Volgograd military hospital dates back to July 24, 1941, when on the basis of the regional children's bone tuberculosis sanatorium in Krasnodar was transformed into 2150th military hospital consisted of 240 beds. Since May 1944 relocated in the city of Stalingrad became a garrison hospital. Today the hospital is a multidisciplinary health centre of the Russian Defense Ministry. Annually, the hospital performed at least 3000 surgical procedures, including more than 37%--are complex. In surgery, improved endovideosurgical direction, over 31% of emergency operations performed using this method. Since December 2009 the hospital became a structural division of the District Hospital in 1602 in Rostov on Don. The close connection between the branch and district hospital allows for complex diagnostic situations to consult leading experts, including consultation, thus ensuring the most effective treatment results. PMID- 22545456 TI - [Work intensity and arterial hypertension]. AB - The authors presented dependence of arterial hypertension on work intensity, exemplified by two occupational groups--teachers and electricians, and demonstrated modifying influence of occupation on prevalence of traditional cardiovascular risk factors. PMID- 22545457 TI - [Occupation and health of medical workers in Bashkortostan Republic]. AB - Occupational morbidity analysis covered medical staffers of Bashkortostan Republic over 1997-2010. Findings are that health care is an activity with high occupational risk independent on type of medical establishment, speciality and position. In 1999-2005 significant increase of occupational morbidity in Bashkortostan Republic was seen--up to 4 times over average in the Republic. Afterwards the occupational morbidity among medical staffers decreased significantly, but conditions for its formation still exist. Leading place in occupational morbidity among medical staffers of Bashkortostan Republic appeared to be occupied by infectious diseases presented by tuberculosis and viral hepatitis; second place belongs to skin conditions, the third--to respiratory diseases. Severe infectious and somatic diseases (tuberculosis, viral hepatitis and bronchial asthma) cover more than a half (65.4%) of all primarily diagnosed occupational diseases in medical staffers, that determines high possibility of disablement and early incapacity (44.1%). Complex target program "Basic science for work conditions and health state monitoring in medical staffers of Bashkortostan Republic" was specified for 2010-2015 and is aimed to a model of monitoring system for work conditions and health state of medical staffers, in order to justify management solutions for lower occupational risk and optimized work conditions of medical staffers in Bashkortostan Republic. PMID- 22545458 TI - [Comparative analysis of occupational risk evaluation results through various methodic approaches]. AB - Comparative analysis covered three models of occupational risk evaluation: (1) Method to evaluate risks at workplace, elaborated in Finland and recommended by International Work Safety Agency for Eastern Europe and Central Asia countries; (2) Method elaborated in Research Institute for Occupational Medicine with RAMSc under the direction of N.F. Izmerov and E.I. Denisov; (3) Method evaluating individual occupational risk, with consideration of work conditions and worker's health state, also elaborated in Research Institute for Occupational Medicine with RAMSc and Klin Institute of Work conditions and safety, approved in 2011 as methodic recommendations. Findings are that in contemporary Russia a unified method evaluating occupational risk is more expedient; the first method satisfactorily describes actual ratio of occupational risk levels and could be useful as an additional method for its evaluation, especially for psycho-social factors; the second method does not allow to evaluate occupational risk acceptably if absent longstanding occupational morbidity, but is recommended for risk evaluation in evidence-based medicine; the third method is recommended at federal level to fulfil requirements of Labour Code in Russian Federation and obligatory social insurance purposes. PMID- 22545459 TI - [Evaluation of psycho-social occupational and nonoccupational factors importance for police officers]. AB - The authors evaluate value of psycho-social occupational and nonoccupational factors for police officers. Findings are that the most important stress factors of occupational origin are insufficient time spent with family and friends, negative public attitude to police and work on weekends. Necessity of medical and psychologic changes is justified. PMID- 22545460 TI - [Preventing risk of overexertion in mental workers, depending on work conditions class according to work hardiness parameters]. AB - One of the most important tasks of occupational medicine is prevention of overexertion and occupational diseases in physical workers with various characters and degree of muscular exertion (local, regional and general). The studies demonstrated strong corellation between work conditions class in work hardiness, functional state and level of diseases development among 50 occupational groups examined. The article covers specific and differentiated measures on rational work and rest schedules, and other prophylactic means, with consideration of work conditions class for physical workers. PMID- 22545461 TI - [Contemporary peculiarities of health state formation in future teachers]. AB - Analysis covered health state parameters and results of health state self evaluation in students of teachers' training institute. Morbidity parameters per 100 students are reliably low: within 10 cases for general morbidity, within 20 cases for transitory disablement morbidity. However, unfavorable trend to increase was seen over 5 years for transitory disablement duration and average duration of one disease--that proves increase in neglected diseases share and more severe course. Leading place in general morbidity structure and transitory disablement morbidity is occupied by respiratory and digestive disorders. Questionnaire data on qualitative evaluation of health state could form false favorable opinion. Different questions considerably change the overall evaluation and support the trend revealed through the morbidity analysis. Conclusion is necessity of healthy lifestyle formation in students and improved quality and accessibility of medical care. PMID- 22545462 TI - [Improper nutrition as a factor of parodontal inflammatory conditions at able bodied age]. AB - The study covered actual nutrition in able-bodied individuals having a diagnosed chronic generalized parodontitis. Findings are severe disorders in nutritional staus: severe element disbalance, vitamin insufficiency, fatty acids imbalance in nutrition, lower content of dietary fibers. The nutritional disorders in the examinees prove deep pathogenetic connection of parodontal diseases and internal disorders, associated with nutritional imbalance as well. PMID- 22545463 TI - [Evaluating individual occupational risk in teachers]. AB - The authors analyzed work conditions of comprehensive school teachers according to workplace assessment. Additional studies covered opportunistic pathogens content of air in classrooms. Auxiliary medical examination evaluated health state of the teachers. Individual occupational risk was calculated with consideration of actual work conditions and health state. Comprehensive school teacher's work is characterized by constant or transitory influence by complex of occupational and work hazards that are mostly (according to to workplace assessment) increased work intensity, noise and inadequate illumination parameters. Ambient air of classrooms constantly contains high number of opportunistic pathogens, that could decrease immune system parameters and cause more droplet infections. Individual occupational risk of teachers, calculated with consideration of work conditions and health state parameters, appears to be high and proves high possibility of teachers' health damage at work. Recommendations cover evaluation of biologic factors within the workplace assessment, obligatory preliminary (before employment) and periodic medical examinations for comprehensive school teachers as for workers exposed to occupational hazards. PMID- 22545464 TI - [The preparation procedure of tests for the gas chromatographic determination of fat acids without preliminary extraction of lipids]. AB - The enhancement of the procedure of quantitative gas chromatographic determination of fit acids in biologic liquids samples is proposed. Instead of the conventional Folch procedure of extraction of lipids with subsequent ablution, concentration and methylation of extracts the direct saponification and methylation of vacuum dried liquid samples (50-200 mkl) can be applied. To compare the effectiveness of the proposed and conventional procedures both of them had been applied to evaluate how converge the results of determination of composition of fat acids in whole blood, blood plasma, packed red blood cells, homogenates of hepatic and muscular tissues. The proposed procedure is applied to determine the characteristics of fat acids composition inpatients with ischemic heart disease. PMID- 22545465 TI - [The characteristics of metabolism in patients with fractures of shin and thigh bones depending on immobilization period]. AB - The comprehensive biochemical examination of 20 patients with fractures of shin and thigh bones aged from 18 to 50 years was organized. The treatment consisted of skeletal traction meaning a lingering limitation of locomotive activity The blood sampled at 7th, 14th, 21th, 28th and 35th days after trauma. The blood plasma was analyzed to establish the indicators of protein and purine metabolism, lipoperoxidation processes and antiradical activity. The study established the catabolic direction of metabolism and the intensification of lipoperoxidation processes of the background of decreasing of antiradical activity. The research data can be recommended to apply in controlling the impact of forced limitation of locomotive activity on the course of post-trauma process. PMID- 22545466 TI - [The clinical laboratory evaluation of impact of shock wave on the activity of peptidohydrolase in urine of patients with urolithiasis]. AB - The article presents the results of comprehensive clinical biochemical study of 79 patients with urolithiasis admitted to the urologic department of public clinical hospital No 7 in 2007-2009. The diagnostic evaluation of the impact of shock wave on kidney parenchyma and crystallization processes was implemented. The chromatography-mass spectrometry was applied to analyze the activity of hydrolytic enzymes in urine of patients with urolithiasis underwent the remote lithotripsy sessions. The dependence of the peptidohydrolase activity alteration in urine of patients with urolithiasis after remote lithotripsy from presence/absence of concomitant pyelonephritis was substantiated. This outcome permitted not only to implement the laboratory-based prevention during the pre operational stage but to plan properly the ratio of repeated sessions of lithotripsy. PMID- 22545467 TI - [The endothelin-1 and von Willebrand factor in the development of lung hypertension in children with chronic bronchopulmonary pathology]. AB - The assessment of the indicators of functional state of endothelium (endothelin-1 level and von Willebrand factor activity) was implemented in healthy children and patients with bronchopulmonary pathology with normal and high pressure in pulmonary artery It is established that pulmonary hypertension in children with chronic bronchopulmonary pathology is associated with the endothelium dysfunction (increase of endothelin-1 concentration and activity of von Willebrand factor). The direct dependence of evidence of the pulmonary hypertension from the level of endothelin-1 and activity of von Willebrand factor is proved. The increase of the level of endothelin-1 and the activity of von Willebrand factor is a risk factor of the development of pulmonary hypertension in children with chronic bronchopulmonary pathology. PMID- 22545468 TI - [The choice of laboratory biomarkers for early detection of vibration unfavorable impact on human organism]. AB - The vibration impact on various biochemical, citochemical, immunologic and hematological indicator was studied. It is established that the indicators of oxidative metabolism (the activity of blood superoxide dismutase, neutrophil myeloperoxidase and malonic dialdehyde concentration), the level of immunoglobulin A, M and G, the activity of alkaline and acid phosphatase in neutrophils, the content of creatinine in urine are changed on the pre-clinical stage. The increase of concentration of hemoglobin begins under vibration disease 1 and the character of alteration in erythrocytes volume depends on the evidence of vibration impact. The diagnostic characteristics of various laboratory tests are established The biomarkers are selected to evaluate the health status of workers contacting with vibration. The set of laboratory biomarkers is proposed to apply during the examination of workers contacting with vibration. The implementation of this set permits to detect the early pre-clinical alterations in workers' organism, to assess the evidence of alterations in patients with vibration disease and to establish disorders in patients with late effects of vibration pathology. PMID- 22545469 TI - [The serum erythropoietin under intermediate B-thalassemia]. AB - The study explored the level of serum erythropoietin in patients with intermediate beta-thalassemia to determine possible correlations with hemoglobin level and fetal hemoglobin level and other parameters. The sampling consisted of 58 examined patients with intermediate beta-thalassemia. The contrl group consisted of 30 healthy persons. All patients underwent the identification of erythrocytes count, hemoglobin level, hematocrit indicator, erythrocyte indices (MCV, MCH, MCHC), fetal hemoglobin level, hemoglobin A2 level. Also, to all patients the identification of serum erythropoietin and ferritin levels was applied The presence/absence of relationship between these indicators was established using the correlation coefficient calculation. The study results demonstrated that under intermediate beta-thalassemia are observed statistically valid decrease of level of hemoglobin and erythrocytes, increase of percentage of fetal hemoglobin, hemoglobin A2 ferritin and serum erythropoietin as compared with standard values. The analysis of correlation relationships between indicators under study revealed that under the intermediate beta-thalassemia in many cases the failure of interdependencies of indicators marked as normal are established. The presence of clear-cut inverse interrelationship between serum erythropoietin level and hemoglobin level has to be taken into account in the process of treatment of this disease with medications of recombinant erythropoietin. PMID- 22545470 TI - [The organizational aspects of laboratory diagnostics of acute conditions: a lecture]. AB - The article presents data concerning the prevalence of acute diseases and conditions in the Russian Federation. The main requirements are exposed concerning the laboratory diagnostics of acute conditions. The results of analysis of regulating documents concerning this issue are presented. The list of optimal laboratory tests and organizational options to be implemented in laboratory testing of patients with acute diseases and conditions in medical institutions is developed. The role and importance of principles of evidence medicine in choosing an optimal list of laboratory analysis to diagnose the acute conditions is demonstrated. PMID- 22545471 TI - [The reactants of acute phase of inflammation and anti-inflammatory cytokines under various complications of cardiac infarction]. AB - The article presents the results of analysis of blood serum from 60 patients (aged 58.9 +/- 1.5 years) with Q-genous complicated and non-complicated cardiac infarction. The study evaluated the content of various proteins of acute phase (alpha-2-macrogloblin, alpha-1-antitripsin. lactofferin) and cytokines inducing their synthesis (IL-6, IL-1beta, L-8). The examinations carried out on 1st, 7th and 14th day of development of cardiac infarction. It is demonstrated that under cardiac infarction complicated by cardiogenic shock on first day of diseases high levels of lactoferrin and lower levels of macroglobulin are detected in blood serum. On the 1-7th day of disease the high levels of lactofferin on the background of invariable concentration of macroglobulin accompany the edema and congestive processes in lungs under cardiac infarction. On the 1-7th day the high levels of lL-6 and IL-8 were detected under large-focal cardiac infarction independently of presence/absence of complications. PMID- 22545472 TI - [The structure of flow of patients with intolerance to anesthetics and diagnostic information value of various methods of specific diagnostics in vitro]. AB - The article deals with both the characteristics of flow of patients with intolerance to anesthetics examined with methods of specific diagnostics in vitro and the diagnostic capabilities of these methods. During last 10 years, the flow of patients of this group increased significantly and its structure has changed The analysis demonstrated that from all tests of specific diagnostics the CD45 test is the most informative. PMID- 22545473 TI - [The pathogenic aspects of fat acids metabolism with short chain and production of cytokines in target affected areas of skin under psoriasis]. AB - The article deals with the results of analysis of specters of short-chained fat acids and cytokines in affected skin of patients with psoriasis. The study revealed the significant decrease of short-chained fat acids level, the shift of cytokine profile in the direction of anti-inflammatory factors (interleukins 1L 1beta, IL-8, tumor necrosis factor TNF-alpha, interferon IFN-alpha) and mytogenetic factors (EGF) on the background of stable values of anti-inflammatory cytokine IL-4. The direct pathogenically significant correlation relationships are established between the IL-4 level and the amount of most analyzed short chained fat acids. The negative correlation relationships were established between content of C2 and IL-1beta. PMID- 22545474 TI - [The immune-enzyme testing of titers of serum anti-botulin antibodies type A during immunization of patients with botulin trianiatoxin]. AB - The article discusses the effectiveness of the technique of immune-enzyme detection of anti-botulin antibodies type A in human blood serum. The presence of antibodies is registered in blood serum after second and subsequent immunization with botulin trianatoxin (titer from 1:400 to 1:3200). The establishment of relationship between the registered titers of anti-botulin antibodies and the activity of serum during protection of white mice from toxin revealed the correlation coefficient between these values as 0.58. PMID- 22545475 TI - [The molecular mechanisms of resistance to B-lactams of pathogens of hospital acquired infections]. AB - The data of local microbiologic monitoring was used to study the profiles and mechanisms of resistance to beta-lactams antibiotics of gram-negative isolates of bacteria, pathogens of hospital-acquired infections in hospital reanimation and surgical departments. The study included 210 clinical isolates of pathogens of hospital-acquired infections: Pseudomonas aeruginosa--86 (40.9%), Acinetobacter baumannii--45 (21.4%), Klebsiella pneumoniae--52 (24.8%), Escherichia coli-23 (11.0%), Enterobacter spp.--4 (1.9%). The profiles of resistance to antibiotics were analyzed using the technique of serial micro-dilutions. The detection of the most common and clinically significant gens of beta-lactamases of gram-negative bacteria was implemented using the PCR technique and sequence analysis. The most activity was detected among carbapenems and cephaperazone/sulbactam. The local characteristics of prevalence of gens coding beta-lactamases (TEM, SHV, CTX) in K. pneumoniae and E. coli were established The study detected 11 isolates of P aeruginosa resistant to carbapenems and having genetic determinants of VIM-group and coding metal-beta-lactamases. The discussed data permits to assess the indicators of resistance to beta-lactams antibiotics and basic mechanisms of resistance of causative agents of hospital-acquired infections. The studies of this kind are unique for every type of hospital-acquired infection. The results can be used in the development of the concept of etiotropic and empiric therapy. PMID- 22545477 TI - [The biomarkers of stroke: the progress and issues of diagnostics, prognosis, differentiation and treatment]. PMID- 22545476 TI - [The characteristics of biological properties of E. coli O104:H4--the causative agent of large-scale alimentary ictus in Germany may 2001]. AB - The review presents the characteristics of E. coli O104:H4, the causative agent of large-scale alimentary ictus in Germany in spring time 2011. The antigenic characteristics and factors of E. coli pathogenicity are taken into account. The causative agent has a combination of pathogenic factors of two groups of diarrheigenic Escherichia: shigella similar toxin, specific for entero hemorrhagic E. coli and adhesins of enteroaggregative E. coli. PMID- 22545478 TI - Change: it is what it is. PMID- 22545479 TI - Does nursing make a difference? PMID- 22545480 TI - Understanding stress in the operating room: a step toward improving the work environment. AB - Job-related stress is an important factor predicting staff satisfaction and position turnover among nursing staff, particularly in the operating room. The purpose of this study was to examine the perceived amount of stress elicited by events in the perioperative environment, the frequency of those events, and the impact of those events on the perceived stress of operating room nurses (ORNs) and operating room technologists (ORTs). The Survey on Stress in the OR instrument, which was used to query the subjects, exhibited high internal consistency of all items. The findings indicated that the ORNs and the ORTs exhibited remarkable similarities between stressful events perceived as high and low impact. The two groups agreed that the highest impact stressful event was "pressure to work more quickly." Using the results of this study, OR administrators may be able to redesign the OR environment to minimize the impact of stressful events and thereby improve job satisfaction and minimize nursing staff turnover. PMID- 22545481 TI - [Is there enough what we're doing for COPD?]. PMID- 22545482 TI - [Proportion and site distribution of extrarespiratory tuberculosis in 2007-2010 in Romania]. AB - In the actual context of an increased TB endemia (notification rate of 90.5 per thousand, meaning 21457 cases in 2010, but with a constant decreasing trend in the last 8 years), we wanted to see what is the share and structure of extra respiratory tuberculosis in the period 2007-2010. In the interval 2007-2010 have been registered annually between 1252-1267 extra-respiratory TB cases. Extra respiratory TB have been between 30% and 42,1% from all TB cases registered annually with the extra-pulmonary TB. In the descending order of cases recorded with TB extra respiratory in 2010, the first was extra-thoracic ganglionary TB (244 cases), followed by osteo-articulary (233) and those of meningo-encephalitis and CNS TB (133). Location of TB on the spine remains the most common form of skeletal TB, representing 62.2% (145 cases) of all osteo-articulary locations. The number of registered cases of pericardial effusions TB annually remains steady at 40-50 cases. The number still high of meningo encephalitis TB (severe prognosis, epidemiological severity) involves enhanced accountability measures in TB control of the territory. The collaboration between the pulmonologist and the body specialist constitutes compulsory condition of quality assistance in case of TB extra respiratory sites. PMID- 22545483 TI - [Gastroesophageal reflux and asthma--pathogenetic mechanisms and treatment]. AB - Gastroesophageal reflux and bronchial asthma are frequently encountered comorbidities that maintain an ambivalent relationship, generating a vicious circle where gastroesophageal reflux increases asthmatic symptoms or precipitates bronchial asthma and asthma can trigger or worsen gastroesophageal reflux disease. Pathogenetic mechanisms of these interrelation are imperfectly understood, despite intense concerns of specialists in both areas. There have been incriminated: eso-bronchial constrictor vagal mediated reflexes, bronchial hyperreactivity, neurogenic inflammation induced by hydrochloric acid penetration in the oesofagus, airways hydrochloric acid microaspiration with asthmatic trigger effects, increased bronchial resistance or increased immune response to antigens. Bronchial obstruction and some antiasthmatic medication can decrease lower esophageal sphincter pressure and thus triggering or aggravating gastroesophageal reflux. The diagnosis of the gastroesophageal reflux in asthmatics involves a careful clinical exam, digestive functional test (up to 24 hours monitoring esophageal pH) and esogastroscopy. Gastroesophageal reflux treatment in asthmatic patients claims elimination of both disease risk factors, diet, proton-pump inhibitors. PMID- 22545484 TI - [Romanian national registry for interstitial lung diseases and sarcoidosis (REGIS): rationale and methods]. AB - Interstitial lung diseases (ILD) are a group of extremely heterogeneous conditions (over 200), with low prevalence, but in most cases with severe impact on the quality of life and survival of the patients. The ILD group comprises: idiopathic pulmonary fibrosis, sarcoidosis, hypersensitivity pneumonitis, colagen diseases, vasculitis, eosinophilic pneumonia etc. The prevalence of these diseases is unknown in Romania; the accurate diagnosis needs access to special investigations and expertise with this group of diseases. The authors propose the initiation of a National Registry for Interstitial Lung Diseases and Sarcoidosis (REGIS), based on the lessons learned from other national ILD) registries, which should allow building-up an extended clinical expertise in ILD, evaluating epidemiological data, creating an educational platform for young physicians, better understanding of the outcome and prognosis of these diseases, shaping Romanian Guidelines for the diagnosis and management of ILD, using the data base for clinical research. The registry is started as a pilot in two Romanian centres: "Marius Nasta" Institute of Pneumology in Bucharest and Pneumology Clinic, "Victor Babey" Infectious Diseases Hospital Timisoara. After refining the inclusion criteria for the data base, editing guidelines for ILD diagnosis and launching the registry website, other Romanian centres with interest in ILD will also be able to feed information. PMID- 22545485 TI - [Quality of sleep in students]. AB - Sleep quality is an important factor involved in students' learning process. Using different methods, actual studies suggest that complaints about sleep problems are common in young medical students. The aim of this study was to evaluate if is any relation between factors like medium and lifestyle among students of the University of Medicine and Pharmacy "Grigore T Popa" from Iasi. The study group included 30 students (2 of them were excluded) who performed a polisomnography, self reported Epworth questionnaire and two weeks sleep diary. Coffee, energy drinks, green and black tea and alcohol intake were recorded. In our evaluation it was used sleep disturbance index (SDI), for sleep quality description. In those two weeks, the mean sleep hours was 7.8 (95% CI 7.6-8), greater in female than in male. The results suggest a significant correlation between psychical excitants and sleep fragmentation. More, excessive daytime somnolence declared is not in concordance with sleep quality observed in sleep recorded with polysomnography. It looks to be in correlation with bad sleep habits and psychical excitants intake. PMID- 22545486 TI - The determinants of high school students smoking habits with special focus on teachers smoking in Iran: a population based study. AB - INTRODUCTION: Approval of smoking by friends and teachers is likely to increase the probability of smoking by the students. This study aims to determine whether adolescent smoking is associated with teachers or other students smoking, after controlling for confounders. MATERIALS & METHODS: In a cross sectional study, a representative sample of 4599 students in the third grade were selected from high schools in Tehran. A 21 item questionnaire was administered consisting of demographic and tobacco smoking habit questions. Pattern of adolescent tobacco smoking was compared between two sexes. Association between smoking behavior and perceived exposure to teachers smoking were assessed using bivariate and multivariate analyses, adjusting for parental, best friends and sibling smoking and sex. A multivariate logistic regression model was constructed and adjusted Odds Ratios were estimated. RESULTS: In total, 4591 students, aged 17 to 19 years, consisting of 2092 (45.6%) boys and 2499 (54.4%) girls, with the overall mean age of 17.53 +/- 0.59 years, were recruited. Of the students studied, 250 (12.1%) of boys and 131 (5.3%) of girls reported being current smokers (p = 0.001). The proportion of smoker and non-smoker students reporting to have been exposed to teachers smoking inside the school building was 209 (55.7%) and 1191 (29.3%), respectively (p = 0.001). Of those reporting being exposed to teachers smoking outdoors on school premises, 220 (58.7%) were smokers and 1205 (29.2%) were non-smokers (p = 0.001). After adjusting for sex, smoking habit of father, mother, brothers, sisters and best friends, adolescent perceived exposure to teachers smoking on school premises, but not inside school, was significantly associated with current smoking (OR = 2.1, 95 % CI:1. 7-2. 7). Adolescent exposure to best friend smoking was strongly associated with current smoking after adjusting for above variables (OR=6. 7, 95 % CI:5-9). CONCLUSION: Teachers smoking during school hours and best friend smoking are the two important determinants to be considered in any project aiming to establish tobacco-free schools. PMID- 22545487 TI - Sensitivity of alpha-1 antitrypsin level for inherited deficiency detection in COPD patients. AB - BACKGROUND AND OBJECTIVE: Alpha-1 antitrypsin deficiency is an underdiagnosed condition in patients with chronic obstructive pulmonary disease. Diagnosis of this genetic condition is confirmed by genetic verification of pathology, but for screening purposes quantitative methods can be useful. The aim of our study was to evaluate sensitivity and specificity of quantitative methods for alpha-1 antitrypsin deficiency detection. METHODS: Serum alpha-1 antitrypsin concentrations from patients (n = 1167) with chronic obstructive pulmonary disease, defined according to the GOLD criteria, were analysed by nephelometry, alpha-1 antitrypsin genotype was determined by means of isoelectric-focusing. RESULTS: Eight severe alpha-1 antitrypsin deficiency genotypes in homozygous type (ZZ) and 40 in heterozygous genotype (-Z) were identified. Calculated sensitivity of quantitative alpha-1 antitrypsin measurement by nephelometry for heterozygous PI*Z allele is 45% and for homozygous ZZ genotype is 88%. Specificity of quantitative alpha-1 antitrypsin deficiency determining analysis is 99%. CONCLUSIONS: A case detection program of alpha-1 antitrypsin deficiency in patients with chronic obstructive pulmonary disease using quantitative methods is specific, but due to limited sensitivity should be used only in screening programs. PMID- 22545488 TI - [Efficiency of prognostic scores for the assessment of patients with severe influenza pneumonias]. AB - AIM: To compare the efficiency of some prognostic scores in patients with severe influenza pneumonias. MATERIALS AND METHODS: The study was performed on a cohort of 75 cases of 2009 AH1N1 influenza associated pneumonias. Clinical and laboratory features at admission were used to calculate retrospectively the following prognostic scores: SCAP (Severe Community Acquired Pneumonia), CAP-PIRO (Community Acquired Pneumonia--Predisposition Infection Reaction, Organ failure), SMRT-CO (Systolic blood pressure, Multilobar infiltrates, Respiration rate, Tachycardia, Confusion, Oxygen), IDSA/ATS (Infectious Diseases Society of America/American Thoracic Society). The scores were used to assess two different outcomes--death and need for invasive mechanical ventilation (IMV). The performance of the prognostic tools were assessed using the area under receiver operating characteristic (AUC), and the sensitivity and specificity for identifying high risk patients for severe course of pneumonia. RESULTS: IMV was applied in 29 (38.7%) of studied cases, in 15 (20%) the diseases had a fatal outcome. Despite the fact that all scores had a very good discriminatory power in predicting both outcomes (AUC > 0,8), some of them have a very low sensitivity, in classes corresponding to sever pneumonias, in predicting mortality (IDSA/ATS 0%; 95% CI, 0-21.8%), as well as the need for IMV (IDSA/ATS-0%; 95% CI, 0-11.9%); SCAP-58.6% (95% CI, 38.9-76.5%); CAP-PIRO-58,6% (95% CI, 38.9-76.5%). CONCLUSIONS: The CAP-PIRO and SMRT-CO scores were found to have the best performances to predict death from influenza associated severe pneumonias and the last, also in predicting the need for IVM. Other analyzed scores underestimate the risk of occurrence of both assessed outcomes. PMID- 22545490 TI - [Smoking in movies -- a new way of promotion]. AB - Smoking in movies is a neglected aspect, even in Romania. The tobacco industry find out earlier what could be the impact of smoking on the initiation on smoking in teenagers. Later, we had reactions. In this article I am reviewing, from a epidemiological point of view, the effect of smoking in movies and I am analyzing the modalities of fighting and the actions for winning, also for teenagers, this battle in tobacco control. PMID- 22545491 TI - [The diverse areas of dermatology]. PMID- 22545489 TI - [Videomediastinoscopic transcervical approach of postpneumonectomy left main bronchial fistula]. AB - Bronchopleural fistulas and empyema are the most devastating complications after lung resection. The optimal management remains a major subject of controversy for thoracic surgeons over the wide variety of therapeutic approaches, none suitable for all patients. In 1996 Azorin et al. reported the first successful mediastinoscopic reclosure by stapling of an insufficient bronchial stump after left pneumonectomy using video-assisted mediastinoscopy. The authors report the first national case of left-sided bronchopleural fistula closure using video assisted mediastinoscopy, describing their experience with this technique. A 40 years old woman presented to our unit with left thorax empyema after having undergone left pneumonectomy for TB destructed lung with aspergillosis in another hospital. Bronchoscopy revealed a 15 mm long bronchial stump with insufficiency. Despite all advances made over the last decades in perioperative management, bronchopleural fistula after pneumonectomy remains a significant problem in thoracic surgery. Video-mediastinoscopy is an alternative to the open methods as it allows approaching the bronchial stump via the mediastinum. The dissection of the trachea through its natural route enables bronchial mobilization. Positive factors influencing our decision were the virgin mediastinum with no surgical dissection and no radiation therapy applied. The mediastinoscopic approach for bronchial stump closure after pneumonectomy is a novel option in highly selected patients. This is our choice for a long (at least 10 mm) bronchial stump because its morbidity is minimal compared with transpericardial sternotomy or a transthoracic approach. It warrants minimal surgical trauma; however, skilled surgeons with experience in mediastinoscopy have to be prepared to convert to an open technique immediately. PMID- 22545492 TI - [Scabies in 2012]. AB - Scabies is a parasitic infection known all over the world and particularly in a low socioeconomic context and in institutions. The transmission is mainly direct from skin-to-skin. An increase of cases has been observed in Geneva since October 2011. To confirm the diagnosis, a precise clinical and microbiological examination is required and highly recommended before starting a treatment. Scabies management includes treatment of the patient and his close contacts with antiparasitic drugs as well as thorough cleaning of clothes and bed linen. When available, oral ivermectine is the treatment of choice, topical permethrine is prescribed when ivermectine cannot be used or in association with it in severe presentations. In Switzerland, ivermectine is not readily available, it is expensive and not reimbursed by insurances. PMID- 22545493 TI - [Management of lice infestations, recommendations for 2012]. AB - Pediculosis is the most frequent and contagious ectoparasitic infestation in human, particularly in children from 3 to 8 years of age. Epidemics are observed from time to time, in schools or in adults in prisons. Even though benign, these infections remain unpleasant and can have an important psyco-social impact. Since a few years, caregivers have to face increasing problems while treating lice: appearance of insecticide resistances, lindane's withdrawal from the market and the marketing of new products which are not always well evaluated. This article offers first recalls about pediculoses and then a sum up of the different available treatments with an evidence based management strategy. PMID- 22545494 TI - [Chronic hand eczema, conventional and new treatments]. AB - Chronic hand eczema is a frequent cause of consultation. In Europe and Switzerland, it's one of the main reasons for patients to interrupt their profession. The etiology is pluri-factorial. Atopic patients are more likely predisposed. Pruritus, associated to pain and bleeding, is intense. Psychosocial consequences are huge, making this illness to an important public health problem. Topical treatment and UV-light are the main therapeutical strategy but the results are often disappointing. Recently, alitretinoine (9-cis retinoic acid) became the treatment of second choice with good response, allowing patients to preserve a good quality of life and their job. PMID- 22545495 TI - [Risk of cutaneous squamous cell carcinomas: the role of clinical and pathological reports]. AB - The history of most cutaneous squamous cell carcinomas (CSCC) is limited to the skin. However, about 4% of these malignancies are at risk of metastasis and can be life-threatening. This risk is determined by clinical and histological elements which are individually recognized, but so far staging systems allow us neither to assess a risk score, nor to adopt a standardized therapeutical approach. This article reviews prognostic factors for CSCC, and underlines the need for the clinician to have all clinical and histological elements available, in order to try to define the best therapeutical strategy for each case, following up-to-date recommendations. PMID- 22545496 TI - [Injectable soft tissue fillers: are they medical devices or drugs? Implications for HIV lipodystrophy]. AB - Physical modifications associated to lipodystrophy syndrome in HIV+ patients remain a challenge for management, even in a well controlled chronic infection. Indications, evaluation and filling treatments of facial lipoatrophy are described. Many exogenous filling products are on the market and their use and tolerance profile better known. These medical devices should be closely followed in patients with chronic HIV infection. PMID- 22545497 TI - [Autoinflammatory syndromes in dermatology]. AB - Hereditary periodic fever syndromes, also called autoinflammatory syndromes, are characterized by relapsing fever and additional manifestations such as skin rashes, mucosal manifestations, or arthralgias. Some of these disorders present without fever but with the associated systemic manifestations. The responsible mutated genes have been identified for most of these disorders, which lead to the induction of the uncontrolled and excessive production of interleukin-1beta (IL 1beta). The inhibition of IL-1beta through IL-1 receptor antagonist or monoclonal antibody against IL-1beta is used with success in most of these diseases. In case of TNF-receptor associated periodic syndrome (TRAPS) and paediatric granulomatous arthritis (PGA), TNF-antagonists may also be used; in familial Mediterranean fever (FMF) colchicine remains the first choice. PMID- 22545498 TI - [The impact of childhood caries]. AB - The early childhood caries affect primary dentition before the eruption of the permanent teeth. It is set to extended use of a bottle containing fermentable carbohydrates. The early childhood caries is not only a dental disease: it is a social, cultural and behavioral condition that reflects the practices and beliefs around the child. Swiss data indicate that in aged 2 children, one of for could be affected by this devastating oral disease, mainly in vulnerable populations. The primary care physician has an important role in the screening of preschool children, in determining the risk level of the child for early childhood caries. Physicians can advise families, especially pregnant women, about preventive measures and behavior, leading to a dramatic drop of early childhood caries prevalence. PMID- 22545499 TI - [The changing fertility rate of Maghreb]. PMID- 22545500 TI - [Interprofessional collaboration]. PMID- 22545501 TI - [Autism and antibiotics: the Montagnier question]. PMID- 22545502 TI - [Hypersensitivity to mobile phone emitted electromagnetic radiation]. PMID- 22545503 TI - [The system of medicine is struck with burnout]. PMID- 22545504 TI - [Generation Stonewall]. PMID- 22545505 TI - [Homosexuality in the elderly. "...I also need a shelter for the soul"]. PMID- 22545506 TI - [Mister Gay Switzerland. Education is still important! (interview by Martina Camenzind)]. PMID- 22545507 TI - [Kinesthesia in palliative care. Better quality of life at the end of life]. PMID- 22545508 TI - [Peak days in the pediatric clinic. Conquering the "winter avalanche"]. PMID- 22545509 TI - [Integration of nursing services. Making nursing visible in DRG]. PMID- 22545510 TI - [Leading a nursing team. Leadership - a magnetic force]. PMID- 22545511 TI - [Sierra Leone. Risen from ruins]. PMID- 22545512 TI - ["Should", "must" or "want to"]. PMID- 22545513 TI - [Dunja Nicca. My research results translate directly into general practice]. PMID- 22545514 TI - [The love planet]. PMID- 22545515 TI - [Education in alternative approaches. A plus for the nursing practice]. PMID- 22545516 TI - [Collaboration between a home nursing service and a hospital nursing service. "Connected": in pediatric nursing]. PMID- 22545517 TI - [Inauguration of the Center of Clinical Practice. What happened to you, Mister Jean-Paul?]. PMID- 22545518 TI - [Refusal to eat. A stress situation for nurses]. PMID- 22545519 TI - [Relaxation therapy. Toward a better understanding of oneself]. PMID- 22545520 TI - [Resident rainbow]. PMID- 22545521 TI - ["Bottled life". The water business]. PMID- 22545522 TI - Response of white leghorn chickens to infection with avian leukosis virus subgroup J and infectious bursal disease virus. AB - The effects of viral-induced immunosuppression on the infectious status (viremia and antibody) and shedding of avian leukosis virus (ALV) were studied. Experimental white leghorn chickens were inoculated with ALV subgroup J (ALV-J) and infectious bursal disease virus (IBDV) at day of hatch with the ALV-J ADOL prototype strain Hcl, the Lukert strain of IBDV, or both. Appropriate groups were exposed a second time with the Lukert strain at 2 wk of age. Serum samples were collected at 2 and 4 wk of age for IBDV antibody detection. Samples for ALV-J viremia, antibody detection, and cloacal shedding were collected at 4, 10, 18, and 30 wk of age. The experiment was terminated at 30 wk of age, and birds were necropsied and examined grossly for tumor development. Neoplasias detected included hemangiomas, bile duct carcinoma, and anaplastic sarcoma of the nerve. Control birds and IBDV-infected birds were negative for ALV-J-induced viremia, antibodies, and cloacal shedding throughout experiment. By 10 wk, ALV-J-infected groups began to develop antibodies to ALV-J. However, at 18 wk the incidence of virus isolation increased in both groups, with a simultaneous decrease in antibody levels. At 30 wk, 97% of birds in the ALV-J group were virus positive and 41% were antibody positive. In the ALV-J/IDBV group, 96% of the birds were virus positive at 30 wk, and 27% had antibodies to ALV-J. In this study, infection with a mild classic strain of IBDV did not influence ALV-J infection or antibody production. PMID- 22545523 TI - Natural infection and transmission of a retrovirus closely related to myeloblastosis-associated virus type 1 in egg-type chickens. AB - Myeloblastosis-associated virus type 1 (MAV-1) is an exogenous avian retrovirus with oncogenic potential. MAV-1 was detected in young chicks hatching from eggs produced by an experimental genetic line of egg-type chickens. Transmissibility of MAV-1 had not been documented previously. This investigation was intended to partially characterize the virus involved and to study its transmissibility and oncogenicity in naturally and contact-infected chickens. Commercially produced white and brown layer pullets free of exogenous avian leukosis viruses were commingled at hatch with naturally MAV-1-infected chickens. The original MAV-1 infected chickens were discarded after approximately 8 wk, and the contact exposed chickens were maintained in isolation for 36 wk. Young specific-pathogen free (SPF) single comb white leghorn chickens were added to the group to study possible horizontal transmission of MAV-1 in young chickens. Upon weekly virus isolation attempts, MAV-1 was readily isolated from the contact-exposed white layers but not from the brown layers between 36 and 53 wk of age (18 wk in total). Three-week-old SPF chickens were readily infected with MAV-1 by contact as early as 1 wk postexposure. Throughout 22 hatches derived from the white and brown MAV-1-contact-exposed layers (between 36 and 53 wk of age), MAV-1 was frequently detected in the white layer progeny, whereas the virus was seldom isolated from the progeny produced by the brown layers during the same 18-wk period. MAV-1 induced a persistent infection in some of the SPF chickens that were exposed by contact at 3 wk of age. Gross tumors were not detected in any of the originally infected experimental chickens at 8 wk of age, in the contact exposed brown or white layers at the termination of the study at 53 wks of age, or in the contact-exposed SPF chickens at the end of the study at 12 wk of age. Exogenous avian leukosis-related viruses may still be detected in egg-type chickens, emphasizing the importance of thorough screening before incorporation of experimental genetic material into commercial genetic lines of egg-type chickens. PMID- 22545524 TI - Genetic diversity of avian infectious bronchitis coronavirus in recent years in China. AB - Fifty-six isolates of avian infectious bronchitis virus (IBV) were obtained from different field outbreaks in China in 2010, and they were genotyped by comparison with 19 reference strains in the present study. The results showed that LX4-type isolates are still the predominant IBVs circulating in chicken flocks in China, and these isolates could be grouped further into two clusters. Viruses in each cluster had favored amino acid residues at different positions in the S1 subunit of the spike protein. In addition, a recombination event was observed to have occurred between LX4- and tl/CH/LDT3/03I-type strains, which contributed to the emergence of a new strain. The most important finding of the study is the isolation and identification of Taiwan II-type (TW II-type) strains of IBV in mainland China in recent years. The genome of TW II-type IBV strains isolated in mainland China has experienced mutations and deletions, as demonstrated by comparison of the entire genome sequence with those of IBV strains isolated in Taiwan. Pathogenicity testing and sequence analysis of the 3' terminal untranslated region revealed that TW II-type IBV strains isolated in mainland China have a close relationship with the embryo-passaged, attenuated TW2296/95. PMID- 22545525 TI - Comparison of the prevalence of Salmonella infection in layer hens from commercial layer farms with high and low rodent densities. AB - A comparison on the prevalence of Salmonella infection in layer hens from commercial layer farms with high and low rodent densities was investigated. Out of 280 laying hens sampled from three commercial layer farms with high rodent densities, Salmonella enterica subsp. enterica serovar Enteritidis (Salmonella Enteritidis) was isolated from 20 (7.14%) hens and Salmonella enterica subsp. enterica serovar Infantis (Salmonella Infantis) from three (1.07%) hens. In contrast, layer hens sampled from four commercial layer farms with low rodent densities were negative for any salmonellae. Significant differences (P < 0.05) in the isolation rates of Salmonella from various organs of infected layer hens were also noted. For Salmonella Enteritidis, liver (55.0%) and the oviduct (55.0%) had the highest isolation rates while all Salmonella Infantis isolates were from the oviduct. Pulsed field gel electrophoresis (PFGE) analysis of BlnI digested chromosomal DNA of Salmonella Enteritidis isolated from layer hens and rodents showed similar patterns. PFGE analysis of Salmonella Infantis isolated from layer hens, rodents, eggs, and the environment yielded identical patterns. In this study, the significantly higher prevalence rate (P < 0.05) of Salmonella Enteritidis and Salmonella Infantis in layer hens from high rodent density farms could be attributed to the high rodent population density. The persistent Salmonella Enteritidis and Salmonella Infantis infection inside layer houses may have been amplified by the increasing numbers in the rodent population over the years, which increased the opportunity for environment-rodent-chicken interaction and the transmission of salmonellae to chickens. Monitoring of salmonellae from rodents inside poultry premises is recommended to be an effective additional tool in the assessment of the Salmonella status of layer flocks. PMID- 22545526 TI - Molecular characteristics and pathogenicity of an avian leukosis virus isolated from avian neurofibrosarcoma. AB - Peripheral nerve sheath tumors (PNSTs) are rare in chickens and their etiology remains to be elucidated. In this study, a naturally occurring PNST in a Japanese native fowl (Gallus gallus domesticus) was pathologically examined and the strain of avian leukosis virus (ALV) isolated from the neoplasm was characterized by molecular biological analysis. The fowl presented with a firm subcutaneous mass in the neck. The mass, connected to the adjacent spinal cord (C9-14), was microscopically composed of highly cellular tissue of spindle cells arranged in interlacing bundles, streams, and palisading patterns with Verocay bodies and less cellular tissue with abundant collagen. Immunohistochemically, neoplastic cells were divided into two types: perineurial cells positive for vimentin, glucose transporter 1 (GLUT1), and claudin1; and Schwann cells positive for vimentin, occasionally positive for S-100 alpha/beta but negative for GLUT1. Based on these findings, a diagnosis of neurofibrosarcoma was made. The complete nucleotide sequence of an ALV strain, CTS_5371, isolated from the neoplasm was determined and phylogenetic analysis indicated that the strain was a novel recombinant virus from avian leukosis/sarcoma viruses previously reported. Additionally, experimental infection revealed that CTS_5371 induced the proliferation of Schwann cells and perineurial cells. These results suggest that this ALV strain has the ability to induce PNSTs in chickens. PMID- 22545527 TI - Evaluation of Mycoplasma gallisepticum K-strain as a live vaccine in chickens. AB - We evaluated the pathogenicity of three live Mycoplasma gallisepticum (MG) vaccine candidates by infection via aerosol of 3-wk-old chickens with log phase broth cultures (trial 1). Two of the candidates (K3020 and K4649A) colonized only 10% and 20% of the chickens, respectively, unlike K2101 (K-strain), which was reisolated from all of the vaccinated chickens tested. K-strain inoculation did not result in significant air sac or tracheal lesions in chickens at 10 and 39 days postinfection (P < or = 0.05). The efficacy of K-strain as a live vaccine was evaluated in trial 2, by challenge of vaccinated chickens with virulent R strain via aerosol at 6 wk postvaccination. K-strain vaccination resulted in significant protection from air sac and tracheal lesions (P < or = 0.05). The K strain was further investigated to evaluate transmissibility (trial 3), colonization and persistence of infection following aerosol administration (trial 4), genetic and phenotypic stability following back passage through chickens (trial 5), and vertical transmission (trial 6). The K-strain had a low rate of horizontal transmission; it remained primarily in the respiratory system of inoculated birds and persisted in the upper respiratory tract for the duration of the trial 4 (5 mo). There was no increase in virulence of K-strain when it was back passaged five times through chickens, and no vertical transmission of K strain was detected. K-strain showed great potential as a safe and effective live MG vaccine. PMID- 22545528 TI - An investigation on first-week mortality in layers. AB - The quality of day-old chick placement and management upon arrival have a major impact on first-week mortality (FWM) and subsequent welfare in layers. The present study investigated FWM and causes of FWM in 50 flocks of layers. Post mortem results from 983 chickens showed that 50% died from infections, whereas noninfectious causes, in particular dehydration and nephropathy with visceral gout, made up the remaining causes of mortality. Escherichia coli and Enterococcus faecalis were identified as the most significant bacterial pathogens associated with FWM. Statistical analysis demonstrated a significant correlation between FWM and total mortality during rearing, and a model predicting total mortality in the rearing period based on FWM was established. A statistically significant correlation between FWM and uniformity of the flock was not demonstrated at 1-2 wk of age or at approximately 15 wk of age. Genetic characterization of E. coli and E. faecalis provided evidence for a polyclonal nature of these infections in affected flocks, indicating different sources of infection. Results obtained underline the importance of minimizing FWM to a level less than 1%. PMID- 22545529 TI - Classification of Cryptococcus neoformans and yeast-like fungus isolates from pigeon droppings by colony phenotyping and ITS genotyping and their seasonal variations in Korea. AB - Cryptococcus neoformans (C neoformans) is a frequent cause of invasive fungal disease in immunocompromised human hosts. Ninety-eight samples of pigeon droppings were collected from the pigeon shelters in Seoul, and cultured on birdseed agar (BSA) and Sabouraud dextrose agar (SDA). One hundred yeast-like colonies were selected and identified via phenotype characteristics, such as colony morphology and biochemical characteristics. This was then followed with genotyping via sequencing of the internal transcribed spacer (ITS) region. The colonies were classified into four kinds of colony color types: brown type (BrT), beige type (BeT), pink type (PT), and white type (WT). Numbers of isolated BrT, BeT, PT, and WT colonies were 22 (22%), 30 (30%), 19 (19%), and 39 (39%), respectively. All BrT colonies were identified as C neoformans. BeT were identified as 19 isolates of Cryptococcus laurentii, 10 isolates of Malassezia furfur, and 1 isolate of Cryptococcus uniguttulatus. PT was divided into two colony color types: light-PT (l-PT) and deep-PT (d-PT). Eighteen of l-PT and one of d-PT were identified as Rhodotorula glutinis and Rhodotorula mucilaginosa, respectively. WT were identified as 34 isolates of Cryptococcus guilliermondii, 3 isolates of Cryptococcus zeylanoides, 1 isolate of Cryptococcus sake, and 1 isolate of Stephanoascus ciferrii. Most strains were classified identically with the use of either phenotype or genotyping techniques, but C uniguttulatus and C sake classified by phenotyping were Pseudozyma aphidis and Cryptococcus famata by genotyping. This rapid screening technique of pathogenic yeast-like fungi by only colony characteristics is also expected to be very useful for primary yeast screening. Additionally, we investigated the seasonal variations of C neoformans and other yeast-like fungi from 379 pigeon-dropping samples that were collected from February 2011 to March 2011. We isolated 685 yeast-like fungi from the samples. Almost all C neoformans and yeast-like fungi were isolated in the fall (298 strains, 43.5%) and spring (244 strains, 35.6%). A few yeast-like fungi were isolated in winter (98 strains, 14.3%) and summer (45 strains, 6%). These results would be used as an important indicator related to epidemiology and prevention of pathogenic yeast-like fungi infections transmitted through pigeon droppings. PMID- 22545530 TI - Development of an enzyme-linked immunosorbent assay for the measurement of antibodies against infectious coryza vaccine. AB - Infectious coryza is an acute respiratory disease caused by infection with Avibacterium (Haemophilus) paragallinarum. It is characterized by nasal discharge and facial swelling and is associated with growth retardation and a reduction in egg production. Hemagglutination inhibition (HI) tests are used to estimate vaccine-induced immunity against infectious coryza in vitro; however, these procedures are complicated and their sensitivity is insufficient. To address these problems, an enzyme-linked immunosorbent assay (ELISA) technique using serovar-specific regions of HMTp210 (210 kDa), an outer-membrane protein of A. paragallinarum, was developed to measure the antibodies against infectious coryza. Chickens with an ELISA titer of 0.3 or more did not exhibit clinical signs of infectious coryza against challenge with A. paragallinarum, although their HI antibody titers were negative. On the other hand, chickens with an ELISA titer below 0.3 exhibited clinical signs of the disease with one exception. Antibody prevalence rates on ELISA were 80% and 60% against infection with serovars A and C, respectively, and ELISA also detected antibodies in chickens infected with A. paragallinarum with a sensitivity higher than that of HI tests. Taken together, the ELISA technique developed in this study is a valuable tool for the measurement of antibodies produced against the infectious coryza vaccine or in response to an infection with A. paragallinarum. PMID- 22545531 TI - Pathotypic and molecular characterization of a fowl adenovirus associated with inclusion body hepatitis in Saskatchewan chickens. AB - Inclusion body hepatitis (IBH) is one of the major global disease problems, causing significant economic losses to poultry industry of the United States and Canada. The disease is characterized by its sudden onset and high mortalities. Amongst different serotypes of fowl adenoviruses (FAdVs) associated with IBH, serotype 8 of group I FAdV has been isolated from majority of IBH cases. In present studies, we isolated a FAdV from morbid liver of a 17-day-old broiler from a Saskatchewan broiler farm. This newly isolated virus was designated as IBHV(SK). However, based on the sequence analysis of the L1 region of the hexon gene, the IBHV(SK) may be classified as FAdV 8b strain 764. These studies describe for the first time the complete hexon gene sequence of FAdV serotype 8b. Experimental infection of 2-day-old (n = 48) and 2-wk-old (n = 56) chicks caused 83% and 43% mortalities, respectively. Determination of the complete hexon gene sequence of IBHV(SK) with establishment of a disease model in chickens will facilitate the development of type-specific diagnostic reagents and assays for the evaluation of potential experimental vaccines against pathogenic FAdV infections. PMID- 22545532 TI - Characterization of infectious bursal disease viruses isolated in 2007 from Delmarva commercial broiler chickens. AB - A study was performed in 2007 to isolate and characterize infectious bursal disease viruses (IBDVs) in commercial broilers grown in the Delmarva (DMV) Peninsula region of the United States. Bursae of Fabricius were collected weekly from 1 to 4 wk of age from broilers on 10 farms with a history of poor performance. Microscopic pathology was used to determine the infectious bursal disease (IBD) status of the broilers. Bursae from 1- and 2-wk-old broilers did not show IBD microscopic lesions. Moreover, broilers on 1 of the 10 farms were IBD lesion free at 3 and 4 wk of age. However, 3 of 9 and 9 of 9 farms yielded broilers with IBD-affected bursae from 3- and 4-wk-old commercial broilers, respectively. Ten IBDV isolates were recovered from 3 of 3 lesion-positive bursal pools at 3 wk of age and 7 of 9 lesion-positive bursal pools at 4 wk of age. Analysis of the viral protein (VP) 2 genes identified all isolates as serotype 1 Delaware (Del) variant viruses. Five field isolates, each representing different molecular clades of the Delaware variant viruses, were selected for further study. Experimental infection of specific-pathogen-free white leghorn chickens with isolates DMV/4813/07, DMV/4947/07, DMV/4955/07, DMV/5038/07, and DMV/5041/07 produced gross and microscopic pathology of the bursa consistent with Delaware variant infection. Monoclonal antibody testing showed DMV/4813/07, DMV/4947/07, DMV/ 4955/07, and DMV/5041/07 to be similar to previous recognized variant viruses. However, DMV/5038/07 was found to be unreactive with the monoclonal antibodies that typically recognize reference strains STC, Del E, GLS, RS593, and AL2. In a challenge of immunity study, 10-day-old progeny from breeders immunized with a commercially available inactivated IBDV vaccine containing the Del E and classic strains were protected to a lesser degree against isolate DMV/5038/07 compared to Del E challenge based on microscopic lesion scores (P < 0.01) of the bursa. This result suggests the virus is antigenically different from the Del E strain contained in the vaccine. Collectively, the monoclonal antibody and progeny challenge of immunity findings suggest DMV/5038/07 is antigenically different from the Del E strain contained in the vaccine. PMID- 22545533 TI - Detection of avian influenza viruses and differentiation of H5, H7, N1, and N2 subtypes using a multiplex microsphere assay. AB - In an outbreak of highly pathogenic H5 and H7 avian influenza, rapid analysis of a large number of clinical samples with the potential to rapidly identify the virus subtype is extremely important. Herein, we report on the development of a rapid multiplex microsphere assay for the simultaneous detection of all avian influenza viruses (AIV) as well as the differentiation of H5, H7, N1, and N2 subtypes. A reverse transcriptase-PCR (RT-PCR) reaction, followed by hybridization of the amplified product with specific oligonucleotide probe-coated microspheres, was conducted in a multiplex format. Following incubation with a reporter dye, the fluorescence intensity was measured using a suspension array system. The limit of detection of the probe-coupled microspheres ranged from 1 x 10(5) to 1 x 10(9) copies of RT-PCR amplified product and the sensitivity of the multiplex assay ranged from 1 x 10(2.5) to 1 x 10(3.2) 50% embryo infectious doses of virus. The diagnostic accuracy of the assay, compared to the standard real-time RT-PCR, was evaluated using 102 swab samples from chickens exposed to low pathogenic AIV, and 97.05% of samples gave identical results with both the assays. The calculated specificity of the assay was 97.43%. Although the assay still needs to be validated, it appears to be a suitable diagnostic tool for detection and differentiation of avian influenza virus H5, H7, N1, and N2 subtypes. PMID- 22545534 TI - Effects of novel vaccine/adjuvant complexes on the protective immunity against Eimeria acervulina and transcriptome profiles. AB - SUMMARY. This study investigated the ability of two novel adjuvant formulations, QCDC (Quil A/cholesterol/DDA/ Carbopol) and QCDCR (QCDC/Bay R1005), in combination with a recombinant profilin vaccine, to modulate host protective immunity and to alter gene expression during experimental avian coccidiosis. Vaccination with profilin plus QCDCR significantly reduced the severity of intestinal lesions and increased mitogen-induced lymphocyte proliferation in infected chickens compared with immunization with profilin alone or profilin plus QCDC. Immunization with profilin plus QCDC or profilin plus QCDCR increased body weight gain but had no effect on fecal oocyst shedding of chickens infected with Eimeria acervulina compared with birds vaccinated with profilin alone. The results of global gene expression analysis revealed that, compared with PBS controls, (a) chickens vaccinated with profilin alone had 71 up-regulated and 56 down-regulated mRNA transcripts, (b) chickens immunized with profilin plus QCDC had 198 up-regulated and 247 down-regulated mRNAs, and (c) birds immunized with profilin plus QCDCR had 210 up-regulated and 267 down-regulated mRNAs. Compared with birds vaccinated with profilin alone, (a) chickens given profilin plus QCDC had 60 up-regulated and 104 down-regulated transcripts and (b) chickens immunized with profilin plus QCDCR had 103 up-regulated and 130 down-regulated mRNAs. Finally, chickens vaccinated with profilin plus QCDCR had 193 up-regulated and 204 down-regulated transcripts compared with birds given profilin plus QCDC. Biological function and network analysis revealed that the majority of altered transcripts were encoded by immune-related genes. PMID- 22545535 TI - Mitochondrial inclusion bodies (intracytoplasmic acidophilic droplets) in neurons of chicken spinal cords increase with age. AB - We studied the pathologic features of neurons that contain intracytoplasmic acidophilic droplets (IADs) in chicken spinal cords. The IADs were lustrous spheroid bodies scattered in the cytoplasm of neurons, variable in size, and protein-rich bodies stained eosinophilic with hematoxylin-eosin, acidophilic with Azan, blue indigo with phosphotungstic acid hematoxylin, and yellow-green with Elastica van Gieson stain histopathologically. Ultrastructurally, almost all IADs were observed as homogeneous highly electron-dense spheroid bodies enclosed by double-limited membranes. Small IADs were observed in mitochondria. Anatomically, IAD-CNs were observed only in the ventral horn of the spinal cord between the fourth sacral and third lumbal vertebrae, and they were particularly frequent in the third sacral vertebrae. Their appearance and accumulative amount were likely to increase with age, while the clinical and pathologic significances of IAD-CNs remain unclear. PMID- 22545536 TI - The effect of swab sample choice on the detection of avian influenza in apparently healthy wild ducks. AB - Historically, avian influenza viruses have been isolated from cloacal swab specimens, but recent data suggest that the highly pathogenic avian influenza (HPAI) H5N1 virus can be better detected from respiratory tract specimens. To better understand how swab sample type affects the detection ability of low pathogenic avian influenza (LPAI) viruses we collected and tested four swab types: oropharyngeal swabs (OS), cloacal swabs (CS), the two swab types combined in the laboratory (LCS), and the two swab types combined in the field (FCS). A total of 1968 wild waterfowl were sampled by each of these four methods and tested for avian influenza virus using matrix gene reverse-transcription (RT) PCR. The highest detection rate occurred with the FCS (4.3%) followed by the CS (4.0%). Although this difference did not achieve traditional statistical significance, Bayesian analysis indicated that FCS was superior to CS with an 82% probability. The detection rates for both the LCS (2.4%) and the OS (0.4%) were significantly different from the FCS. In addition, every swab type that was matrix RT-PCR positive was also tested for recovery of viable influenza virus. This protocol reduced the detection rate, but the ordering of swab types remained the same: 1.73% FCS, 1.42% CS, 0.81% LCS, and 0% OS. Our data suggest that the FCS performed at least as well as any other swab type for detecting LPAI viruses in the wild ducks tested. When considering recent studies showing that HPAI H5N1 can be better detected in the respiratory tract, the FCS is the most appropriate sample to collect for HPAI H5N1 surveillance while not compromising LPAI studies. PMID- 22545537 TI - Comparative effects of fumonisins on sphingolipid metabolism and toxicity in ducks and turkeys. AB - Fumonisins (FBs) are mycotoxins that are found worldwide in maize and maize products. Their main toxic effects have been well characterized in poultry, but differences between species have been demonstrated. Ducks appeared very sensitive to toxicity, whereas turkeys are more resistant. At the same time, alterations of sphingolipid metabolism, with an increase of the concentration of the free sphinganine (Sa) in serum and liver, have been demonstrated in the two species, but the link between the toxicity of FBs and Sa accumulation remains difficult to interpret. The aim of the present work was to compare the effects of FBs (10 mg FB1 + FB2/kg body weight) on sphingolipid metabolism in ducks and turkeys. Growth, feed consumption, and serum biochemistry were also investigated to evaluate toxicity. The main results showed that FBs increased Sa concentrations in liver and serum in ducks and turkeys, but these accumulations were not directly correlated with toxicity. Sa accumulation was higher in the livers of turkeys than in ducks, whereas Sa levels were higher in the sera of ducks than in turkeys. Hepatic toxicity was more pronounced in ducks than in turkeys and accompanied a decrease of body weight and an increase of serum biochemistry in ducks but not in turkeys. So, although FBs increase Sa concentration in the livers of both species, this effect is not directly proportional to toxicity. The mechanisms of FB toxicity and/or the mechanisms of protection of ducks and turkeys to the Sa accumulation within the liver remain to be established. PMID- 22545538 TI - Characterization of Newcastle disease viruses isolated from cormorant and gull species in the United States in 2010. AB - Newcastle disease virus (NDV), a member of the genus Avulavirus of the family Paramyxoviridae, is the causative agent of Newcastle disease (ND), a highly contagious disease that affects many species of birds and which frequently causes significant economic losses to the poultry industry worldwide. Virulent NDV (vNDV) is exotic in poultry in the United States; however, the virus has been frequently associated with outbreaks of ND in cormorants, which poses a significant threat to poultry species. Here, we present the characterization of 13 NDV isolates obtained from outbreaks of ND affecting cormorants and gulls in the states of Minnesota, Massachusetts, Maine, New Hampshire, and Maryland in 2010. All 2010 isolates are closely related to the viruses that caused the ND outbreaks in Minnesota in 2008, following the new evolutionary trend observed in cormorant NDV isolates since 2005. Similar to the results obtained with the 2008 isolates, the standard United States Department of Agriculture F-gene real-time reverse-transcription PCR (RRT-PCR) assay failed to detect the 2010 cormorant viruses, whereas all viruses were detected by a cormorant-specific F-gene RRT-PCR assay. Notably, NDV-positive gulls were captured on the eastern shore of Maryland, which represents a significant geographic expansion of the virus since its emergence in North America. This is the first report of vNDV originating from cormorants isolated from wild birds in Maryland and, notably, the first time that genotype V vNDV has been isolated from multiple wild bird species in the United States. These findings highlight the need for constant epidemiologic surveillance for NDV in wild bird populations and for consistent biosecurity measures to prevent the introduction of the agent into domestic poultry flocks. PMID- 22545539 TI - Identification of genes responsible for biofilm formation or virulence in Salmonella enterica serovar pullorum. AB - Salmonella living in biofilms are more resistant to chemical and physical stresses. However, information regarding the regulation of genes involved in biofilm formation for Salmonella enterica serovar Pullorum remains limited. In this study, eight mutants with knockout of genes ompR, rpoS, rfaG, rfbH, rhlE, metE, spiA, or steB from the Salmonella enterica serovar Pullorum strain S6702 were constructed. Phenotypic analysis revealed that all mutants were similar to the wild-type strain in growth rate. Only the ompR mutant showed a complete loss of production ofcurli and biofilm formation. The other mutants showed a modified production of curli and cellulose with less effect related to biofilm formation. The results of animal experiments indicated that the deletion of genes ompR, spiA, rfaG, or metE in wild-type strains contributed to attenuation of virulence in 1-day-old chickens. This study may bring new insights into novel vaccines or therapeutic interventions against Salmonella enterica serovar Pullorum infections. PMID- 22545540 TI - Characterization of encephalitis in wild birds naturally infected by highly pathogenic avian influenza H5N1. AB - During the outbreak of highly pathogenic avian influenza (HPAI) H5N1 in Sweden in 2006, disease and mortality were observed in a number of wild bird species. Encephalitis was one of the most consistent and severe findings in birds submitted for postmortem examination. However, the distribution and severity of the inflammation varied among individuals. This study characterized the encephalitis and the phenotype of the cellular infiltrate in brains of 40 birds of various species naturally infected with HPAI H5N1. Brain sections stained with hematoxylin and eosin and immunostained for influenza A viral antigen were evaluated in parallel to brain sections immunostained with antibodies against T lymphocytes (CD3+), B lymphocytes (CD79a+), macrophages (Lectin RCA-1+), and astrocytes expressing glial fibrillary acidic protein. The virus showed marked neurotropism, and the neuropathology included multifocal to diffuse areas of gliosis and inflammation in the gray matter, neuronal degeneration, neuronophagia, vacuolation of the neuropil, focal necrosis, perivascular cuffing, and meningitis. Broad ranges in severity, neuroanatomical distribution, and type of cellular infiltrate were observed among the different bird species. Since neurotropism is a key feature of HPAI H5N1 infection in birds and other species and because the clinical presentation can vary, the characterization of the inflammation in the brain is important in understanding the pathogenesis of the disease and also has important diagnostic implications for sample selection. PMID- 22545541 TI - Follow-up investigations on different courses of natural avian bornavirus infections in psittacines. AB - To study the course of natural avian bornavirus (ABV) infection, 63 psittacines of three bird collections where ABV had been demonstrated were investigated over a period of 1 yr. The psittacines were clinically observed and swabs of crop and cloaca as well as serum samples were collected three separate times at intervals of 2-6 mo. According to the results of detection of ABV RNA by reverse transcriptase polymerase chain reaction (RT-PCR) and of anti-ABV antibodies by indirect immunofluorescence assay (IIFA), 43 of the birds were found to be infected with ABV. Based on variations in virus shedding and antibody production in combination with the occurrence of proventricular dilatation disease (PDD) related clinical signs, pathological findings, and lethal outcome, four different groups of infected psittacines and a fifth group of noninfected psittacines were identified. Group 1 comprised six birds with various courses of ABV infection and forms of clinical PDD. Groups 2-4 included all birds with subclinical ABV infections: Group 2 contained 13 birds that were consistently (subgroup A, 6 birds) or inconsistently (subgroup B, 7 birds) ABV positive by PCR and serology; group 3 was composed of 13 psittacines exhibiting only anti-ABV antibodies; and 8 birds that had positive ABV RNA detection in crop and cloaca, but did not develop anti-ABV specific antibodies, were classified in group 4. Twenty-three out of the 63 psittacines remained free of detectable ABV RNA or anti-ABV antibodies over the whole observation period (group 5). Based on the results, it seems that birds with high ABV RNA load in crop and cloaca combined with high anti-ABV antibodies have a high risk of the development of PDD, indicating that the humoral antibodies do not protect against the disease. The meaning of the detection of ABV RNA and antibodies at a low and inconsistent level for the single bird as well as for the epidemiology of the ABV infection remained unclear in this field study and needs to be further investigated. PMID- 22545542 TI - Serologic testing for aspergillosis in commercial broiler chickens and turkeys. AB - Sera samples from commercial broiler chickens and turkeys diagnosed with respiratory and disseminated aspergillosis were tested for the presence of antigen and antibody to Aspergillus. Antigen detection consisted of testing for two cell-wall components, beta-glucan and galactomannan, which have been used extensively in human medicine. There were significantly higher levels of galactomannan in all broiler chicken submissions (100%) and antibody to Aspergillus in 6 out of 9 submissions (66.6%) vs. control birds. Beta-glucan analyses did not show any differences among levels in the broiler chicken groups. There were significantly higher levels of galactomannan antigen in 4 out of 7 submissions (57.1%) of aspergillosis in commercial turkeys, while only 2 out of 7 submissions (28.5%) had higher levels of antibody to Aspergillus vs. the control group. This study shows that diagnosis of respiratory and disseminated aspergillosis may be performed by detection of galactomannan antigenemia and antibodies in broiler chickens and to an extent in turkeys. PMID- 22545543 TI - Diversity of genome segment B from infectious bursal disease viruses in the United States. AB - Several phylogenetic lineages of the infectious bursal disease virus (IBDV) genome segment B have been identified. Although this genome segment has been shown to contribute to virulence, little is known about the genetic lineages that exist in the United States. The nucleotide genome segment B sequences of 67 IBDV strains collected from 2002 to 2011 in the United States were examined. Although they were from nine different states, a majority (47) of these viruses were from California. A 722-base pair region near the 5' end of genome segment B, starting at nucleotide 168 and ending at 889, was examined and compared to sequences available in GenBank. The nucleotide sequence alignment revealed that mutations were frequently observed and that they were uniformly spaced throughout the region. When the predicted amino acids were aligned, amino acids at positions 145, 146, and 147 were found to change frequently. Six different amino acid triplets were observed and the very virulent (vv) IBDV strains (based on presence of vvIBDV genome segment A sequence) all had the triplet T145, D146, and N147. None of the non-vvIBDV strains had this TDN triplet. Phylogenetic analysis of the 67 nucleotide sequences revealed four significant genome segment B lineages among the U.S. viruses. One of these included the genome segment B typically found in vvIBDV and three contained non-vvIBDV genome segment B sequences. When the available sequences in GenBank were added to the analysis, two additional lineages were observed that did not contain U.S. viruses; one included viruses from China and the other contained viruses from the Ivory Coast. Although the samples tested do not represent all poultry producing regions in the United States, serotype 1 viruses from states outside California all belonged to one genome segment B lineage. The other three lineages observed in the United States were populated with viruses exclusively found in California, except the serotype 2 lineage, where the type strain was a serotype 2 virus from Ohio. The data provide further evidence for the importance of genome segment B identification during routine molecular diagnosis of all IBDV strains. PMID- 22545544 TI - Astroviruses as causative agents of poultry enteritis: genetic characterization and longitudinal studies on field conditions. AB - Astroviruses (AstVs) are nonenveloped RNA small round viruses (SRVs) with a genome of 6.8-7.9 kb. Known avian AstVs are spread worldwide; they have been associated with poult enteritis and mortality syndrome in the United States and reported in Italy in intensive turkey and guinea fowl flocks. Nevertheless, their real prevalence and their pathogenic role in avian enteritis affecting Italian flocks is far from clear. Negative staining electron microscopy (nsEM) is used for the routine diagnosis of avian enteric SRVs, although it cannot distinguish morphologically similar particles. Enzyme-linked immunosorbent assay (ELISA), reverse-transcription PCR (RT-PCR), and genomic sequencing are now used for this specific purpose. We analyzed 329 samples of chicken, turkey, and guinea fowl intestinal contents from Italian poultry flocks. Most samples were from enteritis outbreaks, but we also included samples from three longitudinal studies (one on 11 broiler flocks and the other two on a guinea fowl flock). We first examined the samples with nsEM. SRVs, including AstVs, are often associated with rotaviruses and were the most commonly detected morphotypes in avian enteric diseases. We then analyzed 124 of the samples with an RT-PCR targeting the open reading frame (ORF)-1b of AstV. This gene codes for an RNA-dependent polymerase. We then sequenced and genetically analyzed the RT-PCR positive samples. Phylogenetic analysis distinguished three defined clusters: the first included guinea fowl AstVs and turkey AstVs-2; the second, chicken AstVs; and the third was formed by avian nephritis viruses (ANVs). No strains clustered with turkey AstVs-1. The results indicate that ORF-1b presents certain genetic variability, even among AstVs from the same species. In longitudinal studies, samples retrieved from the same shed were homogeneous, with some exceptions suggesting possible coexistence of different genetic types in the same unit. The finding of ANV-like viruses in commercial guinea fowls underlines the genetic variability of AstVs and strengthens the hypothesis of a varied intraherd situation. PMID- 22545545 TI - Evaluation of plasma (1-->3) beta-D-glucan concentrations in birds naturally and experimentally infected with aspergillus fumigatus. AB - Avian aspergillosis, most often caused by Aspergillus fumigatus, is a common and devastating disease affecting a range of bird species. Early diagnosis is difficult and often unreliable. The current study evaluated the utility of measuring (1-->3)-beta-D-glucan (BG) concentrations in avian plasma samples to aid in the diagnosis of aspergillosis. We evaluated a commercially available BG assay (Fungitell, Beacon Diagnostics) using 178 plasma samples from naturally infected, experimentally infected, and aspergillosis-free birds. Although there was variation in BG concentration, as reflected by high standard deviations, seabirds with confirmed aspergillosis had the highest mean BG concentrations (M = 3098.7 pg/dl, SD = 5022.6, n = 22) followed by companion avian species and raptors with confirmed aspergillosis (M = 1033.8 pg/dl, SD = 1531.6, n = 19) and experimentally infected Japanese quail (Coturnix japonica; M = 1066.5 pg/dl, SD = 1348.2, n = 17). Variation in severity of disease, differences among species of birds with and without disease, and also different levels in environmental exposure likely contribute to the differences among avian groups. The overall sensitivity and specificity of the BG test for diagnosis of aspergillosis in birds was 60.0 and 92.7%, respectively, with an overall optimized avian cut offvalue of > or = 461 pg/dl for positive disease. Our findings suggest that, although BG concentrations are highly variable between and within different avian groups, it could serve as a useful adjunctive diagnostic test for aspergillosis that is applicable to multiple avian species in some settings, particularly as a negative predictor of infection. PMID- 22545546 TI - Recombinant Iss as a potential vaccine for avian colibacillosis. AB - Avian pathogenic Escherichia coli (APEC) cause colibacillosis, a disease which is responsible for significant losses in poultry. Control of colibacillosis is problematic due to the restricted availability of relevant antimicrobial agents and to the frequent failure of vaccines to protect against the diverse range of APEC serogroups causing disease in birds. Previously, we reported that the increased serum survival gene (iss) is strongly associated with APEC strains, but not with fecal commensal E. coli in birds, making iss and the outer membrane protein it encodes (Iss) candidate targets for colibacillosis control procedures. Preliminary studies in birds showed that their immunization with Iss fusion proteins protected against challenge with two of the more-commonly occurring APEC serogroups (O2 and O78). Here, the potential of an Iss-based vaccine was further examined by assessing its effectiveness against an additional and widely occurring APEC serogroup (O1) and its ability to evoke both a serum and mucosal antibody response in immunized birds. In addition, tissues of selected birds were subjected to histopathologic examination in an effort to better characterize the protective response afforded by immunization with this vaccine. Iss fusion proteins were administered intramuscularly to four groups of 2-wk-old broiler chickens. At 2 wk postimmunization, chickens were challenged with APEC strains of the O1, O2, or O78 serogroups. One week after challenge, chickens were euthanatized, necropsied, any lesions consistent with colibacillosis were scored, and tissues from these birds were taken aseptically. Sera were collected pre immunization, postimmunization, and post-challenge, and antibody titers to Iss were determined by enzyme-linked immunosorbent assay (ELISA). Also, air sac washings were collected to determine the mucosal antibody response to Iss by ELISA. During the observation period following challenge, 3/12 nonimmunized chickens, 1/12 chickens immunized with 10 microg of GST-Iss, and 1/12 chickens immunized with 50 microg of GST-Iss died when challenged with the O78 strain. No other deaths occurred. Immunized chickens produced a serum and mucosal antibody response to Iss and had significantly lower lesion scores than nonimmunized chickens following challenge, regardless of the challenge strain. This study expands on our previous report of the value of Iss as an immunoprotective antigen and demonstrates that immunization with Iss can provide significant protection of chickens against challenge with three different E. coli strains. PMID- 22545547 TI - Use of FTA sampling cards for molecular detection of avian influenza virus in wild birds. AB - Current avian influenza (AI) virus surveillance programs involving wild birds rely on sample collection methods that require refrigeration or low temperature freezing to maintain sample integrity for virus isolation and/or reverse transcriptase (RT) PCR. Maintaining the cold chain is critical for the success of these diagnostic assays but is not always possible under field conditions. The aim of this study was to test the utility of Finders Technology Associates (FTA) cards for reliable detection of AI virus from cloacal and oropharyngeal swabs of wild birds. The minimum detectable titer was determined, and the effect of room temperature storage was evaluated experimentally using multiple egg-propagated stock viruses (n = 6). Using real time RT-PCR, we compared results from paired cloacal swab and samples collected on FTA cards from both experimentally infected mallards (Anasplatyrhynchos) and hunter-harvested waterfowl sampled along the Texas Gulf Coast. Based on the laboratory trials, the average minimal detectable viral titer was determined to be 1 x 10(4.7) median embryo infectious dose (EID50)/ml (range: 1 x 10(4.3) to 1 x 10(5.4) EID50/ml), and viral RNA was consistently detectable on the FTA cards for a minimum of 20 days and up to 30 days for most subtypes at room temperature (23 C) storage. Real-time RT-PCR of samples collected using the FTA cards showed fair to good agreement in live birds when compared with both real-time RT-PCR and virus isolation of swabs. AI virus detection rates in samples from several wild bird species were higher when samples were collected using the FTA cards compared with cloacal swabs. These results suggest that FTA cards can be used as an alternative sample collection method when traditional surveillance methods are not possible, especially in avian populations that have historically received limited testing or situations in which field conditions limit the ability to properly store or ship swab samples. PMID- 22545548 TI - Pathogenicity and immunogenicity of different recombinant Newcastle disease virus clone 30 variants after in ovo vaccination. AB - Even though Newcastle disease virus (NDV) live vaccine strains can be applied to 1-day-old chickens, they are pathogenic to chicken embryos when given in ovo 3 days before hatch. Based on the reverse genetics system, we modified recombinant NDV (rNDV) established from lentogenic vaccine strain Clone 30 by introducing specific mutations within the fusion (F) and hemagglutinin-neuraminidase (HN) proteins, which have recently been suggested as being responsible for attenuation of selected vaccine variants (Mast et al. Vaccine 24:1756-1765, 2006) resulting in rNDV49. Another recombinant (rNDVGu) was generated to correct sequence differences between rNDV and vaccine strain NDV Clone 30. Recombinant viruses rNDV, rNDV49, and rNDVGu have reduced virulence compared with NDV Clone 30, represented by lower intracerebral pathogenicity indices and elevated mean death time. After in ovo inoculation, hatchability was comparable for all infected groups. However, only one chicken from the NDV Clone 30 group survived a 21-day observation period; whereas, the survival rate of hatched chicks from groups receiving recombinant NDV was between 40% and 80%, with rNDVGu being the most pathogenic virus. Furthermore, recombinant viruses induced protection against challenge infection with virulent NDV 21 days post hatch. Differences in antibody response of recombinant viruses indicate that immunogenicity is correlated to virulence. In summary, our data show that point mutations can reduce virulence of NDV. However, alteration of specific amino acids in F and HN proteins of rNDV did not lead to further attenuation as indicated by their pathogenicity for chicken after in ovo inoculation. PMID- 22545549 TI - Molecular epidemiologic investigation of lentogenic Newcastle disease virus from domestic birds at live bird markets in Korea. AB - A Newcastle disease surveillance program was conducted at live bird markets in Korea to expand our epidemiologic understanding of the disease in Korea. During the surveillance program, 10 lentogenic Newcastle disease viruses (NDVs) were isolated and identified from apparently healthy chickens and ducks at live bird markets. The lentogenic viruses had sequence motifs of either 112GKQGRL117 (n = 8) or 112GRQGRL117 (n = 2) at the F0 cleavage site. Sequencing and phylogenetic analyses of NDV isolates based on the hypervariable region of the F protein revealed two different genotypes: genotypes I (n = 8) and II (n = 2). Genotype I viruses were most closely related to the NDV V4 strain (n = 7) or the NDV Ulster 2C strain (n = 1). In contrast, genotype II viruses clustered with the NDV vaccine strains (LaSota and VG/GA) that are commonly used as live vaccines in Korea. The epidemiologic importance of NDV at live bird markets in Korea is discussed. PMID- 22545550 TI - Persistence of Histomonas meleagridis in or on materials used in poultry houses. AB - Histomonas meleagridis is the causative agent of blackhead disease or histomonosis in turkeys, and previous research suggests that this parasite survives poorly outside of hosts except within heterakid nematodes. However, we investigated the viability of H. meleagridis in or on several artificially contaminated materials kept at ambient room temperature (22 +/- 2 C) to mimic the situation in the field. The protozoan survived for up to 1 hr on wood, rubber, and metal; up to 3 hr on egg-tray cartons, egg shells, and bricks; up to 6 hr on straw, turkey feathers, and feed; and up to 9 hr in nonchlorinated tap water and fecal matter. Therefore, contaminated water, fresh fecal matter, or both could play a role in transmission of the parasite within and among poultry houses rather than other materials tested in this study. PMID- 22545551 TI - Comparison of pooling 11 or 5 oropharyngeal swabbings for detecting avian influenza virus by real-time reverse transcription-PCR in broiler chickens. AB - The effect of pooling 11 or 5 oropharyngeal (O/P) swabbings on detecting avian influenza virus (AIV) by real-time reverse transcription (RRT)-PCR was evaluated. The model used for the evaluation was designed to minimize viral load and, thus, assess the effect of the pooling on detection. Two-week-old broiler chickens were inoculated via the intranasal route with the low pathogenicity chicken/Maryland/Minh Ma/04 H7N2 strain or remained uninoculated. On days 2, 3, 4, 5, 7, 9, 11, and 14 postinoculation (PI), O/P swabbings were collected from individual infected birds and pooled with either 10 or 4 O/P swabs from uninfected broilers to produce 10 replicate pools of 11 or 5 swabbings, respectively. AIV was readily detected (80%-100%) by RRT-PCR in the pools of 11 and pools of 5 swabbings from days 2 through 5 PI. Detection in pools of both types decreased to similar levels on day 7 (40% for the pools of 11 and 50% for the pools of 5). AIV was not detected on day 9, 11, and 14 PI in pools of either size. On a given sample day PI, mean cycle threshold (Ct) values were consistently higher (lower genome levels) in the pools of 11 compared to the pools of 5. These differences were statistically significant on days 3 and 5 PI, yet Ct values associated with both types of pools were clearly interpretable as AIV positive. PMID- 22545552 TI - Clostridium perfringens alpha-toxin and NetB toxin antibodies and their possible role in protection against necrotic enteritis and gangrenous dermatitis in broiler chickens. AB - Necrotic enteritis (NE) and gangrenous dermatitis (GD) are important infectious diseases of poultry. Although NE and GD share a common pathogen, Clostridium perfringens, they differ in other important aspects such as clinical signs, pathologic symptoms, and age of onset. The primary virulence factors of C perfringens are its four major toxins (alpha, beta, epsilon, iota) and the newly described NE B-like (NetB) toxin. While neutralizing antibodies against some C perfingens toxins are associated with protection against infection in mammals, the serologic responses of NE- and GD-afflicted birds to these toxins have not been evaluated. Therefore, we measured serum antibody levels to C perfringens alpha-toxin and NetB toxin in commercial birds from field outbreaks of NE and GD using recombinant toxin-based enzyme-linked immunosorbent assay (ELISA). Initially, we used this ELISA system to detect antibody titers against C perfringens alpha-toxin and NetB toxin that were increased in birds experimentally coinfected with Eimeria maxima and C perfringens compared with uninfected controls. Next, we applied this ELISA to field serum samples from flock-mated birds with or without clinical signs of NE or GD. The results showed that the levels of antibodies against both toxins were significantly higher in apparently healthy chickens compared to birds with clinical signs of NE or GD, suggesting that these antitoxin antibodies may play a role in protection against NE and GD. PMID- 22545553 TI - Ecology of influenza virus in wild bird populations in Central Asia. AB - The study provides the results of avian influenza virus surveillance in Central Asia during 2003-2009. We have analyzed 2604 samples from wild birds. These samples were collected in Kazakhstan (279), Mongolia (650), and Russia (1675). Isolated viruses from samples collected in Mongolia (13 isolates) and in Russia (4 isolates) were described. Virological analysis has shown that six isolates belong to the H3N6 subtype and five isolates belong to the H4N6 subtype. Two H1N1 influenza viruses, one H10N7 virus, two H3N8 viruses, and an H13N8 virus that is new for Central Asia have been also isolated. Samples were taken from birds of six orders, including several species preferring water and semiaquatic biotopes, one species preferring dry plain regions, and one more species that can inhabit both dry and water biotopes. PMID- 22545554 TI - Description of Eimeria pavonina (coccidia) of peafowl in Germany. AB - There are only a few reports about the occurrence of coccidia in peafowl and no reports about the occurrence of Eimeria spp. in peafowl kept in Europe. Here, we describe the occurrence of Eimeria pavonina in diseased peafowl from Germany. In January 2011, one young peacock kept in an aviary showed a marked depression. No parasites were detected in samples from the diseased bird, but in samples of birds from the same and other aviaries, coccidian counts were between 400/g and 66,000/g. All peacocks were treated with toltrazuril. After treatment, the clinical condition of the diseased bird improved but, two weeks afterwards, other birds in the aviary were still shedding coccidia in their feces. Based on morphology, the coccidia were identified as E. pavonina. Parts of the 18s rRNA gene and the cytochrome oxidase subunit 1 (cox-1) gene were sequenced. A phylogenetic tree based on the 18s rRNA sequence placed the Eimeria sp. from peafowl closest to Eimeria spp. found in pheasants and partridges as well as to Eimeria meleagrimitis. A phylogenetic tree based on the sequence of cox-1 in contrast suggested a closer relationship to Eimeria necatrix and Eimeria tenella. PMID- 22545555 TI - Genetic characterization of a pigeon paramyxovirus type 1 isolated from Columba livia in Uruguay. AB - SUMMARY. The isolation and molecular characterization of pigeon paramyxovirus type 1 (PPMV-1) from a sick racing pigeon in Uruguay is reported for the first time. Hemagglutination inhibition (HI) tests were performed to detect antibodies against avian paramyxovirus serotype 1 (APMV-1), and a HI titer of 1/32 was obtained. Tracheal and cloacal swabs were processed by real-time reverse transcription-polymerase chain reaction (rRT-PCR) with the use of the National Veterinary Services Laboratory-U.S. Department of Agriculture validated matrix (M) gene assay and were positive for APMV-1. Viral isolation in embryonated chicken eggs confirmed the molecular detection of the isolate. A fragment corresponding to the 3' region of the fusion (F) protein gene was amplified by RT PCR, and subsequently sequenced. The deduced amino acid sequence at the F protein cleavage site displayed the motif 112RRQKR/F117. Phylogenetic analysis of this part of the genome allowed the isolated virus to be grouped in the lineage VIb/ 4b, which suggests that it shares the same ecologic niche with other PPMV-1 that were found in the region, and it is not imported as other European or North American viruses. PMID- 22545556 TI - Causes of morbidity and mortality of wild aquatic birds at Billabong Sanctuary, Townsville, North Queensland, Australia. AB - Infectious diseases are common causes of significant morbidity and mortality events of wild aquatic birds (WABs) worldwide. Reports of Australian events are infrequent. A 3-yr passive surveillance program investigating the common causes of morbidity and mortality of WABs was conducted at Billabong Sanctuary near Townsville, North Queensland, from April 2007 to March 2010. Forty-two carcasses were obtained and evaluated by clinico-pathologic, histologic, bacteriologic, and virologic (molecular) examinations. Morbidity and mortality were sporadic and more commonly observed in chicks and juvenile birds in April than other months of the year. Morbid birds were frequently unable to walk. Hemorrhagic lesions and infiltration of lymphocytes in various organs were the most common findings in dead birds. Identified bacterial diseases that could cause bird mortality were colibacillosis, pasteurellosis, and salmonellosis. Salmonella serotypes Virchow and Hvittingfoss were isolated from an Australian white ibis (Threskiornis molucca) chick and two juvenile plumed whistling ducks (Dendrocygna eytoni) in April 2007. These strains have been previously isolated from humans in North Queensland. A multiplex real time reverse transcriptase-PCR (rRT-PCR) detected Newcastle disease viral RNA (class 2 type) in one adult Australian pelican (Pelecanus conspicillatus) and a juvenile plumed whistling duck. No avian influenza viral RNA was detected from any sampled birds by the rRT-PCR for avian influenza. This study identified the public health importance of Salmonella in WABs but did not detect the introduction of the high pathogenicity avian influenza H5N1 virus in the population. A successful network was established between the property owner and the James Cook University research team through which dead birds, with accompanying information, were readily obtained for analysis. There is an opportunity for establishing a long-term passive disease surveillance program for WABs in North Queensland, an important region in Australian biosecurity, thus potentially significantly benefitting public health in the region and the country. PMID- 22545557 TI - Serologic evidence of avian influenza H9N2 and paramyxovirus type 1 infection in emus (Dromaius novaehollandiae) in India. AB - An avian influenza (AI) surveillance was undertaken in Maharashtra state, India during the period 2010-2011. There are no reports of AI surveillance in emus from India. A total of 202 blood samples and 467 tracheal and cloacal swabs were collected from eight emu farms. A hemagglutination inhibition (HI) assay was performed for detection of antibodies against AI H5N1, H7N1, H9N2, and avian paramyxovirus type 1 (APMV-1) viruses. A microneutralization (MN) assay was performed to confirm the presence of neutralizing antibodies against AI H9N2 and to compare with HI assays. A total of 28.2% and 28.7% of samples were positive for antibodies against AI H9N2 by HI and MN assays, respectively, using > or = 1:40 as a cut-off titer; 15.3% samples were positive for APMV-1 by HI assay using a > or = 1:10 cut-off titer. Seropositivity of AI H9N2 was nil in the grower (<1 yr) age group and highest (78%) in the breeder (2-3 yr) age group, whereas seropositivity against APMV-1 was observed in all age groups. Performance of both HI and MN assays was similar, suggesting the utility of using the MN assay along with HI assay for surveillance studies. This is the first report of the seroprevalence of AI H9N2 and APMV-1 in emus in India. PMID- 22545558 TI - Suppression of the coffee ring effect by hydrosoluble polymer additives. AB - A simple and novel method has been demonstrated for avoiding coffee ring structure based on hydrosoluble polymer additives during droplet evaporation. The polymer additives lead to the motion of the contact line (CL) resulted from the viscosity and Marangoni effect. The viscosity provides a large resistance to the radially outward flow. It results in a small amount of spheres deposited at droplet edge, which do not facilitate the pinning of the CL. The Marangoni effect resulted from the variation of polymer concentration at droplet edge during droplet evaporation contributes to the motion of the CL. Thus, uniform and ordered macroscale SiO(2) microspheres deposition is achieved. What's more, the coffee ring effect can be eliminated by different hydrosoluble polymer. This method will be applicable to a wide of aqueous system and will be of great significance for extensive applications of droplet deposition in biochemical assays and material deposition. PMID- 22545559 TI - Toxicogenomic responses of nanotoxicity in Daphnia magna exposed to silver nitrate and coated silver nanoparticles. AB - Applications for silver nanomaterials in consumer products are rapidly expanding, creating an urgent need for toxicological examination of the exposure potential and ecological effects of silver nanoparticles (AgNPs). The integration of genomic techniques into environmental toxicology has presented new avenues to develop exposure biomarkers and investigate the mode of toxicity of novel chemicals. In the present study we used a 15k oligonucleotide microarray for Daphnia magna, a freshwater crustacean and common indicator species for toxicity, to differentiate between particle specific and ionic silver toxicity and to develop exposure biomarkers for citrate-coated and PVP-coated AgNPs. Gene expression profiles revealed that AgNO(3) and AgNPs have distinct expression profiles suggesting different modes of toxicity. Major biological processes disrupted by the AgNPs include protein metabolism and signal transduction. In contrast, AgNO(3) caused a downregulation of developmental processes, particularly in sensory development. Metal responsive and DNA damage repair genes were induced by the PVP AgNPs, but not the other treatments. In addition, two specific biomarkers were developed for the environmental detection of PVP AgNPs; although further verification under different environmental conditions is needed. PMID- 22545560 TI - High-quality metal oxide core/shell nanowire arrays on conductive substrates for electrochemical energy storage. AB - The high performance of a pseudocapacitor electrode relies largely on a scrupulous design of nanoarchitectures and smart hybridization of bespoke active materials. We present a powerful two-step solution-based method for the fabrication of transition metal oxide core/shell nanostructure arrays on various conductive substrates. Demonstrated examples include Co(3)O(4) or ZnO nanowire core and NiO nanoflake shells with a hierarchical and porous morphology. The "oriented attachment" and "self-assembly" crystal growth mechanisms are proposed to explain the formation of the NiO nanoflake shell. Supercapacitor electrodes based on the Co(3)O(4)/NiO nanowire arrays on 3D macroporous nickel foam are thoroughly characterized. The electrodes exhibit a high specific capacitance of 853 F/g at 2 A/g after 6000 cycles and an excellent cycling stability, owing to the unique porous core/shell nanowire array architecture, and a rational combination of two electrochemically active materials. Our growth approach offers a new technique for the design and synthesis of transition metal oxide or hydroxide hierarchical nanoarrays that are promising for electrochemical energy storage, catalysis, and gas sensing applications. PMID- 22545561 TI - Engineering particles for therapeutic delivery: prospects and challenges. AB - Nanoengineered particles that can facilitate drug formulation and passively target tumors have reached the clinic in recent years. These early successes have driven a new wave of significant innovation in the generation of advanced particles. Recent developments in enabling technologies and chemistries have led to control over key particle properties, including surface functionality, size, shape, and rigidity. Combining these advances with the rapid developments in the discovery of many disease-related characteristics now offers new opportunities for improving particle specificity for targeted therapy. In this Perspective, we summarize recent progress in particle-based therapeutic delivery and discuss important concepts in particle design and biological barriers for developing the next generation of particles. PMID- 22545562 TI - The same old elephant .... PMID- 22545563 TI - Clinical phenomenology of childhood abuse-related complex PTSD in a population of female patients: patterns of personality disturbance. AB - OBJECTIVE: Complex posttraumatic stress disorder (PTSD) involves a variety of personality disturbances presumed to result from repeated interpersonal trauma such as child abuse. As Complex PTSD patients are a heterogeneous population, we searched for clinically relevant personality-based subtypes. METHOD: This study used a cluster analysis of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), Axis II features within a sample of 71 female outpatients with systematically assessed child abuse-related Complex PTSD. RESULTS: Two main subtypes were found: adaptive and nonadaptive. The latter was further differentiated into withdrawn, alienated, suffering, and aggressive subtypes, characterized by different levels of introversion and disinhibition. Among the nonadaptive subtypes, the severity of Complex PTSD symptoms was lowest in the withdrawn (introverted only) subtype. The subtypes differed in their level of dissociation and depression but did not differ regarding PTSD symptoms, trauma history, or parental bonding characteristics. CONCLUSION: Confirming earlier findings, our study found personality-based Complex PTSD subtypes, which could implicate differential treatment needs and results. PMID- 22545564 TI - Trauma severity and defensive emotion-regulation reactions as predictors of forgetting childhood trauma. AB - Using a retrospective survey, we studied a sample of 1,679 college women to determine whether reports of prior forgetting of childhood sexual abuse, physical abuse, and other traumas could be explained by trauma severity and individual differences in the use of defensive emotion-regulation reactions (i.e., repressive coping, dissociation, and fantasy proneness). Among victims of physical abuse (but not sexual abuse or other types of trauma), those who experienced severe abuse and used defensive reactions were sometimes more likely to report temporary forgetting of abuse but other times less likely to report forgetting. We also found unanticipated main effects of trauma severity on temporary forgetting. Our results provide an understanding of victims' experiences of forgetting by demonstrating the importance of considering unique effects of trauma type, different aspects of trauma severity, and victims' defensive reactions to trauma. PMID- 22545565 TI - Psychophysiological investigations in depersonalization disorder and effects of electrodermal biofeedback. AB - Previous studies investigating depersonalization disorder (DPD) report a lower baseline skin conductance level (SCL) and attenuated skin conductance response (SCR) to emotive stimuli. We hypothesized that increasing physiological arousal levels via electrodermal biofeedback may ameliorate disembodiment and emotional numbing symptomatology. Real-time versus sham biofeedback yielded a significant SCL increase after just 3 real-time biofeedback sessions in healthy volunteers. Subsequently, a randomized controlled biofeedback trial was administered with DPD patients. Findings were not replicated as SCL tended to fall, curiously more substantially in the real-time condition, concomitant with increased low- and high-frequency heart rate variability. To further investigate abnormal autonomic regulation in DPD, we compared basal autonomic activity between patients and healthy volunteers and found the former to be significantly more labile, indexed by greater nonspecific SCRs and higher resting SCLs. Rather than low sympathetic arousal, DPD might be better characterized by abnormal autonomic regulation affecting emotional and physiological responsivity. PMID- 22545566 TI - Dissociation in sexually abused Puerto Rican children: a replication utilizing social workers as informers. AB - This study explores dissociative symptoms in 3 different groups of Puerto Rican children. Data were collected on 40 children with documented sexual abuse history, 39 children with psychiatric disorders but without a history of sexual abuse, and 40 community control children. Dissociative symptoms were assessed with the child using the Trauma Symptom Checklist for Children (TSCC); a social worker answered the Child Dissociative Checklist (CDC). Results indicated that children with sexual abuse obtained significantly different scores on both the TSCC and the CDC. Further analysis indicated that child and social worker reports of dissociative symptoms were highly correlated (r = .73). Furthermore, 30% of the children in the sexual abuse group scored at or above the cutoff point of 12 on the CDC, which is indicative of a dissociative disorder. None of the children in the other 2 groups obtained such a score. The results suggest that children with documented sexual abuse victimization demonstrate a significant number of dissociative phenomena that not only are subjectively experienced but also can be observed by a non-family member. Finally, as nearly a third of the abused children obtained a score of 12 or higher on the CDC, the next step is to prepare clinicians to conduct a proper and formal diagnosis assessment of dissociative disorders. PMID- 22545568 TI - Psychoform and somatoform dissociation and PTSD in deaf adults. AB - Both deafness and dissociation disconnect people from certain aspects of the external environment. Dissociation among the deaf population has been largely neglected as an area of scientific investigation. The purpose of this study was twofold: first, to examine the psychometrics of 2 dissociation measures--the Dissociation scale of the Trauma Symptom Inventory (TSI) and the Somatoform Dissociation Questionnaire-20 (SDQ-20); and second, to evaluate the relationship between dissociation and posttraumatic stress disorder (PTSD) in deaf adults. A diverse sample of 79 deaf adults was assessed using the Clinician-Administered PTSD Scale, the TSI, and the SDQ-20. Results provided support for the concept of psychoform dissociation, as measured by the TSI Dissociation scale, in deaf adults. However, somatoform dissociation, as measured by the SDQ-20, showed lower internal consistency. The SDQ-5, a shortened version of the SDQ-20, was unreliable in the current sample. Deaf adults were significantly higher on psychoform dissociation than the norm samples of hearing adults. As in hearing samples, dissociation--both psychoform and somatoform--was significantly related to PTSD symptoms. In addition, those with dissociative PTSD displayed significantly more symptoms of depression, anger, impaired self-reference, tension reduction behavior, and somatoform dissociation than did the nondissociative PTSD group. PMID- 22545567 TI - Dissociative experiences during sexual behavior among a sample of adults living with HIV infection and a history of childhood sexual abuse. AB - Little attention has been given to the occurrence of dissociative symptoms during sexual behavior in adults who have experienced childhood sexual abuse (CSA). For this study, 57 adults living with HIV infection who had experienced CSA and were entering a treatment study for traumatic stress completed study assessments and clinical interviews, including a 15-item scale of dissociative experiences during sexual behavior. Predictor variables included Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision diagnoses of posttraumatic stress disorder (PTSD) and dissociative disorders, rape by an intimate partner, duration of CSA, number of perpetrators of CSA, and current sexual satisfaction. A multiple regression analysis was conducted to identify significant associations between predictors and dissociation during sex. Mean differences by clinical diagnosis were also examined. Results indicated that PTSD, dissociative disorders, rape by an intimate partner, duration of CSA, and number of perpetrators of CSA were associated with increased dissociation during sexual behavior. Dissociation during sex likely increases vulnerability to sexual revictimization and risky sexual behavior. Standard behavioral prevention interventions may be ineffective for sexual situations when dissociation occurs, and prevention efforts should be integrated with mental health care for those who have experienced CSA. PMID- 22545572 TI - Evaluation of the impact of H2O, O2, and SO2 on postcombustion CO2 capture in metal-organic frameworks. AB - Molecular modeling methods are used to estimate the influence of impurity species: water, O(2), and SO(2) in flue gas mixtures present in postcombustion CO(2) capture using a metal organic framework, HKUST-1, as a model sorbent material. Coordinated and uncoordinated water effects on CO(2) capture are analyzed. Increase of CO(2) adsorption is observed for both cases, which can be attributed to the enhanced binding energy between CO(2) and HKUST-1 due to the introduction of a small amount of water. Density functional theory calculations indicate that the binding energy between CO(2) and HKUST-1 with coordinated water is ~1 kcal/mol higher than that without coordinated water. It is found that the improvement of CO(2)/N(2) selectivity induced by coordinated water may mainly be attributed to the increased CO(2) adsorption on the hydrated HKUST-1. On the other hand, the enhanced selectivity induced by uncoordinated water in the flue gas mixture can be explained on the basis of the competition of adsorption sites between water and CO(2) (N(2)). At low pressures, a significant CO(2)/N(2) selectivity increase is due to the increase of CO(2) adsorption and decrease of N(2) adsorption as a consequence of competition of adsorption sites between water and N(2). However, with more water molecules adsorbed at higher pressures, the competition between water and CO(2) leads to the decrease of CO(2) adsorption capacity. Therefore, high pressure operation should be avoided in HKUST-1 sorbents for CO(2) capture. In addition, the effects of O(2) and SO(2) on CO(2) capture in HKUST-1 are investigated: The CO(2)/N(2) selectivity does not change much even with relatively high concentrations of O(2) in the flue gas (up to 8%). A slightly lower CO(2)/N(2) selectivity of a CO(2)/N(2)/H(2)O/SO(2) mixture is observed compared with that in a CO(2)/N(2)/H(2)O mixture, especially at high pressures, due to the strong SO(2) binding with HKUST-1. PMID- 22545574 TI - A high-symmetry coordination cage from 38- or 62-component self-assembly. AB - Artificial molecular architecture from a large number of subcomponents (>50) via self-assembly remains a formidable challenge for chemists. Reaction of 38 components [14 Ni(2+) and 24 N-methyl-1-(4-imidazolyl)methanimine] under solvothermal conditions reproducibly leads to the formation of a high-symmetry coordination cage. This polyhedral cage can also be obtained in high yield by self-assembly of 62 commercially available subcomponents (24 methylamine, 24 4 formylimidazole, and 14 Ni(2+)) under mild conditions involving synchronized formation of both dynamic covalent bonds and coordination bonds. Guest molecules (e.g., water, methylamine, and methanol) are randomly imprisoned in the cage. PMID- 22545573 TI - Routine delivery of artemisinin-based combination treatment at fixed health facilities reduces malaria prevalence in Tanzania: an observational study. AB - BACKGROUND: Artemisinin-based combination therapy (ACT) has been promoted as a means to reduce malaria transmission due to their ability to kill both asexual blood stages of malaria parasites, which sustain infections over long periods and the immature derived sexual stages responsible for infecting mosquitoes and onward transmission. Early studies reported a temporal association between ACT introduction and reduced malaria transmission in a number of ecological settings. However, these reports have come from areas with low to moderate malaria transmission, been confounded by the presence of other interventions or environmental changes that may have reduced malaria transmission, and have not included a comparison group without ACT. This report presents results from the first large-scale observational study to assess the impact of case management with ACT on population-level measures of malaria endemicity in an area with intense transmission where the benefits of effective infection clearance might be compromised by frequent and repeated re-infection. METHODS: A pre-post observational study with a non-randomized comparison group was conducted at two sites in Tanzania. Both sites used sulphadoxine-pyrimethamine (SP) monotherapy as a first-line anti-malarial from mid-2001 through 2002. In 2003, the ACT, artesunate (AS) co-administered with SP (AS + SP), was introduced in all fixed health facilities in the intervention site, including both public and registered non-governmental facilities. Population-level prevalence of Plasmodium falciparum asexual parasitaemia and gametocytaemia were assessed using light microscopy from samples collected during representative household surveys in 2001, 2002, 2004, 2005 and 2006. FINDINGS: Among 37,309 observations included in the analysis, annual asexual parasitaemia prevalence in persons of all ages ranged from 11% to 28% and gametocytaemia prevalence ranged from <1% to 2% between the two sites and across the five survey years. A multivariable logistic regression model was fitted to adjust for age, socioeconomic status, bed net use and rainfall. In the presence of consistently high coverage and efficacy of SP monotherapy and AS + SP in the comparison and intervention areas, the introduction of ACT in the intervention site was associated with a modest reduction in the adjusted asexual parasitaemia prevalence of 5 percentage-points or 23% (p < 0.0001) relative to the comparison site. Gametocytaemia prevalence did not differ significantly (p = 0.30). INTERPRETATION: The introduction of ACT at fixed health facilities only modestly reduced asexual parasitaemia prevalence. ACT is effective for treatment of uncomplicated malaria and should have substantial public health impact on morbidity and mortality, but is unlikely to reduce malaria transmission substantially in much of sub-Saharan Africa where individuals are rapidly re infected. PMID- 22545575 TI - Endotracheal intubation with airtraq(r) versus storz(r) videolaryngoscope in children younger than two years - a randomized pilot-study. AB - BACKGROUND: New laryngoscopes have become available for use in small children. The aim of the study was to compare the Storz(r) videolaryngoscope (SVL) to the Airtraq(r) Optical laryngoscope (AOL) for tracheal intubation in children younger than two years of age who had a normal airway assessment. Our hypothesis was that the SVL would have a better success rate than the AOL. METHODS: Ten children aged 2 years or younger scheduled for elective cleft lip/palate surgery were included. The anesthesia was standardized and a Cormack-Lehane (CL)-score was obtained using a Macintosh laryngoscope. After randomization CL-score and endotracheal tube positioning in front of the glottis was performed with one device, followed by the same procedure and intubation with the other device. The video-feed was recorded along with real-time audio. The primary endpoint was the success rate, defined as intubation in first attempt. Secondary endpoints were the time from start of laryngoscopy to CL-score, tube positioning in front of the glottis, and intubation. RESULTS: Two intubation attempts were needed in two of five patients randomized to the SVL. The difference in time (SVL vs. AOL) to CL-score was 4.5 sec (p = 0.0449). The difference in time (SVL vs. AOL) to tube positioning was 11.6 sec (p = 0.0015). Time to intubation was 29.0 sec for SVL and 15.8 sec for AOL. CONCLUSION: No difference in the success rate of endotracheal intubation could be established in this ten patient sample of children younger than two years with a normal airway assessment scheduled for elective cleft lip/palate surgery. However, the Airtraq(r) Optical videolaryngoscope showed a number of time related advantages over the Storz(r) videolaryngoscope. Because of the small sample size a larger trial is needed to confirm these findings. Both devices were considered safe in all intubations. TRIAL REGISTRATION: ClinicalTrials.gov; Identifier NCT01090726. PMID- 22545576 TI - Auscultatory versus oscillometric measurement of blood pressure in octogenarians. AB - BACKGROUND: Auscultatory measurement using a sphygmomanometer has been the predominant method for clinical estimation of blood pressure, but it is now rapidly being replaced by oscillometric measurement. OBJECTIVE: To compare blood pressure by auscultatory and oscillometric measurements in patients >= 80 years. METHOD: 100 patients had blood pressure measured by auscultation with a sphygmomanometer and by an electronic device using the oscillometric method. For each patient the mean of two blood pressures with each method measured within 15 min were compared. RESULTS: The mean age of participants was 85.8 years; 55.8% were women. The correlation coefficient for systolic blood pressure was 0.88 and for diastolic 0.79. Differences between auscultatory and oscillometric values were less than 10 mmHg in 70.6% of systolic blood pressures and in 83.2% for diastolic. Arrhythmia and hypertension did not influence the results, and there was no correlation between the magnitude of the differences and the level of blood pressure. CONCLUSION: Agreement between oscillometric and auscultatory measurements of blood pressure in octogenarians was found to be less than required by validation protocols. However, semi-automatic equipment, which is observer-independent, may be used even in the very elderly, particularly if multiple readings are performed. PMID- 22545577 TI - Electron transport in SiGe alloy nanowires in the ballistic regime from first principles. AB - Silicon-germanium alloying is emerging as one of the most promising strategies to engineer heat transport at the nanoscale. Here, we perform first-principles electron transport calculations to assess at what extent such approach can be followed without worsening the electrical conduction properties of the system, providing then a path toward high-efficiency thermoelectric materials. PMID- 22545578 TI - Up-regulation of P-glycoprotein is involved in the increased paclitaxel resistance in human esophageal cancer radioresistant cells. AB - OBJECTIVE: Development of drug and radiation resistance is one of the major causes of cancer treatment failure with chemoradiotherapy. Whether radiotherapy affects drugs resistance in esophageal cancer cells remain to be determined. The purpose of the study was to investigate the change of drug-sensitivity and P glycoprotein (P-gp) expression in ionization radiation-induced human esophageal cancer radioresistant cells. MATERIALS AND METHODS: Radioresistant cells were established by means of continuous fractionated gamma-ray irradiation on human esophageal squamous cancer cell line EC9706. The radiosensitivity and drug sensitivity between established radioresistant cells and parental cells were detected by a colony-forming assay and 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di phenytetrazoliumromide (MTT) assay, respectively. The expressions of multidrug resistance type 1 gene (MDR1) mRNA and protein for P-gp were detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot methods. The roles of P-gp activity in irradiation-induced drugs resistance were studied by using verapamil, an inhibitor of P-gp activity. RESULTS: The esophageal cancer radioresistant cells showed an increased cisplatin or paclitaxel resistance. Compared with their parental cells, the expressions of MDR1 mRNA and protein for P-gp were increased significantly in radioresistant cells. Verapamil reduced paclitaxel resistance but had no effect on cisplatin resistance in human esophageal cancer radioresistant cells. CONCLUSIONS: These results suggested that up-regulation of P-gp is involved in the increased paclitaxel resistance but not cisplatin resistance in ionization radiation-induced human esophageal squamous cancer radioresistant cells. PMID- 22545579 TI - Tobacco cessation Clinical Practice Guideline use by rural and urban hospital nurses: a pre-implementation needs assessment. AB - BACKGROUND: This study was a pre-program evaluation of hospital-based nurses' tobacco intervention beliefs, confidence, training, practice, and perceived intervention barriers and facilitators. It was designed to identify relevant information prior to implementing tobacco cessation guidelines across a large northern rural region, home to 1 urban and 12 rural hospitals. METHODS: This cross-sectional survey was distributed by nurse managers to nurses in the 13 hospitals and returned by nurses (N = 269) via mail to the researchers. RESULTS: Nurses were somewhat confident providing cessation interventions, agreed they should educate patients about tobacco, and 94% perceived tobacco counselling as part of their role. Although only 11% had received cessation training, the majority reported intervening, even if seldom--91% asked about tobacco-use, 96% advised quitting, 89% assessed readiness to quit, 88% assisted with quitting, and 61% arranged post-discharge follow-up. Few performed any of these steps frequently, and among those who intervened, the majority spent < 10 minutes. The most frequently performed activities tended to take the least amount of time, while the more complex activities (e.g., teaching coping skills and pharmacotherapy education) were seldom performed. Patient-related factors (quitting benefits and motivation) encouraged nurses to intervene and work related factors discouraged them (time and workloads). There were significant rural-urban differences--more rural nurses perceived intervening as part of their role, reported having more systems in place to support cessation, reported higher confidence for intervening, and more frequently assisted patients with quitting and arranged follow-up. CONCLUSIONS: The findings showed nurses' willingness to engage in tobacco interventions. What the majority were doing maps onto the recommended minimum of 1-3 minutes but intervention frequency and follow-up were suboptimal. The rural-urban differences suggest a need for more research to explore the strengths of rural practice which could potentially inform approaches to smoking cessation in urban hospitals. PMID- 22545580 TI - Electronic transport in porphyrin supermolecule-gold nanoparticle assemblies. AB - Temperature-dependent transport of hybrid structures consisting of gold nanoparticle arrays functionalized by conjugated organic molecules [(4' thiophenyl)ethynyl-terminated meso-to-meso ethyne-bridged (porphinato)zinc(II) complexes] that possess exceptional optical and electronic properties was characterized. Differential conductance analysis distinguished the functional forms of the temperature and voltage dependences for a range of sample particles and molecular attachments. Thermally assisted tunneling describes transport for all cases and the associated mechanistic parameters can be used to determine the relative roles of activation energy, work function, and so forth. These results provide the basis on which to examine plasmon-influenced conduction in hybrid systems. PMID- 22545581 TI - Actuarial risk assessment in sexually motivated intimate-partner violence. AB - The present study is the first independent cross-validation of the Ontario Domestic Assault Risk Assessment (ODARA) and the Domestic Violence Risk Appraisal Guide (DVRAG) using an incarcerated high-risk sample (N = 66) of offenders released from the Austrian Prison System who have committed at least one sexually motivated offense against their actual or former intimate partners. The mean follow-up period was approximately 55 months. Both instruments showed evidence for their reliability and predictive accuracy, supporting the cross-cultural transferability of these risk assessment instruments. For the prediction of domestic violence recidivism, ODARA and DVRAG yield good predictive accuracy (area under the receiver operating characteristic curve, AUC = .71), and for general criminal and general violent recidivism, both instruments exhibit moderate effect sizes (AUC = .66-.71). Also, the results provide evidence for the discriminant validity of the ODARA. When examining the association between individual ODARA items and recidivism, only a few items were found to be related to domestic violence recidivism. The integration of the Psychopathy Checklist Revised (PCL-R) does not add any incremental predictive accuracy to the ODARA, suggesting that ODARA items capture antisocial and psychopathic traits sufficiently even in incarcerated high-risk offenders. PMID- 22545582 TI - Myths and realities of female-perpetrated terrorism. AB - The authors examined the backgrounds and social experiences of female terrorists to test conflicting accounts of the etiology of this offending group. Data on 222 female terrorists and 269 male terrorists were examined across 8 variables: age at first involvement, educational achievement, employment status, immigration status, marital status, religious conversion, criminal activity, and activist connections. The majority of female terrorists were found to be single, young (<35 years old), native, employed, educated to at least secondary level, and rarely involved in criminality. Compared with their male counterparts, female terrorists were equivalent in age, immigration profile, and role played in terrorism, but they were more likely to have a higher education attainment, less likely to be employed, and less likely to have prior activist connections. The results clarify the myths and realities of female-perpetrated terrorism and suggest that the risk factors associated with female involvement are distinct from those associated with male involvement. PMID- 22545583 TI - Innumeracy and unpacking: bridging the nomothetic/idiographic divide in violence risk assessment. AB - Structured methods to assess violence risk have proliferated in recent years, but such methods are not uncontroversial. A "core controversy" concerns the extent to which an actuarial risk estimate derived at the group level should-morally, logically, or mathematically-apply to any particular individual within the group. This study examines the related psychological question: When do people apply group-level risk estimates to the individual case? We manipulated whether an actuarial risk estimate is "unpacked;" that is, whether the risk factors on which the estimate is based are articulated. Our findings indicate that the degree of unpacking (e.g., listing six vs. three risk factors) increased the likelihood that jury-eligible citizens will apply an actuarial risk estimate in their decision to civilly commit a particular respondent. Unpacking also increased the perceived relevance of the group-level risk estimate to the individual case. We then split the sample based on self-reported numeracy, defined as "ability with or knowledge of numbers." Numeracy moderates the unpacking effect in that unpacking only made a difference for the innumerate participants. The psychological approach we take to the question of group-to-individual inference is not limited to violence-risk assessment, and may apply to many other areas of law in which group-to-individual inferences are frequently, if controversially, made. PMID- 22545584 TI - Judging cheaters: is substance misuse viewed similarly in the athletic and academic domains? AB - The present study examines how individuals judge others who use performance enhancing drugs in two different domains--the athletic domain and the academic domain. Approximately 1,200 males in their freshman year of college completed a questionnaire that included two scenarios. One scenario described an athlete who misused anabolic steroids to help him succeed at a sporting event. The other described a college student who misused Adderall to help him succeed on his midterm exams. Participants rated the extent to which they thought the target had cheated and the extent to which they felt the substances were necessary for success. Results showed participants believed the athlete was more of a cheater than the student, and this difference got larger as past prescription stimulant misuse increased. Results also demonstrated that participants felt Adderall was more necessary than anabolic steroids for bringing about success. Contributions to the literature on zero-sum and non-zero-sum domains are discussed. Implications for future research and efforts to prevent substance misuse are described. PMID- 22545585 TI - Coping with racial discrimination: the role of substance use. AB - Three studies tested the hypothesis that the relation between perceived racial discrimination and substance use reported in previous research is moderated by use of substances as a coping mechanism. Studies 1 and 2 were experimental studies of African American adolescents' and young adults' reactions to a discrimination experience. Results revealed that those who endorsed substance use as-coping reported more willingness to use substances after experiencing discrimination. Study 3 was a prospective study of the relation between perceived discrimination and substance use over an 8-year period in African American adolescents. Results demonstrated that discrimination is associated with increases in substance use, but only among adolescents who endorse substance use as-coping. Together, these three studies provide evidence that experiencing discrimination has both short- and long-term detrimental effects on African Americans' substance use, but significantly more so for those who adopt a pattern of using substances as a coping mechanism. PMID- 22545587 TI - Engineering of an environmentally responsive beta roll peptide for use as a calcium-dependent cross-linking domain for peptide hydrogel formation. AB - We have created a set of rationally designed peptides that form calcium-dependent hydrogels based on the beta roll peptide domain. In the absence of calcium, the beta roll domain is intrinsically disordered. Upon the addition of calcium, the peptide forms a beta helix secondary structure. We have designed two variations of our beta roll domain. First, we have mutated one face of the beta roll domain to contain leucine residues so that the calcium-dependent structural formation leads to dimerization through hydrophobic interactions. Second, an alpha-helical leucine zipper domain is appended to the engineered beta roll domain as an additional means of forming intermolecular cross-links. This full peptide construct forms a hydrogel only in calcium-rich environments. The resulting structural and mechanical properties of the supramolecular assemblies are compared with the wild-type domain using several biophysical techniques including circular dichroism, FRET, bis-ANS binding and microrheology. The calcium responsiveness and rheological properties of the leucine beta roll containing construct confirm the potential of this allosterically regulated scaffold to serve as a cross-linking domain for stimulus-responsive biomaterials development. PMID- 22545586 TI - Harm reduction services as a point-of-entry to and source of end-of-life care and support for homeless and marginally housed persons who use alcohol and/or illicit drugs: a qualitative analysis. AB - BACKGROUND: Homeless and marginally housed persons who use alcohol and/or illicit drugs often have end-of-life care needs that go unmet due to barriers that they face to accessing end-of-life care services. Many homeless and marginally housed persons who use these substances must therefore rely upon alternate sources of end-of-life care and support. This article explores the role of harm reduction services in end-of-life care services delivery to homeless and marginally housed persons who use alcohol and/or illicit drugs. METHODS: A qualitative case study design was used to explore end-of-life care services delivery to homeless and marginally housed persons in six Canadian cities. A key objective was to explore the role of harm reduction services. 54 health and social services professionals participated in semi-structured qualitative interviews. All participants reported that they provided care and support to this population at end-of-life. RESULTS: Harm reduction services (e.g., syringe exchange programs, managed alcohol programs, etc.) were identified as a critical point-of-entry to and source of end of-life care and support for homeless and marginally housed persons who use alcohol and/or illicit drugs. Where possible, harm reduction services facilitated referrals to end-of-life care services for this population. Harm reduction services also provided end-of-life care and support when members of this population were unable or unwilling to access end-of-life care services, thereby improving quality-of-life and increasing self-determination regarding place-of death. CONCLUSIONS: While partnerships between harm reduction programs and end-of life care services are identified as one way to improve access, it is noted that more comprehensive harm reduction services might be needed in end-of-life care settings if they are to engage this underserved population. PMID- 22545588 TI - Capulet and Slingshot share overlapping functions during Drosophila eye morphogenesis. AB - BACKGROUND: CAP/Capulet (Capt), Slingshot (Ssh) and Cofilin/Twinstar (Tsr) are actin-binding proteins that restrict actin polymerization. Previously, it was shown that low resolution analyses of loss-of-function mutations in capt, ssh and tsr all show ectopic F-actin accumulation in various Drosophila tissues. In contrast, RNAi depletion of capt, tsr and ssh in Drosophila S2 cells all affect actin-based lamella formation differently. Whether loss of these three related genes might cause the same effect in the same tissue remains unclear. METHODS: Loss-of-function mutant clones were generated using the MARCM or EGUF system whereas overexpression clones were generated using the Flip-out system. Immunostaining were then performed in eye imaginal discs with clones. FRAP was performed in cultured eye discs. RESULTS: Here, we compared their loss-of function phenotype at single-cell resolution, using a sheet of epithelial cells in the Drosophila eye imaginal disc as a model system. Surprisingly, we found that capt and ssh, but not tsr, mutant cells within and posterior to the morphogenetic furrow (MF) shared similar phenotypes. The capt/ssh mutant cells possessed: (1) hexagonal cell packing with discontinuous adherens junctions; and (2) largely complementary accumulation of excessive phosphorylated myosin light chain (p-MLC) and F-actin rings at the apical cortex. We further showed that the capt/ssh mutant phenotypes depended on the inactivation of protein kinase A (PKA) and activation of Rho. CONCLUSIONS: Although Capt, Ssh and Tsr were reported to negatively regulate actin polymerization, we found that Capt and Ssh, but not Tsr, share overlapping functions during eye morphogenesis. PMID- 22545589 TI - Effect of endoplasmic reticulum stress on inflammation and adiponectin regulation in human adipocytes. AB - The endoplasmic reticulum (ER) of adipocytes plays a major role in the assembly and secretion of adipokines. The levels of serum adiponectin, secreted by adipocytes, are decreased in insulin resistance, diabetes, and obesity. The role of ER stress in downregulating adiponectin levels has been demonstrated in mouse models of obesity. Studies examining human adipose tissue have indicated that there is an increase in the ER stress transcript HSPA5 with increased body mass index (BMI). However, it is not established whether ER stress results in changes in adiponectin levels or multimerization in human adipocytes. We examined whether the induction of ER stress using tunicamycin, thapsigargin, or palmitate alters the messenger RNA (mRNA) and protein expression of adiponectin and the mRNA expression of chaperones ERP44 and ERO1 in adult-derived human adipocyte stem (ADHAS) cells. ER stress was measured using key indicators of ER stress-HSPA5, ERN1, CHOP, and GADD34, as well as changes in eIF2alpha phosphorylation. Because ER stress is suggested to be the proximal cause of inflammation in adipocytes, we further examined the change in inflammatory status by quantitating the change in Ikappabeta-alpha protein following the induction of ER stress. Our studies indicate that: (1) ER stress markers were increased to a higher degree using tunicamycin or thapsigargin compared to palmitate; (2) ER stress significantly decreased adiponectin mRNA in response to tunicamycin and thapsigargin, but palmitate did not decrease adiponectin mRNA levels. In all three instances, the induction of ER stress was accompanied by a decrease in adiponectin protein as well as adiponectin multimerization. All three inducers of ER stress increased tumor necrosis factor-alpha (TNF-alpha) mRNA and decreased Ikappabeta-alpha protein in adipocytes. The data suggest that ER stress modifies adiponectin secretion and induces inflammation in ADHAS cells. PMID- 22545590 TI - Relationship between the preoperative body mass index and the resolution of metabolic syndrome following Roux-en-Y gastric bypass. AB - BACKGROUND: The increased prevalence of overweight and obesity has reached alarming proportions worldwide and has serious health implications, including an association with an increase in metabolic syndrome. Among the methods to control metabolic syndrome, bariatric surgery plays an important role and can provide a significant improvement in the components of metabolic syndrome. OBJECTIVE: The aim of this study was to determine the relationship between the preoperative body mass index (BMI) and the postoperative resolution of metabolic syndrome [using the National Cholesterol Education Program (NCEP ATP III criteria)] in patients undergoing Roux-en-Y gastric bypass (RYGB). METHODS: Retrospective analysis of a consecutive series of cases, stratified by BMI into three groups (group 1, BMI <40 kg/m(2), group 2, BMI 40-49.9 kg/m(2), and group 3, BMI 50 >= kg/m(2)) consisting of both sexes between 20 and 60 years of age. The cohort consisted of 149 patients undergoing RYGB. Anthropometric, biochemical, and clinical evaluations were performed preoperatively and then at 30 and 180 days postoperatively. RESULTS: The average age was 40 years, and the patients were predominately female (72%). At the end of the study period, all groups showed a significant reduction in metabolic syndrome compared with preoperative levels. Logistic regression showed a higher percentage of metabolic syndrome in patients in group 3 after 180 days. CONCLUSION: There was significant resolution of metabolic syndrome in all groups, independently of the preoperative BMI. However, in group 3 (BMI >= 50 kg/m(2)), 22% of individuals still presented with metabolic syndrome at 180 days postoperatively (P=0.03). PMID- 22545591 TI - Coherent and incoherent interactions between cofacial pi-conjugated oligomer dimers in macrocycle templates. AB - The interactions between two pi-conjugated oligomers templated in molecular scaffolds are revealed as a function of separation and orientation, providing models of intermolecular interactions in bulk organic semiconductor materials. For a variety of dimer geometries (acyclic and macrocyclic) of the same model oligomer, no change in fluorescence spectra, fluorescence dynamics, or low temperature single-molecule emission characteristics is observed. A small red shift and slowing of fluorescence in the most closely spaced macrocyclic dimer structure is thought to arise both due to an intramolecular solvatochromic shift as well as from weak intramolecular aggregate formation. No corresponding effect is observed in bulk films of the acyclic model oligomer, implying the absence of intermolecular aggregate or excimer formation due to random relative dipole orientations. The largest effect of intramolecular geometry of the model dimer structures is seen in transient fluorescence depolarization, where an open ring geometry leads to rapid depolarization, compared to the corresponding macrocycle, due to the presence of a range of molecular transition dipole moment orientations. Self-assembled monolayers of the molecules on HOPG investigated by scanning-tunneling microscopy further illustrate the conformational variability of the open dimers in contrast to the fixed conformation of the closed dimers. PMID- 22545592 TI - Ochratoxin A removal from red wine by several oenological fining agents: bentonite, egg albumin, allergen-free adsorbents, chitin and chitosan. AB - The ability of several oenological fining agents to remove ochratoxin A (OTA) from red wine was studied. The adsorbents tested were activated sodium bentonite, egg albumin, allergen-free adsorbents (complex PVPP, plant protein and amorphous silica (complex) and high molecular weight gelatine), and the non-toxic biodegradable polymers (chitin and chitosan). Several dosages within the oenological use range were tested and the wine pH, colour parameters and polyphenol concentration impact associated with each fining agent were studied. Generally, OTA removal achieved in all treatments was higher when the adsorbent dosage increased, but the impact on wine quality also was higher. Chitin at 50 g hl(-1) removed 18% the OTA without affecting significantly the wine-quality parameters. At the highest dosage tested the gelatine and complex treatments achieved greater OTA removal (up to 39-40%) compared with bentonite, egg albumin and chitin. Moreover, the gelatine and the complex had a lower impact on colour parameters and polyphenol concentration compared with chitosan, whilst OTA was reduced to around 40%. Chitosan achieved the greatest OTA removal (67%), but it strongly affected the wine-quality parameters. Otherwise, bentonite showed a relative efficiency to remove OTA, but the CI value decreased considerably. The egg albumin treatment only removed OTA up to 16% and moreover affected strongly the CI value and CIELab parameters. The results of this survey showed that the non-toxic chitin adsorbent and the allergen-free adsorbents tested could be considered as alternative fining agents to reduce OTA in red wine. PMID- 22545593 TI - Suture type and ultrasound-indicated cerclage efficacy. AB - OBJECTIVE: To assess whether type of suture material affects cerclage efficacy for preterm birth (PTB) prevention. METHODS: Secondary analysis of a multicenter trial of ultrasound-indicated cerclage for short cervical length (CL), in which women with prior spontaneous PTB at 16-33 6/7 weeks, a singleton gestation and CL < 25 mm between 16-22 6/7 weeks, were randomized to McDonald cerclage or no cerclage. Outcomes of women who underwent cerclage were analyzed by type of suture material, comparing polyester braided thread (MersileneTM or EthibondTM) to Mersilene tapeTM. Primary outcome was PTB < 35 weeks. RESULTS: 138 women underwent McDonald cerclage: 84 (61%) received polyester braided thread and 46 (33%) Mersilene tapeTM. Eight (6%) received monofilament suture and were excluded from analysis. Rates of PTB < 35 weeks were similar, 35% for polyester braided thread vs 24% for Mersilene tapeTM (p = .24). Birth gestational age was also similar among the 2 groups (p = .18). CONCLUSION: Type of suture material may not affect ultrasound-indicated cerclage efficacy in high-risk women with short CL, but further study is needed. Polyester braided thread (MersileneTM or EthibondTM) and polyester braided Mersilene tapeTM seem to have similar efficacy. PMID- 22545594 TI - Modeling multiple response processes in judgment and choice. AB - In this article, I show how item response models can be used to capture multiple response processes in psychological applications. Intuitive and analytical responses, agree-disagree answers, response refusals, socially desirable responding, differential item functioning, and choices among multiple options are considered. In each of these cases, I show that the response processes can be measured via pseudoitems derived from the observed responses. The estimation of these models via standard software programs that allow for missing data is also discussed. The article concludes with two detailed applications that illustrate the prevalence of multiple response processes. PMID- 22545595 TI - On effect size. AB - The call for researchers to report and interpret effect sizes and their corresponding confidence intervals has never been stronger. However, there is confusion in the literature on the definition of effect size, and consequently the term is used inconsistently. We propose a definition for effect size, discuss 3 facets of effect size (dimension, measure/index, and value), outline 10 corollaries that follow from our definition, and review ideal qualities of effect sizes. Our definition of effect size is general and subsumes many existing definitions of effect size. We define effect size as a quantitative reflection of the magnitude of some phenomenon that is used for the purpose of addressing a question of interest. Our definition of effect size is purposely more inclusive than the way many have defined and conceptualized effect size, and it is unique with regard to linking effect size to a question of interest. Additionally, we review some important developments in the effect size literature and discuss the importance of accompanying an effect size with an interval estimate that acknowledges the uncertainty with which the population value of the effect size has been estimated. We hope that this article will facilitate discussion and improve the practice of reporting and interpreting effect sizes. PMID- 22545597 TI - Why confessions trump innocence. AB - As illustrated by the story of Amanda Knox and many others wrongfully convicted, false confessions often trump factual innocence. Focusing on consequences, recent research suggests that confessions are powerfully persuasive as a matter of logic and common sense; that many false confessions contain richly detailed narratives and accurate crime facts that appear to betray guilty knowledge; and that confessions in general can corrupt other evidence from lay witnesses and forensic experts-producing an illusion of false support. This latter phenomenon, termed "corroboration inflation," suggests that pretrial corroboration requirements as well as the concept of "harmless error" on appeal are based on an erroneous presumption of independence among items of evidence. In addition to previously suggested reforms to police practices that are designed to curb the risk of false confessions, measures should be taken as well to minimize the rippling consequences of those confessions. PMID- 22545596 TI - Disruptive innovations for designing and diffusing evidence-based interventions. AB - Evidence-based therapeutic and preventive intervention programs (EBIs) have been growing exponentially. Yet EBIs have not been broadly adopted in the United States. In order for our EBI science to significantly reduce disease burden, we need to critically reexamine our scientific conventions and norms. Innovation may be spurred by reexamining the traditional biomedical model for validating, implementing, and diffusing EBI products and science. The model of disruptive innovations suggests that we reengineer EBIs on the basis of their most robust features in order to serve more people in less time and at lower cost. A disruptive innovation provides a simpler and less expensive alternative that meets the essential needs for the majority of consumers and is more accessible, scalable, replicable, and sustainable. Examples of disruptive innovations from other fields include minute clinics embedded in retail chain drug stores, $2 generic eyeglasses, automated teller machines, and telemedicine. Four new research approaches will be required to support disruptive innovations in EBI science: synthesize common elements across EBIs; experiment with new delivery formats (e.g., consumer controlled, self-directed, brief, paraprofessional, coaching, and technology and media strategies); adopt market strategies to promote and diffuse EBI science, knowledge, and products; and adopt continuous quality improvement as a research paradigm for systematically improving EBIs, based on ongoing monitoring data and feedback. EBI science can have more impact if it can better leverage what we know from existing EBIs in order to inspire, engage, inform, and support families and children to adopt and sustain healthy daily routines and lifestyles. PMID- 22545598 TI - Prosodic temporal alignment of co-speech gestures to speech facilitates referent resolution. AB - Using a referent detection paradigm, we examined whether listeners can determine the object speakers are referring to by using the temporal alignment between the motion speakers impose on objects and their labeling utterances. Stimuli were created by videotaping speakers labeling a novel creature. Without being explicitly instructed to do so, speakers moved the creature during labeling. Trajectories of these motions were used to animate photographs of the creature. Participants in subsequent perception studies heard these labeling utterances while seeing side-by-side animations of two identical creatures in which only the target creature moved as originally intended by the speaker. Using the cross modal temporal relationship between speech and referent motion, participants identified which creature the speaker was labeling, even when the labeling utterances were low-pass filtered to remove their semantic content or replaced by tone analogues. However, when the prosodic structure was eliminated by reversing the speech signal, participants no longer detected the referent as readily. These results provide strong support for a prosodic cross-modal alignment hypothesis. Speakers produce a perceptible link between the motion they impose upon a referent and the prosodic structure of their speech, and listeners readily use this prosodic cross-modal relationship to resolve referential ambiguity in word learning situations. PMID- 22545600 TI - Listeners retune phoneme categories across languages. AB - Native listeners adapt to noncanonically produced speech by retuning phoneme boundaries by means of lexical knowledge. We asked whether a second language lexicon can also guide category retuning and whether perceptual learning transfers from a second language (L2) to the native language (L1). During a Dutch lexical-decision task, German and Dutch listeners were exposed to unusual pronunciation variants in which word-final /f/ or /s/ was replaced by an ambiguous sound. At test, listeners categorized Dutch minimal word pairs ending in sounds along an /f/-/s/ continuum. Dutch L1 and German L2 listeners showed boundary shifts of a similar magnitude. Moreover, following exposure to Dutch accented English, Dutch listeners also showed comparable effects of category retuning when they heard the same speaker speak her native language (Dutch) during the test. The former result suggests that lexical representations in a second language are specific enough to support lexically guided retuning, and the latter implies that production patterns in a second language are deemed a stable speaker characteristic likely to transfer to the native language; thus retuning of phoneme categories applies across languages. PMID- 22545599 TI - Spatial attention modulates the precedence effect. AB - Communication and navigation in real environments rely heavily on the ability to distinguish objects in acoustic space. However, auditory spatial information is often corrupted by conflicting cues and noise such as acoustic reflections. Fortunately the brain can apply mechanisms at multiple levels to emphasize target information and mitigate such interference. In a rapid phenomenon known as the precedence effect, reflections are perceptually fused with the veridical primary sound. The brain can also use spatial attention to highlight a target sound at the expense of distracters. Although attention has been shown to modulate many auditory perceptual phenomena, rarely does it alter how acoustic energy is first parsed into objects, as with the precedence effect. This brief report suggests that both endogenous (voluntary) and exogenous (stimulus-driven) spatial attention have a profound influence on the precedence effect depending on where they are oriented. Moreover, we observed that both types of attention could enhance perceptual fusion while only exogenous attention could hinder it. These results demonstrate that attention, by altering how auditory objects are formed, guides the basic perceptual organization of our acoustic environment. PMID- 22545601 TI - A familiar-size Stroop effect: real-world size is an automatic property of object representation. AB - When we recognize an object, do we automatically know how big it is in the world? We employed a Stroop-like paradigm, in which two familiar objects were presented at different visual sizes on the screen. Observers were faster to indicate which was bigger or smaller on the screen when the real-world size of the objects was congruent with the visual size than when it was incongruent--demonstrating a familiar-size Stroop effect. Critically, the real-world size of the objects was irrelevant for the task. This Stroop effect was also present when only one item was present at a congruent or incongruent visual size on the display. In contrast, no Stroop effect was observed for participants who simply learned a rule to categorize novel objects as big or small. These results show that people access the familiar size of objects without the intention of doing so, demonstrating that real-world size is an automatic property of object representation. PMID- 22545602 TI - On the prevalence of directly retrieved autobiographical memories. AB - In this study, we used process measures to understand how people recall autobiographical memories in response to different word cues. In Experiment 1, participants provided verbal protocols when cued by object and emotion words. Participants also reported whether memories had come directly to mind. The self reports and independent ratings of the verbal protocols indicated that directly recalled memories are much faster and more frequent than generated memories and are more prevalent when cued by objects than emotions. Experiment 2 replicated these results without protocols to eliminate any demand characteristics or output interference associated with the protocol method. In Experiment 3, we obtained converging results using a different method for assessing retrieval strategies by asking participants to assess the amount of information required to retrieve memories. The greater proportion of fast direct retrievals when memories are cued by objects accounts for reaction time differences between object and emotion cues, and not the commonly accepted explanation based on ease of retrieval. We argue for a dual-strategies approach that disputes generation as the canonical form of autobiographical memory retrieval and discuss the implication of these findings for the representation of personal events in autobiographical memory. PMID- 22545603 TI - On the flexibility of social source memory: a test of the emotional incongruity hypothesis. AB - A popular hypothesis in evolutionary psychology posits that reciprocal altruism is supported by a cognitive module that helps cooperative individuals to detect and remember cheaters. Consistent with this hypothesis, a source memory advantage for faces of cheaters (better memory for the cheating context in which these faces were encountered) was observed in previous studies. Here, we examined whether positive or negative expectancies would influence source memory for cheaters and cooperators. A cooperation task with virtual opponents was used in Experiments 1 and 2. Source memory for the emotionally incongruent information was enhanced relative to the congruent information: In Experiment 1, source memory was best for cheaters with likable faces and for cooperators with unlikable faces; in Experiment 2, source memory was better for smiling cheater faces than for smiling cooperator faces, and descriptively better for angry cooperator faces than for angry cheater faces. Experiments 3 and 4 showed that the emotional incongruity effect generalizes to 3rd-party reputational information (descriptions of cheating and trustworthy behavior). The results are inconsistent with the assumption of a highly specific cheater detection module. Focusing on expectancy-incongruent information may represent a more efficient, general, and hence more adaptive memory strategy for remembering exchange relevant information than focusing only on cheaters. PMID- 22545605 TI - How L2 words are stored: the episodic L2 hypothesis. AB - This article reports findings from 3 experiments examining whether 2nd language (L2) words are represented in episodic memory, as originally proposed by Jiang and Forster (2001). Experiment 1 was a direct replication of Jiang and Forster, testing highly proficient Chinese-English bilinguals. Masked translation priming was obtained in an episodic recognition task from L2 to the 1st language (L1) for studied "old" L1 targets but not for unstudied "new" targets. This experiment also confirmed the translation asymmetry generally found in lexical decision tasks, namely, priming in the L1-L2 direction but not in the L2-L1 direction. Experiment 2 showed that recently learned words in an unfamiliar language (therefore, words that are obviously represented episodically) could also prime their L1 translations in an episodic recognition task but not in a lexical decision task. Finally, in Experiment 3, masked repetition priming was used with an episodic recognition memory task. For native speakers of English, repetition (L1-L1) priming is obtained only for old words, because there is no episodic representation for new words. However, Chinese-English bilinguals tested with the same items showed repetition (L2-L2) priming for both old and new words, indicating that the new L2 words were represented episodically as well. Overall, the results from these 3 experiments support the hypothesis that L2 words are represented in episodic memory. Finally, the mechanisms behind why L2-L1 translation priming can be obtained in episodic recognition and not in lexical decision are discussed. PMID- 22545604 TI - Mediator-based encoding strategies in source monitoring in young and older adults. AB - Past research has examined the contribution of mediator-based encoding strategies (interactive imagery and sentence generation) to individual (particularly age related) differences in associative memory exclusively in the paired-associates paradigm. In the present study, we examined young and older adults' mediator based strategy use on source-monitoring tasks. Participants spontaneously used mediator-based strategies to encode about 30% to 40% of word-source pairs and were able to follow instructions to use the specific mediator-based strategy of interactive imagery; mediator-based strategy use was associated with higher source memory and explained variance in source memory. There were no age-related differences in the patterns of mediator-based strategy production and utilization. Age-related differences in source memory were explained by age related declines in the ability to bind information in memory (incidental memory for digit-symbol associations) but not by encoding strategy production. Results underscore the importance of assessing encoding strategy use for understanding individual differences in source memory. PMID- 22545607 TI - The role of orthography in the semantic activation of neighbors. AB - There is now considerable evidence that a letter string can activate semantic information appropriate to its orthographic neighbors (e.g., Forster & Hector's, 2002, TURPLE effect). This phenomenon is the focus of the present research. Using Japanese words, we examined whether semantic activation of neighbors is driven directly by orthographic similarity alone or whether there is also a role for phonological similarity. In Experiment 1, using a relatedness judgment task in which a Kanji word-Katakana word pair was presented on each trial, an inhibitory effect was observed when the initial Kanji word was related to an orthographic and phonological neighbor of the Katakana word target but not when the initial Kanji word was related to a phonological but not orthographic neighbor of the Katakana word target. This result suggests that phonology plays little, if any, role in the activation of neighbors' semantics when reading familiar words. In Experiment 2, the targets were transcribed into Hiragana, a script they are typically not written in, requiring readers to engage in phonological coding. In that experiment, inhibitory effects were observed in both conditions. This result indicates that phonologically mediated semantic activation of neighbors will emerge when phonological processing is necessary in order to understand a written word (e.g., when that word is transcribed into an unfamiliar script). PMID- 22545606 TI - Location memory for dots in polygons versus cities in regions: evaluating the category adjustment model. AB - We conducted 3 experiments to examine the category adjustment model (Huttenlocher, Hedges, & Duncan, 1991) in circumstances in which the category boundaries were irregular schematized polygons made from outlines of maps. For the first time, accuracy was tested when only perceptual and/or existing long term memory information about identical locations was cued. Participants from Alberta, Canada and California received 1 of 3 conditions: dots-only, in which a dot appeared within the polygon, and after a 4-s dynamic mask the empty polygon appeared and the participant indicated where the dot had been; dots-and-names, in which participants were told that the first polygon represented Alberta/California and that each dot was in the correct location for the city whose name appeared outside the polygon; and names-only, in which there was no first polygon, and participants clicked on the city locations from extant memory alone. Location recall in the dots-only and dots-and-names conditions did not differ from each other and had small but significant directional errors that pointed away from the centroids of the polygons. In contrast, the names-only condition had large and significant directional errors that pointed toward the centroids. Experiments 2 and 3 eliminated the distribution of stimuli and overall screen position as causal factors. The data suggest that in the "classic" category adjustment paradigm, it is difficult to determine a priori when Bayesian cue combination is applicable, making Bayesian analysis less useful as a theoretical approach to location estimation. PMID- 22545608 TI - Schema bias in source monitoring varies with encoding conditions: support for a probability-matching account. AB - Two experiments examined reliance on schematic knowledge in source monitoring. Based on a probability-matching account of source guessing, a schema bias will only emerge if participants do not have a representation of the source-item contingency in the study list, or if the perceived contingency is consistent with schematic expectations. Thus, the account predicts that encoding conditions that affect contingency detection also affect schema bias. In Experiment 1, the schema bias commonly found when schematic information about the sources is not provided before encoding was diminished by an intentional source-memory instruction. In Experiment 2, the depth of processing of schema-consistent and schema inconsistent source-item pairings was manipulated. Participants consequently overestimated the occurrence of the pairing type they processed in a deep manner, and their source guessing reflected this biased contingency perception. Results support the probability-matching account of source guessing. PMID- 22545610 TI - A negative effect of repetition in episodic memory. AB - One of the foundational principles of human memory is that repetition (i.e., being presented with a stimulus multiple times) improves recall. In the current study a group of participants who studied a list of cue-target pairs twice recalled fewer targets than a group who studied the pairs only once, a negative repetition effect. Such a demonstration is novel yet theoretically motivated. Though participants in each condition studied the same set of cue-target pairs, those who studied the pairs twice were initially presented with the pairs in a way that hindered organizational processing. Even after a 2nd presentation when the pairs were presented in a manner that should facilitate organizational processing (the same presentation given to participants who received the list only once), participants did not capitalize on the structure and consequently recalled fewer targets. The results offer compelling support for the item specific-relational account. PMID- 22545609 TI - Diffusion model drift rates can be influenced by decision processes: an analysis of the strength-based mirror effect. AB - Improving memory for studied items (targets) often helps participants reject nonstudied items (lures), a pattern referred to as the strength-based mirror effect (SBME). Criss (2010) demonstrated the SBME in diffusion model drift rates; that is, the target drift rate was higher and the lure drift rate was lower for lists of words studied 5 times versus lists of words studied once. She interpreted the drift rate effect for lures as evidence for the differentiation process, whereby strong memory traces produce a poorer match to lure items than do weak memory traces. However, she noted that strength may have also affected a model parameter called the drift criterion-a participant-controlled decision parameter that defines the zero point in drift rate. We directly contrasted the differentiation and drift-criterion accounts by manipulating list strength either at both encoding and retrieval (which produces a differentiation difference in the studied traces) or at retrieval only (which equates differentiation from the study list but provides the opportunity to change decision processes based on strength). Across 3 experiments, results showed that drift rates for lures were lower on strong tests than on weak tests, and this effect was observed even when strength was varied at retrieval alone. Therefore, results provided evidence that the SBME is produced by changes in decision processes, not by differentiation of memory traces. PMID- 22545611 TI - Speaker knowledge influences the comprehension of pragmatic inferences. AB - Inferring what speakers mean from what they say requires consideration of what they know. For instance, depending on the speaker's level of expertise, uttering Some squirrels hibernate can imply that not all squirrels hibernate, or it might imply the weaker proposition that the speaker does not know whether all squirrels hibernate. The present study examines the extent to which speaker knowledge influences implied meanings as well as the timing of any such influence. Using a self-paced presentation, participants read sentences containing some in contexts where a speaker should know whether all was true, or where the speaker merely might know whether all was true. This knowledge manipulation was found to have immediate and reliable effects on the type of inference that was drawn. In contrast, knowledge played no role when the same meanings were conveyed literally. This work thus demonstrates that perceivers consider the speaker's knowledge state incrementally to establish the speaker's communicative goals. PMID- 22545612 TI - Implicit sequence learning based on instructed task set. AB - How does the way we code and control actions influence automatic skill acquisition processes? Wenke and Frensch (2005) showed that instructions can lead participants to code spatial responses based on color. Here, we tested in 3 experiments to what extent response labeling and instruction-based response coding can determine what is learned in implicit sequence learning. Instructions mapped 4 gray shape stimuli to 1 of the 4 keys each in a serial reaction task, referring to the keys in terms of either their color or their spatial location. In Experiments 1 and 2 we found that people in the color instruction conditions used color for action control and acquired sequence knowledge containing color: They were susceptible to irrelevant stimulus colors at transfer and could transfer color sequence knowledge to a new arrangement of response positions and fingers, whereas participants who had received spatial instructions could not. Implicit sequence learning was thus surprisingly flexible. Depending on whether an arbitrary nonspatial response feature was used or not used to explain the stimulus-response mappings, we either found or did not find evidence that this feature became part of action control and sequence learning. Furthermore, Experiment 3 suggested that response position might become part of the sequence knowledge even if instructions do not emphasize this response feature. Together, the findings suggest that implicit sequence learning is based on action control, which in turn strongly, but not entirely, depends on which response features are used to explain the stimulus-response mappings in the instructions. PMID- 22545613 TI - Imagined actions aren't just weak actions: task variability promotes skill learning in physical practice but not in mental practice. AB - Early research on visual imagery led investigators to suggest that mental visual images are just weak versions of visual percepts. Later research helped investigators understand that mental visual images differ in deeper and more subtle ways from visual percepts. Research on motor imagery has yet to reach this mature state, however. Many authors have implicitly subscribed to the view that motor images are just weak versions of physical actions. We tested this view by comparing motor learning in variable practice conditions with motor learning in constant practice conditions when participants either physically or mentally practiced golf-putting. We found that physical and mental practice both resulted in significant learning but that variable practice was only better than constant practice when participants practiced physically. This outcome was not predicted by the hypothesis that motor imagery is just a weaker form of real-action experience. PMID- 22545614 TI - Instruction-based task-rule congruency effects. AB - In the present study, we investigated the functional characteristics of task sets that were never applied before and were formed only on the basis of instructions. We tested if such task sets could elicit a task-rule congruency effect, which implies the automatic activation of responses in the context of another task. To this end, a novel procedure was developed that revealed instruction-based task rule congruency effects in 2 experiments. Although the effect seems quite general (Experiment 1), it still necessitates the formation of a task set, as it cannot be induced by the mere maintenance of instructions in declarative working memory (Experiment 2). We conclude that a task set representing only key features of an upcoming task can be formed on the basis of instructions alone to such a degree that it can automatically trigger a response tendency in another task. Implications of our results for the impact of instructions on performance in general and for the occurrence of task-rule congruency effects in particular are discussed. PMID- 22545615 TI - Memory indexing: a novel method for tracing memory processes in complex cognitive tasks. AB - We validate an eye-tracking method applicable for studying memory processes in complex cognitive tasks. The method is tested with a task on probabilistic inferences from memory. It provides valuable data on the time course of processing, thus clarifying previous results on heuristic probabilistic inference. Participants learned cue values of decision alternatives that were arranged within spatial frames. Later, they were told about the validities of cue dimensions and performed memory-based binary choice tasks: first, according to spontaneously adopted decision strategies and, subsequently, according to instructed decision strategies (a noncompensatory lexicographic strategy and a compensatory equal weighting strategy). During decision making, participants saw only the empty spatial frames without cue values. The spontaneously adopted and instructed decision strategies were reflected in discriminable gaze patterns on the empty spatial frames. When retrieving information no longer visible, participants tended to fixate on locations at which information was visible during the learning phase (the looking-at-nothing phenomenon). Gaze patterns were consistent with cue-wise and alternative-wise patterns of information search predicted for the instructed decision strategies as well as for the spontaneously adopted strategies identified based on decision outcomes. These findings extend previous results on the connection between memory and gaze. Furthermore, the successful application of memory indexing suggests its wider applicability in studying memory-based tasks. PMID- 22545616 TI - Working-memory load and temporal myopia in dynamic decision making. AB - We examined the role of working memory (WM) in dynamic decision making by having participants perform decision-making tasks under single-task or dual-task conditions. In 2 experiments participants performed dynamic decision-making tasks in which they chose 1 of 2 options on each trial. The decreasing option always gave a larger immediate reward but caused future rewards for both options to decrease. The increasing option always gave a smaller immediate reward but caused future rewards for both options to increase. In each experiment we manipulated the reward structure such that the decreasing option was the optimal choice in 1 condition and the increasing option was the optimal choice in the other condition. Behavioral results indicated that dual-task participants selected the immediately rewarding decreasing option more often, and single-task participants selected the increasing option more often, regardless of which option was optimal. Thus, dual-task participants performed worse on 1 type of task but better on the other type. Modeling results showed that single-task participants' data were most often best fit by a win-stay, lose-shift (WSLS) rule-based model that tracked differences across trials, and dual-task participants' data were most often best fit by a Softmax reinforcement learning model that tracked recency-weighted average rewards for each option. This suggests that manipulating WM load affects the degree to which participants focus on the immediate versus delayed consequences of their actions and whether they employ a rule-based WSLS strategy, but it does not necessarily affect how well people weigh the immediate versus delayed benefits when determining the long-term utility of each option. PMID- 22545617 TI - Mixing strong and weak targets provides no evidence against the unequal-variance explanation of zROC slope: a comment on Koen and Yonelinas (2010). AB - Koen and Yonelinas (2010; K&Y) reported that mixing classes of targets that had short (weak) or long (strong) study times had no impact on zROC slope, contradicting the predictions of the encoding variability hypothesis. We show that they actually derived their predictions from a mixture unequal-variance signal detection (UVSD) model, which assumes 2 discrete levels of strength instead of the continuous variation in learning effectiveness proposed by the encoding variability hypothesis. We demonstrated that the mixture UVSD model predicts an effect of strength mixing only when there is a large performance difference between strong and weak targets, and the strength effect observed by K&Y was too small to produce a mixing effect. Moreover, we re-analyzed their experiment along with another experiment that manipulated the strength of target items. The mixture UVSD model closely predicted the empirical mixed slopes from both experiments. The apparent misfits reported by K&Y arose because they calculated the observed slopes using the actual range of z-transformed false alarm rates in the data, but they computed the predicted slopes using an extended range from - 5 to 5. Because the mixed predictions follow a slightly curved zROC function, different ranges of scores have different linear slopes. We used the actual range in the data to compute both the observed and predicted slopes, and this eliminated the apparent deviation between them. PMID- 22545619 TI - Reciprocal relations between recovery and work engagement: the moderating role of job stressors. AB - In this paper, we examined the within-person relations between morning recovery level (i.e., feeling refreshed and replenished) and work engagement throughout the day, and between work engagement throughout the day and the subsequent recovery level at the end of the workday. We hypothesized that job stressors (situational constraints, job demands) moderate these relations. A diary study over 1 workweek with 2 measurement occasions per day (N = 111 persons) provided support for most of the hypotheses: Morning recovery level predicted work engagement, and work engagement predicted subsequent recovery level at the end of the workday after controlling for morning recovery level. As predicted, situational constraints attenuated these relations, but job demands did not. The results suggest that recovery translates into employee work engagement, and work engagement, in turn, prevents a loss in recovery level throughout the day, particularly when situational constraints are low. Situational constraints seem to interrupt the reciprocal processes between recovery level and work engagement. PMID- 22545618 TI - Improving delayed face recognition in Alzheimer's disease by differential outcomes. AB - OBJECTIVE: Previous studies have demonstrated the benefit of the differential outcomes procedure (DOP) in human learning. In the present study we aimed to explore whether the DOP might also help to overcome the face recognition memory deficit commonly observed in Alzheimer's disease (AD) patients. METHOD: A delayed matching-to-sample task was used. Participants were instructed to choose which of the 4 alternative faces (comparison stimuli) matched the previously seen face (sample stimulus). Either short (5 seconds) or long (25 seconds) delays were interposed between the sample and the comparison stimuli. In the differential outcomes condition each sample face was paired with its own outcome. In contrast, in the nondifferential condition, outcomes were randomly arranged. RESULTS: The differential outcomes effect (DOE) was evident in the AD patients with both accuracy and latency data. That is, they showed a significantly better and faster delayed face recognition when differential outcomes were arranged. The analyses also revealed a significant main effect of delay; participants were slower in the 25 seconds condition than in the 5 seconds condition, but the difference was higher in the patients than in the controls. CONCLUSIONS: These findings demonstrate, to our knowledge for the first time, that face recognition memory in patients with Alzheimer is improved when differential outcomes are used and draw attention to the potential of this procedure as a therapeutic technique. PMID- 22545620 TI - Better understanding work unit goal orientation: Its emergence and impact under different types of work unit structure. AB - With a multisource sample comprising 1,150 employees and 230 supervisors, we investigate the effect of leader goal orientation on leader's perceptions of unit performance. We propose that a leader's goal orientation indirectly impacts performance perceptions via the shared achievement goal adopted within the unit (i.e., unit goal orientation). Further, we hypothesize that the presence and impact of unit goal orientation depend on the work unit structure. We find general support for this moderated mediation model, with the strongest evidence being associated with the learning and prove dimensions of goal orientation. PMID- 22545621 TI - Academics' experiences of a respite from work: effects of self-critical perfectionism and perseverative cognition on postrespite well-being. AB - This longitudinal study examined relations between personality and cognitive vulnerabilities and the outcomes of a respite from work. A sample of 77 academic employees responded to week-level measures of affective well-being before, during, and on 2 occasions after an Easter respite. When academics were classified as being either high or low in a self-critical form of perfectionism (doubts about actions), a divergent pattern of respite to postrespite effects was revealed. Specifically, during the respite, the 2 groups of academics experienced similar levels of well-being. However, during postrespite working weeks, the more perfectionistic academics reported significantly higher levels of fatigue, emotional exhaustion, and anxiety. The greater deterioration in well-being experienced by perfectionist academics when first returning to work was mediated by their tendency for perseverative cognition (i.e., worry and rumination) about work during the respite itself. These findings support the view that the self critical perfectionist vulnerability is activated by direct exposure to achievement-related stressors and manifested through perseverative modes of thinking. PMID- 22545622 TI - On the value of aiming high: the causes and consequences of ambition. AB - Ambition is a commonly mentioned but poorly understood concept in social science research. We sought to contribute to understanding of the concept by developing and testing a model in which ambition is a middle-level trait (Cantor, 1990) predicted by more distal characteristics but, due to its teleological nature, more proximally situated to predict career success. A 7-decade longitudinal sample of 717 high-ability individuals from the Terman life-cycle study (Terman, Sears, Cronbach, & Sears, 1989) was used in the current study. Results indicated that ambition was predicted by individual differences-conscientiousness, extraversion, neuroticism, and general mental ability-and a socioeconomic background variable: parents' occupational prestige. Ambition, in turn, was positively related to educational attainment, occupation prestige, and income. Ambition had significant total effects with all of the endogenous variables except mortality. Overall, the results support the thesis that ambition is a middle-level trait-related to but distinct from more distal individual difference variables-that has meaningful effects on career success. PMID- 22545623 TI - Life cycle carbon footprint of shale gas: review of evidence and implications. AB - The recent increase in the production of natural gas from shale deposits has significantly changed energy outlooks in both the US and world. Shale gas may have important climate benefits if it displaces more carbon-intensive oil or coal, but recent attention has discussed the potential for upstream methane emissions to counteract this reduced combustion greenhouse gas emissions. We examine six recent studies to produce a Monte Carlo uncertainty analysis of the carbon footprint of both shale and conventional natural gas production. The results show that the most likely upstream carbon footprints of these types of natural gas production are largely similar, with overlapping 95% uncertainty ranges of 11.0-21.0 g CO(2)e/MJ(LHV) for shale gas and 12.4-19.5 g CO(2)e/MJ(LHV) for conventional gas. However, because this upstream footprint represents less than 25% of the total carbon footprint of gas, the efficiency of producing heat, electricity, transportation services, or other function is of equal or greater importance when identifying emission reduction opportunities. Better data are needed to reduce the uncertainty in natural gas's carbon footprint, but understanding system-level climate impacts of shale gas, through shifts in national and global energy markets, may be more important and requires more detailed energy and economic systems assessments. PMID- 22545624 TI - Atomistic insights into the conversion reaction in iron fluoride: a dynamically adaptive force field approach. AB - Nanoscale metal fluorides are promising candidates for high capacity lithium ion batteries, in which a conversion reaction upon exposure to Li ions enables access to the multiple valence states of the metal cation. However, little is known about the molecular mechanisms and the reaction pathways in conversion that relate to the need for nanoscale starting materials. To address this reaction and the controversial role of intercalation in a promising conversion material, FeF(2), a dynamically adaptive force field that allows for a change in ion charge during reactions is applied in molecular dynamics simulations. Results provide the atomistic view of this conversion reaction that forms nanocrystals of LiF and Fe(0) and addresses the important controversy regarding intercalation. Simulations of Li(+) exposure on the low energy FeF(2) (001) and (110) surfaces show that the reaction initiates at the surface and iron clusters as well as crystalline LiF are formed, sometimes via an amorphous Li-F. Li intercalation is also observed as a function of surface orientation and rate of exposure to the Li, with different behavior on (001) and (110) surfaces. Intercalation along [001] rapid transport channels is accompanied by a slight reduction of charge density on multiple nearby Fe ions per Li ion until enough Li saturates a region and causes the nearby Fe to lose sufficient charge to become destabilized and form the nanocluster Fe(0). The resultant nanostructures are fully consistent with postconversion TEM observations, and the simulations provide the solution to the controversy regarding intercalation versus conversion and the atomistic rationale for the need for nanoscale metal fluoride starting particles in conversion cathodes. PMID- 22545625 TI - Influence of dipole-dipole interactions on coverage-dependent adsorption: CO and NO on Pt(111). AB - Density functional theory (DFT) calculations of energetic, geometric, vibrational, and electrostatic properties of different arrangements of CO and NO at quarter and half monolayer coverage on Pt(111) are presented. Differences in the extents of electron back-donation from the Pt surface to these molecules cause the low-coverage adsorbate dipoles to have opposite signs at atop and more highly coordinated bridge or fcc sites. These dipoles of opposite sign occupy adjacent positions in the experimentally observed atop-bridge or atop-fcc high coverage arrangements, leading to attractive electrostatic interactions and concomitant changes in dipole moments, bond lengths, and vibrational frequencies. The interaction energies are estimated by charge partitioning to extract individual dipoles from the mixed arrangement and by calculations of field-dipole interactions. These estimated dipole interactions contribute significantly (20 60%) to the DFT-calculated relative stability of mixed arrangements over atop-, bridge-, or fcc-only arrangements and thus play an important role in coverage dependent adsorption. We further extend these analyses to a range of molecules with varying dipole moments and show that the general nature of these interactions is not limited to CO and NO. PMID- 22545627 TI - Deciphering the role of GLUT4 N-glycosylation in adipocyte and muscle cell models. AB - GLUT4 (glucose transporter 4) is responsible for the insulin-induced uptake of glucose by muscle and fat cells. In non-stimulated (basal) cells, GLUT4 is retained intracellularly, whereas insulin stimulation leads to its translocation from storage compartments towards the cell surface. How GLUT4 is retained intracellularly is largely unknown. Previously, aberrant GLUT4 N-glycosylation has been linked to increased basal cell-surface levels, while N-glycosylation deficient GLUT4 was found to be quickly degraded. As recycling and degradation of GLUT4 are positively correlated, we hypothesized that incorrect N-glycosylation of GLUT4 might reduce its intracellular retention, resulting in an increased cell surface recycling, in increased basal cell-surface levels, and in enhanced GLUT4 degradation. In the present study, we have investigated N-glycosylation-deficient GLUT4 in detail in 3T3-L1 preadipocytes, 3T3-L1 adipocytes and L6 myoblasts. We have found no alterations in retention, insulin response, internalization or glucose transport activity. Degradation of the mutant molecule was increased, although once present at the cell surface, its degradation was identical with that of wild-type GLUT4. Our findings indicate that N-glycosylation is important for efficient trafficking of GLUT4 to its proper compartments, but once the transporter has arrived there, N-glycosylation plays no further major role in its intracellular trafficking, nor in its functional activity. PMID- 22545626 TI - Transplantation of insulin-producing cells from umbilical cord mesenchymal stem cells for the treatment of streptozotocin-induced diabetic rats. AB - BACKGROUND: Although diabetes mellitus (DM) can be treated with islet transplantation, a scarcity of donors limits the utility of this technique. This study investigated whether human mesenchymal stem cells (MSCs) from umbilical cord could be induced efficiently to differentiate into insulin-producing cells. Secondly, we evaluated the effect of portal vein transplantation of these differentiated cells in the treatment of streptozotocin-induced diabetes in rats. METHODS: MSCs from human umbilical cord were induced in three stages to differentiate into insulin-producing cells and evaluated by immunocytochemistry, reverse transcriptase, and real-time PCR, and ELISA. Differentiated cells were transplanted into the liver of diabetic rats using a Port-A catheter via the portal vein. Blood glucose levels were monitored weekly. RESULTS: Human nuclei and C-peptide were detected in the rat liver by immunohistochemistry. Pancreatic beta-cell development-related genes were expressed in the differentiated cells. C peptide release was increased after glucose challenge in vitro. Furthermore, after transplantation of differentiated cells into the diabetic rats, blood sugar level decreased. Insulin-producing cells containing human C-peptide and human nuclei were located in the liver. CONCLUSION: Thus, a Port-A catheter can be used to transplant differentiated insulin-producing cells from human MSCs into the portal vein to alleviate hyperglycemia among diabetic rats. PMID- 22545629 TI - In situ TEM creation and electrical characterization of nanowire devices. AB - We demonstrate the observation and measurement of simple nanoscale devices over their complete lifecycle from creation to failure within a transmission electron microscope. Devices were formed by growing Si nanowires, using the vapor-liquid solid method, to form bridges between Si cantilevers. We characterize the formation of the contact between the nanowire and the cantilever, showing that the nature of the connection depends on the flow of heat and electrical current during and after the moment of contact. We measure the electrical properties and high current failure characteristics of the resulting bridge devices in situ and relate these to the structure. We also describe processes to modify the contact and the nanowire surface after device formation. The technique we describe allows the direct analysis of the processes taking place during device formation and use, correlating specific nanoscale structural and electrical parameters on an individual device basis. PMID- 22545630 TI - Measurements and planes assessed during second-trimester scans in Brazil: an online survey. AB - OBJECTIVE: The purpose of this study was to estimate what measurements and planes are being assessed during second-trimester scan in Brazil, some characteristics from performing physicians and whether informed consent is being asked. METHODS: Invitational e-mails were sent for all physicians registered in the database from three institutions. Participants who agreed to participate were directed to an online survey consisting 21 questions. All participants who agreed to participate and sent the online survey were included. We excluded participants who sent an incomplete survey; those who perform <= 10 second-trimester scans per month and those who do not work in Brazil. RESULTS: A total of 41,847 invitational e-mails were submitted, and 467 participants were included in the final analysis. We observed a relatively low proportion of participants examining some important planes from fetal heart: only approximately 80% usually examine the five-chamber and three-vessel views and only 44.3% examine the tracheal view. Regarding the expertise of examiners, we observed that 10.7% of participants do not have any certificate acknowledged by our official institutions. Additionally, only 7.9% of the participants ask for signed informed consent before examination. CONCLUSIONS: Specific guidelines are still missing. A relatively high proportion of second trimester scan do not evaluate even what is suggested to be performed in a routine second-trimester scan. PMID- 22545632 TI - Preventing childhood depression. PMID- 22545631 TI - Pyroelectric nanogenerators for harvesting thermoelectric energy. AB - Harvesting thermoelectric energy mainly relies on the Seebeck effect that utilizes a temperature difference between two ends of the device for driving the diffusion of charge carriers. However, in an environment that the temperature is spatially uniform without a gradient, the pyroelectric effect has to be the choice, which is based on the spontaneous polarization in certain anisotropic solids due to a time-dependent temperature variation. Using this effect, we experimentally demonstrate the first application of pyroelectric ZnO nanowire arrays for converting heat energy into electricity. The coupling of the pyroelectric and semiconducting properties in ZnO creates a polarization electric field and charge separation along the ZnO nanowire as a result of the time dependent change in temperature. The fabricated nanogenerator has a good stability, and the characteristic coefficient of heat flow conversion into electricity is estimated to be ~0.05-0.08 Vm(2)/W. Our study has the potential of using pyroelectric nanowires to convert wasted energy into electricity for powering nanodevices. PMID- 22545633 TI - Experiences of major depression: individuals' perspectives on the ability to understand and handle the illness. AB - In all social groups, major depression is an increasingly serious problem in modern society. Important aspects of a person's capacity for recovery are the person's own understanding of the illness and the ability to use this understanding to manage the illness. The aim of this study is to describe how individuals with major depression understand their illness and use their understanding to handle it. Twenty participants treated in community care for major depression as determined by the Diagnostic and Statistical Manual of Mental Disorders were interviewed between February and June, 2008. Content analysis of the interviews revealed three major themes: (1) awakening insight, (2) strategies for understanding and managing, and (3) making use of understanding, each with additional subthemes. Individual understandings of the illness varied and led to differences in the ways participants were able to handle their depression. In clinical care it is essential to support an individual's understanding of depression and his or her use of that understanding to handle the illness. PMID- 22545634 TI - An examination of depressive symptoms and drinking patterns in first year college students. AB - Depression and alcohol use are often found in college students, particularly during their first year. The current study assessed the interrelationship of alcohol use and specific depression symptoms. A large sample (n = 869) of first year students were invited to participate via the Internet. Results indicated that specific depression symptoms correlated with alcohol consumption. Self reported heavy, problem drinkers experienced significantly higher Beck Depression Inventory scores than all other groups. Our findings highlight the importance of screening for both alcohol use and depressed mood in college students. PMID- 22545635 TI - Autism in Vietnam: the case for the development and evaluation of an information book to be distributed at the time of diagnosis. AB - Autism is not generally well understood by the community in the West or in Asia. A diagnosis of autism is distressing for all families. When families receive the diagnosis they are often not able to fully appreciate what it means or process the information given to them. Booklets exist in English that contain relevant autism related information but few have been evaluated. In Vietnam, parents do not have ready access to autism related information. This paper makes the case for offering a Vietnamese language information resource/booklet for parents to be distributed at the beginning of the diagnostic process and evaluating its usefulness. In developed countries autism has been recognised since the 1940s (Kanner, 1943). More recently it is being increasingly recognised in children with average and above intelligence. In Vietnam, a Western view of autism is just developing. Consequently community resources are undeveloped. The community, in general, and health services for children, in particular, have a rudimentary understanding of autism. This paper discusses a Western understanding of autism, autism in Vietnam, and suggests one possible strategy for addressing the educational needs around autism in Vietnam. PMID- 22545636 TI - Changes in persistent delusions in schizophrenia using guided self-determination: a single case study. AB - Delusions in persons with schizophrenia who have limited insight have been targeted with different treatment modalities with equivocal results. Working with the Guided Self-Determination method used in shared decision-making and problem solving, a 55-year-old male diagnosed with schizophrenia gained insight into his own delusions during a period of six weeks with individual training. The case study is based on qualitative data, reflection sheets, and interview and field notes from the Guided Self-Determination training. The patient's new insight developed in a process from resistance to receptiveness and then from doubt to reaching a new system in his thoughts. PMID- 22545637 TI - Transgender identity development as represented by a group of transgendered adults. AB - The world of persons who identify as transgendered is complex making its representation in an article challenging. This article represents work done to raise awareness among all health professionals about the lives and experiences of transgendered persons, who receive little coverage in our textbooks, professional journals, or student experiences. Transgendered lives cannot be simply summed up as a community of people who feel like they are "in the wrong body." Their experiences, issues, and identities are complex, but worthy of the time, energy, patience, and caring it takes to learn about them. We took a postmodern feminist stance to explore transgendered adults' first-hand accounts of identity development. The research question guiding the analysis presented here was: How do transgendered individuals describe their experiences of recognizing, acknowledging, and developing their identity as transgendered? Participants' stories about how they came to recognize and experience their identity as transgendered, analyzed from a lifespan perspective, displayed a similar pattern of life experience, reflected in three prominent themes: an early sense of body mind dissonance, negotiating and managing identities, and the process of transition. The process that participants describe, beginning with childhood and ending with transition and the resolution of bodily discomfort, appears to be staged and developmental in nature. Further exploration into this process and comparison with other developmental theories may yield a model of normal, non pathological development as transgendered. PMID- 22545638 TI - Postpartum stressors: a content analysis. AB - A qualitative content analysis was conducted on narratives written by 127 mothers at four to six weeks postpartum. This study aimed to identify and compare postpartum stressors to the Tennessee Postpartum Stress Scale (TPSS). The TPSS is a guide to common postpartum stressors and an instrument to assess postpartum stress. Most participants in this study were white (91%), married (72%), and not working (70%). Eighteen stressor categories aggregated into two themes: Stressors Arising within the Maternal-Newborn Dyad and Stressors External to the Maternal Newborn Dyad. Sixteen of 20 items on the TPSS were identified in the narratives. No stressor categories outside the TPSS were identified. PMID- 22545639 TI - Prescription drug monitoring programs, a response to doctor shopping: purpose, effectiveness, and directions for future research. AB - Prescription drug abuse is a major worldwide problem and its incidence is on the rise, resulting in a huge societal cost. Prescription drug monitoring programs (PDMPs) are electronic databases that collect data on controlled substances so that health care providers can access the data and deter abuse, doctor shopping, and diversion. Currently only a few countries, including the United States and France, have operational PDMPs. The purpose of this paper is to review the literature on prescription drug monitoring programs. There is a paucity of research articles in this area; only 11 articles were published on this topic and relevant in the last ten years. Four themes were identified, (1) the effect of PDMPs on prescribing practices and the effect of PDMPs on the public, (2) the effect of PDMPs on prescribing practices and multiple provider episodes, (3) the effect of PDMPs on prescribing practices and characteristics of patients, and (4) health care professionals' perspectives on PDMPs. Studies have shown that PDMPs decrease diversion and doctor shopping. Despite implementation of PDMPs, prescription drug rates for controlled substances and abuse rates have risen. There is an urgent need for understanding and research on this topic so that action can be taken. PMID- 22545640 TI - The relationships between attitudes toward seclusion and levels of burnout, staff satisfaction, and therapeutic optimism in a district health service. AB - The main purpose of this study was to investigate the relationships between attitudes toward seclusion and levels of burnout, staff satisfaction, and therapeutic optimism. Staff at one district health service inpatient unit (n = 54) completed surveys on their attitudes toward seclusion and levels of burnout, staff satisfaction, and therapeutic optimism. Several moderately large correlations were found between perceiving the patients as feeling punished by seclusion and intrinsic satisfaction (r(s) = -.45, p = .001), and between patients asking to go to the seclusion room and personal accomplishment (r(s) = .39, p = .002). In general, however, most correlations were small or negligible in size. The influence of nurses on the practice of seclusion was clear, with 72% of participants indicating it was nurses who most often make decisions regarding seclusion. Some participants appear to have a broad interpretation of when seclusion should be used, raising doubts about whether it is being employed solely as a measure of last resort. Given their high level of involvement in seclusions, nurses need to be actively involved in organisation-wide initiatives to reduce the use of this practice. PMID- 22545641 TI - Faith community nursing: supporting mental health during life transitions. AB - The Faith Community Nurse can be an important agent in supporting the mental health of individuals during important life transitions by providing social support, spiritual care, referral services, and health education. Faith communities often include individuals of many generations; the young and old, newly married and recently widowed, new parents, and families whose young adults have recently left home. Nurses who provide care in these settings will likely have unique and frequent opportunities to provide mental health services and referrals to individuals experiencing transitions related to crisis, hospitalization, death, and other important life changes. Faith Community Nurses are at the frontline, aiding faith communities in supporting holistic health of the mind, body, and spirit. PMID- 22545642 TI - Registered nurse workforce trends for new entrants age 23-26: hope for the psychiatric nursing workforce shortage. PMID- 22545643 TI - Lurasidone (latuda(r)): an atypical antipsychotic. AB - Lurasidone is a new atypical antipsychotic that has demonstrated positive effects on psychosis, mood, and cognition. This improved efficacy and safety profile for the treatment of schizophrenia. Its overall tolerability profile seems to be comparable to the other atypical antipsychotics. Perhaps its more potent blockade on the 5HT7 receptor will give it more of an advantage in treating the negative symptoms as well as improve cognitive and depressive symptoms associated with schizophrenia. Additionally, it does not appear to have any significant adverse impact on the metabolic profile, such as weight, glucose, or lipid metabolism. Lurasidone is also associated with good cardiovascular tolerability without widening of the QT interval. The use of this medication may be of particular interest in patients presenting with endocrine or cardiovascular abnormalities. The average price for a 30-day supply of lurasidone is $475.98. PMID- 22545646 TI - Building a house on shifting sand: methodological considerations when evaluating the implementation and adoption of national electronic health record systems. AB - BACKGROUND: A commitment to Electronic Health Record (EHR) systems now constitutes a core part of many governments' healthcare reform strategies. The resulting politically-initiated large-scale or national EHR endeavors are challenging because of their ambitious agendas of change, the scale of resources needed to make them work, the (relatively) short timescales set, and the large number of stakeholders involved, all of whom pursue somewhat different interests. These initiatives need to be evaluated to establish if they improve care and represent value for money. METHODS: Critical reflections on these complexities in the light of experience of undertaking the first national, longitudinal, and sociotechnical evaluation of the implementation and adoption of England's National Health Service's Care Records Service (NHS CRS). RESULTS/DISCUSSION: We advance two key arguments. First, national programs for EHR implementations are likely to take place in the shifting sands of evolving sociopolitical and sociotechnical and contexts, which are likely to shape them in significant ways. This poses challenges to conventional evaluation approaches which draw on a model of baseline operations -> intervention -> changed operations (outcome). Second, evaluation of such programs must account for this changing context by adapting to it. This requires careful and creative choice of ontological, epistemological and methodological assumptions. SUMMARY: New and significant challenges are faced in evaluating national EHR implementation endeavors. Based on experiences from this national evaluation of the implementation and adoption of the NHS CRS in England, we argue for an approach to these evaluations which moves away from seeing EHR systems as Information and Communication Technologies (ICT) projects requiring an essentially outcome-centred assessment towards a more interpretive approach that reflects the situated and evolving nature of EHR seen within multiple specific settings and reflecting a constantly changing milieu of policies, strategies and software, with constant interactions across such boundaries. PMID- 22545647 TI - Electrospun zwitterionic poly(sulfobetaine methacrylate) for nonadherent, superabsorbent, and antimicrobial wound dressing applications. AB - Zwitterionic poly(sulfobetaine methacrylate) (PSBMA) has been well studied for its superhydrophilic and ultralow biofouling properties, making it a promising material for superabsorbent and nonadherent wound dressings. Electrospinning provides multiple desirable features for wound dressings, including high absorptivity due to high surface-area-to-volume ratio, high gas permeation, and conformability to contour of the wound bed. The goal of this work is to develop a fibrous membrane of PSBMA via electrospinning and evaluate its properties related to wound dressing applications. Being superhydrophilic, PSBMA fibers fabricated by a conventional electrospinning method would readily dissolve in water, whereas if cross-linker is added, the formation of hydrogel would prevent electrospinning. A three-step polymerization-electrospinning-photo-cross-linking process was developed in this work to fabricate the cross-linked electrospun PSBMA fibrous membrane. Such electrospun membrane was stable in water and exhibited high water absorption of 353% (w/w), whereas the PSBMA hydrogel only absorbed 81% water. The electrospun membrane showed strong resistance to protein adsorption and cell attachment. Bacterial adhesion studies using Gram negative P. aeruginosa and Gram positive S. epidermidis showed that the PSBMA electrospun membrane was also highly resistant to bacterial adhesion. The Ag(+)-impregnated electrospun PSBMA membrane was shown microbicidal, against both S. epidermidis and P. aeruginosa. Such electrospun PSBMA membrane is ideal for a novel type of nonadherent, superabsorbent, and antimicrobial wound dressing. The superior water absorption aids in fluid removal from highly exudating wounds while keeping the wound hydrated to support healing. Because of the resistance to protein, cell, and bacterial adhesion, the dressing removal will neither cause patients' pain nor disturb the newly formed tissues. The dressing also prevents the attachment of environmental bacteria and offers broad-spectrum antimicrobial activity. It is the first work to develop the water-stable electrospun PSBMA membrane, which has great potential for wound dressing and other applications. PMID- 22545648 TI - How can insulin initiation delivery in a dual-sector health system be optimised? A qualitative study on healthcare professionals' views. AB - BACKGROUND: The prevalence of type 2 diabetes is increasing at an alarming rate in developing countries. However, glycaemia control remains suboptimal and insulin use is low. One important barrier is the lack of an efficient and effective insulin initiation delivery approach. This study aimed to document the strategies used and proposed by healthcare professionals to improve insulin initiation in the Malaysian dual-sector (public-private) health system. METHODS: In depth interviews and focus group discussions were conducted in Klang Valley and Seremban, Malaysia in 2010-11. Healthcare professionals consisting of general practitioners (n = 11), medical officers (n = 8), diabetes educators (n = 3), government policy makers (n = 4), family medicine specialists (n = 10) and endocrinologists (n = 2) were interviewed. We used a topic guide to facilitate the interviews, which were audio recorded, transcribed verbatim and analysed using a thematic approach. RESULTS: Three main themes emerged from the interviews. Firstly, there was a lack of collaboration between the private and public sectors in diabetes care. The general practitioners in the private sector proposed an integrated system for them to refer patients to the public health services for insulin initiation programmes. There could be shared care between the two sectors and this would reduce the disproportionately heavy workload at the public sector. Secondly, besides the support from the government health authority, the healthcare professionals wanted greater involvement of non government organisations, media and pharmaceutical industry in facilitating insulin initiation in both the public and private sectors. The support included: training of healthcare professionals; developing and disseminating patient education materials; service provision by diabetes education teams; organising programmes for patients' peer group sessions; increasing awareness and demystifying insulin via public campaigns; and subsidising glucose monitoring equipment. Finally, the healthcare professionals proposed the establishment of multidisciplinary teams as a strategy to increase the rate of insulin initiation. Having team members from different ethnic backgrounds would help to overcome language and cultural differences when communicating with patients. CONCLUSION: The challenges faced by a dual-sector health system in delivering insulin initiation may be addressed by greater collaborations between the private and public sectors and governmental and non-government organisations, and among different healthcare professionals. PMID- 22545649 TI - High-sensitive troponin T and N-terminal-brain-natriuretic-peptide predict outcome in symptomatic aortic stenosis. AB - OBJECTIVES: Aortic stenosis (AS) and atherosclerosis share similarities when it comes to risk factors and disease progression. Like in other heart diseases, we hypothesized that biomarkers like high-sensitive troponin T (hsTnT), N-terminal pro-brain-natriuretic-peptide (NT-proBNP) and high-sensitive C-reactive protein (hsCRP) could be useful in risk stratification. DESIGN: A total of 136 patients (57% men, mean age 74 years), referred for evaluation of AS (valve area 0.62 cm(2), left ventricular ejection fraction 64%) were consecutively enrolled in the study. The relationship between hsTnT, hsCRP and NT-proBNP, different echocardiographic parameters of AS and cardiac function were investigated as well as their relation to all-cause mortality. RESULTS: In contrast to hsCRP, hsTnT and NT-proBNP were individually correlated with prognosis. Regression analysis identified diabetes and the combination of hsTnT and NT-proBNP as significant predictors of all-cause mortality. When analyzing patients without surgery separately, only the combination of hsTnT and NT-proBNP were identified as a significant predictor of all-cause mortality in multivariable analysis. CONCLUSION: The combination of NT-proBNP and hsTnT came out as the strongest predictor of outcome irrespective of surgical treatment or not and could be of particular interest in risk-stratification in AS-patients. The results should be confirmed in prospective studies both in symptomatic and asymptomatic patients. PMID- 22545650 TI - Prospects of implant with locking plate in fixation of subtrochanteric fracture: experimental demonstration of its potential benefits on synthetic femur model with supportive hierarchical nonlinear hyperelastic finite element analysis. AB - BACKGROUND: Effective fixation of fracture requires careful selection of a suitable implant to provide stability and durability. Implant with a feature of locking plate (LP) has been used widely for treating distal fractures in femur because of its favourable clinical outcome, but its potential in fixing proximal fractures in the subtrochancteric region has yet to be explored. Therefore, this comparative study was undertaken to demonstrate the merits of the LP implant in treating the subtrochancteric fracture by comparing its performance limits against those obtained with the more traditional implants; angle blade plate (ABP) and dynamic condylar screw plate (DCSP). MATERIALS AND METHODS: Nine standard composite femurs were acquired, divided into three groups and fixed with LP (n = 3), ABP (n = 3) and DCSP (n = 3). The fracture was modeled by a 20 mm gap created at the subtrochanteric region to experimentally study the biomechanical response of each implant under both static and dynamic axial loading paradigms. To confirm the experimental findings and to understand the critical interactions at the boundaries, the synthetic femur/implant systems were numerically analyzed by constructing hierarchical finite element models with nonlinear hyperelastic properties. The predictions from the analyses were then compared against the experimental measurements to demonstrate the validity of each numeric model, and to characterize the internal load distribution in the femur and load bearing properties of each implant. RESULTS: The average measurements indicated that the constructs with ABP, DCPS and LP respectively had overall stiffness values of 70.9, 110.2 and 131.4 N/mm, and exhibited reversible deformations of 12.4, 4.9 and 4.1 mm when the applied dynamic load was 400 N and plastic deformations of 11.3, 2.4 and 1.4 mm when the load was 1000 N. The corresponding peak cyclic loads to failure were 1100, 1167 and 1600 N. The errors between the displacements measured experimentally or predicted by the nonlinear hierarchical hyperelastic model were less than 18 %. In the implanted femur heads, the principal stresses were spatially heterogeneous for ABP and DCSP but more homogenous for LP, meaning LP had lower stress concentrations. CONCLUSION: When fixed with the LP implant, the synthetic femur model of the subtrochancteric fracture consistently exceeds in the key biomechanical measures of stability and durability. These capabilities suggest increased resistance to fatigue and failure, which are highly desirable features expected of functional implants and hence make the LP implant potentially a viable alternative to the conventional ABP or DCSP in the treatment of subtrochancteric femur fractures for the betterment of clinical outcome. PMID- 22545651 TI - Chiral phosphoric acid-catalyzed enantioselective and diastereoselective spiroketalizations. AB - Catalytic enantioselective and diastereoselective spiroketalizations with BINOL derived chiral phosphoric acids are reported. The chiral catalyst can override the inherent preference for the formation of thermodynamic spiroketals, and highly selective formation of nonthermodynamic spiroketals could be achieved under the reaction conditions. PMID- 22545652 TI - The COPD pipeline XVI. PMID- 22545653 TI - Assessing measurement invariance of familism and parental respect across race/ethnicity in adolescents. AB - BACKGROUND: Familism and parental respect are culturally derived constructs rooted in Hispanic and Asian cultures, respectively. Measures of these constructs have been utilized in research and found to predict delays in substance use initiation and reduced levels of use. However, given that these measures are explicitly designed to tap constructs that are considered important by different racial/ethnic groups, there is a risk that the measurement properties may not be equivalent across groups. METHODS: This study evaluated the measurement equivalence of measures of familism and parental respect in a large and diverse sample of middle school students in Southern California (n = 5646) using a multiple group confirmatory factor analysis approach. RESULTS: Results showed little evidence of measurement variance across four racial/ethnic groups (African American, Hispanic, Asian, and non-Hispanic White), supporting the continued use of these measures in diverse populations. Some differences between latent variable means were identified - specifically that the Hispanic group and the white group differed on familism. CONCLUSIONS: No evidence of invariance was found. However, the item distributions were highly positively skewed, indicating a tendency for youth to endorse the most positive response, which may reduce the reliability of the measures and suggests that refinement is possible. PMID- 22545655 TI - Disc disease and back pain in young adults. AB - Questions from patients about pain conditions and analgesic pharmacotherapy and responses from authors are presented to help educate patients and make them more effective self-advocates. This article contains a brief description of disc disease in young adults resulting in chronic low back pain. Topics including causes of early degeneration of disc, therapies, and suggestions for strengthening the discs are discussed. PMID- 22545656 TI - Chiral nanoporous metal-metallosalen frameworks for hydrolytic kinetic resolution of epoxides. AB - Chiral nanoporous metal-organic frameworks are constructed by using dicarboxyl functionalized chiral Ni(salen) and Co(salen) ligands. The Co(salen)-based framework is shown to be an efficient and recyclable heterogeneous catalyst for hydrolytic kinetic resolution (HKR) of racemic epoxides with up to 99.5% ee. The MOF structure brings Co(salen) units into a highly dense arrangement and close proximity that enhances bimetallic cooperative interactions, leading to improved catalytic activity and enantioselectivity in HKR compared with its homogeneous analogues, especially at low catalyst/substrate ratios. PMID- 22545654 TI - AWSEM-MD: protein structure prediction using coarse-grained physical potentials and bioinformatically based local structure biasing. AB - The associative memory, water mediated, structure and energy model (AWSEM) is a coarse-grained protein force field. AWSEM contains physically motivated terms, such as hydrogen bonding, as well as a bioinformatically based local structure biasing term, which efficiently takes into account many-body effects that are modulated by the local sequence. When combined with appropriate local or global alignments to choose memories, AWSEM can be used to perform de novo protein structure prediction. Herein we present structure prediction results for a particular choice of local sequence alignment method based on short residue sequences called fragments. We demonstrate the model's structure prediction capabilities for three levels of global homology between the target sequence and those proteins used for local structure biasing, all of which assume that the structure of the target sequence is not known. When there are no homologues in the database of structures used for local structure biasing, AWSEM calculations produce structural predictions that are somewhat improved compared with prior works using related approaches. The inclusion of a small number of structures from homologous sequences improves structure prediction only marginally, but when the fragment search is restricted to only homologous sequences, AWSEM can perform high resolution structure prediction and can be used for kinetics and dynamics studies. PMID- 22545657 TI - Introduction to the special issue: infant EEG comes of age. PMID- 22545658 TI - Recording infant ERP data for cognitive research. AB - Researchers from different backgrounds have an increasing interest in investigating infant cognitive development using electroencephalogram (EEG) recordings. Although EEG measurements are suitable for infants, the method poses several challenges including setting up an infant-friendly, but interference-free lab environment and designing age-appropriate stimuli and paradigms. Certain specifics of infant EEG data have to be considered when deriving event-related potentials (ERPs) to investigate cognitive processes in the developing brain. The present article summarizes the practical aspects of conducting ERP research with infants and describes how researchers typically deal with the specific challenges entailed in this work. PMID- 22545659 TI - Brain-behavior relations in infancy: integrative approaches to examining infant looking behavior and event-related potentials. AB - This article describes three approaches to conducting integrated research on brain-behavior relations in infancy. These approaches include: conducting an integrative study that tests the same cognitive construct using behavioral and event-related potential (ERP) measures in separate experiments, measuring behavior and ERPs in different phases of the same experiment, and measuring behavior and ERPs simultaneously. We review studies that have utilized these approaches with a specific focus on research on infant visual attention and recognition memory, and discuss the application of cortical source localization with infant ERP data. Advantages and disadvantages of each approach are discussed and suggestions are made for future research. PMID- 22545660 TI - A meta-analysis investigating factors underlying attrition rates in infant ERP studies. AB - In this meta-analysis, we examined interrelationships between characteristics of infant event-related potential (ERP) studies and their attrition rates. One hundred and forty-nine published studies provided information on 314 experimental groups of which 181 provided data on attrition. A random effects meta-analysis revealed a high average attrition rate of 49.2%. Additionally, we used meta regression for 178 groups with attrition data to analyze which variables best explained attrition variance. Our main findings were that the nature of the stimuli-visual, auditory, or combined as well as if stimuli were animated influenced exclusion rates from the final analysis and that infant age did not alter attrition rates. PMID- 22545662 TI - Novel machine learning methods for ERP analysis: a validation from research on infants at risk for autism. AB - Machine learning and other computer intensive pattern recognition methods are successfully applied to a variety of fields that deal with high-dimensional data and often small sample sizes such as genetic microarray, functional magnetic resonance imaging (fMRI) and, more recently, electroencephalogram (EEG) data. The aim of this article is to discuss the use of machine learning and discrimination methods and their possible application to the analysis of infant event-related potential (ERP) data. The usefulness of two methods, regularized discriminant function analyses and support vector machines, will be demonstrated by reanalyzing an ERP dataset from infants ( Elsabbagh et al., 2009 ). Using cross validation, both methods successfully discriminated above chance between groups of infants at high and low risk of a later diagnosis of autism. The suitability of machine learning methods for the use of single trial or averaged ERP data is discussed. PMID- 22545663 TI - Effect of humic acid on pyrene removal from water by polycation-clay mineral composites and activated carbon. AB - Pyrene removal by polycation-montmorillonite (MMT) composites and granulated activated carbon (GAC) in the presence of humic acid (HA) was examined. Pyrene, HA, and sorbent interactions were characterized by FTIR, fluorescence and zeta measurements, adsorption, and column filtration experiments. Pyrene binding coefficients to the macromolecules were in the order of PVPcoS (poly-4 vinylpiridine-co-styrene) > HA > PDADMAC (poly diallyl-dimethyl-ammonium chloride), correlating to pyrene-macromolecules compatibility. Electrostatic interactions explained the high adsorption of HA to both composites (~100%), whereas HA adsorption by GAC was low. Pyrene removal by the composites, unlike GAC, was enhanced in the presence of HA; removal by PDADMAC-MMT increased from ~50 (k(d) = 2.2 * 10(3) kg/L) to ~70% (k(d) = 2.4 * 10(3) kg/L) in the presence of HA. This improvement was attributed to the adsorption of pyrene-HA complexes. PVPcoS-MMT was most efficient in removing pyrene (k(d) = 1.1 * 10(4) kg/L, >95% removal) which was explained in terms of specific pi donor-pi acceptor interactions. Pyrene uptake by column filters of GAC reached ~50% and decreased to ~30% in the presence of HA. Pyrene removal by the PVPcoS-MMT filter was significantly higher (100-85% removal), exhibiting only a small decrease in the presence of HA. The utilization of HA as an enhancing agent in pollutant removal is novel and of major importance in water treatment. PMID- 22545661 TI - The utility of EEG band power analysis in the study of infancy and early childhood. AB - Research employing electroencephalographic (EEG) techniques with infants and young children has flourished in recent years due to increased interest in understanding the neural processes involved in early social and cognitive development. This review focuses on the functional characteristics of the alpha, theta, and gamma frequency bands in the developing EEG. Examples of how analyses of EEG band power have been applied to specific lines of developmental research are also discussed. These examples include recent work on the infant mu rhythm and action processing, frontal alpha asymmetry and approach-withdrawal tendencies, and EEG power measures in the study of early psychosocial adversity. PMID- 22545664 TI - Design of a modular tetrameric scaffold for the synthesis of membrane-localized D peptide inhibitors of HIV-1 entry. AB - The highly conserved HIV-1 gp41 "pocket" region is a promising target for inhibiting viral entry. PIE12-trimer is a protease-resistant trimeric d-peptide inhibitor that binds to this pocket and potently blocks HIV entry. PIE12-trimer also possesses a reserve of binding energy that provides it with a strong genetic barrier to resistance ("resistance capacitor"). Here, we report the design of a modular scaffold employing PEGs of discrete lengths for the efficient optimization and synthesis of PIE12-trimer. This scaffold also allows us to conjugate PIE12-trimer to several membrane-localizing cargoes, resulting in dramatically improved potency and retention of PIE12-trimer's ability to absorb the impact of resistance mutations. This scaffold design strategy should be of broad utility for the rapid prototyping of multimeric peptide inhibitors attached to potency- or pharmacokinetics-enhancing groups. PMID- 22545666 TI - The effect of high-fat diet on extinction and renewal. AB - Diets high in saturated fats are linked to health problems and impairments in cognitive function in humans. Recent evidence suggests that exposure to a high fat diet can impair rats' ability to appropriately inhibit responding to stimuli that are reinforced in some circumstances but not in others. Here, we examined the effects of exposure to a high-fat diet on the context-specific renewal of extinguished responding. Rats first received pairings of a noise stimulus with a food reinforcer. After 14 days of exclusive access to either a high-fat or a matched control diet, rats received nonreinforced presentations (extinction) of the noise in either the same context in which they were trained or a different context. Finally, responding to the noise was evaluated in the original training context in all rats. In control rats, substantial renewal was observed; that is, responding was greater if extinction was conducted in a context different from that of training and testing. Renewal was significantly less robust in rats fed the high-fat diet despite evidence that they were at least as sensitive to context change as control rats. Implications of these results for models of relapse and treatments for phobias, addiction, and overeating are discussed. PMID- 22545667 TI - Nanoparticles and surfaces presenting antifungal, antibacterial and antiviral properties. AB - Here, we present new antimicrobial nanoparticles based on silica nanoparticles (SNPs) coated with a quaternary ammonium cationic surfactant, didodecyldimethylammonium bromide (DDAB). Depending on the initial concentration of DDAB, SNPs immobilize between 45 and 275 MUg of DDAB per milligram of nanoparticle. For high concentrations of DDAB adsorbed to SNP, a bilayer is formed as confirmed by zeta potential measurements, thermogravimetry, and diffuse reflectance infrared Fourier transform (DRIFT) analyses. Interestingly, these nanoparticles have lower minimal inhibitory concentrations (MIC) against bacteria and fungi than soluble surfactant. The electrostatic interaction of the DDAB with the SNP is strong, since no measurable loss of antimicrobial activity was observed after suspension in aqueous solution for 60 days. We further show that the antimicrobial activity of the nanoparticle does not require the leaching of the surfactant from the surface of the NPs. The SNPs may be immobilized onto surfaces with different chemistry while maintaining their antimicrobial activity, in this case extended to a virucidal activity. The versatility, relative facility in preparation, low cost, and large antimicrobial activity of our platform makes it attractive as a coating for large surfaces. PMID- 22545668 TI - Effect of yearly conditions and management practices on ochratoxin A production in Sultana Seedless vineyards. AB - Sun drying of seedless grapes (Vitis vinifera cv. Sultanina) is widely practised in the western Aegean Region providing Turkey with a significant share in the world trade of sultanas. Research was initiated in 1998 to determine the incidence of ochratoxin A (OTA), to identify the major factors resulting in contamination and to develop techniques to reduce or prevent contamination. This paper assesses OTA formation in five experimental vineyards located in Manisa province of Turkey between 1998 and 2003. The cultural practices recorded were tillage (type and timing), fertilisation, plant protection, irrigation, trellising, pruning, GA(3) application, harvest maturity and date, and drying practices (type of drying yard, dipping into alkaline solution, length of drying period). In the experimental vineyards, no OTA was found at veraison. OTA levels in grapes harvested at fresh maturity ranged between = 2), and upon removal of the templating anion the tetrahedral M(4)L(6) cages rearrange into different coordination assemblies. The exchange selectivity among EO(4)(n-) oxoanions has been investigated with (77)Se NMR spectroscopy using (77)SeO(4)(2-) as an anionic probe, which found the following selectivity trend: PO(4)(3-) ? CrO(4)(2-) > SO(4)(2-) > SeO(4)(2-) > MoO(4)(2-) > WO(4)(2-). In addition to the complementarity and flexibility of the cage receptor, a combination of factors have been found to contribute to the observed anion selectivity, including the anions' charge, size, hydration, basicity, and hydrogen-bond acceptor abilities. PMID- 22545672 TI - Persistent disparities in cholesterol screening among immigrants to the United States. AB - BACKGROUND: This study compared differences in cholesterol screening among immigrant populations and US born race/ethnic groups and whether improving access to health care reduced differences in screening. METHODS: Self-reported cholesterol screening for adults was calculated from multivariate logistic regression analysis of the 1988-2008 National Health and Nutrition Examination Surveys (N = 17,118). Immigrant populations were classified by place of birth and length of residency. RESULTS: After adjusting for individual characteristics and access to health care, the multivariate adjusted probability of cholesterol screening is significantly lower for persons originating from Mexico (70.9%) compared to persons born in the US (80.1%) or compared to US born Hispanic persons (77.8%). Adjustment for access to care did significantly reduce the difference in screening rates between immigrants and natives because the rate for natives remained the same, but the rate for immigrants improved. For example, the difference in screening between US born persons and persons born in Mexico was reduced by nearly 10% after adjustment for access to care. CONCLUSIONS: There are persistent disparities in cholesterol screening for immigrants, particularly recent immigrants from Mexico, but improved access to health care may be a viable policy intervention to reduce disparities. PMID- 22545674 TI - Hybrid silicon nanocone-polymer solar cells. AB - Recently, hybrid Si/organic solar cells have been studied for low-cost Si photovoltaic devices because the Schottky junction between the Si and organic material can be formed by solution processes at a low temperature. In this study, we demonstrate a hybrid solar cell composed of Si nanocones and conductive polymer. The optimal nanocone structure with an aspect ratio (height/diameter of a nanocone) less than two allowed for conformal polymer surface coverage via spin coating while also providing both excellent antireflection and light trapping properties. The uniform heterojunction over the nanocones with enhanced light absorption resulted in a power conversion efficiency above 11%. Based on our simulation study, the optimal nanocone structures for a 10 MUm thick Si solar cell can achieve a short-circuit current density, up to 39.1 mA/cm(2), which is very close to the theoretical limit. With very thin material and inexpensive processing, hybrid Si nanocone/polymer solar cells are promising as an economically viable alternative energy solution. PMID- 22545673 TI - Testing an aflatoxin B1 gene signature in rat archival tissues. AB - Archival tissues from laboratory studies represent a unique opportunity to explore the relationship between genomic changes and agent-induced disease. In this study, we evaluated the applicability of qPCR for detecting genomic changes in formalin-fixed, paraffin-embedded (FFPE) tissues by determining if a subset of 14 genes from a 90-gene signature derived from microarray data and associated with eventual tumor development could be detected in archival liver, kidney, and lung of rats exposed to aflatoxin B1 (AFB1) for 90 days in feed at 1 ppm. These tissues originated from the same rats used in the microarray study. The 14 genes evaluated were Adam8, Cdh13, Ddit4l, Mybl2, Akr7a3, Akr7a2, Fhit, Wwox, Abcb1b, Abcc3, Cxcl1, Gsta5, Grin2c, and the C8orf46 homologue. The qPCR FFPE liver results were compared to the original liver microarray data and to qPCR results using RNA from fresh frozen liver. Archival liver paraffin blocks yielded 30 to 50 MUg of degraded RNA that ranged in size from 0.1 to 4 kB. qPCR results from FFPE and fresh frozen liver samples were positively correlated (p <= 0.05) by regression analysis and showed good agreement in direction and proportion of change with microarray data for 11 of 14 genes. All 14 transcripts could be amplified from FFPE kidney RNA except the glutamate receptor gene Grin2c; however, only Abcb1b was significantly upregulated from control. Abundant constitutive transcripts, S18 and beta-actin, could be amplified from lung FFPE samples, but the narrow RNA size range (25-500 bp length) prevented consistent detection of target transcripts. Overall, a discrete gene signature derived from prior transcript profiling and representing cell cycle progression, DNA damage response, and xenosensor and detoxication pathways was successfully applied to archival liver and kidney by qPCR and indicated that gene expression changes in response to subchronic AFB1 exposure occurred predominantly in the liver, the primary target for AFB1-induced tumors. We conclude that an evaluation of gene signatures in archival tissues can be an important toxicological tool for evaluating critical molecular events associated with chemical exposures. PMID- 22545675 TI - On the value of homology models for virtual screening: discovering hCXCR3 antagonists by pharmacophore-based and structure-based approaches. AB - Human chemokine receptor CXCR3 (hCXCR3) antagonists have potential therapeutic applications as antivirus, antitumor, and anti-inflammatory agents. A novel virtual screening protocol, which combines pharmacophore-based and structure based approaches, was proposed. A three-dimensional QSAR pharmacophore model and a structure-based docking model were built to virtually screen for hCXCR3 antagonists. The hCXCR3 antagonist binding site was constructed by homology modeling and molecular dynamics (MD) simulation. By combining the structure-based and ligand-based screenings results, 95% of the compounds satisfied either pharmacophore or docking score criteria and would be chosen as hits if the union of the two searches was taken. The false negative rates were 15% for the pharmacophore model, 14% for the homology model, and 5% for the combined model. Therefore, the consistency of the pharmacophore model and the structural binding model is 219/273 = 80%. The hit rate for the virtual screening protocol is 273/286 = 95%. This work demonstrated that the quality of both the pharmacophore model and homology model can be measured by the consistency of the two models, and the false negatives in virtual screening can be reduced by combining two virtual screening approaches. PMID- 22545676 TI - Submicron-size biodegradable polymer-based didanosine particles for treating HIV at early stage: an in vitro study. AB - Human immunodeficiency viruses (HIV) hide themselves in macrophages at the early stage of infection. Delivering drug in a sustained manner from polymeric nanoparticles in those cells could control the disease effectively. The study was intended to develop poly(d,l-lactic-co-glycolic acid)-based nanoparticles containing didanosine and to observe their uptake by macrophages in vitro. Various physicochemical evaluations related to nanoparticles, such as drug excipient interaction, surface morphology, particle size, zeta potential, polydispersity index, drug loading, in vitro drug release and nanoparticle-uptake by macrophages in vitro were determined. Homogenising speeds and drug-polymer ratio varied drug loading and polydispersity index of nanoparticles, providing sustained drug release. Dimethyl sulphoxide/polyethylene glycol improved drug loading predominantly. Nanoparticle-uptake by macrophages was concentration dependent. Experimental nanoparticles successfully transported didanosine to macrophages in vitro, suggesting reduction of dose, thus minimising toxicity and side effects. Developed nanoparticle may control HIV infection effectively at an early stage. PMID- 22545679 TI - Mesothelioma incidence surveillance systems and claims for workers' compensation. Epidemiological evidence and prospects for an integrated framework. AB - BACKGROUND: Malignant mesothelioma is an aggressive and lethal tumour strongly associated with exposure to asbestos (mainly occupational). In Italy a large proportion of workers are protected from occupational diseases by public insurance and an epidemiological surveillance system for incident mesothelioma cases. METHODS: We set up an individual linkage between the Italian national mesothelioma register (ReNaM) and the Italian workers' compensation authority (INAIL) archives. Logistic regression models were used to identify and test explanatory variables. RESULTS: We extracted 3270 mesothelioma cases with occupational origins from the ReNaM, matching them with 1625 subjects in INAIL (49.7%); 91.2% (1,482) of the claims received compensation. The risk of not seeking compensation is significantly higher for women and the elderly. Claims have increased significantly in recent years and there is a clear geographical gradient (northern and more developed regions having higher claims rates). The highest rates of compensation claims were after work known to involve asbestos. CONCLUSIONS: Our data illustrate the importance of documentation and dissemination of all asbestos exposure modalities. Strategies focused on structural and systematic interaction between epidemiological surveillance and insurance systems are needed. PMID- 22545681 TI - Including mixed methods research in systematic reviews: examples from qualitative syntheses in TB and malaria control. AB - BACKGROUND: Health policy makers now have access to a greater number and variety of systematic reviews to inform different stages in the policy making process, including reviews of qualitative research. The inclusion of mixed methods studies in systematic reviews is increasing, but these studies pose particular challenges to methods of review. This article examines the quality of the reporting of mixed methods and qualitative-only studies. METHODS: We used two completed systematic reviews to generate a sample of qualitative studies and mixed method studies in order to make an assessment of how the quality of reporting and rigor of qualitative-only studies compares with that of mixed-methods studies. RESULTS: Overall, the reporting of qualitative studies in our sample was consistently better when compared with the reporting of mixed methods studies. We found that mixed methods studies are less likely to provide a description of the research conduct or qualitative data analysis procedures and less likely to be judged credible or provide rich data and thick description compared with standalone qualitative studies. Our time-related analysis shows that for both types of study, papers published since 2003 are more likely to report on the study context, describe analysis procedures, and be judged credible and provide rich data. However, the reporting of other aspects of research conduct (i.e. descriptions of the research question, the sampling strategy, and data collection methods) in mixed methods studies does not appear to have improved over time. CONCLUSIONS: Mixed methods research makes an important contribution to health research in general, and could make a more substantial contribution to systematic reviews. Through our careful analysis of the quality of reporting of mixed methods and qualitative-only research, we have identified areas that deserve more attention in the conduct and reporting of mixed methods research. PMID- 22545682 TI - Development of a selective chemical etch to improve the conversion efficiency of Zn-rich Cu2ZnSnS4 solar cells. AB - Improvement of the efficiency of Cu(2)ZnSnS(4) (CZTS)-based solar cells requires the development of specific procedures to remove or avoid the formation of detrimental secondary phases. The presence of these phases is favored by the Zn rich and Cu-poor conditions that are required to obtain device-grade layers. We have developed a selective chemical etching process based on the use of hydrochloric acid solutions to remove Zn-rich secondary phases from the CZTS film surface, which are partly responsible for the deterioration of the series resistance of the cells and, as a consequence, the conversion efficiency. Using this approach, we have obtained CZTS-based devices with 5.2% efficiency, which is nearly twice that of the devices we have prepared without this etching process. PMID- 22545680 TI - Vascular memory: can we broaden the concept of the metabolic memory? AB - Based on the results of recent randomized, controlled clinical trials and analyses of their follow-up periods the concept of metabolic memory cannot be restricted to antihyperglycaemic treatment only, rather it can be extended to lipid-lowering and antihypertensive treatment and even life-style modification. This broadened concept can be designated as vascular memory. According to this new concept, not only immediate and short-term but long-term effects of the metabolic and cardiovascular risk milieu are of great importance. Consequently, early and intensive lifestyle interventions, treatment of hyperglycaemia, lipid abnormalities and hypertension can result in beneficial effects on cardiovascular outcomes even in the long run. On the contrary, failing in target-oriented treatment from early detection of abnormalities can be associated with life threatening cardiovascular events subsequently. Additional experimental studies are needed to characterize the exact pathomechanism of vascular memory and further clinical trials are also essential to explore its real clinical significance. PMID- 22545683 TI - High-performance asymmetric supercapacitor based on graphene hydrogel and nanostructured MnO2. AB - We have successfully fabricated an asymmetric supercapacitor with high energy and power densities using graphene hydrogel (GH) with 3D interconnected pores as the negative electrode and vertically aligned MnO(2) nanoplates on nickel foam (MnO(2)-NF) as the positive electrode in a neutral aqueous Na(2)SO(4) electrolyte. Because of the desirable porous structure, high specific capacitance and rate capability of GH and MnO(2)-NF, complementary potential window of the two electrodes, and the elimination of polymer binders and conducting additives, the asymmetric supercapacitor can be cycled reversibly in a wide potential window of 0-2.0 V and exhibits an energy density of 23.2 Wh kg(-1) with a power density of 1.0 kW kg(-1). Energy density of the asymmetric supercapacitor is significantly improved in comparison with those of symmetric supercapacitors based on GH (5.5 Wh kg(-1)) and MnO(2)-NF (6.7 Wh kg(-1)). Even at a high power density of 10.0 kW kg(-1), the asymmetric supercapacitor can deliver a high energy density of 14.9 Wh kg(-1). The asymmetric supercapacitor also presents stable cycling performance with 83.4% capacitance retention after 5000 cycles. PMID- 22545684 TI - Characterization of an acetyltransferase that detoxifies aromatic chemicals in Legionella pneumophila. AB - Legionella pneumophila is an opportunistic pathogen and the causative agent of Legionnaires' disease. Despite being exposed to many chemical compounds in its natural and man-made habitats (natural aquatic biotopes and man-made water systems), L. pneumophila is able to adapt and survive in these environments. The molecular mechanisms by which this bacterium detoxifies these chemicals remain poorly understood. In particular, the expression and functions of XMEs (xenobiotic-metabolizing enzymes) that could contribute to chemical detoxification in L. pneumophila have been poorly documented at the molecular and functional levels. In the present paper we report the identification and biochemical and functional characterization of a unique acetyltransferase that metabolizes aromatic amine chemicals in three characterized clinical strains of L. pneumophila (Paris, Lens and Philadelphia). Strain-specific sequence variations in this enzyme, an atypical member of the arylamine N acetyltransferase family (EC 2.3.1.5), produce enzymatic variants with different structural and catalytic properties. Functional inactivation and complementation experiments showed that this acetyltransferase allows L. pneumophila to detoxify aromatic amine chemicals and grow in their presence. The present study provides a new enzymatic mechanism by which the opportunistic pathogen L. pneumophila biotransforms and detoxifies toxic aromatic chemicals. These data also emphasize the role of XMEs in the environmental adaptation of certain prokaryotes. PMID- 22545685 TI - Sleep, cognition, and behavioral problems in school-age children: a century of research meta-analyzed. AB - Clear associations of sleep, cognitive performance, and behavioral problems have been demonstrated in meta-analyses of studies in adults. This meta-analysis is the first to systematically summarize all relevant studies reporting on sleep, cognition, and behavioral problems in healthy school-age children (5-12 years old) and incorporates 86 studies on 35,936 children. Sleep duration shows a significant positive relation with cognitive performance (r = .08, confidence interval [CI] [.06, .10]). Subsequent analyses on cognitive subdomains indicate specific associations of sleep duration with executive functioning (r = .07, CI [.02, .13]), with performance on tasks that address multiple cognitive domains (r = .10, CI = [.05, .16]), and with school performance (r = .09, CI [.06, .12]), but not with intelligence. Quite unlike typical findings in adults, sleep duration was not associated with sustained attention and memory. Methodological issues and brain developmental immaturities are proposed to underlie the marked differences. Shorter sleep duration is associated with more behavioral problems (r = .09, CI [.07, .11]). Subsequent analyses on subdomains of behavioral problems showed that the relation holds for both internalizing (r = .09, CI [.06, .12]) and externalizing behavioral problems (r = .08, CI [.06, .11]). Ancillary moderator analyses identified practices recommended to increase sensitivity of assessments and designs in future studies. In practical terms, the findings suggest that insufficient sleep in children is associated with deficits in higher order and complex cognitive functions and an increase in behavioral problems. This is particularly relevant given society's tendency towards sleep curtailment. PMID- 22545686 TI - Bayesian just-so stories in psychology and neuroscience. AB - According to Bayesian theories in psychology and neuroscience, minds and brains are (near) optimal in solving a wide range of tasks. We challenge this view and argue that more traditional, non-Bayesian approaches are more promising. We make 3 main arguments. First, we show that the empirical evidence for Bayesian theories in psychology is weak. This weakness relates to the many arbitrary ways that priors, likelihoods, and utility functions can be altered in order to account for the data that are obtained, making the models unfalsifiable. It further relates to the fact that Bayesian theories are rarely better at predicting data compared with alternative (and simpler) non-Bayesian theories. Second, we show that the empirical evidence for Bayesian theories in neuroscience is weaker still. There are impressive mathematical analyses showing how populations of neurons could compute in a Bayesian manner but little or no evidence that they do. Third, we challenge the general scientific approach that characterizes Bayesian theorizing in cognitive science. A common premise is that theories in psychology should largely be constrained by a rational analysis of what the mind ought to do. We question this claim and argue that many of the important constraints come from biological, evolutionary, and processing (algorithmic) considerations that have no adaptive relevance to the problem per se. In our view, these factors have contributed to the development of many Bayesian "just so" stories in psychology and neuroscience; that is, mathematical analyses of cognition that can be used to explain almost any behavior as optimal. PMID- 22545687 TI - How the Bayesians got their beliefs (and what those beliefs actually are): comment on Bowers and Davis (2012). AB - Bowers and Davis (2012) criticize Bayesian modelers for telling "just so" stories about cognition and neuroscience. Their criticisms are weakened by not giving an accurate characterization of the motivation behind Bayesian modeling or the ways in which Bayesian models are used and by not evaluating this theoretical framework against specific alternatives. We address these points by clarifying our beliefs about the goals and status of Bayesian models and by identifying what we view as the unique merits of the Bayesian approach. PMID- 22545688 TI - Is that what Bayesians believe? reply to Griffiths, Chater, Norris, and Pouget (2012). AB - Griffiths, Chater, Norris, and Pouget (2012) argue that we have misunderstood the Bayesian approach. In their view, it is rarely the case that researchers are making claims that performance in a given task is near optimal, and few, if any, researchers adopt the theoretical Bayesian perspective according to which the mind or brain is actually performing (or approximating) Bayesian computations. Rather, researchers are said to adopt something more akin to what we called the methodological Bayesian approach, according to which Bayesian models are statistical tools that allow researchers to provide teleological explanations of behavior. In our reply we argue that many Bayesian researchers often appear to be make claims regarding optimality, and often appear to be making claims regarding how the mind computes at algorithmic and implementational levels of descriptions. We agree that some Bayesian theorists adopt the methodological approach, but we question the value of this approach. If Bayesian theories in psychology and neuroscience are only designed to provide insights into teleological questions, we expect that many readers have misunderstood, and hence there is a pressing need to clarify what Bayesian theories of cognition are all about. PMID- 22545689 TI - Invisible and exploited children: a shame on us all. PMID- 22545690 TI - Nature of communication: voices of 11-14 year old African-American girls and their mothers in regard to talking about sex. AB - BACKGROUND: Within the female population between the ages of 13 and 19, African Americans (AA) made up 70% of the cases of HIV seroconversionwithin the US in 2006. In light of this health disparity, prevention strategies should begin prior to age 13. The primary sex educator in families is the mother. Examining how mothers communicate with their daughters about sex and how their daughters respond could help healthcare professionals develop interventions to decrease this population's sexual risk. OBJECTIVE: This qualitative study explored what AA mothers say to their daughters about sex, in what context the discussions occur, and how the daughters respond to their mothers' messages. METHODS: Forty-two mother-daughter dyads were recruited from 4 inner-city community centers. Seven separate groups were conducted with mothers and daughters (ages 11-14) using focus group methodology and principles of Participatory Action Research. RESULTS: Four codes emerged from the data, reflecting both verbal and nonverbal sexual communication. These were: level of disclosure; mixed messages; emotional tone; and knowing. CONCLUSIONS: Both becoming less reactive and more knowledgeable about her daughter's information processing may facilitat mother to create an environment that provide a positive emotional tone. This can then lead to increasing the daughter's comfort in initiatin a conversation with her mother about her intimate feelings and experiences. IMPLICATIONS: Findings from this study could assist in developing interventions geared towards open sexual communication with the goal of delaying sexual debut. PMID- 22545691 TI - Risk-taking behaviors engaged in by early adolescents while on school property. AB - PURPOSE: This longitudinal study was guided by a Youth Resilience Framework. The study purpose was to examine the influence of protective resources, contextual factors, and risk factors in middle childhood (grades 4-6) on health-risk behaviors (e.g., smoking cigarettes, using marijuana, drinking alcohol, carrying a weapon) engaged in on school property by early adolescents (grade 7) who live in rural central Texas. METHODS: Students in grades 4 to 6, a majority of whom were Mexican American (54.3%) and male (56.4%), completed surveys annually until the 7th grade. Generalized estimating equations were run to determine predictors of 7th graders' health-risk behaviors on school property. RESULTS: Engaging in healthy behaviors, knowing others cared about them, and having a sense of competence in middle childhood (grades 4-6) were found to be protective factors, while having a large family size and the expectation that they would not complete school were found to be risk factors for engaging in health risk behaviors in 7th grade. PRACTICE IMPLICATIONS: These findings show the influence of family and schools as environments that can offer protection from health-risk behaviors in early adolescence. PMID- 22545692 TI - Families of children with autism: behaviors of children, community support and coping. AB - BACKGROUND: The diagnosis of autism for children (from birth to age 21) continues to increase, with the current rate being 1 in 110 children in the US. Besides financial strain, families often experience reduced quality of life due to disruptive behaviors related to autism. Research indicates that social support for families of children with autism improves family coping and adaptation. METHOD: A descriptive, correlational, cross-sectional study was conducted with 38 parents of children with autism. Using the McCubbin and Patterson (1983) model of family behavior, associations among behaviors of children with autism, community support for family, and family coping were analyzed. RESULTS: Findings of this study indicate an association between increased community supports and increased family coping strategies (r=.451; p=.005). Results also suggest the levels of disruptive behaviors associated with autism vary, community support can be but is not always helpful, and that the family's ability to cope with the challenges of autism is important to the family. PMID- 22545695 TI - Estimating the accuracy of neurocognitive effort measures in the absence of a "gold standard". AB - Psychologists frequently use symptom validity tests (SVTs) to help determine whether evaluees' test performance or reported symptoms accurately represent their true functioning and capability. Most studies evaluating the accuracy of SVTs have used either known-group comparisons or simulation designs, but these approaches have well-known limitations (potential misclassifications or lack of ecological validity). This study uses latent class modeling (LCM) implemented in a Bayesian framework to estimate SVT classification accuracy based on data obtained from real-life forensic evaluations. We obtained archival data from 1,301 outpatient evaluees who underwent testing with the Computerized Assessment of Response Bias (CARB), the Test of Memory Malingering (TOMM), and the Word Memory Test (WMT) in a forensic evaluation context. Under various data models, Markov chain Monte Carlo methods implemented via WinBUGS converged to target distributions that permitted Bayesian estimates of SVT accuracy. Under the most plausible model (conditional dependence in test results), classification accuracies (expressed as area under the "trapezoidal" receiver operating characteristic curve +/- standard deviation) were as follows: CARB = 0.765 +/- 0.030, WMT = 0.929 +/- 0.020, and TOMM = 0.771 +/- 0.034. At decision thresholds that hold false positive rates at 0.02, the SVTs would detect invalid responses (true positives) at rates of approximately 35%, 65%, and 49%, respectively, for the 3 tests. Though LCM methods have limitations, this study suggests that they offer an approach to SVT evaluation that avoids methodological pitfalls of known group research designs while retaining ecological validity that is absent in simulation studies. PMID- 22545694 TI - Dimensionality, hierarchical structure, age generalizability, and criterion validity of the GAIN's Behavioral Complexity Scale. AB - This study used Rasch measurement model criteria and traditional psychometric strategies to examine key psychometric properties of the Behavioral Complexity Scale (BCS), a widely used measure of externalizing disorders that focuses on attention deficit, hyperactivity, and conduct disorders. With a sample of 7,435 persons being screened for substance use disorders, the BCS was found to (a) be unidimensional, (b) have a hierarchical severity structure, (c) be generalizable to both youths and adults, and (d) meet hypothesized correlations with criterion variables. The BCS performed well as a unidimensional measure. The Rasch severity hierarchy of attention deficit to hyperactivity to conduct disorders provided a perspective that suggested that a dimensional measure could be used as an alternative and, in some ways, as an improvement to categorical diagnosis and common dimensional approaches. The finding of 3 low-severity conduct disorder items also supported a revision of categorical criteria, especially in substance use disorders. PMID- 22545696 TI - Predicting drug court treatment completion using the MMPI-2-RF. AB - We examined the ability of the Minnesota Multiphasic Personality Inventory-2 Restructured Form (MMPI-2-RF; Ben-Porath & Tellegen, 2008) substantive scales to predict Drug Court treatment completion in a sample of individuals identified as being at risk for failure to complete the program. Higher scores on MMPI-2-RF scales Behavior/Externalizing Dysfunction, Antisocial Behavior, Aberrant Experiences, Juvenile Conduct Problems, Aggression, and Disconstraint-Revised were associated with increased risk for failure to complete treatment. These results are consistent with previous findings (O'Reilly, 2007; Sellbom, Ben Porath, Baum, Erez, & Gregory, 2008) regarding treatment completion. Gender was also found to be associated with treatment completion, with females being more likely to complete the Drug Court program than males. Zero-order correlations and relative risk analyses indicated that the MMPI-2-RF can provide useful information regarding risk factors for failure to complete Drug Court treatment. Limitations and future directions are discussed. PMID- 22545697 TI - The predictive validity of the PTSD Checklist in a nonclinical sample of combat exposed National Guard troops. AB - After returning from an extended combat deployment to Iraq, 348 National Guard soldiers were administered the PTSD Checklist (PCL-M), and the Beck Depression Inventory II (BDI-II) followed, on average, 3 months later by structured diagnostic interviews including the Clinician-Administered PTSD Scale (CAPS) for the Diagnostic and Statistical Manual of Mental Disorders (4th ed.). There were 6.5% of the soldiers who met diagnostic criteria for posttraumatic stress disorder (PTSD) based on structured interview. The predictive validity of the PCL was examined and contrasted with the predictive validity of the BDI-II in identifying soldiers meeting CAPS diagnosis for PTSD. The best identified PCL cut scores produced between 65% and 76% false positive errors when used as the sole source for identification of enduring PTSD. Comparison of prediction between the PCL and the BDI-II in identifying PTSD suggested that both instruments may be operating through tapping generalized distress rather than specific aspects of the disorder. PMID- 22545698 TI - Development and validation of the Delinquency Reduction Outcome Profile (DROP) in a sample of incarcerated juveniles: a multiconstruct/multisituational scoring approach. AB - The Delinquency Reduction Outcome Profile (DROP) is a novel situational-judgment test (SJT) designed to measure social decision making in delinquent youth. The DROP includes both a typical SJT scoring method, which captures the deviation of an individual response from an "ideal" expert-based response pattern, as well as a novel "Multiconstruct-Multisituational" (MCMS) factor-scoring method, enabling the assessment "in context" of latent dimensions reflecting stable decision making tendencies. The authors present the development and validation of the DROP across 2 studies establishing its reliability and internal and concurrent validity using a sample of 1,922 young detainees and a sample of juveniles from the community. The authors also discuss the potential usefulness of the DROP as a prognostic tool to predict recidivism for delinquent youth and to monitor changes in intervention programs designed to improve social decision-making skills. Benefits of the MCMS scoring approach for SJT literature and psychological measurement are also discussed. PMID- 22545699 TI - The Laboratory Parenting Assessment Battery: development and preliminary validation of an observational parenting rating system. AB - Investigations of contributors to and consequences of the parent-child relationship require accurate assessment of the nature and quality of parenting. The present study describes the development and psychometric evaluation of the Laboratory Parenting Assessment Battery (Lab-PAB), an observational rating system that assesses parenting behaviors during the early childhood years. Dyadic parent child interaction was assessed observationally in a community sample of 154 families (154 mothers, 154 fathers, 154 biological children 3-6 years old). Parenting behaviors were rated with a comprehensive coding system that assessed a broad range of relevant constructs drawn from the literatures on parenting, attachment, affect, and interpersonal relationships. A series of psychometrically informed data reduction strategies ultimately yielded 5 parenting scales (Involvement, Positivity, Hostility, Intrusiveness, Discipline). Scores on the Lab-PAB parenting scales demonstrated adequate internal consistency and interrater reliability in our sample, as well as convergence with measures of related constructs. The use of this standardized observational measure has the potential to further future longitudinal investigations of the effects of parent , child-, and family-level factors on the quality of parenting, and of parenting on child outcomes. PMID- 22545700 TI - Further evaluation of the psychometric properties of the Acceptance and Action Questionnaire-II. AB - The Acceptance and Action Questionnaire-II (AAQ-II) is a self-report measure designed to assess experiential avoidance as conceptualized in acceptance and commitment therapy (ACT). The current study is the first to evaluate the psychometric properties of the AAQ-II in a large sample of adults (N = 376) with mild to moderate levels of depression and anxiety who participated in a study on the effects of an ACT intervention. The internal construct validity and local measurement precision were investigated by fitting the data to a unidimensional item response theory (IRT) model, and the incremental validity of the AAQ-II beyond mindfulness, as measured by the Five Facet Mindfulness Questionnaire, was assessed. Results of the IRT analyses suggest that the AAQ-II is a unidimensional measure of experiential avoidance and has satisfactory reliability for group comparisons in mild to moderately depressed and anxious populations. Item functioning was found to be independent of gender and slightly dependent on age in this sample. Furthermore, the AAQ-II showed incremental validity beyond 5 mindfulness facets in explaining depression, anxiety, and positive mental health. This study suggests the AAQ-II shows promise as a useful tool for the measurement of experiential avoidance in mild to moderately depressed and anxious populations. PMID- 22545702 TI - Cycloisomerization versus hydration reactions in aqueous media: a Au(III)-NHC catalyst that makes the difference. AB - A novel water-soluble Au(III)-NHC complex has been synthesized and successfully applied in the intramolecular cyclization of gamma-alkynoic acids into enol lactones under biphasic toluene/water conditions, thus representing a rare example of an active and selective catalyst for this transformation in aqueous media. Remarkably, competing alkyne hydration processes were not observed, even during the desymmetrization reaction of challenging 1,6-diyne substrates. In addition, after phase separation, the water-soluble Au(III) catalyst could be recycled 10 times without loss of activity or selectivity. PMID- 22545703 TI - A locked nucleic acid oligonucleotide targeting microRNA 122 is well-tolerated in cynomolgus monkeys. AB - MicroRNA 122 (miR-122) is liver specific, fine-tunes lipid metabolism, and is required for hepatitis C virus (HCV) abundance. Miravirsen, an oligonucleotide with locked nucleic acid, binds to miR-122, potently inhibiting its activity. We aimed at determining the safety of the miR-122 antagonism in vivo in 6 to 10 cynomolgus monkeys/group intravenously treated with a range of dose levels twice weekly for 4 weeks. Survival, body weights, clinical signs, and cardiovascular and ophthalmologic parameters were unaffected. Anticipated hypolipidemia due to the inhibition of miR-122 was observed in all treated animals. Only the highest dose level produced distinct transient prolongations of clotting times, slight alternative complement pathway activation, and a reversible increase of hepatic transaminases. Distribution half-life was 10-20 minutes, and accumulation was mainly in the kidney and liver with slow elimination. Microscopic examinations revealed granulated Kupffer cells and lymph node macrophages, cytoplasmic vacuolation in proximal renal tubules, and hepatocytes. The granules were most likely phagolysosomes containing miravirsen. A slightly increased incidence of hepatocyte apoptosis was observed in some monkeys given the highest dose; otherwise, there was no evidence of treatment-related degenerative changes in any organ. In conclusion, the maximal inhibition of miR-122 was associated with limited phenotypic changes, indicating that the clinical assessment of miravirsen as host factor antagonist for treatment of HCV infections is warranted. PMID- 22545704 TI - Protonation states of the catalytic dyad of beta-secretase (BACE1) in the presence of chemically diverse inhibitors: a molecular docking study. AB - In this molecular docking study, the protonation states of the catalytic Asp dyad of the beta-secretase (BACE1) enzyme in the presence of eight chemically diverse inhibitors have been predicted. BACE1 catalyzes the rate-determining step in the generation of Alzheimer amyloid beta peptides and is widely considered as a promising therapeutic target. All the inhibitors were redocked into their corresponding X-ray structures using a combination of eight different protonation states of the Asp dyad for each inhibitor. Five inhibitors were primarily found to favor two different monoprotonated states, and the remaining three favor a dideprotonated state. In addition, five of them exhibited secondary preference for a diprotonated state. These results show that the knowledge of a single protonation state of the Asp dyad is not sufficient to search for the novel inhibitors of BACE1 and the most plausible state for each inhibitor must be determined prior to conducting in-silico screening. PMID- 22545705 TI - Molecular modeling assisted hapten design to produce broad selectivity antibodies for fluoroquinolone antibiotics. AB - Antibodies with a wide recognition profile of fluoroquinolone antibiotics have been produced based on chemical criteria, theoretical studies, and molecular modeling assisted hapten design. The immunizing hapten preserves the most important and characteristic epitopes of this antibiotic family. The studies have taken into consideration the zwitterionic character of most of the fluoroquinolones and the relative concentration of the different species in equilibrium at physiologic pH. The hapten is prepared in the form of a stable prehapten through a 5 step synthetic pathway. Immediately before conjugation, the immunizing hapten is obtained by removing the diphenylmethane protecting group. The specificity of the antibodies obtained is directed toward the common area defined by the fluorine atom at position 6 and the beta-ketoacid moiety. The ELISA developed is able to recognize with very good detectability important fluoroquinolones used in the veterinary field such as ciprofloxacin (CPFX, IC(50), 0.35 MUg L(-1)), enrofloxacin (ERFX, IC(50), 0.65 MUg L(-1)), danofloxacin (DNFX, IC(50), 7.31 MUg L(-1)), difloxacin (DFX, IC(50), 0.91 MUg L( 1)), sarafloxacin (SRFX, IC(50), 0.96 MUg L(-1)), norfloxacin (NRFX, IC(50), 0.78 MUg L(-1)), ofloxacin (OFX, IC(50), 1.84 MUg L(-1)), flumequine (Flume, IC(50), 3.91 MU gL(-1)), marbofloxacin (MBFX, IC(50), 4.30 MU gL(-1)), and oxolinic acid (OXO, IC(50), 23.53 MUg L(-1)). The results presented here demonstrate that the antibody affinity is strongly affected by the presence of divalent cations, owing to their complexation with the fluoroquinolone molecules. Moreover, the outcome from the effect of the pH on the immunochemical assays suggests that the selectivity could be modulated with the pH due to the zwitterionic character of the fluoroquinolones and as a function of their different pK(a) values. PMID- 22545706 TI - DHR123: an alternative probe for assessment of ROS in human spermatozoa. AB - The aim of this study was to assess the potential of dihydrorhodamine 123 (DHR123) to measure oxidative stress produced by human spermatozoa. The results were compared with 2', 7'-dichlorodihydrofluorescein diacetate (DCFH-DA) that is routinely used for assessment of H(2)O(2) produced by spermatozoa. Fluorescence intensity and percentage R123 and DCF positive sperm were measured by flow cytometry. The optimal condition for assessment of reactive oxygen species (ROS) produced by sperm with DHR123 was 0.05 uM for 1 million sperm per ml for 20 minutes. The results of ROS measurement by DHR123 showed a significant correlation (r= +0.818, P<0.001) with DCFH-DA staining. Immunofluorescence of sperm stained with DHR123 revealed ROS production in the sperm mid-piece. In addition a significant correlation was observed between oxidant production assessed by DHR123 and semen parameters. Therefore, DHR123 may be considered a suitable probe for estimating oxidants produced by human spermatozoa, and can present heterogeneity in oxidant production between different samples. PMID- 22545708 TI - Structural Evolution during geopolymerization from an early age to consolidated material. AB - Time-resolved rheology, small angle X-ray scattering (SAXS), and electron paramagnetic resonance (EPR) techniques were used to study the polymerization of geopolymers. These polymers are inorganically synthesized by the alkaline activation of an aluminosilicate source (metakaolin) in aqueous solution. The influence of the alkali activator (Na(+), K(+), and Cs(+)) was investigated at room temperature. As observed through the variation of the viscoelastic moduli (G', G"), curing proceeds in steps that are well pronounced when NaOH is used. These steps correspond to a specific dissolution/polycondensation mechanism and are smoothed when the size of the alkali cations increases. This size effect also has an impact on the gelation time (maximum of tan delta). Structural analysis through SAXS experiments allows us to characterize these mechanisms on the nanoscale and to show that the growth of the geopolymer is due to the aggregation of oligomers with a size that is even smaller than the cation is chaotropic. Finally, water behavior during geopolymerization was assessed by using a spin probe. The results show that the spin-probe signal progressively disappears during the first moment of the reaction and reappears when the solid polymeric gel is formed, highlighting the role of water molecules in the different chemical reactions during the process. The EPR signal is in fact increasingly masked as the ion size decreases (because of the strength of the hydration shell). At the end of the reaction, some water molecules were released within the pores, restoring the visibility of the isotropic spin-probe signal. PMID- 22545707 TI - The MULTICOM toolbox for protein structure prediction. AB - BACKGROUND: As genome sequencing is becoming routine in biomedical research, the total number of protein sequences is increasing exponentially, recently reaching over 108 million. However, only a tiny portion of these proteins (i.e. ~75,000 or < 0.07%) have solved tertiary structures determined by experimental techniques. The gap between protein sequence and structure continues to enlarge rapidly as the throughput of genome sequencing techniques is much higher than that of protein structure determination techniques. Computational software tools for predicting protein structure and structural features from protein sequences are crucial to make use of this vast repository of protein resources. RESULTS: To meet the need, we have developed a comprehensive MULTICOM toolbox consisting of a set of protein structure and structural feature prediction tools. These tools include secondary structure prediction, solvent accessibility prediction, disorder region prediction, domain boundary prediction, contact map prediction, disulfide bond prediction, beta-sheet topology prediction, fold recognition, multiple template combination and alignment, template-based tertiary structure modeling, protein model quality assessment, and mutation stability prediction. CONCLUSIONS: These tools have been rigorously tested by many users in the last several years and/or during the last three rounds of the Critical Assessment of Techniques for Protein Structure Prediction (CASP7-9) from 2006 to 2010, achieving state-of-the-art or near performance. In order to facilitate bioinformatics research and technological development in the field, we have made the MULTICOM toolbox freely available as web services and/or software packages for academic use and scientific research. It is available at http://sysbio.rnet.missouri.edu/multicom_toolbox/. PMID- 22545709 TI - Higher expression of Caveolin-1 inhibits human small cell lung cancer (SCLC) apoptosis in vitro. AB - Small cell lung cancer (SCLC) is the most aggressive type of lung cancer, and its treatment is closely associated with apoptosis. Caveolin-1 plays an important role in the development of a variety of human cancers. This study sought to investigate the influence of Caveolin-1 on the apoptosis of SCLC in vitro. We demonstrate that higher expression of Caveolin-1 leads to inhibition of cisplatin and Ultraviolet Radiation (UVR)-induced apoptosis in SCLC cells; and also could decrease caspase-3 activity and increase the stability of Bcl-2 at the protein level. Our findings illuminate a potential molecular mechanism regarding CAV-1's role as anti-apoptosis protein. PMID- 22545710 TI - Direct imaging the upconversion nanocrystal core/shell structure at the subnanometer level: shell thickness dependence in upconverting optical properties. AB - Lanthanide-doped upconversion nanoparticles have shown considerable promise in solid-state lasers, three-dimensional flat-panel displays, and solar cells and especially biological labeling and imaging. It has been demonstrated extensively that the epitaxial coating of upconversion (UC) core crystals with a lattice matched shell can passivate the core and enhance the overall upconversion emission intensity of the materials. However, there are few papers that report a precise link between the shell thickness of core/shell nanoparticles and their optical properties. This is mainly because rare earth fluoride upconversion core/shell structures have only been inferred from indirect measurements to date. Herein, a reproducible method to grow a hexagonal NaGdF(4) shell on NaYF(4):Yb,Er nanocrystals with monolayer control thickness is demonstrated for the first time. On the basis of the cryo-transmission electron microscopy, rigorous electron energy loss spectroscopy, and high-angle annular dark-field investigations on the core/shell structure under a low operation temperature (96 K), direct imaging the NaYF(4):Yb,Er@NaGdF(4) nanocrystal core/shell structure at the subnanometer level was realized for the first time. Furthermore, a strong linear link between the NaGdF(4) shell thickness and the optical response of the hexagonal NaYF(4):Yb,Er@NaGdF(4) core/shell nanocrystals has been established. During the epitaxial growth of the NaGdF(4) shell layer by layer, surface defects of the nanocrystals can be gradually passivated by the homogeneous shell deposition process, which results in the obvious enhancement in overall UC emission intensity and lifetime and is more resistant to quenching by water molecules. PMID- 22545711 TI - Solution-based synthesis of crystalline silicon from liquid silane through laser and chemical annealing. AB - We report a solution process for the synthesis of crystalline silicon from the liquid silane precursor cyclohexasilane (Si(6)H(12)). Polysilane films were crystallized through thermal and laser annealing, with plasma hydrogenation at atmospheric pressure generating further structural changes in the films. The evolution from amorphous to microcrystalline is characterized using scanning electron microscopy (SEM), atomic force microscopy (AFM), Raman spectroscopy and impedance spectroscopy. A four-decade enhancement in the electrical conductivity is attributed to a disorder-order transition in a bonded Si network. Our results demonstrate a potentially attractive approach that employs a solution process coupled with ambient postprocessing to produce crystalline silicon thin films. PMID- 22545712 TI - Interplay of metalloligand and organic ligand to tune micropores within isostructural mixed-metal organic frameworks (M'MOFs) for their highly selective separation of chiral and achiral small molecules. AB - Four porous isostructural mixed-metal-organic frameworks (M'MOFs) have been synthesized and structurally characterized. The pores within these M'MOFs are systematically tuned by the interplay of both the metalloligands and organic ligands which have enabled us not only to direct their highly selective separation of chiral alcohols 1-phenylethanol (PEA), 2-butanol (BUT), and 2 pentanol (2-PEN) with the highest ee up to 82.4% but also to lead highly selective separation of achiral C(2)H(2)/C(2)H(4) separation. The potential application of these M'MOFs for the fixed bed pressure swing adsorption (PSA) separation of C(2)H(2)/C(2)H(4) has been further examined and compared by the transient breakthrough simulations in which the purity requirement of 40 ppm in the outlet gas can be readily fulfilled by the fixed bed M'MOF-4a adsorber at ambient conditions. PMID- 22545717 TI - Single-atom ligand changes affect breathing in an extended metal-organic framework. AB - 2-Phenylpyridine-5,4'-dicarboxylic acid (1, dcppy), a derivative of 4,4' biphenyldicarboxylic (2, bpdc) was used as the organic linking component for several metal-organic frameworks (MOFs). The pyridine component of 1 does not interfere with the solvothermal synthetic procedure, and hence both 1 and 2 form similar isoreticular MOFs. Zr(4+)-based UiO-67-dcppy, Al(3+)-based DUT-5-dcppy, Zn(2+)-based DMOF-1-dcppy, and interpenetrated Zn(2+)-based BMOF-1-dcppy were readily synthesized from 1. Similarly, isostructural frameworks from 2 were prepared (UiO-67, DUT-5, DMOF-1-bpdc, and interpenetrated BMOF-1-bpdc). The structures and physical properties of these frameworks were characterized by powder X-ray diffraction (PXRD), single X-ray diffraction (XRD), thermogravimetric analysis (TGA), and gas sorption analysis. Generally, frameworks prepared from 1 or 2 displayed similar properties; however, gas sorption data showed that BMOF-1-dcppy displayed a very large hysteresis with N(2) and CO(2) suggestive of possible framework flexibility. In contrast, the analogous framework prepared from 2 (BMOF-1-bpdc) showed low uptake of N(2) and CO(2). The substantial difference in the gas sorption behavior of these MOFs is attributed to the pyridine nature of 1 that results in weakened pi-pi interactions between the interpenetrated nets. PMID- 22545713 TI - A rapid low-cost real-time PCR for the detection of Klebsiella pneumonia carbapenemase genes. AB - BACKGROUND: Klebsiella pneumonia carbapenemases (KPCs) are able to hydrolyze the carbapenems, which cause many bacteria resistance to multiple classes of antibiotics, so the rapid dissemination of KPCs is worrisome. Laboratory identification of KPCs-harboring clinical isolates would be a key to limit the spread of the bacteria. This study would evaluate a rapid low-cost real-time PCR assay to detect KPCs. METHODS: Real-time PCR assay based on SYBR GreenIwas designed to amplify a 106 bp product of the blaKPC gene from the 159 clinical Gram-negative isolates resistant to several classes of -lactam antibiotics through antimicrobial susceptibility testing. We confirmed the results of real time PCR assay by the conventional PCR-sequencing. At the same time, KPCs of these clinical isolates were detected by the modified Hodge test (MHT). Then we compared the results of real-time PCR assay with those of MHT from the sensitivity and specificity. Moreover, we evaluated the sensitivity of the real time PCR assay. RESULTS: The sensitivity and specificity of the results of the real-time PCR assay compared with those of MHT was 29/29(100%) and 130/130(100%), respectively. The results of the real-time PCR and the MHT were strongly consistent (Exact Sig. (2-tailed) =1. 000; McNemar test). The real-time PCR detection limit was about 0.8 cfu using clinical isolates. CONCLUSION: The real time PCR assay could rapidly and accurately detect KPCs -harboring strains with high analytical sensitivity and specificity. PMID- 22545716 TI - Luminal lactate in acute pancreatitis--validation and relation to disease severity. AB - BACKGROUND: Increased rectal luminal lactate concentration may be associated with the severity of the septic shock and high dose of vasopressors. It suggests hypoperfusion of the gut mucosa. This is potentially associated with bacterial translocation from the gut leading to local and systemic inflammation. In acute pancreatitis (AP) bacterial translocation is considered as the key event leading to infection of necrotic pancreatic tissue and high severity of illness. METHODS: We used rectal luminal equilibration dialysis for the measurement of gut luminal lactate in 30 consecutive patients admitted to hospital due to acute pancreatitis to test the hypothesis that a single measurement of rectal luminal lactate predicts the severity of acute pancreatitis, the length of hospital stay, the need of intensive care and ultimately, mortality. We also tested the physiological validity of luminal lactate concentration by comparing it to luminal partial tension of oxygen. Additionally, a comparison between two different L-lactate analyzers was performed. RESULTS: High rectal luminal lactate was associated with low mucosal partial tension of oxygen (R = 0.57, p = 0.005) thereby indicating the physiological validity of the method. Rectal luminal lactate at the hospital admission was not associated with the first day or the highest SOFA score, CRP level, hospital length of stay, length of stay in intensive care or mortality. In this cohort of unselected consecutive patients with acute pancreatitis we observed a tendency of increased rectal lactate in the severe cases. Low precision and high bias was observed between two lactate analyzers. CONCLUSIONS: The association between rectal luminal lactate and oxygen tension indicates that luminal lactate is a marker mucosal anaerobiosis. Comparison between two different analyzers showed poor, non-constant precision over the range of lactate concentrations. Rectal luminal lactate concentration at the time of hospital admission did not predict the severity of pancreatitis. PMID- 22545718 TI - Jacobsen protocols for large-scale epoxidation of cyclic dienyl sulfones: application to the (+)-pretazettine core. AB - A Jacobsen epoxidation protocol using H2O2 as oxidant was designed for the large scale preparation of various epoxy vinyl sulfones. A number of cocatalysts were screened, and pH control led to increased reaction rate, higher turnover number, and improved reliability. PMID- 22545720 TI - Revealing and concealing Ill identity: a performance narrative of IBD disclosure. AB - Revealing a hidden, chronic illness is a risky and vulnerable act. Ill individuals often remain socially stigmatized, and those who live with invisible illness must legitimize their ill identity since they infrequently look sick. For individuals with inflammatory bowel disease (IBD), disclosing one's illness carries unique challenges because of the grotesque and taboo nature of the disease. To this end, the bathroom or "water closet" is more than a functional place-it is a space to hide one's ill identity. For many, the point of departure from safety to vulnerability occurs when there is a desire to disclose. In this descriptive essay, revelation of an invisible illness, IBD, and disclosure to others are explored as embodied and situated communication. Through performance narrative, the author shares stories of her disclosive moments to inform others about IBD, explores how the water closet can be a metaphoric boundary, examines various strategies used in revealing hidden illness, and offers possible implications for IBD disclosure to the self and relationships with others. PMID- 22545719 TI - Lack of CC chemokine ligand 2 differentially affects inflammation and fibrosis according to the genetic background in a murine model of steatohepatitis. AB - Expression of CCL2 (CC chemokine ligand 2) (or monocyte chemoattractant protein 1) regulates inflammatory cell infiltration in the liver and adipose tissue, favouring steatosis. However, its role in the pathogenesis of steatohepatitis is still uncertain. In the present study, we investigated the development of non alcoholic steatohepatitis induced by an MCD diet (methionine/choline-deficient diet) in mice lacking the CCL2 gene on two different genetic backgrounds, namely Balb/C and C57/Bl6J. WT (wild-type) and CCL2-KO (knockout) mice were fed on a lipid-enriched MCD diet or a control diet for 8 weeks. In Balb/C mice fed on the MCD diet, a lack of CCL2 was associated with lower ALT (alanine transaminase) levels and reduced infiltration of inflammatory cells, together with a lower generation of oxidative-stress-related products. Sirius Red staining demonstrated pericellular fibrosis in zone 3, and image analysis showed a significantly lower matrix accumulation in CCL2-KO mice. This was associated with reduced hepatic expression of TGF-beta (transforming growth factor-beta), type I procollagen, TIMP-1 (tissue inhibitor of metalloproteinases-1) and alpha-smooth muscle actin. In contrast, in mice on a C57Bl/6 background, neither ALT levels nor inflammation or fibrosis were significantly different comparing WT and CCL2-KO animals fed on an MCD diet. In agreement, genes related to fibrogenesis were expressed to comparable levels in the two groups of animals. Comparison of the expression of several genes involved in inflammation and repair demonstrated that IL (interleukin)-4 and the M2 marker MGL-1 (macrophage galactose-type C-type lectin 1) were differentially expressed in Balb/C and C57Bl/6 mice. No significant differences in the degree of steatosis were observed in all groups of mice fed on the MCD diet. We conclude that, in experimental murine steatohepatitis, the effects of CCL2 deficiency are markedly dependent on the genetic background. PMID- 22545723 TI - Examining equity in access to long-lasting insecticide nets and artemisinin-based combination therapy in Anambra State, Nigeria. AB - BACKGROUND: In order to achieve universal health coverage, the government of Anambra State, southeast Nigeria has distributed free Long-lasting Insecticide treated Nets (LLINs) to the general population and delivered free Artemisinin based Combination Therapy (ACT) to pregnant women and children less than 5 years. However, the levels of coverage with LLINS and ACTs is not clear, especially coverage of different socio-economic status (SES) population groups. This study was carried out to determine the level of coverage and access to LLINs and ACTs amongst different SES groups. METHODS: A questionnaire was used to collect data from randomly selected households in 19 local government areas of the State. Selected households had a pregnant woman and/or a child less than 5 years. The lot quality assurance sampling (LQAS) methodology was used in sampling. The questionnaire explored the availability and utilization of LLINs and ACTs from 2394 households. An asset-based SES index was used to examine the level of access of LLINS and ACTs to different SES quintiles. RESULTS: It was found that 80.5% of the households had an LLIN and 64.4% of the households stated that they actually used the nets the previous night. The findings showed that 42.3% of pregnant women who had fever within the past month received ACTs, while 37.5% of children<5 years old who had malaria in the past month had received ACTs. There was equity in ownership of nets for the range 1-5 nets per household. No significant SES difference was found in use of ACTs for treatment of malaria in children under five years old and in pregnant women. CONCLUSIONS: The free distribution of LLINs and ACTs increased household coverage of both malaria control interventions and bridged the equity gap in access to them among the most vulnerable groups. PMID- 22545721 TI - Mammalian target of rapamycin signaling in diabetic cardiovascular disease. AB - Diabetes mellitus currently affects more than 170 million individuals worldwide and is expected to afflict another 200 million individuals in the next 30 years. Complications of diabetes as a result of oxidant stress affect multiple systems throughout the body, but involvement of the cardiovascular system may be one of the most severe in light of the impact upon cardiac and vascular function that can result in rapid morbidity and mortality for individuals. Given these concerns, the signaling pathways of the mammalian target of rapamycin (mTOR) offer exciting prospects for the development of novel therapies for the cardiovascular complications of diabetes. In the cardiovascular and metabolic systems, mTOR and its multi-protein complexes of TORC1 and TORC2 regulate insulin release and signaling, endothelial cell survival and growth, cardiomyocyte proliferation, resistance to beta-cell injury, and cell longevity. Yet, mTOR can, at times, alter insulin signaling and lead to insulin resistance in the cardiovascular system during diabetes mellitus. It is therefore vital to understand the complex relationship mTOR and its downstream pathways hold during metabolic disease in order to develop novel strategies for the complications of diabetes mellitus in the cardiovascular system. PMID- 22545724 TI - Ancient wood of the Acqualadrone rostrum: materials history through gas chromatography/mass spectrometry and sulfur X-ray absorption spectroscopy. AB - In 2008 the rostrum from an ancient warship was recovered from the Mediterranean near Acqualadrone, Sicily. To establish its provenance and condition, samples of black and brown rostrum wood were examined using sulfur K-edge X-ray absorption spectroscopy (XAS) and gas chromatography/mass spectrometry (GC/MS). GC/MS of pyrolytic volatiles yielded only guaiacyl derivatives, indicating construction from pinewood. A derivatized extract of black wood yielded forms of abietic acid and sandaracopimaric acid consistent with pine pitch waterproofing. Numerical fits to the sulfur K-edge XAS spectra showed that about 65% of the endogenous sulfur consisted of thiols and disulfides. Elemental sulfur was about 2% and 7% in black and brown wood, respectively, while pyritic sulfur was about 12% and 6%. About 2% of the sulfur in both wood types was modeled as trimethylsulfonium, possibly reflecting biogenic (dimethylsulfonio)propionate. High-valent sulfur was exclusively represented by sulfate esters, consistent with bacterial sulfotransferase activity. Traces of chloride were detected, but no free sulfate ion. In summary, the rostrum was manufactured of pine wood and subsequently waterproofed with pine pitch. The subsequent 2300 years included battle, foundering, and marine burial followed by anoxia, bacterial colonization, sulfate reduction, and mobilization of transition metals, which produced pyrite and copious appended sulfur functionality. PMID- 22545726 TI - Direct observation of triplet state mediated decarboxylation of the neutral and anion forms of ketoprofen in water-rich, acidic, and PBS solutions. AB - The decarboxylation reaction of KP in different acetonitrile-water mixtures producing a carbanion or biradical intermediate is investigated by using femtosecond transient absorption and nanosecond time-resolved resonance Raman spectroscopies to unveil the mechanism of the photochemistry of KP. The irradiation of either the neutral or anion forms of KP leads to the excited singlet state KP species transforming into a corresponding triplet state KP species via a highly efficient intersystem crossing, and then, a triplet state mediated decarboxylation reaction occurs to generate a carbanion intermediate in the phosphate buffer solutions or a biradical species in the water-rich or acidic solutions examined here. PMID- 22545725 TI - Association between ovarian hormones and smoking behavior in women. AB - Studies examining the association between menstrual cycle phases and smoking behavior in women have yielded mixed results. The purpose of this study was to elucidate the associations between ovarian hormones and smoking by directly measuring ovarian hormone levels and obtaining a laboratory assessment of smoking behaviors. Four hypotheses were tested: Increased smoking will be associated with (1) low absolute levels of estradiol and progesterone; (2) decreasing (i.e., dynamic changes in) estradiol and progesterone; (3) lower ratios of progesterone to estradiol; and (4) higher ratios of estradiol to progesterone. Female smokers (>=10 cigarettes/day) with regular menstrual cycles were recruited as part of a larger, ongoing study examining the influence of ovarian hormones on smoking cessation treatment. Participants completed 2 study visits, including a 1-hr ad lib smoking topography session, which provided a detailed assessment of smoking behavior. Both the change in hormone levels over time and the relative ratios of ovarian hormones were associated with smoking behavior, but each to a limited extent. Decreases in estradiol (r = -.21, p = .048) and decreases in progesterone (r = -.23, p = .03) were associated with increased puff intensity. Lower ratios of progesterone to estradiol were associated with a greater number of puffs (r = .26, p = .01) and weight of cigarettes smoked (r = -.29, p = .005). The best predictors of smoking behavior were the ratio of progesterone to estradiol (z = 2.7, p = .004) and the change in estradiol and progesterone over time (z = -2.1, p = .02). This pattern of results may help to explain inconsistent findings in previous studies and suggest potential mechanisms by which hormones influence nicotine addiction. PMID- 22545727 TI - T3DB: an integrated database for bacterial type III secretion system. AB - BACKGROUND: Type III Secretion System (T3SS), which plays important roles in pathogenesis or symbiosis, is widely expressed in a variety of gram negative bacteria. However, lack of unique nomenclature for T3SS genes has hindered T3SS related research. It is necessary to set up a knowledgebase integrating T3SS related research data to facilitate the communication between different research groups interested in different bacteria. DESCRIPTION: A T3SS-related Database (T3DB) was developed. T3DB serves as an integrated platform for sequence collection, function annotation, and ortholog classification for T3SS related apparatus, effector, chaperone and regulatory genes. The collection of T3SS containing bacteria, T3SS-related genes, function annotation, and the ortholog information were all manually curated from literature. BPBAac, a highly efficient T3SS effector prediction tool, was also implemented. CONCLUSIONS: T3DB is the first systematic platform integrating well-annotated T3SS-related gene and protein information to facilitate T3SS and bacterial pathogenecity related research. The newly constructed T3 ortholog clusters may faciliate effective communication between different research groups and will promote de novo discoveries. Besides, the manually-curated high-quality effector and chaperone data are useful for feature analysis and evolutionary studies of these important proteins. PMID- 22545728 TI - The absence of heat shock protein HSP101 affects the proteome of mature and germinating maize embryos. AB - Maize heat shock protein HSP101 accumulates during embryo maturation and desiccation and persists at high levels during the first 24 h following kernel imbibition in the absence of heat stress. This protein has a known function in disaggregation of high molecular weight complexes and has been proposed to be a translational regulator of specific mRNAs. Here, a global proteomic approach was used to identify changes in the maize proteome due to the absence of HSP101 in embryos from mature-dry or 24 h-imbibed kernels. A total of 26 protein spots from the mature dry embryo exhibited statistically significant expression changes in the L10 inbred hsp101 mutant (hsp101-m5::Mu1/hsp101-m5::Mu1) line as compared to the corresponding wild type (Hsp101/Hsp101). Additional six spots reproducibly showed qualitative changes between the mutant and wild-type mature and germinating embryos. Several chaperones, translation-related proteins, actin, and enzymes participating in cytokinin metabolism were identified in these spots by tandem mass-spectrometry (MS). The proteomic changes partially explain the altered root growth and architecture observed in young hsp101 mutant seedlings. In addition, specific protein de novo synthesis was altered in the 24 h-imbibed mutant embryos indicating that maize HSP101 functions as both chaperone and translational regulator during germination. Supporting this, HSP101 was found as part of Cap-binding and translation initiation complexes during early kernel imbibition. Overall, these findings expose the relevance of maize HSP101 for protein synthesis and balance mechanisms during germination. PMID- 22545729 TI - Effect of chirality and length on the penetrability of single-walled carbon nanotubes into lipid bilayer cell membranes. AB - The ability of carbon nanotubes to enter the cell membrane acting as drug delivery vehicles has yielded a plethora of experimental investigations, mostly with inconclusive results because of the wide spectra of carbon nanotube structures. Because of the virtual impossibility of synthesizing CNTs with distinct chirality, we report a parametric study on the use of molecular dynamics to provide better insight into the effect of the carbon nanotube chirality and the aspect ratio on the interaction with a lipid bilayer membrane. The simulation results indicated that a single-walled carbon nanotube utilizes different time evolving mechanisms to facilitate their internalization within the membrane. These mechanisms comprise both penetration and endocytosis. It was observed that carbon nanotubes with higher aspect ratios penetrate the membrane faster whereas shorter nanotubes undergo significant rotation during the final stages of endocytosis. Furthermore, nanotubes with lower chiral indices developed significant adhesion with the membrane. This adhesion is hypothesized to consume some of the carbon nanotube energy, thus resulting in longer times for the nanotube to translocate through the membrane. PMID- 22545730 TI - Electrical resistivity of assembled transparent inorganic oxide nanoparticle thin layers: influence of silica, insulating impurities, and surfactant layer thickness. AB - The electrical properties of transparent, conductive layers prepared from nanoparticle dispersions of doped oxides are highly sensitive to impurities. Production of cost-effective thin conducting films for consumer electronics often employs wet processing such as spin and/or dip coating of surfactant-stabilized nanoparticle dispersions. This inherently results in entrainment of organic and inorganic impurities into the conducting layer leading to largely varying electrical conductivity. Therefore, this study provides a systematic investigation on the effect of insulating surfactants, small organic molecules and silica in terms of pressure dependent electrical resistivity as a result of different core/shell structures (layer thickness). Application of high temperature flame synthesis gives access to antimony-doped tin oxide (ATO) nanoparticles with high purity. This well-defined starting material was then subjected to representative film preparation processes using organic additives. In addition ATO nanoparticles were prepared with a homogeneous inorganic silica layer (silica layer thickness from 0.7 to 2 nm). Testing both organic and inorganic shell materials for the electronic transport through the nanoparticle composite allowed a systematic study on the influence of surface adsorbates (e.g., organic, insulating materials on the conducting nanoparticle's surface) in comparison to well-known insulators such as silica. Insulating impurities or shells revealed a dominant influence of a tunneling effect on the overall layer resistance. Mechanical relaxation phenomena were found for 2 nm insulating shells for both large polymer surfactants and (inorganic) SiO(2) shells. PMID- 22545731 TI - Topological ferroelectric bistability in a polarization-modulated orthogonal smectic liquid crystal. AB - We report a bent-core liquid crystal (LC) compound exhibiting two fluid smectic phases in which two-dimensional, polar, orthorhombic layers order into three dimensional ferroelectric states. The lower-temperature phase has a uniform polarization field which responds in an analog fashion to applied electric field. The higher-temperature phase is a new smectic state with periodic undulation of the polarization, structurally modulated layers, and a bistable response to applied electric field which originates in the periodically splay-modulated bulk of the LC rather than by surface stabilization at the cell boundaries. PMID- 22545732 TI - Four nucleophilic additions to alkenynedioic acid derivatives in tandem; efficient one-pot synthesis of bicyclo[4.2.0]octenols. AB - When alkenynedioic acid derivatives were treated with a Grignard reagent, tandem cyclization and the incorporation of two molecules of the Grignard reagent occurred to give stereodefined bicyclo[4.2.0]octenols via four nucleophilic additions. PMID- 22545733 TI - Synthesis and characterization of N-[2-P(i-Pr)2-4-methylphenyl]2- (PNP) pincer tin(IV) and tin(II) complexes. AB - N-[2-P(i-Pr)(2)-4-methylphenyl](2)(-) (PNP) pincer complexes of tin(IV) and tin(II), [(PNP)SnCl(3)] (2) and [(PNP)SnN(SiMe(3))(2)] (3), respectively, were prepared and characterized by X-ray diffraction, solution and solid state NMR spectroscopy, and (119)Sn Mossbauer spectroscopy. Furthermore, (119)Sn cross polarization magic angle spinning NMR spectroscopic data of [Sn(NMe(2))(2)](2) are reported. Compound 2 is surprisingly stable toward air, but attempts to substitute chloride ligands caused decomposition. PMID- 22545734 TI - Advanced glycation end products impair the migration, adhesion and secretion potentials of late endothelial progenitor cells. AB - BACKGROUND: Endothelial progenitor cells (EPCs), especially late EPCs, play a critical role in endothelial maintenance and repair, and postnatal vasculogenesis. Advanced glycation end products (AGEs) have been shown to impair EPC functions, such as proliferation, migration and adhesion. However, their role in the regulation of the production of vasoactive substances in late EPCs is less well defined. METHODS: Passages of 3~5 EPCs, namely late EPCs, were cultured with different concentrations (0~500 MUg/ml) of AGEs, and the apoptosis, adhesion and migration were subsequently determined. The release of vasoactive substances, such as stromal cell-derived factor-1 (SDF-1), nitric oxide (NO), prostaglandin I2 (PGI2), plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA), and in addition the activity of superoxide dismutase (SOD), were evaluated by ELISA. At the same time, the gene and protein expressions of CXCR4 were assayed by real-time RT-PCR and western-blot. RESULTS: AGEs promoted late EPC apoptosis. Moreover, AGEs impaired late EPC migration and adhesion in a concentration-dependent manner. Accordingly, the production of SDF-1 was decreased by AGEs. Although the CXCR4 expressions of late EPCs were up-regulated for AGE concentrations of 50, 100 or 200 MUg/ml, a marked decrease was observed for the higher concentration of 500 MUg/ml. Furthermore, co-culturing with AGEs decreased the levels of NO, t-PA, PGI2, and the activity of SOD but up-regulated the production of PAI-1. CONCLUSION: Our data provide evidence that AGEs play an important role in impairing late EPC functions, which could contribute to the development of vascular diseases in diabetes. PMID- 22545735 TI - Dietary L-arginine supplementation reduces Methotrexate-induced intestinal mucosal injury in rat. AB - BACKGROUND: Arginine (ARG) and nitric oxide maintain the mucosal integrity of the intestine in various intestinal disorders. In the present study, we evaluated the effects of oral ARG supplementation on intestinal structural changes, enterocyte proliferation and apoptosis following methotrexate (MTX)-induced intestinal damage in a rat. METHODS: Male rats were divided into four experimental groups: Control rats, CONTR-ARG rats, were treated with oral ARG given in drinking water 72 hours before and 72 hours following vehicle injection, MTX rats were treated with a single dose of methotrexate, and MTX-ARG rats were treated with oral ARG following injection of MTX. Intestinal mucosal damage, mucosal structural changes, enterocyte proliferation and enterocyte apoptosis were determined 72 hours following MTX injection. RT-PCR was used to determine bax and bcl-2 mRNA expression. RESULTS: MTX-ARG rats demonstrated greater jejunal and ileal bowel weight, greater ileal mucosal weight, greater ileal mucosal DNA and protein levels, greater villus height in jejunum and ileum and crypt depth in ileum, compared to MTX animals. A significant decrease in enterocyte apoptosis in the ileum of MTX-ARG rats (vs MTX) was accompanied by decreased bax mRNA and protein expression and increased bcl-2 protein levels. CONCLUSIONS: Treatment with oral ARG prevents mucosal injury and improves intestinal recovery following MTX- injury in the rat. PMID- 22545736 TI - Technology-enhanced maintenance of treatment gains in eating disorders: efficacy of an intervention delivered via text messaging. AB - OBJECTIVE: Given the lack of maintenance interventions for eating disorders, a program delivered via the short message service (SMS) and text messaging was developed to support patients after their discharge from inpatient treatment. METHOD: The efficacy of the intervention was studied in a randomized controlled trial. Additionally, its impact on the utilization of outpatient treatment during follow-up was investigated. One hundred sixty-five female patients with bulimia nervosa or a related eating disorder not otherwise specified were randomly assigned to a control group (treatment as usual; TAU) or an intervention group (SMS-based maintenance intervention; SMS). After hospital discharge, participants in the intervention group submitted a weekly symptom report via text message for 16 weeks and received tailored feedback. Primary outcome was the rate of partial remission 8 months after discharge from inpatient treatment. RESULTS: The difference in remission rates reached significance in the intent-to-treat analyses (SMS = 51.2%; TAU = 36.1%), chi2(1) = 3.81, p = .05, and approached significance in the completer analysis (SMS = 59.2%; TAU = 43.5%), chi2(1) = 3.44, p = .06. There were no differences in the utilization of outpatient treatment. Remission rates between the intervention and control groups were not significantly different among patients who used outpatient treatment (63.2% vs. 55.6%), chi2(1) = 0.44, p = .51. A significant difference was found in those who did not utilize such treatment (54.5% vs. 30.3%), chi2(1) = 3.97, p = .046. CONCLUSION: The aftercare intervention was efficacious in enhancing treatment outcome after discharge from inpatient treatment. PMID- 22545737 TI - Cognitive behavioral therapy for adherence and depression (CBT-AD) in HIV infected injection drug users: a randomized controlled trial. AB - OBJECTIVE: Depression and substance use, the most common comorbidities with HIV, are both associated with poor treatment adherence. Injection drug users comprise a substantial portion of individuals with HIV in the United States and globally. The present study tested cognitive behavioral therapy for adherence and depression (CBT-AD) in patients with HIV and depression in active substance abuse treatment for injection drug use. METHOD: This is a 2-arm, randomized controlled trial (N = 89) comparing CBT-AD with enhanced treatment as usual (ETAU). Analyses were conducted for two time-frames: (a) baseline to post-treatment and (b) post treatment to follow-up at 3 and 6 months after intervention discontinuation. RESULTS: At post-treatment, the CBT-AD condition showed significantly greater improvement than ETAU in MEMS (electronic pill cap) based adherence, gammaslope = 0.8873, t(86) = 2.38, p = .02; dGMA-raw = 0.64, and depression, assessed by blinded assessor: Mongomery-Asberg Depression Rating Scale, F(1, 79) = 6.52, p < .01, d = 0.55; clinical global impression, F(1, 79) = 14.77, p < .001, d = 0.85. After treatment discontinuation, depression gains were maintained, but adherence gains were not. Viral load did not differ across condition; however, the CBT-AD condition had significant improvements in CD4 cell counts over time compared with ETAU, gammaslope = 2.09, t(76) = 2.20, p = .03, dGMA-raw = 0.60. CONCLUSIONS: In patients managing multiple challenges including HIV, depression, substance dependence, and adherence, CBT-AD is a useful way to integrate treatment of depression with an adherence intervention. Continued adherence counseling is likely needed, however, to maintain or augment adherence gains in this population. PMID- 22545738 TI - The relation between changes in patients' interpersonal impact messages and outcome in treatment for chronic depression. AB - OBJECTIVE: Interpersonal theories posit that chronically depressed individuals have hostile and submissive styles in their social interactions, which may undermine their interpersonal effectiveness and maintain their depression. Recent findings support this theory and also show that patients' interpersonal impact messages, as perceived by their psychotherapists, change in theoretically predicted ways following cognitive-behavioral analysis system of psychotherapy (CBASP) alone or with medication. This study extended these previous findings by examining whether such changes were associated with their depression change and response status. METHOD: Data derived from a large clinical trial for chronic depression compared the efficacy of CBASP, nefazodone, and their combination. To assess patients' impact messages, CBASP clinicians completed the Impact Message Inventory (IMI; Kiesler & Schmidt, 1993) following an early and late session. Our subsample (N = 259) consisted of patients in the CBASP and combined conditions who had depression severity data for at least 1 post-randomization visit and whose clinicians completed at least 1 IMI rating. We used hierarchical linear modeling (HLM) to calculate IMI change scores and to model depression change. We used HLM and logistic regression to test our predictor questions. RESULTS: As hypothesized, decreases in patients' hostile-submissive impact messages were significantly associated with depression reduction (gamma = 0.27, 95% CI [0.11, 0.43], p < .01) and favorable treatment response (B = -0.05, 95% CI [-0.09, 0.01], p = .03), regardless of treatment condition. CONCLUSIONS: The findings support CBASP theory, suggesting that interpersonal change is related to depression reduction among chronically depressed patients. PMID- 22545740 TI - Do anxiety-disordered children need to come into the clinic for efficacious treatment? AB - OBJECTIVE: This study compared 3 experimental conditions: wait-list, therapist supported bibliotherapy, and individual therapy, in the treatment of child anxiety. METHOD: Participants were 55 children (25 girls and 30 boys), aged 7 to 14 years diagnosed with an anxiety disorder, and their parents. Families were assigned using a modified random assignment process to 1 of the 3 conditions. The intervention evaluated in the 2 active treatment conditions was a family-focused, cognitive-behavioral program. RESULTS: At posttreatment, participants in both treatment conditions had improved significantly on both diagnostic and questionnaire outcome measures compared with participants in the wait-list condition, with no differences demonstrated between the treatment conditions. Thus, at posttreatment, 0% of children in the wait-list condition were anxiety diagnosis free, compared with 95% in the therapist-supported bibliotherapy condition and 78.3% in the individual therapy condition. There was no significant difference between diagnostic status at posttreatment between the 2 treatment conditions. Participants assigned to a treatment condition were reassessed at 3 month and 6-month follow-up. Treatment gains were maintained in both conditions across the follow-up period. CONCLUSION: In light of the fact that more than 80% of anxiety-disordered children never receive treatment, these data suggest that therapist-supported bibliotherapy represents a cost-effective means of reaching a greater number of anxious children. PMID- 22545739 TI - Trauma and posttraumatic stress symptoms predict alcohol and other drug consequence trajectories in the first year of college. AB - OBJECTIVE: College matriculation begins a period of transition into adulthood, one that is marked by new freedoms and responsibilities. This transition also is marked by an escalation in heavy drinking and other drug use as well as a variety of use-related negative consequences. Trauma and symptoms of posttraumatic stress disorder (PTSD) may affect alcohol and drug problems and, thus, may be a point of intervention. Yet, no studies have examined trauma, PTSD, and alcohol and drug problem associations during this developmental period. The present study provides such an examination. METHOD: Matriculating college students (N = 997) completed surveys in September (Time 1) and at 5 subsequent time points (Time 2-Time 6) over their 1st year of college. With latent growth analysis, trajectories of alcohol- and drug-related consequences were modeled to examine how trauma (No Criterion A Trauma, Criterion A Only, No PTSD Symptoms) and PTSD (partial or full) symptom status predicted these trajectories. RESULTS: Results showed substantial risk for alcohol- and other drug-related negative consequences that is conferred by the presence of PTSD at matriculation. Those with both partial and full PTSD started the year with more alcohol and drug consequences. These individuals showed a steeper decrease in consequences in the 1st semester, which leveled off as the year progressed. Both alcohol and drug consequences remained higher for those in the PTSD group throughout the academic year. Hyperarousal symptoms showed unique effects on substance consequence trajectories. Risk patterns were consistent for both partial and full PTSD symptom presentations. Trajectories did not vary by gender. CONCLUSIONS: Interventions that offer support and resources to students entering college with PTSD may help to ameliorate problem substance use and may ultimately facilitate a stronger transition into college and beyond. PMID- 22545741 TI - Impact of metacognitive acceptance on body dissatisfaction and negative affect: engagement and efficacy. AB - OBJECTIVE: To investigate engagement in metacognitive acceptance and subsequent efficacy with respect to decreasing 2 risk factors for disordered eating, body dissatisfaction (BD), and negative affect (NA). METHOD: In a pilot experiment, 20 female undergraduates (Mage = 24.35, SD = 9.79) underwent a BD induction procedure, received acceptance training using brief written instructions, and were then assessed on engagement in the technique. In a second experiment in which acceptance training was enhanced through the use of video format and a guided experiential exercise, 80 female undergraduates (mean age = 23.59, SD = 8.98) were randomized to an acceptance or control group following the same BD induction. Outcome measures were taken at baseline, postinduction, and posttreatment and consisted of separate visual analogue scales for weight and appearance satisfaction and the NA subscale of the Positive and Negative Affect Scale. Baseline assessments included the Eating Disorder Inventory-BD, Difficulties in Emotion Regulation Scale, Ways of Coping Questionnaire, and the Five Facet Mindfulness Questionnaire. RESULTS: Enhanced training significantly increased engagement in acceptance. Nonengagement was associated with NA, emotion regulation difficulties, and avoidant coping. Acceptance training significantly increased weight and appearance satisfaction and reduced NA relative to control, with no significant differences between those who did and did not engage. Intervention effects were moderated by mindfulness, emotion regulation difficulty, and avoidant coping. CONCLUSIONS: Findings provide clarification regarding engagement and lend further support for the utility of acceptance, with particular benefit identified for those "at risk" for emotion regulation difficulty. PMID- 22545742 TI - Psychopathology, Iraq and Afghanistan service, and suicide among Veterans Health Administration patients. AB - OBJECTIVE: Despite concerns regarding elevated psychiatric morbidity and suicide among veterans returning from Operations Enduring Freedom and Iraqi Freedom (OEF/OIF), little is known about the impact of psychiatric conditions on the risk of suicide in these veterans. To inform tailored suicide prevention efforts, it is important to assess interrelationships between OEF/OIF status, psychiatric morbidity, and suicide mortality. This study sought to examine potential associations between OEF/OIF status and suicide mortality among individuals receiving care in the Department of Veterans Affairs health system, the Veterans Health Administration (VHA). Analyses assessed potential interactions between OEF/OIF status and psychiatric conditions as predictors of suicide. METHOD: Analyses included data for all individuals who received VHA services during fiscal year (FY) 2007 or FY08 and were alive at the start of FY08 (N = 5,772,282). RESULTS: For this cohort, there were 1,920 suicide deaths in FY08, including 96 among OEF/OIF veterans. Controlling for demographic factors, psychiatric conditions, OEF/OIF status, and the interaction between psychiatric conditions and OEF/OIF status, no main effects of OEF/OIF status were observed. However, a significant interaction was found between psychiatric conditions and OEF/OIF status. Specifically, having a diagnosed mental health condition was associated with a greater risk of suicide among OEF/OIF veterans (hazard ratio [HR] = 4.41; 95% confidence interval [CI]: 2.57, 7.55; p < .01) than among non OEF/OIF veterans (HR = 2.48; 95% CI [2.27, 2.71]; p < .01). CONCLUSION: These findings highlight the importance of mental health screening and intervention for OEF/OIF veterans. PMID- 22545743 TI - Kinetic competition model and size-dependent phase selection in 1-D nanostructures. AB - The first phase selection and the phase formation sequence between metal and silicon (Si) couples are indispensably significant to microelectronics. With increasing scaling of device dimension to nano regime, established thermodynamic and kinetic models in bulk and thin film fail to apply in 1-D nanostructures. Herein, we present an unique size-dependent first phase formation sequence in 1-D nanostructures, with Ni-Si as the model system. Interfacial-limited phase which forms the last in thin film, NiSi(2), appears as the dominant first phase at 300 800 degrees C due to the elimination of continuous grain boundaries in 1-D silicides. On the other hand, theta-Ni(2)Si, the most competitive diffusion limited phase takes over NiSi(2) and wins out as the first phase in small diameter nanowires at 800 degrees C. Kinetic parameters extracted from in situ transmission electron microscope studies and a modified kinetic growth competition model quantitatively explain this observation. An estimated critical diameter from the model agrees reasonably well with observations. PMID- 22545744 TI - Political polarization projection: social projection of partisan attitude extremity and attitudinal processes. AB - What influences perceptions of political polarization? The authors examine the polarization of people's own political attitudes as a source of perceived polarization: Individuals with more extreme partisan attitudes perceive greater polarization than individuals with less extreme partisan attitudes. This "polarization projection" was demonstrated in 3 studies in which people estimated the distribution of others' political attitudes: one study with a nationally representative sample concerning the 2008 presidential election, and 2 studies concerning university students evaluating a policy regarding scarce resource allocation. These studies demonstrate that polarization projection occurs simultaneously with and independently of simple projection, the tendency to assume that others share one's partisan political attitudes. Polarization projection may occur partly because people assume that others engage in similar attitudinal processes as the self, such as extensive thought and emotional arousal. The projection of various attitudinal processes was demonstrated in a study concerning health care reform policies. Further supporting this explanation, polarization projection increased when people introspected about their own attitudinal processes, which increased the accessibility of those processes. Implications for perceptions of partisanship, social judgment, and civic behavior are discussed. PMID- 22545745 TI - A dual-motive model of scapegoating: displacing blame to reduce guilt or increase control. AB - The authors present a model that specifies 2 psychological motives underlying scapegoating, defined as attributing inordinate blame for a negative outcome to a target individual or group, (a) maintaining perceived personal moral value by minimizing feelings of guilt over one's responsibility for a negative outcome and (b) maintaining perceived personal control by obtaining a clear explanation for a negative outcome that otherwise seems inexplicable. Three studies supported hypotheses derived from this dual-motive model. Framing a negative outcome (environmental destruction or climate change) as caused by one's own harmful actions (value threat) or unknown sources (control threat) both increased scapegoating, and these effects occurred indirectly through feelings of guilt and perceived personal control, respectively (Study 1), and were differentially moderated by affirmations of moral value and personal control (Study 2). Also, scapegoating in response to value threat versus control threat produced divergent, theoretically specified effects on self-perceptions and behavioral intentions (Study 3). PMID- 22545746 TI - How sex puts you in gendered shoes: sexuality-priming leads to gender-based self perception and behavior. AB - Scripts for sexual behavior dictate that women be submissive and tender and that men be assertive and dominant, reflecting the stereotypical view of women as communal and of men as agentic. Six experiments tested the hypothesis that exposure to sexuality cues causes men's and women's momentary self-perceptions and concomitant behavior to become more gender-typical. Using both pictorial and verbal prime materials that were presented both supraliminally and subliminally, we found that sex-priming strengthened gender-based self-perceptions (i.e., faster self-categorization as a woman or man; Study 1), heightened identification with one's own gender (Study 2), increased gender self-stereotyping (Study 3), and elicited greater submissiveness in women's behavior and greater assertiveness in men's behavior (Studies 4 and 5). These findings indicate that sex-priming causes self-perception and social behavior to become "attuned" to gender stereotypes. Study 6 demonstrated that these sex-priming effects can be eliminated by modern gender role primes. The potentially detrimental effects of sex-priming and possible countermeasures are discussed. PMID- 22545747 TI - Motivated social categorization: fundamental motives enhance people's sensitivity to basic social categories. AB - This article presents an evolutionary framework for identifying the characteristics people use to categorize members of their social world. Findings suggest that fundamental social motives lead people to implicitly categorize social targets based on whether those targets display goal-relevant phenotypic traits. A mate-search prime caused participants to categorize opposite-sex targets (but not same-sex targets) based on their level of physical attractiveness (Experiment 1). A mate-guarding prime interacted with relationship investment, causing participants to categorize same-sex targets (but not opposite sex targets) based on their physical attractiveness (Experiment 2). A self protection prime interacted with chronic beliefs about danger, increasing participants' tendency to categorize targets based on their racial group membership (Black or White; Experiment 3). This work demonstrates that people categorize others based on whether they display goal-relevant characteristics reflecting high levels of perceived desirability or threat. Social categorization is guided by fundamental evolved motives designed to enhance adaptive social outcomes. PMID- 22545748 TI - Uneasy lies the head that wears the crown: the link between guilt proneness and leadership. AB - We propose that guilt proneness is a critical characteristic of leaders and find support for this hypothesis across 3 studies. Participants in the first study rated a set of guilt-prone behaviors as more indicative of leadership potential than a set of less guilt-prone behaviors. In a follow-up study, guilt-prone participants in a leaderless group task engaged in more leadership behaviors than did less guilt-prone participants. In a third, and final, study, we move to the field and analyze 360 degrees feedback from a group of young managers working in a range of industries. The results indicate that highly guilt-prone individuals were rated as more capable leaders than less guilt-prone individuals and that a sense of responsibility for others underlies the positive relationship between guilt proneness and leadership evaluations. PMID- 22545749 TI - Update on incretin hormones. AB - The incretin hormones glucagon-like-peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released from the intestine following oral ingestion of nutrients. Incretins promote insulin secretion, while GLP-1 also inhibits glucagon release and gastric emptying, minimizing postprandial glucose excursions. The incretins share similar effects on the pancreatic beta cell; however, there are a number of differences in extrapancreatic actions. Type 2 diabetes (T2DM) is associated with abnormal incretin physiology, and although treatment with GIP is ineffective, GLP-1 effects are preserved. The current incretin-based approaches to T2DM include the GLP-1 agonists that are resistant to the serine protease dipeptidylpeptidase-4 (DPP4), which normally rapidly degrades the incretins, and DPP4 inhibitors (DPP4i). Incretin-based treatments have provoked much interest due to use-associated weight loss (GLP-1 agonists), minimal hypoglycemia, and potential for positive effects on pancreatic beta cell biology and the cardiovascular system. However, the long-term safety of these agents has yet to be established. This review outlines the current understanding of incretin biology, available data pertaining to incretin-based treatment in T2DM, and differences between GLP-1 and DPP4i therapy. PMID- 22545750 TI - Low dose ionising radiation leads to a NF-kappaB dependent decreased secretion of active IL-1beta by activated macrophages with a discontinuous dose-dependency. AB - PURPOSE: Therapy with low doses of ionising radiation (X-rays) exerts anti inflammatory effects. Little is known about whether and how low doses of X-ray treatment modulate the inflammatory phenotype of macrophages, especially the secretion of Interleukin-1beta (IL-1beta). MATERIALS AND METHODS: Macrophages were differentiated from human THP-1 monocytes, activated with lipopolysaccharide (LPS), treated with distinct low doses of X-rays, and co-activated with monosodium urate crystals (MSU) to induce inflammasome activation. Secretion of IL-1beta was analysed by an enzyme-linked immunosorbent assay (ELISA) and Western blot. Furthermore, we analysed the intracellular amounts of the serine/threonine protein kinase B (named: Akt), mitogen-activated protein kinase p38 (p38), the v rel reticuloendotheliosis viral oncogene homolog A (RelA), and pro- and cleaved IL-1beta. RESULTS: Low dose X-rays led to decreased secretion of active IL-1beta in a manner discontinuous with dose which was most pronounced after 0.5 or 0.7 Gy. Passive release of lactate dehydrogenase (LDH) was not influenced by X-rays. The decreased secretion of IL-1beta correlated with reduced translocation of RelA, being part of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) complex, into the nucleus. After 0.5 or 0.7 Gy of X-rays, the intracellular protein amounts of up (p38) and downstream molecules (Akt) of NF kappaB were reduced in activated macrophages, as were the pro- and cleaved forms of IL-1beta. CONCLUSIONS: Distinct low doses of X-rays induce an anti inflammatory phenotype of activated macrophages by lowering the amount of secreted IL-1beta in a NF-kappaB dependent manner. PMID- 22545751 TI - Response to antiretroviral therapy of HIV type 1-infected children in urban and rural settings of Uganda. AB - From 2006 to 2011, a cohort study was conducted among 1000 children resident in urban and rural settings of Uganda to ascertain and compare the response to antiretroviral therapy (ART) among urban versus rural children and the factors associated with this response. Clinical, immunological, and virological parameters were ascertained at baseline and weeks 24, 48, 96, and 144 after ART initiation. Adherence to ART was assessed at enrollment by self-report (SR) and pill counts (PC). Overall, 499/948 (52.6%) children were resident in rural areas, 504/948 (53.1%) were male, and their mean age was 11.9+/-4.4 years (urban children) and 11.4+/-4.1 years (rural children). The urban children were more likely to switch to second-line ART at a rate of 39.9 per 1000 person-years (95% CI: 28.2-56.4) versus 14.9 per 1000 person-years (95% CI: 8.7-25.7), p=0.0038, develop any new WHO 3/4 events at 127/414 (30.7%) versus 108/466 (23.2%), p=0.012, and have a higher cumulative incidence of hospitalization of 54/449 (12.0%) versus 32/499 (6.4%), p=0.003, when compared to rural children. No differences were observed in mean changes in weight, height, CD4 count and percentage, and hemoglobin and viral load between urban and rural children. Adherence of >=95% was observed in 88.2% of urban versus 91.3% of rural children by SR (p=0.130), and in 78.8% of urban versus 88.8% of rural children by PC (p<0.0001). In this study rural children had more favorable clinical outcomes and were more likely to adhere optimally to ART than urban children. PMID- 22545752 TI - Medullary thyroid carcinoma: who's on first? PMID- 22545753 TI - Subcellular distribution of the sodium iodide symporter in benign and malignant thyroid tissues. AB - BACKGROUND: Membranous expression of the sodium iodide symporter (NIS) is a prerequisite for iodide uptake in thyrocytes. Previous studies reported heterogeneous results on the relative frequency of staining in various pathological conditions of the thyroid. The present study aimed at determining membranous staining by using confocal laser microscopy in benign and malignant thyroid diseases, complemented in a subgroup of patients with recurrent or metastatic disease with functional findings of radioiodine uptake (RIU). METHODS: There were 380 malignant thyroid tumors (145 papillary, 51 follicular, 87 Hurthle cell, and 97 undifferentiated thyroid carcinomas [UTC]), 115 benign adenomas, 62 diffuse goiters, 89 inflammatory conditions (Graves', Hashimoto, Thyroiditis deQuervain, and lymphocytic thyroiditis), and 179 normal tissues (NT, fetal, and adult). These were subjected to NIS (two different antibodies) and thyroglobulin (TG) staining and evaluated by confocal microscopy. RESULTS: In a subgroup of 50 samples from patients with recurrent or metastatic disease, NIS staining was correlated with the RIU. As compared with NT, Graves' patients had significantly higher positive NIS membrane staining (>97% vs. 69%) whereas patients with Hashimoto, lymphocytic thyroiditis but also benign adenomas scored lower than NT (56.7% and 55.8% vs. 69%). Depending on their differentiation NIS staining was significantly lower in thyroid carcinomas in parallel with TG staining with only 1/97 UTCs being positive. RIU was more frequently detectable than NIS staining. CONCLUSION: Confocal staining strictly evaluating only membranous expression of NIS has not used on a large scale before this study. We confirm the loss of membranous NIS in benign but more prominently in malignant thyroid tumors. NIS staining of diagnostic tissues cannot be used to predict RIU. PMID- 22545755 TI - A school-based comprehensive lifestyle intervention among chinese kids against obesity (CLICK-Obesity): rationale, design and methodology of a randomized controlled trial in Nanjing city, China. AB - BACKGROUND: The prevalence of childhood obesity among adolescents has been rapidly rising in Mainland China in recent decades, especially in urban and rich areas. There is an urgent need to develop effective interventions to prevent childhood obesity. Limited data regarding adolescent overweight prevention in China are available. Thus, we developed a school-based intervention with the aim of reducing excess body weight in children. This report described the study design. METHODS/DESIGN: We designed a cluster randomized controlled trial in 8 randomly selected urban primary schools between May 2010 and December 2013. Each school was randomly assigned to either the intervention or control group (four schools in each group). Participants were the 4th graders in each participating school. The multi-component program was implemented within the intervention group, while students in the control group followed their usual health and physical education curriculum with no additional intervention program. The intervention consisted of four components: a) classroom curriculum, (including physical education and healthy diet education), b) school environment support, c) family involvement, and d) fun programs/events. The primary study outcome was body composition, and secondary outcomes were behaviour and behavioural determinants. DISCUSSION: The intervention was designed with due consideration of Chinese cultural and familial tradition, social convention, and current primary education and exam system in Mainland China. We did our best to gain good support from educational authorities, school administrators, teachers and parents, and to integrate intervention components into schools' regular academic programs. The results of and lesson learned from this study will help guide future school-based childhood obesity prevention programs in Mainland China. TRIAL REGISTRATION: REGISTRATION NUMBER: ChiCTR-ERC-11001819. PMID- 22545756 TI - Near-present and future distribution of Anopheles albimanus in Mesoamerica and the Caribbean Basin modeled with climate and topographic data. AB - BACKGROUND: Anopheles albimanus is among the most important vectors of human malaria in Mesoamerica and the Caribbean Basin (M-C). Here, we use topographic data and 1950-2000 climate (near present), and future climate (2080) layers obtained from general circulation models (GCMs) to project the probability of the species' presence, p(s), using the species distribution model MaxEnt. RESULTS: The projected near-present distribution parameterized with 314 presence points related well to the known geographic distribution in the study region. Different model experiments suggest that the range of An. albimanus based on near-present climate surfaces covered at least 1.27 million km2 in the M-C, although 2080 range was projected to decrease to 1.19 million km2. Modeled p(s) was generally highest in Mesoamerica where many of the original specimens were collected. MaxEnt projected near-present maximum elevation at 1,937 m whereas 2080 maximum elevation was projected at 2,118 m. 2080 climate scenarios generally showed increased p(s) in Mesoamerica, although results varied for northern South America and no major range expansion into the mid-latitudes was projected by 2080. CONCLUSIONS: MaxEnt experiments with near present and future climate data suggest that An. albimanus is likely to invade high-altitude (>2,000 m) areas by 2080 and therefore place many more people at risk of malaria in the M-C region even though latitudinal range expansion may be limited. PMID- 22545757 TI - A molecular view on the role of cholesterol upon membrane insertion, aggregation, and water accessibility of the antibiotic lipopeptide trichogin GA IV as revealed by EPR. AB - Trichogin GA IV is a membrane-active lipopeptide, the antibiotic activity of which was proposed to be based on its capability to induce leakage due to formation of pores into the bacterial cell membrane. However, less attention has been paid to its biological selectivity, i.e., discrimination between bacterial versus cholesterol containing (mammalian) membranes. This is the reason which motivated us to study the role of cholesterol on penetration of the peptide into the membrane and formation of water channels. The ESEEM technique was used to measure the modulation amplitudes for TOAC spin-labeled trichogin GA IV peptide analogues in hydrated membranes of phosphatidylcholine (PC) lipid in the presence of 50 mol % cholesterol-d7. From the interaction between the nitroxide spin-label and the nearby located deeply membrane inserted deuterons, the N-terminus was found to be positioned at the core of the membrane. Separately, ESEEM measurements for the FTOAC-8 labeled peptide, but in D2O hydrated cholesterol/PC membranes, provide strong evidence for the polar C-terminus situated near the membrane surface. The apparently too high modulation amplitude measured for the buried FTOAC-1 label is likely attributed to the presence of peptide associated water. In cholesterol depleted membrane, however, the long axes of the helical molecules are found oriented parallel to the membrane surface even at high peptide concentration. Continuous wave EPR spectroscopy indicates that, for cholesterol containing membrane, peptide insertion is accompanied by self aggregation of parallelly aligned transmembrane peptide molecules, while for cholesterol lacking membranes they are monomolecularly distributed. Thus, cholesterol tends to stabilize the transmembrane peptide aggregate. PMID- 22545759 TI - A total synthesis prompts the structure revision of haouamine B. AB - A concise asymmetric approach to the indeno-tetrahydropyridine core of the unusual alkaloid haouamine B allowed for an investigation of a biomimetic oxidative phenol coupling as a proposed biosynthetic step, and ultimately provided access to the published structure of the natural product. As a consequence of our synthetic studies, the structure of haouamine B has been revised. PMID- 22545760 TI - Whole cell biosynthesis of a functional oligosaccharide, 2'-fucosyllactose, using engineered Escherichia coli. AB - BACKGROUND: 2'-Fucosyllactose (2-FL) is a functional oligosaccharide present in human milk which protects against the infection of enteric pathogens. Because 2 FL can be synthesized through the enzymatic fucosylation of lactose with guanosine 5'-diphosphate (GDP)-l-fucose by alpha-1,2-fucosyltransferase (FucT2), an 2-FL producing Escherichia coli can be constructed through overexpressing genes coding for endogenous GDP- l-fucose biosynthetic enzymes and heterologous fucosyltransferase. RESULTS: The gene for FucT2 from Helicobacter pylori was introduced to the GDP-l-fucose producing recombinant E. coli BL21 star(DE3) strain. However, only small amount of 2-FL was produced in a batch fermentation because the E. coli BL21star(DE3) strain assimilated lactose instead of converting to 2-FL. As an alternative host, the E. coli JM109(DE3) strain which is incapable of assimilating lactose was chosen as a 2-FL producer. Whole cell biosynthesis of 2-FL from lactose was investigated in a series of batch fermentations using various concentrations of lactose. The results of batch fermentations showed that lactose was slowly assimilated by the engineered E. coli JM109(DE3) strain and 2-FL was synthesized without supplementation of another auxiliary sugar for cell growth. A maximum 2-FL concentration of 1.23 g/l was obtained from a batch fermentation with 14.5 g/l lactose. The experimentally obtained yield (g 2-FL/g lactose) corresponded to 20% of the theoretical maximum yield estimated by the elementary flux mode (EFM) analysis. CONCLUSIONS: The experimental 2-FL yield in this study corresponded to about 20% of the theoretical maximum yield, which suggests further modifications via metabolic engineering of a host strain or optimization of fermentation processes might be carried out for improving 2-FL yield. Improvement of microbial production of 2-FL from lactose by engineered E. coli would increase the feasibility of utilizing 2 FL as a prebiotic in various foods. PMID- 22545761 TI - Computational studies of the metal-binding site of the wild-type and the H46R mutant of the copper, zinc superoxide dismutase. AB - Impairment of the Zn(II)-binding site of the copper, zinc superoxide dismutase (CuZnSOD) protein is involved in a number of hypotheses and explanations for the still unknown toxic gain of function mutant varieties of CuZnSOD that are associated with familial forms of amyotrophic lateral sclerosis (ALS). In this work, computational chemistry methods have been used for studying models of the metal-binding site of the ALS-linked H46R mutant of CuZnSOD and of the wild-type variety of the enzyme. By comparing the energy and electronic structure of these models, a plausible explanation for the effect of the H46R mutation on the zinc site is obtained. The computational study clarifies the role of the D124 and D125 residues for keeping the structural integrity of the Zn(II)-binding site, which was known to exist but its mechanism has not been explained. Earlier results suggest that the explanation for the impairment of the Zn(II)-site proposed in this work may be useful for understanding the mechanism of action of the ALS linked mutations in CuZnSOD in general. PMID- 22545758 TI - Genetic characterization of Plectorhinchus mediterraneus yields important clues about genome organization and evolution of multigene families. AB - BACKGROUND: Molecular and cytogenetic markers are of great use for to fish characterization, identification, phylogenetics and evolution. Multigene families have proven to be good markers for a better understanding of the variability, organization and evolution of fish species. Three different tandemly-repeated gene families (45S rDNA, 5S rDNA and U2 snDNA) have been studied in Plectorhinchus mediterraneus (Teleostei: Haemulidae), at both molecular and cytogenetic level, to elucidate the taxonomy and evolution of these multigene families, as well as for comparative purposes with other species of the family. RESULTS: Four different types of 5S rDNA were obtained; two of them showed a high homology with that of Raja asterias, and the putative implication of a horizontal transfer event and its consequences for the organization and evolution of the 5S rDNA have been discussed. The other two types do not resemble any other species, but in one of them a putative tRNA-derived SINE was observed for the first time, which could have implications in the evolution of the 5S rDNA. The ITS-1 sequence was more related to a species of another different genus than to that of the same genus, therefore a revision of the Hamulidae family systematic has been proposed. In the analysis of the U2 snDNA, we were able to corroborate that U2 snDNA and U5 snDNA were linked in the same tandem array, and this has interest for tracing evolutionary lines. The karyotype of the species was composed of 2n = 48 acrocentric chromosomes, and each of the three multigene families were located in different chromosome pairs, thus providing three different chromosomal markers. CONCLUSIONS: Novel data can be extracted from the results: a putative event of horizontal transfer, a possible tRNA-derived SINE linked to one of the four 5S rDNA types characterized, and a linkage between U2 and U5 snDNA. In addition, a revision of the taxonomy of the Haemulidae family has been suggested, and three cytogenetic markers have been obtained. Some of these results have not been described before in any other fish species. New clues about the genome organization and evolution of the multigene families are offered in this study. PMID- 22545762 TI - Efficacy of codelivery of dual AAV2/5 vectors in the murine retina and hippocampus. AB - Recombinant adeno-associated virus (AAV) represents an efficient system for neuronal transduction. However, a potential drawback of AAV is its restricted packaging capacity of approximately 5 kb. To bypass this limitation, a number of dual- and triple-vector strategies divide the transgene(s) between two or three AAVs. The success of these approaches relies directly on efficient cotransduction of the component AAVs. Although proof of concept for these stratagems has been demonstrated, the underlying cotransduction rate has not been analyzed quantitatively. In this study, cotransduction efficiencies in both retina and hippocampus have been investigated, using two reporter AAVs expressing either a green (GFP) or red (DsR) fluorescent protein. Transduction efficiencies were monitored via microscopy, flow cytometry, and quantitative PCR. After viral transduction with 1.5*10(9) viral particles of each of the reporter AAVs, approximately one-third of the retinal cells expressed one or both transgenes at levels detectable by native fluorescence. Notably, the majority of the remaining retinal cells were also transduced and expressed the reporters at lower levels, which were detectable only by immunolabeling. Flow cytometric analysis demonstrated cotransduction rates of up to 55% with the two reporter AAVs in retinal cells. Modifying the ratio of the two coadministered AAVs resulted in altered mRNA expression levels of the two reporter genes in cotransduced cell populations. The study suggests that codelivery of AAV is an efficient means of expanding the therapeutic application of AAV in neurons. PMID- 22545763 TI - Evolution of monogamy, paternal investment, and female life history in Peromyscus. AB - The timing of reproductive development and associated trade-offs in quantity versus quality of offspring produced across the life span are well documented in a wide range of species. The relation of these aspects of maternal life history to monogamy and paternal investment in offspring is not well studied in mammals, due in part to the rarity of the latter. By using five large, captive-bred populations of Peromyscus species that range from promiscuous mating with little paternal investment (P. maniculatus bairdii) to social and genetic monogamy with substantial paternal investment (P. californicus insignis), we modeled the interaction between monogamy and female life history. Monogamy and high paternal investment were associated with smaller litter size, delayed maternal reproduction that extended over a longer reproductive life span, and larger, higher quality offspring. The results suggest monogamy and paternal investment can alter the evolution of female life-history trajectories in mammals. PMID- 22545764 TI - Spatial memory in captive American black bears (Ursus americanus). AB - The spatial memory and foraging strategies of four adult captive-born American black bears (Ursus americanus) were explored in four experiments using a simulated foraging task. In the first three experiments, each session consisted of two phases separated by a delay: During the exploration phase, subjects foraged among a set of baited and unbaited sites. During the delay, the same locations were rebaited and subjects were released again and allowed to search the sites (search phase). In Experiments 1a and 1b, different sites were baited each day and the interval between exploration and search was short (4 hr or 15 min). Subjects were not accurate at recovering the food items in either experiment. In Experiment 2, an "informed forager" paradigm was used in which one subject was given privileged knowledge about the location of the food during the exploration phase and was later released with an "uninformed" competitor during the search phase. The bears did not achieve above-chance recovery accuracy even in the presence of a competitor. In Experiment 3, the same two of four sites were continually baited and the bears were released simultaneously over a period of 20 days, with each baiting separated by 2 or 3 days. As a group, the bears' foraging accuracy with repeated baiting and longer intervals approached greater than chance accuracy. Results suggest some limitations on bears' use of spatial memory in captive environments, but reveal the potential for use of spatial memory over longer delays. PMID- 22545765 TI - Apes (Gorilla gorilla, Pan paniscus, P. troglodytes, Pongo abelii) versus corvids (Corvus corax, C. corone) in a support task: the effect of pattern and functionality. AB - Apes (Gorilla gorilla, Pan paniscus, P. troglodytes, Pong abelii) and corvids (Corvus corax, C. corone) are among the most proficient and flexible tool users in the animal kingdom. Although it has been proposed that this is the result of convergent evolution, little is known about whether this is limited to behavior or also includes the underlying cognitive mechanisms. We compared several species of apes (bonobos, chimpanzees, gorillas, and orangutans) and corvids (carrion crows and common ravens) using exactly the same paradigm: a support task with elements from the classical patterned-string tasks. Corvids proved able to solve at least an easy pattern, whereas apes outperformed corvids with respect to the complexity of the patterns solved, the relative number of subjects solving each problem, and the speed to reach criterion. We addressed the question of whether subjects based their choices purely on perceptual cues or on a more abstract understanding of the problem. This was done by using a perceptually very similar but causally different condition where instead of paper strips there were strip shapes painted on a platform. Corvids' performance did not differ between conditions, whereas apes were able to solve the real but not the painted task. This shows that apes were not basing their choices just on spatial or arbitrary perceptual cues. Instead, and unlike corvids, they must have had some causal knowledge of the task. PMID- 22545766 TI - The validation of a French-language version of the Aging Perceptions Questionnaire (APQ) and its extension to a population aged 55 and over. AB - BACKGROUND: Several studies have shown the influence of the perceptions of aging on the cognitive functioning and the mental and physical health of older people. These relationships have not to date been studied in France where validated instruments are lacking. The primary objective of this study was to validate a French-language version of the Aging Perceptions Questionnaire (APQ) in the French general population aged 65 and over. The secondary objective was to study the stability of the dimensions of this instrument among participants aged 55 to 64. METHODS: The study was proposed to the cohort of the Observatoire Regional du Vieillissement (OPREVI) (observatory of aging), located in a small town in Poitou Charentes (western France). An anonymous questionnaire including the APQ was sent by mail to inhabitants aged 55 and over. The original English language APQ was described with adults aged 65 and older. It has 32 items distributed on 7 dimensions: timeline chronic and cyclical, positive and negative consequences, positive and negative control and emotional representations. RESULTS: 656 adults participated in this survey (286 men, 370 women). Among those aged 65 and over (n = 94), the seven-factor structure estimated by confirmatory factor analysis was coherent with original findings. Internal consistency as evaluated by Cronbach alpha, was between 0.83 for consequences negative and 0.52 for control negative. Several dimensions were strongly correlated. Among participants aged 55 to 64 (n = 262), the same factorial model yielded an acceptable fit. Multi-group confirmatory factor analysis concluded to approximate factorial invariance between the two age groups with a null delta in comparative fit index. CONCLUSION: This study among French people aged 65 and over, added further evidence of the multidimensional structure of the French version of the APQ which is superimposed to the dimensions of the original Irish version. The same factorial structure applies acceptably to the younger group (aged 55-64). The OPREVI study is ongoing, and will collect data on the physical, material and social characteristics of participants. It will therefore be possible to analyse the variables associated with the perceptions of aging. On the basis of an individual's perceptions of aging as captured by this questionnaire, and his or her clinical profile, tailored multi-dimensional assistance could be made available aiming to provide incentives to anticipate or to adapt to difficulties. PMID- 22545767 TI - Carbon nanohorns as a high-performance carrier for MnO2 anode in lithium-ion batteries. AB - MnO(2) nanoflakes coated on carbon nanohorns (CNHs) has been synthesized via a facile solution method and evaluated as anode for lithium-ion batteries. By using CNHs as buffer carrier, MnO(2)/CNH composite displays an excellent capacity of 565 mA h/g measured at a high current density of 450 mA/g after 60 cylces. PMID- 22545768 TI - Interpersonal coordination tendencies shape 1-vs-1 sub-phase performance outcomes in youth soccer. AB - This study investigated the influence of interpersonal coordination tendencies on performance outcomes of 1-vs-1 sub-phases in youth soccer. Eight male developing soccer players (age: 11.8 +/- 0.4 years; training experience: 3.6 +/- 1.1 years) performed an in situ simulation of a 1-vs-1 sub-phase of soccer. Data from 82 trials were obtained with motion-analysis techniques, and relative phase used to measure the space-time coordination tendencies of attacker-defender dyads. Approximate entropy (ApEn) was then used to quantify the unpredictability of interpersonal interactions over trials. Results revealed how different modes of interpersonal coordination emerging from attacker-defender dyads influenced the 1 vs-1 performance outcomes. High levels of space-time synchronisation (47%) and unpredictability in interpersonal coordination processes (ApEn: 0.91 +/- 0.34) were identified as key features of an attacking player's success. A lead-lag relation attributed to a defending player (34% around -30 degrees values) and a more predictable coordination mode (ApEn: 0.65 +/- 0.27, P < 0.001), demonstrated the coordination tendencies underlying the success of defending players in 1-vs-1 sub-phases. These findings revealed how the mutual influence of each player on the behaviour of dyadic systems shaped emergent performance outcomes. More specifically, the findings showed that attacking players should be constrained to exploit the space-time synchrony with defenders in an unpredictable and creative way, while defenders should be encouraged to adopt postures and behaviours that actively constrain the attacker's actions. PMID- 22545769 TI - Telerehabilitation needs: a bidirectional survey of health professionals and individuals with spinal cord injury in South Korea. AB - OBJECTIVE: To assess multiple facets of awareness, understanding, value, needs, and desirability to resolve issues regarding unmet medical needs of individuals with a disability by adopting telerehabilitation. The survey included collection and analysis of current services as well as of supplementary and future services of rehabilitative interventions in South Korea. STUDY DESIGN AND PARTICIPANTS: Thirty-six health professionals who were members of the Korean Academy of Rehabilitation Medicine and 57 individuals with spinal cord injury responded to a survey of those belonging to two non-profit professional groups, one group belonging to the Korean Spinal Cord Injury Association and joining the National Spinal Cord Injury Wheelchair Games and the other group belonging to the Jeong Sang-Hye (High Quad Spinal Cord Injury Association) and having joined one of the focus groups of the Korea National Rehabilitation Research Institute. The two surveys were designed specifically for investigating each group's perspectives of awareness, understanding, value, needs, and desirability of telerehabilitation. RESULTS: The survey responses indicated that there is great interest in the possibility of telerehabilitative services among individuals with spinal cord injury. In particular, there was a strong interest expressed in services that can be used to resolve issues on unmet medical needs of individuals with a disability related to health monitoring, sustaining health, rehabilitation interventions, and independence of activities of daily living. CONCLUSIONS: Telerehabilitation holds great promise as a bridge to traditional face-to-face clinical service delivery. From the results, there are a few categories in the survey that indicate notable differences between the two groups regarding the awareness, desirability, order of preference in rehabilitation service, and telerehabilitation expenses. PMID- 22545770 TI - IL28B CC genotype is associated with higher all-cause mortality in antiretroviral treated HIV-infected patients. AB - Il28B single nucleotide polymorphisms were found to influence interferon lambda expression, resulting in changes in hepatitis C virus (HCV)-RNA serum levels as well as the HIV-RNA set point prior to combined antiretroviral therapy (cART). To date, there is limited information on the influence of this polymorphism on survival in HIV-infected, treatment-naive, and antiretroviral-treated patients. Longitudinal data from 484 patients diagnosed with HIV infection (including 406 on cART) were analyzed to investigate the association between Il28B rs 1979860 variants and all-cause mortality. Kaplan-Meyer and Cox models were used to calculate the hazard ratio associated with IL28B genotypes predictive of a greater likelihood of survival for patients prior to the introduction of cART and for patients on cART. The IL28B genotype frequencies were 41.7% (n=202) for CC, 46.5% (n=225) for CT, and 11.7% (n=57) for TT patients. The CC variant was associated with higher mortality (46 cases, 22.8%) compared to other genotypes [n=31 (13.8%) and n=7 (12.3%) for CT and TT, respectively, p=0.02]. IL28 genotypes did not influence the survival probability prior to treatment initiation (HR 1.04, 95% CI: 0.84-1.24, p=0.68). In antiretroviral-treated patients, after adjustment for gender, baseline CD4 count, CDC category at HIV diagnosis, and age (multivariate HR 1.75, 95% CI: 1.20-2.30, p=0.047), the CC genotype was associated with a decreased probability of survival when compared to the non-CC genotype (univariate HR 1.8, 95% CI: 1.28-2.34, p=0.029). IL28B rs12979860 genotypes influence mortality risk in HIV-infected, antiretroviral treated patients. The effect may be related to higher baseline plasma HIV viremia and possibly altered immune reconstitution associated with interferon lambda expression. PMID- 22545771 TI - Assembly of N,N-disubstituted hydrazines and 1-aryl-1H-indazoles via copper catalyzed coupling reactions. AB - CuI-catalyzed coupling of N-acyl-N'-substituted hydrazines with aryl iodides takes place at 60-90 degrees C to afford N-acyl-N',N'-disubstituted hydrazines regioselectively and thereby gives a facile method for assembling N,N-diaryl hydrazines. N-Acyl-N'-substituted hydrazines can also react with 2 bromoarylcarbonylic compounds at 60-125 degrees C under the catalysis of CuI/4 hydroxy-l-proline to provide 1-aryl-1H-indazoles. PMID- 22545772 TI - Use of small-molecule crystal structures to address solubility in a novel series of G protein coupled receptor 119 agonists: optimization of a lead and in vivo evaluation. AB - G protein coupled receptor 119 (GPR119) is viewed as an attractive target for the treatment of type 2 diabetes and other elements of the metabolic syndrome. During a program toward discovering agonists of GPR119, we herein describe optimization of an initial lead compound, 2, into a development candidate, 42. A key challenge in this program of work was the insolubility of the lead compound. Small-molecule crystallography was utilized to understand the intermolecular interactions in the solid state and resulted in a switch from an aryl sulphone to a 3-cyanopyridyl motif. The compound was shown to be effective in wild-type but not knockout animals, confirming that the biological effects were due to GPR119 agonism. PMID- 22545774 TI - Benzoic acid fermentation from starch and cellulose via a plant-like beta oxidation pathway in Streptomyces maritimus. AB - BACKGROUND: Benzoic acid is one of the most useful aromatic compounds. Despite its versatility and simple structure, benzoic acid production using microbes has not been reported previously. Streptomyces are aerobic, Gram-positive, mycelia forming soil bacteria, and are known to produce various kinds of antibiotics composed of many aromatic residues. S. maritimus possess a complex amino acid modification pathway and can serve as a new platform microbe to produce aromatic building-block compounds. In this study, we carried out benzoate fermentation using S. maritimus. In order to enhance benzoate productivity using cellulose as the carbon source, we constructed endo-glucanase secreting S. maritimus. RESULTS: After 4 days of cultivation using glucose, cellobiose, or starch as a carbon source, the maximal level of benzoate reached 257, 337, and 460 mg/l, respectively. S. maritimus expressed beta-glucosidase and high amylase-retaining activity compared to those of S. lividans and S. coelicolor. In addition, for effective benzoate production from cellulosic materials, we constructed endo glucanase-secreting S. maritimus. This transformant efficiently degraded the phosphoric acid swollen cellulose (PASC) and then produced 125 mg/l benzoate. CONCLUSIONS: Wild-type S. maritimus produce benzoate via a plant-like beta oxidation pathway and can assimilate various carbon sources for benzoate production. In order to encourage cellulose degradation and improve benzoate productivity from cellulose, we constructed endo-glucanase-secreting S. maritimus. Using this transformant, we also demonstrated the direct fermentation of benzoate from cellulose. To achieve further benzoate productivity, the L phenylalanine availability needs to be improved in future. PMID- 22545773 TI - MASiVEdb: the Sirevirus Plant Retrotransposon Database. AB - BACKGROUND: Sireviruses are an ancient genus of the Copia superfamily of LTR retrotransposons, and the only one that has exclusively proliferated within plant genomes. Based on experimental data and phylogenetic analyses, Sireviruses have successfully infiltrated many branches of the plant kingdom, extensively colonizing the genomes of grass species. Notably, it was recently shown that they have been a major force in the make-up and evolution of the maize genome, where they currently occupy ~21% of the nuclear content and ~90% of the Copia population. It is highly likely, therefore, that their life dynamics have been fundamental in the genome composition and organization of a plethora of plant hosts. To assist studies into their impact on plant genome evolution and also facilitate accurate identification and annotation of transposable elements in sequencing projects, we developed MASiVEdb (Mapping and Analysis of SireVirus Elements Database), a collective and systematic resource of Sireviruses in plants. DESCRIPTION: Taking advantage of the increasing availability of plant genomic sequences, and using an updated version of MASiVE, an algorithm specifically designed to identify Sireviruses based on their highly conserved genome structure, we populated MASiVEdb (http://bat.infspire.org/databases/masivedb/) with data on 16,243 intact Sireviruses (total length >158Mb) discovered in 11 fully-sequenced plant genomes. MASiVEdb is unlike any other transposable element database, providing a multitude of highly curated and detailed information on a specific genus across its hosts, such as complete set of coordinates, insertion age, and an analytical breakdown of the structure and gene complement of each element. All data are readily available through basic and advanced query interfaces, batch retrieval, and downloadable files. A purpose-built system is also offered for detecting and visualizing similarity between user sequences and Sireviruses, as well as for coding domain discovery and phylogenetic analysis. CONCLUSION: MASiVEdb is currently the most comprehensive directory of Sireviruses, and as such complements other efforts in cataloguing plant transposable elements and elucidating their role in host genome evolution. Such insights will gradually deepen, as we plan to further improve MASiVEdb by phylogenetically mapping Sireviruses into families, by including data on fragments and solo LTRs, and by incorporating elements from newly-released genomes. PMID- 22545775 TI - Reliability of the Danish version of the McGill Ingestive Skills Assessment for observation-based measures during meals. AB - AIM: To establish measurement equivalence in terms of reliability of the Danish version of the Canadian McGill ingestive skills assessment (MISA) for use by occupational therapists. METHODS: A cross-sectional two-rater and test-retest design was applied. A total of 102 elderly medical patients were included consecutively, and were video-recorded during a meal. Raters were paired randomly for each video-case, which was re-scored within three to eight weeks. Reliability was evaluated with the intra-class correlation coefficients (ICC), the standard error of measurement (SEM), the smallest detectable change (SDC), and limits of agreement (LOA). RESULTS: Inter-rater reliability was good to excellent (ICC (1.1) 0.61-0.84) and intra-rater reliability was excellent (ICC (3.1) 0.84-0.93). For the total scale, SEM was 7% between raters and 4% in repeated measurement by the same rater. For the absolute total scale range on 86 points, the SDC was 15.8 between raters and 10.3 in repeated measurement by the same rater. CONCLUSIONS: The reliability of the Danish MISA equals the original version and is suitable for clinical practice. When extending the evaluation of the reproducibility, weaker precision was evident when measurements are repeated by different raters than by the same rater. Therefore further investigation of rater effects is recommended. PMID- 22545776 TI - Mothering differently: narratives of mothers with intellectual disability whose children have been compulsorily removed. AB - BACKGROUND: Despite the frequency with which mothers with intellectual disability have their children removed, little theoretical or empirical work has understood the mothers' perspectives on this. A few studies have reported mothers' feelings of grief and loss and their sense of powerlessness in the child protection system. METHOD: This qualitative study explores the daily life narratives of 7 mothers with intellectual disability following the involuntarily removal of their children. RESULTS: For most mothers, having a child removed was not a one-off experience. The serial nature of the experience yielded 3 different narratives, lived out in different ways. In some cases, women told a different narrative for each of their removed children. All women remained focused on their children in care. CONCLUSIONS: The multiple and varied narratives of mothers with intellectual disability who have children in care suggest that their support needs may differ from each other and over time. How their support needs might best be met remains an unanswered question. Further research is also needed to identify any adverse health and social consequences for mothers with children in care as well as the effects on their children. PMID- 22545777 TI - Laparoscopic reconstruction for obstructive megaureter: single institution experience with short- and intermediate-term outcomes. AB - PURPOSE: To narrate our experience with laparoscopic reconstruction of obstructive megaureter (MGU) and assess the intermediate-term outcome achieved. PATIENTS AND METHODS: Patients were evaluated in detail including presenting complaints, biochemical profile, and imaging (ultrasonography [USG], diuretic renography [DR], magnetic resonance urography [MRU], and voiding cystourethrography [VCUG]). All patients with a diagnosis of obstructive MGU and salvageable renal unit were offered laparoscopic reconstruction. The standard laparoscopic exercise included ureteral adhesiolysis until the pathologic segment, dismemberment, straightening of the lower ureter, excisional tapering, and a nonrefluxing ureteroneocystostomy. Operative and postoperative parameters were recorded. Patients were evaluated postprocedure on a 3-month schedule. Follow-up imaging included USG and VCUG at 6 months and 1 year postprocedure and then at yearly intervals. MRU and DR were repeated at 1 year postprocedure. RESULTS: Twelve patients (13 units-11 unilateral, and 1 bilateral) underwent laparoscopic tailoring and reimplantation for obstructive MGU. Mean age was 98.6 months. All patients were male. Mean body mass index was 17.69 kg/m(2). Presenting complaints were flank pain (n=8) and recurrent urinary infection (n=12). All procedures were completed via a laparoscopic approach. Mean operation duration was 183 minutes, and mean blood loss was 75 mL. Mean duration of hospital stay was 2.1 days. No major intraoperative or postoperative happenings were recorded. All patients were asymptomatic at follow-up with stable renal profile. Follow-up MRU revealed a decrease in ureteral and upper tract dilatation with satisfactory drainage in all. Follow-up VCUG demonstrated grade I vesicoureteral reflux in one patient. Eight patients completed 3-year follow-up with a satisfactory outcome. CONCLUSION: Laparoscopic reconstruction of obstructive MGU offers satisfactory immediate- and intermediate-term outcome without undue prolonged morbidity. PMID- 22545778 TI - Impacts of atomistic coating on thermal conductivity of germanium nanowires. AB - By using nonequilibrium molecular dynamics simulations, we demonstrated that thermal conductivity of germanium nanowires can be reduced more than 25% at room temperature by atomistic coating. There is a critical coating thickness beyond which thermal conductivity of the coated nanowire is larger than that of the host nanowire. The diameter-dependent critical coating thickness and minimum thermal conductivity are explored. Moreover, we found that interface roughness can induce further reduction of thermal conductivity in coated nanowires. From the vibrational eigenmode analysis, it is found that coating induces localization for low-frequency phonons, while interface roughness localizes the high-frequency phonons. Our results provide an available approach to tune thermal conductivity of nanowires by atomic layer coating. PMID- 22545779 TI - Diffusion mechanism of lithium ion through basal plane of layered graphene. AB - Coexistence of both edge plane and basal plane in graphite often hinders the understanding of lithium ion diffusion mechanism. In this report, two types of graphene samples were prepared by chemical vapor deposition (CVD): (i) well defined basal plane graphene grown on Cu foil and (ii) edge plane-enriched graphene layers grown on Ni film. Electrochemical performance of the graphene electrode can be split into two regimes depending on the number of graphene layers: (i) the corrosion-dominant regime and (ii) the lithiation-dominant regime. Li ion diffusion perpendicular to the basal plane of graphene is facilitated by defects, whereas diffusion parallel to the plane is limited by the steric hindrance that originates from aggregated Li ions adsorbed on the abundant defect sites. The critical layer thickness (l(c)) to effectively prohibit substrate reaction using CVD-grown graphene layers was predicted to be ~6 layers, independent of defect population. Our density functional theory calculations demonstrate that divacancies and higher order defects have reasonable diffusion barrier heights allowing lithium diffusion through the basal plane but neither monovacancies nor Stone-Wales defect. PMID- 22545780 TI - Photochromic metal complexes: photoregulation of both the nonlinear optical and luminescent properties. AB - A series of dithienylethene (DTE)-containing 2,2'-bipyridine ligands and their zinc(II) diacetate, zinc(II) dichloro, rhenium(I) tricarbonyl bromo, and ruthenium(II) bis(bipyridine) complexes have been designed and synthesized, and their photochromic, photophysical, and quadratic nonlinear optical properties have been studied. Upon UV irradiation at 350 nm, the ligands and complexes undergo ring closure of the DTE units, with a good to excellent photocyclization yield. In the case of the Re(I) and Ru(II) complexes, the photocyclization of the DTE units can also be triggered using visible light, upon excitation into the metal-to-ligand charge-transfer (MLCT) bands at 400 and 490 nm, respectively. Molecular quadratic nonlinear optical (NLO) responses of the complexes have been determined by using either the electrical field induced second harmonic generation (EFISH) or harmonic light scattering (HLS) technique at 1910 nm. These studies reveal a large increase of the second-order NLO activity after UV irradiation and subsequent formation of the ring-closed isomers. This efficient enhancement clearly reflects the delocalization of the pi-electron system and the formation of strong push-pull chromophores in the closed forms. The combination of the photochromic DTE-based bipyridine ligand with luminescent Re(I) and Ru(II) fragments also allows the photoregulation of the emission, leading to an efficient quenching of the ligand-based 77 K luminescence and demonstrating that the photocontrol of two optical properties, linear and nonlinear, could be achieved by using the same photochromic ligand. PMID- 22545781 TI - Stable organic-inorganic hybrid of polyaniline/alpha-zirconium phosphate for efficient removal of organic pollutants in water environment. AB - In this article, organic-inorganic hybrid materials of polyaniline/alpha zirconium phosphate (PANI/alpha-ZrP) was synthesized by in situ oxidative polymerization reaction and characterized by Fourier transformed infrared (FTIR), field-emission scanning electron microscopic (FE-SEM) and X-ray diffraction (XRD). The results showed that polyaniline (PANI) was successfully grown on the surface of alpha-zirconium phosphate (alpha-ZrP) nanoplates. The PANI/alpha-ZrP nanocomposites were further applied to remove methyl orange (MO), which was used as a model of organic pollutants in aqueous solution. A synergistic effect of PANI and alpha-ZrP on promoting the adsorption removal of MO was observed. The PANI/alpha-ZrP nanocomposites exhibited excellent maximum adsorption capacity toward MO (377.46 mg g(-1)), which is superior to that of PANI nanotubes (254.15 mg g(-1)) and much higher than that of many other adsorbents. The adsorption isotherms of MO can be well-fitted with the Langmuir model and the adsorption kinetics follows the pseudo-second-order model. MO adsorption decreased with increasing solution pH at pH > 4.0 implying that MO adsorption on PANI/alpha-ZrP may via electrostatic interactions between amine and imine groups on the surface of PANI/alpha-ZrP and MO molecules. This study implies that the hybrid materials of PANI/alpha-ZrP can be suggested as potential adsorbents to remove organic dyes from large volumes of aqueous solutions. PMID- 22545782 TI - Role of the juxtamembrane region of cytoplasmic loop 3 in the gating and conductance of the cystic fibrosis transmembrane conductance regulator chloride channel. AB - Opening and closing of the cystic fibrosis transmembrane conductance regulator chloride channel are controlled by interactions of ATP with its cytoplasmic nucleotide binding domains (NBDs). The NBDs are connected to the transmembrane pore via four cytoplasmic loops. These loops have been suggested to play roles both in channel gating and in forming a cytoplasmic extension of the channel pore. To investigate the structure and function of one of these cytoplasmic loops, we have used patch clamp recording to investigate the accessibility of cytoplasmically applied cysteine-reactive reagents to cysteines introduced into loop 3. We find that methanethiosulfonate (MTS) reagents modify cysteines introduced at 14 of 16 sites studied in the juxtamembrane region of loop 3, in all cases leading to inhibition of channel function. In most cases, both the functional effects of modification and the rate of modification were similar for negatively and positively charged MTS reagents. Single-channel recordings indicated that, at all sites, inhibition was the result of an MTS reagent-induced decrease in channel open probability; in no case was the Cl(-) conductance of open channels altered by modification. These results indicate that loop 3 is readily accessible to the cytoplasm and support the involvement of this region in the control of channel gating. However, our results do not support the hypothesis that this region is close enough to the Cl(-) permeation pathway to exert any influence on permeating Cl(-) ions. We propose that either the cytoplasmic pore is very wide or cytoplasmic Cl(-) ions use other routes to access the transmembrane pore. PMID- 22545783 TI - A proteomic analysis of liver after ethanol binge in chronically ethanol treated rats. AB - BACKGROUND: Binge ethanol in rats after chronic ethanol exposure augments necrosis and steatosis in the liver. In this study, two-dimensional gel electrophoresis proteomic profiles of liver of control, chronic ethanol, control binge, and chronic ethanol- binge were compared. RESULTS: The proteomic analysis identified changes in protein abundance among the groups. The levels of carbonic anhydrase 3 (CA3) were decreased after chronic ethanol and decreased further after chronic ethanol-binge. Ethanol binge alone in control rats had no effect on this protein suggesting its possible role in increased susceptibility to injury by binge after chonic ethanol treatment. A protein spot, in which both cytosolic isocitrate dehydrogenase (IDH1) and glutamine synthetase (GS) were identified, showed a small decrease after chronic ethanol binge but western blot demonstrated significant decrease only for glutamine synthetase in chronic ethanol treated rats. The level of gluathione S-transferase mu isoform (GSTM1) increased after chronic ethanol but was lower after chronic ethanol-binge compared to chronic ethanol treatment. The protein levels of the basic form of protein disulfide isomerase associated protein 3 (PDIA3) were significantly decreased and the acidic forms were increased after chronic ethanol- binge but not in chronic ethanol treated rats or ethanol binge in control rats. The significant changes in proteome profile in chronic ethanol binge were accompanied by a marked increase in liver injury as evidenced by enhanced steatosis, necrosis, increased 4 hydroxynonenal labeled proteins, CYP2E1 expression, and decreased histone H2AX phosphorylation. CONCLUSIONS: Given the role of CA3, IDH1 and GST in oxidative stress; PDIA3 in protein quality control, apoptosis and DNA repair and decreased glutamine synthetase as a sensitive marker of pericentral liver injury this proteome study of chronic ethanol-binge rat model identifies these proteins for the first time as molecular targets with potential role in progression of liver injury by binge ethanol drinking. PMID- 22545785 TI - Simultaneous nucleophilic-substituted and electrostatic interactions for thermal switching of spiropyran: a new approach for rapid and selective colorimetric detection of thiol-containing amino acids. AB - Complementary electrostatic interaction between the zwitterionic merocyanine and dipolar molecules has emerged as a common strategy for reversibly structural conversion of spiropyrans. Herein, we report a concept-new approach for thermal switching of a spiropyran that is based on simultaneous nucleophilic-substitution reaction and electrostatic interaction. The nucleophilic-substitution at spiro carbon atom of a spiropyran is promoted due to electron-deficient interaction induced by 6- and 8-nitro groups, which is responsible for the isomerization of the spiropyran by interacting with thiol-containing amino acids. Further, the electrostatic interaction between the zwitterionic merocyanine and the amino acids would accelerate the structural conversion. As proof-of-principle, we outline the route to glutathione (GSH)-induced ring-opening of 6,8-dinitro 1',3',3'-trimethylspiro [2H-1-benzopyran-2,2'-indoline] (1) and its application for rapid and sensitive colorimetric detection of GSH. In ethanol-water (1:99, v/v) solution at pH 8.0, the free 1 exhibited slight-yellow color, but the color changed clearly from slight-yellow to orange-yellow when GSH was introduced into the solution. Ring-opening rate of 1 upon accession of GSH in the dark is 0.45 s( 1), which is 4 orders of magnitude faster in comparison with the rate of the spontaneous thermal isomerization. The absorbance enhancement of 1 at 480 nm was in proportion to the GSH concentration of 2.5 * 10(-8)-5.0 * 10(-6) M with a detection limit of 1.0 * 10(-8) M. Furthermore, due to the specific chemical reaction between the probe and target, color change of 1 is highly selective for thiol-containing amino acids; interferences from other biologically active amino acids or anions are minimal. PMID- 22545784 TI - Incorporation and controlled release of silyl ether prodrugs from PRINT nanoparticles. AB - Asymmetric bifunctional silyl ether (ABS) prodrugs of chemotherapeutics were synthesized and incorporated within 200 nm * 200 nm particles. ABS prodrugs of gemcitabine were selected as model compounds because of the difficulty to encapsulate a water-soluble drug within a hydrogel. The resulting drug delivery systems were degraded under acidic conditions and were found to release only the parent or active drug. Furthermore, changing the steric bulk of the alkyl substituents on the silicon atom could regulate the rate of drug release and, therefore, the intracellular toxicity of the gemcitabine-loaded particles. This yielded a family of novel nanoparticles that could be tuned to release drug over the course of hours, days, or months. PMID- 22545786 TI - Radical cystectomy over the age of 75 is safe and increases survival. AB - BACKGROUND: Radical cystectomy (RC) is probably underused in elderly patients due to a potential increased postoperative complication risk, as reflected by their considerable comorbidities. Our objective was to estimate the overall complication rate and investigate a potential benefit to patients over the age of 75 subjected to RC in terms of disease-free survival. METHODS: A total of 81 patients, 61 men and 20 women, from two urological departments, with a mean age of 79.2 +/- 3.7 years, participated in the study. The mean follow-up period was 2.6 +/- 1.6 years. All patients underwent RC with pelvic lymphadenectomy. An ileal conduit, an orthotopic ileal neobladder and cutaneous ureterostomies were formed in 48.1%, 6.2% and 45.7% of the patients, respectively. The perioperative and 90-day postoperative complications were recorded and classified according to the modified Clavien classification system. Survival plots were created based on the oncological outcome and several study parameters. RESULTS: The perioperative morbidity rate was 43.2%; the 90-day morbidity rate was 37%, while the 30-day, 90 day and overall mortality rates were 3.7%, 3.7% and 21%, respectively. Overall mortality rates were recorded at the final year of data gathering (2009). Increased age, increased body mass index (BMI), longer hospitalization and age adjusted Charlson comorbidity index (ACCI) more than six, were associated with greater hazard for 90-day morbidity. The cumulative mortality / metastasis-free rates for one, two, three and five years were 88.7%, 77.5%, 70.4%, and 62.3%, respectively. Tumour stage and positive nodes were prognostic predictors for oncological outcome. CONCLUSIONS: RC in patients over 75 is justified and feasible, due to acceptable complication rates and high 5-year cancer-specific survival, which support an aggressive approach. Prospective studies are needed for the verification of the above results. PMID- 22545787 TI - A neuroconstructivist model of past tense development and processing. AB - We present a neural network model of learning and processing the English past tense that is based on the notion that experience-dependent cortical development is a core aspect of cognitive development. During learning the model adds and removes units and connections to develop a task-specific final architecture. The model provides an integrated account of characteristic errors during learning the past tense, adult generalization to pseudoverbs, and dissociations between verbs observed after brain damage in aphasic patients. We put forward a theory of verb inflection in which a functional processing architecture develops through interactions between experience-dependent brain development and the structure of the environment, in this case, the statistical properties of verbs in the language. The outcome of this process is a structured processing system giving rise to graded dissociations between verbs that are easy and verbs that are hard to learn and process. In contrast to dual-mechanism accounts of inflection, we argue that describing dissociations as a dichotomy between regular and irregular verbs is a post hoc abstraction and is not linked to underlying processing mechanisms. We extend current single-mechanism accounts of inflection by highlighting the role of structural adaptation in development and in the formation of the adult processing system. In contrast to some single-mechanism accounts, we argue that the link between irregular inflection and verb semantics is not causal and that existing data can be explained on the basis of phonological representations alone. This work highlights the benefit of taking brain development seriously in theories of cognitive development. PMID- 22545788 TI - Lack of a benign interpretation bias in social anxiety disorder. AB - Cognitive models of social anxiety posit that recurrent interpretation of ambiguous information as threatening maintains symptoms (e.g. Clark & Wells, 1995, pp. 69-93, Social phobia: Diagnosis, assessment, and treatment. New York: Guilford Press; Rapee & Heimberg, 1997, pp. 741-756, Behavior Research and Therapy, 35). However, biased interpretation may also be represented as a failure to make a benign interpretation of the ambiguous event. Furthermore, interpretation bias can be characterized by both an online (automatic) component and an offline (effortful) component (Hirsch & Clark, 2004, pp. 799-825, Clinical Psychology Review, 24). To measure both benign and threat biases, as well as examine the effect of social anxiety on offline versus online interpretations, Beard and Amir (2009, pp. 1135-1141, Behaviour Research and Therapy, 46) developed the Word Sentence Association Paradigm (WSAP). In the current study, we administered the WSAP to a group of participants diagnosed with social anxiety disorder (SAD) as well as to a group of non-anxious control (NAC) participants. We found that participants with SAD demonstrated a lack of benign online bias, but not an online threat bias when compared to NACs. However, when examining offline biases, SAD patients endorsed social threat interpretations and rejected benign social interpretations to a greater degree than non-anxious individuals. Our results, when taken together, clearly implicate the role of reduced bias toward benign information in SAD. PMID- 22545789 TI - Gas-phase kinetics study of reaction of OH radical with CH3NHNH2 by second-order multireference perturbation theory. AB - The gas-phase kinetics of H-abstraction reactions of monomethylhydrazine (MMH) by OH radical was investigated by second-order multireference perturbation theory and two-transition-state kinetic model. It was found that the abstractions of the central and terminal amine H atoms by the OH radical proceed through the formation of two hydrogen bonded preactivated complexes with energies of 6.16 and 5.90 kcal mol(-1) lower than that of the reactants, whereas the abstraction of methyl H atom is direct. Due to the multireference characters of the transition states, the geometries and ro-vibrational frequencies of the reactant, transition states, reactant complexes, and product complexes were optimized by the multireference CASPT2/aug-cc-pVTZ method, and the energies of the stationary points of the potential energy surface were refined at the QCISD(T)/CBS level via extrapolation of the QCISD(T)/cc-pVTZ and QCISD(T)/cc-pVQZ energies. It was found that the abstraction reactions of the central and two terminal amine H atoms of MMH have the submerged energy barriers with energies of 2.95, 2.12, and 1.24 kcal mol(-1) lower than that that of the reactants respectively, and the abstraction of methyl H atom has a real energy barrier of 3.09 kcal mol(-1). Furthermore, four MMH radical-H(2)O complexes were found to connect with product channels and the corresponding transition states. Consequently, the rate coefficients of MMH + OH for the H-abstraction of the amine H atoms were determined on the basis of a two-transition-state model, with the total energy E and angular momentum J conserved between the two transition-state regions. In units of cm(3) molecule( 1) s(-1), the rate coefficient was found to be k(1) = 3.37 * 10(-16)T(1.295) exp(1126.17/T) for the abstraction of the central amine H to form the CH(3)N(*)NH(2) radical, k(2) = 2.34 * 10(-17)T(1.907) exp(1052.26/T) for the abstraction of the terminal amine H to form the trans-CH(3)NHN(*)H radical, k(3) = 7.41 * 10(-20)T(2.428) exp(1343.20/T) for the abstraction of the terminal amine H to form the cis-CH(3)NHN(*)H radical, and k(4) = 9.13 * 10(-21)T(2.964) exp( 114.09/T) for the abstraction of the methyl H atom to form the C(*)H(2)NHNH(2) radical, respectively. Assuming that the rate coefficients are additive, the total rate coefficient of these theoretical predictions quantitatively agrees with the measured rate constant at temperatures of 200-650 K, with no adjustable parameters. PMID- 22545790 TI - Alcohol use disorder, smoking and dental fear among adults in Finland. AB - OBJECTIVE: This study investigated the association between dental fear and alcohol use disorder and smoking controlling for age, gender and attained level of education as well as anxiety and depressive disorders. MATERIALS AND METHODS: Nationally representative data on Finnish adults, 30 + years old (n = 5953), were gathered in interviews. Dental fear was measured in an interview using the question: 'How afraid are you of visiting a dentist?' The alternatives for replying were: 'Not at all', 'Somewhat' and 'Very'. Alcohol use, anxiety and depressive disorders were assessed with a standardized structured psychiatric interview based on DSM-IV criteria. The question on regularity of smoking gave three reply alternatives: smoking 'Daily', 'Occasionally' or 'Not at all'. RESULTS: When socio-demographics and anxiety and depressive disorders were controlled for, those with lifetime alcohol use disorder were more likely to have high dental fear than were those without this disorder. When smoking was added to the model, those who smoked regularly were more likely to have high dental fear than those who smoked occasionally or not at all. In this model, alcohol use disorder was not statistically significantly associated with dental fear. CONCLUSIONS: The results of this study support the suggestion that some individuals may have personality traits that make them vulnerable to substance use disorders and dental fear. PMID- 22545792 TI - Antibacterial anthraquinone derivatives from a sea anemone-derived fungus Nigrospora sp. AB - Chemical investigation of a marine-derived fungus Nigrospora sp., isolated from an unidentified sea anemone, yielded two new hydroanthraquinone analogues, 4a-epi 9alpha-methoxydihydrodeoxybostrycin (1) and 10-deoxybostrycin (2), together with seven known anthraquinone derivatives (3-9). The structures of the two new compounds were established through extensive NMR spectroscopy as well as a single crystal X-ray diffraction analysis using Cu Kalpha radiation. The antibacterial activities of compounds 1-9 and 10 acetyl derivatives (6a, 7a, 8a-8g, 9a) were evaluated in vitro. Compound 6a, the acetylated derivative of 6, exhibited promising activity against Bacillus cereus with an MIC value of 48.8 nM, which was stronger than that of the positive control ciprofloxacin (MIC = 1250 nM). Analysis of the antibacterial screening data for the metabolites and their acetyl derivatives revealed the key structural features required for this activity. PMID- 22545793 TI - Stereoselective synthesis of all stereoisomers of orthogonally protected cyclobutane-1,2-diamine and some chemoselective transformations. AB - The four stereoisomers of protected cyclobutane-1,2-diamine have been prepared in an enantio- and diastereocontrolled manner through stereodivergent synthetic routes starting from a half-ester as a common chiral precursor. Orthogonal protection allows the chemoselective manipulation of both amino groups as shown in this work. PMID- 22545791 TI - Recent advances in engineering the central carbon metabolism of industrially important bacteria. AB - This paper gives an overview of the recent advances in engineering the central carbon metabolism of the industrially important bacteria Escherichia coli, Bacillus subtilis, Corynobacterium glutamicum, Streptomyces spp., Lactococcus lactis and other lactic acid bacteria. All of them are established producers of important classes of products, e.g. proteins, amino acids, organic acids, antibiotics, high-value metabolites for the food industry and also, promising producers of a large number of industrially or therapeutically important chemicals. Optimization of existing or introduction of new cellular processes in these microorganisms is often achieved through manipulation of targets that reside at major points of central metabolic pathways, such as glycolysis, gluconeogenesis, the pentose phosphate pathway and the tricarboxylic acid cycle with the glyoxylate shunt. Based on the huge progress made in recent years in biochemical, genetic and regulatory studies, new fascinating engineering approaches aim at ensuring an optimal carbon and energy flow within central metabolism in order to achieve optimized metabolite production. PMID- 22545794 TI - Monolithic moral frameworks: how are the ethics of palliative sedation discussed in the clinical literature? AB - A variety of moral frameworks can assist clinicians in making ethical decisions. In examining articles on palliative sedation and terminal extubation, we were struck that bioethical discussions uniformly appealed to principlism and especially to the rule of double effect. Other moral frameworks were rarely invoked, an observation consistent with Daniel Callahan's assertion that principlism has a "blocking effect" on broader ethical deliberation. We review here the principle of double effect as it applies to clinical acts that may hasten death, and present one radically different ethical formulation developed by Dan Brock. We then offer brief examples of how clinicians might use other moral frameworks to assess the ethics of preemptive sedation for terminal extubation. We argue for greater moral pluralism in approaching end-of-life decisions. PMID- 22545796 TI - Outcomes of the First Armenian International Congress on Telemedicine and eHealth "ARMTELEMED: Road to the Future" October 14-16, 2011 Yerevan, Armenia. PMID- 22545795 TI - Characterization of host microRNAs that respond to DNA virus infection in a crustacean. AB - BACKGROUND: MicroRNAs (miRNAs) are key posttranscriptional regulators of gene expression that are implicated in many processes of eukaryotic cells. It is known that the expression profiles of host miRNAs can be reshaped by viruses. However, a systematic investigation of marine invertebrate miRNAs that respond to virus infection has not yet been performed. RESULTS: In this study, the shrimp Marsupenaeus japonicus was challenged by white spot syndrome virus (WSSV). Small RNA sequencing of WSSV-infected shrimp at different time post-infection (0, 6, 24 and 48 h) identified 63 host miRNAs, 48 of which were conserved in other animals, representing 43 distinct families. Of the identified host miRNAs, 31 were differentially expressed in response to virus infection, of which 25 were up regulated and six down-regulated. The results were confirmed by northern blots. The TargetScan and miRanda algorithms showed that most target genes of the differentially expressed miRNAs were related to immune responses. Gene ontology analysis revealed that immune signaling pathways were mediated by these miRNAs. Evolutionary analysis showed that three of them, miR-1, miR-7 and miR-34, are highly conserved in shrimp, fruit fly and humans and function in the similar pathways. CONCLUSIONS: Our study provides the first large-scale characterization of marine invertebrate miRNAs that respond to virus infection. This will help to reveal the molecular events involved in virus-host interactions mediated by miRNAs and their evolution in animals. PMID- 22545797 TI - Telehealth physician oversight over direct to consumer testing: doctors working with patients towards patient empowerment. AB - OBJECTIVE: Patient empowerment has increased the demand for direct to consumer (DTC) laboratory testing. Multiple professional societies and advocacy groups have raised concerns over how DTC laboratory testing is being offered to consumers without proper physician oversight. Physician telehealth services can properly oversee DTC laboratory testing in a safe and medically sound manner. MATERIALS: Using telehealth protocols and standards established by professional health organizations and state regulators, physician telehealth oversight in DTC laboratory test ordering can be effective to increase patient access to healthcare services. RESULTS: With proper physician oversight in test interpretation, post-test counseling, and information collaboration, DTC laboratory testing can remain a reliable and convenient option for consumers. Working within the channel of distribution of most DTC laboratory testing, physician telehealth services can properly oversee DTC laboratory testing in a safe and medically sound manner to ensure that proper test interpretation, counseling, and information collaboration are achieved. CONCLUSIONS: Physician telehealth services can properly oversee DTC laboratory testing to ensure that proper test interpretation, counseling, and information collaboration are achieved. PMID- 22545798 TI - Higher mass-independent isotope fractionation of methylmercury in the pelagic food web of Lake Baikal (Russia). AB - Mercury undergoes several transformations that influence its stable isotope composition during a number of environmental and biological processes. Measurements of Hg isotopic mass-dependent (MDF) and mass-independent fractionation (MIF) in food webs may therefore help to identify major sources and processes leading to significant bioaccumulation of methylmercury (MeHg). In this work, delta(13)C, delta(15)N, concentration of Hg species (MeHg, inorganic Hg), and stable isotopic composition of Hg were determined at different trophic levels of the remote and pristine Lake Baikal ecosystem. Muscle of seals and different fish as well as amphipods, zooplankton, and phytoplankton were specifically investigated. MDF during trophic transfer of MeHg leading to enrichment of heavier isotopes in the predators was clearly established by delta(202)Hg measurements in the pelagic prey-predator system (carnivorous sculpins and top predator seals). Despite the low concentrations of Hg in the ecosystem, the pelagic food web reveals very high MIF Delta(199)Hg (3.15-6.650/00) in comparison to coastal fish (0.26-1.650/00) and most previous studies in aquatic organisms. Trophic transfer does not influence MIF signature since similar Delta(199)Hg was observed in sculpins (4.59 +/- 0.550/00) and seal muscles (4.62 +/- 0.600/00). The MIF is suggested to be mainly controlled by specific physical and biogeochemical characteristics of the water column. The higher level of MIF in pelagic fish of Lake Baikal is mainly due to the bioaccumulation of residual MeHg that is efficiently turned over and photodemethylated in deep oligotrophic and stationary (i.e., long residence time) freshwater columns. PMID- 22545800 TI - Control of conformer population and product selectivity and stereoselectivity in competitive photocyclization/rearrangement of chiral donor-acceptor dyad. AB - The conformer population and the relative excitation efficiency of each conformer, assessed by theoretical and experimental examinations, enabled us to precisely control the chemo- and diastereoselectivities of the competitive photocyclization/rearrangement reaction of a chiral donor-acceptor (D/A) dyad by irradiation wavelength, solvent polarity, and reaction temperature. Manipulating the ground- and excited-state conformer equilibria is essential for critically controlling the intramolecular D/A system, in sharp contrast to the rather divergent excited species involved in relevant intermolecular systems. PMID- 22545801 TI - A computer-based intervention to reduce internalized heterosexism in men. AB - Internalized heterosexism (IH) is a strong predictor of the psychological well being of lesbian, gay, bisexual (LGB), or other same-sex attracted individuals. To respond to the call for interventions to address IH, the current study developed and tested an online intervention to reduce IH among gay, bisexual, and other same-sex attracted men. A total of 367 self-identified same-sex attracted adult males were recruited through various nationwide LGB-related sources and were assigned by birth month to either the experimental condition (focusing on IH reduction) or the control condition (a similarly structured invention focusing on stress management); 290 of these participants completed the intervention and all post-intervention measures. Mean levels of IH were compared by condition, indicating significant differences on the IH global score and 2 of the 3 IH subscale scores between the participants in the 2 conditions. The study findings support the promise of using the Internet to deliver IH interventions. Implications for research and practice are discussed. PMID- 22545802 TI - Previous mental health service utilization and change in clients' depressive symptoms. AB - Although a potentially important factor in case conceptualization and treatment planning, the impact of previous treatment on subsequent counseling response has received little empirical attention. Using archival data, this study aimed to (a) report the prevalence of previous treatment utilization in a counseling population, (b) examine potential differences in symptom severity by treatment history, and (c) test whether the rate of change in symptoms over a course of counseling is moderated by previous treatment utilization, when also accounting for initial severity. A sample of 1,262 college students presenting for treatment in university/college counseling centers across the United States provided information on previous treatment history and completed the Counseling Center Assessment of Psychological Symptoms, administered at intake and up to 4 additional time points, with an average of 3-5 weeks between assessments. Data from the 13-item Depression subscale were used for the present study. Half the clients reported previous counseling, one third psychotropic medication, and one tenth psychiatric hospitalization. Previous treatment was associated with increased baseline depressive symptom severity. Results from latent growth curve models showed that previous counseling and medication correlated with a slower rate of symptom response, and previous counseling reduced the probability of being labeled a treatment responder. Previous counseling remained a significant predictor of counseling response when controlling for baseline severity. Hypothesized mechanisms through which previous treatment experience impacts subsequent treatment response remain largely theoretical and should be the focus of future research. PMID- 22545803 TI - Changes in Australian disability service use by selected primary disability groups 2003-2010. PMID- 22545804 TI - Adequacy of low dose computed tomography in patients presenting with acute urinary colic. AB - BACKGROUND AND PURPOSE: Noncontrast abdominal/pelvic CT is the current imaging standard for patients who present with acute urinary colic. Conventional CT, however, exposes the patient to significant amounts of ionizing radiation, which is cumulative when additional CTs are used to monitor stone migration, outcomes, etc. We sought to maintain diagnostic adequacy while decreasing our patients' radiation exposure from CT by using a reduced tube current, an abbreviated scanning area, and the use of coronal reformatted images. PATIENTS AND METHODS: Between March 3, 2011 and October 31, 2011, 101 consecutive adult patients with suspected urinary colic were evaluated with a "low" dose CT. If the suspected calculus(i) was not seen, the patient underwent immediate conventional CT imaging customized to their body habitus. Radiation exposure for each patient was calculated using an established formula of dose length product and scan length. The effective total radiation dose was measured in millisieverts (mSv). RESULTS: Overall, 84 patients had an upper tract calculus(i) consistent with the clinical suspicion. Of these, 76 (90%) were adequately imaged with low dose and 8 (10%) with conventional noncontrast CTs. The mean effective radiation dose in the 76 low dose stone-positive CTs was 2.14 mSV (median 2.10 mSv). This was almost seven fold lower than the mean conventional stone-positive CT dose of 14.5 mSv (median 13.1 mSv). CONCLUSIONS: Low dose noncontrast CT provided adequate imaging to guide optimal urologic management in the majority of our patients. This modality offered a significantly lower ionizing radiation dose and should be considered in patients who present with acute urinary colic. PMID- 22545805 TI - Surgical congenital central nervous system anomalies in a tropical teaching hospital. AB - BACKGROUND: Surgical congenital malformations of the central nervous system (CNS) are structural defects with potential for morbidity and mortality more so if intervention is delayed. AIM: To determine the frequency and pattern of surgical CNS anomalies in our region. METHODS: We carried out a hospital-based prospective observational study of all consecutive children who presented to our unit over a 2-year period. Brain computerised tomography and/or magnetic resonance imaging was performed on all patients suspected of having cranial CNS abnormalities. RESULTS: There were 94 children with surgical congenital anomalies of the CNS during the study period, with a male to female ratio of 1:1.1. There was no parental consanguinity in all the cases neither were there any history of preconception use of folic acid in all the mothers of the patients. Prenatal ultrasound was done after the first trimester in 91 cases (97%), but anomaly was noted in only 23 cases (25.3%). Eighty-six percent of the patients presented after the first month of life. Though there was a general delay in presentation, patients with neural tube defect tended to present much earlier compared to others (p = 0.005). Likewise, patients with spinal anomalies tend to be seen much earlier. CONCLUSIONS: Late presentation of CNS anomalies is still the norm in our region. The result makes a case for an aggressive approach to periconceptional folic acid supplementation for our women and policy to encourage fortification of a staple food with folic acid. A nationwide effort to fully clarify the epidemiology is needed so as to indicate where the community and governmental resources, including educational efforts should be directed. PMID- 22545806 TI - A chemical screening system for glucocorticoid stress hormone signaling in an intact vertebrate. AB - Glucocorticoids, steroid hormones of the adrenal gland, are an integral part of the stress response and regulate glucose metabolism. Natural and synthetic glucocorticoids are widely used in anti-inflammatory therapy but can have severe side effects. In vivo tests are needed to identify novel glucocorticoids and to screen compounds for unwanted effects on glucocorticoid signaling. We created the Glucocorticoid Responsive In vivo Zebrafish Luciferase activitY assay to monitor glucocorticoid signaling in vivo. The GRIZLY assay detects stress-induced glucocorticoid production in single zebrafish larvae, measures disruption of glucocorticoid signaling by an organotin pollutant metabolite, and specifically identifies a compound stimulating endogenous glucocorticoid production in a chemical screen. Our assay has broad applications in stress research, environmental monitoring, and drug discovery. PMID- 22545807 TI - First structural characterization of neutral, base-stabilized group 15 pentaazides: single crystal X-ray structures of dmap-As(N3)5 and dmap-Sb(N3)5. AB - Two neutral group 15-pentaazides dmap-As(N(3))(5) (1) and dmap-Sb(N(3))(5) (2) were synthesized and structurally characterized for the first time (dmap = 4 dimethylaminopyridine). Base-stabilization was confirmed to be very suitable for the kinetic stabilization of highly explosive covalent main group polyazides. PMID- 22545799 TI - Surface organelles assembled by secretion systems of Gram-negative bacteria: diversity in structure and function. AB - Gram-negative bacteria express a wide variety of organelles on their cell surface. These surface structures may be the end products of secretion systems, such as the hair-like fibers assembled by the chaperone/usher (CU) and type IV pilus pathways, which generally function in adhesion to surfaces and bacterial bacterial and bacterial-host interactions. Alternatively, the surface organelles may be integral components of the secretion machinery itself, such as the needle complex and pilus extensions formed by the type III and type IV secretion systems, which function in the delivery of bacterial effectors inside host cells. Bacterial surface structures perform functions critical for pathogenesis and have evolved to withstand forces exerted by the external environment and cope with defenses mounted by the host immune system. Given their essential roles in pathogenesis and exposed nature, bacterial surface structures also make attractive targets for therapeutic intervention. This review will describe the structure and function of surface organelles assembled by four different Gram negative bacterial secretion systems: the CU pathway, the type IV pilus pathway, and the type III and type IV secretion systems. PMID- 22545808 TI - Integration of hexagonal boron nitride with quasi-freestanding epitaxial graphene: toward wafer-scale, high-performance devices. AB - Hexagonal boron nitride (h-BN) is a promising dielectric material for graphene based electronic devices. Here we investigate the potential of h-BN gate dielectrics, grown by chemical vapor deposition (CVD), for integration with quasi freestanding epitaxial graphene (QFEG). We discuss the large scale growth of h-BN on copper foil via a catalytic thermal CVD process and the subsequent transfer of h-BN to a 75 mm QFEG wafer. X-ray photoelectron spectroscopy (XPS) measurements confirm the absence of h-BN/graphitic domains and indicate that the film is chemically stable throughout the transfer process, while Raman spectroscopy indicates a 42% relaxation of compressive stress following removal of the copper substrate and subsequent transfer of h-BN to QFEG. Despite stress-induced wrinkling observed in the films, Hall effect measurements show little degradation (<10%) in carrier mobility for h-BN coated QFEG. Temperature dependent Hall measurements indicate little contribution from remote surface optical phonon scattering and suggest that, compared to HfO(2) based dielectrics, h-BN can be an excellent material for preserving electrical transport properties. Graphene transistors utilizing h-BN gates exhibit peak intrinsic cutoff frequencies >30 GHz (2.4* that of HfO(2)-based devices). PMID- 22545810 TI - Ionic liquid based on alpha-amino acid anion and N7,N9-dimethylguaninium cation ([dMG][AA]): theoretical study on the structure and electronic properties. AB - The interactions between five amino acid based anions ([AA](-) (AA = Gly, Phe, His, Try, and Tyr)) and N7,N9-dimethylguaninium cation ([dMG](+)) have been investigated by the hybrid density functional theory method B3LYP together with the basis set 6-311++G(d,p). The calculated interaction energy was found to decrease in magnitude with increasing side-chain length in the amino acid anion. The interaction between the [dMG](+) cation and [AA](-) anion in the most stable configurations of ion pairs is a hydrogen bonding interaction. These hydrogen bonds (H bonds) were analyzed by the quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analysis. Finally, several correlations between electron densities in bond critical points of hydrogen bonds and interaction energy as well as vibrational frequencies in the most stable configurations of ion pairs have been checked. PMID- 22545809 TI - Application of polymer quantum dot-enzyme hybrids in the biosensor development and test paper fabrication. AB - Both glutathione capped CdTe quantum dots (QDs) and enzymes were encapsulated with poly(diallyldimethylammonium chloride) (PDDA) via electrostatic attraction to form hybrid films. The obtained PDDA QD-enzyme hybrids feature both high fluorescence and biorecognition. In the obtained hybrid materials, the fluorescence emission of the QDs was stable for at least 3 months, and the structure and activity of the enzyme was also well maintained as the Michaelis constant of tyrosinase was determined to be 0.90 mmol/L, which is just 2 times higher than that of free enzyme. This hybrid material was then utilized as a platform for the development of biosensors based on the quenching effects of the enzymatic products on the emission of the QDs with a kind of phenol (catechol) and glucose as example analytes. The detection limits of catechol and glucose were 1.0 * 10(-5) and 5.0 * 10(-6) mol/L, respectively. Moreover, this hybrid material was applied to the fabrication of test paper for these two analytes. The test paper was very stable with respect to the fluorescence of the QDs and the activity of the enzyme maintained for at least 1 month. PMID- 22545811 TI - Tuning the surface charge properties of epitaxial InN nanowires. AB - We have investigated the correlated surface electronic and optical properties of [0001]-oriented epitaxial InN nanowires grown directly on silicon. By dramatically improving the epitaxial growth process, we have achieved, for the first time, intrinsic InN both within the bulk and at nonpolar InN surfaces. The near-surface Fermi-level was measured to be ~0.55 eV above the valence band maximum for undoped InN nanowires, suggesting the absence of surface electron accumulation and Fermi-level pinning. This result is in direct contrast to the problematic degenerate two-dimensional electron gas universally observed on grown surfaces of n-type degenerate InN. We have further demonstrated that the surface charge properties of InN nanowires, including the formation of two-dimensional electron gas and the optical emission characteristics can be precisely tuned through controlled n-type doping. At relatively high doping levels in this study, the near-surface Fermi-level was found to be pinned at ~0.95-1.3 eV above the valence band maximum. Through these trends, well captured by the effective mass and ab initio materials modeling, we have unambiguously identified the definitive role of surface doping in tuning the surface charge properties of InN. PMID- 22545812 TI - Alzheimer's disease amyloid beta-protein mutations and deletions that define neuronal binding/internalization as early stage nonfibrillar/fibrillar aggregates and late stage fibrils. AB - Accumulation of amyloid beta-protein (Abeta) in neurons has been demonstrated to precede its formation as amyloid plaques in the extracellular space in Alzheimer's disease (AD) patients. Consequently, intraneuronal Abeta accumulation is thought to be a critical first step in the fatal cascade of events that leads to neuronal degeneration in AD. Understanding the structural basis of neuronal binding and uptake of Abeta might lead to potential therapeutic targets that could block this binding and the subsequent neurodegeneration that leads to the pathogenesis of AD. Previously, we demonstrated that mutation of the two adjacent histidine residues of Abeta40 (H13,14G) resulted in a significant decrease in its level of binding to PC12 cells and mouse cortical/hippocampal neurons. We now demonstrate that the weakened neuronal binding follows the mutation order of H13G < H14G < H13,14G, which suggests that the primary domain for neuronal binding of Abeta40 involves histidine at position 13. A novel APP mutation (E693Delta) that produced a variant Abeta lacking glutamate 22 (E22Delta) in Japanese pedigrees was recently identified to have AD-type dementia without amyloid plaque formation but with extensive intraneuronal Abeta in transfected cells and transgenic mice expressing this deletion. Deletion of glutamate 22 of Abeta40 resulted in a 6 fold enhancement of PC12 neuronal binding that was not decreased by the H13G mutation. The dose-dependent enhanced binding of E22Delta explains the high level of intraneuronal Abeta seen in this pedigree. Fluorescence anisotropy experiments at room temperature showed very rapid aggregation with increased tyrosine rigidity of Abeta39E22Delta, Abeta41E22Delta, and Abeta42 but not Abeta40. This rigidity was decreased but not eliminated by prior treatment with dimethyl sulfoxide. Surprisingly, all peptides showed an aggregated state when evaluated by transmission electron microscopy, with Abeta39E22Delta having early stage fibrils, which was also verified by atomic force microscopy. This aggregation was not affected by centrifugation or pretreatment with organic solvents. The enhanced neuronal binding of Abeta, therefore, results from aggregate binding to neurons, which requires H13 for Abeta40 but not for E22Delta or Abeta42. These latter proteins display increased tyrosine rigidity that likely masks the H13 residue, or alternatively, the H13 residue is not required for neuronal binding of these proteins as it is for Abeta40. Late state fibrils also showed enhanced neuronal binding for E22Delta but not Abeta40 with subsequent intraneuronal accumulation in lysosomes. This suggests that there are multiple pathways of binding/internalization for the different Abeta proteins and their aggregation states or fibrillar structure. PMID- 22545813 TI - Synthesis of bisethylnorspermine lipid prodrug as gene delivery vector targeting polyamine metabolism in breast cancer. AB - Progress in the development of nonviral gene delivery vectors continues to be hampered by low transfection activity and toxicity. Here we proposed to develop a lipid prodrug based on a polyamine analogue bisethylnorspermine (BSP) that can function dually as gene delivery vector and, after intracellular degradation, as active anticancer agent targeting dysregulated polyamine metabolism. We synthesized a prodrug of BSP (LS-BSP) capable of intracellular release of BSP using thiolytically sensitive dithiobenzyl carbamate linker. Biodegradability of LS-BSP contributed to decreased toxicity compared with nondegradable control L BSP. BSP showed a strong synergistic enhancement of cytotoxic activity of TNF related apoptosis-inducing ligand (TRAIL) in human breast cancer cells. Decreased enhancement of TRAIL activity was observed for LS-BSP when compared with BSP. LS BSP formed complexes with plasmid DNA and mediated transfection activity comparable to DOTAP and L-BSP. Our results show that BSP-based vectors are promising candidates for combination drug/gene delivery. PMID- 22545814 TI - 1,3-Dipolar cycloaddition reactions of azomethine ylides with a cellulose-derived chiral enone. A novel route for organocatalysts development. AB - Cellulose-derived chiral pyrrolidines were synthesized in excellent yields, regioselectivities, and stereoselectivities via a 1,3-dipolar cycloaddition reaction between levoglucosenone and azomethine ylides. An unprecedented isomerization event led to a new family of pyrrolidines with an unusual relative stereochemistry. Preliminary results showed that these compounds are promising organocatalysts for iminium ion-based asymmetric Diels-Alder reactions. PMID- 22545816 TI - Implementing the chronic care model for frail older adults in the Netherlands: study protocol of ACT (frail older adults: care in transition). AB - BACKGROUND: Care for older adults is facing a number of challenges: health problems are not consistently identified at a timely stage, older adults report a lack of autonomy in their care process, and care systems are often confronted with the need for better coordination between health care professionals. We aim to address these challenges by introducing the geriatric care model, based on the chronic care model, and to evaluate its effects on the quality of life of community-dwelling frail older adults. METHODS/DESIGN: In a 2-year stepped-wedge cluster randomised clinical trial with 6-monthly measurements, the chronic care model will be compared with usual care. The trial will be carried out among 35 primary care practices in two regions in the Netherlands. Per region, practices will be randomly allocated to four allocation arms designating the starting point of the intervention. PARTICIPANTS: 1200 community-dwelling older adults aged 65 or over and their primary informal caregivers. Primary care physicians will identify frail individuals based on a composite definition of frailty and a polypharmacy criterion. Final inclusion criterion: scoring 3 or more on a disability case-finding tool. INTERVENTION: Every 6 months patients will receive a geriatric in-home assessment by a practice nurse, followed by a tailored care plan. Expert teams will manage and train practice nurses. Patients with complex care needs will be reviewed in interdisciplinary consultations. EVALUATION: We will perform an effect evaluation, an economic evaluation, and a process evaluation. Primary outcome is quality of life as measured with the Short Form-12 questionnaire. Effect analyses will be based on the "intention-to-treat" principle, using multilevel regression analysis. Cost measurements will be administered continually during the study period. A cost-effectiveness analysis and cost-utility analysis will be conducted comparing mean total costs to functional status, care needs and QALYs. We will investigate the level of implementation, barriers and facilitators to successful implementation and the extent to which the intervention manages to achieve the transition necessary to overcome challenges in elderly care. DISCUSSION: This is one of the first studies assessing the effectiveness, cost-effectiveness and implementation process of the chronic care model for frail community-dwelling older adults. TRIAL REGISTRATION: The Netherlands National Trial Register NTR2160. PMID- 22545817 TI - Fecal contamination and diarrheal pathogens on surfaces and in soils among Tanzanian households with and without improved sanitation. AB - Little is known about the extent or pattern of environmental fecal contamination among households using low-cost, on-site sanitation facilities, or what role environmental contamination plays in the transmission of diarrheal disease. A microbial survey of fecal contamination and selected diarrheal pathogens in soil (n = 200), surface (n = 120), and produce samples (n = 24) was conducted in peri urban Bagamoyo, Tanzania, among 20 households using private pit latrines. All samples were analyzed for E. coli and enterococci. A subset was analyzed for enterovirus, rotavirus, norovirus GI, norovirus GII, diarrheagenic E. coli, and general and human-specific Bacteroidales fecal markers using molecular methods. Soil collected from the house floor had significantly higher concentrations of E. coli and enterococci than soil collected from the latrine floor. There was no significant difference in fecal indicator bacteria levels between households using pit latrines with a concrete slab (improved sanitation) versus those without a slab. These findings imply that the presence of a concrete slab does not affect the level of fecal contamination in the household environment in this setting. Human Bacteroidales, pathogenic E. coli, enterovirus, and rotavirus genes were detected in soil samples, suggesting that soil should be given more attention as a transmission pathway of diarrheal illness in low-income countries. PMID- 22545819 TI - Influence of reinforcing materials on strain of maxillary complete denture. AB - OBJECTIVE: A maxillary complete denture has been a common prosthetic treatment for people with edentulous maxillas. The fracture and deformation of dentures are recurrent and common problems for denture-wearers. Consequently, reinforcement materials are embedded in the denture base to prevent fracture and deformation. The purpose of this study was to examine the influence of reinforcing materials on the strain within the acrylic base of a maxillary complete denture. MATERIALS AND METHODS: Three reinforcements (cast cobalt-chromium bar; glass fibers; and cobalt-chromium wire) were embedded in the bases and a strain-gauge was attached at three positions (labial, middle and posterior) at the mid-line of the polished surface of each denture. A vertical occlusal load of 49 N was applied to the left and right side in the region of the 1st premolar and the 1st molar. Comparisons of the strain were made via ANOVA. RESULTS: The strain of the denture base with a cast cobalt-chromium reinforcement was significantly (p < 0.05) smaller than that with the other reinforcements. CONCLUSIONS: This result suggested that a cast cobalt-chromium reinforcement helps to reduce the risk of fracture and deformation of a maxillary complete denture. PMID- 22545818 TI - De novo synthesis of trans-10, cis-12 conjugated linoleic acid in oleaginous yeast Yarrowia lipolytica. AB - BACKGROUND: Conjugated linoleic acid (CLA) has many well-documented beneficial physiological effects. Due to the insufficient natural supply of CLA and low specificity of chemically produced CLA, an effective and isomer-specific production process is required for medicinal and nutritional purposes. RESULTS: The linoleic acid isomerase gene from Propionibacterium acnes was expressed in Yarrowia lipolytica Polh. Codon usage optimization of the PAI and multi-copy integration significantly improved the expression level of PAI in Y. lipolytica. The percentage of trans-10, cis-12 CLA was six times higher in yeast carrying the codon-optimized gene than in yeast carrying the native gene. In combination with multi-copy integration, the production yield was raised to approximately 30-fold. The amount of trans-10, cis-12 CLA reached 5.9% of total fatty acid yield in transformed Y. lipolytica. CONCLUSIONS: This is the first report of production of trans-10, cis-12 CLA by the oleaginous yeast Y. lipolytica, using glucose as the sole carbon source through expression of linoleic acid isomerase from Propionibacterium acnes. PMID- 22545820 TI - Changes in couples' communication as a result of a male-involvement family planning intervention. AB - Research suggests that spousal communication and male involvement in decision making can positively influence family-planning use and continuation. However, few existing studies explore the dynamics of this communication and how they factor into family-planning decision making. Building upon a recent evaluation of a theory-based male-involvement intervention in Malawi, this study aimed to fill this gap by examining the role of communication in the intervention's success, through semi-structured in-depth interviews with male participants and female partners of study participants. Results support the idea that communication is an integral component of successful interventions to increase male involvement in family planning. Participants reported improvements in spousal communication, increased frequency of communication, and an increase in shared decision making as a result of the study, which directly contributed to their family-planning use. This effect was often mediated through increased knowledge or reduced male opposition to family planning. Further analysis of communication and decision making dynamics revealed shifts in gendered communication norms, leading to improvements in spousal relationships in addition to contraceptive uptake. This study shows that interventions can and should encourage spousal communication and shared decision making, and it provides an effective model for involving men in family-planning use. PMID- 22545822 TI - "Hired guns," "charlatans," and their "voodoo psychobabble": case law references to various forms of perceived bias among mental health expert witnesses. AB - Although in principle the legal system expects and professional ethics demand that expert witnesses be unbiased and objective in their forensic evaluations, anecdotal evidence suggests that accusations of financial bias, partisanship, and other forms of nonobjectivity are common. This descriptive survey of published legal cases expands on an earlier case law review (Mossman, 1999) attempting to encapsulate and summarize key issues concerning perceptions or allegations of bias in mental health expert witness testimony. Using a series of search terms reflecting various potential forms of accusatory bias, a total of 160 published civil and criminal court cases were identified in which 185 individuals (e.g., attorneys, trial and appellate judges, other witnesses) made one or more references to clinicians' alleged lack of neutrality. Allegations most typically involved describing the expert as having an opinion that was "for sale," or as a partisan or advocate for one side, although aspersions also were made concerning "junk science" testimony and comparing mental health experts to mystics and sorcerers. Our results indicate that diverse forms of bias that go beyond financial motives are alleged against mental health experts by various players in the legal system. Means are discussed by which experts can attempt to reduce the impact of such allegations. PMID- 22545821 TI - Group-based treatment for internalized stigma among persons with severe mental illness: findings from a randomized controlled trial. AB - Elevated internalized stigma is common and is linked to subjective and objective outcomes for severe mental illness. The authors developed a manualized group based intervention (Narrative Enhancement/Cognitive Therapy; NECT) to address internalized stigma in severe mental illness. The purpose of the present study was to evaluate the feasibility and effectiveness of NECT. In total, 144 individuals were screened at two sites to evaluate if they met criteria for "elevated" internalized stigma; 39 and were eligible were randomized to NECT or to treatment as usual (TAU) and were assessed at baseline, posttreatment, and 3 month follow-up. Fifteen of the 21 individuals assigned to NECT were classified as "exposed" to treatment. Intent-to-treat analyses found no significant difference between the NECT and TAU groups. A comparison of exposed versus unexposed participants noted trends for exposed participants to have improved more in two aspects of self-stigma as well as insight. We conclude that NECT is feasible and tolerable, but findings did not support the hypothesis that NECT was more effective than TAU, although small sample size and significant dropout may have restricted the ability to detect an effect. PMID- 22545823 TI - Soldiers' perceptions of resilience training and postdeployment adjustment: validation of a measure of resilience training content and training process. AB - Group randomized trials of a resilience training program (formerly Battlemind training) demonstrated effectiveness of the program in reducing postdeployment adjustment problems among military personnel. These results are promising, but program evaluation is a dynamic, multifaceted task, and many questions remain. This article is designed to address one component of resilience training program evaluation: soldiers' perceptions of the training. Specifically, a self-report measure assessing attitudes and satisfaction in domains theorized to be important to resilience training was developed. This measure was administered to 782 soldiers who participated in a 1-hr resilience training session at 4-months postdeployment. Several mental health outcomes (e.g., alcohol problems, posttraumatic stress symptoms, physical health symptoms, unit morale) were assessed before training and 6 months later. Structural validity, internal consistency, concurrent validity, and predictive validity of the measure were examined. Analyses identified two factors reflecting attitudes toward Training Content and Training Process. The factors demonstrated good internal consistency, and both correlated with overall training satisfaction and mental health-related attitudes. In addition, both factors predicted significant positive change in a set of mental health outcomes at 6-month follow-up. Implications for postdeployment resilience training are discussed. PMID- 22545824 TI - Primary care-mental health integration and treatment retention among Iraq and Afghanistan war veterans. AB - Despite the high prevalence of posttraumatic stress disorder (PTSD) and medical comorbidity among veterans from Iraq/Afghanistan (OEF/OIF), keeping these patients engaged in health care is challenging. Primary Care-Mental Health Integration (PC-MHI), an initiative in the Veterans Health Administration (VA), sought to improve access to mental health care from within primary care. This study examined the lag between first PC-MHI visit and next mental/medical care visit, if any, and the relationship of PC-MHI with short-term (subsequent year) and long-term (4 years later) use of VA. We identified 2,470 OEF/OIF veterans receiving care during fiscal year 2006 (FY06) in a regional VA health care system. Unconditional survival analysis modeled time to next mental/medical visit and logistic regression modeled short- and long-term care as a function of PC MHI, demographics, and clinical covariates. Of 181 patients in the PC-MHI program, 60%/18% returned for mental/medical care within 1 month, and 82%/74% within 1 year. Sixty-one percent (1,503) were still using the VA in FY09. Short term mental care was related to prior-year PC-MHI. Consistent correlates of short and long-term mental/medical care included physical comorbidity and Priority 1 status. Most patients attended mental health appointments subsequent to PC-MHI, and PC-MHI was correlated with mental health treatment retention in adjusted models for our cohort. Need for treatment, notably VA Priority 1 status and physical comorbidity, were the primary correlates of care-seeking. Developing innovative approaches to engaging new veterans in care remains imperative as multiple options will be necessary to meet the needs of these complex patients. PMID- 22545827 TI - Management of a colon perforation during pediatric percutaneous nephrolithotomy. AB - Percutaneous nephrolithotomy (PCNL) is one of the most common treatment options in the management of kidney stones in children. While colon perforation during PCNL is reported as a rare complication in adults, there are scarce data regarding colon perforation during pediatric PCNL. We report the successful management of colon perforation occurring during PCNL and of a renal stone in a 6 year-old child. Moreover, we describe the procedure to be followed for colon perforation in children. PMID- 22545815 TI - Multilocus genetics to reconstruct aeromonad evolution. AB - BACKGROUND: Aeromonas spp. are versatile bacteria that exhibit a wide variety of lifestyles. In an attempt to improve the understanding of human aeromonosis, we investigated whether clinical isolates displayed specific characteristics in terms of genetic diversity, population structure and mode of evolution among Aeromonas spp. A collection of 195 Aeromonas isolates from human, animal and environmental sources was therefore genotyped using multilocus sequence analysis (MLSA) based on the dnaK, gltA, gyrB, radA, rpoB, tsf and zipA genes. RESULTS: The MLSA showed a high level of genetic diversity among the population, and multilocus-based phylogenetic analysis (MLPA) revealed 3 major clades: the A. veronii, A. hydrophila and A. caviae clades, among the eleven clades detected. Lower genetic diversity was observed within the A. caviae clade as well as among clinical isolates compared to environmental isolates. Clonal complexes, each of which included a limited number of strains, mainly corresponded to host associated subsclusters of strains, i.e., a fish-associated subset within A. salmonicida and 11 human-associated subsets, 9 of which included only disease associated strains. The population structure was shown to be clonal, with modes of evolution that involved mutations in general and recombination events locally. Recombination was detected in 5 genes in the MLSA scheme and concerned approximately 50% of the STs. Therefore, these recombination events could explain the observed phylogenetic incongruities and low robustness. However, the MLPA globally confirmed the current systematics of the genus Aeromonas. CONCLUSIONS: Evolution in the genus Aeromonas has resulted in exceptionally high genetic diversity. Emerging from this diversity, subsets of strains appeared to be host adapted and/or "disease specialized" while the A. caviae clade displayed an atypical tempo of evolution among aeromonads. Considering that A. salmonicida has been described as a genetically uniform pathogen that has adapted to fish through evolution from a variable ancestral population, we hypothesize that the population structure of aeromonads described herein suggested an ongoing process of adaptation to specialized niches associated with different degrees of advancement according to clades and clusters. PMID- 22545828 TI - Photoluminescence properties, molecular structures, and theoretical study of heteroleptic silver(I) complexes containing diphosphine ligands. AB - The homoleptic complex [Ag(L)(2)]PF(6) (1) and heteroleptic complexes [Ag(L)(L(Me))]BF(4) (2) and [Ag(L)(L(Et))]BF(4) (3) [L = 1,2 bis(diphenylphosphino)benzene, L(Me) = 1,2-bis[bis(2 methylphenyl)phosphino]benzene, and L(Et) = 1,2-bis[bis(2 ethylphenyl)phosphino]benzene] were synthesized and characterized. X-ray crystallography demonstrated that 1-3 possess tetrahedral structures. Photophysical studies and time-dependent density functional theory calculations of 1-3 revealed that alkyl substituents at the ortho positions of peripheral phenyl groups in the diphosphine ligands have a significant influence on the energy and intensity of phosphorescence of the complex in solution at room temperature. The results can be interpreted in terms of the geometric preferences of each complex in the ground and excited states. The homoleptic complex 1 exhibits weak orange phosphorescence in solution arising from its flat structure in the triplet state, while heteroleptic complexes 2 and 3 show strong green phosphorescence from triplet states with tetrahedral structure. Larger interligand steric interactions in 2 and 3 caused by their bulkier ligands probably inhibit geometric relaxation within the excited-state lifetimes, leading to higher energy phosphorescence than that observed for 1. NMR experiments revealed that 2 and 3 in solution possess structures that are much more immobilized than that of 1; fluxional motion is completely suppressed in 2 and 3. Accordingly, conformational changes of 2 and 3 are expected to be suppressed by the alkyl substituents not only in the ground state but also in excited states. Consequently, nonradiative decay of the excited states of 2 and 3 occurs less efficiently than in 1. As a result, the quantum yields of phosphorescence for 2 and 3 are 6 times larger than that for the homoleptic complex 1. PMID- 22545825 TI - Development stage-specific proteomic profiling uncovers small, lineage specific proteins most abundant in the Aspergillus Fumigatus conidial proteome. AB - BACKGROUND: The pathogenic mold Aspergillus fumigatus is the most frequent infectious cause of death in severely immunocompromised individuals such as leukemia and bone marrow transplant patients. Germination of inhaled conidia (asexual spores) in the host is critical for the initiation of infection, but little is known about the underlying mechanisms of this process. RESULTS: To gain insights into early germination events and facilitate the identification of potential stage-specific biomarkers and vaccine candidates, we have used quantitative shotgun proteomics to elucidate patterns of protein abundance changes during early fungal development. Four different stages were examined: dormant conidia, isotropically expanding conidia, hyphae in which germ tube emergence has just begun, and pre-septation hyphae. To enrich for glycan-linked cell wall proteins we used an alkaline cell extraction method. Shotgun proteomic resulted in the identification of 375 unique gene products with high confidence, with no evidence for enrichment of cell wall-immobilized and secreted proteins. The most interesting discovery was the identification of 52 proteins enriched in dormant conidia including 28 proteins that have never been detected in the A. fumigatus conidial proteome such as signaling protein Pil1, chaperones BipA and calnexin, and transcription factor HapB. Additionally we found many small, Aspergillus specific proteins of unknown function including 17 hypothetical proteins. Thus, the most abundant protein, Grg1 (AFUA_5G14210), was also one of the smallest proteins detected in this study (M.W. 7,367). Among previously characterized proteins were melanin pigment and pseurotin A biosynthesis enzymes, histones H3 and H4.1, and other proteins involved in conidiation and response to oxidative or hypoxic stress. In contrast, expanding conidia, hyphae with early germ tubes, and pre-septation hyphae samples were enriched for proteins responsible for housekeeping functions, particularly translation, respiratory metabolism, amino acid and carbohydrate biosynthesis, and the tricarboxylic acid cycle. CONCLUSIONS: The observed temporal expression patterns suggest that the A. fumigatus conidia are dominated by small, lineage-specific proteins. Some of them may play key roles in host-pathogen interactions, signal transduction during conidial germination, or survival in hostile environments. PMID- 22545829 TI - Gender difference in the relation blood pressure-left ventricular mass and geometry in newly diagnosed arterial hypertension. AB - Much evidence suggests sexual dimorphism in the relationship linking blood pressure (BP) to both left ventricular mass (LVM) and geometry in hypertension. To better evaluate gender-associated characteristics in the relation BP-LVM among newly diagnosed hypertension (24-h average ambulatory BP monitoring, ABPM, > 125/80 mmHg), we measured indexed LVM and relative wall thickness (RWT) by standardized echographic methods in 209 Caucasian drug-naive subjects, of whom 162 (100M/62F) were recognized to be hypertensive. Mean office systolic (SBP)/diastolic (DBP), 24-h average and night-time BP values were similar between sexes and significantly related to indexed LVM in both genders. Daytime SBP was significantly related to indexed LVM only in females (r =0.41; p =0.0008 in women; r =0.11; p = NS in males), while LVM was more sensitive to day-to-night SBP change in females. RWT was, on the contrary, significantly related to ABPM values only in males. All these findings were confirmed after adjusting for possible confounders. Percentage of LVM variance explained by 24-h average, daytime or night-time SBP values were higher in females than in males (17% vs 3%; 11% vs 1%; and 17% vs 8%). In conclusion, in early hypertension, LVM was significantly associated with daytime BP and more sensitive to reduced percentage of night BP fall in females. LVM variance explained by ABPM SBP was much higher in females than in males. RWT, expressing concentric LVM remodelling was, conversely, more related to BP increase in males. PMID- 22545831 TI - Socioeconomic status, ethnicity, culture, and immigration: examining the potential mechanisms underlying Mexican-origin adolescents' organized activity participation. AB - The integrative model for child development and ecodevelopmental theory suggest that macro factors, such as socioeconomic status, ethnicity, culture, and immigration influence the settings in which adolescents engage. The goal of this investigation was to use a combination of deductive and inductive qualitative analysis to describe the mechanisms by which these macro factors might be related to Mexican-origin adolescents' participation in organized after-school activities. Qualitative data were collected through focus group interviews with 44 adolescents, 50 parents, and 18 activity leaders from 2 neighborhoods that varied in ethnic composition and average family income. Results indicated that family socioeconomic status might be related to adolescents' participation through financial resources and parents' work. Ethnicity was identified as a predictor of participation via experiences with ethnic discrimination, particularly in the neighborhood with a low percentage of Hispanic families. Cultural values and practices were related to participants' preferences for particular activities (e.g., bilingual, church-sponsored) and adolescents' participation in activities. Immigration seemed to be a factor in parents' familiarity with and beliefs about organized activities. PMID- 22545832 TI - Incorporating religiosity into a developmental model of positive family functioning across generations. AB - This study evaluated a developmental model of intergenerational continuity in religiosity and its association with observed competency in romantic and parent child relationships across 2 generations. Using multi-informant data from the Family Transitions Project, a 20-year longitudinal study of families that began during early adolescence (N = 451), we found that parental religiosity assessed during youths' adolescence was positively related to youths' own religiosity during adolescence, which, in turn, predicted their religiosity after the transition to adulthood. The findings also supported the theoretical model guiding the study, which proposes that religiosity acts as a personal resource that will be uniquely and positively associated with the quality of family relationships. Especially important, the findings demonstrate support for the role of religiosity in a developmental process that promotes positive family functioning after addressing earlier methodological limitations in this area of study, such as cross-sectional research designs, single informant measurement, retrospective reports, and the failure to control for other individual differences. PMID- 22545833 TI - Everything under control? The effects of age, gender, and education on trajectories of perceived control in a nationally representative German sample. AB - Perceived control is an important variable for various demands involved in successful aging. However, perceived control is not set in stone but rather changes throughout the life course. The aim of this study was to identify cross sectional age differences and longitudinal mean-level changes as well as rank order changes in perceived control with respect to gender and education. Furthermore, changes in income and health were analyzed to explain trajectories of perceived control. In a large and representative sample of Germans across all of adulthood, 9,484 individuals gave information about their perceived control twice over a period of 6 years. Using locally weighted smoothing (LOESS) curves and latent structural equation modeling, four main findings were revealed: (a) Perceived control increased until ages 30-40, then decreased until about age 60, and increased slightly afterwards. (b) The rank order of individuals in perceived control was relatively unstable, especially in young adulthood, and reached a plateau at about age 40. (c) Men perceived that they had more control than did women, but there were no gender differences in the development of perceived control. (d) Individuals with more education perceived that they had more control than those with less education, and there were slight differences in the development of perceived control dependent on education. Taken together, these findings offer important insights into the development of perceived control across the life span. PMID- 22545834 TI - I can talk you into it: theory of mind and persuasion behavior in young children. AB - We investigated links between persuasive behavior and theory of mind (ToM) understanding using a novel naturalistic peer persuasion task in which children were invited to convince an interactive puppet to eat raw broccoli or brush his teeth. Sixty-three 3- to 8-year-olds (M age = 6 years, 6 months) took part in the persuasion task and were also given a battery of first-order and advanced false belief tests. As predicted, the number of independent persuasive arguments children produced was significantly associated with false belief scores, even after controlling for age and verbal ability. PMID- 22545836 TI - Development of heuristic bias detection in elementary school. AB - Although human reasoning is often biased by intuitive heuristics, recent studies have shown that adults and adolescents detect the biased nature of their judgments. The present study focused on the development of this critical bias sensitivity by examining the detection skills of young children in elementary school. Third and 6th graders were presented with child-friendly versions of classic base-rate problems in which a cued heuristic response could be inconsistent or consistent with the base rates. After each problem children were asked to indicate their subjective response confidence to assess their bias detection skills. Results indicated that 6th graders showed a clear confidence decrease when they gave a heuristic response that conflicted with the base rates. However, this confidence decrease was not observed for 3rd graders, suggesting that they did not yet acknowledge that their judgment was not fully warranted. Implications for the development of efficient training programs and the debate on human rationality are discussed. PMID- 22545835 TI - Patterns of children's adrenocortical reactivity to interparental conflict and associations with child adjustment: a growth mixture modeling approach. AB - Examining children's physiological functioning is an important direction for understanding the links between interparental conflict and child adjustment. Utilizing growth mixture modeling, the present study examined children's cortisol reactivity patterns in response to a marital dispute. Analyses revealed three different patterns of cortisol responses, consistent with both a sensitization and an attenuation hypothesis. Child-rearing disagreements and perceived threat were associated with children exhibiting a rising cortisol pattern, whereas destructive conflict was related to children displaying a flat pattern. Physiologically rising patterns were also linked with emotional insecurity and internalizing and externalizing behaviors. Results supported a sensitization pattern of responses as maladaptive for children in response to marital conflict, with evidence also linking an attenuation pattern with increased family risk. The findings of the present study support children's adrenocortical functioning as one mechanism through which interparental conflict is related to children's coping responses and psychological adjustment. PMID- 22545837 TI - The emergence of probabilistic reasoning in very young infants: evidence from 4.5 and 6-month-olds. AB - How do people make rich inferences from such sparse data? Recent research has explored this inferential ability by investigating probabilistic reasoning in infancy. For example, 8- and 11-month-old infants can make inferences from samples to populations and vice versa (Denison & Xu, 2010a; Xu & Denison, 2009; Xu & Garcia, 2008a). The current experiment investigates the developmental origins of this probabilistic inference mechanism with 4.5- and 6-month-old infants. Infants were shown 2 large boxes, 1 containing a ratio of 4 pink to 1 yellow balls, the other containing the opposite ratio. The experimenter sampled from, for example, the mostly pink box and removed a sample of either 4 pink and 1 yellow balls or 4 yellow and 1 pink balls on alternating trials. Six-month-olds but not 4.5-month-olds looked longer at the 4 yellow and 1 pink sample (the improbable outcome) than at the 4 pink and 1 yellow sample (the probable outcome). PMID- 22545838 TI - Early influences and later outcomes associated with developmental trajectories of Eriksonian fidelity. AB - Although Eriksonian theory suggests that adolescents' sense of fidelity is a key component of healthy development, research on this psychosocial construct has been limited. The current study developed an index of youth fidelity, examined the developmental course of this construct, explored the influence of contextual factors on different fidelity trajectories, and tested if trajectories were associated with later indicators of adolescents' positive development. Participants included 1,941 ethnically diverse youth (61% female) participants in the 4-H Study of Positive Youth Development who were recruited from schools and youth development programs across the United States. Results suggested that three types of developmental trajectories existed among youth: high and increasing, moderate and increasing, and low and decreasing. Fidelity group membership varied in relation to social relationships and psychosocial and behavioral characteristics (i.e., contribution, substance use, and delinquency). Girls were more likely than boys to be in the highest fidelity trajectories. Directions for future research and implications for enhancing the thriving of adolescents are discussed. PMID- 22545839 TI - Adolescents' emotional reactivity across relationship contexts. AB - Adolescents' emotional reactivity in family, close friendships, and romantic relationships was examined in a community-based sample of 416 two-parent families. Six waves of annual data were analyzed using structural equation modeling. Emotional reactivity to interparental conflict during early adolescence was associated prospectively with adolescents' reactivity to conflict in friendships and romantic relationships during middle adolescence. Close friendship reactivity partially explained the prospective association between reactivity to interparental conflict and romantic relationship reactivity. The association between perceived emotional reactivity and relationship conflict was stronger for girls than boys. Results have important developmental implications regarding adolescents' emotional reactivity across salient interpersonal contexts during adolescence. PMID- 22545840 TI - The multifaceted impact of peer relations on aggressive-disruptive behavior in early elementary school. AB - Following a large, diverse sample of 4,096 children in 27 schools, this study evaluated the impact of 3 aspects of peer relations, measured concurrently, on subsequent child aggressive-disruptive behavior during early elementary school: peer dislike, reciprocated friends' aggressiveness, and classroom levels of aggressive-disruptive behavior. Teachers rated child aggressive-disruptive behavior in 1st and 3rd grades, and peer relations were assessed during 2nd grade. Results indicated that heightened classroom aggressive-disruptive behavior levels were related to proximal peer relations, including an increased likelihood of having aggressive friends and lower levels of peer dislike of aggressive disruptive children. Controlling for 1st grade aggressive-disruptive behavior, the three 2nd grade peer experiences each made unique contributions to 3rd grade child aggressive-disruptive behavior. These findings replicate and extend a growing body of research documenting the multifaceted nature of peer influence on aggressive-disruptive behavior in early elementary school. They highlight the importance of the classroom ecology and proximal peer relations in the socialization of aggressive-disruptive behavior. PMID- 22545841 TI - Age and gender differences in motivational manifestations of the Big Five from age 16 to 60. AB - The present cross-sectional study investigated age and gender differences in motivational manifestations of the Big Five in a large German-speaking Internet sample (N = 19,022). Participants ranging in age from 16 to 60 years completed the Five Individual Reaction Norms Inventory (FIRNI; Denissen & Penke, 2008a), and two traditional Big Five measures. Age differences were found suggesting that mean levels of neuroticism and extraversion are negatively associated with age, whereas agreeableness and conscientiousness are positively associated. Openness to experience demonstrated a curvilinear association with age, with the highest mean levels in midlife. Gender differences were found suggesting that women, on average, have higher levels of neuroticism, extraversion, and agreeableness, while men are more open to experience. Neither the main effect of gender nor Age * Gender interactions were significant in the case of conscientiousness. In comparison to the 2 traditional Big Five measures, age differences in the motivational manifestations of the Big Five as assessed by the FIRNI were more pronounced, which might be explained by the greater developmental plasticity of flexible motivational processes or the intraindividual phrasing of the items of the FIRNI, compared to the kinds of behavioral descriptions that are emphasized in traditional Big Five items. The further study of such motivational processes might contribute to a better understanding of personality development. PMID- 22545843 TI - Deficit, difference, or both? Autism and neurodiversity. AB - The neurodiversity movement challenges the medical model's interest in causation and cure, celebrating autism as an inseparable aspect of identity. Using an online survey, we examined the perceived opposition between the medical model and the neurodiversity movement by assessing conceptions of autism and neurodiversity among people with different relations to autism. Participants (N = 657) included autistic people, relatives and friends of autistic people, and people with no specified relation to autism. Self-identification as autistic and neurodiversity awareness were associated with viewing autism as a positive identity that needs no cure, suggesting core differences between the medical model and the neurodiversity movement. Nevertheless, results suggested substantial overlap between these approaches to autism. Recognition of the negative aspects of autism and endorsement of parenting practices that celebrate and ameliorate but do not eliminate autism did not differ based on relation to autism or awareness of neurodiversity. These findings suggest a deficit-as-difference conception of autism wherein neurological conditions may represent equally valid pathways within human diversity. Potential areas of common ground in research and practice regarding autism are discussed. PMID- 22545842 TI - The role of language in concern and disregard for others in the first years of life. AB - We examined the associations between language skills and concern and disregard for others in young children assessed longitudinally at ages 14, 20, 24, and 36 months, testing the hypothesis that language skills have a specific role (distinct from that of general cognitive ability) in the development of concern and disregard for others. We found that higher language skills predicted higher concern for others and lower disregard for others even after controlling for general cognitive ability, whereas the association between general cognitive ability and concern/disregard for others was not significant after controlling for language skills. Language skills at 14 months predicted concern for others at 36 months, and results suggested that the relations between language skills and concern and disregard for others begin early in development. Gender differences in concern and disregard for others were at least partially explained by differences in language skills. These results support the specific role of language skills in concern and disregard for others. PMID- 22545844 TI - Peer sexual harassment and disordered eating in early adolescence. AB - Peer sexual harassment is a pervasive problem in schools and is associated with a variety of negative mental health outcomes. Objectification theory suggests that sexual attention in the form of peer harassment directs unwanted attention to the victim's body and may lead to a desire to alter the body via disordered eating. In the current study, we used latent growth modeling with a sample of 406 U.S. adolescents to examine the relationship between longitudinal trends in peer sexual harassment from 5th to 9th grade and disordered eating in 9th grade. Longitudinal trends in self-surveillance were proposed as a mediator of the relationships. Results indicated that the relationship between upsetting sexual harassment at 5th grade and disordered eating symptoms at 9th grade was mediated by self-surveillance at 5th grade. Girls reported more upsetting sexual harassment, more self-surveillance, and thus more disordered eating than boys did. These results are in accord with objectification theory, which proposes that sexual harassment is a form of sexual objectification and may lead to self surveillance and disordered eating. PMID- 22545846 TI - The emergence of flexible spatial strategies in young children. AB - The development of spatial navigation in children depends not only on remembering which landmarks lead to a goal location but also on developing strategies to deal with changes in the environment or imperfections in memory. Using cue combination methods, the authors examined 3- and 4-year-old children's memory for different types of spatial cues and the spatial strategies that they use when those cues are in conflict. Children were taught to search for a toy in 1 of 4 possible hiding locations. Children were then tested on transformations of the array of locations. The transformations dissociated the different types of cues by putting them in conflict with one another. The authors were especially interested in the use of a majority strategy, by which children choose to search in the location indicated by the greatest number of cue types rather than relying on a preferred cue type. Children's memory for spatial cues and their strategies varied both by age and by experimental setup. In Experiment 1, both 3- and 4-year-old children preferred to use the distinct landmarks coincident with the hiding locations over any other types of cues and showed no use of a majority strategy. However, in Experiment 2, when the coincident landmarks were moved adjacent to the hiding locations, both 3- and 4-year-old children preferred to search in the position of the hiding location relative to the array. Furthermore, 4-year-old children in Experiment 2 showed better memory for individual types of cues and the emergence of a majority strategy. PMID- 22545845 TI - Affective and cardiovascular responding to unpleasant events from adolescence to old age: complexity of events matters. AB - Two studies investigated the overpowering hypothesis as a possible explanation for the currently inconclusive empirical picture on age differences in affective responding to unpleasant events. The overpowering hypothesis predicts that age differences in affective responding are particularly evident in highly resource demanding situations that overtax older adults' capacities. In Study 1, we used a mobile phone-based experience-sampling technology in 378 participants 14-86 years of age. Participants reported their momentary negative affect and occurrences of unpleasant events on average 54 times over 3 weeks. In Study 2, a subsample of 92 participants wore an ambulatory psycho-physiological monitoring system for 24 hr while pursuing their daily routines and additionally completed an average of 7 mobile phone-based experience-sampling reports. Affective responding was analyzed by comparing, within persons, affective states in situations without and with preceding unpleasant events. Results support the overpowering hypothesis: When dealing with complex unpleasant events that affected multiple life domains, both psychological (Study 1) and cardiovascular (Study 2) responding to unpleasant events were more pronounced the older the participants were. When dealing with circumscribed unpleasant events, however, no age differences in psychological responding were observed (Study 1), and cardiovascular responding was even less pronounced the older the participants were (Study 2). These findings are consistent with the notion of preserved affect regulation throughout adulthood, as long as the resource demands exerted by an event do not overtax the individual's capacities. We conclude that the overpowering hypothesis can bridge previously opposing positions regarding age differences in affective responding. PMID- 22545847 TI - Beyond mental health: an evolutionary analysis of development under risky and supportive environmental conditions: an introduction to the special section. AB - Evolutionary approaches to behavior have increasingly captured the attention and imagination of academics and laypeople alike. One part of this trend has been the increasing influence of evolutionary theory in developmental science. The articles in this special section of Developmental Psychology attempt to demonstrate why an evolutionary analysis is needed to more fully understand the contexts and contingencies of development. The 3 theoretical articles articulate the core evolutionary logic underlying conditional adaptation (and maladaptation) to both stressful and supportive environmental conditions over development. These theoretical articles are then followed by 9 empirical articles that test these evolutionary-developmental theories and hypotheses. Finally, 6 commentaries evaluate the prospects, pitfalls, and implications of this body of work. PMID- 22545848 TI - Evolving science in adolescence: comment on Ellis et al. (2012). AB - Ellis et al. (2012) bring an evolutionary perspective to bear on adolescent risky behavioral development, clinical practice, and public policy. The authors offer important insights that (a) some risky behaviors may be adaptive for the individual and the species by being hard-wired due to fitness benefits and (b) interventions might be more successful if they move with, rather than against, the natural tendencies of an adolescent. Ellis and colleagues criticize the field of developmental psychopathology, but we see the 2 fields as complementary. Their position would be enhanced by integrating it with contemporary perspectives on dynamic cascades through which normative behavior turns into genuinely maladaptive outcomes, dual processes in adolescent neural development, and adolescent decision making. Finally, they rightly note that innovation is needed in interventions and policies toward adolescent problem behavior. PMID- 22545849 TI - Match fitness: development, evolution, and behavior: comment on Frankenhuis and Del Giudice (2012). AB - The application of evolutionary thinking to human physical and psychological medicine suggests several pathways through which evolutionary processes affect risk of disease. Among these is the concept of mismatch between an individual and its environment, either because the environment has changed for the whole species (evolutionary novelty) or because the environment has changed for an individual during its lifetime (developmental mismatch). Here we set a discussion of maladaptation and mismatch as a cause of psychopathology (Frankenhuis & Del Giudice, 2012) in the broader framework of developmental plasticity and life history trade-offs. PMID- 22545850 TI - Exploring the dynamics of development and evolution: comment on Blair and Raver (2012). AB - Blair and Raver (2012) have provided an organism-in-environment conceptualization of the development of stress response physiology and its relation to the development of self-regulation. They argue that we must consider the context in which self-regulation and stress reactivity occur to understand their implications for developmental outcome. More generally, they present a cogent argument for why it is necessary to think developmentally when considering the effects of early experience on subsequent physical, emotional, cognitive, and social development. Blair and Raver's article also highlights a persistent challenge for developmental theory--how to make sense of the relationship among the various timescales over which phenotypes develop and change occurs. Their efforts to identify the factors involved in the variability and stability of self regulation over different timescales demonstrate the dividends of integrating developmental and evolutionary perspectives to better understand the malleability of phenotypic development. PMID- 22545851 TI - The adaptive basis of psychosocial acceleration: comment on Beyond Mental Health, Life History Strategies articles. AB - Four of the articles published in this special section of Developmental Psychology build on and refine psychosocial acceleration theory. In this short commentary, we discuss some of the adaptive assumptions of psychosocial acceleration theory that have not received much attention. Psychosocial acceleration theory relies on the behavior of caregivers being a reliable cue of broader ecological conditions and on those ecological conditions being somewhat stable over the individual's lifetime. There is a scope for empirical and theoretical work investigating the range of environments over which these assumptions hold, to understand more deeply why it is that early life family environment exerts such reliable effects on later life-history strategy. PMID- 22545852 TI - Differential susceptibility experiments: going beyond correlational evidence: comment on beyond mental health, differential susceptibility articles. AB - Reviewing the studies on differential susceptibility presented in this section, we argue that the time is ripe to go beyond correlational designs to differential susceptibility experiments. In such experiments, randomization prevents hidden moderator effects on the environment and guarantees the independence of moderator and outcome, while the environment is manipulated and assessed in standard ways. Correlational studies generate a priori expectations about crucial moderators (e.g., temperament, biological sensitivity, and genetics). We discuss the differential susceptibility experiments available up until now and conclude that these experiments are feasible and contribute in unique ways to our conceptions of differential susceptibility. PMID- 22545853 TI - Adaptive calibration of children's physiological responses to family stress: the utility of evolutionary developmental theory: comment on Del Giudice et al. (2012) and Sturge-Apple et al. (2012). AB - Children's physiological reactions to stress are presented from the broader theoretical perspective of adaptive calibration to the environment, as rooted in life history theory. Del Giudice, Hinnant, Ellis, and El-Sheikh (2012) focus on children's physiological responses to a stressful task as a consequence of their history of family stress. Sturge-Apple, Davies, Martin, Cicchetti, and Hentges (2012) focus on the ways that children respond to a novel laboratory manipulation as a combined function of their temperament patterns and the harshness of their parental environment. The theoretical perspective employed provides an overarching framework that not only accounts for the findings presented here but also has heuristic value for future research on responses to early environmental risk. Future work in this area will benefit by inclusion of additional sympathetic nervous system (SNS) markers and neurotransmitters, inclusion of the role of gene expression in adaptive calibration, broader consideration of protective factors in the child's environment, and longitudinal work demonstrating the effects of adaptive calibration on children's future life history strategies and outcomes. PMID- 22545854 TI - Neuromodulation of behavioral and cognitive development across the life span. AB - Among other mechanisms, behavioral and cognitive development entail, on the one hand, contextual scaffolding and, on the other hand, neuromodulation of adaptive neurocognitive representations across the life span. Key brain networks underlying cognition, emotion, and motivation are innervated by major transmitter systems (e.g., the catecholamines and acetylcholine). Thus, the maturation and senescence of neurotransmitter systems have direct implications for life span development. Recent progress in molecular genetics has opened new avenues for investigating neuromodulation of behavioral and cognitive development. This special section features 6 selected reviews of recent cognitive genetic evidence on the roles of dopamine and other transmitters in different domains of behavioral and cognitive development, ranging from temperament, executive control, and working memory to motivation and goal-directed behavior in different life periods. PMID- 22545855 TI - Effects of categorical labels on similarity judgments: a critical evaluation of a critical analysis: comment on Noles and Gelman (2012). AB - Noles and Gelman (2012) attempt to critically reevaluate the claim that linguistic labels affect children's judgments of visual similarity. They report results of an experiment that used a modified version of Sloutsky and Fisher's (2004) task and conclude that "labels do not generally affect children's perceptual similarity judgments; rather, children's reliance on labels to make similarity judgments appears to be attributable to flaws in the methodological approaches used in prior studies" (p. 890). In this comment we demonstrate that these conclusions are based on inadequate analyses and reporting of statistics and are inconsistent with Noles and Gelman's own data. Instead, their data show a perfect replication of Sloutsky and Fisher (2004) and present further evidence that linguistic labels affect similarity judgment of young children. PMID- 22545856 TI - Disentangling similarity judgments from pragmatic judgments: Response to Sloutsky and Fisher (2012). AB - Sloutsky and Fisher (2012) attempt to reframe the results presented in Noles and Gelman (2012) as a pure replication of their original work validating the similarity, induction, naming, and categorization (SINC) model. However, their critique fails to engage with the central findings reported in Noles and Gelman, and their reanalysis fails to examine the key comparison of theoretical interest. In addition to responding to the points raised in Sloutsky and Fisher's (2012) critique, we elaborate on the pragmatic factors and methodological flaws present in Sloutsky and Fisher (2004) that biased children's similarity judgments. Our careful replication of that study suggests that, rather than measuring the influence of labels on judgments of perceptual similarity, the original design measured sensitivity to the pragmatics of task demands. Together, the results reported in Noles and Gelman and the methodological problems highlighted here represent a serious challenge to the validity of the SINC model specifically and the words-as-features view more generally. (PsycINFO Database Record (c) 2012 APA, all rights reserved). PMID- 22545857 TI - Protein discrimination using fluorescent gold nanoparticles on plasmonic substrates. AB - Fluorescent gold nanoparticle (GNP) is an easily synthesized and biocompatible optical platform for sensing and imaging with tunable near-infrared (NIR) emission. However, the relatively low fluorescence (FL) quantum yield limits the further improvement of sensitivity and application. Here, we find that, on plasmonic substrates, the FL intensity of protein-directed synthesized GNPs can be enhanced significantly (~20-fold). Moreover, protein analytes can interact with GNPs and influence the enhanced fluorescence process so that we can obtain distinct FL image patterns. Then, using the array-based sensing strategy, protein discrimination can be achieved. In our present experiment, five GNPs were used as sensing elements and 10 kinds of proteins at three concentrations (0.2, 0.5, and 1 MUM) were successfully identified. This array-based sensing strategy using enhanced-fluorescence from GNPs is highly sensitive and differentiable, expanding the application field of GNPs. PMID- 22545858 TI - Self-assembled electrical biodetector based on reduced graphene oxide. AB - Large-scale fabrication of graphene-based devices is an aspect of great importance for various applications including chemical and biological sensing. Toward this goal, we present here a novel chemical route for the site-specific realization of devices based on reduced graphene oxide (RGO). Electrodes patterned by photolithography are modified with amino functional groups through electrodeposition. The amine groups function as hooks for the attachment of graphene oxide flakes selectively onto the electrodes. Graphene-like electrical behavior is attained by a subsequent thermal annealing step. We show that this anchoring strategy can be scaled-up to obtain RGO devices at a wafer scale in a facile manner. The scalability of our approach coupled with the use of photolithography is promising for the rapid realization of graphene-based devices. We demonstrate one possible application of the fabricated RGO devices as electrical biosensors through the immunodetection of amyloid beta peptide. PMID- 22545859 TI - P53 deletion is independently associated with increased age and decreased survival in a cohort of Chinese patients with diffuse large B-cell lymphoma. AB - The purpose of the study was to compare cytogenetic profiles and survivals between elderly and non-elderly Chinese patients with diffuse large B-cell lymphoma (DLBCL). We identified 50 patients with DLBCL and divided them by age into elderly (>=60 years) and non-elderly (< 60 years) groups. We detected deletion of P53 or translocations in Bcl-2, Bcl-6 or c-myc genes by fluorescence in situ hybridization (FISH). P53 deletion was significantly more common in elderly versus non-elderly patients (62% vs. 17%, respectively, p=0.001) There were no significant differences in rates of Bcl-2, Bcl-6 or c-myc gene rearrangements between elderly and non-elderly patients (p>0.25 for each). Median survival was significantly longer in non-elderly compared to elderly patients. P53 deletion was an independent prognostic factor for decreased survival in patients with DLBCL, independent of age. In conclusion, P53 deletion as detected by FISH is associated with both increased age and decreased survival in Chinese patients with DLBCL. This association with decreased survival is at least partly independent of age. P53 deletion could serve as a prognostic factor in DLBCL independent of or in combination with age. PMID- 22545860 TI - Activity and crystal structure of Arabidopsis thaliana UDP-N-acetylglucosamine acyltransferase. AB - The UDP-N-acetylglucosamine (UDP-GlcNAc) acyltransferase, encoded by lpxA, catalyzes the first step of lipid A biosynthesis in Gram-negative bacteria, the (R)-3-hydroxyacyl-ACP-dependent acylation of the 3-OH group of UDP-GlcNAc. Recently, we demonstrated that the Arabidopsis thaliana orthologs of six enzymes of the bacterial lipid A pathway produce lipid A precursors with structures similar to those of Escherichia coli lipid A precursors [Li, C., et al. (2011) Proc. Natl. Acad. Sci. U.S.A. 108, 11387-11392]. To build upon this finding, we have cloned, purified, and determined the crystal structure of the A. thaliana LpxA ortholog (AtLpxA) to 2.1 A resolution. The overall structure of AtLpxA is very similar to that of E. coli LpxA (EcLpxA) with an alpha-helical-rich C terminus and characteristic N-terminal left-handed parallel beta-helix (LbetaH). All key catalytic and chain length-determining residues of EcLpxA are conserved in AtLpxA; however, AtLpxA has an additional coil and loop added to the LbetaH not seen in EcLpxA. Consistent with the similarities between the two structures, purified AtLpxA catalyzes the same reaction as EcLpxA. In addition, A. thaliana lpxA complements an E. coli mutant lacking the chromosomal lpxA and promotes the synthesis of lipid A in vivo similar to the lipid A produced in the presence of E. coli lpxA. This work shows that AtLpxA is a functional UDP-GlcNAc acyltransferase that is able to catalyze the same reaction as EcLpxA and supports the hypothesis that lipid A molecules are biosynthesized in Arabidopsis and other plants. PMID- 22545861 TI - In vitro selection of functional lantipeptides. AB - In this report we present a method to identify functional artificial lantipeptides. In vitro translation coupled with an enzyme-free protocol for posttranslational modification allows preparation of more than 10(11) different lanthionine containing peptides. This diversity can be searched for functional molecules using mRNA-lantipeptide display. We validated this approach by isolating binders toward Sortase A, a transamidase which is required for virulence of Staphylococcus aureus. The interaction of selected lantipeptides with Sortase A is highly dependent on the presence of a (2S,6R)-lanthionine in the peptide and an active conformation of the protein. PMID- 22545863 TI - Multidimensional conducting polymer nanotubes for ultrasensitive chemical nerve agent sensing. AB - Tailoring the morphology of materials in the nanometer regime is vital to realizing enhanced device performance. Here, we demonstrate flexible nerve agent sensors, based on hydroxylated poly(3,4-ethylenedioxythiophene) (PEDOT) nanotubes (HPNTs) with surface substructures such as nanonodules (NNs) and nanorods (NRs). The surface substructures can be grown on a nanofiber surface by controlling critical synthetic conditions during vapor deposition polymerization (VDP) on the polymer nanotemplate, leading to the formation of multidimensional conducting polymer nanostructures. Hydroxyl groups are found to interact with the nerve agents. Representatively, the sensing response of dimethyl methylphosphonate (DMMP) as a simulant for sarin is highly sensitive and reversible from the aligned nanotubes. The minimum detection limit is as low as 10 ppt. Additionally, the sensor had excellent mechanical bendability and durability. PMID- 22545862 TI - Hypochlorous acid and hydrogen peroxide-induced negative regulation of Salmonella enterica serovar Typhimurium ompW by the response regulator ArcA. AB - BACKGROUND: Hydrogen peroxide (H2O2) and hypochlorous acid (HOCl) are reactive oxygen species that are part of the oxidative burst encountered by Salmonella enterica serovar Typhimurium (S. Typhimurium) upon internalization by phagocytic cells. In order to survive, bacteria must sense these signals and modulate gene expression. Growing evidence indicates that the ArcAB two component system plays a role in the resistance to reactive oxygen species. We investigated the influx of H2O2 and HOCl through OmpW and the role of ArcAB in modulating its expression after exposure to both toxic compounds in S. Typhimurium. RESULTS: H2O2 and HOCl influx was determined both in vitro and in vivo. A S. Typhimurium ompW mutant strain (?ompW) exposed to sub-lethal levels of H2O2 and HOCl showed a decreased influx of both compounds as compared to a wild type strain. Further evidence of H2O2 and HOCl diffusion through OmpW was obtained by using reconstituted proteoliposomes. We hypothesized that ompW expression should be negatively regulated upon exposure to H2O2 and HOCl to better exclude these compounds from the cell. As expected, qRT-PCR showed a negative regulation in a wild type strain treated with sub-lethal concentrations of these compounds. A bioinformatic analysis in search for potential negative regulators predicted the presence of three ArcA binding sites at the ompW promoter region. By electrophoretic mobility shift assay (EMSA) and using transcriptional fusions we demonstrated an interaction between ArcA and one site at the ompW promoter region. Moreover, qRT PCR showed that the negative regulation observed in the wild type strain was lost in an arcA and in arcB mutant strains. CONCLUSIONS: OmpW allows the influx of H2O2 and HOCl and is negatively regulated by ArcA by direct interaction with the ompW promoter region upon exposure to both toxic compounds. PMID- 22545864 TI - Mild and ligand-free Pd(II)-catalyzed conjugate additions to hindered gamma substituted cyclohexenones. AB - Ligand-free cationic Pd(II) catalyst with NaNO3 as an additive is a highly active catalytic system for conjugate additions to sterically hindered gamma-substituted cyclohexenones. More challenging gammagamma- and betagamma-substrates also react well to produce products with quaternary centers in good dr. The conjugate additions occur in a diastereoselective fashion under mild, practical and air stable conditions, using readily available commercial reagents. PMID- 22545865 TI - Recurrent 6th nerve palsy in a child following different live attenuated vaccines: case report. AB - BACKGROUND: Recurrent benign 6th nerve palsy in the paediatric age group is uncommon, but has been described following viral and bacterial infections. It has also been temporally associated with immunization, but has not been previously described following two different live attenuated vaccines. CASE PRESENTATION: A case is presented of a 12 month old Caucasian boy with recurrent benign 6th nerve palsy following measles-mumps-rubella and varicella vaccines, given on separate occasions with complete recovery following each episode. No alternate underlying etiology was identified despite extensive investigations and review. CONCLUSIONS: The majority of benign 6th nerve palsies do not have a sinister cause and have an excellent prognosis, with recovery expected in most cases. The exact pathophysiology is unknown, although hypotheses including autoimmune mechanisms and direct viral invasion could explain the pathophysiology behind immunization related nerve palsies. It is important to rule out other aetiologies with thorough history, physical examination and investigations. There is limited information in the literature regarding the safety of a repeat dose of a live vaccine in this setting. Future immunizations should be considered on a case-by case basis. PMID- 22545866 TI - Effect of bark beetle infestation on secondary organic aerosol precursor emissions. AB - Bark beetles are a potentially destructive force in forest ecosystems; however, it is not known how insect attacks affect the atmosphere. The emissions of volatile organic compounds (VOCs) were sampled i.) from bark beetle infested and healthy lodgepole pine (Pinus contorta var. latifolia) trees and ii.) from sites with and without active mountain pine beetle infestation. The emissions from the trunk and the canopy were collected via sorbent traps. After collection, the sorbent traps were extracted with hexane, and the extracts were separated and detected using gas chromatography/mass spectroscopy. Canister samples were also collected and analyzed by a multicolumn gas chromatographic system. The samples from bark beetle infested lodgepole pine trees suggest a 5- to 20-fold enhancement in total VOCs emissions. Furthermore, increases in the beta phellandrene emissions correlated with bark beetle infestation. A shift in the type and the quantity of VOC emissions can be used to identify bark beetle infestation but, more importantly, can lead to increases in secondary organic aerosol from these forests as potent SOA precursors are produced. PMID- 22545867 TI - Myxobacteria: natural pharmaceutical factories. AB - Myxobacteria are amongst the top producers of natural products. The diversity and unique structural properties of their secondary metabolites is what make these social microbes highly attractive for drug discovery. Screening of products derived from these bacteria has revealed a puzzling amount of hits against infectious and non-infectious human diseases. Preying mainly on other bacteria and fungi, why would these ancient hunters manufacture compounds beneficial for us? The answer may be the targeting of shared processes and structural features conserved throughout evolution. PMID- 22545868 TI - Circadian cortisol profiles, anxiety and depressive symptomatology, and body mass index in a clinical population of obese children. AB - Obesity is highly co-morbid with anxiety and/or depression in children, conditions that may further worsen the metabolic and cardiovascular risks for obese individuals. Dysregulation of the hypothalamic-pituitary-adrenal axis is involved in the pathophysiology of anxiety disorders, depression, and obesity, and diverse cortisol concentrations may be found in obese children, depending on their degree of psychological distress. The aim of this study was to examine cortisol profiles among obese children with or without symptoms of anxiety and depression. A group of 128 children (53% females; mean age +/- SD: 11.2 +/- 2.2 years) derived from a pediatric obesity clinic were studied. Anxiety and depressive symptomatology were assessed with appropriate instruments. Morning serum and five diurnal salivary cortisol concentrations were measured. Obese children were 3.1/2.3 times more likely to report state and trait anxiety, respectively, and 3.6 times more likely to report depressive symptoms than children of the same age group, from a contemporary Greek sample. Trait anxiety and noon salivary cortisol concentrations were significantly positively correlated (p = 0.002). Overall, salivary cortisol concentrations were increased in children with anxiety or depression symptomatology compared to obese children without any affective morbidity (p = 0.02) and to those with anxiety and depression co-morbidity (p = 0.02). In conclusion, in obese children, emotional distress expressed by symptoms of anxiety and/or depression is associated with circadian cortisol profiles reflecting a potential pathway for further morbidity. Longitudinal studies may reveal a role of cortisol in linking obesity, anxiety, and depression to the development of further psychological and physical morbidity. PMID- 22545869 TI - Evaluation of the potential airborne release of carbon nanofibers during the preparation, grinding, and cutting of epoxy-based nanocomposite material. AB - The National Institute for Occupational Safety and Health conducted an initial, task-based comparative assessment to determine the potential for release of carbon nanofibers (CNFs) during dry material handling, wet cutting, grinding, and sanding (by machine and hand) of plastic composite material containing CNFs. Using a combination of direct-reading instruments and filter-based air sampling methods for airborne mass and transmission electron microscopy (TEM), concentrations were measured and characterized near sources of particle generation, in the breathing zone of the workers, and in the general work area. Tasks such as surface grinding of composite material and manually transferring dry CNFs produced substantial increases in particle number concentration (range = 20,000-490,000 1-cm(-3)). Concomitant increases in mass concentration were also associated with most tasks. Nearly 90% of all samples examined via TEM indicated that releases of CNFs do occur and that the potential for exposure exists. These findings also indicate that improperly designed, maintained, or installed engineering controls may not be completely effective in controlling releases. Unprotected skin exposure to CNFs was noted in two instances and indicated the need for educating workers on the need for personal protective equipment. [Supplementary materials are available for this article. Go to the publisher's online edition of Journal of Occupational and Environmental Hygiene for the following free supplemental resource: a PDF file containing information on materials, evaluated processes, personal protective equipment, and existing ventilation/engineering controls.]. PMID- 22545871 TI - Competencies of front-line managers in supported accommodation: issues for practice and future research. AB - BACKGROUND: Front-line managers of supported accommodation for people with intellectual disability are assumed to have a key role in the realisation of outcomes for service users. Yet, their job has been little researched. A job analysis from Minnesota that identified 142 competencies required of effective front-line managers was used to examine what was expected of the equivalent position in Victoria, Australia. METHODS: These competencies formed the basis of semistructured interviews with an extreme sample of 16 high-performing house supervisors and 5 more senior managers. RESULTS: Ninety-two percent of the original competences were retained, with changes in language and terminology to reflect the local context. Emergent findings highlighted the importance of house supervisors' "orientations." CONCLUSIONS: The findings support the proposition that the front-line manager's job is underpinned by core competencies and that the role merits further study. Issues of wider significance for human service organisations and researchers are discussed. PMID- 22545872 TI - Broadband unidirectional scattering by magneto-electric core-shell nanoparticles. AB - Core-shell nanoparticles have attracted surging interests due to their flexibly tunable resonances and various applications in medical diagnostics, biosensing, nanolasers, and many other fields. The core-shell nanoparticles can support simultaneously both electric and magnetic resonances, and when the resonances are properly engineered, entirely new properties can be achieved. Here we study core shell nanoparticles that support both electric and artificial magnetic dipolar modes, which are engineered to coincide spectrally with the same strength. We reveal that the interferences of these two resonances result in azimuthally symmetric unidirectional scattering, which can be further improved by arranging the nanoparticles in a chain, with both azimuthal symmetry and vanishing backward scattering preserved over a wide spectral range. We also demonstrate that the vanishing backward scattering is preserved, even for random particle distributions, which can find applications in the fields of nanoantennas, photovoltaic devices, and nanoscale lasers that require backward scattering suppressions. PMID- 22545870 TI - Participation and quality of life in children with Duchenne muscular dystrophy using the International Classification of Functioning, Disability, and Health. AB - BACKGROUND: Duchenne muscular dystrophy (DMD) is characterized by muscle damage and progressive loss of muscle function in male children. DMD is one of the most devastating genetically linked neuromuscular diseases for which there is currently no cure. Most clinical studies for DMD utilize a standard protocol for measurement exploring pathophysiology, muscle strength and timed tasks. However, we propose that examining broader components of health as emphasized by the International Classification of Functioning, Disability and Health-Children and Youth Version (ICF-CY) may be of great value to children and their families, and important outcomes for future clinical trials. METHODS: Fifty boys with DMD and 25 unaffected age-matched boys completed two self-report measures: the Children's Assessment of Participation and Enjoyment and the Pediatric Quality of Life InventoryTM 4.0. We investigated differences between the two groups with regard to participation in life activities and perceived quality of life (QoL). Additionally, we compared participation in activities and QoL in both cohorts of younger and older boys. RESULTS: Participation in physical activities was significantly lower in boys with DMD than unaffected boys. Perceived QoL was markedly diminished in children with DMD relative to unaffected controls, except in the emotional domain. The amount of time boys engage in an activity, as well as participation in social activities, declined for our older boys with DMD but no changes were observed for our older unaffected boys. For both groups, QoL remained constant over time. CONCLUSIONS: The ICF-CY provides a conceptual framework and specific terminology that facilitates investigation of the consequences of impairment in children and youth. Our study is one of the first to explore participation in a cohort of boys with DMD. It was not surprising that activities of choice for boys with DMD were less physical in nature than unaffected boys their age, but the consequences of less social engagement as the boys with DMD age is of great concern. Results from our study underscore the need to further evaluate activities that children elect to participate in, with special emphasis on facilitators and barriers to participation and how participation changes throughout the course of a disease. PMID- 22545873 TI - Impairment of heart rate recovery index in autosomal-dominant polycystic kidney disease patients without hypertension. AB - BACKGROUND: We aimed to determine the status of the autonomic nervous system in patients with autosomal-dominant polycystic kidney disease (ADPKD) who were normotensive and had normal renal function. METHODS: A total of 28 normotensive ADPKD patients with normal renal function and 30 healthy control subjects consented to participate in the study. Heart rate recovery (HRR) indices were defined as the reduction in heart rate from the rate at peak exercise to the rate at the 1st, 2nd, 3rd and 5th minutes after the cessation of the exercise stress test; these results were indicated HRR(1), HRR(2), HRR(3) and HRR(5), respectively. RESULTS: The 1st- and 2nd-minute HRR indices of patients with ADPKD were significantly lower than those of the healthy control group (27.1+/-7.9 vs 32.0+/-7.9; p=0.023 and 46.9+/-11.5 vs 53.0+/-9.0; p=0.029, respectively). Similarly, HRR indices after the 3rd and 5th minutes of the recovery period were significantly lower in patients with ADPKD when compared with indices in the control group (56.7+/-12.0 vs 65.1+/-11.2; p=0.008 and 62.5+/-13.8 vs 76.6+/ 15.5; p =0.001, respectively). CONCLUSION: Impaired HRR index is associated with normotensive early-stage ADPKD patients. Increased renal ischemia and activation of the renin-angiotensin-aldosterone system (RAAS) may contribute to impairment in the autonomic nervous system in these patients before the development of hypertension. Even if ADPKD patients are normotensive, there appears to be an association with autonomic dysfunction and polycystic kidney disease. PMID- 22545874 TI - Recanalization of femoropopliteal chronic total occlusions using the ENABLER-P Balloon Catheter System. AB - PURPOSE: To evaluate the safety and effectiveness of a new system to facilitate intraluminal advancement of conventional guidewires through chronic total occlusions (CTO) of the superficial femoral artery (SFA) and popliteal artery. METHODS: The ENABLER-P Balloon Catheter System uses a unique balloon-anchoring mechanism and an automated balloon inflation device for steady, controlled advancement of a standard non-hydrophilic guidewire. The system was evaluated in 37 patients (22 men; mean age 67 years (range 41-87) with femoropopliteal CTOs averaging 86 mm in length (range 10-340). The device was used in a variety of occlusions, including heavily calcified, long, and fibrotic lesions. After successful guidewire recanalization facilitated by the system, occluded arterial segments were treated conventionally with balloon angioplasty, atherectomy, and stents as appropriate. RESULTS: The primary endpoint of successful crossing was achieved in 86% (32/37) of the overall study population. The average activation time for successful crossing was 5.3 minutes (range 0.4-22). Of the 32 cases successfully crossed with the ENABLER-P System, all but 1 was successfully recanalized. One (3%) device-related complication occurred when the wire was advanced into a side branch when treating a 300-mm-long flush ostial SFA occlusion; the resulting perforation was managed with a covered stent without further sequelae. CONCLUSION: This novel system, which provides enhanced force to a standard guidewire tip for controlled intraluminal advancement, is a promising device for the treatment of peripheral CTOs. PMID- 22545875 TI - Commentary: The ENABLER-P Balloon Catheter System: a new and exciting tool for recanalization of femoropopliteal CTOs. PMID- 22545876 TI - Tissue plasminogen activator-assisted hematoma evacuation to relieve abdominal compartment syndrome after endovascular repair of ruptured abdominal aortic aneurysm. AB - PURPOSE: To describe our experience with a novel technique to decompress abdominal compartment syndrome after endovascular aneurysm repair (EVAR) of ruptured abdominal aortic aneurysm (rAAA). METHODS: From January 2003 to April 2010, 13 patients (12 men; mean age 75 years) treated for rAAA with EVAR underwent tissue plasminogen activator (tPA)-assisted decompression for intra abdominal hypertension. All of the patients but one had intra-abdominal pressure >20 mmHg, with signs of multiple organ failure or abdominal perfusion pressure <60 mmHg. With computed tomography guidance, a drain was inserted into the retroperitoneal hematoma, and tPA solution was injected to facilitate evacuation of the coagulated hematoma and decrease the abdominal pressure. RESULTS: In the 13 patients, the mean intra-abdominal pressure decreased from 23.5 mmHg (range 12 35) to 16 mmHg (range 10-28.5). A mean 1520 mL (range 170-2900) of blood was evacuated. Urine production (mean 130 mL/h, range 50-270) increased in 7 patients at 24 hours after tPA-assisted decompression; among the 5 patients in which urine output did not increase, 3 underwent hemodialysis by the 30-day follow-up. One patient did not respond with clinical improvement and required laparotomy. The 30 day, 90-day, and 1-year mortality was 38% (5/13 patients); none of the deaths was related to the decompression technique. CONCLUSION: tPA-assisted decompression of abdominal compartment syndrome after EVAR can decrease the intra-abdominal pressure and could be useful in preventing multiple organ failure. It is a minimally invasive technique that can be used in selected cases but does not replace laparotomy or retroperitoneal surgical procedures as the gold standard treatments. PMID- 22545877 TI - Commentary: Abdominal compartment syndrome post EVAR: new therapies are keenly needed, but is tPA-assisted hematoma evacuation the answer? PMID- 22545878 TI - Early follow-up after endovascular aneurysm repair: is the first postoperative computed tomographic angiography scan necessary? AB - PURPOSE: To examine whether initial postoperative computed tomographic angiography (CTA) is needed in all patients undergoing endovascular aneurysm repair (EVAR). METHODS: A total of 105 consecutive patients underwent EVAR with standard infrarenal devices in our department between November 2009 and May 2011. Five patients were excluded due to severe renal insufficiency, leaving 100 (85 men; median age 73 years, range 46-91) eligible for prospective enrollment in a triple-modality early postoperative follow-up protocol [intraoperative completion angiography, postoperative duplex ultrasonography (DUS), and plain abdominal radiography). Findings were compared for sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) against the first postoperative CTA results for the detection of endoleaks or other signs of EVAR failure. RESULTS: There were 10 inconclusive DUS examinations. In the remaining 90 patients, DUS had 75.0% sensitivity, 95.4% specificity, 85.7% PPV, and 91.5% NPV for the detection of endoleaks. The intraoperative angiogram, DUS, and abdominal radiograph combined resulted in 87.5% sensitivity and 95.4% specificity, with a 65.6% PPV and 94.8% NPV for the detection of endoleaks. In 2 patients who required a reintervention for endoleak in the early postoperative period, both endoleaks were correctly detected by the triple-modality early postoperative follow-up protocol. CONCLUSION: An early follow-up protocol consisting of an intraoperative completion angiogram, DUS, and abdominal radiograph shows a high sensitivity and NPV for the detection of endoleaks and should detect early migration or kinking of the stent-graft. An initial postoperative CTA is not necessary for most patients undergoing EVAR and should be reserved for those individuals in whom the aforementioned modalities are inconclusive or show signs of endoleak or other EVAR failure. PMID- 22545879 TI - A novel method to estimate iliac tortuosity in evaluating EVAR access. AB - PURPOSE: To subjectively and objectively evaluate the methods used for preoperative assessment of iliac artery tortuosity in patients with abdominal aortic aneurysms (AAA). METHODS: Iliac artery tortuosity was assessed retrospectively in 188 patients (160 men; mean age 73 years) diagnosed with AAA at our clinic in 2006 and 2007. All patients underwent preoperative computed tomography (CT) with predominantly thin-slice acquisitions. CT data were analyzed in a dedicated 3-dimensional workstation to perform centerline-of-flow measurements on 376 iliac arteries. Iliac tortuosity was evaluated using the following methods: (1) subjective grading (none, mild, moderate, severe) by 2 experienced observers, (2) calculating the modified iliac tortuosity index based on the published reporting standards for endovascular aneurysm repair, and (3) using the shortest distance between the aortic bifurcation and the common femoral artery (CFA) on axial CT scans as a surrogate for the tortuosity index. Correlation between the objective methods was assessed, and all 3 methods were evaluated for intra- and interobserver agreement. RESULTS: (1) The intra- and interobserver agreement was substantial (kappa = 0.71 and kappa = 0.65, respectively) for subjective grading, but few variations were found in the calculated tortuosity indexes between the subjective groups. (2) Intra- and interobserver correlations when measuring the iliac tortuosity index were strong (r = 0.94 and r = 0.79, respectively), with good intra- and interobserver agreement. (3) The new method had a strong correlation with iliac tortuosity index (r = 0.78); segregating the iliac arteries into 3 length categories (<10 cm, 10-15 cm, >15 cm), the mean iliac tortuosity indexes were 2.0 +/- 0.37, 1.6 +/- 0.21, and 1.1 +/- 0.27, respectively (p<0.001). This strong correlation was not seen when measuring the iliac artery length in CLF reconstruction (r = 0.31), proving little variation in CLF length among patients. CONCLUSION: Subjective grading of iliac artery tortuosity had substantial agreement between investigators but cannot be recommended as a surrogate for the tortuosity index in access evaluation. The iliac artery tortuosity index is most accurate, but complex and time-consuming. As the CLF length varies only slightly among patients, the new method using the shortest aortic bifurcation-CFA distance on an axial CT scan is a good substitute for the iliac tortuosity index and can often replace it clinically. PMID- 22545880 TI - Off-the-shelf fenestrated endografts: a realistic option for more than 70% of patients with juxtarenal aneurysms. AB - PURPOSE: To evaluate the suitability of a standardized fenestrated endograft in patients with juxtarenal abdominal aortic aneurysms. METHODS: High resolution computed tomographic angiograms from 100 consecutive patients (96 men; mean age 72 years) with juxta- (n = 78) and pararenal (n = 22) aneurysms treated electively between 2005 and 2010 with custom-made fenestrated endografts were reviewed. A centerline of flow reconstruction was carried out in a 3D imaging workstation to precisely define the aortic morphology, including aortic diameters and distances between visceral and renal arteries. The applicability of 2 different "off-the-shelf" standardized fenestrated endografts designed by the manufacturer was evaluated in this cohort. Both designs included 2 fenestrations for the renal arteries, 1 for the superior mesenteric artery (SMA), and a scallop for the celiac trunk. The designs differed in the lengths of the SMA to renal fenestration and renal to renal fenestration. RESULTS: Endovascular treatment with one or both "off-the-shelf" endografts was deemed possible in 72 patients (56 with design 1, 52 with design 2, and 36 with both endografts). Of the 28 patients who were not candidates for a standardized fenestrated stent-graft of either design, the primary cause was a right renal artery that did not match the position of its corresponding fenestration. CONCLUSION: Standardized fenestrated designs suitable for endovascular treatment of >70% of patients with juxta- and pararenal aneurysms currently treated with custom-made fenestrated endografts will soon be available. This new generation of endografts will permit rapid treatment of a large majority of patients requiring fenestrated endograft repair. PMID- 22545881 TI - Ventana fenestrated stent-graft system for endovascular repair of juxtarenal aortic aneurysms. AB - PURPOSE: To describe the initial use of an off-the-shelf fenestrated stent-graft system for endovascular repair of juxtarenal abdominal aortic aneurysms. TECHNIQUE: The off-the-shelf Ventana fenestrated stent-graft system consists of a 25-mm IntuiTrak self-expanding bifurcated stent-graft implanted at the aortic bifurcation. A Ventana self-expanding fenestrated proximal extension stent-graft is overlapped with the bifurcated body distally and sealed proximally in the visceral segment with a 4-cm-long scallop below and around the SMA and celiac artery, obviating the need for an infrarenal neck. Movable, non-reinforced, 3-mm fenestrations for the renal arteries can be expanded to 10 mm. The 22-F delivery system includes 6.5-F guide sheaths pre-inserted through the stent-graft fenestrations so that the renal arteries are cannulated before the fenestrated stent-graft is deployed. The Xpand renal stent-grafts, with a proximal segment intended for flaring in the aorta, are delivered on 5-F or 6-F balloon catheters through the 6.5-F guide sheaths. The technique is illustrated in 2 patients (76 and 77 years of age) with significant comorbidities and juxtarenal aortic aneurysms measuring 5.9 and 7.4 mm, respectively, who were enrolled in an ongoing prospective trial ( www.ClinicalTrials.gov identifier NCT01348828 ) of this new device. Patient 1 had a 28-mm fenestrated stent-graft system with the aligned fenestration configuration deployed, while the stent-graft in Patient 2 was 32 mm in diameter and had offset fenestrations to accommodate the renal artery geometry. Mean fluoroscopy times were 27 and 35 minutes, and the contrast volumes were 72 and 67 mL. Total procedure times were 84 and 71 minutes. The aneurysms were effectively excluded in uneventful procedures, with no migration, endoleak, or renal dysfunction at 6-month follow-up. CONCLUSION: There exists an unmet clinical need for a broadly applicable endovascular option for repair of more complex juxtarenal or pararenal aortic aneurysms. These cases suggest that endovascular repair of such aneurysms using the Ventana fully integrated off-the shelf stent-graft system is safe and feasible. PMID- 22545882 TI - Commentary: Challenges for off-the-shelf fenestrated stent-grafting. PMID- 22545883 TI - Midterm outcomes after treatment of type II endoleaks associated with aneurysm sac expansion. AB - PURPOSE: To examine the outcomes following interventions for type II endoleaks in patients with aneurysm sac expansion after endovascular aneurysm repair (EVAR). METHODS: A retrospective review was conducted of all patients who underwent treatment for type II endoleak from July 2001 to September 2010 in a single center. In this time period, 29 (4.7%) patients (22 men; mean age 78.6 years, range 54-87) were identified as having a type II endoleak and enlargement of the aneurysm sac, meeting the criterion for treatment. All patients had at least one attempted percutaneous intervention. Patients were followed both clinically and radiographically, with computed tomographic angiography every 3 to 12 months, over a follow-up period that ranged from 1 to 10 years (mean 3.5). RESULTS: Forty eight interventions were performed on the 29 patients. Of these, 15 (56%) patients underwent multiple (2-4) procedures. Of the 11 endoleaks with an isolated inferior mesenteric artery identified as the source, initial success for transarterial embolization at 2 years was 72%, with 2 of the failures having successful secondary interventions. For the 18 endoleaks with a lumbar source, the success of the initial intervention was 17% at 2 years; repeated embolization attempts produced a 40% secondary success rate. Seven (24%) patients had continued endoleak despite multiple treatment attempts; 3 ultimately required elective aortic graft explantation. There were no ruptures or deaths during the study period. In a comparison of type II endoleak patients who had stable aneurysm sacs and those who had persistent sac expansion, the only significant differences in preoperative anatomical characteristics were a lower prevalence of mural thrombus (p = 0.036) and longer right iliac arteries (p = 0.012) in the group with sac expansion. Independent predictors of type II endoleak were mural thrombus (p<0.001), patent lumbar arteries (p = 0.004), aneurysm length (p = 0.011), and iliac artery length (p = 0.004). CONCLUSION: This study demonstrates that most patients require multiple reinterventions to treat type II endoleaks; specifically, lumbar artery embolization carries a low midterm success rate. PMID- 22545884 TI - Type II endoleaks after endovascular repair of abdominal aortic aneurysms: fate of the aneurysm sac and neck changes during long-term follow-up. AB - PURPOSE: To evaluate the frequency of type II endoleaks after endovascular aneurysm repair (EVAR) and to compare sac diameter and neck changes in patients with type II endoleak to endoleak-free patients with at least 3-year imaging follow-up. METHODS: Among 407 consecutive EVAR patients, 109 patients (101 men; mean age 72.1 years, range 55-86) had at least 3-year computed tomography (CT) data and no type I or III endoleak. In this cohort, 49 patients presented with a type II endoleak at some time and 60 patients had no endoleak. Patients with type II endoleaks were further divided into subgroups based on the vessel origin and the perfusion status (persistent or transient). The course of the perfusion status of type II endoleaks and changes in the aneurysm sac diameters, neck diameters, and renal to stent-graft distances (RSD) were evaluated in the defined groups. Reintervention and death rates were also reported. RESULTS: The mean follow-up was 68.1 +/- 23.8 months. Compared to the no endoleak group, overall sac diameter increased significantly in the type II endoleak group (p = 0.007), but vessel origin did not have any influence. With regard to the perfusion status of type II endoleaks, aneurysm sac changes were significantly higher (p = 0.002) in the persistent endoleak group. During the study period, the increase in the proximal neck diameter was significantly higher in the no endoleak group compared to the type II endoleak group (p = 0.025). No significant difference was found in RSD changes between the defined groups. Reinterventions were performed in 20 (18.3%) patients (13 for type II endoleak); 2 (1.8%) patients without type II endoleak died of ruptured aneurysm. CONCLUSION: Persistent type II endoleaks led to significant aneurysm sac enlargement, but without increased mortality or rupture rates. PMID- 22545886 TI - Commentary: Type II endoleaks: still the crux of EVAR? PMID- 22545885 TI - Current evidence is insufficient to define an optimal threshold for intervention in isolated type II endoleak after endovascular aneurysm repair. AB - PURPOSE: To report a systematic review and meta-regression of the association between the threshold for intervention in patients with isolated type II endoleak after endovascular aneurysm repair (EVAR) and the fate of the aneurysm sac. METHODS: Medline, trial registries, conference proceedings, and article reference lists were searched to identify case series reporting sac outcomes following a specific treatment threshold for isolated type II endoleak. Articles were classified by the threshold for intervention as conservative, selective (intervention for >5-mm sac expansion or persistent type II endoleak >6 months), or aggressive (any type II endoleak or persistent for >3 months) and sac outcomes were extracted for review. Standard meta-regression to estimate the pooled odds ratios (OR), presented with the 95% confidence interval (CI), was performed to identify whether an aggressive, selective, or conservative threshold for intervention was associated with sac expansion or sac regression. RESULTS: Ten series were analyzed that reported the outcomes of isolated type II endoleak in 231 patients; of these, 56 patients were treated at an aggressive threshold, 104 at a selective threshold, and 71 at a conservative threshold. The majority (194/231, 84.0%) demonstrated either stable or shrinking sacs during follow-up. No ruptures occurred. Meta-regression demonstrated no evidence that any strategy, compared to using a conservative approach, reduced sac expansion (aggressive estimated OR 0.70, 95% CI 0.15 to 3.31, p = 0.60; selective estimated OR 1.72, 95% CI 0.49 to 6.00, p = 0.34) or improved sac regression (aggressive estimated OR 0.55, 95% CI 0.02 to 16.94, p = 0.69; selective estimated OR 5.54, 95% CI 0.39 to 79.21, p = 0.17). CONCLUSION: There is inadequate information to support any one threshold for intervention. The rarity of rupture and sac expansion confirms the predominantly benign nature of isolated type II endoleak. In the absence of statistical support for a uniform approach to this problem, patient and physician preference remain key. Prospective data are still needed to investigate whether an optimum management algorithm can be devised. PMID- 22545888 TI - In situ laser fenestration for revascularization of the left subclavian artery during emergent thoracic endovascular aortic repair. AB - PURPOSE: To present midterm outcomes of thoracic endovascular aortic repair (TEVAR) with laser fenestration to revascularize the left subclavian artery (LSA) as an alternative to debranching. METHODS: Six symptomatic patients (3 men; mean age of 50 years) underwent emergent TEVAR with LSA revascularization via laser graft fenestration. Three patients had large thoracic aortic aneurysms (2 secondary to chronic dissection); 1 patient had an acute symptomatic type B aortic dissection, and 2 patients had intramural hematomas. Emergent TEVAR was carried out with deployment of a Dacron endograft over the orifice of the left LSA. Through retrograde brachial access, a 0.018-inch wire was placed at the ostium of the LSA followed by laser catheter fenestration of the graft. A 10-mm covered stent was deployed through the fenestration to traverse the endograft and LSA; the endograft portion of the covered stent was flared. RESULTS: Laser fenestration was successful in 5 of 6 attempts; 1 fenestration was abandoned secondary to an acute LSA takeoff in a type III aortic arch. In this case, the stent was placed as a snorkel to successfully revascularize the LSA with no adverse consequences. There were no fenestration-related complications and no neurological morbidity. At a mean 8-month follow-up (range 1-17), no patients had died, and all LSA stents were patent, with no fenestration-related endoleaks on imaging. CONCLUSION: In situ retrograde laser fenestration is a feasible and effective option for revascularizing the LSA during emergent TEVAR. Longer follow up is necessary to determine the durability of this technique. PMID- 22545887 TI - Valiant thoracic stent-graft deployed with the new captivia delivery system: procedural and 30-day results of the Valiant Captivia registry. AB - PURPOSE: To evaluate procedural and 30-day outcomes of thoracic endovascular aortic repair (TEVAR) employing the Valiant Thoracic Stent Graft with the Captivia Delivery System. METHODS: Enrollment in the study ( www.ClinicalTrials.com identifier NCT01181947) included all eligible patients implanted with the Valiant Captivia System retrospectively and prospectively at 15 sites in Europe and Turkey between October 2009 and June 2010. In the 100 treated patients (81 men; mean age 64.6 +/- 12.0 years, range 25-87), indications included descending thoracic aortic aneurysm (TAA, 49.0%) and aortic dissection (42.0%). RESULTS: Technical success was 100.0%, with no misaligned deployments or aortic perforations. Mean follow-up was 68.9 +/- 34.9 days (range 20-147, median 61). The 30-day rate of all-cause mortality was 4.0% (all 4 cases procedure related, 3 device-related). Retrograde type A dissection occurred in 2 patients. The only conversion to open surgery was successful in a patient experiencing intraoperative aneurysm rupture. Stroke occurred in 4 (4.0%) patients and paraplegia in 1 (1.0%). Among 66 patients with 30-day imaging studies evaluable for endoleak, 4 (6.1%) had type I and 7 (10.6%) had type II endoleak; there were no types III or IV. Within 30 days, no secondary endovascular procedures were required due to endoleak. One patient with type II endoleak died 3 weeks postimplantation before scheduled embolization. CONCLUSION: In this analysis of procedural and 30-day results, the high technical success and clinical outcome rates showed that the Valiant Thoracic Stent Graft with the new Captivia Delivery System has promising capacity to treat a variety of thoracic aortic conditions in a range of anatomies. PMID- 22545889 TI - Drug-eluting vs. bare metal stents for symptomatic vertebral artery stenosis. AB - PURPOSE: To evaluate the immediate and long-term outcomes of drug-eluting stent (DES) vs. bare metal stent (BMS) for symptomatic vertebral artery stenosis (VAS). METHODS: From 2003 to 2010, 206 consecutive patients (158 men; mean age 66.8 years) underwent DES (sirolimus-eluting or paclitaxel-eluting) or BMS placement for symptomatic extracranial and intracranial stenoses in 219 vertebral arteries. The technical success, clinical success, periprocedural complications, target vessel revascularization (TVR), and overall survival were compared between the DES and BMS groups. RESULTS: The technical success rate was 98.3% (119/121) for the DES group vs. 100% for the BMS group (p = 0.503). The clinical success rate was 95.5% (107/112) for the DES group vs. 97.9% (92/94) for the BMS group (p = 0.592). No periprocedural death or stroke occurred. The overall periprocedural complication rate was 2.7% (3/112) in the DES group vs. 4.3% (4/94) in BMS group (p = 0.813). The median follow-up was 43 months (range 3-95) for the DES group and 46 months (range 6-89) for BMS. At last follow-up, the TVR rate was 6.3% (7/112) for the DES group vs. 20.2% (19/94) for the BMS group (p = 0.003); 4 (3.6%) patients in the DES group and 8 (8.5%) patients in the BMS group experienced a VBS stroke (p = 0.132). By life-table analysis, the 5-year TVR rate was 4.5% (5/112) for the DES group vs. 19.1% (18/94) for the BMS group (p = 0.001). No difference was detected in the overall survival curves between the groups (p = 0.500). CONCLUSION: Both DES and BMS are feasible, safe, and effective for symptomatic VAS. However, DES can significantly decrease the TVR rate in the long term compared with BMS. PMID- 22545890 TI - The use of vascular closure devices outside the catheterization laboratory after neurointerventional procedures is safe and effective: evidence from a retrospective study. AB - PURPOSE: To investigate the feasibility and safety of vascular closure device (VCD) deployment outside the catheterization laboratory. METHODS: Medical records were reviewed of all 799 patients (396 men; mean age 56 +/- 16 years) who underwent deployment of 918 VCDs following diagnostic or therapeutic neurointerventional procedures over a 2-year period at 2 comprehensive stroke centers. The rates of major vascular complications in patients undergoing VCD deployment in and outside the catheterization laboratory were compared. Major vascular complications were adjudicated using definitions by the Society of Interventional Radiology; comparisons were made between different procedure types and closure devices. RESULTS: During the observation period, 103 (11.2%) of 918 VCD deployments were performed outside the catheterization laboratory. Age, gender, procedure type, and device types were not different between the groups. A total of 10 (1.1%) major vascular complications occurred, including dissection requiring angioplasty (n = 1), hematoma requiring blood transfusion (n = 4), pseudoaneurysm requiring thrombin injection (n = 2), and lower limb ischemia necessitating surgical removal of the VCD (n = 3). Rates of major vascular complications were not significantly different between VCDs deployed inside the catheterization laboratory [1.0% (8/815)] compared to outside [1.9% (2/103), p = 0.3]. CONCLUSION: VCD deployment outside the catheterization laboratory does not increase the rate of major vascular complications and may be an alternative approach for femoral artery hemostasis when VCD deployment needs to be deferred. PMID- 22545891 TI - Commentary: using vascular closure devices outside the operating room: no reason for homesickness! PMID- 22545892 TI - A comparative analysis of bench-top performance assessment of distal protection filters in transient flow conditions. AB - PURPOSE: To compare the performance in vitro of 6 distal protection filters (DPFs) on the basis of filtration ability and effects on pressure gradient and vascular impedance in a flow model of the internal carotid artery (ICA). METHODS: Six DPFs (Accunet, Angioguard, FilterWire, Gore Embolic Filter, NAV6, and SpiderFX) were evaluated in a physiologically realistic flow loop. A blood analog was heated to body temperature and circulated by a pulsatile pump outputting a time-varying flow rate representative of the ICA. The ICA flow model was a highly curved tube representing a challenging site for filter deployment. The DPFs were deployed at the apex of the curved segment, and 2 sizes of microspheres (143 and 200 um) were injected to simulate embolization. The capture efficiency, pressure gradient, normalized pressure gradient, and vascular impedance were calculated. RESULTS: The Gore filter had high capture efficiency (143 um: 99.97%; 200 um: 100.00%) with relatively small increases in pressure gradient (143 um: +27%; 200 um: +20%) and vascular impedance (143 um: +23.4%; 200 um: +6.1%) after particles were injected. Spider had the lowest capture efficiency (143 um: 1.50%; 200 um: 19.34%, p<0.0005), while NAV6 (143 um: +916%, p<0.0005) and Accunet (200 um: +179%, p<0.0005) yielded the largest pressure gradient increases. CONCLUSION: A bench-top flow apparatus exhibiting physiologically realistic conditions was developed by combining pulsatile flow and a body temperature blood analog. Using microspheres larger than the pore size of most of the DPFs, the device-wall apposition has an important effect on the overall filter performance and the global fluid dynamics in the flow model. PMID- 22545893 TI - Commentary: Experimental, ex vivo, and bench testing to evaluate embolic/distal protection devices: useful or wasteful? PMID- 22545894 TI - Paclitaxel-coated balloon angioplasty vs. plain balloon dilation for the treatment of failing dialysis access: 6-month interim results from a prospective randomized controlled trial. AB - PURPOSE: To report the 6-month results of a prospective randomized trial investigating angioplasty with paclitaxel-coated balloons (PCB) vs. plain balloon angioplasty (BA) for the treatment of failing native arteriovenous fistulae (AVF) or prosthetic arteriovenous grafts (AVG). METHODS: The enrollment criteria for this non-inferiority hypothesis trial included clinical signs of failing dialysis access with angiographic documentation of a significant venous stenotic lesion in patients with AVF or AVG circuits. From March to December 2010, 40 patients (29 men; mean age 64.1 +/- 14.3 years) were randomized to undergo either PCB dilation (n = 20) or standard BA (n = 20) of a stenosed venous outflow lesion. Regular angiographic follow-up was scheduled bimonthly. Study outcome measures included device success (<30% residual stenosis without postdilation), procedural success (<30% residual stenosis), and primary patency of the treated lesion (<50% angiographic restenosis and no need for any interim repeat procedures). RESULTS: Baseline and procedural variables were comparably distributed between both groups. Device success was 9/20 (45%) for the PCB device vs. 20/20 (100%) for standard control BA (p<0.001). Procedural success was 100% in both groups after further high-pressure post-dilation as necessary. There were no major or minor complications in either group. At 6 months, cumulative target lesion primary patency was significantly higher after PCB application (70% in PCB group vs. 25% in BA group, p<0.001; HR 0.30, 95% CI 0.12 to 0.71, p<0.006). CONCLUSION: PCB angioplasty improves patency after angioplasty of venous stenoses of failing vascular access used for dialysis. PMID- 22545895 TI - Thrombus Obliteration by Rapid Percutaneous Endovenous Intervention in Deep Venous Occlusion (TORPEDO) trial: midterm results. AB - PURPOSE: To present midterm results from a randomized study comparing the safety and efficacy of percutaneous endovenous intervention (PEVI) + anticoagulation vs. anticoagulation alone in the reduction of venous thromboembolism (VTE) and post thrombotic syndrome (PTS) in acute symptomatic proximal deep venous thrombosis (DVT). METHODS: The TORPEDO trial was a randomized study to demonstrate superiority of PEVI in the reduction of the VTE and PTS at 6 months; in that trial, 183 patients (103 men; mean age 61 +/- 11 years) with symptomatic proximal DVT were randomized to receive PEVI + anticoagulation (n = 91) or anticoagulation alone (n = 92). PEVI consisted of one or more of a combination of thrombectomy, balloon venoplasty, stenting, and/or local low-dose thrombolytic therapy. RESULTS: At 6 months, recurrent VTE developed in 2.3% of the PEVI + anticoagulation group vs. 14.8% in the anticoagulation only group (p = 0.003); PTS developed in 3.4% vs. 27.2% (p<0.001), respectively. At a mean follow-up of 30 +/- 5 months (range 12-41), 88 patients in the PEVI + anticoagulation group and 81 patients in the anticoagulation only group reached target follow-up. Recurrent VTE developed in 4 (4.5%) of the 88 PEVI + anticoagulation patients vs. 13 (16%) of the 81 patients receiving anticoagulation only (p = 0.02). PTS developed in 6 (6.8%) of the PEVI + anticoagulation group vs. 24 (29.6%) of the anticoagulation only group (p<0.001). CONCLUSION: In patients with proximal DVT, PEVI is superior to anticoagulation alone in the reduction of VTE and PTS. This benefit, which appears early in the course of treatment, extends to >2.5 years. PMID- 22545896 TI - Historical overview of venous valve prostheses for the treatment of deep venous valve insufficiency. AB - Almost 3% of people in the Western world will suffer from a venous disease at some time in their lives, but as yet there are very few effective treatments for the venous system. When the valves become incompetent, they allow backflow and subsequent pooling of blood in the lower extremities. Current clinical therapies for the elimination of deep reflux are very invasive and provide short-lasting results. Thus, there is an urgent need for technological evolution of implantable valves and, if possible, with minimally invasive techniques. This review provides a basic history of the discovery of deep vein valves and various designs of prosthetic vein valves that have been evaluated in animal models and clinical studies. PMID- 22545897 TI - Percutaneous venous valve designs for treatment of deep venous insufficiency. AB - At present, no widely accepted surgical options exist for treating chronic deep venous insufficiency (CDVI). Experimental efforts to improve catheter-based management for CDVI have shown disappointing results, hindering application of these techniques in the clinical arena. A review of the literature focusing on technical aspects of valve stent design was conducted. Eight experimental studies were scrutinized to derive data on (1) stent design and configuration; (2) valve design, composition, and configuration; (3) delivery system; (4) functional outcome; and (5) histology to provide a basis for the design of a new prosthetic venous valve. The analysis of available experimental data found that all prosthetic valve designs currently under development/testing rely on some type of a stent to act as a carrier or frame for valve attachment. Most valve models reviewed were for the most part implanted safely and accurately, with good short term patency and competency. The most commonly reported adverse event was thrombosis, which limited durability. It is assumed that valve configuration determines long-term results after repair. Hence, the newly proposed valve design consisted of 2 stent rings without barbs to fix the valve in the host vein. Because a little reflux might actually benefit the patency of the valve, the valve cusp in the new design forms a billowing "sail" that does not completely open or close, which also prevents the valve cusp from sticking to the wall. This technology remains of great interest to the interventionist and all physicians who are involved in the care for patients with advanced chronic venous disease. Valve design remains a challenge, but promising new valve substitutes such as the one outlined here are under evaluation. PMID- 22545899 TI - Pendant polymer:amino-beta-cyclodextrin:siRNA guest:host nanoparticles as efficient vectors for gene silencing. AB - A novel siRNA delivery vector has been developed, based on the self-assembly of monosubstituted cationic beta-CD derivatives with a poly(vinyl alcohol)MW27kD (PVA) main-chain polymer bearing poly(ethylene glycol)MW2000 (PEG) and acid labile cholesterol-modified (Chol) grafts through an acid-sensitive benzylidene acetal linkage. These components were investigated for their ability to form nanoparticles with siRNA using two different assembly schemes, involving either precomplexation of the pendant Chol-PVA-PEG polymer with the cationic beta-CD derivatives before siRNA condensation or siRNA condensation with the cationic beta-CD derivatives prior to addition of Chol-PVA-PEG to engage host:guest complexation. The pendant polymer:amino-beta-CD:siRNA complexes were shown to form nanoparticles in the size range of 120-170 nm, with a slightly negative zeta potential. Cell viability studies in CHO-GFP cells shows that these materials have 10(3)-fold lower cytotoxicities than 25 kD bPEI, while maintaining gene silencing efficiencies that are comparable to those of benchmark transfection reagents such as bPEI and Lipofectamine 2000. These results suggest that the degradable Chol-PVA-PEG polymer is able to self-assemble in the presence of siRNA and cationic-beta-CD to form nanoparticles that are an effective and low-toxicity vehicle for delivering siRNA cargo to target cells. PMID- 22545900 TI - Analysis of microRNA-induced silencing complex-involved microRNA-target recognition by single-molecule fluorescence resonance energy transfer. AB - MicroRNAs (miRNAs) are important regulators of gene expression that control almost every physiological and pathological process. Although the complementarity between the seed region of a miRNA and its target mRNA is usually deemed as the key determinant in the miRNA-target recognition in animals, the mechanism of their recognition still remains enigmatic as more and more exceptions challenge the seed rule. Herein, we employ single-molecule fluorescence resonance energy transfer (smFRET) to investigate human miRNA-induced silencing complex (miRISC) involved miRNA-target recognition with either perfect base pairing or poor seed match in real time. Our results demonstrate that the recognition between mammalian miRNA and its target with perfect base pairing proceeds in a two-state model as prokaryotic guide DNA-mediated recognition, suggesting a conserved pattern of guide RNA/DNA strand recognition. In addition to the general rule of miRNA-target recognition, our results reveal that annealing between miRNA and its target with poor seed match proceeds in a stepwise way, which is in accordance with the increase in the number of conformational states of miRNA-target duplex accommodated by the miRISC, suggesting the structural plasticity of human miRISC to conciliate the mismatches in seed region. This new dynamic information revealed by smFRET has an important implication for comprehensive understanding of the role of miRISC in the target recognition in mammals. PMID- 22545902 TI - Supporting adolescents in a rapidly urbanising China. AB - China is a country experiencing urgent and rapid urbanisation as it integrates Western ways of knowing and being. These rapid changes pose particular challenges for adolescents negotiating constructs of identity between worldviews. This paper will present a report on observations made on a recent scoping visit by two nurse academics to three Chinese cities. An ecological framework will be used to discuss and critique emerging health issues for adolescents. These were identified as 'early love', 'internet use and abuse', 'physical violence' and 'stealing'. Community health nurses are challenged to make sense of these issues and how best to support adolescents, their families and communities. Contexts of care for community health nurses are also problematic as adolescent education takes priority as a driver for economic growth. Accordingly, this paper will also explore enablers and barriers for this group of community health nurses. PMID- 22545901 TI - Rhesus monkeys (Macaca mulatta) and capuchin monkeys (Cebus apella) remember future responses in a computerized task. AB - Planning is an important aspect of many daily activities for humans. Planning involves forming a strategy in anticipation of a future need. However, evidence that nonhuman animals can plan for future situations is limited, particularly in relation to the many other kinds of cognitive capacities that they appear to share with humans. One critical aspect of planning is the ability to remember future responses, or what is called prospective coding. Two monkey species (Macaca mulatta and Cebus apella) performed a series of computerized tasks that required encoding a future response at the outset of each trial. Monkeys of both species showed competence in all tests that were given, providing evidence that they anticipated future responses and that they appropriately engaged in those responses when the time was right for such responses. In addition, some tests demonstrated that monkeys even remembered future responses that were not as presently motivating as were other aspects of the task environment. These results indicated that monkeys could anticipate future responses and retain and implement those responses when appropriate. PMID- 22545903 TI - An emic view of caring for self: grandmothers who care for children of mothers with substance use disorders. AB - In the US more than 3.4 million children live with a mother who has a substance abuse disorder (SUD) and at some time in their life will be cared for by a grandmother. Most studies have focused on the economic, physical and emotional burdens of the conflated role of mother/grandmother. This study explores how 11 grandmothers cared for themselves while caring for the children of mothers with SUDs. The domain of inquiry was the self-care practices of grandmothers from an emic (generic) view. An assumption of the study was that the grandmothers represent a unique sub culture of women with particular beliefs, values and practices. An ethnographic approach was used to collect data from observations, in-depth interviews, and participant observation in various community settings. Patterns and themes revealed relational aspects of caring for self focused on the emic beliefs of self-care. The themes of being obligated and dedicated; distancing oneself as a reasoned action; and accepting the magnitude of the problem clearly identified the ability of grandmothers to take actions and make decisions about how to care for themselves. Leininger's three modes of care are represented in a schema of the emic view of caring for self. The schema is an illustration of the dynamic capacity of grandmothers to know and meet their own self-care demands and needs in order to care for their grandchildren. The need for increased awareness to change public policy and legislation related to the complex issues of caregiving by grandparents is addressed. PMID- 22545904 TI - Social support for mothers in illness: a multifaceted phenomenon. AB - BACKGROUND: Many women privilege the mothering role over other areas of their lives, and for ill women, it can be difficult to relinquish maternal responsibility. Not being able to mother in their usual way can have consequences for women's wellbeing and view of themselves as 'good' mothers. METHOD: In this study, 77 mothers of dependent children were interviewed about their experiences of illness, and the social support they received. RESULTS: Despite their illnesses, participants in this study continued to feel they were primarily responsible for the wellbeing and care of their children, and were distressed if they were unable to adequately fulfil the primary carer role. As participants sometimes found it difficult to care for their children, help with childcare emerged as an important element of social support. Seeking assistance with care for children revealed a tension between support that was accessible and support that was acceptable. CONCLUSION: Mothering while ill is difficult and women facing illness may need encouragement to accept help to continue to meet their maternal responsibilities. Nurses are in an excellent position to encourage women to identify and draw upon sources of support to assist them in maintaining their mothering role while ill. PMID- 22545905 TI - Parents' perceptions of care-giving to a child with attention deficit hyperactivity disorder: an exploratory study. AB - Attention deficit hyperactivity disorder (ADHD) is the most common neurobehavioral childhood disorder in which parental care-giving is found very stressful. Limited qualitative research is found on their care-giving experiences. This study aimed to explore Chinese parents' experiences of care giving to a child with ADHD at home. It was conducted at one Child and Adolescent Mental Health Unit in Hong Kong using qualitative exploratory approach. A purposive sample of 12 parents was recruited. Semi-structured interviews were conducted, each lasting about one hour. Content analysis was used to analyze the data. From the interview data, four themes were identified, including: concept of the illness, barriers to child care in ADHD, psychological effects in care giving, and positive aspects of care-giving. The parents indicated a variety of life problems and health concerns in care-giving. The findings may help nurses understand the perceptions and barriers towards parental care of a child with ADHD in a Chinese population and consider parents' educational needs in care giving. PMID- 22545906 TI - Critical moments in preschool obesity: the call for nurses and communities to assess and intervene. AB - Thirty years ago obesity was rarely seen in children but is now described as a world wide pandemic. Previous research has focused on school age children; however, researchers have now identified critical moments of development during uterine life and early infancy where negative factors or insults could cause permanent changes in the structure and function of tissues and lead to epigenetic changes. Obesity in preschool children can cause premature and long term chronic health problems; has been associated with academic and social difficulties in kindergarten children; difficulty with social relationships; increased feelings of sadness, loneliness and anxiety; and negative self image in children as young as 5 years of age. The importance of identifying children under the age of five with obesity and associated risks is important yet less than half of health professionals intervene in cases of preschool obesity. This paper explores the concerns around antenatal and preschool obesity and the challenges for nurses and midwives in assessing and providing appropriate interventions for children and families in community settings. PMID- 22545907 TI - Community-based child health nurses: an exploration of current practice. AB - The purpose of this research was to define, the practice domain of community based child health nursing in light of widespread political, economic and social changes in Western Australia. The project was conducted by a group of nurse researchers with experience in child health nursing from the School of Nursing and Midwifery at Curtin University and the Child and Adolescent Community Health Division at the Department of Health, Western Australia. The overall aim of the project was to map the scope of nursing practice in the community child health setting in Western Australia and to identify the decision making framework that underpins this nursing specialty. Given the widespread social, economic and health service management changes, it was important for nurses involved with, or contemplating a career in, community-based child health to have the role accurately defined. In addition, consumer expectations of the service needed to be explored within the current climate. A descriptive qualitative study was used for this project. A purposive sample of 60 participants was drawn from the pool of child health nurses in the South Metropolitan Community Health Service, North Metropolitan Health Service and Western Australian Country Health Service. Following ethical approval data was collected via participants keeping a 2-week work diary. The data was coded and thematic analysis was applied. Several themes emerged from the analysis which were validated by follow up focus group interviews with participants. This clearly demonstrated common, recurring issues. The results identified that the community-based child health nurses are currently undertaking a more complex and expanded child health service role for an increasingly diverse client population, over their traditional practices which are still maintained. Excessive workloads and lack of human and non human resources also presented challenges. There are increasing requirements for child health nurses to engage in community development and capacity building, often through a multidisciplinary partnership, which requires them to have sound brokerage and facilitation skills to enable community inclusion and inter-agency collaboration at the local level. The study has highlighted the importance and multifaceted nature of the role of the community-based child health nurse. To enable them to function optimally, the following suggestions/recommendations are offered. These being: More physical resources be allocated to community-based child health nursing More resources allocated to assist community-based child health nurses to support culturally and linguistically diverse families Mapping of child health nurses' workloads The development of community health client dependency rating criteria reflecting the social determinants of health in order for health service refinement of staffing allocations based on an acuity scale Specific staff development opportunities to reflect the increased workload complexity Managerial support for the implementation of formal clinical (reflective) supervision Additional clerical assistance with non-nursing duties. PMID- 22545908 TI - Adding value to stretched communities through nursing actions: the Wellington South Nursing Initiative. AB - Nurses provide health services to many groups with unmet health needs. Communities with consistently unmet needs are generally 'stretched' as they are under pressure. For children and families this pressure impacts their ability to live healthy lifestyles. The Wellington South Nursing Initiative involves two nurses providing an innovative population-based nursing service to stretched urban communities, particularly children and families, predominantly through networking and project work. Projects are specifically focused activities developed and implemented to address areas of health need. The projects cluster around five overarching areas: enhancing individual and community potential, growing safer families and communities, minimising negative harmful or risky behaviour, maximising general health and wellbeing and addressing specific health needs. Critical elements of the nurses' practice are the use of public health principles combined with a community development approach, relational practice and working for sustainability. The initiative provides important insights into how nurses can enter and work with communities and enhance the potential of children, families and the wider community. PMID- 22545909 TI - Commonalities and challenges: a review of Australian state and territory maternity and child health policies. AB - Nurses and midwives play a key role in providing universal maternal, child and family health services in Australia. However, the Australian federation of states and territories has resulted in policy frameworks that differ across jurisdictions and services that are fragmented across disciplines and sectors. This paper reports the findings of a study that reviewed and synthesised current Australian service policy or frameworks for maternity and child health services in order to identify the degree of commonality across jurisdictions and the compatibility with international research on child development. Key maternity and child health service policy documents in each jurisdiction were sourced. The findings indicate that current policies were in line with international research and policy directions, emphasising prevention and early intervention, continuity of care, collaboration and integrated services. The congruence of policies suggests the time is right to consider the introduction of a national approach to universal maternal, child health services. PMID- 22545910 TI - Information and communication technology (ICT) use in child and family nursing: what do we know and where to now? AB - Whilst the use of information and communication technology (ICT) in acute care services has been well documented, less is known about the impact of computerising community-based primary care such as child and family health nursing services. This self-complete survey of 606 nurses working in the Victorian Maternal and Child Health (MCH) service (response rate 60%) found that the predominantly older workforce were confident with the use of ICT. This contrasts with findings from the acute sector where older nurses had lower ICT confidence. The survey revealed a variation in ICT support and a lack of data collection system compatibility. Professional education resources were not able to be effectively used in all locally supplied computers. Although MCH nurses have adapted well to computerisation, there is room for improvement. Appropriate resourcing, education and infrastructure support are areas that need to be addressed and would benefit from an overarching body responsible for development and quality assurance. PMID- 22545911 TI - Surviving the adversity of childlessness: fostering resilience in couples. AB - In contemporary Western society, infertility has the capacity to impact greatly on couples, emotionally and socially. In the face of such infertility, couples are able to seek assisted reproductive technologies to assist in the pursuit of biological parenthood. These technologies are not infallible though, and the likelihood of success remains small. Therefore it is inevitable that some couples will remain childless, and this has been associated with grief and adversity. Findings present the narratives of participant couples' through and beyond the many adversities encountered due to remaining childless despite infertility treatment. Regardless of theories that seek to pathologise couples experiencing this type of adversity, participant couples demonstrated resilience in redirecting their energies into areas of their lives where they could achieve positive outcomes. This research highlights the importance of caring for couples rather than individuals undergoing infertility treatment. It provides support for approaches that foster couples' relationships with the aim of promoting individuals' resilience. PMID- 22545913 TI - Exploring the molecular linkage of protein stability traits for enzyme optimization by iterative truncation and evolution. AB - The stability of proteins is paramount for their therapeutic and industrial use and, thus, is a major task for protein engineering. Several types of chemical and physical stabilities are desired, and discussion revolves around whether each stability trait needs to be addressed separately and how specific and compatible stabilizing mutations act. We demonstrate a stepwise perturbation-compensation strategy, which identifies mutations rescuing the activity of a truncated TEM beta-lactamase. Analyses relating structural stress with the external stresses of heat, denaturants, and proteases reveal our second-site suppressors as general stability centers that also improve the full-length enzyme. A library of lactamase variants truncated by 15 N-terminal and three C-terminal residues (Bla NDelta15CDelta3) was subjected to activity selection and DNA shuffling. The resulting clone with the best in vivo performance harbored eight mutations, surpassed the full-length wild-type protein by 5.3 degrees C in T(m), displayed significantly higher catalytic activity at elevated temperatures, and showed delayed guanidine-induced denaturation. The crystal structure of this mutant was determined and provided insights into its stability determinants. Stepwise reconstitution of the N- and C-termini increased its thermal, denaturant, and proteolytic resistance successively, leading to a full-length enzyme with a T(m) increased by 15.3 degrees C and a half-denaturation concentration shifted from 0.53 to 1.75 M guanidinium relative to that of the wild type. These improvements demonstrate that iterative truncation-optimization cycles can exploit stability trait linkages in proteins and are exceptionally suited for the creation of progressively stabilized variants and/or downsized proteins without the need for detailed structural or mechanistic information. PMID- 22545912 TI - Association of genetic, psychological and behavioral factors with sleep bruxism in a Japanese population. AB - Sleep bruxism is a sleep-related movement disorder that can be responsible for various pains and dysfunctions in the orofacial region. The aim of the current case-control association study was to investigate the association of genetic, psychological and behavioral factors with sleep bruxism in a Japanese population. Non-related participants were recruited and divided into either a sleep bruxism group (n = 66) or control group (n = 48) by clinical diagnoses and 3-night masseter electromyographic recordings by means of a portable miniature device. The Epworth Sleepiness Scale, Temperament and Character Inventory, NEO-Five Factor Inventory and custom-made questionnaires that asked about familial aggregation, alcohol intake, caffeine intake, cigarette smoking, past stressful life events, daytime tooth-contacting habit, temporomandibular disorder, daily headache, snoring, apnea/hypopnea symptoms, leg-restlessness symptoms and nocturnal-myoclonus symptoms were administered. In addition, 13 polymorphisms in four genes related to serotonergic neurotransmission (SLC6A4, HTR1A, HTR2A and HTR2C) were genotyped. These factors were compared between case (sleep bruxism) and control groups in order to select potential predictors of sleep-bruxism status. The statistical procedure selected five predictors: Epworth Sleepiness Scale, leg-restlessness symptoms, rs6313 genotypes, rs2770304 genotypes and rs4941573 genotypes. A multivariate stepwise logistic regression analysis between the selected predictors and sleep-bruxism status was then conducted. This analysis revealed that only the C allele carrier of HTR2A single nucleotide polymorphism rs6313 (102C>T) was associated significantly with an increased risk of sleep bruxism (odds ratio = 4.250, 95% confidence interval: 1.599-11.297, P = 0.004).This finding suggests a possible genetic contribution to the etiology of sleep bruxism. PMID- 22545914 TI - A 12-month evaluation of health-related quality of life outcomes of methadone maintenance program in a rural Malaysian sample. AB - This paper focuses on the evaluation of addiction program effectiveness which involves changes in health-related quality of life (HRQoL) profile. This study was conducted from 2007 until 2010 at a rural methadone maintenance treatment center in Malaysia to assess HRQoL outcomes before and after treatment. Fifty seven respondents completed the WHOQOL-BREF at baseline, 6 months, and 12 months postintervention. Data were analyzed using nonparametric techniques (SPSS 15). Significant and positive HRQoL impacts were demonstrated. Future studies with larger sample are encouraged. This study was supported by the Ministry of Health Malaysia. PMID- 22545915 TI - When and how to perform surveillance imaging in patients with lymphoma, and is it worth it? PMID- 22545916 TI - Hybrid multiferroic nanostructure with magnetic-dielectric coupling. AB - The development of methods to economically synthesize single wire structured multiferroic systems with room temperature spin-charge coupling is expected to be important for building next-generation multifunctional devices with ultralow power consumption. We demonstrate the fabrication of a single nanowire multiferroic system, a new geometry, exhibiting room temperature magnetodielectric coupling. A coaxial nanotube/nanowire heterostructure of barium titanate (BaTiO(3), BTO) and cobalt (Co) has been synthesized using a template assisted method. Room temperature ferromagnetism and ferroelectricity were exhibited by this coaxial system, indicating the coexistence of more than one ferroic interaction in this composite system. PMID- 22545917 TI - Effect of basic fibroblast growth factor (FGF-2) in combination with beta tricalcium phosphate on root coverage in dog. AB - OBJECTIVE: In root coverage treatment, periodontal regeneration in gingival recession-type defects is an important challenge for the periodontist. The aim of this study was to histometrically investigate the effect of combined use of basic fibroblast growth factor (FGF-2) and beta tricalcium phosphate (beta-TCP) on root coverage in dogs. MATERIALS AND METHODS: Sixteen adult beagle dogs were used. Buccal gingival recession defects were surgically created bilaterally in the maxillary canines. The defects in each animal were randomly assigned to: (1) an FGF-2 alone (control) group or (2) FGF-2/beta-TCP (experimental) group. At 2, 4 or 8 weeks following surgery, specimens were obtained and subjected to microscopic examination and histometric assessment. RESULTS: Inhibition of epithelial down-growth was observed in both groups. At week 2, in the newly formed connective tissue at the coronal portion, the FGF-2/beta-TCP group showed significantly greater numbers of proliferating cell nuclear antigen-positive cells than the FGF-2 group (55.8 +/- 4.8 vs 12.0 +/- 1.4, p < 0.01). In the FGF 2/beta-TCP group, new attachment was observed at 8 weeks and the extent of new bone and cementum formation was significantly greater in the FGF-2/beta-TCP group than that in the FGF-2 alone group. In both groups, the dentin surface beneath the new cementum presented minor irregularities, but no replacement resorption was observed. CONCLUSIONS: FGF-2 used in combination with beta-TCP enhances formation of new bone and cementum without significant root resorption in root coverage in this dog model. This combination warrants further investigation in periodontal regeneration in root coverage treatment. PMID- 22545918 TI - Dinuclear zinc catalyzed asymmetric spirannulation reaction: an umpolung strategy for formation of alpha-alkylated-alpha-hydroxyoxindoles. AB - A highly diastereo- and enantioselective formal [3 + 2] cycloaddition of alpha,beta-unsaturated esters and 3-hydroxyoxindoles catalyzed by a dinuclear zinc-ProPhenol complex is reported. The stereoselective Michael additions of 3 hydroxyoxindoles and the subsequent transesterifications afford spirocyclic delta lactones. PMID- 22545919 TI - Polymorphisms in the mitochondrial oxidative phosphorylation chain genes as prognostic markers for colorectal cancer. AB - BACKGROUND: Currently, the TNM classification of malignant tumours based on clinicopathological staging remains the standard for colorectal cancer (CRC) prognostication. Recently, we identified the mitochondrial oxidative phosphorylation chain as a consistently overrepresented category in the published gene expression profiling (GEP) studies on CRC prognosis. METHODS: We evaluated associations of putative regulatory single nucleotide polymorphisms (SNPs) in genes from the oxidative phosphorylation chain with survival and disease prognosis in 613 CRC patients from Northern Germany (PopGen cohort). RESULTS: Two SNPs in the 3' untranslated region of UQCRB (complex III), rs7836698 and rs10504961, were associated with overall survival (HR = 0.52, 95% CI 0.32-0.85 and HR = 0.64, 95% CI 0.42-0.99, for TT carriers). These associations were restricted to the group of patients with cancer located in the colon (HR = 0.42, 95% CI 0.22-0.82 and HR = 0.46, 95% CI 0.25-0.83). Multivariate analysis indicated that both markers might act as independent prognostic markers. Additionally, the TT carriers were ~2 times more likely to develop tumours in the colon than in the rectum. Two SNPs in COX6B1 (complex IV) were associated with lymph node metastasis in a dominant model (rs6510502, OR = 1.75, 95% CI 1.20 2.57; rs10420252, OR = 1.68, 95% CI 1.11-2.53); rs6510502 was associated also with distant metastasis (OR = 1.67, 95% CI 1.09-2.56 in a dominant model). CONCLUSIONS: This is the first report suggesting that markers in genes from the mitochondrial oxidative chain might be prognostic factors for CRC. Additional studies replicating the presented findings are needed. PMID- 22545920 TI - Does stage III chronic kidney disease always progress to end-stage renal disease? A ten-year follow-up study. AB - OBJECTIVE: Clinically, it may be appropriate to subdivide patients with stage 3 chronic kidney disease (CKD) into two subgroups, as they show different risks for kidney outcomes. This study evaluated the proportion of patients with stage 3 CKD who progressed to stage 4 or 5 CKD over 10 years and independent predictors of progression of renal dysfunction. It sought to validate whether stage 3 CKD patients should be subdivided. MATERIAL AND METHODS: This retrospective cohort study enrolled 347 stage 3 CKD patients between January 1997 and December 1999, who were followed up through June 2010. The baseline clinical characteristics and outcomes were compared in patients with stage 3A [45 =0.3). Convergent and discriminant validity was supported by the higher correlations to the arrhythmia-specific SCL compared to the generic SF-36. Concurrent validity was evaluated and there were sufficiently, but not extremely strong correlations found between the ASTA symptom scale and SCL. CONCLUSIONS: The nine items of the ASTA symptom scale were found to have good psychometric properties in patients with different forms of arrhythmias. Arrhythmia patients suffer from both frequent and disabling symptoms. The validated ASTA questionnaire can be an important contribution to PROs regarding symptom burden in arrhythmia patients. PMID- 22545928 TI - Lyin' eyes: ocular-motor measures of reading reveal deception. AB - Our goal was to evaluate an alternative to current methods for detecting deception in security screening contexts. We evaluated a new cognitive-based test of deception that measured participants' ocular-motor responses (pupil responses and reading behaviors) while they read and responded to statements on a computerized questionnaire. In Experiment 1, participants from a university community were randomly assigned to either a "guilty" group that committed one of two mock crimes or an "innocent" group that only learned about the crime. Participants then reported for testing, where they completed the computer administered questionnaire that addressed their possible involvement in the crimes. Experiment 2 also manipulated participants' incentive to pass the test and difficulty of statements on the test. In both experiments, guilty participants had increased pupil responses to statements answered deceptively; however, they spent less time fixating on, reading, and rereading those statements than statements answered truthfully. These ocular-motor measures were optimally weighted in a discrimination function that correctly classified 85% of participants as either guilty or innocent. Findings from Experiment 2 indicated that group discrimination was improved with greater incentives to pass the test and the use of statements with simple syntax. The present findings suggest that two cognitive processes are involved in deception-vigilance and strategy-and that these processes are reflected in different ocular-motor measures. The ocular motor test reported here represents a new approach to detecting deception that may fill an important need in security screening contexts. PMID- 22545929 TI - Recovering faces from memory: the distracting influence of external facial features. AB - Recognition memory for unfamiliar faces is facilitated when contextual cues (e.g., head pose, background environment, hair and clothing) are consistent between study and test. By contrast, inconsistencies in external features, especially hair, promote errors in unfamiliar face-matching tasks. For the construction of facial composites, as carried out by witnesses and victims of crime, the role of external features (hair, ears, and neck) is less clear, although research does suggest their involvement. Here, over three experiments, we investigate the impact of external features for recovering facial memories using a modern, recognition-based composite system, EvoFIT. Participant constructors inspected an unfamiliar target face and, one day later, repeatedly selected items from arrays of whole faces, with "breeding," to "evolve" a composite with EvoFIT; further participants (evaluators) named the resulting composites. In Experiment 1, the important internal-features (eyes, brows, nose, and mouth) were constructed more identifiably when the visual presence of external features was decreased by Gaussian blur during construction: higher blur yielded more identifiable internal-features. In Experiment 2, increasing the visible extent of external features (to match the target's) in the presented face arrays also improved internal-features quality, although less so than when external features were masked throughout construction. Experiment 3 demonstrated that masking external-features promoted substantially more identifiable images than using the previous method of blurring external-features. Overall, the research indicates that external features are a distractive rather than a beneficial cue for face construction; the results also provide a much better method to construct composites, one that should dramatically increase identification of offenders. PMID- 22545930 TI - Take the first heuristic, self-efficacy, and decision-making in sport. AB - Can taking the first (TTF) option in decision-making lead to the best decisions in sports contexts? And, is one's decision-making self-efficacy in that context linked to TTF decisions? The purpose of this study was to examine the role of the TTF heuristic and self-efficacy in decision-making on a simulated sports task. Undergraduate and graduate students (N = 72) participated in the study and performed 13 trials in each of two video-based basketball decision tasks. One task required participants to verbally generate options before making a final decision on what to do next, while the other task simply asked participants to make a decision regarding the next move as quickly as possible. Decision-making self-efficacy was assessed using a 10-item questionnaire comprising various aspects of decision-making in basketball. Participants also rated their confidence in the final decision. Results supported many of the tenets of the TTF heuristic, such that people used the heuristic on a majority of the trials (70%), earlier generated options were better than later ones, first options were meaningfully generated, and final options were meaningfully selected. Results did not support differences in dynamic inconsistency or decision confidence based on the number of options. Findings also supported the link between self-efficacy and the TTF heuristic. Participants with higher self-efficacy beliefs used TTF more frequently and generated fewer options than those with low self-efficacy. Thus, not only is TTF an important heuristic when making decisions in dynamic, time pressure situations, but self-efficacy plays an influential role in TTF. PMID- 22545931 TI - Inaugural meeting of the malaria policy advisory committee to the WHO: conclusions and recommendations. AB - The Malaria Policy Advisory Committee to the World Health Organization met for the first time from 31 January to 2 February 2012 in Geneva, Switzerland. This article provides a summary of the discussions, conclusions and recommendations from that meeting, as part of the newly launched Malaria Journal thematic series "WHO Malaria Policy Advisory Committee: Reports and Recommendations".Summaries are provided, referencing the relevant background documents, for the meeting sessions on global malaria control, drug resistance and containment, rapid diagnostic test procurement criteria, larviciding, classification of countries for elimination, estimating malaria cases and deaths, and seasonal malaria chemoprevention. Policy statements, position statements, and guidelines that will arise from the MPAC meeting conclusions and recommendations will be formally issued and disseminated to World Health Organization member states by the World Health Organization Global Malaria Programme. PMID- 22545932 TI - Consultation training of nurses for cardiovascular prevention - a randomized study of 2 years duration. AB - The aim of this study was to increase patients' adherence to the treatment of hypertension through the consultation training of nurses. Thirty-three nurses were included in the study. In the intervention group (IG), 19 nurses took part in a 3-day residential training course on the Stages of Change model, Motivational Interviewing and guidelines for cardiovascular prevention, and recruited 153 patients. Sixteen nurses in the control group (CG) recruited 59 patients. A decrease in systolic and diastolic blood pressure and total cholesterol was noticed in both groups over the 2 years. Heart rate (p = 0.027), body mass index (p = 0.019), weight (p = 0.0001), waist (p = 0.041), low-density lipoprotein-cholesterol (p = 0.0001), the waist-hip ratio (p = 0.024), and perceived stress (p = 0.001) decreased to any great extent only in the IG. After 2 years, 52.6% of the patients in the IG (p = 0.13) reached the target of <= 140/90 mmHg in blood pressure compared with 39.2% in the CG. For self-reported physical activity, there was a significant (p = 0.021) difference between the groups. The beneficial effects of the consultation training on patients' weight parameters, physical activity, perceived stress and the proportion of patients who achieved blood pressure control emphasize consultation training and the use of behavioural models in motivating patients to adhere to treatment. PMID- 22545933 TI - Family members' unique perspectives of the family: examining their scope, size, and relations to individual adjustment. AB - Using the McMaster Family Assessment Device (Epstein, Baldwin, & Bishop, 1983) and incorporating the perspectives of adolescent, mother, and father, this study examined each family member's "unique perspective" or nonshared, idiosyncratic view of the family. We used a modified multitrait-multimethod confirmatory factor analysis that (a) isolated for each family member's 6 reports of family dysfunction the nonshared variance (a combination of variance idiosyncratic to the individual and measurement error) from variance shared by 1 or more family members and (b) extracted common variance across each family member's set of nonshared variances. The sample included 128 families from a U.S. East Coast metropolitan area. Each family member's unique perspective generalized across his or her different reports of family dysfunction and accounted for a sizable proportion of his or her own variance in reports of family dysfunction. In addition, after holding level of dysfunction constant across families and controlling for a family's shared variance (agreement regarding family dysfunction), each family member's unique perspective was associated with his or her own adjustment. Future applications and competing alternatives for what these "unique perspectives" reflect about the family are discussed. PMID- 22545934 TI - Examining the validity of the family investment and stress models and relationship to children's school readiness across five cultural groups. AB - Using the Early Childhood Longitudinal Study, Birth Cohort (ECLS-B) dataset, this study examined whether the family investment and the family stress models generalized to non-European American (EA) families. Specifically, we examined whether parenting processes mediated the association between family demographics and children's school readiness, and whether the pathways vary across cultural groups. Both models were most salient for EAs followed by African Americans (AAs) and Spanish-speaking Hispanics, but less so for English-speaking Hispanics (EHs) and Asian Americans. Findings indicated that sensitive parenting was a salient mediator between family demographics and children's school readiness for all groups except EHs; negative parenting and parent-child activities were salient mediators for EAs only. PMID- 22545935 TI - The impact of the transition to cohabitation on relationship functioning: cross sectional and longitudinal findings. AB - Most Americans now live together before they marry but little is known about how the transition from dating to cohabiting affects relationships. In two studies, we compared dating and cohabiting relationships in terms of commitment and several indices of relationship quality. In Study 1, we used a nationally representative sample of 1,294 unmarried individuals in opposite sex relationships who completed surveys by mail. Findings showed that cohabiting relationships were characterized by more commitment, lower satisfaction, more negative communication, and more physical aggression than dating (noncohabiting) relationships; controlling for selection factors mitigated some of these differences. Study 2 used a subsample of the Study 1 sample to longitudinally examine how transitioning from dating to cohabiting changes a relationship on the same dimensions. Six waves of mailed surveys spanning 20 months were employed. Findings of Study 2 indicated that individuals experienced declines in most indices of relationship quality as well as in interpersonal commitment after cohabitation began, though the frequency of sex increased temporarily. Constraints to stay together substantially increased with cohabitation and over time. Implications of these findings for future research are discussed. PMID- 22545936 TI - Discrepancies between patients' and partners' perceptions of unsupportive behavior in chronic obstructive pulmonary disease. AB - The literature on chronic diseases indicates that partner support, as perceived by patients, contributes to well-being of patients in either a positive or a negative way. Previous studies indicated that patients' and partners' perceptions of unsupportive partner behavior are only moderately related. Our aim was (1) to investigate whether discrepancies between patients' and partners' perceptions of two types of unsupportive partner behavior-overprotection and protective buffering-were associated with the level of distress reported by patients with chronic obstructive pulmonary disease (COPD) and (2) to evaluate whether the direction of the differences between patients' and partners' perceptions was associated with distress (i.e., whether patient distress was associated with greater patient or greater partner reports of unsupportive partner behavior). A cross-sectional study was performed using the data of a sample of 68 COPD patients and their spouses. Distress was assessed using the Hopkins Symptom Checklist-25. Patients' and partners' perceptions of unsupportive partner behavior were assessed with a questionnaire measuring overprotection and protective buffering. Distress was independently associated with patients' perceptions of protective buffering and discrepancies in spouses' perceptions of overprotection. Regarding the direction of the discrepancy, we found that greater partner reports of overprotection as compared with patient reports were related to more distress in COPD patients. Our study showed that patients' distress was associated not only with patients' perceptions, but also with discrepancies between patients' and partners' perceptions of unsupportive partner behavior. PMID- 22545937 TI - The communication of emotion during conflict in married couples. AB - This study investigated emotion during interpersonal conflicts between mates. It addressed questions about how clearly couples express emotion (encoding), how accurately they recognize each other's emotion (decoding), and how well they distinguish between types of negative emotion. It was theorized that couples express and perceive both: (a) event-specific emotions, which are unique to particular people on particular occasions, and (b) contextual-couple emotions, which reflect the additive effect of emotions across different events and across both partners. Eighty-three married couples engaged in a series of two conflict conversations. Self-report ratings, observer ratings, and partner ratings were used to assess two types of negative emotion: hard emotion (e.g., angry or annoyed) and soft emotion (e.g., sad or hurt). Couples were reasonably accurate in encoding, decoding, and in distinguishing between types of emotion. Emotion expression was strongly associated with general levels of contextual-couple emotion summed across two conversations, whereas emotion perception was more closely tied to specific events. Hard emotion was readily perceived when it was overtly expressed, and soft emotion could sometimes be recognized even when it was not expressed clearly. PMID- 22545938 TI - Feasibility and reliability of physical fitness tests in older adults with intellectual disability: a pilot study. AB - BACKGROUND: Physical fitness is relevant for wellbeing and health, but knowledge on the feasibility and reliability of instruments to measure physical fitness for older adults with intellectual disability is lacking. METHODS: Feasibility and test-retest reliability of a physical fitness test battery (Box and Block Test, Response Time Test, walking speed, grip strength, 30-s chair stand, 10-m Incremental Shuttle Walking Test and the Extended Modified Back-Saver Sit-and Reach Test) were investigated in older adults with ID in a convenience sample of 36 older adults (mean 65.9, range 50-89 years), with differing levels of intellectual disability and mobility. RESULTS AND CONCLUSION: All tests to measure physical fitness in older adults with ID had moderate to excellent feasibility and had sufficient test-retest reliability (ICCs .63-.96). No statistically significant learning effects were found. PMID- 22545939 TI - Synthesis, activity evaluation, and docking analysis of barbituric acid aryl hydrazone derivatives as RSK2 inhibitors. AB - The 90 kDa ribosomal S6 kinases (RSKs), especially RSK2, have attracted attention for the development of new anticancer agents. Through structural optimization of the hit compound 1 from our previous study, a series of barbituric acid aryl hydrazone analogues were designed and synthesized as potential RSK2 inhibitors. The most potent one, compound 9, showed a higher activity against RSK2 with an IC50 value of 1.95 MUM. To analyze and elucidate their structure-activity relationship, the homology model of RSK2 N-terminal kinase domain was built and molecular docking simulations were performed, which provide helpful clues to design new inhibitors with desired activities. PMID- 22545940 TI - A comparison of the reactivating efficacy of a novel bispyridinium oxime K203 with currently available oximes in VX agent-poisoned rats. AB - The ability of a novel bispyridinium oxime K203 to reactivate VX agent-inhibited acetylcholinesterase was compared with the reactivating efficacy of four commonly used oximes (obidoxime, trimedoxime, methoxime, HI-6) using in vivo model. Our results showed that the reactivating efficacy of the oxime HI-6 is higher than the reactivating efficacy of the other oximes studied including the oxime K203 although the differrences between the oxime HI-6 and some other oximes are not significant, especially in the blood. Based on the obtained data, we can conclude that the antidotal treatment involving the oxime HI-6 brings the higher benefit for the antidotal treatment of acute poisonings with VX agent than other oximes. PMID- 22545941 TI - Design, synthesis and biological evaluation of novel L-isoserine tripeptide derivatives as aminopeptidase N inhibitors. AB - Aminopeptidase N (APN/CD13) is one of the essential proteins for tumour invasion, angiogenesis and metastasis as it is over-expressed on the surface of different tumour cells. Based on our previous work that L-isoserine dipeptide derivatives were potent APN inhibitors, we designed and synthesized L-isoserine tripeptide derivatives as APN inhibitors. Among these compounds, one compound 16l (IC50 = 2.51 +/- 0.2 uM) showed similar inhibitory effect compared with control compound Bestatin (IC50 = 6.25 +/- 0.4 uM) and it could be used as novel lead compound for the APN inhibitors development as anticancer agents in the future. PMID- 22545942 TI - Eco-friendly plasmonic sensors: using the photothermal effect to prepare metal nanoparticle-containing test papers for highly sensitive colorimetric detection. AB - Convenient, rapid, and accurate detection of chemical and biomolecules would be a great benefit to medical, pharmaceutical, and environmental sciences. Many chemical and biosensors based on metal nanoparticles (NPs) have been developed. However, as a result of the inconvenience and complexity of most of the current preparation techniques, surface plasmon-based test papers are not as common as, for example, litmus paper, which finds daily use. In this paper, we propose a convenient and practical technique, based on the photothermal effect, to fabricate the plasmonic test paper. This technique is superior to other reported methods for its rapid fabrication time (a few seconds), large-area throughput, selectivity in the positioning of the NPs, and the capability of preparing NP arrays in high density on various paper substrates. In addition to their low cost, portability, flexibility, and biodegradability, plasmonic test paper can be burned after detecting contagious biomolecules, making them safe and eco friendly. PMID- 22545943 TI - Early childhood development when second-trimester ultrasound dating disagrees with last menstrual period: a prospective cohort study. AB - BACKGROUND: When an ultrasound-based estimate of gestational age (GA) is less (greater) than an estimate based on a definite last menstrual period, the fetus may grow slower (faster) than average. While the association between these discrepancies in GA estimates and adverse perinatal outcomes has been examined extensively, there is scant evidence about long-term effects, such as child neurodevelopment. METHODS: Using data from a prospective cohort study titled, NICHD Study of Successive Small-for-Gestational Age Births, we examined if GA discrepancies in early second trimester of pregnancy (17 weeks' gestation) are associated with: (1) impaired motor and mental function at 13 months (measured using Bayley Scales of Infant Development (Bayley)), and (2) impaired cognitive development at five years (assessed by Wechsler Preschool and Primary Scale of Intelligence - Revised Intelligence Quotient (WPPSI-R)) in the infant. The study population consisted of 572 (30% of the overall sample of 1,945) women who presented for prenatal care in Norway and Sweden between 1986 and 1988. RESULTS: Our results showed that GA discrepancies in early second trimester are significantly associated with birthweight. We found no significant relationship, however, with the Bayley development scores at 13 months and with the WPPSI-R IQ measures at five years. CONCLUSIONS: GA discrepancies at 17 weeks' gestation are not associated child neurodevelopment. These discrepancies do, however, relate to birthweights, providing a basis for detecting fetal growth patterns early in the second trimester of pregnancy. Our study, however, was unable to evaluate the impact of first-trimester discrepancies on impaired neurodevelopment in the infant. PMID- 22545946 TI - Two-step asymmetric reaction using the frozen chirality generated by spontaneous crystallization. AB - N,N-diallyl-4-methyl-1-propyl-2-quinolone-3-carboxamide afforded chiral crystals of a P2(1) crystal system by spontaneous crystallization. The molecular chirality in the crystal was retained after the crystals were dissolved in a solvent at a low temperature, and the frozen molecular chirality was effectively transferred to the products by a two-step reaction involving hydrogenation and intermolecular photocycloaddition reactions. PMID- 22545945 TI - In vitro evaluation of calcium oxalate monohydrate crystals influenced by Costus igneus aqueous extract. AB - OBJECTIVE: Calcium oxalate monohydrate (COM) crystals are frequently found in urinary calculi (stones). MATERIAL AND METHODS: COM crystals were grown by the single diffusion gel growth technique and the inhibitory effects of aqueous extracts of leaves, stems and rhizome of Costus igneus on the growth of COM crystals were studied. RESULTS: With an increase in the concentration of aqueous extract of C. igneus, the weight of the formed crystals was gradually reduced from 2.15 to 0.07 g(leaves), 0.06 g (rhizome) and 0.03 g (stem). The crystals harvested from the COM were characterized by Fourier transform infrared spectroscopy to confirm the functional groups and powder X-ray diffraction analyses to confirm the crystalline phases of COM crystals. A scanning electron microscopy study confirmed that the morphology of the crystals changed from hexagonal (COM) to bipyramids of calcium oxalate dihydrate (COD). CONCLUSIONS: This study confirms that using aqueous extracts of stem and rhizome of C. igneus can promote the formation of COD crystals and reduce the nucleation rate of COM crystals, a major component of calcium urinary stones. PMID- 22545944 TI - Long-circulating 15 nm micelles based on amphiphilic 3-helix peptide-PEG conjugates. AB - Generating stable, multifunctional organic nanocarriers will have a significant impact on drug formulation. However, it remains a significant challenge to generate organic nanocarriers with a long circulation half-life, effective tumor penetration, and efficient clearance of metabolites. We have advanced this goal by designing a new family of amphiphiles based on coiled-coil 3-helix bundle forming peptide-poly(ethylene glycol) conjugates. The amphiphiles self-assemble into monodisperse micellar nanoparticles, 15 nm in diameter. Using the 3-helix micelles, a drug loading of ~8 wt % was obtained using doxorubicin and the micelles showed minimal cargo leakage after 12 h of incubation with serum proteins at 37 degrees C. In vivo pharmacokinetics studies using positron emission tomography showed a circulation half-life of 29.5 h and minimal accumulation in the liver and spleen. The demonstrated strategy, by incorporating unique protein tertiary structure in the headgroup of an amphiphile, opens new avenues to generate organic nanoparticles with tunable stability, ligand clustering, and controlled disassembly to meet current demands in nanomedicine. PMID- 22545947 TI - Sex differences in the spatial representation of number. AB - There is a large body of accumulated evidence from behavioral and neuroimaging studies regarding how and where in the brain we represent basic numerical information. A number of these studies have considered how numerical representations may differ between individuals according to their age or level of mathematical ability, but one issue rarely considered is whether the representational acuity or automaticity of using numerical representations differs between the sexes. We report 4 studies that suggest that male participants show a stronger influence of the spatial representation of number as revealed through the spatial numerical association of response codes (SNARC) effect, through the numerical distance effect (NDE), and through number-line estimations. Evidence for a sex difference in processing number was present for parity decisions (Experiment 1), color decisions (Experiment 2), number-line estimations (Experiment 3), and magnitude decisions (Experiment 4). We argue that this pattern of results reflects a sex difference in either the acuity of representation or reliance upon spatial representations of number, and that this difference may arise due to differences in the parietal lobes of men and women. PMID- 22545948 TI - Bacteriophage inactivation by UV-A illuminated fullerenes: role of nanoparticle virus association and biological targets. AB - Inactivation rates of the MS2 bacteriophage and (1)O(2) generation rates by four different photosensitized aqueous fullerene suspensions were in the same order: aqu-nC(60) < C(60)(OH)(6) ~ C(60)(OH)(24) < C(60)(NH(2))(6). Alterations to capsid protein secondary structures and protein oxidation were inferred by detecting changes in infrared vibrational frequencies and carbonyl groups respectively. MS2 inactivation appears to be the result of loss of capsid structural integrity (localized deformation) and the reduced ability to eject genomic RNA into its bacterial host. Evidence is also presented for possible capsid rupture in MS2 exposed to UV-A illuminated C(60)(NH(2))(6) through TEM imagery and detection of RNA infrared fingerprints in ATR-FTIR spectra. Fullerene virus mixtures were also directly visualized in the aqueous phase using a novel enhanced darkfield transmission optical microscope fitted with a hyperspectral imaging (HSI) spectrometer. Perturbations in intermolecular extended chains, HSI, and electrostatic interactions suggest that inactivation is a function of the relative proximity between nanoparticles and viruses and (1)O(2) generation rate. MS2 log survival ratios were linearly related to CT (product of (1)O(2) concentration C and exposure time T) demonstrating the applicability of classical Chick-Watson kinetics for all fullerenes employed in this study. Results suggest that antiviral properties of fullerenes can be increased by adjusting the type of surface functionalization and extent of cage derivatization thereby increasing the (1)O(2) generation rate and facilitating closer association with biological targets. PMID- 22545949 TI - Electronic level scheme in boron- and phosphorus-doped silicon nanowires. AB - We report the first observation of the electronic level scheme in boron (B)- and phosphorus (P)-doped nanowires (NWs). The NWs' morphology dramatically depends on the doping impurity while a few deep electronic levels appear in both kinds of nanowires, independently of the doping type. We demonstrate that the doping impurities induce the same shallow levels as in bulk silicon. The presence of two donor levels in the lower half-bandgap is also revealed. In both kinds of NWs, B- and P-doped, the donor level (0/+) at E(v) + 0.36 eV of the gold-hydrogen complex is observed. This means that the gold diffusion from the NW tip introduces an electronically active level, which might negatively affects the electrical characteristics of the NWs. In P-doped NWs, we observed a further donor level at 0.26 eV above the valence band due to the phosphorus-vacancy pairs, the E-center, well-known in bulk silicon. These findings seriously question both diffusion modeling of impurities in NWs and the technological aspects arising from this. PMID- 22545950 TI - Does treatment adherence correlates with health related quality of life? Findings from a cross sectional study. AB - BACKGROUND: Although medication adherence and health-related quality of life (HRQoL) are two different outcome measures, it is believed that adherence to medication leads to an improvement in overall HRQoL. The study aimed to evaluate the association between medication adherence and HRQoL. METHODS: A questionnaire based cross-sectional study design was undertaken with hypertension patients attending public hospitals in Quetta city, Pakistan. HRQoL was measured by Euroqol EQ-5D. Medication adherence was assessed by the Drug Attitude Inventory. Descriptive statistics was used to tabulate demographic and disease-related information. Spearmans correlation was used to assess the association between the study variables. All analysis was performed using SPSS 17.0. RESULTS: Among 385 study patients, the mean age (SD) was 39.02 (6.59), with 68.8% of males dominating the entire cohort. The mean (SD) duration of hypertension was 3.010.939years. Forty percent (n=154) had a bachelors degree level of education with 34.8% (n=134) working in the private sector. A negative and weak correlation (0.77) between medication adherence and EQ-5D was reported. In addition, a negative weak correlation (0.120) was observed among medication adherence and EQ VAS. CONCLUSIONS: Correlations among the study variables were negligible and negative. Hence, there is no apparent relationship between the variables. PMID- 22545951 TI - Absorption spectra and photochemical reactions in a unique photoactive protein, middle rhodopsin MR. AB - Photoactive proteins with cognate chromophores are widespread in organisms, and function as light-energy converters or receptors for light-signal transduction. Rhodopsins, which have retinal (vitamin A aldehyde) as their chromophore within their seven transmembrane alpha-helices, are classified into two groups, microbial (type-1) and animal (type-2) rhodopsins. In general, light absorption by type-1 or type-2 rhodopsins triggers a trans-cis or cis-trans isomerization of the retinal, respectively, initiating their photochemical reactions. Recently, we found a new microbial rhodopsin (middle rhodopsin, MR), binding three types of retinal isomers in its original state: all-trans, 13-cis, and 11-cis. Here, we identified the absolute absorption spectra of MR by a combination of high performance liquid chromatography (HPLC) and UV-vis spectroscopy under varying light conditions. The absorption maxima of MR with all-trans, 13-cis, or 11-cis retinal are located at 485, 479, and 495 nm, respectively. Their photocycles were analyzed by time-resolved laser spectroscopy using various laser wavelengths. In conclusion, we propose that the photocycles of MR are MR(trans) -> MR(K):lifetime = 93 MUs -> MR(M):lifetime = 12 ms -> MR, MR(13-cis) -> MR(O-like):lifetime = 5.1 ms -> MR, and MR(11-cis) -> MR(K-like):lifetime = 8.2 MUs -> MR, respectively. Thus, we demonstrate that a single photoactive protein drives three independent photochemical reactions. PMID- 22545952 TI - Psychometric properties of the disease-specific health-related quality of life instrument VascuQoL in a Swedish setting. AB - BACKGROUND: Traditional outcome measures in peripheral arterial disease (PAD) provide insufficient information regarding patient benefit. It has therefore been suggested to add patient-reported outcome measures. The main aim of this study was to validate the Swedish Vascular Quality of Life questionnaire (VascuQoL) version, a patient-reported PAD-specific health-related quality of life (HRQoL) instrument. METHODS: Two-hundred PAD patients were consecutively recruited from two university hospitals. Out of the 200 subjects, 129 had intermittent claudication and 71 had critical limb ischemia. Mean age was 70 +/- 9 y and 57% of the participants were male. All patients completed SF-36 and VascuQoL at the vascular outpatient clinic, when evaluated for invasive treatment. Risk factors and physiological parameters were registered. Construct validity was tested by correlation analysis versus SF-36 and was also assessed with multitrait/multi item scaling analysis (MTMI). Sensitivity analysis regarding disease severity identification was performed. Reliability was assessed with Cronbach's alpha and responsiveness by standardized response mean (SRM) calculations. RESULTS: Significant correlations were demonstrated between relevant subscales of VascuQoL and SF-36. MTMI showed acceptable construct validity, but some scaling-errors. VascuQoL significantly (p < 0.001) discriminated claudicants from critical limb ischemia patients. Cronbach's alpha was 0.94 and SRM 1.02 (sum score). CONCLUSIONS: The Swedish version of VascuQoL is valid and quantifies central aspects of HRQoL in PAD patients. Sensitivity analysis showed high ability to differentiate between disease severity and SRM illustrated excellent responsiveness. The relative abundance of items however makes use in the everyday clinical setting somewhat difficult. PMID- 22545953 TI - Chloroplastic Hsp100 chaperones ClpC2 and ClpD interact in vitro with a transit peptide only when it is located at the N-terminus of a protein. AB - BACKGROUND: Clp/Hsp100 chaperones are involved in protein quality control. They act as independent units or in conjunction with a proteolytic core to degrade irreversibly damaged proteins. Clp chaperones from plant chloroplasts have been also implicated in the process of precursor import, along with Hsp70 chaperones. They are thought to pull the precursors in as the transit peptides enter the organelle. How Clp chaperones identify their substrates and engage in their processing is not known. This information may lie in the position, sequence or structure of the Clp recognition motifs. RESULTS: We tested the influence of the position of the transit peptide on the interaction with two chloroplastic Clp chaperones, ClpC2 and ClpD from Arabidopsis thaliana (AtClpC2 and AtClpD). The transit peptide of ferredoxin-NADP+ reductase was fused to either the N- or C terminal end of glutathione S-transferase. Another fusion with the transit peptide interleaved between two folded proteins was used to probe if AtClpC2 and AtClpD could recognize tags located in the interior of a polypeptide. We also used a mutated transit peptide that is not targeted by Hsp70 chaperones (TP1234), yet it is imported at a normal rate. The fusions were immobilized on resins and the purified recombinant chaperones were added. After a washing protocol, the amount of bound chaperone was assessed. Both AtClpC2 and AtClpD interacted with the transit peptides when they were located at the N-terminal position of a protein, but not when they were allocated to the C-terminal end or at the interior of a polypeptide. CONCLUSIONS: AtClpC2 and AtClpD have a positional preference for interacting with a transit peptide. In particular, the localization of the signal sequence at the N-terminal end of a protein seems mandatory for interaction to take place. Our results have implications for the understanding of protein quality control and precursor import in chloroplasts. PMID- 22545954 TI - Stability of gametocyte-specific Pfs25-mRNA in dried blood spots on filter paper subjected to different storage conditions. AB - BACKGROUND: Real-time quantitative nucleic acid sequence-based amplification (QT NASBA) is a sensitive method for detection of sub-microscopic gametocytaemia by measuring gametocyte-specific mRNA. Performing analysis on fresh whole blood samples is often not feasible in remote and resource-poor areas. Convenient methods for sample storage and transport are urgently needed. METHODS: Real-time QT-NASBA was performed on whole blood spiked with a dilution series of purified in-vitro cultivated gametocytes. The blood was either freshly processed or spotted on filter papers. Gametocyte detection sensitivity for QT-NASBA was determined and controlled by microscopy. Dried blood spot (DBS) samples were subjected to five different storage conditions and the loss of sensitivity over time was investigated. A formula to approximate the loss of Pfs25-mRNA due to different storage conditions and time was developed. RESULTS: Pfs25-mRNA was measured in time to positivity (TTP) and correlated well with the microscopic counts and the theoretical concentrations of the dilution series. TTP results constantly indicated higher amounts of RNA in filter paper samples extracted after 24 hours than in immediately extracted fresh blood. Among investigated storage conditions freezing at -20 degrees C performed best with 98.7% of the Pfs25-mRNA still detectable at day 28 compared to fresh blood samples. After 92 days, the RNA detection rate was only slightly decreased to 92.9%. Samples stored at 37 degrees C showed most decay with only 64.5% of Pfs25-mRNA detectable after one month. The calculated theoretical detection limit for 24 h-old DBS filter paper samples was 0.0095 (95% CI: 0.0025 to 0.0380) per MUl. CONCLUSIONS: The results suggest that the application of DBS filter papers for quantification of Plasmodium falciparum gametocytes with real-time QT-NASBA is practical and recommendable. This method proved sensitive enough for detection of sub microscopic densities even after prolonged storage. Decay rates can be predicted for different storage conditions as well as durations. PMID- 22545955 TI - Fibrillin-1 genotype and risk of prevalent hypertension: a study in two independent populations. AB - OBJECTIVE: Mutations in the fibrillin-1 gene are the cause of Marfan syndrome. We wanted to investigate the relationship between a mutation in this gene and risk of prevalent hypertension. METHODS: In a cross-sectional study, the effect of a G A substitution in intron 27 in the fibrillin-1 gene (rs11856553) on risk of prevalent hypertension was studied in two large population-based studies: the Health 2006 study, consisting of 3193 women and men, age 18-69 years, and the MONICA10 study, consisting of 2408 women and men, age 41-72 years. In 1646 MONICA10 participants, blood pressure (BP) was also measured by 24-h ambulatory recordings. RESULTS: Among the 3193 Health 2006 participants 23 had the G-A variant, and among the 2408 MONICA10 participants 18 had the G-A variant. In Health 2006, the odds ratio estimate (95% confidence intervals) for the G-A variant for risk of hypertension, defined as systolic (S) BP >= 140 mmHg or diastolic (D) BP >= 90 mmHg or on antihypertensive medicine, was 2.67 (1.14 6.18), p = 0.022. The corresponding figure for moderate to severe hypertension, defined as SBP >= 160 mmHg or DBP >= 100 mmHg, was 9.68 (4.24-22.12), p < 0.0001. In MONICA10, the odds ratio estimate (95% confidence intervals) for the G-A variant for risk of moderate to severe ambulatory hypertension, defined as 24-h mean SBP >= 150 mmHg or 24-h mean DBP >= 90 mmHg, was 5.73 (1.96-16.7), p = 0.0014. CONCLUSION: The G-A substitution in the fibrillin-1 gene (rs11856553) is a rare genetic variant that is associated with an increased risk of prevalent hypertension, particularly of moderate to severe prevalent hypertension. PMID- 22545956 TI - Stabilizing catalytic pathways via redundancy: selective reduction of microalgae oil to alkanes. AB - A new route to convert crude microalgae oils using ZrO(2)-promoted Ni catalysts into diesel-range alkanes in a cascade reaction is presented. Ni nanoparticles catalyze the selective cleavage of the C-O of fatty acid esters, leading to the hydrogenolysis of triglycerides. Hydrogenation of the resulting fatty acids to aldehydes (rate-determining step) is uniquely catalyzed via two parallel pathways, one via aldehyde formation on metallic Ni and the second via a synergistic action by Ni and ZrO(2) through adsorbing the carboxylic groups at the oxygen vacancies of ZrO(2) to form carboxylates and subsequently abstracting the alpha-hydrogen atom to produce ketene, which is in turn hydrogenated to aldehydes and decarbonylated on Ni nanoparticles. PMID- 22545957 TI - Client factors as predictors of restraint and seclusion in people with intellectual disability. AB - BACKGROUND: To gain more insight into the antecedent factors of restraint in institutionalised people with intellectual disability (ID), the role played by several demographic and psychological client variables was investigated. METHODS: The data of 475 people (age range 12-95 years) who were residents in a Dutch institution for people with ID were collected. The severity of restraint was rated on an ordinal scale. RESULTS: None of the demographic variables height, weight, age, or length of stay were related to the application of restraint. Significant predictors were the psychological variables: low adaptive functioning, the presence of challenging behaviours, and a relatively high intellectual level. Of the challenging behaviours, specifically behaviours other than actual aggressiveness proved to be predictors of restraint. CONCLUSIONS: The fact that actual aggressiveness plays a minor role in predicting restraint is a new finding and should be further examined in future research. PMID- 22545958 TI - Detection and zoonotic potential of Trichinella spp. from free-range pig farming in Greece. AB - Trichinellosis is a serious parasitic zoonosis, which is widely distributed around the world. Pork meat is still the predominant source of outbreaks of human trichinellosis in many countries. The aim of this study is to examine the impact of Trichinella spp. as an important risk factor on the free-range pig farming sector in Greece. In 2009, during routine testing for the detection of Trichinella larvae at slaughterhouses and the National Reference Laboratory for Parasites (NRL), a total of 826,426 pigs were tested with the magnetic stirrer method for Trichinella spp. at slaughterhouses, including 2,892 samples from free range pigs. Two positive samples were detected: one positive for Trichinella britovi and one positive for Trichinella spp. (unspecified) in the samples from wild farmed free-range pigs. It is alarming that one of these cases was connected with clinical signs of trichinellosis in five persons of the same family in northeastern Greece, who consumed undercooked pork meat from a free-range pig farm. During 2010, a total number of 1,295,034 pigs were tested with same method, including 4,159 samples from free-range pig farms. Five positive samples for Trichinella spp. (unspecified) were detected from 4,159 free-range pigs tested by the Greek NRL. Moreover, 363 serum samples from free-range pigs were serologically tested with enzyme-linked immunosorbent assay (ELISA). Moreover, 363 serum samples from farmed free-range pigs were serologically tested with ELISA, and 15 samples were found positive. Finally, the present study is the first report of detection of T. britovi in Greece. In conclusion, based on the results of the present study, Trichinella spp. is a high-risk factor for the free range pig farming in Greece. PMID- 22545959 TI - Virulence profiling and disease association of verocytotoxin-producing Escherichia coli O157 and non-O157 isolates in Belgium. AB - Whereas the association of verocytotoxin-producing Escherichia coli (VTEC) O157:H7 with the hemolytic uremic syndrome (HUS) is well established, the medical importance of many non-O157 serotypes remains unclear. Using polymerase chain reaction (PCR), we have investigated the distribution of the pathogenicity island O island 122 (OI-122) and other virulence genes in VTEC belonging to seropathotypes (SPT) A through D, and assessed their association with human disease. Two hundred sixty-five VTEC isolated from human stools comprising 52 O157 (of which 14 associated with HUS) and 213 non-O157 isolates (of which 19 associated with HUS) were studied. A complete OI-122 (COI-122) was detected in all O157, but in only 35 (16.4%) of non-O157 strains. A progressive decrease in the frequency of COI-122 was observed from SPT A through D, with a concomitant increase in the frequencies of incomplete and absent OI-122. We focused on the variable virulence profiles of the non-O157 serotypes and found that COI-122 was also more frequently present in isolates associated with HUS (p=0.001). The individual genes vtx2, eae, espP, as well as the OI-122-associated genes sen, nleB, nleE, and the efa gene cluster were significantly more often present in non O157 VTEC associated with HUS. Non-O157 isolates carrying the combined virulence profile vtx2-nleE-efa showed the strongest association with HUS (p<0.0001). Molecular risk assessment by determination of virulence profiles of individual isolates may be useful in the identification of highly virulent non-O157 strains. We showed that the detection of a specific gene combination could assist in identifying non-O157 VTEC isolates that pose a serious public health concern. PMID- 22545960 TI - Incidence and antimicrobial resistance profiling of Campylobacter in retail chicken livers and gizzards. AB - Campylobacter species are one of the leading causes of foodborne disease in the United States. Campylobacter jejuni and Campylobacter coli are the two main species that are of concern to human health, and they cause approximately 95% of human infections. The number of studies investigating Campylobacter in chicken livers and gizzards is very limited in the literature. The objective of this study was to determine the prevalence of Campylobacter jejuni and Campylobacter coli in retail chicken livers and gizzards purchased from grocery stores in the Tulsa, Oklahoma, area and to further characterize the isolates obtained through antimicrobial susceptibility testing. A total of 202 retail chilled chicken livers and gizzards (159 livers and 43 gizzards) were purchased on a weekly basis from several grocery stores. The overall prevalence of Campylobacter in chicken livers and gizzards was 136/202 (67%), where 69/202 (34%) of the samples were contaminated with Campylobacter jejuni and 66/202 (33%) with Campylobacter coli. While the prevalence of Campylobacter in chicken livers was 77%, its prevalence in chicken gizzards was lower at 33%. The prevalence of Campylobacter jejuni was slightly higher in chicken livers (36%) than gizzards (26%), while the prevalence of Campylobacter coli was significantly higher in the chicken livers (40%) than chicken gizzards (7%). The prevalence of resistance among C. jejuni and C. coli isolates recovered against 16 antimicrobials were as follows: amoxicillin (98%, 99%), ampicillin (32%, 55%), azithromycin (10%, 25%), cephalothin (92%, 99%), chloramphenicol (4%, 12%), ciprofloxacin (58%, 48%), clindamycin (5%, 19%), doxycycline (39%, 66%), erythromycin (6%, 32%), gentamicin (9%, 43%), kanamycin (11%, 43%), nalidixic acid (50%, 43%), oxytetracycline (99%, 100%), streptomycin (3%, 18%), tetracycline (37%, 60%), and tilmicosin (9%, 16%). Multidrug resistance was higher among Campylobacter coli than Campylobacter jejuni isolates. PMID- 22545961 TI - Anisakis simplex sensu stricto and Anisakis pegreffii: biological characteristics and pathogenetic potential in human anisakiasis. AB - Anisakiasis is one of the most common fishborne helminthic diseases in Japan, which is contracted by ingesting the larvae of the nematode Anisakis spp. carried by marine fish. Anisakis simplex sensu stricto (s.s.) and A. pegreffii are the dominant species in fish caught offshore Japan. The present study aimed to identify the anisakid species infecting Japanese patients and determine whether there is any difference in the pathogenetic potential of A. simplex (s.s.) and A. pegreffii. In total, 41 and 301 Anisakis larvae were isolated from Japanese patients and chub mackerel (Scomber japonicus), respectively; these were subjected to molecular identification using polymerase chain reaction targeted at a ribosomal DNA internal transcribed spacer region. Chub mackerel larvae were further examined for survival in artificial gastric juice (pH 1.8) for 7 days and for invasiveness on 0.75% solid agar over a 24-h interval. All clinical isolates, including those of asymptomatic, acute, and chronic infections as well as those from the stomach, small intestine, colon, and stool, were identified as A. simplex (s.s.). Chub mackerel harbored A. simplex (s.s.) and A. pegreffii larvae, together with a few larvae of other anisakid species. A. simplex (s.s.) larvae from chub mackerel tolerated the artificial gastric juice better than A. pegreffii, with 50% mortality in 2.6 and 1.4 days, respectively. In addition, A. simplex (s.s.) penetrated the agar at significantly higher rates than A. pegreffii. These results show that A. simplex (s.s.) larvae have the potential to survive acidic gastric juice to some extent and penetrate the stomach, small intestine, or colon in infected humans. PMID- 22545962 TI - Seroprevalence of Toxoplasma gondii in beef cattle and dairy cattle in northeast China. AB - The seroprevalence of Toxoplasma gondii in beef cattle and dairy cattle in Heilongjiang Province, northeast China, was surveyed between April 2009 and May 2011. A total of 1803 (693 beef cattle and 1110 dairy cattle) serum samples were collected from 10 administrative regions rearing beef cattle and dairy cattle, and antibodies to T. gondii were examined by indirect hemagglutination (IHA) test. The overall seroprevalence of T. gondii in beef cattle and dairy cattle was 2.6% (46/1803), and the prevalence in beef cattle (3.0%) was slightly higher than that in dairy cattle (2.3%). The prevalence of antibodies in adult animals was higher than that in calves, but the differences among the age groups were not significant (p>0.05). The seroprevalence in female (3.4%) and male (2.5%) beef cattle was not statistically significant (p>0.05). Though the prevalence in intensively reared beef cattle and dairy cattle was lower than that in semi intensively reared animals, the difference was not statistically significant (p>0.05). The results of this survey indicated the presence of T. gondii infection in beef cattle and dairy cattle in Heilongjiang Province, the coldest province in China, which may cause economic losses to the local livestock industry, and may be a source of T. gondii infection for humans in this region. PMID- 22545963 TI - Agonists for 13 trace amine-associated receptors provide insight into the molecular basis of odor selectivity. AB - Trace amine-associated receptors (TAARs) are vertebrate olfactory receptors. However, ligand recognition properties of TAARs remain poorly understood, as most are "orphan receptors" without known agonists. Here, we identify the first ligands for many rodent TAARs and classify these receptors into two subfamilies based on the phylogeny and binding preference for primary or tertiary amines. Some mouse and rat orthologs have similar response profiles, although independent Taar7 gene expansions led to highly related receptors with altered ligand specificities. Using chimeric TAAR7 receptors, we identified an odor contact site in transmembrane helix III that functions as a selectivity filter. Homology models based on the beta(2) adrenergic receptor structure indicate spatial proximity of this site to the ligand. Gain-of-function mutations at this site created olfactory receptors with radically altered odor recognition properties. These studies provide new TAAR ligands, valuable tools for studying receptor function, and general insights into the molecular pharmacology of G protein coupled receptors. PMID- 22545964 TI - Complete mitochondrial genome of the Amur stickleback Pungitius sinensis (Gasterosteiformes, Gasterosteidae). AB - The complete mitochondrial genome was sequenced from the Amur stickleback Pungitius sinensis. The genome sequence was 16,581 bp in size, and the gene order and contents were identical with those of previously reported fish mitochondrial genomes. Of 13 protein-coding genes (PCGs), four genes (ND2, CO2, ND4, Cytb) had incomplete stop codons. The base composition of P. sinensis showed anti-G bias (9.53%) on the third position of PCGs. PMID- 22545966 TI - Charge injection in high-kappa gate dielectrics of single-walled carbon nanotube thin-film transistors. AB - We investigate charge injection into the gate dielectric of single-walled carbon nanotube thin-film transistors (SWCNT-TFTs) having Al(2)O(3) and HfO(2) gate dielectrics. We demonstrate the use of electric field gradient microscopy (EFM) to identify the sign and approximate the magnitude of the injected charge carriers. Charge injection rates and saturation levels are found to differ between electrons and holes and also vary according to gate dielectric material. Electrically, Al(2)O(3) gated devices demonstrate smaller average hysteresis and notably higher average on-state current and p-type mobility than those gated by HfO(2). These differences in transfer characteristics are attributed to the charge injection, observed via EFM, and correlate well with differences in tunneling barrier height for electrons and holes formed in the conduction and valence at the SWCNT/dielectric interface, respectively. This work emphasizes the need to understand the SWCNT/dielectric interface to overcome charge injection that occurs in the focused field region adjacent to SWCNTs and indicates that large barrier heights are key to minimizing the effect. PMID- 22545965 TI - The complete mitochondrial genome of an ectoparasitic monopisthocotylean fluke Benedenia hoshinai (Monogenea: Platyhelminthes). AB - An exponential growth of mitochondrial genome information has brought significant progress in understanding the organismal phylogeny and mitochondrial genome evolution for many metazoans including platyhelminth groups. In this study, we determined the complete mitochondrial genome sequence for Benedenia hoshinai, an ectoparasitic monogenean species, and compared it with its congener Benedenia seriolae. The complete mitochondrial genome is 13,554 bp in length and contains 12 protein-coding genes (lacking the atp8 gene), 2 rRNA genes, and 22 tRNA genes, all encoded in the same direction as found in all other platyhelminth species sequenced to date. The gene arrangement of B. hoshinai mtDNA is almost identical to B. seriolae, differing only by the translocation of trnT between cox1 and rrnL. It is unclear whether the shared position of trnT between B. hoshinai and Gyrodactylus represents evidence for their phylogenetic affinity; testing this hypothesis requires further mitogenomic evidence. PMID- 22545967 TI - Interactions between verapamil and digoxin in Langendorff-perfused rat hearts: the role of inhibition of P-glycoprotein in the heart. AB - P-glycoprotein (P-gp) is expressed in tumour cells as well as normal tissues including heart. Modulation of P-gp transport in vivo may lead to increased drug penetrance to tissues with resulting increases in toxicity. We aimed to investigate the effects of P-gp on the isolated heart by digoxin infusion in the absence and presence of verapamil. The study was performed in Langendorff isolated perfused rat hearts. After a 20 min. stabilisation period with Tyrode Buffer, digoxin (125 MUg/5 mL) was infused for 10 min. in the control group (n = 7). The same dose of digoxin was infused during perfusion with verapamil (1 nm) containing Tyrode Buffer (n = 8) in the study group. Outflow concentration and cardiac parameters of digoxin were measured at frequent intervals for 40 min. AUEC((0-40 min)) for left ventricular developed pressure was significantly increased in the presence of verapamil (4260 +/- 39.37 mmHg min versus 4607 +/- 98.09 mmHg min; 95% CI -587.7 to -105.8; p = 0.0083). The significant increases in left ventricular developed pressure were at 20, 25, 30, 35 and 40 min. AUC((0 40 min)) value for outflow digoxin concentration-time curve was significantly lower in the presence of verapamil. Verapamil increased the positive inotropic effect of digoxin, probably through the inhibition of P-gp, which effluxes digoxin out of cardiac cells. PMID- 22545968 TI - A comparison of neuroprotective efficacy of the oxime K203 and its fluorinated analogue (KR-22836) with obidoxime in Tabun-poisoned rats. AB - The ability of the newly developed bispyridinium compound K203 and its fluorinated analogue KR-22836 to reduce tabun-induced acute neurotoxic signs and symptoms was compared with the currently available reactivator of acetylcholinesterase-obidoxime. Tabun-induced neurotoxicity and the neuroprotective effects of all tested oximes in combination with atropine in rats poisoned with tabun at a sublethal dose (200 MUg/kg intramuscularly (i.m.); 80% of LD(50) value) were monitored by a functional observational battery at 24 hr after tabun challenge. The results indicate that all tested oximes combined with atropine were able to survive tabun-poisoned rats 24 hr after tabun challenge while one non-treated tabun-poisoned rat died within 24 hr after tabun poisoning. All tested oximes combined with atropine were able to decrease tabun-induced neurotoxicity in the case of sublethal poisoning but they did not eliminate all tabun-induced acute neurotoxic signs and symptoms. While the ability to reduce tabun-induced acute neurotoxicity of obidoxime and K203 was similar, the neuroprotective efficacy of KR-22836 was slightly higher compared to other tested oximes. Thus, the newly developed fluorinated analogue of K203, called KR-22836, is able to slightly increase the neuroprotective effectiveness of antidotal treatment of acute tabun poisonings compared to K203 and currently available obidoxime. PMID- 22545969 TI - Evaluation of cisplatin in combination with beta-elemene as a regimen for prostate cancer chemotherapy. AB - Cisplatin is one of the most potent chemotherapeutic agents for the treatment of many types of solid tumours. Nevertheless, it is not the first-line drug for prostate cancer chemotherapy, because prostate tumour cells exhibit intrinsic and acquired resistance to cisplatin. We have previously demonstrated that beta elemene, a novel plant-derived anti-neoplastic with low toxicity, inhibits lung and ovarian carcinoma cell growth in vitro. In the present study, we explored the therapeutically chemosensitizing effect of beta-elemene on cisplatin anti-tumour efficacy in androgen-independent prostate cancer cells as well as the underlying mechanism. beta-Elemene significantly increased cisplatin cytotoxicity in the androgen-independent prostate carcinoma cell lines DU145 and PC-3. In addition, beta-elemene markedly promoted cisplatin-induced apoptotic cell death in both cell lines, as determined by three different apoptosis assays. beta-Elemene augmented the cisplatin-induced activation of caspase-3/7/10 and caspase-9, cleavage of caspase-3 and -9, suppression of Bcl-2 and Bcl-X(L) expression, and release of cytochrome c from mitochondria in these cells. Thus, beta-elemene enhancement of cisplatin-induced apoptosis via mitochondrial activation of the caspase-mediated apoptotic pathway may account for the augmented anti-cancer potency of cisplatin in prostate cancer. Cisplatin combined with beta-elemene as a chemosensitizer or adjuvant warrants further study and may be potentially useful as a first-line treatment of androgen-independent prostate carcinomas. PMID- 22545970 TI - Contribution of vasoactive eicosanoids and nitric oxide production to the effect of selective cyclooxygenase-2 inhibitor, NS-398, on endotoxin-induced hypotension in rats. AB - Our previous studies with the use of non-selective cyclooxygenase (COX) inhibitor, indomethacin, demonstrated that prostanoids produced during endotoxaemia increase inducible nitric oxide synthase (iNOS) protein expression and nitric oxide synthesis, and decrease cyctochrome P450 (CYP) 4A1 protein expression and CYP 4A activity. The results suggest that dual inhibition of iNOS and COX by indomethacin restores blood pressure presumably due to increased production of 20-hydroxyeicosatetraenoic acid (20-HETE) derived from CYP 4A in endotoxaemic rats. The present study examined whether increased levels of vasoconstrictor eicosanoids, 20-HETE, prostaglandin F(2alpha) (PGF(2alpha) )and thromboxane A(2) (TxA(2) ), would contribute to the effect of selective COX-2 inhibition to prevent endotoxin (ET)-induced fall in blood pressure associated with an increase in the production of vasodilator prostanoids, prostaglandin I(2) (PGI(2) ) and prostaglandin E(2) (PGE(2) ) and nitric oxide synthesis. Mean arterial blood pressure fell by 31 mmHg and heart rate (HR) rose by 90 beats/min. in male Wistar rats treated with ET (10 mg/kg, i.p.). The fall in mean arterial pressure and increase in HR were associated with increased levels of 6-keto prostaglandin F(1alpha) (6-keto-PGF(1alpha) ), PGE(2) , TxB(2) , and nitrite in the serum, kidney, heart, thoracic aorta and/or superior mesenteric artery. Systemic and renal 20-HETE and PGF(2alpha) levels were also decreased in endotoxaemic rats. These effects of ET were prevented by a selective COX-2 inhibitor, N-(2-cyclohexyloxy-4-nitrophenyl)methansulphonamide (10 mg/kg, i.p.), given 1 hr after injection of ET. These data suggest that an increase in 20-HETE and PGF(2alpha) levels associated with decreased production of PGI(2) , PGE(2) , and TxA(2) , and nitric oxide synthesis contributes to the effect of selective COX-2 inhibitor to prevent the hypotension during rat endotoxaemia. PMID- 22545971 TI - Does Pregabalin (Lyrica((r)) ) help patients reduce their use of benzodiazepines? A comparison with gabapentin using the Norwegian Prescription Database. AB - Pregabalin (Lyrica((r)) ) may have an anxiolytic effect. It has also been reported that the use of this drug helps prevent excessive use of benzodiazepines. The aim of the present study was to examine if pregabalin reduced the intake of benzodiazepines. In a pharmacoepidemiological study, we compared pregabalin to the older drug gabapentin (Neurontin((r)) ) in the Norwegian Prescription Database. The database has total capture of all prescribed drugs outside institutions. We identified all prescriptions for the two drugs for patients aged 18-69 years between 2004 and 2007. Patients were grouped as psychiatric patients, patients with epilepsy, patients with neuropathic pain or non-specified users. We measured the use of benzodiazepines 182 days before and after the initiation of treatment with pregabalin and gabapentin. Between 15% and 29% of the patients were able to stop using benzodiazepines after starting pregabalin or gabapentin treatment. Psychiatric patients who started pregabalin were able to reduce the amount of benzodiazepines used by 48%, compared to only 14% among starters of gabapentin. This study shows that some patients reduced their use of benzodiazepines substantially after starting pregabalin. PMID- 22545972 TI - Tailored text messaging intervention for HIV adherence: a proof-of-concept study. AB - OBJECTIVE: This study sought to determine if dynamically tailored medication messages delivered to people living with HIV (PLWH) via text messaging would be well received and enhance adherence and clinical outcomes. METHODS: A preexperimental proof-of-concept study with 52 men who have sex with men (MSM) recruited from a health clinic focused on promoting the well-being of gay, lesbian, bisexual, and transgender people. Inclusion criteria were being an English speaking HIV-positive MSM, aged 25 or older. Participants also had to agree to allow access to their medical records, have a cell phone, and be able to receive text messages over the 3-month intervention period. Participants completed baseline surveys that assessed various demographic, social, and health questions; received text messages over 3 months; answered weekly adherence questions via two-way messaging; and completed a follow-up survey at the end of the intervention period. Clinical outcomes were abstracted from participants' medical records at baseline and follow-up. Self-reported medication adherence and clinical outcomes, including CD4 counts and viral load. RESULTS: Participants were receptive to the text messaging intervention, and reported reading and liking the messages. Self-reported medication adherence significantly improved among participants who began the study as nonadherent and received tailored medication reminders. Overall viral load significantly decreased and CD4 count significantly increased from baseline to follow-up. CONCLUSIONS: The results demonstrate that using two-way text messaging to dynamically tailor adherence messages may enhance adherence and improve important clinical outcomes for PLWH. PMID- 22545973 TI - Perceived partner responsiveness moderates the association between received emotional support and all-cause mortality. AB - OBJECTIVE: The aim of this study was to investigate whether perceived partner responsiveness (PPR) moderates the association between received partner emotional support (RPES) and all-cause mortality in a national U.S. sample. METHOD: Data were from the National Survey of Midlife Development in the United States, a national probability survey of health and aging. Participants included respondents who were married or cohabiting with a romantic partner. RESULTS: Hierarchical logistic regression analyses indicated that after adjusting for demographics, physical health status, health behaviors, psychological symptoms, and personality traits, high RPES was associated with increased mortality risk among participants who reported low PPR, but it was unrelated to mortality risk among participants who reported high PPR. CONCLUSIONS: This study is the first to document that perceived partner responsiveness moderates the association between received partner emotional support and mortality risk, thus contributing to the literature on the contextual factors altering the effects of received support on health outcomes. PMID- 22545974 TI - Sedentary behaviors of adults in relation to neighborhood walkability and income. AB - OBJECTIVE: Sedentary (sitting) time is a newly identified risk factor for obesity and chronic diseases, which is behaviorally and physiologically distinct from lack of physical activity. To inform public health approaches to influencing sedentary behaviors, an understanding of correlates is required. METHODS: Participants were 2,199 adults aged 20-66 years living in King County/Seattle, WA, and Baltimore, MD, regions, recruited from neighborhoods high or low on a "walkability index" (derived from objective built environment indicators) and having high or low median incomes. Cross-sectional associations of walkability and income with total sedentary time (measured by accelerometers and by self report) and with self-reported time in seven specific sitting-related behaviors were examined. RESULTS: Neighborhood walkability and income were unrelated to measures of total sitting time. Lower neighborhood walkability was significantly associated with more driving time (difference of 18.2 min/day, p < .001) and more self-reported TV viewing (difference of 14.5 min/day, p < .001). Residents of higher income neighborhoods reported more computer/Internet and reading time, and they had more objectively measured sedentary time. CONCLUSIONS: Neighborhood walkability was not related to total sedentary time but was related to two specific sedentary behaviors associated with risk for obesity-driving time and TV viewing time. Future research could examine how these prevalent and often prolonged sedentary behaviors mediate relationships between neighborhood walkability and overweight/obesity. Initiatives to reduce chronic disease risk among residents of both higher-and lower-income low-walkable neighborhoods should include a focus on reducing TV viewing time and other sedentary behaviors and enacting policies that can lead to the development or redevelopment of more walkable neighborhoods. (PsycINFO Database Record (c) 2012 APA, all rights reserved). PMID- 22545975 TI - Gender composition of preadolescents' friendship groups moderates peer socialization of body change behaviors. AB - OBJECTIVE: Peer socialization may be an important contributor to the rising prevalence of diet and muscle gain behaviors (i.e., body change behaviors) in adolescence. The present study longitudinally examined body change behaviors in preadolescents' friendship groups as predictors of preadolescents' own body change behaviors. It was predicted that peer socialization effects would vary according to the gender composition of preadolescents' friendship group. METHOD: Participants (N = 648, 48.8% female) were in grades 6 through 8 at Time 1 and reported their dieting and muscle-gaining behavior at three time points approximately 1 year apart. Friendship groups were identified from preadolescents' friendship nominations. Body mass index and pubertal timing were included in analyses as control variables. A multiple group latent growth curve model was used to examine hypotheses. RESULTS: Socialization of body change behaviors in preadolescent friendship groups was observed only under certain conditions. For members of all-male friendship groups, preadolescents' dieting trajectories were predicted from friends' average level of dieting. CONCLUSION: Peer socialization effects are associated with trajectories of preadolescents' body change behaviors, particularly among all-male groups. Future research would benefit from incorporating the friendship group context into the study of health risk behaviors in preadolescents. PMID- 22545976 TI - "Decentering" reflects psychological flexibility in people with chronic pain and correlates with their quality of functioning. AB - OBJECTIVE: Acceptance and mindfulness-based treatments for chronic pain attempts to alter the impact of pain-related thoughts and feelings on behavior without necessarily changing the thoughts and feelings themselves. A process called "decentering" appears relevant to these treatments because it includes the capacity to observe thoughts and feelings from a detached perspective, as transient events in the mind, that do not necessarily reflect reality or the self. This study examines relations of decentering with other processes related to "psychological flexibility" and the daily functioning of people with chronic pain. METHOD: Consecutive adults seeking treatment for chronic pain (N = 150) provided data for the study by completing a set of measures, including a measure of decentering, the Experiences Questionnaire (EQ). RESULTS: The EQ demonstrated adequate internal consistency reliability, and correlation results supported its validity. Decentering significantly correlated with anxiety, depression, and psychosocial disability. In multiple regression analyses it added a significant increment to explained variance in the prediction of depression and psychosocial disability. Across all measures of functioning, pain acceptance and decentering combined accounted for an average of 23.6% of variance while pain accounted for 2.5%. CONCLUSIONS: People with chronic pain may benefit from the capacity to contact their thoughts and feelings from a perspective as a "separate observer," to see them as transient, and to experience them as cognitively "defused." PMID- 22545977 TI - Cognitive-behavioral stress management and psychological well-being in HIV+ racial/ethnic minority women with human papillomavirus. AB - OBJECTIVE: This study is a secondary analysis examining the effects of a cognitive-behavioral stress management (CBSM) intervention on indicators of positive psychological well-being and negative psychological well-being in HIV positive racial/ethnic minority women at risk for cervical cancer due to human papillomavirus (HPV) infection and/or cervical intraepithelial lesions (CIN). METHOD: Racial/ethnic minority women with HIV and HPV and/or CIN I were randomized to a 10-week CBSM group or a 1-day psychoeducational seminar. Participants completed a battery of measures of positive and negative psychological well-being at 3 time points: preintervention, 3 months postenrollment, and 9 months postenrollment. RESULTS: Women in the CBSM group reported significant increases in domains of positive well-being, with no changes among women in the psychoeducational seminar, F(6, 63) = 2.42, p < .05, eta2 = .19. There were no significant changes in domains of negative well-being across time for either group, F(2, 65) = 2.60, p = .08, eta2 = .07. CONCLUSION: These findings suggest that racial/ethnic minority women with HIV at risk for cervical cancer who were randomized to a 10-week CBSM group experienced enhanced positive well-being. The lack of effects on negative well-being may be due to the relatively low levels of negative well-being present in this sample at study entry. Future research should examine whether these effects are replicated in a randomized controlled trial of women with biopsy-confirmed CIN who present with greater distress levels that also employs a time-equivalent comparison condition. PMID- 22545978 TI - Patterns of success: online self-monitoring in a web-based behavioral weight control program. AB - OBJECTIVES: Online weight control technologies could reduce barriers to treatment, including increased ease and convenience of self-monitoring. Self monitoring consistently predicts outcomes in behavioral weight loss programs; however, little is known about patterns of self-monitoring associated with success. METHOD: The current study examines 161 participants (92% women; 31% African American; mean body mass index = 35.7 +/- 5.7) randomized to a 6-month online behavioral weight control program that offered weekly group "chat" sessions and online self-monitoring. Self-monitoring log-ins were continuously monitored electronically during treatment and examined in association with weight change and demographics. Weekend and weekday log-ins were examined separately and length of periods of continuous self-monitoring were examined. RESULTS: We found that 91% of participants logged in to the self-monitoring webpage at least once. Over 6 months, these participants monitored on an average of 28% of weekdays and 17% of weekend days, with most log-ins earlier in the program. Women were less likely to log-in, and there were trends for greater self-monitoring by older participants. Race, education, and marital status were not significant predictors of self-monitoring. Both weekday and weekend log-ins were significant independent predictors of weight loss. Patterns of consistent self-monitoring emerged early for participants who went on to achieve greater than a 5% weight loss. CONCLUSIONS: Patterns of online self-monitoring were strongly associated with weight loss outcomes. These results suggest a specific focus on consistent self monitoring early in a behavioral weight control program might be beneficial for achieving clinically significant weight losses. PMID- 22545979 TI - Parenting styles and body mass index trajectories from adolescence to adulthood. AB - OBJECTIVE: Parenting styles such as authoritarian, disengaged, or permissive are thought to be associated with greater adolescent obesity risk than an authoritative style. This study assessed the relationship between parenting styles and changes in body mass index (BMI) from adolescence to young adulthood. METHOD: The study included self-reported data from adolescents in the National Longitudinal Study of Adolescent Health. Factor mixture modeling, a data-driven approach, was used to classify participants into parenting style groups based on measures of acceptance and control. Latent growth modeling (LGM) identified patterns of developmental changes in BMI. After a number of potential confounders were controlled for, parenting style variables were entered as predictors of BMI trajectories. Analyses were also conducted for male and female individuals of 3 racial-ethnic groups (Hispanic, black, white) to assess whether parenting styles were differentially associated with BMI trajectories in these 6 groups. RESULTS: Parenting styles were classified into 4 groups: authoritarian, disengaged, permissive, and balanced. Compared with the balanced parenting style, authoritarian and disengaged parenting styles were associated with a less steep average BMI increase (linear slope) over time, but also less leveling off (quadratic) of BMI over time. Differences in BMI trajectories were observed for various genders and races, but the differences did not reach statistical significance. CONCLUSION: Adolescents who reported having parents with authoritarian or disengaged parenting styles had greater increases in BMI as they transitioned to young adulthood despite having a lower BMI trajectory through adolescence. PMID- 22545981 TI - Undertreatment of anxiety and depression in patients with an implantable cardioverter-defibrillator: impact on health status. AB - OBJECTIVE: Twenty-five to 33% of patients with an implantable cardioverter defibrillator (ICD) experience anxiety and depression, but it is not known whether their symptoms are adequately treated. We investigated (a) whether patients with clinically relevant symptoms of distress received appropriate treatment, and (b) whether patients not treated for their emotional distress reported poorer health status using a prospective study design. METHODS: A consecutive cohort of 448 first-time patients with an ICD (21% women; mean age, 58 +/- 12 years) completed the Hospital Anxiety and Depression Scale (HADS) and the Short Form Health Survey 36 (SF-36). Information on psychological treatment was obtained via purpose-designed questions. RESULTS: At baseline, 35.5% of patients were emotionally distressed, of which 70.2% received no psychological treatment. At 12 months postimplantation, 24.3% of all patients had clinically significant levels of distress, of which 58.3% received no treatment. Patients experiencing distress but without treatment reported a significantly poorer health status than patients without distress and treatment (all ps < 0.001) and compared to patients without emotional distress who did receive treatment (ps varying between p = .027 and p < .001 for six subscales). Health status was better on four subscales than for patients with emotional distress and treatment (ps varying between p = .034 and p < .001). CONCLUSIONS: There was a serious gap between the need for psychological treatment and the actual delivery of treatment, with consequences to patients' health status. Detection and adequate treatment of distress in ICD patients remains an important target in this patient group in order to safeguard health status postimplantation. (PsycINFO Database Record (c) 2012 APA, all rights reserved). PMID- 22545980 TI - Disentangling the roles of parental monitoring and family conflict in adolescents' management of type 1 diabetes. AB - OBJECTIVE: Less parental monitoring of adolescents' diabetes self-care and more family conflict are each associated with poorer diabetes outcomes. However, little is known about how these two family factors relate with one another in the context of self-care and glycemic control. Diabetes self-care was evaluated as a mediator of the associations among parental monitoring, family conflict, and glycemic control in early adolescents with type 1 diabetes. METHODS: Adolescent parent dyads (n = 257) reported on the frequency of parental monitoring, family conflict, and diabetes self-care. Hemoglobin A1c was abstracted from medical charts. Structural equation modeling was used for mediation analysis. RESULTS: A mediation model linking parental involvement and family conflict with A1c through diabetes self-care fit the data well. Monitoring and conflict were inversely correlated (beta = -0.23, p < .05) and each demonstrated indirect associations with A1c (standardized indirect effects -0.13 and 0.07, respectively) through their direct associations with self-care (beta = 0.39, p < .001 and beta = -0.19, p < .05, respectively). Conflict also was positively associated with higher A1c (beta = 0.31, p < .01). CONCLUSIONS: Elevated family conflict and less parental monitoring are risk factors for poorer glycemic control, and diabetes self-care is one mediator linking these variables. Interventions to promote parental monitoring of diabetes management during early adolescence may benefit from emphasizing strategies to prevent or reduce family conflict. PMID- 22545983 TI - A continuous homologation of esters: an efficient telescoped reduction olefination sequence. AB - A continuous protocol for the two-carbon homologation of esters to alpha,beta unsaturated esters is described. This multireactor homologation telescopes an ester reduction, phosphonate deprotonation, and Horner-Wadsworth-Emmons olefination, thus converting a three-operation procedure into a single, uninterrupted system that eliminates the need for isolation or purification of the aldehyde intermediates. The homologated products are obtained in high yield and selectivity. PMID- 22545982 TI - Adjuvant chemotherapy of pT1a and pT1b breast carcinoma: results from the NEMESI study. AB - BACKGROUND: The prognosis of pT1a-pT1b breast cancer (BC) used to be considered very good, with a 10-y RFS of 90%. However, some retrospective studies reported a 10-y RFS of 81%-86% and suggested benefit from adjuvant systemic therapy. METHODS: To evaluate the variables that determined the choice of adjuvant chemotherapy and the type of chemotherapy delivered in pT1a-pT1b BC, we analysed the small tumours enrolled in the NEMESI study. RESULTS: Out of 1,894 patients with pathological stage I-II BC enrolled in NEMESI, 402 (21.2%) were pT1a-pT1b. Adjuvant chemotherapy was delivered in 127/402 (31.59%). Younger age, grading G3, high proliferative index, ER-negative and HER2-positive status were significantly associated with the decision to administer adjuvant chemotherapy. An anthracycline without taxane regimen was administered in 59.1% of patients, anthracycline with taxane in 24.4%, a CMF-like regimen in 14.2% and taxane in 2.4%. Adjuvant chemotherapy was administered in 88.4% triple-negative and 73.46% HER2-positive pT1a-pT1b BC. Adjuvant trastuzumab was delivered in 30/49 HER2 positive BC (61.2%). CONCLUSIONS: Adjuvant chemotherapy was delivered in 31.59% T1a-pT1b BC treated at 63 Italian oncological centres from January 2008 to June 2008. The choice to deliver chemotherapy was based on biological prognostic factors. Anthracycline-based chemotherapy was administered in 83.5% patients. PMID- 22545984 TI - Urinary tract stone disease: are all problems solved? AB - During the past four decades there have been dramatic developments in the methods used for active stone removal from the urinary tract, and the need for open surgery has been almost entirely replaced by extracorporeal shockwave lithotripsy, percutaneous surgery, ureteroscopy and retrograde intrarenal surgery. Residual fragments and the pronounced risk of recurrent stone formation remain important problems for the future development of urolithology and for the optimal low-risk management of this large group of patients. It is emphasized that all aspects of the care of patients with stone disease are the responsibility of the urologist. PMID- 22545985 TI - Rapid quantification of clostridial epsilon toxin in complex food and biological matrixes by immunopurification and ultraperformance liquid chromatography-tandem mass spectrometry. AB - Epsilon toxin (ETX) is one of the most lethal toxins produced by Clostridium species and is considered as a potential bioterrorist weapon. Here, we present a rapid mass spectrometry-based method for ETX quantification in complex matrixes. As a prerequisite, naturally occurring prototoxin and toxin species were first structurally characterized by top-down and bottom-up experiments, to identify the most pertinent peptides for quantification. Following selective ETX immunoextraction and trypsin digestion, two proteotypic peptides shared by all the toxin forms were separated by ultraperformance liquid chromatography (UPLC) and monitored by ESI-MS (electrospray ionization-mass spectrometry) operating in the multiple reaction monitoring mode (MRM) with collision-induced dissociation. Thorough protocol optimization, i.e., a 15 min immunocapture, a 2 h enzymatic digestion, and an UPLC-MS/MS detection, allowed the whole quantification process including the calibration curve to be performed in less than 4 h, without compromising assay robustness and sensitivity. The assay sensitivity in milk and serum was estimated at 5 ng.mL(-1) for ETX, making this approach complementary to enzyme linked immunosorbent assay (ELISA) techniques. PMID- 22545989 TI - Heteroaggregation of multiwalled carbon nanotubes and hematite nanoparticles: rates and mechanisms. AB - The heteroaggregation rates of negatively charged multiwalled carbon nanotubes (CNTs) and positively charged hematite nanoparticles (HemNPs) were obtained over a broad range of nanoparticle distributions using time-resolved dynamic light scattering (DLS). Binary systems comprising CNTs and HemNPs were prepared using low ionic strength solutions to minimize the concurrent occurrence of homoaggregation. To elucidate the mechanisms of heteroaggregation, the structures of CNT-HemNP aggregates were observed using cryogenic transmission electron microscopy (cryo-TEM). An initial increase in the CNT concentration, while keeping the HemNP concentration constant, resulted in a corresponding increase in the rate of heteroaggregation, which occurred through the bridging of HemNPs by CNT strands. At the optimal CNT/HemNP mass concentration ratio (CNT/HemNP ratio) of 0.0316, the heteroaggregation rate reached 3.3 times of the HemNP homoaggregation rate in the diffusion-limited regime. Increasing the CNT/HemNP ratio above the optimal value, however, led to a dramatic decrease in the growth rate of heteroaggregates, likely through a blocking mechanism. In the presence of humic acid, the trends in the variation of the heteroaggregation rate with CNT/HemNP ratio were similar to that in the absence of humic acid. However, as the humic acid concentration was increased, the maximum aggregate growth rate decreased due to the lessening in the available surface of the HemNPs that CNTs can attach to through favorable electrostatic interaction. PMID- 22545990 TI - A mixed methods study to evaluate the clinical and cost-effectiveness of a self managed exercise programme versus usual physiotherapy for chronic rotator cuff disorders: protocol for the SELF study. AB - BACKGROUND: Shoulder pain is the third most common reason for consultation with a physiotherapist and up to 26% of the general population might be expected to experience an episode at any one time. Disorders of the shoulder muscles and tendons (rotator cuff) are thought to be the commonest cause of this pain. The long-term outcome is frequently poor despite treatment. This means that many patients are exposed to more invasive treatment, e.g. surgery, and/or long-term pain and disability.Patients with this disorder typically receive a course of physiotherapy which might include a range of treatments. Specifically the value of exercise against gravity or resistance (loaded exercise) in the treatment of tendon disorders is promising but appears to be under-used. Loaded exercise in other areas of the body has been favourably evaluated but further investigation is needed to evaluate the impact of these exercises in the shoulder and particularly the role of home based or supervised exercise versus usual treatment requiring clinic attendance. METHODS/DESIGN: A single-centre pragmatic unblinded parallel group randomised controlled trial will evaluate the effectiveness of a self-managed loaded exercise programme versus usual clinic based physiotherapy. A total of 210 study participants with a primary complaint of shoulder pain suggestive of a rotator cuff disorder will be recruited from NHS physiotherapy waiting lists and allocated to receive a programme of self-managed exercise or usual physiotherapy using a process of block randomisation with sealed opaque envelopes. Baseline assessment for shoulder pain, function and quality of life will be undertaken with the Shoulder Pain & Disability Index, the Patient Specific Functional Scale and the SF-36. Follow-up evaluations will be completed at 3, 6 and 12 months by postal questionnaire. Both interventions will be delivered by NHS Physiotherapist's.An economic analysis will be conducted from an NHS and Personal Social Services perspective to evaluate cost-effectiveness and a qualitative investigation will be undertaken to develop greater understanding of the experience of undertaking or prescribing exercise as a self-managed therapy. TRIAL REGISTRATION NUMBER: ISRCTN84709751. PMID- 22545991 TI - Can DNA-binding proteins of replisome tautomerize nucleotide bases? Ab initio model study. AB - Ab initio quantum-chemical study of specific point contacts of replisome proteins with DNA modeled by acetic acid with canonical and mutagenic tautomers of DNA bases methylated at the glycosidic nitrogen atoms was performed in vacuo and continuum with a low dielectric constant (epsilon ~ 4) corresponding to a hydrophobic interface of protein-nucleic acid interaction. All tautomerized complexes were found to be dynamically unstable, because the electronic energies of their back-reaction barriers do not exceed zero-point vibrational energies associated with the vibrational modes whose harmonic vibrational frequencies become imaginary in the transition states of the tautomerization reaction. Additionally, based on the physicochemical arguments, it was demonstrated that the effects of biomolecular environment cannot ensure dynamic stabilization. This result allows suggesting that hypothetically generated by DNA-binding proteins of replisome rare tautomers will have no impact on the total spontaneous mutation due to the low reverse barrier allowing a quick return to the canonical form. PMID- 22545992 TI - Network properties of protein-decoy structures. AB - Convergence of the vast sequence space of proteins into a highly restricted fold/conformational space suggests a simple yet unique underlying mechanism of protein folding that has been the subject of much debate in the last several decades. One of the major challenges related to the understanding of protein folding or in silico protein structure prediction is the discrimination of non native structures/decoys from the native structure. Applications of knowledge based potentials to attain this goal have been extensively reported in the literature. Also, scoring functions based on accessible surface area and amino acid neighbourhood considerations were used in discriminating the decoys from native structures. In this article, we have explored the potential of protein structure network (PSN) parameters to validate the native proteins against a large number of decoy structures generated by diverse methods. We are guided by two principles: (a) the PSNs capture the local properties from a global perspective and (b) inclusion of non-covalent interactions, at all-atom level, including the side-chain atoms, in the network construction accommodates the sequence dependent features. Several network parameters such as the size of the largest cluster, community size, clustering coefficient are evaluated and scored on the basis of the rank of the native structures and the Z-scores. The network analysis of decoy structures highlights the importance of the global properties contributing to the uniqueness of native structures. The analysis also exhibits that the network parameters can be used as metrics to identify the native structures and filter out non-native structures/decoys in a large number of data sets; thus also has a potential to be used in the protein 'structure prediction' problem. PMID- 22545993 TI - Accurate prediction of protein structural classes using functional domains and predicted secondary structure sequences. AB - Protein structural class prediction is one of the challenging problems in bioinformatics. Previous methods directly based on the similarity of amino acid (AA) sequences have been shown to be insufficient for low-similarity protein data sets. To improve the prediction accuracy for such low-similarity proteins, different methods have been recently proposed that explore the novel feature sets based on predicted secondary structure propensities. In this paper, we focus on protein structural class prediction using combinations of the novel features including secondary structure propensities as well as functional domain (FD) features extracted from the InterPro signature database. Our comprehensive experimental results based on several benchmark data-sets have shown that the integration of new FD features substantially improves the accuracy of structural class prediction for low-similarity proteins as they capture meaningful relationships among AA residues that are far away in protein sequence. The proposed prediction method has also been tested to predict structural classes for partially disordered proteins with the reasonable prediction accuracy, which is a more difficult problem comparing to structural class prediction for commonly used benchmark data-sets and has never been done before to the best of our knowledge. In addition, to avoid overfitting with a large number of features, feature selection is applied to select discriminating features that contribute to achieve high prediction accuracy. The selected features have been shown to achieve stable prediction performance across different benchmark data-sets. PMID- 22545994 TI - Using principal component analysis and support vector machine to predict protein structural class for low-similarity sequences via PSSM. AB - The accurate identification of protein structure class solely using extracted information from protein sequence is a complicated task in the current computational biology. Prediction of protein structural class for low-similarity sequences remains a challenging problem. In this study, the new computational method has been developed to predict protein structural class by fusing the sequence information and evolution information to represent a protein sample. To evaluate the performance of the proposed method, jackknife cross-validation tests are performed on two widely used benchmark data-sets, 1189 and 25PDB with sequence similarity lower than 40 and 25%, respectively. Comparison of our results with other methods shows that the proposed method by us is very promising and may provide a cost-effective alternative to predict protein structural class in particular for low-similarity data-sets. PMID- 22545995 TI - The prediction of protein structural class using averaged chemical shifts. AB - Knowledge of protein structural class can provide important information about its folding patterns. Many approaches have been developed for the prediction of protein structural classes. However, the information used by these approaches is primarily based on amino acid sequences. In this study, a novel method is presented to predict protein structural classes by use of chemical shift (CS) information derived from nuclear magnetic resonance spectra. Firstly, 399 non homologue (about 15% identity) proteins were constructed to investigate the distribution of averaged CS values of six nuclei ((13)CO, (13)Calpha, (13)Cbeta, (1)HN, (1)Halpha and (15)N) in three protein structural classes. Subsequently, support vector machine was proposed to predict three protein structural classes by using averaged CS information of six nuclei. Overall accuracy of jackknife cross-validation achieves 87.0%. Finally, the feature selection technique is applied to exclude redundant information and find out an optimized feature set. Results show that the overall accuracy increased to 88.0% by using the averaged CSs of (13)CO, (1)Halpha and (15)N. The proposed approach outperformed other state-of-the-art methods in terms of predictive accuracy in particular for low similarity protein data. We expect that our proposed approach will be an excellent alternative to traditional methods for protein structural class prediction. PMID- 22545996 TI - Predicting protein oxidation sites with feature selection and analysis approach. AB - Protein oxidation is a ubiquitous post-translational modification that plays important roles in various physiological and pathological processes. Owing to the fact that protein oxidation can also take place as an experimental artifact or caused by oxygen in the air during the process of sample collection and analysis, and that it is both time-consuming and expensive to determine the protein oxidation sites purely by biochemical experiments, it would be of great benefit to develop in silico methods for rapidly and effectively identifying protein oxidation sites. In this study, we developed a computational method to address this problem. Our method was based on the nearest neighbor algorithm in which, however, the maximum relevance minimum redundancy and incremental feature selection approaches were incorporated. From the initial 735 features, 16 features were selected as the optimal feature set. Of such 16 optimized features, 10 features were associated with the position-specific scoring matrix conservation scores, three with the amino acid factors, one with the propensity of conservation of residues on protein surface, one with the side chain count of carbon atom deviation from mean, and one with the solvent accessibility. It was observed that our prediction model achieved an overall success rate of 75.82%, indicating that it is quite encouraging and promising for practical applications. Also, the 16 optimal features obtained through this study may provide useful clues and insights for in-depth understanding the action mechanism of protein oxidation. PMID- 22545997 TI - Structural dynamics of full-length retroviral integrase: a molecular dynamics analysis. AB - HIV integrase catalyzes the integration between host and viral DNA and is considered as an interesting target for treating HIV. Knowledge of the complete structure of integrase is inevitable to describe the communicative inter-domain interactions affecting the HIV integration and disintegration process and hence the study on full-length integrase turns out to be an essential task. In this investigation, a structure of full-length integrase is designed to analyze the global dynamics of integrase dimer and monomers (with and without the C-terminal, 270-288 amino acids) for a period of 20 ns. The molecular dynamics analysis and the subsequent DynDom analysis reveal (i) a stable dynamics of dimeric CCD and NTD domains and (ii) CCD-alpha11-mediated rotational-cum-translational CTD motion as the functional dynamics of IN dimer. This observation supports that (i) aggregation enhances the integrase activity and (ii) flexible CTD for its cis and trans coordination with CCD. The role of C-loop over the dynamics of integrase is also explored, which unveils that the spatial arrangement of integrase domains is changed during dynamics in the absence of C-loop. In essence, here we report a C loop-dependent structural dynamics of integrase and the active dynamics of integrase in dimer. Further studies on C-loop sensing mechanism and the multimerization of integrase would provide insight into HIV integration and disintegration processes. Supplementary material. Movies generated from molecular dynamics trajectory showing the CTD dynamics of IN structures (monomers with & without C-loop and dimer) are linked online to this article. The remaining supplementary data can be downloaded from the author's server at the URL http://ramutha.bicpu.edu.in . PMID- 22545998 TI - Structure and reorientational dynamics of angiotensin I and II: a microscopic physical insight. AB - We present a study of structural analysis and reorientational dynamics of Angiotensin I (AngI) and Angiotensin II (AngII) in aqueous solution. AngI is a decapeptide that acts as a precursor to the octapeptide AngII in the Renin Angiotensin-Aldosterone system for blood pressure regulation. Experimental structural characterization of these peptides, carried out with circular dichroism and infrared spectroscopy, showed that the angiotensins are mostly disordered but exhibit a measurable population of ordered structures at room temperature. Interestingly, these change from the unordered polyproline-like conformation for AngI to a more compact and ordered conformation for AngII as the length of the peptide is decreased. Anisotropy decay measurements with picosecond time resolution indicate slower overall tumbling and a greater amplitude of internal motion in AngI compared to AngII, consistent with more compact and less flexible structure of the active form of the peptide. To model the microscopic behavior of the peptides, 2-MUs molecular dynamics simulation trajectories were generated for AngI and AngII, at 300 K using the OPLS-AA potential and SPC water. The structures sampled in the simulations mostly agree with the experimental results, showing the prevalence of disordered structures, turns, and polyproline helices. Additionally, the computational results predict fewer sampled conformations, tighter side-chain packing and marked increase of Phe8 solvent accessibility upon AngI truncation to AngII. Our combined approach of experiment and extensive computer simulation thus yields new information on the conformational dynamics of the angiotensins, helping provide insight into the structural basis for the potency of AngI relative to AngII. PMID- 22545999 TI - Sequence analysis of serum albumins reveals the molecular evolution of ligand recognition properties. AB - Serum albumin (SA) is a circulating protein providing a depot and carrier for many endogenous and exogenous compounds. At least seven major binding sites have been identified by structural and functional investigations mainly in human SA. SA is conserved in vertebrates, with at least 49 entries in protein sequence databases. The multiple sequence analysis of this set of entries leads to the definition of a cladistic tree for the molecular evolution of SA orthologs in vertebrates, thus showing the clustering of the considered species, with lamprey SAs (Lethenteron japonicum and Petromyzon marinus) in a separate outgroup. Sequence analysis aimed at searching conserved domains revealed that most SA sequences are made up by three repeated domains (about 600 residues), as extensively characterized for human SA. On the contrary, lamprey SAs are giant proteins (about 1400 residues) comprising seven repeated domains. The phylogenetic analysis of the SA family reveals a stringent correlation with the taxonomic classification of the species available in sequence databases. A focused inspection of the sequences of ligand binding sites in SA revealed that in all sites most residues involved in ligand binding are conserved, although the versatility towards different ligands could be peculiar of higher organisms. Moreover, the analysis of molecular links between the different sites suggests that allosteric modulation mechanisms could be restricted to higher vertebrates. PMID- 22546000 TI - Novel aryl beta-aminocarbonyl derivatives as inhibitors of Trypanosoma cruzi trypanothione reductase: binding mode revised by docking and GRIND2-based 3D-QSAR procedures. AB - Trypanothione reductase has long been investigated as a promising target for chemotherapeutic intervention in Chagas disease, since it is an enzyme of a unique metabolic pathway that is exclusively present in the pathogen but not in the human host, which has the analog Glutathione reductase. In spite of the present data-set includes a small number of compounds, a combined use of flexible docking, pharmacophore perception, ligand binding site prediction, and Grid Independent Descriptors GRIND2-based 3D-Quantitative Structure-Activity Relationships (QSAR) procedures allowed us to rationalize the different biological activities of a series of 11 aryl beta-aminocarbonyl derivatives, which are inhibitors of Trypanosoma cruzi trypanothione reductase (TcTR). Three QSAR models were built and validated using different alignments, which are based on docking with the TcTR crystal structure, pharmacophore, and molecular interaction fields. The high statistical significance of the models thus obtained assures the robustness of this second generation of GRIND descriptors here used, which were able to detect the most important residues of such enzyme for binding the aryl beta-aminocarbonyl derivatives, besides to rationalize distances among them. Finally, a revised binding mode has been proposed for our inhibitors and independently supported by the different methodologies here used, allowing further optimization of the lead compounds with such combined structure- and ligand-based approaches in the fight against the Chagas disease. PMID- 22546001 TI - Association of the genetic variants of luteinizing hormone, luteinizing hormone receptor and polycystic ovary syndrome. AB - BACKGROUND: High circulating luteinizing hormone (LH) level is a typical biochemical feature of polycystic ovary syndrome (PCOS) whose pathophysiology is still unclear. Certain mutations of LH and LH receptor (LHR) may lead to changes in bioactivity of these hormones. The aim of this study was determine the role of the LH and LHR polymorphisms in the pathogenesis of PCOS using a genetic approach. METHODS: 315 PCOS women and 212 controls were screened for the gene variants of LH G1052A and LHR rs61996318 polymorphisms by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). RESULTS: PCOS patients had significantly more A allele frequency of LH G1052A mutations than controls (p=0.001). Within PCOS group, carriers of LH 1052A allele had lower LH (p=0.05) and higher fasting glucose levels (p=0.04). No subjects were identified with LHR rs61996318 polymorphisms. A new LHR single nucleotide polymorphism (SNP) was found without clear association with PCOS. CONCLUSIONS: Results suggested LH G1052A mutation might influence PCOS susceptibility and phenotypes. PMID- 22546002 TI - Pluronic F108 coating decreases the lung fibrosis potential of multiwall carbon nanotubes by reducing lysosomal injury. AB - We compared the use of bovine serum albumin (BSA) and pluronic F108 (PF108) as dispersants for multiwalled carbon nanotubes (MWCNTs) in terms of tube stability as well as profibrogenic effects in vitro and in vivo. While BSA-dispersed tubes were a potent inducer of pulmonary fibrosis, PF108 coating protected the tubes from damaging the lysosomal membrane and initiating a sequence of cooperative cellular events that play a role in the pathogenesis of pulmonary fibrosis. Our results suggest that PF108 coating could serve as a safer design approach for MWCNTs. PMID- 22546003 TI - Selected deposition of high-quality aluminum film by liquid process. AB - For generation of a fine aluminum pattern by conventional vacuum processing, it is necessary not only to use complex and costly instruments but also to perform an additional etching process, which may result in physical and chemical damage to the target film surface. Herein we report a simple solution process for the selected deposition of an Al pattern. Al is obtained from the decomposition of alane under dehydrogenation catalysis of a Pt nanocrystalline pattern on a substrate at ~105-120 degrees C, while the self-decomposition of alane in solution is avoided in the presence of high-boiling-point amine. This deposited film generates Al crystals with a diameter of several hundred nanometers, following an epitaxial growth to a continual film. The obtained film shows high conductivity, with a resistivity close to that of bulk Al. PMID- 22546004 TI - Metal-catalyzed nitrogen-atom transfer methods for the oxidation of aliphatic C-H bonds. AB - For more than a century, chemists have endeavored to discover and develop reaction processes that enable the selective oxidation of hydrocarbons. In the 1970s, Abramovitch and Yamada described the synthesis and electrophilic reactivity of sulfonyliminoiodinanes (RSO(2)N?IPh), demonstrating the utility of this new class of reagents to function as nitrene equivalents. Subsequent investigations by Breslow, Mansuy, and Muller would show such oxidants to be competent for alkene and saturated hydrocarbon functionalization when combined with transition metal salts or metal complexes, namely those of Mn, Fe, and Rh. Here, we trace our own studies to develop N-atom transfer technologies for C-H and pi-bond oxidation. This Account discusses advances in both intra- and intermolecular amination processes mediated by dirhodium and diruthenium complexes, as well as the mechanistic foundations of catalyst reactivity and arrest. Explicit reference is given to questions that remain unanswered and to problem areas that are rich for discovery. A fundamental advance in amination technology has been the recognition that iminoiodinane oxidants can be generated in situ in the presence of a metal catalyst that elicits subsequent N-atom transfer. Under these conditions, both dirhodium and diruthenium lantern complexes function as competent catalysts for C-H bond oxidation with a range of nitrogen sources (e.g., carbamates, sulfamates, sulfamides, etc.), many of which will not form isolable iminoiodinane equivalents. Practical synthetic methods and applications thereof have evolved in parallel with inquiries into the operative reaction mechanism(s). For the intramolecular dirhodium-catalyzed process, the body of experimental and computational data is consistent with a concerted asynchronous C-H insertion pathway, analogous to the consensus mechanism for Rh carbene transfer. Other studies reveal that the bridging tetracarboxylate ligand groups, which shroud the dirhodium core, are labile to exchange under standard reaction conditions. This information has led to the generation of chelating dicarboxylate dinuclear rhodium complexes, exemplified by Rh(2)(esp)(2). The performance of this catalyst system is unmatched by other dirhodium complexes in both intra- and intermolecular C-H amination reactions. Tetra-bridged, mixed valent diruthenium complexes function as effective promoters of sulfamate ester oxidative cyclization. These catalysts can be crafted with ligand sets other than carboxylates and are more resistant to oxidation than their dirhodium counterparts. A range of experimental and computational mechanistic data amassed with the tetra-2-oxypyridinate diruthenium chloride complex, [Ru(2)(hp)(4)Cl], has established the insertion event as a stepwise pathway involving a discrete radical intermediate. These data contrast dirhodium-catalyzed C-H amination and offer a cogent model for understanding the divergent chemoselectivity trends observed between the two catalyst types. This work constitutes an important step toward the ultimate goal of achieving predictable, reagent-level control over product selectivity. PMID- 22546006 TI - Emigration preferences and plans among medical students in Poland. AB - BACKGROUND: Migration and ethical recruitment of health care workers is receiving increased attention worldwide. Europe's aging population is creating new opportunities for medical doctors for finding employment in other countries, particularly those of a better standard of living. METHODS: We conducted a survey among 1214 medical students in five out of eleven universities in Poland with medical schools in October 2008. A series of statistical tests was applied to analyse the characteristics of potential migrants. Projections were obtained using statistical analyses: descriptive, multifactorial logistic regression and other statistical methods . RESULTS: We can forecast that 26-36% of Polish medical students will emigrate over the next few years; 62% of respondents estimated the likelihood of emigration at 50%. Students in their penultimate year of study declared a stronger desire to migrate than those in the final year. At the same time, many students were optimistic about career opportunities in Poland. Also noted among students were: the decline in interest in leaving among final year students, their moderate elaboration of departure plans, and their generally optimistic views about the opportunities for professional development in Poland. CONCLUSIONS: The majority of Polish students see the emigration as a serious alternative to the continuation of their professional training. This trend can pose a serious threat to the Polish health care system, however the observed decline of the interest in leaving among final year students, the moderate involvement in concrete departure plans and the optimistic views about the opportunities for professional development in Poland suggest that the actual scale of brain drain of young Polish doctors due to emigration will be more limited than previously feared. PMID- 22546005 TI - Maternal immune activation by poly I:C induces expression of cytokines IL-1beta and IL-13, chemokine MCP-1 and colony stimulating factor VEGF in fetal mouse brain. AB - BACKGROUND: Maternal viral infection during pregnancy is associated with an increase in the incidence of psychiatric disorders with presumed neurodevelopmental origin, including autism spectrum disorders and schizophrenia. The enhanced risk for developing mental illness appears to be caused by deleterious effects of innate immune response-associated factors on the development of the central nervous system, which predispose the offspring to pathological behaviors in adolescence and adulthood. To identify the immune response-associated soluble factors that may affect central nervous system development, we examined the effect of innate immune response activation by polyriboinosinic-polyribocytidylic acid (poly(I:C)), a synthetic analogue of viral double-stranded RNA, on the expression levels of pro- and anti-inflammatory cytokines, chemokines and colony stimulating factors in fetal and postnatal mouse brain 6 h and 24 h after treatment. METHODS: C57BL/6J pregnant mice (gestational day 16) or newborn mice (postnatal day 4) received a single intraperitoneal injection of the synthetic analogue of viral double-stranded RNA poly(I:C) (20 mg/kg). Thirty-two immune response-associated soluble factors, including pro- and anti-inflammatory cytokines, chemokines and colony stimulating factors, were assayed 6 h and 24 h after poly(I:C) injection using multiplexed bead-based immunoassay (Milliplex Map) and processed in a Luminex 100 IS instrument. RESULTS: Maternal exposure to poly(I:C) at gestational day 16 induced a significant increase in cytokines interleukin (IL)-1beta, IL-7 and IL-13; chemokines monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein (MIP)-1alpha, interferon gamma-induced protein (IP)-10 and monokine induced by IFN-gamma (MIG); and in the colony stimulating factor vascular endothelial growth factor (VEGF) in the fetal brain. IL-1beta showed the highest concentration levels in fetal brains and was the only cytokine significantly up regulated 24 h after maternal poly(I:C) injection, suggesting that IL-1beta may have a deleterious impact on central nervous system development. In contrast, poly(I:C) treatment of postnatal day 4 pups induced a pronounced rise in chemokines and colony stimulating factors in their brains instead of the pro inflammatory cytokine IL-1beta. CONCLUSIONS: This study identified a significant increase in the concentration levels of the cytokines IL-1beta and IL-13, the chemokine MCP-1 and the colony stimulating factor VEGF in the developing central nervous system during activation of an innate immune response, suggesting that these factors are mediators of the noxious effects of maternal immune activation on central nervous system development, with potential long-lasting effects on animal behavior. PMID- 22546007 TI - Phylogeographic analysis reveals significant spatial genetic structure of Incarvillea sinensis as a product of mountain building. AB - BACKGROUND: Incarvillea sinensis is widely distributed from Southwest China to Northeast China and in the Russian Far East. The distribution of this species was thought to be influenced by the uplift of the Qinghai-Tibet Plateau and Quaternary glaciation. To reveal the imprints of geological events on the spatial genetic structure of Incarvillea sinensis, we examined two cpDNA segments ( trnH- psbA and trnS- trnfM) in 705 individuals from 47 localities. RESULTS: A total of 16 haplotypes was identified, and significant genetic differentiation was revealed (GST =0.843, NST = 0.975, P < 0.05). The survey detected two highly divergent cpDNA lineages connected by a deep gap with allopatric distributions: the southern lineage with higher genetic diversity and differentiation in the eastern Qinghai-Tibet Plateau, and the northern lineage in the region outside the Qinghai-Tibet Plateau. The divergence between these two lineages was estimated at 4.4 MYA. A correlation between the genetic and the geographic distances indicates that genetic drift was more influential than gene flow in the northern clade with lower diversity and divergence. However, a scenario of regional equilibrium between gene flow and drift was shown for the southern clade. The feature of spatial distribution of the genetic diversity of the southern lineage possibly indicated that allopatric fragmentation was dominant in the collections from the eastern Qinghai-Tibet Plateau. CONCLUSIONS: The results revealed that the uplift of the Qinghai-Tibet Plateau likely resulted in the significant divergence between the lineage in the eastern Qinghai-Tibet Plateau and the other one outside this area. The diverse niches in the eastern Qinghai-Tibet Plateau created a wide spectrum of habitats to accumulate and accommodate new mutations. The features of genetic diversity of populations outside the eastern Qinghai Tibet Plateau seemed to reveal the imprints of extinction during the Glacial and the interglacial and postglacial recolonization. Our study is a typical case of the significance of the uplift of the Qinghai-Tibet Plateau and the Quaternary Glacial in spatial genetic structure of eastern Asian plants, and sheds new light on the evolution of biodiversity in the Qinghai-Tibet Plateau at the intraspecies level. PMID- 22546008 TI - Posttransplant mortality risk assessment for adult-to-adult right-lobe living donor liver recipients with benign end-stage liver disease. AB - OBJECTIVE: A model for living donor liver transplantation (LDLT) outcomes, in concert with pretransplant disease severity assessment, would facilitate informed decision-making on both sides considering donation and transplantation. So far, however, few of studies have focused on models specifically for adult-to-adult right-lobe LDLT recipients with benign end-stage liver diseases. Therefore, we aimed to develop such a prognostic model based on easily obtainable and objective pretransplant characteristics. METHODS: With data retrospectively collected on 120 recipients, we used Cox proportional-hazards regression to analyze six donor characteristics and 33 pretransplant recipient variables for correlation with posttransplant mortality. In both a modeling set and a prospective validation set with 30 recipients, the performances of the new Cox model, MELD, and MELD-Na+ were assessed by measuring both calibration ability and discriminative power with the Hosmer-Lemeshow test and receiver operating characteristic analysis, respectively. RESULTS: By univariate and multivariate analysis, donor age, serum total bilirubin, creatinine, and HBV-DNA level were significantly associated with posttransplant mortality. The Cox model, employing these four variables, yielded good calibration ability in the modeling set chi2 = 2.465, p = 0.653) and the validation set chi2 = 2.836, p = 0.586), and high discriminative power in the modeling set (c-statistic = 0.826, p = 0.001) and validation set (c-statistic = 0.816, p = 0.028). The calibration ability and discriminative power of MELD and MELD-Na+ in both sets were poor. CONCLUSIONS: The newly derived Cox model was valuable in posttransplant mortality risk assessment for adult-to-adult right lobe LDLT recipients with benign end-stage liver diseases. PMID- 22546010 TI - Protein conformation-controlled rebinding barrier of NO and its binding trajectories in myoglobin and hemoglobin at room temperature. AB - The effect of the solvent viscosity on the dynamics of NO rebinding to myoglobin (Mb) and hemoglobin (Hb) was examined by femtosecond (fs) time-resolved vibrational spectroscopy after photodeligation of NO from MbNO and HbNO in various viscous solutions at 283 K using a 580 nm excitation pulse. The rebinding kinetics of NO to both Mb and Hb were nonexponential, but their dependence on the solvent viscosity was different. The rate of NO rebinding to Mb increased with increasing solution viscosity, which was achieved by increasing the glycerol content in glycerol/water mixture. In contrast, the rate of NO rebinding to Hb was independent of the solution viscosity but faster than the fastest rate of NO rebinding observed in Mb. The dynamics of conformational relaxation of the protein after deligation were also measured by probing the evolution of the amide band. The effect of the solvent viscosity on the kinetics of conformational relaxation in both proteins was also quite different. The conformational relaxation of Mb became slower with increasing solution viscosity. On the other hand, the conformational relaxation of Hb was independent of the solution viscosity but slower than the slowest kinetics of Mb. The inverse correlation in the kinetics of conformational relaxation and NO rebinding suggests that the barrier of NO rebinding increases as the conformation of the protein relaxes toward the deligated structure after NO dissociation. The rebinding kinetics of NO to both proteins was well described by a kinetic model incorporating a time dependent barrier for rebinding and exponential translocations between three states for dissociated NO. PMID- 22546009 TI - Glucose-6-phosphate dehydrogenase deficiency, chlorproguanil-dapsone with artesunate and post-treatment haemolysis in African children treated for uncomplicated malaria. AB - BACKGROUND: Malaria is a leading cause of mortality, particularly in sub-Saharan African children. Prompt and efficacious treatment is important as patients may progress within a few hours to severe and possibly fatal disease. Chlorproguanil dapsone-artesunate (CDA) was a promising artemisinin-based combination therapy (ACT), but its development was prematurely stopped because of safety concerns secondary to its associated risk of haemolytic anaemia in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. The objective of the study was to assess whether CDA treatment and G6PD deficiency are risk factors for a post treatment haemoglobin drop in African children<5 years of age with uncomplicated malaria. METHODS: This case-control study was performed in the context of a larger multicentre randomized clinical trial comparing safety and efficacy of four different ACT in children with uncomplicated malaria. Children, who after treatment experienced a haemoglobin drop>=2 g/dl (cases) within the first four days (days 0, 1, 2, and 3), were compared with those without an Hb drop (controls). Cases and controls were matched for study site, sex, age and baseline haemoglobin measurements. Data were analysed using a conditional logistic regression model. RESULTS: G6PD deficiency prevalence, homo- or hemizygous, was 8.5% (10/117) in cases and 6.8% (16/234) in controls (p=0.56). The risk of a Hb drop>=2 g/dl was not associated with either G6PD deficiency (adjusted odds ratio (AOR): 0.81; p=0.76) or CDA treatment (AOR: 1.28; p=0.37) alone. However, patients having both risk factors tended to have higher odds (AOR: 11.13; p=0.25) of experiencing a Hb drop>=2 g/dl within the first four days after treatment, however this finding was not statistically significant, mainly because G6PD deficient patients treated with CDA were very few. In non-G6PD deficient individuals, the proportion of cases was similar between treatment groups while in G6PD-deficient individuals, haemolytic anaemia occurred more frequently in children treated with CDA (56%) than in those treated with other ACT (29%), though the difference was not significant (p=0.49). CONCLUSION: The use of CDA for treating uncomplicated malaria may increase the risk of haemolytic anaemia in G6PD-deficient children. PMID- 22546011 TI - Antibiotic-resistant enterococci in seawater and sediments from a coastal fish farm. AB - The aim of this study was to detect and characterize antibiotic-resistant enterococci in seawater and sediment from a Mediterranean aquaculture site where no antibiotics are used. Colonies (650) grown on Slanetz-Bartley (SB) agar were amplified on antibiotic-supplemented SB, and erythromycin (ERY), tetracycline (TET), and ampicillin (AMP) MICs were determined. Of 75 resistant isolates (17 to TET, 5 to ERY, and 45 to AMP), 5 Enterococcus faecalis, 25 E. faecium, 5 E. casseliflavus, 1 E. gallinarum, 1 E. durans, and 23 Enterococcus spp. were identified by genus- and species-specific polymerase chain reaction (PCR). tet(M), tet(O), tet(L), tet(K), erm(B), erm(A), erm(C), mef, msr, blaZ, and int(Tn916) were sought by PCR, including an improved multiplex PCR assay targeting tet(M), tet(L), and erm(B). Tet(M) was the most frequent TET resistance gene; msr(C) was the sole ERY resistance gene detected. blaZ was found in 29/45 AMP-resistant isolates; however, no beta-lactamase production was detected. Antibiotic-resistant enterococci were recovered 2 km off the coast despite the absence of selective pressure exerted by antibiotic use. The occurrence of resistant strains in the absence of the tested genes may indicate the presence of less common resistance determinants. This first evidence of resistant enterococci at a Mediterranean aquaculture site suggests the existence of a marine reservoir of antibiotic resistances potentially transmissible to virulent strains that could be affected by mariculture in an antibiotic-independent manner. PMID- 22546012 TI - Development and psychometric properties the Barriers to Access to Care Evaluation scale (BACE) related to people with mental ill health. AB - BACKGROUND: Many people with mental illness do not seek or delay seeking care. This study aimed to develop, and provide an initial validation of, a comprehensive measure for assessing barriers to access to mental health care including a 'treatment stigma' subscale, and to present preliminary evidence about the prevalence of barriers experienced by adults currently or recently using secondary mental health services in the UK. METHODS: The Barriers to Access to Care Evaluation scale (BACE) was developed from items in existing scales, systematic item reduction, and feedback from an expert group. It was completed in an online survey by 117 individuals aged 18 and over who had received care from secondary mental health services in the past 12 months. Internal consistency, test-retest reliability, convergent validity (correlation of treatment stigma subscale with the Stigma Scale for Receiving Psychological Help (SSRPH) and with the Internalised Stigma of Mental Illness Scale (ISMI)), respondent opinion and readability were assessed. RESULTS: The BACE items were found to have acceptable test-retest reliability as all but one of the items exceeded the criterion for moderate agreement. The treatment stigma subscale had acceptable test-retest reliability and good internal consistency. As hypothesised the subscale was significantly positively correlated with the SSRPH and the ISMI demonstrating convergent validity. The developmental process ensured content validity. Respondents gave the BACE a median rating of 8 on the 10-point quality scale. Readability scores indicated the measure can be understood by the average 11 to 12 year-old. The most highly endorsed barrier was 'concern that it might harm my chances when applying for jobs'. The scale was finalised into a 30-item measure with a 12-item treatment stigma subscale. CONCLUSIONS: There is preliminary evidence demonstrating the reliability, validity and acceptability of the BACE. It can be used to ascertain key barriers to access to mental health care which may help to identify potential interventions to increase care seeking and service use. Further research is needed to establish its factor analytic structure and population norms. PMID- 22546013 TI - Fluorine end-capped optical fibers for photosensitizer release and singlet oxygen production. AB - The usefulness of a fiber optic technique for generating singlet oxygen and releasing the pheophorbide photosensitizer has been increased by the fluorination of the porous Vycor glass tip. Singlet oxygen emerges through the fiber tip with 669-nm light and oxygen, releasing the sensitizer molecules upon a [2 + 2] addition of singlet oxygen with the ethene spacer and scission of a dioxetane intermediate. Switching from a nonfluorinated to a fluorinated glass tip led to a clear reduction of the adsorbtive affinity of the departing sensitizer with improved release into homogeneous toluene solution and bovine tissue, but no difference was found in water since the sensitizer was insoluble. High surface coverage of the nonafluorohexylsilane enhanced the cleavage efficiency by 15% at the ethene site. The fluorosilane groups also caused crowding and seemed to reduce access of (1)O(2) to the ethene site, which attenuated the total quenching rate constant k(T), although there was less wasted (1)O(2) (from surface physical quenching) at the fluorosilane-coated than the native SiOH silica. The observations support a quenching mechanism that the replacement of the SiOH groups for the fluorosilane C-H and C-F groups enhanced the (1)O(2) lifetime at the fiber tip interface due to less efficient electronic-to-vibronic energy transfer. PMID- 22546015 TI - Electric field effects on armchair MoS2 nanoribbons. AB - Ab initio density functional theory calculations are performed to investigate the electronic structure of MoS(2) armchair nanoribbons in the presence of an external static electric field. Such nanoribbons, which are nonmagnetic and semiconducting, exhibit a set of weakly interacting edge states whose energy position determines the band gap of the system. We show that, by applying an external transverse electric field, E(ext), the nanoribbon band gap can be significantly reduced, leading to a metal-insulator transition beyond a certain critical value. Moreover, the presence of a sufficiently high density of states at the Fermi level in the vicinity of the metal-insulator transition leads to the onset of Stoner ferromagnetism that can be modulated, and even extinguished, by E(ext). In the case of bilayer nanoribbons we further show that the band gap can be changed from indirect to direct by applying a transverse field, an effect that might be of significance for opto-electronics applications. PMID- 22546014 TI - Relationship between vitamin B12, folate and homocysteine levels and H. pylori infection in patients with functional dyspepsia: a cross-section study. AB - BACKGROUND: H. pylori infection has been associated with many micronutrient deficiencies. There is a dearth of data from communities with nutritional deficiencies and high prevalence of H. pylori infection. The aim of this study was to determine the impact of H. pylori infection on serum levels of vitamin B(12), folate and homocysteine in patients with functional dyspepsia (FD). METHODS: One hundred and thirty-two patients with FD undergoing gastroscopy were enrolled. The serum was analyzed for B(12), folate and homocysteine levels before gastroscopy. H. pylori infection was diagnosed by histopathological examination of gastric biopsies and urea breath test. An independent sample t-test and the Mann-Whitney test were used to compare mean serum concentrations of biomarkers between H. pylori-positive and H. pylori-negative groups of patients. A Chi square test was performed to assess the differences among proportions, while Spearman's rho was used for correlation analysis between levels of B(12) and homocysteine. RESULTS: The mean age of the group was 40.3 +/- 11.5 (19-72) years. Folate deficiency was seen in 43 (34.6%), B(12) deficiency in 30 (23.1%) and hyperhomocysteinemia in 60 (46.2%) patients. H. pylori was present in 80 (61.5%) patients with FD while it was absent in 50 (38.5%). Mean serum levels of B(12), folate and homocysteine in the H. pylori-positive group of patients were not significantly different from the levels in the H. pylori-negative group (357 +/- 170 vs. 313 +/- 136 pg/mL; p = 0.13), (4.35 +/- 1.89 vs. 4.42 +/- 1.93 ng/mL; p = 0.84); (15.88 +/- 8.97 vs. 16.62 +/- 7.82 MUmol/L; p = 0.24); respectively.B(12) deficiency (<=200 pg/mL) was 23.8% in the H. pylori-positive patients versus 22.0% in the H. pylori-negative patients. Folate deficiency (<=3.5 ng/mL) was 33.8% in the H. pylori-positive group versus 36% in the H. pylori-negative group. Hyperhomocysteinemia (>15 MUmol/L) was present in 46.2% of H. pylori-positive patients compared to 44% in the H. pylori-negative group. Correlation analysis indicated that serum B(12) levels were inversely associated with serum levels of homocysteine in patients with FD (rho = -0.192; p = 0.028). CONCLUSIONS: This study demonstrated an inverse relationship between serum levels of B(12) and homocysteine in patients with FD. Moreover, no impact of the presence of H. pylori was found on B(12), folate and homocysteine levels in such patients. PMID- 22546019 TI - Activities of asymmetric dimethylarginine-related enzymes in white adipose tissue are associated with circulating lipid biomarkers. AB - BACKGROUND: Asymmetric NG,NG-dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is regulated by the enzymatic participants of synthetic and metabolic processes, i.e., type I protein N-arginine methyltransferase (PRMT) and dimethylarginine dimethylaminohydrolase (DDAH). Previous reports have demonstrated that circulating ADMA levels can vary in patients with type 1 and type 2 diabetes mellitus (T2DM). White adipose tissue expresses the full enzymatic machinery necessary for ADMA production and metabolism; however, modulation of the activities of adipose ADMA-related enzymes in T2DM remains to be determined. METHODS: A rodent model of T2DM using 11- and 20-week old Goto Kakizaki (GK) rats was used. The expression and catalytic activity of PRMT1 and DDAH1 and 2 in the white adipose tissues (periepididymal, visceral and subcutaneous fats) and femur skeletal muscle tissue were determined by immunoblotting, in vitro methyltransferase and in vitro citrulline assays. RESULTS: Non-obese diabetic GK rats showed low expression and activity of adipose PRMT1 compared to age-matched Wistar controls. Adipose tissues from the periepididymal, visceral and subcutaneous fats of GK rats had high DDAH1 expression and total DDAH activity, whereas the DDAH2 expression was lowered below the control value. This dynamic of ADMA-related enzymes in white adipose tissues was distinct from that of skeletal muscle tissue. GK rats had lower levels of serum non-esterified fatty acids (NEFA) and triglycerides (TG) than the control rats. In all subjects the adipose PRMT1 and DDAH activities were statistically correlated with the levels of serum NEFA and TG. CONCLUSION: Activities of PRMT1 and DDAH in white adipose tissues were altered in diabetic GK rats in an organ-specific manner, which was reflected in the serum levels of NEFA and TG. Changes in adipose ADMA-related enzymes might play a part in the function of white adipose tissue. PMID- 22546016 TI - The prognostic value of expression of HIF1alpha, EGFR and VEGF-A, in localized prostate cancer for intermediate- and high-risk patients treated with radiation therapy with or without androgen deprivation therapy. AB - PURPOSE: Androgens stimulate the production of hypoxia-inducible factor (HIF1alpha) and ultimately vascular endothelial growth factor (VEGF-A). Additionally, epithelial growth factor (EGF) mediates HIF1alpha production. Carbonic anhydrase IX (CAIX) expression is associated with tumor cell hypoxia in a variety of malignancies. This study assesses the prognostic relation between HIF1alpha, VEGF-A, EGF Receptor and CAIX expression by immunochemistry in diagnostic samples of patients with intermediate- and high-risk localized prostate cancer treated with radiation therapy, with or without androgen deprivation therapy (ADT). MATERIALS AND METHODS: Between 1994 and 2004, 103 prostate cancer patients (mean age, 68.7 +/- 6.2), with prostate cancer (mean PSA, 13.3 +/- 3.7), were treated with radiation therapy (RT, median dose, 74 Gy). Fifty seven (55.3%) patients received ADT (median duration, 6 months; range, 0 - 24). Median follow-up was 97.6 months (range, 5.9 - 206.8). RESULTS: Higher EGFR expression was significantly (p = 0.04) correlated with higher Gleason scores. On univariate analysis, HIF1alpha nuclear expression was a significant (p = 0.02) prognostic factor for biological progression-free survival (bPFS). A trend towards significance (p = 0.05) was observed with EGFR expression and bPFS. On multivariate analysis, low HIF1alpha nuclear (p = 0.01) and high EGFR (p = 0.04) expression remained significant adverse prognostic factors. CONCLUSIONS: Our study suggests that high nuclear expression of HIF1alpha and low EGFR expression in diagnostic biopsies of prostate cancer patients treated with RT +/- ADT is associated with a good prognosis. PMID- 22546020 TI - Application of the Rasch rating scale model to the assessment of quality of life of persons with intellectual disability. AB - BACKGROUND: Most instruments that assess quality of life have been validated by means of the classical test theory (CTT). However, CTT limitations have resulted in the development of alternative models, such as the Rasch rating scale model (RSM). The main goal of this paper is testing and improving the psychometric properties of the INTEGRAL Quality of Life Scale (i.e., fit statistics, person and item reliability coefficients) with RSM. METHOD: The sample comprised 271 Spanish adults with intellectual disability. RESULTS: The results showed that the data fitted the model, point-biserial correlations were adequate, items showed precision, reliability of items (.98) and persons (.89) were adequate, and the response categories were suitable (thresholds were ordered). However, one item ("I feel excluded from society") did not fit the model and a few items were too easy for participants to achieve. CONCLUSIONS: Although it seems necessary to include more difficult items and to delete one, the INTEGRAL Scale is a useful instrument with evidence of validity. PMID- 22546021 TI - Editorial: programmable shunts versus nonprogrammable shunts. PMID- 22546022 TI - Nonprogrammable and programmable cerebrospinal fluid shunt valves: a 5-year study. AB - OBJECT: Programmable valves (PVs) for shunting CSF have increasingly replaced nonprogrammable valves (NPVs). There have been only a few longer-term studies (>= 5 years) conducted that have compared the effectiveness of NPVs with that of PVs for children with hydrocephalus, and only 1 study has reported NPVs as being favorable over PVs. The objective of this retrospective study was to compare the long-term survival of these 2 types of shunt valves. METHODS: The authors collected data for all patients who underwent CSF shunt insertion or revision between January 1, 2000, and December 31, 2008. Patients underwent follow-up for a minimum of 2 years postoperatively. Statistical analyses were done using chi square, Kaplan-Meier survival curve, and multivariate analyses. RESULTS: A total of 616 valves were implanted, of which 313 were PVs and 303 were NPVs. Of these, 253 were original shunt implantations and 363 were revisions. The proportion of 5 year survival for NPVs (45.8%) was significantly higher than that for PVs (19.8%) (p = 0.0005, log-rank). The NPVs that survived longer than 6 months also survived through the 5th year better than the PVs (p = 0.0001). CONCLUSIONS: The authors' data suggest that NPVs survive longer than PVs in children, but there is a need for prospective, case-control studies to confirm these data. PMID- 22546023 TI - Experience with a gravitational valve in the management of symptomatic overdrainage in children with shunts. AB - OBJECT: Symptomatic overdrainage in children with shunt-treated hydrocephalus represents one of the more difficult shunt-related diseases and may require repeated surgery. Gravity-assisted valve design has become a standard device to avoid overdrainage in many European pediatric hydrocephalus centers. However, the use of a gravitational valve for relieving symptoms associated with overdrainage has not yet been addressed. The goal of this study was to evaluate the effectiveness of a gravitational valve in the treatment of symptomatic overdrainage in children with shunts. METHODS: Seventeen children with an adjustable shunt system and symptomatic overdrainage were treated by insertion of a gravitational valve. Clinical and radiological outcome were monitored for a minimum of 12 months after surgery. RESULTS: Implantation of a gravitational valve resulted in either resolution (n = 12) or improvement (n = 5) of the symptoms. In 1 patient, symptoms remained almost unchanged and the gravitational valve had to be upgraded, resulting in resolution of the symptoms. During follow up, the pressure setting of the adjustable differential pressure valve had to be changed in 7 patients. CONCLUSIONS: The gravitational valve was effective in improving symptomatic overdrainage in the majority of patients in the present study. Because the ideal pressure setting for a given patient is hard to determine a priori, adjustable valve systems appear to be beneficial. PMID- 22546025 TI - Marvelous medicine: the untold story of the Wade-Dahl-Till valve. AB - On December 5, 1960, 4-month-old Theo Dahl, the only son of best-selling author Roald Dahl (1916-1990), had his skull shattered in a horrific traffic accident. What began as a personal tragedy for the Dahl family would soon evolve into a dogged crusade by Dahl to expand upon preexisting valve technology with the goal of developing a shunt that would not become obstructed. Based upon exclusive access to private archives of the Dahl estate, as well as interviews with those involved, this article tells the intricate tale of one famous father's drive to significantly alter the natural history of pediatric hydrocephalus. Dahl's collaboration with British toymaker Stanley Wade and pioneering pediatric neurosurgeons Joseph Ransohoff, Kenneth Shulman, and Kenneth Till to create the Wade-Dahl-Till (WDT) valve is examined in detail. The ensuing rift between the American and British contingents, the valve's multiple design revisions, and the goal of creating an affordable shunt for children in developing countries are among the issues addressed. The development of the WDT valve marked a significant turning point in the surgical management of pediatric hydrocephalus in general and in shunt valve technology in particular. PMID- 22546026 TI - Controlled hypotension and blood loss during frontoorbital advancement. AB - OBJECT: Controlled hypotension is routinely used during open repair of craniosynostosis to decrease blood loss, although this benefit is unproven. In this study the authors analyzed the longitudinal relationships between intraoperative mean arterial pressure (MAP) and calculated blood loss (CBL) during frontoorbital advancement (FOA) for craniosynostosis. METHODS: The authors reviewed the records of infants with craniosynostosis who had undergone primary FOA between 1997 and 2009. Anesthesia records provided preoperative and serial intraoperative MAP. Interval measures of CBL had been determined during the course of the operation. The longitudinal relationships between MAP(mean), MAP(change), and CBL(change) were assessed over the same time interval and compared between adjacent time intervals to determine the directionality of associations. RESULTS: Ninety infants (44 males and 46 females) underwent FOA at a mean age and weight of 10.7 +/- 12.9 months and 9.0 +/- 7.0 kg, respectively. The average intraoperative MAP was 56.1 +/- 4.8 mm Hg, 22.6 +/- 12.1% lower than preoperative baseline. A negative correlation was found between CBL(change) and MAP(mean) over the same interval (r = -0.31, p < 0.05), and an inverse relationship was noted between CBL(change) of the previous interval and MAP(change) of the next interval (r = -0.07, p < 0.05). Finally, there was no significant association between MAP(change) of the previous interval and CBL(change) of the next interval. CONCLUSIONS: Calculated blood loss demonstrated a negative correlation with MAP during FOA. Directionality testing indicated that MAP did not affect intraoperative blood loss; instead, blood loss drove changes in MAP. Overall, these findings challenge the benefit of controlled hypotension during open craniofacial repair. PMID- 22546024 TI - Center effect and other factors influencing temporization and shunting of cerebrospinal fluid in preterm infants with intraventricular hemorrhage. AB - OBJECT: There is little consensus regarding the indications for surgical CSF diversion (either with implanted temporizing devices [reservoir or subgaleal shunt] or shunt alone) in preterm infants with posthemorrhagic hydrocephalus. The authors determined clinical and neuroimaging factors associated with the use of surgical CSF diversion among neonates with intraventricular hemorrhage (IVH), and describe variations in practice patterns across 4 large pediatric centers. METHODS: The use of implanted temporizing devices and conversion to permanent shunts was examined in a consecutive sample of 110 neonates surgically treated for IVH related to prematurity from the 4 clinical centers of the Hydrocephalus Clinical Research Network (HCRN). Clinical, neuroimaging, and so-called processes of care factors were analyzed. RESULTS: Seventy-three (66%) of the patients underwent temporization procedures, including 50 ventricular reservoir and 23 subgaleal shunt placements. Center (p < 0.001), increasing ventricular size (p = 0.04), and bradycardia (p = 0.07) were associated with the use of an implanted temporizing device, whereas apnea, occipitofrontal circumference (OFC), and fontanel assessments were not. Implanted temporizing devices were converted to permanent shunts in 65 (89%) of the 73 neonates. Only a full fontanel (p < 0.001) and increased ventricular size (p = 0.002) were associated with conversion of the temporizing devices to permanent shunts, whereas center, OFCs, and clot characteristics were not. CONCLUSIONS: Considerable center variability exists in neurosurgical approaches to temporization of IVH in prematurity within the HCRN; however, variation between centers is not seen with permanent shunting. Increasing ventricular size-rather than classic clinical findings such as increasing OFCs-represents the threshold for either temporization or shunting of CSF. PMID- 22546027 TI - Follow-up imaging to detect recurrence of surgically treated pediatric arteriovenous malformations. AB - OBJECT: The true postoperative incidence of arteriovenous malformation (AVM) recurrence in the pediatric population remains largely unreported. Some literature suggests that delayed imaging studies should be obtained at 6 months to 1 year after negative findings on a postoperative angiogram. The aim of this study was to describe the timing of AVM recurrences after resection and the neuroimaging modalities on which the recurrences were detected. METHODS: This study was performed in a retrospective cohort of all pediatric patients treated surgically for AVM resection by a single neurosurgeon between 2005 and 2010. Patients were followed after resection with MR angiography (MRA) or conventional angiography, when possible, at various time points. A visual scale for compactness of the initial AVM nidus was used, and the score was correlated with probability of recurrence after surgery. RESULTS: A total of 28 patients (13 female, 15 male) underwent an AVM resection. In 18 patients (64.3%) an intraoperative angiogram was obtained. In 4 cases the intraoperative angiogram revealed residual AVM, and repeat resections were performed immediately. Recurrent AVMs were found in 4 children (14.3%) at 50, 51, 56, and 60 weeks after the initial resection. Recurrence risk was 0.08 per person-year. No patient with normal results on an angiogram obtained at 1 year developed a recurrence on either a 5-year angiogram or one obtained at 18 years of age. All patients with recurrence had a compactness score of 1 (diffuse AVM); a lower compactness score was associated with recurrence (p = 0.0003). CONCLUSIONS: All recurrences in this cohort occurred less than 15 months from the initial resection. The authors recommend intraoperative angiography to help ensure complete resection at the time of the surgery. Follow-up vascular imaging is crucial for detecting recurrent AVMs, and conventional angiography is preferred because MRA can miss smaller AVMs. One-year follow-up imaging detected these recurrences, and no one who had negative results on an angiogram obtained at 1 year had a late recurrence. However, not all of the patients have been followed for 5 years or until 18 years of age, so longer follow-up is required for these patients. A lower compactness score predicted recurrent AVM in this cohort. PMID- 22546029 TI - Clinicopathological analysis of nonfunctioning pituitary adenomas in patients younger than 25 years of age. AB - OBJECT: The authors evaluated the pathological and clinical characteristics of young patients with clinically nonfunctioning pituitary adenomas (NFPAs). METHODS: Twenty-one patients (13 males and 8 females) with NFPAs who were 25 years of age or younger (mean 20 years, range 13-25 years) were retrospectively investigated. The following factors were examined: results of conventional light microscopy, immunohistochemistry, and electron microscopy; clinical symptoms; tumor size and invasion on MRI; and clinical course after therapeutic procedures such as surgery and adjuvant radiotherapy. RESULTS: Two major significant findings in young patients with NFPAs were noted. First, silent subtype 3 adenomas were common, whereas silent gonadotroph adenomas were rare. Second, silent subtype 3 adenomas in young patients tended to be clinically and radiologically aggressive. CONCLUSIONS: To correct the morphological diagnosis, NFPAs in young patients should be examined by immunohistochemical analysis and electron microscopy, as well as by light microscopy. The authors' results provide information that will be useful when making decisions regarding the treatment of young patients with NFPAs. PMID- 22546028 TI - Corticospinal tract mapping in children with ruptured arteriovenous malformations using functionally guided diffusion-tensor imaging. AB - Arteriovenous malformations (AVMs) can lead to distortion or reorganization of functional brain anatomy, making localization of eloquent white matter tracts challenging. To improve the accuracy of corticospinal tract (CST) mapping, recent studies have examined the use of functional imaging techniques to help localize cortical motor activations and use these as seed points to reconstruct CSTs using diffusion-tensor imaging (DTI). The authors examined the role of pretreatment functionally guided DTI CST mapping in 3 children with ruptured AVMs. In 2 patients, magnetoencephalography motor activations were adjacent to the nidus and/or hemorrhagic cavity. However, in 1 child, functional MRI motor activations were detected in both hemispheres, suggestive of partial transfer of cortical motor function. In all children, quantitative analysis showed that fractional anisotropy values and fiber density indices were reduced in the CSTs of the hemisphere harboring the AVM compared with the unaffected side. In 2 children, CST caliber was slightly diminished, corresponding to no motor deficit in 1 patient and a temporary motor deficit in the other. In contrast, 1 child demonstrated marked reduction and displacement of the CSTs, correlating with severe motor deficit. Preoperative motor tractography data were loaded onto the intraoperative neuronavigation platform to guide complete resection of the AVM in 2 cases without permanent neurological deficits. These preliminary results confirm the feasibility of CST mapping in children with ruptured AVMs using functionally guided DTI tractography. Prospective studies are needed to assess the full value of this technique in the risk stratification, prognosis, and multimodality management of pediatric AVMs. PMID- 22546030 TI - Possible differentiation of cerebral glioblastoma into pleomorphic xanthoastrocytoma: an unusual case in an infant. AB - The authors describe an infant girl who, at 10 months of age, presented with a large right parietooccipital tumor causing increased intracranial pressure, mass effect, and midline shift. The tumor was completely resected, and the entirety of the histology was consistent with glioblastoma. She was subsequently placed on adjuvant high-dose chemotherapy consisting of carboplatin, vincristine, and temozolomide, according to Head Start III, Regimen C. Three months after the complete resection, tumor recurrence was noted on MR imaging, during the third cycle of chemotherapy, and biopsy revealed malignant astrocytoma. Given the recurrence and the patient's intolerance to chemotherapy, a palliative course was pursued. Unexpectedly, the patient was alive and had made significant developmental improvements 18 months into palliation. Subsequently, however, signs of increased intracranial pressure developed and imaging demonstrated a very large new tumor growth at the site of prior resection. The recurrence was again fully resected, but microscopy surprisingly revealed pleomorphic xanthoastrocytoma throughout. The clinicopathological and genetic features of this girl's unusual neoplasm are detailed and potential pathogenic hypotheses are explored in this report. PMID- 22546031 TI - Hyponatremia with intracranial malignant tumor resection in children. AB - OBJECT: Intracranial neoplasms are the second most common childhood cancer, and lead to significant morbidity and mortality. Hyponatremia is a complication associated with neurosurgical procedures, but children undergoing intracranial tumor resection have not been selectively studied. In this study, the authors aimed to determine the incidence and risk factors associated with hyponatremia among children undergoing intracranial neoplasm resection. METHODS: A retrospective cohort was compiled using the 2006 Kids' Inpatient Database to identify children younger than 21 years of age who underwent intracranial neoplasm resection. Hyponatremia was ascertained by diagnosis codes. Bivariate analyses were conducted using chi-square and Mann-Whitney U-tests. Logistic regression models were developed to evaluate factors associated with hyponatremia in bivariate analyses. RESULTS: Hyponatremia occurred in 205 (8.7%) of 2343 annual weighted cases, and was independently associated with tumor location in the deep brain structures and ventricles compared with the cortical area (adjusted odds ratio [aOR] 2.4; 95% CI 1.1-5.3). Hyponatremia was also associated with obstructive hydrocephalus (aOR 2.7; 95% CI 1.7-4.3) and emergency department admission (aOR 1.7; 95% CI 1.1-2.4). Hyponatremia was significantly associated with mechanical ventilation, ventriculostomy placement, ventriculoperitoneal shunt placement, and sepsis. Hyponatremia was also associated with a significantly longer average length of stay (24.6 vs 10.2 days), higher average charges ($191,000 vs $92,000), and a higher percentage of discharges to intermediate-care facilities. CONCLUSIONS: Hyponatremia commonly occurs with resection of intracranial malignant tumors, especially for lesions located in the deep brain and in patients with obstructive hydrocephalus. Hyponatremia was associated with higher morbidity. Further research is needed to develop targeted monitoring and intervention strategies to decrease perioperative hyponatremia and to determine if this could decrease the number of complications in this specialized population. PMID- 22546032 TI - Chemotherapy administration directly into the fourth ventricle in a nonhuman primate model. AB - OBJECT: The authors hypothesized that chemotherapy infusions directly into the fourth ventricle might potentially play a role in treating malignant fourth ventricular tumors. The study tested the safety and pharmacokinetics of short- and long-term infusions of methotrexate into the fourth ventricle in a new nonhuman primate model. METHODS: Six rhesus monkeys underwent posterior fossa craniectomy and catheter insertion into the fourth ventricle. In Group I (3 animals), catheters were externalized, and lumbar drain catheters were placed simultaneously to assess CSF distribution after short-term methotrexate infusions. In 2 animals, methotrexate (0.5 mg) was infused into the fourth ventricle daily for 5 days. Serial CSF and serum methotrexate levels were measured. The third animal had a postoperative neurological deficit, and the experiment was aborted prior to methotrexate administration. In Group II (3 animals), catheters were connected to a subcutaneously placed port for subsequent long-term methotrexate infusions. In 2 animals, 4 cycles of intraventricular methotrexate, each consisting of 4 daily infusions (0.5 mg), were administered over 8 weeks. The third animal received 3 cycles, and then the experiment was terminated due to self-inflicted wound breakdown. All animals underwent detailed neurological evaluations, MRI, and postmortem histological analysis. RESULTS: No neurological deficits were noted after intraventricular methotrexate infusions. Magnetic resonance images demonstrated catheter placement within the fourth ventricle and no signal changes in the brainstem or cerebellum. Histologically, two Group I animals, one of which did not receive methotrexate, had several small focal areas of brainstem injury. Two Group II animals had a small (<= 1-mm) focus of axonal degeneration in the midbrain. Intraventricular and meningeal inflammation was noted in 4 animals after methotrexate infusions (one from Group I and all three from Group II). In all Group II animals, inflammation extended minimally into brainstem parenchyma. Serum methotrexate levels were undetectable or negligible in both groups, ranging from 0.00 to 0.06 MUmol/L. In Group I, the mean peak methotrexate level in fourth ventricle CSF exceeded that in the lumbar CSF by greater than 10-fold. Statistically significant differences between fourth ventricle and lumbar AUC (area under the concentration-time curve) were detected at peaks (p = 0.04) but not at troughs (p = 0.50) or at all time collection points (p = 0.12). In Group II, peak fourth ventricle CSF methotrexate levels ranged from 84.62 to 167.89 MUmol/L (mean 115.53 +/- 15.95 MUmol/L [SD]). Trough levels ranged from 0.06 to 0.55 MUmol/L (mean 0.22 +/- 0.13 MUmol/L). CONCLUSIONS: Methotrexate can be infused into the fourth ventricle in nonhuman primates without clinical or radiographic evidence of injury. Observed inflammatory and other histological changes had no clinical correlate. This approach may have pharmacokinetic advantages over current treatment paradigms. Further experiments are warranted to determine if fourth ventricular chemotherapy infusions may benefit patients with malignant fourth ventricular tumors. PMID- 22546033 TI - Intramedullary spinal neurenteric cyst with fluid-fluid level. AB - Spinal neurenteric cysts are rare intradural extramedullary lesions of the spine, commonly located in the cervical and thoracic regions. The majority localize ventral to the spinal cord and are associated with other vertebral anomalies. Here, the authors report a rare case of a 3-year-old boy presenting with a 1-week history of meningismus followed by rapid-onset (over a few hours) paraplegia. Magnetic resonance imaging revealed an intramedullary cystic lesion with a fluid fluid level in the cervicothoracic region of the spinal cord without associated bony or soft tissue abnormalities. To the best of the authors' knowledge, such clinical and radiological presentation of a spinal neurenteric cyst has never been reported. A brief review of the pertinent literature is presented, and the possible pathophysiology of such a presentation is also discussed. PMID- 22546034 TI - Is postresective intraoperative electrocorticography predictive of seizure outcomes in children? AB - OBJECT: Intraoperative electrocorticography (ECoG) is commonly used to guide the extent of resection, especially in lesion-associated intractable epilepsy. Interictal epileptiform discharges on postresective ECoG (post-ECoG) have been predictive of seizure recurrence in some studies, particularly in adults undergoing medial temporal lobectomy, frontal lesionectomy, or low-grade glioma resection. The predictive value of postresective discharges in pediatric epilepsy surgery has not been extensively studied. METHODS: The authors retrospectively examined the charts of all 52 pediatric patients who had undergone surgery with post-ECoG and had more than 1 year of follow-up between October 1, 2003, and October 1, 2009. RESULTS: Of the 52 pediatric patients, 37 patients showed residual discharges at the end of their resection and 73% of these patients were seizure free, whereas 15 patients had no residual discharges and 60% of them were seizure-free, which was not significantly different (p = 0.36, chi-square). CONCLUSIONS: Electrocorticography-guided surgery was associated with excellent postsurgical outcome. Although this sample size was too small to detect a subtle difference, absence of epileptiform discharges on post-ECoG does not appear to predict seizure freedom in all pediatric patients referred for epilepsy surgery. Future studies with larger study samples would be necessary to confirm this finding and determine whether post-ECoG may be useful in some subsets of pediatric epilepsy surgery candidates. PMID- 22546035 TI - Association of magnetic resonance imaging identification of mesial temporal sclerosis with pathological diagnosis and surgical outcomes in children following epilepsy surgery. AB - OBJECT: Mesial temporal sclerosis (MTS) is widely recognized as a significant underlying cause of temporal lobe epilepsy. Magnetic resonance imaging is routinely used in the preoperative evaluation of children with epilepsy. The purpose of this study was to evaluate the prevalence, reliability, and prognostic value of MRI identification of MTS and MRI findings indicative of MTS in a series of patients who underwent resection of the medial temporal lobe for medically refractory epilepsy. METHODS: The authors reviewed the medical records and preoperative MRI reports of 25 patients who had undergone medial temporal resections (anterior temporal lobectomy or functional hemispherotomy) for medically intractable epilepsy. The preoperative MRI studies were presented for blinded review by 2 neuroradiologists who independently evaluated the radiographs for selected MTS features and provided a final interpretation. To quantify interrater agreement and accuracy, the findings of the 2 blinded neuroradiologists, the nonblinded clinical preoperative radiology report, and the final pathology interpretation were compared. RESULTS: The preoperative MRI studies revealed MTS in 6 patients (24%), and histopathological analysis verified MTS in 8 (32%) of 25 specimens. Six MRI features of MTS were specifically evaluated: 1) increased hippocampal signal intensity, 2) reduced hippocampal size, 3) atrophy of the ipsilateral hippocampal collateral white matter, 4) enlarged ipsilateral temporal horn, 5) reduced gray-white matter demarcation in the temporal lobe, and 6) decreased temporal lobe size. The most prevalent feature of MTS identified on MRI was a reduced hippocampal size, found in 11 of the MRI studies (44%). Analysis revealed moderate interrater agreement for MRI identification of MTS between the 2 blinded neuroradiologists and the nonblinded preoperative report (Cohen kappa 0.40-0.59). Interrater agreement was highly variable for different MTS features indicative of MTS, ranging from poor to near perfect. Agreement was highest for increased hippocampal signal and decreased temporal lobe size and was consistently poor for reduced gray-white matter demarcation. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and proportion perfect agreement were highest for increased hippocampal signal and reduced hippocampal size. An MRI finding of MTS was not predictive of seizure outcome in this small series. CONCLUSIONS: Mesial temporal sclerosis identification on brain MRI in children evaluated for medial temporal resections has a PPV of 55%-67% and an NPV of 79%-87%. Increased hippocampal signal and reduced hippocampal size were associated with high predictive values, while gray-white differentiation and an enlarged temporal horn were not predictive of MTS. Seizure outcome following medial temporal resections was not associated with MRI findings of MTS or MRI abnormalities indicative of MTS in this small sample size. PMID- 22546036 TI - Impact of an injury prevention program on teenagers' knowledge and attitudes: results of the Pense Bem-Caxias do Sul Project. AB - OBJECT: Trauma is the leading cause of mortality and morbidity in children, young people, and working-age adults. Because of the high incidence of intentional and unintentional injuries in young people, it is necessary to implement injury prevention programs and measure the efficacy of these initiatives. The authors evaluated the effectiveness of an injury-prevention program in high school students in a city in southern Brazil. METHODS: In a randomized controlled study, 1049 high school students were divided into a control group and intervention group. The study was conducted in the following 3 stages: a questionnaire was applied 1 week before the educational intervention (P0), shortly after the intervention (P1), and 5 months later (P3). In the control group, a questionnaire based on the Pense Bem Project was applied at the 3 time stages, without any intervention between the stages. RESULTS: The postintervention analysis evidenced a slight change in knowledge about unintentional spinal cord and brain injuries. Regarding attitudes, the only significant improvement after the intervention lecture was in the use of helmets, which remained high 5 months later. A substantial number of students only partially agreed with using safety behaviors. The only significant postintervention change was the major agreement to check swimming pool depth before entering the water (P0 89% and P1 97.8%, p < 0.001; P2 92.8%, p = 0.005). CONCLUSIONS: An educational intervention based on a single lecture improved students' knowledge of traumatic brain and spinal cord injuries, but this type of intervention did not modify most attitudes toward injury prevention. Clinical trial registration no.: U1111-1121-0192. PMID- 22546037 TI - Letter to the editor: Spina bifida and neuropsychology. PMID- 22546038 TI - Letter to the editor: optic nerve sheath diameter and intracranial pressure. PMID- 22546039 TI - Adjuvant treatment of HER2-positive breast cancer: winning efforts continue to improve HER2-positive patient outcome long-term. AB - Randomized adjuvant trials continue to show significant reductions in distant recurrence and death for early-stage women treated with adjuvant trastuzumab. BCIRG-006 showed superior disease-free and overall survival of two trastuzumab containing regimens in comparison to a non-trastuzumab-containing regimen. The rates of disease-free and overall survival were not statistically different for the two trastuzumab-containing arms. Ongoing study is needed to identify markers of resistance to trastuzumab and incorporate newer agents in the adjuvant setting in order to further decrease rates of distant recurrence and death from HER2 positive breast cancer. PMID- 22546040 TI - Toxoplasma gondii sexual cross in a single naturally infected feline host: generation of highly mouse-virulent and avirulent clones, genotypically different from clonal types I, II and III. AB - Tachyzoite clones obtained from a single Toxoplasma gondii oocyst field sample were genotyped and characterized regarding mouse virulence. PCR-RFLP genotyping of tachyzoites initially isolated from interferon-gamma-knockout (GKO) mice, BALB/c mice and VERO cell culture using the nine independent, unlinked genetic markers nSAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1 and Apico revealed mixed T. gondii infections showing combinations of type II and type III alleles at different loci. Forty-five individual clones were obtained from all mixed T. gondii tachyzoite cell cultures by limiting dilution. Sixteen T. gondii clones showed type III alleles at all loci and 29 clones displayed a combination of type II and type III alleles at different loci. Five clone groups were identified in total, four of which include T. gondii clones that showed a non-canonical allele pattern and have never been described in natural infections before. All tested clones, except two, were highly virulent in BALB/c mice. The isolation of different non-canonical T. gondii clones originating from an oocyst sample of a single naturally infected cat demonstrate that sexual recombination as well as re assortment of chromosomes via a sexual cross of T. gondii occur under natural conditions and result in the emergence of clones with increased virulence in mice. PMID- 22546042 TI - Spirituality and chaplaincy in palliative care. PMID- 22546041 TI - Cross-sectional analysis of association between socioeconomic status and utilization of primary total hip joint replacements 2006-7: Australian Orthopaedic Association National Joint Replacement Registry. AB - BACKGROUND: The utilization of total hip replacement (THR) surgery is rapidly increasing, however few data examine whether these procedures are associated with socioeconomic status (SES) within Australia. This study examined primary THR across SES for both genders for the Barwon Statistical Division (BSD) of Victoria, Australia. METHODS: Using the Australian Orthopaedic Association National Joint Replacement Registry data for 2006-7, primary THR with a diagnosis of osteoarthritis (OA) among residents of the BSD was ascertained. The Index of Relative Socioeconomic Disadvantage was used to measure SES; determined by matching residential addresses with Australian Bureau of Statistics census data. The data were categorised into quintiles; quintile 1 indicating the most disadvantaged. Age- and sex-specific rates of primary THR per 1,000 person years were reported for 10-year age bands using the total population at risk. RESULTS: Females accounted for 46.9% of the 642 primary THR performed during 2006-7. THR utilization per 1,000 person years was 1.9 for males and 1.5 for females. The highest utilization of primary THR was observed in those aged 70-79 years (males 6.1, and females 5.4 per 1,000 person years). Overall, the U-shaped pattern of THR across SES gave the appearance of bimodality for both males and females, whereby rates were greater for both the most disadvantaged and least disadvantaged groups. CONCLUSIONS: Further work on a larger scale is required to determine whether relationships between SES and THR utilization for the diagnosis of OA is attributable to lifestyle factors related to SES, or alternatively reflects geographic and health system biases. Identifying contributing factors associated with SES may enhance resource planning and enable more effective and focussed preventive strategies for hip OA. PMID- 22546043 TI - Facing fears and counting blessings: a case study of a chaplain's faithful companioning a cancer patient. AB - This article offers a case study of a long-term chaplaincy care relationship between a woman with recurrent leukemia and an experienced oncology chaplain at a comprehensive cancer center. The case includes an extensive description of the encounters between the patient and the chaplain; a spiritual/religious assessment that includes a spiritual/religious profile and a portrait of the needs, interventions, and outcomes within the case; and a discussion of some key issues in the case, including what aspects regarding the overall care was healing. Although a number of issues were addressed, the author argues that the essence of the care and healing occurred through the faithful companioning of the chaplain. The author articulates an understanding of faithful companioning. PMID- 22546044 TI - A pastoral theologian's response to the case study. AB - This response to a case study of a long-term chaplaincy care relationship between a woman with recurrent leukemia and an experienced oncology chaplain at a comprehensive cancer center expresses a clinical attitude formed within three contexts-pastoral psychotherapy, the supervision of psychoanalytically-oriented psychotherapy, and pastoral theology-through which case studies are to be engaged, concurrently, in multiple ways. Illustrating this attitude, the response outlines four distinct "readings" (Ricoeur) of the case study that express different approaches: a personal engagement that a reader can feel; an empathic openness to the plausibility of the chaplain's account; a recognition of the complexity of the report and of the care as constituted of different disciplines and guilds; and an awareness of the difference and distance between a patient's experience and a caregiver's interpretation of a patient's experience. PMID- 22546045 TI - The chaplain as faithful companion: a response to King's case study. AB - This article is a response to a case study describing the spiritual care provided over an 18-month period by an experienced professional chaplain at a prominent cancer center to a woman undergoing stem cell transplantation following therapy for relapsed leukemia. The author, a professional chaplain at another cancer center, reviews the spiritual assessment, interventions, and outcomes presented by the attending chaplain. The author's comments are organized about the chaplain's characterization of the seven parts of the patient's spiritual profile: courage, meaning, psychological issues, courage and growth in facing spiritual/religious struggle, rituals, community, and authority. The purpose of the response is to engage those inside and outside the discipline of health care chaplaincy in a conversation about the specific aspects of providing spiritual care in health care settings. PMID- 22546046 TI - Three doors to spiritual reflection: ethnographic research on the role of emotion, images, and sacred texts in spiritual reflection done by non-chaplaincy health care professionals. AB - This is an ethnographic study exploring the role of emotion, images, and sacred texts in the spiritual reflection of non-chaplaincy health care professionals who offer spiritual care to their patients. Purposeful sampling of 20 health care professionals was employed. These non-chaplaincy professionals were interviewed and the researchers also kept field notes on the cultures in which they worked. Both interviews and field notes were transcribed and analyzed using the constant comparative method of data analysis. Findings indicate that emotion and images are the main doors that these professionals use to reflect spiritually on their practice of spiritual care. Sacred texts are the third door. Outcomes of the use of feelings and emotions in spiritual reflection are a deeper sense of peace, grounding and letting go, that is, transformation. Recommendations for collaboration with chaplains and further research are offered. PMID- 22546047 TI - Forgiveness and health: psycho-spiritual integration and the promotion of better healthcare. AB - Psychology and religiousness/spirituality continue to be perceived as incongruent and incompatible, often resulting in a disconnection and suboptimal level of collaboration between the two fields to the detriment of healthcare. Nevertheless, forgiveness, or an absence of ill will, is a construct central to both mainstream world religion/spirituality and the field of psychology. Understanding and recognizing the construct of forgiveness and its mutually central application can foster increased collaboration between the fields. As a result, individually and collectively, the two fields will be better able to expand and further develop their many shared principles in the service of better healthcare. PMID- 22546048 TI - A survey of chaplains' roles in pediatric palliative care: integral members of the team. AB - To date, the field of health care chaplaincy has had little information about how pediatric palliative care (PPC) programs meet the spiritual needs of patients and families. We conducted a qualitative study consisting of surveys of 28 well established PPC programs in the United States followed by interviews with medical directors and professional chaplains in 8 randomly selected programs among those surveyed. In this report, we describe the PPC chaplain activities, evidence regarding chaplain integration with the PPC team, and physician and chaplain perspectives on the chaplains' contributions. Chaplains described their work in terms of processes such as presence, while physicians emphasized outcomes of chaplains' care such as improved communication. Learning to translate what they do into the language of outcomes will help chaplains improve health care colleagues' understanding of chaplains' contributions to care for PPC patients and their families. In addition, future research should describe the spiritual needs and resources of PPC patients and families and examine the contribution chaplains make to improved outcomes for families and children facing life limiting illnesses. PMID- 22546050 TI - Metabolomics: the final frontier? PMID- 22546049 TI - Mechanically durable and highly conductive elastomeric composites from long single-walled carbon nanotubes mimicking the chain structure of polymers. AB - By using long single-walled carbon nanotubes (SWNTs) as a filler possessing the highest aspect ratio and small diameter, we mimicked the chain structure of polymers in the matrix and realized a highly conductive elastomeric composite (30 S/cm) with an excellent mechanical durability (4500 strain cycles until failure), far superior to any other reported conductive elastomers. This exceptional mechanical durability was explained by the ability of long and traversing SWNTs to deform in concert with the elastomer with minimum stress concentration at their interfaces. The conductivity was sufficient to operate many active electronics components, and thus this material would be useful for practical stretchable electronic devices. PMID- 22546051 TI - Detecting and destroying cancer cells in more than one way with noble metals and different confinement properties on the nanoscale. AB - Today, 1 in 2 males and 1 in 3 females in the United States will develop cancer at some point during their lifetimes, and 1 in 4 males and 1 in 5 females in the United States will die from the disease. New methods for detection and treatment have dramatically improved cancer care in the United States. However, as improved detection and increasing exposure to carcinogens has led to higher rates of cancer incidence, clinicians and researchers have not balanced that increase with a similar decrease in cancer mortality rates. This mismatch highlights a clear and urgent need for increasingly potent and selective methods with which to detect and treat cancers at their earliest stages. Nanotechnology, the use of materials with structural features ranging from 1 to 100 nm in size, has dramatically altered the design, use, and delivery of cancer diagnostic and therapeutic agents. The unique and newly discovered properties of these structures can enhance the specificities with which biomedical agents are delivered, complementing their efficacy or diminishing unintended side effects. Gold (and silver) nanotechnologies afford a particularly unique set of physiological and optical properties which can be leveraged in applications ranging from in vitro/vivo therapeutics and drug delivery to imaging and diagnostics, surgical guidance, and treatment monitoring. Nanoscale diagnostic and therapeutic agents have been in use since the development of micellar nanocarriers and polymer-drug nanoconjugates in the mid-1950s, liposomes by Bangham and Watkins in the mid-1960s, and the introduction of polymeric nanoparticles by Langer and Folkman in 1976. Since then, nanoscale constructs such as dendrimers, protein nanoconjugates, and inorganic nanoparticles have been developed for the systemic delivery of agents to specific disease sites. Today, more than 20 FDA-approved diagnostic or therapeutic nanotechnologies are in clinical use with roughly 250 others in clinical development. The global market for nano-enabled medical technologies is expected to grow to $70-160 billion by 2015, rivaling the current market share of biologics worldwide. In this Account, we explore the emerging applications of noble metal nanotechnologies in cancer diagnostics and therapeutics carried out by our group and by others. Many of the novel biomedical properties associated with gold and silver nanoparticles arise from confinement effects: (i) the confinement of photons within the particle which can lead to dramatic electromagnetic scattering and absorption (useful in sensing and heating applications, respectively); (ii) the confinement of molecules around the nanoparticle (useful in drug delivery); and (iii) the cellular/subcellular confinement of particles within malignant cells (such as selective, nuclear-targeted cytotoxic DNA damage by gold nanoparticles). We then describe how these confinement effects relate to specific aspects of diagnosis and treatment such as (i) laser photothermal therapy, optical scattering microscopy, and spectroscopic detection, (ii) drug targeting and delivery, and (iii) the ability of these structures to act as intrinsic therapeutic agents which can selectively perturb/inhibit cellular functions such as division. We intend to provide the reader with a unique physical and chemical perspective on both the design and application of these technologies in cancer diagnostics and therapeutics. We also suggest a framework for approaching future research in the field. PMID- 22546052 TI - Bioceramic-mediated trophic factor secretion by mesenchymal stem cells enhances in vitro endothelial cell persistence and in vivo angiogenesis. AB - Mesenchymal stem cells (MSCs) seeded in composite implants formed of hydroxyapatite (HA) and poly (lactide-co-glycolide) (PLG) exhibit increased osteogenesis and enhanced angiogenic potential. Endothelial colony-forming cells (ECFCs) can participate in de novo vessel formation when implanted in vivo. The aim of this study was to determine the capacity of HA-PLG composites to cotransplant MSCs and ECFCs, with the goal of accelerating vascularization and resultant bone formation. The incorporation of HA into PLG scaffolds improved the efficiency of cell seeding and ECFC survival in vitro. We observed increases in mRNA expression and secretion of potent angiogenic factors by MSCs when cultured on HA-PLG scaffolds compared to PLG controls. Upon implantation into an orthotopic calvarial defect, ECFC survival on composite scaffolds was not increased in the presence of MSCs, nor did the addition of ECFCs enhance vascularization beyond increases observed with MSCs alone. Microcomputed tomography (micro-CT) performed on explanted calvarial tissues after 12 weeks revealed no significant differences between treatment groups for bone volume fraction (BVF) or bone mineral density (BMD). Taken together, these results provide evidence that HA-containing composite scaffolds seeded with MSCs can enhance neovascularization, yet MSC-secreted trophic factors do not consistently increase the persistence of co-transplanted ECFCs. PMID- 22546053 TI - The effects of midwives' job satisfaction on burnout, intention to quit and turnover: a longitudinal study in Senegal. AB - BACKGROUND: Despite working in a challenging environment plagued by persistent personnel shortages, public sector midwives in Senegal play a key role in tackling maternal mortality. A better understanding of how they are experiencing their work and how it is affecting them is needed in order to better address their needs and incite them to remain in their posts. This study aims to explore their job satisfaction and its effects on their burnout, intention to quit and professional mobility. METHODS: A cohort of 226 midwives from 22 hospitals across Senegal participated in this longitudinal study. Their job satisfaction was measured from December 2007 to February 2008 using a multifaceted instrument developed in West Africa. Three expected effects were measured two years later: burnout, intention to quit and turnover. Descriptive statistics were reported for the midwives who stayed and left their posts during the study period. A series of multiple regressions investigated the correlations between the nine facets of job satisfaction and each effect variable, while controlling for individual and institutional characteristics. RESULTS: Despite nearly two thirds (58.9%) of midwives reporting the intention to quit within a year (mainly to pursue new professional training), only 9% annual turnover was found in the study (41/226 over 2 years). Departures were largely voluntary (92%) and entirely domestic. Overall the midwives reported themselves moderately satisfied; least contented with their "remuneration" and "work environment" and most satisfied with the "morale" and "job security" facets of their work. On the three dimensions of the Maslach Burnout Inventory, very high levels of emotional exhaustion (80.0%) and depersonalization (57.8%) were reported, while levels of diminished personal accomplishment were low (12.4%). Burnout was identified in more than half of the sample (55%). Experiencing emotional exhaustion was inversely associated with "remuneration" and "task" satisfaction, actively job searching was associated with being dissatisfied with job "security" and voluntary quitting was associated with dissatisfaction with "continuing education". CONCLUSIONS: This study found that although midwives seem to be experiencing burnout and unhappiness with their working conditions, they retain a strong sense of confidence and accomplishment in their work. It also suggests that strategies to retain them in their positions and in the profession should emphasize continuing education. PMID- 22546054 TI - Current challenges in de novo plant genome sequencing and assembly. AB - Genome sequencing is now affordable, but assembling plant genomes de novo remains challenging. We assess the state of the art of assembly and review the best practices for the community. PMID- 22546056 TI - A review of the clinical utility of INR to monitor and guide administration of prothrombin complex concentrate to orally anticoagulated patients. AB - BACKGROUND AND OBJECTIVES: The number of patients treated with oral anticoagulation (OAC) is increasing and these patients are monitored by International Normalized Ratio (INR). Bleeding complications are common and we speculate if this is related to the limitation of INR only reflecting the initiation steps of the haemostatic process. The objective of the present review was to reassess the evidence for using INR as a tool to guide administration of prothrombin complex concentrates (PCC) to OAC patients. A Medline and Cochrane database search was conducted using the following keywords: prothrombin complex concentrate, reversal of oral anticoagulation and international normalized ratio (INR). Thirty-three articles were contracted and a total of ten studies were eligible after applying inclusion and exclusion criteria encompassing only 339 patients. No consensus regarding optimal target INR value to aim for when reversing OAC was found. In three of the studies it was reported that patients reaching their target INR continued to bleed, whereas three studies reviewed reported good haemostatic response also in patients that did not reach their target INR. The present review found limited evidence for the usefulness of INR as a tool to monitor and guide reversal of OAC induced coagulopathy in patients with PCC, which is expected given that it is a plasma-based assay only reflecting a limited part of the haemostatic process. PMID- 22546057 TI - Ultrafast vibrational dynamics of water confined in phospholipid reverse micelles. AB - Ultrafast dynamics of OH stretching excitations of H2O confined in dioleoylphosphatidylcholine (DOPC) reverse micelles, a phospholipid model system, are studied in femtosecond pump-probe experiments. Measurements in a wide range of hydration show that spectral diffusion within the OH stretching band accelerates substantially with increasing water content. Concomitantly, the OH stretching lifetime decreases from approximately 500 fs at a 1:1 ratio of water and DOPC molecules (w0 = 1) to 300 fs for large water pools (ratio 16:1, w0 = 16). Two-color pump-probe studies mapping the ultrafast OH bending response after OH stretch excitation demonstrate that the relaxation pathway of the OH stretch vibration involves the OH bending mode. After OH stretch relaxation at high hydration levels, vibrational excess energy is randomized within the water pool and then transferred to the surrounding solvent. PMID- 22546058 TI - Autism in adult life. PMID- 22546059 TI - Adults with autism spectrum disorders. AB - In the decades since autism was first formally described in the 1940s, there have been major advances in research relating to diagnosis, causation, and treatment approaches for children with this condition. However, research into prognosis, outcomes, or effective interventions for adults with autism spectrum disorders (ASDs) is much more limited. In this paper, we review studies of outcome in adulthood. The findings indicate that, as adults, many people with ASD, including those of normal IQ, are significantly disadvantaged regarding employment, social relationships, physical and mental health, and quality of life. Support to facilitate integration within the wider society is frequently lacking, and there has been almost no research into ways of developing more effective intervention programs for adults. Moreover, most of the research on outcome has involved relatively young people in their 20s and 30s-much less is known about outcomes for people with ASD as they reach mid-late adulthood. Systematic follow-up studies from childhood through adulthood are needed if we are to gain a better understanding of trajectories of development over the lifespan, to identify the factors that influence prognosis, and to determine how these factors exert their effects and how they may be modified to ensure a better future. PMID- 22546055 TI - Emerging complexities of APOBEC3G action on immunity and viral fitness during HIV infection and treatment. AB - The enzyme APOBEC3G (A3G) mutates the human immunodeficiency virus (HIV) genome by converting deoxycytidine (dC) to deoxyuridine (dU) on minus strand viral DNA during reverse transcription. A3G restricts viral propagation by degrading or incapacitating the coding ability of the HIV genome. Thus, this enzyme has been perceived as an innate immune barrier to viral replication whilst adaptive immunity responses escalate to effective levels. The discovery of A3G less than a decade ago led to the promise of new anti-viral therapies based on manipulation of its cellular expression and/or activity. The rationale for therapeutic approaches has been solidified by demonstration of the effectiveness of A3G in diminishing viral replication in cell culture systems of HIV infection, reports of its mutational footprint in virions from patients, and recognition of its unusually robust enzymatic potential in biochemical studies in vitro. Despite its effectiveness in various experimental systems, numerous recent studies have shown that the ability of A3G to combat HIV in the physiological setting is severely limited. In fact, it has become apparent that its mutational activity may actually enhance viral fitness by accelerating HIV evolution towards the evasion of both anti-viral drugs and the immune system. This body of work suggests that the role of A3G in HIV infection is more complex than heretofore appreciated and supports the hypothesis that HIV has evolved to exploit the action of this host factor. Here we present an overview of recent data that bring to light historical overestimation of A3G's standing as a strictly anti-viral agent. We discuss the limitations of experimental systems used to assess its activities as well as caveats in data interpretation. PMID- 22546060 TI - Services for adults with an autism spectrum disorder. AB - The need for useful evidence about services is increasing as larger numbers of children identified with an autism spectrum disorder (ASD) age toward adulthood. The objective of this review was to characterize the topical and methodological aspects of research on services for supporting success in work, education, and social participation among adults with an ASD and to propose recommendations for moving this area of research forward. We reviewed the literature published in English from 2000 to 2010 and found that the evidence base about services for adults with an ASD is underdeveloped and can be considered a field of inquiry that is relatively unformed. Extant research does not reflect the demographic or impairment heterogeneity of the population, the range of services that adults with autism require to function with purposeful lives in the community, and the need for coordination across service systems and sectors. Future studies must examine issues related to cost and efficiency, given the broader sociopolitical and economic context of service provision. Further, future research needs to consider how demographic and impairment heterogeneity have implications for building an evidence base that will have greater external validity. PMID- 22546061 TI - Metabolic monitoring training program implementation in the community setting was associated with improved monitoring in second-generation antipsychotic-treated children. AB - OBJECTIVE: To determine whether implementation of a metabolic monitoring training program (MMTP) in an urban community-based setting improved monitoring in children treated with second-generation antipsychotics (SGAs) and changed prescription rates of SGAs to children. METHOD: The MMTP was implemented in the Vancouver Coastal Health Child and Youth Mental Health Teams (CYMHTs) on January 1, 2009. A retrospective review of paper charts and electronic records for children seen at the CYMHTs from September 1, 2007, to May 1, 2010, was performed to collect the following data: age, sex, foster care, immigrant status, Axis I diagnosis, and medications. In SGA-treated children, anthropometric measurements and blood work completed at baseline and 3, 6, and 12 months were also collected. RESULTS: Among the 1114 children seen pre-MMTP and 1262 children seen post-MMTP implementation, 174 (15.4%) and 81 (6.4%), respectively, were SGA-treated (P < 0.001). Among the SGA-treated children seen at the CYMHTs after MMTP implementation, 38.3% had a copy of the MMTP in their paper chart. Metabolic monitoring increased by up to 40% at baseline (P < 0.01), 20% at 3 (P < 0.01) and 6 months (P < 0.01), and 18% at 12 months after MMTP implementation. CONCLUSIONS: Implementation of an MMTP was associated with significantly improved monitoring rates of anthropometric and blood work parameters at baseline and the 3- and 6 month time points, with a trend for improvement at the 12-month time point, in SGA-treated children cared for in urban community mental health clinics. In addition, a 56% decrease in SGA prescriptions was observed following MMTP implementation in this population. PMID- 22546062 TI - Comparing the clinical presentation of first-episode psychosis across different migrant and ethnic minority groups in Montreal, Quebec. AB - OBJECTIVE: To explore differences in severity and nature of symptoms of first episode psychosis (FEP) according to ethnic group and migrant status. METHOD: We administered rating scales to assess positive and negative symptoms, as well as general psychopathology, to 301 consecutive patients presenting with an FEP within a defined catchment area in Montreal, Quebec, classified according to ethnicity and migrant status. Symptom scores of Euro-Canadian patients without a recent history of migration, that is, the reference group (n = 145), were compared with those of African and Afro-Caribbean (n = 39), Asian (n = 27), Central and South American (n = 15), Middle Eastern and North African (n = 24), and European and North American (n = 39) patients. RESULTS: Except for referral source, there were no significant differences between ethnic groups on any demographic variables. The African and Afro-Caribbean group had a higher level of negative symptoms (especially alogia) and general psychopathology scores on the Positive and Negative Syndrome Scale (especially, uncooperativeness, preoccupation, and poor attention), compared with the reference group. Ethnic groups did not differ on the Scale for the Assessment of Positive Symptoms scores. CONCLUSIONS: A comparison of FEP patients from different ethnic groups and native-born Euro-Canadians revealed no significant differences in the nature of positive symptoms at first presentation or in age at onset, suggesting that there was no evidence for the hypothesis that ethnic minorities are misdiagnosed as psychotic. Increased severity of negative symptoms and general psychopathology, specifically among the black ethnic minority group, may have implications for the role of ethnicity for the treatment and outcome of the initial episode of psychotic disorders. PMID- 22546063 TI - Perceived relational evaluation as a predictor of self-esteem and mood in people with a psychotic disorder. AB - OBJECTIVE: There is evidence that social support predicts self-esteem and related moods for people with psychotic disorders. However, there has been little investigation of relative importance of specific components of social support. Evidence from social psychology suggests that perceived relational evaluation (PRE) or the extent to which people see others as valuing them, is a particularly important determinant of self-esteem and mood. Our study compared the importance of PRE and other types of social support, in predicting self-esteem and depressive mood, anxiety, and anger-hostility in a sample of patients in an early intervention program for psychotic disorders. METHOD: One hundred and two patients of the Prevention and Early Intervention Program for Psychoses in London, Ontario, completed measures of PRE, appraisal, tangible and general emotional social support, self-esteem, and mood. In addition, ratings of positive and negative symptoms were completed for all participants. RESULTS: In general, perceived relational value was the most important predictor of self-esteem and mood. These relations were not a result of confounding with positive or negative symptoms. CONCLUSIONS: PRE appears to be a particularly important aspect of social support in predicting self-esteem and mood states. Possible implications of these findings and future research directions are discussed. PMID- 22546064 TI - Conformance to evidence-based treatment recommendations in schizophrenia treatment services. AB - OBJECTIVE: To assess quality of health care provided in a representative Canadian mental health service using conformance to evidence-based treatment recommendations, and to examine differences from published US results. METHOD: We used a cross-sectional cohort design involving a randomly selected sample of patients diagnosed with schizophrenia attending 1 of 3 mental health clinics in 1 Canadian regional health system. The sample size was calculated to detect differences with the US sample. Conformance criteria were based on a published protocol. Data were collected using patient interviews and a structured review of health records. Conformance to 9 key Schizophrenia Patient Outcomes Research Team recommendations was assessed. RESULTS: Conformance ranged between 58% and 90% for pharmacological recommendations, and 0% to 81% for psychosocial recommendations. No patients who met criteria for assertive case management had been referred to an assertive case management team. Significant differences in conformance rates to some treatment recommendations were found between Canadian and published US results. CONCLUSIONS: It proved possible to assess health care quality using process measures of conformance to treatment recommendations. Conformance to clinical recommendations for pharmacotherapy is higher than for psychosocial therapies. The absence of barriers to access for pharmacological therapies likely enhances the higher conformance to these recommendations. Limited or variable access to psychosocial services, specifically assertive community treatment, likely negatively affects conformance to psychosocial treatment recommendations. Methodological limitations preclude drawing conclusions on comparisons between Canadian and US services. PMID- 22546065 TI - Is mental health in the Canadian population changing over time? AB - OBJECTIVE: Mental health in populations may be deteriorating, or it may be improving, but there is little direct evidence to support either possibility. Our objective was to examine secular trends in mental health indicators from national data sources. METHODS: We used data (1994-2008) from the National Population Health Survey and from a series of cross-sectional studies (Canadian Community Health Survey) conducted in 2001, 2003, 2005, and 2007. We calculated population weighted proportions and also generated sex-specific, age-standardized estimates of major depressive episode prevalence, distress, professionally diagnosed mood disorders, antidepressant use, self-rated perceived mental health, and self-rated stress. RESULTS: Major depression prevalence did not change over time. No changes in the frequency of severe distress were seen. However, there were increases in reported diagnoses of mood disorders and an increasing proportion of the population reported that they were taking antidepressants. The proportion of the population reporting that their life was extremely stressful decreased, but the proportion reporting poor mental health did not change. CONCLUSIONS: Measures based on assessment of symptoms showed no evidence of change over time. However, the frequency of diagnosis and treatment appears to be increasing and perceptions of extreme stress are decreasing. These changes probably reflect changes in diagnostic practice, mental health literacy, or willingness to report mental health concerns. However, no direct evidence of changing mental health status was found. PMID- 22546066 TI - A polynomial time algorithm for calculating the probability of a ranked gene tree given a species tree. AB - BACKGROUND: The ancestries of genes form gene trees which do not necessarily have the same topology as the species tree due to incomplete lineage sorting. Available algorithms determining the probability of a gene tree given a species tree require exponential computational runtime. RESULTS: In this paper, we provide a polynomial time algorithm to calculate the probability of a ranked gene tree topology for a given species tree, where a ranked tree topology is a tree topology with the internal vertices being ordered. The probability of a gene tree topology can thus be calculated in polynomial time if the number of orderings of the internal vertices is a polynomial number. However, the complexity of calculating the probability of a gene tree topology with an exponential number of rankings for a given species tree remains unknown. CONCLUSIONS: Polynomial algorithms for calculating ranked gene tree probabilities may become useful in developing methodology to infer species trees based on a collection of gene trees, leading to a more accurate reconstruction of ancestral species relationships. PMID- 22546067 TI - Endpoints for randomised controlled trials in systemic lupus erythematosus. PMID- 22546068 TI - Ultrasound imaging for the rheumatologist XXXVIII. Sonographic assessment of the hip in psoriatic arthritis patients. AB - OBJECTIVES: The aims of our study were to investigate the prevalence of ultrasound (US) pathological abnormalities in the hip of psoriatic arthritis (PsA) patients and compare them with the clinical findings. METHODS: Sixty-five PsA patients were enrolled in the study. Bilateral examination of the hip was performed to detect joint effusion, synovial hypertrophy, irregularity of femoral head and neck profile as seen in erosions and/or osteophytes. RESULTS: Joint effusion was detected in 20 out of 130 hips (15%). Synovial hypertrophy was present in 12 out of 20 hips (60%) associated with effusion (9.3% of all hip joints) and only 1 of them showed PD signal. Small effusion without synovial proliferation was imaged in 8 out of 20 hips (40%). On the whole 14 out of 65 patients (21%) had joint effusion with or without synovial hypertrophy using US. No erosions of the femoral head and neck profile were detected whilst osteophytes were imaged in 27 joints (20%). No US abnormalities were demonstrated in 18 hips with pain/tenderness on physical examination, whilst joint effusion was seen in 8 joints which were asymptomatic. CONCLUSIONS: US is a useful imaging method to evaluate hip involvement in PsA that could be integrated into routine PsA management even if patients do not complain of hip involvement. PMID- 22546069 TI - The cost of care of rheumatoid arthritis and ankylosing spondylitis patients in tertiary care rheumatology units in Turkey. AB - OBJECTIVES: To determine the direct and indirect costs due to rheumatoid arthritis (RA) and ankylosing spondylitis (AS) patients in Turkey. METHODS: An expert panel was convened to estimate the direct and indirect costs of care of patients with RA and AS in Turkey. The panel was composed of 22 experts chosen from all national tertiary care rheumatology units (n=53). To calculate direct costs, the medical management of RA and AS patients was estimated using 'cost-of illness' methodology. To measure indirect costs, the number of days of sick leave, the extent of disability, and the levels of early retirement and early death were also evaluated. Lost productivity costs were calculated using the 'human capital approach', based on the minimum wage. RESULTS: The total annual direct costs were 2,917.03 Euros per RA patient and 3,565.9 Euros for each AS patient. The direct costs were thus substantial, but the indirect costs were much higher because of extensive morbidity and mortality rates. The total annual indirect costs were 7,058.99 Euros per RA patient and 6,989.81 for each AS patient. Thus, the total cost for each RA patient was 9,976.01 Euros and that for an AS patient 10,555.72 Euros, in Turkey. CONCLUSIONS: From the societal perspective, both RA and AS have become burden in Turkey. The cost of lost productivity is higher than the medical cost. Another important conclusion is that indirect costs constitute 70% and 66% of total costs in patients with RA and AS, respectively. PMID- 22546070 TI - Economic burden of osteoporosis in women: data from the 2008 French hospital database (PMSI). AB - OBJECTIVES: To estimate the number and costs of hospitalisations associated with osteoporosis in France. METHODS: Data for women aged 50 years and over were extracted from the 2008 French Hospital National Database. Criteria for acute care were established according to ICD-10 codes related to osteoporosis. As coding rules are not systematically used, an additional extraction which included surgical stays for hip fractures was performed in order to be more exhaustive. The two datasets were merged and duplicate stays excluded. Among women hospitalised in acute care during 2008, we selected those progressing to rehabilitation care within the year. We assessed the numbers of hospitalisations and women, proportion of surgical management, length of stay in acute care and numbers of rehabilitation days and costs. Hospital costs were calculated according to the National Hospital Tariff and National Scale of Costs, respectively, for acute and rehabilitation care based on 2009 tariffs. RESULTS: There were 67.807 hospitalisations (64.793 patients) associated with osteoporosis; 83% of total hospitalisations were in patients aged >=75 years. A total of 80% of hospitalisations were associated with surgical management of fractures and 31.458 patients (49%) progressed from hospitalisation to rehabilitation. The mean +/-SD length of stay was 12+/-8 days for hospitalisation and 43+/-31 days for rehabilitation care. The overall cost of hospitalisations was ?415.4 million, of which 4.2% was related to medical devices. The overall cost of rehabilitation was ?331.8 million. CONCLUSIONS: In 2008, postmenopausal osteoporosis was associated with a substantial economic burden at hospital in France. PMID- 22546072 TI - Sensory integration and activities of daily living in children with developmental coordination disorder. AB - OBJECTIVE: The aim of our study was to evaluate sensory integration and activities of daily living in children with developmental coordination disorder SUBJECTS AND METHODS: 37 cases with developmental coordination disorder and 35 healthy age-matched peers were included in this study. Ayres Southern California Sensory Integration Test was used for evaluating the sensory integration and Functional Independence Measure for Children (WeeFIM) was used for evaluating the activities of daily living. RESULTS: Significant differences were found in the visual shape perception, position in space, and design copying (p < 0.05). According to the results of somatosensory perception tests, significant differences were found in kinesthesia, manual form perception, finger identification, figure-ground perception, localization of tactile stimuli, double tactile stimuli perception (p < 0.05). Control group was better in motor planning (p < 0.05). Comprehension, expression, social communication, problem solving, and memory skills were significant in favor of the control group (p < 0.05). Graphestesia and self-care domain was found to be correlated (r = 0,491, p = 0.002) between the groups. DISCUSSION: Special education and rehabilitation programs including sensory integration therapy and motor performance will increase independence in the activities of daily living in children with developmental coordination disorder. PMID- 22546071 TI - Involvement of the skin during bluetongue virus infection and replication in the ruminant host. AB - Bluetongue virus (BTV) is a double stranded (ds) RNA virus (genus Orbivirus; family Reoviridae), which is considered capable of infecting all species of domestic and wild ruminants, although clinical signs are seen mostly in sheep. BTV is arthropod-borne ("arbovirus") and able to productively infect and replicate in many different cell types of both insects and mammalian hosts. Although the organ and cellular tropism of BTV in ruminants has been the subject of several studies, many aspects of its pathogenesis are still poorly understood, partly because of inherent problems in distinguishing between "virus replication" and "virus presence".BTV replication and organ tropism were studied in a wide range of infected sheep tissues, by immuno-fluorescence-labeling of non structural or structural proteins (NS2 or VP7 and core proteins, respectively) using confocal microscopy to distinguish between virus presence and replication. These results are compared to gross and microscopic pathological findings in selected organs from infected sheep. Replication was demonstrated in two major cell types: vascular endothelial cells, and agranular leukocytes which morphologically resemble lymphocytes, monocytes/macrophages and/or dendritic cells. Two organs (the skin and tonsils) were shown to support relatively high levels of BTV replication, although they have not previously been proposed as important replication sites during BTV infection. The high level of BTV replication in the skin is thought to be of major significance for the pathogenesis and transmission of BTV (via biting insects) and a refinement of our current model of BTV pathogenesis is discussed. PMID- 22546073 TI - Prospective multi-center study of oncologic outcomes of robot-assisted partial nephrectomy for pT1 renal cell carcinoma. AB - BACKGROUND: Partial nephrectomy has been increasingly recommended over radical nephrectomy for the management of small renal masses based on improved renal functional outcomes without sacrifice of oncologic effectiveness. Robot-assisted partial nephrectomy (RAPN) has been introduced in an effort to offer another minimally invasive option for nephron-sparing surgery. However, reports of RAPN have been limited to short-term perioperative outcomes. The goal of this study is to report and evaluate the initial oncologic outcomes of RAPN. Utilizing prospectively obtained data on RAPN performed by four surgeons at four separate tertiary care centers, we selected patients with unilateral, localized, non familial, pathologically-confirmed pT1 renal cell carcinoma and a minimum post operative follow-up of 12 months. METHODS: Utilizing prospectively obtained data on RAPN performed by four surgeons at four separate tertiary care centers, we selected patients with unilateral, localized, non-familial, pathologically confirmed pT1 renal cell carcinoma and a minimum post-operative follow-up of 12 months. Survival analysis (disease-free, cancer-specific, and overall survival) was performed, and Kaplan-Meier curves were generated. RESULTS: RAPN was performed in 124 patients with a median tumor size of 3.0 cm (IQR 2.2-4.2 cm). Median follow-up was 29 months (range 12-46 months). Positive parenchymal surgical margins occurred in two patients (1.6 %), both of whom were recurrence free at 30 and 34 months after surgery. The three-year Kaplan-Meier estimated disease-free survival was 94.9 %, cancer-specific survival was 99.1%, and overall survival was 97.3 %. CONCLUSIONS: In our cohort of patients with small renal carcinomas who were followed for a median of 29 months, recurrence and survival outcomes were similar to those reported for open and laparoscopic partial nephrectomy. Further long-term outcomes will be needed to definitively claim that RAPN is oncologically equivalent to other surgical approaches. PMID- 22546074 TI - Remote, local, and chemical programming of healable multishape memory polymer nanocomposites. AB - We show that the combination of remote, local, and chemical programming of the multishape memory effects offers unparalleled shape and function control in carbon nanotube-Nafion composites. This strategy not only allows the high fidelity encoding and extraction of designed material shapes at different length scales (macro, micro, and nano) but also enables the reversible tunability of material functions, such as shape memorizability, mechanical properties, surface hydrophobicity, and material resealability, in a single nanocomposite. PMID- 22546075 TI - PTHrP and breast cancer: more than hypercalcemia and bone metastases. AB - Parathyroid hormone-related protein (PTHrP) causes hypercalcemia in cancer patients. PTHrP is required for normal breast development and has been shown to promote bone metastases from breast cancers. However, whether the protein also contributes to the formation of primary tumors has been unclear. Two recent papers suggest it may. First, a report in Nature Genetics identified the PTHrP locus as a new breast cancer susceptibility gene. Second, a paper in Journal of Clinical Investigation demonstrated that PTHrP promotes tumor growth and metastases in MMTV-PyMT mice. These studies implicate PTHrP in the development and growth of primary breast tumors and underscore the need for further research. PMID- 22546076 TI - Multiple factors and pathways involved in hepatic very low density lipoprotein apoB100 overproduction in Otsuka Long-Evans Tokushima Fatty rats. AB - AIMS: Overproduction of hepatic very low-density lipoprotein (VLDL) particles is a major abnormality of lipoprotein dysregulation in type 2 diabetes (T2D). We sought to examine the relationship between systemic/hepatic inflammation associated with insulin resistance and apolipoprotein (apo)B100-containing VLDL production. METHODS AND RESULTS: At the age of 19 wks, Otsuka Long-Evans Tokushima Fatty (OLETF) rats showed systemic inflammation (plasma TNF-alpha and interleukin (IL)-6 levels increased), insulin resistance (plasma retinol binding protein 4 and soluble CD36 levels were higher), dyslipidemia and fatty liver (plasma and liver triglyceride and cholesterol levels were higher as well as total VLDL-, VLDL(1)-, VLDL(2)-apoB100 and VLDL-triglycerides were overproduced), compared with the control rats. In livers of OLETF rats, mRNA levels of tnf, il1b and il6 were increased, but an anti-inflammatory protein, zinc finger protein 36, and its mRNA expression were decreased. We also found that the liver mRNA, protein levels, and tyrosine phosphorylation (pY) of insulin receptor (InsR) substrate (IRS) 2, but not IRS1, were decreased in OLETF rats; pY of InsR and Akt protein and phospho-Akt (ser437) were also reduced; but protein tyrosine phosphatase-1B protein was overexpressed. The gene expressions of glucose transporters 1 and 2, and glycogen synthase were decreased, but phosphatase and tensin homolog deleted on chromosome ten and glycogen synthase kinase 3beta mRNAs were overexpressed, compared with the controls. Sterol regulatory element binding protein-1c mRNA, ATP-binding cassette transporter A1 mRNA, microsomal triglyceride transfer protein mRNA/protein, and CD36 mRNA/protein levels were increased and lipoprotein lipase and Niemann-Pick c1-like1 mRNA levels were decreased, which are all involved in lipogenesis. Decreased sirtuins1-3 mRNA levels were also observed in OLETF rats. CONCLUSIONS: These abnormal genes, proteins expression and phosphorylation of multiple pathways related to inflammatory, insulin signaling and lipogenesis may be important underlying factors in VLDL-apoB100 particles overproduction observed in T2D. Our data contribute to the further understanding of an association of dyslipoproteinemia with systemic metabolic disorders, fatty liver and dysregulated hepatic metabolic pathways. PMID- 22546077 TI - Urinary excretion of platinum, arsenic and selenium of cancer patients from the Antofagasta region in Chile treated with platinum-based drugs. AB - BACKGROUND: Arsenic exposure increases the risk of non-cancerous and cancerous diseases. In the Antofagasta region in Chile, an established relationship exists between arsenic exposure and the risk of cancer of the bladder, lung and skin. Platinum-based drugs are first-line treatments, and many works recognise selenium as a cancer-fighting nutrient. We characterised the short-term urinary excretion amounts of arsenic, selenium and platinum in 24-h urine samples from patients with lung cancer and those with cancer other than lung treated with cisplatin or/and carboplatin. As - Se - Pt inter-element relationships were also investigated. RESULTS: The amounts of platinum excreted in urine were not significantly different between patients with lung cancer and those with other cancers treated with cisplatin, despite the significant variation in platinum amounts supplied from platinum-based drugs. In general, the analytical amounts of excreted selenium were greater than those for arsenic, which could imply that platinum favours the excretion of selenium. For other types of cancers treated with drugs without platinum, excretion of selenium was also greater than that of arsenic, suggesting an antagonist selenium-anti-cancer drug relationship. CONCLUSIONS: Regards the baseline status of patients, the analytical amounts of excreted Se is greater than those for As, particularly, for cisplatin chemotherapy. This finding could imply that for over the As displacement Pt favours the excretion of Se. The analytical amounts of excreted Se were greater than those for As, either with and without Pt-containing drugs, suggesting an antagonist Se-anti-cancer drug relationship. However, it seemed that differences existed between As - Se - Pt inter-element associations in patients treated for lung cancer in comparison with those treated for cancer other than lung. Therefore, knowledge obtained in this work, can contribute to understanding the arsenic cancer mechanism and the As - Se - Pt inter-element association for lung cancer and other types of cancer, which in some cases respond at a linear mathematical model. PMID- 22546078 TI - Meeting report: Signal transduction meets systems biology. AB - In the 21st century, systems-wide analyses of biological processes are getting more and more realistic. Especially for the in depth analysis of signal transduction pathways and networks, various approaches of systems biology are now successfully used. The EU FP7 large integrated project SYBILLA (Systems Biology of T-cell Activation in Health and Disease) coordinates such an endeavor. By using a combination of experimental data sets and computational modelling, the consortium strives for gaining a detailed and mechanistic understanding of signal transduction processes that govern T-cell activation. In order to foster the interaction between systems biologists and experimentally working groups, SYBILLA co-organized the 15th meeting "Signal Transduction: Receptors, Mediators and Genes" together with the Signal Transduction Society (STS). Thus, the annual STS conference, held from November 7 to 9, 2011 in Weimar, Germany, provided an interdisciplinary forum for research on signal transduction with a major focus on systems biology addressing signalling events in T-cells. Here we report on a selection of ongoing projects of SYBILLA and how they were discussed at this interdisciplinary conference. PMID- 22546079 TI - N'-Nitro-2-hydrocarbylidenehydrazinecarboximidamides: design, synthesis, crystal structure, insecticidal activity, and structure-activity relationships. AB - A novel series of acyclic imine-substituted nitenpyram analogues were designed and synthesized from nitroaminoguanidine, and their structures were confirmed using X-ray diffraction crystallography. Preliminary bioassays showed that the target molecules exhibited good activities against aphids in laboratory (Myzus persicae Sulzer) and field trials (M. persicae Sulzer and Brevicoryne brassicae Linnaeus). Comparative molecular field analysis and comparative molecular similarity indices analysis were employed to develop a three-dimensional quantitative structure-activity relationship model that describes the insecticidal activity of 21 neonicotinoid derivatives. Simple synthesis, low cost, and good insecticidal activity have made this series of compounds become very promising candidates for future commercial pesticides. PMID- 22546081 TI - Low back pain and lumbar radiculopathy as harbingers of acute myeloid leukemia recurrence in a patient with myeloid sarcoma. AB - Myeloid sarcoma (MS) is an extra-osseous, solid collection of myeloblasts. It is associated with myeloid leukemias, and rarely affects the spine. The most common clinical presentation of MS in spine patients is some form of pain related to compression of neural elements. Given that MS is rare, and its imaging characteristics are similar to other more common diagnoses, it is frequently missed on initial presentation. We present a 28-year-old female, in her fifth year of remission from AML, with low back pain and right lumbar radiculopathy. Initially, the leading diagnosis was schwannoma in preference to neurofibroma; however, intra-operative pathology and subsequent bone marrow biopsy revealed the tumor to be MS. This report highlights the difficulties of diagnosis of MS in patients in remission from acute myeloid leukemia. Thus, in patients with a history of leukemia, MS should be considered in the differential diagnosis of any epidural or nerve root tumor. Timely diagnosis and treatment are key to optimal outcomes. PMID- 22546080 TI - Porcine reproductive and respiratory syndrome virus nonstructural protein 2 contributes to NF-kappaB activation. AB - BACKGROUND: Nuclear factor-kappaB (NF-kappaB) is an inducible transcription factor that plays a key role in inflammation and immune responses, as well as in the regulation of cell proliferation and survival. Previous studies by our group and others have demonstrated that porcine reproductive and respiratory syndrome virus (PRRSV) infection could activate NF-kappaB in MARC-145 cells and alveolar macrophages. The nucleocapsid (N) protein was identified as an NF-kappaB activator among the structural proteins encoded by PRRSV; however, it remains unclear whether the nonstructural proteins (Nsps) contribute to NF-kappaB activation. In this study, we identified which Nsps can activate NF-kappaB and investigated the potential mechanism(s) by which they act. RESULTS: By screening the individual Nsps of PRRSV strain WUH3, Nsp2 exhibited great potential to activate NF-kappaB in MARC-145 and HeLa cells. Overexpression of Nsp2 induced IkappaBalpha degradation and nuclear translocation of NF-kappaB. Furthermore, Nsp2 also induced NF-kappaB-dependent inflammatory factors, including interleukin (IL)-6, IL-8, COX-2, and RANTES. Compared with the Nsp2 of the classical PRRSV strain, the Nsp2 of highly pathogenic PRRSV (HP-PRRSV) strains that possess a 30 amino acid (aa) deletion in Nsp2 displayed greater NF-kappaB activation. However, the 30-aa deletion was demonstrated to not be associated with NF-kappaB activation. Further functional domain analyses revealed that the hypervariable region (HV) of Nsp2 was essential for NF-kappaB activation. CONCLUSIONS: Taken together, these data indicate that PRRSV Nsp2 is a multifunctional protein participating in the modulation of host inflammatory response, which suggests an important role of Nsp2 in pathogenesis and disease outcomes. PMID- 22546082 TI - Low-energy vibrational dynamics of cesium borate glasses. AB - Low-temperature specific heat and inelastic light scattering experiments have been performed on a series of cesium borate glasses and on a cesium borate crystal. Raman measurements on the crystalline sample have revealed the existence of cesium rattling modes in the same frequency region where glasses exhibit the boson peak (BP). These localized modes are supposed to overlap with the BP in cesium borate glasses affecting its magnitude. Their influence on the low frequency vibrational dynamics in glassy samples has been considered, and their contribution to the specific heat has been estimated. Evidence for a relation between the changes of the BP induced by the increased amount of metallic oxide and the variations of the elastic medium has been provided. PMID- 22546083 TI - The survival impact of systematic lymphadenectomy in endometrial cancer with the use of propensity score matching analysis. AB - OBJECTIVE: We sought to evaluate whether patients with endometrial cancer in the Surveillance, Epidemiology, and End Results database who underwent lymphadenectomy demonstrate improved survival. STUDY DESIGN: The study population comprised 50,969 patients. The 3-year cause-specific survival was tested by using propensity score matching (PSM) analysis. RESULTS: The PSM analysis generated a balanced, matched cohort in which baseline characteristics were not significantly different. The benefit of systematic lymphadenectomy appears to be significant for presumed stage I International Federation of Gynecology and Obstetrics grade 3 cancers and presumed stages II-III cancer. The omission of lymphadenectomy in stage I did not appear to show a deleterious survival consequence if the differentiation grade was moderate (grade 2) or well (grade 1). CONCLUSION: Using PSM analysis, our results show no evidence of benefit in terms of survival for systematic lymphadenectomy in women with stage I endometrial cancer, except for grade 3 cancers. PMID- 22546084 TI - Optimal stimulation settings for CMAP scan registrations. AB - BACKGROUND: The CMAP (Compound Muscle Action Potential) scan is a non-invasive electrodiagnostic tool, which provides a quick and visual assessment of motor unit potentials as electrophysiological components that together constitute the CMAP. The CMAP scan records the electrical activity of the muscle (CMAP) in response to transcutaneous stimulation of the motor nerve with gradual changes in stimulus intensity. Large MUs, including those that result from collateral reinnervation, appear in the CMAP scan as so-called steps, i.e., clearly visible jumps in CMAP amplitude. The CMAP scan also provides information on nerve excitability. This study aims to evaluate the influence of the stimulation protocol used on the CMAP scan and its quantification. METHODS: The stimulus frequency (1, 2 and 3 Hz), duration (0.05, 0.1 and 0.3 ms), or number (300, 500 and 1000 stimuli) in CMAP scans of 23 subjects was systematically varied while the other two parameters were kept constant. Pain was measured by means of a visual analogue scale (VAS). Non-parametric paired tests were used to assess significant differences in excitability and step variables and VAS scores between the different stimulus parameter settings. RESULTS: We found no effect of stimulus frequency on CMAP scan variables or VAS scores. Stimulus duration affected excitability variables significantly, with higher stimulus intensity values for shorter stimulus durations. Step variables showed a clear trend towards increasing values with decreasing stimulus number. CONCLUSIONS: A protocol delivering 500 stimuli at a frequency of 2 Hz with a 0.1 ms pulse duration optimized CMAP scan quantification with a minimum of subject discomfort, artefact and duration of the recording. CMAP scan variables were influenced by stimulus duration and number; hence, these need to be standardized in future studies. PMID- 22546085 TI - Suppression of feline coronavirus replication in vitro by cyclosporin A. AB - The feline infectious peritonitis virus (FIPV) is a member of the feline coronavirus family that causes FIP, which is incurable and fatal in cats. Cyclosporin A (CsA), an immunosuppressive agent that targets the nuclear factor pathway of activated T-cells (NF-AT) to bind cellular cyclophilins (CyP), dose dependently inhibited FIPV replication in vitro. FK506 (an immunosuppressor of the pathway that binds cellular FK506-binding protein (FKBP) but not CyP) did not affect FIPV replication. Neither cell growth nor viability changed in the presence of either CsA or FK506, and these factors did not affect the NF-AT pathway in fcwf-4 cells. Therefore, CsA does not seem to exert inhibitory effects via the NF-AT pathway. In conclusion, CsA inhibited FIPV replication in vitro and further studies are needed to verify the practical value of CsA as an anti-FIPV treatment in vivo. PMID- 22546086 TI - Hydroxylated PBDEs induce developmental arrest in zebrafish. AB - The ubiquitous spread of polybrominated diphenyl ethers (PBDEs) has led to concerns regarding the metabolites of these congeners, in particular hydroxylated PBDEs. There are limited studies regarding the biological interactions of these chemicals, yet there is some concern they may be more toxic than their parent compounds. In this study three hydroxylated PBDEs were assessed for toxicity in embryonic zebrafish: 3-OH-BDE 47, 5-OH-BDE 47, and 6-OH-BDE 47. All three congeners induced developmental arrest in a concentration-dependent manner; however, 6-OH-BDE 47 induced adverse effects at lower concentrations than the other congeners. Furthermore, all three induced cell death; however apoptosis was not observed. In short-term exposures (24-28 hours post fertilization), all hydroxylated PBDEs generated oxidative stress in the region corresponding to the cell death at 5 and 10 ppm. To further investigate the short-term effects that may be responsible for the developmental arrest observed in this study, gene regulation was assessed for embryos exposed to 0.625 ppm 6-OH-BDE 47 from 24 to 28 hpf. Genes involved in stress response, thyroid hormone regulation, and neurodevelopment were significantly upregulated compared to controls; however, genes related to oxidative stress were either unaffected or downregulated. This study suggests that hydroxylated PBDEs disrupt development, and may induce oxidative stress and potentially disrupt the cholinergic system and thyroid hormone homeostasis. PMID- 22546087 TI - The H1-H2 domain of the alpha1 isoform of Na+-K+-ATPase is involved in ouabain toxicity in rat ventricular myocytes. AB - The composition of different isoforms of Na+-K+-ATPase (NKA, Na/K pump) in ventricular myocytes is an important factor in determining the therapeutic effect and toxicity of cardiac glycosides (CGs) on heart failure. The mechanism whereby CGs cause these effects is still not completely clear. In the present study, we prepared two site-specific antibodies (SSA78 and WJS) against the H1-H2 domain of alpha1 and alpha2 isoforms of NKA in rat heart, respectively, and compared their influences on the effect of ouabain (OUA) in isolated rat ventricular myocytes. SSA78 or WJS, which can specifically bind with the alpha1 or alpha2 isoform, were assessed with enzyme linked immunosorbent assay (ELISA), Western blot and immunofluorescent staining methods. Preincubation of myocytes with SSA78 inhibited low OUA affinity pump current but not high OUA affinity pump current, reduced the rise in cytosolic calcium concentration ([Ca2+](i)), attenuated mitochondrial Ca2+ overload, restored mitochondrial membrane potential reduction, and delayed the decrease of the myocardial contractile force as well as the occurrence of arrhythmic contraction induced by high concentrations (1 mM) but not low concentrations (1 MUM) of OUA. Similarly, preincubation of myocytes with WJS inhibited high OUA affinity pump current, reduced the increase of [Ca2+](i) and the contractility induced by 1 MUM but not that induced by 1 mM OUA. These results indicate that the H1-H2 domain of the NKA alpha1 isoform mediates OUA induced cardiac toxicity in rat ventricular myocytes, and inhibitors for this binding site may be used as an adjunct to CGs treatment for cardiovascular disease. PMID- 22546088 TI - Activation of K+ channels and Na+/K+ ATPase prevents aortic endothelial dysfunction in 7-day lead-treated rats. AB - Seven day exposure to a low concentration of lead acetate increases nitric oxide bioavailability suggesting a putative role of K+ channels affecting vascular reactivity. This could be an adaptive mechanism at the initial stages of toxicity from lead exposure due to oxidative stress. We evaluated whether lead alters the participation of K+ channels and Na+/K+)-ATPase (NKA) on vascular function. Wistar rats were treated with lead (1st dose 4 MUg/100 g, subsequent doses 0.05 MUg/100g, im, 7 days) or vehicle. Lead treatment reduced the contractile response of aortic rings to phenylephrine (PHE) without changing the vasodilator response to acetylcholine (ACh) or sodium nitroprusside (SNP). Furthermore, this treatment increased basal O2- production, and apocynin (0.3 MUM), superoxide dismutase (150 U/mL) and catalase (1000 U/mL) reduced the response to PHE only in the treated group. Lead also increased aortic functional NKA activity evaluated by K+-induced relaxation curves. Ouabain (100 MUM) plus L-NAME (100 MUM), aminoguanidine (50 MUM) or tetraethylammonium (TEA, 2 mM) reduced the K+-induced relaxation only in lead-treated rats. When aortic rings were precontracted with KCl (60 mM/L) or preincubated with TEA (2 mM), 4-aminopyridine (4-AP, 5 mM), iberiotoxin (IbTX, 30 nM), apamin (0.5 MUM) or charybdotoxin (0.1 MUM), the ACh-induced relaxation was more reduced in the lead-treated rats. Additionally, 4-AP and IbTX reduced the relaxation elicited by SNP more in the lead-treated rats. Results suggest that lead treatment promoted NKA and K+ channels activation and these effects might contribute to the preservation of aortic endothelial function against oxidative stress. PMID- 22546089 TI - Information systems on human resources for health: a global review. AB - BACKGROUND: Although attainment of the health-related Millennium Development Goals relies on countries having adequate numbers of human resources for health (HRH) and their appropriate distribution, global understanding of the systems used to generate information for monitoring HRH stock and flows, known as human resources information systems (HRIS), is minimal. While HRIS are increasingly recognized as integral to health system performance assessment, baseline information regarding their scope and capability around the world has been limited. We conducted a review of the available literature on HRIS implementation processes in order to draw this baseline. METHODS: Our systematic search initially retrieved 11 923 articles in four languages published in peer-reviewed and grey literature. Following the selection of those articles which detailed HRIS implementation processes, reviews of their contents were conducted using two person teams, each assigned to a national system. A data abstraction tool was developed and used to facilitate objective assessment. RESULTS: Ninety-five articles with relevant HRIS information were reviewed, mostly from the grey literature, which comprised 84 % of all documents. The articles represented 63 national HRIS and two regionally integrated systems. Whereas a high percentage of countries reported the capability to generate workforce supply and deployment data, few systems were documented as being used for HRH planning and decision making. Of the systems examined, only 23 % explicitly stated they collect data on workforce attrition. The majority of countries experiencing crisis levels of HRH shortages (56 %) did not report data on health worker qualifications or professional credentialing as part of their HRIS. CONCLUSION: Although HRIS are critical for evidence-based human resource policy and practice, there is a dearth of information about these systems, including their current capabilities. The absence of standardized HRIS profiles (including documented processes for data collection, management, and use) limits understanding of the availability and quality of information that can be used to support effective and efficient HRH strategies and investments at the national, regional, and global levels. PMID- 22546091 TI - Blood-brain barrier disruption in CCL2 transgenic mice during pertussis toxin induced brain inflammation. AB - BACKGROUND: The chemokine CCL2 has an important role in the recruitment of inflammatory cells into the central nervous system (CNS). A transgenic mouse model that overexpresses CCL2 in the CNS shows an accumulation of leukocytes within the perivascular space surrounding vessels, and which infiltrate into the brain parenchyma following the administration of pertussis toxin (PTx). METHODS: This study used contrast-enhanced magnetic resonance imaging (MRI) to quantify the extent of blood-brain barrier (BBB) disruption in this model pre- and post PTx administration compared to wild-type mice. Contrast-enhanced MR images were obtained before and 1, 3, and 5 days after PTx injection in each animal. After the final imaging session fluorescent dextran tracers were administered intravenously to each mouse and brains were examined histologically for cellular infiltrates, BBB leakage and tight junction protein. RESULTS: BBB breakdown, defined as a disruption of both the endothelium and glia limitans, was found only in CCL2 transgenic mice following PTx administration and seen on MR images as focal areas of contrast enhancement and histologically as dextrans leaking from blood vessels. No evidence of disruption in endothelial tight junctions was observed. CONCLUSION: Genetic and environmental stimuli were needed to disrupt the integrity of the BBB in this model of neuroinflammation. PMID- 22546092 TI - Rectal Dieulafoy lesions: a rare etiology of chronic lower gastrointestinal bleeding. PMID- 22546090 TI - Epitope reactions can be gauged by relative antibody discriminating specificity (RADS) values supported by deletion, substitution and cysteine bridge formation analyses: potential uses in pathogenesis studies. AB - BACKGROUND: Epitope-mapping of infectious agents is essential for pathogenesis studies. Since polyclonal antibodies (PAbs) and monoclonal antibodies (MAbs) are always polyspecific and can react with multiple epitopes, it is important to distinguish between specific and non-specific reactions. Relative antibody discriminating specificity (RADS) values, obtained from their relative ELISA reactions with L-amino acid peptides prepared in the natural versus reverse orientations (x-fold absorbance natural/absorbance reverse = RADS value) may be valuable for this purpose.PAbs generated against the dengue type-2 virus (DENV-2) nonstructural-1 (NS1) glycoprotein candidate vaccine also reacted with both DENV envelope (E) glycoproteins and blood-clotting proteins. New xKGSx/xSGKx amino acid motifs were identified on DENV-2 glycoproteins, HIV-1 gp41 and factor IXa. Their potential roles in DENV and HIV-1 antibody-enhanced replication (AER) and auto-immunity were assessed.In this study, a) RADS values were determined for MAbs and PAbs, generated in congeneic (H2: class II) mice against DENV NS1 glycoprotein epitopes, to account for their cross-reaction patterns, and b) MAb 1G5.3 reactions with xKGSx/xSGKx motifs present in the DENV-4 NS1, E and HIV-1 glycoproteins and factor IXa were assessed after the introduction of amino acid substitutions, deletions, or intra-/inter-cysteine (C-C) bridges. RESULTS: MAbs 1H7.4, 5H4.3, 3D1.4 and 1G5.3 had high (4.23- to 16.83-fold) RADS values against single epitopes on the DENV-2 NS1 glycoprotein, and MAb 3D1.4 defined the DENV complex-conserved LX1 epitope. In contrast, MAbs 1G5.4-A1-C3 and 1C6.3 had low (0.47- to 1.67-fold) RADS values against multiple epitopes. PAb DENV complex reactions occurred through moderately-high (2.77- and 3.11-fold) RADS values against the LX1 epitope. MAb 1G5.3 reacted with xSGKx motifs present in DENV-4 NS1 and E glycoproteins, HIV-1 gp41 and factor IXa, while natural C-C bridge formations or certain amino acid substitutions increased its binding activity. CONCLUSIONS: These results: i) were readily obtained using a standard 96-well ELISA format, ii) showed the LX1 epitope to be the immuno-dominant DENV complex determinant in the NS1 glycoprotein, iii) supported an antigenic co-evolution of the DENV NS1 and E glycoproteins, and iv) identified methods that made it possible to determine the role of anti-DENV PAb reactions in viral pathogenesis. PMID- 22546093 TI - Primary leiomyosarcoma of the abdominal wall. PMID- 22546094 TI - Laparoscopic detorsion and cecopexy for treatment of cecal volvulus. PMID- 22546095 TI - A very rare complication of acute appendicitis: appendicocutaneous fistula. PMID- 22546096 TI - Localized malignant peritoneal mesothelioma arising in the mesentery of the ascending colon. PMID- 22546097 TI - Upper gastrointestinal hemorrhage caused by duodenal angiosarcoma. PMID- 22546098 TI - Incarcerated spigelian hernia after colonoscopy. PMID- 22546099 TI - Reactive nodular fibrous pseudotumor of the gastrointestinal tract and mesentery giving multiple hepatic deposits and associated with colon cancer. PMID- 22546100 TI - Retroperitoneal neuroendocrine carcinoma with extrinsic compression of ascending colon. PMID- 22546101 TI - Cholecystenteric fistula: the spectrum of disease and treatment modalities. PMID- 22546102 TI - Venous pseudoaneurysm as a late complication of hemodialysis. PMID- 22546103 TI - Partial duodenectomy with end-to-end anastomosis for duodenal gastrointestinal stromal tumor. PMID- 22546104 TI - A modified and simplified technique for laparoscopic tube jejunostomy. PMID- 22546105 TI - Hetastarch use in bariatric surgery: word of caution. PMID- 22546106 TI - Small cell lung cancer metastasizing to the colon in a colovesicular fistula in the setting of diverticulitis. PMID- 22546107 TI - A lesser omental hernia through both the gastrocolic and gastrohepatic omenta. PMID- 22546108 TI - Squamous cell carcinoma of the pancreas presenting with upper gastrointestinal bleeding. PMID- 22546109 TI - A novel strategy for the management of acute hemorrhage from an atrio-esophageal fistula after atrial ablation. PMID- 22546110 TI - Adolescent male adenoid cystic breast carcinoma. PMID- 22546111 TI - Epithelial-myoepithelial carcinoma of the lung. PMID- 22546112 TI - Gallstone ileus ten days after laparoscopic cholecystectomy. PMID- 22546113 TI - Delayed repair of a traumatic lumbar hernia with renal rupture. PMID- 22546114 TI - Splenic artery embolization in a 7-year-old with blunt traumatic splenic rupture. PMID- 22546115 TI - Post splenectomy tumor lysis syndrome. PMID- 22546116 TI - Richter's epigastric hernia with transverse colon strangulation. PMID- 22546117 TI - Successful multimodality treatment of a young woman with Hughes-Stovin syndrome. PMID- 22546118 TI - Department of Surgery, Mercer University School of Medicine, and the Medical Center of Central Georgia. PMID- 22546119 TI - Dr. Louis G. Britt, University of Tennessee Center for the Health Sciences surgical educator and mentor. PMID- 22546120 TI - Management and outcomes of colovesical fistula repair. AB - This large retrospective study presents the largest colovesical fistula (CVF) series to date. We report on recurrence risk factors and patient satisfaction based on quality of life after CVF repair. Approval was obtained from The Mount Sinai School of Medicine Institutional Review Board, and a retrospective review was performed from 2003 to 2010 involving 72 consecutive patients who underwent a colovesical fistula repair. The CVF recurrence rate was 11 per cent. Ten percent of our patients who had a history of radiation therapy were at a significantly higher risk of developing a recurrence. Noted recurrence rates were significantly higher in advanced bladder repairs compared with simple repair (P = 0.022). The modified (Gastrointestinal Quality of Life Index) surveys showed overall patient satisfaction score was 3.6, out of a maximum score of 4, regardless of the type of repair or any postoperative complications. Our study found the CVF recurrence rate to be 11 per cent. Patients at higher risk of recurrence include those needing advanced bladder repair, those with "complex" CVF, and those whose fistulas involve the urethra. Patient satisfaction was found to be more closely linked to the resolution of CVF symptoms, irrespective of the type of repair performed or development of postoperative complications. PMID- 22546121 TI - The effect of multiple wire localization in breast conservation. AB - Variability exists regarding the surgical technique in breast conservation therapy. The purpose of this project was to determine differences between single (SH) or flanking (FH) hooked needle localization wires used for nonpalpable breast lesions. We retrospectively reviewed 201 female patients at a single institution from 2004 to 2008. All patients had biopsy-proven ductal carcinoma in situ or invasive disease. Comparisons were made in regard to margin status, reoperation, completion mastectomy, size of lesion, and breast specimen volume. SH was placed in 122 patients (61%) and FH in 79 patients (39%). In SH, 23 patients (18%) had positive margins and 31 patients (25%) had reoperations as compared with 31 patients (25%) with positive margin and 36 patients (44%) in the FH cohort (P = 0.039 and 0.0037). Average lesion size and volume resected was 1.5 cm and 137 cm(3) in SH and 2.85 cm and 188 cm(3) in FH, respectively (P = 0.0001 and 0.006). Positive margins were associated with lesion size and not volume of tissue excised. The FH technique was associated with more positive margins, reoperation, and completion mastectomy. PMID- 22546122 TI - Manometric evaluation of internal anal sphincter after fissurectomy and anoplasty for chronic anal fissure: a prospective study. AB - Chronic anal fissure (CAF) is a common painful clinical disease and its pathogenesis remains poorly understood. After failure of pharmacological therapy, that is the first-line treatment, surgical sphincterotomy remains the treatment of choice although it is followed by a high rate of anal incontinence resulting from the sphincter damage; therefore, the research of a sphincter-saving surgical option has become an important goal. The aim of this study was to evaluate the manometric modifications and the incidence of anal incontinence after fissurectomy and anoplasty with advancement skin flap in patients affected by CAF with hypertonia of the internal anal sphincter (IAS). Fifteen patients affected by CAF with hypertonia of IAS, unresponsive to medical therapy, were enrolled. All subjects underwent fissurectomy and anoplasty with advancement skin flap. Anorectal manometry was performed preoperatively and after 6 and 12 months from surgery. Maximum resting pressure (MRP), maximum squeeze pressure (MSP), ultraslow wave activity (USWA), fissure healing, anal continence, and postoperative complications were recorded. All patients healed within 30 days from surgery. No intra- or postoperative complications were recorded except for a case of partial donor site break. No significant modifications of MSP were detected. Six months after surgery, MRP was higher with respect to healthy subjects but significantly reduced in comparison to baseline levels. At 12 months, it was higher have versus 6-month values but significantly lower versus preoperative values. USWA was significantly represented in patients with CAF versus healthy subject. Both at 6 and 12 months, they decreased significantly with respect to preoperative values without significant differences versus healthy subjects. Both at 6 and 12 months, anal continence did not differ with respect to preoperative time. The fissurectomy with anoplasty resulted in a high healing rate without surgical sequelae or anal incontinence. Also, it was able to reduce IAS pressure in the same manner as surgical sphincterotomy or forceful dilatation. PMID- 22546123 TI - Lymph node ratio is a significant predictor of disease-specific mortality in patients undergoing esophagectomy for cancer. AB - The seventh edition of the American Joint Committee on Cancer esophageal cancer staging system classifies nodal status by the number of malignant nodes (LNMs) found. This may be confounded by variations in lymphadenectomy and specimen review. The ratio of lymph nodes containing metastases to the total nodes excised (LNR) has been suggested as an alternative. We seek to validate the use of LNR for staging and determine the effect of the total lymph node yield (LNY) on its accuracy. A review of our prospective esophageal database identified 94 patients who underwent esophagectomy for cancer at out institution from 1992 until 2010. Univariate and multivariate analyses were performed. The mean age of our patients was 59.4 years. Transthoracic esophagectomy was performed in all but three instances. The majority of tumors were adenocarcinoma, 76 per cent. Overall survival at 2 and 5 years was 52 and 29 per cent, respectively. LNY correlated with LNM (r = 0.302, P = 0.001) but not LNR (r = 0.012, P = 0.912). Using Kaplan Meier analysis, LNR had no effect on disease-specific (DS) survival (P = 0.803). However, a Cox proportional hazards regression model showed LNR to be a significant predictor of DS mortality (hazard ratio, 9.47; P = 0.049). The lack of correlation between LNR and LNY suggests that LNR may be a more robust staging method when LNY is low. Furthermore, LNR was found to be a significant predictor of DS mortality when controlling for other factors influencing survival. However, neither a staging system based on LNR nor its efficacy compared with the current system could be determined from these data. PMID- 22546124 TI - The effect of trauma center designation on organ donor outcomes in Southern California. AB - We sought to investigate the effect of trauma center designation on organ donor outcomes during a 5-year period. A retrospective study of the southern California regional Organ Procurement Organization database comparing trauma centers (n = 25) versus nontrauma centers (n = 171) and Level I (n = 7) versus Level II (n = 18) trauma centers between 2004 and 2008 was performed. A total of 16,830 referrals were evaluated and 44 per cent were from trauma centers. When compared with nontrauma centers (n = 171), trauma centers (n = 25) had a higher percentage of medically suitable eligible deaths (29 vs 16%, P < 0.001), total eligible deaths (22 vs 12%, P < 0.001), and eligible donors (14 vs 7%, P < 0.001). Trauma Centers had a significantly higher number of organs procured per donor (4.0 +/- 1.6 vs 3.5 +/- 1.6, P < 0.001), organs transplanted per donor (OTPD) (3.6 +/- 1.8 vs 2.8 +/- 1.8, P < 0.001), and higher organ yield (per cent 4 or greater OTPD [48 vs 31%, P < 0.001]). No significant differences were found between Level I and Level II trauma centers. Trauma centers demonstrate significantly better organ donor outcomes compared with nontrauma centers. Factors responsible for improved outcomes at trauma centers should be evaluated, reproduced, and disseminated to nontrauma centers to alleviate the growing organ shortage crisis. PMID- 22546125 TI - Surgical anatomy and morphologic variations of umbilical structures. AB - The umbilicus is the main access route to the abdominal cavity in laparoscopic surgeries. However, its anatomical configuration is rarely studied in the surgical and anatomical literature. With introduction of laparoendoscopic single site surgery and considering the significant number of primary and postoperative umbilical hernias, we felt the necessity to comprehensively study the umbilical structures and analyze their protective function against hernias. Twenty-four embalmed cadavers were studied in the anatomy laboratory of Case Western Reserve University. Round hepatic, median and medial ligaments, umbilical ring, umbilical and umbilicovesicular fasciae, and pattern of attachment to the ring were dissected and measured. Mean age was 82.1 years, ranging between 56 and 96 years, with a male-to-female ratio of 1.4:1. Ninety-two per cent was white and 8 per cent black adults. According to shape and attachment pattern of ligaments, umbilical ring is classified into five types. Hernia incidence was 25 per cent. All hernia cases lacked the umbilical fascia and the round hepatic ligament was not attached to the inferior border of the ring. The umbilical ring and its morphologic relation with adjacent ligaments are described and classified into five types. In contrary to sparse existing literature, we propose that umbilical fascia is continuation and condensation of umbilicovesicular rather than transversalis fascia. It was absent in cadavers forming conjoined median and medial ligaments with a single insertion site to the ring. Round ligament insertion to the inferior border of the ring provides another protective factor. These two protective measures were absent in all the observed umbilical hernias. PMID- 22546126 TI - Ten years of mechanical complications of central venous catheterization in trauma patients. AB - The study purpose was to determine the incidence of mechanical complications (MC) associated with central venous catheterization (CVC) and to evaluate their impact on outcomes. This was a retrospective review of trauma morbidity and mortality records at a Level I trauma center (1999 to 2009). Demographics and outcomes were extracted for all trauma patients with CVC. Patients developing MC were compared with those who did not. Four thousand eight hundred eighteen lines were placed in 2935 patients. Of these, 1.5 per cent (n = 73) had MC. A total of 64.4 per cent (n = 47) were pneumothoraces followed by arterial cannulation at 8.2 per cent (n = 6) and thrombosis at 6.8 per cent (n = 5). The rate of MC by access site was: subclavian 1.8 per cent (n = 52), internal jugular 1.2 per cent (n = 10), and femoral 0.3 per cent (n = 3) (P value for trend = 0.001). Change in management was required in 31.5 per cent (n = 23). Number of lines (P < 0.001), Injury Severity Score (P < 0.001), body mass index less than 20 kg/m(2) (P = 0.036), and chest Abbreviated Injury Score greater than 3 (P = 0.034) were significant predictors of MC. Patients with MC had a longer intensive care unit length of stay (18.8 +/- 25.7 vs 11.4 +/- 13.3; adjusted odds ratio, 5.75; 95% confidence interval, 2.24-9.25; P = 0.001). Incidence of MC was 1.5 per cent. Complications were clinically significant in 31.5 per cent and resulted in longer intensive care unit stays. PMID- 22546128 TI - Social media, surgeons, and the Internet: an era or an error? AB - According to the National Research Corporation, 1 in 5 Americans use social media sites to obtain healthcare information. Patients can easily access information on medical conditions and medical professionals; however physicians may not be aware of the nature and impact of this information. All physicians must learn to use the Internet to their advantage and be acutely aware of the disadvantages. Surgeons are in a unique position because, unlike in the primary care setting, less time is spent developing a long-term relationship with the patient. In this literature review, we discuss the impact of the Internet, social networking websites, and physician rating websites and make recommendations for surgeons about managing digital identity and maintaining professionalism. PMID- 22546127 TI - The indications for nonsurgical management in patients with colorectal perforation after colonoscopy. AB - Recently, the risk of colonic perforation has been increasing with the increased frequency of advanced therapeutic endoscopy. However, guidelines for the management of colon perforations after colonoscopy have not been established. This study aimed to evaluate the indications for nonsurgical management. This study was conducted as a case-control study with 22 patients who were managed for colorectal perforations after colonoscopy from June 2004 to July 2009. Colonoscopy was performed in 12 patients (54.4%) for diagnostic purposes and 10 (45.5%) for therapeutic reasons. The most common site of perforation was the sigmoid colon (77.3%). Five patients underwent nonsurgical treatment, and 17 patients received surgical treatment. The duration of hospital stay did not differ significantly between the two groups. Abdominal pain and fever were significantly more commonly encountered in the surgical management group (P = 0.043 and 0.011, respectively). All of the patients who were suitable for nonsurgical treatment were diagnosed within 24 hours and received bowel preparation before the colonoscopy. The nonsurgical treatment of colonic perforation after colonoscopy could be feasible in afebrile patients with less severe abdominal pain. Moreover, cases that were diagnosed within 24 hours and received bowel preparation before colonoscopy were associated with better outcomes. PMID- 22546129 TI - Burn-center quality improvement: are burn outcomes dependent on admitting facilities and is there a volume-outcome "sweet-spot"? AB - Risk factors of mortality in burn patients such as inhalation injury, patient age, and percent of total body surface area (%TBSA) burned have been identified in previous publications. However, little is known about the variability of mortality outcomes between burn centers and whether the admitting facilities or facility volumes can be recognized as predictors of mortality. De-identified data from 87,665 acute burn observations obtained from the National Burn Repository between 2003 and 2007 were used to estimate a multivariable logistic regression model that could predict patient mortality with reference to the admitting burn facility/facility volume, adjusted for differences in age, inhalation injury, %TBSA burned, and an additional factor, percent full thickness burn (%FTB). As previously reported, all three covariates (%TBSA burned, inhalation injury, and age) were found to be highly statistically significant risk factors of mortality in burn patients (P value < 0.0001). The additional variable, %FTB, was also found to be a statistically significant determinant, although it did not greatly improve the multivariable model. The treatment/admitting facility was found to be an independent mortality predictor, with certain hospitals having increased odds of death and others showing a protective effect (decreased odds ratio). Hospitals with high burn volumes had the highest risk of mortality. Mortality outcomes of patients with similar risk factors (%TBSA burned, inhalation injury, age, and %FTB) are significantly affected by the treating facility and their admission volumes. PMID- 22546130 TI - Lower mediastinal lymph node metastasis is an independent survival factor of Siewert type II and III adenocarcinomas in the gastroesophageal junction. AB - We examined clinicopathological features and surgical outcomes in patients with adenocarcinoma in the gastroesophageal junction (GEJ), while also analyzing the survival factors that have a prognostic impact. Between 1991 and 2009, 61 patients with tumors in the GEJ (Siewert type II and III) underwent primary surgical resection. Thirty of 61 patients had type II tumors (49.2%) and 31 had type III tumors (50.8%). The tumor size was larger in type III tumors than type II tumors (P = 0.0026). The overall 5-year survival rates in patients with type II tumors and type III tumors were 44.2 per cent and 41.4 per cent, respectively, with no significant differences (P = 0.1888). The independent survival factors were lower mediastinal lymph node metastasis (P = 0.0323) and a noncurative resection (P = 0.0442). The independent survival factors for patients who underwent curative resections were the tumor size (P = 0.0422), M category (P = 0.0489), and lower mediastinal lymph node metastasis (P = 0.0482). This study showed lower mediastinal lymph node metastasis to be an independent survival factor, and also suggested that lower mediastinal lymph node metastasis was associated with distant metastasis in patients with adenocarcinoma in the GEJ (Siewert type II and III). Therefore, the preoperative early detection of such metastasis is important to improve patient survival. PMID- 22546131 TI - A double-blind, randomized, active-controlled study for post-hemorrhoidectomy pain management with liposome bupivacaine, a novel local analgesic formulation. AB - This randomized, active-controlled study evaluated the extent and duration of analgesia after administration of liposome bupivacaine (LB), a novel formulation of bupivacaine, compared with bupivacaine HCl given via local infiltration in excisional hemorrhoidectomy. One hundred patients were randomly assigned to receive a single dose of bupivacaine HCl 75 mg (0.25% with 1:200,000 epinephrine) or LB 66, 199, or 266 mg upon completion of hemorrhoidectomy. Postoperative pain intensity was assessed using a numeric rating scale at rest to calculate a cumulative pain score (area under the curve). Cumulative pain scores were significantly lower with LB at each study dose (P < 0.05) compared with bupivacaine HCl 72 hours after surgery. Post hoc analysis showed that mean total postoperative opioid consumption was statistically significantly lower for the LB 266-mg group compared with the bupivacaine HCl group during the 12- to 72-hour postoperative period (P = 0.019). Median time to first opioid use was 19 hours for LB 266 mg versus 8 hours for bupivacaine HCl (P = 0.005). Incidence of opioid related adverse events was 4 per cent for LB 266 mg compared with 35 per cent for bupivacaine HCl (P = 0.007). Local infiltration with LB resulted in significantly reduced postsurgical pain compared with bupivacaine HCl in patients after hemorrhoidectomy surgery. PMID- 22546132 TI - Peritonitis from perforated appendicitis: stress response after laparoscopic or open treatment. AB - Elevated intra-abdominal pressure during laparoscopy may promote systemic inflammatory response. In patients with generalized peritonitis from perforated appendicitis, we sought to compare acute phase response and immunologic status from laparoscopic and open approach. One hundred and forty-seven consecutive patients underwent appendectomy for perforated appendicitis (73 patients had laparoscopic appendectomy and 74 patients had open appendectomy. Bacteremia, endotoxemia, white blood cells, peripheral lymphocytes subpopulation, human leukocyte antigen-DR (HLA-DR), neutrophil-elastase, interleukin-1 and 6 (IL-1 and 6), and C-reactive protein were investigated. One hour after intervention, bacteremia was significantly higher in the open group compared with the laparoscopic group (P < 0.05). A significantly higher concentration of systemic endotoxin was detected intraoperatively in the open group of patients in comparison with the laparoscopic group (P < 0.05). Laparotomy caused a significant increase in neutrophil concentration, neutrophil-elastase, IL-1 and 6, and C-reactive protein and a decrease of HLA-DR. We recorded 6 cases (8.1%) of intra-abdominal abscess in the open group and one (1.3%) in the laparoscopic group (P < 0.05). Open appendectomy, in case of peritonitis, increased the incidence of bacteremia, endotoxemia, and systemic inflammation compared with laparoscopic appendectomy. Early enhanced postoperative systemic inflammation may cause lower transient immunologic defense after laparotomy (decrease of HLA DR), leading to enhanced sepsis in these patients. PMID- 22546133 TI - Pneumoperitoneum after percutaneous endoscopic gastrostomy among adults in the intensive care unit: incidence, predictive factors, and clinical significance. AB - The significance of post percutaneous endoscopic gastrostomy (PEG) pneumoperitoneum (PNP) is unclear. We studied patients in our intensive car unit who underwent PEG placement to better understand the significance of post PEG PNP at our institution. We identified all intensive care unit patients who underwent PEG placement between the years of 2000 and 2009. A review of 318 consecutive PEG procedures was performed. Radiographic imaging was reviewed for up to 14 days post PEG, noting the presence of PNP. The presence of common comorbidities and PEG-related complications were recorded. Of the 318 patients, radiologic imaging was not taken within 14 days in 37 patients. Forty-five patients were found to have PNP on imaging for an incidence of 16 per cent (45/281). Eight patients were found to require either surgical or endoscopic emergent intervention post PEG. Four of these had PNP on imaging. Post PEG PNP was associated with increased likelihood for complications requiring emergent surgical intervention (P = 0.0078) and 30-day mortality post PEG insertion (P = 0.0216). The presence of common comorbid conditions was not a significant determinant of post PEG PNP. PMID- 22546134 TI - Laparoscopic approach in patients with recurrent Crohn's disease. AB - The purpose of this study is to review our experience with laparoscopic management of Crohn's disease including patients with prior Crohn's-related abdominal surgery. All cases of Crohn's patients who underwent laparoscopic attempt for management of disease from April 2005 to October 2010 (n = 130) at a single institution were retrospectively reviewed. Evaluated datapoints include: prior abdominal surgery for Crohn's disease, operative time, rate of conversion, and complication rate. Of the 130 patients, 82 (63.1%) patients had no prior abdominal surgery and 48 (36.9%) patients had previous bowel surgery with mean age of 35.3 (3.5-79) and 41.3 (15-66) years, respectively. Operative time with no prior surgery was 106 (23-245) minutes, and with prior surgery was 100 (26-229) minutes. Estimated blood loss with no prior surgery was 116 (5-800) mL, and with prior surgery was 123 (5-800) mL. Conversion from laparoscopic to open surgery in those with no prior surgery was 17.1 per cent and in those with prior surgery, 20.8 per cent (P = 0.64). Postoperative complications were found in 13 patients (15.9%) without prior abdominal surgery and 13 patients (27.1%) with prior surgery (P = 0.17). The most common postoperative complication in both groups was infection/abscess (8.5%). The laparoscopic management of recurrent Crohn's disease is a safe and technically feasible option, even in those patients with prior history of Crohn's-related abdominal surgery, with a low complication rate and low conversion rate. The utility of the laparoscopic approach in Crohn's patients faced with repeat abdominal procedures may be beneficial in the long term and should be considered as a method to limit morbidity. PMID- 22546135 TI - Total parathyroidectomy versus subtotal parathyroidectomy in the treatment of tertiary hyperparathyroidism. AB - The purposes of this study are to evaluate the merits of surgical treatment, including subtotal parathyroidectomy (SP) and total parathyroidectomy (TP), in patients with tertiary hyperparathyroidism (THPT) and compare the outcome of the two surgical options. Medical records of patients undergoing parathyroidectomy for THPT were retrospectively reviewed and long-term outcomes between the two groups were compared. Fourteen out of 488 renal transplantation recipients required parathyroidectomy for THPT during a 24-year follow-up period with a median follow-up of 35.5 [interquartile range (IQR), 19.3-133.3] months. All patients had hypercalcemia, whereas 13 had varying symptoms and one was asymptomatic. Median serum calcium level decreased from 12.4 (IQR, 11.9-12.6) mg/dL preoperatively to 8.9 (IQR, 8.1-9.4) mg/dL postoperatively (P = 0.001), whereas median intact parathyroid hormone (iPTH) dropped from a preoperative level of 340.5 (IQR, 247-540) pg/mL to 55.1 (IQR, 24.4-66.4) pg/mL after surgery (P = 0.018). Comparison between patients receiving TP and SP revealed no difference in incidence of recurrence or permanent complications, whereas the former had significantly lower calcium levels (P = 0.048) and higher phosphorus levels (P = 0.017) compared with the latter. Moreover, a significant reduction in calcium level was noted in TP group on long-term follow-up compared with their immediately postoperative level (8.1 vs 9.0 mg/dL, respectively, P < 0.05), whereas there was no significant decrease in SP group. We concluded that parathyroidectomy is efficient and safe in treating THPT. Because TP would increase the risk of hypocalcemia, a less radical procedure (SP) is preferred. PMID- 22546136 TI - Perioperative core body temperatures effect on outcome after colorectal resections. AB - The World Health Organization has set a standard of maintaining a core body temperature above 36 degrees C in the perioperative period. The purpose of this study was to examine the relationship between both intraoperative temperature (IOT) and immediate postop core body temperature as it relates to postop complications. A retrospective analysis of a prospective database of patients who underwent an elective segmental colectomy without a stoma, for 3 diagnoses was performed. Six postoperative outcomes were examined: length of stay (LOS), placement of a nasogastric tube, return to the operating room, placement of an interventional drain, diagnosed leak, and surgical site infection (SSI). Statistics were calculated using a two-sample Wilcoxon rank-sum (Mann-Whitney) test. Seventy-nine patients met the inclusion criteria and there were no preoperative differences between the groups (those with a postop complication vs without). LOS > 9 days (36.64 degrees C vs 35.98 degrees C; P = 0.011) and clinical leak (37.06 degrees C vs 35.99 degrees C; P = 0.005) both had a statistically higher average IOT than those who did not. Patients with SSI trended to a higher IOT (36.44 degrees C vs 35.99 degrees C; P = 0.062). When the last IOT recorded was compared with the six outcomes, again length of stay and leak both were statistically significant (P = 0.018, P = 0.012) showing a higher temperature related to a higher complication rate. No other complications were related to IOT, nor did postop temperature relate to complication. In our data, relatively lower IOTs were protective for LOS and clinical leaks, with a trend of lower SSI rates. Further research is needed to fully endorse or refute the absolute recommendations for core body temperature. PMID- 22546137 TI - Laparoscopic sleeve gastrectomy after simultaneous pancreas-kidney transplant. PMID- 22546138 TI - An evaluation of the effect of wind speed on trauma admissions and injury severity at a midwest level I trauma center. PMID- 22546139 TI - Acute perforated appendicitis secondary to sarcoidosis. PMID- 22546140 TI - Anastomotic rupture after brachial artery repair is associated with soft tissue deficiency. PMID- 22546141 TI - Radioembolization-induced gastroduodenal ulcer. PMID- 22546142 TI - The incidence of neurogenic shock after spinal cord injury in patients admitted to a high-volume level I trauma center. PMID- 22546143 TI - In vivo sodium release and saltiness perception in solid lipoprotein matrices. 2. Impact of oral parameters. AB - This study aimed to investigate the relationships between sodium release, saltiness, and oral parameters during the eating of lipoprotein matrices (LPM). Sodium release and saltiness relative to 10 LPM were recorded during normal mastication by five subjects with differing oral parameters (chewing efficiency and salivary flow rate). The LPM samples varied in composition (dry matter, fat, salt, and pH levels) and represented a broad range of hardness. Mastication was recorded using electromyography simultaneously with sensory assessment. Differences in chewing behavior could explain most of the variability in sodium release and saltiness among subjects. Subjects with a higher chewing force and lower salivary flow rate experienced higher levels of sodium release and saltiness. In terms of the LPM, sodium release and saltiness were affected by either chewing behavior or food composition. PMID- 22546144 TI - Controlled release and assembly of drug nanoparticles via pH-responsive polymeric micelles: a theoretical study. AB - Tumor tissues often have a pH value lower than normal tissues, and this difference suggests a promising way of targeted cancer therapy by using pH controlled drug delivery systems. On the basis of the mean-field theory, we present a theoretical methodology to predict the self-assembly and disassembly of pH-responsive polymers and nanoparticles in an ionic solution. It is found that vesicles, cylindrical, and spherical micelles can rapidly disassemble and release contained nanoparticles in a narrow pH range. The model is further used to study the controlled assembly of pH-sensitive drug with significantly improved encapsulation efficiency. This method is also applicable for the design of controlled delivery nanodevices for various biomedical applications. PMID- 22546145 TI - Retrograde tracing and toe spreading after experimental autologous nerve transplantation and crush injury of the sciatic nerve: a descriptive methodological study. AB - Evaluation of functional and structural recovery after peripheral nerve injury is crucial to determine the therapeutic effect of a nerve repair strategy. In the present study, we examined the relationship between the structural evaluation of regeneration by means of retrograde tracing and the functional analysis of toe spreading. Two standardized rat sciatic nerve injury models were used to address this relationship. As such, animals received either a 2 cm sciatic nerve defect (neurotmesis) followed by autologous nerve transplantation (ANT animals) or a crush injury with spontaneous recovery (axonotmesis; CI animals). Functional recovery of toe spreading was observed over an observation period of 84 days. In contrast to CI animals, ANT animals did not reach pre-surgical levels of toe spreading. After the observation period, the lipophilic dye DiI was applied to label sensory and motor neurons in dorsal root ganglia (DRG; sensory neurons) and spinal cord (motor neurons), respectively. No statistical difference in motor or sensory neuron counts could be detected between ANT and CI animals.In the present study we could indicate that there was no direct relationship between functional recovery (toe spreading) measured by SSI and the number of labelled (motor and sensory) neurons evaluated by retrograde tracing. The present findings demonstrate that a multimodal approach with a variety of independent evaluation tools is essential to understand and estimate the therapeutic benefit of a nerve repair strategy. PMID- 22546146 TI - Clinical review: International comparisons in critical care - lessons learned. AB - Critical care medicine is a global specialty and epidemiologic research among countries provides important data on availability of critical care resources, best practices, and alternative options for delivery of care. Understanding the diversity across healthcare systems allows us to explore that rich variability and understand better the nature of delivery systems and their impact on outcomes. However, because the delivery of ICU services is complex (for example, interplay of bed availability, cultural norms and population case-mix), the diversity among countries also creates challenges when interpreting and applying data. This complexity has profound influences on reported outcomes, often obscuring true differences. Future research should emphasize determination of resource data worldwide in order to understand current practices in different countries; this will permit rational pandemic and disaster planning, allow comparisons of in-ICU processes of care, and facilitate addition of pre- and post ICU patient data to better interpret outcomes. PMID- 22546148 TI - GMO detection using a bioluminescent real time reporter (BART) of loop mediated isothermal amplification (LAMP) suitable for field use. AB - BACKGROUND: There is an increasing need for quantitative technologies suitable for molecular detection in a variety of settings for applications including food traceability and monitoring of genetically modified (GM) crops and their products through the food processing chain. Conventional molecular diagnostics utilising real-time polymerase chain reaction (RT-PCR) and fluorescence-based determination of amplification require temperature cycling and relatively complex optics. In contrast, isothermal amplification coupled to a bioluminescent output produced in real-time (BART) occurs at a constant temperature and only requires a simple light detection and integration device. RESULTS: Loop mediated isothermal amplification (LAMP) shows robustness to sample-derived inhibitors. Here we show the applicability of coupled LAMP and BART reactions (LAMP-BART) for determination of genetically modified (GM) maize target DNA at low levels of contamination (0.1-5.0% GM) using certified reference material, and compare this to RT-PCR. Results show that conventional DNA extraction methods developed for PCR may not be optimal for LAMP-BART quantification. Additionally, we demonstrate that LAMP is more tolerant to plant sample-derived inhibitors, and show this can be exploited to develop rapid extraction techniques suitable for simple field based qualitative tests for GM status determination. We also assess the effect of total DNA assay load on LAMP-BART quantitation. CONCLUSIONS: LAMP-BART is an effective and sensitive technique for GM detection with significant potential for quantification even at low levels of contamination and in samples derived from crops such as maize with a large genome size. The resilience of LAMP-BART to acidic polysaccharides makes it well suited to rapid sample preparation techniques and hence to both high throughput laboratory settings and to portable GM detection applications. The impact of the plant sample matrix and genome loading within a reaction must be controlled to ensure quantification at low target concentrations. PMID- 22546149 TI - Phytochemical and antimicrobial investigations of stilbenoids and flavonoids isolated from three species of Combretaceae. AB - The antimicrobial activity and chemistry of the African Combretaceae has been well studied in recent years. The present study aimed to investigate the phytochemistry and antimicrobial activity of lesser known members of this family viz. C. hereroense, C. apiculatum and C. collinum. Pulverized leaves of C. collinum and C. apiculatum, and the fruit of C. hereroense were extracted with organic solvents and subjected to preparative chromatography. Seventeen phenolic constituents including four phenanthrenes from the fruit of C. hereroense and two known bibenzyls (including a combretastatin) from the leaves of C. collinum were isolated. The compounds were then subsequently tested for their antimicrobial activity against Candida albicans, Mycobacterium fortuitum, Staphylococcus aureus, Escherichia coli and Proteus vulgaris. Pinocembrin showed excellent activity against C. albicans (MIC - 6.25 MUg/ml), superior to that of the positive control, fluconazole and against S. aureus (MIC - 12.5 mg/ml). The phenanthrenes (compounds 1, 2, 3 and 5) showed some activity against M. fortuitum and S. aureus with a uniform MIC of 25 MUg/ml. From this study it was evident that most stilbenoids and flavonoids from the selected Combretaceae have little or no antimicrobial activity. PMID- 22546147 TI - Cytotoxicity and cellular uptake of tri-block copolymer nanoparticles with different size and surface characteristics. AB - BACKGROUND: Polymer nanoparticles (PNP) are becoming increasingly important in nanomedicine and food-based applications. Size and surface characteristics are often considered to be important factors in the cellular interactions of these PNP, although systematic investigations on the role of surface properties on cellular interactions and toxicity of PNP are scarce. RESULTS: Fluorescent, monodisperse tri-block copolymer nanoparticles with different sizes (45 and 90 nm) and surface charges (positive and negative) were synthesized, characterized and studied for uptake and cytotoxicity in NR8383 and Caco-2 cells. All types of PNP were taken up by the cells. The positive smaller PNP45 (45 nm) showed a higher cytotoxicity compared to the positive bigger PNP(90) (90 nm) particles including reduction in mitochondrial membrane potential (DeltaPsi(m)), induction of reactive oxygen species (ROS) production, ATP depletion and TNF-alpha release. The negative PNP did not show any cytotoxic effect. Reduction in mitochondrial membrane potential (DeltaPsi(m)), uncoupling of the electron transfer chain in mitochondria and the resulting ATP depletion, induction of ROS and oxidative stress may all play a role in the possible mode of action for the cytotoxicity of these PNP. The role of receptor-mediated endocytosis in the intracellular uptake of different PNP was studied by confocal laser scanning microscopy (CLSM). Involvement of size and charge in the cellular uptake of PNP by clathrin (for positive PNP), caveolin (for negative PNP) and mannose receptors (for hydroxylated PNP) were found with smaller PNP45 showing stronger interactions with the receptors than bigger PNP(90). CONCLUSIONS: The size and surface characteristics of polymer nanoparticles (PNP; 45 and 90 nm with different surface charges) play a crucial role in cellular uptake. Specific interactions with cell membrane-bound receptors (clathrin, caveolin and mannose) leading to cellular internalization were observed to depend on size and surface properties of the different PNP. These properties of the nanoparticles also dominate their cytotoxicity, which was analyzed for many factors. The effective reduction in the mitochondrial membrane potential (DeltaPsi(m)), uncoupling of the electron transfer chain in mitochondria and resulting ATP depletion, induction of ROS and oxidative stress likely all play a role in the mechanisms behind the cytotoxicity of these PNP. PMID- 22546150 TI - Strictosidinic acid, isolated from Psychotria myriantha Mull. Arg. (Rubiaceae), decreases serotonin levels in rat hippocampus. AB - Psychotria is a complex genus whose neotropical species are known by the presence of glucosidic monoterpene indole alkaloids. These compounds are able to display a large range of effects on the central nervous system, such as anxiolytic, antidepressant, analgesic, and impairment of learning and memory acquisition. The aims of this study were to investigate the effects displayed by strictosidinic acid, isolated from Psychotria myriantha Mull. Arg. (Rubiaceae) leaves, on monoamine levels in rat hippocampus and on monoamine oxidase activity. A significance (p<0.01) of 83.5% reduction in 5-HT levels was observed after intra hippocampal injection (20 MUg/MUl). After treatment by intraperitoneal route (10 mg/kg), a 63.4% reduction in 5-HT levels and a 67.4% reduction in DOPAC values were observed. The results indicate that strictosidinic acid seems to act on 5-HT system in rat hippocampus, possibly inhibiting precursor enzymes of 5-HT biosynthesis. The decrease verified in DOPAC levels suggests a role of strictosidinic acid in the dopaminergic transmission, probably due to an inhibition of monoamine oxidase activity, confirmed by the enzymatic assay, which demonstrated an inhibitory effect on MAO A in rat brain mitochondria. PMID- 22546151 TI - Family leadership styles and adolescent dietary and physical activity behaviors: a cross-sectional study. AB - BACKGROUND: Transformational leadership is conceptualized as a set of behaviors designed to inspire, energize and motivate others to achieve higher levels of functioning, and is associated with salient health-related outcomes in organizational settings. Given (a) the similarities that exist between leadership within organizational settings and parenting within families, and (b) the importance of the family environment in the promotion of adolescent health enhancing behaviors, the purpose of this exploratory study was to examine the cross-sectional relationships between parents' transformational leadership behaviors and adolescent dietary and physical activity behaviors. METHODS: 857 adolescents (aged 13-15, mean age = 14.70 yrs) completed measures of transformational parenting behaviors, healthful dietary intake and leisure-time physical activity. Regression analyses were conducted to examine relationships between family transformational leadership and adolescent health outcomes. A further 'extreme group analysis' was conducted by clustering families based on quartile splits. A MANCOVA (controlling for child gender) was conducted to examine differences between families displaying (a) HIGH levels of transformational parenting (consistent HIGH TP), (b) LOW levels of transformational parenting (consistent LOW TP), and (c) inconsistent levels of transformational parenting (inconsistent HIGH-LOW TP). RESULTS: Results revealed that adolescents' perceptions of family transformational parenting were associated with both healthy dietary intake and physical activity. Adolescents who perceived their families to display the highest levels of transformational parenting (HIGH TP group) displayed greater healthy eating and physical activity behaviors than adolescents who perceived their families to display the lowest levels of transformational parenting behaviors (LOW TP group). Adolescents who perceived their families to display inconsistent levels of transformational parenting behaviors (HIGH-LOW TP group) displayed the same levels of healthy eating behaviors as those adolescents from the LOW TP group. For physical activity behaviors, adolescents who perceived their families to display inconsistent levels of transformational parenting behaviors (HIGH-LOW TP group) did not differ in terms of physical activity than those in either the HIGH TP or LOW TP group. CONCLUSIONS: Family transformational parenting behaviors were positively associated with both healthful dietary intake and leisure-time physical activity levels amongst adolescents. The findings suggest that transformational leadership theory is a useful framework for understanding the relationship between family leadership behaviors and adolescent health outcomes. PMID- 22546152 TI - Condensation and decondensation of DNA by cationic surfactant, spermine, or cationic surfactant-cyclodextrin mixtures: macroscopic phase behavior, aggregate properties, and dissolution mechanisms. AB - The macroscopic phase behavior and other physicochemical properties of dilute aqueous mixtures of DNA and the cationic surfactant hexadecyltrimethylammounium bromide (CTAB), DNA and the polyamine spermine, or DNA, CTAB, and (2 hydroxypropyl)-beta-cyclodextrin (2HPbetaCD) were investigated. When DNA is mixed with CTAB we found, with increasing surfactant concentration, (1) free DNA coexisting with surfactant unimers, (2) free DNA coexisting with aggregates of condensed DNA and CTAB, (3) a miscibility gap where macroscopic phase separation is observed, and (4) positively overcharged aggregates of condensed DNA and CTAB. The presence of a clear solution beyond the miscibility gap cannot be ascribed to self-screening by the charges from the DNA and/or the surfactant; instead, hydrophobic interactions among the surfactants are instrumental for the observed behavior. It is difficult to judge whether the overcharged mixed aggregates represent an equilibrium situation or not. If the excess surfactant was not initially present, but added to a preformed precipitate, redissolution was, in consistency with previous reports, not observed; thus, kinetic effects have major influence on the behavior. Mixtures of DNA and spermine also displayed a miscibility gap; however, positively overcharged aggregates were not identified, and redissolution with excess spermine can be explained by electrostatics. When 2HPbetaCD was added to a DNA-CTAB precipitate, redissolution was observed, and when it was added to the overcharged aggregates, the behavior was essentially a reversal of that of the DNA-CTAB system. This is attributed to an effectively quantitative formation of 1:1 2HPbetaCD-surfactant inclusion complexes, which results in a gradual decrease in the concentration of effectively available surfactant with increasing 2HPbetaCD concentration. PMID- 22546154 TI - [Anticoagulant therapy in 2012--individualized treatment--also for the elderly]. PMID- 22546153 TI - The relationship between inspiratory lung function parameters and airway hyper responsiveness in subjects with mild to moderate COPD. AB - BACKGROUND: The aim of this study was to evaluate the effects of increasing doses of inhaled histamine on the forced expiratory volume in one second (FEV1), inspiratory lung function parameters (ILPs) and dyspnea in subjects with mild to moderate chronic obstructive pulmonary disease (COPD) METHODS: Thirty-nine (27 males and 12 females) stable COPD patients (GOLD stages I and II) inhaled a maximum of six sequential doses of histamine according to ERS standards until one of these provocative doses produced a 20% decrease in FEV1 (PD20). The effects on the FEV1, the forced inspiratory volume in one second (FIV1), inspiratory capacity (IC), forced inspiratory flow at 50% of the vital capacity (FIF50), peak inspiratory flow (PIF) and dyspnea score by a visual analogue scale (VAS) were measured and investigated after each dose step RESULTS: After each dose of histamine, declines in all of the lung function parameters were detected; the largest decrease was observed in the FEV1. At the PD20 endpoint, more FEV1 responders than ILP responders were found. Among the ILPs, the FIV1 and IC best predicted which patients would reach the PD20 endpoint. No significant correlations were found between any of the lung function parameters and the VAS results CONCLUSIONS: In COPD patients, the FEV1 and ILPs declined after each dose of inhaled histamine. FEV1 was more sensitive to histamine than the ILPs. Of the ILPs, FIV1 and IC were the best predictors of reaching the PD20 endpoint. No statistically significant correlations were found between the lung function parameters and the degree of dyspnea. PMID- 22546155 TI - [Paracetamol or NSAID for relief treatment in febrile children]. PMID- 22546156 TI - [Ibuprofen is more effective than paracetamol in lowering the temperature in febrile children]. AB - In Denmark, the traditional choice for treating fever and pain in children is paracetamol. In other countries ibuprofen or a combination of paracetamol and ibuprofen is preferred. The literature describing the two medications for children is being reviewed. It is concluded that ibuprofen seems to be more effective in reducing fever when compared to paracetamol. The two types of medications are equally effective when it comes to treating pain in children. PMID- 22546157 TI - [Carnitine transporter deficiency is a hereditary disease with a high incidence in the Faroe Islands]. AB - The Faroe Islands has a high incidence of carnitine transporter deficiency (CTD) and several other autosomal recessive diseases. This article describes the reason for the high frequency, in view of the Faroese history and the diagnosis of CTD. Few individuals founded the Faroese population in the 9th century, and subsequent geographic isolation limited genetic diversity in the Islands. PMID- 22546158 TI - [Lack of clear guidelines for authorship in multicentre studies]. AB - Determining authorship in multicentre studies can be difficult because of the large number of contributors and collaborators. Different experiences and recommendations regarding authorship and byline listing emphasize the importance of transparency and communication before, during, and after manuscript preparation. More specifically, written publication policies, regular meetings, and different scoring systems can be considered. It is important to reduce potential disincentives for engaging in multicentre studies. Therefore, clear guidelines for authorship assignment are necessary. PMID- 22546159 TI - [Urological problems in pregnancy, birth, and puerperium--a systematic review]. AB - Urological problems in pregnancy represent a diagnostic and therapeutic challenge. Urinary tract symptoms in pregnant women comprise urinary tract infections, urolithiasis, hydronephrosis, urinary retention, urinary frequency and urinary incontinence. The primary purpose of this paper was to link our current understanding of the urinary tract anatomy and physiology to urinary tract symptoms in pregnancy and puerperium and the secondary purpose was to provide a review on diagnosis and management of these. PMID- 22546160 TI - [A 10-kg ovarian mucinous cystadenoma in a 13 year-old girl]. AB - A 13 year-old girl was admitted to hospital with abdominal pain and weight gain. The physical examination showed pronounced abdominal distension, but slim extremities. A magnetic resonance imaging scan revealed a left cystic ovarian tumour. The ovarian tumour was removed and the weight turned out to be 10.3 kg. Pathology showed a borderline mucinous cystadenoma. Ovarian tumours represent less than 2% of all tumours in girls under the age of 16. In this age group 50% of the ovarian tumours are neoplastic and 60% derive from the surface epithelia of the ovary. PMID- 22546161 TI - [Fatal Clostridium sordellii infection originated in an ovarian cyst]. AB - Clostridium sordellii is a Gram-positive bacterium which can cause a serious toxic shock syndrome with a mortality of up to 69%. C. sordellii is a part of the normal vaginal flora in up to 10% of all women. This case describes a fatal case of a healthy 49 year-old woman with a C. sordellii-infection originating from an ovarian cyst. Quick diagnosis is difficult because of the non-specific flu-like symptoms. Survival requires immediate source control and specific antibiotic therapy capable of suppressing toxin production. In rodents superantigen antibodies have shown neutralizing effects. PMID- 22546162 TI - [Complete proximal hamstring tendon rupture can be misinterpreted as muscle rupture]. AB - Complete proximal hamstring tendon rupture is a rare injury which untreated can lead to reduced strength, pain and dysaesthesia corresponding to the sciatic nerve. We report a case of complete hamstring tendon rupture in a 50 year-old woman who was treated with surgical reinsertion of the tendon to the ischial tuberosity. Surgical repair should be considered in active patients, who desire a high level of physical activity. Surgery should preferably be performed in the first 2-3 weeks after injury, as delayed surgery is complicated by scar tissue in close relation to the sciatic nerve. PMID- 22546163 TI - [A testis tumour in an 82 year-old]. AB - An 82 year-old man presented with a unilateral tumour in the right testis. A complete orchiectomy was subsequently performed. Histological examination showed a malign germ cell tumour of yolk sac type. Rete testis invasion was present, but there was no vascular or lymphatic invasion and the tumour did not extend tunica albuginea. Computed tomography of the abdomen caused no suspicion of metastasis and there were no elevated tumour markers postoperative. Yolk sac tumour in the elderly is very uncommon, but the diagnosis is important since it has a different clinical behaviour than juvenile yolk sac tumours. PMID- 22546164 TI - [Spontaneous cholecystocutaneous fistula presenting in the right breast]. AB - We report a case of an 89 year-old woman, with an abscess in the right breast. On incision the abscess produced bile. Ultrasound scan, computed tomography, magnetic resonance imaging and endoscopic retrograde cholangiopancreatography showed a fistula from a subphrenic abscess to the breast. Conservative treatment was insufficient and the condition only resolved after open cholecystectomy. During the latest 50 years, less than 20 cases of cholecystocutaneous fistula have been reported. Perforation to the breast has not previously been described. PMID- 22546165 TI - [Carney complex: a syndrome with cardial, cutaneous and neuronal tumours]. AB - A 12 year-old boy presented with neurological symptoms and was found to have a left atrial myxoma. Characteristic facial skin pigmentation raised a suspicion of Carney complex, a rare autosomal dominant disease, which includes cutaneous changes, atrial myxomas and neuroendocrine tumours. The boy's mother had similar skin pigmentation and on subsequent cardiac echocardiography she was found to have left and right atrial myxomas. Both mother and child underwent successful surgical resection of the myxomas. PMID- 22546166 TI - [Endoscopic complication: unsuspected impact of gastroscope into the oesophagus in a patient with a large hiatal hernia]. AB - Gastroscopy is used world-wide and it is considered as a safe procedure. In a case study we describe an impaction of a gastroscope into the oesophagus. A gastroscopy in full narcosis was performed on a patient with a large size hiatal hernia. During the procedure the gastroscope recurved into the oesophagus. With the assistance of another gastroscope and fluoroscopic guidance the gastroscope was removed successfully. This complication may occur more often than described in literature. PMID- 22546167 TI - [Primary Epstein-Barr virus infections with neurological complications in two middle-aged men]. AB - Primary infections with Epstein-Barr virus (EBV) often lead to infectious mononucleosis with sore throat, lymphadenopathy and hepatitis, especially in youngsters. However, neurological complications can occur even in immunocompetent individuals. We report two case stories of two middle-aged men with primary EBV infections who presented severe neurological manifestations of the disease, but both fully recovered. Hepatitis was present in both cases, but not the classical mononucleosis. The cases stress that clinicians should be aware of these rare courses of primary EBV infections. PMID- 22546168 TI - [Unilateral atypical neck pain in Eagle syndrome]. AB - This article is an introduction to Eagle syndrome as a differential diagnosis in patients with lateral neck pain, a symptom, which is often difficult to diagnose and where the accepted treatment covers a variety of forms. This was the case for a 51 year-old man with lateral neck pain and a crunchy sensation/sound when he turned his head. After years of pain, the right examination and a computed tomography finally suggested Eagle syndrome. The patient had severe symptoms and was treated with an operation by which part of the ossificated stylohyoid ligament was removed. The operation relieved him of all his symptoms. PMID- 22546169 TI - [Picture of the month: extravasation of silicone]. PMID- 22546170 TI - Unique vascular protective properties of natural products: supplements or future main-line drugs with significant anti-atherosclerotic potential? AB - Natural health products (NHP) which include minerals, vitamins and herbal remedies are not generally considered by medical practitioners as conventional medicines and as such are not frequently prescribed by health centre's as either main-line or supplemental treatments. In the field of cardiovascular medicine, studies have shown that typically, less than half of patients suffering from coronary syndromes chose to take any form of NHP supplement and these products are rarely recommended by their medical practitioner. Vascular/endothelial cell damage is a key instigator of coronary arterial plaque development which often culminates in thrombosis and myocardial infarction (MI). Current treatment for patients known to be at risk of primary or secondary (MI) includes lipid lowering statins, anti-clotting agents (e.g. tissue plasminogen activator; tPA) and drugs for stabilization of blood pressure such as beta-blockers. However, evidence has been building which suggests that components of at least several NHP (e.g. aged garlic extract (AGExt), resveratrol and green tea extracts (GTE)) may have significant vascular protective effects through reduction of oxidative stress, lowering of blood pressure, reduction in platelet aggregation, vasodilation and inhibition of abnormal angiogenesis. Therefore, in this review we will discuss in detail the potential of these substances (chosen on the basis of their potency and complimentarity) as anti-atherosclerotic agents and the justification for their consideration as main-line additional supplements or prescriptions. PMID- 22546171 TI - Intestinal health benefits of the water-soluble carbohydrate concentrate of wild grape ( Vitis thunbergii ) in hamsters. AB - The dose-response relationship of the water-soluble carbohydrate concentrate (WSCC) from wild grape ( Vitis thunbergii Sieb. & Zucc.) on intestinal health was investigated in this study. WSCC contained carbohydrates up to 71.9 g/100 g, including arabinose-rich pectic polysaccharide, hemicelluloses, glucose, and fructose. The consumption of WSCC (0.5 and 1.5 g/100 g of diet) effectively (P < 0.05) shortened gastrointestinal transit time (-62.3 to -63.0%), decreased toxic cecal ammonia (-59.3 to -63.0%) and daily fecal ammonia output (-29.7 to -41.4%), decreased the activities of fecal beta-glucuronidase (-78.6%), beta-glucosidase ( 80.5 to -87.5%), mucinase (-64.6 to -72.7%), and urease (-83.2 to -86.0%), increased fecal moisture content (116-129%), and also increased short-chain fatty acid levels in cecal contents (1.8-3.3-fold). These findings suggested that consumption of wild grape WSCC might diminish the exposure of intestinal mucosa to toxic ammonia and other detrimental compounds and, hence exert, favorable effects on improving gastrointestinal milieu. PMID- 22546172 TI - Clinical review: the hospital of the future - building intelligent environments to facilitate safe and effective acute care delivery. AB - The translation of knowledge into rational care is as essential and pressing a task as the development of new diagnostic or therapeutic devices, and is arguably more important. The emerging science of health care delivery has identified the central role of human factor ergonomics in the prevention of medical error, omission, and waste. Novel informatics and systems engineering strategies provide an excellent opportunity to improve the design of acute care delivery. In this article, future hospitals are envisioned as organizations built around smart environments that facilitate consistent delivery of effective, equitable, and error-free care focused on patient-centered rather than provider-centered outcomes. PMID- 22546173 TI - Interaction of counterions with subtilisin in acetonitrile: insights from molecular dynamics simulations. AB - A recent X-ray structure has enabled the location of chloride and cesium ions on the surface of subtilisin Carlsberg in acetonitrile soaked crystals. (1) To complement the previous study and analyze the system in solution, molecular dynamics (MD) simulations, in acetonitrile, were performed using this structure. Additionally, Cl(-) and Cs(+) ions were docked on the protein surface and this system was also simulated. Our results indicate that chloride ions tend to stay close to the protein, whereas cesium ions frequently migrate to the solvent. The distribution of the ions around the enzyme surface is not strongly biased by their initial locations. Replacing cesium by sodium ions showed that the distribution of the two cations is similar, indicating that Cs(+) can be used to find the binding sites of cations like Na(+) and K(+), which, unlike Cs(+), have physiological and biotechnological roles. The Na(+)Cl(-) is more stable than the Cs(+)Cl(-) ion pair, decreasing the probability of interaction between Cl(-) and subtilisin. The comparison of water and acetonitrile simulations indicates that the solvent influences the distribution of the ions. This work provides an extensive theoretical analysis of the interaction between ions and the model enzyme subtilisin in a nonaqueous medium. PMID- 22546174 TI - Kaempferol as a flavonoid induces osteoblastic differentiation via estrogen receptor signaling. AB - BACKGROUND: Flavonoids, a group of compounds mainly derived from vegetables and herbal medicines, chemically resemble estrogen and some have been used as estrogen substitutes. Kaempferol, a flavonol derived from the rhizome of Kaempferia galanga L., is a well-known phytoestrogen possessing osteogenic effects that is also found in a large number of plant foods.The herb K. galanga is a popular traditional aromatic medicinal plant that is widely used as food spice and in medicinal industries. In the present study, both the estrogenic and osteogenic properties of kaempferol are evaluated. METHODS: Kaempferol was first evaluated for its estrogenic properties, including its effects on estrogen receptors. The osteogenic properties of kaempferol were further determined its induction effects on specific osteogenic enzymes and genes as well as the mineralization process in cultured rat osteoblasts. RESULTS: Kaempferol activated the transcriptional activity of pERE-Luc (3.98 +/- 0.31 folds at 50 MUM) and induced estrogen receptor alpha (ERalpha) phosphorylation in cultured rat osteoblasts, and this ER activation was correlated with induction and associated with osteoblast differentiation biomarkers, including alkaline phosphatase activity and transcription of osteoblastic genes, e.g., type I collagen, osteonectin, osteocalcin, Runx2 and osterix. Kaempferol also promoted the mineralization process of osteoblasts (4.02 +/- 0.41 folds at 50 MUM). ER mediation of the kaempferol-induced effects was confirmed by pretreatment of the osteoblasts with an ER antagonist, ICI 182,780, which fully blocked the induction effect. CONCLUSION: Our results showed that kaempferol stimulates osteogenic differentiation of cultured osteoblasts by acting through the estrogen receptor signaling. PMID- 22546176 TI - An online survey of Australian physicians reported practice with the off-label use of nebulised frusemide. AB - BACKGROUND: Off-label prescribing is common in palliative care. Despite inconsistent reports of the benefit of nebulised frusemide for breathlessness, its use continues to be reported. METHODS: An online survey was emailed to 249 members of the Australian and New Zealand Society of Palliative Medicine to estimate the use of nebulised frusemide for breathlessness by Australian physicians involved in palliative care in the previous 12 months. RESULTS: There were 52/249 (21%) respondents to the survey. The majority (44/52; 85%) had not prescribed nebulised frusemide in the previous 12 months. The most common (18/44; 43%) reason for not prescribing nebulised frusemide was a belief that there was not enough evidence to support its use. Whilst only a few respondents (8/52; 15%) reported having used nebulised frusemide, all that had used it thought there was at least some benefit in relieving breathlessness. CONCLUSION: This report adds to the series of case studies reporting some benefit from nebulised frusemide in relieving breathlessnes. PMID- 22546175 TI - Effects of wood smoke particles from wood-burning stoves on the respiratory health of atopic humans. AB - BACKGROUND: There is growing evidence that particulate air pollution derived from wood stoves causes acute inflammation in the respiratory system, increases the incidence of asthma and other allergic diseases, and increases respiratory morbidity and mortality. The objective of this study was to evaluate acute respiratory effects from short-term wood smoke exposure in humans. Twenty non smoking atopic volunteers with normal lung function and without bronchial responsiveness were monitored during three different experimental exposure sessions, aiming at particle concentrations of about 200 MUg/m(3), 400 MUg/m(3), and clean air as control exposure. A balanced cross-over design was used and participants were randomly allocated to exposure orders. Particles were generated in a wood-burning facility and added to a full-scale climate chamber where the participants were exposed for 3 hours under controlled environmental conditions. Health effects were evaluated in relation to: peak expiratory flow (PEF), forced expiratory volume in the first second (FEV1), and forced vital capacity (FVC). Furthermore, the effects were assessed in relation to changes in nasal patency and from markers of airway inflammation: fractional exhaled nitric oxide (FENO), exhaled breath condensate (EBC) and nasal lavage (NAL) samples were collected before, and at various intervals after exposure. RESULTS: No statistically significant effect of wood smoke exposure was found for lung function, for FENO, for NAL or for the nasal patency. Limited signs of airway inflammation were found in EBC. CONCLUSION: In conclusion, short term exposure with wood smoke at a concentration normally found in a residential area with a high density of burning wood stoves causes only mild inflammatory response. PMID- 22546177 TI - n-Butanol partitioning and phase behavior in DPPC/DOPC membranes. AB - Membrane phase behavior and fluidization have been examined in heterogeneous membranes composed of dipalmitoylphosphatidylcholine (DPPC, a saturated lipid) and dioleoylphosphatidylcholine (DOPC, an unsaturated lipid) at n-butanol concentrations below and above the interdigitation threshold of DPPC. Our results show that the presence of DOPC did not influence the interdigitation concentration of n-butanol on DPPC (0.1-0.13 M) despite the fact that DOPC increased n-butanol partitioning into the membranes. When DPPC was the continuous phase, up to equimolar DPPC:DOPC, n-butanol partitioning into gel or interdigitated DPPC was only slightly affected by the presence of DOPC. In this case a "cooperative effect" of DOPC + n-butanol eliminated the DPPC pretransition phase and yielded an untilted gel-like phase. When DOPC was the continuous phase, more n-butanol was needed to cause DPPC interdigitation (0.2 M), which was attributed to n-butanol residing at the interface between DOPC and DPPC domains. To our knowledge, this is the first study to examine the effects of n-butanol partitioning on membranes composed of saturated and unsaturated lipids that exhibit coexisting phase states. PMID- 22546178 TI - Seasonal variation in accelerometer-determined sedentary behaviour and physical activity in children: a review. AB - AIM: To undertake a review of the methods and findings of published research evaluating the influence of season on accelerometer-determined sedentary behaviour (SB) and physical activity (PA) in children. METHODS: A literature search was carried out using PubMed, Embase, Medline and Web of Science up to, and including, June 2011. The search strategy focused on four key elements: children, SB or PA, season and accelerometer. Articles were eligible for inclusion if they were published in English, included healthy study participants aged <= 18 years, reported at least one outcome variable derived from accelerometer-determined measurements, and compared SB or PA between two or more seasons, or controlled for season of measurement. Eligible papers were reviewed and evidence tables compiled reporting on publication year, country studied, study recruitment, consent rate, sample descriptives, study design, accelerometer protocol, valid accelerometer data receipt, season definition, statistical methods and key findings. RESULTS: Sixteen of 819 articles were eligible for inclusion: children aged two to five years, six to twelve, or six to 18 years were included in five, six and five articles respectively. Six articles were from the UK, six from other European countries, three from the USA and one from New Zealand. Study sample sizes ranged from 64 to 5595. PA was reported in all articles but SB in only three. Only four studies were longitudinal and none of these reported SB. Seasonal variation in PA was reported in all UK studies, being highest in summer and lowest in winter. In four non-UK studies seasonal variation in PA was not found. Findings were inconclusive for SB. CONCLUSION: There is sufficient evidence to support public health interventions aimed at increasing PA during winter in UK children. No conclusions can be drawn regarding the effect of season on children's SB reflecting few studies of small sample size, lack of repeat measures, incomparable definitions of season and inconsistent accelerometer protocols. Future research should determine factors that drive seasonal patterns in PA and SB in children such as age, sex, and geographic and climatic setting to inform interventions and target populations. PMID- 22546181 TI - Stereochemical effect revealed in self-assemblies based on archaeal lipid analogues bearing a central five-membered carbocycle: a SAXS study. AB - The relative stereochemistry (cis or trans) of a 1,3-disubstituted cyclopentane unit in the middle of tetraether archaeal bipolar lipid analogues was found to have a dramatic influence on their supramolecular self-assembly properties. SAXS studies of two synthetic diastereomeric archaeal lipids bearing two lactosyl polar head groups at opposite ends revealed different lyotropic behaviors. The cis isomer led to L(c)-L(alpha)-Q(II) transitions whereas the trans isomer retained an L(alpha) phase from 20 to 100 degrees C. These main differences originate from the conformational equilibrium (pseudorotation) of 1,3 disubstituted cyclopentanes. Indeed, this pseudorotation exhibits quite similar orientations of the two substituents in a trans isomer whereas several orientations of the two alkyl chains are expected in a cis-1,3-dialkyl cyclopentane, thus authorizing more conformational flexibility in the lipid packing. PMID- 22546179 TI - Quantitative cross-validation and content analysis of the 450k DNA methylation array from Illumina, Inc. AB - BACKGROUND: The newly released 450k DNA methylation array from Illumina, Inc. offers the possibility to analyze more than 480,000 individual CpG sites in a user friendly standardized format. In this study the relationship between the beta-values provided by the Illumina, Inc. array for each individual CpG dinucleotide and the quantitative methylation levels obtained by pyrosequencing were analyzed. In addition, the representation of microRNA genes and imprinted loci on the Illumina, Inc. array was assessed in detail. Genomic DNA from 4 human breast cancer cell lines (IPH-926, HCC1937, MDA-MB-134, PMC42) and 18 human breast cancer specimens as well as 4 normal mammary epithelial fractions was analyzed on 450k DNA methylation arrays. The beta-values for 692 individual CpG sites from 62 different genes were cross-validated using conventional quantitative pyrosequencing. FINDINGS: The newly released 450k methylation array from Illumina, Inc. shows a high concordance with quantitative pyrosequencing if identical CpG sites are analyzed in cell lines (Spearman r = 0.88, p ? 0.0001), which is somewhat reduced in primary tumor specimens (Spearman r = 0.86, p ? 0.0001). 80.7% of the CpG sites show an absolute difference in methylation level of less than 15 percentage points. If different CpG sites in the same CpG islands are targeted the concordance is lower (r = 0.83 in cell lines and r = 0.7 in primary tumors). The number of CpG sites representing microRNA genes and imprinted loci is very heterogeneous (range: 1 - 70 CpG sites for microRNAs and 1 - 288 for imprinted loci). CONCLUSIONS: The newly released 450k methylation array from Illumina, Inc. provides a genome-wide quantitative representation of DNA methylation aberrations in a convenient format. Overall, the congruence with pyrosequencing data is very good. However, for individual loci one should be careful to translate the beta-values directly into percent methylation levels. PMID- 22546180 TI - Lymphatic trafficking kinetics and near-infrared imaging using star polymer architectures with controlled anionic character. AB - Targeted lymphatic delivery of nanoparticles for drug delivery and imaging is primarily dependent on size and charge. Prior studies have observed increased lymphatic uptake and retentions of over 48 h for negatively charged particles compared to neutral and positively charged particles. We have developed new polymeric materials that extend retention over a more pharmaceutically relevant 7 day period. We used whole body fluorescence imaging to observe in mice the lymphatic trafficking of a series of anionic star poly-(6-O-methacryloyl-D galactose) polymer-NIR dye (IR820) conjugates. The anionic charge of polymers was increased by modifying galactose moieties in the star polymers with succinic anhydride. Increasing anionic nature was associated with enhanced lymphatic uptake up to a zeta potential of ca.-40 mV; further negative charge did not affect lymphatic uptake. Compared to the 20% acid-conjugate, the 40-90% acid-star polymer conjugates exhibited a 2.5- to 3.5-fold increase in lymphatic uptake in both the popliteal and iliac nodes. The polymer conjugates exhibited node half lives of 2-20 h in the popliteal nodes and 19-114 h in the deeper iliac nodes. These polymer conjugates can deliver drugs or imaging agents with rapid lymphatic uptake and prolonged deep-nodal retention; thus they may provide a useful vehicle for sustained intralymphatic drug delivery with low toxicity. PMID- 22546182 TI - Analysis of common and emerging brominated flame retardants in house dust using ultrasonic assisted solvent extraction and on-line sample preparation via column switching with liquid chromatography-mass spectrometry. AB - Brominated flame retardants (BFRs) are persistent and widespread chemicals. Therefore human beings are exposed to BFRs. House dust may be one source of exposure and contains a lot of xenobiotics in relatively high concentrations. In contrast to common GC-MS based methods here an online LC-MS/MS method is presented to quantify 16 BFRs in dust using ultrasonic solvent extraction as a single sample work up step. LOQ from 0.6 (tetrabromobisphenol A) to 80 (polybrominated diphenylethers (BDE 28) ng/g dust were achieved. Data for accuracy, precision and recovery are presented and are comparable to common LC MS/MS methods in different matrices. In addition 5 real house dust samples were analyzed with high concentration (535 ng/g) for bis(2-ethyl-1 hexyl)tetrabromophthalate which is a novel alternative BFRs to replace common BDE's. PMID- 22546183 TI - 30th Anniversary of the invention of scanning tunneling microscopy (STM). PMID- 22546184 TI - "Oh yes, oh yes, these are the atoms!" A personal recollection from the times of the invention of the STM. AB - The scanning tunneling microscope, invented and developed in the 1980s in the IBM research laboratory in Ruschlikon, has become the dominent scientific tool in surface science and together with its younger brother the atomic force microscope, is widely used also in many other modern research areas. This account contains very personal anecdotal memories from a colleague who worked in a neighboring lab in Ruschlikon describing some events at the periphery of the development of this ingenious instrument. PMID- 22546185 TI - Scanning probe microscopy of atoms and molecules on insulating films: from imaging to molecular manipulation. AB - Scanning tunneling microscopy (STM) and atomic force microscopy (AFM) of single atoms and molecules on ultrathin insulating films have led to a wealth of novel observations and insights. Based on the reduced electronic coupling to the metallic substrate, these techniques allow the charge state of individual atoms to be controlled, orbitals of individual molecules to be imaged and metal molecule complexes to be built up. Near-contact AFM adds the unique capabilities of imaging and probing the chemical structure of single molecules with atomic resolution. With the help of atomic/molecular manipulation techniques, chemical binding processes and molecular switches can be studied in detail. PMID- 22546186 TI - Scanning tunneling microscopy and spectroscopy of supported nanostructures. AB - Recent advances in low-temperature scanning tunneling microscopy (STM) and spectroscopy (STS) have provided new opportunities for the investigation of the local geometric, electronic, magnetic, and optical properties of nanostructures. This review focuses on the presentation and discussion of single molecules, supramolecular assemblies, and other nanostructures; all research results obtained in our laboratory. The emphasis is directed to the observation of new effects, where the properties of matter at the nanoscale differ from those at the mesoscopic or macroscopic scale: small is different. This fact is illustrated for the conservation of chirality in a hierarchical supramolecular assembly of organic molecules and for local light emission from supported molecules. The latter indicates a possible route towards an optical spectroscopic analysis on the scale of single molecules. PMID- 22546187 TI - Electron transport at surfaces and interfaces. AB - Here we present two techniques which give insight on transport phenomena with atomic resolution. Ballistic electron emission microscopy is used to study the ballistic transport through layered heterogeneous systems. The measured ballistic fraction of the tunneling current provides information about lossless transport channels through metallic layers and organic adsorbates. The transport characteristics of Bi(111)/Si Schottky devices and the influence of the organic adsorbates perylene tetracaboxylic dianhydride acid and C(60) on the ballistic current are discussed. Scanning tunneling potentiometry gives access to the lateral transport along a surface, thus scattering processes within two dimensional electron systems for the Bi(111) surface and the Si(111)(?3 * ?3)-Ag surface could be visualized. PMID- 22546188 TI - Modifying the STM tip for the ' ultimate ' imaging of the Si(111)-7*7 surface and metal-supported molecules. AB - We report on high-resolution STM measurements with modified probe tips. First, both the rest atoms and adatoms of a Si(111)-7*7 surface are observed simultaneously. The visibility of rest atoms is dependent upon the sample bias voltage (less than -0.7 V) and is enhanced by sharpening the tip, which is rationalized by first-principles calculations. Second, a tip with a perylene molecule adsorbed at its apex is used to discriminate the molecular states and the metal states of the underlying Ag(110) surface, which is attributable to a mismatch between the energy levels of the functionalized tip and the adsorbates on silver. Lastly, high-resolution images of iron phthalocyanine (FePc) and zinc phthalocyanine (ZnPc) molecules on Au(111) are obtained by using an O(2) terminated tip, and the images reveal rich intramolecular features arising from molecular orbitals that are not observed when using clean metallic tips. PMID- 22546189 TI - Dynamics in self-assembled organic monolayers at the liquid/solid interface revealed by scanning tunneling microscopy. AB - The liquid/solid interface provides an interesting medium for molecular self assembly and scanning tunneling microscopy is the preferred technique to analyse the structural features of the surface-supported self-assembled monolayers in this medium. An interesting aspect is the phenomenon of molecular dynamics at the liquid/solid interface. In this mini-review, we report on our efforts and strategies to investigate and even induce molecular dynamics at the liquid/solid interface, bringing insight to various kinds of processes such as conformational, translational and adsorption/desorption dynamics. PMID- 22546190 TI - Electrochemical scanning tunneling microscopy. AB - The electrochemical scanning tunneling microscope was the first tool for the investigation of solid-liquid interfaces that allowed in situ real space imaging of electrode surfaces at the atomic level. Therefore it quickly became an important addition to the repertoire of methods for the determination of the local surface structure as well as the dynamics of reactions and processes taking place at surfaces in an electrolytic environment. In this short overview we present several examples to illustrate the powerful capabilities of the EC-STM, including the observation of clean metal surfaces as well as the adsorption of thin metal layers, specifically adsorbed anions and non-specifically adsorbed organic cations. In several cases the electrode potential has a significant influence on structure and reactivity of the surface that can be explained by the observations made with the EC-STM. PMID- 22546191 TI - The art of catching and probing single molecules. AB - Probing the electronic properties of an individual molecule is a far from trivial task. In order to measure, for instance, the conductance of a single molecule, the molecule must be contacted by two nanoscopic electrodes. Here we will give two examples of how a single molecule can be caught between two metallic electrodes. In the first example the conductance of a single octanethiol molecule is measured by trapping the molecule between an atomic Pt chain on a semiconductor surface and the apex of a scanning tunneling microscope tip. In the second example a Cu-phthalocyanine molecule is caught between two adjacent nanowires on a semiconductor surface. In this 'bridge' adsorption configuration the core of the CuPc molecule, i.e. the Cu atom, is fully decoupled from the underlying substrate. The electronic properties of the core of Cu-phthalocyanine molecule are probed with scanning tunneling spectroscopy. PMID- 22546192 TI - Spin-polarized scanning tunneling microscopy: breakthroughs and highlights. AB - The principle of scanning tunneling microscopy, an imaging method with atomic resolution capability invented by Binnig and Rohrer in 1982, can be adapted for surface magnetism studies by using magnetic probe tips. The contrast mechanism of this so-called spin-polarized scanning tunneling microscopy, or SP-STM, relies on the tunneling magneto-resistance effect, i.e. the tip-sample distance as well as the differential conductance depend on the relative magnetic orientation of tip and sample. To illustrate the working principle and the unique capabilities of SP-STM, this compilation presents some key experiments which have been performed on various magnetic surfaces, such as the topological antiferromagnet Cr(001), a double-layer of Fe which exhibits a stripe- domain pattern with about 50 nm periodicity, and the Mn monolayer on W(110), where the combination of experiment and theory reveal an antiferromagnetic spin cycloid. Recent experimental results also demonstrate the suitability of SP-STM for studies of dynamic properties, such as the spin relaxation time of single magnetic nanostructures. PMID- 22546195 TI - ATRPases: enzymes as catalysts for atom transfer radical polymerization. PMID- 22546197 TI - Mesenchymal stem cells augment neurogenesis in the subventricular zone and enhance differentiation of neural precursor cells into dopaminergic neurons in the substantia nigra of a parkinsonian model. AB - Growing evidence has demonstrated that neurogenesis in the subventricular zone (SVZ) is significantly decreased in Parkinson's disease (PD). Modulation of endogenous neurogenesis would have a significant impact on future therapeutic strategies for neurodegenerative diseases. In the present study, we investigated the augmentative effects of human mesenchymal stem cells (hMSCs) on neurogenesis in a PD model. Neurogenesis was assessed in vitro with 1-methyl-4 phenylpyridinium (MPP(+)) treatment using neural precursor cells (NPCs) isolated from the SVZ and in vivo with a BrdU-injected animal model of PD using 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Immunochemical analyses were used to measure neurogenic activity. The number of BrdU-ir cells in the SVZ and the substantia nigra (SN) was significantly increased in the hMSC-treated PD group compared with the MPTP-only-treated group. Double-stained cells for BrdU and tyrosine hydroxylase were notably observed in the SN of hMSC-treated PD animals, and they did not colocalize with the nuclear matrix; however, double-stained cells were not detected in the SN of the MPTP-induced PD animal model. Furthermore, hMSC administration increased the expression of the epidermal growth factor receptor (EGFR) in the SVZ of PD animals, and the coculture of hMSCs significantly increased the release of EGF in the medium of MPP(+)-treated NPCs. The present study demonstrated that hMSC administration significantly augmented neurogenesis in both the SVZ and SN of PD animal models, which led to increased differentiation of NPCs into dopaminergic neurons in the SN. Additionally, hMSC induced modulation of EGF seems to be an underlying contributor to the enhancement of neurogenesis by hMSCs. The modulation of endogenous adult neurogenesis to repair the damaged PD brain using hMSCs would have a significant impact on future strategies for PD treatment. PMID- 22546198 TI - Simultaneous determination of pesticides, polycyclic aromatic hydrocarbons, polychlorinated biphenyls and phthalate esters in human adipose tissue by gas chromatography-tandem mass spectrometry. AB - This paper describes a method for the simultaneous determination of 284 environmental contaminants, including 57 pesticides, 15 polycyclic aromatic hydrocarbons (PAHs), 209 polychlorinated biphenyls (PCBs) and 3 phthalate esters (PAEs), in adipose tissue samples. For the first time, a gas chromatography tandem mass spectrometry (GC-MS/MS) method following a homogenised extraction using acetonitrile and purification by gel permeation chromatography (GPC) was used. Various performance characteristics, such as the limit of detection (LOD), limit of quantification (LOQ), linear range, recovery and precision, were determined for each analyte. The LOD for most analytes was below 0.01 mg/kg. The recoveries and relative standard deviations (RSDs) were determined by spiking untreated samples with the analytes at the LOQ, 2*LOQ and 4*LOQ levels. The average recovery for most pesticides was between 70% and 120% and the precision values, expressed as RSD, were all below 20.4% (n=6). This method may provide an efficient tool for evaluating the extent of exposure to organic contaminants using human adipose tissue. PMID- 22546199 TI - Development and validation of a subcritical fluid extraction and high performance liquid chromatography assay for medroxyprogesterone in aquatic products. AB - A simple, rapid and sensitive method was developed for the determination of medroxyprogesterone in aquatic products by extraction with subcritical 1,1,1,2 tetrafluoroethane (R134a) and high performance liquid chromatography (HPLC). A response surface methodology (RSM) was adopted to optimise extraction pressure, temperature and co-solvent volume. The optimum extraction conditions predicted within the experimental ranges were as follows: pressure, 3 MPa; temperature, 25 degrees C; and co-solvent volume, 6 ml. The analysis was carried out on Zorbax SB C18 column (4.6 mm * 150 mm, 5 MUm) with the mobile phase acetonitrile-water (55:45, v/v), flow rate 1.0 ml/min, temperature 30 degrees C and wavelength 240 nm. Good linearity of detection was obtained for medroxyprogesterone between concentrations of 50-250 ng/ml, r2=0.999. The method was validated using samples fortified with medroxyprogesterone at levels of 10, 30 and 50 ng/g, the mean recovery exceeds 90%, and the RSD values were less than 10%. PMID- 22546200 TI - Design, synthesis and antiviral activity of novel quinazolinones. AB - HIV-1 integrase (IN) is a validated therapeutic target for antiviral drug design. However, the emergence of viral strains resistant to clinically studied IN inhibitors demands the discovery of novel inhibitors that are structurally as well as mechanistically different. Herein, a series of quinazolinones were designed and synthesized as novel HIV-1 inhibitors. The new synthetic route provides a practical method for the preparation of 5-hydroxy quinazolinones. Primary bioassay results indicated that most of the quinazolinones possess anti HIV activity, especially for compound 11b with 77.5% inhibition rate at 10 MUM emerged as a new active lead. Most of the synthesized compounds were also found to exhibit good anti-TMV activity, of which compo und 9a showed similar in vivo anti-TMV activity to commercial plant virucide Ribavirin. This work provides a new and efficient approach to evolve novel multi-functional antiviral agents by rational integration and optimization of previously reported antiviral agents. PMID- 22546201 TI - Human endometrial cell coculture reduces the endocrine disruptor toxicity on mouse embryo development. AB - BACKGROUNDS: Previous studies suggested that endocrine disruptors (ED) are toxic on preimplantation embryos and inhibit development of embryos in vitro culture. However, information about the toxicity of endocrine disruptors on preimplantation development of embryo in human reproductive environment is lacking. METHODS: Bisphenol A (BPA) and Aroclor 1254 (polychlorinated biphenyls) were used as endocrine disruptors in this study. Mouse 2-cell embryos were cultured in medium alone or vehicle or co-cultured with human endometrial epithelial layers in increasing ED concentrations. RESULTS: At 72 hours the percentage of normal blastocyst were decreased by ED in a dose-dependent manner while the co-culture system significantly enhanced the rate and reduced the toxicity of endocrine disruptors on the embryonic development in vitro. CONCLUSIONS: In conclusion, although EDs have the toxic effect on embryo development, the co-culture with human endometrial cell reduced the preimplantation embryo from it thereby making human reproductive environment protective to preimplantation embryo from the toxicity of endocrine disruptors. PMID- 22546203 TI - Novel inhibitors of heat shock protein Hsp70-mediated luciferase refolding that bind to DnaJ. AB - Inhibitors of both heat shock proteins Hsp90 and Hsp70 have been identified in assays measuring luciferase refolding containing rabbit reticulocyte lysate or purified chaperone components. Here, we report the discovery of a series of phenoxy-N-arylacetamides that disrupt Hsp70-mediated luciferase refolding by binding to DnaJ, the bacterial homolog of human Hsp40. Inhibitor characterization experiments demonstrated negative cooperativity with respect to DnaJ and luciferase concentration, but varying the concentration of ATP had no effect on potency. Thermal shift analysis suggested a direct interaction with DnaJ, but not with Hsp70. These compounds may be useful tools for studying DnaJ/Hsp40 in various cellular processes. PMID- 22546202 TI - Genetic architecture of body size in mammals. AB - Much of the heritability for human stature is caused by mutations of small-to medium effect. This is because detrimental pleiotropy restricts large-effect mutations to very low frequencies. PMID- 22546205 TI - An unusually cold active nitroreductase for prodrug activations. AB - A set of PCR primers based on the genome sequence were used to clone a gene encoding a hypothetical nitroreductases (named as Ssap-NtrB) from uropathogenic staphylococcus, Staphylococcus saprophyticus strain ATCC 15305, an oxygen insensitive flavoenzyme. Activity studies of the translation product revealed that the nitroreductase catalyses two electron reduction of a nitroaromatic drug of nitrofurazone (NFZ), cancer prodrugs of CB1954 and SN23862 at optimum temperature of 20 degrees C together with retaining its maximum activity considerably at 3 degrees C. The required electrons for such reduction could be supplied by either NADH or NADPH with a small preference for the latter. The gene was engineered for heterologous expression in Escherichia coli, and conditions were found in which the enzyme was produced in a mostly soluble form. The recombinant enzyme was purified to homogeneity and physical, spectral and catalytical properties were determined. The findings lead us to propose that Ssap NtrB represents a novel nitro reductase with an unusual cold active property, which has not been described previously for prodrug activating enzymes of nitroreductases. PMID- 22546204 TI - Recent developments and biological activities of thiazolidinone derivatives: a review. AB - Thiazolidinone is considered as a biologically important active scaffold that possesses almost all types of biological activities. Successful introduction of ralitoline as a potent anti-convulsant, etozoline as a antihypertensive, pioglitazone as a hypoglycemic agent and thiazolidomycin activity against streptomyces species proved potential of thiazolidinone moiety. This diversity in the biological response profile has attracted the attention of many researchers to explore this skeleton to its multiple potential against several activities. This review is complementary to earlier reviews and aims to review the work reported on various biological activities of thiazolidinone derivatives from year 2000 to the beginning of 2011. Data are presented for active compounds, some of which have passed the preclinical testing stage. PMID- 22546206 TI - Synthesis and evaluation of gamma-lactam analogs of PGE2 as EP4 and EP2/EP4 agonists. AB - To identify topically effective EP4 agonists and EP2/EP4 dual agonists with excellent subtype selectivity, further optimization of the 16-phenyl omega-chain moiety of the gamma-lactam 5-thia prostaglandin E analog and the 2 mercaptothiazole-4-carboxylic acid analog were undertaken. Rat in vivo evaluation of these newly identified compounds as their poly (lactide-co-glycolide) microsphere formulation, from which sustained release of the test compound is possible, led us to discover compounds that showed efficacy in a rat bone fracture healing model after its topical administration without serious influence on blood pressure and heart rate. A structure-activity relationship study is also presented. PMID- 22546207 TI - Synthesis, anticonvulsant activity, and neuropathic pain-attenuating activity of N-benzyl 2-amino-2-(hetero)aromatic acetamides. AB - N-Benzyl 2-acetamido-2-substituted acetamides, where the 2-substituent is a (hetero)aromatic moiety, are potent anticonvulsants. We report the synthesis and whole animal pharmacological evaluation of 16 analogues where the terminal 2 acetyl group was removed to give the corresponding primary amino acid derivatives (PAADs). Conversion to the PAAD structure led to a substantial drop in seizure protection in animal tests, demonstrating the importance of the N-acetyl moiety for anticonvulsant activity. However, several of the PAADs displayed notable pain attenuating activities in a mouse model. PMID- 22546208 TI - Synthesis and cytotoxic activity of new acridine-thiazolidine derivatives. AB - Although their exact role in controlling tumour growth and apoptosis in humans remains undefined, acridine and thiazolidine compounds have been shown to act as tumour suppressors in most cancers. Based on this finding, a series of novel hybrid 5-acridin-9-ylmethylene-3-benzyl-thiazolidine-2,4-diones were synthesised via N-alkylation and Michael reaction. The cell viability was analysed using a 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and DNA interaction assays were performed using electrochemical techniques. PMID- 22546210 TI - Support for routine use of metabolic stress testing in hypertrophic cardiomyopathy. PMID- 22546209 TI - Patterns and loss of sexual activity in the year following hospitalization for acute myocardial infarction (a United States National Multisite Observational Study). AB - A multisite observational study of sexual activity-related outcomes in patients enrolled in the TRIUMPH registry during hospitalization for an acute myocardial infarction (AMI) was conducted to identify patterns and loss of sexual activity 1 year after hospitalization for AMI. Gender-specific multivariable hierarchical models were used to identify correlates of loss of sexual activity including physician counseling. Main outcome measurements included "loss of sexual activity" (less frequent or no sexual activity 1 year after an AMI in those who were sexually active in the year before the AMI) and 1-year mortality. Mean ages were 61.1 years for women (n = 605) and 58.6 years for men (n = 1,274). Many were sexually active in the year before and 1 year after hospitalization (44% and 40% of women, 74% and 68% of men, respectively). One third of women and 47% of men reported receiving hospital discharge instructions about resuming sex. Those who did not receive instructions were more likely to report loss of sexual activity (women, adjusted relative risk 1.44, 95% confidence interval 1.16 to 1.79; men, adjusted relative risk 1.27, 95% confidence interval 1.11 to 1.46). One year mortality after AMI was similar in those who reported sexual activity in the first month after AMI (2.1%) and those who were sexually inactive (4.1%, p = 0.08). In conclusion, although many patients were sexually active before AMI, only a minority received discharge counseling about resuming sexual activity. Lack of counseling was associated with loss of sexual activity 1 year later. Mortality was not significantly increased in patients who were sexually active soon after their AMI. PMID- 22546211 TI - Balloon angioplasty for congenital aortic valve stenosis. PMID- 22546212 TI - Is there a role of implantable cardioverter defibrillator in sudden unexpected death in epilepsy? PMID- 22546213 TI - Statins in patients with renal dysfunction. PMID- 22546215 TI - Effects of Coptis extract combined with chemotherapeutic agents on ROS production, multidrug resistance, and cell growth in A549 human lung cancer cells. AB - BACKGROUND: Non-small cell lung cancer is associated with high expression of multidrug resistance (MDR) proteins and low production of reactive oxygen species (ROS). Coptis extract (COP), a Chinese medicinal herb, and its major constituent, berberine (BER), have anticancer properties. This study aims to investigate the effects of COP and BER combined with chemotherapeutic agents, including fluorouracil (5-FU), camptothecin (CPT), and paclitaxel (TAX), on cell proliferation, ROS production, and MDR in A549 human non-small cell lung cancer cells. METHODS: A549 cells were treated with different doses of COP and BER, combined with 5-FU, CPT, and TAX. Cell viability was measured by an XTT (2,3-bis (2-methoxy-4- nitro-5-sulfophenyl)-2 H-tetrazolium-5-carboxanilide) assay. Intracellular ROS levels were determined by measuring the oxidative conversion of cell permeable 2',7'-dichlorofluorescein diacetate to fluorescent dichlorofluorescein. MDR of A549 cells was assessed by rhodamine 123 retention assay. RESULTS: Both COP and BER significantly inhibited A549 cell growth in a dose-dependent manner. Combinations of COP or BER with chemotherapeutic agents (5 FU, CPT, and TAX) exhibited a stronger inhibitory effect on A549 cell growth. In addition, COP and BER increased ROS production and reduced MDR in A549 cells. CONCLUSION: As potential adjuvants to chemotherapy for non-small cell lung cancer, COP and BER increase ROS production, reduce MDR, and enhance the inhibitory effects of chemotherapeutic agents on A549 cell growth. PMID- 22546214 TI - The neural basis of syntactic deficits in primary progressive aphasia. AB - Patients with primary progressive aphasia (PPA) vary considerably in terms of which brain regions are impacted, as well as in the extent to which syntactic processing is impaired. Here we review the literature on the neural basis of syntactic deficits in PPA. Structural and functional imaging studies have most consistently associated syntactic deficits with damage to left inferior frontal cortex. Posterior perisylvian regions have been implicated in some studies. Damage to the superior longitudinal fasciculus, including its arcuate component, has been linked with syntactic deficits, even after gray matter atrophy is taken into account. These findings suggest that syntactic processing depends on left frontal and posterior perisylvian regions, as well as intact connectivity between them. In contrast, anterior temporal regions, and the ventral tracts that link frontal and temporal language regions, appear to be less important for syntax, since they are damaged in many PPA patients with spared syntactic processing. PMID- 22546216 TI - Seroprevalence of Leptospira Hardjo in the Irish suckler cattle population. AB - BACKGROUND: Prior to the present study, the seroprevalence of leptospirosis in Irish suckler herds was unknown. In this study, we describe the herd and animal level prevalence of Leptospira Hardjo infection in the Irish suckler cattle population. For the purposes of the study, the 26 counties of the Republic of Ireland were divided into 6 regions from which a representative number of herds were selected. A herd was considered eligible for sampling if it was not vaccinating against leptospirosis and if it contained >= 9 breeding animals of beef breed >= 12 months of age. In total, 288 randomly selected herds were eligible for inclusion in the seroprevalence dataset analysis. Serological testing was carried out using a commercially available monoclonal antibody capture ELISA, (sensitivity 100%; specificity 86.67%). RESULTS: Herds were categorised as either "Free from Infection" or "Infected" using the epidemiological software tool, FreeCalc 2.0. Using this classification, 237 herds were "Infected" (82.29%). The South West and South East regions had the highest herd prevalence. The regional effect on herd prevalence was largely mirrored by breeding herd size. A true animal-level prevalence of 41.75% was calculated using the epidemiological software tool, TruePrev. There was a statistically significant regional trend, with true prevalence being highest in the South East (P < 0.05). The median Breeding Herd Size (BHS), when categorised into quartiles, had a statistically significant influence on individual animal true seroprevalence (P < 0.001); true seroprevalence increased with increasing BHS. CONCLUSIONS: Leptospirosis is a widespread endemic disease in the Republic of Ireland. It is possible that economic losses due to leptospirosis in unvaccinated Irish suckler herds may be underestimated. PMID- 22546217 TI - Deprivation of arginine by recombinant human arginase in prostate cancer cells. AB - BACKGROUND: Recombinant human arginase (rhArg) has been developed for arginine deprivation therapy in cancer, and is currently under clinical investigation. During pre-clinical evaluation, rhArg has exhibited significant anti proliferative activity in cancer cells deficient in the expression of ornithine carbamoyl transferase (OCT). Interestingly, a variety of cancer cells such as melanoma and prostate cancer deficient in argininosuccinate synthetase (ASS) are sensitive to arginine deprivation by arginine deiminase. In this study, we investigated levels of gene expression of OCT and ASS, and the effects of rhArg in human prostate cancer cells: LNCaP (androgen-dependent), PC-3 and DU-145 (both androgen-independent). RESULTS: Quantitative real-time PCR showed minimal to absent gene expression of OCT, but ample expression of ASS expression in all 3 cell lines. Cell viability assay after 72-h exposure of rhArg showed all 3 lines had half maximal inhibitory concentration less than or equal to 0.02 U/ml. Addition of ornithine to cell culture media failed to rescue these cells from rhArg-mediated cytotoxicity.Decreased phosphorylation of 4E-BP1, a downstream effector of mammalian target of rapamycin (mTOR), was noted in DU-145 and PC-3 after exposure to rhArg. Moreover, there was no significant apoptosis induction after arginine deprivation by rhArg in all 3 prostate cancer cell lines. CONCLUSION: rhArg causes significant cytotoxicity in LNCaP, DU-145 and PC-3 prostate cancer cells which all demonstrate decreased OCT expression. Inhibition of mTOR manifested by hypophosphorylation of 4E-BP1 suggests autophagy is involved as alternative cell death mechanism. rhArg demonstrates a promising novel agent for prostate cancer treatment. PMID- 22546219 TI - Rhodamine B and 2-acetamido-1,3,6-tri-O-acetyl-4-deoxy-4-fluoro-D-glucopyranose (F-GlcNAc) inhibit chondroitin/dermatan and keratan sulphate synthesis by different mechanisms in bovine chondrocytes. AB - MPS disorders result from a deficiency or absence of glycosaminoglycan (GAG) degrading enzymes leading to an imbalance between the synthesis and degradation of GAGs and their subsequent accumulation in a range of cells. The inhibition of GAG synthesis using small chemical inhibitors has been proposed as a novel therapeutic approach to treatment. Several inhibitors have been shown to decrease heparan sulphate GAG synthesis and in this study we evaluated a novel fluorinated analog of N-acetylglucosamine (2-acetamido-1,3,6-tri-O-acetyl-4-deoxy-4-fluoro-D glucopyranose (F-GlcNAc)) and rhodamine B for their ability to also inhibit the synthesis of chondroitin/dermatan and keratan sulphate GAGs present in bovine cartilage. Both inhibitors decreased GAG synthesis in chondrocyte monolayer culture and in cartilage chip explant culture in a dose dependent manner. Both inhibitors decreased the size of newly synthesised proteoglycans and in the case of F-GlcNAc this was due to a decrease in newly synthesised GAG chain size. Rhodamine B, however, did not affect GAG chain size, while both inhibitors decreased the amount of chondroitin/dermatan and keratan sulphate GAG equally. The expression of genes responsible for the initiation and elongation of chondroitin/dermatan sulphate and keratan sulphate GAGs were downregulated in the presence of rhodamine B but not in the presence of F-GlcNAc. Thus the 2 inhibitors appear to have differing effects on GAG synthesis, with F-GlcNAc inhibiting the epimerisation of UDP-GlcNAc to UDP-GalNAc thus decreasing the availability of monosaccharides for addition to the growing GAG chain, whereas rhodamine B is more likely to reduce the number of GAG chains. Together with previous data these 2 inhibitors are capable of non-specific inhibition of GAG synthesis, reducing the production of chondroitin/dermatan sulphate, keratan sulphate and heparan sulphate GAGs. As such they would be applicable to therapy in a range of MPS disorders. PMID- 22546218 TI - Correlates of children's time-specific physical activity: a review of the literature. AB - Assessment of correlates of physical activity occurring at different times of the day, locations and contexts, is imperative to understanding children's physical activity behaviour. The purpose of this review was to identify the correlates of children's physical activity (aged 8-14 years) occurring during the school break time and after-school periods. A review was conducted of the peer-reviewed literature, published between 1990 and January 2011. A total of 22 studies (12 school break time studies, 10 after-school studies) were included in the review. Across the 22 studies, 17 studies were cross-sectional and five studies were interventions. In the school break time studies, 39 potential correlates were identified, of which gender and age were consistently associated with school break time physical activity in two or more studies, and family affluence, access to a gym, access to four or more physical activity programs and the condition of a playing field were all associated with school break time physical activity in only one study. Access to loose and fixed equipment, playground markings, size of and access to play space and the length of school break time were all positively associated with changes in school break time physical activity in intervention studies. Thirty-six potential correlates of after-school physical activity were identified. Gender (with boys more active), younger age, lower body mass index (for females), lower TV viewing/playing video games, and greater access to facilities were associated with higher levels of after-school physical activity in two or more studies. Parent supervision was negatively associated with females' after-school physical activity in one study. This review has revealed a relatively small number of studies investigating the school break time and after school periods in the specified age range and only a few correlates have demonstrated a consistent association with physical activity. This highlights the infancy of this area and a need for further investigation into time-specific physical activity behaviour so that interventions designed for these specific periods can target the important correlates. PMID- 22546220 TI - Synergistic anti-proliferative effects of gambogic acid with docetaxel in gastrointestinal cancer cell lines. AB - BACKGROUND: Gambogic acid has a marked anti-tumor effect for gastric and colorectal cancers in vitro and in vivo. However, recent investigations on gambogic acid have focused mainly on mono-drug therapy, and its potential role in cancer therapy has not been comprehensively illustrated. This study aimed to assess the interaction between gambogic acid and docetaxel on human gastrointestinal cancer cells and to investigate the mechanism of gambogic acid plus docetaxel treatment-induced apoptotic cell death. METHODS: MTT assay was used to determine IC(50) values in BGC-823, MKN-28, LOVO and SW-116 cells after gambogic acid and docetaxel administration. Median effect analysis was applied for determination of synergism and antagonism. Synergistic interaction between gambogic acid and docetaxel was evaluated using the combination index (CI) method. Furthermore, cellular apoptosis was analyzed by Annexin-V and propidium iodide (PI) double staining. Additionally, mRNA expression of drug-associated genes, i.e., beta-tublin III and tau, and the apoptosis-related gene survivin, were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: Gambogic acid provided a synergistic effect on the cytotoxicity induced by docetaxel in all four cell lines. The combined application of gambogic acid and docetaxel enhanced apoptosis in gastrointestinal cancer cells. Moreover, gambogic acid markedly decreased the mRNA expression of docetaxel-related genes, including beta-tubulin III, tau and survivin, in BGC-823 cells. CONCLUSIONS: Gambogic acid plus docetaxel produced a synergistic anti tumor effect in gastrointestinal cancer cells, suggesting that the drug combination may offer a novel treatment option for patients with gastric and colorectal cancers. PMID- 22546221 TI - Clinical review: Respiratory monitoring in the ICU - a consensus of 16. AB - Monitoring plays an important role in the current management of patients with acute respiratory failure but sometimes lacks definition regarding which 'signals' and 'derived variables' should be prioritized as well as specifics related to timing (continuous versus intermittent) and modality (static versus dynamic). Many new techniques of respiratory monitoring have been made available for clinical use recently, but their place is not always well defined. Appropriate use of available monitoring techniques and correct interpretation of the data provided can help improve our understanding of the disease processes involved and the effects of clinical interventions. In this consensus paper, we provide an overview of the important parameters that can and should be monitored in the critically ill patient with respiratory failure and discuss how the data provided can impact on clinical management. PMID- 22546223 TI - Jumping translocation of 15q24-qter resulting in partial trisomy: a case report. AB - We report on a jumping translocation with five different cell lines detected in four tissues in a 2-year-old patient. This rare type of chromosomal abnormality (not more than 30 cases published so far) proved to be a series of non-reciprocal translocations of the 15q24-qter donor chromosome segment to the telomeric region of chromosomes 5q, 10q, 16q and 19p, respectively. The process, in addition to a few cells without translocation, resulted in partial trisomy of 15q24-qter which was associated with somatic overdevelopment in the patient, with hemihypertrophy and minor anomalies. The phenotype of our patient was different from that of the other two patients found in the literature having the same donor chromosome segment involved in a similar rearrangement. Possibly, the difference in the phenotype lies in the various ratios of somatic mosaicism with five cell lines, in particular the presence of normal one which is extremely rare in patients with jumping translocation. Here we discuss the various ways on how the rearrangement could arise. PMID- 22546222 TI - Cloning and characterization of a trypsin-like serine protease gene, a novel regeneration-related gene from Apostichopus japonicus. AB - Trypsin-like serine protease (TLS) plays an important role in many physiological processes including wound healing, phlogosis reaction, blood clotting, regeneration etc. In this paper, a 1216 bp full-length cDNA sequence of TLS including 39 bp 5' UTR and 355 bp 3'UTR coding for a theoretical 273 amino acids protein was cloned from Apostichopus japonicus by means of the RACE technique for the first time. Bioinformatic analysis revealed that the gene with a 20 residues N-terminal signal peptide and a conserved C-terminal domain belongs to the trypsin-like serine protease superfamily. His78, Asp130 and Ser223 are the principal residues of the catalytic center. In-situ hybridization (ISH) analysis revealed that the TLS gene was widely distributed in different tissues. The expression patterns during different regeneration stages of the TLS gene in the body wall, intestine and respiratory trees were investigated using real-time quantitative PCR. The results show that there was a remarkable and temporary up regulation of TLS gene expression in the body wall within 1h and subsequent down regulation of TLS similar to intestine and respiratory trees. With the recovery of tissues, the expression level of the TLS gene was gradually up-regulated and finally reached normal levels. TLS was regulated during different regeneration stages suggesting that TLS is important in the regeneration process of A. japonicus. PMID- 22546224 TI - Idesolide inhibits the adipogenic differentiation of mesenchymal cells through the suppression of nitric oxide production. AB - Obesity is a major health problem worldwide and can increase the risk for several chronic diseases, including diabetes and cardiovascular disease. In this study, we screened small compounds isolated from natural products for the development of an anti-obesity drug. Among them, idesolide, a spiro compound isolated from the fruits of Idesia polycarpa Maxim, showed a significant suppression of the adipogenic differentiation in mesenchymal cells, as indicated by the decrease in fat droplets and expression of adipogenic marker genes such as aP2 and adiponectin. Idesolide inhibits the PPARgamma-mediated gene transcription in a dose-dependent manner, revealed by luciferase reporter gene assay. During adipogenic differentiation, idesolide inhibits nitric oxide production through the suppression of iNOS expression, and the increased adipogenic differentiation by arginine, the substrate for NOS, is significantly inhibited by idesolide, suggesting that the inhibition of nitric oxide production plays a major role in idesolide-induced adipogenic suppression. Taken together, the results reveal that idesolide has anti-adipogenic activity and highlight its potential in the prevention and treatment of obesity. PMID- 22546225 TI - The gender difference of selective serotonin reuptake inhibitor, fluoxetine in adult rats with stress-induced gastric ulcer. AB - We investigated the gender difference of selective serotonin reuptake inhibitor, fluoxetine in adult rats with stress-induced gastric ulcer. The rats were randomly divided into six groups: Group I, control males and group II, control females; group III, acute cold restraint stressed males and group IV, acute cold restraint stressed females; group V, fluoxetine-treated stressed males and group VI, fluoxetine-treated stressed females. Acute cold restraint stress was established by fixing the four limbs of the rat and placing it in a refrigerator at 4 degrees C for 3h. Fluoxetine was given intraperitoneal in a single dose of 10mg/kg/day. After 2 weeks, stomach and brain tissues were collected for the assay of gastric malonaldehyde (MDA), catalase, nitric oxide (NO) and cortical gamma aminobutyric acid (GABA). Stressed animals exhibited increased total acidity in association with decreased gastric secretion volume. Gastric MDA was increased while gastric catalase, NO, and cortical GABA were decreased in stressed male rats when compared to stressed females. However, fluoxetine administration attenuated these stress-induced changes especially in stressed male animals. Stressed male rats were more responsive to the antiulcer effect of fluoxetine more than stressed females. However, fluoxetine might be considered to be the first-choice drug in depressive patients with gastric ulcers in the future. PMID- 22546226 TI - Cathepsin E induces itch-related response through the production of endothelin-1 in mice. AB - This study investigated the pruritogenic potency of cathepsin E, an aspartic protease, and its mechanisms in mice. An intradermal injection of cathepsin E to the rostral back elicited scratching, an itch-associated response, of the injection site. This action was inhibited by the aspartic protease inhibitor pepstatin A, the endothelin ET(A) receptor antagonist BQ-123, and the opioid receptor antagonists naltrexone and naloxone, but not by the H(1) histamine receptor antagonist terfenadine, the proteinase-activated receptor-2 antagonist FSLLRY-NH(2), or mast cell deficiency. Pepstatin A inhibited scratching induced by intradermal injection of the mast-cell degranulator compound 48/80, but not by tryptase, a mast-cell mediator. An intradermal injection of cathepsin E increased endothelin-1 levels in the skin at the injection site. Preproendothelin-1 mRNA was present in primary cultures of keratinocytes, and immunohistochemistry using an antibody recognizing endothelin-1 and big-endothelin-1 revealed immunoreactivity in the epidermis, especially in the prickle and granular cell layers, but not in the basal cell layer. These results suggest that cathepsin E is an endogenous itch inducer, and that its action is mediated at least in part by the production of endothelin-1 in the epidermis. PMID- 22546227 TI - Brain-derived neurotrophic factor expression after acute administration of ethanol. AB - Earlier findings suggest that, in addition to its well-known neurotrophic role, brain-derived neurotrophic factor (BDNF) is also involved in the rewarding and reinforcing effects of drugs of abuse. The purpose of the present study was to examine the effects of acute administration of ethanol (1.25 or 2.5 g/kg i.p.) on the expression profile of BDNF in the rat brain by determining the BDNF mRNA expression in the frontal cortex, nucleus accumbens, amygdala, hippocampus, and ventral tegmental area. Ethanol decreased BDNF mRNA levels dose-dependently in the hippocampus, and after the higher ethanol dose in the frontal cortex, nucleus accumbens and amygdala, while increasing them in the ventral tegmental area. Furthermore, BDNF mRNA expression was found to be regulated in a temporally different manner in all investigated brain areas. These data suggest that BDNF is involved in the acute effects of ethanol, but separate brain areas may be differentially engaged in the mediation of these effects. PMID- 22546228 TI - Ginsenoside Rb1 inhibits the carotid neointimal hyperplasia induced by balloon injury in rats via suppressing the phenotype modulation of vascular smooth muscle cells. AB - This study aims to investigate the effects of ginsenoside Rb(1) on vascular intimal hyperplasia in rats and explore the mechanisms. The rat vascular neointimal hyperplasia model was made by rubbing the endothelia of carotid artery with a balloon and Rb(1) (10 and 30 mg/kg/day) was given the day after surgery for 14 consecutive days. The neointimal hyperplasia level and the degree of vascular smooth muscle cells (VSMCs) proliferation were evaluated by histopathology and by calculating the proliferating cell nuclear antigen (PCNA) positive expression percentage; protein expressions of PCNA, phosphorylation extracellular signal-regulated kinase 1/2 (pERK1/2), smooth muscle alpha-actin (SM alpha-actin), and the mRNA expressions of proto-oncogene c-myc, SM alpha actin, SM-emb (embryonic smooth muscle myosin heavy chain) and p38 MAPK were detected by immunohistochemistry and Real Time RT-PCR, respectively. Compared with the endothelia rubbing model group, Rb(1) 10 and 30 mg/kg/day medication significantly ameliorated the neointimal hyperplasia (P<0.05), and decreased the positive expression percentage of PCNA(P<0.05). Rb(1) medication also significantly decreased the elevated protein expression of pERK1/2 and the mRNA expression of c-myc(P<0.05), and tended to reduce the expression of p38 MAPK mRNA. Endothelial rubbing increased the SM-emb mRNA expression, but decreased the expression of SM alpha-actin mRNA which was reversed by Rb(1) (P<0.05). The results indicate that Rb(1) inhibits the vascular neointimal hyperplasia induced by balloon-injury in rats via suppressing the VSMC proliferation, which may be involved in part the inhibition of pERK1/2 protein and related to its inhibition on VSMC phenotype modulation. PMID- 22546229 TI - The analgesic activity of biphalin and its analog AM 94 in rats. AB - Biphalin is an opioid linear octapeptide, which displays a broad affinity for all opioid receptors (MU, delta and kappa), as well as exceptionally high antinociceptive activity. AM 94 is a biphalin analog and a selective agonist at MU and delta opioid receptors. This study investigated the antinociceptive profile of AM 94. All antinociception evaluations were made in adult male rats using the hot-plate test. AM 94 proved to induce greater and longer antinociception compared to biphalin following intracebroventricular (1 nmol/kg) and intravenous administration (1200 nmol/kg) as evaluated by % maximum possible effect (M.P.E.), when administered intracerebroventricularly and intravenously and sustained analgesia up to 210 min. The antinociceptive activities of biphalin and AM 94 were antagonized by naloxone (10mg/kg intraperitoneally). Our data suggest that AM 94 could be regarded as a novel pharmacologically active opioid compound for eliciting potent and sustained analgesia after central and peripheral administration. PMID- 22546230 TI - Inhibition of cystathionine gamma-lyase and the biosynthesis of endogenous hydrogen sulphide ameliorates gentamicin-induced nephrotoxicity. AB - Clinical use of gentamicin over prolonged periods is limited because of dose- and time-dependent nephrotoxicity. Primarily, lysosomal phospholipidosis, intracellular oxidative stress and heightened inflammation have been implicated. Hydrogen sulphide is an endogenously produced signal transduction molecule with strong anti-inflammatory, anti-apoptotic and cytoprotective properties. In several models of inflammatory disease however, tissue damage has been associated with increased activity of cystathionine gamma-lyase, biosynthesis of hydrogen sulphide and activation of leukocytes. The aim of this study was to determine effects of inhibiting hydrogen sulphide biosynthesis by DL-propargyl glycine (an irreversible inhibitor of cystathionine gamma-lyase) on inflammation, necrosis and renal function, following treatment with gentamicin in rats. Adult female Sprague-Dawley rats were divided into six groups and treated with; physiological saline, sodium hydrosulphide, DL-propargyl glycine, gentamicin, a combination of gentamicin and sodium hydrosulphide, or gentamicin and DL-propargyl glycine respectively. Gentamicin-induced histopathological changes including inflammatory cell infiltration and tubular necrosis were attenuated by co-administering gentamicin with DL-propargyl glycine (P<0.05 compared to saline controls and P<0.05 compared to gentamicin only). Similarly, DL-propargyl glycine caused a significant reduction (P<0.05) in lipid peroxidation, production of superoxide and the activation of tumour necrosis factor-alpha in gentamicin-treated animals. These data show that protective effects of DL-propargyl glycine might be related at least in part, to the reduced inflammatory responses observed in animals treated with both gentamicin and DL-propargyl glycine. Thus, enzyme systems involved in hydrogen sulphide biosynthesis may offer a viable therapeutic target in alleviating the nephrotoxic effects of gentamicin. PMID- 22546231 TI - Melagatran, a direct thrombin inhibitor, but not edoxaban, a direct factor Xa inhibitor, nor heparin aggravates tissue factor-induced hypercoagulation in rats. AB - There are concerns that some anticoagulants can paradoxically increase thrombogenesis under certain circumstances. We have shown that low-dose administration of a direct thrombin inhibitor, melagatran, significantly worsens the coagulation status induced by tissue factor injection in rats. We compared the effect of inhibition of thrombin and factor Xa for their potential to aggravate tissue factor-induced coagulation in rats. Hypercoagulation was induced by the injection of 2.8 U/kg tissue factor after administration of melagatran, heparin and edoxaban in rats. Blood samples were collected 10min after tissue factor injection. Platelet numbers, thrombin-antithrombin complex concentrations and plasma compound concentrations were measured. Though a high dose of melagatran (1mg/kg, i.v.) suppressed platelet consumption and thrombin antithrombin complex generation induced by tissue factor, lower doses of melagatran (0.01, 0.03 and 0.1mg/kg, i.v.) significantly enhanced platelet consumption and thrombin-antithrombin complex generation. In addition, although melagatran (3mg/kg, i.v.) improved coagulation status when tissue factor was given 5min after the drug administration, and 2, 4 and 8h after melagatran dosing, it deteriorated coagulation status. These results were well explained by the plasma melagatran concentration. Low concentrations (15-234ng/ml) of melagatran aggravated coagulation status whereas it was mended by high concentrations (1190ng/ml or more) of the compound. In contrast, edoxaban and heparin did not show any exacerbation under these examination conditions. These results show that subtherapeutic concentrations of melagatran are associated with coagulation pathway activation, whereas factor Xa inhibition with edoxaban has a low risk of paradoxical hypercoagulation. PMID- 22546232 TI - Prostanoid-mediated inotropic responses are attenuated in failing human and rat ventricular myocardium. AB - Prostanoid-modulatory approaches in heart failure patients have displayed effects which may seem to be mutually incompatible. Both treatment with prostanoids and inhibition of prostanoid synthesis have resulted in increased mortality in heart failure patients. Currently, it is unknown if prostanoids mediate contractile effects in failing human heart and if this can explain some of the clinical effects seen after prostanoid modulatory treatments. Therefore, the objectives of this study were to determine if prostanoids could elicit direct inotropic responses in human ventricle, and if so to determine if they are modified in failing ventricle. Contractile force was measured in left ventricular strips from non-failing or failing human and rat hearts. The ratio of phosphorylated to non phosphorylated myosin light chain 2 (MLC-2) was measured by Western blotting in myocardial strips, and the levels of prostanoid FP receptor mRNA and protein were measured in rat by real-time RT-PCR and receptor binding assays. In non-failing human hearts, prostanoids evoked a positive inotropic effect and an increase of MLC-2 phosphorylation which was absent in failing human hearts. In failing rat heart, the prostanoid FP receptor-mediated inotropic response and prostanoid FP receptor-density was reduced by ~40-50% compared to non-failing rat heart. Prostanoids mediate a sustained positive inotropic response in non-failing heart, which appears to be down regulated in failing heart. The pathophysiological significance of changes in prostanoid-mediated inotropic support in the failing heart remains to be determined. PMID- 22546233 TI - The inhibition of the nitric oxide-cGMP-PKG-JNK signaling pathway avoids the development of tolerance to the local antiallodynic effects produced by morphine during neuropathic pain. AB - Tolerance to the local antiallodynic effects of morphine, DPDPE ([D-Pen(2),D Pen(5)]-Enkephalin) or JWH-015 ((2-methyl-1-propyl-1H-indol-3-yl)-1 naphthalenylmethanone) after their repeated administration during neuropathic pain was evaluated. The role of the nitric oxide-cGMP-protein kinase G (PKG)-c Jun N-terminal kinase (JNK) signaling pathway on the peripheral morphine-induced tolerance after the chronic constriction of sciatic nerve in mice was also assessed. The mechanical and thermal antiallodynic effects produced by a high dose of morphine, DPDPE or JWH-015 subplantarly administered daily from days 10 to 20 after nerve injury were estimated with the von Frey filaments and cold plate tests. The antiallodynic effects of the repeated administration of morphine combined with a sub-analgesic dose of a selective inducible nitric oxide synthase (NOS2) (L-N(6)-(1-iminoethyl)-lysine; L-NIL), L-guanylate cyclase (1H [1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; ODQ), PKG ((Rp)-8-(para chlorophenylthio)guanosine-3',5'-cyclic monophosphorothioate; Rp-8-pCPT-cGMPs) or JNK (anthra[1,9-cd]pyrazol-6(2H)-one; SP600125) inhibitor from days 10 to 20 after injury were also evaluated. The repeated administration of morphine, but not DPDPE or JWH-015, produced a rapid development of tolerance to its mechanical and thermal antiallodynic effects in sciatic nerve-injured mice. The co administration of morphine with L-NIL, ODQ, Rp-8-pCPT-cGMPs or SP600125 avoided the development of morphine antiallodynic tolerance after nerve injury. These findings reveal that the repeated local administration of DPDPE or JWH-015 did not induce antinociceptive tolerance after sciatic nerve injury-induced neuropathic pain. Our data also indicate that the peripheral nitric oxide-cGMP PKG-JNK signaling pathway participates in the development of morphine tolerance after nerve injury and propose the inactivation of this pathway as a promising strategy to avoid morphine tolerance during neuropathic pain. PMID- 22546234 TI - Effect of valsartan on the pathological progression of hepatic fibrosis in rats with type 2 diabetes. AB - Currently there is no effective treatment for nonalcoholic fatty liver disease (NAFLD), especially hepatic fibrosis induced by type 2 diabetes. Valsartan maybe has beneficial effect on the liver disease. The aim of the present study was to investigate the effect of valsartan on the pathological progression of hepatic fibrosis in rats with type 2 diabetes. An animal model of hepatic fibrosis with type 2 diabetes was developed using a high-sucrose, high-fat diet and low-dose streptozotocin. Valsartan (15 mg/kg/day, i.g.) was orally administered for four months. The livers were removed to make hematoxylin-eosin (HE) staining and Picric acid-Sirius red staining, and immunohistochemistry staining of alpha smooth-muscle-actin (alpha-SMA), transforming growth factor beta1 (TGF-beta1), tumor necrosis factor (TNF-alpha) and monocyte chemotactic protein-1 (MCP-1). Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining was performed to detect hepatocyte apoptosis. The liver mitochondria were isolated to measure the mitochondrial respiratory function. The results showed that valsartan significantly alleviated the lesion of hepatic steatosis and hepatic fibrosis by HE staining and Picric acid-Sirius red staining. Immunohistochemical staining suggested that the expression of alpha-SMA, TGF beta1, TNF-alpha and MCP-1 in liver tissue of diabetic rats was markedly reduced by valsartan. TUNEL staining showed that there were fewer TUNEL-positive apoptotic hepatocytes in valsartan group. In addition, valsartan restored the injured hepatic mitochondrial respiratory function. The findings demonstrated that valsartan prevented the pathological progression of hepatic fibrosis in type 2 diabetic rats, correlated with reducing alpha-SMA, TGF-beta1, TNF-alpha and MCP 1 expression, also anti-apoptosis and mitochondria-protective potential. PMID- 22546235 TI - Clinical practice in radioembolization of hepatic malignancies: a survey among interventional centers in Europe. AB - OBJECTIVES: A survey was conducted to give an overview about the practice of radioembolization in malignant liver tumors by European centers. METHODS: A questionnaire of 23 questions about the interventional center, preinterventional patient evaluation, the radioembolization procedure and aftercare were sent to 45 European centers. RESULTS: The response rate was 62.2% (28/45). The centers performed 1000 (median = 26) radioembolizations in 2009 and 1292 (median = 40) in 2010. Most centers perform preinterventional evaluation and radioembolization on an inpatient basis. An arterioportal shunt not amendable to preinterventional embolization is considered a contraindication. During preinterventional angiography, the gastroduodenal artery is embolized by 71%, the right gastric artery by 59%, and the cystic artery by 41%. In case of bilobar disease, yttrium 90 microspheres are infused into the common hepatic artery (14%) or separately into left and right hepatic artery (86%). 33% prefer a time interval between right and left liver lobe radioembolization to prevent radiation induced liver disease. 43% of the respondents do not prescribe prophylactic medication after radioembolization. In case of iatrogenic manipulation to the biliary duct system most centers perform radioembolization with prophylactic antibiotics. CONCLUSIONS: Despite standardization of the procedure, there are some differences in how radioembolization of liver tumors is performed in Europe. PMID- 22546236 TI - Membrane microdomains emergence through non-homogeneous diffusion. AB - BACKGROUND: In the classical view, cell membrane proteins undergo isotropic random motion, that is a 2D Brownian diffusion that should result in an homogeneous distribution of concentration. It is, however, far from the reality: Membrane proteins can assemble into so-called microdomains (sometimes called lipid rafts) which also display a specific lipid composition. We propose a simple mechanism that is able to explain the colocalization of protein and lipid rafts. RESULTS: Using very simple mathematical models and particle simulations, we show that a variation of membrane viscosity directly leads to variation of the local concentration of diffusive particles. Since specific lipid phases in the membrane can account for diffusion variation, we show that, in such a situation, the freely diffusing proteins (or any other component) still undergo a Brownian motion but concentrate in areas of lower diffusion. The amount of this so-called overconcentration at equilibrium issimply related to the ratio of diffusion coefficients between zones of high and low diffusion. Expanding the model to include particle interaction, we show that inhomogeneous diffusion can impact particles clusterization as well. The clusters of particles were more numerous and appear for a lower value of interaction strength in the zones of low diffusion compared to zones of high diffusion. CONCLUSION: Provided we assume stable viscosity heterogeneity in the membrane, our model propose a simple mechanism to explain particle concentration heterogeneity. It has also a non trivial impact on density of particles when interaction is added. This could potentially have an impact on membrane chemical reactions and oligomerization. PMID- 22546237 TI - Antibacterial activity of glutathione-coated silver nanoparticles against Gram positive and Gram negative bacteria. AB - In the present paper, we study the mechanism of antibacterial activity of glutathione (GSH) coated silver nanoparticles (Ag NPs) on model Gram negative and Gram positive bacterial strains. Interference in bacterial cell replication is observed for both cellular strains when exposed to GSH stabilized colloidal silver in solution, and microbicidal activity was studied when GSH coated Ag NPs are (i) dispersed in colloidal suspensions or (ii) grafted on thiol functionalized glass surfaces. The obtained results confirm that the effect of dispersed GSH capped Ag NPs (GSH Ag NPs) on Escherichia coli is more intense because it can be associated with the penetration of the colloid into the cytoplasm, with the subsequent local interaction of silver with cell components causing damages to the cells. Conversely, for Staphylococcus aureus, since the thick peptidoglycan layer of the cell wall prevents the penetration of the NPs inside the cytoplasm, the antimicrobial effect is limited and seems related to the interaction with the bacterial surfaces. Experiments on GSH Ag NPs grafted on glass allowed us to elucidate more precisely the antibacterial mechanism, showing that the action is reduced because of GSH coating and the limitation of the translational freedom of NPs. PMID- 22546238 TI - Introduction of virtual microscopy in routine surgical pathology--a hypothesis and personal view from Europe. AB - The technology of whole image acquisition from histological glass slides (Virtual slides, (VS)) and its associated software such as image storage, viewers, and virtual microscopy (VM), has matured in the recent years. There is an ongoing discussion whether to introduce VM into routine diagnostic surgical pathology (tissue-based diagnosis) or not, and if these are to be introduced how best to do this. The discussion also centres around how to substantially define the mandatory standards and working conditions related to introducing VM. This article briefly describes some hypotheses alongside our perspective and that of several of our European colleagues who have experienced VS and VM either in research or routine praxis. After consideration of the different opinions and published data the following statements can be derived: 1. Experiences from static and remote telepathology as well as from daily routine diagnoses, confirm that VM is a diagnostic tool that can be handled with the same diagnostic accuracy as conventional microscopy; at least no statistically significant differences (p > 0.05) exist. 2. VM possesses several practical advantages in comparison to conventional microscopy; such as digital image storage and retrieval and contemporary display of multiple images (acquired from different stains, and/or different cases). 3. VM enables fast and efficient feedback between the pathologist and the laboratory in terms of ordered additional stains, automated access to the latest research for references, and fast consultation with outstanding telepathology experts. 4. Industry has already invested "big money" into this technology which certainly will be of influence in its future development. The main constraints against VM include the questionable reimbursement of the initial investment, the missing direct and short term financial benefit, and the loss of potential biological identity between the patient and the examined tissue. This article tries to analyze and evaluate the factors that influence the implementation of VM into routine tissue-based diagnosis, for example in combination with predictive diagnosis. It focuses on describing the advantages of modern and innovative electronically based communication technology. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1245603103708547. PMID- 22546239 TI - The role of glutamic acid 73 in adrenomedullin interactions with rodent AM2 receptors. AB - Adrenomedullin (AM) is a peptide, which is important for vascular development. There is much interest in the clinical potential of its receptors. The mode of AM binding to its receptors is poorly understood. Previous studies have identified amino acid Glu74, which is found in the receptor activity-modifying protein (RAMP3) subunit of the AM(2) receptor as important for high affinity AM interactions with this receptor. Its reciprocal residue in RAMP1 (Trp) impedes AM interactions in the closely related human calcitonin gene-related peptide (CGRP) receptor. The Glu is conserved in RAMP3 across species, supporting its role in contributing to AM binding. We mutated this residue in rat and mouse RAMP3 to Ala, Lys and Trp to determine its function in rodent AM(2) receptors. Only the Trp substitution in mouse RAMP3 produced a substantial reduction in AM potency. However, mutation of the Lys found in rat RAMP1 to Glu enhanced AM potency. Although Glu is highly conserved in RAMP3, this work suggests that it may only make a small or indirect contribution to AM interactions. Nevertheless, the equivalent amino acid in RAMP1 may serve to impair high affinity AM interactions. PMID- 22546240 TI - Review of Dercum's disease and proposal of diagnostic criteria, diagnostic methods, classification and management. AB - DEFINITION AND CLINICAL PICTURE: We propose the minimal definition of Dercum's disease to be generalised overweight or obesity in combination with painful adipose tissue. The associated symptoms in Dercum's disease include fatty deposits, easy bruisability, sleep disturbances, impaired memory, depression, difficulty concentrating, anxiety, rapid heartbeat, shortness of breath, diabetes, bloating, constipation, fatigue, weakness and joint aches. CLASSIFICATION: We suggest that Dercum's disease is classified into: I. Generalised diffuse form A form with diffusely widespread painful adipose tissue without clear lipomas, II. Generalised nodular form - a form with general pain in adipose tissue and intense pain in and around multiple lipomas, and III. Localised nodular form - a form with pain in and around multiple lipomas IV. Juxtaarticular form - a form with solitary deposits of excess fat for example at the medial aspect of the knee. EPIDEMIOLOGY: Dercum's disease most commonly appears between the ages of 35 and 50 years and is five to thirty times more common in women than in men. The prevalence of Dercum's disease has not yet been exactly established. AETIOLOGY: Proposed, but unconfirmed aetiologies include: nervous system dysfunction, mechanical pressure on nerves, adipose tissue dysfunction and trauma. DIAGNOSIS AND DIAGNOSTIC METHODS: Diagnosis is based on clinical criteria and should be made by systematic physical examination and thorough exclusion of differential diagnoses. Advisably, the diagnosis should be made by a physician with a broad experience of patients with painful conditions and knowledge of family medicine, internal medicine or pain management. The diagnosis should only be made when the differential diagnoses have been excluded. DIFFERENTIAL DIAGNOSIS: Differential diagnoses include: fibromyalgia, lipoedema, panniculitis, endocrine disorders, primary psychiatric disorders, multiple symmetric lipomatosis, familial multiple lipomatosis, and adipose tissue tumours. GENETIC COUNSELLING: The majority of the cases of Dercum's disease occur sporadically. A to G mutation at position A8344 of mitochondrial DNA cannot be detected in patients with Dercum's disease. HLA (human leukocyte antigen) typing has not revealed any correlation between typical antigens and the presence of the condition. MANAGEMENT AND TREATMENT: The following treatments have lead to some pain reduction in patients with Dercum's disease: Liposuction, analgesics, lidocaine, methotrexate and infliximab, interferon alpha-2b, corticosteroids, calcium-channel modulators and rapid cycling hypobaric pressure. As none of the treatments have led to long lasting complete pain reduction and revolutionary results, we propose that Dercum's disease should be treated in multidisciplinary teams specialised in chronic pain. PROGNOSIS: The pain in Dercum's disease seems to be relatively constant over time. PMID- 22546241 TI - A metagenomic study of diet-dependent interaction between gut microbiota and host in infants reveals differences in immune response. AB - BACKGROUND: Gut microbiota and the host exist in a mutualistic relationship, with the functional composition of the microbiota strongly affecting the health and well-being of the host. Thus, it is important to develop a synthetic approach to study the host transcriptome and the microbiome simultaneously. Early microbial colonization in infants is critically important for directing neonatal intestinal and immune development, and is especially attractive for studying the development of human-commensal interactions. Here we report the results from a simultaneous study of the gut microbiome and host epithelial transcriptome of three-month-old exclusively breast- and formula-fed infants. RESULTS: Variation in both host mRNA expression and the microbiome phylogenetic and functional profiles was observed between breast- and formula-fed infants. To examine the interdependent relationship between host epithelial cell gene expression and bacterial metagenomic-based profiles, the host transcriptome and functionally profiled microbiome data were subjected to novel multivariate statistical analyses. Gut microbiota metagenome virulence characteristics concurrently varied with immunity related gene expression in epithelial cells between the formula-fed and the breast-fed infants. CONCLUSIONS: Our data provide insight into the integrated responses of the host transcriptome and microbiome to dietary substrates in the early neonatal period. We demonstrate that differences in diet can affect, via gut colonization, host expression of genes associated with the innate immune system. Furthermore, the methodology presented in this study can be adapted to assess other host-commensal and host-pathogen interactions using genomic and transcriptomic data, providing a synthetic genomics-based picture of host commensal relationships. PMID- 22546242 TI - Phase 1 dose-ranging study of ezatiostat hydrochloride in combination with lenalidomide in patients with non-deletion (5q) low to intermediate-1 risk myelodysplastic syndrome (MDS). AB - BACKGROUND: Ezatiostat, a glutathione S-transferase P1-1 inhibitor, promotes the maturation of hematopoietic progenitors and induces apoptosis in cancer cells. RESULTS: Ezatiostat was administered to 19 patients with non-deletion(5q) myelodysplastic syndrome (MDS) at one of two doses (2000 mg or 2500 mg/day) in combination with 10 mg of lenalidomide on days 1-21 of a 28-day cycle. No unexpected toxicities occurred and the incidence and severity of adverse events (AEs) were consistent with that expected for each drug alone. The most common non hematologic AEs related to ezatiostat in combination with lenalidomide were mostly grade 1 and 2 fatigue, anorexia, nausea, diarrhea, and vomiting; hematologic AEs due to lenalidomide were thrombocytopenia, neutropenia, and anemia. One of 4 evaluable patients (25%) in the 2500/10 mg dose group experienced an erythroid hematologic improvement (HI-E) response by 2006 MDS International Working Group (IWG) criteria. Four of 10 evaluable patients (40%) in the 2000 mg/10 mg dose group experienced an HI-E response. Three of 7 (43%) red blood cell (RBC) transfusion-dependent patients became RBC transfusion independent, including one patient for whom prior lenalidomide monotherapy was ineffective. Three of 5 (60%) thrombocytopenic patients had an HI-platelet (HI-P) response. Bilineage HI-E and HI-P responses occurred in 3 of 5 (60%), 1 of 3 with HI-E and HI-N (33%), and 1 of 3 with HI-N and HI-P (33%). One of 3 patients (33%) with pancytopenia experienced a complete trilineage response. All multilineage responses were observed in the 2000/10 mg doses recommended for future studies. CONCLUSIONS: The tolerability and activity profile of ezatiostat co-administered with lenalidomide supports the further development of ezatiostat in combination with lenalidomide in MDS and also encourages studies of this combination in other hematologic malignancies where lenalidomide is active. PMID- 22546243 TI - Impact of immune-metabolic interactions on age-related thymic demise and T cell senescence. AB - Emerging evidence indicates that the immune and metabolic interactions control several aspects of the aging process and associated chronic diseases. Among several sites of immune-metabolic interactions, thymic demise represents a particularly puzzling phenomenon because even in metabolically healthy middle aged individuals the majority of thymic space is replaced with ectopic lipids. The new T cell specificities can only be generated in a functional thymus and, peripheral proliferation of pre-existing T cell clones provides limited immune vigilance in the elderly. Therefore, it is hypothesized that the strategies that enhance thymic-lymphopoiesis may extend healthspan. Recent data suggest that byproducts of thymic fatty acids and lipids result in accumulation of 'lipotoxic DAMPs' (damage associated molecular patterns), which triggers the innate immune sensing mechanism like inflammasome activation which links aging to thymic demise. The immune-metabolic interaction within the aging thymus produces a local pro-inflammatory state that directly compromises the thymic stromal microenvironment, thymic-lymphopoiesis and serves a precursor of systemic immune dysregulation in the elderly. New evidence also suggests that ectopic thymic adipocytes may develop from specific intrathymic stromal cell precursors instead of a passive process that is simply a consequence of thymic lymphopenia. Thus the complex bidirectional interactions between metabolic and immune systems may link aging to health, T cell senescence, and associated diseases. This review discusses the immune-metabolic mechanisms during aging - with implications for developing future therapeutic strategies for living well beyond the expected. PMID- 22546244 TI - Horse heart cytochrome c entrapped into the hydrated liquid-crystalline phases of phytantriol: X-ray diffraction and Raman spectroscopic characterization. AB - Small angle X-ray diffraction (SAXD), resonance Raman (RR) spectroscopy with 413 nm excitation, and non-resonance Raman technique with 785 nm excitation were used to probe the influence of entrapped cytochrome c (Cyt c) on the structure of hydrated phytantriol (Phyt) liquid-crystalline phases as well as conformational changes of heme group and secondary structure of the protein. SAXD measurements indicated that incorporation of Cyt c affects both nanostructure dimensions and type of liquid-crystalline phases of hydrated Phyt. The unit cell dimensions decrease with increasing Cyt c concentration for all phases. In addition, protein perturbs the nanostructure of Q(230) and Q(224) liquid-crystalline phases of hydrated Phyt to such an extent that they transform into the Q(229) phase with the Im3m space group. RR data revealed that entrapment of oxidized Cyt c into the Q(230) phase at 1 wt.% content results in near complete reduction of central iron ion of the heme group, while its low-spin state and six-ligand coordination configuration are preserved. Based on the analysis of heme out-of-plane folding vibration near 568 cm(-1) (gamma(21)) and nu(48) mode at 633 cm(-1), it was demonstrated that the protein matrix tension on the heme group is relaxed upon incorporation of protein into Q(230) phase. Non-resonant Raman bands of difference spectra showed the preservation of alpha-helix secondary structure of Cyt c in the liquid-crystalline phase at relatively high (5 wt.%) content. The Cyt c induced spectroscopic changes of Phyt bands were found to be similar as decrease in temperature. PMID- 22546246 TI - Postmortem ventilation: a new method for improved detection of pulmonary pathologies in forensic imaging. AB - Postmortem imaging has gained prominence in the field of forensic pathology. Even with experience in this procedure, difficulties arise in evaluating pathologies of the postmortem lung. The effect of postmortem ventilation with applied pressures of 10, 20, 30 and 40 mbar was evaluated in 10 corpses using simultaneous postmortem computed tomography (pmCT) scans. Ventilation was performed via a continuous positive airway pressure mask (n=5), an endotracheal tube (n=4) and a laryngeal mask (n=1) using a portable home care ventilator. The lung volumes were measured and evaluated by a segmentation technique based on reconstructed CT data. The resulting changes to the lungs were analyzed. Postmortem ventilation at 40 mbar induced a significant (p<0.05) unfolding of the lungs, with a mean volume increase of 1.32 l. Small pathologies of the lung such as scarring and pulmonary nodules as well as emphysema were revealed, while inner livores were reduced. Even though lower ventilation pressures resulted in a significant (p<0.05) volume increase, pathologies were best evaluated when a pressure of 40 mbar was applied, due to the greater reduction of the inner livores. With the ventilation-induced expansion of the lungs, a decrease in the heart diameter and gaseous distension of the stomach was recognized. In conclusion, postmortem ventilation is a feasible method for improving evaluation of the lungs and detection of small lung pathologies. This is because of the volume increase in the air-filled portions of the lung and reduced appearance of inner livores. PMID- 22546245 TI - Autoimmune pancreatitis and non-necrotizing acute pancreatitis: computed tomography pattern. AB - OBJECTIVES: To retrospectively differentiate diffuse autoimmune pancreatitis from non-necrotizing acute pancreatitis at clinical onset with multi detector row computed tomography. METHODS: 36 Patients suffering from diffuse autoimmune pancreatitis (14) or non-necrotizing acute pancreatitis (22) were enrolled. Qualitative analysis included stranding, retroperitoneal fluid film, capsule-like rim enhancement and pleural effusion. In quantitative analysis pancreatic density was measured in all phases. The vascularization behaviour was assessed using the relative enhancement rate across all phases. RESULTS: Pancreatic density resulted lower in non-necrotizing acute pancreatitis compared to diffuse autoimmune pancreatitis patients in pre-contrast phase and higher in pancreatic phase. Relative enhancement rate evaluation confirmed different vascularization behaviours of the two diseases. Only non-necrotizing acute pancreatitis Patients presented peripancreatic stranding and fluid in the retromesenteric interfascial plane. CONCLUSIONS: Multi detector row computed tomography is a useful technique for differentiating diffuse autoimmune pancreatitis from non-necrotizing acute pancreatitis at clinical onset. Peripancreatic stranding and retroperitoneal fluid film, characteristic of non-necrotizing acute pancreatitis, and late-phase peripheral rim enhancement, characteristic of diffuse autoimmune pancreatitis, provide qualitative clues to the differentiation. A quantitative study of contrast enhancement patterns, considering the relative enhancement rate, can assist in the differential diagnoses of two diseases. PMID- 22546247 TI - A new method for quantitative determination of dimemorfan in human plasma using monolithic silica solid-phase extraction tips. AB - Dimemorfan was extracted from human plasma samples (100 MUL) using MonoTip C(18) tips, which were packed with a C(18)-bonded monolithic silica gel attached to the inside of the tip. The samples, which contained dimemorfan and trimeprazine as an internal standard (IS), were mixed with 300 MUL of distilled water and 50 MUL of 1M glycine-sodium hydroxide buffer (pH 10). The mixture was extracted onto the C(18) phase of the tip by 20 sequential aspirating/dispensing cycles using a manual micropipettor. The analytes retained on the C(18) phase were then eluted with methanol by five sequential aspirating/dispensing cycles. The eluate was injected directly into a gas chromatograph and detected by a mass spectrometer with selected ion monitoring in positive electron ionization mode. An Equity-5 fused silica capillary column (30 m * 0.32 mm i.d., film thickness 0.25 MUm) gave adequate separation of the dimemorfan, IS, and impurities. The recoveries of dimemorfan and the IS spiked into plasma were >=83%. The regression equation for dimemorfan showed excellent linearity from 0.25 to 32.0 ng/100 MUL of plasma, and the limit of detection was 0.125 ng/100 MUL of plasma. The maximum intra-day and inter-day relative standard deviations were 13%, while accuracy ranged from 88% to 105%. Dimemorfan was stable for at least 12 h at 4 degrees C, 4 weeks at -80 degrees C, and three freeze-thaw cycles in plasma. This new method is expected to have application as a pretreatment for the rapid, simple, and quantitative determination of dimemorfan in plasma samples. PMID- 22546248 TI - How to catch child pornographers in France? The entrapment. PMID- 22546249 TI - Administration of rotenone enhanced voluntary alcohol drinking behavior in C57BL/6J mice. AB - Rotenone, a commonly used lipophic pesticide, is a high-affinity mitochondrial complex I inhibitor. The aim of this project is to study the causal relationship between changes of brain monoamine levels and drinking behavior in rotenone treated mice. In the first experiment, we investigated the effects of acute exposure to rotenone (20 mg/kg, p.o.) on the 8-h time limited-access alcohol drinking behavior and brain monoamine levels in C57BL/6J mice at 0, 2, 8 and 24 h. Dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and 5 hydroxyindoleacetic acid (5HIAA) levels in the nucleus accumbens (ACC), caudate putamen (C/P) and lateral hypothalamus (LH) of rotenone-treated mice were decreased at 2 and/or 8 h. Rotenone-exposed mice showed a suppression of voluntary alcohol intake at 4 and 8 h, but total daily alcohol intake did not differ significantly between the two groups. The effects of chronic exposure to rotenone (1, 5, 10 and 20 mg/kg, p.o. for 30 days) on the alcohol drinking behavior and monoamine levels of rotenone-exposed mice (10 mg/kg, p.o.) were investigated in the second experiment. The mice treated with rotenone showed increases in alcohol drinking behavior. Levels of DA and 5-HT in the ACC and C/P of chronic rotenone-treated mice were decreased, while the ratios of DOPAC to DA in the ACC and C/P and of 5HIAA to 5-HT in the ACC, C/P and DRN were increased significantly. Tyrosine hydroxylase immunoreactivity of chronic rotenone-treated mice (10 mg/kg, p.o.) slightly were decreased in both the striatum and the substantia nigra. Ethanol and acetaldehyde metabolism was not significantly different between mice treated with rotenone (10 mg/kg, p.o.) and controls. It was suggested that rotenone-treated mice had increased alcohol drinking behavior associated with increases in the DA turnover ratios of ACC and striatum to compensate for the neural degeneration. PMID- 22546251 TI - Continuous and segmented flow microfluidics: applications in high-throughput chemistry and biology. AB - This account highlights some of our recent activities focused on developing microfluidic technologies for application in high-throughput and high-information content chemical and biological analysis. Specifically, we discuss the use of continuous and segmented flow microfluidics for artificial membrane formation, the analysis of single cells and organisms, nanomaterial synthesis and DNA amplification via the polymerase chain reaction. In addition, we report on recent developments in small-volume detection technology that allow access to the vast amounts of chemical and biological information afforded by microfluidic systems. PMID- 22546252 TI - Developing new methods for the mono-end functionalization of living ring opening metathesis polymers. AB - In this article we present a review of our recent results in one area of research we are involved in. All research efforts in our group focus on functional polymers and new ways of gaining higher levels of control with regard to the placement of functional groups within these polymers. Here, the living ring opening metathesis polymerization (ROMP) will be reviewed for which end functionalization methods had been rare until very recently. Polymers carrying particular functional groups only at the chain-ends are, however, very interesting for a variety of industrial and academic applications. Polymeric surfactants and polymer-protein conjugates are two examples for the former and polymer-beta-sheet-peptide conjugates one example for the latter. The functionalization of macroscopic or nanoscopic surfaces often relies on mono-end functional polymers. Complex macromolecular architectures are often constructed from macromolecules carrying exactly one functional group at their chain- end. The ring opening metathesis polymerization is particularly interesting in this context as it is one of the most functional group tolerant polymerization methods known. Additionally, high molecular weight polymers are readily accessible with this technique, a feature that living radical polymerizations often struggle to achieve. Finding new ways of functionalizing the polymer chain-end of ROMP polymers has therefore been a task long overdue. Here, we present our contribution to this area of research. PMID- 22546253 TI - Nanoparticles and cells: an interdisciplinary approach. AB - In this article we present an overview of some of our research in the field of nanoscience. By combining two different scientific backgrounds (chemistry and biology), we investigate nanoparticle-cell interactions from different angles. This requires an interdisciplinary approach involving material synthesis and characterization, cell biology (biochemistry) and microscopy. In particular, we describe the synthesis and magnetic properties of superparamagnetic iron oxide nanoparticles as well as their behavior in cell culture, evaluate different visualization and detection methods, and investigate the interaction of such magnetic particles with immune cells. PMID- 22546254 TI - Sputtered cathodes for polymer electrolyte fuel cells: insights into potentials, challenges and limitations. AB - The level of Pt loadings in polymer electrolyte fuel cells (PEFC) is still one of the main hindrances for implementation of PEFCs into the market. Therefore, new catalyst and electrode preparation methods such as sputtering are of current interest, because they allow thin film production and have many cost saving advantages for electrode preparation. This paper summarises some of the most important studies done for sputtered PEFCs, including non carbon supported electrodes. Furthermore, it will be shown that an understanding of the main morphological differences between sputtered and ink-based electrodes is crucial for a better understanding of the resulting fuel cell performance. Especially, the electrochemical surface area (ECSA) plays a key role for a further increase in PEFC performance of sputtered electrodes. The higher surface specific activities i(k,spec) of sputtered compared to ink-based electrodes will be discussed as advantage of the thin film formation. The so- called particle size effect, known in literature for several years, will be discussed as reason for the higher i(k,spec) of sputtered electrodes. Therefore, a model system on a rotating disc electrode (RDE) was studied. For sputtered PEFC cathodes Pt loadings were lowered to 100 MUg(Pt)/cm(2), yet with severe performance losses compared to ink-based electrodes. Still, for Pt sputtered electrodes on a carbon support structure remarkably high current densities of 0.46 A/cm(2) at 0.6 V could be achieved. PMID- 22546255 TI - From theory to bench experiment by computer-assisted drug design. AB - Tight integration of computer-assisted molecular design with practical realization by medicinal chemistry will be essential for finding next-generation drugs that are optimized for multiple pharmaceutically relevant properties. ETH Zurich has established an interdisciplinary research group devoted to exploring the potential of this scientific approach by combining expertise from pharmaceutical chemistry and computer sciences. In this article, some of the group's activities and projects are presented. A current focus is on machine learning applications aiming at hit and lead structure identification by virtual screening and de novo design. The central concept of 'adaptive fitness landscapes' is highlighted along with practical examples from drug discovery projects. PMID- 22546256 TI - Surface and interfacial chemistry. AB - Based on a molecular approach combining controlled surface chemistry, advanced spectroscopic methods, in particular solid-state NMR, and computational chemistry, it is possible to develop single-site species and to control the growth of nanoparticles on supports. This allows the generation of highly efficient catalysts combining the advantages of both homogeneous and heterogeneous catalysts and function materials with defined properties. PMID- 22546259 TI - CyBy(2): a structure-based data management tool for chemical and biological data. AB - We report the development of a powerful data management tool for chemical and biological data: CyBy(2). CyBy(2) is a structure-based information management tool used to store and visualize structural data alongside additional information such as project assignment, physical information, spectroscopic data, biological activity, functional data and synthetic procedures. The application consists of a database, an application server, used to query and update the database, and a client application with a rich graphical user interface (GUI) used to interact with the server. PMID- 22546260 TI - Two bronze medals for Switzerland at the 43rd International Chemistry Olympiad in Ankara, Turkey. AB - At the 2011 International Chemistry Olympiad in Ankara, with 71 participating countries, Switzerland achieved two bronze medals thanks to two outstanding students. PMID- 22546262 TI - Results from an experimental trial at a Head Start center to evaluate two meal service approaches to increase fruit and vegetable intake of preschool aged children. AB - BACKGROUND: Strategies to increase fruit and vegetable consumption of preschool aged children are needed. OBJECTIVES: Evaluate the independent effects of the following meal service strategies on intake of fruits and vegetables of preschool children: 1.) Serving fruits and vegetables in advance of other menu items as part of traditional family style meal service; and 2.) Serving meals portioned and plated by providers. METHODS: Fifty-three preschool aged children completed a randomized crossover experiment conducted at a Head Start center in Minneapolis, MN. Over a six week trial period each of the experimental meal service strategies (serving fruits and vegetable first and serving meals portioned by providers) was implemented during lunch service for two one-week periods. Two one-week control periods (traditional family style meal service with all menu items served at once) were also included over the six week trial period. Childrens lunch intake was observed as a measure of food and nutrient intake during each experimental condition. RESULTS: Fruit intake was significantly higher (p<0.01) when fruits and vegetables were served in advance of other meal items (0.40 servings/meal) compared to the traditional family style meal service control condition when they were served in tandem with other menu items (0.32 servings/meal). Intakes of some nutrients found in fruits (vitamin A and folate) were concomitantly higher. In contrast, fruit and vegetable intakes were significantly lower and energy intake significantly higher during the provider portioned compared with control condition. CONCLUSIONS: Serving fruits in advance of other meal items may be a low cost easy to implement strategy for increasing fruit intake in young children. However, serving vegetables first does not appear to increase vegetable intake. Results provide support for current recommendations for traditional family style meal service in preschool settings. PMID- 22546263 TI - Amalgam or composite resin? Factors influencing the choice of restorative material. AB - OBJECTIVES: This study aimed to investigate the patient and tooth factors associated with selection of restorative material in direct posterior restorations in young adults from a population-based birth cohort. METHODS: A representative sample (n=720) of all 5914 births occurring in Pelotas in 1982 were prospectively investigated, and posterior restorations were assessed in 2006, when the patients were 24 years old. Tooth-related variables (individual level) included restorative material (amalgam or composite), type of tooth, size of cavity, and estimated time in mouth. Data regarding demographic and socio economic characteristics, oral health, and service utilization patterns during the life course were also assessed (contextual level). RESULTS: Logistic Regression Multilevel models showed that individuals who have accessed dental services by private insurance by age 15 [odds ratio (OR)=1.66 (0.93-2.95)] and who had a higher dental caries index at age 15 (high DMFT tertile) [OR 2.89 (1.59 5.27)] presented more amalgam restorations in the posterior teeth. From tooth level variables, the frequency of amalgams decreases with increasing number of surfaces enrolled in the cavity preparation (p<0.001) and was almost 5 times greater in molars than in premolars. CONCLUSIONS: The present findings suggest that variables related to type of dental service, dental caries (higher DMFT index), and cavity characteristics (tooth type, size) determine the choice of dentists for restorative materials. Other individual characteristics such as demographic and socioeconomic status have not influenced this choice. CLINICAL SIGNIFICANCE: This is the first population-based study that assesses the determinant factors for the choice of dentists for composite or amalgam in posterior direct restorations, showing that, independently of socioeconomic and demographic characteristics, type of payment of dental services and clinical factors are associated with this choice. PMID- 22546264 TI - Optical properties of enamel and translucent composites by diffuse reflectance measurements. AB - OBJECTIVES: The aim of this study was to evaluate the optical properties of natural enamel and translucent composites by diffuse reflectance measurements and Kubelka-Munk's theory. METHODS: Twenty natural enamel slabs and 80 composite replicas using four brands of translucent composites (Gradia Direct, Venus, Brilliant New line and Beautiful II; n=20) were evaluated at thicknesses of 1.0mm. The spectral distributions of enamel and composites were measured by means of a reflectance spectrophotometer. Optical constants including scattering coefficient (S), absorption coefficient (K), light reflectivity (RI) and infinite optical thickness (X(infinity)) were calculated from the spectral reflectance data using Kubelka's equations. Paired t-tests were performed to evaluate the differences of optical constants (S, K, RI and X(infinity)) between natural enamel and composites. RESULTS: The optical constants S and K decreased with increasing wavelength, while RI and X(infinity) increased with increasing wavelength within the visible spectrum. The values of enamel were in the range of the optical constants of these composites within the visible spectrum. However, there were significant differences of optical constants (S, K, RI and X(infinity)) between enamel and translucent composites (p<0.05). CONCLUSIONS: The optical constants of translucent composites were not completely consistent with that of natural enamel. In addition, the optical properties of these translucent composites varied with the brands of the composites. PMID- 22546266 TI - Early administration of corticosteroids and mortality. PMID- 22546265 TI - Inhibition of erosive dissolution by sodium fluoride: evidence for a dose response. AB - OBJECTIVES: The aim of this study was to investigate the protective effects of sodium fluoride solutions and commercial mouthrinses on hydroxyapatite (HA) dissolution in citric acid in vitro, with and without a salivary pellicle. METHODS: A rapid-throughput HA solubility-reduction model was employed in which HA dissolution was quantified using ion chromatography. Two HA substrates were selected, a high-resolution powder and 80 MUm diameter beads, and studied in the presence and absence of a salivary pellicle (pooled human saliva, 2 h). Immediately prior to acid exposure, substrates were exposed to one of a number of pre-treatments that included aqueous fluoride (F(-)) solutions and commercially available mouthrinses with F(-) concentrations of 0-450 MUg/g (as NaF). Dissolution reduction was calculated relative to a deionised water negative control. RESULTS: For aqueous solutions and mouthrinses, a fluoride dose-response was observed with a plateau around 100 MUg/g F(-) for both HA substrates, with or without pellicle. Concentrations as low as 10 MUg/g F(-) significantly reduced HA dissolution. The HA substrate had little impact on the fluoride dose-response, and the fluoride was equally effective in the presence of a pellicle as in its absence. CONCLUSIONS: Fluoride significantly reduced HA dissolution at concentrations of 10 MUg/g and higher. A fluoride dose-response was seen at low concentrations. This study illustrates the use of a powerful rapid-throughput HA solubility-reduction model for investigating HA dissolution in citric acid in the presence of dissolution inhibitors. CLINICAL SIGNIFICANCE: A single exposure to fluoride solutions with fluoride concentrations and exposure time representative of brushing or rinsing with mainstream oral care products was shown to significantly inhibit HA dissolution under conditions relevant to dental erosion. A similar efficacy was observed in the presence and absence of salivary pellicle. PMID- 22546267 TI - Emerging areas in the field of infection prevention through hand hygiene initiatives. PMID- 22546268 TI - Patient-centered hand hygiene: the next step in infection prevention. AB - Hand hygiene has been recognized as the most important means of preventing the transmission of infection, and great emphasis has been placed on ways to improve hand hygiene compliance by health care workers (HCWs). Despite increasing evidence that patients' flora and the hospital environment are the primary source of many infections, little effort has been directed toward involving patients in their own hand hygiene. Most previous work involving patients has included patients as monitors or auditors of hand hygiene practices by their HCWs. This article reviews the evidence on the benefits of including patients more directly in hand hygiene initiatives, and uses the framework of patient-centered safety initiatives to provide recommendations for the timing and implementation of patient hand hygiene protocols. It also addresses key areas for further research, practice guideline development, and implications for training of HCWs. PMID- 22546269 TI - Bundling hand hygiene interventions and measurement to decrease health care associated infections. AB - Proper performance of hand hygiene at key moments during patient care is the most important means of preventing health care-associated infections (HAIs). With increasing awareness of the cost and societal impact caused by HAIs has come the realization that hand hygiene improvement initiatives are crucial to reducing the burden of HAIs. Multimodal strategies have emerged as the best approach to improving hand hygiene compliance. These strategies use a variety of intervention components intended to address obstacles to complying with good hand hygiene practices, and to reinforce behavioral change. Although research has substantiated the effectiveness of the multimodal design, challenges remain in promoting widespread adoption and implementation of a coordinated approach. This article reviews elements of a multimodal approach to improve hand hygiene and advocates the use of a "bundled" strategy. Eight key components of this bundle are proposed as a cohesive program to enable the deployment of synergistic, coordinated efforts to promote good hand hygiene practice. A consistent, bundled methodology implemented at multiple study centers would standardize processes and allow comparison of outcomes, validation of the methodology, and benchmarking. Most important, a bundled approach can lead to sustained infection reduction. PMID- 22546270 TI - Hand hygiene must be enabled and promoted. PMID- 22546271 TI - Point-of-care hand hygiene: preventing infection behind the curtain. AB - Best practices for hand hygiene provide indications for performance of hand hygiene at specific points in time during patient care. For hand hygiene to prevent infections, hand hygiene resources must be readily available to health care workers whenever required. This article reviews practices and recommendations intended to facilitate hand hygiene behavior at the point of care (POC) within the health care setting. Key aspects of POC hand hygiene include the provision of alcohol-based hand rub products, integration of dispensing solutions within the patient zone, consideration of patient care workflow, and dispenser designs that optimize acceptance and usage. PMID- 22546273 TI - Young women's adolescent experiences of oral sex: relation of age of initiation to sexual motivation, sexual coercion, and psychological functioning. AB - Research examining oral sex during adolescence tends to investigate only potential negative consequences without considering its place in sexual development or distinctions between cunnilingus and fellatio. Using retrospective reports from 418 undergraduate women, we examined the relations among young women's ages of initiation of both cunnilingus and fellatio and sexual motives, experiences of sexual coercion, and indicators of psychological functioning. Age at cunnilingus initiation was unrelated to sexual coercion or psychological functioning; however it was related to engaging in sex for personal stimulation and gratification (personal drive motive) and to feel agentic, assertive, and skillful (power motive). Age at fellatio initiation was related to feelings of inferiority compared to others and a devaluing of the self (interpersonal sensitivity). Findings challenge the unilateral assumption that all adolescent sexual activity is negative and indicate the need for future research distinguishing between cunnilingus and fellatio. PMID- 22546272 TI - Vitamin D receptor expression and neoadjuvant therapy in esophageal adenocarcinoma. AB - Esophageal adenocarcinoma carries a poor prognosis. Tumor response to neoadjuvant therapy is a key prognostic factor in patients with adenocarcinoma of the esophagus, but is inconsistent. Identifying tumor characteristics that portend a favorable response to neoadjuvant therapy would be a valuable clinical tool. The anticancer actions of vitamin D and its receptor may have implications. In this study, 15 biopsy specimens were procured retrospectively from patients being treated for adenocarcinoma of the esophagus. The tissue was immunostained for the vitamin D receptor and compared on the basis of response to neoadjuvant therapy. Tumors that did not respond to neoadjuvant therapy had greater expression of VDR than tumors that responded completely. Expression of VDR declined with tumor de differentiation. The data suggest that a relationship between vitamin D receptor expression and response to neoadjuvant therapy is plausible. PMID- 22546274 TI - Understanding local population genetics of tsetse: the case of an isolated population of Glossina palpalis gambiensis in Burkina Faso. AB - Tsetse flies are the vectors of human and animal trypanosomiases. For tsetse eradication programs, it is crucial to be able to identify and target isolated populations, because they can be targeted for eradication without risk of reinvasion. However, most data that are available on non-isolated populations fail to find how these populations are locally structured, because Wahlund effect (admixture of individuals from genetically different units) always interfere with interpretations. In this paper, we investigated the genetic population structure of a possibly isolated population of Glossina palpalis gambiensis in a sacred wood in South Burkina Faso, using microsatellite DNA markers. We found that genotypic proportions in this population were in agreement with random mating model and that these tsetse were genetically highly differentiated from other populations of the same Mouhoun river basin only a few kilometers away, confirming its genetic isolation. The population also displayed substantial temporal differentiation in a two years period that lead to an estimate of effective population size of ~100 individuals. The fact that no Wahlund effect was identified allowed us to accurately measure the basic genetic parameters of this isolated population. Identifying such isolated and small populations is crucial for eradication programs and should be implemented more often. PMID- 22546275 TI - Vestibular toxicity of cis-2-pentenenitrile in the rat. AB - cis-2-Pentenenitrile, an intermediate in the synthesis of nylon and other products, causes permanent behavioral deficits in rodents. Other low molecular weight nitriles cause degeneration either of the vestibular sensory hair cells or of selected neuronal populations in the brain. Adult male Long-Evans rats were exposed to cis-2-pentenenitrile (0, 1.25, 1.50, 1.75, or 2.0mmol/kg, oral, in corn oil) and assessed for changes in open field activity and rating scores in a test battery for vestibular dysfunction. Surface preparations of the vestibular sensory epithelia were observed for hair cell loss using scanning electron microscopy. A separate experiment examined the impact of pre-treatment with the universal CYP inhibitor,1-aminobenzotriazole, on the effect of cis-2 pentenenitrile on vestibular rating scores. The occurrence of degenerating neurons in the central nervous system was assessed by Fluoro-Jade C staining. cis 2-Pentenenitrile had a dose-dependent effect on body weight. Rats receiving 1.50mmol/kg or more of cis-2-pentenenitrile displayed reduced rearing activity in the open field and increased rating scores on the vestibular dysfunction test battery. Hair cell loss was observed in the vestibular sensory epithelia and correlated well with the behavioral deficits. Pre-treatment with 1 aminobenzotriazole blocked the behavioral effect. Fluoro-Jade C staining did not reveal significant neuronal degeneration in the central nervous system apart from neurite labeling in the olfactory glomeruli. We conclude that cis-2 pentenenitrile causes vestibular toxicity in a similar way to allylnitrile, cis crotononitrile and 3,3'-iminodipropionitrile (IDPN), and also shares other targets such as the olfactory system with these other nitriles. The present data also suggest that CYP-mediated bioactivation is involved in cis-2-pentenenitrile toxicity. PMID- 22546276 TI - The anxiolytic effect of testosterone in the rat is mediated via the androgen receptor. AB - Endogenous and exogenous testosterone affects several behavioural traits as shown in human and animal studies. The effects of testosterone can be mediated via androgen or oestrogen receptors, but also via rapid non-genomic effects. The aim of this study was to evaluate whether a single testosterone injection has effects, mediated via the androgen receptor, on anxiety in intact male rats. We hypothesised that administration of testosterone will have an anxiolytic effect, mediated by the androgen receptor. Intact adult male Wistar rats were divided into groups: control, flutamide, testosterone and testosterone with flutamide. Testosterone and flutamide (as an androgen receptor blocker) were applied once, intramuscularly, at a dose of 5mg/kg. Twenty four hours later, rats underwent the following behavioural tests to analyse anxiety: open field test, elevated plus maze and light-dark box. Testosterone was measured in plasma to confirm elevated levels in groups that received testosterone. The levels of testosterone were 2.5 3 fold higher amongst rats administered with testosterone compared to controls. Flutamide did not affect plasma testosterone concentrations. Testosterone administration had no effect on anxiety in the open field and elevated plus maze. In the light-dark transition task, testosterone increased the time spent in the light part of the maze by 80%, an effect which was blocked by flutamide, and which was in support of our hypothesis. Flutamide-treated rats spent more time in the central square of the open field. Using the light-dark box we have shown that a single injection of testosterone decreases anxiety in adult male rats. This effect of increased testosterone was mediated via the androgen receptor as flutamide blocked the anxiolytic effect of exogenous testosterone. Treatment with flutamide blocked the effects of endogenous testosterone and had anxiolytic effects in the open field, suggesting a non-linear relationship between genomic effects of T and anxiety. PMID- 22546277 TI - Role of ATP-sensitive K+ channels in the antinociception induced by non-steroidal anti-inflammatory drugs in streptozotocin-diabetic and non-diabetic rats. AB - There is evidence that systemic sulfonylureas block diclofenac-induced antinociception in normal rat, suggesting that diclofenac activates ATP-sensitive K(+) channels. However, there is no evidence for the systemic interaction between different non-steroidal anti-inflammatory drugs (NSAIDs) and sulfonylureas in streptozotocin (STZ)-diabetic rats. Therefore, this work was undertaken to determine whether two sulfonylureas, glibenclamide and glipizide, have any effect on the systemic antinociception that is induced by diclofenac (30 mg/kg), lumiracoxib (56 mg/kg), meloxicam (30 mg/kg), metamizol (56 mg/kg) and indomethacin (30 mg/kg) using the non-diabetic and STZ-diabetic rat formalin test. Systemic injections of NSAIDs produced dose-dependent antinociception during the second phase of the test in both non-diabetic and STZ-diabetic rats. Systemic pretreatment with glibenclamide (10 mg/kg) and glipizide (10 mg/kg) blocked diclofenac-induced systemic antinociception in the second phase of the test (P<0.05) in both non-diabetic and STZ-diabetic rats. In contrast, pretreatment with glibenclamide or glipizide did not block lumiracoxib-, meloxicam-, metamizol-, and indomethacin-induced systemic antinociception (P>0.05) in both groups. Results showed that systemic NSAIDs are able to produce antinociception in STZ-diabetic rats. Likewise, data suggest that diclofenac, but not other NSAIDs, activated K(+) channels to induce its systemic antinociceptive effect in the non-diabetic and STZ-diabetic rat formalin test. PMID- 22546278 TI - Semi-open rhinoplasty: a new maxillofacial technique. AB - BACKGROUND: Rhinoplasty "open" represents a surgical technique to access to the internal structures of the nose; it is an alternative to more traditional "closed" rhinoplasty. However, both these techniques have some advantages and some disadvantages. In this work the authors describe a case that shows the steps of a new surgical technique: the "semi-open" rhinoplasty. METHODS: The "semi open" technique is performed by making an incision to access on the mucosa of both the nostrils, and through this access we separate the cartilages of the columella from the alar cartilages, debriding them at the domus. With such access we can perform any type of rhinoplasty surgery with functional or aesthetic purposes. DISCUSSIONS: Traditional techniques have undoubtedly some advantages and some disadvantages. The "semi-open" technique has the several advantages of the open technique, and it does not involve the presence of post-surgical scars. CONCLUSIONS: This innovative technique provides great predictability and minimal postoperative discomfort, with no aesthetic damage. PMID- 22546279 TI - Examining the mechanisms that link beta-amyloid and alpha-synuclein pathologies. AB - beta-amyloid (Abeta) and alpha-synuclein (alpha-syn) are aggregation-prone proteins typically associated with two distinct neurodegenerative disorders: Alzheimer's disease (AD) and Parkinson's disease. Yet alpha-syn was first found in association with AD plaques several years before being linked to Parkinson's disease or Lewy body formation. Nowadays, a large subset of AD patients (~50%) is well recognized to co-exhibit significant alpha-syn Lewy body pathology. Unfortunately, these AD Lewy body variant patients suffer from additional symptoms and an accelerated disease course. Basic research has begun to show that Abeta and alpha-syn may act synergistically to promote the aggregation and accumulation of each other. While the exact mechanisms by which these proteins interact remain unclear, growing evidence suggests that Abeta may drive alpha-syn pathology by impairing protein clearance, activating inflammation, enhancing phosphorylation, or directly promoting aggregation. This review examines the interactions between Abeta and alpha-syn and proposes potential mechanistic links between Abeta accumulation and alpha-syn pathogenesis. PMID- 22546280 TI - Clinical applications of mesenchymal stem cells. AB - Mesenchymal stem cells (MSC) have generated a great amount of enthusiasm over the past decade as a novel therapeutic paradigm for a variety of diseases. Currently, MSC based clinical trials have been conducted for at least 12 kinds of pathological conditions, with many completed trials demonstrating the safety and efficacy. This review provides an overview of the recent clinical findings related to MSC therapeutic effects. Roles of MSCs in clinical trials conducted to treat graft-versus-host-disease (GVHD) and cardiovascular diseases are highlighted. Clinical application of MSC are mainly attributed to their important four biological properties- the ability to home to sites of inflammation following tissue injury when injected intravenously; to differentiate into various cell types; to secrete multiple bioactive molecules capable of stimulating recovery of injured cells and inhibiting inflammation and to perform immunomodulatory functions. Here, we will discuss these four properties. Moreover, the issues surrounding clinical grade MSCs and principles for MSC therapeutic approaches are also addressed on the transition of MSCs therapy from bench side to bedside. PMID- 22546281 TI - Computer-assisted virtual technology in intracapsular condylar fracture with two resorbable long-screws. AB - Our aim was to fix intracapsular condylar fractures (ICF) with two resorbable long screws using preoperative computer-assisted virtual technology. From February 2008 to July 2011, 19 patients with ICF were treated with two resorbable long screws. Preoperatively we took panoramic radiographs and spiral computed tomography (CT). Depending on their digital imaging and communications in medicine (DICOM) data, the dislocated condylar segments were restored using the SimPlant ProTM software, version 11.04. The mean (SD) widths of the condylar head and neck from lateral to medial were 19.01 (1.28)mm and 13.84 (1.13)mm, respectively. In all patients, the mandibles and the ICF seen intraoperatively corresponded with the preoperative three-dimensional and virtual reposition. All patients were followed up for 6-46 months (mean 21). Occlusion and mouth opening had been restored completely in all but one patient, and absolute anatomical reduction was also achieved in most cases. Computer-assisted virtual technology plays an important part in the diagnosis of ICF, as well as in its preoperative design. Fixation with only two resorbable long screws is an effective and reliable method for fixing ICF. PMID- 22546282 TI - Topological analysis of protein co-abundance networks identifies novel host targets important for HCV infection and pathogenesis. AB - BACKGROUND: High-throughput methods for obtaining global measurements of transcript and protein levels in biological samples has provided a large amount of data for identification of 'target' genes and proteins of interest. These targets may be mediators of functional processes involved in disease and therefore represent key points of control for viruses and bacterial pathogens. Genes and proteins that are the most highly differentially regulated are generally considered to be the most important. We present topological analysis of co-abundance networks as an alternative to differential regulation for confident identification of target proteins from two related global proteomics studies of hepatitis C virus (HCV) infection. RESULTS: We analyzed global proteomics data sets from a cell culture study of HCV infection and from a clinical study of liver biopsies from HCV-positive patients. Using lists of proteins known to be interaction partners with pathogen proteins we show that the most differentially regulated proteins in both data sets are indeed enriched in pathogen interactors. We then use these data sets to generate co-abundance networks that link proteins based on similar abundance patterns in time or across patients. Analysis of these co-abundance networks using a variety of network topology measures revealed that both degree and betweenness could be used to identify pathogen interactors with better accuracy than differential regulation alone, though betweenness provides the best discrimination. We found that though overall differential regulation was not correlated between the cell culture and liver biopsy data, network topology was conserved to an extent. Finally, we identified a set of proteins that has high betweenness topology in both networks including a protein that we have recently shown to be essential for HCV replication in cell culture. CONCLUSIONS: The results presented show that the network topology of protein co-abundance networks can be used to identify proteins important for viral replication. These proteins represent targets for further experimental investigation that will provide biological insight and potentially could be exploited for novel therapeutic approaches to combat HCV infection. PMID- 22546283 TI - Meta-analysis of internet-delivered interventions to increase physical activity levels. AB - Many internet-delivered physical activity behaviour change programs have been developed and evaluated. However, further evidence is required to ascertain the overall effectiveness of such interventions. The objective of the present review was to evaluate the effectiveness of internet-delivered interventions to increase physical activity, whilst also examining the effect of intervention moderators. A systematic search strategy identified relevant studies published in the English language from Pubmed, Proquest, Scopus, PsychINFO, CINHAL, and Sport Discuss (January 1990 - June 2011). Eligible studies were required to include an internet delivered intervention, target an adult population, measure and target physical activity as an outcome variable, and include a comparison group that did not receive internet-delivered materials. Studies were coded independently by two investigators. Overall effect sizes were combined based on the fixed effect model. Homogeneity and subsequent exploratory moderator analysis was undertaken. A total of 34 articles were identified for inclusion. The overall mean effect of internet-delivered interventions on physical activity was d = 0.14 (p = 0.00). Fixed-effect analysis revealed significant heterogeneity across studies (Q = 73.75; p = 0.00). Moderating variables such as larger sample size, screening for baseline physical activity levels and the inclusion of educational components significantly increased intervention effectiveness. Results of the meta-analysis support the delivery of internet-delivered interventions in producing positive changes in physical activity, however effect sizes were small. The ability of internet-delivered interventions to produce meaningful change in long-term physical activity remains unclear. PMID- 22546285 TI - Regulation of intestinal cancer stem cells. AB - Colorectal tumours harbour a sub-population of cells with stem like properties termed 'cancer stem cells', which are believed to ultimately drive cancer growth. This review discusses recent advances in our understanding of both normal and cancer intestinal stem cells, with emphasis on similarities and differences. Specifically we discuss the role of the Wnt, Notch and BMP pathways and their roles in both stem cell proliferation and differentiation. Furthermore we discuss the emerging role of microRNA and the influence of environmental factors such as tumour associated myofibroblasts and hypoxia on cancer stem cell regulation. PMID- 22546286 TI - Epigenetic biomarkers in lung cancer. AB - Lung cancer mortality is strongly associated with the predominant diagnosis of late stage lesions that hampers effective therapy. Molecular biomarkers for early lung cancer detection is an unmet public health need and the lung cancer research community worldwide is putting a lot of effort to utilise major lung cancer population programmes in order to develop such molecular tools. The study of cancer epigenetics in the last decade has radically altered our views in cancer pathogenesis, providing new insights in biomarker development for risk assessment, early detection and therapeutic stratification. DNA methylation and miRNAs have rapidly emerged as potential biomarkers in body fluids showing promise to assist the clinical management of lung cancer. These new developments are exemplified in this review, demonstrating the huge potential of clinical cancer epigenetics, but also critically discussing the necessary validation steps to bring epigenetic biomarkers towards clinical implementation and the weaknesses of current biomarker studies. PMID- 22546287 TI - Estrogen receptor positive breast cancer identified by 95-gene classifier as at high risk for relapse shows better response to neoadjuvant chemotherapy. AB - A 95-gene classifier (95-GC) recently developed by us can predict the risk of relapse for ER-positive and node-negative breast cancer patients with high accuracy. This study investigated association of risk classification by 95-GC with response to neoadjuvant chemotherapy (NAC). Tumor biopsy samples obtained preoperatively from 72 patients with ER-positive breast cancer were classified by 95-GC into high-risk and low-risk for relapse. Pathological complete response (pCR) rate was numerically higher for high-risk (15.8%) than low-risk patients (8.8%) although the difference was not statistically significant. Pathological response evaluated in terms of the pathological partial response (pPR) rate (loss of tumor cells in more than two-thirds of the primary tumor) showed a significant association (P=0.005) between the high-risk patients and a high pPR rate. Besides, external validation study using the public data base (GSE25066) showed that the pCR rate (16.4%) for high-risk patients (n=128) was significantly (P=0.003) higher than for low-risk patients (5.7%) (n=159). These results demonstrate that the high-risk patients for relapse show a higher sensitivity to chemotherapy and thus are likely to benefit more from adjuvant chemotherapy. PMID- 22546284 TI - Genetic determinants of metabolism in health and disease: from biochemical genetics to genome-wide associations. AB - Increasingly sophisticated measurement technologies have allowed the fields of metabolomics and genomics to identify, in parallel, risk factors of disease; predict drug metabolism; and study metabolic and genetic diversity in large human populations. Yet the complementarity of these fields and the utility of studying genes and metabolites together is belied by the frequent separate, parallel applications of genomic and metabolomic analysis. Early attempts at identifying co-variation and interaction between genetic variants and downstream metabolic changes, including metabolic profiling of human Mendelian diseases and quantitative trait locus mapping of individual metabolite concentrations, have recently been extended by new experimental designs that search for a large number of gene-metabolite associations. These approaches, including metabolomic quantitiative trait locus mapping and metabolomic genome-wide association studies, involve the concurrent collection of both genomic and metabolomic data and a subsequent search for statistical associations between genetic polymorphisms and metabolite concentrations across a broad range of genes and metabolites. These new data-fusion techniques will have important consequences in functional genomics, microbial metagenomics and disease modeling, the early results and implications of which are reviewed. PMID- 22546288 TI - SV40 T/t-common polypeptide enhances the sensitivity of HER2-overexpressing human cancer cells to anticancer drugs cisplatin and doxorubicin. AB - HER2-overexpressing cancer cells are resistant to cisplatin (CDDP) and doxorubicin (DXR). Here we report that SV40 T/t-common polypeptide could specifically sensitize HER2-overexpressing cancer cells to CDDP and DXR and specifically enhance CDDP- or DXR-induced apoptosis in these cells. This activity of T/t-common may be attributed to its ability to inhibit Bcl-2 and Bcl-XL and to suppress ERK activity in CDDP- or DXR-treated HER2-overexpressing cancer cells. T/t-common could enhance the antitumor activity of DXR on HER2-overexpressing ovarian tumor in NOD/SCID mice, suggesting that combination therapy using T/t common and chemotherapeutic agents may provide a new approach for treating HER2 overexpressing cancers. PMID- 22546289 TI - Progenitor cell mobilizing treatments prevent experimental transplant arteriosclerosis. PMID- 22546290 TI - [The prescription and the Twelve Tasks of Hercules: beyond the active ingredient]. PMID- 22546291 TI - [Public Health injury surveillance: still an unresolved matter]. PMID- 22546292 TI - Preventable mortality evaluation in the ICU. AB - Mortality is the most widely measured outcome parameter. Improvement of this outcome parameter in critical care is nowadays expected not to come from new technologies or treatment, but from delivering the right care at the right moment in a safe way. The measurement of mortality as an outcome parameter confronts us with a problem in providing follow-up to the results. Especially when proven structure and process interventions are applied already, the cause of a suboptimal performance cannot be deduced easily. One possibility is to evaluate the causes of death and to judge preventability. In this article we explore the opportunities and difficulties of a tool to evaluate preventable mortality in the ICU. PMID- 22546293 TI - Anti-glomerular basement membrane antibody disease: a rare autoimmune disorder affecting the kidney and the lung. AB - Anti-glomerular basement membrane antibody disease is a rare, but well characterized cause of glomerulonephritis. By definition serum anti-GBM antibody and/or a linear binding of IgG detected by direct immunofluorescence (IF) in a histological specimen of the kidney or the lung have to be detected. These antibodies can lead to acute rapid progressive glomerulonephritis(RPGN) and/or pulmonary hemorrhage (PH) because of collagen similarities in the basement membrane. Principally anti-GBM antibody disease can be divided into two groups: anti-GBM antibody disease without PH was regarded as renal-limited anti-GBM antibody disease and that with PH was defined as Goodpasture's syndrome (GPS). The important determinant for the response of therapy and long term diagnosis on anti-GBM disease is early diagnosis to prevent endstage renal disease. Therefore, standard treatment is a combined therapy of plasmapherisis, prednisolone and cyclophosphamide. The aim of this review is an overview of the pathogenesis, clinical presentation, diagnosis and treatment of anti-GBM disease. PMID- 22546294 TI - Systematic evaluations regarding interparticular mass transfer in spheronization. AB - Pellets are frequently used in pharmaceutical applications. The extrusion spheronization process is a well-established technique used to produce pellets of a spherical shape and narrow size distribution. In this process, cylindrical extrudates are transformed into spherical pellets by spheronization. Most established mechanisms consider only breakage and deformation to explain pellet formation. An interaction between the rounding extrudates via adhesion of fine particles was not considered for many years. This study deals with the evolution of pellet properties over time during the spheronization process in order to quantify the influence of pellet interactions on their properties. Therefore the most important pelletization aids (MCCI, MCCII and kappa-carrageenan) were investigated using acetaminophen as a model drug and lactose as a filler. In the first seconds of the spheronization process, a high fine fraction was seen which decreased during the process. Simultaneously, the material transferred between the pellets increased. However the fine fraction is not high enough to explain the mass transfer; therefore a direct transfer between the pellets was assumed. The pelletization aid has a huge influence on the amount of mass transferred. Whereas kappa-carrageenan leads to a quite low mass transfer of 15%, MCCI and MCCII show higher values up to 25%. PMID- 22546295 TI - Decoupling the role of image size and calorie intake on gastric retention of swelling-based gastric retentive formulations: pre-screening in the dog model. AB - Gastric retention is postulated as an approach to improve bioavailability of compounds with narrow absorption windows. To elucidate the role of image size on gastric retention and pharmacokinetics, formulations with different image sizes and swelling kinetics but similar dissolution rates were designed and imaged in dogs. Diet had a clear effect, with increasing calorific intake prolonging retention in the dog model. In contrast to clinical observations, no obvious effect of image size on gastric retention was observed in the dog, with the larger gastric retentive (GR) and smaller controlled release (CR) formulations both demonstrating similar gastric emptying. Comparable pharmacokinetic profiles were observed for the two formulations, corroborating the imaging data and providing evidence of similar in vivo dissolution rates and dosage form integrity in the dog. Food, specifically meal composition, resulted in comparable enhancements in exposure in the dog and clinic due to prolonged gastric retention. However, differentiating retention based on image size in the dog was not feasible due to the smaller pyloric aperture compared to humans. This work illustrates that the dog is capable of determining the pharmacokinetic advantage of gastric retention relative to immediate release (IR) or CR formulations, however, has limited value in differentiating between CR and GR formulations. PMID- 22546296 TI - Immunogenicity of protein aggregates--concerns and realities. AB - Protein aggregation is one of the key challenges in the development of protein biotherapeutics. It is a critical product quality issue as well as a potential safety concern due to the increased immunogenicity potential of these aggregates. The overwhelming safety concern has led to an increased development effort and regulatory scrutiny in recent years. The main purposes of this review are to examine the literature data on the relationship between protein aggregates and immunogenicity, to highlight the linkage and existing inconsistencies/uncertainties, and to propose directions for future investigations/development. PMID- 22546297 TI - Improvement of heat transfer by means of ultrasound: Application to a double-tube heat exchanger. AB - A new kind of ultrasonically-assisted heat exchanger has been designed, built and studied. It can be seen as a vibrating heat exchanger. A comprehensive description of the overall experimental set-up is provided, i.e. of the test rig and the acquisition system. Data acquisition and processing are explained step-by step with a detailed example of graph obtained and how, from these experimental data, energy balance is calculated on the heat exchanger. It is demonstrated that ultrasound can be used efficiently as a heat transfer enhancement technique, even in such complex systems as heat exchangers. PMID- 22546298 TI - Chest ultrasonography in the ICU. AB - Chest diagnostic imaging is essential when dealing with a critically ill patient. At present, direct visualization of the lung parenchyma is performed with a chest x-ray and computed tomography with the patient in the supine position. The relative ease of bedside ultrasound examination and the availability of user friendly, inexpensive, portable equipment have made chest ultrasonography an interesting and alternative method in various situations, because it offers accurate information that is of therapeutic and diagnostic relevance. We describe equipment and examination technique, normal findings, and chest ultrasonography signs detected in some pathological situations, such as pneumothorax, consolidations, pleural effusions, ARDS, and pulmonary edema. PMID- 22546299 TI - Humidification during invasive and noninvasive mechanical ventilation: 2012. AB - We searched the MEDLINE, CINAHL, and Cochrane Library databases for articles published between January 1990 and December 2011. The update of this clinical practice guideline is based on 184 clinical trials and systematic reviews, and 10 articles investigating humidification during invasive and noninvasive mechanical ventilation. The following recommendations are made following the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) scoring system: 1. Humidification is recommended on every patient receiving invasive mechanical ventilation. 2. Active humidification is suggested for noninvasive mechanical ventilation, as it may improve adherence and comfort. 3. When providing active humidification to patients who are invasively ventilated, it is suggested that the device provide a humidity level between 33 mg H(2)O/L and 44 mg H(2)O/L and gas temperature between 34 degrees C and 41 degrees C at the circuit Y-piece, with a relative humidity of 100%. 4. When providing passive humidification to patients undergoing invasive mechanical ventilation, it is suggested that the HME provide a minimum of 30 mg H(2)O/L. 5. Passive humidification is not recommended for noninvasive mechanical ventilation. 6. When providing humidification to patients with low tidal volumes, such as when lung-protective ventilation strategies are used, HMEs are not recommended because they contribute additional dead space, which can increase the ventilation requirement and P(aCO(2)). 7. It is suggested that HMEs are not used as a prevention strategy for ventilator associated pneumonia. PMID- 22546300 TI - The importance of a multidisciplinary approach to VAP prevention: the role of the respiratory therapist. PMID- 22546301 TI - Automatic tube compensation: is it worthwhile? PMID- 22546302 TI - Acute application of noninvasive ventilation outside the ICU: when is it safe? PMID- 22546303 TI - Errors in Turbuhaler technique in a Spanish population of asthmatic patients. PMID- 22546304 TI - Long term success of 6 implants supporting a mandibular screw-retained fixed dental prosthesis: a clinical report. AB - Dental implant therapy has become successful with improved surgical and prosthodontic techniques. However, most clinical trials, even though well controlled, are limited in longevity. There are few clinical reports that show long-term results with dental implants. Although there are many similarities among criteria for success in these studies, these criteria may vary from what the individual patient reports as a success. This clinical report describes the 28-year successful clinical outcome of a 62-year-old woman with dental implants supporting a mandibular screw-retained fixed dental prosthesis. PMID- 22546305 TI - Myofunctional therapy as an aid to prosthodontic treatment after hemiglossectomy: a clinical report. AB - Although several reports describe the prosthetic management of patients after hemiglossectomy, the techniques are related to the fabrication of the prostheses, no reports on maximizing the functional potential of the remaining tongue musculature and surrounding tissues were identified by the authors. This clinical report describes the use of myofunctional therapy as an aid to the maxillofacial prosthodontic rehabilitation of an edentulous patient who was diagnosed with invasive squamous cell carcinoma of the tongue and underwent hemiglossectomy. Myofunctional therapy was introduced before, during, and after the fabrication of conventional maxillary and mandibular complete dentures. Muscle exercises were devised to improve the posture and muscular tonus of the remaining tongue, and thus help with mastication and adaptation to the mandibular denture. Myofunctional therapy improved the posture and function of the remaining tongue, providing acceptable mastication and increased stability of the mandibular denture. PMID- 22546306 TI - Techniques for incorporation of attachments in implant-retained overdentures with unsplinted abutments. AB - A variety of techniques have been reported in the literature for the incorporation of attachments in implant-retained partial and complete overdentures with unsplinted or individual abutments. Three important elements that are necessary in describing any technique for incorporation of attachments are the type of final impression method (tissue-level impression, abutment-level impression, or implant-level impression), stage of overdenture fabrication (record base stage, denture-processing stage, or denture insertion stage) and nature of technique (direct or indirect). This article reviews 7 different techniques for the incorporation of attachments in implant-retained complete and partial overdentures. Discussion of indications, contraindications, advantages, and disadvantages of each technique is provided to aid the clinician in making an appropriate choice. PMID- 22546307 TI - Evaluation of the optical properties of CAD-CAM generated yttria-stabilized zirconia and glass-ceramic laminate veneers. AB - STATEMENT OF PROBLEM: When feldspathic porcelain (FP) laminate veneers are used to mask tooth discoloration that extends into the dentin, significant tooth reduction is needed to provide space for the opaque layer and optimize the bonding of the restoration. PURPOSE: The purpose of this study was to investigate the color effect of trial insertion paste (TP), composite resin abutment (CRA), and veneer regions on the optical properties of feldspathic porcelain (FP), yttria-stabilized zirconia (Y-TZP), and IPS e.max CAD HT (IEC) veneers. MATERIAL AND METHODS: A melamine tooth was prepared for a laminate veneer on a model, and a definitive cast was made. The definitive die was scanned by using the TurboDent System (TDS), then 30 CRA were machined and 10 veneers were fabricated for each ceramic material (FP, Y-TZP, IEC). The optical properties of different veneer materials, CRA (A(1), A(2), A(3)) and TP (bleach XL, opaque white, transparent, and yellow) were evaluated in the cervical, body, and incisal regions with a spectrophotometer. Results were analyzed by using 1-way ANOVA (.05). RESULTS: The color difference for all the veneers was affected by TP and CRA colors in different regions. The mean values for the Y-TZP veneer color coordinates (L*: 74 +/-0.34, a*: 0.09 +/-0.20, and b*: 17.43 +/-0.44) were significantly different (P<.001) from those of IEC veneers (L*: 70.15 +/-0.23, a*: -0.69 +/-0.073, and b*:11.48 +/-0.30) and FP veneers (L*: 70.00 +/-0.86, a*: - 0.28 +/-0.203, and b*: 13.86 +/-1.08). There was no difference between IEC for L* and FP. Significant difference was detected (P<.001) in color coordinates among the 3 veneer materials for a* and b*. CONCLUSIONS: The TP color affected the color difference for all veneer materials except the Y-TZP, while there was no effect on the CRA color. The magnitude of color coordinates changed as a function of TP color and veneer material. PMID- 22546308 TI - Comparison of different grinding procedures on the flexural strength of zirconia. AB - STATEMENT OF PROBLEM: The surface of zirconia ceramic is damaged during grinding, which may affect the mechanical properties of the material. PURPOSE: The purpose of this study was to compare the biaxial flexural strength of zirconia after different grinding procedures and to measure the temperature rise from grinding. MATERIAL AND METHODS: Forty disk-shaped zirconia specimens (15 * 1.2 mm) with a smaller disk in the center of each disk (1 * 3 mm) were divided into 4 groups (n=10). The specimens were ground with a high-speed handpiece and micromotor with 2 different grinding protocols, continual grinding and periodic grinding (10 seconds grinding with 10 seconds duration), until the smaller disk was removed. Control specimens without the center disk (n=10) were analyzed without grinding. The biaxial flexural strengths of the disks were determined in a universal testing machine at a crosshead speed of 0.5 mm/min. The fracture strength (MPa) was recorded, and the results were analyzed using a 1-way ANOVA, Tukey HSD test, Student's t test, and Pearson correlation test (alpha=05). RESULTS: All grinding procedures significantly decreased flexural strength (P<.01). The mean flexural strength of the high-speed handpiece groups was higher (815 MPa) than that of the micromotor groups (718 MPa). The temperature values obtained from micromotor grinding (127 degrees C) were significantly higher than those from high-speed handpiece grinding (63 degrees C) (P<.01). CONCLUSIONS: Grinding zirconia decreased flexural strength. Zirconia material ground with a high-speed handpiece run continually caused the least reduction in flexural strength. PMID- 22546309 TI - A retrospective analysis of 102 zirconia single crowns with knife-edge margins. AB - STATEMENT OF PROBLEM: Clinical reports of feldspathic porcelain veneered-zirconia crowns placed on teeth with knife-edge marginal finish lines have recently been presented but with data available for only a limited number of crowns in the anterior maxilla. PURPOSE: This retrospective study evaluated the clinical success and survival of feldspathic porcelain veneered-zirconia crowns fabricated with knife-edge margins in a private practice. MATERIAL AND METHODS: One hundred and two teeth (51 anterior, 51 posterior) were prepared with knife-edge margins and restored with feldspathic porcelain veneered-zirconia crowns. The modified California Dental Association (CDA) criteria were used to clinically evaluate subjects recalled between May and December 2010. Data were analyzed with descriptive statistics. RESULTS: The mean follow-up time was 20.9 months (SD, 13.6; range, 10-72). One tooth had to be extracted because of an endodontic problem not related with the restoration, 2 crowns had minor chipping of the veneering porcelain, while no crowns exhibited fracture of the zirconia core. CONCLUSIONS: In this retrospective evaluation, feldspathic porcelain veneered zirconia crowns with knife-edge margins provided clinical performance similar to that reported with other margin designs. PMID- 22546310 TI - Effect of three endodontic sealers on the bond strength of prefabricated fiber posts luted with three resin cements. AB - STATEMENT OF PROBLEM: There is limited information in the literature regarding the effect of eugenol-based sealers on the bond strength of resin-bonded endodontic posts. PURPOSE: The purpose of this study was to evaluate the effect of 1 resin-based and 2 different eugenol-based endodontic sealers on the bond strength of prefabricated fiber posts luted with 3 different resin cements. MATERIAL AND METHODS: One hundred thirty-five prefabricated fiber posts were luted into extracted single-rooted teeth with 1 of 3 composite resin cements (Rely X Unicem, Paracore, and Variolink II). Specimens were divided into 3 groups with 45 teeth each. The first 2 groups were obturated with gutta percha and 1 of 2 eugenol-based endodontic sealers (Endofil, Tubli-Seal). The third group was obturated with a resin-based root canal sealer (AH26). The forces required for dislodgment of posts from their prepared post spaces were recorded by using a universal testing machine. Data were collected and a 2-way ANOVA was applied to the mean retentive strengths of various combinations of sealer and cement. A Tukey multiple comparison test was performed to determine which groups were significantly different (alpha=.05). RESULTS: Endofil and Tubli-Seal (eugenol based sealers) groups had significantly lower bond strengths for the posts than the AH26 group (P<.001). There was no significant difference between the means of post bond strength for the Endofil and Tubli-Seal groups. There was significant difference among the means of post bond strength for all 3 cement groups (P<.05). CONCLUSIONS: Endofil and Tubli-Seal (eugenol-based) sealers demonstrated significantly reduced mean bond strength for prefabricated fiber posts luted with resin cement. Rely X Unicem resin cement exhibited higher mean bond strength than with Paracore and Variolink II resin cements when a eugenol sealer was used. PMID- 22546311 TI - Smile characterization by U.S. white, U.S. Asian Indian, and Indian populations. AB - STATEMENT OF PROBLEM: With growing demand for high esthetic standards, dentists must understand patient perception and incorporate their preferences into treatment. However, little is known about how cultural and ethnic differences influence esthetic perception. PURPOSE: The purpose of this study was to determine whether differences in ethnic background, including the possibility of assimilation, affected a layperson's perception of esthetic and smile characteristics. MATERIAL AND METHODS: A survey was developed containing images that were digitally manipulated into a series of barely perceptible steps, changing 1 smile parameter to form a strip of images that displayed that parameter over a wide range. Data were collected with a customized program which randomly displayed a single image and allowed the subject to use the mouse to adjust an on-screen slider according to displayed instructions, that is, "Please move the slider to select the image you find to be most ideal"; or "Please move the slider to select the first image that you find unattractive." A convenience sample (n=288) comprised of U.S. whites, U.S. Asian Indians, and Indians living in India was surveyed. This sample provided a power of .86 to detect a difference of +/-1.5 mm. Subjects evaluated images showing the smile arc, buccal corridor, gingival display, vertical overlap, lateral incisal step, maxillary midline to midface, and maxillary to mandibular midline. Rater reliability was assessed with the Fleiss-Cohen weighted Kappa (Kw) statistic and corresponding 95% confidence interval after each question was repeated in a random sequence. Choice differences due to ethnicity were assessed with a multiple randomization test and the adjusted P value with the step-down Bonferrroni method of Holm (alpha=.05). RESULTS: The Kw for the 17 variables in all 3 groups ranged from 0.11 for ideal vertical overlap to 0.64 for ideal buccal corridor space. Overall reliability was fair to moderate. Differences attributed to ethnicity were demonstrated between the Asian Indians and U.S. whites. Differences attributed to assimilation were demonstrated between U.S. Asian Indians and Asian Indians. Differences between U.S. Asian Indians and U.S. whites can be instructive and demonstrate the relative power of ethnicity and assimilation. A difference between these groups shows the power of ethnicity and no difference between these groups shows the power of assimilation. The ratings of the Asian Indians and the U.S. whites showed a clinically significant difference for Ideal Buccal Corridor and Maximum Smile Arc. There were no significant differences between the U.S. Asian Indians and Asian Indians. There were clinically significant differences between the U.S. Asian Indians and U.S. whites only for Ideal Buccal Corridor. CONCLUSIONS: Ethnicity had a significant effect on the esthetic choices for Buccal Corridor and Smile Arc. There is no conclusive evidence for assimilation. PMID- 22546312 TI - Finite element analysis of maxillary bone stress caused by Aramany Class IV obturator prostheses. AB - STATEMENT OF PROBLEM: The retention of an Aramany Class IV removable partial dental prosthesis can be compromised by a lack of support. The biomechanics of this obturator prosthesis result in an unusual stress distribution on the residual maxillary bone. PURPOSE: This study evaluated the biomechanics of an Aramany Class IV obturator prosthesis with finite element analysis and a digital 3-dimensional (3-D) model developed from a computed tomography scan; bone stress was evaluated according to the load placed on the prosthesis. MATERIAL AND METHODS: A 3-D model of an Aramany Class IV maxillary resection and prosthesis was constructed. This model was used to develop a finite element mesh. A 120 N load was applied to the occlusal and incisal platforms corresponding to the prosthetic teeth. Qualitative analysis was based on the scale of maximum principal stress; values obtained through quantitative analysis were expressed in MPa. RESULTS: Under posterior load, tensile and compressive stresses were observed; the tensile stress was greater than the compressive stress, regardless of the bone region, and the greatest compressive stress was observed on the anterior palate near the midline. Under an anterior load, tensile stress was observed in all of the evaluated bone regions; the tensile stress was greater than the compressive stress, regardless of the bone region. CONCLUSIONS: The Aramany Class IV obturator prosthesis tended to rotate toward the surgical resection when subjected to posterior or anterior loads. The amount of tensile and compressive stress caused by the Aramany Class IV obturator prosthesis did not exceed the physiological limits of the maxillary bone tissue. (J Prosthet Dent 2012;107:336-342). PMID- 22546313 TI - Reinforcement of an existing implant-retained complete dental prosthesis for use in compensatory techniques by a patient missing an upper limb. AB - The purpose of this article is to describe the adaptation of a method suggested for prevention of fractures of partial removable dental prostheses to the reinforcement of an existing implant-retained fixed complete dental prosthesis (IRFCDP). The patient, an upper limb amputee, had subjected the original IRFCDP to parafunctional forces generated from use as a replacement hand in a compensatory technique commonly taught in rehabilitation. Advantages of the technique are that it provides an alternative to remaking the entire prosthesis, which was otherwise satisfactory; it adapts to a variety of situations involving anterior tooth reinforcement; and it offers a potential solution to anterior prosthetic tooth damage caused by other types of parafunction. It may also be adaptable to the reinforcement of other types of prostheses. A disadvantage is the possible need to provide a new interim prosthesis or modify an existing one while laboratory repair procedures are completed. Following reinforcement of the IRFCDP, no tooth damage was evident after one year of use. (J Prosthet Dent 2012;107:343-345). PMID- 22546314 TI - Activation of survival pathways in the degenerating retina of rd10 mice. AB - Blinding diseases of the retina are frequently characterized by loss of photoreceptor cells. The retinal degeneration 10 (rd10) mouse expresses a mutant form of rod phosphodiesterase leading to autosomal recessive photoreceptor degeneration. In contrast to rd1, rd10 mice have remaining rod function mimicking more closely most forms of human Retinitis Pigmentosa. Here we use morphology, biochemistry, retinal whole mounts, real-time PCR, Western blotting and immunofluorescence to compile a comprehensive report on progression of retinal degeneration in the rd10 retina up to one year of age. We show that retinal development, morphology, gene expression pattern and retinal vasculature was normal until postnatal day 15. Thereafter, a bi-phasic pattern of rod cell death emerged with a first rapid phase peaking around 3 weeks of age followed by a slower second phase. Death of cone cells followed with a delay and vessel dropout was prominent in the retinal periphery of 6 months old rd10 mice. At one year of age, RPE atrophy was evident. The degenerating retina rapidly induced expression of transcriptional regulators Atf3 and Cebpd. Induction of Atf3 was transient and lasted only for several days at the beginning of degeneration whereas levels of Cebpd remained elevated throughout the period of photoreceptor loss. Several protective genes such as Lif, Edn2 and Fgf2 which are implicated in a potent endogenous survival pathway, and Mt1 and Mt2 were strongly upregulated in the rd10 retina. In addition, increased expression of Casp1 and Il1b suggested an inflammatory response. PMID- 22546316 TI - Trans-local ties, local ties and psychological well-being among rural-to-urban migrants in Shanghai. AB - During the past three decades, an estimated 200 million rural residents have moved to urban centers in China. They are "sojourners" in the cities and maintain close ties with their home communities, which we term trans-local ties. This paper examines the relationship between migrants' social ties and their mental health, and contrasts the trans-local ties with migrants' ties in the receiving communities, which are termed local ties. We expect that for the migrants, trans local ties foster better mental health not only through providing emotional support but also through generating favorable social comparisons; whereas local ties may furnish important social support, but may also produce negative social comparisons. We use data collected in Shanghai to test our expectations. We compare the migrants to a sample of Shanghai natives to assess patterns of relationship between social ties and mental health that are unique to the migrants. We find that for the migrants, more numerous trans-local ties are associated with better mental health, whereas the number of local ties is not a significant predictor. This pattern is not observed among the Shanghai natives. Moreover, for migrants, trans-local ties foster a favorable evaluation of their status in Shanghai and buffer their perception of discrimination; in contrast, more numerous local ties tend to be associated with a more negative perception of social status. The findings highlight an often-overlooked pathway between social ties and health outcomes, namely, through influencing social comparison and perceived social status. This study also suggests that in addition to reducing institutional and personal discrimination, facilitating close bonds between the migrants and their home communities may be a productive way to foster their well being, in the context of contemporary urban China. PMID- 22546315 TI - Circulating microRNAs in cancer: origin, function and application. AB - MicroRNAs (miRNAs) are a class of small non-coding RNAs that regulate gene expression at the posttranscriptional level. The dysregulation of miRNAs has been linked to a series of diseases, including various types of cancer. Since their discovery in the circulation of cancer patients, there has been a steady increase in the study of circulating miRNAs as stable, non-invasive biomarkers. However, the origin and function of circulating miRNAs has not been systematically elucidated. In this review, we summarize the discovery of circulating miRNAs and their potential as biomarkers. We further emphasize their possible origin and function. Finally, we discuss the application and existing questions surrounding circulating miRNAs in cancer diagnostics. Although several challenges remain to be concerned, circulating miRNAs could be useful, non-invasive biomarkers for cancer diagnosis. PMID- 22546317 TI - Evaluating the Ozioma cancer news service: a community randomized trial in 24 U.S. cities. AB - OBJECTIVE: This community randomized trial evaluated effects of the Ozioma News Service on the amount and quality of cancer coverage in Black weekly newspapers in 24 U.S. cities. METHOD: We created and operated Ozioma, the first cancer information news service specifically for Black newspapers. Over 21 months, Ozioma developed community- and race-specific cancer news releases for each of 12 Black weekly newspapers in intervention communities. Cancer coverage in these papers was tracked before and during the intervention and compared to 12 Black newspapers in control communities. RESULTS: From 2004 to 2007, we coded 9257 health and cancer stories from 3178 newspaper issues. Intervention newspapers published approximately 4 times the expected number of cancer stories compared to control newspapers (p(12,21 mo)<.01), and also saw an increase in graphics (p(12,21 mo)<.01), local relevance (p(12 mo)=.01), and personal mobilization (p(12 mo)<.10). However, this increased coverage supplanted other health topics and had smaller graphics (NS), had less community mobilization (p(21 mo)=.01), and is less likely to be from a local source (NS). CONCLUSION: Providing news releases with localized and race-specific features to minority-serving media outlets can increase the quantity of cancer coverage. Results are mixed for the journalistic and public health quality of this increased cancer coverage in Black newspapers. PMID- 22546319 TI - Effect of relevance on amygdala activation and association with the ventral striatum. AB - While the amygdala historically has been implicated in emotional stimuli processing, recent data suggest a general role in parceling out the relevance of stimuli, regardless of their emotional properties. Using functional magnetic resonance imaging, we tested the relevance hypothesis by investigating human amygdala responses to emotionally neutral stimuli while manipulating their relevance. The task was operationalized as highly relevant if a subsequent opportunity to respond for a reward depended on response accuracy of the task, and less relevant if the reward opportunity was independent of task performance. A region of interest analysis revealed bilateral amygdala activations in response to the high relevance condition compared to the low relevance condition. An exploratory whole-brain analysis yielded robust similar results in bilateral ventral striatum. A subsequent functional connectivity analysis demonstrated increased connectivity between amygdala and ventral striatum for the highly relevant stimuli compared to the less relevant stimuli. These findings suggest that the amygdala's processing profile goes beyond detection of emotions per se, and directly support the proposed role in relevance detection. In addition, the findings suggest a close relationship between amygdala and ventral striatal activity when processing relevant stimuli. Thus, the results may indicate that human amygdala modulates ventral striatum activity and subsequent behaviors beyond that observed for emotional cues, to encompass a broader range of relevant stimuli. PMID- 22546320 TI - Correlation of released HMGB1 levels with the degree of islet damage in mice and humans and with the outcomes of islet transplantation in mice. AB - Establishing reliable islet potency assay is a critical and unmet issue for clinical islet transplantation. Recently, we reported that islets contained high levels of high mobility group box 1 (HMGB1) and damaged islets released HMGB1 in a mouse model. In this study, we hypothesized that the amount of released HMGB1 could reflect the degree of islet damage, and could predict the outcome of islet transplantation. Four groups of damaged mouse islets and three groups of damaged human islets were generated by hypoxic conditions. These islets were assessed by in vivo (transplantation) and in vitro (released HMGB1 levels, released C-peptide levels, PI staining, TUNEL staining, ATP/DNA, and glucose-stimulated insulin release test) assays. In addition, the ability of each assay to distinguish between noncured (n = 13) and cured (n = 7) mice was assessed. The curative rates of STZ-diabetic mice after receiving control, hypoxia-3h, hypoxia-6h, and hypoxia 24h mouse islets were 100%, 40%, 0%, and 0%, respectively. Only amounts of released HMGB1 and ratio of PI staining significant increased according to the degree of damages in both human and mouse islets. In terms of predictability of curing diabetic mice, amounts of released HMGB1 showed the best sensitivity (100%), specificity (100%), positive (100%), and negative predictive values (100%) among all the assays. The amount of released HMGB1 reflected the degree of islet damage and correlated with the outcome of islet transplantation in mice. Hence, released HMGB1 levels from islets should be a useful marker to evaluate the potency of isolated islets. PMID- 22546318 TI - Calibrating the BOLD signal during a motor task using an extended fusion model incorporating DOT, BOLD and ASL data. AB - Multimodal imaging improves the accuracy of the localization and the quantification of brain activation when measuring different manifestations of the hemodynamic response associated with cerebral activity. In this study, we incorporated cerebral blood flow (CBF) changes measured with arterial spin labeling (ASL), Diffuse Optical Tomography (DOT) and blood oxygen level-dependent (BOLD) recordings to reconstruct changes in oxy- (DeltaHbO(2)) and deoxyhemoglobin (DeltaHbR). Using the Grubb relation between relative changes in CBF and cerebral blood volume (CBV), we incorporated the ASL measurement as a prior to the total hemoglobin concentration change (DeltaHbT). We applied this ASL fusion model to both synthetic data and experimental multimodal recordings during a 2-s finger-tapping task. Our results show that the new approach is very powerful in estimating DeltaHbO(2) and DeltaHbR with high spatial and quantitative accuracy. Moreover, our approach allows the computation of baseline total hemoglobin concentration (HbT(0)) as well as of the BOLD calibration factor M on a single subject basis. We obtained an average HbT(0) of 71 MUM, an average M value of 0.18 and an average increase of 13% in cerebral metabolic rate of oxygen (CMRO(2)), all of which are in agreement with values previously reported in the literature. Our method yields an independent measurement of M, which provides an alternative measurement to validate the hypercapnic calibration of the BOLD signal. PMID- 22546321 TI - Concentration of endogenous estrogens and estrogen metabolites in the NCI-60 human tumor cell lines. AB - BACKGROUND: Endogenous estrogens and estrogen metabolites play an important role in the pathogenesis and development of human breast, endometrial, and ovarian cancers. Increasing evidence also supports their involvement in the development of certain lung, colon and prostate cancers. METHODS: In this study we systemically surveyed endogenous estrogen and estrogen metabolite levels in each of the NCI-60 human tumor cell lines, which include human breast, central nerve system, colon, ovarian, prostate, kidney and non-small cell lung cancers, as well as melanomas and leukemia. The absolute abundances of these metabolites were measured using a liquid chromatography-tandem mass spectrometry method that has been previously utilized for biological fluids such as serum and urine. RESULTS: Endogenous estrogens and estrogen metabolites were found in all NCI-60 human tumor cell lines and some were substantially elevated and exceeded the levels found in well known estrogen-dependent and estrogen receptor-positive tumor cells such as MCF-7 and T-47D. While estrogens were expected to be present at high levels in cell lines representing the female reproductive system (that is, breast and ovarian), other cell lines, such as leukemia and colon, also contained very high levels of these steroid hormones. The leukemia cell line RMPI-8226 contained the highest levels of estrone (182.06 pg/106 cells) and 17beta-estradiol (753.45 pg/106 cells). In comparison, the ovarian cancer cell line with the highest levels of these estrogens contained only 19.79 and 139.32 pg/106 cells of estrone and 17beta-estradiol, respectively. The highest levels of estrone and 17beta estradiol in breast cancer cell lines were only 8.45 and 87.37 pg/106 cells in BT 549 and T-47D cells, respectively. CONCLUSIONS: The data provided evidence for the presence of significant amounts of endogenous estrogens and estrogen metabolites in cell lines not commonly associated with these steroid hormones. This broad discovery of endogenous estrogens and estrogen metabolites in these cell lines suggest that several human tumors may be beneficially treated using endocrine therapy aimed at estrogen biosynthesis and estrogen-related signaling pathways. PMID- 22546322 TI - Notes about the uses of plants by one of the last healers in the Basilicata region (South Italy). AB - BACKGROUND: The paper refers to the knowledge and uses of plants and to the linked ritual practices as referred by Matteo (It.'Zi Matteo', En. 'Uncle Matthew'), one of the last elder healers in the Basilicata Region (South Italy). Particular attention is also paid to the uses of 'Vruca' (Tamarix gallica L.) as a medicinal and magical plant used to heal common warts on various parts of the body. METHODS: After obtaining prior informed consent, we collected data through an open interview about the uses of the plants and on the associated ritual practices. For each species, data were collected that included the vernacular names, preparation, plant parts utilized and their method of use. RESULTS: The uses of 52 taxa are described. Among these, 43 are or were employed medicinally, eight as culinary foodstuffs, and 4 for domestic, handicraft or ethnoveterinary uses. Among the major findings: the ritual and magical use of Tamarix gallica L. to heal warts is described in detail; so far, no records of similar use were found in any Italian ethnobotanical studies conducted in southern Italy. CONCLUSION: Phytotherapy in the Basilicata region is practiced by elderly people who resort to medicinal plants for mild illnesses; we interviewed one of those traditional healers who is very experienced in the field, and possesses rich ethno-pharmacological knowledge. PMID- 22546324 TI - Fetoplacental angiogenesis in diabetes mellitus. PMID- 22546323 TI - Trehalose treatment suppresses inflammation, oxidative stress, and vasospasm induced by experimental subarachnoid hemorrhage. AB - BACKGROUND: Subarachnoid hemorrhage (SAH) frequently results in several complications, including cerebral vasospasm, associated with high mortality. Although cerebral vasospasm is a major cause of brain damages after SAH, other factors such as inflammatory responses and oxidative stress also contribute to high mortality after SAH. Trehalose is a non-reducing disaccharide in which two glucose units are linked by alpha,alpha-1,1-glycosidic bond, and has been shown to induce tolerance to a variety of stressors in numerous organisms. In the present study, we investigated the effect of trehalose on cerebral vasospasm, inflammatory responses, and oxidative stress induced by blood in vitro and in vivo. METHODS: Enzyme immunoassay for eicosanoids, pro-inflammatory cytokines, and endothelin-1, and western blotting analysis for cyclooxygenase-2, inducible nitric oxide synthase, and inhibitor of NF-kappaB were examined in macrophage like cells treated with hemolysate. After treatment with hemolysate and hydrogen peroxide, the levels of lipid peroxide and amounts of arachidonic acid release were also analyzed. Three hours after the onset of experimental SAH, 18 Japanese White rabbits received an injection of saline, trehalose, or maltose into the cisterna magna. Angiographic and histological analyses of the basilar arteries were performed. In a separate study, the femoral arteries from 60 rats were exposed to fresh autologous blood. At 1, 3, 5, 7, 10, and 20 days after treatment, cryosections prepared from the femoral arteries were histologically analyzed. RESULTS: When cells were treated with hemolysate, trehalose inhibited the production of several inflammatory mediators and degradation of the inhibitor of NF-kappaB and also suppressed the lipid peroxidation, the reactive oxygen species-induced arachidonic acid release in vitro. In the rabbit model, trehalose produced an inhibitory effect on vasospasm after the onset of experimental SAH, while maltose had only a moderate effect. When the rat femoral arteries exposed to blood were investigated for 20 days, histological analysis revealed that trehalose suppressed vasospasm, inflammatory response, and lipid peroxidation. CONCLUSIONS: These data suggest that trehalose has suppressive effects on several pathological events after SAH, including vasospasm, inflammatory responses, and lipid peroxidation. Trehalose may be a new therapeutic approach for treatment of complications after SAH. PMID- 22546325 TI - Haemophilus pittmaniae respiratory infection in a patient with siderosis: a case report. AB - INTRODUCTION: Haemophilus pittmaniae was described in 2005 as a new species distantly related to Haemophilus parainfluenzae. This member of the human saliva microbiota has also been further isolated from various body fluids without formal description of the patients. CASE PRESENTATION: We report the case of H. pittmaniae isolate made from a sputum specimen collected from a 58-year-old Caucasian man with a massive fibrotic form of siderosis who was awaiting lung transplantation. Identification of the isolate was ascertained by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and 16S rRNA gene sequencing. H. pittmaniae was considered to be responsible for the worsening of the patient's chronic respiratory failure and was successfully treated with oral amoxicillin. CONCLUSION: H. pittmaniae should be regarded as a new pathogen responsible for respiratory tract infection in patients with chronic lung diseases. PMID- 22546327 TI - Power-injectable peripherally inserted central catheters: a step-down access or a real alternative to standard central venous lines? PMID- 22546326 TI - Congenital heart block: evidence for a pathogenic role of maternal autoantibodies. AB - During pregnancy in autoimmune conditions, maternal autoantibodies are transported across the placenta and may affect the developing fetus. Congenital heart block (CHB) is known to associate with the presence of anti-Ro/SSA and anti La/SSB antibodies in the mother and is characterized by a block in signal conduction at the atrioventricular (AV) node. The mortality rate of affected infants is 15% to 30%, and most live-born children require lifelong pacemaker implantation. Despite a well-recognized association with maternal anti-Ro/La antibodies, CHB develops in only 1% to 2% of anti-Ro-positive pregnancies, indicating that other factors are important for establishment of the block. The molecular mechanisms leading to complete AV block are still unclear, and the existing hypotheses fail to explain all aspects of CHB in one comprehensive model. In this review, we discuss the different specificities of maternal autoantibodies that have been implicated in CHB as well as the molecular mechanisms that have been suggested to operate, focusing on the evidence supporting a direct pathogenic role of maternal antibodies. Autoantibodies targeting the 52-kDa component of the Ro antigen remain the antibodies most closely associated with CHB. In vitro experiments and animal models of CHB also point to a major role for anti-Ro52 antibodies in CHB pathogenesis and suggest that these antibodies may directly affect calcium regulation in the fetal heart, leading to disturbances in signal conduction or electrogenesis or both. In addition, maternal antibody deposits are found in the heart of fetuses dying of CHB and are thought to contribute to an inflammatory reaction that eventually induces fibrosis and calcification of the AV node, leading to a complete block. Considering that CHB has a recurrence rate of 12% to 20% despite persisting maternal autoantibodies, it has long been clear that maternal autoantibodies are not sufficient for the establishment of a complete CHB, and efforts have been made to identify additional risk factors for this disorder. Therefore, recent studies looking at the influence of genetic and environmental factors will also be discussed. PMID- 22546328 TI - Relationships between otoacoustic emissions and a proxy measure of cochlear length derived from the auditory brainstem response. AB - Brief tones of 1.0 and 8.0 kHz were used to evoke auditory brainstem responses (ABRs), and the differences between the wave-V latencies for those two frequencies were used as a proxy for cochlear length. The tone bursts (8 ms in duration including 2-ms rise/fall times, and 82 dB in level) were, or were not, accompanied by a continuous, moderately intense noise band, highpass filtered immediately above the tone. The proxy values for length were compared with various measures of otoacoustic emissions (OAEs) obtained from the same ears. All the correlations were low, suggesting that cochlear length, as measured by this proxy at least, is not strongly related to the various group and individual differences that exist in OAEs. Female latencies did not differ across the menstrual cycle, and the proxy length measure exhibited no sex difference (either for menses females vs. males or midluteal females vs. males) when the highpass noises were used. However, when the subjects were partitioned into Whites and Non Whites, a substantial sex difference in cochlear length did emerge for the White group, although the correlations with OAEs remained low. Head size was not highly correlated with any of the ABR measures. PMID- 22546329 TI - RNA-based vaccines. AB - Nucleic acid vaccines consisting of plasmid DNA, viral vectors or RNA may change the way the next generation vaccines are produced, as they have the potential to combine the benefits of live-attenuated vaccines, without the complications often associated with live-attenuated vaccine safety and manufacturing. Over the past two decades, numerous clinical trials of plasmid DNA and viral vector-based vaccines have shown them to be safe, well-tolerated and immunogenic. Yet, sufficient potency for general utility in humans has remained elusive for DNA vaccines and the feasibility of repeated use of viral vectors has been compromised by anti-vector immunity. RNA vaccines, including those based on mRNA and self-amplifying RNA replicons, have the potential to overcome the limitations of plasmid DNA and viral vectors. Possible drawbacks related to the cost and feasibility of manufacturing RNA vaccines are being addressed, increasing the likelihood that RNA-based vaccines will be commercially viable. Proof of concept for RNA vaccines has been demonstrated in humans and the prospects for further development into commercial products are very encouraging. PMID- 22546330 TI - Invasive Escherichia coli vaccines expressing Brucella melitensis outer membrane proteins 31 or 16 or periplasmic protein BP26 confer protection in mice challenged with B. melitensis. AB - Because of the serious economic and medical consequences of brucellosis, efforts are to prevent infection of domestic animals through vaccines. Many disadvantages are associated with the current Brucella melitensis Rev.1 vaccine prompting development of alternative vaccines and delivery. Escherichia coli (DH5alpha) was engineered to express a plasmid containing the inv gene from Yersinia pseudotuberculosis and the hly gene from Listeria monocytogenes. These recombinant invasive E. coli expressing B. melitensis outer membrane proteins (Omp31 or 16) or the periplasmic protein BP26 were evaluated for protection of mice against virulent B. melitensis. Importantly, these invasive E. coli vaccines induced significant protection against B. melitensis challenged mice. Invasive E. coli may be an ideal vaccine platform with natural adjuvant properties for application against B. melitensis since the E. coli delivery system is non pathogenic and can deliver antigens to antigen-presenting cells promoting cellular immune responses. PMID- 22546331 TI - Public perspectives on consent for the linkage of data to evaluate vaccine safety. AB - INTRODUCTION: We sought community opinion on consent alternatives when linking childhood immunisation and hospital attendance records for the purpose of vaccine safety surveillance. METHODS: We conducted computer-assisted telephone interviewing (CATI) of a sample of rural and metropolitan residents of South Australia in 2011. RESULTS: Of 2002 households interviewed (response rate 55.6%), 96.4% supported data linkage for postmarketing surveillance of vaccines; very few were completely opposed (1.5%) or undecided (2.2%). The majority (75.3%) trusted the privacy protections used in data linkage and most wished to have minimal or no direct involvement, preferring either opt-out consent (40.4%) or no consent (30.6%). A quarter of respondents (24.6%) favoured opt-in consent, but their preferences were divergent; half requested consent be sought prior to every use (11.4%) while the remainder preferred to give broad consent just once (3.4%) or renewed at periodic intervals (9.8%). Over half of the respondents gave higher priority to rapid vaccine safety surveillance (56.5%) rather than first seeking parental consent (26.6%) and one in seven was undecided (14.5%). Although 91.6% of respondents believed childhood vaccines are safe, over half (53.1%) were very or somewhat concerned that a vaccine could cause a serious reaction. Nevertheless, 92.4% of the parents in the sample (556/601) reported every child in their care as being fully immunised according to the National Immunisation Program schedule. Only 3.7% of parents (22/601) reported one or more children as under immunised, and 3.9% (23/601) reported that none of their children were immunised. CONCLUSIONS: This survey demonstrates that data linkage for vaccine safety surveillance has substantial community support and that a system utilising opt-out consent or no consent was preferred to one using opt-in consent. These findings should inform public health policy and practice; data linkage should be established where feasible to address limitations in passive surveillance systems. PMID- 22546332 TI - Indirect, out-of-pocket and medical costs from influenza-related illness in young children. AB - BACKGROUND: Studies have documented direct medical costs of influenza-related illness in young children, however little is known about the out-of-pocket and indirect costs (e.g., missed work time) incurred by caregivers of children with medically attended influenza. OBJECTIVE: To determine the indirect, out-of-pocket (OOP), and direct medical costs of laboratory-confirmed medically attended influenza illness among young children. METHODS: Using a population-based surveillance network, we evaluated a representative group of children aged <5 years with laboratory-confirmed, medically attended influenza during the 2003 2004 season. Children hospitalized or seen in emergency department (ED) or outpatient settings in surveillance counties with laboratory-confirmed influenza were identified and data were collected from medical records, accounting databases, and follow-up interviews with caregivers. Outcome measures included work time missed, OOP expenses (e.g., over-the-counter medicines, travel expenses), and direct medical costs. Costs were estimated (in 2009 US Dollars) and comparisons were made among children with and without high risk conditions for influenza-related complications. RESULTS: Data were obtained from 67 inpatients, 121 ED patients and 92 outpatients with laboratory-confirmed influenza. Caregivers of hospitalized children missed an average of 73 work hours (estimated cost $1456); caregivers of children seen in the ED and outpatient clinics missed 19 ($383) and 11 work hours ($222), respectively. Average OOP expenses were $178, $125 and $52 for inpatients, ED-patients and outpatients, respectively. OOP and indirect costs were similar between those with and without high risk conditions (p>0.10). Medical costs totaled $3990 for inpatients and $730 for ED-patients. CONCLUSIONS: Out-of-pocket and indirect costs of laboratory confirmed and medically attended influenza in young children are substantial and support the benefits of vaccination. PMID- 22546333 TI - Long-term 24-h levodopa/carbidopa gel infusion in Parkinson's disease. PMID- 22546334 TI - Actigraphic study of tremor before and after treatment with zonisamide in patients with Parkinson's disease. PMID- 22546335 TI - Inwardly rectifying potassium channel Kir4.1 is localized at the calyx endings of vestibular afferents. AB - Inwardly rectifying potassium (Kir) channel Kir4.1 (also called Kcnj10) is expressed in various cells such as satellite glial cells. It is suggested that these cells would absorb excess accumulated K(+) from intercellular space which is surrounded by these cell membranes expressing Kir4.1. In the vestibular system, loss of Kir4.1 results in selective degeneration of type I hair cells despite normal development of type II hair cells. The mechanisms underlying this developmental disorder have been unclear, because it was thought that Kir4.1 is only expressed in glial cells throughout the entire nervous system. Here, we show that Kir4.1 is expressed not only in glial cells but also in neurons of the mouse vestibular system. In the vestibular ganglion, Kir4.1 mRNA is transcribed in both satellite cells and neuronal somata, whereas Kir4.1 protein is expressed only in satellite cells. On the other hand, in the vestibular sensory epithelia, Kir4.1 protein is localized at the calyx endings of vestibular afferents, which surround type I hair cells. Kir4.1 protein expression in the vestibular sensory epithelia is detected beginning after birth, and its localization gradually adopts a calyceal shape until type I hair cells are mature. Kir4.1 localized at the calyx endings may play a role in the K(+)-buffering action of vestibular afferents surrounding type I hair cells. PMID- 22546336 TI - Early and late activity in somatosensory cortex reflects changes in bodily self consciousness: an evoked potential study. AB - How can we investigate the brain mechanisms underlying self-consciousness? Recent behavioural studies on multisensory bodily perception have shown that multisensory conflicts can alter bodily self-consciousness such as in the "full body illusion" (FBI) in which changes in self-identification with a virtual body and tactile perception are induced. Here we investigated whether experimental changes in self-identification during the FBI are accompanied by activity changes in somatosensory cortex by recording somatosensory-evoked potentials (SEPs). To modulate self-identification, participants were filmed by a video camera from behind while their backs were stroked, either synchronously (illusion condition) or asynchronously (control condition) with respect to the stroking seen on their virtual body. Tibial nerve SEPs were recorded during the FBI and analysed using evoked potential (EP) mapping. Tactile mislocalisation was measured using the crossmodal congruency task. SEP mapping revealed five sequential periods of brain activation during the FBI, of which two differed between the illusion condition and the control condition. Activation at 30-50 ms (corresponding to the P40 component) in primary somatosensory cortex was stronger in the illusion condition. A later activation at ~110-200 ms, likely originating in higher-tier somatosensory regions in parietal cortex, was stronger and lasted longer in the control condition. These data show that changes in bodily self-consciousness modulate activity in primary and higher-tier somatosensory cortex at two distinct processing steps. We argue that early modulations of primary somatosensory cortex may be a consequence of (1) multisensory integration of synchronous vs. asynchronous visuo-tactile stimuli and/or (2) differences in spatial attention (to near or far space) between the conditions. The later activation in higher tier parietal cortex (and potentially other regions in temporo-parietal and frontal cortex) likely reflects the detection of visuo-tactile conflicts in the asynchronous condition. PMID- 22546338 TI - High frequency stimulation alters motor maps, impairs skilled reaching performance and is accompanied by an upregulation of specific GABA, glutamate and NMDA receptor subunits. AB - High frequency stimulation (HFS) has the potential to interfere with learning and memory. HFS and motor skill training both lead to potentiation of the stimulated network and alter motor map expression. However, the extent to which HFS can interfere with the learning and performance of a skilled motor task and the resulting effect on the representation of movement has not been examined. Moreover, the molecular mechanisms associated with HFS and skilled motor training on the motor cortex are not known. We hypothesized that HFS would impair performance on a skilled reaching task, and would be associated with alterations in motor map expression and protein levels compared to non-stimulated and untrained controls. Long Evans Hooded rats were chronically implanted with stimulating and recording electrodes in the corpus callosum and frontal neocortex, respectively. High frequency theta burst stimulation or sham stimulation was applied once daily for 20 sessions. The rats were divided into five groups: control, HFS and assessed at 1 week post stimulation, HFS and assessed 3 weeks post stimulation, reach trained, and HFS and reach trained. A subset of rats from each group was assessed with either intracortical microstimulation (ICMS) to examine motor map expression or Western blot techniques to determine protein expression of several excitatory and inhibitory receptor subunits. Firstly, we found that HFS resulted in larger and reorganized motor maps, and lower movement thresholds compared to controls. This was associated with an up-regulation of the GABA(A)alpha1 and NR1 receptor subunits 3 weeks after the last stimulation session only. Stimulation affected skilled reaching performance in a subset of all stimulated rats. Rats that were poor performers had larger rostral forelimb areas, higher proximal and lower distal movement thresholds compared to rats that were good performers after stimulation. Reach training alone was associated with an up-regulation of GABA(A)alpha1, alpha2, GluR2, NR1 and NR2A compared to controls. HFS and reach-trained rats showed an up-regulation of GABA(A)alpha2 compared to stimulated rats that were not reach-trained. Therefore, we have shown that HFS induces significant plasticity in the motor cortex, and has the potential to disrupt performance on a skilled motor task. PMID- 22546339 TI - Evolutionary and comparative aspects of nitric oxide, carbon monoxide and hydrogen sulfide. AB - The concept that non-respiratory gases, such as nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H(2)S) functioned as signaling moieties is a relatively recent development, due in part to their ephemeral existence in biological tissues. However, from an evolutionary perspective these gases dominated the prebiotic and anoxic Earth and were major contributors to the origin of life and the advent of eukaryotic animals. As Earth's oxygen levels rose, NO, CO and H(2)S disappeared from the environment and cells began to utilize their now well-developed metabolic pathways to compartmentalize and regulate these three gases for signaling purposes. Ironically, many of the signaling pathways have become now intimately involved in regulating oxygen delivery and their evolution has continued well into the vertebrates. This review examines the role NO, CO and H(2)S played in early life and their regulatory roles in oxygen delivery during the course of vertebrate evolution. PMID- 22546340 TI - Asthmatic cough and airway oxidative stress. AB - The mechanisms of cough in asthma are unclear. Asthma is associated with an oxidative stress. Many reactive oxygen species sensitize or activate sensory C fibers which are capable to induce cough. It was hypothesized that oxidative stress in the airways might contribute to the cough severity in asthma. Exhaled breath condensate samples were collected in ten healthy and 26 asthmatic subjects. The concentration of 8-isoprostane was measured. In addition, the subjects filled in Leicester Cough Questionnaire and underwent cough provocation tests with dry air hyperpnoea and hypertonic saline, among other measurements. Among the asthmatic subjects, high 8-isoprostane was associated with severe cough response to hyperpnoea (p=0.001), low Leicester Cough Questionnaire values (indicating severe subjective cough, p=0.02), and usage of combination asthma drugs (p=0.03-0.04). However, the 8-isoprostane concentrations did not differ significantly between the healthy and the asthmatic subjects. Airway oxidative stress may be associated with experienced cough severity and measured cough sensitivity in asthma. PMID- 22546341 TI - Occurrence and characterization of Acanthamoeba similar to genotypes T4, T5, and T2/T6 isolated from environmental sources in Brasilia, Federal District, Brazil. AB - Species of Acanthamoeba can cause keratitis and brain infections. The characterization of environmental isolates is necessary to analyze the risk of human infection. We aimed at identifying and genotyping Acanthamoeba isolates from soil, swimming pools, and water features in Brasilia, Federal District, Brazil, as well as determining their physiological characteristics and pathogenic potential. Among the 18 isolates studied, eight were similar to genotype T5, five to T4, and one to T2/T6, classified by the sequence analysis of 18S rDNA. Genotypes of four isolates were not determined. Ten isolates (55%) grew at 37 degrees C and seven (39%) grew in media with 1.5M mannitol, which are the physiological parameters associated with pathogenic Acanthamoeba; also, four isolates from swimming pools presented high pathogenic potential. Our results indicate a widespread distribution of potentially pathogenic Acanthamoeba T4, T5, and T2/T6 in different environmental sources in Brasilia, revealing the potential risk of human infection and the need of preventive measures. PMID- 22546343 TI - 2H NMR studies of liquid crystal elastomers: macroscopic vs. molecular properties. PMID- 22546342 TI - IgG4-related inflammatory pseudotumor of the central nervous system responsive to mycophenolate mofetil. AB - Orbital apex and skull base masses often present with neuro-ophthalmic signs and symptoms. Though the localization of these syndromes and visualization of the responsible lesion on imaging is typically straightforward, definitive diagnosis usually relies on biopsy. Immunohistochemistry is important for categorization and treatment planning. IgG4-related disease is emerging as a pathologically defined inflammatory process that can occur in multiple organ systems. We present two patients with extensive inflammatory mass lesions of the central nervous system with immunohistochemistry positive for IgG4 and negative for ALK-1 as examples of meningeal based IgG4-related inflammatory pseudotumors. In both patients, there was treatment response to mycophenolate mofetil. PMID- 22546337 TI - Dendritic spine pathology in schizophrenia. AB - Schizophrenia is a neurodevelopmental disorder whose clinical features include impairments in perception, cognition and motivation. These impairments reflect alterations in neuronal circuitry within and across multiple brain regions that are due, at least in part, to deficits in dendritic spines, the site of most excitatory synaptic connections. Dendritic spine alterations have been identified in multiple brain regions in schizophrenia, but are best characterized in layer 3 of the neocortex, where pyramidal cell spine density is lower. These spine deficits appear to arise during development, and thus are likely the result of disturbances in the molecular mechanisms that underlie spine formation, pruning, and/or maintenance. Each of these mechanisms may provide insight into novel therapeutic targets for preventing or repairing the alterations in neural circuitry that mediate the debilitating symptoms of schizophrenia. PMID- 22546344 TI - Field-cycling NMR relaxometry of viscous liquids and polymers. PMID- 22546345 TI - Knockdown of glucose-regulated protein 78 decreases the invasion, metalloproteinase expression and ECM degradation in hepatocellular carcinoma cells. AB - BACKGROUND: We have reported previously that overexpression of glucose-regulated protein 78 (GRP78) promotes the invasion of hepatocellular carcinoma. However, whether GRP78 knockdown affects the extracellular matrix degradation has not been elucidated. Here we are going to determine whether GRP78 knockdown affect the ECM degradation and the role of MMP-2 and MMP-9 in these process in hepatocellular carcinoma cells. METHODS: Human hepatocellular carcinoma cell line SMMC7721 and HepG2 were cultured in DMEM supplemented with 10% FBS, RT-PCR and western blot were used to detect the endogenous expression of GRP78, MMP-2, MMP-9 and TIMP-2 in SMMC7721 and HepG2. GRP78 shRNAs were transfected using lipofection2000. Transwell assay and wound healing assay were used to analyze the invasion of each transfectant. Gelatin zymography and FITC-gelatin degradation assay were employed to investigate the capabilities of ECM degradation of each transfectant. MTT assay was used to determine the proliferation status. Western blot was employed to detect the expression of matrix metalloproteinase 2(MMP-2), MMP-9, MMP-14, and tissue inhibitor of metalloproteinases 2(TIMP-2), focal adhesion kinase (FAK), ERK1/2, JNK and Src. RESULTS: According to the expression levels of GRP78, MMP-2, MMP-9, MMP-14 and TIMP-1 in hepatocellular carcinoma cell lines SMMC7721 and hepG2, we used SMMC7721 as the in vitro invasion model for further functional analysis. Using this model, we found that GRP78 knockdown decreased the invasion of tumor cells, and this inhibitory effect was independent of cell proliferation. In hepatocellular carcinoma cells, Grp78 knockdown inhibited ECM degradation and the decreased activity and expression of MMP-2, but not MMP-9 contributed largely to this impact. Further analysis revealed that the decreased activity and expression of MMP-2 is mediated by JNK. CONCLUSION: Knockdown of GRP78 decreases ECM degradation, and downregulates the expression and activity of MMP-2 and TIMP 2. These results further demonstrate that GRP78 is a potential target for inhibiting the invasion of hepatocellular carcinoma cells. PMID- 22546346 TI - Dexamethasone reduces bilirubin-induced toxicity and IL-8 and MCP-1 release in human NT2-N neurons. AB - The mechanisms of neurotoxicity induced by unconjugated bilirubin (UCB) in newborns are incompletely understood. UCB may cause both necrotic and apoptotic neuronal death. We explored UCB toxicity and release of cytokines in human NT2-N neurons and the effect of dexamethasone on these processes. Cultured NT2-N neurons were exposed to UCB, and neuronal damage was evaluated by LDH release and MTT cleavage. After 96 hours, 2 MUM UCB significantly increased release of IL-8 and MCP-1, but not IL-13, IP-10, PDGF, or VEGF. Dexamethasone significantly lowered the UCB-induced increase in MCP-1 release, and attenuated UCB-induced neuronal damage assessed with MTT cleavage and LDH release. For comparison, the effects of hydrogen peroxide on cytokine formation and neuronal damage were tested. Hydrogen peroxide increased MCP-1, IP-10, and VEGF, but not IL-8, IL-13, or PDGF. Dexamethasone inhibited the hydrogen peroxide-induced increase in MCP-1 and IP-10. We conclude that UCB causes release of IL-8 and MCP-1 in cultured human NT2-N neurons. Dexamethasone reduces UCB-induced cytokine release and protects against UCB-induced toxicity. PMID- 22546347 TI - Rat thalamic alpha4beta2 neuronal nicotinic acetylcholine receptor occupancy assay using LC-MS/MS. AB - INTRODUCTION: In vivo brain receptor occupancy has been the key assay in driving preclinical drug discovery program and there is a need to hasten this screening step. Radiolabeled methods, which are time consuming and expensive, are most widely employed to measure receptor occupancy. Thus we sought to develop and validate an alternative novel approach for measuring rat brain alpha4beta2 neuronal nicotinic acetylcholine receptor occupancy using high performance liquid chromatography combined with tandem mass spectrometric detector (LC-MS/MS). METHODS: Tracer optimization studies like in vivo dose and time dependent brain regional distribution; saturation binding and blocking study with nicotine and atropine were carried out for ZW-104 in rats. Assay validity was tested by pretreatment with potent alpha4beta2 ligands; TC-1734, cytisine, ABT-089, ABT-594 and A-366833. Receptor occupancy along with plasma and brain exposure levels of alpha4beta2 ligand was measured in the same set of animals. RESULTS: The regional distribution of ZW-104 in rat was found to be, thalamus>frontal cortex>striatum>hippocampus>cerebellum, and is in accordance with the distribution and regional densities of alpha4beta2 nAChRs measured using [18F]ZW 104 in mice and baboons. Pretreatment with nicotine and alpha4beta2 ligands dose dependently reduced the binding of ZW-104 in the thalamus. Non-nicotinic antagonist atropine did not alter the binding of ZW-104 in the thalamus, indicating the tracer specificity. The ED50 values calculated for occupancy were found to be 3.01, 0.83, 14.81, 0.001 and 0.11 mg/kg for TC-1734, cytisine, ABT 089, ABT-594, and A-366833, respectively. DISCUSSION: These findings demonstrate that non-radiolabeled ZW-104 is suitable for determining the alpha4beta2 receptor occupancy in rat brain. The LC-MS/MS based receptor occupancy assay is a rapid method and allows the generation of occupancy data along with the brain and plasma concentration in the same group of animals. PMID- 22546348 TI - B12Hn and B12Fn: planar vs icosahedral structures. AB - Using density functional theory and quantum Monte Carlo calculations, we show that B12Hn and B12Fn (n = 0 to 4) quasi-planar structures are energetically more favorable than the corresponding icosahedral clusters. Moreover, we show that the fully planar B12F6 cluster is more stable than the three-dimensional counterpart. These results open up the possibility of designing larger boron-based nanostructures starting from quasi-planar or fully planar building blocks. PMID- 22546349 TI - Diversity of use and local knowledge of wild edible plant resources in Nepal. AB - BACKGROUND: Wild edible plants (WEP) provide staple and supplement foods, as well as cash income to local communities, thus favouring food security. However, WEP are largely ignored in land use planning and implementation, economic development, and biodiversity conservation. Moreover, WEP-related traditional knowledge is rapidly eroding. Therefore, we designed this study to fulfill a part of the knowledge gap by providing data on diversity, traditional knowledge, economic potential, and conservation value of WEP from Nepal. METHODS: The information was collected through focus group discussions and key informant interviews. Percentage of general utility of the plants among the study communities was evaluated using the Chi-square (chi(2)) test of homogeneity. High priority species were identified after consultation with the local stakeholders followed by scoring based on defined criteria. Pairwise ranking was used to assess ethnoecological knowledge to identify the threats to WEP. RESULTS: We documented 81 species belonging to Angiosperms (74), Pteridophytes (5), and Fungi (2). Most of the species were used as fruits (44 species) followed by vegetables (36). Almost half of the species (47%) were also used for purposes other than food. From the species with market value (37% of the total), 10 were identified as high priority species. Pairwise ranking revealed that WEP are threatened mostly by habitat destruction, land-use change and over-harvesting. Some of these plants are crop wild relatives and could thus be used for crop improvement. Interestingly, our study also revealed that young people who spend most of the time in the forest as herdsmen are particularly knowledgeable of wild fruit plants. CONCLUSION: We provide empirical evidence from a relatively large area of Nepal about diversity and status of WEP, as well as methodological insights about the proper knowledge holders to consult. Regarding the unique and important knowledge they have on WEP, young people should be included when recruiting participants to ethnobotanical studies or to any type of consultation about WEP. The habit of using wild edible plants is still alive and is a traditional culinary practice that demonstrates rich traditional knowledge of local people. WEP were found to be important for livelihood as well as showing great potential for crop improvement. Priority species should be promoted for income generation activities through sustainable collection and trade. Communities should engage in minimizing the threats to these valuable resources. PMID- 22546351 TI - An investigation of PreMCI: subtypes and longitudinal outcomes. AB - BACKGROUND/AIMS: To investigate the clinical features and rates of progression of conditions that are not considered to be normal, but do not fulfill criteria for mild cognitive impairment (MCI). METHODS: We longitudinally evaluated 269 elderly subjects who did not meet formal criteria for MCI at baseline but had: (1) a clinical history suggesting MCI without neuropsychological deficits (PreMCI Clinical); or (2) neuropsychological deficits on one or more memory measures in conjunction with a negative clinical examination (amnestic PreMCI-NP) or were normal on both neuropsychological and clinical examination. RESULTS: The rate of progression to MCI or dementia over an average of 2- to 3 years was 3.7% for no cognitive impairment subjects, whereas it was significantly greater for all PreMCI subtypes (22.0% for PreMCI-Clinical, 38.9% for amnestic PreMCI-NP subjects with two or more memory impairments). Among PreMCI subjects as a whole, lower baseline scores on object memory and category fluency tests were the best predictors of progression to MCI or dementia. Cardiovascular risk factors, Parkinsonian symptoms, and hippocampal atrophy were not associated with progression. CONCLUSION: Distinct PreMCI subtypes defined on the basis of clinical and neuropsychological evaluations were found to have distinct characteristics, but both subtypes demonstrated elevated risk for progression to MCI or dementia. Despite the lack of evidence of clinical impairment, subjects with neuropsychological deficits in two memory domains were particularly at increased risk for progression of their deficits. PMID- 22546352 TI - Serum antibodies to periodontal pathogens are a risk factor for Alzheimer's disease. AB - BACKGROUND: Chronic inflammation in periodontal disease has been suggested as a potential risk factor in Alzheimer's disease (AD). The purpose of this study was to examine serum antibody levels to bacteria of periodontal disease in participants who eventually converted to AD compared with the antibody levels in control subjects. METHODS: Serum samples from 158 participants in the Biologically Resilient Adults in Neurological Studies research program at the University of Kentucky were analyzed for immunoglobulin G antibody levels to seven oral bacteria associated with periodontitis, including Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Campylobacter rectus, Treponema denticola, Fusobacterium nucleatum, Tannerella forsythia, and Prevotella intermedia. All 158 participants were cognitively intact at baseline venous blood draw. In all, 81 of the participants developed either mild cognitive impairment (MCI) or AD or both, and 77 controls remained cognitively intact in the years of follow-up. Antibody levels were compared between controls and subjects with AD at baseline draw and after conversion and controls and subjects with MCI at baseline draw and after conversion using the Wilcoxon rank-sum test. AD and MCI participants were not directly compared. Linear regression models were used to adjust for potential confounding. RESULTS: Antibody levels to F nucleatum and P intermedia were significantly increased (alpha = 0.05) at baseline serum draw in the patients with AD compared with controls. These results remained significant when controlling for baseline age, Mini-Mental State Examination score, and apolipoprotein epsilon 4 status. CONCLUSIONS: This study provides initial data that demonstrate elevated antibodies to periodontal disease bacteria in subjects years before cognitive impairment and suggests that periodontal disease could potentially contribute to the risk of AD onset/progression. Additional cohort studies profiling oral clinical presentation with systemic response and AD and prospective studies to evaluate any cause-and-effect association are warranted. PMID- 22546353 TI - Cognitive and structural magnetic resonance imaging features of Lewy body dementia and Alzheimer's disease. AB - OBJECTIVE: To assess medial temporal atrophy (MTA) and atrophy adjacent to the third ventricle (Peri-IIIVent) on brain magnetic resonance images as biomarkers for the diagnosis of Alzheimer's disease (AD) and Lewy body dementia (LBD), and to assess the relationship between biomarkers and clinical and functional measures. METHODS: Subjects diagnosed with no cognitive impairment (n = 30), AD (n = 30), or LBD (n = 31) were evaluated with the Mini-Mental State Examination, Multiple Delayed Recall Test, Category Fluency Test, Clinical Dementia Rating Sum of Boxes score, Functional Assessment Questionnaire, and the Unified Parkinson's Disease Rating Scale. A validated visual rating system was used to rate MTA, and volumetric studies were performed to measure total intracranial and hippocampal volumes. Additionally, linear measurements of third ventricle width, Peri-IIIVent height, and Peri-IIIVent width were performed. RESULTS: Subjects with AD and those with LBD were equivalent with respect to age and levels of cognitive impairment. Atrophy in medial temporal and Peri-IIIVent regions was greater among both patients with AD and those with LBD compared with subjects with no cognitive impairment. The best discriminators of AD from LBD were the severity of MTA, using visual rating, and the severity of memory impairment. Only subjects with LBD showed significant correlations between Unified Parkinson's Disease Rating Scale scores and Peri-IIIVent atrophy measures. CONCLUSIONS: Mild AD could be distinguished from mild LBD by the severity of MTA and memory impairment. The severity of parkinsonism was associated with the severity of atrophy in the third ventricular region, but was not a good discriminator between AD and LBD. PMID- 22546354 TI - Nonsteroidal anti-inflammatory drug use and the risk of cognitive impairment and Alzheimer's disease. AB - BACKGROUND: Some observational studies have established an association between exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) and a decreased risk of subsequently developing Alzheimer's disease (AD). Mild cognitive impairment or cognitive impairment, not dementia (CIND) is more likely to convert to AD, and no specific preventive method is currently available. The objective of this study was to determine the association of NSAID use in 5276 cognitively normal subjects of the Canadian Study of Health and Aging, a 10-year population-based cohort study, with the incidence of CIND, AD, and all-cause dementia. METHODS: Hazard ratios were calculated from Cox proportional hazards models with age as the time scale according to three study samples including 824 cases of dementia (563 cases of AD), 630 cases of dementia (435 cases of AD), and 883 cases of CIND, respectively. Adjustments were made for gender, education, lifestyle factors, comorbid diseases, and vascular risk factors. RESULTS: Lower risks for AD and all cause dementia were significantly associated with the use of any NSAIDs and the salicylates without barbiturates subgroup in the study sample including subjects with CIND at baseline. There was a weak association between any NSAIDs and the risk of CIND (hazard ratio, 0.87; 95% confidence interval, 0.76-1.00). CONCLUSION: These results suggest that there is an association between NSAID use and a lower incidence of AD and, to a lesser extent, of CIND. PMID- 22546355 TI - The draft "National Plan" to address Alzheimer's disease - National Alzheimer's Project Act (NAPA). AB - This perspective updates the status of the "National Plan to Address Alzheimer's Disease" and the recommendations of the NAPA Advisory Council's Sub-committee on Research. Here, we identify some of the critical issues the future reiterations of the National Plan should consider during implementation phase of the plan. The Journal invites the scientific community to contribute additional ideas and suggestions towards a national research initiative. PMID- 22546356 TI - The epidemiology of Alzheimer's disease: laying the foundation for drug design, conduct, and analysis of clinical trials. AB - Epidemiological studies increasingly inform Alzheimer's disease (AD) public health impact, prevention strategies, drug targets, therapeutic interventions, and clinical trial design. For this reason, the Alzheimer's Association Research Roundtable convened an international group of AD experts with experience in conducting both observational and clinical trials for a meeting on October 19 and 20, 2010, in Washington, DC, to discuss the role of epidemiologic studies in AD research and therapeutic advances. Topics included wellness markers and risk factors, with a focus on special populations such as those at elevated risk, super agers, and underserved populations. Discussions also highlighted lessons learned from observational studies of aging, cardiovascular disease, and other disease areas, as well as how new technologies have enabled the gathering of data relevant to drug development and clinical trial conduct. PMID- 22546358 TI - Networks of polysaccharides with hydrophilic and hydrophobic characteristics in the presence of co-solute. AB - The present investigation deals with the changing network morphology of agarose and high methoxy pectin when mixed with polydextrose as co-solute at concentrations varying up to high level of solids. Thermomechanical analysis and micro-imaging were performed using small deformation dynamic oscillation in shear, modulated differential scanning calorimetry and environment scanning electron microscopy. Fourier transform infrared spectroscopy and wide angle X-ray diffraction were practised to examine the nature of interactions between polymer and co-solute, and the extent of amorphicity of preparations. We observed a decline in the mechanical strength of aqueous agarose preparations upon addition of high levels of polydextrose, which should be attributed to reduced enthalpic content of the coil-to-helix transition of the polysaccharide network. Glass transition phenomena were observed at subzero temperatures in condensed preparations, hence further arguing for the formation of a lightly cross-linked agarose network with changing solvent quality. High levels of co-solute induce formation of weak pectin gels at elevated temperatures (even at 95 degrees C), which with lowering temperature exhibit increasing strength. This results in the formation of rubbery pectin gels at ambient temperature, which upon controlled cooling to subzero temperatures convert to a clear glass earlier than the agarose counterparts. PMID- 22546357 TI - Applications of metabolomics for understanding the action of peroxisome proliferator-activated receptors (PPARs) in diabetes, obesity and cancer. AB - The peroxisome proliferator-activated receptors (PPARs) are a set of three nuclear hormone receptors that together play a key role in regulating metabolism, particularly the switch between the fed and fasted state and the metabolic pathways involving fatty-acid oxidation and lipid metabolism. In addition, they have a number of important developmental and regulatory roles outside metabolism. The PPARs are also potent targets for treating type II diabetes, dyslipidemia and obesity, although a number of individual agonists have also been linked to unwanted side effects, and there is a complex relationship between the PPARs and the development of cancer. This review examines the part that metabolomics, including lipidomics, has played in elucidating the roles PPARs have in regulating systemic metabolism, as well as their role in aspects of drug-induced cancer and xenobiotic metabolism. These studies have defined the role PPARdelta plays in regulating fatty-acid oxidation in adipose tissue and the interaction between aging and PPARalpha in the liver. The potential translational benefits of these approaches include widening the role of PPAR agonists and improved monitoring of drug efficacy. PMID- 22546359 TI - Effects of macromolecular crowding on refolding of recombinant human brain-type creatine kinase. AB - In this study, we quantitatively measured the effects of the macromolecular crowding agents, polyethylene glycol 2000 (PEG 2000), dextran 70, and calf thymus DNA (CT DNA), on the refolding and aggregation of recombinant human brain-type creatine kinase (rHBCK) denatured by guanidine hydrochloride (GdnHCl). The results showed that there is more aggregation in the presence of either a single crowding agent or in a mixture of crowding agents than in the absence of crowding agents, especially in the presence of a mixture containing CT DNA and PEG 2000 (or dextran 70). In the presence of high concentrations of PEG 2000 (100 g/L), dextran 70 (100 g/L), and CT DNA (15 g/L), the refolding yield remarkably decreased from 70% to 20%, 52% and 57%, respectively. A remarkable decrease in the refolding yield and rate with mixed crowding agent containing CT DNA and PEG 2000 (or dextran 70) was also observed. In comparison to refolding in the presence of 100 g/L PEG 2000, the refolding yields and rates improved in the presence of a mixture of PEG 2000 and dextran 70. We speculate that the crowding agents can favor both correct folding and misfolding/aggregation of denatured rHBCK. Though it is not known what combination of crowding agents most accurately reflects the physiological environment within a cell, we believe our study could contribute to the understanding of protein folding and the factors that contribute to proper conformation and function in the intracellular environment. PMID- 22546360 TI - Isolation and identification of chitin in the black coral Parantipathes larix (Anthozoa: Cnidaria). AB - Until now, there is a lack of knowledge about the presence of chitin in numerous representatives of corals (Cnidaria). However, investigations concerning the chitin-based skeletal organization in different coral taxa are significant from biochemical, structural, developmental, ecological and evolutionary points of view. In this paper, we present a thorough screening for the presence of chitin within the skeletal formations of a poorly investigated Mediterranean black coral, Parantipathes larix (Esper, 1792), as a typical representative of the Schizopathidae family. Using a wide array variety of techniques ((13)C solid state NMR, Fourier transform infrared (FTIR), Raman, NEXAFS, Morgan-Elson assay and Calcofluor White Staining), we unambiguously show for the first time that chitin is an important component within the skeletal stalks as well as pinnules of this coral. PMID- 22546361 TI - Between-day reliability of a method for non-invasive estimation of muscle composition. AB - Tensiomyography is a method for valid and non-invasive estimation of skeletal muscle fibre type composition. The validity of selected temporal tensiomyographic measures has been well established recently; there is, however, no evidence regarding the method's between-day reliability. Therefore it is the aim of this paper to establish the between-day repeatability of tensiomyographic measures in three skeletal muscles. For three consecutive days, 10 healthy male volunteers (mean+/-SD: age 24.6 +/- 3.0 years; height 177.9 +/- 3.9 cm; weight 72.4 +/- 5.2 kg) were examined in a supine position. Four temporal measures (delay, contraction, sustain, and half-relaxation time) and maximal amplitude were extracted from the displacement-time tensiomyogram. A reliability analysis was performed with calculations of bias, random error, coefficient of variation (CV), standard error of measurement, and intra-class correlation coefficient (ICC) with a 95% confidence interval. An analysis of ICC demonstrated excellent agreement (ICC were over 0.94 in 14 out of 15 tested parameters). However, lower CV was observed in half-relaxation time, presumably because of the specifics of the parameter definition itself. These data indicate that for the three muscles tested, tensiomyographic measurements were reproducible across consecutive test days. Furthermore, we indicated the most possible origin of the lowest reliability detected in half-relaxation time. PMID- 22546363 TI - Accelerometers for ECT seizures? PMID- 22546362 TI - Role of non-immune mechanisms of muscle damage in idiopathic inflammatory myopathies. AB - Idiopathic inflammatory myopathies (IIMs) comprise a group of autoimmune diseases that are characterized by symmetrical skeletal muscle weakness and muscle inflammation with no known cause. Like other autoimmune diseases, IIMs are treated with either glucocorticoids or immunosuppressive drugs. However, many patients with an IIM are frequently resistant to immunosuppressive treatments, and there is compelling evidence to indicate that not only adaptive immune but also several non-immune mechanisms play a role in the pathogenesis of these disorders. Here, we focus on some of the evidence related to pathologic mechanisms, such as the innate immune response, endoplasmic reticulum stress, non immune consequences of MHC class I overexpression, metabolic disturbances, and hypoxia. These mechanisms may explain how IIM-related pathologic processes can continue even in the face of immunosuppressive therapies. These data indicate that therapeutic strategies in IIMs should be directed at both immune and non immune mechanisms of muscle damage. PMID- 22546364 TI - Age and obesity-associated changes in the expression and activation of components of the AMPK signaling pathway in human right atrial tissue. AB - BACKGROUND: Obesity is associated with an increased incidence of left ventricular hypertrophy, diastolic dysfunction, heart failure, and premature cardiac aging. In the heart, intrinsic activation of the AMP-dependent protein kinase (AMPK) plays a pivotal role in the stress response to ischemia and hypertrophy. Furthermore, AMPK is an important regulator of cardiac mitochondrial biogenesis. The purpose of the present study was to investigate the influence of obesity and aging on the AMPK signaling pathway in human cardiac tissue. METHODS: 60 male cardiac surgery patients were included in the study and divided into 4 groups (old normal weight: ON; old obese: OO; young normal weight: YN, young obese: YO) according to their body mass index (18.5-25: normal weight or 30-35: obese) and age (<55 years: young or >70: old) with 15 patients each. Right atrial tissue (RA) was analyzed for the expression of the AMPK upstream kinases CAMKK and LKB1, activation of AMPK as well as phosphorylation of the AMPK downstream targets ACC, eEF2, mTOR and eNOS. Epicardial adipose tissue was analyzed for the expression of the endogenous AMPK activator adiponectin. The metabolic state of all patients was further characterized in fasting blood samples. RESULTS: Old patients (ON, OO) and young obese (YO) subjects displayed higher fasting glucose, insulin and leptin serum levels compared to the young, normal weight group, although HbA1c was below the threshold required for the diagnosis of type 2 diabetes. Serum adiponectin as well as total adiponectin protein expression in epicardial adipose tissue was decreased in these three groups. Analyses of adiponectin isoforms by native gel electrophoresis revealed significant differences in the high molecular weight (HMW) isoforms between the groups. Despite the low total serum adiponectin and HMW adiponectin, AMPK activation was high in the RA of obese patients (YO, OO). Among the AMPK upstream kinases, LKB1 expression showed a strong positive correlation with AMPK activation. While the phosphorylation of the AMPK downstream targets mTOR, eEF-2 and ACC was not altered, phospho-eNOS was significantly lower in old patients (ON, OO). Despite strong AMPK activation, mitochondrial biogenesis and respiration were impaired in old (ON, OO) and young obese (YO) subjects. CONCLUSION: These data indicate that obesity and aging result in significant changes although many direct parameters in the AMPK signaling pathway are not changed in the same direction. LKB1 may represent a stronger activator of the AMPK pathway than adiponectin or the CAMKKs in human right atrial tissue. PMID- 22546365 TI - Effects of orally administered antioxidants on micronuclei and sister chromatid exchange frequency in workers professionally exposed to antineoplastic agents. AB - The widespread use of antineoplastic drugs in cancer treatment increased concern about possible hazard to workers involved in the preparation and administration of these drugs. In the present study, the effects of commercial antioxidative drug Oligogal Se on genome protection were analyzed in 15 nurses handling the antineoplastic drugs at the Oncology Department in comparison to twenty healthy volunteers. The nurses took antioxidant mixture Oligogal Se, consisting of vitamins C, E, A and selenium, one capsule per day, over a period of 6 months. Genome damage was measured in peripheral blood lymphocytes by usage of sister chromatid exchange test and the cytokinesis-block micronuclei test. The frequency of sister chromatid exchange (SCE) and micronuclei (MN) in the exposed group was significantly higher when compared to the control group (SCE, p<0.05; MN, p<0.01 respectively). After antioxidant supplementation, the frequency of sister chromatid exchange and micronuclei decreased (p<0.05) when compared with the values from the beginning of the study, but were still above the values of the control group. The effects of confounding factors such as cigarette smoking and cytostatics exposure time were also evaluated. The data indicated that Oligogal Se contributed to the decreasing of genome damages in workers handling the cytostatics. PMID- 22546366 TI - Major and minor arsenic compounds accounting for the total urinary excretion of arsenic following intake of blue mussels (Mytilus edulis): a controlled human study. AB - Blue mussels (Mytilus edulis) accumulate and biotransform arsenic (As) to a larger variety of arsenicals than most seafood. Eight volunteers ingested a test meal consisting of 150 g blue mussel (680 MUg As), followed by 72 h with an identical, low As controlled diet and full urine sampling. We provide a complete speciation, with individual patterns, of urinary As excretion. Total As (tAs) urinary excretion was 328 +/- 47 MUg, whereof arsenobetaine (AB) and dimethylarsinate (DMA) accounted for 66% and 21%, respectively. Fifteen minor urinary arsenicals were quantified with inductively coupled plasma mass spectrometry (ICPMS) coupled to reverse-phase, anion and cation-exchange high performance liquid chromatography (HPLC). Thio-arsenicals and non-thio minor arsenicals (including inorganic As (iAs) and methylarsonate (MA)) contributed 10% and 7% of the total sum of species excretion, respectively, but there were large individual differences in the excretion patterns. Apparently, formation of thio arsenicals was negatively correlated to AB formation and excretion, possibly indicating a metabolic interrelationship. The results may be of toxicological relevance since DMA and MA have been classified as possibly carcinogenic, and six of the excreted As species were thio-arsenicals which recently have been recognized as toxic, while iAs toxicity is well known. PMID- 22546367 TI - Chemical compositions and properties of Schinus areira L. essential oil on airway inflammation and cardiovascular system of mice and rabbits. AB - The main purpose was to investigate the effects of essential plant-oil of Schinus areira L. on hemodynamic functions in rabbits, as well as myocardial contractile strength and airways inflammation associated to bacterial endotoxin lipopolysaccharide (LPS) in mice. This study shows the important properties of the essential oil (EO) of S. areira studied and these actions on lung with significant inhibition associated to LPS, all of which was assessed in mice bronchoalveolar lavage fluid and evidenced by stability of the percentage of alveolar macrophages, infiltration of polymorphonuclear leukocytes and tumor necrosis factor-alpha concentration, and without pathway modifications in conjugated dienes activity. Clinical status (morbidity or mortality), macroscopic morphology and lung/body weight index were unaffected by the administration of the EO S. areira. Furthermore, the ex vivo analysis of isolated hearts demonstrated the negative inotropic action of the EO of S. areira in a mice model, and in rabbits changes in the hemodynamic parameters, such as a reduction of systolic blood pressure. We conclude that EO S. areira could be responsible for modifications on the cardiovascular and/or airway parameters. PMID- 22546368 TI - Biomass for energy in the European Union - a review of bioenergy resource assessments. AB - This paper reviews recent literature on bioenergy potentials in conjunction with available biomass conversion technologies. The geographical scope is the European Union, which has set a course for long term development of its energy supply from the current dependence on fossil resources to a dominance of renewable resources. A cornerstone in European energy policies and strategies is biomass and bioenergy. The annual demand for biomass for energy is estimated to increase from the current level of 5.7 EJ to 10.0 EJ in 2020. Assessments of bioenergy potentials vary substantially due to methodological inconsistency and assumptions applied by individual authors. Forest biomass, agricultural residues and energy crops constitute the three major sources of biomass for energy, with the latter probably developing into the most important source over the 21st century. Land use and the changes thereof is a key issue in sustainable bioenergy production as land availability is an ultimately limiting factor. PMID- 22546369 TI - Human umbilical cord Wharton's jelly stem cells: immune property genes assay and effect of transplantation on the immune cells of heart failure patients. AB - Stem cells derived from umbilical cord Wharton's jelly (WJSCs) are not immunogenic and have immunosuppressive effects. To evaluate the related mechanisms and the effect of transplantation on body immune cells, we examined immune property genes expression in WJSCs and levels of T-lymphocytes subgroups and immunoglobulins (Ig) in heart failure (HF) patients with and without WJSCs transplantation. WJSCs express immune tolerance genes HLA-E, HLA-G and HLA-F and immunomodulation genes VEGF, TGFbeta1, HGF, HMOX1, IL1beta, IL-6, LIF, LGALS 1/3/8, COX1/2 and PTGE, while they do not express immune response-related genes HLA-DR, HLA-DQ, HLA-DP, CD80, CD86, CD40 and CD40L. No obvious changes of T lymphocytes subgroups and plasma IgG/IgM were observed in HF patients with WJSCs transplantation. Our results suggest that the immune properties of WJSCs are due to the expression of immune avoidance and immunomodulation genes in the absence of immune response-related genes. WJSCs are secure in immunological aspects when used as seed cells for cardiac repair. PMID- 22546370 TI - An unusual cause of recurrent diarrhea with small intestinal "polyposis". Nodular lymphoid hyperplasia of the small intestine. PMID- 22546372 TI - An unusual ileum tumor in a young woman. Perivascular epithelioid cell tumor of gastrointestinal tract. PMID- 22546373 TI - Similarity of the ruminal bacteria across individual lactating cows. AB - Dairy cattle hold enormous significance for man as a source of milk and meat. Their remarkable ability to convert indigestible plant mass into these digestible food products resides in the rumen - an anaerobic chambered compartment - in the bovine digestive system. The rumen houses a complex microbiota which is responsible for the degradation of plant material, consequently enabling the conversion of plant fibers into milk and meat and determining their quality and quantity. Hence, an understanding of this complex ecosystem has major economic implications. One important question that is yet to be addressed is the degree of conservation of rumen microbial composition across individual animals. Here we quantified the degree of similarity between rumen bacterial populations of 16 individual cows. We used real-time PCR to determine the variance of specific ruminal bacterial species with different metabolic functions, revealing that while some bacterial strains vary greatly across animals, others show only very low variability. This variance could not be linked to the metabolic traits of these bacteria. We examined the degree of similarity in the dominant bacterial populations across all animals using automated ribosomal intergenic spacer analysis (ARISA), and identified a bacterial community consisting of 32% operational taxonomic units (OTUs) shared by at least 90% of the animals and 19% OTUs shared by 100% of the animals. Looking only at the presence or absence of each OTU gave an average similarity of 75% between each cow pair. When abundance of each OTU was added to the analysis, this similarity decreased to an average of less than 60%. Thus, as suggested in similar recent studies of the human gut, a bovine rumen core microbiome does exist, but taxa abundance may vary greatly across animals. PMID- 22546374 TI - The choice of the intravenous fluid influences the tolerance of acute normovolemic anemia in anesthetized domestic pigs. AB - INTRODUCTION: The correction of hypovolemia with acellular fluids results in acute normovolemic anemia. Whether the choice of the infusion fluid has an impact on the maintenance of oxygen (O2) supply during acute normovolemic anemia has not been investigated so far. METHODS: Thirty-six anesthetized and mechanically ventilated pigs were hemodiluted to their physiological limit of anemia tolerance, reflected by the individual critical hemoglobin concentration (Hbcrit). Hbcrit was defined as the Hb-concentration corresponding with the onset of supply-dependency of total body O2-consumption (VO2). The hemodilution protocol was randomly performed with either tetrastarch (6% HES 130/0.4, TS group, n = 9), gelatin (3.5% urea-crosslinked polygeline, GEL-group, n = 9), hetastarch (6% HES 450/0.7, HS-group, n = 9) or Ringer's solution (RS-group, n = 9). The primary endpoint was the dimension of Hbcrit, secondary endpoints were parameters of central hemodynamics, O2 transport and tissue oxygenation. RESULTS: In each animal, normovolemia was maintained throughout the protocol. Hbcrit was met at 3.7 +/- 0.6 g/dl (RS), 3.0 +/- 0.6 g/dl (HS P < 0.05 vs. RS), 2.7 +/- 0.6 g/dl (GEL, P < 0.05 vs. RS) and 2.1 +/- 0.4 g/dl (TS, P < 0.05 vs. GEL, HS and RS). Hemodilution with RS resulted in a significant increase of extravascular lung water index (EVLWI) and a decrease of arterial oxygen partial pressure (paO2), and O2 extraction ratio was increased, when animals of the TS-, GEL- and HS-groups met their individual Hbcrit. CONCLUSIONS: The choice of the intravenous fluid has an impact on the tolerance of acute normovolemic anemia induced by acellular volume replacement. Third-generation tetrastarch preparations (e.g., HES 130/0.4) appear most advantageous regarding maintenance of tissue oxygenation during progressive anemia. The underlying mechanism includes a lower degree of extravasation and favourable effects on microcirculatory function. PMID- 22546376 TI - Altering gait by way of stimulation of the plantar surface of the foot: the immediate effect of wearing textured insoles in older fallers. AB - BACKGROUND: Evidence suggests that textured insoles can alter gait and standing balance by way of enhanced plantar tactile stimulation. However, to date, this has not been explored in older people at risk of falling. This study investigated the immediate effect of wearing textured insoles on gait and double-limb standing balance in older fallers. METHODS: Thirty older adults >65 years (21 women, mean [SD] age 79.0 [7.1]), with self-reported history of >=2 falls in the previous year, conducted tests of level-ground walking over 10 m (GAITRite system), and double-limb standing with eyes open and eyes closed over 30 seconds (Kistler force platform) under two conditions: wearing textured insoles (intervention) and smooth (control) insoles in their usual footwear. RESULTS: Wearing textured insoles caused significantly lower gait velocity (P = 0.02), step length (P = 0.04) and stride length (P = 0.03) compared with wearing smooth insoles. No significant differences were found in any of the balance parameters (P > 0.05). CONCLUSIONS: A textured insole worn by older adults with a history of falls significantly lowers gait velocity, step length and stride length, suggesting that this population may not have an immediate benefit from this type of intervention. The effects of prolonged wear remain to be investigated. PMID- 22546375 TI - Silver nanoparticles-mediated G2/M cycle arrest of renal epithelial cells is associated with NRF2-GSH signaling. AB - Silver nanoparticles (nAg) are known to evoke reactive oxygen species (ROS) generation and consequent cell damage. The transcription factor NF-E2-related factor 2 (NRF2) controls both the basal and inducible expression of multiple antioxidant genes. This study was aimed to investigate the role of NRF2 in nAg induced renal epithelial cell damage. nAg treatment intensified DNA damage and G2/M cell cycle arrest by nAg in NRF2 knockdown HK-2 (NRF2i) compared with the control cells. As a signaling mechanism associated with nAg-mediated growth arrest, the levels of phospho-CDC25C and phospho-CDC2 were significantly increased in NRF2i. Target gene analysis revealed that nAg-mediated increase in gamma-glutamate cysteine ligase expression is NRF2-dependent: nAg-treated NRF2i showed a reduction in glutathione (GSH) content and elevation in ROS level in comparison with the control cells. Additionally, pretreatment of N-acetylcystein in nAg-treated NRF2i alleviated ROS-mediated DNA damage and G2/M cell cycle arrest, while GSH depletion exacerbated DNA damage and cell cycle arrest in the control cells. Taken together, these results suggest that NRF2-mediated GSH increase plays a protective role in nAg-induced DNA damage and subsequent G2/M cell cycle arrest in human renal epithelial cells. PMID- 22546377 TI - Sacrospinous ligaments anterior apical anchoring for needle-guided mesh is a safe option: a cadaveric study. AB - OBJECTIVE: To evaluate the feasibility and safety of using the sacro-spinous ligament (SSL) as a fixation point for anterior-apical pelvic floor compartment mesh implants. The apical support achieved with the sacro-spinous ligament mesh fixation is considered adequate, as it provides a high and stronger anchoring point. Even though, meshes for anterior pelvic floor reconstruction are traditionally anchored to the arcus tendineous fascia pelvis (ATFP). The authors presumed that fixing the anterior mesh to the sacro-spinous ligament instead of the ATFP is both feasible and safe. The present study evaluated the anatomical aspects and relations of a modified tissue passage with sacro-spinous fixation of the anterior apical mesh arms. METHODS: In 5 embalmed female cadavers and 1 fresh female cadaver, the apical arms of the anterior needle-guided mesh were placed through the SSLs rather than through the ATFP, using a transgluteal approach. The distances between the mesh arms and the ureters and uterine arteries were measured. RESULTS: The minimal final distance between the mesh arms and the ureters or uterine arteries was 1.5 cm in the embalmed cadavers, but only 5 mm in the fresh cadaver. However, when analyzing the procedure carefully, it was noted that during dissection the ureters and arteries were pushed medially by the surgeon's finger, thus the operative procedure did not entail any real risk of injury to these structures. The introduced surgical needle caused no trauma to any adjacent cadaveric organs. CONCLUSIONS: Anterior pelvic floor meshes may be safely anchored to the SSL, thus potentially improving the apical support. PMID- 22546378 TI - Effects of intravesical dexpanthenol use on lipid peroxidation and bladder histology in a chemical cystitis animal model. AB - OBJECTIVE: To demonstrate the effects of intravesical dexpanthenol use on bladder histology and lipid peroxidation in a chemical cystitis animal model. METHODS: Thirty-five New Zealand rabbits were divided into 3 groups. Cystitis was conducted with transurethral intravesical hydrochloric acid instillation on the subjects in groups I and II. Then, Group I subjects were transurethrally administered intravesical dexpanthenol therapy twice a week, Group II subjects were given only intravesical isotonic NaCl instillation, and Group III subjects were administered intravesical isotonic NaCl instillation without conducting chemical cystitis to create the same stress. Treatment schemes of all groups were arranged in the same manner. After 6-week therapy, the rabbits were sacrificed and histopathologic investigations were carried out to demonstrate changes in the urinary bladder. Serum and tissue malondialdehyde (MDA) values were examined to investigate the effect of dexpanthenol on lipid peroxidation. RESULTS: We observed that the basal membrane and mucosal integrity were maintained, inflammatory cells were suppressed, and MDA levels decreased in group I, which received dexpanthenol therapy. However, it was also observed that mucosal integrity was spoiled, numerous inflammatory cells were accumulated, and MDA levels were significantly increased in group II, which was administered isotonic NaCl. CONCLUSION: In light of our findings, intravesical dexpanthenol therapy could be a new therapeutic approach in the treatment of interstitial cystitis because of its low cost and acceptable side effects. PMID- 22546379 TI - Understanding criteria for surveillance of patients with a small renal mass. AB - OBJECTIVE: To better delineate which factors influence the decision to undergo active surveillance of small renal masses. METHODS: We identified 204 consecutive patients at our institution with clinical Stage T1 renal masses from June 2009 through June 2010. A variety of demographic and clinical characteristics were measured. Based on our previous work, the "ideal" criteria for active surveillance included tumor size <= 4 cm, Charlson comorbidity index of >= 2, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of >= 2, and estimated glomerular filtration rate <60 mL/min. We performed sensitivity analyses to identify the characteristics associated with choice of active surveillance and compared these with our "ideal" criteria. RESULTS: Of the 204 patients, 73 (36%) and 131 (64%) underwent active surveillance and treatment, respectively. The patients undergoing active surveillance versus treatment differed with respect to distance from hospital >60 miles (P = .04), ECOG PS of >= 2 (P < .01), tumor size (P < .01), multifocality (P = .03), endophytic nature of lesion (P = .04), and whether the patient's surgeon generally used a robotic, laparoscopic, or open approach (P = .01). Neither the baseline estimated glomerular filtration rate (P = .91) nor the Charlson comorbidity index (P = .69) were significant factors. The combination of tumor size <3 cm, ECOG PS of >= 2, and an endophytic lesion were most predictive of active surveillance. CONCLUSION: Patient, tumor, and surgeon characteristics all influence the choice of active surveillance. From the sensitivity analyses, active surveillance was driven by a tumor size <3 cm, poor PS (ie, ECOG PS of >= 2), and an endophytic lesion. PMID- 22546380 TI - Editorial comment. PMID- 22546381 TI - Complementary and alternative medicine use, patient-reported outcomes, and treatment satisfaction among men with localized prostate cancer. AB - OBJECTIVE: To evaluate the association between complementary and alternative medicine (CAM) use, satisfaction with treatment, and patient-reported outcomes after treatment. METHODS: The Prostate CAncer Therapy Selection Study prospectively surveyed patients newly diagnosed with localized prostate cancer about their treatment decision-making process and outcomes. The Prostate CAncer Therapy Selection Study recruited patients from 3 geographic areas through hospital-based urology clinics and community urology practices. RESULTS: More than 700 patients completed the baseline and follow-up surveys. More than 50% of respondents reported using CAM; this decreased to 39% if prayer was excluded as a type of CAM. On multivariate analysis, factors related to communication with the treating physician, but not CAM use, were associated with treatment satisfaction. The likelihood of stability or improvement in urinary, bowel, and sexual function at 6 months was related to the choice of primary therapy but was unrelated to CAM use. CONCLUSION: In the present prospective observational study, CAM use was highly prevalent but unrelated to treatment satisfaction or changes in functional status. The effect of CAM on these endpoints remains to be established in comparative effectiveness studies. PMID- 22546382 TI - Higher RENAL Nephrometry Score is predictive of longer warm ischemia time and collecting system entry during laparoscopic and robotic-assisted partial nephrectomy. AB - OBJECTIVE: To investigate the predictive value of the RENAL Nephrometry Score (RNS) on operative outcomes during both laparoscopic partial nephrectomy (LPN) and robotic-assisted partial nephrectomy (RPN). METHODS: We reviewed 67 consecutive patients with suspicious renal lesions and available radiographic data who underwent LPN or RPN by a single surgeon. Data included operative type, body mass index (BMI), gender, age, and side of tumor. RNSs were recorded using either magnetic resonance imaging or computed tomography scans. Warm ischemia time (WIT), estimated blood loss (EBL), and collecting system entry (CSE) were the endpoints for the analyses. RESULTS: Total RNS entered as a continuous or dichotomous variable (<7 or >= 7), R-score, and N-score were independent predictors of WIT on multivariable analyses (P <.001, P = .001, P = .026, and P <.01, respectively). The total RNS and N-score were predictive of CSE in univariate analysis (P <.001). Neither total RNS nor its individual components were predictive of EBL. CONCLUSION: Total RNS, as well as the N- and R-scores, can help predict both longer WIT and CSE during LPN and RPN. The RNS and its individual components may be useful in the preoperative planning and counseling of patients undergoing LPN or RPN. PMID- 22546383 TI - Transperitoneal laparoscopic dismembered pyeloplasty in unusual circumstances--is the outcome comparable to that achieved in familiar pathologies? AB - OBJECTIVE: To compare the operative outcome, morbidity profile, and functional outcome after transperitoneal laparoscopic dismembered pyeloplasty for ureteropelvic junction obstruction in unusual circumstances (intrinsic pathology in anomalous kidneys or unusual extrinsic pathologies; group 1) to the outcome after this procedure in familiar pathologies (normally located kidneys with intrinsic dysfunctional segment or extrinsic compression due to a crossing vessel; group 2). METHODS: The patients were evaluated in detail. All patients underwent transperitoneal laparoscopic dismembered pyeloplasty. The operative and postoperative parameters were recorded. Patients were followed up after the procedure on a 3-month protocol. Imaging was repeated at 1 year. No intervention during the follow-up period (ie, nephrostomy, ureteral stenting, or redo pyeloplasty) and improvement in the hydronephrosis grade and diuretic renogram parameters was interpreted as procedural success. The operative, postoperative, and follow-up parameters in the 2 groups were compared. RESULTS: Group 1 included 17 patients with intrinsic pathologic features and renal anomalies with ureteropelvic junction obstruction due to unusual extrinsic pathology. All procedures were successfully completed with the laparoscopic approach. A significant difference was noted in the mean operative duration (group 1, 196.9 +/- 10.3 minutes; group 2, 125.44 minutes, P = .00). The other operative and postoperative parameters were comparable. No significant operative or postoperative events were noted. A total of 14 patients (group 1) completed the 1 year follow-up protocol. The success rate was 92.9% (13 of 14) in group 1 and 97.9% (44 of 45) in group 2 (P = .42). CONCLUSION: The procedural duration for laparoscopic dismembered pyeloplasty in unusual circumstances is longer than in familiar pathologies. However, the morbidity profile and functional outcome in these 2 scenarios were comparable. PMID- 22546384 TI - Perioperative outcomes of robotic-assisted partial nephrectomy in elderly patients: a matched-cohort study. AB - OBJECTIVE: To compare elderly patients undergoing robotic assisted partial nephrectomy (RAPN) with a match cohort of younger patients. Investigating the benefits of minimally invasive RAPN including faster convalescence and decreased postoperative narcotic use make this an attractive option in patients with advanced age and numerous comorbidities. METHODS: A retrospective review of 250 consecutive patients who underwent robotic-assisted partial nephrectomy (RAPN) for a solitary renal tumor from June 2006 to May 2010 at our institution was performed. Thirty-seven patients >= 70 years (G70) who underwent 38 robotic partial nephrectomy (RPN) procedures were identified. This group was matched with 38 patients <70 years (L70) who underwent 38 RPN procedures at our institution. Functional, perioperative, and oncological outcomes of RAPN in patients >= 70 years old were analyzed. RESULTS: Overall, the median tumor size was 2.65 cm. Tumor characteristics, renal function, nephrometry score, and incidence of renal cancer in lesions were similar between the L70 and G70 groups. The two groups showed no differences in American Society of Anesthesiologists scores of 1-4 or Charlson comorbidity index score. Perioperative and postoperative outcomes showed no variation between L70 and G70 patients. Postoperative complications rate of 21% and 31.6% in the L70 and G70 groups, respectively, showed no difference (P < .48). There were 5 deaths, 3 of which occurred in the G70 group (8.1%) at a median of 22 months after surgery. CONCLUSION: RAPN for small renal masses offers a safe alternative for patients >70 years of age, with no increase in perioperative and postoperative morbidity and mortality. Age may not be predictive of perioperative complications. PMID- 22546385 TI - Editorial comment. PMID- 22546387 TI - Face, content, and construct validation of the da Vinci Skills Simulator. AB - OBJECTIVE: To report on assessments of face, content, and construct validity for the commercially available da Vinci Skills Simulator (dVSS). METHODS: A total of 38 subjects participated in this prospective study. Participants were classified as novice (0 robotic cases performed), intermediate (1-74 robotic cases), or expert (>= 75 robotic cases). Each subject completed 5 exercises. Using the metrics available in the simulator software, the performances of each group were compared to evaluate construct validation. Immediately after completion of the exercises, each subject completed a questionnaire to evaluate face and content validation. RESULTS: The novice group consisted of 18 medical students and 1 resident. The intermediate group included 6 residents, 1 fellow, and 2 faculty urologist. The expert group consisted of 2 residents, 1 fellow, and 7 faculty surgeons. The mean number of robotic cases performed by the intermediate and expert groups was 29.2 and 233.4, respectively. An overall significant difference was observed in favor of the more experienced group in 4 skill sets. When intermediates and experts were combined into a single "experienced" group, they significantly outperformed novices in all 5 exercises. Intermediates and experts rated various elements of the simulators realism at an average of 4.1/5 and 4.3/5, respectively. All intermediate and expert participants rated the simulator's value as a training tool as 4/5 or 5/5. CONCLUSION: Our study supports the face, content, and construct validation attributed to the dVSS. These results indicate that the simulator may be most useful to novice surgeons seeking basic robot skills acquisition. PMID- 22546389 TI - National trends in surgical therapy for benign prostatic hyperplasia in the United States (2000-2008). AB - OBJECTIVE: To report an update of the change in usage trends for different surgical treatments of benign prostatic hyperplasia (BPH) among the United States Medicare population data from 2000-2008. The rate of usage of thermotherapy and laser therapy in the surgical treatment of BPH has been changing over the past decade in conjunction with a steady decrease of transurethral resection of the prostate (TURP). METHODS: Using the 100% Medicare carrier file for the years 2000 2008, we calculated counts and population-adjusted rates of BPH surgery. Rates of TURP, thermotherapy, and laser-using modalities were calculated and compared in relation to age, race, clinical setting, and reimbursement. RESULTS: After years of a steady rise, the total rate of all BPH procedures peaked in 2005 at 1078/100,000 and then declined by 15.4% to 912/100,000 in 2008. TURP rates continued to decline from 670 in 2000 to 351/100,000 in 2008. Rates of microwave thermoablation peaked in 2006 at 266/100,000 and then declined 26% in 2008. Laser vaporization almost completely replaced laser coagulation and in 2008 was the most commonly performed procedure second to TURP, with the majority performed as outpatient procedures (70%) and an increasing percentage in the office (12%). Men between ages 70 and 75 had the highest rate of procedures. Reimbursement rates correlate using some but not all procedures. Racial disparities reported previously appear to have resolved. CONCLUSION: Surgical treatment of BPH continues to change rapidly. TURP continues to decline and laser vaporization is the fastest growing modality. There is a big shift toward outpatient/office procedures. Reimbursement rates do not appear to have a consistent effect on usage. PMID- 22546390 TI - Editorial comment. PMID- 22546388 TI - Role of isotope selection in long-term outcomes in patients with intermediate risk prostate cancer treated with a combination of external beam radiotherapy and low-dose-rate interstitial brachytherapy. AB - OBJECTIVE: To examine the rates of long-term biochemical recurrence-free survival (BRFS) with respect to isotope in intermediate-risk prostate cancer treated with external beam radiotherapy (EBRT) and brachytherapy. METHODS: A total of 242 consecutive patients with intermediate-risk prostate cancer were treated with iodine-125 ((125)I) or palladium-103 ((103)Pd) implants after EBRT (range 45.0 50.4 Gy) from 1996 to 2002. Of the 242 patients, 119 (49.2%) were treated with (125)I and 123 (50.8%) with (103)Pd. Multivariate Cox regression analysis was used to analyze BRFS, defined according to the Phoenix definition (prostate specific antigen nadir plus 2 ng/mL) with respect to Gleason score, stage, pretreatment prostate-specific antigen level, and source selection. Late genitourinary/gastrointestinal toxicities were assessed using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scale. RESULTS: At a median follow-up of 10 years, the BRFS rate was 77.3%. A statistically significant difference was found in the 10-year BRFS rate between the (125)I- and (103)Pd-treated groups (82.7% and 70.6%, respectively; P = .001). The addition of hormonal therapy did not improve the 10-year BRFS rate (77.6%) compared with RT alone (77.1%; P = .22). However, a statistically significant difference in the BRFS rate was found with the addition of hormonal therapy to (103)Pd, improving the 10-year BRFS rate for (73.8%) compared with (103)Pd alone (69.1%; P = .008). On multivariate analysis, isotope type ((103)Pd vs (125)I), pretreatment prostate-specific antigen level >10 ng/mL, and greater tumor stage increased the risk of recurrence by 2.6-fold (P = .007), 5.9-fold (P < .0001), and 1.7-fold (P = .14), respectively. CONCLUSION: (125)I renders a superior rate of BRFS compared with (103)Pd when used with EBRT. Hormonal therapy does not provide additional benefit in patients with intermediate-risk prostate cancer treated with a combination of EBRT and brachytherapy, except for the addition of hormonal therapy to (103)Pd. PMID- 22546392 TI - Comparison of harmful gases produced during GreenLight High-Performance System laser prostatectomy and transurethral resection of the prostate. AB - OBJECTIVE: To compare the gases generated from GreenLight High-Performance System (HPS) laser prostatectomy with Urosol or normal saline solution and transurethral resection and vaporization of the prostate (TURVP) with Urosol. METHODS: A total of 36 smoke samples were collected from a continuous irrigation suction system attached to a Tenax absorber during transurethral surgery of the prostate. The gases were qualitatively and quantitatively analyzed by gas chromatography-mass spectrometry equipped with a purge and trap sample injector. RESULTS: The gas produced during TURVP contained propylene, allene, isobutylene, 1,3-butadiene, vinyl acetylene, mercaptomethane, ethyl acetylene, diacetylene, 1-pentene, ethanol, piperylene, propenylacetylene, 1,4-pentadiene, cyclopentadiene, acrylnitrile, and butyrolacton. The types and amount of gas produced during HPS laser prostatectomy were fewer and smaller than during TURVP. However, 1,3 butadiene, a well-known human carcinogen, was also generated by HPS laser prostatectomy. HPS laser prostatectomy with saline produced a greater amount and number of gases than HPS laser prostatectomy with Urosol. CONCLUSION: The surgical smoke produced from TURVP and HPS laser prostatectomy contains potentially harmful chemical compounds, although HPS laser prostatectomy produced less surgical smoke than TURVP. Urosol produced fewer types and a smaller amount of gas than normal saline during HPS laser prostatectomy. PMID- 22546393 TI - Editorial comment. PMID- 22546395 TI - Ileal urinary reservoir in pediatric population: objective assessment of long term sequelae with time-to-event analysis. AB - OBJECTIVE: To evaluate the long-term outcomes of an ileal urinary reservoir in children. METHODS: This was a longitudinal study of pediatric patients who had undergone total ileal substitution of the bladder. Continence status was assessed, and all patients were evaluated for kidney function and biochemical profile. Standardized growth charts were used to assess linear growth. To assess bone mineral density, dual-emission x-ray absorptiometry scanning was performed. Clavien's scale was used to report and grade the long-term complications and their timing. We used a simple quality of life questionnaire to assess the effect of the procedure on the quality of life of the growing child. RESULTS: A total of 17 patients were included; 3 with orthotopic and 14 with continent cutaneous reservoirs. After a mean follow-up of 87.3 months, all patients were voiding with clean intermittent catheterization, with a 94% final continence rate. Two patients (11.7%) had an estimated glomerular filtration rate of <= 45 mL/min/1.73 m(2) at the last follow-up examination. However, no clinically manifest metabolic acidosis was detected. No anemia or neurologic deficit was detected, with a low normal serum level of vitamin B(12) in 2 patients (11.7%) and a low level in 1 patient (5.7%). One patient (5.7%) had chronic diarrhea. Low bone mineral density was found in 4 patients (22.8%), with 3 patients (17.1%) not exceeding the fifth percentile of height for age. High-grade complications (grade 3a-5) represented 64.5% of the complications, and the need for reintervention occurred late in the follow-up period. A high level of quality of life satisfaction was reported (88.5%). CONCLUSION: Ileal neobladder construction allows child to pass into adolescence dry with more confidence and self-esteem, with no external urine collection set. However, long-term follow-up is mandatory to maintain the positive outcome. PMID- 22546396 TI - Safety and efficacy of periurethral constrictor implantation for the treatment of post-radical prostatectomy incontinence. AB - OBJECTIVE: To assess safety and efficacy of the periurethral constrictor for the treatment of postprostatectomy urinary incontinence. METHODS: Periurethral constrictor is a minimally invasive, low-cost (? 2000) device based on an adjustable occlusive mechanism. From December 2004 to March 2010 the device was implanted in 66 patients with mild to severe incontinence (3 or more pads per day) through a 3- to 5-cm perineal incision. Median surgical time was 35 minutes (range 25-60). Discharge occurred on day 1 after removing the indwelling urethral catheter. RESULTS: In 4 cases (6%), the device was removed because of infection/periurethral erosion. At 18 months, 62 patients were valuable; continence was recovered totally in 49 cases (79%), partially in 9 (15%) cases, and remained unchanged in 4 (6%). No one needed self-catheterization to empty the bladder. CONCLUSION: Periurethral constrictor improved continence in most of the patients. Nevertheless, a larger series and longer follow-up are needed to confirm safety and to test durability. PMID- 22546397 TI - Editorial comment. PMID- 22546399 TI - Re: Isen et al.: Experience with the diagnosis and management of symptomatic ureteric stones during pregnancy (Urology 2012;79:508-512). PMID- 22546401 TI - Re: Moore et al.: Treatment of vesicoureteral reflux in adults by endoscopic injection (Urology 2011;77:1284-1287). PMID- 22546403 TI - Re: Goktas et al.: SWL in lower calyceal calculi: evaluation of the treatment results in children and adults? (Urology 2011;78:1402-1406). PMID- 22546405 TI - Re: Twardowski et al.: Phase II study of aflibercept (VEGF-Trap) in patients with recurrent or metastatic urothelial cancer: a California Cancer Consortium Trial (Urology 2010;76:923-926). PMID- 22546407 TI - Re: Liao et al.: Serum C-reactive protein levels are associated with residual urgency symptoms in patients with benign prostatic hyperplasia after medical treatment. (Urology 2011;78:1373-1379). PMID- 22546408 TI - Re: Rourke et al.: Effect of wound closure on buccal mucosal graft harvest site morbidity: results of a randomized prospective trial (Urology 2012;79:443-447). PMID- 22546409 TI - Re: Binbay et al.: Does pelvicaliceal system anatomy affect success of percutaneous nephrolithotomy? (Urology 2011;78:737-738). PMID- 22546410 TI - Selenium and lycopene attenuate cisplatin-induced testicular toxicity associated with oxidative stress in Wistar rats. AB - OBJECTIVE: To investigate the potential protective effects of selenium and lycopene, either alone or in combination, for cisplatin-induced oxidative stress and testicular dysfunction in male rats. METHODS: A total of 50 adult male Wistar rats were divided into 5 groups of 10 animals each, as follows: control group (treated with placebo); cisplatin-alone group; cisplatin + lycopene group; cisplatin + selenium group; and cisplatin + selenium + lycopene group. The weights and dimensions of testes, epididymes, and accessory glands as well as sperm concentration, motility, and proportion of normal morphology were assessed. Testicular tissue malondialdehyde (MDA) and glutathione (GSH) levels, as well as superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activities, and plasma testosterone were determined. RESULTS: Cisplatin treatment caused significant reductions in weights and dimensions of testes, epididymes, and accessory glands, sperm concentration, motility, and proportion of normal morphology, enzymatic and nonenzymatic antioxidants, and plasma testosterone levels. There was significantly increased MDA. The co-administration of selenium and lycopene, either separately or in combination, significantly attenuated the harmful effects of cisplatin-induced lipid peroxidation, oxidative stress, loss of genital organ weight and dimensions, as well as function of reproductive organs collectively in the Wistar rat model. The combination of selenium and lycopene was more effective than supplementation of either agent alone in preventing cisplatin-induced testicular damage. CONCLUSION: Selenium and lycopene supplementation reduced cisplatin-induced testicular toxicity, improved testicular function and prevented cisplatin-related injury to the rat testes by suppression of oxidative stress. PMID- 22546411 TI - Functional role of muscarinic receptor subtypes in calcium sensitization and their contribution to rho-kinase and protein kinase C pathways in contraction of human detrusor smooth muscle. AB - OBJECTIVE: We investigated the role of muscarinic receptor subtypes in calcium sensitization and their contribution to rho-kinase (ROK) and protein kinase C (PKC) pathways in carbachol (CCh)-induced contraction of human detrusor smooth muscle (DSM). MATERIALS AND METHODS: alpha-toxin-permeabilized human DSM strips were prepared and mounted horizontally to record isometric force. The roles of M(2) and M(3) muscarinic receptors in Ca(2+) sensitization were studied using selective antagonists of M(2) (AF-DX116) and M(3) (4-DAMP) receptor subtypes. The effects of a selective inhibitor of ROK, Y-27632, and a selective inhibitor of PKC, bisindolylmaleimide I (GF-109203X), were also studied on contraction induced by 10 MUM CCh with 100 MUM guanosine triphosphate at a fixed 1 MUM [Ca(2+)](i) after preincubation with 1 MUM AF-DX116 or 1 MUM 4-DAMP. RESULTS: Carbachol induced Ca(2+) sensitization was predominantly inhibited by 4-DAMP compared with AF-DX116. Four-DAMP equivalently inhibited the relaxation effect of 5 MUM GF 109203X as well as that of 5 MUM Y-27632 on CCh-induced Ca(2+) sensitization. AF DX116 reduced the relaxation effect of Y-27632 to a greater degree than GF 109203X. CONCLUSION: The results of the present study have demonstrated the predominant role of M(3) receptor subtype in Ca(2+) sensitization and the relative contribution to ROK and PKC pathways. Our study also shows that the ROK pathway is dominant compared with the PKC pathway after M(2) receptor activation, which in turn is inferior, but not negligible, in producing Ca(2+) sensitization. PMID- 22546412 TI - Unusual presentation of bilateral ureteroceles with ureterolithiasis in a patient after robotic prostatectomy. AB - We present a unique case of incidentally discovered symptomatic, stone-laden ureteroceles after robotic prostatectomy at a high-volume institution. The 2 month postoperative timeline to presentation and laser unroofing management strategy for bilateral ureteroceles after robotic prostatectomy are described. PMID- 22546413 TI - Upper ureteric obstruction secondary to entrapment between twin segments of inferior vena cava--an unusual occurrence. AB - A retrocaval ureter is a rare congenital cause of upper ureteric obstruction that results from entrapment of the upper ureter by the inferior vena cava (IVC) as it courses posterior to the cava. We report an interesting scenario of upper ureteric obstruction secondary to entrapment between twin segments of IVC. PMID- 22546415 TI - Detection of visual events along the apparent motion trace in patients with paranoid schizophrenia. AB - Dysfunctional prediction in sensory processing has been suggested as a possible causal mechanism in the development of delusions in patients with schizophrenia. Previous studies in healthy subjects have shown that while the perception of apparent motion can mask visual events along the illusory motion trace, such motion masking is reduced when events are spatio-temporally compatible with the illusion, and, therefore, predictable. Here we tested the hypothesis that this specific detection advantage for predictable target stimuli on the apparent motion trace is reduced in patients with paranoid schizophrenia. Our data show that, although target detection along the illusory motion trace is generally impaired, both patients and healthy control participants detect predictable targets more often than unpredictable targets. Patients had a stronger motion masking effect when compared to controls. However, patients showed the same advantage in the detection of predictable targets as healthy control subjects. Our findings reveal stronger motion masking but intact prediction of visual events along the apparent motion trace in patients with paranoid schizophrenia and suggest that the sensory prediction mechanism underlying apparent motion is not impaired in paranoid schizophrenia. PMID- 22546414 TI - Experimental Actinobacillus pleuropneumoniae challenge in swine: comparison of computed tomographic and radiographic findings during disease. AB - BACKGROUND: In pigs, diseases of the respiratory tract like pleuropneumonia due to Actinobacillus pleuropneumoniae (App) infection have led to high economic losses for decades. Further research on disease pathogenesis, pathogen-host interactions and new prophylactic and therapeutic approaches are needed. In most studies, a large number of experimental animals are required to assess lung alterations at different stages of the disease. In order to reduce the required number of animals but nevertheless gather information on the nature and extent of lung alterations in living pigs, a computed tomographic scoring system for quantifying gross pathological findings was developed. In this study, five healthy pigs served as control animals while 24 pigs were infected with App, the causative agent of pleuropneumonia in pigs, in an established model for respiratory tract disease. RESULTS: Computed tomographic (CT) findings during the course of App challenge were verified by radiological imaging, clinical, serological, gross pathology and histological examinations. Findings from clinical examinations and both CT and radiological imaging, were recorded on day 7 and day 21 after challenge. Clinical signs after experimental App challenge were indicative of acute to chronic disease. Lung CT findings of infected pigs comprised ground-glass opacities and consolidation. On day 7 and 21 the clinical scores significantly correlated with the scores of both imaging techniques. At day 21, significant correlations were found between clinical scores, CT scores and lung lesion scores. In 19 out of 22 challenged pigs the determined disease grades (not affected, slightly affected, moderately affected, severely affected) from CT and gross pathological examination were in accordance. Disease classification by radiography and gross pathology agreed in 11 out of 24 pigs. CONCLUSIONS: High-resolution, high-contrast CT examination with no overlapping of organs is superior to radiography in the assessment of pneumonic lung lesions after App challenge. The new CT scoring system allows for quantification of gross pathological lung alterations in living pigs. However, computed tomographic findings are not informative of the etiology of respiratory disease. PMID- 22546416 TI - Ultra-long Pt nanolawns supported on TiO2-coated carbon fibers as 3D hybrid catalyst for methanol oxidation. AB - In this study, TiO2 thin film photocatalyst on carbon fibers was used to synthesize ultra-long single crystalline Pt nanowires via a simple photoreduction route (thermally activated photoreduction). It also acted as a co-catalytic material with Pt. Taking advantage of the high-aspect ratio of the Pt nanostructure as well as the excellent catalytic activity of TiO2, this hybrid structure has the great potential as the active anode in direct methanol fuel cells. The electrochemical results indicate that TiO2 is capable of transforming CO-like poisoning species on the Pt surface during methanol oxidation and contributes to a high CO tolerance of this Pt nanowire/TiO2 hybrid structure. PMID- 22546417 TI - Trendelenburg or Trendelenberg, what's in a name? PMID- 22546418 TI - Surgical simulation: where have we come from? Where are we now? Where are we going? AB - It is now clear to most stakeholders that acquisition of surgical psychomotor skills is best achieved outside of the clinical operating room, in the context of a simulated environment. Endoscopic simulation can be accomplished using simple "box" simulators or video trainers, and virtual reality simulation is now possible using microprocessor-controlled systems. Structured surgical training performed outside of the operating room environment is relatively new to health care, a circumstance different from the process of pilot training, in which simulation has been a mainstay for more than 75 years and in which virtual reality simulation is now the norm. Those charged with surgical education are faced with a dilemma as, while attempting to understand the basic goals of simulation, they are simultaneously faced with choice between relatively inexpensive video trainers and the often prohibitively expensive virtual reality systems. This article explores the history of simulation, reports the results of a modified systematic review of currently available systems and performance, and identifies the gaps in current research and development. It is apparent that available video trainers provide the opportunity for skill development that at present is not surpassed by virtual reality systems. In the future, there will likely be an increasing role for virtual reality; however, challenges remain that include determination of the appropriate metrics and system design, and the fiscal resources necessary for the required hardware and related software development. PMID- 22546419 TI - Localized subendometrial leiomyomatosis at hysteroscopy. PMID- 22546420 TI - Recurrent torsion of a noncystic adnexa after plication of the utero-ovarian ligament. PMID- 22546421 TI - Uterine smooth muscle tumors of uncertain malignant potential: diagnostic challenges and therapeutic dilemmas. Report of 2 cases and review of the literature. AB - Morphologically, there exist variants of uterine smooth muscle tumors that cannot be clearly interpreted and classified as benign or malignant. Because their behavior and clinical prognosis is also uncertain, the World Health Organization has termed these "smooth muscle tumors of uncertain malignant potential" (STUMP). Herein we describe 2 cases, present a review of the literature, and highlight the diagnostic challenges and therapeutic dilemmas associated with uterine STUMP in myomectomy specimens from women who wish to maintain or enhance their fertility. The clinical course of residual STUMP remains speculative. PMID- 22546422 TI - Liability exposure for surgical robotics instructors. AB - Surgical robotics instructors provide an essential service in improving the competency of novice gynecologic surgeons learning robotic surgery and advancing surgical skills on behalf of patients. However, despite best intentions, robotics instructors and the gynecologists who use their services expose themselves to liability. The fear of litigation in the event of a surgical complication may reduce the availability and utility of robotics instructors. A better understanding of the principles of duty of care and the physician-patient relationship, and their potential applicability in a court of law likely will help to dismantle some concerns and uncertainties about liability. This commentary is not meant to discourage current and future surgical instructors but to raise awareness of liability issues among robotics instructors and their students and to recommend certain preventive measures to curb potential liability risks. PMID- 22546423 TI - Disseminated peritoneal leiomyomatosis with endometriosis. AB - Herein is described the case of a 41-year-old woman with disseminated peritoneal leiomyomatosis with distinct endometriosis. The pathogenesis of both conditions is as yet unclear; however, the 2 main hypotheses are discussed. Metaplastic origin from the secondary mullerian system has been suggested, as well as metastatic development. Inasmuch as spontaneous regression is likely, and the course of the disease can be influenced by hormonal withdrawal, operative measures could be refined to ensure the correct diagnosis and benignity. PMID- 22546424 TI - Cystically degenerated leiomyoma of the rectosigmoid managed laparoscopically at 13 weeks of gestation. AB - The safety of laparoscopic management of adnexal masses in pregnancy has been documented. Herein we report laparoscopic removal during pregnancy of a cystically degenerated leiomyoma of the sigmoid colon, which had been mistaken for an adnexal mass. When smooth muscle gastrointestinal tumors are observed, it is important that they be characterized with appropriate markers so that postoperative treatment can be individualized to the patient. PMID- 22546425 TI - Combined preoperative angiography with transient uterine artery embolization makes laparoscopic surgery for massive myomatous uteri a reasonable option: case reports. AB - Herein are reported perioperative outcomes in 2 women who underwent laparoscopic myomectomy and hysterectomy to treat massive leiomyomas. Although we counseled the patients about the high risk of conversion to laparotomy, we would not have attempted the laparoscopic approach without a preoperative angiogram and transient uterine artery embolization. Preoperative angiography and selective embolization enable identification of an aberrant parasitic blood supply and minimization of intraoperative bleeding. In the appropriate hands, these tools make a minimally invasive surgical approach possible even for the largest myomatous specimens. PMID- 22546426 TI - Hysteroscopic sterilization in an immunosuppressed patient. AB - Essure sterilization produces a local benign tissue response resulting in bilateral occlusion of the fallopian tubes 3 months after insertion. There is a precautionary warning about performing this procedure on immunosuppressed patients. We present a case of successful bilateral tubal occlusion with Essure in a patient with a history of kidney transplantation and receiving immunosuppressive medications. PMID- 22546427 TI - Inferior epigastric artery pseudoaneurysm following trocar injury. AB - Herein is described the development of an inferior epigastric pseudoaneurysm caused by a trocar injury during laparoscopic surgery. After the accessory trocar was placed in the left lower quadrant, the patient's condition became clinically unstable, requiring blood transfusions postoperatively and transfer to our tertiary care center. On arrival, she continued to have pain, with a palpable tender mass in the left lower quadrant. A computed tomography scan revealed a 5 * 6-cm mass in the anterior rectus sheath, with central hyperattenuation. This was better characterized at ultrasonography. The findings were consistent with an unstable pseudoaneurysm from the left inferior epigastric artery, with surrounding hematoma. Urgent embolization was performed by Interventional Radiology using coils inserted distal, into, and proximal to the pseudoaneurysm. The patient's condition was stable after the procedure, and she returned to the referring hospital for convalescence. Pseudoaneurysm of the inferior epigastric artery from a trocar injury is a rare occurrence. This case is the first report of a pseudoaneurysm forming in the inferior epigastric artery resulting from a trocar injury during gynecologic surgery. PMID- 22546428 TI - Sacral nerve infiltrative endometriosis presenting as perimenstrual right-sided sciatica and bladder atonia: case report and description of surgical technique. AB - Endometriosis infiltrating the sacral nerve roots is a rarely reported manifestation of the disease. The objectives of this article are to report such a case and to describe the surgical technique for laparoscopic decompression of sacral nerve roots and treatment of endometriosis at this site. The patient as a 38-year-old woman who had undergone 2 previous laparoscopic procedures for electrocoagulation of peritoneal endometriosis and self-reported perimenstrual right-sided sciatica and urinary retention. Clinical examination revealed allodynia (pain from a stimulus that does not normally cause pain) on the S2 to S4 dermatomes and hypoesthesia on part of the S3 dermatome. Magnetic resonance imaging showed an endometriotic nodule infiltrating the anterior rectal wall. Laparoscopic exploration of the sacral nerve roots demonstrated vascular compression of the lumbosacral trunk and endometriosis entrapping the S2 to S4 sacral nerve roots, with an endometrioma inside S3. The endometriosis was removed from the sacral nerve roots and detached from the sacral bone, and a nodulectomy of the anterior rectal wall was performed. Normal urinary function was restored on postoperative day 2, and pain resolved after a period of post-decompression. Intrapelvic causes of entrapment of sacral nerve roots are rarely described in the current literature, either because of misdiagnosis or actual rareness of the condition. Recognition of the clinical markers for these lesions may lead to an increase in diagnosis and specific treatment. PMID- 22546430 TI - Letter to the editor. PMID- 22546431 TI - Letter to the editor. PMID- 22546432 TI - A 10-year study of steady employment and non-vocational outcomes among people with serious mental illness and co-occurring substance use disorders. AB - OBJECTIVE: Employment promotes recovery for persons with serious mental illness by providing extra income and a valued social role, but the impact of employment on other psychosocial and clinical outcomes remains unclear. This study examined non-vocational outcomes in relation to steady employment over 10 years among people with serious mental illness and co-occurring substance use disorders. METHODS: Researchers interviewed people with co-occurring disorders at baseline and yearly for 10 years and tracked employment in relation to five non-vocational outcomes: independent living, psychiatric symptoms, substance use disorder, healthy (non-substance-abusing) relationships, and life satisfaction. Latent class trajectory analysis identified steady workers, and mixed-effects regression models compared steady workers with non-workers. RESULTS: Both steady workers (n=51) and non-workers (n=79) improved substantially; for example, a majority of each group achieved independent housing and stable remission of substance use disorders. Steady workers achieved independent housing and higher quality of life during the first 5 years of follow-up, but the two groups achieved similar outcomes by 10 years. CONCLUSIONS: People with co-occurring disorders can improve markedly. Those with steady employment may improve faster, but those without employment may achieve similar long-term outcomes at a slower pace. PMID- 22546433 TI - Biological parameters of Scirtothrips dorsalis (Thysanoptera: Thripidae) on selected hosts. AB - Since its establishment in Florida in 2005, Scirtothrips dorsalis Hood, a highly polyphagous species, has become an economically important pest of ornamental plants and a potentially significant pest of vegetable and fruit crops. Fruit and vegetable production in Florida is trending toward significant adoption of organic methods and use of widely dispersed small fields in rapidly urbanizing landscapes. Landscape plants may serve as refugia from which S. dorsalis recruits can disperse to nearby fruit and vegetable plantings. Therefore, information on this pest's biology including how it is affected by various host species is needed to develop effective integrated pest management (IPM) programs. In the greenhouse and laboratory condition, we studied the effects of various host plants, development, diel flight activity, oviposition, and demographics of S. dorsalis. The pest preferred Jalapeno pepper and Knockout rose over the other hosts, and it was most active between 1000 and 1600 hours EST. Irrespective of the host species, the duration of each of the immature stadia varied within a narrow range, and their respective sizes were quite similar. Demographic parameters quantified included gross reproduction rate (GRR), net reproductive rate (R(o)), intrinsic rate of increase per day (R(m)), finite rate of increase per day (lambda), and mean generation time (T). The pest population may increase by a factor of ~ 1.09/d, so that it may double in 8 or 9 d. The above information should be helpful in the development of sound programs to manage S. dorsalis on various crops and in the formulation of detection strategies by quarantine officers. PMID- 22546434 TI - Landscape analysis of adult codling moth (Lepidoptera: Tortricidae) distribution and dispersal within typical agroecosystems dominated by apple production in central Chile. AB - We analyzed the spatial distribution and dispersal of codling moth, Cydia pomonella (L.), adults within two heterogeneous agroecosystems typical of central Chile: commercial apple, Malus domestica Borkhausen, orchards surrounded by various unmanaged host plants. Both a geostatistical analysis of catches of adult males with a grid of sex pheromone-baited traps and an immunological self-marking technique combined with traps baited with a male and female attractant were used. The spatial analyses identified the key sources of moths within these diverse landscapes. Codling moth catches in traps were spatially associated within distances of ~ 150-300 m. Similarly, the mean distance from the immunological self-marking plots within the commercial apple orchard to the traps that captured marked adults was 282 m. In contrast, the mean distance in the capture of marked moths from unmanaged self-marking plots to a commercial orchard was 828 m. These data suggest that the success of any future area-wide management programs for codling moth in Chilean pome fruit must include a component for managing or removing noncommercial hosts that surround orchards. This analysis also suggests that the selection pressure for resistance imposed by insecticide sprays within managed orchards is likely dampened by the influx of susceptible moths from unmanaged sites common in central Chile. PMID- 22546435 TI - Species composition and population dynamics of thrips (Thysanoptera) in mango orchards of northern peninsular Malaysia. AB - Thrips are key pests of mango, Mangifera indica (L.), in Malaysia, including the Northern Peninsular. As Penang has year-round equatorial climate and high of rainfall, the populations of thrips may be subject to variations in composition and size. With a goal of developing an appropriate control strategy, a survey was conducted in Penang to determine species composition and abundance in relation to some environmental factors. Sprayed and unsprayed orchards were sampled on weekly basis through two flowering seasons of 2009 using CO(2) collection technique. Larval population falling into the ground to pupate and adults emerging from the soil were investigated in both orchards. Thrips hawaiiensis (Morgan) and Scirtothrips dorsalis (Hood) were the most prevalent species in the sprayed and the unsprayed orchards, respectively. The abundance of thrips was high during the flowering period of the dry season and decreased during the flowering period of the rainy season. This latter period coincided with decreased temperature and increased relative humidity. Percentage of adult emergence from the soil was lower in the rainy season than recorded in the dry season in both orchards. Taken together, these observations suggest that T. hawaiiensis and S. dorsalis are the main thrips species pests of mango panicles in Penang. Direct control with insecticides focusing on these two species may help to reduce cosmetic injuries and other damages on mango fruits. PMID- 22546436 TI - Effects of adjacent habitat on populations of stink bugs (Heteroptera: Pentatomidae) in cotton as part of a variable agricultural landscape in South Carolina. AB - The distribution of phytophagous stink bugs and associated boll injury in margins of cotton fields bordering various agronomic crops and woodlands were studied in 2007 and 2008. Two commercial cotton fields, ranging in size from 7.8 to 12.1 ha in Barnwell and Lee Counties, SC, were sampled weekly each year along predetermined transects at 0, 5, 10, and 25 m from the outside margin into the cotton field. Stink bugs were sampled using a ground cloth (0.91 by 0.91 m), and quarter-sized bolls (~ 2.5 cm in diameter) were collected and examined for internal damage. Density (bugs/row-m) of total stink bugs (adults plus nymphs) was greatest in cotton adjacent to peanut. Boll injury was significantly greater in cotton adjacent to soybean and peanut than in cotton next to other habitats, including corn, cotton, and woodlands, during midseason. Density of nymphs was greatest in cotton adjacent to peanut during mid and late season. Densities of total stink bugs and adults were greatest in cotton immediately adjacent (0 m) to all bordering crops and decreased as distance from the margin increased. Boll injury was greatest in cotton immediately adjacent (0 m) to the bordering crop in mid and late season. Because densities of stink bugs and boll injury vary spatially and temporally along field margins of cotton and can vary significantly based on the adjacent crop, such factors should be considered when developing integrated pest management strategies in cotton. PMID- 22546437 TI - Harvestman (Opiliones) fauna associated with Maine lowbush blueberry fields in the major production areas of Washington and Hancock counties. AB - Over a period of 19 yr, the harvestman (Opiliones) community associated with the lowbush blueberry agro-ecosystem in Maine was studied. Eight species representing five genera, four subfamilies, and two families of harvestmen belonging to the suborder Eupnoi were collected. The harvestman community was dominated by two introduced, synanthropic species: Phalangium opilio in all but 1 yr (that year dominated by Rilaena triangularis). Rilaena was recorded for the first time from eastern North America. Relative abundance of harvestman adults increases throughout the season and the temporal pattern of trap capture does not refute speculated life cycles of the harvestmen being univoltine with overwintering eggs. Some blueberry management practices were found to affect trap capture. We did find that on average (with opposite results 1 yr) trap captures are greater in pruned fields than in fruit-bearing fields. Organic fields were found to have higher relative abundance of harvestmen than conventionally managed fields. Conventionally managed fields with reduced-risk insecticides showed no difference in harvestmen relative abundance compared with those conventionally managed fields using the older more persistent organophosphate insecticides. Insecticide trials with common insecticides used in blueberry insect pest management showed that the organophosphate insecticide, phosmet, and the pyrethroid insecticide, esfenvalerate, were detrimental to P. opilio adults when exposed to leaf residues, whereas the reduced-risk insecticide, spinosad, showed no negative effects compared with nonsprayed foliage. PMID- 22546438 TI - An experimental analysis of grasshopper community responses to fire and livestock grazing in a northern mixed-grass prairie. AB - The outcomes of grasshopper responses to both vertebrate grazing and fire vary across grassland ecosystems, and are strongly influenced by local climactic factors. Thus, the possible application of grazing and fire as components of an ecologically based grasshopper management strategy must be investigated in regional studies. In this study, we examined the effects of grazing and fire on grasshopper population density and community composition in a northern Great Plains mixed-grass prairie. We employed a large-scale, replicated, and fully factorial manipulative experimental design across 4 yr to examine the separate and interactive effects of three grazing systems in burned and unburned habitats. Grasshopper densities were low throughout the 4-yr study and 1 yr of pretreatment sampling. There was a significant fire by grazing interaction effect on cumulative density and community composition, resulting from burned season long grazing pastures having higher densities than unburned pastures. Shannon diversity and grasshopper species richness were significantly higher with twice over rotational livestock grazing. The ability to draw strong conclusions regarding the nature of species composition shifts and population changes in the presence of fire and grazing is complicated by the large site differences and low grasshopper densities. The results reinforce the importance of long-term research to examine the effects of habitat manipulation on grasshopper population dynamics. PMID- 22546439 TI - Ant diversity and distribution in Acadia National Park, Maine. AB - Exotic ant species are a primary threat to ant biological diversity, posing a negative impact to native ant communities. In this study, we examine species richness of ants (family Formicidae) in Acadia National Park, ME, as a fundamental step toward understanding the present impact of the exotic species Myrmica rubra on native ant species. Twelve habitat types were sampled, along six transects, with pitfall traps, visual searching, bait traps, and leaf litter extraction, and the aid of 34 volunteers. We report 42 species of ants in Acadia National Park, comprising five subfamilies (Amblyoponinae, Dolichoderinae, Formicinae, Myrmicinae, and Ponerinae) and 15 genera; the cataloged species represents 75% of the species originally recorded in the area by Procter (1946). Our findings suggest M. rubra is currently not a dominant species throughout the entire island. However, where this species has invaded locally, few competing native species coexist. The species Lasius alienus, Formica subsericea, Myrmica detritinodis, Camponotus herculeanus, Formica argentea, Formica aserva, and Tapinoma sessile occurred most often in our survey. We report the ant species Amblyopone pallipes and Dolichoderus mariae as two new records for the state of Maine. PMID- 22546440 TI - Diversity of Anastrepha spp. (Diptera: Tephritidae) and associated braconid parasitoids from native and exotic hosts in southeastern Bahia, Brazil. AB - We documented fruit fly-host associations and infestation rates over 5 yr in the state of Bahia, Brazil, by systematically collecting native and introduced fruits in backyard and commercial orchards, experimental stations, and patches of native vegetation. Fruit were collected in multiple sites in the southern and southernmost regions of Bahia. A total of 942.22 kg from 27 fruit species in 15 plant families was collected throughout this study. Of these, 15 plant species from six families were infested by Anastrepha species. A total of 11,614 fruit flies was reared from the fruit (5,178 females and 6,436 males). No specimens of Ceratitis capitata (Wiedemann) were recovered. Eleven Anastrepha species were recovered from the collected fruit: Anastrepha antunesi Lima (0.04%), Anastrepha distincta Greene (0.1%), Anastrepha fraterculus (Wiedemann) (53.5%), Anastrepha leptozona Hendel (4.5%), Anastrepha manihoti Lima (0.1%), Anastrepha montei Lima (1.0%), Anastrepha obliqua (Macquart) (33.0%), Anastrepha pickeli Lima (2.0%), Anastrepha serpentina (Wiedemann) (1.0%), Anastrepha sororcula Zucchi (3.0%), and Anastrepha zenildae Zucchi (1.8%). We recovered 1,265 parasitoids (Hymenoptera: Braconidae) from Anastrepha pupae. Three species of braconids were found to parasitize larvae of nine Anastrepha species. The most common parasitoid species recovered was Doryctobracon areolatus (Szepligeti) (81.7%), followed by Utetes anastrephae (Viereck) (12.2%) and Asobara anastrephae (Muesebeck) (6.1%). We report A. fraterculus infesting Malay apple Syzygium malaccense (L.) Merr. & L. M. Perry and A. fraterculus, A. sororcula, and A. zenildae infesting araza Eugenia stipitata McVaugh for the first time in Brazil. PMID- 22546441 TI - Web orientation and prey resources for web-building spiders in eastern hemlock. AB - We examined the arthropod community on eastern hemlock, Tsuga canadensis (L.) Carr, in the context of its role in providing potential prey items for hemlock associated web-weaving spiders. Using sticky traps simulating spider webs, we evaluated what prey items are available to web-weaving spiders in eastern hemlock based on web orientation (horizontal versus vertical) and cardinal direction. We found that the overwhelming majority (>70%) of prey items available to spiders in hemlock canopies were Diptera. Psocoptera, Hymenoptera, and Hemiptera comprised most of the remaining potential prey. A significant direction * orientation interaction, and greater trap capture in some direction orientation combinations, suggests that spiders might locate their webs in eastern hemlock canopies for thermoregulatory purposes, ultimately optimizing prey capture. We also evaluated these findings in the context of hemlock infestation by the invasive hemlock woolly adelgid, Adelges tsugae Annand. The adelgid is a sedentary insect with a mobile crawler stage that provides a readily available, easily obtained food source for predators in hemlock canopies. However, an abundance of alternative prey will affect within canopy spider distribution and the potential intensity with which spiders consume these prey. Understanding the response of spiders to potential prey availability is essential to understanding the trophic interactions involving these predators and their potential for influencing herbivore populations. PMID- 22546442 TI - Wood-nesting ants and their parasites in forests and coffee agroecosystems. AB - Agricultural intensification is linked to reduced species richness and may limit the effectiveness of predators in agricultural systems. We studied the abundance, diversity, and species composition of wood-nesting ants and frequency of parasitism of poneromorph ants in coffee agroeco systems and a forest fragment in Chiapas, Mexico. In three farms differing in shade management and in a nearby forest fragment, we surveyed ants nesting in rotten wood. We collected pupae of all poneromorph ants encountered, and incubated pupae for 15 d to recover emerging ant parasites. If no parasites emerged, we dissected pupae to examine for parasitism. Overall, we found 63 ant morphospecies, 29 genera, and 7 subfamilies from 520 colonies. There were no significant differences in ant richness or abundance between the different sites. However, there were significant differences in the species composition of ants sampled in the four different sites. The parasitism rates of ants differed according to site; in the forest 77.7% of species were parasitized, and this number declined with increasing intensification in traditional polyculture (40%),commercial polyculture (25%), and shade monoculture (16.6%). For three of four poneromorph species found in >1 habitat, parasitism rates were higher in the more vegetatively complex sites. The result that both ant species composition and ant parasitism differed among by site indicates that coffee management intensification affects wood-nesting ant communities. Further, coffee intensification may significantly alter interactions between ants and their parasites, with possible implications for biological control in coffee agroecosystems. PMID- 22546443 TI - The influence of forest stand and site characteristics on the composition of exotic dominated ambrosia beetle communities (Coleoptera: Curculionidae: Scolytinae). AB - Economic and biological consequences are associated with exotic ambrosia beetles and their fungal associates. Despite this, knowledge of ambrosia beetles and their ecological interactions remain poorly understood, especially in the oak hickory forest region. We examined how forest stand and site characteristics influenced ambrosia beetle habitat use as evaluated by species richness and abundance of ambrosia beetles, both the native component and individual exotic species. We documented the species composition of the ambrosia beetle community, flight activity, and habitat use over a 2-yr period by placing flight traps in regenerating clearcuts and older oak-hickory forest stands differing in topographic aspect. The ambrosia beetle community consisted of 20 species with exotic ambrosia beetle species dominating the community. Similar percentages of exotic ambrosia beetles occurred among the four forest habitats despite differences in stand age and aspect. Stand characteristics, such as stand age and forest structure, influenced ambrosia beetle richness and the abundances of a few exotic ambrosia beetle species and the native ambrosia beetle component. Topographic aspect had little influence on ambrosia beetle abundance or species richness. Older forests typically have more host material than younger forests and our results may be related to the amount of dead wood present. Different forms of forest management may not alter the percent contribution of exotic ambrosia beetles to the ambrosia beetle community. PMID- 22546444 TI - Population growth of Aphis gossypii and Myzus persicae (Hemiptera: Aphididae) in the presence of Linepithema humile and Tapinoma sessile (Hymenoptera: Formicidae). AB - Invasive ant species can have dramatic impacts on native ants, through direct predation and by usurping common resources. Most invasive ants and many native ants use honeydew, produced by phloem-sucking hemipterans. Because colonies of invasive ants can become very large after establishment, these ants may facilitate greater hemipteran trophobiont population growth compared with their sympatric native ant counterparts. We examined the population growth of an aphid mutualist, Aphis gossypii, and a nonmutualist, Myzus persicae, exposed to two Dolichoderine ants, Linepithema humile, a globally widespread invasive species, and Tapinoma sessile, a widespread co-occurring native ant, in North America in an enemy-free laboratory study. L. humile worker foraging activity was at least twice that of T. sessile, and populations of the myrmecophile, A. gossypii, were greater when exposed to L. humile than T. sessile, possibly caused, in part, by more frequent encounters with L. humile. L. humile ignored M. persicae when A. gossypii was absent, whereas T. sessile preyed on it. Both ant species preyed on M. persicae when A. gossypii was also present. This suggested that both ants may assess nutritional gains from aphid species (i.e., honeydew versus body tissue), eliminating less productive aphids competing for host plant space. Through their impact on populations of hemipteran mutualists, we suggest that colonies of L. humile and perhaps other invasive ants may acquire more honeydew than native ants, thereby fueling colony growth that leads to numerical dominance and widespread success in introduced environments. PMID- 22546445 TI - Larval competition between Aphidius ervi and Praon volucre (Hymenoptera: Braconidae: Aphidiinae) in Macrosiphum euphorbiae (Hemiptera: Aphididae). AB - Interspecific competition between parasitoid larvae may influence the size, structure, and stability of the population, leading to a reduction in total parasitism and thus restricting the pest control. Aphidius ervi (Haliday) and Praon volucre (Haliday) are endoparasitoids that possess a wide host range and present considerable potential for the biological control of the aphid Macrosiphum euphorbiae (Thomas). The larval competition between A. ervi and P. volucre, and the possible intrinsic competitive superiority of one of the parasitoids in M. euphorbiae, have been studied. In single parasitism experiments, mated parasitoid females (n=10) were maintained individually in contact with M. euphorbiae hosts (n=30) inside petri dishes containing lettuce leaf discs and maintained in environmental chamber at 22 +/- 1 degrees C, 70 +/- 10% RH, and 12-h photophase. The multiple parasitism experiments consisted of exposing single parasitized aphids (n=120) to the second parasitoid species. Two oviposition events were performed with a 4-h interval between them, namely the following: sequence A (oviposition by A. ervi, followed by P. volucre) and sequence B (oviposition by P. volucre, followed by A. ervi). Oviposition sequence A generated 24 A. ervi and 55 P. volucre adults, whereas oviposition sequence B generated 23 and 49 adults. P. volucre is an intrinsically superior competitor compared with A. ervi, and the use of the two species simultaneously may result in competitive exclusion and influence the stability of the parasitoid population. PMID- 22546446 TI - Host instar susceptibility and selection and interspecific competition of three introduced parasitoids of the mealybug Paracoccus marginatus (Hemiptera: Pseudococcidae). AB - Three previously introduced parasitoids (Acerophagus papayae Noyes and Schauff, Anagyrus loecki Noyes and Menezes, and Pseudleptomastix mexicana Noyes and Schauff [Hymenoptera: Encyrtidae]) of the mealybug Paracoccus marginatus Williams and Granara de Willink (Hemiptera: Pseudococcidae) were studied for their host instar susceptibility and sex ratio, host instar selection, and interspecific competition in the laboratory. All three parasitoids were able to develop in the second instars, third-instar females, and adult females of P. marginatus. No progeny emerged from first-instar mealybugs. The proportion of female emergence was increased with increasing host size. Parasitoids selected their host instars for oviposition when they had a choice. Between second- and third-instar hosts, A. papayae and P. mexicana had significantly higher parasitism in second-instar mealybugs, whereas A. loecki had higher parasitism in the third-instar mealybugs. When competed with either one or two parasitoid species, A. papayae was significantly more successful in second-instar hosts and A. loecki was significantly more successful in third-instar mealybugs. P. mexicana was significantly less competitive when with A. papayae in both second and third instars, with A. loecki in third instars and with both A. papayae and A. loecki in second and third instars. Overall, A. papayae provided a better control of the host, when present singly or with the other two parasitoids. This information is important in evaluating the efficiency of A. papayae, A. loecki, and P. mexicana and understanding the outcome of their recovery and establishment in field studies conducted in Florida. PMID- 22546447 TI - Measuring the impact of biotic factors on populations of immature emerald ash borers (Coleoptera: Buprestidae). AB - Cohorts of emerald ash borer larvae, Agrilus planipennis Fairmaire, were experimentally established in July of 2008 on healthy green ash (Fraxinus pennsylvanica) trees in two wooded plots at each of three sites near Lansing, MI, by caging gravid emerald ash borer females or placing laboratory-reared eggs on trunks (0.5-2 m above the ground) of selected trees. One plot at each site was randomly chosen for release of two introduced larval parasitoids, Tetrastichus planipennisi Yang (Hymenoptera: Eulophidae) and Spathius agrili Yang (Hymenoptera: Braconidae), whereas the other served as the control. Stage specific mortality factors and rates were measured for all experimentally established cohorts and for associated wild (i.e., naturally occurring) emerald ash borer immature stages via destructive sampling of 2.5 m (above the ground) trunk sections of cohort-bearing trees in the spring and fall of 2009. Host tree defense was the most important mortality factor, causing 32.0 to 41.1% mortality in the experimental cohorts and 17.5 to 21.5% in wild emerald ash borer stages by spring 2009, and 16.1 to 29% for the remaining experimental cohorts, and 9.9 to 11.8% for wild immature emerald ash borer stages by fall 2009. Woodpecker predation was the second most important factor, inflicting no mortality in the experimental cohorts but causing 5.0 to 5.6% mortality to associated wild emerald ash borer stages by spring 2009 and 9.2 to 12.8% and 3.2 to 17.7%, respectively, for experimental cohorts and wild emerald ash borer stages by fall 2009. Mortality from disease in both the experimental and wild cohorts was low (<3%) in both the spring and fall sample periods. In the fall 2009 samples, ~ 1.5% of experimental cohorts and 0.8% of the wild emerald ash borer stages were parasitized by T. planipennisi. While there were no significant differences in mortality rates because of parasitism between parasitoid-release and control plots, T. planipennisi was detected in each of the three release sites by the end of the study but was not detected in the experimental cohorts or associated wild larvae in any of the three control plots. PMID- 22546448 TI - Astylus atromaculatus (Coleoptera: Melyridae): abundance and role in pollen dispersal in Bt and non-Bt cotton in South Africa. AB - In South Africa, modified Bt (Cry1 Ac) cotton cultivars and organic ones coexist. This raises the question of the risk of dissemination of genetically modified (GM) pollen to non-GM crops by visiting insects. We inventoried the flower visiting insects in Bt and non-Bt cotton fields of the South African Highveld region and investigated their role in pollen dispersal. Their diversity and abundance varied slightly among sites, with Astylus atromaculatus as the predominant insect on both Bt and non-Bt cotton flowers. The other major flower visiting species were Apis mellifera and solitary Apidae. No differences were found in the abundance of each taxum between Bt and non-Bt cotton except for Scoliidae and Nitidulidae, which were scarce overall (<0.5%) but more abundant on the non-Bt flowers in the central area of the field at one site. The pollen load on A. atromaculatus was as high as on Apis mellifera. Cage tests showed that A. atromaculatus can pollinate female cotton plants by transferring pollen from male donor plants. In the field, the flight range of this insect was generally short (25 m), but it can occasionally reach up to 200 m or even more. This study therefore highlights that A. atromaculatus, commonly regarded as a pest, could be an unexpected but efficient pollinator. Because its population density can be high, this species could mediate unwanted cotton pollen flow when distances between coexiting fields are not sufficient. PMID- 22546449 TI - Interaction between western corn rootworm (Coleoptera: Chrysomelidae) larvae and root-infecting Fusarium verticillioides. AB - A greenhouse experiment was conducted to evaluate the effect of soil-dwelling larvae of the western corn rootworm, Diabrotica virgifera virgifera LeConte, on infection of maize roots by the mycotoxin-producing plant-pathogenic fungus, Fusarium verticillioides (Saccardo) Nirenberg (synonym=Fusarium moniliforme Sheldon). The time and order of application of F. verticillioides and western corn rootworm were varied in three different treatments to investigate the influence of timing on root colonization of F. verticillioides and western corn rootworm larval development. Root feeding by western corn rootworm larvae increased root colonization by F. verticillioides (as determined by real-time polymerase chain reaction) up to 50-fold when a high inoculum (10(7) spores/plant) of F. verticillioides was applied before western corn rootworm eggs were added. This effect was stronger the earlier F. verticillioides was applied relative to the time of western corn rootworm egg application but was only significant for the high F. verticillioides inoculum density treatment; F. verticillioides colonization was not increased when a low F. verticillioides inoculum density (10(6) spores/plant) was applied. F. verticillioides slightly suppressed larval development in that the ratio of second- to third-instar larvae was higher in treatments with F. verticillioides than without F. verticillioides. F. verticillioides reduced western corn rootworm head capsule width when applied before or simultaneously with western corn rootworm. The results of this study are discussed focusing on conditions that favor root colonization by F. verticillioides and its influence on western corn rootworm larval development. PMID- 22546450 TI - Host plant phenology affects performance of an invasive weevil, Phyllobius oblongus (Coleoptera: Curculionidae), in a northern hardwood forest. AB - We investigated how host plant phenology and plant species affected longevity, reproduction, and feeding behavior of an invasive weevil. Phyllobius oblongus L. (Coleoptera: Curculionidae) is common in northern hardwood forests of the Great Lakes Region. Adults emerge in spring, feed on foliage of woody understory plants, and oviposit in the soil. Preliminary data indicate that adults often feed on sugar maple, Acer saccharum Marshall, foliage early in the season, then feed on other species such as raspberry, Rubus spp. Whether this behavior reflects temporal changes in the quality of A. saccharum tissue or merely subsequent availability of later-season plants is unknown. We tested adult P. oblongus in laboratory assays using young (newly flushed) sugar maple foliage, old (2-3 wk postflush) sugar maple foliage, and raspberry foliage. Raspberry has indeterminate growth, thus always has young foliage available for herbivores. Survival, oviposition, and leaf consumption were recorded. In performance assays under no-choice conditions, mated pairs were provided one type of host foliage for the duration of their lives. In behavioral choice tests, all three host plants were provided simultaneously and leaf area consumption was compared. Adults survived longer on and consumed greater amounts of young maple and raspberry foliage than old maple foliage. P. oblongus preferred young maple foliage to old maple foliage early in the season, however, later in the growing season weevils showed less pronounced feeding preferences. These results suggest how leaf phenology, plant species composition, and feeding plasticity in host utilization may interact to affect P. oblongus population dynamics. PMID- 22546451 TI - Host plant effects on development and reproduction of the glassy-winged sharpshooter, Homalodisca vitripennis (Homoptera: Cicadellidae). AB - Development, survivorship, longevity, reproduction, and life table parameters of the glassy-winged sharpshooter, Homalodisca vitripennis (Germar), were examined in the laboratory using three host plants, sunflower (Helianthus annuus L.), Chrysanthemum morifolium L., and euonymus (Euonymus japonica Thurb.). Females deposited similar-sized egg masses on all three plants. Hatching was highest with eggs deposited on euonymus and lowest for those deposited on sunflower. Embryonic development time among host plants was similar while nymph development time was shortest on sunflower and longest on euonymus. Nymph survival to adulthood ranged from 32% on euonymus to 82% for those reared on sunflower. Adult females had similar life spans on sunflower and chrysanthemum. H. vitripennis completed a lengthy egg-to-adult development on euonymus, however, mating did not occur. The onset of mating was contingent on maturation of adult females. The majority of mating activity occurred within the first three days after onset. Premating periods ranged from 6 to 7 d on sunflower to 27 d on chrysanthemum, with overall mating rates of 77.4 and 19.8%, respectively. Females typically mated more than once and they had the longest oviposition period and highest egg production on sunflower; ~ 50 and 67% of total number of eggs were deposited within first 45 d after the start of oviposition on sunflower and chrysanthemum, respectively. Adult size and weight related to which host plant was consumed throughout development. Greater intrinsic and finite rates of increase and net reproduction rate, and shorter population doubling time occurred when the sharpshooters were allowed to develop on sunflower. The overall developmental and reproductive parameters obtained in this study indicate that a mixed host plant system, composed of sunflower and euonymus or chrysanthemum plants, is an efficient means for optimizing egg production and colony maintenance of the glassy-winged sharpshooter. PMID- 22546452 TI - Field observations of climbing behavior and seed predation by adult ground beetles (Coleoptera: Carabidae) in a lowland area of the temperate zone. AB - Granivory is a specialized food habit in the predominantly carnivorous beetle family Carabidae. Most studies of carabid granivory have been conducted under laboratory conditions; thus, our knowledge of the feeding ecology of granivorous carabids in the field is insufficient. I conducted field observations of climbing behavior and seed predation by adult carabids in a lowland area of eastern Japan, from early October to late November in 2008. This is the first systematic field observation of the feeding ecology of granivorous carabids in the temperate zone. In total, 176 carabid individuals of 11 species were observed, with 108 individuals feeding on plant seeds/flowers. Each carabid species was primarily observed feeding on a particular plant species. Frequently observed combinations were: Amara gigantea Motschulsky on Humulus scandens (Loureiro) Merrill (Moraceae) seed, Amara lucens Baliani on Artemisia indica Willdenow (Asteraceae) flower, and Amara macronota (Solsky) and Harpalus (Pseudoophonus) spp. on Digitaria ciliaris (Retzius) Koeler (Poaceae) seed. In all but one species, the sex ratio of individuals observed feeding was female biased. In Am. gigantea and Am. macronota, a larger proportion of females than males ate seeds. In the three Amara species, copulations on plants, with the female feeding on its seeds/flowers, were often observed. These observations may indicate that, whereas females climb onto plants to feed on seeds, males climb to seek females for copulation rather than forage. Because granivorous carabids play important roles as weed-control agents in temperate agro-ecosystems, the present results would provide valuable basic information for future studies on this subject. PMID- 22546453 TI - Soybean cyst nematode effects on soybean aphid preference and performance in the laboratory. AB - Herbivores on plants frequently interact via shared resources. Studies that have examined performance of herbivores in the presence of other herbivores, however, have often focused on above-ground feeding guilds and relatively less research has examined interactions between below- and above-ground consumers. We examine how soybean aphid, Aphis glycines (Matsumura) an above-ground phloem-feeding herbivore, interacts with a below-ground plant parasite, soybean cyst nematode, Heterodera glycines (Ichinohe) through their shared host plant, soybean (Glycine max L). Laboratory experiments evaluated the preference of alate (flight capable) soybean aphids toward plants either infected with soybean cyst nematode or uninfected controls in a simple choice arena. Alate soybean aphids preferred uninfected soybean over soybean cyst nematode-infected plants: 48 h after the releases of alate aphids in the center of the arena, 67% more aphids were found on control soybean compared with nematode infected plants. No-choice feeding assays were also conducted using clip cages and apterous (flight-incapable) aphids to investigate effect of soybean cyst nematode infection of soybean on aphid performance. These studies had mixed results: in one set of experiments overall aphid population growth at 7 d was not statistically different between control and soybean cyst nematode-infected plants. A different experiment using a life-table analysis found that apterous aphids feeding on soybean cyst nematode infected plants had significantly greater finite rate of increase (lambda), intrinsic rate of increase (r(m)), and net reproductive rate (R(o)) compared with aphids reared on uninfected (control) soybean plants. We conclude that the below ground herbivore, soybean cyst nematode, primarily influences soybean aphid behavior rather than performance. PMID- 22546454 TI - Development and parasitism by Aphelinus certus (Hymenoptera: Aphelinidae), a parasitoid of Aphis glycines (Hemiptera: Aphididae). AB - Since its introduction in 2000, the soybean aphid (Aphis glycines Matsumura) has been a serious pest of soybean in North America. Currently, insecticide application is the only recommended control method. However, a number of natural enemies have the potential to regulate soybean aphid populations. In 2007, Aphelinus certus Yasnosh, a soybean aphid parasitoid native to Asia, was found in commercial soybean fields in Ontario. This is the first record of this species in North America. To evaluate the potential biological control services provided by A. certus for soybean aphid management, temperature-dependent developmental parameters and functional response to soybean aphid were determined. A. certus is capable of completing its development between temperatures of 15.3 and 30.2 degrees C. The lower thresholds of development for the egg-mummy and mummy-adult life stages were determined to be 9.1 and 11.6 degrees C, respectively. The lethal temperature of development for the egg-mummy and mummy-adult life stages were 29.5 and 31.0 degrees C, respectively. In this temperature range, A. certus did not exhibit temperature-dependent mortality; however, parasitism rate increased with temperature. A. certus exhibited a type II functional response to the soybean aphid. PMID- 22546455 TI - Effects of larval density on flight potential of the beet webworm, Loxostege sticticalis (Lepidoptera: Pyralidae). AB - Tethered-flight techniques were used to investigate the flight potential of 1-d old adult beet webworm, Loxostege sticticalis L. (Lepidoptera: Pyralidae), reared at densities of1, 10, 20, 30, and 40 larvae per 650-ml jar. Larval density had a significant effect on the flight potential, including total flight duration, distance, average velocity, and longest flight duration. Adults reared at a density of 10 larvae per jar, and those reared in isolation displayed the greatest and poorest flight capacity,respectively, relative to the other density treatments. Larval density also significantly affected length of the preoviposition period. Females with longer preoviposition period usually showed greater flight potential, and preoviposition period was positively correlated with flight potential. Body weight, water content, and triglyceride content of the moths were significantly affected by larval density, whereas glycogen content was not. Triglyceride content of adults reared at the different larval densities corresponded to the observed differences inflight potential, whereas water content and body weight were not related to their flight potential. These results suggest that larval density exerts a significant influence on preoviposition period and triglyceride content, which in turn influence flight potential of adult L. sticticalis. PMID- 22546456 TI - Functional response of larval and adult stages of Hippodamia variegata (Coleoptera: Coccinellidae) to different densities of Aphis fabae (Hemiptera: Aphididae). AB - We compare the efficiencies of different stages of Hippodamia variegata (Coleoptera: Coccinellidae) preying on Aphis fabae (Scolpoli) (Hemiptera: Aphididae) by estimating the functional responses of all stages. The experiments were carried out on leaf disks in petri dishes with 15-20 replicates. Our results revealed that all larval instars and adult males and females of H. variegata exhibited type II functional responses on different densities of prey. The rate of searching efficiency and handling time were estimated as 0.063 h(-1) and 6.933 h for first instar, 0.059 h(-1) and 3.343 h for second instar, 0.103 h(-1) and 1.909 h for third instar, 0.114 h(-1) and 0.455 h for fourth instar, 0.159 h(-1) and 1.194 h for male, 0.093 h(-1) and 0.409 h for female, respectively. Thus, handing time decreased from first instar to female. Handling times of males were significantly greater than those of females. The most effective stages of H. variegata were females, fourth instars, and males. The efficiency of females was nearly three times greater than that of males. The voracity of larval stages and male and female adults of H. variegata were estimated as 2.93, 5.85, 12.13, 45.13, 18.33, and 44.60 (aphids/d), respectively. PMID- 22546457 TI - Phorid flies, Pseudacteon spp. (Diptera: Phoridae), affect forager size ratios of red imported fire ants Solenopsis invicta (Hymenoptera: Formicidae) in Texas. AB - Multiple species of Pseudacteon phorid flies (Diptera: Phoridae) are currently being released throughout the southern United States to aid biological control of red imported fire ants, Solenopsis invicta Buren (Hymenoptera: Formicidae). It is anticipated that these flies will interfere with S. invicta foraging, allowing native ant assemblages to outcompete S. invicta for available resources. Numerous studies have shown a decrease in S. invicta foraging intensity when exposed to phorids. This study documents a behavioral change in phorid-exposed S. invicta colonies at a phorid release site in central Texas. Significant differences in forager size ratios were detected between phorid-exposed and phorid-absent colonies. A similar phenomenon was recently documented in the native range of these insects in South America as well. Experimental manipulation of ratios of S. invicta worker sizes has been shown to have important effects on colony success. This newly documented phorid-mediated S. invicta colony-level effect represents a significant shift in S. invicta foraging dynamics and may provide an additional mechanism by which phorids can influence S. invicta populations in their United States range. PMID- 22546458 TI - Interspecific competition and territory defense mechanisms of Coptotermes formosanus and Coptotermes gestroi (Isoptera: Rhinotermitidae). AB - Coptotermes formosanus Shiraki and C. gestroi (Wasmann) are the most widely distributed species of the genus and occur sympatrically in the subtropics. Results of two bioassays in the current study showed that C. gestroi was more aggressive than C. formosanus. In the petri-dish bioassays, C. gestroi won most of the agonistic encounters over C. formosanus. In the two-dimensional foraging arena bioassays, over 73% tunnel interceptions observed in the 18 replications were caused by progressing tunnels of C. gestroi encountering the tunnels of C. formosanus. Tunnel interception of the two species resulted in minor agonistic interactions. Both species quickly buried the connected tunnel at multiple locations. Termite cadavers resulting from agonistic behavior appeared to have induced sand deposition that resulted in tunnel blockages and deterred reopening of these blockages. Sealing individual tunnels in response to encounters with other species acts to prevent further agonism and mortality, and on a broad scale, the aggregate of such blocked tunnels may come to define the borders between adjacent colonies. PMID- 22546459 TI - Detection of and monitoring for Aedes albopictus (Diptera: Culicidae) in suburban and sylvatic habitats in north central Florida using four sampling techniques. AB - A sampling study using a BG-Sentinel trap baited with CO(2), a gravid trap baited with an oak-pine infusion, a human subject, and a vegetative aspirator was conducted to compare their reliability at detecting Aedes albopictus Skuse in suburban and sylvatic habitats. We collected 73,849 mosquitoes, representing 29 species from 11 genera over a 20-wk period. The BG-Sentinel trap accounted for over 85% of all Ae. albopictus captured and was significantly more effective at detecting the presence of Ae. albopictus compared with the other three techniques. Landing counts provided the fewest mosquito species (n = 10), yet provided a quick and effective weekly assessment of the major biting species and were the most effective method for sampling Ae. albopictus within a 10-min period. Fewer Ae. albopictus were sampled from sylvatic habitats compared with suburban ones. Sampling criteria advantageous for surveying Ae. albopictus and other mosquito species are discussed. PMID- 22546460 TI - Grass thrips (Anaphothrips obscurus) (Thysanoptera: Thripidae) population dynamics and sampling method comparison in timothy. AB - Sampling studies were conducted on grass thrips, Anaphothrips obscurus (Muller) (Thysanoptera: Thripidae), in timothy, Phleum pratense L. These studies were used to compare the occurrence of brachypterous and macropterous thrips across sampling methods, seasons, and time of day. Information about the population dynamics of this thrips was also revealed. Three absolute and two relative methods were tested at three different dates within a season and three different daily times during four harvest periods. Thrips were counted and different phenotypes were recorded from one of the absolute methods. Absolute methods were the most similar to one another over time of day and within seasonal dates. Relative methods varied in assessing thrips population dynamics over time of day and within seasonal dates. Based on thrips collected from the plant and sticky card counts, macropterous individuals increased in the spring and summer. Thrips aerially dispersed in the summer. An absolute method, the beat cup method (rapping timothy inside a plastic cup), was among the least variable sampling methods and was faster than direct observations. These findings parallel other studies, documenting the commonality of diel and diurnal effects on sampled arthropod abundance and the seasonal effects on population abundance and structure. These studies also demonstrate that estimated population abundance can be markedly affected by temporal patterns as well as shifting adult phenotypes. PMID- 22546461 TI - Captures of pest fruit flies (Diptera: Tephritidae) and nontarget insects in BioLure and torula yeast traps in Hawaii. AB - MultiLure traps were deployed in a Hawaiian orchard to compare the attraction of economically important fruit flies and nontarget insects to the three-component BioLure and torula yeast food lures. Either water or a 20% propylene glycol solution was used to dissolve the torula yeast or as capture fluid in BioLure traps. Torula yeast in water was more attractive than BioLure for male and female Bactrocera cucurbitae (Coquillett) and Bactrocera dorsalis (Hendel) and as attractive for Ceratitis capitata (Wiedemann), and the addition of propylene glycol significantly inhibited the attractiveness of torula yeast. The known synergistic effect of propylene glycol with BioLure, resulting in increased captures of Anastrepha flies, was not observed with Bactrocera. Nontarget Drosophilidae, Neriidae, Phoridae, Calliphoridae, Sarcophagidae, and Muscidae were more strongly attracted to BioLure, and both lures collected Chloropidae equally. As with fruit flies, propylene glycol in torula yeast significantly decreased nontarget captures. The results therefore suggest that torula yeast in water is a more effective attractant than BioLure for pest Bactrocera while minimizing nontarget captures. PMID- 22546462 TI - Developmental times and life table statistics of Aulacorthum solani (Hemiptera: Aphididae) at six constant temperatures, with recommendations on the application of temperature-dependent development models. AB - Aulacorthum solani (Kaltenbach) (known as foxglove aphid or glasshouse potato aphid) is a pest of increasing economic importance in several agricultural crops worldwide, including greenhouse vegetables and ornamentals. Developmental rates and age-specific life tables for a North American population of A. solani on pansy (Viola * wittrockiana) (Gams.) were determined at six constant temperatures, and comparisons were made to previous studies of A. solani from differing geographic regions and host crops. On pansy, A. solani developed fastest at 25 degrees C, passing through the four nymphal instars in an average of 6.9 d. The highest intrinsic rates of population increase (0.410 and 0.445) and shortest population doubling times (1.69 and 1.56 d) were recorded at 20 and 25 degrees C, respectively. Average total fecundity remained high from 10 to 20 degrees C (74-68 nymphs/adult); a significant decrease to 39 nymphs/adult occurred at 25 degrees C. For calculating developmental thresholds, we present here a method of adjusting the lower developmental threshold (t(min)) using estimates from nonlinear models to provide an improved estimate of the thermal constant (K, in degree-days). We also call attention to the necessity of using a simulation method to estimate the true upper developmental threshold (t(max)) and optimum developmental temperature (t(opt)) from the Lactin-2 model of temperature dependent development. PMID- 22546463 TI - Embryonic developmental rates of northern grasshoppers (Orthoptera: Acrididae): implications for climate change and habitat management. AB - Accurate models of temperature-dependent embryonic developmental rates are important to assess the effects of a changing climate on insect life cycles and to suggest methods of population management by habitat manipulation. Embryonic development determines the life cycle of many species of grasshoppers, which, in cold climates, spend two winters in the egg stage. Increasing temperatures associated with climate change in the subarctic could potentiate a switch to a univoltine life cycle. However, egg hatch could be delayed by maintaining a closed vegetative canopy, which would lower soil temperatures by shading the soil surface. Prediapause and postdiapause embryonic developmental rates were measured in the laboratory over a wide range of temperatures for Melanoplus borealis Fieber and Melanoplus sanguinipes F. (Orthoptera: Acrididae) A model was fit to the data and used to predict dates of egg hatch in the spring and prediapause development in the fall under different temperature regimens. Actual soil temperatures were recorded at several locations over 5 yr. To simulate climate warming, 2, 3, or 4 degrees C was added to each hourly recorded temperature. Results suggest that a 2, 3, or 4 degrees C increase in soil temperatures will result in eggs hatching ~ 3, 5, or 7 d earlier, respectively. An increase of 3 degrees C would be required to advance prediapause development enough to allow for a portion of the population to be univoltine in warmer years. To simulate shading, 2 and 4 degrees C were subtracted from observed temperatures. A 4 degrees C decrease in temperatures could potentially delay hatch by 8 d. PMID- 22546464 TI - Influence of generation and photoperiod on larval development of Lobesia botrana (Lepidoptera: Tortricidae). AB - The influence of generation (under field conditions) and photoperiod (under laboratory conditions) on Lobesia botrana larvae development was studied. Some larvae were collected during three annual generations in two grape-growing areas of northeastern Italy, and others were individually reared in the laboratory from egg to pupa on an artificial diet under two different photoperiod conditions (respectively, daylight 16 h/d [long day {LD}] and 14 h/d [short day {SD}]). The mandible lengths of collected larvae were measured and the data analyzed morphometrically to determine the number of larval instars. In the laboratory study, the number of larval moultings, the mandible length of each instar, the development time from hatching larva to pupa, and the pupal weight were considered. The measurement of mandible lengths of larvae collected in the field indicated the existence of five larval instars in all three annual generations, but the size of the two oldest larval instars was significantly higher for third generation larvae than for the previous generations. Under laboratory conditions, the larvae usually exhibited five instars, but the mandible lengths of larvae and the pupa size were greater for individuals reared under SD. These also took a greater number of days to develop from hatching larvae to pupae. Because a larger size of the final larval instar occurs in individuals that produce diapausing pupae under SD in both the laboratory and the field, a positive association between larval size and the probability of surviving the winter can be inferred. PMID- 22546465 TI - Northward expansion of the invasive Linepithema humile (Hymenoptera: Formicidae) in the eastern United States is constrained by winter soil temperatures. AB - The invasive Argentine ant, Linepithema humile (Mayr) (Hymenoptera: Formicidae) has been evident in the North Carolina Piedmont, United States for 90 yr but has failed to spread further north. We investigated the mechanisms preventing this expansion. The Argentine ant ceases foraging at temperatures below 5 degrees C and we hypothesized that winter soil temperatures at higher latitudes restricted foraging long enough to cause colony starvation. We tested if the Argentine ant could successfully feed at temperatures below 5 degrees C and found that colonies would starve. We subjected Argentine ant nests to a range of sub- and above freezing temperatures and measured worker mortality at various time intervals. We found that Argentine ant colonies will collapse after 8.5 d at 5 degrees C. Argentine ants can escape ambient cold temperatures by moving nests into the soil column. We tested how deeply into the soil Argentine ant queens and workers need to move to survive winter in North Carolina. Soil temperatures in the North Carolina Piedmont do not fall below 5 degrees C for longer than nine consecutive days; therefore, Argentine ant colonies need only to retreat a few centimeters into the soil column to escape unsuitable temperatures. Winter soil temperature data from four climate stations situated from latitudes 35 degrees , the current Eastern United States latitudinal limit for Argentine ant population expansion, to 39 degrees were searched for periods where soil temperatures would have led to colony extirpation. North of their current distributions, extended periods of soil temperatures below 5 degrees C regularly occur, preventing Argentine ant colonies from persisting. PMID- 22546466 TI - Seasonal adaptations to day length in ecotypes of Diorhabda spp. (Coleoptera: Chrysomelidae) inform selection of agents against saltcedars (Tamarix spp.). AB - Seasonal adaptations to daylength often limit the effective range of insects used in biological control of weeds. The leaf beetle Diorhabda carinulata (Desbrochers) was introduced into North America from Fukang, China (latitude 44 degrees N) to control saltcedars (Tamarix spp.), but failed to establish south of 38 degrees N latitude because of a mismatched critical daylength response for diapause induction. The daylength response caused beetles to enter diapause too early in the season to survive the duration of winter at southern latitudes. Using climate chambers, we characterized the critical daylength response for diapause induction (CDL) in three ecotypes of Diorhabda beetles originating from 36, 38, and 43 degrees N latitudes in Eurasia. In a field experiment, the timing of reproductive diapause and voltinism were compared among ecotypes by rearing the insects on plants in the field. CDL declined with latitude of origin among Diorhabda ecotypes. Moreover, CDL in southern (<39 degrees N latitude) ecotypes was shortened by more than an hour when the insects were reared under a fluctuating 35-15 degrees C thermoperiod than at a constant 25 degrees C. In the northern (>42 degrees N latitude) ecotypes, however, CDL was relatively insensitive to temperature. The southern ecotypes produced up to four generations when reared on plants in the field at sites south of 38 degrees N, whereas northern ecotypes produced only one or two generations. The study reveals latitudinal variation in how Diorhabda ecotypes respond to daylength for diapause induction and how these responses affect insect voltinism across the introduced range. PMID- 22546467 TI - Temperature-dependent development and life table parameters of Octodonta nipae (Coleoptera: Chrysomelidae). AB - The effect of temperature on the development, survivorship, fecundity, and life table parameters of Octodonta nipae (Maulik) (Coleoptera: Chrysomelidae), was studied at seven constant temperatures of 17.5, 20, 22.5, 25, 27.5, 30, and 32.5 degrees C. Preliminary experiments showed that no development was observed at 15 and 35 degrees C. All individuals completed development and females laid eggs from 20 to 30 degrees C. There was a significant decrease in male and female longevity with increasing temperatures from 20 to 30 degrees C. The longest and shortest longevity were 203.5 and 73.7 d for males, and 178.7 and 57.6 d for females, respectively. Females produced on average 62.7, 88.9, 116.8, 70.0, and 47.3 eggs and the life expectancy for a newborn egg was 171.6, 148.7, 114.9, 89.2, and 94.8 d at 20, 22.5, 25, 27.5 and 30 degrees C, respectively. Life history data were analyzed by using an age-stage, two-sex life table. The intrinsic rate of increase (r) and the finite rate of increase (lambda) of O. nipae increased with increasing temperatures from 20 to 30 degrees C, while the mean generation time (T) decreased within this temperature range. The r was 0.0155, 0.0249, 0.0339, 0.0361, and 0.0383 d(-1) at 20, 22.5, 25, 27.5, and 30 degrees C, respectively. The net reproductive rate (r(0)) was highest at 25 degrees C (35.0 offspring), and lowest at 20 degrees C (17.0 offspring). T was shortest at 30 degrees C (76.4 d). The results showed that temperature greatly affected the fecundity and life table parameters of O. nipae, and a suitable temperature for population development and fecundity was at 25 degrees C. The life table data can be used for the projection of population growth and evaluation of control programs. PMID- 22546468 TI - Historical demography and phylogeography of a specialist bark beetle, Dendroctonus pseudotsugae Hopkins (Curculionidae: Scolytinae). AB - Contemporary distribution of North American species has been shaped by past glaciation events during the Quaternary period. However, their effects were not as severe in the southern Rocky Mountains and Northern Mexico as elsewhere in North America. In this context, we test hypotheses about the historical demography of Dendroctonus pseudotsugae, based on 136 haplotypes of mitochondrial cytochrome oxidase I. The phylogenetic analysis yielded four haplogroups corresponding to northwestern United States and southwestern Canada (NUS), southwestern United States (Arizona, SUS), northwestern Mexico (Sierra Madre Occidental, SMOC), and northeastern Mexico (Sierra Madre Oriental, SMOR). Predictions of demographic expansion were examined through neutrality tests against population growth and mismatch distribution. Results showed that the NUS and SMOC haplogroups have experienced demographic expansion events, whereas the SUS and SMOR haplogroups have not. Divergence times between pairs of haplogroups were estimated from early to middle Pleistocene. The longer divergence time between NUS and all other haplogroups could be the result of refugia within the Pacific Northwest and northern Rocky Mountains and long-term isolation from southernmost populations in Mexico. The results obtained in this study are in agreement with the evolutionary history of the host Douglas-fir, as the warmer climates of interglacial periods pushed conifers northward of Colorado, New Mexico, and Arizona, whereas environmental changes reduced the population size of Douglas-fir and forced fragmentation of distribution range southward into northern Mexico. PMID- 22546469 TI - Frequency of Bt resistance alleles in Helicoverpa armigera in the Xinjiang cotton planting region of China. AB - Helicoverpa armigera Hubner (Lepidoptera: Noctuidae) is a key insect pest of cotton in Xinjiang cotton-planting region of northwest China. In this region, cotton is grown on average ~ 1.65 million ha (1.53 ~ 1.80 million ha) annually in largely monoculture agricultural landscapes, similarly to cropping systems in the United States or Australia. Under such cropping regimes, naturally occurring refuges (with non-Bt crops) may be insufficient to prevent H. armigera resistance development to Bt toxins. Therefore, we assessed frequency of alleles conferring resistance to Cry1Ac toxin of F(1) and F(2) offspring of H. armigera isofemale lines from two distinct localities in the region during 2005-2009. More specifically, a total of 224 isofemale lines was collected from Korla County (~ 70% Bt cotton adoption) and 402 lines from Shache County (~ 5% Bt cotton planting). Subsequent offspring was screened on Cry1Ac artificial diet. From 2005 to 2009, resistance gene frequency in Korla fluctuated between 0.0000 and 0.0040, while being 0.0000-0.0008 in individuals collected from Shache, and there were no significant increases in both counties from 2005 to 2009. Relative average development rates (RADRs) of larvae in F(1) tests showed significant increases from Korla, but not in Shache. RADR of F(1) larvae is significantly correlated with RADR of F(2) offspring, indicating genetic variation in response to toxin in field H. armigera population. Although the occurrence of Cry1Ac resistance alleles was low in Xinjiang cotton-planting region of China, particular attention should be given to H. armigera resistance development in Korla County. PMID- 22546470 TI - Cancer detection and biopsy classification using concurrent histopathological and metabolomic analysis of core biopsies. AB - BACKGROUND: Metabolomics, the non-targeted interrogation of small molecules in a biological sample, is an ideal technology for identifying diagnostic biomarkers. Current tissue extraction protocols involve sample destruction, precluding additional uses of the tissue. This is particularly problematic for high value samples with limited availability, such as clinical tumor biopsies that require structural preservation to histologically diagnose and gauge cancer aggressiveness. To overcome this limitation and increase the amount of information obtained from patient biopsies, we developed and characterized a workflow to perform metabolomic analysis and histological evaluation on the same biopsy sample. METHODS: Biopsies of ten human tissues (muscle, adrenal gland, colon, lung, pancreas, small intestine, spleen, stomach, prostate, kidney) were placed directly in a methanol solution to recover metabolites, precipitate proteins, and fix tissue. Following incubation, biopsies were removed from the solution and processed for histology. Kidney and prostate cancer tumor and benign biopsies were stained with hemotoxylin and eosin and prostate biopsies were subjected to PIN-4 immunohistochemistry. The methanolic extracts were analyzed for metabolites on GC/MS and LC/MS platforms. Raw mass spectrometry data files were automatically extracted using an informatics system that includes peak identification and metabolite identification software. RESULTS: Metabolites across all major biochemical classes (amino acids, peptides, carbohydrates, lipids, nucleotides, cofactors, xenobiotics) were measured. The number (ranging from 260 in prostate to 340 in colon) and identity of metabolites were comparable to results obtained with the current method requiring 30 mg ground tissue. Comparing relative levels of metabolites, cancer tumor from benign kidney and prostate biopsies could be distinguished. Successful histopathological analysis of biopsies by chemical staining (hematoxylin, eosin) and antibody binding (PIN 4, in prostate) showed cellular architecture and immunoreactivity were retained. CONCLUSIONS: Concurrent metabolite extraction and histological analysis of intact biopsies is amenable to the clinical workflow. Methanol fixation effectively preserves a wide range of tissues and is compatible with chemical staining and immunohistochemistry. The method offers an opportunity to augment histopathological diagnosis and tumor classification with quantitative measures of biochemicals in the same tissue sample. Since certain biochemicals have been shown to correlate with disease aggressiveness, this method should prove valuable as an adjunct to differentiate cancer aggressiveness. PMID- 22546471 TI - Interleukin-6 regulates anti-arthritic effect of methotrexate via reduction of SLC19A1 expression in a mouse arthritis model. AB - INTRODUCTION: Methotrexate (MTX) enters cells via the reduced folate carrier SLC19A1, suggesting that SLC19A1 is associated with the efficacy of MTX. We here examined the relationship between the efficacy of MTX and the expression of SLC19A1 in glucose 6-phosphate isomerase (GPI)-induced arthritis. We found that interleukin-6 (IL-6) regulated the expression of SLC19A1, so we studied the effect of a combination of MTX and anti-mouse IL-6 receptor antibody (MR16-1). METHODS: GPI-induced arthritis was induced by intradermal immunization with recombinant GPI. MTX was given from the first day of immunization. Mice were injected once with MR16-1 10 days after immunization. The levels of SLC19A1 mRNA in whole hind limbs and immune cells were measured. Synovial cells from arthritic mice were cultured with cytokines, and cell proliferation and gene expressions were measured. RESULTS: MTX inhibited the development of GPI-induced arthritis; however, the efficacy of MTX gradually diminished. SLC19A1 expression in immunized mice with arthritis was lower than in intact mice; moreover, SLC19A1 expression in arthritic mice was further decreased when they were treated with MTX. IL-6 was highly expressed in whole hind limbs of arthritic mice. In an in vitro study using synovial cells from arthritic mice, IL-6 + soluble IL-6 receptor (sIL-6R) weakened the anti-proliferative effect of MTX and reduced SLC19A1 expression. Finally, although MR16-1 did not improve arthritis at all when administered on day 10, MTX in combination with MR16-1 more potently reduced the development of arthritis than did MTX alone. When used in combination with MTX, MR16-1 apparently reversed the decrease in SLC19A1 induced by MTX alone. CONCLUSIONS: In the present study, we demonstrated for the first time that IL-6 reduced the efficacy of MTX by decreasing the expression of SLC19A1, which is important for MTX uptake into cells. PMID- 22546472 TI - Inverse cue priming is not limited to masks with relevant features. AB - Apart from positive priming effects, masked prime stimuli can impair responses to a subsequent target stimulus which shares response-critical features in contrast to a target assigned to the opposite response. This counterintuitive phenomenon is called inverse priming (or negative compatibility effect). Here we examine the generality of this phenomenon beyond priming of motor responses. We used a non motor cue-priming paradigm to study the underlying mechanism of inverse priming for relevant features masks which include task-relevant stimulus features and for irrelevant masks which omit task-relevant features. We found inverse cue-priming effects with both types of masks. With task-irrelevant masks inverse cue-priming was emphasized in those participants being unable to perceive the prime. The existence of inverse non-motor priming under conditions where simple perceptual interactions between the stimuli are ruled out as the source of inverse priming is at odds with the view that inverse priming reflects motor inhibition. Alternatives are discussed. PMID- 22546473 TI - Zen meditation and access to information in the unconscious. AB - In two experiments and two different research paradigms, we tested the hypothesis that Zen meditation increases access to accessible but unconscious information. Zen practitioners who meditated in the lab performed better on the Remote Associate Test (RAT; Mednick, 1962) than Zen practitioners who did not meditate. In a new, second task, it was observed that Zen practitioners who meditated used subliminally primed words more than Zen practitioners who did not meditate. Practical and theoretical implications are discussed. PMID- 22546474 TI - Growth and physicochemical properties of L-phenylalaninium maleate: a novel nonlinear optical crystal. AB - Single crystals of novel organic nonlinear optical material, L-phenylalaninium maleate (LPM) having dimensions up to 10 * 6 * 6 mm(3) were grown by slow evaporation solution growth technique at room temperature. The grown crystals were confirmed by single crystal X-ray diffraction studies and the various functional groups were identified by FT-IR spectroscopic analysis. The optical properties were studied by optical absorption, second harmonic generation (SHG), photoconductivity and photoluminescence (PL) studies and reported for the first time. The optical band gap energy and SHG efficiency were found to be 4.85 eV and 1.5 times higher than KDP crystals. Negative photoconducting nature was confirmed by photoconductivity studies. Photoluminescence studies confirm the suitability of the sample for blue and green radiations. The title compound was also subjected to TG/DTA analysis and dielectric studies. Layer like growth pattern was analyzed by SEM micrograph. PMID- 22546475 TI - One-step labeling of degenerative neurons in unfixed brain tissue samples using Fluoro-Jade C. AB - Neurodegeneration is the underlying cause of a vast majority of neurological disorders and often a result of brain trauma, stroke, or neurotoxic insult. Here we describe a simple method for labeling degenerating neurons in unfixed brain tissue samples. This method could provide a new avenue for identifying and harvesting degenerative neurons from unfixed brain tissues for subsequent molecular analyses. PMID- 22546476 TI - Microdialysis probes alter presynaptic regulation of dopamine terminals in rat striatum. AB - The insertion of microdialysis probes into the rat striatum disrupts dopaminergic activity near the probe track. The present study suggests that a substantial fraction of DA terminals near the probe track (200 MUm) survive the probe implantation itself but that the surviving terminals experience altered presynaptic inhibition. We found that probe implantation did not just alter the amplitude of evoked dopamine responses recorded by voltammetry, but also changed their temporal profile in a fashion similar to that previously observed by quinpirole, an agonist of dopamine D2 autoreceptors. Altered presynaptic inhibition is supported by a hypersensitivity of evoked dopamine responses recorded near to microdialysis probes to raclopride, a D2 antagonist. Further, we found that evoked dopamine release was also hypersensitive to a final dose of the dopamine transporter inhibitor, nomifensine. PMID- 22546477 TI - Volume conduction effects in brain network inference from electroencephalographic recordings using phase lag index. AB - In this paper, we test the performance of a synchronicity estimator widely applied in Neuroscience, phase lag index (PLI), for brain network inference in EEG. We implement the four sphere head model to simulate the volume conduction problem present in EEG recordings and measure the activity at the scalp of surrogate sources located at the brain level. Then, networks are estimated under the null hypothesis (independent sources) using PLI, coherence (R) and phase coherence (PC) for the volume conduction and no volume conduction (NVC) cases. It is known that R and PC are highly influenced by volume conduction, leading to the inference of clustered grid networks. PLI was designed to solve this problem. Our simulations show that PLI is partially invariant to volume conduction. The networks found by PLI show small-worldness, with a clustering coefficient higher than random networks. On the contrary, PLI-NVC obtains networks whose distribution is closer to random networks indicating that the high clustering shown by PLI networks are caused by volume conduction. The influence of volume conduction in PLI might lead to biased results in brain network inference from EEG if this behaviour is ignored. PMID- 22546480 TI - Mitotane exhibits dual effects on steroidogenic enzymes gene transcription under basal and cAMP-stimulating microenvironments in NCI-H295 cells. AB - Adrenocortical carcinoma (ACC) is an extremely rare and aggressive endocrine malignancy with a poor prognosis. The most common symptom of ACC is hypercortisolism (Cushing's syndrome), which has the highest mortality. Mitotane is used as a steroidogenesis inhibitor for Cushing's syndrome or as a chemical adrenalectomy drug for ACC. Mitotane induces adrenal cortex necrosis, mitochondrial membrane impairment, and irreversible binding to CYP proteins. In this study, we explored the molecular effect of mitotane on steroidogenesis in human adrenocortical cancer NCI-H295 cells. Mitotane (10-40MUM) inhibited basal and cAMP-induced cortisol secretion but did not cause cell death. Mitotane exhibited an inhibitory effect on the basal expression of StAR and P450scc protein. Furthermore, 40MUM of mitotane significantly diminished StAR, CYP11A1 and CYP21 mRNA expression. HSD3B2 and CYP17 seem to be insensitive to mitotane. The stimulatory effects of mitotane on CYP11B1 were more remarkable than its inhibitory effects. In contrast, the activation of cAMP signaling strongly elevated the expression of all these genes. Mitotane (40MUM) almost completely neutralized this positive effect and returned 8-Br-cAMP-induced StAR, CYP11A1, CYP17 and CYP21 mRNA to control levels. After cAMP activation, mitotane did not change the levels of CYP11B1 mRNA. The present study demonstrates that mitotane can inhibit cortisol biosynthesis due to a non-specific interference with the gene transcription of steroidogenic enzymes under both basal and 8-Br-cAMP activated conditions in NCI-H295 cells. We also identified that StAR and CYP11A1 key enzymes that participate in the rate-limiting step of steroidogenesis, were more sensitive to mitotane. In addition, the biphasic effect of mitotane on CYP11B1 was also elucidated. PMID- 22546482 TI - Comprehensive and interdisciplinary patient education and counseling programs for highly distressed patients with rheumatic diseases - a need in rheumatology care and a challenge to outcome research. PMID- 22546478 TI - MAPK/ERK-dependent translation factor hyperactivation and dysregulated laminin gamma2 expression in oral dysplasia and squamous cell carcinoma. AB - Lesions displaying a variety of dysplastic changes precede invasive oral and epidermal squamous cell carcinoma (SCC); however, there are no histopathological criteria for either confirming or staging premalignancy. SCCs and dysplasias frequently contain cells that abnormally express the gamma2 subunit of laminin 332. We developed cell culture models to investigate gamma2 dysregulation. Normal human keratinocytes displayed density-dependent repression of gamma2, whereas premalignant keratinocytes and SCC cells overexpressed gamma2 and secreted laminin assembly intermediates. Neoplastic cells had hyperactive EGFR/MAPK(ERK) signaling coordinate with overexpressed gamma2, and EGFR and MEK inhibitors normalized gamma2 expression. Keratinocytes engineered to express HPV16 E6 or activated mutant HRAS, cRAF1, or MEK1 lost density repression of gamma2 and shared with neoplastic cells signaling abnormalities downstream of ERK, including increased phosphorylation of S6 and eIF4 translation factors. Notably, qPCR results revealed that gamma2 overexpression was not accompanied by increased gamma2 mRNA levels, consistent with ERK-dependent, eIF4B-mediated translation initiation of the stem-looped, 5'-untranslated region of gamma2 mRNA in neoplastic cells. Inhibitors of MEK, but not of TORC1/2, blocked S6 and eIF4B phosphorylation and gamma2 overexpression. Immunostaining of oral dysplasias identified gamma2 overexpression occurring within fields of basal cells that had elevated p-S6 levels. These results reveal a causal relationship between ERK dependent translation factor activation and laminin gamma2 dysregulation and identify new markers of preinvasive neoplastic change during progression to SCC. PMID- 22546481 TI - Production and effect of aldonic acids during enzymatic hydrolysis of lignocellulose at high dry matter content. AB - BACKGROUND: The recent discovery of accessory proteins that boost cellulose hydrolysis has increased the economical and technical efficiency of processing cellulose to bioethanol. Oxidative enzymes (e.g. GH61) present in new commercial enzyme preparations have shown to increase cellulose conversion yields. When using pure cellulose substrates it has been determined that both oxidized and unoxidized cellodextrin products are formed. We report the effect of oxidative activity in a commercial enzyme mix (Cellic CTec2) upon overall hydrolysis, formation of oxidized products and impact on beta-glucosidase activity. The experiments were done at high solids loadings using a lignocellulosic substrate simulating commercially relevant conditions. RESULTS: The Cellic CTec2 contained oxidative enzymes which produce gluconic acid from lignocellulose. Both gluconic and cellobionic acid were produced during hydrolysis of pretreated wheat straw at 30% WIS. Up to 4% of released glucose was oxidized into gluconic acid using Cellic CTec2, whereas no oxidized products were detected when using an earlier cellulase preparation Celluclast/Novozym188. However, the cellulose conversion yield was 25% lower using Celluclast/Novozym188 compared to Cellic CTec2. Despite the advantage of the oxidative enzymes, it was shown that aldonic acids could be problematic to the hydrolytic enzymes. Hydrolysis experiments revealed that cellobionic acid was hydrolyzed by beta-glucosidase at a rate almost 10-fold lower than for cellobiose, and the formed gluconic acid was an inhibitor of the beta-glucosidase.Interestingly, the level of gluconic acid varied significantly with temperature. At 50 degrees C (SHF conditions) 35% less gluconic acid was produced compared to at 33 degrees C (SSF conditions). We also found that in the presence of lignin, no reducing agent was needed for the function of the oxidative enzymes. CONCLUSIONS: The presence of oxidative enzymes in Cellic CTec2 led to the formation of cellobionic and gluconic acid during hydrolysis of pretreated wheat straw and filter paper. Gluconic acid was a stronger inhibitor of beta-glucosidase than glucose. The formation of oxidized products decreased as the hydrolysis temperature was increased from 33 degrees to 50 degrees C. Despite end-product inhibition, the oxidative cleavage of the cellulose chains has a synergistic effect upon the overall hydrolysis of cellulose as the sugar yield increased compared to using an enzyme preparation without oxidative activity. PMID- 22546483 TI - Imaging cells and sub-cellular structures with ultrahigh resolution full-field X ray microscopy. AB - Our experimental results demonstrate that full-field hard-X-ray microscopy is finally able to investigate the internal structure of cells in tissues. This result was made possible by three main factors: the use of a coherent (synchrotron) source of X-rays, the exploitation of contrast mechanisms based on the real part of the refractive index and the magnification provided by high resolution Fresnel zone-plate objectives. We specifically obtained high-quality microradiographs of human and mouse cells with 29 nm Rayleigh spatial resolution and verified that tomographic reconstruction could be implemented with a final resolution level suitable for subcellular features. We also demonstrated that a phase retrieval method based on a wave propagation algorithm could yield good subcellular images starting from a series of defocused microradiographs. The concluding discussion compares cellular and subcellular hard-X-ray microradiology with other techniques and evaluates its potential impact on biomedical research. PMID- 22546484 TI - Effect of annexin-A1 peptide treatment during lung inflammation induced by lipopolysaccharide. AB - Lung endotoxemia is characterized by neutrophil accumulation, increased vascular permeability and parenchymal injury. This can also affect the endogenous pathways that operate in the host to keep inflammation under control. Here, we demonstrate differential expression of annexin-A1 (AnxA1) protein in mice after the local or intraperitoneal administration of lipopolysaccharide (LPS; 1 mg/kg) in mice and the regulation of the endotoxemic inflammation after the pre-treatment with the AnxA1 peptidomimetic Ac2-26. The intranasal administration of LPS induced the leukocyte migration and cytokine release to the alveolar space, whereas the peritoneal administration of LPS generated a deregulated cellular and cytokine response, with a marked degree of leukocyte adhesion in the microcirculation. The peptide Ac2-26 pre-treatment inhibited the leukocyte migration and the pro inflammatory cytokine release. Also, it induced the expression of endogenous AnxA1 and the anti-inflammatory cytokine IL-10. In conclusion, our data obtained from endotoxemia induced by local or intraperitoneal LPS administration suggested that the molecular mechanisms induced by AnxA1 peptidomimetic Ac2-26 lead to the regulation of leukocyte activation/migration and cytokine production induced by LPS. PMID- 22546485 TI - Long-acting beta2 agonists and corticosteroids restore the reduction of histone deacetylase activity and inhibit H2O2-induced mediator release from alveolar macrophages. AB - BACKGROUND: Treatment of COPD with a combination of long-acting beta(2) agonists and corticosteroids is currently used worldwide. The mechanisms of the anti inflammatory effects and their associations with histone deacetylase (HDAC) activity remain unclear. METHODS: Human alveolar macrophages were isolated and stimulated with H(2)O(2) in the presence of varying concentrations of long-acting beta(2) agonists and corticosteroids. Supernatants were collected for IL-8 and MMP-9 measurements. Cell lysates were analyzed for HDAC (mainly HDAC1/HDAC2) activity. Quantitative real-time PCR was performed to determine the levels of IL 8 and MMP-9 mRNA. RESULTS: Both long-acting beta(2) agonists, salmeterol and formoterol, and corticosteroids, fluticasone and budesonide, showed anti inflammatory effects to a certain extent on H(2)O(2)-induced IL-8 and MMP-9 release in alveolar macrophages. Combinations of long-acting beta(2) agonists and corticosteroids exerted greater effects to suppress mediator release, and both transcription and translation of IL-8 and MMP-9 were inhibited. It seemed that the levels of IL-8 and MMP-9 after H(2)O(2) stimulation were inversely associated with the activity of HDAC. H(2)O(2) stimulation resulted in a significant decrease in HDAC activity and was associated with an increase in mediator release. In contrast, treatment with long-acting beta(2) agonists, corticosteroids or theophylline restored the H(2)O(2)-induced decrease in HDAC activity and inhibited mediator release. CONCLUSION: Combinations of long-acting beta(2) agonists and corticosteroids exerted greater effects on the suppression of mediator release in relation to the enhancement of HDAC activity. This supports at least in part the likely contribution of anti-inflammatory effects of long-acting beta(2) agonists and corticosteroids to the clinical benefits seen in COPD patients. PMID- 22546486 TI - Detection of MHC class II expression on human basophils is dependent on antibody specificity but independent of atopic disposition. AB - A debate has recently arisen as to whether murine basophils can function as antigen presenting cells in allergic inflammation. However, mouse and human basophils differ considerably, and the expression of MHC class II on human basophils has been investigated as a proxy for their capability of antigen presentation but conflicting results have emerged. In this technical note, we show that an antibody specific for all three MHC class II subtypes (HLA-DR, -DP, and -DQ), leads to a significantly higher amount of MHC class II+ basophils compared to antibodies specific for HLA-DR only. A significant difference was also observed between the HLA-DR specific antibodies, indicating that the choice of antibody is crucial. Furthermore, critical compensation was essential to avoid false HLA-DR+ basophils. Finally, we found that detection of MHC class II on human basophils was independent of atopic disposition. PMID- 22546488 TI - Variable regions in the sushi domains 6-7 and 19-20 of factor H in animals and human lead to change in the affinity to factor H binding protein of Borrelia. AB - Borrelia binds host's complement regulatory factor H (fH) to evade complement attack. However, binding affinities between fH-binding-proteins (FHBPs) of Borrelia and fH from various hosts are disparate. Experiments performed to unfold the underlying molecular basis of this disparity revealed that recombinant BbCRASP-1 (major FHBP of Borrelia burgdorferi) neither interacted with sushi 6-7, nor with sushi 19-20 domains of fH in cattle and pig, however, showed binding affinity to both sushi domains of human fH, sushi 6-7 of mouse and sushi 19-20 of sheep. Further, peptide-spot assay revealed three major binding sites (sushi 6:(335-346), sushi 7:(399-410) and sushi 20:(1205-1227)) in human fH that can form BbCRASP-1:fH interface, while (337)HENMR(341) residues in sushi 6 are crucial for rigid BbCRASP-1:fH complex formation. Amino acid stretches DTIEFTCRYGYRPRTALHTFRTT in ovine sushi 19-20 and SAYWEKVYVQGQ in mouse sushi 7 were important sites for fH:BbCRASP-1 interaction. Comparative analysis of the amino acid sequences of sushi 6 of cattle, pig and human revealed that bovine and porcine fH lack methionine and arginine in HENMR pocket, that may impede formation of fH:BbCRASP-1 interface. Increasing numbers of FHBPs from animal and human pathogens are being discovered, thus results presented here can be important benchmark for study of other FHBPs:FH interactions. PMID- 22546487 TI - Nebulized anticoagulants for acute lung injury - a systematic review of preclinical and clinical investigations. AB - BACKGROUND: Data from interventional trials of systemic anticoagulation for sepsis inconsistently suggest beneficial effects in case of acute lung injury (ALI). Severe systemic bleeding due to anticoagulation may have offset the possible positive effects. Nebulization of anticoagulants may allow for improved local biological availability and as such may improve efficacy in the lungs and lower the risk of systemic bleeding complications. METHOD: We performed a systematic review of preclinical studies and clinical trials investigating the efficacy and safety of nebulized anticoagulants in the setting of lung injury in animals and ALI in humans. RESULTS: The efficacy of nebulized activated protein C, antithrombin, heparin and danaparoid has been tested in diverse animal models of direct (for example, pneumonia-, intra-pulmonary lipopolysaccharide (LPS)-, and smoke inhalation-induced lung injury) and indirect lung injury (for example, intravenous LPS- and trauma-induced lung injury). Nebulized anticoagulants were found to have the potential to attenuate pulmonary coagulopathy and frequently also inflammation. Notably, nebulized danaparoid and heparin but not activated protein C and antithrombin, were found to have an effect on systemic coagulation. Clinical trials of nebulized anticoagulants are very limited. Nebulized heparin was found to improve survival of patients with smoke inhalation-induced ALI. In a trial of critically ill patients who needed mechanical ventilation for longer than two days, nebulized heparin was associated with a higher number of ventilator-free days. In line with results from preclinical studies, nebulization of heparin was found to have an effect on systemic coagulation, but without causing systemic bleedings. CONCLUSION: Local anticoagulant therapy through nebulization of anticoagulants attenuates pulmonary coagulopathy and frequently also inflammation in preclinical studies of lung injury. Recent human trials suggest nebulized heparin for ALI to be beneficial and safe, but data are very limited. PMID- 22546489 TI - Plasma protein changes in horse after prolonged physical exercise: a proteomic study. AB - Physical exercise induces various stress responses and metabolic adaptations that have not yet been completely elucidated. Novel biomarkers are needed in sport veterinary medicine to monitor training levels and to detect subclinical conditions that can develop into exercise-related diseases. In this study, protein modifications in horse plasma induced by prolonged, aerobic physical exercise were investigated by using a proteomic approach based on 2-DE and combined mass spectrometry procedures. Thirty-eight protein spots, associated with expression products of 13 genes, showed significant quantitative changes; spots identified as membrane Cu amine oxidase, alpha-1 antitrypsin, alpha-1 antitrypsin-related protein, caeruloplasmin, alpha-2 macroglobulin and complement factor C4 were augmented in relative abundance after the race, while haptoglobin beta chain, apolipoprotein A-I, transthyretin, retinol binding protein 4, fibrinogen gamma chain, complement factor B and albumin fragments were reduced. These results indicate that prolonged physical exercise affects plasma proteins involved in pathways related to inflammation, coagulation, immune modulation, oxidant/antioxidant activity and cellular and vascular damage, with consequent effects on whole horse metabolism. PMID- 22546490 TI - Comparative proteomic analysis reveals that caspase-1 and serine protease may be involved in silkworm resistance to Bombyx mori nuclear polyhedrosis virus. AB - The silkworm Bombyx mori is of great economic value. The B. mori nuclear polyhedrosis virus (BmNPV) is one of the most common and severe pathogens for silkworm. Although certain immune mechanisms exist in silkworms, most silkworms are still susceptible to BmNPV infection. Interestingly, BmNPV infection resistance in some silkworm strains is varied and naturally existing. We have previously established a silkworm strain NB by genetic cross, which is highly resistant to BmNPV invasion. To investigate the molecular mechanism of silkworm resistance to BmNPV infection, we employed proteomic approach and genetic cross to globally identify proteins differentially expressed in parental silkworms NB and 306, a BmNPV-susceptible strain, and their F(1) hybrids. In all, 53 different proteins were found in direct cross group (NB?, 306?, F(1) hybrid) and 21 in reciprocal cross group (306?, NB?, F(1) hybrid). Gene ontology and KEGG pathway analyses showed that most of these different proteins are located in cytoplasm and are involved in many important metabolisms. Caspase-1 and serine protease expressed only in BmNPV-resistant silkworms, but not in BmNPV-susceptible silkworms, which was further confirmed by Western blot. Taken together, our data suggests that both caspase-1 and serine protease play a critical role in silkworm resistance against BmNPV infection. PMID- 22546491 TI - Photodynamic therapy in the management of potentially malignant and malignant oral disorders. AB - Photodynamic therapy (PDT) is a minimally-invasive surgical tool successfully targeting premalignant and malignant disorders in the head and neck, gastrointestinal tract, lungs and skin with greatly reduced morbidity and disfigurement. The technique is simple, can commonly be carried out in outpatient clinics, and is highly acceptable to patients. The role of photodynamic therapy in the management of oral potentially malignant disorders and early oral cancer is being discussed. PMID- 22546492 TI - Assessment of behavioral changes associated with oral meloxicam administration at time of dehorning in calves using a remote triangulation device and accelerometers. AB - BACKGROUND: Dehorning is common in the cattle industry, and there is a need for research evaluating pain mitigation techniques. The objective of this study was to determine the effects of oral meloxicam, a non-steroidal anti-inflammatory, on cattle behavior post-dehorning by monitoring the percent of time spent standing, walking, and lying in specific locations within the pen using accelerometers and a remote triangulation device. Twelve calves approximately ten weeks of age were randomized into 2 treatment groups (meloxicam or control) in a complete block design by body weight. Six calves were orally administered 0.5 mg/kg meloxicam at the time of dehorning and six calves served as negative controls. All calves were dehorned using thermocautery and behavior of each calf was continuously monitored for 7 days after dehorning using accelerometers and a remote triangulation device. Accelerometers monitored lying behavior and the remote triangulation device was used to monitor each calf's movement within the pen. RESULTS: Analysis of behavioral data revealed significant interactions between treatment (meloxicam vs. control) and the number of days post dehorning. Calves that received meloxicam spent more time at the grain bunk on trial days 2 and 6 post-dehorning; spent more time lying down on days 1, 2, 3, and 4; and less time at the hay feeder on days 0 and 1 compared to the control group. Meloxicam calves tended to walk more at the beginning and end of the trial compared to the control group. By day 5, the meloxicam and control group exhibited similar behaviors. CONCLUSIONS: The noted behavioral changes provide evidence of differences associated with meloxicam administration. More studies need to be performed to evaluate the relationship of behavior monitoring and post-operative pain. To our knowledge this is the first published report demonstrating behavioral changes following dehorning using a remote triangulation device in conjunction with accelerometers. PMID- 22546493 TI - Inhibition of kupffer cell activity improves transplantation of human adipose derived stem cells and liver functions. AB - Numerous approaches to cell transplantation of the hepatic or the extrahepatic origin into liver tissue have been developed; however, the efficiency of cell transplantation remains low and liver functions are not well corrected. The liver is a highly immunoreactive organ that contains many resident macrophages known as Kupffer cells. Here, we show that the inhibition of Kupffer cell activity improves stem cell transplantation into liver tissue and corrects some of the liver functions under conditions of liver injury. We found that, when Kupffer cells were inhibited by glycine, numerous adipose-derived stem cells (ASCs) were successfully transplanted into livers, and these transplanted cells showed hepatoprotective effects, including decrease of liver injury factors, increase of liver regeneration, and albumin production. On the contrary, injected ASCs without glycine recruited numerous Kupffer cells, not lymphocytes, and showed low transplantation efficiency. Intriguingly, successfully transplanted ASCs in liver tissue modulated Kupffer cell activity to inhibit tumor necrosis factor-alpha secretion. Thus, our data show that Kupffer cell inactivation is an important step in order to improve ASC transplantation efficiency and therapeutic potential in liver injuries. In addition, the hepatoprotective function of glycine has synergic effects on liver protection and the engraftment of ASCs. PMID- 22546495 TI - The painful black umbilicus. PMID- 22546494 TI - Canalization of the evolutionary trajectory of the human influenza virus. AB - BACKGROUND: Since its emergence in 1968, influenza A (H3N2) has evolved extensively in genotype and antigenic phenotype. However, despite strong pressure to evolve away from human immunity and to diversify in antigenic phenotype, H3N2 influenza shows paradoxically limited genetic and antigenic diversity present at any one time. Here, we propose a simple model of antigenic evolution in the influenza virus that accounts for this apparent discrepancy. RESULTS: In this model, antigenic phenotype is represented by a N-dimensional vector, and virus mutations perturb phenotype within this continuous Euclidean space. We implement this model in a large-scale individual-based simulation, and in doing so, we find a remarkable correspondence between model behavior and observed influenza dynamics. This model displays rapid evolution but low standing diversity and simultaneously accounts for the epidemiological, genetic, antigenic, and geographical patterns displayed by the virus. We find that evolution away from existing human immunity results in rapid population turnover in the influenza virus and that this population turnover occurs primarily along a single antigenic axis. CONCLUSIONS: Selective dynamics induce a canalized evolutionary trajectory, in which the evolutionary fate of the influenza population is surprisingly repeatable. In the model, the influenza population shows a 1- to 2-year timescale of repeatability, suggesting a window in which evolutionary dynamics could be, in theory, predictable. PMID- 22546496 TI - Sexuality, pre-conception counseling and urological management of pregnancy for young women with spina bifida. AB - A great number of newborns with spina bifida now survive with a growing life expectancy. Support with regard to sexual issues is essential in the management of adolescents with spina bifida, who require specific knowledge of sexual problems related to their disability. Women with spina bifida are usually fertile and need pre-conception counseling. Furthermore, compared to healthy women they have a higher chance of conceiving a child with spina bifida, so they are treated with periconceptional folic acid supplements. In addition pregnancies in women with spina bifida require adequate management of secondary conditions, mainly urological issues, which are exacerbated during pregnancy. This article gives an overview of sexual education, sex functioning and sexual activity among adolescents with spina bifida. Moreover, we aim to support young women with spina bifida, providing pre-conception counseling and practical guidelines essential for the urological management of their pregnancy. PMID- 22546497 TI - Fludarabine-based conditioning for marrow transplantation from unrelated donors in severe aplastic anemia: early results of a cyclophosphamide dose deescalation study show life-threatening adverse events at predefined cyclophosphamide dose levels. AB - Excessive adverse events were encountered in a Phase I/II study of cyclophosphamide (CY) dose deescalation in a fludarabine-based conditioning regimen for bone marrow transplantation from unrelated donors in patients with severe aplastic anemia. All patients received fixed doses of antithymocyte globulin, fludarabine, and low-dose total body irradiation. The starting CY dose was 150 mg/kg, with deescalation to 100 mg/kg, 50 mg/kg, or 0 mg/kg. CY dose level 0 mg/kg was closed due to graft failure in 3 of 3 patients. CY dose level 150 mg/kg was closed due to excessive organ toxicity (n = 6) or viral pneumonia (n = 1), resulting in the death of 7 of 14 patients. CY dose levels 50 and 100 mg/kg remain open. Thus, CY at doses of 150 mg/kg in combination with total body irradiation (2 Gy), fludarabine (120 mg/m(2)), and antithymocyte globulin was associated with excessive organ toxicity. PMID- 22546499 TI - Genome-wide association studies with metabolomics. AB - Genome-wide association studies (GWAS) analyze the genetic component of a phenotype or the etiology of a disease. Despite the success of many GWAS, little progress has been made in uncovering the underlying mechanisms for many diseases. The use of metabolomics as a readout of molecular phenotypes has enabled the discovery of previously undetected associations between diseases and signaling and metabolic pathways. In addition, combining GWAS and metabolomic information allows the simultaneous analysis of the genetic and environmental impacts on homeostasis. Most success has been seen in metabolic diseases such as diabetes, obesity and dyslipidemia. Recently, associations between loci such as FADS1, ELOVL2 or SLC16A9 and lipid concentrations have been explained by GWAS with metabolomics. Combining GWAS with metabolomics (mGWAS) provides the robust and quantitative information required for the development of specific diagnostics and targeted drugs. This review discusses the limitations of GWAS and presents examples of how metabolomics can overcome these limitations with the focus on metabolic diseases. PMID- 22546498 TI - Chronically lowering sympathetic activity protects sympathetic nerves in spleens from aging F344 rats. AB - In the present study, we investigated how increased sympathetic tone during middle-age affects the splenic sympathetic neurotransmission. Fifteen-month-old (M) F344 rats received rilmenidine (0, 0.5 or 1.5mg/kg/day, i.p. for 90 days) to lower sympathetic tone. Controls for age were untreated 3 or 18M rats. We report that rilmenidine (1) reduced plasma and splenic norepinephrine concentrations and splenic norepinephrine turnover, and partially reversed the sympathetic nerve loss; and (2) increased beta-adrenergic receptor (beta-AR) density and beta-AR stimulated cAMP production. Collectively, these findings suggest a protective effect of lowering sympathetic tone on sympathetic nerve integrity, and enhanced sympathetic neurotransmission in secondary immune organs. PMID- 22546500 TI - Anti-MJ/NXP-2 autoantibody specificity in a cohort of adult Italian patients with polymyositis/dermatomyositis. AB - INTRODUCTION: Autoantibodies in patients with polymyositis/dermatomyositis (PM/DM) are associated with unique subsets, clinical course and outcome. Anti-MJ antibodies, which recognize the nuclear protein NXP-2/MORC3, are reported in ~25% of juvenile DM. Prevalence and clinical significance of anti-MJ antibodies in adult Italian PM/DM patients were studied. METHODS: Sera from 58 consecutive adult Italian PM/DM patients were analyzed by immunoprecipitation of 35S-labeled K562 cells extract, ELISA (anti-MJ, Jo-1), Western blot and indirect immunofluorescence. Clinical associations were analyzed using information from medical charts. RESULTS: Anti-MJ antibodies were the most prevalent specificity (17%) found mainly in DM (30%, 8 cases) vs 8% of PM (2 cases, P = 0.02). Comparing 10 anti-MJ (+) vs 48 anti-MJ (-) cases, DM was more common (P = 0.03), and age at onset was younger in anti-MJ (+) (P = 0.0006). In anti-MJ (+), heliotrope rash (P = 0.01) and calcinosis (P = 0.09) were more frequent. None of them had heart or lung involvement, or malignancy. Myopathy in anti-MJ (+) patients responded well to therapy and none of them had elevated CPK at last visit (0% vs 25% in anti-MJ (-)). Only 60% of anti-MJ (+) showed immunofluorescent nuclear dots staining, despite PML localization of NXP-2/MORC3. CONCLUSIONS: Anti-MJ antibodies are the most frequent specificity in our cohort of adult Italian PM/DM. Anti-MJ (+) were associated with young onset DM, calcinosis, no internal organ involvement and good response of myopathy to therapy. Anti-MJ reported in juvenile DM is also found in adult PM/DM, and could be a new useful biomarker. PMID- 22546501 TI - Nicotine stimulated bone marrow-derived dendritic cells could augment HBV specific CTL priming by activating PI3K-Akt pathway. AB - Our previous studies have revealed that nicotine-treated immature dendritic cells (imDCs) have anti-tumor effects in murine lymphoma models. The present study is to explore HBV-specific CTL priming and its cytolytic activities of nicotine treated murine DCs, the mechanism of alpha7 nicotinic acetylcholine receptor (nAChR) up-regulation by nicotine and the efficiency of nicotine with other cytokines. To address these hypotheses, bone marrow-derived imDCs were stimulated by nicotine and expression of alpha7 nAChR was firstly determined by flow cytometry and Western blot. Then, DCs-dependent HBV-specific T cell proliferation and IL-12 secretion were secondly determined by BrdU cell proliferation assay and ELISA, respectively. The HBV-specific CTL priming and its activities were further explored by intraperitoneal transfer of nicotine treated imDCs. The mechanism of nicotine up-regulating alpha7 nAChR was finally explored by Western blot. The results showed that: first, the maximal activation of PI3K and Akt was reached at 30 and 60-120 min respectively after nicotine stimulation. Nicotine up-regulated the expression of alpha7 nAChR by activating PI3K-Akt pathway in murine DCs; secondly, nicotine stimulation could enhance DCs' ability of HBV-specific T cell proliferation and IL-12 secretion; thirdly, adoptive transfer of nicotine stimulated DCs could induce HBV specific CTL priming in vivo and those CTL had cytolytic activities; fourthly, nicotine had equal efficiencies to 2 ng/ml IFN gamma in DCs-mediated T cell proliferation. All these data presented here indicated that nicotine treated imDCs might be considered as a potential candidate for HBV immunotherapy. PMID- 22546502 TI - Retinoic acid receptor beta deficiency reduces splenic dendritic cell population in a conditional mouse line. AB - Different studies have shown that retinoids and their receptors [retinoic acid receptors (RARs) and retinoid X receptors (RXRs)] have crucial effects on the differentiation and function of myeloid cells such as Dendritic cells (DCs) and the development of lymphoid tissue. However, the relationship between RARbeta expression and DCs has not been previously studied in vivo. This work examined the effect of decreased RARbeta expression on the number (and probably on differentiation) of splenic DCs and the structure of spleen using a conditional mouse that partially ablates floxed RARbeta gene (RARbeta(L-/L-) mice). Our results showed that RARbeta is expressed mainly in cells of the splenic White Pulp (WP) zone of Wild type mice. As expected, low levels of RARbeta expression were detected in the spleen of RARbeta(L-/L-) conditional mice. These results were consistent with a decrease in the population of splenic CD11c(+)MHC-II(+) cells. Histopathological analyses of conditional mice spleen indicated defects in cell organization and structure. The expression of Toll-like receptor 2 was also down-regulated in the spleen of these mice. These results suggest that RARbeta is involved in splenic cell organization as well as in the maintenance of splenic DCs population, indicating that RARbeta expression is important in homeostasis of immune system components. PMID- 22546503 TI - miR-155 mediates suppressive effect of progesterone on TLR3, TLR4-triggered immune response. AB - It has been demonstrated that progesterone has immune suppressive properties and can inhibit Toll-like receptor 4 (TLR4)-triggered immune response. Multiple microRNAs are induced in innate immune cells, among them miR-155, miR-146a and miR-21 are particularly ubiquitous. In this study, we investigated the potential roles of miR-155 in progesterone-mediated regulation of innate immune responses. We found that progesterone pre-treatment suppressed LPS- and poly(I:C)-induced miR-155 expression in macrophages. Increasing the activity of miR-155, significantly attenuated the progesterone's inhibition on LPS-induced IL-6 as well as LPS- and poly(I:C)-induced IFN-beta expression in macrophages. Furthermore, we demonstrated that progesterone up-regulated LPS-induced SOCS1 expression while overexpression of miR-155 inhibited SOCS1 expression. In conclusion, the present study has demonstrated that progesterone suppresses TLRs triggered immune response by regulating miR-155, and the decreased miR-155 contributes to inhibit TLR-induced IL-6 and IFN-beta via increased SOCS1 expression. PMID- 22546504 TI - Four day inhibition of prolyl oligopeptidase causes significant changes in the peptidome of rat brain, liver and kidney. AB - Prolyl oligopeptidase (PREP) cleaves short peptides at the C-side of proline. Although several proline containing neuropeptides have been shown to be efficiently cleaved by PREP in vitro, the actual physiological substrates of this peptidase are still a matter of controversy. The aim of this study was to evaluate the changes in the peptidome of rat tissues caused by a repeated 4-day administration of the potent and specific PREP inhibitor KYP-2047, using our recently developed iTRAQ-based technique. We found tissue-dependent changes in the levels of specific subsets of peptides mainly derived from cytosolic proteins. Particularly in the kidney, where the levels of cytochrome c oxidase were found decreased, many of the altered peptides originated from mitochondrial proteins being involved in energy metabolism. However, in the hypothalamus, we found significant changes in peptides derived from hormone precursors. We could not confirm a role of PREP as the metabolising enzyme for beta-endorphin, galanin, octadecaneuropeptide, neuropeptide-glutamic acid-isoleucine, substance P, somatostatin, enkephalin and neuropeptide Y. Furthermore, changes in the degradation patterns of some of these neuropeptides, and also most of those derived from other larger proteins, did not follow specificity to proline. After a 4-day treatment, we found a significant amount of peptides, all derived from secreted pro-proteins, being cleaved with pair of basic residue specificity. In vitro experiments indicated that PREP modifies the endogenous dibasic residue specific proteolysis, in a KYP-2047 sensitive way. These findings suggest that PREP may act indirectly within the routes leading to the specific peptide changes that we observed. The data reported here suggest a wider tissue specific physiological role of PREP rather than the mere metabolism of proline containing active peptides and hormones. PMID- 22546505 TI - Leptin and the central control of feeding behavior. AB - The discovery of leptin by Friedman and coll. in 1995 was a major step forward in our comprehensive view of energy homeostasis. Since the original paper, a tremendous amount of work has been performed in laboratories all over the world. Many recent reviews have described this work in details. In the present review, we focus on the role of leptin on food intake. It is accepted by most authors working in this field that the control of food intake can be divided in two closely-related system: the homeostatic system and the hedonic system. Leptin has been shown to act on both systems. PMID- 22546507 TI - One-year follow-up changes in weight are associated with changes in blood pressure in young Mexican adults. AB - OBJECTIVE: Increasing overweight and obesity rates in Mexico have been associated with increases in mortality from cardiovascular disease (CVD). This study assessed changes in body mass index (BMI) and body weight over 1 year, and explored whether these were associated with changes in CVD risk factors of blood pressure and fasting glucose in a cohort of young Mexican adults. STUDY DESIGN: Longitudinal data were obtained from a cohort of young Mexican adults applying to college. METHODS: Data were collected from college applicants for the 2008 academic year who re-applied in 2009. In total, 795 college applicants aged 18-20 years, of both sexes (48% males and 52% females), were included in the study. The screen included height, weight, and systolic (SBP) and diastolic (DBP) blood pressure measurements plus a blood draw following an overnight fast for fasting glucose. RESULTS: At baseline, 31.8% of the participants were overweight or obese. The mean 1-year change in body weight and BMI were 0.80 kg and 0.35 kg/m(2), respectively. One-year changes in body weight and BMI were associated with increased SBP and DBP for both men and women (P < 0.05), independent of baseline BMI. A weight gain of 5% or more was positively associated with increases in blood pressure among women (P < 0.05), but not among men. A weight loss of 5% or more was associated with reductions in SBP among women. CONCLUSIONS: One-year changes in weight were associated with changes in blood pressure. PMID- 22546508 TI - Plant catalases: peroxisomal redox guardians. AB - While genomics and post-genomics studies have revealed that plant cell redox state is controlled by a complex genetic network, available data mean that catalase must continue to be counted among the most important of antioxidative enzymes. Plants species analyzed to date contain three catalase genes, and comparison of expression patterns and information from studies on mutants suggests that the encoded proteins have relatively specific roles in determining accumulation of H(2)O(2) produced through various metabolic pathways. This review provides an update on the different catalases and discusses their established or likely physiological functions. Particular attention is paid to regulation of catalase expression and activity, intracellular trafficking of the protein from cytosol to peroxisome, and the integration of catalase function into the peroxisomal antioxidative network. We discuss how plants deficient in catalase are not only key tools to identify catalase functions, but are also generating new insight into H(2)O(2) signalling in plants and the potential importance of peroxisomal and other intracellular processes in this signalling. PMID- 22546510 TI - Expression profile and interactions of hnRNP A3 within hnRNP/mRNP complexes in mammals. AB - The hnRNP A/B family contains abundant nuclear proteins with major roles in alternative splicing and the ability for nucleo-cytoplasmic shuttling. Compared to the best known members of this family (hnRNP A1, A2/B1), hnRNP A3 is a relatively less known protein. We report herein immunochemical studies with the hnRNP A3 isoforms (A3a and A3b) that provided evidence for species-specific expression. The unspliced A3a was found in human and murine cells, while the spliced A3b was a unique and abundant isoform in mouse/rat. In addition, a tissue specific variation was observed in mice, as the brain was the only tissue found to overexpress hnRNP A3a. Both hnRNP A3a and A3b were able to stably associate with immunoselected hnRNP and mRNP complexes. Use of the auxiliary domain of hnRNP A3 in pull-down assays on human cell extracts revealed its unique ability to form a network of interactions not only with other A/B proteins but also with additional hnRNPs. All interactions, except those of hnRNP A1, were highly enhanced by previous RNase A digestion of the extracts. Our findings revealed novel characteristics of hnRNP A3 and supported its extensive involvement in the many aspects of mRNA maturation processes along with the other hnRNP A/B proteins. PMID- 22546509 TI - Stabilization of the Escherichia coli DNA polymerase III epsilon subunit by the theta subunit favors in vivo assembly of the Pol III catalytic core. AB - Escherichia coli DNA polymerase III holoenzyme (HE) contains a core polymerase consisting of three subunits: alpha (polymerase), epsilon (3'-5' exonuclease), and theta. Genetic experiments suggested that theta subunit stabilizes the intrinsically labile epsilon subunit and, furthermore, that theta might affect the cellular amounts of Pol III core and HE. Here, we provide biochemical evidence supporting this model by analyzing the amounts of the relevant proteins. First, we show that a DeltaholE strain (lacking theta subunit) displays reduced amounts of free epsilon. We also demonstrate the existence of a dimer of epsilon, which may be involved in the stabilization of the protein. Second, theta, when overexpressed, dissociates the epsilon dimer and significantly increases the amount of Pol III core. The stability of epsilon also depends on cellular chaperones, including DnaK. Here, we report that: (i) temperature shift-up of DeltadnaK strains leads to rapid depletion of epsilon, and (ii) overproduction of theta overcomes both the depletion of epsilon and the temperature sensitivity of the strain. Overall, our data suggest that epsilon is a critical factor in the assembly of Pol III core, and that this is role is strongly influenced by the theta subunit through its prevention of epsilon degradation. PMID- 22546511 TI - Normalizing for biology: accounting for technical and biological variation in levels of reference gene and insulin-like growth factor 1 (igf1) transcripts in fish livers. AB - Feeding, fasting and re-feeding is a common experimental paradigm for studying growth endocrinology. Herein we demonstrate dynamic changes in the livers of coho salmon under these conditions and how changes in liver composition can influence quantification and interpretation of liver gene expression data. A three-week fast resulted in decreases in hepatosomatic index (liver size), liver glycogen content, and liver DNA concentration. In addition, significant differences were found in liver transcript levels from fed and fasted fish for the reference genes, arp and ef1a, when these were normalized to total RNA. We took the additional step of normalizing reference gene transcript levels to the liver homogenate RNA/DNA ratio to account for differences in RNA yield/cell and the number of cells sampled, normalizing to transcript number per cell rather than transcript number per unit RNA. After this additional step no significant differences in liver transcript levels of reference genes were found. The significance of these results was illustrated by normalizing liver transcript levels of insulin-like growth factor 1 (igf1) to ef1a transcript levels or ef1a transcript levels by RNA/DNA. The different normalization strategies resulted in differing patterns of change in igf1 transcript levels between fed and fasted fish. The novelty of this work rests in a two-step normalization process, attempting to account for both 1) technical errors in reverse transcription and qPCR reactions, and 2) biological variance in liver samples. PMID- 22546512 TI - Scorpions regulate their energy metabolism towards increased carbohydrate oxidation in response to dehydration. AB - Scorpions successfully inhabit some of the most arid habitats on earth. During exposure to desiccating stress water is mobilized from the scorpion hepatopancreas to replenish the hemolymph and retain hydration and osmotic stability. Carbohydrate catabolism is advantageous under these conditions as it results in high metabolic water production rate, as well as the release of glycogen-bound water. Hypothesizing that metabolic fuel utilization in scorpions is regulated in order to boost body water management under stressful conditions we used a comparative approach, studying energy metabolism during prolonged desiccation in four species varying in resistance performance. We used respirometry for calculating respiratory gas exchange ratios, indicative of metabolic fuel utilization, and measured metabolic fuel contents in the scorpion hepatopancreas. We found that hydrated scorpions used a mixture of metabolic fuels (respiratory exchange rates, RER~0.9), but a shift towards carbohydrate catabolism was common during prolonged desiccation stress. Furthermore, the timing of metabolic shift to exclusive carbohydrate oxidation (RER not different from 1.0) was correlated with desiccation resistance of the respective studied species, suggesting triggering by alterations to hemolymph homeostasis. PMID- 22546514 TI - We are what we eat: how the diet of infants affects their gut microbiome. AB - Simultaneous analysis of the gut microbiome and host gene expression in infants reveals the impact of diet (breastfeeding versus formula) on host-microbiome interactions. PMID- 22546515 TI - Influence of the polyanion on the physico-chemical properties and biological activities of polyanion/DNA/polycation ternary polyplexes. AB - It was recently reported that polyanion/DNA/polycation ternary polyplexes markedly improve gene transfection activity in comparison with the original DNA/polycation binary polyplexes. In this study to explore the influence of the polyanion on the physico-chemical properties and biological activity of polyanion/pDNA/polycation ternary polyplexes four types of biocompatible polyanions were selected, mainly based on the acid strength of the anionic functional groups and the molecular rigidity on forming ternary polyplexes with 25 kDa polyethyleneimine and DNA. Polyanion loosening of the DNA polyplex, weakening of the adsorption of serum proteins and improving of cellular uptake, which are thought to be important factors leading to a high transfection efficiency of DNA ternary polyplexes, were specifically investigated. Electrophoresis retardation analysis indicated that the loosening capacity of polyanions depended on the pK(a) value of the functional anion groups as well as the flexibility of the polyanion. The low pK(a) and flexible structure of the polyanions tended to loosen the compact DNA polyplexes. Thermodynamic analysis by isothermal titration calorimetry provided direct evidence about the serum protein DNA ternary polyplex interactions. The polyanion/pDNA/polycation ternary polyplexes exhibited obviously lower binding affinities and less adsorption to serum proteins compared with the original DNA/polycation binary polyplexes. These relatively stable DNA ternary polyplexes maintained high levels of cellular uptake and intracellular accumulation in serum-containing medium that correlated with their high transfection efficiency. In contrast, the original pDNA/polycation binary polyplexes became clustered by strong adsorption of large amounts of serum proteins, leading to a sharp reduction in cellular uptake and intracellular accumulation, and thus low gene transfer efficiency. These results provide a basis for the development of polyanion/DNA/polycation ternary polyplexes for polyfection. PMID- 22546513 TI - Interaction among apoptosis-associated sequence variants and joint effects on aggressive prostate cancer. AB - BACKGROUND: Molecular and epidemiological evidence demonstrate that altered gene expression and single nucleotide polymorphisms in the apoptotic pathway are linked to many cancers. Yet, few studies emphasize the interaction of variant apoptotic genes and their joint modifying effects on prostate cancer (PCA) outcomes. An exhaustive assessment of all the possible two-, three- and four-way gene-gene interactions is computationally burdensome. This statistical conundrum stems from the prohibitive amount of data needed to account for multiple hypothesis testing. METHODS: To address this issue, we systematically prioritized and evaluated individual effects and complex interactions among 172 apoptotic SNPs in relation to PCA risk and aggressive disease (i.e., Gleason score >= 7 and tumor stages III/IV). Single and joint modifying effects on PCA outcomes among European-American men were analyzed using statistical epistasis networks coupled with multi-factor dimensionality reduction (SEN-guided MDR). The case-control study design included 1,175 incident PCA cases and 1,111 controls from the prostate, lung, colo-rectal, and ovarian (PLCO) cancer screening trial. Moreover, a subset analysis of PCA cases consisted of 688 aggressive and 488 non-aggressive PCA cases. SNP profiles were obtained using the NCI Cancer Genetic Markers of Susceptibility (CGEMS) data portal. Main effects were assessed using logistic regression (LR) models. Prior to modeling interactions, SEN was used to pre process our genetic data. SEN used network science to reduce our analysis from > 36 million to < 13,000 SNP interactions. Interactions were visualized, evaluated, and validated using entropy-based MDR. All parametric and non-parametric models were adjusted for age, family history of PCA, and multiple hypothesis testing. RESULTS: Following LR modeling, eleven and thirteen sequence variants were associated with PCA risk and aggressive disease, respectively. However, none of these markers remained significant after we adjusted for multiple comparisons. Nevertheless, we detected a modest synergistic interaction between AKT3 rs2125230 PRKCQ rs571715 and disease aggressiveness using SEN-guided MDR (p = 0.011). CONCLUSIONS: In summary, entropy-based SEN-guided MDR facilitated the logical prioritization and evaluation of apoptotic SNPs in relation to aggressive PCA. The suggestive interaction between AKT3-PRKCQ and aggressive PCA requires further validation using independent observational studies. PMID- 22546516 TI - High mesenchymal stem cell seeding densities in hyaluronic acid hydrogels produce engineered cartilage with native tissue properties. AB - Engineered cartilage based on adult mesenchymal stem cells (MSCs) is an alluring goal for the repair of articular defects. However, efforts to date have failed to generate constructs with sufficient mechanical properties to function in the demanding environment of the joint. Our findings with a novel photocrosslinked hyaluronic acid (HA) hydrogel suggest that stiff gels (high HA concentration, 5% w/v) foster chondrogenic differentiation and matrix production, but limit overall functional maturation due to the inability of the formed matrix to diffuse away from the point of production and form a contiguous network. In the current study, we hypothesized that increasing the MSC seeding density would decrease the required diffusional distance, and so expedite the development of functional properties. To test this hypothesis bovine MSCs were encapsulated at seeding densities of either 20,000,000 or 60,000,000 cells ml(-1) in 1%, 3%, and 5% (w/v) HA hydrogels. Counter to our hypothesis the higher concentration HA gels (3% and 5%) did not develop more rapidly with increased MSC seeding density. However, the biomechanical properties of the low concentration (1%) HA constructs increased markedly (nearly 3-fold with a 3-fold increase in seeding density). To ensure that optimal nutrient access was delivered, we next cultured these constructs under dynamic culture conditions (with orbital shaking) for 9 weeks. Under these conditions 1% HA seeded at 60,000,000 MSCs ml(-1) reached a compressive modulus in excess of 1 MPa (compared with 0.3-0.4 MPa for free swelling constructs). This is the highest level we have reported to date in this HA hydrogel system, and represents a significant advance towards functional stem cell-based tissue engineered cartilage. PMID- 22546517 TI - Novel silk fibroin/elastin wound dressings. AB - Silk fibroin (SF) and elastin (EL) scaffolds were successfully produced for the first time for the treatment of burn wounds. The self-assembly properties of SF, together with the excellent chemical and mechanical stability and biocompatibility, were combined with elastin protein to produce scaffolds with the ability to mimic the extracellular matrix (ECM). Porous scaffolds were obtained by lyophilization and were further crosslinked with genipin (GE). Genipin crosslinking induces the conformational transition from random coil to beta-sheet of SF chains, yielding scaffolds with smaller pore size and reduced swelling ratios, degradation and release rates. All results indicated that the composition of the scaffolds had a significant effect on their physical properties, and that can easily be tuned to obtain scaffolds suitable for biological applications. Wound healing was assessed through the use of human full thickness skin equivalents (EpidermFT). Standardized burn wounds were induced by a cautery and the best re-epithelialization and the fastest wound closure was obtained in wounds treated with 50SF scaffolds; these contain the highest amount of elastin after 6 days of healing in comparison with other dressings and controls. The cytocompatibility demonstrated with human skin fibroblasts together with the healing improvement make these SF/EL scaffolds suitable for wound dressing applications. PMID- 22546518 TI - Gender differences in incidence and determinants of disability in activities of daily living among elderly individuals: SABE study. AB - Determining the groups that are most susceptible to developing disability is essential to establishing effective prevention and rehabilitation strategies. The aim of the present study was to determine gender differences in the incidence of disability regarding activities of daily living (ADL) and determinants among elderly residents of Sao Paulo, Brazil. In 2000, 1634 elderly with no difficulties regarding ADL (modified Katz Index) were selected. These activities were reassessed in 2006 and disability was the outcome for the analysis of determinants. The following characteristics were analyzed at baseline: socio demographic, behavioral, health status, medications, falls, hospitalizations, depressive symptoms, cognition, handgrip, mobility and balance. The incidence density was 42.4/1000 women/year and 17.5/1000 men/year. After adjusting for socioeconomic status and health conditions, women with chronic diseases and social vulnerability continued to have a greater incidence of disability. The following were determinants of the incidence of disability: age and depressive symptoms in both genders; stroke and slowness on the sit-and-stand test among men; and osteoarthritis and sedentary lifestyle among women. Better cognitive performance and handgrip strength were protective factors among men and women, respectively. Adverse clinical and social conditions determine differences between genders regarding the incidence of disability. Decreased mobility and balance and health conditions that affect the central nervous system or lead to impaired cognition disable men more, whereas a sedentary lifestyle, reduction in muscle strength and conditions that affect the osteoarticular system disable women more. PMID- 22546519 TI - Optimization of the examination posture in spinal curvature assessment. AB - To decrease the influence of postural sway during spinal measurements, an instrumented fixation posture (called G) was proposed and tested in comparison with the free standing posture (A) using the DTP-3 system in a group of 70 healthy volunteers. The measurement was performed 5 times on each subject and each position was tested by a newly developed device for non-invasive spinal measurements called DTP-3 system. Changes in postural stability of the spinous processes for each subject/the whole group were evaluated by employing standard statistical tools. Posture G, when compared to posture A, reduced postural sway significantly in all spinous processes from C3 to L5 in both the mediolateral and anterioposterior directions. Posture G also significantly reduced postural sway in the vertical direction in 18 out of 22 spinous processes. Importantly, posture G did not significantly influence the spinal curvature. PMID- 22546520 TI - The effect of three years of TNFalpha blocking therapy on markers of bone turnover and their predictive value for treatment discontinuation in patients with ankylosing spondylitis: a prospective longitudinal observational cohort study. AB - INTRODUCTION: The aim of this study was to investigate the effect of three years of tumor necrosis factor-alpha (TNF-alpha) blocking therapy on bone turnover as well as to analyze the predictive value of early changes in bone turnover markers (BTM) for treatment discontinuation in patients with ankylosing spondylitis (AS). METHODS: This is a prospective cohort study of 111 consecutive AS outpatients who started TNF-alpha blocking therapy. Clinical assessments and BTM were assessed at baseline, three and six months, as well as at one, two, and three years. Z-scores of BTM were calculated to correct for age and gender. Bone mineral density (BMD) was assessed yearly. RESULTS: After three years, 72 patients (65%) were still using their first TNF-alpha blocking agent. In these patients, TNF-alpha blocking therapy resulted in significantly increased bone-specific alkaline phosphatase, a marker of bone formation; decreased serum collagen-telopeptide (sCTX), a marker of bone resorption; and increased lumbar spine and hip BMD compared to baseline. Baseline to three months decrease in sCTX Z-score (HR: 0.394, 95% CI: 0.263 to 0.591), AS disease activity score (ASDAS; HR: 0.488, 95% CI: 0.317 to 0.752), and physician's global disease activity (HR: 0.739, 95% CI: 0.600 to 0.909) were independent inversely related predictors of time to treatment discontinuation because of inefficacy or intolerance. Early decrease in sCTX Z-score correlated significantly with good long-term response regarding disease activity, physical function and quality of life. CONCLUSIONS: Three years of TNF-alpha blocking therapy results in a bone turnover balance that favors bone formation, especially mineralization, in combination with continuous improvement of lumbar spine BMD. Early change in sCTX can serve as an objective measure in the evaluation of TNF alpha blocking therapy in AS, in addition to the currently used more subjective measures. PMID- 22546521 TI - Low natural levels of Nosema ceranae in Apis mellifera queens. AB - Queens are the primary female reproductive individuals in honey bee colonies and, while they are generally free from Nosema ceranae infection, they are nevertheless susceptible. We sought to determine whether queens are naturally infected by N. ceranae, as these infections could be a factor in the rapid spread of this parasite. Queens were analyzed using real-time PCR and included larval queens, newly emerged, and older mated queens. Overall, we found that all tissues we examined were infected with N. ceranae at low levels but no samples were infected with Nosema apis. The infection of the ovaries and spermatheca suggests the possibility of vertical transmission of N. ceranae. PMID- 22546522 TI - Impaired spatial working memory learning and performance in normal aged rhesus monkeys. AB - Aged non-human primates may have deficits in a variety of cognitive functions. However, it is possible that at least some age-related performance deficits relate to a deficit in initial task learning. To assess this, aged rhesus monkeys were trained to perform a Self-Ordered Spatial Search (SOSS) task using the same training and testing parameters used previously with normal young animals. Aged animals failed to reach criterion at the easiest task level. In an attempt to improve learning, a group of aged animals were first trained on SOSS using a standard 5s ITI, followed by trials with low inter-trial interference (e.g., a stimulus used in a trial would not be used again for the next 2 trials) or with trials in which the spatial distance between the stimuli on the screen was maximized. Because performance improved but failed to reach criterion, this was followed by sessions with increasing ITIs (from 5 s to 10 or 15 s). Only increasing the ITI improved the performance of the aged animals enough to allow them to learn the task to criterion. Once the criterion was reached, memory was taxed by increasing the delay between stimulus presentations and increasing the number of spatial positions to be remembered. Performance declined for young animals, but even more so for aged animals. The results of the present study suggests that aged primates have difficulty initially learning a complex working memory task, and that the ITI may be an important parameter to manipulate to improve learning. However, once the task is learned, performance of aged animals is inferior to that of young animals, particularly when memory demands are increased. PMID- 22546523 TI - Differential roles of the dorsal hippocampal regions in the acquisition of spatial and temporal aspects of episodic-like memory. AB - Episodic memory refers to the recollection of what, where and when an event occurred. Computational models suggest that the dentate gyrus (DG) and the CA3 hippocampal subregions are involved in pattern separation and the rapid acquisition of episodes, while CA1 is involved in the formation of a temporal context. Most of the studies performed to test this hypothesis failed to simultaneously address the aspects of episodic memory. Recently, a new task of object recognition was validated in rats. In the first sample trial, the rat is exposed to four copies of an object. In second sample, the rat is exposed to four copies of a different object. In the test trial, two copies of each of the previous objects are presented. One copy of the object used in sample trial one is located in a different place, and it is expected to be the most explored. Our goal was to evaluate whether the pharmacological inactivation of the dorsal DG/CA3 and CA1 subregions could differentially impair the acquisition of the task. Inactivation of the DG/CA3 subregions impaired the spatial discrimination, while the temporal discrimination was preserved. Rats treated with muscimol in CA1 explored all the objects equally well, irrespective of place or presentation time. Our results are consistent with computational models that postulate a role for DG/CA3 in rapid encoding and in spatial pattern separation, and a role for CA1 in the in the formation of the temporal context of events and as well as in detecting spatial novelty. PMID- 22546524 TI - Progesterone and estradiol-17beta as a potential method for pregnancy diagnosis in the collared peccary (Pecari tajacu). AB - In this study, the period of pregnancy of nine collared peccary females has been monitored through the analysis of serum progesterone and estradiol-17beta profiles. Serum concentrations of progesterone increased by Day 4 after conception, reaching concentrations of 33.4+/-5.6 ng/mL on Day 10. Between Days 10 and 130 progesterone values were maintained between 20 and 60 ng/mL. In the collared peccary, embryonic estradiol synthesis is first observed in the systemic circulation by Day 15 of pregnancy. Between Days 0 and 50 of pregnancy, average estradiol-17beta concentrations were between 0 and 30 pg/mL. From Day 75 of pregnancy onwards, estradiol concentrations were constantly increasing, reaching maximum concentrations (131.4+/-40.8 pg/mL) on the day of parturition. The combined study of serum progesterone and estradiol-17beta concentrations as a potential method for early pregnancy diagnosis presented the best overall accuracy (73%) when the threshold was established at 20 ng/mL serum progesterone and 20 pg/mL serum estradiol. Nevertheless, the accuracy for diagnosing pregnancy of females at mid and late pregnancy was 78% and 95%, respectively. The analysis of the sexual hormones during pregnancy could be a useful tool as a potential pregnancy diagnosis and an efficient predictor of the day of parturition in the captive collared peccary. PMID- 22546525 TI - Cognitive and neurological sequelae after stereoendoscopic disconnection of a hypothalamic hamartoma. A case study. AB - Hypothalamic hamartomas (HH) are congenital malformations of the hypothalamus, often generating medically refractory gelastic seizures. There is great risk of progression to various complex partial and generalized seizures and of cognitive and behavioral deterioration. Hence, various surgical approaches have been introduced to resect or disconnect the HH from surrounding tissue, and stereoendoscopic disconnection has been advocated as one of the most lenient approaches to sessile HH embedded in the third ventricle. In fact, no long-term neurological or cognitive impairments have hitherto been reported after this procedure. Yet, unforeseen complications may arise in any surgical intervention on this region. We found serious deterioration of memory and reading skills by comprehensive neuropsychological assessments pre- and postoperatively in a child who, before surgery, was age-appropriate with respect to cognitive, emotional, and behavioral development. The child also contracted a permanent oculomotor paresis. Our results are discussed in light of previous relevant findings. PMID- 22546526 TI - Infection of human THP-1 cells with dormant Mycobacterium tuberculosis. AB - Dormant, non-replicating Mycobacterium tuberculosis H37Rv strain cultured in hypoxic conditions was used to infect THP-1 cells. CFUs counting, Kinyoun staining and electron microscopy showed that dormant bacilli infected THP-1 cells at a rate similar to replicating M. tuberculosis, but failed to grow during the first 6 days of infection. The absence of growth was specific to the intracellular compartment, as demonstrated by efficient growth in liquid medium. Quantification of beta-actin mRNA recovered from infected cells showed that, in contrast with log-phase bacteria, infection with dormant bacilli determined a reduced THP-1 cell death. Gene expression of intracellular non-replicating bacteria showed a pattern typical of a dormant state. Intracellular dormant bacteria induced the activation of genes associated to a proinflammatory response in THP-1 cells. Though, higher levels of TNFalpha, IL-1beta and IL-8 mRNAs compared to aerobic H37Rv infected cells were not paralleled by increased cytokine accumulation in the supernatants. Moreover, dormant bacilli induced a higher expression of inducible cox-2 gene, accompanied by increased PGE2 secretion. Overall, our data describe a new model of in vitro infection using dormant M. tuberculosis that could provide the basis for understanding how non replicating bacilli survive intracellularly and influence the maintenance of the hypoxic granuloma. PMID- 22546527 TI - TLP01, an mshA mutant of Vibrio cholerae O139 as vaccine candidate against cholera. AB - No commercially live vaccine against cholera caused by Vibrio cholerae O139 serogroup is available and it is currently needed. Virulent O139 strain CRC266 was genetically modified by firstly deleting multiple copies of the filamentous phage CTXphi, further tagging by insertion of the endoglucanase A coding gene from Clostridium thermocellum into the hemagglutinin/protease gene and finally deleting the mshA gene, just to improve the vaccine biosafety. One of the derived strains designated as TLP01 showed full attenuation and good colonizing capacity in the infant mouse cholera model, as well as highly immunogenic properties in the adult rabbit and rat models. Since TLP01 lacks MSHA fimbriae, it is refractory to infection with another filamentous phage VGJphi and therefore protected of acquiring CTXphi from a recombinant hybrid VGJphi/CTXphi. This strategy could reduce the possibilities of stable reversion to virulence out of the human gut. Furthermore, this vaccine strain was impaired to produce biofilms under certain culture conditions, which might have implications for the strain survival in natural settings contributing to vaccine biosafety as well. The above results has encouraged us to consider TLP01 as a live attenuated vaccine strain having an adequate performance in animal models, in terms of attenuation and immunogenicity, so that it fulfills the requirements to be evaluated in human volunteers. PMID- 22546528 TI - Progression of microstructural putamen alterations in a case of symptomatic recurrent seizures using diffusion tensor imaging. AB - Microstructural alterations of the putamen were recently reported in patients with partial and generalized epilepsy disorders. However, it is unknown whether these alterations pre-exist or are secondary to recurrent seizures. Here we investigated the progression of putamen fractional anisotropy (FA) alterations in a case of recurrent psychomotor seizures using longitudinal diffusion tensor imaging (DTI) shortly before (DTI-1) and after a psychomotor seizure (DTI-2). We obtained FA values of a hypothesis-guided putamen region-of-interest (ROI) and seven exploratory ROIs. FA values from both DTIs were compared with reference values from 19 controls. Relative to controls, the patient's putamen FA was increased at DTI-1 (13% left putamen, 7% right putamen), an effect that was exacerbated at DTI-2 (24% left putamen (p<0.05), 20% right putamen). In the exploratory ROIs we found FA reductions in the corticospinal tract, temporal lobe, and occipital lobe (p<0.05) relative to controls at DTI-1 and DTI-2. In contrast to the putamen, all exploratory ROIs showed no relevant FA change between DTI-1 and DTI-2. These results suggest that recurrent seizures may lead to progressive microstructural putamen alterations. PMID- 22546529 TI - Comparing the functional consequences of human stem cell transplantation in the irradiated rat brain. AB - Radiotherapy is a frontline treatment for the clinical management of CNS tumors. Although effective in eradicating tumor cells, radiotherapy also depletes neural stem and progenitor cells in the hippocampus that are important for neurogenesis and cognitive function. Consequently, the use of radiation to control primary and metastatic brain tumors often leads to debilitating and progressive cognitive decrements in surviving patients, representing a serious medical condition that, to date, has no satisfactory, long-term solutions. As a result, we have explored the use of stem cells as therapeutic agents to improve cognition after radiotherapy. Our past work has demonstrated the capability of cranially transplanted human embryonic (hESCs) and neural (hNSCs) stem cells to functionally restore cognition in rats 1 and 4 months after head-only irradiation. We have now expanded our cognitive analyses with hESCs and quantified both survival and differentiated fates of engrafted cells at 1 and 4 months after irradiation. Our findings indicate the capability of hESC transplantation to ameliorate radiation-induced cognitive dysfunction 1 month following cranial irradiation, using a hippocampal-dependent novel place recognition task. Irradiated animals not engrafted with stem cells experienced prolonged and significant cognitive dysfunction. Stereological estimates indicated that 35% and 17% of the transplanted hESCs survived at 1 and 4 months postgrafting, respectively. One month after irradiation and grafting, phenotypic analyses revealed that 26% and 31% of the hESCs differentiated into neurons and astrocytes, while at the 4-month time, neuronal and astrocytic differentiation was 7% and 46%, respectively. Comparison between present and past data with hESCs and hNSCs demonstrates equivalent cognitive restoration and a preference of hNSCs to commit to neuronal versus astrocytic lineages over extended engraftment times. Our data demonstrate the functional utility of human stem cell replacement strategies for ameliorating the adverse effects of cranial irradiation on cognition. PMID- 22546530 TI - Human erythrocytes and neuroblastoma cells are in vitro affected by sodium orthovanadate. AB - Research on biological influence of vanadium has gained major importance because it exerts potent toxic, mutagenic, and genotoxic effects on a wide variety of biological systems. However, hematological toxicity is one of the less studied effects. The lack of information on this issue prompted us to study the structural effects induced on the human erythrocyte membrane by vanadium (V). Sodium orthovanadate was incubated with intact erythrocytes, isolated unsealed human erythrocyte membranes (IUM) and molecular models of the erythrocyte membrane. The latter consisted of bilayers of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE), phospholipid classes located in the outer and inner monolayers of the human erythrocyte membrane, respectively. This report presents evidence in order that orthovanadate interacted with red cell membranes as follows: a) in scanning electron microscopy (SEM) studies it was observed that morphological changes on human erythrocytes were induced; b) fluorescence spectroscopy experiments in isolated unsealed human erythrocyte membranes (IUM) showed that an increase in the molecular dynamics and/or water content at the shallow depth of the lipids glycerol backbone at concentrations as low as 50MUM was produced; c) X-ray diffraction studies showed that orthovanadate 0.25-1mM range induced increasing structural perturbation to DMPE; d) somewhat similar effects were observed by differential scanning calorimetry (DSC) with the exception of the fact that DMPC pretransition was shown to be affected; and e) fluorescence spectroscopy experiments performed in DMPC large unilamellar vesicles (LUV) showed that at very low concentrations induced changes in DPH fluorescence anisotropy at 18 degrees C. Additional experiments were performed in mice cholinergic neuroblastoma SN56 cells; a statistically significant decrease of cell viability was observed on orthovanadate in low or moderate concentrations. PMID- 22546531 TI - Colonizing the heart from the epicardial side. AB - The clinical use of stem cells, such as bone marrow-derived and, more recently, resident cardiac stem cells, offers great promise for treatment of myocardial infarction and heart failure. The epicardium-derived cells have also attracted attention for their angiogenic paracrine actions and ability to differentiate into cardiomyocytes and vascular cells when activated during cardiac injury. In a recent study, Chong and colleagues have described a distinct population of epicardium-derived mesenchymal stem cells that reside in a perivascular niche of the heart and have a broad multilineage potential. Exploring the therapeutic capacity of these cells will be an exciting future endeavor. PMID- 22546532 TI - Oral acetazolamide after Boston keratoprosthesis in Stevens-Johnson syndrome. AB - BACKGROUND: Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a rare but severe and sometimes fatal condition associated with exposure to medications; sulfamethoxazole is among the most common causes. We sought to address the safety of acetazolamide, a chemically related compound, in patients with prior SJS/TEN and glaucoma. A retrospective case series is described of patients at the Massachusetts Eye and Ear Infirmary who underwent keratoprosthesis surgery for corneal blindness from SJS/TEN, and later required oral acetazolamide for elevated intraocular pressure. FINDINGS: Over the last 10 years, 17 patients with SJS/TEN received a Boston keratoprosthesis. Of these, 11 developed elevated intraocular pressure that required administration of oral acetazolamide. One of 11 developed a mild allergic reaction, but no patient experienced a recurrence of SJS/TEN or any severe adverse reaction. CONCLUSION: Although an increase in the rate of recurrent SJS/TEN due to oral acetazolamide would not necessarily be apparent after treating only 11 patients, in our series, acetazolamide administration was well tolerated without serious sequela. PMID- 22546533 TI - The Arabidopsis clock: time for an about-face? AB - Three recent studies have altered thinking on the role of TIMING OF CAB EXPRESSION 1 (TOC1), a core element in the plant circadian oscillator. PMID- 22546534 TI - CO2 lasers in the management of potentially malignant and malignant oral disorders. AB - The CO2 laser was invented in 1963 by Kumar Patel. Since the early 1970s, CO2 laser has proved to be an effective method of treatment for patients with several types of oral lesions, including early squamous cell carcinoma.Laser surgery of oral premalignant disorders is an effective tool in a complete management strategy which includes careful clinical follow-up, patient education to eliminate risk factors, reporting and biopsying of suspicious lesions and any other significant lesions. However, in a number of patients, recurrence and progression to malignancy remains a risk. CO2 laser resection has become the preferred treatment for small oral and oropharyngeal carcinomas. Laser resection does not require reconstructive surgery. There is minimal scarring and thus, optimum functional results can be expected.New and improved applications of laser surgery in the treatment of oral and maxillofacial/head and neck disorders are being explored. As more surgeons become experienced in the use of lasers and as our knowledge of the capabilities and advantages of this tool expands, lasers may play a significant role in the management of different pathologies. PMID- 22546535 TI - Functional performance and inflammatory cytokines after squat exercises and whole body vibration in elderly individuals with knee osteoarthritis. AB - OBJECTIVE: To investigate the effects of squat exercises combined with whole-body vibration on the plasma concentration of inflammatory markers and the functional performance of elderly individuals with knee osteoarthritis (OA). DESIGN: Clinical, prospective, randomized, single-blinded study. SETTING: Exercise physiology laboratory. PARTICIPANTS: Elderly subjects with knee OA (N=32) were divided into 3 groups: (1) squat exercises on a vibratory platform (platform group, n=11); (2) squat exercises without vibration (squat group, n=10); and (3) the control group (n=11). INTERVENTIONS: The structured program of squat exercises in the platform and squat groups was conducted 3 times per week, on alternate days, for 12 weeks. MAIN OUTCOME MEASURES: Plasma soluble tumor necrosis factor-alpha receptors 1 (sTNFR1) and 2 (sTNFR2) were measured using immunoassays (the enzyme-linked immunosorbent assay method). The Western Ontario and McMaster Universities Osteoarthritis Index questionnaire was used to evaluate self-reported physical function, pain, and stiffness. The 6-minute walk test, the Berg Balance Scale, and gait speed were used to evaluate physical function. RESULTS: In the platform group, there were significant reductions in the plasma concentrations of the inflammatory markers sTNFR1 and sTNFR2 (P<.001 and P<.05, respectively) and self-reported pain (P<.05) compared with the control group, and there was an increase in balance (P<.05) and speed and distance walked (P<.05 and P<.001, respectively). In addition, the platform group walked faster than the squat group (P<.01). CONCLUSIONS: The results suggest that whole-body vibration training improves self-perception of pain, balance, gait quality, and inflammatory markers in elderly subjects with knee OA. PMID- 22546536 TI - Current pain and fear of pain contribute to reduced maximum voluntary contraction of neck muscles in patients with chronic neck pain. AB - OBJECTIVE: To assess a range of physical and psychological factors and determine which factors contribute the most to reduced strength in patients with neck pain. DESIGN: Regression. SETTING: Laboratory. PARTICIPANTS: Women with chronic neck pain (n=34) and healthy controls (n=14). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Neck flexion, extension, and lateral flexion maximum voluntary contractions (MVC) were measured in patients and healthy controls. Additional parameters were collected for the patient group including: (1) questionnaires measuring general health (Medical Outcomes Study 36-Item Short-Form Health Survey), pain intensity, disability (Neck Disability Index [NDI]; Patient Specific Functional Scale), and fear of movement (Fear-Avoidance Beliefs Questionnaire [FABQ]), (2) pressure pain thresholds, (3) cross-sectional area of selected neck muscles, and (4) surface electromyography from selected neck muscles during a multidirectional isometric task. Univariate and multivariate regression analyses were applied with the average MVC (average of flexion, extension, and lateral flexion MVC) as the dependent variable. RESULTS: The average MVC was significantly lower in patients (mean +/- SD, 130.0+/-6.0N) compared with controls (166.9+/-11.7N; P<.01). Univariate regression of the average MVC with the FABQ, NDI, or pain experienced during the MVC gave R(2) values of 13.4%, 13.8%, and 21.1%, respectively. Collectively, the FABQ and pain experienced during the MVCs resulted in an R(2) of 26.6% and the FABQ, contraction pain, and NDI, an R(2) of 28.2%. CONCLUSIONS: The average maximum voluntary force produced in neck flexion, extension, and lateral flexion is inversely and moderately correlated with the pain experienced during maximal contraction, fear of movement, and aspects of neck disability in patients with chronic neck pain. PMID- 22546537 TI - Gene duplication and the evolution of plant MADS-box transcription factors. AB - Since the first MADS-box transcription factor genes were implicated in the establishment of floral organ identity in a couple of model plants, the size and scope of this gene family has begun to be appreciated in a much wider range of species. Over the course of millions of years the number of MADS-box genes in plants has increased to the point that the Arabidopsis genome contains more than 100. The understanding gained from studying the evolution, regulation and function of multiple MADS-box genes in an increasing set of species, makes this large plant transcription factor gene family an ideal subject to study the processes that lead to an increase in gene number and the selective birth, death and repurposing of its component members. Here we will use examples taken from the MADS-box gene family to review what is known about the factors that influence the loss and retention of genes duplicated in different ways and examine the varied fates of the retained genes and their associated biological outcomes. PMID- 22546538 TI - V-ATPase, ScNhx1p and yeast vacuole fusion. AB - Membrane fusion is the last step in trafficking pathways during which membrane vesicles fuse with target organelles to deliver cargos. It is a central cellular reaction that plays important roles in signal transduction, protein sorting and subcellular compartmentation. Recent progress in understanding the roles of ion transporters in vacuole fusion in yeast is summarized in this article. It is becoming increasingly evident that the vacuolar proton pump V-ATPase and vacuolar Na+/H+ antiporter ScNhx1p are key components of the vacuole fusion machinery in yeast. Yeast ScNhx1p regulates vacuole fusion by controlling the luminal pH. V ATPases serve a dual role in vacuolar integrity in which they regulate both vacuole fusion and fission reactions in yeast. Fission defects are epistatic to fusion defects. Vacuole fission depends on the proton translocation activity of the V-ATPase; by contrast, the fusion reaction does not need the transport activity but requires the physical presence of the proton pump. V0, the membrane integral sector of the V-ATPase, forms trans-complexes between the opposing vacuoles in the terminal phase of vacuole fusion where the V0trans-complexes build a continuous proteolipid channel at the fusion site to mediate the bilayer fusion. PMID- 22546539 TI - Imipramine inhibits adipogenic differentiation in both 3T3-L1 preadipocytes and mouse marrow stromal cells. AB - Imipramine (IM) has been widely used clinically for the treatment of mental disorders. Its actions on tissues or organs other than the nervous system also need to be understood for its proper clinical use. In this study, the effects of IM on adipogenic differentiation in both 3T3-L1 preadipocytes and mouse marrow stromal cells (MSCs) were investigated. The results showed that fewer adipocytic cells were developed from 3T3-L1 preadipocytes in the presence of 0.001 to 1 MUmol/L of IM as compared to control. Similar inhibitory effect was also observed in mouse MSCs. The decrease in the formation of adipocytes was accompanied with significant down-regulation at mRNA expression of the early adipogenic transcription factor, peroxisome proliferator-activated receptor gamma2 (PPARgamma2). Western blot analysis further revealed that the protein expression of PPARgamma2 was reduced markedly in cells treated with IM at concentrations of 0.01, 0.1 and 1 MUmol/L, suggesting that the suppression on PPARgamma2 was involved in IM's inhibition on MSCs adipogenesis. Moreover, IM at the above concentrations could stimulate the mRNA expression of beta2-adrenergic receptor (AR) and beta3-AR, which implicated that the effect of IM on adipogenic differentiation was partially mediated by beta-ARs. Our results demonstrated for the first time that the conventional antidepressive imipramine exerts accompanied inhibitory effect on adipocyte formation, which may have possible clinical implications. PMID- 22546540 TI - Identification of sheep ovary genes potentially associated with off-season reproduction. AB - Off-season reproduction is a favorable economic trait for sheep industry. Hu sheep, an indigenous Chinese sheep breed, demonstrates a higher productivity of lambs and displays year-around oestrous behavior under proper nutrition and environment. The genetic basis behind these traits, however, is not well understood. In order to identify genes associated with the off-season reproduction, we constructed a suppression subtractive hybridization (SSH) cDNA library using pooled ovary mRNAs of 6 oestrous Hu females as a tester and the pooled ovary mRNAs of 6 non-oestrous Chinese Merino females as a driver. A total of 382 resulting positive clones were obtained after the SSH. We identified 114 differentially up-regulated genes in oestrous Hu sheep by using subsequent screening and DNA sequencing, of which 8 were previously known, 93 were reported for the first time in sheep, and 13 were novel with no significant homology to any sequence in the DNA databases. Functions of the genes identified are related to cell division, signal transduction, structure, metabolism, or cell defense. To validate the results of SSH, 6 genes (Ntrk2, Ppap2b, Htra1, Nid1, Serpine2 and Foxola) were selected for conformational analysis using quantitative real-time PCR (qRT-PCR), and two of them (Htral and Foxo1a) were verified by Northern blot. All of the 6 genes were differentially up-regulated in the ovary of oestrous Hu. It is obvious that off-season reproduction is a complex trait involving multiple genes in multiple organs. This study helps to provide a foundation for the final identification of functional genes involved in the sheep ovary. PMID- 22546541 TI - A commercial formulation of glyphosate inhibits proliferation and differentiation to adipocytes and induces apoptosis in 3T3-L1 fibroblasts. AB - Glyphosate-based herbicides are extensively used for weed control all over the world. Therefore, it is important to investigate the putative toxic effects of these formulations which include not only glyphosate itself but also surfactants that may also be toxic. 3T3-L1 fibroblasts are a useful tool to study adipocyte differentiation, this cell line can be induced to differentiate by addition of a differentiation mixture containing insulin, dexamethasone and 3-isobutyl-1 methylxanthine. We used this cell line to investigate the effect of a commercial formulation of glyphosate (GF) on proliferation, survival and differentiation. It was found that treatment of exponentially growing cells with GF for 48h inhibited proliferation in a dose-dependent manner. In addition, treatment with GF dilution 1:2000 during 24 or 48h inhibited proliferation and increased cell death, as evaluated by trypan blue-exclusion, in a time-dependent manner. We showed that treatment of 3T3-L1 fibroblasts with GF increased caspase-3 like activity and annexin-V positive cells as evaluated by flow cytometric analysis, which are both indicative of induction of apoptosis. It was also found that after the removal of GF, remaining cells were able to restore proliferation. On the other hand, GF treatment severely inhibited the differentiation of 3T3-L1 fibroblasts to adipocytes. According to our results, a glyphosate-based herbicide inhibits proliferation and differentiation in this mammalian cell line and induces apoptosis suggesting GF-mediated cellular damage. Thus, GF is a potential risk factor for human health and the environment. PMID- 22546543 TI - Four in one--the unusual manifestation of coarctation syndrome in young adult person. PMID- 22546542 TI - Inhibition of Th17 differentiation by anti-TNF-alpha therapy in uveitis patients with Behcet's disease. AB - INTRODUCTION: The purpose of this study was to determine whether anti-tumour necrosis factor alpha (anti-TNF-alpha) antibody, infliximab, can inhibit T helper 17 (Th17) differentiation in uveitis patients who have Behcet's disease (BD). METHODS: To measure inflammatory cytokines, ocular fluid samples from BD patients being treated with infliximab were collected. Cluster of differentiation 4 (CD4)+ T cells from BD patients with active uveitis were co-cultured with anti-cluster of differentiation 3/cluster of differentiation 28 (CD3/CD28) antibodies in the presence of infliximab. For the induction of Th17 cells, CD4+ T cells from BD patients were co-cultured with anti-CD3/CD28, anti-interferon-gamma (anti-IFN gamma), anti-interleukin-4 (anti-IL-4), and recombinant proteins such as interleukin-1 beta (IL-1beta), interleukin-6 (IL-6), interleukin-23 (IL-23), and TNF-alpha. The BD T cells were co-cultured with infliximab, and the production of interleukin-17 (IL-17) was evaluated by ELISA and flow cytometry, and the expression of retinoid-acid receptor-related orphan receptor gamma t (RORgammat) was also evaluated by flow cytometry. In addition, intraocular cells collected from mice with experimental autoimmune uveitis (EAU) were used for the assay with anti-TNF-alpha blocking antibody. RESULTS: Ocular fluids from active uveitis patients who have BD contained significant amounts of inflammatory cytokines such as IFN-gamma, IL-2, TNF-alpha, IL-6, and IL-17, while ocular fluids from infliximab patients did not contain any inflammatory cytokines. Activated CD4+ T cells from BD patients produced large amounts of TNF-alpha and IL-17, whereas T cells in the presence of infliximab failed to produce these cytokines. Polarized Th17 cell lines from BD patients produced large amounts of IL-17, and Th17 cells exposed to infliximab had significantly reduced IL-17 production. Polarized BD Th17 cells expressed large amounts of transcription factor RORgammat. In contrast, in vitro-treated infliximab Th17 cells expressed less RORgammat. Moreover, intraocular T cells from EAU mice had a high population of IL-17+ cells, and retinal antigen-specific T cells from EAU mice produced large amounts of IL-17 in the presence of retinal peptide. However, the EAU T cells produced less IL-17 if the T cells were treated with anti-TNF-alpha antibody. CONCLUSIONS: These results indicate that anti-TNF-alpha therapy suppresses effector T-cell differentiation in BD patients with uveitis. Thus, suppression of effector T-cell differentiation by anti-TNF-alpha therapy may provide protection from severe ocular inflammation in BD. PMID- 22546544 TI - Deterioration from improved heart failure status in a recipient of a cardiac resynchronization therapy-defibrillator (CRT-D) following a single inappropriate shock. PMID- 22546545 TI - Survivors of sudden cardiac death with history of depression are not at significantly greater risk of recurrent arrhythmias and death. PMID- 22546546 TI - Vaccine potential of recombinant antigens of Theileria annulata and Hyalomma anatolicum anatolicum against vector and parasite. AB - In an attempt to develop vaccine against Hyalomma anatolicum anatolicum and Theileria annulata, three antigens were expressed in prokaryotic expression system and protective potentiality of the antigens was evaluated in cross bred calves. Two groups (grs. 1 and 4) of male cross-bred (Bos indicus * Bos taurus) calves were immunized with rHaa86, a Bm86 ortholog of H. a. anatolicum, while one group of calves (gr. 2) were immunized with cocktails of two antigens viz., surface antigens of T. annulata (rSPAG1, rTaSP). One group each was kept as negative controls (grs. 3 and 5). The animals of groups 1, 2 and 3 were challenged with T. annulata infected H. a. anatolicum adults while the animals of groups 1, 3, 4 and 5 were challenged with uninfected adult ticks. A significantly high (p<0.05) antibody responses to all the three antigens were detected in immunized calves, but the immune response was comparatively higher with rHaa86 followed by rTaSP and rSPAG1. Upon challenge with T. annulata infected ticks, animals of all groups showed symptoms of the disease but there was 50% survival of calves of group 1 while all non immunized control calves (group 3) and rSPAG1+rTaSP immunized calves died. The rHaa86 antigen was found efficacious to protect calves against more than 71.4-75.5% of the challenge infestation. The experiment has given a significant clue towards the development of rHaa86 based vaccine against both H. a. anatolicum and T. annulata. PMID- 22546547 TI - Apparent tick paralysis by Rhipicephalus sanguineus (Acari: Ixodidae) in dogs. AB - Certain tick species including Ixodes holocyclus can inoculate neurotoxins that induce a rapid, ascending flaccid paralysis in animals. Rhipicephalus sanguineus, the most widespread tick of dogs, is recognized as a vector of several pathogens causing diseases in dogs and humans. A single report suggests its role as cause of paralysis in dogs. This study presents the clinical history of 14 young dogs heavily infested by R. sanguineus (intensity of infestation, 63-328) in an endemic area of southern Italy. During May to June of 2011, dogs were presented at the clinical examination with neurological signs of different degrees (e.g., hind limb ataxia, generalized lethargy, and difficulty in movements). All animals were treated with acaricides and by manual tick removal but ten of them died within a day, displaying neurological signs. The other 4 dogs recovered within 3 days with acaricidal and supportive treatment. Twelve dogs were positive by blood smear examination for Hepatozoon canis with a high parasitemia, two also for Babesia vogeli and two were negative for hemoparasites. Low-grade thrombocytopenia, hypoalbuminemia, and pancytopenia were the haematological alterations most frequently recorded. Other causes of neurological disease in dogs were excluded and the diagnosis of tick paralysis by R. sanguineus was confirmed (ex juvantibus) by early and complete recovery of 4 dogs following acaricidal treatment and tick removal. PMID- 22546548 TI - Nuclear receptor mediated mechanisms of macrophage cholesterol metabolism. AB - Macrophages comprise a family of multi-faceted phagocytic effector cells that differentiate "in situ" from circulating monocytes to exert various functions including clearance of foreign pathogens as well as debris derived from host cells. Macrophages also possess the ability to engulf and metabolize lipids and this way connect lipid metabolism and inflammation. The molecular link between these processes is provided by certain members of the nuclear receptor family. For instance, peroxisome proliferator activated receptors (PPAR) and liver X receptors (LXR) are able to sense the dynamically changing lipid environment and translate it to gene expression changes in order to modulate the cellular phenotype. Atherosclerosis embodies both sides of this coin: it is a disease in which macrophages with altered cholesterol metabolism keep the arteries in a chronically inflamed state. A large body of publications has accumulated during the past few decades describing the role of nuclear receptors in the regulation of macrophage cholesterol homeostasis, their contribution to the formation of atherosclerotic plaques and their crosstalk with inflammatory pathways. This review will summarize the most recent findings from this field narrowly focusing on the contribution of various nuclear receptors to macrophage cholesterol metabolism. PMID- 22546550 TI - A family of cyclophilin-like molecular chaperones in Plasmodium falciparum. AB - The cyclophilins are a large family of proteins implicated in folding, transport and regulation of other proteins and are potential drug targets in cancer and in some viral and parasitic infections. The functionality of cyclophilins appears to depend on peptidyl-prolyl cis-trans isomerase (foldase) and/or molecular chaperone activities. In this study we assessed the peptidyl-prolyl isomerase and chaperone activities of 8 members of the Plasmodium falciparum cyclophilin family, all produced recombinantly using a common host/vector system. While only two of these proteins had isomerase activity, all of them displayed chaperone function as judged by the ability to prevent the thermal aggregation of model substrates. We suggest that the cyclophilins constitute a family of molecular chaperones in malarial parasites that complement the functions of other chaperones such as the heat-shock proteins. PMID- 22546549 TI - Correlation between secosteroid-induced vitamin D receptor activity in melanoma cells and computer-modeled receptor binding strength. AB - To define the interaction of novel secosteroids produced by the action of cytochrome P450scc with vitamin D receptor (VDR), we used a human melanoma line overexpressing VDR fused with enhanced green fluorescent protein (EGFP) and tested the ligand induced translocation of VDR from the cytoplasm to the nucleus. Hydroxyderivatives of vitamin D(3) with a full length (D(3)) side chain and hydroxy-secosteroids with a shortened side chain (pD) stimulated VDR translocation and inhibited proliferation, however, with different potencies. In general the D(3) were more potent than pD analogues. Molecular modeling of the binding of the secosteroids to the VDR genomic binding pocket (G-pocket) correlated well with the experimental data for VDR translocation. In contrast, docking scores for the non-genomic binding site of the VDR were poor. In conclusion, both the length of the side chain and the number and position of hydroxyl groups affect the activation of VDR by novel secosteroids. PMID- 22546551 TI - Quantitative assessment of effects of phase aberration and noise on high-frame rate imaging. AB - The goal of this paper is to quantitatively study effects of phase aberration and noise on high-frame-rate (HFR) imaging using a set of traditional and new parameters. These parameters include the traditional -6-dB lateral resolution, and new parameters called the energy ratio (ER) and the sidelobe ratio (SR). ER is the ratio between the total energy of sidelobe and the total energy of mainlobe of a point spread function (PSF) of an imaging system. SR is the ratio between the peak value of the sidelobe and the peak value of the mainlobe of the PSF. In the paper, both simulation and experiment are conducted for a quantitative assessment and comparison of the effects of phase aberration and noise on the HFR and the conventional delay-and-sum (D&S) imaging methods with the set of parameters. In the HFR imaging method, steered plane waves (SPWs) and limited-diffraction beams (LDBs) are used in transmission, and received signals are processed with the Fast Fourier Transform to reconstruct images. In the D&S imaging method, beams focused at a fixed depth are used in transmission and dynamically focused beams are used in reception for image reconstruction. The simulation results show that the average differences between the -6-dB lateral beam widths of the HFR imaging and the D&S imaging methods are -0.1337mm for SPW and -0.1481mm for LDB, which means that the HFR imaging method has a higher lateral image resolution than the D&S imaging method since the values are negative. In experiments, the average differences are also negative, i.e., 0.2804mm for SPW and -0.3365mm for LDB. The results for the changes of ER and SR between the HFR and the D&S imaging methods have negative values, too. After introducing phase aberration and noise, both simulations and experiments show that the HFR imaging method has also less change in the -6-dB lateral resolution, ER, and SR as compared to the conventional D&S imaging method. This means that the HFR imaging method is less sensitive to the phase aberration and noise. Based on the study of the new parameters on the HFR and the D&S imaging methods, it is expected that the new parameters can also be applied to assess quality of other imaging methods. PMID- 22546552 TI - Mechanisms elevating ORMDL3 expression in recurrent wheeze patients: role of Ets 1, p300 and CREB. AB - The first genetic factor identified for childhood asthma by genome-wide association study (GWAS) is the locus on chromosome 17q21, harboring the Orosomucoid 1-like 3 (ORMDL3) gene. ORMDL3 is implicated in facilitation of endoplasmic reticulum-mediated inflammatory responses, believed to underlie its association with asthma. In the present study, we demonstrated that mRNA expression of ORMDL3 is significantly increased in the peripheral blood of recurrent wheeze patients compared with normal control subjects by real-time RT PCR. To elucidate the molecular mechanisms involved in human ORMDL3 regulation, we cloned and characterized the promoter region of ORMDL3. Applying 5'-rapid amplification of cDNA end analysis (RACE), we revealed that ORMDL3 gene used multiple transcriptional start sites (TSSs). Using a series of 5' deletion promoter plasmids in luciferase reporter assays, we identified that the proximal minimal promoter of ORMDL3 was located within the region -84/+58 relative to the TSS. Mutational analysis, RNA interference experiments and sequential chromatin immunoprecipitation (ChIP) assay demonstrated that transcriptional activity of the ORMDL3 gene was cooperatively regulated by multiple transcription factors, including Ets-1, p300 and CREB. The expression levels of Ets-1, p300 and CREB were increased in the peripheral blood of recurrent wheeze patients compared with normal control subjects and showed a strong linear correlation with the expression of ORMDL3. Our findings indicate that Ets-1, p300 and CREB binding to the promoter region drive the ORMDL3 transcription. PMID- 22546553 TI - Economies of scale. PMID- 22546554 TI - Gut--liver axis: the impact of gut microbiota on non alcoholic fatty liver disease. AB - AIM: To examine the impact of gut microbiota on non alcoholic fatty liver disease (NAFLD) pathogenesis. DATA SYNTHESIS: Emerging evidence suggests a strong interaction between gut microbiota and liver. Receiving approximately 70% of its blood supply from the intestine, the liver represents the first line of defence against gut-derived antigens. Intestinal bacteria play a key role in the maintenance of gut-liver axis health. Disturbances in the homeostasis between bacteria- and host-derived signals at the epithelial level lead to a break in intestinal barrier function and may foster "bacterial translocation", defined as the migration of bacteria or bacterial products from the intestinal lumen to mesenteric lymph nodes or other extraintestinal organs and sites. While the full repertoire of gut-derived microbial products that reach the liver in health and disease has yet to be explored, the levels of bacterial lipopolysaccharide, a component of the outer membrane of Gram-negative bacteria, are increased in the portal and/or systemic circulation in several types of chronic liver diseases. Derangement of the gut flora, particularly small intestinal bacterial overgrowth, occurs in a large percentage (20-75%) of patients with chronic liver disease. In addition, evidence implicating the gut-liver axis in the pathogenesis of metabolic liver disorders has accumulated over the past ten years. CONCLUSIONS: Complex metabolic diseases are the product of multiple perturbations under the influence of triggering factors such as gut microbiota and diet, thus, modulation of the gut microbiota may represent a new way to treat or prevent NAFLD. PMID- 22546555 TI - Autophagy in the intestinal epithelium is not involved in the pathogenesis of intestinal tumors. AB - Autophagy has been demonstrated to be associated with the pathogenesis of cancer, but no consensus has been reached about its precise role. Therefore, we investigated whether autophagy in the intestinal epithelium is involved in the pathogenesis of intestinal tumors. To evaluate the relationship between autophagy and intestinal tumors, GFP-LC3-APC(min/+) mice were generated by mating GFP-LC3 transgenic mice with APC(min/+) mice. Autophagy was weakly induced in the intestinal polyp regions of the mice in comparison to their non-polyp regions. Under starved conditions, autophagy was not induced in the polyp regions, whereas it was observed in the non-polyp regions. Then, to examine whether a lack of autophagy in the intestinal epithelium enhances the induction of intestinal tumor, Atg7flox/flox:vil-cre-APC(min/+) mice, in which Atg7 had been conditionally deleted in the intestinal epithelium, were generated by mating Atg7flox/flox:vil-cre mice with APC(min/+) mice. However, there was no significant difference in the number of intestinal polyps between the Atg7flox/flox:vil-cre-APC(min/+) and the corresponding control Atg7flox/flox APC(min/+) mice. These results indicate that autophagy in the intestinal epithelium is not involved in the pathogenesis of intestinal tumors, and future research should focus on regulating autophagy as a form of cancer therapy. PMID- 22546556 TI - Noscapine induces mitochondria-mediated apoptosis in human colon cancer cells in vivo and in vitro. AB - Noscapine, a phthalide isoquinoline alkaloid derived from opium, has been widely used as a cough suppressant for decades. Noscapine has recently been shown to potentiate the anti-cancer effects of several therapies by inducing apoptosis in various malignant cells without any detectable toxicity in cells or tissues. However, the mechanism by which noscapine induces apoptosis in colon cancer cells remains unclear. The signaling pathways by which noscapine induces apoptosis were investigated in colon cancer cell lines treated with various noscapine concentrations for 72 h, and a dose-dependent inhibition of cell viability was observed. Noscapine effectively inhibited the proliferation of LoVo cells in vitro (IC(50)=75 MUM). This cytotoxicity was reflected by cell cycle arrest at G(2)/M and subsequent apoptosis, as indicated by increased chromatin condensation and fragmentation, the upregulation of Bax and cytochrome c (Cyt-c), the downregulation of survivin and Bcl-2, and the activation of caspase-3 and caspase 9. Moreover, in a xenograft tumor model in mice, noscapine injection clearly inhibited tumor growth via the induction of apoptosis, which was demonstrated using a TUNEL assay. These results suggest that noscapine induces apoptosis in colon cancer cells via mitochondrial pathways. Noscapine may be a safe and effective chemotherapeutic agent for the treatment of human colon cancer. PMID- 22546557 TI - Intracellular trafficking of superparamagnetic iron oxide nanoparticles conjugated with TAT peptide: 3-dimensional electron tomography analysis. AB - Internalisation of nanoparticles conjugated with cell penetrating peptides is a promising approach to various drug delivery applications. Cell penetrating peptides such as transactivating transcriptional activator (TAT) peptides derived from HIV-1 proteins are effective intracellular delivery vectors for a wide range of nanoparticles and pharmaceutical agents thanks to their amicable ability to enter cells and minimum cytotoxicity. Although different mechanisms of intracellular uptake and localisation have been proposed for TAT conjugated nanoparticles, it is necessary to visualise the particles on a 3-D plane in order to investigate the actual intracellular uptake and localisation. Here, we study the intracellular localisation and trafficking of TAT peptide conjugated superparamagnetic ion oxide nanoparticles (TAT-SPIONs) using 3-D electron tomography. 3-D tomograms clearly show the location of TAT-SPIONs in a cell and their slow release from the endocytic vesicles into the cytoplasm. The present methodology may well be utilised for further investigations of the behaviours of nanoparticles in cells and eventually for the development of nano drug delivery systems. PMID- 22546558 TI - Structural insights into the metabolism of 2-chlorodibenzofuran by an evolved biphenyl dioxygenase. AB - The biphenyl dioxygenase of Burkholderia xenovorans LB400 (BphAE(LB400)) is a Rieske-type oxygenase that catalyzes the stereospecific oxygenation of many heterocyclic aromatics including dibenzofuran. In a previous work, we evolved BphAE(LB400) and obtained BphAE(RR41). This variant metabolizes dibenzofuran and 2-chlorodibenzofuran more efficiently than BphAE(LB400). However, the regiospecificity of BphAE(RR41) toward these substrates differs. Dibenzofuran is metabolized principally through a lateral dioxygenation whereas 2 chlorodibenzofuran is metabolized principally through an angular dioxygenation. In order to explain this difference, we examined the crystal structures of both substrate-bound forms of BphAE(RR41) obtained under anaerobic conditions. This structure analysis, in combination with biochemical data for a Ser283Gly mutant provided evidences that the substrate is compelled to move after oxygen-binding in BphAE(RR41):dibenzofuran. In BphAE(RR41):2-chlorodibenzofuran, the chlorine atom is close to the side chain of Ser283. This contact is missing in the BphAE(RR41):dibenzofuran, and strong enough in the BphAE(RR41):2 chlorodibenzofuran to help prevent substrate movement during the catalytic reaction. PMID- 22546559 TI - Identification of mirtrons in rice using MirtronPred: a tool for predicting plant mirtrons. AB - Studies from flies and insects have reported the existence of a special class of miRNA, called mirtrons that are produced from spliced-out introns in a DROSHA independent manner. The spliced-out lariat is debranched and refolded into a stem loop structure resembling the pre-miRNA, which can then be processed by DICER into mature ~21 nt species. The mirtrons have not been reported from plants. In this study, we present MirtronPred, a web based server to predict mirtrons from intronic sequences. We have used the server to predict 70 mirtrons in rice introns that were put through a stringent selection filter to shortlist 16 best sequences. The prediction accuracy was subsequently validated by northern analysis and RT-PCR of a predicted Os-mirtron-109. The target sequences for this mirtron were also found in the rice degradome database. The possible role of the mirtron in rice regulon is discussed. The MirtronPred web server is available at http://bioinfo.icgeb.res.in/mirtronPred. PMID- 22546561 TI - Do desert locust hoppers develop gregarious characteristics by watching a video? AB - Various sensory stimuli have been suggested to induce gregarious body coloration in locusts, but most previous studies ignored the importance of substrate color. This study tested the effects of visual, olfactory and tactile stimuli from other locusts on the induction of gregarious body coloration in single (isolated reared) Schistocerca gregaria nymphs housed in yellow-green cups. Odor from gregarious (crowd-reared) locusts, which is believed to induce black patterns in single locusts, had little effect when applied to visually isolated nymphs at the 2nd stadium onward, and all test nymphs remained green without black patterns at the last stadium, as in controls reared without odor and visual stimuli. Visual stimuli alone induced black patterns when a single solitarious nymph was allowed to see other locusts in another cup. The degree of black patterns increased as the number of locusts shown increased, and some test nymphs developed body coloration typically observed in gregarious forms. A classical morphometric ratio (hind femur length/head width) shifted toward the value typical of gregarious forms when the single nymphs were allowed to see 5 or 10 locusts. Single nymphs also developed black patterns when presented green conspecific nymphs and adults of two hemipteran species kept in another cup. No synergetic effects of visual and odor stimuli were detected. Movies of locusts, crickets and tadpoles were found effective in inducing black patterns in single locusts. Ontogenetic variation in the sensitivity to crowding and experimental methodology might be responsible for some discrepancies in the conclusions among different researchers. PMID- 22546560 TI - Random forests for genomic data analysis. AB - Random forests (RF) is a popular tree-based ensemble machine learning tool that is highly data adaptive, applies to "large p, small n" problems, and is able to account for correlation as well as interactions among features. This makes RF particularly appealing for high-dimensional genomic data analysis. In this article, we systematically review the applications and recent progresses of RF for genomic data, including prediction and classification, variable selection, pathway analysis, genetic association and epistasis detection, and unsupervised learning. PMID- 22546562 TI - Duration of prepupal summer dormancy regulates synchronization of adult diapause with winter temperatures in bees of the genus Osmia. AB - Osmia (Osmia) bees are strictly univoltine and winter as diapausing adults. In these species, the timing of adult eclosion with the onset of wintering conditions is critical, because adults exposed to long pre-wintering periods show increased lipid loss and winter mortality. Populations from warm areas fly in February-March and are exposed to longer growth seasons than populations from colder areas, which fly in April-May. Given their inability to produce an extra generation, early-flying populations should develop more slowly than late-flying populations and thus avoid the negative consequences of long pre-wintering periods. In this study we compare the development under natural and laboratory conditions of phenologically-distinct populations in two Osmia species. Early flying populations took ~2 months longer to develop than late-flying populations. Differences between populations in larval and pupal period duration were very small, whereas the prepupal period was much longer in early-flying populations. In contrast to the larval and pupal stages, the prepupal stage showed a non linear response to temperature, was strongly affected by thermoperiod, and exhibited minimum respiration rates. Coupled with other lines of evidence, these results suggest that the prepupal period in Osmia corresponds to a summer diapause, and its duration may be under local selection to synchronize adult eclosion with the onset of winter temperatures. We discuss the implications of our results relative to current expectations of global warming. PMID- 22546563 TI - Enhancement of long-term angiogenic efficacy of adipose stem cells by delivery of FGF2. AB - Stem cell transplantation can induce neovascularization. Regenerated blood vessels should remain stable for a long-term period in order to function as new blood vessels in ischemic tissues. Here we show that local delivery of FGF2 enhances the long-term (12weeks) angiogenic efficacy of human adipose-derived stem cells (hADSCs) implanted into mouse ischemic hindlimbs. Following transplantation of hADSCs into ischemic hindlimbs of mice, hADSC viability was significantly higher in the hADSC+FGF2 group at 4 and 12weeks post transplantation than in the hADSC only group. Furthermore, hADSCs produced higher levels of angiogenic growth factors (i.e., fibroblast growth factor 2, vascular endothelial growth factor, hepatocyte growth factor, and platelet-derived growth factor) at both time points. As a result, the density of arterioles in the ischemic hindlimb muscle was significantly higher in the hADSC+FGF2 group than in either hADSC or FGF2 only group at both time points. The number of arterioles with larger diameters was significantly greater in the hADSC+FGF2 group than in the other groups at 12weeks, and increased in the hADSC+FGF2 group as the time period increased from 4weeks to 12weeks post-transplantation. This suggests that FGF2 delivery to hADSC transplantation sites enhances long-term angiogenic efficacy of hADSCs transplanted into ischemic tissues. PMID- 22546566 TI - Quality assuring GPs and their practices. PMID- 22546567 TI - Leadership and management for all doctors. PMID- 22546564 TI - Elephant transcriptome provides insights into the evolution of eutherian placentation. AB - The chorioallantoic placenta connects mother and fetus in eutherian pregnancies. In order to understand the evolution of the placenta and provide further understanding of placenta biology, we sequenced the transcriptome of a term placenta of an African elephant (Loxodonta africana) and compared these data with RNA sequence and microarray data from other eutherian placentas including human, mouse, and cow. We characterized the composition of 55,910 expressed sequence tag (i.e., cDNA) contigs using our custom annotation pipeline. A Markov algorithm was used to cluster orthologs of human, mouse, cow, and elephant placenta transcripts. We found 2,963 genes are commonly expressed in the placentas of these eutherian mammals. Gene ontology categories previously suggested to be important for placenta function (e.g., estrogen receptor signaling pathway, cell motion and migration, and adherens junctions) were significantly enriched in these eutherian placenta-expressed genes. Genes duplicated in different lineages and also specifically expressed in the placenta contribute to the great diversity observed in mammalian placenta anatomy. We identified 1,365 human lineage specific, 1,235 mouse lineage-specific, 436 cow lineage-specific, and 904 elephant-specific placenta-expressed (PE) genes. The most enriched clusters of human-specific PE genes are signal/glycoprotein and immunoglobulin, and humans possess a deeply invasive human hemochorial placenta that comes into direct contact with maternal immune cells. Inference of phylogenetically conserved and derived transcripts demonstrates the power of comparative transcriptomics to trace placenta evolution and variation across mammals and identified candidate genes that may be important in the normal function of the human placenta, and their dysfunction may be related to human pregnancy complications. PMID- 22546568 TI - Primary care research after the Act: why commissioners and academia need to work together. PMID- 22546569 TI - Better prevention of stroke through screening for atrial fibrillation. PMID- 22546570 TI - Not just another primary care workforce crisis .... PMID- 22546571 TI - Not just another primary care workforce crisis .... PMID- 22546573 TI - The BJGP. PMID- 22546574 TI - Calling time on the 10-minute consultation. PMID- 22546575 TI - Calling time on the 10-minute consultation. PMID- 22546576 TI - The training capacity of general practice revisited: advanced training practices. PMID- 22546577 TI - Situating general practice training in the general practice context. PMID- 22546578 TI - Payment for performance and the QOF: are we doing the right thing? PMID- 22546579 TI - Communicating risk to patients and the public. PMID- 22546580 TI - Viewpoint: Mind the gap. PMID- 22546581 TI - Outside the box: The fire within. PMID- 22546582 TI - Economic crisis and primary care reform in Greece: driving the wrong way? PMID- 22546587 TI - Safeguarding patients against stem cell tourism. PMID- 22546589 TI - Diagnosis and management of polymyalgia rheumatica. PMID- 22546590 TI - Multisource feedback questionnaires in appraisal and for revalidation: a qualitative study in UK general practice. AB - BACKGROUND: UK revalidation plans for doctors include obtaining multisource feedback from patient and colleague questionnaires as part of the supporting information for appraisal and revalidation. AIM: To investigate GPs' and appraisers' views of using multisource feedback data in appraisal, and of the emerging links between multisource feedback, appraisal, and revalidation. DESIGN AND SETTING: A qualitative study in UK general practice. METHOD: In total, 12 GPs who had recently completed the General Medical Council multisource feedback questionnaires and 12 appraisers undertook a semi-structured, telephone interview. A thematic analysis was performed. RESULTS: Participants supported multisource feedback for formative development, although most expressed concerns about some elements of its methodology (for example, 'self' selection of colleagues, or whether patients and colleagues can provide objective feedback). Some participants reported difficulties in understanding benchmark data and some were upset by their scores. Most accepted the links between appraisal and revalidation, and that multisource feedback could make a positive contribution. However, tensions between the formative processes of appraisal and the summative function of revalidation were identified. CONCLUSION: Participants valued multisource feedback as part of formative assessment and saw a role for it in appraisal. However, concerns about some elements of multisource feedback methodology may undermine its credibility as a tool for identifying poor performance. Proposals linking multisource feedback, appraisal, and revalidation may limit the use of multisource feedback and appraisal for learning and development by some doctors. Careful consideration is required with respect to promoting the accuracy and credibility of such feedback processes so that their use for learning and development, and for revalidation, is maximised. PMID- 22546591 TI - Patients' views of pay for performance in primary care: a qualitative study. AB - BACKGROUND: Many countries use pay-for-performance schemes to reward family practices financially for achieving quality indicators. The views of patients on pay for performance remain largely unexplored. AIM: To gain the views of family practice patients on the United Kingdom pay-for-performance Quality and Outcomes Framework (QOF). DESIGN AND SETTING: Interviews with 52 patients were conducted in 15 family practices across England. All patients had at least one long-term condition that had been diagnosed before the introduction of the QOF in 2004. METHOD: Semi-structured interviews analysed using open explorative thematic coding. RESULTS: Few patients had heard of the QOF or had noticed changes to the structure or process of their care. However, where they were noted, changes to consultations such as increased use of computers and health checks initiated by the GP or practice nurse were seen as good practice. The majority of patients were surprised to hear their practice received bonuses for doing 'simple things'. Some patients also raised concerns over potential unintended consequences of pay for-performance frameworks, such as a reduced focus on non-incentivised areas. CONCLUSION: This study adds a unique patient perspective to the debate around the impact of pay-for-performance schemes and consequences on patient care. Patients' views, experiences, and concerns about pay for performance mostly chime with previously described opinions of primary care staff. Patient surprise and concern around incentivising basic processes of care shows how patient views are vital when monitoring and evaluating a scheme that is designed to improve patient care. PMID- 22546592 TI - Quality of prescribing in care homes and the community in England and Wales. AB - BACKGROUND: Care home residents are vulnerable to the adverse effects of prescribing but there is limited monitoring in the UK. AIM: To compare prescribing quality in care homes in England and Wales with the community and with US nursing homes. DESIGN AND SETTING: Cross-sectional analysis of a UK primary care database and comparison with the US National Nursing Home Survey including 326 general practices in 2008-2009 in England and Wales, with 10 387 care home and 403 259 community residents aged 65 to 104 years. METHOD: Comparison of age- and sex-standardised use of 'concern' and common drug groups in the last 90 days and potentially inappropriate prescribing based on a consensus list of medications best avoided in older people (Beers criteria). RESULTS: Compared to the community, care home residents were more likely to receive 'concern' drugs, including benzodiazepines (relative risk (RR) = 2.05, 95% confidence interval (CI) = 1.90 to 2.22), anticholinergic antihistamines (RR = 2.78, 95% CI = 2.38 to 3.23), loop diuretics (RR = 1.47, 95% CI = 1.41 to 1.53), and antipsychotics (RR = 22.7, 95% CI = 20.6 to 24.9). Use of several common drug groups, including laxatives, antidepressants, and antibiotics, was higher, but use of cardiovascular medication was lower. Thirty-three per cent (95% CI = 31.7% to 34.3%) of care home residents in England and Wales received potentially inappropriate medication, compared to 21.4% (95% CI = 20.9% to 21.8%) in the community. The potentially inappropriate prescribing rate in US nursing homes was similar to England and Wales. CONCLUSION: Care home prescribing has the potential for improvement. High use of anticholinergic and psychotropic medication may contribute to functional and cognitive decline. The targeting and effectiveness of medication reviews in care homes needs to be improved. PMID- 22546593 TI - Chronic disease detection and access: does access improve detection, or does detection make access more difficult? AB - BACKGROUND: The recorded detection of chronic disease by practices is generally lower than the prevalence predicted by population surveys. AIM: To determine whether patient-reported access to general practice predicts the recorded detection rates of chronic diseases in that setting. DESIGN AND SETTING: A cross sectional study involving 146 general practices in Leicestershire and Rutland, England. METHOD: The numbers of patients recorded as having chronic disease (coronary heart disease, chronic obstructive pulmonary disease, hypertension, diabetes) were obtained from Quality and Outcomes Framework (QOF) practice disease registers for 2008-2009. Characteristics of practice populations (deprivation, age, sex, ethnicity, proportion reporting poor health, practice turnover, list size) and practice performance (achievement of QOF disease indicators, patient experience of being able to consult a doctor within 2 working days and book an appointment >2 days in advance) were included in regression models. RESULTS: Patient characteristics (deprivation, age, poor health) and practice characteristics (list size, turnover, QOF achievement) were associated with recorded detection of more than one of the chronic diseases. Practices in which patients were more likely to report being able to book appointments had reduced recording rates of chronic disease. Being able to consult a doctor within 2 days was not associated with levels of recorded chronic disease. CONCLUSION: Practices with high levels of deprivation and older patients have increased rates of recorded chronic disease. As the number of patients recorded with chronic disease increased, the capacity of practices to meet patients' requests for appointments in advance declined. The capacity of some practices to detect and manage chronic disease may need improving. PMID- 22546594 TI - Are UK primary care teams formally identifying patients for palliative care before they die? AB - BACKGROUND: The palliative care approach has the potential to improve care for patients with progressive life-threatening illnesses from the time of diagnosis. Policy and clinical directives in the UK advocate early identification. AIM: To determine the extent to which practices identify patients for palliative care, including factors influencing early identification and possible effects on place of death. DESIGN AND SETTING: Qualitative and quantitative data were collected from six general practices from three Scottish NHS boards and analysed. METHOD: Records of patients who had died in the previous 6 months were analysed and interviews with practice staff (n = 21) and with patients currently on the practice palliative care register and bereaved relatives (n = 14) were conducted. In addition, a practice meeting was observed. RESULTS: In total, 29% of patients who died were recorded as being on the practice palliative care register before death. Two-thirds of patients with cancer were recorded on the register, but for those with non-malignant conditions only around 20% had any palliative care documented. This was a result of GPs not finding the current guidelines useful and being reluctant to discuss palliative care overtly with patients early in their illness. Palliative care services and documentation were geared towards patients with cancer. More district nurses than GPs saw the benefits of inclusion on the palliative care register. Only 25% of patients on the register died in hospital. CONCLUSION: Most patients with advanced progressive illnesses, especially those with non-malignant disease, are not being formally identified for a palliative care approach before they die. Those identified are more likely to benefit from coordinated care and may be more likely to die at home. PMID- 22546595 TI - Factors supporting good partnership working between generalist and specialist palliative care services: a systematic review. AB - BACKGROUND: The care that most people receive at the end of their lives is provided not by specialist palliative care professionals but by generalists such as GPs, district nurses and others who have not undertaken specialist training in palliative care. A key focus of recent UK policy is improving partnership working across the spectrum of palliative care provision. However there is little evidence to suggest factors which support collaborative working between specialist and generalist palliative care providers. AIM: To explore factors that support partnership working between specialist and generalist palliative care providers. DESIGN: Systematic review. METHOD: A systematic review of studies relating to partnership working between specialist and generalist palliative care providers was undertaken. Six electronic databases were searched for papers published up until January 2011. RESULTS: Of the 159 articles initially identified, 22 papers met the criteria for inclusion. Factors supporting good partnership working included: good communication between providers; clear definition of roles and responsibilities; opportunities for shared learning and education; appropriate and timely access to specialist palliative care services; and coordinated care. CONCLUSION: Multiple examples exist of good partnership working between specialist and generalist providers; however, there is little consistency regarding how models of collaborative working are developed, and which models are most effective. Little is known about the direct impact of collaborative working on patient outcomes. Further research is required to gain the direct perspectives of health professionals and patients regarding collaborative working in palliative care, and to develop appropriate and cost effective models for partnership working. PMID- 22546596 TI - Exploration of GPs' views and use of the fit note: a qualitative study in primary care. AB - BACKGROUND: Sickness certification constitutes daily clinical practice for GPs. In April 2010, the UK sickness certification system changed to reflect the evidence that work is generally good for health and a new Statement of Fitness for Work - the 'fit note' - was introduced. Sickness certification is a contentious topic among GPs and the proposed fit note generated mixed reviews. AIM: To explore GPs' views and use of the fit note during its first year of operation. DESIGN AND SETTING: Qualitative interview study of GPs based in different geographical locations across the UK. METHOD: GPs (n = 15), who were recruited from a national sample, participated in semi-structured telephone interviews which were subject to constant comparative analysis. RESULTS: Overall, the fit note was well received. GPs recognised that work is generally good for health and felt the fit note facilitated using an earlier return to work as a negotiation tool. GPs perceive employers as the major obstacle to early return to work. There were reports of scepticism towards the system that negatively impacted on some GPs' operation of sickness certification. Feedback over the fit note's impact on employer behaviour and the return of a mechanism that enables GPs to request early independent assessments would be welcomed. CONCLUSION: A revised approach is needed to address the scepticism towards the sickness certification system that persists among some GPs. New strategies need to be designed to engage employers in facilitating an early return to work and to enable the objectives of the medical statement reforms to be achieved. PMID- 22546597 TI - Exploring patients' reasons for declining contact in a cognitive behavioural therapy randomised controlled trial in primary care. AB - BACKGROUND: The difficulties of recruiting individuals into mental health trials are well documented. Few studies have collected information from those declining to take part in research, in order to understand the reasons behind this decision. AIM: To explore patients' reasons for declining to be contacted about a study of the effectiveness of cognitive behavioural therapy as a treatment for depression. DESIGN AND SETTING: Questionnaire and telephone interview in general practices in England and Scotland. METHOD: Patients completed a short questionnaire about their reasons for not taking part in research. Semi structured telephone interviews were conducted with a purposive sample to further explore reasons for declining. RESULTS: Of 4552 patients responding to an initial invitation to participate in research involving a talking therapy, 1642 (36%) declined contact. The most commonly selected reasons for declining were that patients did not want to take part in a research study (n = 951) and/or did not want to have a talking therapy (n = 688) (more than one response was possible). Of the decliners, 451 patients agreed to an interview about why they declined. Telephone interviews were completed with 25 patients. Qualitative analysis of the interview data indicated four main themes regarding reasons for non participation: previous counselling experiences, negative feelings about the therapeutic encounter, perceived ineligibility, and misunderstandings about the research. CONCLUSION: Collecting information about those who decline to take part in research provides information on the acceptability of the treatment being studied. It can also highlight concerns and misconceptions about the intervention and research, which can be addressed by researchers or recruiting GPs. This may improve recruitment to studies and thus ultimately increase the evidence base. PMID- 22546598 TI - 'You know what boys are like': pre-diagnosis experiences of parents of children with autism spectrum conditions. AB - BACKGROUND: The importance of early identification and intervention for children with autism spectrum conditions (ASC) has been established. However, there are often considerable delays from initial concern (by parent or professional) to diagnosis. Little is known about parents' experiences of primary care in the pre diagnosis period. AIM: To identify feasible improvements to the management of primary care consultations with parents of children who might have ASC. DESIGN AND SETTING: UK-based qualitative interview study. METHOD: Semi-structured interviews with a diverse qualitative sample of 24 parents of children, aged between 3 and 11 years, who were diagnosed with ASC. RESULTS: Three types of parental concern emerged: first, parents who had no concerns about their children's development before their diagnosis; secondly, parents who reported that they had some concerns but had not raised them with health professionals (passive concern); and thirdly, parents who had raised concerns about their children with health professionals (active concern). The passively concerned parents could not pin down exactly what it was about their children's development that concerned them. Many of the actively concerned parents had been prematurely reassured by health professionals that there was nothing wrong. This left them feeling isolated and alone. Actively concerned parents who already had a child diagnosed with ASC did not experience a delay in diagnosis. CONCLUSION: Health professionals should acknowledge parents' concerns carefully; contrary to intentions, early reassurance may result in parents feeling that their concerns have not been heard. Parents may be the best resource in identifying ASC. PMID- 22546599 TI - Clinical leadership: individual advancement, political authority, and a lack of direction? PMID- 22546600 TI - The challenge of commissioning for populations. PMID- 22546601 TI - Practice accreditation: the European perspective. PMID- 22546602 TI - The D-Dimer test in combination with a decision rule for ruling out deep vein thrombosis in primary care: diagnostic technology update. PMID- 22546603 TI - Genetic differences in response properties of rostral ventromedial medulla neurons to the MU-opioid receptor agonist DAMGO in mouse inbred strains. AB - BACKGROUND: Opioid sensitivity varies among individuals. Although opioids can act partly in the rostral ventromedial medulla (RVM), which has a major role in pain perception, individual differences in the functions of the RVM in response to opioids have not been elucidated. Pain-related behavior among inbred mouse strains may reflect individual differences in sensitivity to pain. We therefore investigated the changes in action potentials of RVM neurons in response to opioid in different mouse strains. METHODS: Two inbred strains of mice (A/J and CBA/J) were used. Their behavior to noxious stimuli was measured after intracerebroventricular injection of the MU-opioid receptor agonist, DAMGO. Using an in vivo extracellular recording technique, action potentials from single RVM neurons and their functional type (ON-like, OFF-like, or NEUTRAL-like cell) were identified. Evoked responses of the RVM neurons to noxious stimuli were recorded before and after DAMGO administration. RESULTS: The behavioral study showed that the dose-dependent antinociceptive effect in the A/J strain was significantly stronger than in the CBA/J strain. The electrophysiological study showed that the number of inhibitory OFF-like cells in A/J mice was significantly larger than in CBA/J mice (P<0.01), and that the evoked responses of neurons of A/J mice were inhibited significantly more than in CBA/J mice both for ON-like and OFF-like cells (P<0.01). CONCLUSIONS: The strain differences in the physiological properties of RVM neurons corresponded to the behavioral strain differences. Genetic differences may contribute to the interindividual variation seen in opioid-induced analgesia. PMID- 22546604 TI - Progressing preclinical drug candidates: strategies on preclinical safety studies and the quest for adequate exposure. AB - Drug discovery lead optimization teams face many diverse challenges in the search for drug development candidates. This includes understanding the toxicology profile of a candidate, and some strategies call for in vivo preclinical safety studies to be moved increasingly earlier in the discovery phase to increase the likelihood of success in development. One of the final hurdles in these pursuits is achieving adequate exposure to support safety margins for human clinical trials. In this article, we describe several strategies on early toxicology studies along with various enabling formulation methods that can be employed to achieve optimal oral absorption. These two elements of research together can significantly increase the speed preclinical drug candidates can move through development, and the overall probability of success in identifying viable new drugs. PMID- 22546605 TI - Increase in claudin-2 expression by an EGFR/MEK/ERK/c-Fos pathway in lung adenocarcinoma A549 cells. AB - In human adenocarcinoma, claudin-2 expression is higher than that in normal lung tissue, but the regulatory mechanism of its expression has not been clarified. In human adenocarcinoma A549 cells, claudin-2 level time-dependently increased under the control conditions. In contrast, claudin-1 expression remained constant for 24h. The concentration of epidermal growth factor (EGF) in medium time dependently increased, which was inhibited by matrix metalloproteinase (MMP) inhibitor II, an inhibitor of MMP-1, 3, 7, and 9. MMP inhibitor II decreased claudin-2 and phosphorylated ERK1/2 (p-ERK1/2) levels, which were recovered by EGF. Both claudin-2 and p-ERK1/2 levels were decreased by EGF neutralizing antibody, EGF receptor (EGFR) siRNA, AG1478, an inhibitor of EGFR, U0126, an inhibitor of MEK, and the exogenous expression of dominant negative-MEK. These results suggest that EGF is secreted from A549 cells by MMP and increases claudin 2 expression mediated via the activation of an EGFR/MEK/ERK pathway. The inhibition of the signaling pathway decreased phosphorylated c-Fos and nuclear c Fos levels. The introduction of c-Fos siRNA decreased claudin-2 level without affecting claudin-1. The promoter activity of human claudin-2 was decreased by AG1478 and U0126. Furthermore, the activity was decreased by the deletion or mutation of the AP-1 binding site of claudin-2 promoter. Chromatin immunoprecipitation and avidin-biotin conjugated DNA assays showed that c-Fos binds to the AP-1 binding site. We suggest that a secreted EGF up-regulates the transcriptional activity of claudin-2 mediated by the activation of an EGFR/MEK/ERK/c-Fos pathway in A549 cells. PMID- 22546606 TI - The relevance of the non-canonical PTS1 of peroxisomal catalase. AB - Catalase is sorted to peroxisomes via a C-terminal peroxisomal targeting signal 1 (PTS1), which binds to the receptor protein Pex5. Analysis of the C-terminal sequences of peroxisomal catalases from various species indicated that catalase never contains the typical C-terminal PTS1 tripeptide-SKL, but invariably is sorted to peroxisomes via a non-canonical sorting sequence. We analyzed the relevance of the non-canonical PTS1 of catalase of the yeast Hansenula polymorpha (-SKI). Using isothermal titration microcalorimetry, we show that the affinity of H. polymorpha Pex5 for a peptide containing -SKI at the C-terminus is 8-fold lower relative to a peptide that has a C-terminal -SKL. Fluorescence microscopy indicated that green fluorescent protein containing the -SKI tripeptide (GFP-SKI) has a prolonged residence time in the cytosol compared to GFP containing -SKL. Replacing the -SKI sequence of catalase into -SKL resulted in reduced levels of enzymatically active catalase in whole cell lysates together with the occurrence of catalase protein aggregates in the peroxisomal matrix. Moreover, the cultures showed a reduced growth yield in methanol-limited chemostats. Finally, we show that a mutant catalase variant that is unable to properly fold mislocalizes in protein aggregates in the cytosol. However, by replacing the PTS1 into -SKL the mutant variant accumulates in protein aggregates inside peroxisomes. Based on our findings we propose that the relatively weak PTS1 of catalase is important to allow proper folding of the enzyme prior to import into peroxisomes, thereby preventing the accumulation of catalase protein aggregates in the organelle matrix. PMID- 22546607 TI - Epidemic of prescription opiate abuse and neonatal abstinence. PMID- 22546608 TI - Neonatal abstinence syndrome and associated health care expenditures: United States, 2000-2009. AB - CONTEXT: Neonatal abstinence syndrome (NAS) is a postnatal drug withdrawal syndrome primarily caused by maternal opiate use. No national estimates are available for the incidence of maternal opiate use at the time of delivery or NAS. OBJECTIVES: To determine the national incidence of NAS and antepartum maternal opiate use and to characterize trends in national health care expenditures associated with NAS between 2000 and 2009. DESIGN, SETTING, AND PATIENTS: A retrospective, serial, cross-sectional analysis of a nationally representative sample of newborns with NAS. The Kids' Inpatient Database (KID) was used to identify newborns with NAS by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code. The Nationwide Inpatient Sample (NIS) was used to identify mothers using diagnosis related groups for vaginal and cesarean deliveries. Clinical conditions were identified using ICD-9-CM diagnosis codes. NAS and maternal opiate use were described as an annual frequency per 1000 hospital births. Missing hospital charges (<5% of cases) were estimated using multiple imputation. Trends in health care utilization outcomes over time were evaluated using variance-weighted regression. All hospital charges were adjusted for inflation to 2009 US dollars. MAIN OUTCOME MEASURES: Incidence of NAS and maternal opiate use, and related hospital charges. RESULTS: The separate years (2000, 2003, 2006, and 2009) of national discharge data included 2920 to 9674 unweighted discharges with NAS and 987 to 4563 unweighted discharges for mothers diagnosed with antepartum opiate use, within data sets including 784,191 to 1.1 million discharges for children (KID) and 816,554 to 879,910 discharges for all ages of delivering mothers (NIS). Between 2000 and 2009, the incidence of NAS among newborns increased from 1.20 (95% CI, 1.04-1.37) to 3.39 (95% CI, 3.12-3.67) per 1000 hospital births per year (P for trend < .001). Antepartum maternal opiate use also increased from 1.19 (95% CI, 1.01-1.35) to 5.63 (95% CI, 4.40-6.71) per 1000 hospital births per year (P for trend < .001). In 2009, newborns with NAS were more likely than all other hospital births to have low birthweight (19.1%; SE, 0.5%; vs 7.0%; SE, 0.2%), have respiratory complications (30.9%; SE, 0.7%; vs 8.9%; SE, 0.1%), and be covered by Medicaid (78.1%; SE, 0.8%; vs 45.5%; SE, 0.7%; all P < .001). Mean hospital charges for discharges with NAS increased from $39,400 (95% CI, $33,400 $45,400) in 2000 to $53,400 (95% CI, $49,000-$57,700) in 2009 (P for trend < .001). By 2009, 77.6% of charges for NAS were attributed to state Medicaid programs. CONCLUSION: Between 2000 and 2009, a substantial increase in the incidence of NAS and maternal opiate use in the United States was observed, as well as hospital charges related to NAS. PMID- 22546609 TI - Use of Moringa oleifera seed extracts to reduce helminth egg numbers and turbidity in irrigation water. AB - Water from wastewater-polluted streams and dug-outs is the most commonly used water source for irrigation in urban farming in Ghana, but helminth parasite eggs in the water represent health risks when used for crop production. Conventional water treatment is expensive, requires advanced technology and often breaks down in less developed countries so low cost interventions are needed. Field and laboratory based trials were carried out in order to investigate the effect of the natural coagulant Moringa oleifera (MO) seed extracts in reducing helminh eggs and turbidity in irrigation water, turbid water, wastewater and tap water. In medium to high turbid water MO extracts were effective in reducing the number of helminth eggs by 94-99.5% to 1-2 eggs per litre and the turbidity to 7-11 NTU which is an 85-96% reduction. MO is readily available in many tropical countries and can be used by farmers to treat high turbid water for irrigation, however, additional improvements of water quality, e.g. by sand filtration, is suggested to meet the guideline value of <= 1 helminth egg per litre and a turbidity of <= 2 NTU as recommended by the World Health Organization and the U.S. Environmental Protection Agency for water intended for irrigation. A positive correlation was established between reduction in turbidity and helminth eggs in irrigation water, turbid water and wastewater treated with MO. This indicates that helminth eggs attach to suspended particles and/or flocs facilitated by MO in the water, and that turbidity and helminth eggs are reduced with the settling flocs. However, more experiments with water samples containing naturally occurring helminth eggs are needed to establish whether turbidity can be used as a proxy for helminth eggs. PMID- 22546610 TI - Serum proteomics for biomarker discovery in nonalcoholic fatty liver disease. AB - Proteomic platforms have gained increasing attention in the clinical spectrum of nonalcoholic fatty liver disease (NAFLD). This approach allows for the unbiased discovery of circulating biochemical markers, i.e., it is not limited to known molecules of presumed importance. This manuscript provides an overview of proteomic serum biomarker discovery in NAFLD. Hemoglobin is currently the most widely replicated proteomic circulating biomarker of NAFLD; it was identified as a biomarker of fatty liver in two distinct proteomic studies and subsequently validated using distinct analytical methods by independent research groups in large replication cohorts. Given the increasing availability of numerous serum samples and the refinement of the technological platforms available to scrutinize the blood proteome, large collaborative studies between academia and industry are warmly encouraged to identify novel, unbiased circulating biomarkers of NAFLD. PMID- 22546611 TI - High incidence of severe neutropenia after gemcitabine-based chemotherapy in Chinese cancer patients with CDA 79A>C mutation. AB - Cytidine deaminase (CDA) is a crucial enzyme in gemcitabine inactivation. Mutations in CDA gene have been found to influence the activity of CDA enzyme, which might lead to altered pharmacokinetics profile and clinical outcome of gemcitabine. In this study, the screening for the presence of CDA 79A>C and CDA 208G>A was performed by allele-specific PCR and restriction fragment length polymorphism, respectively. No difference in CDA allele frequencies was found between Chinese cancer patients and healthy volunteers. The frequencies for CDA 79A>C and 208G>A in the studied population were 12.2% and 1.0%, respectively. While a high incidence of grade 3-4 neutropenia was noted as 5 out of 8 (62.5%) patients heterozygous or homozygous for CDA 79A>C mutation developed it, in patients homozygous for the wild-type allele, the incidence was only 17.2% (5 out of 29) (p=0.021). Our study suggests that CDA 79A>C mutation might be a potential risk factor of gemcitabine-induced neutropenia toxicity. PMID- 22546612 TI - Diagnostic value of transferrin. AB - Despite the growing interest in hepcidin and other relatively new biomarkers, guidelines and clinical pathways continue to recommend traditional markers, such as serum transferrin (Tf) and ferritin, as laboratory tests for the diagnostic evaluation of iron-related disorders. In this study, we aimed to critically evaluate the diagnostic role of Tf relying on the highest level of available evidence by a comprehensive literature search. The role of Tf in iron deficiency (ID) and iron overload (IO) syndrome as well as a risk marker was evaluated. The low accuracy of Tf and Tf saturation (TS) in the diagnosis and management of ID conditions does not permit definitively recommending their use, even if recently published guidelines still consider the TS investigation as a complementary test for ferritin. If a tissue IO is suspected, TS is often used, even if it may not be the best test for detecting this condition. Nevertheless, clinical guidelines strongly recommend the use of TS as a first-level test for performing genetic diagnosis of hereditary hemochromatosis. Recently reported data indicating elevated TS as a risk factor for diabetes mellitus, cancer, and total mortality, may provide useful additions to the debate over whether or not to screen for IO using TS. PMID- 22546613 TI - In vivo structure-function analysis of human Dicer reveals directional processing of precursor miRNAs. AB - Dicer is an RNase III family endoribonuclease and haploinsufficient tumor suppressor that processes mature miRNAs from the 5' (5p) or 3' (3p) arm of hairpin precursors. In murine Dicer knockout fibroblasts, we expressed human Dicer with point mutations in the RNase III, helicase, and PAZ domains and characterized miRNA expression by Northern blot and massively parallel sequencing of small RNAs. We report that inactivation of the RNase IIIA domain results in complete loss of 3p-derived mature miRNAs, but only partial reduction in 5p derived mature miRNAs. Conversely, inactivation of the RNase IIIB domain by mutation of D1709, a residue mutated in a subset of nonepithelial ovarian cancers, results in complete loss of 5p-derived mature miRNAs, including the tumor-suppressive let-7 family, but only partial reduction in 3p-derived mature miRNAs. Mutation of the PAZ domain results in global reduction of miRNA processing, while mutation of the Walker A motif in the helicase domain of Dicer does not alter miRNA processing. These results provide insight into the biochemical activity of human Dicer in vivo and, furthermore, suggest that mutation of the clinically relevant residue D1709 within the RNase IIIB results in a uniquely miRNA-haploinsufficient state in which the let-7 family of tumor suppressor miRNAs is lost while a complement of 3p-derived miRNAs remains expressed. PMID- 22546614 TI - Metabotropic glutamate 7 (mGlu7) receptor: a target for medication development for the treatment of cocaine dependence. AB - Brain glutamate has been shown to play an important role in reinstatement to drug seeking, a behavior considered to be of relevance to relapse to drug taking in humans. Therefore, glutamate receptors, in particular metabotropic glutamate (mGlu) receptors, have become important targets for medication development for the treatment of drug dependence. In this review article, we focus on the mGlu7 receptor subtype, and discuss recent findings with AMN082, a selective mGlu7 receptor allosteric agonist, in animal models with relevance to drug dependence. Systemic or local administration of AMN082 into the nucleus accumbens (NAc), a critical brain region involved in reward and drug dependence processes, inhibited the reinforcing and motivational effects of cocaine, heroin and ethanol, as assessed by the intravenous drug self-administration procedure. In addition, AMN082 inhibited the reward-enhancing effects induced by cocaine, as assessed in the intracranial self-stimulation procedure, and cocaine- or cue-induced reinstatement of drug-seeking behavior. In vivo microdialysis studies indicated that systemic or intra-NAc administration of AMN082 significantly decreased extracellular gamma-aminobutyric acid (GABA) and elevated extracellular glutamate, but had no effect on extracellular dopamine in the NAc, suggesting that a non-dopaminergic mechanism underlies the effects of AMN082 on the actions of cocaine. Further, data indicated that AMN082-induced changes in glutamate were the net effect of two actions: one is the direct inhibition of glutamate release by activation of mGlu7 receptors on glutamatergic neurons; another is the indirect increases of glutamate release mediated by decreases in GABA transmission. These increases in extracellular glutamate functionally antagonized cocaine-induced inhibition of NAc-ventral pallidum GABAergic neurotransmission, and therefore, the rewarding effects of cocaine. In addition, elevated extracellular glutamate activated presynaptic mGlu2/3 autoreceptors which in turn inhibited cocaine priming- or cue-induced enhancement of glutamate release and reinstatement of drug-seeking behavior. Taken together, these findings suggest that the mGlu7 receptor is an important target for medication development for the treatment of drug dependence. AMN082 or other mGlu7 receptor allosteric agonists may have potential as novel pharmacotherapies for cocaine addiction. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. PMID- 22546615 TI - The metabotropic glutamate receptor 8 agonist (S)-3,4-DCPG reverses motor deficits in prolonged but not acute models of Parkinson's disease. AB - Metabotropic glutamate receptors (mGlus) are 7 Transmembrane Spanning Receptors (7TMs) that are differentially expressed throughout the brain and modulate synaptic transmission at both excitatory and inhibitory synapses. Recently, mGlus have been implicated as therapeutic targets for many disorders of the central nervous system, including Parkinson's disease (PD). Previous studies have shown that nonselective agonists of group III mGlus have antiparkinsonian effects in several animal models of PD, suggesting that these receptors represent promising targets for treating the motor symptoms of PD. However, the relative contributions of different group III mGlu subtypes to these effects have not been fully elucidated. Here we report that intracerebroventricular (icv) administration of the mGlu(8)-selective agonist (S)-3,4-dicarboxyphenylglycine (DCPG [ 2.5, 10, or 30 nmol]) does not alleviate motor deficits caused by acute (2 h) treatment with haloperidol or reserpine. However, following prolonged pretreatment with haloperidol (three doses evenly spaced over 18-20 h) or reserpine (18-20 h), DCPG robustly reverses haloperidol-induced catalepsy and reserpine-induced akinesia. Furthermore, DCPG (10 nmol, icv) reverses the long lasting catalepsy induced by 20 h pretreatment with the decanoate salt of haloperidol. Finally, icv administration of DCPG ameliorates forelimb use asymmetry caused by unilateral 6-hydroxydopamine lesion of substantia nigra dopamine neurons. These findings suggest that mGlu(8) may partially mediate the antiparkinsonian effects of group III mGlu agonists in animal models of PD in which dopamine depletion or blockade of D(2)-like dopamine receptors is prolonged and indicate that selective activation of mGlu(8) may represent a novel therapeutic strategy for alleviating the motor symptoms of PD. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. PMID- 22546617 TI - Retention of a new-defined intron changes pharmacology and kinetics of the full length P2X2 receptor found in myenteric neurons of the guinea pig. AB - P2X2 plays an important role in ATP signaling in guinea pig myenteric plexus. Here, we cloned and characterized three P2X2 isoforms expressed in myenteric neurons. RT/PCR was used to amplify the cDNA of P2X2 variants. These were expressed in Xenopus oocytes, and nucleotide-induced membrane currents were recorded with the two-electrode voltage clamp technique. Three P2X2 cDNAs were identified in myenteric single neurons, named P2X2-1, P2X2-2 and P2X2-4. Based on the analysis of the structural organization of these variants we predicted that P2X2-2 is the fully processed variant, which lead us to propose a new exon-intron arrangement of P2X2 receptor gene with 12 exons and 11 introns. In agreement with this new model, the intron 11 is retained in P2X2-1 and P2X2-4 variants by alternative splicing. Expression of P2X2-1, P2X2-2 and P2X2-4 were found in 92, 42 and 37%, respectively, out of 40 analyzed single neurons. P2X2-4 does not form functional channels, and homomeric channels formed by P2X2-1 and P2X2-2 have different pharmacological profile. Thus, the former receptor is more sensitive to ATP, BzATP, and PPADS, whereas, suramin inhibited both receptors in a biphasic- and monophasic-manner, respectively. alpha,beta-meATP has very low efficacy on either channel. Furthermore, ionic currents mediated by P2X2-1 have slower desensitization than P2X2-2. These results indicate that P2X2-1 was the most common P2X2 transcript in myenteric neurons and displays significant phenotypical changes implicating that retention of the intron 11 plays a major role in ATP signaling in the intestinal myenteric plexus. PMID- 22546616 TI - The brain GABA-benzodiazepine receptor alpha-5 subtype in autism spectrum disorder: a pilot [(11)C]Ro15-4513 positron emission tomography study. AB - GABA (gamma-amino-butyric-acid) is the primary inhibitory neurotransmitter in the human brain. It has been proposed that the symptoms of autism spectrum disorders (ASDs) are the result of deficient GABA neurotransmission, possibly including reduced expression of GABAA receptors. However, this hypothesis has not been directly tested in living adults with ASD. In this preliminary investigation, we used Positron Emission Tomography (PET) with the benzodiazepine receptor PET ligand [(11)C]Ro15-4513 to measure alpha1 and alpha5 subtypes of the GABAA receptor levels in the brain of three adult males with well-characterized high functioning ASD compared with three healthy matched volunteers. We found significantly lower [(11)C]Ro15-4513 binding throughout the brain of participants with ASD (p < 0.0001) compared with controls. Planned region of interest analyses also revealed significant reductions in two limbic brain regions, namely the amygdala and nucleus accumbens bilaterally. Further analysis suggested that these results were driven by lower levels of the GABAA alpha5 subtype. These results provide initial evidence of a GABAA alpha5 deficit in ASD and support further investigations of the GABA system in this disorder. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'. PMID- 22546618 TI - Etiology of acute diarrhea due to enteropathogenic bacteria in Beijing, China. AB - OBJECTIVES: Acute diarrhea is of great concern due to considerable morbidity and mortality worldwide. The causative bacteria leading to acute diarrhea in general population remains unclear in China. This study was conducted to determine the etiology of acute diarrhea using a sentinel hospital-based surveillance network in Beijing. METHODS: Active surveillance was implemented from April 2010 to December 2011 on two random days per week by enrolling every tenth diarrheal patients admitted to seventeen intestinal clinics. Shigella spp., Vibrio spp, Salmonella spp., diarrheagenic Escherichia coli and other genera of bacteria, were investigated from 4803 outpatients with acute diarrhea by microbiological methods. RESULTS: The pathogenic bacteria recovered out from fecal samples of 968 (20.2%) patients had the following profile: Shigella spp. (5.9%) was the most prevalent pathogen, Vibrio parahaemolyticus (5.2%), Salmonella spp. (3.9%) and enteropathogenic E. coli (EPEC) (0.9%) had from the second to fourth highest prevalence, respectively. Of the 55 co-infections detected, V. parahaemolyticus was the most common pathogen from 28 cases (50.9%), with the main combination of V. parahaemolyticus and Salmonella. The highest proportion of all causative bacteria was found in adults aged 20-39 year and in summer as well as early autumn. The clinical symptoms associated with specific bacterial infection, such as fever, abdominal pain, tenesmus, nausea, vomiting, and watery and bloody stool, were observed frequently in diarrheal patients. CONCLUSION: Shigella spp., V. parahaemolyticus, Salmonella spp., and EPEC are important enteropathogenic bacteria causing acute diarrhea in Beijing. To execute reasonable interventions, the comprehensive and continuous surveillance is needed to identify the prevalence of different enteropathogeic bacteria. PMID- 22546619 TI - Epidemiology and clinical characteristics of parainfluenza virus 3 outbreak in a Haemato-oncology unit. AB - OBJECTIVES: We describe molecular investigations of a large hospital outbreak of parainfluenza virus type 3 (PIV3), in which 32 patients became infected. We outline infection control measures that successfully limited further spread of PIV3 in a Haemato-oncology unit. METHODS: Clinical retrospective review of infected haemato-oncology patients was undertaken. PIV3 haemagglutinin sequences from each case (n = 32) and local epidemiologically unlinked controls (n = 53) were compared to identify potential linkage. RESULTS: PIV3-infected patients presented with upper (n = 18) and lower (n = 11) respiratory tract infections, 3 showed pyrexia only and one was asymptomatic. All symptomatic patients received antibiotics; bacterial co-infection was confirmed in eleven patients. PIV3 infections were associated with lower mortality than documented previously; three of the PIV3-infected patients died (3/32; 9%). All deaths were associated with relapsed malignancies, and PIV3 was not believed to be the primary cause of death in any of these patients. Sequences from 27 cases clustered closely together, consistent with nosocomial infections from PIV3 circulating within the ward. Factors favouring transmission were high patient turnaround between the day treatment unit and in-patient ward, and limited isolation facilities for immunocompromised and infected patients, especially within the day treatment unit. New infections reduced to baseline levels three days after enhanced infection control interventions were introduced. CONCLUSIONS: Molecular epidemiological analysis provided evidence for nosocomial transmission of PIV3 infection that facilitated effective implementation of infection control measures. These were instrumental in restricting further spread of the virus among high-risk patients. PMID- 22546620 TI - Adipose tissue cells, lipotransfer and cancer: a challenge for scientists, oncologists and surgeons. AB - Despite recent evidence of the cancer-promoting role of adipose tissue-derived progenitor and differentiated cells, the use of lipotransfer for tissue/organ reconstruction after surgical removal of cancer is increasing worldwide. Here we discuss in a multidisciplinary fashion the preclinical data connecting obesity, adipose cells and cancer progression, as well as the clinical data concerning safety of lipotransfer procedures in cancer patients. A roadmap towards a more rationale use of lipotransfer in oncology is urgently needed and should include preclinical studies to dissect the roles of different adipose tissue-derived cells, the evaluation of drugs currently candidate to inhibit the interaction between adipose and tumor cells, and carefully designed clinical trials to investigate the safety of lipotransfer procedures in cancer patients. PMID- 22546622 TI - Systematic identification of pharmacogenomics information from clinical trials. AB - Recent progress in high-throughput genomic technologies has shifted pharmacogenomic research from candidate gene pharmacogenetics to clinical pharmacogenomics (PGx). Many clinical related questions may be asked such as 'what drug should be prescribed for a patient with mutant alleles?' Typically, answers to such questions can be found in publications mentioning the relationships of the gene-drug-disease of interest. In this work, we hypothesize that ClinicalTrials.gov is a comparable source rich in PGx related information. In this regard, we developed a systematic approach to automatically identify PGx relationships between genes, drugs and diseases from trial records in ClinicalTrials.gov. In our evaluation, we found that our extracted relationships overlap significantly with the curated factual knowledge through the literature in a PGx database and that most relationships appear on average 5 years earlier in clinical trials than in their corresponding publications, suggesting that clinical trials may be valuable for both validating known and capturing new PGx related information in a more timely manner. Furthermore, two human reviewers judged a portion of computer-generated relationships and found an overall accuracy of 74% for our text-mining approach. This work has practical implications in enriching our existing knowledge on PGx gene-drug-disease relationships as well as suggesting crosslinks between ClinicalTrials.gov and other PGx knowledge bases. PMID- 22546621 TI - Genetic testing in domestic cats. AB - Varieties of genetic tests are currently available for the domestic cat that support veterinary health care, breed management, species identification, and forensic investigations. Approximately thirty-five genes contain over fifty mutations that cause feline health problems or alterations in the cat's appearance. Specific genes, such as sweet and drug receptors, have been knocked out of Felidae during evolution and can be used along with mtDNA markers for species identification. Both STR and SNP panels differentiate cat race, breed, and individual identity, as well as gender-specific markers to determine sex of an individual. Cat genetic tests are common offerings for commercial laboratories, allowing both the veterinary clinician and the private owner to obtain DNA test results. This article will review the genetic tests for the domestic cat, and their various applications in different fields of science. Highlighted are genetic tests specific to the individual cat, which are a part of the cat's genome. PMID- 22546624 TI - Continuous operation of a fluidized bed reactor for the removal of estrogens by immobilized laccase on Eupergit supports. AB - The feasibility of the operation of a fluidized bed reactor for the removal of estrogens by immobilized laccase was investigated in order to improve the degradation yields and enzyme stability previously obtained with packed bed reactors. High removal levels (between 76 and 90%) and significantly prolonged stability of the biocatalyst over 16 days were attained. In parallel, a decrease up to 90% in the estrogenic activity of the effluent was measured. Thus, the technology presented seems a promising tool to increase the applicability of laccases in bioremediation processes. PMID- 22546623 TI - A multicentre, randomized study of telmisartan versus carvedilol for prevention of atrial fibrillation recurrence in hypertensive patients. AB - INTRODUCTION: Atrial remodelling, leading to atrial fibrillation (AF), is mediated by the renin-angiotensin-aldosterone system. METHODS: Mild hypertensive outpatients (systolic/diastolic blood pressure 140-159/90-99 mmHg) in sinus rhythm who had experienced >= 1 electrocardiogram (ECG)-documented AF episode in the previous six months received randomly telmisartan 80 mg/day or carvedilol 25 mg/day. Blood pressure and 24-hour ECG were monitored monthly for one year; patients were asked to report symptomatic AF episodes and to undergo an ECG as early as possible. RESULTS: One hundred and thirty-two patients completed the study (telmisartan, n=70; carvedilol, n=62). Significantly fewer AF episodes were reported with telmisartan versus carvedilol (14.3% vs. 37.1%; p<0.003). Left atrial diameter, assessed by echocardiography, was similar with telmisartan and carvedilol (3.4+/-2.3 cm vs. 3.6+/-2.4 cm). At study end, both regimes significantly reduced mean left ventricular mass index, but the reduction obtained with telmisartan was significantly greater than with carvedilol (117.8+/ 10.7 vs. 124.7+/-14.5; p<0.0001). Mean blood pressure values were not significantly different between the groups (telmisartan 154/97 to 123/75 mmHg; p<0.001; carvedilol 153/94 to 125/78 mmHg; p<0.001). CONCLUSIONS: Telmisartan was significantly more effective than carvedilol in preventing recurrent AF episodes in hypertensive AF patients, despite a similar lowering of blood pressure. PMID- 22546626 TI - Polybrominated diphenyl ethers in soils of the modern Yellow River Delta, China: occurrence, distribution and inventory. AB - The Yellow River is the second largest river in China. In this study, the levels of polybrominated diphenyl ethers (PBDEs) in the modern Yellow River Delta (mYRD) were firstly reported. Twenty PBDE congeners in soil/sediment samples from mYRD were measured. The total PBDE concentrations ranged from non-detectable to 18257ngkg(-1) with a mean value of 836ngkg(-1). BDE-209 was the dominant congener, accounting for ~86.1-99.5% of the total PBDEs. The congener profiles of PBDEs with higher abundances of BDE-153 and BDE-183 were similar to those in sediment of the Bohai Sea, indicating that they shared similar sources. The concentrations and congener patterns varied among different regions. Higher levels of PBDEs were found in the middle area (MA), and more complicated congener compositions were also observed in the MA, whereas lower levels of PBDEs were found in the modern course (MC) and the old course (OC). Much more PBDEs were detected in the top layer (TL) soil where more congeners were also held compared to lower soil layers, implying that more PBDEs were emitted into this area in recent years/decades. Organic matter controlled the PBDE distribution in the soil. Soil in this area might be a source of BDE209 for the Bohai Sea. PMID- 22546627 TI - Suppressive effect of polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans and dioxin-like polychlorinated biphenyls transfer from feed to eggs of laying hens by activated carbon as feed additive. AB - In this study, we investigated the suppressive effect of polychlorinated dibenzo p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like polychlorinated biphenyls (DL-PCBs) transfer from the feed to the eggs of laying hens by using activated carbon as a feed additive. Four groups of six hens (White Leghorn egg-layers; age, 11weeks) were housed as two control groups and two exposure groups for a period of 20weeks. Two control groups were fed with either the basal feed "Control" or basal feed additing activated carbon "Control+C". Another two exposure groups were fed with feed contaminated (about 6ng TEQ kg(-1) feed) by standard solutions of PCDDs/PCDFs and DL-PCBs "Exposure" alone and contaminated feed adding activated carbon "Exposure+C". There was no significant effect on each groups for the growth rate, biochemical blood components, and egg production: these were around the standard levels for poultry in general. Moreover the results in this study showed the availability of activated carbon as a feed additive owing to the reduction in the risk of food pollution by PCDDs/PCDFs and DL-PCBs. The concentration in the eggs of the Exposure group gradually increased following the start of egg-laying but reached a steady state after about 1month. In contrast, the concentration for the Exposure+C group was stationary and below the maximum EU level (6pgTEQg(-1)fat). In comparison to the Exposure group, the Exposure+C group showed a significant decline in the percentage of bioaccumulation into the egg. This reduction due to activated carbon was also observed in the muscle and abdominal fat. The reductions were compound- and congener-dependent for DL-PCBs as follows: PCDDs/PCDFs, non-ortho PCBs, and mono-ortho-PCBs were more than 90%, 80%, and 50%, respectively, irrespective of the type of tissues. Fat soluble vitamin concentrations in the eggs of the Exposure+C group showed lower trends than the Exposure group. The gamma-tocopherol and alpha-tocopherol concentrations in eggs of Exposure+C group showed a significant reduction of about 40%. However, the addition of activated carbon into animal feed could obviate the remote potential for accidents causing unintentional food pollution with PCDDs/PCDFs and DL-PCBs. PMID- 22546625 TI - Increased total volume and dopamine beta-hydroxylase immunoreactivity of carotid body in spontaneously hypertensive rats. AB - Under hypertension, it has been reported that the carotid body (CB) is enlarged and noradrenaline (NA) content in CB is increased. Therefore, it is hypothesized that morphological and neurochemical changes in CB are induced in hypertensive animal models. In the present study, we examined the morphological features and dopamine beta-hydroxylase (DBH) immunoreactivity in CB of spontaneously hypertensive rats (SHR/Izm) and Wistar Kyoto rats (WKY/Izm). The CB of SHR/Izm was elongated in terms of the cross section of center and was enlarged in the reconstructed images compared with that of WKY/Izm, and the total volume of CB in SHR/Izm (0.048 +/- 0.004 mm3) was significantly (p<0.05) increased compared with the value in WKY/Izm (0.032 +/- 0.006 mm3). By immunohistochemistry, immunoreactivity for tyrosine hydroxylase in CB was mainly observed in glomus cells and the immunostaining properties were similar between WKY/Izm and SHR/Izm. On the other hand, DBH immunoreactivity was mainly observed in nerve fibers around blood vessels and observed in a few glomus cells in CB of WKY/Izm. The number of glomus cells with strong DBH immunoreactivity was increased in SHR/Izm compared with that in WKY/Izm. In conclusion, the present study exhibited the enlargement of CB as three-dimensional image and revealed the enhanced immunoreactivity for DBH of glomus cells in SHR/Izm. These results suggest that the morphology of CB is affected by the effect of sympathetic nerve and that the signal transduction from CB is regulated by NA in glomus cells under hypertensive conditions. PMID- 22546628 TI - Short- and long-chain perfluorinated acids in sewage sludge from Shanghai, China. AB - Perfluorinated acids (PFAs) are the subject of increasingly intense environmental research. In this study, sewage sludge samples were collected from 25 wastewater treatment plants (WWTPs) in Shanghai, China to evaluate the levels and profile of C3-C14 PFAs. The results showed a ubiquitous PFAs contamination of sewage sludge in Shanghai with the total PFAs (?PFAs) range of 126-809 ng g(-1)dw. Perfluorooctanoic acid (PFOA) was found to be the dominant PFA pollutant and its concentration ranged from 23.2 to 298 ng g(-1)dw, much higher than the levels in other countries. Moreover, concentrations of short-chain PFAs (6)-diglucopyranosides-induced cell death in human leukemia cells is dependent on caspases. AB - A series of alkyl alpha/beta-(1->6)-diglucopyranosides 1-12 were synthesized and assessed for cytotoxicity against HL-60, U937, Molt-3 and MCF-7 cancer cell lines. The menthyl derivatives displayed strong cytotoxic properties showing IC(50) values between 6 and 16 MUM. Furthermore, we demonstrated that the selected synthetic (+)-menthyl beta-(1->6)-diglucopyranoside 5 induces apoptotic cell death in human leukemia cells through a mechanism that involves activation of multiple caspases. Cell death was completely prevented by the non-specific caspase inhibitor z-VAD-fmk and found to be associated with the release of cytochrome c, an increase in the expression of Bax levels and a decrease in the generation of reactive oxygen species. PMID- 22546670 TI - Remarkably fast and selective aromatization of Hantzsch esters with MoOCl4 and MoCl5: a chemical model for possible biologically relevant properties of molybdenum-containing enzymes. AB - Mo(VI) and Mo(V) salts both react selectively with Hantzsch esters to produce substitute pyridines in good-to-excellent yield (75-99%). The remarkable reactivity and selectivity of MoOCl(4) under reflux of acetonitrile and MoCl(5) in dichloromethane at room temperature encouraged us to propose that molybdenum containing enzymes (such as xanthine or aldehyde oxidase) also participate to some degree in the metabolism of 1,4-dihydropyridine drugs in the liver analogous to NADH in the respiratory chain. PMID- 22546671 TI - Investigation of the binding pocket of human hematopoietic prostaglandin (PG) D2 synthase (hH-PGDS): a tale of two waters. AB - The inhibition of hH-PGDS has been proposed as a potential target for the development of anti-allergic and anti-inflammatory drugs. Herein we describe our investigation of the binding pocket of this important enzyme and our observation that two water molecules bind to our inhibitors and the enzyme. A series of compounds were prepared to the probe the importance of the water molecules in determining the binding affinity of the inhibitors to the enzyme. The study provides insight into the binding requirements for the design of potent hH-PGDS inhibitors. PMID- 22546672 TI - Simple, fast and efficient synthesis of beta-keto esters from the esters of heteroaryl compounds, its antimicrobial study and cytotoxicity towards various cancer cell lines. AB - A series of beta-keto esters were synthesized from heteroaryl esters and ethyl acetate using LiHMDS as base at -50 to -30 degrees C. The increase in yields of cross condensed product were observed and the percentage of self condensed product was reduced drastically by applying the suitable base (LiHMDS), solvent and the minimum amount of ethyl acetate. All these beta-keto esters were characterized using (1)H NMR, (13)C NMR and mass spectral data. A plausible mechanism is also depicted to prove the formation of trans-esterified products. All the synthesized compounds were subjected to test for their cytotoxicity towards various cancer cell lines and also tested for their antimicrobial activity towards various bacterial and fungal strains and some of them were found to have promising activity. PMID- 22546673 TI - Utilization of [11C]phosgene for radiosynthesis of N-(2-{3-[3,5 bis(trifluoromethyl)]phenyl[11C]ureido}ethyl)glycyrrhetinamide, an inhibitory agent for proteasome and kinase in tumors. AB - N-(2-{3-[3,5-Bis(trifluoromethyl)]phenylureido}ethyl)glycyrrhetinamide (2), an ureido-substituted derivative of glycyrrhetinic acid (1), has been reported to display potent inhibitory activity for proteasome and kinase, which are overexpressed in tumors. In this study, we labeled this unsymmetrical urea 2 using [(11)C]phosgene ([(11)C]COCl(2)) as a labeling agent with the expectation that [(11)C]2 could become a positron emission tomography ligand for the imaging of proteasome and kinase in tumors. The strategy for the radiosynthesis of [(11)C]2 was to react hydrochloride of 3,5-bis(trifluoromethyl)aniline (4.HCl) with [(11)C]COCl(2) to possibly give isocyanate [(11)C]6, followed by the reaction of [(11)C]6 with N-(2-aminoethyl)glycyrrhetinamide (3). PMID- 22546674 TI - Spectaflavoside A, a new potent iron chelating dimeric flavonol glycoside from the rhizomes of Zingiber spectabile Griff. AB - The rhizomes of Zingiber spectabile yielded a new dimeric flavonol glycoside for which the name kaempferol-3-O-(4"-O-acetyl)-alpha-L-rhamnopyranoside-(I-6,II-8) kaempferol-3-O-(4"-O-acetyl)-alpha-L-rhamnopyranoside; spectaflavoside A (1) was proposed, along with kaempferol and its four acetylrhamnosides (2-6), demethoxycurcumin (7) and curcumin (8). The structure of spectaflavoside A was elucidated by spectroscopic methods including, 1D and 2D NMR techniques. This is the first report on the occurrence of a dimeric flavonol glycoside in the Zingiberaceae and the second in nature. Spectaflavoside A was found to be a potent iron chelating agent. PMID- 22546675 TI - Wake promoting agents: search for next generation modafinil, lessons learned: part III. AB - In searching for a next generation molecule to the novel wake promoting agent modafinil (compound 1), a series of fluorene-derived wakefulness enhancing agents were developed and evaluated in rat. Extensive pharmacokinetic studies of a potent member of the series (compound 15) revealed that the wake promotion activity of the analog was likely due to an active metabolite (compound 3). PMID- 22546676 TI - BC-spiro-estradiols. Synthesis and estrogen receptor binding affinity of four new estradiol isomers. AB - The synthesis of four new isomers of estradiol in which the ring A to ring C planes are perpendicular to each other as a result of a spiro BC ring junction is described. Heterocyclic analogs and carbocyclic homologs of these compounds are also reported. Estrogen receptor binding studies show that the spiro compounds with the natural stereochemistry at C9 bind almost as strongly as estradiol but with greater beta to alpha selectivity. These studies show that the estrogen receptors can readily accommodate isomers of estrogen with substantially different fixed shapes than the native ligand. PMID- 22546677 TI - Synthesis and biological evaluation of ticagrelor derivatives as novel antiplatelet agents. AB - Ticagrelor (1) is the first reversible P2Y12 receptor antagonist blocking adenine diphosphate (ADP)-induced platelet aggregation with rapid onset and offset of effects. In this study, synthesis of ticagrelor and its derivatives has been accomplished in a convergent way. The compound design was based on modifications of ticagrelor and its major metabolite (33) in order to ameliorate their pharmacokinetic properties and dosing profile. The final compounds (1a-g, 35a-g) were evaluated for their inhibitory effect on ADP-induced platelet aggregation in rats. The assay results showed that some compounds (e.g., 1b, 1d, 33, 35b, 35f) exhibited comparable potency with that of ticagrelor. PMID- 22546678 TI - Single agent maintenance therapy for advanced stage non-small cell lung cancer: a meta-analysis. AB - BACKGROUND: Maintenance therapy is a new treatment paradigm for advanced non small cell lung cancer (NSCLC). We conducted a meta-analysis of randomized studies with single agent maintenance therapy. METHODS: An electronic literature search of public databases (MEDLINE, EMBASE, Cochrane library) and manual search of relevant conference proceedings was performed. A formal meta-analysis was conducted using Comprehensive Meta Analysis software (Version 2.0). Outcome data were pooled and reported as hazard ratio (HR). The primary outcome of interest was overall survival (OS) and secondary outcome was progression free survival (PFS). RESULTS: Twelve studies were included (5 meeting abstracts, 7 full manuscripts) with a total of 4286 patients (maintenance arm/control arm - 2449/1837, median age 61 years, males - 69%). The OS (HR 0.86, 95% confidence intervals [CI] 0.80-0.92; P=0.0003) and PFS (HR 0.80, 95% CI 0.77-0.84; P<0.0001) were superior with maintenance therapy. 'Switch' maintenance was associated with significant OS and PFS improvement (OS HR 0.84, 95% CI 0.77-0.91; P=0.00026; PFS HR 0.62, 95% CI 0.57-0.67; P<0.0001). Despite a modest improvement in PFS (HR 0.90, 95%CI 0.85-0.95; P=0.007), "continuation" maintenance was not associated with survival benefit (HR 0.927, 95%CI 0.78-1.09; P=0.33). Improvements in OS and PFS were observed with both EGFR-targeted agents (HR 0.83, 95% CI 0.74-0.92; P=0.004; HR 0.64, 95% CI 0.58-0.71 P<0.0001) and cytotoxic agents (HR 0.89, 95% CI 0.80-0.98; P=0.018; HR 0.85, 95% CI 0.80-0.89; P<0.0001). CONCLUSIONS: Single agent maintenance therapy improves overall survival, though statistical significance was only noted with 'switch' maintenance. PMID- 22546679 TI - A novel encapsulation of N,N-diethyl-3-methylbenzamide (DEET) favorably modifies skin absorption while maintaining effective evaporation rates. AB - N,N-diethyl-3-methylbenzamide (DEET) is popular insect repellent which is considered safe and effective, yet is subject to considerable skin absorption. Skin absorption decreases effective repellency since less DEET is available for evaporation. We have investigated the extent to which DEET skin absorption can be reduced and evaporation sustained through encapsulation. DEET permeation through human skin in vitro was measured for an ethanolic solution standard and for two novel topical controlled-release formulations in which the DEET active material was temporarily sequestered within a permeable, charged-film microcapsule. Evaporation measurements were gathered using Tenax TA cartridges and a sampling pump drawing air over the skin. Three formulations were studied: a previously reported microcapsule formulation (Formulation A); a newly-developed microcapsule formulation (Formulation B); and a non-encapsulated ethanol control solution. Formulation B led to a 30% reduction in DEET permeation versus control. The two microcapsule DEET formulations exhibited 36-40% higher cumulative evaporation from the skin than did the control. The vapor trapping measurements in vitro show that Formulation B provided more than 48h of effective evaporation rate for repellency, while Formulation A provided less than 35h and the ethanol control less than 15h. This establishes a technical advantage for the controlled-release approach. PMID- 22546681 TI - Dendrimer type bio-reducible polymer for efficient gene delivery. AB - Arginine-grafted bio-reducible poly(disulfide amine) (ABP) was incorporated into the poly(amido amine) (PAMAM) dendrimer, creating a high molecular weight bio reducible polymer, PAM-ABP, to overcome the limitations of the low molecular weight ABP. The newly synthesized PAM-ABP was studied to determine its efficacy as a gene delivery carrier. The PAM-ABP demonstrated superior condensing ability for plasmid DNA through the formation of compact nanosized polyplexes. These compact polyplexes enhanced cellular uptake and were less susceptible to reducing agents, resulting in greater transfection efficiency compared to ABP alone. Based on these results, this newly developed PAM-ABP polyplex is a promising delivery system for clinical gene therapy. PMID- 22546682 TI - Block ionomer complexes of PEG-block-poly(4-vinylbenzylphosphonate) and cationic surfactants as highly stable, pH responsive drug delivery system. AB - A new family of block ionomer complexes (BIC) formed by poly(ethylene glycol) block-poly(4-vinylbenzylphosphonate) (PEG-b-PVBP) and various cationic surfactants was prepared and characterized. These complexes spontaneously self assembled in aqueous solutions into particles with average size of 40-60nm and remained soluble over the entire range of the compositions of the mixtures including stoichiometric electroneutral complexes. Solution behavior and physicochemical properties of such BIC were very sensitive to the structure of cationic surfactants. Furthermore, such complexation was used for incorporation of cationic anti-cancer drug, doxorubicin (DOX), into the core of BIC with high loading capacity and efficiency. The DOX/PEG-b-PVBP BIC also displayed high stability against dilution, changes in ionic strength. Furthermore, DOX release at the extracellular pH of DOX/PEG-b-PVBP BIC was slow. It was greatly increased at the acidic pH mimicking the endosomal/lysosomal environment. Confocal fluorescence microscopy using live MCF-7 breast cancer cells suggested that DOX/PEG-b-PVBP BICs are transported to lysosomes. Subsequently, the drugs are released and exert cytotoxic effect killing these cancer cells. These findings indicate that the obtained complexes can be attractive candidates for delivery of cationic drugs to tumors. PMID- 22546680 TI - In vivo delivery of cell-permeable antisense hypoxia-inducible factor 1alpha oligonucleotide to adipose tissue reduces adiposity in obese mice. AB - Ongoing research has gradually recognized and understood the importance of adipose tissue (AT) angiogenesis as a key modulating factor of adipogenesis in the development of obesity. Previously, we carried out the first in vitro demonstration of the down-regulation of hypoxic angiogenesis during adipogenesis using cell-permeable chemical conjugates composed of antisense hypoxia-inducible factor 1alpha (HIF1alpha) oligonucleotide (ASO) and low-molecular weight protamine (LMWP). To further confirm the in vivo feasibility, we administered ASO LMWP conjugates (AL) to diet-induced obese (DIO) mice by intraperitoneal injection (IP). Results showed that the AL conjugates significantly reduced the body weight, total fat tissue weight, and plasma lipid concentrations in the mice. Moreover, the AL conjugates not only decreased liver weight and hepatic triglyceride concentration but also significantly attenuated subcutaneous adipocyte cell size, which was conversely increased in the AL-untreated high-fat diet (HFD) group. Interestingly, more blood vessels were observed in the HFD group than in the lean group, indicating that blood vessel development could induce growth of the fat mass. This pattern was reversed in the AL-treated groups, which displayed a decrease in blood vessel density compared to the AL untreated HFD group. This study presents the first in vivo evidence, in an obese mouse model, of the feasibility of achieving a biological treatment modality for obesity by blocking the angiogenic transcriptional factor HIF1alpha, thereby limiting angiogenesis, via the use of an adipose tissue-permeable ASO-LMWP. PMID- 22546684 TI - Stent implantation in the superficial femoral artery: short thrombelastometry derived coagulation times identify patients with late in-stent restenosis. AB - INTRODUCTION: The mechanisms of restenosis, the recurrence of luminal narrowing, are complex and incompletely understood to date. Thrombin, the pivotal enzyme in haemostasis, presumably contributes to the formation of in-stent restenosis (ISR). It was therefore the aim of our study to investigate whether blood coagulation/thrombin generation plays a critical role in the formation of ISR in peripheral artery disease patients with stent angioplasty in the superficial femoral artery. MATERIALS AND METHODS: We aimed to examine in this retrospective study whether patients with high-degree restenosis (50-75% lumen diameter reduction, n=20) are in a hypercoaguable state implying enhanced readiness to generate thrombin compared to patients with low-degree restenosis (<50% lumen diameter reduction, n=14). RESULTS: The coagulation tests calibrated automated thrombography, activated partial thromboplastin time, platelet aggregation, platelet adhesion, fibrinogen, and microparticles' procoagulant activity did not indicate a different coagulation status in the two patient groups. However, the thrombelastometry-derived value Coagulation Time (CT) was significantly shorter in the high-degree restenosis group (p=0.012), indicating a hypercoagulable state of patients with high-degree restenosis. Under our experimental conditions, CTs shorter than 444.5s identify patients at high risk (sensitivity=95%) for luminal narrowing. CONCLUSIONS: Our study supports the assumption that blood coagulation/thrombin generation plays a critical role in the development of ISR in peripheral arteries after stent insertion and that the thrombelastometry derived CT might be a suitable value to identify peripheral artery disease patients at risk for development of high-degree in-stent restenosis in the superficial femoral artery. PMID- 22546683 TI - Minimizing acylation of peptides in PLGA microspheres. AB - The main objective of this study was to characterize and find mechanisms to prevent acylation of therapeutic peptides encapsulated in glucose-star poly(d,l lactic-co-glycolic acid) (PLGA) microspheres. The effect of addition of divalent cation salts CaCl(2), MnCl(2) as well as carboxymethyl chitosan (CMCS) on inhibition of acylation of octreotide (Oct), salmon calcitonin (sCT), and human parathyroid hormone (hPTH) was evaluated. Peptide content and integrity inside the degrading microspheres was monitored by reversed-phase high performance liquid chromatography (HPLC) and mass spectrometry during release incubation under physiological conditions. The extent of peptide acylation was strongly inhibited in the formulations containing divalent cations and/or CMCS as excipients, although specific effects were dependent on the specific peptide and excipient combinations. Both inorganic cations improved stability of Oct and hPTH but not sCT. Addition of CMCS alone was ineffective. Combining inorganic cations with CMCS improved stability of Oct and sCT but it had no effect on hPTH stability. The operative stabilization mechanisms are consistent with blocking peptide-PLGA interactions by a) directly competing for PLGA interactions with dications and/or b) increasing peptide affinity in the stabilizer phase within PLGA pores. Hence, inorganic multivalent cations are general stabilizers against peptide acylation, the effect of which may be augmented in certain instances with addition of CMCS. PMID- 22546685 TI - Synthesis and characterization of unsymmetrical oxidovanadium complexes: DNA binding, cleavage studies and antitumor activities. AB - Four oxidovanadium(IV) complexes, [VO(hntdtsc)(phen)] (1), [VO(hntdtsc)(bpy)] (2) (hntdtsc=2-hydroxy-1-naphthaldehyde thiosemicarbazone, phen=1,10-phenanthroline), [VO(satsc)(phen)] (3) and [VO(satsc)(bpy)] (4) (satsc=salicylaldehyde thiosemicarbazone, bpy=2,2'-bipyridine) have been synthesized and characterized. The results show that complexes 1, 2, 3 and 4 interact with DNA through intercalative mode and can efficiently cleave the plasmid pBR 322 DNA. It is interesting to note that these four complexes present highly cytotoxic activities against Myeloma cell (Ag8.653) and Gliomas cell (U251) lines. Complex 1 was found to be the most potent antitumor agent among the four complexes. PMID- 22546686 TI - Development of metal-chelating inhibitors for the Class II fructose 1,6 bisphosphate (FBP) aldolase. AB - It has long been suggested that the essential and ubiquitous enzyme fructose 1,6 bisphosphate (FBP) aldolase could be a good drug target against bacteria and fungi, since lower organisms possess a metal-dependant (Class II) FBP aldolase, as opposed to higher organisms which possess a Schiff-base forming (Class I) FBP aldolase. We have tested the capacity of derivatives of the metal-chelating compound dipicolinic acid (DPA), as well a thiol-containing compound, to inhibit purified recombinant Class II FBP aldolases from Mycobacterium tuberculosis, Pseudomonas aeruginosa, Bacillus cereus, Bacillus anthracis, and from the Rice Blast causative agent Magnaporthe grisea. The aldolase from M. tuberculosis was the most sensitive to the metal-chelating inhibitors, with an IC(50) of 5.2 MUM with 2,3-dimercaptopropanesulfonate (DMPS) and 28 MUM with DPA. DMPS and the synthesized inhibitor 6-(phosphonomethyl)picolinic acid inhibited the enzyme in a time-dependent, competitive fashion, with second order rate constants of 273 and 270 M(-1) s(-1) respectively for the binding of these compounds to the M. tuberculosis aldolase's active site in the presence of the substrate FBP (K(M) 27.9 MUM). The most potent first generation inhibitors were modeled into the active site of the M. tuberculosis aldolase structure, with results indicating that the metal chelators tested cannot bind the catalytic zinc in a bidentate fashion while it remains in its catalytic location, and that most enzyme-ligand interactions involve the phosphate binding pocket residues. PMID- 22546687 TI - Dose, dose-rate and field size effects on cell survival following exposure to non uniform radiation fields. AB - For the delivery of intensity-modulated radiation therapy (IMRT), highly modulated fields are used to achieve dose conformity across a target tumour volume. Recent in vitro evidence has demonstrated significant alterations in cell survival occurring out-of-field which cannot be accounted for on the basis of scattered dose. The radiobiological effect of area, dose and dose-rate on out-of field cell survival responses following exposure to intensity-modulated radiation fields is presented in this study. Cell survival was determined by clonogenic assay in human prostate cancer (DU-145) and primary fibroblast (AG0-1522) cells following exposure to different modulated field configurations delivered using a X-Rad 225 kVp x-ray source. Uniform survival responses were compared to in- and out-of-field responses in which 25-99% of the cell population was shielded. Dose delivered to the out-of-field region was varied from 1.6-37.2% of that delivered to the in-field region using different levels of brass shielding. Dose rate effects were determined for 0.2-4 Gy min-1 for uniform and modulated exposures with no effect seen in- or out-of-field. Survival responses showed little dependence on dose rate and area in- and out-of-field with a trend towards increased survival with decreased in-field area. Out-of-field survival responses were shown to scale in proportion to dose delivered to the in-field region and also local dose delivered out-of-field. Mathematical modelling of these findings has shown survival response to be highly dependent on dose delivered in- and out of-field but not on area or dose rate. These data provide further insight into the radiobiological parameters impacting on cell survival following exposure to modulated irradiation fields highlighting the need for refinement of existing radiobiological models to incorporate non-targeted effects and modulated dose distributions. PMID- 22546688 TI - Luteinizing hormone reduces the activity of the NPR2 guanylyl cyclase in mouse ovarian follicles, contributing to the cyclic GMP decrease that promotes resumption of meiosis in oocytes. AB - In preovulatory ovarian follicles of mice, meiotic prophase arrest in the oocyte is maintained by cyclic GMP from the surrounding granulosa cells that diffuses into the oocyte through gap junctions. The cGMP is synthesized in the granulosa cells by the transmembrane guanylyl cyclase natriuretic peptide receptor 2 (NPR2) in response to the agonist C-type natriuretic peptide (CNP). In response to luteinizing hormone (LH), cGMP in the granulosa cells decreases, and as a consequence, oocyte cGMP decreases and meiosis resumes. Here we report that within 20 min, LH treatment results in decreased guanylyl cyclase activity of NPR2, as determined in the presence of a maximally activating concentration of CNP. This occurs by a process that does not reduce the amount of NPR2 protein. We also show that by a slower process, first detected at 2h, LH decreases the amount of CNP available to bind to the receptor. Both of these LH actions contribute to decreasing cGMP in the follicle, thus signaling meiotic resumption in the oocyte. PMID- 22546689 TI - In vivo Wnt signaling tracing through a transgenic biosensor fish reveals novel activity domains. AB - The creation of molecular tools able to unravel in vivo spatiotemporal activation of specific cell signaling events during cell migration, differentiation and morphogenesis is of great relevance to developmental cell biology. Here, we describe the generation, validation and applications of two transgenic reporter lines for Wnt/beta-catenin signaling, named TCFsiam, and show that they are reliable and sensitive Wnt biosensors for in vivo studies. We demonstrate that these lines sensitively detect Wnt/beta-catenin pathway activity in several cellular contexts, from sensory organs to cardiac valve patterning. We provide evidence that Wnt/beta-catenin activity is involved in the formation and maintenance of the zebrafish CNS blood vessel network, on which sox10 neural crest-derived cells migrate and proliferate. We finally show that these transgenic lines allow for screening of Wnt signaling modifying compounds, tissue regeneration assessment as well as evaluation of potential Wnt/beta-catenin genetic modulators. PMID- 22546690 TI - The long non-coding RNA, MHM, plays a role in chicken embryonic development, including gonadogenesis. AB - MHM is a chicken Z chromosome-linked locus that is methylated and transcriptionally silent in male cells, but is hypomethylated and transcribed into a long non-coding RNA in female cells. MHM has been implicated in both localised dosage compensation and sex determination in the chicken embryo, but direct evidence is lacking. We investigated the potential role of MHM in chicken embryonic development, using expression analysis and retroviral-mediated mis expression. At embryonic stages, MHM is only expressed in females. Northern blotting showed that both sense and antisense strands of the MHM locus are transcribed, with the sense strand being more abundant. Whole mount in situ hybridization confirmed that the sense RNA is present in developing female embryos, notably in gonads, limbs, heart, branchial arch and brain. Within these cells, the MHM RNA is localized to the nucleus. The antisense transcript is lowly expressed and has a cytoplasmic localization in cells. Mis-expression of MHM sense and antisense sequences results in overgrowth of tissues in which transcripts are predominantly expressed. This includes altered asymmetric ovarian development in females. In males, MHM mis-expression impairs gonadal expression of the testis gene, DMRT1. Both MHM sense and antisense mis-expression cause brain abnormalities, while MHM sense causes an increase in male-biased embryo mortality. These results indicate that MHM has a role in chicken normal embryonic development, including gonadal sex differentiation. PMID- 22546691 TI - Postnatal subventricular zone of the neocortex contributes GFAP+ cells to the rostral migratory stream under the control of Sip1. AB - The rostral migratory stream (RMS) is composed of neuroblasts migrating from the striatal SVZ to the olfactory bulb through a meshwork of GFAP- expressing astrocytes called the glial tube. So far, the origin of the glial tube astrocytes was attributed to differentiation of Type-B stem cells of the striatal SVZ. The true identity of these cells (Type-B stem cells versus immature/mature astrocytes) is also unclear. By analyzing a neocortex-specific conditional knockout of the transcriptional repressor Sip1 (Smad-interacting protein 1), we have now identified a novel pool of progenitors located within the dorsal SVZ (dSVZ) at early postnatal stages that differentiate into GFAP+ cells of the glial tube. We show that Sip1, expressed in postmitotic cortical neurons, controls the size of this dorsal progenitor pool possibly through cell-extrinsic mechanisms. Lack of Sip1 in the neocortex causes an expansion of this population leading to an increased production of GFAP+ astrocytes/Type-B stem cells in the glial tube, and a denser intercalation of these cells with Dcx+ neuroblasts of the RMS, the consequence of which is not yet clear. Neocortex-specific Sip1 deletion also led to an expansion of Dcx+ and Tbr2+ progenitor populations in the dSVZ. We show that the dSVZ progenitors (possibly remnants of embryonic radial glia) differentiate exclusively into BLBP+ cells which migrate into the RMS and mature into GFAP+ astrocytes/Type-B stem cells at around two weeks of postnatal development. In summary, our work shows that Sip1 controls the generation of GFAP+ cells of the RMS by regulating the size of a novel progenitor pool located in the postnatal dSVZ. PMID- 22546692 TI - Interaction of Wnt3a, Msgn1 and Tbx6 in neural versus paraxial mesoderm lineage commitment and paraxial mesoderm differentiation in the mouse embryo. AB - Paraxial mesoderm is the tissue which gives rise to the skeletal muscles and vertebral column of the body. A gene regulatory network operating in the formation of paraxial mesoderm has been described. This network hinges on three key factors, Wnt3a, Msgn1 and Tbx6, each of which is critical for paraxial mesoderm formation, since absence of any one of these factors results in complete absence of posterior somites. In this study we determined and compared the spatial and temporal patterns of expression of Wnt3a, Msgn1 and Tbx6 at a time when paraxial mesoderm is being formed. Then, we performed a comparative characterization of mutants in Wnt3a, Msgn1 and Tbx6. To determine the epistatic relationship between these three genes, and begin to decipher the complex interplay between them, we analyzed double mutant embryos and compared their phenotypes to the single mutants. Through the analysis of molecular markers in mutants, our data support the bipotential nature of the progenitor cells for paraxial mesoderm and establish regulatory relationships between genes involved in the choice between neural and mesoderm fates. PMID- 22546693 TI - Epicardially derived fibroblasts preferentially contribute to the parietal leaflets of the atrioventricular valves in the murine heart. AB - The importance of the epicardium for myocardial and valvuloseptal development has been well established; perturbation of epicardial development results in cardiac abnormalities, including thinning of the ventricular myocardial wall and malformations of the atrioventricular valvuloseptal complex. To determine the spatiotemporal contribution of epicardially derived cells to the developing fibroblast population in the heart, we have used a mWt1/IRES/GFP-Cre mouse to trace the fate of EPDCs from embryonic day (ED)10 until birth. EPDCs begin to populate the compact ventricular myocardium around ED12. The migration of epicardially derived fibroblasts toward the interface between compact and trabecular myocardium is completed around ED14. Remarkably, epicardially derived fibroblasts do not migrate into the trabecular myocardium until after ED17. Migration of EPDCs into the atrioventricular cushion mesenchyme commences around ED12. As development progresses, the number of EPDCs increases significantly, specifically in the leaflets which derive from the lateral atrioventricular cushions. In these developing leaflets the epicardially derived fibroblasts eventually largely replace the endocardially derived cells. Importantly, the contribution of EPDCs to the leaflets derived from the major AV cushions is very limited. The differential contribution of EPDCs to the various leaflets of the atrioventricular valves provides a new paradigm in valve development and could lead to new insights into the pathogenesis of abnormalities that preferentially affect individual components of this region of the heart. The notion that there is a significant difference in the contribution of epicardially and endocardially derived cells to the individual leaflets of the atrioventricular valves has also important pragmatic consequences for the use of endocardial and epicardial cre mouse models in studies of heart development. PMID- 22546699 TI - Charcot-Marie-Tooth neuropathy due to a novel EGR2 gene mutation with mild phenotype--usefulness of human mapping chip linkage analysis in a Czech family. AB - Charcot-Marie-Tooth neuropathies (CMT) are a group of clinically and genetically heterogeneous disorders of the peripheral nervous system. Selection of candidate disease genes for mutation analysis is sometimes difficult since more than 40 genes and loci are known to be associated with CMT neuropathies. Hence a Czech family Cz-CMT with demyelinating type of autosomal dominant CMT disease was investigated by genome-wide linkage analysis by means of single-nucleotide polymorphism (SNP) arrays. Among 35 regions with linkage, five carried known CMT genes. In the final result a novel early growth response 2 - missense mutation c.1235 A>G, p.Glu412Gly was found. Surprisingly, the more severely affected proband carried an additional heterozygous myelin protein zero variant p.Asp246Asn detected previously, which may modify the phenotype. However, this MPZ variant is benign in heterozygous state alone, because it is also carried by the patient's healthy father. PMID- 22546701 TI - Pulsed radiofrequency enhances morphine analgesia in neuropathic rats. AB - This study examined the effects of pulsed radiofrequency (PRF) on sciatic nerve ligation-induced mechanical pain hypersensitivity in rats. The nociceptive threshold was evaluated using the paw pressure vocalization test. Seven days after nerve ligation, animals receiving a single PRF session (120 s/2 Hz/45 V/42 degrees C) on L4-5-6 dorsal root ganglia ipsilateral to a chronic constriction injury (CCI) showed a reduced sensory hypersensitivity at H4 6 and 1 day after PRF as compared with animals without PRF. One day after PRF, the effect of morphine (2 mg/kg, subcutaneous) increased the nociceptive threshold in the no PRF/CCI group and more extensively in PRF/CCI animals. These results showed that PRF might represent an interesting strategy not only to reduce neuropathic pain but also to enhance the efficacy of morphine in patients with neuropathic pain, well known to be opioid resistant. PMID- 22546700 TI - A French family with Charcot-Marie-Tooth disease related to simultaneous heterozygous MFN2 and GDAP1 mutations. AB - Either dominantly inherited mutations in MFN2 encoding mitofusin 2 or GDAP1 encoding ganglioside-induced differentiation associated protein 1 may be associated with mild neuropathy. The proband, a 41-year-old woman, and her daughter present a severe axonal form of Charcot-Marie-Tooth (CMT) disease. Both are heterozygous for the well-described mild variant p.R120W in GDAP1, which was transmitted by the pauci symptomatic proband's mother. Given that they had an early onset in the first decade and delayed walking acquisition, the other genes implicated in axonal forms of CMT disease were analyzed. A second mutation truncating MFN2 (p.Val160fsX26) was found in the proband and her daughter. This mutation was transmitted by the proband's father who has normal neurological examination. The proband underwent two nerve biopsies which showed an axonal degeneration, myelin modifications, and intra-axonal mitochondria with distorted cristae. Such abnormal mitochondria have been reported in cases with autosomal dominant MFN2 mutations and in one patient with an autosomal recessive GDAP1 mutation. Our two cases show that heterozygous truncation of MFN2, which is silent at least until the sixth decade, when combined with the mild p.R120W GDAP1 variant, leads to a severe neuropathy. This supports the emerging hypothesis of cumulative effects of MFN2 and GDAP1 mutation. PMID- 22546702 TI - Gray matter correlates of Trait and Ability models of emotional intelligence. AB - Research suggests that emotional intelligence capacities may be related to the functional integrity of the corticolimbic regions including the ventromedial prefrontal cortex, insula, and amygdala. No study has yet examined regional brain volumes in relation to the two dominant models of emotional intelligence: the Ability model, which posits a set of specific demonstrable capabilities for solving emotional problems, and the Trait model, which proposes a set of stable emotional competencies that can be assessed through subjectively rated self report scales. In 36 healthy participants, we correlated scores on the Mayer Salovey-Caruso Emotional Intelligence Test (an Ability measure) and the Bar-On Emotional Quotient Inventory (a Trait measure) with regional brain volumes using voxel-based morphometry. Total Mayer-Salovey-Caruso Emotional Intelligence Test scores were positively correlated with the left insula grey matter volume. The Strategic emotional intelligence subscale correlated positively with the left ventromedial prefrontal cortex and insular volume. In contrast, for the Bar-On Emotional Quotient Inventory, Stress Management scores correlated positively with the bilateral ventromedial prefrontal cortex volume. Amygdala volumes were unrelated to emotional intelligence measures. Findings support the role of the ventromedial prefrontal cortex and insula as key nodes in the emotional intelligence circuitry. PMID- 22546694 TI - Enhanced expression of VEGF-A in beta cells increases endothelial cell number but impairs islet morphogenesis and beta cell proliferation. AB - There is a reciprocal interaction between pancreatic islet cells and vascular endothelial cells (EC) in which EC-derived signals promote islet cell differentiation and islet development while islet cell-derived angiogenic factors promote EC recruitment and extensive islet vascularization. To examine the role of angiogenic factors in the coordinated development of islets and their associated vessels, we used a "tet-on" inducible system (mice expressing rat insulin promoter-reverse tetracycline activator transgene and a tet-operon angiogenic factor transgene) to increase the beta cell production of vascular endothelial growth factor-A (VEGF-A), angiopoietin-1 (Ang1), or angiopoietin-2 (Ang2) during islet cell differentiation and islet development. In VEGF-A overexpressing embryos, ECs began to accumulate around epithelial tubes residing in the central region of the developing pancreas (associated with endocrine cells) as early as embryonic day 12.5 (E12.5) and increased dramatically by E16.5. While alpha and beta cells formed islet cell clusters in control embryos at E16.5, the increased EC population perturbed endocrine cell differentiation and islet cell clustering in VEGF-A overexpressing embryos. With continued overexpression of VEGF-A, alpha and beta cells became scattered, remained adjacent to ductal structures, and never coalesced into islets, resulting in a reduction in beta cell proliferation and beta cell mass at postnatal day 1. A similar impact on islet morphology was observed when VEGF-A was overexpressed in beta cells during the postnatal period. In contrast, increased expression of Ang1 or Ang2 in beta cells in developing or adult islets did not alter islet differentiation, development, or morphology, but altered islet EC ultrastructure. These data indicate that (1) increased EC number does not promote, but actually impairs beta cell proliferation and islet formation; (2) the level of VEGF-A production by islet endocrine cells is critical for islet vascularization during development and postnatally; (3) angiopoietin-Tie2 signaling in endothelial cells does not have a crucial role in the development or maintenance of islet vascularization. PMID- 22546703 TI - Neuropsychiatric disorders: does semiology of psychogenic nonepileptic seizures matter? PMID- 22546704 TI - Don't ask, don't tell, don't publish. PMID- 22546705 TI - The science of sex. PMID- 22546706 TI - New race and ethnicity standards: elucidating health disparities in diabetes. AB - The concepts of race and ethnicity are useful for understanding the distribution of disease in the population and for identifying at-risk groups for prevention and treatment efforts. The U.S. Department of Health and Human Services recently updated the race and ethnicity classifications in order to more effectively monitor health disparities. Differences in chronic disease mortality rates are contributing to race and ethnic health disparities in life expectancy in the United States. The prevalence of diabetes is higher in African Americans and Hispanics compared to white Americans, and parallel trends are seen in diabetes risk factors, including physical inactivity, dietary patterns, and obesity. Further research is required to determine the extent to which the observed differences in diabetes prevalence are attributable to differences in lifestyle versus other characteristics across race and ethnic groups. PMID- 22546707 TI - Efficient recombinant parvovirus production with the help of adenovirus-derived systems. AB - Rodent parvoviruses (PV) such as rat H-1PV and MVM, are small icosahedral, single stranded, DNA viruses. Their genome includes two promoters P4 and P38 which regulate the expression of non-structural (NS1 and NS2) and capsid proteins (VP1 and VP2) respectively(1). They attract high interest as anticancer agents for their oncolytic and oncosuppressive abilities while being non-pathogenic for humans(2). NS1 is the major effector of viral cytotoxicity(3). In order to further enhance their natural antineoplastic activities, derivatives from these vectors have been generated by replacing the gene encoding for the capsid proteins with a therapeutic transgene (e.g. a cytotoxic polypeptide, cytokine, chemokine, tumour suppressor gene etc.)(4). The recombinant parvoviruses (recPVs) vector retains the NS1/2 coding sequences and the PV genome telomeres which are necessary for viral DNA amplification and packaging. Production of recPVs occurs only in the producer cells (generally HEK293T), by co-transfecting the cells with a second vector (pCMV-VP) expressing the gene encoding for the VP proteins (Fig. 1)(4). The recPV vectors generated in this way are replication defective. Although recPVs proved to possess enhanced oncotoxic activities with respect to the parental viruses from which they have been generated, their production remains a major challenge and strongly hampers the use of these agents in anti cancer clinical applications. We found that introduction of an Ad-5 derived vector containing the E2a, E4(orf6) and the VA RNA genes (e.g. pXX6 plasmid) into HEK293T improved the production of recPVs by more than 10 fold in comparison to other protocols in use. Based on this finding, we have constructed a novel Ad-VP helper that contains the genomic adenoviral elements necessary to enhance recPVs production as well as the parvovirus VP gene unit(5). The use of Ad-VP-helper, allows production of rec-PVs using a protocol that relies entirely on viral infection steps (as opposed to plasmid transfection), making possible the use of cell lines that are difficult to transfect (e.g. NB324K) (Fig. 2). We present a method that greatly improves the amount of recombinant virus produced, reducing both the production time and costs, without affecting the quality of the final product(5). In addition, large scale production of recPV (in suspension cells and bioreactors) is now conceivable. PMID- 22546714 TI - Triethylammonium bis(tetrafluoromethylsulfonyl)amide protic ionic liquid as an electrolyte for electrical double-layer capacitors. AB - This study describes the preparation, characterization and application of [Et(3)NH][TFSA], either neat or mixed with acetonitrile, as an electrolyte for supercapacitors. Thermal and transport properties were evaluated for the neat [Et(3)NH][TFSA], and the temperature dependence of viscosity and conductivity can be described by the VTF equation. The evolution of conductivity with the addition of acetonitrile rendered it possible to determine the optimal mixture at 25 degrees C, with a weight fraction of acetonitrile of 0.5. This mixture was also evaluated for transport properties, and showed a Newtonian behavior, as the neat PIL. An electrochemical study demonstrated, at first, a passivation on Al after the second cyclic voltammogram. Subsequently, the electrochemical window was estimated using a three-electrode cell to 4 V on a platinum electrode, and to 2.5 V on activated carbon. Finally, the neat PIL was found to exhibit good performances as promising electrolyte for supercapacitor applications. PMID- 22546713 TI - Metabolomic analysis of rat serum in streptozotocin-induced diabetes and after treatment with oral triethylenetetramine (TETA). AB - BACKGROUND: The prevalence, and associated healthcare burden, of diabetes mellitus is increasing worldwide. Mortality and morbidity are associated with diabetic complications in multiple organs and tissues, including the eye, kidney and cardiovascular system, and new therapeutics to treat these complications are required urgently. Triethylenetetramine (TETA) is one such experimental therapeutic that acts to chelate excess copper (II) in diabetic tissues and reduce oxidative stress and cellular damage. METHODS: Here we have performed two independent metabolomic studies of serum to assess the suitability of the streptozotocin (STZ)-induced rat model for studying diabetes and to define metabolite-related changes associated with TETA treatment. Ultraperformance liquid chromatography-mass spectrometry studies of serum from non diabetic/untreated, non-diabetic/TETA-treated, STZ-induced diabetic/untreated and STZ-induced diabetic/TETA-treated rats were performed followed by univariate and multivariate analysis of data. RESULTS: Multiple metabolic changes related to STZ induced diabetes, some of which have been reported previously in other animal and human studies, were observed, including changes in amino acid, fatty acid, glycerophospholipid and bile acid metabolism. Correlation analysis suggested that treatment with TETA led to a reversal of diabetes-associated changes in bile acid, fatty acid, steroid, sphingolipid and glycerophospholipid metabolism and proteolysis. CONCLUSIONS: Metabolomic studies have shown that the STZ-induced rat model of diabetes is an appropriate model system to undertake research into diabetes and potential therapies as several metabolic changes observed in humans and other animal models were also observed in this study. Metabolomics has also identified several biological processes and metabolic pathways implicated in diabetic complications and reversed following treatment with the experimental therapeutic TETA. PMID- 22546716 TI - WHOLEheart study participant acceptance of wholegrain foods. AB - This qualitative study explored the concept of acceptance of wholegrain foods in an adult population in the UK. Data was generated via focus groups with volunteers from a randomised controlled wholegrain based dietary intervention study (the WHOLEheart study). WHOLEheart volunteers, who did not habitually eat wholegrain foods, were randomised to one of three experimental regimes: (1) incorporating 60 g/day whole grains into the diet for 16 weeks; (2) incorporating 60 g/day whole grains into the diet for 8 weeks, doubling to 120 g/day for the following 8 weeks; (3) a control group. Focus groups to examine factors relating to whole grain acceptability were held one month post-intervention. For participants incorporating whole grains into their diet, acceptance was dependent upon: (a) 'trial acceptance', relating to the taste, preparation and perceived impact of the wholegrain foods on wellbeing, and (b) 'dietary acceptance' which involved the compatibility and substitutability of whole grains with existing ingredients and meal patterns. Barriers to sustained intake included family taste preferences, cooking skills, price and availability of wholegrain foods. Although LDL lowering benefits of eating whole grains provided the impetus for the WHOLEheart study, participants' self-reported benefits of eating wholegrain foods included perceived naturalness, high fibre content, superior taste, improved satiety and increased energy levels provided a stronger rationale for eating whole grains. PMID- 22546715 TI - A bone marrow toxicity model for 223Ra alpha-emitter radiopharmaceutical therapy. AB - Ra-223, an alpha-particle emitting bone-seeking radionuclide, has recently been used in clinical trials for osseous metastases of prostate cancer. We investigated the relationship between absorbed fraction-based red marrow dosimetry and cell level-dosimetry using a model that accounts for the expected localization of this agent relative to marrow cavity architecture. We show that cell level-based dosimetry is essential to understanding potential marrow toxicity. The GEANT4 software package was used to create simple spheres representing marrow cavities. Ra-223 was positioned on the trabecular bone surface or in the endosteal layer and simulated for decay, along with the descendants. The interior of the sphere was divided into cell-size voxels and the energy was collected in each voxel and interpreted as dose cell histograms. The average absorbed dose values and absorbed fractions were also calculated in order to compare those results with previously published values. The absorbed dose was predominantly deposited near the trabecular surface. The dose cell histogram results were used to plot the percentage of cells that received a potentially toxic absorbed dose (2 or 4 Gy) as a function of the average absorbed dose over the marrow cavity. The results show (1) a heterogeneous distribution of cellular absorbed dose, strongly dependent on the position of the cell within the marrow cavity; and (2) that increasing the average marrow cavity absorbed dose, or equivalently, increasing the administered activity resulted in only a small increase in potential marrow toxicity (i.e. the number of cells receiving more than 4 or 2 Gy), for a range of average marrow cavity absorbed doses from 1 to 20 Gy. The results from the trabecular model differ markedly from a standard absorbed fraction method while presenting comparable average dose values. These suggest that increasing the amount of radioactivity may not substantially increase the risk of toxicity, a result unavailable to the absorbed fraction method of dose calculation. PMID- 22546717 TI - Tuberculosis in Saudi Arabia: prevalence and antimicrobial resistance. AB - Tuberculosis is a serious contagious disease caused by Mycobacterium tuberculosis and is endemic in many countries. Over the past two decades, there has been an increase in the number of multidrug-resistant TB and extensively drug-resistant TB cases around the world. As in many countries, TB is common in Saudi Arabia. The disease is particularly relevant in the Kingdom because of its population dynamics including a large number of resident expatriates mainly from TB endemic regions and the influx of millions of pilgrims to the country each year during the Hajj and Umrah seasons. This review investigates the prevalence and antimicrobial resistance among M. tuberculosis isolates from Saudi Arabia, highlighting the variations in rates in different geographical areas with particularly high rates in the main cities and regions hosting the annual pilgrimage. The review also refers to the measures needed to prevent and control TB transmission in the country. PMID- 22546718 TI - Low frequency of ertapenem-resistant intra-abdominal isolates of Escherichia coli from Latin America: susceptibility, ESBL-occurrence, and molecular characterisation (SMART 2008-2009). AB - The Study for Monitoring Antimicrobial Resistance Trends is an ongoing multi-year surveillance study that tracks worldwide antimicrobial resistance trends among aerobic and facultatively anaerobic Gram-negative bacilli isolated from intra abdominal infections. During 2008-2009, 1366 isolates of Escherichia coli were collected from 19 investigator sites in 11 Latin American countries. Of the 1366 isolates, 323 (23.6%) were extended spectrum beta-lactamase (ESBL)-positive. Overall, the most effective agents tested were imipenem, ertapenem, and amikacin with susceptibilities of >=96%. Against ESBL-positive isolates, only imipenem and ertapenem exhibited susceptibility >=90%. Based on the use of the new Clinical and Laboratory Standards Institute clinical breakpoints for ertapenem (resistance >=1 MUg/ml), resistance to ertapenem among all E. coli isolates was only 0.3% (4/1366) throughout the region, ranging from 0% in several countries up to 1.2% in Ecuador. Against ESBL-positive isolates only, resistance to ertapenem in Latin America overall was 0.9% (3/323), with a maximum of 9.1% (1/11) observed in Argentina. PMID- 22546719 TI - Serotype distribution and antimicrobial resistance of invasive Streptococcus pneumoniae isolates in Bulgaria before the introduction of pneumococcal conjugate vaccine. AB - The 10-valent pneumococcal conjugate vaccine (PCV10) was introduced as a mandatory vaccine in Bulgaria in April 2010. We report on the serotype distribution and the antimicrobial resistance of 222 invasive Streptococcus pneumoniae isolates collected from all age groups before the introduction of PCV10. PCV7, PCV10, and PCV13 covered 43.7, 59.9, and 78.8% of all invasive pneumococcal strains, and 64.2, 79.1, and 89.6% of isolates involving children less than 5 years of age. Penicillin resistance was found in 30.1% of the isolates responsible for meningitis and in 5.0% of isolates responsible for other invasive infections. Overall, erythromycin resistance was found in 19.4% of all invasive strains. The erm(B) was the most prevalent pneumococcal macrolide resistance genotype (63.2%) and dual mechanisms of both genes the erm(B) and mef(E) were detected in 15.8% of 19 erythromycin resistant isolates during the period 2006-2010. The prevalence and spread of serotypes 19F, 6B, and 19A during the last period may have contributed to the high predominance of erm(B) genotype in comparison of mef genotype, which was predominant in our country among erythromycin-resistant isolates before 2005. Continuing surveillance is required after the recent introduction of PCV10 in order to observe future developments of any serotype changes in the Bulgarian population, as well as surveillance of antimicrobial susceptibility of invasive S. pneumoniae isolates. PMID- 22546720 TI - Effect of nikkomycin Z and 50% human serum on the killing activity of high concentration caspofungin against Candida species using time-kill methodology. AB - Caspofungin and nikkomycin Z (NIK) efficacy alone and in combination were tested against seven Candida species showing or not showing paradoxical growth (PG) against caspofungin in time-kill test in RPMI-1640. Selected isolates against caspofungin and NIK were also tested in 50% serum. PG was always eliminated by NIK as well as by serum. In the serum, 1 and 16 MUg/ml caspofungin yielded 0.14 4.0 and 0.34-4.0 log CFU decreases from the starting inocula for C. albicans, C. glabrata, C. tropicalis, and C. dubliniensis, respectively. CFU decrease (0.10 2.08 log) at 16 MUg/ml, but not at lower caspofungin concentration was noted against C. parapsilosis, C. orthopsilosis, and C. metapsilosis. One C. parapsilosis isolate was not inhibited even by 16 MUg/ml caspofungin. Caspofungin against C. albicans, C. glabrata, C. tropicalis, and C. dubliniensis maintained its activity in serum at even 1 MUg/ml concentration. PG seems to an in vitro phenomenon, without clinical relevance. PMID- 22546722 TI - Determination of doripenem penetration into human prostate tissue and assessment of dosing regimens for prostatitis based on site-specific pharmacokinetic pharmacodynamic evaluation. AB - Prostatic hypertrophy patients prophylactically received a 0.5-hour infusion of doripenem (250 or 500 mg) before transurethral resection of the prostate. Doripenem concentrations in plasma and prostate tissue were measured chromatographically, and analysed pharmacokinetically using a three-compartment model. The approved doripenem regimens were assessed based on the time above the minimum inhibitory concentration for bacteria (T>MIC, % of 24 hours), an indicator for antibacterial effects, at the prostate. The prostate tissue/plasma ratios were 17.3% for the maximum drug concentration and 18.7% for the area under the drug concentration-time curve, and they were irrespective of the dose. Against Escherichia coli and Klebsiella species isolates, 500 mg once daily achieved a >90% probability of attaining the bacteriostatic target (20% T>MIC) in prostate tissue, and 500 mg twice daily achieved a >90% probability of attaining the bactericidal target (40% T>MIC) in prostate tissue. PMID- 22546721 TI - Penetration of prulifloxacin into sinus mucosa of patients undergoing paranasal sinus elective endoscopic surgery. AB - The aim of this study was to assess the concentration of ulifloxacin, the active metabolite of prulifloxacin, in sinuses mucosa and plasma of patients with chronic rhinosinusitis, requiring sinus elective endoscopic surgery. Thirty-nine patients (30 males, 9 females; age range 22-77 years) with chronic sinusitis were enrolled, 35 were treated with the investigational medication. Samples from four untreated patients were used to validate the analytical method, while four treated patients dropped out before surgery. One 600 mg prulifloxacin tablet once daily was administered for 5 days before surgery. The last dosing was scheduled from 2 to 12 hours from tissue and plasma sampling. In each patient, two samples of paranasal sinus mucosa (from ethmoid and turbinate, respectively) and one blood sample were collected. Concentrations of ulifloxacin in plasma and sinuses mucosa were measured using validated bioanalytical LC/MS/MS methods. Individual and mean ulifloxacin concentrations in tissues were always higher than the relevant plasma levels. The highest concentrations were observed between 2.5 and 4.5 hours after the last dosing in all districts. The mean tissue/plasma ratios were 2.5 and 3.0 for ethmoid and turbinate, respectively. Data expressed as Area Under the Curves (AUC+/-SD) showed that ulifloxacin concentrations in the ethmoid were slightly higher (18.68+/-6.48 MUg/g*h) than in turbinate (15.00+/-2.89 MUg/g*h), and definitely higher than in plasma (6.32+/-1.14 MUg/ml*h). The AUC ratios between tissues and plasma were 3.0 for ethmoides and 2.4 for turbinates. One patient reported two treatment-related episodes of diarrhea, which spontaneously resolved after the drug suspension. Results from this study seem to suggest that prulifloxacin showed good distribution in sinus tissues, where it reaches concentrations significantly higher than in plasma. These findings strongly call for confirmatory clinical trials in patients with bacterial rhinosinusitis. PMID- 22546723 TI - Effects of first antiretroviral regimen on lipid levels in HIV (+) individuals. AB - OBJECTIVE: To evaluate the long-term effects of different boosted protease inhibitors (bPIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) based antiretroviral regimens on lipid levels in HIV seropositive individuals who have not received lipid-lowering agents. METHODS: Data consisted of 595 patients participating in the population-based Athens Multicenter Cohort Study who were consistently followed up during 1996-2008. RESULTS: In naive patients, lipid parameters increased sharply during the first 3 months of antiretroviral therapy and reached a plateau level approximately 6-9 months after therapy initiation. The plateau levels remained almost stable for up to 3.5 years. In general, bPIs exerted a more pronounced effect compared to NNRTIs. CONCLUSIONS: The administration of PI- or NNRTI-based regimens especially in naive but also in unboosted PI experienced patients provoked a sharp increase in lipid levels that remained stable in higher levels for more than 3 years. PMID- 22546724 TI - Expression and induction by dexamethasone of ABC transporters and nuclear receptors in a human T-lymphocyte cell line. AB - The efficacy of drugs acting within lymphocytes, like antiretroviral drugs in the treatment of HIV infection, depends on their intracellular concentrations modulated by efflux proteins like ABCB1 (P-glycoprotein). In lymphocytes, two glucocorticoids, prednisone and prednisolone, have been shown to induce ABCB1 activity. Yet, no data exist regarding dexamethasone (DEX). We report the modulation of ABC transporters and nuclear receptors' expression by DEX in a commonly used model of human lymphocytes. CCRF-CEM cells were exposed to DEX (100 nM, 2 MUM) for 24 to 72 hours. ABCB1 activity was measured using DiOC(6) efflux in flow cytometry. Gene expression levels were quantified by qRT-PCR. ABCB1 activity and mRNA expression increased with DEX concentrations and incubation times. DEX (1 MUM, 24 h) increased significantly ABCB1 and GR mRNA expression levels by around 8- and 3.5-fold, respectively (P<10(-6)). ABCB1 induction by DEX in CCRF-CEM cells suggests a potential risk of interaction in lymphocytes when associating DEX to ABCB1 substrates in antiretroviral multitherapies in vivo. PMID- 22546725 TI - Simplification to monotherapy with lopinavir/ritonavir in adolescents with vertically acquired HIV-1 infection. AB - In recent years, the use of boosted protease inhibitors monotherapy has become increasingly important, especially considering the advantages in terms of costs, tolerability, and simplification. Despite that, knowledge about the efficacy and safety of this approach in HIV-1-infected adolescents who have acquired HIV-1 infection through perinatal transmission is still limited. We report here our experience with two adolescents who have been successfully treated with lopinavir/ritonavir monotherapy. PMID- 22546726 TI - Imipenem resistance in Pseudomonas aeruginosa of animal origin. PMID- 22546727 TI - Biofilm production by Candida isolates from a survey of invasive fungal infections in Italian intensive care units. PMID- 22546728 TI - Cross-language identification of long-term average speech spectra in Korean and English: toward a better understanding of the quantitative difference between two languages. AB - OBJECTIVE: To identify the quantitative differences between Korean and English in long-term average speech spectra (LTASS). DESIGN: Twenty Korean speakers, who lived in the capital of Korea and spoke standard Korean as their first language, were compared with 20 native English speakers. For the Korean speakers, a passage from a novel and a passage from a leading newspaper article were chosen. For the English speakers, the Rainbow Passage was used. The speech was digitally recorded using GenRad 1982 Precision Sound Level Meter and GoldWave(r) software and analyzed using MATLAB program. RESULTS: There was no significant difference in the LTASS between the Korean subjects reading a news article or a novel. For male subjects, the LTASS of Korean speakers was significantly lower than that of English speakers above 1.6 kHz except at 4 kHz and its difference was more than 5 dB, especially at higher frequencies. For women, the LTASS of Korean speakers showed significantly lower levels at 0.2, 0.5, 1, 1.25, 2, 2.5, 6.3, 8, and 10 kHz, but the differences were less than 5 dB. Compared with English speakers, the LTASS of Korean speakers showed significantly lower levels in frequencies above 2 kHz except at 4 kHz. The difference was less than 5 dB between 2 and 5 kHz but more than 5 dB above 6 kHz. CONCLUSIONS: To adjust the formula for fitting hearing aids for Koreans, our results based on the LTASS analysis suggest that one needs to raise the gain in high-frequency regions. PMID- 22546729 TI - Differential recognition of pitch patterns in discrete and gliding stimuli in congenital amusia: evidence from Mandarin speakers. AB - This study examined whether "melodic contour deafness" (insensitivity to the direction of pitch movement) in congenital amusia is associated with specific types of pitch patterns (discrete versus gliding pitches) or stimulus types (speech syllables versus complex tones). Thresholds for identification of pitch direction were obtained using discrete or gliding pitches in the syllable /ma/ or its complex tone analog, from nineteen amusics and nineteen controls, all healthy university students with Mandarin Chinese as their native language. Amusics, unlike controls, had more difficulty recognizing pitch direction in discrete than in gliding pitches, for both speech and non-speech stimuli. Also, amusic thresholds were not significantly affected by stimulus types (speech versus non speech), whereas controls showed lower thresholds for tones than for speech. These findings help explain why amusics have greater difficulty with discrete musical pitch perception than with speech perception, in which continuously changing pitch movements are prevalent. PMID- 22546730 TI - Right up there: hemispatial and hand asymmetries of altitudinal pseudoneglect. AB - BACKGROUND: Pseudoneglect is a normal left sided spatial bias observed with attempted bisections of horizontal lines and a normal upward bias observed with attempted bisections of vertical lines. Horizontal pseudoneglect has been attributed to right hemispheric dominance for the allocation of attention. The goal of this study was to test the hypothesis that the upward bias in vertical line bisection may also relate to right hemispheric dominance for the allocation of attention and/or action-intention. METHODS: Twenty right handed healthy adults were asked to bisect vertical lines presented in the midsagittal plane (center space) and in sagittal planes to the left and right of the midsagittal plane (left and right hemispace) when using a pen held in either the right or left hand. RESULTS: Vertical line bisections were biased upward in all three sagittal planes and higher in left than right hemispace. However, bisections made with the left hand were lower than those made with the right hand. DISCUSSION: Whereas these results suggest a left hemispace-right hemispheric visuospatial attentional upward bias and a relative left hemispheric-right hand upward action-intentional bias, further studies are needed to document this intentional versus attentional bias and to understand the brain mechanisms that produce these biases. PMID- 22546731 TI - How chunks, long-term working memory and templates offer a cognitive explanation for neuroimaging data on expertise acquisition: a two-stage framework. AB - Our review of research on PET and fMRI neuroimaging of experts and expertise acquisition reveals two apparently discordant patterns in working-memory-related tasks. When experts are involved, studies show activations in brain regions typically activated during long-term memory tasks that are not observed with novices, a result that is compatible with functional brain reorganization. By contrast, when involving novices and training programs, studies show a decrease in brain regions typically activated during working memory tasks, with no functional reorganization. We suggest that the latter result is a consequence of practice periods that do not allow important structures to be completely acquired: knowledge structures (i.e., Ericsson and Kintsch's retrieval structures; Gobet and Simon's templates) and in a lesser way, chunks. These structures allow individuals to improve performance on working-memory tasks, by enabling them to use part of long-term memory as working memory, causing a cerebral functional reorganization. Our hypothesis is that the two brain activation patterns observed in the literature are not discordant, but involve the same process of expertise acquisition in two stages: from decreased activation to brain functional reorganization. The dynamic of these two physiological stages depend on the two above-mentioned psychological constructs: chunks and knowledge structures. PMID- 22546732 TI - Evaluation of dose-volume metrics for microbeam radiation therapy dose distributions in head phantoms of various sizes using Monte Carlo simulations. AB - This work evaluates four dose-volume metrics applied to microbeam radiation therapy (MRT) using simulated dosimetric data as input. We seek to improve upon the most frequently used MRT metric, the peak-to-valley dose ratio (PVDR), by analyzing MRT dose distributions from a more volumetric perspective. Monte Carlo simulations were used to calculate dose distributions in three cubic head phantoms: a 2 cm mouse head, an 8 cm cat head and a 16 cm dog head. The dose distribution was calculated for a 4 * 4 mm2 microbeam array in each phantom, as well as a 16 * 16 mm2 array in the 8 cm cat head, and a 32 * 32 mm2 array in the 16 cm dog head. Microbeam widths of 25, 50 and 75 um and center-to-center spacings of 100, 200 and 400 um were considered. The metrics calculated for each simulation were the conventional PVDR, the peak-to-mean valley dose ratio (PMVDR), the mean dose and the percentage volume below a threshold dose. The PVDR ranged between 3 and 230 for the 2 cm mouse phantom, and between 2 and 186 for the 16 cm dog phantom depending on geometry. The corresponding ranges for the PMVDR were much smaller, being 2-49 (mouse) and 2-46 (dog), and showed a slightly weaker dependence on phantom size and array size. The ratio of the PMVDR to the PVDR varied from 0.21 to 0.79 for the different collimation configurations, indicating a difference between the geometric dependence on outcome that would be predicted by these two metrics. For unidirectional irradiation, the mean lesion dose was 102%, 79% and 42% of the mean skin dose for the 2 cm mouse, 8 cm cat and 16 cm dog head phantoms, respectively. However, the mean lesion dose recovered to 83% of the mean skin dose in the 16 cm dog phantom in intersecting cross-firing regions. The percentage volume below a 10% dose threshold was highly dependent on geometry, with ranges for the different collimation configurations of 2-87% and 33-96% for the 2 cm mouse and 16 cm dog heads, respectively. The results of this study illustrate that different dose-volume metrics exhibit different functional dependences on MRT geometry parameters, and suggest that reliance on the PVDR as a predictor of therapeutic outcome may be insufficient. PMID- 22546733 TI - The effects of active warming on patient temperature and pain after total knee arthroplasty. AB - BACKGROUND: Total knee arthroplasty (TKA) is a procedure with associated risks of inadvertent perioperative hypothermia and significant postoperative pain. Hypothermia may affect patients' experience of postoperative pain, although the link is not well understood. OBJECTIVE: The aim of this prospective, randomized controlled trial was to determine the efficacy of a patient-controlled active warming gown in optimizing patients' perioperative body temperature and in diminishing postoperative pain after TKA. METHODS: Thirty patients who would be undergoing TKA received either a standard hospital gown and prewarmed standard cotton blanket (n = 15) or a patient-controlled, forced-air warming gown (n = 15). RESULTS: Although pain scores were not significantly different in the two groups (P = 0.08), patients who received warming gowns had higher temperatures (P < 0.001) in the postanesthesia care unit, used less opioid (P = 0.05) after surgery, and reported more satisfaction (P = 0.004) with their thermal comfort than did patients who received standard blankets. These findings indicate that patient-controlled, forced-air warming gowns can enhance perioperative body temperature and improve patient satisfaction. Patients who use warming gowns may also need less opioid to manage their postoperative pain. CONCLUSIONS: Nurses should ensure that effective patient warming methods are employed in all patients, particularly in patients with compromised thermoregulatory systems (such as older adults), and in surgeries considered to be exceptionally painful (such as TKA). PMID- 22546734 TI - Posterior reversible encephalopathy syndrome: a case study. AB - OVERVIEW: Posterior reversible encephalopathy syndrome (PRES) is a rare neurologic disorder characterized by an acute increase in blood pressure, and by headaches, altered mental status, seizures, and visual loss. It is usually seen on computed tomographic scans as white-matter vasogenic edema predominantly affecting the posterior occipital and parietal lobes of the brain. Risk factors include malignant hypertension, eclampsia, medications such as immunosuppressants (including tacrolimus and cyclosporine), chemotherapy, biotherapy, and renal failure. Early recognition of the signs and symptoms of PRES, particularly identifying and treating high blood pressure, can prevent permanent neurologic disability. PMID- 22546735 TI - Occult infection with hepatitis C virus: friend or foe? AB - Hepatitis C virus (HCV) infection is a global pandemic associated with a growing disease burden due to cirrhosis and the consequent morbidity and mortality. Transmission is largely via blood-to-blood contact. Following primary infection, a minority of individuals clear the infection predominantly via cellular immune mechanisms, whereas the majority become chronically infected. Recent data suggest that a third outcome may also be possible, termed 'occult' infection in which subjects who are known, or suspected to have previously been infected with HCV, no longer have viral RNA in their serum at levels detectable by sensitive commercial assays, but do have virus detected by ultra-sensitive techniques. Occult infection has also been detected in peripheral blood mononuclear cells, which may indicate an extra-hepatic reservoir of the virus. Although the clinical significance of occult infection remains unknown, most authors have raised concerns of recrudescent infection. Here we critically review the published literature, suggest further avenues of investigation and propose that occult infection may be beneficial to the host by maintaining immunological memory to protect against reinfection. PMID- 22546736 TI - Aberrant accumulation of interleukin-10-secreting neutrophils in TRAF2-deficient mice. AB - Highly coordinated expression of inflammatory and anti-inflammatory cytokines is crucial for maintaining homeostasis of the gut that is constantly exposed to large amounts of commensal bacteria. We have previously reported that tumor necrosis factor (TNF) receptor-associated factor (Traf)2(-/-) mice spontaneously develop severe colitis and that the development of colitis largely depends on TNFalpha-dependent apoptosis of colonic epithelial cells. However, the detailed molecular mechanisms underlying the immunological disorders of Traf2(-/-) mice are not fully understood. Here we show that interleukin (IL)-10-secreting neutrophils accumulated in peripheral blood and bone marrow (BM) cells from Traf2(-/-) mice compared with those from wild-type mice. Treatment of Traf2(-/-) mice with neutralizing antibody against TNFalpha or crossing Traf2(-/-) mice with Tnfr1(-/-) mice reduced the percentages of IL-10-secreting neutrophils, suggesting that the development of IL-10-secreting neutrophils largely depended on TNFalpha signals. Moreover, stimulation of BM cells from wild-type mice with lipopolysaccharide and Pam3CS(K)4, a ligand for Toll-like receptor 4 and 2, respectively, induced differentiation of BM cells into IL-10-secreting neutrophils. These results suggest that the development of IL-10-secreting neutrophils is not restricted to Traf2(-/-) mice, but could be generalized to wild-type mice under certain conditions such as inflammation. Finally, combined treatment of Traf2(-/-) mice with neutralizing antibodies against TNFalpha and IL 10, but not each antibody alone, substantially ameliorated colitis and prolonged survival. Together, abrogation of immunosuppressive conditions mediated by IL-10 secreting neutrophils might be an alternative strategy to treat chronic inflammatory diseases at least under certain conditions. PMID- 22546737 TI - Quantitative high-throughput metabolomics: a new era in epidemiology and genetics. PMID- 22546738 TI - First layer compression and transition to standing second layer of terephthalic acid on Cu(100). AB - Terephthalic acid on metal surfaces is a system of high interest for interfacial layers as well as for use in generating surface nanostructures by supramolecular self-assembly. Here we demonstrate structural transitions upon compression of the first layer as well as a significant transition from a flat lying chemisorbed first monolayer to a standing second layer. The second layer structure is stable at 150 degrees C, but a weakly bound state is observed to desorb molecularly below that temperature, likely a transient mobile state during annealing. Molecular resolution scanning tunnelling microscopy is complemented by X-ray photoelectron spectroscopy and thermal desorption spectroscopy in this study. These results provide general insight in the development of self-assembled organic thin films at surfaces, especially with regard to the nature of the metal/organic interface and growth transitions to maximize first layer packing and obtain a second layer that bridges commensurability with the substrate and a more bulk-like structure. PMID- 22546739 TI - Cutaneous leishmaniasis in the dorsal skin of hamsters: a useful model for the screening of antileishmanial drugs. AB - Traditionally, hamsters are experimentally inoculated in the snout or the footpad. However in these sites an ulcer not always occurs, measurement of lesion size is a hard procedure and animals show difficulty to eat, breathe and move because of the lesion. In order to optimize the hamster model for cutaneous leishmaniasis, young adult male and female golden hamsters (Mesocricetus auratus) were injected intradermally at the dorsal skin with 1 to 1.5 x l0(7) promastigotes of Leishmania species and progression of subsequent lesions were evaluated for up to 16 weeks post infection. The golden hamster was selected because it is considered the adequate bio-model to evaluate drugs against Leishmania as they are susceptible to infection by different species. Cutaneous infection of hamsters results in chronic but controlled lesions, and a clinical evolution with signs similar to those observed in humans. Therefore, the establishment of the extent of infection by measuring the size of the lesion according to the area of indurations and ulcers is feasible. This approach has proven its versatility and easy management during inoculation, follow up and characterization of typical lesions (ulcers), application of treatments through different ways and obtaining of clinical samples after different treatments. By using this method the quality of animal life regarding locomotion, search for food and water, play and social activities is also preserved. PMID- 22546740 TI - Diabetes buddies: peer support through a mobile phone buddy system. AB - PURPOSE: The purpose of this study is to test the feasibility and acceptability of a mobile phone-based peer support intervention among women in resource-poor settings to self-manage their diabetes. Secondary goals were to evaluate the intervention's effectiveness to motivate diabetes-related health choices. METHODS: Women with diabetes (n = 22) in Cape Town, South Africa, participated in a 12-week program focused on providing and applying knowledge of health routines to manage diabetes. Women were linked with a buddy via a mobile phone for support and were questioned daily about a health behavior via text message. Women were assessed at recruitment and then 3 and 6 months later by a trained interviewer using a mobile phone for data collection. The women were evaluated on technology uptake, reduction of body mass index, blood glucose levels, and increases in positive coping and general health-seeking behaviors. RESULTS: Women exchanged 16 739 text messages to buddies and received 3144 texts from the project. Women responded to 29% of texted questions (n = 1321/14 582). Women attended at least 9 of 12 possible intervention sessions; a third attended all 12 sessions (n = 8/22). Between baseline and 3 months, women increased their sleep and reported a higher level of positive action and social support coping, yet blood glucose increased by 3.3 points. From 3 to 6 months, spiritual hope decreased and diastolic blood pressure increased. One year later, the 22 women continue to attend meetings. CONCLUSIONS: Mobile phones are an easy and reliable way to provide peer support and disseminate health messages. Both positive and negative changes were observed in this pilot study. PMID- 22546741 TI - Correlates of medication nonadherence among Latinos with type 2 diabetes. AB - PURPOSE: The purpose of this study is to assess factors related to diabetes medication nonadherence in a sample of predominantly Spanish-speaking Mexican origin adults residing along the US-Mexico border. METHODS: As part of a randomized controlled trial, 302 patients randomly sampled from a clinic roster completed a baseline interview. Medication nonadherence was assessed with the Morisky Medication Adherence Scale. Consistent with the framework proposed by Venturini et al, four factors were examined: patient-related attributes, drug regimen characteristics and complexity, health status, and patient-provider interaction characteristics. RESULTS: Sixty percent of the patients were classified as nonadherent. Men, those who engaged in diabetes control behaviors less frequently, and individuals with depression were more likely to be classified as nonadherent. Among those who were Spanish-dominant, education and self-rated health also were significantly and negatively related to medication adherence; patients with a high school education or greater and those who more positively rated their health were more likely to be classified as nonadherent compared to those with less than a high school education and those who rated their health as poor. CONCLUSIONS: Results reflect potentially higher medication nonadherence rates for Latinos with type 2 diabetes living in rural communities along the US-Mexico border. Additionally, this study supports the need to address strategies to support medication adherence, including addressing depression, for diabetes control. Strategies to promote adherence among Latino men are sorely needed, as are strategies to address forgetfulness and carelessness regarding diabetes medicine taking. PMID- 22546742 TI - The microbiota of the gut in preschool children with normal and excessive body weight. AB - The aim of this study was to investigate the gut microbiota in preschool children with and without overweight and obesity. Twenty overweight or obese children and twenty children with BMI within the normal range (age: 4-5 years) were recruited from the south of Sweden. The gut microbiota was accessed by quantitative PCR (qPCR) and terminal restriction fragment length polymorphism and calprotectin was measured in feces. Liver enzymes were quantified in obese/overweight children. The concentration of the gram-negative family Enterobacteriaceae was significantly higher in the obese/overweight children (P = 0.036), whereas levels of Desulfovibrio and Akkermansia muciniphila-like bacteria were significantly lower in the obese/overweight children (P = 0.027 and P = 0.030, respectively). No significant differences were found in content of Lactobacillus, Bifidobacterium or the Bacteroides fragilis group. The diversity of the dominating bacterial community tended to be less diverse in the obese/overweight group, but the difference was not statistically significant. Concentration of Bifidobacterium was inversely correlated to alanine aminotransferase (ALT) in obese/overweight children. The fecal levels of calprotectin did not differ between the study groups. These findings indicate that the gut microbiota differed among preschool children with obesity/overweight compared with children with BMI within the normal range. PMID- 22546743 TI - The relation of adiposity to cognitive control and scholastic achievement in preadolescent children. AB - Adiposity may be negatively associated with cognitive function in children. However, the findings remain controversial, in part due to the multifaceted nature of cognition and perhaps the lack of accurate assessment of adiposity. The aim of this study was to clarify the relation of weight status to cognition in preadolescent children using a comprehensive assessment of cognitive control, academic achievement, and measures of adiposity. Preadolescent children between 7 and 9 years (n = 126) completed Go and NoGo tasks, as well as the Wide Range Achievement Test 3rd edition (WRAT3), which measures achievement in reading, spelling, and arithmetic. In addition to BMI, fat mass was measured using dual energy X-ray absorptiometry (DXA). Data were analyzed with multiple regression analysis, controlling for confounding variables. Analyses revealed that BMI and fat mass measured via DXA were negatively associated with cognitive control, as children with higher BMI and fat mass exhibited poorer performance on the NoGo task requiring extensive amounts of inhibitory control. By contrast, no relation of weight status to performance was observed for the Go task requiring smaller amounts of cognitive control. Higher BMI and fat mass were also associated with lower academic achievement scores assessed on the WRAT3. These data suggest that adiposity is negatively and selectively associated with cognitive control in preadolescent children. Given that cognitive control has been implicated in academic achievement, the present study provides an empirical basis for the negative relationship between adiposity and scholastic performance. PMID- 22546748 TI - Effectiveness of a decision-training aid on referral prioritization capacity: a randomized controlled trial. AB - BACKGROUND: In the community mental health field, occupational therapy students lack the capacity to prioritize referrals effectively. OBJECTIVE: The purpose of this study was to test the effectiveness of a clinical decision-training aid on referral prioritization capacity. DESIGN: A double-blind, parallel-group, randomized controlled trial was conducted using a judgment analysis approach. SETTING: Each participant used the World Wide Web to prioritize referral sets at baseline, immediate posttest, and 2-wk follow-up. The intervention group was provided with training after baseline testing; control group was purely given instructions to continue with the task. PARTICIPANTS: One hundred sixty-five students were randomly allocated to intervention (n = 87) or control (n = 81). Intervention. Written and graphical descriptions were given of an expert consensus standard explaining how referral information should be used to prioritize referrals. MEASUREMENTS: Participants' prioritization ratings were correlated with the experts' ratings of the same referrals at each stage of testing, as well as to examine the effect on mean group scores, regression weights, and the lens model indices. RESULTS: At baseline, no differences were found between control and intervention on rating capacity or demographic characteristics. Comparison of the difference in mean correlation baseline scores of the control and intervention group compared with immediate posttest showed a statistically significant result that was maintained at 2-wk follow-up. The effect size was classified as large. At immediate posttest and follow-up, the intervention group improved rating capacity, whereas the control group's capacity remained poor. The results of this study indicate that the decision-training aid has a positive effect on referral prioritization capacity. CONCLUSIONS: This freely available, Web-based decision-training aid will be a valuable adjunct to the education of these novice health professionals internationally. PMID- 22546749 TI - Expected net present value of sample information: from burden to investment. AB - The Expected Value of Information Framework has been proposed as a method for identifying when health care technologies should be immediately reimbursed and when any reimbursement should be withheld while awaiting more evidence. This framework assesses the value of obtaining additional evidence to inform a current reimbursement decision. This represents the burden of not having the additional evidence at the time of the decision. However, when deciding whether to reimburse now or await more evidence, decision makers need to know the value of investing in more research to inform a future decision. Assessing this value requires consideration of research costs, research time, and what happens to patients while the research is undertaken and after completion. The investigators describe a development of the calculation of the expected value of sample information that assesses the value of investing in further research, including an only-in research strategy and an only-with-research strategy. PMID- 22546750 TI - Choosing between hospitals: the influence of the experiences of other patients. AB - OBJECTIVE: Publicly available information on hospital performance is increasing, with the aim to support consumers when choosing a hospital. Besides general hospital information and information on outcomes of care, there is increasing availability of systematically collected information on experiences of other patients. The aim of this study was to assess the influence of previous patients' experiences relative to other information when choosing a hospital for surgical treatment. METHODS: Three hundred thirty-seven patient volunteers and 280 healthy volunteers (response rate of 52.4% and 93.3%, respectively) filled out an Internet-based questionnaire that included an adaptive choice-based conjoint analysis. They were asked to select hospital characteristics they would use for future hospital choice, compare hospitals, and choose the overall best hospital. Based on the respondents' choices, the relative importance (RI) of each hospital characteristic for each respondent was estimated using hierarchical Bayes estimation. RESULTS: Information based on previous patients' experience was considered at least as important as information provided by hospitals. "Report card regarding physician's expertise" had the highest RI (16.83 [15.37-18.30]) followed by "waiting time for outpatient clinic appointment" (14.88 [13.42 16.34]) and "waiting time for surgery" (7.95 [7.12-8.78]). Patient and healthy volunteers considered the same hospital attributes to be important, except that patient volunteers assigned greater importance to "positive judgment about physician communication" (7.65 v. 5.80, P < 0.05) and lower importance to "complications" (2.56 v. 4.22, P < 0.05). CONCLUSION: Consumers consider patient experience-based information at least as important as hospital-based information. They rely most on information regarding physicians' expertise, waiting time, and physicians' communication when choosing a hospital. PMID- 22546751 TI - Osteopathy improves the severity of irritable bowel syndrome: a pilot randomized sham-controlled study. AB - BACKGROUND: Effective therapies for irritable bowel syndrome (IBS) are disappointing. Therefore, IBS patients have a growing interest for alternative medicines including osteopathy. AIM: We aimed to evaluate the effect of osteopathy on the severity of IBS in a randomized sham-controlled trial. METHODS: We prospectively assigned 30 patients with IBS (23F, 7M, mean age 45.8+/-16.4 years) fulfilling the Rome III criteria in a 2/1 ratio to receive either osteopathy or sham osteopathy. Two separate sessions were performed at a 7-day interval (days 0 and 7) with a further 3 weeks of follow-up (day 28). The primary outcome included at least a 25% improvement in the IBS severity score at day 7. The secondary outcomes included the impact of IBS on quality of life, psychological factors, and bowel habits. RESULTS: The severity of IBS decreased in both groups at days 7 and 28. At day 7, this decrease was significantly more marked in patients receiving osteopathy compared with those receiving the sham procedure (-32.2+/-29.1 vs. -9.0+/-16.0, mean difference normalized to the baseline P=0.01). This difference did not persist at day 28 (P=0.4). Both anxiety and depression scores decreased without difference between groups. Stool frequency and consistency were not significantly modified. CONCLUSION: Osteopathy improves the severity of IBS symptoms and its impact on quality of life. Osteopathy should therefore be considered for future research as an effective complementary alternative medicine in the management of IBS symptoms. PMID- 22546752 TI - gamma-Glutamyl transferase: a marker of nonalcoholic fatty liver disease in patients with the metabolic syndrome. AB - OBJECTIVE: The incidence of metabolic syndrome has increased in Mexico and nonalcoholic fatty liver disease (NAFLD) is a common complication. The authors aimed to evaluate the role of hepatic enzymes as biomarkers for NAFLD in patients presenting metabolic syndrome. METHODS: We studied 193 nondiabetic individuals with metabolic syndrome identified from a population-based cross-sectional survey. To identify NAFLD, real-time gray-scale abdominal ultrasound was performed, and the right, left, and caudate hepatic lobules were observed to assess the size, echogenicity, and borders of the liver. All individuals answered a questionnaire for risk factors, and anthropometric measures and blood pressure were obtained. The concentration of hepatic enzymes and insulin in blood was measured and the Homeostatic Model Assessment index was calculated. RESULTS: A total of 160 individuals were identified as presenting NAFLD (82.9%). Body weight, BMI, and the waist-hip ratio increased as a direct result of the presence and severity of fatty liver. A similar situation was observed in the levels of triglyceride and hepatic enzymes aspartate aminotransferase and gamma glutamyltransferase (GGT), basal insulin level, and the Homeostatic Model Assessment index. In a multivariate model, the variables associated with the occurrence of NAFLD were sex, triglyceride and GGT levels, and obesity. CONCLUSION: The main factors that predict the occurrence of NAFLD are levels of triglyceride and GGT in the blood, as well as obesity. The accumulation of fat in the liver, in addition to increased oxidation and oxidative stress at the hepatic level, may be the mechanisms through which these factors increase the risk of NAFLD. PMID- 22546753 TI - N-acetyl-cysteine in the treatment of Parkinson's disease. What are we waiting for? AB - Parkinson's disease is an age-related neurodegenerative disorder that is ameliorated with levodopa. However, long-term use of this drug is limited by motor complications, postural instability and dementia resulting in the progression of the disease. Insights into the organization of the basal ganglia and knowledge of the mechanisms responsible for cell death in Parkinson's disease has permitted the development of putative neuro-protective drugs that might slow the disease progression. Although no drug has yet been established to alter the rate of disease progression, recent publications have confirmed previous results and hypotheses about the probable role of thiolic antioxidants on Parkinson's disease, demonstrating a significant reduction of dopaminergic neuronal degeneration in alpha-synuclein over expressing mice treated with oral N-acetyl cysteine. This thiolic antioxidant is a modified form of the natural amino acid cysteine, which is the precursor of the most potent intracellular antioxidant glutathione. Besides, increasing evidence has been accumulated in the last 10years about the beneficial effects of this thiolic antioxidant in experimental and pathologic states of the nervous system, including against neurotoxic substances. The present paper put forward the existing rationale evidence for the use of N-acetyl-cysteine alone or in combination with levodopa in the clinical management of this neurodegenerative disorder. PMID- 22546754 TI - HIF-1alpha/VEGF signaling pathway may play a dual role in secondary pathogenesis of cervical myelopathy. AB - Cervical spondylotic myelopathy (CSM) is one of the most common spinal cord disorders affecting the elderly. Yet the exact pathophysiology of CSM remains unclear. Vascular response to initial mechanical compression and associated ischemia may involve in secondary pathophysiology. Chronic compressive lesions to cervical cord resulting in lack of perfusion have established considerable evidences to support ischemia as an important pathogenesis both in patients and animal models, a similarity as that of acute spinal cord injury (SCI). In hypoxic condition following SCI, the up-regulation of vascular endothelial growth factor (VEGF), is consistent with increasing hypoxia induced factor-1alpha (HIF-1alpha) in acute periods. HIF-1alpha/VEGF signaling pathway is thought to play a dual role following SCI. In one hand, VEGF was demonstrated to be correlated with angiogenesis (protecting vascular endothelial cells, increasing blood vessel density and improving regional blood flow), neurogenesis (antiapoptotic, neurotrophic, attenuate axonal degradation), and locomotor ability improvement. In other hand, some studies revealed that VEGF have limited therapeutic effect, even exacerbate the secondary damage following SCI. VEGF administrations in acute or subacute periods result in elevation of blood-spinal cord barrier (BSCB) permeability even last for chronic course. BSCB permeability elevation initiates a secondary cascade of events involving excitotoxicity, infiltration of leukocytes and tissue edema. With comprehensive understanding of temporal and spatial of HIF-1alpha/VEGF signaling pathway, development of therapeutic strategies to promote new vessel growth while minimize the deleterious effects of VEGF-induced microvascular permeability, and thereby improve neurologic function, seems to be feasible and promising. PMID- 22546755 TI - Lipoxin receptor agonist, may be a potential treatment for hemorrhagic shock induced acute lung injury. AB - The main pathogenesis of acute lung injury induced by hemorrhagic shock is increasingly recognized as an inflammatory process. BML-111, a lipoxin receptor agonist, has been demonstrated to promote acute inflammatory resolution by reduction of pro-inflammatory cytokines, attenuation of neutrophilic infiltration, and increasing macrophage phagocytosis of apoptotic neutrophils. Meanwhile, lipoxins and lipoxin analogues have been reported to play pro resolving and anti-inflammatory effects in many disease models including cerebral ischemia, dorsal air pouch, peritonitis, and so on. Therefore, we hypothesize that BML-111 may be implicated in pathogenesis of hemorrhagic shock-induced acute lung injury. PMID- 22546756 TI - Cyclooxygenase-2 inhibitors induce anoikis in osteosarcoma via PI3K/Akt pathway. AB - COX-2, an inducible enzyme, is associated with inflammatory diseases and carcinogenesis. Overexpression of COX-2 occurs in many human malignancies, including osteosarcoma. In our study, we reported that Celecoxib, a cyclooxygenase-2 inhibitor, induces apoptosis in human osteosarcoma cell line MG 63 via down-regulation of PI3K/Akt. PI3K/Akt plays an essential role in the cell/extracellar matrix (ECM) and cell/cell adhesion. We hypothesize that COX-2 inhibitors induce anoikis in osteosarcoma via PI3K/Akt, resulted in lack of correct attachment and the down-regulations of beta-catenin, TrkB and E-cadherin, which play an essential role in the cell/extracellar matrix (ECM) and cell/cell adhesion. Meanwhile, apoptosis also be disclosed, such as DNA fragments and apoptotic bodies, activation of caspase-8, 9 and cleavage of PARP. With wortmannin, a specific PI3K inhibitor can simulate the effect of COX-2 inhibitors. If our hypothesis is correct, COX-2 inhibitors could cut down the occurrence of metastasis and facilitate the patient who may benefit from addition of COX-2 inhibitors to standard cytotoxic therapy. PMID- 22546757 TI - Allocentric lock in anorexia nervosa: new evidences from neuroimaging studies. AB - Individuals with anorexia nervosa (AN) have a disturbance in the way in which their body is experienced and tend to evaluate negatively their own body and body parts. It is controversial whether these symptoms are secondary to dysfunctions in the neuronal processes related to appetite and emotional regulation or reflect a primary disturbance in the way the body is experienced and remembered. According to the "Allocentric Lock Hypothesis--ALH" (http://dx.doi.org/10.1016/j.mehy.2011.10.039) individuals with AN may be locked to an allocentric (observer view) negative memory of the body that is no more updated by contrasting egocentric representations driven by perception. Recent neuroimaging studies are showing several structural and functional alterations in frame- and memory-related body-image-processing brain circuits that may support ALH. PMID- 22546758 TI - The extracellular signal-regulated kinase pathway may play an important role in mediating antidepressant-stimulated hippocampus neurogenesis in depression. AB - Understanding the reasons for the delayed action of antidepressants in patients with depression is an important step in the effort to understand the etiology and course of this disabling condition. Researches using animal models of depression find that depression is associated with impaired neurogenesis and structural plasticity in specific regions of the brain. Chronic treatment with antidepressants increases neurogenesis and reduces animal behaviors that are associated with depression. Other studies suggests that neurogenesis is an important component of the mechanism of action of both antidepressants and mood stabilizers. Moreover, the time course of increased neurogenesis is parallel to that of the behavioral effects, and animals with higher baseline hippocampus neurogenesis have a more rapid response to antidepressants. However, the molecular mechanisms that link antidepressants, neurogenesis and behavioral changes remain unknown. Previous research has shown that the extracellular signal regulated kinase (ERK) signaling pathway plays an important role in regulating neurogenesis and synaptic plasticity in the brain and is activated by antidepressants and mood stabilizers. We hypothesize that the ERK pathway is the mechanism by which antidepressants regulate neurogenesis in the hippocampus and, thus, should be considered a potential target for the development of new antidepressants. PMID- 22546759 TI - Hair follicle stem cells derived from single rat vibrissa via organ culture reconstitute hair follicles in vivo. AB - Hair follicle stem cells (HFSCs) are potentially useful for the treatment of skin injuries and diseases. To achieve clinical application, a prerequisite must be accomplished: harvesting enough HFSCs from limited skin biopsy. The commonly used sorting approach for isolating HFSCs, however, suffers from its intrinsic disadvantages, such as requirement of large-scale skin biopsy. Here, we report an efficient organ culture method to isolate and expand rat HFSCs from limited skin biopsy and these HFSCs could reconstitute the epidermis and the hair follicles (HFs). Seventy-three percent of cultured HFs formed hair follicle stem cell colonies from the bulge, and a single hair follicle provided all the HFSCs used in this research, demonstrating the high efficiency of this method. Quantitative RT-PCR and immunofluorescent staining results revealed that these stem cells obtained from the bulge highly expressed basal layer markers K14 and alpha-6 integrin, epithelial stem cell marker P63, and bulge stem cell marker K15. After long-term culture in vitro, GFP-labeled hair follicle stem cells formed new hair follicles, epidermis, and sebaceous glands following xenotransplantation into the back of nude mice. This study indicated that multipotent hair follicle stem cells could be efficiently harvested through organ culture from limited skin material-even a single hair follicle-and reconstitute hair follicles in vivo after long-term expansion culture, providing the basis for future clinical applications. PMID- 22546760 TI - Topotecan plus carboplatin and paclitaxel in first-line treatment of advanced ovarian cancer: a meta-analysis of randomized controlled trials. AB - OBJECTIVE: To evaluate whether the addition of topotecan can improve the efficacy of carboplatin and paclitaxel in first-line treatment of advanced epithelial ovarian cancer. METHODS: Meta-analysis was performed using a random effects model. RESULTS: Four randomized controlled trials with a total of 3632 patients were identified and included in the meta-analysis. No significant differences were observed in terms of progression-free survival (P=0.400), overall survival (P=0.502) and overall response rate (P=0.953) between patients treated with topotecan plus carboplatin and paclitaxel versus carboplatin and paclitaxel. However, there were significantly higher rates of grade 3-4 leucopenia (P=0.024), neutropenia (P<0.001), anaemia (P<0.001), and thrombopenia (P<0.001) in the topotecan plus carboplatin and paclitaxel group. No significant differences were observed in grade 3-4 nausea (P=0.352) and vomiting (P=0.092) between these two groups. CONCLUSION: Topotecan plus carboplatin and paclitaxel did not improve survival outcomes and caused more haematological toxicity for advanced ovarian cancer. PMID- 22546761 TI - Antimicrobial susceptibility among E. faecalis and E. faecium from France, Germany, Italy, Spain and the UK (T.E.S.T. Surveillance Study, 2004-2009). AB - We report on antimicrobial activity against E. faecalis and E. faecium collected in France, Germany, Italy, Spain, and the UK between 2004 and 2009 as part of the Tigecycline Evaluation and Surveillance Trial (UK in vitro data not included due to low isolate numbers). Overall, 1.1% (n=23/2068) of E. faecalis and 11.5% (n=103/893) of E. faecium were vancomycin-resistant. High levels of minocycline resistant E. faecalis were reported in Germany, Spain, France, and Italy (40.2 44.2%); levofloxacin resistance was high in Germany, Italy, and Spain (31.1 41.6%). Minocycline non-susceptibility increased significantly among E. faecalis in Spain and Italy (P<0.001). No tigecycline-resistant E. faecalis were reported. Among E. faecium, resistance ranged from 72.9% (France) to 93.3% (Germany) for ampicillin, from 56.1% (France) to 90.2% (Germany) for levofloxacin, and from 75.3% (Italy) to 94.7% (Germany) for penicillin. Levofloxacin non-susceptibility increased significantly among E. faecium in France and Spain (P<0.001). The lowest rates of antimicrobial resistance among E. faecium were reported for tigecycline (2/893; 0.2%) and linezolid (3/893; 0.3%). PMID- 22546762 TI - Prevalence of Ureaplasma urealyticum and Mycoplasma hominis infection in unselected infertile men. AB - In this study, we investigated the prevalence of Ureaplasma urealyticum and Mycoplasma hominis infection among 250 unselected infertile men, the presence of urogenital symptoms in infected men and the effects of these microorganisms on the conventional sperm parameters. Urethral samples were obtained using a swab inserted 3-4 cm into the urethral meatus. Ureaplasma urealyticum and Mycoplasma hominis were detected by the kit Mycofast R evolution 3 Elitech Microbiology (Elitech Microbiology, Signes, France). Ureaplasma urealyticum was detected in 15.6% of the cases and Mycoplasma hominis in 3.6%. One patients had a co infection with both pathogens. About 41% of the infertile patients with mycoplasma infection had urogenital symptoms. A lower number of patients with mycoplasma infection had normal sperm parameters compared with non-infected infertile men, but this frequency showed only a trend compared to non-infected patients (Chi-square=3.61; P=0.057), and a significantly higher percentage of patients with oligo-astheno-teratozoospermia (Chi-square=127.3; P<0.0001), or asthenozoospermia alone (Chi-square=5.74; P<0.05) compared to non-infected infertile patients. In conclusion, this study showed an elevated prevalence of Ureaplasma urealyticum and Mycoplasma hominis infection in unselected men attending an infertility outpatient clinic and that the presence of these microorganisms is associated with a higher percentage of patients with abnormal sperm parameters. PMID- 22546763 TI - In vitro activity of tigecycline against Acinetobacter baumannii isolates from a teaching hospital in Malaysia. AB - The In vitro susceptibility of clinical and environmental isolates of Acinetobacter baumannii to tigecycline and other antibiotics was determined by disk diffusion method. The E-test was used to determine the minimum inhibitory concentration (MIC). The growth curves of tigecycline treated environmental and clinical strains were established. Fifty-seven percent and 75% of the clinical and environmental isolates were MDR strains, respectively. Ninety-five percent of the clinical isolates were susceptible to tigecycline and 5% showed intermediate resistance with MIC ranging between 0.032 and 3 mg/l. Tigecycline susceptible and intermediate resistance among the environmental isolates were 40% and 60%, respectively, with a significantly lower MIC range of 0.5-4 mg/l. The bacterial growth curves demonstrated the higher ability of the environmental strains to tolerate the antibiotic effects than the clinical strains. The relatively high resistance profile among the environmental isolate suggests an insidious emergence of tigecycline resistance amongst A. baumannii. Strict infection control procedures are imperative to prevent the dissemination of tigecycline resistant A. baumannii strains in the hospital environment. PMID- 22546764 TI - Rapid molecular technique analysis of a KPC-3-producing Klebsiella pneumoniae outbreak in an Italian surgery unit. AB - The rapid emergence of KPC-producing Klebsiella pneumoniae has become a serious problem in health-care settings, increasing in frequency worldwide. These infections are worrisome, since the antimicrobial treatment options for infections due to multidrug-resistant strains are very limited, and outbreaks must be rapidly detected and controlled. A semi-automated, repetitive-sequence based PCR (rep-PCR) instrument (DiversiLab system) was evaluated in comparison with the pulse-field gel electrophoresis (PFGE) and multilocus sequence typing to investigate the outbreak of KPC-producing K. pneumoniae in a surgery unit at the University Hospital of Verona, Italy, as a rapid method for outbreak investigations. A selection of seven epidemiologically related K. pneumoniae showing resistance to carbapenem and three epidemiologically unrelated K. pneumoniae isolates were collected from patient with hospital-acquired infection. Among the epidemiologically related isolates, PFGE and Rep-PCR identified a unique pattern with more than 90% of homology. The concordance between DiversiLab and PFGE results confirmed the usefulness of rapid molecular techniques to investigate outbreaks due to multidrug-resistant bacteria. Moreover, this result could meet the international need for a harmonised typing tool, allowing the implementation of strict control measures to prevent dissemination of these organisms in health-care settings. PMID- 22546765 TI - Extended-spectrum and metallo-beta-lactamases among ceftazidime-resistant Pseudomonas aeruginosa in Riyadh, Saudi Arabia. AB - We investigated the extended-spectrum (ESBLs) and metallo-beta-lactamases (MBLs) among Pseudomonas aeruginosa isolates in Saudi Arabia. Disc susceptibility testing was performed on 200 P. aeruginosa isolates collected during 2010 at the Armed Forces Hospital in Riyadh, with MIC testing and phenotypic screening for ESBLs and MBLs carried out on those found to be ceftazidime resistant. Genes for ESBLs and MBLs were sought by PCR. Thirty-nine (19.5%) P. aeruginosa isolates were ceftazidime resistant, mostly with considerable resistance to other antibiotics except colistin. Twenty-three of these 39 (59%) appeared ESBL positive and 16 (41%) had MBLs. bla(VEB), and bla(GES) genes were found in 20 (86.95%), and 5 (21.74%) of 23 ESBL-positive isolates, respectively whilst bla(VIM) was detected in all 16 MBL-producers. bla(OXA-10-like) often accompanied bla(VEB), bla(VIM) or bla(GES). Several isolates had similar antibiogram and beta lactamase profiles, and may represent outbreaks; nevertheless, the collection was not dominated by any single clone. This dominance of acquired ceftazidime inactivating beta-lactamases, often in combination is in contrast to the situation in Europe and the USA, where most ceftazidime resistance in P. aeruginosa is attributable to AmpC and efflux. PMID- 22546766 TI - Intravitreal tigecycline treatment in experimental Acinetobacter baumannii endophthalmitis. AB - PURPOSE: To investigate the clinical and microbiological effectivity of intravitreal tigecycline in an experimental rabbit endophthalmitis model caused by imipenem resistant Acinetobacter baumannii. MATERIALS AND METHODS: Forty-eight eyes of 24 New Zealand white albino rabbits were divided into six groups (n=8 in each). The right eyes were divided into three groups and defined as infected group; left eyes were divided into three groups and defined as uninfected group. Infected group received 0.1 ml intravitreal A. baumannii suspension. Twenty-four hours after bacterial inoculation, group 1 received 1 mg/0.1 ml tigecycline and group 2 received 0.5 mg/0.1 ml tigecycline. Group 3 eyes received no treatment. In group 4, 0.1 ml of saline solution was injected. Groups 5 and 6 were received intravitreal tigecycline injection of 1 mg/0.1 ml and 0.5 mg/0.1 ml respectively. The eyes were enucleated for histopathological evaluation on the sixth day. Clinical and histological scoring systems were used to evaluate clinical and histological severity of the intraocular infection. RESULTS: The mean clinical scores of the six groups at the sixth day were 11+/-1.92, 12.4+/-6.2, 8.5+/-2.7, 0, 3+/-1.3, and 3+/-1.4 respectively. Mean histopathological scores were 7.8+/ 2.8, 7.0+/-1.5, 5.6+/-1.4, 0, 0, and 0 respectively. There was no significant difference in mean clinical and histopathological scores of infected group (groups 1, 2 and 3). There was significant difference in mean clinical scores of groups 5 and 6 compared with group 4. Groups 4, 5 and 6 showed normal histological structure in histopathological evaluation and showed no significant difference. Microbiological cure was achieved in all infected eyes. CONCLUSIONS: Experimental rabbit endophthalmitis model caused by imipenem resistant A. baumannii was microbiologically cured by intravitreal tigecycline injection. However, a hypersensitivity-like reaction due to intravitreal application of tigecycline limits the use of this antimicrobial agent in A. baumannii endophthalmitis. PMID- 22546769 TI - Oral therapy of catheter-associated bacteriuria (CAB) in the era of antibiotic resistance: nitrofurantoin revisited. PMID- 22546768 TI - Clinical experience with daptomycin in Italy: results from a registry study of the treatment of Gram-positive infections between 2006 and 2009. AB - The purpose of this study was to evaluate post-marketing efficacy and safety data for therapy with daptomycin (DAP) in Italy. Data from patients treated with DAP at 30 centres between January 2006 and July 2009 were analysed according to the protocol of the EU-CORE(SM). In 359 patients, DAP was most commonly prescribed for skin and skin-structure infections (55%), infective endocarditis (13%), and bacteraemia (12.5%). DAP was associated with rapid improvement, and clinical success rates ranging from 77 to 91%, despite almost half of the patient population being >=65 years of age, 86% having significant underlying disease, and many being affected by drug-resistant pathogens. Staphylococcus aureus represented 35% of all pathogens isolated. Success rates for all staphylococcal and enterococcal infections were >80%, including methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA). Clinical outcomes were similar for DAP whether used as first- or second-line therapy. DAP was well tolerated even with prolonged treatment. PMID- 22546767 TI - Gentamicin pharmacokinetics during continuous venovenous hemofiltration in critically ill septic patients. AB - OBJECTIVE: Current dosing recommendations for administration of gentamicin to septic patients with acute kidney injury (AKI) on continuous venovenous hemofiltration (CVVH) at a filtration rate of 45 ml/kg/h are missing. AIM: To describe gentamicin pharmacokinetics and to find an optimal dosing regimen in patients on CVVH. METHODS: Seven adult patients were included. Patients received loading dose of 240 mg followed by application of maintenance dose every 24 hours. Maintenance dose was adjusted according to gentamicin C(max)/MIC ratio and drug levels simulation using a pharmacokinetic programme. RESULTS: Median total clearance (0.59-0.79 ml/min/kg) was similar to patients with normal renal function; median volume of distribution was higher than observed in non-septic patients (about 0.5 l/kg versus 0.25 l/kg). Patients with diuresis required an increase of gentamicin dose to reach C(max)/MIC ratio. CONCLUSION: Septic patients with AKI on CVVH (45 ml/kg/h) require a loading dose of 240 mg, followed by therapeutic drug monitoring to optimize maintenance dose. PMID- 22546770 TI - Induction of myocardial infarction in adult zebrafish using cryoinjury. AB - The mammalian heart is incapable of significant regeneration following an acute injury such as myocardial infarction(1). By contrast, urodele amphibians and teleost fish retain a remarkable capacity for cardiac regeneration with little or no scarring throughout life(2,3). It is not known why only some non-mammalian vertebrates can recreate a complete organ from remnant tissues(4,5). To understand the molecular and cellular differences between regenerative responses in different species, we need to use similar approaches for inducing acute injuries. In mammals, the most frequently used model to study cardiac repair has been acute ischemia after a ligation of the coronary artery or tissue destruction after cryoinjury(6,7). The cardiac regeneration in newts and zebrafish has been predominantly studied after a partial resection of the ventricular apex(2,3). Recently, several groups have established the cryoinjury technique in adult zebrafish(8-10). This method has a great potential because it allows a comparative discussion of the results obtained from the mammalian and non-mammalian species. Here, we present a method to induce a reproducible disc shaped infarct of the zebrafish ventricle by cryoinjury. This injury model is based on rapid freezing-thawing tissue, which results in massive cell death of about 20% of cardiomyocytes of the ventricular wall. First, a small incision was made through the chest with iridectomy scissors to access the heart. The ventricular wall was directly frozen by applying for 23-25 seconds a stainless steel cryoprobe precooled in liquid nitrogen. To stop the freezing of the heart, fish water at room temperature was dropped on the tip of the cryoprobe. The procedure is well tolerated by animals, with a survival rate of 95%. To characterize the regenerative process, the hearts were collected and fixed at different days after cryoinjury. Subsequently, the specimen were embedded for cryosectioning. The slides with sections were processed for histological analysis, in situ hybridization and immunofluorescence. This undertaking enhances our understanding of the factors that are required for the regenerative plasticity in the zebrafish, and provide new insights into the machinery of cardiac regeneration. A conceptual and molecular understanding of heart regeneration in zebrafish will impact both developmental biology and regenerative medicine. PMID- 22546771 TI - Reducing catheter-associated urinary tract infections in home care: a performance improvement project. AB - The Performance Improvement Department of one home healthcare agency (HHA) identified an increase in the rate of catheter-associated urinary tract infections (CAUTI) during 2009. An investigation was undertaken to identify factors that contributed to this increase and an action plan was implemented to reduce the rate of infections. Modifications were made to the surveillance process to align the infection rate calculation with Centers for Disease Control and Prevention (CDC) guidelines and staff education was undertaken to ensure utilization of evidence-based practice. An overall reduction in the CAUTI rate was achieved through this multifactorial approach. PMID- 22546772 TI - Obesity and the risk and outcome of infection. AB - The interactions between obesity and infectious diseases have recently received increasing recognition as emerging data have indicated an association between obesity and poor outcome in pandemic H1N1 influenza infection. Obesity is an established risk factor for surgical-site infections, nosocomial infections, periodontitis and skin infections. Several studies indicate that acute pancreatitis is more severe in the obese. Data are controversial and limited as regards the association between obesity and the risk and outcome of community acquired infections such as pneumonia, bacteremia and sepsis and obesity and the course of HIV infection. As the cause-effect relationship between obesity and infection remains obscure in many infectious diseases, further studies are warranted. The consequences of obesity may have substantial effects on the global burden of infectious diseases. PMID- 22546775 TI - Decreased intestinal nutrient response in diet-induced obese rats: role of gut peptides and nutrient receptors. AB - BACKGROUND AND AIMS: Diet-induced obesity (DIO) is an excellent model for examining human obesity comprising both genotypic and environmental (diet) factors. Decreased responsiveness to peripheral satiety signaling may be responsible for the hyperphagia in this model. In this study, we investigated responses to nutrient-induced satiation in outbred DIO and DIO-resistant (DR) rats fed a high-energy/high-fat (HE/HF) diet as well as intestinal satiety peptide content, intestinal nutrient-responsive receptor abundance and vagal anorectic receptor expression. METHODS: Outbred DIO and DR rats fed a HE/HF diet were tested for short-term feeding responses following nutrient (glucose and intralipid (IL)) gastric loads. Gene and protein expressions of intestinal satiety peptides and fatty acid-responsive receptors were examined from isolated proximal intestinal epithelial cells and cholecystokinin-1 receptor (CCK-1R) and leptin receptor (LepR) mRNA from the nodose ganglia of DIO and DR animals. RESULTS: DIO rats were less responsive to IL- (P<0.05) but not glucose-induced suppression of food intake compared with DR rats. DIO rats exhibited decreased CCK, peptide YY (PYY) and glucagon-like peptide-1 (GLP-1; P<0.05 for each) protein expression compared with DR rats. Also, DIO rats expressed more G-protein coupled receptor 40 (GPR40; P<0.0001), GPR41 (P<0.001) and GPR120 (P<0.01) relative to DR rats. Finally, there were no differences in mRNA expression for CCK-1R and LepR in the nodose ganglia of DIO and DR rats. CONCLUSIONS: Development of DIO may be partly due to decreased fat-induced satiation through low levels of endogenous satiety peptides, and changes in intestinal nutrient receptors. PMID- 22546773 TI - The proof is in the pudding: children prefer lower fat but higher sugar than do mothers. AB - OBJECTIVE: Although there are established age-related differences in sweet preferences, it remains unknown whether children differ from mothers in their preference for and perception of fat (creaminess). We examined whether individual differences in sucrose and fat preferences and perception are related to age, genotype and lifestyle. SUBJECTS: Children 5-10 years-old (n=84) and their mothers (n=67) chose the concentration of sucrose and fat most preferred in pudding and sucrose most preferred in water using identical, two-alternative, forced-choice procedures, and ranked pudding samples for intensity of sweetness and creaminess. Subjects were also weighed and measured for height, as well as genotyped for a sweet-receptor gene (TAS1R3). RESULTS: Children preferred higher concentrations of sucrose in water (P=0.03) and in pudding (P=0.05) and lower concentrations of fat in pudding (P<0.01) than did mothers. Children and mothers were equally able to rank the intensity of different concentrations of fat (P=0.12) but not sucrose in pudding (P=0.01). Obese and lean children and mothers did not differ in preferences, but obese mothers were less able to correctly rank the concentration of fat in pudding than were lean mothers (P=0.03). Mothers who smoked preferred a higher concentration of sucrose than did those who never smoked (P<0.01). Individual differences in sweet preference were associated with genetic variation within the TAS1R3 gene in mothers but not children (P=0.04). CONCLUSION: Irrespective of genotype, children prefer higher concentrations of sugar but lower concentrations of fat in puddings than do their mothers. Thus, reduced-fat foods may be better accepted by children than adults. PMID- 22546774 TI - PNPLA3 gene-by-visceral adipose tissue volume interaction and the pathogenesis of fatty liver disease: the NHLBI family heart study. AB - BACKGROUND: Fatty liver disease (FLD) is characterized by increased intrahepatic triglyceride content with or without inflammation and is associated with obesity, and features of the metabolic syndrome. Several recent genome-wide association studies have reported an association between single-nucleotide polymorphism rs738409 in the (patatin-like phospholipase domain-containing protein 3) PNPLA3 gene and FLD. Liver attenuation (LA; hounsfield units, HU) by computed tomography is a non-invasive measure of liver fat, with lower values of HU indicating higher liver fat content. Clinically, a LA value of ?40 HU indicates moderate-to-severe hepatic steatosis. OBJECTIVE: We investigated whether missense rs738409 PNPLA3 interacted with abdominal visceral adipose tissue (VAT) volume (cm) to reduce LA (that is, increased liver fat) in 1019 European American men and 1238 European American women from the Family Heart Study. METHODS: We used linear regression to test the additive effect of genotype, abdominal VAT, and their multiplicative interaction on LA adjusted for age, body mass index, high-density lipoprotein cholesterol, insulin resistance, serum triglycerides, abdominal subcutaneous adipose tissue and alcohol intake. RESULTS: In men and women combined, the interaction between each copy of the rs738409 variant allele (minor allele frequency 0.23) and 100 cm/150 mm slice VAT decreased LA by 2.68+/-0.35 HU (P<0.01). The interaction of 100 cm VAT and the variant allele was associated with a greater decrease in LA in women than men (-4.8+/-0.6 and -2.2+/-0.5 HU, respectively). CONCLUSIONS: The interaction between genotype and VAT volume suggest key differences in the role of PNPLA3 genotype in conjunction with abdominal VAT in liver fat accrual. The stronger association of the PNPLA3 genotype and liver fat in women suggests that women may be more sensitive to liver fat accumulation in the setting of increased visceral fat, compared with men. The presence of the PNPLA3 variant genotype, particularly in the context of high VAT content may have an important role in FLD. PMID- 22546776 TI - Cerebrospinal fluid xenin levels during body mass reduction: no evidence for obesity-associated defective transport across the blood-brain barrier. AB - CONTEXT: Recent studies have shown that xenin can act in the hypothalamus, reducing food intake through a leptin- and melanocortin system-independent mechanism. OBJECTIVE: To evaluate the impact of body mass reduction on the blood and cerebrospinal fluid (CSF) levels of xenin. DESIGN AND SETTING: Thirteen obese patients (11 women) selected for roux-in-Y gastric bypass surgery were evaluated before and approximately 8 months after surgery. Xenin was determined in serum and CSF by radioimmunoassay. RESULTS: As compared with lean subjects, obese patients have increased blood levels of xenin, which reduce after surgery. There are significant correlations between blood xenin and blood leptin and insulin levels. CSF concentration of xenin is ~10-fold lower than blood levels, and is significantly higher in obese subjects as compared with lean ones, returning to normal levels after body mass reduction. There is a significant linear correlation between CSF and blood levels of xenin. CONCLUSION: Xenin is present in the human CSF in a concentration ~10-fold lower than the blood. Both blood and CSF xenin are correlated with blood levels of important markers of adiposity, leptin and insulin. The levels of CSF xenin are linearly correlated with blood xenin, independently of patient body mass, suggesting that either its transport across the blood-brain barrier is not saturated in the concentration range detected in this study or that there is a coordinated release of xenin from the periphery and the CNS. PMID- 22546777 TI - Temporal changes in bias of body mass index scores based on self-reported height and weight. AB - OBJECTIVES: To investigate temporal changes in the bias associated with self reported (as opposed to measured) body mass index (BMI) and explore the relationship of such bias to changing social attitudes towards obesity. METHODS: Using data from the National Health and Nutrition Examination Survey covering two time periods, 1988-1994 and 2005-2008, discrepancy scores between self-reported vs measured BMI were generated. Changes in the sensitivity of BMI categories based on self-reports were examined for six weight groups, both for the US adult population as a whole and major demographic groups. Linear regression models were used to examine temporal changes in average bias, as well as attitudes about weight within each weight category and by demographic group. RESULTS: Between 2005-2008 and 1988-1994, the bias towards underestimation of a person's BMI based on interview responses has declined among obese individuals, a trend evident in virtually all demographic subgroups explored. Conversely, most demographic groups showed little change in the extent of bias among underweight and normal-weight individuals. Although the 2005-2008 survey respondents underestimated their measured BMI more than the 1988-1994 respondents, this shift can be entirely explained by the increased prevalence of obesity in more recent years. In fact, obese individuals in 2005-2008 were less likely to overreport their height and underreport their weight than their counterparts in the 1988-1994. Evidence from responses to questions about ideal weight and desire to lose weight point in the direction of a shift in social attitudes, which may make it easier to 'admit' to greater weight in surveys. CONCLUSION: Over the past 20 years, the bias in self reported height and weight has declined leading to more accurate BMI categorizations based on self-report. This change is likely to affect efforts to find correction factors to adjust BMI scores based on self-reported height and weight. PMID- 22546779 TI - Stress fractures in runners. AB - Many runners in the United States are at risk for stress-related injuries, which are largely preventable. Severity and recovery vary, and can range from uneventful to surgical intervention. This article explores risks, pathophysiology, diagnostic considerations, and rehabilitation. Prevention strategies are also outlined. PMID- 22546778 TI - Birth cohort effects among US-born adults born in the 1980s: foreshadowing future trends in US obesity prevalence. AB - BACKGROUND: Obesity prevalence stabilized in the US in the first decade of the 2000s. However, obesity prevalence may resume increasing if younger generations are more sensitive to the obesogenic environment than older generations. METHODS: We estimated cohort effects for obesity prevalence among young adults born in the 1980s. Using data collected from the National Health and Nutrition Examination Survey between 1971 and 2008, we calculated obesity for respondents aged between 2 and 74 years. We used the median polish approach to estimate smoothed age and period trends; residual non-linear deviations from age and period trends were regressed on cohort indicator variables to estimate birth cohort effects. RESULTS: After taking into account age effects and ubiquitous secular changes, cohorts born in the 1980s had increased propensity to obesity versus those born in the late 1960s. The cohort effects were 1.18 (95% CI: 1.01, 1.07) and 1.21 (95% CI: 1.02, 1.09) for the 1979-1983 and 1984-1988 birth cohorts, respectively. The effects were especially pronounced in Black males and females but appeared absent in White males. CONCLUSIONS: Our results indicate a generational divergence of obesity prevalence. Even if age-specific obesity prevalence stabilizes in those born before the 1980s, age-specific prevalence may continue to rise in the 1980s cohorts, culminating in record-high obesity prevalence as this generation enters its ages of peak obesity prevalence. PMID- 22546780 TI - HPV & age-appropriate cervical cancer prevention for adolescents. AB - Over the last decade, new information about human papillomavirus infection has increased the healthcare community's understanding of the natural history of the disease and cervical cancer. Advances in screening, management, and diagnosis continue to refine clinicians' efforts to prevent cervical cancer in adolescent females. PMID- 22546781 TI - Microbleeds in postmortem brains of patients with Alzheimer disease: a T2* weighted gradient-echo 7.0 T magnetic resonance imaging study. AB - This study aims to determine the distribution and to quantify microbleeds (MBs) in postmortem brains of patients with Alzheimer disease (AD) on T2*-weighted gradient-echo 7.0 T magnetic resonance imaging. Twenty-eight AD brains were compared with 5 controls. The AD brains were subdivided further: 18 without and 10 with additional severe cerebral amyloid angiopathy (AD-CAA). The distribution and the number of cortical focal signal intensity losses, representing MBs, were assessed on coronal sections at the frontal, the central, and the occipital level of a cerebral hemisphere. MBs prevailed in the central sections (P=0.005) of AD brains without CAA, whereas in AD-CAA brains, they were more frequent in all coronal sections (P<=0.002). They prevailed in the deep cortical layers of the AD brains and of the controls (P<=0.03). They were significantly increased in all cortical layers of the AD-CAA brains (P<=0.04), compared with the controls. MBs prevalence in brains of AD patients had a different topographic distribution according to the absence or presence of severe CAA. PMID- 22546782 TI - Spongiform change in dementia with Lewy bodies and Alzheimer disease. AB - BACKGROUND: Dementia with Lewy bodies (DLB) is characterized neuropathologically by brainstem and cortical Lewy bodies and Lewy neurites, neuronal loss in brainstem nuclei, and Alzheimer disease (AD) pathology. Previous studies have suggested that spongiform change in the entorhinal cortex may also be a pathologic feature; however, this change has not been well characterized. DESIGN/METHOD: An autopsy series of 40 subjects with DLB and 40 subjects with AD were matched on age, sex, and last Mini Mental State Examination before death. Using semistereological methods on representative sections through the transentorhinal and perirhinal cortices, quantitative counts and semiquantitative grading of vacuolization were performed by 1 rater (A.S.) blinded to subjects' diagnoses. In addition, electron microscopy of representative sections was performed. RESULTS: Vacuolization was 4- to 5-fold more prominent in the perirhinal, as compared with transentorhinal, cortex. Moderate to severe vacuolization was found in 57.5% of DLB, but only 7.5% of AD subjects. There were statistically significant differences between mean numbers of vacuoles in the perirhinal (DLB mean=27.91; AD mean=2.35; P<0.001) and transentorhinal (DLB mean=5.92; AD mean=0.5; P<0.001) cortices in DLB as well as AD cases. Electron microscopy revealed both axonal and dendritic pathology, with dilatation, vacuole formation, and abnormal membranous profiles. CONCLUSIONS: Although the exact mechanism remains to be elucidated, vacuolization seems to be more specific for DLB than AD, with disproportionate involvement of the perirhinal cortex. PMID- 22546783 TI - COGNOS: care for people with cognitive dysfunction: a national observational study. AB - Care plans are intended to improve the independence and functioning of patients with cognitive dysfunction and support the caregivers involved. They are an integral part of the Belgian reimbursement procedure for cholinesterase inhibitors. This nationwide, multicenter, observational study examined the content and implementation of the care plan along with patient satisfaction in community-dwelling patients newly diagnosed with Alzheimer disease in Belgium. The patients' opinion of their quality of life was measured using Anamnestic Comparative Self-Assessment (ACSA) scale. A total of 720 participants (453 female) were enrolled with 86.0% (619/719) living at home alone or with their spouse/partner. Cognitive problems (627/717, 87.4%) were the main reason for initiation of the consultation. Most patients had a caregiver (646/719, 89.8%): generally the spouse/partner (351/646, 54.3%) or a child (232/646, 35.9%). A total of 511 patients (71.0%) were prescribed a cholinesterase inhibitor after the initial consultation. A total of 236 care plans were advised with 169 (71.6%) realized and 157 of these (92.9%) considered adequate. Most patients were satisfied with the help received in the care plan (service satisfaction range, 80.0% to 98.6% of patients). Quality of life as rated by the patient significantly increased between baseline (average ACSA score: 5.2+/-2.4) and follow-up (5.8+/-2.1). The use of care plans appears to improve management of care for Alzheimer disease patients. PMID- 22546784 TI - Biodegradation of 2-chlorophenol (2CP) in an anaerobic sequencing batch reactor (ASBR). AB - The aim of this study is to contribute to the knowledge about anaerobic digestion of 2-chlorophenol (2CP) in an anaerobic sequencing batch reactor (ASBR). Two reactors were set up (ASBR(A) and ASBR(B)). The ASBR(A) was fed with 2 chlorophenol (28-196 mg 2CP-C/L) and no other exogenous electron donor. The ASBR(B) was fed with a mixture of 2CP (28-196 mg 2CP-C/L) and phenol (28-196 mg phenol-C/L) as an electron donor. The process evaluation was conducted by three means: first by substrate consumption efficiency (E(2CP)), second, by biogas yield (Y(biogas-C/2CP-C)) and third, by the specific consumption rates (q(2CP)) as response variables. The 2CP consumption efficiency (90 +/- 0.4%) was not influenced by the increase in the concentrations tested. In both reactors ASBR(A) and ASBR(B), both concentration as well as speed increased. Concentration increased from 28 to 114 mg 2CP-C/L. The specific consumption rate (q(2CP)) values were fivefold higher. However, a decrease of 37% was observed at 140 mg 2CP-C/L and one of 72% at 196 mg 2CP-C/L. The biogas yields (0.80 +/- 0.06) remained stable in both reactors. In both reactors the biogas yield decreased to 78 +/- 3% at 196 mg 2CP-C/L. We might assume this decrease was due to the accumulation of VFA. Finally, poor sludge settleability was determined only in the SBR(B) reactor at 140 and 196 mg 2CP-C/L. An increase was observed in both SVI <= 140 +/- 5 mL/g and over exopolymeric protein <=120 mg EP/L. PMID- 22546785 TI - The sorption of lead, cadmium, copper and zinc ions from aqueous solutions on a raw diatomite from Algeria. AB - The adsorption of Cu(2+), Zn(2+), Cd(2+) and Pb(2+) ions from aqueous solution by Algerian raw diatomite was studied. The influences of different sorption parameters such as contact pH solution, contact time and initial metal ions concentration were studied to optimize the reaction conditions. The metals ions adsorption was strictly pH dependent. The maximum adsorption capacities towards Cu(2+), Zn(2+), Cd(2+) and Pb(2+) were 0.319, 0.311, 0.18 and 0.096 mmol g(-1), respectively. The kinetic data were modelled using the pseudo-first-order and pseudo-second-order kinetic equations. Among the kinetic models studied, the pseudo-second-order equation was the best applicable model to describe the sorption process. Equilibrium isotherm data were analysed using the Langmuir and the Freundlich isotherms; the results showed that the adsorption equilibrium was well described by both model isotherms. The negative value of free energy change DeltaG indicates feasible and spontaneous adsorption of four metal ions on raw diatomite. According to these results, the high exchange capacities of different metal ions at high and low concentration levels, and given the low cost of the investigated adsorbent in this work, Algerian diatomite was considered to be an excellent adsorbent. PMID- 22546786 TI - Comparison of surface functional groups and metal uptake efficiency of rice husk harvested from different climatic zones. AB - Rice husk (RH) is a very effective natural adsorbent for fast removal of heavy metal cations from water solutions. Application of RH for removal of some heavy metal ions, such as Ni, Zn, Mn, Co, Cu, Pb and Cd from water solutions has been studied and different maximum adsorption capacities and a variety of optimized conditions were reported in the literature. In this work, the efficiency of RH harvested from different climatic regions was studied. For this proposal, different RH samples were collected from three different climatic regions of Iran (nominated as RH1 to RH3); their removal efficiencies of heavy metal cations of Ni(2+), Cu(2+) and Cd(2+) were investigated and compared. The adsorption data at optimum conditions could be assessed well by both Langmuir and Freundlich models. Statistical analysis of the results of adsorption isotherms showed that different RH samples have different efficiencies in uptake of these heavy metal ions. The RH samples were characterized using Fourier transform infrared spectroscopy and Boehm titration, which indicated that amounts of functional groups differed between RHs that are grown in different climatic conditions. PMID- 22546787 TI - Non-parametric error distribution analysis from the laboratory calibration of various rainfall intensity gauges. AB - The analysis of counting and catching errors of both catching and non-catching types of rain intensity gauges was recently possible over a wide variety of measuring principles and instrument design solutions, based on the work performed during the recent Field Intercomparison of Rainfall Intensity Gauges promoted by World Meteorological Organization (WMO). The analysis reported here concerns the assessment of accuracy and precision of various types of instruments based on extensive calibration tests performed in the laboratory during the first phase of this WMO Intercomparison. The non-parametric analysis of relative errors allowed us to conclude that the accuracy of the investigated RI gauges is generally high, after assuming that it should be at least contained within the limits set forth by WMO in this respect. The measuring principle exploited by the instrument is generally not very decisive in obtaining such good results in the laboratory. Rather, the attention paid by the manufacturer to suitably accounting and correcting for systematic errors and time-constant related effects was demonstrated to be influential. The analysis of precision showed that the observed frequency distribution of relative errors around their mean value is not indicative of an underlying Gaussian population, being much more peaked in most cases than can be expected from samples extracted from a Gaussian distribution. The analysis of variance (one-way ANOVA), assuming the instrument model as the only potentially affecting factor, does not confirm the hypothesis of a single common underlying distribution for all instruments. Pair-wise multiple comparison analysis revealed cases in which significant differences could be observed. PMID- 22546788 TI - Activated carbon fiber filler in aerated bioreactor for industrial wastewater treatment. AB - The aerated bioreactor is a promising technology for wastewater treatment. Activated carbon fiber (ACF) used as a biomembrane carrier in wastewater disposal has attracted much more concern recently. The high modulus polyacrylonitrile (PAN)-based ACF was successfully used as a biomembrane carrier for hard-to biodegrade industrial organic wastewater disposal in a lab-scale aerated biomembrane reactor at room temperature. The biocompatibility test shows that the biomembrane grows quickly on the ACF filler (ACFF) surface; bacteria and microzoon can breed on the ACFF surface at high chemical oxygen demand (COD) concentration. The COD removal rate tests show that the ACFF bioreactor has high capability to remove COD. PMID- 22546789 TI - Effectiveness of pressurised carbon dioxide for inactivation of Escherichia coli isolated from sewage sludge. AB - This research explored the possible application of pressurised carbon dioxide (P CO(2)), a promising non-thermal sterilisation technique, for the treatment of sewage sludge (SS) before anaerobic digestion to inactivate pathogenic microorganisms. Escherichia coli was selected as the test organism and was isolated from SS and maintained in pure culture. The growth curve of the isolated strain was determined by measuring the optical density (OD) in liquid culture medium and relating this information to the spread plate count so that a culture of known cell density could be grown for optimisation experiments. Inactivation of E. coli was enhanced by increase in pressure (1,500, 2,000 and 2,800 kPa) and treatment time (from 0.75 to 24 h). A short exposure time at high pressure was sufficient to provide a degree of inactivation which could also be achieved by longer exposure at lower pressure. Complete inactivation (8 log(10) reduction) was possible at all three pressures. scanning (SEM) and transmission (TEM) electron microscopy studies of E. coli treated with P CO(2) revealed that the cell walls were ruptured, and the cytoplasm was unevenly distributed and had lost its density, indicating the possible leakage of intracellular substances. PMID- 22546790 TI - Application of ionic liquids for the removal of heavy metals from wastewater and activated sludge. AB - This paper presents the results of adsorption studies on the removal of heavy metals (Cr, Cu, Cd, Ni, Pb and Zn) from standard solutions, real wastewater samples and activated sewage sludge using a new technique of liquid-liquid extraction using quaternary ammonium and phosphonium ionic liquids (ILs). Batch sorption experiments were conducted using the ILs [PR4][TS], [PR4][MTBA], [A336][TS] and [A336][MTBA]. Removal of these heavy metals from standard solutions were not effective, however removal of heavy metals from the industrial effluents/wastewater treatment plants were satisfactory, indicating that the removal depends mainly on the composition of the wastewater and cannot be predicted with standard solutions. Removal of heavy metals from activated sludge proved to be more successful than conventional methods such as incineration, acid extraction, thermal treatment, etc. For the heavy metals Cu, Ni and Zn, >=90% removal was achieved. PMID- 22546791 TI - Fate of pharmaceuticals and bacteria in stored urine during precipitation and drying of struvite. AB - Experiments were conducted to measure the behaviour of eight pharmaceuticals during urine treatment as part of the project 'SANIRESCH - Sustainable sanitary recycling Eschborn'. Urine was collected from 200 people in a public building via waterless urinals and NoMix toilets. It was then stored at room temperature at different pH values to analyse the extent to which bacteria and pharmaceuticals are eliminated over time. Although a partial elimination of pharmaceuticals could be detected, the storage at defined pH values cannot be advised. As the persons tested used pharmaceuticals with different structures, in different amounts and at varying intervals, this method of treatment is insufficient for removing them from urine. Precipitating the urine with MgO, washing it with saturated struvite solution and drying it at 30 degrees C will result in a free-flowing granular powder of struvite (NH(4)MgPO(4).6H(2)O) that is free of pharmaceuticals and pathogens and can be used as fertiliser and a source of nitrogen, magnesium and phosphorus. PMID- 22546792 TI - An integrated urban drainage system model for assessing renovation scheme. AB - Due to sustained economic growth in China over the last three decades, urbanization has been on a rapidly expanding track. In recent years, regional industrial relocations were also accelerated across the country from the east coast to the west inland. These changes have led to a large-scale redesign of urban infrastructures, including the drainage system. To help the reconstructed infrastructures towards a better sustainability, a tool is required for assessing the efficiency and environmental performance of different renovation schemes. This paper developed an integrated dynamic modeling tool, which consisted of three models for describing the sewer, the wastewater treatment plant (WWTP) and the receiving water body respectively. Three auxiliary modules were also incorporated to conceptualize the model, calibrate the simulations, and analyze the results. The developed integrated modeling tool was applied to a case study in Shenzhen City, which is one of the most dynamic cities and facing considerable challenges for environmental degradation. The renovation scheme proposed to improve the environmental performance of Shenzhen City's urban drainage system was modeled and evaluated. The simulation results supplied some suggestions for the further improvement of the renovation scheme. PMID- 22546793 TI - Pressure retarded osmosis for energy production: membrane materials and operating conditions. AB - Pressure retarded osmosis (PRO) is a novel membrane process to produce energy. PRO has the potential to convert the osmotic pressure difference between fresh water (i.e. river water) and seawater to electricity. Moreover, it can recover energy from highly concentrated brine in seawater desalination. Nevertheless, relatively little research has been undertaken for fundamental understanding of the PRO process. In this study, the characteristics of the PRO process were examined using a proof-of-concept device. Forward osmosis (FO), reverse osmosis (RO), and nanofiltration (NF) membranes were compared in terms of flux rate and concentration polarization ratio. The results indicated that the theoretical energy production by PRO depends on the membrane type as well as operating conditions (i.e. back pressure). The FO membrane had the highest energy efficiency while the NF membrane had the lowest efficiency. However, the energy production rate was low due to high internal concentration polarization (ICP) in the PRO membrane. This finding suggests that the control of the ICP is essential for practical application of PRO for energy production. PMID- 22546794 TI - Decolorization and mineralization of Diarylide Yellow 12 (PY12) by photo-Fenton process: the Response Surface Methodology as the optimization tool. AB - The Response Surface Methodology (RSM) was applied as a tool for the optimization of the operational conditions of the photo-degradation of highly concentrated PY12 wastewater, resulting from a textile industry located in the suburbs of Medellin (Colombia). The Box-Behnken experimental Design (BBD) was chosen for the purpose of response optimization. The photo-Fenton process was carried out in a laboratory-scale batch photo-reactor. A multifactorial experimental design was proposed, including the following variables: the initial dyestuff concentration, the H(2)O(2) and the Fe(+2) concentrations, as well as the UV wavelength radiation. The photo-Fenton process performed at the optimized conditions resulted in ca. 100% of dyestuff decolorization, 92% of COD and 82% of TOC degradation. A kinetic study was accomplished, including the identification of some intermediate compounds generated during the oxidation process. The water biodegradability reached a final DBO(5)/DQO = 0.86 value. PMID- 22546795 TI - Comparative studies on the differently operated trains of the North-Budapest Wastewater Treatment Plant. AB - In order to reduce the pollution load of the Danube, the North-Budapest Wastewater Treatment Plant has been upgraded to enhanced nitrogen removal by establishing a new activated sludge treatment line and modifying the existing unit for nitrification and denitrification. As both the influent flow rate and the influent chemical oxygen demand (COD), biological oxygen demand (BOD(5)) and total suspended solids (TSS) concentration levels remained far below the design values, setting one fourth of the reactor volume out of operation in the Old Line, and operating the nitrification reactor of the New Line with part-time aeration proved to be possible. Analytical data as well as simulation studies supported the advantage of the intermittent-aeration process in efficient N removal. However, the lengths of the aerated periods have to be increased with decreasing temperature, and thereby effluent total nitrogen (TN) concentration can increase due to decreasing denitrification efficiency. Potential occurrence of low-dissolved oxygen (DO) bulking should be hindered through applying an efficient anoxic selector system. PMID- 22546796 TI - Improving the sludge disintegration efficiency of sonication by combining with alkalization and thermal pre-treatment methods. AB - One of the most serious problems encountered in biological wastewater treatment processes is the production of waste activated sludge (WAS). Sonication, which is an energy-intensive process, is the most powerful sludge pre-treatment method. Due to lack of information about the combined pre-treatment methods of sonication, the combined pre-treatment methods were investigated and it was aimed to improve the disintegration efficiency of sonication by combining sonication with alkalization and thermal pre-treatment methods in this study. The process performances were evaluated based on the quantities of increases in soluble chemical oxygen demand (COD), protein and carbohydrate. The releases of soluble COD, carbohydrate and protein by the combined methods were higher than those by sonication, alkalization and thermal pre-treatment alone. Degrees of sludge disintegration in various options of sonication were in the following descending order: sono-alkalization > sono-thermal pre-treatment > sonication. Therefore, it was determined that combining sonication with alkalization significantly improved the sludge disintegration and decreased the required energy to reach the same yield by sonication. In addition, effects on sludge settleability and dewaterability and kinetic mathematical modelling of pre-treatment performances of these methods were investigated. It was proven that the proposed model accurately predicted the efficiencies of ultrasonic pre-treatment methods. PMID- 22546797 TI - High rate composting of herbal pharmaceutical industry solid waste. AB - High rate composting studies of hard to degrade herbal wastes were conducted in a 3.5 m(3) capacity rotary drum composter. Studies were spread out in four trials: In trial 1 and 2, one and two turns per day rotation was observed, respectively, by mixing of herbal industry waste with cattle (buffalo) manure at a ratio of 3:1 on wet weight basis. In trial 3 inocula was added in raw waste to enhance the degradation and in trial 4 composting of a mixture of vegetable market waste and herbal waste was conducted at one turn per day. Results demonstrated that the operation of the rotary drum at one turn a day (trial 1) could provide the most conducive composting conditions and co-composting (trial 4) gave better quality compost in terms of temperature, moisture, nitrogen, and Solvita maturity index. In addition a FT-IR study also revealed that trial 1 and trial 4 gave quality compost in terms of stability and maturity due to the presence of more intense peaks in the aromatic region and less intense peaks were found in the aliphatic region compared with trial 2 and trial 3. PMID- 22546798 TI - High rate nitrogen removal by the CANON process at ambient temperature. AB - Completely autotrophic nitrogen removal over nitrite (CANON) is a cost-effective nitrogen removal process. Implementation of the CANON process relies on the cooperation of ammonium-oxidizing and Anammox bacteria, as well as the inhibition of nitrite-oxidizing bacteria. Strict limitations on dissolved oxygen (DO) concentration in the reactor, and the addition of sufficient inorganic carbon in the influent, were adopted as the main operational strategies. The reactor was fed with synthetic inorganic wastewater composed mainly of NH(4)(+)-N, and operated for 106 days. Stable nitrogen removal rates (NRR) of around 1.4 kg N m( 3) d(-1) were obtained at ambient temperature. Morphological characteristics and analysis of bacterial community confirmed the formation of functional outer aerobic and inner anaerobic granular sludge, providing evidence of stable nitrogen removal. PMID- 22546799 TI - Comparison between a moving bed bioreactor and a fixed bed bioreactor for biological phosphate removal and denitrification. AB - Moving bed bioreactors (MBBR) and fixed bed bioreactors (FBBR) were compared for biological phosphorus removal and denitrification. The sorption denitrification P elimination (S-DN-P) process was selected for this study. Results indicated that all nutrients were removed by the FBBR process compared with the MBBR process: 19.8% (total COD), 35.5% (filtered COD), 27.6% (BOD(5)), 62.2% (acetate), 78.5% (PO(4)-P), and 54.2% (NO(3)-N) in MBBR; 49.7% (total COD), 54.0% (filtered COD), 63.2% (BOD(5)), 99.6% (acetate), 98.6% (PO(4)-P), and 75.9% (NO(3)-N) in FBBR. The phosphate uptake and NO(3)-N decomposition in the FBBR process during the denitrification phase were much higher than for the MBBR process despite being of shorter duration. Results obtained from this study are helpful in elucidating the practical implications of using MBBR and FBBR for the removal of bio-P and denitrification from wastewater. PMID- 22546800 TI - Continuous thermal hydrolysis and anaerobic digestion of sludge. Energy integration study. AB - Experimental data obtained from the operation in a pilot plant are used to perform mass and energy balances to a global process combining units of thermal hydrolysis (TH) of secondary sludge, anaerobic digestion (AD) of hydrolysed secondary sludge together with fresh primary sludge, and cogeneration from biogas by using a gas engine in which the biogas produces electricity and heat from the exhaust gases. Three scenarios were compared, corresponding to the three digesters operated: C (conventional AD, 17 days residence time), B (combined TH + AD, same time), and A (TH + AD at half residence time). The biogas production of digesters B and A was 33 and 24% better, respectively when compared with C. In the case of the combined TH + AD process (scenarios A and B), the key factors in the energy balance were the recovery of heat from hot streams, and the concentration of sludge. The results of the balances showed that for 8% DS concentration of the secondary sludge tested in the pilot plant, the process can be energetically self-sufficient, but a fraction of the biogas must by-pass the gas engine to be directly burned. From an economic point of view, scenario B is more profitable in terms of green energy and higher waste removal, while scenario A reduces the digester volume required by a half. Considering a population of 100,000 inhabitants, the economic benefit is 87,600 ?/yr for scenario A and 132,373 ?/yr for B. This value can be increased to 223,867 ?/yr by increasing the sludge concentration of the feeding to the TH unit to a minimum value that allows use of all the biogas to produce green energy. This concentration is 13% DS, which is still possible from a practical point of view. Additional benefits gained with the combined TH + AD process are the enhancement of the digesters rheology and the possibility of getting Class A biosolids. The integration study presented here set the basis for the scale-up to a demonstration plant. PMID- 22546801 TI - Treating wastewater with high oil and grease content using an Anaerobic Membrane Bioreactor (AnMBR). Filtration and cleaning assays. AB - An Anaerobic Membrane Bioreactor (AnMBR) pilot plant was studied to improve certain operational conditions of AnMBRs that treat high oil and grease wastewaters discharged from a snacks factory. A comparison of its performance and behavior was made with an upflow anaerobic reactor throughout the first eight weeks of its operation. Raw snack food wastewater was characterized by oil and grease concentrations of up to 6,000 mg/l, with chemical oxygen demand (COD) and biological oxygen demand (BOD(5)) concentrations of up to 22,000 and 10,300 mg/l, respectively. The AnMBR achieved COD removal efficiencies of 97% at an organic loading rate (OLR) of 5.1 kg COD/m(3) d. The filtration flux, and the suction, backwash and relaxation times for each cycle were all varied: an 11 min filtration time involving 10 s pre-relaxation, 20 s backwash and 70 s post relaxation was finally selected. The filtration flux for long-term operation was between 6.5 and 8.0 l/m(2) h. The study also tested physical cleaning strategies such as intensive backwashing cycles and extended relaxation mode, and different chemical cleaning methods, such as chemically enhanced backwash on air and chemical cleaning by immersion. PMID- 22546803 TI - Sorption of benzoic acid from aqueous solution by cetyltrimethylammonium bromide modified birnessite. AB - Layered manganese oxide (birnessite) has been studied for its use as catalytic materials. The research presented in this study investigates the sorption of benzoic acid from water on synthesized cetyltrimethylammonium bromide modified birnessite (CTAB-birnessite). The synthesized CTAB-birnessite was characterized by X-ray powder diffraction (XRD). The experimental results of sorption kinetic were well fitted to the pseudo-second-order equation. The sorption isotherms were linear at different pH values, and it indicates a partition mechanism. Up to about 53% of the dissolved benzoic acid was sorbed by CTAB-birnessite; in contrast, only 16% of the dissolved benzoic acid was sorbed by birnessite. These results indicate that CTAB-birnessite can be a potential sorbent for benzoic acid removal. PMID- 22546802 TI - Catalytic ozonation of oxalic acid using carbon nanofibres on macrostructured supports. AB - Carbon nanofibres (CNFs) were grown on different macrostructured supports such as cordierite monoliths, carbon felts and sintered metal fibres. The resulting composites exhibited excellent resistance to attrition/corrosion and its porosity is mainly due to mesoporous structures. The CNF/structured materials were tested in the ozonation of oxalic acid in a conventional semi-batch reactor after being crushed to powder form, and in a newly designed reactor that may operate in semi batch or continuous operation. The CNFs supported on the different structured materials exhibited high catalytic activity in the mineralization of oxalic acid. PMID- 22546804 TI - Bacterial diversity on different surfaces in urban freshwater. AB - Microbial loads in freshwater systems have important implications in biogeochemical cycling in urban environments. Immersed surfaces in freshwaters provide surfaces for bacterial attachment and growth. Microorganisms that adhere initially to these surfaces play a critical role in biofilm formation and sustenance. Currently, there is little understanding on the type of organisms that initially adhere to different surfaces in urban canals. In this study, water from an urban stormwater canal was employed to allow bacteria to attach to different surfaces in a flowcell apparatus and understand the differences and changes in bacterial community structure. Bacterial communities were highly diverse on different surfaces as indicated by Jaccard's indices of 0.14-0.56. Bacteria on aluminium were the most diverse and on Plexiglas the least. Bacterial communities were highly dynamic in the early attachment phase and it changed by 59% between 3 and 6 h on aluminium. Specificity of attachment to surfaces was observed for some bacteria. Judicious use of materials in urban aquatic environment would help mitigate microbial load in urban waters. PMID- 22546805 TI - The impact of metal transport processes on bioavailability of free and complex metal ions in methanogenic granular sludge. AB - Bioavailability of metals in anaerobic granular sludge has been extensively studied, because it can have a major effect on metal limitation and metal toxicity to microorganisms present in the sludge. Bioavailability of metals can be manipulated by bonding to complexing molecules such as ethylenediaminetetraacetate (EDTA) or diethylenetriaminepentaacetate (DTPA). It has been shown that although the stimulating effect of the complexed metal species (e.g. [CoEDTA](2-)) is very fast, it is not sustainable when applied to metal-limited continuously operated reactors. The present paper describes transport phenomena taking place inside single methanogenic granules when the granules are exposed to various metal species. This was done using magnetic resonance imaging (MRI). The MRI results were subsequently related to technological observations such as changes in methanogenic activity upon cobalt injection into cobalt-limited up-flow anaerobic sludge blanket (UASB) reactors. It was shown that transport of complexed metal species is fast (minutes to tens of minutes) and complexed metal can therefore quickly reach the entire volume of the granule. Free metal species tend to interact with the granular matrix resulting in slower transport (tens of minutes to hours) but higher final metal concentrations. PMID- 22546806 TI - Photocatalytic degradation of p-nitrophenol by zinc oxide particles. AB - The degradation of p-nitrophenol (PNP) by ZnO particles has been studied. With increasing PNP loading the degradation rate decreased. The mineralization of PNP was rather slow compared with the degradation. With a decrease in particle diameter or an increase in surface area, the degradation rate significantly increased. The degradation capability with solar irradiation was found to be superior to UV light irradiation. It was found that 30 mg L(-1) of PNP was completely degraded by solar light with the accumulated UV light of around 23 kJ L(-1) at ZnO dosage of 5 g L(-1). The degradation PNP by ZnO with UV light or solar light was faster than that by TiO(2). PMID- 22546807 TI - Toxicity and treatability of leachate: application of UASB reactor for leachate treatment from Okhla landfill, New Delhi. AB - This study reports applicability of upflow anaerobic sludge blanket (UASB) process to treat the leachate from a municipal landfill located in Delhi. A laboratory scale reactor was operated at an organic loading rate of 3.00 kg chemical oxygen demand (COD)/m(3) d corresponding to a hydraulic retention time (HRT) of 12 h for over 8 months. The effect of toxicity of leachate, and feed composition on the treatability of leachate was evaluated. Average COD of the leachate, during the study period varied between 8,880 and 66,420 mg/l. Toxicity of the leachate used during a period of 8 months varied from LC50 1.22 to 12.35 for 96 h. The removal efficiency of soluble COD ranged between 91 and 67% for fresh leachate and decreased drastically from 90 to 35% for old leachate having high toxicity. The efficiency varied from 81 to 65%. The reactor performed more efficiently for the treatment of fresh leachate (less toxic, LC50 11.64, 12.35, and 12.15 for 96 h) as compared with old leachate (more toxic, LC50 1.22 for 96 h). Toxicity of the leachate affected its treatment potential by the UASB. PMID- 22546808 TI - Case study on the implementation of deammonification for the process water treatment of Munich WWTPs. AB - The two-staged WWTP 'Gut Grosslappen' has a capacity of 2 mio. PE. It comprises a pre-denitrification in the first stage using recirculation from the nitrifying second stage. A residual post-denitrification in a downstream sand filter is required in order to achieve the effluent standards. Presently the process water from sludge digestion is treated separately by nitrification/denitrification. Due to necessary reconstruction of the biological stages, the process water treatment was included in the future overall process concept of the WWTP. A case study was conducted comparing the processes nitritation/denitrititation and deammonification with nitrification/denitrification including their effect on the operational costs of the planned main flow treatment. Besides the different operating costs the investment costs required for the process water treatment played a significant role. Six cases for the process water treatment were compared. As a result, in Munich deammonification can only be recommended for long-term future developments, due to the high investment costs, compared with the nitritation/denitritation alternative realizable in existing tanks. The savings concerning aeration, sludge disposal and chemicals were not sufficient to compensate for the additional investment costs. Due to the specific circumstances in Munich, for the time being the use of existing tanks for nitritation/denitritation proved to be most economical. PMID- 22546811 TI - Tuning the wavelength of electrochemiluminescence by anodic potential: a design using non-Kekule-structured iridium-ruthenium luminophores. AB - Setting up spatially separated HOMO and LUMO regions in a non-Kekule structured trinuclear Ir(III)-Ru(II)-Ir(III) system and using oxidative-reduction electrochemiluminescence leads to emissions that are not detected in photoluminescence. Moreover, the new design allows tuning of the wavelength of emission in a stepless fashion as a function of the selected potential range. PMID- 22546810 TI - Nutrition, weight gain and eating behavior in pregnancy: a review of experimental evidence for long-term effects on the risk of obesity in offspring. AB - Obesity has reached near epidemic proportions in the developed world. As reproductive age women are a part of this trend, the effect of maternal obesity on the developing fetus must be investigated. In this review, we evaluated the experimental evidence relating maternal nutritional status and eating behavior before and during pregnancy on the risk of obesity in the offspring. The studies were compiled and selected based on their methodologies, study design and relevance. The analyzed studies were compiled to quantify, if possible, the relationship between maternal and offspring weight. Descriptive and observational studies were also included if they were seminal in the field. Based on the current data, maternal obesity is a critical factor exacerbating multigenerational obesity. Mechanistic studies, mainly in animals, have identified potential areas for intervention which might limit transmission of adverse risk factors for obesity from mothers to infants during pregnancy. PMID- 22546812 TI - Application of inorganic chemistry for non-cancer therapeutics. PMID- 22546809 TI - Metabolomics of human breast cancer: new approaches for tumor typing and biomarker discovery. AB - Breast cancer is the most common cancer in women worldwide, and the development of new technologies for better understanding of the molecular changes involved in breast cancer progression is essential. Metabolic changes precede overt phenotypic changes, because cellular regulation ultimately affects the use of small-molecule substrates for cell division, growth or environmental changes such as hypoxia. Differences in metabolism between normal cells and cancer cells have been identified. Because small alterations in enzyme concentrations or activities can cause large changes in overall metabolite levels, the metabolome can be regarded as the amplified output of a biological system. The metabolome coverage in human breast cancer tissues can be maximized by combining different technologies for metabolic profiling. Researchers are investigating alterations in the steady state concentrations of metabolites that reflect amplified changes in genetic control of metabolism. Metabolomic results can be used to classify breast cancer on the basis of tumor biology, to identify new prognostic and predictive markers and to discover new targets for future therapeutic interventions. Here, we examine recent results, including those from the European FP7 project METAcancer consortium, that show that integrated metabolomic analyses can provide information on the stage, subtype and grade of breast tumors and give mechanistic insights. We predict an intensified use of metabolomic screens in clinical and preclinical studies focusing on the onset and progression of tumor development. PMID- 22546813 TI - The neuroblast assay: an assay for the generation and enrichment of neuronal progenitor cells from differentiating neural stem cell progeny using flow cytometry. AB - Neural stem cells (NSCs) can be isolated and expanded in large-scale, using the neurosphere assay and differentiated into the three major cell types of the central nervous system (CNS); namely, astrocytes, oligodendrocytes and neurons. These characteristics make neural stem and progenitor cells an invaluable renewable source of cells for in vitro studies such as drug screening, neurotoxicology and electrophysiology and also for cell replacement therapy in many neurological diseases. In practice, however, heterogeneity of NSC progeny, low production of neurons and oligodendrocytes, and predominance of astrocytes following differentiation limit their clinical applications. Here, we describe a novel methodology for the generation and subsequent purification of immature neurons from murine NSC progeny using fluorescence activated cell sorting (FACS) technology. Using this methodology, a highly enriched neuronal progenitor cell population can be achieved without any noticeable astrocyte and bona fide NSC contamination. The procedure includes differentiation of NSC progeny isolated and expanded from E14 mouse ganglionic eminences using the neurosphere assay, followed by isolation and enrichment of immature neuronal cells based on their physical (size and internal complexity) and fluorescent properties using flow cytometry technology. Overall, it takes 5-7 days to generate neurospheres and 6-8 days to differentiate NSC progeny and isolate highly purified immature neuronal cells. PMID- 22546814 TI - Effect of slaughter weight and breed on instrumental and sensory meat quality of suckling kids. AB - The effects of breed and slaughter weight on chemical composition, fatty acid groups, texture, and sensory characteristics of meat of 141 suckling male kids from 5 Spanish breeds were studied. There was a decrease in texture and lightness and hue angle with the increase of the slaughter weight. Fatty acid composition was correlated with the intramuscular fat content. All the breeds except MO had values of n-6/n-3 ratio below 4, which is the healthy limit recommended, and a low atherogenic index as well as a low intramuscular fat content. A multivariate analysis discriminated light kid, which had the most tender and juicy meat, from heavy kid which had more intense kid and milk odours. Blanca Andaluza and Pirenaica had most tender and juicy meat. The effect of slaughter weight on meat traits should be considered separately for each breed to find the most appropriate meat according to consumers preferences. PMID- 22546815 TI - Advances in apoptotic mediated proteolysis in meat tenderisation. AB - Meat tenderness is considered to be one of the most important attributes of meat quality; however it is also one of the most variable. Ultimate meat tenderness is influenced by the amount of intramuscular connective tissue, the length of the sarcomere and also the proteolytic potential of the muscle. Post-mortem proteolysis by endogenous proteases causes the weakening of myofibril structures and associated proteins, which results in tenderisation. The caspase proteolytic system was first identified to be a potential contributor to post-mortem proteolysis and tenderisation in 2002. Since then research has both supported and challenged this hypothesis. The purpose of this review is to examine the experimental evidence available for caspases' involvement in post-mortem proteolysis, and to highlight cross-talk between this proteolytic system and the calpain system, a known contributor to meat tenderisation. PMID- 22546816 TI - The labile lipid fraction of meat: from perceived disease and waste to health and opportunity. AB - The fatty acid composition of beef and pork has been stigmatized due to their relationships with several diseases from cardiovascular disease to cancer. Meat lipids are, however, one of the few components of meat that can be modified in content and composition, and can present opportunities for value added production and health promotion. Until regulations and policies are in place to define requirements for fatty acid enrichment, however, the process remains relatively academic. Once practical goals are in place for fatty acid enrichment in meat, both theory and practice need to converge for successful production of fatty acid enriched meat. The present review covers aspects of policy in Canada, and requirements for research networks to respond to theoretical and practical challenges associated with production of fatty acid enriched meat. Finally, needs for education and marketing are outlined which must be in place to truly realize a transition of meat lipids from perceived disease and waste to health and opportunity. PMID- 22546817 TI - Does mechanism matter? Unrelated neurotoxicants converge on cell cycle and apoptosis during neurodifferentiation. AB - Mechanistically unrelated developmental neurotoxicants often produce neural cell loss culminating in similar functional and behavioral outcomes. We compared an organophosphate pesticide (diazinon), an organochlorine pesticide (dieldrin) and a metal (Ni(2+)) for effects on the genes regulating cell cycle and apoptosis in differentiating PC12 cells, an in vitro model of neuronal development. Each agent was introduced at 30MUM for 24 or 72h, treatments devoid of cytotoxicity. Using microarrays, we examined the mRNAs encoding nearly 400 genes involved in each of the biological processes. All three agents targeted both the cell cycle and apoptosis pathways, evidenced by significant transcriptional changes in 40-45% of the cell cycle-related genes and 30-40% of the apoptosis-related genes. There was also a high degree of overlap as to which specific genes were affected by the diverse agents, with 80 cell cycle genes and 56 apoptosis genes common to all three. Concordance analysis, which assesses stringent matching of the direction, magnitude and timing of the transcriptional changes, showed highly significant correlations for pairwise comparisons of all the agents, for both cell cycle and apoptosis. Our results show that otherwise disparate developmental neurotoxicants converge on common cellular pathways governing the acquisition and programmed death of neural cells, providing a specific link to cell deficits. Our studies suggest that identifying the initial mechanism of action of a developmental neurotoxicant may be strategically less important than focusing on the pathways that converge on common final outcomes such as cell loss. PMID- 22546819 TI - To what extent should para-aortic lymphadenectomy be carried out for surgically staged endometrial cancer? AB - OBJECTIVE: To investigate the involvement of lymph nodes in para-aortic (PA) region particularly above and below the inferior mesenteric artery (IMA) in patients with endometrial cancer who had complete systemic pelvic and PA lymphadenectomy. METHODS: A total of 165 consecutive patients with endometrial cancer surgically staged from January 2008 to March 2011 in the gynecologic oncology unit of a tertiary maternity center, Zekai Tahir Burak Hospital, Ankara, Turkey, were included retrospectively. All patients had complete pelvic and PA lymphadenectomy. RESULTS: Nineteen women had any metastasis in pelvic and/or PA region. Twelve women (7.3%) had only pelvic, 5 women (3%) had both pelvic and PA, and 2 women had isolated PA metastasis. There were 6 patients (3.7%) with PA nodal metastasis above the IMA. Four patients with PA node involvement had positive nodes above the IMA without any metastasis below the IMA. In binary logistic regression analysis, PA metastasis above the IMA was associated with lymphovascular space invasion, pelvic metastasis, and tumor size. CONCLUSIONS: Isolated PA metastasis is rare in endometrial cancer. If pelvic nodes are involved, PA metastasis is likely, and PA lymphadenectomy should be performed up to renal vessels so as not to miss occult metastasis in higher regions particularly above the IMA. PMID- 22546818 TI - Methylmercury tolerance is associated with the humoral stress factor gene Turandot A. AB - Methylmercury (MeHg) is an environmental neurotoxicant that targets the developing nervous system. In an effort to understand mechanisms of MeHg toxicity we have identified candidate genes that confer tolerance to MeHg using a Drosophila model. Whole genome transcript profiling of developing larval brains of MeHg-tolerant and non-tolerant flies has identified Turandot A (TotA) as a potential MeHg tolerance gene. TotA is a secreted humoral stress response factor in Drosophila that is a direct target of conserved innate immunity signaling pathways. Here we characterize TotA expression in newly generated isogenic lines (isolines) of flies derived from our previously established MeHg-tolerant and non tolerant populations. TotA mRNA transcript and protein expression is seen to be higher in the tolerant isolines than the non-tolerant lines. Elevated TotA expression in the tolerant lines was seen to span all the larval developmental stages pointing toward a difference in the TotA gene regulation between the MeHg tolerant and non-tolerant strains. We show that TotA is most highly expressed in the fat body (liver equivalent) and is selectively upregulated in the fat body of tolerant flies relative to brain and gut tissues. Fat body-specific transgenic expression of TotA invokes MeHg tolerance as seen by enhanced development of flies reared on MeHg food. In addition, cell based assays show that high TotA expressing C6 cells are more tolerant to MeHg than the low TotA expressing S2 cells. Knockdown of TotA in the C6 cells trends toward a reduction in MeHg tolerance. Identification of TotA as a MeHg tolerance gene suggests a role for conserved cytokine/immune signaling pathways in modulating MeHg toxicity. PMID- 22546820 TI - The role of positron emission tomography following radiosurgical treatment of malignant lung lesions. AB - OBJECTIVE: To establish response patterns in PET following stereotactic body radiotherapy (SBRT) of malignant lung lesions. METHODS: Patients with malignant lung lesions treated with SBRT were retrospectively reviewed. All patients received 40-52 Gy in three to five equal fractions. An independent, blinded radiologist reassessed all 18F-fluoro-deoxy-glucose PET/computed tomography scans to determine the tumor maximum standardized uptake value (SUVmax) and size changes. RESULTS: Thirty-nine patients were included in this study. Of the 47 lesions treated, there were 22 primary and 25 metastatic lung lesions. In total, 86 PET/computed tomography studies were reviewed. The mean SUVmax values decreased markedly and stabilized after 6 months following the treatment of primary lesions. Metastatic lesions showed greater variability, with an overall increase in SUVmax values until 6 months and decrease thereafter. Of the eight local failures, the mean SUVmax and size change from nadir values to biopsy proven failure were 117 and 215%; however, it was difficult to measure the size of five lesions because of fibrotic changes. Statistical analysis revealed metastatic tumors to be associated with poorer local control (P=0.028). No correlation was found between size or pretreatment SUVmax and outcome. CONCLUSION: Anticipated SUVmax and size patterns following SBRT remain a challenge due to surrounding tissue reactions. Nonetheless, marked SUVmax changes can aid in determining local failure. Increases in size were also observed in local failures; however, localized fibrosis challenges its utility in distinguishing failures from a normal tissue response. A larger series needs to be examined to better establish the correlation of PET responses to overall survival and local control. PMID- 22546821 TI - The effect of functional compensation among duplicate genes can constrain their evolutionary divergence. AB - Gene duplicates have the inherent property of initially being functionally redundant. This means that they can compensate for the effect of deleterious variation occurring at one or more sister sites. Here, I present data bearing on evolutionary theory that illustrates the manner in which any functional adaptation in duplicate genes is markedly constrained because of the compensatory utility provided by a sustained genetic redundancy. Specifically, a two-locus epistatic model of paralogous genes was simulated to investigate the degree of purifying selection imposed, and whether this would serve to impede any possible biochemical innovation. Three population sizes were considered to see if, as expected, there was a significant difference in any selection for robustness. Interestingly, physical linkage between tandem duplicates was actually found to increase the probability of any neofunctionalization and the efficacy of selection, contrary to what is expected in the case of singleton genes. The results indicate that an evolutionary trade-off often exists between any functional change under either positive or relaxed selection and the need to compensate for failures due to degenerative mutations, thereby guaranteeing the reliability of protein production. PMID- 22546822 TI - Molecular evaluation of genetic diversity and association studies in rice (Oryza sativa L.). AB - In the present study, we tested rice genotypes that included un(der)exploited landraces of Tamil Nadu along with indica and japonica test cultivars to ascertain their genetic diversity structure. Highly polymorphic microsatellite markers were used for generating marker segregation data. A novel measure, allele discrimination index, was used to determine subpopulation differentiation power of each marker. Phenotypic data were collected for yield and component traits. Pattern of molecular differentiation separated indica and japonica genotypes; indica genotypes had two subpopulations within. Landraces were found to have indica genome, but formed a separate subgroup with low linkage disequilibrium. The landraces further separated into distinct group in both hierarchical clustering analysis using neighbour-joining method as well as in the model based population structure analysis. Japonica and the remaining indica cultivars formed two other distinct groups. Linkage disequilibrium observed in the whole population was considerably reduced in subpopulations. Low linkage disequilibrium of landforms suggests their narrow adaptation in local geographical niche. Many population specific alleles could be identified particularly for japonica cultivars and landraces. Association analysis revealed nine marker-trait associations with three agronomic traits, of which 67% were previously reported. Although the testing landraces together with known cultivars had permitted genomewide association mapping, the experiment offers scope to study more landraces collected from the entire geographical region for drawing more reliable information. PMID- 22546823 TI - Development of SSR markers and construction of a linkage map in jute. AB - Jute is an important natural fibre crop, which is only second to cotton in its importance at the global level. It is mostly grown in Indian subcontinent and has been recently used for the development of genomics resources.We recently initiated a programme to develop simple sequence repeat markers and reported a set of 2469 SSR that were developed using four SSR-enriched libraries (Mir et al. 2009). In this communication, we report an additional set of 607 novel SSR in 393 SSR containing sequences. However, primers could be designed for only 417 potentially useful SSR. Polymorphism survey was carried out for 374 primer pairs using two parental genotypes (JRO 524 and PPO4) of a mapping population developed for fibre fineness; only 66 SSR were polymorphic. Owing to a low level of polymorphism between the parental genotypes and a high degree of segregation distortion in recombinant inbred lines, genotypic data of only 53 polymorphic SSR on the mapping population consisting of 120 RIL could be used for the construction of a linkage map; 36 SSR loci were mapped on six linkage groups that covered a total genetic distance of 784.3 cM. Hopefully, this map will be enriched with more SSR loci in future and will prove useful for identification of quantitative trait loci/genes for molecular breeding involving improvement of fibre fineness and other related traits in jute. PMID- 22546824 TI - Genetics of flowering time in bread wheat Triticum aestivum: complementary interaction between vernalization-insensitive and photoperiod-insensitive mutations imparts very early flowering habit to spring wheat. AB - Time to flowering in the winter growth habit bread wheat is dependent on vernalization (exposure to cold conditions) and exposure to long days (photoperiod). Dominant Vrn-1 (Vrn-A1, Vrn-B1 and Vrn-D1) alleles are associated with vernalization independent spring growth habit. The semidominant Ppd-D1a mutation confers photoperiod-insensitivity or rapid flowering in wheat under short day and long day conditions. The objective of this study was to reveal the nature of interaction between Vrn-1 and Ppd-D1a mutations (active alleles of the respective genes vrn-1 and Ppd-D1b). Twelve Indian spring wheat cultivars and the spring wheat landrace Chinese Spring were characterized for their flowering times by seeding them every month for five years under natural field conditions in New Delhi. Near isogenic Vrn-1 Ppd-D1 and Vrn-1 Ppd-D1a lines constructed in two genetic backgrounds were also phenotyped for flowering time by seeding in two different seasons. The wheat lines of Vrn-A1a Vrn-B1 Vrn-D1 Ppd-D1a, Vrn-A1a Vrn B1 Ppd-D1a and Vrn-A1a Vrn-D1 Ppd-D1a (or Vrn-1 Ppd-D1a) genotypes flowered several weeks earlier than that of Vrn-A1a Vrn-B1 Vrn-D1 Ppd-D1b, Vrn-A1b Ppd-D1b and Vrn-D1 Ppd-D1b (or Vrn-1 Ppd-D1b) genotypes. The flowering time phenotypes of the isogenic vernalization-insensitive lines confirmed that Ppd-D1a hastened flowering by several weeks. It was concluded that complementary interaction between Vrn-1 and Ppd-D1a active alleles imparted super/very-early flowering habit to spring wheats. The early and late flowering wheat varieties showed differences in flowering time between short day and long day conditions. The flowering time in Vrn-1 Ppd-D1a genotypes was hastened by higher temperatures under long day conditions. The ambient air temperature and photoperiod parameters for flowering in spring wheat were estimated at 25 degrees C and 12 h, respectively. PMID- 22546826 TI - Interploidy interspecific hybridization in Fuchsia. PMID- 22546825 TI - Characterization of variation and quantitative trait loci related to terpenoid indole alkaloid yield in a recombinant inbred line mapping population of Catharanthus roseus. AB - Improved Catharanthus roseus cultivars are required for high yields of vinblastine, vindoline and catharanthine and/or serpentine and ajmalicine, the pharmaceutical terpenoid indole alkaloids. An approach to derive them is to map QTL for terpenoid indole alkaloids yields, identify DNA markers tightly linked to the QTL and apply marker assisted selection. Towards the end, 197 recombinant inbred lines from a cross were grown over two seasons to characterize variability for seven biomass and 23 terpenoid indole alkaloids content-traits and yield traits. The recombinant inbred lines were genotyped for 178 DNA markers which formed a framework genetic map of eight linkage groups (LG), spanning 1786.5 cM, with 10.0 cM average intermarker distance. Estimates of correlations between traits allowed selection of seven relatively more important traits for terpenoid indole alkaloids yields. QTL analysis was performed on them using single marker (regression) analysis, simple interval mapping and composite interval mapping procedures. A total of 20 QTL were detected on five of eight LG, 10 for five traits on LG1, five for four traits on LG2, three for one trait on LG3 and one each for different traits on LG three and four. QTL for the same or different traits were found clustered on three LG. Co-location of two QTL for biomass traits was in accord of correlation between them. The QTL were validated for use in marker assisted selection by the recombinant inbred line which transgressively expressed 16 traits contributory to the yield vinblastine, vindoline and catharanthine from leaves and roots that possessed favourable alleles of 13 relevant QTL. PMID- 22546827 TI - Association of four apolipoprotein B polymorphisms with lipid profile and stenosis in Tunisian coronary patients. PMID- 22546828 TI - Barriers to gene flow in interspecific hybridization in Fuchsia L. (Onagraceae). PMID- 22546829 TI - Association between OPG, RANK and RANKL gene polymorphisms and susceptibility to acute coronary syndrome in Korean population. PMID- 22546830 TI - Screening of three Mediterranean phenylketonuria mutations in Tunisian families. PMID- 22546831 TI - Expression of LDOC1 mRNA in leucocytes of patients with Down's syndrome. PMID- 22546832 TI - Genetic diversity analysis of Tinospora cordifolia germplasm collected from northwestern Himalayan region of India. PMID- 22546833 TI - Transcriptional changes of mitochondrial genes in irradiated cells proficient or deficient in p53. PMID- 22546834 TI - Multiparent intercross populations in analysis of quantitative traits. AB - Most traits of interest to medical, agricultural and animal scientists show continuous variation and complex mode of inheritance. DNA-based markers are being deployed to analyse such complex traits, that are known as quantitative trait loci (QTL). In conventional QTL analysis, F2, backcross populations, recombinant inbred lines, backcross inbred lines and double haploids from biparental crosses are commonly used. Introgression lines and near isogenic lines are also being used for QTL analysis. However, such populations have major limitations like predominantly relying on the recombination events taking place in the F1 generation and mapping of only the allelic pairs present in the two parents. The second generation mapping resources like association mapping, nested association mapping and multiparent intercross populations potentially address the major limitations of available mapping resources. The potential of multiparent intercross populations in gene mapping has been discussed here. In such populations both linkage and association analysis can be conductted without encountering the limitations of structured populations. In such populations, larger genetic variation in the germplasm is accessed and various allelic and cytoplasmic interactions are assessed. For all practical purposes, across crop species, use of eight founders and a fixed population of 1000 individuals are most appropriate. Limitations with multiparent intercross populations are that they require longer time and more resource to be generated and they are likely to show extensive segregation for developmental traits, limiting their use in the analysis of complex traits. However, multiparent intercross population resources are likely to bring a paradigm shift towards QTL analysis in plant species. PMID- 22546835 TI - Multi-platform characterization of the human cerebrospinal fluid metabolome: a comprehensive and quantitative update. AB - BACKGROUND: Human cerebral spinal fluid (CSF) is known to be a rich source of small molecule biomarkers for neurological and neurodegenerative diseases. In 2007, we conducted a comprehensive metabolomic study and performed a detailed literature review on metabolites that could be detected (via metabolomics or other techniques) in CSF. A total of 308 detectable metabolites were identified, of which only 23% were shown to be routinely identifiable or quantifiable with the metabolomics technologies available at that time. The continuing advancement in analytical technologies along with the growing interest in CSF metabolomics has led us to re-visit the human CSF metabolome and to re-assess both its size and the level of coverage than can be achieved with today's technologies. METHODS: We used five analytical platforms, including nuclear magnetic resonance (NMR), gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), direct flow injection-mass spectrometry (DFI-MS/MS) and inductively coupled plasma-mass spectrometry (ICP-MS) to perform quantitative metabolomics on multiple human CSF samples. This experimental work was complemented with an extensive literature review to acquire additional information on reported CSF compounds, their concentrations and their disease associations. RESULTS: NMR, GC-MS and LC-MS methods allowed the identification and quantification of 70 CSF metabolites (as previously reported). DFI-MS/MS allowed the quantification of 78 metabolites (6 acylcarnitines, 13 amino acids, hexose, 42 phosphatidylcholines, 2 lyso-phosphatidylcholines and 14 sphingolipids), while ICP-MS provided quantitative results for 33 metal ions in CSF. Literature analysis led to the identification of 57 more metabolites. In total, 476 compounds have now been confirmed to exist in human CSF. CONCLUSIONS: The use of improved metabolomic and other analytical techniques has led to a 54% increase in the known size of the human CSF metabolome over the past 5 years. Commonly available metabolomic methods, when combined, can now routinely identify and quantify 36% of the 'detectable' human CSF metabolome. Our experimental works measured 78 new metabolites that, as per our knowledge, have not been reported to be present in human CSF. An updated CSF metabolome database containing the complete set of 476 human CSF compounds, their concentrations, related literature references and links to their known disease associations is freely available at the CSF metabolome database. PMID- 22546836 TI - Three is not a crowd: efficient sensitization of TiO2 by a bulky trichromic trisheteroleptic cycloruthenated dye. AB - A cyclometalated Ru dye bearing two triphenylamine groups to augment light absorption exhibits a power conversion efficiency (PCE) in excess of 7% in the dye-sensitized solar cell despite having a large molecular footprint on TiO(2). PMID- 22546837 TI - Toxicity in patients receiving adjuvant docetaxel + hormonal treatment after radical radiotherapy for intermediate or high-risk prostate cancer: a preplanned safety report of the SPCG-13 trial. AB - BACKGROUND: Radical radiotherapy (RT) combined with androgen deprivation therapy is currently the standard treatment for elderly patients with localized intermediate- or high-risk prostate cancer (PC). To increase the recurrence-free and overall survival, we conducted an adjuvant, randomized trial using docetaxel (T) in PC patients (Scandinavian Prostate Cancer Group trial 13). METHODS: The inclusion criteria are the following: men >18 and <=75 years of age, WHO/ECOG performance status 0--1, histologically proven PC within 12 months before randomization and one of the following: T2, Gleason 7 (4+3), PSA >10; T2, Gleason 8--10, any PSA; or any T3 tumors. Neoadjuvant/adjuvant hormone therapy is mandatory for all patients. The patients were randomized to receive six cycles of T (75 mgm(-2) d 1. cycle 21 d) or no docetaxel after radical RT (with a minimum tumor dose of 74 Gy). This study identifier number is NTC 006653848 (http://www.clinicaltrials.org). RESULTS: In this preplanned safety analysis of 100 patients, T treatment induced grade (G) 3 adverse events (AEs) in 15 patients (30%) and G4 AEs in 30 patients (60%), mainly due to bone marrow toxicity. Neutropenia G3--4 was observed in 72% of the patients, febrile neutropenia was found in 24% of patients, neutropenic infection in 10% of patients and G3 infection without neutropenia in 4% of patients. Nonhematological G3 AEs were rare: anorexia, diarrhea, mucositis, nausea, pain (1 patient each) and fatigue (5). Other severe serious AEs related to T were pulmonary embolism and renal failure. However, only three patients discontinued T before completing the planned six cycles. No deaths had occurred. No patients in the control arm experienced G3--4 toxicities at 12 weeks after the randomization. CONCLUSIONS: Adjuvant docetaxel chemotherapy after radiotherapy has a higher frequency of neutropenia than previous studies on patients with metastatic disease. Otherwise, the treatment was quite well tolerated. PMID- 22546838 TI - Role of squalene synthase in prostate cancer risk and the biological aggressiveness of human prostate cancer. AB - BACKGROUND: We previously conducted a genome-wide linkage analysis of Japanese nuclear families affected with prostate cancer and showed that the susceptibility to prostate cancer was closely linked to D8S550 at 8p23. The role of farnesyl diphosphate farnesyltransferase (FDFT1), which is located under the peak marker D8S550 at 8p23, and squalene synthase, the enzyme encoded by FDFT1, in prostate cancer was studied. METHODS: The association among common variants of FDFT1 with prostate cancer risk, the promoter activities of FDFT1 with different genotypes and the effects of inhibition of squalene synthase were studied, and the FDFT1 transcript levels of human prostate samples were quantified. RESULTS: The A allele of rs2645429 was significantly associated with prostate cancer risk in a Japanese familial prostate cancer population. Rs2645429 was located in the promoter region of FDFT1, and the AA genotype showed significantly increased promoter activity. The knockdown of FDFT1 mRNA expression or squalene synthase inhibition led to a significant decrease in prostate cancer cell proliferation. Additionally, human prostate cancer specimens expressed significantly higher levels of FDFT1 mRNA compared with noncancerous specimens. Finally, aggressive cancers showed higher transcript levels. CONCLUSIONS: FDFT1 and its encoded enzyme, squalene synthase, may play an important role in prostate cancer development and its aggressive phenotypes. PMID- 22546840 TI - Recent developments in asymmetric multicomponent reactions. AB - Multicomponent reactions (MCRs) receive increasing attention because they address both diversity and complexity in organic synthesis. Thus, in principle diverse sets of relatively complex structures can be generated from simple starting materials in a single reaction step. The ever increasing need for optically pure compounds for pharmaceutical and agricultural applications as well as for catalysis promotes the development of asymmetric multicomponent reactions. In recent years, asymmetric multicomponent reactions have been applied to the total synthesis of various enantiopure natural products and commercial drugs, reducing the number of required reaction steps significantly. Although many developments in diastereoselective MCRs have been reported, the field of catalytic enantioselective MCRs has just started to blossom. This critical review describes developments in both diastereoselective and catalytic enantioselective multicomponent reactions since 2004. Significantly broadened scopes, new techniques, more environmentally benign methods and entirely novel MCRs reflect the increasingly inventive paths that synthetic chemist follow in this field. Until recently, enantioselective transition metal-catalyzed MCRs represented the majority of catalytic enantioselective MCRs. However, metal contamination is highly undesirable for drug synthesis. The emergence of organocatalysis greatly influences the quest for new asymmetric MCRs. PMID- 22546841 TI - Quantification of fungal colonization, sporogenesis, and production of mycotoxins using kernel bioassays. AB - The rotting of grains by seed-infecting fungi poses one of the greatest economic challenges to cereal production worldwide, not to mention serious risks to human and animal health. Among cereal production, maize is arguably the most affected crop, due to pathogen-induced losses in grain integrity and mycotoxin seed contamination. The two most prevalent and problematic mycotoxins for maize growers and food and feed processors are aflatoxin and fumonisin, produced by Aspergillus flavus and Fusarium verticillioides, respectively. Recent studies in molecular plant-pathogen interactions have demonstrated promise in understanding specific mechanisms associated with plant responses to fungal infection and mycotoxin contamination(1,2,3,4,5,6). Because many labs are using kernel assays to study plant-pathogen interactions, there is a need for a standardized method for quantifying different biological parameters, so results from different laboratories can be cross-interpreted. For a robust and reproducible means for quantitative analyses on seeds, we have developed in-lab kernel assays and subsequent methods to quantify fungal growth, biomass, and mycotoxin contamination. Four sterilized maize kernels are inoculated in glass vials with a fungal suspension (10(6)) and incubated for a predetermined period. Sample vials are then selected for enumeration of conidia by hemocytometer, ergosterol-based biomass analysis by high performance liquid chromatography (HPLC), aflatoxin quantification using an AflaTest fluorometer method, and fumonisin quantification by HPLC. PMID- 22546842 TI - Ezetimibe: A biomarker for efficacy of liver directed UGT1A1 gene therapy for inherited hyperbilirubinemia. AB - As recently demonstrated in patients with factor IX deficiency, adeno-associated virus (AAV)-mediated liver-directed therapy is a viable option for inherited metabolic liver disorders. Our aim is to treat Crigler-Najjar syndrome type I (CN I), an inherited severe unconjugated hyperbilirubinemia, as a rare recessive inherited disorder. Because the number of patients eligible for this approach is small, the efficacy can only be demonstrated by a beneficial effect on the pathophysiology in individual patients. Serum bilirubin levels in potential candidates have been monitored since birth, providing an indication of their pathophysiology. Adjuvant phototherapy to prevent brain damage reduces serum unconjugated bilirubin (UCB) levels in CN I patients to the level seen in the milder form of the disease, CN type II. This therapy increases the excretion of UCB, thereby complicating the use of UCB and conjugated bilirubin levels in serum as biomarkers for the gene therapy we try to develop. Therefore, a suitable biomarker that is not affected by phototherapy is currently needed. To this end, we have investigated whether estradiol, ethinylestradiol or ezetimibe could be used as markers for uridine 5'-di-phospho-glucuronosyltransferase isoform 1A1 (UGT1A1) activity restored by AAV gene therapy in Gunn rats, a relevant animal model for CN I. Of these compounds, ezetimibe appeared most suitable because its glucuronidation rate in untreated control Gunn rats is low. Subsequently, ezetimibe glucuronidation was studied in both untreated and AAV-treated Gunn rats and the results suggest that it may serve as a useful serum marker for restored hepatic UGT1A1 activity. PMID- 22546843 TI - Influence of gilaburu (Viburnum opulus) juice on 1,2-dimethylhydrazine (DMH) induced colon cancer. AB - In this study, the effects of gilaburu (Viburnum opulus) juice on colon tumorogenesis were investigated. Eight weeks old Balb-C male mice received subcutaneous injections of 1,2-dimethylhydrazine (DMH) (20 mg/kg body weight) once a week for 12 weeks. Both the sham control (group 1) and the DMH control (group 2) groups received drinking water alone, whereas the mice of groups 3 and 4 received gilaburu juice for 30 weeks (started with first DMH injection) and for 18 weeks (started after last DMH injection), respectively. Eighteen weeks after the last DMH injection, all mice were killed and the histogenesis of colon tumors was investigated from the paraffin-embedded sections of colon, which were stained with hematoxylin-eosin. The sites and incidences of tumoral lesions (low-grade dysplasia, high-grade dysplasia, intramucosal carcinoma and invasive carcinoma) were analyzed and compared with control. The results showed that the body weights of the mice were similar in all the groups. No tumoral lesions were found in group 1. Colon tumors developed in all DMH-treated mice (groups 2, 3 and 4). In these groups, the greatest numbers of tumor lesions were detected in the distal colon, followed by the mid-colon and only a few in the proximal colon. There was a reduction in the mean total number of tumor lesion in groups 3 (8.5) and 4 (8.3), when compared to group 2 (11.3). The incidence of invasive carcinoma in group 3 was significantly lower than group 2 (p < 0.05). On the basis of these results, we conclude that gilaburu juice may be useful for the prevention of colon cancer at the initiation stage. PMID- 22546844 TI - Serum levels of copper, selenium and manganese in forestry workers testing IgG positive for Brucella, Borrelia, and Rickettsia. AB - The aim of this study is to measure the alterations in the trace levels of serum copper (Cu), selenium (Se), and manganese (Mn) in forestry workers testing immunoglobulin G (IgG)-positive for Brucella, Borrelia, and Rickettsia. The study was conducted on a sample of 758 subjects (560 male and 198 female). All the subjects underwent medical examinations, which investigated particularly the presence of clinical signs compatible with zoonoses, and routine blood tests from venous blood sample, which tested previous immunisation versus cited microorganisms and serum concentration of Cu, Se, and Mn. The subjects were divided according to IgG positivity versus the cited microorganisms. The group of subjects with IgG positive versus Brucella showed statistically significant higher Cu levels than controls, while the Mn levels were not; the group of subjects with IgG positive versus Rickettsia showed higher levels of all three tested metals. The concentration of the examined metals did not show statistically significant difference between IgG-positive subjects versus subjects with Borrelia compared to controls. These data could confirm the role of both Cu and Se in the regulation of immune response. PMID- 22546846 TI - Increase in the prevalence of multiple sclerosis over a 17-year period in Osona, Catalonia, Spain. AB - The prevalence of multiple sclerosis in the south of Europe seems to be higher than previously considered. This study aimed to probe a possible increase in the prevalence of multiple sclerosis (MS) in Osona over the past 17 years. This was a cross-sectional study including MS-confirmed cases from several sources of information. Crude and adjusted prevalence rates were obtained. One hundred and twenty patients fulfilled the study criteria. The crude prevalence of MS was 79.9 (95% CI: 66.3-95.6) per 100,000 inhabitants and 91.2 (95% CI: 75.5-109.2) per 100,000 among Spanish born individuals. The prevalence of multiple sclerosis cases in Osona has increased over the past 17 years to being one of the highest reported in Spain. PMID- 22546847 TI - Cognitive reserve and patient-reported outcomes in multiple sclerosis. AB - BACKGROUND: Adaptation and compensation in the face of changing pathology may be better understood by considering the concept of cognitive reserve, which may protect against disability in multiple sclerosis (MS). OBJECTIVES: The present work investigates the relationship between cognitive reserve and demographic characteristics, health behaviors, and patient-reported outcomes (PROs). METHODS: Cross-sectional data (n=1142) were drawn from the North American Research Committee on MS (NARCOMS) Registry, from whom additional survey data were collected. Cognitive reserve was measured using the Stern and Sole-Padulles measures, the O*NET occupational classification system, and the Godin Leisure Time Exercise Questionnaire. PROs were assessed using generic (SF -12v2, Perceived Deficits Questionnaire, Ryff Psychological Well-Being, Diener Satisfaction with Life Scale) and disease-specific (Patient-Determined Disease Steps, Performance Scales) measures. Psychometric analysis created unidimensional cognitive reserve subscales. Regression models examined relationships between cognitive reserve, demographic characteristics, and PROs. RESULTS: The cognitive reserve measures assessed distinct but related constructs. Individuals with high cognitive reserve were more likely to report lower levels of perceived disability and perceived cognitive deficits, and higher levels of physical health, mental health, and well-being. Both active and passive reserve are associated with better outcomes, independent of demographic factors, and these associations apply to both generic and disease-specific outcomes. CONCLUSIONS: This expanded measurement of cognitive reserve captures both the passive and active aspects of the construct, and there is a consistent and substantial relationship with PROs. Individuals with high passive and/or active reserve are healthier and experience higher levels of well-being. PMID- 22546848 TI - Assessment of ropinirole as a reinforcer in rhesus monkeys. AB - BACKGROUND: Ropinirole, a D(2)/D(3)/5-HT(1A) agonist, is used for the treatment of Parkinson's disease and restless leg syndrome, and is currently being evaluated as a treatment for cocaine dependence. However, there is little information available on ropinirole's reinforcing effects. METHODS: The current study tested ropinirole in monkeys (n=7) trained to self administer cocaine on a fixed-ratio 25 (FR 25) schedule of reinforcement to determine if it would function as a reinforcer. In addition, a behavioral economics approach was used in four monkeys to compare the reinforcing effectiveness of ropinirole to cocaine. RESULTS: Cocaine (0.01-0.3 mg/kg/injection) functioned as a reinforcer in all monkeys under the FR 25 schedule, and ropinirole (0.01-0.1mg/kg/injection) functioned as a reinforcer in all but one. Furthermore, cocaine was a more effective reinforcer than ropinirole as indexed by demand functions. CONCLUSION: The current data indicate that ropinirole has reinforcing effects in monkeys, although its effectiveness as a reinforcer is relatively weak. PMID- 22546849 TI - Psychosocial precursors and physical consequences of workplace violence towards nurses: a longitudinal examination with naturally occurring groups in hospital settings. AB - BACKGROUND: Workplace violence towards nurses is prevalent and consequential, contributing to nurses' reduced health and safety, worsened job attitudes, and compromised productivity. OBJECTIVES: To examine if organizational violence prevention climate as perceived by nurses predicts nurses' physical violence exposure and if physical violence exposure predicts nurses' somatic symptoms and musculoskeletal disorder symptoms. DESIGN: A two-wave longitudinal design with naturally occurring groups, with a 6-month interval. METHODS: Analysis of covariance and logistic regression were applied to test the proposed hypotheses among 176 nurses from two hospitals in the U.S. who participated in both surveys required by this study. All nurses from the two hospitals were recruited to participate voluntarily. The response rate was 30% for the first survey and 36% for the follow-up survey. Among the subjects, only 8 were male. On average, the subjects were about 45 years old, had a job tenure of about 17 years, and worked approximately 37 h per week. RESULTS: Violence prevention climate, specifically the dimension of perceived pressure against violence prevention, predicted nurses' chance of being exposed to physical violence over six months (odds ratio 1.69), with no evidence found that violence exposure affected change in climate reports. In addition, results supported that nurses' physical violence exposure had effects on somatic symptoms, and upper body, lower extremity, and low back pain over six months. CONCLUSIONS: Findings of this study suggest that reducing organizational pressure against violence prevention will help decrease the chance of nurses' physical violence exposure and benefit their health and safety. PMID- 22546850 TI - Biomarker discovery in human cerebrospinal fluid: the need for integrative metabolome and proteome databases. AB - The number of metabolites identified in human cerebrospinal fluid (CSF) has steadily increased over the past 5 years, and in this issue of Genome Medicine David Wishart and colleagues provide a comprehensive update that brings the number of metabolites listed in the CSF metabolome database to 476 compounds. There is now a need for an integrative metabolome-proteome CSF database to maximize the impact of this achievement in biomedical research. Only by such efforts can we hope to unravel the complexity of molecular pathophysiological processes. PMID- 22546851 TI - Hydrogen bond-mediated recognition of the chemical warfare agent soman (GD). AB - NMR titration studies in acetonitrile-d(3)/DMSO-d(6) mixtures demonstrate that diindolylurea-based receptors can form complexes with the organophosphorus nerve agent soman in organic solution. PMID- 22546852 TI - 14-3-3 regulates the LNK/JAK2 pathway in mouse hematopoietic stem and progenitor cells. AB - Hematopoietic stem and progenitor cell (HSPC) functions are governed by intricate signaling networks. The tyrosine kinase JAK2 plays an essential role in cytokine signaling during hematopoiesis. The adaptor protein LNK is a critical determinant of this process through its inhibitory interaction with JAK2, thereby limiting HSPC self-renewal. LNK deficiency promotes myeloproliferative neoplasm (MPN) development in mice, and LNK loss-of-function mutations are found in human MPNs, emphasizing its pivotal role in normal and malignant HSPCs. Here, we report the identification of 14-3-3 proteins as LNK binding partners. 14-3-3 interfered with the LNK-JAK2 interaction, thereby alleviating LNK inhibition of JAK2 signaling and cell proliferation. Binding of 14-3-3 required 2 previously unappreciated serine phosphorylation sites in LNK, and we found that their phosphorylation is mediated by glycogen synthase kinase 3 and PKA kinases. Mutations of these residues abrogated the interaction and augmented the growth inhibitory function of LNK. Conversely, forced 14-3-3 binding constrained LNK function. Furthermore, interaction with 14-3-3 sequestered LNK in the cytoplasm away from the plasma membrane-proximal JAK2. Importantly, bone marrow transplantation studies revealed an essential role for 14-3-3 in HSPC reconstitution that can be partially mitigated by LNK deficiency. We believe that, together, this work implicates 14-3 3 proteins as novel and positive HSPC regulators by impinging on the LNK/JAK2 pathway. PMID- 22546853 TI - microRNA-206 promotes skeletal muscle regeneration and delays progression of Duchenne muscular dystrophy in mice. AB - Skeletal muscle injury activates adult myogenic stem cells, known as satellite cells, to initiate proliferation and differentiation to regenerate new muscle fibers. The skeletal muscle-specific microRNA miR-206 is upregulated in satellite cells following muscle injury, but its role in muscle regeneration has not been defined. Here, we show that miR-206 promotes skeletal muscle regeneration in response to injury. Genetic deletion of miR-206 in mice substantially delayed regeneration induced by cardiotoxin injury. Furthermore, loss of miR-206 accelerated and exacerbated the dystrophic phenotype in a mouse model of Duchenne muscular dystrophy. We found that miR-206 acts to promote satellite cell differentiation and fusion into muscle fibers through suppressing a collection of negative regulators of myogenesis. Our findings reveal an essential role for miR 206 in satellite cell differentiation during skeletal muscle regeneration and indicate that miR-206 slows progression of Duchenne muscular dystrophy. PMID- 22546854 TI - Zona glomerulosa cells of the mouse adrenal cortex are intrinsic electrical oscillators. AB - Aldosterone, which plays a central role in the regulation of blood pressure, is produced by zona glomerulosa (ZG) cells of the adrenal gland. When dysregulated, aldosterone is pathogenic and contributes to the development and progression of cardiovascular and renal disease. Although sustained production of aldosterone requires persistent Ca2+ entry through low-voltage activated Ca2+ channels, isolated ZG cells are considered nonexcitable, with recorded membrane voltages that are too hyperpolarized to permit Ca2+ entry. Here, we show that mouse ZG cells within adrenal slices spontaneously generate membrane potential oscillations of low periodicity. This innate electrical excitability of ZG cells provides a platform for the production of a recurrent Ca2+ signal that can be controlled by Ang II and extracellular potassium, the 2 major regulators of aldosterone production. We conclude that native ZG cells are electrical oscillators, and that this behavior provides what we believe to be a new molecular explanation for the control of Ca2+ entry in these steroidogenic cells. PMID- 22546855 TI - Rorgammat+ innate lymphocytes and gammadelta T cells initiate psoriasiform plaque formation in mice. AB - Psoriasis is a common, relapsing inflammatory skin disease characterized by erythematous scaly plaques. Histological manifestations of psoriasis include keratinocyte dysregulation and hyperproliferation, elongated rete ridges, and inflammatory infiltrates consisting of T cells, macrophages, dendritic cells, and neutrophils. Despite the availability of new effective drugs to treat psoriasis, the underlying mechanisms of pathogenesis are still poorly understood. Recent studies have shown that Aldara cream, used to treat benign skin abnormalities, triggers psoriasis-like disease in humans and mice and have implicated Th17 cells in disease initiation. Using this as a model, we found a predominant role for the Th17 signature cytokines IL-17A, IL-17F, and IL-22 in psoriasiform plaque formation in mice. Using gene-targeted mice, we observed that loss of Il17a, Il17f, or Il22 strongly reduced disease the severity of psoriasis. However, we found that Th17 cells were not the primary source of these pathogenic cytokines. Rather, IL-17A, IL-17F, and IL-22 were produced by a skin-invading population of gammadelta T cells and RORgammat(+) innate lymphocytes. Furthermore, our findings establish that RORgammat(+) innate lymphocytes and gammadelta T cells are necessary and sufficient for psoriatic plaque formation in an experimental disease model that closely resembles human psoriatic plaque formation. PMID- 22546856 TI - Glutathione deficiency in type 2 diabetes impairs cytokine responses and control of intracellular bacteria. AB - Individuals with type 2 diabetes are at increased risk of acquiring melioidosis, a disease caused by Burkholderia pseudomallei infection. Although up to half of melioidosis patients have underlying diabetes, the mechanisms involved in this increased susceptibility are unknown. We found that B. pseudomallei-infected PBMCs from diabetic patients were impaired in IL-12p70 production, which resulted in decreased IFN-gamma induction and poor bacterial killing. The defect was specific to the IL-12-IFN-gamma axis. Defective IL-12 production was also observed during Mycobacterium tuberculosis infection, in which diabetes is likewise known to be a strong risk factor. In contrast, IL-12 production in diabetic cells was not affected upon Salmonella enterica infection or in response to TLR2, -3, -4, and -5 ligands. Poor IL-12 production correlated with a deficiency in intracellular reduced glutathione (GSH) concentrations in diabetic patients. Addition of GSH or N-acetylcysteine to PBMCs selectively restored IL-12 and IFN-gamma production and improved bacterial killing. Furthermore, the depletion of GSH in mice led to increased susceptibility to melioidosis, reduced production of IL-12p70, and poorer disease outcome. Our data thus establish a link between GSH deficiency in diabetes and increased susceptibility to melioidosis that may open up new therapeutic avenues to protect diabetic patients against some intracellular bacterial pathogens. PMID- 22546857 TI - CD19 is a major B cell receptor-independent activator of MYC-driven B lymphomagenesis. AB - PAX5, a B cell-specific transcription factor, is overexpressed through chromosomal translocations in a subset of B cell lymphomas. Previously, we had shown that activation of immunoreceptor tyrosine-based activation motif (ITAM) proteins and B cell receptor (BCR) signaling by PAX5 contributes to B lymphomagenesis. However, the effect of PAX5 on other oncogenic transcription factor-controlled pathways is unknown. Using a MYC-induced murine lymphoma model as well as MYC-transformed human B cell lines, we found that PAX5 controls c-MYC protein stability and steady-state levels. This promoter-independent, posttranslational mechanism of c-MYC regulation was independent of ITAM/BCR activity. Instead it was controlled by another PAX5 target, CD19, through the PI3K-AKT-GSK3beta axis. Consequently, MYC levels in B cells from CD19-deficient mice were sharply reduced. Conversely, reexpression of CD19 in murine lymphomas with spontaneous silencing of PAX5 boosted MYC levels, expression of its key target genes, cell proliferation in vitro, and overall tumor growth in vivo. In human B-lymphomas, CD19 mRNA levels were found to correlate with those of MYC activated genes. They also negatively correlated with the overall survival of patients with lymphoma in the same way that MYC levels do. Thus, CD19 is a major BCR-independent regulator of MYC-driven neoplastic growth in B cell neoplasms. PMID- 22546858 TI - SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice. AB - Chronic obstructive pulmonary disease/emphysema (COPD/emphysema) is characterized by chronic inflammation and premature lung aging. Anti-aging sirtuin 1 (SIRT1), a NAD+-dependent protein/histone deacetylase, is reduced in lungs of patients with COPD. However, the molecular signals underlying the premature aging in lungs, and whether SIRT1 protects against cellular senescence and various pathophysiological alterations in emphysema, remain unknown. Here, we showed increased cellular senescence in lungs of COPD patients. SIRT1 activation by both genetic overexpression and a selective pharmacological activator, SRT1720, attenuated stress-induced premature cellular senescence and protected against emphysema induced by cigarette smoke and elastase in mice. Ablation of Sirt1 in airway epithelium, but not in myeloid cells, aggravated airspace enlargement, impaired lung function, and reduced exercise tolerance. These effects were due to the ability of SIRT1 to deacetylate the FOXO3 transcription factor, since Foxo3 deficiency diminished the protective effect of SRT1720 on cellular senescence and emphysematous changes. Inhibition of lung inflammation by an NF-kappaB/IKK2 inhibitor did not have any beneficial effect on emphysema. Thus, SIRT1 protects against emphysema through FOXO3-mediated reduction of cellular senescence, independently of inflammation. Activation of SIRT1 may be an attractive therapeutic strategy in COPD/emphysema. PMID- 22546859 TI - STIM1 regulates calcium signaling in taste bud cells and preference for fat in mice. AB - Understanding the mechanisms underlying oro-gustatory detection of dietary fat is critical for the prevention and treatment of obesity. The lipid-binding glycoprotein CD36, which is expressed by circumvallate papillae (CVP) of the mouse tongue, has been implicated in oro-gustatory perception of dietary lipids. Here, we demonstrate that stromal interaction molecule 1 (STIM1), a sensor of Ca(2+) depletion in the endoplasmic reticulum, mediates fatty acid-induced Ca(2+) signaling in the mouse tongue and fat preference. We showed that linoleic acid (LA) induced the production of arachidonic acid (AA) and lysophosphatidylcholine (Lyso-PC) by activating multiple phospholipase A2 isoforms via CD36. This activation triggered Ca(2+) influx in CD36-positive taste bud cells (TBCs) purified from mouse CVP. LA also induced the production of Ca(2+) influx factor (CIF). STIM1 was found to regulate LA-induced CIF production and the opening of multiple store-operated Ca(2+) (SOC) channels. Furthermore, CD36-positive TBCs from Stim1-/- mice failed to release serotonin, and Stim1-/- mice lost the spontaneous preference for fat that was observed in wild-type animals. Our results suggest that fatty acid-induced Ca(2+) signaling, regulated by STIM1 via CD36, might be implicated in oro-gustatory perception of dietary lipids and the spontaneous preference for fat. PMID- 22546861 TI - Constitutively, pathologically, profoundly. PMID- 22546860 TI - The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans. AB - Nonalcoholic fatty liver disease (NAFLD) is associated with all features of the metabolic syndrome. Although deposition of excess triglycerides within liver cells, a hallmark of NAFLD, is associated with a loss of insulin sensitivity, it is not clear which cellular abnormality arises first. We have explored this in mice overexpressing carbohydrate responsive element-binding protein (ChREBP). On a standard diet, mice overexpressing ChREBP remained insulin sensitive, despite increased expression of genes involved in lipogenesis/fatty acid esterification and resultant hepatic steatosis (simple fatty liver). Lipidomic analysis revealed that the steatosis was associated with increased accumulation of monounsaturated fatty acids (MUFAs). In primary cultures of mouse hepatocytes, ChREBP overexpression induced expression of stearoyl-CoA desaturase 1 (Scd1), the enzyme responsible for the conversion of saturated fatty acids (SFAs) into MUFAs. SFA impairment of insulin-responsive Akt phosphorylation was therefore rescued by the elevation of Scd1 levels upon ChREBP overexpression, whereas pharmacological or shRNA-mediated reduction of Scd1 activity decreased the beneficial effect of ChREBP on Akt phosphorylation. Importantly, ChREBP-overexpressing mice fed a high fat diet showed normal insulin levels and improved insulin signaling and glucose tolerance compared with controls, despite having greater hepatic steatosis. Finally, ChREBP expression in liver biopsies from patients with nonalcoholic steatohepatitis was increased when steatosis was greater than 50% and decreased in the presence of severe insulin resistance. Together, these results demonstrate that increased ChREBP can dissociate hepatic steatosis from insulin resistance, with beneficial effects on both glucose and lipid metabolism. PMID- 22546862 TI - Uncovering the role of genomic "dark matter" in human disease. AB - The human genome encodes thousands of long noncoding RNAs (lncRNAs). Although most remain functionally uncharacterized biological "dark matter," lncRNAs have garnered considerable attention for their diverse roles in human biology, including developmental programs and tumor suppressor gene networks. As the number of lncRNAs associated with human disease grows, ongoing research efforts are focusing on their regulatory mechanisms. New technologies that enable enumeration of lncRNA interaction partners and determination of lncRNA structure are well positioned to drive deeper understanding of their functions and involvement in pathogenesis. In turn, lncRNAs may become targets for therapeutic intervention or new tools for biotechnology. PMID- 22546863 TI - Copolymer-supported heterogeneous organocatalyst for asymmetric aldol addition in aqueous medium. AB - In the current study, a convenient and simple way is presented to synthesize a novel type of supported heterogeneous organocatalyst in 21-81% yield by the copolymerization of 9-amino-9-deoxy-epi-cinchonine organocatalyst with acrylonitrile using AIBN as radical initiator. The chemical compositions (x/y) and weight-average molecular weights of copolymers 1a-d were determined by (1)H NMR and GPC analysis respectively. Their porous and layered structure, and surface morphology were characterized by nitrogen adsorption-desorption, XRD and TEM. In the asymmetric aldol addition of p-nitrobenzaldehyde to cyclohexanone and 1-hydroxy-2-propanone in water, all the supported organocatalysts 1a-d afforded excellent isolated yields (90.2-94.7%) and stereoselectivities (96.8-97.8%ee anti, anti/syn = 91/9). The highest catalytic property (96% yield, anti/syn = 90/10 and 99%ee anti) in water as the sole solvent was achieved under the optimized conditions. Compared with cyclohexanone, cyclopentanone and acetone showed the less desired enantioselectivities in the same aldol reactions. At the end of the aldol reaction, the copolymer-supported organocatalyst 1a was readily recovered in 95-98% yield from reaction mixture by simple filtration using an organic membrane. Even in the fifth run, there was no significant loss in catalytic activity and stereocontrol (94.3% yield, 97.2%ee anti, anti/syn = 90/10). After continuous reuse five times, there was some drop in catalytic activity and stereoselectivity. PMID- 22546865 TI - Circulating N-terminal pro-B-type natriuretic peptide in fetal anemia before and after treatment. AB - BACKGROUND: N-terminal pro-B-type natriuretic peptide (ntproBNP) is an established marker of heart failure in adult cardiology. We analyzed nt-proBNP in the circulation of fetuses with increased volume load secondary to anemia and investigated the effect of treatment on nt-proBNP concentration. METHODS: Fetuses undergoing intrauterine transfusion (IUT) were examined. nt-proBNP was measured before IUT and correlated with hemoglobin concentrations, ultrasonographic findings, and Doppler measurements of the peak systolic velocity of the middle cerebral artery (MCA-PSV). RESULTS: A total of 27 patients (7 with hydrops) and 78 controls were examined. nt-proBNP was markedly elevated in anemia (P < 0.001). Concentrations were highest in hydropic fetuses (P < 0.03); no differences were present in hemoglobin and MCA-PSV values between hydropic and nonhydropic cases. In fetuses undergoing multiple IUTs nt-proBNP normalized after the third IUT, whereas hemoglobin and MCA-PSV remained abnormal. CONCLUSION: Levels of circulating nt-proBNP correlate well with the degree of myocardial workload in the hyperdynamic state of fetal anemia. We hypothesize that normalization of nt proBNP after serial transfusions is an indicator of myocardial adjustment to chronic anemia. nt-proBNP measurement may be useful in the management of fetal anemia, particularly in cases at risk of hydrops and fetuses requiring multiple transfusions. PMID- 22546864 TI - Pediatric sarcomas: translating molecular pathogenesis of disease to novel therapeutic possibilities. AB - Pediatric sarcomas represent a diverse group of rare bone and soft tissue malignancies. Although the molecular mechanisms that propel the development of these cancers are not well understood, identification of tumor-specific translocations in many sarcomas has provided significant insight into their tumorigenesis. Each fusion protein resulting from these chromosomal translocations is thought to act as a driving force in the tumor, either as an aberrant transcription factor (TF), constitutively active growth factor, or ligand-independent receptor tyrosine kinase. Identification of transcriptional targets or signaling pathways modulated by these oncogenic fusions has led to the discovery of potential therapeutic targets. Some of these targets have shown considerable promise in preclinical models and are currently being tested in clinical trials. This review summarizes the molecular pathology of a subset of pediatric sarcomas with tumor-associated translocations and how increased understanding at the molecular level is being translated to novel therapeutic advances. PMID- 22546866 TI - Residual dormant cancer stem-cell foci are responsible for tumor relapse after antiangiogenic metronomic therapy in hepatocellular carcinoma xenografts. AB - Hepatocellular carcinoma (HCC) is the fifth most common solid tumor and the third leading cause of cancer-related deaths. Currently available chemotherapeutic options are not curative due in part to tumor resistance to conventional therapies. We generated orthotopic HCC mouse models in immunodeficient NOD/SCID/IL2rgamma null mice by injection of human alpha-feto protein (hAFP)- and/or luciferase-expressing HCC cell lines and primary cells from patients, where tumor growth and spread can be accurately monitored in a non-invasive way. In this model, low-dose metronomic administration of cyclophosphamide (LDM-CTX) caused complete regression of the tumor mass. A significant increase in survival (P<0.0001), reduced aberrant angiogenesis and hyperproliferation, and decrease in the number of circulating tumor cells were found in LDM-CTX-treated animals, in comparison with untreated mice. Co-administration of LDM-CTX with anti-VEGF therapy further improved the therapeutic efficacy. However, the presence of residual circulating hAFP levels suggested that some tumor cells were still present in livers of treated mice. Immunohistochemistry revealed that those cells had a hAFP+/CD13+/PCNA- phenotype, suggesting that they were dormant cancer stem cells (CSC). Indeed, discontinuation of therapy resulted in tumor regrowth. Moreover, in-vitro LDM-CTX treatment reduced hepatosphere formation in both number and size, and the resulting spheres were enriched in CD13+ cells indicating that these cells were particularly resistant to therapy. Co-treatment of the CD13-targeting drug, bestatin, with LDM-CTX leads to slower tumor growth and a decreased tumor volume. Therefore, combining a CD13 inhibitor, which targets the CSC-like population, with LDM-CTX chemotherapy may be used to eradicate minimal residual disease and improve the treatment of liver cancer. PMID- 22546875 TI - Colorectal cancer: translation of biological pathways into molecular imaging. PMID- 22546867 TI - Gene disruption of the calcium channel Orai1 results in inhibition of osteoclast and osteoblast differentiation and impairs skeletal development. AB - Calcium signaling plays a central role in the regulation of bone cells, although uncertainty remains with regard to the channels involved. In previous studies, we determined that the calcium channel Orai1 was required for the formation of multinucleated osteoclasts in vitro. To define the skeletal functions of calcium release-activated calcium currents, we compared the mice with targeted deletion of the calcium channel Orai1 to wild-type littermate controls, and examined differentiation and function of osteoblast and osteoclast precursors in vitro with and without Orai1 inhibition. Consistent with in vitro findings, Orai1(-/-) mice lacked multinucleated osteoclasts. Yet, they did not develop osteopetrosis. Mononuclear cells expressing osteoclast products were found in Orai1(-/-) mice, and in vitro studies showed significantly reduced, but not absent, mineral resorption by the mononuclear osteoclast-like cells that form in culture from peripheral blood monocytic cells when Orai1 is inhibited. More prominent in Orai1(-/-) mice was a decrease in bone with retention of fetal cartilage. Micro computed tomography showed reduced cortical ossification and thinned trabeculae in Orai1(-/-) animals compared with controls; bone deposition was markedly decreased in the knockout mice. This suggested a previously unrecognized role for Orai1 within osteoblasts. Analysis of osteoblasts and precursors in Orai1(-/-) and control mice showed a significant decrease in alkaline phosphatase-expressing osteoblasts. In vitro studies confirmed that inhibiting Orai1 activity impaired differentiation and function of human osteoblasts, supporting a critical function for Orai1 in osteoblasts, in addition to its role as a regulator of osteoclast formation. PMID- 22546876 TI - Microbial challenge tests on nonradioactive TiO2-based 68Ge/68Ga generator columns. AB - OBJECTIVES: The aim of this study was to test the survival of microorganisms in eluents used for (68)Ge/(68)Ga generators and for regeneration of nonradioactive (68)Ge/(68)Ga generator columns after high microbial load. Nonradioactive generator columns were loaded with various microorganisms and tested to determine whether the microorganisms were proliferating or surviving in eluates of the columns. MATERIALS AND METHODS: TiO(2) columns used in a commercially available (68)Ge/(68)Ga generators for absorption of (68)Ge were loaded with greater than 10(7) colony-forming units (CFU) of Staphylococcus aureus, Clostridium sporogenes, Candida albicans, Helicobacter pylori, Aspergillus niger and Deinococcus radiodurans. Columns were eluted with 0.1 N HCl under standard eluting conditions. Elutions, over a prolonged time period, were tested for endotoxins, sterility and number of CFU. RESULTS: Initial tests on the eluent (0.1 N HCl) already showed limited survival of microorganisms. Using TiO(2) generator columns, even with a higher load of microorganisms no survival of any microorganism could be detected in subsequent elutions, neither in colony-forming unit assays nor in sterility testing. In addition, endotoxin tests showed no elevated levels in any of the eluent samples, even days after incubation. CONCLUSION: The conditions used in this type of (68)Ge/(68)Ga generator are highly unfavourable for survival or growth of microorganisms. The risks associated with incidental microbial contaminations during the lifetime of such a generator are therefore very low. PMID- 22546877 TI - Added value of early 18F-FDOPA PET/CT acquisition time in medullary thyroid cancer. AB - The aim of this study was to determine whether early acquisition of F fluorodihydroxyphenylalanine (F-FDOPA) PET/CT could improve the detection of medullary thyroid cancer (MTC). We retrospectively compared early (median time: 15 min) and delayed (median time: 94 min) acquisitions, positive on at least one of the two phases, in 15 dual-phase F-FDOPA PET/CT examinations performed on 14 patients referred for initial staging (one examination), suspected recurrence (eight examinations) or restaging of MTC (six examinations). Among the 14 true positive (TP) examinations, more lesions (51 vs. 43) or more intense uptake (mean SUVmax=4 vs. 2.4, P<0.05) was observed on early versus delayed phases, regardless of the anatomical site of disease (lymph node, liver or bone). The only false positive case, a reactive lymph node, was visible only on the delayed acquisition. Early acquisition appeared to be more appropriate in the detection of MTC lesions compared with acquisition at 60 min or later. PMID- 22546878 TI - Group 12 metal zwitterionic thiolate compounds: preparation and structural characterization. AB - Reactions of TabHPF(6) (Tab = 4-(trimethylammonio)benzenethiolate) with three equiv. of M(OAc)(2).2H(2)O (M = Zn, Cd) gave rise to two tetranuclear adamantane like compounds, [M(4)(MU-Tab)(6)(Tab)(4)](PF(6))(8).S (.S: M = Zn, S = DMF.4H(2)O; .S: M = Cd, S = DMF.5H(2)O). The similar reactions of MCl(2) (M = Zn, Cd, Hg) with four equiv. of TabHPF(6) in the presence of Et(3)N afforded three mononuclear compounds [M(Tab)(4)](PF(6))(2).S (.S: M = Zn, S = 2(H(2)O)(0.5); .S: M = Cd, S = 2(H(2)O)(0.5); .S: M = Hg, S = 2DMF). Treatment of the precursor complex or with equimolar MCl(2) and two equiv. of TabHPF(6) and Et(3)N produced one dinuclear compounds [M(MU-Tab)(Tab)(2)](2)(PF(6))(4).2DMF.2H(2)O (.2DMF.2H(2)O: M = Zn; .2DMF.2H(2)O: M = Hg) while analogous reactions of with CdCl(2).2H(2)O gave rise to [Cd(MU-Tab)(2)(Tab)](2)(PF(6))(4).2DMF (.2DMF). These compounds were characterized by elemental analysis, IR spectra, UV-Vis spectra, (1)H NMR and single-crystal X-ray crystallography. In or , four M(2+) ions and six S atoms of Tab ligands constitute an adamantane-like [M(4)(MU-S)(6)] cage in which each M(2+) ion is tetrahedrally coordinated by one terminal S and three bridged S atoms from four different Tab ligands. In , each M(2+) center of the [M(Tab)(4)](2+) dication is tetrahedrally coordinated by four S atoms of Tab ligand. Two [M(Tab)(2)](2+) dications in or are further bridged by a pair of Tab ligands to form a dimeric [M(MU-Tab)(Tab)(2)](2)(4+) structure. Each dimeric [(Tab)Cd(MU-Tab)(2)Cd(Tab)](4+) unit in is linked to its two neighboring units via two couples of bridging Tab ligands, thereby generating a unique 1D cationic chain. These results may provide useful information on interpreting structural data of MTs containing group 12 metals. PMID- 22546879 TI - Stereotactic radiosurgery for gynecologic cancer. AB - Stereotactic body radiotherapy (SBRT) distinguishes itself by necessitating more rigid patient immobilization, accounting for respiratory motion, intricate treatment planning, on-board imaging, and reduced number of ablative radiation doses to cancer targets usually refractory to chemotherapy and conventional radiation. Steep SBRT radiation dose drop-off permits narrow 'pencil beam' treatment fields to be used for ablative radiation treatment condensed into 1 to 3 treatments. Treating physicians must appreciate that SBRT comes at a bigger danger of normal tissue injury and chance of geographic tumor miss. Both must be tackled by immobilization of cancer targets and by high-precision treatment delivery. Cancer target immobilization has been achieved through use of indexed customized Styrofoam casts, evacuated bean bags, or body-fix molds with patient independent abdominal compression.(1-3) Intrafraction motion of cancer targets due to breathing now can be reduced by patient-responsive breath hold techniques,(4) patient mouthpiece active breathing coordination,(5) respiration correlated computed tomography,(6) or image-guided tracking of fiducials implanted within and around a moving tumor.(7-9) The Cyberknife system (Accuray [Sunnyvale, CA]) utilizes a radiation linear accelerator mounted on a industrial robotic arm that accurately follows patient respiratory motion by a camera tracked set of light-emitting diodes (LED) impregnated on a vest fitted to a patient.(10) Substantial reductions in radiation therapy margins can be achieved by motion tracking, ultimately rendering a smaller planning target volumes that are irradiated with submillimeter accuracy.(11-13) Cancer targets treated by SBRT are irradiated by converging, tightly collimated beams. Resultant radiation dose to cancer target volume histograms have a more pronounced radiation "shoulder" indicating high percentage target coverage and a small high-dose radiation "tail." Thus, increased target conformality comes at the expense of decreased dose uniformity in the SBRT cancer target. This may have implications for both subsequent tumor control in the SBRT target and normal tissue tolerance of organs at-risk. Due to the sharp dose falloff in SBRT, the possibility of occult disease escaping ablative radiation dose occurs when cancer targets are not fully recognized and inadequate SBRT dose margins are applied. Clinical target volume (CTV) expansion by 0.5 cm, resulting in a larger planning target volume (PTV), is associated with increased target control without undue normal tissue injury.(7,8) Further reduction in the probability of geographic miss may be achieved by incorporation of 2-[(18)F]fluoro-2-deoxy-D-glucose ((18)F-FDG) positron emission tomography (PET).(8) Use of (18)F-FDG PET/CT in SBRT treatment planning is only the beginning of attempts to discover new imaging target molecular signatures for gynecologic cancers. PMID- 22546881 TI - Screening embryos may lead to stigma. PMID- 22546884 TI - Patients driving alternative medicine boom. PMID- 22546882 TI - Association between different growth curve definitions of overweight and obesity and cardiometabolic risk in children. AB - BACKGROUND: Overweight and obesity in young people are assessed by comparing body mass index (BMI) with a reference population. However, two widely used reference standards, the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) growth curves, have different definitions of overweight and obesity, thus affecting estimates of prevalence. We compared the associations between overweight and obesity as defined by each of these curves and the presence of cardiometabolic risk factors. METHODS: We obtained data from a population-representative study involving 2466 boys and girls aged 9, 13 and 16 years in Quebec, Canada. We calculated BMI percentiles using the CDC and WHO growth curves and compared their abilities to detect unfavourable levels of fasting lipids, glucose and insulin, and systolic and diastolic blood pressure using receiver operating characteristic curves, sensitivity, specificity and kappa coefficients. RESULTS: The z scores for BMI using the WHO growth curves were higher than those using the CDC growth curves (0.35-0.43 v. 0.12-0.28, p < 0.001 for all comparisons). The WHO and CDC growth curves generated virtually identical receiver operating characteristic curves for individual or combined cardiometabolic risk factors. The definitions of overweight and obesity had low sensitivities but adequate specificities for cardiometabolic risk. Obesity as defined by the WHO or CDC growth curves discriminated cardiometabolic risk similarly, but overweight as defined by the WHO curves had marginally higher sensitivities (by 0.6%-8.6%) and lower specificities (by 2.6%-4.2%) than the CDC curves. INTERPRETATION: The WHO growth curves show no significant discriminatory advantage over the CDC growth curves in detecting cardiometabolic abnormalities in children aged 9-16 years. PMID- 22546886 TI - Herpetic whitlow. PMID- 22546885 TI - Baseline Q waves as a prognostic modulator in patients with ST-segment elevation: insights from the PLATO trial. AB - BACKGROUND: Baseline Q waves may provide additional value compared with time from the onset of symptoms in predicting outcomes for patients with ST-segment elevation. We evaluated whether baseline Q waves superseded time from symptom onset as a prognostic marker of one-year mortality in patients with ST-segment elevation acute coronary syndrome. Our study was derived from data from patients undergoing primary percutaneous coronary intervention within 24 hours in the PLATelet inhibition and patient Outcomes trial METHODS: Q waves on the baseline electrocardiogram were evaluated by a blinded core laboratory. We assessed the associations between baseline Q waves and time from symptom onset to percutaneous coronary intervention with peak biomarkers, ST-segment resolution on the discharge electrocardiogram, and one-year all-cause and vascular mortality. RESULTS: Of 4341 patients with ST-segment elevation, 46% had baseline Q waves. Compared to those without Q waves, those with baseline Q waves were older, more frequently male, had higher heart rates, more advanced Killip class and had a longer time between the onset of symptoms and percutaneous coronary intervention. They also had higher one-year all-cause mortality than patients without baseline Q waves (baseline Q waves: 4.9%; no baseline Q waves: 2.8%; hazard ratio [HR] 1.78, 95% confidence interval [CI] 1.29-2.45, p < 0.001). Complete ST-segment resolution was greatest and all-cause mortality lowest among those with symptom onset three hours or less before percutaneous coronary intervention and no baseline Q waves. After multivariable adjustment, baseline Q waves, but not time from symptom onset, were associated with a significant increase in all-cause mortality (adjusted HR 1.42, 95% CI 1.10-2.01, p = 0.046) and vascular mortality (adjusted HR 1.58, 95% CI 1.09-2.28, p = 0.02). INTERPRETATION: The presence of baseline Q waves provides useful additional prognostic insight into the clinical outcome of patients with ST-segment elevation. Clinical Trials.gov registration no. NCT00391872. PMID- 22546887 TI - Evaluating professorial halos. PMID- 22546889 TI - Imperfect measure of hospital safety. PMID- 22546890 TI - Minimizing injection pain in local anesthesia. PMID- 22546891 TI - ST-elevation myocardial infarction: is there time for Q waves? PMID- 22546892 TI - Bloom fading from e-health golden wattle. PMID- 22546893 TI - Highly water soluble multi-layer graphene nanoribbons and related honey-comb carbon nanostructures. AB - Multi-layer graphene nanoribbons have been made highly water soluble (4.7 mg ml( 1)) and stable for the first time by repetitious derivatization with p carboxyphenyldiazonium salt; similarly, single-walled carbon nanotubes (4.8 mg ml(-1)) and ultra-short carbon nanotubes (50 mg ml(-1)) can also be made highly soluble by the methodology. PMID- 22546894 TI - Synthesis of novel enantiomerically pure tetra-carbohydrazide cyclophane macrocycles. AB - A total of twelve novel enantiomerically pure tetra-carbohydrazide cyclophane macrocycles have been synthesised in quantitative yields by reacting chiral (4R,5R)- and (4S,5S)-1,3-dioxolane-4,5-dicarbohydrazides with aromatic bis aldehydes in a [2 + 2]-cyclocondensation reaction. The compounds show a dynamic behaviour in solution, which has been rationalized in terms of an unprecedented conformational interconversion between two conformers one stabilised by intramolecular hydrogen bonding and pi-pi stacking interactions. PMID- 22546895 TI - Intravenous buspirone for the prevention of postoperative nausea and vomiting. AB - RATIONALE: Buspirone, a partial 5HT(1A) agonist and D2 and D3 antagonist, has shown promising antiemetic efficacy when given parenterally in animal models, but its efficacy for the prevention of postoperative nausea and vomiting (PONV) is unknown. OBJECTIVE: To study the efficacy and dose-responsiveness of intravenous buspirone for the prevention of PONV. METHODS: A randomised, double-blind, placebo-controlled study was performed in adults at moderate to high PONV risk undergoing surgery with a general anaesthetic. Patients were randomised to receive an intravenous dose of buspirone (0.3, 1.0, 2.0, 3.0 mg) or placebo at the end of surgery. The primary endpoint was the cumulative 24-h PONV incidence (i.e. any nausea and/or vomiting). Vomiting included retching. Nausea was defined as a score of >= 4 on an 11-point verbal rating scale running from zero (no nausea) to ten (the worst nausea imaginable). RESULTS: A total of 257 patients received the study drug and fulfilled the criteria for inclusion in the primary efficacy and safety analyses. With placebo, the mean 24-h PONV incidence was 49.0 % (90 % confidence interval [CI] 37.5-60.5 %). With buspirone, that incidence ranged from a mean of 40.8 % (29.3-52.4 %) in the 1 mg arm to 58.0 % (46.5-69.5 %) in the 0.3 mg arm (P > 0.05 for all comparisons). There was no difference between placebo and buspirone at any dose for any other efficacy endpoint, nor in the number or severity of adverse events or any other safety measures. CONCLUSION: We were unable to show that intravenous single-dose buspirone, at the tested dose-range, was effective at preventing PONV in surgical adult patients. The present study emphasises the difficulty in extrapolating from animal models of emesis to clinical efficacy in PONV. PMID- 22546896 TI - Comparison of the effect of mesalazine and sulfasalazine on laboratory parameters: a retrospective observational study. AB - PURPOSE: Mesalazine and sulfasalazine are commonly used drugs for the treatment of inflammatory bowel disease. However, there have been few reports with a strict statistical analysis comparing the effects of mesalazine and sulfasalazine on laboratory test results. Therefore, we designed a retrospective cohort study to investigate whether or not differences in clinical laboratory parameters exist between mesalazine and sulfasalazine users. METHODS: We used data from the Clinical Data Warehouse of Nihon University School of Medicine to identify cohorts of new mesalazine users (n = 303) and sulfasalazine users (n = 67). We used a multivariate regression model and regression adjustment with the propensity score to adjust for differences in baseline covariates between mesalazine and sulfasalazine users, and compared serum levels of creatinine, urea nitrogen, aspartate aminotransferase, alanine aminotransferase, and hematological parameters including red and white blood cell counts and platelet count. RESULTS: After adjustment, in sulfasalazine users, the mean values for all tests showed no significant change between baseline and during the exposure period. In contrast, in mesalazine users, the mean WBC and platelet counts during the exposure period were significantly lower than those at baseline. Furthermore, mean serum urea nitrogen level during the exposure period was significantly higher than that at baseline. In terms of mean changes in laboratory test values during the exposure period compared with baseline, the reduction of platelet count in mesalazine users was significant in comparison to that in sulfasalazine users. CONCLUSION: Our findings suggested that the hematological adverse effects of mesalazine treatment might be greater than those of sulfasalazine treatment. PMID- 22546897 TI - A UPR-independent infection-specific role for a BiP/GRP78 protein in the control of antimicrobial peptide expression in C. elegans epidermis. AB - The nematode C. elegans responds to infection by the fungus Drechmeria coniospora with a rapid increase in the expression of antimicrobial peptide genes. To investigate further the molecular basis of this innate immune response, we took a two-dimensional difference in-gel electrophoresis (2D-DIGE) approach to characterize the changes in host protein that accompany infection. We identified a total of 68 proteins from differentially represented spots and their corresponding genes. Through class testing, we identified functional categories that were enriched in our proteomic data set. One of these was "protein processing in endoplasmic reticulum," pointing to a potential link between innate immunity and endoplasmic reticulum function. This class included HSP-3, a chaperone of the BiP/GRP78 family known to act coordinately in the endoplasmic reticulum with its paralog HSP-4 to regulate the unfolded protein response (UPR). Other studies have shown that infection of C. elegans can provoke a UPR. We observed, however, that in adult C. elegans infection with D. coniospora did not induce a UPR, and conversely, triggering a UPR did not lead to an increase in expression of the well-characterized antimicrobial peptide gene nlp-29. On the other hand, we demonstrated a specific role for hsp-3 in the regulation of nlp-29 after infection that is not shared with hsp-4. Epistasis analysis allowed us to place hsp-3 genetically between the Tribbles-like kinase gene nipi-3 and the protein kinase C delta gene tpa-1. The precise function of hsp-3 has yet to be determined, but these results uncover a hitherto unsuspected link between a BiP/GRP78 family protein and innate immune signaling. PMID- 22546898 TI - Biofilm formed by a hypervirulent (hypermucoviscous) variant of Klebsiella pneumoniae does not enhance serum resistance or survival in an in vivo abscess model. AB - A new hypervirulent (hypermucoviscous) clinical variant of Klebsiella pneumoniae (hvKP) has emerged over the last decade. Our goal is to identify new mechanisms, which increase the virulence hvKP. It has been shown that hvKP strains produce more biofilm than "classical" stains of K. pneumoniae, therefore we hypothesized that biofilm formation may contribute to the pathogenesis of systemic infection. To test this hypothesis, transposon mutants of the model pathogen hvKP1 were generated and screened for decreased production of biofilm. Three mutant constructs with disruptions in glnA [putatively encodes glutamine synthetase, hvKP1 glnA:: EZ::TN < KAN-2 > (glnA::Tn)], sucD [putatively encodes succinyl-CoA synthase alpha subunit, hvKP1 sucD:: EZ::TN < KAN-2 > (sucD::Tn)], and tag [putatively encodes transcriptional antiterminator of glycerol uptake operon, hvKP1 tag:: EZ::TN < KAN-2 > (tag::Tn)] were chosen for further characterization and use in biologic studies. Quantitative assays performed in rich laboratory medium and human ascites confirmed the phenotype and a hypermucoviscosity assay established that capsule production was not affected. However, compared with its wild-type parent, neither planktonic cells nor biofilms of glnA::Tn, sucD::Tn and tag::Tn displayed a change to the bactericidal activity of 90% human serum. Likewise, when assessed in a rat subcutaneous abscess model, the growth and survival of glnA::Tn, sucD::Tn and tag::Tn in abscess fluid was similar to hvKP1. In this report we identify three new genes that contribute to biofilm formation in hvKP1. However, decreased biofilm production due to disruption of these genes does not affect the sensitivity of these mutant constructs to 90% human serum when in planktonic form or within a biofilm. Further, their virulence in an in vivo abscess model was unaffected. PMID- 22546899 TI - The potential of nitric oxide releasing therapies as antimicrobial agents. AB - Nitric oxide (NO) is a short-lived, diatomic, lipophilic gas that plays an integral role in defending against pathogens. Among its many functions are involvement in immune cell signaling and in the biochemical reactions by which immune cells defend against bacteria, fungi, viruses and parasites. NO signaling directs a broad spectrum of processes, including the differentiation, proliferation, and apoptosis of immune cells. When secreted by activated immune cells, NO diffuses across cellular membranes and exacts nitrosative and oxidative damage on invading pathogens. These observations led to the development of NO delivery systems that can harness the antimicrobial properties of this evanescent gas. The innate microbicidal properties of NO, as well as the antimicrobial activity of the various NO delivery systems, are reviewed. PMID- 22546901 TI - A novel method for infecting Drosophila adult flies with insect pathogenic nematodes. AB - Drosophila has been established as an excellent genetic and genomic model to investigate host-pathogen interactions and innate immune defense mechanisms. To date, most information on the Drosophila immune response derives from studies that involve bacterial, fungal or viral pathogens. However, immune reactions to insect parasitic nematodes are still not well characterized. The nematodes Heterorhabditis bacteriophora live in symbiosis with the entomopathogenic bacteria Photorhabdus luminescens, and they are able to invade and kill insects. Interestingly, Heterorhabditis nematodes are viable in the absence of Photorhabdus. Techniques for infecting Drosophila larvae with these nematodes have been previously reported. Here, we have developed a method for infecting Drosophila adult flies with Heterorhabditis nematodes carrying (symbiotic worms) or lacking (axenic worms) their associated bacteria. The protocol we present can be readily adapted for studying parasitic strategies of other insect nematodes using Drosophila as the host infection model. PMID- 22546900 TI - The role of inflammasome modulation in virulence. AB - Pathogens frequently exist in an immunological balancing act with their host. Pathogens must not only replicate within a host but also transmit effectively between hosts to perpetuate their species. On the other hand, the host seeks to maintain homeostasis by clearing pathogens. The inflammasome is a multi-protein complex that can induce cell death and processes IL-1beta and additional proinflammatory substrates. In this review we discuss the pathogen specific modulation of inflammasome activation and the role this plays in virulence and disease pathology. PMID- 22546902 TI - Mouse models for the study of fungal pneumonia: a collection of detailed experimental protocols for the study of Coccidioides, Cryptococcus, Fusarium, Histoplasma and combined infection due to Aspergillus-Rhizopus. AB - Mouse models have facilitated the study of fungal pneumonia. In this report, we present the working protocols of groups that are working on the following pathogens: Aspergillus, Coccidioides, Cryptococcus, Fusarium, Histoplasma and Rhizopus. We describe the experimental procedures and the detailed methods that have been followed in the experienced laboratories to study pulmonary fungal infection; we also discuss the anticipated results and technical notes, and provide the practical advices that will help the users of these models. PMID- 22546903 TI - Regulation of phenotypic transitions in the fungal pathogen Candida albicans. AB - The human commensal fungus Candida albicans can cause not only superficial infections, but also life-threatening disease in immunocompromised individuals. C. albicans can grow in several morphological forms. The ability to switch between different phenotypic forms has been thought to contribute to its virulence. The yeast-filamentous growth transition and white-opaque switching represent two typical morphological switching systems, which have been intensively studied in C. albicans. The interplay between environmental factors and genes determines the morphology of C. albicans. This review focuses on the regulation of phenotypic changes in this pathogenic organism by external environmental cues and internal genes. PMID- 22546904 TI - Dissecting novel virulent determinants in the Burkholderia cepacia complex. AB - Prevention and control of infectious diseases remains a major public health challenge and a number of highly virulent pathogens are emerging both in and beyond the hospital setting. Despite beneficial aspects such as use in biocontrol and bioremediation exhibited by members of the Burkholderia cepacia complex (Bcc) some members of this group have recently gained attention as significant bacterial pathogens due to their high levels of intrinsic antibiotic resistance, transmissibility in nosocomial settings, persistence in the presence of antimicrobials and intracellular survival capabilities. The Bcc are opportunistic pathogens and their arsenal of virulence factors includes proteases, lipases and other secreted exoproducts, including secretion system-associated effectors. Deciphering the function of virulence factors and assessment of novel therapeutic strategies has been facilitated by use of diverse non-vertebrate hosts (the fly Drosophila melanogaster, the microscopic nematode Caenorhabditis elegans, the zebrafish and the greater Galleria mellonella wax moth caterpillar larvae). Researchers are now employing sophisticated approaches to dissect the virulence determinants of Bcc with the ultimate goal being the development of novel anti infective countermeasures. This editorial will highlight selected recent research endeavors aimed at dissecting adaptive responses and the virulence factor portfolio of Burkholderia species. PMID- 22546905 TI - What does it take to stick around? Molecular insights into biofilm formation by uropathogenic Escherichia coli. AB - Existence in the biofilm state lends bacteria the opportunity to enjoy, at least for a finite amount of time, the benefits of a multicellular entity. The order of events leading to biofilm formation and disassembly has been the topic of interest for numerous studies, aiming to identify factors and mechanisms that underlie this dynamic developmental process. Of particular import is research leveraged at delineating biofilm formation by medically relevant microorganisms, as prevention or eradication of biofilm from medical devices and from within the host pose a serious challenge in the healthcare setting. Recent research describes how a transcriptional regulator modulates biofilm formation in uropathogenic Escherichia coli (UPEC) by affecting the expression of the type 1 adhesive organelles in response to extracellular signals. PMID- 22546906 TI - Acinetobacter baumannii: an emerging opportunistic pathogen. AB - Acinetobacter baumannii is an opportunistic bacterial pathogen primarily associated with hospital-acquired infections. The recent increase in incidence, largely associated with infected combat troops returning from conflict zones, coupled with a dramatic increase in the incidence of multidrug-resistant (MDR) strains, has significantly raised the profile of this emerging opportunistic pathogen. Herein, we provide an overview of the pathogen, discuss some of the major factors that have led to its clinical prominence and outline some of the novel therapeutic strategies currently in development. PMID- 22546907 TI - Inhibition of bacterial superoxide defense: a new front in the struggle between host and pathogen. PMID- 22546908 TI - A Burkholderia cepacia complex non-ribosomal peptide-synthesized toxin is hemolytic and required for full virulence. AB - Members of the Burkholderia cepacia complex (Bcc) have recently gained notoriety as significant bacterial pathogens due to their extreme levels of antibiotic resistance, their transmissibility in clinics, their persistence in bacteriostatic solutions, and their intracellular survival capabilities. As pathogens, the Bcc are known to elaborate a number of virulence factors including proteases, lipases and other exoproducts, as well as a number of secretion system associated effectors. Through random and directed mutagenesis studies, we have identified a Bcc gene cluster capable of expressing a toxin that is both hemolytic and required for full Bcc virulence. The Bcc toxin is synthesized via a non-ribosomal peptide synthetase mechanism, and appears to be related to the previously identified antifungal compound burkholdine or occidiofungin. Further testing shows mutations to this gene cluster cause a significant reduction in both hemolysis and Galleria mellonella mortality. Mutation to a glycosyltransferase gene putatively responsible for a structural-functional toxin variant causes only partial reduction in hemolysis. Molecular screening identifies the Bcc species containing this gene cluster, of which several strains produce hemolytic activity. PMID- 22546909 TI - Salicylate increases the expression of marA and reduces in vitro biofilm formation in uropathogenic Escherichia coli by decreasing type 1 fimbriae expression. AB - Escherichia coli is one of the most frequent bacteria implicated in biofilm formation, which is a dynamic process whose first step consists in bacteria adhesion to surfaces through type 1 fimbriae. Salicylate induces a number of morphological and physiological alterations in bacteria including the activation of the transcriptional regulator MarA. In this report the effects of salicylate on biofilm formation and their relationship with MarA were studied. An inverse relationship was observed between in vitro biofilm formation and salicylate concentration added to the culture medium. Salicylate increases the expression of marA and decreases the expression of fimA and fimB genes in the wild-type strain. In addition, the fimA and fimB expression was decreased in a MarR mutant in which marA was also overexpressed. In conclusion, the expression of type 1 fimbriae in presence of salicylate may be regulated by the level of marA expression through fimB regulator, albeit through neither the ompX nor the tolC genes. PMID- 22546911 TI - Single-cell profiling of developing and mature retinal neurons. AB - Highly specialized, but exceedingly small populations of cells play important roles in many tissues. The identification of cell-type specific markers and gene expression programs for extremely rare cell subsets has been a challenge using standard whole-tissue approaches. Gene expression profiling of individual cells allows for unprecedented access to cell types that comprise only a small percentage of the total tissue(1-7). In addition, this technique can be used to examine the gene expression programs that are transiently expressed in small numbers of cells during dynamic developmental transitions(8). This issue of cellular diversity arises repeatedly in the central nervous system (CNS) where neuronal connections can occur between quite diverse cells(9). The exact number of distinct cell types is not precisely known, but it has been estimated that there may be as many as 1000 different types in the cortex itself(10). The function(s) of complex neural circuits may rely on some of the rare neuronal types and the genes they express. By identifying new markers and helping to molecularly classify different neurons, the single-cell approach is particularly useful in the analysis of cell types in the nervous system. It may also help to elucidate mechanisms of neural development by identifying differentially expressed genes and gene pathways during early stages of neuronal progenitor development. As a simple, easily accessed tissue with considerable neuronal diversity, the vertebrate retina is an excellent model system for studying the processes of cellular development, neuronal differentiation and neuronal diversification. However, as in other parts of the CNS, this cellular diversity can present a problem for determining the genetic pathways that drive retinal progenitors to adopt a specific cell fate, especially given that rod photoreceptors make up the majority of the total retinal cell population(11). Here we report a method for the identification of the transcripts expressed in single retinal cells (Figure 1). The single-cell profiling technique allows for the assessment of the amount of heterogeneity present within different cellular populations of the retina(2,4,5,12). In addition, this method has revealed a host of new candidate genes that may play role(s) in the cell fate decision-making processes that occur in subsets of retinal progenitor cells(8). With some simple adjustments to the protocol, this technique can be utilized for many different tissues and cell types. PMID- 22546912 TI - [Biomarkers in rheumatology. Biomarkers and imaging for the diagnosis and stratification of rheumatoid arthritis and spondylarthritis in the ArthroMark network funded by the Federal Ministry of Education and Research]. AB - The introduction of biologics has continuously increased the demand for biomarkers for early diagnosis and therapeutic stratification. ArthroMark, a research network funded by the Federal Ministry of Education and Research, aims to establish such biomarkers for rheumatoid arthritis and spondyloarthritides. Biobanks and previous work on genotyping, gene expression and autoreactivity profiling build the basis. Bioinformatic networks will help to harmonize the investigations and a clinical study with modern imaging techniques to characterize the functional relevance of the new biomarkers as effectively as possible. To validate the markers for diagnostic application the network aims to expand gradually. PMID- 22546914 TI - Cutaneous B-cell lymphoma in a Perdido Key Beach mouse (Peromyscus poliontus trissyllepsis). AB - The Perdido Key beach mouse (Peromyscus poliontus trissyllepsis) is an endangered mammal indigenous to the panhandle beaches of Northwest Florida. A captive 3.5-y old female mouse was evaluated because of severe pruritus, diffuse alopecia, skin reddening, and ulcerations over the dorsum of her body. Initial skin biopsy of the affected area suggested bacterial dermatitis but was inconclusive. Despite empiric antibiotic, anthelmintic, and antihistamine treatments, she continued to decline and developed severe ulcerations over the majority of her body. Postmortem histopathologic evaluation led to a tentative diagnosis of epitheliotropic lymphoma, suggestive of a mycosis fungoides T-cell-type cutaneous lymphoma. However, immunohistochemistry results challenged this diagnosis, indicating that the lesion was actually an epidermotropic B-cell lymphoma. Spontaneous cutaneous B-cell lymphomas are rare in rodents and had not previously been reported to occur in Perdido Key beach mice. This case report provides initial evidence that the Perdido Key beach mouse is susceptible to cutaneous B cell lymphoma. PMID- 22546913 TI - Fecal corticosterone levels in RCAN1 mutant mice. AB - Regulator of calcineurin 1 (RCAN1) is related to the expression of human neurologic disorders such as Down syndrome, Alzheimer disease, and chromosome 21q deletion syndrome. We showed here that RCAN1-knockout mice exhibit reduced innate anxiety as indicated by the elevated-plus maze. To examine whether glucocorticoids contribute to this phenotype, we measured fecal corticosterone in male wildtype and RCAN1-knockout mice and in male and female transgenic mice with neuronal overexpression of RCAN1 (Tg-RCAN1(TG)). We found no difference in fecal corticosterone levels of RCAN1-knockout mice and their wildtype littermates. As expected, we found differences between sexes in fecal corticosterone levels. In addition, we found higher levels of excreted corticosterone in Tg-RCAN1(TG) female mice as compared with female wildtype mice. Our data indicate normal diurnal corticosterone production in RCAN1 mutant mice and do not suggest a causal role in either the cognitive or anxiety phenotypes exhibited by RCAN1 knockout mice. PMID- 22546915 TI - A new apparatus and surgical technique for the dual perfusion of human tumor xenografts in situ in nude rats. AB - We present a new perfusion system and surgical technique for simultaneous perfusion of 2 tissue-isolated human cancer xenografts in nude rats by using donor blood that preserves a continuous flow. Adult, athymic nude rats (Hsd:RH Foxn1(rnu)) were implanted with HeLa human cervical or HT29 colon adenocarcinomas and grown as tissue-isolated xenografts. When tumors reached an estimated weight of 5 to 6 g, rats were prepared for perfusion with donor blood and arteriovenous measurements. The surgical procedure required approximately 20 min to complete for each tumor, and tumors were perfused for a period of 150 min. Results showed that tumor venous blood flow, glucose uptake, lactic acid release, O(2) uptake and CO(2) production, uptake of total fatty acid and linoleic acid and conversion to the mitogen 13-HODE, cAMP levels, and activation of several marker kinases were all well within the normal physiologic, metabolic, and signaling parameters characteristic of individually perfused xenografts. This new perfusion system and technique reduced procedure time by more than 50%. These findings demonstrate that 2 human tumors can be perfused simultaneously in situ or ex vivo by using either rodent or human blood and suggest that the system may also be adapted for use in the dual perfusion of other organs. Advantages of this dual perfusion technique include decreased anesthesia time, decreased surgical manipulation, and increased efficiency, thereby potentially reducing the numbers of laboratory animals required for scientific investigations. PMID- 22546916 TI - Effects of increased dietary cholesterol with carbohydrate restriction on hepatic lipid metabolism in Guinea pigs. AB - Excessive lipid accumulation within hepatocytes, or hepatic steatosis, is the pathognominic feature of nonalcoholic fatty liver disease (NAFLD), a disease associated with insulin resistance and obesity. Low-carbohydrate diets (LCD) improve these conditions and were implemented in this study to potentially attenuate hepatic steatosis in hypercholesterolemic guinea pigs. Male guinea pigs (n = 10 per group) were randomly assigned to consume high cholesterol (0.25 g/100 g) in either a LCD or a high-carbohydrate diet (HCD) for 12 wk. As compared with HCD, plasma LDL cholesterol was lower and plasma triglycerides were higher in animals fed the LCD diet, with no differences in plasma free fatty acids or glucose. The most prominent finding was a 40% increase in liver weight in guinea pigs fed the LCD diet despite no differences in hepatic cholesterol or triglycerides between the LCD and the HCD groups. Regardless of diet, all livers had severe hepatic steatosis on histologic examination. Regression analysis suggested that liver weight was independent of body weight and liver mass was independent of hepatic lipid content. LCD livers had more proliferating hepatocytes than did HCD livers, suggesting that in the context of cholesterol induced hepatic steatosis, dietary carbohydrate restriction enhances liver cell proliferation. PMID- 22546917 TI - Magnetic resonance imaging (MRI) assessment of ventricular remodeling after myocardial infarction in rabbits. AB - To understand the structure-function relationship in the postinfarcted myocardium in rabbits, we induced cardiac ischemia by ligating the left circumflex coronary artery. Sham controls underwent thoracotomy only. At 7 and 30 d after ligation, cardiac MRI was conducted by using pulse-oxymetry-gated cine acquisition to provide complete phases of the heartbeat. The rabbits were anesthetized under 1.5% isoflurane ventilation, and ultrafast techniques made breath-hold 3D coverage in different cardiac axes feasible. Viability imaging was performed after intravenous injection of 0.15 mmol/kg gadolinium to assess the extent of infarction. Data (n >= 6) are presented as mean +/- SEM and analyzed by ANOVA and ANCOVA. In postligation rabbits, end-systolic (mean +/- SEM, 2.3 +/- 0.3 mL) and end-diastolic (4.2 +/- 0.4 mL) volumes were increased compared with preligation values (end-systolic, 1.1 +/- 0.1 mL; end-diastolic, 2.98 +/- 0.2 mL). Ejection fraction was influenced adversely by the presence of scar tissue at both 7 and 30 d after ligation and apparently nonlinear with the heart rate. Cardiac force was increased in the basal region in both end-systole and end-diastole in postligation hearts but progressively decreased toward the apex. Late gadolinium enhancement delineated 15.2 +/- 5.8% myocardial infarction at 7 d after ligation and 14.5 +/- 5.8% at 30 d, with limited wall motion and wall thinness. Compensatory wall thickening was present in the basal region when compared with that in preligation hearts. MRI offers detailed spatial resolution and tissue characterization after myocardial infarction. PMID- 22546918 TI - Osteoblastic osteosarcoma in a rabbit. AB - An osteosarcoma developed in the tarsal joint region involving the distal tibia of a domestic rabbit (Oryctolagus cuniculus). Micrometastases were present in the lungs. Histologically the tumor was composed of ovoid to short-spindle cells with abundant giant cells, producing irregular islands of osteoids. The tumor cells were immunopositive with antiosteocalcin monoclonal antibody, consistent with their derivation from osteoblasts. According to review of 10 published cases, productive osteoblasic osteosarcoma is the most common bone tumor in rabbits, with half of all cases developing in the skull or facial bones. PMID- 22546919 TI - Anomalous right coronary artery originating from the left sinus of Valsalva in a Yucatan minipig. AB - A 39.2-kg, castrated male Yucatan minipig (Sus scrofa domestica) was presented for enrollment in a coronary artery study. Angiography revealed an anomalous right coronary artery originating from the left sinus of Valsalva. The left anterior descending, left circumflex, and anomalous right coronary arteries were implanted with metallic stents without complications. The minipig remained on the study for 3 mo until it reached its predetermined study endpoint, during which time it showed no clinical signs of disease. Histologic examination of the implanted coronary arteries revealed no differences between the normal (left anterior descending and left circumflex arteries) and the anomalous right coronary artery. Swine are important models for coronary research. Although several cases of anomalous human coronary arteries have been documented, the current case is the first report of a coronary artery anomaly in a minipig. PMID- 22546920 TI - Chronic diseases in captive geriatric female Chimpanzees (Pan troglodytes). AB - The current aging population of captive chimpanzees is expected to develop age related diseases and present new challenges to providing their veterinary care. Spontaneous heart disease and sudden cardiac death are the main causes of death in chimpanzees (especially of male animals), but little is known about the relative frequency of other chronic diseases. Furthermore, female chimpanzees appear to outlive the males and scant literature addresses clinical conditions that affect female chimpanzees. Here we characterize the types and prevalence of chronic disease seen in geriatric (older than 35 y) female chimpanzees in the colony at Alamogordo Primate Facility. Of the 16 female chimpanzees that fit the age category, 87.5% had some form of chronic age-related disease. Cardiovascular related disease was the most common (81.25%) followed by metabolic syndrome (43.75%) and renal disease (31.25%). These data show the incidence of disease in geriatric female chimpanzees and predict likely medical management challenges associated with maintaining an aging chimpanzee population. PMID- 22546922 TI - Polyostotic fibrous dysplasia in a cynomolgus Macaque (Macaca fascicularis). AB - A 2.3-y-old female cynomolgus macaque (Macaca fascicularis) presented with a broken right tibia and fibula. Radiographs showed multiple cyst-like defects in all long bones. We suspected that both fractures were pathologic because they occurred through these defects. Ultrasonography, MRI, and dual X-ray absorptiometry revealed that the defects were filled with soft tissue. Grossly, the bones were abnormal in shape, and a gelatinous material filled the defects and the surrounding marrow cavity. Histologically, the gelatinous material was composed of fibrin and cartilage; few normal bone cells were seen. Genetic testing revealed extra material on the short arm of chromosome 8 in all tissues examined, but no copy number alterations of likely clinical significance were observed, and no abnormalities were found that were unique to the lesions. In light of the clinical signs and radiographic and pathologic findings, polyostotic fibrous dysplasia was diagnosed. This report represents the first documented case of fibrous dysplasia in a cynomolgus macaque. PMID- 22546921 TI - Chronic anemia and effects of iron supplementation in a research colony of adult Rhesus macaques (Macaca mulatta). AB - A cohort of rhesus macaques used in neuroscience research was found at routine examinations to have chronic anemia (spun Hct less than 30%). Four anemic (Hct, 24.8% +/- 3.4%) and 10 control (39.6% +/- 2.9%) macaques were assessed to characterize the anemia and determine probable cause(s); some animals in both groups had cephalic implants. Diagnostic tests included CBC, bone marrow evaluations, iron panels, and serum erythropoietin and hepcidin concentrations. Serum iron and ferritin were 15.8 +/- 11.1 MUg/dL and 103.8 +/- 53.1 ng/mL, respectively, for the anemic group compared with 109.8 +/- 23.8 MUL/dL and 88.5 +/- 41.9 ng/mL, respectively, for the control group. Erythropoietin levels were 16.2 to over 100 mU/mL for the anemic macaques compared with 0 to 1.3 mU/mL for the control group. Hepcidin results were similar in both groups. Because the findings of low iron, high erythropoietin, and normal hepcidin in the anemic macaques supported iron-deficiency anemia or anemia of chronic disease combined with iron-deficiency anemia, a regimen of 4 doses of iron dextran was provided. In treated macaques, Hct rose to 36.3% +/- 6.8%, serum iron levels increased to 94.0 +/- 41.9 MUg/dL, and erythropoietin levels fell to 0.15 to 0.55 mU/mL. Maintenance of normal Hct was variable between macaques and reflected individual ongoing clinical events. PMID- 22546923 TI - Osteochondromatosis in a Rhesus macaque (Macaca mulatta). AB - A 5-y-old, male, rhesus macaque (Macaca mulatta) presented with a prominent mass slightly anteriomedial to the right stifle. On exam, multiple radiopaque masses were identified protruding from the mid- and distal femur. Lateral and anteroposterior radiographs of the right stifle region revealed multiple exophytic masses arising from the femur, with mild bony reaction of the proximal tibia. Histologic examination of biopsy tissue revealed woven and lamellar bone with granulation tissue and skeletal muscle. Because the macaque was exhibiting no lameness or signs of pain, we decided to monitor the progression of the masses. Minimal change was noted during the time prior to study termination at 6.5 y of age. Necropsy revealed that the bony masses were cartilage-capped lesions arising near the growth plate of the distal femur and midshaft of the femur and tibia. Histologic examination revealed chondro-osseous exophytic growths that blended imperceptibly with the cortex and spongiosa of the femur, consistent with a final diagnosis of multiple osteochondromas. PMID- 22546924 TI - RhoA-induced cytoskeletal tension controls adaptive cellular remodeling to mechanical signaling. AB - The ability to measure real-time mechanosensitive events at the subcellular level in response to discrete mechanical stimulation is a critical component in understanding mechanically-induced cellular remodeling. Vascular smooth muscle cells (VSMC) were transfected with RhoA constructs (wild type, dominant negative or constitutively active) or treated with ML-7 to induce specific cytoskeletal tension characteristics prior to mechanical stimulation. Tensile stress was applied to live VSMC using an atomic force microscope probe functionalized with extracellular matrix (ECM) proteins. The ECM induces selective integrin activation and focal adhesion formation, enabling direct manipulation of cortical actin through an active ECM-integrin-actin linkage. Therefore, locally induced mechanosensitive events triggered downstream activation of intracellular signaling pathways responsible for actin and focal adhesion remodeling throughout the cell. Integration of mechanical stimulation with simultaneous fluorescence imaging by spinning-disk confocal and total internal reflection fluorescence microscopy enabled visualization and quantification of molecular dynamic events at the sub-cellular level in real-time. Results provide evidence that the pre existing cytoskeletal tension affects the actomyosin apparatus which in turn coordinates the ability of the cell to adapt to the externally applied stress. RhoA activation induced high cytoskeletal tension that correlated with increased stress fiber formation, cell stiffness, integrin activation and myosin phosphorylation. In contrast, blocking Rho-kinase or myosin function was characterized by low cytoskeletal tension with a decreased level of stress fiber formation, lower cell stiffness and integrin activation. Our findings show that VSMC sense and adapt to physical microenvironmental changes by a coordinated response of the actomyosin apparatus necessary to establish a new homeostatic state. PMID- 22546926 TI - Aryl(hydro)boranes: versatile building blocks for boron-doped pi-electron materials. AB - Boron-containing pi-conjugated molecules offer a substantial application potential in the field of organic electronics. During the last decade, aryl(hydro)boranes have established themselves as versatile novel building blocks for sophisticated boron-doped materials. This perspective article comprehensively discusses key structural motifs and reactivity patterns of recently developed aryl(hydro)boranes and shows how these have been used for the synthesis of macromolecular organoboranes through hydroboration polymerisation, ring-opening polymerisation and condensation polymerisation protocols. PMID- 22546925 TI - Applications of 3-aminolactams: design, synthesis, and biological evaluation of a library of potential dimerisation inhibitors of HIV1-protease. AB - In the context of our studies on the applications of 3-aminolactams as conformationally restricted pseudodipeptides, we report here the synthesis of a library of potential dimerisation inhibitors of HIV1-protease. Two of the pseudopeptides were active on the wild type virus (HIV1) at micromolar levels (EC(50)). Although the peptides showed lower anti-viral activity than previously reported dimerisation inhibitors, our results demonstrate that the piperidone moiety does not prevent cell penetration, and hence that such derivatization is compatible with potential anti-HIV treatment. PMID- 22546927 TI - Low molecular weight protein enrichment on mesoporous silica thin films for biomarker discovery. AB - The identification of circulating biomarkers holds great potential for non invasive approaches in early diagnosis and prognosis, as well as for the monitoring of therapeutic efficiency.(1-3) The circulating low molecular weight proteome (LMWP) composed of small proteins shed from tissues and cells or peptide fragments derived from the proteolytic degradation of larger proteins, has been associated with the pathological condition in patients and likely reflects the state of disease.(4,5) Despite these potential clinical applications, the use of Mass Spectrometry (MS) to profile the LMWP from biological fluids has proven to be very challenging due to the large dynamic range of protein and peptide concentrations in serum.(6) Without sample pre-treatment, some of the more highly abundant proteins obscure the detection of low-abundance species in serum/plasma. Current proteomic-based approaches, such as two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and shotgun proteomics methods are labor-intensive, low throughput and offer limited suitability for clinical applications.(7-9) Therefore, a more effective strategy is needed to isolate LMWP from blood and allow the high throughput screening of clinical samples. Here, we present a fast, efficient and reliable multi-fractionation system based on mesoporous silica chips to specifically target and enrich LMWP.(10,11) Mesoporous silica (MPS) thin films with tunable features at the nanoscale were fabricated using the triblock copolymer template pathway. Using different polymer templates and polymer concentrations in the precursor solution, various pore size distributions, pore structures, connectivity and surface properties were determined and applied for selective recovery of low mass proteins. The selective parsing of the enriched peptides into different subclasses according to their physicochemical properties will enhance the efficiency of recovery and detection of low abundance species. In combination with mass spectrometry and statistic analysis, we demonstrated the correlation between the nanophase characteristics of the mesoporous silica thin films and the specificity and efficacy of low mass proteome harvesting. The results presented herein reveal the potential of the nanotechnology-based technology to provide a powerful alternative to conventional methods for LMWP harvesting from complex biological fluids. Because of the ability to tune the material properties, the capability for low-cost production, the simplicity and rapidity of sample collection, and the greatly reduced sample requirements for analysis, this novel nanotechnology will substantially impact the field of proteomic biomarker research and clinical proteomic assessment. PMID- 22546930 TI - New domino heteroannulation of enaminones: synthesis of diverse fused naphthyridines. AB - A series of new poly-functionalized fused naphthyridine derivatives were synthesized via a three-component reaction of aldehyde, 2-aminoprop-1-ene-1,1,3 tricarbonitrile and enaminone in EtOH using EtONa as a base. During these reaction processes, the domino construction of fused naphthyridine skeleton with concomitant formation of two new pyridine rings was readily achieved via base promoted three-component reactions in a one-pot operation. The procedures are facile, avoiding time-consuming and costly syntheses, tedious work-up and purifications of precursors. PMID- 22546932 TI - Cementless short stem hip arthroplasty METHA(r) as an encouraging option in adults with osteonecrosis of the femoral head. AB - INTRODUCTION: The implantation of a total hip arthroplasty is the standard treatment for patients with progressive osteonecrosis. However, there is uncertainty about the type of arthroplasty that provides the best outcome and whether short stem arthroplasty represents a reasonable alternative for young patients in order to have more options in case of revision. This uncertainty exists due to the lack of studies analysing contemporary short stem arthroplasty in osteonecrosis. AIM: The aim of this study was to determine the outcome of the METHA((r)) short stem arthroplasty in patients with progressive osteonecrosis. PATIENTS AND METHODS: This study evaluated the clinical and radiological short- to midterm results after implantation of the cementless short stem arthroplasty METHA((r)). 73 hips in 64 patients with progessive osteonecrosis after implantation of the METHA((r)) arthroplasty were investigated by measuring the clinical outcome, the Harris Hip Score (HHS) and visual analogue pain scale for the preoperative stage and follow-up. Radiological analyses of X-rays were conducted to assess the bone ingrowth as well as subsidence, osteolysis or fracture. RESULTS: The pain scale improved from preoperatively 7.8 to postoperatively 1.7, while the HHS increased from 41.4 to 90.6 points 34 months post-surgery. Complications associated with revision of the METHA((r)) short stem included two traumatic femoral shaft fracture and one deep infection. The radiological assessment showed good bone ingrowth in all patients despite osteonecrosis. CONCLUSION: The study confirms encouraging results as well as good bone ingrowth of the cementless short stem arthroplasty METHA((r)) even in patients with osteonecrosis. PMID- 22546928 TI - A comparative study of respiratory syncytial virus (RSV) prophylaxis in premature infants within the Canadian Registry of Palivizumab (CARESS). AB - We examined the dosing regimens, compliance, and outcomes of premature infants who received palivizumab within the Canadian Registry of Palivizumab (CARESS). Infants receiving >=1 dose of palivizumab during the 2006-2011 respiratory syncytial virus (RSV) seasons were recruited across 30 sites. Respiratory illness events were captured monthly. Infants <=32 completed weeks gestational age (GA) (Group 1) were compared to 33-35 completed weeks GA infants (Group 2) following prophylaxis. In total, 6,654 patients were analyzed (Group 1, n = 5,183; Group 2, n = 1,471). The mean GA was 29.9 +/- 2.9 versus 34.2 +/- 2.2 weeks for Groups 1 and 2, respectively. Group differences were significant (all p-values <0.05) for the following: proportion of males, Caucasians, siblings, multiple births, maternal smoking, smoking during pregnancy, household smokers, >5 household individuals, birth weight, and enrolment age. Overall, infants received 92.6 % of expected injections. Group 1 received significantly more injections, but a greater proportion of Group 2 received injections within recommended intervals. The hospitalization rates were similar for Groups 1 and 2 for respiratory illness (4.7 % vs. 3.7 %, p = 0.1) and RSV (1.5 % vs. 1.4 %, p = 0.3). Neither the time to first respiratory illness [hazard ratio = 0.9, 95 % confidence interval (CI) 0.7-1.2, p = 0.5] nor to first RSV hospitalization (hazard ratio = 1.3, 95 % CI 0.8-2.2, p = 0.3) were different. Compliance with RSV prophylaxis is high. Despite the higher number of palivizumab doses in infants <=32 completed weeks GA, the two groups' respiratory illness and RSV-positive hospitalization rates were similar. PMID- 22546933 TI - The polyvinyl alcohol sponge model implantation. AB - Wound healing is a complicated, multistep process involving many cell types, growth factors and compounds(1-3). Because of this complexity, wound healing studies are most comprehensive when carried out in vivo. There are many in vivo models available to study acute wound healing, including incisional, excisional, dead space, and burns. Dead space models are artificial, porous implants which are used to study tissue formation and the effects of substances on the wound. Some of the commonly used dead space models include polyvinyl alcohol (PVA) sponges, steel wire mesh cylinders, expanded polytetrafluoroethylene (ePTFE) material, and the Cellstick(1,2). Each dead space model has its own limitations based on its material's composition and implantation methods. The steel wire mesh cylinder model has a lag phase of infiltration after implantation and requires a long amount of time before granulation tissue formation begins(1). Later stages of wound healing are best analyzed using the ePTFE model(1,4). The Cellstick is a cellulose sponge inside a silicon tube model which is typically used for studying human surgery wounds and wound fluid(2). The PVA sponge is limited to acute studies because with time it begins to provoke a foreign body response which causes a giant cell reaction in the animal(5). Unlike other materials, PVA sponges are easy to insert and remove, made of inert and non biodegradable materials and yet are soft enough to be sectioned for histological analysis(2,5). In wound healing the PVA sponge is very useful for analyzing granulation tissue formation, collagen deposition, wound fluid composition, and the effects of substances on the healing process(1,2,5). In addition to its use in studying a wide array of attributes of wound healing, the PVA sponge has also been used in many other types of studies. It has been utilized to investigate tumor angiogenesis, drug delivery and stem cell survival and engraftment(1,2,6,7). With its great alterability, prior extensive use, and reproducible results, the PVA sponge is an ideal model for many studies(1,2). Here, we will describe the preparation, implantation and retrieval of PVA sponge disks (Figure 1) in a mouse model of wound healing. PMID- 22546934 TI - Small RNAs and virulence in bacterial pathogens. PMID- 22546936 TI - Experimental tools to identify RNA-protein interactions in Helicobacter pylori. AB - Helicobacter pylori, one of the most prevalent human pathogens, used to be thought to lack small regulatory RNAs (sRNAs) which are otherwise considered abundant in all bacteria. However, our recent analysis of the primary transcriptome of H. pylori discovered an unexpectedly large number of sRNAs, and suggested that this model organism also uses riboregulation to control the expression of its genes. Nonetheless, whereas most enterobacterial sRNAs require the RNA chaperone Hfq for function, Epsilonproteobacteria including H. pylori seem to have no Hfq homologue, which prompted us to search for other auxiliary proteins in sRNA-mediated regulation. Therefore, we have developed two orthogonal methods to isolate and investigate in vivo and in vitro assembled RNA-protein complexes in H. pylori: (i) an affinity chromatography strategy based on aptamer tagged sRNAs of interest to identify their protein binding partners; and (ii) a rapid method for chromosomal FLAG-tagging of proteins to facilitate co immunoprecipitation of associated RNA species. Using these methods, we have identified RNA-protein interactions between the ribosomal protein S1 and various mRNAs and sRNAs of H. pylori. Moreover, both methods reported a stable RNA protein complex between the abundant HPnc6910 sRNA and HP1334, a protein of unknown function that is encoded downstream of HPnc6910. Given that 50% of all bacteria may lack Hfq, our methods can be useful to identify RNA-protein interactions in a wider range of bacterial pathogens. PMID- 22546935 TI - sRNAs and the virulence of Salmonella enterica serovar Typhimurium. AB - The combination of genomics and high-throughput cDNA sequencing technologies has facilitated the identification of many small RNAs (sRNAs) that play a central role in the post-transcriptional gene regulation of Salmonella enterica serovar Typhimurium. To date, most of the functionally characterized sRNAs have been involved in the regulation of processes which are not directly linked to virulence. Just five sRNAs have been found to affect the ability of Salmonella to replicate within mammalian cells, but the precise regulatory mechanisms that are used by sRNAs to control Salmonella pathogenicity at the post-transcriptional level remain to be identified. It is anticipated that an improved understanding of sRNA biology will shed new light on the virulence of Salmonella. PMID- 22546937 TI - Deep sequencing defines the transcriptional map of L. pneumophila and identifies growth phase-dependent regulated ncRNAs implicated in virulence. AB - The bacterium Legionella pneumophila is found ubiquitously in aquatic environments and can cause a severe pneumonia in humans called Legionnaires' disease. How this bacterium switches from intracellular to extracellular life and adapts to different hosts and environmental conditions is only partly understood. Here we used RNA deep sequencing from exponentially (replicative) and post exponentially (virulent) grown L. pneumophila to analyze the transcriptional landscape of its entire genome. We established the complete operon map and defined 2561 primary transcriptional start sites (TSS). Interestingly, 187 of the 1805 TSS of protein-coding genes contained tandem promoters of which 93 show alternative usage dependent on the growth phase. Similarly, over 60% of 713 here identified ncRNAs are phase dependently regulated. Analysis of their conservation among the seven L. pneumophila genomes sequenced revealed many strain specific differences suggesting that L. pneumophila contains a highly dynamic pool of ncRNAs. Analysis of six ncRNAs exhibiting the same expression pattern as virulence genes showed that two, Lppnc0584 and Lppnc0405 are indeed involved in intracellular growth of L. pneumophila in A. castellanii. Furthermore, L. pneumophila encodes a small RNA named RsmX that functions together with RsmY and RsmZ in the LetA-CsrA regulatory pathway, crucial for the switch to the virulent phenotype. Together our data provide new insight into the transcriptional organization of the L. pneumophila genome, identified many new ncRNAs and will provide a framework for the understanding of virulence and adaptation properties of L. pneumophila. PMID- 22546939 TI - Small RNAs in streptococci. AB - The group of streptococci includes species responsible for severe diseases in humans. To adapt to their environment and infect their hosts, streptococci depend on precise regulation of gene expression. The last decade has witnessed increasing findings of small RNAs (sRNAs) having regulatory functions in bacteria. More recently, genome-wide screens revealed that streptococcal genomes also encode multiple sRNAs. Some sRNAs including the class of CRISPR RNAs (crRNAs) play critical roles in streptococcal adaptation and virulence. Analysis of sRNA mechanisms uncovered three sRNAs that target in trans mRNA (FasX), sRNA (tracrRNA) and DNA (crRNA). Overall, the current understanding of sRNA-mediated regulation in streptococci remains very limited. Given the complexity of regulatory networks and the number of recently predicted sRNAs, future research should reveal new functions and mechanisms for the streptococcal sRNAs. Here, we provide a comprehensive summary of the information available on the topic. PMID- 22546940 TI - Current knowledge on regulatory RNAs and their machineries in Staphylococcus aureus. AB - Staphylococcus aureus is one of the major human pathogens, which causes numerous community-associated and hospital-acquired infections. The regulation of the expression of numerous virulence factors is coordinated by complex interplays between two component systems, transcriptional regulatory proteins, and regulatory RNAs. Recent studies have identified numerous novel RNAs comprising cis-acting regulatory RNAs, antisense RNAs, small non coding RNAs and small mRNAs encoding peptides. We present here several examples of RNAs regulating S. aureus pathogenicity and describe various aspects of antisense regulation. PMID- 22546938 TI - Non-coding RNA and its potential role in Mycobacterium tuberculosis pathogenesis. AB - It is estimated that one third of the human population is infected with Mycobacterium tuberculosis. Efforts to understand the molecular basis of its gene regulation have been focused on identification of protein encoding genes and regulons implicated in pathogenesis. Recently, a number of studies have described the identification of several non-coding RNAs that are likely to contribute significantly to the regulatory networks responsible for adaptation and virulence in M. tuberculosis. We have reviewed emerging information on the presence and abundance of different types of non-coding RNA in M. tuberculosis and consider their potential contribution to the adaptive responses that underlie disease pathogenesis. PMID- 22546943 TI - Molybdenum- and tungsten(II) monometallic 3-(2-pyridyl)pyrazole and bimetallic 3 (2-pyridyl)pyrazolate complexes. AB - Molybdenum and tungsten complexes containing the pypzH (3-(2-pyridyl)pyrazole) ligand as a chelating bidentate are prepared: [Mo(CO)(4)(pypzH)], cis [MoBr(eta(3)-allyl)(CO)(2)(pypzH)], cis-[MoCl(eta(3)-methallyl)(CO)(2)(pypzH)], [MI(2)(CO)(3)(pypzH)] (M = Mo, W) from [Mo(CO)(4)(NBD)] or the adequate bis(acetonitrile) complexes. The deprotonation of the molybdenum allyl or methallyl complexes affords the bimetallic complexes [cis-{Mo(eta(3) allyl)(CO)(2)(MU(2)-pypz)}](2) or [cis-{Mo(eta(3)-methallyl)(CO)(2)(MU(2) pypz)}](2) (MU(2)-pypz = MU(2)-3-(2-pyridyl-kappa(1)N)pyrazolate-2kappa(1)N). The allyl complex was subjected to an electrochemical study, which shows a marked connection between both metallic centres through the bridging pyridylpyrazolates. PMID- 22546941 TI - Non-coding sRNAs regulate virulence in the bacterial pathogen Vibrio cholerae. AB - Vibrio cholerae is the waterborne bacterium responsible for worldwide outbreaks of the acute, potentially fatal cholera diarrhea. The primary factors this human pathogen uses to cause the disease are controlled by a complex regulatory program linking extracellular signaling inputs to changes in expression of several critical virulence genes. Recently it has been uncovered that many non-coding regulatory sRNAs are important components of the V. cholerae virulence regulon. Most of these sRNAs appear to require the RNA-binding protein, Hfq, to interact with and alter the expression of target genes, while a few sRNAs appear to function by an Hfq-independent mechanism. Direct base-pairing between the sRNAs and putative target mRNAs has been shown in a few cases but the extent of each sRNAs regulon is not fully known. Genetic and biochemical methods, coupled with computational and genomics approaches, are being used to validate known sRNAs and also to identify many additional putative sRNAs that may play a role in the pathogenic lifestyle of V. cholerae. PMID- 22546944 TI - Total synthesis of ent-calystegine B4 via nitro-Michael/aldol reaction. AB - Optically active ent-calystegine B4 was prepared in 13 steps from commercially available chiral L-dimethyl tartrate. The synthesis was achieved by the Michael addition and the aldol reaction of nitromethane to form cycloheptanone in a stereoselective manner. Reduction of the nitro group in the presence of Boc(2)O accomplished an efficient conversion to amino cycloheptanone, which readily afforded the desired ent-calystegine B4. PMID- 22546942 TI - Short-term clinical and osteoimmunological effects of scaling and root planing complemented by simple or repeated laser phototherapy in chronic periodontitis. AB - The aim of this study was to evaluate the clinical, anti-inflammatory, and osteoimmunological benefits of the single (PT) and repeated laser phototherapy (rPT) as an adjunctive treatment of inflamed periodontal tissue. Twenty-seven patients with chronic periodontitis were randomly divided into three groups of nine patients each in order to undergo scaling and root planing (SRP), SRP followed by one session of adjunctive PT (Day 1; SRP + PT), or SRP followed by adjunctive repeated PT five times in 2 weeks (Days 1, 2, 4, 7, and 11; SRP + rPT). For phototherapy session, a diode laser (lambda = 670 nm, 200 mW, 60 s/tooth) was applied into the sulcus. Clinical parameters, including full-mouth plaque score, full-mouth bleeding score, probing pocket depth, and clinical attachment level were recorded. Samples of gingival crevicular fluid (GCF) were taken at baseline, 4, and 8 weeks after treatment. Interleukin 1 beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), receptor activator of nuclear factor kappaBeta ligand (RANKL), and osteoprotegerin (OPG) levels in the collected GCF were measured. PT used in a single or repeated doses, does not produce a significant reduction in the clinical parameters essayed (p > 0.05). Levels of IL 1beta in GCF were significantly reduced in SRP + PT and SRP + rPT groups compared with the SRP group (p < 0.05). However, the SRP + rPT group showed a significant reduction of pro-inflammatory cytokine TNF-alpha and RANKL/OPG ratio at 4 weeks post-treatment compared with the SRP + PT and SRP groups (p < 0.05). SRP + PT group also showed a significant reduction in TNF-alpha and RANKL/OPG ratio at 8 weeks post-treatment compared with the SRP group (p < 0.05). PT exerts a biostimulative effect on the periodontal tissue. Multiple sessions of PT showed a faster and greater tendency to reduce proinflammatory mediators and RANKL/OPG ratio. PMID- 22546945 TI - Diacylglycerol kinase zeta negatively regulates CXCR4-stimulated T lymphocyte firm arrest to ICAM-1 under shear flow. AB - T lymphocyte arrest within microvasculature is an essential process in immune surveillance and the adaptive immune response. Integrins and chemokines coordinately regulate when and where T cells stop under flow via chemokine triggered inside-out activation of integrins. Diacylglycerol kinases (DGKs) regulate the levels of diacylglycerol (DAG) which in turn determine the activation of guanine nucleotide exchange factors (GEFs) and Ras proximity 1 (Rap1) molecules crucial to the activation of integrin lymphocyte function associated antigen 1 (LFA-1). However, how the level of DGK regulates chemokine stimulated LFA-1-mediated T cell arrest under flow is unknown. Using a combination of experiment and computational modeling, we demonstrate that DGKzeta is a crucial regulator of CXCL12-triggered T cell arrest on surfaces presenting inter-cellular adhesion molecule 1 (ICAM-1). Using flow chamber assays, we found that the deficiency of DGKzeta in T cells significantly increased firm arrest to ICAM-1-coated substrates and shortened the time to stop without altering the rolling velocity. These results suggest that DGKzeta levels affect LFA-1-mediated T cell firm arrest, but not P-selectin-mediated rolling during CXCL12 stimulation. We accurately simulated the role of DGKzeta in firm arrest of T cells computationally using an Integrated-Signaling Adhesive Dynamics (ISAD). In the absence of DGK catalytic reaction, the model cells rolled for a significantly shorter time before arrest, compared to when DGK molecules were present. Predictions of our model for T cell arrest quantitatively match experimental results. Overall these results demonstrate that DGKzeta is a negative regulator of CXCL12-triggered inside-out activation of LFA-1 and firm adhesion of T cells under shear flow. PMID- 22546947 TI - Impact of liberal use of mediolateral episiotomy on the incidence of obstetric anal sphincter tear. AB - PURPOSE: To assess the impact of liberal compared with restrictive use of mediolateral episiotomy on the incidence of obstetric anal sphincter tear (OAST). METHODS: Data between the years 1999-2001 (era 1) when liberal mediolateral episiotomy was applied were compared with the years 2004-2008 (era 2) when restricted mediolateral episiotomy was implemented. Liberal mediolateral episiotomy was done for fetal or maternal indications, while restrictive mediolateral episiotomy was done when a tear was imminent. Primary outcome was the incidence of OAST. RESULTS: A total of 25,170 women who delivered vaginally were included. After adjusting for potential confounders, the incidence of OAST was found to be significantly higher in era 2 (0.4 %) compared to era 1 (0.1 %), (p = 0.02; adjusted OR 2.23; 95 % CI, 1.16-4.29). Among primiparous women, the incidence of mediolateral episiotomy was 71.8 and 27.1 % in eras 1 and 2, respectively (p < 0.001), and the incidence of OAST was 0.2 and 1 % in eras 1 and 2, respectively (p = 0.009; adjusted OR 4.15; 95 % CI, 1.42-12.10). Among multiparous women, the incidence of OAST did not differ significantly (p = 0.52). Returning to the liberal policy among primiparous women only, 124 deliveries are needed to prevent one OAST. CONCLUSION: Liberal compared to restrictive use of mediolateral episiotomy may be a sphincter-saving procedure among primiparous women. PMID- 22546946 TI - Polymorphisms in genes HSD17B1 and HSD17B2 and uterine leiomyoma risk in Chinese women. AB - PURPOSE: To evaluate the association of HSD17B1 and HSD17B2 gene polymorphisms with uterine leiomyoma in Chinese women. METHODS: 121 Chinese women with clinically diagnosed uterine leiomyoma and 217 healthy normal Chinese women were investigated to compare three single nucleotide polymorphisms (SNPs) (rs605059 and rs676387 of HSD17B1 gene and rs8191246 of HSD17B2 gene) by polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing method. RESULTS: All the SNPs were polymorphisms in Chinese women. Frequencies of rs605059 AA genotype and A allele were significantly increased in patients with uterine leiomyoma compared to healthy controls (GG vs. AA, OR 0.40, 95 % CI 0.20 0.82; G vs. A, OR 0.68, 95 % CI 0.50-0.94). CONCLUSION: The results suggest that the genotype of HSD17B1 rs605059 may play a role in the tumourgenesis of uterine leiomyoma. PMID- 22546948 TI - The Bishop Score as a determinant of labour induction success: a systematic review and meta-analysis. AB - PURPOSE: To evaluate the association between the Bishop Score and successful induction. STUDY STRATEGY AND SELECTION CRITERIA: We searched the PubMed and the lists of references of relevant studies to identify reports on the association between Bishop Score and achieving active phase of labour or vaginal delivery. DATA COLLECTION AND ANALYSIS: We abstracted crude or adjusted measures of association from studies. Summary odds ratio (OR) and summary hazard ratio (HR), and 95 % confidence interval (95 % CI) were obtained by random effects meta analysis. Study heterogeneity was assessed using the I (2) test. RESULTS: Fifty nine studies met the inclusion criteria. Analyses with crude ORs showed that women with higher versus lower Bishop Score were more likely to achieve vaginal delivery either with no time limit for this to occur, or within a certain time interval; the summary ORs according to the Bishop Score cutoff ranged from 1.98 (95 % CI: 1.58-2.48; I (2) = 36.6 %) to 5.48 (95 % CI: 1.67-17.96; I (2) = 0.0 %) and from 2.15 (95 % CI: 1.36-3.40; I (2) = 0.0 %) to 4.22 (95 % CI: 2.48-7.17; I (2) = 11.0 %), respectively. Summary estimates per unit increase in the Bishop Score, based on adjusted ORs, showed a positive association with achieving vaginal delivery, either with no time limit (OR(summary) = 1.33; 95 % CI: 1.13 1.56; I (2) = 66.1 %) or within a certain time interval (OR(summary) = 1.52; 95 % CI: 1.37-1.70; I (2) = 42.4 %). Summary HRs per unit increase in Bishop Score showed an association with induction to vaginal delivery (HR(summary) = 1.28; 95 % CI: 1.21-1.36; I (2) = 0.0 %), but not with induction to active phase (HR(summary) = 1.21; 95 % CI: 0.88-1.68; I (2) = 70.7 %) time interval. CONCLUSIONS: Bishop Score seems be a determinant of achieving vaginal delivery and is associated with induction-to-vaginal delivery time interval. PMID- 22546949 TI - Prevalence and type distribution of high-risk human papillomavirus infections among women in Wufeng County, China. AB - OBJECTIVE: The aim of this survey was to assess the prevalence and type distribution of oncogenic human papillomavirus (HPV) infections among women in Wufeng County of Hubei province, where the cervical cancer mortality rate is the highest in China Cervical. METHODS: DNA samples were collected from 1,100 women, then screened and quantified by a multi-fluorescent, quantitative real-time PCR assay. The cervical DNA samples were then re-typed by real-time PCR using seven pair primers of high-risk (HR) HPVs designed to detect types 16, 31, 18/45, 33, 52, 58, and 67. RESULTS: The overall prevalence of HR HPVs was 11.14 % (95 % CI, 9.74-13.72 %) in Wufeng County, which was not statistically different between Tu (12.17 %; 95 % CI, 10.03-12.34 %) and Han nationality (8.95 %; 95 % CI, 3.55 14.35 %). Among different types of HPV, HPV 16 was the most frequently detected genotype, followed by HPV 52, 58, 18/45, and 31. The most prevalent types of HR HPV in Tu nationality were HPV 16, 52, and 58, and the most prevalent types of HR HPV in Han nationality were HPV 16, 33, and 18/45. The overall prevalence of HPV was highest in the 20-24 year age group (21.43 %; 95 % CI, 17.56-25.30 %) and the prevalence of HR HPV was associated with education. CONCLUSIONS: HPV 16, 52, and 58 are common genotypes in Wufeng County, and support the hypothesis that second generation HPV prophylactic vaccines, including HPV 52 and 58, may offer higher protection for women in China and other areas of Asia. The findings of this study contribute to preventive and screening measures in clinical practice. PMID- 22546950 TI - A short narrative review of the feasibility of adopting mild ovarian stimulation for IVF as the current standard of care. AB - INTRODUCTION: Mild ovarian stimulation has been conceived, proposed and implemented in clinical practice as a safer and cheaper alternative to conventional strategies of controlled ovarian hyperstimulation in preparation for in vitro fertilization (IVF). Our aim was to summarize the key evidence on this topic and explore its possible role as the standard treatment option for women undergoing IVF. MATERIALS AND METHODS: A short narrative review of the existing literature, with emphasis on mild ovarian stimulation clinical and cost effectiveness, as well as treatment limitations. RESULTS: Numerous studies highlight mild ovarian stimulation's favorable characteristics with respect to oocyte/embryo quality, reduced patient risk, and ease of intervention. There is, however, a need for high-quality laboratory environment. Limitations regarding poor responders, older women, or those seeking ovarian stimulation for non infertility indications should also be considered. Finally, outcomes on the cumulative success rates and the cost effectiveness of mild ovarian stimulation remain inconclusive. CONCLUSION: Mild ovarian stimulation protocols for IVF should currently be implemented only in carefully selected populations. Further research is needed to clarify the remaining controversies in this IVF approach. PMID- 22546951 TI - Ischemic stroke recurrence during pregnancy: a case series and a review of the literature. AB - PURPOSE: Aims of the study were to determine the risk of stroke recurrence in a case series of women with a history of ischemic stroke and to review current available literature on this issue. METHODS: Charts from patients referring to the obstetrical service of our Institute were reviewed to identify pregnant women with a history of ischemic stroke. Demographic, historical and clinical data were collected from outpatient and inpatient charts. Women were contacted at least 6 months after delivery to assess maternal and neonatal health. A review of the literature regarding pregnancy in women with a history of ischemic stroke was also performed. RESULTS: Twenty-four pregnant women with a history of ischemic stroke referred to our Institution. All women received prophylaxis to prevent stroke recurrence during pregnancy. No recurrent episode was recorded in our series (0.0 %, 95% CI 0.0-11.3 %). One woman had a TIA. Considering collective data from the literature and from the present study, five cases of stroke recurrence out of 184 pregnancies were identified, corresponding to a rate of 2.7 % (95% CI 1.0-5.8 %). All of them were under prophylactic treatment at the time of stroke. Thrombophilia and preeclampsia may represent predisposing conditions for recurrence during pregnancy. CONCLUSIONS: Stroke recurrence in pregnant women with a history of ischemic stroke is uncommon, but not rare and prophylactic treatment does not fully protect against it. Further evidence is required to better clarify clinical factors predisposing to recurrence. PMID- 22546952 TI - Cytomegalovirus and rubella seroprevalence in pregnant women in Izmir/Turkey: follow-up and results of pregnancy outcome. AB - PURPOSE: It is aimed to determine the Rubella and CMV prevalence in the pregnant women in Izmir and to research the effect of these infections on the course of pregnancy in the pregnant women exposed to infection during pregnancy. METHODS: The pregnant women applied to pregnancy outpatient department during 2001-2008 have been examined with enzyme-linked fluorescent assay (VIDAS; bioMerieux) method in terms of Rubella and CMV IgM and IgG antibodies and CMV IgG avidity test. RESULTS: Totally 5,959 pregnant women were included in the study. The seropositivity rates for Rubella and CMV were found as 97.8 and 98.3 %, IgM positivity rates were found as 0.37 and 0.18 %, respectively. Curettage was recommended to the pregnant women in which Rubella IgM positivity was detected in the first trimester of the pregnancy. Eight of the pregnant women in which IgM was found as positive after the 20th week of pregnancy were examined and three intrauterine growth retardation, one hypospadias and three normal deliveries were seen in these pregnant women. Any congenital anomaly finding was not detected in the pregnant women with positive CMV IgM. CONCLUSIONS: Seroprevalence values are high for Rubella and CMV in our region. It can be recommended not to check the pregnant women routinely for this purpose with the good implementation of Rubella vaccine programs. PMID- 22546953 TI - Pathogenesis of endometriosis: the role of genetics, inflammation and oxidative stress. AB - INTRODUCTION: Endometriosis is defined as the presence of endometrial tissue outside the uterine cavity. MATERIALS AND METHODS: The etiology of this multifactorial disease is still unresolved and an increasing number of studies suggest that genetic, hormonal, environmental, immunological and oxidative factors may all play an important role in the pathogenesis of this disorder. CONCLUSIONS: In this literature review, inflammatory activity, oxidative stress as well as genetic abnormalities and mutations have been studied in an effort to identify factors predisposing to endometriosis. PMID- 22546954 TI - Analysis of mitochondrial DNA sequence variants in patients with polycystic ovary syndrome. AB - PURPOSE: To understand the role of mitochondrial DNA (mtDNA) mutations in patients with polycystic ovary syndrome (PCOS). METHODS: A total of 57 women with PCOS and 38 controls were recruited in this study, mutational analysis of mitochondrial genome was performed using polymerase chain reaction and under a direct sequence analysis. RESULTS: Sequence characterization of mitochondrial genome showed a distinct set of polymorphisms mainly focused on oxidative phosphorylation (OXPHOS) complex, in addition, six variants in mitochondrial tRNA genes, including tRNA(Gln), tRNA(Cys), tRNA(Asp), tRNA(Lys), tRNA(Arg) and tRNA(Glu) were also identified in PCOS patients. Interestingly, these variants occurred at highly conserved nucleotides of corresponding tRNAs, which are important for tRNA stability level and biochemical function. CONCLUSIONS: Mutations in mtDNA, especially the OXPHOS complex and tRNAs, may be associated with PCOS patients, thus, our results shed new insight into the pathogenesis of PCOS. PMID- 22546955 TI - Reexamination of the assessment criteria for rheumatoid arthritis disease activity based on comparison of the Disease Activity Score 28 with other simpler assessment methods. AB - OBJECTIVE: To explore simpler and possibly more appropriate tools than the conventional Disease Activity Score 28 (DAS28) for assessing rheumatoid arthritis (RA) and to derive more reliable DAS28-based criteria. METHODS: The capabilities of assessing disease activities in 250 RA patients were compared between DAS28 and other methods, including the Simplified DA Index (SDAI), Clinical DA Index (CDAI), and Routine Assessment of Patient Index Data-3 (RAPID-3). RESULTS: SDAI and CDAI showed a good correlation and consistency with DAS28, whereas RAPID-3 yielded inferior results. In terms of remission criteria, DAS28 was less stringent than SDAI or CDAI; when RA remission was reexamined based on more stringent SDAI or CDAI criteria, cut-off values for DAS28-C-reactive protein of <1.72 were considered to be appropriate. The conventional DAS28 was considered to be appropriate for assessing low, middle and high disease activities because it provides criteria similar to or more stringent than those of other methods, while SDAI and CDAI were considered to be simpler and more appropriate criteria for assessing remission. CONCLUSION: For assessing remission, DAS28-CRP provides the most appropriate criterion of the methods compared when the currently used cut off value of 2.3 is lowered to a new value of 1.72. PMID- 22546956 TI - Agarose gel electrophoresis for the separation of DNA fragments. AB - Agarose gel electrophoresis is the most effective way of separating DNA fragments of varying sizes ranging from 100 bp to 25 kb(1). Agarose is isolated from the seaweed genera Gelidium and Gracilaria, and consists of repeated agarobiose (L- and D-galactose) subunits(2). During gelation, agarose polymers associate non covalently and form a network of bundles whose pore sizes determine a gel's molecular sieving properties. The use of agarose gel electrophoresis revolutionized the separation of DNA. Prior to the adoption of agarose gels, DNA was primarily separated using sucrose density gradient centrifugation, which only provided an approximation of size. To separate DNA using agarose gel electrophoresis, the DNA is loaded into pre-cast wells in the gel and a current applied. The phosphate backbone of the DNA (and RNA) molecule is negatively charged, therefore when placed in an electric field, DNA fragments will migrate to the positively charged anode. Because DNA has a uniform mass/charge ratio, DNA molecules are separated by size within an agarose gel in a pattern such that the distance traveled is inversely proportional to the log of its molecular weight(3). The leading model for DNA movement through an agarose gel is "biased reptation", whereby the leading edge moves forward and pulls the rest of the molecule along(4). The rate of migration of a DNA molecule through a gel is determined by the following: 1) size of DNA molecule; 2) agarose concentration; 3) DNA conformation(5); 4) voltage applied, 5) presence of ethidium bromide, 6) type of agarose and 7) electrophoresis buffer. After separation, the DNA molecules can be visualized under uv light after staining with an appropriate dye. By following this protocol, students should be able to: Understand the mechanism by which DNA fragments are separated within a gel matrix Understand how conformation of the DNA molecule will determine its mobility through a gel matrix Identify an agarose solution of appropriate concentration for their needs Prepare an agarose gel for electrophoresis of DNA samples Set up the gel electrophoresis apparatus and power supply Select an appropriate voltage for the separation of DNA fragments Understand the mechanism by which ethidium bromide allows for the visualization of DNA bands Determine the sizes of separated DNA fragments. PMID- 22546957 TI - Fear of falling and coexisting sensory difficulties as predictors of mobility decline in older women. AB - BACKGROUND: Mobility decline, the coexistence of several sensory difficulties and fear of falling (FOF) are all common concerns in older people; however, knowledge about the combined effect of FOF and coexisting sensory difficulties on mobility is lacking. METHODS: Data on self-reported FOF, difficulties in hearing, vision, balance, and walking 2 km were gathered with a structured questionnaire among 434 women aged 63-76 years at baseline and after a 3-year follow-up. Logistic regression models were used for analyses. RESULTS: Every third participant reported difficulties in walking 2 km at baseline. In cross-sectional analysis, the odds ratio for difficulties in walking 2 km was higher among persons who reported FOF compared with persons without FOF and the odds increased with the increasing number of sensory difficulties. Persons who reported FOF and who had three sensory difficulties had almost fivefold odds (odds ratio = 4.7, 95% confidence interval = 1.9-11.7) for walking difficulties compared with those who reported no FOF and no sensory difficulties. Among the 290 women without walking difficulties at baseline, 54 participants developed difficulty in walking 2 km during the 3-year follow-up. Odds ratio for incident walking difficulty was 3.5 (95% confidence interval = 1.6-7.8) in participants with FOF and with 2-3 sensory difficulties compared with persons without FOF and with at most one sensory difficulty at baseline. CONCLUSIONS: Older women who have several coexisting sensory difficulties combined with FOF are particularly vulnerable to mobility decline. Avoidance of walking as a result of FOF is likely to be reinforced when multiple sensory difficulties hinder reception of accurate information about the environment, resulting in accelerated decline in walking ability. PMID- 22546958 TI - Relation of driving status to incident life space constriction in community dwelling older persons: a prospective cohort study. AB - BACKGROUND: Maintaining spatial movement through the environment is an important feature of healthy aging. We examined whether being licensed to drive is associated with maintaining spatial movement in older persons initially reporting maximum spatial mobility. METHODS: From the Rush Memory and Aging Project, 571 nondemented, community-dwelling older persons were identified with (i) baseline data on driving status, (ii) baseline report of spatial mobility to the largest life space zone, and (iii) at least one annual follow-up evaluation. Incident constriction of life space was the primary outcome of interest. RESULTS: Over an average follow-up of 4.3 years, 303 participants reported incident constriction of life space. In a proportional hazards model adjusted for age, sex, and education, having a valid driver's license at baseline was associated with a decreased hazard of reporting a life space constriction (hazard ratio = 0.39; 95% confidence interval = 0.29-0.54). Results were unchanged after controlling for number of vascular risk factors and vascular diseases, low visual acuity, social isolation, and gait speed. Of participants reporting incident life space constriction, 188 subsequently reported reexpansion of spatial mobility to the largest zone of life space. Having a valid driver's license was associated with a greater likelihood of life space recovery (hazard ratio = 2.00; 95% confidence interval = 1.27-3.17). CONCLUSION: In older persons, having a valid driving license was associated with reduced hazard of reporting life space constriction and a greater likelihood of life space recovery if incident life space constriction occurred. PMID- 22546959 TI - Indicators of childhood quality of education in relation to cognitive function in older adulthood. AB - BACKGROUND: The association between years of education and cognitive function in older adults has been studied extensively, but the role of quality of education is unknown. We examined indicators of childhood educational quality as predictors of cognitive performance and decline in later life. METHODS: Participants included 433 older adults (52% African American) who reported living in Alabama during childhood and completed in-home assessments of cognitive function at baseline and 4 years later. Reports of residence during school years were matched to county-level data from the 1935 Alabama Department of Education report for school funding (per student), student-teacher ratio, and school year length. A composite measure of global cognitive function was utilized in analyses. Multilevel mixed effects models accounted for clustering of educational data within counties in examining the association between cognitive function and the educational quality indices. RESULTS: Higher student-teacher ratio was associated with worse cognitive function and greater school year length was associated with better cognitive function. These associations remained statistically significant in models adjusted for education level, age, race, gender, income, reading ability, vascular risk factors, and health behaviors. The observed associations were stronger in those with lower levels of education (<=12 years), but none of the education quality measures were related to 4-year change in cognitive function. CONCLUSIONS: Educational factors other than years of schooling may influence cognitive performance in later life. Understanding the role of education in cognitive aging has substantial implications for prevention efforts as well as accurate identification of older adults with cognitive impairment. PMID- 22546960 TI - Development of the computer-adaptive version of the Late-Life Function and Disability Instrument. AB - BACKGROUND: Having psychometrically strong disability measures that minimize response burden is important in assessing of older adults. METHODS: Using the original 48 items from the Late-Life Function and Disability Instrument and newly developed items, a 158-item Activity Limitation and a 62-item Participation Restriction item pool were developed. The item pools were administered to a convenience sample of 520 community-dwelling adults 60 years or older. Confirmatory factor analysis and item response theory were employed to identify content structure, calibrate items, and build the computer-adaptive testings (CATs). We evaluated real-data simulations of 10-item CAT subscales. We collected data from 102 older adults to validate the 10-item CATs against the Veteran's Short Form-36 and assessed test-retest reliability in a subsample of 57 subjects. RESULTS: Confirmatory factor analysis revealed a bifactor structure, and multi dimensional item response theory was used to calibrate an overall Activity Limitation Scale (141 items) and an overall Participation Restriction Scale (55 items). Fit statistics were acceptable (Activity Limitation: comparative fit index = 0.95, Tucker Lewis Index = 0.95, root mean square error approximation = 0.03; Participation Restriction: comparative fit index = 0.95, Tucker Lewis Index = 0.95, root mean square error approximation = 0.05). Correlation of 10-item CATs with full item banks were substantial (Activity Limitation: r = .90; Participation Restriction: r = .95). Test-retest reliability estimates were high (Activity Limitation: r = .85; Participation Restriction r = .80). Strength and pattern of correlations with Veteran's Short Form-36 subscales were as hypothesized. Each CAT, on average, took 3.56 minutes to administer. CONCLUSIONS: The Late-Life Function and Disability Instrument CATs demonstrated strong reliability, validity, accuracy, and precision. The Late-Life Function and Disability Instrument CAT can achieve psychometrically sound disability assessment in older persons while reducing respondent burden. Further research is needed to assess their ability to measure change in older adults. PMID- 22546961 TI - Association of a Modified Physiologic Index with mortality and incident disability: the Health, Aging, and Body Composition study. AB - BACKGROUND: Indexes constructed from components may identify individuals who age well across systems. We studied the associations of a Modified Physiologic Index (systolic blood pressure, forced vital capacity, Digit Symbol Substitution Test score, serum cystatin-C, serum fasting glucose) with mortality and incident disability. METHODS: Data are from the Health, Aging, and Body Composition study on 2,737 persons (51.2% women, 40.3% black) aged 70-79 years at baseline and followed on average 9.3 (2.9) years. Components were graded 0 (healthiest), 1 (middle), or 2 (unhealthiest) by tertile or clinical cutpoints and summed to calculate a continuous index score (range 0-10). We used multivariate Cox proportional hazards regression to calculate risk of death or disability and determined accuracy predicting death using the area under the curve. RESULTS: Mortality was 19% greater per index unit (p < .05). Those with highest index scores (scores 7-10) had 3.53-fold greater mortality than those with lowest scores (scores 0-2). The unadjusted index (c-statistic = 0.656, 95% CI 0.636 0.677, p < .0001) predicted death better than age (c-statistic = 0.591, 95% CI 0.568-0.613, p < .0001; for comparison, p < .0001). The index attenuated the age association with mortality by 33%. A model including age and the index did not predict death better than the index alone (c-statistic = 0.671). Prediction was improved with the addition of other markers of health (c-statistic = 0.710, 95% CI 0.689-0.730). The index was associated with incident disability (adjusted hazard ratio per index unit = 1.04, 95% CI 1.01-1.07). CONCLUSIONS: A simple index of available physiologic measurements was associated with mortality and incident disability and may prove useful for identifying persons who age well across systems. PMID- 22546962 TI - Mycangia of ambrosia beetles host communities of bacteria. AB - The research field of animal and plant symbioses is advancing from studying interactions between two species to whole communities of associates. High throughput sequencing of microbial communities supports multiplexed sampling for statistically robust tests of hypotheses about symbiotic associations. We focus on ambrosia beetles, the increasingly damaging insects primarily associated with fungal symbionts, which have also been reported to support bacteria. To analyze the diversity, composition, and specificity of the beetles' prokaryotic associates, we combine global sampling, insect anatomy, 454 sequencing of bacterial rDNA, and multivariate statistics to analyze prokaryotic communities in ambrosia beetle mycangia, organs mostly known for transporting symbiotic fungi. We analyze six beetle species that represent three types of mycangia and include several globally distributed species, some with major economic importance (Dendroctonus frontalis, Xyleborus affinis, Xyleborus bispinatus-ferrugineus, Xyleborus glabratus, Xylosandrus crassiusculus, and Xylosandrus germanus). Ninety six beetle mycangia yielded 1,546 bacterial phylotypes. Several phylotypes appear to form the core microbiome of the mycangium. Three Mycoplasma (originally thought restricted to vertebrates), two Burkholderiales, and two Pseudomonadales are repeatedly present worldwide in multiple beetle species. However, no bacterial phylotypes were universally present, suggesting that ambrosia beetles are not obligately dependent on bacterial symbionts. The composition of bacterial communities is structured by the host beetle species more than by the locality of origin, which suggests that more bacteria are vertically transmitted than acquired from the environment. The invasive X. glabratus and the globally distributed X. crassiusculus have unique sets of bacteria, different from species native to North America. We conclude that the mycangium hosts in multiple vertically transmitted bacteria such as Mycoplasma, most of which are likely facultative commensals or parasites. PMID- 22546963 TI - The dark side of the lung: unveiling regional lung ventilation with electrical impedance tomography. PMID- 22546964 TI - Short-term, mild hypothermia can increase the beneficial effect of permissive hypotension on uncontrolled hemorrhagic shock in rats. AB - BACKGROUND: Our previous and other studies have shown that hypotensive or hypothermic resuscitation have beneficial effects on uncontrolled hemorrhagic shock. Whether hypothermia can increase the beneficial effect of hypotensive resuscitation on hemorrhagic shock is not known. METHODS: Two-hundred and twenty Sprague-Dawley rats were used to make uncontrolled hemorrhagic shock. Before bleeding was controlled, rats received normotensive or hypotensive resuscitation (target mean arterial pressure at 80 or 50 mmHg) in combination with normal (37 degrees C) or mild hypothermia (34 degrees C) (phase II). After bleeding was controlled, rats received whole blood and lactated Ringer's solution resuscitation for 2 h (phase III). The animal survival, blood loss, fluid requirement, cardiac output, and coagulation functions, as well as vital organ function, mitochondrial function, and energy metabolism of liver, kidney and intestines, were noted. RESULTS: Short-term, mild hypothermia before bleeding was controlled increased the beneficial effect of hypotensive resuscitation. Hypothermia further decreased blood loss, oxygen consumption, and functional damage to the liver, kidney, and intestines during hypotensive resuscitation, protected mitochondrial function and energy metabolism (activity of Na(+)-K(+) ATPase), and further improved survival time and survival rate (hypothermic/hypotensive combined group: survival rate, 9/10; survival time, 616 min; normothermic/normotensive group: 1/10, 256 min; hypothermic/normotensive group: 4/10, 293 min). Hypothermia slightly inhibited coagulation function. CONCLUSION: Mild hypothermia before bleeding is controlled can increase the beneficial effect of hypotensive resuscitation on uncontrolled hemorrhagic shock. The mechanism underlying the benefits of short-term hypothermia may be related to the decrease in oxygen consumption and metabolism, and protection of mitochondrial and organ functions. PMID- 22546965 TI - Autologous transplantation of peripheral blood-derived circulating endothelial progenitor cells attenuates endotoxin-induced acute lung injury in rabbits by direct endothelial repair and indirect immunomodulation. AB - BACKGROUND: Studies have demonstrated the role of circulating endothelial progenitor cells (EPCs) in maintaining normal endothelial function and in endothelial repairing. This study was aimed to observe the protective effects of autologous transplantation of circulating EPCs against endotoxin-induced acute lung injury in rabbits and to investigate the underlying mechanisms. METHODS: One hundred-and-fifty rabbits were enrolled. After acute lung injury was induced by endotoxin, autologous circulating EPCs, endothelial cell, or normal saline were transfused intravenously, respectively. Pao(2)/FiO(2) ratios, concentrations of plasma nitric oxide, malonyldialdehyde, and activity of superoxide dismutase were examined. The lung wet-to-dry weight ratios were counted; polymorphonuclear cell ratios and areas of hyaline membrane formation and hemorrhage were measured. The levels of interleukin-1beta, E-selectin, intercellular adhesion molecule-1, interleukin-10, vascular endothelial growth factor protein, and inducible nitric oxide synthase protein were analyzed. RESULTS: Pao(2)/FiO(2) ratios were significantly increased with EPC transfusion. Infiltration of polymorphonuclear cells, lung wet-to-dry weight ratios, and area of hyaline membrane and hemorrhage in lung tissue were significantly decreased after EPC transplantation. Plasma level of nitric oxide and malondialdehyde were significantly inhibited, and the activity of superoxide dismutase was enhanced in the EPC-treated animals. EPC transplantation significantly increased level of interleukin-10 and vascular endothelial growth factor protein and reduced levels of interleukin-1beta, E selectin, intercellular adhesion molecule-1, and inducible nitric oxide synthase in injury lung tissues. CONCLUSIONS: Autologous transplantation of circulating EPCs can partly restore the pulmonary endothelial function and effectively attenuate endotoxin-induced acute lung injury by direct endothelial repair and indirect immunomodulation of antioxidation and antiinflammation. PMID- 22546966 TI - Effect of perioperative systemic alpha2 agonists on postoperative morphine consumption and pain intensity: systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Systemic alpha2 agonists are believed to reduce pain and opioid requirements after surgery, thus decreasing the incidence of opioid-related adverse effects, including hyperalgesia. METHODS: The authors searched for randomized placebo-controlled trials testing systemic alpha2 agonists administrated in surgical patients and reporting on postoperative cumulative opioid consumption and/or pain intensity. Meta-analyses were performed when data from 5 or more trials and/or 100 or more patients could be combined. RESULTS: Thirty studies (1,792 patients, 933 received clonidine or dexmedetomidine) were included. There was evidence of postoperative morphine-sparing at 24 h; the weighted mean difference was -4.1 mg (95% confidence interval, -6.0 to -2.2) with clonidine and -14.5 mg (-22.1 to -6.8) with dexmedetomidine. There was also evidence of a decrease in pain intensity at 24 h; the weighted mean difference was -0.7 cm (-1.2 to -0.1) on a 10-cm visual analog scale with clonidine and -0.6 cm (-0.9 to -0.2) with dexmedetomidine. The incidence of early nausea was decreased with both (number needed to treat, approximately nine). Clonidine increased the risk of intraoperative (number needed to harm, approximately nine) and postoperative hypotension (number needed to harm, 20). Dexmedetomidine increased the risk of postoperative bradycardia (number needed to harm, three). Recovery times were not prolonged. No trial reported on chronic pain or hyperalgesia. CONCLUSIONS: Perioperative systemic alpha2 agonists decrease postoperative opioid consumption, pain intensity, and nausea. Recovery times are not prolonged. Common adverse effects are bradycardia and arterial hypotension. The impact of alpha2 agonists on chronic pain or hyperalgesia remains unclear because valid data are lacking. PMID- 22546967 TI - Hospital stay and mortality are increased in patients having a "triple low" of low blood pressure, low bispectral index, and low minimum alveolar concentration of volatile anesthesia. AB - BACKGROUND: Low mean arterial pressure (MAP) and deep hypnosis have been associated with complications and mortality. The normal response to high minimum alveolar concentration (MAC) fraction of anesthetics is hypotension and low Bispectral Index (BIS) scores. Low MAP and/or BIS at lower MAC fractions may represent anesthetic sensitivity. The authors sought to characterize the effect of the triple low state (low MAP and low BIS during a low MAC fraction) on duration of hospitalization and 30-day all-cause mortality. METHODS: Mean intraoperative MAP, BIS, and MAC were determined for 24,120 noncardiac surgery patients at the Cleveland Clinic, Cleveland, Ohio. The hazard ratios associated with combinations of MAP, BIS, and MAC values greater or less than a reference value were determined. The authors also evaluated the association between cumulative triple low minutes, and excess length-of-stay and 30-day mortality. RESULTS: Means (+/-SD) defining the reference, low, and high states were 87 +/- 5 mmHg (MAP), 46 +/- 4 (BIS), and 0.56 +/- 0.11 (MAC). Triple lows were associated with prolonged length of stay (hazard ratio 1.5, 95% CI 1.3-1.7). Thirty-day mortality was doubled in double low combinations and quadrupled in the triple low group. Triple low duration >=60 min quadrupled 30-day mortality compared with <=15 min. Excess length of stay increased progressively from <=15 min to >=60 min of triple low. CONCLUSIONS: The occurrence of low MAP during low MAC fraction was a strong and highly significant predictor for mortality. When these occurrences were combined with low BIS, mortality risk was even greater. The values defining the triple low state were well within the range that many anesthesiologists tolerate routinely. PMID- 22546968 TI - Assays for human telomerase activity: progress and prospects. AB - Human telomerase is a ribonucleoprotein complex that functions as a telomere terminal transferase by adding multiple TTAGGG hexamer repeats using its integral RNA as the template. There is a very strong association between telomerase activity and malignancy in nearly all types of cancer, suggesting that telomerase could be used not only as a diagnostic and prognostic marker but also as a therapeutic target for managing cancer. The significant progress in biomedical telomerase research has necessitated the development of new bioanalytical methods for the rapid, sensitive, and reliable detection of telomerase activity in a particular cell or clinical tissue and body fluids. In this review, we highlight some of the latest methods for identifying telomerase activity and inhibition and discuss some of the challenges for designing innovative telomerase assays. We also summarise the current technologies and speculate on future directions for telomerase testing. PMID- 22546981 TI - Thyroid nodule recognition based on feature selection and pixel classification methods. AB - Statistical approach is a valuable way to describe texture primitives. The aim of this study is to design and implement a classifier framework to automatically identify the thyroid nodules from ultrasound images. Using rigorous mathematical foundations, this article focuses on developing a discriminative texture analysis method based on texture variations corresponding to four biological areas (normal thyroid, thyroid nodule, subcutaneous tissues, and trachea). Our research follows three steps: automatic extraction of the most discriminative first-order statistical texture features, building a classifier that automatically optimizes and selects the valuable features, and correlating significant texture parameters with the four biological areas of interest based on pixel classification and location characteristics. Twenty ultrasound images of normal thyroid and 20 that present thyroid nodules were used. The analysis involves both the whole thyroid ultrasound images and the region of interests (ROIs). The proposed system and the classification results are validated using the receiver operating characteristics which give a better overall view of the classification performance of methods. It is found that the proposed approach is capable of identifying thyroid nodules with a correct classification rate of 83 % when whole image is analyzed and with a percent of 91 % when the ROIs are analyzed. PMID- 22546982 TI - Observer performance using virtual pathology slides: impact of LCD color reproduction accuracy. AB - The use of color LCDs in medical imaging is growing as more clinical specialties use digital images as a resource in diagnosis and treatment decisions. Telemedicine applications such as telepathology, teledermatology, and teleophthalmology rely heavily on color images. However, standard methods for calibrating, characterizing, and profiling color displays do not exist, resulting in inconsistent presentation. To address this, we developed a calibration, characterization, and profiling protocol for color-critical medical imaging applications. Physical characterization of displays calibrated with and without the protocol revealed high color reproduction accuracy with the protocol. The present study assessed the impact of this protocol on observer performance. A set of 250 breast biopsy virtual slide regions of interest (half malignant, half benign) were shown to six pathologists, once using the calibration protocol and once using the same display in its "native" off-the-shelf uncalibrated state. Diagnostic accuracy and time to render a decision were measured. In terms of ROC performance, Az (area under the curve) calibrated = 0.8570 and Az uncalibrated = 0.8488. No statistically significant difference (p = 0.4112) was observed. In terms of interpretation speed, mean calibrated = 4.895 s; mean uncalibrated = 6.304 s which is statistically significant (p = 0.0460). Early results suggest a slight advantage diagnostically for a properly calibrated and color-managed display and a significant potential advantage in terms of improved workflow. Future work should be conducted using different types of color images that may be more dependent on accurate color rendering and a wider range of LCDs with varying characteristics. PMID- 22546983 TI - Development of a next-generation automated DICOM processing system in a PACS-less research environment. AB - The use of clinical imaging modalities within the pharmaceutical research space provides value and challenges. Typical clinical settings will utilize a Picture Archive and Communication System (PACS) to transmit and manage Digital Imaging and Communications in Medicine (DICOM) images generated by clinical imaging systems. However, a PACS is complex and provides many features that are not required within a research setting, making it difficult to generate a business case and determine the return on investment. We have developed a next-generation DICOM processing system using open-source software, commodity server hardware such as Apple Xserve(r), high-performance network-attached storage (NAS), and in house-developed preprocessing programs. DICOM-transmitted files are arranged in a flat file folder hierarchy easily accessible via our downstream analysis tools and a standard file browser. This next-generation system had a minimal construction cost due to the reuse of all the components from our first generation system with the addition of a second server for a few thousand dollars. Performance metrics were gathered and the system was found to be highly scalable, performed significantly better than the first-generation system, is modular, has satisfactory image integrity, and is easier to maintain than the first-generation system. The resulting system is also portable across platforms and utilizes minimal hardware resources, allowing for easier upgrades and migration to smaller form factors at the hardware end-of-life. This system has been in production successfully for 8 months and services five clinical instruments and three pre-clinical instruments. This system has provided us with the necessary DICOM C-Store functionality, eliminating the need for a clinical PACS for day-to-day image processing. PMID- 22546984 TI - Role of the 1,25D3-MARRS receptor in the 1,25(OH)2D3-stimulated uptake of calcium and phosphate in intestinal cells. AB - We have used mice with a targeted knockout (KO) of the 1,25D(3)-MARRS receptor (ERp57/PDIA3) in intestine to study rapid responses to 1,25-dihydroxyvitamin D(3) [1,25D(3)] with regards to calcium or phosphate uptake. Western analyses indicated the presence of the 1,25D(3)-MARRS receptor in littermate (LM) mice, but not KO mice. Saturation analyses for [(3)H]1,25D(3) binding revealed comparable affinities for the hormone in lysates from female and male LM, but a reduced B(max) in females. Binding in lysates from KO mice was absent or severely reduced. Enterocytes from KO mice failed to respond to hormone with regard to either ion uptake, while cells from LM mice exhibited an increase in uptake. For calcium uptake, the protein kinase (PK) A pathway mediated the response to 1,25D(3). Enterocytes from LM mice responded to 1,25D(3) with enhanced PKA activity, while cells from KO mice did not, although both cell types responded to forskolin. Calcium transport in LM mice in vivo was greater than in KO mice. Cells from LM and KO mice had cell surface VDR; however, anti-VDR antibodies had no effect on ion uptake. Unlike chicks, the PKC pathway was not involved in phosphate uptake. As in chicks and rats, intestinal cells from adult male mice lost the ability to respond to 1,25D(3) with enhanced phosphate uptake, whereas in female mice, uptake in cells from adults was greater than that observed in young mice. Finally, when we tested phosphate uptake in vivo, we found that young female mice had a much greater rate of transport than young male mice. PMID- 22546985 TI - Steroidal carbonitriles as potential aromatase inhibitors. AB - Estrogens, responsible for the growth of hormone-dependant breast cancer are biosynthesized from androgens involving aromatase enzyme in the last rate limiting step. Inhibition of aromatase is an efficient approach for the prevention and treatment of breast cancer. Novel 4-phenylthia derivatives (2, 3 and 7) have been synthesized as aromatase inhibitors. The synthesized compounds (2, 3 and 7) exhibited noticeable enzyme inhibiting activity. Kinetics study of these compounds (2, 3, and 7) showed negligible inhibition of the enzyme under conditions conducive for irreversible inhibition of the enzyme. Introduction of unsaturation at C-4, C-1 & 4 or C-4 & 6 (compounds 5, 9 and 11) was observed to not be an effective strategy for entrancing aromatase inhibiting activity in 17 oxo-16beta-carbonitrile derivatives. The D-seco derivatives (13-15 and 17) having unsaturation at C-4, C-1 & 4 or C-4 & 6 along with carbonitrile function in ring D showed complete loss of aromatase inhibiting activity. PMID- 22546986 TI - Letter re: "Hospital Variation in 30-Day Mortality After Colorectal Cancer Surgery in Denmark: The Contribution of Hospital Volume and Patient Characteristics.". PMID- 22546989 TI - 25 Years of AIDS: recording progress and future challenges. PMID- 22546988 TI - Inflammation markers after randomization to abacavir/lamivudine or tenofovir/emtricitabine with efavirenz or atazanavir/ritonavir. AB - BACKGROUND: The effect of specific antiretrovirals on inflammation is unclear. METHODS: A5224s was a substudy of A5202, which randomized HIV-infected treatment naive patients to blinded abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) with open-label efavirenz (EFV) or atazanavir/ritonavir (ATV/r) in a factorial design. Our analysis compared changes in inflammation markers from baseline to week 24 between ABC/3TC and TDF/FTC. Secondary analyses included changes at week 96 and comparisons of EFV vs. ATV/r. RESULTS: Analyses included 244 patients (85% male, 48% white non-Hispanic), median age 39 years, HIV-1 RNA 4.6 log10 copies/ml, CD4 240 cells/MUl. TNF-alpha, soluble receptors of TNF-alpha (sTNFR)-I and II, soluble vascular cellular adhesion molecule (sVCAM)-1 and soluble intercellular adhesion molecule (sICAM)-1 decreased significantly at weeks 24 and 96, without significant differences between components (P >= 0.44). At week 24, ABC/3TC had a greater high sensitivity C-reactive protein (hsCRP) mean fold change than TDF/FTC {1.43 vs. 0.88, estimated mean fold change percentage difference [Delta] 61.5% [95% confidence interval (CI) 13.6%, 129.5%]; P = 0.008}. Similar results were seen at week 96 (P = 0.021). At week 24 (but not 96), EFV had a greater hsCRP mean fold change than ATV/r [1.41 vs. 0.88; Delta = 60.2% (12.6%, 127.7%); P = 0.009]. IL-6 decreased significantly at week 24 with TDF/FTC but not with ABC/3TC (between components P = 0.019). At week 96, IL-6 decreased significantly in both nucleoside reverse transcriptase inhibitor components (between-components P = 0.11). IL-6 changes were not significantly different between ATV/r and EFV at either time point (P >= 0.89). CONCLUSIONS: Soluble TNF-receptors and adhesion molecules decreased following treatment initiation and did not differ by regimens. Differences were seen on hsCRP and IL-6 changes with ABC/3TC vs. TDF/FTC and on hsCRP with EFV vs. ATV/r. PMID- 22546990 TI - The effects of HIV and combination antiretroviral therapy on white matter integrity. AB - OBJECTIVE: HIV preferentially affects white matter in the brain. Although combination antiretroviral therapy (cART) reduces HIV viral load within the brain, continued inflammation can persist. We investigated the effect of HIV and cART on white matter integrity. DESIGN: We used diffusion tensor imaging (DTI) to examine the effects of HIV and cART on white matter integrity within the corpus callosum and centrum semiovale (CSO). METHODS: Neuropsychological testing and DTI measures (fractional anisotropy, mean diffusivity, axial diffusivity, radial diffusivity) were obtained from 21 HIV-uninfected controls, 21 HIV-infected patients naive to cART (HIV+/cART-), and 21 HIV+ patients receiving stable cART (HIV+/cART+). A subset of the HIV+/cART- individuals (n=10) was assessed before and 6 months after receiving medications. Differences among the cross-sectional groups were assessed using an analysis of variance, whereas paired t-tests evaluated longitudinal changes. RESULTS: HIV+/cART- participants had significantly lower mean diffusivity, axial diffusivity, and radial diffusivity for the corpus callosum and CSO compared to HIV- controls and HIV+/cART+ individuals. No significant difference existed between HIV- controls and HIV+/cART+ patients. cART initiation significantly improved mean diffusivity, radial diffusivity, and axial diffusivity, but not fractional anisotropy, in the corpus callosum and CSO in some HIV-infected patients. CONCLUSION: Observed decreases in DTI parameters between HIV+/cART+ and HIV+/cART- individuals could reflect the presence of inflammatory cells or cytotoxic edema in HIV+/cART- patients. Initiating cART could lead to a reduction in neuro-inflammation and improvement in DTI measures. Future DTI studies may be useful for evaluating the efficacy higher brain penetrating cART regimens. PMID- 22546991 TI - Pharmacokinetics of nevirapine in HIV-infected children under 3 years on rifampicin-based antituberculosis treatment. AB - OBJECTIVE: There is an urgent need to optimize cotreatment for children with tuberculosis and HIV infection. We described nevirapine pharmacokinetics in Zambian children aged less than 3 years, cotreated with nevirapine, lamivudine and stavudine in fixed-dose combination (using WHO weight bands) and rifampicin based antituberculosis treatment. DESIGN: Twenty-two children received antituberculosis and antiretroviral therapy (ART) concurrently for 4 weeks before pharmacokinetic sampling. Plasma nevirapine concentrations were determined in samples taken immediately before, and 1, 2 and 6 h after an observed dose. Nevirapine pharmacokinetics were compared with those in 16 children aged less than 3 years without tuberculosis. RESULTS: Twenty-two children were treated for HIV/TB coinfection, 10 of whom were girls. One boy was excluded from analysis for nonadherence. The median age was 1.6 years (range: 0.7-3.2). Median weight was 8.0 kg (range: 5.1-10.5). The baseline CD4% was 13.1 (range: 3.9-43.6). Median predose concentration of nevirapine was 2.93 mg/l (range: 1.06-11.4), and peak concentration was 6.33 mg/l (range: 2.61-14.5). The nevirapine AUC up to 12 h was estimated as 52.0 mg.h/l (range: 22.6-159.7) compared with 90.9 mg.h/l (range: 40.4-232.1) in children without tuberculosis (P < 0.001). Predose concentrations of nevirapine were less than 3.0 mg/l in 11 children on tuberculosis treatment versus none of the 16 children without tuberculosis treatment (P = 0.001). AUC was 41% (95% CI: 23-54%) lower in children with tuberculosis than without tuberculosis (P < 0.001) after adjusting for dose per square meter. CONCLUSION: : We found substantial reductions in nevirapine concentrations in young children receiving rifampicin. Further studies are needed to define the pharmacokinetics, safety and efficacy of adjusted doses of nevirapine-based ART in young children with tuberculosis. PMID- 22546993 TI - Ruthenium cryptates with an unusual selectivity for nitrate. AB - The synthesis of two new tripodal complexes [Ru(L3)](PF(6))(2) and [Ru(L4)](PF(6))(2), encapsulating a ruthenium(II) cation, has been successfully achieved and the products fully characterized, including by X-ray structural determination. The smaller cavity, built around a tris(2-aminoethyl)amido scaffold demonstrated only moderate and predictable interactions with a range of anions and no significant spectroscopic change with nitrate, chloride and bromide, although dihydrogen phosphate did result in an almost stoichiometric precipitation. The expansion of the cavity to include the more rigid 1,3,5 benzenetricarbonylamide group creates a larger cavity, which shows a decrease in the emission on the introduction of chloride, bromide, hydrogen sulfate and nitrate salts, with the (1)H NMR titrations giving a surprisingly high binding affinity for nitrate over the smaller and simpler halides. PMID- 22546992 TI - Long-term effects of psychosocial work stress in midlife on health functioning after labor market exit--results from the GAZEL study. AB - OBJECTIVES: To study long-term effects of psychosocial work stress in mid-life on health functioning after labor market exit using two established work stress models. METHODS: In the frame of the prospective French Gazel cohort study, data on psychosocial work stress were assessed using the full questionnaires measuring the demand-control-support model (in 1997 and 1999) and the effort-reward imbalance model (in 1998). In 2007, health functioning was assessed, using the Short Form 36 mental and physical component scores. Multivariate regressions were calculated to predict health functioning in 2007, controlling for age, gender, social position, and baseline self-perceived health. RESULTS: Consistent effects of both work stress models and their single components on mental and physical health functioning during retirement were observed. Effects remained significant after adjustment including baseline self-perceived health. Whereas the predictive power of both work stress models was similar in the case of the physical composite score, in the case of the mental health score, values of model fit were slightly higher for the effort-reward imbalance model (R(2): 0.13) compared with the demand-control model (R2: 0.11). CONCLUSIONS: Findings underline the importance of working conditions in midlife not only for health in midlife but also for health functioning after labor market exit. PMID- 22546994 TI - Regulating the suppressors: apoptosis and inflammation govern the survival of tumor-induced myeloid-derived suppressor cells (MDSC). AB - Immune suppressive myeloid-derived suppressor cells (MDSC) are present in most cancer patients where they inhibit innate anti-tumor immunity and are a significant obstacle to cancer immunotherapy. Inflammation is a known inducer of Gr1(+)CD11b(+) MDSC; however, the factors/conditions that regulate MDSC survival and half-life have not been identified. We have used mass spectrometry (MS) and proteomic analysis to identify proteins and pathways that regulate MDSC survival. This analysis revealed high expression of caspase family proteins and the Fas FasL, p38 MAPK, and TGFbeta pathways, suggesting that Fas-FasL apoptosis regulates MDSC survival. Flow cytometry, confocal microscopy, and western blot analyses confirmed the MS findings and demonstrated that Fas(+) MDSC are susceptible to Fas-mediated killing in vitro. In vivo studies with FasL-deficient and Fas-deficient mice demonstrated that Fas-FasL interactions are essential for MDSC apoptosis and for rejection of established metastatic disease and survival and that FasL(+) T cells are the effector population mediating MDSC apoptosis. MS findings validated by biological experiments demonstrated that inflammation increases MDSC levels by protecting MDSC from Fas-mediated apoptosis, possibly by activating p38 MAPK. These results demonstrate that MDSC half-life in vivo is regulated by FasL(+) T cells and that inflammation increases MDSC levels by conferring resistance to Fas-mediated apoptosis and identifies T cells as the relevant effector cells causing MDSC apoptosis in vivo. This newly recognized mechanism for regulating MDSC levels identifies potential new targets for decreasing MDSC in cancer patients. PMID- 22546995 TI - Establishment of microbial eukaryotic enrichment cultures from a chemically stratified antarctic lake and assessment of carbon fixation potential. AB - Lake Bonney is one of numerous permanently ice-covered lakes located in the McMurdo Dry Valleys, Antarctica. The perennial ice cover maintains a chemically stratified water column and unlike other inland bodies of water, largely prevents external input of carbon and nutrients from streams. Biota are exposed to numerous environmental stresses, including year-round severe nutrient deficiency, low temperatures, extreme shade, hypersalinity, and 24-hour darkness during the winter (1). These extreme environmental conditions limit the biota in Lake Bonney almost exclusively to microorganisms (2). Single-celled microbial eukaryotes (called "protists") are important players in global biogeochemical cycling (3) and play important ecological roles in the cycling of carbon in the dry valley lakes, occupying both primary and tertiary roles in the aquatic food web. In the dry valley aquatic food web, protists that fix inorganic carbon (autotrophy) are the major producers of organic carbon for organotrophic organisms (4, 2). Phagotrophic or heterotrophic protists capable of ingesting bacteria and smaller protists act as the top predators in the food web (5). Last, an unknown proportion of the protist population is capable of combined mixotrophic metabolism (6, 7). Mixotrophy in protists involves the ability to combine photosynthetic capability with phagotrophic ingestion of prey microorganisms. This form of mixotrophy differs from mixotrophic metabolism in bacterial species, which generally involves uptake dissolved carbon molecules. There are currently very few protist isolates from permanently ice-capped polar lakes, and studies of protist diversity and ecology in this extreme environment have been limited (8, 4, 9, 10, 5). A better understanding of protist metabolic versatility in the simple dry valley lake food web will aid in the development of models for the role of protists in the global carbon cycle. We employed an enrichment culture approach to isolate potentially phototrophic and mixotrophic protists from Lake Bonney. Sampling depths in the water column were chosen based on the location of primary production maxima and protist phylogenetic diversity (4, 11), as well as variability in major abiotic factors affecting protist trophic modes: shallow sampling depths are limited for major nutrients, while deeper sampling depths are limited by light availability. In addition, lake water samples were supplemented with multiple types of growth media to promote the growth of a variety of phototrophic organisms. RubisCO catalyzes the rate limiting step in the Calvin Benson Bassham (CBB) cycle, the major pathway by which autotrophic organisms fix inorganic carbon and provide organic carbon for higher trophic levels in aquatic and terrestrial food webs (12). In this study, we applied a radioisotope assay modified for filtered samples (13) to monitor maximum carboxylase activity as a proxy for carbon fixation potential and metabolic versatility in the Lake Bonney enrichment cultures. PMID- 22546997 TI - Clinical significance of lymph node micrometastasis in gastric cancer. AB - Recently, the existence of lymph node micrometastasis (LNM), including isolated tumor cells, has been focused on during the development of molecular diagnostic tools for lymph node metastasis in various malignant neoplasms. In particular, immunohistochemistry and reverse transcription-polymerase chain reaction have been reported to be available for the detection of LNM in gastric cancer. However, at present, the clinical significance of LNM remains unclear in patients with gastric cancer. Therefore, we cannot strategically make light of this issue in clinical management. Currently, minimally invasive treatments, such as endoscopic submucosal dissection and laparoscopic surgery with personalized lymphadenectomy, are widely performed in consideration of postsurgical quality of life (QOL). However, it is important to maintain the balance between QOL and curability when selecting surgical treatments for patients with gastric cancer. If minimally invasive surgery based on LNM status was established for patients with early gastric cancer, it could be performed safely. We reviewed the clinical significance of LNM as an important strategic target in patients with gastric cancer. PMID- 22546998 TI - Choroidal neovascularization and bevacizumab therapy in Aicardi syndrome. PMID- 22546999 TI - Visual rehabilitation with keratoprosthesis after tenonplasty as the primary globe-saving procedure for severe ocular chemical injuries. AB - PURPOSE: To analyze the outcome (functional and anatomic) of eyes that underwent tenonplasty as the primary globe-saving procedure in severe ocular chemical injuries (grade V-VI Dua's classification). METHODS: The records of patients who underwent tenonplasty for associated scleral ischemia in severe chemical burns in our institute between October 2005 and June 2011 were analyzed retrospectively. Out of 31 eyes that underwent tenonplasty, 21 belonged to grade V and VI of Dua's classification with diffuse scleral ischemia for which a four-quadrant tenonplasty was performed and only these 21 eyes were included for further analysis. The time to presentation following chemical injury, the need for revision surgeries, the time to complete epithelization, the procedures performed for ocular surface reconstruction and for visual rehabilitation and their outcome, both functional and anatomic, were analyzed. RESULTS: Of the 21 eyes of 13 patients, four were unilateral and nine were bilateral cases of chemical injury. The mean time to presentation following chemical injury was 14.61 days. Tenonplasty with amniotic membrane transplantation (AMT) was performed as the primary surgery. Revision tenonplasty was required in six eyes (seven procedures), the mean time to complete epithelization of the ocular surface was 5.4 +/- 4.03 months. Of the 21 eyes, three lost perception of light following phthisis, evisceration for corneal infection, and uncontrolled glaucoma. Eighteen of 21 eyes were salvaged anatomically, of which ten eyes of 13 patients underwent surgery for visual rehabilitation. Among the unilateral cases, two eyes underwent ex vivo limbal stem cell transplant (LSCT) with or without keratoplasty for further visual rehabilitation. Among the patients with bilateral burns, visual rehabilitative procedure was performed in only one eye. Modified osteo-odonto keratoprosthesis (MOOKP) was performed in five eyes, Boston type 1 keratoprosthesis in two eyes, and penetrating keratoplasty with keratolimbal allograft with systemic immunosuppression in one eye. One patient with bilateral injury is awaiting Boston keratoprosthesis type 1 for one eye. Of these eight eyes (bilateral injuries), all achieved a BCVA of 20/200 or better over a mean follow-up period of 27.37 +/- 14.5 months following visual rehabilitative procedure. CONCLUSIONS: Tenonplasty has a globe-saving role in eyes with severe chemical injuries with associated scleral ischemia, by accelerating the healing process. Further on, these eyes can undergo visual rehabilitative procedures and our results highlight the feasibility of achieving a good functional outcome following anatomical stability. The role of tenonplasty to salvage the eye in the initial management of chemical injury, the need for multiple surgeries, close follow-up, and monitoring of intraocular pressure prior to and after procedures for visual rehabilitation cannot be underemphasized. PMID- 22547000 TI - Density and strength distribution in the human subchondral bone plate of the patella. AB - PURPOSE: The aim of this study was to map the strength distribution of the human patella and correlate it to the subchondral bone plate density obtained by means of computed tomographyosteoabsorptiometry (CT-OAM). METHODS: Measurements were performed at 34 standardized points on each patella. The mineralization patterns of the subchondral bone plate of 20 patellae were displayed with the help of CT OAM. False-coloured distribution patterns for our measurements were generated. The mechanical strength was determined at the same points by indentation testing. RESULTS: We showed that neither the density nor the mechanical strength is distributed homogeneously but exhibited regular, reproducible distribution patterns which mirror long-term stress distribution in articular surfaces. A direct correlation was found between both parameters in the subchondral bone plate. CONCLUSION: The correlation of density and mechanical strength makes CT OAM a valuable tool to assess and monitor changes in the strength of the subchondral bone plate in vivo. PMID- 22547001 TI - Retrograde loading of nerves, tracts, and spinal roots with fluorescent dyes. AB - Retrograde labeling of neurons is a standard anatomical method(1,2) that has also been used to load calcium and voltage-sensitive dyes into neurons(3-6). Generally, the dyes are applied as solid crystals or by local pressure injection using glass pipettes. However, this can result in dilution of the dye and reduced labeling intensity, particularly when several hours are required for dye diffusion. Here we demonstrate a simple and low-cost technique for introducing fluorescent and ion-sensitive dyes into neurons using a polyethylene suction pipette filled with the dye solution. This method offers a reliable way for maintaining a high concentration of the dye in contact with axons throughout the loading procedure. PMID- 22547002 TI - Rural Embedded Assistants for Community Health (REACH) network: first-person accounts in a community-university partnership. AB - Community research and action projects undertaken by community-university partnerships can lead to contextually appropriate and sustainable community improvements in rural and urban localities. However, effective implementation is challenging and prone to failure when poorly executed. The current paper seeks to inform rural community-university partnership practice through consideration of first-person accounts from five stakeholders in the Rural Embedded Assistants for Community Health (REACH) Network. The REACH Network is a unique community university partnership aimed at improving rural health services by identifying, implementing, and evaluating innovative health interventions delivered by local caregivers. The first-person accounts provide an insider's perspective on the nature of collaboration. The unique perspectives identify three critical challenges facing the REACH Network: trust, coordination, and sustainability. Through consideration of the challenges, we identified several strategies for success. We hope readers can learn their own lessons when considering the details of our partnership's efforts to improve the delivery infrastructure for rural healthcare. PMID- 22547003 TI - Activation of muscarinic receptors increases the activity of the granule neurones of the rat dorsal cochlear nucleus--a calcium imaging study. AB - Acetylcholine modulates the function of the cochlear nucleus via several pathways. In this study, the effects of cholinergic stimulation were studied on the cytoplasmic Ca(2+) concentration of granule neurones of the rat dorsal cochlear nucleus (DCN). Ca(2+) transients were recorded in Oregon-Green-BAPTA 1 loaded brain slices using a calcium imaging technique. For the detection, identification and characterisation of the Ca(2+) transients, a wavelet analysis based method was developed. Granule cells were identified on the basis of their size and localisation. The action potential-coupled character of the Ca(2+) transients of the granule cells was established by recording fluorescence changes and electrical activity simultaneously. Application of the cholinergic agonist carbamyl-choline (CCh) significantly increased the frequency of the Ca(2+) transients (from 0.37 to 6.31 min(-1), corresponding to a 17.1-fold increase; n = 89). This effect was antagonised by atropine, whereas CCh could still evoke an 8.3-fold increase of the frequency of the Ca(2+) transients when hexamethonium was present. Using immunolabelling, the expression of both type 1 and type 3 muscarinic receptors (M1 and M3 receptors, respectively) was demonstrated in the granule cells. Application of 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (an M3-specific antagonist) prevented the onset of the CCh effect, whereas an M1 specific antagonist (pirenzepine) was less effective. We conclude that cholinergic stimulation increases the activity of granule cells, mainly by acting on their M3 receptors. The modulation of the firing activity of the granule cells, in turn, may modify the firing of projection neurones and may adjust signal processing in the entire DCN. PMID- 22547005 TI - Radiotherapy in metastatic ewing sarcoma. AB - OBJECTIVE: To review an institutional experience with radiotherapy (RT) in patients with metastatic Ewing sarcoma. METHODS: Thirty patients with metastatic Ewing sarcoma were considered. Twenty-nine received multiagent chemotherapy, whereas 22 had local therapy, which included RT in 14, surgery in 5, and surgery followed by RT in 3. RESULTS: The 5-year overall survival rate was 22.1%. On multivariate analysis, presence of uncommon sites of metastasis (brain, liver, spleen) (P<0.0001) and use of local therapy to the primary site (P<0.001) were adverse factors for survival. Local control was not achieved in the 8 patients receiving only chemotherapy. All long-term survivors had local therapy including RT to metastatic bony sites and whole-lung irradiation for pulmonary metastasis. CONCLUSIONS: The presence of uncommon sites of metastasis confers a worse prognosis. Aggressive primary treatment including RT to metastatic sites should be considered in these patients. PMID- 22547004 TI - Channel catfish, Ictalurus punctatus (Rafinesque), tetraspanin membrane protein family: identification, characterization and phylogenetic analysis of tetraspanin 3 and tetraspanin 7 (CD231) transcripts. AB - Tetraspanins, a large cell surface protein superfamily characterized by having four transmembrane domains, play many critical roles in physiological and pathological processes. In this study, we report the identification, characterization and phylogenetic analysis of the channel catfish tetraspanin 3 and tetraspanin 7 (CD231) transcripts. The full-length nucleotide sequences of tetraspanin 3 and tetraspanin 7 cDNA have 1,453 and 1,842 base pairs, respectively. Analysis of the nucleotide sequences reveals that each has one open reading frame (ORF). The ORF of tetraspanin 3 appears to encode 241 amino acids with calculated molecular mass of 26.8 kDa, while the ORF of tetraspanin 7 potentially encodes 251 amino acids with calculated molecular mass of 27.9 kDa. By comparison with the human counterparts, the channel catfish tetraspanin 3 and tetraspanin 7 peptides have four transmembrane domains, three intracellular domains and two (small and large) extracellular domains. In addition, several characteristic features critical for structure and functions in mammalian tetraspanins are also conserved in channel catfish tetraspanin 3 and tetraspanin 7. The transcripts were detected by RT-PCR in restrictive organs. These results with those from our previous studies on other channel catfish tetraspanins provide important information for further investigating the roles of various tetraspanins in channel catfish infection with microorganisms. PMID- 22547006 TI - Optic glioma in children: a retrospective analysis of 101 cases. AB - AIM: To evaluate the clinical characteristics and long-term outcome of pediatric patients with optic glioma. PATIENTS AND METHODS: A total of 101 patients with optic glioma newly diagnosed between 1975 and 2008 were evaluated retrospectively. COPP (cyclophosphamide, vincristine, procarbazine, prednisolone) and cisplatin plus etoposide were the most commonly used chemotherapy regimens. Radiotherapy was administered in patients with progressive or unresponsive disease. RESULTS: The median age at the time of diagnosis was 6 years, and the male/female ratio was 1.15. The most common referral complaint was strabismus. The most common site of optic glioma was the hypothalamic-chiasmatic region (31.7%). Fifty-three patients (52.5%) had neurofibromatosis type 1 (NF-1). Treatment consisted of surgery, radiotherapy, and chemotherapy. Forty-nine patients (48.5%) underwent surgery, which was predominantly subtotal resection, radiotherapy was administered to 39.4%, and 30 patients received chemotherapy. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 65.8% and 88.4%, respectively, and the 10-year PFS and OS were 54.2% and 83.4%, respectively, with an 8-year median follow-up. OS was significantly lower in patients with hypothalamo-chiasmatic involvement and significantly higher in patients with NF-1. The 5- and 10-year PFS rates were significantly higher in patients 10 years or older at diagnosis (P=0.0001) and in patients with intraorbital involvement (P=0.032). Eighteen patients (17.8%) died of disease. CONCLUSIONS: Patients with NF-l and those older than 10 years have a better prognosis, whereas patients younger than 3 years and those with hypothalamic chiasmatic optic glioma have a worse outcome. Further studies are needed to find appropriate treatment strategies. PMID- 22547007 TI - A two-cohort phase I study of weekly oxaliplatin and gemcitabine, then oxaliplatin, gemcitabine, and erlotinib during radiotherapy for unresectable pancreatic carcinoma. AB - OBJECTIVES: Gemcitabine is a potent radiosensitizer. When combined with standard radiotherapy (XRT) the gemcitabine dose must be reduced to about 10% of its conventional dose. Oxaliplatin and erlotinib also have radiosensitizing properties. Oxaliplatin and gemcitabine have demonstrated synergy in vitro. We aimed to determine the maximum tolerated dose of oxaliplatin and gemcitabine with concurrent XRT, then oxaliplatin, gemcitaibine, and erlotinib with XRT in the treatment of locally advanced and low-volume metastatic pancreatic or biliary cancer. METHODS: A modified 3+3 dose-escalation design was used for testing 4 dose levels of oxaliplatin and gemcitabine given once weekly for a maximum of 6 weeks with daily XRT in fractions of 1.8 Gy to a total dose of 50.4 Gy. Dose limiting toxicity (DLT) was defined as any grade 4 toxicity or grade 3 toxicity resulting in a treatment delay of >1 week. In addition, dose reduction in 2 of the 3 patients in a given cohort was counted as a DLT in dose escalation deescalation rule in the modified 3+3 design. RESULTS: Eighteen patients were enrolled, all with pancreatic cancer. Grade 4 transaminitis in a patient in cohort 3 resulted in cohort expansion. Cohort 4, the highest planned dose cohort, had no DLTs. The recommended phase II dose is oxaliplatin 50 mg/m(2)/wk with gemcitabine 200 mg/m(2)/wk and 50.4 Gy XRT. The most prevalent grade 3 toxicities were nausea (22%), elevated transaminases (17%), leucopenia (17%), and hyperglycemia (17%). Median progression-free survival was 7.1 months (95% confidence interval, 4.6-11.1 mo) and median overall survival was 10.8 months (95% confidence interval, 7.1-16.7 mo). The addition of erlotinib was poorly tolerated at the first planned dose level, but full study of the combination was hindered by early closure of the study. CONCLUSIONS: Weekly oxaliplatin 50 mg/m/wk combined with gemcitabine 200 mg/m/wk and XRT for pancreatic cancer has acceptable toxicity and interesting activity. PMID- 22547008 TI - A new method to predict values for postoperative lung function and surgical risk of lung resection by quantitative breath sound measurements. AB - OBJECTIVES: We evaluated quantitative acoustic measurements, as a simpler alternative to perfusion scintigraphy, for estimation of predicted postoperative (ppo) lung function after resection surgery in our patient population. METHODS: Patients with lung cancer, considered as candidates for lung resection, were enrolled in the study. All patients underwent lung function testing and quantitative breath sound testing by vibration response imaging (VRI) on the same day. A subset of patients also had perfusion testing. Forced expiratory volume in 1 second (FEV(1)) and diffusing capacity of the lung for carbon monoxide (DLCO) predictions derived from VRI testing were compared with perfusion values and actual FEV(1) values at 1 month postoperatively. RESULTS: Fifty-three subjects (40 males; age 66+/-8 y) participated. There was high correlation between both methods for the calculation of ppoFEV(1)% (R=0.94; n=39) and ppoFEV (L) (R=0.90; n=39). PpoFEV(1) were 58+/-18% versus 56+/-20% and 1.69+/-0.49 L versus 1.62+/ 0.52 L, based on perfusion and VRI methods, respectively. In 92% (36/39) of calculations, the difference between the 2 methods was <10%. High correlations also existed between VRI and perfusion for the calculation of ppoDLCO% (R=0.95; n=37) and ppoDLCO mL/min/mm Hg (R=0.90; n=37). VRI predictions showed good correlation for the 34 patients with actual postoperative lung function (R=0.88 and R=0.80 for FEV(1)% and FEV(1)L, respectively). Accuracy of the VRI to predict surgical risk (<40% cutoff threshold for ppo values) compared with actual postoperative values was 85% (29/34). CONCLUSIONS: Predictions of postoperative lung function using VRI agree well with radionuclide techniques and actual measured postoperative values. VRI may provide a noninvasive, simpler alternative for estimation of ppo values, particularly when perfusion testing is not readily available. PMID- 22547009 TI - Stereotactic radiosurgery for retreatment of gross perineural invasion in recurrent cutaneous squamous cell carcinoma of the head and neck. AB - OBJECTIVES: To report outcomes, failure patterns, and toxicity after stereotactic radiosurgery (SRS) for recurrent head and neck cutaneous squamous cell carcinoma with gross perineural invasion (GPNI). METHODS: Ten patients who received SRS as part of retreatment for recurrent head and neck cutaneous squamous cell carcinoma with GPNI were included. All patients exhibited clinical and radiologic evidence of GPNI before SRS. Previous treatments included surgery alone in 3 patients and surgery with adjuvant external beam radiotherapy (EBRT) in 7 patients. Retreatment included SRS alone in 2 and EBRT boosted with SRS in 8 patients. Magnetic resonance images were obtained every 3 to 6 months after SRS to track failure patterns. RESULTS: At a median 22-month follow-up, the 2-year progression free and overall survival rates were 20% and 50%, respectively. Seven patients exhibited local failures, all of which occurred outside both SRS and EBRT fields. Five local failures occurred in previously clinically uninvolved cranial nerves (CNs). CN disease spreads through 3 distinct patterns: among different branches of CN V; between CNs V and VII; and between V1 and CNs III, IV, and/or VI. Five patients experienced side effects potentially attributable to radiation. CONCLUSIONS: Although there is excellent in-field control with this approach, the rate of out-of-field failures remains unacceptably high. We found that the majority of failures occurred in previously clinically uninvolved CNs often just outside treatment fields. Novel treatment strategies targeting this mode of perineural spread are needed. PMID- 22547010 TI - Sorafenib in advanced hepatocellular carcinoma: hypertension as a potential surrogate marker for efficacy. AB - BACKGROUND: Advanced hepatocellular cancer (HCC) is an incurable disease with limited options for systemic treatment. Sorafenib was approved for advanced HCC based on trials in patients with Child-Pugh class A. We reviewed our experience retrospectively in patients with HCC who were treated with sorafenib with a focus on Child-Pugh B (CP-B) liver cirrhosis and effect of hypertension (HTN) on survival. METHODS: We retrospectively reviewed medical charts of patients with documented advanced HCC who received sorafenib since 2007. Survival data were plotted according to Child-Pugh class and HTN. RESULTS: Results of 41 patients 39% had CP-B. Eighty-five percent were male and 67% had HCC due to viral hepatitis. Fifty-six percent received localized treatment before sorafenib. Five percent had a partial response and 39% had stable disease. Time to progression and overall survival (OS) for all patients were 3.2 and 6.2 months, respectively. Time to progression and OS were 4 and 8.4 months in Child-Pugh class A patients and 2 and 3.2 months in CP-B patients, which were statistically significant. Patients who had documented HTN while on treatment according to Common Terminology Criteria for Adverse Events version 3.0 had significantly better OS (18.2 vs. 4.5 mo; P=0.016). CONCLUSIONS: Development of HTN with sorafenib seems to be associated with a favorable effect on prognosis. Future trials should examine this observation. PMID- 22547011 TI - Lymph node ratio is an independent prognostic factor in gastric cancer after curative resection (R0) regardless of the examined number of lymph nodes. AB - OBJECTIVES: The purpose of this study was to evaluate the outcome of the ratio between metastatic and examined lymph nodes (N ratio) in gastric cancer patients with <15 examined lymph nodes after curative resection. METHODS: A retrospective study of 710 patients who underwent radical gastrectomy (R0) for gastric cancer from January 1980 to December 2000 was analyzed statistically to identify the N ratio. Patients with <15 examined lymph nodes (group 1, n=327) and those with >=15 examined lymph nodes (group 2, n=383) were analyzed separately. N ratio categories were identified as follows: N ratio 0, 0%; N ratio 1, 1% to 9%; N ratio 2, 10% to 25%; and N ratio 3, >25%. All the enrolled categories were evaluated by the best cutoff approach. RESULTS: The univariate analysis showed that age, tumor site, tumor size, surgery, T categories, number of metastatic nodes, and N ratio significantly affected prognosis in groups 1 and 2. By multivariate analysis, the N ratio (but not the TNM N category) classification was retained as an independent prognostic factor in groups 1 and 2 compared with the N category system. However, patients with N1 disease in group 1 obtained a better postoperative prognosis than those with N1 disease in group 2 according to the N stage classification (P=0.003). When the N ratio classification was applied, no significant differences were found for N ratios 0, 1, 2, or 3 between the 2 groups (P>0.05). CONCLUSIONS: The metastatic lymph node ratio is an independent prognostic factor regardless of the examined number of lymph nodes. In predicting the prognosis of gastric cancer, the staging system based on the metastatic lymph node ratio is more reliable than the system based on the number of metastatic lymph nodes regardless of the examined number of lymph nodes. This can help improve the TNM staging classification of gastric cancer and reduce the International Union Against Cancer N categories of stage migration. PMID- 22547012 TI - Predicting acute and persistent neuropathy associated with oxaliplatin. AB - OBJECTIVES: We sought to predict oxaliplatin-associated peripheral neuropathy during modified FOLFOX6 (mFOLFOX6) therapy. METHODS: Equal numbers of male and female patients with previously untreated, primary or recurrent colorectal cancer were followed through a first course of mFOLFOX6 with 85 mg/m2 oxaliplatin every 2 weeks. Accounting for correlation among a subject's cycle, logistic regression estimated per cycle risk of acute (under 14 d) and persistent (14 d or more) neuropathy. Proportional hazards regression predicted time to persistent neuropathy. RESULTS: Among mFOLFOX6 recipients (n = 50, age 58.9 +/- 10.1 y), 36% received concomitant bevacizumab. Of the total number of cycles, 94.2% (422/448) were evaluable. Most (84%) subjects reported neuropathy at least once; 74% reported acute and 48% reported persistent symptoms. On multivariate analysis, risk factors shared by acute and persistent neuropathy were body surface area >2.0, acute neuropathy in a past cycle, and lower body weight. In addition, risk of acute neuropathy decreased with age (adjusted for renal function and winter season), whereas risk of persistent neuropathy increased with cumulative dose of oxaliplatin and persistent neuropathy in a past cycle. Concomitant bevacizumab was not a risk factor when administered in stage IV disease but was associated with persistent neuropathy when administered experimentally in stage III. Females had no increased risk of either form of neuropathy. After 3 cycles, weight, body surface area, and prior acute neuropathy predicted time to persistent neuropathy. CONCLUSIONS: Routinely available clinical factors predict acute and persistent neuropathy associated with oxaliplatin. When validated, the proposed prognostic score for persistent neuropathy can help clinicians counsel patients about chemotherapy. PMID- 22547013 TI - Absence of bone marrow toxicity in elderly patients treated with recombinant human thyroid-stimulating hormone and empirically dosed radioiodine for thyroid cancer. AB - OBJECTIVES: The purpose of this paper is to evaluate the rate of clinically significant bone marrow toxicity in elderly patients after recombinant human thyroid-stimulating hormone (rhTSH) and empirically dosed radioiodine therapy for thyroid cancer. METHODS: This is a retrospective review of 15 patients with differentiated thyroid cancer that were at least 70 years old at the time of their first radioiodine treatment at our institution administered by the authors under a protocol involving an empiric dose prescription and preparation with rhTSH rather than hypothyroidism. The median dose per administration was 203 mCi and the median total dose per patient was 234 mCi. One third of the patients had at least 1 positive posttreatment whole-body scan and the other two thirds all had negative posttreatment whole-body scans. The primary study endpoint was a red cell, white cell, or platelet count below the lower limit of the normal range that produced symptoms or resulted in a recommendation for treatment. Complete blood count follow-up was at least 1 year in all patients, with a median value of 4 years. RESULTS: There was no evidence of clinically important bone marrow toxicity from radioiodine therapy in the patients in this study. No patient required treatment for anemia, leucopenia, or thrombocytopenia. CONCLUSIONS: In patients with normal renal function, clinically significant bone marrow toxicity from radioiodine therapy is highly unlikely with rhTSH preparation and empiric dosing with <250 mCi per administration and total cumulative doses <350 mCi. PMID- 22547014 TI - Decreased total MKP-1 protein levels predict poor prognosis in breast cancer. AB - BACKGROUND: MKP-1 dephosphorylates and inactivates MAPKs, whose constitutive activations have been associated with human cancers. RESULTS: We found that total MKP-1 protein levels were decreased in 63.7 % of breast cancer tissues compared with the paired noncancerous breast tissues. Decreased MKP-1 protein levels were correlated with increased tumor stage and positive recurrence and were associated with poor survival, even when using a multivariate Cox regression model. Intriguingly, nuclear MKP-1 staining was positively correlated with ER status. In vitro, tamoxifen increased MKP-1 expression in ER-positive but not ER-negative breast cancer cells. ER-specific siRNA was able to attenuate tamoxifen-induced MKP-1 expression. Furthermore, tamoxifen prolonged the duration of MKP-1 elevation and the binding time of ER to the promoter of the MKP-1/DUSP-1 gene compared with estrogen. CONCLUSIONS: Our results suggest that alterations of MKP 1 may serve as a prognostic factor in breast cancer. In addition, the regulation of MKP-1 may be related to the ER. PMID- 22547015 TI - Liver resection for multiple colorectal liver metastases with surgery up-front approach: bi-institutional analysis of 736 consecutive cases. AB - BACKGROUND: Preoperative chemotherapy has become more common in the management of multiple resectable colorectal liver metastases; however, the benefit is unclear. This study examined clinical outcomes following liver resection for multiple colorectal liver metastases with the surgery up-front approach. METHODS: Data collected prospectively over a 16-year period for 736 patients who underwent hepatic resection at two different centers were reviewed. Patients were divided into three groups depending on the number of tumors as follows: group A, between one and three tumors (n = 493); group B, between four and seven tumors (n = 141); and group C, eight or more tumors (n = 102). RESULTS: The 5-year overall and recurrence-free survival rates were 51 and 21 %, respectively, for the entire patient cohort, 56 and 29 % in group A, 41 and 12 % in group B, and 33 and 1.7 % in group C. Multivariate analysis showed that decreased survival was associated with positive lymph node metastasis of the primary tumor, the presence of extrahepatic tumors, a maximum liver tumor size >5 cm, and tumor exposure during liver resection. CONCLUSIONS: In patients with multiple liver metastases, the number of liver metastases has less impact on the prognosis than other prognostic factors. Complete resection with repeat metastasectomy offers a chance of cure even in patients with numerous colorectal liver metastases (i.e., those with eight or more nodules). A further prospective study is necessary to clarify the optimal setting of preoperative chemotherapy. PMID- 22547016 TI - Management of Grave's disease is improved by total thyroidectomy. AB - BACKGROUND: A retrospective analysis was performed on 267 consecutive patients with Graves' disease (GD). The principal aim of this study was to evaluate the risk for recurrence and complications when changing the surgical method from subtotal (ST) to total thyroidectomy (TT). METHODS: Information from 267 consecutive patients operated on for GD between 2000 and 2006 was collected at Uppsala University Hospital (143) and Falun County Hospital (128). There were 229 women and 38 men. Four patients were operated on twice. A total of 40 STs and 229 TTs were performed. Results were compared to those of a previous cohort from the same hospital, with a majority of STs (157/176) performed from 1980 to 1992. RESULTS: The risk for relapse of GD was reduced from 20 to 3.3 % after the shift from ST to TT. In terms of surgical complications, 2.2 % demonstrated permanent vocal cord paralysis and 4.5 % had persistent hypocalcemia, not significant when compared to the previous cohort. In spite of TT, there were four recurrences, all due to remnant thyroid tissue high up at the hyoid bone. Changing the surgical method did not affect postoperative progression of dysthyroid ophthalmopathy (DO, 7.0 vs. 7.5 %). There were no differences in outcome with respect to which hospital the patients had their operation. CONCLUSION: Change from ST to TT dramatically reduced the risk for recurrence of GD without increasing the rate of complications. TT is not more effective than ST in hampering progression of DO as has been advocated by some. Careful surgical dissection up to the hyoid bone is necessary to avoid recurrence. PMID- 22547017 TI - Right hepatectomy in patients over 70 years of age: an analysis of liver function and outcome. AB - BACKGROUND: As a consequence of the increase in life expectancy, hepatobiliary surgeons have to deal with an emerging aged population. We aimed to analyze the liver function and outcome after right hepatectomy (RH) in patients over 70 years of age. METHODS: From January 2006 to December 2009, we prospectively collected data of 207 consecutive elective hepatectomies. In patients who had RH, cardiac risk was assessed by a dedicated preoperative workup. Liver failure (LF) was defined by the "fifty-fifty" criteria at postoperative day 5 (POD) and morbidity by the Clavien-Dindo classification. Liver function tests (LFTs) and short-term outcome were retrospectively analyzed in patients over (elderly group, EG) and younger (young group, YG) than 70 years of age. RESULTS: Eighty-seven consecutive RH were performed during the study period. Indication for surgery included 90 % malignancy in 47 % of patients requiring preoperative chemotherapy. ASA grade > 2 (44 vs. 16 %, p = 0.027), ischemic heart disease (17 vs. 5 %, p = 0.076), and preoperative cardiac failure (26 vs. 2 %, p < 0.001) were more frequent in the EG (n = 23) than in the YG (n = 64). Both groups were similar regarding rates of normal liver parenchyma, chemotherapy and intraoperative parameters. The overall morbidity rates were comparable, but the serious complication (grades III-V) rate was relatively higher in the EG (39 vs. 25 %, p = 0.199), particularly in patients with diabetes mellitus (100 vs. 29 %, p = 0.04) and those who had additional nonhepatic surgery (67 vs. 35 %, p = 0.110) and transfusions (44 vs. 30 %, p = 0.523). The 90-day mortality rate was similar (9 % in the EG vs. 3 % in the YG, p = 0.28) and was related to heart failure in the EG. LFTs showed a similar trend from POD 1 to 8, and patients >=70 years of age had no liver failure. CONCLUSIONS: Age >=70 years alone is not a contraindication to RH. However, major morbidity is particularly higher in the elderly with diabetes. This high-risk group should be closely monitored in the postoperative course. Liver function is not altered in the elderly patient after RH. PMID- 22547018 TI - Surgical outcome of liver transection by the crush-clamping technique combined with Harmonic FOCUSTM. AB - BACKGROUND: New energy devices are constantly being introduced for all types of surgery, including liver surgery. These devices help surgeons perform operations. Meanwhile, intraoperative blood loss is a concern of liver surgeons. Various methods to reduce intraoperative bleeding during liver resection have been reported. There are some reports that the use of energy devices was effective for liver transection. Recently, the Harmonic FOCUSTM (HF), an ultrasonically activated device, was developed. The shape of the HF is similar to that of Kelly forceps. Hepatectomy can be performed by the clamp-crushing method using the HF instead of Kelly forceps. We obtained good results of liver resection with the HF, and report these outcomes in this study. METHODS: From November 2009 to March 2011, a total of 51 patients underwent hepatectomy with the use of the HF. The control group consisted of 59 patients who underwent hepatectomy without the HF from February 2009 to September 2009. The surgical outcomes were evaluated and compared retrospectively. RESULTS: Mean blood loss was 640 mL in the HF group compared to 1,176 mL in the control group. The number of patients needing a blood transfusion was smaller in the HF group (p = 0.02). Mean operative time was shorter in the HF group (171 vs. 235 min, p < 0.001). All these surgical outcomes were significantly better in the HF group. Postoperative morbidity was not increased in the HF group, and we could perform liver transection safely. CONCLUSION: The crush-clamping method combined with the HF is effective for liver transection. Liver resection can be performed quickly using this method. PMID- 22547019 TI - Neonatal neuroblastoma needs the aggressive treatment? AB - BACKGROUND: Routine antenatal ultrasound scans increased the detection of the neuroblastoma (NB) in neonates. We reviewed the treatment outcome and clinical presentation of neonatal NB. METHODS: We included patients who had pathologically confirmed NB presented within 28 days after birth from January 1999 to December 2010. RESULTS: There were 17 patients (8 females and 9 males), which consist of 16 % of total NB cases of children in our institution. Nine were followed from prenatal period as an abdominal mass and eight were presented postnatally (5 abdominal distensions, 2 tachypnea, and 1 persistent jaundice). The primary lesion was located in adrenal gland in ten patients, retroperitoneum in four, and posterior mediastinum in three. The tumor size was median 4.1 cm (range, 3-7). The stage of the patients were as follows: stage 1 in six, stage 2 in one, stage 3 in three, stage 4S in five, and stage 4 in two. Six patients were in the low risk group, seven were intermediate-risk group, and four were high-risk group. Thirteen showed favorable histology among 15 specimens. Five patients (29.4 %) showed MYCN amplification. The median follow-up period was 78.4 months (range, 17.4-138.6). Fifteen of 17 (88.2 %) are alive without evidence of recurrences and two patients of stage 4S with MYCN amplification in high-risk group died. CONCLUSIONS: The overall survival of neonatal NB is 88.2 %, but we observed a high ratio of stage 4 and stage 4S tumors and MYCN amplification. We suggested that early treatment might be better for neonatal NB more than 3 cm in size. Aggressive treatment for neonatal NB could bring more favorable outcome. PMID- 22547021 TI - Dementia and poor surgical outcomes: reinventing the wheel or providing empirical evidence? PMID- 22547022 TI - Discriminative stimulus properties of N-desmethylclozapine, the major active metabolite of the atypical antipsychotic clozapine, in C57BL/6 mice. AB - N-desmethylclozapine (NDMC) is the major active metabolite of the atypical antipsychotic drug clozapine and may contribute to the therapeutic efficacy of clozapine. Although they share many pharmacological features, it is noteworthy that NDMC is a partial dopamine D2 and cholinergic muscarinic M1/M4 agonist, whereas clozapine is a weak dopamine D2 receptor inverse agonist/antagonist and a nonselective muscarinic antagonist. To better understand the in-vivo pharmacological mechanisms of these drugs, male C57BL/6NHsd-wild-type mice were trained to discriminate 10.0 mg/kg NDMC from vehicle in a two-lever drug discrimination procedure for food reward. It was found that the parent drug clozapine fully substituted for NDMC, whereas the typical antipsychotic drug haloperidol (dopamine D2 antagonist) and the atypical antipsychotic drug aripiprazole (D2 partial agonist) did not substitute for NDMC. These results demonstrated that clozapine and its major metabolite NDMC share in-vivo behavioral properties (i.e. discriminative stimulus properties) that are likely due to shared pharmacological mechanisms that differ from other antipsychotic drugs. The discriminative stimulus properties of NDMC probably reflect a compound cue similar to that of its parent drug clozapine due to its diverse binding profile. PMID- 22547023 TI - Ixodes ricinus is the dominant questing tick in forest habitats in Romania: the results from a countrywide dragging campaign. AB - In 2010 and 2011, questing ticks were collected from 188 forested locations in all the 41 counties of Romania using the dragging method. The total of 13,771 ticks collected belonged to eleven species: Ixodes ricinus (86.9 %), Dermacentor marginatus (9.5 %), Haemaphysalis punctata (2.6 %), H. concinna (0.6 %), H. sulcata (0.3 %), H. parva (0.1 %), Hyalomma marginatum (0.02 %), D. reticulatus (0.02 %), I. crenulatus (0.007 %), I. hexagonus (0.007 %) and I. laguri (0.007 %). Ixodes ricinus was present in 97.7 % (n = 180) of locations, occurring exclusively in 41.7 % of the locations, whereas it was the dominant species in 38.8 % of the other locations, accounting for over 70 % of the total tick community. The following most common questing ticks were D. marginatus, H. punctata and H. concinna. Ixodes ricinus co-occurred with one, two or three sympatric species. The occurrence of D. reticulatus in forested habitats from Romania was found to be accidental. PMID- 22547025 TI - Induced neural stem cells: a new tool for studying neural development and neurological disorders. PMID- 22547024 TI - S-acylation-dependent association of the calcium sensor CBL2 with the vacuolar membrane is essential for proper abscisic acid responses. AB - Calcineurin B-like (CBL) proteins contribute to decoding calcium signals by interacting with CBL-interacting protein kinases (CIPKs). Currently, there is still very little information about the function and specific targeting mechanisms of CBL proteins that are localized at the vacuolar membrane. In this study, we focus on CBL2, an abundant vacuolar membrane-localized calcium sensor of unknown function from Arabidopsis thaliana. We show that vacuolar targeting of CBL2 is specifically brought about by S-acylation of three cysteine residues in its N-terminus and that CBL2 S-acylation and targeting occur by a Brefeldin A insensitive pathway. Loss of CBL2 function renders plants hypersensitive to the phytohormone abscisic acid (ABA) during seed germination and only fully S acylated and properly vacuolar-targeted CBL2 proteins can complement this mutant phenotype. These findings define an S-acylation-dependent vacuolar membrane targeting pathway for proteins and uncover a crucial role of vacuolar calcium sensors in ABA responses. PMID- 22547026 TI - Structural insight into the regulation of MOF in the male-specific lethal complex and the non-specific lethal complex. PMID- 22547027 TI - Structural basis for the impact of phosphorylation on the activation of plant receptor-like kinase BAK1. PMID- 22547028 TI - Disseminating ASD interventions: a pilot study of a distance learning program for parents and professionals. AB - There is a need for the adaptation of training in evidence-based interventions to non-traditional methods, particularly for individuals working with children with autism spectrum disorders (ASD). An internet-based self-directed distance learning program was created to teach reciprocal imitation training, a naturalistic behavioral intervention aimed at increasing imitation in children with ASD. A single-subject multiple-baseline design study evaluated the effect of the program on changes in therapist (sample 1) and parent (sample 2) knowledge and behavior, and changes in child behavior. Adult participants improved their knowledge and use of the intervention techniques, and child participants improved their rates of imitation. Results suggest that a self-directed distance learning program may be effective for disseminating evidence-based practices to individuals working with children with ASD. PMID- 22547030 TI - Embolization of incompetent pelvic veins for the treatment of recurrent varicose veins in lower limbs and pelvic congestion syndrome. AB - PURPOSE: We present our experience with embolization of incompetent pelvic veins (IPV) in women with recurrence of varicose veins (VV) in lower limbs, as well as symptoms of pelvic congestion syndrome (PCS), after first surgery. In addition, we evaluated the effects of embolization in decreasing the symptoms of VV before surgery as well as its effects on PCS symptoms. MATERIALS AND METHODS: We included 10 women who had consulted a vascular surgeon because of recurrent VV in lower limbs after surgery. All of these patients were included in the study because they also had symptoms of PCS, probably due to IPV. In patients who had confirmed IPV, we performed embolization before a second surgery. VV and PCS were assessed before and at 3 months after embolization (before the second surgery) using a venous clinical severity score (VCSS) and a visual analog pain scale (VAS), respectively. Patients were controlled between 3 and 6 months after embolization. Paired Student t test analysis was used for comparing data before and after embolization. RESULTS: Fifteen vein segments in 10 women were suitable for embolization. There was a significant (p < 0.001) decrease of VCSS after embolization, and recurrence of VV was not detected within a period of 6 months. There was also significant (p < 0.01) relief of chronic pelvic pain related to PCS evaluated using VAS at 3 months after embolization. CONCLUSION: Embolization decreases the risk of VV recurrence after surgery and also improves PCS symptoms in women with VV in lower limbs and IPV. PMID- 22547029 TI - Ultrastructural study of plasmodesmata in the brown alga Dictyota dichotoma (Dictyotales, Phaeophyceae). AB - Plasmodesmata are intercellular bridges that directly connect the cytoplasm of neighboring cells and play a crucial role in cell-to-cell communication and cell development in multicellular plants. Although brown algae (Phaeophyceae, Heterokontophyta) are phylogenetically distant to land plants, they nevertheless possess a complex multicellular organization that includes plasmodesmata. In this study, the ultrastructure and formation of plasmodesmata in the brown alga Dictyota dichotoma were studied using transmission electron microscopy and electron tomography with rapid freezing and freeze substitution. D. dichotoma possesses plasma membrane-lined, simple plasmodesmata without internal endoplasmic reticulum (desmotubule). This structure differs from those in land plants. Plasmodesmata were clustered in regions with thin cell walls and formed pit fields. Fine proteinaceous "internal bridges" were observed in the cavity. Ultrastructural observations of cytokinesis in D. dichotoma showed that plasmodesmata formation began at an early stage of cell division with the formation of tubular pre-plasmodesmata within membranous sacs of the cytokinetic diaphragm. Clusters of pre-plasmodesmata formed the future pit field. As cytokinesis proceeded, electron-dense material extended from the outer surface of the mid region of the pre-plasmodesmata and finally formed the nascent cell wall. From these results, we suggest that pre-plasmodesmata are associated with cell wall development during cytokinesis in D. dichotoma. PMID- 22546987 TI - The effect of efavirenz versus nevirapine-containing regimens on immunologic, virologic and clinical outcomes in a prospective observational study. AB - OBJECTIVE: To compare regimens consisting of either efavirenz or nevirapine and two or more nucleoside reverse transcriptase inhibitors (NRTIs) among HIV infected, antiretroviral-naive, and AIDS-free individuals with respect to clinical, immunologic, and virologic outcomes. DESIGN: Prospective studies of HIV infected individuals in Europe and the US included in the HIV-CAUSAL Collaboration. METHODS: Antiretroviral therapy-naive and AIDS-free individuals were followed from the time they started an NRTI, efavirenz or nevirapine, classified as following one or both types of regimens at baseline, and censored when they started an ineligible drug or at 6 months if their regimen was not yet complete. We estimated the 'intention-to-treat' effect for nevirapine versus efavirenz regimens on clinical, immunologic, and virologic outcomes. Our models included baseline covariates and adjusted for potential bias introduced by censoring via inverse probability weighting. RESULTS: A total of 15 336 individuals initiated an efavirenz regimen (274 deaths, 774 AIDS-defining illnesses) and 8129 individuals initiated a nevirapine regimen (203 deaths, 441 AIDS-defining illnesses). The intention-to-treat hazard ratios [95% confidence interval (CI)] for nevirapine versus efavirenz regimens were 1.59 (1.27, 1.98) for death and 1.28 (1.09, 1.50) for AIDS-defining illness. Individuals on nevirapine regimens experienced a smaller 12-month increase in CD4 cell count by 11.49 cells/MUl and were 52% more likely to have virologic failure at 12 months as those on efavirenz regimens. CONCLUSIONS: Our intention-to-treat estimates are consistent with a lower mortality, a lower incidence of AIDS-defining illness, a larger 12-month increase in CD4 cell count, and a smaller risk of virologic failure at 12 months for efavirenz compared with nevirapine. PMID- 22547031 TI - Identification and characterization of a novel class of atypical dopamine receptor agonists. AB - PURPOSE: The D3 dopamine receptor exhibits tolerance and slow response termination (SRT) properties that are not exhibited by the closely-related D2 dopamine receptor. We previously demonstrated that the induction of tolerance elicits a unique conformational change in the D3 receptor. Here we tested the hypothesis that the tolerance and SRT properties of the D3 receptor are ligand dependent. METHODS: We used pharmacophore modeling and in silico screening approaches coupled with electrophysiological and biochemical methods to identify and functionally characterize the novel dopamine receptor agonists. RESULTS: We identified cis-8-OH-PBZI (PBZI), FAUC73 and an additional novel compound, ES609, which although they are full D3 receptor agonists, do not induce the tolerance and SRT properties of the D3 receptor. In addition, PBZI has full intrinsic activity at D2L, is a partial agonist at D2S and exhibits functional selectivity at D4.2 dopamine receptors. ES609 is a partial agonist at D2S, D2L and D4.2 receptors, and exhibits functional selectivity at D2L and D4.2 dopamine receptors. CONCLUSION: We have discovered a novel class of atypical dopamine receptor agonists that include three structurally dissimilar compounds. These new agonists will help determine the physiological and pathophysiological relevance of D3 receptor tolerance and SRT properties. PMID- 22547034 TI - The early stages of taxol biosynthesis: an interim report on the synthesis and identification of early pathway metabolites. AB - The biosynthesis of the anti-cancer drug taxol (paclitaxel) has required the collaborative efforts of several research groups to tackle the synthesis and labeling of putative biosynthetic intermediates, in concert with the identification, cloning and functional expression of the biosynthetic genes responsible for the construction of this complex natural product. Based on a combination of precursor labeling and incorporation experiments, and metabolite isolation from Taxus spp., a picture of the complex matrix of pathway oxygenation reactions following formation of the first committed intermediate, taxa 4(5),11(12)-diene, is beginning to emerge. An overview of the current state of knowledge on the early-stages of taxol biosynthesis is presented. PMID- 22547035 TI - Cloning, expression and characterization of meso-2,3-butanediol dehydrogenase from Klebsiella pneumoniae. AB - The budC gene encoding the meso-2,3-BDH from Klebsiella pneumoniae XJ-Li was expressed in E. coli BL21 (DE3) pLys. Hypothetical amino acid sequence alignments revealed that the enzyme belongs to the short chain dehydrogenase/reductase family. After purification and refolding, the recombinant enzyme had activities of 218 U/mg for reduction of acetoin and 66 U/mg for oxidation of meso-2,3 butanediol. Highest activities were at pH 8.0 and 9.0 respectively. These are higher than other meso-2,3-butanediol dehydrogenases from K. pneumoniae. The low K (m) value (0.65 mM) for acetoin indicated that the enzyme can easily reduce acetoin to meso-2,3-butanediol. There were no significant activities towards 2R,3R-2,3-butanediol, 1,4-butanediol and 2S,3S-2,3-butanediol, suggesting that the enzyme has a high stereospecificity for the meso-dihydric alcohol. PMID- 22547032 TI - Anticancer and immunostimulatory activity by conjugate of paclitaxel and non toxic derivative of LPS for combined chemo-immunotherapy. AB - PURPOSE: Cancer is a multifactorial syndrome; hence, multidimensional therapy with a chemo-immunotherapeutic conjugate could be more effective in curing the disease. METHODS: We used SP-LPS, a bio-polymer having potent immunostimulatory activity, for conjugation with paclitaxel to make a chemo-immunotherapeutic conjugate. Its physicochemical characterization was done by HPLC, NMR and IR spectra. Stability was measured at different pH, temperature and in tissue homogenates. Chemotherapeutic and immunostimulatory activity was evaluated in vitro and also in tumor microenvironment. RESULTS: The conjugate self assembled into nanoparticulate structure, probably due to micelle formation. Stability was pH and temperature dependent. The conjugate exhibited chemotherapeutic and immunotherapeutic activity in vitro. In vivo antitumor activity was significantly higher and a higher percentage of activated immune cells were found in the tumor microenvironment of the conjugate-treated mice as compared to Taxol(r)-treated group. CONCLUSIONS: This conjugate is a potential chemo-immunotherapeutic compound for the treatment of cancer with advantages over present day chemotherapy with Taxol in terms of higher anticancer activity, less toxicity and ease of delivery. PMID- 22547036 TI - Down-regulation of miRNA-221 triggers osteogenic differentiation in human stem cells. AB - Despite interesting in silico evidence, the specific role of mir-221 in osteogenesis has not been studied. We evaluated the osteogenic induction of transient-transfected anti-mir-221 in human unrestricted somatic stem cells and human mesenchymal stem cells both transcriptionally and translationally. In transfected unrestricted somatic stem cells, transcriptions of some osteogenic markers were twice that of the control and translations of osteopontin and osteocalcin were increased from 9 to 39 % and from 0 to 21 %, respectively. Up regulation of transcribed osteogenic markers in transfected mesenchymal stem cells were 50 times greater than controls while no significant change in translations were observed. Prior to these analyses, the authenticity of stem cells, their osteogenic differentiation and transfection efficiency were verified. Transient modulation of mir-221 therefore suggests a mechanism for rapid induction of osteogenesis as a useful strategy for cell-based therapy. PMID- 22547037 TI - Construction of Escherichia coli strains producing L-serine from glucose. AB - L-Serine is usually produced from glycine. We have genetically engineered Escherichia coli to produce L-serine from glucose intracellularly. D-3 Phosphoglycerate dehydrogenase (PGDH, EC 1.1.1.95) in E. coli catalyzes the first committed step in L-serine formation but is inhibited by L-serine. To overcome this feedback inhibition, both the His(344) and Asn(346) residues of PGDH were converted to alanine and the mutated PGDH (PGDH(dr)) became insensitive to L serine. However, overexpression of PGDH(dr) gave no significant increase of L serine accumulation but, when L-serine deaminase genes (sdaA, sdaB and tdcG) were deleted, serine accumulated: (1) deletion of sdaA gave up to 0.03 mmol L serine/g; (2) deletion of both sdaA and sdaB accumulated L-serine up to 0.09 mmol/g; and (3) deletion of sdaA, sdaB and tdcG gave up to 0.13 mmol L-serine/g cell dry wt. PMID- 22547038 TI - Nitrite as a candidate substrate in microbial fuel cells. AB - Current generation using nitrite as substrate (pH 6.9, 40 mgN l(-1)) in a nitrite fed microbial fuel cell was investigated under anaerobic and aerobic anodic conditions as an alternative to the biological nitrite oxidation process. Cell current, coulombic efficiency (CE) and power generation of 0.04 mA, 30 +/- 2 % and 19.3 +/- 3.3 MUW m(-2), respectively, were observed under anaerobic conditions while complete nitrite degradation (no current) was obtained under aerobic conditions. Switching from aerobic to anaerobic anode enhanced the CE and power generation (39 +/- 1 % and 29 +/- 4.3 MUW m(-2)). PMID- 22547039 TI - Therapeutic hypothermia and reliability of somatosensory evoked potentials in predicting outcome after cardiopulmonary arrest. AB - The loss of the N20 component on testing median somatosensory evoked potentials (SSEP) has been established as the most reliable indicator of unfavorable prognosis in post-cardiopulmonary arrest patients. With the intervention of therapeutic hypothermia in the management of patients who remain comatose following cardiopulmonary arrest that association is now in dispute. Abandoning SSEP as a key prognostic indicator of neurologic outcome would be a serious loss and cannot be justified. PMID- 22547040 TI - Implementation of a model of robotic tele-presence (RTP) in the neuro-ICU: effect on critical care nursing team satisfaction. AB - INTRODUCTION: Robotic tele-presence (RTP) is a form of mobile telemedicine, which enables a direct face-to-face rapid response by the physician, instead of the traditional telephonic paradigm. We hypothesized that a model of RTP for after hour ICU rounds and emergencies would be associated with improved ICU nurse satisfaction. METHODS: We implemented a prospective nighttime multidisciplinary ICU round time, using RTP at our neuro-ICU. To test for critical ICU nurse team satisfaction, a questionnaire was implemented. The primary outcome was nurse satisfaction measured through a questionnaire with answers trichotomized into: agreement, disagreement, and no opinion. The occurrence of outcomes was compared between the groups by chi2 or Fisher exact tests for the difference in proportions (PD) with Bonferroni correction for multiple pairwise comparisons. RESULTS: In total, 34 nurses completed the pre-survey and 40 nurses completed the post-survey. Night nurses were more likely to agree that RTP was associated with: ICU physicians being sufficiently available in the ICU (agreement 6-20%, PD 14%, p = 0.008), present during acute emergencies (agreement 44-65%, PD 21%, p = 0.007), and had enough time to get questions answered from the physician team (agreement 41-53%, PD 11%, p = NS). CONCLUSIONS: This data suggest improvement in critical care nursing team satisfaction with a model of RTP in the neuroscience ICU, particularly during nighttime hours. RTP is a tool that may enhance communication among components of the ICU team. PMID- 22547041 TI - The values of cerebrovascular pressure reactivity and brain tissue oxygen pressure reactivity in experimental anhepatic liver failure. AB - BACKGROUND: We investigated in a porcine model of anhepatic acute liver failure (ALF), the value of two parameters describing cerebrovascular autoregulatory capacity, pressure reactivity index (PRx) and brain tissue oxygen pressure reactivity (ORx), regarding their power to predict the development of intracranial hypertension. METHODS: In six pigs, hepatectomy was performed. Only one animal was sham operated. All animals received neuromonitoring including arterial blood pressure, intracranial pressure (ICP), and brain tissue partial oxygen pressure (P(br)O(2)). The average time of neuromonitoring was 31.0 h. Cerebral perfusion pressures (CPP), cerebrovascular pressure reactivity index (PRx) and brain tissue oxygen reactivity index (ORx) were calculated. RESULTS: Perioperative disturbance of AR improved within 4 h after surgery. From 6 to 16 h post hepatectomy, ICP did slowly increase by 4 mmHg from baseline; CPP remained stable around 40 mmHg. PRx and ORx, however, indicated in this period a progressive loss of AR, reflected in a decrease of P(br)O(2) despite unchanged CPP. Beyond 16 h, ICP rose quickly. At CPP levels below 35 mmHg, P(br)O(2) fell to ischemic levels. CONCLUSIONS: The loss of cerebrovascular autoregulatory capacity, indicated by a rise of PRx and ORx precedes the final crisis of uncontrollable intracranial hypertension in this animal model by hours. During this phase cerebral blood flow, as reflected in tissue oxygenation, deteriorates despite unchanged CPP. Monitoring of AR during ALF therefore seems to carry the power to identify a risk for development of critical CBF and intracranial hypertension. PMID- 22547042 TI - Serum anti-Mullerian hormone levels correlate with ovarian response in idiopathic hypogonadotropic hypogonadism. AB - PURPOSE: The role of serum AMH levels in prediction of ovarian response in idiopathic hypogonadotropic hypogonadism (IHH) was evaluated. MATERIAL METHOD(S): Twelve patients with IHH underwent controlled ovarian hyperstimulation (COH) for IVF were enrolled in this prospective study. Serum AMH levels were studied on the 2nd or 3rd day of an induced menstrual cycle by a preceding low-dose oral contraceptive pill treatment. A fixed dose (150-300 IU/day) of hMG was given in all COH cycles. Correlations between serum AMH levels, COH outcomes and embryological data were investigated. RESULTS: Mean serum AMH levels was 3.47 +/- 2.15 ng/mL and mean serum peak estradiol was 2196 +/- 1705 pg/mL. Mean number of follicles >14 mm, >17 mm on hCG day and MII oocytes were 4.14 +/- 3.2, 4 +/- 2.5 and 7.28 +/- 3.5, respectively. Mean number of grade A embryos and transferred embryos were 3.28 +/- 2.4 and 2.5 +/- 0.7, respectively. The clinical pregnancy rate per patient was 41.6 % (5/12). Positive correlations were observed between serum AMH levels and MII oocytes (r = 0.84), grade A embryos (r = 0.85), serum peak estradiol levels (r = 0.87), and number of follicles >14 mm (r = 0.83) and >17 mm (r = 0.81) on hCG day, respectively. CONCLUSION: AMH appears as a promising marker of ovarian response in patients with IHH undergoing IVF. PMID- 22547043 TI - Enhanced light extraction in ITO-free OLEDs using double-sided printed electrodes. AB - We show how nanoimprint lithographic techniques are particularly suited for the realization of OLED device structures. We tested them to realize nanopatterned metallic electrodes containing photonic crystals to couple the light out and plasmonic crystals showing extraordinary transmission. At similar current densities, a two-fold electroluminescence is achieved with devices having double sided structured metallic electrodes as compared to a control OLED with an ITO anode. The use of combined nanoimprint lithography processes has the potential to expand the performance range of various organic optoelectronic devices. PMID- 22547044 TI - Effects of chronic pain on quality of life and depression in patients with spinal cord injury. AB - DESIGN: A cross-sectional study. OBJECTIVE: To assess the effects of pain on quality of life (QoL), functional independence and depression in patients with spinal cord injury (SCI). SETTING: An inpatient rehabilitation center. METHODS: A total of 140 patients (104 M, 36 F) with SCI who underwent inpatient rehabilitation treatment were examined. A questionnaire including clinical variables was applied. Motor score of Functional Independence Measure was used to assess daily-life activities, the 36-Item Medical Outcomes Short-Form Health (SF 36) for QoL and Beck Depression Inventory (BDI) for depression. Patients were then divided into those having chronic pain (Group I) and those without any pain (Group II), and groups were compared according to demographic and clinical variables. RESULTS: The most common causes of SCI were falls (35.0%) and motor vehicle accidents (34.2%). Chronic pain was present in 78% of patients. Patients employed before injury and patients who had complete injury had lower Numerical Rating Scale scores (P<0.05). SCI patients with chronic pain had higher depression ratings and their BDI scores were correlated with some of the SF-36 domains (general health, vitality, social functioning and mental health). Only bodily pain and social functioning (P<0.05) scores were found to be lower in Group I (P<0.05) when compared with Group II. CONCLUSION: As mood and QoL are negatively affected with pain in SCI patients, we suggest that chronic pain should always be treated in a multidisciplinary setting where pharmacological, physical and psychological therapies are combined. PMID- 22547045 TI - Estimating the glomerular filtration rate using serum cystatin C levels in patients with spinal cord injuries. AB - STUDY DESIGN: Prospective cohort study. OBJECTIVES: To investigate the relationship between (51)chromium-ethylene-diamine-tetra-acetate ((51)Cr-EDTA) clearance, serum cystatin C (CysC), serum creatinine, creatinine clearance and estimated glomerular filtration rate (eGFR(MDRD), MDRD stands for modification of diet in renal disease) based on the serum creatinine in patients with complete or incomplete spinal cord injury (SCI) and to develop and evaluate a GFR-estimating equation using serum CysC. SETTINGS: Spinal Cord Injury Unit, Viborg Regional Hospital, Viborg, Denmark. METHODS: Ninety-eight men and 47 women with SCI were included in the study. Serum CysC levels were measured by an automated particle enhanced nephelometric immunoassay, serum and urine creatinine levels were measured by an enzymatic method traceable to the IDMS creatinine reference method, and (51)Cr-EDTA clearance was measured by a multiple plasma sample method. RESULTS: The area under the curves (AUCs) in the non-parametric receiver operating characteristics (ROC) plots for serum CysC were compared with serum creatinine and to eGFR(MDRD) and revealed a significant difference (P-value < 0.05) for all SCI patients. There was no significant difference between the AUC for serum CysC compared with the AUC for creatinine clearance. GFR (ml min(-1) per 1.73 m(2)) can be calculated from serum CysC values (mg l(-1)) using the equation eGFR(CysC) = 212.exp(0.914.CysC). The model accurately predicted the GFR of 88% of patients within +/- 30% of the measured GFR, and it was able to predict the GFR of 50% of patients within +/- 10% of the measured GFR. CONCLUSION: In patients with SCI, GFR can be estimated independent of age, sex and muscle mass by a newly developed equation based on a single serum CysC value. PMID- 22547047 TI - How do we define a neuro-ophthalmologist? PMID- 22547046 TI - Gainful employment and risk of mortality after spinal cord injury: effects beyond that of demographic, injury and socioeconomic factors. AB - OBJECTIVE: To evaluate the association of three levels of gainful employment with the risk of mortality after traumatic spinal cord injury (SCI) while controlling for known predictors of mortality status (including education and income). STUDY DESIGN: Prospective cohort study. SETTING: A total of 20 federally funded SCI Model Systems of care in the United States. METHODS: Participants included 7955 adults with traumatic SCI. Preliminary assessments were conducted between 1995 and 2006. Mortality status was determined by the Social Security Death Index (1308 deaths). A two-stage logistic regression model was used to estimate the chance of dying in any given year. Life expectancy was calculated under different economic assumptions. RESULTS: Compared with those who were working 30+ h per week, the odds of mortality was 1.37 for those who worked 1-29 h and 1.67 for those who were unemployed. The addition of gainful employment only modestly reduced the effects of household income and education, both of which remained significant. For instance, the odds of mortality for household income (referent $75 000+) decreased from 1.50 to 1.38 for $25 000-$75 000 and from 2.10 to 1.82 for < $25 000. Life expectancy varied widely depending on socioeconomic characteristics more than doubling under certain assumptions. CONCLUSION: Substantial variation in mortality is attributable to employment, above and beyond the effects of previously established demographic, injury and socioeconomic predictors. Although some excess mortality may be the inevitable consequence of SCI, risk is substantially increased with poor socioeconomic characteristics. PMID- 22547048 TI - Health-related quality of life and utility scores in short-term survivors of pediatric acute lymphoblastic leukemia. AB - PURPOSE: Increase of survival in pediatric acute lymphoblastic leukemia (ALL) has made outcomes such as health-related quality of life (HRQL) and economic burden more important. To make informed decisions on the use of healthcare resources, costs as well as utilities need to be taken into account. Among the preference based HRQL instruments, the Health Utilities Index (HUI) is the most employed in pediatric cancer. Information on utility scores during ALL treatment and in long term survivors is available, but utility scores in short-term survivors are lacking. This study assesses utility scores, health state, and HRQL in short-term (6 months to 4 years) ALL survivors. METHODS: Cross-sectional single-center cohort study of short-term ALL survivors using HUI3 proxy assessments. RESULTS: Thirty-three survivors (median 1.5 years off treatment) reported 14 unique health states. The majority of survivors (61 %) enjoyed a perfect health, but 21 % had three affected attributes. Overall, HRQL was nonsignificantly lower compared to the norm, although the difference was large and may be clinically relevant. Cognition was significantly impaired (p = 0.03). CONCLUSION: Although 61 % of short-term survivors of ALL report no impairment, the health status of the other patients lead to a clinically important impaired HRQL compared to norms. Prospective studies assessing utility scores associated with pediatric ALL should be performed, enabling valid and reliable cost-utility analyses for policy makers to make informed decisions. PMID- 22547049 TI - Chronic pain, healthcare utilization, and quality of life following gastrointestinal surgery. AB - OBJECTIVES: Our aim in this pilot study was to identify potential predictors of chronic post-surgical pain (CPSP) and other outcomes to consider for inclusion in future prospective studies of CPSP following abdominal gastrointestinal surgery. METHODS: We followed 76 surgical patients during this prospective single-centre cohort study. Pain characteristics, health-related quality of life (HRQOL), and healthcare utilization were assessed preoperatively, at six weeks postoperatively, and at six months postoperatively. Statistical analyses included descriptive statistics and repeated measures analysis of variance. RESULTS: Prior to surgery, 42% of patients reported no pain, 18% reported remote pain, and 33% reported pain at the surgical site. Six months after surgery, 29% of patients with preoperative remote pain and 35% of patients with preoperative pain at the surgical site reported CPSP. Pain-related interference declined from the preoperative to postoperative period; however, six months after surgery almost one-third of participants continued to report pain-related interference with mood (28%), sleep (30%), and enjoyment of life (30%). Consistent with studies of other surgical procedures, measures of anxiety and depression were associated with an increased risk of CPSP. During the six months following surgery, 12% of patients visited the Emergency Department, 15% visited non-traditional providers, and 9.2% visited a walk-in clinic for pain. Compared with Canadian norms, HRQOL was poorer in all domains preoperatively, in all domains but mental health six weeks postoperatively, and in most domains six months postoperatively. CONCLUSION: This feasibility study provides a template for future studies of CPSP following gastrointestinal surgery. Results suggest a substantial burden of persistent pain, healthcare utilization, and decreased HRQOL. Larger-scale studies that are similarly designed will serve to identify predictors of CPSP in this surgical population. PMID- 22547050 TI - The Royal College written examination: is curriculum driving assessment or vice versa? PMID- 22547054 TI - Envisioning an enzymatic Diels-Alder reaction by in situ acid-base catalyzed diene generation. AB - We present and evaluate a new and potentially efficient route for enzyme-mediated Diels-Alder reactions, utilizing general acid-base catalysis. The viability of employing the active site of ketosteroid isomerase is demonstrated. PMID- 22547055 TI - Exploration of biguanido-oxovanadium complexes as potent and selective inhibitors of protein tyrosine phosphatases. AB - The inhibitory effects of three biguanido-oxovanadium complexes ([VO(L(1 3))(2)].nH(2)O: HL(1) = metformin, HL(2) = phenformin, HL(3) = moroxydine) against four protein tyrosine phosphatases (PTPs) and an alkaline phosphatase (ALP) were investigated. The complexes display strong inhibition against PTP1B and TCPTP (IC(50), 80-160 nM), a bit weaker inhibition against HePTP (IC(50), 190 410 nM) and SHP-1(IC(50), 0.8-3.3 MUM) and much weaker inhibition against ALP (IC(50), 17-35 MUM). Complex 3 is about twofold less potent against PTP1B, TCPTP and HePTP than complexes 1 and 2, while complex 2 inhibits SHP-1 more strongly (about three to fourfold) than the other two complexes. These results suggest that the structures of the ligands slightly influence the potency and selectivity against PTPs. The complexes inhibit PTP1B and ALP with a typical competitive type. PMID- 22547053 TI - The challenge of individualised risk assessment and therapy planning in elderly high-risk myelodysplastic syndromes (MDS) patients. AB - Myelodysplastic syndromes (MDS) represent one of the most frequent and serious haematologic diseases of the elderly. Effective therapies exist ranging from best supportive care to haematologic stem cell transplantation (HSCT). Decision making, however, is rather complex in this group of patients because ageing is a multidimensional process involving not only physiological changes but also changes in functional, social, emotional and cognitive capacities. All these factors can have a significant impact on the efficacy and tolerability of a potential therapy and therefore have to be thoroughly assessed before deciding on individual treatment regimens. Risk assessment tools are available both to classify the stage and prognosis of MDS and to meet the needs of elderly patients. A tool explicitly focussing on elderly MDS patients, however, is still missing. The current report approached this issue by combining the well established MDS-risk score 'International Prognostic Scoring System' (IPSS) with the 'Multidimensional Geriatric Assessment' (MGA). As decision making is most complex in high-risk MDS patients, the new algorithm is presented exemplarily for this group of patients. In a first step, MDS-related risk is identified using IPSS, in a second step, patients are assigned to one of three risk categories of the MGA (go-go/fit, slow-go/vulnerable, no-go/frail). While go-go patients might be subjected to therapies comparable to those given to younger patients, in no-go patients, a palliative therapy combined with best supportive care will probably be most appropriate. In slow-go patients, age-related life expectancy taken from public age statistics should be compared to the MDS-related life expectancy. Based on this combined assessment procedure and also on treatment tolerance in terms of the expectations/wishes of the patient and his/her family, an individualised therapeutic approach should be developed. Specific treatment recommendations for these three groups of patients are given, including HSCT, azanucleosides and best supportive care. To illustrate its practicability, i.e. the implementation of the novel algorithm in clinical practice, the case of an elderly high-risk MDS patient is presented and discussed in detail. This new algorithm will facilitate the identification of the very particular needs and conditions of elderly MDS patients in clinical practice. Based on this, individually tailored therapeutic approaches can be developed--the prerequisite for the best possible clinical outcome. PMID- 22547056 TI - Preliminary results of cannulated screw fixation for isolated pubic ramus fractures. AB - Isolated pubic ramus fractures are common fractures in the elderly, and treatment is typically non-operative. Up to 35 % of patients have a prolonged hospital stay due to pain. A small number of these patients do not respond to standard (non operative) treatment. We retrospectively reviewed six patients with isolated pubic ramus fractures and persistent pain who were treated with percutaneous retrograde pubic ramus screw fixation. The study group consisted of six women with an average age of 81 years (72-86 years). Patients with symptomatic posterior pelvic ring injuries were excluded. All patients showed improvement after surgery, with three patients pain free and three patients with reduced pain. The mean time spent in the hospital was 9 days (range 3-18 days). There were complications post-operatively: two patients had pneumonia, two with confusional states, and one patient had a urinary tract infection. Despite these events, which are associated with surgery in patients with comorbidites from advanced age, retrograde pubic ramus screw fixation is an effective treatment option for patients with persistent pain from isolated pubic fractures. PMID- 22547057 TI - Protein kinase C (PKC) activity regulates functional effects of Kvbeta1.3 subunit on KV1.5 channels: identification of a cardiac Kv1.5 channelosome. AB - K(v)1.5 channels are the primary channels contributing to the ultrarapid outward potassium current (I(Kur)). The regulatory K(v)beta1.3 subunit converts K(v)1.5 channels from delayed rectifiers with a modest degree of slow inactivation to channels with both fast and slow inactivation components. Previous studies have shown that inhibition of PKC with calphostin C abolishes the fast inactivation induced by K(v)beta1.3. In this study, we investigated the mechanisms underlying this phenomenon using electrophysiological, biochemical, and confocal microscopy approaches. To achieve this, we used HEK293 cells (which lack K(v)beta subunits) transiently cotransfected with K(v)1.5+K(v)beta1.3 and also rat ventricular and atrial tissue to study native alpha-beta subunit interactions. Immunocytochemistry assays demonstrated that these channel subunits colocalize in control conditions and after calphostin C treatment. Moreover, coimmunoprecipitation studies showed that K(v)1.5 and K(v)beta1.3 remain associated after PKC inhibition. After knocking down all PKC isoforms by siRNA or inhibiting PKC with calphostin C, K(v)beta1.3-induced fast inactivation at +60 mV was abolished. However, depolarization to +100 mV revealed K(v)beta1.3-induced inactivation, indicating that PKC inhibition causes a dramatic positive shift of the inactivation curve. Our results demonstrate that calphostin C-mediated abolishment of fast inactivation is not due to the dissociation of K(v)1.5 and K(v)beta1.3. Finally, immunoprecipitation and immunocytochemistry experiments revealed an association between K(v)1.5, K(v)beta1.3, the receptor for activated C kinase (RACK1), PKCbetaI, PKCbetaII, and PKCtheta in HEK293 cells. A very similar K(v)1.5 channelosome was found in rat ventricular tissue but not in atrial tissue. PMID- 22547058 TI - Cyclin K-containing kinase complexes maintain self-renewal in murine embryonic stem cells. AB - Protein phosphorylation plays an important role in the regulation of self-renewal and differentiation of embryonic stem cells. However, the responsible intracellular kinases are not well characterized. Here, we discovered that cyclin K protein was highly expressed in pluripotent embryonic stem cells but low in their differentiated derivatives or tissue-specific stem cells. Upon cell differentiation, the level of cyclin K protein was decreased. Furthermore, knockdown of cyclin K led to cell differentiation, which could be rescued by an expression construct resistant to RNA interference. Surprisingly, cyclin K did not interact with CDK9 protein in cells as thought previously. Instead, it associated with CrkRS (also known as CDK12) and CDC2L5 (also known as CDK13). Similar to cyclin K, both CDK12 and CDK13 proteins were highly expressed in murine embryonic stem cells and were decreased upon cell differentiation. Importantly, knockdown of either kinase resulted in differentiation. Thus, our studies have uncovered two novel protein kinase complexes that maintain self renewal in embryonic stem cells. PMID- 22547059 TI - RNA processing and modification protein, carbon catabolite repression 4 (Ccr4), arrests the cell cycle through p21-dependent and p53-independent pathway. AB - Ccr4d is a new member of the Ccr4 (carbon catabolite repression 4) family of proteins that are implicated in the regulation of mRNA stability and translation through mRNA deadenylation. However, Ccr4d is not believed to be involved in mRNA deadenylation. Thus, its biological function and mechanistic activity remain to be determined. Here, we report that Ccr4d is broadly expressed in various normal tissues, and the expression of Ccr4d is markedly down-regulated during cell cycle progression. We showed that Ccr4d inhibits cell proliferation and induces cell cycle arrest at G(1) phase. Our experiments further revealed that Ccr4d regulates the expression of p21 in a p53-independent manner. Mechanistic studies indicated that Ccr4d strongly bound to the 3'-UTR of p21 mRNA, leading to the stabilization of p21 mRNA. Interestingly, we found that the expression of Ccr4d is down regulated in various tumor tissues. Collectively, our data indicate that Ccr4d functions as an anti-proliferating protein through the induction of cell cycle arrest via a p21-dependent and p53-independent pathway and suggest that Ccr4d might have an important role in carcinogenesis. PMID- 22547060 TI - Pink1 kinase and its membrane potential (Deltapsi)-dependent cleavage product both localize to outer mitochondrial membrane by unique targeting mode. AB - The Parkinson disease-associated kinase Pink1 is targeted to mitochondria where it is thought to regulate mitochondrial quality control by promoting the selective autophagic removal of dysfunctional mitochondria. Nevertheless, the targeting mode of Pink1 and its submitochondrial localization are still not conclusively resolved. The aim of this study was to dissect the mitochondrial import pathway of Pink1 by use of a highly sensitive in vitro assay. Mutational analysis of the Pink1 sequence revealed that its N terminus acts as a genuine matrix localization sequence that mediates the initial membrane potential (Deltapsi)-dependent targeting of the Pink1 precursor to the inner mitochondrial membrane, but it is dispensable for Pink1 import or processing. A hydrophobic segment downstream of the signal sequence impeded complete translocation of Pink1 across the mitochondrial inner membrane. Additionally, the C-terminal end of the protein promoted the retention of Pink1 at the outer membrane. Thus, multiple targeting signals featured by the Pink1 sequence result in the final localization of both the full-length protein and its major Deltapsi-dependent cleavage product to the cytosolic face of the outer mitochondrial membrane. Full-length Pink1 and deletion constructs resembling the natural Pink1 processing product were found to assemble into membrane potential-sensitive high molecular weight protein complexes at the mitochondrial surface and displayed similar cytoprotective effects when expressed in vivo, indicating that both species are functionally relevant. PMID- 22547062 TI - Melanopsin is highly resistant to light and chemical bleaching in vivo. AB - Melanopsin is the photopigment of mammalian intrinsically photosensitive retinal ganglion cells, where it contributes to light entrainment of circadian rhythms, and to the pupillary light response. Previous work has shown that the melanopsin photocycle is independent of that used by rhodopsin (Tu, D. C., Owens, L. A., Anderson, L., Golczak, M., Doyle, S. E., McCall, M., Menaker, M., Palczewski, K., and Van Gelder, R. N. (2006) Inner retinal photoreception independent of the visual retinoid cycle. Proc. Natl. Acad. Sci. U.S.A. 103, 10426-10431). Here we determined the ability of apo-melanopsin, formed by ex vivo UV light bleaching, to use selected chromophores. We found that 9-cis-retinal, but not all-trans retinal or 9-cis-retinol, is able to restore light-dependent ipRGC activity after bleaching. Melanopsin was highly resistant to both visible-spectrum photic bleaching and chemical bleaching with hydroxylamine under conditions that fully bleach rod and cone photoreceptor cells. These results suggest that the melanopsin photocycle can function independently of both rod and cone photocycles, and that apo-melanopsin has a strong preference for binding cis retinal to generate functional pigment. The data support a model in which retinal is continuously covalently bound to melanopsin and may function through a reversible, bistable mechanism. PMID- 22547061 TI - Caveolin-1 inhibits expression of antioxidant enzymes through direct interaction with nuclear erythroid 2 p45-related factor-2 (Nrf2). AB - The Nrf2 (nuclear erythroid 2 p45-related factor-2) signaling pathway is known to play a pivotal role in a variety of oxidative stress-related human disorders. It has been reported recently that the plasma membrane resident protein caveolin-1 (Cav-1) can regulate expression of certain antioxidant enzymes and involves in the pathogenesis of oxidative lung injury, but the detailed molecular mechanisms remain incompletely understood. Here, we demonstrated that Cav-1 inhibited the expression of antioxidant enzymes through direct interaction with Nrf2 and subsequent suppression of its transcriptional activity in lung epithelial Beas-2B cells. Cav-1 deficiency cells exhibited higher levels of antioxidant enzymes and were more resistant to oxidative stress induced cytotoxicity, whereas overexpression of Cav-1 suppressed the induction of these enzymes and further augmented the oxidative cell death. Cav-1 constitutively interacted with Nrf2 in both cytosol and nucleus. Stimulation of 4-hydroxynonenol increased the Cav-1 Nrf2 interaction in cytosol but disrupted their association in the nucleus. Knockdown of Cav-1 also disassociated the interaction between Nrf2 and its cytoplasmic inhibitor Keap1 (Kelch-like ECH-associated protein 1) and increased the Nrf2 transcription activity. Mutation of the resembling Cav-1 binding motif on Nrf2 effectively attenuated their interaction, which exhibited higher transcription activity and induced higher levels of antioxidant enzymes relative to the wild-type control. Altogether, these studies clearly demonstrate that Cav 1 inhibits cellular antioxidant capacity through direct interaction with Nrf2 and subsequent suppression of its activity, thereby implicating in certain oxidative stress-related human pathologies. PMID- 22547063 TI - Characterization of chloroplastic fructose 1,6-bisphosphate aldolases as lysine methylated proteins in plants. AB - In pea (Pisum sativum), the protein-lysine methyltransferase (PsLSMT) catalyzes the trimethylation of Lys-14 in the large subunit (LS) of ribulose 1,5 bisphosphate carboxylase/oxygenase (Rubisco), the enzyme catalyzing the CO(2) fixation step during photosynthesis. Homologs of PsLSMT, herein referred to as LSMT-like enzymes, are found in all plant genomes, but methylation of LS Rubisco is not universal in the plant kingdom, suggesting a species-specific protein substrate specificity of the methyltransferase. In this study, we report the biochemical characterization of the LSMT-like enzyme from Arabidopsis thaliana (AtLSMT-L), with a focus on its substrate specificity. We show that, in Arabidopsis, LS Rubisco is not naturally methylated and that the physiological substrates of AtLSMT-L are chloroplastic fructose 1,6-bisphosphate aldolase isoforms. These enzymes, which are involved in the assimilation of CO(2) through the Calvin cycle and in chloroplastic glycolysis, are trimethylated at a conserved lysyl residue located close to the C terminus. Both AtLSMT-L and PsLSMT are able to methylate aldolases with similar kinetic parameters and product specificity. Thus, the divergent substrate specificity of LSMT-like enzymes from pea and Arabidopsis concerns only Rubisco. AtLSMT-L is able to interact with unmethylated Rubisco, but the complex is catalytically unproductive. Trimethylation does not modify the kinetic properties and tetrameric organization of aldolases in vitro. The identification of aldolases as methyl proteins in Arabidopsis and other species like pea suggests a role of protein lysine methylation in carbon metabolism in chloroplasts. PMID- 22547064 TI - MicroRNA-148a promotes myogenic differentiation by targeting the ROCK1 gene. AB - MicroRNAs are evolutionarily conserved small RNAs that post-transcriptionally regulate gene expression and have emerged as critical regulators of skeletal muscle development. Here, we identified miR-148a as a novel myogenic microRNA that mediated myogenic differentiation. The expression levels of miR-148a increased during C2C12 myoblast differentiation. Overexpression of miR-148a significantly promoted myogenic differentiation of both C2C12 myoblast and primary muscle cells. Blocking the function of miR-148a with a 2'-O-methylated antisense oligonucleotide inhibitor repressed C2C12 myoblast differentiation. Using a bioinformatics approach, we identified Rho-associated coiled-coil containing protein kinase 1 (ROCK1), a known inhibitor of myogenesis, as a target of miR-148a. A dual-luciferase reporter assay was used to demonstrate that miR 148a directly targeted the 3'-UTR of ROCK1. In addition, the overexpression of miR-148a decreased the protein expression of ROCK1 in C2C12 myoblast and primary muscle cells. Furthermore, ROCK1 inhibition with specific siRNA leaded to accelerated myogenic differentiation progression, underscoring a negative regulatory function of ROCK1 in myogenesis. Therefore, our results revealed a novel mechanism in which miR-148a positively regulates myogenic differentiation via ROCK1 down-regulation. PMID- 22547065 TI - Suppressor of cytokine signaling 3 inhibits breast tumor kinase activation of STAT3. AB - Breast tumor kinase (Brk) was originally isolated from a human metastatic breast tumor, but also is found expressed in other epithelial tumors and in a subset of normal epithelia. Brk is a tyrosine kinase and its expression in breast carcinoma has been linked to tumor progression. The signal transducer and activator of transcription 3 (STAT3) is one of the substrate targets of Brk, and elevated tyrosine phosphorylation of STAT3 is known to contribute to oncogenesis. Conventional activation of STAT3 occurs in response to cytokine stimulation of Janus tyrosine kinases (JAK). One of the negative regulators discovered in cytokine signaling of the JAK-STAT pathway is the suppressor of cytokine signaling 3 (SOCS3). In this report we describe the finding that SOCS3 can also inhibit the unconventional target, Brk. Investigation of the mechanism by which SOCS3 inhibits Brk reveals the SOCS3 protein binds to Brk primarily via its SH2 domain, and its main inhibitory effect is mediated by the SOCS3 kinase inhibitory region (KIR). SOCS3 has only a modest effect on promoting Brk degradation, and this requires the C-terminal SOCS box domain. SOCS3 is the only known inhibitor of Brk, and knowledge of the mechanisms by which SOCS3 inhibits Brk may lead to methods that block Brk in cancer progression. PMID- 22547066 TI - L-Sox5 and Sox6 proteins enhance chondrogenic miR-140 microRNA expression by strengthening dimeric Sox9 activity. AB - Sox9 plays a critical role in early chondrocyte initiation and promotion as well as repression of later maturation. Fellow Sox family members L-Sox5 and Sox6 also function as regulators of cartilage development by boosting Sox9 activation of chondrocyte-specific genes such as Col2a1 and Agc1; however, the regulatory mechanism and other target genes are largely unknown. MicroRNAs are a class of short, non-coding RNAs that act as negative regulators of gene expression by promoting target mRNA degradation and/or repressing translation. Analysis of genetically modified mice identified miR-140 as a cartilage-specific microRNA that could be a critical regulator of cartilage development and homeostasis. Recent findings suggest Sox9 promotes miR-140 expression, although the detailed mechanisms are not fully understood. In this study we demonstrate that the proximal upstream region of pri-miR-140 has chondrogenic promoter activity in vivo. We found an L-Sox5/Sox6/Sox9 (Sox trio) response element and detailed binding site in the promoter region. Furthermore, detailed analysis suggests the DNA binding and/or transactivation ability of Sox9 as a homodimer is boosted by L Sox5 and Sox6. These findings provide new insight into cartilage-specific gene regulation by the Sox trio. PMID- 22547067 TI - Prevention of premature fusion of calvarial suture in GLI-Kruppel family member 3 (Gli3)-deficient mice by removing one allele of Runt-related transcription factor 2 (Runx2). AB - Mutations in the gene encoding the zinc finger transcription factor GLI3 (GLI Kruppel family member 3) have been identified in patients with Grieg cephalopolysyndactyly syndrome in which premature fusion of calvarial suture (craniosynostosis) is an infrequent but important feature. Here, we show that Gli3 acts as a repressor in the developing murine calvaria and that Dlx5, Runx2 type II isoform (Runx2-II), and Bmp2 are expressed ectopically in the calvarial mesenchyme, which results in aberrant osteoblastic differentiation in Gli3 deficient mouse (Gli3(Xt-J/Xt-J)) and resulted in craniosynostosis. At the same time, enhanced activation of phospho-Smad1/5/8 (pSmad1/5/8), which is a downstream mediator of canonical Bmp signaling, was observed in Gli3(Xt-J/Xt-J) embryonic calvaria. Therefore, we generated Gli3;Runx2 compound mutant mice to study the effects of decreasing Runx2 dosage in a Gli3(Xt-J/Xt-J) background. Gli3(Xt-J/Xt-J) Runx2(+/-) mice have neither craniosynostosis nor additional ossification centers in interfrontal suture and displayed a normalization of Dlx5, Runx2-II, and pSmad1/5/8 expression as well as sutural mesenchymal cell proliferation. These findings suggest a novel role for Gli3 in regulating calvarial suture development by controlling canonical Bmp-Smad signaling, which integrates a Dlx5/Runx2-II cascade. We propose that targeting Runx2 might provide an attractive way of preventing craniosynostosis in patients. PMID- 22547068 TI - NAD+ levels control Ca2+ store replenishment and mitogen-induced increase of cytosolic Ca2+ by Cyclic ADP-ribose-dependent TRPM2 channel gating in human T lymphocytes. AB - Intracellular NAD(+) levels ([NAD(+)](i)) are important in regulating human T lymphocyte survival, cytokine secretion, and the capacity to respond to antigenic stimuli. NAD(+)-derived Ca(2+)-mobilizing second messengers, produced by CD38, play a pivotal role in T cell activation. Here we demonstrate that [NAD(+)](i) modifications in T lymphocytes affect intracellular Ca(2+) homeostasis both in terms of mitogen-induced [Ca(2+)](i) increase and of endoplasmic reticulum Ca(2+) store replenishment. Lowering [NAD(+)](i) by FK866-mediated nicotinamide phosphoribosyltransferase inhibition decreased the mitogen-induced [Ca(2+)](i) rise in Jurkat cells and in activated T lymphocytes. Accordingly, the Ca(2+) content of thapsigargin-sensitive Ca(2+) stores was greatly reduced in these cells in the presence of FK866. When NAD(+) levels were increased by supplementing peripheral blood lymphocytes with the NAD(+) precursors nicotinamide, nicotinic acid, or nicotinamide mononucleotide, the Ca(2+) content of thapsigargin-sensitive Ca(2+) stores as well as cell responsiveness to mitogens in terms of [Ca(2+)](i) elevation were up-regulated. The use of specific siRNA showed that the changes of Ca(2+) homeostasis induced by NAD(+) precursors are mediated by CD38 and the consequent ADPR-mediated TRPM2 gating. Finally, the presence of NAD(+) precursors up-regulated important T cell functions, such as proliferation and IL-2 release in response to mitogens. PMID- 22547069 TI - Probing structural selectivity of synthetic heparin binding to Stabilin protein receptors. AB - As one of the most widely used drugs worldwide, heparin is an essential anticoagulant required for surgery, dialysis, treatment of thrombosis, cancer, and general circulatory management. Stabilin-2 is a scavenger clearance receptor with high expression in the sinusoidal endothelium of liver. It is believed that Stabilin-2 is the primary receptor for the clearance of unfractionated and low molecular weight heparins in the liver. Here, we identify the modifications and length of the heparin polymer that are required for binding and endocytosis by both human Stabilin receptors: Stabilin-2 and its homolog Stabilin-1 (also found in liver endothelium). Using enzymatically synthesized (35)S-labeled heparan sulfate oligomers, we identified that sulfation of the 3-OH position of N sulfated glucosamine (GlcNS) is the most beneficial modification for binding and endocytosis via both Stabilin receptors. In addition, our data suggest that a decasaccharide is the minimal size for binding to the Stabilin receptors. These findings define the physical parameters of the heparin structure required for efficient clearance from blood circulation. These results will also aid in the design of synthetic heparins with desired clearance rates. PMID- 22547070 TI - Laminin interactions with head and neck cancer cells under low fluid shear conditions lead to integrin activation and binding. AB - Lymphatic metastasis of cancer cells involves movement from the primary tumor site to the lymph node, where the cells must be able to productively lodge and grow. It is there that tumor cells encounter cellular and non-cellular constituent elements that make up the lymph node parenchyma. Our work shows that head and neck squamous cell carcinoma (HNSCC) cell lines are able to bind to laminin, fibronectin, vitronectin, and hyaluronic acid, which are extracellular matrix elements within the lymph node parenchyma. HNSCC cell lines bound to laminin under lymphodynamic low shear stress (0.07 dynes/cm(2)), consistent with lymph flow via beta1 integrins, including alpha2beta1, alpha3beta1, and alpha6beta1. Binding occurred in the presence of shear stress and not in the absence of flow. Additionally, tumor cell binding to laminin under flow did result in calcium signaling. Our data indicate a novel role for beta1 integrin mediated binding of HNSCC cells to laminin under conditions of lymphodynamic flow that results in intracellular calcium signaling within the cancer cell. PMID- 22547071 TI - Rab5 proteins regulate activation and localization of target of rapamycin complex 1. AB - The mechanistic target of rapamycin (mTOR) complex 1 is regulated by small GTPase activators and localization signals. We examine here the role of the small GTPase Rab5 in the localization and activation of TORC1 in yeast and mammalian cells. Rab5 mutants disrupt mTORC1 activation and localization in mammalian cells, whereas disruption of the Rab5 homolog in yeast, Vps21, leads to decreased TORC1 function. Additionally, regulation of PI(3)P synthesis by Rab5 and Vps21 is essential for TORC1 function in both contexts. PMID- 22547072 TI - Conformational differences between two amyloid beta oligomers of similar size and dissimilar toxicity. AB - Several protein conformational disorders (Parkinson and prion diseases) are linked to aberrant folding of proteins into prefibrillar oligomers and amyloid fibrils. Although prefibrillar oligomers are more toxic than their fibrillar counterparts, it is difficult to decouple the origin of their dissimilar toxicity because oligomers and fibrils differ both in terms of structure and size. Here we report the characterization of two oligomers of the 42-residue amyloid beta (Abeta42) peptide associated with Alzheimer disease that possess similar size and dissimilar toxicity. We find that Abeta42 spontaneously forms prefibrillar oligomers at Abeta concentrations below 30 MUm in the absence of agitation, whereas higher Abeta concentrations lead to rapid formation of fibrils. Interestingly, Abeta prefibrillar oligomers do not convert into fibrils under quiescent assembly conditions but instead convert into a second type of oligomer with size and morphology similar to those of Abeta prefibrillar oligomers. Strikingly, this alternative Abeta oligomer is non-toxic to mammalian cells relative to Abeta monomer. We find that two hydrophobic peptide segments within Abeta (residues 16-22 and 30-42) are more solvent-exposed in the more toxic Abeta oligomer. The less toxic oligomer is devoid of beta-sheet structure, insoluble, and non-immunoreactive with oligomer- and fibril-specific antibodies. Moreover, the less toxic oligomer is incapable of disrupting lipid bilayers, in contrast to its more toxic oligomeric counterpart. Our results suggest that the ability of non-fibrillar Abeta oligomers to interact with and disrupt cellular membranes is linked to the degree of solvent exposure of their central and C-terminal hydrophobic peptide segments. PMID- 22547073 TI - Identification of NOG as a specific breast cancer bone metastasis-supporting gene. AB - Metastasis requires numerous biological functions that jointly provide tumor cells from a primary site to seed and colonize a distant organ. Some of these activities are selected for in the primary site, whereas others are acquired at the metastatic niche. We provide molecular evidence showing that the BMP inhibitor, NOG, provides metastatic breast cancer cells with the ability to colonize the bone. NOG expression is acquired during the late events of metastasis, once cells have departed from the primary site, because it is not enriched in primary tumors with high risk of bone relapse. On the contrary, breast cancer bone metastatic lesions do select for high levels of NOG expression when compared with metastasis to the lung, liver, and brain. Pivotal to the bone colonization functions is the contribution of NOG to metastatic autonomous and nonautonomous cell functions. Using genetic approaches, we show that when NOG is expressed in human breast cancer cells, it facilitates bone colonization by fostering osteoclast differentiation and bone degradation and also contributes to metastatic lesions reinitiation. These findings reveal how aggressive cancer cell autonomous and nonautonomous functions can be mechanistically coupled to greater bone metastatic potential. PMID- 22547074 TI - Independent recognition of Staphylococcus aureus by two receptors for phagocytosis in Drosophila. AB - Integrin betanu, one of two beta subunits of Drosophila integrin, acts as a receptor in the phagocytosis of apoptotic cells. We here examined the involvement of this receptor in defense against infection by Staphylococcus aureus. Flies lacking integrin betanu died earlier than control flies upon a septic but not oral infection with this bacterium. A loss of integrin betanu reduced the phagocytosis of S. aureus and increased bacterial growth in flies. In contrast, the level of mRNA of an antimicrobial peptide produced upon infection was unchanged in integrin betanu-lacking flies. The simultaneous loss of integrin betanu and Draper, another receptor involved in the phagocytosis of S. aureus, brought about a further decrease in the level of phagocytosis and accelerated death of flies compared with the loss of either receptor alone. A strain of S. aureus lacking lipoteichoic acid, a cell wall component serving as a ligand for Draper, was susceptible to integrin betanu-mediated phagocytosis. In contrast, a S. aureus mutant strain that produces small amounts of peptidoglycan was less efficiently phagocytosed by larval hemocytes, and a loss of integrin betanu in hemocytes reduced a difference in the susceptibility to phagocytosis between parental and mutant strains. Furthermore, a series of experiments revealed the binding of integrin betanu to peptidoglycan of S. aureus. Taken together, these results suggested that Draper and integrin betanu cooperate in the phagocytic elimination of S. aureus by recognizing distinct cell wall components, and that this dual recognition system is necessary for the host organism to survive infection. PMID- 22547075 TI - DNA damage induces NF-kappaB-dependent microRNA-21 up-regulation and promotes breast cancer cell invasion. AB - NF-kappaB activation induced by genotoxic treatment in cancer cells has been associated with therapeutic resistance in multiple human malignancies. Therapeutic resistance also correlates with high metastatic potential in human cancers, including breast cancer. Whether genotoxic treatment-activated NF-kappaB also contributes to cancer metastasis following radiation and chemotherapy is unclear. Here, we show that chemotherapeutic drug-induced NF-kappaB activation promotes breast cancer cell migration and invasion. The increased metastatic potential is dependent on IL-6 induction mediated by genotoxic NF-kappaB activation. Moreover, genotoxic treatment also up-regulates oncogenic microRNA-21 (miR-21) expression through eliciting NF-kappaB recruitment to the miR-21 promoter region, where it cooperates with signal transducer and activator of transcription 3 (STAT3) to activate miR-21 transcription. DNA damage-induced histone H3 phosphorylation via activated MSK1 creates an open chromatin structure for NF-kappaB/STAT3-driven transactivation of miR-21. NF-kappaB-dependent IL-6 up regulation is responsible for STAT3 activation and recruitment to the miR-21 promoter upon genotoxic stress. Induction of miR-21 may enable cancer cells to elude DNA damage-induced apoptosis and enhance the metastatic potential of breast cancer cells through repressing expression of PTEN and PDCD4. Our data support a critical role of DNA damage-induced NF-kappaB activation in promoting cancer metastasis following genotoxic treatment, and NF-kappaB-dependent miR-21 induction may contribute to both therapeutic resistance and metastasis in breast cancer. PMID- 22547076 TI - Pre-treatment hormonal receptor status and Ki67 index predict pathologic complete response to neoadjuvant trastuzumab/taxanes but not disease-free survival in HER2 positive breast cancer patients. AB - Trastuzumab-containing neoadjuvant chemotherapy achieves a pathologic complete response (pCR) rate of about 40 % in HER2-positive breast cancers, and pCR predicts better survival. A cohort of 102 consecutive Chinese HER2-positive stage II/III patients with neoadjuvant trastuzumab/taxanes were retrospectively analyzed, to evaluate the role of hormonal receptor (HR) status and Ki67 index, along with other parameters, in pCR and survival prediction. pCR rate of the cohort was 44.1 % (45/102). Fifty-three patients were HR-positive and 49 were HR negative. Median Ki67 index was 40 %, and 49 patients had a high Ki67 index (>40 %) whereas 53 had a low Ki67 index (<=40 %). HR status and Ki67 index were confirmed as the only two parameters associated with pCR in multivariate analysis (hazard ratio = 2.952; 95 % CI, 1.227-7.105; P = 0.016 for HR status and hazard ratio = 2.583, 95 % CI 1.107-6.026, P = 0.028 for Ki67 index). Patients with coexisting HR-negative and high Ki67 index had higher pCR rate (69.2 %), compared to those with either HR-negative alone or high Ki67 alone (hazard ratio = 3.038; 95 % CI, 1.102-8.372; P = 0.029), and to those with coexisting HR-positive and low Ki67 index as well (hazard ratio = 7.071; 95 % CI, 2.150-23.253; P = 0.001). In a median follow-up duration of 25.9 months, 11 disease-free survival events (DFS) were recorded. pCR predicted better DFS (log rank P = 0.018) and was the only significant factor in Cox regression analysis (hazard ratio = 0.184; 95 % CI, 0.038-0.893; P = 0.036). Our study indicates that HR status and Ki67 index are predictors for pCR but not for DFS in HER2-positive patients with neoadjuvant trastuzumab/taxanes, which deserves further investigations. PMID- 22547078 TI - Influence of gaseous VOC concentration on the diversity and biodegradation performance of microbial communities. AB - In this work, the influence of toluene gas concentration on the isolation of toluene degrading microbial communities from activated sludge was studied. Toluene biodegradation at gas phase concentration of 10 g m(-3) (R1) resulted in process instability with removal efficiencies (RE) lesser than 33 %, while operation at toluene gas phase concentrations of 300 mg m(-3) (R2) and 11 mg m( 3) (R3) was stable with RE ranging from 74 to 94 %. The consortium isolated in R1 exhibited the highest tolerance toward toluene but the lowest biodegradation performance at trace level VOC concentrations. Despite R2 and R3 showed a similar sensitivity toward toluene toxicity, the microbial community from R2 supported the most efficient toluene biodegradation at trace level VOC concentrations. The Shannon-Wiener index showed an initial biodiversity decrease from 3.2 to 2.0, 1.9 and 2.7 in R1, R2 and R3, respectively. However, while R2 and R3 were able to recover their initial diversity levels by day 48, this loss in diversity was permanent in R1. These results showed that traditional inoculum isolation/acclimation techniques based on the exposure of the inoculum to high VOC concentrations, where toxicity tolerance plays a key role, may result in a poor abatement performance when the off-gas stream is diluted. PMID- 22547077 TI - Acquisition of resistance of pancreatic cancer cells to 2-methoxyestradiol is associated with the upregulation of manganese superoxide dismutase. AB - Acquired resistance of cancer cells to anticancer drugs or ionizing radiation (IR) is one of the major obstacles in cancer treatment. Pancreatic cancer is an exceptional aggressive cancer, and acquired drug resistance in this cancer is common. Reactive oxygen species (ROS) play an essential role in cell apoptosis, which is a key mechanism by which radio- or chemotherapy induce cell killing. Mitochondria are the major source of ROS in cells. Thus, alterations in the expression of mitochondrial proteins, involved in ROS production or scavenging, may be closely linked to the resistance of cancer cells to radio- or chemotherapy. In the present study, we generated a stable cell line by exposing pancreatic cancer cells to increasing concentrations of ROS-inducing, anticancer compound 2-methoxyestradiol (2-ME) over a 3-month period. The resulting cell line showed strong resistance to 2-ME and contained an elevated level of ROS. We then used a comparative proteomics method to profile the differential expression of mitochondrial proteins between the parental and the resistant cells. One protein identified to be upregulated in the resistant cells was manganese superoxide dismutase (SOD2), a mitochondrial protein that converts superoxide radicals to hydrogen peroxides. Silencing of SOD2 resensitized the resistant cells to 2-ME, and overexpression of SOD2 led the parental cells to 2-ME resistance. In addition, the 2-ME-resistant cells also showed resistance to IR. Our results suggest that upregulation of SOD2 expression is an important mechanism by which pancreatic cancer cells acquire resistance to ROS-inducing, anticancer drugs, and potentially also to IR. PMID- 22547079 TI - Selective IgA deficiency: clinical and laboratory features of 118 children in Turkey. AB - Selective IgA deficiency (IgAD) is considered as the most common primary immunodeficiency. Although the vast majority of affected individuals are asymptomatic, symptomatic patients suffer from recurrent infections, allergies and autoimmune diseases. In the present study, we aimed to investigate the clinical and laboratory features of children with IgAD in a tertiary children's hospital in Turkey. The medical records of 118 patients (63 males, 55 females) aged 4-18 years (median: 7 years) seen from 2006 to 2011 were retrospectively reviewed. The most common clinical condition was infectious disease (99 patients, 83.9 %), followed by allergic (51 patients, 43.2 %) and autoimmune (20 patients, 17 %) disorders. Serum IgG, IgM and IgE levels were increased in 61 %, 22 % and 37.3 % of patients, respectively. Serum IgG subclasses were measured in 65 patients, and only 4 (6.2 %) patients had IgG2 subclass deficiency. Autoantibodies (ANA, anti-dsDNA, antigliadin IgA and IgG, tissue transglutaminase IgA and IgG, anti-TPO and anti-TG) were evaluated in 84 patients. Autoantibodies were detected in 26 (31 %) patients, only 10 had an autoimmune disorder. Sixty one patients were followed for more than 6 months (mean: 2 years, range: 0.5-5 years), and none of them resolved during this period. Being the most comprehensive study conducted in Turkey, we believe it has importance in providing significant data on the clinical and laboratory characteristics of children with IgAD. PMID- 22547080 TI - Pregnancy and the methyltransferase genotype independently influence the arsenic methylation phenotype. AB - OBJECTIVES: The methyltransferase genotype and pregnancy both influence the arsenic metabolism phenotype, but it is unknown whether these factors interact, explaining the drastic changes in the efficiency of arsenic metabolism observed among pregnant women. The aim of this study was to evaluate the relative contribution of the methyltransferase genotype and pregnancy to the arsenic metabolism phenotype. METHODS: We studied longitudinally the arsenic metabolite pattern in urine (at approximately gestational weeks 8, 14, and 30) of 303 women exposed to arsenic through drinking water and food in rural Bangladesh. Urinary arsenic metabolites were measured by high-performance liquid chromatography inductively coupled plasma mass spectrometry. Data were available on genotypes for 16 polymorphisms, combined as haplotypes, in three methyltransferases: arsenic(+III)methyltransferase (AS3MT) and DNA-methyltransferases 1a and 3b (DNMT1a and DNMT3b). Changes in the arsenic metabolite pattern over time were evaluated by haplotype using logistic quantile regression. RESULTS: All four AS3MT haplotypes and all three DNMT1a haplotypes significantly influenced the metabolite pattern in the pregnant women, with consistent effects of genotype over the entire course of pregnancy. No interaction was found between the haplotypes and pregnancy-related changes in the arsenic metabolism phenotype. DNMT3b haplotypes did not significantly influence the metabolite pattern. We observed a pregnancy-attributable decrease of 5.7% in the most risk-associated monomethylated metabolite, methylarsonic acid, whereas changes between 1.6 and 5.3% of methylarsonic acid could be attributed to haplotypes of AS3MT and DNMT1a. CONCLUSION: Independent of the genotype, the efficiency of arsenic methylation increased markedly over the course of pregnancy. The effect of pregnancy on the metabolite pattern during the observational period was greater than the effect of genotype. PMID- 22547081 TI - The 18 kDa translocator protein influences angiogenesis, as well as aggressiveness, adhesion, migration, and proliferation of glioblastoma cells. AB - BACKGROUND: It is known that the mitochondrial 18 kDa translocator protein (TSPO) is present in almost all peripheral tissues and also in glial cells in the brain. TSPO levels are typically enhanced in correlation with tumorigenesis of cancer cells including glioblastoma. Relevant for angiogenesis, TSPO is also present in almost all cells of the cardiovascular system. METHODS: We studied the effect of TSPO knockdown by siRNA on various aspects of tumor growth of U118MG glioblastoma cells in two in-vivo models: a nude mouse model with intracerebral implants of U118MG glioblastoma cells and implantation of U118MG glioblastoma cells on the chorionallantoic membrane (CAM) of chicken embryos. In vitro, we further assayed the influence of TSPO on the invasive potential of U118MG cells. RESULTS: TSPO knockdown increased tumor growth in both in-vivo models compared with the scrambled siRNA control. Angiogenesis was also increased by TSPO knockdown as determined by a CAM assay. TSPO knockdown led to a decrease in adhesion to the proteins of the extracellular matrix, including fibronectin, collagen I, collagen IV, laminin I, and fibrinogen. TSPO knockdown also led to an enhancement in the migratory capability of U118MG cells, as determined in a modified Boyden chamber. Application of the TSPO ligand 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3 isoquinolinecarboxamide (PK 11195) at a concentration of 25 umol/l in the in vitro models yielded results similar to those obtained on TSPO knockdown. We found no effects of PK 11195 on TSPO protein expression. Interestingly, at low nmol/l concentrations (around 1 nmol/l), PK 11195 enhanced adhesion to collagen I, suggesting a bimodal concentration effect of PK 11195. CONCLUSION: Intact TSPO appears to be able to counteract the invasive and angiogenic characteristics related to the aggressiveness of U118MG glioblastoma cells in vivo and in vitro. PMID- 22547083 TI - Effect of P450 oxidoreductase variants on the metabolism of model substrates mediated by CYP2C9.1, CYP2C9.2, and CYP2C9.3. AB - OBJECTIVES: CYP2C9 is a microsomal cytochrome P450 that receives electrons from P450 oxidoreductase (POR) to metabolize about 15% of clinically used drugs. Similar to many P450 enzymes, CYP2C9 is polymorphic, with the hypomorphic *2 and *3 variants accounting for about 20% of White alleles. POR is also polymorphic, with the amino acid sequence variant A503V accounting for 19-37% of alleles in different populations. We aimed to understand how polymorphisms in these two interacting proteins might affect drug metabolism. METHODS: We assayed the activities of CYP2C9.1, CYP2C9.2, and CYP2C9.3 to metabolize diclofenac, flurbiprofen, and tolbutamide using a wild type or one of four POR variants (Q153R, A287P, R457H, and A503V). Human CYP2C9 and POR variants were expressed in bacteria, purified, and reconstituted in vitro and the Michaelis constant and maximum velocity were measured with each CYP2C9/POR combination and each substrate. RESULTS: With wild-type POR, the CYP2C9 activities were CYP2C9.1>CYP2C9.2>>CYP2C9.3 with all three substrates. Both the common A503V polymorphism and the rare Q153R variant showed modest increases in activity with all three CYP2C9 isoforms and all three substrates. This is in contrast to previous studies in which A503V showed a modest loss of function with CYP1A2, CYP2C19, CYP2D6, CYP3A4, and CYP17A1. The disease-causing POR variants A287P and R457H had a very low or unmeasurable activity with all CYP2C9 isoforms and all substrates, which is consistent with their low activities with other CYPs. CONCLUSION: POR variants affect CYP2C9 activities. The impact of a POR variant on catalysis varies with the isoform of CYP2C9 and the assay substrate. PMID- 22547084 TI - Organizational and individual conditions associated with depressive symptoms among nursing home residents over time. AB - PURPOSE: To examine the effect of organizational culture and climate on depressive symptoms among nursing home residents. DESIGN AND METHODS: Using a pooled cross-sectional design, this study examines a sample of 23 nursing homes, 1,114 employees, and 5,497 residents. Depressive symptoms were measured using the Minimum Data Set, Depression Rating Scale. Organizational culture and climate were measured using the Organizational Social Context Scale. Data were analyzed using hierarchical linear modeling. RESULTS: Depressive symptoms were associated with 2 dimensions of organizational culture (proficiency and resistance), 3 dimensions of climate (stress, engagement, and functionality), geographic location, facility size, staffing ratios, and impairments in activities of daily living and cognition. IMPLICATIONS: Findings suggest that values and beliefs that guide behavior in an organization and employees' perceived impact of the work environment of their well-being have a significant impact on resident mental health. PMID- 22547085 TI - "I don't want to die like that ...": the impact of significant others' death quality on advance care planning. AB - PURPOSE OF THE STUDY: I examine whether 5 aspects of a significant other's death quality (pain, decision-making capacity, location, problems with end-of life care, and preparation) affect whether one does advance care planning (ACP). I also identify specific aspects of others' deaths that respondents say triggered their own planning. DESIGN AND METHODS: Data are from the New Jersey End of Life study, a survey of 305 adults age 55+ seeking care at 2 major New Jersey medical centers. I estimate multivariate logistic regression models for a subsample of 253 participants who recently lost a loved one and provide descriptive findings from an open-ended question regarding the motivation for one's ACP. RESULTS: Multivariate analyses revealed "positive" role model effects; persons who witnessed significant others' deaths that occurred at home, were free of problems associated with end-of-life care, and where advance directives were used are more likely to make end-of-life preparations. Open-ended data showed that 19% cited others' deaths as the main trigger for their own planning, with most citing negative factors (pain, connection to machines, coma) that they hoped to avoid. IMPLICATIONS: Practitioners should encourage patients to use conversations about others' deaths as springboards for discussions about one's own end-of-life care, and to engage in ACP together with family. Implications for health care reform are highlighted. PMID- 22547086 TI - Making sense of intimate partner violence in late life: comments from online news readers. AB - PURPOSE: The purpose of this study was to gain insight into public awareness of intimate partner violence (IPV) in late life by how individuals respond to incidents of IPV reported in the newspaper. DESIGN AND METHODS: Using grounded theory techniques, online news items covering 24 incidents of IPV in late life, and the reader comments posted to them were analyzed. The news items were examined for incident details, story framing, and reporting style. An open coding process (Charmaz, K. [2006]. Constructing grounded theory: A practical guide through qualitative analysis. Thousand Oaks, CA: Sage Publications.) was used to generate a comprehensive understanding of themes and patterns in the comments posted by readers. RESULTS: Few posters indicated that incidents were episodes of IPV. As many posters struggled to make sense of incidents, they attempted to remove guilt from the perpetrator by assigning blame elsewhere. Comments were influenced by personal assumptions and perspectives about IPV, relationships, and old age; reporting style of the news items; and comments posted by other posters. IMPLICATIONS: Altering public views of IPV in late life requires raising awareness through education, reframing the ways in which information is presented, and placing greater emphasis on the context of the violence. By engaging interactive news media, reporters, participatory journalists, and policymakers can enhance public recognition and understanding of IPV in late life. PMID- 22547082 TI - PharmGKB summary: very important pharmacogene information for cytochrome P-450, family 2, subfamily A, polypeptide 6. PMID- 22547087 TI - Clinical diagnoses before age 75 and men's survival to their 85th birthday: the Manitoba follow-up study. AB - PURPOSE: Of all Canadian and American men who live to age 75 years, about half can expect to live to age 85. Our objective is to examine how clinical diagnoses made before age 75 relate to a man's survival to age 85 years. DESIGN AND METHODS: Since 1948, a cohort of 3,983 young men (mean age of 31 years at entry) has been followed with routine contact and medical examinations to prospectively document incident disease. Over 62 years of follow-up, 2,414 of the cohort lived to celebrate their 75th birthday. Of these survivors, 1,060 (44%) died before their 85th birthday. Cox proportional hazard models were used to examine the effects of ischemic heart disease, cancer, cerebrovascular disease, diabetes mellitus, peripheral arterial disease, and chronic obstructive pulmonary disease on all-cause mortality between age 75 and 85 years. RESULTS: Modeled as six binary risk factors at age 75 years, all were significantly (p < .01) and independently related to 10-year mortality. Multivariate risk ratios ranged from 1.36 to 1.46 except for chronic obstructive pulmonary disease with a risk ratio of 1.85 (95% CI: 1.38, 2.49). The cumulative 10-year probability of survival from age 75 to 85 among men with none of these diagnoses was 63%, 52% for any one diagnosis, 39% for two diagnoses, and 22% for three or more diagnoses. IMPLICATIONS: Joint independence of these six common clinical diagnoses implies that each is important and their effects on mortality are cumulative. PMID- 22547088 TI - The importance of neighborhood social cohesion and social capital for the well being of older adults in the community. AB - PURPOSE OF THE STUDY: We aimed to investigate whether social capital (obtaining support through indirect ties such as from neighbors) and social cohesion (interdependencies among neighbors) within neighborhoods positively affect the well being of older adults. DESIGN AND METHODS: This cross-sectional study included 945 of 1,440 (66% response rate) independently living older adults (aged >=70 years) in Rotterdam. We fitted a hierarchical random effects model to account for the hierarchical structure of the study design: 945 older adults (Level 1) nested in 72 neighborhoods (Level 2). RESULTS: Univariate analyses showed that being born in the Netherlands, house ownership, education, income, social capital of individuals, neighborhood security, neighborhood services, neighborhood social capital, and neighborhood social cohesion were significantly related to the well being of older adults. Multilevel analyses showed that social capital of individuals, neighborhood services, neighborhood social capital, and neighborhood social cohesion predicted the well being of older adults. Single and poor older adults reported lower well being than did better off and married older adults. However, the effects of marital status and income were mediated by neighborhood services, social capital, and social cohesion. Neighborhood services, social capital, and social cohesion may act as buffer against the adverse effects of being single and poor on the well being of older adults. IMPLICATIONS: The results of this study support the importance of social capital of individuals, as well as social capital within the neighborhood and social cohesion within the neighborhood for well being of older adults. The well being of older adults may also be enhanced through the improvement of quality of neighborhood services. PMID- 22547089 TI - Efficacy of rituximab in acute refractory or chronic relapsing non-familial idiopathic thrombotic thrombocytopenic purpura: a systematic review with pooled data analysis. AB - Idiopathic thrombotic thrombocytopenic purpura (TTP) occurs primarily due to the formation of autoantibody against ADAMTS13, a specific von Willebrand factor cleaving protease, resulting in low ADAMTS13 activity and subsequent accumulation of large vWF multimers, platelet aggregation and thrombus formation in the microvasculature of tissues. Limited clinical data suggest that the administration of anti-CD20 antibody (rituximab) may be useful in treating acute refractory or chronic relapsing idiopathic TTP. We carried out a systematic review with pooled data analysis using individual patient data to evaluate the efficacy of rituximab in these settings. Fifteen case series and 16 case reports comprising 100 patients were eligible for the study. Median age was 39 years. Male constituted 31 % and female 69 %. Complete remission was seen in 98 %, non response in 2 % and relapse after complete remission in 9 %. For patients with complete remission, median follow-up was 13 months. Median platelet recovery from the first dose of rituximab was 14 days. ADAMTS13 inhibitor positivity and severe ADAMTS13 deficiency were highly predictive of the response to rituximab, implying that these can be useful markers in predicting response to rituximab in acute refractory or chronic relapsing idiopathic TTP. PMID- 22547090 TI - Virus-mediated inhibition of natural cytotoxicity receptor recognition. AB - Natural killer (NK) cells are a part of the innate immune system that functions mainly to kill transformed and infected cells. Their activity is controlled by signals derived from a panel of activating and inhibitory receptors. The natural cytotoxicity receptors (NCRs): NKp30, NKp44, and NKp46 (NCR1 in mice) are prominent among the activating NK cell receptors and they are, notably, the only NK-activating receptors that are able to recognize pathogen-derived ligands. In addition, the NCRs also recognize cellular ligands, the identity of which remains largely unknown. In this review, we summarize the current knowledge regarding viruses that are recognized by the NCRs, focusing on the diverse immune-evasion mechanisms employed by viruses to escape this detection. We also discuss the unique role the NCRs have in regulating NK cell activity with particular emphasis on the in vivo function of NKp46/NCR1. PMID- 22547092 TI - The application of the diabetes prevention trial-type 1 risk score for identifying a preclinical state of type 1 diabetes. AB - OBJECTIVE: We assessed the utility of the Diabetes Prevention Trial-Type 1 Risk Score (DPTRS) for identifying individuals who are highly likely to progress to type 1 diabetes (T1D) within 2 years. RESEARCH DESIGN AND METHODS: The DPTRS was previously developed from Diabetes Prevention Trial-Type 1 (DPT-1) data and was subsequently validated in the TrialNet Natural History Study (TNNHS). DPTRS components included C-peptide and glucose indexes from oral glucose tolerance testing, along with age and BMI. The cumulative incidence of T1D was determined after DPTRS thresholds were first exceeded and after the first occurrences of glucose abnormalities. RESULTS: The 2-year risks after the 9.00 DPTRS threshold was exceeded were 0.88 and 0.77 in DPT-1 (n = 90) and the TNNHS (n = 69), respectively. In DPT-1, the 2-year risks were much lower after dysglycemia first occurred (0.37; n = 306) and after a 2-h glucose value between 190 and 199 mg/dL was first reached (0.64; n = 59). Among those who developed T1D in DPT-1, the 9.00 threshold was exceeded 0.81 +/- 0.53 years prior to the conventional diagnosis. Postchallenge C-peptide levels were substantially higher (P = 0.001 for 30 min; P < 0.001 for other time points) when the 9.00 threshold was first exceeded compared with the levels at diagnosis. CONCLUSIONS: A DPTRS threshold of 9.00 identifies individuals who are very highly likely to progress to the conventional diagnosis of T1D within 2 years and, thus, are essentially in a preclinical diabetic state. The 9.00 threshold is exceeded well before diagnosis, when stimulated C-peptide levels are substantially higher. PMID- 22547094 TI - Volumetric and surface-based 3D MRI analyses of fetal isolated mild ventriculomegaly: brain morphometry in ventriculomegaly. AB - Diagnosis of fetal isolated mild ventriculomegaly (IMVM) is the most common brain abnormality on prenatal ultrasound. We have set to identify potential alterations in brain development specific to IMVM in tissue volume and cortical and ventricular local surface curvature derived from in utero magnetic resonance imaging (MRI). Multislice 2D T2-weighted MRI were acquired from 32 fetuses (16 IMVM, 16 controls) between 22 and 25.5 gestational weeks. The images were motion corrected and reconstructed into 3D volumes for volumetric and curvature analyses. The brain images were automatically segmented into cortical plate, cerebral mantle, deep gray nuclei, and ventricles. Volumes were compared between IMVM and control subjects. Surfaces were extracted from the segmentations for local mean surface curvature measurement on the inner cortical plate and the ventricles. Linear models were estimated for age-related and ventricular volume associated changes in local curvature in both the inner cortical plate and ventricles. While ventricular volume was enlarged in IMVM, all other tissue volumes were not different from the control group. Ventricles increased in curvature with age along the atrium and anterior body. Increasing ventricular volume was associated with reduced curvature over most of the ventricular surface. The cortical plate changed in curvature with age at multiple sites of primary sulcal formation. Reduced cortical folding was detected near the parieto occipital sulcus in IMVM subjects. While tissue volume appears to be preserved in brains with IMVM, cortical folding may be affected in regions where ventricles are dilated. PMID- 22547093 TI - Benzylamine antihyperglycemic effect is abolished by AOC3 gene invalidation in mice but not rescued by semicarbazide-sensitive amine oxidase expression under the control of aP2 promoter. AB - Semicarbazide-sensitive amine oxidase (SSAO) is a transmembrane enzyme that metabolizes primary amines from endogenous or dietary origin. SSAO is highly expressed in adipose, smooth muscle and endothelial cells. In each of these cell types, SSAO is implicated in different biological functions, such as glucose transport activation, extracellular matrix maturation and leucocyte extravasation, respectively. However, the physiological functions of SSAO and their involvement in pathogenesis remain uncompletely characterized. To better understand the role of adipose tissue SSAO, we investigated whether it was necessary and/or sufficient to produce the antihyperglycemic effect of the SSAO substrate benzylamine, already reported in mice. Therefore, we crossed SSAO deficient mice invalidated for AOC3 gene and transgenic mice expected to express human SSAO in an adipocyte-specific manner, under the control of aP2 promoter. The aP2-human AOC3 construct (aP2-hAOC3) was equally expressed in the adipose tissue of mice expressing or not the native murine form and almost absent in other tissues. However, the corresponding SSAO activity found in adipose tissue represented only 20 % that of control mice. As a consequence, the benzylamine antihyperglycemic effect observed during glucose tolerance test in control was abolished in AOC3-KO mice but not rescued in mice expressing aP2-hAOC3. The capacity of benzylamine or methylamine to activate glucose uptake in adipocytes exhibited parallel variations in the corresponding genotypes. Although the aP2 hAOC3 construct did not allow a total rescue of SSAO activity in adipose tissue, it could be assessed from our observations that adipocyte SSAO plays a pivotal role in the increased glucose tolerance promoted by pharmacological doses of benzylamine. PMID- 22547095 TI - Enhancement of secondary xylem cell proliferation by Arabidopsis cyclin D overexpression in tobacco plants. AB - Secondary xylem is composed of daughter cells produced by the vascular cambium in the stem. Cell proliferation of the secondary xylem is the result of long-range cell division in the vascular cambium. Most xylem cells have a thickened secondary cell wall, representing a large amount of biomass storage. Therefore, regulation of cell division in the vascular cambium and differentiation into secondary xylem is important for biomass production. Cell division is regulated by cell cycle regulators. In this study, we confirm that cell cycle regulators influence cell division in the vascular cambium in tobacco. We produced transgenic tobacco that expresses Arabidopsis thaliana cyclin D2;1 (AtcycD2;1) and AtE2Fa-DPa under the control of the CaMV35S promoter. Each gene is a positive regulator of the cell cycle, and is known to influence the transition from G1 phase to S phase. AtcycD2;1-overexpressing tobacco had more secondary xylem cells when compared with control plants. In order to evaluate cell division activity in the vascular cambium, we prepared a Populus trichocarpa cycB1;1 (PtcycB1;1) promoter containing a destruction box motif for ubiquitination and a beta glucuronidase-encoding gene (PtcycB1;1pro:GUS). In transgenic tobacco containing PtcycB1;1pro:GUS, GUS staining was specifically observed in meristem tissues, such as the root apical meristem and vascular cambium. In addition, mitosis monitoring plants containing AtcycD2;1 had stronger GUS staining in the cambium when compared with control plants. Our results indicated that overexpression of AtcycD enhances cell division in the vascular cambium and increases secondary xylem differentiation in tobacco. KEY MESSAGE: We succeeded in inducing cell proliferation of cambium and enlargement of secondary xylem region by AtcycD overexpression. We also evaluated mitotic activity in cambium using cyclin-GUS fusion protein from poplar. PMID- 22547091 TI - Current perspectives of the signaling pathways directing neural crest induction. AB - The neural crest is a migratory population of embryonic cells with a tremendous potential to differentiate and contribute to nearly every organ system in the adult body. Over the past two decades, an incredible amount of research has given us a reasonable understanding of how these cells are generated. Neural crest induction involves the combinatorial input of multiple signaling pathways and transcription factors, and is thought to occur in two phases from gastrulation to neurulation. In the first phase, FGF and Wnt signaling induce NC progenitors at the border of the neural plate, activating the expression of members of the Msx, Pax, and Zic families, among others. In the second phase, BMP, Wnt, and Notch signaling maintain these progenitors and bring about the expression of definitive NC markers including Snail2, FoxD3, and Sox9/10. In recent years, additional signaling molecules and modulators of these pathways have been uncovered, creating an increasingly complex regulatory network. In this work, we provide a comprehensive review of the major signaling pathways that participate in neural crest induction, with a focus on recent developments and current perspectives. We provide a simplified model of early neural crest development and stress similarities and differences between four major model organisms: Xenopus, chick, zebrafish, and mouse. PMID- 22547096 TI - Psychological factors impacting transition from paediatric to adult care by childhood cancer survivors. AB - PURPOSE: Childhood cancer survivors require life-long care focused on the specific late effects that may arise from their cancer and its treatment. In many centers, survivors are required to transition from follow-up care in a paediatric cancer center, to care provided in an adult care setting. The purpose of this study was to identify the psychological factors involved in this transition to adult care long-term follow-up clinics. METHODS: Qualitative interviews were conducted with ten paediatric survivors still in paediatric care, as well as 28 adult survivors of whom 11 had transitioned successfully to adult care (attended three long-term follow-up (LTFU) appointments consecutively); ten who failed to transition (attended at least one LTFU appointment as an adult, but were inconsistent with subsequent attendance); and seven who had never transitioned (did not attend any LTFU care as an adult). Line-by-line coding was used to establish categories and themes. Constant comparison was used to examine relationships within and across codes and categories. RESULTS: Two overall categories and four subthemes were identified: (1) Identification with being a cancer survivor included the subthemes of 'cancer identity' and 'cancer a thing of the past' and; (2) Emotional components included the subthemes of 'fear and anxiety' and 'gratitude and gaining perspective'. The analysis revealed that the same factor could act as either a motivator or a hindrance to successful transition in different survivors (e.g., fear of recurrence of cancer might be a barrier or a facilitator depending on the survivor's life experience). CONCLUSIONS: Psychological factors are an important consideration when preparing cancer survivors for transition to adult long-term follow-up care. Identifying and addressing the individual psychological needs of childhood cancer survivors may improve the likelihood of their successful transition to adult care. PMID- 22547097 TI - Multiple DNA binding domains mediate the function of the ERCC1-XPF protein in nucleotide excision repair. AB - ERCC1-XPF is a heterodimeric, structure-specific endonuclease that cleaves single stranded/double-stranded DNA junctions and has roles in nucleotide excision repair (NER), interstrand crosslink (ICL) repair, homologous recombination, and possibly other pathways. In NER, ERCC1-XPF is recruited to DNA lesions by interaction with XPA and incises the DNA 5' to the lesion. We studied the role of the four C-terminal DNA binding domains in mediating NER activity and cleavage of model substrates. We found that mutations in the helix-hairpin-helix domain of ERCC1 and the nuclease domain of XPF abolished cleavage activity on model substrates. Interestingly, mutations in multiple DNA binding domains were needed to significantly diminish NER activity in vitro and in vivo, suggesting that interactions with proteins in the NER incision complex can compensate for some defects in DNA binding. Mutations in DNA binding domains of ERCC1-XPF render cells more sensitive to the crosslinking agent mitomycin C than to ultraviolet radiation, suggesting that the ICL repair function of ERCC1-XPF requires tighter substrate binding than NER. Our studies show that multiple domains of ERCC1-XPF contribute to substrate binding, and are consistent with models of NER suggesting that multiple weak protein-DNA and protein-protein interactions drive progression through the pathway. Our findings are discussed in the context of structural studies of individual domains of ERCC1-XPF and of its role in multiple DNA repair pathways. PMID- 22547099 TI - Depression in headaches: chronification. AB - PURPOSE OF REVIEW: Recent evidence supports the suggestion that migraine is a chronic disorder with episodic attacks that increase in frequency in a subgroup of patients, transforming migraine into a refractory chronic condition with poor outcome and severe impact. Among the risk factors for migraine chronification depression figures notably. Early diagnosis and management of risk factors in migraineurs prevent migraine chronification and its consequences. The scope of this article is to review depression as a potential cofactor for migraine chronification. RECENT FINDINGS: Population-based studies revealed that migraineurs often have symptoms of depression, with strongest associations for migraine with aura. Patients with depression also have an increased risk for migraine, migraine with aura in particular. Twin studies showed similar findings. This bidirectional relationship suggests that migraine and depression may share common causative factors, possibly genetically determined, that might control migraine chronification. Migraine patients may develop depression as a result of the demoralizing experience of recurrent and disabling headaches and depressed patients may develop migraine because of increased pain sensitivity, in the basis of a common genetic background. SUMMARY: We suggest that clinicians consider depression as part of migraine management in order to optimize treatment and avoid migraine progression. PMID- 22547098 TI - Vitamin D and multiple sclerosis: epidemiology, immunology, and genetics. AB - PURPOSE OF REVIEW: This review provides a brief update of new research findings on the role of vitamin D in multiple sclerosis (MS). RECENT FINDINGS: Evidence continues to accumulate supporting a protective role for vitamin D in MS risk and progression. Notable recent findings are that high 25-hydroxyvitamin D [25(OH)D] at the time of a first demyelinating event predicts a lower MS risk and a decreased risk of MS among offspring whose mothers had high predicted 25(OH)D levels. While a small vitamin D intervention study did not find an association between vitamin D and MS progression, this study had little statistical power, and larger trials will be needed to assess the therapeutic potential of vitamin D. Recent immunological studies also show modulation of the immune system by vitamin D that may be favorable for preventing or slowing the progression of MS. The demonstration that rare variants in CYP27B1, which encodes the enzyme that converts vitamin D to its active form, are strongly associated with MS risk supports a causal role of vitamin D deficiency as a risk factor for MS. SUMMARY: Research on the nature of the association between vitamin D and MS risk and progression continues to progress; however, additional research on the timing and dose-response relationship will be crucial for designing future prevention and treatment trials. PMID- 22547100 TI - Prevention and management of medication overuse headache. AB - PURPOSE OF REVIEW: This review provides an update on our knowledge regarding prevention and management of medication overuse headache (MOH). RECENT FINDINGS: The prevalence of MOH is 1-2% in the general population worldwide, and because of the tremendous socio-economic cost, it is likely to be the most costly neurological disorder known. MOH has similarities with traditional drug addiction. Use of a brochure on medication overuse can prevent MOH. The Severity of Dependence Scale (SDS) score is a significant predictor of medication overuse among headache patients. Withdrawal of medication is essential in the management of MOH, and simultaneous initiation of prophylactic medication may alleviate this process. Short advice on medication overuse by a physician reduced mean medication days from 22 to 6 days; 76% no longer had medication overuse and 42% no longer had chronic headache. SUMMARY: A brochure and/or the SDS should be used to prevent MOH. Withdrawal is the cornerstone of MOH management. Short advice on MOH is the current most cost effective management method, a method that can be applied anywhere including third world countries. PMID- 22547101 TI - Microvascular decompression for trigeminal neuralgia: update. AB - PURPOSE OF REVIEW: A recent Cochrane systematic review of surgical interventions for trigeminal neuralgia found not a single trial of what is becoming the most popular surgical intervention, namely microvascular decompression (MVD). With an increasing number of anticonvulsant drugs it is likely that patients may not be offered a surgical option for management of their trigeminal neuralgia for many years. RECENT FINDINGS: Current studies repeat much of what is already in the literature but there is an increasing appreciation of the value of preoperative imaging and the need to be more precise with the diagnosis. The search for prognosticators for good outcomes continues to dominate the literature. SUMMARY: Microvascular decompression in correctly diagnosed patients is probably the most effective therapy. However, high-quality prospective studies of MVD in a population that has been well phenotyped and which is assessed pre and postoperatively using psychometrically tested questions, administered at regular intervals by independent observers, are needed to provide clear evidence of its superiority over medical therapies. PMID- 22547102 TI - CD8-mediated inflammatory central nervous system disorders. AB - PURPOSE OF REVIEW: In central nervous system (CNS) autoimmune disorders, CD8+ T cells have been reported to exert cytotoxic as well as regulatory functions. In virus-induced (meningo) encephalitis, they are essential for viral clearance, but can also cause severe immunopathology. This review aims to summarize the multifaceted roles CD8+ T cells can play in inflammatory CNS disorders. RECENT FINDINGS: Recent evidence for a role of CD8+ T cells in multiple sclerosis comes from genetic association studies confirming a protective effect of the HLA-A0201 allele. Besides their dominance in white matter lesions, CD8+ T cells contribute to immune infiltrates in cortical demyelinating lesions. Having infiltrated the CNS, CD8+ T cells migrate along an inflammation-induced fibrous network. Although CD8+ T cells are generally considered to be crucial for acute viral clearance, they can also induce autoimmune-like immunopathology by, for example, encountering a virus in adulthood while being at the same time latently infected by a related virus. Inadequate control of latent viruses under immunosuppressive treatments or immunodeficiencies is becoming increasingly important in neurology clinical work. SUMMARY: Future research should aim at identifying the specificity and functional phenotype of brain-infiltrating CD8+ T cells in autoimmune diseases and viral immunopathology in order to develop therapeutic strategies specifically targeting CNS-relevant immune reactions. PMID- 22547103 TI - Neural stem cell transplantation in central nervous system disorders: from cell replacement to neuroprotection. AB - PURPOSE OF REVIEW: Transplantation of neural stem/precursor cells (NPCs) has been proposed as a promising therapeutic strategy in almost all neurological disorders characterized by the failure of central nervous system (CNS) endogenous repair mechanisms in restoring the tissue damage and rescuing the lost function. Nevertheless, recent evidence consistently challenges the limited view that transplantation of these cells is solely aimed at protecting the CNS from inflammatory and neurodegenerative damage through cell replacement. RECENT FINDINGS: Recent preclinical data confirmed that transplanted NPCs may also exert a 'bystander' neuroprotective effect and identified a series of molecules - for example, immunomodulatory substances, neurotrophic growth factors, stem cell regulators as well as guidance molecules - whose in-situ secretion by NPCs is temporally and spatially orchestrated by environmental needs. A better understanding of the molecular and cellular mechanisms sustaining this 'therapeutic plasticity' is of pivotal importance for defining crucial aspects of the bench-to-beside translation of neural stem cell therapy, that is route and timing of administration as well as the best cellular source. Further insight into those latter issues is eagerly expected from the ongoing phase I/II clinical trials, while, on the other hand, new cellular sources are being developed, mainly by exploiting the new possibilities offered by cellular reprogramming. SUMMARY: Nowadays, the research on NPC transplantation in neurological disorders is advancing on two different fronts: on one hand, recent preclinical data are uncovering the molecular basis of NPC therapeutic plasticity, offering a more solid rational framework for the design of clinical studies. On the other hand, pilot trials are highlighting the safety and feasibility issues of neural stem cell transplantation that need to be addressed before efficacy could be properly evaluated. PMID- 22547104 TI - Immune mechanisms of stroke. AB - PURPOSE OF REVIEW: Only recently has it been realized that immune mechanisms contribute to the pathophysiology of ischemic stroke, which for many years was regarded mainly as a vascular disease. These immunologic processes are present during all stages of stroke and involve both the innate and adaptive immune systems. This review highlights the latest findings related to the 'immunology of stroke'. RECENT FINDINGS: During the early phase of an ischemic insult, 'danger signals' such as ATP are released from dying tissue to subsequently attract inflammatory cells. Unexpectedly, T cells have been identified as prominent mediators of stroke-induced tissue damage. Whereas during the acute stage of infarction T cells act independently from antigen-specific stimuli but rather interact with thrombotic pathways, antigen-dependent T-cell activation might be relevant at later stages. Moreover, certain T-cell subsets like gammadelta T cells or regulatory T cells are able to influence stroke outcome either in a detrimental or beneficial way. Finally, proof-of-principle studies using FTY720 or VLA-4 blockers have demonstrated that the concept of 'immunomodulation in stroke' is feasible. SUMMARY: The insight that ischemic stroke at least in part is an immune-mediated disease may open new avenues for the treatment of this devastating neurologic condition. PMID- 22547105 TI - In vitro chemoenzymatic and in vivo biocatalytic syntheses of new beauvericin analogues. AB - New beauvericins have been synthesized using the nonribosomal peptide synthetase BbBEAS from the entomopathogenic fungus Beauveria bassiana. Chemical diversity was generated by in vitro chemoenzymatic and in vivo whole cell biocatalytic syntheses using either a B. bassiana mutant or an E. coli strain expressing the bbBeas gene. PMID- 22547106 TI - Tumour characteristics among women with very low-risk breast cancer. AB - It has been proposed that a proportion of non-palpable breast cancers that are diagnosed through mammography represents a very low-risk subgroup of cancers that may not affect survival (overdiagnosis). The salient pathologic features of cancers in this theoretical subgroup are not known, and therefore, it is not possible to predict which patients have a cancer of this type. We reviewed the clinical characteristics and survival experiences of 715 patients with an invasive breast cancer of 5.0 cm or less. The tumour from each patient was represented in triplicate on a tissue microarray. Cases were divided into low risk and moderate-/high-risk categories based on lymph node status and palpability. Low-risk cancers were those that were non-palpable, node-negative and were only detected by mammographic screening. All other cancers were high/moderate risk. The two groups of cancer patients were compared for a number of tumour characteristics, based on immunohistochemistry. There were 79 low-risk cancers and 636 moderate-/high-risk cancers. The low-risk cancers were characterized by ER-positivity, PR-positivity, HER2-negativity, ck5/6-negativity, EGFR-negativity and p53-negativity. About 54 of the 79 low-risk cancers (68 %) were of the luminal A subtype versus 335 of 636 moderate-/high-risk cancers (53 %; p = 0.008). Among 42 women with a non-palpable, mammogram-detected PR+ HER2- cancer of 5.0 cm or less, the 15-year distant recurrence-free survival rate was 100 %. Small breast cancers that are PR+ and HER2- and that are detectable by mammogram alone have a very low risk of recurrence. A proportion of these may represent examples of overdiagnosis. PMID- 22547107 TI - A phase II trial of capecitabine in combination with the farnesyltransferase inhibitor tipifarnib in patients with anthracycline-treated and taxane-resistant metastatic breast cancer: an Eastern Cooperative Oncology Group Study (E1103). AB - Capecitabine produces an objective response rate of up to 25% in anthracycline treated, taxane-resistant metastatic breast cancer (MBC). The farnesyltransferase inhibitor tipifarnib inhibits Ras signaling and has clinical activity when used alone in MBC. The objective of this study was to determine the efficacy and safety of tipifarnib-capecitabine combination in MBC patients who were previously treated with an anthracycline and progressed on taxane therapy. Eligible patients received oral capecitabine 1,000 mg/m2 twice daily plus oral tipifarnib 300 mg twice daily on days 1-14 every 21 days. The primary endpoint was ORR. The trial was powered to detect an improvement in response rate from 25 to 40%. Among 63 eligible, partial response occurred in six patients (9.5%; 90% CI 4.2-17.9%), median progression-free survival was 2.6 months (95% CI 2.1-4.4), and median overall survival was 11.4 months (95% CI 7.7-14.0). Dose modifications were required for 43 patients (68%) for either tipifarnib and/or capecitabine. Grades 3 and 4 toxicities were seen in 30 patients (44%; 90% CI 44.4-67.0%) and 11 patients (16%; 90% CI 10.8-29.0%), respectively. The most common grade 3 toxicities included neutropenia, nausea, and vomiting; and the most common grade 4 toxicity was neutropenia (8 out of 11 cases). The tipifarnib-capecitabine combination is not more effective than capecitabine alone in MBC patients who were previously treated with an anthracycline and taxane therapy. PMID- 22547110 TI - Subclinical leptospirosis may impair athletic performance in racing horses. AB - The infection by Leptospira in horses, in both its acute disease and subclinical forms, is very common, particularly in endemic regions. Therefore, the objective of this study was to evaluate the effects of subclinical leptospirosis in the athletic performance of racing thoroughbred horses. Athletic performance of 119 racing Thoroughbred horses from Rio de Janeiro, Brazil, was calculated by assigning a point value for the results in racing (performance index (PI)), and serology for leptospirosis was conducted. A total of 85 (71.4 %) horses showed reactive titers (>= 100), and of which 52 had high titers (34 with 400 and 18 with >= 800). Although those animals had high titers against Leptospira, no clinical signs associated with leptospirosis were observed. Seventeen (89.5 %) out of the 19 horses with substandard performance were seroreactive with high titers, in contrast with 35 % of seroreactivity in horses with good athletic performance (P < 0.0001). Additionally, seroreactivity to leptospirosis was more often observed in horses with substandard athletic performance in contrast to those with good performance (P < 0.0001, odds ratio 15.8). The Average PI of this group increased to 133 % after treatment (P < 0.0001). Leptospirosis may impair performance in racing horses, and antibiotic therapy may improve the performance of affected animals. PMID- 22547108 TI - Prognostic value of biologic subtype and the 21-gene recurrence score relative to local recurrence after breast conservation treatment with radiation for early stage breast carcinoma: results from the Eastern Cooperative Oncology Group E2197 study. AB - The present study was performed to evaluate the significance of biologic subtype and 21-gene recurrence score relative to local recurrence and local-regional recurrence after breast conservation treatment with radiation. Eastern Cooperative Oncology Group E2197 was a prospective randomized clinical trial that compared two adjuvant systemic chemotherapy regimens for patients with operable breast carcinoma with 1-3 positive lymph nodes or negative lymph nodes with tumor size >1.0 cm. The study population was a subset of 388 patients with known 21 gene recurrence score and treated with breast conservation surgery, systemic chemotherapy, and definitive radiation treatment. Median follow-up was 9.7 years (range = 3.7-11.6 years). The 10-year rates of local recurrence and local regional recurrence were 5.4 % and 6.6 %, respectively. Neither biologic subtype nor 21-gene Recurrence Score was associated with local recurrence or local regional recurrence on univariate or multivariate analyses (all P >= 0.12). The 10-year rates of local recurrence were 4.9 % for hormone receptor positive, HER2 negative tumors, 6.0 % for triple negative tumors, and 6.4 % for HER2-positive tumors (P = 0.76), and the 10-year rates of local-regional recurrence were 6.3, 6.9, and 7.2 %, respectively (P = 0.79). For hormone receptor-positive tumors, the 10-year rates of local recurrence were 3.2, 2.9, and 10.1 % for low, intermediate, and high 21-gene recurrence score, respectively (P = 0.17), and the 10-year rates of local-regional recurrence were 3.8, 5.1, and 12.0 %, respectively (P = 0.12). For hormone receptor-positive tumors, the 21-gene recurrence score evaluated as a continuous variable was significant for local regional recurrence (hazard ratio 2.66; P = 0.03). The 10-year rates of local recurrence and local-regional recurrence were reasonably low in all subsets of patients. Neither biologic subtype nor 21-gene recurrence score should preclude breast conservation treatment with radiation. PMID- 22547109 TI - Pre-clinical studies of Notch signaling inhibitor RO4929097 in inflammatory breast cancer cells. AB - Basal breast cancer, common among patients presenting with inflammatory breast cancer (IBC), has been shown to be resistant to radiation and enriched in cancer stem cells. The Notch pathway plays an important role in self-renewal of breast cancer stem cells and contributes to inflammatory signaling which promotes the breast cancer stem cell phenotype. Herein, we inhibited Notch signaling using a gamma secretase inhibitor, RO4929097, in an in vitro model that enriches for cancer initiating cells (3D clonogenic assay) and conventional 2D clonogenic assay to compare the effect on radiosensitization of the SUM149 and SUM190 IBC cell lines. RO4929097 downregulated the Notch target genes Hes1, Hey1, and HeyL, and showed a significant reduction in anchorage independent growth in SUM190 and SUM149. However, the putative self-renewal assay mammosphere formation efficiency was increased with the drug. To assess radiosensitization of putative cancer stem cells, cells were exposed to increasing doses of radiation with or without 1 MUM RO4929097 in their standard (2D) and self-renewal enriching (3D) culture conditions. In the conventional 2D clonogenic assay, RO4929097 significantly sensitized SUM190 cells to ionizing radiation and has a modest radiosensitization effect in SUM149 cells. In the 3D clonogenic assays, however, a radioprotective effect was seen in both SUM149 and SUM190 cells at higher doses. Both cell lines express IL-6 and IL-8 cytokines known to mediate the efficacy of Notch inhibition and to promote self-renewal of stem cells. We further showed that RO429097 inhibits normal T-cell synthesis of some inflammatory cytokines, including TNF alpha, a potential mediator of IL-6 and IL-8 production in the microenvironment. These data suggest that additional targeting agents may be required to selectively target IBC stem cells through Notch inhibition, and that evaluation of microenvironmental influences may shed further light on the potential effects of this inhibitor. PMID- 22547111 TI - Condensed tannins from Sesbania sesban and Desmodium intortum as a means of Haemonchus contortus control in goats. AB - Two experiments were conducted to determine whether the proanthocyanidin (condensed tannin)-containing forage legumes Desmodium intortum cv Greenleaf and Sesbania sesban (accession 15019) could be integrated into a feeding management strategy as a means of Haemonchus contortus control in goats. The anthelmintic effects of condensed tannin extracts from the two legumes on H. contortus L(3) larvae were studied in an in vitro larval migration inhibition system. The extracts inhibited larval migration in a dose-dependent manner, and at concentrations from 1,000 MUg/ml condensed tannin, the extract from D. intortum caused a significantly higher inhibition of larval migration than did the corresponding concentrations of the S. sesban extract (P < 0.01). Prolonged feeding of tanniniferous forage legumes showed that animals receiving D. intortum had the lowest total worm burden, the lowest female to male parasite ratio, the lowest number of eggs in the uterus of each female worm and the lowest per capita fecundity (P < 0.01). However, there was no change in the performance (weight gain) of parasite-infected goats probably due to incomplete removal of the parasite or prolonged confinement of goats in small pens, which calls for further investigation. However, since there is no single efficient method in control of parasites, based on the obtained data from this experiment, integrated feeding of D. intortum with other suitable method of parasite control is thus suggested. PMID- 22547112 TI - Pharmaceutical cost distribution in childhood chronic kidney disease. AB - BACKGROUND: Chronic kidney disease (CKD) is associated with significant economic burdens to both patients and the healthcare system, but pharmaceutical cost analyses are uncommon despite drug therapy being a cornerstone of CKD management. METHODS: This observational, retrospective review of drug cost distribution at a single tertiary care pediatric nephrology program in Canada was conducted on prevalent patients with CKD aged 1 month to 20 years, between 1 January and 31 December 2009. RESULTS: The time-adjusted annual pharmaceutical cost of our cohort (n = 148) was just below US $250,000 with a cost per patient per year of $1,800. The highest costs were in the growth and nutrition category, followed by anemia, hypertension and bone metabolism. Total drug cost per patient increased as CKD stage advanced. Adherence was not demonstrated in any drug category, and the mean daily pill burden was nine (range 2-23). CONCLUSIONS: This study has shown that while the annual pharmaceutical costs on a per patient basis are similar between children and adults, the cost distribution is very different. An increase in awareness of the unique needs of the pediatric population should allow for more cost-effective financial planning in pediatric CKD clinics. PMID- 22547113 TI - Converging evidence for central 5-HT effects in acute tryptophan depletion? PMID- 22547114 TI - The emerging spectrum of allelic variation in schizophrenia: current evidence and strategies for the identification and functional characterization of common and rare variants. AB - After decades of halting progress, recent large genome-wide association studies (GWAS) are finally shining light on the genetic architecture of schizophrenia. The picture emerging is one of sobering complexity, involving large numbers of risk alleles across the entire allelic spectrum. The aims of this article are to summarize the key genetic findings to date and to compare and contrast methods for identifying additional risk alleles, including GWAS, targeted genotyping and sequencing. A further aim is to consider the challenges and opportunities involved in determining the functional basis of genetic associations, for instance using functional genomics, cellular models, animal models and imaging genetics. We conclude that diverse approaches will be required to identify and functionally characterize the full spectrum of risk variants for schizophrenia. These efforts should adhere to the stringent standards of statistical association developed for GWAS and are likely to entail very large sample sizes. Nonetheless, now more than any previous time, there are reasons for optimism and the ultimate goal of personalized interventions and therapeutics, although still distant, no longer seems unattainable. PMID- 22547115 TI - Epigenetic regulation of BDNF expression according to antidepressant response. PMID- 22547116 TI - Stressing new neurons into depression? PMID- 22547117 TI - Corticotropin-releasing factor and urocortin regulate spine and synapse formation: structural basis for stress-induced neuronal remodeling and pathology. AB - Dendritic spines are important sites of excitatory neurotransmission in the brain with their function determined by their structure and molecular content. Alterations in spine number, morphology and receptor content are a hallmark of many psychiatric disorders, most notably those because of stress. We investigated the role of corticotropin-releasing factor (CRF) stress peptides on the plasticity of spines in the cerebellum, a structure implicated in a host of mental illnesses, particularly of a developmental origin. We used organotypic slice cultures of the cerebellum and restraint stress in behaving animals to determine whether CRF in vitro and stress in vivo affects Purkinje cell (PC) spine density. Application of CRF and urocortin (UCN) to cerebellar slice cultures increased the density of spines on PC signaling via CRF receptors (CRF Rs) 1 and 2 and RhoA downregulation, although the structural phenotypes of the induced spines varied, suggesting that CRF-Rs differentially induce the outgrowth of functionally distinct populations of spines. Furthermore, CRF and UCN exert a trophic effect on the surface contact between synaptic elements by increasing active zones and postsynaptic densities and facilitating the alignment of pre- and post-synaptic membranes of synapses on PCs. In addition, 1 h of restraint stress significantly increased PC spine density compared with those animals that were only handled. This study provides unprecedented resolution of CRF pathways that regulate the structural machinery essential for synaptic transmission and provides a basis for understanding stress-induced mental illnesses. PMID- 22547118 TI - Building community resilience: what can the United States learn from experiences in other countries? AB - OBJECTIVES: Community resilience (CR) is emerging as a major public policy priority within disaster management and is one of two key pillars of the December 2009 US National Health Security Strategy. However, there is no clear agreement on what key elements constitute CR. We examined exemplary practices from international disaster management to validate the elements of CR, as suggested by Homeland Security Presidential Directive 21 (HSPD-21), to potentially identify new elements and to identify practices that could be emulated or adapted to help build CR. METHODS: We extracted detailed information relevant to CR from unpublished case studies we had developed previously, describing exemplary practices from international natural disasters occurring between 1985 and 2005. We then mapped specific practices against the five elements of CR suggested by HSPD-21. RESULTS: We identified 49 relevant exemplary practices from 11 natural disasters in 10 countries (earthquakes in Mexico, India, and Iran; volcanic eruption in Philippines; hurricanes in Honduras and Cuba; floods in Bangladesh, Vietnam, and Mozambique; tsunami in Indian Ocean countries; and typhoon in Vietnam). Of these, 35 mapped well against the five elements of CR: community education, community empowerment, practice, social networks, and familiarity with local services; 15 additional practices were related to physical security and economic security. The five HSPD-21 CR elements and two additional ones we identified were closely related to one another; social networks were especially important to CR. CONCLUSIONS: While each disaster is unique, the elements of CR appear to be broadly applicable across countries and disaster settings. Our descriptive study provides retrospective empirical evidence that helps validate, and adds to, the elements of CR suggested by HSPD-21. It also generates hypotheses about factors contributing to CR that can be tested in future analytic or experimental research. PMID- 22547121 TI - Relationship between long working hours and depression in two working populations: a structural equation model approach. AB - OBJECTIVES: To test the hypothesis that relationship reported between long working hours and depression was inconsistent in previous studies because job demand was treated as a confounder. METHODS: Structural equation modeling was used to construct five models, using work-related factors and depressive mood scale obtained from 218 clerical workers, to test for goodness of fit and was externally validated with data obtained from 1160 sales workers. Multiple logistic regression analysis was also performed. RESULTS: The model that showed that long working hours increased depression risk when job demand was regarded as an intermediate variable was the best fitted model (goodness-of-fit index/root mean-square error of approximation: 0.981 to 0.996/0.042 to 0.044). The odds ratio for depression risk with work that was high demand and 60 hours or more per week was estimated at 2 to 4 versus work that was low demand and less than 60 hours per week. CONCLUSIONS: Long working hours increased depression risk, with job demand being an intermediate variable. PMID- 22547119 TI - Milk intake is inversely related to body mass index and body fat in girls. AB - Dairy foods comprise a range of products with varying nutritional content. The intake of dairy products (DPs) has been shown to have beneficial effects on body weight and body fat. This study aimed to examine the independent association between DP intake, body mass index (BMI), and percentage body fat (%BF) in adolescents. A cross-sectional, school-based study was conducted with 1,001 adolescents (418 boys), ages 15-18 years, from the Azorean Archipelago, Portugal. Anthropometric measurements were recorded (weight and height), and %BF was assessed using bioelectric impedance analysis. Adolescent food intake was measured using a self-administered, semiquantitative food frequency questionnaire. Data were analyzed separately for girls and boys, and separate multiple linear regression analysis was used to estimate the association between total DP, milk, yogurt, and cheese intake, BMI, and %BF, adjusting for potential confounders. For boys and girls, respectively, total DP consumption was 2.6 +/- 1.9 and 2.9 +/- 2.5 servings/day (P = 0.004), while milk consumption was 1.7 +/- 1.4 and 2.0 +/- 1.7 servings/day (P = 0.001), yogurt consumption was 0.5 +/- 0.6 and 0.4 +/- 0.7 servings/day (P = 0.247), and cheese consumption was 0.4 +/- 0.6 and 0.5 +/- 0.8 servings/day (P = 0.081). After adjusting for age, birth weight, energy intake, protein, total fat, sugar, dietary fiber, total calcium intake, low-energy reporters, parental education, pubertal stage, and physical activity, only milk intake was negatively associated with BMI and %BF in girls (respectively, girls: beta = -0.167, P = 0.013; boys: beta = -0.019, P = 0.824 and girls: beta = -0.143, P = 0.030; boys: beta = -0.051, P = 0.548). CONCLUSION: We found an inverse association between milk intake and both BMI and %BF only in girls. PMID- 22547122 TI - A case-crossover study of ambient particulate matter and cardiovascular and respiratory medical encounters among US military personnel deployed to southwest Asia. AB - OBJECTIVE: To evaluate the impact of ambient particulate matter (PM) on acute cardiorespiratory morbidity among US military personnel in southwest Asia. METHODS: We linked ambient PM data collected between December 2005 and June 2007 with personnel, medical, and meteorological data. We implemented a case-crossover analysis to estimate base-specific associations and pooled those estimates using meta-analytic methods. RESULTS: The adjusted odds ratios for a 10-MUg/m increase in ambient PM2.5 and a qualifying medical encounter were 0.92 (95% confidence interval [CI]: 0.77 to 1.11) and 1.01 (95% CI: 0.95 to 1.07) for the current (lag_0) and previous (lag_1) days. The estimates for a 10-MUg/m increase in PM10 were 0.99 (95% CI: 0.97 to 1.03) at lag_0, and 1.00 (95% CI: 0.97 to 1.02) at lag_1. CONCLUSIONS: No statistically significant associations between PM and cardiorespiratory outcomes were observed in this young, relatively healthy, deployed military population. PMID- 22547124 TI - Establishing links between health and productivity in the New Zealand workforce. AB - OBJECTIVE: To provide the first investigation of individual health behaviors and measures of work performance in New Zealand. METHODS: Health risk assessments were completed by 747 adults aged 18 to 65 years. Associations between measures of productivity and health risk factors were assessed using multiple stepwise regression. RESULTS: Participants with low to moderate psychological distress levels and who were physically active reported a work performance 6.5% (P < 0.001) and 3.5% (P < 0.001) higher, respectively. Furthermore, high psychological distress and smoking accounted for 16.8 (P < 0.001) and 11.6 (P = 0.038) additional absentee hours over the previous 4 weeks. CONCLUSIONS: The impact that psychological distress, physical inactivity, and smoking have on productivity suggests that employers may benefit from contributing to health promotion within the workplace. PMID- 22547123 TI - Individual augmentee deployment and newly reported mental health morbidity. AB - OBJECTIVE: To investigate the association between US Navy individual augmentee (IA) deployers, who may lack the protective effects of unit cohesion and social support, and newly reported mental health. METHODS: Responses from the Millennium Cohort Study questionnaires were examined for 2086 Navy deployers in this prospective exploratory study. Multivariable logistic regression was used to evaluate IA deployment and newly reported mental health symptoms. RESULTS: After adjusting for covariates, IA deployment was not significantly associated with newly reported posttraumatic stress disorder (odds ratio = 1.02; 95% confidence interval: 0.53-1.95) or mental health symptoms (odds ratio = 1.03; 95% confidence interval: 0.66-1.60) compared with non-IA deployment. CONCLUSION: IA deployment was not associated with increased risk for posttraumatic stress disorder or mental health symptoms following deployment. It is likely that social isolation was not highly influential among Navy IAs in this study. PMID- 22547125 TI - [Refractive predictability and stability of three-piece versus single-piece intraocular lenses in patients with high axial myopia]. AB - BACKGROUND: Based on previous data on single-piece and three-piece intraocular lenses (IOLs) there is no evidence for significant differences in decentration, tilt and refractive shift. The purpose of the current study was to compare single piece and three-piece IOLs in patients with high axial myopia. MATERIAL AND METHODS: A total of 68 eyes of 50 patients with high axial myopia (axis length >= 28.00 mm) with and without cataract who underwent complication-free phacoemulsification and IOL implantation were retrospectively examined. To compare single-piece and three-piece IOLs, the patients were retrospectively grouped depending on IOL type: group 1 acrylic single-piece IOL (n = 37; ACR6D SE, Corneal, France) and group 2 acrylic three-piece IOL with fixed haptic frame (n = 31; AF-1 UY, Hoya, Japan). Patient files were analyzed regarding best spectacle-corrected visual acuity (BSCVA), refractive predictability and stability. RESULTS: In this study the mean BSCVA was determined as 0.22 +/- 0.12 logMAR and 0.13 +/- 0.11 logMAR 6 months postoperatively for the ACR6D SE group and the AF-1 UV group, respectively (p = 0.09). Refractive predictability was less accurate in the ACR6D SE (+ 1.75 +/- 2.2 dpt) compared to the AF-1 UV (- 0.37 +/- 1.1) treated eyes (p = 0.001). Refractive stability, defined as the difference in diopters between the first week and the sixth month after surgery, resulted in + 0.40 +/- 1.7 dpt and -0.16 +/- 1.2 dpt for the ACR6D SE and the AF 1 UV, respectively (p = 0.022). CONCLUSIONS: The three-piece AF-1 UV showed satisfactory refractive predictability and stability in patients with high axial myopia. The ACR6D SE has a high refractive unpredictability and should not be used in eyes with high axial myopia. PMID- 22547126 TI - [Visual rehabilitation training for homonymous field defects]. AB - Homonymous field defects cause reading and orientation disorders. The reading disorder depends on the size of the macular sparing, the side of the field defect (unfavorable in reading direction) and spontaneous adaptive mechanisms. Methods which support compensation strategies should be recommended as evidence-based training procedures: optokinetic training with scrolled text for reading disorders and saccade training for orientation disorders. By optimized utilization of the total field of gaze, general exploration of the environment, reaction times during search tasks and quality of life can be improved. PMID- 22547127 TI - [Fundus autofluorescence in multiple evanescent white dot syndrome]. AB - Multiple evanescent white dot syndrome (MEWDS), an entity belonging to the group of white dot syndromes, is characterized by pale spots at the posterior pole as a sign of inflammatory changes in the choroid and pigment epithelium. These spots are sometimes difficult to define by fundoscopy. Besides angiography fundus autofluorescence has been shown to be an excellent, noninvasive method to demonstrate these subretinal spots in MEWDS. PMID- 22547128 TI - Postoperative pain after corneal collagen cross-linking. AB - PURPOSE: To evaluate the postoperative pain after corneal collagen cross-linking (CXL). METHODS: : This prospective study included 178 consecutive eyes of 135 patients with progressive keratoconus who underwent CXL at Sadalla Amin Ghanem Eye Hospital, Joinville, Brazil. Pain was assessed postoperatively using the need for analgesia with 30 mg of codeine (Tylex) and by the patients' subjective evaluation on the Wong-Baker FACES Pain Rating Scale at the end of each day until postoperative day (PO) 5. Correlation of postoperative pain with maximum keratometric reading and central corneal thickness, which were assessed preoperatively, was investigated. RESULTS: Mean patient age was 23.38 +/- 5.86 years. Mean (+/-SD) patient-scored pain decreased significantly (P < 0.05) from 2.78 (+/-1.68) on the day of surgery (immediate postoperative period, iPO) to 0.12 (+/-0.46) on PO5. The mean number of codeine pills was 0.94, 0.72, and 0.28 at iPO, PO1, and PO2, respectively, showing a significant decrease at each time point. Statistical analysis showed significant (P < 0.05) correlation between age and pain at PO3 and PO4 (the younger the patients the greater the pain) and between age and the number of codeine pills on iPO. There was no significant correlation between mean overall pain and preoperative apical keratometry (P = 0.546) and pachymetry (P = 0.072) readings. CONCLUSIONS: CXL postoperative pain can be intense, especially in the first 3 days, even with an aggressive pain control regimen; however, pain and the need for analgesia decreased significantly on each consecutive day. Pain was significantly correlated with the patient's age. PMID- 22547130 TI - The d10 route to dye-sensitized solar cells: step-wise assembly of zinc(II) photosensitizers on TiO2 surfaces. AB - Dye-sensitized solar cells have been assembled using a sequential approach: a TiO(2) surface was functionalized with an anchoring ligand, followed by metallation with Zn(OAc)(2) or ZnCl(2), and subsequent capping with a chromophore functionalized 2,2':6',2''-terpyridine; the DSCs exhibit surprisingly good efficiencies confirming the effectiveness of the new strategy for zinc-based DSC fabrication. PMID- 22547131 TI - Editorial: Orchestration of macrophage polarization by polyamines. PMID- 22547133 TI - Editorial: Acute pancreatitis and neutrophil gelatinase MMP9: don't get me started! PMID- 22547132 TI - Editorial: HDAC inhibition begets more MDSCs. PMID- 22547134 TI - Wiskott-Aldrich syndrome with IgA nephropathy: a case report and literature review. AB - The pathogenesis of renal involvement in Wiskott-Aldrich syndrome (WAS) is unclear and renal outcome is generally poor in such situations. Here we present the case of an 8-year-old boy with WAS who developed hematuria, proteinuria, and declining renal function that did not improve with the combined use of immunosuppressive agents and angiotensin-converting-enzyme inhibitor. Renal pathology revealed IgA nephropathy (IgAN). The patient underwent splenectomy for refractory thrombocytopenia. The proteinuria remitted and renal function improved after splenectomy, long-term antibiotic prophylaxis, and tapering of immunosuppressive agents. PMID- 22547135 TI - Bronchiolitis obliterans organizing pneumonia (BOOP) after renal transplantation. AB - A 42-year-old renal transplant recipient was admitted with fever, anorexia, malaise, nonproductive cough, and dyspnea of 1-week duration. Multiple cultures of blood, sputum, and urine were negative. The possibility of bronchiolitis obliterans with organizing pneumonia (BOOP) was considered when pulmonary infiltrate did not respond to conventional antibiotic therapy. High-resolution computed tomography of the chest revealed patchy air-space consolidation and ground-glass opacities, predominantly located in the periphery of the lungs. Cultures and stains of bronchoalveolar lavage specimen and bronchoscopic biopsy of lung tissue were negative for organisms such as Pneumocystis (carinii) jiroveci, bacteria, Mycobacterium tuberculosis, cytomegalovirus, fungi, and atypical germs, and showed evidence of BOOP. The patient recovered completely after treatment with steroids. PMID- 22547136 TI - Prostate cancer mortality and birth or adult residence in the southern United States. AB - PURPOSE: Although there are few confirmed risk factors for prostate cancer (PCa), mortality rates are known to vary geographically across the United States. PCa mortality is higher among black and younger white men in a band of states spanning from Washington DC to Louisiana (the "PCa belt"). This study assessed the associations of birth and adult residence in the PCa belt with PCa mortality among black and white men and trends in these associations over time. METHODS: PCa-specific mortality rates in 1980, 1990, and 2000 for black and white men born in the continental US, aged 40-89, were calculated by linking national mortality records with population data based on birth state, state of residence at the census, race, and age. PCa belt (Washington DC, Virginia, North Carolina, South Carolina, Georgia, Mississippi, Alabama, and Louisiana) birth was cross classified against PCa belt adult residence. RESULTS: Black men born in the PCa belt had elevated PCa mortality in 1980, 1990, and 2000. Associations were independent of adult residence in the PCa belt. For example, in 2000, black men aged 65-89 who were born in the PCa belt but no longer lived there in adulthood had an odds ratio of 1.19 (1.14-1.24) for PCa mortality compared to black men born and residing outside the PCa belt. The PCa belt was not associated with PCa mortality among whites. CONCLUSIONS: Geographically patterned childhood exposures, for example, differences in social or environmental conditions, or behavioral norms, may influence PCa mortality. PMID- 22547137 TI - Infrared femtosecond laser preionization in secondary ion mass spectrometry of silver surface. AB - An alternative secondary ion mass spectrometry utilizing laser preionization is introduced. The native Ag sample surface is first irradiated with laser pulse (100 fs duration, 10(10)-10(11) W/cm(2) intensity, 1240 nm wavelength) and subsequently bombarded with primary ions (Bi(3)(+), 10 ns duration, 25 keV energy). Multiple correlation patterns are observed in the mass spectra, confirming the mutual laser-secondary ion mass spectrometry (SIMS) interplay in the preionization mechanism. The Ag(+), C(3)H(5)(+), C(3)H(5)O(3)(+), and AgOH(+), C(4)H(5)O(4)(+) are observed with the shallow and steep increasing of intensities at 1.3 * 10(11) W/cm(2) and 1.5 * 10(11) W/cm(2), respectively. Two ionization mechanisms are identified, the ion sputtering regime for intensities of less than 1.4 * 10(11) W/cm(2) and the multiphoton ionization at higher intensities. The Ag saturation intensity obtained from fitting is 2.4 * 10(13) W/cm(2), close to the one reported for postionization. The proposed preionization approach might eliminate the need for high peak power/high intensity laser source and, moreover, the experiment geometry ensures that large areas of the sample are affected by the laser beam. PMID- 22547138 TI - Comparative study of the glycan specificities of cell-bound human tandem-repeat type galectin-4, -8 and -9. AB - Adhesion/growth-regulatory galectins (gals) exert their functionality by the cis/trans-cross-linking of distinct glycans after initial one-point binding. In order to define the specificity of ensuing association events leading to cross linking, we recently established a cell-based assay using fluorescent glycoconjugates as flow cytometry probes and tested it on two human gals (gal-1 and -3). Here we present a systematic study of tandem-repeat-type gal-4, -8 and 9 loaded on Raji cells resulting in the following key insights: (i) all three gals bound to oligolactosamines; (ii) binding to ligands with Galbeta1-3GlcNAc or Galbeta1-3GalNAc as basic motifs was commonly better than that to canonical Galbeta1-4GlcNAc; (iii) all three gals bound to 3'-O-sulfated and 3'-sialylated disaccharides mentioned above better than that to parental neutral forms and (iv) histo-blood group ABH antigens were the highest affinity ligands in both the cell and the solid-phase assay. Fine specificity differences were revealed as follows: (i) gal-8 and -9, but not gal-4, bound to disaccharide Galbeta1-3GlcNAc; (ii) increase in binding due to negatively charged substituents was marked only in the case of gal-4 and (iii) gal-4 and -8 bound preferably to histo-blood group A glycans, whereas gal-9 targeted B-type glycans. Experiments with single carbohydrate recognition domains (CRDs) of gal-4 showed that the C-CRD preferably bound to ABH glycans, whereas the N-CRD associated with oligolactosamines. In summary, the comparative analysis disclosed the characteristic profiles of glycan reactivity for the accessible CRD of cell-bound gals. These results indicate the distinct sets of functionality for these three members of the same subgroup of human gals. PMID- 22547139 TI - Microduplications disrupting the MYT1L gene (2p25.3) are associated with schizophrenia. AB - Childhood-onset schizophrenia (COS) is a rare severe form of schizophrenia that may have greater salient genetic risk. Despite evidence for high heritability, conclusive genetic causes of schizophrenia remain elusive. Recent genomic technologies in concert with large case-control cohorts have led to several associations of highly penetrant rare copy number variants (CNVs) and schizophrenia. We previously reported two patients with COS who carried a microduplication disrupting the PXDN and MYT1L genes at 2p25.3. This rate of duplications within our COS population (N=92) is significantly higher than that in 2026 healthy controls (P=0.002). As a replication, we report a meta-analysis of four recently published studies that together provide strong evidence for an association between variably sized microduplications involving the MYT1L gene and schizophrenia. None have reported this separately. Altogether, among 5325 patients and 9279 controls, 10 microduplications were observed: nine in patients and one in a control (odds ratio=15.7, P=0.001). Further, the 2% rate observed in our COS patients is also significantly higher than the rate in adult-onset cases (0.14%, odds ratio=16.6, P=0.01). This report adds to the growing body of literature implicating rare CNVs as risk factors for schizophrenia and shows that some risk CNVs are more common among extreme early-onset cases. PMID- 22547140 TI - Association of rs2069459 in the CDK5 gene with dyslexia in a German cohort. PMID- 22547141 TI - Association mapping for pre-harvest sprouting resistance in white winter wheat. AB - Association mapping identified quantitative trait loci (QTLs) and the markers linked to pre-harvest sprouting (PHS) resistance in an elite association mapping panel of white winter wheat comprising 198 genotypes. A total of 1,166 marker loci including DArT and SSR markers representing all 21 chromosomes of wheat were used in the analysis. General and mixed linear models were used to analyze PHS data collected over 4 years. Association analysis identified eight QTLs linked with 13 markers mapped on seven chromosomes. A QTL was detected on each arm of chromosome 2B and one each on chromosome arms 1BS, 2DS, 4AL, 6DL, 7BS and 7DS. All except the QTL on 7BS are located in a location similar to previous reports and, if verified, the QTL on 7BS is likely to be novel. Principal components and the kinship matrix were used to account for the presence of population structure but had only a minor effect on the results. Although, none of the QTLs was highly significant across all environments, a QTL on the long arm of chromosome 4A was detected in three different environments and also using the best linear unbiased predictions over years. Although previous reports have identified this as a major QTL, its effects were minor in our biparental mapping populations. The results of this study highlight the benefits of association mapping and the value of using elite material in association mapping for plant breeding programs. PMID- 22547142 TI - Excess mortality and morbidity during the July 2006 heat wave in Porto, Portugal. AB - The purpose of this study was to understand the effects of the July 2006 heat wave through the use of the heat index, in mortality (all causes) and morbidity (all causes, respiratory and circulatory diseases) in general, and in people over 74 years and by gender, in Porto. In this paper, the Poisson generalized additive regression model was used to estimate the impact of apparent temperature (heat index) and daily mortality and morbidity during the July 2006 heat wave. Daily mortality, morbidity and heat index were correlated with lags of apparent temperature up to 7 days using Pearson correlation. For a 1 degrees C increase in mean apparent temperature we observed a 2.7 % (95 % CI: 1.7-3.6 %) increase in mortality (all cause), a 1.7 % (95 % CI: 0.6-2.9 %) increase in respiratory morbidity, a 2.2 % (95 % CI: 0.4-4.1 %) increase in respiratory morbidity in women, a 5.4 % (95%CI: 1.1-6.6 %) increase in chronic obstructive pulmonary morbidity, and a 7.5 % (95 % CI: 1.3-14.1 %) increase in chronic obstructive pulmonary morbidity in women, for the entire population. For people >= 75 years, our results showed a 3.3 % increase (95 % CI: 1.7-5.0 %) in respiratory morbidity, a 2.7 % (95 % CI: 0.4-5.1 %) increase in respiratory morbidity in men, a 3.9 % (95 %CI: 1.6-6.3 %) increase in respiratory morbidity in women, a 7.0 % (95 % CI: 1.1-13.2 %) in chronic obstructive pulmonary disease, and a 9.0 % (95 % CI: 0.3-18.5 %) in chronic obstructive pulmonary disease in women. The use of heat index in a Mediterranean tempered climate enabled the identification of the effects of the July 2006 heat wave in mortality due to all causes and in respiratory morbidity of the general population, as well as in respiratory morbidity of individuals with more than 74 years of age. PMID- 22547143 TI - Added value of pharmacogenetic testing in predicting statin response: results from the REGRESS trial. AB - It was investigated whether pharmacogenetic factors, both as single polymorphism and as gene-gene interactions, have an added value over non-genetic factors in predicting statin response. Five common polymorphisms were selected in apolipoprotein E, angiotensin-converting enzyme, hepatic lipase and toll-like receptor 4. Linear regression models were built and compared on R(2) to estimate the added value of single polymorphisms and gene-gene interactions. The selected polymorphisms and the gene-gene interactions had a small added value in predicting change in low-density lipoprotein cholesterol levels (LDL-c) as response to statins over the non-genetic predictors (P=0.104), and also in predicting LDL-c in non-treated patients (P=0.016). Moreover, four gene-gene interactions with statin therapy were identified. The added value of genetic factors over non-genetic variables is for the greater part produced by gene-gene interactions. This underlines the importance to examine gene-gene interactions in future (pharmaco)genetic research. PMID- 22547144 TI - The PPAR alpha gene is associated with triglyceride, low-density cholesterol and inflammation marker response to fenofibrate intervention: the GOLDN study. AB - As a peroxisome proliferator-activated receptor alpha (PPARalpha) agonist, fenofibrate favorably modulates dyslipidemia and inflammation markers, which are associated with cardiovascular risk. To determine whether variation in the PPARalpha receptor gene was associated with lipid and inflammatory marker response, we conducted a 3-week trial of fenofibrate in 861 men and women. Mixed linear models that controlled for age and sex, as well as family pedigree and study center, were constructed using single-nucleotide polymorphisms (SNPs) in the PPARalpha gene as predictors and changes in fasting triglycerides (TGs), cholesterol and inflammatory markers as outcomes. Significant associations with low-density cholesterol and interleukin-2 (P<0.001) responses to fenofibrate were found. Although there were suggestive associations with tumor necrosis factor alpha and TG responses (P<0.05), these did not survive the correction for multiple testing. We conclude that variants in the PPARalpha gene may contribute to future pharmacogenomic paradigms seeking to predict fenofibrate responders from both an anti-dyslipidemic and anti-inflammatory perspective. PMID- 22547145 TI - Pauwels' osteotomy for surgical correction of infantile coxa vara. AB - Infantile coxa vara can be corrected by valgus osteotomies, but recurrence is high. Achieving an Hilgenreiner epiphyseal angle (HEA) of 40 degrees or less prevents recurrence. In this study, Pauwels' osteotomy is stabilized using a rigid method of fixation. The aim of the study is to confirm previous reports regarding the correction of the physeal inclination to 40 degrees or less to prevent recurrence. Thirty-one hips with infantile coxa vara were subjected to an intertrochanteric Y-shaped valgus osteotomy. In 27 hips, the HEA was corrected to 40 degrees or less and none had a recurrence. This study confirms previous recommendations regarding the correction of HEA to 40 degrees or less to avoid recurrence. PMID- 22547146 TI - The incidence of congenital scoliosis in infants with tetralogy of Fallot based on chest radiographs. AB - Early diagnosis is critical in patients with congenital scoliosis to identify vertebral defects that have a high risk for progression. A review of the medical records and chest radiographs for 562 patients who underwent corrective surgery for tetralogy of Fallot (TOF) at our institution between 1992 and 2007 was conducted. Of the 364 patients examined in the study, 12 patients (3.3%), six girls and six boys, had a positive diagnosis of congenital scoliosis confirmed by examination of radiographs. This incidence is significantly higher than both the incidence reported in prior studies (0-1.4%) and in the general population (0.05 0.10%). Given that patients with TOF routinely undergo chest radiograph, physicians examining chest radiographs of TOF patients should be aware of the potential for congenital scoliosis to provide early diagnosis and referral for orthopaedic evaluation and treatment. PMID- 22547147 TI - Congenital trigger thumb in children: electron microscopy and immunohistochemical analysis of the first annular pulley. AB - Although numerous studies have been performed on congenital trigger thumb (CTT), the pathogenesis is still unknown. Cytocontractile proteins and myofibroblasts are present during soft-tissue contraction, and they may have a role in CTT. The aim of the study is to clarify the immunohistochemical and the electron microscopy characteristics of the first annular (A-1) pulley in CTT. The specimens from the A-1 pulleys were collected from 22 children with CTT. Electron microscopy was used to study the last five specimens. Immunohistochemistry staining demonstrated that all specimens stained positively for vimentin and for alpha-smooth muscle actin, and stained negatively for desmin. Electron microscopy showed fibroblasts in collagenous matrix, which contain vimentin-like material and associated at the surface with elastin-like tubular matrix filaments and elastin fibers. In two specimens, a few cells showed markers of myofibroblastic differentiation. The presence of the cytocontractile proteins and myofibroblasts suggests proliferation of fibrous tissues during either the intrauterine or extrauterine phase of development and may account for the presence of congenital stenosis at the level of the A-1 pulley. We believe that CTT may be developmental; if the process started in the intrauterine phase it might present as a fixed flexion contracture and will show mature fibroblasts. If the process started in the extrauterine phase, it might present as triggering first and will show myofibroblastic changes, then with the maturation of the fibrous tissue, result in a fixed flexion contracture. PMID- 22547148 TI - Role of wing pronation in evasive steering of locusts. AB - Evasive steering is crucial for flying in a crowded environment such as a locust swarm. We investigated how flying locusts alter wing-flapping symmetry in response to a looming object approaching from the side. Desert locusts (Schistocerca gregaria) were tethered to a rotatable shaft that allowed them to initiate a banked turn. A visual stimulus of an expending disk on one side of the locust was used to evoke steering while recording the change in wingbeat kinematics and electromyography (EMG) of metathoracic wing depressors. Locusts responded to the looming object by rolling to the contralateral direction. During turning, EMG of hindwing depressors showed an omission of one action potential in the subalar depressor (M129) of the hindwing inside the turn. This omission was associated with increased pronation of the same wing, reducing its angle-of attack during the downstroke. The link between spike-omission in M129 and wing pronation was verified by stimulating the hindwing depressor muscles with an artificial motor pattern that included the misfire of M129. These results suggest that hindwing pronation is instrumental in rotating the body to the side opposite of the approaching threat. Turning away from the threat would be highly adaptive for collision avoidance when flying in dense swarms. PMID- 22547149 TI - Sustaining cardiac claudin-5 levels prevents functional hallmarks of cardiomyopathy in a muscular dystrophy mouse model. AB - Identification of new molecular targets in heart failure could ultimately have a substantial positive impact on both the health and financial aspects of treating the large heart failure population. We originally identified reduced levels of the cell junction protein claudin-5 specifically in heart in the dystrophin/utrophin-deficient (Dmd(mdx);Utrn(-/-)) mouse model of muscular dystrophy and cardiomyopathy, which demonstrates physiological hallmarks of heart failure. We then showed that at least 60% of cardiac explant samples from patients with heart failure resulting from diverse etiologies also have reduced claudin-5 levels. These claudin-5 reductions were independent of changes in other cell junction proteins previously linked to heart failure. The goal of this study was to determine whether sustaining claudin-5 levels is sufficient to prevent the onset of histological and functional indicators of heart failure. Here, we show the proof-of-concept rescue experiment in the Dmd(mdx);Utrn(-/-) model, in which claudin-5 reductions were originally identified. Expression of claudin-5 4 weeks after a single administration of recombinant adeno-associated virus (rAAV) containing a claudin-5 expression cassette prevented the onset of physiological hallmarks of cardiomyopathy and improved histological signs of cardiac damage. This experiment demonstrates that claudin-5 may represent a novel treatment target for prevention of heart failure. PMID- 22547150 TI - Design and selection of Toca 511 for clinical use: modified retroviral replicating vector with improved stability and gene expression. AB - Retroviral replicating vectors (RRVs) are a nonlytic alternative to oncolytic replicating viruses as anticancer agents, being selective both for dividing cells and for cells that have defects in innate immunity and interferon responsiveness. Tumor cells fit both these descriptions. Previous publications have described a prototype based on an amphotropic murine leukemia virus (MLV), encoding yeast cytosine deaminase (CD) that converts the prodrug 5-fluorocytosine (5-FC) to the potent anticancer drug, 5-fluorouracil (5-FU) in an infected tumor. We report here the selection of one lead clinical candidate based on a general design goal to optimize the genetic stability of the virus and the CD activity produced by the delivered transgene. Vectors were tested for titer, genetic stability, CD protein and enzyme activity, ability to confer susceptibility to 5-FC, and preliminary in vivo antitumor activity and stability. One vector, Toca 511, (aka T5.0002) encoding an optimized CD, shows a threefold increased specific activity in infected cells over infection with the prototype RRV and shows markedly higher genetic stability. Animal testing demonstrated that Toca 511 replicates stably in human tumor xenografts and, after 5-FC administration, causes complete regression of such xenografts. Toca 511 (vocimagene amiretrorepvec) has been taken forward to preclinical and clinical trials. PMID- 22547151 TI - Hematopoietic stem cell and gene therapy corrects primary neuropathology and behavior in mucopolysaccharidosis IIIA mice. AB - Mucopolysaccharidosis IIIA (MPS IIIA or Sanfilippo disease) is a neurodegenerative disorder caused by a deficiency in the lysosomal enzyme sulfamidase (SGSH), catabolizing heparan sulfate (HS). Affected children present with severe behavioral abnormalities, sleep disturbances, and progressive neurodegeneration, leading to death in their second decade. MPS I, a similar neurodegenerative disease accumulating HS, is treated successfully with hematopoietic stem cell transplantation (HSCT) but this treatment is ineffectual for MPS IIIA. We compared HSCT in MPS IIIA mice using wild-type donor cells transduced ex vivo with lentiviral vector-expressing SGSH (LV-WT-HSCT) versus wild-type donor cell transplant (WT-HSCT) or lentiviral-SGSH transduced MPS IIIA cells (LV-IIIA-HSCT). LV-WT-HSCT results in 10% of normal brain enzyme activity, near normalization of brain HS and GM2 gangliosides, significant improvements in neuroinflammation and behavioral correction. Both WT-HSCT and LV-IIIA-HSCT mediated improvements in GM2 gangliosides and neuroinflammation but were less effective at reducing HS or in ameliorating abnormal HS sulfation and had no significant effect on behavior. This suggests that HS may have a more significant role in neuropathology than neuroinflammation or GM2 gangliosides. These data provide compelling evidence for the efficacy of gene therapy in conjunction with WT-HSCT for neurological correction of MPS IIIA where conventional transplant is ineffectual. PMID- 22547153 TI - Formation of SnS nanoflowers for lithium ion batteries. AB - SnS nanoflowers containing hierarchically organized nanosheet subunits were synthesized using a simple solution route, and they function as lithium ion battery anodes that maintain high capacities and coulombic efficiencies over 30 cycles. PMID- 22547152 TI - The impact of delaying radical nephrectomy for stage II or higher renal cell carcinoma. AB - PURPOSE: To evaluate the impact of surgical waiting time (SWT) on outcomes of patients who underwent radical nephrectomy for stage II or higher renal cell carcinoma (RCC). METHODS: Of the 1,732 patients who underwent surgery for RCC between 1989 and 2007, medical records of 319 with clinical stage II or higher RCC without distant metastases were retrospectively reviewed. Ten patients with SWT greater than 3 months were excluded from analysis, and we compared pathological upstaging and survival rates between patients with SWT <1 month (234/319, 73.3 %) and 1-3 months (75/319, 23.5 %). RESULTS: Clinicopathological characteristics between two groups were not different except the presence of symptom. The pathological upstaging was higher in patients with SWT of 1-3 months but statistically not significant. SWT of 1-3 months was not an independent predictor of pathological upstaging, recurrence-free survival (RFS; p = 0.896), or cancer-specific survival (CSS; p = 0.737). On subgroup analysis by TNM stage (cT2NxcM0 and cT3-4NxcM0), SWT of 1-3 months was not an independent predictor of pathological upstaging and was not associated with RFS or CSS. SWT, treated as a continuous variable, was also not an independent predictor of outcome in any subgroup. Similar results were found in symptomatic patients. CONCLUSIONS: The outcomes of patients with prolonged SWT did not differ from those of most patients who underwent nephrectomy within 1 month. In patients with stage II or higher RCC who underwent nephrectomy within 3 months after diagnosis, prolonged SWT was not an independent predictor of pathological upstaging, RFS, or CSS. PMID- 22547154 TI - Models under scrutiny--the strengths and limitations of our theoretical frameworks: a comment on Holla et al. PMID- 22547156 TI - Gridiron greenery. PMID- 22547155 TI - Predicting human papillomavirus vaccine uptake in young adult women: comparing the health belief model and theory of planned behavior. AB - BACKGROUND: Although theories of health behavior have guided thousands of studies, relatively few studies have compared these theories against one another. PURPOSE: The purpose of the current study was to compare two classic theories of health behavior-the Health Belief Model (HBM) and the Theory of Planned Behavior (TPB)-in their prediction of human papillomavirus (HPV) vaccination. METHODS: After watching a gain-framed, loss-framed, or control video, women (N = 739) ages 18-26 completed a survey assessing HBM and TPB constructs. HPV vaccine uptake was assessed 10 months later. RESULTS: Although the message framing intervention had no effect on vaccine uptake, support was observed for both the TPB and HBM. Nevertheless, the TPB consistently outperformed the HBM. Key predictors of uptake included subjective norms, self-efficacy, and vaccine cost. CONCLUSIONS: Despite the observed advantage of the TPB, findings revealed considerable overlap between the two theories and highlighted the importance of proximal versus distal predictors of health behavior. PMID- 22547157 TI - Are we allowing patients to return to participation too soon? PMID- 22547158 TI - Antegrade versus retrograde. PMID- 22547159 TI - Associated factors for accelerated growth in childhood: a systematic review. AB - Several studies have shown that accelerated growth in the postnatal period is critical for the development of chronic diseases. The term catch-up has been used for the accelerated growth of children who have suffered some sort of restriction of nutrition or oxygen supply. However, accelerated growth has been observed among children who have an appropriate birth weight for their gestational age (AGA) and with no apparent morbidity. Therefore, this systematic review was carried out on the associated factors of accelerated growth, or catch-up, using the Medline/Pubmed database. Only cohort studies written in Portuguese, English or Spanish, with children between zero and 12 years old who presented accelerated growth or catch-up as the outcome were included. Out of the 2,155 articles found, 9 were selected. There is no uniformity in the operational definition of accelerated growth, or in the concept of catch-up. According to this review, accelerated growth is associated with primiparity, maternal smoking during pregnancy, lower birth weight, and early weaning. The main limitations in the available literature are the high number of follow-up losses and the lack of control for confounding factors. The determinants of accelerated growth still need to be studied further, especially among AGA children. PMID- 22547161 TI - Monetary rewards influence retrieval orientations. AB - Reward anticipation during learning is known to support memory formation, but its role in retrieval processes is so far unclear. Retrieval orientations, as a reflection of controlled retrieval processing, are one aspect of retrieval that might be modulated by reward. These processes can be measured using the event related potentials (ERPs) elicited by retrieval cues from tasks with different retrieval requirements, such as via changes in the class of targeted memory information. To determine whether retrieval orientations of this kind are modulated by reward during learning, we investigated the effects of high and low reward expectancy on the ERP correlates of retrieval orientation in two separate experiments. The reward manipulation at study in Experiment 1 was associated with later memory performance, whereas in Experiment 2, reward was directly linked to accuracy in the study task. In both studies, the participants encoded mixed lists of pictures and words preceded by high- or low-reward cues. After 24 h, they performed a recognition memory exclusion task, with words as the test items. In addition to a previously reported material-specific effect of retrieval orientation, a frontally distributed, reward-associated retrieval orientation effect was found in both experiments. These findings suggest that reward motivation during learning leads to the adoption of a reward-associated retrieval orientation to support the retrieval of highly motivational information. Thus, ERP retrieval orientation effects not only reflect retrieval processes related to the sought-for materials, but also relate to the reward conditions with which items were combined during encoding. PMID- 22547162 TI - Identification and phylogenetic analysis of orf viruses isolated from outbreaks in goats of Assam, a northeastern state of India. AB - Two outbreaks of orf virus (ORFV) (a parapoxvirus) infection in goats, which occurred in Golaghat and Kamrup districts of Assam, a northeastern part of India, were investigated. The disease was diagnosed by standard virological and molecular techniques. The entire protein-coding region of B2L gene of two isolates were cloned and sequenced. Phylogenetic analysis based on B2L amino acid sequences showed that the ORFVs identified in these outbreaks were closely related to each other and both were closer to ORFV-Shahjahanpur 82/04 isolate from north India. The present study revealed that the precise characterization of the genomic region (B2L gene) might provide evidence for the genetic variation and movement of circulating ORFV strains in India. PMID- 22547164 TI - Unexpected renal toxicity associated with SGX523, a small molecule inhibitor of MET. AB - PURPOSE: SGX523 is an orally bio-available, ATP competitive, small molecule inhibitor of MET, binding the kinase domain active site in a novel mode. Two phase 1, open-label, dose-escalation studies of SGX523 were conducted to evaluate both interrupted and continuous dosing schedules. METHODS: Thirty-six patients per study were planned to be enrolled. The first study explored a 21-day cycle with SGX523 administered on an intermittent schedule at a starting dose of 60 mg PO BID for 14 days followed by 7 days of rest. The second protocol explored a continuous 28-day dosing schedule with SGX523 administered at a starting dose of 20 mg PO BID for 28 days without rest. RESULTS: A total of 10 patients were enrolled, 2 on the intermittent dosing protocol and 8 on the continuous dosing protocol. All 6 patients that received daily doses of >= 80 mg developed unexpected renal failure manifested by an early rise of serum blood urea nitrogen and creatinine. Human PK analysis revealed the formation of two insoluble metabolites at levels not seen in the rat or dog preclinical toxicology studies. Subsequent primate toxicology and toxicokinetic evaluation replicated human findings, and histological examination of the monkey kidneys revealed the formation of crystals both within the renal tubules and within giant cell macrophages. CONCLUSION: Two-species toxicology studies of SGX523 did not predict the occurrence of renal toxicity in the human. Subsequent primate toxicology studies suggest the cause of the renal failure seen in humans was a crystal nephropathy secondary to insoluble metabolites. SGX523 is no longer in clinical development. PMID- 22547163 TI - Integrated preclinical and clinical development of S-trans, trans Farnesylthiosalicylic Acid (FTS, Salirasib) in pancreatic cancer. AB - PURPOSE: S-trans,trans-Farnesylthiosalicylic Acid (FTS, salirasib) inhibits Ras dependent cell growth by dislodging all isoforms of Ras, including mutant Ras, from the plasma membrane. This study evaluated the activity, safety, and toxicity of salirasib in preclinical models and patients with metastatic pancreatic adenocarcinoma (PDA). PATIENTS AND METHODS: In the preclinical study, salirasib was tested, alone and in combination with gemcitabine, in patient derived xenografts (PDX) of PDA. In the clinical study, treatment-naive patients with advanced, metastatic PDA were treated with a standard dose schedule of gemcitabine and salirasib 200-800 mg orally (PO) twice daily (bid) for 21 days every 28 days. Tissue from preclinical models and patients' biopsies were collected pre-treatment and on Cycle (C) 1, Day (D) 9 to characterize the effect of gemcitabine and salirasib on activated Ras protein levels. Plasma samples for pharmacokinetics were collected for salirasib administered alone and in combination. RESULTS: Salirasib inhibited the growth of 2/14 PDX models of PDA and modulated Ras signaling in these tumors. Nineteen patients were enrolled. No DLTs occurred. Common adverse events included hematologic and gastrointestinal toxicities and fatigue. The median overall survival was 6.2 months and the 1 year survival 37 %. In 2 patients in whom paired tissue biopsies were available, Ras and KRas protein levels were decreased on C1D9. Salirasib exposure was not altered by gemcitabine and did not correlate with PD outcomes. CONCLUSION: The combination of gemcitabine and salirasib appears well-tolerated, with no alteration of salirasib exposure, and exerted clinical and PD activity in PDA. PMID- 22547165 TI - Ultrasound-guided supraclavicular central venous catheterization in patients with malignant hematologic diseases. AB - We present two cases of central venous catheterization (CVC) in which an ultrasound-guided in-plane approach was used. Case 1 was a 60-year-old man with acute myelogenous leukemia in whom a right supraclavicular CVC was performed. He had pancytopenia (leukocytes 2,000/MUL; erythrocytes 350 * 10(4)/MUL; platelets 5.6 * 10(4)/MUL), and abnormal coagulability (prothrombin time-international normalized ratio 1.35). A linear array transducer was positioned cephalad to the right clavicle and rotated 30 degrees clockwise. The 21-gauge needle was manipulated from outside of the transducer. A CV catheter (CV legaforce EX((r)); Terumo Co., Japan) was placed and stitched near the right clavicle. The patient felt no discomfort caused by the catheter. Case 2 was a 64-year-old women with malignant lymphoma whose right internal jugular vein was surrounded by abnormally enlarged lymph nodes. CVC was performed by the in-plane supraclavicular approach, avoiding puncture of the lymph node. This novel CVC technique is useful to minimize the risk of complications and patient discomfort by indwelling catheter. PMID- 22547166 TI - Hodgkin lymphoma in patients with HIV infection: a review. AB - Hodgkin lymphoma (HL) is one of the most common types of non-AIDS-defining tumors in the HIV-infected. Its incidence however seems to have increased under highly active anti-retroviral therapy (HAART). HIV-HL is a different entity from HL in HIV-negative subjects with a poorer prognosis that is associated with tumor subtype, EBV-infection, and "B" symptoms. Despite the aggressive nature of the disease, clinical outcome has improved with combination therapies including appropriately timed antiretroviral strategies and the quality of supportive care notably the use of hematopoietic growth factors. More intensive chemotherapy regimens with or without autologous stem cell transplantation appear to improve survival. Functional imaging such as positron emission tomography and computed tomography (FDG-PET) may help guide treatment strategy and minimize long-term toxicity. PMID- 22547167 TI - Comparison of color fundus photographs and fundus autofluorescence images in measuring geographic atrophy area. AB - PURPOSE: To assess the agreement between color fundus photographs (CFP) and fundus autofluorescence (FAF) images when measuring geographic atrophy (GA) area and reproducibility of measurements between graders. Frequency and disagreement types were also determined. METHODS: Eyes with GA secondary to age-related macular degeneration had CFP and FAF imaging on the same day. Seventy-two eyes from 72 patients were included in the analysis. Three graders calculated GA area using digital imaging software. Main outcome measures included agreement between graders for GA area on both FAF and CFP and agreement between both imaging modalities. RESULTS: The intraclass correlation for the 3 graders for FAF images was 0.99 (95% confidence interval, 0.98-0.99). For CFP, it was 0.96 (95% confidence interval, 0.94-0.97). The intraclass correlation between imaging modalities for Graders 1, 2, and 3 were 0.93, 0.85, and 0.87, respectively. Sensitivities to detect involvement of fovea (CFP, 86-97%; FAF, 72-93%) and specificities to detect sparing of fovea (CFP, 74-76%; FAF, 59-88%) overlapped between imaging modalities. CONCLUSION: Both CFP and FAF imaging are reliable for measuring GA area. Interobserver agreement was slightly higher for FAF images. Although the high agreement between modalities suggests that either would be appropriate for measuring GA area, using both may be the best approach for following GA progression. PMID- 22547160 TI - The role of adiponectin in cancer: a review of current evidence. AB - Excess body weight is associated not only with an increased risk of type 2 diabetes and cardiovascular disease (CVD) but also with various types of malignancies. Adiponectin, the most abundant protein secreted by adipose tissue, exhibits insulin-sensitizing, antiinflammatory, antiatherogenic, proapoptotic, and antiproliferative properties. Circulating adiponectin levels, which are determined predominantly by genetic factors, diet, physical activity, and abdominal adiposity, are decreased in patients with diabetes, CVD, and several obesity-associated cancers. Also, adiponectin levels are inversely associated with the risk of developing diabetes, CVD, and several malignancies later in life. Many cancer cell lines express adiponectin receptors, and adiponectin in vitro limits cell proliferation and induces apoptosis. Recent in vitro studies demonstrate the antiangiogenic and tumor growth-limiting properties of adiponectin. Studies in both animals and humans have investigated adiponectin and adiponectin receptor regulation and expression in several cancers. Current evidence supports a role of adiponectin as a novel risk factor and potential diagnostic and prognostic biomarker in cancer. In addition, either adiponectin per se or medications that increase adiponectin levels or up-regulate signaling pathways downstream of adiponectin may prove to be useful anticancer agents. This review presents the role of adiponectin in carcinogenesis and cancer progression and examines the pathophysiological mechanisms that underlie the association between adiponectin and malignancy in the context of a dysfunctional adipose tissue in obesity. Understanding of these mechanisms may be important for the development of preventive and therapeutic strategies against obesity-associated malignancies. PMID- 22547168 TI - Clinical and psychosocial factors associated with needs for care: an Arab experience with a sample of treated community-dwelling persons with schizophrenia. AB - OBJECTIVES: To (1) highlight the profile of the needs for care among a sample of persons with schizophrenia, using the Camberwell Assessment of Needs (CAN-EU), in comparison with the international data; (2) assess the association of patients' needs with socio-demographics, clinical characteristics and objective quality of life (QOL); and (3) compare the perceptions of patients with those of the staff. METHOD: Consecutive outpatients in stable condition were interviewed with the CAN EU and measures of QOL and psychopathology. RESULTS: There were 130 patients (68.5% men, mean age 36.8). The highest frequency of unmet needs was for money (29.2%). About a fifth of the subjects expressed unmet needs for six other items, including accommodation. The mean total needs was 8.67(7.1), the total met needs was 5.29 and total unmet needs was 3.38. The dimension with the highest frequency (40%) of unmet needs (functioning) is constituted by items that are related to family care at home. Staff identified significantly more needs than patients. Higher levels of needs were significantly associated with severity of psychopathology and negative affect, and not participating in outdoor activities. The mean number of needs was similar to reports from developing countries and higher than those from European countries. The met/unmet need ratio was similar to European data. CONCLUSION: Despite free health services and family support, a number of our treated community-dwelling persons with schizophrenia had problems meeting basic and health-care needs. The findings call for a consideration of techniques for enhancing the capability of families to cope with the care of patients. PMID- 22547169 TI - Pharmacogenetics: Point-of-care genetic testing--a new frontier explored. PMID- 22547170 TI - Barriers to translating EU and US CVD guidelines into practice in China. AB - With the increasing globalization of clinical research and evidence, clinical practice guidelines (CPGs) developed by the European Union (EU) and the USA are also becoming increasingly international. However, these CPGs can encounter barriers to their practical application. In this Perspectives article, we analyze the main obstacles to the application of EU and US CPGs for cardiovascular diseases from the unique perspective of China, and highlight some potential problems in the globalization of CPGs. Currently, China and other countries with limited independent evidence for CPG development must localize or adapt the CPGs developed by the EU, the USA, or international medical organizations, with systematic consideration of cost-effectiveness and alternative strategies on the basis of the available evidence from the native populations. At the same time, comprehensive capabilities to collect and review clinical evidence to produce population-specific CPGs should be developed. PMID- 22547171 TI - New conduction abnormalities after TAVI--frequency and causes. AB - Transcatheter aortic valve implantation (TAVI) is increasingly used to treat patients with aortic stenosis who are considered to be too high-risk for surgical replacement of the aortic valve. Although the procedural risks are decreasing, the occurrence of new conduction abnormalities remains a vexing issue. Both left bundle branch block and atrioventricular dissociation can affect prognosis after TAVI. Understanding the intimate relationship between the atrioventricular conduction axis and the aortic root, in addition to elucidation of factors related specifically to the procedure, devices, and patients, might help to reduce these conduction abnormalities. The purpose of this Review is to assess, and offer insights into, the available information on the frequency of new conduction abnormalities associated with TAVI, their anatomical and procedural causes, and their clinical consequences. PMID- 22547172 TI - Biomarkers in acute heart failure--state of the art. AB - The role of biomarkers in the management of patients with acute heart failure (HF) has evolved rapidly in the past several years. Representing a major burden on health systems, acute HF has increased the need for earlier diagnosis, better risk stratification, and cost-effective treatment to reduce rates of hospitalization. Biomarker-guided diagnosis and treatment have become essential, especially in the acute setting to which the majority of the patients with acute HF initially present. Studies clearly demonstrate the complexity of these patients, who commonly have multiple comorbidities necessitating an integrative approach. Several groundbreaking studies conducted in the past decade have demonstrated how biomarkers, individually or in combination, can outperform conventional laboratory tests used in the emergency department as well as in hospitalized patients with acute HF. In this Review, we will provide an update on biomarkers considered state of the art in the diagnosis and management of patients with acute HF. PMID- 22547173 TI - Direct thrombin inhibitors in cardiovascular disease. AB - Limitations of commonly used anticoagulants, unfractionated heparin, low molecular-weight heparin, and oral vitamin K antagonists have prompted the development of alternative therapies. Direct thrombin inhibitors are a new class of anticoagulants that bind directly to thrombin and inhibit its interaction with substrates. In this Review, we critically examine the evidence from randomized controlled trials for the efficacy and safety of the parenteral direct thrombin inhibitors bivalirudin and argatroban, and the novel oral direct thrombin inhibitor dabigatran etexilate, in cardiovascular and thrombotic disease. PMID- 22547175 TI - Adaptation to thermally variable environments: capacity for acclimation of thermal limit and heat shock response in the shrimp Palaemonetes varians. AB - In the context of climate change, there is a sustained interest in understanding better the functional mechanisms by which marine ectotherms maintain their physiological scope and define their ability to cope with thermal changes in their environment. Here, we present evidence that the variable shrimp Palaemonetes varians shows genuine acclimation capacities of both the thermal limit (CT(max)) and the heat shock response (hsp70 induction temperature). During cold acclimation to 10 degrees C, the time lag to adjust the stress gene expression to the current environmental temperature proved to exceed 1 week, thereby highlighting the importance of long-term experiments in evaluating the species' acclimation capacities. Cold and warm-acclimated specimens of P. varians can mobilise the heat shock response (HSR) at temperatures above those experienced in nature, which suggests that the species is potentially capable of expanding its upper thermal range. The shrimp also survived acute heat shock well above its thermal limit without subsequent induction of the HSR, which is discussed with regard to thermal adaptations required for life in highly variable environments. PMID- 22547176 TI - Generation of cyclopenta[c]chromenes via a palladium-catalyzed reaction of 2 alkynylphenol with 2-alkynylvinyl bromide. AB - A palladium-catalyzed tandem reaction of 2-alkynylphenol with 2-alkynylvinyl bromide gives rise to cyclopenta[c]chromenes in good yields. Three bonds are formed during the process and a double insertion of triple bonds is believed to be the key step. PMID- 22547177 TI - Neuronal organization of the hemiellipsoid body of the land hermit crab, Coenobita clypeatus: correspondence with the mushroom body ground pattern. AB - Malacostracan crustaceans and dicondylic insects possess large second-order olfactory neuropils called, respectively, hemiellipsoid bodies and mushroom bodies. Because these centers look very different in the two groups of arthropods, it has been debated whether these second-order sensory neuropils are homologous or whether they have evolved independently. Here we describe the results of neuroanatomical observations and experiments that resolve the neuronal organization of the hemiellipsoid body in the terrestrial Caribbean hermit crab, Coenobita clypeatus, and compare this organization with the mushroom body of an insect, the cockroach Periplaneta americana. Comparisons of the morphology, ultrastructure, and immunoreactivity of the hemiellipsoid body of C. clypeatus and the mushroom body of the cockroach P. americana reveal in both a layered motif provided by rectilinear arrangements of extrinsic and intrinsic neurons as well as a microglomerular organization. Furthermore, antibodies raised against DC0, the major catalytic subunit of protein kinase A, specifically label both the crustacean hemiellipsoid bodies and insect mushroom bodies. In crustaceans lacking eyestalks, where the entire brain is contained within the head, this antibody selectively labels hemiellipsoid bodies, the superior part of which approximates a mushroom body's calyx in having large numbers of microglomeruli. We propose that these multiple correspondences indicate homology of the crustacean hemiellipsoid body and insect mushroom body and discuss the implications of this with respect to the phylogenetic history of arthropods. We conclude that crustaceans, insects, and other groups of arthropods share an ancestral neuronal ground pattern that is specific to their second-order olfactory centers. PMID- 22547174 TI - The genetics of the opioid system and specific drug addictions. AB - Addiction to drugs is a chronic, relapsing brain disease that has major medical, social, and economic complications. It has been established that genetic factors contribute to the vulnerability to develop drug addiction and to the effectiveness of its treatment. Identification of these factors may increase our understanding of the disorders, help in the development of new treatments and advance personalized medicine. In this review, we will describe the genetics of the major genes of the opioid system (opioid receptors and their endogenous ligands) in connection to addiction to opioids, cocaine, alcohol and methamphetamines. Particular emphasis is given to association and functional studies of specific variants. We will provide information on the sample populations and the size of each study, as well as a list of the variants implicated in association with addiction-related phenotypes, and with the effectiveness of pharmacotherapy for addiction. PMID- 22547178 TI - Variations in haematological parameters and erythrocyte osmotic fragility of pigs during hot-dry and harmattan season in Northern Guinea Savanna zone of Nigeria. AB - Experiments were performed with the aim of investigating the effect of season on haematological parameters and erythrocyte osmotic fragility (EOF) of pigs. A total of 23 local pigs including males, non-pregnant and non-nursing females, aged 9 to 12 months were used for the study, ten animals were used during the hot dry season and thirteen during the harmattan season. Blood sample was taken from each animal for the determination of EOF and other haematological parameters as well as total protein. The PCV value of 39.7+/-1.9 % obtained during the hot-dry season was significantly higher than 32.00 +/- 0.9 % obtained during the harmattan season. Total leucocyte count of 18,836.5+/-1727.1 obtained during the harmattan season was higher than the value 15,920.00+/-1119.1 recorded during the hot-dry season. The neutrophil:lymphocyte ratio value was significantly higher during the harmattan season, with a value of 0.61+/-0.0 than the recorded value of 0.43+/-0.0 during the hot-dry season. The percentage haemolysis values obtained during the harmattan season at NaCl concentration of 0.5-0.9 % with a value of 92.03+/-0.02 % respectively were significantly higher than those recorded during the hot-dry season. In conclusion, the haematological values showed that harmattan season was more stressful to pigs than the hot-dry season in the Northern Guinea Savanna zone of Nigeria. PMID- 22547180 TI - Analysis of heterogeneity of Copia-like retrotransposons in the genome of cassava (Manihot esculenta Crantz). AB - Retrotransposons are ubiquitous in eukaryotic genomes and now proving to be useful genetic tools for genetic diversity and phylogenetic analyses, especially in plants. In order to assess the diversity of Ty1/Copia-like retrotransposons of cassava, we used PCR primers anchored on the conserved domains of reverse transcriptases (RTs) to amplify cassava Ty1/Copia-like RT. The PCR product was cloned and sequenced. Sequences analysis of the clones revealed the presence of 69 families of Ty1/Copia-like retrotransposon in the genome of cassava. Comparative analyses of the predicted amino acid sequences of these clones with those of other plants showed that retroelements of this class are very heterogeneous in cassava. Cassava is widely grown for its edible roots in the tropical and subtropical regions of the world. Cassava roots, though poor in protein, are rich in starch (makes up about 80% of the dry matter), vitamin C, carotenes, calcium and potassium. It has a great commercial importance as a source of starch and starch based products. Realizing the importance of cassava, it stands out as a crop to benefit from biotechnology development. Heterogeneity of Mecops (Manihot esculenta copia-like Retrotransposons) showed that they may be useful for genetic diversity and phylogenetic analyses of cassava germplasm. PMID- 22547179 TI - Some characteristic relaxant effects of aqueous leaf extract of Andrographis paniculata and andrographolide on guinea pig tracheal rings. AB - The ethnomedicinal uses of the aqueous leaf extract of Andrographis paniculata Nees (AP) include treatment of pain and inflammation, malaria, asthma and common cold. We designed this study to characterize some effects of AP and those of its andrographolide constituent. Guinea pig tracheal rings suspended in organ baths containing PSS were precontracted with histamine or carbachol and then exposed to cumulative concentrations of AP, andographolide or theophylline. The effect of AP was tested in Ca2+-depleted tracheal rings stimulated with the EC50 of histamine in Ca2+-free PSS. IC50 and Emax values were calculated for each relaxant. Results showed that both AP and andrographolide possessed relaxant effects on the tracheal smooth muscle. While AP was more effective on histamine-induced contraction, andrographolide and theophylline were more effective on carbachol induced contraction. The IC50 values of andrographolide were significantly higher than those of theophylline in the two contractile agents. The presence of AP significantly attenuated the contractile force produced by 6.4 x 10(-3) M Ca2+ in Ca2+-depleted rings. It is concluded that andographolide contributes at least in part to the relaxant action of AP on tracheal smooth muscles. The mechanism of action is related to inhibition of Ca2+ influx into tracheal smooth muscle cells. PMID- 22547181 TI - Smooth muscle relaxant evaluation of Jatropha curcas Linn (Euphorbiaceae) and isolation of triterpenes. AB - Jatropha curcas is a herbal preparation used in the tropics for the treatment of threatened abortion and related problems associated with pregnancy. The Stem bark of Jatropha curcas is used ethno medicinally in Nigeria especially in the eastern part of the country for the treatment of infertility and spontaneous abortion (miscarriage). The present study was undertaken in order to validate the folkloric claim, using scientific experimental procedures and bioassay guided fractionation. The crude powdered sample was subjected to phytochemical screening testing for the presence of alkaloids, tannins, saponins and carbohydrates. Chromatographic analysis (TLC and VLC) were carried out using various solvent systems. The effect of methanolic extracts on rat uterine contractions was studied in vitro, in 40ml organ baths containing physiological salt solution of De Jalon maintained at 370C, aerated with 95% O2 and 5% CO2 with an isometric transducer connected an UgoBasile recorder under a resting tension of 750mg. The result of the phytochemical screening revealed the presence of glycosides, tannins, saponins and alkaloids. The extract abolished significantly the spontaneous contraction of the uterus and reduced acetylcholine induced uterine contractions at a dose of 50mg/ml. The tocolytic effects indicate the presence of active principle(s) which would explain the ethno medicinal use of the stem bark of Jatropha curcas to treat spontaneous abortion. PMID- 22547182 TI - Effect of restraint stress on nociceptive responses in rats: role of the histaminergic system. AB - Stress induced analgesia (SIA) is well known, but the reverse phenomenon, hyperalgesia is poorly documented. This study investigated the role of the histaminergic system in restraint stress hyperalgesia in rats, using thermal stimulation method (hot plate and tail flick tests). Paw licking and tail withdrawal latencies were taken before and after restraint for about one hour. Significant decreases (p<0.05) were obtained in these latencies after the restraint in both tests. Administration of H1 and H2 receptor blockers, chlorpheniramine and cimetidine respectively 30 mins before the restraint still resulted in significant reductions (p<0.05) in these latencies, connoting the persistence of hyperalgesia, showing that histamine H1 and H2 receptors did not participate in the mechanism of restraint stress hyperalgesia. We therefore suggest a histaminergic independent mechanism for restraint stress induced hyperalgesia. PMID- 22547183 TI - Thyroid hormone receptor-mediated transcription is suppressed by low dose phthalate. AB - SUMMARY: Phthalates are synthetic chemicals used mainly as solvents, additives and plasticizers in polyvinylchloride (PVC) products to increase their flexibility. Phthalate plasticizers are not chemically bound to PVC, so they easily leach into the environment. There is currently heightened concern about potential health risk, especially endocrine disrupting effects associated with the use of these chemicals. We therefore investigated the effects of phthalate on thyroid hormone receptor (TR)-mediated transcription using transient transfection studies and found that low dose phthalate (10-7) M suppressed thyroid hormone (TH)-induced TR-mediated transcription by 30%. We further examined the effect of phthalate on TR-thyroid hormone response element (TRE) binding, and found no dissociation of TR from TRE. Phthalate did not also dissociate coactivator (steroid receptor coactivator-1) from TR neither did it recruit corepressor (nuclear corepressor; NCoR) to TR in the presence of TH. Our results indicate that low phthalate can disrupt TR-mediated gene expression and interfere with TH balance in TH-sensitive organs including the developing brain. PMID- 22547184 TI - Biochemical and histologic presentations of female Wistar rats administered with different doses of paracetamol/methionine. AB - This study was carried out to compare the hepatoprotective effect of methionine on paracetamol treated rats at both the peaks of toxicity and absorption. Female Wistar rats were divided into 17 groups consisting of eight rats per group and treated with different doses of paracetamol/methionine (5:1). Each control rat received 5 ml of physiologic saline. The study was terminated at two different end points -the 4th and 16th hours. Results show that rats administered with toxic doses (1000 mg/kg, 3000 mg/kg, 5000 mg/kg BW) of paracetamol exhibited significant increases in the levels of ALT, AST, gamma- GT compared with controls. These increases were much higher at the 16th than 4th hour but serum total protein, albumin and globulin were significantly decreased by the end of the 16th hour. Histology results of rats in the 3000 and 5000 mg/kg (by the end of the 16th hour) confirmed hepatic damage, light microscopic evaluation of liver showed remarkable centrilobular necrosis. Moreover, the presence of mononuclear cells in liver section of rats intoxicated with APAP (5000 mg/kg) suggests a possible involvement of inflammatory process which resulted in regurgitation of bilirubin leading to its elevated level as well as increase activity of ALP. The hepatoprotective effect of methionine, on the other hand, was demonstrated in these rats at the 4th and 16th hours, and both results were comparable and therefore not significantly different but elevation in GGT level still persisted. In conclusion, data obtained from this study suggest that these agents may be capable of inducing GGT, although further study is required to establish a possible relationship between methionine and this enzyme in some other animal species. PMID- 22547185 TI - Effect of honey intake on serum cholesterol, triglycerides and lipoprotein levels in albino rats and potential benefits on risks of coronary heart disease. AB - The beneficial effect of honey has been widely reported particularly in the treatment of wounds and gastrointestinal tract disorders. However there is paucity of reports on its effect on the plasma high density lipoproteins (HDL), very low density lipoproteins (VLDL), low density lipoproteins (LDL) and triglycerides (TG) including cholesterol levels despite common consumption of honey worldwide including, Nigeria. The effect of the widely consumed unrefined Nigeria honey on plasma HDL, VLDL, LDL, TG, cholesterol and cardiovascular risk predictive index (CVPI) was studied using 20 adult male albino rats to ascertain its scientific and clinical relevance. The rats were randomly assigned into 2 groups, the control and honey-fed (test) groups, ten in each group. The rats weighed between 190-200gm at the start of the study. The control group was fed on normal rat (Pfizer-Nigeria) while the test group was fed on normal rat feed and honey (1ml of honey was added to 10ml of drinking water given once every day) for 22 weeks. At the end of the experiment, the rats were anesthetized with thiopentone sodium and blood collected by cardiac puncture. Serum TG, HDL, VLDL, LDL and total cholesterol in the control and the test groups were determined. The results showed significant increase in the level of plasma TG, HDL, and VLDL in the test group when compared with the control group. In contrast, there were significant decreases in the levels of plasma LDL and total cholesterol in the test when compared with the control group. Computed values of CVPI showed significant increase in the test values compared to that of the control. It is concluded that consumption of unrefined Nigeria honey significantly improved lipid profile and computed cardiovascular disease predictive index in male albino rats. PMID- 22547186 TI - Effect of chloroquine phosphate and toxic concentrations of lead acetate on Ca2+ ATPase activity in isolates and clones of Plasmodium falciparum. AB - The basal activity of Ca2+-ATPase in two isolates (NL56, UNC) and two clones (D6, W2) of P.falciparum was assessed. The effects of various concentrations of chloroquine phosphate and toxic concentrations of lead acetate were also evaluated in the clones and strains of P.falciparum. The Ca2+-ATPase activity was measured by monitoring the rate of release of inorganic phosphate from the gamma position of ATP on spectrophotometer at 820nm wavelength. The various concentrations of chloroquine (3, 6, 9, 12, 18ug/ml) and lead acetate (5, 10, 20, 30, 40ug/ml) on Ca2+-ATPase activity were measured respectively. Chloroquine phosphate inhibited Ca2+-ATPase activity in both the isolates and the cloned strains of P.falciparum in concentration dependent manner. Median Inhibitory concentration of chloroquine (MIC50) estimated from the plot of activity against chloroquine concentration was found to be 2.6mg/ml at pH 7.4 for both the isolates and cloned strains examined. Lead acetate at concentrations 5-20ug/ml inhibited Ca2+-ATPase activity in concentration dependent manner in clone W2 (Chloroquine resistant strain) while the same range of concentrations of lead acetate stimulated the activity of the enzyme in clone D6 (Chloroquine sensitive strain).The inhibitory effect of lead acetate on the enzyme in clone D6 was observed at concentrations above 20ug/ml. The result also suggests that lead ions could modulate and moderate calcium ion homeostasis in P. falciparum via its effect on Ca2+-ATPase activity. Also sufficient influx of lead ions into P. falciparum may transform the biochemical or bioenergetics nature of chloroquine sensitive strain of P. falciparum (D6) to that similar to chloroquine resistant strain (W2). In conclusion, inhibition of Ca2+-ATPase activity of P.falciparum may be part of the mechanism of action of chloroquine in its use as chemotherapy for malaria. The study implies that populations simultaneously exposed to lead pollution and malaria infection may experience failure in chloroquine therapy. PMID- 22547188 TI - Predictors of asymptomatic malaria in pregnancy. AB - A number of studies have described malaria parasitaemia in pregnancy as mostly an asymptomatic condition, however information about predictors of asymptomatic malaria is largely lacking. We investigated the prevalence of symptoms and potential predictors of asymptomatic malaria in pregnant women attending Ante Natal Clinic (ANC) of two public maternity hospitals in Ibadan, Southwest Nigeria. Demographic data, history of previous and present pregnancy were obtained from the subjects and blood smears were examined for malaria diagnosis by light microscopy. Seventy - seven parasitaemic pregnant women attending antenatal clinic were evaluated for presence or absence of symptoms that may be associated with malaria. Thirty-seven women (48%) were asymptomatic whereas 40 (52%) presented with symptoms such as weakness, headache and general body ache and fever. Parasite density was significantly higher in symptomatic patients (P = 0.042), while asymptomatic patients had low level parasitaemia but significantly higher gametocyte carriage (P = 0.035). In conclusion, parasitaemic pregnant women resident in hyper- or holo-endemic malaria region are likely to be symptomatic with increasing density of the parasitaemia. PMID- 22547189 TI - Modulating effect of aqueous extract of Telfairia occidentalis on induced cyanide toxicity in rats. AB - The effect of lyophilised aqueous extract of Telfairia occidentalis (TO) on induced cyanide toxicity in rats was investigated. Twenty 3-week old male wistar albino rats were randomly distributed into one control and three treatment groups of five rats each: control group (group1), group treated with 3mg/kg body wt of cyanide only (group2), group treated with 3mg/kg body wt. each of cyanide and extract (group3), and a group treated with 3mg/kg Body wt of extract only (group4) were used for the investigation. Cyanide toxicity reduced both food and water intake (p<0.05), while the food intake was improved in group3, this effect of the extract on food was not observed on water intake. Cyanide reduced average body weight of rats significantly (p<0.05). The reduction effect of cyanide on body weight was countered by Telfairia occidentalis extract. The extract did not have an observable effect on rats' body weight. Ocular lesion was observed in 67% of rats in group2 . This ocular effect of cyanide was mitigated significantly by Telfairia occidentalis as only 17% of the rats in group3 had ocular lesion. Cyanide toxicity produced nasal discharge in 39% of the rat population in group2 while there was a partial but considerable reduction (21%) in the severity of nasal discharge in group 3. There was no significant difference (p>0.05) in the organ/body wt.ratio between the treatments and the control groups for all the organs examined in the study. Biochemical analysis of liver enzymes showed that cyanide (group2) damaged the liver as there was significantly elevated presence (p<0.05) of Aspartate aminotransferase (AST) and Alanine aminotransferase (ALP) above those of the control group. The damaging effect of cyanide on the liver was ameliorated by Telfairia occidentalis considerably.Histopathological effect of cyanide toxicity on the organs examined included multifocal degeneration and necrosis of the liver, mild kidney congestion and congestion of the brain. These effects were moderated mildly by Telfairia occidentalis. Group 4, treated with the vegetable alone had none of the observed histopathology in the organs examined. We concluded that lyophilised aqueous extracts of Telfairia occidentalis showed good potential as a safe antidote for cyanide poisoning when administered concomitantly or very shortly after ingestion of sub-lethal dose of cyanide. However, further bioassay guided fractionation and analytical studies are needed to identify the actual chemical compound or molecule in the vegetable responsible for or associated with the observed effects. PMID- 22547187 TI - Haematological values in pregnant women in Port Harcourt, Nigeria II: Serum iron and transferrin, total and unsaturated iron binding capacity and some red cell and platelet indices. AB - Previous studies on the normal values of serum iron, unsaturated iron binding capacity, total iron binding capacity, serum transferrin, percent transferrin saturation, red cell distribution width, and various platelet indices: Platelet count, mean platelet volume, platelet distribution width, plateletcrit and platelet larger cell ratio in pregnant subjects in Nigeria are relatively scanty. Present study aims to determine the values of these parameters in apparently healthy pregnant subjects residing in Port Harcourt south eastern Nigeria; and help establish normal reference ranges of these parameters for the population under reference. Cross sectional prospective study involving 220 female subjects attending for the first time, the ante-natal clinics of a tertiary health care facility in Port Harcourt. Subjects were divided into 73, 75 and 72 subjects in the first, second and third trimester of pregnancy respectively. Serum iron and unsaturated iron binding capacity, red cell distribution width, platelet count and platelet distribution width were determined by automated methods; total iron binding capacity, serum transferrin concentrations, percent transferrin saturation, mean platelet volume and plateletcrit were calculated using appropriate formulas. The values of serum iron, unsaturated iron binding capacity, total iron binding capacity and serum transferrin concentrations were found to show significant variations between the various trimesters of pregnancy. However, while serum iron showed significant decreases during pregnancy; unsaturated iron binding capacity, total iron binding capacity and serum transferrin concentrations were found to show significant increases during pregnancy amongst our subjects (p<0.05). By contrast the values of red cell distribution width, platelet count, mean platelet volume, platelet distribution width, plateletcrit and platelet larger cell ratio did not show any significant differences at the different trimesters of pregnancy in our subjects (p>0.05). The present study reports, for the first time, normative values for these parameters in apparently healthy pregnant subjects in Port Harcourt south eastern Nigeria. Apparently, increases in unsaturated and total iron binding capacity and serum transferrin values seen amongst our subjects with increasing gestation may perhaps be a mechanism to ensure a fetal adequate iron delivery on account of the decreasing serum iron concentration with gestation in our subjects. The study suggests that values of serum transferrin are perhaps a more useful screening tool for iron deficiency anemia during pregnancy amongst our subjects. PMID- 22547190 TI - Academic stress and menstrual disorders among female undergraduates in Uyo, South Eastern Nigeria - the need for health education. AB - The aim of this study was to determine the association between academic stress and menstrual disorders among female undergraduates in Uyo, South Eastern Nigeria. Three hundred and ninety-three (393) female students of the University of Uyo, ages between 16 and 35 years were randomly selected from different departments in the University, and studied during the 2009/2010 academic session. Menstrual history and Student's Stress Assessment Questionnaire (SSAQ) were used for this assessment. They were distributed for participants to fill out. Prevalence of menstrual disorder among participants was 34.6%. A direct association between menstrual disorder and academic stress was observed. Commonest menstrual disorder was menorrhagia (37.5%). Others were: Pre-menstrual Syndrome (PMS 33.1%), Oligomenorrhea 19.9% and amenorrhea 5.9% (P<0.05). Those who experienced academic stress had about 2 times chances of having menstrual disorders (OR : 2.0, C.I = 1.224-2.837) at P<0.05. This study demonstrated a significant association between academic stress and menstrual disorder among females undergraduate in Uyo, South Eastern Nigeria. PMID- 22547191 TI - Effects of a12-week endurance exercise program on adiposity and flexibility of Nigerian perimenopausal and postmenopausal women. AB - Menopause is a sign of aging in the woman. Loss of ovarian function induces a reduction in resting metabolic rate, physical energy expenditure, fat-free mass and abdominal adipose tissue accumulation. Location of adipose tissue deposit in abdominal region plays an important role in occurrence of hyperlipidemia, diabetes, hypertension and atherosclerosis. Although regular participation in physical exercise have been suggested to improve adiposity and body flexibility which are important health related components of physical fitness, few published studies are available on the effect of exercise on Nigerian menopausal women. This study investigated effects of a twelve-week endurance exercise program (EEP) on central and abdominal obesity as well as flexibility of perimenopausal and postmenopausal Nigerian women. The study employed a pretest- posttest control group design comprising a sample of 175 apparently healthy, literate, sedentary women within age range 40-59 years. They were workers in state and federal establishments in Ibadan North Local Government Area of Oyo State, Nigeria. Based on history of their last menstrual period, women with regular or irregular menstrual cycle status were allocated into perimenopausal group and those who no longer menstruated into postmenopausal group. A table of random numbers was used for further allocation into perimenopausal exercise group (PEMEG, 45), postmenopausal exercise group (POMEG, 45) perimenopausal control group (PEMCG, 42) and postmenopausal control group (POMCG, 43). Waist Hip Ratio (WHR), Body Mass Index (BMI) as well as Hip and Trunk Flexibility (HTF) were evaluated at baseline and 4weekly intervals until end of 12th week. EEP consisted of a 10 station circuit of cardiovascular endurance, flexibility, coordination, abdominal and pelvic floor muscle exercises. Data were analyzed using descriptive and inferential statistics. Mean age of participants was 52.3+/-4.1 years, 95% C.I (51.64-52.88) years. Significant reduction occurred between baseline and end of 12th week mean values of WHR in PEMEG (0.86 +/- 0.08 vs 0.71 +/- 0.07)and POMEG groups (0.88+/- 0.06 vs0.77 +/- 0.07) while significant increases were observed between baseline values and end of 12th week mean values of HTF in PEMEG (18.84 +/- 4.23vs28.27+/- 3.82) and POMEG (19.51 +/- 4.02vs25.97+/- 2.36) (p<0.05). Significant changes did not occur in BMI in both groups even though mean differences were observed in baseline values compared with end of 12th week mean values of these variables. In PEMCG and POMCG groups, there were no observable changes in mean values of WHR, BMI and HTF from baseline to end of study. Participation in endurance exercise program is essential for perimenopausal and postmenopausal Nigerian women for improved central and abdominal adiposity as well as flexibility. PMID- 22547192 TI - Sulphadoxine-pyrimethamine alters the antioxidant defense system in blood of rabbit. AB - Sulphadoxine-pyrimethamine (SP) despite reported resistance remains an important drug of choice for the treatment and control of malaria in most endemic areas. Exacerbation of intra-erythrocytic oxidative stress might contribute to the process of elimination of malaria parasites in the body. The effect of treatment with SP on the antioxidant defense system was investigated using rabbit as a model. Ten male rabbits were divided into two groups of five animals each. The first group was administered with normal saline and served as control. The second group received a single dose of SP (26.25mg/kg body weight). Blood samples were collected before and at 6, 12 and 24 h after drug administration. Activity of cellular enzymatic antioxidants, superoxide dismutase (SOD) and catalase (CAT), and level of reduced glutathione (GSH) were assayed using standard spectrophotometric methods. Serum lipid peroxidation was assessed by the formation of thiobarbituric acid reactive species (TBARS) while protein content was assayed by the method of Lowry et al., 1951. SOD activity was observed to increase progressively by 4.9, 63.4 and 120.8% at 6, 12 and 24 h respectively, after drug administration. Similarly, CAT activity increased by 44.5, 82.6 and 116.3% at 6, 12 and 24 h, respectively. TBARS level also increased significantly by 45.5, 118.2 and 186.4%, respectively. However, the level of GSH decreased by 41.9% at 6 h and remained so up till the 12 h, but by 24 h after drug administration, the level of the thiol substance has increased considerably up to 48.4% above the baseline level. SP treatment altered the antioxidant defense system in blood and may therefore induce oxidative stress by generating reactive oxygen species. This might play significant role in the therapeutic and adverse effects associated with the drug. PMID- 22547193 TI - Antihypertensive properties of Allium sativum (garlic) on normotensive and two kidney one clip hypertensive rats. AB - Allium sativum (garlic) is reported to act as an antihypertensive amidst an inconsistency of evidence. In this study, we investigated the cardiovascular effects of aqueous garlic extracts (AGE) on normotensive and hypertensive rats using the two-kidney one-clip (2K1C) model. Mean arterial blood pressure (MAP) and heart rate (HR) were measured in normotensive and 2K1C rat models anesthetized with thiopentone sodium (50 mg/kg body weight i.p.) through the left common carotid artery connected to a recording apparatus. The jugular vein was cannulated for administration of drugs. Intravenous injection of AGE (5-20 mg/kg) caused a significant (p<0.05) decrease in both MAP and HR in a dose-dependent manner in both the normotensive and 2K1C models, with more effects on normotensive than 2K1C rat model. The dose of 20mg/kg of AGE significantly (p<0.05) reduced systolic (16.7 +/- 2.0%), diastolic (26.7 +/- 5.2%), MAP (23.1 +/- 3.6%) and HR (38.4 +/- 4.3%) in normotensive rats. In 2K1C group, it significantly reduced systolic (22.2 +/- 2.1 %), diastolic (30.6 +/- 3.2%), MAP (28.2 +/- 3.1%) and HR (45.2 +/- 3.5%) from basal levels. Pulse pressure was significantly elevated (33.3 +/-5.1%) in the 2K1C group. Pretreatment of the animals with muscarinic receptor antagonist, atropine (2 mg/kg, i.v.), did not affect the hypotensive and the negative chronotropic activities of the extract. AGE caused a decrease in blood pressure and bradycardia by direct mechanism not involving the cholinergic pathway in both normotensive and 2K1C rats, suggesting a likely involvement of peripheral mechanism for hypotension. PMID- 22547195 TI - First report of drug-induced esophagitis by deferasirox. AB - Deferasirox is a new oral iron chelator used to treat transfusional iron overload. We describe a case of a 79-year-old man with myelodysplastic syndrome (MDS) who developed esophagitis induced by deferasirox. He repeatedly received multiple red blood cell transfusions after a diagnosis of MDS. Two years after starting red blood cell transfusions, he was diagnosed with iron overload, and was then started on deferasirox at 1 g/day with about 400 ml of water. He was admitted to our institution because he was unable to swallow his own saliva 1 month after starting deferasirox. Esophagogastroendoscopy revealed white-coated mucosa covering the entire esophagus. A component analysis of biopsy specimens using high-performance liquid chromatography identified deferasirox. Symptoms resolved within about 2 weeks after discontinuing deferasirox, and repeated endoscopy showed marked improvement of esophagitis after 1 month. Re administration of deferasirox was not attempted. Unfortunately, the patient died due to pneumonia 6 months after administration of deferasirox was started. This is the first report of drug-induced esophagitis associated with deferasirox. PMID- 22547197 TI - Perceptual fluency can be used as a cue for categorization decisions. AB - Learning in the prototype distortion task is thought to involve perceptual learning in which category members experience an enhanced visual response (Ashby & Maddox. Annual Review of Psychology, 56, 149-178, 2005). This response likely leads to more-efficient processing, which in turn may result in a feeling of perceptual fluency for category members. We examined the perceptual-fluency hypothesis by manipulating fluency independently from category membership. We predicted that when perceptual fluency was induced using subliminal priming, this fluency would be misattributed to category membership and would affect categorization decisions. In a prototype distortion task, the participants were more likely to judge stimuli that were not members of the category as category members when the nonmembers were made perceptually fluent with a matching subliminal prime. This result suggests that perceptual fluency can be used as a cue during some categorization decisions. In addition, the results provided converging evidence that some types of categorization are based on perceptual learning. PMID- 22547196 TI - Initial low-dose valganciclovir as a preemptive therapy is effective for cytomegalovirus infection in allogeneic hematopoietic stem cell transplant recipients. AB - Preemptive therapy for cytomegalovirus (CMV) infection in allogeneic hematopoietic stem cell transplant (HSCT) patients is effective in decreasing the incidence of CMV disease. Intravenous ganciclovir is a commonly used preemptive therapy, but as we have recently shown, oral valganciclovir (VGC) is a useful alternative. However, the optimal dose of VGC has not been determined. We prospectively evaluated the efficacy and toxicity of an initial low-dose of VGC (900 mg QD) as preemptive therapy in 20 patients with low-level CMV antigenemia following allogeneic HSCT. Patients were screened weekly for CMV pp65 antigenemia after engraftment. Preemptive therapy with VGC (900 mg QD) was initiated if more than two CMV antigen-positive cells per 50,000 leukocytes were detected. CMV antigen-positive cells disappeared from all 20 patients after 14-29 days (median 20 days) of VGC treatment. None of the patients developed CMV disease nor did they require more than the conventional VGC dose (900 mg BID). Neutropenia (<500/MUL) developed in three patients who required granulocyte-colony stimulating factor support, but there were no other significant side effects. These observations suggest that the initial dose of VGC in preemptive therapy for CMV can be safely decreased to 900 mg QD for patients with low-level CMV antigenemia. PMID- 22547198 TI - Search for a diagnostic/prognostic biomarker for the brain cancer glioblastoma multiforme by 2D-DIGE-MS technique. AB - The prognosis of patients with glioblastoma multiforme, the most malignant adult glial brain tumor, remains poor in spite of advances in treatment procedures, including surgical resection, irradiation, and chemotherapy. Genetic heterogeneity of glioblastoma warrants extensive studies to gain a thorough understanding of the biology of this tumor. While there have been several studies of global transcript profiling of glioma with the identification of gene signatures for diagnosis and disease management, translation into clinics is yet to happen. In the present study, we report a novel proteomic approach by using two-dimensional difference gel electrophoresis followed by spot picking and analysis of proteins/peptides by Mass spectrometry. We report at least ten different novel proteins/peptides as identified by this technique which are differentially expressed in this cancer and could be of further importance for diagnostic, therapeutic, and prognostic approaches. PMID- 22547199 TI - The therapeutic function of the chemokine RANTES on the H22 hepatoma ascites model. AB - This study aimed at analyzing the therapeutic function of the chemokine RANTES on the H22 hepatoma ascites model and preliminarily explore the mechanism of RANTES in malignant ascites to provide an important reference for applying chemokines in anti-tumor therapy. The murine H22 hepatoma ascites model was used. Three treatment groups were analyzed: a RANTES treatment group, an IL-2 control group, and an NS control group. Two regimens of early treatment and late treatment were designed, and the therapeutic effect of RANTES on malignant ascites was studied by measuring changes in mouse body weight and abdominal circumference and observing the survival time. The expression of TNF-alpha, IFN-gamma, TGF-beta1, and MCP-1 in mouse ascites was detected by ELISA, and the chemotactic function of RANTES on B lymphocytes and T lymphocytes was analyzed by flow cytometry. In the early and late treatment regimens, RANTES could effectively inhibit the increase in mouse body weight and abdominal circumference in the murine H22 hepatoma ascites model. The secretion of TNF-alpha and IFN-gamma, which had anti-tumor effects, was higher in the RANTES treatment group than in the control groups (P < 0.05), whereas the secretion of TGF-beta1 and MCP-1, which promoted tumor growth, invasion, and metastasis, was lower than in the control groups (P < 0.05). RANTES had chemotactic effects on CD4(+) and CD8(+) T lymphocytes; therefore, the percentage of CD3, CD4, and CD8 in the mouse ascites in the RANTES treatment group was significantly higher than in the NS control and IL-2 treatment groups, and the CD4/CD8 ratio was also significantly higher. RANTES can effectively inhibit the increase in body weight and abdominal circumference and significantly extend survival time in mice in the H22 hepatoma ascites model. PMID- 22547200 TI - Inhibitory effect of Styrax Japonica Siebold et al. Zuccarini glycoprotein (38 kDa) on interleukin-1beta and induction proteins in chromium(VI)-treated BNL CL.2 cells. AB - Chromium(VI) [Cr(VI)] induces chronic inflammation in hepatocytes. Inflammation has been shown to play an important role in tumorigenesis, tumor progression, and metastasis. To examine the effects of the Styrax Japonica Siebold et al. Zuccarini (SJSZ) glycoprotein on inflammation in BNL CL.2 cells, we evaluated the activities of c-Jun NH(2)-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), nuclear factor (NF)-kappaB (p50 and p65), and inflammation-related factors [cyclooxygenase (COX)-2, inducible nitric oxide syntheses (iNOS) and interleukin (IL)-1beta] in Cr-induced BNL CL.2 cells using immunoblot analysis and RT-PCR. We also used two-dimensional gel electrophoresis (2-DE) to compare between treatments. To determine which proteins are induced by Cr(VI), we evaluated total protein lysates using 2-DE. After Cr(VI) treatment, total protein lysates were prepared and resolved by 2-DE. The results obtained from this study demonstrated that the SJSZ glycoprotein (50 MUg/ml) inhibits expression of JNK, ERK, NF-kappaB, and the expression of COX-2, iNOS, and IL-1beta. Moreover, the results obtained from 2DE showed that four proteins out of nine proteins were relatively expressed strongly, while the rest of them were relatively appeared weakly on the gel. Taken together, these data indicate that the SJSZ glycoprotein prevents expression of COX-2, iNOS, and IL-1beta by blocking NF-kappaB and MAPKs in Cr(VI)-induced BNL CL.2 cells. PMID- 22547201 TI - Passive stretch reduces calpain activity through nitric oxide pathway in unloaded soleus muscles. AB - Unloading in spaceflight or long-term bed rest induces to pronounced atrophy of anti-gravity skeletal muscles. Passive stretch partially resists unloading induced atrophy of skeletal muscle, but the mechanism remains elusive. The aims of this study were to investigate the hypotheses that stretch tension might increase protein level of neuronal nitric oxide synthase (nNOS) in unloaded skeletal muscle, and then nNOS-derived NO alleviated atrophy of skeletal muscle by inhibiting calpain activity. The tail-suspended rats were used to unload rat hindlimbs for 2 weeks, at the same time, left soleus muscle was stretched by applying a plaster cast to fix the ankle at 35 degrees dorsiflexion. Stretch partially resisted atrophy and inhibited the decreased protein level and activity of nNOS in unloaded soleus muscles. Unloading increased frequency of calcium sparks and elevated intracellular resting and caffeine-induced Ca(2+) concentration ([Ca(2+)]i) in unloaded soleus muscle fibers. Stretch reduced frequency of calcium sparks and restored intracellular resting and caffeine induced Ca(2+) concentration to control levels in unloaded soleus muscle fibers. The increased protein level and activity of calpain as well as the higher degradation of desmin induced by unloading were inhibited by stretch in soleus muscles. In conclusion, these results suggest that stretch can preserve the stability of sarcoplasmic reticulum Ca(2+) release channels which prevents the elevated [Ca(2+)]i by means of keeping nNOS activity, and then the enhanced protein level and activity of calpain return to control levels in unloaded soleus muscles. Therefore, stretch can resist in part atrophy of unloaded soleus muscles. PMID- 22547203 TI - Biologic differences between various inhibitors of the BLyS/BAFF pathway: should we expect differences between belimumab and other inhibitors in development? AB - For the first time in more than 50 years, the US Food and Drug Administration has approved a drug specifically for the treatment of systemic lupus erythematosus (SLE). This drug, belimumab, is a monoclonal antibody that neutralizes the B-cell survival factor, B-lymphocyte stimulator (BLyS). Although belimumab has demonstrated a very favorable safety profile, many SLE patients have failed to clinically improve from belimumab therapy. Three additional BLyS antagonists (atacicept, blisibimod, tabalumab) are currently undergoing clinical testing. These antagonists subtly differ from belimumab in their biologic targets, and each is administered through a route (subcutaneous) that differs from the route through which belimumab is currently delivered (intravenous). Whether these differences will have meaningful consequences for efficacy and safety remains to be determined. PMID- 22547205 TI - An innovative approach for locally advanced stage III cutaneous melanoma: radiotherapy, followed by nodal dissection. AB - Patients with advanced nodal melanoma are typically managed with a regional nodal dissection; however, they have a high rate of distant relapse after surgery. This study assesses the role of preoperative radiotherapy to assist with the regional control in this subset of patients. Patients who had histologically confirmed stage III malignant melanoma and were treated with preoperative radiotherapy between 2004 and 2011 were eligible. All patients were staged with computer tomography and most with [F]-fluorodeoxyglucose (FDG) PET. Patients received preoperative radiotherapy, followed by a planned regional dissection at 12-14 weeks from completion with assessment of clinical, radiological and pathological responses. The primary outcome measure was the 1-year actuarial in-field control. There were 12 patients, with nine having disease of the axilla. All patients received radiotherapy up to a median dose of 48 Gy in 20 fractions, with seven patients achieving a partial clinical response. Ten patients proceeded to surgery, with four patients developing minor wound complications. The FDG-PET response did not appear to correlate with the pathological response. The 1-year in-field control rate was 92% (95% confidence interval 54-99) and the 1-year relapse-free survival was 54% (95% confidence interval 21-78). For selected patients with high-volume regional disease, we have successfully used preoperative radiotherapy, followed by a nodal dissection. Whether this type of protocol is of value in a more general group of patients with high-volume regional disease is currently under investigation. PMID- 22547204 TI - Human cyclooxygenase-1 activity and its responses to COX inhibitors are allosterically regulated by nonsubstrate fatty acids. AB - Recombinant human prostaglandin endoperoxide H synthase-1 (huPGHS-1) was characterized. huPGHS-1 has a single high-affinity heme binding site per dimer and exhibits maximal cyclooxygenase (COX) activity with one heme per dimer. Thus, huPGHS-1 functions as a conformational heterodimer having a catalytic monomer (E(cat)) with a bound heme and an allosteric monomer (E(allo)) lacking heme. The enzyme is modestly inhibited by common FAs including palmitic, stearic, and oleic acids that are not COX substrates. Studies of arachidonic acid (AA) substrate turnover at high enzyme-to-substrate ratios indicate that nonsubstrate FAs bind the COX site of E(allo) to modulate the properties of E(cat). Nonsubstrate FAs slightly inhibit huPGHS-1 but stimulate huPGHS-2, thereby augmenting AA oxygenation by PGHS-2 relative to PGHS-1. Nonsubstrate FAs potentiate the inhibition of huPGHS-1 activity by time-dependent COX inhibitors, including aspirin, all of which bind E(cat). Surprisingly, preincubating huPGHS-1 with nonsubstrate FAs in combination with ibuprofen, which by itself is a time independent inhibitor, causes a short-lived, time-dependent inhibition of huPGHS 1. Thus, in general, having a FA bound to E(allo) stabilizes time-dependently inhibited conformations of E(cat). We speculate that having an FA bound to E(allo) also stabilizes E(cat) conformers during catalysis, enabling half of sites of COX activity. PMID- 22547206 TI - Regional air pollution caused by dioxins from numerous emission sources: lessons from a domestic experience in Japan. AB - In this study, a large-scale field study was performed in order to distinguish between the contribution of the municipal solid waste incinerator and small clustered industrial waste incinerators in Fuchu city. The dioxin concentrations when only the municipal solid waste incinerator was being operated were found to range from 0.047 to 0.090 pg TEQ/m(3). The dioxin concentrations when only the clustered small industrial waste incinerators were being operated ranged from 0.085 to 0.25 pg TEQ/m(3). The concentrations in ambient air were more strongly affected by the clustered industrial waste incinerators than the municipal solid waste incinerator. Furthermore, the predicted concentrations by an atmospheric dispersion simulation model were consistent with the measured concentrations. From these results, the dioxin concentrations in ambient air were attributed primarily to the clustered small industrial waste incinerators. PMID- 22547207 TI - Unpacking the black box: countering the problem of inadequate intervention descriptions in research reports. PMID- 22547209 TI - Combined intravitreal ranibizumab and photodynamic therapy for polypoidal choroidal vasculopathy. AB - PURPOSE: To clarify the efficacy of combined therapy with intravitreal ranibizumab injections and photodynamic therapy in patients with symptomatic polypoidal choroidal vasculopathy. METHODS: We retrospectively reviewed 28 naive eyes of 28 patients (17 men, 11 women; mean age, 73.4 years; range, 55-85 years) with 20/40 or less baseline visual acuity treated with 3 consecutive monthly intravitreal injections of ranibizumab (0.5 mg/0.05 mL) and photodynamic therapy and followed-up for at least 12 months. Photodynamic therapy was administered 1 day or 2 days after the initial injection of ranibizumab. RESULTS: : The mean best-corrected visual acuity levels significantly (P < 0.0001) improved from 0.33 at baseline to 0.61 at 12 months. The mean improvement in best-corrected visual acuity 12 months from baseline was 2.65 lines. The best-corrected visual acuity at 12 months improved in 15 eyes (53.6%) by >=3 lines and was stable (defined as a loss of <3 lines of vision) in 13 eyes (46.4%). The central retinal thickness significantly (P < 0.0001) decreased from 366 um to 151 um at 12 months. The mean numbers of photodynamic therapy treatments and injections during 12 months including the treatments during the initial regimen were 1.1 and 3.7, respectively. No complications developed. CONCLUSION: Combined intravitreal ranibizumab and photodynamic therapy for polypoidal choroidal vasculopathy maintained or improved visual acuity and reduced the exudation without adverse events. PMID- 22547210 TI - Grape marc extract acts as elicitor of plant defence responses. AB - Plant protection based on novel alternative strategies is a major concern in agriculture to sustain pest management. The marc extract of red grape cultivars reveals plant defence inducer properties. Treatment with grape marc extract efficiently induced hypersensitive reaction-like lesions with cell death evidenced by Evans Blue staining of tobacco leaves. Examination of the infiltration zone and the surrounding areas under UV light revealed the accumulation of autofluorescent compounds. Both leaf infiltration and a foliar spray of the red grape extract on tobacco leaves induced defence gene expression. The PR1 and PR2 target genes were upregulated locally and systemically in tobacco plants following grape marc extract treatment. The grape extract elicited an array of plant defence responses making this natural compound a potential phytosanitary product with a challenging issue and a rather attractive option for sustainable agriculture and environmentally friendly practices. PMID- 22547211 TI - The effects of glyphosate and aminopyralid on a multi-species plant field trial. AB - In the United States, the US EPA has the responsibility for the registration of pesticides. For the protection of nontarget terrestrial plants this requires two simple greenhouse tests (seedling emergence and vegetative vigor), each done with ten species grown individually. Indications of unacceptable effects levels equivalent to environmental exposure can lead to field testing which is not well defined. Our objective was to develop a regional field test that is simple, economical, geographically flexible and with endpoints of ecological significance and compare the results with the standard greenhouse tests. Three native Oregon plant species were grown together with an introduced species. The experiment was replicated at two locations and repeated for 3 years with glyphosate applied at 0, 0.01 (8.3 g/ha), 0.1 (83.2 g/ha), and 0.2 (166.4 g/ha) * FAR (Field Application Rate of 832 gm/ha acid equivalent) and 2 years with aminopyralid applied at 0, 0.037 (4.6 g/ha), 0.136 (16.7 g/ha), and 0.5 (61.5 g/ha) * FAR (123 g/ha acid equivalent). With glyphosate, plant height and volume decreased with increasing herbicide concentration for all species, and for nearly all farm * year combinations. With aminopyralid, one species died at nearly all concentrations, sites and years, while the effects on the other three species were less pronounced and variable. The relative rank in glyphosate sensitivity among species in the field studies differed from the ranking from greenhouse studies, with Cynososurs echinatus the most sensitive in the field but Prunella vulgaris the most sensitive in the greenhouse. With aminopyralid, sensitivity generally was similar for all species in the greenhouse as in the field. The results suggest that a simple field test can be successfully designed to investigate the ecological effects of herbicides on plant communities and supplement information gained from greenhouse tests performed in controlled environments. PMID- 22547212 TI - Anular delamination strength of human lumbar intervertebral disc. AB - INTRODUCTION: Progression of intervertebral disc (IVD) herniation does not occur exclusively in a linear manner through the anulus fibrosus (AF), but can migrate circumferentially due to localized AF delamination. Consequently, resistance to delamination is an important factor in determining risk of herniation progression. The inter-lamellar matrix located between the AF layers is responsible for resisting this delamination; however, its mechanical properties are largely unknown. This study aimed to determine the mechanical properties of the inter-lamellar matrix in human AF samples via a peel test. MATERIALS AND METHODS: Seventeen human IVDs (degeneration grades of 2-3) were obtained from six lumbar spines. From these 17 discs, 53 tissue samples were obtained from the superficial and deep regions of the anterior and posterior AF. Samples were dissected into a 'T' configuration to facilitate a T-peel test (or 180-degree peel test) by initiating delamination between the two middle AF layers. RESULTS: Peel strength was found to be 33 % higher in tissues obtained from the superficial AF region as compared with the deep region (p = 0.047). CONCLUSION: This finding may indicate a higher resistance to delamination in the superficial AF, and as a result, delamination and herniation progression may occur more readily in the deeper layers of the AF. PMID- 22547216 TI - Targeted therapies: Manufacturer sponsorship bias in economic analyses matters. PMID- 22547213 TI - A retrospective study of congenital osseous anomalies at the craniocervical junction treated by occipitocervical plate-rod systems. AB - PURPOSE: To evaluate the effectiveness of posterior occipitocervical reconstruction using the anchors of cervical pedicle screws and plate-rod systems for patients with congenital osseous anomalies at the craniocervical junction. METHODS: Twenty patients with congenital osseous lesions who underwent posterior occipitocervical fusion using the anchors of cervical pedicle screws and plate rod systems for reduction and fixation from 1996 to 2009 were reviewed. The lesions included os odontoideum, occipitalization of the atlas, congenital C2-3 fusion, congenital atlantoaxial subluxation, congenital basilar invagination and combined anomalies. The clinical assessment and the measurements of the images were performed preoperatively, postoperatively and at most recent follow-up. RESULTS: The combined deformity of flexion of the occipitoatlantoaxial complex and invagination of the odontoid process associated with congenital osseous lesions at the craniocervical junction was corrected by application of combined forces of extension and distraction between the occiput and the cervical pedicle screws. Preoperative myelopathy improved in 94.7% patients. The mean Ranawat value, Redlund-Johnnell value, atlantodental distance, occiput (O)-C2 angle, and C2-C7 lordosis angle improved postoperatively and was sustained at most recent follow-up. The mean cervicomedullary angle improved from 129.3 degrees preoperatively to 153.3 degrees postoperatively. The mean range of motion at the lower adjacent motion segment remained unchanged at most recent follow-up. The fusion rate was 95%. CONCLUSIONS: The results of the present study indicate that posterior occipitocervical reconstruction using the anchors of cervical pedicle screws and plate-rod systems is an effective technique for treatment of deformities and/or instability caused by congenital osseous anomalies at the craniocervical junction. PMID- 22547215 TI - Gastrointestinal cancer: Salvage chemotherapy in gastric cancer--more than a straw? PMID- 22547217 TI - Haematological cancer: Gemtuzumab ozogamicin in acute myeloid leukaemia. PMID- 22547218 TI - The treatment of severe hepatitis B virus reactivation after chemotherapy. PMID- 22547219 TI - Palliative care: Analgesia prescribing in the USA--no gain, much pain. PMID- 22547202 TI - Molecular and functional properties of P2X receptors--recent progress and persisting challenges. AB - ATP-gated P2X receptors are trimeric ion channels that assemble as homo- or heteromers from seven cloned subunits. Transcripts and/or proteins of P2X subunits have been found in most, if not all, mammalian tissues and are being discovered in an increasing number of non-vertebrates. Both the first crystal structure of a P2X receptor and the generation of knockout (KO) mice for five of the seven cloned subtypes greatly advanced our understanding of their molecular and physiological function and their validation as drug targets. This review summarizes the current understanding of the structure and function of P2X receptors and gives an update on recent developments in the search for P2X subtype-selective ligands. It also provides an overview about the current knowledge of the regulation and modulation of P2X receptors on the cellular level and finally on their physiological roles as inferred from studies on KO mice. PMID- 22547220 TI - CNS cancer: Don't hedge(hog) your bets. PMID- 22547222 TI - Retraction. Latitude affects degree of advancement in laying by birds in response to food supplementation: a meta-analysis. PMID- 22547221 TI - Improvement of cardiovascular risk prediction using coronary imaging: subclinical atherosclerosis: the memory of lifetime risk factor exposure. AB - Deaths from diseases of the heart are decreasing. Cardiovascular diseases (CVD) will be the main cause of morbidity and mortality in 2015 according to a WHO report. The main problem is related to the long-time delay between the start of the development of atherosclerosis in young adults and the manifestation many decades later. Despite a recent decline in a CVD mortality rate in men and women, the main problem is related to the acute manifestation as the acute coronary syndrome, which leads 30-50% of subjects to sudden and fatal outcomes. In addition, about 20% of first and recurrent acute myocardial infarctions are silent. The lifetime risk of coronary artery disease after 40 years is 49% for men and 32% for women. That means, we are confronted with a major health care problem. This is even more obvious, when the rate of coronary heart disease deaths out of the hospital are taken into account which amount to 70% in 2007. These data are confirmed for Europe despite a strong decline of hospital deaths. Another problem is related to the fact that the number of sudden cardiac death amounts to >300 000 in the general US population. It is about 10 times higher than in those patients who are defined as prone to sudden death due to low ejection fraction, ventricular arrhythmias, and acute myocardial infarction. For cardiologists, this general topic becomes even more obvious, because even well known cardiologists experienced early (<=65 years) sudden cardiac deaths such as RW Campbell, JM Isner, PA Poole-Wilson, H Drexler, and recently the paediatric cardiologist from Hannover, A Wessels. These events underline again what has been emphasized 15 years ago by the MONICA study that two-thirds of patients die outside the hospital and that we have to concentrate on primary and secondary prevention, also in memory of these colleagues. This review will demonstrate the potential value of coronary artery calcification screening which can be used as a sign of subclinical coronary arteriosclerosis for improved risk prediction, the first step to prevention. Subclinical atherosclerosis represents the vessel memory of risk factor exposure. PMID- 22547223 TI - Accumulation of instability in serial differentiation and reprogramming of parthenogenetic human cells. AB - Human leukocyte antigen-homozygous parthenogenetic stem cells (pSC) could provide a source of progenitors for regenerative medicine, lowering the need for immune suppression in patients. However, the high level of homozygosis and the lack of a paternal genome might pose a safety challenge for their therapeutic use, and no study so far has evaluated the spread and significance of gene expression changes across serial potency changes in these cells. We performed serial rounds of differentiation and reprogramming to assess pSC gene expression stability, likely of epigenetic source. We first derived pSC from activated MII oocytes, and differentiated them to parthenogenetic mesenchymal stem cells (pMSC). We then proceeded to induce pluripotency in pMSC by over expression of the four transcription factors Oct4, Sox2, Klf4 and c-Myc. pMSC-derived iPS (piPS) were further differentiated into secondary pMSC (pMSC-II). At every potency change, we characterized the obtained lines both molecularly and by functional differentiation, and performed an extensive genome-wide expression study by microarray analysis. Although overall gene expression of parthenogenetic cells resembled that of potency-matched biparental lines, significantly broader changes were brought about upon secondary differentiation of piPS to pMSC-II compared with matched biparental controls; our results highlight the effect of the interplay of epigenetic reprogramming on a monoparental background, as well as the importance of heterozygosis and biparental imprinting for stable epigenetic reprogramming. PMID- 22547225 TI - Thermal stability limits of proteins in solution and adsorbed on a hydrophobic surface. AB - A coarse-grained Monte Carlo simulation is used to study thermal denaturation of small proteins in an infinitely dilute solution and adsorbed on a flat hydrophobic surface. Intermolecular interactions are modeled using the Miyazawa Jernigan (MJ) knowledge-based potential for implicit solvent with the BULDG hydrophobicity scale. We analyze the thermal behavior of lysozyme for its prevalence of alpha-helices, fibronectin for its prevalence of beta-sheets, and a short single helical peptide. Protein dimensions and contact maps are studied in detail before and during isothermal adsorption and heating. The MJ potential is shown to correctly predict the native conformation in solution under standard conditions, and the anticipated thermal stabilization of adsorbed proteins is observed when compared with heating in solution. The helix of the peptide is found to be much less stable thermally than the helices of lysozyme, reinforcing the importance of long-range forces in defining the protein structure. Contact map analysis of the adsorbed proteins shows correlation between the hydrophobicity of the secondary structure and their thermal stability on the surface. PMID- 22547224 TI - A t(1;11) translocation linked to schizophrenia and affective disorders gives rise to aberrant chimeric DISC1 transcripts that encode structurally altered, deleterious mitochondrial proteins. AB - Disrupted-In-Schizophrenia 1 (DISC1) was identified as a risk factor for psychiatric illness through its disruption by a balanced chromosomal translocation, t(1;11)(q42.1;q14.3), that co-segregates with schizophrenia, bipolar disorder and depression. We previously reported that the translocation reduces DISC1 expression, consistent with a haploinsufficiency disease model. Here we report that, in lymphoblastoid cell lines, the translocation additionally results in the production of abnormal transcripts due to the fusion of DISC1 with a disrupted gene on chromosome 11 (DISC1FP1/Boymaw). These chimeric transcripts encode abnormal proteins, designated CP1, CP60 and CP69, consisting of DISC1 amino acids 1-597 plus 1, 60 or 69 amino acids, respectively. The novel 69 amino acids in CP69 induce increased alpha-helical content and formation of large stable protein assemblies. The same is predicted for CP60. Both CP60 and CP69 exhibit profoundly altered functional properties within cell lines and neurons. Both are predominantly targeted to mitochondria, where they induce clustering and loss of membrane potential, indicative of severe mitochondrial dysfunction. There is currently no access to neural material from translocation carriers to confirm these findings, but there is no reason to suppose that these chimeric transcripts will not also be expressed in the brain. There is thus potential for the production of abnormal chimeric proteins in the brains of translocation carriers, although at substantially lower levels than for native DISC1. The mechanism by which inheritance of the translocation increases risk of psychiatric illness may therefore involve both DISC1 haploinsufficiency and mitochondrial deficiency due to the effects of abnormal chimeric protein expression. GenBank accession numbers: DISC1FP1 (EU302123), Boymaw (GU134617), der 11 chimeric transcript DISC1FP1 exon 2 to DISC1 exon 9 (JQ650115), der 1 chimeric transcript DISC1 exon 4 to DISC1FP1 exon 4 (JQ650116), der 1 chimeric transcript DISC1 exon 6 to DISC1FP1 exon 3a (JQ650117). PMID- 22547226 TI - Essential features of Chiari II malformation in MR imaging: an interobserver reliability study--part 1. AB - PURPOSE: Brain MR imaging is essential in the assessment of Chiari II malformation in clinical and research settings concerning spina bifida. However, the interpretation of morphological features of the malformation on MR images may not always be straightforward. In an attempt to select those features that unambiguously characterize the Chiari II malformation, we investigated the interobserver reliability of all its well-known MR features. METHODS: Brain MR images of 79 children [26 presumed to have Chiari II malformation, 36 presumed to have no cerebral abnormalities, and 17 children in whom some Chiari II malformation features might be present; mean age 10.6 (SD 3.2; range, 6-16) years] were blindly and independently reviewed by three observers. They rated 33 morphological features of the Chiari II malformation as present, absent, or indefinable in three planes (sagittal, axial, and coronal). The interobserver reliability was assessed using kappa statistics. RESULTS: Twenty-three of the features studied turned out to be unreliable, whereas the interobserver agreement was almost perfect (kappa value > 0.8) for nine features (eight in the sagittal plane and one in the axial plane, but none in the coronal plane). CONCLUSIONS: This study presents essential features of the Chiari II malformation on MR images by ruling out the unreliable features. Using these features may improve the assessment of Chiari II malformation in clinical and research settings. PMID- 22547228 TI - Water in the gas phase. PMID- 22547227 TI - Diagnostic utility and correlation of tumor markers in the serum and cerebrospinal fluid of children with intracranial germ cell tumors. AB - PURPOSE: In order to predict whether tumor markers assist in the histopathologic diagnosis of germ cell tumors (GCTs), we analyzed the correlation of beta human chorionic gonadotropin (betahCG) and alpha-fetoprotein (AFP) in serum and cerebrospinal fluid (CSF) samples at baseline and subsequent follow-up examinations. METHOD: A retrospective study of patients diagnosed with intracranial GCTs between July 1985 and February 2011 at our institution was conducted to review clinical, surgical, radiological, laboratory, and histopathologic data. RESULTS: Of the 67 patients eligible for the study, 42 had germinomas and 25 non-germinomatous GCTs. At baseline, serum and CSF AFP agreed in 97.9 % of patients (Cohen's Kappa 0.93). Baseline betahCG samples agreed in only 72.5 % of patients (Cohen's Kappa 0.46). In most cases, values were higher in serum for AFP and in CSF for betahCG. ROC curves estimated from logistic regression model indicated that CSF and serum samples had almost equal diagnostic utility, and the DeLong test showed that the difference in area under curves was not statistically significant. During follow-up (185 paired CSF and serum values from 43 patients), 90.3 % of AFP values correlated between CSF and serum (Cohen's Kappa 0.22, showing fair agreement). For betahCG, 96.2 % of values agreed in serum and CSF (Cohen's Kappa 0.61). CONCLUSIONS: In some patients, intracranial GCTs can be diagnosed based solely upon positive serum AFP values. In addition, marker values from serum only may be sufficient to predict tumor relapse at interval follow-up examinations. PMID- 22547229 TI - Pressure effects on water vapour lines: beyond the Voigt profile. AB - A short overview of recent results on the effects of pressure (collisions) regarding the shape of isolated infrared lines of water vapour is presented. The first part of this study considers the basic collisional quantities, which are the pressure-broadening and -shifting coefficients, central parameters of the Lorentzian (and Voigt) profile and thus of any sophisticated line-shape model. Through comparisons of measured values with semi-classical calculations, the influences of the molecular states (both rotational and vibrational) involved and of the temperature are analysed. This shows the relatively unusual behaviour of H(2)O broadening, with evidence of a significant vibrational dependence and the fact that the broadening coefficient (in cm(-1) atm(-1)) of some lines increases with temperature. In the second part of this study, line shapes beyond the Voigt model are considered, thus now taking 'velocity effects' into account. These include both the influence of collisionally induced velocity changes that lead to the so-called Dicke narrowing and the influence of the dependence of collisional parameters on the speed of the radiating molecule. Experimental evidence of deviations from the Voigt shape is presented and analysed. The interest of classical molecular dynamics simulations, to model velocity changes, together with semi-classical calculations of the speed-dependent collisional parameters for line-shape predictions from 'first principles', are discussed. PMID- 22547230 TI - Spectroscopic measurement of the vapour pressure of ice. AB - We present a laser absorption technique to measure the saturation vapour pressure of hexagonal ice. This method is referenced to the triple-point state of water and uses frequency-stabilized cavity ring-down spectroscopy to probe four rotation-vibration transitions of at wavenumbers near 7180 cm(-1). Laser measurements are made at the output of a temperature-regulated standard humidity generator, which contains ice. The dynamic range of the technique is extended by measuring the relative intensities of three weak/strong transition pairs at fixed ice temperature and humidity concentration. Our results agree with a widely used thermodynamically derived ice vapour pressure correlation over the temperature range 0 degrees C to -70 degrees C to within 0.35 per cent. PMID- 22547231 TI - Development and recent evaluation of the MT_CKD model of continuum absorption. AB - Water vapour continuum absorption is an important contributor to the Earth's radiative cooling and energy balance. Here, we describe the development and status of the MT_CKD (MlawerTobinCloughKneizysDavies) water vapour continuum absorption model. The perspective adopted in developing the MT_CKD model has been to constrain the model so that it is consistent with quality analyses of spectral atmospheric and laboratory measurements of the foreign and self continuum. For field measurements, only cases for which the characterization of the atmospheric state has been highly scrutinized have been used. Continuum coefficients in spectral regions that have not been subject to compelling analyses are determined by a mathematical formulation of the spectral shape associated with each water vapour monomer line. This formulation, which is based on continuum values in spectral regions in which the coefficients are well constrained by measurements, is applied consistently to all water vapour monomer lines from the microwave to the visible. The results are summed-up (separately for the foreign and self) to obtain continuum coefficients from 0 to 20 000 cm(-1). For each water vapour line, the MT_CKD line shape formulation consists of two components: exponentially decaying far wings of the line plus a contribution from a water vapour molecule undergoing a weak interaction with a second molecule. In the MT_CKD model, the first component is the primary agent for the continuum between water vapour bands, while the second component is responsible for the majority of the continuum within water vapour bands. The MT_CKD model should be regarded as a semi-empirical model with strong constraints provided by the known physics. Keeping the MT_CKD continuum consistent with current observational studies necessitates periodic updates to the water vapour continuum coefficients. In addition to providing details on the MT_CKD line shape formulation, we describe the most recent update to the model, MT_CKD_2.5, which is based on an analysis of satellite- and ground-based observations from 2385 to 2600 cm(-1) (approx. 4 MUm). PMID- 22547232 TI - Water vapour foreign-continuum absorption in near-infrared windows from laboratory measurements. AB - For a long time, it has been believed that atmospheric absorption of radiation within wavelength regions of relatively high infrared transmittance (so-called 'windows') was dominated by the water vapour self-continuum, that is, spectrally smooth absorption caused by H(2)O--H(2)O pair interaction. Absorption due to the foreign continuum (i.e. caused mostly by H(2)O--N(2) bimolecular absorption in the Earth's atmosphere) was considered to be negligible in the windows. We report new retrievals of the water vapour foreign continuum from high-resolution laboratory measurements at temperatures between 350 and 430 K in four near infrared windows between 1.1 and 5 MUm (9000-2000 cm(-1)). Our results indicate that the foreign continuum in these windows has a very weak temperature dependence and is typically between one and two orders of magnitude stronger than that given in representations of the continuum currently used in many climate and weather prediction models. This indicates that absorption owing to the foreign continuum may be comparable to the self-continuum under atmospheric conditions in the investigated windows. The calculated global-average clear-sky atmospheric absorption of solar radiation is increased by approximately 0.46 W m(-2) (or 0.6% of the total clear-sky absorption) by using these new measurements when compared with calculations applying the widely used MTCKD (Mlawer-Tobin-Clough-Kneizys Davies) foreign-continuum model. PMID- 22547233 TI - The water vapour self- and water-nitrogen continuum absorption in the 1000 and 2500 cm(-1) atmospheric windows. AB - The pure water vapour and water-nitrogen continuum absorption in the 1000 and 2500 cm(-1) atmospheric windows has been studied using a 2 m base-length White type multi-pass cell coupled with a BOMEM DA3-002 Fourier transform infrared spectrometer. The measurements were carried out at the National Institute of Standards and Technology (NIST, Gaithersburg, MD) over the course of several years (2004, 2006-2007, 2009). New data on the H(2)O:N(2) continuum in the 1000 cm(-1) window are presented and summarized along with the other experimental results and the continuum model. The experimental data reported on the water vapour continuum in these atmospheric windows basically agree with the most reliable laboratory data from the other sources. The MT_CKD (Mlawer-Tobin-Clough Kneizys-Davies) continuum model significantly departs from the experimental data in both windows. The deviation observed includes the continuum magnitude, spectral behaviour and temperature dependence. In the 2500 cm(-1) region, the model does not allow for the nitrogen fundamental collision-induced absorption (CIA) band intensity enhancement caused by H(2)O:N(2) collisions and underestimates the actual absorption by over two orders of magnitude. The water vapour continuum interpretation as a typical CIA spectrum is reviewed and discussed. PMID- 22547234 TI - Absolute high spectral resolution measurements of surface solar radiation for detection of water vapour continuum absorption. AB - Solar-pointing Fourier transform infrared (FTIR) spectroscopy offers the capability to measure both the fine scale and broadband spectral structure of atmospheric transmission simultaneously across wide spectral regions. It is therefore suited to the study of both water vapour monomer and continuum absorption behaviours. However, in order to properly address this issue, it is necessary to radiatively calibrate the FTIR instrument response. A solar-pointing high-resolution FTIR spectrometer was deployed as part of the 'Continuum Absorption by Visible and Infrared radiation and its Atmospheric Relevance' (CAVIAR) consortium project. This paper describes the radiative calibration process using an ultra-high-temperature blackbody and the consideration of the related influence factors. The result is a radiatively calibrated measurement of the solar irradiation at the ground across the IR region from 2000 to 10 000 cm( 1) with an uncertainty of between 3.3 and 5.9 per cent. This measurement is shown to be in good general agreement with a radiative-transfer model. The results from the CAVIAR field measurements are being used in ongoing studies of atmospheric absorbers, in particular the water vapour continuum. PMID- 22547235 TI - Airborne and satellite remote sensing of the mid-infrared water vapour continuum. AB - Remote sensing of the atmosphere from space plays an increasingly important role in weather forecasting. Exploiting observations from the latest generation of weather satellites relies on an accurate knowledge of fundamental spectroscopy, including the water vapour continuum absorption. Field campaigns involving the Facility for Airborne Atmospheric Measurements research aircraft have collected a comprehensive dataset, comprising remotely sensed infrared radiance observations collocated with accurate measurements of the temperature and humidity structure of the atmosphere. These field measurements have been used to validate the strength of the infrared water vapour continuum in comparison with the latest laboratory measurements. The recent substantial changes to self-continuum coefficients in the widely used MT_CKD (Mlawer-Tobin-Clough-Kneizys-Davies) model between 2400 and 3200 cm(-1) are shown to be appropriate and in agreement with field measurements. Results for the foreign continuum in the 1300-2000 cm(-1) band suggest a weak temperature dependence that is not currently included in atmospheric models. A one-dimensional variational retrieval experiment is performed that shows a small positive benefit from using new laboratory-derived continuum coefficients for humidity retrievals. PMID- 22547236 TI - Recent advances in measurement of the water vapour continuum in the far-infrared spectral region. AB - We present a new derivation of the foreign-broadened water vapour continuum in the far-infrared (far-IR) pure rotation band between 24 MUm and 120 MUm (85-420 cm(-1)) from field data collected in flight campaigns of the Continuum Absorption by Visible and IR radiation and Atmospheric Relevance (CAVIAR) project with Imperial College's Tropospheric Airborne Fourier Transform Spectrometer (TAFTS) far-IR spectro-radiometer instrument onboard the Facility for Airborne Atmospheric Measurement (FAAM) BAe-146 research aircraft; and compare this new derivation with those recently published in the literature in this spectral band. This new dataset validates the current Mlawer-Tobin-Clough-Kneizys-Davies (MT CKD) 2.5 model parametrization above 300 cm(-1), but indicates the need to strengthen the parametrization below 300 cm(-1), by up to 50 per cent at 100 cm( 1). Data recorded at a number of flight altitudes have allowed measurements within a wide range of column water vapour environments, greatly increasing the sensitivity of this analysis to the continuum strength. PMID- 22547237 TI - An adiabatic model for calculating overtone spectra of dimers such as (H(2)O)(2). AB - The near-infrared and visible wavelength spectrum of the water dimer is considered to be the major contributor to the so-called water continuum at these wavelengths. However, theoretical models of this spectrum require the simultaneous treatment of both monomer and dimer excitations. A model for treating this problem is proposed which is based upon a Franck-Condon-like separation between the monomer and dimer vibrational motions. In this model, one of the monomers is treated as the chromophore and its absorption is assumed to be given by its, possibly perturbed, vibrational band intensity. The main computational issue is the treatment of separate monomer and dimer motions. Various approaches for obtaining dimer vibration-rotation tunnelling spectra that allow for monomer motion are explored. These approaches include ways of treating the adiabatic separation of dimer vibrational modes from monomer vibrational modes. We classify the adiabatic separation methods under four main approaches: namely fixed-geometry, free-monomer, perturbed-monomer and coupled-monomer methods. The latter being the most computationally expensive as the monomer wave functions are dependent on the dimer coordinates. For each of these approaches, expectation values over the full potential are calculated for the given monomer vibrational wave functions. Various full (named VAP 2pD in the text) and partial (VAP (+p)D) averaging techniques are outlined to calculate the vibrationally averaged, monomer state-dependent, dimer interaction potentials. The computational costs associated with application of these techniques to the water dimer are estimated and the prospects for full calculations based on this approach are assessed. PMID- 22547238 TI - Infrared shifts of the water dimer from the fully flexible ab initio HBB2 potential. AB - We report calculations of the infrared shifts for the water dimer, as obtained from the recent ab initio fully flexible HBB2 potential of Bowman and co-workers. The rovibrational calculations, which formally are 12-dimensional plus overall rotation, were performed within the [6+6]d adiabatic separation which decouples the 'fast' intramolecular modes from the 'slow' intermolecular ones. Apart from this decoupling, each set of modes is treated in a fully variational approach. The intramolecular motion was described in terms of Radau coordinates, using the f-embedding formulation of Wei & Carrington, and neglecting the rovibrational Coriolis coupling terms. Within this adiabatic approximation, the intermolecular motion is handled in a similar way as for rigid monomers, except for the rotational constants B's, averaged over intramolecular modes that depend now on the intermolecular geometry. Comparison with experimental data shows an excellent overall agreement. PMID- 22547239 TI - H(2)O--N(2) collision-induced absorption band intensity in the region of the N(2) fundamental: ab initio investigation of its temperature dependence and comparison with laboratory data. AB - The present paper aims at ab initio and laboratory evaluation of the N(2) collision-induced absorption band intensity arising from interactions between N(2) and H(2)O molecules at wavelengths of around 4 MUm. Quantum chemical calculations were performed in the space of five intermolecular coordinates and varying N--N bond length using Moller-Plesset perturbation and CCSD(T) methods with extrapolation of the electronic energy to the complete basis set. This made it possible to construct the intermolecular potential energy surface and to define the surface of the N--N dipole derivative with respect to internal coordinate. The intensity of the nitrogen fundamental was then calculated as a function of temperature using classical integration. Experimental spectra were recorded with a BOMEM DA3-002 FTIR spectrometer and 2 m base-length multipass White cell. Measurements were conducted at temperatures of 326, 339, 352 and 363 K. The retrieved water-nitrogen continuum significantly deviates from the MT_CKD model because the relatively strong nitrogen absorption induced by H(2)O was not included in this model. Substantial uncertainties in the measurements of the H(2)O-N(2) continuum meant that quantification of any temperature dependence was not possible. The comparison of the integrated N(2) fundamental band intensity with our theoretical estimates shows reasonably good agreement. Theory indicates that the intensity as a function of temperature has a minimum at approximately 500 K. PMID- 22547240 TI - State-resolved spectroscopy of high vibrational levels of water up to the dissociative continuum. AB - We summarize here our experimental studies of the high rovibrational energy levels of water. The use of double-resonance vibrational overtone excitation followed by energy-selective photofragmentation and laser-induced fluorescence detection of OH fragments allowed us to measure previously inaccessible rovibrational energies above the seventh OH-stretch overtone. Extension of the experimental approach to triple-resonance excitation provides access to rovibrational levels via transitions with significant transition dipole moments (mainly OH-stretch overtones) up to the dissociation threshold of the O-H bond. A collisionally assisted excitation scheme enables us to probe vibrations that are not readily accessible via pure laser excitation. Observation of the continuous absorption onset yields a precise value for the O-H bond dissociation threshold, 41 145.94 +/- 0.15 cm(-1). Finally, we detect long-lived resonances as sharp peaks in spectra above the dissociation threshold. PMID- 22547241 TI - Global spectroscopy of the water monomer. AB - Given the large energy required for its electronic excitation, the most important properties of the water molecule are governed by its ground potential energy surface (PES). Novel experiments are now able to probe this surface over a very extended energy range, requiring new theoretical procedures for their interpretation. As part of this study, a new, accurate, global spectroscopic quality PES and a new, accurate, global dipole moment surface are developed. They are used for the computation of the high-resolution spectrum of water up to the first dissociation limit and beyond as well as for the determination of Stark coefficients for high-lying states. The water PES has been determined by combined ab initio and semi-empirical studies. As a first step, a very accurate, global, ab initio PES was determined using the all-electron, internally contracted multi reference configuration interaction technique together with a large Gaussian basis set. Scalar relativistic energy corrections are also determined in order to move the energy determinations close to the relativistic complete basis set full configuration interaction limit. The electronic energies were computed for a set of about 2500 geometries, covering carefully selected configurations from equilibrium up to dissociation. Nuclear motion computations using this PES reproduce the observed energy levels up to 39 000 cm(-1) with an accuracy of better than 10 cm(-1). Line positions and widths of resonant states above dissociation show an agreement with experiment of about 50 cm(-1). An improved semi-empirical PES is produced by fitting the ab initio PES to accurate experimental data, resulting in greatly improved accuracy, with a maximum deviation of about 1 cm(-1) for all vibrational band origins. Theoretical results based on this semi-empirical surface are compared with experimental data for energies starting at 27 000 cm(-1), going all the way up to dissociation at about 41 000 cm(-1) and a few hundred wavenumbers beyond it. PMID- 22547242 TI - Water in exoplanets. AB - Exoplanets--planets orbiting around stars other than our own Sun--appear to be common. Significant research effort is now focused on the observation and characterization of exoplanet atmospheres. Species such as water vapour, methane, carbon monoxide and carbon dioxide have been observed in a handful of hot, giant, gaseous planets, but cooler, smaller planets such as Gliese 1214b are now analysable with current telescopes. Water is the key chemical dictating habitability. The current observations of water in exoplanets from both space and the ground are reviewed. Controversies surrounding the interpretation of these observations are discussed. Detailed consideration of available radiative transfer models and linelists are used to analyse these differences in interpretation. Models suggest that there is a clear need for data on the pressure broadening of water transitions by H(2) at high temperatures. The reported detections of water appear to be robust, although final confirmation will have to await the better quality observational data provided by currently planned dedicated space missions. PMID- 22547243 TI - Models of very-low-mass stars, brown dwarfs and exoplanets. AB - Within the next few years, GAIA and several instruments aiming to image extrasolar planets will be ready. In parallel, low-mass planets are being sought around red dwarfs, which offer more favourable conditions, for both radial velocity detection and transit studies, than solar-type stars. In this paper, the authors of a model atmosphere code that has allowed the detection of water vapour in the atmosphere of hot Jupiters review recent advances in modelling the stellar to substellar transition. The revised solar oxygen abundances and cloud model allow the photometric and spectroscopic properties of this transition to be reproduced for the first time. Also presented are highlight results of a model atmosphere grid for stars, brown dwarfs and extrasolar planets. PMID- 22547244 TI - Water in star- and planet-forming regions. AB - In this paper, we discuss the astronomical search for water vapour in order to understand the disposition of water in all its phases throughout the processes of star and planet formation. Our ability to detect and study water vapour has recently received a tremendous boost with the successful launch and operation of the Herschel Space Observatory. Herschel spectroscopic detections of numerous transitions in a variety of astronomical objects, along with previous work by other space-based observatories, will be threaded throughout this paper. In particular, we present observations of water tracing the earliest stage of star birth where it is predominantly frozen as ice. When a star is born, the local energy release by radiation liberates ices in its surrounding envelope and powers energetic outflows that appear to be water factories. In these regions, water plays an important role in the gas physics. Finally, we end with an exploration of water in planet-forming discs surrounding young stars. The availability of accurate molecular data (frequencies, collisional rate coefficients and chemical reaction rates) is crucial to analyse the observations at each of these steps. PMID- 22547245 TI - The zone of social abandonment in cultural geography: on the street in the United States, inside the family in India. AB - This essay examines the spaces across societies in which persons with severe mental illness lose meaningful social roles and are reduced to "bare life." Comparing ethnographic and interview data from the United States and India, we suggest that these processes of exclusion take place differently: on the street in the United States, and in the family household in India. We argue that cultural, historical, and economic factors determine which spaces become zones of social abandonment across societies. We compare strategies for managing and treating persons with psychosis across the United States and India, and demonstrate that the relative efficiency of state surveillance of populations and availability of public social and psychiatric services, the relative importance of family honor, the extent to which a culture of psychopharmaceutical use has penetrated social life, and other historical features, contribute to circumstances in which disordered Indian persons are more likely to be forcefully "hidden" in domestic space, whereas mentally ill persons in the United States are more likely to be expelled to the street. However, in all locations, social marginalization takes place by stripping away the subject's efficacy in social communication. That is, the socially "dead" lose communicative efficacy, a predicament, following Agamben, we describe as "bare voice." PMID- 22547246 TI - ESWT for tendinopathy: technology and clinical implications. AB - PURPOSE: The general consensus that tendinopathy, at least in the chronic stage, is mainly a degenerative condition and inflammation plays a minor role has led to a shift from treatments that target inflammation towards treatment options that promote regeneration. One of these treatments is extracorporeal shockwave therapy (ESWT), a physical therapy modality that uses pressure waves to treat tendinopathy. This review was undertaken to give an overview of the literature concerning this treatment, and special attention is given to the differences between focused and radial ESWT. METHODS: A narrative description of wave characteristics, generation methods and in vitro effects of ESWT is given. The literature on ESWT as a treatment for one common tendinopathy, patellar tendinopathy, was systematically reviewed. RESULTS: Waves that are generated for focused and radial ESWT have very different physical characteristics. It is unclear how these characteristics are related to clinical effectiveness. Studies into the biological effects of ESWT have mainly used focused shockwave therapy, showing a number of effects of shockwaves on biological tissue. The systematic review of studies into the clinical effects of ESWT for patellar tendinopathy showed conflicting evidence for its effectiveness. CONCLUSION: Physical characteristics of focused and radial waves differ substantially, but effect on clinical effectiveness is unclear. Whereas in vitro studies often show the effects of ESWT on tendon tissue, results of clinical studies are inconsistent. Based on the review of the literature, suggestions are given for the use of ESWT in clinical practice regarding timing and treatment parameters. PMID- 22547247 TI - Failure of tibial polyethylene insert locking mechanism in posterior stabilized arthroplasty. AB - Tibial insert locking mechanisms are intended to limit interface motion and to prevent backside wear in contemporary modular knee designs. The author describes a case of failure of the polyethylene insert locking mechanism in one design of primary total knee arthroplasty. Loosening of the locking clip was observed within 6 weeks of the index operation without any trauma. The possible mechanism of disengagement is discussed. This rare cause for knee failure has to be recognized because it leads to early revision. PMID- 22547248 TI - Percutaneous lateral ulnar collateral ligament reconstruction. AB - PURPOSE: Open surgical reconstruction of the lateral ulnar collateral ligament is the standard treatment for symptomatic posterolateral rotatory instability of the elbow. It involves dissection and retraction of the lateral elbow muscles, which have been shown to be secondary stabilizers of the lateral elbow. We introduce a new muscle-protecting technique for single-strand lateral ulnar collateral ligament reconstruction and report on the isometry and primary stability when compared with a conventional muscle-splitting procedure. It was hypothesized that percutaneous lateral ulnar collateral ligament reconstruction provided isometry over the range of motion and that stability was comparable with a conventional open procedure. METHODS: In sixteen human cadaver arms, the intact and the lateral collateral ligament complex-deficient situation was tested. Open lateral ulnar collateral ligament reconstruction was performed using a single-strand palmaris graft with humeral and ulnar tenodesis screw fixation. Posterolateral rotational stability was compared with a new reconstruction method, which percutaneously places a single-strand palmaris graft with humeral and ulnar tenodesis screw fixation. RESULTS: Both open and percutaneous lateral ulnar collateral ligament reconstruction provided isometry over the range of motion and restored posterolateral stability to that of the intact situation. No significant differences between open and percutaneous reconstruction were found. CONCLUSIONS: Percutaneous lateral ulnar collateral ligament reconstruction aims to preserve the lateral elbow muscles and to minimize soft tissue dissection. It has been shown that in an in vitro setup, this new procedure provides isometry over the range of motion and sufficiently restores posterolateral rotatory stability. PMID- 22547249 TI - Prospective clinical and radiological two-year results after patellofemoral arthroplasty using an implant with an asymmetric trochlea design. AB - PURPOSE: The purpose was to prospectively evaluate the two-year results after implantation of the Journey PFJ((r)) (Smith & Nephew, Andover, MA). The authors hypothesized that patellofemoral arthroplasty would result in improved outcomes after 24 months in patients treated with an isolated procedure as well as in patients demonstrating concomitant patellofemoral instability (PFI), which were treated with a combined surgical procedure. METHODS: Patients were included between 02/2006 and 08/2008. According to the history and clinical findings, patients were grouped into group I with no history or clinical signs of PFI, and patients with concomitant PFI were assorted to group II. Patients were then treated with an isolated (group I) or a combined (group II) surgical procedure to additionally treat the PFI. Visual analogue scale (VAS), Lysholm score and WOMAC score were recorded preoperatively, 6, 12 and 24 months postoperatively. Patellar height was evaluated according to the index of Caton-Deschamps (CDI), and osteoarthritic changes were evaluated according to Kellgren and Lawrence. RESULTS: A total of 25 patients were enrolled, of them three discontinued interventions and were excluded from final analysis. An isolated implantation of the Journey PFJ((r)) was performed in 14 patients (group I) and a combined procedure in 8 (group II). Daily pain and clinical scores significantly improved at 6, 12 and 24 months compared to preoperative values (P < 0.05). Significant decrease (P = 0.02) of mean CDI could be noticed. Significant increase in tibiofemoral OA within the medial but not in the lateral tibiofemoral joint was assessed (P = 0.011; n.s.). CONCLUSIONS: Patellofemoral arthroplasty using the Journey((r)) PFJ for treatment of significant patellofemoral OA demonstrated improved clinical scores at the 2-year follow-up in both groups. Comparing the primary OA (I) and OA + instability (II) groups, patients with patellofemoral OA treated with a combined procedure for concomitant stabilization of patellofemoral instability may benefit more from such a combined procedure, than patients treated with an isolated procedure for treatment of isolated patellofemoral OA. LEVEL OF EVIDENCE: Prospective case series, Level III. PMID- 22547250 TI - Bilateral idiopathic osteonecrosis of the major tubercle of the humerus. AB - Bilateral osteonecrosis of the tuberculum majus has not been reported in the literature. A case of bilateral avascular necrosis of the tuberculum majus is presented associated with smoking and occasional alcohol consumption as risk factors, which was successfully treated with non-operative treatment. LEVEL OF EVIDENCE: Case report, Level V. PMID- 22547251 TI - The effect of different doses of aerobic exercise training on exercise blood pressure in overweight and obese postmenopausal women. AB - OBJECTIVE: Abnormally elevated exercise blood pressure is associated with an increased risk of cardiovascular disease. Aerobic exercise training has been shown to reduce exercise blood pressure. However, it is unknown whether these improvements occur in a dose-dependent manner. The purpose of the present study was to determine the effect of different doses of aerobic exercise training on exercise blood pressure in obese postmenopausal women. METHODS: Participants (N = 404) were randomized to one of four groups--groups with 4, 8, or 12 kcal/kg of energy expenditure per week or a nonexercise control group--for 6 months. Exercise blood pressure was obtained during the 50-watt stage of a cycle ergometer maximal exercise test. RESULTS: There was a significant reduction in systolic blood pressure at 50 watts in the 4 kcal/kg per week (-10.9 mm Hg, P < 0.001), 8 kcal/kg per week (-9.9 mm Hg, P = 0.022), and 12 kcal/kg per week ( 13.7 mm Hg, P < 0.001) compared with control (-4.2 mm Hg). Only the highest exercise training dose significantly reduced diastolic blood pressure (-4.3 mm Hg, P = 0.033) compared with control. In addition, resting blood pressure was not altered after exercise training (P > 0.05) compared with control and was not associated with changes in exercise systolic (r = 0.09, P = 0.09) or diastolic (r = 0.10, P = 0.08) blood pressure. CONCLUSIONS: Aerobic exercise training reduces exercise blood pressure and may be more modifiable than changes in resting blood pressure. A high dose of aerobic exercise is recommended to successfully reduce both exercise systolic and diastolic blood pressure and therefore may attenuate the cardiovascular disease risk associated with abnormally elevated exercise blood pressure. PMID- 22547253 TI - Interpretation of ground-level ozone episodes with atmospheric stability index measurement. AB - PURPOSE: This paper presents a novel approach to interpret ground-level O(3) with the measured atmospheric stability index (ASI). METHODS: O(3) concentrations were monitored by automatic analysers at three types of stations: traffic site, residential site and regional background site in 2005, and the ASI was simultaneously measured by observing radon and its short-lived decay products. RESULTS: The observed results showed a clear annual variation of O(3) concentrations with a maximum in spring, relatively high at the regional background site over 120 ppb, and lower at the residential and traffic sites at about 70 ppb. ASI gives information about the dilution properties of the lower boundary layer and allows to highlight the relevant role of the dilution factor in determining atmospheric pollution events. We demonstrated the analysis of O(3) night peak episodes with vertical wind and ASI. CONCLUSIONS: With the advantage of ASI and vertical wind profiles, it was possible to isolate particular photochemical pollution phenomena of O(3) peaks from the free troposphere reservoir or formed by local reactions. This shows that the index constitutes a powerful and valuable tool for describing O(3) night-peak episodes at background station. PMID- 22547252 TI - Surgical menopause and nonvertebral fracture risk among older US women. AB - OBJECTIVE: The aim of this study was to determine whether older postmenopausal women with a history of bilateral oophorectomy before natural menopause (surgical menopause) have a higher risk of nonvertebral postmenopausal fracture than women with natural menopause. METHODS: We used 21 years of prospectively collected incident fracture data from the ongoing Study of Osteoporotic Fractures, a cohort study of community-dwelling women without previous bilateral hip fracture who were 65 years or older at enrollment, to determine the risk of hip, wrist, and any nonvertebral fracture. chi(2) and t tests were used to compare the two groups on important characteristics. Multivariable Cox proportional hazards regression models stratified by baseline oral estrogen use status were used to estimate the risk of fracture. RESULTS: Baseline characteristics differed significantly among the 6,616 women within the Study of Osteoporotic Fractures who underwent either surgical (1,157) or natural (5,459) menopause, including mean age at menopause (44.3 +/- 7.4 vs 48.9 +/- 4.9 y, P < 0.001) and current use of oral estrogen (30.2% vs 6.5%, P < 0.001). Fracture rates were not significantly increased for surgical versus natural menopause, even among women who had never used oral estrogen (hip fracture: hazard ratio [HR], 0.87; 95% CI, 0.63-1.21; wrist fracture: HR, 1.10; 95% CI, 0.78-1.57; any nonvertebral fracture: HR, 1.11; 95% CI, 0.93-1.32). CONCLUSIONS: These data provide some reassurance that the long term risk of nonvertebral fracture is not substantially increased for postmenopausal women who experienced premenopausal bilateral oophorectomy, compared with postmenopausal women with intact ovaries, even in the absence of postmenopausal estrogen therapy. PMID- 22547254 TI - Approach for detecting mutagenicity of biodegraded and ozonated pharmaceuticals, metabolites and transformation products from a drinking water perspective. AB - Many pharmaceuticals and related metabolites are not efficiently removed in sewage treatment plants and enter into surface water. There, they might be subject of drinking water abstraction and treatment by ozonation. In this study, a systematic approach for producing and effect-based testing of transformation products (TPs) during the drinking water ozonation process is proposed. For this, two pharmaceutical parent substances, three metabolites and one environmental degradation product were investigated with respect to their biodegradability and fate during drinking water ozonation. The Ames test (TA98, TA100) was used for the identification of mutagenic activity present in the solutions after testing inherent biodegradability and/or after ozonation of the samples. Suspicious results were complemented with the umu test. Due to the low substrate concentration required for ozonation, all ozonated samples were concentrated via solid phase extraction (SPE) before performing the Ames test. With the exception of piracetam, all substances were only incompletely biodegradable, suggesting the formation of stable TPs. Metformin, piracetam and guanylurea could not be removed completely by the ozonation process. We received some evidence that technical TPs are formed by ozonation of metformin and piracetam, whereas all tested metabolites were not detectable by analytical means after ozonation. In the case of guanylurea, one ozonation TP was identified by LC/MS. None of the experiments showed an increase of mutagenic effects in the Ames test. However, the SPE concentration procedure might lead to false-positive results due to the generation of mutagenic artefacts or might lead to false-negative results by missing adequate recovery efficiency. Thus, these investigations should always be accompanied by process blank controls that are carried out along the whole ozonation and SPE procedure. The study presented here is a first attempt to investigate the significance of transformation products by a systematic approach. However, the adequacy and sensitivity of the methodology need to be further investigated. The approach of combining biodegradation and ozonation with effect based assays is a promising tool for the early detection of potential hazards from TPs as drinking water contaminants. It can support the strategy for the evaluation of substances and metabolites in drinking water. A multitude of possible factors which influence the results have to be carefully considered, among them the selectivity and sensibility of the mutagenicity test applied, the extraction method for concentrating the relevant compounds and the biocompatibility of the solvent. Therefore, the results have to be carefully interpreted, and possible false-negative and false-positive results should be considered. PMID- 22547255 TI - Considerations regarding the etiology and future treatment of autosomal recessive versus idiopathic Parkinson disease. AB - OPINION STATEMENT: We postulate that the frequently encountered grouping of different Parkinson disease (PD) variants into a single pathogenetic concept rather than differentiation into its molecular subtypes-has hindered progress toward curative interventions. Parkinsonism is a clinical syndrome that in rare cases can be explained by a single genetic event or by a single environmental cause, thereby leading to monogenic PD and secondary parkinsonism, respectively. Under the former category, mutations in both alleles of the Parkin-encoding PARK2 gene leads to young-onset, autosomal recessive PD, in which neurodegeneration is restricted to dopamine-producing cells of the brainstem. Under the latter category, exposure to one of several environmental factors with neuroanatomic selectivity can cause rapid-onset, secondary parkinsonism most likely irrespective of the patient's age and genetic makeup. Sandwiched between these two extreme and rare types, the most common variant is referred to as late-onset, idiopathic PD. In extension of a disease model first proposed by Braak et al., we consider idiopathic PD the result of an encounter between one or several environmental triggers and one or more susceptibility alleles. Importantly, this interaction produces a pre-motor syndrome followed by the typical PD phenotype over a period of decades. In our opinion, this pathophysiological process should thus be viewed as a "complex disease." As is true for many complex human disorders, successful intervention for the common PD variant will likely occur when genetic leads as well as environmental contributors are targeted in parallel. However, successful proof-of-concept studies could arrive sooner, namely for select PD variants that can be attributed to a single genetic event and that are neuropathologically restricted. Therefore, the authors decided to focus the second portion of their review on treatment considerations regarding autosomal recessive PD cases that are caused by Parkin deficiency. We briefly draw attention to aspects of existing pharmacological and surgical therapies as they relate to the PARK2-linked variant; thereafter, we comment on new research avenues that are aimed at future therapeutic interventions to eventually slow or arrest the progression of a first variant of PD. PMID- 22547256 TI - Spinal cord compression. AB - OPINION STATEMENT: Malignant epidural spinal cord compression (MESCC) remains a common neuro-oncologic emergency with high associated morbidity. Despite widespread availability of MRI, the diagnosis frequently goes unmade until myelopathy supervenes, which is unfortunate because the strongest predictor of neurologic outcome with treatment is the neurologic status when treatment is initiated. Once the diagnosis of MESCC is suspected, patients with neurologic deficits should be started on high-dose corticosteroids (eg, dexamethasone, 10 100 mg intravenously, followed by 16 to 100 mg/d in divided doses). Definitive therapy of MESCC almost always includes radiation therapy and in some cases surgical intervention; factors considered include the patient's performance status and extent of visceral and skeletal disease, spinal stability, the tumor's underlying radiosensitivity, and the degree of spinal cord compression. Patients with spinal instability or radioresistant tumors are likely to have a much better neurologic outcome with tumor resection and spinal stabilization prior to radiation; the same may also pertain to patients with moderately radiosensitive tumors who have good life expectancy in terms of their systemic tumor. Conventional radiation has historically been beneficial after surgery and in patients who are not surgical candidates. Recent studies suggest a role for stereotactic body radiation therapy in patients with spinal metastasis from radioresistant tumors and in patients who have received prior standard radiotherapy, so long as the spinal cord has been decompressed. PMID- 22547257 TI - Microsurgery in the hypercoagulable patient: review of the literature. AB - Improved techniques in microvascular surgery over the last several decades have led to the increased use of free tissue transfers as a mode of reconstructing difficult problems with a high success rate. However, undiagnosed thrombophilias have been associated with microsurgery free flap failures. We present a case of successful free tissue transfer in a patient with lupus anticoagulant and review the literature. PMID- 22547258 TI - The reliability and advantages of the sentinel vein as a microsurgical recipient vessel. AB - Free flaps to the scalp, calvaria, and anterior and middle cranial fossae are typically transferred to the superficial temporal artery and vein. Occasionally the superficial temporal vein is unsuitable for microvascular anastomosis. In such cases, we have had success using the sentinel vein, a perforating vein located in the anterior aspect of the deep temporal fat pad. This article describes the pertinent anatomy, our clinical experience, and the advantages of the sentinel vein as a microsurgical recipient vessel. PMID- 22547259 TI - Energy analysis of weak electron-donor-acceptor complexes and water clusters with the perturbation theory based on the locally projected molecular orbitals: charge transfer and dispersion terms. AB - The third order single excitation perturbation theory corrected with the dispersion energy based on the locally projected molecular orbital was applied to study the weak electron-donor-acceptor (charge-transfer) complexes and the hydrogen bonds in the water clusters. In the weak electron-donor-acceptor complexes, the dispersion energy is larger than the charge-transfer energy in absolute value. The dispersion energy is as large as the charge-transfer energy in the hydrogen bond. The cage form of (H(2)O)(6) is the most stable among eight isomers examined, because the dispersion energy is the largest among them. PMID- 22547260 TI - Reproductive endocrinology: Infertility treatment in PCOS--is metformin in from the cold? PMID- 22547261 TI - Therapy: Neuroendocrine cancer--are two radionuclides better than one? PMID- 22547262 TI - Localization of a site of action for benzofuroindole-induced potentiation of BKCa channels. AB - As previously reported, the activity of the large-conductance calcium (Ca(2+)) activated potassium (K(+)) (BK(Ca)) channel is strongly potentiated from the extracellular side of the cell membrane by certain benzofuroindole derivatives. Here, the mechanism of action of one of the most potent activators, 4-chloro-7 (trifluoromethyl)-10H-benzofuro[3,2-b]indole-1-carboxylic acid (CTBIC), is characterized. This compound, Compound 22 in the previous report (Chembiochem 6:1745-1748, 2005), potentiated the activity of the channel by shifting its conductance-voltage relationship toward the more negative direction. Cotreatment with CTBIC reduced the affinity of charybdotoxin, a peptide pore-blocker, whereas that of tetraethylammonium, a small pore-blocking quaternary ammonium, was not significantly altered. Guided by these results, scanning mutagenesis of the outer vestibule of the BK(Ca) channel was launched to uncover the molecular determinants that affect CTBIC binding. Alanine substitution of several amino acid residues in the turret region and the S6 helix of the channel decreased potentiation by CTBIC. Homology modeling and molecular dynamics simulation showed that some of these residues formed a CTBIC binding pocket between two adjacent alpha-subunits in the outer vestibule of the channel. Thus, it can be envisioned that benzofuroindole derivatives stabilize the open conformation of the channel by binding to the residues clustered across the extracellular part of the subunit interface. The present results indicate that the interface between different alpha-subunits of the BK(Ca) channel may play a critical role in the modulation of channel activity. Therefore, this interface represents a potential therapeutic target site for the regulation of K(+) channels. PMID- 22547263 TI - Insulin resistance is associated with elevated serum pigment epithelium-derived factor (PEDF) levels in morbidly obese patients. AB - Obesity is a significant risk factor for developing diabetes. Pigment epithelium derived factor (PEDF) has been identified by experimental and clinical studies as both a causative and counter-regulatory factor in the metabolic syndrome. We set out to determine whether serum PEDF levels correlated with the degree of insulin resistance in morbidly obese patients. Sera from 53 patients who were evaluated prior to gastric bypass surgery were analyzed for PEDF levels using a commercial ELISA. None of the patients were on diabetes medications prior to enrollment. Baseline data included BMI, serum glucose and insulin, and homeostasis model assessment (HOMA) scores. Patients were stratified based on HOMA score and glucose levels into three groups: insulin sensitive (IS): HOMA <2 and glucose <126; insulin resistant (IR): HOMA >2 and glucose <=126; and diabetes mellitus (DM): HOMA >2 and glucose >126. Pre- and post-gastric bypass sera from 12 patients were obtained for serial assessment of metabolic parameters and PEDF levels. PEDF secretion was assessed in primary human hepatocytes, HCC cells, and cultured adipocytes in the absence and presence of high glucose media. No significant differences in age, gender, and BMI were found among the three groups. PEDF levels were similar between IR patients and the other groups, but were significantly higher in DM compared to IS patients (p = 0.01). Serum PEDF in individual patients declined significantly after gastric bypass (p = 0.006). High glucose media led to significantly higher PEDF release by human hepatocytes in vitro (p = 0.016). These data demonstrate that serum PEDF concentrations better relate to insulin resistance than to adiposity and suggest that PEDF expression is closely linked to the development of insulin resistance. PMID- 22547264 TI - Acute and chronic fluctuations in blood glucose levels can increase oxidative stress in type 2 diabetes mellitus. AB - In order to investigate whether short- or long-term glycemic fluctuations could induce oxidative stress and chronic inflammation, we evaluated the relationships between glycemic variability, oxidative stress markers, and high-sensitivity C reactive protein (hs-CRP). We enrolled 34 patients with type 2 diabetes. As a measure of short-term glycemic variability, mean amplitude of glycemic excursions (MAGE) was computed from continuous glucose monitoring system data. For determining long-term glycemic variability, we calculated the standard deviation (SD) of hemoglobin A1c (HbA1c) levels measured over a 2-year period. Levels of oxidative stress markers: 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), thiobarbituric acid-reactive substance (TBARS), 8-hydroxydeoxyguanosine (8-OHdG), and hs-CRP were measured. MAGE was significantly correlated with the SD of HbA1c levels (r = 0.73, p < 0.001) but not with HbA1c level. The levels of hs-CRP, TBARS, 8-OHdG, and 8-iso-PGF2alpha were significantly correlated with MAGE (r = 0.54, p = 0.001; r = 0.82, p < 0.001; r = 0.70, p < 0.001; r = 0.60, p < 0.001) and the SD of HbA1c levels (r = 0.53, p = 0.001; r = 0.73, p < 0.001; r = 0.69, p < 0.001; r = 0.43, p = 0.01) but not with HbA1c level. Relationships between 8 iso-PGF2alpha and MAGE or the SD of HbA1c levels remained significant after adjusting for other markers of diabetic control (R(2) = 0.684, R(2) = 0.595, p < 0.001, respectively). Both acute and chronic blood glucose variability can induce oxidative stress and chronic inflammation. PMID- 22547266 TI - Mammographic system performance using an image reading qualification method. AB - Our goal was to evaluate mammography systems based on microcalcifications and fiber detection using a statistical phantom (ALVIM, model TRM 18-209, Nuclear Associates) image readings. ALVIM phantom images were acquired under diverse exposure conditions with various equipments, and 5 radiologists with similar expertise reported their findings. The reading performance in the detection of microcalcifications and fibers of different sizes was measured by simulation of equivalent breast tissue with 4.5 and 6.5 cm thicknesses. We determined kappa values, ROC curves, and kappa probability density and detection rates with dedicated software developed locally. The statistical results generated three kappa (K) ranges that allowed quantification of the detection performance at three quality levels: unacceptable (K <= 0.64), achievable (K >= 0.70) and acceptable (0.64 < K < 0.70). An extensive database permitted a comparison of the reading performance with 99.5% reliability (p < 0.005). The comparison showed a larger dispersion of the kappa values for the images with low contrast generated with mammography equipment which was not properly calibrated, showing that the method is able to detect the performance changes associated with the loss of image quality. PMID- 22547267 TI - Investigation of the stability of commercial neutron probes. AB - At the Paul Scherrer Institute's Calibration Laboratory, neutron reference fields are provided for the calibration of ambient and personal dose equivalent (rate) metres and passive dosemeters. To ensure traceability to the standards of the Physikalisch-Technische Bundesanstalt (PTB) in Germany, the neutron fields are characterised by means of a PTB-calibrated Berthold LB6411 neutron probe which is used as a secondary standard. The LB6411 detector suffers from an unstable, increasing dose rate reading in the order of up to +5 % (according to the manufacturers, this is due to a charging effect in the (3)He proportional counter). In a calibration, this instability is usually corrected for based on the reading obtained with a test source. In this work, the instability was investigated by means of measurements under irradiation with ambient dose equivalent rates up to 24 mSv h(-1) for up to 20 h and compared with the behaviour of an LB6419 and a Thermo Wendi-2 probe. The reading of the instruments was found to reach a plateau, e.g. it becomes stable after ~90 min during irradiation with 10 mSv h(-1) neutrons. The plateau is reached faster for higher dose rates. This supports the interpretation as a charging effect in the proportional counter. The effect could also be duplicated in an irradiation with photons from a (137)Cs source. The decay time of the accumulated charge was found to be very long, i.e. the instrument showed a stable reproducible reading for up to 6 h after the plateau was reached. From these observations, a conditioning procedure was derived which ensures a stable operation of the instrument after an irradiation of the instrument preceding its use in the reference measurements. PMID- 22547268 TI - Induction and activation of antiviral enzyme 2',5'-oligoadenylate synthetase by in vitro transcribed insulin mRNA and other cellular RNAs. AB - Double-stranded RNA (dsRNA) can induce antiviral enzyme 2',5'-oligoadenylate synthetase (2'5'AS) expression and activate latent 2'5'AS. Our previous data have shown pancreatic beta cells are sensitive to dsRNA-induced 2'5'AS expression, and constitutive high basal 2'5'AS expression is associated with susceptibility to developing type 1 diabetes (T1D), a disease due to pancreatic beta cell loss. Here we report that in vitro transcribed human insulin mRNA induces the activation of human OAS gene promoter sequences, and specifically and dose dependently induces 2'5'AS expression in murine pancreatic betaTC3 cells. Over expression of dsRNA receptor retinoic acid-inducible gene-1 enhances insulin mRNA induced 2'5'AS expression. In vitro transcribed insulin and other mRNAs, as well as total cellular RNAs, activate latent 2'5'AS in vitro with activation ability likely associated with the sequence and length of individual mRNAs or the sample source of total cellular RNA. Insulin mRNA does not show any specificity to activate 2'5'AS, but total cellular RNA from betaTC3 cells has high activation ability. Constitutive 2'5'AS expression in betaTC3 cells leads to cell proliferation inhibition and apoptosis. Our study suggests the possibility of cellular RNA-regulated 2'5'AS expression and activation, and the potential risk of high insulin gene transcription in pancreatic beta cells, and may help explain genetic predisposition to T1D associated with INS VNTR class I alleles. PMID- 22547270 TI - ERBB2-induced inflammation in lung carcinogenesis. AB - ERBB2/HER2/NEU, a member of the epidermal growth factor receptor family, is overexpressed in more than 25 % of non-small cell lung cancer and is considered to be a significant and independent prognostic factor in lung cancer. Here we generated a lung specific HER2 overexpressing transgenic mouse model. In this model, HER2 was driven by the human surfactant protein-C promoter to investigate the role of the HER2 oncogene in pulmonary carcinogenesis and progression. Notably, significant pathological changes, including lymphocyte infiltration and mesenchymal cells hyperplasia, were found in the lung tissue of transgenic mice aged from 4 to 12 months. The occurrence and severity of those lesions increased as the mice aged. Some inflammatory factors, such as tumor necrosis factor, interleukin 1 and interleukin 6, were upregulated in lung tissue of transgenic mice compared with that of wild-type mice, implying that long-term HER2 overexpression could induce serious lung inflammation and some precancerous lesions. This model would be useful for studying the mechanism of HER2 involvement in lung carcinogenesis and for understanding the relationship between carcinogenesis and inflammation. PMID- 22547269 TI - Antioxidative potential of lactobacilli isolated from the gut of Indian people. AB - Oxidative stress is one of the major causes of degenerative conditions occurring at cellular level with serious health implications. This study was aimed at investigating the antioxidative potentials of probiotic lactobacilli of Indian gut origin and their ability to augment antioxidant defense enzyme systems in the host cells under oxidative stress conditions. A total of 39 Lactobacillus cultures were assessed for their resistance against reactive oxygen species. Most of the cultures were moderately to strongly resistant towards 0.4 mM H(2)O(2). The Lactobacillus isolate CH4 was the most H(2)O(2) resistant culture with only 0.06 log cycle reduction. Majority of the cultures demonstrated high resistance towards hydroxyl ions and Lp21 was the most resistant with log count reduction of 0.20 fold only. Almost all the cultures were also quite resistant to superoxide anions. Lp21 also showed the highest superoxide dismutase content (0.8971 U). Amongst the 39 cultures, Lactobacillus spp. S3 showed the highest total antioxidative activity of 77.85 +/- 0.13 % followed by Lp55 (56.1 +/- 1.2 %) in terms of per cent inhibition of linolenic acid oxidation. Lp9 up-regulated the expression of superoxide dismutase 2 gene in HT-29 cells both at 0.1 mM (1.997 folds) and 1.0 mM H(2)O(2) (2.058 folds) concentrations. In case of glutathione peroxidase-1, Lp9, Lp91 and Lp55 showed significant (P < 0.001) up-regulation in the gene expression to the level of 5.451, 8.706 and 10.083 folds, respectively when HT-29 was challenged with 0.1 mM H(2)O(2). The expression of catalase gene was also significantly up-regulated by all the cultures at 0.1 mM H(2)O(2) conditions. It can be concluded that the antioxidative efficacy of the putative probiotic lactobacilli varied considerably between species and strains and the potential strains can be explored as prospective antioxidants to manage oxidative stress induced diseases. PMID- 22547271 TI - A proteomic analysis of storage stress responses in Ipomoea batatas (L.) Lam. tuberous root. AB - During post-harvest storage, tuberous roots of sweet potato (Ipomoea batatas L. Lam.) usually undergo a biotic and abiotic stress influencing protein expression pattern and substance contents. This research compared the change of total proteins and carbohydrate content in tuberous roots of sweet potato during the storage period. The result of the two-dimensional electrophoresis analysis demonstrated that there were 25 differentially expressed proteins between day 0 and day 75 during the storage. Among these proteins, 11 proteins were down regulated and the other 14 were up-regulated. The results from MALDI-TOF-TOF/MS analyses and mascot database searching showed that 11 of the 25 differentially expressed proteins were identified as store-stress regulated proteins. It was also found that the proteins involved in the energy metabolism and the stress response were drastically up-regulated, whereas those in biomacromolecule synthesis were markedly down-regulated. Meanwhile, under the experimental conditions, the content of the starch and the cellulose was decreased by more than a quarter and the amylase activity was increased moderately. PMID- 22547272 TI - One novel SNP of growth hormone gene and its associations with growth and carcass traits in ducks. AB - In this study, the growth hormone (GH) gene was studied as a candidate gene for growth and carcass traits of three duck populations (Cherry Valley duck, Muscovy duck and Jingjiang duck). Three pairs of primers were designed to detect single nucleotide polymorphisms of introns 2, 3 and 4 of the GH gene by polymerase chain reaction-restriction fragment length polymorphism and sequencing methods. Only the products amplified from intron 2 displayed polymorphism. The results showed one novel polymorphism: a variation in intron 2 of GH gene (C172T, JN408701 and JN408702). It was associated with some growth and carcass traits in three duck populations including birth weight, 8-week weight, carcass weight, breast muscle weight, leg muscle weight, eviscerated weight, lean meat rate, dressing percentage, etc. And the TT and CT genotypes were associated with superior growth and carcass traits in carcass weight, dressing percentage and percentage of eviscerated weight. Therefore, the variation in intron 2 of GH may be a molecular marker for superior growth and carcass traits in above duck populations. PMID- 22547273 TI - Multi-layer phase analysis: quantifying the elastic properties of soft tissues and live cells with ultra-high-frequency scanning acoustic microscopy. AB - Scanning acoustic microscopy is potentially a powerful tool for characterizing the elastic properties of soft biological tissues and cells. In this paper, we present a method, multi-layer phase analysis (MLPA), which can be used to extract local speed of sound values, for both thin tissue sections mounted on glass slides and cultured cells grown on cell culture plastic, with a resolution close to 1 MUm. The method exploits the phase information that is preserved in the interference between the acoustic wave reflected from the substrate surface and internal reflections from the acoustic lens. In practice, a stack of acoustic images are captured beginning with the acoustic focal point 4 MUm above the substrate surface and moving down in 0.1-MUm increments. Scanning parameters, such as acoustic wave frequency and gate position, were adjusted to obtain optimal phase and lateral resolution. The data were processed offline to extract the phase information with the contribution of any inclination in the substrate removed before the calculation of sound speed. Here, we apply this approach to both skin sections and fibroblast cells, and compare our data with the V(f) (voltage versus frequency) method that has previously been used for characterization of soft tissues and cells. Compared with the V(f) method, the MPLA method not only reduces signal noise but can be implemented without making a priori assumptions with regards to tissue or cell parameters. PMID- 22547274 TI - Angiogenesis imaging by spatiotemporal analysis of ultrasound contrast agent dispersion kinetics. AB - The key role of angiogenesis in cancer growth has motivated extensive research with the goal of noninvasive cancer detection by blood perfusion imaging. However, the results are still limited and the diagnosis of major forms of cancer, such as prostate cancer, are currently based on systematic biopsies. The difficulty in the detection of angiogenesis partly resides in a complex relationship between angiogenesis and perfusion. This may be overcome by analysis of the dispersion kinetics of ultrasound contrast agents. Determined by multipath trajectories through the microvasculature, dispersion permits a better characterization of the microvascular architecture and, therefore, more accurate detection of angiogenesis. In this paper, a novel dispersion analysis method is proposed for prostate cancer localization. An ultrasound contrast agent bolus is injected intravenously. Spatiotemporal analysis of the concentration evolution measured at different pixels in the prostate is used to assess the local dispersion kinetics of the injected agent. In particular, based on simulations of the convective diffusion equation, the similarity between the concentration evolutions at neighbor pixels is the adopted dispersion measure. Six measurements in patients, compared with the histology, provided a receiver operating characteristic curve integral equal to 0.87. This result was superior to that obtained by the previous approaches reported in the literature. PMID- 22547275 TI - Design and performance of Huffman sequences in medical ultrasound coded excitation. AB - This paper deals with coded-excitation techniques for ultrasound medical echography. Specifically, linear Huffman coding is proposed as an alternative approach to other widely established techniques, such as complementary Golay coding and linear frequency modulation. The code design is guided by an optimization procedure that boosts the signal-to-noise ratio gain (GSNR) and, interestingly, also makes the code robust in pulsed-Doppler applications. The paper capitalizes on a thorough analytical model that can be used to design any linear coded-excitation system. This model highlights that the performance in frequency-dependent attenuating media mostly depends on the pulse-shaping waveform when the codes are characterized by almost ideal (i.e., Kronecker delta) autocorrelation. In this framework, different pulse shapers and different code lengths are considered to identify coded signals that optimize the contrast resolution at the output of the receiver pulse compression. Computer simulations confirm that the proposed Huffman codes are particularly effective, and that there are scenarios in which they may be preferable to the other established approaches, both in attenuating and non-attenuating media. Specifically, for a single scatterer at 150 mm in a 0.7-dB/(MHz.cm) attenuating medium, the proposed Huffman design achieves a main-to-side lobe ratio (MSR) equal to 65 dB, whereas tapered linear frequency modulation and classical complementary Golay codes achieve 35 and 45 dB, respectively. PMID- 22547277 TI - A low-complexity adaptive beamformer for ultrasound imaging using structured covariance matrix. AB - In recent years, adaptive beamforming methods have been successfully applied to medical ultrasound imaging, resulting in simultaneous improvement in imaging resolution and contrast. These improvements have been achieved at the expense of higher computational complexity, with respect to the conventional non-adaptive delay-and-sum (DAS) beamformer, in which computational complexity is proportional to the number of elements, O(M). The computational overhead results from the covariance matrix inversion needed for computation of the adaptive weights, the complexity of which is cubic with the subarray size, O(L(3)). This is a computationally intensive procedure, which makes the implementation of adaptive beamformers less attractive in spite of their advantages. Considering that, in medical ultrasound applications, most of the energy is scattered from angles close to the steering angle, assuming spatial stationarity is a good approximation, allowing us to assume the Toeplitz structure for the estimated covariance matrix. Based on this idea, in this paper, we have applied the Toeplitz structure to the spatially smoothed covariance matrix by averaging the entries along all subdiagonals. Because the inverse of the resulting Toeplitz covariance matrix can be computed in O(L(2)) operations, this technique results in a greatly reduced computational complexity. By using simulated and experimental RF data-point targets as well as cyst phantoms-we show that the proposed low-complexity adaptive beamformer significantly outperforms the DAS and its performance is comparable to that of the minimum variance beamformer, with reduced computational complexity. PMID- 22547276 TI - Harmonic spatial coherence imaging: an ultrasonic imaging method based on backscatter coherence. AB - We introduce a harmonic version of the short-lag spatial coherence (SLSC) imaging technique, called harmonic spatial coherence imaging (HSCI). The method is based on the coherence of the second-harmonic backscatter. Because the same signals that are used to construct harmonic B-mode images are also used to construct HSCI images, the benefits obtained with harmonic imaging are also obtained with HSCI. Harmonic imaging has been the primary tool for suppressing clutter in diagnostic ultrasound imaging, however secondharmonic echoes are not necessarily immune to the effects of clutter. HSCI and SLSC imaging are less sensitive to clutter because clutter has low spatial coherence. HSCI shows favorable imaging characteristics such as improved contrast-to-noise ratio (CNR), improved speckle SNR, and better delineation of borders and other structures compared with fundamental and harmonic B-mode imaging. CNRs of up to 1.9 were obtained from in vivo imaging of human cardiac tissue with HSCI, compared with 0.6, 0.9, and 1.5 in fundamental B-mode, harmonic B-mode, and SLSC imaging, respectively. In vivo experiments in human liver tissue demonstrated SNRs of up to 3.4 for HSCI compared with 1.9 for harmonic B-mode. Nonlinear simulations of a heart chamber model were consistent with the in vivo experiments. PMID- 22547278 TI - Regional cardiac motion and strain estimation in three-dimensional echocardiography: a validation study in thick-walled univentricular phantoms. AB - Automatic quantification of regional left ventricular deformation in volumetric ultrasound data remains challenging. Many methods have been proposed to extract myocardial motion, including techniques using block matching, phase-based correlation, differential optical flow methods, and image registration. Our lab previously presented an approach based on elastic registration of subsequent volumes using a B-spline representation of the underlying transformation field. Encouraging results were obtained for the assessment of global left ventricular function, but a thorough validation on a regional level was still lacking. For this purpose, univentricular thick-walled cardiac phantoms were deformed in an experimental setup to locally assess strain accuracy against sonomicrometry as a reference method and to assess whether regions containing stiff inclusions could be detected. Our method showed good correlations against sonomicrometry: r(2) was 0.96, 0.92, and 0.84 for the radial (epsilon(RR)), longitudinal (epsilon(LL)), and circumferential (epsilon(CC)) strain, respectively. Absolute strain errors and strain drift were low for epsilon(LL) (absolute mean error: 2.42%, drift: 1.05%) and epsilon(CC) (error: 1.79%, drift: -1.33%) and slightly higher for epsilon(RR) (error: 3.37%, drift: 3.05%). The discriminative power of our methodology was adequate to resolve full transmural inclusions down to 17 mm in diameter, although the inclusion-to-surrounding tissue stiffness ratio was required to be at least 5:2 (absolute difference of 39.42 kPa). When the inclusion-to-surrounding tissue stiffness ratio was lowered to approximately 2:1 (absolute difference of 22.63 kPa), only larger inclusions down to 27 mm in diameter could still be identified. Radial strain was found not to be reliable in identifying dysfunctional regions. PMID- 22547279 TI - Minimum variance beamforming applied to ultrasound imaging with a partially shaded aperture. AB - Shadowing of an imaging aperture occurs when ultrasound beams are partially obstructed by an acoustically hard tissue, e.g., bone tissue. This effect leads to reduced resolution and, in some cases, geometrical distortion. In this paper, we initially introduce a binary apodization model to simulate effects of the shadowing on the point scatterers located close to a bone structure. Further, in a simulation study and an in vitro experiment, the minimum variance (MV) beamforming method is employed to image scatterers partly located in the shadow of bone. We show that the MV beamformer can result in a distorted image when the imaging aperture is highly obstructed by the bone structure. This distortion can be seen as an apparent lateral shift of the point spread function and a decrease in the sensitivity. Based on the signal power across the aperture, we adaptively determine the shadowed elements and discard their corresponding data from the covariance matrix to improve the MV beamformer performance. This modified MV beamformer can retain the resolution and compensate for the apparent lateral shifting and signal attenuation for the shadowed point scatterers. PMID- 22547280 TI - Ultrasonic assessment of extracellular matrix content in healing Achilles tendon. AB - Although several imaging modalities have been utilized to observe tendons, assessing injured tendons by tracking the healing response over time with ultrasound is a desirable method which is yet to be realized. This study examines the use of ultrasound for non-invasive monitoring of the healing process of Achilles tendons after surgical transection. The overall extracellular matrix content of the transection site is monitored and quantified as a function of time. B-mode images (built from successive A-scan signatures) of the injury site were obtained and compared to biomechanical properties. A quantitative measure of tendon healing using the extracellular matrix (ECM) content of the injury site was analyzed using linear regression with all biomechanical measures. Contralateral tendons were used as controls. The trend in the degree of ECM regrowth in the 4 weeks following complete transection of excised tendons was found to be most closely paralleled with that of linear stiffness (R(2) = 0.987, p < .05) obtained with post-ultrasound biomechanical tests. Results suggest that ultrasound can be an effective imaging technique in assessing the degree of tendon healing, and can be used to correlate structural properties of Achilles tendons. PMID- 22547281 TI - Application of 1-D transient elastography for the shear modulus assessment of thin-layered soft tissue: comparison with supersonic shear imaging technique. AB - Elasticity estimation of thin-layered soft tissues has gained increasing interest propelled by medical applications like skin, corneal, or arterial wall shear modulus assessment. In this work, the authors propose one-dimensional transient elastography (1DTE) for the shear modulus assessment of thin-layered soft tissue. Experiments on three phantoms with different elasticities and plate thicknesses were performed. First, using 1DTE, the shear wave speed dispersion curve inside the plate was obtained and validated with finite difference simulation. No dispersive effects were observed and the shear wave speed was directly retrieved from time-of-flight measurements. Second, the supersonic shear imaging (SSI) technique (considered to be a gold standard) was performed. For the SSI technique, the propagating wave inside the plate is guided as a Lamb wave. Experimental SSI dispersion curves were compared with finite difference simulation and fitted using a generalized Lamb model to retrieve the plate bulk shear wave speed. Although they are based on totally different mechanical sources and induce completely different diffraction patterns for the shear wave propagation, the 1DTE and SSI techniques resulted in similar shear wave speed estimations. The main advantage of the 1DTE technique is that bulk shear wave speed can be directly retrieved without requiring a dispersion model. PMID- 22547283 TI - Generation and detection of higher-order mode clusters of guided waves (HOMC-GW) using meander-coil EMATs. AB - This paper reports on a new means of generating higher-order mode clusters of guided waves (HOMC-GW) using a meander-coil (MC) electromagnetic acoustic transducer (EMAT) in plates at frequencies significantly higher than the lower order plate modes. These wave modes are considerably less dispersive and they occur at much higher frequency-thickness (f x d) products. Our studies cover the f x d range of 13 to 20 MHz.mm. Experimental measurements were carried out on Al plate samples of different thicknesses using three different EMAT coil periods. To understand the generation and propagation characteristics of HOMC-GW with EMATs, several simulations were carried out using 2-D finite element models at different f x d products. These simulations captured all features observed in the experiments. The time-frequency smoothed pseudo Wigner-Ville distribution (SPWVD) was used to analyze the HOMC-GW modes. Defect detection measurements using HOMC GW generated using EMATs were made on Al plates with machined defects. PMID- 22547282 TI - Simulation of noninvasive blood pressure estimation using ultrasound contrast agent microbubbles. AB - The microbubble ultrasound contrast agent (UCA) has been widely recognized as a potential noninvasive tool for blood pressure measurement. However, UCA indices such as the shift in the resonance frequency and echo amplitude have problems of low resolution, nonlinear relationship with blood pressure, etc. In this paper, a novel UCA index, the shift in the subharmonic optimal driving frequency (SSODF) of microbubbles, is proposed. The effectiveness of the index for estimating blood pressure was evaluated by performing a microbubble acoustic response simulation. The behavior of commercial UCA microbubbles was investigated as a function of the driving acoustic pressure (in kilopascals) and ambient overpressure (in millimeters of mercury). Simulation results showed that for a 1.6-MUm-diameter microbubble, SSODF increased linearly with the overpressure in a range of 0 to 200 mmHg and was maximum (2.07 MHz) at 380 kPa. Changes of the overpressure as small as 5 mmHg can be detected using SSODF. For a population of microbubbles with a Gaussian size distribution (mean diameter: 1.6 MUm, standard deviation: 0.2 MUm), SSODF was 1.7 MHz at 280 kPa. With further experimental validation, the proposed method may be developed as a novel noninvasive technique for accurate blood pressure measurement. PMID- 22547284 TI - Voltage-controlled double-resonance quartz oscillator using variable-capacitance diode. AB - In this work, we present a variable-frequency quartz crystal oscillator that is able to oscillate at LC resonance under frequency locking of a quartz crystal resonance, with the frequency tuning realized by variable-capacitance diodes. This circuit shows a steep transition between LC oscillation modes to quartz crystal double-resonance, which shows a characteristic change in the oscillation frequency. Control voltage of this diode is precisely adjusted from the low side to higher values and conversely in the vicinity of the oscillation mode transition. The transition of the oscillation modes is experimentally demonstrated and compared with an algebraic analysis. PMID- 22547285 TI - Analysis of a monolithic, two-dimensional array of quartz crystal microbalances loaded by mass layers with nonuniform thickness. AB - We study free thickness-shear vibrations of a monolithic, two-dimensional, and periodic array of quartz crystal microbalances loaded by mass layers with gradually varying thickness. A theoretical analysis is performed using Mindlin's two-dimensional plate equation. It is shown that the problem is mathematically governed by Mathieu's equation with a spatially varying coefficient. A periodic solution for resonant frequencies and modes is obtained and used to examine the effects of the mass layers. Results show that the vibration may be trapped or untrapped under the mass layers. The trapped modes decay differently in the two in-plane directions of the plate. The mode shapes and the decay rate of the trapped modes are sensitive to the mass layer thickness. PMID- 22547286 TI - Velocity measurement by vibro-acoustic Doppler. AB - We describe the theoretical principles of a new Doppler method, which uses the acoustic response of a moving object to a highly localized dynamic radiation force of the ultrasound field to calculate the velocity of the moving object according to Doppler frequency shift. This method, named vibro-acoustic Doppler (VAD), employs two ultrasound beams separated by a slight frequency difference, Deltaf, transmitting in an X-focal configuration. Both ultrasound beams experience a frequency shift because of the moving objects and their interaction at the joint focal zone produces an acoustic frequency shift occurring around the low-frequency (Deltaf) acoustic emission signal. The acoustic emission field resulting from the vibration of the moving object is detected and used to calculate its velocity. We report the formula that describes the relation between Doppler frequency shift of the emitted acoustic field and the velocity of the moving object. To verify the theory, we used a string phantom. We also tested our method by measuring fluid velocity in a tube. The results show that the error calculated for both string and fluid velocities is less than 9.1%. Our theory shows that in the worst case, the error is 0.54% for a 25 degrees angle variation for the VAD method compared with an error of -82.6% for a 25 degrees angle variation for a conventional continuous wave Doppler method. An advantage of this method is that, unlike conventional Doppler, it is not sensitive to angles between the ultrasound beams and direction of motion. PMID- 22547287 TI - A photoacoustic imager with light illumination through an infrared-transparent silicon CMUT array. AB - A novel hardware design and preliminary experimental results for photoacoustic imaging are reported in this paper. This imaging system makes use of an infrared transparent capacitive micromachined ultrasonic transducer (CMUT) chip for ultrasound reception and illuminates the image target through the CMUT array. The cascaded arrangement between the light source and transducer array allows for a more compact imager head and results in more uniform illumination. Taking advantage of the low optical absorption coefficient of silicon in the near infrared spectrum as well as the broad acoustic bandwidth that CMUTs provide, an infrared-transparent CMUT array has been developed for ultrasound reception. The center frequency of the polysilicon-membrane CMUT devices used in this photoacoustic system is 3.5 MHz, with a fractional bandwidth of 118% in reception mode. The silicon substrate of the CMUT array has been thinned to 100 MUm and an antireflection dielectric layer is coated on the back side to improve the infrared-transmission rate. Initial results show that the transmission rate of a 1.06-MUm Nd:Yag laser through this CMUT chip is 12%. This transmission rate can be improved if the thickness of silicon substrate and the thin-film dielectrics in the CMUT structure are properly tailored. Imaging of a metal wire phantom using this cascaded photoacoustic imager is demonstrated. PMID- 22547288 TI - Third-order parametric array generated by distantly spaced primary ultrasonic tones. AB - Traditional parametric arrays are produced by a second-order nonlinear interaction between two primary ultrasonic tones that are close in frequency, resulting in a difference tone that is in the audio band. This article presents a parametric array produced by a third-order nonlinear interaction between two primary ultrasonic tones that are distantly spaced in frequency such that one tone is approximately the second harmonic of the other. The result is a third order lower intermodulation (IM3) tone in the audio band with greater directivity and lower side lobe amplitude than comparable second-order fields. Measurements are presented that compare the directivity of 1-, 2-, and 4-kHz difference tones to that of 1-, 2-, and 4-kHz IM3 lower tones. Furthermore, a cascaded second order approach for N-element transducer arrays is used to model third-order scattering with good agreement between measurement and theory. PMID- 22547289 TI - Experimental measurements and finite element analysis of the coupled vibrational characteristics of piezoelectric shells. AB - Piezoelectric plates can provide low-frequency transverse vibrational displacements and high-frequency planar vibrational displacements, which are usually uncoupled. However, piezoelectric shells can induce three-dimensional coupled vibrational displacements over a large frequency range. In this study, three-dimensional coupled vibrational characteristics of piezoelectric shells with free boundary conditions are investigated using three different experimental methods and finite element numerical modeling. For the experimental measurements, amplitude-fluctuation electronic speckle pattern interferometry (AF-ESPI) is used to obtain resonant frequencies and radial, lateral, and angular mode shapes. This optical technique utilizes a real-time, full-field, non-contact optical system that measures both the natural frequency and corresponding vibration mode shape simultaneously. The second experimental technique used, laser Doppler vibrometry (LDV), is a pointwise displacement measurement method that determines the resonant frequencies of the piezoelectric shell. An impedance analyzer is also used to determine the resonant frequencies of the piezoelectric shell. The experimental results of the resonant frequencies and mode shapes for the piezoelectric shell are verified with a numerical finite element model. Excellent agreement between the experimental and numerical results is found for the three dimensional coupled vibrational characteristics of the piezoelectric shell. It is noted in this study that there is no coupled phenomenon at low frequencies over which radial modes dominate. However, three-dimensional coupled vibrational modes do occur at high resonant frequencies over which lateral or angular modes dominate. PMID- 22547290 TI - Optimum beamforming for sidelobe reduction in ultrasound imaging. AB - A constrained adaptive beamforming in a deterministic sense is considered for side lobe reduction, leading to an adaptive weighting of the uniform delay-and sum beamformer; based upon this, the coherence factor and other similar methods are interpreted as beamforming methods. A generalized form of the weighting factor for the side lobe reduction is also established. It is shown through simulations that restricting the apodization vector to a parametric representation through a discrete Fourier transform or discrete cosine transform can result in higher quality images with fewer artifacts and enhanced contrast properties compared with images obtained through the coherence factor-like methods. PMID- 22547291 TI - Propagation of the Anisimkin Jr.' and quasi-longitudinal acoustic plate modes in low-symmetry crystals of arbitrary orientation. AB - The Anisimkin Jr. (AN) acoustic plate mode having dominant and depth-independent longitudinal displacement (u(1) >> u(2), u(3); u(1) ~ constant) is numerically found in tetragonal 4mm Li(2)B(4)O(7) crystal with one of the low-symmetry orientations (Euler angles 89 degrees , 37 degrees , 104 degrees ), as an example. The quasi-longitudinal (QL) modes with dominant and depth-dependent longitudinal displacement (u(1) >> u(2), u(3); u(1) ? constant) are experimentally detected along several propagation directions Theta in 128 degrees y-LiNbO(3) plate, where Theta = 0 degrees , 30 degrees , 60 degrees , and 90 degrees with respect to the x-axis. Compared with more symmetrical plate materials and orientations, the displacement profiles of the AN and QL modes in lower-symmetry counterparts are qualitatively the same, but their phase profiles are more complicated. Moreover, like any acoustic wave, all plate modes in anisotropic crystals suffer from beam steering, in general. The power flow angles of the modes propagating in a fixed direction are different and depend on the mode order n. PMID- 22547292 TI - Five-mode frequency spectra of x3-dependent modes in AT-cut quartz resonators. AB - We study straight-crested waves and vibration modes with variations along the x(3) direction only in an AT-cut quartz plate resonator near the operating frequency of the fundamental thickness-shear mode. Mindlin's two-dimensional equations for anisotropic crystal plates are used. Dispersion relations and frequency spectra of the five relevant waves are obtained. It is found that, to avoid unwanted couplings between the resonator operating mode and other undesirable modes, in addition to certain known values of the plate length/thickness ratio that need to be avoided, an additional series of discrete values of the plate length/thickness ratio also must be excluded. PMID- 22547293 TI - Frequency-domain-based strain estimation and high-frame-rate imaging for quasi static elastography. AB - In freehand elastography, quasi-static tissue compression is applied through the ultrasound probe, and the corresponding axial strain is estimated by calculating the time shift between consecutive echo signals. This calculation typically suffers from a poor signal-to-noise ratio or from the decorrelation between consecutive echoes resulting from an erroneous axial motion impressed by the operator. This paper shows that the quality of elastograms can be improved through the integration of two distinct techniques in the strain estimation procedure. The first technique evaluates the displacement of the tissue by analyzing the phases of the echo signal spectra acquired during compression. The second technique increases the displacement estimation robustness by averaging multiple displacement estimations in a high-frame-rate imaging system, while maintaining the typical elastogram frame-rate. The experimental results, obtained with the Ultrasound Advanced Open Platform (ULA-OP) and a cyst phantom, demonstrate that each of the proposed methods can independently improve the quality of elastograms, and that further improvements are possible through their combination. PMID- 22547294 TI - Wideband linear power amplifier for high-frequency ultrasonic coded excitation imaging. AB - Linear power amplifiers are critical components in ultrasonic imaging systems that implement chirp-coded excitation. Bench-top commercial power amplifiers are usually used in academic laboratories for high-frequency ultrasound imaging, and the imaging performance depends greatly on these general-purpose instruments. To achieve a wide dynamic range, a power amplifier consisting of two stages is developed for chirp-coded ultrasound imaging applications through the implementation of custom-designed broadband 1:1 transformers and the optimization of feedback circuits. The amplifier has broad bandwidth (5 to 135 MHz), maintaining a linearity up to the 1-dB gain compression point (P1dB) of 41.5 dBm, allowing 16 dBm input power level at 60 MHz. The mean and the maximum values of output third-order intercept points (OIP3) are 51.8 and 53.5 dBm, respectively, between 20 and 110 MHz. With 12 dBm input power, the gain of the amplifier varies between 24 and 29 dB, offering a uniformity which would allow excitation of a 70 MHz single-element transducer with windowed chirp-coded bursts sweeping from 40 to 100 MHz. The performance in high-frequency ultrasound imaging is evaluated with a wire phantom. Echo signal-to-noise ratio (eSNR) of the designed amplifier is 7 dB better than a commercial amplifier, and spatial resolution is maintained. PMID- 22547295 TI - Quantitative imaging of nonlinear shear modulus by combining static elastography and shear wave elastography. AB - The study of new tissue mechanical properties such as shear nonlinearity could lead to better tissue characterization and clinical diagnosis. This work proposes a method combining static elastography and shear wave elastography to derive the nonlinear shear modulus by applying the acoustoelasticity theory in quasi incompressible soft solids. Results demonstrate that by applying a moderate static stress at the surface of the investigated medium, and by following the quantitative evolution of its shear modulus, it is possible to accurately and quantitatively recover the local Landau (A) coefficient characterizing the shear nonlinearity of soft tissues. PMID- 22547296 TI - Production and function of jasmonates in nodulated roots of soybean plants inoculated with Bradyrhizobium japonicum. AB - Little is known regarding production and function of endogenous jasmonates (JAs) in root nodules of soybean plants inoculated with Bradyrhizobium japonicum. We investigated (1) production of jasmonic acid (JA) and 12-oxophytodienoic acid (OPDA) in roots of control and inoculated plants and in isolated nodules; (2) correlations between JAs levels, nodule number, and plant growth during the symbiotic process; and (3) effects of exogenous JA and OPDA on nodule cell number and size. In roots of control plants, JA and OPDA levels reached a maximum at day 18 after inoculation; OPDA level was 1.24 times that of JA. In roots of inoculated plants, OPDA peaked at day 15, whereas JA level did not change appreciably. Shoot dry matter of inoculated plants was higher than that of control at day 21. Chlorophyll a decreased more abruptly in control plants than in inoculated plants, whereas b decreased gradually in both cases. Exogenous JA or OPDA changed number and size of nodule central cells and peripheral cells. Findings from this and previous studies suggest that increased levels of JA and OPDA in control plants are related to senescence induced by nutritional stress. OPDA accumulation in nodulated roots suggests its involvement in "autoregulation of nodulation." PMID- 22547297 TI - The NIMH Child Emotional Faces Picture Set (NIMH-ChEFS): a new set of children's facial emotion stimuli. AB - With the emergence of new technologies, there has been an explosion of basic and clinical research on the affective and cognitive neuroscience of face processing and emotion perception. Adult emotional face stimuli are commonly used in these studies. For developmental research, there is a need for a validated set of child emotional faces. This paper describes the development of the National Institute of Mental Health Child Emotional Faces Picture Set (NIMH-ChEFS), a relatively large stimulus set with high quality, color images of the emotional faces of children. The set includes 482 photographs of fearful, angry, happy, sad and neutral child faces with two gaze conditions: direct and averted gaze. In this paper we describe the development of the NIMH-ChEFS and data on the set's validity based on ratings by 20 healthy adult raters. Agreement between the a priori emotion designation and the raters' labels was high and comparable with values reported for commonly used adult picture sets. Intensity, representativeness, and composite "goodness" ratings are also presented to guide researchers in their choice of specific stimuli for their studies. These data should give researchers confidence in the NIMH-ChEFS's validity for use in affective and social neuroscience research. PMID- 22547298 TI - Anxiety disorders and comorbid depression in community dwelling older adults. AB - Anxiety disorder is a common psychiatric problem during late-life, and frequently co-occurs with depression. High comorbidity between anxiety and depression may partly be explained by the definition of the disorders and the assessment of both disorders with one instrument at the same time. The current study investigates the relation of current and past depression with anxiety disorders in the Rotterdam Study, a large population-based cohort study of older adults in the Netherlands (n study population = 5565). DSM-IV anxiety disorder was ascertained with the Munich version of the Composite International Diagnostic Interview. DSM IV depression was diagnosed with the Schedules for Clinical Assessment of Neuropsychiatry (SCAN) on a different day. Past depression was assessed from general practitioners' records, self-report, and a prior SCAN interview. Of the 457 persons with an anxiety disorder, 11.6% had a comorbid major depression, and another 6.3% had other depressive syndromes. However, 49.3% of persons with an anxiety disorder experienced or had in the past experienced a depressive episode. Our study suggests that comorbid depression in older adults with anxiety disorders may be less prevalent than previously suggested. However, the relation of current anxiety disorders with past depression is substantial. PMID- 22547299 TI - Effect of gold nanosphere surface chemistry on protein adsorption and cell uptake in vitro. AB - Gold nanoparticles exhibit unique spectral properties that make them ideal for biosensing, imaging, drug delivery, and other therapeutic applications. Interaction of gold nanoparticles within biological environments is dependent on surface characteristics, which may rely on particular capping agents. In this study, gold nanospheres (GNS) synthesized with different capping agents- specifically citric acid (CA) and tannic acid (TA)--were compared for serum protein adsorption and cellular uptake into a lung epithelial cell line (A549). Both GNS samples exhibited noticeable protein adsorption based on surface charge data after exposure to serum proteins. Light scattering measurements revealed that GNS-CA-protein composites were smaller and less dense compared to GNS-TA protein composites. The cell uptake characteristics of these nanoparticles were also different. GNS-CA formed large clusters and elicited high uptake, while GNS TA were taken up as discrete particles, possibly through nonendosomal mechanisms. These results indicate that the capping agents used for GNS synthesis result in unique biological interactions. PMID- 22547300 TI - Wnt signaling in the pathogenesis of multiple sclerosis-associated chronic pain. AB - Many multiple sclerosis (MS) patients develop chronic pain, but the underlying pathological mechanism is unknown. Mice with experimental autoimmune encephalomyelitis (EAE) have been widely used to model MS-related neurological complications, including CNS demyelination, neuroinflammation and motor impairments. Similar to MS patients, EAE mice also develop chronic pain. We are interested in elucidating the potential involvement of Wnt signaling in the pathogenesis of chronic pain in EAE mice. In this study, we characterized the expression of Wnt signaling proteins in the spinal cord dorsal horn (SCDH) of EAE mice, by immunoblotting and immunostaining. The EAE model was created by immunization of adult mice (C57BL/6, 10 weeks) with myelin oligodendrocyte glycoprotein (MOG) 35-55. Robust mechanical hyperalgesia and allodynia were developed in both fore- and hindpaws of the EAE mice. Wnt3a, a prototypical Wnt ligand for the canonical pathway, was significantly increased in the SCDH of the EAE mice. Another key protein in the canonical pathway, beta-catenin, was also significantly up-regulated. In addition, Wnt5a, a prototypic Wnt ligand for the non-canonical pathway, and its receptor (co-receptor) Ror2 were also up-regulated in the SCDH of the EAE mice. We further found that Wnt5a antagonist Box5 and beta catenin inhibitor indomethacin attenuated mechanical allodynia in the EAE mice. Our data collectively suggest that Wnt signaling pathways are up-regulated in the SCDH of the EAE mice and that aberrant activation of Wnt signaling contributes to the development of EAE-related chronic pain. PMID- 22547301 TI - MTA1: a prognosis indicator of postoperative patients with esophageal carcinoma. AB - BACKGROUND: To investigate the overexpression of Metastasis-associated gene 1(MTA1) protein and its relationship to the prognosis in esophageal squamous cell cancer after esophagectomy. METHODS: 174 patients with middle third squamous cell carcinoma of the esophagus underwent complete resection in Provincial Hospital Affiliated to Shandong University between January 2002 and January 2005. The overexpression of MTA1 protein was detected by immunohistochemistry. Kaplan-Meier method was performed to calculate the survival rate, Cox regression multivariate analysis was performed to determine independent prognostic factors. RESULTS: MTA1 protein overexpression rate in T1, T2, and T3 patients was separately 25.0, 31.9, and 53%, the difference of MTA1 protein overexpression between them was statistically significant (p = 0.017). The overexpression of MTA1 protein in patients with lymph node metastasis was significantly higher than those without metastasis (p = 0.042). MTA1 protein overexpression correlated with significantly worsened 5-year survival for all patients as well as those with T2 and T3 tumors, N0 nodal status or N1 nodal status. However, no significant correlations with T1 patients (p = 0.061). The result of Cox analysis demonstrated that N stage and MTA1 protein overexpression were independent prognostic factors. CONCLUSION: MTA1 protein overexpression was detected in esophageal squamous cell carcinoma and was found to be significantly associated with the T stage. The patients with MTA1 protein overexpression had a significantly lower 5-year survival rate than without MTA1 protein overexpression. Lymph node metastasis and MTA1 protein overexpression were independent prognostic factors. PMID- 22547302 TI - Transapical minimally invasive aortic valve implantation and conventional aortic valve replacement in octogenarians. AB - OBJECTIVE: Transcatheter aortic valve implantation (TAVI) has been developed to minimize the operative trauma in high-risk patients. Patient selection for TAVI is still subject to debate and octogenarians are often regarded as high-risk patients. METHODS: In this single-center study, data of 169 octogenarians who received conventional AVR (90) or TAVI (79) have been analyzed retrospectively according to the endpoint definitions of the Valve Academic Research Consortium to answer the following questions: (a) Should patients due to their age of 80 years or older be considered as high risk? (b) Is the EuroSCORE a suitable tool for estimating mortality after AVR or TAVI in octogenarians? (c) Is TAVI the procedure of choice for octogenarians? RESULTS: TAVI patients showed higher comorbid conditions concerning an existing renal dysfunction (31 vs. 56%, p = 0.001), peripheral vascular disease (6 vs. 30%, p < 0.001), diabetes (19% vs. 49%, p < 0.001), a decreased ejection fraction (LVEF < 30%: 2 vs. 13%, p < 0.05), and pulmonary hypertension (23 vs. 48%; p < 0.005) with an increase of the perioperative risk represented by logistic EuroSCORE (AVR 11% +/- 1.27 vs. TAVI 38% +/- 1.35; p < 0.0005) and STS Score (7% +/- 0.52 vs. 14% +/- 0.56; p < 0.0005). All-cause and cardiovascular-cause in-hospital or 30-day mortality was 5.6% (n = 5) and 3.4% (n = 3) in the AVR cohort and 8.8% (n = 7) and 7.6% (n = 6) in TAVI-patients (p = 0.55; p = 0.31), respectively. The overall combined safety endpoint at 30 days was 22.2% (n = 20) in AVR patients and 29.1% (n = 23) with regard to the TAVI group (p = 38). Analysis of cerebrovascular complications, vascular complications, and pacemaker revealed no significant differences. In the AVR group, actuarial survival at 6 months and 1 and 2 years was 89, 78, and 74%, respectively. Data of the TAVI patients are only available for a follow-up of 6 months and revealed a survival of 85%. CONCLUSION: AVR and TAVI in octogenarians show comparable results, but the analyzed cohorts differ significantly in their risk profile. The results indicate an overrated perioperative mortality using the EuroSCORE but on the other hand logistic EuroSCORE represents articulately the different risk profile of the two groups. For this reason, we consider the EuroSCORE still to be a useful tool for preoperative risk assessment. Moreover, octogenarians cannot per se be considered as "true high risk" patients. Differentiated clinical judgment is most important for reasonable decision making. PMID- 22547303 TI - Midterm follow-up of patients with perioperative myocardial infarction after coronary artery bypass surgery: clinical significance of different treatment strategies. AB - BACKGROUND: The purpose of the study was to analyze the causes of postoperative myocardial infarction (PMI) and the impact of different treatment strategies on (1) postoperative outcome, (2) major adverse events (MACE), and (3) postoperative Canadian Cardiovascular Society (CCS) at 3-year follow-up. PATIENTS: Between May 2001 and July 2006, 113 patients with PMI were categorized in three groups: (A) conservative therapy (50 patients); (B) percutaneous coronary intervention (PCI) (25 patients), and (C) re-CABG (38 patients). RESULTS: Overall in-hospital mortality was 7.1% (n = 8), being 10.0% in group A (n = 5), 4.0% in group B (n = 1) and 5.3% (n = 2) in group C (p = n.s.), respectively. The cumulative survival rates at 3 years were 90% for group A, 92% for group B, and 89.5% for group C (p = n.s). The MACE rate at 3-year follow-up for all patients was 27.4% and was significantly higher in group A (34%) and group B (36%) compared with group C (13.2%) (p = 0.05). Mean CCS was significantly reduced at follow-up in the groups compared with the preoperative angina class. However, group B and C showed a significant improvement in CCS compared with group A (p = 0.044/p < 0.001). Further group C was superior to group B (p = 0.032). CONCLUSION: At 3 years of follow-up, this study showed no survival benefits from any therapeutical procedure; however patients treated with re-CABG had better freedom from repeat revascularization procedures and from MACCE. In addition, the conservative and PCI group had a higher incidence of recurrence of angina. PMID- 22547304 TI - Incidence of deep sternal wound infection is not reduced with autologous platelet rich plasma in high-risk cardiac surgery patients. AB - BACKGROUND: Deep sternal wound infections (DSWI) remain a devastating complication in cardiac surgery applying full sternotomy. As the risk profile in cardiac surgery changed toward an older and sicker population, the incidence of DSWI increases. Platelet rich plasma (PRP) holds promise in tissue regeneration with respect to bone regeneration, reduction of bleeding, and accelerated wound healing. The effect of PRP on DSWI was investigated in high-risk patients undergoing cardiac surgery with full sternotomy. METHODS: 196 consecutive patients at risk of DSWI were randomized to application of autologous PRP before sternal wiring (n = 97) or control (n = 99). All patients underwent cardiac surgery on cardiopulmonary bypass with cardioplegic cardiac arrest. Endpoint was occurrence of DSWI requiring revision surgery. RESULTS: Demographic, intraoperative, and perioperative variables as well as risk factors were comparable between groups. Incidence of DSWI was not different between the PRP group and the control-group (6/97 (6.2%) vs. 3/99 (3.0%); n.s.). CONCLUSIONS: Local application of autologous PRP in cardiac surgery patients with full sternotomy at high risk for sternal complications did not reduce the incidence of DSWI. PMID- 22547305 TI - Use of Impella 5L for acute allograft rejection postcardiac transplant. AB - The contribution of acute allograft rejection to posttransplant mortality has decreased over time primarily due to improvements in maintenance immunosuppression and in the diagnosis and treatment of rejection. Nevertheless, acute heart allograft rejection remains an important clinical problem.2 In the setting of an acute allograft rejection, mechanical circulatory support has been provided by a variety of devices, ranging from intra-aortic balloon pumps (IABP) to extracorporeal membrane oxygenators (ECMO), left ventricular assist devices (LVADs) and biventricular assist devices (BIVADs).2 We present a 45-year-old patient with cardiogenic shock secondary to acute allograft rejection after orthotopic heart transplantation. Patient continued to have poor hemodynamics and low cardiac output despite being on high doses of inotropes and an aggressive immunosuppression. Hence, a decision was made to support the hemodynamics with an Impella LP 5.0 (Abiomed Inc, Danvers, MA) left ventricular assist device (LVAD). PMID- 22547306 TI - Midterm results of beating heart coronary bypass surgery for non-left internal thoracic artery anastomosis according to grafting design and implications of intraoperative flow characteristics on graft patency. AB - The aim of the present study was to investigate the midterm patency of coronary artery bypass grafting (CABG) surgery according to the grafting design and intraoperative flow characteristics. Between March 2007 and July 2008, 218 beating heart CABG patients were prospectively divided into two groups according to the non-left internal thoracic artery (LITA) bypass grafting design; Group I (n = 161, aorta-saphenous vein) and Group II (n = 57, LITA-radial artery composite grafting). Preoperative patient characteristics and the additive EuroSCORE were similar between the two groups (p = 0.82). Mean flow (mL/min) and pulsatility index were measured intraoperatively and coronary multidetector computed tomography (MDCT) was performed immediately and 1 year postoperatively. For the non-LITA bypasses, the mean flow was significantly greater in group I than in group II (27.9 +/- 17.7 mL/min vs. 17.6 +/- 12.6 mL/min, p < 0.001). Uni- and multivariate analysis showed the grafting design (group I) to be the only predictive factor for the favorable midterm patency of the non-LITA grafts (p < 0.001). There were no significant intergroup differences in the incidence of complications including that of stroke or death in the immediate postoperative period. A total of four patients had cerebral events: three in group I (1.87%) and one in group II (1.75%). The overall rates of freedom from graft occlusion for the non-LITA to LAD bypasses at 100, 200, and 300 days were 99, 98, and 89%, respectively, in group I, and 95, 88, and 70%, respectively, in group II (P < 0.01). Overall freedom from graft occlusion for LITA to LAD bypasses showed no significant differences between the two groups (98 vs. 93%, p = 0.053). The results suggest superior intraoperative flow characteristics of the direct aorta saphenous vein bypass grafting design to be attributable for its favorable patency results. PMID- 22547307 TI - Liver: Potential of autotaxin as a diagnostic marker and therapeutic target for itch of cholestasis. PMID- 22547308 TI - IBS: Disease mechanisms in IBS. PMID- 22547310 TI - IBD: Poor outcomes after Clostridium difficile infection in IBD. PMID- 22547309 TI - Vitamin B12 transport from food to the body's cells--a sophisticated, multistep pathway. AB - Vitamin B(12) (B(12); also known as cobalamin) is a cofactor in many metabolic processes; deficiency of this vitamin is associated with megaloblastic anaemia and various neurological disorders. In contrast to many prokaryotes, humans and other mammals are unable to synthesize B(12). Instead, a sophisticated pathway for specific uptake and transport of this molecule has evolved. Failure in the gastrointestinal part of this pathway is the most common cause of nondietary induced B(12) deficiency disease. However, although less frequent, defects in cellular processing and further downstream steps in the transport pathway are also known culprits of functional B(12) deficiency. Biochemical and genetic approaches have identified novel proteins in the B(12) transport pathway--now known to involve more than 15 gene products--delineating a coherent pathway for B(12) trafficking from food to the body's cells. Some of these gene products are specifically dedicated to B(12) transport, whereas others embrace additional roles, which explains the heterogeneity in the clinical picture of the many genetic disorders causing B(12) deficiency. This Review describes basic and clinical features of this multistep pathway with emphasis on gastrointestinal transport of B(12) and its importance in clinical medicine. PMID- 22547311 TI - Genetic characterization of gliomas arising in patients with multiple sclerosis. AB - The co-occurrence of gliomas and multiple sclerosis (MS) in the same patient is uncommon, but a well-reported phenomenon. Most have been high grade astrocytic tumors that developed after the diagnosis of MS, leading authors to postulate that chronic gliosis in demyelinative plaques might be the underlying substrate for secondary induction of a glial neoplasm. Until recently, however, genetic tools have not been available to test the hypothesis that high grade gliomas might arise from longstanding chronic gliosis, with transformation to low grade glioma, and eventually GBM, i.e., be secondary GBMs. We searched our surgical neuropathology and MS Brain Bank databases over the past 25 years (1987-2011) and identified eight cases of co-occurring MS and glioma. After careful review to guarantee both diagnoses, cases were studied by fluorescence in situ hybridization for genetic markers appropriate to diagnosis, as well as by direct sequencing for IDH1/2 and P53. No unusual genetic features were detected in our cohort; further, the 4 GBMs we did identify did not have clinical features of secondary glioblastomas nor did any of the four manifest IDH-1 immunohistochemical expression or IDH1/2 mutations, as might be expected in secondary GBMs. Conversely, PTEN loss and EGFR expression, features often found in primary GBMs, but seldom identified in secondary GBMs, were found in 3 of 4 GBMs. We conclude that gliomas in MS patients have genetic features paralleling counterparts in non-MS patients. There is no strong genetic evidence for GBMs to be secondary GBMs. PMID- 22547312 TI - Lack of an association human dioxin detoxification gene polymorphisms with endometriosis in Japanese women: results of a pilot study. AB - OBJECTIVES: Endometriosis is a chronic disease caused by the presence of endometrial tissue in ectopic locations outside the uterus. Chronic exposure to the environmental pollutant dioxin has been correlated with an increased incidence in the development of endometriosis in non-human primates. We have therefore examined whether there is an association between the polymorphisms of ten dioxin detoxification genes and endometriosis in Japanese women. METHODS: This was a pilot study in which 100 patients with endometriosis and 143 controls were enrolled. The prevalence of five microsatellite and 28 single nucleotide polymorphism markers within ten dioxin detoxification genes (AhR, AHRR, ARNT, CYP1A1, CYP2E1, EPHX1, GSTM1, GSTP1, GSTT1, NAT2) was examined. RESULTS: Taking into account that this analysis was a preliminary study due to its small sample size and genetic power, the results did not show any statistically significant difference between the cases and controls for any of the allele and genotype frequency distributions examined. In addition, no significant associations between the allele/genotype of all polymorphisms and the stage (I-II or III-IV) of endometriosis were observed. CONCLUSION: Based on the findings of this pilot study, we conclude the polymorphisms of the ten dioxin detoxification genes analyzed did not contribute to the etiology of endometriosis among our patients. PMID- 22547313 TI - Application of carbon nanotubes in neurology: clinical perspectives and toxicological risks. AB - Nanomedicine is an emerging field that proposes the application of precisely engineered nanomaterials for the prevention, diagnosis and therapy of certain diseases, including neurological pathologies. Carbon nanotubes (CNT) are a new class of nanomaterials, which have been shown to be promising in different areas of nanomedicine. In this review, the application of CNT interfacing with the central nervous system (CNS) will be described, and representative examples of neuroprosthetic devices, such as neuronal implants and electrodes will be discussed. Furthermore, the possible application of CNT-based materials as regenerative matrices of neuronal tissue and as delivery systems for the therapy of CNS will be presented. PMID- 22547314 TI - Suffruyabiosides A and B, two new monoterpene diglycosides from moutan cortex. AB - Two new monoterpene diglycosides, suffruyabiosides A and B, and seven known compounds 3-9 were isolated from Moutan Cortex (root cortex of Paeonia suffruticosa Andrews). The structures were elucidated on the basis of 2D NMR spectral data. Suffruyabiosides A and B are rare monoterpene diglycosides, including a cellobiose in the molecules. Salicylpaeoniflorin (4) had a antiproliferation effect similar to paeoniflorin (3) on human lung adenocarcinoma epitherial A549 cells. Galloylpaeoniflorin (8) and salicylpaeoniflorin (4) revealed a more pronounced radical scavenging effect than a-tocopherol (positive control). An increase in the number of phenolic hydroxyl groups produced a more effective radical scavenging effect [8 > mudanpioside E (6) > oxypaeoniflorin (5)]. Comparison of the effects of 4 and 5 showed that o-substitution with a phenolic hydroxyl group was more effective than p-substitution. The results suggest that salicylpaeoniflorin (4) may be useful as a cytotoxic and a radical scavenging agent. PMID- 22547315 TI - The biological effects of ivabradine in cardiovascular disease. AB - A large number of studies in healthy and asymptomatic subjects, as well as patients with already established cardiovascular disease (CAD) have demonstrated that heart rate (HR) is a very important and major independent cardiovascular risk factor for prognosis. Lowering heart rate reduces cardiac work, thereby diminishing myocardial oxygen demand. Several experimental studies in animals, including dogs and pigs, have clarified the beneficial effects of ivabradine associated with HR lowering. Ivabradine is a selective inhibitor of the hyperpolarisation activated cyclic-nucleotide-gated funny current (If) involved in pacemaker generation and responsiveness of the sino-atrial node (SAN), which result in HR reduction with no other apparent direct cardiovascular effects. Several studies show that ivabradine substantially and significantly reduces major risks associated with heart failure when added to guideline-based and evidence-based treatment. However the biological effect of ivabradine have yet to be studied. This effects can appear directly on myocardium or on a systemic level improving endothelial function and modulating immune cell migration. Indeed ivabradine is an 'open-channel' blocker of human hyperpolarization-activated cyclic nucleotide gated channels of type-4 (hHCN4), and a 'closed-channel' blocker of mouse HCN1 channels in a dose-dependent manner. At endothelial level ivabradine decreased monocyte chemotactin protein-1 mRNA expression and exerted a potent anti-oxidative effect through reduction of vascular NADPH oxidase activity. Finally, on an immune level, ivabradine inhibits the chemokine-induced migration of CD4-positive lymphocytes. In this review, we discuss the biological effects of ivabradine and highlight its effects on CAD. PMID- 22547316 TI - A new and efficient method for the synthesis of 3,4-disubstituted pyrrolidine-2,5 diones. AB - A newly found reaction for the synthesis of 3,4-disubstituted 1-hydroxy pyrrolidine-2,5-diones from 3-substituted coumarins and nitromethane has been elaborated. The reaction involved a simple and convenient experimental procedure. The applicability of the rearrangement reaction is determined. PMID- 22547317 TI - MALDI-TOF MS analysis of native and permethylated or benzimidazole-derivatized polysaccharides. AB - MALDI-TOF MS provides rapid and sensitive analyses of larger biomolecules. However, MS analyses of polysaccharide have been reported to have lower sensitivity compared to peptides and proteins. Here, we investigated some polysaccharides chemically derivatized by permethylation and ortho-phenylene diamine (OPD) tagging. Methylated glycan is obviously able to improve the sensitivity for mass spectrometry detection. Oxidative condensation by UV activation tagging to saccharides by OPD and peptide-OPD also improve the sensitivity of MALDI-TOF MS analyses. Polysaccharides including dextran, glucomannan, arabinoxylan, arabinogalactan and beta-1,3-glucan, isolated from nutritional supplements of Ganoderma lucidum and Saccharomyces pastorianus were measured using MALDI-TOF MS with 2,5-dihydroxybenzoic acid (2,5-DHB) as the matrix. These glycans were also derivatized to methylated and benzimidazole tagged glycans by chemical transformation for molecular weight analysis. The derivatized polysaccharides showed excellent MALDI-TOF MS signal enhancement in the molecular weight range from 1 to 5 kDa. Here, we demonstrate an efficient method to give glycan-benzimidazole (glycan-BIM) derivatives for polysaccharide determination in MALDI-TOF MS. Therefore, permethylated or benzimidazole derivatized polysaccharides provide a new option for polysaccharide analysis using MALDI-TOF MS. PMID- 22547318 TI - Synthesis and antimicrobial evaluation of some pyrazole derivatives. AB - Reaction of a series of (E)-3-phenyl-4-(p-substituted phenyl)-3-buten-2-ones with p-sulfamylphenyl hydrazine in glacial acetic acid gave the corresponding hydrazones, subsequent treatment of which with 30% HCl afforded pyrazole-1 sulphonamides. On the other hand, refluxing of chalcones with either thiosemicarbazide or isonicotinic acid hydrazide in ethanol containing a few drops of acetic acid gave pyrazoline-1-thiocarboxamides and isonicotinoyl pyrazolines, respectively. The structures of the synthesized compounds were determined on the basis of their elemental analyses and spectroscopic data. The antimicrobial activity of the newly isolated heterocyclic compounds was evaluated against Gram-positive, Gram-negative bacteria and fungi. Most of the compounds showed a moderate degree of potent antimicrobial activity. PMID- 22547319 TI - Synthesis and biological evaluation of new ligustrazine derivatives as anti-tumor agents. AB - To discover new anti-cancer agents with multi-effect and low toxicity, a series of ligustrazine derivatives were synthesized using several effective anti-tumor ingredients of Shiquandabu Wan as starting materials. Our idea was enlightened by the "combination principle" in drug discovery. The ligustrazine derivatives' anti tumor activities were evaluated on the HCT-8, Bel-7402, BGC-823, A-549 and A2780 human cancer cell lines. In addition the angiogenesis activities were valued by the chick chorioallantoic membrane (CAM) assay. 1,7-bis(4-(3,5,6-Trimethylpyrazin 2-yl)-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (4) and 3 alpha,12 alpha dihydroxy-5beta-dholanic acid-3,5,6-trimethylpyrazin-2-methyl ester (5) not only displayed antiproliferative activities on these cancer cells, but also dramatically suppressed normal angiogenesis in CAM. The LD50 value of the compound 5 exceeded 3.0 g/kg by oral administration in mice. PMID- 22547320 TI - Bioassay-guided antidiabetic study of Phaleria macrocarpa fruit extract. AB - An earlier anti-hyperglycemic study with serial crude extracts of Phaleria macrocarpa (PM) fruit indicated methanol extract (ME) as the most effective. In the present investigation, the methanol extract was further fractionated to obtain chloroform (CF), ethyl acetate (EAF), n-butanol (NBF) and aqueous (AF) fractions, which were tested for antidiabetic activity. The NBF reduced blood glucose (p < 0.05) 15 min after administration, in an intraperitoneal glucose tolerance test (IPGTT) similar to metformin. Moreover, it lowered blood glucose in diabetic rats by 66.67% (p < 0.05), similar to metformin (51.11%), glibenclamide (66.67%) and insulin (71.43%) after a 12-day treatment, hence considered to be the most active fraction. Further fractionation of NBF yielded sub-fractions I (SFI) and II (SFII), and only SFI lowered blood glucose (p < 0.05), in IPGTT similar to glibenclamide. The ME, NBF, and SFI correspondingly lowered plasma insulin (p < 0.05) and dose-dependently inhibited glucose transport across isolated rat jejunum implying an extra-pancreatic mechanism. Phytochemical screening showed the presence of flavonoids, terpenes and tannins, in ME, NBF and SFI, and LC-MS analyses revealed 9.52%, 33.30% and 22.50% mangiferin respectively. PM fruit possesses anti-hyperglycemic effect, exerted probably through extra-pancreatic action. Magniferin, contained therein may be responsible for this reported activity. PMID- 22547321 TI - Hydrophilic carotenoids: recent progress. AB - Carotenoids are substantially hydrophobic antioxidants. Hydrophobicity is this context is rather a disadvantage, because their utilization in medicine as antioxidants or in food chemistry as colorants would require some water dispersibility for their effective uptake or use in many other ways. In the past 15 years several attempts were made to synthetize partially hydrophilic carotenoids. This review compiles the recently synthetized hydrophilic carotenoid derivatives. PMID- 22547322 TI - Blood lead levels in schoolchildren living near an industrial zone in Cali, Colombia: the role of socioeconomic condition. AB - This study aimed to determine Blood Lead Levels (BLL) in schoolchildren 6-14 years old exposed to industrial sources of lead and evaluated the role of socioeconomic condition. A cross-sectional study was conducted in an area likely to be exposed to industrial pollutants in northern Cali (i.e., distance and wind direction) and in a "non-exposed" area. In children in two schools of corresponding study areas, venous samples (5 ml) were collected to determine BLL by graphite furnace absorption spectrometry. Using regression models, we evaluated the association between risk factors to BLL and the effect of modification with variables of socioeconomic condition. We enrolled 350 schoolchildren. Schoolchildren in the exposed area had higher prevalence of BLL of >= 5 MUg/dl (44.2 vs. 8.2 %, p = 0.000) than those in non-exposed area. A positive association was found between exposure and BLL of >= 5 MUg/dl (prevalence ratios (PR), 6.68; 95 % confidence interval (95 % CI), 3.95, 11.29). Demographic characteristics and socioeconomic condition such as age (PR, 1.45; 95 % CI, 1.03, 2.04), sex (PR, 1.84; 95 % CI, 1.30, 2.60), race (PR, 2.32; 95 % CI, 1.39, 3.89) and socioeconomic position (SEP; PR, 2.02; 95 % CI, 1.35, 3.04) were statistically significant and independently associated with BLL. There was a synergistic interaction between exposure to the industrial zone and SEP for higher BLL (coefficient, 0.80; 95 % CI, 0.17, 1.43). Residence in the northern urban area of Cali exposed to pollutants of an industrial zone is associated to an increased risk of higher BLL, especially among children from low SEC who are at greater risk of exposure and susceptibility. PMID- 22547323 TI - Comparison between two thermoplastic root canal obturation techniques regarding extrusion of root canal filling--a retrospective in vivo study. AB - OBJECTIVES: The aim of this study was to compare two different thermoplastic techniques--a core-carrier technique (Thermafil) and warm vertical compaction--in terms of overextension of root canal filling in vivo. MATERIALS AND METHODS: Flaring of 88 teeth was conducted using Pro Files .04 as finishing files, and the teeth were obturated using Thermafil. Flaring of 74 teeth was performed using Pro Files .06 as finishing files, and the teeth were obturated using warm vertical compaction. RESULTS: Seventy (80 %) of the teeth obturated using Thermafil and 31 (42 %) teeth obturated using warm vertical compaction show extruded root canal filling. In contrast to Thermafil, there is a higher rate of extruded root canal filling of teeth with more than one root canal using warm vertical compaction. CONCLUSION: Thermafil demonstrated a higher rate of extruded root canal filling compared to warm vertical compaction. Warm vertical compaction is a more predictable method of filling compared to Thermafil. CLINICAL RELEVANCE: Root canal filling extrusion will cause irritation of the surrounding tissue and impair repair processes. In the present in vivo study, there was a higher rate of root canal filling extrusion using Thermafil compared to warm vertical compaction. PMID- 22547324 TI - Mandibular bone changes in 24 years and skeletal fracture prediction. AB - OBJECTIVES: The objectives of the investigation were to describe changes in mandibular bone structure with aging and to compare the usefulness of cortical and trabecular bone for fracture prediction. MATERIALS AND METHODS: From 1968 to 1993, 1,003 women were examined. With the help of panoramic radiographs, cortex thickness was measured and cortex was categorized as: normal, moderately, or severely eroded. The trabeculation was assessed as sparse, mixed, or dense. RESULTS: Visually, the mandibular compact and trabecular bone transformed gradually during the 24 years. The compact bone became more porous, the intertrabecular spaces increased, and the radiographic image of the trabeculae seemed less mineralized. Cortex thickness increased up to the age of 50 and decreased significantly thereafter. At all examinations, the sparse trabeculation group had more fractures (71-78 %) than the non-sparse group (27-31 %), whereas the severely eroded compact group showed more fractures than the less eroded groups only in 1992/1993, 24 years later. Sparse trabecular pattern was associated with future fractures both in perimenopausal and older women (relative risk (RR), 1.47-4.37) and cortical erosion in older women (RR, 1.35-1.55). RR for future fracture associated with a severely eroded cortex increased to 4.98 for cohort 1930 in 1992/1993. RR for future fracture associated with sparse trabeculation increased to 11.43 for cohort 1922 in 1992/1993. CONCLUSION: Dental radiographs contain enough information to identify women most at risk of future fracture. CLINICAL RELEVANCE: When observing sparse mandibular trabeculation, dentists can identify 40-69 % of women at risk for future fractures, depending on participant age at examination. PMID- 22547325 TI - Differential changes of extracellular aspartate and glutamate in the striatum of domestic chicken evoked by high potassium or distress: an in vivo microdialysis study. AB - It has long been proposed that L: -aspartate (Asp) is an excitatory neurotransmitter similar to L: -glutamate (Glu) but with distinct signaling properties. The presence of Asp in excitatory synapses of the medial striatum/nucleus accumbens of domestic chicks suggests that Asp plays a role of neurotransmitter also in the avian brain. Neurotransmitters are released from the presynaptic bouton mostly by Ca(2+) dependent exocytosis. We used in vivo microdialysis to monitor the simultaneous changes of the extracellular levels of Asp and Glu in the medial striatum of young post-hatch domestic chicks. Microdialysis samples were collected from freely moving birds at 5 min intervals and analysed off-line using capillary electrophoresis. Event-related elevations of extracellular Glu and Asp concentrations in response to handling stress and to high KCl (50 mM) were observed. Increase of Glu and Asp on handling stress was 200 and 250 %, whereas on KCl stimulation the values were 300 and 1,000 %, respectively, if stress was applied before high KCl, and 150 and 200 %, respectively, in the absence of stress. In most cases, the amino acids showed correlated changes, Asp concentrations being consistently smaller at resting but exceeding Glu during stimulation. Using Ca(2+) free medium, the KCl triggered elevation of Glu was reduced. When KCl stimulation was combined with tetrodotoxin infusion, there was no significant elevation in Asp or in Glu suggesting that most of the extracellular excitatory amino acids were released by synaptic mechanisms. The results support the suggestion that Asp is co-released with Glu and may play a signaling role (as distinct from that of glutamate) in the striatum of birds. PMID- 22547326 TI - An unprecedented switching of the second-order nonlinear optical response in aggregate bis(salicylaldiminato)zinc(II) Schiff-base complexes. AB - A luminescent bis(salicylaldiminato)zinc(II) Schiff-base complex, 1, is characterized by a concentration dependent second-order nonlinear optical response, related to the degree of aggregation of the complex in a dichloromethane solution. The formation of the monomeric adduct, by addition of a Lewis base, such as pyridine, to concentrated solutions of 1, leads to a switch on of the quadratic hyperpolarizability. This represents an unprecedented mode of NLO switching in molecular materials. PMID- 22547328 TI - Barriers to knowledge production, knowledge translation, and urban health policy change: ideological, economic, and political considerations. AB - In this paper, we consider social forces that affect the processes of both knowledge production and knowledge translation in relation to urban health research. First, we briefly review our conceptual model, derived from a social conflict framework, to outline how unequal power relations and health inequalities are causally linked. Second, we critically discuss ideological, political, and economic barriers that exist within academia that affect knowledge production related to urban health and health inequalities. Third, we broaden the scope of our analysis to examine how the ideological, political, and economic environment beyond the academy creates barriers to health equity policy making. We conclude with some key questions about the role that knowledge translation can possibly play in light of these constraints on research and policy for urban health. PMID- 22547327 TI - Directly observed versus self-administered antiretroviral therapies: preference of HIV-positive jailed inmates in San Francisco. AB - Directly observed therapy (DOT) of antiretroviral (ARV) medications has beneficial effects on HIV treatment for incarcerated inmates but has been associated with limited continuation after release and inadvertent disclosure of HIV status. Guided self-administered therapy (g-SAT) may be a preferred method of ARV delivery and may encourage medication-taking behavior. We surveyed the preference of 102 HIV-positive jailed inmates at the San Francisco City and County Jails regarding receiving ARVs via DOT versus g-SAT while incarcerated. Participants overwhelmingly preferred g-SAT over DOT. PMID- 22547329 TI - Effectivity of freeze-dried form of Lactobacillus fermentum AD1-CCM7421 in dogs. AB - The impact of probiotic supplementation of canine-derived strain Lactobacillus fermentum AD1-CCM7421 in freeze-dried form on quantitative composition of microbiota and short-chain fatty acid profile in feces of dogs was demonstrated by two independent studies (straightforward repeated-measures model; study I: a dose of 2 g per dog for 2 weeks, 10(8) CFU/g, n = 12; study II: 1 g per dog for 1 week, 10(7) CFU/g, n = 11. The results revealed a significant increase of lactic acid bacteria population persisting also after the cessation of probiotic application in both studies. A reduction of clostridia (study I, p (sum) < 0.01) and tested Gram-negative bacterial genera (coliforms, Aeromonas sp., Pseudomonas sp., study II, p < 0.05) was also detected. The strain AD1-CCM7421 colonized the canine digestive tract in sufficient numbers (10(5)-10(6) CFU/g) and it persisted in the majority of dogs after cessation of probiotic application. An increase of short-chain fatty acid concentrations (study I: butyric, succinic, valeric, formic acid) especially in the early post-treatment phase (p < 0.05) most likely led to a decrease of fecal pH value (p < 0.05) without negative influence on fecal consistency throughout the studies. PMID- 22547330 TI - Analysis of region-specific changes in gene expression upon treatment with citalopram and desipramine reveals temporal dynamics in response to antidepressant drugs at the transcriptome level. AB - RATIONALE: The notion that the onset of action of antidepressant drugs (ADs) takes weeks is widely accepted; however, the sequence of events necessary for therapeutic effects still remains obscure. OBJECTIVE: We aimed to evaluate a time course of ADs-induced alterations in the expression of 95 selected genes in 4 regions of the rat brain: the prefrontal and cingulate cortices, the dentate gyrus of the hippocampus, and the amygdala. METHODS: We employed RT-PCR array to evaluate changes during a time-course (1, 3, 7, 14, and 21 days) of treatments with desipramine (DMI) and citalopram (CIT). In addition to repeated treatment, we also conducted acute treatment (a single dose of drug followed by the same time intervals as the repeated doses). RESULTS: Time-dependent and structure specific changes in gene expression patterns allowed us to identify spatiotemporal differences in the molecular action of two ADs. Singular value decomposition analysis revealed differences in the global gene expression profiles between treatment types. The numbers of characteristic modes were generally smaller after CIT treatment than after DMI treatment. Analysis of the dynamics of gene expression revealed that the most significant changes concerned immediate early genes, whose expression was also visualized by in situ hybridization. Transcription factor binding site analysis revealed an over representation of serum response factor binding sites in the promoters of genes that changed upon treatment with both ADs. CONCLUSIONS: The observed gene expression patterns were highly dynamic, with oscillations and peaks at various time points of treatment. Our study also revealed novel potential targets of antidepressant action, i.e., Dbp and Id1 genes. PMID- 22547331 TI - Varenicline decreases alcohol consumption in heavy-drinking smokers. AB - RATIONALE: Emerging evidence suggests that the alpha4beta2 form of the nicotinic acetylcholine receptor (nAChR) modulates the rewarding effects of alcohol. The nAChR alpha4beta2 subunit partial agonist varenicline (ChantixTM), which is approved by the Food and Drug Administration for smoking cessation, also decreases ethanol consumption in rodents (Steensland et al., Proc Natl Acad Sci U S A 104:12518-12523, 2007) and in human laboratory and open-label studies (Fucito et al., Psychopharmacology (Berl) 215:655-663, 2011; McKee et al., Biol Psychiatry 66:185-190 2009). OBJECTIVES: We present a randomized, double-blind, 16-week study in heavy-drinking smokers (n = 64 randomized to treatment) who were seeking treatment for their smoking. The study was designed to determine the effects of varenicline on alcohol craving and consumption. Outcome measures included number of alcoholic drinks per week, cigarettes per week, amount of alcohol craving per week, cumulative cigarettes and alcoholic drinks consumed during the treatment period, number of abstinent days, and weekly percentage of positive ethyl glucuronide and cotinine screens. RESULTS: Varenicline significantly decreases alcohol consumption (chi (2) = 35.32, p < 0.0001) in smokers. Although varenicline has previously been associated with suicidality and depression, side effects were low in this study and declined over time in the varenicline treatment group. CONCLUSIONS: Varenicline can produce a sustained decrease in alcohol consumption in individuals who also smoke. Further studies are warranted to assess varenicline efficacy in treatment-seeking alcohol abusers who do not smoke and to ascertain the relationship between varenicline effects on smoking and drinking. PMID- 22547333 TI - Automatic model-based contour detection of left ventricle myocardium from cardiac CT images. AB - PURPOSE: For accurate evaluation of myocardial perfusion on computed tomography images, precise identification of the myocardial borders of the left ventricle (LV) is mandatory. In this article, we propose a method to detect the contour of LV myocardium automatically and accurately. METHODS: Our detection method is based on active shape model. For precise detection, we estimate the pose and shape parameters separately by three steps: LV coordinate system estimation, myocardial shape estimation, and transformation. In LV coordinate system estimation, we detect heart features followed by the entire LV by introducing machine-learning approach. Since the combination of two types feature detection covers the LV variation, such as pose or shape, we can estimate the LV coordinate system robustly. In myocardial shape estimation, we minimize the energy function including pattern error around myocardium with adjustment of pattern model to input image using estimated concentration of contrast dye. Finally, we detect LV myocardial contours in the input images by transforming the estimated myocardial shape using the matrix composed of the vectors calculated by the LV coordinate system estimation. RESULTS: In our experiments with 211 images from 145 patients, mean myocardial contours point-to-point errors for our method as compared to ground truth were 1.02 mm for LV endocardium and 1.07 mm for LV epicardium. The average computation time was 2.4 s (on a 3.46 GHz processor with 2-multithreading process). CONCLUSIONS: Our method achieved accurate and fast myocardial contour detection which may be sufficient for myocardial perfusion examination. PMID- 22547332 TI - NMDA receptor involvement in antidepressant-like effect of pioglitazone in the forced swimming test in mice. AB - RATIONALE: Previously, we showed that pioglitazone exerts its antidepressant-like effect through peroxisome proliferator-activated receptor gamma receptors and demonstrated the possible involvement of calcium-dependent nitric oxide synthase inhibitors. Based upon the in vitro results, pioglitazone reduces N-methyl-D aspartate (NMDA)-mediated calcium currents in hippocampal neurons. OBJECTIVE: In this study, we evaluated the involvement of the NMDA receptor (NMDAR) on the antidepressant-like effect of pioglitazone in the forced swimming test (FST) in mice. METHOD: After the assessment of locomotor activity in the open-field test, mice were forced to swim individually and the immobility time of the last 4 min was evaluated. Pioglitazone was administered orally with doses of 5, 10, and 20 mg/kg 4 h before FST. To assess the involvement of NMDARs in the possible antidepressant-like effect of pioglitazone, a selective glutamate receptor agonist, NMDA (75 mg/kg, intraperitoneally [i.p.] or 20 ng/mouse, intracerebroventricularly [i.c.v.]), was administered before pioglitazone (20 mg/kg). To further determine a possible role of NMDARs in this effect, a noncompetitive antagonist of the NMDA, MK-801 (0.05 mg/kg, i.p. or 100 ng/mouse, i.c.v.), was coadministered with pioglitazone (10 mg/kg) 4 h prior to FST. RESULTS: Pioglitazone (20 mg/kg) administered 4 h prior to FST significantly reduced the immobility time. Coadministration of the noneffective doses of pioglitazone and MK-801 revealed an antidepressant-like effect in FST. Moreover, NMDA significantly reversed the antidepressant-like effect of pioglitazone administered 4 h prior to FST. CONCLUSION: The antidepressant-like effect of pioglitazone in the FST is mediated partly through NMDAR signaling. This study provides a new approach for the treatment of depression. PMID- 22547334 TI - Cost-effectiveness of bulk-tank milk testing for surveys to demonstrate freedom from infectious bovine rhinotracheitis and bovine enzootic leucosis in Switzerland. AB - In Switzerland, annual surveys to substantiate freedom from infectious bovine rhinotracheitis (IBR) and enzootic bovine leucosis (EBL) are implemented by a random allocation of farms to the respective survey as well as blood sampling of individual animals at farm level. Contrary to many other European countries, bulk tank milk (BTM) samples have not been used for active cattle disease surveillance for several years in Switzerland. The aim of this project was to provide a financial comparison between the current surveillance programme consisting of blood sampling only and a modified surveillance programme including BTM sampling. A financial spreadsheet model was used for cost comparison. Various surveillance scenarios were tested with different sample sizes and sampling frequencies for BTM samples. The costs could be halved without compromising the power to substantiate the freedom from IBR and EBL through the surveillance programme. Alternatively, the sensitivity could be markedly increased when keeping the costs at the actual level and doubling the sample size. The risk-based sample size of the actual programme results in a confidence of 94,18 % that the farm level prevalence is below 0,2 %. Which the doubled sample size, the confidence is 99,69 % respectively. PMID- 22547335 TI - [Is bovine leishmaniasis spreading in Switzerland?]. AB - The purpose of the present study was based upon the first diagnosed bovine cutaneous leishmaniasis in a cow in Switzerland in April 2009. We continued descriptively the search for other bovine cases in Switzerland. We carried out similar investigations in the original farm where the case had occurred, and in parallel also in the neighboring farm. Additionally, veterinary practitioners sent us an overall of 12 suspected cases of bovine leishmaniasis. Following diagnostic investigations, all cases were negative for Leishmania. The occurrence of this infection appears therefore to be a very rare event. Finally some differential diagnoses are discussed. PMID- 22547336 TI - [Chronic diseases of the nose and nasal sinuses in cats: a retrospective study]. AB - In this retrospective study of 41 cats with chronic nasal disease diagnoses included nasal neoplasia (n = 19), idiopathic chronic rhinosinusitis (ICRS) (n = 12), nasopharyngeal polyps (n = 3), foreign bodies (n = 2), nasopharyngeal stenosis (n = 1) and nasal aspergillosis (n = 1). In 3 cats diagnosis could not be established despite thorough work-up. Gender, indoor or outdoor housing, quality or quantity of nasal discharge, bacteriological findings of nasal flushes, radiology and CT findings did not differ significantly between cats with neoplasia and cats with ICRS. Cats with neoplasia were older (3 - 15, median 11 years) and showed clinical signs for a shorter period of time (1 - 8, median 2 months) than cats with ICRS (age 1 - 13, median 7.5 years; signs: 1 - 36, median 5 months). In all cats with neoplasia a mass was detected rhinoscopically, while this was only seen in 30 % of cats with ICRS. The exact diagnosis has to be established by examination of biopsy samples. A combination of physical examination, imaging studies and rhinoscopy with cytological and histopathological examination of samples enhances the likelihood for a correct diagnosis. PMID- 22547337 TI - Proposal for a new radiological index to determine skull conformation in the dog. PMID- 22547340 TI - Administrative data algorithms to identify second breast cancer events following early-stage invasive breast cancer. AB - BACKGROUND: Studies of breast cancer outcomes rely on the identification of second breast cancer events (recurrences and second breast primary tumors). Cancer registries often do not capture recurrences, and chart abstraction can be infeasible or expensive. An alternative is using administrative health-care data to identify second breast cancer events; however, these algorithms must be validated against a gold standard. METHODS: We developed algorithms using data from 3152 women in an integrated health-care system who were diagnosed with stage I or II breast cancer in 1993-2006. Medical record review served as the gold standard for second breast cancer events. Administrative data used in algorithm development included procedures, diagnoses, prescription fills, and cancer registry records. We randomly divided the cohort into training and testing samples and used a classification and regression tree analysis to build algorithms for classifying women as having or not having a second breast cancer event. We created several algorithms for researchers to use based on the relative importance of sensitivity, specificity, and positive predictive value (PPV) in future studies. RESULTS: The algorithm with high specificity and PPV had 89% sensitivity (95% confidence interval [CI] = 84% to 92%), 99% specificity (95% CI = 98% to 99%), and 90% PPV (95% CI = 86% to 94%); the high-sensitivity algorithm had 96% sensitivity (95% CI = 93% to 98%), 95% specificity (95% CI = 94% to 96%), and 74% PPV (95% CI = 68% to 78%). CONCLUSIONS: Algorithms based on administrative data can identify second breast cancer events with high sensitivity, specificity, and PPV. The algorithms presented here promote efficient outcomes research, allowing researchers to prioritize sensitivity, specificity, or PPV in identifying second breast cancer events. PMID- 22547341 TI - A comment on "Separation of chiral molecules: a way to homochirality". PMID- 22547343 TI - Ionising irradiation alters the dynamics of human long interspersed nuclear elements 1 (LINE1) retrotransposon. AB - It is important to identify the mechanism by which ionising irradiation induces various genomic alterations in the progeny of surviving cells. Ionising irradiation activates mobile elements like retrotransposons, although the mechanism of its phenomena consisting of transcriptions and insertions of the products into new sites of the genome remains unclear. In this study, we analysed the effects of sparsely ionising X-rays and densely ionising carbon-ion beams on the activities of a family of active retrotransposons, long interspersed nuclear elements 1 (L1). We used the L1/reporter knock-in human glioma cell line, NP 2/L1RP-enhanced GFP (EGFP), that harbours full-length L1 tagged with EGFP retrotransposition detection cassette (L1RP-EGFP) in the chromosomal DNA. X-rays and carbon-ion beams similarly increased frequencies the transcription from L1RP EGFP and its retrotransposition. Short-sized de novo L1RP-EGFP insertions with 5' truncation were induced by X-rays, while full-length or long-sized insertions (>5 kb, containing ORF1 and ORF2) were found only in cell clones irradiated by the carbon-ion beams. These data suggest that X-rays and carbon-ion beams induce different length of de novo L1 insertions, respectively. Our findings thus highlight the necessity to investigate the mechanisms of mutations caused by transposable elements by ionising irradiation. PMID- 22547344 TI - Sunlight and vitamin D affect DNA damage, cell division and cell death in human lymphocytes: a cross-sectional study in South Australia. AB - The ultraviolet (UV)-B spectrum in solar UV radiation is essential for stimulating the epidermal production of vitamin D but also damages DNA and causes cancer in exposed cells. We examined the role of solar UV in inducing DNA damage in blood lymphocytes and the possible modulation of this damage by serum 25 hydroxy vitamin D (25(OH)D) in 207 male and female participants from South Australia. Personal solar UV exposure was estimated from hours of outdoor exposure recalled at the time of blood collection for analysis of DNA damage in lymphocytes, using the cytokinesis-block micronucleus cytome (CBMN-cyt) assay and of serum 25(OH)D. We examined the association between solar UV exposure, serum 25(OH)D and DNA damage using multiple linear regression, with age, sex, body mass index and alcohol consumption as covariates. The frequency of cells with micronuclei (a biomarker of chromosome breakage or loss) increased with increasing sun exposure [% increase = 5.24; 95% confidence interval (CI): 0.35 to 10.37 P-value = 0.04] but cells with nucleoplasmic bridges (a biomarker of misrepair of DNA strand breaks or telomere end fusions) decreased (% increase = 8.38; 95% CI: -14.32 to -2.03 P-value = 0.01). There was also a fall in the nuclear division index (NDI) (% increase = -1.01; 95% CI: -2.00 to 0.00 P-value = 0.05), suggesting diminished mitogenic response and, possibly, immune suppression. There was no overall relationship between 25(OH)D and DNA damage. There were, however, weak modulating effects of 25(OH)D on the associations of solar UV exposure with micronucleus formation and with NDI (P-interaction = 0.03 and 0.05, respectively), where the increase in micronuclei and fall in NDI with increasing solar UV were greater at serum 25(OH)D levels <50 nmol/l. Thus, the influence of solar UV exposure in causing DNA damage or immune suppression in internal tissues may be stronger when vitamin D levels are low. PMID- 22547345 TI - Probing into the biological processes influenced by ESC factor and oncoprotein HMGA2 using iPSCs. AB - Induced pluripotent stem cells (iPSCs) are rapidly evolving into an important research tool due to their close resemblance with pluripotent embryonic stem cells (ESCs). Of particular interest at this point are iPSC applications in disease modeling and drug discovery/testing. The high mobility group AT-hook 2 (HMGA2) protein is a nonhistone chromatin factor normally expressed in ESCs and during early developmental stages. Aberrant HMGA2 expression is associated, for example, with abnormal body stature, diabetes mellitus, heart development and uterine leiomyomas. Furthermore, the protein is re-expressed in many primary tumor cells and plays an important role in metastasis. Here we used iPSC formation in conjunction with exogenous human HMGA2 expression to gain insight into biological functions of HMGA2. Gene expression profiling and gene ontology analyses showed that anatomical development and cell adhesion/differentiation processes are strongly affected by HMGA2. This could help to uncover, at the molecular level, some of the known phenotypic consequences of aberrant HMGA2 expression. Furthermore, our data showed that expression of key diabetes susceptibility genes is influenced by HMGA2, which revealed an interesting link to the recently indentified Lin28/let-7 pathway regulating mammalian glucose metabolism. Contrary to a previous report, our results indicate that HMGA2 is not involved in the regulation of telomerase gene expression. Finally, our data support a model in which tight regulation of intracellular HMGA2 levels is important both to maintain a pluripotent ESC state and to induce differentiation into certain cell lineages during later developmental stages. PMID- 22547346 TI - Induced expression of STIM1 sensitizes intestinal epithelial cells to apoptosis by modulating store-operated Ca2+ influx. AB - INTRODUCTION: Apoptosis plays a critical role in the maintenance of gut mucosal epithelial homeostasis and is tightly regulated by numerous factors including intracellular Ca(2+). Canonical transient receptor potential channel-1 (TRPC1) is expressed in intestinal epithelial cells (IECs) and functions as a store-operated Ca(2+) channel. We have recently demonstrated that increased TRPC1 activity sensitizes IECs to apoptosis, but the upstream signaling initiating TRPC1 activation remains elusive. The novel protein, stromal interaction molecule 1 (STIM1), is shown to act as a store Ca(2+) sensor, and it can rapidly translocate to the plasma membrane where it directly interacts with TRPC1. The current study determined whether STIM1 plays an important role in the regulation of IEC apoptosis by activating TRPC1 channel activity. METHODS: Studies were conducted in IEC-6 cells (derived from rat intestinal crypts) and stable TRPC1-transfected IECs (IEC-TRPC1). Apoptosis was induced by tumor necrosis factor-alpha (TNF alpha)/cycloheximide (CHX), and intracellular free Ca(2+) concentration ([Ca(2+)](cyt)) was measured by fluorescence digital imaging analysis. Functions of STIM1 were investigated by specific siRNA (siSTIM1) and ectopic overexpression of the constitutively active STIM1 EF-hand mutants. RESULTS: Stable STIM1 transfected IEC-6 cells (IEC-STIM1) showed increased STIM1 protein expression (~5 fold) and displayed a sustained increase in Ca(2+) influx after Ca(2+) store depletion (~2 fold). Susceptibility of IEC-STIM1 cells to TNF-alpha/CHX-induced apoptosis increased significantly as measured by changes in morphological features, DNA fragmentation, and caspase-3 activity. Apoptotic cells were increased from ~20% in parental IEC-6 cells to ~40% in stable IEC-STIM1 cells 4 h after exposure to TNF-alpha/CHX (p<0.05). In addition, stable IEC-TRPC1 cells also exhibited an increased sensitivity to TNF-alpha/CHX-induced apoptosis, which was prevented by STIM1 silencing through siSTIM1 transfection. STIM1 silencing by siSTIM1 also decreased Ca(2+) influx after store depletion in cells overexpressing TRPC1. Levels of Ca(2+) influx due to store depletion were decreased by ~70% in STIM1-silenced populations. Similarly, exposure of IEC-STIM1 cells to Ca(2+)-free medium also blocked increased sensitivity to apoptosis. CONCLUSIONS: These results indicate that (1) STIM1 plays an important role in the regulation of IEC apoptosis by altering TRPC1 activity and (2) ectopic STIM1 expression sensitizes IECs to apoptosis through induction in TRPC1-mediated Ca(2+) influx. PMID- 22547347 TI - Use of the falciform ligament flap for closure of the esophageal hiatus in giant paraesophageal hernia. AB - OBJECTIVES: Laparoscopic repair of a giant paraesophageal hiatal hernia remains a challenging procedure. Several techniques have been developed in efforts to achieve tension-free reconstruction of the esophageal hiatus. In this report, we describe a technique whereby the falciform ligament is used as an autologous onlay flap to achieve tension-free closure of the crural defect of a giant paraesophageal hernia (GPEH). DISCUSSION: Use of the falciform ligament as a vascularized autologous onlay flap is a safe and effective procedure to obtain closure of the crural defect of a GPEH. The falciform ligament should be adequately mobilized from the anterior abdominal wall to prevent lateral tension on the flap, but care must be taken to avoid devascularization. Interrupted vertical mattress sutures are used to fix the falciform ligament to the left and right hiatal crurae. PMID- 22547348 TI - Impact on quality of life after pancreatoduodenectomy: a prospective study comparing preoperative and postoperative scores. AB - INTRODUCTION: Few studies compare the direct impact of pancreatoduodenectomy (PD) on the patient's quality of life (QOL). The effect of PD in QOL, comparing the preoperative vs. postoperative status, was analyzed. METHOD: A prospective single center study was performed. PD patients in a 2-year period were included. A general QOL instrument was applied preoperative, 1, 3, 6, and 12 months after surgery and compared with national norms. RESULTS: Thirty-seven patients were recruited. Twenty of 37 were female. Ampullary carcinoma 14/37, ductal adenocarcinoma in 9/37, and other malignant neoplasms 14/37 were diagnosed. Mortality was absent; 48.6% had complications, 13.5 % required reoperation. Three (median) and 4 (mode) questionnaires were answered per individual. 85 % answered the last questionnaire. 4/37 had cancer related death before a year. Median follow-up was 29 (3-72) months. QOL diminished a month after surgery, physical function (67 vs 40, p<0.0001) and emotional role (37 vs 17, p<0.032) did so significantly. Three months after surgery QOL improved yet not significantly. Six and 12 months postoperatively, physical role (9 vs 49, p=0.001), physical pain (51 vs 71, p=0.01), social function (52 vs 63, p=0.014), vitality (54 vs 64, p=0.018), and emotional role (41 vs 69, p=0.006) improved significantly. DISCUSSION: PD has a favorable impact in quality of life as demonstrated by the improvement of most parameters assessed in the postoperative period. PMID- 22547349 TI - Extramammary Paget disease in peristomal skin: report of a unique case. AB - PURPOSE: Extramammary Paget disease is a rare neoplasm most often found in the perianal area which can be primary in origin or secondary from underlying colorectal adenocarcinoma with epidermotropic spreading. However, the occurrence of extramammary Paget disease has not been described in peristomal skin. METHODS: We describe a single case of Paget disease in the peristomal skin of a 61-year old woman with ulcerative colitis who underwent a proctocolectomy 33 years prior to now with chronic intestinal obstruction and an area of "ectopic mucosa" adjacent to her ileostomy. The patient was taken to surgery for exploratory laparotomy and revision of her stoma. RESULTS: Macroscopic and microscopic examinations of the peristomal lesion demonstrated Paget disease with intraepidermal spreading of dysplastic intestinal/glandular cells but no invasive adenocarcinoma in the peristomal skin after extensive sampling. CONCLUSIONS: To our knowledge, this is the first reported case of extramammary Paget disease occurring in peristomal skin. The current case emphasizes the importance of recognizing such disease and the potential for associated neoplasia in patients with intestinal stomas. PMID- 22547350 TI - In vitro-in vivo correlations: tricks and traps. AB - In vitro-in vivo correlation (IVIVC) is a biopharmaceutical tool recommended to be used in development of formulation. When validated, it can speed up development of formulation, be used to fix dissolution limits and also as surrogate of in vivo study. However, as do all tools, it presents limitations and traps. The aim of the present paper is to investigate five common traps which could limit either the setting or use of IVIVC (1) using mean or individual values; (2) correction of absolute bioavailability; (3) correction of lag time and time scaling; (4) flip-flop model; and (5) predictability corrections. PMID- 22547352 TI - Comparison of standard- and nano-flow liquid chromatography platforms for MRM based quantitation of putative plasma biomarker proteins. AB - The analytical performance of a standard-flow ultra-high-performance liquid chromatography (UHPLC) and a nano-flow high-performance liquid chromatography (HPLC) system, interfaced to the same state-of-the-art triple-quadrupole mass spectrometer, were compared for the multiple reaction monitoring (MRM)-mass spectrometry (MS)-based quantitation of a panel of 48 high-to-moderate-abundance cardiovascular disease-related plasma proteins. After optimization of the MRM transitions for sensitivity and testing for chemical interference, the optimum sensitivity, loading capacity, gradient, and retention-time reproducibilities were determined. We previously demonstrated the increased robustness of the standard-flow platform, but we expected that the standard-flow platform would have an overall lower sensitivity. This study was designed to determine if this decreased sensitivity could be compensated for by increased sample loading. Significantly fewer interferences with the MRM transitions were found for the standard-flow platform than for the nano-flow platform (2 out of 103 transitions compared with 42 out of 103 transitions, respectively), which demonstrates the importance of interference-testing when nano-flow systems are used. Using only interference-free transitions, 36 replicate LC/MRM-MS analyses resulted in equal signal reproducibilities between the two platforms (9.3 % coefficient of variation (CV) for 88 peptide targets), with superior retention-time precision for the standard-flow platform (0.13 vs. 6.1 % CV). Surprisingly, for 41 of the 81 proteotypic peptides in the final assay, the standard-flow platform was more sensitive while for 9 of 81 the nano-flow platform was more sensitive. For these 81 peptides, there was a good correlation between the two sets of results (R(2) = 0.98, slope = 0.97). Overall, the standard-flow platform had superior performance metrics for most peptides, and is a good choice if sufficient sample is available. PMID- 22547353 TI - Fast quantitative determination of platinum in liquid samples by laser-induced breakdown spectroscopy. AB - The potential of laser-induced breakdown spectroscopy (LIBS) for the rapid determination of platinum in liquid silicone oils has been evaluated in the framework of on-line process control. A comparison of LIBS sensitivity between three setups designed for liquid analysis (static, liquid jet and flowing liquid) was performed using a 266 nm Nd/YAG laser irradiation. Best results were obtained using the flowing liquid setup and a similar limit of detection was obtained using the liquid jet. The effect of different buffer gases (Ar, He, N(2), etc.) on the signal sensitivity was studied in liquid jet analysis and best values were obtained with a nitrogen sheath gas. Detection limits were in the 100 mg/kg range for both setups. Quantitative determination of platinum in real liquid samples was also investigated using both liquid jet and flowing liquid setups. Calibration curves were plotted for Pt with the liquid jet and the flowing liquid setups under optimised temporal acquisition parameters (delay time and gate width). A normalisation using a silicon line was applied and recovery ranged from 3 to 15% for Pt in catalyst samples with both setups showing that LIBS is a sensitive and accurate method for on-line applications. PMID- 22547351 TI - Predicting the effects of anti-angiogenic agents targeting specific VEGF isoforms. AB - Vascular endothelial growth factor (VEGF) is a key mediator of angiogenesis, whose effect on cancer growth and development is well characterized. Alternative splicing of VEGF leads to several different isoforms, which are differentially expressed in various tumor types and have distinct functions in tumor blood vessel formation. Many cancer therapies aim to inhibit angiogenesis by targeting VEGF and preventing intracellular signaling leading to tumor vascularization; however, the effects of targeting specific VEGF isoforms have received little attention in the clinical setting. In this work, we investigate the effects of selectively targeting a single VEGF isoform, as compared with inhibiting all isoforms. We utilize a molecular-detailed whole-body compartment model of VEGF transport and kinetics in the presence of breast tumor. The model includes two major VEGF isoforms, VEGF(121) and VEGF(165), receptors VEGFR1 and VEGFR2, and co receptors Neuropilin-1 and Neuropilin-2. We utilize the model to predict the concentrations of free VEGF, the number of VEGF/VEGFR2 complexes (considered to be pro-angiogenic), and the receptor occupancy profiles following inhibition of VEGF using isoform-specific anti-VEGF agents. We predict that targeting VEGF(121) leads to a 54% and 84% reduction in free VEGF in tumors that secrete both VEGF isoforms or tumors that overexpress VEGF(121), respectively. Additionally, 21% of the VEGFR2 molecules in the blood are ligated following inhibition of VEGF(121), compared with 88% when both isoforms are targeted. Targeting VEGF(121) reduces tumor free VEGF and is an effective treatment strategy. Our results provide a basis for clinical investigation of isoform-specific anti-VEGF agents. PMID- 22547354 TI - Protein determination in serum and whole blood by attenuated total reflectance infrared spectroscopy. AB - Attenuated total reflectance mid-infrared spectra of serum and blood samples were obtained from 4,000 to 600 cm(-1). Models for the determination of albumin, immunoglobulin, total globulin, and albumin/globulin coefficients were established for serum samples, using reference data obtained by capillary electrophoresis. Based on the use of the amide bands I and II regions, the relative root mean square error of prediction (RRMSEP) was 4.9, 14.9, 4.5, and 7.1% for albumin, immunoglobulin, total globulin, and albumin/globulin coefficients, respectively, determined in an independent validation set of 120 samples using 200 samples for calibration. Additionally, the use of Kennard-Stone method for the selection of a representative calibration subset of samples provided comparable results using only 60 samples. For whole blood analysis, hemoglobin was determined in 40 validation samples using models built from 40 calibration independent samples with RRMSEP of 8.3, 5.5, and 4.9% with models built from direct spectra in the first case and from sample spectra recorded after lysis by sodium dodecyl sulfate and freezing, respectively, for the last two ones. The developed methodologies offer green alternatives for patient diagnosis in a few minutes, minimizing the use of reagents and residues and being adaptable for its use as a point-of-care method. PMID- 22547355 TI - Multiple novel modes of action involved in the in vitro neurotoxic effects of tetrabromobisphenol-A. AB - Neurotoxicological data on the widely used brominated flame retardant tetrabromobisphenol-A (TBBPA) is limited. Since recent studies indicated that inhibitory GABA(A) and excitatory alpha(4)beta(2) nicotinic acetylcholine (nACh) receptors are sensitive targets for persistent organic pollutants, we investigated the effects of TBBPA on these receptors, expressed in Xenopus oocytes, using the two-electrode voltage-clamp technique. Our results demonstrate that TBBPA acts as full (>= 10 MUM) and partial (>= 0.1 MUM) agonist on human GABA(A) receptors, whereas it acts as antagonist (>= 10 MUM) on human alpha(4)beta(2) nACh receptors. Next, neuronal B35 cells were used to further study the effects of TBBPA on calcium-permeable nACh receptors using single-cell fluorescent calcium imaging. These results demonstrate that TBBPA (>= 1 MUM) inhibits acetylcholine (ACh) receptors as evidenced by a reduction in the ACh evoked increases in the intracellular calcium concentration ([Ca(2+)](i)). Additionally, TBBPA (> 1 MUM) induced a strong and concentration-dependent increase in basal [Ca(2+)](i) in B35 cells. Similarly, TBBPA (> 1 MUM) increases basal [Ca(2+)](i) in dopaminergic PC12 cells. This increase is also evident under calcium-free conditions, indicating it originates from intracellular calcium stores. Moreover, depolarization-evoked increases in [Ca(2+)](i) are strongly reduced by TBBPA (>= 1 MUM), indicating TBBPA-induced inhibition of voltage-gated calcium channels. Our in vitro studies thus demonstrate that TBBPA exerts several adverse effects on functional neurotransmission endpoints with effect concentrations that are only two orders of magnitude below the highest cord serum concentrations. Although epidemiological proof for adverse TBBPA effects is lacking, our data justify the quest for flame retardants with reduced neurotoxic potential. PMID- 22547356 TI - Application of MALDI-TOF-mass spectrometry to proteome analysis using stain-free gel electrophoresis. AB - The combination of MALDI-TOF-mass spectrometry with gel electrophoretic separation using protein visualization by staining procedures involving such as Coomassie Brilliant Blue has been established as a widely used approach in proteomics. Although this approach has been shown to present high detection sensitivity, drawbacks and limitations frequently arise from the significant background in the mass spectrometric analysis. In this chapter we describe an approach for the application of MALDI-MS to the mass spectrometric identification of proteins from one-dimensional (1D) and two-dimensional (2D) gel electrophoretic separation, using stain-free detection and visualization based on native protein fluorescence. Using the native fluorescence of aromatic protein amino acids with UV transmission at 343 nm as a fast gel imaging system, unstained protein spots are localized and, upon excision from gels, can be proteolytically digested and analyzed by MALDI-MS. Following the initial development and testing with standard proteins, applications of the stain-free gel electrophoretic detection approach to mass spectrometric identification of biological proteins from 2D-gel separations clearly show the feasibility and efficiency of this combination, as illustrated by a proteomics study of porcine skeleton muscle proteins. Major advantages of the stain-free gel detection approach with MALDI-MS analysis are (1) rapid analysis of proteins from 1D- and 2D-gel separation without destaining required prior to proteolytic digestion, (2) the low detection limits of proteins attained, and (3) low background in the MALDI-MS analysis. PMID- 22547357 TI - Alkene synthesis through transition metal-catalyzed cross-coupling of N tosylhydrazones. AB - In this chapter, alkene synthesis based on the reaction of N-tosylhydrazones is described. The reactivity of tosylhydrazones is determined by either the acidity of alpha-proton and hydrazone proton or the electropositivity of the carbon of C=N bond. This leads to diverse reactivities and a series of N-tosylhydrazone based olefination methodologies. Both non-catalytic and transition metal catalyzed olefinations from N-tosylhydrazones are introduced in this chapter. Most of the transition metal-catalyzed reactions proceed via metal carbene transformations. The synthesis of alkenes through Pd-catalyzed cross-coupling reactions of N-tosylhydrazones is particularly attractive and will be discussed in detail. PMID- 22547358 TI - [Essential hypertension - which genes can be held responsible for it?]. AB - Hypertension is a common heritable cardiovascular risk factor. Some rare monogenic forms of hypertension have been described, but the majority of patients suffer from essential hypertension, for whom the underlying genetic mechanisms are not clear. Essential hypertension is a complex trait, involving multiple genes and environmental factors. Recently, progress in the identification of common genetic variants associated with essential hypertension has been made due to large-scale international collaborative projects. In this article we review the new research methods used as well as selected recent findings in this field. PMID- 22547359 TI - [Hypertension therapy in patients with renal artery stenosis]. AB - Renovascular hypertension is due to reduced renal parenchymal perfusion. The correct diagnosis can be difficult. It is important to note that the demonstration of renal artery stenosis in a patient with hypertension does not necessarily constitute renovascular hypertension. Often, clinically nonsignificant and asymptomatic renal artery stenosis are found in patients with essential hypertension, or renal failure of other origin. Renovascular disease is a complex disorder with various clinical presentations. In patients with significant renovascular hypertension plasma renin is increased. For this reason the therapy aims to block the renin-angiotensin-aldosterone system. Bilateral renal artery stenosis causes renal sodium retention. In this situation a diuretic drug has to be added to the therapy. Endovascular or surgical therapy has to be considered in patients with flash pulmonary edema or fibromuscular dysplasia. The control of cardiovascular risk factors is important. PMID- 22547360 TI - [Glomerulonephritis and vasculitis as causes of arterial hypertension]. AB - The various types of glomerulonephritis, including many forms of vasculitis, are responsible for about 15% of cases of end-stage renal disease (ESRD). Arterial hypertension represents a frequent finding in patients suffering from glomerulonephritis or vasculitis and hypertension also serves as an indicator for these severe types of diseases. In addition, there are symptoms and signs like hematuria, proteinuria and renal failure. Especially, rapidly progressive glomerulonephritis (RPGN) constitutes a medical emergency and must not be missed by treating physicians. This disease can either occur limited to the kidneys or in the context of a systemic inflammatory disorder, like a vasculitis. If left untreated, RPGN can lead to a necrotizing destruction of glomeruli causing irreversible kidney damage within several months or even weeks. With respect to the immunologically caused vasculitis, there are - depending upon the severity and type of organ involved - many clinical warning signs to be recognized, such as arterial hypertension, hemoptysis, arthalgias, muscle pain, palpable purpura, hematuria, proteinuria and renal failure. In addition, constitutional signs, such as fever and loss of body weight may occur concurrently. Investigations of glomerulonephritis or vasculitis must contain a careful and complete examination of family history and medications used by the respective patient. Thereafter, a thorough clinical examination must follow, including skin, joints and measurement of arterial blood pressure. In addition, a spectrum of laboratory analyses is required in blood, such as full blood screen, erythrocyte sedimentation rate, CRP, creatinine, urea and glucose, and in urine, including urinalysis looking for hematuria, red cell casts and proteinuria. Importantly, proteinuria needs to be quantified by the utilization of a random urine sample. Proteinuria > 3g/d is diagnostic for a glomerular damage. These basic tests are usually followed by more specialized analyses, such as a screening for infections, including search for HIV, hepatitis B or C and various bacteria, and for systemic inflammatory diseases, including tests for antibodies, such as ANA, anti-dsDNA, ANCA, anti-GBM and anti-CCP. In cases of membranous nephropathy, antibodies against phospholipase-A2-receptor need to be looked for. Depending upon the given clinical circumstances and the type of disease, a reasonable tumor screening must be performed, especially in cases of membranous and minimal-change nephropathy. Finally, radiological examinations will complete the initial work-up. In most cases, at least an ultrasound of the kidney is mandatory. Thereafter, in most cases a renal biopsy is required to establish a firm diagnosis to define all treatment options and their chance of success. The elimination of a specific cause for a given glomerulonephritis or vasculitis, such as an infection, a malignancy or a drug-related side-effect, remains the key principle in the management of these diseases. ACE-inhibitors, angiotensin receptor-blockers, aldosteron antagonists and renin-inhibitors remain the mainstay in the therapy of arterial hypertension with proteinuria. Only in cases of persistently high proteinuria, ACE-inhibitors and angiotensin receptor blockers can be prescribed in combination. Certain types of glomerulonephritis and essentially all forms of vasculitis require some form of more specific anti-inflammatory therapy. Respective immunosuppressive drug regimens contain traditionally medications, such as glucocorticoids (e. g. prednisone), cyclosporine A, mycophenolate mofetil, cyclophosphamide, and azathioprine. With respect to more severe forms of glomerulonephritis and vasculitis, the antibody rituximab represents a new and less toxic alternative to cyclophosphamide. Finally, in certain special cases, like Goodpasture's syndrome or severe ANCA-positive vasculitis, a plasma exchange will be useful and even required. PMID- 22547361 TI - [Childhood's determinants for high blood pressure in adulthood]. AB - Hypertension has been estimated to affect 20 - 25% of the adult population and represents an important risk factor for cardiovascular disease like coronary heart disease, stroke and peripheral artery occlusive disease. In addition, hypertension supports the development and progression of chronic kidney insufficiency. The interaction of multiple genetic and environmental factors are felt to influence the level of blood pressure. Epidemiological data in the sixties and seventies demonstrated a correlation between cardiovascular disease and infant mortality in the same population. In the late eighties Barker and coworkers described a strong correlation between low birth weight and increased risk for the development of cardiovascular complications. It has been supposed that factors influencing the intrauterine growth and development can lead to adult cardiovascular diseases, known as the concept of "fetal programming". Beside the effect of fetal programming, multiple (preventable and non preventable) factors determine the blood pressure level in childhood, which will define adult blood pressure level through the blood pressure tracking from childhood to adulthood. Hence, the prevention of cardiovascular disease in adulthood begins in childhood through identification of preventable risk factors as for example obesity and passive smoking and recognition of risk groups like small for gestational age or preterm children. PMID- 22547362 TI - [Hypertension in the elderly]. AB - Many aspects of hypertension diagnosis and treatment are similar in young and old patients. However, some differences exist. Due to the increasing vascular stiffness most elderly patients have isolated systolic hypertension and its prevalence in the population is high. Blood pressure should be measured in the sitting position and also with the patient standing to exclude orthostatic hypotension, a frequent problem in elderly patients. Pseudohypertension, a source of inadequate measurements in elderly patients, should be recognized. In comparison to other health problems there is good scientific evidence for antihypertensive treatment in elderly patients. As treatment does not only improve survival, but also reduces cardiovascular events such as non-fatal stroke or myocardial infarction, antihypertensive therapy is an important measure to prevent functional decline and disability. PMID- 22547363 TI - [Arterial Hypertension - when are which combination therapies useful?]. AB - Arterial hypertension is a widely prevalent risk factor for cardiovascular diseases with well documented harmful effects on the heart and the vascular system. Despite a broad antihypertensive drug armamentarium control of hypertension is worldwide suboptimal. Daily practice as well as large intervention trials show that single-drug therapy often fails to adequately control blood pressure (BP). Therefore, the early introduction of a combination therapy may lead to a better and more rapid BP lowering effect, particularly in patients with more than stage I hypertension or in patients with mild hypertension and high cardiovascular risk. In addition, side effects of an antihypertensive drug can be prevented by a meaningful (low dose) combination with a second antihypertensive agent. Moreover, combination of antihypertensive drugs, especially if provided fixed, may substantially improve compliance. However, the choice of the drug combination primarily relates on the demographic features and co-morbidities of the patient. Although BP lowering is the main determinant of cardiovascular risk reduction in the treatment of hypertension, some antihypertensive drugs may exhibit protective effects beyond BP reduction that have to be considered when antihypertensive drugs are combined. In recent large intervention studies, the combination of an ACE inhibitor with a calcium channel blocker was especially advantageous in high risk hypertensive patients. The addition of a thiazide type diuretic to a blocker of the renin-angiotensin system is also sensible and popular with numerous available fixed combinations. PMID- 22547364 TI - [Psychosomatic medicine and arterial hypertension - love it or leave it?]. AB - Over the last two decades modern psychosomatic research has found multiple evidence for an impact of psychosocial factors on the control of arterial blood pressure as well as the development of arterial hypertension. This narrative review focuses first on the current stress concept and factors that influence the degree of blood pressure change following a psychosocial stressor. Second, relevant psychosocial factors associated with blood pressure are presented such as marital status, social support, socioeconomic status and work conditions. In addition, the influence of personality and cognition on blood pressure will be discussed. The second part focuses on the outcome of cognitive-behavioral therapies and relaxation techniques as a means to effectively control blood pressure. In conclusion, there is now good evidence showing that psychosocial factors and stressors may increase blood pressure. The working environment, the socioeconomic status as well as aspects of personality and cognitive factors like rumination may also impact blood pressure with to an extent that is clinically relevant. With respect to therapeutic options, cognitive-behavioral interventions, combined with relaxation techniques all fitting the needs of the individual patient best can offer a clinically meaningful contribution of an effective blood pressure control. PMID- 22547365 TI - [Drug-independent blood pressure control through the autonomous nervous system]. AB - Arterial hypertension is a chronic disease with a therapeutical challenge for the patient and the physician involved. Patient-independent techniques with good efficacy and tolerability are wanted. The autonomous nervous system insufficiently therapeutically exploited to date, is now approachable by two types of intervention: renal nerve ablation, an endovascular approach without remaining foreign body, and BAT, baroreflex activating therapy using an implantable device stimulating the carotid sinus. The blood pressure lowering potency of BAT appears more than with renal nerve ablation and also clinical study data are more prevalent. With both treatment options the patients having the most profit are insufficiently defined. Given this knowledge, any form of secondary hypertension needs to be excluded beforehand. PMID- 22547366 TI - Serum vitamin D levels are decreased and associated with thyroid volume in female patients with newly onset Graves' disease. PMID- 22547367 TI - The association between metabolic syndrome and bone mineral density: a meta analysis. AB - Previous researches demonstrate uncertainty about the effect of metabolic syndrome (MS) on bone. We performed a meta-analysis to investigate the association of MS with bone mineral density (BMD) of spine and femoral neck (FN). In this meta-analysis, searches of Medline, Embase, Cochrane Library, Chinese biological medical database and China national knowledge infrastructure were undertaken to identify studies in humans of the association between MS and BMD. Random effects model was used for this meta-analysis. The results of our research were reported using the Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines. A total of 11 studies (including an outlier study) with 13,122 subjects were included in our research. We detected a significant overall association of MS with increased BMD of spine (weighted mean difference, WMD = 0.027, 95 % confidence interval, CI [0.011, 0.042]) and no significant overall association of MS with BMD of FN (WMD = 0.008, CI [-0.011, 0.026]). Subgroup analyses indicated significant association between MS and increased BMD of spine in subjects whose BMD was measured by dual-energy X-ray absorptiometry (DXA) scanner manufactured by Hologic Inc., subjects diagnosed by International Diabetes Federation criteria and subjects diagnosed by National Cholesterol Education Program's Adult Treatment Panel III (NCEP-ATP III) criteria. And significant association between MS and increased BMD of FN in Caucasian subjects, subjects whose BMD was measured by DXA scanner manufactured by Hologic Inc. and subjects diagnosed by NCEP-ATP III criteria was also found. Our meta-analysis suggests that MS has no clear influence on BMD, or its influence maybe beneficial. PMID- 22547368 TI - Upper tract urothelial cell carcinoma presenting as fever of unknown origin and acid-sterile pyuria. PMID- 22547369 TI - A modified Khorana risk assessment score for venous thromboembolism in cancer patients receiving chemotherapy: the Protecht score. PMID- 22547370 TI - Design of lipid-based formulations for oral administration of poorly water soluble drug fenofibrate: effects of digestion. AB - Lipid-based drug carriers are likely to have influence on bioavailability through enhanced solubilization of the drug in the gastrointestinal tract. The study was designed to investigate the lipid formulation digestibility in the simulated gastro intestinal media. Fenofibrate was formulated in representative Type II, IIIA, IIIB and IV self-emulsifying/microemulsifying lipid delivery systems (SEDDS and SMEDDS designed for oral administration) using various medium-chain glyceride components, non-ionic surfactants and cosolvents as excipients. Soybean oil was used only as an example of long-chain triglycerides to compare the effects of formulation with their counterparts. The formulations were subjected to in vitro digestion specifically to predict the fate of the drug in the gastro intestinal tract after exposure of the formulation to pancreatic enzymes and bile. In vitro digestion experiments were carried out using a pH-stat maintained at pH 7.5 for 30 min using intestinal fluids simulating the fed and fasted states. The digestion rate was faster and almost completed in Type II and IIIA systems. Most of the surfactants used in the studies are digestible. However, the high concentration of surfactant and/or cosolvent used in Type IIIB or IV systems lowered the rate of digestion. The digestion of medium-chain triglycerides was faster than long-chain triglycerides, but kept comparatively less drug in the post digestion products. Medium-chain mixed glycerides are good solvents for fenofibrate as rapidly digested but to improve fenofibrate concentration in post digestion products the use of long-chain mixed glycerides are suggested for further investigations. PMID- 22547372 TI - Results of Conserve Plus(r) metal-on-metal hip resurfacing for post-traumatic arthritis and osteonecrosis. AB - The safety and efficacy of metal-on-metal surface arthroplasty in post-traumatic arthritis and post-traumatic osteonecrosis (PT OA and PT ON) cases has not previously been thoroughly investigated. This study compared the outcomes of metal-on-metal hip resurfacing (HR) in patients performed for an indication of OA secondary to trauma to compared to PT ON. Metal-on-metal resurfacing arthroplasties were performed on 62 hips, 43 with PT OA and 19 with PT ON with secondary osteoarthritis. There were 51 males and 11 females. All patients were followed up clinically and radiographically with a mean follow-up of 87.2 months. Clinical outcome scores, survivorship, and radiographs were compared between the PT OA and PT ON group. The clinical outcomes for the PT ON and PT OA groups were similar with a survival rate of 95% (95% CI 82.1% to 98.8%) for the PT OA group alone at 8 years and 91% for those with PT OA with ON at 8 years (95% CI 50.8% 98.7%). The Kaplan-Meier survivorship curves for the cohorts of PT OA and PT ON patients were not statistically significantly different (Log rank, p=0.6036). Metal-on-metal hip resurfacing appears to be a safe and effective procedure for the treatment of both post-traumatic osteoarthritis and osteonecrosis. PMID- 22547371 TI - Intranasal deferoxamine improves performance in radial arm water maze, stabilizes HIF-1alpha, and phosphorylates GSK3beta in P301L tau transgenic mice. AB - Deferoxamine (DFO), a metal chelator, has been previously reported to slow the loss of spatial memory in a mouse model of amyloid accumulation when delivered intranasally (IN). In this study, we determined whether IN DFO also has beneficial effects in the P301L mouse, which accumulates hyperphosphorylated tau. Mice were intranasally treated three times per week with either 10% DFO (2.4 mg) or saline for 5 months, and a battery of behavioral tests were conducted before tissue collection and biochemical analyses of brain tissue with Western blot and ELISA. Wild-type (WT) mice statistically outperformed transgenic (TG) saline mice in the radial arm water maze, while performance of TG-DFO mice was not different than WT mice, suggesting improved performance in the radial arm water maze. Other behavioral changes were not evident. Beneficial changes in brain biochemistry were evident in DFO-treated mice for several proteins. The TG mice had significantly less pGSK3beta and HIF-1alpha, with more interleukin-1beta and total protein oxidation than wild-type controls, and for each protein, DFO treatment significantly reduced these differences. There was not a significant decrease in phosphorylated tau in brain tissue of DFO-treated mice at the sites we measured. These data suggest that IN DFO is a potential treatment not only for Alzheimer's disease, but also for other neurodegenerative diseases and psychiatric disorders in which GSK3beta and HIF-1alpha play a prominent role. PMID- 22547374 TI - Minimally invasive sliding hip screw insertion technique. AB - Sliding hip screws (SHS) are commonly used for fixation of extra-capsular hip fractures, and there is increasing use of minimally invasive methods of insertion of such devices. We describe a case series of 579 consecutive patients operated on by the senior author using such a technique. Data were collected prospectively and analysed retrospectively. The technique involves a 5cm incision, retraction of vastus lateralis superiorly by a chain retractor, and use of a SHS clamp to stabilise the plate on the femur. The patients had a mean age of 81 years, surgery time of 43 minutes and hospital stay of 17 days. 77% were female and 35% required a blood transfusion post-operatively. Everyone was mobilised fully weight-bearing post-operatively. Follow-up was at six weeks for radiographic review and then subsequently at one year. The commonest complications were superficial wound infection (1.7%), detachment of the plate (0.9%) and cut-out of the lag screw (0.5%). PMID- 22547373 TI - Post-operative radiographic factors and patient-reported outcome after total hip replacement. AB - Although total hip replacement (THR) is considered a very successful surgical intervention, a proportion of patients experience persistent pain or disability, and/or dissatisfaction with the outcome of surgery. Our aim was to determine whether post-operative radiographic variables were predictive of patient-reported pain, function and satisfaction after primary THR. At 1-3 years after surgery patients completed the WOMAC Pain scale, WOMAC Function scale and a validated measure of satisfaction with the outcome of surgery. Post-operative radiographs taken prior to discharge were graded for the restoration of offset, restoration of leg length, anteroposterior (AP) alignment of the femoral stem and AP acetabular inclination. Binary logistic regression was used to identify whether radiographic variables were significant predictors of patient-reported outcome scores. Radiographic and patient-reported outcomes data were available for 452 THR patients. No radiographic predictors were found to be significant predictors of patient reported pain, function or satisfaction at 1-3 years after THR. This highlights that patients with continuing problems after THR may benefit from a thorough multidisciplinary assessment to diagnose the underlying cause of the problems. PMID- 22547375 TI - Prevalence of dementia in elderly patients with hip fracture. AB - Hip fractures occur commonly and are a cause of disability for older adults and lead to increased dependence and requirements for social support. Dementia is one of the possible risk factors for falling and hip fracture, a potential source for complications during surgery and during the postoperative period, difficulties in rehabilitation and a risk factor for hip fracture reccurence. However, in previous studies of hip fracture patients, cognitive status has not been formally assessed during the inpatient stay and diagnosis was based only on previous history. Additionally, no previous studies have compared prevalence of dementia between elderly patients with hip fracture and patients with other surgical pathology. Our aim was to define whether dementia was more prevalent in older subjects with hip fracture than in other elderly patients undergoing surgery. In this study, we prospectively assessed all patients aged 68 and older admitted to our hospital for hip fracture surgery during a one year period and compared them with age and gender matched patients attending other surgical departments. 80 hip fracture patients and 80 controls were assessed for dementia. Dementia was common in both groups, presumably reflecting the advanced mean age of both groups and cognitive deterioration due to hospitalization-status. Dementia was significantly higher in the hip fracture group (85%) compared to the control group (61.5%; p=0.002). Dementia is very common in older patients admitted for surgery to a general hospital and extremely common in those with hip fracture. It seems that dementia is under diagnosed in elderly hospitalised patients. Our data confirm that dementia is a major risk factor for hip fracture in the elderly. PMID- 22547376 TI - Comment on: "Outcome of short proximal femoral nail antirotation and dynamic hip screw for fixation of unstable trochanteric fractures. A randomised prospective comparative trial". PMID- 22547377 TI - Bilateral subtrochanteric fractures in tumour-induced osteomalacia caused by a nasal haemangiopericytoma. AB - Bilateral insufficiency fractures of the proximal femur often have a pathological basis. Diagnosis of rare causes of insufficiency fractures can be challenging. Tumour-induced osteomalacia (TIO) is a rare paraneoplastic syndrome of mesenchymal tumours which leads to hypophosphataemia and osteomalacia. Suspected pathological fractures should be investigated thoroughly including a fasting serum phosphate level. Further investigations should include serum levels of fibroblast growth factor 23 (FGF23) which is a peptide hormone secreted by mesenchymal tumours. Available imaging modalities include Octreotide scanning which detects somatostatin receptors commonly expressed on mesenchymal tumours. After localisation and resection of the tumour, a full recovery from TIO is achievable. PMID- 22547379 TI - Reducing the revision rate: rationalise the range and adopt an actuarial approach. PMID- 22547378 TI - Association of hip joint effusion volume with early osteonecrosis of the femoral head. AB - This study aimed to examine the association between hip joint effusion volume and osteonecrosis of the femoral head (ONFH) using the Association Research Circulation Osseous (ARCO) classification. Patients (n = 403) who were diagnosed with ONFH were enrolled between February 2005 and December 2008. Only patients (n = 109) with complete clinical and imaging data and at early to mid ARCO stage (I III) were eligible for further analysis, including 94 males and 15 females. All the included patients had hip joint radiographic examinations (anteroposterior and frog-leg views) and magnetic resonance imaging scans (axial and coronal views). Out of 109 patients included in this study, 185 hip joints were involved (unilateral disease in 33 patients and bilateral diseases in 76 patients). The patients had a mean age of 39 +/- 11 years (range, 13-70). All the affected hip joints exhibited effusion, classified as grade 1 (n = 70, 37.8%), grade 2 (n = 62, 33.5%), and grade 3 (n = 53, 28.7%). The volume of joint effusion varied significantly among stage I, II, and III (X2 = 29.210, P < 0.05). The effusion volume did not differ significantly among stage IIA, IIB, and IIC (X2 = 0.103, P > 0.05), whereas it differed significantly among stage IIIA, IIIB, and IIIC (X2 =11.556, P < 0.05). The volume of hip joint effusion was associated with the ARCO stage, and increased over the staging. PMID- 22547380 TI - Long-term patient-reported outcomes after total hip replacement: comparison to the general population. AB - Hip replacement is one of the most common elective procedures performed in the NHS, with patients generally reporting good mid-term outcomes. However, patient reported long-term outcomes have been less well studied. The aim of this study was to explore the extent of variation in long-term patient reported outcomes after total hip replacement (THR), and to compare outcomes to a control population without THR. All patients who had undergone primary THR at one centre 12-16 years ago and who had previously completed an Oxford hip score (OHS) 5-8 years post-operatively were invited to complete a postal OHS. Participants in the control group who had not undergone hip or knee replacement also completed an OHS. The Oxford hip score (OHS) was completed by 407 THR patients and 927 controls. The median score of 18 for the THR patients was significantly worse than the median score of 12 for the control group (p <0.001). Similar results were found when comparisons were stratified by age. There was considerable variation in change in OHS from 5-8 years to 12-16 years post-operatively, although a significant worsening in outcome was found only in patients over 80 years old. Patients continue to report good functional outcomes at 12-16 years after THR, although function is signficantly worse than the general population who have not undergone THR. PMID- 22547381 TI - Comment on: "Developmental dysplasia in male infants: risk factors, instability and ultrasound screening". PMID- 22547383 TI - Bone remodelling around a cementless straight THA stem: a prospective dual-energy X-ray absorptiometry study. AB - The design of the Bicontact(r) stem (BBraun, Aesculap, Tuttlingen, Germany) and the implantation technique have undergone no major alterations in the last 20 years leading, and good clinical results have been reported. The aim of our study was to investigate whether the implant encourages beneficial bone remodelling. Twenty-four patients were included in a prospective dual-energy X-ray absorptiometry (DEXA) study of this stem, after appropriate statistical power analysis. Preoperative and postoperative (1 week, 6 months, and 12 months) clinical and DEXA examinations were performed. The Harris Hip Score increased significantly by 39 points. The strongest decreases in BMD were observed in the greater trochanter region (-11%) and the calcar (-12%). In the second half of the study period the bone mineral density recovered slightly and even returned to baseline values in the lesser trochanter region. Therefore, proximal load transfer and physiological bone remodelling around the Bicontact(r) stem appeared to be achieved. PMID- 22547382 TI - Analysis of bone formation on porous and calcium phosphate-coated acetabular cups: a randomised clinical [18F]fluoride PET study. AB - We present a study using Fluoride-Positron Emission Tomography (F-PET/CT) to analyse new bone formation in periacetabular bone adjacent to press fit cups following THA. In 16 THA (8 patients) with bilateral hip osteoarthritis simultaneous bilateral total hip arthroplasty (THA) was performed, employing electrochemically applied calcium phosphate coated (HA) cups or porous-coated (PC) cups allocated at random to compare the two sides. A reference group of 13 individuals with a normal healthy hip was used to determine 'normal' bone metabolism. [18F]fluoride -PET/CT was used to analyze bone formation adjacent to the cups 1 week, 4 months and 12 months after surgery. Clinical and radiographic evaluation was performed preoperatively, postoperatively and at 2 years. Bone forming activity had a mean of 5.71, 4.69 and 3.47 SUV around the HA- and 5.04, 4.80 and 3.50 SUV around the PC-cups at 1 week, 4 months and 12 months respectively. Normal bone metabolism was 3.68 SUV. After 1 year activity had declined to normal levels for both groups. The clinical results were good in all cases. HA coating resulted in higher uptake indicating higher bone forming activity after 1 week. F-PET/CT is a valuable tool to analyse bone formation and secondary stabilisation of an acetabular cup. PMID- 22547384 TI - The surgical anatomy of intra-abdominal prosthetic dislocation during hip arthroplasty. AB - Hip replacement surgery remains one of the most successful and common operations in modern orthopaedics. Many surgical approaches to the hip have been described. A potential anatomical weakness exists between the hip joint and the retroperitoneal space. We describe this potential space, which lies superficial to iliopsoas and its importance in hip replacement surgery. The clinical relevance of this space is illustrated by 2 cases of retro-peritoneal migration of prosthetic femoral heads and the consequences of these. PMID- 22547385 TI - Maxillofacial trauma and seat belt: a 10-year retrospective study. AB - INTRODUCTION: Brazil is among the countries with the highest prevalence of people injured by traffic accidents, showing that in 2008, levels reached 18.3 victims for 100,000 habitants were victims of traffic accidents. MATERIALS AND METHODS: This retrospective study involved data collected from treated patients' charts at seven different hospitals located in three different cities all in the state of Sao Paulo, Brazil. Information was obtained through a standardized form, which was designed to investigate the epidemiologic features of maxillofacial traumas, restricted to victims of car accidents. RESULTS: Three hundred ninety-six patients were victims of car crashes with mean age 29.75 years. The age group 18 30 years showed an association with facial trauma in 96 patients, 41.56 % of whom reported using seat belt. Le Fort I, II and III (70 %) and mandible (63.11 %) were more associated with body traumas and seat belt use. The most common soft tissue lesion was laceration with 189 cases (42.3 %). The treatment way was assessed, 93 (23 %) were treated surgically and 303 (77 %) underwent conservative treatment. DISCUSSION: Classically, it is known front seat belt use was positively correlated with back seat belt use, healthy diet, dental and general health, regular walking, adequate sleep and no smoking. Accidents involving cars occurred more frequently in age group 18-30 years, suffering more general traumas and representing the nonusers group that wore fewer seat belts, caused, perhaps, by bigger access of the youth to cars, driving in high speed and to an inefficient fiscalization of the traffic laws. PMID- 22547386 TI - The varying faces of gall bladder carcinoma: pictorial essay. AB - The objective of this review is to highlight the pertinent imaging features and potential pitfalls in the diagnosis and staging of gall bladder carcinoma. This condition is notoriously non-specific on imaging on many occasions, particularly in its early stages; gall bladder carcinoma shows numerous features that overlap with a large number of benign conditions, leading to delayed diagnosis and incurable disease. Radiologists should be familiar with its typical and atypical imaging features. PMID- 22547387 TI - Diagnostic accuracy of dual-time-point 18F-FDG PET/CT for the detection of axillary lymph node metastases in breast cancer patients. AB - BACKGROUND: The diagnostic accuracy of FDG-PET/CT for the detection of axillary lymph node metastases in breast cancer patients acquired 60 min after FDG administration is reported to be only moderate, especially due to low sensitivity. PURPOSE: To test whether a delayed scan 90 min after FDG administration could enhance the diagnostic accuracy of FDG-PET/CT for the detection of axillary lymph node metastases. MATERIAL AND METHODS: Thirty-eight women suffering from primary breast cancer (mean age 52 years; range 25-78 years; standard deviation 14 years) underwent a pre-therapeutic dual-time-point FDG PET/CT scan. The maximum standardized uptake value (SUVmax) of axillary lymph nodes was measured at two different time points (time point T1: 60 min after FDG injection, time point T2: 90 min after FDG injection). SUVmax of axillary lymph nodes at T1 and T2 were assessed for statistical significance using a paired Wilcoxon-Test (P < 0.05). At T1 a qualitative analysis of the FDG-PET/CT scan was performed to define physiologic and metastatic lymph nodes. At T2 an increase of the SUVmax of at least 3.75% over time was rated as indicating malignancy. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and the accuracy of FDG-PET/CT for the detection of axillary lymph node metastases was calculated at time points T1 and T2. Statistically significant differences were determined using Fisher's exact test (P < 0.05). Histopathology served as the standard of reference. A compartment based analysis was done. RESULTS: Axillary lymph nodes had a mean SUVmax of 1.6 (range 0.6-10.8; SD 1.9) at T1 and a mean SUVmax of 1.8 (range 0.5-17.9; SD 3.5) at T2. This difference was statistically significant (P = 0.047). The sensitivity, specificity, PPV, NPV, and accuracy of FDG-PET/CT for the detection of axillary lymph node metastases was 81%, 100%, 100%, 88%, and 92% at T1, and 88%, 50%, 56%, 85%, and 66% at T2, respectively. This difference was not statistically significant (P = 0.27). CONCLUSION: There is a slight increase of the FDG accumulation of axillary lymph nodes between 60 and 90 min after FDG administration. This increase did not translate into a statistical significant enhancement of the diagnostic accuracy of FDG-PET/CT for the detection of axillary lymph nodes. Especially due to false-positive results a delayed FDG PET/CT scan 90 min after FDG administration is not able to enhance the diagnostic accuracy for the detection of lymph node metastases. PMID- 22547388 TI - Transarterial chemoembolization for hepatocellular carcinoma after transjugular intrahepatic portosystemic shunt. AB - BACKGROUND: The decreased portal blood flow and the potential decrease in arterial nutrient hepatic blood flow after creation of a transjugular intrahepatic portosystemic shunt (TIPS) makes the treatment of hepatocellular carcinoma (HCC) challenging. PURPOSE: To evaluate the safety and efficacy of transarterial chemoembolization (TACE) after TIPS in patients with HCC. MATERIAL AND METHODS: From 1998 to 2009, 20 patients underwent selective (segmental or subsegmental) TACE for HCC after TIPS. Among 20 patients, seven patients had undergone one to three sessions of TACE for HCC before TIPS creation. TACE was performed using a mixture of iodized oil and cisplatin, and absorbable gelatin sponge particles. Tumor response, complications, and patient survival were evaluated after TACE. RESULTS: After TACE, 14 of the 20 (70%) patients showed a tumor response, with only one (5%) experiencing a TACE-related major complication, spontaneous bacterial peritonitis. None of the patients who underwent TACE after TIPS died within 30 days. During the follow-up period (range 2.2-107 months; mean 32.6 months), 18 patients died and two remained alive. The median survival period after TACE was 23 months. Multivariate Cox regression analysis showed that tumor stage was the only independent prognostic factor for patient survival (P = 0.049). CONCLUSION: Selective TACE may be safe and effective for the palliative treatment of HCC in patients with TIPS. Late tumor stage ( >=III) was poor prognostic factor for determining the patient survival period after post-TIPS TACE. PMID- 22547389 TI - Forensic pathology and miscarriages of justice. PMID- 22547390 TI - KH domains with impaired nucleic acid binding as a tool for functional analysis. AB - In eukaryotes, RNA-binding proteins that contain multiple K homology (KH) domains play a key role in coordinating the different steps of RNA synthesis, metabolism and localization. Understanding how the different KH modules participate in the recognition of the RNA targets is necessary to dissect the way these proteins operate. We have designed a KH mutant with impaired RNA-binding capability for general use in exploring the role of individual KH domains in the combinatorial functional recognition of RNA targets. A double mutation in the hallmark GxxG loop (GxxG-to-GDDG) impairs nucleic acid binding without compromising the stability of the domain. We analysed the impact of the GDDG mutations in individual KH domains on the functional properties of KSRP as a prototype of multiple KH domain-containing proteins. We show how the GDDG mutant can be used to directly link biophysical information on the sequence specificity of the different KH domains of KSRP and their role in mRNA recognition and decay. This work defines a general molecular biology tool for the investigation of the function of individual KH domains in nucleic acid binding proteins. PMID- 22547391 TI - PCAF regulates the stability of the transcriptional regulator and cyclin dependent kinase inhibitor p27 Kip1. AB - P27(Kip1) (p27) is a member of the Cip/Kip family of cyclin-dependent kinase inhibitors. Recently, a new function of p27 as transcriptional regulator has been reported. It has been shown that p27 regulates the expression of target genes mostly involved in splicing, cell cycle, respiration and translation. We report here that p27 directly binds to the transcriptional coactivator PCAF by a region including amino acids 91-120. PCAF associates with p27 through its catalytic domain and acetylates p27 at lysine 100. Our data showed that overexpression of PCAF induces the degradation of p27 whereas in contrast, the knockdown of PCAF stabilizes the protein. A p27 mutant in which K100 was substituted by arginine (p27-K100R) cannot be acetylated by PCAF and has a half-life much higher than that of p27WT. Moreover, p27-K100R remains stable along cell-cycle progression. Ubiquitylation assays and the use of proteasome inhibitors indicate that PCAF induces p27 degradation via proteasome. We also observed that knockdown of skp2 did not affect the PCAF induced degradation of p27. In conclusion, our data suggest that the p27 acetylation by PCAF regulates its stability. PMID- 22547392 TI - Expression pattern and prognostic significance of IGFBP isoforms in anaplastic astrocytoma. AB - The role of insulin-like growth factors and their regulatory proteins (IGFBP isoforms) in gliomas, particularly glioblastoma, has been a subject of active research in recent years. There is paucity of literature on their expression and impact on clinical outcome in anaplastic astrocytomas. To evaluate the expression patterns of IGFBP isoforms in anaplastic astrocytoma and correlate with clinical outcome, a retrospective study of 53 adult patients operated for supratentorial lobar anaplastic astrocytoma was performed. The protein expression of IGFBP isoforms (IGFBP-2, -3, -5 and -7), was studied by immunohistochemistry on all samples. The patients were followed up and outcome was documented. The median age at presentation in the present study was 35 years. The pattern of staining was intra cytoplasmic, homogenous and diffuse for IGFBP-2, -3 and -5 and granular for IGFBP-7. IGFBP-2 expression was significantly low in anaplastic astrocytoma as compared to other isoforms (P < 0.001). IGFBP-3 expression was higher than the other isoforms. However, its' expression correlated with favorable overall survival and demonstrated a trend towards significance on univariate analysis. The present study is the first of its kind to describe comprehensively the pattern of expression of IGFBP isoforms (IGFBP-2, -3, -5 and -7) in anaplastic astrocytomas. IGFBP-2 and IGFBP-3 expression patterns and correlation to prognosis were distinct in anaplastic astrocytoma patients, contradictory to what has been reported in glioblastoma, thus giving further evidence that anaplastic astrocytomas are molecularly distinct from glioblastoma. PMID- 22547393 TI - Should rheumatologists retain ownership of fibromyalgia? A survey of Ontario rheumatologists. AB - Fibromyalgia is a controversial widespread chronic pain disorder that includes a wide constellation of somatic and emotional symptoms. This study surveyed the opinion of Ontario rheumatologists with respect to their beliefs about the nature and management of fibromyalgia. A key objective was to ascertain if rheumatologists should continue to be the main care providers for these patients. A survey comprising 13 questions was sent electronically to all 150 Ontario rheumatologists. The questionnaire was designed to obtain demographic data as well as opinions regarding different aspects of fibromyalgia. Data were analysed descriptively, and comparisons were made using chi-square tests. A total of 80 respondents completed our survey for a completion rate of 53 %. The majority had completed their training in Canada (85 %) and had been practising for more than 15 years (50 %). Key findings were: (1) 71 % believe that rheumatologists should not retain ownership of fibromyalgia, (2) 55 % believe that fibromyalgia is primarily a psychosomatic illness as opposed to a physical illness, (3) 89 % believe that the family physician should be the main care provider for these patients, and (4) rheumatologists who consider fibromyalgia to be a physical illness were also significantly more likely to believe that rheumatologists should retain ownership of this disease (p = 0.023) and were more likely to continue managing these patients in their practice (p = 0.011). The majority of Ontario rheumatologists do not wish to retain ownership of fibromyalgia. However, most of them continue to manage these patients, even though they believe that the family physician should be the main care provider for patients with fibromyalgia. Rheumatologists may be providing care to these patients primarily because this care is not available to them from their primary care physicians. PMID- 22547395 TI - High frequency of activated natural killer and natural killer T-cells in patients with new onset of type 2 diabetes mellitus. AB - Chronic low-grade inflammation is crucial for the development of insulin resistance and type 2 diabetes mellitus (T2DM), and immunocompetent cells, such as T-cells, B-cells, mast cells and macrophages, regulate the pathogenesis of T2DM. However, little is known about the role of natural killer (NK) and natural killer T (NKT) cells in the pathogenic process of T2DM. A total of 16 patients with new onset T2DM and nine healthy subjects were recruited, and the frequency of peripheral blood activated and inhibitory NK and NKT cells in individual subjects was determined by flow cytometry. The frequency of spontaneous and inducible interferon gamma (IFN-gamma) and CD107a(+) NK cells was further examined, and the potential association of the frequency of NK cells with clinical measures was analyzed. While there was no significant difference in the frequency of peripheral blood NK and NKT cells between patients and controls, the frequency of NKG2D(+) NK and NKT cells in patients was significantly higher than those in the controls (P = 0.011). In contrast, the frequency of NKG2A(+) and KIR2DL3(+) inhibitory NK and NKT cells in patients was significantly lower than those in the controls (P = 0.002, P < 0.0001, respectively). Furthermore, the frequencies of NKG2D(+) NK cells were correlated significantly with the values of body mass index in patients. Moreover, the frequencies of spontaneous and inducible CD107a(+), but not IFN-gamma-secreting, NK cells in patients were significantly higher than those in the controls (P < 0.004, P < 0.0001). Our data indicated that a higher frequency of activated NK cells may participate in the obesity-related chronic inflammation involved in the pathogenesis of T2DM. PMID- 22547394 TI - The role of chemokines in the pathogenesis of neurotropic flaviviruses. AB - Neurotropic flaviviruses are important emerging and reemerging arthropod-borne pathogens that cause significant morbidity and mortality in humans and other vertebrates worldwide. Upon entry and infection of the CNS, these viruses can induce a rapid inflammatory response characterized by the infiltration of leukocytes into the brain parenchyma. Chemokines and their receptors are involved in coordinating complex leukocyte trafficking patterns that regulate viral pathogenesis in vivo. In this review, we will summarize the current literature on the role of chemokines in regulating the pathogenesis of West Nile, Japanese encephalitis, and tick-borne encephalitis virus infections in mouse models and humans. Understanding how viral infections trigger chemokines, the key cellular events that occur during the infection process, as well as the immunopathogenic role of these cells, are critical areas of research that may ultimately guide a much needed effort toward developing specific immunomodulators and/or antiviral therapeutics. PMID- 22547396 TI - Developing an action plan for patient radiation safety in adult cardiovascular medicine. Proceedings from the Duke University Clinical Research Institute/American College of Cardiology Foundation/American Heart Association Think Tank Held on February 28, 2011. AB - Technological advances and increased utilization of medical testing and procedures have prompted greater attention to ensuring the patient safety of radiation use in the practice of adult cardiovascular medicine. In response, representatives from cardiovascular imaging societies, private payers, government and nongovernmental agencies, industry, medical physicists, and patient representatives met to develop goals and strategies toward this end; this report provides an overview of the discussions. This expert "think tank" reached consensus on several broad directions including: the need for broad collaboration across a large number of diverse stakeholders; clarification of the relationship between medical radiation and stochastic events; required education of ordering and providing physicians, and creation of a culture of safety; development of infrastructure to support robust dose assessment and longitudinal tracking; continued close attention to patient selection by balancing the benefit of cardiovascular testing and procedures against carefully minimized radiation exposures; collation, dissemination, and implementation of best practices; and robust education, not only across the healthcare community but also to patients, the public, and media. Finally, because patient radiation safety in cardiovascular imaging is complex, any proposed actions need to be carefully vetted (and monitored) for possible unintended consequences. PMID- 22547398 TI - Tests that may be overused or misused in cardiology: the Choosing Wisely campaign. PMID- 22547397 TI - Optimal reproducibility of gated sestamibi and thallium myocardial perfusion study left ventricular ejection fractions obtained on a solid-state CZT cardiac camera requires operator input. AB - AIM: To evaluate the reproducibility of serial re-acquisitions of gated Tl-201 and Tc-99m sestamibi left ventricular ejection fraction (LVEF) measurements obtained on a new generation solid-state cardiac camera system during myocardial perfusion imaging and the importance of manual operator optimization of left ventricular wall tracking. METHODS: Resting blinded automated (auto) and manual operator optimized (opt) LVEF measurements were measured using ECT toolbox (ECT) and Cedars-Sinai QGS software in two separate cohorts of 55 Tc-99m sestamibi (MIBI) and 50 thallium (Tl-201) myocardial perfusion studies (MPS) acquired in both supine and prone positions on a cadmium zinc telluride (CZT) solid-state camera system. Resting supine and prone automated LVEF measurements were similarly obtained in a further separate cohort of 52 gated cardiac blood pool scans (GCBPS) for validation of methodology and comparison. Appropriate use of Bland-Altman, chi-squared and Levene's equality of variance tests was used to analyse the resultant data comparisons. RESULTS: For all radiotracer and software combinations, manual checking and optimization of valve planes (+/- centre radius with ECT software) resulted in significant improvement in MPS LVEF reproducibility that approached that of planar GCBPS. No difference was demonstrated between optimized MIBI/Tl-201 QGS and planar GCBPS LVEF reproducibility (P = .17 and P = .48, respectively). ECT required significantly more manual optimization compared to QGS software in both supine and prone positions independent of radiotracer used (P < .02). CONCLUSIONS: Reproducibility of gated sestamibi and Tl-201 LVEF measurements obtained during myocardial perfusion imaging with ECT toolbox or QGS software packages using a new generation solid-state cardiac camera with improved image quality approaches that of planar GCBPS however requires visual quality control and operator optimization of left ventricular wall tracking for best results. Using this superior cardiac technology, Tl-201 reproducibility also appears at least equivalent to sestamibi for measuring LVEF. PMID- 22547399 TI - Understanding the role of uncertainty on learning and retention of predator information. AB - Due to the highly variable nature of predation risk, prey animals need to continuously collect information regarding the risk posed by predators. One question that ensues is how long to use this information for? An adaptive framework of predator-related information use predicted that certainty should influence the duration for which information regarding the threatening nature of a species is used in decision-making. It predicts that uncertainty contributes to the reduction in the duration of information use, due to the cost of displaying antipredator behaviours towards non-threatening species. Here, we test this prediction using repetition of conditioning events as a way to increase the certainty associated with the predatory nature of a novel salamander for woodfrog tadpoles. Tadpoles were conditioned 1, 2 or 4 times to recognize a novel salamander as a predator and subsequently tested for their response to the salamander 1 day or 11 days post-conditioning. We found that conditioning repetition did not affect the intensity with which tadpoles learned to respond to the salamander after 1 day. However, after 11 days, tadpoles with fewer conditionings responded to the salamander with a weaker intensity than those that received more conditionings. Our results provide support for the model prediction that an increase in the certainty associated with correctly identifying a predator leads to longer retention of the threat. PMID- 22547400 TI - Endovascular suitability and outcome after open surgery for ruptured abdominal aortic aneurysm. AB - BACKGROUND: Endovascular repair of ruptured abdominal aortic aneurysm (rAAA) has rapidly gained popularity, but superior results may be biased by patient selection. The aim was to investigate whether suitability for endovascular repair predicted survival, irrespective of technique of repair. METHODS: Two blinded investigators independently evaluated preoperative computed tomography angiograms of a consecutive cohort of patients with rAAA. Patients were categorized either 'suitable' or 'unsuitable' for endovascular repair, if assessments agreed. If assessments disagreed, they were classified 'borderline suitable'. Correlations between endovascular suitability and clinical outcome were adjusted for suspected confounding factors and tested for robustness using sensitivity analyses. RESULTS: A total of 248 patients with rAAA from January 2001 to December 2010 were included, of whom 237 (95.6 per cent) underwent open repair. Seventy patients (28.2 per cent) were classified as 'suitable' and 100 (40.3 per cent) as 'unsuitable' for endovascular repair; 63 (25.4 per cent) were considered 'borderline suitable'. Fifteen (6.0 per cent) could not be assessed and were included in the sensitivity analyses. The postoperative 30-day mortality rate was 15.3 per cent (38 deaths). Multiple logistic regression demonstrated that the odds of perioperative death increased 9.21 (95 per cent confidence interval 2.16 to 39.23) fold for 'unsuitable' rAAA (P = 0.003) and 6.80 (1.47 to 31.49) fold for 'borderline' rAAA (P = 0.014), compared with 'suitable' rAAA. This selection effect was robust across sensitivity analyses and sustained for at least 5 years of follow-up. CONCLUSION: Endovascular suitability was an independent and strongly positive predictor of survival after open repair of rAAA. PMID- 22547401 TI - State of living kidney donation in Europe. AB - For more than two decades, living donation has been an important part of kidney transplantation. This article discusses commonalities and differences of living donation across Europe, focussing on donor risks and ways to support the donor and enhance living donation practices. PMID- 22547402 TI - A pediatric sporadic hemiplegic migraine case with perfusion abnormality in perfusion MRI and Diamox 99mTc-HMPAO SPECT. PMID- 22547403 TI - Coleen Murphy: how to stay young at heart, body, and mind. PMID- 22547404 TI - Minimizing the "re" in review. AB - There is a troubling trend in scientific publishing for manuscripts to undergo multiple, often lengthy, rounds of review, resulting in significant delays to publication. JCB is announcing new procedures to streamline its editorial process and eliminate unnecessary delays. PMID- 22547405 TI - Cell migration: fibroblasts find a new way to get ahead. AB - Fibroblasts migrate on two-dimensional (2D) surfaces by forming lamellipodia actin-rich extensions at the leading edge of the cell that have been well characterized. In this issue, Petrie et al. (2012. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201201124) show that in some 3D environments, including tissue explants, fibroblasts project different structures, termed lobopodia, at the leading edge. Lobopodia still assemble focal adhesions; however, similar to membrane blebs, they are driven by actomyosin contraction and do not accumulate active Rac, Cdc42, and phosphatidylinositol 3-kinases. PMID- 22547406 TI - Matrix nanotopography as a regulator of cell function. AB - The architecture of the extracellular matrix (ECM) directs cell behavior by providing spatial and mechanical cues to which cells respond. In addition to soluble chemical factors, physical interactions between the cell and ECM regulate primary cell processes, including differentiation, migration, and proliferation. Advances in microtechnology and, more recently, nanotechnology provide a powerful means to study the influence of the ECM on cell behavior. By recapitulating local architectures that cells encounter in vivo, we can elucidate and dissect the fundamental signal transduction pathways that control cell behavior in critical developmental, physiological, and pathological processes. PMID- 22547409 TI - Screening for pre-eclampsia using serum placental growth factor and endoglin with Down's syndrome Quadruple test markers. AB - OBJECTIVE: To estimate the pre-eclampsia screening performance of placental growth factor (PlGF) and endoglin with second-trimester Quadruple test markers used for antenatal Down's syndrome screening. METHODS: A nested case-control study of 88 pregnant women with known early second-trimester Down's syndrome Quadruple test marker levels who subsequently developed pre-eclampsia and 275 unaffected controls. Frozen maternal serum samples were thawed and assayed for PlGF and endoglin. Monte Carlo simulation was used to estimate the pre-eclampsia screening performance of a pre-eclampsia detection algorithm using the Quadruple test markers with or without the addition of PlGF and/or endoglin. RESULTS: Median PlGF was 33% lower (95% confidence interval 24-41%) and endoglin 31% (20 43%) higher in pre-eclampsia than in unaffected pregnancies. Adding PlGF to the Quadruple test markers increased the pre-eclampsia detection rate from 34% to 45% at a 5% false-positive rate - it increased it to 43% with endoglin and to 50% with both. The corresponding estimates for early pre-eclampsia (before 36 weeks' gestation) were a few percentage points higher (48%, 48% and 55% respectively). Including information on parity, pre-eclampsia in a previous pregnancy, family history (woman's mother) and assuming a pre-eclampsia prevalence of 2%, the detection rates for a 5% false-positive rate were 39% with the Quadruple test markers, 48% with addition of endoglin, 49% with addition of PlGF, and 54% with addition of both. CONCLUSIONS: Adding PlGF to the Quadruple test Down's syndrome screening markers improves pre-eclampsia screening performance. There is a modest extra benefit in also adding the measurement of endoglin. PMID- 22547407 TI - ALIX binds a YPX(3)L motif of the GPCR PAR1 and mediates ubiquitin-independent ESCRT-III/MVB sorting. AB - The sorting of signaling receptors to lysosomes is an essential regulatory process in mammalian cells. During degradation, receptors are modified with ubiquitin and sorted by endosomal sorting complex required for transport (ESCRT) 0, -I, -II, and -III complexes into intraluminal vesicles (ILVs) of multivesicular bodies (MVBs). However, it remains unclear whether a single universal mechanism mediates MVB sorting of all receptors. We previously showed that protease-activated receptor 1 (PAR1), a G protein-coupled receptor (GPCR) for thrombin, is internalized after activation and sorted to lysosomes independent of ubiquitination and the ubiquitin-binding ESCRT components hepatocyte growth factor-regulated tyrosine kinase substrate and Tsg101. In this paper, we report that PAR1 sorted to ILVs of MVBs through an ESCRT-III-dependent pathway independent of ubiquitination. We further demonstrate that ALIX, a charged MVB protein 4-ESCRT-III interacting protein, bound to a YPX(3)L motif of PAR1 via its central V domain to mediate lysosomal degradation. This study reveals a novel MVB/lysosomal sorting pathway for signaling receptors that bypasses the requirement for ubiquitination and ubiquitin-binding ESCRTs and may be applicable to a subset of GPCRs containing YPX(n)L motifs. PMID- 22547408 TI - Nonpolarized signaling reveals two distinct modes of 3D cell migration. AB - We search in this paper for context-specific modes of three-dimensional (3D) cell migration using imaging for phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and active Rac1 and Cdc42 in primary fibroblasts migrating within different 3D environments. In 3D collagen, PIP3 and active Rac1 and Cdc42 were targeted to the leading edge, consistent with lamellipodia-based migration. In contrast, elongated cells migrating inside dermal explants and the cell-derived matrix (CDM) formed blunt, cylindrical protrusions, termed lobopodia, and Rac1, Cdc42, and PIP3 signaling was nonpolarized. Reducing RhoA, Rho-associated protein kinase (ROCK), or myosin II activity switched the cells to lamellipodia-based 3D migration. These modes of 3D migration were regulated by matrix physical properties. Specifically, experimentally modifying the elasticity of the CDM or collagen gels established that nonlinear elasticity supported lamellipodia-based migration, whereas linear elasticity switched cells to lobopodia-based migration. Thus, the relative polarization of intracellular signaling identifies two distinct modes of 3D cell migration governed intrinsically by RhoA, ROCK, and myosin II and extrinsically by the elastic behavior of the 3D extracellular matrix. PMID- 22547410 TI - Persistence of uncontrolled cardiovascular risk factors in patients treated with percutaneous interventions for stable coronary artery disease not receiving cardiac rehabilitation. AB - BACKGROUND: Cardiac rehabilitation programmes are strongly recommended for all forms of coronary artery disease to reduce recurrent events and mortality. Few patients seem to participate in these programmes after elective percutaneous coronary intervention (PCI). The aim of this study was to assess changes in lifestyle and risk factors after PCI for patients with stable disease and not included in cardiac rehabilitation programmes. METHODS: We prospectively enrolled 207 consecutive patients with stable disease who underwent a first elective PCI. Follow up was performed at 13.0 +/- 3.2 months for 94.7%; 28 patients were excluded due to participation in a cardiac rehabilitation programme. Baseline values from admission sheets were compared to follow up values collected from the treating physician. RESULTS: At follow up, systolic and diastolic blood pressures dropped (p = 0.001) as well as the prevalence of hypertension (p < 0.001). Significant reductions in cholesterol (p < 0.001) and blood glucose (p = 0.004) were also noted. Low-density lipoprotein levels stayed outside target in 47.2% and high-density lipoprotein levels in 75.0% of patients initially presenting with lipid disorders. Obesity prevalence remained high at follow up. Only 45.6% were performing regular physical exercise and 8.3% of smokers quit smoking. Only 13.3% attended any form of dietary advice programme. HADS-A score was 5.1 +/- 3.9 and the HADS-D score was 3.8 +/- 3.6. SF 36 questionnaire revealed a good quality of life with a mean value of 45.6 for physical and 42.9 for mental wellbeing. CONCLUSION: A considerable percentage of patients receiving PCI for stable angina do not achieve lifestyle and risk factor goals and therefore remain at increased risk for recurrent events. Efforts should be initiated to better implement guidelines that strongly recommend secondary prevention through cardiac rehabilitation after elective PCI. PMID- 22547411 TI - The neurologist's dilemma: MS is a grey matter disease that standard clinical and MRI measures cannot assess adequately--no. PMID- 22547412 TI - The neurologist's dilemma: MS is a grey matter disease that standard clinical and MRI measures cannot assess adequately--yes. PMID- 22547413 TI - The neurologist's dilemma: MS is a grey matter disease that standard clinical and MRI measures cannot assess adequately--commentary. PMID- 22547420 TI - Dose-finding clinical trial design for ordinal toxicity grades using the continuation ratio model: an extension of the continual reassessment method. AB - BACKGROUND: Various dose-finding clinical trial designs, including the continual reassessment method (CRM), dichotomize toxicity outcomes based on prespecified dose-limiting toxicity (DLT) criteria. This loss of toxicity information is particularly inefficient due to the small sample sizes in phase I trials, especially when Common Terminology Criteria for Adverse Events (CTCAE v4.0) are an established ordinal toxicity grading classification already used in the clinical practice. PURPOSE: The purpose of this simulation study is to incorporate ordinal toxicity grades as specified by CTCAE v4.0 using a continuation ratio (CR) model in the likelihood-based CRM. METHODS: This simulation study compares the CR model design to the dichotomous CRM as well as an ordinal CRM that implements the proportional odds (PO) model. We compare six scenarios for model performance based on various safety and efficiency criteria and consider a range of dose-toxicity relationship models, including CR models, PO models, and models that violate the PO assumption. RESULTS: The ordinal CRM performs as well as the dichotomous CRM in all scenarios considered, especially in situations where the starting dose is overly toxic, the ordinal designs show slight improvement in the estimation of the maximum tolerated dose (MTD) and fewer median patients exposed to excessively toxic dose levels as compared to the binary CRM. We also find slight discrepancies in the performance between the PO model and CR model; however, the differences were not substantial enough to strongly recommend one model over the other. LIMITATIONS: The CR model design does require slightly more input from clinical investigators prior to the start of the trial as compared to the dichotomous CRM. Investigators must specify the distribution of toxicity grades at the expected dose levels for a 10% and 90% DLT rate in this CR design. However, an R package will help with the implementation of this ordinal design. CONCLUSIONS: While the ordinal designs did not perform significantly better than the binary counterpart, we were able to incorporate maximal toxicity information available into a feasible dose-finding design without compromising overall design performance. PMID- 22547422 TI - Treatment of graves' disease with antithyroid drugs in the first trimester of pregnancy and the prevalence of congenital malformation. AB - BACKGROUND: Several reports have suggested that propylthiouracil (PTU) may be safer than methimazole (MMI) for treating thyrotoxicosis during pregnancy because congenital malformations have been associated with the use of MMI during pregnancy. OBJECTIVES: We investigated whether in utero exposure to antithyroid drugs resulted in a higher rate of major malformations than among the infants born to a control group of pregnant women. METHODS: We reviewed the cases of women with Graves' disease who became pregnant. The pregnancy outcomes of 6744 women were known, and there were 5967 live births. MMI alone had been used to treat 1426 of the women, and 1578 women had been treated with PTU alone. The 2065 women who had received no medication for the treatment of Graves' disease during the first trimester served as the control group. The remaining women had been treated with potassium iodide, levothyroxine, or more than one drug during the first trimester. The antithyroid drugs were evaluated for associations with congenital malformations. RESULTS: The overall rate of major anomalies in the MMI group was 4.1% (50 of 1231), and it was significantly higher than the 2.1% (40 of 1906) in the control group (P = 0.002), but there was no increase in the overall rate of major anomalies in the PTU group in comparison with the control group (1.9%; 21 of 1399; P = 0.709). Seven of the 1231 newborns in the MMI group had aplasia cutis congenita, six had an omphalocele, seven had a symptomatic omphalomesenteric duct anomaly, and one had esophageal atresia. Hyperthyroidism in the first trimester of pregnancy did not increase the rate of congenital malformation. CONCLUSIONS: In utero exposure to MMI during the first trimester of pregnancy increased the rate of congenital malformations, and it significantly increased the rate of aplasia cutis congenita, omphalocele, and a symptomatic omphalomesenteric duct anomaly. PMID- 22547421 TI - Considerations in the rationale, design and methods of the Strategic Timing of AntiRetroviral Treatment (START) study. AB - BACKGROUND: Untreated human immunodeficiency virus (HIV) infection is characterized by progressive depletion of CD4+ T lymphocyte (CD4) count leading to the development of opportunistic diseases (acquired immunodeficiency syndrome (AIDS)), and more recent data suggest that HIV is also associated with an increased risk of serious non-AIDS (SNA) diseases including cardiovascular, renal, and liver diseases and non-AIDS-defining cancers. Although combination antiretroviral treatment (ART) has resulted in a substantial decrease in morbidity and mortality in persons with HIV infection, viral eradication is not feasible with currently available drugs. The optimal time to start ART for asymptomatic HIV infection is controversial and remains one of the key unanswered questions in the clinical management of HIV-infected individuals. PURPOSE: In this article, we outline the rationale and methods of the Strategic Timing of AntiRetroviral Treatment (START) study, an ongoing multicenter international trial designed to assess the risks and benefits of initiating ART earlier than is currently practiced. We also describe some of the challenges encountered in the design and implementation of the study and how these challenges were addressed. METHODS: A total of 4000 study participants who are HIV type 1 (HIV-1) infected, ART naive with CD4 count > 500 cells/uL are to be randomly allocated in a 1:1 ratio to start ART immediately (early ART) or defer treatment until CD4 count is <350 cells/uL (deferred ART) and followed for a minimum of 3 years. The primary outcome is time to AIDS, SNA, or death. The study had a pilot phase to establish feasibility of accrual, which was set as the enrollment of at least 900 participants in the first year. RESULTS: Challenges encountered in the design and implementation of the study included the limited amount of data on the risk of a major component of the primary endpoint (SNA) in the study population, changes in treatment guidelines when the pilot phase was well underway, and the complexities of conducting the trial in a geographically wide population with diverse regulatory requirements. With the successful completion of the pilot phase, more than 1000 participants from 100 sites in 23 countries have been enrolled. The study will expand to include 237 sites in 36 countries to reach the target accrual of 4000 participants. CONCLUSIONS: START is addressing one of the most important questions in the clinical management of ART. The randomization provided a platform for the conduct of several substudies aimed at increasing our understanding of HIV disease and the effects of antiretroviral therapy beyond the primary question of the trial. The lessons learned from its design and implementation will hopefully be of use to future publicly funded international trials. PMID- 22547423 TI - Are women with thicker cortices in the femoral shaft at higher risk of subtrochanteric/diaphyseal fractures? The study of osteoporotic fractures. AB - CONTEXT: Femoral shaft cortical thickening has been mentioned in reports of atypical subtrochanteric and diaphyseal (S/D) femur fractures, but it is unclear whether thickening precedes fracture or results from a preceding stress fracture and what role bisphosphonates might play in cortical thickening. OBJECTIVE: Our objective was to examine the relationship of cortical thickness to S/D fracture risk as well as establish normal reference values for femoral cortical thickness in a large population-based cohort of older women. DESIGN: Using pelvic radiographs obtained in 1986-1988, we measured femoral shaft cortical thickness 3 cm below the lesser trochanter in women in the Study of Osteoporotic Fractures. We measured this in a random sample and in those with S/D fractures and femoral neck and intertrochanteric fractures. Low-energy S/D fractures were identified from review of radiographic reports obtained between 1986 and 2010. Radiographs to evaluate atypia were not available. Analysis used case-cohort, proportional hazards models. OUTCOMES: Cortical thickness as a risk factor for low-energy S/D femur fractures as well as femoral neck and intertrochanteric fractures in the Study of Osteoporotic Fractures, adjusting for age and bone mineral density in proportional hazards models. RESULTS: After age adjustment, women with thinner medial cortices were at a higher risk of S/D femur fracture, with a relative hazard of 3.94 (95% confidence interval = 1.23-12.6) in the lowest vs. highest quartile. Similar hazard ratios were seen for femoral neck and intertrochanteric fractures. Medial or total cortical thickness was more strongly related to fracture risk than lateral cortical thickness. CONCLUSIONS: In primarily bisphosphonate-naive women, we found no evidence that thick femoral cortices placed women at higher risk for low-energy S/D femur fractures; in fact, the opposite was true. Women with thin cortices were also at a higher risk for femoral neck and intertrochanteric fractures. Whether cortical thickness among bisphosphonate users plays a role in atypical S/D fractures remains to be determined. PMID- 22547424 TI - First-degree relatives of type 2 diabetic patients have reduced expression of genes involved in fatty acid metabolism in skeletal muscle. AB - CONTEXT: First-degree relatives of patients with type 2 diabetes (FH+) have been shown to have decreased energy expenditure and decreased expression of mitochondrial genes in skeletal muscle. In previous studies, it has been difficult to distinguish whether mitochondrial dysfunction and differential regulation of genes are primary (genetic) or due to reduced physical activity, obesity, or other correlated factors. OBJECTIVE: The aim of this study was to investigate whether mitochondrial dysfunction is a primary defect or results from an altered metabolic state. DESIGN: We compared gene expression in skeletal muscle from 24 male subjects with FH and 26 without FH matched for age, glucose tolerance, VO(2peak) (peak oxygen uptake), and body mass index using microarrays. Additionally, type fiber composition, mitochondrial DNA content, and citrate synthase activity were measured. The results were followed up in an additional cohort with measurements of in vivo metabolism. RESULTS: FH+ vs. FH- subjects showed reduced expression of mitochondrial genes (P = 2.75 * 10(-6)), particularly genes involved in fatty acid metabolism (P = 4.08 * 10(-7)), despite similar mitochondrial DNA content. Strikingly, a 70% reduced expression of the monoamine oxidase A (MAOA) gene was found in FH+ vs. FH- individuals (P = 0.0009). Down-regulation of the genes involved in fat metabolism was associated with decreased in vivo fat oxidation and increased glucose oxidation examined in an additional cohort of elderly men. CONCLUSIONS: These results suggest that genetically altered fatty acid metabolism predisposes to type 2 diabetes and propose a role for catecholamine-metabolizing enzymes like MAOA in the regulation of energy metabolism. PMID- 22547426 TI - Stochastic exploration of ambiguities for nonrigid shape recovery. AB - Recovering the 3D shape of deformable surfaces from single images is known to be a highly ambiguous problem because many different shapes may have very similar projections. This is commonly addressed by restricting the set of possible shapes to linear combinations of deformation modes and by imposing additional geometric constraints. Unfortunately, because image measurements are noisy, such constraints do not always guarantee that the correct shape will be recovered. To overcome this limitation, we introduce a stochastic sampling approach to efficiently explore the set of solutions of an objective function based on point correspondences. This allows us to propose a small set of ambiguous candidate 3D shapes and then use additional image information to choose the best one. As a proof of concept, we use either motion or shading cues to this end and show that we can handle a complex objective function without having to solve a difficult nonlinear minimization problem. The advantages of our method are demonstrated on a variety of problems including both real and synthetic data. PMID- 22547427 TI - Robust Simultaneous Registration and Segmentation with sparse error reconstruction. AB - We introduce a fast and efficient variational framework for Simultaneous Registration and Segmentation (SRS) applicable to a wide variety of image sequences. We demonstrate that a dense correspondence map (between consecutive frames) can be reconstructed correctly even in the presence of partial occlusion, shading, and reflections. The errors are efficiently handled by exploiting their sparse nature. In addition, the segmentation functional is reformulated using a dual Rudin-Osher-Fatemi (ROF) model for fast implementation. Moreover, nonparametric shape prior terms that are suited for this dual-ROF model are proposed. The efficacy of the proposed method is validated with extensive experiments on both indoor, outdoor natural and biological image sequences, demonstrating the higher accuracy and efficiency compared to various state-of-the art methods. PMID- 22547425 TI - Variants in DENND1A are associated with polycystic ovary syndrome in women of European ancestry. AB - CONTEXT: A genome-wide association study has identified three loci (five independent signals) that confer risk for polycystic ovary syndrome (PCOS) in Han Chinese women. Replication is necessary to determine whether the same variants confer risk for PCOS in women of European ancestry. OBJECTIVE: The objective of the study was to test whether these PCOS risk variants in Han Chinese women confer risk for PCOS in women of European ancestry. DESIGN: This was a case control study. SETTING: The study was conducted at deCODE Genetics in Iceland and two academic medical centers in the United States. PATIENTS: Cases were 376 Icelandic women and 565 and 203 women from Boston, MA, and Chicago, IL, respectively, all diagnosed with PCOS by the National Institutes of Health criteria. Controls were 16,947, 483, and 189 women not known to have PCOS from Iceland, Boston, and Chicago, respectively. INTERVENTION: There were no interventions. MAIN OUTCOMES: Main outcomes were allele frequencies for seven variants in PCOS cases and controls. RESULTS: Two strongly correlated Han Chinese PCOS risk variants on chromosome 9q33.3, rs10986105[C], and rs10818854[A], were replicated in samples of European ancestry with odds ratio of 1.68 (P = 0.00033) and odds ratio of 1.53 (P = 0.0019), respectively. Other risk variants at 2p16.3 (rs13405728), 2p21 (rs12468394, rs12478601, and rs13429458), and 9q33.3 (rs2479106), or variants correlated with them, did not associate with PCOS. The same allele of rs10986105 that increased the risk of PCOS also increased the risk of hyperandrogenism in women without PCOS from Iceland and demonstrated a stronger risk for PCOS defined by the National Institutes of Health criteria than the Rotterdam criteria. CONCLUSIONS: We replicated one of the five Chinese PCOS association signals, represented by rs10986105 and rs10818854 on 9q33, in individuals of European ancestry. Examination of the subjects meeting at least one of the Rotterdam criteria for PCOS suggests that the variant may be involved in the hyperandrogenism and possibly the irregular menses of PCOS. PMID- 22547428 TI - Tree-structured CRF models for interactive image labeling. AB - We propose structured prediction models for image labeling that explicitly take into account dependencies among image labels. In our tree-structured models, image labels are nodes, and edges encode dependency relations. To allow for more complex dependencies, we combine labels in a single node and use mixtures of trees. Our models are more expressive than independent predictors, and lead to more accurate label predictions. The gain becomes more significant in an interactive scenario where a user provides the value of some of the image labels at test time. Such an interactive scenario offers an interesting tradeoff between label accuracy and manual labeling effort. The structured models are used to decide which labels should be set by the user, and transfer the user input to more accurate predictions on other image labels. We also apply our models to attribute-based image classification, where attribute predictions of a test image are mapped to class probabilities by means of a given attribute-class mapping. Experimental results on three publicly available benchmark datasets show that in all scenarios our structured models lead to more accurate predictions, and leverage user input much more effectively than state-of-the-art independent models. PMID- 22547429 TI - Appearance-based gaze estimation using visual saliency. AB - We propose a gaze sensing method using visual saliency maps that does not need explicit personal calibration. Our goal is to create a gaze estimator using only the eye images captured from a person watching a video clip. Our method treats the saliency maps of the video frames as the probability distributions of the gaze points. We aggregate the saliency maps based on the similarity in eye images to efficiently identify the gaze points from the saliency maps. We establish a mapping between the eye images to the gaze points by using Gaussian process regression. In addition, we use a feedback loop from the gaze estimator to refine the gaze probability maps to improve the accuracy of the gaze estimation. The experimental results show that the proposed method works well with different people and video clips and achieves a 3.5-degree accuracy, which is sufficient for estimating a user's attention on a display. PMID- 22547430 TI - CoSLAM: collaborative visual SLAM in dynamic environments. AB - This paper studies the problem of vision-based simultaneous localization and mapping (SLAM) in dynamic environments with multiple cameras. These cameras move independently and can be mounted on different platforms. All cameras work together to build a global map, including 3D positions of static background points and trajectories of moving foreground points. We introduce intercamera pose estimation and intercamera mapping to deal with dynamic objects in the localization and mapping process. To further enhance the system robustness, we maintain the position uncertainty of each map point. To facilitate intercamera operations, we cluster cameras into groups according to their view overlap, and manage the split and merge of camera groups in real time. Experimental results demonstrate that our system can work robustly in highly dynamic environments and produce more accurate results in static environments. PMID- 22547431 TI - Detecting phenotype-specific interactions between biological processes from microarray data and annotations. AB - High throughput technologies enable researchers to measure expression levels on a genomic scale. However, the correct and efficient biological interpretation of such voluminous data remains a challenging problem. Many tools have been developed for the analysis of GO terms that are over- or under-represented in a list of differentially expressed genes. However, a previously unexplored aspect is the identification of changes in the way various biological processes interact in a given condition with respect to a reference. Here, we present a novel approach that aims at identifying such interactions between biological processes that are significantly different in a given phenotype with respect to normal. The proposed technique uses vector-space representation, SVD-based dimensionality reduction, differential weighting, and bootstrapping to asses the significance of the interactions under the multiple and complex dependencies expected between the biological processes. We illustrate our approach on two real data sets involving breast and lung cancer. More than 88 percent of the interactions found by our approach were deemed to be correct by an extensive manual review of literature. An interesting subset of such interactions is discussed in detail and shown to have the potential to open new avenues for research in lung and breast cancer. PMID- 22547433 TI - LNA: fast protein structural comparison using a Laplacian characterization of tertiary structure. AB - Abstract-In the last two decades, a lot of protein 3D shapes have been discovered, characterized, and made available thanks to the Protein Data Bank (PDB), that is nevertheless growing very quickly. New scalable methods are thus urgently required to search through the PDB efficiently. This paper presents an approach entitled LNA (Laplacian Norm Alignment) that performs a structural comparison of two proteins with dynamic programming algorithms. This is achieved by characterizing each residue in the protein with scalar features. The feature values are calculated using a Laplacian operator applied on the graph corresponding to the adjacency matrix of the residues. The weighted Laplacian operator we use estimates, at various scales, local deformations of the topology where each residue is located. On some benchmarks, which are widely shared by the community, we obtain qualitatively similar results compared to other competing approaches, but with an algorithm one or two order of magnitudes faster. 180,000 protein comparisons can be done within 1 second with a single recent Graphical Processing Unit (GPU), which makes our algorithm very scalable and suitable for real-time database querying across the web. PMID- 22547434 TI - Refining regulatory networks through phylogenetic transfer of information. AB - The experimental determination of transcriptional regulatory networks in the laboratory remains difficult and timeconsuming, while computational methods to infer these networks provide only modest accuracy. The latter can be attributed partly to the limitations of a single-organism approach. Computational biology has long used comparative and evolutionary approaches to extend the reach and accuracy of its analyses. In this paper, we describe ProPhyC, a probabilistic phylogenetic model and associated inference algorithms, designed to improve the inference of regulatory networks for a family of organisms by using known evolutionary relationships among these organisms. ProPhyC can be used with various network evolutionary models and any existing inference method. Extensive experimental results on both biological and synthetic data confirm that our model (through its associated refinement algorithms) yields substantial improvement in the quality of inferred networks over all current methods. We also compare ProPhyC with a transfer learning approach we design. This approach also uses phylogenetic relationships while inferring regulatory networks for a family of organisms. Using similar input information but designed in a very different framework, this transfer learning approach does not perform better than ProPhyC, which indicates that ProPhyC makes good use of the evolutionary information. PMID- 22547432 TI - Gene selection using iterative feature elimination random forests for survival outcomes. AB - Although many feature selection methods for classification have been developed, there is a need to identify genes in high-dimensional data with censored survival outcomes. Traditional methods for gene selection in classification problems have several drawbacks. First, the majority of the gene selection approaches for classification are single-gene based. Second, many of the gene selection procedures are not embedded within the algorithm itself. The technique of random forests has been found to perform well in high-dimensional data settings with survival outcomes. It also has an embedded feature to identify variables of importance. Therefore, it is an ideal candidate for gene selection in high dimensional data with survival outcomes. In this paper, we develop a novel method based on the random forests to identify a set of prognostic genes. We compare our method with several machine learning methods and various node split criteria using several real data sets. Our method performed well in both simulations and real data analysis.Additionally, we have shown the advantages of our approach over single-gene-based approaches. Our method incorporates multivariate correlations in microarray data for survival outcomes. The described method allows us to better utilize the information available from microarray data with survival outcomes. PMID- 22547436 TI - Thiazide and thiazide-like diuretics: perspectives on individualization of drug and dose based on therapeutic index. PMID- 22547435 TI - Nighttime blood pressure dipping in young adults and coronary artery calcium 10 15 years later: the coronary artery risk development in young adults study. AB - Nighttime blood pressure (BP) dipping can be quantified as the ratio of mean nighttime (sleep) BP to mean daytime (awake) BP. People whose dipping ratio is >= 0.90 have been referred to as nondippers, and nondipping is associated with cardiovascular disease events. We examined the relationship between systolic nighttime BP dipping in young adults and the presence of coronary artery calcium (CAC) 10 to 15 years later using data from the ambulatory BP monitoring substudy of the Coronary Artery Risk Development in Young Adults Study. Among 239 participants with adequate measures of both nighttime and daytime readings and coronary artery calcium, the systolic BP dipping ratio ranged from 0.72 to 1.24 (mean, 0.88; SD, 0.06), and CAC was present 10 to 15 years later in 54 participants (22.6%). Compared with those whose systolic BP dipping ratio ranged from 0.88 to 0.92 (quartile 3), the 57 participants (23.9%) with less pronounced or absent dipping (ratio, 0.92-1.24; quartile 4) had an unadjusted odds ratio of 4.08 (95% CI, 1.48-11.2) for the presence of CAC. The 60 participants (25.1%) with a more pronounced dipping (ratio, 0.72-0.85; quartile 1) also had greater odds for presence of CAC (odds ratio, 4.76 [95% CI, 1.76-12.9]). When modeled as a continuous predictor, a U-shaped relationship between systolic BP dipping ratio and future CAC was apparent and persisted after adjustment for multiple potential confounders (P<0.001 for quadratic term). Both failure of systolic BP to dip sufficiently and "overdipping" during nighttime may be associated with future subclinical coronary atherosclerosis. PMID- 22547437 TI - Fructose likely does have a role in hypertension. PMID- 22547438 TI - Gene trapping uncovers sex-specific mechanisms for upstream stimulatory factors 1 and 2 in angiotensinogen expression. AB - A single-nucleotide polymorphism (C/A) located within an E-box at the -20 position of the human angiotensinogen (AGT) promoter may regulate transcriptional activation through differential recruitment of the transcription factors upstream stimulatory factor (USF) 1 and 2. To study the contribution of USF1 on AGT gene expression, mice carrying a (-20C) human AGT (hAGT) transgene were bred with mice harboring a USF1 gene trap allele designed to knock down USF1 expression. USF1 mRNA was reduced relative to controls in liver (9 +/- 1%), perigenital adipose (16 +/- 3%), kidney (17 +/- 1%), and brain (34 +/- 2%) in double-transgenic mice. This decrease was confirmed by electrophoretic mobility shift assay. Chromatin immunoprecipitation analyses revealed a decrease in USF1, with retention of USF2 binding at the hAGT promoter in the liver of male mice. hAGT expression was reduced in the liver and other tissues of female but not male mice. The decrease in endogenous AGT expression was insufficient to alter systolic blood pressure at baseline but caused reduced systolic blood pressure in female USF1 gene trap mice fed a high-fat diet. Treatment of USF1 knockdown males with intravenous adenoviral short hairpin RNA targeting USF2 resulted in reduced expression of USF1, USF2, and hAGT protein. Our data from chromatin immunoprecipitation assays suggests that this decrease in hAGT is attributed to decreased USF2 binding to the hAGT promoter. In conclusion, both USF1 and USF2 are essential for AGT transcriptional regulation, and distinct sex-specific and tissue-specific mechanisms are involved in the activities of these transcription factors in vivo. PMID- 22547439 TI - Combined effect of angiotensin II receptor blocker and either a calcium channel blocker or diuretic on day-by-day variability of home blood pressure: the Japan Combined Treatment With Olmesartan and a Calcium-Channel Blocker Versus Olmesartan and Diuretics Randomized Efficacy Study. AB - Day-by-day home blood pressure (BP) variability (BPV) was reported to be associated with increased cardiovascular risk. We aimed to test the hypothesis that the angiotensin II receptor blocker/calcium-channel blocker combination decreases day-by-day BPV more than the angiotensin II receptor blocker/diuretic combination does and investigated the mechanism underlying the former reduction. We enrolled 207 hypertensive subjects treated with olmesartan monotherapy for 12 weeks. The subjects were randomly assigned to treatment with hydrochlorothiazide (n = 104) or azelnidipine (n = 103) for 24 weeks. Home BP was taken in triplicate with a memory-equipped device in the morning and evening, respectively, for 5 consecutive days before each visit. Visits occurred at 4-week intervals. Home BPV was defined as within-individual SD of the 5-day home BP. Arterial stiffness was assessed by aortic pulse wave velocity at baseline and 24 weeks later. The reductions in home systolic BP were similar between the 2 groups, whereas the SD of home systolic BP decreased more in the azelnidipine group than in the hydrochlorothiazide group during the follow-up period (follow-up mean: 6.3 versus 7.1 mm Hg; P = 0.007). In the azelnidipine group, the change in aortic pulse wave velocity was independently associated with the change in SD of home systolic BP (regression coefficient +/- SE = 0.79 +/- 0.37; P = 0.036). This study demonstrated that the angiotensin II receptor blocker/calcium-channel blocker combination improved home BPV in addition to home BP reduction and that the reduction in home BPV was partly attributable to the arterial stiffness reduction by this combination. PMID- 22547441 TI - Effects of prehypertension and hypertension subtype on cardiovascular disease in the Asia-Pacific Region. AB - The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure defined blood pressure (BP) levels of 120 to 139/80 to 89 mm Hg as prehypertension and those of >= 140/90 mm Hg as hypertension. Hypertension can be divided into 3 categories, isolated diastolic (IDH; systolic BP <140 mm Hg and diastolic BP >= 90 mmHg), isolated systolic (systolic BP >= 140 mm Hg and diastolic BP <90 mmHg), and systolic diastolic hypertension (systolic BP >= 140 mm Hg and diastolic BP >= 90 mmHg). Although there is clear evidence that isolated systolic hypertension and systolic diastolic hypertension increase the risks of future vascular events, there remains uncertainty about the effects of IDH. The objective was to determine the effects of prehypertension and hypertension subtypes (IDH, isolated systolic hypertension, and systolic-diastolic hypertension) on the risks of cardiovascular disease (CVD) in the Asia-Pacific Region. The Asia Pacific Cohort Studies Collaboration is an individual participant data overview of cohort studies in the region. This analysis included a total of 346570 participants from 36 cohort studies. Outcomes were fatal and nonfatal CVD. The relationship between BP categories and CVD was explored using a Cox proportional hazards model adjusted for age, cholesterol, and smoking and stratified by sex and study. Compared with normal BP (<120/80 mmHg), hazard ratios (95% CIs) for CVD were 1.41 (1.31-1.53) for prehypertension, 1.81 (1.61-2.04) for IDH, 2.18 (2.00-2.37) for isolated systolic hypertension, and 3.42 (3.17-3.70) for systolic-diastolic hypertension. Separately significant effects of prehypertension and hypertension subtypes were also observed for coronary heart disease, ischemic stroke, and hemorrhagic stroke. In the Asia-Pacific region, prehypertension and all hypertension subtypes, including IDH, thus clearly predicted increased risks of CVD. PMID- 22547440 TI - Age-related decline in reendothelialization capacity of human endothelial progenitor cells is restored by shear stress. AB - Aging is associated with dysfunction of endothelial progenitor cells (EPCs), and shear stress has a beneficial impact on EPC function; however, the effects of aging and shear stress on the endothelial repair capacity of EPCs after arterial injury have not been reported. Here we investigated the influence of aging and shear stress on the reendothelialization capacity of human EPCs and the related molecular mechanism. Compared with EPCs isolated from young subjects, EPCs from the elderly displayed an impaired migration and adhesion in vitro and demonstrated a significantly reduced reendothelialization capacity in vivo after transplantation into nude mice with carotid artery denudation injury. Shear stress pretreatment enhances the migration, adhesion, and reendothelialization capacity in both young and elderly EPCs; however, it was to a greater extent in EPCs from the elderly. Although basal CXC chemokine receptor 4 (CXCR4) expression was similar in EPCs from the 2 age groups, the stromal cell derived factor 1 induced CXCR4 and Janus kinase 2 phosphorylations were much lower in the elderly than in young EPCs. Shear stress treatment upregulated CXCR4 expression and phosphorylation and, importantly, restored the stromal cell-derived factor 1/CXCR4-dependent Janus kinase 2 phosphorylation in the elderly EPCs. Furthermore, short hairpin RNA-mediated knockdown of CXCR4 expression or pretreatment with Janus kinase 2 inhibitor diminished the enhancement in the migration, adhesion, and reendothelialization capacity of the elderly EPCs from shear stress treatments. Thus, our study demonstrates that upregulation of the CXCR4/Janus kinase 2 pathway by shear stress contributes to the enhanced reendothelialization capacity of EPCs from elderly men. PMID- 22547442 TI - Aldosterone inhibits antifibrotic factors in mouse hypertensive heart. AB - The renin-angiotensin-aldosterone system is involved in the arterial hypertension associated cardiovascular remodeling. In this context, the development of cardiac fibrosis results from an imbalance between profibrotic and antifibrotic pathways, in which the role of aldosterone is yet not established. To determine the role of intracardiac aldosterone in the development of myocardial fibrosis during hypertension, we used a double transgenic model (AS-Ren) of cardiac hyperaldosteronism (AS) and systemic hypertension (Ren). The 9-month-old hypertensive mice had cardiac fibrosis, and hyperaldosteronism enhanced the fibrotic level. The mRNA levels of connective tissue growth factor and transforming growth factor-beta1 were similarly increased in Ren and AS-Ren mice compared with wild-type and AS mice, respectively. Hyperaldosteronism combined with hypertension favored the macrophage infiltration (CD68(+) cells) in heart, and enhanced the mRNA level of monocyte chemoattractant protein 1, osteopontin, and galectin 3. Interestingly, in AS-Ren mice the hypertension-induced increase in bone morphogenetic protein 4 mRNA and protein levels was significantly inhibited, and B-type natriuretic peptide expression was blunted. The mineralocorticoid receptor antagonist eplerenone restored B-type natriuretic peptide and bone morphogenetic protein 4 levels and decreased CD68 and galectin 3 levels in AS-Ren mice. Finally, when hypertension was induced by angiotensin II infusion in wild-type and AS mice, the mRNA profiles did not differ from those observed in Ren and AS-Ren mice, respectively. The aldosterone-induced inhibition of B-type natriuretic peptide and bone morphogenetic protein 4 expression was confirmed in vitro in neonatal mouse cardiomyocytes. Altogether, we demonstrate that, at the cardiac level, hyperaldosteronism worsens hypertension-induced fibrosis through 2 mineralocorticoid receptor-dependent mechanisms, activation of inflammation/galectin 3-induced fibrosis and inhibition of antifibrotic factors (B-type natriuretic peptide and bone morphogenetic protein 4). PMID- 22547444 TI - Role of angiotensinogen and relative aldosterone excess in salt-sensitive hypertension. PMID- 22547443 TI - Meta-analysis of dose-response relationships for hydrochlorothiazide, chlorthalidone, and bendroflumethiazide on blood pressure, serum potassium, and urate. AB - Thiazide and thiazide-like diuretics are widely used in the management of hypertension, but recently the equivalence of hydrochlorothiazide and chlorthalidone for blood pressure (BP) lowering and prevention of cardiovascular disease has been questioned. We performed a meta-analysis to characterize the dose-response relationships for 3 commonly prescribed thiazide diuretics, hydrochlorothiazide, chlorthalidone, and bendroflumethiazide, on BP, serum potassium, and urate. Randomized, double-blind, parallel placebo-controlled trials meeting the following criteria, >= 2 different monotherapy dose arms, follow-up duration >= 4 weeks, and baseline washout of medication >= 2 weeks, were identified using Embase (1980-2010 week 50), Medline (1950-2010 November week 3), metaRegister of Controlled Trials, and Cochrane Central. A total of 26 trials examined hydrochlorothiazide, 3 examined chlorthalidone, and 1 examined bendroflumethiazide. Studies included a total of 4683 subjects in >53 comparison arms. Meta-regression of the effect of thiazides on systolic BP showed a log linear relationship with a potency series: bendroflumethiazide>chlorthalidone>hydrochlorothiazide. The estimated dose of each drug predicted to reduce systolic BP by 10 mm Hg was 1.4, 8.6, and 26.4 mg, respectively, and there was no evidence of a difference in maximum reduction of systolic BP by high doses of different thiazides. Potency series for diastolic BP, serum potassium, and urate were similar to those seen for systolic BP. Hydrochlorothiazide, chlorthalidone, and bendroflumethiazide have markedly different potency. This may account for differences in the antihypertensive effect between hydrochlorothiazide and chlorthalidone using standard dose ranges. PMID- 22547445 TI - Identification of a novel vasoconstrictor peptide specific for the systemic circulation. AB - Some small molecular weight peptides possess potent vasoactive properties. Herein we have identified the laminin nonapeptide (LNP) CDPGYIGSR as a novel vasoconstrictive agent. Isometric force measurements revealed that LNP induced vasoconstriction in small and large murine arteries in a dose-dependent fashion; LNP also increased vascular tone in human mammary arteries. The vasoactive response was specific for the nonapeptide, because neither scrambled nor very similar peptide sequences modulated vascular tone. As an underlying mechanism we found in [Ca(2+)](i) imaging experiments that the nonapeptide induced transmembrane [Ca(2+)](i) influx in vascular smooth muscle cells. Patch clamp experiments showed that LNP activated nonselective cation channels, causing depolarization of the membrane potential and opening of L-type Ca(2+) channels. The functional effect of LNP was also assessed with catheter measurements in mice in vivo and confirmed vasoconstriction. This effect was restricted to the systemic circulation, because measurements with the perfused lung system demonstrated that LNP did not alter vascular tone in pulmonary arteries. Thus, LNP is a vasoconstrictor in mouse and human arteries, and its vasoactivity is restricted to the systemic vasculature. PMID- 22547446 TI - Calcium antagonist added to angiotensin receptor blocker: a recipe for reducing blood pressure variability?: evidence from day-by-day home blood pressure monitoring. PMID- 22547447 TI - Endothelial nitric oxide synthase polymorphism rs3918226 associated with hypertension does not affect plasma nitrite levels in healthy subjects. PMID- 22547448 TI - Vascular rejuvenation through the stromal cell-derived factor 1alpha/CXC chemokine receptor type 4/Janus kinase 2 signalling pathway. PMID- 22547449 TI - Folate receptor alpha expression in lung cancer: diagnostic and prognostic significance. AB - With the advent of targeted therapies directed towards folate receptor alpha, with several such agents in late stage clinical development, the sensitive and robust detection of folate receptor alpha in tissues is of importance relative to patient selection and perhaps prognosis and prediction of response. The goal of the present study was to evaluate the expression of folate receptor alpha in non small cell lung cancer specimens to determine its frequency of expression and its potential for prognosis. The distribution of folate receptor alpha expression in normal tissues as well as its expression and relationship to non-small cell lung cancer subtypes was assessed by immunohistochemistry using tissue microarrays and fine needle aspirates and an optimized manual staining method using the recently developed monoclonal antibody 26B3. The association between folate receptor alpha expression and clinical outcome was also evaluated on a tissue microarray created from formalin fixed paraffin embedded specimens from patients with surgically resected lung adenocarcinoma. Folate receptor alpha expression was shown to have a high discriminatory capacity for lung adenocarcinomas versus squamous cell carcinomas. While 74% of adenocarcinomas were positive for folate receptor alpha expression, our results found that only 13% of squamous cell carcinomas were FRA positive (p<0.0001). In patients with adenocarcinoma that underwent surgical resection, increased folate receptor alpha expression was associated with improved overall survival (Hazard Ratio 0.39, 95% CI 0.18-0.85). These data demonstrate the diagnostic relevance of folate receptor alpha expression in non small cell lung cancer as determined by immunohistochemistry and suggest that determination of folate receptor alpha expression provides prognostic information in patients with lung adenocarcinoma. PMID- 22547451 TI - Advances in reflective oxygen saturation monitoring with a novel in-ear sensor system: results of a human hypoxia study. AB - Pulse oximetry is a well-established, noninvasive photoplethysmographic method to monitor vital signs. It allows us to measure cardiovascular parameters, such as heart rate and arterial oxygen saturation, and is considered an essential monitoring tool in clinical routine. However, since many of the conventional systems work in transmission mode, they can only be applied to the thinner or peripheral parts of the body, such as a finger tip. This has the major disadvantage that, in case of shock-induced centralization and a resulting drop in perfusion, such systems cannot ensure valid measurements. Therefore, we developed a reflective in-ear sensor system that can be worn in the ear channel like a headphone. Because the sensor is integrated in an ear mold and positioned very close to the trunk, reliable measurement is expected even in case of centralization. An additional advantage is that the sensor is comfortable to wear and has considerable resistance to motion artifacts. In this paper, we report on hypoxia studies with ten healthy participants which were performed to analyze the system with regard to the detection of heart rate and arterial oxygen saturation. It was shown earlier that, due to the high signal quality, heart rate can easily be detected. Using the conventional calculation principle, based on Beer Lambert's law combined with a single-point calibration method, we now demonstrate that the detection of arterial oxygen saturation in the human ear canal is possible using reflective saturation sensors. PMID- 22547450 TI - Identification of hemodynamically optimal coronary stent designs based on vessel caliber. AB - Coronary stent design influences local patterns of wall shear stress (WSS) that are associated with neointimal growth, restenosis, and the endothelialization of stent struts. The number of circumferentially repeating crowns N(C) for a given stent design is often modified depending on the target vessel caliber, but the hemodynamic implications of altering N(C) have not previously been studied. In this investigation, we analyzed the relationship between vessel diameter and the hemodynamically optimal N(C) using a derivative-free optimization algorithm coupled with computational fluid dynamics. The algorithm computed the optimal vessel diameter, defined as minimizing the area of stent-induced low WSS, for various configurations (i.e., N(C)) of a generic slotted-tube design and designs that resemble commercially available stents. Stents were modeled in idealized coronary arteries with a vessel diameter that was allowed to vary between 2 and 5 mm. The results indicate that the optimal vessel diameter increases for stent configurations with greater N(C), and the designs of current commercial stents incorporate a greater N(C) than hemodynamically optimal stent designs. This finding suggests that reducing the N(C) of current stents may improve the hemodynamic environment within stented arteries and reduce the likelihood of excessive neointimal growth and thrombus formation. PMID- 22547452 TI - Quantifying information transfer through a head-attached vibrotactile display: principles for design and control. AB - Vibrotactile displays can extend the perception capabilities of visually impaired persons. Placing such devices on the head promises easy attachment and detachment without reducing other interaction abilities. However, the effectiveness of head attached vibrotactile displays has never been thoroughly tested. This paper presents the results obtained from experiments with 22 subjects equipped with a display containing 12 coin-type motors equally spaced in a horizontal plane around the upper head region. Our display allowed single- as well as multimotor activation with up to six simultaneously active motors. We identified the minimum and comfort strength of vibrotactile stimulation, and measured the precision in perceiving the accurate number of active motors as well as the precision in localizing the stimuli on the head. While subjects identified the correct number of active motors in 94% of the cases when presented with only one active motor, this precision dropped to 40% for two and down to 5% for five simultaneously active motors. This strongly suggests to avoid multipoint stimulation even though the precision of localizing a position of a stimulus on the head is barely affected by the number of simultaneously active motors. Localization precision, however, varied significantly with the region of the head suggesting that the most front and back regions of the head should be avoided if high precision is required. PMID- 22547453 TI - Precise segmentation of 3-D magnetic resonance angiography. AB - Accurate automatic extraction of a 3-D cerebrovascular system from images obtained by time-of-flight (TOF) or phase contrast (PC) magnetic resonance angiography (MRA) is a challenging segmentation problem due to the small size objects of interest (blood vessels) in each 2-D MRA slice and complex surrounding anatomical structures (e.g., fat, bones, or gray and white brain matter). We show that due to the multimodal nature of MRA data, blood vessels can be accurately separated from the background in each slice using a voxel-wise classification based on precisely identified probability models of voxel intensities. To identify the models, an empirical marginal probability distribution of intensities is closely approximated with a linear combination of discrete Gaussians (LCDG) with alternate signs, using our previous EM-based techniques for precise linear combination of Gaussian-approximation adapted to deal with the LCDGs. The high accuracy of the proposed approach is experimentally validated on 85 real MRA datasets (50 TOF and 35 PC) as well as on synthetic MRA data for special 3-D geometrical phantoms of known shapes. PMID- 22547454 TI - Statistical shape model-based femur kinematics from biplane fluoroscopy. AB - Studying joint kinematics is of interest to improve prosthesis design and to characterize postoperative motion. State of the art techniques register bones segmented from prior computed tomography or magnetic resonance scans with X-ray fluoroscopic sequences. Elimination of the prior 3D acquisition could potentially lower costs and radiation dose. Therefore, we propose to substitute the segmented bone surface with a statistical shape model based estimate. A dedicated dynamic reconstruction and tracking algorithm was developed estimating the shape based on all frames, and pose per frame. The algorithm minimizes the difference between the projected bone contour and image edges. To increase robustness, we employ a dynamic prior, image features, and prior knowledge about bone edge appearances. This enables tracking and reconstruction from a single initial pose per sequence. We evaluated our method on the distal femur using eight biplane fluoroscopic drop landing sequences. The proposed dynamic prior and features increased the convergence rate of the reconstruction from 71% to 91%, using a convergence limit of 3 mm. The achieved root mean square point-to-surface accuracy at the converged frames was 1.48 +/- 0.41 mm. The resulting tracking precision was 1-1.5 mm, with the largest errors occurring in the rotation around the femoral shaft (about 2.5 degrees precision). PMID- 22547455 TI - Interactive lesion segmentation with shape priors from offline and online learning. AB - In medical image segmentation, tumors and other lesions demand the highest levels of accuracy but still call for the highest levels of manual delineation. One factor holding back automatic segmentation is the exemption of pathological regions from shape modelling techniques that rely on high-level shape information not offered by lesions. This paper introduces two new statistical shape models (SSMs) that combine radial shape parameterization with machine learning techniques from the field of nonlinear time series analysis. We then develop two dynamic contour models (DCMs) using the new SSMs as shape priors for tumor and lesion segmentation. From training data, the SSMs learn the lower level shape information of boundary fluctuations, which we prove to be nevertheless highly discriminant. One of the new DCMs also uses online learning to refine the shape prior for the lesion of interest based on user interactions. Classification experiments reveal superior sensitivity and specificity of the new shape priors over those previously used to constrain DCMs. User trials with the new interactive algorithms show that the shape priors are directly responsible for improvements in accuracy and reductions in user demand. PMID- 22547456 TI - Generalized unequal error protection LT codes for progressive data transmission. AB - The original design of standard digital fountain codes assumes that the coded information symbols are equally important. In many applications, some source symbols are more important than others, and they must be recovered prior to the rest. Unequal Error Protection (UEP) designs are attractive solutions for such source transmissions. In this study, we introduce a more generalized design for the first universal fountain code design, LT codes, that makes it particularly suited for progressive bit stream transmissions. We apply the generalized LT codes to a progressive source and show that it has better UEP properties than other published results in the literature. For example, using the proposed generalization, we obtained up to 1.7dB PSNR gain in a progressive image transmission scenario over the two major UEP fountain code designs. PMID- 22547457 TI - Subject-specific and pose-oriented facial features for face recognition across poses. AB - Most face recognition scenarios assume that frontal faces or mug shots are available for enrollment to the database, faces of other poses are collected in the probe set. Given a face from the probe set, one needs to determine whether a match in the database exists. This is under the assumption that in forensic applications, most suspects have their mug shots available in the database, and face recognition aims at recognizing the suspects when their faces of various poses are captured by a surveillance camera. This paper considers a different scenario: given a face with multiple poses available, which may or may not include a mug shot, develop a method to recognize the face with poses different from those captured. That is, given two disjoint sets of poses of a face, one for enrollment and the other for recognition, this paper reports a method best for handling such cases. The proposed method includes feature extraction and classification. For feature extraction, we first cluster the poses of each subject's face in the enrollment set into a few pose classes and then decompose the appearance of the face in each pose class using Embedded Hidden Markov Model, which allows us to define a set of subject-specific and pose-priented (SSPO) facial components for each subject. For classification, an Adaboost weighting scheme is used to fuse the component classifiers with SSPO component features. The proposed method is proven to outperform other approaches, including a component-based classifier with local facial features cropped manually, in an extensive performance evaluation study. PMID- 22547458 TI - A decentralized mechanism for improving the functional robustness of distribution networks. AB - Most real-world distribution systems can be modeled as distribution networks, where a commodity can flow from source nodes to sink nodes through junction nodes. One of the fundamental characteristics of distribution networks is the functional robustness, which reflects the ability of maintaining its function in the face of internal or external disruptions. In view of the fact that most distribution networks do not have any centralized control mechanisms, we consider the problem of how to improve the functional robustness in a decentralized way. To achieve this goal, we study two important problems: 1) how to formally measure the functional robustness, and 2) how to improve the functional robustness of a network based on the local interaction of its nodes. First, we derive a utility function in terms of network entropy to characterize the functional robustness of a distribution network. Second, we propose a decentralized network pricing mechanism, where each node need only communicate with its distribution neighbors by sending a "price" signal to its upstream neighbors and receiving "price" signals from its downstream neighbors. By doing so, each node can determine its outflows by maximizing its own payoff function. Our mathematical analysis shows that the decentralized pricing mechanism can produce results equivalent to those of an ideal centralized maximization with complete information. Finally, to demonstrate the properties of our mechanism, we carry out a case study on the U.S. natural gas distribution network. The results validate the convergence and effectiveness of our mechanism when comparing it with an existing algorithm. PMID- 22547459 TI - On combining multiple features for cartoon character retrieval and clip synthesis. AB - How do we retrieve cartoon characters accurately? Or how to synthesize new cartoon clips smoothly and efficiently from the cartoon library? Both questions are important for animators and cartoon enthusiasts to design and create new cartoons by utilizing existing cartoon materials. The first key issue to answer those questions is to find a proper representation that describes the cartoon character effectively. In this paper, we consider multiple features from different views, i.e., color histogram, Hausdorff edge feature, and skeleton feature, to represent cartoon characters with different colors, shapes, and gestures. Each visual feature reflects a unique characteristic of a cartoon character, and they are complementary to each other for retrieval and synthesis. However, how to combine the three visual features is the second key issue of our application. By simply concatenating them into a long vector, it will end up with the so-called "curse of dimensionality," let alone their heterogeneity embedded in different visual feature spaces. Here, we introduce a semisupervised multiview subspace learning (semi-MSL) algorithm, to encode different features in a unified space. Specifically, under the patch alignment framework, semi-MSL uses the discriminative information from labeled cartoon characters in the construction of local patches where the manifold structure revealed by unlabeled cartoon characters is utilized to capture the geometric distribution. The experimental evaluations based on both cartoon character retrieval and clip synthesis demonstrate the effectiveness of the proposed method for cartoon application. Moreover, additional results of content-based image retrieval on benchmark data suggest the generality of semi-MSL for other applications. PMID- 22547460 TI - Activity density map visualization and dissimilarity comparison for eldercare monitoring. AB - In this paper, we present a methodology for analyzing passive infrared motion sensor data logged in the homes of seniors. The objective is to capture activity patterns that represent different health conditions. Recognizing changes in the activity patterns can then be used to provide early detection of health changes. A visualization of motion sensor data is introduced in the form of a density map that uses different colors to show varying levels of activity. For evaluating the activity density level accurately, time away from home is determined first using a system of fuzzy rules. In addition, a dissimilarity between two density maps is computed using texture features for automatically determining changes in activity patterns, which may indicate a health problem. The activity density maps are being used in an aging in place senior housing community to aid clinicians in early illness detection. Three case studies of elderly residents are included to illustrate how the density map and dissimilarity measure can be used to track general activity level and daily patterns over time, showing changes in physical, cognitive, and mental health. PMID- 22547461 TI - Peripheral electrical stimulation triggered by self-paced detection of motor intention enhances motor evoked potentials. AB - This paper proposes the development and experimental tests of a self-paced asynchronous brain-computer interfacing (BCI) system that detects movement related cortical potentials (MRCPs) produced during motor imagination of ankle dorsiflexion and triggers peripheral electrical stimulations timed with the occurrence of MRCPs to induce corticospinal plasticity. MRCPs were detected online from EEG signals in eight healthy subjects with a true positive rate (TPR) of 67.15 +/- 7.87% and false positive rate (FPR) of 22.05 +/-9.07%. The excitability of the cortical projection to the target muscle (tibialis anterior) was assessed before and after the intervention through motor evoked potentials (MEP) using transcranial magnetic stimulation (TMS). The peak of the evoked potential significantly (P=0.02) increased after the BCI intervention by 53 +/- 43% (relative to preintervention measure), although the spinal excitability (tested by stretch reflexes) did not change. These results demonstrate for the first time that it is possible to alter the corticospinal projections to the tibialis anterior muscle by using an asynchronous BCI system based on online motor imagination that triggered peripheral stimulation. This type of repetitive proprioceptive feedback training based on self-generated brain signal decoding may be a requirement for purposeful skill acquisition in intact humans and in the rehabilitation of persons with brain damage. PMID- 22547462 TI - [Reflections on the enforcement of the genetic code of Act No. XXI of 2008]. AB - The genetic code of Act No. XXI of 2008 is a milestone in the national codification of Hungarian human genetic studies and research. The code is in conformity with international as well as EU legislations. It guarantees full enforcement of both the right to self-determination and the rules of the profession. The criteria of legal functioning are institutional accreditation, regular auditing, decreed government control, and coordinated network structure. Further government and ministerial decrees are necessitated for its enforcement. PMID- 22547463 TI - [The correlation between smoking, environmental tobacco smoke and preterm birth]. AB - The rate of preterm births is very high in Hungary; it was 8.9% of the total livebirths in 2010. Preterm birth (<37 weeks) has a considerable health impact, because it is responsible for 85% of infant mortality and morbidity as well as for numerous chronic diseses in the long-term. Many maternal and fetal diseases can be identified in the background, but in a number of cases, preterm labor begins unexpectedly, without any prodrome. Presumably, the socioeconomic background and the presence of harmful lifestyle factors are related to preterm birth in these cases. Tobacco smoking is the most frequent harmful health behavior. At national level, the rate of smoking during pregnancy was 14.4% in the last 13 years, but in some counties, this proportion mounted to 25%. In these counties, the prevalence of preterm births also exceeds the national average. This summary highlights the factors related to disadvantaged socio-economic status that can be responsible for the higher number of preterm birth cases. PMID- 22547464 TI - [New possibility in the oral glucose lowering treatment of type 2 diabetes mellitus: sodium-glucose co-transporter-2 inhibitors]. AB - Sodium-glucose co-transporters (SGLTs) have a key role in the re-absorption of glucose in the kidneys. Therefore, inhibition of SGLTs may provide a novel therapeutic strategy for diabetes mellitus. SGLT2 inhibitors enhance renal glucose excretion by inhibiting renal glucose re-absorption and reduce plasma glucose level, as well as they decrease the body weight. Their action is insulin independent and they improve insulin resistance in diabetes mellitus. Numerous SGLT2 inhibitors have been developed and evaluated in clinical trials. Phase III trials are needed to assess the safety of SGLT2 inhibitors. Results suggest that the beneficial effects of SGLT2 inhibition might be achieved without the development of significant side effects. PMID- 22547465 TI - [Hungarian data on inflammatory bowel diseases: analytical data on ulcerative colistis]. AB - Prospective data collection seems to be essential in evidence-based medicine. Because of the new therapeutic options, the need for standard data collection and testing has significantly increased. In Hungary, a registry for patients with inflammatory bowel disease has already been set up, which makes it possible for clinicians to collect prospective data on their patients. AIM: Basic characteristics of the database of patients with ulcerative colitis are presented in this paper. METHODS: The inflammatory bowel disease registry uses the programme of Microsoft Access database management system. Data are stored in a central server. RESULTS: The incidence of inflammatory bowel diseases has been permanently increasing in Hungary; however, its overall prevalence is still low among the European countries. The frequent administration of immunosuppressive medications (azathioprine and corticosteroids) and their increased doses worsen the estimation of the activity. CONCLUSIONS: 1., It would be very useful to gain prospective data from all national centres. This kind of database would be able to give a complete picture regarding the Hungarian therapeutical practice. 2., Medications of patients may alter the clinical value of the laboratory findings in the process of determining the severity of the disease. PMID- 22547466 TI - [Prof. Dr. Ildiko Kriszbacher (1964-2012)]. PMID- 22547467 TI - [The Bible--with the eyes of the physician III]. PMID- 22547469 TI - Wavelet-based resolution recovery using an anatomical prior provides quantitative recovery for human population phantom PET [11C]raclopride data. AB - The objective of this study was to evaluate a resolution recovery (RR) method using a variety of simulated human brain [11C]raclopride positron emission tomography (PET) images. Simulated datasets of 15 numerical human phantoms were processed by a wavelet-based RR method using an anatomical prior. The anatomical prior was in the form of a hybrid segmented atlas, which combined an atlas for anatomical labelling and a PET image for functional labelling of each anatomical structure. We applied RR to both 60 min static and dynamic PET images. Recovery was quantified in 84 regions, comparing the typical 'true' value for the simulation, as obtained in normal subjects, simulated and RR PET images. The radioactivity concentration in the white matter, striatum and other cortical regions was successfully recovered for the 60 min static image of all 15 human phantoms; the dependence of the solution on accurate anatomical information was demonstrated by the difficulty of the technique to retrieve the subthalamic nuclei due to mismatch between the two atlases used for data simulation and recovery. Structural and functional synergy for resolution recovery (SFS-RR) improved quantification in the caudate and putamen, the main regions of interest, from -30.1% and -26.2% to -17.6% and -15.1%, respectively, for the 60 min static image and from -51.4% and -38.3% to -27.6% and -20.3% for the binding potential (BP(ND)) image, respectively. The proposed methodology proved effective in the RR of small structures from brain [11C]raclopride PET images. The improvement is consistent across the anatomical variability of a simulated population as long as accurate anatomical segmentations are provided. PMID- 22547470 TI - Tipping the balance of benefits and harms to favor screening mammography starting at age 40 years: a comparative modeling study of risk. AB - BACKGROUND: Timing of initiation of screening for breast cancer is controversial in the United States. OBJECTIVE: To determine the threshold relative risk (RR) at which the harm-benefit ratio of screening women aged 40 to 49 years equals that of biennial screening for women aged 50 to 74 years. DESIGN: Comparative modeling study. DATA SOURCES: Surveillance, Epidemiology, and End Results program, Breast Cancer Surveillance Consortium, and medical literature. TARGET POPULATION: A contemporary cohort of women eligible for routine screening. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTION: Mammography screening starting at age 40 versus 50 years with different screening methods (film, digital) and screening intervals (annual, biennial). OUTCOME MEASURES: BENEFITS: life-years gained, breast cancer deaths averted; harms: false-positive mammography findings; harm-benefit ratios: false-positive findings/life-years gained, false-positive findings/deaths averted. RESULTS OF BASE-CASE ANALYSIS: Screening average-risk women aged 50 to 74 years biennially yields the same false-positive findings/life years gained as biennial screening with digital mammography starting at age 40 years for women with a 2-fold increased risk above average (median threshold RR, 1.9 [range across models, 1.5 to 4.4]). The threshold RRs are higher for annual screening with digital mammography (median, 4.3 [range, 3.3 to 10]) and when false-positive findings/deaths averted is used as an outcome measure instead of false-positive findings/life-years gained. The harm-benefit ratio for film mammography is more favorable than for digital mammography because film has a lower false-positive rate. RESULTS OF SENSITIVITY ANALYSIS: The threshold RRs changed slightly when a more comprehensive measure of harm was used and were relatively insensitive to lower adherence assumptions. LIMITATION: Risk was assumed to influence onset of disease without influencing screening performance. CONCLUSION: Women aged 40 to 49 years with a 2-fold increased risk have similar harm-benefit ratios for biennial screening mammography as average-risk women aged 50 to 74 years. Threshold RRs required for favorable harm-benefit ratios vary by screening method, interval, and outcome measure. PRIMARY FUNDING SOURCE: National Cancer Institute. PMID- 22547471 TI - Hospital strategies for reducing risk-standardized mortality rates in acute myocardial infarction. AB - BACKGROUND: Despite recent improvements in survival after acute myocardial infarction (AMI), U.S. hospitals vary 2-fold in their 30-day risk-standardized mortality rates (RSMRs). Nevertheless, information is limited on hospital-level factors that may be associated with RSMRs. OBJECTIVE: To identify hospital strategies that were associated with lower RSMRs. DESIGN: Cross-sectional survey of 537 hospitals (91% response rate) and weighted multivariate regression by using data from the Centers for Medicare & Medicaid Services to determine the associations between hospital strategies and hospital RSMRs. SETTING: Acute care hospitals with an annualized AMI volume of at least 25 patients. PARTICIPANTS: Patients hospitalized with AMI between 1 January 2008 and 31 December 2009. MEASUREMENTS: Hospital performance improvement strategies, characteristics, and 30-day RSMRs. RESULTS: In multivariate analysis, several hospital strategies were significantly associated with lower RSMRs and in aggregate were associated with clinically important differences in RSMRs. These strategies included holding monthly meetings to review AMI cases between hospital clinicians and staff who transported patients to the hospital (RSMR lower by 0.70 percentage points), having cardiologists always on site (lower by 0.54 percentage points), fostering an organizational environment in which clinicians are encouraged to solve problems creatively (lower by 0.84 percentage points), not cross-training nurses from intensive care units for the cardiac catheterization laboratory (lower by 0.44 percentage points), and having physician and nurse champions rather than nurse champions alone (lower by 0.88 percentage points). Fewer than 10% of hospitals reported using at least 4 of these 5 strategies. LIMITATION: The cross sectional design demonstrates statistical associations but cannot establish causal relationships. CONCLUSION: Several strategies, which are currently implemented by relatively few hospitals, are associated with significantly lower 30-day RSMRs for patients with AMI. PRIMARY FUNDING SOURCE: The Agency for Healthcare Research and Quality, the United Health Foundation, and the Commonwealth Fund. PMID- 22547472 TI - Serum 25-hydroxyvitamin D concentration and risk for major clinical disease events in a community-based population of older adults: a cohort study. AB - BACKGROUND: Circulating concentrations of 25-hydroxyvitamin D [25-(OH)D] are used to define vitamin D deficiency. Current clinical 25-(OH)D targets based on associations with intermediate markers of bone metabolism may not reflect optimal levels for other chronic diseases and do not account for known seasonal variation in 25-(OH)D concentration. OBJECTIVE: To evaluate the relationship of 25-(OH)D concentration with the incidence of major clinical disease events that are pathophysiologically relevant to vitamin D. DESIGN: Cohort study. SETTING: The Cardiovascular Health Study conducted in 4 U.S. communities. Data from 1992 to 2006 were included in this analysis. PARTICIPANTS: 1621 white older adults. MEASUREMENTS: Serum 25-(OH)D concentration (using a high-performance liquid chromatography-tandem mass spectrometry assay that conforms to National Institute of Standards and Technology reference standards) and associations with time to a composite outcome of incident hip fracture, myocardial infarction, cancer, or death. RESULTS: Over a median 11-year follow-up, the composite outcome occurred in 1018 participants (63%). Defining events included 137 hip fractures, 186 myocardial infarctions, 335 incidences of cancer, and 360 deaths. The association of low 25-(OH)D concentration with risk for the composite outcome varied by season (P = 0.057). A concentration lower than a season-specific Z score of -0.54 best discriminated risk for the composite outcome and was associated with a 24% higher risk in adjusted analyses (95% CI, 9% to 42%). Corresponding season specific 25-(OH)D concentrations were 43, 50, 61, and 55 nmol/L (17, 20, 24, and 22 ng/mL) in winter, spring, summer, and autumn, respectively. LIMITATION: The observational study was restricted to white participants. CONCLUSION: Threshold concentrations of 25-(OH)D associated with increased risk for relevant clinical disease events center near 50 nmol/L (20 ng/mL). Season-specific targets for 25 (OH)D concentration may be more appropriate than static targets when evaluating health risk. PRIMARY FUNDING SOURCE: National Institutes of Health. PMID- 22547474 TI - Is geriatric medicine terminally ill? PMID- 22547473 TI - Risk factors for breast cancer for women aged 40 to 49 years: a systematic review and meta-analysis. AB - BACKGROUND: Identifying risk factors for breast cancer specific to women in their 40s could inform screening decisions. PURPOSE: To determine what factors increase risk for breast cancer in women aged 40 to 49 years and the magnitude of risk for each factor. DATA SOURCES: MEDLINE (January 1996 to the second week of November 2011), Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (fourth quarter of 2011), Scopus, reference lists of published studies, and the Breast Cancer Surveillance Consortium. STUDY SELECTION: English language studies and systematic reviews of risk factors for breast cancer in women aged 40 to 49 years. Additional inclusion criteria were applied for each risk factor. DATA EXTRACTION: Data on participants, study design, analysis, follow-up, and outcomes were abstracted. Study quality was rated by using established criteria, and only studies rated as good or fair were included. Results were summarized by using meta-analysis when sufficient studies were available or from the best evidence based on study quality, size, and applicability when meta-analysis was not possible. Data from the Breast Cancer Surveillance Consortium were analyzed with proportional hazards models by using partly conditional Cox regression. Reference groups for comparisons were set at U.S. population means. DATA SYNTHESIS: Sixty-six studies provided data for estimates. Extremely dense breasts on mammography or first-degree relatives with breast cancer were associated with at least a 2-fold increase in risk for breast cancer. Prior breast biopsy, second-degree relatives with breast cancer, or heterogeneously dense breasts were associated with a 1.5- to 2.0-fold increased risk; current use of oral contraceptives, nulliparity, and age 30 years or older at first birth were associated with a 1.0- to 1.5-fold increased risk. LIMITATIONS: Studies varied by measures, reference groups, and adjustment for confounders, which could bias combined estimates. Effects of multiple risk factors were not considered. CONCLUSION: Extremely dense breasts and first-degree relatives with breast cancer were each associated with at least a 2-fold increase in risk for breast cancer in women aged 40 to 49 years. Identification of these risk factors may be useful for personalized mammography screening. PRIMARY FUNDING SOURCE: National Cancer Institute. PMID- 22547475 TI - Treating our societal scotoma: the case for investing in geriatrics, our nation's future, and our patients. PMID- 22547476 TI - The Affordable Care Act is constitutional. PMID- 22547477 TI - Risk-based mammography screening: an effort to maximize the benefits and minimize the harms. PMID- 22547478 TI - Is every defect really a treasure? PMID- 22547479 TI - Tell me not. PMID- 22547480 TI - Access to the medical record. PMID- 22547481 TI - Acute and subacute neck pain. PMID- 22547482 TI - Acute and subacute neck pain. PMID- 22547483 TI - Bilateral enlargement of the lacrimal glands from IgG4-related systemic disease. PMID- 22547484 TI - Retinal toxicity in users of "poppers". PMID- 22547486 TI - Sarcoidosis. PMID- 22547485 TI - Summaries for patients: Vitamin D levels and risk for major clinical disease events. PMID- 22547487 TI - The value ground of nursing. AB - The aim of this literature study was to suggest a value ground for nursing anchored in two ethical principles: the principle of human value and the right to experience a meaningful life. Previous nursing research between the years 2000 and 2009 was analysed. Presented values suggested in this value ground are thus in line with the nursing context and science of today. Statements within ethical literature have been used in order to formulate arguments aimed at supporting the values that were found in the study. In the literature study six values were found: trust, nearness, sympathy, support, knowledge and responsibility. These values hold equal status and are not presented in hierarchical order. They vary due to the persons involved, nursing situations and cultural surroundings, but have the common requirement of being non-excluding. In order to implement the values within the value ground, two prerequisites are discussed and claimed as essential: ethical dialogue and a caring encounter between care provider and patients. PMID- 22547488 TI - Patients' silence following healthcare staff's ethical transgressions. AB - The aim of this study was to examine to what extent patients remained silent to the health care system after they experienced abusive or wrongful incidents in health care. Female patients visiting a women's clinic in Sweden (n = 530) answered the transgressions of ethical principles in Health care questionnaire (TEP), which was constructed to measure patients' abusive experiences in the form of staff's transgressions of ethical principles in health care. Of all the patients, 63.6% had, at some point, experienced staff's transgressions of ethical principles, and many perceived these events as abusive and wrongful. Of these patients, 70.3% had remained silent to the health care system about at least one transgression. This silence is a loss of essential feedback for the health care system and should not automatically be interpreted as though patients are satisfied. PMID- 22547489 TI - Best interests determination within the Singapore context. AB - Familialism is a significant mindset within Singaporean culture. Its effects through the practice of familial determination and filial piety, which calls for a family centric approach to care determination over and above individual autonomy, affect many elements of local care provision. However, given the complex psychosocial, political and cultural elements involved, the applicability and viability of this model as well as that of a physician-led practice is increasingly open to conjecture. This article will investigate some of these concerns before proffering a decision-making process based upon a multidisciplinary team approach. It will be shown that such a multidimensional and multiprofessional approach is more in keeping with the inclusive and patient centred ethos of palliative care than prevailing practices. It will be shown that such an approach will also be better placed to deliver holistic, coherent and sensitive end-of-life care that palliative care espouses. PMID- 22547490 TI - Implied consent and nursing practice: ethical or convenient? AB - Nursing professionals in a variety of practice settings routinely use implied consent. This form of consent is used in place of or in conjunction with informed or explicit consent. This article looks at one aspect of a qualitative exploratory study conducted in a Day of Surgery Admission unit. This article focuses on the examination of nurses' understandings of implied consent and its use in patient care in nursing practice. Data were collected through one-on-one interviews and analysed using a thematic analysis. Nurses participating in this study revealed that they routinely used implied consent in their nursing practice. This article will look at whether implied consent supports or impedes a patient's autonomy. PMID- 22547493 TI - Editorial: the great first national primary debate. PMID- 22547491 TI - Image navigation as a means to expand the boundaries of fluorescence-guided surgery. AB - Hybrid tracers that are both radioactive and fluorescent help extend the use of fluorescence-guided surgery to deeper structures. Such hybrid tracers facilitate preoperative surgical planning using (3D) scintigraphic images and enable synchronous intraoperative radio- and fluorescence guidance. Nevertheless, we previously found that improved orientation during laparoscopic surgery remains desirable. Here we illustrate how intraoperative navigation based on optical tracking of a fluorescence endoscope may help further improve the accuracy of hybrid surgical guidance. After feeding SPECT/CT images with an optical fiducial as a reference target to the navigation system, optical tracking could be used to position the tip of the fluorescence endoscope relative to the preoperative 3D imaging data. This hybrid navigation approach allowed us to accurately identify marker seeds in a phantom setup. The multispectral nature of the fluorescence endoscope enabled stepwise visualization of the two clinically approved fluorescent dyes, fluorescein and indocyanine green. In addition, the approach was used to navigate toward the prostate in a patient undergoing robot-assisted prostatectomy. Navigation of the tracked fluorescence endoscope toward the target identified on SPECT/CT resulted in real-time gradual visualization of the fluorescent signal in the prostate, thus providing an intraoperative confirmation of the navigation accuracy. PMID- 22547494 TI - Acute respiratory illness and health-seeking behavior in Egyptian villages: enhancing pandemic preparedness by understanding local realities. AB - The emergence of influenza viruses has raised awareness worldwide about influenza pandemic risks. Pandemic preparedness emphasizes development of risk communication and surveillance systems. The objective was to explore community classification of Acute Respiratory Illness (ARI) and health-seeking behaviors. Twenty in-depth interviews and 18 focus group discussions were conducted with caretakers in Egypt. The interviews were recorded, transcribed, and analyzed using the thematic analysis. ARI terminology contained few terms, usage of them was complex, and microorganism not part of illness explanation. Severe ARI was associated with social stigma. Homecare included extensive use of medications. In mild and severe ARI, health-seeking determinants varied. Classification of ARI parallels World Health Organization case definitions for ARI, facilitating risk communication. Homecare practices are social norms that can be expanded to include messages on ARI. Risk communication strategies and surveillance systems need to consider socio-cultural understanding of ARI. PMID- 22547495 TI - Meanings of smoking among adolescents in Chiang Mai, Thailand. AB - The Meanings of Smoking Index-2 (MSI-2) was administered to 2516 Thai adolescents in an urban, suburban, rural, and vocational high school. Factor analysis identified six meanings of smoking factor domains: coping, social image, stimulation, weight, independence, and difficulty refusing smoking. Logistic regression analyses determined that the strongest positive association with smoking behavior and ever smoking was the coping domain, and coping was also positively associated with susceptibility to smoking. The individual meaning item which most differentiated current smokers from nonsmokers was "keeps from being bored" and the dimension of stimulation (gives more energy, helps to concentrate, helps to study, gives something to do) was positively associated with current smoking. Findings suggest that meanings of smoking is important because it can provide guidance to health educators and other health professionals in tailoring smoking prevention and cessation interventions by identifying and targeting meanings that are salient within specific adolescent populations. PMID- 22547496 TI - Using the theory of planned behavior to predict two types of snack food consumption among Midwestern upper elementary children: implications for practice. AB - This study examined the extent to which constructs of the theory of planned behavior (TPB) can predict the consumption of two types of snack foods among elementary school children. A 15-item instrument tested for validity and reliability measuring TPB constructs was developed and administered to 167 children. Snack foods were evaluated using a modified 24-hour recall method. On average, children consumed 302 calories from snack foods per day. Stepwise multiple regression found that attitudes, subjective norms, and perceived control accounted for 44.7% of the variance for intentions. Concurrently, intentions accounted for 11.3% of the variance for calorically-dense snack food consumption and 8.9% of the variance for fruit and vegetable snack consumption. Results suggest that the theory of planned behavior is an efficacious theory for these two behaviors. Future interventions should consider using this theoretical framework and aim to enhance children's attitudes, perceived control, and subjective norms towards snack food consumption. PMID- 22547497 TI - Practice and content of sex education among adolescents in a family setting in rural southwest Nigeria. AB - A descriptive cross-sectional study to assess adolescents' view of the practice and content of sex education within the family setting in a rural Nigerian community and explore whether there is any association between parental communication on sex and adolescents' sexual debut and habits. Simple random sampling was utilized, while a semi-structured questionnaire was used to collect data from 350 respondents. Data analysis was by the Statistical Package for Social Sciences (SPSS version 11). Majority of the respondents (48.8%) were late adolescents, 291 (85.1%) had had sex education, most (45.7%) of whom were exposed between ages 10 and 14 years. The main content of parental sex education was HIV/AIDS prevention (51.9%), avoidance of pregnancy (40.9%), abstinence (38.1%), and basic information about reproduction and biology (35.4%). Poor attitude to parental communication on sex was associated with a higher likelihood of pre marital sex (p = 0.001). Curiosity was the most common major reason for sexual debut. This emphasizes the importance of early sex education within the family setting and its possible impact in delaying sexual initiation. Promotion of parent-child communication about sexual issues is vital in order to improve the reproductive health of the adolescents in this environment. Community-based health education intervention programs for parents are recommended. PMID- 22547498 TI - Assessing public-private reproductive health efforts to reach young married couples in rural Bangladesh. AB - Young married couples (YMC) in Bangladesh receive insufficient attention from service providers for reproductive health and family planning needs. The ACQUIRE Project, undertaken by EngenderHealth, Bangladesh, provides intervention for service providers, social and local leaders, and mothers-in-law as effective agents of channeling information to YMCs. EngenderHealth, in collaboration with the public sector, examined the extent to which an intervention program enhances overall quality of services, respondents' knowledge and attitude, and service seeking behavior related to reproductive health issues. A quasi-experimental design with two matching groups, one watching the intervention, was used. The endline survey was carried out 10 months after the Baseline survey. Key informants interviews and FGDs were conducted. The findings were mixed. Importantly, young married men and women need friendly services and service providers with positive attitudes. PMID- 22547501 TI - An x-ray CT polymer gel dosimetry prototype: I. Remnant artefact removal. AB - In this study a new x-ray CT polymer gel dosimetry (PGD) filtering technique is presented for the removal of (i) remnant ring and streak artefacts, and (ii) 'structured' noise in the form of minute, intrinsic gel density fluctuations. It is shown that the noise present within x-ray CT PGD images is not purely stochastic (pixel by pixel) in nature, but rather is 'structured', and hence purely stochastic-based noise-removal filters fail in removing this significant, unwanted noise component. The remnant artefact removal (RAR) technique is based on a class of signal stripping (i.e. baseline-estimation) algorithms typically used in the estimation of unwanted non-uniform baselines underlying spectral data. Here the traditional signal removal algorithm is recast, whereby the 'signal' that is removed is the structured noise and remnant artefacts, leaving the desired polymer gel dose distribution. The algorithm is extended to 2D and input parameters are optimized for PGD images. RAR filter results are tested on (i) synthetic images with measured gel background images added, in order to accurately represent actual noise present in PGD images, and (ii) PGD images of a three-field gel irradiation. RAR results are compared to a top-performing noise filter (adaptive mean, AM), used in previous x-ray CT PGD studies. It is shown that, in all cases, the RAR filter outperforms the AM filter, particularly in cases where either (i) a low-dose gel image has been acquired or (ii) the signal to-noise ratio of the PG image is low, as in the case when a low number of image averages are acquired within a given experiment. Guidelines for the implementation of the RAR filter are given. PMID- 22547502 TI - Iron - too much of a good thing. PMID- 22547503 TI - Clinical fMRI: a pre-surgical test in patients with medically intractable epilepsy. PMID- 22547504 TI - Amplitude-integrated electroencephalography: a runaway horse? PMID- 22547505 TI - Neurocysticercosis: a foreign parasite looking for "permanent resident" status? PMID- 22547506 TI - Functional MRI applications in epilepsy surgery. AB - Functional magnetic resonance imaging (fMRI) is a non-invasive neuroimaging technique that has grown rapidly in popularity over the past decade. It is already prevalent in psychology, cognitive and basic neuroscience research and is being used increasingly as a tool for clinical decision-making in epilepsy. It has been used to determine language location and laterality in patients, sometimes eliminating the need for invasive tests. fMRI can been used pre surgically to guide resection margins, preserving eloquent cortex. Other fMRI paradigms assessing memory, visual and somatosensory systems have limited clinical applications currently, but show great promise. Simultaneous recording of electroencephalogram (EEG) and fMRI has also provided insights into the networks underlying seizure generation and is increasingly being used in epilepsy centres. In this review, we present some of the current clinical applications for fMRI in the pre-surgical assessment of epilepsy patients, and examine a number of new techniques that may soon become clinically relevant. PMID- 22547507 TI - Amyloid and Alzheimer's disease: inside and out. AB - Alzheimer's disease (AD) is poised to become the most serious healthcare issue of our generation. The leading theory of AD pathophysiology is the Amyloid Cascade Hypothesis, and clinical trials are now proceeding based on this hypothesis. Here, we review the original evidence for the Amyloid Hypothesis, which was originally focused on the extracellular deposition of beta amyloid peptides (Abeta) in large fibrillar aggregates, as well as how this theory has been extended in recent years to focus on highly toxic small soluble amyloid oligomers. We will also examine emerging evidence that Abeta may actually begin to accumulate intracellularly in lysosomes, and the role for intracellular Abeta and lysosomal dysfunction may play in AD pathophysiology. Finally, we will review the clinical implications of these findings. PMID- 22547508 TI - Dynamic radiosurgery at the Toronto - Bayview Regional Cancer Centre, 1988-2007. AB - Dynamic radiosurgery was first developed in Montreal and was subsequently adopted at the Toronto-Bayview Regional Cancer Centre in 1988. At that time radiosurgery was in its infancy in Canada. The opportunity of offering highly conformal radiation treatments for intracranial targets presented numerous technical challenges notably in the area of quality assurance. This review chronicles the development of radiosurgery at the Toronto-Bayview Regional Cancer Centre and summarises the successes and failures of the program over the following two decades. PMID- 22547509 TI - Clinical overlap between Jakob-Creutzfeldt disease and Lewy body disease. AB - OBJECTIVE: Sporadic Jakob-Creutzfeldt disease (sCJD) and dementia with Lewy bodies (DLB) have overlapping clinical symptoms that can lead to their misdiagnosis. We delineated the clinical overlap between sCJD and DLB, and assessed the value of magnetic resonance imaging (MRI) to differentiate between them. METHODS: Medical records, MRI, electroencephalogram (EEG) and cerebrospinal fluid (CSF) were reviewed from 56 sCJD and 30 DLB subjects. RESULTS: 46% of sCJD subjects met probable DLB criteria and 40% of DLB subjects met probable CJD criteria. A greater proportion of sCJD subjects had cerebellar signs (66% vs. 10%, p<0.001), myoclonus (64% vs. 30%, p=0.002), and visual symptoms (other than hallucinations) (61% vs. 7%, p<0.001), whereas more DLB subjects had hallucinations (70% vs. 39%, p=0.007) and fluctuations (57% vs. 23%, p=0.002). Cortical and/or basal ganglia MRI diffusion weighted imaging hyperintensities consistent with sCJD were seen in 96% of sCJD subjects but in none with DLB. Logistic regression in sCJD revealed that those meeting probable DLB criteria were more likely to have occipital lobe involvement on MRI (OR 1.4, p=0.058, model p=0.022). Parietal lobe involvement on MRI was a predictor of "Other Focal Cortical signs" (OR 1.9, p=0.021). EEG and CSF assessments lacked sensitivity for sCJD as 48% of sCJD patients had a negative EEG; 67% of the 36 sCJD patents with a CSF evaluation had a negative or inconclusive 14-3-3 result. Too few DLB patients had EEG or CSF to assess their utility. CONCLUSION: Sporadic CJD and DLB have significant symptom overlap. MRI helps differentiate these diseases and is related to the signs/symptoms observed in sCJD. PMID- 22547510 TI - Brain region specific monoamine and oxidative changes during restraint stress. AB - BACKGROUND AND PURPOSE: Stress-induced central effects are regulated by brain neurotransmitters, glucocorticoids and oxidative processes. Therefore, we aimed to evaluate the simultaneous alterations in the monoamine and antioxidant systems in selected brain regions (frontal cortex, striatum and hippocampus) at 1 hour (h) and 24h following the exposure of restraint stress (RS), to understand their initial response and possible crosstalk. METHODS AND RESULTS: RS (150 min immobilization) significantly increased the dopamine levels in the frontal cortex and decreased them in the striatum and hippocampus, with selective increase of dopamine metabolites both in the 1h and 24h RS groups compared to control values. The serotonin and its metabolite levels were significantly increased in both time intervals, while noradrenaline levels were decreased in the frontal cortex and striatum only. The activities of superoxide dismutase, glutathione peroxidase and the levels of lipid peroxidation were significantly increased with significant decrease of glutathione levels in the frontal cortex and striatum both in the 1h and 24h RS groups. There was no significant change in the catalase activity in any group. In the hippocampus, the glutathione levels were significantly decreased only in the 1h RS group. CONCLUSIONS: Our study implies that the frontal cortex and striatum are more sensitive to oxidative burden which could be related to the parallel monoamine perturbations. This provides a rational look into the simultaneous compensatory central mechanisms operating during acute stress responses which are particular to precise brain regions and may have long lasting effects on various neuropathological alterations. PMID- 22547511 TI - A review of cases of human cysticercosis in Canada. AB - OBJECTIVE: Review of human cysticercosis in Canada, to estimate the magnitude of the disease and to describe the pattern of disease expression in this country. METHODS: MEDLINE and manual search of case reports and case series of patients with cysticercosis diagnosed in Canada. Abstracted data included year of diagnosis, citizenship status, clinical manifestations, and form of cysticercosis. FINDINGS: A total of 21 articles reporting 60 patients were found. Forty (67%) of these patients were diagnosed in the past two decades. Most cases came from Ontario (n=43) and Quebec (n=14). Immigrants accounted for 96% of the 28 cases in whom citizenship information was available. Neurocysticercosis was observed in 55 patients, and isolated compromise of striated muscles in the remaining five. Seizures was the primary or sole manifestation of the disease in 72% of patients, and most of them had parenchymal brain cysticerci (either viable cysts or calcifications). Two of seven patients were positive for Taenia eggs. In no case were household contacts of the patients investigated for taeniasis. CONCLUSIONS: An increasing number of patients with cysticercosis have been reported from Canada in the past two decades, suggesting that the prevalence of this parasitic disease may be on the rise. While most cases occur in immigrants, it is possible that at least some of these patients had acquired the disease in Canada. PMID- 22547512 TI - Magnesium as an effective adjunct therapy for drug resistant seizures. AB - OBJECTIVE: To explore the use of magnesium (Mg), an endogenous ion and enzymatic co-factor used in a variety of medical applications, for the treatment of epileptic seizures resistant to traditional medical therapy. BACKGROUND: For almost a century, Mg has been used as prophylaxis and treatment of seizures associated with eclampsia. Mg is a CNS depressant, with numerous functions intracellularly and extracellularly. However, because of the availability of well studied anticonvulsant drugs, Mg has not been tested widely in the treatment of epileptic seizures. METHODS: A retrospective chart review of 22 cases of drug resistant epilepsy, where a trial of empiric oral Mg supplementation (mainly in the form of Mg-oxide) was conducted. RESULTS: Oral Mg supplementation was associated with a significant decrease in the number of seizure days per month, from 15.3 +/- 13.2 (mean +/- SD) to 10.2 +/- 12.6 at first follow up (3-6 months, p=0.021), and to 7.8 +/- 10.0 seizure days/month at second follow up (6-12 months, p=0.004). Thirty-six percent had a response rate of 75% or greater at second follow-up. Two patients reported seizure freedom. Most patients were well maintained on MgO 420 mg twice a day, or in 2 cases, Mg Lactate, without significant adverse effects, the most frequent being diarrhea (4/22). DISCUSSION: These results suggest that oral Mg supplementation may prove to be a worthwhile adjunctive medication in treating drug intractable epilepsy. CONCLUSIONS: A prospective, double-blinded, placebo controlled study is warranted to evaluate the potential of Mg for the treatment of drug-resistant seizures. PMID- 22547513 TI - Epileptiform activity in neurocritical care patients. AB - BACKGROUND: Non-convulsive seizures have been reported to be common in neurocritical care patients. Many jurisdictions do not have sufficient resources to enable routine continuous electroencephalography (cEEG) and instead use primarily intermittent EEG, for which the diagnostic yield remains uncertain. Determining risk factors for epileptiform activity and seizures could help identify patients who might particularly benefit from EEG monitoring. METHODS: We performed a cohort study involving neurocritical care patients with admission Glascow Coma Scale (GCS) scores <= 12, who underwent >= 1 EEG. EEGs were reviewed for presence of interictal discharges, periodic epileptiform discharges (PEDs), and seizures. Multivariate analysis was used to identify predictors of these findings and to describe their prognostic implications. RESULTS: 393 patients met inclusion criteria. 34 underwent cEEG, usually because epileptiform activity was first detected on a routine EEG. The prevalence of PEDs or electrographic seizures was 13%, and was highest with anoxic encephalopathy and central nervous system infections. Other independent predictors for epileptiform activity included a history of convulsive seizure(s), increasing age, deeper coma, and female gender. Although patients with epileptiform activity had higher mortality, this association disappeared after adjustment for confounders. CONCLUSION: Approximately 7-8 neurocritical care patients must undergo intermittent EEG monitoring in order to diagnose one with PEDs or seizures. The predictors we identified could potentially help guide use of resources. Repeated intermittent studies, or cEEG, should be considered in patients with multiple risk factors, or when interictal discharges are identified on an initial EEG. It remains unclear whether aggressive prevention and treatment of electrographic seizures improves neurologic outcomes. PMID- 22547514 TI - Carotid artery angioplasty and stenting for patients less than 70 years-of-age. AB - BACKGROUND: Recent studies have suggested that carotid artery angioplasty and stenting (CAS) is a safe alternative to carotid endarterectomy (CEA) in average risk patients <70 years of age. We examined a consecutive series of patients who underwent CAS in order to determine the influence of patient age on outcome. METHODS: A retrospective, longitudinal cohort study of consecutive patients who underwent CAS at St. Michael's Hospital, Canada between January 2001 and November 2010 was performed. The outcome measures were 30-day stroke and 30-day composite death, stroke and acute myocardial infarction (MI). Patients were stratified based on age <70 and >= 70 years. RESULTS: One hundred and fifty-nine patients underwent 165 CAS procedures. The 30-day risk of stroke was 3.8% while the composite outcome of death/stroke/MI was 8.2%. When stratified by age <70 and >= 70 years, the 30-day stroke rate was 0% versus 7.4% (p=0.03), and the composite outcome of death/stroke/MI was 2.6% versus 13.6% (p=0.02), respectively. CONCLUSIONS: Patients <70 years of age undergoing CAS have a low rate of major complications, comparing favourably with historical CEA adverse event rates, and supporting the recent carotid stenosis literature that in the younger population CAS has a similar complication rate compared to CEA. PMID- 22547515 TI - NASCET percent stenosis semi-automated versus manual measurement on CTA. AB - PURPOSE: To compare North American Symptomatic Carotid Endarterectomy Trial (NASCET) stenosis values and NASCET grade categorization (mild, moderate, severe) of semi-automated vessel analysis software versus manual measurements on computed tomography angiography (CTA). METHODS: There were four observers. Two independently analyzed 81 carotid artery CTAs using semi-automated vessel analysis software according to a blinded protocol. The software measured the narrowest stenosis in millimeters (mm), distal internal carotid artery (ICA) in mm, and calculated percent stenosis based on NASCET criteria. One of these two observers performed this task twice on each carotid, the second analysis was delayed two months in order to mitigate recall bias. Two other observers manually measured the narrowest stenosis in mm, distal ICA in mm, and calculated NASCET percent stenosis in a blinded fashion. The calculated NASCET stenoses were categorized into mild, moderate, or severe. Chi square and analysis of variance (ANOVA) were used to test for statistical differences. RESULTS: ANOVA did not find a statistically significant difference in the mean percent stenosis when comparing the two manual measurements, the two semi-automated measurements, and the repeat semi-automated. Chi square demonstrated that the distribution of grades of stenosis were statistically different (p<0.05) between the manual and semiautomated grades. Semi-automated vessel analysis tended to underestimate the degree of stenosis compared to manual measurement. CONCLUSION: The mean percentage stenosis determined by semi-automated vessel analysis is not significantly different from manual measurement. However, when the data is categorized into mild, moderate and severe stenosis, there is a significant difference between semi-automated and manual measurements. The semi-automated software tends to underestimate the stenosis grade compared to manual measurement. PMID- 22547516 TI - Conus medullaris syndrome as a complication of radioisotope cisternography. AB - OBJECTIVE: Conus medullaris syndrome (CMS) is a clinical neurologic syndrome caused by a conus medullaris lesion. CMS is a heterogeneous entity with various etiologies such as trauma or a space-occupying lesion. Multiple cases of CMS following spinal anesthesia have been reported, but CMS after radioisotope (RI) cisternography has not yet been reported. METHODS: We present four patients who developed CMS after RI cisternography. RESULTS: All experienced neurological deficits such as paraparesis, sensory loss, and urinary incontinence three to four days after RI cisternography. Two showed abnormalities on lumbar magnetic resonance imaging, and three had complete symptom resolution within ten weeks. CONCLUSIONS: The pathomechanism of the CMS is unclear, but we hypothesize that RI neurotoxicity might be responsible. It is possible that the use of low-dose 99mTc DTPA or an alternative diagnostic tool such as magnetic resonance cisternography could help to prevent this complication. PMID- 22547517 TI - MS patients report excellent compliance with oral prednisone for acute relapses. AB - BACKGROUND: Multiple Sclerosis is characterized by relapses separated by periods of relative quiescence. High dose intravenous corticosteroid pulses for three to five days is the current standard for the treatment of acute relapses, but recent evidence supports the use of equivalent doses of oral therapy as an alternative. The highest single dose preparation of oral prednisone is a 50mg tablet, requiring patients to take 25 tablets a day. Questions regarding compliance with this oral regimen have been raised. OBJECTIVES: To determine whether MS patients are complaint with 1,250 mg of oral prednisone daily for acute relapses. METHODS: Between November 2008 and December 2009, all patients diagnosed with an acute relapse in the London (Ontario) MS clinic were prospectively identified. If treatment with oral prednisone was initiated, subjects were given a survey to be mailed anonymously to the clinic. RESULTS: Sixty eight MS relapses were diagnosed and treated with corticosteroids in 66 patients of which 60 (58 subjects) were treated with 1,250 mg prednisone. Fifty-three (91.4%) surveys were returned. The reported compliance rate was high at 94.3% (50/53) with only one patient reporting being unable to take all the required pills due to intolerance. Most subjects (43, 86.0%) encountered at least one side effect, most commonly insomnia, mood changes and increased appetite. Two thirds of subjects (69.8%) indicated a preference for oral medication for future relapses. CONCLUSION: High dose (1,250 mg) oral prednisone is an acceptable therapy to MS patients for the treatment of acute relapses with a high rate of compliance. PMID- 22547518 TI - The impact of amplitude-integrated electroencephalography on NICU practice. AB - OBJECTIVE: To examine how the introduction of amplitude-integrated electroencephalography (aEEG) to our neonatal intensive care unit (NICU) influenced clinical practice. METHODS: This was a retrospective study examining clinical practice three years before and three years after the introduction of aEEG monitors to our NICU. A time series analysis was performed to explore whether aEEG introduction was associated with changes in the rates of conventional EEGs performed, neurology consultations and neonates diagnosed with seizures. RESULTS: Following aEEG introduction, the total number of conventional EEGs performed remained constant; however, there was significant shift in conventional EEG utilization towards neonates receiving fewer multiple EEGs and more single EEGs. There was no change in the rate of neurology consultations or the number of neonates diagnosed with seizures. CONCLUSIONS: Introduction of aEEG monitors to our NICU has led to less reliance on conventional EEG as a tool for the serial evaluation of brain function. Since the number of neonates diagnosed with seizures did not increase, aEEG monitoring did not appear to uncover a significant subgroup of patients with subclinical seizures that would previously have gone undetected. Conventional EEG and aEEG are complementary tools for the assessment of newborn cerebral function. PMID- 22547519 TI - Concussion knowledge among medical students and neurology/neurosurgery residents. AB - BACKGROUND AND OBJECTIVES: Concussion is a prevalent brain injury in the community. While primary prevention strategies need to be enhanced, it is also important to diagnose and treat concussions expertly and expeditiously to prevent serious complications that may be life-threatening or long lasting. Therefore, physicians should be knowledgeable about the diagnosis and management of concussions. The present study assesses Ontario medical students' and residents' knowledge of concussion management. METHODS: A survey to assess the knowledge and awareness of the diagnosis and treatment of concussions was developed and administered to graduating medical students (n= 222) and neurology and neurosurgery residents (n = 80) at the University of Toronto. RESULTS: Residents answered correctly significantly more of the questions regarding the diagnosis and management of concussions than the medical students (mean = 5.8 vs 4.1, t= 4.48, p<0.01). Gender, participation in sports, and personal concussion history were not predictive of the number of questions answered correctly. Several knowledge gaps were identified in the sample population as a whole. Approximately half of the medical students and residents did not recognize chronic traumatic encephalopathy (n = 36) or the second impact syndrome (n = 44) as possible consequences of repetitive concussions. Twenty-four percent of the medical students (n = 18) did not think that "every concussed individual should see a physician" as part of management. CONCLUSIONS: A significant number of medical students and residents have incomplete knowledge about concussion diagnosis and management. This should be addressed by targeting this population during undergraduate medical education. PMID- 22547520 TI - Multiple cerebral infarcts in patient with Moyamoya disease. PMID- 22547521 TI - Hyperperfusion secondary to middle cerebral artery stenting. PMID- 22547522 TI - Iniencephaly in an adult patient. PMID- 22547523 TI - Spinal CSF leaks: mimicker of primary headache disorder in a child. PMID- 22547524 TI - Delayed restricted diffusion in carbon monoxide leukoencephalopathy. PMID- 22547525 TI - A novel PANK2 gene mutation with sudden-onset dystonia. PMID- 22547526 TI - Isolated dysphagia after a small posterolateral medullary infarct: a case report. PMID- 22547527 TI - An x-ray CT polymer gel dosimetry prototype: II. Gel characterization and clinical application. AB - This article reports on the dosimetric properties of a new N-isopropylacrylamide, high %T, polymer gel formulation (19.5%T, 23%C), optimized for x-ray computed tomography (CT) polymer gel dosimetry (PGD). In addition, a new gel calibration technique is introduced together with an intensity-modulated radiation therapy (IMRT) treatment validation as an example of a clinical application of the new gel dosimeter. The dosimetric properties investigated include the temporal stability, spatial stability, batch reproducibility and dose rate dependence. The polymerization reaction is found to stabilize after 15 h post-irradiation. Spatial stability investigations reveal a small overshoot in response for gels imaged later than 36 h post-irradiation. Based on these findings, it is recommended that the new gel formulation be imaged between 15-36 h after irradiation. Intra- and inter-batch reproducibility are found to be excellent over the entire range of doses studied (0-28 Gy). A significant dose rate dependence is found for gels irradiated between 100-600 MU min-1. Overall, the new gel is shown to have promising characteristics for CT PGD, however the implication of the observed dose rate dependence for some clinical applications remains to be determined. The new gel calibration method, based on pixel-by-pixel matching of dose and measured CT numbers, is found to be robust and to agree with the previously used region of interest technique. Pixel-by-pixel calibration is the new recommended standard for CT PGD. The dose resolution for the system was excellent, ranging from 0.2-0.5 Gy for doses between 0-20 Gy and 0.3-0.6 Gy for doses beyond 20 Gy. Comparison of the IMRT irradiation with planned doses yields excellent results: gamma pass rate (3%, 3 mm) of 99.3% at the isocentre slice and 93.4% over the entire treated volume. PMID- 22547528 TI - Internet based computer tailored feedback on sunscreen use. AB - BACKGROUND: Skin cancer incidence rates signify the need for effective programs for the prevention of skin cancer and for helping skin cancer patients. Internet and computer tailored (CT) technology fosters the development of highly individualized health communication messages. Yet, reactions to Internet CT programs may differ per level of involvement and education level and remain understudied. OBJECTIVE: First, we identified perceptions concerning sunscreen use in Dutch adults and assessed differences in differences between the general public and skin cancer patients, and between low and high educated respondents. Second, we assessed program evaluations of these groups about a new Dutch CT Internet-based program promoting sunscreen use, and potential differences between groups METHODS: A cross-sectional research design was used. In total, 387 respondents participated and filled out an online questionnaire based on the I Change Model assessing socio-demographics, history of skin cancer, sunscreen use, and beliefs about sunscreen use. The responses were fed into a computer program that generated personal tailored feedback on screen; next we assessed their program evaluations RESULTS: Of the 132 patients, 92 were female (69.7%) and 40 were male (30.3%). In the general population (N = 225), 139 (54.5%) respondents were female and 116 (45.5%) were male. Men (50.9 years) were 8 years older than women (43.1 years). Most patients were diagnosed with basal cell carcinoma (N = 65; 49.2%), followed by melanoma (N = 28; 21.2%) and squamous cell carcinoma (N = 10; 7.6%); 22% (N = 29) did not remember their skin cancer type. Patients had higher knowledge levels, felt significantly more at risk, were more convinced of the pros of sunscreen, experienced more social support to use sunscreen, had higher self-efficacy, and made more plans to use sunscreen than respondents without skin cancer (N=255; all P's< .01). Low (N=196) educated respondents scored lower on knowledge (P<.003) but made more action plans (P<.03) than higher educated respondents (N=191). The CT feedback was evaluated positively by all respondents, and scored a 7.8 on a 10 point scale. Yet, patients evaluated the CT program slightly more (P<.05) positive (8.1) than non-patients. (7.6). Lower educated respondents were significantly (P<.05) more positive about the advantages of the program. CONCLUSIONS: First, involvement with skin cancer was reflected in more positive beliefs toward sunscreen use in patients in comparison with non-patients. Second, the CT Internet program was well accepted by both patients and non-patients, and low and high educated respondents, perhaps because higher educated respondents were more knowledgeable about sunscreen use and skin cancer. Third, a pro-active approach as conducted in our study is very well suited to reach various groups of people and is more likely to be successful than a reactive approach. PMID- 22547529 TI - The GABA excitatory/inhibitory shift in brain maturation and neurological disorders. AB - Ionic currents and the network-driven patterns they generate differ in immature and adult neurons: The developing brain is not a "small adult brain." One of the most investigated examples is the developmentally regulated shift of actions of the transmitter GABA that inhibit adult neurons but excite immature ones because of an initially higher intracellular chloride concentration [Cl(-)](i), leading to depolarizing and often excitatory actions of GABA instead of hyperpolarizing and inhibitory actions. The levels of [Cl(-)](i) are also highly labile, being readily altered transiently or persistently by enhanced episodes of activity in relation to synaptic plasticity or a variety of pathological conditions, including seizures and brain insults. Among the plethora of channels, transporters, and other devices involved in controlling [Cl(-)](i), two have emerged as playing a particularly important role: the chloride importer NKCC1 and the chloride exporter KCC2. Here, the authors stress the importance of determining how [Cl(-)](i) is dynamically regulated and how this affects brain operation in health and disease. In a clinical perspective, agents that control [Cl(-)](i) and reinstate inhibitory actions of GABA open novel therapeutic perspectives in many neurological disorders, including infantile epilepsies, autism spectrum disorders, and other developmental disorders. PMID- 22547531 TI - Interpositional arthroplasty of the first metatarsophalangeal joint using a regenerative tissue matrix for the treatment of advanced hallux rigidus: 5-year case series follow-up. AB - BACKGROUND: Painful osteoarthritis of the first metatarsophalangeal (MTP) joint, known as hallux rigidus, can be difficult to treat in young and active patients that who fail conservative treatment. The purpose of this study is to report the 5-year follow-up of a joint preservation technique for the treatment of advanced hallux rigidus. METHODS: Preservation of the first MTP joint is performed using a human acellular dermal regenerative matrix as an interpositional arthroplasty graft. A retrospective chart review was performed and compared with follow-up modified American Orthopedic Foot and Ankle scores (AOFAS) obtained by telephone. Of the first 9 consecutive patients in the original study cohort, 6 patients were available for follow-up. The outcome measures include AOFAS modified for pain and function, reoperation rates, and overall satisfaction with the procedure. RESULTS: The average follow-up was 5.43 years. No patient had a subsequent fusion or additional procedure performed on their first MTP joint. Average preoperative modified AOFAS were 38 (range, 34 to 43). Average postoperative AOFAS were 65.8 (range, 58 to 68). All patients were satisfied with their results. CONCLUSION: Interpositional arthroplasty of the first MTP joint using a regenerative tissue matrix has led to reliable pain relief and preserved function at an average follow-up of 5.4 years in 6 patients. The authors recommend this technique to active patients with advanced hallux rigidus who want to delay a fusion of their first MTP joint. PMID- 22547532 TI - Operative management of common forefoot deformities: a representative survey of Australian orthopaedic surgeons. AB - BACKGROUND: Hallux valgus and hallux rigidus are common conditions for which numerous operative interventions have been described in the literature. Various clinical and radiological measurements have been used to help grade severity and to guide treatment. MATERIALS AND METHODS: A survey was e-mailed to all members of the Australian Orthopaedic Association. Questions were asked regarding respondents' demographics as well as their preferred treatment for 3 separate cases of hallux valgus and hallux rigidus of varying severity. They were specifically asked about type of deformity correction and type of fixation. The responses were collected and statistically analyzed. RESULTS: The authors collected the answers of 454 respondents with a response rate of 36%. There was a disproportionately large percentage of respondents who were members of the Australian Orthopaedic Foot and Ankle Society. Preferred treatments were different for the 3 different cases. Older surgeons were more likely to use Chevron osteotomies, and Australian Orthopaedic Foot and Ankle Society members were more likely to use a scarf. Scarf osteotomy was preferred by more than 50% for the cases of moderate and severe hallux valgus, whereas first metatarsophalangeal joint fusion was preferred for the case with significant arthritic changes. CONCLUSIONS: There are significant associations between the surgeons' age and expertise and their training and their preferred operative intervention. Considerable differences were found in the practice of the general orthopaedic surgeons and the foot and ankle specialists. Despite the large number of surgical options available for hallux valgus, only a small number were preferred by the majority of surgeons. Although anecdotally aware that lesser deformity is treated with distal osteotomies and more severe deformity with a proximal osteotomy, the authors are unaware of any current literature that verifies this. PMID- 22547533 TI - Long-term functional outcome of bilateral spontaneous and simultaneous Achilles tendon ruptures. AB - Bilateral simultaneous ruptures are rare comprising less than 1% of all Achilles tendon ruptures. Risk factors for bilateral ruptures include chronic diseases and medications such as corticosteroids and fluoroquinolones. There is little in the literature on the long-term functional outcome of bilateral Achilles tendon ruptures. This article present a series of 3 cases of simultaneous and spontaneous bilateral Achilles tendon ruptures with a minimum of 5-year follow up suggesting a good functional outcome. PMID- 22547530 TI - The angular gyrus: multiple functions and multiple subdivisions. AB - There is considerable interest in the structural and functional properties of the angular gyrus (AG). Located in the posterior part of the inferior parietal lobule, the AG has been shown in numerous meta-analysis reviews to be consistently activated in a variety of tasks. This review discusses the involvement of the AG in semantic processing, word reading and comprehension, number processing, default mode network, memory retrieval, attention and spatial cognition, reasoning, and social cognition. This large functional neuroimaging literature depicts a major role for the AG in processing concepts rather than percepts when interfacing perception-to-recognition-to-action. More specifically, the AG emerges as a cross-modal hub where converging multisensory information is combined and integrated to comprehend and give sense to events, manipulate mental representations, solve familiar problems, and reorient attention to relevant information. In addition, this review discusses recent findings that point to the existence of multiple subdivisions in the AG. This spatial parcellation can serve as a framework for reporting AG activations with greater definition. This review also acknowledges that the role of the AG cannot comprehensibly be identified in isolation but needs to be understood in parallel with the influence from other regions. Several interesting questions that warrant further investigations are finally emphasized. PMID- 22547534 TI - The jones fracture classification, management, outcome, and complications: a systematic review. AB - BACKGROUND: The Jones fracture has been a topic of controversy ever since being first described by Sir Robert Jones himself in 1902. The aim of this review is to summarize the classification, management, outcome, and complications of this particular injury. METHODS: The authors conducted a systematic review of the scientific literature regarding the Jones fracture. RESULTS: There was no consistent approach to the Jones fracture classification. The rate of nonunion with nonoperative treatment is high in both acute and chronic cases. Surgical intervention reduces the incidence of nonunion, but the complication rate of surgery is high. CONCLUSIONS: Surgical intervention for the acute Jones fracture should be reserved for the athletic individual because there is a clear advantage in terms of time to return to sporting activity. Nonoperative treatment remains a viable alternative to surgery in all acute and delayed cases, providing there is no established nonunion and the patient is aware of the implications. PMID- 22547535 TI - The effect of goniometric alignment on passive ankle dorsiflexion range of motion among patients following ankle arthrodesis or arthroplasty. AB - Goniometric measurement is a standard method used to quantify limited ankle dorsiflexion (DF). However, compensatory motion at the subtalar and midtarsal joints might also contribute to the amount of ankle DF obtained by goniometric measurements. The purpose of this study was to examine the effect of goniometric alignment on DF range of motion measurement among patients following ankle arthrodesis or arthroplasty and age- and gender-matched controls. A total of 22 participants were recruited to participate in this observational cohort study, including 7 patients following total ankle arthroplasty (2 male, 5 female; mean age = 67.5 years, standard deviation [SD] = 9.6 years), 4 patients following ankle arthrodesis (2 male, 2 female; mean age = 70.5 years, SD = 5.2 years), and 11 age- and gender-matched controls (4 male, 7 female; mean age 67.5 years, SD = 9.0 years). Two investigators measured and recorded ankle DF passive range of motion (PROM) using a randomly determined sequence of 2 alignment methods: (1) the distal aspect of the lateral calcaneus, and (2) the fifth metatarsal. One sample t tests were performed to assess differences in ankle DF between the 2 different alignment methods. Significantly greater degrees of DF were obtained when aligning with the fifth metatarsal versus the lateral calcaneus on the patients' uninvolved sides and the randomly selected side of matched controls (P < .05) but not on the patients' operative side (P > .05). This study found that more degrees of DF PROM are measured when aligning a goniometer with the fifth metatarsal versus the calcaneus on the uninvolved side of patients and matched controls. LEVELS OF EVIDENCE: Diagnostic, Level IV. PMID- 22547536 TI - Cosmetic results of wedge resection of nail matrix (Winograd technique) in the treatment of ingrown toenail. AB - OBJECTIVE: The purpose of this retrospective study is to evaluate the cosmetic results of wedge resection of the nail matrix (Winograd technique) in the treatment of ingrown toenail. MATERIALS AND METHODS: This study retrospectively reviewed medical charts of 68 patients with 75 ingrown toenails who underwent surgical correction with the Winograd technique between January, 2008, and December, 2009, at the Orthopaedics and Traumatology Department, Antalya Education and Research Hospital. For the final follow-up, patients were contacted by telephone and completed a telephone questionnaire. Recurrence, cosmetic results, and satisfaction of the patients were the major outcome measures. RESULTS: There was recurrence in 9 patients (13.2%). The mean recurrence time was 6.7 months (range = 2-12 months). All recurrences involved the lateral border of the toenail. Cosmetic ratings were statistically lower in female patients (P = .005). The reasons for poor and acceptable cosmetic results were proximal incision scar and narrowing of the nail plate. CONCLUSION: Wedge resection of nail matrix has a considerably high recurrence rate. Furthermore, narrowing of the nail plate is a disadvantage of this procedure. All patients should be informed about the possibility of recurrence and disfigurement in their toenails (narrow nail plate). Particularly, female patients who care about the cosmesis may be dissatisfied with this surgical technique. PMID- 22547537 TI - MagnetoHemoDynamics in the aorta and electrocardiograms. AB - This paper addresses a complex multi-physical phenomenon involving cardiac electrophysiology and hemodynamics. The purpose is to model and simulate a phenomenon that has been observed in magnetic resonance imaging machines: in the presence of a strong magnetic field, the T-wave of the electrocardiogram (ECG) gets bigger, which may perturb ECG-gated imaging. This is due to a magnetohydrodynamic (MHD) effect occurring in the aorta. We reproduce this experimental observation through computer simulations on a realistic anatomy, and with a three-compartment model: inductionless MHD equations in the aorta, bi domain equations in the heart and electrical diffusion in the rest of the body. These compartments are strongly coupled and solved using finite elements. Several benchmark tests are proposed to assess the numerical solutions and the validity of some modeling assumptions. Then, ECGs are simulated for a wide range of magnetic field intensities (from 0 to 20 T). PMID- 22547538 TI - Online schools and children with special health and educational needs: comparison with performance in traditional schools. AB - BACKGROUND: In the United States, primary and secondary online schools are institutions that deliver online curricula for children enrolled in kindergarten through 12th grade (K-12). These institutions commonly provide opportunities for online instruction in conjunction with local schools for students who may need remediation, have advanced needs, encounter unqualified local instructors, or experience scheduling conflicts. Internet-based online schooling may potentially help children from populations known to have educational and health disadvantages, such as those from certain racial or ethnic backgrounds, those of low socioeconomic status, and children with special health care needs (CSHCN). OBJECTIVE: To describe the basic and applied demographics of US online-school users and to compare student achievement in traditional versus online schooling environments. METHODS: We performed a brief parental survey in three states examining basic demographics and educational history of the child and parents, the child's health status as measured by the CSHCN Screener, and their experiences and educational achievement with online schools and class(es). Results were compared with state public-school demographics and statistical analyses controlled for state-specific independence. RESULTS: We analyzed responses from 1971 parents with a response rate of 14.7% (1971/13,384). Parents of online-school participants were more likely to report having a bachelor's degree or higher than were parents of students statewide in traditional schools, and more of their children were white and female. Most notably, the prevalence of CSHCN was high (476/1971, 24.6%) in online schooling. Children who were male, black, or had special health care needs reported significantly lower grades in both traditional and online schools. However, when we controlled for age, gender, race, and parental education, parents of CSHCN or black children reported significantly lower grades in online than in traditional schooling (adjusted odds ratio [aOR] 1.45, 95% confidence interval [CI] 1.29-1.62 for CSHCN, P < .001; aOR 2.73, 95% CI 2.11-3.53 for black children, P < .001.) In contrast, parents with a bachelor's degree or higher reported significantly higher online-school grades than traditional-school grades for their children (aOR 1.45, 95% CI 1.15-1.82, P < .001). CONCLUSIONS: The demographics of children attending online schools do not mirror those of the state-specific school populations. CSHCN seem to opt into online schools at a higher rate. While parents report equivalent educational achievement in online and traditional classrooms, controlling for known achievement risks suggests that CSHCN and black children have lower performance in online than in traditional schools. Given the millions of students now in online schools, future studies must test whether direct assistance in online schools, such as taking individualized education plans into consideration, will narrow known disparities in educational success. Only then can online schools emerge as a true educational alternative for at-risk populations. PMID- 22547540 TI - Endocrine-responsive breast cancer special types: who cares? PMID- 22547539 TI - Colorectal cancer pulmonary oligometastases: pooled analysis and construction of a clinical lung metastasectomy prognostic model. AB - BACKGROUND: Although resecting colorectal cancer (CRC) pulmonary metastasis is associated with long-term survival, identification of prognostic groups is needed for future randomized trials, and construction of a lung metastasectomy prognostic model (LMPM) is warranted. PATIENTS AND METHODS: We searched the PubMed database for retrospective studies evaluating prognostic factors following resecting CRC lung metastasis. Individual patient data were analyzed. Independent prognostic factors were used to construct an LMPM. RESULTS: Between 1983 and 2008, 1112 metastasectomies were carried out on 927 patients included in eight studies. Five-year survival rate was 54.3% following the first lung resection. Multivariate analysis identified three independently poor prognostic factors: pre thoracotomy carcinoembryonic antigen >=5 ng/ml, disease-free interval <36 months, and more than one metastatic lesion. Patients with good-, intermediate-, and high risk groups according to the LMPM had a 5-year survival of 68.2%, 46.4%, and 26.1%, respectively (P < 0.001). Perioperative chemotherapy and previously resected liver metastasis had no influence on survival. CONCLUSIONS: The low- and intermediate-risk groups have a good chance of long-term survival following metastasectomy. However, more studies are needed to investigate whether surgery offers any advantage over systemic therapy for the poor-risk group. PMID- 22547541 TI - Outcome and clinical-biological characteristics of patients with advanced breast cancer undergoing removal of ovarian/pelvic metastases. AB - BACKGROUND: Patients with metastatic breast cancer to the ovary, without tumor debulking and after systemic therapy, have a 5-year survival rate < 10%. PATIENTS AND METHODS: We analyzed a series of 37 patients, operated in one institution over 10 years, for both the primary tumor (PT) and ovarian/pelvic metastases (OPM). Estrogen receptors (ER), progesterone receptors (PgR), HER-2 and Ki-67 were determined. RESULTS: Patients were predominantly young: 27 (73%) patients were < 50 years. Average ER/PgR expression did not change significantly between PT (mean ER = 66%, PgR = 35%) and OPM (mean ER = 67%, PgR = 28%). Median time to OPM was 42 months (range 0-176); 5-year OS after OPM was 51% (95% confidence interval 32% to 67%). When combining ER and PgR status, patients with ER > 50% on both PT and OPM and with PgR > 50% on PT and/or OPM (good prognosis, 11 patients) had a better outcome versus0 patients with ER and PgR <= 50% on both PT and OPM (bad prognosis, eight patients) and also versus the remaining patients (intermediate prognosis, 18 patients), P value = 0.010. CONCLUSION: Patients with OPM from breast cancer show a favorable prognosis after tumor debulking, whether it was radical or not, especially when a high expression of ER and PgR is present in both PT and OPM. PMID- 22547542 TI - Extranodal natural killer/T-cell lymphoma from skin or soft tissue: suggestion of treatment from multinational retrospective analysis. AB - BACKGROUND: Clinical features and outcomes of extranodal natural killer/T-cell lymphoma (ENKL) arising from extranasal sites are not fully understood. The purpose of this study was to study the prognosis and treatment outcome of skin/soft tissue primary ENKL. PATIENTS AND METHODS: This multicenter retrospective study included 48 patients with skin/soft tissue primary ENKL diagnosed from 1993 to 2010. RESULTS: Patients with Ann Arbor stage I, T1-2N0M0 by International Society for Cutaneous Lymphomas-European Organization of Research and Treatment of Cancer TNM (tumour-node-metastasis) stage, International prognostic index score of 0-1, and a Korean prognostic index (KPI) score of 0-1 were associated with better survival. Four of five patients with T1 2N0M0 disease achieved complete response with radiation alone. In disseminated disease, only 6 of 13 patients responded to anthracycline-containing chemotherapy, and all the two patients receiving SMILE showed response. CONCLUSION: In conclusion, we identified the prognostic value of KPI, and we suggest a treatment recommendation according to the TNM (tumour-node-metastasis) stage. Radiotherapy with/without chemotherapy seemed to be optimal in localized disease. In advanced stages, a more aggressive treatment regimen with newer agents should be sought. PMID- 22547543 TI - Surfactant protein D facilitates Cryptococcus neoformans infection. AB - Concurrent with the global escalation of the AIDS pandemic, cryptococcal infections are increasing and are of significant medical importance. Furthermore, Cryptococcus neoformans has become a primary human pathogen, causing infection in seemingly healthy individuals. Although numerous studies have elucidated the virulence properties of C. neoformans, less is understood regarding lung host immune factors during early stages of fungal infection. Based on our previous studies documenting that pulmonary surfactant protein D (SP-D) protects C. neoformans cells against macrophage-mediated defense mechanisms in vitro (S. Geunes-Boyer et al., Infect. Immun. 77:2783-2794, 2009), we postulated that SP-D would facilitate fungal infection in vivo. To test this hypothesis, we examined the role of SP-D in response to C. neoformans using SP-D-/- mice. Here, we demonstrate that mice lacking SP-D were partially protected during C. neoformans infection; they displayed a longer mean time to death and decreased fungal burden at several time points postinfection than wild-type mice. This effect was reversed by the administration of exogenous SP-D. Furthermore, we show that SP-D bound to the surface of the yeast cells and protected the pathogenic microbes against macrophage-mediated defense mechanisms and hydrogen peroxide (H2O2) induced oxidative stress in vitro and in vivo. These findings indicate that C. neoformans is capable of coopting host SP-D to increase host susceptibility to the yeast. This study establishes a new paradigm for the role played by SP-D during host responses to C. neoformans and consequently imparts insight into potential future preventive and/or treatment strategies for cryptococcosis. PMID- 22547544 TI - Nocardia brasiliensis induces an immunosuppressive microenvironment that favors chronic infection in BALB/c mice. AB - Nocardia brasiliensis is an intracellular microorganism and the most common etiologic agent of actinomycetoma in the Americas. Several intracellular pathogens induce an immunosuppressive microenvironment through increases in CD4+ Foxp3+ regulatory T cells (Treg), thus downregulating other T-cell subpopulations and assuring survival in the host. In this study, we determined whether N. brasiliensis modulates T-lymphocyte responses and their related cytokine profiles in a murine experimental model. We also examined the relationship between N. brasiliensis immunomodulation and pathogenesis and bacterial survival. In early infection, Th17/Tc17 cells were increased at day 3 (P < 0.05) in footpad tissue and spleen. Treg subpopulations peaked at days 7 and 15 (P < 0.01) in the footpad and spleen, respectively. Transforming growth factor beta1 (TGF-beta1) and interleuki-10 (IL-10) are cytokines known for their immunosuppressive effects. During early and chronic infections, these cytokines were elevated with increased TGF-beta1 levels from days 3 to 30 (P < 0.01) and sustained IL-10 expression throughout infection compared to uninfected mice. IL-6 production was increased at day 3 (P < 0.01), whereas gamma interferon (IFN-gamma), IL-17A, and IL-23 levels were highest at day 15 postinfection (P < 0.01) when a decrease in the bacterial load (>1 log) was also observed (P < 0.05). After these changes, at 30 to 60 days postinfection, IFN-gamma production was decreased, whereas the expression of anti-inflammatory cytokines and the bacterial load again increased (P < 0.05). The increment in Treg cells and the related cytokine profile correlated with reduced inflammation at day 15 (P < 0.05) in the footpad. We conclude that N. brasiliensis modulates the immune system to induce an immunosuppressive microenvironment that benefits its survival during the chronic stage of infection. PMID- 22547545 TI - Interleukin-10 induction is an important virulence function of the Yersinia pseudotuberculosis type III effector YopM. AB - Pathogenic Yersinia species modulate host immune responses through the activity of a plasmid-encoded type III secretion system and its associated effector proteins. One effector, YopM, is a leucine-rich-repeat-containing protein that is important for virulence in murine models of Yersinia infection. Although the mechanism by which YopM promotes virulence is unknown, we previously demonstrated that YopM was required for the induction of high levels of the immunosuppressive cytokine interleukin-10 (IL-10) in sera of C57BL/6J mice infected with Yersinia pseudotuberculosis. To determine if IL-10 production is important for the virulence function of YopM, C57BL/6J or congenic IL-10-/- mice were infected intravenously with wild-type or yopM mutant Y. pseudotuberculosis strains. Analysis of cytokine levels in serum and bacterial colonization in the spleen and liver showed that YopM is required for IL-10 induction in C57BL/6J mice infected with either the IP32953 or the 32777 strain of Y. pseudotuberculosis, demonstrating that the phenotype is conserved in the species. In single-strain infections, the ability of the 32777DeltayopM mutant to colonize the liver was significantly increased by the delivery of exogenous IL-10 to C57BL/6J mice. In mixed infections, the competitive advantage of a yopM+ 32777 strain over an isogenic yopM mutant to colonize spleen and liver, as observed for C57BL/6J mice, was significantly reduced in IL-10-/- animals. Thus, by experimentally controlling IL-10 levels in a mouse infection model, we obtained evidence that the induction of this cytokine is an important mechanism by which YopM contributes to Y. pseudotuberculosis virulence. PMID- 22547546 TI - Brucella abortus invasion of osteoblasts inhibits bone formation. AB - Osteoarticular brucellosis is the most common presentation of the active disease in humans. Loss of bone is a serious complication of localized bacterial infection of bones or the adjacent tissue, and brucellosis proved not to be the exception. The skeleton is a dynamic organ system which is constantly remodeled. Osteoblasts are responsible for the deposition of bone matrix and are thought to facilitate the calcification and mineralization of the bone matrix, and their function could be altered under infectious conditions. In this article, we describe immune mechanisms whereby Brucella abortus may invade and replicate within osteoblasts, inducing apoptosis, inhibiting mineral and organic matrix deposition, and inducing upregulation of RANKL expression. Additionally, all of these mechanisms contributed in different ways to bone loss. These processes implicate the activation of signaling pathways (mitogen-activated protein kinases [MAPK] and caspases) involved in cytokine secretion, expression of activating molecules, and cell death of osteoblasts. In addition, considering the relevance of macrophages in intracellular Brucella survival and proinflammatory cytokine secretion in response to infection, we also investigated the role of these cells as modulators of osteoblast survival, differentiation, and function. We demonstrated that supernatants from B. abortus-infected macrophages may also mediate osteoblast apoptosis and inhibit osteoblast function in a process that is dependent on the presence of tumor necrosis factor alpha (TNF-alpha). These results indicate that B. abortus may directly and indirectly harm osteoblast function, contributing to the bone and joint destruction observed in patients with osteoarticular complications of brucellosis. PMID- 22547547 TI - NOD2 signaling contributes to host defense in the lungs against Escherichia coli infection. AB - Bacterial pneumonia remains a significant cause of mortality in the United States. The innate immune response is the first line of defense against invading bacteria. Neutrophil recruitment to the lungs is the first step in a multistep sequence leading to bacterial clearance. Ligand interaction with pattern recognizing receptors (PRRs) leads to chemokine production, which drives neutrophils to the site of infection. Although we demonstrated that RIP2 is important for host defense in the lungs against Escherichia coli, the individual roles of NOD1 and NOD2 in pulmonary defense have not been addressed. Here, we explored the role of NOD2 in neutrophil-mediated host defense against an extracellular pathogen, E. coli. We found enhanced bacterial burden and reduced neutrophil and cytokine/chemokine levels in the lungs of NOD2-/- mice following E. coli infection. Furthermore, we observed reduced activation of NF-kappaB and mitogen-activated protein kinases (MAPKs) in the lungs of NOD2-/- mice upon E. coli challenge. Moreover, NOD2-/- neutrophils show impaired intracellular bacterial killing. Using NOD2/RIP2-/- mice, we observed bacterial burden and neutrophil accumulation in the lungs similar to those seen with NOD2-/- mice. In addition, bone marrow-derived macrophages obtained from NOD2/RIP2-/- mice demonstrate a reduction in activation of NF-kappaB and MAPKs similar to that seen with NOD2-/- mice in response to E. coli. These findings unveil a previously unrecognized role of the NOD2-RIP2 axis for host defense against extracellular Gram-negative bacteria. This pathway may represent a novel target for the treatment of lung infection/inflammation. PMID- 22547548 TI - Ehrlichia chaffeensis TRP32 interacts with host cell targets that influence intracellular survival. AB - Ehrlichia chaffeensis is an obligately intracellular bacterium that exhibits tropism for mononuclear phagocytes and survives by evading host cell defense mechanisms. Recently, molecular interactions of E. chaffeensis tandem repeat proteins 47 and 120 (TRP47 and -120) and the eukaryotic host cell have been described. In this investigation, yeast two-hybrid analysis demonstrated that an E. chaffeensis type 1 secretion system substrate, TRP32, interacts with a diverse group of human proteins associated with major biological processes of the host cell, including protein synthesis, trafficking, degradation, immune signaling, cell signaling, iron metabolism, and apoptosis. Eight target proteins, including translation elongation factor 1 alpha 1 (EF1A1), deleted in azoospermia (DAZ) associated protein 2 (DAZAP2), ferritin light polypeptide (FTL), CD63, CD14, proteasome subunit beta type 1 (PSMB1), ring finger and CCCH-type domain 1 (RC3H1), and tumor protein p53-inducible protein 11 (TP53I11) interacted with TRP32 as determined by coimmunoprecipitation assays, colocalization with TRP32 in HeLa and THP-1 cells, and/or RNA interference. Interactions between TRP32 and host targets localized to the E. chaffeensis morulae or in the host cell cytoplasm adjacent to morulae. Common or closely related interacting partners of E. chaffeensis TRP32, TRP47, and TRP120 demonstrate a molecular convergence on common cellular processes and molecular cross talk between Ehrlichia TRPs and host targets. These findings further support the role of TRPs as effectors that promote intracellular survival. PMID- 22547549 TI - Fusobacterium nucleatum and Tannerella forsythia induce synergistic alveolar bone loss in a mouse periodontitis model. AB - Tannerella forsythia is strongly associated with chronic periodontitis, an inflammatory disease of the tooth-supporting tissues, leading to tooth loss. Fusobacterium nucleatum, an opportunistic pathogen, is thought to promote dental plaque formation by serving as a bridge bacterium between early- and late colonizing species of the oral cavity. Previous studies have shown that F. nucleatum species synergize with T. forsythia during biofilm formation and pathogenesis. In the present study, we showed that coinfection of F. nucleatum and T. forsythia is more potent than infection with either species alone in inducing NF-kappaB activity and proinflammatory cytokine secretion in monocytic cells and primary murine macrophages. Moreover, in a murine model of periodontitis, mixed infection with the two species induces synergistic alveolar bone loss, characterized by bone loss which is greater than the additive alveolar bone losses induced by each species alone. Further, in comparison to the single species infection, mixed infection caused significantly increased inflammatory cell infiltration in the gingivae and osteoclastic activity in the jaw bones. These data show that F. nucleatum subspecies and T. forsythia synergistically stimulate the host immune response and induce alveolar bone loss in a murine experimental periodontitis model. PMID- 22547551 TI - Can holism be practiced in a biomedical setting? A qualitative study of the integration of complementary medicine to a surgical department. AB - In recent decades, complementary medicine (CM) has been increasingly integrated to conventional healthcare organizations, in which the biomedical profession clearly maintains dominance. Our objective was to investigate empirically what integration and 'holism' mean to the diverse professional groups involved and whether treatment becomes more holistic when CM is integrated. A qualitative study was conducted in a general surgery department at a public hospital in Israel. Data were collected by means of observations of medical encounters and daily work, and 30 in-depth interviews with medical directors, surgeons, senior nurses, CM practitioners and hospitalized patients. We found that most of the interviewed nurses, surgeons and directors and some patients believed that CM treatments were of value in addressing the psychological needs of patients within this predominantly somatic-oriented department. To CM practitioners and some of the patients, integration means introducing and practicing a holistic outlook in this biomedical context, which involves elements such as Qi, energy, soul and spirit. Such practices were directed to a suitable audience, namely, patients as well as conventional medical staff who were willing to explore a holistic approach. We concluded that patient care tends to become more comprehensive when CM is integrated. Despite the overall dominance of biomedicine, holistic CM practices were introduced to the biomedical setting of the hospital. Yet, the question whether holistic CM practices and perceptions will eventually lead nurses and physicians toward paradigmatic integration, has still to be examined. PMID- 22547550 TI - VirK is a periplasmic protein required for efficient secretion of plasmid-encoded toxin from enteroaggregative Escherichia coli. AB - Despite the autotransporter (AT) moniker, AT secretion appears to involve the function of periplasmic chaperones. We identified four periplasmic proteins that specifically bound to plasmid-encoded toxin (Pet), an AT produced by enteroaggregative Escherichia coli (EAEC). These proteins include the 17-kDa Skp chaperone and the 37-kDa VirK protein. We found that the virK gene is present in different Enterobacteriaceae. VirK bound to misfolded conformations of the Pet passenger domain, but it did not bind to the folded passenger domain or to the beta domain of Pet. Assays with an EAECDeltavirK mutant and its complemented version showed that, in the absence of VirK, Pet was not secreted but was instead retained in the periplasm as proteolytic fragments. In contrast, Pet was secreted from a Deltaskp mutant. VirK was not required for the insertion of porin proteins into the outer membrane but assisted with insertion of the Pet beta domain into the outer membrane. Loss of VirK function blocked the EAEC-mediated cytotoxic effect against HEp-2 cells. Thus, VirK facilitates the secretion of the AT Pet by maintaining the passenger domain in a conformation that both avoids periplasmic proteolysis and facilitates beta-domain insertion into the outer membrane. PMID- 22547553 TI - The resilient subject: exploring subjectivity, identity and the body in narratives of resilience. AB - International research and policy interest in resilience has increased enormously during the last decade. Resilience is now considered to be a valuable asset or resource with which to promote health and well-being and forms part of a broader trend towards strength based as opposed to deficit models of health. And while there is a developing critique of resilience's conceptual limits and normative assumptions, to date there is less discussion of the subject underpinning these notions, nor related issues of subjectivity, identity or the body. Our aim in this article is to begin to address this gap. We do so by re-examining the subject within two established narratives of resilience, as 'found' and 'made'. We then explore the potential of a third narrative, which we term resilience 'unfinished'. This latter story is informed by feminist poststructural understandings of the subject, which in turn, resonate with recently articulated understandings of an emerging psychosocial subject and the contribution of psychoanalysis to these debates. We then consider the potential value of this poststructural, performative and embodied psychosocial subject and discuss the implications for resilience theory, practice and research. PMID- 22547552 TI - 'Cancer doesn't have an age': genetic testing and cancer risk management in BRCA1/2 mutation-positive women aged 18-24. AB - Increasingly, 18-24-year-old women from hereditary breast/ovarian cancer (HBOC) families are pursuing genetic testing, despite their low absolute risks of breast and ovarian cancer and the fact that evidence-based management options used with older high-risk women are not generally available. Difficult clinical decisions in older carriers take on substantially more complexity and value-laden import in very young carriers. As a result, many of the latter receive highly personal and emotionally charged cancer risk information in a life context where management strategies are not well defined. We analyzed 32 in-depth interviews with BRCA1/2 mutation-positive women aged 18-24 using techniques of grounded theory and interpretive description. Participants described feeling vulnerable to a cancer diagnosis but in a quandary regarding their care because evidence-based approaches to management have not been developed and clinical trials have not been undertaken. Our participants demonstrated a wide range of genetic and health literacy. Inconsistent recommendations, surveillance fatigue, and the unpredictability of their having health insurance coverage for surgical risk reducing procedures led several to contemplate risk-reducing mastectomy before age 25. Parents remained a primary source of emotional and financial support, slowing age-appropriate independence and complicating patient privacy. Our findings suggest that, for 18-24-year-olds, readiness to autonomously elect genetic testing, to fully understand and act on genetic information, and to confidently make decisions with life-long implications are all evolving processes. We comment on the tensions between informed consent, privacy, and the unique developmental needs of BRCA1/2 mutation-positive women just emerging into their adult years. PMID- 22547554 TI - Safer radiologic imaging of otolaryngologic disease in children. AB - The use of medical imaging is commonplace in children with otolaryngologic disease, with a not insignificant and increasing exposure to ionizing radiation from such diagnostic imaging. Radiation exposure imparts potential cancer risk, particularly in children, who have long life expectancies and are more sensitive to the adverse effects of ionizing radiation. We summarize these issues, with a focus on computed tomography (CT) in children. The otolaryngologist plays a key role optimizing the use and minimizing the risk of diagnostic imaging in children by ordering the correct test at the best time for the right reasons. In concert with radiology colleagues and informed parents, we can improve the safety of radiologic imaging for the children we diagnose and treat. PMID- 22547555 TI - Role of chronic lymphocytic thyroiditis in central node metastasis of papillary thyroid carcinoma. AB - OBJECTIVE: (1) To investigate the role of chronic lymphocytic thyroiditis (CLT) in central node metastasis of papillary thyroid carcinoma (PTC) and (2) to evaluate the presence of chronic lymphocytic thyroiditis according to PTC specific molecular markers. STUDY DESIGN: Historical cohort study. SETTING: Academic medical center. SUBJECTS AND METHODS: All patients who underwent total thyroidectomy with central neck dissection for PTC at Oregon Health & Science University between 2005 and 2010 were screened for the presence of CLT and reviewed for clinical prognostic factors. Patients with inadequate central neck dissections were excluded. Molecular markers for PTC were analyzed on archived tumor samples. RESULTS: A total of 139 patients met selection criteria. The rate of CLT was 43.8%. The rate of central node positivity was 63%. Presence of CLT was associated with a significantly lower proportion of central node metastases (49% vs 74%, P = .003) and angiolymphatic invasion (31% vs 15%, P = .03). There was no significant difference in mean age, tumor size, and extracapsular extension. Molecular genotyping did not reveal a significant difference in the types of mutations found in both groups. CONCLUSION: The data indicate a lower incidence of central compartment lymph node metastasis in those with CLT in this patient population, suggesting a potential protective role in tumor spread. The equal distribution of tumor mutations between the carcinomas with and without evidence of CLT argues against a mutation-specific antigen as the immunologic stimulus. Further research is needed to characterize the role of autoimmunity in thyroid cancer. PMID- 22547556 TI - Involvement of minor salivary glands in the pathogenesis of peritonsillar abscess. AB - OBJECTIVES: To study the relationship between peritonsillar abscess (PTA) and minor salivary glands surrounding the palatine tonsils. STUDY DESIGN: Prospective population-based study. SETTINGS: Tertiary care university hospital. SUBJECTS AND METHOD: Prospective study including 41 patients with PTA and 6 patients with a neck abscess. Amylase levels of the pus and serum were measured and compared between the 2 groups. Clinical data regarding hospitalization length and recurrence rate were also collected. RESULTS: Of the 41 patients with PTA, 7 suffered from recurrent PTA. Average level of amylase in the pus of the PTA group was 3841 U/L versus 7.7 U/L in the neck abscess group (P < .001; median, 62 vs 9.5). Serum amylase was higher in the PTA group (49.3 U/L vs 37.3 U/L; P = .008). There were no recurrences in PTA patients with amylase greater than 65 U/dL in the pus in 0 of 20 (0%) versus 7 of 21 (33%) for amylase lower than 65 U/L (P = .01). CONCLUSION: High amylase in the pus lends further support for involvement of minor salivary glands. However, high recurrence rates related to low amylase in the pus imply an additional pathogenesis possibly related to tonsillar infection. It is possible that both minor salivary glands as well as tonsillar infection play a role in the pathogenesis of peritonsillar infections. PMID- 22547557 TI - Endoscopic endonasal resection of anterior skull base meningiomas. AB - OBJECTIVE: Anterior cranial fossa (ACF) meningiomas are difficult to surgically manage. Endoscopic transnasal approaches have increasingly been used as a minimally invasive route and thus offer significant advantages. However, a paucity of literature describing the intraoperative challenges and postoperative outcomes of this technique still exists. STUDY DESIGN: Case series with chart review. SETTING: The Royal Adelaide Hospital, Flinders Medical Centre, Wellington Hospital. SUBJECTS AND METHODS: Fifteen consecutive patients who underwent endoscopic resection of ACF meningiomas between 2004 and 2010 by the South Australian and Wellington Skull Base Units. Demographic and clinical information was compiled by reviewing patient charts and operation notes. Safety and efficacy of the procedure, role of a team approach, and areas for further improvement were analyzed. RESULTS: Of the patients, 87% were women. Tumor locations: 8 olfactory groove, 2 tuberculum sellae, 1 clinoidal, 1 jugum sphenoidale, 1 planum sphenoidale, 1 subfrontal, and 1 midline ACF floor. Commonest presenting symptom was visual change. Mean volume of tumor was 25.69 cm(3), with a size area of 7.28 cm(2). Five were revision cases. None had previous endonasal surgery. Average operating times decreased over time. Gross total removal was achieved in 14, with no deaths. Four patients had postoperative cerebrospinal fluid (CSF) leak. Rate of CSF leak decreased over time. Sixty percent of patients reported visual improvement. Two patients had radiological evidence of recurrence. CONCLUSION: ACF meningiomas can be safely removed endonasally, offering significant advantages over the traditional transcranial approach for suitable tumors. Early audit of this approach shows results achieved by this unit are comparable with the published literature. PMID- 22547558 TI - A novel case of transient right ventricular failure in a patient with respiratory distress. AB - Right ventricular (RV) failure is characterized by an inability to pump blood into the pulmonary circulation and can often lead to hemodynamic instability. Common causes of RV failure include left ventricular (LV) failure, RV infarction, sepsis, cor pulmonale due to acute respiratory distress syndrome, pulmonary emboli, or pulmonary hypertension. We report the case of a 61-year-old woman with no significant pulmonary or cardiac disease who presented with hypoxic respiratory failure in the setting of opioid overdose. She remained obtunded despite naloxone treatment and required endotracheal intubation as well as norepinephrine therapy for persistent hypotension. A transthoracic echocardiogram demonstrated isolated severe RV dysfunction without any LV abnormalities. Cardiac catheterization showed no obstructive coronary artery disease, pulmonary hypertension, or elevated left atrial pressures, and chest imaging only revealed signs of aspiration. Over the next 6 days, the patient's cardiac and respiratory function improved, and a repeat echocardiogram demonstrated complete normalization of RV function. This case demonstrates a novel finding that marked, but transient, RV dysfunction can occur in the setting of acute respiratory failure. PMID- 22547559 TI - Successful bovine arch replacement for a type A acute aortic dissection in a pregnant woman with severe haemodynamic compromise. AB - Acute aortic dissection is very uncommon in pregnant women and the acute type A aortic dissection carries a high mortality rate outside specialized centres. There are a few cases reported with successful outcomes for the mother and the foetus from major cardiac centres. We are reporting our first experience of acute aortic dissection during the third trimester of pregnancy in a patient with Marfan features, profound haemodynamic compromise on arrival and a bovine aortic arch. Both the mother and the baby are doing well two years postoperatively. PMID- 22547560 TI - An unusual cause of acute abdominal pain after cardiac surgery: acute epiploic appendagitis. AB - Abdominal complications following cardiac surgery remain unusual, but are associated with high mortality. The most common abdominal surgical complications are mesenteric ischaemia, diverticulitis, pancreatitis, gastrointestinal bleeding and cholecystitis. We describe a case of a 73-year old woman with acute abdominal pain mimicking cholecystitis on day 10 after aortic valve replacement. An abdominal examination showed tenderness of the right upper quadrant with Murphy's sign. Complete blood count, blood chemistries and urinalysis were normal as were the abdominal and chest X-rays and abdominal ultrasonography. The abdominal computed-tomography (CT) scan enabled us to rule out cholecystitis, as it demonstrated the typical appearance of epiploic appendagitis on the right colon, 1 cm below the gallbladder. Epiploic appendagitis results from twisting, kinking or venous thrombosis of an epiploic appendage. Depending on its localization, it mimics many diagnoses requiring surgery: colitis, diverticulitis, appendicitis and cholecystitis. An abdominal CT scan is the diagnostic imaging tool of choice. All physicians involved in post-cardiac surgery care should be aware of this self limiting disease that usually resolves with non-steroidal anti-inflammatory drugs and watchful waiting, and to avoid unnecessary surgery because the spontaneous evolution of epiploic appendagitis is usually benign. PMID- 22547562 TI - Changes in knee joint biomechanics following balance and technique training and a season of Australian football. AB - PURPOSE: Determine if balance and technique training (BTT) implemented adjunct to normal Australian football (AF) training reduces external knee loading during sidestepping. Additionally, the authors determined if an athlete's knee joint kinematics and kinetics change over a season of AF. METHODOLOGY: Eight amateur level AF clubs (n=1,001 males) volunteered to participate in either 28 weeks of BTT or a 'sham' training (ST) adjunct to their normal preseason and regular training. A subset of 34 athletes (BTT, n=20; ST, n=14) were recruited for biomechanical testing in weeks 1-7 and 18-25 of the 28-week training intervention. During biomechanical testing, participants completed a series running, preplanned (PpSS) and unplanned sidestepping (UnSS) tasks. A linear mixed model (alpha=0.05) was used to determine if knee kinematics and peak moments during PpSS and UnSS were influenced by BTT and/or a season of AF. RESULTS: Both training groups significantly (p=0.025) decreased their peak internal-rotation knee moments during PpSS, and significantly (p=0.022) increased their peak valgus knee moments during UnSS following their respective training interventions. CONCLUSIONS: BTT was not effective in changing an athlete's knee joint biomechanics during sidestepping when conducted in 'real-world' training environments. Following normal AF training, the players had different changes to their knee joint biomechanics during both preplanned and unplanned sidestepping. When performing an unplanned sidestepping task in the latter half of a playing season, athletes are at an increased risk of ACL injury. The authors therefore recommend both sidestepping tasks are performed during biomechanical testing when assessing the effectiveness of prophylactic training protocols. PMID- 22547563 TI - Unrecognised ringside concussive injury in amateur boxers. AB - OBJECTIVES: Concussion is common in contact sports such as boxing. Diagnosis of concussion depends on symptom report or recognition of clinical features, and true incidence may be underestimated. Persistent morbidity is a possible risk of repeated or unrecognised concussion. This study aimed to evaluate pre and postbout cognitive performance in motivated amateur boxers in order to detect objective evidence of unrecognised cognitive impairment suggestive of concussive injury. METHODS: The study employed a prospective and observational design. Participants were amateur boxers who won at least one bout in a single elimination competition. Optimal preparticipation performance using a computerised cognitive assessment tool (CCAT, Axon Sports) and no significant deterioration in cognitive performance within 24 h postbout were required to compete. All boxers were screened for clinical evidence of concussion by a ringside physician. RESULTS: Of approximately 200 competing boxers, 96 were eligible having won at least one of the total 160 bouts. Mean age was 21.3 (SD 1.9) years (range 18.5-29.7). Of these, 17 (10.6%) failed their first postbout CCAT, with 12 (71%) passing a repeat test. Of the five remaining boxers, there were two boxers (1.3% of bouts) not suspected of a concussion after their bouts, who showed evolving slowing in cognitive performance typical of a concussion. CONCLUSIONS: Cognitive impairment, as detected by subtle deterioration in reaction time measures, can occur in amateur boxers postbout that is not recognised at ringside. Although the vast majority of bouts were conducted safely, unrecognised injury may occur and be detectable using objective computerised cognitive assessment. PMID- 22547561 TI - The relationship of femoral neck shaft angle and adiposity to greater trochanteric pain syndrome in women. A case control morphology and anthropometric study. AB - OBJECTIVE: To evaluate if pelvic or hip width predisposed women to developing greater trochanteric pain syndrome (GTPS). DESIGN: Prospective case control study. PARTICIPANTS: Four groups were included in the study: those gluteal tendon reconstructions (n=31, GTR), those with conservatively managed GTPS (n=29), those with hip osteoarthritis (n=20, OA) and 22 asymptomatic participants (ASC). METHODS: Anterior-posterior pelvic x-rays were evaluated for femoral neck shaft angle; acetabular index, and width at the lateral acetabulum, and the superior and lateral aspects of the greater trochanter. Body mass index, and waist, hip and greater trochanter girth were measured. Data were analysed using a one-way analysis of variance (ANOVA; posthoc Scheffe analysis), then multivariate analysis. RESULTS: The GTR group had a lower femoral neck shaft angle than the other groups (p=0.007). The OR (95% CI) of having a neck shaft angle of less than 134 degrees , relative to the ASC group: GTR=3.33 (1.26 to 8.85); GTPS=1.4 (0.52 to 3.75); OA=0.85 (0.28 to 2.61). The OR of GTR relative to GTPS was 2.4 (1.01 to 5.6). No group difference was found for acetabular or greater trochanter width. Greater trochanter girth produced the only anthropometric group difference (mean (95% CI) in cm) GTR=103.8 (100.3 to 107.3), GTPS=105.9 (100.2 to 111.6), OA=100.3 (97.7 to 103.9), ASC=99.1 (94.7 to 103.5), (ANOVA: p=0.036). Multivariate analysis confirmed adiposity is associated with GTPS. CONCLUSION: A lower neck shaft angle is a risk factor for, and adiposity is associated with, GTPS in women. PMID- 22547564 TI - Usefulness of three-dimensional transthoracic echocardiography for the classification of congenital bicuspid aortic valve in children. AB - AIMS: Because the classification of congenital bicuspid aortic valve (BAV) is of importance to predict a possible valvular dysfunction, we sought to assess the feasibility, the reproducibility, and the accuracy of three-dimensional transthoracic echocardiography (3D-TTE) to accurately depict the morphology of the leaflets in a BAV. METHODS AND RESULTS: Seventy-two consecutive children, who were suspected of having a BAV on two-dimensional transthoracic echocardiography (2D-TTE), were included in this prospective study. 2D-TTE and 3D-TTE views of a BAV were recorded by the same investigator, and then were analysed separately by two confirmed paediatric cardiologists. For each of these two imaging techniques, the spatial position of cusps and raphes was noted for each patient. Intra observer concordance and inter-observer concordance were evaluated to assess the reproducibility of the techniques. Feasibility of 3D-TTE was 100%. Median acquisition time of 3D-TTE was 117 (98.5-176.8) s. Image quality seemed to be better with 3D-TTE compared with 2D-TTE. When using 3D-TTE, the diagnosis was reconsidered for 12 patients (17%). Only 44.4% of uncertain BAV cases identified by 2D-TTE were confirmed by 3D-TTE. Furthermore, 3D-TTE seems to provide a better visualization of the leaflet morphology, leading to reclassification for 34.4% (95% CI 22.9-47.3) of the patients. Agreement for the BAV classification between 2D-TTE and 3D-TTE was therefore moderate (kappa = 0.46). Both inter-observer concordance and intra-observer concordance were good (kappa = 0.91 and kappa = 0.93, respectively) for 3D-TTE. CONCLUSION: 3D-TTE is feasible and provides accurate description of a BAV in children. Compared with 2D-TTE, 3D-TTE seems to enable a better visualization of the structural geometry of the leaflets. PMID- 22547565 TI - What makes a chloroplast? Reconstructing the establishment of photosynthetic symbioses. AB - Earth is populated by an extraordinary diversity of photosynthetic eukaryotes. Many eukaryotic lineages contain chloroplasts, obtained through the endosymbiosis of a wide range of photosynthetic prokaryotes or eukaryotes, and a wide variety of otherwise non-photosynthetic species form transient associations with photosynthetic symbionts. Chloroplast lineages are likely to be derived from pre existing transient symbioses, but it is as yet poorly understood what steps are required for the establishment of permanent chloroplasts from photosynthetic symbionts. In the past decade, several species that contain relatively recently acquired chloroplasts, such as the rhizarian Paulinella chromatophora, and non photosynthetic taxa that maintain photosynthetic symbionts, such as the sacoglossan sea slug Elysia, the ciliate Myrionecta rubra and the dinoflagellate Dinophysis, have emerged as potential model organisms in the study of chloroplast establishment. In this Commentary, we compare recent molecular insights into the maintenance of chloroplasts and photosynthetic symbionts from these lineages, and others that might represent the early stages of chloroplast establishment. We emphasise the importance in the establishment of chloroplasts of gene transfer events that minimise oxidative stress acting on the symbiont. We conclude by assessing whether chloroplast establishment is facilitated in some lineages by a mosaic of genes, derived from multiple symbiotic associations, encoded in the host nucleus. PMID- 22547566 TI - Reactive oxygen and nitrogen species generation, antioxidant defenses, and beta cell function: a critical role for amino acids. AB - Growing evidence indicates that the regulation of intracellular reactive oxygen species (ROS) and reactive nitrogen species (RNS) levels is essential for maintaining normal beta-cell glucose responsiveness. While long-term exposure to high glucose induces oxidative stress in beta cells, conflicting results have been published regarding the impact of ROS on acute glucose exposure and their role in glucose stimulated insulin secretion (GSIS). Although beta cells are considered to be particularly vulnerable to oxidative damage, as they express relatively low levels of some peroxide-metabolizing enzymes such as catalase and glutathione (GSH) peroxidase, other less known GSH-based antioxidant systems are expressed in beta cells at higher levels. Herein, we discuss the key mechanisms of ROS/RNS production and their physiological function in pancreatic beta cells. We also hypothesize that specific interactions between RNS and ROS may be the cause of the vulnerability of pancreatic beta cells to oxidative damage. In addition, using a hypothetical metabolic model based on the data available in the literature, we emphasize the importance of amino acid availability for GSH synthesis and for the maintenance of beta-cell function and viability during periods of metabolic disturbance before the clinical onset of diabetes. PMID- 22547567 TI - Perspectives for metabolomics in testosterone replacement therapy. AB - Testosterone is the major circulating androgen in men but exhibits an age-related decline in the ageing male. Late-onset hypogonadism or androgen deficiency syndrome (ADS) is a 'syndromic' disorder including both a persistent low testosterone serum concentration and major clinical symptoms, including erectile dysfunction, low libido, decreased muscle mass and strength, increased body fat, decreased vitality or depressed mood. Given its unspecific symptoms, treatment goals and monitoring parameters, this review will outline the various uncertainties concerning the diagnosis, therapy and monitoring of ADS to date. Literature was identified primarily through searches for specific investigators in the PubMed database. No date or language limits were applied in the literature search for the present review. The current state of research, showing that metabolomics is starting to have an impact not only on disease diagnosis and prognosis but also on drug treatment efficacy and safety monitoring, will be presented, and the application of metabolomics to improve the clinical management of ADS will be discussed. Finally, the scientific opportunities presented by metabolomics and other -omics as novel and promising tools for biomarker discovery and individualised testosterone replacement therapy in men will be explored. PMID- 22547569 TI - Selective cleavage of human sex hormone-binding globulin by kallikrein-related peptidases and effects on androgen action in LNCaP prostate cancer cells. AB - Stimulation of the androgen receptor via bioavailable androgens, including testosterone and testosterone metabolites, is a key driver of prostate development and the early stages of prostate cancer. Androgens are hydrophobic and as such require carrier proteins, including sex hormone-binding globulin (SHBG), to enable efficient distribution from sites of biosynthesis to target tissues. The similarly hydrophobic corticosteroids also require a carrier protein whose affinity for steroid is modulated by proteolysis. However, proteolytic mechanisms regulating the SHBG/androgen complex have not been reported. Here, we show that the cancer-associated serine proteases, kallikrein-related peptidase (KLK)4 and KLK14, bind strongly to SHBG in glutathione S-transferase interaction analyses. Further, we demonstrate that active KLK4 and KLK14 cleave human SHBG at unique sites and in an androgen-dependent manner. KLK4 separated androgen-free SHBG into its two laminin G-like (LG) domains that were subsequently proteolytically stable even after prolonged digestion, whereas a catalytically equivalent amount of KLK14 reduced SHBG to small peptide fragments over the same period. Conversely, proteolysis of 5alpha-dihydrotestosterone (DHT)-bound SHBG was similar for both KLKs and left the steroid binding LG4 domain intact. Characterization of this proteolysis fragment by [(3)H]-labeled DHT binding assays revealed that it retained identical affinity for androgen compared with full-length SHBG (dissociation constant = 1.92 nM). Consistent with this, both full-length SHBG and SHBG-LG4 significantly increased DHT-mediated transcriptional activity of the androgen receptor compared with DHT delivered without carrier protein. Collectively, these data provide the first evidence that SHBG is a target for proteolysis and demonstrate that a stable fragment derived from proteolysis of steroid-bound SHBG retains binding function in vitro. PMID- 22547568 TI - Androgen effects on adipose tissue architecture and function in nonhuman primates. AB - The differential association of hypoandrogenism in men and hyperandrogenism in women with insulin resistance and obesity suggests that androgens may exert sex specific effects on adipose and other tissues, although the underlying mechanisms remain poorly understood. Moreover, recent studies also suggest that rodents and humans may respond differently to androgen imbalance. To achieve better insight into clinically relevant sex-specific mechanisms of androgen action, we used nonhuman primates to investigate the direct effects of gonadectomy and hormone replacement on white adipose tissue. We also employed a novel ex vivo approach that provides a convenient framework for understanding of adipose tissue physiology under a controlled tissue culture environment. In vivo androgen deprivation of males did not result in overt obesity or insulin resistance but did induce the appearance of very small, multilocular white adipocytes. Testosterone replacement restored normal cell size and a unilocular phenotype and stimulated adipogenic gene transcription and improved insulin sensitivity of male adipose tissue. Ex vivo studies demonstrated sex-specific effects of androgens on adipocyte function. Female adipose tissue treated with androgens displayed elevated basal but reduced insulin-dependent fatty acid uptake. Androgen stimulated basal uptake was greater in adipose tissue of ovariectomized females than in adipose tissue of intact females and ovariectomized females replaced with estrogen and progesterone in vivo. Collectively, these data demonstrate that androgens are essential for normal adipogenesis in males and can impair essential adipocyte functions in females, thus strengthening the experimental basis for sex specific effects of androgens in adipose tissue. PMID- 22547570 TI - Lxralpha regulates the androgen response in prostate epithelium. AB - Benign prostatic hyperplasia is a nonmalignant enlargement of the prostate that commonly occurs in older men. We show that liver X receptor (Lxr)-alpha knockout mice (lxralpha(-/-)) develop ventral prostate hypertrophy, correlating with an overaccumulation of secreted proteins in prostatic ducts and an alteration of vesicular trafficking in epithelial cells. In the fluid of the lxralpha(-/-) prostates, spermine binding protein is highly accumulated and shows a 3000-fold increase of its mRNA. This overexpression is mediated by androgen hypersensitivity in lxralpha(-/-) mice, restricted to the ventral prostate. Generation of chimeric recombinant prostates demonstrates that Lxralpha is involved in the establishment of the epithelial-mesenchymal interactions in the mouse prostate. Altogether these results point out the crucial role of Lxralpha in the homeostasis of the ventral prostate and suggest lxralpha(-/-) mice may be a good model to investigate the molecular mechanisms of benign prostatic hyperplasia. PMID- 22547571 TI - Color constancy investigated via partial hue-matching. AB - Each hue is believed to be made up of the four component hues (yellow, blue, red, and green). A hue consisting of just one component hue is called unitary (or unique). A new technique--partial hue-matching--has been used to reveal the component and unitary hues for a sample of 32 Munsell papers, which were illuminated by neutral, yellow, blue, green, and red lights and assessed by four normal trichromatic observers. The same set of four component hues has been found under both the neutral and the chromatic illuminations for all of the observers. On average, more than 87% of the papers containing a particular component hue under the neutral illumination also have this component hue when lit by the chromatic lights. However, only a quarter of the papers perceived as unitary under the neutral illumination continues being perceived as unitary under all of the chromatic illuminations. In other words, most unitary colors shift along the hue circle due to change in an illuminant's chromaticity. Still, this shift of unitary colors is relatively small: On average, it does not exceed one Munsell hue step. PMID- 22547574 TI - Prevalence of women's violent and nonviolent offending behavior: a comparison of self-reports, victims' reports, and third-party reports. AB - This study assessed women's violent and nonviolent offending, using data from two online student samples (men and women: n = 344), reporting on either being a perpetrator and witness (women) or being a victim and witness (men). A comprehensive measure of general violence, intimate partner violence (IPV), and nonviolent offending was collected. From women's self-reports, 59.9% reported perpetrating general violent offenses, 58.1% reported perpetrating IPV offenses and 85.6% reported perpetrating nonviolent offenses. Correlations showed that women were involved in a variety of offenses and demonstrated the interrelatedness of general violence and IPV, and of violent and nonviolent offenses. Regression analysis confirmed the close association between partner and general violence, and found that drug offenses were also related to the former and criminal damage to the latter. Overall, the prevalence data demonstrated women's involvement in all types of offending, and a similar pattern of offending was supported across data sources. Limitations of the sampling method and measures are discussed. PMID- 22547573 TI - Selected melanocortin 1 receptor single-nucleotide polymorphisms differentially alter multiple signaling pathways. AB - The melanocortin 1 receptor (MC1R) is a highly polymorphic G protein-coupled receptor, which is known to modulate pigmentation and inflammation. In the current study, we investigated the pharmacological effects of select single nucleotide polymorphisms (SNPs) (V60L, R163Q, and F196L). After transient expression of MC1Rs in human embryonic kidney 293 cells, basal and ligand-induced cAMP signaling and mitogen-activated protein kinase (MAPK) activation were assessed by using luciferase reporter gene assays and Western blot analysis, respectively. All receptor variants showed decreased basal cAMP activity. With the V60L and F196L variants, the decrease in constitutive activity was attributable, at least in part, to a reduction in surface expression. The F196L variant also displayed a significant reduction in potency for both the peptide agonist alpha-melanocyte-stimulating hormone (alpha-MSH) and the small-molecule agonist 1-[1-(3-methyl-L-histidyl-O-methyl-D-tyrosyl)-4-phenyl-4-piperidinyl]-1 butanone (BMS-470539). In MAPK signaling assays, the F196L variant showed decreased phospho-extracellular signal-regulated kinase levels after stimulation with either alpha-MSH or BMS-470539. In contrast, the R163Q variant displayed a selective loss of alpha-MSH-induced MAPK activation; whereas responsiveness to the small-molecule agonist BMS-470539 was preserved. Further assessment of MC1R variants in A549 cells, an in vitro model of inflammation, revealed an enhanced inflammatory response resulting from expression of the F196L variant (versus the wild-type MC1R). This alteration in function was restored by treatment with BMS 470539. Overall, these studies illustrate novel signaling profiles linked to distinct MC1R SNPs. Furthermore, our investigations highlight the potential for small-molecule drugs to rescue the function of MC1R variants that show reduced basal and/or alpha-MSH stimulated activity. PMID- 22547572 TI - Modulation of purinergic neuromuscular transmission by phorbol dibutyrate is independent of protein kinase C in murine urinary bladder. AB - Parasympathetic control of murine urinary bladder consists of contractile components mediated by both muscarinic and purinergic receptors. Using intracellular recording techniques, the purinergic component of transmission was measured as both evoked excitatory junctional potentials (EJPs) in response to electrical field stimulation and spontaneous events [spontaneous EJPs (sEJPs)]. EJPs, but not sEJPs, were abolished by the application of the Na(+) channel blocker tetrodotoxin and the Ca(2+) channel blocker Cd(2+). Both EJPs and sEJPs were abolished by the application of the P2X(1) antagonist 8,8' [carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino)]bis 1,3,5-naphthalenetrisulfonic acid hexasodium salt (NF279). Application of phorbol dibutyrate (PDBu) increased electrically evoked EJP amplitudes with no effect on mean sEJP amplitudes. Similar increases in EJP amplitudes were produced by PDBu in the presence of either the nonselective protein kinase inhibitor staurosporine or the specific protein kinase C (PKC) inhibitor 2-[1-(3 dimethylaminopropyl)indol-3-yl]-3-(indol-3-yl) maleimide (GF109203X). These results suggest that PDBu increases the purinergic component of detrusor transmission through increasing neurogenic ATP release via a PKC-independent mechanism. PMID- 22547575 TI - A qualitative examination of ethical and legal considerations regarding dating violence. AB - Despite the increased attention to dating violence among adolescents and young adults, limited information is available on ethical and legal considerations specific to this population. Therefore, this qualitative study explores 21 trainees' and practitioners' conceptualization of ethical and legal issues pertaining to adolescent dating violence. Data are collected through focus groups included as part of an ethics and legal issues seminar. Six themes are identified to illustrate ethical and legal issues concerning dating violence: knowledge, client welfare, counseling interventions, informed consent and disclosure, barriers, and counselor reactions. PMID- 22547577 TI - Tumor-derived tissue factor activates coagulation and enhances thrombosis in a mouse xenograft model of human pancreatic cancer. AB - Cancer patients often have an activated clotting system and are at increased risk for venous thrombosis. In the present study, we analyzed tissue factor (TF) expression in 4 different human pancreatic tumor cell lines for the purpose of producing derivative tumors in vivo. We found that 2 of the lines expressed TF and released TF-positive microparticles (MPs) into the culture medium. The majority of TF protein in the culture medium was associated with MPs. Only TF positive cell lines activated coagulation in nude mice, and this activation was abolished by an anti-human TF Ab. Of the 2 TF-positive lines, only one produced detectable levels of human MP TF activity in the plasma when grown orthotopically in nude mice. Surprisingly, < 5% of human TF protein in plasma from tumor-bearing mice was associated with MPs. Mice with TF-positive tumors and elevated levels of circulating TF-positive MPs had increased thrombosis in a saphenous vein model. In contrast, we observed no difference in thrombus weight between tumor-bearing and control mice in an inferior vena cava stenosis model. The results of the present study using a xenograft mouse model suggest that tumor TF activates coagulation, whereas TF on circulating MPs may trigger venous thrombosis. PMID- 22547578 TI - Expression of COX-2 on Reed-Sternberg cells is an independent unfavorable prognostic factor in Hodgkin lymphoma treated with ABVD. AB - Cyclooxygenase 2 (COX-2) is an inflammatory enzyme involved in the pathogenesis and prognosis of several malignancies. In the present study, we investigated the prognostic value of COX-2 expression in a large (N = 242), uniformly treated Hodgkin lymphoma (HL) population from the Spanish Network of HL using tissue microarrays. Univariate and multivariate analysis was done, including comparing the most recognized clinical variables: the early- and advanced-stage subgroups. COX-2 was expressed on Reed-Sternberg cells in 37% of patients. There were no differences in the distribution of clinical variables according to COX-2 expression. With a median follow-up time of 58 months, PFS at 5 years was 60% and 79% for COX-2(+) and COX-2(-) patients, respectively (P = .003). The overall survival was 73% and 91%, respectively (P < .001). The major impact on prognosis was observed in the early AA stage (I-II) group. In fact, in these low-risk groups the expression of COX-2 defined a group with significantly worse progression-free and overall survival. In conclusion, COX-2 was expressed on Reed Sternberg cells in one-third of HL patients and was a major independent, unfavorable prognostic factor in early-stage HL. We conclude that COX-2 may be a major prognostic variable in HL and a potential therapeutic target. PMID- 22547579 TI - Infusion of hemolyzed red blood cells within peripheral blood stem cell grafts in patients with and without sickle cell disease. AB - Peripheral blood stem cell (PBSC) infusions are associated with complications such as elevated blood pressure and decreased creatinine clearance. Patients with sickle cell disease experience similar manifestations, and some have postulated release of plasma-free hemoglobin with subsequent nitric oxide consumption as causative. We sought to evaluate whether the infusion of PBSC grafts containing lysed red blood cells (RBCs) leads to the toxicity observed in transplant subjects. We report a prospective cohort study of 60 subjects divided into 4 groups based on whether their infusions contained dimethyl sulfoxide (DMSO) and lysed RBCs, no DMSO and fresh RBCs, DMSO and no RBCs, or saline. Our primary end point, change in maximum blood pressure compared with baseline, was not significantly different among groups. Tricuspid regurgitant velocity and creatinine levels also did not differ significantly among groups. Our data do not support free hemoglobin as a significant contributor to toxicity associated with PBSC infusions. This study was registered at clinicaltrials.gov (NCT00631787). PMID- 22547580 TI - Beyond Hox: the role of ParaHox genes in normal and malignant hematopoiesis. AB - During the past decade it was recognized that homeobox gene families such as the clustered Hox genes play pivotal roles both in normal and malignant hematopoiesis. More recently, similar roles have also become apparent for members of the ParaHox gene cluster, evolutionarily closely related to the Hox gene cluster. This is in particular found for the caudal-type homeobox genes (Cdx) genes, known to act as upstream regulators of Hox genes. The CDX gene family member CDX2 belongs to the most frequent aberrantly expressed proto-oncogenes in human acute leukemias and is highly leukemogenic in experimental models. Correlative studies indicate that CDX2 functions as master regulator of perturbed HOX gene expression in human acute myeloid leukemia, locating this ParaHox gene at a central position for initiating and maintaining HOX gene dysregulation as a driving leukemogenic force. There are still few data about potential upstream regulators initiating aberrant CDX2 expression in human leukemias or about critical downstream targets of CDX2 in leukemic cells. Characterizing this network will hopefully open the way to therapeutic approaches that target deregulated ParaHox genes in human leukemia. PMID- 22547581 TI - How I treat POEMS syndrome. AB - POEMS syndrome is a paraneoplastic syndrome whose acronym stands for less than half of the defining features of the disease, that is, polyradiculoneuropathy, organomegaly, potentially including coexisting Castleman disease, endocrinopathy, monoclonal plasma cell neoplasm, and skin changes. The other important features include papilledema, extravascular volume overload, sclerotic bone lesions, thrombocytosis, elevated VEGF, and abnormal pulmonary function. The diagnosis is based on having both the polyradiculoneuropathy and the monoclonal plasma cell disorder, and at least 1 of the other 3 major criteria (Castleman disease, sclerotic bone lesions, or elevated VEGF) and at least one minor criterion. The diagnosis is often delayed with intervening incorrect diagnoses of chronic inflammatory demyelinating polyradiculoneuropathy, myeloproliferative disorder, and monoclonal gammopathy of undetermined significance. Prompt treatment directed at the underlying plasma cell clone produces dramatic responses in the majority of patients. Although there are no randomized clinical trial data to direct best therapy, for patients with disseminated disease, high-dose chemotherapy with peripheral blood transplantation has yielded durable benefit, whereas radiation therapy is typically effective for patients with a more localized presentation. More universal recognition of and more scientific inquiry into the underpinnings of the disease will provide direction toward the best treatment strategies in the future. PMID- 22547582 TI - Multiple inhibitory ligands induce impaired T-cell immunologic synapse function in chronic lymphocytic leukemia that can be blocked with lenalidomide: establishing a reversible immune evasion mechanism in human cancer. AB - Cancer immune evasion is an emerging hallmark of disease progression. We have demonstrated previously that impaired actin polymerization at the T-cell immunologic synapse is a global immune dysfunction in chronic lymphocytic leukemia (CLL). Direct contact with tumor cells induces defective actin polarization at the synapse in previously healthy T cells, but the molecules mediating this dysfunction were not known. In the present study, we show via functional screening assays that CD200, CD270, CD274, and CD276 are coopted by CLL cells to induce impaired actin synapse formation in both allogeneic and autologous T cells. We also show that inhibitory ligand-induced impairment of T cell actin dynamics is a common immunosuppressive strategy used by both hematologic (including lymphoma) and solid carcinoma cells. This immunosuppressive signaling targets T-cell Rho-GTPase activation. Of clinical relevance, the immunomodulatory drug lenalidomide prevented the induction of these defects by down-regulating tumor cell-inhibitory molecule expression. These results using human CLL as a model cancer establish a novel evasion mechanism whereby malignant cells exploit multiple inhibitory ligand signaling to down regulate small GTPases and lytic synapse function in global T-cell populations. These findings should contribute to the design of immunotherapeutic strategies to reverse T-cell tolerance in cancer. PMID- 22547584 TI - Aberrant mural cell recruitment to lymphatic vessels and impaired lymphatic drainage in a murine model of pulmonary fibrosis. AB - Pulmonary fibrosis is a progressive disease with unknown etiology that is characterized by extensive remodeling of the lung parenchyma, ultimately resulting in respiratory failure. Lymphatic vessels have been implicated with the development of pulmonary fibrosis, but the role of the lymphatic vasculature in the pathogenesis of pulmonary fibrosis remains enigmatic. Here we show in a murine model of pulmonary fibrosis that lymphatic vessels exhibit ectopic mural coverage and that this occurs early during the disease. The abnormal lymphatic vascular patterning in fibrotic lungs was driven by expression of platelet derived growth factor B (PDGF-B) in lymphatic endothelial cells and signaling through platelet-derived growth factor receptor (PDGFR)-beta in associated mural cells. Because of impaired lymphatic drainage, aberrant mural cell coverage fostered the accumulation of fibrogenic molecules and the attraction of fibroblasts to the perilymphatic space. Pharmacologic inhibition of the PDGF B/PDGFR-beta signaling axis disrupted the association of mural cells and lymphatic vessels, improved lymphatic drainage of the lung, and prevented the attraction of fibroblasts to the perilymphatic space. Our results implicate aberrant mural cell recruitment to lymphatic vessels in the pathogenesis of pulmonary fibrosis and that the drainage capacity of pulmonary lymphatics is a critical mediator of fibroproliferative changes. PMID- 22547583 TI - Unexpected frequency of Upshaw-Schulman syndrome in pregnancy-onset thrombotic thrombocytopenic purpura. AB - Pregnancy may be complicated by a rare but life-threatening disease called thrombotic thrombocytopenic purpura (TTP). Most cases of TTP are due to an acquired autoimmune or hereditary (Upshaw-Schulman syndrome [USS]) severe deficiency of a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS13). In the present study, we performed a cross sectional analysis of the national registry of the French Reference Center for Thrombotic Microangiopathies from 2000-2010 to identify all women who were pregnant at their initial TTP presentation. Among 592 adulthood-onset TTP patients with a severe ADAMTS13 deficiency, 42 patients with a pregnancy-onset TTP were included. Surprisingly, the proportion of USS patients (n = 10 of 42 patients [24%]; confidence interval, 13%-39%) with pregnancy-onset TTP was much higher than that in adulthood-onset TTP in general (less than 5%) and was mostly related to a cluster of ADAMTS13 variants. In the present study, subsequent pregnancies in USS patients not given prophylaxis were associated with very high TTP relapse and abortion rates, whereas prophylactic plasmatherapy was beneficial for both the mother and the baby. Pregnancy-onset TTP defines a specific subgroup of patients with a strong genetic background. This study was registered at www.clinicaltrials.gov as number NCT00426686 and at the Health Authority, French Ministry of Health, as number P051064. PMID- 22547585 TI - Tissue-specific differentiation of a circulating CCR9- pDC-like common dendritic cell precursor. AB - The ontogenic relationship between the common dendritic cell (DC) progenitor (CDP), the committed conventional DC precursor (pre-cDC), and cDC subpopulations in lymphoid and nonlymphoid tissues has been largely unraveled. In contrast, the sequential steps of plasmacytoid DC (pDC) development are less defined, and it is unknown at which developmental stage and location final commitment to the pDC lineage occurs. Here we show that CCR9(-) pDCs from murine BM which enter the circulation and peripheral tissues have a common DC precursor function in vivo in the steady state, in contrast to CCR9(+) pDCs which are terminally differentiated. On adoptive transfer, the fate of CCR9(-) pDC-like precursors is governed by the tissues they enter. In the BM and liver, most transferred CCR9(-) pDC-like precursors differentiate into CCR9(+) pDCs, whereas in peripheral lymphoid organs, lung, and intestine, they additionally give rise to cDCs. CCR9( ) pDC-like precursors which are distinct from pre-cDCs can be generated from the CDP. Thus, CCR9(-) pDC-like cells are novel CDP-derived circulating DC precursors with pDC and cDC potential. Their final differentiation into functionally distinct pDCs and cDCs depends on tissue-specific factors allowing adaptation to local requirements under homeostatic conditions. PMID- 22547586 TI - Men's health: intricately linked in a symbiotic relationship manner. PMID- 22547587 TI - Method to our madness or madness in our methods? Pitfalls in trial methodology. PMID- 22547588 TI - New International Society of Pediatric Oncology Boston Ototoxicity Grading Scale for pediatric oncology: still room for improvement. PMID- 22547589 TI - Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. AB - PURPOSE: This phase I study evaluated elotuzumab, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma (MM). PATIENTS AND METHODS: Three cohorts were enrolled and treated with elotuzumab (5.0, 10, or 20 mg/kg intravenously) on days 1, 8, 15, and 22 of a 28-day cycle in the first two cycles, and days 1 and 15 of each subsequent cycle; lenalidomide 25 mg orally [PO] on days 1 to 21; and dexamethasone 40 mg PO weekly. Dose-limiting toxicities (DLTs) were assessed during cycle 1 of each cohort, and clinical responses were evaluated during each cycle. The first five patients received up to six cycles of therapy; subsequent patients were treated until disease progression. RESULTS: Twenty-nine patients with advanced MM and a median of three prior MM therapies were enrolled; 28 patients were treated, three each in the 5.0-mg/kg and 10-mg/kg cohorts and 22 in the 20-mg/kg cohort. No DLTs were observed up to the maximum proposed dose of 20 mg/kg. The most frequent grade 3 to 4 toxicities were neutropenia (36%) and thrombocytopenia (21%). Two patients experienced a serious infusion reaction (one grade 4 anaphylactic reaction and one grade 3 stridor) during the first treatment cycle. Objective responses were obtained in 82% (23 of 28) of treated patients. After a median of 16.4 months follow-up, the median time to progression was not reached for patients in the 20-mg/kg cohort who were treated until disease progression. CONCLUSION: The combination of elotuzumab, lenalidomide, and low-dose dexamethasone was generally well tolerated and showed encouraging response rates in patients with relapsed or refractory MM. PMID- 22547590 TI - Donor-derived fat tissue as a source for lipofilling after allogeneic hematopoietic cell transplantation. PMID- 22547591 TI - Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non small-cell lung cancer: final results of a phase III trial. AB - PURPOSE: This phase III trial compared the efficacy and safety of albumin-bound paclitaxel (nab-paclitaxel) plus carboplatin with solvent-based paclitaxel (sb paclitaxel) plus carboplatin in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: In all, 1,052 untreated patients with stage IIIB to IV NSCLC were randomly assigned 1:1 to receive 100 mg/m(2) nab-paclitaxel weekly and carboplatin at area under the concentration-time curve (AUC) 6 once every 3 weeks (nab-PC) or 200 mg/m(2) sb-paclitaxel plus carboplatin AUC 6 once every 3 weeks (sb-PC). The primary end point was objective overall response rate (ORR). RESULTS: On the basis of independent assessment, nab-PC demonstrated a significantly higher ORR than sb-PC (33% v 25%; response rate ratio, 1.313; 95% CI, 1.082 to 1.593; P = .005) and in patients with squamous histology (41% v 24%; response rate ratio, 1.680; 95% CI, 1.271 to 2.221; P < .001). nab-PC was as effective as sb-PC in patients with nonsquamous histology (ORR, 26% v 25%; P = .808). There was an approximately 10% improvement in progression-free survival (median, 6.3 v 5.8 months; hazard ratio [HR], 0.902; 95% CI, 0.767 to 1.060; P = .214) and overall survival (OS; median, 12.1 v 11.2 months; HR, 0.922; 95% CI, 0.797 to 1.066; P = .271) in the nab-PC arm versus the sb-PC arm, respectively. Patients >= 70 years old and those enrolled in North America showed a significantly increased OS with nab-PC versus sb-PC. Significantly less grade >= 3 neuropathy, neutropenia, arthralgia, and myalgia occurred in the nab-PC arm, and less thrombocytopenia and anemia occurred in the sb-PC arm. CONCLUSION: The administration of nab-PC as first-line therapy in patients with advanced NSCLC was efficacious and resulted in a significantly improved ORR versus sb-PC, achieving the primary end point. nab-PC produced less neuropathy than sb-PC. PMID- 22547592 TI - Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double blind, multicenter phase II study. AB - PURPOSE: Ipilimumab, which is an anti-cytotoxic T-cell lymphocyte-4 monoclonal antibody, showed a survival benefit in melanoma with adverse events (AEs) managed by protocol-defined guidelines. A phase II study in lung cancer assessed the activity of ipilimumab plus paclitaxel and carboplatin. PATIENTS AND METHODS: Patients (N = 204) with chemotherapy-naive non-small-cell lung cancer (NSCLC) were randomly assigned 1:1:1 to receive paclitaxel (175 mg/m(2)) and carboplatin (area under the curve, 6) with either placebo (control) or ipilimumab in one of the following two regimens: concurrent ipilimumab (four doses of ipilimumab plus paclitaxel and carboplatin followed by two doses of placebo plus paclitaxel and carboplatin) or phased ipilimumab (two doses of placebo plus paclitaxel and carboplatin followed by four doses of ipilimumab plus paclitaxel and carboplatin).Treatment was administered intravenously every 3 weeks for <= 18 weeks (induction). Eligible patients continued ipilimumab or placebo every 12 weeks as maintenance therapy. Response was assessed by using immune-related response criteria and modified WHO criteria. The primary end point was immune related progression-free survival (irPFS). Other end points were progression-free survival (PFS), best overall response rate (BORR), immune-related BORR (irBORR), overall survival (OS), and safety. RESULTS: The study met its primary end point of improved irPFS for phased ipilimumab versus the control (hazard ratio [HR], 0.72; P = .05), but not for concurrent ipilimumab (HR, 0.81; P = .13). Phased ipilimumab also improved PFS according to modified WHO criteria (HR, 0.69; P = .02). Phased ipilimumab, concurrent ipilimumab, and control treatments were associated with a median irPFS of 5.7, 5.5, and 4.6 months, respectively, a median PFS of 5.1, 4.1, and 4.2 months, respectively, an irBORR of 32%, 21% and 18%, respectively, a BORR of 32%, 21% and 14%, respectively, and a median OS of 12.2, 9.7, and 8.3 months. Overall rates of grade 3 and 4 immune-related AEs were 15%, 20%, and 6% for phased ipilimumab, concurrent ipilimumab, and the control, respectively. Two patients (concurrent, one patient; control, one patient) died from treatment-related toxicity. CONCLUSION: Phased ipilimumab plus paclitaxel and carboplatin improved irPFS and PFS, which supports additional investigation of ipilimumab in NSCLC. PMID- 22547593 TI - Gender disparities in patients with melanoma: breaking the glass ceiling. PMID- 22547594 TI - Superior outcome of women with stage I/II cutaneous melanoma: pooled analysis of four European Organisation for Research and Treatment of Cancer phase III trials. AB - PURPOSE: Several studies observed a female advantage in the prognosis of cutaneous melanoma, for which behavioral factors or an underlying biologic mechanism might be responsible. Using complete and reliable follow-up data from four phase III trials of the European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group, we explored the female advantage across multiple end points and in relation to other important prognostic indicators. PATIENTS AND METHODS: Patients diagnosed with localized melanoma were included in EORTC adjuvant treatment trials 18832, 18871, 18952, and 18961 and randomly assigned during the period of 1984 to 2005. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% CIs for women compared with men, adjusted for age, Breslow thickness, body site, ulceration, performed lymph node dissection, and treatment. RESULTS: A total of 2,672 patients with stage I/II melanoma were included. Women had a highly consistent and independent advantage in overall survival (adjusted HR, 0.70; 95% CI, 0.59 to 0.83), disease-specific survival (adjusted HR, 0.74; 95% CI, 0.62 to 0.88), time to lymph node metastasis (adjusted HR, 0.70; 95% CI, 0.51 to 0.96), and time to distant metastasis (adjusted HR, 0.69; 95% CI, 0.59 to 0.81). Subgroup analysis showed that the female advantage was consistent across all prognostic subgroups (with the possible exception of head and neck melanomas) and in pre- and postmenopausal age groups. CONCLUSION: Women have a consistent and independent relative advantage in all aspects of the progression of localized melanoma of approximately 30%, most likely caused by an underlying biologic sex difference. PMID- 22547595 TI - Chromosomal instability (CIN) phenotype, CIN high or CIN low, predicts survival for colorectal cancer. AB - PURPOSE: To examine whether chromosomal instability (CIN) phenotype, determined by the severity of CIN, can predict survival for stages II and III colorectal cancer (CRC). PATIENTS AND METHODS: We determined microsatellite instability (MSI) and loss of heterozygosity (LOH) status in 1,103 patients (training [n = 845] and validation [n = 258] sets with stages II and III CRC). The LOH ratio was defined as the frequency of LOH in chromosomes 2p, 5q, 17p, and 18q. According to the LOH ratio, non-MSI high tumors were classified as CIN high (LOH ratio >= 33%) or CIN low (LOH ratio < 33%). CIN-high tumors were subclassified as CIN high (mild type; LOH ratio < 75%) or CIN high (severe type; LOH ratio >= 75%). We used microarrays to identify a gene signature that could classify the CIN phenotype and evaluated its ability to predict prognosis. RESULTS: CIN high showed the worst survival (P < .001), whereas there was no significant difference between CIN low and MSI high. CIN high (severe type) showed poorer survival than CIN high (mild type; P < .001). Multivariate analysis revealed that CIN phenotype was an independent risk factor for disease-free and overall survival, respectively, in both the training (P < .001 and P = .0155) and validation sets (P < .001 and P = .0076). Microarray analysis also revealed that survival was significantly poorer in those with the CIN-high than in the CIN-low gene signature (P = .0203). In a validation of 290 independent CRCs (GSE14333), the CIN-high gene signature showed significantly poorer survival than the CIN-low signature (P = .0047). CONCLUSION: The CIN phenotype is a predictive marker for survival and may be used to select high-risk patients with stages II and III CRC. PMID- 22547596 TI - Panobinostat in patients with relapsed/refractory Hodgkin's lymphoma after autologous stem-cell transplantation: results of a phase II study. AB - PURPOSE: Hodgkin's lymphoma (HL) has no standard of care for patients who are relapsed or refractory to autologous stem-cell transplantation (ASCT). This phase II study examined safety and activity of panobinostat in this population. PATIENTS AND METHODS: Panobinostat 40 mg was administered orally three times per week. The primary end point was objective response rate (ORR) based on investigator assessment of radiologic imaging. Secondary end points included ORR by independent central review, time to response (TTR), duration of response (DOR), progression-free survival (PFS), overall survival, and safety. Exploratory biomarker analyses were performed. RESULTS: The 129 treated patients (median age, 32 years; range, 18 to 75 years) were heavily pretreated with a median of four (range, two to seven) prior systemic regimens, and 41% did not respond to the regimen immediately preceding panobinostat. Tumor reductions occurred in 96 patients (74%). Objective response was achieved by 35 patients (27%), including 30 (23%) partial responses and five (4%) complete responses. The median TTR was 2.3 months, median DOR was 6.9 months, and median PFS was 6.1 months. The estimated 1-year overall survival rate was 78%. Common nonhematologic adverse events (AEs)-diarrhea, nausea, vomiting, and fatigue-were generally grade 1 and 2. Most common grade 3 and 4 hematologic AEs-thrombocytopenia, anemia, and neutropenia-were manageable. Early reductions in thymus and activation-regulated chemokine were observed in patients achieving complete or partial response. CONCLUSION: In the largest, prospective, multicenter, international trial conducted in heavily pretreated patients with HL who relapsed or were refractory to ASCT, panobinostat monotherapy demonstrated antitumor activity, resulting in durable responses. PMID- 22547597 TI - Under-representation of older adults in cancer registration trials: known problem, little progress. PMID- 22547598 TI - Clinical impact of NOTCH1 and/or FBXW7 mutations, FLASH deletion, and TCR status in pediatric T-cell lymphoblastic lymphoma. AB - PURPOSE: Pediatric T-cell lymphoblastic lymphomas (T-LBL) are commonly treated on T-cell acute lymphoblastic leukemia (T-ALL) -derived protocols. Therapeutic stratification based on response to the prephase treatment and on minimal residual disease assessment is well established in T-ALL but is not easy to extrapolate to T-LBL. The identification of molecular prognostic markers at diagnosis in T-LBL could provide an alternative for early therapeutic stratification. Our study determines the frequency and prognostic value of NOTCH1/FBXW7 mutations (N/F(mut)), FLASH deletion at chromosome 6q, and TCR rearrangements in a prospective cohort of pediatric T-LBL. PATIENTS AND METHODS: Pathologic samples were obtained at diagnosis for 54 patients treated according to the EuroLB02 protocol in France. N/F(mut) were identified by direct sequencing and allelic dosage was used to detect FLASH and TCRgamma deletions, which were interpreted in conjunction with TCRgamma, TCRbeta, and TCRdelta rearrangements. RESULTS: N/F(mut) were found in 55% of T-LBL patients, in whom they were associated with improved event-free survival (P < .01) and overall survival (P < .01). FLASH monoallelic deletions were observed in 18% of patients; they were predominantly N/F wild-type (six of nine) and tended to be of inferior prognosis (P = .09). Absence of biallelic TCRgamma deletion (ABD) was seen in 7%, all of which were N/F(mut) and identified a poor prognosis group (P = .02). On multivariate analysis of N/F(mut), TCRgamma ABD, and FLASH deletion, only N/F(mut) was an independent factor for good prognosis. CONCLUSION: Mutational status of NOTCH1/FBXW7 represents a promising marker for early therapeutic stratification in pediatric T-LBL. PMID- 22547599 TI - Exploring the benefits of early access to palliative care in advanced lung cancer: living better, living longer, or both? PMID- 22547600 TI - Long-term analysis of the IFM 99 trials for myeloma: cytogenetic abnormalities [t(4;14), del(17p), 1q gains] play a major role in defining long-term survival. AB - PURPOSE: In multiple myeloma, many prognostic parameters have been proposed. However, all of these predict shorter survival. To identify patients with a longer life expectancy, we updated the data of patients treated in the IFM (Intergroupe Francophone du Myelome) 99-02 and 99-04 trials. PATIENTS AND METHODS: A series of 520 patients was analyzed. Median follow-up was 90.5 months. To perform a comprehensive analysis of the major prognostic factors, we reanalyzed all patients for 1q gains [in addition to updating del(13), t(4;14), and del(17p) analyses]. RESULTS: It was possible to identify a subgroup of patients (representing 20% of total patients) with an 8-year survival of 75%. These patients were defined by the absence of t(4;14), del(17p), and 1q gain and beta(2)-microglobulin less than 5.5 mg/L. CONCLUSION: We propose that all patients with newly diagnosed multiple myeloma be evaluated for these three chromosomal changes, not only to define high-risk patients but also to identify those with a longer life expectancy. PMID- 22547601 TI - CS1-directed monoclonal antibody therapy for multiple myeloma. PMID- 22547602 TI - Treatment outcomes in black and white children with cancer: results from the SEER database and St Jude Children's Research Hospital, 1992 through 2007. AB - PURPOSE: Treatment outcome for black patients with cancer has been significantly worse than for their white counterparts. We determined whether recent improved treatment had narrowed the gap in outcome between black and white pediatric patients. PATIENTS AND METHODS: In a parallel comparison, we analyzed survival by disease category between black and white patients with childhood cancer registered in one of the 17 cancer registries of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program or treated at St Jude Children's Research Hospital, which provides comprehensive treatment to all patients regardless of their ability to pay, from 1992 to 2000 and from 2001 to 2007. RESULTS: Analysis of the SEER data indicated that in both study periods, black patients had significantly poorer rates of survival than did white patients, with the exception of a few types of cancer. Despite significantly improved treatment outcomes for patients who were treated from 2001 to 2007, the racial difference in survival has actually widened for acute myeloid leukemia and neuroblastoma. By contrast, in the cohorts treated at St Jude Children's Research Hospital, there were no significant differences in survival between black and white patients in either study period, regardless of the cancer type. Importantly, the outcome of treatment for acute lymphoblastic leukemia, acute myeloid leukemia, and retinoblastoma has improved in parallel for both races during the most recent study period. CONCLUSION: With equal access to comprehensive treatment, black and white children with cancer can achieve the same high cure rates. PMID- 22547603 TI - Platinum-induced ototoxicity in children: a consensus review on mechanisms, predisposition, and protection, including a new International Society of Pediatric Oncology Boston ototoxicity scale. AB - PURPOSE: The platinum chemotherapy agents cisplatin and carboplatin are widely used in the treatment of adult and pediatric cancers. Cisplatin causes hearing loss in at least 60% of pediatric patients. Reducing cisplatin and high-dose carboplatin ototoxicity without reducing efficacy is important. PATIENTS AND METHODS: This review summarizes recommendations made at the 42nd Congress of the International Society of Pediatric Oncology (SIOP) in Boston, October 21-24, 2010, reflecting input from international basic scientists, pediatric oncologists, otolaryngologists, oncology nurses, audiologists, and neurosurgeons to develop and advance research and clinical trials for otoprotection. RESULTS: Platinum initially impairs hearing in the high frequencies and progresses to lower frequencies with increasing cumulative dose. Genes involved in drug transport, metabolism, and DNA repair regulate platinum toxicities. Otoprotection can be achieved by acting on several these pathways and generally involves antioxidant thiol agents. Otoprotection is a strategy being explored to decrease hearing loss while maintaining dose intensity or allowing dose escalation, but it has the potential to interfere with tumoricidal effects. Route of administration and optimal timing relative to platinum therapy are critical issues. In addition, international standards for grading and comparing ototoxicity are essential to the success of prospective pediatric trials aimed at reducing platinum-induced hearing loss. CONCLUSION: Collaborative prospective basic and clinical trial research is needed to reduce the incidence of irreversible platinum-induced hearing loss, and optimize cancer control. Wide use of the new internationally agreed-on SIOP Boston ototoxicity scale in current and future otoprotection trials should help facilitate this goal. PMID- 22547604 TI - Phase I pharmacologic and pharmacodynamic study of the gamma secretase (Notch) inhibitor MK-0752 in adult patients with advanced solid tumors. AB - PURPOSE: Aberrant Notch signaling has been implicated in the pathogenesis of many human cancers. MK-0752 is a potent, oral inhibitor of gamma-secretase, an enzyme required for Notch pathway activation. Safety, maximum-tolerated dose, pharmacokinetics (PKs), pharmacodynamics, and preliminary antitumor efficacy were assessed in a phase I study of MK-0752. PATIENTS AND METHODS: MK-0752 was administered in three different schedules to patients with advanced solid tumors. Hair follicles were collected at higher dose levels to assess a gene signature of Notch inhibition. RESULTS: Of 103 patients who received MK-0752, 21 patients received a continuous once-daily dosing at 450 and 600 mg; 17 were dosed on an intermittent schedule of 3 of 7 days at 450 and 600 mg; and 65 were dosed once per week at 600, 900, 1,200, 1,500, 1,800, 2,400, 3,200, and 4,200 mg. The most common drug-related toxicities were diarrhea, nausea, vomiting, and fatigue. PKs (area under the concentration-time curve and maximum measured plasma concentration) increased in a less than dose proportional manner, with a half life of approximately 15 hours. Significant inhibition of Notch signaling was observed with the 1,800- to 4,200-mg weekly dose levels, confirming target engagement at those doses. One objective complete response and an additional 10 patients with stable disease longer than 4 months were observed among patients with high-grade gliomas. CONCLUSION: MK-0752 toxicity was schedule dependent. Weekly dosing was generally well tolerated and resulted in strong modulation of a Notch gene signature. Clinical benefit was observed, and rational combination trials are currently ongoing to maximize clinical benefit with this novel agent. PMID- 22547605 TI - Randomized phase II trial of erlotinib alone or with carboplatin and paclitaxel in patients who were never or light former smokers with advanced lung adenocarcinoma: CALGB 30406 trial. AB - PURPOSE: Erlotinib is clinically effective in patients with non-small-cell lung cancer (NSCLC) who have adenocarcinoma, are never or limited former smokers, or have EGFR mutant tumors. We investigated the efficacy of erlotinib alone or in combination with chemotherapy in patients with these characteristics. PATIENTS AND METHODS: Patients with advanced NSCLC (adenocarcinoma) who were epidermal growth factor receptor tyrosine kinase inhibitor and chemotherapy naive never or light former smokers (smokers of > 100 cigarettes and <= 10 pack years and quit >= 1 year ago) were randomly assigned to continuous erlotinib or in combination with carboplatin and paclitaxel (ECP) for six cycles followed by erlotinib alone. The primary end point was progression-free survival (PFS). Tissue collection was mandatory. RESULTS: PFS was similar (5.0 v 6.6 months; P = .1988) in patients randomly assigned to erlotinib alone (arm A; n = 81) or to ECP (arm B; n = 100). EGFR mutation analysis was possible in 91% (164 of 181) of patients, and EGFR mutations were detected in 40% (51 of 128) of never smokers and in 42% (15 of 36) of light former smokers. In arm A, response rate (70% v 9%), PFS (14.1 v 2.6 months), and overall survival (OS; 31.3 v 18.1 month) favored EGFR-mutant patients. In arm B, response rate (73% v 30%), PFS (17.2 v 4.8 months), and OS (38.1 v 14.4 months) favored EGFR-mutant patients. Incidence of grades 3 to 4 hematologic (2% v 49%; P < .001) and nonhematologic (24% v 52%; P < .001) toxicity was greater in patients treated with ECP. CONCLUSION: Erlotinib and erlotinib plus chemotherapy have similar efficacy in clinically selected populations of patients with advanced NSCLC. EGFR mutations identify patients most likely to benefit. PMID- 22547606 TI - Polyendocrine treatment in estrogen receptor-positive breast cancer: a "FACT" yet to be proven. PMID- 22547607 TI - Deferasirox reduces serum ferritin and labile plasma iron in RBC transfusion dependent patients with myelodysplastic syndrome. AB - PURPOSE: This 3-year, prospective, multicenter trial assessed the safety and efficacy of deferasirox in low- or intermediate-1-risk myelodysplastic syndrome (MDS). PATIENTS AND METHODS: Eligible patients had serum ferritin >= 1,000 MUg/L and had received >= 20 units of RBCs with ongoing transfusion requirements. The starting dose of deferasirox was 20 mg/kg/d, with dose escalation up to 40 mg/kg/d permitted. RESULTS: A total of 176 patients were enrolled, and 173 patients received therapy. Median serum ferritin decreased 23% in the 53% of patients who completed 12 months of treatment (n = 91), 36.7% in patients who completed 2 years (n = 49), and 36.5% in patients who completed 3 years (n = 33) despite continued transfusion requirement. Reduction in serum ferritin significantly correlated with ALT improvement (P < .001). Labile plasma iron (LPI) was measured quarterly during the first year of the study. Sixty-eight patients (39.3%) had elevated LPI at baseline. By week 13, LPI levels normalized in all patients with abnormal baseline level. Fifty-one (28%) of 173 patients experienced hematologic improvement by International Working Group 2006 criteria; of these, only seven patients received growth factors or MDS therapy. Over the 3 year study, 138 (79.8%) of 173 patients discontinued therapy, 43 patients (24.8%) because of adverse events or disease progression and 23 patients (13.2%) because of abnormal laboratory values. The most common drug-related adverse events were gastrointestinal disturbances and increased serum creatinine. There were 28 deaths, none of which were considered related to deferasirox. CONCLUSION: Deferasirox reduces serum ferritin and LPI in transfusion-dependent patients with MDS. A subset of patients had an improvement in hematologic and hepatic parameters. PMID- 22547608 TI - Pulmonary sarcoid-like granulomatosis induced by ipilimumab. PMID- 22547609 TI - Her wedding. PMID- 22547610 TI - Autologous and allogeneic stem-cell transplantation for transformed chronic lymphocytic leukemia (Richter's syndrome): A retrospective analysis from the chronic lymphocytic leukemia subcommittee of the chronic leukemia working party and lymphoma working party of the European Group for Blood and Marrow Transplantation. AB - PURPOSE: Patients with Richter's syndrome (RS) have a poor prognosis with conventional chemotherapy. The aim of this study was to evaluate the outcome after autologous stem-cell transplantation (autoSCT) or allogeneic stem-cell transplantation (alloSCT) in RS. PATIENTS AND METHODS: A survey was sent to all European Group for Blood and Marrow Transplantation centers assessing transplantations performed for RS. Eligibility criteria included a diagnosis of RS or secondary lymphoma before SCT, age >= 18 years, and SCT performed from 1997 to 2007. Data were analyzed by descriptive statistics and methods from survival analysis. RESULTS: Fifty-nine patients were registered. Thirty-four patients had received autoSCT, mostly because of chemotherapy-sensitive disease, and 25 had received alloSCT, with 36% being refractory to chemotherapy at SCT. In 18 allograft recipients (72%), reduced-intensity conditioning (RIC) was used. Three year estimates of the probabilities of overall survival and relapse-free survival (RFS) and the cumulative incidences of relapse and nonrelapse mortality were 36%, 27%, 47%, and 26% for alloSCT and 59%, 45%, 43%, and 12% for autoSCT, respectively. Taking into account the limitations set by the low number of events and age younger than 60 years, chemotherapy-sensitive disease and RIC were found to be associated with superior RFS after alloSCT in multivariate analysis. Factors with a significant impact on autoSCT could not be identified. CONCLUSION: Patients with RS who are sensitive to induction chemotherapy appear to benefit from consolidation with transplantation strategies, and prolonged survival was observed in a proportion of patients. PMID- 22547611 TI - Brentuximab vedotin and panobinostat: new drugs for Hodgkin's lymphoma--can they make one of medical oncology's chemotherapy success stories more successful? PMID- 22547612 TI - Artemisinin-derived dimer diphenyl phosphate is an irreversible inhibitor of human cytomegalovirus replication. AB - We previously reported that among a series of artemisinin-derived monomers and dimers, dimer diphenyl phosphate (838) was the most potent inhibitor of human cytomegalovirus (CMV) replication. Our continued investigation of a prototypic artemisinin monomer (artesunate [AS]) and dimer (838) now reveals that both compounds have specific activity against CMV but do not inhibit lytic replication of human herpesvirus 1 or 2 or Epstein-Barr virus. AS and 838 inhibited CMV replication during the first 24 h of the virus replication cycle, earlier than the time of ganciclovir (GCV) activities and prior to DNA synthesis. Neither compound inhibited virus entry. Quantification of DNA replication and virus yield revealed a similar level of inhibition by GCV, but AS and 838 had a 10-fold higher inhibition of virus yield than of DNA replication, suggesting that artemisinins could inhibit CMV through multiple steps: a predominant early inhibition and possibly an additional step following DNA replication. During the strong early CMV inhibition, the transcription of immediate-early genes was not significantly downregulated, and viral protein expression was reduced only after 48 h. AS and GCV were reversible CMV inhibitors, but the inhibition of CMV replication by 838 was irreversible. Combinations of GCV and 838 as well as GCV and AS were highly synergistic. Finally, treatment with 838, but not AS, prior to CMV infection demonstrated strong anti-CMV activity. These findings illustrate the unique activities of dimer 838, including early and irreversible CMV inhibition, possibly by tight binding to its target. PMID- 22547613 TI - HDQ, a potent inhibitor of Plasmodium falciparum proliferation, binds to the quinone reduction site of the cytochrome bc1 complex. AB - The mitochondrial bc(1) complex is a multisubunit enzyme that catalyzes the transfer of electrons from ubiquinol to cytochrome c coupled to the vectorial translocation of protons across the inner mitochondrial membrane. The complex contains two distinct quinone-binding sites, the quinol oxidation site of the bc(1) complex (Q(o)) and the quinone reduction site (Q(i)), located on opposite sides of the membrane within cytochrome b. Inhibitors of the Q(o) site such as atovaquone, active against the bc(1) complex of Plasmodium falciparum, have been developed and formulated as antimalarial drugs. Unfortunately, single point mutations in the Q(o) site can rapidly render atovaquone ineffective. The development of drugs that could circumvent cross-resistance with atovaquone is needed. Here, we report on the mode of action of a potent inhibitor of P. falciparum proliferation, 1-hydroxy-2-dodecyl-4(1H)quinolone (HDQ). We show that the parasite bc(1) complex--from both control and atovaquone-resistant strains- is inhibited by submicromolar concentrations of HDQ, indicating that the two drugs have different targets within the complex. The binding site of HDQ was then determined by using a yeast model. Introduction of point mutations into the Q(i) site, namely, G33A, H204Y, M221Q, and K228M, markedly decreased HDQ inhibition. In contrast, known inhibitor resistance mutations at the Q(o) site did not cause HDQ resistance. This study, using HDQ as a proof-of-principle inhibitor, indicates that the Q(i) site of the bc(1) complex is a viable target for antimalarial drug development. PMID- 22547614 TI - Bactericidal activity of ACH-702 against nondividing and biofilm Staphylococci. AB - Many bacterial infections involve slow or nondividing bacterial growth states and localized high cell densities. Antibiotics with demonstrated bactericidal activity rarely remain bactericidal at therapeutic concentrations under these conditions. The isothiazoloquinolone (ITQ) ACH-702 is a potent, bactericidal compound with activity against many antibiotic-resistant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). We evaluated its bactericidal activity under conditions where bacterial cells were not dividing and/or had slowed their growth. Against S. aureus cultures in stationary phase, ACH-702 showed concentration-dependent bactericidal activity and achieved a 3-log-unit reduction in viable cell counts within 6 h of treatment at >= 16* MIC values; in comparison, the bactericidal quinolone moxifloxacin and the additional comparator compounds vancomycin, linezolid, and rifampin at 16* to 32* MICs showed little or no bactericidal activity against stationary-phase cells. ACH-702 at 32* MIC retained bactericidal activity against stationary-phase S. aureus across a range of inoculum densities. ACH-702 did not kill cold-arrested cells yet remained bactericidal against cells arrested by protein synthesis inhibitors, suggesting that its bactericidal activity against nondividing cells requires active metabolism but not de novo protein synthesis. ACH-702 also showed a degree of bactericidal activity at 16* MIC against S. epidermidis biofilm cells that was superior to that of moxifloxacin, rifampin, and vancomycin. The bactericidal activity of ACH-702 against stationary-phase staphylococci and biofilms suggests potential clinical utility in infections containing cells in these physiological states. PMID- 22547615 TI - Systematic analysis of metallo-beta-lactamases using an automated database. AB - Metallo-beta-lactamases (MBLs) are enzymes that hydrolyze beta-lactam antibiotics, resulting in bacterial resistance to these drugs. These proteins have caused concerns due to their facile transference, broad substrate spectra, and the absence of clinically useful inhibitors. To facilitate the classification, nomenclature, and analysis of MBLs, an automated database system was developed, the Metallo-beta-Lactamase Engineering Database (MBLED) (http://www.mbled.uni-stuttgart.de). It contains information on MBLs retrieved from the NCBI peptide database while strictly following the nomenclature by Jacoby and Bush (http://www.lahey.org/Studies/) and the generally accepted class B beta-lactamase (BBL) standard numbering scheme for MBLs. The database comprises 597 MBL protein sequences and enables systematic analyses of these sequences. A systematic analysis employing the database resulted in the generation of mutation profiles of assigned IMP- and VIM-type MBLs, the identification of five MBL protein entries from the NCBI peptide database that were inconsistent with the Jacoby and Bush nomenclature, and the identification of 15 new IMP candidates and 9 new VIM candidates. Furthermore, the database was used to identify residues with high mutation frequencies and variability (mutation hot spots) that were unexpectedly distant from the active site located in the betabeta sandwich: positions 208 and 266 in the IMP family and positions 215 and 258 in the VIM family. We expect that the MBLED will be a valuable tool for systematically cataloguing and analyzing the increasing number of MBLs being reported. PMID- 22547616 TI - Impact of cefepime therapy on mortality among patients with bloodstream infections caused by extended-spectrum-beta-lactamase-producing Klebsiella pneumoniae and Escherichia coli. AB - Extended-spectrum-beta-lactamase (ESBL)-producing pathogens are associated with extensive morbidity and mortality and rising health care costs. Scant data exist on the impact of antimicrobial therapy on clinical outcomes in patients with ESBL bloodstream infections (BSI), and no large studies have examined the impact of cefepime therapy. A retrospective 3-year study was performed at the Detroit Medical Center on adult patients with BSI due to ESBL-producing Klebsiella pneumoniae or Escherichia coli. Data were collected from the medical records of study patients at five hospitals between January 2005 and December 2007. Multivariate analysis was performed using logistic regression. One hundred forty five patients with BSI due to ESBL-producing pathogens, including K. pneumoniae (83%) and E. coli (16.5%), were studied. The mean age of the patients was 66 years. Fifty-one percent of the patients were female, and 79.3% were African American. Fifty-three patients (37%) died in the hospital, and 92 survived to discharge. In bivariate analysis, the variables associated with mortality (P < 0.05) were presence of a rapidly fatal condition at the time of admission, use of gentamicin as a consolidative therapeutic agent, and presence of one or more of the following prior to culture date: mechanical ventilation, stay in the intensive care unit (ICU), and presence of a central venous catheter. In multivariate analysis, the predictors of in-hospital mortality included stay in the intensive care unit (odds ratio [OR], 2.17; 95% confidence interval [CI], 0.98 to 4.78), presence of a central-line catheter prior to positive culture (OR, 2.33; 95% CI, 0.77 to 7.03), presence of a rapidly fatal condition at the time of admission (OR, 5.13; 95% CI, 2.13 to 12.39), and recent prior hospitalization (OR, 1.92; 95% CI, 0.83 to 4.09). When carbapenems were added as empirical therapy to the predictor model, there was a trend between empirical carbapenem therapy and decreased mortality (OR, 0.61; 95% CI, 0.26 to 1.50). When added to the model, receipt of empirical cefepime alone (n = 43) was associated with increased mortality, although this association did not reach statistical significance (OR, 1.66; 95% CI, 0.71 to 3.87). The median length of hospital stay was shorter for patients receiving empirical cefepime than for those receiving empirical or consolidated carbapenem therapy. In multivariate analysis, empirical therapy with cefepime for BSI due to an ESBL-producing pathogen was associated with a trend toward an increased mortality risk and empirical carbapenem therapy was associated with a trend toward decreased mortality risk. PMID- 22547618 TI - Function of cytochrome P450 enzymes MycCI and MycG in Micromonospora griseorubida, a producer of the macrolide antibiotic mycinamicin. AB - The cytochrome P450 enzymes MycCI and MycG are encoded within the mycinamicin biosynthetic gene cluster and are involved in the biosynthesis of mycinamicin II (a 16-membered macrolide antibiotic produced by Micromonospora griseorubida). Based on recent enzymatic studies, MycCI is characterized as the C-21 methyl hydroxylase of mycinamicin VIII, while MycG is designated multifunctional P450, which catalyzes hydroxylation and also epoxidation at C-14 and C-12/13 on the macrolactone ring of mycinamicin. Here, we confirm the functions of MycCI and MycG in M. griseorubida. Protomycinolide IV and mycinamicin VIII accumulated in the culture broth of the mycCI disruption mutant; moreover, the mycCI gene fragment complemented the production of mycinamicin I and mycinamicin II, which are produced as major mycinamicins by the wild strain M. griseorubida A11725. The mycG disruption mutant did not produce mycinamicin I and mycinamicin II; however, mycinamicin IV accumulated in the culture broth. The mycG gene was located immediately downstream of the self-resistance gene myrB. The mycG gene under the control of mycGp complemented the production of mycinamicin I and mycinamicin II. Furthermore, the amount of mycinamicin II produced by the strain complemented with the mycG gene under the control of myrBp was approximately 2-fold higher than that produced by the wild strain. In M. griseorubida, MycG recognized mycinamicin IV, mycinamicin V, and also mycinamicin III as the substrates. Moreover, it catalyzed hydroxylation and also epoxidation at C-14 and C-12/13 on these intermediates. However, C-14 on mycinamicin I was not hydroxylated. PMID- 22547617 TI - In vitro activity of ertapenem versus ceftriaxone against Neisseria gonorrhoeae isolates with highly diverse ceftriaxone MIC values and effects of ceftriaxone resistance determinants: ertapenem for treatment of gonorrhea? AB - Clinical resistance to the currently recommended extended-spectrum cephalosporins (ESCs), the last remaining treatment options for gonorrhea, is being reported. Gonorrhea may become untreatable, and new treatment options are crucial. We investigated the in vitro activity of ertapenem, relative to ceftriaxone, against N. gonorrhoeae isolates and the effects of ESC resistance determinants on ertapenem. MICs were determined using agar dilution technique or Etest for international reference strains (n = 17) and clinical N. gonorrhoeae isolates (n = 257), which included the two extensively drug-resistant (XDR) strains H041 and F89 and additional isolates with high ESC MICs, clinical ESC resistance, and other types of clinical high-level and multidrug resistance (MDR). Genetic resistance determinants for ESCs (penA, mtrR, and penB) were sequenced. In general, the MICs of ertapenem (MIC(50) = 0.032 MUg/ml; MIC(90) = 0.064 MUg/ml) paralleled those of ceftriaxone (MIC(50) = 0.032 MUg/ml; MIC(90) = 0.125 MUg/ml). The ESC resistance determinants mainly increased the ertapenem MIC and ceftriaxone MIC at similar levels. However, the MIC ranges for ertapenem (0.002 to 0.125 MUg/ml) and ceftriaxone (<0.002 to 4 MUg/ml) differed, and the four (1.5%) ceftriaxone-resistant isolates (MIC = 0.5 to 4 MUg/ml) had ertapenem MICs of 0.016 to 0.064 MUg/ml. Accordingly, ertapenem had in vitro advantages over ceftriaxone for isolates with ceftriaxone resistance. These in vitro results suggest that ertapenem might be an effective treatment option for gonorrhea, particularly for the currently identified ESC-resistant cases and possibly in a dual antimicrobial therapy regimen. However, further knowledge regarding the genetic determinants (and their evolution) conferring resistance to both antimicrobials, and clear correlates between genetic and phenotypic laboratory parameters and clinical treatment outcomes, is essential. PMID- 22547619 TI - Heme protein and hydroxyarginase necessary for biosynthesis of D-cycloserine. AB - We have recently cloned a D-cycloserine (DCS) biosynthetic gene cluster that consists of 10 genes, designated dcsA~dcsJ, from Streptomyces lavendulae ATCC 11924 (16). In the predicted pathway of hydroxyurea (HU) formation in DCS biosynthesis, L-arginine (L-Arg) must first be hydroxylated, prior to the hydrolysis of N(omega)-hydroxy-L-arginine (NHA) by DcsB, an arginase homolog. The hydroxylation of L-Arg is known to be catalyzed by nitric oxide synthase (NOS). In this study, to verify the supply route of HU, we created a dcsB-disrupted mutant, DeltadcsB. While the mutant lost DCS productivity, its productivity was restored by complementation of dcsB, and also by the addition of HU but not NHA, suggesting that HU is supplied by DcsB. A NOS-encoding gene, nos, from S. lavendulae chromosome was cloned, to create a nos-disrupted mutant. However, the mutant maintained the DCS productivity, suggesting that NOS is not necessary for DCS biosynthesis. To clarify the identity of an enzyme necessary for NHA formation, a dcsA-disrupted mutant, designated DeltadcsA, was also created. The mutant lost DCS productivity, whereas the DCS productivity was restored by complementation of dcsA. The addition of NHA to the culture medium of DeltadcsA mutant was also effective to restore DCS production. These results indicate that the dcsA gene product, DcsA, is an enzyme essential to generate NHA as a precursor in the DCS biosynthetic pathway. Spectroscopic analyses of the recombinant DcsA revealed that it is a heme protein, supporting an idea that DcsA is an enzyme catalyzing hydroxylation. PMID- 22547620 TI - RmtF, a new member of the aminoglycoside resistance 16S rRNA N7 G1405 methyltransferase family. AB - Multidrug-resistant clinical isolate Klebsiella pneumoniae BM4686 was highly resistant to 4,6-disubstituted 2-deoxystreptamines and to fortimicin. Resistance was due to the presence, on the 40-kb non-self-transferable plasmid pIP849, of the rmtF gene which was cotranscribed with the upstream aac(6')-Ib gene. The deduced RmtF protein had 25 to 46% identity with members of the N7 G1405 family of aminoglycoside resistance 16S rRNA methyltransferases. PMID- 22547621 TI - Characterization of a transmissible plasmid encoding VEB-1 and VIM-1 in Proteus mirabilis. PMID- 22547622 TI - Decline and rise of the antimicrobial susceptibility of Streptococcus pneumoniae isolated from middle ear fluid in children: influence of changes in circulating serotypes. AB - Changes in the antimicrobial susceptibility of Streptococcus pneumoniae causing otitis media were studied in 916 isolates from children <5 years old between 1999 and 2010 in a region of northern Spain. The rate of antimicrobial resistance decreased between the period before the introduction of the heptavalent pneumococcal conjugate vaccine (from 1999 to 2001) and the period from 2005 to 2007. However, in 2008 to 2010, resistance rates increased again due to the spread of serotype 19A, especially the multidrug-resistant ST320 and ST276 clones. PMID- 22547623 TI - Rifapentine is not more active than rifampin against chronic tuberculosis in guinea pigs. AB - Rifamycins are key sterilizing drugs in the current treatment of active tuberculosis (TB). Daily dosing of rifapentine (P), a potent rifamycin with high intracellular accumulation, in place of rifampin (R) in the standard antitubercular regimen significantly shortens the duration of treatment needed to prevent relapse in a murine model of active TB. We undertook the current study to compare directly the activities of human-equivalent doses of P and R in a guinea pig model of chronic TB, in which bacilli are predominantly extracellular within human-like necrotic granulomas. Hartley strain guinea pigs were aerosol infected with ~200 bacilli of Mycobacterium tuberculosis H37Rv, and treatment given 5 days/week was initiated 6 weeks later. R at 100 mg/kg of body weight and P at 100 mg/kg were given orally alone or in combination with isoniazid (H) at 60 mg/kg and pyrazinamide (Z) at 300 mg/kg. Culture-positive relapse was assessed in subgroups of guinea pigs after completion of 1 and 2 months of treatment. Human equivalent doses of R and P showed equivalent bactericidal activity when used alone and in combination therapy. In guinea pigs treated with rifampin, isoniazid, and pyrazinamide (RHZ) or PHZ, microbiological relapse occurred in the lungs of 8/10 animals treated for 1 month and in 0/10 animals treated for 2 months. Substitution of P for R in the standard antitubercular regimen did not shorten the time to cure in this guinea pig model of chronic TB. Data from ongoing clinical trials comparing the activity of these two drugs are awaited to determine the relevance of the guinea pig TB model in preclinical drug screening. PMID- 22547624 TI - HIV-1 tropism evolution after short-term maraviroc monotherapy in HIV-1-infected patients. AB - We analyzed the evolution of viral tropism after 8 days of maraviroc monotherapy, i.e., we used the maraviroc clinical test (MCT), in 21 patients with and 14 without virological response to the drug (MCT(+) and MCT(-) patients, respectively). No increases in CXCR4 inferred viral loads (X4IVLs) were observed in MCT(+) patients, while X4IVLs increased only in MCT(-) patients, with X4IVLs of >2 log(10) HIV RNA copies/ml. These results shed light on the evolution of viral tropism under a CCR5 antagonist in vivo. PMID- 22547625 TI - In vitro antiviral characteristics of HIV-1 attachment inhibitor BMS-626529, the active component of the prodrug BMS-663068. AB - BMS-663068 is the phosphonooxymethyl prodrug of BMS-626529, a novel small molecule attachment inhibitor that targets HIV-1 gp120 and prevents its binding to CD4(+) T cells. The activity of BMS-626529 is virus dependent, due to heterogeneity within gp120. In order to better understand the anti-HIV-1 spectrum of BMS-626529 against HIV-1, in vitro activities against a wide variety of laboratory strains and clinical isolates were determined. BMS-626529 had half maximal effective concentration (EC(50)) values of <10 nM against the vast majority of viral isolates; however, susceptibility varied by >6 log(10), with half-maximal effective concentration values in the low pM range against the most susceptible viruses. The in vitro antiviral activity of BMS-626529 was generally not associated with either tropism or subtype, with few exceptions. Measurement of the binding affinity of BMS-626529 for purified gp120 suggests that a contributory factor to its inhibitory potency may be a relatively long dissociative half-life. Finally, in two-drug combination studies, BMS-626529 demonstrated additive or synergistic interactions with antiretroviral drugs of different mechanistic classes. These results suggest that BMS-626529 should be active against the majority of HIV-1 viruses and support the continued clinical development of the compound. PMID- 22547626 TI - Mouse model for efficacy testing of antituberculosis agents via intrapulmonary delivery. AB - Here we describe an experimental murine model that allows for aerosolized antituberculosis drug efficacy testing. Intrapulmonary aerosol delivery of isoniazid, capreomycin, and amikacin to mice with pulmonary infection of Mycobacterium tuberculosis demonstrated efficacy in reducing pulmonary bacterial loads similar to that seen by standard drug delivery methods, even when lower concentrations of drugs and fewer doses were used in the aerosolized drug regimens. Interestingly, intrapulmonary delivery of isoniazid also reduced the bacterial load in the spleen. PMID- 22547627 TI - Colistin distribution in the peritoneal fluid of a patient with severe peritonitis. PMID- 22547628 TI - The order Bacillales hosts functional homologs of the worrisome cfr antibiotic resistance gene. AB - The cfr gene encodes the Cfr methyltransferase that methylates a single adenine in the peptidyl transferase region of bacterial ribosomes. The methylation provides resistance to several classes of antibiotics that include drugs of clinical and veterinary importance. This paper describes a first step toward elucidating natural residences of the worrisome cfr gene and functionally similar genes. Three cfr-like genes from the order Bacillales were identified from BLAST searches and cloned into plasmids under the control of an inducible promoter. Expression of the genes was induced in Escherichia coli, and MICs for selected antibiotics indicate that the cfr-like genes confer resistance to PhLOPSa (phenicol, lincosamide, oxazolidinone, pleuromutilin, and streptogramin A) antibiotics in the same way as the cfr gene. In addition, modification at A2503 on 23S rRNA was confirmed by primer extension. Finally, expression of the Cfr like proteins was verified by SDS gel electrophoresis of whole-cell extracts. The work shows that cfr-like genes exist in the environment and that Bacillales are natural residences of cfr-like genes. PMID- 22547629 TI - Validation of the rapid fluorescent focus inhibition test for rabies virus neutralizing antibodies in clinical samples. AB - Monoclonal antibodies are successful biologics in treating a variety of diseases, including the prevention or treatment of viral infections. CL184 is a 1:1 combination of two human monoclonal IgG1 antibodies (CR57 and CR4098) against rabies virus, produced in the PER.C6 human cell line. The two antibodies are developed as replacements of human rabies immune globulin (HRIG) and equine rabies immune globulin (ERIG) in postexposure prophylaxis (PEP). The rapid fluorescent focus inhibition test (RFFIT) is a cell-based virus neutralization assay which is usually performed to determine the biological potency of a vaccine and to measure the levels of protection against rabies in humans and animals. In order to confirm the suitability of this assay as a pharmacodynamic assay, we conducted a validation using both HRIG- and CL184-spiked serum samples and sera from vaccinated donors. The validation results met all analytical acceptance criteria and showed that HRIG and CL184 serum concentrations can be compared. Stability experiments showed that serum samples were stable in various suboptimal conditions but that rabies virus should be handled swiftly once thawed. We concluded that the assay is suitable for the measurement of polyclonal and monoclonal rabies neutralizing antibodies in clinical serum samples. PMID- 22547630 TI - Physical activity and body mass index and their associations with the development of type 2 diabetes in korean men. AB - The authors examined the independent and combined associations of physical activity and obesity with incident type 2 diabetes among 675,496 Korean men from the database of the National Health Insurance Corporation. During an average follow-up of 7.5 years (1996-2005), 52,995 men developed type 2 diabetes. Men with overweight, obese I, and obese II classifications had 1.47, 2.05, and 3.69 times higher risk of type 2 diabetes, respectively, compared with normal weight men, and men with low, medium, and high activity had 5%, 10%, and 9% lower risk of type 2 diabetes, respectively, compared with inactive men after adjustment for confounders and physical activity or body mass index for each other. Overweight and obesity were detrimental within all activity categories, and meeting the activity recommendations (medium and high activity) was beneficial at all body mass index levels. Meeting the activity recommendations appeared to attenuate some negative effects of overweight or obesity, and the increased risk of type 2 diabetes due to inactivity was lower in normal weight men. Both preventing overweight or obesity and increasing physical activity are important to reduce the global epidemic of type 2 diabetes, regardless of body weight and activity levels. PMID- 22547631 TI - Data-based theoretical identification of subcellular calcium compartments and estimation of calcium dynamics in cardiac myocytes. AB - In cardiac cells, Ca(2+) release flux (J(rel)) via ryanodine receptors (RyRs) from the sarcoplasmic reticulum (SR) has a complex effect on the action potential (AP). Coupling between J(rel) and the AP occurs via L-type Ca(2+) channels (I(Ca)) and the Na(+)/Ca(2+) exchanger (I(NCX)). We used a combined experimental and modelling approach to study interactions between J(rel), I(Ca) and I(NCX) in porcine ventricular myocytes.We tested the hypothesis that during normal uniform J(rel), the interaction between these fluxes can be represented as occurring in two myoplasmic subcompartments for Ca(2+) distribution, one (T-space) associated with RyR and enclosed by the junctional portion of the SR membrane and corresponding T-tubular portion of the sarcolemma, the other (M-space) encompassing the rest of the myoplasm. I(Ca) and I(NCX) were partitioned into subpopulations in the T-space and M-space sarcolemma. We denoted free Ca(2+) concentrations in T-space and M-space Ca(t) and Ca(m), respectively. Experiments were designed to allow separate measurements of I(Ca) and I(NCX) as a function of J(rel). Inclusion of T-space in themodel allowed us to reproduce in silico the following important experimental results: (1) hysteresis of I(NCX) dependence on Ca(m); (2) delay between peak I(NCX) and peak Ca(m) during caffeine application protocol; (3) delay between I(NCX) and Ca(m) during Ca(2+)-induced-Ca(2+) release; (4) rapid I(Ca) inactivation (within 2 ms) due to J(rel), with magnitude graded as a function of the SR Ca(2+) content; (5) time delay between I(Ca) inactivation due to J(rel) and Ca(m). Partition of 25% NCX in T-space and 75% in M-space provided the best fit to the experimental data. Measured Ca(m) and I(Ca) or I(NCX) were used as input to the model for estimating Ca(t). The actual model computed Ca(t), obtained by simulating specific experimental protocols, was used as a gold standard for comparison. The model predicted peak Ca(t) in the range of 6-25 MUM, with time to equilibrium of Ca(t) with Ca(m) of ~350 ms. These Ca(t) values are in the range of LCC and RyR sensitivity to Ca(2+). An increase of the SR Ca(2+) load increased the time to equilibrium. The I(Ca)-based estimation method was most accurate during the ascending phase of Ca(t). The I(NCX)-based method provided a good estimate for the descending phase of Ca(t). Thus, application of both methods in combination provides the best estimate of the entire Ca(t) time course. PMID- 22547632 TI - Differential regulation of the InsP3 receptor type-1 and -2 single channel properties by InsP3, Ca2+ and ATP. AB - An elevation of intracellular Ca2+ levels as a result of InsP3 receptor (InsP3R) activity represents a ubiquitous signalling pathway controlling a wide variety of cellular events. InsP3R activity is tightly controlled by the levels of the primary ligands, InsP3, Ca2+ and ATP. Importantly, InsP3Rs are regulated by Ca2+ i in a biphasic manner. Ca2+ release through all InsP3R family members is also modulated dramatically by ATP, albeit with sub-type-specific properties. To ascertain if a common mechanism can account for ATP and Ca2+ regulation of these InsP3R family members, we examined the effects of [ATP] on the Ca2+ dependency of rat InsP3R-1 (rInsP3R-1) and mouse InsP3R-2 (mInsP3R-2) activity expressed in DT40-3KO cells. We used the on-nucleus patch clamp recording technique with various [ATP], [InsP3] and [Ca2+] in the patch pipette and measured single InsP3R channel activity in stably transfected DT40 cells. Under identical conditions, at saturating [InsP3] and [ATP], the activity of rInsP3R-1 and mInsP3R-2 was essentially identical in terms of single channel conductance, maximal achievable open probability (Po) and the [Ca2+] required for activation and inhibition of activity. However, in contrast to rInsP3R-1 at saturating [InsP3], the activity of mInsP3R-2 was unaffected by [ATP]. At lower [InsP3], ATP had dramatic effects on mInsP3R-2 Po, but unlike the rInsP3R-1, this did not occur by altering the relative Ca2+ dependency, but by simply increasing the maximally achievable Po at a particular [InsP3] and [Ca2+]. [InsP3] did not alter the biphasic regulation of activity by Ca2+ in either rInsP3R-1 or mInsP3R-2. Analysis of the single channel kinetics indicated that Ca2+ and ATP modulate the Po predominately by facilitating extended bursting activity of the channel but the underlying biophysical mechanism appears to be distinct for each receptor. Subtype-specific regulation of InsP3R channel activity probably contributes to the fidelity of Ca2+ signalling in cells expressing these receptor subtypes. PMID- 22547633 TI - Human phase response curve to a 1 h pulse of bright white light. AB - The phase resetting response of the human circadian pacemaker to light depends on the timing of exposure and is described by a phase response curve (PRC). The current study aimed to construct a PRC for a 1 h exposure to bright white light (~8000 lux) and to compare this PRC to a <3 lux dim background light PRC. These data were also compared to a previously completed 6.7 h bright white light PRC and a <15 lux dim background light PRC constructed under similar conditions. Participants were randomized for exposure to 1 h of either bright white light (n=18) or <3 lux dim background light (n=18) scheduled at 1 of 18 circadian phases. Participants completed constant routine (CR) procedures in dim light (<3 lux) before and after the light exposure to assess circadian phase. Phase shifts were calculated as the difference in timing of dim light melatonin onset (DLMO) during pre- and post-stimulus CRs. Exposure to 1 h of bright white light induced a Type 1 PRC with a fitted peak-to-trough amplitude of 2.20 h. No discernible PRC was observed in the <3 lux dim background light PRC. The fitted peak-to-trough amplitude of the 1 h bright light PRC was ~40% of that for the 6.7 h PRC despite representing only 15% of the light exposure duration, consistent with previous studies showing a non-linear duration-response function for the effects of light on circadian resetting. PMID- 22547634 TI - 'Autonomic conflict': a different way to die during cold water immersion? AB - Cold water submersion can induce a high incidence of cardiac arrhythmias in healthy volunteers. Submersion and the release of breath holding can activate two powerful and antagonistic responses: the 'cold shock response' and the 'diving response'. The former involves the activation of a sympathetically driven tachycardia while the latter promotes a parasympathetically mediated bradycardia. We propose that the strong and simultaneous activation of the two limbs of the autonomic nervous system ('autonomic conflict') may account for these arrhythmias and may, in some vulnerable individuals, be responsible for deaths that have previously wrongly been ascribed to drowning or hypothermia. In this review, we consider the evidence supporting this claim and also hypothesise that other environmental triggers may induce autonomic conflict and this may be more widely responsible for sudden death in individuals with other predisposing conditions. PMID- 22547635 TI - Plasticity of spatial hearing: behavioural effects of cortical inactivation. AB - The cerebral cortex plays a critical role in perception and in learning-induced plasticity. We show that reversibly silencing any of the main regions of auditory cortex impairs the ability of adult ferrets to localize sound, with the largest deficit seen after deactivating the primary fields. Although these animals had no trouble localizing longer sound bursts, their performance dropped considerably when auditory spatial cues were altered by occluding one ear with an earplug. In contrast to control ferrets, which recovered their localization abilities with intensive training, adaptation to an earplug was impaired following cortical inactivation, with the greatest disruption in plasticity observed after silencing higher-level cortical areas. These findings imply regional differences in the processing of spatial information across the auditory cortex. PMID- 22547636 TI - Motor-cortical oscillations in early stages of Parkinson's disease. AB - Pathophysiological changes in basal ganglia-thalamo-cortical circuits are well established in idiopathic Parkinson's disease (PD). However, it remains open whether such alterations already occur at early stages representing a characteristic neurophysiological marker of PD. Therefore, the present study aims at elucidating changes of synchronised oscillatory activity in early PD patients. In this study, we performed whole-head magnetoencephalography (MEG) in a resting condition and during steady state contraction of the more severely affected forearm in 10 drug-naive, de novo patients, in 10 early-stage patients with chronic medication and in 10 age-matched control subjects. While cortico-muscular coherence (CMC) did not differ between groups, patients showed increased sensori motor cortical power at beta frequency (13-30 Hz) during rest as well as during isometric contraction compared to controls. In healthy control subjects the power of the contralateral hemisphere was significantly suppressed during isometric contraction. By contrast, both hemispheres were activated equally strongly in de novo patients. In medicated patients, the pattern was found to be reversed. Contralateral beta power was significantly correlated with motor impairment during isometric contraction but not during rest. The present results suggest that the reduced ability of the primary motor cortex to disengage from increased beta band oscillations during the execution of movements is an early marker of PD. PMID- 22547638 TI - Changes and advancements in the state-of-the-art that continue to benefit patients. PMID- 22547637 TI - Surface fluid absorption and secretion in small airways. AB - Native small airways must remain wet enough to be pliable and support ciliary clearance, but dry enough to remain patent for gas flow. The airway epithelial lining must both absorb and secrete ions to maintain a critical level of fluid on its surface. Despite frequent involvement in lung diseases, the minuscule size has limited studies of peripheral airways. To meet this challenge, we used a capillary to construct an Ussing chamber (area <1 mm(2)) to measure electrolyte transport across small native airways (~1 mm o) from pig lung. Transepithelial potentials (V(t)) were recorded in open circuit conditions while applying constant current pulses across the luminal surface of dissected airways to calculate transepithelial electrical conductance (G(t)) and equivalent short circuit current (I(eq)(sc)) in the presence and absence of selected Na(+) and Cl( ) transport inhibitors (amiloride, GlyH-101, Niflumic acid) and agonists (Forskolin + IBMX, UTP). Considered together the responses suggest an organ composed of both secreting and absorbing epithelia that constitutively and concurrently transport fluids into and out of the airway, i.e. in opposite directions. Since the epithelial lining of small airways is arranged in long, accordion-like rows of pleats and folds that run axially down the lumen, we surmise that cells within the pleats are mainly secretory while the cells of the folds are principally absorptive. This structural arrangement could provide local fluid transport from within the pleats toward the luminal folds that may autonomously regulate the local surface fluid volume for homeostasis while permitting acute responses to maintain clearance. PMID- 22547639 TI - Commentary on: can minimized cardiopulmonary bypass systems be safer? PMID- 22547640 TI - Pressure and oxygen debt on bypass - potential quality markers of perfusion? AB - No markers of quality of perfusion pressure and oxygen delivery during cardiopulmonary bypass (CPB), to complement rewarming rate, maximum temperature on rewarming, lowest haematocrit, and blood glucose, exist. Using the electronic acquisition of blood pressure on bypass (JOCAP system), the percentage of time perfusion pressure was below 30, 40, 50, 60 and 70 mmHg, average deviance, confidence interval, median, mode, standard deviation, variance, and average, maximum and cumulative oxygen debt were calculated. Numerous different readouts of achievement of maintenance of constant pressure on bypass and oxygen debt are now easily achievable with perfusion electronic data management systems. Mean, median, and mode offer poor discrimination of pressure control during CPB. Percentage of time perfusion pressure was below 30, 40, 50, 60 and 70 mmHg, average deviance, confidence interval, and standard deviation all have discriminatory power, but need clinical correlation for their significance. A composite score involving non-pressure readouts (e.g. oxygen delivery, arterial and venous saturations, and flow rates) may need to be integrated into any perfusion quality marker. Assessment of adequacy of constant perfusion pressure and oxygen delivery may allow the scientific evaluation of pressure and oxygen delivery on bypass for patients to be compared accurately. Currently, in studies involving CPB, blood pressure targets are stated with no quantitative assessment of adequacy of achievement of these targets. Electronic data monitoring during cardiopulmonary bypass, when correlated with clinical outcome, may help to provide a marker of quality of perfusion pressure during CPB and may, indeed, allow patient-specific perfusion pressure strategies to be developed. PMID- 22547641 TI - A successful percutaneous closure of ventricular septal defect following septal myectomy in patients with hypertrophic obstructive cardiomyopathy. AB - Postoperative ventricular septal defect (post-op VSD) after septal myectomy in patients with hypertrophic obstructive cardiomyopathy is a rare and unexpected complication. We report a case of successful percutaneous closure of VSD following septal myectomy and mitral valve replacement in a patient with intrinsic mitral valve disease and severe mitral valve regurgitation together with hypertrophic obstructive cardiomyopathy. PMID- 22547642 TI - Blood support in coronary bypass surgery. PMID- 22547643 TI - The clinically relevant topic of a combined crystalloid and colloid fluid concept is investigated. PMID- 22547645 TI - Stan Brock: providing free care to America's uninsured. PMID- 22547644 TI - Late onset type 1 diabetes. PMID- 22547646 TI - Work of 125 aid agencies failed to create lasting rehabilitation services in Haiti, study shows. PMID- 22547647 TI - The golden age of the placebo. PMID- 22547648 TI - Pharmacists should provide oral contraceptive services, says NHS report. PMID- 22547649 TI - Better access to birth control would reduce stress on global resources, report says. PMID- 22547650 TI - Internet supplier of fake Viagra is ordered to pay back 14.4m pound. PMID- 22547651 TI - Resident CD141 (BDCA3)+ dendritic cells in human skin produce IL-10 and induce regulatory T cells that suppress skin inflammation. AB - Human skin immune homeostasis, and its regulation by specialized subsets of tissue-residing immune sentinels, is poorly understood. In this study, we identify an immunoregulatory tissue-resident dendritic cell (DC) in the dermis of human skin that is characterized by surface expression of CD141, CD14, and constitutive IL-10 secretion (CD141(+) DDCs). CD141(+) DDCs possess lymph node migratory capacity, induce T cell hyporesponsiveness, cross-present self-antigens to autoreactive T cells, and induce potent regulatory T cells that inhibit skin inflammation. Vitamin D(3) (VitD3) promotes certain phenotypic and functional properties of tissue-resident CD141(+) DDCs from human blood DCs. These CD141(+) DDC-like cells can be generated in vitro and, once transferred in vivo, have the capacity to inhibit xeno-graft versus host disease and tumor alloimmunity. These findings suggest that CD141(+) DDCs play an essential role in the maintenance of skin homeostasis and in the regulation of both systemic and tumor alloimmunity. Finally, VitD3-induced CD141(+) DDC-like cells have potential clinical use for their capacity to induce immune tolerance. PMID- 22547652 TI - Dll4-Notch signaling in Flt3-independent dendritic cell development and autoimmunity in mice. AB - Delta-like ligand 4 (Dll4)-Notch signaling is essential for T cell development and alternative thymic lineage decisions. How Dll4-Notch signaling affects pro-T cell fate and thymic dendritic cell (tDC) development is unknown. We found that Dll4 pharmacological blockade induces accumulation of tDCs and CD4(+)CD25(+)FoxP3(+) regulatory T cells (T(reg) cells) in the thymic cortex. Both genetic inactivation models and anti-Dll4 antibody (Ab) treatment promote de novo natural T(reg) cell expansion by a DC-dependent mechanism that requires major histocompatibility complex II expression on DCs. Anti-Dll4 treatment converts CD4(-)CD8(-)c-kit(+)CD44(+)CD25(-) (DN1) T cell progenitors to immature DCs that induce ex vivo differentiation of naive CD4(+) T cells into T(reg) cells. Induction of these tolerogenic DN1-derived tDCs and the ensuing expansion of T(reg) cells are Fms-like tyrosine kinase 3 (Flt3) independent, occur in the context of transcriptional up-regulation of PU.1, Irf-4, Irf-8, and CSF-1, genes critical for DC differentiation, and are abrogated in thymectomized mice. Anti Dll4 treatment fully prevents type 1 diabetes (T1D) via a T(reg) cell-mediated mechanism and inhibits CD8(+) T cell pancreatic islet infiltration. Furthermore, a single injection of anti-Dll4 Ab reverses established T1D. Disease remission and recurrence are correlated with increased T(reg) cell numbers in the pancreas draining lymph nodes. These results identify Dll4-Notch as a novel Flt3 alternative pathway important for regulating tDC-mediated T(reg) cell homeostasis and autoimmunity. PMID- 22547653 TI - Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. AB - Despite a growing understanding of the link between intestinal inflammation and resident gut microbes, longitudinal studies of human flora before initial onset of intestinal inflammation have not been reported. Here, we demonstrate in murine and human recipients of allogeneic bone marrow transplantation (BMT) that intestinal inflammation secondary to graft-versus-host disease (GVHD) is associated with major shifts in the composition of the intestinal microbiota. The microbiota, in turn, can modulate the severity of intestinal inflammation. In mouse models of GVHD, we observed loss of overall diversity and expansion of Lactobacillales and loss of Clostridiales. Eliminating Lactobacillales from the flora of mice before BMT aggravated GVHD, whereas reintroducing the predominant species of Lactobacillus mediated significant protection against GVHD. We then characterized gut flora of patients during onset of intestinal inflammation caused by GVHD and found patterns mirroring those in mice. We also identified increased microbial chaos early after allogeneic BMT as a potential risk factor for subsequent GVHD. Together, these data demonstrate regulation of flora by intestinal inflammation and suggest that flora manipulation may reduce intestinal inflammation and improve outcomes for allogeneic BMT recipients. PMID- 22547655 TI - HSP90 inhibition by 17-DMAG attenuates oxidative stress in experimental atherosclerosis. AB - AIMS: Reactive oxygen species (ROS) participate in atherogenesis through different mechanisms including oxidative stress and inflammation. Proteins implicated in both processes, such as mitogen-activated protein kinase kinase (MEK) and some NADPH oxidase (NOX) subunits, are heat shock protein-90 (HSP90) client proteins. In this work, we investigated the antioxidant properties of the HSP90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) in experimental atherosclerosis. METHODS AND RESULTS: Treatment of ApoE(-/-) mice with 17-DMAG (2 mg/kg every 2 days for 10 weeks) decreased ROS levels and extracellular signal-regulated kinase (ERK) activation in aortic plaques compared with control animals. Accordingly, treatment of rat vascular smooth muscle cells (VSMCs) with 17-DMAG increased HSP27 and HSP70 and inhibited ERK activation. Interestingly, 17-DMAG diminished NADPH oxidase dependent ROS production in VSMCs and monocytes. In addition, a marked reduction in NADPH oxidase dependent ROS production was observed with HSP90siRNA and the opposite pattern with HSP70siRNA. 17-DMAG also diminished the expression of Nox1 and Nox organizer-1 (Noxo1) in VSMCs and monocytes. Interestingly, 17-DMAG was able to modulate ROS-induced monocyte to macrophage differentiation. Finally, higher expression of Nox1 and Noxo1 was found in the inflammatory region of human atherosclerotic plaques, colocalizing with VSMCs, macrophages, and ROS-producing cells. CONCLUSION: Our results suggest that HSP90 inhibitors interfere with oxidative stress and modulate experimental atherosclerosis development through reduction in pro oxidative factors. PMID- 22547654 TI - B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6 producing B cells. AB - B cells have paradoxical roles in autoimmunity, exerting both pathogenic and protective effects. Pathogenesis may be antibody independent, as B cell depletion therapy (BCDT) leads to amelioration of disease irrespective of autoantibody ablation. However, the mechanisms of pathogenesis are poorly understood. We demonstrate that BCDT alleviates central nervous system autoimmunity through ablation of IL-6-secreting pathogenic B cells. B cells from mice with experimental autoimmune encephalomyelitis (EAE) secreted elevated levels of IL-6 compared with B cells from naive controls, and mice with a B cell-specific IL-6 deficiency showed less severe disease than mice with wild-type B cells. Moreover, BCDT ameliorated EAE only in mice with IL-6-sufficient B cells. This mechanism of pathogenesis may also operate in multiple sclerosis (MS) because B cells from MS patients produced more IL-6 than B cells from healthy controls, and this abnormality was normalized with B cell reconstitution after Rituximab treatment. This suggests that BCDT improved disease progression, at least partly, by eliminating IL-6-producing B cells in MS patients. Taking these data together, we conclude that IL-6 secretion is a major mechanism of B cell-driven pathogenesis in T cell-mediated autoimmune disease such as EAE and MS. PMID- 22547656 TI - Chaotic homes and children's disruptive behavior: a longitudinal cross-lagged twin study. AB - Chaotic home lives are correlated with behavior problems in children. In the study reported here, we tested whether there was a cross-lagged relation between children's experience of chaos and their disruptive behaviors (conduct problems and hyperactivity-inattention). Using genetically informative models, we then tested for the first time whether the influence of household chaos on disruptive behavior was environmentally mediated and whether genetic influences on children's disruptive behaviors accounted for the heritability of household chaos. We measured children's perceptions of household chaos and parents' ratings of children's disruptive behavior at ages 9 and 12 in a sample of 6,286 twin pairs from the Twins Early Development Study (TEDS). There was a phenotypic cross lagged relation between children's experiences of household chaos and their disruptive behavior. In genetically informative models, we found that the effect of household chaos on subsequent disruptive behavior was environmentally mediated. However, genetic influences on disruptive behavior did not explain why household chaos was heritable. PMID- 22547657 TI - What people desire, feel conflicted about, and try to resist in everyday life. AB - In the present study, we used experience sampling to measure desires and desire regulation in everyday life. Our analysis included data from 205 adults, who furnished a total of 7,827 reports of their desires over the course of a week. Across various desire domains, results revealed substantial differences in desire frequency and strength, the degree of conflict between desires and other goals, and the likelihood of resisting desire and the success of this resistance. Desires for sleep and sex were experienced most intensively, whereas desires for tobacco and alcohol had the lowest average strength, despite the fact that these substances are thought of as addictive. Desires for leisure and sleep conflicted the most with other goals, and desires for media use and work brought about the most self-control failure. In addition, we observed support for a limited resource model of self-control employing a novel operationalization of cumulative resource depletion: The frequency and recency of engaging in prior self-control negatively predicted people's success at resisting subsequent desires on the same day. PMID- 22547658 TI - Personalized persuasion: tailoring persuasive appeals to recipients' personality traits. AB - Persuasive messages are more effective when they are custom-tailored to reflect the interests and concerns of the intended audience. Much of the message-framing literature has focused on the advantages of using either gain or loss frames, depending on the motivational orientation of the target group. In the current study, we extended this research to examine whether a persuasive appeal's effectiveness can be increased by aligning the message framing with the recipient's personality profile. For a single product, we constructed five advertisements, each designed to target one of the five major trait domains of human personality. In a sample of 324 survey respondents, advertisements were evaluated more positively the more they cohered with participants' dispositional motives. These results suggest that adapting persuasive messages to the personality traits of the target audience can be an effective way of increasing the messages' impact, and highlight the potential value of personality-based communication strategies. PMID- 22547661 TI - Mitochondrial dysfunction in glaucoma: closing the loop. PMID- 22547660 TI - Proteoliposome-based capillary electrophoresis for screening membrane protein inhibitors. AB - A method for screening of monoamine oxidase (MAO) inhibitor was carried out using capillary electrophoresis (CE) based on the interaction of MAO and its substrate kynuramine (Kyn). Bioactive proteoliposome was reconstituted by liposome and MAO and then was applied as the pseudostationary phase (PSP) of CE to mimic the interaction between the enzyme and its substrate. N-prolmrgyl-R-2-heptylamine (R 2-HPA) and rasagiline [N-propargyl-1-(R)-aminoindan], which are two kinds of MAO inhibitors, were added into the running buffers containing proteoliposome. The results showed that the relative migration time ratio (RMTR * 10(-1)) values of Kyn were enhanced from 8.88 to 9.31 with an increase of the concentrations of rasagiline from 10(-6) to 1 mM. However, the RMTR values of Kyn were enhanced from 8.83 to 9.14 with an increase of the concentrations of R-2-HPA from 10(-6) to 1 mM. The RMTR value of Kyn in the presence of rasagiline was larger than that in the presence of R-2-HPA when rasagiline and R-2-HPA were at the same concentration. The results indicated that the interaction between Kyn and MAO was weakened with the increase of the inhibitors. In addition, the results of offline incubation showed that the inhibitions of rasagiline were 100.0, 72.1, 51.8 and 5.4% at the concentration of 1, 10(-2), 10(-4) and 10(-6) mM; moreover, the inhibitions of R-2-HPA were 70.0, 44.9, 4.1 and 0.9% at the concentrations of 1, 10(-2), 10(-4) and 10(-6) mM. The inhibition efficiency of rasagiline was stronger than that of R-2-HPA at the same concentration. Additionally, the interaction between Kyn and liposome was also investigated. This newly developed method might provide a potential tool for screening MAO inhibitor. PMID- 22547659 TI - Brassinosteroid action in flowering plants: a Darwinian perspective. AB - The year 2012 marks the 150th anniversary of the publication of Charles Darwin's first botanical book, on the fertilization of orchids (1862), wherein he described pollen grains and outlined his evolutionary principles with respect to plant research. Five decades later, the growth-promoting effect of extracts of Orchid pollen on coleoptile elongation was documented. These studies led to the discovery of a new class of phytohormones, the brassinosteroids (BRs) that were isolated from rapeseed (Brassica napus) pollen. These growth-promoting steroids, which regulate height, fertility, and seed-filling in crop plants such as rice (Oryza sativa), also induce stress- and disease resistance in green algae and angiosperms. The origin and current status of BR-research is described here, with reference to BR-action and -signal transduction, and it is shown that modern high yield rice varieties with erect leaves are deficient in endogenous BRs. Since brassinosteroids induce pathogen resistance in rice plants and hence can suppress rice blast- and bacterial blight-diseases, genetic manipulation of BR biosynthesis or -perception may be a means to increase crop production. Basic research on BR activity in plants, such as Arabidopsis and rice, has the potential to increase crop yields further as part of a 21th century 'green biotech-revolution' that can be traced back to Darwin's classical breeding experiments. It is concluded that 'Nothing in brassinosteroid research makes sense except in the light of Darwinian evolution' and the value of basic science is highlighted, with reference to the genetic engineering of better food crops that may become resistant to a variety of plant diseases. PMID- 22547662 TI - Antistaphylococcal activity of DNA-interactive pyrrolobenzodiazepine (PBD) dimers and PBD-biaryl conjugates. AB - OBJECTIVES: Pyrrolobenzodiazepine (PBD) dimers, tethered through inert propyldioxy or pentyldioxy linkers, possess potent bactericidal activity against a range of Gram-positive bacteria by virtue of their capacity to cross-link duplex DNA in sequence-selective fashion. Here we attempt to improve the antibacterial activity and cytotoxicity profile of PBD-containing conjugates by extension of dimer linkers and replacement of one PBD unit with phenyl substituted or benzo-fused heterocycles that facilitate non-covalent interactions with duplex DNA. METHODS: DNase I footprinting was used to identify high-affinity DNA binding sites. A staphylococcal gene microarray was used to assess epidemic methicillin-resistant Staphylococcus aureus 16 phenotypes induced by PBD conjugates. Molecular dynamics simulations were employed to investigate the accommodation of compounds within the DNA helix. RESULTS: Increasing the length of the linker in PBD dimers led to a progressive reduction in antibacterial activity, but not in their cytotoxic capacity. Complex patterns of DNA binding were noted for extended PBD dimers. Modelling of DNA strand cross-linking by PBD dimers indicated distortion of the helix. A majority (26 of 43) of PBD-biaryl conjugates possessed potent antibacterial activity with little or no helical distortion and a more favourable cytotoxicity profile. Bactericidal activity of PBD-biaryl conjugates was determined by inability to excise covalently bound drug molecules from bacterial duplex DNA. CONCLUSIONS: PBD-biaryl conjugates have a superior antibacterial profile compared with PBD dimers such as ELB-21. We have identified six PBD-biaryl conjugates as potential drug development candidates. PMID- 22547663 TI - Inorganic polyphosphate is a potent activator of the mitochondrial permeability transition pore in cardiac myocytes. AB - Mitochondrial dysfunction caused by excessive Ca2+ accumulation is a major contributor to cardiac cell and tissue damage during myocardial infarction and ischemia-reperfusion injury (IRI). At the molecular level, mitochondrial dysfunction is induced by Ca2+-dependent opening of the mitochondrial permeability transition pore (mPTP) in the inner mitochondrial membrane, which leads to the dissipation of mitochondrial membrane potential (DeltaPsim), disruption of adenosine triphosphate production, and ultimately cell death. Although the role of Ca2+ for induction of mPTP opening is established, the exact molecular mechanism of this process is not understood. The aim of the present study was to test the hypothesis that the adverse effect of mitochondrial Ca2+ accumulation is mediated by its interaction with inorganic polyphosphate (polyP), a polymer of orthophosphates linked by phosphoanhydride bonds. We found that cardiac mitochondria contained significant amounts (280+/-60 pmol/mg of protein) of short-chain polyP with an average length of 25 orthophosphates. To test the role of polyP for mPTP activity, we investigated kinetics of Ca2+ uptake and release, DeltaPsim and Ca2+-induced mPTP opening in polyP-depleted mitochondria. polyP depletion was achieved by mitochondria-targeted expression of a polyP hydrolyzing enzyme. Depletion of polyP in mitochondria of rabbit ventricular myocytes led to significant inhibition of mPTP opening without affecting mitochondrial Ca2+ concentration by itself. This effect was observed when mitochondrial Ca2+ uptake was stimulated by increasing cytosolic [Ca2+] in permeabilized myocytes mimicking mitochondrial Ca2+ overload observed during IRI. Our findings suggest that inorganic polyP is a previously unrecognized major activator of mPTP. We propose that the adverse effect of polyphosphate might be caused by its ability to form stable complexes with Ca2+ and directly contribute to inner mitochondrial membrane permeabilization. PMID- 22547664 TI - Gating properties of the P2X2a and P2X2b receptor channels: experiments and mathematical modeling. AB - Adenosine triphosphate (ATP)-gated P2X2 receptors exhibit two opposite activation dependent changes, pore dilation and pore closing (desensitization), through a process that is incompletely understood. To address this issue and to clarify the roles of calcium and the C-terminal domain in gating, we combined biophysical and mathematical approaches using two splice forms of receptors: the full-size form (P2X2aR) and the shorter form missing 69 residues in the C-terminal domain (P2X2bR). Both receptors developed conductivity for N-methyl-D-glucamine within 2 6 s of ATP application. However, pore dilation was accompanied with a decrease rather than an increase in the total conductance, which temporally coincided with rapid and partial desensitization. During sustained agonist application, receptors continued to desensitize in calcium-independent and calcium-dependent modes. Calcium-independent desensitization was more pronounced in P2X2bR, and calcium-dependent desensitization was more pronounced in P2X2aR. In whole cell recording, we also observed use-dependent facilitation of desensitization of both receptors. Such behavior was accounted for by a 16-state Markov kinetic model describing ATP binding/unbinding and activation/desensitization. The model assumes that naive receptors open when two to three ATP molecules bind and undergo calcium-independent desensitization, causing a decrease in the total conductance, or pore dilation, causing a shift in the reversal potential. In calcium-containing media, receptor desensitization is facilitated and the use dependent desensitization can be modeled by a calcium-dependent toggle switch. The experiments and the model together provide a rationale for the lack of sustained current growth in dilating P2X2Rs and show that receptors in the dilated state can also desensitize in the presence of calcium. PMID- 22547666 TI - SSR-marker analysis of the intracultivar phenotypic variation discovered within 3 soybean cultivars. AB - Genetic variation within homogeneous gene pools in various crops is assumed to be very limited. One objective of this study was to use 144 simple sequence repeat (SSR) markers to determine if the single-plant lines selected at ultra-low plant density in honeycomb designs within the soybean cultivars Benning, Haskell, and Cook had unique SSR genetic fingerprints. Another objective was to investigate if the variation found was the result of residual genetic heterozygosity that could be detected in the original gene pool where selection initiated. Our results showed that the phenotypic variation for seed protein content and seed weight has a genotypic component identified by the SSR band variation. The 7 lines from Haskell had a total of 63 variant alleles, the 5 lines from Benning had 34 variant alleles, and the 7 lines from Cook had 34 variant alleles, therefore, possessing unique genetic fingerprints. Most of the intracultivar SSR band variation discovered was the result of residual heterozygosity in the initial plant selected to become the cultivar. More specifically, 82% of the SSR variant alleles were traced in the Benning Foundation seed source, 93% in the Haskell seed source, and 82% in the Cook seed source. The remaining variant bands (18% for Benning, 7% for Haskell, and 18% for Cook) could not be detected in the Foundation seed source and were likely the result of mutation or some other mechanism generating de novo variation. These results provide evidence that genetic variation among individual plants is present even in homogeneous gene pools and can be further utilized in breeding programs. PMID- 22547665 TI - The intrinsic energy of the gating isomerization of a neuromuscular acetylcholine receptor channel. AB - Nicotinic acetylcholine receptor (AChR) channels at neuromuscular synapses rarely open in the absence of agonists, but many different mutations increase the unliganded gating equilibrium constant (E0) to generate AChRs that are active constitutively. We measured E0 for two different sets of mutant combinations and by extrapolation estimated E0 for wild-type AChRs. The estimates were 7.6 and 7.8*10(-7) in adult-type mouse AChRs (-100 mV at 23 degrees C). The values are in excellent agreement with one obtained previously by using a completely different method (6.5*10(-7), from monoliganded gating). E0 decreases with depolarization to the same extent as does the diliganded gating equilibrium constant, e-fold with ~60 mV. We estimate that at -100 mV the intrinsic energy of the unliganded gating isomerization is +8.4 kcal/mol (35 kJ/mol), and that in the absence of a membrane potential, the intrinsic chemical energy of this global conformational change is +9.4 kcal/mol (39 kJ/mol). Na+ and K+ in the extracellular solution have no measureable effect on E0, which suggests that unliganded gating occurs with only water occupying the transmitter binding sites. The results are discussed with regard to the energy changes in receptor activation and the competitive antagonism of ions in agonist binding. PMID- 22547667 TI - Cardiovascular health behavior and health factor changes (1988-2008) and projections to 2020: results from the National Health and Nutrition Examination Surveys. AB - BACKGROUND: The American Heart Association's 2020 Strategic Impact Goals target a 20% relative improvement in overall cardiovascular health with the use of 4 health behavior (smoking, diet, physical activity, body mass) and 3 health factor (plasma glucose, cholesterol, blood pressure) metrics. We sought to define current trends and forward projections to 2020 in cardiovascular health. METHODS AND RESULTS: We included 35 059 cardiovascular disease-free adults (aged >=20 years) from the National Health and Nutrition Examination Survey 1988-1994 and subsequent 2-year cycles during 1999-2008. We calculated population prevalence of poor, intermediate, and ideal health behaviors and factors and also computed a composite, individual-level Cardiovascular Health Score for all 7 metrics (poor=0 points; intermediate=1 point; ideal=2 points; total range, 0-14 points). Prevalence of current and former smoking, hypercholesterolemia, and hypertension declined, whereas prevalence of obesity and dysglycemia increased through 2008. Physical activity levels and low diet quality scores changed minimally. Projections to 2020 suggest that obesity and impaired fasting glucose/diabetes mellitus could increase to affect 43% and 77% of US men and 42% and 53% of US women, respectively. Overall, population-level cardiovascular health is projected to improve by 6% overall by 2020 if current trends continue. Individual-level Cardiovascular Health Score projections to 2020 (men=7.4 [95% confidence interval, 5.7-9.1]; women=8.8 [95% confidence interval, 7.6-9.9]) fall well below the level needed to achieve a 20% improvement (men=9.4; women=10.1). CONCLUSIONS: The American Heart Association 2020 target of improving cardiovascular health by 20% by 2020 will not be reached if current trends continue. PMID- 22547668 TI - Wicked problems and worthy pursuits: resolving to meet American Heart Association 2020 Impact Goals. PMID- 22547669 TI - Key concepts in the evaluation of screening approaches for heart disease in children and adolescents: a science advisory from the American Heart Association. PMID- 22547670 TI - Electronic control devices: science, law, and social responsibility. PMID- 22547671 TI - Sudden cardiac arrest and death following application of shocks from a TASER electronic control device. AB - BACKGROUND: The safety of electronic control devices (ECDs) has been questioned. The goal of this study was to analyze in detail cases of loss of consciousness associated with ECD deployment. METHODS AND RESULTS: Eight cases of TASER X26 ECD induced loss of consciousness were studied. In each instance, when available, police, medical, and emergency response records, ECD dataport interrogation, automated external defibrillator information, ECG strips, depositions, and autopsy results were analyzed. First recorded rhythms were ventricular tachycardia/fibrillation in 6 cases and asystole (after ~ 30 minutes of nonresponsiveness) in 1 case. An external defibrillator reported a shockable rhythm in 1 case, but no recording was made. This report offers evidence detailing the mechanism by which an ECD can produce transthoracic stimulation resulting in cardiac electrical capture and ventricular arrhythmias leading to cardiac arrest. CONCLUSIONS: ECD stimulation can cause cardiac electrical capture and provoke cardiac arrest resulting from ventricular tachycardia/ventricular fibrillation. After prolonged ventricular tachycardia/ventricular fibrillation without resuscitation, asystole develops. PMID- 22547672 TI - Mortality in coronary artery bypass grafting: what's next? PMID- 22547673 TI - Risk score for predicting long-term mortality after coronary artery bypass graft surgery. AB - BACKGROUND: No simplified bedside risk scores have been created to predict long term mortality after coronary artery bypass graft surgery. METHODS AND RESULTS: The New York State Cardiac Surgery Reporting System was used to identify 8597 patients who underwent isolated coronary artery bypass graft surgery in July through December 2000. The National Death Index was used to ascertain patients' vital statuses through December 31, 2007. A Cox proportional hazards model was fit to predict death after CABG surgery using preprocedural risk factors. Then, points were assigned to significant predictors of death on the basis of the values of their regression coefficients. For each possible point total, the predicted risks of death at years 1, 3, 5, and 7 were calculated. It was found that the 7-year mortality rate was 24.2 in the study population. Significant predictors of death included age, body mass index, ejection fraction, unstable hemodynamic state or shock, left main coronary artery disease, cerebrovascular disease, peripheral arterial disease, congestive heart failure, malignant ventricular arrhythmia, chronic obstructive pulmonary disease, diabetes mellitus, renal failure, and history of open heart surgery. The points assigned to these risk factors ranged from 1 to 7; possible point totals for each patient ranged from 0 to 28. The observed and predicted risks of death at years 1, 3, 5, and 7 across patient groups stratified by point totals were highly correlated. CONCLUSION: The simplified risk score accurately predicted the risk of mortality after coronary artery bypass graft surgery and can be used for informed consent and as an aid in determining treatment choice. PMID- 22547674 TI - Telomerase recruitment requires both TCAB1 and Cajal bodies independently. AB - The ability of most cancer cells to grow indefinitely relies on the enzyme telomerase and its recruitment to telomeres. In human cells, recruitment depends on the Cajal body RNA chaperone TCAB1 binding to the RNA subunit of telomerase (hTR) and is also thought to rely on an N-terminal domain of the catalytic subunit, hTERT. We demonstrate that coilin, an essential structural component of Cajal bodies, is required for endogenous telomerase recruitment to telomeres but that overexpression of telomerase can compensate for Cajal body absence. In contrast, recruitment of telomerase was sensitive to levels of TCAB1, and this was not rescued by overexpression of telomerase. Thus, although Cajal bodies are important for recruitment, TCAB1 has an additional role in this process that is independent of these structures. TCAB1 itself localizes to telomeres in a telomerase-dependent but Cajal body-independent manner. We identify a point mutation in hTERT that largely abolishes recruitment yet does not affect association of telomerase with TCAB1, suggesting that this region mediates recruitment by an independent mechanism. Our results demonstrate that telomerase has multiple independent requirements for recruitment to telomeres and that the function of TCAB1 is to directly transport telomerase to telomeres. PMID- 22547675 TI - Functional association between eyegone and HP1a mediates wingless transcriptional repression during development. AB - The eyegone (eyg) gene encodes Eyg, a transcription factor of the Pax family with multiple roles during Drosophila development. Although Eyg has been shown to act as a repressor, nothing is known about the mechanism by which it represses its target genes. Here, we show that Eyg forms a protein complex with heterochromatin protein 1a (HP1a). Both proteins bind to the same chromatin regions on polytene chromosomes and act cooperatively to suppress variegation and mediate gene silencing. In addition, Eyg binds to a wingless (wg) enhancer region, recruiting HP1a to assemble a closed, heterochromatin-like conformation that represses transcription of the wg gene. We describe here the evidence that suggests that Eyg, encoded by eyegone (eyg), represses wingless (wg) during eye development by association with HP1a. We show that Eyg forms a protein complex with HP1a and both proteins colocalize on salivary gland polytene chromosomes. Using position effect variegation (PEV) experiments, we demonstrated that eyg has a dose dependent effect on heterochromatin gene silencing and identified a genetic interaction with HP1a in this process. We further demonstrated that HP1a binds to the same wg enhancer element as Eyg. DNase I sensitivity assays indicated that this enhancer region has a closed heterochromatin-like conformation, which becomes open in eyg mutants. In these mutants, much less HP1a binds to the wg enhancer region, as shown by ChIP experiments. Furthermore, as previously described for Eyg, a reduction in the amount of HP1a in the eye imaginal disc derepresses wg. Together, our results suggest a model in which Eyg specifically binds to the wg enhancer region, recruiting HP1a to that site. The recruitment of HP1a prevents transcription by favoring a closed, heterochromatin-like structure. Thus, for the first time, we show that HP1a plays a direct role in the repression of a developmentally regulated gene, wg, during Drosophila eye development. PMID- 22547676 TI - Transient neonatal diabetes mellitus gene Zac1 impairs insulin secretion in mice through Rasgrf1. AB - The biallelic expression of the imprinted gene ZAC1/PLAGL1 underlies ~ 60% of all cases of transient neonatal diabetes mellitus (TNDM) that present with low perinatal insulin secretion. Molecular targets of ZAC1 misexpression in pancreatic beta cells are unknown. Here, we identified the guanine nucleotide exchange factor Rasgrf1 as a direct Zac1/Plagl1 target gene in murine beta cells. Doubling Zac1 expression reduced Rasgrf1 expression, the stimulus-induced activation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3 kinase (PI3K) pathways, and, ultimately, insulin secretion. Normalizing Rasgrf1 expression reversed this phenotype. Moreover, the transplantation of Zac1 overexpressing beta cells failed to reinstate euglycemia in experimental diabetic mice. In contrast, Zac1 expression did not interfere with the signaling of the glucagon-like peptide 1 receptor (GLP-1R), and the GLP-1 analog liraglutide improved hyperglycemia in transplanted experimental diabetic mice. This study unravels a mechanism contributing to insufficient perinatal insulin secretion in TNDM and raises new prospects for therapy. PMID- 22547677 TI - Histone ADP-ribosylation facilitates gene transcription by directly remodeling nucleosomes. AB - The packaging of DNA into nucleosomes imposes obstacles on gene transcription, and histone-modifying and nucleosome-remodeling complexes work in concert to alleviate these obstacles so as to facilitate transcription. Emerging evidence shows that chromatin-associated poly(ADP-ribose) polymerase 1 (PARP-1) and its enzymatic activity facilitate inflammatory gene transcription and modulate the inflammatory response in animal models. However, the molecular mechanisms by which PARP-1 enzymatic activity facilitates transcription are not well understood. Here we show that through an intracellular signaling pathway, lipopolysaccharide (LPS) stimulation induces PARP-1 enzymatic activity and the ADP-ribosylation of histones at transcriptionally active and accessible chromatin regions in macrophages. In vitro DNase I footprinting and restriction endonuclease accessibility assays reveal that histone ADP-ribosylation directly destabilizes histone-DNA interactions in the nucleosome and increases the site accessibility of the nucleosomal DNA to nucleases. Consistent with this, LPS stimulation-induced ADP-ribosylation at the nucleosome-occupied promoters of il 1beta, mip-2, and csf2 facilitates NF-kappaB recruitment and the transcription of these genes in macrophages. Therefore, our data suggest that PARP-1 enzymatic activity facilitates gene transcription through increasing promoter accessibility by histone ADP-ribosylation. PMID- 22547678 TI - IkappaB kinase alpha phosphorylation of TRAF4 downregulates innate immune signaling. AB - Despite their homology, IkappaB kinase alpha (IKKalpha) and IKKbeta have divergent roles in NF-kappaB signaling. IKKbeta strongly activates NF-kappaB while IKKalpha can downregulate NF-kappaB under certain circumstances. Given this, identifying independent substrates for these kinases could help delineate their divergent roles. Peptide substrate array technology followed by bioinformatic screening identified TRAF4 as a substrate for IKKalpha. Like IKKalpha, TRAF4 is atypical within its family because it is the only TRAF family member to negatively regulate innate immune signaling. IKKalpha's phosphorylation of serine-426 on TRAF4 was required for this negative regulation. Binding to the Crohn's disease susceptibility protein, NOD2, is required for TRAF4 phosphorylation and subsequent inhibition of NOD2 signaling. Structurally, serine 426 resides within an exaggerated beta-bulge in TRAF4 that is not present in the other TRAF proteins, and phosphorylation of this site provides a structural basis for the atypical function of TRAF4 and its atypical role in NOD2 signaling. PMID- 22547679 TI - The tumor necrosis factor receptor stalk regions define responsiveness to soluble versus membrane-bound ligand. AB - The family of tumor necrosis factor receptors (TNFRs) and their ligands form a regulatory signaling network that controls immune responses. Various members of this receptor family respond differently to the soluble and membrane-bound forms of their respective ligands. However, the determining factors and underlying molecular mechanisms of this diversity are not yet understood. Using an established system of chimeric TNFRs and novel ligand variants mimicking the bioactivity of membrane-bound TNF (mTNF), we demonstrate that the membrane proximal extracellular stalk regions of TNFR1 and TNFR2 are crucial in controlling responsiveness to soluble TNF (sTNF). We show that the stalk region of TNFR2, in contrast to the corresponding part of TNFR1, efficiently inhibits both the receptor's enrichment/clustering in particular cell membrane regions and ligand-independent homotypic receptor preassembly, thereby preventing sTNF induced, but not mTNF-induced, signaling. Thus, the stalk regions of the two TNFRs not only have implications for additional TNFR family members, but also provide potential targets for therapeutic intervention. PMID- 22547680 TI - Origins and formation of histone methylation across the human cell cycle. AB - The connections between various nuclear processes and specific histone posttranslational modifications are dependent to a large extent on the acquisition of those modifications after histone synthesis. The reestablishment of histone posttranslational modifications after S phase is especially critical for H3K9 and H3K27 trimethylation, both of which are linked with epigenetic memory and must be stably transmitted from one cellular generation to the next. This report uses a proteomic strategy to interrogate how and when the cell coordinates the formation of histone posttranslational modifications during division. Paramount among the findings is that H3K9 and H3K27 trimethylation begins during S phase but is completed only during the subsequent G(1) phase via two distinct pathways from the unmodified and preexisting dimethylated states. In short, we have systematically characterized the temporal origins and methylation pathways for histone posttranslational modifications during the cell cycle. PMID- 22547682 TI - Loss of the retinoblastoma tumor suppressor protein in murine calvaria facilitates immortalization of osteoblast-adipocyte bipotent progenitor cells characterized by low expression of N-cadherin. AB - The retinoblastoma gene, RB1, is frequently inactivated in a subset of tumors, including retinoblastoma and osteosarcoma (OS). One characteristic of OS, as well as other tumors in which RB1 is frequently inactivated, is the lack of N-cadherin mediated cell-cell adhesions. The frequent inactivation of RB1 and parallel loss of N-cadherin expression in OS prompted us to ask whether these observations are directly related to each other. In this study, we observed reduced N-cadherin expression in RB1(-/-) calvarial osteoblasts. In addition, RB1(-/-) cell lines had increased migration potential compared to their RB1(+/+) counterparts. These properties of RB1(-/-) cell lines correlated with an adipogenic potential lacking in RB1(+/+) cell lines, suggesting that each property is present in an immature progenitor cell. The isolation of a cell population with low surface expression of N-cadherin and enhanced adipogenic ability supports this view. Interestingly, the acute loss of pRb does not affect N-cadherin expression or migration or confer adipogenic potential to immortalized RB1(+/+) calvarial cells, suggesting that these traits are not a direct consequence of pRb loss; rather, pRb loss leads to the expansion and immortalization of an immature progenitor pool characterized by these properties. PMID- 22547681 TI - Growth inhibition by miR-519 via multiple p21-inducing pathways. AB - The microRNA miR-519 robustly inhibits cell proliferation, in turn triggering senescence and decreasing tumor growth. However, the molecular mediators of miR 519-elicited growth inhibition are unknown. Here, we systematically investigated the influence of miR-519 on gene expression profiles leading to growth cessation in HeLa human cervical carcinoma cells. By analyzing miR-519-triggered changes in protein and mRNA expression patterns and by identifying mRNAs associated with biotinylated miR-519, we uncovered two prominent subsets of miR-519-regulated mRNAs. One subset of miR-519 target mRNAs encoded DNA maintenance proteins (including DUT1, EXO1, RPA2, and POLE4); miR-519 repressed their expression and increased DNA damage, in turn raising the levels of the cyclin-dependent kinase (cdk) inhibitor p21. The other subset of miR-519 target mRNAs encoded proteins that control intracellular calcium levels (notably, ATP2C1 and ORAI1); their downregulation by miR-519 aberrantly elevated levels of cytosolic [Ca(2+)] storage in HeLa cells, similarly increasing p21 levels in a manner dependent on the Ca(2+)-activated kinases CaMKII and GSK3beta. The rises in levels of DNA damage, the Ca(2+) concentration, and p21 levels stimulated an autophagic phenotype in HeLa and other human carcinoma cell lines. As a consequence, ATP levels increased, and the level of activity of the AMP-activated protein kinase (AMPK) declined, further contributing to the elevation in the abundance of p21. Our results indicate that miR-519 promotes DNA damage, alters Ca(2+) homeostasis, and enhances energy production; together, these processes elevate the expression level of p21, promoting growth inhibition and cell survival. PMID- 22547683 TI - NEUROG2 drives cell cycle exit of neuronal precursors by specifically repressing a subset of cyclins acting at the G1 and S phases of the cell cycle. AB - Proneural NEUROG2 (neurogenin 2 [Ngn2]) is essential for neuronal commitment, cell cycle withdrawal, and neuronal differentiation. Although NEUROG2's influence on neuronal commitment and differentiation is beginning to be clarified, its role in cell cycle withdrawal remains unknown. We therefore set out to investigate the molecular mechanisms by which NEUROG2 induces cell cycle arrest during spinal neurogenesis. We developed a large-scale chicken embryo strategy, designed to find gene networks modified at the onset of NEUROG2 expression, and thereby we identified those involved in controlling the cell cycle. NEUROG2 activation leads to a rapid decrease of a subset of cell cycle regulators acting at G(1) and S phases, including CCND1, CCNE1/2, and CCNA2 but not CCND2. The use of NEUROG2VP16 and NEUROG2EnR, acting as the constitutive activator and repressor, respectively, indicates that NEUROG2 indirectly represses CCND1 and CCNE2 but opens the possibility that CCNE2 is also repressed by a direct mechanism. We demonstrated by phenotypic analysis that this rapid repression of cyclins prevents S phase entry of neuronal precursors, thus favoring cell cycle exit. We also showed that cell cycle exit can be uncoupled from neuronal differentiation and that during normal development NEUROG2 is in charge of tightly coordinating these two processes. PMID- 22547684 TI - mRNA 3' tagging is induced by nonsense-mediated decay and promotes ribosome dissociation. AB - For a range of eukaryote transcripts, the initiation of degradation is coincident with the addition of a short pyrimidine tag at the 3' end. Previously, cytoplasmic mRNA tagging has been observed for human and fungal transcripts. We now report that Arabidopsis thaliana mRNA is subject to 3' tagging with U and C nucleotides, as in Aspergillus nidulans. Mutations that disrupt tagging, including A. nidulans cutA and a newly characterized gene, cutB, retard transcript degradation. Importantly, nonsense-mediated decay (NMD), a major checkpoint for transcript fidelity, elicits 3' tagging of transcripts containing a premature termination codon (PTC). Although PTC-induced transcript degradation does not require 3' tagging, subsequent dissociation of mRNA from ribosomes is retarded in tagging mutants. Additionally, tagging of wild-type and NMD-inducing transcripts is greatly reduced in strains lacking Upf1, a conserved NMD factor also required for human histone mRNA tagging. We argue that PTC-induced translational termination differs fundamentally from normal termination in polyadenylated transcripts, as it leads to transcript degradation and prevents rather than facilitates further translation. Furthermore, transcript deadenylation and the consequent dissociation of poly(A) binding protein will result in PTC-like termination events which recruit Upf1, resulting in mRNA 3' tagging, ribosome clearance, and transcript degradation. PMID- 22547685 TI - BNip3 regulates mitochondrial function and lipid metabolism in the liver. AB - BNip3 localizes to the outer mitochondrial membrane, where it functions in mitophagy and mitochondrial dynamics. While the BNip3 protein is constitutively expressed in adult liver from fed mice, we have shown that its expression is superinduced by fasting of mice, consistent with a role in responses to nutrient deprivation. Loss of BNip3 resulted in increased lipid synthesis in the liver that was associated with elevated ATP levels, reduced AMP-regulated kinase (AMPK) activity, and increased expression of lipogenic enzymes. Conversely, there was reduced beta-oxidation of fatty acids in BNip3 null liver and also defective glucose output under fasting conditions. These metabolic defects in BNip3 null liver were linked to increased mitochondrial mass and increased hepatocellular respiration in the presence of glucose. However, despite elevated mitochondrial mass, an increased proportion of mitochondria exhibited loss of mitochondrial membrane potential, abnormal structure, and reduced oxygen consumption. Elevated reactive oxygen species, inflammation, and features of steatohepatitis were also observed in the livers of BNip3 null mice. These results identify a role for BNip3 in limiting mitochondrial mass and maintaining mitochondrial integrity in the liver that has consequences for lipid metabolism and disease. PMID- 22547689 TI - Brain natriuretic peptide in term pregnancy. AB - OBJECTIVE: To determine the normal range of serum brain natriuretic peptide (BNP) in uncomplicated, singleton term pregnant patients. STUDY DESIGN: Serum for analysis of BNP was drawn at admission to labor and delivery (= 104), prior to administration of intravenous fluid. RESULTS: Median BNP was 20 pg/mL, with an interquartile range of 20 pg/mL (range 5-70 pg/mL; or a mean +/- standard deviation [SD] of 23 +/- 16 pg/mL). Brain natriuretic peptide negatively correlated with prepregnant (r = -.24, P < .05) and pregnant weight (r = -26, P < .01) and with heart rate (r = -.35, P < 0.001); heart rate was also positively correlated with BMI (r = .32). Brain natriuretic peptide levels were higher in Hispanic than African American women, independent of body mass index (BMI) and heart rate. CONCLUSIONS: Brain natriuretic peptide values found in term pregnant patients are similar to those of prepregnant women of reproductive age. Brain natriuretic peptide levels appear to be set by conditions present in the prepregnant condition and maintained, despite changes in plasma volume, systemic vascular resistance, and cardiac output. PMID- 22547690 TI - Projections of cancer mortality risks using spatio-temporal P-spline models. AB - Cancer mortality risk estimates are essential for planning resource allocation and designing and evaluating cancer prevention and management strategies. However, mortality figures generally become available after a few years, making necessary to develop reliable procedures to provide current and near future mortality risks. In this work, a spatio-temporal P-spline model is used to provide predictions of mortality/incidence counts. The model is appropriate to capture smooth temporal trends and to predict cancer mortality/incidence counts in different regions for future years. The prediction mean squared error of the forecast values as well as an appropriate estimator are derived. Spanish prostate cancer mortality data in the period 1975-2008 will be used to illustrate results with a focus on cancer mortality forecasting in 2009-2011. PMID- 22547686 TI - The super elongation complex family of RNA polymerase II elongation factors: gene target specificity and transcriptional output. AB - The elongation stage of transcription is highly regulated in metazoans. We previously purified the AFF1- and AFF4-containing super elongation complex (SEC) as a major regulator of development and cancer pathogenesis. Here, we report the biochemical isolation of SEC-like 2 (SEC-L2) and SEC-like 3 (SEC-L3) containing AFF2 and AFF3 in association with P-TEFb, ENL/MLLT1, and AF9/MLLT3. The SEC family members demonstrate high levels of polymerase II (Pol II) C-terminal domain kinase activity; however, only SEC is required for the proper induction of the HSP70 gene upon stress. Genome-wide mRNA-Seq analyses demonstrated that SEC L2 and SEC-L3 control the expression of different subsets of genes, while AFF4/SEC plays a more dominant role in rapid transcriptional induction in cells. MYC is one of the direct targets of AFF4/SEC, and SEC recruitment to the MYC gene regulates its expression in different cancer cells, including those in acute myeloid or lymphoid leukemia. These findings suggest that AFF4/SEC could be a potential therapeutic target for the treatment of leukemia or other cancers associated with MYC overexpression. PMID- 22547687 TI - Phosphoproteomic analysis of leukemia cells under basal and drug-treated conditions identifies markers of kinase pathway activation and mechanisms of resistance. AB - Protein kinase signaling is fundamental to cell homeostasis and is deregulated in all cancers but varies between patients. Understanding the mechanisms underlying this heterogeneity is critical for personalized targeted therapies. Here, we used a recently established LC-MS/MS platform to profile protein phosphorylation in acute myeloid leukemia cell lines with different sensitivities to kinase inhibitors. The compounds used in this study were originally developed to target Janus kinase, phosphatidylinositol 3-kinase, and MEK. After further validation of the technique, we identified several phosphorylation sites that were inhibited by these compounds but whose intensities did not always correlate with growth inhibition sensitivity. In contrast, several hundred phosphorylation sites that correlated with sensitivity/resistance were not in general inhibited by the compounds. These results indicate that markers of pathway activity may not always be reliable indicators of sensitivity of cancer cells to inhibitors that target such pathways, because the activity of parallel kinases can contribute to resistance. By mining our data we identified protein kinase C isoforms as one of such parallel pathways being more active in resistant cells. Consistent with the view that several parallel kinase pathways were contributing to resistance, inhibitors that target protein kinase C, MEK, and Janus kinase potentiated each other in arresting the proliferation of multidrug-resistant cells. Untargeted/unbiased approaches, such as the one described here, to quantify the activity of the intended target kinase pathway in concert with the activities of parallel kinase pathways will be invaluable to personalize therapies based on kinase inhibitors. PMID- 22547691 TI - Therapeutic procedures for coronary vasospasm-induced polymorphic ventricular tachycardia. AB - Coronary vasospasm is an unusual cause of angina and myocardial ischemia, with the potential to provoke acute myocardial infarction, malignant cardiac arrhythmias, and sudden cardiac death. The diagnosis is largely clinical and requires a high index of suspicion. Provocation studies are rarely performed due to the risks of the procedure and the relatively low incidence of disease. A subset of patients does not respond to conventional medical therapy and a paucity of evidence exists to guide therapy. While generally believed a multifocal phenomenon, there have been reports of successful treatment of focal, refractory vasospasm with coronary stent implantation. Furthermore, consideration of an implantable cardioverter defibrillator is warranted when vasospasm is complicated by lethal ventricular arrhythmias. PMID- 22547692 TI - Management of allergic bronchopulmonary aspergillosis: a review and update. AB - Since the first description of allergic bronchopulmonary aspergillosis (ABPA) in the 1950s there have been numerous studies that have shed light on the characteristics and immunopathogenesis of this disease. The increased knowledge and awareness have resulted in earlier diagnosis and treatment of patients with this condition. This article aims to provide a summary and updates on ABPA by reviewing the results of recent studies on this disease with a focus on articles published within the last 5 years. A systematic search of PubMed/Medline with keywords of ABPA or allergic bronchopulmonary aspergillosis was performed. All selected articles were reviewed with a focus on findings of articles published from December 2006 to December 2011. The relevant findings are summarized in this paper. PMID- 22547693 TI - Crystal structure of cell adhesion molecule nectin-2/CD112 and its binding to immune receptor DNAM-1/CD226. AB - The nectin and nectin-like molecule (Necl) family includes important cell adhesion molecules (CAMs) characterized by their Ig-like nature. Such CAMs regulate a broad spectrum of cell-cell interactions, including the interaction between NK cells and cytotoxic T lymphocytes (CTLs) and their target cells. CAM members nectin-2 (CD112) and Necl-5 (CD155) are believed to form homodimers (for nectin-2) or heterodimers in their functions for cell adhesion, as well as to interact with immune costimulatory receptor DNAX accessory molecule 1 (DNAM-1) (CD226) to regulate functions of both NK and CTL cells. However, the structural basis of the interactive mode of DNAM-1 with nectin-2 or Necl-5 is not yet understood. In this study, a soluble nectin-2 Ig-like V-set domain (nectin-2v) was successfully prepared and demonstrated to bind to both soluble ectodomain and cell surface-expressed full-length DNAM-1. The 1.85-A crystal structure of nectin 2v displays a perpendicular homodimer arrangement, revealing the homodimer characteristics of the nectin and Necls. Further mutational analysis indicated that disruption of the homodimeric interface of nectin-2v led to a failure of the homodimer formation, as confirmed by crystal structure and biochemical properties of the mutant protein of nectin-2v. Interestingly, the monomer mutant also loses DNAM-1 binding, as evidenced by cell staining with tetramers and surface plasmon resonance assays. The data indicate that interaction with DNAM-1 requires either the homodimerization or engagement of the homodimeric interface of nectin-2v. These results have implications for immune intervention of tumors or autoimmune diseases in the DNAM-1/nectin-2-dependent pathway. PMID- 22547694 TI - The size of the plasmacytoid dendritic cell compartment is a multigenic trait dominated by a locus on mouse chromosome 7. AB - Plasmacytoid dendritic cells (pDC) compose one of the many distinct dendritic cell subsets. The primary function of pDC is to potently produce type 1 IFNs upon stimulation, which is highly relevant in antiviral responses. Consequently, the ability to manipulate the size of the pDC compartment in vivo may increase the capacity to clear viral infections. In an attempt to identify genetic loci affecting the size of the pDC compartment, defined by both the proportion and absolute number of pDC, we undertook an unbiased genetic approach. Linkage analysis using inbred mouse strains identified a locus on chromosome 7 (Pdcc1) significantly linked to both the proportion and the absolute number of pDC in the spleen. Moreover, loci on either chromosome 11 (Pdcc2) or 9 (Pdcc3) modified the effect of Pdcc1 on chromosome 7 for the proportion and absolute number of pDC, respectively. Further analysis using mice congenic for chromosome 7 confirmed Pdcc1, demonstrating that variation within this genetic interval can regulate the size of the pDC compartment. Finally, mixed bone marrow chimera experiments showed that both the proportion and the absolute number of pDC are regulated by cell-intrinsic hematopoietic factors. Our findings highlight the multigenic regulation of the size of the pDC compartment and will facilitate the identification of genes linked to this trait. PMID- 22547695 TI - Cyr61 induces IL-6 production by fibroblast-like synoviocytes promoting Th17 differentiation in rheumatoid arthritis. AB - Cysteine-rich protein 61 (Cyr61)/CCN1 is a product of an immediate early gene and functions in mediating cell adhesion and inducing cell migration. We previously showed that increased production of Cyr61 by fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) promotes FLS proliferation and participates in RA pathogenesis with the IL-17-dependent pathway. However, whether Cyr61 in turn regulates Th17 cell differentiation and further enhances inflammation of RA remained unknown. In the current study, we explored the potential role of Cyr61 as a proinflammatory factor in RA pathogenesis. We found that Cyr61 treatment dramatically induced IL-6 production in FLS isolated from RA patients. Moreover, IL-6 production was attenuated by Cyr61 knockdown in FLS. Mechanistically, we showed that Cyr61 activated IL-6 production via the alphavbeta5/Akt/NF-kappaB signaling pathway. Further, using a coculture system consisting of purified CD4(+) T cells and RA FLS, we found that RA FLS stimulated Th17 differentiation, and the pro-Th17 differentiation effect of RA FLS can be attenuated or stimulated by Cyr61 RNA interference or addition of exogenous Cyr61, respectively. Finally, using the collagen-induced arthritis animal model, we showed that treatment with the anti-Cyr61 mAb led to reduction of IL-6 levels, decrease of Th17 response, and attenuation of inflammation and disease progression in vivo. Taken together, our results reveal a novel role of Cyr61 in promoting Th17 development in RA via upregulation of IL-6 production by FLS, thus adding a new layer into the functional interplay between FLS and Th17 in RA pathogenesis. Our study also suggests that targeting of Cyr61 may represent a novel strategy in RA treatment. PMID- 22547696 TI - Dectin-1 stimulation induces suppressor of cytokine signaling 1, thereby modulating TLR signaling and T cell responses. AB - Suppressor of cytokine signaling (SOCS) proteins serve as negative regulators of cytokine receptor signaling. However, SOCS proteins are not only induced via the JAK/STAT pathway, but are also transcribed on triggering of pattern recognition receptors such as TLRs. We now show that SOCS1 can also be induced by the non-TLR pattern recognition receptor Dectin-1 in murine bone marrow-derived dendritic cells and macrophages (BMMs). The C-type lectin Dectin-1 binds to yeasts and signals either in an autonomous manner or can be triggered in combination with TLRs. In our study, SOCS1 was expressed independently of any TLR engagement as a direct target gene of the Dectin-1 ligand Zymosan. Induction of SOCS1 was mediated by a novel pathway encompassing the tyrosine kinases Src and Syk that activated the downstream kinase proline-rich tyrosine kinase 2. Proline-rich tyrosine kinase 2, in turn, caused activation of the MAPK ERK, thereby triggering SOCS1 induction. SOCS1 did not modulate Dectin-1 signaling but affected TLR signaling, leading to decreased and abbreviated NF-kappaB activation in BMMs triggered by TLR9. Furthermore, IL-12 and IL-10 secretion were inhibited by SOCS1. We additionally observed that IL-17-producing Th cells were clearly increased by SOCS1 in BMMs. Our results show that SOCS1 is expressed via a new, NF-kappaB-independent pathway in Dectin-1-triggered murine BMMs and influences TLR cross talk and T cell priming. PMID- 22547697 TI - Defining GM-CSF- and macrophage-CSF-dependent macrophage responses by in vitro models. AB - GM-CSF and M-CSF (CSF-1) induce different phenotypic changes in macrophage lineage populations. The nature, extent, and generality of these differences were assessed by comparing the responses to these CSFs, either alone or in combination, in various human and murine macrophage lineage populations. The differences between the respective global gene expression profiles of macrophages, derived from human monocytes by GM-CSF or M-CSF, were compared with the differences between the respective profiles for macrophages, derived from murine bone marrow cells by each CSF. Only 17% of genes regulated differently by these CSFs were common across the species. Whether a particular change in relative gene expression is by direct action of a CSF can be confounded by endogenous mediators, such as type I IFN, IL-10, and activin A. Time-dependent differences in cytokine gene expression were noted in human monocytes treated with the CSFs; in this system, GM-CSF induced a more dramatic expression of IFN regulated factor 4 (IRF4) than of IRF5, whereas M-CSF induced IRF5 but not IRF4. In the presence of both CSFs, some evidence of "competition" at the level of gene expression was observed. Care needs to be exercised when drawing definitive conclusions from a particular in vitro system about the roles of GM-CSF and M-CSF in macrophage lineage biology. PMID- 22547699 TI - Essential role of IL-4 and IL-4Ralpha interaction in adaptive immunity of zebrafish: insight into the origin of Th2-like regulatory mechanism in ancient vertebrates. AB - The roles of IL-4 and IL-4Ralpha in Th2-mediated immunity have been well characterized in humans and other mammals. In contrast, few reports have been documented in ancient vertebrates. Several putative IL-4- and IL-4Ralpha-like molecules were identified recently from a few fish species, providing preliminary insight into the occurrence of Th2-type immunity in teleosts. However, functional determination still is required to address this hypothesis. To this end, these two molecules were characterized functionally in zebrafish (Danio rerio). Besides the identification of a full-length IL-4Ralpha molecule and an isoform lacking most of the cytoplasmic region as predicted previously, two novel alternatively spliced soluble variants with the extracellular domain only also were identified. Zebrafish IL-4Ralpha (DrIL-4Ralpha) shared overall conserved structural features of the IL-4Ralpha family. Immunofluorescence staining showed that DrIL-4Ralpha distributed on B cells. In vitro binding assays demonstrated that zebrafish IL-4 (DrIL-4) can bind specifically to DrIL-4Ralpha. In vivo administration of DrIL-4 significantly upregulated B cell proliferation and Ab production. These DrIL-4 elicited immune responses were downregulated by the administration of zebrafish soluble IL-4Ralpha or by DrIL-4Ralpha blockade using anti-DrIL-4Ralpha Abs. In addition, Th2-related cytokines or transcription factors were upregulated by DrIL 4. The DrIL-4-DrIL-4Ralpha interaction promoted CD40 expression on B cells and enhanced the CD154-CD40 costimulatory response, both of which are crucial for the initiation of Th2-type immunity. To our knowledge, this is the first report showing that a possible Th2-mediated regulatory mechanism may have appeared before the divergence of teleosts and mammals. These results add greater insight into the evolutionary history of adaptive immunity. PMID- 22547698 TI - Delays and diversions mark the development of B cell responses to Borrelia burgdorferi infection. AB - B cell responses modulate disease during infection with Borrelia burgdorferi, the causative agent of Lyme disease, but are unable to clear the infection. Previous studies have demonstrated that B. burgdorferi infection induces predominantly T independent B cell responses, potentially explaining some of these findings. However, others have shown effects of T cells on the isotype profile and the magnitude of the B. burgdorferi-specific Abs. This study aimed to further investigate the humoral response to B. burgdorferi and its degree of T cell dependence, with the ultimate goal of elucidating the mechanisms underlying the failure of effective immunity to this emerging infectious disease agent. Our study identifies distinct stages in the B cell response using a mouse model, all marked by the generation of unusually strong and persistent T-dependent and T independent IgM Abs. The initial phase is dominated by a strong T-independent accumulation of B cells in lymph nodes and the induction of specific Abs in the absence of germinal centers. A second phase begins around week 2.5 to 3, in which relatively short-lived germinal centers develop in lymph nodes, despite a lymph node architecture that lacks clearly demarcated T and B cell zones. This response failed, however, to generate appreciable numbers of long-lived bone marrow plasma cells. Finally, there is a slow accumulation of long-lived Ab-secreting plasma cells in bone marrow, reflected by a strong but ultimately ineffective serum Ab response. Overall, the study indicates that B. burgdorferi might evade B cell immunity by interfering with its response kinetics and quality. PMID- 22547700 TI - TRPV1 deletion enhances local inflammation and accelerates the onset of systemic inflammatory response syndrome. AB - The transient receptor potential vanilloid 1 (TRPV1) is primarily localized to sensory nerve fibers and is associated with the stimulation of pain and inflammation. TRPV1 knockout (TRPV1KO) mice show enhanced LPS-induced sepsis compared with wild type (WT). This implies that TRPV1 may have a key modulatory role in increasing the beneficial and reducing the harmful components in sepsis. We investigated immune and inflammatory mechanisms in a cecal ligation and puncture (CLP) model of sepsis over 24 h. CLP TRPV1KO mice exhibited significant hypothermia, hypotension, and organ dysfunction compared with CLP WT mice. Analysis of the inflammatory responses at the site of initial infection (peritoneal cavity) revealed that CLP TRPV1KO mice exhibited: 1) decreased mononuclear cell integrity associated with apoptosis, 2) decreased macrophage tachykinin NK(1)-dependent phagocytosis, 3) substantially decreased levels of nitrite (indicative of NO) and reactive oxygen species, 4) increased cytokine levels, and 5) decreased bacteria clearance when compared with CLP WT mice. Therefore, TRPV1 deletion is associated with impaired macrophage-associated defense mechanisms. Thus, TRPV1 acts to protect against the damaging impact of sepsis and may influence the transition from local to a systemic inflammatory state. PMID- 22547701 TI - Wnt5a induces a tolerogenic phenotype of macrophages in sepsis and breast cancer patients. AB - A well-orchestrated inflammatory reaction involves the induction of effector functions and, at a later stage, an active downregulation of this potentially harmful process. In this study we show that under proinflammatory conditions the noncanonical Wnt protein, Wnt5a, induces immunosuppressive macrophages. The suppressive phenotype induced by Wnt5a is associated with induction of IL-10 and inhibition of the classical TLR4-NF-kappaB signaling. Interestingly, this phenotype closely resembles that observed in reprogrammed monocytes in sepsis patients. The Wnt5a-induced feedback inhibition is active both during in vitro LPS stimulation of macrophages and in patients with sepsis caused by LPS containing, gram-negative bacteria. Furthermore, using breast cancer patient tissue microarrays, we find a strong correlation between the expression of Wnt5a in malignant epithelial cells and the frequency of CD163(+) anti-inflammatory tumor-associated macrophages. In conclusion, our data point out Wnt5a as a potential target for an efficient therapeutic modality in severe human diseases as diverse as sepsis and malignancy. PMID- 22547702 TI - Protective role of reactive oxygen species in endotoxin-induced lung inflammation through modulation of IL-10 expression. AB - Reactive oxygen species (ROS) generated by NADPH oxidase are generally known to be proinflammatory, and it seems to be counterintuitive that ROS play a critical role in regulating the resolution of the inflammatory response. However, we observed that deficiency of the p47(phox) component of NADPH oxidase in macrophages was associated with a paradoxical accentuation of inflammation in a whole animal model of noninfectious sepsis induced by endotoxin. We have confirmed this observation by interrogating four separate in vivo models that use complementary methodology including the use of p47(phox-/-) mice, p47(phox-/-) bone marrow chimera mice, adoptive transfer of macrophages from p47(phox-/-) mice, and an isolated perfused lung edema model that all point to a relationship between excessive acute inflammation and p47(phox) deficiency in macrophages. Mechanistic data indicate that ROS deficiency in both cells and mice results in decreased production of IL-10 in response to treatment with LPS, at least in part, through attenuation of the Akt-GSK3-beta signal pathway and that it can be reversed by the administration of rIL-10. Our data support the innovative concept that generation of ROS is essential for counterregulation of acute lung inflammation. PMID- 22547703 TI - Altered Ig hypermutation pattern and frequency in complementary mouse models of DNA polymerase zeta activity. AB - To test the hypothesis that DNA polymerase zeta participates in Ig hypermutation, we generated two mouse models of Pol zeta function: a B cell-specific conditional knockout and a knock-in strain with a Pol zeta mutagenesis-enhancing mutation. Pol zeta-deficient B cells had a reduction in mutation frequency at Ig loci in the spleen and in Peyer's patches, whereas knock-in mice with a mutagenic Pol zeta displayed a marked increase in mutation frequency in Peyer's patches, revealing a pattern that was similar to mutations in yeast strains with a homologous mutation in the gene encoding the catalytic subunit of Pol zeta. Combined, these data are best explained by a direct role for DNA polymerase zeta in Ig hypermutation. PMID- 22547704 TI - CD40 stimulates a "feed-forward" NF-kappaB-driven molecular pathway that regulates IFN-beta expression in carcinoma cells. AB - IFN-beta and the CD40L (CD154) share important roles in the antiviral and antitumor immune responses. In this study, we show that CD40 receptor occupancy results in IFN-beta upregulation through an unconventional "feed-forward" mechanism, which is orchestrated by canonical NF-kappaB and involves the sequential de novo synthesis of IFN regulatory factor (IRF)1 and Viperin (RSAD2), an IRF1 target. RelA (p65) NF-kappaB, IRF1, and Viperin-dependent IRF7 binding to the IFN-beta promoter largely controls its activity. However, full activation of IFN-beta also requires the parallel engagement of noncanonical NF-kappaB2 signaling leading to p52 recruitment to the IFN-beta promoter. These data define a novel link between CD40 signaling and IFN-beta expression and provide a telling example of how signal propagation can be exploited to ensure efficient regulation of gene expression. PMID- 22547705 TI - IL-10+ CTLA-4+ Th2 inhibitory cells form in a Foxp3-independent, IL-2-dependent manner from Th2 effectors during chronic inflammation. AB - Activated Th cells influence other T cells via positive feedback circuits that expand and polarize particular types of response, but little is known about how they may also initiate negative feedback against immunopathological reactions. In this study, we demonstrate the emergence, during chronic inflammation, of GATA 3(+) Th2 inhibitory (Th2i) cells that express high levels of inhibitory proteins including IL-10, CTLA-4, and granzyme B, but do so independently of Foxp3. Whereas other Th2 effectors promote proliferation and IL-4 production by naive T cells, Th2i cells suppress proliferation and IL-4 production. We show that Th2i cells develop directly from Th2 effectors, in a manner that can be promoted by effector cytokines including IL-2, IL-10, and IL-21 ex vivo and that requires T cell activation through CD28, Card11, and IL-2 in vivo. Formation of Th2i cells may act as an inbuilt activation-induced feedback inhibition mechanism against excessive or chronic Th2 responses. PMID- 22547707 TI - The changing standard of care. PMID- 22547706 TI - NLRC4 inflammasome-mediated production of IL-1beta modulates mucosal immunity in the lung against gram-negative bacterial infection. AB - Bacterial flagellin is critical to mediate NLRC4 inflammasome-dependent caspase-1 activation. However, Shigella flexneri, a nonflagellated bacterium, and a flagellin (fliC) knockout strain of Pseudomonas aeruginosa are known to activate NLRC4 in bone marrow-derived macrophages. Furthermore, the flagellin-deficient fliC strain of P. aeruginosa was used in a mouse model of peritonitis to show the requirement of NLRC4. In a model of pulmonary P. aeruginosa infection, flagellin was shown to be essential for the induction of NLRC4-dependent caspase-1 activation. Moreover, in all P. aeruginosa studies, IL-1beta production was attenuated in NLRC4(-/-) mice; however, the role of IL-1beta in NLRC4-mediated innate immunity in the lungs against a nonflagellated bacterium was not explored. In this article, we report that NLRC4 is important for host survival and bacterial clearance, as well as neutrophil-mediated inflammation in the lungs following Klebsiella pneumoniae infection. NLRC4 is essential for K. pneumoniae induced production of IL-1beta, IL-17A, and neutrophil chemoattractants (keratinocyte cell-derived chemokines, MIP-2, and LPS-induced CXC chemokines) in the lungs. NLRC4 signaling in hematopoietic cells contributes to K. pneumoniae induced lung inflammation. Furthermore, exogenous IL-1beta, but not IL-18 or IL 17A, partially rescued survival, neutrophil accumulation, and cytokine/chemokine expression in the lungs of NLRC4(-/-) mice following infectious challenge. Furthermore, IL-1R1(-/-) mice displayed a decrease in neutrophilic inflammation in the lungs postinfection. Taken together, these findings provide novel insights into the role of NLRC4 in host defense against K. pneumoniae infection. PMID- 22547708 TI - Minority practitioners. PMID- 22547710 TI - HPV and oral health. PMID- 22547712 TI - Response from Drs. Syrjanen and Rautava. PMID- 22547711 TI - Response from Dr. Cleveland and colleagues. PMID- 22547713 TI - Bitemark analysis. PMID- 22547716 TI - The assessment of dentofacial esthetics in restorative dentistry: a review of the literature. AB - BACKGROUND: The authors conducted a literature review to determine how dentofacial esthetics can be evaluated in restorative dentistry and which quantifiable clinical parameters can be used for this assessment of dentofacial esthetics. TYPES OF STUDIES REVIEWED: The authors selected 35 studies that focused on assessment strategies for dental professionals. The primary inclusion criteria were intraoral and extraoral esthetic assessment methods and indexes or rating scales evaluating esthetics in restorative dentistry. RESULTS: The studies' protocols and assessment methods were heterogeneous. The authors grouped the studies into six categories according to topic: golden proportion, soft tissue measurement, smile and smile line assessment, orofacial indexes and scales, incisor proportion and angulation, and facial esthetics. These categories included various esthetic parameters, including the smile line, lip line, incisal offset, location of dental and facial midline, incisor angulations and width to height ratios of the maxillary anterior teeth, gingival contour, and root coverage and papilla height. These parameters should be considered when providing dental treatment in the anterior area, as they allow for quantification and objective judgment. CLINICAL IMPLICATIONS: The findings of this review might increase interest in a comprehensive dental esthetic index that allows for objective quantification and intrastudy and interstudy comparison of dental treatment outcomes. PMID- 22547715 TI - An analysis of dentists' incomes, 1996-2009. AB - BACKGROUND: The U.S. economy is beginning to recover from the most significant contraction since the Great Depression. Several sectors, including dentistry, have experienced reduced consumer demand and reduced earnings. Focusing on general practitioners, the authors analyzed trends in various factors that drive dentists' income to identify which of these factors are most important in explaining the recent decline. They then offer their views on future trends in dentists' net income levels. METHODS: The authors used data from a nationally representative survey of dentists maintained by the American Dental Association (ADA) and data from the Agency for Healthcare Research and Quality's Medical Expenditure Panel Survey to analyze trends in real gross billings per visit, rates of collection of gross billings, number of visits to a dentist, percentage of the population who visited a dentist, population to dentist ratio and average real practice expenses. RESULTS: The authors found that the recent decrease in dentists' net income levels was driven primarily by a decrease in utilization of dental care on the part of the population. Moreover, this decline in dental care use, although most pronounced during the economic downturn, appeared to have started before the downturn began. This suggests that more factors than solely the economic recession are affecting changes in dental care utilization patterns. CONCLUSIONS: The authors' findings suggest that average real net income for dentists may not necessarily recover to prerecession levels once economic conditions in the United States improve. This finding, combined with the potential implications of health care reform for dentistry, causes the authors to believe the future prospects related to dentists' net income levels remain uncertain. PMID- 22547717 TI - Pigmented lesion of the ear. PMID- 22547718 TI - The effect of long-term disinfection on clinical contact surfaces. AB - BACKGROUND: The author measured the effect long-term disinfection had on common types of dental office environmental surfaces. METHODS: The author tested nine common dental surfaces and six spray disinfectants, as well as a tap water control. The author used the "spray-wipe-spray" method with paper towels to disinfect the surfaces. Each surface was disinfected 1,920 times, which was an estimate of the number of cleanings per year. After every 100 disinfections, the author conducted blood removal testing of the surface, which monitored residual blood and disinfectant cleaning ability. RESULTS: The surface that was most difficult to clean was textured vinyl, followed by smooth vinyl, enameled metal, service line rubber hosing and brushed aluminum. Diluted bleach affected surfaces the most, which resulted in higher blood removal scores. CONCLUSIONS: When compared with the control, Birex SE had equal or better cleaning scores across time, which might indicate that its use caused little change in the integrity of the surfaces. The results for the other disinfectants varied. CLINICAL IMPLICATIONS: Disinfectants should have good antimicrobial activity and minimal negative impact on the integrity of the surfaces being disinfected. Effective disinfection is highly dependent on efficient cleaning (removal of the bioburden present). PMID- 22547720 TI - Correlates of change in self-perceived oral health among older adults in Brazil: findings from the Health, Well-Being and Aging Study. AB - BACKGROUND: Identifying changes in the oral health status of older populations, and their predictors and explanations, is necessary for public health planning. The authors assessed patterns of change in oral health-related quality of life in a large cohort of older adults in Brazil during a five-year period and evaluated associations between baseline characteristics and those changes. METHODS: The sample consisted of 747 older people enrolled in a Brazilian cohort study called the Health, Well-Being and Aging (Saude, Bem-estar e Envelhecimento [SABE]) Study. Trained examiners measured participants' self-perceived oral health by using the General Oral Health Assessment Index (GOHAI). The authors calculated changes in the overall GOHAI score and in the scores for each of the GOHAI's three dimensions individually by subtracting the baseline score from the score at follow-up. A positive difference indicated improvement in oral health, a negative difference indicated a decline and a difference of zero indicated no change. RESULTS: The authors found that 48.56 percent of the participants experienced a decline in oral health and 33.48 percent experienced an improvement. Participants with 16 or more missing teeth and eight or more years of education were more likely to have an improvement in total GOHAI score. Deterioration was more likely to occur among those with two or more diseases. Improvement and decline in GOHAI functional scores were related to the number of missing teeth. The authors found no significant model for the change in the psychosocial score, and self-rated general health was the only variable related to both improvement and decline in pain or discomfort scores. CONCLUSIONS: The authors observed a bidirectional change in self-perceived oral health, with deterioration predominating. The strongest predictor of improvement in the total GOHAI score was the number of missing teeth, whereas the number of diseases was the strongest predictor of deterioration. CLINICAL IMPLICATIONS: Dental professionals and policymakers need to know the directions of change in older adults' oral health to establish treatment priorities and evaluate the impact of services directed at this population. PMID- 22547721 TI - Pulp extirpation within 14 days after tooth replantation reduces inflammatory root resorption. PMID- 22547719 TI - Outcomes of endodontic therapy in general practice: a study by the Practitioners Engaged in Applied Research and Learning Network. AB - BACKGROUND: The authors undertook a study involving members of a dental practice based research network to determine the outcome and factors associated with success and failure of endodontic therapy. METHODS: Members in participating practices (practitioner-investigators [P-Is]) invited the enrollment of all patients seeking treatment in the practice who had undergone primary endodontic therapy and restoration in a permanent tooth three to five years previously. If a patient had more than one tooth so treated, the P-I selected as the index tooth the tooth treated earliest during the three- to five-year period. The authors excluded from the study any teeth that served as abutments for removable partial dentures or overdentures, third molars and teeth undergoing active orthodontic endodontic therapy. The primary outcome was retention of the index tooth. Secondary outcomes, in addition to extraction, that defined failure included clinical or radiographic evidence (or both) of periapical pathosis, endodontic retreatment or pain on percussion. RESULTS: P-Is in 64 network practices enrolled 1,312 patients with a mean (standard deviation) time to follow-up of 3.9 (0.6) years. During that period, 3.3 percent of the index teeth were extracted, 2.2 percent underwent retreatment, 3.6 percent had pain on percussion and 10.6 percent had periapical radiolucencies for a combined failure rate of 19.1 percent. The presence of preoperative periapical radiolucency with a diagnosis of either irreversible pulpitis or necrotic pulp was associated with failure after multivariate analysis, as were multiple canals, male sex and Hispanic/Latino ethnicity. CONCLUSIONS: These results suggest that failure rates for endodontic therapy are higher than previously reported in general practices, according to results of studies based on dental insurance claims data. CLINICAL IMPLICATIONS: The results of this study can help guide the practitioner in deciding the most appropriate course of therapy for teeth with irreversible pulpitis, necrotic pulp or periapical periodontitis. PMID- 22547722 TI - Human trafficking and the dental professional. AB - BACKGROUND: "Human trafficking" is a term for a modern form of slavery. It is a criminal human rights violation and a significant health issue. Dental professionals can assist in recognizing victims of trafficking. METHODS: The author conducted a PubMed search of the English-language literature through May 2011, which yielded no articles meeting the search criteria "dentistry" and "human trafficking prostitution." Given these results, the author reviewed articles published in medical journals, reports from both governmental and nongovernmental agencies and lay literature. RESULTS: The author examines the present state of human trafficking and provides information--including specific questions to ask--to help dentists identify victims. In addition, the author suggests means of notifying authorities and assisting trafficking victims. He also examines the health care needs of these patients. CONCLUSION: Human trafficking is a global problem, with thousands of victims in the United States, including many women and children. Dentists have a responsibility to act for the benefit of others, which includes detecting signs of abuse and neglect. CLINICAL IMPLICATIONS: Dental professionals are on the front lines with respect to encountering and identifying potential victims who seek dental treatment. Dentists can combat human trafficking by becoming informed and by maintaining vigilance in their practices. PMID- 22547723 TI - The importance of practice valuation. PMID- 22547724 TI - For the dental patient. Restoring your smile with dentures. PMID- 22547725 TI - The effect of at-home bleaching and toothbrushing on removal of coffee and cigarette smoke stains and color stability of enamel. AB - BACKGROUND: The authors conducted a study to evaluate the stain removal ability of tooth bleaching and simulated toothbrushing after coffee and cigarette smoke staining and to determine the enamel susceptibility to restaining. METHODS: The authors used a colorimeter to determine the baseline color of 40 bovine labial enamel surfaces according to the Commission Internationale de l'Eclairage L*a*b* coordinates. They immersed one-half of the specimens in coffee and exposed one half to cigarette smoke in a smoking machine. They took color measurements again and determined the color change from baseline (DeltaE1) for each group. The authors divided each group into two subgroups and subjected the specimens to at home bleaching (one hour per day for 21 days) or simulated toothbrushing (120 cycles per day for 21 days), followed by another color measurement (DeltaE2). The authors repeated both staining procedures (that is, cigarette smoke and coffee) and followed them with a third color measurement (DeltaE3). They analyzed the data by using a two-way analysis of variance and the Tukey test (alpha = 5 percent). RESULTS: Both staining procedures resulted in similar values for DeltaE1. The specimens stained with coffee and cigarette smoke exhibited a significant reduction in color change after bleaching (P < .05). However, toothbrushing resulted in a significantly reduced color change only for cigarette smoke-stained specimens (P < .001). The discoloration in coffee-stained specimens increased after restaining, irrespective of the stain removal method (P < .05). CONCLUSIONS: The study results show that at-home bleaching removed both coffee and cigarette smoke staining. The restaining potential was greater for specimens stained with coffee than for those stained with cigarette smoke, regardless of the removal method used. CLINICAL IMPLICATIONS: Six percent hydrogen peroxide at home bleaching was effective in removing stains caused by coffee or cigarette smoke. However, continued frequent consumption of coffee can increase the staining susceptibility of enamel. PMID- 22547726 TI - Primary care providers and practice locations: examining the relationships. AB - BACKGROUND: The authors conducted a study in which they explored the geographical distributions of primary care dentists, physicians and pharmacists to determine if a spatial pattern existed between provider types across cities in Iowa. METHODS: The authors analyzed practice locations of primary care providers, including dentists, pharmacists and physicians, at the city and county levels in Iowa for 2000 and 2010. They categorized cities on the basis of types of primary care providers in each city and compared population characteristics. RESULTS: Among cities with primary care providers of any type, the most common scenario was for all three provider types to be found together. Several cities that had at least one physician and pharmacist but no dentist in 2000 gained one by 2010. CONCLUSIONS: There appears to be a heterarchy of primary care providers in Iowa cities, with pharmacists more prevalent than physicians and dentists. CLINICAL IMPLICATIONS: Communities with at least one physician and pharmacist but no dentist may be able to offer new or relocating dentists a competitive opportunity for practice. PMID- 22547727 TI - Laparoscopic or open distal gastrectomy after neoadjuvant chemotherapy for operable gastric cancer, a randomized Phase II trial (LANDSCOPE trial). AB - This randomized Phase II trial will compare the efficacy and safety of laparoscopy-assisted D2 distal gastrectomy and open distal D2 gastrectomy after neoadjuvant chemotherapy for patients with macroscopically resectable serosa positive gastric cancer. When R0/R1 surgery is achieved, patients receive S-1 chemotherapy for 1-year post-operatively. The primary endpoint is the 3-year disease-free survival. The sample size to test the hypothesis of the non inferiority of laparoscopy-assisted D2 distal gastrectomy to open distal D2 gastrectomy is 80. This trial will be able to appraise the use of the laparoscopic approach as a curative D2 distal gastrectomy after neoadjuvant chemotherapy for gastric cancer. PMID- 22547728 TI - Defining PET standardized uptake value threshold for tumor delineation with metastatic lymph nodes in head and neck cancer. AB - OBJECTIVE: Hot spots of F-18 fluorodeoxyglucose positron emission tomograms are variable in size according to window settings of standardized uptake values. The purpose of this study was to determine the standardized uptake value threshold that represents the target volume. METHODS: Sixty-three patients who underwent fluorodeoxyglucose positron emission tomographic computed tomography and were diagnosed as having head and neck cancer with cervical lymphadenopathy were studied. The horizontal and vertical diameters of metastatic lymph nodes (LN-CT) were measured at the center of computed tomographic images. Of the corresponding nodes, the maximal standardized uptake value (SUVmax) and standardized uptake value profiles along the central horizontal and vertical axes were calculated on positron emission tomographic images (LN-PET). On the standardized uptake value profiles, the standardized uptake value levels (SUVeq) where the size of LN-PET was equivalent to the diameters of LN-CT were obtained. The regression formula between SUVeq and SUVmax was obtained. The regression formula of SUVeq was validated in subsequent 30 positron emission tomographic computed tomography studies. RESULTS: The mean horizontal and vertical diameters of LN-CT were 14.9 and 16.4 mm, respectively. SUVmax ranged from 1.88 to 9.07, and SUVeq was between 1.16 and 6.42. The regression formula between SUVeq and SUVmax was as follows: SUVeq = 1.21 + 0.34 * SUVmax (coefficient of correlation: R = 0.69). The validation study resulted in a good correlation between the volume of lymph nodes on computed tomography and positron emission tomographic computed tomography (R(2) = 0.93). CONCLUSIONS: The formula with a relatively high coefficient of correlation is considered to indicate that SUVeq is not constant, but is a complex of an absolute standardized uptake value and is proportional to SUVmax. PMID- 22547729 TI - The role of informed consent in tuberculosis testing and screening. PMID- 22547730 TI - Another brick in the wall: adrenomedullin and prognosis in community-acquired pneumonia. PMID- 22547731 TI - Progress in modelling acute lung injury in a pre-clinical mouse model. PMID- 22547732 TI - Stitching and switching: the impact of discontinuous lung function reference equations. PMID- 22547733 TI - Bronchial and alveolar components of exhaled nitric oxide and their relationship. PMID- 22547734 TI - Efficacy of nebulised liposomal amphotericin B in the attack and maintenance treatment of ABPA. PMID- 22547736 TI - Risk factors for drug-resistant tuberculosis patients in Lithuania, 2002-2008. PMID- 22547737 TI - Early tuberculosis treatment monitoring by Xpert(R) MTB/RIF. PMID- 22547735 TI - Proficiency testing of first- and second-line anti-tuberculosis drugs in Italy. PMID- 22547738 TI - New opportunities in tuberculosis control. PMID- 22547739 TI - Which is the principal early-life infection-related risk factor for asthma? PMID- 22547740 TI - Linezolid: safety and efficacy monitoring. PMID- 22547742 TI - Recommendations for epidemiological studies on COPD. PMID- 22547745 TI - Use of implantable cardioverter defibrillators in patients with left ventricular assist devices. AB - Patients with left ventricular assist devices (LVADs) are at high risk of sustained ventricular arrhythmias, but these may be remarkably well tolerated and the association with sudden death is unclear. Many patients who receive an LVAD already have an implantable cardioverter defibrillator (ICD). While it is standard practice to reactivate a previously implanted ICD in an LVAD recipient, this should include discussion of the revised risks and benefits of ICD therapy following LVAD implantation. In particular, patients should be warned that they might receive a significant number of ICD shocks that may not be life saving. When ICDs are reactivated, device programming should minimize the risk of repeated shocks for non-sustained or well-tolerated ventricular arrhythmias. Implantation of a primary prevention ICD after implantation of an LVAD is not supported by current evidence, poses potential risks, and should be the subject of a clinical trial before it becomes standard practice. PMID- 22547746 TI - Opening a treasure chest: glomerular proteome analyses of formalin-fixed paraffin embedded kidney tissue in the investigation of diabetic nephropathy. PMID- 22547747 TI - Can inhibition of proteasomes or NF-kappaB help control idiopathic nephrotic syndrome? PMID- 22547748 TI - Measurement of serum soluble Klotho levels in CKD 5D patients: useful tool or dispensable biomarker? PMID- 22547749 TI - Cellular adaptive changes in AKI: mitigating renal hypoxic injury. AB - Hypoxia plays a role in ischemic, toxic and sepsis-induced acute kidney injury. Evolving hypoxia triggers renal adaptive responses that may mitigate the insult, leading to sublethal forms of cell injury. The unique capability of the kidney to downregulate oxygen consumption for tubular transport could represent one such adaptive response which promotes maintenance of renal oxygenation, thereby preserving cellular integrity. Tran et al. recently explored a novel mechanism that might prevent tubular damage by downregulation of mitochondrial biogenesis and oxygen consumption. Using expression profiling of kidney RNA in endotoxemic rodents and complementary studies in vitro and in PGC-1alpha knockout mice, they found a sepsis-related decline in PPARgamma coactivator-1alpha (PGC-1alpha) expression and of PGC-1alpha-dependent genes involved in oxidative phosphorylation. This response may explain their observation of a paradoxical preservation of kidney oxygenation and structural integrity in sepsis, despite reduced renal blood flow and oxygen delivery. Thus, resetting of mitochondrial respiration and oxygen consumption during sepsis might be added to the growing list of adaptive responses that occur during hypoxic stress. This review will focus on these mechanisms that mitigate evolving hypoxic injury, even at the expense of transient renal dysfunction. PMID- 22547751 TI - Pre-dialysis creatinine and interdialytic change in creatinine as nutritional markers in haemodialysis patients. PMID- 22547750 TI - Primary hyperoxaluria Type 1: indications for screening and guidance for diagnosis and treatment. AB - Primary hyperoxaluria Type 1 is a rare autosomal recessive inborn error of glyoxylate metabolism, caused by a deficiency of the liver-specific enzyme alanine:glyoxylate aminotransferase. The disorder results in overproduction and excessive urinary excretion of oxalate, causing recurrent urolithiasis and nephrocalcinosis. As glomerular filtration rate declines due to progressive renal involvement, oxalate accumulates leading to systemic oxalosis. The diagnosis is based on clinical and sonographic findings, urine oxalate assessment, enzymology and/or DNA analysis. Early initiation of conservative treatment (high fluid intake, pyridoxine, inhibitors of calcium oxalate crystallization) aims at maintaining renal function. In chronic kidney disease Stages 4 and 5, the best outcomes to date were achieved with combined liver-kidney transplantation. PMID- 22547752 TI - Glomerular density and progression. PMID- 22547754 TI - Hemodynamics in the cardiac catheterization laboratory of the 21st century. PMID- 22547755 TI - Prevention of venous thromboembolism in total knee and hip replacement. PMID- 22547756 TI - Food and Drug Administration's Obesity Drug Guidance Document: a short history. PMID- 22547757 TI - Left ventricular cardiac cyst: unusual echocardiographic appearance of a cardiac hemangioma. PMID- 22547758 TI - Common carotid artery dissection caused by a frontal thrust in Kendo (Japanese swordsmanship). PMID- 22547760 TI - Letter by Ahmed regarding article, "Second internal thoracic artery versus radial artery in coronary artery bypass grafting: a long-term, propensity score-matched follow-up study". PMID- 22547761 TI - Letter by Edelman et al regarding article, "Second internal thoracic artery versus radial artery in coronary artery bypass grafting: a long-term, propensity score-matched follow-up study". PMID- 22547762 TI - Letter by Yasue et al regarding article, "Mechanisms of coronary artery spasm". PMID- 22547763 TI - Letter by Singh regarding article, "Peak oxygen uptake correlates with survival without clinical deterioration in ambulatory children with dilated cardiomyopathy". PMID- 22547764 TI - Non-apical pacing: the right place to the right patient. PMID- 22547765 TI - Safety and efficacy of programming a high number of antitachycardia pacing attempts for fast ventricular tachycardia: a prospective study. AB - AIMS: Little is known about the optimal number of antitachycardia pacing (ATP) attempts to programme in the fast ventricular tachycardia (FVT) zone. We sought to analyse the long-term efficacy and safety of programming a high number of ATP attempts for FVTs. METHODS AND RESULTS: All patients receiving an implantable cardioverter/defibrillator (ICD) for coronary artery disease or dilated cardiomyopathy for primary and secondary prevention between 2000 and 2009 were prospectively included. Implantable cardioverter/defibrillators were programmed to deliver 10 ATP attempts for FVT cycle lengths (CLs) of 250-300 ms (200-240 b.p.m.) before shock delivery (5 bursts, then 5 ramps; 8-10 extrastimuli at 81 88% FVT CL; minimal pacing CL 180 ms). Among 770 patients included and followed for 40.6 +/- 25.6 months, 137 (17.8%) experienced a total of 1839 FVTs, 1713 of which were ATP-terminated (unadjusted efficacy = 93.1%, adjusted = 81.7%), 106 ATP-accelerated (5.8%), and 20 ATP-resistant (1.1%). The majority of FVT episodes were successfully treated by one or two attempts (98.3%). However, patient-based analysis showed that 17 (12.4%), 8 (5.8%), and 5 patients (2.1%) had at least one episode treated by three or more, four or more, and five or more ATP attempts. The benefit of this strategy was reduced after five attempts. The majority of FVT episodes was asymptomatic and diagnosed at device interrogation during follow-up: syncope and pre-syncope occurred in only 0.2 and 0.4% of episodes, respectively. CONCLUSION: Programming a high number of ATP attempts (up to five ATP attempts) in the FVT zone is both safe and efficient and could prevent shocks in numerous ICD recipients. PMID- 22547766 TI - Long-term follow-up after cryoablation for adolescent atrioventricular nodal reentrant tachycardia: recurrence is not predictable. AB - AIMS: Data about the long-term outcome after cryoablation for atrioventricular nodal reentrant tachycardia (AVNRT) in the paediatric population indicate that recurrence rates are higher with cryo than with radiofrequency energy (RF). The purpose of this study was to review our institutional long-term outcome after cryoablation for AVNRT and to seek for predictors of recurrence. METHODS AND RESULTS: Forty-nine patients (28 female, age 14 +/- 2.7 years) undergoing slow pathway modulation or ablation for AVNRT at our institution from 2004 to 2008 were included in the study. Acute success was obtained in all patients (100%) with a mean procedure time of 164 +/- 50 min and a mean fluoroscopy time of 13 +/ 8 min. During a follow-up time of 30 +/- 1.9 months, AVNRT recurrence occurred in 11/49 patients (22.4%). Age, sex, number of cryomappings or ablations, catheter tip (4 mm vs. 6 mm), or ablation endpoint (slow-pathway ablation vs. modulation) were not predictive for recurrence. In eight patients, reablation using cryo was performed. All these patients remained free of arrhythmia symptoms during a follow-up of 30 +/- 8 months following the second procedure. CONCLUSION: Although cryoablation for the treatment for AVNRT in paediatric and adolescent patients is safe and associated with a high acute success rate, AVNRT recurrence occurs in 22% of patients during long-term follow-up without identifiable predictors for recurrence. A second cryoablation procedure leads to a success rate of 100% during long-term follow-up. PMID- 22547768 TI - Value of the aVR lead in differential diagnosis of atrioventricular nodal reentrant tachycardia. AB - AIMS: Despite the several electrocardiographic (ECG) criteria, misclassification may still occur in differential diagnosis of the regular paroxysmal supraventricular tachycardia (PSVT). The aim of the present study was to evaluate the diagnostic accuracy of the aVR lead in ECG differentiation of atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular reciprocating tachycardia (AVRT). METHODS AND RESULTS: A 12-lead ECG was recorded in 150 consecutive patients (96 women, mean age, 45 +/- 13.5 years) with drug refractory regular PSVT during both sinus rhythm and tachycardia. All ECGs were reviewed by two experienced electrophysiologists who had no knowledge of the tachycardia mechanism. The ECG recordings were evaluated for standard criteria as well as our newly proposed criterion of pseudo-r' in the lead aVR. Mechanism of arrhythmia was confirmed by the electrophysiological study and the successful catheter ablation. Patients with AVNRT were older (50 +/- 10 vs. 37 +/- 15 years, P = 0.001), predominantly female (71 vs. 53%, P = 0.03), and presented with slower tachycardia (175 +/- 25 vs. 186 +/- 26 b.p.m., P = 0.01). Among the ECG criteria of the AVRT diagnosis, visible P-wave with RP interval >= 100 ms had highest diagnostic accuracy (sensitivity 79%, specificity 87%, and positive predictive value 79%). For AVNRT diagnosis, pseudo-r' in aVR had a higher sensitivity, specificity, and predictive values compared with the conventional criteria of the pseudo-r' in V1 and pseudo-s in inferior leads (all P < 0.05). CONCLUSIONS: New criterion of pseudo-r' in lead aVR appears to be more accurate than the standard ECG criteria for ECG diagnosis of AVNRT. PMID- 22547767 TI - First inappropriate implantable cardioverter defibrillator therapy is often due to inaccurate device programming: analysis of the French OPERA registry. AB - AIMS: Inappropriate therapy delivered by implantable cardioverter defibrillators (ICDs) remains a challenge. The OPERA registry measured the times to, and studied the determinants of, first appropriate (FAT) and inappropriate (FIT) therapies delivered by single-, dual- and triple-chamber [cardiac resynchronization therapy defibrillator (CRT-D)] ICD. METHODS AND RESULTS: We entered 636 patients (mean age = 62.0 +/- 13.5 years; 88% men) in the registry, of whom 251 received single , 238 dual-, and 147 triple-chamber ICD, for primary (30.5%) or secondary (69.5%) indications. We measured times to FAT and FIT as a function of multiple clinical characteristics, examined the effects of various algorithm components on the likelihood of FAT and FIT delivery, and searched for predictors of FAT and FIT. Over 22.8 +/- 8.8 months of observation, 184 patients (28.9%) received FAT and 70 (11.0%) received FIT. Ventricular tachycardia (VT) was the trigger of 88% of FAT, and supraventricular tachycardia was the trigger of 91% of FIT. The median times to FIT (90 days; range 49-258) and FAT (171 days; 50-363) were similar. The rate of FAT was higher (P <0.001) in patients treated for secondary than primary indications, while that of FIT were similar in both groups. Out of 57 analysable FIT, 27 (47.4%) could have been prevented by fine tuning the device programming like the sustained rate duration or the VT discrimination algorithm. CONCLUSIONS: First inappropriate therapy occurred in 11% of 636 ICD recipients followed for ~2 years. Nearly 50% of FIT could have been prevented by improving device programming. PMID- 22547769 TI - Calcium- and integrin-binding protein-1 and calcineurin are upregulated in the right atrial myocardium of patients with atrial fibrillation. AB - AIMS: The aim of this study was to determine whether altered expression and distribution of calcium- and integrin-binding protein-1 (CIB1) is involved in the pathogenesis of different types of patients with atrial fibrillation (AF) associated with valvular heart disease (VHD). METHODS AND RESULTS: Right atrial specimens obtained from 65 patients undergoing valve replacement surgery were divided into three groups: sinus rhythm group (n= 24), paroxysmal atrial fibrillation group (PaAF; n= 10), and persistent atrial fibrillation group (PeAF; AF lasting >6 month; n= 31). The expression levels of mRNA and protein content for CIB1, calcineurin B, calcineurin A, and Na(+)-Ca(2+) exchanger-1 (NCX1) were measured. We also measured the combination of CIB1 with calcineurin B, L-type Ca(2+) channel, and NCX1 using immunoprecipitation. Expression of mRNA and protein content of CIB1, calcineurin B, calcineurin A, and NCX1 was increased in the AF group. Calcium- and integrin-binding protein-1 interacted with calcineurin B and L-type Ca(2+) channel. Surprisingly, CIB1 also combined with NCX1. CONCLUSIONS: The CIB1 and calcineurin expression was increased in AF atrial tissue and was related to the type of AF. This finding suggests that CIB1 may be involved in the pathogenesis of AF in VHD patients. PMID- 22547770 TI - Crizotinib for ALK-rearranged non-small cell lung cancer: a new targeted therapy for a new target. AB - Crizotinib (PF02341066, Xalkori; Pfizer) was recently approved by the U.S. Food and Drug Administration for treatment of ALK-positive non-small cell lung cancer (NSCLC) as defined by a jointly approved diagnostic test using a break-apart fluorescence in situ hybridization assay. The approval was based on dramatic response rates in ALK-positive NSCLC patients of 54% to 61% in phase I and II trials. To date, the overall disease control rates in these trials are close to 90%. Progression-free survival approaches 10 months. This review focuses on the ALK-inhibitory activity of crizotinib in preclinical and clinical trials that led to approval, as well as the diagnostic methods to classify patients with ALK positive NSCLC. Although these patients represent a small subset of all patients with NSCLC, the rapid time course from identification of this unique target to an approved targeted therapy with striking benefit serves as a paradigm for the development of targeted therapeutics in an era of personalized medicine. PMID- 22547771 TI - LY2109761 attenuates radiation-induced pulmonary murine fibrosis via reversal of TGF-beta and BMP-associated proinflammatory and proangiogenic signals. AB - PURPOSE: Radiotherapy is used for the treatment of lung cancer, but at the same time induces acute pneumonitis and subsequent pulmonary fibrosis, where TGF-beta signaling is considered to play an important role. EXPERIMENTAL DESIGN: We irradiated thoraces of C57BL/6 mice (single dose, 20 Gy) and administered them a novel small-molecule TGF-beta receptor I serine/threonine kinase inhibitor (LY2109761) orally for 4 weeks before, during, or after radiation. Noninvasive lung imaging including volume computed tomography (VCT) and MRI was conducted 6, 16, and 20 weeks after irradiation and was correlated to histologic findings. Expression profiling analysis and protein analysis was conducted in human primary fibroblasts. RESULTS: Radiation alone induced acute pulmonary inflammation and lung fibrosis after 16 weeks associated with reduced life span. VCT, MRI, and histology showed that LY2109761 markedly reduced inflammation and pulmonary fibrosis resulting in prolonged survival. Mechanistically, we found that LY2109761 reduced p-SMAD2 and p-SMAD1 expression, and transcriptomics revealed that LY2109761 suppressed expression of genes involved in canonical and noncanonical TGF-beta signaling and downstream signaling of bone morphogenetic proteins (BMP). LY2109761 also suppressed radiation-induced inflammatory [e.g., interleukin (IL)-6, IL-7R, IL-8] and proangiogenic genes (e.g., ID1) indicating that LY2109761 achieves its antifibrotic effect by suppressing radiation-induced proinflammatory, proangiogenic, and profibrotic signals. CONCLUSION: Small molecule inhibitors of the TGF-beta receptor I kinase may offer a promising approach to treat or attenuate radiation-induced lung toxicity or other diseases associated with fibrosis. PMID- 22547772 TI - Combining antiangiogenics to overcome resistance: rationale and clinical experience. AB - Antiangiogenic therapies are now well established in oncology clinical practice; however, despite initial optimism, the results of late-phase trials, especially in the adjuvant setting, have largely proved disappointing. In the context of metastatic disease, resistance to antiangiogenic agents arises through a range of mechanisms, including the development of alternative angiogenic pathways. One of the proposed strategies to overcome this resistance is to combine antiangiogenic agents with different mechanisms of action. Early-phase clinical trials assessing the tolerability and efficacy of different combinations of antiangiogenic drugs, including those that target the VEGF pathway or the angiopoietins, as well as vascular disrupting agents, are increasing in number. An example of this strategy is the combination of sorafenib and bevacizumab, which has elicited major responses in different tumor types, including ovarian carcinoma and glioblastoma. However, overlapping and cumulative toxicities pose a real challenge. This review summarizes the preclinical rationale for this approach and current clinical experience in combining antiangiogenic therapies. PMID- 22547774 TI - Teaching neuroimages: a prematurely aging patient presenting with severe leukoaraiosis and stroke. PMID- 22547773 TI - Ribonucleotide reductase large subunit (RRM1) gene expression may predict efficacy of adjuvant mitotane in adrenocortical cancer. AB - PURPOSE: Mitotane is the most broadly used systemic therapy for adrenocortical carcinoma (ACC), but its mechanism of action and possible predictors of treatment response are currently poorly defined. Our aim was to evaluate the gene expression of ribonucleotide reductase large subunit 1 (RRM1) and excision repair cross-complementation group 1 (ERCC1) in ACC as potential biomarkers for clinical outcome and response to mitotane. EXPERIMENTAL DESIGN: Forty-five and 47 tissue samples from two cohorts (Orbassano, Italy; Wuerzburg, Germany) of completely resected ACC were centrally analyzed using real-time PCR for RRM1 and ERCC1 expression. Fifty-four patients received surgery alone and 38 received adjuvant mitotane after surgery. Clinical and pathologic features were highly comparable in the two series. H295R and SW-13 ACC cell lines were also used for pharmacologic tests. RESULTS: ERCC1 gene expression was not associated to clinical outcome. In contrast, high RRM1 gene expression was associated to shorter disease-free survival (DFS) and overall survival at both univariate and multivariate analysis. In patients with low RRM1 gene expression, adjuvant mitotane was associated with improved DFS, whereas this effect was lost in cases with high RMM1 expression. In vitro mitotane induced strong up regulation of RRM1 transcription (up to 25-fold increase) in mitotane-insensitive SW-13 but not in mitotane-sensitive H295R cells. Furthermore, RRM1 silencing in SW-13 cells induced sensitivity to mitotane. CONCLUSION: Our in vitro and in vivo data indicate that RRM1 gene expression is functionally associated to mitotane sensitivity and support a possible role of RRM1 determination as a novel molecular biomarker predicting response to adjuvant mitotane in ACC. PMID- 22547776 TI - Teaching neuroImages: MRI changes in superficial siderosis. PMID- 22547777 TI - Variations in daily cigarette consumption on work days compared with nonwork days and associations with quitting: findings from the international tobacco control four-country survey. AB - INTRODUCTION: We explore whether reported daily cigarette consumption differs between work days and nonwork days and whether variation in consumption between work days and nonwork days influences quitting and abstinence from smoking. We also explore whether effects are independent of measures of addiction and smoking restrictions at work and home. METHODS: Data were from 5,732 respondents from the first five waves of the International Tobacco Control Four-Country Survey, occurring between 2002 and 2006. Respondents were current smokers employed outside the home. Variation in daily cigarette consumption on work days compared with nonwork days at one wave was used to predict the likelihood of making an attempt and the likelihood of maintaining a quit attempt for at least a month at the next wave. Generalized estimating equations were used to combine data for multiple waves. RESULTS: Just under half reported smoking more on a nonwork day, a little over a third reported no difference, and around one fifth reported smoking more on a work day. Controlling for possible confounding factors, smoking more on a work day was associated with making quit attempts. Among people who made a quit attempt, variation in consumption did not consistently predict one month's abstinence, being positive in Australia, but negative in the United Kingdom. CONCLUSION: Those who smoke more on work days try to quit more. Country differences for success may be related to the extent of bans on smoking, with those smoking more on work days more likely to succeed where bans in workplaces and public places were more prevalent, such as Australia at the time. PMID- 22547778 TI - Smoking family, secondhand smoke exposure at home, and quitting in adolescent smokers. AB - INTRODUCTION: This study investigated the associations of smoking family and secondhand smoke (SHS) exposure at home with quit attempts and smoking cessation among adolescents. METHODS: Students from 85 randomly selected secondary schools in Hong Kong were surveyed using an anonymous self-administered questionnaire on SHS exposure at home and outside the home in the past 7 days, quit attempts, smoking cessation, sociodemographic characteristics, and smoking status of family members and peers. Families with 1 or more smoking members (excluding the subject) were classified as smoking families and otherwise as nonsmoking families. Logistic regression yielded adjusted odds ratios (AORs) for quit attempts and smoking cessation in smoking families with or without SHS exposure at home compared with nonsmoking families. RESULTS: Of 4,361 students who had smoked in the past 12 months, 70.3% were living with smokers and 52.8% were exposed to SHS at home. Compared with nonsmoking families, the AORs (95% CI) for making at least 1 quit attempt in the past 12 months were 0.80 (0.61-1.05) for 0 day, 0.80 (0.63-1.04) for 1-3 days, and 0.65 (0.50-0.86) for 4-7 days of SHS exposure at home. The corresponding AORs (95% CI) for smoking cessation were 0.58 (0.48-0.70), 0.45 (0.35-0.58), and 0.49 (0.41-0.60) (p for trend <.001). Any SHS exposure at home was associated with 28% and 53% lower odds of quit attempts and smoking cessation, respectively. CONCLUSIONS: Living with smoker(s) and especially being exposed to SHS at home may hinder quit attempts and smoking cessation among Chinese adolescent smokers. PMID- 22547779 TI - Management of neonates with suspected or proven early-onset bacterial sepsis. AB - With improved obstetrical management and evidence-based use of intrapartum antimicrobial therapy, early-onset neonatal sepsis is becoming less frequent. However, early-onset sepsis remains one of the most common causes of neonatal morbidity and mortality in the preterm population. The identification of neonates at risk for early-onset sepsis is frequently based on a constellation of perinatal risk factors that are neither sensitive nor specific. Furthermore, diagnostic tests for neonatal sepsis have a poor positive predictive accuracy. As a result, clinicians often treat well-appearing infants for extended periods of time, even when bacterial cultures are negative. The optimal treatment of infants with suspected early-onset sepsis is broad-spectrum antimicrobial agents (ampicillin and an aminoglycoside). Once a pathogen is identified, antimicrobial therapy should be narrowed (unless synergism is needed). Recent data suggest an association between prolonged empirical treatment of preterm infants (>=5 days) with broad-spectrum antibiotics and higher risks of late onset sepsis, necrotizing enterocolitis, and mortality. To reduce these risks, antimicrobial therapy should be discontinued at 48 hours in clinical situations in which the probability of sepsis is low. The purpose of this clinical report is to provide a practical and, when possible, evidence-based approach to the management of infants with suspected or proven early-onset sepsis. PMID- 22547780 TI - Home care of children and youth with complex health care needs and technology dependencies. AB - Children and youth with complex medical issues, especially those with technology dependencies, experience frequent and often lengthy hospitalizations. Hospital discharges for these children can be a complicated process that requires a deliberate, multistep approach. In addition to successful discharges to home, it is essential that pediatric providers develop and implement an interdisciplinary and coordinated plan of care that addresses the child's ongoing health care needs. The goal is to ensure that each child remains healthy, thrives, and obtains optimal medical home and developmental supports that promote ongoing care at home and minimize recurrent hospitalizations. This clinical report presents an approach to discharging the child with complex medical needs with technology dependencies from hospital to home and then continually addressing the needs of the child and family in the home environment. PMID- 22547781 TI - CDKF;1 and CDKD protein kinases regulate phosphorylation of serine residues in the C-terminal domain of Arabidopsis RNA polymerase II. AB - Phosphorylation of conserved Y1S2P3T4S5P6S7 repeats in the C-terminal domain of largest subunit of RNA polymerase II (RNAPII CTD) plays a central role in the regulation of transcription and cotranscriptional RNA processing. Here, we show that Ser phosphorylation of Arabidopsis thaliana RNAPII CTD is governed by CYCLIN DEPENDENT KINASE F;1 (CDKF;1), a unique plant-specific CTD S7-kinase. CDKF;1 is required for in vivo activation of functionally redundant CYCLIN-DEPENDENT KINASE Ds (CDKDs), which are major CTD S5-kinases that also phosphorylate in vitro the S2 and S7 CTD residues. Inactivation of CDKF;1 causes extreme dwarfism and sterility. Inhibition of CTD S7-phosphorylation in germinating cdkf;1 seedlings is accompanied by 3'-polyadenylation defects of pre-microRNAs and transcripts encoding key regulators of small RNA biogenesis pathways. The cdkf;1 mutation also decreases the levels of both precursor and mature small RNAs without causing global downregulation of the protein-coding transcriptome and enhances the removal of introns that carry pre-microRNA stem-loops. A triple cdkd knockout mutant is not viable, but a combination of null and weak cdkd;3 alleles in a triple cdkd123* mutant permits semidwarf growth. Germinating cdkd123* seedlings show reduced CTD S5-phosphorylation, accumulation of uncapped precursor microRNAs, and a parallel decrease in mature microRNA. During later development of cdkd123* seedlings, however, S7-phosphorylation and unprocessed small RNA levels decline similarly as in the cdkf;1 mutant. Taken together, cotranscriptional processing and stability of a set of small RNAs and transcripts involved in their biogenesis are sensitive to changes in the phosphorylation of RNAPII CTD by CDKF;1 and CDKDs. PMID- 22547784 TI - "Public access" to scientific literature? PMID- 22547782 TI - Biochemical and structural characterization of the Arabidopsis bifunctional enzyme dethiobiotin synthetase-diaminopelargonic acid aminotransferase: evidence for substrate channeling in biotin synthesis. AB - Diaminopelargonic acid aminotransferase (DAPA-AT) and dethiobiotin synthetase (DTBS) catalyze the antepenultimate and the penultimate steps, respectively, of biotin synthesis. Whereas DAPA-AT and DTBS are encoded by distinct genes in bacteria, in biotin-synthesizing eukaryotes (plants and most fungi), both activities are carried out by a single enzyme encoded by a bifunctional gene originating from the fusion of prokaryotic monofunctional ancestor genes. In few angiosperms, including Arabidopsis thaliana, this chimeric gene (named BIO3-BIO1) also produces a bicistronic transcript potentially encoding separate monofunctional proteins that can be produced following an alternative splicing mechanism. The functional significance of the occurrence of a bifunctional enzyme in biotin synthesis pathway in eukaryotes and the relative implication of each of the potential enzyme forms (bifunctional versus monofunctional) in the plant biotin pathway are unknown. In this study, we demonstrate that the BIO3-BIO1 fusion protein is the sole protein form produced by the BIO3-BIO1 locus in Arabidopsis. The enzyme catalyzes both DAPA-AT and DTBS reactions in vitro and is targeted to mitochondria in vivo. Our biochemical and kinetic characterizations of the pure recombinant enzyme show that in the course of the reaction, the DAPA intermediate is directly transferred from the DAPA-AT active site to the DTBS active site. Analysis of several structures of the enzyme crystallized in complex with and without its ligands reveals key structural elements involved for acquisition of bifunctionality and brings, together with mutagenesis experiments, additional evidences for substrate channeling. PMID- 22547785 TI - Sailing to Byzantium: Eugene P. Kennedy (1919-2011). PMID- 22547783 TI - The Fanconi anemia ortholog FANCM ensures ordered homologous recombination in both somatic and meiotic cells in Arabidopsis. AB - The human hereditary disease Fanconi anemia leads to severe symptoms, including developmental defects and breakdown of the hematopoietic system. It is caused by single mutations in the FANC genes, one of which encodes the DNA translocase FANCM (for Fanconi anemia complementation group M), which is required for the repair of DNA interstrand cross-links to ensure replication progression. We identified a homolog of FANCM in Arabidopsis thaliana that is not directly involved in the repair of DNA lesions but suppresses spontaneous somatic homologous recombination via a RecQ helicase (At-RECQ4A)-independent pathway. In addition, it is required for double-strand break-induced homologous recombination. The fertility of At-fancm mutant plants is compromised. Evidence suggests that during meiosis At-FANCM acts as antirecombinase to suppress ectopic recombination-dependent chromosome interactions, but this activity is antagonized by the ZMM pathway to enable the formation of interference-sensitive crossovers and chromosome synapsis. Surprisingly, mutation of At-FANCM overcomes the sterility phenotype of an At-MutS homolog4 mutant by apparently rescuing a proportion of crossover-designated recombination intermediates via a route that is likely At-MMS and UV sensitive81 dependent. However, this is insufficient to ensure the formation of an obligate crossover. Thus, At-FANCM is not only a safeguard for genome stability in somatic cells but is an important factor in the control of meiotic crossover formation. PMID- 22547786 TI - Letters to the Editor: Junctophilins and SR docking in muscle. PMID- 22547788 TI - Irregular topography at the Earth's inner core boundary. AB - Compressional seismic wave reflected off the Earth's inner core boundary (ICB) from earthquakes occurring in the Banda Sea and recorded at the Hi-net stations in Japan exhibits significant variations in travel time (from -2 to 2.5 s) and amplitude (with a factor of more than 4) across the seismic array. Such variations indicate that Earth's ICB is irregular, with a combination of at least two scales of topography: a height variation of 14 km changing within a lateral distance of no more than 6 km, and a height variation of 4-8 km with a lateral length scale of 2-4 km. The characteristics of the ICB topography indicate that small-scale variations of temperature and/or core composition exist near the ICB, and/or the ICB topographic surface is being deformed by small-scale forces out of its thermocompositional equilibrium position and is metastable. PMID- 22547789 TI - A programmable droplet-based microfluidic device applied to multiparameter analysis of single microbes and microbial communities. AB - We present a programmable droplet-based microfluidic device that combines the reconfigurable flow-routing capabilities of integrated microvalve technology with the sample compartmentalization and dispersion-free transport that is inherent to droplets. The device allows for the execution of user-defined multistep reaction protocols in 95 individually addressable nanoliter-volume storage chambers by consecutively merging programmable sequences of picoliter-volume droplets containing reagents or cells. This functionality is enabled by "flow-controlled wetting," a droplet docking and merging mechanism that exploits the physics of droplet flow through a channel to control the precise location of droplet wetting. The device also allows for automated cross-contamination-free recovery of reaction products from individual chambers into standard microfuge tubes for downstream analysis. The combined features of programmability, addressability, and selective recovery provide a general hardware platform that can be reprogrammed for multiple applications. We demonstrate this versatility by implementing multiple single-cell experiment types with this device: bacterial cell sorting and cultivation, taxonomic gene identification, and high-throughput single-cell whole genome amplification and sequencing using common laboratory strains. Finally, we apply the device to genome analysis of single cells and microbial consortia from diverse environmental samples including a marine enrichment culture, deep-sea sediments, and the human oral cavity. The resulting datasets capture genotypic properties of individual cells and illuminate known and potentially unique partnerships between microbial community members. PMID- 22547790 TI - Changing resonator geometry to boost sound power decouples size and song frequency in a small insect. AB - Despite their small size, some insects, such as crickets, can produce high amplitude mating songs by rubbing their wings together. By exploiting structural resonance for sound radiation, crickets broadcast species-specific songs at a sharply tuned frequency. Such songs enhance the range of signal transmission, contain information about the signaler's quality, and allow mate choice. The production of pure tones requires elaborate structural mechanisms that control and sustain resonance at the species-specific frequency. Tree crickets differ sharply from this scheme. Although they use a resonant system to produce sound, tree crickets can produce high amplitude songs at different frequencies, varying by as much as an octave. Based on an investigation of the driving mechanism and the resonant system, using laser Doppler vibrometry and finite element modeling, we show that it is the distinctive geometry of the crickets' forewings (the resonant system) that is responsible for their capacity to vary frequency. The long, enlarged wings enable the production of high amplitude songs; however, as a mechanical consequence of the high aspect ratio, the resonant structures have multiple resonant modes that are similar in frequency. The drive produced by the singing apparatus cannot, therefore, be locked to a single frequency, and different resonant modes can easily be engaged, allowing individual males to vary the carrier frequency of their songs. Such flexibility in sound production, decoupling body size and song frequency, has important implications for conventional views of mate choice, and offers inspiration for the design of miniature, multifrequency, resonant acoustic radiators. PMID- 22547791 TI - Nanodiamonds and wildfire evidence in the Usselo horizon postdate the Allerod Younger Dryas boundary. AB - The controversial Younger Dryas impact hypothesis suggests that at the onset of the Younger Dryas an extraterrestrial impact over North America caused a global catastrophe. The main evidence for this impact--after the other markers proved to be neither reproducible nor consistent with an impact--is the alleged occurrence of several nanodiamond polymorphs, including the proposed presence of lonsdaleite, a shock polymorph of diamond. We examined the Usselo soil horizon at Geldrop-Aalsterhut (The Netherlands), which formed during the Allerod/Early Younger Dryas and would have captured such impact material. Our accelerator mass spectrometry radiocarbon dates of 14 individual charcoal particles are internally consistent and show that wildfires occurred well after the proposed impact. In addition we present evidence for the occurrence of cubic diamond in glass-like carbon. No lonsdaleite was found. The relation of the cubic nanodiamonds to glass like carbon, which is produced during wildfires, suggests that these nanodiamonds might have formed after, rather than at the onset of, the Younger Dryas. Our analysis thus provides no support for the Younger Dryas impact hypothesis. PMID- 22547792 TI - Greater India Basin hypothesis and a two-stage Cenozoic collision between India and Asia. AB - Cenozoic convergence between the Indian and Asian plates produced the archetypical continental collision zone comprising the Himalaya mountain belt and the Tibetan Plateau. How and where India-Asia convergence was accommodated after collision at or before 52 Ma remains a long-standing controversy. Since 52 Ma, the two plates have converged up to 3,600 +/- 35 km, yet the upper crustal shortening documented from the geological record of Asia and the Himalaya is up to approximately 2,350-km less. Here we show that the discrepancy between the convergence and the shortening can be explained by subduction of highly extended continental and oceanic Indian lithosphere within the Himalaya between approximately 50 and 25 Ma. Paleomagnetic data show that this extended continental and oceanic "Greater India" promontory resulted from 2,675 +/- 700 km of North-South extension between 120 and 70 Ma, accommodated between the Tibetan Himalaya and cratonic India. We suggest that the approximately 50 Ma "India"-Asia collision was a collision of a Tibetan-Himalayan microcontinent with Asia, followed by subduction of the largely oceanic Greater India Basin along a subduction zone at the location of the Greater Himalaya. The "hard" India-Asia collision with thicker and contiguous Indian continental lithosphere occurred around 25-20 Ma. This hard collision is coincident with far-field deformation in central Asia and rapid exhumation of Greater Himalaya crystalline rocks, and may be linked to intensification of the Asian monsoon system. This two-stage collision between India and Asia is also reflected in the deep mantle remnants of subduction imaged with seismic tomography. PMID- 22547793 TI - Nucleotide-dependent mechanism of Get3 as elucidated from free energy calculations. AB - The unique topology of tail-anchored (TA) proteins precludes them from utilizing the well-studied cotranslational translocation mechanism of most transmembrane proteins, forcing them into a distinct, posttranslational pathway. In yeast, this process is the guided entry of TA-proteins (GET) pathway, which utilizes a combination of cytosolic and transmembrane proteins to identify a TA protein, transfer it, and insert it into the endoplasmic reticulum membrane. At the center of this mechanism is the Get3 homodimer, which transfers a TA protein between the two GET phases by leveraging energy gained in ATP binding and hydrolysis to undergo significant structural changes from "open" to "closed" conformations. We present all-atom molecular dynamics simulations of Get3 in multiple nucleotide states, and through rigorous potential of mean force calculations, compute the free energy landscape of the Get3 opening/closing pathway. Results agree well with experiments on the nucleotide bias of Get3 open and closed structures in the crystallographically observed no-nucleotide, two ATP, and two ADP states, and also reveal their populations in the asymmetric one ATP and one ADP cases. Structures also compare well with the recently observed "semiopen" conformation and suggest that Get3 may sample this state free in solution and not just when bound to Get1, as observed in experiments. Finally, we present evidence for a unique, "wide-open" conformation of Get3. These calculations describe the nucleotide-dependent thermodynamics of Get3 in solution, and improve our understanding of its mechanism in each phase of the GET cycle. PMID- 22547794 TI - Improving the efficiency of water splitting in dye-sensitized solar cells by using a biomimetic electron transfer mediator. AB - Photoelectrochemical water splitting directly converts solar energy to chemical energy stored in hydrogen, a high energy density fuel. Although water splitting using semiconductor photoelectrodes has been studied for more than 40 years, it has only recently been demonstrated using dye-sensitized electrodes. The quantum yield for water splitting in these dye-based systems has, so far, been very low because the charge recombination reaction is faster than the catalytic four electron oxidation of water to oxygen. We show here that the quantum yield is more than doubled by incorporating an electron transfer mediator that is mimetic of the tyrosine-histidine mediator in Photosystem II. The mediator molecule is covalently bound to the water oxidation catalyst, a colloidal iridium oxide particle, and is coadsorbed onto a porous titanium dioxide electrode with a Ruthenium polypyridyl sensitizer. As in the natural photosynthetic system, this molecule mediates electron transfer between a relatively slow metal oxide catalyst that oxidizes water on the millisecond timescale and a dye molecule that is oxidized in a fast light-induced electron transfer reaction. The presence of the mediator molecule in the system results in photoelectrochemical water splitting with an internal quantum efficiency of approximately 2.3% using blue light. PMID- 22547795 TI - Hydrodynamic stretching of single cells for large population mechanical phenotyping. AB - Cell state is often assayed through measurement of biochemical and biophysical markers. Although biochemical markers have been widely used, intrinsic biophysical markers, such as the ability to mechanically deform under a load, are advantageous in that they do not require costly labeling or sample preparation. However, current techniques that assay cell mechanical properties have had limited adoption in clinical and cell biology research applications. Here, we demonstrate an automated microfluidic technology capable of probing single-cell deformability at approximately 2,000 cells/s. The method uses inertial focusing to uniformly deliver cells to a stretching extensional flow where cells are deformed at high strain rates, imaged with a high-speed camera, and computationally analyzed to extract quantitative parameters. This approach allows us to analyze cells at throughputs orders of magnitude faster than previously reported biophysical flow cytometers and single-cell mechanics tools, while creating easily observable larger strains and limiting user time commitment and bias through automation. Using this approach we rapidly assay the deformability of native populations of leukocytes and malignant cells in pleural effusions and accurately predict disease state in patients with cancer and immune activation with a sensitivity of 91% and a specificity of 86%. As a tool for biological research, we show the deformability we measure is an early biomarker for pluripotent stem cell differentiation and is likely linked to nuclear structural changes. Microfluidic deformability cytometry brings the statistical accuracy of traditional flow cytometric techniques to label-free biophysical biomarkers, enabling applications in clinical diagnostics, stem cell characterization, and single-cell biophysics. PMID- 22547796 TI - Quantitative patterns of stylistic influence in the evolution of literature. AB - Literature is a form of expression whose temporal structure, both in content and style, provides a historical record of the evolution of culture. In this work we take on a quantitative analysis of literary style and conduct the first large scale temporal stylometric study of literature by using the vast holdings in the Project Gutenberg Digital Library corpus. We find temporal stylistic localization among authors through the analysis of the similarity structure in feature vectors derived from content-free word usage, nonhomogeneous decay rates of stylistic influence, and an accelerating rate of decay of influence among modern authors. Within a given time period we also find evidence for stylistic coherence with a given literary topic, such that writers in different fields adopt different literary styles. This study gives quantitative support to the notion of a literary "style of a time" with a strong trend toward increasingly contemporaneous stylistic influence. PMID- 22547797 TI - QnAs with Kirk R. Smith. Interview by Nicholette Zeliadt. PMID- 22547798 TI - Toxic fibrillar oligomers of amyloid-beta have cross-beta structure. AB - Although amyloid fibers are found in neurodegenerative diseases, evidence points to soluble oligomers of amyloid-forming proteins as the cytotoxic species. Here, we establish that our preparation of toxic amyloid-beta(1-42) (Abeta42) fibrillar oligomers (TABFOs) shares with mature amyloid fibrils the cross-beta structure, in which adjacent beta-sheets adhere by interpenetration of protein side chains. We study the structure and properties of TABFOs by powder X-ray diffraction, EM, circular dichroism, FTIR spectroscopy, chromatography, conformational antibodies, and celluar toxicity. In TABFOs, Abeta42 molecules stack into short protofilaments consisting of pairs of helical beta-sheets that wrap around each other to form a superhelix. Wrapping results in a hole along the superhelix axis, providing insight into how Abeta may form pathogenic amyloid pores. Our model is consistent with numerous properties of Abeta42 fibrillar oligomers, including heterogenous size, ability to seed new populations of fibrillar oligomers, and fiber-like morphology. PMID- 22547799 TI - Acetylated STAT3 is crucial for methylation of tumor-suppressor gene promoters and inhibition by resveratrol results in demethylation. AB - The mechanisms underlying hypermethylation of tumor-suppressor gene promoters in cancer is not well understood. Here, we report that lysine acetylation of the oncogenic transcription factor STAT3 is elevated in tumors. We also show that genetically altering STAT3 at Lys685 reduces tumor growth, which is accompanied by demethylation and reactivation of several tumor-suppressor genes. Moreover, mutating STAT3 at Lys685 disrupts DNA methyltransferase 1-STAT3 interactions in cultured tumor cells and in tumors. These observations are confirmed by treatment with an acetylation inhibitor, resveratrol. Furthermore, reduction of acetylated STAT3 in triple-negative breast cancer cells leads to demethylation and activation of the estrogen receptor-alpha gene, sensitizing the tumor cells to antiestrogens. Our results also demonstrate a correlation between STAT3 acetylation and methylation of estrogen receptor-alpha in melanoma, which predicts melanoma progression. Taken together, these results suggest a role of STAT3 acetylation in regulating CpG island methylation, which may partially explain aberrant gene silencing in cancer. These findings also provide a rationale for targeting acetylated STAT3 for chemoprevention and cancer therapy. PMID- 22547800 TI - BK potassium channel modulation by leucine-rich repeat-containing proteins. AB - Molecular diversity of ion channel structure and function underlies variability in electrical signaling in nerve, muscle, and nonexcitable cells. Regulation by variable auxiliary subunits is a major mechanism to generate tissue- or cell specific diversity of ion channel function. Mammalian large-conductance, voltage- and calcium-activated potassium channels (BK, K(Ca)1.1) are ubiquitously expressed with diverse functions in different tissues or cell types, consisting of the pore-forming, voltage- and Ca(2+)-sensing alpha-subunits (BKalpha), either alone or together with the tissue-specific auxiliary beta-subunits (beta1-beta4). We recently identified a leucine-rich repeat (LRR)-containing membrane protein, LRRC26, as a BK channel auxiliary subunit, which causes an unprecedented large negative shift (~140 mV) in voltage dependence of channel activation. Here we report a group of LRRC26 paralogous proteins, LRRC52, LRRC55, and LRRC38 that potentially function as LRRC26-type auxiliary subunits of BK channels. LRRC52, LRRC55, and LRRC38 produce a marked shift in the BK channel's voltage dependence of activation in the hyperpolarizing direction by ~100 mV, 50 mV, and 20 mV, respectively, in the absence of calcium. They along with LRRC26 show distinct expression in different human tissues: LRRC26 and LRRC38 mainly in secretory glands, LRRC52 in testis, and LRRC55 in brain. LRRC26 and its paralogs are structurally and functionally distinct from the beta-subunits and we designate them as a gamma family of the BK channel auxiliary proteins, which potentially regulate the channel's gating properties over a spectrum of different tissues or cell types. PMID- 22547802 TI - Profile of Anthony J. McMichael. PMID- 22547801 TI - Reversal of muscle insulin resistance by weight reduction in young, lean, insulin resistant offspring of parents with type 2 diabetes. AB - To examine the role of intramyocellular lipid (IMCL) accumulation as well as circulating cytokines, branched-chain amino acids and acylcarnitines in the pathogenesis of muscle insulin resistance in healthy, young, lean insulin resistant offspring of parents with type 2 diabetes (IR offspring), we measured these factors in plasma and used (1)H magnetic resonance spectroscopy to assess IMCL content and hyperinsulinemic-euglycemic clamps using [6,6-(2)H(2)] glucose to assess rates of insulin-stimulated peripheral glucose metabolism before and after weight reduction. Seven lean (body mass index < 25 kg/m(2)), young, sedentary IR offspring were studied before and after weight stabilization following a hypocaloric (1,200 Kcal) diet for ~9 wks. This diet resulted in an average weight loss of 4.1 +/- 0.6 kg (P < 0.0005), which was associated with an ~30% reduction of IMCL from 1.1 +/- 0.2% to 0.8 +/- 0.1% (P = 0.045) and an ~30% improvement in insulin-stimulated muscle glucose uptake [3.7 +/- 0.3 vs. 4.8 +/- 0.1 mg/(kg-min), P = 0.01]. This marked improvement in insulin-stimulated peripheral insulin responsiveness occurred independently of changes in plasma concentrations of TNF-alpha, IL-6, total adiponectin, C-reactive protein, acylcarnitines, and branched-chain amino acids. In conclusion, these data support the hypothesis that IMCL accumulation plays an important role in causing muscle insulin resistance in young, lean IR offspring, and that both are reversible with modest weight loss. PMID- 22547804 TI - Subcortical encoding of sound is enhanced in bilinguals and relates to executive function advantages. AB - Bilingualism profoundly affects the brain, yielding functional and structural changes in cortical regions dedicated to language processing and executive function [Crinion J, et al. (2006) Science 312:1537-1540; Kim KHS, et al. (1997) Nature 388:171-174]. Comparatively, musical training, another type of sensory enrichment, translates to expertise in cognitive processing and refined biological processing of sound in both cortical and subcortical structures. Therefore, we asked whether bilingualism can also promote experience-dependent plasticity in subcortical auditory processing. We found that adolescent bilinguals, listening to the speech syllable [da], encoded the stimulus more robustly than age-matched monolinguals. Specifically, bilinguals showed enhanced encoding of the fundamental frequency, a feature known to underlie pitch perception and grouping of auditory objects. This enhancement was associated with executive function advantages. Thus, through experience-related tuning of attention, the bilingual auditory system becomes highly efficient in automatically processing sound. This study provides biological evidence for system-wide neural plasticity in auditory experts that facilitates a tight coupling of sensory and cognitive functions. PMID- 22547803 TI - Inversion of neurovascular coupling by subarachnoid blood depends on large conductance Ca2+-activated K+ (BK) channels. AB - The cellular events that cause ischemic neurological damage following aneurysmal subarachnoid hemorrhage (SAH) have remained elusive. We report that subarachnoid blood profoundly impacts communication within the neurovascular unit-neurons, astrocytes, and arterioles-causing inversion of neurovascular coupling. Elevation of astrocytic endfoot Ca(2+) to ~400 nM by neuronal stimulation or to ~300 nM by Ca(2+) uncaging dilated parenchymal arterioles in control brain slices but caused vasoconstriction in post-SAH brain slices. Inhibition of K(+) efflux via astrocytic endfoot large-conductance Ca(2+)-activated K(+) (BK) channels prevented both neurally evoked vasodilation (control) and vasoconstriction (SAH). Consistent with the dual vasodilator/vasoconstrictor action of extracellular K(+) ([K(+)](o)), [K(+)](o) <10 mM dilated and [K(+)](o) >20 mM constricted isolated brain cortex parenchymal arterioles with or without SAH. Notably, elevation of external K(+) to 10 mM caused vasodilation in brain slices from control animals but caused a modest constriction in brain slices from SAH model rats; this latter effect was reversed by BK channel inhibition, which restored K(+)-induced dilations. Importantly, the amplitude of spontaneous astrocytic Ca(2+) oscillations was increased after SAH, with peak Ca(2+) reaching ~490 nM. Our data support a model in which SAH increases the amplitude of spontaneous astrocytic Ca(2+) oscillations sufficiently to activate endfoot BK channels and elevate [K(+)](o) in the restricted perivascular space. Abnormally elevated basal [K(+)](o) combined with further K(+) efflux stimulated by neuronal activity elevates [K(+)](o) above the dilation/constriction threshold, switching the polarity of arteriolar responses to vasoconstriction. Inversion of neurovascular coupling may contribute to the decreased cerebral blood flow and development of neurological deficits that commonly follow SAH. PMID- 22547805 TI - Requirement of Rad18 protein for replication through DNA lesions in mouse and human cells. AB - In yeast, the Rad6-Rad18 ubiquitin conjugating enzyme plays a critical role in promoting replication although DNA lesions by translesion synthesis (TLS). In striking contrast, a number of studies have indicated that TLS can occur in the absence of Rad18 in human and other mammalian cells, and also in chicken cells. In this study, we determine the role of Rad18 in TLS that occurs during replication in human and mouse cells, and show that in the absence of Rad18, replication of duplex plasmids containing a cis-syn TT dimer or a (6-4) TT photoproduct is severely inhibited in human cells and that mutagenesis resulting from TLS opposite cyclobutane pyrimidine dimers and (6-4) photoproducts formed at the TT, TC, and CC dipyrimidine sites in the chromosomal cII gene in UV irradiated mouse cells is abolished. From these and other observations with Rad18, we conclude that the Rad6-Rad18 enzyme plays an essential role in promoting replication through DNA lesions by TLS in mammalian cells. In contrast, the dispensability of Rad18 for TLS in chicken DT40 cells would suggest that the role of the Rad6-Rad18 enzyme complex has diverged considerably between chicken and mammals, raising the possibility that TLS mechanisms differ among them. PMID- 22547806 TI - Regulators of G protein signaling RGS7 and RGS11 determine the onset of the light response in ON bipolar neurons. AB - The time course of signaling via heterotrimeric G proteins is controlled through their activation by G-protein coupled receptors and deactivation through the action of GTPase accelerating proteins (GAPs). Here we identify RGS7 and RGS11 as the key GAPs in the mGluR6 pathway of retinal rod ON bipolar cells that set the sensitivity and time course of light-evoked responses. We showed using electroretinography and single cell recordings that the elimination of RGS7 did not influence dark-adapted light-evoked responses, but the concurrent elimination of RGS11 severely reduced their magnitude and dramatically slowed the onset of the response. In RGS7/RGS11 double-knockout mice, light-evoked responses in rod ON bipolar cells were only observed during persistent activation of rod photoreceptors that saturate rods. These observations are consistent with persistently high G-protein activity in rod ON bipolar cell dendrites caused by the absence of the dominant GAP, biasing TRPM1 channels to the closed state. PMID- 22547807 TI - Common patterns and disease-related signatures in tuberculosis and sarcoidosis. AB - In light of the marked global health impact of tuberculosis (TB), strong focus has been on identifying biosignatures. Gene expression profiles in blood cells identified so far are indicative of a persistent activation of the immune system and chronic inflammatory pathology in active TB. Definition of a biosignature with unique specificity for TB demands that identified profiles can differentiate diseases with similar pathology, like sarcoidosis (SARC). Here, we present a detailed comparison between pulmonary TB and SARC, including whole-blood gene expression profiling, microRNA expression, and multiplex serum analytes. Our analysis reveals that previously disclosed gene expression signatures in TB show highly similar patterns in SARC, with a common up-regulation of proinflammatory pathways and IFN signaling and close similarity to TB-related signatures. microRNA expression also presented a highly similar pattern in both diseases, whereas cytokines in the serum of TB patients revealed a slightly elevated proinflammatory pattern compared with SARC and controls. Our results indicate several differences in expression between the two diseases, with increased metabolic activity and significantly higher antimicrobial defense responses in TB. However, matrix metallopeptidase 14 was identified as the most distinctive marker of SARC. Described communalities as well as unique signatures in blood profiles of two distinct inflammatory pulmonary diseases not only have considerable implications for the design of TB biosignatures and future diagnosis, but they also provide insights into biological processes underlying chronic inflammatory disease entities of different etiology. PMID- 22547808 TI - Trapping and structure determination of an intermediate in the allosteric transition of aspartate transcarbamoylase. AB - X-ray crystallography and small-angle X-ray scattering (SAXS) in solution have been used to show that a mutant aspartate transcarbamoylase exists in an intermediate quaternary structure between the canonical T and R structures. Additionally, the SAXS data indicate a pH-dependent structural alteration consistent with either a pH-induced conformational change or a pH-induced alteration in the T to R equilibrium. These data indicate that this mutant is not a model for the R state, as has been proposed, but rather represents the enzyme trapped along the path of the allosteric transition between the T and R states. PMID- 22547810 TI - Natural and sexual selection in a monogamous historical human population. AB - Whether and how human populations exposed to the agricultural revolution are still affected by Darwinian selection remains controversial among social scientists, biologists, and the general public. Although methods of studying selection in natural populations are well established, our understanding of selection in humans has been limited by the availability of suitable datasets. Here, we present a study comparing the maximum strengths of natural and sexual selection in humans that includes the effects of sex and wealth on different episodes of selection. Our dataset was compiled from church records of preindustrial Finnish populations characterized by socially imposed monogamy, and it contains a complete distribution of survival, mating, and reproductive success for 5,923 individuals born 1760-1849. Individual differences in early survival and fertility (natural selection) were responsible for most variation in fitness, even among wealthier individuals. Variance in mating success explained most of the higher variance in reproductive success in males compared with females, but mating success also influenced reproductive success in females, allowing for sexual selection to operate in both sexes. The detected opportunity for selection is in line with measurements for other species but higher than most previous reports for human samples. This disparity results from biological, demographic, economic, and social differences across populations as well as from failures by most previous studies to account for variation in fitness introduced by nonreproductive individuals. Our results emphasize that the demographic, cultural, and technological changes of the last 10,000 y did not preclude the potential for natural and sexual selection in our species. PMID- 22547809 TI - Revival of the abandoned therapeutic wortmannin by nanoparticle drug delivery. AB - One of the promises of nanoparticle (NP) carriers is the reformulation of promising therapeutics that have failed clinical development due to pharmacologic challenges. However, current nanomedicine research has been focused on the delivery of established and novel therapeutics. Here we demonstrate proof of the principle of using NPs to revive the clinical potential of abandoned compounds using wortmannin (Wtmn) as a model drug. Wtmn is a potent inhibitor of phosphatidylinositol 3' kinase-related kinases but failed clinical translation due to drug-delivery challenges. We engineered a NP formulation of Wtmn and demonstrated that NP Wtmn has higher solubility and lower toxicity compared with Wtmn. To establish the clinical translation potential of NP Wtmn, we evaluated the therapeutic as a radiosensitizer in vitro and in vivo. NP Wtmn was found to be a potent radiosensitizer and was significantly more effective than the commonly used radiosensitizer cisplatin in vitro in three cancer cell lines. The mechanism of action of NP Wtmn radiosensitization was found to be through the inhibition of DNA-dependent protein kinase phosphorylation. Finally, NP Wtmn was shown to be an effective radiosensitizer in vivo using two murine xenograft models of cancer. Our results demonstrate that NP drug-delivery systems can promote the readoption of abandoned drugs such as Wtmn by overcoming drug delivery challenges. PMID- 22547811 TI - Archaeology as a social science. AB - Because of advances in methods and theory, archaeology now addresses issues central to debates in the social sciences in a far more sophisticated manner than ever before. Coupled with methodological innovations, multiscalar archaeological studies around the world have produced a wealth of new data that provide a unique perspective on long-term changes in human societies, as they document variation in human behavior and institutions before the modern era. We illustrate these points with three examples: changes in human settlements, the roles of markets and states in deep history, and changes in standards of living. Alternative pathways toward complexity suggest how common processes may operate under contrasting ecologies, populations, and economic integration. PMID- 22547812 TI - Maturation cleavage of the murine leukemia virus Env precursor separates the transmembrane subunits to prime it for receptor triggering. AB - The Env protein of murine leukemia virus matures by two cleavage events. First, cellular furin separates the receptor binding surface (SU) subunit from the fusion-active transmembrane (TM) subunit and then, in the newly assembled particle, the viral protease removes a 16-residue peptide, the R-peptide from the endodomain of the TM. Both cleavage events are required to prime the Env for receptor-triggered activation. Cryoelectron microscopy (cryo-EM) analyses have shown that the mature Env forms an open cage-like structure composed of three SU TM complexes, where the TM subunits formed separated Env legs. Here we have studied the structure of the R-peptide precursor Env by cryo-EM. TM cleavage in Moloney murine leukemia virus was inhibited by amprenavir, and the Envs were solubilized in Triton X-100 and isolated by sedimentation in a sucrose gradient. We found that the legs of the R-peptide Env were held together by trimeric interactions at the very bottom of the Env. This suggested that the R-peptide ties the TM legs together and that this prevents the activation of the TM for fusion. The model was supported by further cryo-EM studies using an R-peptide Env mutant that was fusion-competent despite an uncleaved R-peptide. The Env legs of this mutant were found to be separated, like in the mature Env. This shows that it is the TM leg separation, normally caused by R-peptide cleavage, that primes the Env for receptor triggering. PMID- 22547813 TI - Malignant hyperthermia susceptibility arising from altered resting coupling between the skeletal muscle L-type Ca2+ channel and the type 1 ryanodine receptor. AB - Malignant hyperthermia (MH) susceptibility is a dominantly inherited disorder in which volatile anesthetics trigger aberrant Ca(2+) release in skeletal muscle and a potentially fatal rise in perioperative body temperature. Mutations causing MH susceptibility have been identified in two proteins critical for excitation contraction (EC) coupling, the type 1 ryanodine receptor (RyR1) and Ca(V)1.1, the principal subunit of the L-type Ca(2+) channel. All of the mutations that have been characterized previously augment EC coupling and/or increase the rate of L type Ca(2+) entry. The Ca(V)1.1 mutation R174W associated with MH susceptibility occurs at the innermost basic residue of the IS4 voltage-sensing helix, a residue conserved among all Ca(V) channels [Carpenter D, et al. (2009) BMC Med Genet 10:104-115.]. To define the functional consequences of this mutation, we expressed it in dysgenic (Ca(V)1.1 null) myotubes. Unlike previously described MH linked mutations in Ca(V)1.1, R174W ablated the L-type current and had no effect on EC coupling. Nonetheless, R174W increased sensitivity of Ca(2+) release to caffeine (used for MH diagnostic in vitro testing) and to volatile anesthetics. Moreover, in Ca(V)1.1 R174W-expressing myotubes, resting myoplasmic Ca(2+) levels were elevated, and sarcoplasmic reticulum (SR) stores were partially depleted, compared with myotubes expressing wild-type Ca(V)1.1. Our results indicate that Ca(V)1.1 functions not only to activate RyR1 during EC coupling, but also to suppress resting RyR1-mediated Ca(2+) leak from the SR, and that perturbation of Ca(V)1.1 negative regulation of RyR1 leak identifies a unique mechanism that can sensitize muscle cells to MH triggers. PMID- 22547814 TI - Mycobacterium tuberculosis Eis protein initiates suppression of host immune responses by acetylation of DUSP16/MKP-7. AB - The intracellular pathogen Mycobacterium tuberculosis (Mtb) causes tuberculosis. Enhanced intracellular survival (Eis) protein, secreted by Mtb, enhances survival of Mycobacterium smegmatis (Msm) in macrophages. Mtb Eis was shown to suppress host immune defenses by negatively modulating autophagy, inflammation, and cell death through JNK-dependent inhibition of reactive oxygen species (ROS) generation. Mtb Eis was recently demonstrated to contribute to drug resistance by acetylating multiple amines of aminoglycosides. However, the mechanism of enhanced intracellular survival by Mtb Eis remains unanswered. Therefore, we have characterized both Mtb and Msm Eis proteins biochemically and structurally. We have discovered that Mtb Eis is an efficient N(epsilon)-acetyltransferase, rapidly acetylating Lys55 of dual-specificity protein phosphatase 16 (DUSP16)/mitogen-activated protein kinase phosphatase-7 (MKP-7), a JNK-specific phosphatase. In contrast, Msm Eis is more efficient as an N(alpha) acetyltransferase. We also show that Msm Eis acetylates aminoglycosides as readily as Mtb Eis. Furthermore, Mtb Eis, but not Msm Eis, inhibits LPS-induced JNK phosphorylation. This functional difference against DUSP16/MKP-7 can be understood by comparing the structures of two Eis proteins. The active site of Mtb Eis with a narrow channel seems more suitable for sequence-specific recognition of the protein substrate than the pocket-shaped active site of Msm Eis. We propose that Mtb Eis initiates the inhibition of JNK-dependent autophagy, phagosome maturation, and ROS generation by acetylating DUSP16/MKP-7. Our work thus provides insight into the mechanism of suppressing host immune responses and enhancing mycobacterial survival within macrophages by Mtb Eis. PMID- 22547815 TI - Climate change impacts of US reactive nitrogen. AB - Fossil fuel combustion and fertilizer application in the United States have substantially altered the nitrogen cycle, with serious effects on climate change. The climate effects can be short-lived, by impacting the chemistry of the atmosphere, or long-lived, by altering ecosystem greenhouse gas fluxes. Here we develop a coherent framework for assessing the climate change impacts of US reactive nitrogen emissions, including oxides of nitrogen, ammonia, and nitrous oxide (N(2)O). We use the global temperature potential (GTP), calculated at 20 and 100 y, in units of CO(2) equivalents (CO(2)e), as a common metric. The largest cooling effects are due to combustion sources of oxides of nitrogen altering tropospheric ozone and methane concentrations and enhancing carbon sequestration in forests. The combined cooling effects are estimated at -290 to 510 Tg CO(2)e on a GTP(20) basis. However, these effects are largely short-lived. On a GTP(100) basis, combustion contributes just -16 to -95 Tg CO(2)e. Agriculture contributes to warming on both the 20-y and 100-y timescales, primarily through N(2)O emissions from soils. Under current conditions, these warming and cooling effects partially offset each other. However, recent trends show decreasing emissions from combustion sources. To prevent warming from US reactive nitrogen, reductions in agricultural N(2)O emissions are needed. Substantial progress toward this goal is possible using current technology. Without such actions, even greater CO(2) emission reductions will be required to avoid dangerous climate change. PMID- 22547816 TI - Cytotoxic immunological synapses do not restrict the action of interferon-gamma to antigenic target cells. AB - Following antigen recognition on target cells, effector T cells establish immunological synapses and secrete cytokines. It is thought that T cells secrete cytokines in one of two modes: either synaptically (i.e., toward antigenic target cells) or multidirectionally, affecting a wider population of cells. This paradigm predicts that synaptically secreted cytokines such as IFN-gamma will preferentially signal to antigenic target cells contacted by the T cell through an immunological synapse. Despite its physiological significance, this prediction has never been tested. We developed a live-cell imaging system to compare the responses of target cells and nonantigenic bystanders to IFN-gamma secreted by CD8+, antigen-specific, cytotoxic T cells. Both target cells and surrounding nontarget cells respond robustly. This pattern of response was detected even at minimal antigenic T-cell stimulation using low doses of antigenic peptide, or altered peptide ligands. Although cytotoxic immunological synapses restrict killing to antigenic target cells, the effects of IFN-gamma are more widespread. PMID- 22547817 TI - Tumor-targeted TNFalpha stabilizes tumor vessels and enhances active immunotherapy. AB - Solid tumors are intrinsically resistant to immune rejection. Abnormal tumor vasculature can act as a barrier for immune cell migration into tumors. We tested whether targeting IFNgamma and/or TNFalpha into pancreatic neuroendocrine tumors can alleviate immune suppression. We found that intratumoral IFNgamma causes rapid vessel loss, which does not support anti-tumor immunity. In contrast, low dose TNFalpha enhances T-cell infiltration and overall survival, an effect that is exclusively mediated by CD8(+) effector cells. Intriguingly, lymphocyte influx does not correlate with increased vessel leakiness. Instead, low-dose TNFalpha stabilizes the vascular network and improves vessel perfusion. Inflammatory vessel remodeling is, at least in part, mediated by tumor-resident macrophages that are reprogrammed to secrete immune and angiogenic modulators. Moreover, inflammatory vessel remodeling with low-dose TNFalpha substantially improves antitumor vaccination or adoptive T-cell therapy. Thus, low-dose TNFalpha promotes both vessel remodeling and antitumor immune responses and acts as a potent adjuvant for active immunotherapy. PMID- 22547819 TI - Unexpected fold in the circumsporozoite protein target of malaria vaccines. AB - Circumsporozoite (CS) protein is the major surface component of Plasmodium falciparum sporozoites and is essential for host cell invasion. A vaccine containing tandem repeats, region III, and thrombospondin type-I repeat (TSR) of CS is efficacious in phase III trials but gives only a 35% reduction in severe malaria in the first year postimmunization. We solved crystal structures showing that region III and TSR fold into a single unit, an "alphaTSR" domain. The alphaTSR domain possesses a hydrophobic pocket and core, missing in TSR domains. CS binds heparin, but alphaTSR does not. Interestingly, polymorphic T-cell epitopes map to specialized alphaTSR regions. The N and C termini are unexpectedly close, providing clues for sporozoite sheath organization. Elucidation of a unique structure of a domain within CS enables rational design of next-generation subunit vaccines and functional and medicinal chemical investigation of the conserved hydrophobic pocket. PMID- 22547818 TI - Cutaneous beta-human papillomavirus E6 proteins bind Mastermind-like coactivators and repress Notch signaling. AB - The Notch signaling pathway is a key determinant in keratinocyte differentiation and growth cycle arrest, and has been reported to have a tumor suppressor function in skin. The papillomavirus life cycle is intricately linked to the differentiation status of keratinocytes. Papillomaviruses are associated with benign proliferative epithelial lesions in their respective hosts. Although human papillomaviruses (HPVs) associated with genital tract lesions have been extensively studied, studies of the cutaneous HPVs are more limited. In particular, it is well established that the E6 proteins of high-risk HPVs of the alpha-genus such as HPV16 and HPV18 mediate the degradation of p53 by its association with the ubiquitin ligase E6AP. In contrast, less is known about the cellular activities of the cutaneous HPVs of the beta-genus. By using an unbiased proteomic approach, we identify MAML1 and other members of the Notch transcription complex as high-confidence cellular interacting proteins of E6 proteins of the beta-genus HPVs and of the bovine papillomavirus type 1 associated with cutaneous fibropapillomas. We show that bovine papillomavirus type 1 and beta-HPV E6 repress Notch transcriptional activation, and that this repression is dependent on an interaction with MAML1. Finally, we show that the expression levels of endogenous Notch target genes are repressed by beta-HPV E6 proteins. These findings elucidate a mechanism of viral antagonism of Notch signaling, and suggest that Notch signaling is an important epithelial cell pathway target for the beta-HPVs. PMID- 22547820 TI - Kinetic mechanism for HIV-1 neutralization by antibody 2G12 entails reversible glycan binding that slows cell entry. AB - Despite structural knowledge of broadly neutralizing monoclonal antibodies (NMAbs) complexed to HIV-1 gp120 and gp41 envelope glycoproteins, virus inactivation mechanisms have been difficult to prove, in part because neutralization assays are complex and were previously not understood. Concordant with recent evidence that HIV-1 titers are determined by a race between entry of cell-attached virions and competing inactivation processes, we show that NMAb 2G12, which binds to gp120 N-glycans with alpha (1, 2)-linked mannose termini and inhibits replication after passive transfer into patients, neutralizes by slowing entry of adsorbed virions. Accordingly, apparent neutralization is attenuated when a kinetically competing virus inactivation pathway is blocked. Moreover, removing 2G12 from media causes its dissociation from virions coupled to accelerated entry and restored infectivity, demonstrating the reversibility of neutralization. A difference between 2G12 dissociation and infectivity recovery rates implies that the inhibited complexes at virus-cell junctions contain several 2G12's that must dissociate before entry commences. Quantitative microscopy of 2G12 binding and dissociation from single virions and studies using a split CCR5 coreceptor suggest that 2G12 competitively inhibits interactions between gp120's V3 loop and the tyrosine sulfate-containing CCR5 amino terminus, thereby reducing assembly of complexes that catalyze entry. These results reveal a unique reversible kinetic mechanism for neutralization by an antibody that binds near a critical V3 region in the glycan shield of gp120. PMID- 22547821 TI - Brain anomalies in children exposed prenatally to a common organophosphate pesticide. AB - Prenatal exposure to chlorpyrifos (CPF), an organophosphate insecticide, is associated with neurobehavioral deficits in humans and animal models. We investigated associations between CPF exposure and brain morphology using magnetic resonance imaging in 40 children, 5.9-11.2 y, selected from a nonclinical, representative community-based cohort. Twenty high-exposure children (upper tertile of CPF concentrations in umbilical cord blood) were compared with 20 low-exposure children on cortical surface features; all participants had minimal prenatal exposure to environmental tobacco smoke and polycyclic aromatic hydrocarbons. High CPF exposure was associated with enlargement of superior temporal, posterior middle temporal, and inferior postcentral gyri bilaterally, and enlarged superior frontal gyrus, gyrus rectus, cuneus, and precuneus along the mesial wall of the right hemisphere. Group differences were derived from exposure effects on underlying white matter. A significant exposure * IQ interaction was derived from CPF disruption of normal IQ associations with surface measures in low-exposure children. In preliminary analyses, high-exposure children did not show expected sex differences in the right inferior parietal lobule and superior marginal gyrus, and displayed reversal of sex differences in the right mesial superior frontal gyrus, consistent with disruption by CPF of normal behavioral sexual dimorphisms reported in animal models. High-exposure children also showed frontal and parietal cortical thinning, and an inverse dose response relationship between CPF and cortical thickness. This study reports significant associations of prenatal exposure to a widely used environmental neurotoxicant, at standard use levels, with structural changes in the developing human brain. PMID- 22547822 TI - Caenorhabditis elegans POT-2 telomere protein represses a mode of alternative lengthening of telomeres with normal telomere lengths. AB - Canonical telomere repeats at chromosome termini can be maintained by a telomerase-independent pathway termed alternative lengthening of telomeres (ALT). Human cancers that survive via ALT can exhibit long and heterogeneous telomeres, although many telomerase-negative tumors possess telomeres of normal length. Here, we report that Caenorhabditis elegans telomerase mutants that survived via ALT possessed either long or normal telomere lengths. Most ALT strains displayed end-to-end chromosome fusions, suggesting that critical telomere shortening occurred before or concomitant with ALT. ALT required the 9-1-1 DNA damage response complex and its clamp loader, HPR-17. Deficiency for the POT-2 telomere binding protein promoted ALT in telomerase mutants, overcame the requirement for the 9-1-1 complex in ALT, and promoted ALT with normal telomere lengths. We propose that telomerase-deficient human tumors with normal telomere lengths could represent a mode of ALT that is facilitated by telomere capping protein dysfunction. PMID- 22547823 TI - Amino acid coevolution induces an evolutionary Stokes shift. AB - The process of amino acid replacement in proteins is context-dependent, with substitution rates influenced by local structure, functional role, and amino acids at other locations. Predicting how these differences affect replacement processes is difficult. To make such inference easier, it is often assumed that the acceptabilities of different amino acids at a position are constant. However, evolutionary interactions among residue positions will tend to invalidate this assumption. Here, we use simulations of purple acid phosphatase evolution to show that amino acid propensities at a position undergo predictable change after an amino acid replacement at that position. After a replacement, the new amino acid and similar amino acids tend to become gradually more acceptable over time at that position. In other words, proteins tend to equilibrate to the presence of an amino acid at a position through replacements at other positions. Such a shift is reminiscent of the spectroscopy effect known as the Stokes shift, where molecules receiving a quantum of energy and moving to a higher electronic state will adjust to the new state and emit a smaller quantum of energy whenever they shift back down to the original ground state. Predictions of changes in stability in real proteins show that mutation reversals become less favorable over time, and thus, broadly support our results. The observation of an evolutionary Stokes shift has profound implications for the study of protein evolution and the modeling of evolutionary processes. PMID- 22547824 TI - Calpain cleaves and activates the TRPC5 channel to participate in semaphorin 3A induced neuronal growth cone collapse. AB - The nonselective cation channel transient receptor potential canonical (TRPC)5 is found predominantly in the brain and has been proposed to regulate neuronal processes and growth cones. Here, we demonstrate that semaphorin 3A-mediated growth cone collapse is reduced in hippocampal neurons from TRPC5 null mice. This reduction is reproduced by inhibition of the calcium-sensitive protease calpain in wild-type neurons but not in TRPC5(-/-) neurons. We show that calpain-1 and calpain-2 cleave and functionally activate TRPC5. Mutation of a critical threonine at position 857 inhibits calpain-2 cleavage of the channel. Finally, we show that the truncated TRPC5 predicted to result from calpain cleavage is functionally active. These results indicate that semaphorin 3A initiates growth cone collapse via activation of calpain that in turn potentiates TRPC5 activity. Thus, TRPC5 acts downstream of semaphorin signaling to cause changes in neuronal growth cone morphology and nervous system development. PMID- 22547825 TI - Orthodenticle and Kruppel homolog 1 regulate Drosophila photoreceptor maturation. AB - Neurons present a wide variety of morphologies that are associated with their specialized functions. However, to date very few pathways and factors regulating neuronal maturation, including morphogenesis, have been identified. To address this issue we make use here of the genetically amenable developing fly photoreceptor (PR). Whereas this sensory neuron is specified early during retinal development, its maturation spans several days. During this time, this neuron acquires specialized membrane domains while undergoing extensive polarity remodeling. In this study, we identify a pathway in which the conserved homeobox protein Orthodenticle (Otd) acts together with the ecdysone receptor (EcR) to directly repress the expression of the transcription factor (TF) Kruppel homolog 1 (Kr-h1). We demonstrate that this pathway is not required to promote neuronal specification but is crucial to regulate PR maturation. PR maturation includes the remodeling of the cell's epithelial features and associated apical membrane morphogenesis. Furthermore, we show that hormonal control coordinates PR differentiation and morphogenesis with overall development. This study demonstrates that during PR differentiation, transient repression of Kr-h1 represents a key step regulating neuronal maturation. Down-regulation of Kr-h1 expression has been previously associated with instances of neuronal remodeling in the fly brain. We therefore conclude that repression of this transcription factor represents a key step, enabling remodeling and maturation in a wide variety of neurons. PMID- 22547827 TI - Apoptotic marginal zone deletion of anti-Sm/ribonucleoprotein B cells. AB - CD40L is excessively produced in both human and murine lupus and plays a role in lupus pathogenesis. To address how excess CD40L induces autoantibody production, we crossed CD40L-transgenic mice with the anti-DNA H-chain transgenic mouse lines 3H9 and 56R, well-characterized models for studying B-cell tolerance to nuclear antigens. Excess CD40L did not induce autoantibody production in 3H9 mice in which anergy maintains self-tolerance, nor did it perturb central tolerance, including deletion and receptor editing, of anti-DNA B cells in 56R mice. In contrast, CD40L/56R mice restored a large number of marginal zone (MZ) B cells reactive to Sm/ribonucleoprotein (RNP) and produced autoantibody, whereas these B cells were deleted by apoptosis in MZ of 56R mice. Thus, excess CD40L efficiently blocked tolerance of Sm/RNP-reactive MZ B cells, leading to production of anti Sm/RNP antibody implicated in the pathogenesis of lupus. These results suggest that self-reactive B cells such as anti-Sm/RNP B cells, which somehow escape tolerance in the bone marrow and migrate to MZ, are tolerized by apoptotic deletion in MZ and that a break in this tolerance may play a role in the pathogenesis of lupus. PMID- 22547826 TI - Immature integration and segregation of emotion-related brain circuitry in young children. AB - The human brain undergoes protracted development, with dramatic changes in expression and regulation of emotion from childhood to adulthood. The amygdala is a brain structure that plays a pivotal role in emotion-related functions. Investigating developmental characteristics of the amygdala and associated functional circuits in children is important for understanding how emotion processing matures in the developing brain. The basolateral amygdala (BLA) and centromedial amygdala (CMA) are two major amygdalar nuclei that contribute to distinct functions via their unique pattern of interactions with cortical and subcortical regions. Almost nothing is currently known about the maturation of functional circuits associated with these amygdala nuclei in the developing brain. Using intrinsic connectivity analysis of functional magnetic resonance imaging data, we investigated developmental changes in functional connectivity of the BLA and CMA in twenty-four 7- to 9-y-old typically developing children compared with twenty-four 19- to 22-y-old healthy adults. Children showed significantly weaker intrinsic functional connectivity of the amygdala with subcortical, paralimbic, and limbic structures, polymodal association, and ventromedial prefrontal cortex. Importantly, target networks associated with the BLA and CMA exhibited greater overlap and weaker dissociation in children. In line with this finding, children showed greater intraamygdala connectivity between the BLA and CMA. Critically, these developmental differences were reproducibly identified in a second independent cohort of adults and children. Taken together, our findings point toward weak integration and segregation of amygdala circuits in young children. These immature patterns of amygdala connectivity have important implications for understanding typical and atypical development of emotion-related brain circuitry. PMID- 22547828 TI - One influenza virus particle packages eight unique viral RNAs as shown by FISH analysis. AB - Influenza A virus possesses a segmented genome of eight negative-sense, single stranded RNAs. The eight segments have been shown to be represented in approximately equal molar ratios in a virus population; however, the exact copy number of each viral RNA segment per individual virus particles has not been determined. We have established an experimental approach based on multicolor single-molecule fluorescent in situ hybridization (FISH) to study the composition of viral RNAs at single-virus particle resolution. Colocalization analysis showed that a high percentage of virus particles package all eight different segments of viral RNAs. To determine the copy number of each RNA segment within individual virus particles, we measured the photobleaching steps of individual virus particles hybridized with fluorescent probes targeting a specific viral RNA. By comparing the photobleaching profiles of probes against the HA RNA segment for the wild-type influenza A/Puerto Rico/8/34 (PR8) and a recombinant PR8 virus carrying two copies of the HA segment, we concluded that only one copy of HA segment is packaged into a wild type virus particle. Our results showed similar photobleaching behaviors for other RNA segments, suggesting that for the majority of the virus particles, only one copy of each RNA segment is packaged into one virus particle. Together, our results support that the packaging of influenza viral genome is a selective process. PMID- 22547829 TI - Bergmann glia modulate cerebellar Purkinje cell bistability via Ca2+-dependent K+ uptake. AB - Recent studies have shown that cerebellar Bergmann glia display coordinated Ca(2+) transients in live mice. However, the functional significance of Bergmann glial Ca(2+) signaling remains poorly understood. Using transgenic mice that allow selective stimulation of glial cells, we report here that cytosolic Ca(2+) regulates uptake of K(+) by Bergmann glia, thus providing a powerful mechanism for control of Purkinje cell-membrane potential. The decline in extracellular K(+) evoked by agonist-induced Ca(2+) in Bergmann glia transiently increased spike activity of Purkinje cells in cerebellar slices as well as in live anesthetized mice. Thus, Bergmann glia play a previously unappreciated role in controlling the membrane potential and thereby the activity of adjacent Purkinje cells. PMID- 22547830 TI - Transcription factors c-Myc and CDX2 mediate E-selectin ligand expression in colon cancer cells undergoing EGF/bFGF-induced epithelial-mesenchymal transition. AB - Sialyl Lewis x (sLe(x)) and sialyl Lewis a (sLe(a)) glycans are expressed on highly metastatic colon cancer cells. They promote extravasation of cancer cells and tumor angiogenesis via interacting with E-selectin on endothelial cells. Recently, epithelial-mesenchymal transition (EMT) has been noted as a critical phenotypic alteration in metastatic cancer cells. To address the association between sLe(x/a) expression and EMT, we assessed whether sLe(x/a) are highly expressed on colon cancer cells undergoing EMT. Treatment of HT29 and DLD-1 cells with EGF and/or basic FGF (bFGF) induced EMT and significantly increased sLe(x/a) expression resulting in enhanced E-selectin binding activity. The transcript levels of the glycosyltransferase genes ST3GAL1/3/4 and FUT3 were significantly elevated and that of FUT2 was significantly suppressed by the treatment. We provide evidence that ST3GAL1/3/4 and FUT3 are transcriptionally up-regulated by c-Myc with probable involvement of Ser62 phosphorylation, and that FUT2 is transcriptionally down-regulated through the attenuation of CDX2. The contribution of c-Myc and CDX2 to the sLe(x/a) induction was proved to be significant by knockdown or forced expression experiments. Interestingly, the cells undergoing EMT exhibited significantly increased VEGF secretion, which can promote tumor angiogenesis in cooperation with sLe(x/a). Finally, immunohistological study indicated high E-selectin ligand expression on cancer cells undergoing EMT in vivo, supporting their coexistence observed in vitro. These results suggest a significant link between sLe(x/a) expression and EMT in colon cancer cells and a pivotal role of c-Myc and CDX2 in regulating sLe(x/a) expression during EMT. PMID- 22547832 TI - Rejoinder for "Meta-analysis for surrogacy: accelerated failure time models and semi-competing risks modelling" PMID- 22547831 TI - Historical effects on beta diversity and community assembly in Amazonian trees. AB - We present a unique perspective on the role of historical processes in community assembly by synthesizing analyses of species turnover among communities with environmental data and independent, population genetic-derived estimates of among community dispersal. We sampled floodplain and terra firme communities of the diverse tree genus Inga (Fabaceae) across a 250-km transect in Amazonian Peru and found patterns of distance-decay in compositional similarity in both habitat types. However, conventional analyses of distance-decay masked a zone of increased species turnover present in the middle of the transect. We estimated past seed dispersal among the same communities by examining geographic plastid DNA variation for eight widespread Inga species and uncovered a population genetic break in the majority of species that is geographically coincident with the zone of increased species turnover. Analyses of these and 12 additional Inga species shared between two communities located on opposite sides of the zone showed that the populations experienced divergence 42,000-612,000 y ago. Our results suggest that the observed distance decay is the result not of environmental gradients or dispersal limitation coupled with ecological drift--as conventionally interpreted under neutral ecological theory--but rather of secondary contact between historically separated communities. Thus, even at this small spatial scale, historical processes seem to significantly impact species' distributions and community assembly. Other documented zones of increased species turnover found in the western Amazon basin or elsewhere may be related to similar historical processes. PMID- 22547833 TI - High-Dimensional Heteroscedastic Regression with an Application to eQTL Data Analysis. AB - We consider the problem of high-dimensional regression under non-constant error variances. Despite being a common phenomenon in biological applications, heteroscedasticity has, so far, been largely ignored in high-dimensional analysis of genomic data sets. We propose a new methodology that allows non-constant error variances for high-dimensional estimation and model selection. Our method incorporates heteroscedasticity by simultaneously modeling both the mean and variance components via a novel doubly regularized approach. Extensive Monte Carlo simulations indicate that our proposed procedure can result in better estimation and variable selection than existing methods when heteroscedasticity arises from the presence of predictors explaining error variances and outliers. Further, we demonstrate the presence of heteroscedasticity in and apply our method to an expression quantitative trait loci (eQTLs) study of 112 yeast segregants. The new procedure can automatically account for heteroscedasticity in identifying the eQTLs that are associated with gene expression variations and lead to smaller prediction errors. These results demonstrate the importance of considering heteroscedasticity in eQTL data analysis. PMID- 22547836 TI - The ethics of pet food marketing - a comment. PMID- 22547834 TI - Feline leukemia virus and feline immunodeficiency virus article - a comment. PMID- 22547837 TI - Yes, you should be concerned. PMID- 22547838 TI - Veterinary medical ethics. PMID- 22547839 TI - Respiratory disease caused by Mycoplasma bovis is enhanced by exposure to bovine herpes virus 1 (BHV-1) but not to bovine viral diarrhea virus (BVDV) type 2. AB - To determine if previous exposure to bovine viral diarrhea virus (BVDV) and bovine herpes virus 1 (BHV-1) type 2 affects the onset of disease caused by Mycoplasma bovis, 6- to 8-month-old beef calves were exposed to BVDV or BHV-1 4 d prior to challenge with a suspension of 3 clinical isolates of M. bovis. Animals were observed for clinical signs of disease and at necropsy, percent abnormal lung tissue and presence of M. bovis were determined. Most animals pre-exposed to BHV-1 type 2 but not BVDV developed M. bovis-related respiratory illness. In a second trial, we determined that a 100-fold reduction in the number of M. bovis bacteria administered to BHV-1 exposed animals reduced the percentage of abnormal lung tissue but not the severity of clinical signs. We conclude that previous exposure to BHV-1 but not BVDV type 2 was a necessary cause of M. bovis-related respiratory diseases in our disease model. PMID- 22547840 TI - Palatal sclerotherapy for the treatment of intermittent dorsal displacement of the soft palate in 51 standardbred racehorses. AB - This retrospective study evaluated the efficacy and side effects of palatal sclerotherapy in standardbred racehorses suspected to have intermittent dorsal displacement of the soft palate (IDDSP). Fifty-one horses were treated with multiple endoscopically guided injections of 3% sodium tetradecyl sulfate in the soft palate. Two groups were identified: those that had respiratory noises during exercise (n = 27) and those that did not (n = 24). Treatment was well-tolerated. Furthermore, horses significantly reduced their racing times for the last 400 m compared with their times before treatment and even when their times were compared to the mean times for horses in the same race. In conclusion, palatal sclerotherapy appears to be a suitable alternative therapeutic option for horses suspected to have IDDSP. PMID- 22547841 TI - Factors influencing complete tumor excision of mast cell tumors and soft tissue sarcomas: a retrospective study in 100 dogs. AB - The recommended treatment for soft tissue sarcomas (STS) and mast cell tumors (MCT) is complete surgical removal, provided that the tumor is amenable to surgical excision. The objective of this study was to evaluate possible risk factors for incomplete surgical excision of skin and subcutaneous STS and MCT in 100 dogs treated with wide excision with curative intent. Decreased body weight was a risk factor (P = 0.03, odd's ratio = 0.96) as well as increased tumor size (1.4% increase in risk of incomplete excision per cm(2); P = 0.02). Gender, age, breed, location, grade, tumor type, re-excision, and level of surgeon's training (P = 0.0711) were not significant. Veterinary surgery residents were at increased risk of incompleteness of excision compared with ACVS surgeons and ACVS surgeons with additional training in surgical oncology. PMID- 22547842 TI - Rectus abdominis muscle flap for repair of prepubic tendon rupture in 8 dogs. AB - The clinical use and outcome of the rectus abdominis muscle flap to repair prepubic hernias were evaluated retrospectively. Medical records (2002-2007) of 8 dogs that had a rectus abdominis muscle flap to repair traumatic prepubic tendon rupture were reviewed. Only minor donor site complications were noted, including self-limiting ventral and hind-limb swelling. No long-term complications including recurrence of hernia were noted. The results of this study indicate that the rectus abdominis muscle flap is a clinically useful option for repairing prepubic tendon rupture in dogs. PMID- 22547844 TI - Rib fracture in a horse during an endurance race. AB - We describe a fatal case, in which a horse suffered a fall and as a consequence, rib fractures. Diagnosis was made postmortem and the horse died without showing clear signs of respiratory dysfunction. The retrospective reports of injuries can be important to reduce these traumatic events and to avoid fatalities. PMID- 22547843 TI - Survival and echocardiographic data in dogs with congestive heart failure caused by mitral valve disease and treated by multiple drugs: a retrospective study of 21 cases. AB - This retrospective study reports the survival time [onset of congestive heart failure (CHF) to death from any cause] of 21 dogs with mitral regurgitation (MR) and CHF treated with a combination of furosemide, angiotensin-converting enzyme inhibitor (ACEI, benazepril, or enalapril), pimobendan, spironolactone, and amlodipine. Baseline echocardiographic data: end-systolic and end-diastolic volume indices (ESVI and EDVI), left atrium to aorta ratio (LA/Ao), and regurgitant fraction (RF) are reported. Median survival time (MST) was 430 d. Initial dosage of furosemide (P = 0.0081) and LA/Ao (P = 0.042) were negatively associated with survival. Baseline echocardiographic indices (mean +/- standard deviation) were 40.24 +/- 16.76 for ESVI, 161.48 +/- 44.49 mL/m(2) for EDVI, 2.11 +/- 0.75 for LA/Ao, and 64.71 +/- 16.85% for RF. Combining furosemide, ACEI, pimobendan, spironolactone, and amlodipine may result in long survival times in dogs with MR and CHF. Severity of MR at onset of CHF is at least moderate. PMID- 22547845 TI - Thrombosis of the cranial vena cava in a cow with bronchopneumonia and traumatic reticuloperitonitis. AB - This paper reports the clinical findings, surgical and medical management, and necropsy of a 6-year-old cow with thrombosis of the cranial vena cava and thrombo embolic pneumonia following traumatic reticuloperitonitis. The clinical diagnosis was confirmed by necropsy. PMID- 22547846 TI - A primitive neuroectodermal tumor with extension into the cranial vault in a dog. AB - This paper reports the clinical findings, cytology, diagnostic imaging, and necropsy of an unusual case of a peripheral nervous system neoplasm which, subsequent to a 6-month clinical history, extended into the cranial vault. Necropsy and histology confirmed the diagnosis of a peripheral primitive neuroectodermal tumor. PMID- 22547847 TI - Situs inversus totalis associated with subaortic stenosis, restrictive ventricular septal defect, and tricuspid dysplasia in an adult dog. AB - A rare association between situs inversus totalis (SIT), restrictive ventricular septal defect, severe subaortic stenosis, and tricuspid dysplasia was observed in an adult mixed-breed dog. Primary ciliary dyskinesia and Kartagener's syndrome were excluded. After 15 mo the dog died suddenly. The association between SIT and congenital heart diseases is discussed. PMID- 22547848 TI - Idiopathic chylothorax and lymphedema in 2 whippet littermates. AB - Idiopathic chylothorax and limb edema was diagnosed in two 2-year-old male whippet siblings. The fact that the 2 related animals developed similar clinical signs at a young age may suggest a congenital or hereditary etiology. PMID- 22547849 TI - Congenital cardiac anomalies in an English bulldog. AB - A 4-year-old male castrated English bulldog was referred to the Atlantic Veterinary College for evaluation of exercise intolerance, multiple syncopal episodes, and a grade IV/VI heart murmur. The dog was shown to have 3 congenital cardiac anomalies: atrial septal defect, mitral valve dysplasia, and subaortic stenosis. Medical management consisted of exercise restriction, atenolol, pimobendan, and taurine. PMID- 22547850 TI - How much is your practice worth? PMID- 22547851 TI - Diagnostic ophthalmology. PMID- 22547852 TI - Actions occurring at the state and local levels of public health. PMID- 22547853 TI - Raising awareness of viral hepatitis: National Hepatitis Testing Day, May 19. PMID- 22547854 TI - Setting an agenda for advancing young worker safety in the U.S. and Canada. AB - Scholars and practitioners from multiple perspectives, including developmental science, sociology, business, medicine, and public health, have considered the implications of employment for young people. We summarize a series of meetings designed to synthesize information from these perspectives and derive recommendations to guide research, practice, and policy with a focus on young worker safety and health. During the first three meetings, participants from the United States and Canada considered invited white papers addressing developmental issues, public health data and findings, as well as programmatic advances and evaluation needs. At the final meeting, the participants recommended both research and policy directions to advance understanding and improve young worker safety. PMID- 22547855 TI - Protecting adolescents' right to seek treatment for sexually transmitted diseases without parental consent: the Arizona experience with Senate Bill 1309. AB - In 2010, Senate Bill 1309 included language to repeal an existing Arizona law that enables minors younger than 18 years of age to seek diagnosis and treatment of sexually transmitted diseases (STDs) without parental consent. Numerous implications were identified that would have stemmed from parental consent provisions originally proffered in Senate Bill 1309. These implications included diminished access to essential health services among minors, exacerbated existing health disparities, increased health-care spending costs, and thwarted efforts to curb the spread of STDs. Lastly, minors would have been deprived of existing privacy protections concerning their STD-related medical information. This case study describes how collaborative advocacy efforts resulted in the successful amendment of Senate Bill 1309 to avert the negative sexual and reproductive health outcomes among adolescents stemming from the potential repeal of their existing legal right to seek STD treatment without parental consent. PMID- 22547856 TI - Return of epidemic dengue in the United States: implications for the public health practitioner. AB - Conditions that facilitate sustained dengue transmission exist in the United States, and outbreaks have occurred during the past decade in Texas, Hawaii, and Florida. More outbreaks can also be expected in years to come. To combat dengue, medical and public health practitioners in areas with mosquito vectors that are competent to transmit the virus must be aware of the threat of reemergent dengue, and the need for early reporting and control to reduce the impact of dengue outbreaks. Comprehensive dengue control includes human and vector surveillance, vector management programs, and community engagement efforts. Public health, medical, and vector-control communities must collaborate to prevent and control disease spread. Policy makers should understand the role of mosquito abatement and community engagement in the prevention and control of the disease. PMID- 22547857 TI - From SARS to 2009 H1N1 influenza: the evolution of a public health incident management system at CDC. AB - The organization of the response to infectious disease outbreaks by public health agencies at the federal, state, and local levels has historically been based on traditional public health functions (e.g., epidemiology, surveillance, laboratory, infection control, and health communications). Federal guidance has established a framework for the management of domestic incidents, including public health emergencies. Therefore, public health agencies have had to find a way to incorporate traditional public health functions into the common response framework of the National Incident Management System. One solution is the development of a Science Section, containing public health functions, that is equivalent to the traditional incident command system sections. Public health agencies experiencing difficulties in developing incident management systems should consider the feasibility and suitability of creating a Science Section to allow a more seamless and effective coordination of a public health response, while remaining consistent with current federal guidance. PMID- 22547858 TI - An explanation for the recent increase in the fall death rate among older Americans: a subgroup analysis. AB - OBJECTIVE: We sought to explain the recent increase in the death rate from falls among Americans aged 65 years and older. METHODS: Using the CDC WONDER online database, a longitudinal analysis of subgroups of fall mortality based on the International Classification of Diseases, 10th Revision (ICD-10) was conducted in older adults and in younger people. We used linear regression to examine the statistical significance of trends in mortality rates during 1999-2007. RESULTS: The overall mortality rate from falls increased by 55% among older Americans (>=65 years of age) during 1999-2007, from 29 per 100,000 population to 45 per 100,000 population. For those aged >=65 years, the largest increase by far (698%) occurred in the subgroup "other falls on the same level," followed by a moderate increase in falls involving wheelchairs or furniture (48%). The steepest increases at all ages occurred from 1999 to 2000, after ICD-10 took effect. State level analysis confirmed the findings for the entire United States. From 1999 to 2007, total mortality from falls decreased by 5% in people younger than 45 years of age and increased by 44% for those aged 45-64 years; mortality from "other falls on the same level" increased by 202% and 431%, respectively, in these age groups. CONCLUSIONS: Because the reported minor increases in emergency department and hospitalization rates for falls were insignificant, the almost sevenfold increase in death rates from "other falls on the same level" strongly suggests an effect of improved reporting quality. PMID- 22547859 TI - A tale of two gonorrhea epidemics: results from the STD surveillance network. AB - OBJECTIVE: An increasing proportion of gonorrhea in the United States is diagnosed in the private sector, posing a challenge to existing national surveillance systems. We described gonorrhea epidemiology outside sexually transmitted disease (STD) clinic settings. METHODS: Through the STD Surveillance Network (SSuN), health departments in the San Francisco, Seattle, Denver, Minneapolis, and Richmond, Virginia, metropolitan areas interviewed systematic samples of men and women reported with gonorrhea by non-STD clinic providers from 2006 through 2008. RESULTS: Of 2,138 interviews, 10.0% were from San Francisco, 26.4% were from Seattle, 25.2% were from Denver, 22.9% were from Minneapolis, and 15.5% were from Richmond. A total of 1,165 women were interviewed; 70.1% (815/1,163) were <=24 years of age, 51.3% (598/1,165) were non-Hispanic black, and 19.0% (213/1,121) reported recent incarceration of self or sex partner. Among 610 men who have sex with only women, 50.9% were <=24 years of age, 65.1% were non-Hispanic black, 14.1% reported incarceration of self or sex partner, and 16.7% reported anonymous sex. Among 363 men who have sex with men (MSM), 20.9% were <=24 years of age, 61.6% were non-Hispanic white, 39.8% reported anonymous sex, 35.7% reported using the Internet to meet sex partners, and 12.1% reported methamphetamine use. CONCLUSIONS: These data identified two concurrent gonorrhea epidemics in minority populations: a young, black, heterosexual epidemic with frequently reported recent incarceration, and an older, mostly white MSM epidemic with more frequently reported anonymous sex, Internet use to meet sex partners, and methamphetamine use. PMID- 22547860 TI - Using disability-adjusted life years to assess the burden of disease and injury in Rhode Island. AB - OBJECTIVES: Disability-adjusted life years (DALYs) measure the burden of disease and injury in a population. We tested the feasibility of calculating DALYs to assess the burden of disease and injury in Rhode Island (RI). METHODS: We computed DALYs for the 2008 RI population using methods developed by the World Health Organization, Harvard University, and the World Bank. DALYs are a composite measure that sum years of life lost (YLLs) due to premature mortality with years lived with disability (YLDs). We calculated crude mortality, YLLs, YLDs, and DALYs for 90 major health conditions for RI and stratified them by gender and age. Calculations for YLLs and YLDs were based on five-year averages. We compared our results with U.S. and Los Angeles County, California, estimates. RESULTS: A DALYs ranking produces a different picture of RI's disease and injury burden than does mortality-based ranking. Of 90 major health conditions assessed for RI, six of the top 10 causes for mortality and DALYs were the same, but were ranked differently: ischemic heart disease, cerebrovascular disease, Alzheimer dementia and other dementias, trachea/bronchus/lung cancer, chronic obstructive pulmonary disease, and diabetes mellitus. These six conditions accounted for 59% of deaths but only 35% of DALYs. Causes and rank orders for DALYs differed between males and females and among age groups. CONCLUSIONS: Including nonfatal health conditions in an assessment of population health provides a different picture than traditional mortality-based assessments. This study demonstrates the feasibility and constraints of using DALYs to assess the burden of disease and injury at the state level. PMID- 22547861 TI - The Colorado Violent Death Reporting System (COVDRS): validity and utility of the Veteran status variable. AB - OBJECTIVE: Using the Veterans Affairs Beneficiary Identification Record Locator Subsystem (BIRLS) as the criterion database, we evaluated the sensitivity and specificity of the death certificate information in the Colorado Violent Death Reporting System (COVDRS) to determine Veteran status for those who died by suicide. METHODS: The study sample consisted of 3,820 individuals aged 18 years and older who died by suicide in Colorado from January 1, 2004, through December 31, 2008. To determine agreement on Veteran status, COVDRS data were submitted to the Veterans Benefits Administration for linkage to the BIRLS using Social Security numbers. RESULTS: Sensitivity and specificity of the Veteran status information on the death certificate were 93.1% (95% confidence interval [CI] 90.7, 95.2) and 91.7% (95% CI 90.5, 92.8), respectively. The overall agreement between the death certificate and the BIRLS on Veteran status was very good (kappa = 0.76; 95% CI 0.74, 0.79). CONCLUSIONS: This study of 3,820 suicide deaths in Colorado demonstrated a high level of agreement between the COVDRS Veteran status variable and the BIRLS. Such findings offer support for using the COVDRS in studying factors associated with suicide in the Veteran population. PMID- 22547862 TI - Integration of syndromic surveillance data into public health practice at state and local levels in North Carolina. AB - OBJECTIVES: We sought to describe the integration of syndromic surveillance data into daily surveillance practice at local health departments (LHDs) and make recommendations for the effective integration of syndromic and reportable disease data for public health use. METHODS: Structured interviews were conducted with local health directors and communicable disease nursing staff from a stratified random sample of LHDs from May through September 2009. Interviews captured information on direct access to the North Carolina syndromic surveillance system and on the use of syndromic surveillance information for outbreak management, program management, and the creation of reports. We analyzed syndromic surveillance system data to assess the number of signals resulting in a public health response. RESULTS: Syndromic surveillance data were used for outbreak investigation (19% of respondents) and program management and report writing (43% of respondents); a minority reported use of both syndromic and reportable disease data for these purposes (15% and 23%, respectively). Receiving data from frequent system users was associated with using data for these purposes (p=0.016 and p=0.033, respectively, for syndromic and reportable disease data). A small proportion of signals (<25%) resulted in a public health response. CONCLUSIONS: Use of syndromic surveillance data by North Carolina local public health authorities resulted in meaningful public health action, including both case investigation and program management. While useful, the syndromic surveillance data system was oriented toward sensitivity rather than efficiency. Successful incorporation of new surveillance data is likely to require systems that are oriented toward efficiency. PMID- 22547865 TI - Experience of a public health colorectal cancer testing program in Maryland. PMID- 22547863 TI - Patient and clinician ethical perspectives on the 2006 Centers for Disease Control and prevention HIV testing methods. AB - OBJECTIVES: CDC 2006 recommendations for new HIV testing methods in U.S. health care settings (opt-out approach, general medical consent, and optional prevention counseling) have been the subject of a public ethical debate. Ethical concerns might limit their implementation and affect expanded HIV screening efforts. We compared clinicians' and patients' perspectives on the ethical concerns raised about, justifications provided in support of, and preferences for the 2006 CDC recommended HIV testing methods for the U.S. health-care setting, in contrast with the 2001 CDC-recommended HIV testing methods (opt-in approach, specific written consent, and mandatory prevention counseling). METHODS: We conducted a non-inferiority trial and survey of 249 clinicians and random samples of 1,013 of their patients at three emergency departments and three ambulatory care clinics at university-affiliated hospitals in Rhode Island from June to December 2007. RESULTS: Clinicians found the 2006 CDC HIV testing methods to be more ethically concerning than the 2001 testing methods (i.e., ethically inferior), while patients had few ethical concerns. In regard to ethical justifications cited for the 2006 CDC HIV testing methods, clinicians were more supportive of the ethical justifications cited for using an opt-out approach and general medical consent, while patients were more supportive of the justifications for optional HIV prevention counseling. Clinicians showed a relatively greater preference for the opt-out approach and use of general medical consent, while patients had a relatively greater preference for optional HIV prevention counseling. CONCLUSIONS: Clinicians and their patients hold divergent ethical perspectives on CDC's 2006 HIV testing methods. The results indicate an opportunity to review not only these but also future HIV testing recommendations, as well as how they are presented for implementation. PMID- 22547867 TI - The ACA: implications for the accessibility and quality of breast and cervical cancer prevention and treatment services. PMID- 22547869 TI - Using GIS for administrative decision-making in a local public health setting. PMID- 22547870 TI - Oral health care for people living with HIV/AIDS. PMID- 22547871 TI - New approaches to oral health care for people living with HIV/AIDS. PMID- 22547872 TI - Increasing access to oral health care for people living with HIV/AIDS in the U.S.: baseline evaluation results of the Innovations in Oral Health Care Initiative. AB - OBJECTIVES: We provide an overview of the Health Resources and Services Administration HIV/AIDS Bureau's Special Projects of National Significance Innovations in Oral Health Care Initiative, describe the models developed by the 15 demonstration sites and associated evaluation center, and present initial descriptive data about the characteristics of the multisite evaluation study sample. METHODS: Baseline data were collected from May 2007-August 2009 for 2,469 adults living with HIV/AIDS who had been without dental care, except for emergency care, for 12 months or longer. Variables included sociodemographic characteristics, HIV status, medical care, history of dental care and oral health symptoms, oral health practices, and physical and mental health quality of life. Descriptive statistics of baseline variables were calculated. RESULTS: The study sample included 2,469 adults who had been HIV-positive for a decade; most were engaged in HIV care. The majority (52.4%) of patients had not seen a dentist in more than two years; 48.2% reported an unmet oral health-care need since testing positive for HIV, and 63.2% rated the health of their teeth and gums as "fair" or "poor." CONCLUSIONS: This study is the largest to examine oral health care among people living with HIV/AIDS in more than a decade. The need for access to oral health care among members of this HIV-positive patient sample is greater than in the general population, following previous trends. Findings from our study reinforce the necessity for continued federal and statewide advocacy and support for oral health programs targeting people living with HIV/AIDS; findings can be extended to other vulnerable populations. PMID- 22547873 TI - Correlates of unmet dental care need among HIV-positive people since being diagnosed with HIV. AB - OBJECTIVES: We analyzed the characteristics of people living with HIV/AIDS (PLWHA) who reported unmet oral health needs since testing positive and compared those characteristics with people reporting no unmet health needs. We also identified barriers to accessing oral health care for PLWHA. METHODS: We collected data from 2,469 HIV-positive patients who had not received oral health care in the previous 12 months and who had accessed care at Health Resources and Service Administration-funded Special Projects of National Significance Innovations in Oral Health Care Initiative demonstration sites. The outcome of interest was prior unmet oral health needs. We explore barriers to receiving oral health care, including cost, access, logistics, and personal factors. Bivariate tests of significance and generalized estimating equations were used in analyses. RESULTS: Nearly half of the study participants reported unmet dental care needs since their HIV diagnosis. People reporting unmet needs were more likely to be non-Hispanic white, U.S.-born, and HIV-positive for more than one year, and to have ever used crack cocaine or crystal methamphetamine. The top three reported barriers to oral care were cost, access to dental care, and fear of dental care. Additional reported barriers were indifference to dental care and logistical issues. CONCLUSION: Innovative strategies are needed to increase access to and retention in oral health care for PLWHA. Key areas for action include developing strategies to reduce costs, increase access, and reduce personal barriers to receiving dental care, particularly considering the impact of poor oral health in this population. PMID- 22547874 TI - Methamphetamine use and dental problems among adults enrolled in a program to increase access to oral health services for people living with HIV/AIDS. AB - OBJECTIVE: We examined the association between methamphetamine (meth) use and dental problems in a large sample of HIV-positive adults. METHODS: We gathered data from 2,178 interviews across 14 sites of the U.S. Health Resources and Services Administration HIV/AIDS Bureau's Special Projects of National Significance Innovations in Oral Health Care Initiative from May 2007 to August 2010. We used multivariate generalized estimating equations to test the association between meth use and dental problems, adjusting for potential confounders. RESULTS: Past and current meth use was significantly associated with more dental problems. The study also found that poor self-reported mental health status, fewer years since testing positive for HIV, a history of forgoing dental care, less frequent teeth brushing, poor self-reported oral health status, oral pain, grinding or clenching teeth, some alcohol use, more years of education, and self-reported men-who-have-sex-with-men HIV risk exposure (compared with other exposure routes) were significantly associated with dental problems. CONCLUSION: Individuals who are HIV-positive with a history of meth use experience access barriers to oral health care and more dental problems. Our study demonstrated that it is possible to recruit this population into dental care. Findings suggest that predisposing, enabling, and need factors can serve as demographic, clinical, and behavioral markers for recruiting people living with HIV/AIDS into oral health programs that can mitigate dental problems. PMID- 22547875 TI - Dental anxiety and the use of oral health services among people attending two HIV primary care clinics in Miami. AB - OBJECTIVES: We examined factors associated with dental anxiety among a sample of HIV primary care patients and investigated the independent association of dental anxiety with oral health care. METHODS: Cross-sectional data were collected in 2010 from 444 patients attending two HIV primary care clinics in Miami-Dade County, Florida. Corah Dental Anxiety Scores and use of oral health-care services were obtained from all HIV-positive patients in the survey. RESULTS: The prevalence of moderate to severe dental anxiety in this sample was 37.8%, while 7.9% of the sample was characterized with severe dental anxiety. The adjusted odds of having severe dental anxiety were 3.962 times greater for females than for males (95% confidence interval [CI] 1.688, 9.130). After controlling for age, ethnicity, gender, education, access to dental care, and HIV primary clinic experience, participants with severe dental anxiety had 69.3% lower adjusted odds of using oral health-care services within the past 12 months (vs. longer than 12 months ago) compared with participants with less-than-severe dental anxiety (adjusted odds ratio = 0.307, 95% CI 0.127, 0.742). CONCLUSION: A sizable number of patients living with HIV have anxiety associated with obtaining needed dental care. Routine screening for dental anxiety and counseling to reduce dental anxiety are supported by this study as a means of addressing the impact of dental anxiety on the use of oral health services among HIV-positive individuals. PMID- 22547876 TI - Retention of people living with HIV/AIDS in oral health care. AB - OBJECTIVE: We identified factors associated with retention in oral health care for people living with HIV/AIDS (PLWHA) and the impact of care retention on oral health-related outcomes. METHODS: We collected interview, laboratory value, clinic visit, and service utilization data from 1,237 HIV-positive patients entering dental care from May 2007 to August 2009, with at least an 18-month observation period. Retention in care was defined as two or more dental visits at least 12 months apart. We conducted multivariate regression using generalized estimating equations to explore factors associated with retention in care. RESULTS: In multivariate analysis, patients who received oral health education were 5.91 times as likely (95% confidence interval 3.73, 9.39) as those who did not receive this education to be retained in oral health care. Other factors associated with care retention included older age, taking antiretroviral medications, better physical health status, and having had a dental visit in the past two years. Patients retained in care were more likely to complete their treatment plans and attend a recall visit. Those retained in care experienced fewer oral health symptoms and less pain, and better overall health of teeth and gums. CONCLUSIONS: Retention in oral health care was associated with positive oral health outcomes for this sample of PLWHA. The strongest predictor of retention was the receipt of oral health education, suggesting that training in oral health education is an important factor when considering competencies for new dental professionals, and that patient education is central to the development of dental homes, which are designed to engage and retain people in oral health care over the long term. PMID- 22547877 TI - Access to oral health care and self-reported health status among low-income adults living with HIV/AIDS. AB - OBJECTIVE: We identified factors associated with improved self-reported health status in a sample of people living with HIV/AIDS (PLWHA) following enrollment in oral health care. METHODS: Data were collected from 1,499 enrollees in the Health Resources and Services Administration HIV/AIDS Bureau's Special Projects of National Significance Innovations in Oral Health Care Initiative. Data were gathered from 2007-2010 through in-person interviews at 14 sites; self-reported health status was measured using the SF-8TM Health Survey's physical and mental health summary scores. Utilization records of oral health-care services provided to enrollees were also obtained. Data were analyzed using general estimating equation linear regression. RESULTS: Between baseline and follow-up, we found that physical health status improved marginally while mental health status improved to a greater degree. For change in physical health status, a decrease in oral health problems and lack of health insurance were significantly associated with improved health status. Improved mental health status was associated with a decrease in oral health problems at the last available visit and no pain or distress in one's teeth or gums at the last available visit. CONCLUSION: For low income PLWHA, engagement in a program to increase access to oral health care was associated with improvement in overall well-being as measured by change in the SF 8 Health Survey. These results contribute to the knowledge base about using the SF-8 to assess the impact of clinical interventions. For public health practitioners working with PLWHA, findings suggest that access to oral health care can help promote well-being for this vulnerable population. PMID- 22547878 TI - Increasing access to oral health care for people living with HIV/AIDS in rural Oregon. AB - Access to oral health care for people living with HIV/AIDS is a severe problem. This article describes the design and impact of an Innovations in Oral Health Care Initiative program, funded through the Health Resources and Services Administration HIV/AIDS Bureau's Special Projects of National Significance (SPNS) program, that expanded oral health-care services for these individuals in rural Oregon. From April 2007 to August 2010, 473 patients received dental care (exceeding the target goal of 410 patients) and 153 dental hygiene students were trained to deliver oral health care to HIV-positive patients. The proportion of patients receiving oral health care increased from 10% to 65%, while the no-show rate declined from 40% to 10%. Key implementation components were leveraging SPNS funding and services to create an integrated delivery system, collaborations that resulted in improved service delivery systems, using dental hygiene students to deliver oral health care, enhanced care coordination through the services of a dental case manager, and program capacity to adjust to unanticipated needs. PMID- 22547880 TI - Financing oral health care for low-income adults living with HIV/AIDS. PMID- 22547879 TI - Patient perspectives on improving oral health-care practices among people living with HIV/AIDS. AB - This qualitative study explored the impact on oral health-care knowledge, attitudes, and practices among 39 people living with HIV/AIDS (PLWHA) participating in a national initiative aimed at increasing access to oral health care. Personal values and childhood dental experiences, beliefs about the importance of oral health in relation to HIV health, and concerns for appearance and self-esteem were found to be determinants of oral health knowledge and practice. Program participation resulted in better hygiene practices, improved self-esteem and appearance, relief of pain, and better physical and emotional health. In-depth exploration of the causes for these changes revealed a desire to continue with dental care due to the dental staff and environmental setting, and a desire to maintain overall HIV health, including oral health. Our findings emphasize the importance of addressing both personal values and contextual factors in providing oral health-care services to PLWHA. PMID- 22547881 TI - Sleep modifies metabolism. PMID- 22547882 TI - Sleep, sleep apnea, diabetes, and the metabolic syndrome: the role of treatment. PMID- 22547883 TI - A step toward solving the sleep/pain puzzle. PMID- 22547884 TI - Monozygotic twins affected with Kleine-Levin syndrome. PMID- 22547885 TI - Sleep duration and body mass index in twins: a gene-environment interaction. AB - STUDY OBJECTIVES: To examine whether sleep duration modifies genetic and environmental influences on body mass index (BMI). DESIGN: Genotype-environment interaction twin study. SETTING: University of Washington Twin Registry. PATIENTS OR PARTICIPANTS: A population-based sample of US twins (1,088 pairs, 604 monozygotic, 484 dizygotic; 66% female; mean age = 36.6 yr, standard deviation (SD) = 15.9 yr). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Participants self reported information on height, weight, and sleep. Mean BMI was calculated as 25.3 kg/m2 (SD = 5.4) and mean habitual sleep duration was 7.2 hr/night (SD = 1.2). Data were analyzed using biometric genetic interaction models. Overall the heritability of sleep duration was 34%. Longer sleep duration was associated with decreased BMI (P < 0.05). The heritability of BMI when sleep duration was < 7 hr (h2 = 70%) was more than twice as large as the heritability of BMI when sleep duration was >= 9 hr (h2 = 32%); this interaction was significant (P < 0.05). CONCLUSIONS: Shorter sleep duration is associated with increased BMI and increased genetic influences on BMI, suggesting that shorter sleep duration increases expression of genetic risks for high body weight. At the same time, longer sleep duration may suppress genetic influences on body weight. Future research aiming to identify specific genotypes for BMI may benefit by considering the moderating role of sleep duration. PMID- 22547887 TI - A controlled trial of CPAP therapy on metabolic control in individuals with impaired glucose tolerance and sleep apnea. AB - STUDY OBJECTIVES: To address whether treatment of sleep apnea improves glucose tolerance. DESIGN: Randomized, double-blind crossover study. SETTING: Sleep clinic referrals. PATIENTS: 50 subjects with moderate to severe sleep apnea (AHI > 15) and impaired glucose tolerance. INTERVENTIONS: Subjects were randomized to 8 weeks of CPAP or sham CPAP, followed by the alternate therapy after a one-month washout. After each treatment, subjects underwent 2-hour OGTT, polysomnography, actigraphy, and measurements of indices of glucose control. MEASUREMENTS AND RESULTS: The primary outcome was normalization of the mean 2-h OGTT; a secondary outcome was improvement in the Insulin Sensitivity Index (ISI (0,120). Subjects were 42% men, mean age of 54 (10), BMI of 39 (8), and AHI of 44 (27). Baseline fasting glucose was 104 (12), and mean 2-h OGTT was 110 (57) mg/dL. Seven subjects normalized their mean 2-h OGTT after CPAP but not after sham CPAP, while 5 subjects normalized after sham CPAP but not after CPAP. Overall, there was no improvement in ISI (0,120) between CPAP and sham CPAP (3.6%; 95% CI: [-2.2%, 9.7%]; P = 0.22). However, in those subjects with baseline AHI >= 30 (n = 25), there was a 13.3% (95% CI: [5.2%, 22.1%]; P < 0.001) improvement in ISI (0,120) and a 28.7% (95%CI: [-46.5%, -10.9%], P = 0.002) reduction in the 2-h insulin level after CPAP compared to sham CPAP. CONCLUSIONS: This study did not show that IGT normalizes after CPAP in subjects with moderate sleep apnea and obesity. However, insulin sensitivity improved in those with AHI >= 30, suggesting beneficial metabolic effects of CPAP in severe sleep apnea. Clinical trials information: ClinicalTrials.gov Identifier: NCT01385995. PMID- 22547888 TI - Learning, attention/hyperactivity, and conduct problems as sequelae of excessive daytime sleepiness in a general population study of young children. AB - STUDY OBJECTIVES: Although excessive daytime sleepiness (EDS) is a common problem in children, with estimates of 15%; few studies have investigated the sequelae of EDS in young children. We investigated the association of EDS with objective neurocognitive measures and parent reported learning, attention/hyperactivity, and conduct problems in a large general population sample of children. DESIGN: Cross-sectional. SETTING: Population based. PARTICIPANTS: 508 children from The Penn State Child Cohort. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Children underwent a 9-h polysomnogram, comprehensive neurocognitive testing, and parent rating scales. Children were divided into 2 groups: those with and without parent reported EDS. Structural equation modeling was used to examine whether processing speed and working memory performance would mediate the relationship between EDS and learning, attention/hyperactivity, and conduct problems. Logistic regression models suggest that parent-reported learning, attention/hyperactivity, and conduct problems, as well as objective measurement of processing speed and working memory are significant sequelae of EDS, even when controlling for AHI and objective markers of sleep. Path analysis demonstrates that processing speed and working memory performance are strong mediators of the association of EDS with learning and attention/hyperactivity problems, while to a slightly lesser degree are mediators from EDS to conduct problems. CONCLUSIONS: This study suggests that in a large general population sample of young children, parent-reported EDS is associated with neurobehavioral (learning, attention/hyperactivity, conduct) problems and poorer performance in processing speed and working memory. Impairment due to EDS in daytime cognitive and behavioral functioning can have a significant impact on children's development. PMID- 22547886 TI - Daytime sleepiness in obesity: mechanisms beyond obstructive sleep apnea--a review. AB - Increasing numbers of overweight children and adults are presenting to sleep medicine clinics for evaluation and treatment of sleepiness. Sleepiness negatively affects quality of life, mental health, productivity, and safety. Thus, it is essential to comprehensively address all potential causes of sleepiness. While many obese individuals presenting with hypersomnolence will be diagnosed with obstructive sleep apnea and their sleepiness will improve with effective therapy for sleep apnea, a significant proportion of patients will continue to have hypersomnolence. Clinical studies demonstrate that obesity without sleep apnea is also associated with a higher prevalence of hypersomnolence and that bariatric surgery can markedly improve hypersomnolence before resolution of obstructive sleep apnea. High fat diet in both humans and animals is associated with hypersomnolence. This review critically examines the relationships between sleepiness, feeding, obesity, and sleep apnea and then discusses the hormonal, metabolic, and inflammatory mechanisms potentially contributing to hypersomnolence in obesity, independent of sleep apnea and other established causes of excessive daytime sleepiness. PMID- 22547889 TI - Increased fragmentation of rest-activity patterns is associated with a characteristic pattern of cognitive impairment in older individuals. AB - STUDY OBJECTIVES: Aging is accompanied by changes in cognitive function, and changes in rest-activity patterns. Previous work has demonstrated associations between global rest-activity measures and cognitive performance on a number of tasks. Recently, we demonstrated that aging is associated with changes in the minute-to-minute fragmentation of rest-activity patterns in addition to changes in amounts of rest and activity. Given the body of experimental evidence linking sleep fragmentation with decrements in cognitive function in animals and humans, we hypothesized that increased fragmentation of rest-activity patterns would be associated with decreased cognitive function in older individuals. DESIGN: Cross sectional. PARTICIPANTS: 700 community-dwelling individuals from the Rush Memory and Aging Project. MEASUREMENTS AND RESULTS: We obtained up to 11 days of actigraphic recordings in subjects' home environments and quantified the fragmentation of rest and activity using a recently developed state transition metric. We tested the associations between this metric and performance in 5 cognitive domains. Greater fragmentation of both rest and activity were associated with lower levels of cognitive performance, and this association was independent of total amounts of rest or activity. There was a characteristic pattern of cognitive deficits associated with rest and activity fragmentation, with preferential involvement of perceptual speed, semantic memory, working memory, and visuospatial abilities, and relative sparing of episodic memory. CONCLUSIONS: The fragmentation of periods of rest and activity is a clinically important characteristic of rest-activity patterns that correlates with cognitive performance in older individuals. PMID- 22547891 TI - The role of NREM sleep instability in child cognitive performance. AB - STUDY OBJECTIVES: Based on recent reports of the involvement of cyclic alternating pattern (CAP) in cognitive functioning in adults, we investigated the association between CAP parameters and cognitive performance in healthy children. DESIGN: Polysomnographic assessment and standardized neurocognitive testing in healthy children. SETTINGS: Sleep laboratory. PARTICIPANTS: Forty-two children aged 7.6 +/- 2.7 years, with an even distribution of body mass percentile (58.5 +/- 25.5) and SES reflective of national norms. MEASUREMENTS: Analysis of sleep macrostructure following the R&K criteria and of cyclic alternating pattern (CAP). The neurocognitive tests were the Stanford Binet Intelligence Scale (5(th) edition) and a Neuropsychological Developmental Assessment (NEPSY) RESULTS: Fluid reasoning ability was positively associated with CAP rate, particularly during SWS and with A1 total index and A1 index in SWS. Regression analysis, controlling for age and SES, showed that CAP rate in SWS and A1 index in SWS were significant predictors of nonverbal fluid reasoning, explaining 24% and 22% of the variance in test scores, respectively. CONCLUSION: This study shows that CAP analysis provides important insights on the role of EEG slow oscillations (CAP A1) in cognitive performance. Children with higher cognitive efficiency showed an increase of phase A1 in total sleep and in SWS. PMID- 22547890 TI - Sleep characteristics of self-reported long sleepers. AB - BACKGROUND: Self-reported long habitual sleep durations (>= 9 h per night) consistently predict increased mortality. We compared objective sleep parameters of self-reported long versus normal duration sleepers to determine whether long sleepers truly sleep more or have an underlying sleep abnormality. METHODS: Older men participating in the Osteoporotic Fractures in Men Study (MrOS) were recruited for a comprehensive sleep assessment, which included wrist actigraphy, overnight polysomnography (PSG), and a question about usual nocturnal sleep duration. RESULTS: Of the 3134 participants (mean age 76.4 +/- 5.6; 89.9% Caucasian), 1888 (60.2%) reported sleeping 7-8 h (normal sleepers) and 174 (5.6%) reported >= 9 h (long sleepers). On actigraphy, long sleepers spent on average 63.0 min more per night in bed (P < 0.001), slept 42.8 min longer (P < 0.001), and spent 6.8 min more per day napping (P = 0.01). Based on PSG, the apnea hypopnea index, periodic limb movement index, arousal index, and sleep stage distribution did not differ. After adjusting for differences in demographics, comorbidities, and medication usage, self-reported long sleepers continued to spend more time in bed and sleep more, based on both actigraphy and PSG. Each additional 30 min in bed or asleep as measured by actigraphy increased the odds of being a self-reported long-sleeper 1.74-fold and 1.33-fold, respectively (P < 0.001 for both). CONCLUSIONS: On objective assessment, self-reported long sleepers spend more time in bed and more time asleep than normal duration sleepers. This is not explained by differences in comorbidity or sleep disorders. PMID- 22547892 TI - Sleep's influence on a reflexive form of memory that does not require voluntary attention. AB - STUDY OBJECTIVES: Studies to date have examined the influence of sleep on forms of memory that require voluntary attention. The authors examine the influence of sleep on a form of memory that is acquired by passive viewing. DESIGN: Induction of the McCollough effect, and measurement of perceptual color bias before and after induction, and before and after intervening sleep, wake, or visual deprivation. SETTING: Sound-attenuated sleep research room. PARTICIPANTS: 13 healthy volunteers (mean age = 23 years; age range = 18-31 years) with normal or corrected-to-normal vision. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: ) ENCODING: sleep preceded adaptation. On separate nights, each participant slept for an average of 0 (wake), 1, 2, 4, or 7 hr (complete sleep). Upon awakening, the participant's baseline perceptual color bias was measured. Then, he or she viewed an adapter consisting of alternating red/horizontal and green/vertical gratings for 5 min. Color bias was remeasured. The strength of the aftereffect is the postadaptation color bias relative to baseline. A strong orientation contingent color aftereffect was observed in all participants, but total sleep duration (TSD) prior to the adaptation did not modulate aftereffect strength. Further, prior sleep provided no benefit over prior wake. Retention: sleep followed adaptation. The procedure was similar except that adaptation preceded sleep. Postadaptation sleep, irrespective of its duration (1, 3, 5, or 7 hr), arrested aftereffect decay. By contrast, aftereffect decay was arrested during subsequent wake only if the adapted eye was visually deprived. CONCLUSIONS: Sleep as well as passive sensory deprivation enables the retention of a color aftereffect. Sleep shelters this reflexive form of memory in a manner akin to preventing sensory interference. PMID- 22547893 TI - Decision making and executive functions in REM sleep behavior disorder. AB - STUDY OBJECTIVES: This study was designed to assess decision making and executive functions in patients with idiopathic REM sleep behavior disorder (iRBD). IRBD is often seen as an early sign of later evolving neurodegenerative disease, most importantly Parkinson disease (PD) and Lewy body dementia (DLB). It has been proposed that iRBD patients show a cognitive profile similar to patients with PD. DESIGN: All participants performed an extensive test battery tapping executive functions as well as the IOWA gambling task, which measures decision making under ambiguity. SETTING: University hospital sleep disorders center. PARTICIPANTS: 16 iRBD patients and 45 age- and education-matched controls. INTERVENTION: N.A. MEASUREMENTS AND RESULTS: Compared with controls, iRBD patients showed disadvantageous decision making under ambiguity and did not learn by feedback over the task. IRBD patients' decision pattern was characterized by the lack of a consistent strategy, as indicated by frequent shifts between the single choices. A high proportion of iRBD patients (75%) showed random performance or worse even at the end of the task. No group differences were found in tasks assessing information sampling, flexibility and categorization, problem solving, and impulsivity. CONCLUSIONS: As suggested by the present investigation, iRBD patients may show difficulties in decision making under ambiguity in a stage when other cognitive functions are relatively well preserved. Whether this is driven by subgroups of patients prone to develop PD or DLB has to be assessed by follow up investigations. PMID- 22547894 TI - Deciphering the temporal link between pain and sleep in a heterogeneous chronic pain patient sample: a multilevel daily process study. AB - OBJECTIVES: Because insomnia is a common comorbidity of chronic pain, scientific and clinical interest in the relationship of pain and sleep has surged in recent years. Although experimental studies suggest a sleep-interfering property of pain and a pain-enhancing effect of sleep deprivation/fragmentation, the temporal association between pain and sleep as experienced by patients is less understood. The current study was conducted to examine the influence of presleep pain on subsequent sleep and sleep on pain reports the next day, taking into consideration other related psychophysiologic variables such as mood and arousal. DESIGN: A daily process study, involving participants to monitor their pain, sleep, mood, and presleep arousal for 1 wk. Multilevel modeling was used to analyze the data. SETTING: In the patients' natural living and sleeping environment. PATIENTS: One hundred nineteen patients (73.9% female, mean age = 46 years) with chronic pain and concomitant insomnia. MEASUREMENT: An electronic diary was used to record patients' self-reported sleep quality/efficiency and ratings of pain, mood, and arousal at different times of the day; actigraphy was also used to provide estimates of sleep efficiency. RESULTS: Results indicated that presleep pain was not a reliable predictor of subsequent sleep. Instead, sleep was better predicted by presleep cognitive arousal. Although sleep quality was a consistent predictor of pain the next day, the pain-relieving effect of sleep was only evident during the first half of the day. CONCLUSIONS: These findings challenge the often-assumed reciprocal relationship between pain and sleep and call for a diversification in thinking of the daily interaction of these 2 processes. PMID- 22547895 TI - Clinical and polysomnographic predictors of the natural history of poor sleep in the general population. AB - STUDY OBJECTIVES: Approximately 8-10% of the general population suffers from chronic insomnia, whereas another 20-30% of the population has insomnia symptoms at any given time (i.e., poor sleep). However, few longitudinal studies have examined risk factors of the natural history of poor sleep, and none have examined the role of polysomnographic (PSG) variables. DESIGN: Representative longitudinal study. SETTING: Sleep laboratory. PARTICIPANTS: From a random, general population sample of 1,741 individuals of the adult Penn State Cohort, 1,395 were followed up after 7.5 yr. MEASUREMENTS: Full medical evaluation and 1 night PSG at baseline and telephone interview at follow-up. RESULTS: The rate of incident poor sleep was 18.4%. Physical (e.g., obesity, sleep apnea, and ulcer) and mental (e.g., depression) health conditions and behavioral factors (e.g., smoking and alcohol consumption) increased the odds of incident poor sleep as compared to normal sleep. The rates of persistent, remitted, and poor sleepers who developed chronic insomnia were 39%, 44%, and 17%, respectively. Risk factors for persistent poor sleep were physical health conditions combined with psychologic distress. Shorter objective sleep duration and a family history of sleep problems were risk factors for poor sleep evolving into chronic insomnia. CONCLUSIONS: Poor sleep appears to be primarily a symptom of physical and mental health conditions, whereas the persistence of poor sleep is associated with psychologic distress. Importantly, sleep apnea appears to be associated with incident poor sleep but not with chronic insomnia. Finally, this study suggests that objective short sleep duration in poor sleepers is a biologic marker of genetic predisposition to chronic insomnia. PMID- 22547896 TI - Discharge patterns of human tensor palatini motor units during sleep onset. AB - STUDY OBJECTIVES: Upper airway muscles such as genioglossus (GG) and tensor palatini (TP) reduce activity at sleep onset. In GG reduced muscle activity is primarily due to inspiratory modulated motor units becoming silent, suggesting reduced respiratory pattern generator (RPG) output. However, unlike GG, TP shows minimal respiratory modulation and presumably has few inspiratory modulated motor units and minimal input from the RPG. Thus, we investigated the mechanism by which TP reduces activity at sleep onset. DESIGN: The activity of TP motor units were studied during relaxed wakefulness and over the transition from wakefulness to sleep. SETTING: Sleep laboratory. PARTICIPANTS: Nine young (21.4 +/- 3.4 years) males were studied on a total of 11 nights. INTERVENTION: Sleep onset. MEASUREMENTS AND RESULTS: Two TP EMGs (thin, hooked wire electrodes), and sleep and respiratory measures were recorded. One hundred twenty-one sleep onsets were identified (13.4 +/- 7.2/subject), resulting in 128 motor units (14.3 +/- 13.0/subject); 29% of units were tonic, 43% inspiratory modulated (inspiratory phasic 18%, inspiratory tonic 25%), and 28% expiratory modulated (expiratory phasic 21%, expiratory tonic 7%). There was a reduction in both expiratory and inspiratory modulated units, but not tonic units, at sleep onset. Reduced TP activity was almost entirely due to de-recruitment. CONCLUSIONS: TP showed a similar distribution of motor units as other airway muscles. However, a greater proportion of expiratory modulated motor units were active in TP and these expiratory units, along with inspiratory units, tended to become silent over sleep onset. The data suggest that both expiratory and inspiratory drive components from the RPG are reduced at sleep onset in TP. PMID- 22547897 TI - Tolerance and efficacy of sodium oxybate in childhood narcolepsy with cataplexy: a retrospective study. AB - Narcolepsy with cataplexy is a sleep disorder characterized by excessive daytime sleepiness, irresistible sleep episodes, and sudden loss of muscle tone (cataplexy) mostly triggered by emotions. Narcolepsy with cataplexy is a disabling lifelong disorder frequently arising during childhood. Pediatric narcolepsy often results in severe learning and social impairment. Improving awareness about this condition increases early diagnosis and may allow patients to rapidly access adequate treatments, including pharmacotherapy and/or non medication-based approaches. Even though children currently undergo pharmacotherapy, data about safety and efficacy in the pediatric population are scarce. Lacking international guidelines as well as drugs registered for childhood narcolepsy with cataplexy, physicians have no other alternative but to prescribe in an off-label manner medications identical to those recommended for adults. We retrospectively evaluated 27 children ranging from 6 to 16 years old, suffering from narcolepsy with cataplexy, who had been treated with off-label sodium oxybate and had been followed in a clinical setting. Throughout a semi structured interview, we documented the good efficacy and tolerability of sodium oxybate in the majority of the patients. This study constitutes a preliminary step towards a further randomized controlled trial in childhood narcolepsy with cataplexy. PMID- 22547898 TI - Diurnal fluctuation in histidine decarboxylase expression, the rate limiting enzyme for histamine production, and its disorder in neurodegenerative diseases. AB - STUDY OBJECTIVES: Neuronal histamine shows diurnal rhythms in rodents and plays a major role in the maintenance of vigilance. No data are available on its diurnal fluctuation in humans, either in health or in neurodegenerative disorders such as Parkinson disease (PD), Alzheimer disease (AD), or Huntington disease (HD), all of which are characterized by sleep-wake disturbances. DESIGN: Quantitative in situ hybridization was used to study the mRNA expression of histidine decarboxylase (HDC), the key enzyme of histamine production in the tuberomammillary nucleus (TMN) in postmortem human hypothalamic tissue, obtained from 33 controls and 31 patients with a neurodegenerative disease-PD (n = 15), AD (n = 9), and HD (n = 8)-and covering the full 24-h cycle with respect to clock time of death. RESULTS: HDC-mRNA levels in controls were found to be significantly higher during the daytime than at night (e.g., 08:01-20:00 versus 20:01-08:00, P = 0.004). This day-night fluctuation was markedly different in patients with neurodegenerative diseases. CONCLUSION: The diurnal fluctuation of HDC-mRNA expression in human TMN supports a role for neuronal histamine in regulating day-night rhythms. Future studies should investigate histamine rhythm abnormalities in neurodegenerative disorders. CITATION: Shan L; Hofman MA; van Wamelen DJ; Van Someren EJW; Bao AM; Swaab DF. Diurnal fluctuation in histidine decarboxylase expression, the rate limiting enzyme for histamine production, and its disorder in neurodegenerative diseases. PMID- 22547899 TI - Variance Estimation in Censored Quantile Regression via Induced Smoothing. AB - Statistical inference in censored quantile regression is challenging, partly due to the unsmoothness of the quantile score function. A new procedure is developed to estimate the variance of Bang and Tsiatis's inverse-censoring-probability weighted estimator for censored quantile regression by employing the idea of induced smoothing. The proposed variance estimator is shown to be asymptotically consistent. In addition, numerical study suggests that the proposed procedure performs well in finite samples, and it is computationally more efficient than the commonly used bootstrap method. PMID- 22547900 TI - Spatial Stress and Strain Distributions of Viscoelastic Layers in Oscillatory Shear. AB - One of the standard experimental probes of a viscoelastic material is to measure the response of a layer trapped between parallel surfaces, imposing either periodic stress or strain at one boundary and measuring the other. The relative phase between stress and strain yields solid-like and liquid-like properties, called the storage and loss moduli, respectively, which are then captured over a range of imposed frequencies. Rarely are the full spatial distributions of shear and normal stresses considered, primarily because they cannot be measured except at boundaries and the information was not deemed of particular interest in theoretical studies. Likewise, strain distributions throughout the layer were traditionally ignored except in a classical protocol of Ferry, Adler and Sawyer, based on snapshots of standing shear waves. Recent investigations of thin lung mucus layers exposed to oscillatory stress (breathing) and strain (coordinated cilia), however, suggest that the wide range of healthy conditions and environmental or disease assaults lead to conditions that are quite disparate from the "surface loading" and "gap loading" conditions that characterize classical rheometers. In this article, we extend our previous linear and nonlinear models of boundary stresses in controlled oscillatory strain to the entire layer. To illustrate non-intuitive heterogeneous responses, we characterize experimental conditions and material parameter ranges where the maximum stresses migrate into the channel interior. PMID- 22547901 TI - Evaluation of the white test for the intraoperative detection of bile leakage. AB - We assess whether the White test is better than the conventional bile leakage test for the intraoperative detection of bile leakage in hepatectomized patients. This study included 30 patients who received elective liver resection. Both the conventional bile leakage test (injecting an isotonic sodium chloride solution through the cystic duct) and the White test (injecting a fat emulsion solution through the cystic duct) were carried out in the same patients. The detection of bile leakage was compared between the conventional method and the White test. A bile leak was demonstrated in 8 patients (26.7%) by the conventional method and in 19 patients (63.3%) by the White test. In addition, the White test detected a significantly higher number of bile leakage sites compared with the conventional method (Wilcoxon signed-rank test; P < 0.001). The White test is better than the conventional test for the intraoperative detection of bile leakage. Based on our study, we recommend that surgeons investigating bile leakage sites during liver resections should use the White test instead of the conventional bile leakage test. PMID- 22547902 TI - Effects of long term polyarthritis and subsequent NSAID treatment on activity with disassociation of tactile allodynia in the mouse. AB - Chronic pain has profound effects on activity. Previous reports indicate chronic inflammatory conditions result in reduced activity which normalizes upon pain treatment. However, there is little systematic investigation of this process. Rheumatoid arthritis is an autoimmune disorder that causes significant joint pain. The K/BxN serum transfer mouse has been characterized as a model for rheumatoid arthritis and chronic pain. We investigated the activity of mice following K/BxN serum transfer vs. control serum and observed the activity changes following delivery of an NSAID, ketorolac. Previous studies have used running wheels and laser beams to monitor activity; we chose to validate a model using cost-effective infrared sensors on individual cages. Each mouse had its baseline activity obtained, which showed significant variation between individual C57Bl/6 mice. Arthritic mice had significantly decreased activity for only the first 11 nights. Conversely, previous work has shown that these animals display tactile allodynia that persists for at least 45 days. Mice were treated with ketorolac in their drinking water (10mg/kg, 15mg/kg, or 20mg/kg) for nights 6-8. The two highest doses showed significant normalization of activity levels. Four nights after ketorolac was stopped, treated animals were still significantly more active than control. The reversal of the reduced activity provides support that the depression relates to the arthritic pain state of the animal. These results indicate the efficacy of activity monitoring to better investigate behavior in persistent pain states. However, insofar as depressed activity reflects pain and disability, the present work raises questions as to the relevance of the tactile thresholds in defining behaviorally relevant pain states. PMID- 22547903 TI - Evaluation of serum adipokines in peripheral arterial occlusive disease. AB - AIM: Out study aimed to assess the serum levels of adipokines in patients with peripheral arterial occlusive disease (PAOD) caused by atherosclerosis. METHODS: Serum samples were obtained from 221 patients. One hundred and forty patients, (26 females and 114 males) met the inclusion criteria and were assigned into the case group. Eighty one patients (17 females and 64 males), were included in the control group. Circulating plasma levels of adiponectin, leptin, resistin, and TNF-alpha were measured using the enzyme-linked immunosorbent assay (ELISA) method. RESULTS: Significant lower levels of adiponectin were present (P = 0.0061) in PAOD patients (2380.23 +/- 1634.42 pg/mL) compared to the control group (3065.06 +/- 1901.2 pg/mL). The mean value of leptin (2844.42 +/- 3301.08 pg/mL) and resistin (2047.81+/-3301.08 pg/mL) patients included in the PAOD group was higher, as compared to the control group. Statistically significant difference was found between the two groups for leptin (P = 0.0332) and for resistin (P = 0.0352). No statistically significant difference for TNF-alpha was found between the two groups (P > 0.05). CONCLUSION: The markers of inflammation secreted by the adipose tissue (adiponectin, leptin, resistin) showed significant differences in patients from the case group (with PAOD) compared to the control group. PMID- 22547904 TI - Concentration kinetics of serum MMP-9 and TIMP-1 after blunt multiple injuries in the early posttraumatic period. AB - Metalloproteinases are secreted in response to a variety of inflammatory mediators and inhibited by tissue inhibitors of matrixmetalloproteinases (TIMPs). Two members of these families, MMP-9 and TIMP-1, were differentially expressed depending on clinical parameters in a previous genomewide mRNA analysis. The aim of this paper was now to evaluate the posttraumatic serum levels and the time course of both proteins depending on distinct clinical parameters. 60 multiple traumatized patients (ISS > 16) were included. Blood samples were drawn on admission and 6 h, 12 h, 24 h, 48 h, and 72 h after trauma. Serum levels were quantified by ELISA. MMP-9 levels significantly decreased in the early posttraumatic period (P < 0.05) whereas TIMP-1 levels significantly increased in all patients (P < 0.05). MMP-9 and TIMP-1 serum concentration kinetics became manifest in an inversely proportional balance. Furthermore, MMP-9 presented a stronger decrease in patients with severe trauma and non-survivors in contrast to minor traumatized patients (ISS <= 33) and survivors, initially after trauma. PMID- 22547905 TI - The role of the vagus nerve: modulation of the inflammatory reaction in murine polymicrobial sepsis. AB - The particular importance of the vagus nerve for the pathophysiology of peritonitis becomes more and more apparent. In this work we provide evidence for the vagal modulation of inflammation in the murine model of colon ascendens stent peritonitis (CASP). Vagotomy significantly increases mortality in polymicrobial sepsis. This effect is not accounted for by the dilatation of gastric volume following vagotomy. As the stimulation of cholinergic receptors by nicotine has no therapeutic effect, the lack of nicotine is also not the reason for the reduced survival rate. In fact, increased septic mortality is a consequence of the absent modulating influence of the vagus nerve on the immune system: we detected significantly elevated serum corticosterone levels in vagotomised mice 24 h following CASP and a decreased ex vivo TNF-alpha secretion of Kupffer cells upon stimulation with LPS. In conclusion, the vagus nerve has a modulating influence in polymicrobial sepsis by attenuating the immune dysregulation. PMID- 22547906 TI - Mobilization of CD34+CXCR4+ stem/progenitor cells and the parameters of left ventricular function and remodeling in 1-year follow-up of patients with acute myocardial infarction. AB - Mobilization of stem cells in acute MI might signify the reparatory response. Aim of the Study. Prospective evaluation of correlation between CD34+CXCR4+ cell mobilization and improvement of LVEF and remodeling in patients with acute MI in 1-year followup. Methods. 50 patients with MI, 28 with stable angina (SAP), and 20 individuals with no CAD (CTRL). CD34+CXCR4+ cells, SDF-1, G-CSF, troponin I (TnI) and NT-proBNP were measured on admission and 1 year after MI. Echocardiography and ergospirometry were carried out after 1 year. Results. Number of CD34+CXCR4+ cells in acute MI was significantly higher in comparison with SAP and CTRL, but lower in patients with decreased LVEF <=40%. In patients who had significant LVEF increase >=5% in 1 year FU the number of cells in acute MI was significantly higher versus patients with no LVEF improvement. Number of cells was positively correlated (r = 0,41, P = 0,031) with absolute LVEF change and inversely with absolute change of ESD and EDD in 1-year FU. Mobilization of CD34+CXCR4+ cells in acute MI was negatively correlated with maximum TnI and NT proBNP levels. Conclusion. Mobilization of CD34+CXCR4+ cells in acute MI shows significant positive correlation with improvement of LVEF after 1 year. PMID- 22547907 TI - Differential expression of sphingosine-1-phosphate receptors in abdominal aortic aneurysms. AB - OBJECTIVE: Inflammation plays a key role in the pathophysiology of abdominal aortic aneurysms (AAAs). Newly discovered Sphingosine-1-Phosphate Receptors (S1P receptors) are critical in modulating inflammatory response via prostaglandin production. The aim of the current study was to investigate the expression of different S1P receptors in AAAs and compared with normal aortas at the protein level. MATERIALS AND METHODS: Aortic specimens were harvested during aortic reconstructive surgery for the AAA group or during organ transplant for the control group. The protein expression of S1P1, 2 and 3 in AAAs and normal aortas was assessed by Western blotting and immunohistochemical analysis. RESULTS: There were 40 AAAs and 20 control aortas collected for the receptor analysis. For Western blot analysis, S1P1 expression was not detected in either group; S1P2 protein was constitutively detected in both types of aortas but its expression level was significantly decreased by 73% (P < 0.05) in AAAs compared with the control group. In contrast, strong S1P3 expression was detected in AAAs aortas but not in normal aortas. Immumohistochemical staining showed similar results, except a weak S1P3 signal was detectable in normal aortas. CONCLUSIONS: Western blot and staining results consistently showed the down-regulation of the S1P2 protein with simultaneous up-regulation of the S1P3 protein in AAAs. Since those newly discovered receptors play an important role in the inflammatory cascade, the modulating of S1P signaling, particularly via S1P2 and S1P3, could represent novel therapeutic targets in future AAA treatments. PMID- 22547908 TI - Posttraumatic immune response and its modulation. PMID- 22547909 TI - C-peptide: a new mediator of atherosclerosis in diabetes. AB - Diabetes type 2 and insulin resistance are the risk factors for cardiovascular disease. It is already known that atherosclerosis is an inflammatory disease, and a lot of different factors are involved in its onset. C-peptide is a cleavage product of proinsulin, an active substance with a number of effects within different complications of diabetes. In this paper we discuss the role of C peptide and its effects in the development of atherosclerosis in type 2 diabetic patients. PMID- 22547911 TI - An Evaluation of Six Brief Interventions that Target Drug-Related Problems in Correctional Populations. AB - Finding brief effective treatments for criminal justice populations is a major public need. The CJ-DATS Targeted Intervention for Corrections (TIC), which consists of six brief interventions (Communication, Anger, Motivation, Criminal Thinking, Social Networks, and HIV/Sexual Health), were tested in separate federally-funded randomized control studies. In total, 1,573 criminal justice involved individuals from 20 correction facilities participated (78% males; 54% white). Multi-level repeated measures analyses found significant gains in knowledge, attitudes, and psychosocial functioning (criteria basic to Knowledge, Attitude, and Practices (KAP) and TCU Treatment Process Models). While improvements were less consistent in criminal thinking, overall evidence supported efficacy for the TIC interventions. PMID- 22547910 TI - Inflammation and the peritoneal membrane: causes and impact on structure and function during peritoneal dialysis. AB - Peritoneal dialysis therapy has increased in popularity since the end of the 1970s. This method provides a patient survival rate equivalent to hemodialysis and better preservation of residual renal function. However, technique failure by peritonitis, and ultrafiltration failure, which is a multifactorial complication that can affect up to 40% of patients after 3 years of therapy. Encapsulant peritoneal sclerosis is an extreme and potentially fatal manifestation. Causes of inflammation in peritoneal dialysis range from traditional factors to those related to chronic kidney disease per se, as well as from the peritoneal dialysis treatment, including the peritoneal dialysis catheter, dialysis solution, and infectious peritonitis. Peritoneal inflammation generated causes significant structural alterations including: thickening and cubic transformation of mesothelial cells, fibrin deposition, fibrous capsule formation, perivascular bleeding, and interstitial fibrosis. Structural alterations of the peritoneal membrane described above result in clinical and functional changes. One of these clinical manifestations is ultrafiltration failure and can occur in up to 30% of patients on PD after five years of treatment. An understanding of the mechanisms involved in peritoneal inflammation is fundamental to improve patient survival and provide a better quality of life. PMID- 22547912 TI - Pelvic inflammatory disease. PMID- 22547913 TI - Prevention of human papillomavirus-related malignancies of the female genital tract. PMID- 22547914 TI - Emotional-based practice. PMID- 22547915 TI - Manipulative practice in the cervical spine: a survey of IFOMPT member countries. AB - The International Federation of Orthopaedic Manipulative Physical Therapists (IFOMPT) aims to achieve worldwide promotion of excellence and unity in clinical and academic standards for manual and musculoskeletal physical therapists. To this end, IFOMPT has sponsored several conference panel sessions and a survey of Member Organizations (MOs) and Registered Interest Groups (RIGs) regarding current cervical spine manipulation and pre-manipulative screening practice in each country. The purpose of this study was to determine common elements of cervical spine manipulative practice and pre-manipulative screening between countries. In late 2007, a questionnaire investigating recommended pre manipulative screening protocol/guideline use, informed consent regarding risks, screening procedures, and treatment/manipulation technique was sent to all twenty MOs and five RIGs. The response rate was 88%. The main findings of the survey included: 77% of respondent organizations use pre-manipulative guidelines, with Australian guidelines the most frequently adopted internationally (36%); recommendations concerning the provision of information about the possibility of serious adverse events is not standard practice in all countries (50%); positional tests for vertebrobasilar insufficiency are used by all respondent organizations; craniovertebral ligament testing is sometimes taught as a pre manipulative screening tool (36%); the use of upper cervical spine manipulation has declined in some countries (41%); and of the respondent organizations that continue to teach upper cervical manipulation, most (70%) minimize the rotation component. The findings of this research will inform an IFOMPT international standard for screening the cervical region prior to orthopaedic manual therapy intervention. The development of an IFOMPT endorsed document will be of assistance to manual therapy clinicians worldwide in safely managing disorders of the cervical spine. PMID- 22547916 TI - An investigation of the relationship between measures of pain intensity, pain affect, and disability, in patients with shoulder dysfunction. AB - OBJECTIVES: Numerous outcomes measures can be used to capture and differentiate change in different constructs comprising recovery. Consequently, patients are often burdened by completing a number of measures which involves considerable time and effort. The purpose of this longitudinal, observational study was to identify the number of dimensions in a battery of self-report findings in a patient population who received shoulder injections to investigate the association of the instruments. METHODS: Ninety-nine subjects, with diagnoses of adhesive capsulitis, labral injuries, rotator cuff injuries, and osteoarthritis completed outcomes measures including five different forms of pain intensity measures, the McGill Short Form Questionnaire, and the Disabilities of the Arm, Shoulder, and Hand Questionnaire. Change scores were calculated at 4 weeks and an exploratory factor analysis (EFA) with varimax rotation was used to analyze dimensionality. The relationship between the raw scores of the seven measures was investigated using a correlation matrix. RESULTS: The EFA yielded only one factor and the raw score correlations demonstrated very strong, significant associations. The finding of a single factor suggests that in this sample of patients, only one dimension of change, most likely a change in pain, is represented by the seven individual outcomes measures. DISCUSSION: In this isolated example, one outcomes measure would have been sufficient in determining outcome and could have reduced the administrative burden to the caregivers and the patients. PMID- 22547917 TI - Immediate effects of anterior to posterior talocrural joint mobilizations following acute lateral ankle sprain. AB - Restrictions in ankle dorsiflexion range of motion (ROM) have been associated with decreased posterior talar glide in individuals with an acute lateral ankle sprain. Talocrural joint mobilizations may be used to restore joint arthrokinematics. Our purpose was to examine the effects of a single bout of anterior to posterior (AP) talocrural joint mobilization on self-reported function, dorsiflexion ROM, and posterior talar translation in individuals with an acute lateral ankle sprain. This single-blinded, randomized controlled trial utilized 17 volunteers (nine treatment and eight control) with an acute lateral ankle sprain (grade I/II) who were immobilized for a period of 1-7 days. The treatment group received a single 30-second bout of grade III AP talocrural joint mobilization the day their immobilization device was removed, while the control group did not receive any intervention. Active dorsiflexion ROM and posterior talar translation were assessed before, immediately after, and 24 hours after receipt of the treatment or control interventions. Self-reported function and pain were assessed before and 24 hours after the receipt of the treatment or control interventions using the foot and ankle disability index. Collectively all groups demonstrated improved dorsiflexion ROM and self-reported function. There was a significant decrease in pain perception at 24-hour follow-up for the treatment group. A single bout of AP talocrural joint mobilizations may not have an immediate effect on ankle dorsiflexion ROM, posterior talar translation, or self-reported function; however, they may have an immediate effect on pain perception in individuals with an acute lateral ankle sprain. PMID- 22547918 TI - Ultrasound analysis of the vertebral artery during non-thrust cervical translatoric spinal manipulation. AB - OBJECTIVE: Cervical translatoric spinal manipulation (TSM) techniques have been suggested as a safer alternative to cervical thrust rotatory techniques. The objective of this study was to determine the effect of three C5-C6 non-thrust TSM techniques on vertebral artery (VA) lumen diameter (LD) and two blood flow velocity parameters. The two-tailed research hypothesis was that the TSM techniques would result in a significant change (increase or decrease) in blood flow velocity and arterial LD at the C5-C6 intertransverse portion of the VA. METHODS: In a sample of 30 subjects representative of a clinical population, color-coded duplex Doppler diagnostic ultrasound imaging was used to collect data on LD, peak systolic velocity (PSV), and end diastolic velocity with the cervical spine positioned in neutral and in three different manipulation positions. Pair wise mean differences between measurements at baseline (neutral position) and in all three manipulation positions were analyzed using two-tailed paired t-tests with alpha set at 0.05. RESULTS: Of the 18 paired comparisons, there were four statistically significant differences between measurements in the neutral position and a manipulation position, three concerning LD and one PSV. DISCUSSION: The three significant differences in LD ranged from 4.6 to 3.2% and were not associated with changes in blood flow velocity. The one significant change in PSV was only 6.6 cm/s. A value that still greatly exceeded the end diastolic velocity. No subject experienced symptoms associated with VA compromise. This study has provided evidence for the safety of the three lower cervical non-thrust TSM techniques on the current population studied. Further study is required on thrust versus non-thrust TSM techniques and on levels other than C5-C6. PMID- 22547919 TI - The assessment of function: How is it measured? A clinical perspective. AB - Testing for outcome or performance can take many forms; including multiple iterations of self-reported measures of function (an assessment of the individual's perceived dysfunction) and/or clinical special tests (which are primarily assessments of impairments). Typically absent within these testing mechanisms is whether or not one can perform a specific task associated with function. The paper will operationally define function, discuss the construct of function within the disablement model, will overview the multi-dimensional nature of 'function' as a concept, will examine the current evidence for functional testing methods, and will propose a functional testing continuum. Limitations of functional performance testing will be discussed including recommendations for future research. PMID- 22547921 TI - Management of chronic ankle pain using joint mobilization and ASTYM(r) treatment: a case report. AB - Treatment of ankle sprains predominately focuses on the acute management of this condition; less emphasis is placed on the treatment of ankle sprains in the chronic phase of recovery. Manual therapy, in the form of joint mobilization and manipulation, has been shown to be effective in the management of this condition, but the combination of joint mobilization and manipulation in tandem with ASTYM(r) treatment has not been explored. The purpose of this case report is to chronicle the management of a patient with chronic ankle pain who was treated with manual therapy including manipulation and ASTYM treatment. As a result of a fall down stairs 6 months previously, the patient sustained a severe ankle sprain. The soft tissue damage was accompanied by bony disruptions which warranted the patient spending 3 weeks in a walking boot. At the initial evaluation, the patient reported difficulty with descending stairs reciprocally and not being able to run more than 4 minutes on the treadmill before the pain escalated to the level that she had to stop running. After five sessions of therapy consisting of joint mobilization, manipulation and ASTYM, the patient was able to descend stairs and run 40 minutes without pain. PMID- 22547922 TI - A mechanical diagnosis and treatment (MDT) approach for a patient with discogenic low back pain and a relevant lateral component: a case report. AB - Patients with a lateral lumbar shift are often managed with a frontal plane, manual correction first described by McKenzie. However, there is a subset of patients that require a frontal plane correction who do not demonstrate a lateral shift. Both of these patient groups have what is termed a relevant lateral component (RLC). The subset of patients who have an RLC, without a shift, has received very little attention in the literature to date. This case report describes a patient with no shift who had a remarkable disc extrusion identified by magnetic resonance imaging (MRI). The patient responded nicely to a combination of frontal and transverse plane loading strategies in six treatments using the mechanical diagnosis and treatment (MDT) evaluation and treatment system. The case report is unique in the literature in that it describes a patient with no apparent frontal plane, lumbar deformity that had documented evidence of a large disc extrusion and who responded to a variation of McKenzie's flexion-rotation mobilization. The centralization phenomenon was demonstrated immediately when a non-weight bearing, multiplanar, loading strategy was administered. PMID- 22547920 TI - Short-term response of hip mobilizations and exercise in individuals with chronic low back pain: a case series. AB - STUDY DESIGN: A case series of consecutive patients with chronic low back pain. BACKGROUND AND PURPOSE: In patients with chronic low back pain (CLBP), the importance of impairments at the hip joints is unclear. However, it has been postulated that impairments at the hip joints may contribute to CLBP. The purpose of this case series was to investigate the short-term outcomes in patients with CLBP managed with impairment-based manual therapy and exercise directed at the hip joints. METHODS: EIGHT CONSECUTIVE PATIENTS (MEAN AGE: 43.9 years) with a primary report of CLBP (>6 months) without radiculopathy were treated with a standardized approach of manual physical therapy and exercise directed at bilateral hip impairments for a total of three sessions over approximately 1 week. At initial examination, all patients completed a numeric rating pain scale (NPRS), Oswestry disability index (ODI), fear-avoidance beliefs questionnaire (FABQ), and patient-specific functional scale (PSFS). At the second and third treatment sessions, each patient completed all outcome measures as well as the Global Rating of Change (GROC). RESULTS: Five of the eight (62.5%) patients reported 'moderately better' or higher (>+4) on the GROC at the third session, indicating a moderate improvement in self-reported symptoms. These five individuals also experienced a 24.4% reduction in ODI scores. DISCUSSION: This case series suggests that an impairment-based approach directed at the hip joints may lead to improvements in pain, function, and disability in patients with CLBP. A neurophysiologic mechanism may be a plausible explanation regarding the clinical outcomes of this study. A larger, well-controlled trial is needed to determine the potential effectiveness of this approach with patients with CLBP. PMID- 22547923 TI - Therapist as operator or interactor? Moving beyond the technique. PMID- 22547924 TI - Association of the pre-internship objective structured clinical examination in final year medical students with comprehensive written examinations. AB - AIM: The purpose of this study is to evaluate the association of the pre internship Objective Structured Clinical Examination (OSCE) in final year medical students with comprehensive written examinations. SUBJECTS AND MATERIAL: All medical students of October 2004 admission who took part in the October 2010 National Comprehensive Pre-internship Examination (NCPE) and pre-internship OSCE were included in the study (n = 130). OSCE and NCPE scores and medical grade point average (GPA) were collected. RESULTS: GPA was highly correlated with NCPE (r = 0.76 and P<0.001) and moderately with OSCE (r = 0.68 and P < 0.001). Similarly a moderate correlation was observed between NCPE and OSCE scores(r = 0.6 and P < 0.001).Linear stepwise regression shows r(2) of a model applying GPA as predictor of OSCE score is 0.46 (beta = 0.68 and P < 0.001), while addition of gender to the model increases r(2) to 0.59 (beta = 0.61 and 0.36, for GPA and male gender, respectively and P < 0.001). Logistic forward regression models shows male gender and GPA are the only dependent predictors of high score in OSCE. OR of GPA and male gender for high OSCE score are 4.89 (95% CI = 2.37 10.06) and 6.95 (95% CI = 2.00-24.21), respectively (P < 0.001). DISCUSSION: Our findings indicate OSCE and examination which mainly evaluate knowledge, judged by GPA and NCPE are moderately to highly correlated. Our results illustrate the interwoven nature of knowledge and clinical skills. In other words, certain level of knowledge is crucial for appropriate clinical performance. Our findings suggest neither OSCE nor written forms of assessments can replace each other. They are complimentary and should also be combined by other evaluations to cover all attributes of clinical competence efficiently. PMID- 22547926 TI - Using medical history embedded in biometrics medical card for user identity authentication: data representation by AVT hierarchical data tree. AB - User authentication has been widely used by biometric applications that work on unique bodily features, such as fingerprints, retina scan, and palm vessels recognition. This paper proposes a novel concept of biometric authentication by exploiting a user's medical history. Although medical history may not be absolutely unique to every individual person, the chances of having two persons who share an exactly identical trail of medical and prognosis history are slim. Therefore, in addition to common biometric identification methods, medical history can be used as ingredients for generating Q&A challenges upon user authentication. This concept is motivated by a recent advancement on smart-card technology that future identity cards are able to carry patents' medical history like a mobile database. Privacy, however, may be a concern when medical history is used for authentication. Therefore in this paper, a new method is proposed for abstracting the medical data by using attribute value taxonomies, into a hierarchical data tree (h-Data). Questions can be abstracted to various level of resolution (hence sensitivity of private data) for use in the authentication process. The method is described and a case study is given in this paper. PMID- 22547925 TI - PEDF and VEGF-A output from human retinal pigment epithelial cells grown on novel microcarriers. AB - Human retinal pigment epithelial (hRPE) cells have been tested as a cell-based therapy for Parkinson's disease but will require additional study before further clinical trials can be planned. We now show that the long-term survival and neurotrophic potential of hRPE cells can be enhanced by the use of FDA-approved plastic-based microcarriers compared to a gelatin-based microcarrier as used in failed clinical trials. The hRPE cells grown on these plastic-based microcarriers display several important characteristics of hRPE found in vivo: (1) characteristic morphological features, (2) accumulation of melanin pigment, and (3) high levels of production of the neurotrophic factors pigment epithelium derived factor (PEDF) and vascular endothelial growth factor-A (VEGF-A). Growth of hRPE cells on plastic-based microcarriers led to sustained levels (>1 ng/ml) of PEDF and VEGF-A in conditioned media for two months. We also show that the expression of VEGF-A and PEDF is reciprocally regulated by activation of the GPR143 pathway. GPR143 is activated by L-DOPA (1 MUM) which decreased VEGF-A secretion as opposed to the previously reported increase in PEDF secretion. The hRPE microcarriers are therefore novel candidate delivery systems for achieving long-term delivery of the neuroprotective factors PEDF and VEGF-A, which could have a value in neurodegenerative conditions such as Parkinson's disease. PMID- 22547928 TI - Immunohistochemical expression and prognostic value of CD97 and its ligand CD55 in primary gallbladder carcinoma. AB - BACKGROUND: CD97 as a member of the EGF-TM7 family with adhesive properties plays an important role in tumor aggressiveness by binding its cellular ligand CD55, which is a complement regulatory protein expressed by cells to protect them from bystander complement attack. Previous studies have shown that CD97 and CD55 both play important roles in tumor dedifferentiation, migration, invasiveness, and metastasis. The aim of this study was to investigate CD97 and CD55 expression in primary gallbladder carcinoma (GBC) and their prognostic significance. METHODS: Immunohistochemistry was used to investigate the expression of CD97 and CD55 proteins in 138 patients with GBC. RESULTS: CD97 and CD55 were absent or only weakly expressed in the normal epithelium of the gallbladder but in 69.6% (96/138) and 65.2% (90/138) of GBC, respectively, remarkably at the invasive front of the tumors. In addition, CD97 and CD55 expressions were both significantly associated with high histologic grade (both P = 0.009), advanced pathologic T stage (P = 0.01 and 0.009, resp.) and clinical stage (both P = 0.009), and positive venous/lymphatic invasion (both P = 0.009). Multivariate analyses showed that CD97 (hazard ratio, 3.236; P = 0.02) and CD55 (hazard ratio, 3.209; P = 0.02) expressions and clinical stage (hazard ratio, 3.918; P = 0.01) were independent risk factor for overall survival. CONCLUSION: Our results provide convincing evidence for the first time that the expressions of CD97 and CD55 are both upregulated in human GBC. The expression levels of CD97 and CD55 in GBC were associated with the severity of the tumor. Furthermore, CD97 and CD55 expressions were independent poor prognostic factors for overall survival in patients with GBC. PMID- 22547927 TI - Patient-derived xenografts of non small cell lung cancer: resurgence of an old model for investigation of modern concepts of tailored therapy and cancer stem cells. AB - Current chemotherapy regimens have unsatisfactory results in most advanced solid tumors. It is therefore imperative to devise novel therapeutic strategies and to optimize selection of patients, identifying early those who could benefit from available treatments. Mouse models are the most valuable tool for preclinical evaluation of novel therapeutic strategies in cancer and, among them, patient derived xenografts models (PDX) have made a recent comeback in popularity. These models, obtained by direct implants of tissue fragments in immunocompromised mice, have great potential in drug development studies because they faithfully reproduce the patient's original tumor for both immunohistochemical markers and genetic alterations as well as in terms of response to common therapeutics They also maintain the original tumor heterogeneity, allowing studies of specific cellular subpopulations, including their modulation after drug treatment. Moreover PDXs maintain at least some aspects of the human microenvironment for weeks with the complete substitution with murine stroma occurring only after 2-3 passages in mouse and represent therefore a promising model for studies of tumor microenvironment interaction. This review summarizes our present knowledge on mouse preclinical cancer models, with a particular attention on patient-derived xenografts of non small cell lung cancer and their relevance for preclinical and biological studies. PMID- 22547929 TI - Molecular characterization of a fully human chimeric T-cell antigen receptor for tumor-associated antigen EpCAM. AB - The transduction of T cells to express chimeric T-cell antigen receptor (CAR) is an attractive strategy for adaptive immunotherapy for cancer, because the CAR can redirect the recognition specificity of T cells to tumor-associated antigens (TAAs) on the surface of target cells, thereby avoiding the limitations of HLA restriction. However, there are considerable problems with the clinical application of CAR, mostly due to its xenogeneic components, which could be immunogenic in humans. Moreover, while extensive studies on the CARs have been performed, the detailed molecular mechanisms underlying the activation of CAR grafted T cells remain unclear. In order to eliminate potential immunogenicity and investigate the molecular basis of the CAR-mediated T-cell activation, we constructed a novel CAR (CAR57-28zeta) specific for one of the most important TAAs, epithelial cell adhesion molecule (EpCAM), using only human-derived genes. We revealed that in Jurkat T cells, lentivirally expressed CAR57-28zeta can transmit the T-cell-activating signals sufficient to induce IL-2 production upon EpCAM stimulation. An immunofluorescent analysis clearly showed that the CAR57 28zeta induces the formation of signaling clusters containing endogenous CD3zeta at the CAR/EpCAM interaction interface. These results suggest that this CAR gene may be safely and effectively applied for adaptive T-cell immunotherapy. PMID- 22547930 TI - Combined QM/MM study of thyroid and steroid hormone analogue interactions with alphavbeta3 integrin. AB - Recent biochemical studies have identified a cell surface receptor for thyroid and steroid hormones that bind near the arginine-glycine-aspartate (RGD) recognition site on the heterodimeric alphavbeta3 integrin. To further characterize the intermolecular interactions for a series of hormone analogues, combined quantum mechanical and molecular mechanical (QM/MM) methods were used to calculate their interaction energies. All calculations were performed in the presence of either calcium (Ca(2+)) or magnesium (Mg(2+)) ions. These data reveal that 3,5'-triiodothyronine (T(3)) and 3,5,3',5'-tetraiodothyroacetic acid (T(4)ac) bound in two different modes, occupying two alternate sites, one of which is along the Arg side chain of the RGD cyclic peptide site. These orientations differ from those of the other ligands whose alternate binding modes placed the ligands deeper within the RGD binding pocket. These observations are consistent with biological data that indicate the presence of two discrete binding sites that control distinct downstream signal transduction pathways for T(3). PMID- 22547931 TI - Telavancin for the treatment of nosocomial pneumonia caused by methicillin resistant Staphylococcus aureus (MRSA). AB - Telavancin is a bactericidal lipoglycopeptide antibiotic that is structurally related to vancomycin. It demonstrates in vitro activity against a variety of Gram-positive pathogens including, but not limited to, methicillin-resistant Staphylococcus aureus (MRSA). Telavancin is currently FDA-approved for the treatment of complicated skin and skin-structure infections. Recently, two randomized clinical trials demonstrated the efficacy and safety of telavancin compared to vancomycin for the treatment of nosocomial pneumonia. Overall, telavancin has a favorable safety profile. However, mild gastrointestinal disturbances and reversible increases in serum creatinine were observed in clinical studies. Additional clinical studies are needed to evaluate telavancin's efficacy and safety in comparison to other antistaphylococcal agents for the treatment of infections such as bacteremia and endocarditis. PMID- 22547932 TI - Efficacy and safety of venous thromboembolism prophylaxis with apixaban in major orthopedic surgery. AB - Over the last 15 years, low-molecular-weight heparins (LMWHs) have been accepted as the "gold standard" for pharmaceutical thromboprophylaxis in patients at high risk of venous thromboembolism (VTE) in most countries around the world. Patients undergoing major orthopedic surgery (MOS) represent a population with high risk of VTE, which may remain asymptomatic or become symptomatic as deep vein thrombosis or pulmonary embolism. Numerous trials have investigated LMWH thromboprophylaxis in this population and demonstrated high efficacy and safety of these substances. However, LMWHs have a number of disadvantages, which limit the acceptance of patients and physicians, especially in prolonged prophylaxis up to 35 days after MOS. Consequently, new oral anticoagulants (NOACs) were developed that are of synthetic origin and act as direct and very specific inhibitors of different factors in the coagulation cascade. The most developed NOACs are dabigatran, rivaroxaban, and apixaban, all of which are approved for thromboprophylaxis in MOS in a number of countries around the world. This review is focused on the pharmacological characteristics of apixaban in comparison with other NOACs, on the impact of NOAC on VTE prophylaxis in daily care, and on the management of specific situations such as bleeding complications during NOAC therapy. PMID- 22547935 TI - Measurement complexity of adherence to medication. PMID- 22547933 TI - Critical appraisal of ceftaroline in the management of community-acquired bacterial pneumonia and skin infections. AB - Ceftaroline is a novel broad-spectrum cephalosporin beta-lactam antibiotic with activity against methicillin-resistant Staphylococcus aureus (MRSA) as well as multidrug-resistant Streptococcus pneumoniae among other routine Gram positive and Gram negative organisms. It has been approved by the US Food and Drug Administration for treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections (ABSSSIs). Ceftaroline is approved for treatment of ABSSSI due to MRSA, however currently there are no data for pneumonia due to MRSA in humans. Herein we review the major clinical trials as well as ceftaroline microbiology, pharmacokinetics, and safety, followed by a look at further directions for investigation of this new agent. PMID- 22547934 TI - Human normal immunoglobulin in the treatment of primary immunodeficiency diseases. AB - The primary antibody deficiency syndromes are a rare group of disorders that can present at any age, and for which delay in diagnosis remains common. Replacement therapy with immunoglobulin in primary antibody deficiencies increases life expectancy and reduces the frequency and severity of infection. Higher doses of immunoglobulin are associated with reduced frequency of infection. Late diagnosis and delayed institution of immunoglobulin replacement therapy results in increased morbidity with a wide variety of organ-specific complications and increased mortality. Risks of immunoglobulin therapy are minimized by modern manufacturing processes, although patients can experience both immediate and delayed adverse reactions, and concerns remain over the transmission of prions in plasma. Immunoglobulin therapy leads to improvements in overall quality of life, and many of the improvements relate to reduced infection rates and fear of future infections, strongly suggesting that the immunoglobulin therapy itself is the major factor in this improvement. There are limited data on the economic benefits of immunoglobulin therapy, with the fluctuating costs of immunoglobulins making comparison between different studies difficult. However, estimates suggest that early intervention with immunoglobulin replacement compares favorably with prolonged therapy for other more common chronic diseases. PMID- 22547936 TI - Optimal management of giant cell arteritis and polymyalgia rheumatica. AB - Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are clinical diagnoses without "gold standard" serological or histological tests, excluding temporal artery biopsy for GCA. Further, other conditions may mimic GCA and PMR. Treatment with 10-20 mg of prednisolone daily is suggested for PMR or 40-60 mg daily for GCA when temporal arteritis is suspected. This ocular involvement of GCA should be treated as a medical emergency to prevent possible blindness and steroids should be commenced immediately. There are no absolute guidelines as to the dose or duration of administration; the therapeutics of treating this condition and the rate of reduction of prednisolone should be adjusted depending on the individual's response and with consideration of the multiple risks of high dose and long-term glucocorticoids. Optimal management may need to consider the role of low-dose aspirin in reducing complications. Clinicians should also be aware of studies that indicate an increased incidence of large-artery complications with GCA. This clinical area requires further research through future development of radiological imaging to aid the diagnosis and produce a clearer consensus relating to diagnosis and treatment. PMID- 22547937 TI - Interdisciplinary three-step strategy to treat aortic stenosis and coronary artery disease in a patient with end-stage chronic obstructive pulmonary disease. AB - BACKGROUND: Valvular aortic stenosis is a common disease in the elderly, often in multimorbid patients. It is often associated with coronary artery disease and peripheral artery disease. In this situation, the risk of conventional open-heart surgery is too high, and other treatment strategies have to be evaluated. CASE REPORT: A 79-year-old female patient with severe aortic stenosis, coronary artery disease and end-stage chronic obstructive pulmonary disease suffering from dyspnea at rest and permanently dependent on oxygen was treated in three steps. Firstly, her pulmonary infection was treated with antibiotics for 7 days. Then, the left anterior descending artery was stented (bare-metal stent). In the same session, valvuloplasty of the aortic valve was performed. She was sent to rehabilitation to improve her pulmonary condition and took clopidogrel for 4 weeks. Finally, she underwent transapical aortic valve replacement. She was released to rehabilitation on postoperative day 12. CONCLUSION: A combination of modern interventional and minimally invasive surgical techniques to treat aortic stenosis and coronary heart disease can be a viable option for multimorbid patients with extremely high risk in conventional open-heart surgery. PMID- 22547939 TI - Five-year follow-up of a woman with pregnancy and lactation-associated osteoporosis and vertebral fractures. AB - We report the 5-year follow-up of a young woman who developed vertebral fractures after pregnancy and lactation and was treated with active vitamin D hormone. A 32 year-old Japanese woman consulted us because of acute lower back pain caused by L2 and L5 vertebral fractures after pregnancy and lactation. Following cessation of breast-feeding, analgesia, bed rest, and wearing of a hard brace, her lower back pain disappeared within 2 months. After 5 years of treatment with alfacalcidol 1 MUg daily, the lumbar spine (L1, L3, L4) bone mineral density increased by 21.4% following vigorous reductions in bone turnover markers. No osteoporotic fractures occurred, and the vertebral fractures healed. The patient experienced no side effects, including hypercalcemia. Thus, the present case report shows long-term changes in bone turnover markers and lumbar spine bone mineral density, as well as long-term safety of alfacalcidol treatment in a young woman with pregnancy and lactation-associated osteoporosis and vertebral fractures. PMID- 22547940 TI - Stayin' alive: The 2010 Heart and Stroke Foundation of Canada/American Heart Association resuscitation guidelines for newborns and older children. PMID- 22547938 TI - Maximizing neuroprotection: where do we stand? AB - Brain and spinal cord traumas include blunt and penetrating trauma, disease, and required surgery. Such traumas trigger events such as inflammation, infiltration of inflammatory and other cells, oxidative stress, acidification, excitotoxicity, ischemia, and the loss of calcium homeostasis, all of which cause neurotoxicity and neuron death. To prevent trauma-induced neurological deficits and death, each of the many neurotoxic events that occur in parallel or sequentially must be minimized or prevented. Although neuroprotective techniques have been developed that block single neurotoxic events, most provide only limited neuroprotection and are only applied singly. However, because many neurotoxicity triggers arise from common events, an approach for invoking more effective neuroprotection is to apply multiple neuroprotective methods simultaneously before the many neurotoxic triggers and cascades are initiated and become irreversible. This paper first discusses some triggers of neurotoxicity and neuroprotective mechanisms that block them, including hypothermia, alkalinization, and the administration of adenosine. It then examines how the simultaneous application of these techniques provides significantly greater neuroprotection than is provided by any technique alone. The paper also stresses the importance of determining whether the neuroprotection provided by these techniques can be further enhanced by combining them with additional techniques, such as the systemic administration of glucocorticoids. Finally, the paper stresses the absolute critical importance of applying these techniques within the "golden hour" following trauma, before the many neurotoxic events and cascades are manifest and before the neurotoxic cascades become irreversible. PMID- 22547941 TI - Early-onset neonatal sepsis: It is not only group B streptococcus. PMID- 22547942 TI - Letter to the editor. PMID- 22547943 TI - Vision and hearing screening in school settings: Reducing barriers to children's achievement. PMID- 22547944 TI - Case 1: Persistent fever in a toddler. PMID- 22547945 TI - Case 2: Annular erythematous eruption in an infant. PMID- 22547946 TI - Staphylococcus aureus bloodstream infections in children: A population-based assessment. AB - BACKGROUND: Although Staphylococcus aureus is a major cause of bloodstream infections, population-based data on these infections in children are limited. OBJECTIVE: To describe the epidemiology of S aureus bacteremia in children. METHODS: Population-based surveillance for all incident S aureus bacteremias was conducted among children (18 years of age or younger) living in the Calgary Health Region (Alberta) from 2000 to 2006. RESULTS: During the seven-year study, 120 S aureus bloodstream infections occurred among 119 patients; 27% were nosocomial, 18% health care associated and 56% community acquired. The annual incidence was 6.5/100,000 population and 0.094/1000 live births. A total of 52% had a significant underlying condition, and this was higher for nosocomial cases. Bone and joint (40%), bacteremia without a focus (33%), and skin and soft tissue infections (15%) were the most common clinical syndromes. Infections due to methicillin-resistant S aureus were uncommon (occurring in one infection) and three patients (2.5%) died. CONCLUSIONS: S aureus bacteremia is an important cause of morbidity in the paediatric age group. Underlying medical conditions and implanted devices are important risk factors. Methicillin-resistant S aureus and mortality rates are low. PMID- 22547947 TI - A guide to the management of common gastrostomy and gastrojejunostomy tube problems. AB - Gastrostomy (G) and gastrojejunostomy (GJ) tubes are commonly used to enhance nutrition and hydration, and facilitate the administration of medications to children with medically complex conditions. They are considered to be safe and effective interventions for the medical management of these patients; however, they are not without risks. There are common complications associated with G and GJ tubes. Health care providers play an active role in preventing, managing and supporting the patient and parents/caregivers in dealing with these complications. The present article reviews G and GJ tube devices, basic care principles, and how to prevent and manage common complications. Recommendations for how to support and share information with parents/caregivers is provided. PMID- 22547948 TI - Neonatal resuscitation guidelines update: A case-based review. PMID- 22547949 TI - A case-based update: 2010 paediatric basic and advanced life-support guidelines. PMID- 22547950 TI - Universal newborn hearing screening. AB - The present statement reviews the evidence for universal newborn hearing screening (UNHS). A systematic review of the literature was conducted using Medline and using search dates from 1996 to the third week of August 2009. The following search terms were used: neonatal screening AND hearing loss AND hearing disorders. The key phrase "universal newborn hearing screening" was also searched. The Cochrane Central Register of Controlled Trials and systematic reviews was searched. Three systematic reviews, one controlled non-randomized trial and multiple cohort studies were found. It was determined that there was satisfactory evidence to support UNHS. The results of the available literature are consistent and indicate clear evidence that without UNHS, delayed diagnosis leads to significant harm for children and their families; with UNHS, diagnosis and intervention occur earlier; earlier intervention translates to improved language outcomes; and in well-run programs, there is negligible harm from screening. PMID- 22547951 TI - Pregnancy in young women with congenital heart disease: Lesion-specific considerations. AB - Young women with heart disease are increasingly being seen in obstetrical referral centres owing, in large part, to the dramatic improvements in survival of young adults with congenital heart disease in recent years. Although pregnancies in most women with heart disease result in favourable outcomes, there are important exceptions that must be recognized. These exceptions pose a significant mortality risk to the mother and/or the fetus. The present article provides a general framework for the classification of congenital heart lesions in pregnant women as well as a detailed lesion-specific review. PMID- 22547952 TI - Attitudes and practice of Children's Hospital of Eastern Ontario (Ottawa, Ontario) paediatricians and residents toward literacy promotion in Canada. AB - BACKGROUND: Literacy is a critical health issue in Canada. Paediatricians play an important role in improving literacy skills; however, formal training in literacy education and promotion is not currently part of most Canadian paediatric residency programs. OBJECTIVE: To examine the attitudes and practice of paediatricians and residents at the Children's Hospital of Eastern Ontario (CHEO [Ottawa, Ontario]) toward literacy promotion. METHODS: A descriptive, cross sectional survey of CHEO-affiliated paediatricians, residents and fellows was performed. Survey items addressed demographics, attitudes toward literacy, current practice and previous education/training in literacy education through self-reporting. RESULTS: One hundred ninety-seven surveys were distributed, with a response rate of 82%. Ninety-one per cent of respondents reported never having formal training in literacy development and promotion. Seventy-four per cent of respondents believed that low literacy is a significant health issue in Canada; however, only 16% of respondents reported regularly discussing literacy with patients and their families. Thirty-nine per cent of general paediatricians reported discussing literacy with patients and families regularly, compared with 10% of paediatric subspecialists (P<0.01). Seventy-one per cent of respondents believed that literacy education should be a standard part of residency education. CONCLUSIONS: While most respondents identified literacy as an important paediatric issue, most paediatricians did not regularly discuss the importance of literacy with their patients. General paediatricians are most likely to discuss literacy. There is a lack of formal education among paediatricians in literacy development and promotion, and the majority of respondents believe that this should be a standard part of paediatric residency training. PMID- 22547953 TI - Anticipation in lynch syndrome: where we are where we go. AB - Lynch syndrome (LS) is the most common form of inherited predisposition to develop cancer mainly in the colon and endometrium but also in other organ sites. Germline mutations in DNA mismatch repair (MMR) gene cause the transmission of the syndrome in an autosomal dominant manner. The management of LS patients is complicated by the large variation in age at cancer diagnosis which requires these patients to be enrolled in surveillance protocol starting as early as in their second decade of life. Several environmental and genetic factors have been proposed to explain this phenotypic heterogeneity, but the molecular mechanisms remain unknown. Although the presence of genetic anticipation in Lynch syndrome has been suspected since 15 years, only recently the phenomenon has been increasingly reported to be present in different cancer genetic syndromes including LS. While the biological basis of earlier cancer onset in successive generations remains poorly known, recent findings point to telomere dynamics as a mechanism significantly contributing to genetic anticipation in Lynch syndrome and in other familial cancers. In this review, we summarize the clinical and molecular features of Lynch syndrome, with a particular focus on the latest studies that have investigated the molecular mechanisms of genetic anticipation. PMID- 22547954 TI - Prospective of Genomics in Revealing Transmission, Reassortment and Evolution of Wildlife-Borne Avian Influenza A (H5N1) Viruses. AB - The outbreak of highly pathogenic avian influenza (HPAI) H5N1 disease has led to significant loss of poultry and wild life and case fatality rates in humans of 60%. Wild birds are natural hosts for all avian influenza virus subtypes and over120 bird species have been reported with evidence of H5N1 infection. Influenza A viruses possess a segmented RNA genome and are characterized by frequently occurring genetic reassortment events, which play a very important role in virus evolution and the spread of novel gene constellations in immunologically naive human and animal populations. Phylogenetic analysis of whole genome or sub-genomic sequences is a standard means for delineating genetic variation, novel reassortment events, and surveillance to trace the global transmission pathways. In this paper, special emphasis is given to the transmission and circulation of H5N1 among wild life populations, and to the reassortment events that are associated with inter-host transmission of the H5N1 viruses when they infect different hosts, such as birds, pigs and humans. In addition, we review the inter-subtype reassortment of the viral segments encoding inner proteins between the H5N1 viruses and viruses of other subtypes, such as H9N2 and H6N1. Finally, we highlight the usefulness of genomic sequences in molecular epidemiological analysis of HPAI H5N1 and the technical limitations in existing analytical methods that hinder them from playing a greater role in virological research. PMID- 22547955 TI - GJB2 Gene Mutations in Syndromic Skin Diseases with Sensorineural Hearing Loss. AB - The GJB2 gene is located on chromosome 13q12 and it encodes the connexin 26, a transmembrane protein involved in cell-cell attachment of almost all tissues. GJB2 mutations cause autosomal recessive (DFNB1) and sometimes dominant (DFNA3) non-syndromic sensorineural hearing loss. Moreover, it has been demonstrated that connexins are involved in regulation of growth and differentiation of epidermis and, in fact, GJB2 mutations have also been identified in syndromic disorders with hearing loss associated with various skin disease phenotypes. GJB2 mutations associated with skin disease are, in general, transmitted with a dominant inheritance pattern. Nonsyndromic deafness is caused prevalently by a loss-of function, while literature evidences suggest for syndromic deafness a mechanism based on gain-of-function. The spectrum of skin manifestations associated with some mutations seems to have a very high phenotypic variability. Why some mutations can lead to widely varying cutaneous manifestations is poorly understood and in particular, the reason why the skin disease-deafness phenotypes differ from each other thus remains unclear. This review provides an overview of recent findings concerning pathogenesis of syndromic deafness imputable to GJB2 mutations with an emphasis on relevant clinical genotype-phenotype correlations. After describing connexin 26 fundamental characteristics, the most relevant and recent information about its known mutations involved in the syndromic forms causing hearing loss and skin problems are summarized. The possible effects of the mutations on channel expression and function are discussed. PMID- 22547957 TI - Can transcriptomics cut the gordian knot of amyotrophic lateral sclerosis? AB - Amyotrophic lateral sclerosis (ALS) is an adult-onset degenerative disease characterized by the loss of upper and lower motor neurons, progressive muscle atrophy, paralysis and death, which occurs within 2-5 years of diagnosis. Most cases appear sporadically but some are familial, usually inherited in an autosomal dominant pattern. It is postulated that the disease results from the combination of multiple pathogenic mechanisms, which affect not only motor neurons but also non-neuronal neighboring cells. Together with the understanding of this intriguing cell biology, important challenges in the field concern the design of effective curative treatments and the discovery of molecular biomarkers for early diagnosis and accurate monitoring of disease progression. During the last decade, transcriptomics has represented a promising approach to address these questions. In this review, we revisit the major findings of the numerous studies that analyzed global gene expression in tissues and cells from biopsy or post-mortem specimens of ALS patients and related animal models. These studies corroborated the implication of previously described disease pathways, and investigated the role of new genes in the pathological process. In addition, they also identified gene expression changes that could be used as candidate biomarkers for the diagnosis and follow-up of ALS. The limitations of these transcriptomics approaches will be also discussed. PMID- 22547958 TI - The shock of the new: progress in schizophrenia genomics. AB - A growing list of common and rare genetic risk variants are being implicated in schizophrenia susceptibility. As with other complex genetic disorders most of the variance in genetic risk is still to be attributed. What can be learned from progress to date? The available data challenges how we conceptualize schizophrenia and suggests strong aetiological links with other psychiatric and developmental disorders. With the identification of rare copy number risk variants implicating specific genes (e.g. VIPR2 and NRXN1) it is increasingly possible to investigate molecular aetiology in patient subgroups to establish whether schizophrenia represents one or many different disease processes. This review summarizes recent research progress and suggests how the tools of modern genomics and neuroscience can be applied to best understand this devastating disorder. PMID- 22547959 TI - Skull base surgery for the management of deeply invasive scalp cancer. AB - Skin cancer involving the scalp is a common malignancy in the "sun belt areas of the United States." Most early lesions are well managed by primary care physicians and dermatologists. Occasionally we encounter basal cell, squamous cell, and rarely Merkel cell carcinomas that have failed local therapy and present with large tumors invading full thickness scalp, calvarium, and even underlying dura. We describe our experience with 52 such tumors and illustrate their resections and reconstruction. For full thickness lesions we generally do a wide field resection of skin and underlying calvarium followed by dural resection. Reconstruction is usually with dural replacement, calvarial reconstruction with titanium mesh, and cutaneous reconstruction with a musculocutaneous free flap or muscular free flap with an overlying skin graft. Complications, survival rates, and recurrence rates will be presented. PMID- 22547960 TI - Multicompartmental trigeminal schwannomas: management strategies and outcome. AB - Trigeminal schwannomas (TS), though the second most common intracranial schwannomas, represent only 0.8 to 8% of all Schwannomas. Advancement in imaging and microsurgical techniques has led to a remarkable improvement in the outcome of these benign tumors. Multicompartmental TS, though extensive, have an excellent outcome after surgery. In this article, we present our experience in the management of multicompartmental TS (types middle/posterior [MP], middle/extracranial [ME], and middle/posterior and extracranial [MPE]) and outcome in this rather uncommon group of tumors. This retrospective study included all the cases of multicompartmental TS operated at our institute from 1999 to 2009. The medical data were analyzed retrospectively. The demographic profile, clinical features, radiological findings, management strategies, postoperative complications, length of hospitalization, and outcome were noted. Follow-up data were collected from outpatient department records. The range and average duration of follow-up were noted. There were a total of 43 patients with TS operated over this period. Among them, 4 were type B, 5 type C, 11 type D, 18 type E, and 5 type F. The study included 26 patients (4 type B, 18 type E, and 4 type B). A variety of approaches were used to approach the tumor. Of 26, 23 patients had a gross total or near-total excision while 2 patients were lost to follow-up. Among the three patients who had a near-total excision and follow-up magnetic resonance imaging showed a small residual tumor, two are on close follow up with no increase in the size of the tumor over a follow-up period of 3 years, the other patient is a 5-year-old boy who is too young for radiosurgery and is on follow-up. There was no mortality while four patients have had fresh permanent postoperative deficits. Multicompartmental TS are a rare, complex but eminently treatable group of tumors. A variety of surgical approaches can be used to excise the tumor. The choice of approach needs to be individualized with total excision providing excellent results. PMID- 22547961 TI - Review of skull base reconstruction using locoregional flaps and free flaps in children and adolescents. AB - Tumors of the skull base are rare in children, and reconstruction in such patients has rarely been reported. We reviewed 16 cases of skull base reconstruction in patients under 18 years. The study group consisted of 10 boys and 6 girls, whose ages ranged from 2 to 17 years. Of the 16 cases, eight tumors were benign and eight were malignant. Defects were anterior in six cases, lateral in eight cases, and anterolateral in two cases. Reconstruction was performed with locoregional flaps in 11 cases and with free flaps in 5 cases. No significant difference was found between locoregional flaps and free flaps in total operative time, intraoperative blood loss, or postoperative hospital stay. However, in some cases, total operative time, reconstruction time, and blood loss increased to a degree unacceptable for pediatrics. Minor complications occurred in three patients and a major complication occurred in one case. Of four patients, three patients with postoperative complications had undergone chemoradiotherapy. Because of the physical weakness of pediatric patients, complicated reconstructive procedure should be avoided. We believe locoregional flaps will become the first choice for reconstruction. However, if patients have large, complex defects and have received radiotherapy, appropriate free flaps should be used to avoid postoperative complications. PMID- 22547962 TI - Comparison between manual and semiautomated volumetric measurements of pituitary adenomas. AB - Linear measurements have many limitations. The aim of this study is to compare manual and semiautomated volumetric measurements of pituitary adenomas. Magnetic resonance imaging (MRI) scans of 38 patients with pituitary adenomas were analyzed. Preoperative MRI was acquired on a 1.5 T. MRI volumes of the pituitary adenomas were obtained by two methods: manual (MA) and semiautomated (SA). The concurrent validity for SA and MA methods on 38 patients in the form of correlation coefficient was 0.97 (p < 0.0001). The intraobserver and the interobserver correlation coefficients for SA volumes were both 0.98, as for the intraobserver MA volumes were 0.98. Although the results of both methods are comparable, analysis of volumetric measurements by SA method is more time efficient than MA segmentation. Precision in volumetric measurement techniques is likely to increase reliability of posttherapeutic monitoring of pituitary adenomas. PMID- 22547956 TI - Aberrant DNA methylation and prostate cancer. AB - Prostate cancer (PCa) is the most prevalent cancer, a significant contributor to morbidity and a leading cause of cancer-related death in men in Western industrialized countries. In contrast to genetic changes that vary among individual cases, somatic epigenetic alterations are early and highly consistent events. Epigenetics encompasses several different phenomena, such as DNA methylation, histone modifications, RNA interference, and genomic imprinting. Epigenetic processes regulate gene expression and can change malignancy associated phenotypes such as growth, migration, invasion, or angiogenesis. Methylations of certain genes are associated with PCa progression. Compared to normal prostate tissues, several hypermethylated genes have also been identified in benign prostate hyperplasia, which suggests a role for aberrant methylation in this growth dysfunction. Global and gene-specific DNA methylation could be affected by environmental and dietary factors. Among other epigenetic changes, aberrant DNA methylation might have a great potential as diagnostic or prognostic marker for PCa and could be tested in tumor tissues and various body fluids (e.g., serum, urine). The DNA methylation markers are simple in nature, have high sensitivity, and could be detected either quantitatively or qualitatively. Availability of genome-wide screening methodologies also allows the identification of epigenetic signatures in high throughput population studies. Unlike irreversible genetic changes, epigenetic alterations are reversible and could be used for PCa targeted therapies. PMID- 22547963 TI - Qualitative and quantitative radio-anatomical variation of the posterior clinoid process. AB - This study was conducted to investigate the radiological anatomy of the posterior clinoid process (PCP) to highlight preoperative awareness of its variations and its relationships to other skull base landmarks. The PCPs of 36, three dimensional computed tomographic cadaveric heads were evaluated by studying the gross anatomy of the PCP and by measuring the distances between the PCP and other skull base anatomical landmarks relevant to transnasal or transcranial skull base approaches. PCP variations were found in five specimens (14%): in two the dorsum sellae was absent, in one the PCP and the anterior clinoid process (ACP) were connected unilaterally and in two bilaterally. The mean distance between the right/left PCP and the crista galli was 45.14 +/- 4.0 standard deviation (SD_/46.24 +/- 4.5 SD, respectively, while the distance to the middle point of the basion at the level of the foramen magnum was 40.41 +/- 5.1 SD/41.0 +/- 5.2 SD, respectively. The mean distance between the PCP and the ACP was 12.03 +/- 3.18 SD on the right side and 12.11 +/- 2.77 SD on the left. The data provided highlights the importance of careful preoperative evaluation of the PCP and of its relationships to other commonly encountered skull base landmarks. This information may give an idea of the exposure achievable through different transcranial and transnasal approaches. This is especially relevant when neuronavigation is not available. PMID- 22547964 TI - Management of large and giant vestibular schwannomas. AB - The study was conducted to analyze outcomes following surgical management of large and giant vestibular schwannomas and management options for residual disease. This retrospective case note study includes patients who had undergone microsurgical resection of sporadic, large, or giant vestibular schwannomas from 1986 to 2008. Tumors are classified as large if the largest extracanalicular diameter was 3.5 cm or greater and giant if 4.5 cm or greater. The study included 45 patients (33 large, 12 giant tumors), mean tumor size 4.1 cm. Total excision was achieved in 14 cases (31.1%), near-total in 26 (57.8%), and subtotal in 5 (11.1%). Facial nerve outcome was House-Brackmann Grade I/II in 25 cases (55.6%), III/IV in 16 (35.6%), and V/VI in 4 (8.9%). No recurrence has been detected in those undergoing a complete resection. No residual tumor growth been observed in 15 of 26 who underwent near-total resection (57.7%). Of 11 patients, 10 received further treatment as their residual tumors showed growth. In the subtotal excision group, one patient died, three have demonstrated no growth, and one residual tumor has grown slightly but not required intervention. Optimal management for patients with large or giant vestibular schwannomas has yet to be determined. Management decisions must balance long term function with tumor control. PMID- 22547965 TI - Normal life expectancy for paraganglioma patients: a 50-year-old cohort revisited. AB - The objective of this study was to assess the long-term survival of patients with a paraganglioma of the head and neck compared with the survival of the general Dutch population. This historic cohort study was conducted using nationwide historical data of paraganglioma patients. We retrieved a cohort of 86 patients diagnosed with a paraganglioma of the head and neck between 1945 and 1960 in the Netherlands. Dates of death were retrieved from the national bureau of genealogy. Survival after diagnosis was compared with age and sex adjusted survival in the general population, by means of Wilcoxon signed rank test and Kaplan-Meier actuarial survival curves. Although surgery had more complications in the studied era than today and the death of five patients with carotid body tumors caused immediate excess mortality, the survival of the followed cohort was not significantly reduced if compared with the general population. Paragangliomas of the head and neck do not reduce life expectancy. PMID- 22547966 TI - Outcomes of temporal bone resection for locally advanced parotid cancer. AB - This study was conducted to report outcomes and identify factors predictive of survival and recurrence in patients undergoing lateral temporal bone resection (LTBR) as part of an extended radical parotidectomy for parotid cancer. This is a retrospective cohort study which includes all patients undergoing LTBR for parotid cancer between 1994 and 2010 at two affiliated academic centers. Survival and recurrence rates were analyzed using the Kaplan-Meier method and Cox multivariate regression. A total of 12 patients with median follow-up duration of 30.6 months were included: 6 de novo cases and 6 patients referred after local recurrence. Actuarial locoregional control at 2 years was 73%. Most patients (11; 92%) developed disease recurrence with distant metastases the most common site of first failure (83%). Overall and disease-specific survival rates were 80% at 2 years and 22.5% at 5 years. Recurrence-free survival (RFS) was 67% at 2 years and 8.3% at 5 years. On multivariate analysis, surgical margin status was an independent predictor of RFS (hazard ratio = 3.85, p = 0.045). In advanced parotid cancer, LTBR with a goal of gross total resection offers good locoregional control with an acceptable complication rate. The benefits of this surgery must be balanced with the morbidity and low likelihood of long-term survival, with most patients ultimately experiencing disease recurrence and death. PMID- 22547967 TI - Christopher j. Salgado, m.d. And stan j. Monstrey, m.d., ph.d. PMID- 22547968 TI - Aesthetic and functional genital and perineal surgery: female. PMID- 22547969 TI - Normal vulvovaginal, perineal, and pelvic anatomy with reconstructive considerations. AB - A thorough insight into the female genital anatomy is crucial for understanding and performing pelvic reconstructive procedures. The intimate relationship between the genitalia and the muscles, ligaments, and fascia that provide support is complex, but critical to restore during surgery for correction of prolapse or aesthetic reasons. The external female genitalia include the mons pubis, labia majora and minora, clitoris, vestibule with glands, perineal body, and the muscles and fascia surrounding these structures. Through the perineal membrane and the perineal body, these superficial vulvar structures are structurally related to the deep pelvic muscle levator ani with its fascia. The levator ani forms the pelvic floor with the coccygeus muscle and provides vital support to all the pelvic organs and stability to the perineum. The internal female genital organs include the vagina, cervix, uterus, tubes, and ovaries with their visceral fascia. The visceral fascia also called the endopelvic fascia, surrounds the pelvic organs and connects them to the pelvic walls. It is continuous with the paraurethral and paravaginal fascia, which is attached to the perineal membrane. Thus, the internal and external genitalia are closely related to the muscles and fascia, and work as one functioning unit. PMID- 22547970 TI - Aesthetic surgery of the female genitalia. AB - Aesthetic genital surgery seems to have become a fashionable issue nowadays. Many procedures and techniques have been described these last years, but very few long term results or follow up studies are available. The novelty of this aspect of plastic surgery and the lack of evidence-based interventions, have led to a comparison with female genital mutilation. In this article, the authors provide an overview of the possible surgical procedures as well as the general principles of aesthetic surgery of the female genitalia. PMID- 22547971 TI - Reconstruction of congenital defects of the vagina. AB - Congenital absence of the vagina is a relatively rare condition most commonly associated with Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. Historically, several reconstructive techniques have been described to provide for functional vaginal reconstruction on these patients, both operative and nonoperative. Although there are many advantages and disadvantages of the various procedures, one experience with the use of split thickness skin grafts to reconstruct the vagina has produced acceptable functional results with limited donor site morbidity. Careful planning and timing of this form of reconstruction can produce predictable results in patients who are nearing sexual maturity. PMID- 22547972 TI - Reconstruction of acquired perineovulvar defects: a proposal of sequence. AB - Acquired perineovulvar defects are usually the result of excision of vulvar intraepithelial neoplasia (VIN) or invasive squamous cell carcinoma. Because both VIN and vulvar carcinoma have a tendency toward local recurrence, future reconstructive options should be reckoned with during treatment of the primary and all subsequent (pre-) malignant perineovulvar lesions. Hence, a proposal of sequence of reconstructive options for these defects is called for. In cases where local skin flaps suffice, these are preferably designed in such a fashion as not to sever the branches of the internal pudendal vascular system. In cases where either a pudendal thigh flap or an infragluteal flap may be used to close the perineovulvar defect, the pudendal thigh flap is to be preferred to preserve the infragluteal flap for future use. Only when these flaps no longer are available or sufficient to cover the defect should the gluteal thigh flap be applied. The use of myocutaneous flaps is rarely indicated to close isolated superficial perineovulvar defects. PMID- 22547974 TI - Aesthetic and functional male to female genital and perineal surgery: feminizing vaginoplasty. AB - Male to female transsexuals frequently seek feminizing vaginoplasty for "below the waist" conformation, enhancement of sexual identity, and interactive sexual function. The author shares his experience with his first 250 primary surgical procedures. Included is a brief historical background, the patient selection process, some guidelines from the World Professional Association for Transgender Health (standards of care), preoperative evaluation and instructions, surgical technique, postoperative regimen, risk factors, results, complications and management. The patients all underwent feminizing vaginoplasty at the author's ambulatory surgical facility, which includes an overnight stay. The author's results suggest that feminizing vaginoplasty when performed vigilantly on a select group of patients is feasible. PMID- 22547973 TI - Reconstruction of acquired defects of the vagina and perineum. AB - Successful reconstruction of vaginal and perineal defects requires close communication and cooperation between the extirpative and reconstructive surgeon. A variety of reconstructive options is available, dependent on the nature of the defect and extent of the ablative surgery. In all cases, obliteration of pelvic dead space and separation of intraabdominal contents from the perineum are important considerations to ensure uncomplicated perineal wound healing. The decision for vaginal reconstruction is also contingent upon the age, sexual function, and wishes of the patient. In this article, we review options for vaginal and perineal reconstruction in acquired defects. PMID- 22547975 TI - Investigation of a cluster of Candida albicans invasive Candidiasis in a neonatal intensive care unit by pulsed-field gel electrophoresis. AB - Nosocomial invasive candidiasis (IC) has emerged as a major problem in neonatal intensive care units (NICUs). We investigated herein the temporal clustering of six cases of neonatal IC due to Candida albicans in an NICU. Eighteen isolates obtained from the six neonates and two isolates from two health care workers (HCWs) working at the same unit and suffering from fingers' onychomycosis were genotyped by electrophoretic karyotyping (EK) and restriction endonuclease analysis of genomic DNA by using Sfi I (PFGE-Sfi I). PFGE-Sfi I was more effective in discriminating between temporally related isolates. It showed that (i) both HCWs had specific strains excluding them as a source of infections in neonates. (ii) Isolates collected from three neonates were identical providing evidence of their clonal origin and the occurrence of a horizontal transmission of C. albicans in the unit. (iii) The three remaining neonates had specific strains confirming that the IC cases were coincidental. (iv) Microevolution occurred in one catheter-related candidemia case. Our results illustrate the relevance of the molecular approach to investigate suspected outbreaks in hospital surveys and the effectiveness of PFGE-Sfi I for typing of epidemiologically related C. albicans isolates. PMID- 22547977 TI - Sensitivity and selectivity on aptamer-based assay: the determination of tetracycline residue in bovine milk. AB - A competitive enzyme-linked aptamer assay (ELAA) to detect tetracycline in milk was performed by using two different aptamers individually; one is 76 mer-DNA aptamer and the other is 57 mer-RNA aptamer. The best optimum condition was obtained without monovalent ion, Na(+) and also by adding no Mg(2+) ion in the assay buffer, along with RT incubation. The optimized ELAA showed a good sensitivity (LOD of 2.10 * 10(-8) M) with a wide dynamic range (3.16 * 10(-8) M ~ 3.16 * 10(-4) M). In addition, the average R.S.D. across all data points of the curve was less than 2.5% with good recoveries (~101.8%) from the milk media. Thus, this method provides a good tool to monitor tetracycline in milk from MRLs' point of view. However, this ELAA method was not superior to the ELISA method in terms of specificity. This paper describes that it does not always give better sensitivity and specificity in assays even though aptamers have several advantages over antibodies and have been known to be good binders for binding assays. PMID- 22547978 TI - N : P stoichiometry in a forested runoff during storm events: comparisons with regions and vegetation types. AB - Nitrogen and phosphorus are considered the most important limiting elements in terrestrial and aquatic ecosystems. however, very few studies have focused on which is from forested streams, a bridge between these two systems. To fill this gap, we examined the concentrations of dissolved N and P in storm waters from forested watersheds of five regions in Japan, to characterize nutrient limitation and its potential controlling factors. First, dissolved N and P concentrations and the N : P ratio on forested streams were higher during storm events relative to baseflow conditions. Second, significantly higher dissolved inorganic N concentrations were found in storm waters from evergreen coniferous forest streams than those from deciduous broadleaf forest streams in Aichi, Kochi, Mie, Nagano, and with the exception of Tokyo. Finally, almost all the N : P ratios in the storm water were generally higher than 34, implying that the storm water should be P-limited, especially for Tokyo. PMID- 22547976 TI - Plasmalogens inhibit APP processing by directly affecting gamma-secretase activity in Alzheimer's disease. AB - Lipids play an important role as risk or protective factors in Alzheimer's disease (AD). Previously it has been shown that plasmalogens, the major brain phospholipids, are altered in AD. However, it remained unclear whether plasmalogens themselves are able to modulate amyloid precursor protein (APP) processing or if the reduced plasmalogen level is a consequence of AD. Here we identify the plasmalogens which are altered in human AD postmortem brains and investigate their impact on APP processing resulting in Abeta production. All tested plasmalogen species showed a reduction in gamma-secretase activity whereas beta- and alpha-secretase activity mainly remained unchanged. Plasmalogens directly affected gamma-secretase activity, protein and RNA level of the secretases were unaffected, pointing towards a direct influence of plasmalogens on gamma-secretase activity. Plasmalogens were also able to decrease gamma secretase activity in human postmortem AD brains emphasizing the impact of plasmalogens in AD. In summary our findings show that decreased plasmalogen levels are not only a consequence of AD but that plasmalogens also decrease APP processing by directly affecting gamma-secretase activity, resulting in a vicious cycle: Abeta reduces plasmalogen levels and reduced plasmalogen levels directly increase gamma-secretase activity leading to an even stronger production of Abeta peptides. PMID- 22547979 TI - Doppler-guided hemorrhoid artery ligation with Recto-Anal-Repair modification: functional evaluation and safety assessment of a new minimally invasive method of treatment of advanced hemorrhoidal disease. AB - PURPOSE: We present 12-month followup results of functional evaluation and safety assessment of a modification of hemorrhoidal artery ligation (DGHAL) called Recto Anal-Repair (RAR) in treatment of advanced hemorrhoidal disease (HD). METHODS: Patients with grade III and IV HD underwent the RAR procedure (DGHAL combined with restoration of prolapsed hemorrhoids to their anatomical position with longitudinal sutures). Each patient had rectal examination, anorectal manometry, and QoL questionnaire performed before 3 months, and 12 months after RAR procedure. RESULTS: 20 patients completed 12-month followup. There were no major complications. 3 months after RAR, 5 cases of residual mucosal prolapse were detected (25%), while only 3 patients (15%) reported persistence of symptoms. 12 months after RAR, another 3 HD recurrences were detected, to a total of 8 patients (40%) with HD recurrence. Anal pressures after RAR were significantly lower than before (P < 0.05), and the effect was persistent 12 months after RAR. One patient (5%) reported occasional soiling 3 months after RAR. CONCLUSIONS: RAR seems to be a safe method of treatment of advanced HD with no major complications. The procedure has a significant influence on anal pressures, with no evidence of risk of fecal incontinence after the operation. PMID- 22547980 TI - Obesity-related factors in Turkish school children. AB - OBJECTIVE: To determine the prevalence of obesity and its risk factors in Turkish children. METHOD: This cross-sectional survey was conducted on students including 1271 boys and 1206 girls selected from 20 secondary schools in Samsun, Turkey. A predesigned questionnaire was used to elicit the information on individual characteristics. The height and weight of students were measured in their classroom. Obesity was defined as body mass index at or above the 95th percentile for age of the sex-specific CDC growth charts. RESULT: The mean age was 12.8 +/- 0.9 years, and the prevalence of obesity was found at 10.3%. There were higher numbers of obese students in boys than in girls (X(2) = 53.4; P < 0.001). The prevalence of obesity was 10.0% and 16.8% in public and private school students, respectively. The percentage of obese children in students who skipped breakfast was found to be higher than that in the group that consumed 3 meals a day regularly. There was no difference at time spent in sedentary behavior except watching TV, and prevalence of obesity in the group of students watching television over 3 hours per day was higher than that in their counterparts (X(2) = 13.6; P < 0.01). The time of engagement in sports was lower in obese group statistically (F = 8.9; P < 0.001). CONCLUSION: In order to prevent childhood obesity, monitoring children's lifestyle by parents is necessary. PMID- 22547981 TI - Association between levels of IgA antibodies to tissue transglutaminase and gliadin-related nonapeptides in dermatitis herpetiformis. AB - Dermatitis herpetiformis (DH) is an autoimmunity-driven inflammatory blistering dermatosis associated with a gluten-dependent enteropathy. Tissue transglutaminase (tTG) and nonapeptides of gliadin (npG) are considered in its pathomechanism/diagnostics. Here, the diagnostic accuracy of anti-tTG/anti-npG IgA ELISAs in Slavic DH patients with active skin rash was assessed through creating receiver operating characteristic (ROC) curves, determining cutoff values, and calculating correlations between levels of anti-tTG/anti-npG IgA in DH, IgA/neutrophil-mediated non-DH patients and healthy persons. Altogether, sera from 80 Slavic individuals were examined. There were negligible differences between cutoff points obtained by the ELISAs manufacturer and those in this study. There were statistically significant correlations between levels of anti tTG/anti-npG IgA in both DH group and the group of IgA/neutrophil-mediated non-DH dermatoses. There was no such correlation in healthy controls. It seems that IgA autoantibodies to tTG and npG in the IgA/neutrophil-mediated DH are produced in the coordinated way implying their causal relationship. PMID- 22547982 TI - Effect of isosporiasis prevention with toltrazuril on long-term pig performance. AB - The efficacy of toltrazuril treatment was assessed in two experiments in Polish swine herds. Experiment 1 included a toltrazuril treatment group, Group A (n = 410), and untreated control, Group B (n = 386). Time to sale in Group A was 108 days versus 120 days for Group B, with average body weights at sale of 114.2 kg and 108.8 kg, respectively (P < 0.05). In experiment 2, the health status and body weight gain of 238 piglets treated with toltrazuril (Group D) were compared to 235 untreated piglets (Group K). A similar difference was observed in average body weights of slaughtered animals, being on average 104 kg in Group D and 101 kg in Group K (P < 0.01). Animals from Group D were slaughtered 5 days earlier than animals from Group K (day 166 versus day 171). Data from clinical trials suggest treatment of coccidiosis with toltrazuril offering potential for improved animal welfare and yields, however this has remained unproven in field conditions in large swine production facilities. The present study confirms the efficacy of toltrazuril treatment when used in the field and the subsequent positive impact on time to weaning, time to market, and on weight gain at all time points. PMID- 22547983 TI - Subjective outcome evaluation and factors related to perceived effectiveness of the project P.A.T.H.S. in Hong Kong. AB - Based on a sample of 24,457 participated students, the present study investigated participants' subjective evaluation of the Tier 2 Program of the Project P.A.T.H.S. in the 2009/2010 academic year. Participants generally held positive views toward the Tier 2 Program and program instructor and perceived the program to be beneficial to their development. Programs involving adolescents alone were evaluated more positively than programs involving parents and/or teachers. Students' grade and program type did not show significant impact on participants' subjective evaluation of the project. Consistent with previous reports, perceived effectiveness of the program was significantly predicted by students' perceptions about the program and program instructor. These findings provide further support that the Tier 2 Program is effective in promoting positive development among adolescents with greater psychosocial needs. PMID- 22547984 TI - Technologies for beneficial microorganisms inocula used as biofertilizers. AB - The increasing need for environmentaly friendly agricultural practices is driving the use of fertilizers based on beneficial microorganisms. The latter belong to a wide array of genera, classes, and phyla, ranging from bacteria to yeasts and fungi, which can support plant nutrition with different mechanisms. Moreover, studies on the interactions between plant, soil, and the different microorganisms are shedding light on their interrelationships thus providing new possible ways to exploit them for agricultural purposes. However, even though the inoculation of plants with these microorganisms is a well-known practice, the formulation of inocula with a reliable and consistent effect under field conditions is still a bottleneck for their wider use. The choice of the technology for inocula production and of the carrier for the formulation is key to their successful application. This paper focuses on how inoculation issues can be approached to improve the performance of beneficial microorganisms used as a tool for enhancing plant growth and yield. PMID- 22547987 TI - Microstructure and properties of polyhydroxybutyrate-chitosan-nanohydroxyapatite composite scaffolds. AB - Polyhydroxybutyrate-chitosan-hydroxyapatite (PHB-CHT-HAP) composite scaffolds were prepared by the precipitation of biopolymer-nanohydroxyapatite suspensions and following lyophilisation. The propylene carbonate and acetic acid were used as the polyhydroxybutyrate and chitosan solvents, respectively. The high porous microstructure was observed in composites and the macroporosity of scaffolds (pore sizes up to 100 MUm) rose with the chitosan content. It was found the reduction in both the PHB melting (70 degrees C) and thermal degradation temperatures of polyhydroxybutyrate and chitosan biopolymers in composites, which confirms the mutual ineraction between polymers and the decrease of PHB lamellar thickness. No preferential preconcentration of individual biopolymers was verified in composites, and the compressive strengths of macroporous PHB-CHT-HAP scaffolds were approximately 2.5 MPa. The high toxic fluorinated cosolvents were avoided from the preparation process. PMID- 22547986 TI - Natural killer cells and their role in rheumatoid arthritis: friend or foe? AB - Rheumatoid arthritis (RA) is a long-term disease that leads to inflammation of the joints and surrounding tissues. Natural killer (NK) cells are an important part of the innate immune system and are responsible for the first line of defense against pathogens during the initial immune challenge before the adaptive immune system eventually eliminates the infectious burden. NK cells have the capacity to damage normal cells or through interaction with other cells such as dendritic cells, macrophages, and T cells cause autoimmune diseases, such as RA. NK cells isolated from the joints of patients with RA suggest that they may play a role in this disease. However, the involvement of NK cells in RA pathology is not fully elucidated. Both protective and detrimental roles of NK cells in RA have recently been reported. A better understanding of NK cells' role in RA might help to develop new therapeutic strategies for treatment of the RA or other autoimmune diseases. We have decided in this paper to focus on the NK cell biology, and attempt to bring the interested readership of this Journal up to date on the NK cell, specifically its possible relation to RA. PMID- 22547988 TI - Induction of MAP kinase homologues during growth and morphogenetic development of Karnal bunt (Tilletia indica) under the influence of host factor(s) from wheat spikes. AB - Signaling pathways that activate different mitogen-activated protein kinases (MAPKs) in response to certain environmental conditions, play important role in mating type switching (Fus3) and pathogenicity (Pmk1) in many fungi. In order to determine the roles of such regulatory genes in Tilletia indica, the causal pathogen of Karnal bunt (KB) of wheat, semi-quantitative and quantitative RT-PCR was carried out to isolate and determine the expression of MAP kinase homologues during fungal growth and development under in vitro culture. Maximum expression of TiFus3 and TiPmk1 genes were observed at 14th and 21st days of culture and decreased thereafter. To investigate whether the fungus alters the expression levels of same kinases upon interaction with plants, cultures were treated with 1% of host factors (extracted from S-2 stage of wheat spikes). Such treatment induced the expression of MAPks in time dependent manner compared to the absence of host factors. These results suggest that host factor(s) provide certain signal(s) which activate TiFus3 and TiPmk1 during morphogenetic development of T. indica. The results also provides a clue about the role of host factors in enhancing the disease potential due to induction of MAP kinases involved in fungal development and pathogenecity. PMID- 22547989 TI - The effects of environment and physiological cyclicity on the immune system of Viperinae. AB - One of the important aspects of species' survival is connected with global climate changes, which also conditions the epidemiology of infectious diseases. Poikilotherms are exposed, as other species, to climatic influence, especially due to their physiological peculiarities such as important stages of their life cycle: hibernation, shedding, and active phase. The immune system serves as an accurate indicator of the health status and stress levels in these species. This study aimed to monitor the changes of innate (leukocyte subpopulations and total immune globulins) and adaptive immunity (in vitro leukocyte blast transformation) of two viper species, V. berus berus and V. ammodytes ammodytes, endemic in Europe and spread in different regions of Romania during their three major life cycles, hibernation, shedding, and active phase. The results indicated that seasonal variance and cycle rather than species and regional distribution influence the functionality of the immune system. PMID- 22547985 TI - Cell cycle inhibition without disruption of neurogenesis is a strategy for treatment of aberrant cell cycle diseases: an update. AB - Since publishing our earlier report describing a strategy for the treatment of central nervous system (CNS) diseases by inhibiting the cell cycle and without disrupting neurogenesis (Liu et al. 2010), we now update and extend this strategy to applications in the treatment of cancers as well. Here, we put forth the concept of "aberrant cell cycle diseases" to include both cancer and CNS diseases, the two unrelated disease types on the surface, by focusing on a common mechanism in each aberrant cell cycle reentry. In this paper, we also summarize the pharmacological approaches that interfere with classical cell cycle molecules and mitogenic pathways to block the cell cycle of tumor cells (in treatment of cancer) as well as to block the cell cycle of neurons (in treatment of CNS diseases). Since cell cycle inhibition can also block proliferation of neural progenitor cells (NPCs) and thus impair brain neurogenesis leading to cognitive deficits, we propose that future strategies aimed at cell cycle inhibition in treatment of aberrant cell cycle diseases (i.e., cancers or CNS diseases) should be designed with consideration of the important side effects on normal neurogenesis and cognition. PMID- 22547991 TI - Evaluation of clinical and immunopathological features of different infective doses of Trypanosoma cruzi in dogs during the acute phase. AB - Infection with Trypanosoma cruzi is a major risk in Latin America, and dogs are believed to be good models for evaluating Chagas disease. Here, we evaluated the clinical and immunopathological alterations developed by mongrel dogs experimentally infected with different infective doses (2,000, 20,000, and 200,000 metacyclic trypomastigotes of Sylvio X10/4 strain kg(-1) via intraperitoneal). Clinical and electrocardiographic parameters, as well as antibody production and pathologic lesions were evaluated. All three doses of this strain of T. cruzi induced a similar pattern of infection characterized by cardiac arrhythmias and severe and diffuse myocarditis. Specific anti-T. cruzi IgG indicated seroconversion by day 14 after infection, and IgG levels increased during the period of evaluation. Mortality was observed only in dogs infected with the medium or high parasite doses, but not in the group infected with a low dose of 2,000 parasites kg(-1). Infection with a low dose of parasites provides an excellent nonlethal model to evaluate the immunopathology of the acute disease in dogs infected with the Sylvio X10/4 strain of T. cruzi. PMID- 22547990 TI - TNF-alpha promotes IFN-gamma-induced CD40 expression and antigen process in Myb transformed hematological cells. AB - Tumour necrosis factor-alpha, interferon-gamma and interleukin-4 are critical cytokines in regulating the immune responses against infections and tumours. In this study, we investigated the effects of three cytokines on CD40 expression in Myb-transformed hematological cells and their regulatory roles in promoting these cells into dendritic cells. We observed that both interleukin-4 and interferon gamma increased CD40 expression in these hematological cells in a dose-dependent manner, although the concentration required for interleukin-4 was significantly higher than that for interferon-gamma. We found that tumour necrosis factor-alpha promoted CD40 expression induced by interferon-gamma, but not by interleukin-4. Our data showed that tumour necrosis factor-alpha plus interferon-gamma-treated Myb-transformed hematological cells had the greatest ability to take up and process the model antigen DQ-Ovalbumin. Tumour necrosis factor-alpha also increased the ability of interferon-gamma to produce the mixed lymphocyte reaction to allogenic T cells. Furthermore, only cotreatment with tumour necrosis factor-alpha and interferon-gamma induced Myb-transformed hematological cells to express interleukin-6. These results suggest that tumour necrosis factor-alpha plays a key regulatory role in the development of dendritic cells from hematological progenitor cells induced by interferon-gamma. PMID- 22547993 TI - The evaluation of diagnostic role of cardiac troponin T (cTnT) in newborns with heart defects. AB - Heart diseases are a significant cause of morbidity and mortality in newborns. Diagnostic methods are often not sufficient or, in many cases, cannot be used. There is a great advance in medical knowledge concerning biomarkers in the diagnosis of circulatory system in adult patients. Among them, cardiac troponins play the main role. In current literature, there is not enough data concerning the possibility of using them in neonatal cardiac diagnostics. Aim of the Study. To evaluate diagnostic usefulness of cTnT in correlation with other markers of circulatory failure and myocardial damage in newborns with heart defects. Patients and Methods. The study involved 83 newborns up to 46 weeks of postmenstrual age. The exclusion criteria were severe perinatal asphyxia and presence of severe noncardiac diseases. Patients were divided into 2 main groups: group I-54 patients with congenital heart defects (CHDs), and group II (control) 29 healthy neonates. All patients underwent detailed examination of circulatory system. Cardiac troponin T (cTnT) concentrations were evaluated by Roche CARDIAC T Quantitive test. Results. Performed studies revealed that cTnT levels in newborns with heart pathology were significantly higher than in healthy ones. However, cTnT concentrations in patients with CHD did not correlate with clinical symptoms of heart failure, nor with echocardiographic markers of LV function. Type of heart defect did not influence cTnT levels as well. Only hemodynamic significance evaluated by echocardiography influenced the cTnT levels with statistical significance. Conclusions. (1) Statistically significant differences in cTnT levels between newborns with heart defects and healthy subjects were shown. (2) CTnT levels in newborns with heart defects refer only to hemodynamic significance of the defect. PMID- 22547992 TI - Low-dose fluvastatin prevents the functional alterations of endothelium induced by short-term cholesterol feeding in rabbit carotid artery. AB - 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, commonly known as statins, are the medical treatment of choice for hypercholesterolemia. In addition to lowering serum-cholesterol levels, statins appear to promote pleiotropic effects that are independent of changes in serum cholesterol. In this study, we investigated the effects of low-dose fluvastatin on antioxidant enzyme activities (superoxide dismutase, SOD; catalase), total nitrite/nitrate levels, and vascular reactivity in 2% cholesterol-fed rabbits. This diet did not generate any fatty streak lesions on carotid artery wall. However, SOD activity significantly increased with cholesterol feeding whereas the catalase activities decreased. The levels of nitrite/nitrate, stable products of NO degradation, diminished. Moreover, dietary cholesterol reduced vascular responses to acetylcholine, but contractions to serotonin were augmented. Fluvastatin treatment abrogated the cholesterol-induced increase in SOD, increased the levels of nitric oxide metabolites in tissue, and restored both the impaired vascular responses to acetylcholine and the augmented contractile responses to serotonin without affecting plasma-cholesterol levels. Phenylephrine contractions and nitroglycerine vasodilatations did not change in all groups. This study indicated that fluvastatin treatment performed early enough to improve impaired vascular responses may delay cardiovascular complications associated with several cardiovascular diseases. PMID- 22547994 TI - Evaluation of the training program of the project P.A.T.H.S.: findings based on the perspective of the participants from different cohorts. AB - Subjective outcome evaluation findings based on the perspective of the participants participating in a 3-day training program of the Project P.A.T.H.S. are reported in this paper. The findings were based on the data collected from the training workshops conducted between 2005 and 2009 (N = 4.167). Results showed that the respondents had good and positive perceptions of the training program and found it very valuable, particularly with respect to training instructors and familiarization with the project. Besides, the training participants were able to acquire attitude, knowledge and skills that are conducive to the successful implementation of the program. Based on the subjective outcome evaluation findings, it is concluded that the training program was effective in helping the participants to acquire the necessary knowledge, attitudes and skills in implementing the program. PMID- 22547995 TI - Population pharmacokinetics of vancomycin in Thai patients. AB - Population pharmacokinetics of vancomycin in Thai adult patients was determined by non-linear mixed-effects approach using 319 vancomycin serum concentrations from 212 patients. The data were best fitted by a two-compartment model and it was used to examine the effect of patient characteristics on the vancomycin pharmacokinetics. In the final model, there was a linear relationship between vancomycin clearance, CL (L/h), and creatinine clearance calculated by Cockcroft Gault equation, CL(Cr) (mL/min): CL = 0.044 * L(Cr). Meanwhile, volume of central compartment, V(1) (L), was linearly related with the age (years old): V(1) = 0.542 * Age. Intercompartment clearance (Q) and volume of peripheral compartment (V(2)) was 6.95 L/h and 44.2 L, respectively. The interindividual variability for CL, V(1), Q, and V(2) was 35.78, 20.93, 39.50, and 57.27%, respectively. Whereas, the intraindividual variability was 4.51 mg/L. Final model then was applied to predict serum vancomycin concentrations on validation group. Predictive performance revealed a bias of -1.43 mg/L (95% CI: -5.82-2.99) and a precision of 12.2 mg/L (95% CI: -1.60-26.16). In conclusion, population pharmacokinetic of vancomycin in Thai adult patients was developed. The model could be used to create vancomycin dosage regimen in the type of patient similar with the present study. PMID- 22547996 TI - Morphohistology of the digestive tract of the damsel fish Stegastes fuscus (Osteichthyes: Pomacentridae). AB - This study investigated the morphohistology of the digestive tract and the mean intestinal coefficient of the damsel fish Stegastes fuscus captured from the tidal pools of Northeastern Brazil. The wall of the digestive tract of S. fuscus is composed of the tunica mucosa, tunica muscularis, and tunica serosa. The esophagus is short with sphincter and thick distensible wall with longitudinally folded mucosa. Mucous glands are predominant, and the muscular layer of the esophagus presented striated fibers all along its extension. The transition region close to the stomach shows plain and striated muscular fibers. Between the stomach and intestine, there are three pyloric caeca. The intestine is long and thin with four folds around the stomach. The anterior intestine presents folds similar to those of pyloric caeca. The estimated mean intestinal coefficient and characteristics of the digestive system of S. fuscus present morphological adequacy for both herbivorous and omnivorous feeding habits. PMID- 22547997 TI - The Rapid TEG alpha-Angle may be a sensitive predictor of transfusion in moderately injured blunt trauma patients. AB - BACKGROUND: To guide the administration of blood products, coagulation screening of trauma patients should be fast and accurate. The purpose of this study was to identify the correlation between CCT and TEG in trauma, to determine which CCT or TEG parameter is most sensitive in predicting transfusion in trauma, and to define TEG cut-off points for trauma care. METHODS: A six-month, prospective observational study of 76 adult patients with suspected multiple injuries was conducted at a Level 1 trauma centre of a university hospital. Physicians blinded to TEG results made the decision to transfuse based on clinical evaluation. RESULTS: The study results showed that conventional coagulation tests correlate moderately with Rapid TEG parameters (R: 0.44-0.61). Kaolin and Rapid TEG were more sensitive than CCTs, and the Rapid TEG alpha-Angle was identified as the single parameter with the greatest sensitivity (84%) and validity (77%) at a cut off of 74.7 degrees. When the Rapid TEG alpha-Angle was combined with heart rate >75 bpm, or haematocrit < 41%, sensitivity (84%, 88%) and specificity (75%, 73%) were improved. CONCLUSION: Cutoff points for transfusion can be determined with the Rapid TEG alpha-Angle and can provide better sensitivity than CCTs, but a larger study population is needed to reproduce this finding. PMID- 22547998 TI - Effects of amelogenin on proliferation, differentiation, and mineralization of rat bone marrow mesenchymal stem cells in vitro. AB - The aim of this study was to clarify the function of amelogenin, the major protein of enamel matrix derivative, on the proliferation, differentiation, and mineralization of cultured rat bone marrow stem cells (BMSCs), toward the establishment of future bone regenerative therapies. No differences in the morphology of BMSCs or in cell numbers were found between amelogenin addition and additive-free groups. The promotion of ALPase activity and the formation of mineralized nodules were detected at an early stage in amelogenin addition group. In quantitative real-time RT-PCR, mRNA expression of osteopontin, osteonectin, and type I collagen was promoted for 0.5 hours and 24 hours by addition of amelogenin. The mRNA expression of osteocalcin and DMP-1 was also stimulated for 24 hours and 0.5 hours, respectively, in amelogenin addition group. These findings clearly indicate that amelogenin promoted the differentiation and mineralization of rat BMSCs but did not affect cell proliferation or cell morphology. PMID- 22547999 TI - Potential long-term complications of endovascular stent grafting for blunt thoracic aortic injury. AB - Blunt thoracic aortic injury (BTAI) is a rare, but lethal, consequence of rapid deceleration events. Most victims of BTAI die at the scene of the accident. Of those who arrive to the hospital alive, expedient aortic intervention significantly improves survival. Thoracic endovascular aortic repair (TEVAR) has been accepted as the standard of care for BTAI at many centers, primarily due to the convincing evidence of lower mortality and morbidity in comparison to open surgery. However, less attention has been given to potential long-term complications of TEVAR for BTAI. This paper focuses on these complications, which include progressive aortic expansion with aging, inadequate stent graft characteristics, device durability concerns, long-term radiation exposure concerns from follow-up computed tomography scans, and the potential for (Victims of Modern Imaging Technology) VOMIT. PMID- 22548000 TI - Supercooling agent icilin blocks a warmth-sensing ion channel TRPV3. AB - Transient receptor potential vanilloid subtype 3 (TRPV3) is a thermosensitive ion channel expressed in a variety of neural cells and in keratinocytes. It is activated by warmth (33-39 degrees C), and its responsiveness is dramatically increased at nociceptive temperatures greater than 40 degrees C. Monoterpenoids and 2-APB are chemical activators of TRPV3 channels. We found that Icilin, a known cooling substance and putative ligand of TRPM8, reversibly inhibits TRPV3 activity at nanomolar concentrations in expression systems like Xenopus laeves oocytes, HEK-293 cells, and in cultured human keratinocytes. Our data show that icilin's antagonistic effects for the warm-sensitive TRPV3 ion channel occurs at very low concentrations. Therefore, the cooling effect evoked by icilin may at least in part be due to TRPV3 inhibition in addition to TRPM8 potentiation. Blockade of TRPV3 activity by icilin at such low concentrations might have important implications for overall cooling sensations detected by keratinocytes and free nerve endings in skin. We hypothesize that blockage of TRPV3 might be a signal for cool-sensing systems (like TRPM8) to beat up the basal activity resulting in increased cold perception when warmth sensors (like TRPV3) are shut off. PMID- 22548002 TI - Setting standards, saving lives. PMID- 22548003 TI - Revisions to the 2009 american society of clinical oncology/oncology nursing society chemotherapy administration safety standards: expanding the scope to include inpatient settings. AB - In November 2009, ASCO and the Oncology Nursing Society (ONS) jointly published a set of 31 voluntary chemotherapy safety standards for adult patients with cancer, as the end result of a highly structured, multistakeholder process. The standards were explicitly created to address patient safety in the administration of parenteral and oral chemotherapeutic agents in outpatient oncology settings. In January 2011, a workgroup consisting of ASCO and ONS members was convened to review feedback received since publication of the standards, to address interim changes in practice, and to modify the standards as needed. The most significant change to the standards is to extend their scope to the inpatient setting. This change reflects the conviction that the same standards for chemotherapy administration safety should apply in all settings. The proposed set of standards has been approved by the Board of Directors for both ASCO and ONS and has been posted for public comment. Comments were used as the basis for final editing of the revised standards. The workgroup recognizes that the safety of oral chemotherapy usage, nononcology medication reconciliation, and home chemotherapy administration are not adequately addressed in the original or revised standards. A separate process, cosponsored by ASCO and ONS, will address the development of safety standards for these areas. PMID- 22548001 TI - The Caenorhabditis elegans HEN1 ortholog, HENN-1, methylates and stabilizes select subclasses of germline small RNAs. AB - Small RNAs regulate diverse biological processes by directing effector proteins called Argonautes to silence complementary mRNAs. Maturation of some classes of small RNAs involves terminal 2'-O-methylation to prevent degradation. This modification is catalyzed by members of the conserved HEN1 RNA methyltransferase family. In animals, Piwi-interacting RNAs (piRNAs) and some endogenous and exogenous small interfering RNAs (siRNAs) are methylated, whereas microRNAs are not. However, the mechanisms that determine animal HEN1 substrate specificity have yet to be fully resolved. In Caenorhabditis elegans, a HEN1 ortholog has not been studied, but there is evidence for methylation of piRNAs and some endogenous siRNAs. Here, we report that the worm HEN1 ortholog, HENN-1 (HEN of Nematode), is required for methylation of C. elegans small RNAs. Our results indicate that piRNAs are universally methylated by HENN-1. In contrast, 26G RNAs, a class of primary endogenous siRNAs, are methylated in female germline and embryo, but not in male germline. Intriguingly, the methylation pattern of 26G RNAs correlates with the expression of distinct male and female germline Argonautes. Moreover, loss of the female germline Argonaute results in loss of 26G RNA methylation altogether. These findings support a model wherein methylation status of a metazoan small RNA is dictated by the Argonaute to which it binds. Loss of henn-1 results in phenotypes that reflect destabilization of substrate small RNAs: dysregulation of target mRNAs, impaired fertility, and enhanced somatic RNAi. Additionally, the henn-1 mutant shows a weakened response to RNAi knockdown of germline genes, suggesting that HENN-1 may also function in canonical RNAi. Together, our results indicate a broad role for HENN-1 in both endogenous and exogenous gene silencing pathways and provide further insight into the mechanisms of HEN1 substrate discrimination and the diversity within the Argonaute family. PMID- 22548004 TI - US Cancer Center Implementation of ASCO/Oncology Nursing Society Chemotherapy Administration Safety Standards. AB - PURPOSE: Because cancer chemotherapy is a high-risk intervention, ASCO and the Oncology Nursing Society (ONS) established in 2009 consensus- and evidence-based national standards for the safe administration of chemotherapy. We sought to assess the implementation status of the ASCO/ONS chemotherapy administration safety standards. METHODS: A written survey of chemotherapy practices was sent to National Cancer Institute-designated cancer centers. Implementation status of each of 31 chemotherapy administration safety standards was self-reported. RESULTS: Forty-four (80%) of 55 eligible centers responded. Although the majority of centers have fully implemented at least half of the standards, only four centers reported full implementation of all 31. Implementation varied by standard, with the poorest implementation of standards that addressed documentation of chemotherapy planning, agreed-on intervals for laboratory testing, and patient education and consent before initiation of oral or infusional chemotherapy. CONCLUSION: Given wide variation in the implementation of ASCO/ONS chemotherapy administration safety standards at US cancer centers, there are significant opportunities for improvement. PMID- 22548005 TI - A model to estimate human resource needs for the treatment of outpatients with cancer. AB - PURPOSE: Although personnel costs significantly affect cancer health care expenditures, little is known about the relationship between workload, human resource requirements, and associated costs. An empirical model to forecast staffing demand is described according to the yearly caseload of outpatients with cancer beginning active treatment and the number of personnel working hours. METHODS: The oncology department at the University Hospital of Udine (Udine, Italy) is a computerized unit taking care of approximately 1,300 patients per year. Each clinical episode is centrally recorded. We queried the database for the total number of consultations per patient beginning treatment during 2006. With predefined bonds (ie, time limit set for each visit type and annual working hours per employee), we sought to estimate yearly per-patient hours of care and the number of personnel needed. RESULTS: In 2006, each outpatient with cancer beginning active treatment generated an average of 16 clinical evaluations, which in turn translated into 8 and 16 hours of physician and nurse working time, respectively. Assuming an average of 1,672 annual working hours, a need for one physician and three nurses for every 600 patients could be estimated for every 200 novel patients. In the next year, the same caseload induced 4.5 consultations on average; using a similar approach, the demand for additional time and resources was calculated. CONCLUSION: By means of a simple model combining predefined conditions with a centralized record of clinical episodes, we were able to provide a reasonable estimate of human resource requirements and a tool to forecast the staff expenditures of a cancer unit. PMID- 22548006 TI - Hemoglobin trends and anemia treatment resulting from concomitant chemotherapy in community oncology clinics. AB - PURPOSE: This study describes changes in hemoglobin (Hb) levels in patients during chemotherapy before anemia treatment and in those who received no treatment, measuring time from chemotherapy initiation to Hb less than 10 g/dL and anemia treatment initiation. PATIENTS AND METHODS: This retrospective longitudinal cohort study used a database of outpatient oncology practice electronic medical records from January 1, 2006, to August 6, 2009. Unit of analysis was episode of chemotherapy care, beginning at initiation and including consecutive administrations within the next 60 days. Patients received two or more administrations of conventional chemotherapeutic agents, had a cancer diagnosis with at least 60 days of follow-up, and had no myelodysplastic syndrome. A total of 4,864 episodes (4,021 patients) met selection criteria, 73% with baseline Hb of 11 g/dL or greater and 60% receiving no anemia treatment. RESULTS: Episodes without anemia treatment increased from 44.6% (2006) to 77.8% (2009). Erythropoiesis-stimulating agent (ESA) use decreased from 45.4% (2006) to 11.5% (2009). Patients receiving transfusions increased from 3.4% to 8.7% (2006 to 2009; all P < .001). Total proportion of episodes with Hb less than 10 g/dL at anemia treatment increased from 16.2% to 93.1% during the same period (P < .001). Mean Hb values before anemia treatment decreased over time from 10.8 to 8.9 g/dL (2006 to 2009; P < .001). Overall, time from chemotherapy initiation to first anemia treatment increased from 24.7 to 36.9 days (2006 to 2009; P < .01). CONCLUSION: Results suggest increased restrictions were associated with decreased use of ESAs and increased use of transfusions as well as delays in anemia treatment and lower Hb levels before anemia treatment. Additional investigation of the overall impact of delayed treatments on long-term patient outcomes is warranted. PMID- 22548008 TI - Prevalence of self-reported memory problems in adult cancer survivors: a national cross-sectional study. AB - PURPOSE: Cancer and its treatments can impair cognitive function, especially memory, leading to diminished quality of life. Prevalence studies of cancer treatment-related memory impairment have not been conducted in the adult-onset cancer population. METHODS: To determine the prevalence of self-reported memory (SRM) problems in people with and without a history of cancer, we analyzed data from a large, nationally representative sample of the civilian, noninstitutionalized US population. Participants answered the yes-or-no question, "Are you limited in any way because of difficulty remembering or because you experience periods of confusion?" Age, sex, race/ethnicity, education, poverty, and general health were controlled. RESULTS: The sample (N = 9,819) consisted of 4,862 men and 4,957 women age 40 years and older. There were 1,938 blacks, 5,552 whites, 1,998 Hispanics, and 331 participants categorized as other race/multiracial. Of these, 1,305 reported a history of cancer; 8,514 did not. Memory problems were self-reported more often by participants with a history of cancer (14%) than by those without (8%). Having had cancer was independently associated with SRM impairment (adjusted odds ratio, 1.4; 95% CI, 1.08 to 1.83). Other predictors of memory impairment were age, lower education, lower income, and poorer general health (P < .01 for all). Participants with cancer had a 40% greater likelihood of reporting memory problems relative to those without cancer. CONCLUSION: Cancer history independently predicted SRM impairment. Prevalence of SRM impairment in people with a history of cancer/cancer treatment is substantial and increasing. Health care providers should assess and be ready to treat memory impairment in patients with a history of cancer. PMID- 22548007 TI - Cancer survivorship care plans: what can be learned from hospital discharge summaries? AB - The Institute of Medicine panel on cancer survivorship recommended that all patients with cancer and their primary care providers receive a written survivorship care plan that summarizes their initial treatment and provides guidance on post-treatment management. Cancer survivorship care plans aim to improve coordination of care and communication between providers as their patients transition from oncology to primary care settings. As such, survivorship care plans share similarities with hospital discharge summaries, focusing on improving the transition from inpatient to outpatient settings. In this article, we explore potential lessons that may be learned from hospital discharge summaries, which may be used to facilitate the development, implementation, and testing of survivorship care plans. PMID- 22548009 TI - Variation and consternation: access to unfunded cancer drugs in Canada. AB - PURPOSE: New anticancer drugs are improving outcomes for patients with cancer but at significant cost, and some publically funded health care systems have chosen not to fund these medications. Accessing these unfunded drugs concerns patients, challenges their physicians, and raises important policy and legal issues. We assessed Canadian medical oncologists' access to and attitudes toward accessing unfunded intravenous cancer drugs. METHODS: Two hundred twenty-two Canadian medical oncologists outside of Quebec were surveyed. RESULTS: Response rate was 62% (138 of 222). Respondents could access unfunded cancer drugs (49% at their government-funded hospitals; 70% at nongovernment-funded private infusion clinics), but access varied across the country. A majority of respondents (52% to 67%) were comfortable with accessing unfunded drugs in their own institutions and uncomfortable with accessing these drugs in private clinics in Canada or the United States (52% to 61%), but substantial minorities had opposing opinions. The majority of respondents felt all methods of accessing unfunded intravenous cancer drugs should be available (76% in their own center; 60% in private clinics) and used these methods to access these medications (81% in their own institution; 62% in private clinics). CONCLUSION: Access to effective but unfunded cancer drugs varies across Canada. Policymakers need to consider whether this is consistent with articulated values of the system and whether currently planned processes address these inconsistencies. Key stakeholders need to consider the merits of the different means of accessing these drugs to appropriately and fairly integrate access into publically funded health care systems like that of Canada and other systems like that of the United States, which could face similar limits in the future. PMID- 22548011 TI - Treatment patterns among medicaid-eligible women with breast cancer in georgia: are patterns different under the breast and cervical cancer prevention and treatment act? AB - PURPOSE: To investigate breast cancer treatment of patients enrolled under traditional Medicaid categories versus those in the Breast and Cervical Cancer Prevention and Treatment Act (BCCPTA) in Georgia. METHODS: Georgia Comprehensive Cancer Registry linked to Medicaid enrollment files were used to identify 2,048 enrollees with a primary cancer of the breast, of whom 1,046 were enrolled in BCCPTA, 674 were disabled, and 328 were in other Medicaid eligibility groups. Logistic regressions were used to estimate factors associated with the odds of receiving lumpectomy, mastectomy, or other surgery in addition to any drug regimen (hormonal or chemotherapy) and radiation. RESULTS: Women in BCCPTA were more likely to receive any treatment (odds ratio [OR] = 4.71; 95% CI, 2.48 to 8.96), any drug regimen (OR = 3.58; 95% CI, 2.32 to 5.51), any radiation (OR = 1.61; 95% CI, 1.15to 2.24), and any definitive surgery (OR = 2.52; 95% CI, 1.74 to 3.66) than the "other" eligibility group after controlling for covariates. There were no significant differences by eligibility group in the receipt of a lumpectomy versus a mastectomy. However, women in BCCPTA were more likely to receive more adjuvant follow-up after a mastectomy. CONCLUSION: The BCCPTA program in Georgia appears to create a quicker pathway for low-income, previously uninsured women with breast cancer to access services and, in turn, receive more treatment than women enrolled in the other, more traditional Medicaid eligibility groups. Yet the overall rate of adjuvant therapy, whether radiation, hormonal, or chemotherapy, appears to fall short of national criteria. This deserves attention in Georgia and, most likely, Medicaid programs in other states as well. PMID- 22548010 TI - Exposure to and intention to discuss cancer-related internet information among patients with breast cancer. AB - PURPOSE: Previous studies have reported a significant number of patients with breast cancer seek cancer-related information from the Internet. Most studies have asked whether a patient has ever read Internet information since her diagnosis. The purpose of this study was to assess the frequency with which patients with breast cancer come to physician appointments having recently read and intending to discuss cancer-related information from the Internet. PATIENTS AND METHODS: We asked 558 patients with breast cancer who were waiting to see their physicians about their experiences reading cancer-related information from the Internet and their intent to discuss the information in their current visit. RESULTS: Fifteen percent reported reading cancer-related Internet information in the past month. Patients who had read such information in the past month were younger, had been diagnosed more recently, and were more likely to be attending a new visit. Of those who had read in the past month, 45% reported intending to discuss what they had read with their physician. Nineteen percent of patients reported having ever read breast cancer-related Internet information since their diagnosis. CONCLUSION: The proportion of patients with breast cancer planning to discuss Internet information during their current physician visit was relatively small. Few characteristics were associated with recent Internet use or intent to discuss. PMID- 22548012 TI - US Food and Drug Administration Regulation of Medical Devices and Radiation Oncology: Can Reform Improve Safety? AB - Although radiation therapy is highly safe and effective in treating cancer, recent reports of dangerous radiation-related errors have focused a national spotlight on the field of radiation oncology and, more specifically, on the rapidly evolving and complex nature of radiation devices and how they are regulated. The purpose of this review is to explore the issues involved in medical device regulation in radiation oncology. We start with a general review of federal medical device regulation, including explanations of the legal and regulatory framework, and then discuss issues specific to radiation oncology with real-world examples. We also provide our thoughts on potential solutions and reforms to the current system, including better reporting of radiation-related errors in a centralized database, well-defined criteria for establishing substantial equivalence of a new device, and standard postmarket surveillance of radiation devices. Modern radiation therapy is a powerful tool that can help cure many patients' cancers and alleviate others' suffering with limited adverse effects. We must ensure that this promise is never compromised by avoidable mistakes. PMID- 22548014 TI - 2011 Focused Update of 2009 American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non-Small-Cell Lung Cancer. AB - ASCO produced the 2011 Focused Update based on phase III randomized clinical trials published on maintenance chemotherapy, addressing one question from the 2009 Guideline Update on chemotherapy for stage IV NSCLC: what is the optimal duration of first-line chemotherapy for stage IV NSCLC? PMID- 22548013 TI - Patterns of care for non-small-cell lung cancer at an academic institution affiliated with a national cancer institute-designated cancer center. AB - PURPOSE: Evidence-based treatment guidelines for non-small-cell lung cancer (NSCLC) exist to improve the quality of care for patients with this disease. However, how often evidence-based decisions are used for care of NSCLC is poorly understood. PATIENTS AND METHODS: We examined patterns of care and rate of adherence to evidence-based guidelines for 185 new NSCLC patients seen between 2007 and 2009. Evidence-based care status was determined for 150 patients. RESULTS: Eighty-one percent of the patients were white, the mean age was 66 years, 49% were women, 11% were never smokers, 83% had Eastern Cooperative Oncology Group performance status 0 to 1, 49.7% of tumors were adenocarcinomas, 57.1% of never smokers had tumors genotyped (EGFR, ALK, KRAS), and 13.3% participated in clinical trials. The rate of evidence-based treatment adherence was 94.1% (16 of 17), 100% (21 of 21) and 100% (36 of 36) in patients with stages I, II, and III NSCLC, respectively. Stage IV disease, with adherence of 76.3% (58 of 76), was correlated with a higher rate of nonadherence when compared with stages I-III (odds ratio 16.33; 95% CI, 1.94 to 137.73). In patients with stage IV disease, the rate of evidence-based adherence was 95% (72 of 76) for first line therapy, 95.2% (40 of 42) for second-line therapy, and only 33.3% (6 of 18) for third-line therapy (P < .001). There was no significant correlation between evidence-based adherence status and the patient's age, sex, performance status, smoking history, ethnicity, or the treating physician. CONCLUSION: These data point toward the need for improved evidence-based use of resources in the third line setting of stage IV NSCLC. PMID- 22548015 TI - Improving wait time for chemotherapy in an outpatient clinic at a comprehensive cancer center. AB - PURPOSE: We conducted our study at the Ambulatory Treatment Center (ATC) of the MD Anderson Cancer Center, a network of six outpatient treatment units for patients receiving infusion therapies. Excessive patient wait time for chemotherapy was a primary source of ATC patient dissatisfaction. ATC employees expressed frustration, because often, patients arrived physically on time but were not treatment ready. Additionally, ATC staff emphasized challenges associated with obtaining finalized treatment orders for prescheduled appointments (ie, placeholder appointments without associated physician treatment orders). We aimed to decrease mean patient wait time from check-in to treatment in one ATC unit by 25%. METHODS: We studied appointment cycle time in the ATC Green Unit, stratifying appointments by type (ie, prescheduled [no finalized treatment orders] and scheduled [finalized treatment orders]). We obtained mean wait times at baseline (control) and again after our intervention period. We conducted interviews and observations in ATC Green, from which we developed a three-part plan to reduce wait time: increase process efficiency within ATC Green, enhance communications with MD Anderson clinics and centers, and incorporate information technology applications. RESULTS: After our intervention, we observed a 15% decrease in wait time for patients with prescheduled appointments and a 29% decrease for those with scheduled appointments. Overall, there was a 26.8% reduction in mean patient wait time relative to baseline (control). CONCLUSION: We observed a significantly decreased mean patient wait time after implementing our intervention. This decrease may improve patient satisfaction, relieve employee frustration with appointment scheduling, and create opportunities for increasing institutional revenue. PMID- 22548017 TI - Acknowledgment of authors. PMID- 22548016 TI - Reduce risks to patients in your practice. PMID- 22548019 TI - Engaging referring physicians in the clinical trial process. AB - By building relationships with referring physicians and educating them about the clinical trial process, oncologists can help increase trial accrual among patients with cancer. PMID- 22548020 TI - A comparison between a SNOMED CT problem list and the ICD-10-CM/PCS HIPAA code sets. AB - In 2013 the United States will convert from the use of the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) to the use of the International Classification of Diseases, Tenth Revision, Clinical Modification/Procedure Coding System (ICD-10-CM/PCS). This study compares the approximately 5,000 terms in the July 2009 Clinical Observations Recording and Encoding (CORE) Problem List subset of the Systematized Nomenclature of Medicine Clinical Terms (SNOMED CT) terminology produced by the National Library of Medicine with terms found in the January 2009 versions of ICD-10-CM/PCS. The comparison was done by a single individual and used the internally defined concepts of "Exact," "Inexact," "Model" (one SNOMED CT term to many ICD-10-CM/PCS terms), "Not Elsewhere Classified," "Not Otherwise Specified," "Synonym," and "Not Found" to classify the CORE Problem List terms according to the quality of the match. Among the CORE Problem List terms, 6.0 percent were not found in ICD 10-CM/PCS, and 69.1 percent had equivalent ICD-10-CM/PCS terms. The 13.0 percent of terms classified as "Inexact" could also be used directly assuming some acceptable loss of clinical precision. The 11.9 percent of terms classified as "Model" represent differences that require rule-based mapping. The results of this study suggest that ICD-10-CM/PCS meets the intended design goal of increased clinical precision but studies are needed to precisely define the depth of coverage. PMID- 22548021 TI - Lessons learned from an ICD-10-CM clinical documentation pilot study. AB - On October 1, 2013, the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) will be mandated for use in the United States in place of the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). This new classification system will used throughout the nation's healthcare system for recording diagnoses or the reasons for treatment or care. A pilot study was conducted to determine whether current levels of inpatient clinical documentation provide the detail necessary to fully utilize the ICD-10-CM classification system for heart disease, pneumonia, and diabetes cases. The design of this pilot study was cross-sectional. Four hundred ninety-one de-identified records from two sources were coded using ICD-10-CM guidelines and codebooks. The findings of this study indicate that healthcare organizations need to assess clinical documentation and identify gaps. In addition, coder proficiency should be assessed prior to ICD-10-CM implementation to determine the need for further education and training in the biomedical sciences, along with training in the new classification system. PMID- 22548022 TI - Navigating regulatory change: preliminary lessons learned during the healthcare provider transition to ICD-10-CM/PCS. AB - This article presents the findings of a collaborative effort between the Georgetown University Student Consulting Team and Booz Allen Hamilton to interview healthcare providers undergoing the transition to the International Classification of Diseases, Tenth Revision, Clinical Modification/Procedure Coding System (ICD-10-CM/PCS). The goals of this study were to extract a common set of trends, challenges, and lessons learned surrounding the implementation of the ICD-10-CM/PCS code set and to produce actionable information that might serve as a resource for organizations navigating the transition to ICD-10-CM/PCS. The selected survey sample focused on a subset of large hospitals, integrated health systems, and other national industry leaders who are likely to have initiated the implementation process far in advance of the October 2013 deadline. Guided by a uniform survey tool, the team conducted a series of one-on-one provider interviews with department heads, senior staff members, and project managers leading ICD-10-CM/PCS conversion efforts from six diverse health systems. As expected, the integrated health systems surveyed seem to be on or ahead of schedule for the ICD-10-CM/PCS coding transition. However, results show that as of April 2010 most providers were still in the planning stages of implementation and were working to raise awareness within their organizations. Although individual levels of preparation varied widely among respondents, the study identified several trends, challenges, and lessons learned that will enable healthcare providers to assess their own status with respect to the industry and will provide useful insight into best practices for the ICD-10-CM/PCS transition. PMID- 22548023 TI - Preparing for ICD-10-CM/PCS: one payer's experience with general equivalence mappings (GEMs). AB - The International Classification of Diseases, Tenth Edition, Clinical Modification/Procedure Coding System (ICD-10-CM/PCS) has been mandated as the new code set to be used for medical coding in the United States beginning on October 1, 2013, replacing the use of the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). To assist in the transition from ICD 9-CM to ICD-10-CM/PCS, the National Center for Health Statistics developed bidirectional general equivalent mappings (GEMs) between the old and new code sets. This article looks at how the GEMs have been leveraged by Health Care Service Corporation (HCSC) to achieve the goal of transition to ICD-10-CM/PCS. The analysis examines the questions asked and lessons learned in the practical application of the GEMs for the translation of business rules and processes in order to promote a deeper understanding of the data issues involved in the transition from ICD-9-CM to ICD-10-CM/PCS from a payer's perspective. PMID- 22548024 TI - The road to ICD-10-CM/PCS implementation: forecasting the transition for providers, payers, and other healthcare organizations. AB - This article will examine the benefits and challenges of the US healthcare system's upcoming conversion to use of the International Classification of Diseases, Tenth Revision, Clinical Modification/Procedure Coding System (ICD-10 CM/PCS) and will review the cost implications of the transition. Benefits including improved quality of care, potential cost savings from increased accuracy of payments and reduction of unpaid claims, and improved tracking of healthcare data related to public health and bioterrorism events are discussed. Challenges are noted in the areas of planning and implementation, the financial cost of the transition, a shortage of qualified coders, the need for further training and education of the healthcare workforce, and the loss of productivity during the transition. Although the transition will require substantial implementation and conversion costs, potential benefits can be achieved in the areas of data integrity, fraud detection, enhanced cost analysis capabilities, and improved monitoring of patients' health outcomes that will yield greater cost savings over time. The discussion concludes with recommendations to healthcare organizations of ways in which technological advances and workforce training and development opportunities can ease the transition to the new coding system. PMID- 22548026 TI - Heart transplantation in congenital heart disease. PMID- 22548027 TI - Indications for heart transplantation in congenital heart disease. AB - In this review we have looked at indications for cardiac transplantation in congenital heart disease. An outline of the general principles of the use of transplant as a management strategy both as a first line treatment and following other surgical interventions is discussed. We explore the importance of the timing of patient referral and the evaluations undertaken, and how the results of these may vary between patients with congenital heart disease and patients with other causes of end-stage heart failure. The potential complications associated with patients with congenital heart disease need to be both anticipated and managed appropriately by an experienced team. Timing of transplantation in congenital heart disease is difficult to standardize as the group of patients is heterogeneous. We discuss the role and limitations of investigations such as BNP, 6 minute walk, metabolic exercise testing and self estimated physical functioning. We also discuss the suitability for listing. It is clear that congenital heart patients should not be considered to be at uniform high risk of death at transplant. Morbidity varies greatly in the congenital patient population with the failing Fontan circulation having a far higher risk than a failing Mustard circulation. However the underlying issue of imbalance between donor organ supply and demand needs to be addressed as transplant teams are finding themselves in the increasingly difficult situation of supporting growing numbers of patients with a diverse range of pathologies with declining numbers of donor organs. PMID- 22548029 TI - Immunologic considerations in heart transplantation for congenital heart disease. AB - Children and adults with congenital heart disease (CHD) can require interventions that result in immunologic alterations that are different than those seen in patients with cardiomyopathies. Patients with CHD can be exposed to heart surgeries, blood products, valved and non-valved allograft tissue, and mechanical circulatory support, all of which can alter the immunologic status of these patients. This change in immunologic status is most commonly manifested as the development of anti-human leukocyte antigen (HLA) antibodies. This review will delineate a) the causes of anti-HLA anti-body production (often referred to as allosensitization); b) preventive strategies for anti-HLA antibody production before transplantation; c) treatment strategies for those patients who develop anti-HLA antibodies before transplantation; d) consequences of HLA allosensitization after transplantation; and e) treatment of HLA allosensitization and antibody-mediated rejection after transplantation. PMID- 22548028 TI - Impact of pulmonary vascular resistances in heart transplantation for congenital heart disease. AB - Congenital heart disease is one of the major diagnoses in pediatric heart transplantation recipients of all age groups. Assessment of pulmonary vascular resistance in these patients prior to transplantation is crucial to determine their candidacy, however, it is frequently inaccurate because of their abnormal anatomy and physiology. This problem places them at significant risk for pulmonary hypertension and right ventricular failure post transplantation. The pathophysiology of pulmonary vascular disease in children with congenital heart disease depends on their pulmonary blood flow patterns, systemic ventricle function, as well as semilunar valves and atrioventricular valves structure and function. In our review we analyze the pathophysiology of pulmonary vascular disease in children with congenital heart disease and end-stage heart failure, and outline the state of the art pre-transplantation medical and surgical management to achieve reverse remodeling of the pulmonary vasculature by using pulmonary vasodilators and mechanical circulatory support. PMID- 22548030 TI - Heart transplantation for congenital heart disease in the first year of life. AB - Successful infant heart transplantation has now been performed for over 25 years. Assessment of long term outcomes is now possible. We report clinical outcomes for322 patients who received their heart transplant during infancy. Actuarial graft survival for newborn recipients is 59% at 25 years. Survival has improved in the most recent era. Cardiac allograft vasculopathy is the most important late cause of death with an actuarial incidence at 25 years of 35%. Post-transplant lymphoma is estimated to occur in 20% of infant recipients by25 years. Chronic kidney disease grade 3 or worse is present in 31% of survivors. The epidemiology of infant heart transplantation has changed through the years as the results for staged repair improved and donor resources remained stagnant. Most centers now employ staged repair for hypoplastic left heart syndrome and similar extreme forms of congenital heart disease. Techniques for staged repair, including the hybrid procedure, are described. The lack of donors is described with particular note regarding decreased donors due to newer programs for appropriate infant sleep positioning and infant car seats. ABO incompatible donors are a newer resource for maximizing donor resources, as is donation after circulatory determination of death and techniques to properly utilize more donors by expanding the criteria for what is an acceptable donor. An immunological advantage for the youngest recipients has long been postulated, and evaluation of this phenomenon may provide clues to the development of accommodation and/or tolerance. PMID- 22548032 TI - Heart transplantation in biventricular congenital heart disease: indications, techniques, and outcomes. AB - Heart transplantation is an accepted therapeutic modality for end-stage congenital heart disease for both biventricular and univentricular anomalies. Many transplant centers have pushed the limits of transplantation to include patients with high pulmonary vascular resistance, high panel reactive antibodies, positive cross-matches, and ABO-incompatibility. Excellent results have been possible, particularly with the development of improved diagnostic and therapeutic algorithms to prevent and treat rejection, infection, and post transplant lymphoproliferative disease. Late graft failure and chronic rejection remain vexing problems. The vast majority of patients with biventricular congenital heart disease have undergone prior cardiac surgical procedures. Indications for transplantation in this subgroup are primarily progressive refractory heart failure following prior cardiac surgical reconstructive procedures. Contraindications to transplantation mimic those for other forms of end-stage heart disease. A determination of pulmonary vascular resistance is important in listing patients with biventricular congenital heart disease for heart transplantation. Modifications in the implant technique are necessary and vary depending on underlying recipient anatomy. Risk factors for perioperative outcomes in patients with biventricular congenital heart disease include the need for reoperation, the degree of anatomic reconstruction necessary during the implant procedure, and the degree of antibody sensitization, in addition to a number of other recipient and donor factors. Postoperative outcomes and survival are very good but remain inferior to those with cardiomyopathy in most series. In conclusion, patients with end-stage biventricular congenital heart disease represent a complex group of patients for heart transplantation, and require careful evaluation and management to ensure optimal outcomes. PMID- 22548031 TI - Orthotopic heart transplantation in patients with univentricular physiology. AB - Parallel advancements in surgical technique, preoperative and postoperative care, as well as a better understanding of physiology in patients with duct-dependent pulmonary or systemic circulation and a functional single ventricle, have led to superb results in staged palliation of most complex congenital heart disease (CHD) [1]. The Fontan procedure and its technical modifications have resulted in markedly improved outcomes of patients with single ventricle anatomy [2,3,4]. The improved early survival has led to an exponential increase of the proportion of Fontan patients surviving long into adolescence and young adulthood [5]. Improved early and late survival has not yet abolished late mortality secondary to myocardial failure, therefore increasing the referrals for cardiac transplantation [6]. Interstage attrition [7] is moreover expected in staged palliation towards completion of a Fontan-type circulation, while Fontan failure represents a growing indication for heart transplantation [8]. Heart transplantation has therefore become the potential "fourth stage" [9] or a possible alternative to a high-risk Fontan operation [10] in a strategy of staged palliation for single ventricle physiology. Heart transplant barely accounts for 16% of pediatric solid organ transplants [11]. The thirteenth official pediatric heart transplantation report- 2010 [11] indicates that pediatric recipients received only 12.5% of the total reported heart transplants worldwide. Congenital heart disease is not only the most common recipient diagnosis, but also the most powerful predictor of 1-year mortality after OHT. Results of orthotopic heart transplantations (OHT) for failing single ventricle physiology are mixed. Some authors advocate excellent early and mid-term survival after OHT for failing Fontan [9], while others suggest that rescue-OHT after failing Fontan seems unwarranted [10]. Moreover, OHT outcome appears to be different according to the surgical staging towards the Fontan operation and surgical technique of Fontan completion [12].The focus of this report is a complete review of the recent literature on OHT for failing single ventricles, outlining the clinical issues affecting Fontan failure, OHT listing and OHT outcome. These data are endorsed reporting our experience with OHT for failing single ventricle physiology in recent years. PMID- 22548033 TI - Mechanical circulatory support for end-stage heart failure in repaired and palliated congenital heart disease. AB - Approximately one in one hundred children is born with congenital heart disease. Most can be managed with corrective or palliative surgery but a small group will develop severe heart failure, leaving cardiac transplantation as the ultimate treatment option. Unfortunately, due to the inadequate number of available donor organs, only a small number of patients can benefit from this therapy, and mortality remains high for pediatric patients awaiting heart transplantation, especially compared to adults. The purpose of this review is to describe the potential role of mechanical circulatory support in this context and to review current experience. For patients with congenital heart disease, ventricular assist devices are most commonly used as a bridge to cardiac transplantation, an application which has been shown to have several important advantages over medical therapy alone or support with extracorporeal membrane oxygenation, including improved survival to transplant, less exposure to blood products with less immune sensitization, and improved organ function. While these devices may improve wait list mortality, the chronic shortage of donor organs for children is likely to remain a problem into the foreseeable future. Therefore, there is great interest in the development of mechanical ventricular assist devices as potential destination therapy for congenital heart disease patients with end-stage heart failure. This review first discusses the experience with the currently available ventricular assist devices in children with congenital heart disease, and then follows to discuss what devices are under development and may reach the bedside soon. PMID- 22548035 TI - Psychosocial implications during adolescence for infant heart transplant recipients. AB - BACKGROUND & OBJECTIVES: As more heart transplant recipients survive into late adolescence, research addressing long-term psychosocial and neurodevelopmental outcomes is imperative. The limited literature available suggests risk for psychosocial difficulties and lower cognitive, academic, and neuropsychological functioning. This paper reviews topic-related literature and provides preliminary data examining psychosocial and neuropsychological functioning of adolescents who received their heart transplant during infancy. METHOD: This paper offers a literature review AND presents preliminary data from studies conducted through Loma Linda University Children's Hospital (LLUCH). Study one examined psychosocial functioning and quality of life of adolescent infant heart transplant recipients. In study two, cognitive, academic, and neuropsychological data were analyzed. RESULTS: Study 1: Overall psychosocial functioning fell in the Average range, however, a significant percentage of participants presented with difficulties on one or more of the psychosocial domains. Quality of life was also within normal limits, though concerns with general health and bodily discomfort were noted. Study 2: Cognitive functioning was assessed to be Below Average, with 43-62% of the participants demonstrating significant impairments. Neuropsychological functioning yielded significant weakness on language functioning, and mild weakness on visual-motor integration and executive functioning. CONCLUSION: While the majority of the participants demonstrate psychosocial resiliency, a subgroup present with difficulties suggesting the need for intervention. Cognitive/neuropsychological functioning suggests poorer functioning with patterns similar to other high-risk pediatric populations. These results are preliminary and further research on long-term psychosocial and neuropsychological development of pediatric heart transplant recipients is needed to better understand and ameliorate developmental trajectories. PMID- 22548034 TI - Postoperative care of the transplanted patient. AB - The successful delivery of optimal peri-operative care to pediatric heart transplant recipients is a vital determinant of their overall outcomes. The practitioner caring for these patients must be familiar with and treat multiple simultaneous issues in a patient who may have been critically ill preoperatively. In addition to the complexities involved in treating any child following cardiac surgery, caretakers of newly transplanted patients encounter multiple transplant specific issues. This chapter details peri-operative management strategies, frequently encountered early morbidities, initiation of immunosuppression including induction, and short-term outcomes. PMID- 22548036 TI - Potential collaboration with the private sector for the provision of ambulatory care in the Mekong region, Vietnam. AB - BACKGROUND: Over the past two decades, health insurance in Vietnam has expanded nationwide. Concurrently, Vietnam's private health sector has developed rapidly and become an increasingly integral part of the health system. To date, however, little is understood regarding the potential for expanding public-private partnerships to improve health care access and outcomes in Vietnam. OBJECTIVE: To explore possibilities for public-private collaboration in the provision of ambulatory care at the primary level in the Mekong region, Vietnam. DESIGN: We employed a mixed methods research approach. Qualitative methods included focus group discussions with health officials and in-depth interviews with managers of private health facilities. Quantitative methods encompassed facility assessments, and exit surveys of clients at the same private facilities. RESULTS: Discussions with health officials indicated generally favorable attitudes towards partnerships with private providers. Concerns were also voiced, regarding the over- and irrational use of antibiotics, and in terms of limited capacity for regulation, monitoring, and quality assurance. Private facility managers expressed a willingness to collaborate in the provision of ambulatory care, and private providers facilites were relatively well staffed and equipped. The client surveys indicated that 80% of clients first sought treatment at a private facility, even though most lived closer to a public provider. This choice was motivated mainly by perceptions of quality of care. Clients who reported seeking care at both a public and private facility were more satisfied with the latter. CONCLUSIONS: Public-private collaboration in the provision of ambulatory care at the primary level in Vietnam has substantial potential for improving access to quality services. We recommend that such collaboration be explored by Vietnamese policy-makers. If implemented, we strongly urge attention to effectively managing such partnerships, establishing a quality assurance system, and strengthening regulatory mechanisms. PMID- 22548037 TI - Successful Treatment of a Panniculitis-Like Primary Cutaneous T-Cell Lymphoma of the alpha/beta Type with Bexarotene. AB - Subcutaneous panniculitis-like T-cell lymphoma (SPTL) of the alpha/beta type is a rare subtype of non-Hodgkin's lymphoma of the skin. Although these tumors usually run an indolent course, disease-related morbidity is often severe. Clinical findings include subcutaneous tumors located on the extremities or trunk, often accompanied by systemic symptoms like fever or fatigue. Due to the low incidence of SPTL, no standardized therapy has been defined so far and there is currently no curative therapy available for this type of non-Hodgkin's lymphoma. By sharing our experience with bexarotene therapy, we present a safe and potentially improved treatment for patients with SPTL. In the case presented, bexarotene was able to induce remission even after recurrence of disease. PMID- 22548038 TI - Pityriasis lichenoides et varioliformis acuta: case report and review of the literature. AB - We report a case of a 63-year-old man hospitalized for a polymorphous generalized eruption consisting of maculopapules with peripheral scaling, vesicopustules, and ulceronecrotic and crusted lesions measuring 5-20 mm, localized on his trunk and extremities, particularly exuberant in the flexural area. Histopathology showed necrotic keratinocytes with exocytosis of red blood cells and lymphocytes and a dermal perivascular and periadnexal inflammatory infiltrate, composed of CD8+/CD4 /CD30- T cells, indicating the clinical diagnosis of pityriasis lichenoides et varioliformis acuta. He was treated with erythromycin and methylprednisolone reduced gradually over 5 months, with a slow but complete response; the patient was without lesions after 2 years of follow-up. The authors want to remind of this rare entity which may present difficulties in diagnosis and therapy. PMID- 22548039 TI - Cutaneous small vessel vasculitis accompanied by pustulosis palmaris et plantaris. AB - We present the case of a 64-year-old woman who has suffered from pustulosis palmaris et plantaris for 10 years. At the first examination, many erythematous lesions with purpura, blood crusts, and blisters were present in the lower legs and dorsum of the feet. Painful swelling in the sternal region and dorsal pain were also noted. Elevation of the CRP and myogenic enzyme levels, and liver and renal dysfunctions were noted on blood testing. Histopathologically, leukocytoclastic vasculitis was noted in small blood vessels in the whole dermal layers, and deposition of IgM and C3 in the vascular wall was detected by the direct immunofluorescence techniques. Based on these findings, cutaneous small vessel vasculitis was diagnosed. Because the patient complained of a toothache during the clinical course, an X-ray examination was performed. On pantomography, a radicular cyst and apical periodontitis were noted. The tooth symptoms changed with exacerbation and remission of the skin symptoms. These findings indicate that odontogenic infection is very likely to be a cause of cutaneous small vessel vasculitis in a manner similar to pustulosis palmaris et plantaris. PMID- 22548040 TI - Toxic epidermal necrolysis in an irradiated patient treated with a nanocrystalline silver dressing. AB - Toxic epidermal necrolysis syndrome is a severe exfoliative condition, which may be triggered by anticonvulsant medication. We report a case of toxic epidermal necrolysis syndrome in a 43-year-old female who was receiving radiotherapy for brain metastases from a recurring breast cancer and phenytoin. She had 80% total body surface area involvement and recovered successfully with the application of a nanocrystalline silver dressing. PMID- 22548041 TI - A Case of Mycobacterial Skin Disease Caused by Mycobacterium peregrinum, and a Review of Cutaneous Infection. AB - An 83-year-old Japanese man presented with a 2-month history of symptomatic nodules on the left hand. He was not in an immunocompromised condition and reported no causal events. A biopsy specimen demonstrated granulomatous tissue with mixed cell infiltration consisting of neutrophils, histiocytes, lymphocytes, and multinuclear giant cells. No bacillus was detected by PAS, acid-fast stain, immunofluorescent stain or polymerase chain reaction analysis. The isolate was found to be a rapidly growing mycobacterium after 4 weeks of incubation at 25 degrees C on an Ogawa egg slant. Mycobacterium peregrinum was isolated by DNA-DNA hybridization analysis, 16S rRNA gene sequence, and by its production of 3-day arylsulfatase. The patient received 200 mg oral minocycline for 28 weeks. The lesion disappeared after 10 weeks of this treatment. PMID- 22548042 TI - Cystoid macular edema associated with oral antineoplastic agent s-1 in a patient with diabetic retinopathy. AB - A 60-year-old man with neovascular glaucoma due to diabetic retinopathy received an intravitreal injection of 1.25 mg bevacizumab (IVB) followed by extensive panretinal photocoagulation in the right eye. The anterior segment neovascularization regressed within 10 days after IVB. One and a half months later, the patient underwent gastrectomy for stage IIIb gastric cancer. Two months later, he was started on S-1 orally (100 mg/day for 48, 26, and 32 consecutive days in the first, second, and third treatment cycle, respectively). The interval between the first and second treatment cycle was 20 days and between the second and third cycle it was 24 days. The patient developed anemia and diarrhea. At the end of the second S-1 cycle, cystoid macular edema developed in the right eye, although diabetic retinopathy and neovascular glaucoma were stable. Macular edema persisted for 5 months despite another IVB, and disappeared 3 months after termination of S-1 therapy. The time course of the magnitude of macular edema correlated well with the severity of anemia. The macular edema was possibly associated with anemia, which is a major side effect of S-1. Further studies are warranted to investigate the relationship between anemia and macular edema in patients with diabetic retinopathy. PMID- 22548043 TI - Visual Dysfunction of Type I and VI Mucopolysaccharidosis Patients Evaluated with Visual Evoked Cortical Potential. AB - PURPOSE: To evaluate the visual system of patients suffering from type I or VI mucopolysaccharidosis (MPS) by recording the visual evoked cortical potential (VECP). METHODS: Two patients with MPS VI and 2 patients with MPS I were tested before and after enzyme replacement therapy (ERT). A control group of 20 subjects was tested for statistical comparison. VECP was elicited by monocular stimulation with 1-Hz phase-reversal checkerboard patterns at 0.5 and 2 cycles per degree and with 16 degrees of visual field. In all patients, both eyes were tested. VECP amplitude and latency were measured and compared with tolerance limits obtained from controls. RESULTS: MPS I and VI patients have a severe visual impairment that can be quantified by measuring VECPs. Even after several weeks of ERT, the visual impairment remained unaltered, indicating that the treatment had no significant influence on the visual conditions of MPS patients. Visual responses to high spatial frequencies were more deeply impaired than responses to low spatial frequencies. This can be explained by the kind of damage in the visual system that preferentially targets the eye optics. CONCLUSION: VECPs can be used to monitor the degree of visual impairment of MPS patients and to check ERT efficacy. PMID- 22548044 TI - The role of optical coherence tomography in an atypical case of oculocutaneous albinism: a case report. AB - BACKGROUND: Oculocutaneous albinism is a group of autosomal recessive disorders featuring hypopigmentation of the hair, skin and eyes. Ocular signs associated with the disease are nystagmus, decreased visual acuity, hypopigmentation of the retina, foveal hypoplasia, translucency of the iris, macular transparency, photophobia and abnormal decussation of nerve fibers at the chiasm. CASE REPORT: An 8-year-old Caucasian girl presented to our clinic 'Referral Center for Hereditary Retinopathies' of the Second University of Naples with a diagnosis of Stargardt disease and a progressive reduction in visual acuity in both eyes. She underwent a complete ophthalmic examination including standard electroretinography and optical coherence tomography (OCT). A molecular analysis was also performed. Best-corrected visual acuity was 20/30 in the right eye and 20/40 in the left eye. Biomicroscopy of the anterior segment revealed a transparent cornea, in situ and transparent lens and normally pigmented iris. A mild diffuse depigmentation and macular dystrophy were observed at fundus examination. Standard electroretinography showed normal scotopic and photopic responses. OCT revealed high reflectivity across the fovea without depression. The typical OCT pattern led us to direct the molecular analysis towards the genes involved in oculocutaneous albinism. The molecular analysis identified mutations in the TYR gene. CONCLUSION: In this case, the role of OCT was crucial in guiding the molecular analysis for the diagnosis of albinism. OCT is therefore instrumental in similar cases that do not present typical characteristics of a disease. The case also proves the relevance of molecular analysis to confirm clinical diagnoses in hereditary retinal diseases. PMID- 22548045 TI - Refractory coats' disease of adult onset. AB - PURPOSE: We present the case of an 18-year-old Caucasian male with a unilateral macular star and retinal vascular anomalies compatible with adult onset Coats' disease. METHODS: Diagnosis was based on fundoscopic, fluorescein angiography and optical coherence tomography findings. RESULTS: The patient presented to our emergency department with complaints of low vision in his left eye (LE) detected 10 days before. The best-corrected visual acuity in the LE was 20/50. Fundoscopy of the LE evidenced a complete macular star. Optical coherence tomography showed increased retinal thickness, infiltration of the retinal wall, and detachment of the neuroepithelium. Angiography revealed no appreciable diffusion in the macula. Above the superior temporal (ST) arcade, anomalies in the retinal vasculature were found, with interruption of the peripheral vessels and vessels which were 'sausage'-like. After 1 month, the LE vision evolved to hand movements. Laser photocoagulation was performed in the ST quadrant. Intravitreal injection of bevacizumab 1.25 mg/0.05 ml and photodynamic therapy were performed without any significant changes, progression of ST serous detachment of the neuroepithelium, and finally progression to macular fibrosis. DISCUSSION: Coats' disease is usually diagnosed in childhood, but rare cases may occur in adults. Those cases usually have a more indolent course which was not observed in our patient. When there is macular involvement, prognosis is more guarded, despite treatment. PMID- 22548046 TI - Adult coats' disease successfully managed with the dexamethasone intravitreal implant (ozurdex(r)) combined with retinal photocoagulation. AB - PURPOSE: To report a case of Coats' disease managed with the dexamethasone intravitreal implant Ozurdex((r)) (Allergan, Inc., Irvine, Calif., USA) combined with retinal photocoagulation. METHODS: A 46-year-old female with 20/200 visual acuity was diagnosed with Coats' disease with secondary retinal vasoproliferative tumor. An initial approach was performed with an intravitreal injection of the sustained-release dexamethasone implant Ozurdex. After reattachment of the retina, the telangiectatic vessels were treated with laser photocoagulation. RESULTS: The patient's visual acuity improved to 20/25 after the intravitreal Ozurdex. No further recurrences of exudation were evident through the 12-month follow-up. CONCLUSIONS: Ozurdex may be an effective initial therapeutic approach for Coats' disease with immediate anatomical response and visual improvement. PMID- 22548047 TI - High Performance 3D PET Reconstruction Using Spherical Basis Functions on a Polar Grid. AB - Statistical iterative methods are a widely used method of image reconstruction in emission tomography. Traditionally, the image space is modelled as a combination of cubic voxels as a matter of simplicity. After reconstruction, images are routinely filtered to reduce statistical noise at the cost of spatial resolution degradation. An alternative to produce lower noise during reconstruction is to model the image space with spherical basis functions. These basis functions overlap in space producing a significantly large number of non-zero elements in the system response matrix (SRM) to store, which additionally leads to long reconstruction times. These two problems are partly overcome by exploiting spherical symmetries, although computation time is still slower compared to non overlapping basis functions. In this work, we have implemented the reconstruction algorithm using Graphical Processing Unit (GPU) technology for speed and a precomputed Monte-Carlo-calculated SRM for accuracy. The reconstruction time achieved using spherical basis functions on a GPU was 4.3 times faster than the Central Processing Unit (CPU) and 2.5 times faster than a CPU-multi-core parallel implementation using eight cores. Overwriting hazards are minimized by combining a random line of response ordering and constrained atomic writing. Small differences in image quality were observed between implementations. PMID- 22548048 TI - Fagopyrum tataricum (buckwheat) improved high-glucose-induced insulin resistance in mouse hepatocytes and diabetes in fructose-rich diet-induced mice. AB - Fagopyrum tataricum (buckwheat) is used for the treatment of type 2 diabetes mellitus in Taiwan. This study was to evaluate the antihyperglycemic and anti insulin resistance effects of 75% ethanol extracts of buckwheat (EEB) in FL83B hepatocytes by high-glucose (33 mM) induction and in C57BL/6 mice by fructose rich diet (FRD; 60%) induction. The active compounds of EEB (100 MUg/mL; 50 mg/kg bw), quercetin (6 MUg/mL; 3 mg/kg bw), and rutin (23 MUg/mL; 11.5 mg/kg bw) were also employed to treat FL83B hepatocytes and animal. Results indicated that EEB, rutin, and quercetin + rutin significantly improved 2-NBDG uptake via promoting Akt phosphorylation and preventing PPARgamma degradation caused by high-glucose induction for 48 h in FL83B hepatocytes. We also found that EEB could elevate hepatic antioxidant enzymes activities to attenuate insulin resistance as well as its antioxidation caused by rutin and quercetin. Finally, EEB also inhibited increases in blood glucose and insulin levels of C57BL/6 mice induced by FRD. PMID- 22548050 TI - A pair of partially overlapping Arabidopsis genes with antagonistic circadian expression. AB - A large number of plant genes are aligned with partially overlapping genes in antisense orientation. Transcription of both genes would therefore favour the formation of double-stranded RNA, providing a substrate for the RNAi machinery, and enhanced antisense transcription should therefore reduce sense transcript levels. We have identified a gene pair that resembles a model for antisense-based gene regulation as a T-DNA insertion into the antisense gene causes a reduction in antisense transcript levels and an increase in sense transcript levels. The same effect was, however, also observed when the two genes were inserted as transgenes into different chromosomal locations, independent of the sense and antisense gene being expressed individually or jointly. Our results therefore indicate that antagonistic changes in sense/antisense transcript levels do not necessarily reflect antisense-mediated regulation. More likely, the partial overlap of the two genes may have favoured the evolution of antagonistic expression patterns preventing RNAi effects. PMID- 22548049 TI - It is all in the blood: the multifaceted contribution of circulating progenitor cells in diabetic complications. AB - Diabetes mellitus (DM) is a worldwide growing disease and represents a huge social and healthcare problem owing to the burden of its complications. Micro- and macrovascular diabetic complications arise from excess damage through well known biochemical pathways. Interestingly, microangiopathy hits the bone marrow (BM) microenvironment with features similar to retinopathy, nephropathy and neuropathy. The BM represents a reservoir of progenitor cells for multiple lineages, not limited to the hematopoietic system and including endothelial cells, smooth muscle cells, cardiomyocytes, and osteogenic cells. All these multiple progenitor cell lineages are profoundly altered in the setting of diabetes in humans and animal models. Reduction of endothelial progenitor cells (EPCs) along with excess smooth muscle progenitor (SMP) and osteoprogenitor cells creates an imbalance that promote the development of micro- and macroangiopathy. Finally, an excess generation of BM-derived fusogenic cells has been found to contribute to diabetic complications in animal models. Taken together, a growing amount of literature attributes to circulating progenitor cells a multi-faceted role in the pathophysiology of DM, setting a novel scenario that puts BM and the blood at the centre of the stage. PMID- 22548051 TI - Capsule Endoscopy to Detect Normally Positioned Duodenal Papilla: Performance Comparison of SB and SB2. AB - Purpose. PillCam SB2 capsule endoscopy, an upgraded version of widely used SB capsule endoscopy, was examined for its performance by comparing with SB. Methods. Examinees with various indications were enrolled for SB2 capsule endoscopy; subjects were also enlisted for the old SB capsule endoscopy. Number of photo images containing papilla of Vater was counted. Shape of the papilla seen in each image was evaluated by scoring 3 (fully observable papilla), 2 (more than half outline), or 1 (less than half outline) points. Images obtained from SB and SB2 were also subjectively compared; resolution and brightness were scored by six experienced endoscopists. Results. Baseline characteristics of two study groups (n = 30 each) were not significantly different. Number of images of the papilla revealed to show similar results between SB (3.1 +/- 1.1, range 1~5) and SB2 (3.1 +/- 1.5, range 1~8) (P = 0.62). The maximum points of outline of papilla evaluated from each subject were also similar between two groups. New SB2 revealed to be superior to SB in terms of resolution but not significantly different in brightness. Conclusion. Our study showed that superiority of SB2 over SB is rather marginal on examining duodenal papilla. PMID- 22548052 TI - Pharmacokinetics of Hyperthermic Intrathoracic Chemotherapy following Pleurectomy and Decortication. AB - In patients with pseudomyxoma peritonei or peritoneal mesothelioma, direct extension of disease through the hemidiaphragm may result in an isolated progression of tumor within the pleural space. We monitored the intrapleural and plasma levels of mitomycin C and doxorubicin by HPLC assay in order to determine the pharmacokinetic behavior of this intracavitary use of chemotherapy. Our results showed a persistent high concentration of intrapleural drug as compared to plasma concentrations. The increased exposure for mitomycin C was 96, and the increased exposure for doxorubicin was 241. When the clearance of chemotherapy from the thoracic cavity was compared to clearance from the abdomen and pelvis, there was a considerably more rapid clearance from the abdomen as compared to the thorax. The pharmacologic study of intrapleural chemotherapy in these patients provides a strong pharmacologic rationale for regional chemotherapy in this group of patients. PMID- 22548053 TI - Progress and challenges in colorectal cancer screening. AB - Although faecal and endoscopic tests appear to be effective in reducing colorectal cancer incidence and mortality, further technological and organizational advances are expected to improve the performance and acceptability of these tests. Several attempts to improve endoscopic technology have been made in order to improve the detection rate of neoplasia, especially in the proximal colon. Based on the latest evidence on the long-term efficacy of screening tests, new strategies including endoscopic and faecal modalities have also been proposed in order to improve participation and the diagnostic yield of programmatic screening. Overall, several factors in terms of both efficacy and costs of screening strategies, including the high cost of biological therapy for advanced colorectal cancer, are likely to affect the cost-effectiveness of CRC screening in the future. PMID- 22548054 TI - Health-related quality of life in children and adolescents with celiac disease: from the perspectives of children and parents. AB - Aim. To examine how celiac children and adolescents on gluten-free diet valued their health-related quality of life, and if age and severity of the disease at onset affected the children's self-valuation later in life. We also assessed the parents' valuation of their child's quality of life. Methods. The DISABKIDS Chronic generic measure, short versions for both children and parents, was used on 160 families with celiac disease. A paediatric gastroenterologist classified manifestations of the disease at onset retrospectively. Results. Age or sex did not influence the outcome. Children diagnosed before the age of five scored higher than children diagnosed later. Children diagnosed more than eight years ago scored higher than more recently diagnosed children, and children who had the classical symptoms of the disease at onset scored higher than those who had atypical symptoms or were asymptomatic. The parents valuated their children's quality of life as lower than the children did. Conclusion. Health-related quality of life in treated celiac children and adolescents was influenced by age at diagnosis, disease severity at onset, and years on gluten-free diet. The disagreement between child-parent valuations highlights the importance of letting the children themselves be heard about their perceived quality of life. PMID- 22548055 TI - The Interactions between Insulin and Androgens in Progression to Castrate Resistant Prostate Cancer. AB - An association between the metabolic syndrome and reduced testosterone levels has been identified, and a specific inverse relationship between insulin and testosterone levels suggests that an important metabolic crosstalk exists between these two hormonal axes; however, the mechanisms by which insulin and androgens may be reciprocally regulated are not well described. Androgen-dependant gene pathways regulate the growth and maintenance of both normal and malignant prostate tissue, and androgen-deprivation therapy (ADT) in patients exploits this dependence when used to treat recurrent and metastatic prostate cancer resulting in tumour regression. A major systemic side effect of ADT includes induction of key features of the metabolic syndrome and the consistent feature of hyperinsulinaemia. Recent studies have specifically identified a correlation between elevated insulin and high-grade PCa and more rapid progression to castrate resistant disease. This paper examines the relationship between insulin and androgens in the context of prostate cancer progression. Prostate cancer patients present a promising cohort for the exploration of insulin stabilising agents as adjunct treatments for hormone deprivation or enhancers of chemosensitivity for treatment of advanced prostate cancer. PMID- 22548057 TI - Pilot study of an individualised early postpartum intervention to increase physical activity in women with previous gestational diabetes. AB - Optimal strategies to prevent progression towards overt diabetes in women with recent gestational diabetes remain ill defined. We report a pilot study of a convenient, home based exercise program with telephone support, suited to the early post-partum period. Twenty eight women with recent gestational diabetes were enrolled at six weeks post-partum into a 12 week randomised controlled trial of Usual Care (n = 13) versus Supported Care (individualised exercise program with regular telephone support; n = 15). Baseline characteristics (Mean +/- SD) were: Age 33 +/- 4 years; Weight 80 +/- 20 kg and Body Mass Index (BMI) 30.0 +/ 9.7 kg/m(2). The primary outcome, planned physical activity {Median (Range)}, increased by 60 (0-540) mins/week in the SC group versus 0 (0-580) mins/week in the UC group (P = 0.234). Walking was the predominant physical activity. Body weight, BMI, waist circumference, % body fat, fasting glucose and insulin did not change significantly over time in either group. This intervention designed to increase physical activity in post-partum women with previous gestational diabetes proved feasible. However, no measurable improvement in metabolic or biometric parameters was observed over a three month period. PMID- 22548056 TI - Clinical perspectives of urocortin and related agents for the treatment of cardiovascular disease. AB - The effects of corticotropin-releasing hormone, also known as corticotropin releasing factor (CRF), on the cardiovascular system have been intensively researched since its discovery. Moreover, the actions of urocortin (Ucn) I on the cardiovascular system have also been intensively scrutinized following the cloning and identification of its receptor, CRF receptor type 2 (CRFR2), in peripheral tissues including the heart. Given the cardioprotective actions of CRFR2 ligands, the clinical potential of not only Ucn I but also Ucn II and III, which were later identified as more specific ligands for CRFR2, has received considerable attention from researchers. In addition, recent work has indicated that CRF type 1 receptor may be also involved in cardioprotection against ischemic/reperfusion injury. Here we provide a historical overview of research on Ucn I and related agents, their effects on the cardiovascular system, and the clinical potential of the use of such agents to treat cardiovascular diseases. PMID- 22548058 TI - Early Response to Dexamethasone as Prognostic Factor: Result from Indonesian Childhood WK-ALL Protocol in Yogyakarta. AB - Early response to treatment has been shown to be an important prognostic factor of childhood acute lymphoblastic leukemia (ALL) patients in Western studies. We studied this factor in the setting of a low-income province in 165 patients treated on Indonesian WK-ALL-2000 protocol between 1999 and 2006. Poor early response, defined as a peripheral lymphoblasts count of >=1000/MUL after 7 days of oral dexamethasone plus one intrathecal methotrexate (MTX), occurred in 19.4% of the patients. Poor responders showed a higher probability of induction failures compared to good responders (53.1% versus 23.3%, P < 0.01), higher probability of resistant disease (15.6% versus 4.5%, P = 0.02), shorter disease free survival (P = 0.034; 5-year DFS: 24.9% +/- 12.1% versus 48.6% +/- 5.7%), and shorter event-free survival (P = 0.002; 5-year EFS: 9.7% +/- 5.3% versus 26.3% +/ 3.8%). We observed that the percentage of poor responders in our setting was higher than reported for Western countries with prednisone or prednisolone as the steroids. The study did not demonstrate a significant additive prognostic value of early response over other known risk factors (age and white blood cell count) for DFS and only a moderately added value for EFS. PMID- 22548059 TI - Impact of HIV Infection on Medicare Beneficiaries with Lung Cancer. AB - The incidence of lung cancer among individuals infected with the human immunodeficiency virus (HIV) is elevated compared to that among the general population. This study examines the prevalence of HIV and its impact on outcomes among Medicare beneficiaries who are 65 years of age or older and were diagnosed with nonsmall cell lung cancer (NSCLC) between 1997 and 2008. Prevalence of HIV was estimated using the Poisson point estimate and its 95% confidence interval. Relative risks for potential risk factors were estimated using the log-binomial model. A total of 111,219 Medicare beneficiaries met the study criteria. The prevalence of HIV was 156.4 per 100,000 (95% CI: 140.8 to 173.8) and has increased with time. Stage at NSCLC diagnosis did not vary by HIV status. Mortality rates due to all causes were 44%, 76%, and 88% for patients with stage I/II, III, and IV NSCLC, respectively. Across stages of disease, there was no difference between those who were HIV-infected and those who were not with respect to overall mortality. HIV patients, however, were more likely to die of causes other than lung cancer than their immunocompetent counterparts. PMID- 22548061 TI - Resistance of Subtype C HIV-1 Strains to Anti-V3 Loop Antibodies. AB - HIV-1's subtype C V3 loop consensus sequence exhibits increased resistance to anti-V3 antibody-mediated neutralization as compared to the subtype B consensus sequence. The dynamic 3D structure of the consensus C V3 loop crown, visualized by ab initio folding, suggested that the resistance derives from structural rigidity and non-beta-strand secondary protein structure in the N-terminal strand of the beta-hairpin of the V3 loop crown, which is where most known anti-V3 loop antibodies bind. The observation of either rigidity or non-beta-strand structure in this region correlated with observed resistance to antibody-mediated neutralization in a series of chimeric pseudovirus (psV) mutants. The results suggest the presence of an epitope-independent, neutralization-relevant structural difference in the antibody-targeted region of the V3 loop crown between subtype C and subtype B, a difference that we hypothesize may contribute to the divergent pattern of global spread between these subtypes. As antibodies to a variable loop were recently identified as an inverse correlate of risk for HIV infection, the structure-function relationships discussed in this study may have relevance to HIV vaccine research. PMID- 22548060 TI - Molecular Understanding of HIV-1 Latency. AB - The introduction of highly active antiretroviral therapy (HAART) has been an important breakthrough in the treatment of HIV-1 infection and has also a powerful tool to upset the equilibrium of viral production and HIV-1 pathogenesis. Despite the advent of potent combinations of this therapy, the long lived HIV-1 reservoirs like cells from monocyte-macrophage lineage and resting memory CD4+ T cells which are established early during primary infection constitute a major obstacle to virus eradication. Further HAART interruption leads to immediate rebound viremia from latent reservoirs. This paper focuses on the essentials of the molecular mechanisms for the establishment of HIV-1 latency with special concern to present and future possible treatment strategies to completely purge and target viral persistence in the reservoirs. PMID- 22548062 TI - Surface Hardness of Resin Cement Polymerized under Different Ceramic Materials. AB - Objectives. To evaluate the surface hardness of two light-cured resin cements polymerized under different ceramic discs. Methods. 40 experimental groups of 2 light-cured resin cement specimens (Variolink Veneer and NX3) were prepared and polymerized under 5 different ceramic discs (IPS e.max Press HT, LT, MO, HO, and Cercon) of 4 thicknesses (0.5, 1.0, 1.5, and 2.0 mm), Those directly activated of both resin cements were used as control. After light activation and 37 degrees C storage in an incubator, Knoop hardness measurements were obtained at the bottom. The data were analyzed with three-way ANOVA, t-test, and one-way ANOVA. Results. The KHN of NX3 was of significantly higher than that of Variolink Veneer (P < 0.05). The KHN of resin cement polymerized under different ceramic types and thicknesses was significant difference (P < 0.05). Conclusion. Resin cements polymerized under different ceramic materials and thicknesses showed statistically significant differences in KHN. PMID- 22548063 TI - Cultivable anaerobic microbiota of infected root canals. AB - Objective. Periapical periodontitis is an infectious and inflammatory disease of the periapical tissues caused by oral bacteria invading the root canal. In the present study, profiling of the microbiota in infected root canals was performed using anaerobic culture and molecular biological techniques for bacterial identification. Methods. Informed consent was obtained from all subjects (age ranges, 34-71 years). Nine infected root canals with periapical lesions from 7 subjects were included. Samples from infected root canals were collected, followed by anaerobic culture on CDC blood agar plates. After 7 days, colony forming units (CFU) were counted and isolated bacteria were identified by 16S rRNA gene sequencing. Results. The mean bacterial count (CFU) in root canals was (0.5 +/- 1.1) * 10(6) (range 8.0 * 10(1)-3.1 * 10(6)), and anaerobic bacteria were predominant (89.8%). The predominant isolates were Olsenella (25.4%), Mogibacterium (17.7%), Pseudoramibacter (17.7%), Propionibacterium (11.9%) and Parvimonas (5.9%). Conclusion. The combination of anaerobic culture and molecular biological techniques makes it possible to analyze rapidly the microbiota in infected root canals. The overwhelming majority of the isolates from infected root canals were found to be anaerobic bacteria, suggesting that the environment in root canals is anaerobic and therefore support the growth of anaerobes. PMID- 22548064 TI - Cone-beam computed tomography and radiographs in dentistry: aspects related to radiation dose. AB - Introduction. The aim of this study was to discuss the radiation doses associated with plain radiographs, cone-beam computed tomography (CBCT), and conventional computed tomography (CT) in dentistry, with a special focus on orthodontics. Methods. A systematic search for articles was realized by MEDLINE from 1997-March 2011. Results. Twenty-seven articles met the established criteria. The data of these papers were grouped in a table and discussed. Conclusions. Increases in kV, mA, exposure time, and field of view (FOV) increase the radiation dose. The dose for CT is greater than other modalities. When the full-mouth series (FMX) is performed with round collimation, the orthodontic radiographs transmit higher dose than most of the large FOV CBCT, but it can be reduced if used rectangular collimation, showing lower effective dose than large FOV CBCT. Despite the image quality, the CBCT does not replace the FMX. In addition to the radiation dose, image quality and diagnostic needs should be strongly taken into account. PMID- 22548065 TI - Paternal Benzo[a]pyrene Exposure Modulates MicroRNA Expression Patterns in the Developing Mouse Embryo. AB - Little attention has been given to how microRNA expression is affected by environmental contaminants exposure. We investigate the effects of paternal exposure to benzo[a]pyrene (B[a]P) on miRNA expression in the developing mouse embryo. Male mice were exposed to B[a]P (150 mg/kg i.p.), and their sperm was used four days later in in-vitro fertilization experiments. Twenty embryos each from 2-, 8-cell and the blastocyst stage were used for genome-wide miRNA expression profiling. Paternal exposure to B[a]P affected the expression of several miRNAs, and the target genes for some of the dysregulated miRNAs were enriched in many different pathways that are likely to be relevant for the developing mouse embryo. By linking the miRNA target genes to publicly available databases, we identified some miRNA target genes that may serve as global markers of B[a]P-mediated genotoxic stress. The dysregulated miRNAs may provide valuable knowledge about potential transgenerational effects of sublethal exposure to chemicals. PMID- 22548066 TI - Grey zone lymphomas: lymphomas with intermediate features. AB - The current classification of lymphoid neoplasms is based on clinical information, morphology, immunophenotype, and molecular genetic characteristics. Despite technical and scientific progress, some aggressive B-cell lymphomas with features overlapping between two different types of lymphomas remain difficult to classify. The updated 2008 World Health Organization (WHO) classification of Tumours of the Hematopoietic and Lymphoid Tissues has addressed this problem by creation of two new provisional categories of B-cell lymphomas, unclassifiable; one with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma and the second with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma. We review here the diagnostic criteria of these two provisional entities and discuss new scientific findings in light of the 2008 WHO classification. PMID- 22548068 TI - Surgical aspect of facial nerve disorders. PMID- 22548067 TI - Epidemiology, Diagnosis, and Treatment of HIV-Associated Non-Hodgkin Lymphoma in Resource-Limited Settings. AB - Lymphoma was a common complication of HIV infection in the pre-antiretroviral era, and the incidence of HIV-associated lymphoma has dropped dramatically since the introduction of combination antiretroviral therapy (cART) in resource-rich regions. Conversely, lymphoma is an increasingly common complication of HIV infection in resource-limited settings where the prevalence of HIV infection is high. Relatively little is known, however, about the true incidence and optimal treatment regimens for HIV-associated lymphoma in resource-poor regions. We review the epidemiology, diagnosis, and treatment of HIV-associated non-Hodgkin lymphoma in developing nations and highlight areas for further research that may benefit care in both settings. Examples include risk modification and dose modification of chemotherapy based on HIV risk factors, improving our understanding of the current burden of disease through national cancer registries, and developing cost-effective hematopathological diagnostic strategies to optimize care delivery and maximize use of available chemotherapy. PMID- 22548069 TI - Noncleft velopharyngeal insufficiency: etiology and need for surgical treatment. AB - Objective. Velopharyngeal insufficiency (VPI) occurs frequently in cleft palate patients. VPI also occurs in patients without cleft palate, but little is known about this patient population and this presents a diagnostic dilemma. Our goal is to review the etiology of noncleft VPI and the surgical treatment involved. Design/Patients. A retrospective review of VPI patients from 1990 to 2005. Demographic, genetic, speech, and surgical data were collected. We compared the need for surgery and outcomes data between noncleft and cleft VPI patients using a Student's t-test. Results. We identified 43 patients with noncleft VPI, of which 24 were females and 19 were males. The average age at presentation of noncleft VPI was 9.6 years (range 4.5-21). The average patient age at the time of study was 13.4 years. The etiology of VPI in these noncleft patients was neurologic dysfunction 44%, syndrome-associated 35%, postadenotonsillectomy 7%, and multiple causes 14%. The need for surgical intervention in the noncleft VPI group was 37% (15/43) compared to the cleft palate controls, which was 27% (12/43). There was not a statistical difference between these two groups (P > 0.5). Conclusion. Noncleft VPI often occurs in patients who have underlying neurologic disorders or have syndromes. The rate of speech surgery to address VPI is similar to that of cleft palate patients. We propose that newly diagnosed noncleft VPI patients should undergo a thorough neurologic and genetic evaluation prior to surgery. PMID- 22548070 TI - Immunosuppressive exosomes: a new approach for treating arthritis. AB - Rheumatoid arthritis (RA) is a chronic autoimmune disease and one of the leading causes of disability in the USA. Although certain biological therapies, including protein and antibodies targeting inflammatory factors such as the tumor necrosis factor, are effective in reducing symptoms of RA, these treatments do not reverse disease. Also, although novel gene therapy approaches have shown promise in preclinical and clinical studies to treat RA, it is still unclear whether gene therapy can be readily and safely applied to treat the large number of RA patients. Recently, nanosized, endocytic-derived membrane vesicles "exosomes" were demonstrated to function in cell-to-cell communication and to possess potent immunoregulatory properties. In particular, immunosuppressive DC-derived exosomes and blood plasma- or serum-derived exosomes have shown potent therapeutic effects in animal models of inflammatory and autoimmune disease including RA. This paper discusses the current knowledge on the production, efficacy, mechanism of action, and potential therapeutic use of immunosuppressive exosomes for arthritis therapy. PMID- 22548071 TI - Treatment of autoimmune pancreatitis with the anecdotes of the first report. AB - The first case that led researchers to put forward a new concept of autoimmune pancreatitis (AIP) was treated with steroids by gastroenterologists in Tokyo Women's Medical University. It is important to differentiate AIP from pancreatic cancer before treatment with steroids is started. Today, steroids are standard therapy for AIP worldwide. In the Japanese consensus guidelines, steroid therapy is indicated for symptomatic AIP. After management of glucose levels and obstructive jaundice, oral prednisolone is initiated at 0.6 mg/kg/day for 2-4 weeks and is gradually tapered to a maintenance dose of 2.5-5 mg/day over 2-3 months. To prevent relapse, maintenance therapy with low-dose prednisolone is used. For relapsed AIP, readministration or increased doses of steroids are effective. The presence of proximal bile duct stenosis and elevated serum IgG4 levels may be predictive of relapse of AIP. It is necessary to verify the validity of the Japanese regimen of steroid therapy for AIP. The necessity, drugs, and duration of maintenance therapy for AIP need to be clarified by prospective studies. PMID- 22548072 TI - Clinical Aspects of IgG4-Related Orbital Inflammation in a Case Series of Ocular Adnexal Lymphoproliferative Disorders. AB - The most frequent ocular adnexal tumors and simulating lesions are lymphoproliferative disorders (LPDs), including malignant lymphomas and orbital inflammation with lymphoid hyperplasia or infiltration. IgG4-related orbital inflammation (IgG4-ROI) often involves lacrimal glands and other orbital tissues and is an important differential diagnosis. The present study evaluated clinical aspects of IgG4-ROI in a case series of orbital LPD. Sixty-two consecutive cases of orbital LPD, pathologically diagnosed from November, 2004, through March, 2011, were investigated. Histological types were 22 cases with MALT lymphoma, 11 cases with diffuse large B-cell lymphoma (DLBCL), 3 cases with other malignant lymphomas, 16 cases with IgG4-ROI, and 10 cases with non-IgG4-ROI. Ages of the IgG4-ROI group (56 +/- 10 yrs) were significantly lower than the MALT lymphoma (71 +/- 12 yrs) and DLBCL (75 +/- 14 yrs) groups. Orbital lesions other than lacrimal glands were present in six cases including extraocular muscle swelling, mass lesions surrounding the optic nerve, and supraorbital and infraorbital nerves enlargements. Although none of the malignant lymphomas were related to IgG4, previous evidence suggested that malignant lymphomas can arise from IgG4 ROI. Based on this study (26%) and another report (33%), it is likely that nearly a quarter of orbital LPD are IgG4-ROI. PMID- 22548073 TI - Prevalence of HLA-B27 in Patients with Ankylosing Spondylitis in Qatar. AB - Background and Objectives. The human leukocyte antigen HLA-B27 is a class 1 antigen of the major histocompatibility complex and is strongly associated with ankylosing spondylitis (AS). The purpose of the present study is to investigate the distribution of HLA-B27 in patients with AS of different ethnic groups in Qatar. Design and Setting. Study design was cross-sectional and the setting was rheumatology clinics of Hamad General Hospital in Qatar where most of ankylosing spondylitis patients are followed up. Patients and Methods. Patients with diagnosis of AS who met the New York modified criteria for AS were tested for HLA B27. 119 patients were tested for HLA-B27: 66 Arabs, 52 Asians (Indians, Pakistanis, Bengalis, and Iranians), and one Western (Irish). Results. Of all the individuals, 82 were positive (69%) for HLA-B27. Among the Arabs, 49/66 were positive (74%). Among the Asians, 32/52 were positive (61%). Furthermore, Qatari patients (10 males and one female) 9 were positive (82%), 14/19 Jordanians/Palestinians were positive, and 9/10 (90%) Egyptians were positive. Among the Asians, 19/26 Indians were positive (73%), which was similar to the Arabs. Conclusion. HLA-B27 in our small group of Arabs is present in 74%. Comparison with other data will be presented in detail. PMID- 22548075 TI - Pulmonary extramedullary hematopoiesis in a patient with chronic asthma resembling lung cancer: a case report. AB - Background. Extramedullary hematopoiesis is most often seen in reticuloendothelial organs specially spleen, liver, or lymph nodes, and it is rarely seen in lung parenchyma. Almost all reported cases of pulmonary extramedullary hematopoiesis occurred following myeloproliferative disorders specially myelofibrosis. Other less common underlying causes are thalassemia syndromes and other hemoglobinopathies. There was not any reported case of pulmonary extramedullary hematopoiesis in asthmatic patients in the medical literature. Case. Here we reported a 65-year-old lady who was a known case of bronchial asthma with recent developed right lower lobe lung mass. Chest X-ray and CT studies showed an infiltrating mass resembling malignancy. Fine needle aspiration cytology of mass revealed pulmonary extramedullary hematopoiesis. The patient followed for 10 months with serial physical examination and laboratory evaluations which were unremarkable. Conclusion. Extramedullary hematopoiesis of lung parenchyma can be mistaken for lung cancer radiologically. Although previous reported cases occurred with myelofibrosis or hemoglobinopathies, we are reporting the first case of asthma-associated extramedullary hematopoiesis. PMID- 22548074 TI - Stem cell interaction with somatic niche may hold the key to fertility restoration in cancer patients. AB - The spontaneous return of fertility after bone marrow transplantation or heterotopic grafting of cryopreserved ovarian cortical tissue has surprised many, and a possible link with stem cells has been proposed. We have reviewed the available literature on ovarian stem cells in adult mammalian ovaries and presented a model that proposes that the ovary harbors two distinct populations of stem cells, namely, pluripotent, quiescent, very small embryonic-like stem cells (VSELs), and slightly larger "progenitor" ovarian germ stem cells (OGSCs). Besides compromising the somatic niche, oncotherapy destroys OGSCs since, like tumor cells, they are actively dividing; however VSELs persist since they are relatively quiescent. BMT or transplanted ovarian cortical tissue may help rejuvenate the ovarian niche, which possibly supports differentiation of persisting VSELs resulting in neo-oogenesis and follicular development responsible for successful pregnancies. Postnatal oogenesis in mammalian ovary from VSELs may be exploited for fertility restoration in cancer survivors including those who were earlier deprived of gametes and/or gonadal tissue cryopreservation options. PMID- 22548076 TI - Sarcoidosis: psychotherapy and long-term outcome-a case report. AB - Sarcoidosis is a systemic, inflammatory disease of unknown aetiology, influenced by stressful life events and associated with a high incidence of alexithymic personality traits, and of depressive symptoms. The medical literature on sarcoidosis has called for a psychotherapeutic intervention to modify the perceived state of disease, the influence of stressful events and the depressive condition. Few studies have described cases treated with psychotherapy, and no information is available on its long-term outcome. We present the case of a patient with chronic sarcoidosis and periodical reacutizations with constantly pathological ESR. Twenty-four years after the diagnosis, a dynamic supportive expressive psychotherapy for psychosomatic alexithymic patients was added to the medical therapy. At the beginning and at the end of the psychotherapy, and for the long-term outcome evaluations, Kellner's symptom questionnaire (SQ) was used to investigate psychological distress. The SQ scores, initially pathological, were normal at the end of the psychotherapy and for the following three years. Psychotherapy, without antidepressive drugs, resolved the depression. The depressive symptoms disappeared, along with the normalization and stabilization of the ESR. After three years, the outcome was positive. This is the first study describing a successful psychotherapy and its long-term outcome on a patient with sarcoidosis. PMID- 22548077 TI - Novel BRAF Alteration in a Sporadic Pilocytic Astrocytoma. AB - Pilocytic astrocytoma (PA) is the most frequently encountered glial tumor (glioma or astrocytoma) in children. Recent studies have identified alterations in the BRAF serine/threonine kinase gene as the likely causative mutation in these childhood brain tumors. The majority of these genetic changes involve chromosome 7q34 tandem duplication, resulting in aberrant BRAF fusion transcripts. In this paper, we describe a novel KIAA1549:BRAF fusion transcript in a sporadic PA tumor associated with increased ERK activation and review the spectrum of BRAF genetic alterations in this common pediatric low-grade central nervous system neoplasm. PMID- 22548078 TI - Long-term survival after gamma knife radiosurgery in a case of recurrent glioblastoma multiforme: a case report and review of the literature. AB - The management of recurrent glioblastoma is highly challenging, and treatment outcomes remain uniformly poor. Glioblastoma is a highly infiltrative tumor, and complete surgical resection of all microscopic extensions cannot be achieved at the time of initial diagnosis, and hence local recurrence is observed in most patients. Gamma Knife radiosurgery has been used to treat these tumor recurrences for select cases and has been successful in prolonging the median survival by 8 12 months on average for select cases. We present the unique case of a 63-year old male with multiple sequential recurrences of glioblastoma after initial standard treatment with surgery followed by concomitant external beam radiation therapy and chemotherapy (temozolomide). The patient was followed clinically as well as with surveillance MRI scans at every 2-3-month intervals. The patient underwent Gamma Knife radiosurgery three times for 3 separate tumor recurrences, and the patient survived for seven years following the initial diagnosis with this aggressive treatment. The median survival in patients with recurrent glioblastoma is usually 8-12 months after recurrence, and this unique case illustrates that aggressive local therapy can lead to long-term survivors in select situations. We advocate that each patient treatment at the time of recurrence should be tailored to each clinical situation and desire for quality of life and improved longevity. PMID- 22548079 TI - Propofol-remifentanil combination for management of electroconvulsive therapy in a patient with neuroleptic malignant syndrome. AB - Electroconvulsive therapy can be effective in severe or treatment resistant neuroleptic malignant syndrome patients. Anesthesia and use of muscle relaxant agents for electroconvulsive therapy in such patients may encounter anesthesiologists with specific challenges. This case report describes successful management of anesthesia in 28-year-old male patient undergoing eight electroconvulsive therapy sessions for treatment of neuroleptic malignant syndrome. PMID- 22548080 TI - Ocular symptomatology, management, and clinical outcome of a giant intracranial aneurysm. AB - Giant aneurysms of the anterior intracranial circulation are rare, slowly progressive vascular abnormalities, often presenting with neuro-ophthalmological symptoms before they rupture. This is a case of a 55-year-old woman with a double aneurysm of the anterior intracranial circulation, part of which was giant, diagnosed exclusively on the basis of ocular manifestations. We also describe successful management of the case throughout a long follow-up period. PMID- 22548081 TI - Encrusted Ureteral Stent Retrieval Using Flexible Ureteroscopy with a Ho: YAG Laser. AB - A 23-year-old female had bilateral ureteral stents placed due to bilateral renal stones and hydronephrosis. The bilateral ureteral stents were changed every 3 months. A kidney ureter bladder (KUB) film showed left encrustation along the ureteral stent thus necessitating removal; however, the ureteral stent could not be removed cystoscopically. The ureteral stent was, therefore, extracted using flexible ureteroscopy (URS) with a holmium (Ho): yttrium aluminum garnet (YAG) laser. PMID- 22548082 TI - Incidental monotypic (fat-poor) renal angiomyolipoma diagnosed by core needle biopsy. AB - We present the case of a 55-year-old patient with a history of chemotherapy and bone marrow transplantation because of acute myeloid leukaemia. An incidental 4 * 3 cm measuring renal mass was detected while performing a magnetic resonance imaging (MRI) for lumbago. The lesion was suspected to be either a renal cell carcinoma (RCC) or a leukemic infiltration. To decide about further treatment a percutaneous core needle biopsy was performed. Histology showed a monotypic angiomyolipoma, a relatively rare benign renal lesion. Interestingly, in cross sectional imaging, angiomyolipoma was not taken into differential diagnostic account because of lack of a fatty component. Due to bleeding after biopsy the feeding artery of the tumor was occluded by microcoils. This case demonstrates the utility of biopsy of renal tumors, in particular when small tumor-like lesions are incidentally detected to decide about the right treatment and thereby avoiding nephrectomy. PMID- 22548083 TI - Unilateral hydronephrosis and renal damage after acute leukemia. AB - A 14-year-old boy presented with asymptomatic right hydronephrosis detected on routine yearly ultrasound examination. Previously, he had at least two normal renal ultrasonograms, 4 years after remission of acute myeloblastic leukemia, treated by AML-BFM-93 protocol. A function of the right kidney and no damage on the left was confirmed by a DMSA scan. Right retroperitoneoscopic nephrectomy revealed 3 renal arteries with the lower pole artery lying on the pelviureteric junction. Histologically chronic tubulointerstitial nephritis was detected. In the pathogenesis of this severe unilateral renal damage, we suspect the exacerbation of deleterious effects of cytostatic therapy on kidneys with intermittent hydronephrosis. PMID- 22548084 TI - Diagnostic aspects and retinal imaging in ocular toxocariasis: a case report from Italy. AB - Toxocara canis is a nematode parasite, commonly found in dogs. This roundworm parasite can invade the eye, causing visual impairment. Toxocara should be considered as a possible causative agent of posterior and diffuse uveitis, and it could be considered in the differential diagnosis of retinoblastoma. Ocular manifestations vary from severe endophthalmitis to silent incidental findings on a routine examination. We report a case of ocular toxocariasis in a 24-year-old Asiatic female that presented to us complaining of visual impairment. Fundoscopic examination revealed a posterior pole granuloma and exudative retinal detachment along with exudates. Presentation, clinical findings, morphological changes, and treatment are discussed. The enzyme-linked immunosorbent assay serology for Toxocara canis was performed, demonstrating the positivity for IgG and IgE. Treatment with the antihelminthic albendazole was initiated. Fluorescein angiography (FA; HRA 2, Heidelberg engineering) and optical coherence tomography (OCT; Spectralis, Heidelberg tomography) were performed, and results have been reported. PMID- 22548085 TI - Increasing Role of Roof Gutters as Aedes aegypti (Diptera: Culicidae) Breeding Sites in Guadeloupe (French West Indies) and Consequences on Dengue Transmission and Vector Control. AB - During the past ten years, the islands of Guadeloupe (French West Indies) are facing dengue epidemics with increasing numbers of cases and fatal occurrences. The vector Aedes aegypti is submitted to intensive control, with little effect on mosquito populations. The hypothesis that important Ae. aegypti breeding sites are not controlled is investigated herein. For that purpose, the roof gutters of 123 houses were systematically investigated, and the percentage of gutters positive for Ae. aegypti varied from 17.2% to 37.5%, from humid to dry locations. In the dryer location, most of houses had no other breeding sites. The results show that roof gutters are becoming the most important Ae. aegypti breeding sites in some locations in Guadeloupe, with consequences on dengue transmission and vector control. PMID- 22548086 TI - Using a geographical-information-system-based decision support to enhance malaria vector control in zambia. AB - Geographic information systems (GISs) with emerging technologies are being harnessed for studying spatial patterns in vector-borne diseases to reduce transmission. To implement effective vector control, increased knowledge on interactions of epidemiological and entomological malaria transmission determinants in the assessment of impact of interventions is critical. This requires availability of relevant spatial and attribute data to support malaria surveillance, monitoring, and evaluation. Monitoring the impact of vector control through a GIS-based decision support (DSS) has revealed spatial relative change in prevalence of infection and vector susceptibility to insecticides and has enabled measurement of spatial heterogeneity of trend or impact. The revealed trends and interrelationships have allowed the identification of areas with reduced parasitaemia and increased insecticide resistance thus demonstrating the impact of resistance on vector control. The GIS-based DSS provides opportunity for rational policy formulation and cost-effective utilization of limited resources for enhanced malaria vector control. PMID- 22548087 TI - Prenatal characteristics of infants with a neuronal migration disorder: a national-based study. AB - The development of the central nervous system is complex and includes dorsal and ventral induction, neuronal proliferation, and neuronal migration, organization, and myelination. Migration occurs in humans in early fetal life. Pathogenesis of malformations of the central nervous system includes both genetic and environmental factors. Few epidemiological studies have addressed the impact of prenatal exposures. All infants born alive and included in the Swedish Medical Birth Register 1980-1999 were included in the study. By linkage to the Patient Register, 820 children with a diagnosis related to a neuronal migration abnormality were identified. Through copies of referrals for computer tomography or magnetic resonance imaging of the brain, the diagnosis was confirmed in 17 children. Median age of the mothers was 29 years. At the start of pregnancy, four out of 17 women smoked. Almost half of the women had a body mass index that is low or in the lower range of average. All infants were born at term with normal birth weights. Thirteen infants had one or more concomitant diseases or malformations. Two infants were born with rubella syndrome. The impact of low maternal body mass index and congenital infections on neuronal migration disorders in infants should be addressed in future studies. PMID- 22548088 TI - Effectiveness and safety of botulinum toxin type a in children with musculoskeletal conditions: what is the current state of evidence? AB - Children with musculoskeletal conditions experience muscle weakness, difficulty walking and limitations in physical activities. Standard treatment includes physiotherapy, casting, and surgery. The use of botulinum toxins appears as a promising treatment on its own, but usually as an adjunct to other treatment modalities and as an alternative to surgery. The objectives were to establish the evidence on the effectiveness, safety and functional outcome of BTX-A in children with musculoskeletal conditions. A literature search using five electronic databases identified 24 studies that met our inclusion criteria. Two randomized clinical trials were included; most studies were case studies with small sample sizes and no control group. Improvements in gait pattern, function, range of motion, reduction of co-contractions, and avoidance of surgical procedures were found following BTX-A injections. Adverse events were not reported in 10 studies, minor adverse events were reported in 13 children and there were no severe adverse events. Additional doses appear safe. BTX-A is a promising treatment adjunct in improving functional outcomes in children with musculoskeletal conditions. Future studies including larger samples, longer follow-up periods and a comparison group are required to provide evidence on the effectiveness and safety of this drug in children with musculoskeletal conditions. PMID- 22548089 TI - Maternal Recreational Exercise during Pregnancy in relation to Children's BMI at 7 Years of Age. AB - Exposures during fetal life may have long-term health consequences including risk of childhood overweight. We investigated the associations between maternal recreational exercise during early and late pregnancy and the children's body mass index (BMI) and risk of overweight at 7 years. Data on 40,280 mother-child pairs from the Danish National Birth Cohort was used. Self-reported information about exercise was obtained from telephone interviews around gestational weeks 16 and 30. Children's weight and height were reported in a 7-year follow-up and used to calculate BMI and overweight status. Data was analyzed using multiple linear and logistic regression models. Recreational exercise across pregnancy was inversely related to children's BMI and risk of overweight, but all associations were mainly explained by smoking habits, socioeconomic status, and maternal pre pregnancy BMI. Additionally, we did not find exercise intensity or changes in exercise habits in pregnancy related to the children's BMI or risk of overweight. PMID- 22548092 TI - Old and new: influencing health policy debates. PMID- 22548090 TI - Occupational asthma: new low-molecular-weight causal agents, 2000-2010. AB - Background. More than 400 agents have been documented as causing occupational asthma (OA). The list of low-molecular-weight (LMW) agents that have been identified as potential causes of OA is constantly expanding, emphasizing the need to continually update our knowledge by reviewing the literature. Objective. The objective of this paper was to identify all new LMW agents causing occupational asthma reported during the period 2000-2010. Methods. A Medline search was performed using the keywords occupational asthma, new allergens, new causes, and low-molecular-weight agents. Results. We found 39 publications describing 41 new LMW causal agents, which belonged to the following categories: drugs (n = 12), wood dust (n = 11), chemicals (n = 8), metals (n = 4), biocides (n = 3), and miscellaneous (n = 3). The diagnosis of OA was confirmed through SIC for 35 of 41 agents, peak expiratory flow monitoring for three (3) agents, and the clinical history alone for three (3) agents. Immunological tests provided evidence supporting an IgE-mediated mechanism for eight (8) (20%) of the newly described agents. Conclusion. This paper highlights the importance of being alert to the occurrence of new LMW sensitizers, which can elicit OA. The immunological mechanism is explained by a type I hypersensitivity reaction in 20% of all newly described LMW agents. PMID- 22548093 TI - Will paying the piper change the tune? AB - Most provincial governments are considering or introducing changes to hospital funding. Ten years of rapidly increasing expenditures have left them still facing complaints of waiting lists and waiting times. Activity-based funding (ABF) would supplement traditional negotiated global budgets, reimbursing a predetermined amount for each case treated - essentially, a "fee schedule" - thus providing incentives and resources to increase throughput of certain "hot button" procedures and services and to improve efficiency.Maybe. ABF-type systems in other countries date back over 20 years; the results are very mixed. What is clear is that information and reporting requirements are substantial. A host of perverse incentives lurk in ABF. Most Canadian hospitals and provincial governments do not now have the necessary data systems, so are wise to proceed cautiously. PMID- 22548091 TI - Concurrent use of cigarettes and smokeless tobacco in Minnesota. AB - Cigarette smokers are being encouraged to use smokeless tobacco (SLT) in locations where smoking is banned. We examined state-wide data from Minnesota to measure changes over time in the use of SLT and concurrent use of cigarettes and SLT. The Minnesota Adult Tobacco Survey was conducted four times between 1999 and 2010 and has provided state-wide estimates of cigarette smoking, SLT use and concurrent use of SLT by smokers. The prevalence of SLT was essentially unchanged through 2007, then increased significantly between 2007 and 2010 (3.1% versus 4.3%, P < 0.05). Similarly, the prevalence of cigarette smokers who reported using SLT was stable then increased between 2007 and 2010 (4.4% versus 9.6%, P < 0.05). The finding of higher SLT use by smokers could indicate that smokers in Minnesota are in an experimental phase of testing alternative products as they adjust to recent public policies restricting smoking in public places. The findings are suggestive that some Minnesota smokers are switching to concurrent use of cigarettes and SLT. Future surveillance reports will be necessary to confirm the results. PMID- 22548094 TI - Purchasing prescription drugs in Canada: hang together or hang separately. AB - Canada's provincial and territorial governments have expressed an interest in bulk purchasing prescription drugs for many years. We propose they start by purchasing selected generic drugs for the entire population and provide them for little or no cost to patients. This politically popular strategy would significantly reduce drug expenditures and improve population health. PMID- 22548095 TI - Is patient-centred care associated with lower diagnostic costs? AB - A recent report of the Health Council of Canada implies that patient-centred care is related to higher costs. This paper draws the opposite conclusion. A study of 311 family practice patients revealed that the costs for diagnostic tests decreased over four quartiles of patient-centred scores; the more patient-centred the visit, the less the cost for diagnostic testing in the two-month follow-up period. Projecting to the Canadian population, if all family physicians were patient-centred at the level of the highest quartile, one-third of these diagnostic costs would be saved. The paper makes four recommendations and concludes that patient-centred care has a role to play in delivering not only effective but also efficient healthcare services. PMID- 22548096 TI - Family doctors and lower diagnostic imaging costs: how do we get there from here? PMID- 22548097 TI - Is it worthwhile to invest in home care? AB - The objective of this study was to estimate the impact of the First Nations and Inuit Home and Community Care Program (FNIHCCP) on the rates of hospitalization for ambulatory care sensitive conditions (ACSCs) in the province of Manitoba. A population-based time trend analysis was conducted using the de-identified administrative data housed at the Manitoba Centre for Health Policy, including data from 1984/85 to 2004/05. Findings show a significant decline in the rates of hospitalization (all conditions) following the introduction of the FNIHCCP in communities served by health offices (p<0.0001), health centres (p<0.0001) and nursing stations (p=0.0022). Communities served by health offices or health centres also experienced a significant reduction in rates of hospitalization for chronic conditions (p<0.0001).The results of this study suggest that investment in home care resulted in a significant decline in rates of avoidable hospitalization, especially in communities that otherwise had limited access to primary healthcare. PMID- 22548098 TI - Canadian political science and medicare: six decades of inquiry. AB - Based on an extensive sample of the literature, this critical review dissects the principal themes that have animated the Canadian political science profession on the topic of medicare. The review considers the coincidence of economic eras and how these are reflected in the methodological approaches to the study of medicare. As is to be expected, most of the scholarly activity coincides with the economic era marked by fiscal restraint and decreases in social investments (1993 2003). At the same time, the review notes the prevalence of institutionalism as an approach to the topic and the scholarly community's near-consensus on medicare as a defining characteristic of the country and its people. PMID- 22548099 TI - Hospital expenditure as a major driver of nurse labour force participation: evidence from a 10-year period in Canada. AB - This paper examines trends in the nursing labour market in Canada over a period of dramatic fluctuations in hospital expenditures. We add to previous analysis that covered the period 1991-1996 and use Census data from 2001 to examine the relationship between hospital expenditure and nurse labour force participation. We find that shifts in labour force participation over the period 1991-2001 had a significant impact on the nursing supply in Canada. Individuals who were trained in nursing but were working outside the profession in 1996 because of budgetary reductions and layoffs in hospitals had largely been reabsorbed back into nursing jobs by 2001. Our analysis provides further empirical evidence that the labour force participation among individuals trained in nursing is driven to a large extent by demand-side factors. PMID- 22548100 TI - Assessing the acceptability of quality indicators and linkages to payment in primary care in nova scotia. AB - In 2006, the Canadian Institute for Health Information (CIHI) released a comprehensive set of quality indicators (QIs) for primary healthcare (PHC). We explored the acceptability of a subset of these as measures of the technical quality of care and the potential link to payment incentive tools. A modified Delphi approach, based on the RAND consensus panel method, was used with an expert panel composed of PHC providers (family physicians, nurses and nurse practitioners) and decision-makers with no previous experience of "pay for performance." A nine-point Likert scale was used to rate the acceptability of 35 selected CIHI QIs in community practice and the acceptability of a payment mechanism associated with each. QIs rated with disagreement were discussed and re rated in a face-to-face meeting. The panel rated 19 QIs as "acceptable." Payment incentives associated with these QIs were acceptable for 13. Several factors emerged that were common to the less appealing QIs with respect to payment linkage. PMID- 22548101 TI - A global approach to evaluation of health services utilization: concepts and measures. AB - Health services utilization has been the object of many books and papers in the literature. Measures associated with utilization are often a function of volume of services. The objective of this paper is to present a comprehensive approach to the evaluation of health services utilization and of associated measures, using databases. Based on the theoretical framework of Starfield (1998), we analyze health services utilization with the help of indicators that are not directly linked to volume but that indirectly provide an estimate, while also documenting the qualitative aspects of utilization. The indicators mark accessibility, continuity, comprehensiveness and productivity of care. Once the concepts have been defined, we propose their operationalization using the databases. We then present the advantages of multidimensional conceptualization of health services utilization through a simultaneous analysis of these indicators. Researchers and decision-makers in public health and health planning have much to gain from this innovative multidimensional approach, which presents a dynamic conceptualization of health services utilization based on health administrative data.This paper was originally published in French, in the journal Pratiques et Organisation des Soins 2011 42(1): 11-18. PMID- 22548102 TI - Are primary healthcare organizational attributes associated with patient self efficacy for managing chronic disease? AB - Our objective was to explore how individual and primary healthcare (PHC) organizational attributes influence patients' ability in chronic illness self management. We conducted a cohort study, recruiting 776 adults with chronic disease from 33 PHC settings in the province of Quebec. Organizational data on the PHC clinics were obtained from a prior study. Participants were interviewed at baseline, 6 and 12 months, responding to questionnaires on self-efficacy, health status, socio-demographics, healthcare use and experience of care. Multilevel modelling showed that 52.5% of the variance in self-efficacy occurs at the level of the individual and 4.0% at the organizational level. Controlling for diagnosis, patient factors associated with self-efficacy were self-rated health (B coeff 0.76: CI 0.60; 0.92), concurrent depression (B coeff -1.41: CI 1.96; 0.86) and satisfaction with care (B coeff 0.27: CI 0.15; 0.39). None of the organizational attributes was significantly associated with self-efficacy after adjusting for lower-level variables. Patients generally reported receiving little self-management teaching across organizations. PMID- 22548103 TI - Integrated networks in child and youth mental health: a challenging role transformation for child psychiatrists and allied mental health professionals? PMID- 22548104 TI - [Not Available]. AB - OBJECTIVE: The province of Quebec has initiated a vast reform of youth mental health services. This article aims at evaluating the first year of the implementation of first-line services in Lanaudiere's two local service networks. METHODOLOGY: A formative and participatory qualitative evaluation was carried out. Data collection was led by 32 key individuals who were engaged in the implementation of these services or who were involved in the decision-making process. Five semi-directed group interviews were carried out with the committees and teams concerned. The information collected is the object of a descriptive, qualitative content analysis. RESULTS: The implementation of first-line services in youth mental health in the Lanaudiere region has caused partners to mobilize. This fact was identified by the group as a positive element of the establishment of these services. The decision to go ahead with the implementation of these services in spite of a lack of child and adolescent psychiatrists has strengthened these individuals' determination. On the other hand, the implementation of these services has been impeded by the lack of human resources, insufficient doctors, and difficulties with the integration of first-line services and child and adolescent psychiatry. CONCLUSION: Despite certain difficulties and differences between the local service networks in the implementation of first-line services in youth mental health, the establishment of these services seems to have caused an evolution in the institutional and clinical culture in Lanaudiere. PMID- 22548105 TI - Partnership at the forefront of change: documenting the transformation of child and youth mental health services in quebec. AB - OBJECTIVE: The Quebec Plan d'action en sante mentale (PASM) (Mental Health Action Plan) reform, a major transformation of the province's mental health care system, has put primary care rather than hospital-based care at the forefront of mental health service delivery. This study documents perceptions of changes in child and youth mental health (CYMH) services following the reform, as well as facilitators and obstacles to collaboration and partnership in CYMH services, and the specific challenges related to collaboration and partnership when servicing multi-ethnic populations. METHODS: This qualitative participatory research study collected data using semi-structured individual interviews, focus groups and participant observation in community-based health and social service institutions. Thematic analysis was performed. RESULTS: The reform process encountered challenges in building a common culture of care within and between institutions, while collaboration and partnership evolved in a positive direction throughout the study. Study results highlighted the importance of fostering communication at all levels. Collaboration and partnership was facilitated by opportunities for clinical discussions, dialogue on models of care, harmonizing administrative and clinical priorities, and involving key actors and structures. The results revealed difficulties in implementing multidisciplinary work and in negotiating partners' responsibilities. Quality of partnership and collaboration appeared particularly crucial in providing optimal care to vulnerable families, including migrants. CONCLUSION: The PASM reform involved a major and challenging transformation in CYMH services. Continuous dialogue through time and leadership sharing appeared promising to foster this transformation. PMID- 22548106 TI - The family as partner in child mental health care: problem perceptions and challenges to collaboration. AB - OBJECTIVE: The development of the health and social care system has made it increasingly specialized, decentralized and professionalized. Accordingly, demands of efficient approaches to collaboration and integration of services for children, adolescents and their family networks have emerged. The aim of this article is to present and analyze findings from a review of the literature on parents as collaboration partners with professionals. METHOD: A literature review was conducted in two databases. A multifaceted model was developed to depict and analyze collaboration complexity. RESULTS: Preliminary application of the multifaceted collaboration model suggests that first- and second-order therapy positions have different impact on collaborative relationships. CONCLUSION: It is suggested that professionals may want to acknowledge the different impact of first- and second-order positions in interprofessional collaboration involving parents. This may be accomplished by staging a routine requirement for discussion of meta-positions as an introductory theme in the opening stages and as a recurrent theme throughout the collaboration process. PMID- 22548107 TI - Healthy minds/healthy children outreach service: lessons learned after eight years. AB - OBJECTIVES: This article describes the Healthy Minds/Healthy Children Outreach Service (HMHC), an ongoing clinical and educational outreach service which makes use of technology to bridge geographical barriers to help build capacity in front line professionals to meet children's mental health needs in rural areas. METHOD: A description of the HMHC clinical consultation and educational services is given. Utilization patterns of these services are reviewed. RESULTS: Clinical service accounts for approximately 1/3 of the service's activities. Continuing professional development has experienced strong growth since the program's inception eight years ago. The majority of consultees and continuing professional development users have been non-physicians. DISCUSSION: Future challenges for program development include increasing physician involvement and continuing to adapt the program's continuing education program to the multidisciplinary professionals who provide support to children in rural areas. Measuring the program's outcome in terms of its effect on clinical care through knowledge transfer has been difficult to do because of methodological research challenges, while successful research in this area will be helpful to determine how collaborative care models can help in the provision of mental health services to youth in rural communities. The growth of collaboration across various professional disciplines and service sectors demonstrates that programs like HMHC can be effective in meeting some of the unmet needs in providing mental health services to children and youth. PMID- 22548109 TI - Mental Health in Inuit Youth from Nunavik: Clinical Considerations on a Transcultural, Interdisciplinary, Community-oriented Approach. AB - OBJECTIVE: This paper discusses the organization of mental health care for youth in Nunavik and considers how best to adapt care to the sociocultural and geographical specificities of this region. METHOD: Services are described and discussed by a general practitioner and a community worker in Nunavik. RESULTS: Current social and medical care delivery in Nunavik is provided by professionals who are largely non-Inuit and who are supported by Inuit community workers and interpreters. Community workers are key players in the provision of social and mental health care for youth. Efforts are made to adapt care to the sociocultural specificities of Inuit youth, and to locally-based multidisciplinary care addressing the multiple determinants of mental health. CONCLUSION: While efforts to adapt care are ongoing, the ideal model of care integrating transcultural, multidisciplinary and community-oriented approaches are yet to become a reality. Increased communication among care providers is suggested as a way to strengthen the current collaborative model of care. Future goals include having a majority of care being provided locally and building community ownership and governance of care institutions. PMID- 22548108 TI - Referral Patterns and Training Needs in Psychiatry among Primary Care Physicians in Canadian Rural/Remote Areas. AB - OBJECTIVES: This study examined the referral patterns of rural/remote primary care physicians (PCPs) as well as their needs and interests for further training in child/adolescent mental health. METHODS: Surveys were mailed to Canadian rural/remote PCPs requesting participants' demographic information, training and qualifications, referral patterns, and identification of needs and interests for continuing medical education (CME). RESULTS: PCPs were most likely to refer to mental health programs, and excessive wait times are the most common deterrent. Major reasons for referral were to obtain recommendations regarding medications and assessing non-responsive patients. While PCPs expressed higher levels of confidence in making appropriate referrals, they were much less confident in their knowledge and skills in managing mental health problems. Professional development in child/adolescent psychiatry is a moderate or highly perceived CME need. Overall, attention deficit/hyperactivity disorder (ADHD) was the most commonly chosen topic of interest and CME in the community was preferred, but some regional differences emerged. CONCLUSIONS: PCPs viewed limited community resources and self-identified gaps in skills as barriers to service provision. Professional development in child and adolescent mental health for PCPs by preferred modes appears desired. PMID- 22548110 TI - An international perspective on youth mental health: the role of primary health care and collaborative care models. PMID- 22548111 TI - Review of the pharmacotherapy of irritability of autism. AB - OBJECTIVE: To review the randomized controlled trial data regarding pharmacotherapy of irritability of autism. METHOD: A LITERATURE REVIEW WAS CONDUCTED USING THE MEDLINE SEARCH TERMS: 'autism' OR 'autism spectrum disorder' with the following limits: Randomized Controlled Trials (RCTs), human trials, English language. Additional articles were identified from reference information. Trials involving nutritional supplements, hormones or drugs not approved by either Health Canada or the US Food and Drug Administration (FDA) were excluded from analysis. RESULTS: Twenty-three RCTs that met criteria were identified. The greatest number of RCTs involved risperidone, with six of seven placebo controlled risperidone trials reporting statistically significant improvements on the primary outcome measure. Two aripiprazole RCTs and one olanzapine RCT reported statistically significant improvement in primary outcome measures. Haloperidol was superior to both clomipramine and placebo in a head-to-head crossover trial, while risperidone was superior to haloperidol for treatment of behavioural symptoms in a separate head-to-head trial. Clonidine, methylphenidate, valproate and levocarnitine monotherapy were superior to placebo in single RCTs, while adjunctive treatments cyproheptadine, pentoxifylline and topiramate were superior to placebo in small studies when given in combination with an antipsychotic. Adverse events from RCTs were summarized, including weight gain and metabolic effects, if available. CONCLUSION: The bulk of positive RCT evidence for the pharmacotherapy of irritability of autism pertains to FDA approved antipsychotics risperidone and aripiprazole. RCTs supporting efficacy of several alternative and adjunctive agents may afford additional treatment options when optimal antipsychotic doses fail to control symptoms or cause intolerable adverse effects. Behavioural therapy should be employed where possible either before, or in addition to pharmacotherapy. PMID- 22548112 TI - Interview with senator romeo dallaire. PMID- 22548114 TI - Positive and negative regulation of cellular immune responses in physiologic conditions and diseases. AB - The immune system has evolved to allow robust responses against pathogens while avoiding autoimmunity. This is notably enabled by stimulatory and inhibitory signals which contribute to the regulation of immune responses. In the presence of a pathogen, a specific and effective immune response must be induced and this leads to antigen-specific T-cell proliferation, cytokines production, and induction of T-cell differentiation toward an effector phenotype. After clearance or control of the pathogen, the effector immune response must be terminated in order to avoid tissue damage and chronic inflammation and this process involves coinhibitory molecules. When the immune system fails to eliminate or control the pathogen, continuous stimulation of T cells prevents the full contraction and leads to the functional exhaustion of effector T cells. Several evidences both in vitro and in vivo suggest that this anergic state can be reverted by blocking the interactions between coinhibitory molecules and their ligands. The potential to revert exhausted or inactivated T-cell responses following selective blocking of their function made these markers interesting targets for therapeutic interventions in patients with persistent viral infections or cancer. PMID- 22548113 TI - Towards a rational design of an asymptomatic clinical herpes vaccine: the old, the new, and the unknown. AB - The best hope of controlling the herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2) pandemic is the development of an effective vaccine. However, in spite of several clinical trials, starting as early as 1920s, no vaccine has been proven sufficiently safe and efficient to warrant commercial development. In recent years, great strides in cellular and molecular immunology have stimulated creative efforts in controlling herpes infection and disease. However, before moving towards new vaccine strategy, it is necessary to answer two fundamental questions: (i) why past herpes vaccines have failed? (ii) Why the majority of HSV seropositive individuals (i.e., asymptomatic individuals) are naturally "protected" exhibiting few or no recurrent clinical disease, while other HSV seropositive individuals (i.e., symptomatic individuals) have frequent ocular, orofacial, and/or genital herpes clinical episodes? We recently discovered several discrete sets of HSV-1 symptomatic and asymptomatic epitopes recognized by CD4(+) and CD8(+) T cells from seropositive symptomatic versus asymptomatic individuals. These asymptomatic epitopes will provide a solid foundation for the development of novel herpes epitope-based vaccine strategy. Here we provide a brief overview of past clinical vaccine trials, outline current progress towards developing a new generation "asymptomatic" clinical herpes vaccines, and discuss future mucosal "asymptomatic" prime-boost vaccines that could optimize local protective immunity. PMID- 22548115 TI - The modulation of PPARgamma1 and PPARgamma2 mRNA expression by ciglitazone in CD3/CD28-activated naive and memory CD4+ T cells. AB - Given their roles in immune regulation, the expression of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) 1 and 2 isoforms was investigated in human naive (CD45RA+) and memory (CD45RO+) CD4+ T cells. Stimulation of both types of cells via the CD3/CD28 pathway resulted in high expression of both PPARgamma receptors as measured by real-time PCR. Treatment with the PPARgamma agonist, ciglitazone, increased PPARgamma1 expression but decreased PPARgamma2 expression in stimulated naive and memory cells. Furthermore, when present, the magnitude of both PPARgamma receptors expression was lower in naive cells, perhaps suggesting a lower regulatory control of these cells. Similar profiles of selected proinflammatory cytokines were expressed by the two cell types following stimulation. The induction of PPARgamma1 and suppression of PPARgamma2 expressions in naive and memory CD4+ T cells in the presence of ciglitazone suggest that the PPARgamma subtypes may have different roles in the regulation of T-cell function. PMID- 22548116 TI - Atherosclerosis: an integrative East-west medicine perspective. AB - Recent understanding of atherosclerosis and coronary heart disease has shifted the focus from lumen stenosis to vulnerable plaque, from lipid deposit to inflammatory reaction, and from vulnerable plaque to vulnerable patient. This has led to a new direction of treatment consisting of intervening the inflammatory reaction, stabilizing the vulnerable plaque, inhibiting thrombosis after plaque rupture, and treating the vulnerable patient instead of treating lumen stenosis. This seems to mirror the traditional Chinese medicine (TCM) focus on prevention and on the vulnerable patient with treatment matched to the pattern dysfunction and dysregulation using the Chinese herbal medicine multitargeted approach. Given the convergence of both the East and the West conceptualization of atherosclerosis, it is hopeful that the integrative East-West approach will facilitate early detection and more effective treatment of the vulnerable patients with coronary heart disease. PMID- 22548117 TI - Biological Effect of Leaf Aqueous Extract of Caesalpinia pyramidalis in Goats Naturally Infected with Gastrointestinal Nematodes. AB - Forty-eight goats naturally infected with gastrointestinal nematodes were randomly divided into four groups (n = 12): negative control (G1) (untreated), positive control (G2) (treated with doramectin, 1 mL/50 Kg b.w.), and G3 and G4 treated with 2.5 and 5 mg/Kg b.w. of a leaf aqueous extract of Caesalpinia pyramidalis (CP). Fecal and blood samples were regularly collected for the evaluation of fecal egg count (FEC), hematological and immunological parameters to assess the anthelmintic activity. In treated animals with CP, there was noted a significant reduction of 54.6 and 71.2% in the mean FEC (P < 0.05). An increase in IgA levels was observed in G3 and G4 (P < 0.05), during the experimental period, suggesting that it was stimulated by the extract administration. In conclusion, the results showed that CP provoked a protective response in infected animals treated with them. This response could be partly explained by the CP chemical composition. PMID- 22548118 TI - Effect of a New Prokinetic Agent DA-9701 Formulated with Corydalis Tuber and Pharbitidis Semen on Cytochrome P450 and UDP-Glucuronosyltransferase Enzyme Activities in Human Liver Microsomes. AB - DA-9701 is a new botanical drug composed of the extracts of Corydalis tuber and Pharbitidis semen, and it is used as an oral therapy for the treatment of functional dyspepsia in Korea. The inhibitory potentials of DA-9701 and its component herbs, Corydalis tuber and Pharbitidis semen, on the activities of seven major human cytochrome P450 (CYP) enzymes and four UDP glucuronosyltransferase (UGT) enzymes in human liver microsomes were investigated using liquid chromatography-tandem mass spectrometry. DA-9701 and Corydalis tuber extract slightly inhibited UGT1A1-mediated etoposide glucuronidation, with 50% inhibitory concentration (IC(50)) values of 188 and 290 MUg/mL, respectively. DA 9701 inhibited CYP2D6-catalyzed bufuralol 1'-hydroxylation with an inhibition constant (K(i)) value of 6.3 MUg/mL in a noncompetitive manner. Corydalis tuber extract competitively inhibited CYP2D6-mediated bufuralol 1'-hydroxylation, with a K(i) value of 3.7 MUg/mL, whereas Pharbitidis semen extract showed no inhibition. The volume in which the dose could be diluted to generate an IC(50) equivalent concentration (volume per dose index) value of DA-9701 for inhibition of CYP2D6 activity was 1.16 L/dose, indicating that DA-9701 may not be a potent CYP2D6 inhibitor. Further clinical studies are warranted to evaluate the in vivo extent of the observed in vitro interactions. PMID- 22548119 TI - Sulfotanshinone sodium injection for unstable angina pectoris: a systematic review of randomized controlled trials. AB - Objective. To assess the effect of sulfotanshinone sodium injection for unstable angina. Methods. We searched for published and unpublished studies up to June 2011. We included randomized controlled trials that confoundedly addressed the effect of sulfotanshinone sodium injection in the treatment of unstable angina. Results. Twenty-five studies involving 2,377 people were included. There was no evidence that sulfotanshinone sodium alone had better or worse effects to routine western medicine treatments in improving clinical symptoms (RR 1.00, 95% CI 0.90 to 1.11) and ECG (RR 0.97, 95% CI 0.87 to 1.09). However, there was evidence that sulfotanshinone sodium combined with western medications was a better treatment option than western medications alone in improving clinical symptoms (RR 1.28, 95% CI 1.23 to 1.3), ECG (RR 1.26, 95% CI 1.18 to 1.35), C-reaction protein (mean difference 2.10, 95% CI 1.63 to 2.58), and IL-6 (mean difference -3.85, 95% CI 4.10 to -3.60). There was no difference between sulfotanshinone sodium plus western medications and western medications alone affecting mortality (RR 0.50, 95% CI 0.02 to 12.13). Conclusion. Compared with western medications alone, sulfotanshinone sodium combined with western medications may provide more benefits for patients with unstable angina. Further large-scale high-quality trials are warranted. PMID- 22548120 TI - Safety and Efficacy of Tien-Hsien Liquid Practical in Patients with Refractory Metastatic Breast Cancer: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Phase IIa Trial. AB - To evaluate the safety and efficacy of Tien-Hsien Liquid Practical (THL-P), a Chinese herbal mixture, in patients with refractory metastatic breast cancer, we performed a randomized, double-blind, placebo-controlled, parallel-group, phase IIa pilot trial. Patients were randomly assigned to either receive THL-P or matching placebo and followed up every 4 weeks for 24 weeks. The primary endpoint was changes in the global health status/quality of life (GHS/QOL) scale. The secondary endpoints were changes in functional and symptom scales, immunomodulating effects, and adverse events. Sixty-three patients were enrolled between June 2009 and June 2011. The intent-to-treat population included 28 patients in the THL-P group and 11 patients in the placebo group. Compared to the placebo group, the THL-P group had significant improvement from baseline to last visit in GHS/QOL (41.7 versus -33.3; P < 0.05), CD3, CD4/CD8, CD19, CD16+56 positive cells (P < 0.05), and higher levels of physical, role, emotional, and cognitive functioning, as well as decreased fatigue and systemic side effects. Treatment-related adverse events were mild constipation and localized itching, and no serious adverse events were reported. THL-P appears to be a safe alternative adjuvant treatment for patients with refractory metastatic breast cancer, as it effectively improves QOL and palliates cancer-related symptoms. PMID- 22548121 TI - Bioguided Fractionation Shows Cassia alata Extract to Inhibit Staphylococcus epidermidis and Pseudomonas aeruginosa Growth and Biofilm Formation. AB - Plant extracts have a long history to be used in folk medicine. Cassia alata extracts are known to exert antibacterial activity but details on compounds and mechanism of action remain poorly explored. We purified and concentrated the aqueous leaf extract of C. alata by reverse phase-solid phase extraction and screened the resulting CaRP extract for antimicrobial activity. CaRP extract exhibited antimicrobial activity for Pseudomonas aeruginosa, Staphylococcus epidermidis, S. aureus, and Bacillus subtilis. CaRP also inhibited biofilm formation of S. epidermidis and P. aeruginosa. Several bacterial growth inhibiting compounds were detected when CaRP extract was fractionated by TLC chromatography coupled to bioautography agar overlay technique. HPLC chromatography of CaRP extract yielded 20 subfractions that were tested by bioautography for antimicrobial activity against S. aureus and S. epidermidis. Five bioactive fractions were detected and chemically characterized, using high resolution mass spectrometry (qTOF-MS/MS). Six compounds from four fractions could be characterized as kaempferol, kaempferol-O-diglucoside, kaempferol-O glucoside, quercetin-O-glucoside, rhein, and danthron. In the Salmonella/microsome assay CaRP showed weak mutagenicity (MI < 3) only in strain TA98, pointing to a frameshift mutation activity. These results indicate that C. alata leaf extract contains a minimum of 7 compounds with antimicrobial activity and that these together or as single substance are active in preventing formation of bacterial biofilm, indicating potential for therapeutic applications. PMID- 22548122 TI - Natural product nitric oxide chemistry: new activity of old medicines. AB - The use of complementary and alternative medicine (CAM) as a therapy and preventative care measure for cardiovascular diseases (CVD) may prove to be beneficial when used in conjunction with or in place of conventional medicine. However, the lack of understanding of a mechanism of action of many CAMs limits their use and acceptance in western medicine. We have recently recognized and characterized specific nitric oxide (NO) activity of select alternative and herbal medicines that may account for many of their reported health benefits. The ability of certain CAM to restore NO homeostasis both through enhancing endothelial production of NO and by providing a system for reducing nitrate and nitrite to NO as a compensatory pathway for repleting NO bioavailability may prove to be a safe and cost-effective strategy for combating CVD. We will review the current state of science behind NO activity of herbal medicines and their effects on CVD. PMID- 22548123 TI - Testing homeopathy in mouse emotional response models: pooled data analysis of two series of studies. AB - Two previous investigations were performed to assess the activity of Gelsemium sempervirens (Gelsemium s.) in mice, using emotional response models. These two series are pooled and analysed here. Gelsemium s. in various homeopathic centesimal dilutions/dynamizations (4C, 5C, 7C, 9C, and 30C), a placebo (solvent vehicle), and the reference drugs diazepam (1 mg/kg body weight) or buspirone (5 mg/kg body weight) were delivered intraperitoneally to groups of albino CD1 mice, and their effects on animal behaviour were assessed by the light-dark (LD) choice test and the open-field (OF) exploration test. Up to 14 separate replications were carried out in fully blind and randomised conditions. Pooled analysis demonstrated highly significant effects of Gelsemium s. 5C, 7C, and 30C on the OF parameter "time spent in central area" and of Gelsemium s. 5C, 9C, and 30C on the LD parameters "time spent in lit area" and "number of light-dark transitions," without any sedative action or adverse effects on locomotion. This pooled data analysis confirms and reinforces the evidence that Gelsemium s. regulates emotional responses and behaviour of laboratory mice in a nonlinear fashion with dilution/dynamization. PMID- 22548124 TI - A dried yeast fermentate prevents and reduces inflammation in two separate experimental immune models. AB - Diverse and significant benefits against cold/flu symptoms and seasonal allergies have been observed with a dried fermentate (DF) derived from Saccharomyces cerevisiae (EpiCor) in multiple published randomized trials. To determine if DF may influence other immune conditions, two separate animal studies were conducted. Study 1 examined the ability of DF to prevent or reduce inflammation when given orally for 14 days to rats prior to receiving 1% carrageenan (localized inflammation model). DF significantly (P < 0.05) reduced swelling at all time points (1, 2, 3, 6, 12, and 24 hours) versus the control. Edema severity and PGE2 levels were reduced by approximately 50% and 25% (P < 0.05), respectively. Study 2 examined the ability of DF to treat established inflammation induced by type-2 collagen in mice over 4 weeks (autoimmune arthritis model). Significantly reduced arthritis scores, antibody response to type-2 collagen, and interferon-gamma levels were observed compared to controls (all parameters P < 0.05). DF favorably impacts multiple acute and potentially chronic immunologic inflammatory control mechanisms and should be further tested in clinical trials. PMID- 22548125 TI - Multiple Subject Barycentric Discriminant Analysis (MUSUBADA): how to assign scans to categories without using spatial normalization. AB - We present a new discriminant analysis (DA) method called Multiple Subject Barycentric Discriminant Analysis (MUSUBADA) suited for analyzing fMRI data because it handles datasets with multiple participants that each provides different number of variables (i.e., voxels) that are themselves grouped into regions of interest (ROIs). Like DA, MUSUBADA (1) assigns observations to predefined categories, (2) gives factorial maps displaying observations and categories, and (3) optimally assigns observations to categories. MUSUBADA handles cases with more variables than observations and can project portions of the data table (e.g., subtables, which can represent participants or ROIs) on the factorial maps. Therefore MUSUBADA can analyze datasets with different voxel numbers per participant and, so does not require spatial normalization. MUSUBADA statistical inferences are implemented with cross-validation techniques (e.g., jackknife and bootstrap), its performance is evaluated with confusion matrices (for fixed and random models) and represented with prediction, tolerance, and confidence intervals. We present an example where we predict the image categories (houses, shoes, chairs, and human, monkey, dog, faces,) of images watched by participants whose brains were scanned. This example corresponds to a DA question in which the data table is made of subtables (one per subject) and with more variables than observations. PMID- 22548126 TI - Craniosynostosis. PMID- 22548127 TI - CFD and PIV analysis of hemodynamics in a growing intracranial aneurysm. AB - Hemodynamics is thought to be a fundamental factor in the formation, progression, and rupture of cerebral aneurysms. Understanding these mechanisms is important to improve their rupture risk assessment and treatment. In this study, we analyze the blood flow field in a growing cerebral aneurysm using experimental particle image velocimetry (PIV) and computational fluid dynamics (CFD) techniques. Patient-specific models were constructed from longitudinal 3D computed tomography angiography images acquired at 1-y intervals. Physical silicone models were constructed from the computed tomography angiography images using rapid prototyping techniques, and pulsatile flow fields were measured with PIV. Corresponding CFD models were created and run under matching flow conditions. Both flow fields were aligned, interpolated, and compared qualitatively by inspection and quantitatively by defining similarity measures between the PIV and CFD vector fields. Results showed that both flow fields were in good agreement. Specifically, both techniques provided consistent representations of the main intra-aneurysmal flow structures and their change during the geometric evolution of the aneurysm. Despite differences observed mainly in the near wall region, and the inherent limitations of each technique, the information derived is consistent and can be used to study the role of hemodynamics in the natural history of intracranial aneurysms. PMID- 22548128 TI - Engineering a thermo-stable superoxide dismutase functional at sub-zero to >50 degrees C, which also tolerates autoclaving. AB - Superoxide dismutase (SOD) is a critical enzyme associated with controlling oxygen toxicity arising out of oxidative stress in any living system. A hyper thermostable SOD isolated from a polyextremophile higher plant Potentilla atrosanguinea Lodd. var. argyrophylla (Wall. ex Lehm.) was engineered by mutation of a single amino acid that enhanced the thermostability of the enzyme to twofold. The engineered enzyme was functional from sub-zero temperature to >50 degrees C, tolerated autoclaving (heating at 121 degrees C, at a pressure of 1.1 kg per square cm for 20 min) and was resistant to proteolysis. The present work is the first example to enhance the thermostability of a hyper-thermostable protein and has potential to application to other proteins for enhancing thermostability. PMID- 22548129 TI - Superconductivity above 30 K in alkali-metal-doped hydrocarbon. AB - The recent discovery of superconductivity with a transition temperature (T(c)) at 18 K in K(x)picene has extended the possibility of high-T(c) superconductors in organic materials. Previous experience based on similar hydrocarbons, like alkali metal doped phenanthrene, suggested that even higher transition temperatures might be achieved in alkali-metals or alkali-earth-metals doped such polycyclic aromatic-hydrocarbons (PAHs), a large family of molecules composed of fused benzene rings. Here we report the discovery of high-T(c) superconductivity at 33 K in K-doped 1,2:8,9-dibenzopentacene (C(30)H(18)). To our best knowledge, it is higher than any T(c) reported previously for an organic superconductor under ambient pressure. This finding provides an indication that superconductivity at much higher temperature may be possible in such PAHs system and is worthy of further exploration. PMID- 22548130 TI - Deaths from Sickle Cell Disease in Intensive Care Units: Can we do better? PMID- 22548131 TI - A new cellular weapon to kill leukaemic B-cells. PMID- 22548133 TI - Icterus Neonatorum in Near-Term and Term Infants: An overview. AB - Neonatal jaundice is the yellowish discoloration of the skin and/or sclerae of newborn infants caused by tissue deposition of bilirubin. Physiological jaundice is mild, unconjugated (indirect-reacting) bilirubinaemia, and affects nearly all newborns. Physiological jaundice levels typically peak at 5 to 6 mg/dL (86 to 103 MUmol/L) at 72 to 96 hours of age, and do not exceed 17 to 18 mg/dL (291-308 MUmol/L). Levels may not peak until seven days of age in Asian infants, or in infants born at 35 to 37 weeks' gestation. Higher levels of unconjugated hyperbilirubinaemia are considered pathological and occur in a variety of conditions. The clinical features and management of unconjugated hyperbilirubinaemia in healthy near-term and term infants, as well as bilirubin toxicity and the prevention of kernicterus, are reviewed here. The pathogenesis and aetiology of this disorder are discussed separately. PMID- 22548132 TI - Vitamin D Deficiency: This clandestine endemic disease is veiled no more. AB - Recently, scientists have generated a strong body of evidence providing new information about the preventive effect of vitamin D on a broad range of disorders. This evidence suggests that vitamin D is much more than a nutrient needed for bone health; it is an essential hormone required for regulation of a large number of physiological functions. Sufficient concentration of serum 25 hydroxyvitamin D is essential for optimising human health. This article reviews the present state-of-the-art knowledge about vitamin D's status worldwide and refers to recent articles discussing some of the general background of vitamin D, including sources, benefits, deficiencies, and dietary requirements, especially in pregnancy. They offer evidence that vitamin D deficiency could be a major public health burden in many parts of the world, mostly because of sun deprivation. The article also discusses the debate about optimal concentration of circulating serum 25-hydroxyvitamin D, and explores different views on the amount of vitamin D supplementation required to achieve and maintain this concentration. PMID- 22548134 TI - Snoring-induced nerve lesions in the upper airway. AB - The prevalence of habitual snoring is extremely high in the general population, and is reported to be roughly 40% in men and 20% in women. The low-frequency vibrations of snoring may cause physical trauma and, more specifically, peripheral nerve injuries, just as jobs which require workers to use vibrating tools over the course of many years result in local nerve lesions in the hands. Histopathological analysis of upper airway (UA) muscles have shown strong evidence of a varying severity of neurological lesions in groups of snoring patients. Neurophysiological assessment shows evidence of active and chronic denervation and re-innervation in the palatopharyngeal muscles of obstructive sleep apnoea (OSA) patients. Neurogenic lesions of UA muscles induced by vibration trauma impair the reflex dilation abilities of the UA, leading to an increase in the possibility of UA collapse. The neurological factors which are partly responsible for the progressive nature of OSAS warrant the necessity of early assessment in habitual snorers. PMID- 22548135 TI - Emerging Burden of Frail Young and Elderly Persons in Oman: For whom the bell tolls? AB - Recent improvements in health and an increased standard of living in Oman have led to a reduction in environment-related and infectious diseases. Now the country is experiencing an epidemiological transition characterised by a baby boom, youth bulge and increasing longevity. Common wisdom would therefore suggest that Omanis will suffer less ill health. However, a survey of literature suggests that chronic non-communicable diseases are unexpectedly becoming common. This is possibly fuelled by some socio-cultural patterns specific to Oman, as well as the shortcomings of the 'miracle' of health and rapid modernisation. Unfortunately, such new diseases do not spare younger people; a proportion of them will need the type of care usually reserved for the elderly. In addition, due to their pervasive and refractory nature, these chronic non-communicable diseases seem impervious to the prevailing 'cure-oriented' health care system. This situation therefore calls for a paradigm shift: a health care system that goes beyond a traditional cure-orientation to provide care services for the chronically sick of all ages. PMID- 22548136 TI - Adult Sickle Cell Disease: A Five-year Experience of Intensive Care Management in a University Hospital in Oman. AB - OBJECTIVES: Sickle cell disease (SCD) is an inherited disease caused by an abnormal type of haemoglobin. It is one of the most common genetic blood disorders in the Gulf area, including Oman. It may be associated with complications requiring intensive care unit (ICU) admission. This study investigated the causes of ICU admission for SCD patients. METHODS: This was a retrospective analysis of all adult patients >=12 years old with SCD admitted to Sultan Qaboos University Hospital (SQUH) ICU between 1st January 2005 and 31st December 2009. RESULTS: A total number of 49 sickle cell patients were admitted 56 times to ICU. The reasons for admission were acute chest syndrome (69.6%), painful crises (16.1%), multi-organ failure (7.1%) and others (7.2%). The mortality for SCD patients in our ICU was 16.1%. The haemoglobin (Hb) and Hb S levels at time of ICU admission were studied as predictors of mortality and neither showed statistical significance by Student's t-test. The odds ratio, with 95% confidence intervals, was used to study other six organ supportive measures as predictors of mortality. The need for inotropic support and mechanical ventilation was a good predictor of mortality. While the need for non-invasive ventilation, haemofiltration, blood transfusions and exchange transfusions were not significant predictors of mortality. CONCLUSION: Acute chest syndrome is the main cause of ICU admission in SCD patient. Unlike other supportive measures, the use of inotropic support and/or mechanical ventilation is an indicator of high mortality rate SCD patient. PMID- 22548137 TI - Putting Research Findings into Clinical Practice: Feasibility of integrated evidence-based care pathways in otorhinolaryngology head and neck surgery at Sultan Qaboos University Hospital, Oman. AB - OBJECTIVES: A perception exists that clinicians in Oman are reluctant to adopt evidence-based practice (EBP). This pilot study was undertaken to study the feasibility of using EBP pathways at the point of care in otorhinolaryngology head and neck surgery. The ultimate aim was to facilitate EBP with the probability of developing a new system for implementing research findings/translational research at the clinical point of care. METHODS: A cross sectional prospective questionnaire pilot survey of clinicians at Sultan Qaboos University Hospital (SQUH), Oman, a tertiary care medical centre, was undertaken. Respondents included 135 physicians and surgeons with between 3 months and 25 years of clinical experience and included personnel ranging from interns to senior consultants, in areas ranging from primary care to specialist care. RESULTS: Of those polled, 90% (95% confidence interval (CI) 85-95%) either strongly agreed or agreed that evidence-based practice protocols (EBPP) could help in decision making. A total of 87.4% of participants (95% CI 81.8-93%) either strongly agreed or agreed that EBPPs can improve clinical outcomes; 91.8% of participants (95% CI 87.2-96.4%) would use and apply EBPP in day-to-day care if they were available at the point of care and embedded in the hospital information system. CONCLUSIONS: The perception that clinicians at SQUH are reluctant to adopt EBP is incorrect. The introduction of EBP pathways is very feasible at the primary care level. Institutional support for embedding EBP in hospital information systems is needed as well as further outcome research to assess the improvement in quality of care. PMID- 22548138 TI - Caesarean Myomectomy: Feasibility and safety. AB - OBJECTIVES: Caesarean myomectomy has traditionally been discouraged due to fears of intractable haemorrhage and increased postoperative morbidity. However, a number of authors have recently shown that myomectomy during Caesarean section does not increase the risk of haemorrhage or postoperative morbidity. METHODS: We present a series of 8 cases from Sultan Qaboos University Hospital, Oman, where myomectomy was performed during Caesarean section for large lower segment fibroids. Seven were anterior lower segment fibroids, while one was a posterior lower uterine fibroid which interfered with closure of the uterine incision. The antenatal course, perioperative management, and postoperative morbidity are discussed. RESULTS: The average age of the women was 28.7 years and mean gestational age at delivery was 36.75 weeks. Regarding intra-operative blood loss, 1 patient lost 900 ml, 5 patients lost 1-1.5 litres, 2 lost 1.5-2 L, and 1 patient with a 10 x 12 cm fibroid lost 3.2 L. Despite the majority being large myomas (7 of the 8 patients had myomas >5 cm in size) and 50% being intramural, no hysterectomy was required. Stepwise devascularisation was necessary in one case and preoperative placement of uterine balloon catheters was necessary in another. The size of the fibroids was confirmed by histopathology. Myomectomy added 15 minutes to the operating time and 1 day to the hospital stay, but there was no significant postoperative morbidity. Neonatal outcome was good in all patients. CONCLUSION: In selected patients, myomectomy during Caesarean section is a safe and effective procedure at tertiary centres with experienced surgeons. PMID- 22548139 TI - Oxidative Stress and C-Reactive Protein in Patients with Cerebrovascular Accident (Ischaemic Stroke): The role of Ginkgo biloba extract. AB - OBJECTIVES: This study aimed to investigate the presence of oxidative stress and inflammation in ischaemic stroke patients by measuring malondialdehyde (MDA), total antioxidant status (TAS), and highly-sensitivity C-reactive protein (hsCRP) in the early post-ischaemic period, and to determine the role of Ginkgo biloba therapy in correcting the markers of oxidative stress and inflammation. METHODS: This study was conducted at Ibn Seena Hospital, Mosul City, Iraq and included 31 cerebrovascular accident (CVA) patients and 30 healthy controls. Ischaemic stroke patients were divided into two groups: group I (n = 15) received conventional therapy; group II (n = 16) received conventional therapy with G. biloba (1500 mg/day) for 30 days. Blood samples were obtained from patients and controls before treatment and assays done of serum levels of MDA, TAS, and hsCRP. For CVA patients, a post-treatment blood sample was taken and the same parameters reassessed. RESULTS: Compared with the controls, patients' serum levels of MDA, and hsCRP were significantly higher (P <=0.001) and TAS significantly lower. Group I and II patients reported a significant reduction in serum levels of MDA and hsCRP and a significant increase in serum levels of TAS, in comparison with pre-treatment levels. There was no significant difference (P = 0.19) in serum MDA levels between groups I and II, whereas, serum TAS levels were significantly higher (P <=0.01) and hsCRP significantly lower (P <=0.01) in group II. CONCLUSION: Acute stroke is associated with oxidative stress and inflammatory response in the early period. G. biloba plays a potential role in reducing oxidative damage and inflammatory response. PMID- 22548141 TI - Assessment methods of an undergraduate psychiatry course at a saudi university. AB - OBJECTIVES: In Arab countries there are few studies on assessment methods in the field of psychiatry. The objective of this study was to assess the outcome of different forms of psychiatric course assessment among fifth year medical students at King Faisal University, Saudi Arabia. METHODS: We examined the performance of 110 fifth-year medical students through objective structured clinical examinations (OSCE), traditional oral clinical examinations (TOCE), portfolios, multiple choice questions (MCQ), and a written examination. RESULTS: The score ranges in TOCE, OSCE, portfolio, and MCQ were 32-50, 7-15, 5-10 and 22 45, respectively. In regression analysis, there was a significant correlation between OSCE and all forms of psychiatry examinations, except for the MCQ marks. OSCE accounted for 65.1% of the variance in total clinical marks and 31.5% of the final marks (P = 0.001), while TOCE alone accounted for 74.5% of the variance in the clinical scores. CONCLUSIONS: This study demonstrates a consistency among the students' assessment methods used in the psychiatry course, particularly the clinical component, in an integrated manner. This information would be useful for future developments in undergraduate teaching. PMID- 22548140 TI - Psychological health of first-year health professional students in a medical university in the United arab emirates. AB - OBJECTIVES: The aim of this study was to assess the psychological health of first year health professional students and to study sources of student stress. METHODS: All first-year students (N = 125) of the Gulf Medical University (GMU) in Ajman, United Arab Emirates (UAE), were invited to participate in a voluntary, anonymous, self-administered, questionnaire-based survey in January 2011. Psychological health was assessed using the 12-item General Health Questionnaire. A 24-item questionnaire, with items related to academic, psychosocial and health domains was used to identify sources of stress. Pearson's chi-squared test and the Mann-Whitney U-test were used for testing the association between psychological morbidity and sources of stress. RESULTS: A total of 112 students (89.6%) completed the survey and the overall prevalence of psychological morbidity was found to be 33.6%. The main academic-related sources of stress were 'frequency of exams', 'academic workload', and 'time management'. Major psychosocial stressors were 'worries regarding future', 'high parental expectations', 'anxiety', and 'dealing with members of the opposite sex'. Health related issues were 'irregular eating habits', 'lack of exercise', and 'sleep related problems'. Psychological morbidity was not significantly associated with any of the demographic factors studied. However, total stress scores and academics-related domain scores were significantly associated with psychological morbidity. CONCLUSION: Psychological morbidity was seen in one in three first year students attending GMU. While worries regarding the future and parental expectations were sources of stress for many students, psychological morbidity was found to be significantly associated with only the total stress and the academic-related domain scores. PMID- 22548142 TI - Extra-luminal Air Fluid Level on Abdominal X-ray of a Patient with Isolated Jejunal Blow Out: Case report. AB - Patients with trivial blunt abdominal trauma may present with isolated jejunal blow out (IJBO). A high index of suspicion is required as delayed presentation or delayed diagnosis may increase morbidity. Presentation with frank perforation peritonitis can be diagnosed by abdominal X-rays. We report the case of a patient who presented with features of peritonitis 10 days after being injured by a knee kick trauma. An erect abdominal X-ray showed extraluminal air-fluid levels, suggesting a hollow viscous injury which on exploration was found to be IJBO. PMID- 22548143 TI - Ovarian Hernia: A rarity. AB - Ovarian hernias are extremely rare. The prevalence of ovaries and fallopian tubes in operable inguinal hernias is only about 2.9%. We report here an unusual case of an ovary in a hernia sac in an adult female. She presented with symptoms and signs of an incarcerated left inguinal hernia. The left ovary contained a haemorrhagic cyst and, along with the left fallopian tube and broad ligament, these were found in the sac. She underwent a left ovarian cystectomy and the inguinal hernia was repaired with mesh. PMID- 22548144 TI - Unusual presentation of oral squamous cell carcinoma in a young woman. AB - Oral squamous cell carcinoma (OSCC) is the most common oral malignant neoplasm, mainly affecting individuals over 50 years old with a history of tobacco and alcohol use. The occurrence of this oral cancer in individuals under 40 years old is unusual and, when it does occur, shows a weaker relation to those risk factors and a more aggressive clinical course. Due to the paucity of reports in this population, it is difficult to prove its increasing trend. A case of oral squamous cell carcinoma in a 39-year-old woman with no history of tobacco or alcohol use is reported. Clinical and histopathological findings, aetiology, and treatment are discussed. The increasing trend of oral squamous cell carcinoma in young women without known risk factors highlights the need for clinicians to be prepared to diagnose this lesion quickly and precisely, providing a better prognosis, chance of survival, and quality of life for the patient. PMID- 22548145 TI - Amyand's Hernia: Study of four cases and literature review. AB - The presence of the appendix in an inguinal hernial sac is described as Amyand's hernia. It is a rare entity which presents mostly at the exploration of the inguinal canal. The appendix may be apparently normal or have all the features of acute appendicitis with its possible complications. We report four cases of Amyand's hernia which were treated at Sultan Qaboos University Hospital, Oman. All patients underwent appendectomy. In three cases, the inguinal hernia were repaired with Vipro mesh while, in the remaining case, a darning repair was done with Prolene sutures. PMID- 22548146 TI - Acquired methemoglobinaemia. AB - Acquired methemoglobinaemia is a relatively rare condition and, therefore infrequently encountered in acute medical practice. Suspicion of the condition may be triggered when the measured PaO2 is 'out of keeping' with the oxygen saturations that are discovered with pulse oximetry. We describe two separate cases of acquired methemoglobinaemia secondary to the recreational use of alkyl nitrites ('poppers'). The patients presented at separate times to two different teaching hospitals in London, UK. The similarity of these cases has led the authors to conclude that a raised awareness of this potentially fatal condition, and its association with a widely-available recreational drug, is necessary to ensure a correct and timely diagnosis. PMID- 22548147 TI - Lost and found: catastrophic en block embolism of a mechanical prosthetic valve thrombus after thrombolytic therapy. PMID- 22548148 TI - Statin of Preference to Treat Dyslipidaemia in Patients with Renal Dysfunction: Cues from (SATURN). PMID- 22548149 TI - Suture Artefacts: Explored through polarising microscope. PMID- 22548150 TI - Cognitive functions and cognitive reserve in relation to blood pressure components in a population-based cohort aged 53 to 94 years. AB - In 288 men and women from general population in a cross-sectional survey, all neuropsychological tests were negatively associated with age; memory and executive function were also positively related with education. The hypertensives (HT) were less efficient than the normotensives (NT) in the test of memory with interference at 10 sec (MI-10) (-33%, P = 0.03), clock drawing test (CLOX) (-28%, P < 0.01), and mini-mental state examination (MMSE) (-6%, P = 0.02). Lower MMSE, MI-10, and CLOX were predicted by higher systolic (odds ratio, OR, 0.97, P = 0.02; OR 0.98, P < 0.005; OR 0.95, P < 0.001) and higher pulse blood pressure (BP) (OR 0.97, P = 0.02; OR 0.97, P < 0.01; and 0.95, P < 0.0001). The cognitive reserve index (CRI) was 6% lower in the HT (P = 0.03) and was predicted by higher pulse BP (OR 0.82, P < 0.001). The BP vectors of lower MMSE, MI-10, and CLOX were directed towards higher values of systolic and diastolic BP, that of low CRI towards higher systolic and lower diastolic. The label of hypertension and higher values of systolic or pulse BP are associated to worse memory and executive functions. Higher diastolic BP, although insufficient to impair cognition, strengthens this association. CRI is predicted by higher systolic BP associated to lower diastolic BP. PMID- 22548151 TI - Recombinant T-Cell Receptor Ligand (RTL) for Treatment of Multiple Sclerosis: A Double-Blind, Placebo-Controlled, Phase 1, Dose-Escalation Study. AB - Background. Recombinant T-cell receptor ligand 1000 (RTL1000) is a single-chain protein construct containing the outer two domains of HLA-DR2 linked to myelin oligodendrocyte-glycoprotein- (MOG-) 35-55 peptide. Analogues of RTL1000 induce T cell tolerance, reverse clinical and histological disease, and promote repair in experimental autoimmune encephalomyelitis (EAE) in DR2 transgenic, C57BL/6, and SJL/J mice. Objective. Determining the maximum tolerated dose, safety, and tolerability of RTL1000 in multiple sclerosis (MS) subjects. Methods. This was a multicenter, Phase I dose-escalation study in HLA-DR2(+) MS subjects. Consecutive cohorts received RTL1000 doses of 2, 6, 20, 60, 200, and 100 mg, respectively. Subjects within each cohort randomly received a single intravenous infusion of RTL1000 or placebo at a 4 : 2 ratio. Safety monitoring included clinical, laboratory, and brain magnetic resonance imaging (MRI) evaluations. Results. Thirty-four subjects completed the protocol. All subjects tolerated the 2-60 mg doses of RTL1000. Doses >=100 mg caused hypotension and diarrhea in 3 of 4 subjects, leading to discontinuation of further enrollment. Conclusions. The maximum tolerated dose of RTL1000 in MS subjects is 60 mg, comparable to effective RTL doses in EAE. RTL1000 is a novel approach for MS treatment that may induce immunoregulation without immunosuppression and promote neural repair. PMID- 22548152 TI - Financial motivation undermines maintenance in an intensive diet and activity intervention. AB - Financial incentives are widely used in health behavior interventions. However, self-determination theory posits that emphasizing financial incentives can have negative consequences if experienced as controlling. Feeling controlled into performing a behavior tends to reduce enjoyment and undermine maintenance after financial contingencies are removed (the undermining effect). We assessed participants' context-specific financial motivation to participate in the Make Better Choices trial-a trial testing four different strategies for improving four health risk behaviors: low fruit and vegetable intake, high saturated fat intake, low physical activity, and high sedentary screen time. The primary outcome was overall healthy lifestyle change; weight loss was a secondary outcome. Financial incentives were contingent upon meeting behavior goals for 3 weeks and became contingent upon merely providing data during the 4.5-month maintenance period. Financial motivation for participation was assessed at baseline using a 7-item scale (alpha = .97). Across conditions, a main effect of financial motivation predicted a steeper rate of weight regained during the maintenance period, t(165) = 2.15, P = .04. Furthermore, financial motivation and gender interacted significantly in predicting maintenance of healthy diet and activity changes, t(160) = 2.42, P = .016, such that financial motivation had a more deleterious influence among men. Implications for practice and future research on incentivized lifestyle and weight interventions are discussed. PMID- 22548154 TI - Maternal Hyperglycemia Disrupts Histone 3 Lysine 36 Trimethylation of the IGF-1 Gene. AB - In utero environmental adaptation may predispose to lifelong morbidity. Organisms fine-tune gene expression to achieve environmental adaptation by epigenetic alterations of histone markers of gene accessibility. One example of epigenetics is how uteroplacental insufficiency-induced intrauterine growth restriction (IUGR), which predisposes to adult onset insulin resistance, decreases postnatal IGF-1 mRNA variants and the gene elongation mark histone 3 trimethylation of lysine 36 of the IGF-1 gene (H3Me3K36). Limitations in the study of epigenetics exist due to lack of a primary transgenic epigenetic model. Therefore we examined the epigenetic profile of insulin-like growth factor 1 (IGF-1) in a well characterized rat model of maternal hyperglycemia to determine if the epigenetic profile of IGF-1 is conserved in disparate models of in utero adaptation. We hypothesized that maternal hyperglycemia would increase IGF-1 mRNA variants and H3Me3K36. However maternal hyperglycemia decreased hepatic IGF-1 mRNA variants and H3Me3K36. This finding is intriguing given that despite different prenatal insults and growth, both maternal hyperglycemia and IUGR predispose to adult onset insulin resistance. We speculate that H3Me3K36 of the IGF-1 gene is sensitive to the glucose level of the prenatal environment, with resultant alteration of IGF-1 mRNA expression and ultimately vulnerability to adult onset insulin resistance. PMID- 22548153 TI - The Effect of Neonatal Leptin Antagonism in Male Rat Offspring Is Dependent upon the Interaction between Prior Maternal Nutritional Status and Post-Weaning Diet. AB - Epidemiological and experimental studies report associations between overweight mothers and increased obesity risk in offspring. It is unclear whether neonatal leptin regulation mediates this association between overweight mothers and offspring obesity. We investigated the effect of neonatal treatment with a leptin antagonist (LA) on growth and metabolism in offspring of mothers fed either a control or a high fat diet. Wistar rats were fed either a control (CON) or a high fat diet (MHF) during pregnancy and lactation. Male CON and MHF neonates received either saline (S) or a rat-specific pegylated LA on days 3, 5, and 7. Offspring were weaned onto either a control or a high fat (hf) diet. At day 100, body composition, blood glucose, beta-hydroxybutyrate and plasma leptin and insulin were determined. In CON and MHF offspring, LA increased neonatal bodyweights compared to saline-treated offspring and was more pronounced in MHF offspring. In the post-weaning period, neonatal LA treatment decreased hf diet-induced weight gain but only in CON offspring. LA treatment induced changes in body length, fat mass, body temperature, and bone composition. Neonatal LA treatment can therefore exert effects on growth and metabolism in adulthood but is dependent upon interactions between maternal and post-weaning nutrition. PMID- 22548155 TI - Towards Elimination of Mother-to-Child Transmission of HIV: The Impact of a Rapid Results Initiative in Nyanza Province, Kenya. AB - Many HIV-positive pregnant women and infants are still not receiving optimal services, preventing the goal of eliminating mother-to-child transmission (MTCT) and improving maternal child health overall. A Rapid Results Initiative (RRI) approach was utilized to address key challenges in delivery of prevention of MTCT (PMTCT) services including highly active antiretroviral therapy (HAART) uptake for women and infants. The RRI was conducted between April and June 2011 at 119 health facilities in five districts in Nyanza Province, Kenya. Aggregated site level data were compared at baseline before the RRI (Oct 2010-Jan 2011), during the RRI, and post-RRI (Jul-Sep 2011) using pre-post cohort analysis. HAART uptake amongst all HIV-positive pregnant women increased by 40% (RR 1.4, 95% CI 1.2-1.7) and continued to improve post-RRI (RR 1.6, 95% CI 1.4-1.8). HAART uptake in HIV positive infants remained stable (RR 1.1, 95% CI 0.9-1.4) during the RRI and improved by 30% (RR 1.3, 95% CI 1.0-1.6) post-RRI. Significant improvement in PMTCT services can be achieved through introduction of an RRI, which appears to lead to sustained benefits for pregnant HIV-infected women and their infants. PMID- 22548156 TI - Prevalence and Risk Factors Associated with Precancerous Cervical Cancer Lesions among HIV-Infected Women in Resource-Limited Settings. AB - Objective. To assess the prevalence and identified associated risk factors for precancerous cervical cancer lesions among HIV-infected women in resource-limited settings in Kenya. Methods. HIV-infected women attending the ART clinic at the Nazareth Hospital ART clinic between June 2009 and September 2010. Multivariate logistic regression model with odds ratios and 95% confidence intervals (CI) were estimated after controlling for important covariates. Result. A total of 715 women were screened for cervical cancer. The median age of the participants was 40 years (range 18-69 years). The prevalence of precancerous lesions (CINI, CINII, CIN III, ICC) was 191 (26.7%). After controlling for other variables in logistic regression analysis, cervical precancerous lesions were associated with not being on ART therapy; whereby non-ART were 2.21 times more likely to have precancerous lesions than ART patients [(aOR) = 2.21, 95% CI (1.28-3.83)]. Conclusion. The prevalence of precancerous cervical lesions was lower than other similar settings. It is recommended that cancer screening of HIV-infected women should be an established practice. Availability and accessibility of these services can be done through their integration into HIV. Prompt initiation of HAART through an early enrollment into care has an impact on reducing the prevalence and progression of cervical precancerous lesions. PMID- 22548157 TI - Critical Care Nurses Inadequately Assess SAPS II Scores of Very Ill Patients in Real Life. AB - Background. Reliable ICU severity scores have been achieved by various healthcare workers but nothing is known regarding the accuracy in real life of severity scores registered by untrained nurses. Methods. In this retrospective multicentre audit, three reviewers independently reassessed 120 SAPS II scores. Correlation and agreement of the sum-scores/variables among reviewers and between nurses and the reviewers' gold standard were assessed globally and for tertiles. Bland and Altman (gold standard-nurses) of sum scores and regression of the difference were determined. A logistic regression model identifying risk factors for erroneous assessments was calculated. Results. Correlation for sum scores among reviewers was almost perfect (mean ICC = 0.985). The mean (+/-SD) nurse-registered SAPS II sum score was 40.3 +/- 20.2 versus 44.2 +/- 24.9 of the gold standard (P < 0.002 for difference) with a lower ICC (0.81). Bland and Altman assay was +3.8 +/- 27.0 with a significant regression between the difference and the gold standard, indicating overall an overestimation (underestimation) of lower (higher; >32 points) scores. The lowest agreement was found in high SAPS II tertiles for haemodynamics (k = 0.45-0.51). Conclusions. In real life, nurse-registered SAPS II scores of very ill patients are inaccurate. Accuracy of scores was not associated with nurses' characteristics. PMID- 22548158 TI - Bipolar disorder. PMID- 22548159 TI - The effectiveness and clinical usability of a handheld information appliance. AB - Clinical environments are complex, stressful, and safety critical-heightening the demand for technological solutions that will help clinicians manage health information efficiently and safely. The industry has responded by creating numerous, increasingly compact and powerful health IT devices that fit in a pocket, hook to a belt, attach to eyeglasses, or wheel around on a cart. Untethering a provider from a physical "place" with compact, mobile technology while delivering the right information at the right time and at the right location are generally welcomed in clinical environments. These developments however, must be looked at ecumenically. The cognitive load of clinicians who are occupied with managing or operating several different devices during the process of a patient encounter is increased, and we know from decades of research that cognitive overload frequently leads to error. "Technology crowding," enhanced by the plethora of mobile health IT, can actually become an additional millstone for busy clinicians. This study was designed to gain a deeper understanding of clinicians' interactions with a mobile clinical computing appliance (Motion Computing C5) designed to consolidate numerous technological functions into an all-in-one device. Features of usability and comparisons to current methods of documentation and task performance were undertaken and results are described. PMID- 22548160 TI - Academic-service partnerships in nursing: an integrative review. AB - This integrative review summarizes currently available evidence on academic service partnerships in the profession of nursing. More than 300 articles, published primarily in refereed journals, were accessed. Articles (110) were included in this review as they presented detailed and substantive information about any aspect of a nursing academic-service partnership. The majority were anecdotal in nature. Topics clustered around the following categories: pre requisites for successful partnerships, benefits of partnerships, types of partnerships, and workforce development with its themes of academic-practice progression and educational re-design. Many examples of partnerships between academic and service settings were thoroughly described and best practices suggested, most often, however, without formal evaluation of outcomes. Nursing leaders in both settings have a long tradition of partnering with very little replicable evidence to support their efforts. It is critical that future initiatives evaluate the effectiveness of these partnerships, not only to ensure quality of patient outcomes but also to maximize efforts at building capacity for tomorrow's workforce. PMID- 22548161 TI - Facets of parenting a child with hypoplastic left heart syndrome. AB - The purpose of the study was to conceptualize the needs of parents of young children with hypoplastic left heart syndrome (HLHS) to provide a theoretical framework to inform the development of future parent interventions. Participants were parents and grandparents (n = 53) of 15 young children who had undergone the Sano surgical approach for HLHS. Analysis of recorded and transcribed single interviews with each participant was done as directed by interpretive description methodology. A model of five facets of parenting was conceptualized. These included survival parenting, "hands-off" parenting, expert parenting, uncertain parenting, and supported parenting. The facets of parenting delineated through this study provide a theoretical framework that can be used to guide the development and evaluation of interventions for parents of children with complex congenital heart disease and potentially other life-threatening conditions. Each facet constitutes a critical component for educational or psychosocial intervention for parents. PMID- 22548162 TI - Building the clinical bridge to advance education, research, and practice excellence. AB - The University of Michigan School of Nursing and the Health System partnered to develop an undergraduate clinical education model as part of a larger project to advance clinical education, practice, and scholarship with education serving as the clinical bridge that anchors all three areas. The clinical model includes clusters of clinical units as the clinical home for four years of a student's education, clinical instruction through team mentorship, clinical immersion, special skills preparation, and student portfolio. The model was examined during a one-year pilot with junior students. Stakeholders were largely positive. Findings showed that Clinical Faculty engaged in more role modeling of teaching strategies as Mentors assumed more direct teaching used more clinical reasoning strategies. Students reported increased confidence and competence in clinical care by being integrated into the team and the Mentor's assignment. Two new full time faculty roles in the Health System support education, practice, and research. PMID- 22548163 TI - Differences in Perceptions of Patient Safety Culture between Charge and Noncharge Nurses: Implications for Effectiveness Outcomes Research. AB - The implementation of evidence-based practice guidelines can be influenced by nurses' perceptions of the organizational safety culture. Shift-by-shift management of each nursing unit is designated to a subset of staff nurses (charge nurses), whom are often recruited as champions for change. The findings indicate that compared to charge nurses, noncharge nurses were more positive about overall perceptions of safety (P = .05) and teamwork (P < .05). Among charge nurses, significant differences were observed based on the number of years' experience in charge: perception of teamwork within units [F(3, 365) = 3.52, P < .01]; overall perceptions of safety, [F(3, 365) = 4.20, P < .05]; safety grade for work area [F(3, 360) = 2.61, P < .05]; number of events reported within the last month [F(3, 362) = 3.49, P < .05]. These findings provide important insights to organizational contextual factors that may impact effectiveness outcomes research in the future. PMID- 22548164 TI - Is There Anything to Smile about? A Review of Oral Care for Individuals with Intellectual and Developmental Disabilities. AB - Individuals with intellectual and developmental disabilities (I/DD) are at risk for dental disease and face substantial challenges in accessing both routine and preventive dental services. In terms of unmet needs it ranks third, following residential services and employment opportunities for this particular group of people. Poorer oral health status negatively impacts overall health and one's quality of life. Factors contributing to this problem include significantly higher rates of dental caries, periodontal disease, poor oral hygiene, low expectations, fear of treatment, and lack of awareness among individuals and carers. Additional factors include problems accessing dental care or denial of services because of inadequate education and clinical training, inappropriate bias, or inadequate levels of compensation to providers. Strategies to improve service delivery include individualized and coordinated care services, education of individuals, carers, and providers, including both classroom and clinical experiences with special needs patients in dental programs. PMID- 22548165 TI - Becoming Socialized into a New Professional Role: LPN to BN Student Nurses' Experiences with Legitimation. AB - This paper presents findings from a qualitative descriptive study that explored the professional socialization experiences of Licensed Practical Nurses (LPNs) who attended an online university to earn a Baccalaureate degree in nursing (BN), a prerequisite to writing the Canadian Registered Nurse (RN) qualifying exam. The project was framed from a constructivist worldview and Haas and Shaffir's theory of legitimation. Participants were 27 nurses in a Post-LPN to BN program who came from across Canada to complete required practicums. Data was collected from digital recordings of four focus groups held in different cities. Transcripts were analyzed for themes and confirmed with participants through member checking. Two overarching themes were identified and are presented to explain how these unique adult learners sought to legitimize their emerging identity as Registered Nurses (RNs). First, Post-LPN to BN students need little, if any, further legitimation to affirm their identities as "nurse." Second, practicum interactions with instructors and new clinical experiences are key socializing agents. PMID- 22548166 TI - Minilaparoscopic colorectal resections: technical note. AB - Laparoscopic colorectal resections have been shown to provide short-term advantages in terms of postoperative pain, general morbidity, recovery, and quality of life. To date, long-term results have been proved to be comparable to open surgery irrefutably only for colon cancer. Recently, new trends keep arising in the direction of minimal invasiveness to reduce surgical trauma after colorectal surgery in order to improve morbidity and cosmetic results. The few reports available in the literature on single-port technique show promising results. Natural orifices endoscopic techniques still have very limited application. We focused our efforts in standardising a minilaparoscopic technique (using 3 to 5 mm instruments) for colorectal resections since it can provide excellent cosmetic results without changing the laparoscopic approach significantly. Thus, there is no need for a new learning curve as minilaparoscopy maintains the principle of instrument triangulation. This determines an undoubted advantage in terms of feasibility and reproducibility of the procedure without increasing operative time. Some preliminary experiences confirm that minilaparoscopic colorectal surgery provides acceptable results, comparable to those reported for laparoscopic surgery with regard to operative time, morbidity, and hospital stay. Randomized controlled studies should be conducted to confirm these early encouraging results. PMID- 22548170 TI - Peritoneal dialysis. PMID- 22548167 TI - Hypoxic-ischemic injury in the developing brain: the role of reactive oxygen species originating in mitochondria. AB - Mitochondrial dysfunction is the most fundamental mechanism of cell damage in cerebral hypoxia-ischemia and reperfusion. Mitochondrial respiratory chain (MRC) is increasingly recognized as a source for reactive oxygen species (ROS) in the postischemic tissue. Potentially, ROS originating in MRC can contribute to the reperfusion-driven oxidative stress, promoting mitochondrial membrane permeabilization. The loss of mitochondrial membranes integrity during reperfusion is considered as the major mechanism of secondary energy failure. This paper focuses on current data that support a pathogenic role of ROS originating from mitochondrial respiratory chain in the promotion of secondary energy failure and proposes potential therapeutic strategy against reperfusion driven oxidative stress following hypoxia-ischemia-reperfusion injury of the developing brain. PMID- 22548168 TI - Listen, learn, like! Dorsolateral prefrontal cortex involved in the mere exposure effect in music. AB - We used functional magnetic resonance imaging to investigate the neural basis of the mere exposure effect in music listening, which links previous exposure to liking. Prior to scanning, participants underwent a learning phase, where exposure to melodies was systematically varied. During scanning, participants rated liking for each melody and, later, their recognition of them. Participants showed learning effects, better recognising melodies heard more often. Melodies heard most often were most liked, consistent with the mere exposure effect. We found neural activations as a function of previous exposure in bilateral dorsolateral prefrontal and inferior parietal cortex, probably reflecting retrieval and working memory-related processes. This was despite the fact that the task during scanning was to judge liking, not recognition, thus suggesting that appreciation of music relies strongly on memory processes. Subjective liking per se caused differential activation in the left hemisphere, of the anterior insula, the caudate nucleus, and the putamen. PMID- 22548169 TI - Transcranial magnetic stimulation with the maximum voluntary muscle contraction facilitates motor neuron excitability and muscle force. AB - Three trials of transcranial magnetic stimulation (TMS) during the maximum voluntary muscle contraction (MVC) were repeated at 15-minute intervals for 1 hour to examine the effects on motor evoked potentials (MEPs) in the digital muscles and pinching muscle force before and after 4 high-intensity TMSs (test 1 condition) or sham TMS (test 2 condition) with MVC. Under the placebo condition, real TMS with MVC was administered only before and 1 hour after the sham TMS with MVC. Magnetic stimulation at the foramen magnum level (FMS) with MVC was performed by the same protocol as that for the test 2 condition. As a result, MEP sizes in the digital muscles significantly increased after TMS with MVC under test conditions compared with the placebo conditions (P < 0.05). Pinching muscle force was significantly larger 45 minutes and 1 hour after TMS with MVC under the test conditions than under the placebo condition (P < 0.05). FMS significantly decreased MEP amplitudes 60 minutes after the sham TMS with MVC (P < 0.005). The present results suggest that intermittently repeated TMS with MVC facilitates motor neuron excitabilities and muscle force. However, further studies are needed to confirm the effects of TMS with MVC and its mechanism. PMID- 22548171 TI - Skin perfusion pressure is a prognostic factor in hemodialysis patients. AB - Peripheral arterial disease (PAD) is common in hemodialysis patients and predicts a poor prognosis. We conducted a prospective cohort study to identify risk factors for PAD including skin perfusion pressure (SPP) in hemodialysis patients. The cohort included 373 hemodialysis patients among 548 patients who received hemodialysis at Oyokyo Kidney Research Institute, Hirosaki, Japan from August 2008 to December 2010. The endpoints were lower limb survival (peripheral angioplasty or amputation events) and overall survival of 2 years. Our results showed that <70 mmHg SPP was a poor prognosis for the lower limb survival and overall survival. We also identified age, history of cardiovascular disease, presence of diabetes mellitus, smoking history, and SPP < 70 mmHg as independent risk factors for lower limb survival and overall survival. Then, we constructed risk criteria using the significantly independent risk factors. We can clearly stratify lower limb survival and overall survival of the hemodialysis patients into 3 groups. Although the observation period is short, we conclude that SPP value has the potential to be a risk factor that predicts both lower limb survival and the prognosis of hemodialysis patients. PMID- 22548172 TI - RASSF1A and the Taxol Response in Ovarian Cancer. AB - The RASSF1A tumor suppressor gene is frequently inactivated by promoter methylation in human tumors. The RASSF1A protein forms an endogenous complex with tubulin and promotes the stabilization of microtubules. Loss of RASSF1A expression sensitizes cells to microtubule destabilizing stimuli. We have observed a strong correlation between the loss of RASSF1A expression and the development of Taxol resistance in primary ovarian cancer samples. Thus, we sought to determine if RASSF1A levels could dictate the response to Taxol and whether an epigenetic therapy approach might be able to reverse the Taxol resistant phenotype of RASSF1A negative ovarian tumor cells. We found that knocking down RASSF1A expression in an ovarian cancer cell line inhibited Taxol mediated apoptosis and promoted cell survival during Taxol treatment. Moreover, using a combination of small molecule inhibitors of DNA Methyl Transferase enzymes, we were able restore RASSF1A expression and Taxol sensitivity. This identifies a role for RASSF1A in modulating the tumor response to Taxol and provides proof of principal for the use of epigenetic therapy to overcome Taxol resistance. PMID- 22548173 TI - Pathogenetic and Prognostic Significance of Inactivation of RASSF Proteins in Human Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most frequent solid tumors worldwide, with limited treatment options and a dismal prognosis. Thus, there is a strong need to expand the basic and translational research on this deadly disease in order to improve the prognosis of HCC patients. Although the etiologic factors responsible for HCC development have been identified, the molecular pathogenesis of liver cancer remains poorly understood. Recent evidence has shown the frequent downregulation of Ras association domain family (RASSF) proteins both in the early and late stages of hepatocarcinogenesis. Here, we summarize the data available on the pathogenetic role of inactivation of RASSF proteins in liver cancer, the molecular mechanisms responsible for suppression of RASSF proteins in HCC, and the possible clinical implications arising from these discoveries. Altogether, the data indicate that inactivation of the RASSF1A tumor suppressor is ubiquitous in human liver cancer, while downregulation of RASSF2 and RASSF5 proteins is limited to specific HCC subsets. Also, the present findings speak in favour of therapeutic strategies aimed at reexpressing RASSF1A, RASSF2, and RASSF5 genes and/or inactivating the RASSF cellular inhibitors for the treatment of human liver cancer. PMID- 22548175 TI - Endometrial Cancer and Hypermethylation: Regulation of DNA and MicroRNA by Epigenetics. AB - Endometrial cancer is the seventh most common cancer in women worldwide. Therefore elucidation of the pathogenesis and development of effective treatment for endometrial cancer are important. However, several aspects of the mechanism of carcinogenesis in the endometrium remain unclear. Associations with genetic variation and mutations of cancer-related genes have been shown, but these do not provide a complete explanation. Therefore, in recent years, epigenetic mechanisms that do not involve changes in DNA sequences have been examined. Studies aimed at detection of aberrant DNA hypermethylation in cancer cells present in microscopic amounts in vivo and application of the results to cancer diagnosis have also started. Breakdown of the DNA mismatch repair mechanism is thought to play a large role in the development of endometrial cancer, with changes in the expression of the hMLH1 gene being particularly important. Silencing of genes such as APC and CHFR, Sprouty 2, RASSF1A, GPR54, CDH1, and RSK4 by DNA hypermethylation, onset of Lynch syndrome due to hereditary epimutation of hMLH1 and hMSH2 mismatch repair genes, and regulation of gene expression by microRNAs may also underlie the carcinogenic mechanisms of endometrial cancer. Further understanding of these issues may permit development of new therapies. PMID- 22548176 TI - Keeping cool: use of air conditioning by australians with multiple sclerosis. AB - Despite the known difficulties many people with MS have with high ambient temperatures, there are no reported studies of air conditioning use and MS. This study systematically examined air conditioner use by Australians with MS. A short survey was sent to all participants in the Australian MS Longitudinal Study cohort with a response rate of 76% (n = 2,385). Questions included hours of air conditioner use, areas cooled, type and age of equipment, and the personal effects of overheating. Air conditioners were used by 81.9% of respondents, with an additional 9.6% who could not afford an air conditioner. Regional and seasonal variation in air conditioning use was reported, with a national annual mean of 1,557 hours running time. 90.7% reported negative effects from overheating including increased fatigue, an increase in other MS symptoms, reduced household and social activities, and reduced work capacity. Households that include people with MS spend between 4 and 12 times more on keeping cool than average Australian households. PMID- 22548177 TI - Novel Aspects of Nonfasting Lipemia in relation to Vascular Biology. PMID- 22548174 TI - Molecular mechanisms for age-associated mitochondrial deficiency in skeletal muscle. AB - The abundance, morphology, and functional properties of mitochondria decay in skeletal muscle during the process of ageing. Although the precise mechanisms remain to be elucidated, these mechanisms include decreased mitochondrial DNA (mtDNA) repair and mitochondrial biogenesis. Mitochondria possess their own protection system to repair mtDNA damage, which leads to defects of mtDNA-encoded gene expression and respiratory chain complex enzymes. However, mtDNA mutations have shown to be accumulated with age in skeletal muscle. When damaged mitochondria are eliminated by autophagy, mitochondrial biogenesis plays an important role in sustaining energy production and physiological homeostasis. The capacity for mitochondrial biogenesis has shown to decrease with age in skeletal muscle, contributing to progressive mitochondrial deficiency. Understanding how these endogenous systems adapt to altered physiological conditions during the process of ageing will provide a valuable insight into the underlying mechanisms that regulate cellular homeostasis. Here we will summarize the current knowledge about the molecular mechanisms responsible for age-associated mitochondrial deficiency in skeletal muscle. In particular, recent findings on the role of mtDNA repair and mitochondrial biogenesis in maintaining mitochondrial functionality in aged skeletal muscle will be highlighted. PMID- 22548178 TI - Epidemiological profile of patients with cutaneous melanoma in a region of southern Brazil. AB - Cutaneous melanoma (CM) is responsible for 75% of deaths from malignant skin cancer. The incidence of CM in the southern region of Brazil, particularly in the western region of Santa Catarina, is possibly higher than estimated. In this study, the clinical and epidemiological profile of patients with CM treated in the western region of Santa Catarina was examined. A cross-sectional study was performed with patients diagnosed with CM from January 2002 to December 2009, from 78 counties of the western region of the state of Santa Catarina. Data were collected using a protocol adapted from the Brazilian Melanoma Group and 503 patients were evaluated. The incidence and prevalence of CM found in this region are much higher than those found elsewhere in the country. This fact is most likely due to the phenotypic characteristics of the population and the high incidence of UV radiation in this region due to its location in southern Brazil, as is the case in the countries of Oceania. PMID- 22548179 TI - Regulation of hepatic paraoxonase-1 expression. AB - Serum paraoxonase-1 (PON1) is a member of the paraoxonases family (PON1, PON2, and PON3). PON1 is synthesized and secreted by the liver, and in circulation it is associated with HDL. PON1 has antioxidative properties, which are associated with the enzyme's capability to decrease oxidative stress in atherosclerotic lesions and to attenuate atherosclerosis development. Epidemiological evidence demonstrates that low PON1 activity is associated with increased risk of cardiovascular events and cardiovascular disease and is an independent risk factor for coronary artery disease. Therefore, pharmacological modulation of PON1 activity or PON1 gene expression could constitute a useful approach for preventing atherosclerosis. A primary determinant of serum PON1 levels is the availability of the enzyme for release by the liver, the principal site of PON1 production. Together with the enzyme secretion rate, enzymatic turnover, and protein stability, the level of PON1 gene expression is a major determinant of PON1 status. This paper summarizes recent progress in understanding the regulation of PON1 expression in hepatocytes. PMID- 22548180 TI - Advances in alcoholic liver disease. PMID- 22548182 TI - Minimal invasive decompression for lumbar spinal stenosis. AB - Lumbar spinal stenosis is a common condition in elderly patients and may lead to progressive back and leg pain, muscular weakness, sensory disturbance, and/or problems with ambulation. Multiple studies suggest that surgical decompression is an effective therapy for patients with symptomatic lumbar stenosis. Although traditional lumbar decompression is a time-honored procedure, minimally invasive procedures are now available which can achieve the goals of decompression with less bleeding, smaller incisions, and quicker patient recovery. This paper will review the technique of performing ipsilateral and bilateral decompressions using a tubular retractor system and microscope. PMID- 22548181 TI - Lateral interbody fusion for treatment of discogenic low back pain: minimally invasive surgical techniques. AB - Low back pain is one of the most common ailments in the general population, which tends to increase in severity along with aging. While few patients have severe enough symptoms or underlying pathology to warrant surgical intervention, in those select cases treatment choices remain controversial and reimbursement is a substancial barrier to surgery. The object of this study was to examine outcomes of discogenic back pain without radiculopathy following minimally-invasive lateral interbody fusion. Twenty-two patients were treated at either one or two levels (28 total) between L2 and 5. Discectomy and interbody fusion were performed using a minimallyinvasive retroperitoneal lateral transpsoas approach. Clinical and radiographic parameters were analyzed at standard pre- and postoperative intervals up to 24 months. Mean surgical duration was 72.1 minutes. Three patients underwent supplemental percutaneous pedicle screw instrumentation. Four (14.3%) stand-alone levels experienced cage subsidence. Pain (VAS) and disability (ODI) improved markedly postoperatively and were maintained through 24 months. Segmental lordosis increased significantly and fusion was achieved in 93% of levels. In this series, isolated axial low back pain arising from degenerative disc disease was treated with minimally-invasive lateral interbody fusion in significant radiographic and clinical improvements, which were maintained through 24 months. PMID- 22548183 TI - Relationship between Duration of Fluoride Exposure in School-Based Fluoride Mouthrinsing and Effects on Prevention and Control of Dental Caries. AB - The objective of this paper was to assess the effects of school-based fluoride mouthrinsing (S-FMR: weekly using 0.2% NaF solution) in two groups of school children with different periods of exposure to S-FMR in elementary school. Subjects were the S-FMR group consisted of 599 children, participated for six years. The control group consisted of 282 children, participated for less than one year in the sixth year of elementary school. From the results of the present survey, the caries reduction rate of S-FMR in the permanent teeth was 36.6% for DMFT and 42.8% for DMFS, and person rates with DMF, DMFT, DMFS, and CO (questionable caries under observation) were inhibited in both boys and girls. Girls in the control group showed clearly higher values for all parameters of dental caries because of earlier teeth eruption; however, no gender differences were observed in the S-FMR group. As caries prevalence in the first molars accounted for about 85% regardless of participation to S-FMR, and first molar caries were more common in the mandible than in the maxilla, consideration should be given to preventive measures against pit-and-fissure-caries in addition to S FMR. PMID- 22548184 TI - Safety pin suture for management of atonic postpartum hemorrhage. AB - Objective. To assess the efficacy of a new suture technique in controlling severe resistant uterine atonic postpartum hemorrhage. Patients and Methods. This is a retrospective observational study that included thirteen women with uterine atony and postpartum bleeding that did not react to usual medical management. All these women underwent compressing vertical suture technique in which the anterior and posterior walls of the uterus were attached so as to compress the uterus. The suture is transfixed at the uterine fundus, thus eliminating the risk of sutures sliding off at the uterine fundus (safety pin suture). Results. safety pin uterine compression suture was a sufficient procedure to stop the bleeding immediately in 92.2% of the women. None of the women developed complications related to the procedure. Conclusion. A new safety pin suture is a simple and effective procedure to control bleeding in patients with treatment-resistant, life-threatening atonic postpartum hemorrhage with the advantage of eliminating the risk of the sutures sliding off at the uterine fundus. PMID- 22548185 TI - Contemporary surgical management of severe sialorrhea in children. AB - The causes of severe sialorrhea (drooling) are reviewed, and in particular in children in whom it can become a life-long disability. The history of medical and surgical treatments is discussed. A major advance has been the surgical relocation of the submandibular gland ducts with removal of sublingual glands. The results of this operation, technical considerations, and its outcomes in 16 children are presented. There were no significant complications. Caregivers judged the efficacy with a median score of "75%" improvement. The technique has become the most logical and reliable surgical treatment for drooling, with very good control in most cases. In contrast to "Botox" its effects are permanent. PMID- 22548186 TI - Capsaicin, a TRPV1 Ligand, Suppresses Bone Resorption by Inhibiting the Prostaglandin E Production of Osteoblasts, and Attenuates the Inflammatory Bone Loss Induced by Lipopolysaccharide. AB - Capsaicin, a transient receptor potential vanilloid type 1 (TRPV1) ligand, regulates nerve-related pain-sensitive signals, inflammation, and cancer growth. Capsaicin suppresses interleukin-1-induced osteoclast differentiation, but its roles in bone tissues and bone diseases are not known. This study examined the effects of capsaicin on inflammatory bone resorption and prostaglandin E (PGE) production induced by lipopolysaccharide (LPS) in vitro and on bone mass in LPS treated mice in vivo. Capsaicin suppressed osteoclast formation, bone resorption, and PGE production induced by LPS in vitro. Capsaicin suppressed the expression of cyclooxygenase-2 (COX-2) and membrane-bound PGE synthase-1 (mPGES-1) mRNAs and PGE production induced by LPS in osteoblasts. Capsaicin may suppress PGE production by inhibiting the expression of COX-2 and mPGES-1 in osteoblasts and LPS-induced bone resorption by TRPV1 signals because osteoblasts express TRPV1. LPS treatment markedly induced bone loss in the femur in mice, and capsaicin significantly restored the inflammatory bone loss induced by LPS in mice. TRPV1 ligands like capsaicin may therefore be potentially useful as clinical drugs targeting bone diseases associated with inflammatory bone resorption. PMID- 22548187 TI - The risk factors for nosocomial infection in chinese patients with active rheumatoid arthritis in shanghai. AB - Objective. To analyse the potential risk factors of nosocomial infections in patients with active rheumatoid arthritis (RA). Methods. A total of 2452 active RA patients at Hospitals in Shanghai between January 2009 and February 2011 were analyzed. Their demographic and clinical characteristics were compared with those without infection, and the potential risk factors were determined by logistic regression analysis. Results. Multivariate analysis indicated the gender (OR = 0.70, 95% CI 0.53-0.92), duration in hospital (OR = 1.03 , 95%CI 1.01-1.05), number of organs involved (OR = 0.82, 95%CI 0.72-0.92), number of disease modifying antirheumatic drugs ((DMARDs) (OR = 1.22, 95%CI 1.061-1.40)), corticosteroid therapy (OR = 1.02, 95%CI 1.01-1.03), peripheral white blood cell counts ((WBC) (OR = 1.04, 95%CI 1.00-1.08)), levels of serum albumin (OR = 0.98, 95%CI 0.97-0.99), and C-reactive protein ((CRP) (OR = 1.03 , 95%CI 1.01-1.04)) that were significantly associated with the risk of infections. Conclusion. The female patients, longer hospital stay, more organs involved, more DMARDs, corticosteroid usage, high counts of WBC, lower serum albumin, and higher serum CRP were independent risk factors of infections in active RA patients. PMID- 22548188 TI - The diversity issue revisited: international students in clinical environment. AB - Background. Globalization within higher education leads to an increase in cultural and linguistic diversity in student populations. The purpose of this study was to explore culturally diverse health care students' experiences in clinical environment in Finland, and to compare them with those of native Finnish students' participating in the same program. Method. A cross-sectional survey was performed at 10 polytechnic faculties of health care in Finland. 283 respondents (148 international and 95 Finnish students) responded to items concerning clinical rotation. The survey included items grouped as dimensions: (1) welcoming clinical environment, (2) unsupportive clinical environment, (3) approach to cultural diversity, (4) communication, and (5) structural arrangements. Results. International students felt as welcome on their placements as Finnish students. Concerning structural arrangements set up to facilitate preceptorship and approach to cultural diversity in the learning environment, the two groups' opinions were similar. However, international students were more likely than Finnish students to experience their clinical learning environment as unsupportive (P < 0.001). In addition, their experiences of communication with the staff was poorer than that of their Finnish peers' (P = 0.04). Conclusions. Awareness of strategies that enhance understanding, acceptance, and appreciation of cultural and linguistic diversity in any health care setting are needed. PMID- 22548189 TI - Complications of intrathecal baclofen pump: prevention and cure. AB - Increasingly, spasticity is managed with surgically implanted Intrathecal Baclofen pumps. Intrathecal Baclofen pump revision surgery unrelated to programmable pump end-of-life is not uncommon, requiring special attention during pre-, intra-, and postoperative management. We aimed to identify and describe complications of Intrathecal Baclofen pump as well as to report avoidance and management of complications. Methods and Materials. Through 2002-2006, at the department of neurosurgery, Henry Ford and Oakwood Health Systems, Intrathecal Baclofen pumps were implanted in 44 patients: 24 children versus 20 adults; 30 "primary-implant-patients"; 14 "revision-only patients". We evaluated reasons for revision surgeries and diagnostic workup requirements. Results. Eight primary implant-patients required 14 revisions and 7 of revision-only patients needed 13 procedures. Seven patients with slowly increasing baclofen-resistant spasticity had either (i) unsuspected pump-catheter connector defects, (ii) an X-ray documented pump-catheter connector defect, (iii) X-ray-demonstrated fractured catheter with intrathecal fragment. Implant infections occurred in 4 cases. Scintigraphy revealed occult CSF leakage N=1 and intrinsic pump failure N=1. Conclusion. Intrathecal Baclofen pumps, although very gratifying, have a high, technique-related complication incidence during implant life. Meticulous technique, high clinical suspicion, appropriate workup, and timely surgical management can reduce surgical complications of Intrathecal Baclofen pump implantation. PMID- 22548190 TI - The Impact of (18)F-FDG PET CT Prior to Chemoradiotherapy for Stage III/IV Head and Neck Squamous Cell Carcinoma. AB - Introduction. To determine the value of a FDG-PET-CT scan in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) prior to chemoradiotherapy. Materials and Methods. Consecutive patients with stage III or IV HNSCC who had undergone a staging FDG-PET-CT scan prior to chemoradiotherapy between August 2008 and April 2011 were included. Clinical details and conventional imaging (CT and/or MRI) were, retrospectively, reviewed, a TNM stage was assigned, and levels of cervical lymph node involvement were documented. This process was repeated with the addition of FDG-PET-CT. Radiotherapy plans were reviewed for patients with an alteration identified on TNM staging and/or nodal level identification with FDG-PET-CT and potential alterations in radiotherapy planning were documented. Results. 55 patients were included in the analysis. FDG PET-CT altered the TNM stage in 17/55 (31%) of patients, upstaging disease in 11 (20%) and downstaging in 6 (11%); distant metastases were identified by FDG-PET CT in 1 (2%) patient. FDG-PET-CT altered the lymph node levels identified in 22 patients (40%), upclassifying disease in 16 (29%) and downclassifying in 6 (11%). Radiotherapy plans were judged retrospectively to have been altered by FDG-PET-CT in 10 patients (18%). Conclusions. The use of FDG-PET-CT potentially impacts upon both treatment decisions and radiotherapy planning. PMID- 22548191 TI - Epithelial-mesenchymal transition in oral squamous cell carcinoma. AB - Oral cancer is one of the drastic human cancers due to its aggressiveness and high mortality rate. Of all oral cancers, squamous cell carcinoma is the most common accounting for more than 90%. Epithelial-mesenchymal transition (EMT) is suggested to play an important role during cancer invasion and metastasis. Recently, emerging knowledge on EMT in carcinogenesis is explosive, tempting us to analyze previous studies on EMT in oral squamous cell carcinoma (OSCC). In this paper, we have first addressed the general molecular mechanisms of EMT, evidenced by alterations of cell morphology during EMT, the presence of cadherin switching, turning on and turning off of many specific genes, the activation of various signaling pathways, and so on. The remaining part of this paper will focus on recent findings of the investigations of EMT on OSCC. These include the evidence of EMT taking place in OSCC and the signaling pathways employed by OSCC cells during their invasion and metastasis. Collectively, with the large body of new knowledge on EMT in OSCC elaborated here, we are hopeful that targeting treatment for OSCC will be developed. PMID- 22548192 TI - Immune system in the brain: a modulatory role on dendritic spine morphophysiology? AB - The central nervous system is closely linked to the immune system at several levels. The brain parenchyma is separated from the periphery by the blood brain barrier, which under normal conditions prevents the entry of mediators such as activated leukocytes, antibodies, complement factors, and cytokines. The myeloid cell lineage plays a crucial role in the development of immune responses at the central level, and it comprises two main subtypes: (1) resident microglia, distributed throughout the brain parenchyma; (2) perivascular macrophages located in the brain capillaries of the basal lamina and the choroid plexus. In addition, astrocytes, oligodendrocytes, endothelial cells, and, to a lesser extent, neurons are implicated in the immune response in the central nervous system. By modulating synaptogenesis, microglia are most specifically involved in restoring neuronal connectivity following injury. These cells release immune mediators, such as cytokines, that modulate synaptic transmission and that alter the morphology of dendritic spines during the inflammatory process following injury. Thus, the expression and release of immune mediators in the brain parenchyma are closely linked to plastic morphophysiological changes in neuronal dendritic spines. Based on these observations, it has been proposed that these immune mediators are also implicated in learning and memory processes. PMID- 22548193 TI - Divergent roles of p75NTR and Trk receptors in BDNF's effects on dendritic spine density and morphology. AB - Activation of TrkB receptors by brain-derived neurotrophic factor (BDNF) followed by MAPK/ERK signaling increases dendritic spine density and the proportion of mature spines in hippocampal CA1 pyramidal neurons. Considering the opposing actions of p75(NTR) and Trk receptors in several BDNF actions on CNS neurons, we tested whether these receptors also have divergent actions on dendritic spine density and morphology. A function-blocking anti-p75(NTR) antibody (REX) did not affect spine density by itself but it prevented BDNF's effect on spine density. Intriguingly, REX by itself increased the proportion of immature spines and prevented BDNF's effect on spine morphology. In contrast, the Trk receptor inhibitor k-252a increased spine density by itself, and prevented BDNF from further increasing spine density. However, most of the spines in k-252a-treated slices were of the immature type. These effects of k-252a on spine density and morphology required neuronal activity because they were prevented by TTX. These divergent BDNF actions on spine density and morphology are reminiscent of opposing functional signaling by p75(NTR) and Trk receptors and reveal an unexpected level of complexity in the consequences of BDNF signaling on dendritic morphology. PMID- 22548194 TI - Molecular determinants of the spacing effect. AB - Long-term memory formation is sensitive to the pattern of training sessions. Training distributed over time (spaced training) is superior at generating long term memories than training presented with little or no rest interval (massed training). This spacing effect was observed in a range of organisms from invertebrates to humans. In the present paper, we discuss the evidence supporting cyclic-AMP response element-binding protein 2 (CREB), a transcription factor, as being an important molecule mediating long-term memory formation after spaced training. We also review the main upstream proteins that regulate CREB in different model organisms. Those include the eukaryotic translation initiation factor (eIF2alpha), protein phosphatase I (PP1), mitogen-activated protein kinase (MAPK), and the protein tyrosine phosphatase corkscrew. Finally, we discuss PKC activation and protein synthesis and degradation as mechanisms by which neurons decode the spacing intervals. PMID- 22548195 TI - Kalirin, a key player in synapse formation, is implicated in human diseases. AB - Synapse formation is considered to be crucial for learning and memory. Understanding the underlying molecular mechanisms of synapse formation is a key to understanding learning and memory. Kalirin-7, a major isoform of Kalirin in adult rodent brain, is an essential component of mature excitatory synapses. Kalirin-7 interacts with multiple PDZ-domain-containing proteins including PSD95, spinophilin, and GluR1 through its PDZ-binding motif. In cultured hippocampal/cortical neurons, overexpression of Kalirin-7 increases spine density and spine size whereas reduction of endogenous Kalirin-7 expression decreases synapse number, and spine density. In Kalirin-7 knockout mice, spine length, synapse number, and postsynaptic density (PSD) size are decreased in hippocampal CA1 pyramidal neurons; these morphological alterations are accompanied by a deficiency in long-term potentiation (LTP) and a decreased spontaneous excitatory postsynaptic current (sEPSC) frequency. Human Kalirin-7, also known as Duo or Huntingtin-associated protein-interacting protein (HAPIP), is equivalent to rat Kalirin-7. Recent studies show that Kalirin is relevant to many human diseases such as Huntington's Disease, Alzheimer's Disease, ischemic stroke, schizophrenia, depression, and cocaine addiction. This paper summarizes our recent understanding of Kalirin function. PMID- 22548197 TI - African american race and prevalence of atrial fibrillation:a meta-analysis. AB - Background. It has been observed that African American race is associated with a lower prevalence of atrial fibrillation (AF) compared to Caucasian race. To better quantify the association between African American race and AF, we performed a meta-analysis of published studies among different patient populations which reported the presence of AF by race. Methods. A literature search was conducted using electronic databases between January 1999 and January 2011. The search was limited to published studies in English conducted in the United States, which clearly defined the presence of AF in African American and Caucasian subjects. A meta-analysis was performed with prevalence of AF as the primary endpoint. Results. In total, 10 studies involving 1,031,351 subjects were included. According to a random effects analysis, African American race was associated with a protective effect with regard to AF as compared to Caucasian race (odds ratio 0.51, 95% CI 0.44 to 0.59, P < 0.001). In subgroup analyses, African American race was significantly associated with a lower prevalence of AF in the general population, those hospitalized or greater than 60 years old, postcoronary artery bypass surgery patients, and subjects with heart failure. Conclusions. In a broad sweep of subjects in the general population and hospitalized patients, the prevalence of AF in African Americans is consistently lower than in Caucasians. PMID- 22548196 TI - Plasticity of adult sensorimotor system in severe brain infarcts: challenges and opportunities. AB - Functional reorganization forms the critical mechanism for the recovery of function after brain damage. These processes are driven by inherent changes within the central nervous system (CNS) triggered by the insult and further depend on the neural input the recovering system is processing. Therefore these processes interact with not only the interventions a patient receives, but also the activities and behaviors a patient engages in. In recent years, a wide range of research programs has addressed the association between functional reorganization and the spontaneous and treatment-induced recovery. The bulk of this work has focused on upper-limb and hand function, and today there are new treatments available that capitalize on the neuroplasticity of the brain. However, this is only true for patients with mild to moderated impairments; for those with very limited hand function, the basic understanding is much poorer and directly translates into limited treatment opportunities for these patients. The present paper aims to highlight the knowledge gap on severe stroke with a brief summary of the literature followed by a discussion of the challenges involved in the study and treatment of severe stroke and poor long-term outcome. PMID- 22548199 TI - PTH Assays: Understanding What We Have and Forecasting What We Will Have. AB - Parathyroid hormone (PTH) assays have evolved continuously for the last 50 years. Since the first radioimmunoassay was described in 1963, several assays based on immunological identification have been published (first generation assays). The routine assays used nowadays are immunometric "sandwich-type". They are based on two different monoclonal antibodies, one amino-terminal and the other carboxyl terminal specific. These second generation assays are widely available and adapted to most of the automation platforms. The specificity of the amino terminal antibody defines if the immunometric assay measures only the bioactive PTH circulating form (including the first amino terminal amino acids) or the "intact" PTH, which includes, besides bioactive PTH, other "long" carboxyl terminal forms, for example, 7-84-PTH. Assays for "intact" PTH are the most commonly available and the potential advantage of the bioactive PTH assays is still debatable. Next generation of assays will be based on different principles, mainly mass spectrometry in samples submitted to a prior purification and fragmentation steps. These assays will provide information about the whole spectra of PTH peptides in circulation, with a significant increase of the information regarding this biologically important peptide hormone. PMID- 22548200 TI - Nonmotor symptoms of Parkinson's disease. PMID- 22548201 TI - Inflammatory Pathways in Parkinson's Disease; A BNE Microarray Study. AB - The aetiology of Parkinson's disease (PD) is yet to be fully understood but it is becoming more and more evident that neuronal cell death may be multifactorial in essence. The main focus of PD research is to better understand substantia nigra homeostasis disruption, particularly in relation to the wide-spread deposition of the aberrant protein alpha-synuclein. Microarray technology contributed towards PD research with several studies to date and one gene, ALDH1A1 (Aldehyde dehydrogenase 1 family, member A1), consistently reappeared across studies including the present study, highlighting dopamine (DA) metabolism dysfunction resulting in oxidative stress and most probably leading to neuronal cell death. Neuronal cell death leads to increased inflammation through the activation of astrocytes and microglia. Using our dataset, we aimed to isolate some of these pathways so to offer potential novel neuroprotective therapeutic avenues. To that effect our study has focused on the upregulation of P2X7 (purinergic receptor P2X, ligand-gated ion channel, 7) receptor pathway (microglial activation) and on the NOS3 (nitric oxide synthase 3) pathway (angiogenesis). In summary, although the exact initiator of striatal DA neuronal cell death remains to be determined, based on our analysis, this event does not remain without consequence. Extracellular ATP and reactive astrocytes appear to be responsible for the activation of microglia which in turn release proinflammatory cytokines contributing further to the parkinsonian condition. In addition to tackling oxidative stress pathways we also suggest to reduce microglial and endothelial activation to support neuronal outgrowth. PMID- 22548198 TI - Hormone replacement therapy and risk for neurodegenerative diseases. AB - Over the past two decades, there has been a significant amount of research investigating the risks and benefits of hormone replacement therapy (HRT) with regards to neurodegenerative disease. Here, we review basic science studies, randomized clinical trials, and epidemiological studies, and discuss the putative neuroprotective effects of HRT in the context of Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and HIV-associated neurocognitive disorder. Findings to date suggest a reduced risk of Alzheimer's disease and improved cognitive functioning of postmenopausal women who use 17beta-estradiol. With regards to Parkinson's disease, there is consistent evidence from basic science studies for a neuroprotective effect of 17beta-estradiol; however, results of clinical and epidemiological studies are inconclusive at this time, and there is a paucity of research examining the association between HRT and Parkinson's related neurocognitive impairment. Even less understood are the effects of HRT on risk for frontotemporal dementia and HIV-associated neurocognitive disorder. Limits to the existing research are discussed, along with proposed future directions for the investigation of HRT and neurodegenerative diseases. PMID- 22548202 TI - Immune tolerance by induced regulatory T cells in asthma. PMID- 22548203 TI - Updates in the relationship between human rhinovirus and asthma. AB - Human rhinovirus (HRV) is a nonenveloped, single stranded RNA virus belonging to the family Picornaviridae. HRV infections can cause both upper and lower respiratory illnesses in children and adults. Lower respiratory illnesses are more likely to occur in specific high risk groups, including infants, and children and adults with asthma. The relationships between rates of infection and the risk of clinical illness and exacerbation are not completely understood. Recent studies employing polymerase chain reaction and other molecular techniques indicate that there are new branches on the HRV family tree, and one characteristic of recently detected viruses is that they cannot be detected by standard tissue culture. Here we review the current literature and discuss new advances in understanding the link between HRV and asthma. PMID- 22548204 TI - Influence of asthma epidemiology on the risk for other diseases. AB - Asthma is a multifactorial chronic disease affecting a significant proportion of people in the United States and worldwide. Numerous laboratory and epidemiological studies have attempted to understand the etiology and underlying mechanisms of asthma and to identify effective therapies. However, the impact of asthma on the risk for other diseases has drawn little attention. This paper discusses the potential effects of asthma as a risk factor for other diseases, explores the potential mechanisms, and reviews the implications of the findings to clinical practice, public health, and research. PMID- 22548205 TI - Genetic Variations in TXNRD1 as Potential Predictors of Drug-Induced Liver Injury. AB - PURPOSE: Drug-induced liver injury (DILI) is the most common adverse drug reaction; however, it is not easily predicted. We hypothesize that DILI has a common genetic basis. Based on the findings of previous animal studies on toxic hepatitis, we selected the thioredoxin reductase 1 gene (TXNRD1) as a candidate marker of DILI for this genetic association study. METHODS: Records from 118 patients with DILI were extracted from the database of the Adverse Drug Reaction Research Group in South Korea. Causative drugs included antituberculosis drugs (n=68, 57.6%), antibiotics (n=22, 18.6%), antiepileptic drugs (n=7, 5.9%), non steroidal anti-inflammatory drugs (n=5, 4.2%), and others (n=16, 13.7%). Seven single nucleotide polymorphisms (SNPs) in TXNRD1 (rs10735393, rs4964287, rs4595619, rs10861201, rs11111997, rs4246270, and rs4246271) were scored in 118 DILI patients and in 120 drug-matched controls without liver injury. RESULTS: No differences were found between the frequencies of any of the 7 SNPs in the cases and controls; however, a significant association was found between a TTA haplotype composed of rs10735393, rs4964287, and rs4595619 and DILI using an allele model (odds ratio, 1.79; 95% confidence interval, 1.18-2.73; P=0.008; Bonferroni corrected P=0.024). CONCLUSIONS: These results suggest that genetic variations in TXNRD1 favor the development of DILI, although a larger confirmative study is needed. PMID- 22548206 TI - Flow Cytometry-Assisted Basophil Activation Test as a Safe Diagnostic Tool for Aspirin/NSAID Hypersenstivity. AB - PURPOSE: Aspirin and non-steroidal anti-inflammatory drugs (ASA/NSAIDs) are common causes of drug hypersensitivity. An oral provocation test is the only definitive diagnostic test. This study assessed the reliability of a flow cytometry-assisted basophil activation test (FAST) as a safe diagnostic method for ASA/NSAID-induced hypersensitivity, as its high sensitivity and specificity have been demonstrated for many other drugs. METHODS: Eighteen patients and 11 controls were enrolled. Using a Flow-CAST kit(r) (Buhlmann Laboratories AG, Schonenbuch, Switzerland), 29 analyses with aspirin, ibuprofen, and diclofenac were performed by flow cytometry to detect double-positive staining of anti-IgE and anti-CD63. The stimulation index was defined as the activated basophil percentage after drug stimulation/basally active basophil percentage. A stimulation index>=2 and an absolute activated basophil percentage>=5 were considered positive. RESULTS: Patients with hypersensitivity to ASA/NSAIDs were predominantly female, and the prevalence of atopy was higher in patients than in controls. A sensitivity of 61%, specificity of 91%, positive predictive value of 92%, and negative predictive value of 59% were achieved. CONCLUSIONS: FAST is a useful additional method for diagnosis of hypersensitivity reactions to ASA/NSAIDs. Further development is required to increase the sensitivity of the test. PMID- 22548207 TI - The HLA-DRB1 Polymorphism is Associated With Atopic Dermatitis, but not Egg Allergy in Korean Children. AB - PURPOSE: We investigated whether particular HLA-DRB1 polymorphisms contribute to egg allergy development in Korean children with atopic dermatitis (AD). METHODS: HLA-DRB1 alleles were determined by PCR-sequence-specific oligonucleotide (SSO) and PCR-single-strand conformation polymorphism (SSCP) methods in 185 patients with AD and 109 normal control (NC) subjects. AD patients were divided into two groups: 1) AD with egg allergy, consisting of 96 patients with egg allergies as determined by egg-specific immunoglobulin E (IgE) reactivity; and 2) AD without egg allergy, consisting of 89 patients without egg allergies. HLA-DRB1 alleles were classified into functional groups (A, De, Dr, E, Q, R, a). HLA-DRB1 phenotype and functional group frequencies in the AD, AD with egg allergy, and AD without egg allergy groups were compared with those in the NC group. RESULTS: The frequency of DRB1(*)08:02 was decreased in the AD with egg allergy group compared with the AD without egg allergy group (2.1% vs. 10.1%, P=0.021), and DRB1(*)15:01 was increased in the AD with egg allergy group compared with the AD without egg allergy group (22.9% vs. 11.2%, P=0.036). However, significance was lost after Bonferroni correction. HLA-DRB1(*)11:01 had a significantly higher frequency in AD patients compared with NCs (12.4% vs. 1.8%, corrected P=0.048) and was regarded as a susceptibility factor associated with AD. DRB1(*)08:03 was decreased in AD patients compared with NCs (10.8% vs. 19.3%, P=0.043). HLA-DRB1 functional group 'a', which includes DRB1(*)15:01, seemed to be associated with the development of egg allergy in AD (P=0.033), but this result was not significant after Bonferroni correction. CONCLUSIONS: HLA-DRB1 polymorphism is not associated with egg allergy, but HLA-DRB1(*)11:01 is associated with AD in Korean children. PMID- 22548209 TI - Changes in Major Peanut Allergens Under Different pH Conditions. AB - Regional dietary habits and cooking methods affect the prevalence of specific food allergies; therefore, we determined the effects of various pH conditions on major peanut allergens. Peanut kernels were soaked overnight in commercial vinegar (pH 2.3) or acetic acid solutions at pH 1.0, 3.0, or 5.0. Protein extracts from the sera of seven patients with peanut-specific IgE levels >15 kU(A)/L were analyzed by SDS-PAGE and immunolabeling. A densitometer was used to quantify and compare the allergenicity of each protein. The density of Ara h 1 was reduced by treatment with pH 1.0, 3.0, or 5.0 acetic acid, or commercial vinegar. Ara h 2 remained largely unchanged after treatment with pH 5.0 acetic acid, and was decreased following treatment with pH 1.0, 2.3, or 3.0 acetic acid. Ara h 3 and Ara h 6 appeared as a thick band after treatment with pH 1.0 acetic acid and commercial vinegar. IgE-binding intensities to Ara h 1, Ara h 2, and Ara h 3 were significantly reduced after treatment with pH 1.0 acetic acid or commercial vinegar. These data suggest that treatment with acetic acid at various pH values affects peanut allergenicity and may explain the low prevalence of peanut allergy in Korea. PMID- 22548208 TI - Asthma Prevention by Lactobacillus Rhamnosus in a Mouse Model is Associated With CD4(+)CD25(+)Foxp3(+) T Cells. AB - PURPOSE: Probiotic bacteria can induce immune regulation or immune tolerance in allergic diseases. The underlying mechanisms have been recently investigated, but are still unclear. The aim of this study was to evaluate the protective effects of the probiotic Lactobacillus rhamnosus (Lcr35) in a mouse model of asthma and to identify its mechanism of action. METHODS: Lcr35 was administered daily by the oral route at a dosage of 1*10(9) CFU/mouse in BALB/c mice for 7 days before the first sensitization. Clinical parameters and regulatory T (Treg) cells were examined. The role of CD4(+)CD25(+)Foxp3(+) Treg cells was analyzed using a Treg cell-depleting anti-CD25 monoclonal antibody (mAb). RESULTS: Airway hyperresponsiveness, total IgE production, pulmonary eosinophilic inflammation, and splenic lymphocyte proliferation were suppressed after Lcr35 treatment. Th1 (IFN-gamma) and Th2 (IL-4, IL-5, and IL-13) cytokines in the serum were suppressed, and the percentage of CD4(+)CD25(+)Foxp3(+) Treg cells in the spleen was significantly increased in the Lcr35 treatment group. Anti-CD25 mAb administration abolished the protective effects of Lcr35, indicating that CD4(+) CD25(+)Foxp3(+) Treg cells are essential in mediating the activity of Lcr35. CONCLUSIONS: Oral administration of Lcr35 attenuated the features of allergic asthma in a mouse model and induced immune regulation by a CD4(+)CD25(+)Foxp3(+) Treg cell-mediated mechanism. PMID- 22548210 TI - A case of hypereosinophilic syndrome presenting with multiorgan infarctions associated with disseminated intravascular coagulation. AB - Thromboembolism is one of the most critical complications of hypereosinophilic syndrome (HES). We report here a case of multi-organ infarctions related to HES. A 23-year-old woman was referred to our hospital with hemoptysis. Not only pulmonary, but also renal and splenic infarctions were detected on computed tomography images. Blood tests showed profound peripheral eosinophilia. She was diagnosed with HES with disseminated intravascular coagulation (DIC). We initiated infusion of corticosteroids, which effectively suppressed peripheral eosinophilia. However, consumptive coagulopathy did not improve and intracerebral hemorrhage related to thrombosis then developed. Addition of interferon-alpha resulted in the correction of the DIC associated with HES. PMID- 22548211 TI - The first probable case of hereditary angioedema in Vietnam. AB - Hereditary angioedema (HAE) is rare disorder due to C1-inhibitor deficiency (C1 INH) that are debilitating and may be life-threatening. HAE is a lack of consensus concerning diagnosis, therapy, and management, particularly in Vietnam. In this case report, we report a 40-year-old male patient with typical clinical symptoms and family history but he showed normal C4 level, and we could not measure C1q and C1-INH level. However, the diagnosis of HAE can be made based on typical clinical symptoms and the favorable prophylactic response to danazol treatment. Based on these findings, we suggest that he has type I HAE, although he showed normal C4 level. PMID- 22548212 TI - Symmetry and complexity in protein oligomers. PMID- 22548213 TI - Pieter Roelfsema. PMID- 22548214 TI - A lab app for that. PMID- 22548215 TI - Southwestern and Rocky Mountain Division. On Great Plains, Juniper Invasion signals prairies in distress. PMID- 22548216 TI - Science policy. The payoff of federal R&D: iPod, Google, and Human Genome Project. PMID- 22548218 TI - Potential indications for cardiac CT. PMID- 22548219 TI - Diagnosis of extracavitary primary effusion lymphoma by urine cytology. PMID- 22548220 TI - Special issue in memory of Denis Parsons Burkitt. PMID- 22548221 TI - Proceedings of the Food Micro 2010, 22th International ICFMH Symposium, "Microbial Behaviour in the Food Chain", and Food Micro 2010, the 22nd Symposium of the International Committee on Food Microbiology and Hygiene (ICFMH), August 30-September 3, 2010, Copenhagen,Denmark. PMID- 22548222 TI - Proceedings of the 17th Genetic Analysis Workshop, October 13-16, 2010, Boston, MA. PMID- 22548224 TI - Abstracts of the European Magnesium Meeting EUROMAG, June 8-10, 2011 Bologna, Italy. PMID- 22548223 TI - Proceedings of the Seventh International Congress on Uremia Research and Toxicity, May 12-14, 2011, Nagoya, Japan. PMID- 22548225 TI - Safety and inpatient psychiatric treatment: moving the science forward. PMID- 22548226 TI - AJO history of ophthalmology series: William Moon's tactile reading system. PMID- 22548228 TI - Retraction notice to "Curcumin suppresses constitutive activation of AP-1 by downregulation of JunD protein in HTLV-1-infected T-cell lines" [Leuk. Res. 30 (2006) 313-321]. PMID- 22548227 TI - [ Use of N-acetylcysteine for the prevention of contrast-induced nephropathy in rats]. PMID- 22548230 TI - What's new in pediatric resuscitation? A practical update for the anesthesiologist. PMID- 22548229 TI - Nuclear factor I and cerebellar granule neuron development: an intrinsic extrinsic interplay. AB - Granule neurons have a central role in cerebellar function via their synaptic interactions with other neuronal cell types both within and outside this structure. Establishment of these synaptic connections and its control is therefore essential to their function. Both intrinsic as well as environmental mechanisms are required for neuronal development and formation of neuronal circuits, and a key but poorly understood question is how these various events are coordinated and integrated in maturing neurons. In this review, we summarize recent work on the role of the Nuclear Factor I family in the transcriptional programming of cerebellar granule neuron maturation and synapse formation. In particular, we describe (1) the involvement of this family of factors in key developmental steps occurring throughout postmitotic granule neuron development, including dendrite and synapse formation and synaptic receptor expression, and (2) the mediation of these actions by critical downstream gene targets that control cell-cell interactions. These findings illustrate how Nuclear Factor I proteins and their regulons function as a "bridge" between cell-intrinsic and cell-extrinsic interactions to control multiple phases of granule neuron development. PMID- 22548231 TI - Characterization of an Abc1 kinase family gene OsABC1-2 conferring enhanced tolerance to dark-induced stress in rice. AB - Leaf senescence is a complex and highly organized process resulting in numerous changes of gene expression and metabolic procedures. However, the exact mechanisms underlying these changes are not well understood. In this study, we reported a rice (Oryza sativa) T-DNA insertion mutant impaired in an Abc1 kinase family gene with a dwarf and pale-green phenotype. The mutant showed reduced pigment content and photosynthetic efficiency and increased superoxide dismutase activity in leaves. The mutated gene, designated OsABC1-2, is expressed primarily in green tissues and/or organs and encodes a protein localized in chloroplast envelope. Expression of the gene was drastically suppressed by dark treatment. Overexpression of the gene in rice enhanced tolerance to prolonged dark-induced stress. Phylogenetic analysis revealed that the plant Abc1 proteins could be divided into three subgroups and OsAbc1-2 resides in a subgroup with potential chloroplast origin. Our results suggest that divergence has occurred among plant Abc1 family and chloroplast Abc1 kinases play potential roles in regulating dark induced senescence of plants. PMID- 22548232 TI - ESTs library from embryonic stages reveals tubulin and reflectin diversity in Sepia officinalis (Mollusca - Cephalopoda). AB - New molecular resources regarding the so-called "non-standard models" in biology extend the present knowledge and are essential for molecular evolution and diversity studies (especially during the development) and evolutionary inferences about these zoological groups, or more practically for their fruitful management. Sepia officinalis, an economically important cephalopod species, is emerging as a new lophotrochozoan developmental model. We developed a large set of expressed sequence tags (ESTs) from embryonic stages of S. officinalis, yielding 19,780 non redundant sequences (NRS). Around 75% of these sequences have no homologs in existing available databases. This set is the first developmental ESTs library in cephalopods. By exploring these NRS for tubulin, a generic protein family, and reflectin, a cephalopod specific protein family,we point out for both families a striking molecular diversity in S. officinalis. PMID- 22548233 TI - Expression and characterization of a recombinant Cry1Ac crystal protein fused with an insect-specific neurotoxin omega-ACTX-Hv1a in Bacillus thuringiensis. AB - In order to assess possible enhancement of biopesticide activity, the fusion gene of crystal protein gene cry1Ac with the insect-specific neurotoxin omega-ACTX Hv1a gene and egfp was expressed in Bacillus thuringiensis acrystalliferous strain Cry-B under the control of the native gene expression system. The fusion recombinant Cry-B(1Ac-ACTX-EGFP) generally produced two or three small crystal like inclusion bodies in each cell and the GFP signal could be clearly observed. A 166 kDa full-length fusion protein was identified by immunoblot analysis. Virulence of the fusion inclusions was at least fivefold higher toward larvae of Spodoptera exigua. These results demonstrated that a foreign protein could be expressed and accumulate as parasporal inclusions in B. thuringiensis by C terminal fusion with the native endotoxin while retaining partial insecticidal activity. PMID- 22548235 TI - Frequency of C-allylations on oligoglycinates via N-ylides. AB - The highly selective mono-C-allylation of oligoglycinates such as a diethylenetriaminepentaacetate, an iminodiacetate, and an ethylenediaminetetraacetate via insertion of a vacuum operation between the N allylation and C-migration steps is reported. It is contrastive that one-pot N allylation-C-allylation procedure gave a mixture including multiallylated products. In the reaction with N-ylides, gem-C-diallylation and alpha,alpha'-C diallylation of oligoglycinates are strongly inhibited even with the use of an excess of allyl bromide and base. A mechanism to explain this control of the frequency of C-allylation on oligoglycinates via N-ylides is also proposed. PMID- 22548234 TI - High density single-molecule-bead arrays for parallel single molecule force spectroscopy. AB - The assembly of a highly parallel force spectroscopy tool requires careful placement of single-molecule targets on the substrate and the deliberate manipulation of a multitude of force probes. Since the probe must approach the target biomolecule for covalent attachment, while avoiding irreversible adhesion to the substrate, the use of polymer microspheres as force probes to create the tethered bead array poses a problem. Therefore, the interactions between the force probe and the surface must be repulsive at very short distances (<5 nm) and attractive at long distances. To achieve this balance, the chemistry of the substrate, force probe, and solution must be tailored to control the probe surface interactions. In addition to an appropriately designed chemistry, it is necessary to control the surface density of the target molecule in order to ensure that only one molecule is interrogated by a single force probe. We used gold-thiol chemistry to control both the substrate's surface chemistry and the spacing of the studied molecules, through binding of the thiol-terminated DNA and an inert thiol forming a blocking layer. For our single molecule array, we modeled the forces between the probe and the substrate using DLVO theory and measured their magnitude and direction with colloidal probe microscopy. The practicality of each system was tested using a probe binding assay to evaluate the proportion of the beads remaining adhered to the surface after application of force. We have translated the results specific for our system to general guiding principles for preparation of tethered bead arrays and demonstrated the ability of this system to produce a high yield of active force spectroscopy probes in a microwell substrate. This study outlines the characteristics of the chemistry needed to create such a force spectroscopy array. PMID- 22548236 TI - Expression of an apoplast-localized BURP-domain protein from soybean (GmRD22) enhances tolerance towards abiotic stress. AB - The BURP-domain protein family comprises a diverse group of plant-specific proteins that share a conserved BURP domain at the C terminus. However, there have been only limited studies on the functions and subcellular localization of these proteins. Members of the RD22-like subfamily are postulated to associate with stress responses due to the stress-inducible nature of some RD22-like genes. In this report, we used different transgenic systems (cells and in planta) to show that the expression of a stress-inducible RD22-like protein from soybean (GmRD22) can alleviate salinity and osmotic stress. We also performed detailed microscopic studies using both fusion proteins and immuno-electron microscopic techniques to demonstrate the apoplast localization of GmRD22, for which the BURP domain is a critical determinant of the subcellular localization. The apoplastic GmRD22 interacts with a cell wall peroxidase and the ectopic expression of GmRD22 in both transgenic Arabidopsis thaliana and transgenic rice resulted in increased lignin production when subjected to salinity stress. It is possible that GmRD22 regulates cell wall peroxidases and hence strengthens cell wall integrity under such stress conditions. PMID- 22548237 TI - Ochroconis gallopava infection in a patient with chronic granulomatous disease: case report and review of the literature. AB - Ochroconis spp. are dematiaceous fungi and have recently become recognized as the cause of human disease. Infections due to members of this genus have primarily occurred in patients with impaired immunity following organ transplantation or chemotherapy for hematologic malignancies. There is no universally agreed upon therapy or duration of treatment, but amphotericin B and/or triazoles are typically employed. We present a case of Ochroconis gallopava infection in a patient with chronic granulomatous disease (CGD). The organism exhibited elevated minimal inhibitory concentrations against itraconazole (0.5 MUg/ml) and voriconazole (2 MUg/ml) in comparison with results from other studies reported in the literature. This case illustrates the complexities associated with antibiotic susceptibility testing, selection of appropriate drugs, and management in patients with Ochroconis infections. We also review the literature of human infections with Ochroconis to date, and discuss its microbiology to apprise both clinicians and laboratory personnel of this infrequently encountered but potentially aggressive pathogen. PMID- 22548238 TI - Increased hydrophobicity in Malassezia species correlates with increased proinflammatory cytokine expression in human keratinocytes. AB - Malassezia cells stimulate cytokine production by keratinocytes, although this ability differs among Malassezia species for unknown reasons. The aim of this study was to clarify the factors determining the ability to induce cytokine production by human keratinocytes in response to Malassezia species. M. furfur NBRC 0656, M. sympodialis CBS 7222, M. dermatis JCM 11348, M. globosa CBS 7966, M. restricta CBS 7877, and three strains each of M. globosa, M. restricta, M. dermatis, M. sympodialis, and M. furfur maintained under various culture conditions were used. Normal human epidermal keratinocytes (NHEKs) (1 * 10(5) cells) and the Malassezia species (1 * 10(6) cells) were co-cultured, and IL 1alpha, IL-6, and IL-8 mRNA levels were determined. Moreover, the hydrophobicity and beta-1,3-glucan expression at the surface of Malassezia cells were analyzed. The ability of Malassezia cells to trigger the mRNA expression of proinflammatory cytokines in NHEKs differed with the species and conditions and was dependent upon the hydrophobicity of Malassezia cells not beta-1,3-glucan expression. PMID- 22548239 TI - beta(1,3)-glucan synthase complex from Alternaria infectoria, a rare dematiaceous human pathogen. AB - The fungal cell wall polymer beta-(1,3)-D-glucan is synthesized by the enzyme beta-(1,3)- D-glucan synthase that is a complex composed of at least two proteins, Rho1p and Fks1p. Here, we report the nucleotide sequence of a single FKS gene and of the regulatory unit, RHO1 from the dematiaceous pathogenic fungus Alternaria infectoria. The predicted AiFks and AiRho share, respectively, 93% and 100% identity with that of Drechslera tritici-repentis. We also report that the sensitivity to caspofungin of eight different A. infectoria clinical strains is similar, with a MIC > 32 ug/ml and a MEC of 1 ug/ml, except for one strain which had a MEC of 1.4 ug/ml. This same strain exhibited one substitution at the hot spot 2, S1405A, compatible with less susceptible phenotypes, with the other seven strains having no mutations in either hot spot 1 or 2. The relative quantification of the expression of AiFKS and of AiRHO demonstrated a decrease in response to an exposure to caspofungin at 0.5 ug/ml. PMID- 22548240 TI - Hortaea werneckii isolated from silicone scuba diving equipment in Spain. AB - During a survey of black yeasts of marine origin, some isolates of Hortaea werneckii were recovered from scuba diving equipment, such as silicone masks and snorkel mouthpieces, which had been kept under poor storage conditions. These yeasts were unambiguously identified by phenotypic and genotypic methods. Phylogenetic analysis of both the D1/D2 regions of 26S rRNA gene and ITS-5.8S rRNA gene sequences showed three distinct genetic types. This species is the agent of tinea nigra which is a rarely diagnosed superficial mycosis in Europe. In fact this mycosis is considered an imported fungal infection being much more prevalent in warm, humid parts of the world such as the Central and South Americas, Africa, and Asia. Although H. werneckii has been found in hypersaline environments in Europe, this is the first instance of the isolation of this halotolerant species from scuba diving equipment made with silicone rubber which is used in close contact with human skin and mucous membranes. The occurrence of this fungus in Spain is also an unexpected finding because cases of tinea nigra in this country are practically not seen. PMID- 22548241 TI - Inhibitory effect of PGE(2) on the killing of Paracoccidioides brasiliensis by human monocytes can be reversed by cellular activation with cytokines. AB - Paracoccidioides brasiliensis is the etiological agent of paracoccidioidomycosis, a deep mycosis endemic in Latin America. Studies to elucidate the host-parasite relationship in this mycosis have demonstrated that non-activated phagocytes fail to kill the etiologic agent. Investigations of human monocytes have shown that the lack of fungicidal activity is partially associated with the capacity of a high-virulence strain to induce PGE(2) release by these cells. This eicosanoid inhibits production of TNF-alpha, the cytokine involved in cell activation for release of H(2)O(2), the fungicidal metabolite. Cell priming with IFN-gamma was shown to partially reverse this inhibitory effect. In this study, we asked whether monocyte challenge with a low-virulence strain of this fungus would also result in PGE(2) release and consequently inhibition of antifungal activities. We also assessed whether PGE(2,) besides inhibiting production of TNF-alpha, a monocyte-activating cytokine, also affects IL-10. The latter, in contrast to TNF alpha is a monocyte-suppressing cytokine. Finally, we evaluated whether priming cells with other cytokines, namely TNF-alpha and GM-CSF, could be more effective than IFN-gamma in reversing the PGE(2) inhibitory effect. The results revealed that the less virulent P. brasiliensis strain also induces human monocytes to release PGE(2). However, the inhibitory effect of PGE(2) was less pronounced when cells were challenged with this strain than with the more virulent one. It was also demonstrated that PGE(2), while inhibits TNF-alpha production, tends to increase IL-10 levels. Priming with GM-CSF or TNF-alpha was more effective than IFN-gamma in compensating for the inhibitory PGE(2) effect, since these cytokines induce cells to produce higher H(2)O(2) and TNF-alpha levels. PMID- 22548242 TI - Activity of compounds isolated from Baccharis dracunculifolia D.C. (Asteraceae) against Paracoccidioides brasiliensis. AB - Paracoccidioidomycosis is a prevalent systemic mycosis in Latin America which requires prolonged treatment with highly toxic antifungals. Baccharis dracunculifolia is a medicinal plant in Brazil that is a candidate in the search for new drugs. Fractions of the hexanic extracts were obtained using chromatographic procedures and assessed using an antifungal assay with Paracoccidioides brasiliensis (Pb18), tumor cell lines and amastigote forms of Leishmania, L. amazonensis. Four compounds were isolated, i.e., ursolic acid (1), methyl linolenate (2), caryophyllene oxide (3), and trans-nerolidol (4). Compounds 2, 3 and 4 displayed antifungal activity against four isolates of Paracocci dioides with MIC values ranging from 3.9-250 MUg/ml. Only caryophyllene oxide showed differences in the MIC values against Pb18 when the medium was supplemented with ergosterol, which suggested that the compound interacts with ergosterol. Ursolic acid was active in the cytotoxic assays and showed leishmanicidal activity. Scanning electron microscopy demonstrated that compounds 2, 3 and 4 decreased the cell size and produced an irregular cell wall surface on P. brasiliensis cells. The present results showed the biological activities of the isolated compounds and revealed that these compounds may affect the cell surface and growth of P. brasiliensis isolates. PMID- 22548243 TI - Numerical simulation of the insertion process of an uncemented hip prosthesis in order to evaluate the influence of residual stress and contact distribution on the stem initial stability. AB - The long-term success of a cementless total hip arthroplasty depends on the implant geometry and interface bonding characteristics (fit, coating and ingrowth) and on stem stiffness. This study evaluates the influence of stem geometry and fitting conditions on the evolution and distribution of the bone stem contact, stress and strain during and after the hip stem insertion, by means of dynamic finite element techniques. Next, the influence of the mechanical state (bone-stem contact, stress and strain) resulted from the insertion process on the stem initial resistance to subsidence is investigated. In addition, a study on the influence of bone-stem interface conditions (friction) on the insertion process and on the initial stem stability under physiological loading is performed. The results indicate that for a stem with tapered shape the contact in the proximal part of the stem was improved, but contact in the calcar region was achieved only when extra press-fit conditions were considered. Changes in stem geometry towards a more tapered shape and extra press fit and variation in the bone-stem interface conditions (contact amount and high friction) led to a raise in the total insertion force. A direct positive relationship was found between the stem resistance to subsidence and stem geometry (tapering and press fit), bone-stem interface conditions (bone-stem contact and friction interface) and the mechanical status at the end of the insertion (residual stress and strain). Therefore, further studies on evaluating the initial performance of different stem types should consider the parameters describing the bone-stem interface conditions and the mechanical state resulted from the insertion process. PMID- 22548244 TI - Catalytic asymmetric alpha-acylation of tertiary amines mediated by a dual catalysis mode: N-heterocyclic carbene and photoredox catalysis. AB - Cross-coupling reactions are among the most widely utilized methods for C-C bond formation; however, the requirement of preactivated starting materials still presents a major limitation. Methods that take direct advantage of the inherent reactivity of the C-H bond offer an efficient alternative to these methods, negating the requirement for substrate preactivation. In this process, two chemically distinct activation events culminate in the formation of the desired C C bond with loss of H(2) as the only byproduct. Herein we report the catalytic asymmetric alpha-acylation of tertiary amines with aldehydes facilitated by the combination of chiral N-heterocyclic carbene catalysis and photoredox catalysis. PMID- 22548245 TI - Importance of capillary forces in the assembly of carbon nanotubes in a polymer colloid lattice. AB - We highlight the significance of capillary pressure in the directed assembly of nanorods in ordered arrays of colloidal particles. Specifically, we discuss mechanisms for the assembly of carbon nanotubes at the interstitial sites between latex polymer particles during composite film formation. Our study points to general design rules to be considered to optimize the ordering of nanostructures within such polymer matrices. In particular, gaining an understanding of the role of capillary forces is critical. Using a combination of electron microscopy and atomic force microscopy, we show that the capillary forces acting on the latex particles during the drying process are sufficient to bend carbon nanotubes. The extent of bending depends on the flexural rigidity of the carbon nanotubes and whether or not they are present as bundled ensembles. We also show that in order to achieve long-range ordering of the nanotubes templated by the polymer matrix, it is necessary for the polymer to be sufficiently mobile to ensure that the nanotubes are frozen into the ordered network when the film is formed and the capillary forces are no longer dominant. In our system, the polymer is plasticized by the addition of surfactant, so that it is sufficiently mobile at room temperature. Interestingly, the carbon nanotubes effectively act as localized pressure sensors, and as such, the study agrees well with previous theoretical predictions calculating the magnitude of capillary forces during latex film formation. PMID- 22548246 TI - Ram's horn nails. PMID- 22548247 TI - Computed tomographic features of feline nasopharyngeal polyps. AB - The computed tomographic (CT) findings of histopathologically confirmed nasopharyngeal polyps are described in 13 cats. Most polyps were mildly hypoattenuating to adjacent muscles and isoattenuating to soft-tissue (n= 13), homogeneous (n = 12) and with ill-defined borders (n = 10) on precontrast images. After contrast medium administration, the polyps were homogeneous (n = 11), with well-defined borders (n = 13), oval (n = 13), and had rim enhancement (n = 13). Nasopharyngeal polyps were pedunculated in 11 cats with a stalk-like structure connecting the polyp through the auditory tube to an affected tympanic bulla. All cats had at least one tympanic bulla severely affected, with CT images identifying: (1) complete (n = 12) or partial (n = 1) obliteration of either the dorsal or ventral compartments with soft-tissue attenuating material; (2) pathologic expansion (n = 13) with wall thickening (n = 10) that was asymmetric in nine cats; and (3) identification of a polyp-associated stalk-like structure (n = 11). Nine cats had unilateral tympanic bulla disease ipsilateral to the polyp, and four cats had bilateral tympanic bulla disease, most severe ipsilateral to the polyp with milder contralateral pathologic changes. Two cats had minimal osteolysis of the tympanic bulla. Enlargement of the medial retropharyngeal lymph node was seen commonly (n = 8), and in all cats it was ipsilateral to the most affected tympanic bulla. One cat had bilateral lymphadenopathy. CT is an excellent imaging tool for the supportive diagnosis of nasopharyngeal polyps in cats. CT findings of a well-defined mass with strong rim enhancement, mass-associated stalk-like structure, and asymmetric tympanic bulla wall thickening with pathologic expansion of the tympanic bullae are highly indicative of an inflammatory polyp. PMID- 22548249 TI - Protective measures, personal experience, and the affective psychology of time. AB - We examined the role of time and affect in intentions to purchase a risk protective measure (Studies 1 and 2) and explored participant abilities to factor time into the likelihood judgments that presumably underlie such intentions (Study 3). Participants worried more about losing their possessions and were more likely to purchase a protective measure given a longer term lease than a short term lease, but only if their belongings were described in affect-poor terms. If described instead as being particularly special and affect-rich, participants neglected time and were about equally likely to purchase a risk-protective measure for shorter and longer term leases. However, and consistent with prior literature, the cognitive mechanism underlying this time-neglect-with-affect richness effect seemed to be the greater use of the affect heuristic in the shorter term than the longer term. Study 2 results demonstrated that prior experience with having been burglarized amplified the interactive effect of time and affect. Greater deliberation did not attenuate this effect as hypothesized whether deliberation was measured through numeracy or manipulated through instructions. The results of Study 3 indicated that few participants are able to calculate correctly the risk numbers necessary to take time into account. Two possible solutions to encourage more purchases of protective measures in the long term are discussed. PMID- 22548250 TI - Debriefing as a strategic tool for performance improvement. AB - In 2009, two large, West Coast perinatal units began a performance improvement project for obstetric hemorrhage. In this article we discuss the use of structured team debriefings for obstetric hemorrhage cases to measure performance improvement. Lessons learned from debriefings can be vital in gauging if recommended interventions are effectively embedded into clinical practice. Improved outcomes for the project included a 33% decrease in massive transfusions and a 78% decrease in unplanned hysterectomies for one medical center. PMID- 22548251 TI - Overexpression of peroxiredoxin 4 attenuates atherosclerosis in apolipoprotein E knockout mice. AB - AIM: A growing body of evidence has shown that increased formation of oxidized molecules and reactive oxygen species within the vasculature (i.e., the extracellular space) plays a crucial role in the initiation and progression of atherosclerosis and in the formation of unstable plaques. Peroxiredoxin 4 (PRDX4) is the only known secretory member of the antioxidant PRDX family. However, the relationship between PRDX4 and susceptibility to atherosclerosis has remained unclear. RESULTS: To define the role of PRDX4 in hyperlipidemia-induced atherosclerosis, we generated hPRDX4 transgenic (Tg) and apolipoprotein E (apoE) knockout mice (hPRDX4(+/+)/apoE(-/-)). After feeding the mice a high-cholesterol diet, they showed fewer atheromatous plaques, less T-lymphocyte infiltration, lower levels of oxidative stress markers, less necrosis, a larger number of smooth muscle cells, and a larger amount of collagen, resulting in thickened fibrous cap formation and possible stable plaque phenotype as compared with apoE( /-) mice. We also detected greater suppression of apoptosis and decreased Bax expression in hPRDX4(+/+)/apoE(-/-) mice than in apoE(-/-) mice. Bone marrow transplantation from hPRDX4(+/+) donors to apoE(-/-) mice confirmed the antiatherogenic aspects of PRDX4, revealing significantly suppressed atherosclerotic progression. INNOVATION: In this study, we demonstrated for the first time that PRDX4 suppressed the development of atherosclerosis in apoE(-/-) mice fed a high-cholesterol diet. CONCLUSION: These data indicate that PRDX4 is an antiatherogenic factor and, by suppressing oxidative damage and apoptosis, that it may protect against the formation of vulnerable (unstable) plaques. PMID- 22548252 TI - 'Back to the future': how archaeological remains can describe salmon adaptation to climate change. AB - A strategy for species to survive climate change will be to change adaptively their way of life. Understanding rapid adaptation to climate change is therefore a priority for current research. In this issue, Turrero et al. (2012) use an original approach to unravel life history trait responses to climate change in two fish species (Salmo trutta and S. salar). Going against the flow, the authors adopt the strategy of going back to the future by investigating the responses of fish to the warming periods that followed the Last Glacial Period (approximately 30-20,000 years BP). To do this, they analysed Salmo vertebrae from well-dated archaeological sites in northern Spain in order to uncover key life history traits, which they then compared to those of contemporary specimens. They found that, as the climate got warmer, Salmo species tended to reduce the time spent in growing areas and reached spawning areas at a younger age; this tendency began approximately 15,000 years BP and accelerated in contemporary periods. The implication is a lower age at maturity and a lower reproductive success, which they tentatively related to recent declines in population growth rate. This innovative study demonstrates how changes in life history traits are linked both to the population growth rate and to the evolutionary rate under climatic constraints, which may serve as a basis for future conservation research. PMID- 22548253 TI - Classic clover cline clues. AB - Adaptive clines are striking examples of natural selection in action, yet few have been studied in depth. In this issue of Molecular Ecology, Kooyers & Olsen (2012) introduce modern analyses and thinking towards studies of a classical example of the rapid and repeated evolution of latitudinal and altitudinal clines in cyanogenesis in white clover, Trifolium repens L. Recognizing that adaptive clines represent trade-offs in the selective benefits of traits at different ends of a geographical transect, these researchers focus on whether evidence for selection can be found at regional (coarse) and local (fine) scales. After adjusting for population genetic patterns generated by demographic processes, Kooyers and Olsen provide evidence that the cyanogenesis cline is adaptive across a transect from Louisiana to Wisconsin, USA. Within local populations, divergent selection on coupling dominant and recessive alleles that underlie cyanogenesis is predicted to drive populations to gametic phase disequilibrium (LD), a pattern that has been found in several other studies reviewed by Kooyers and Olsen. The absence of LD within any sampled populations in this study leads the authors to suggest that selective patterns within these clines may be more complex than previously proposed, perhaps even following theoretical predictions of a geographic mosaic. PMID- 22548254 TI - Disruption of gene expression in hybrids of the fire ants Solenopsis invicta and Solenopsis richteri. AB - Transcriptome analysis is a powerful tool for unveiling the distribution and magnitude of genetic incompatibilities between hybridizing taxa. The nature of such incompatibilities is closely associated with the evolutionary histories of the parental species and may differ across tissues and between the sexes. In eusocial insects, the presence of castes that experience divergent selection regimes may result in additional distinct patterns of caste-specific hybrid incompatibilities. We analysed levels of expression of >14,000 genes in two life stages of each caste in the fire ants Solenopsis invicta and Solenopsis richteri and in their hybrids. We found strong contributions of both developmental stage and caste to gene expression patterns. In contrast, variability in expression was only weakly associated with taxonomic identity, with hybrid scores falling between those of the two parental species. Hybrid incompatibilities were surprisingly modest, with only 32 genes being mis-expressed, indicating low levels of disruption in gene regulation in hybrids; males and workers each mis expressed at least seven times as many genes as queens. Interestingly, homologues of many of the mis-expressed genes have been implicated in behavioural variation in Drosophila melanogaster. General expression profiles of hybrids consistently were more similar to those of S. richteri than S. invicta, presumably because S. richteri trans-regulatory elements tend to be dominant and/or because there is an overall bias in the genetic composition of the hybrids towards S. richteri. Altogether, our results suggest that selection acting on each caste may contribute differently to interspecific divergence and speciation in this group of ants. PMID- 22548255 TI - Survival after stage IA endometrial cancer; can follow-up be altered? A prospective nationwide Danish survey. AB - OBJECTIVE: To present Danish national survival data on women with early stage endometrial cancer and use these data to discuss the relevance of postoperative follow-up. DESIGN: Prospective study. SETTING: Danish Endometrial Cancer Study (DEMCA). POPULATION: Five hundred and seventy-one FIGO stage IA (1988 classification) endometrial cancer patients prospectively included between 1986 and 1999. All patients had total abdominal hysterectomy and bilateral salpingo oophorectomy without adjuvant therapy. METHODS: The patient and the disease characteristics were drawn from the DEMCA database with cross-references to the national death registry and the national pathology database. Statistical methods included Kaplan-Meier, log-rank and Cox regression analysis. MAIN OUTCOME MEASURES: Survival rates in relation to histopathology. RESULTS: The five year overall survival rate was 88.9% and five year disease-specific survival was 97.3%. Patients with low- (91.8%) and high-risk histopathology (8.2%) were compared. The age-adjusted overall and disease-specific survival differed significantly between women with low- and high-risk histopathology (p = 0.039 and p = 0.004, respectively). The disease-specific survival adjusted for age between patients with well-differentiated endometrioid tumors differed from those with moderately differentiated tumors (p = 0.008, hazard ratio = 3.75, 95% confidence interval 1.41-10.00). Recurrence data were available on 464 patients. Twenty three (3.9%) experienced recurrence. Of these recurrences, 15 of 23 (65%) were vaginal. Death from recurrence was observed in nine of 23 (39%) patients, and five of these nine had vaginal recurrences. CONCLUSIONS: Women with FIGO stage IA endometrial cancer have a very high disease-specific five year survival. Survival was related to histopathology. Follow-up at a highly specialized tertiary care center for patients with an extremely good prognosis may be questioned. PMID- 22548256 TI - Heparin-induced thrombocytopenia (HIT II) in liver transplant recipients: a retrospective multivariate analysis of prognostic factors. AB - We investigated the prevalence of HIT II in liver transplant recipients and analysed associated factors. In recipients with clinically suspected HIT II in the 4Ts pretest clinical scoring system HIPA-assay was performed. Next, 37 clinical variables were analysed retrospectively for their association with HIT II. Factors significantly correlated to our findings in univariate analysis were included in a multivariate model and binary logistic regression analysis. Among 46 recipients 21 patients were suspicious in the 4Ts pretest and 14 of them (30.4%) were diagnosed HIT-antibody positive. Patient's age (P = 0.001), postoperative dialysis (P = 0.028), and postoperative hospital stay (P = 0.035) were significantly associated with development of HIT-antibodies in univariate analysis. Postoperative dialysis and postoperative hospital stay turned out as epiphenomena of patient's age, the only independent predictor (P = 0.021). Using multiple chi(2) -testing, a cut-off could be calculated, assigning patients younger than 59 years to a low risk group and patients of 59 years and older to a high risk group. High incidence of peri-operative HIT II seroconversion in liver transplant recipients is not associated with factors known to induce thrombocyte activation, like blood products or cell-saver. Only patients' age was identified as independent predictor. PMID- 22548257 TI - Association between early preterm birth and periodontitis according to USA and European consensus definitions. AB - OBJECTIVE: Prospective case-control study assessing the association between maternal periodontitis according to the recently issued USA and European consensus definitions and early preterm delivery (<35 weeks gestation). Cases were women delivering between 22 and 34(6/7) weeks of gestation (n = 84) and controls were women delivering at term (>= 37 weeks) (n = 345). METHODS: Periodontal examination at the immediate postpartum period identified periodontitis according to both consensus definitions. A multivariate logistic model was used to assess the association between early preterm delivery and the presence of periodontitis adjusted for confounders. RESULTS: All women had periodontitis by the European consensus definitions. When using the USA definitions, more cases had severe periodontitis than controls (34.5% vs. 17.72%); p = 0.003. After adjustment for main confounders, the association between severe (OR: 2.38; 95% CI: 1.36-4.14) periodontitis and early preterm delivery persisted. The only other independent factor associated with early preterm delivery was vaginal bleeding during pregnancy. CONCLUSIONS: Early preterm delivery is associated with periodontitis when the USA consensus definitions are used. The European definitions revealed inadequate for the study population because of the lack of discrimination power. PMID- 22548258 TI - A computational model to describe the collagen orientation in statically cultured engineered tissues. AB - Collagen provides cardiovascular tissues with the ability to withstand haemodynamic loads. A similar network is essential to obtain in tissue-engineered (TE) samples of the same nature. Yet, the mechanism of collagen orientation is not fully understood. Typically collagen remodelling is linked to mechanical loading. However, TE constructs also show an oriented collagen network when developed under static culture. Experiments under these conditions also indicate that the tissue gradually compacts due to contractile stresses developed in the alpha-actin fibres of the cells. Therefore, it is hypothesised that cellular contractile stresses are responsible for collagen orientation. A model describing the cellular alpha-actin turnover and the stresses developed by them is integrated in a structural constitutive model describing the mechanical behaviour of collagen fibres. Results show that the model can successfully capture the sample compaction, tissue stress generation and its heterogeneous collagen arrangement. PMID- 22548259 TI - Increased prevalence of anti-thyroid antibodies in patients with limited scleroderma: comments on the article by Danielides et al. PMID- 22548260 TI - Risk assessment of amorphous silicon dioxide nanoparticles in a glass cleaner formulation. AB - Since nanomaterials are a heterogeneous group of substances used in various applications, risk assessment needs to be done on a case-by-case basis. Here the authors assess the risk (hazard and exposure) of a glass cleaner with synthetic amorphous silicon dioxide (SAS) nanoparticles during production and consumer use (spray application). As the colloidal material used is similar to previously investigated SAS, the hazard profile was considered to be comparable. Overall, SAS has a low toxicity. Worker exposure was analysed to be well controlled. The particle size distribution indicated that the aerosol droplets were in a size range not expected to reach the alveoli. Predictive modelling was used to approximate external exposure concentrations. Consumer and environmental exposure were estimated conservatively and were not of concern. It was concluded based on the available weight-of-evidence that the production and application of the glass cleaner is safe for humans and the environment under intended use conditions. PMID- 22548261 TI - Contribution of research networks to a clinical trial of antidepressants in people with dementia. AB - BACKGROUND: The Mental Health Research Network and Dementia and Neurodegenerative Diseases Research Network were established in the UK to increase research capacity and activity; the former in mental health generally, and the latter specifically in neurodegenerative disorders including dementia. Little evidence exists on the impact of these networks on research in mental health of older people. AIMS: To examine research network support to a multi-centre randomised controlled trial of antidepressants in people with depression superimposed on dementia. Method Qualitative questionnaires were completed by principal investigators, trial-funded research workers and clinical study officers (CSOs) of the research networks. RESULTS: Research network contribution was much valued by principal investigators and the nine research teams. CSOs boosted the recruitment campaign in a challenging environment and enhanced assessment processes. Some problems with consistency and staff turnover were raised. CONCLUSION: Research network input can make an appreciable difference to the process and outcome of a multi-centre clinical trial. PMID- 22548262 TI - The history of sign language and deaf education in Turkey. AB - Sign language is the natural language of the prelingually deaf people particularly without hearing-speech rehabilitation. Otorhinolaryngologists, regarding health as complete physical, mental and psychosocial well-being, aim hearing by diagnosing deafness as deviance from normality. However, it's obvious that the perception conflicted with the behavior which does not meet the mental and social well-being of the individual also contradicts with the definition mentioned above. This article aims to investigate the effects of hearing-speech target ignoring the sign language in Turkish population and its consistency with the history through statistical data, scientific publications and historical documents and to support critical perspective on this issue. The study results showed that maximum 50% of the deaf benefited from hearing-speech program for last 60 years before hearing screening programs; however, systems including sign language in education were not generated. In the light of these data, it is clear that the approach ignoring sign language particularly before the development of screening programs is not reasonable. In addition, considering sign language being part of the Anatolian history from Hittites to Ottomans, it is a question to be answered that why evaluation, habilitation and education systems excluding sign language are still the only choice for deaf individuals in Turkey. Despite legislative amendments in the last 6-7 years, the primary cause of failure to come into force is probably because of inadequate conception of the issue content and importance, as well as limited effort to offer solutions by academicians and authorized politicians. Within this context, this paper aims to make a positive effect on this issue offering a review for the medical staff, particularly otorhinolaryngologists and audiologists. PMID- 22548263 TI - University of Pennsylvania smell identification test: application to Turkish population. AB - OBJECTIVES: The aim of this study was to investigate whether UPSIT (The University of Pennsylvania Smell Identification Test) clinical olfactory function test is suitable to assess olfactory function in Turkish population. PATIENTS AND METHODS: Fifty healthy Turkish volunteers (21 males, 29 females; mean age 31.5+/ 8.7 years; range 20 to 49 years) who underwent a detailed otorhinolaryngological examination were included in the study. Subjects with abnormal findings suggesting olfactory dysfunction were excluded from the study. UPSIT and Connecticut Chemosensory Clinical Research Center (CCCRC) tests were carried out for each individual separately. RESULTS: Mean CCCRC test score was 6.3+/-0.6 out of 7. Ten volunteers scored between 5-5.75 were considered mild hyposmia, while 40 volunteers scored between 6-7 were evaluated as normosmic. Volunteers correctly identified 21.4+/-4.7 odors out of 40 odors in UPSIT test. CONCLUSION: We concluded that UPSIT test is insufficient for the evaluation of olfactory function in Turkish population. Our results suggest that UPSIT test contains odors which are unfamiliar to Turkish population. Therefore, it is essential to either modify odors of UPSIT test or establish normative data suitable to Turkish population for evaluating the scores to avoid false olfactory function assessment. PMID- 22548264 TI - [The role of sentinel lymph node biopsy in oral cavity cancer]. AB - OBJECTIVES: This study aims to evaluate the role of sentinel lymph node (SLN) biopsy in patients who had clinically N0 oral cavity cancer in the neck assessment. PATIENTS AND METHODS: Between May 2006 and May 2008, nine patients with clinically N0 oral cavity cancer (6 females, 3 males; mean age 57+/-24.7 years; range 31 to 71 years) who underwent surgical treatment were enrolled in this study. Eight of them had corpus linguae carcinoma, while one had lower lip carcinoma. Tumor stages were T1 in four, T2 in four patients, and T4a in one patient. The patients underwent surgery within 8 to 16 hours after lymphoscintigraphy was performed for detecting SLNs. Initially primary tumor was excised. Then, SLNs which were identified by a gamma probe, lifting skin flap of the neck were excised. Neck dissection was performed as scheduled. SLNs were examined in frozen sections. The results of frozen section and definitive histopathological diagnosis of SLNs were compared with each other, as well as the definitive histopathological diagnosis of the dissection materials. RESULTS: In all patients SLNs were completely identified and excised successfully, including one node in one patient, two nodes in six patients and three nodes in two patients. All nodes were localized ipsilaterally in the neck. In addition, the frozen section and definitive histopathological examination results of all nodes were consistent. Biopsy results indicated that eight patients were SLN-negative, while one was SLN-positive. Only one patient was SLN-negative, although the pathological diagnosis was found to be N1. CONCLUSION: Our study results suggests that SLN biopsy may be applicable for early stage oral cavity tumors. PMID- 22548265 TI - Histopathologic examination of routine tonsil and adenoid specimens: is it a necessary approach? AB - OBJECTIVES: This study aims to investigate whether it is necessary to perform histopathologic examination of the specimens of tonsillectomy and/or adenoidectomy. PATIENTS AND METHODS: In this retrospective and multicenter study, 1021 pediatric and adult patients (557 males, 464 females; median age 8 years; range 5 to 13 years) who underwent adenoidectomy and/or tonsillectomy were included. Of the patients, 809 (79.3%) were pediatrics, while 212 (20.7%) were adult. Age, gender, histopathologic diagnosis and risk for malignancy in the patients with malignant diagnosis were reviewed using present patient records. RESULTS: Adenotonsillectomy was performed on 396 patients (38.8%), tonsillectomy on 266 patients (26%) and adenoidectomy on 359 patients (35.2%). Of the 1021 patients, 1011 (99%) received a benign histopathologic diagnosis, while 11 (1%) receieved malignant diagnosis. Malignant diagnosis was present only in adult patients. All patients diagnosed with a malignancy had one or more preoperative risk factors. No unexpected malignant diagnosis was found in any of the patients without preoperative risk factors. CONCLUSION: We concluded that histopathologic diagnosis may not be required for the patients without preoperative risk factors, particularly pediatric patients. PMID- 22548266 TI - [The evaluation of tumor histopathology, location, characteristic, size and thickness of nonmelanoma skin cancers of the head and neck]. AB - OBJECTIVES: This study aims to investigate the characteristic features of tumors and relationship between features in cases who underwent surgery for nonmelanoma skin cancer (NMSC) of the head and neck. PATIENTS AND METHODS: Between December 2007 and March 2011, 106 lesions of 90 cases who underwent excision of NMSC of the head and neck in our clinic were included. The statistical analysis was performed by evaluating the demographic data, histopathologic type, size and thickness of tumor, location, Clark stage, T stage, risk of recurrence and the presence of recurrence, reconstruction technique and success rate of surgery. RESULTS: Basal cell carcinoma (BCC) was approximately two-fold more common than squamous cell carcinoma (SCC). The most common locations of tumors were the nose and lip. Most of lesions (71.7%) were at high-risk of recurrence. When the relationship of histopathologic type with the size and depth of tumor were analyzed, it was found that the size and thickness of tumor in SCC were relatively higher with a statistically significant difference. The relationship between histopathologic type and the location of tumors was also statistically significant. CONCLUSION: Basal cell carcinoma is the most common NMSC of the head and neck. Most of these cases have the potential of high rate of recurrence. The size and thickness of SCC are higher than BCC. PMID- 22548267 TI - [Bone cement or incus interposition in type 2 tympanoplasty: prognostic factors and functional outcomes]. AB - OBJECTIVES: In this study, we compared the functional results of incus interposition and the use of bone cement in patients who underwent type 2 tympanoplasty due to isolated incus defects. PATIENTS AND METHODS: A total of 47 patients including 12 patients with incus interposition and 35 patients with bone cement were enrolled in the study. The middle ear risk indices (MERI) of the patients were evaluated from the patient files. The mean air conduction thresholds at 0.5, 1, 2 and 4 kHz and air-bone gap were estimated, evaluating preoperative and postoperative audiogram results at 12 months of all patients. The success rate of surgery and functional outcomes were compared between the patients of similar MERI groups on which ossicular reconstruction was performed using different methods (bone cement or incus interposition). RESULTS: In all patients, there was a statistical significant improvement in terms of the mean air conductance threshold and decrease in the mean air-bone gap (p<0.001, p=0.001). The comparison of percentage changes of functional gain between incus interposition and bone cement groups showed no statistically significant difference (p=0.542, p=0.534). CONCLUSION: In this study, similar functional outcomes were attained between the patient groups in which type 2 tympanoplasty with either sculptured incus interposition or bone cement was performed. Several factors including the cost of the material to be used, status of the middle ear and ossicles, defect size, and experience of the surgeon should be also considered. PMID- 22548268 TI - A rare late complication after concomitant chemoradiation of an oropharyngeal tumor: cervical necrotizing fasciitis. AB - Chemoradiation is increasingly being used to treat locally advanced head and neck carcinomas. Possible rare complications of this treatment modality have begun to appear, as the number of treated patients increase. In this report, we present a case who underwent chemoradiation due to T3N3M0 tonsil cancer and developed necrotizing fasciitis of the neck at seven months following treatment. The patient recovered fully after treatment with surgical debridement with pectoralis major flap reconstruction and intravenous antibiotherapy. PMID- 22548269 TI - Thyroid metastasis of the primary lung adenocarcinoma: a case report. AB - Metastatic diseases of thyroid are rarely seen. For the patients who had previous malignancy in their history, metastatic lesions should not be ignored in the differential diagnosis of massive lesions in the thyroid gland, even the primary tumor was treated years ago. In this article, we present a case with lung adenocarcinoma which was metastatic to the thyroid gland. PMID- 22548270 TI - Glomus tumor of the nasal vestibulum: a rare clinical presentation. AB - Glomus tumor is an uncommon benign tumor rising from the glomus bodies. It is most often found on limbs and rarely involve the head and neck. In this report, we present the 31st documented case of a intranasal glomus (nasal vestibular) tumor, an extremely rare localization. PMID- 22548271 TI - Giant pleomorphic adenoma of the parotid gland. AB - Pleomorphic adenomas are the most common benign tumors of the salivary glands. These adenomas generally present without pain and are slowly enlarged. However, they can reach enormous sizes, because they are often neglected by the patient and due to late diagnosis and intervention because of fear of surgery or sociocultural factors. This may lead to functional, aesthetic and social problems. In this article, we present a 55-year-old female patient with a giant pleomorphic adenoma in size of 15x15x20 cm, who presented with the complaint of a mass enlarged and swollen for 20 years in her left neck and face and underwent a successful surgery. PMID- 22548272 TI - Non-malignant thyroid disease after exposure to radioactive elements during nuclear explosion: a neglected issue. AB - Recent nuclear explosion in Japan led to a great concern regarding its detrimental effects on health. As obtained data imply the increased risk of thyroid cancer, the prevention is widely suggested. Also the adverse effect of leaked radioactive elements can lead to non-malignant thyroid disease, which is neglected. In this article, non-malignant thyroid disease after exposure to radioactive elements during nuclear explosion was reviewed and discussed. PMID- 22548273 TI - The OsHMA2 transporter is involved in root-to-shoot translocation of Zn and Cd in rice. AB - Zinc (Zn) is an essential micronutrient for plants and humans. Cadmium (Cd) is a Zn analog and one of the most toxic heavy metals to humans. Here we investigated the role of the Zn/Cd transporter OsHMA2. OsHMA2:GFP fusion protein localized to the plasma membrane in onion epidermal cells. The yeast expressing OsHMA2 was able to reverse the growth defect in the presence of excess Zn. The expression of OsHMA2 in rice was observed mainly in the roots where OsHMA2 transcripts were abundant in vascular bundles. Furthermore, Zn and Cd concentrations of OsHMA2 suppressed rice decreased in the leaves, while the Zn concentration increased in the roots compared with the wild type (WT). These results suggest that OsHMA2 plays a role in Zn and Cd loading to the xylem and participates in root-to-shoot translocation of these metals in rice. Furthermore, the Cd concentration in the grains of OsHMA2-overexpressing rice as well as in OsSUT1-promoter OsHMA2 rice decreased to about half that of the WT, although the other metal concentrations were the same as in the WT. A phenotype that reduces only the Cd concentration in rice grains will be very useful for transgenic approaches to food safety. PMID- 22548274 TI - Evidence for the efficacy of statins in animal stroke models: a meta-analysis. AB - Protective effects of statins have been well documented for stroke therapy. Here, we used a systematic review and meta-analysis to assess these evidences. We identified 190 studies using statin treatment in stroke animal models by electronic searching. From those, only studies describing ischemic occlusive stroke and reporting data on infarct volume and/or neurological outcome were included in the analysis (41 publications, 1882 animals). The global estimate effect was assessed by Weighted Mean Difference meta-analysis. Statins reduced infarct volume by 25.12% (20.66%-29.58%, P < 0.001) and consistently, induced an improvement on neurological outcome (20.36% (14.17%-26.56%), P < 0.001). Stratified analysis showed that simvastatin had the greatest effect on infarct volume reduction (38.18%) and neurological improvement (22.94%), whereas bigger infarct reduction was observed giving the statin as a pre-treatment (33.5%) compared with post-treatment (16.02%). The use of pentobarbital sodium, the timing of statin administration, the statement of conflict of interest and the type of statin studied were found to be independent factors in the meta regression, indicating their influence on the results of studies examining statin treatment. In conclusion, this meta-analysis provides further evidences of the efficacy of statins, supporting their potential use for human stroke therapy. PMID- 22548275 TI - Pd(II)-mediated triad multilayers with zinc tetrapyridylporphyrin and pyridine functionalized nano-TiO2 as linkers: assembly, characterization, and photocatalytic properties. AB - Triad hybrid multilayers containing the light sensitizers of zinc tetrapyridylporphyrin (ZnTPyP) and pyridine-functionalized TiO(2) (TiO(2)-Py) nanoparticles were constructed on substrate surfaces with the use of Pd(II) ions as the connectors using the layer-by-layer (LBL) method. The assembly process was monitored using ultraviolet-visible (UV-vis) absorption and X-ray photoelectron spectra as well as scanning electron microscopy and atomic force microscopy. The content of the pyridine substituents in the TiO(2)-Py nanocomposites was about 2% (w/w). The Soret absorption band of ZnTPyP was 24 nm red-shifted in the hybrid multilayers due to a strong intermolecular electronic coupling interaction among porphyrin macrocycles or porphyrin macrocycle/TiO(2)-Py nanoparticles. The average surface density of each ZnTPyP layer was about 1.4 * 10(-10) mol/cm(2). Aggregation of the small TiO(2)-Py nanoparticles to larger domains with sizes up to hundreds of nanometers occurred in the hybrid multilayers; however, such an aggregation behavior was weaker than that in the solutions. The quartz substrate modified with the as-prepared Pd/ZnTPyP/Pd/TiO(2)-Py triad hybrid multilayers was used as a heterogeneous photocatalyst for the degradation of methyl orange (MO) under irradiation (lambda > 420 nm) at room temperature with a catalytic efficiency of about 1.3 * 10(-3) MO/ZnTPyP.s. Without the use of the filter, the catalytic efficiency increased because both ZnTPyP and TiO(2)-Py nanocomposites acted as the light sensitizers. It is suggested that the present heterogeneous catalyst has the advantages of facile separation, high stability, structural controllability on the molecular and nanoscale level, and good recyclability. PMID- 22548276 TI - Population genetic structure and long-distance dispersal among seabird populations: implications for colony persistence. AB - Dramatic local population decline brought about by anthropogenic-driven change is an increasingly common threat to biodiversity. Seabird life history traits make them particularly vulnerable to such change; therefore, understanding population connectivity and dispersal dynamics is vital for successful management. Our study used a 357-base pair mitochondrial control region locus sequenced for 103 individuals and 18 nuclear microsatellite loci genotyped for 245 individuals to investigate population structure in the Atlantic and Pacific populations of the pelagic seabird, Leach's storm-petrel Oceanodroma leucorhoa leucorhoa. This species is under intense predation pressure at one regionally important colony on St Kilda, Scotland, where a disparity between population decline and predation rates hints at immigration from other large colonies. AMOVA, F(ST), Phi(ST) and Bayesian cluster analyses revealed no genetic structure among Atlantic colonies (Global Phi(ST) = -0.02 P > 0.05, Global F(ST) = 0.003, P > 0.05, STRUCTURE K = 1), consistent with either contemporary gene flow or strong historical association within the ocean basin. The Pacific and Atlantic populations are genetically distinct (Global Phi(ST) = 0.32 P < 0.0001, Global F(ST) = 0.04, P < 0.0001, STRUCTURE K = 2), but evidence for interocean exchange was found with individual exclusion/assignment and population coalescent analyses. These findings highlight the importance of conserving multiple colonies at a number of different sites and suggest that management of this seabird may be best viewed at an oceanic scale. Moreover, our study provides an illustration of how long distance movement may ameliorate the potentially deleterious impacts of localized environmental change, although direct measures of dispersal are still required to better understand this process. PMID- 22548277 TI - Epithelial-mesenchymal transition and mesenchymal-epithelial transition are essential for the acquisition of stem cell properties in hTERT-immortalised oral epithelial cells. AB - BACKGROUND INFORMATION: Evidence has shown that mesenchymal-epithelial transition (MET) and epithelial-mesenchymal transition (EMT) are linked to stem cell properties. We currently lack a model showing how the occurrence of MET and EMT in immortalised cells influences the maintenance of stem cell properties. Thus, we established a project aiming to investigate the roles of EMT and MET in the acquisition of stem cell properties in immortalised oral epithelial cells. RESULTS: In this study, a retroviral transfection vector (pLXSN-hTERT) was used to immortalise oral epithelial cells by insertion of the hTERT gene (hTERT(+) oral mucosal epithelial cell line [OME]). The protein and RNA expression of EMT transcriptional factors (Snail, Slug and Twist), their downstream markers (E cadherin and N-cadherin) and embryonic stem cell markers (OCT4, Nanog and Sox2) were studied by reverse transcription PCR and Western blots in these cells. Some EMT markers were detected at both mRNA and protein levels. Adipocytes and bone cells were noted in the multi-differentiation assay, showing that the immortal cells underwent EMT. The differentiation assay for hTERT(+)-OME cells revealed the recovery of epithelial phenotypes, implicating the presence of MET. The stem cell properties were confirmed by the detection of appropriate markers. Altered expression of alpha-tubulin and gamma-tubulin in both two-dimensional-cultured (without serum) and three-dimensional-cultured hTERT(+)-OME spheroids indicated the re-programming of cytoskeleton proteins which is attributed to MET processes in hTERT(+)-OME cells. CONCLUSIONS: EMT and MET are essential for hTERT immortalised cells to maintain their epithelial stem cell properties. PMID- 22548278 TI - The relationship between impaired fasting glucose and self-reported sleep quality in a Chinese population. AB - OBJECTIVE: Decreased sleep quality and duration predicts the development of type 2 diabetes. Prediabetes is an established risk factor for type 2 diabetes and cardiovascular disease. However, there is limited research on the association between prediabetes and sleep quality. The aim of this study is to investigate this relationship in a Chinese population. METHODS: Subjects were recruited from the Prevention Health Center of National Cheng Kung University Hospital. Anthropometric data and metabolic parameters were measured. The diagnoses of impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and diabetes followed the recommendations of the American Diabetes Association. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). RESULTS: A total of 1805 subjects with normal glucose tolerance (NGT, n = 1217), IFG (n = 118), IGT (n = 287), IFG+IGT (n = 80) and newly diagnosed diabetes (NDD, n = 103) were recruited. The global PSQI scores were 6.07 +/- 2.44, 6.74 +/- 3.23, 6.91 +/- 3.51, 6.74 +/- 2.26 and 7.16 +/- 3.49 in subjects with NGT, IFG, IGT, IFG+IGT and NDD, respectively. Multivariate linear regression analysis showed that female gender, smoking, IGT, IFG+IGT and NDD, but not IFG, were independent determinants of global PSQI score. Multivariate logistic regression analysis showed that female gender, IGT, IFG+IGT and NDD, but not IFG, were predictors of poor sleepers. CONCLUSIONS: Subjects with prediabetes and NDD had a significantly higher global PSQI score than those with NGT. Furthermore, female gender, smoking, IGT, IFG+IGT and NDD, but not IFG, were significantly associated with poor sleep quality independent of cardiometabolic risk factors in a Chinese population. PMID- 22548279 TI - Imaging diagnosis: pituitary apoplexy in a cat. AB - A 7-year-old male neutered domestic short-haired cat had depression for 5 months and acute blindness. A lesion at the level of the rostral and middle cranial fossae was suspected. A large pituitary mass compressing the optic chiasm was detected in magnetic resonance images and there was also evidence of recent intratumoral hemorrhage, leading to a diagnosis of pituitary apoplexy; these findings were confirmed at postmortem examination. Pituitary apoplexy is a clinical syndrome characterized by acute neurologic signs related to hemorrhagic infarction within a pituitary tumor. Pituitary apoplexy should be considered in patients with acute onset of blindness and altered mental status. PMID- 22548280 TI - Metal-controlled diastereoselective self-assembly and circularly polarized luminescence of a chiral heptanuclear europium wheel. AB - The chiral dissymmetric tetradentate ligand (S)-6'-(4-phenyloxazolin-2-yl)-2,2' bipyridine-6-carboxylate (S-Phbipox) leads to the diastereoselective assembly of a homochiral Eu(3+) triangle and a highly emissive (quantum yield = 27%) heptanuclear wheel that is the largest example of a chiral luminescent complex of Eu(3+) reported to date. The nuclearity of the assembly is controlled by the solvent and the Eu(3+) cation. All of the compounds show large circularly polarized luminescence with an activity that varies with the nature of the assembly (highest for the homochiral trimer). PMID- 22548281 TI - Detection of aqueous glucose based on a cavity size- and optical-wavelength independent continuous-wave photoacoustic technique. AB - Toward the achievement of noninvasive and continuous monitoring of blood glucose level, we developed a new measurement method based on the continuous-wave photoacoustic (CW-PA) technique and performed the first validation in vitro with calibrated aqueous glucose solutions. The PA technique has been studied in the past but exclusively based on the pulse setup since the CW one exhibits dependence on the cavity dimensions, which is not compatible with the final application requirements. This paper describes a new strategy relying on the monitoring of the resonant-frequency relative shift induced by the change of glucose concentrations rather than amplitude signal levels at a fixed frequency. From in vitro results, we demonstrate a stable and reproducible response to glucose at various cavity dimensions and optical wavelengths, with a slope of 0.19 +/-0.01%/g/dL. From theoretical considerations, this method is consistent with a relative acoustic velocity measurement, which also explains the aforementioned stability. The proposed method then resolves most of the issues usually associated with the CW-PA technique and makes it a potential alternative for the noninvasive and continuous monitoring of glycemia levels. However, experimental determination of sensor responses to albumin and temperature as two potential interferents shows similar levels, which points to the selectivity to glucose as a major issue we should deal with in future development. PMID- 22548282 TI - 64Cu Core-labeled nanoparticles with high specific activity via metal-free click chemistry. AB - A novel strategy based on metal-free "click" chemistry was developed for the copper-64 radiolabeling of the core in shell-cross-linked nanoparticles (SCK NPs). Compared with Cu(I)-catalyzed click chemistry, this metal-free strategy provides the following advantages for Cu-64 labeling of the core of SCK-NPs: (1) elimination of copper exchange between nonradioactive Cu in the catalyst and DOTA chelated Cu-64; (2) elimination of the internal click reactions between the azide and acetylene groups in the same NPs; and (3) increased efficiency of the click reaction because water-soluble Cu(I) does not need to reach the hydrophobic core of the NPs. When 50 mCi Cu-64 was used for the radiolabeling, the specific activity of the radiolabeled product was 975 Ci/MUmol at the end of synthesis, which represents the attachment of ca. 500 Cu-64 atoms per SCK-NP, giving in essence a 500-fold amplification of specific activity of the NP over that of the Cu-64 chelate. To the best of our knowledge, this is the highest specific activity obtained for Cu-64-labeled nanoparticles. PMID- 22548283 TI - Measuring and communicating blood loss during obstetric hemorrhage. AB - Accurate quantification of blood loss is an essential skill necessary to prevent maternal morbidity and mortality associated with obstetric hemorrhage. Visual estimation of blood has been consistently shown to be extremely inaccurate. The nurse plays a pivotal role in quantifying blood loss after birth, recognizing triggers, mobilizing needed interventions, and providing essential communication. PMID- 22548284 TI - Effect of low temperature thermal treatment on soils contaminated with pentachlorophenol and environmentally persistent free radicals. AB - The effect of low temperature thermal treatment on soils from a former Superfund wood-treating site contaminated with pentachlorophenol (PCP) and the environmentally persistent free radical (EPFR), pentachlorophenoxyl, was determined. The pentachlorophenoxyl EPFRs' and the PCP molecules' chemical behavior were simultaneously monitored at temperatures ranging from 25 to 300 degrees C via electron paramagnetic resonance (EPR) spectroscopy and GC-MS analysis, respectively. Two types of thermal treatment were employed: a closed heating (oxygen-starved condition) where the soil was heated under vacuum and an open heating system (oxygen-rich conditions), where the soil was heated in ambient air. EPR analyses for closed heating indicated the EPFR concentration was 2-12 * 10(18) spins/g of soil, with a g-factor and line width (DeltaHp-p) of 2.00311-2.00323 and 4.190-5.472 G, respectively. EPR analyses for the open heating soils revealed a slightly broader and weaker radical signal, with a concentration of 1-10 * 10(18) spins/g of soil, g-factor of 2.00327-2.00341, and DeltaHp-p of 5.209-6.721 G. This suggested the open heating resulted in the formation of a more oxygen-centered structure of the pentachlorophenoxyl radical or additional, similar radicals. The EPFR concentration peaked at 10 * 10(18) spins/g of soil at 100 degrees C for open heating and 12 * 10(18) spins/g at 75 degrees C for closed heating. The half-lives of the EPFRs were 2-24 days at room temperature in ambient air. These results suggest low temperature treatment of soils contaminated with PCP can convert the PCP to potentially more toxic pentachlorophenoxyl EPFRs, which may persist in the environment long enough for human exposure. PMID- 22548285 TI - Genotoxicity of cobalt nanoparticles and ions in Drosophila. AB - Nanogenotoxicology is an emergent area of research, relevant for estimating the potential carcinogenic risk of nanomaterials. Since most of the approaches use in vitro studies, and neglecting the whole organism limits the accuracy of the obtained results, we have used Drosophila melanogaster to study the possible genotoxic potential of cobalt nanoparticles (Co NPs). The wing somatic mutation and recombination test has been the test of choice. This test is based on the principle that the loss of heterozygosis and the corresponding expression of the suitable recessive markers, multiple wing hairs and flare-3 can lead to the formation of mutant clone cells in growing up larvae, which are expressed as mutant spots on the wings of adult flies. Co NPs, as well as the ionic form cobalt chloride, were given to third instar larvae through the food, at concentrations ranging from 0.1 to 10 mM. The results obtained indicate that both cobalt forms are able to induce significant increases in the frequency of mutant clones. Although at low concentrations only Co NPs were genotoxic, the level of genetic damage obtained at the highest dose tested of cobalt chloride (10 mM) showed a significant higher increase in the frequency of total spots than those observed after the treatment with cobalt nanoparticles. As conclusion, our results indicate that Co NPs were able to induce genotoxic activity in the wing spot assay of D. melanogaster, mainly via the induction of somatic recombination. The differences observed in the behaviour of the two selected cobalt forms may result from differences in the uptake. PMID- 22548286 TI - Physical activity promotion in primary health care: results from a German physician survey. AB - BACKGROUND: Primary care physicians are positioned to play an important role in changing physical activity and other health behaviour of their patients. However, little is known about the practice of physical activity promotion in German primary care settings and the factors associated with physical activity promotion. METHODS: 260 randomly selected physicians from the State Medical Association of Baden-Wuerttemberg, Germany, took part in this survey (response rate: 13.3%) and provided data on physical activity promotion (physical activity assessment and advice), attitudes towards health promotion and cooperation activities. Factors associated with physical activity promotion were identified using logistic regression. RESULTS: The physicians who replied had positive attitudes towards health promotion. However, 26.9% reported they had inadequate knowledge to provide counselling and 36.7% felt they were unsuccessful in motivating their patients to increase physical activity. Physical activity assessment and advice occurred in 54.9% of the physicians. Compared to their counterparts, physicians in large cities (odds ratio (OR) 3.93; and 95% confidence interval (95%CI): 1.55-9.99), those convinced to offer their patients a great deal in the way of lifestyle counselling (OR 1.92; 95%CI: 1.09-3.40) and those cooperating with sports clubs (OR 1.75; 95%CI: 1.03-2.96) were more likely to provide physical activity promotion. CONCLUSION: There is a need for interventions to increase the frequency of physical activity promotion by primary care physicians. In particular physicians in rural regions should be assisted and cooperation activities with sports clubs or other health care providers should be encouraged. PMID- 22548287 TI - Wonca: World Organization of National Colleges, Academies and Academic Associations of General Practitioners/Family Physicians. PMID- 22548288 TI - Infectious diseases in primary care; managing the interface between the person and the community. AB - Respiratory infections are still among the most common new diagnoses in primary care. The most frequent reason for encounter is acute cough. General practitioners have to make antibiotic prescribing decisions in a context of diagnostic uncertainty, patient preferences and antimicrobial resistance. There is a causal link between antimicrobial resistance and antibiotic prescribing in primary care. GRACE observational studies (www.grace-lrti.org), show that variation in clinical presentation does not explain the considerable variation in antibiotic prescribing in Europe for adults presenting in primary care with acute cough and that recovery is similar between those treated with any antibiotic, a particular antibiotic class, or no antibiotic. A GRACE randomized controlled trial (RCT) of the effect of antibiotics for acute cough has recruited more patients than all RCTs combined in the current Cochrane Review and will have the power to identify subgroups of patients who will (not) benefit from amoxicillin. Another multi-country GRACE RCT assessing the effect on antibiotic prescribing of largely web-based versions of successful interventions including a C-reactive protein point-of-care test, a communication skill training and an interactive patient booklet is awaited. Given potential long-term cost-effectiveness, the GRACE suite of observational and interventional studies are enhancing the evidence base for reducing diagnostic uncertainty and managing patient expectations in a patient-centred way to achieve greater evidence-based antibiotic prescribing that is likely to help containing antimicrobial resistance. PMID- 22548289 TI - Pruritic plaques in a patient with diabetes. PMID- 22548290 TI - Phosphatidylserine reversibly binds Cu2+ with extremely high affinity. AB - Phosphatidylserine (PS) embedded within supported lipid bilayers was found to bind Cu(2+) from solution with extraordinarily high affinity. In fact, the equilibrium dissociation constant was in the femtomolar range. The resulting complex formed in a 1:2 Cu(2+)-to-PS ratio and quenches a broad spectrum of lipid bound fluorophores in a reversible and pH-dependent fashion. At acidic pH values, the fluorophores were almost completely unquenched, while at basic pH values significant quenching (85-90%) was observed. The pH at which the transition occurred was dependent on the PS concentration and ranged from approximately pH 5 to 8. The quenching kinetics was slow at low Cu(2+) concentrations and basic pH values (up to several hours), while the unquenching reaction was orders of magnitude more rapid upon lowering the pH. This was consistent with diffusion limited complex formation at basic pH but rapid dissociation under acidic conditions. The tight binding of Cu(2+) to PS may have physiological consequences under certain circumstances. PMID- 22548292 TI - The preoperative assessment of deep myometrial invasion by three-dimensional ultrasound versus MRI in endometrial carcinoma. AB - OBJECTIVE: To evaluate the usefulness of three-dimensional ultrasound (3D US), magnetic resonance imaging (MRI) and three-dimensional power Doppler angiography (3D-PDA) in the preoperative assessment of myometrial invasion in endometrial carcinoma. DESIGN: A prospective observational study. SETTING: University hospital. POPULATION: Twenty consecutive patients diagnosed with endometrial carcinoma. METHODS: Preoperative 3 T MRI and 3D US examinations were performed, and the depth of myometrial invasion was assessed. The vascularity indices, vascularization index, flow index and vascularization flow index, were calculated by 3D-PDA. MAIN OUTCOME MEASURES: The results were compared with the final histopathology report after a surgical staging. RESULTS: In detecting deep myometrial invasion, the sensitivity of 3D US, MRI and their combination was 50, 91.7 and 100%, respectively. The specificity was 87.5, 50 and 50%, respectively. There were no significant differences in the 3D-PDA vascularity indices between the two groups. CONCLUSIONS: MRI appears to be more sensitive than 3D US in detecting deep invasion, while 3D US has a better specificity. PMID- 22548293 TI - Clinical diagnosis of metabolic syndrome: predicting new-onset diabetes, coronary heart disease, and allograft failure late after kidney transplant. AB - Metabolic syndrome is associated with coronary heart disease (CHD) and new-onset diabetes after kidney transplant (NODAT). Using data collected from transplant centers worldwide for the Patient Outcomes in Renal Transplantation study, we examined associations of metabolic syndrome (n = 2253 excluding recipients with diabetes pretransplant), CHD (n = 2253), and NODAT (n = 1840 further excluding recipients with diabetes in the first year post-transplant), with the primary outcome of allograft failure. We assessed risk factors associated with secondary outcomes of metabolic syndrome, NODAT, and CHD after adjusting for type of baseline immunosuppression and transplant center effects. Metabolic syndrome prevalence was 39.8% at 12-24 months post-transplant and 35.4% at 36-48 months. Metabolic syndrome was independently associated with NODAT (hazard ratio 3.46, 95% confidence interval 2.40-4.98, P < 0.0001), CHD (2.03, 1.16-3.52, P = 0.013), and allograft failure (1.36, 1.03-1.79, P = 0.028). Allograft failure occurred in 218 patients (14.6%). After adjustment for metabolic syndrome, NODAT (1.63, 1.18 2.24, P = 0.003) and CHD (5.48, 3.27-9.20, P < 0.0001) remained strongly associated with increased risk of allograft failure. Metabolic syndrome, NODAT, and CHD are risk factors for allograft failure. NODAT and CHD are risk factors for allograft failure, independent of metabolic syndrome. PMID- 22548295 TI - MicroRNAs as regulators in normal hematopoietic and leukemia stem cells: current concepts and clinical implications. AB - Relapse after current treatment is one of the main limitations to the complete cure of leukemia, and a concept that leukemia stem cell (LSC) is the major cause of relapse has been proposed. LSCs are derived from normal hematopoietic stem cells (HSCs), residing at the apex of leukemia cells and hiding in the bone marrow (BM) niche to evade chemotherapy. Novel therapy is strongly needed based on the unique features of LSCs to directly target these cells. MicroRNAs (miRNAs), a class of small non-coding RNAs, are now known to play important roles on cancer stem cell maintenance and differentiation. Because of the ability of miRNAs to inactivate either specific genes or entire gene families, strategies based on differential expression levels of miRNAs in LSCs as dominant activators or suppressors of gene activity have emerged as promising new candidate approaches for eradicating LSCs. In this review, we highlight new findings regarding the roles of miRNAs in LSC maintenance of quiescence repression, self renewal, surface marker targeting, and the LSCBM niche interaction. We also discuss recent advances and future challenges to use LSC specific miRNAs as potential therapeutic molecules in eradicating LSCs. PMID- 22548294 TI - Efficient in vitro siRNA delivery and intramuscular gene silencing using PEG modified PAMAM dendrimers. AB - Although siRNA techniques have been broadly applied as a tool for gene knockdown, substantial challenges remain in achieving efficient delivery and in vivo efficacy. In particular, the low efficiency of target gene silencing in vivo is a critical limiting step to the clinical application of siRNA therapies. Poly(amidoamine) (PAMAM) dendrimers are widely used as carriers for drug and gene delivery; however, in vivo siRNA delivery by PAMAM dendrimers remains to be carefully investigated. In this study, the effectiveness of G5 and G6 PAMAM dendrimers with 8% of their surface amines conjugated to MPEG-5000 was studied for siRNA delivery in vitro and for intramuscular in vivo delivery in mice. The results from the PEG-modified dendrimers were compared to the results from the parent dendrimers as well as Lipofectamine 2000 and INTERFERin. Both PEG-modifed dendrimers protect the siRNA from being digested by RNase and gave high transfection efficiency for FITC-labeled siRNA in the primary vascular smooth muscle cells (VSMC) and mouse peritoneal macrophages. The PEG-modified dendrimers achieved knockdown of both plasmid (293A cells) and adenovirus-mediated green fluorescence protein (GFP) expression (Cos7 cells) in vitro with efficiency similar to that shown for Lipofectamine 2000. We further demonstrated in vivo that intramuscular delivery of GFP-siRNA using PEG-modified dendrimer significantly suppressed GFP expression in both transiently adenovirus infected C57BL/6 mice and GFP transgenic mice. PMID- 22548296 TI - Thyroid testing in pregnant women with thyroid dysfunction in Tayside, Scotland: the thyroid epidemiology, audit and research study (TEARS). AB - OBJECTIVE: To investigate the rate of thyroid testing during pregnancy. DESIGN: Population-based, retrospective record-linkage study. SETTING: Health care data on pregnant women in Tayside, Scotland. PARTICIPANTS: All pregnant women who were 18 years and above and who delivered between 1 January 1993 and 31 March 2011 in Tayside were identified. Patients were included in the study if they have had at least three thyroxine prescriptions prior to pregnancy of which at least one prescription was within 6 months prior to pregnancy. MAIN OUTCOME MEASURES: Number of thyroid-stimulating hormone (TSH) assays performed during pregnancy and the changes in dosage of thyroxine prescribed during pregnancy. RESULTS: We identified 950 pregnancies that had thyroxine prescribed prior to pregnancy. Overall, 96.9% (95% CI: 96-98) of these pregnancies had at least one TSH assay performed during or just prior to pregnancy, with 81.2% (95% CI: 79-84) in the first trimester. The prescription of thyroxine was increased in 60.0% (95% CI: 57 63) at any time during pregnancy and in 34.0% (95% CI: 31-37) of pregnancies during the first trimester. Overall, 60% (95% CI: 57-63) of pregnancies had at least one elevated serum TSH during pregnancy with 55% (95% CI: 51-58) in the first trimester. CONCLUSION: The TSH concentration is raised in many pregnancies in women taking long-term thyroxine. PMID- 22548297 TI - Management of diabetes in primary care: a structured-care approach. AB - BACKGROUND: In the Irish Midland Health Service Executive (HSE) Diabetes Structured Care Project, additional resources were targeted at general practice in the absence of a local hospital-based specialized diabetes unit. OBJECTIVE: We assessed the performance of the Midland HSE Diabetes Structured Care programme in 2003, bench-marked against Primary Care Trust (PCT) data from the 2003/2004 National Diabetes Audit for England. METHODS: Data on 947 patients (72% of eligible patients) from all 20 general practices participating in the structured care programme were collected retrospectively over a 12-month period. The data included demographic and clinical variables as well as key process-of-care and intermediate outcome indicators used in the National Diabetes Audit for England. RESULTS: The level of recording of process-of-care measures was near or above the upper quartile for PCTs in England. The proportion of patients with HbA(1c) concentrations at target levels (<6.5%) in the Midlands HSE project (26.8%) was virtually identical to the upper quartile level for PCTs in England (27.4%). The proportion of patients reaching target total cholesterol levels (<5.0 mmol/l) (54.6%) was close to the mean for PCTs in England (56.6%), and performance with regard to target blood pressure levels was equally poor in both the Midlands HSE (18.0%) and in PCTs in England (20.8%). CONCLUSION: Primary-care-led structured care, with relatively limited but well-focused investment, can achieve quality of care for patients with diabetes, comparable to international best practice. PMID- 22548298 TI - Does place of treatment affect prognosis for chronic obstructive pulmonary disease (COPD)? AB - BACKGROUND: It has been shown previously that mortality from acute chronic obstructive pulmonary disease (COPD) is higher at small hospitals than at large teaching hospitals. OBJECTIVE: To examine mortality at this acute stage and referral for further treatment by specialities in Finland, and trends in these between the 1990s and 2000s. METHODS: Data on all periods of treatment for patients over 44 years of age with a principal or subsidiary diagnosis of COPD beginning and ending in 1995-2004 were extracted from the Finnish hospital discharge register. Particular attention was paid to acute-stage treatment periods managed by a general practitioner, pulmonary specialist, or specialist in internal medicine that had begun as emergency admissions and had a principal diagnosis of COPD, and to any further treatment immediately following these. RESULTS: General practitioners referred 5.1% of their acute-stage patients to a specialist in secondary care in 1995-2004. Of the total of 77,445 acute-stage treatment periods, 3% (2328) ended in the death of the patient, implying the loss of 8.3% of the patients involved. The age- and sex-adjusted risk of death attached to treatment periods managed by a general practitioner relative to those managed by a pulmonary specialist was 0.83 (95% CI 0.75-0.91). CONCLUSION: It is quite possible to treat acute exacerbations of COPD efficiently and safely in a health centre hospital ward. New treatment modalities and health service structures seem to have led to a decrease in acute exacerbations of COPD since the year 2000, even though the number of patients with this disease has increased as a consequence of ageing of the population. Further research is required on the efficacy of treatment by a general practitioner, e.g., with data on re hospitalization. PMID- 22548300 TI - Video games as a complementary therapy tool in mental disorders: PlayMancer, a European multicentre study. AB - BACKGROUND: Previous review studies have suggested that computer games can serve as an alternative or additional form of treatment in several areas (schizophrenia, asthma or motor rehabilitation). Although several naturalistic studies have been conducted showing the usefulness of serious video games in the treatment of some abnormal behaviours, there is a lack of serious games specially designed for treating mental disorders. AIM: The purpose of our project was to develop and evaluate a serious video game designed to remediate attitudinal, behavioural and emotional processes of patients with impulse-related disorders. METHOD AND RESULTS: The video game was created and developed within the European research project PlayMancer. It aims to prove potential capacity to change underlying attitudinal, behavioural and emotional processes of patients with impulse-related disorders. New interaction modes were provided by newly developed components, such as emotion recognition from speech, face and physiological reactions, while specific impulsive reactions were elicited. The video game uses biofeedback for helping patients to learn relaxation skills, acquire better self control strategies and develop new emotional regulation strategies. In this article, we present a description of the video game used, rationale, user requirements, usability and preliminary data, in several mental disorders. PMID- 22548301 TI - Retinoic acid-dependent control of MAP kinase phosphatase-3 is necessary for early kidney development in Xenopus. AB - BACKGROUND INFORMATION: In Xenopus, the functional kidney of the tadpole, the pronephros, forms from the kidney field, which is specified at completion of gastrulation. Specification of the kidney field requires retinoic acid (RA) signalling during gastrulation, while fibroblast growth factor (FGF) signals inhibit should be inhibit this process. RESULTS: We have analysed the functional interactions taking place during gastrulation between RA and FGF signals in the lateral marginal zone (LMZ), that is in the environment of unspecified pronephric mesoderm precursors. Inhibition of FGF receptor (FGFR) signalling with SU5402 does not significantly affect expression of genes encoding RA metabolism enzymes and RA receptor-alpha in LMZ explants. Furthermore, SU5402 has no effect on the expression of hoxa1, a major RA target in the LMZ, showing that FGF is not antagonising RA in the LMZ. Disruption of RA signalling affects FGF ligand production to some extent, especially FGF8b, but the strongest effect is the down regulation of the mitogen-activated protein kinase phosphatase-3 (MKP3)-encoding gene, mkp3. A strong up-regulation of mkp3 occurs in response to exogenous RA. This effect is reduced in a context of FGFR inhibition, suggesting that RA and FGF signals are co-operating upstream of mkp3. Mkp3 knockdown results in an inhibition of the kidney field markers pax8 and lhx1 and in a defective development of the pronephros. CONCLUSIONS: FGF is not negatively influencing pronephric specification by antagonising RA signalling. Functional interactions between RA and FGF rather take place at the level of the transcriptional regulation of mkp3, indicating that RA may antagonise FGF signalling at the level of the extracellular signal-regulated kinase (Erk) pathway. A fine tuning of Erk signalling by MKP3 is important for the proper establishment of the kidney field. PMID- 22548302 TI - Orofacial granulomatosis: three case reports illustrating the spectrum of disease and overlap with Crohn's disease. AB - We report three cases of orofacial granulomatosis (OFG) to illustrate the spectrum of this disease, and to discuss the appropriate management steps, consider its overlap with Crohn's disease (CD) and raise its awareness among paediatric dermatologists. The term 'orofacial granulomatosis' was first used in 1985 to describe granulomas in the orofacial region in the absence of any recognized systemic condition. It is uncommon but becoming increasingly recognized in children. The clinical features of the disease may vary greatly, and often present with subtle changes that can be missed. There is a debate about whether OFG exists as a separate condition or whether it is an oral feature of CD, as some patients go on to develop CD several years later. Identifying those most at risk is important, as ongoing investigations may be necessary. The three cases presented in this series illustrate the range of disease signs and symptoms, and the investigations required. PMID- 22548303 TI - Effects of acute treatment with dexamethasone on hemodynamic and histopathological changes in rats. AB - We assessed the time-dependent effects of intraperitoneal (i.p.) and intravenous (i.v.) application of dexamethasone (Dexa) on the mean arterial blood pressure (MAP), heart rate (HR) and total blood volume (TBV). We evaluated also the relation between the effects and immunoreactivities of transforming growth factor beta (TGF-beta), epithelial nitric oxide synthase (eNOS), interleukin-1 beta (IL1 beta) and vascular endothelial growth factor (VEGF) in rat brain, lung and kidney tissues. Rats were anesthetized and while still breathing spontaneously, a tracheotomy and femoral vein and artery catheterizations were performed. To determine TBV using the hemodilution method, 2 ml albumin-electrolyte solutions were applied by i.v. injection. Group 1 (control group) received a 1 ml bolus injection of physiologic saline, Group 2 received 15 mg/kg and Group 3 received 75 mg/kg Dexa i.p. The hematocrit was measured at 10, 20, 60 and 120 min. For each animal, the values of MAP, HR and TBV were measured within 2 h. For immunohistochemical evaluation, anti-TGF-beta, anti-eNOS, anti-IL1-beta and anti VEGF primary antibodies were tested using the avidin-biotin-peroxidase method. TBV was decreased in Group 1 and the increase in MAP was statistically significant. HR values increased slightly. None of the values changed significantly in Group 2. Although TBV was unchanged in Group 3, the decrease in MAP was statistically significant. HR values increased, but the increase was not statistically significant. Mild IL1-beta immunoreactivity and moderate TGF-beta, eNOS and VEGF immunoreactivities were observed in the brain, lung and kidney samples in Group 1. Increased eNOS immunoreactivity in the kidney samples were observed in Group 2. eNOS immunoreactivity was as strong in the brain and the kidney samples in Group 3. Decreased VEGF immunoreactivity was observed in the lung and kidney tissues in Group 3. Significantly decreased TGF-beta immunoreactivity was observed in all tissue samples in Group 3. The decreased MAP values in Group 3 differed from those in Groups 1 and 2. Despite increased eNOS immunoreactivity, especially in brain and kidney, the decrease in VEGF immunoreactivity in Group 3, especially lung and kidney, were consistent with a drop in blood pressure. PMID- 22548304 TI - Factors influencing extract of Hibiscus sabdariffa staining of rat testes. AB - Some plant extracts can be used in biology and medicine to reveal or identify cellular components and tissues. We investigated the effects of time and concentration on staining of histological sections of rat testes by an acidified extract of Hibiscus sabdariffa. An ethanolic extract of H. sabdariffa was diluted using 1% acetic acid in 70% ethanol to stain histological sections of testes at concentrations of 0.2, 0.1 and 0.05 g/ml for 5, 10, 15, 30, 45 and 60 min. The sections of testes were stained deep red. The staining efficiency of H. sabdariffa was greater at a high concentration and required less time to achieve optimal staining. H. sabdariffa is a strongly basic dye that can be used for various diagnostic purposes. Staining time and concentration must be considered to achieve optimal results. PMID- 22548306 TI - Effect of divalent cations on DMPC/DHPC bicelle formation and alignment. AB - Many important classes of biomolecules require divalent cations for optimal activity, making these ions essential for biologically relevant structural studies. Bicelle mixtures composed of short-chain and long-chain lipids are often used in solution- and solid-state NMR structure determination; however, the phase diagrams of these useful orienting media and membrane mimetics are sensitive to other solution components. Therefore, we have investigated the effect of varying concentrations of four divalent cations, Ca(2+), Mg(2+), Zn(2+), and Cd(2+), on cholesterol sulfate-stabilized DMPC/DHPC bicelles. We found that low concentrations of all the divalent ions are tolerated with minimal perturbation. At higher concentrations Zn(2+) and Cd(2+) disrupt the magnetically aligned phase while Ca(2+) and Mg(2+) produce more strongly oriented phases. This result indicates that divalent cations are not only required to maintain the biological activity of proteins and nucleic acids; they may also be used to manipulate the behavior of the magnetically aligned phase. PMID- 22548305 TI - Domain-dependent effects of DAT inhibition in the rat dorsal striatum. AB - The rat dorsal striatum exhibits domain-dependent kinetics of dopamine release and clearance. The present report describes the domain-dependent actions of nomifensine (20 mg/kg i.p.), a competitive dopamine uptake inhibitor, on evoked dopamine responses recorded by voltammetry during electrical stimulation of the medial forebrain bundle. In slow domains, nomifensine increases the initial rate of evoked overflow, increases response overshoot, does not affect the slope of the linear segment of the dopamine clearance profile, and slows the non-linear segment of the clearance profile. In fast domains, nomifensine does not affect the initial rate of overflow, increases the end-of-stimulus overshoot, and decreases the slope of the linear segment of the dopamine clearance profile. Collectively, these findings do not concur with existing models of evoked dopamine release that describe the effect of nomifensine as an increase in the effective KM of dopamine uptake. These findings suggest that dopamine clearance after evoked release is affected by both dopamine uptake and a restricted extracellular diffusion process. PMID- 22548307 TI - Quantifying elbow extension and elbow hyperextension in cricket bowling: a case study of Jenny Gunn. AB - In this study a method for determining elbow extension and elbow abduction for a cricket bowling delivery was developed and assessed for Jenny Gunn who has hypermobility in both elbows and whose bowling action has been repeatedly queried by umpires. Bowling is a dynamic activity which is assessed visually in real time in a cricket match by an umpire. When the legality of a bowler's action is questioned by an umpire a quantitative analysis is undertaken using a marker based motion analysis system. This method of quantifying elbow extension should agree with a visual assessment of when the arm is "straight" and should minimise the effects of marker movement. A set of six markers on the bowling arm were used to calculate elbow angles. Differences of up to 1 degrees for elbow extension and up to 2 degrees for elbow abduction were found when angles calculated from the marker set for static straight arm trials were compared with measurements taken by a chartered sports physiotherapist. In addition comparison of elbow extension angles at ball release calculated from the markers during bowling trials with those measured from high speed video also showed good agreement with mean differences of 0 degrees +/-2 degrees . PMID- 22548308 TI - Modular synthesis of folate conjugated ternary copolymers: polyethylenimine-graft polycaprolactone-block-poly(ethylene glycol)-folate for targeted gene delivery. AB - Folate receptor (FR) is overexpressed in a variety of human cancers. Gene delivery vectors conjugated with folate as a ligand could possibly deliver gene materials into target tumor cells via FR-mediated endocytosis. This study addresses novel folate-conjugated ternary copolymers based on polyethylenimine graft-polycaprolactone-block-poly(ethylene glycol) (PEI-g-PCL-b-PEG-Fol) as targeted gene delivery system using a modular synthesis approach including "click" conjugation of folate moieties with heterobifunctional PEG-b-PCL at PEG terminus and subsequently the introduction of PEI by a Michael addition between folate-PEG-b-PCL and PEI via active PCL terminus. This well-controlled synthetic procedure avoids tedious separation of byproduct. The structure of PEI-g-PCL-b PEG-Fol was confirmed by (1)H NMR and UV spectra. DNA condensation of PEI-g-PCL-b PEG-Fol was tested using a SYBR Gold quenching assay and agarose gel electrophoresis upon heparin competition assay. Although PEI-g-PCL-b-PEG-Fol could condense DNA completely at N/P ratio >2, polyplexes of N/P ratio 10 with sizes of about 120 nm and positive zeta potentials were selected for further biological evaluations due to polyplex stability. An enhancement of cellular uptake of PEI-g-PCL-b-PEG-Fol/pDNA polyplexes was observed in FR overexpressing KB cells in comparison to unmodified PEI-g-PCL-b-PEG, through flow cytometry analysis and confocal laser scanning imaging. Importantly, this enhanced cellular uptake could be inhibited by free folic acid and did not occur in FR-negative A549 cells, demonstrating specific cell uptake by FR-mediated endocytosis. Furthermore, the transfection efficiency of PEI-g-PCL-b-PEG-Fol/pDNA polyplexes was increased approximately 14-fold in comparison to folate-negative polyplexes. Therefore, the PEI-g-PCL-b-PEG-Fol merits further investigation under in vivo conditions for targeting FR overexpressing tumors. PMID- 22548310 TI - Pressure-volume index-based volume calculation of contrast medium for atlanto occipital myelography in dogs. AB - Subarachnoid pressure recordings were made during atlanto-occipital myelography in 45 dogs with clinical signs of spinal disease. Iohexol was injected at a dosage of 0.3 ml/kg body weight and simultaneous pressure values were recorded in the cerebellomedullary cistern. The mean subarachnoid pressure was 9 +/- 3 mmHg before and 70 +/- 32 mmHg at the end of administration. From the pressure change induced by the volume load, the pressure-volume index (PVI) of the subarachnoid space was calculated and found to be in close correlation with body weight and the crown-rump length (r = 0.94 and 0.87). Using the estimated PVI values, the appropriate volume of contrast medium can be calculated for an animal according to body weight. Dogs of a large body size require relatively less contrast medium than small-sized dogs (range 0.17-0.35 ml/kg). This calculated volume is unlikely to increase the subarachnoid pressure above 40 mmHg as a specific pressure limit. Using these data, simplified recommendations for the choice of contrast medium volumes have been generated. PMID- 22548311 TI - Single incision laparoscopic surgery (SILS) in gynaecology: feasibility and operative outcomes. AB - BACKGROUND: Single incision laparoscopic surgery (SILS) represents the latest advancement in minimally invasive surgery, combining the benefits of conventional laparoscopic surgery, such as less pain and faster recovery, with improved cosmesis. Although the successful use of this technique is well reported in general surgery and urology, there is a lack of studies on SILS in gynaecology. AIMS: To evaluate the feasibility, safety, cosmesis and outcome of SILS in gynaecology. METHODS: A prospective case series analysis of 105 women scheduled to undergo surgery by SILS from August 2010 to November 2011. Intra-operative data such as operative time, estimated blood loss, complications, additional ports and hospital stay were collected. Post-operative pain and cosmetic outcomes (scar size) were also recorded. RESULTS: Out of 105 women, SILS was performed for 84 (60 excisions of endometriosis, 13 divisions of adhesions, five hysterectomies, two mesh sacrohysteropexies and four ovarian cystectomies). SILS was not undertaken for 21 women because of a number of factors, including the lack of required equipment (eg bariatric scope, SILS port, roticulating instruments and diathermy leads). Four women required insertion of additional ports because of surgical difficulties. One intra-operative (uterine perforation) and seven post-operative complications (six wound infections and one vault haematoma) occurred. Mean operation times were as follows: mesh sacrohysteropexy 60 min, excision of endometriosis - 55 min, hysterectomy - 150 min, laparoscopic division of adhesions - 62 min and ovarian cystectomy - 40 min. CONCLUSIONS: Our experience shows that SILS is a feasible and safe technique for the surgical management of various gynaecological conditions. Satisfaction is high because of improved cosmesis and reduced analgesic requirements post-operatively. PMID- 22548312 TI - Implementing and sustaining in situ drills to improve multidisciplinary health care training. AB - In situ drills are a key adjunct to evidence-based protocols and established educational programs. Well-planned and conducted drills can further reinforce important educational concepts concerning high-risk events such as maternal hemorrhage, allow the team to develop skills to improve performance, and uncover systems errors. Evaluation of the findings from the drills and topics discussed during debriefing can lead to optimized training and refinement of the patient care setting to support an optimal environment for patient care and safety. PMID- 22548313 TI - Passivation coating on electrospun copper nanofibers for stable transparent electrodes. AB - Copper nanofiber networks, which possess the advantages of low cost, moderate flexibility, small sheet resistance, and high transmittance, are one of the most promising candidates to replace indium tin oxide films as the premier transparent electrode. However, the chemical activity of copper nanofibers causes a substantial increase in the sheet resistance after thermal oxidation or chemical corrosion of the nanofibers. In this work, we utilize atomic layer deposition to coat a passivation layer of aluminum-doped zinc oxide (AZO) and aluminum oxide onto electrospun copper nanofibers and remarkably enhance their durability. Our AZO-copper nanofibers show resistance increase of remarkably only 10% after thermal oxidation at 160 degrees C in dry air and 80 degrees C in humid air with 80% relative humidity, whereas bare copper nanofibers quickly become insulating. In addition, the coating and baking of the acidic PEDOT:PSS layer on our fibers increases the sheet resistance of bare copper nanofibers by 6 orders of magnitude, while the AZO-Cu nanofibers show an 18% increase. PMID- 22548314 TI - Effect of backbone flexibility on charge transfer rates in peptide nucleic acid duplexes. AB - Charge transfer (CT) properties are compared between peptide nucleic acid structures with an aminoethylglycine backbone (aeg-PNA) and those with a gamma methylated backbone (gamma-PNA). The common aeg-PNA is an achiral molecule with a flexible structure, whereas gamma-PNA is a chiral molecule with a significantly more rigid structure than aeg-PNA. Electrochemical measurements show that the CT rate constant through an aeg-PNA bridging unit is twice the CT rate constant through a gamma-PNA bridging unit. Theoretical calculations of PNA electronic properties, which are based on a molecular dynamics structural ensemble, reveal that the difference in the CT rate constant results from the difference in the extent of backbone fluctuations of aeg- and gamma-PNA. In particular, fluctuations of the backbone affect the local electric field that broadens the energy levels of the PNA nucleobases. The greater flexibility of the aeg-PNA gives rise to more broadening, and a more frequent appearance of high-CT rate conformations than in gamma-PNA. PMID- 22548315 TI - Enhanced prostate cancer targeting by modified protease sensitive photosensitizer prodrugs. AB - Prodrugs combining macromolecular delivery systems with site-selective drug release represent a powerful strategy to increase selectivity of anticancer agents. We have adapted this strategy to develop new polymeric photosensitizer prodrugs (PPP) sensitive to urokinase-like plasminogen activator (uPA). In these compounds (to be referred to as uPA-PPPs) multiple copies of pheophorbide a are attached to a polymeric carrier via peptide linkers that can be cleaved by uPA, a protease overexpressed in prostate cancer (PCa). uPA-PPPs are non-phototoxic in their native state but become fluorescent and produce singlet oxygen after uPA mediated activation. In the present work, we studied the influence of side-chain modifications, molecular weight, and overall charge on the photoactivity and pharmacokinetics of uPA-PPPs. An in vitro promising candidate with convertible phototoxicity was then further investigated in vivo. Systemic administration resulted in a selective accumulation and activation of the prodrug in luciferase transfected PC-3 xenografts, resulting in a 4-fold increase in fluorescence emission over time. Irradiation of fluorescent tumors induced immediate tumor cell eradication as shown by whole animal bioluminescence imaging. PDT with uPA PPP could therefore provide a more selective treatment of localized PCa and reduce side effects associated with current radical treatments. PMID- 22548316 TI - Transmissions of serotonin, dopamine, and glutamate are required for the formation of neurotoxicity from Al2O3-NPs in nematode Caenorhabditis elegans. AB - In this study, we investigated genetic mechanisms of neurotransmitters in regulating the formation of adverse effects on locomotion behavior in Al2O3 nanoparticles (NPs)-exposed Caenorhabditis elegans. Al2O3-NPs exposure caused the decrease of locomotion behavior with head thrash and body bend as endpoints. Interestingly, the neurotransmitters of glutamate, serotonin, and dopamine were required for the adverse effects of Al2O3-NPs on locomotion behavior in nematodes. Glutamate transporter EAT-4, serotonin transporter MOD-5, and dopamine transporter DAT-1 might serve as the molecular targets of Al2O3-NPs for neurotoxicity formation. Moreover, the behavioral response of nematodes to Al2O3 NPs exposure was primarily mediated by non-NMDA glutamate receptors GLR-2 and GLR 6, ionotropic serotonin receptor MOD-1, and D1-like dopamine receptor DOP-1. Therefore, Al2O3-NPs exposure influences locomotion behavior of nematodes primarily by impinging on their glutamatergic, serotoninergic, and dopaminergic systems. Our data will shed light on questions surrounding the involvement of neurotransmitters in mediating the adverse behavioral effects from Al2O3-NPs. PMID- 22548317 TI - The chestnut blight fungus world tour: successive introduction events from diverse origins in an invasive plant fungal pathogen. AB - Clonal expansion has been observed in several invasive fungal plant pathogens colonizing new areas, raising the question of the origin of clonal lineages. Using microsatellite markers, we retraced the evolutionary history of introduction of the chestnut blight fungus, Cryphonectria parasitica, in North America and western Europe. Combining discriminant analysis of principal components and approximate Bayesian computation analysis, we showed that several introduction events from genetically differentiated source populations have occurred in both invaded areas. In addition, a low signal of genetic recombination among different source populations was suggested in North America. Finally, two genetic lineages were present in both invaded areas as well as in the native areas, suggesting the existence of genetic lineages with a high capacity to establish in diverse environments and host species. This study confirmed the importance of multiple introductions, but questioned the role of genetic admixture in the success of introduction of a fungal plant pathogen. PMID- 22548318 TI - Indoor air is a significant source of tri-decabrominated diphenyl ethers to outdoor air via ventilation systems. AB - Ventilation of indoor air has been hypothesized to be a source of PBDEs to outdoors. To study this, tri-decabrominated diphenyl ethers were analyzed in outgoing air samples collected inside ventilation systems just before exiting 33 buildings and compared to indoor air samples from microenvironments in each building collected simultaneously. Median ?(10)PBDE (BDE- 28, -47, -99, -153, 183, -197, -206, -207, -208, -209) concentrations in air from apartment, office and day care center buildings were 93, 3700, and 660 pg/m(3) for outgoing air, and 92, 4700, and 1200 pg/m(3) for indoor air, respectively. BDE-209 was the major congener found. No statistically significant differences were seen for individual PBDE concentrations in matched indoor and outgoing air samples, indicating that outgoing air PBDE concentrations are equivalent to indoor air concentrations. PBDE concentrations in indoor and outgoing air were higher than published outdoor air values suggesting ventilation as a conduit of PBDEs, including BDE-209, from indoors to outdoors. BDE-209 and sum of BDE-28, -47, -99, and -153 emissions from indoor air to outdoors were roughly estimated to represent close to 90% of total emissions to outdoor air for Sweden, indicating that contaminated indoor air is an important source of PBDE contamination to outdoor air. PMID- 22548319 TI - Changes in problem-based and routine-based healthcare attendance: a comparison of three national dental health surveys. AB - BACKGROUND: Healthcare utilization either may be guided by a preventive orientation leading to regular visits to the doctor, or it may be triggered by impaired health. Using data from three German national surveys, we wanted to examine whether the effects of income on the utilization of dental health services increased over time owing to the considerable decrease in insurance coverage over the years and the increase in higher out-of-pocket costs from patients. METHODS: Data from three national dental health surveys (1989, 1997 and 2005) were used. The data of all respondents aged between 35 and 44 years were available, and the number of caries-free and unrestored healthy teeth was used as outcome. RESULTS: Over the years, the proportion of routine attenders increased considerably, and the dental health measure used indicates the improvement. The least educated respondents and those with the lowest income profited less than other groups. In spite of higher copayments, the effects of income on the utilization of dental care did not increase over time. Regarding the results of education, a significant effect was only found in the study from 2005. No clear differences between routine- and problem-oriented attenders emerged with respect to the dental health measure chosen. CONCLUSIONS: Material conditions and education had effects on utilization behaviour. Contrary to expectation, increasing copayments did not yield higher effects of income on healthcare utilization. PMID- 22548320 TI - A new xanthone from the bark of Calophyllum thorelii. AB - A new xanthone, calothorexanthone, together with five known compounds, garbogiol, 1,4,8-trihydroxyxanthone, delta-tocotrienol, 1,7-dihydroxyxanthone and globuxanthone, was isolated from a petroleum ether extract of the bark of Calophyllum thorelii. Their structures were established on the basis of spectroscopic methods, mainly one- and two-dimensional NMR. Antioxidant activity of the isolated compounds was tested using DPPH free radical scavenging assay and some exhibited remarkable effects with IC50 of 13.63-17.46 ug mL(-1). PMID- 22548321 TI - The role of social structural factors in treatment of mental health disorder. AB - BACKGROUND: Mental disorder implies a biopsychosocial condition, so adequate mental health treatment involves not just medical and pharmacological care but also psychotherapy or counseling. AIMS: The present study determined how social structural factors might explain accessing of primary care providers and specialty care providers in response to mental disorder, hypothesizing that the two broad types of care differ as to the likelihood of offering minimally adequate treatment. METHOD: We analyzed data from the cross-sectional study called "2000-2001 Healthcare for Communities", employing five imputed data sets to handle missing data and defining minimally adequate treatment of mental disorder as "at least four counseling sessions at any provider and prescribed medication". Results While mental disorder can be treated in primary care or specialty facilities, our results show that minimally adequate treatment (as defined) is most likely to be obtained via specialty care. CONCLUSION: For individuals with mental disorder, accessing only primary care creates social inequity, because care from specialty facilities is comparatively more adequate. PMID- 22548322 TI - Diazonium salt-derived 4-(dimethylamino)phenyl groups as hydrogen donors in surface-confined radical photopolymerization for bioactive poly(2-hydroxyethyl methacrylate) grafts. AB - In this paper we describe a novel methodology for grafting polymers via radical photopolymerization initiated on gold surfaces by aryl layers from diazonium salt precursors. The parent 4-(dimethylamino)benzenediazonium salt was electroreduced on a gold surface to provide 4-(dimethylamino)phenyl (DMA) hydrogen donor layers; free benzophenone in solution was used as a photosensitizer to strip hydrogen from the grafted DMA. This system permitted efficient surface initiation of photopolymerization of 2-hydroxyethyl methacrylate. The resulting poly(2 hydroxyethyl methacrylate) (PHEMA) grafts were found to be very adherent to the surface as they resist total failure after being soaked in the well-known paint stripper methyl ethyl ketone. The PHEMA grafts were reacted with 1,1' carbonyldiimidazole to yield carbamate groups that are able to react readily with amino groups from proteins. The final surface consisted of protein-functionalized PHEMA grafts where bovine serum albumin (BSA) protein is specifically linked to the grafts by covalent bonds. We used X-ray photoelectron spectroscopy to monitor the chemical changes at the gold surface all along the process from the neat gold to the end-protein-functionalized polymer grafts: the PHEMA graft thickness ranged from 7 to 27 nm, and the activation by 1,1'-carbonyldiimidazole reached 37% of the OH groups, which was sufficient for 90% surface coverage of the grafts by BSA. This work conclusively provides a new approach for bridging reactive and functional polymers to surfaces via aryl diazonium salts in a simple, fast, and efficient approach of importance in biomedical and other applications. PMID- 22548323 TI - Palmitoylation of virus proteins. AB - The article summarises the results of more than 30 years of research on palmitoylation (S-acylation) of viral proteins, the post-translational attachment of fatty acids to cysteine residues of integral and peripheral membrane proteins. Analysing viral proteins is not only important to characterise the cellular pathogens but also instrumental to decipher the palmitoylation machinery of cells. This comprehensive review describes methods to identify S-acylated proteins and covers the fundamental biochemistry of palmitoylation: the location of palmitoylation sites in viral proteins, the fatty acid species found in S acylated proteins, the intracellular site of palmitoylation and the enzymology of the reaction. Finally, the functional consequences of palmitoylation are discussed regarding binding of proteins to membranes or membrane rafts, entry of enveloped viruses into target cells by spike-mediated membrane fusion as well as assembly and release of virus particles from infected cells. The topics are described mainly for palmitoylated proteins of influenza virus, but proteins of other important pathogens, such as the causative agents of AIDS and severe acute respiratory syndrome, and of model viruses are discussed. PMID- 22548324 TI - What's the harm in asking about suicidal ideation? AB - Both researchers and oversight committees share concerns about patient safety in the study-related assessment of suicidality. However, concern about assessing suicidal thoughts can be a barrier to the development of empirical evidence that informs research on how to safely conduct these assessments. A question has been raised if asking about suicidal thoughts can result in iatrogenic increases of such thoughts, especially among at-risk samples. The current study repeatedly tested suicidal ideation at 6-month intervals for up to 2-years. Suicidal ideation was measured with the Suicidal Ideation Questionnaire Junior, and administered to adolescents who had previously received inpatient psychiatric care. Change in suicidal ideation was tested using several analytic techniques, each of which pointed to a significant decline in suicidal ideation in the context of repeated assessment. This and previous study outcomes suggest that asking an at-risk population about suicidal ideation is not associated with subsequent increases in suicidal ideation. PMID- 22548325 TI - Morphology-dependent energy transfer dynamics in fluorene-based amphiphile nanoparticles. AB - Nanoparticles are interesting systems to study because of their large range of potential uses in biological imaging and sensing. We investigated molecular nanoparticles formed by fast injection of a small volume of molecularly dissolved fluorene-derivative amphiphilic molecules into a polar solvent, which resulted in solid spherical particles of ~80 nm diameter with high stability. Energy transfer studies were carried out on two-component nanoparticles that contained mixtures of donor and acceptor amphiphiles of various fractions. We conducted time resolved photoluminescence measurements on the two-component nanoparticles in order to determine whether the fundamental donor-acceptor interaction parameter (the Forster radius) depends on the acceptor concentration. The Forster radius was found to be large for very low incorporated acceptor fractions (<0.1%), but it declined with increasing concentration. These changes were concomitant with shifts in the acceptor emission and absorption circular dichroism spectra that indicated an increasing clustering of acceptors into domains as their fraction was raised. In addition, for acceptor fractions below 2% the extracted Forster radii were found to be significantly larger than predicted from donor-acceptor spectral overlap calculations, in accordance with efficient excitation diffusion within the donor matrix, aiding the overall transfer to acceptors. We conclude that energy transfer in two-component nanoparticles shows a complex interplay between phase segregation of the constituent donor and acceptor molecules and excitation diffusion within their domains. PMID- 22548326 TI - Evaluation of dominance-based ordinal multiple regression for variables with few categories. AB - Dominance-based ordinal multiple regression (DOR) is designed to answer ordinal questions about relationships among ordinal variables. Only one parameter per predictor is estimated, and the number of parameters is constant for any number of outcome levels. The majority of existing simulation evaluations of DOR use predictors that are continuous or ordinal with many categories, so the performance of the method is not well understood for ordinal variables with few categories. This research evaluates DOR in simulations using three-category ordinal variables for the outcome and predictors, with a comparison to the cumulative logits proportional odds model (POC). Although ordinary least squares (OLS) regression is inapplicable for theoretical reasons, it was also included in the simulations because of its popularity in the social sciences. Most simulation outcomes indicated that DOR performs well for variables with few categories, and is preferable to the POC for smaller samples and when the proportional odds assumption is violated. Nevertheless, confidence interval coverage for DOR was not flawless and possibilities for improvement are suggested. PMID- 22548327 TI - New sequence-defined polyaminoamides with tailored endosomolytic properties for plasmid DNA delivery. AB - Heterogeneity of polymeric carriers is one of the most elusive obstacles in the development of nonviral gene delivery systems, concealing interaction mechanisms and limiting the use of structure-activity relationship studies. In this report, novel sequence-defined polyaminoamides, prepared by solid-phase assisted synthesis, were used to establish first structure-activity relationships for polymer-based plasmid DNA delivery. By combining a cationic building block with hydrophobic modifications and bioreversible disulfide cross-linking sites, transfection polymers with tailored lytic and DNA binding properties were designed. These polymers demonstrated clear correlation between structure and performance in lysis and DNA binding assays. In vitro studies showed negligible toxicity and highly efficient gene transfer, demonstrating the potential of this platform in the fast, combinatorial development of new transfection polymers. PMID- 22548328 TI - Dynamics of introgressive hybridization assessed by SNP population genomics of coding genes in stocked brook charr (Salvelinus fontinalis). AB - Salmonid fishes rank among species being most severely affected by introgressive hybridization as a result of a long tradition of stocking with hatchery-reared conspecifics. The objectives of this study were (i) to evaluate the genetic consequences of stocking and resulting introgression rates on the genetic integrity of natural populations of brook charr, (ii) to identify genomic regions potentially associated with adaptation to natural and artificial rearing environments, and (iii) to test the null hypothesis that introgression from domesticated brook charr into wild populations is homogeneous among loci. A total of 336 individuals were sampled from nine lakes, which were stocked at different intensities with domestic fish. Individuals were genotyped at 280 SNPs located in transcribed regions and developed by means of next-generation sequencing. As previously reported with microsatellites, we observed a positive relationship between stocking intensity and genetic diversity among stocking groups, and a decrease in population differentiation. Individual admixture proportions also increased with stocking intensity. Moreover, genomic cline analysis revealed 27 SNPs, seven of which were also identified as outliers in a genome scan, which showed an introgression rate either more restricted or enhanced relative to neutral expectations. This indicated that selection, mainly for growth-related biological processes, has favored or hampered the introgression of genomic blocks into the introgressed wild populations. Overall, this study highlights the usefulness of investigating the impact of stocking on the dynamics of introgression of potentially adaptive genetic variation to better understand the consequences of such practice on the genomic integrity of wild populations. PMID- 22548329 TI - Regulation of the glucocorticoid response to stress-related disorders by the Hsp90-binding immunophilin FKBP51. AB - Immunophilin is the collective name given to a family of proteins that bind immunosuppressive drugs: Some immunophilins are Hsp90-binding cochaperones that affect steroid receptor function. Mood and anxiety disorders are stress-related diseases characterized by an impaired function of the mineralocorticoid and glucocorticoid receptors, two of the major regulatory elements of the hypothalamus-pituitary-adrenocortical axis. Genetic variations of the FK506 binding protein of 51-kDa, FKBP51, one of the immunophilins bound to those steroid receptor complexes, were associated with the effectiveness of treatments against depression and with a major risk-factor for the development of post traumatic stress disorders. Interestingly, immunophilins show polymorphisms and some polymorphic isoforms of FKBP51 correlate with a greater impairment of steroid receptor functions. In this review, we discuss different aspects of the role of FKBP51 in such steroid receptor function and the impact of genetic variants of the immunophilin on the dysregulation of the stress response. PMID- 22548331 TI - Anatomic variations of feline internal and external jugular veins. AB - We evaluated 50 feline head and neck computed tomography examinations to determine the prevalence of vascular variation in the internal and external jugular veins. We identified three distinct anatomic conformations of the internal jugular vein. No variation of external jugular vein morphology was detected. Feline patients can have different internal jugular vein morphology that should be recognized for surgical planning. PMID- 22548332 TI - Substituted urea derivatives: a potent class of antidepressant agents. AB - A series of fourteen (14) N-nitrophenyl-N'-(alkyl/aryl)urea and symmetrical 1,3 disubstituted urea derivatives were synthesized and evaluated for their antidepressant activity in mice. Among them, N-(4-nitrophenyl)-N'-(1' phenylethyl)urea (1), demonstrated profound antidepressant property as reflected by significant reduction in the immobility time (89.83%), whereas compounds 2-6 showed activity values between 36 to 59% which were also larger than the standard phenelzine. Compounds 7-9 were less effective in reducing the immobility period of mice 26.20 to 31.01%). This variable magnitude of antidepressant activity appears to be related to the position of the nitro group to the parent molecules 1, 2, and 8. Compound 1 with the nitro group at para position showed to be the most effective antidepressant. However, the activity declined, if the nitro is attached to ortho and meta positions. PMID- 22548333 TI - A QSAR study on novel series of carbonic anhydrase inhibitors hCA IX--tumor associated (hypoxia). AB - This paper presents results of QSAR (Quantitative Structure Activity Relationship) studies realized with the PRECLAV (Property Evaluation by Class Variables) software. The database contains 66 derivatives of aromatic benzene sulfonamides incorporating 1, 3, 5-triazine moieties, fluorophenyl sulfamates, S substituted-2-mercaptobenzenesulfonamide and diazenylbenzenesulfonamides with clinically used CA inhibitors. For each molecule over 3600 descriptors were calculated using programs MOPAC, PRECLAV and DRAGON. A heuristic algorithm selects the best multiple linear regression (MLR) equation showed that the correlation between the observed values and the calculated values of activity is very good (N = 66, Se = 0.263, r(2) = 0.884, F = 92.98, r(2)(cv) = 0.859, Q = 0.794). The virtual molecular fragments that lead to a significant increase of the inhibitor activity of hCA IX are C(3)H(2)N(5)Cl, NH(2), C(6)H(4), C(3)H(5)N(6), COOH, and C(3)HN(6). The virtual fragment--HO, C(5)H(2)NO, C(3)HN(6), leads to a significant decrease of the inhibitor activity value. With a view to external validation, the calibration set includes 50 molecules (Se = 0.256, r(2) = 0.885, F = 69.501, r(2)(cv) = 0.852) and the validation set includes 16 molecules (Se = 0.111, r(2) = 0.87, F = 93.984). Identification of molecules in validation set with high estimated value of inhibitory activity of hCA IX is correct enough to have practical value, even if the calibration/validation set contains aromatic benzene sulfonamides incorporating 1,3,5-triazine moieties and fluor phenyl sulfamates derivatives with very different chemical structures. PMID- 22548330 TI - Role of advanced glycation endproducts and potential therapeutic interventions in dialysis patients. AB - It has been nearly 100 years since the first published report of advanced glycation end products (AGEs) by the French chemist Maillard. Since then, our understanding of AGEs in diseased states has dramatically changed. Especially in the last 25 years, AGEs have been implicated in complications related to aging, neurodegenerative diseases, diabetes, and chronic kidney disease. Although AGE formation has been well characterized by both in vitro and in vivo studies, few prospective human studies exist demonstrating the role of AGEs in patients on chronic renal replacement therapy. As the prevalence of end-stage renal disease (ESRD) in the United States rises, it is essential to identify therapeutic strategies that either delay progression to ESRD or improve morbidity and mortality in this population. This article reviews the role of AGEs, especially those of dietary origin, in ESRD patients as well as potential therapeutic anti AGE strategies in this population. PMID- 22548334 TI - Synthesis and 188Re radiolabelling of dendrimer polyamide amine (PAMAM) folic acid conjugate. AB - Folic acid receptors (FR) are usually over expressed in many cancer cells and are considered as potential targeted therapy agent. Generation of five polyamido amine (PAMAM) dendrimer folic acid conjugate was synthesised and radiolabelled with (188)Re, furthermore the in vitro/in vivo stability was evaluated accordingly. The labelling yield of the conjugate G5-FA-DTPA-(188)Re was 67.1% and its radiochemical purity exceeded 95%. The conjugate also showed high in vitro stability and potential value for further structure modifications and evaluations. PMID- 22548335 TI - Computational approaches to improve aggrecanase-1 inhibitory activity of (4-keto) phenoxy) methyl biphenyl-4-sulfonamide: group based QSAR and docking studies. AB - Group based Quantitative Structure Activity Relationship (GQSAR) was developed for thirty (4-keto-phenoxy) methyl biphenyl-4-sulfonamides which exhibit aggrecanase-1 enzyme inhibitory activity. This enzyme is involved in osteoarthritis. The data is divided into training and test sets, where the latter is used for validating the model. Substitution in the R(1) position plays a major role when compared to substitution in R(2) position. The former position is influenced by two descriptors, namely electrotopological and connectivity indices. R(2) position is influenced by radius of gyration. The statistical parameters for the training set (r(2) = 0.80, r(2)adj = 0.77, q(2) = 0.69, F ratio = 26.80 and standard error = 0.24) and the predicted r(2) (r(2)(test) =0.95) are satisfactory. Docking of the compounds with aggrecanase-1 enzyme showed that there is a strong negative correlation between the binding energy and aggrecanase-1 inhibitory activity. Compounds with the carbonyl substitution interact with the S'1 pocket which is needed for enhanced activity. The two methodologies described here can help in lead optimization. PMID- 22548336 TI - In vitro antibacterial and antifungal activity of salicylanilide pyrazine-2 carboxylates. AB - The development of new antimicrobial agents for the treatment of infectious diseases remains challenging due to the increasing impact of antibiotic resistance. Since salicylanilides and esters of pyrazine-2-carboxylic acid have been described as potential antimicrobials, we have designed and synthesized a series of 2-(phenylcarbamoyl)phenyl pyrazine-2-carboxylates. These were evaluated in vitro for the activity against fungi and Gram-positive and Gram-negative bacteria. All derivatives showed significant antibacterial activity against Gram positive strains (MIC >= 0.98 MUmol/L) including methicillin-resistant Staphylococcus aureus. The most active molecule was 5-chloro-2-(3 chlorophenylcarbamoyl)phenyl pyrazine-2-carboxylate. With one exception these esters were at least partly active against fungi tested strains, in particular against mould strains (MIC >= 1.95 MUmol/L). The most active antifungal agent overall proved to be 2-(4-bromophenylcarbamoyl)-4-chlorophenyl pyrazine-2 carboxylate. PMID- 22548337 TI - Design, synthesis and multidrug resistance reversal activity evaluation of 8 oxocoptisine derivatives. AB - Fifteen derivatives of 8-oxocoptisine were prepared based on that 8-oxocoptisine showed potent reversing effect against human cancer cells charactering multidrug resistance (MDR). The derivatives were evaluated for their growth inhibition and effects on reversing P-gp-mediated MDR against MCF-7/AMD cells. 12, 13-dinitro-8 oxocoptisine (6c), the most potential candidate with weak growth inhibition, significantly increased the sensitivity of adriamycin (ADM) against MCF-7/ADM cells by 213-fold at 10 MUM that was comparable to the reference compound verapamil. The preliminary structure-activity relationships (SARs) of these derivatives were discussed on the basis of the in vitro MDR reversal activities. PMID- 22548338 TI - Design, synthesis and antiproliferative activity of 2-acetamidothiazole-5 carboxamide derivatives. AB - In order to develop a new series of dual inhibitors of SRC and ABL, and to investigate whether the pyrimidin- 4-ylamino moiety is critical for dasatinib's activity, acetyl substitution was adopted as alternate scaffold at the 2-amino group. Eighteen novel dasatinib derivatives were developed by a parallel synthesis approach and evaluated for their antiproliferative effects. Preliminary tests showed that some of the target compounds IId, IIe and IIf manifested strong antiproliferative activity against MCF-7, MDA-MB 231 and HT-29 cells. Easpecially IId proved to be the most potent compound. Structure-activity relationship studies indicate that the introduction of acetyl substitution as alternate scaffold of pyrimidin-4-ylamino reduced the activity. PMID- 22548339 TI - Synthesis of 3-(2, 8, 9-trioxa-5-aza-1-germatricyclo [3.3.3.0] undecane-1-yl)-3 (4-hydroxyl-3-methoxyphenyl)-propionic acid and its inhibitory effect on the cervical tumor U14 in vitro and in vivo. AB - In this study, the novel germatrane compound, 3-(2, 8, 9-trioxa-5-aza-1- germatricyclo [3.3.3.0] undecane-1-yl)-3-(4-hydroxy-3- methoxyphenyl)-propionic acid (1), has been synthesized and its activities against cervical tumor U14 were evaluated in vitro and in vivo. The results have demonstrated that the compound posed significant inhibition on U14 tumor with IC(50) values of 48.57 mg/L in cell-based assay and tumor inhibitory rates of 38.50%, 47.17% and 64.02% (from low dose to high dose) in animal experiment. PMID- 22548340 TI - A QSAR study on a series of pyrrole derivatives acting as lymphocyte-specific kinase (Lck) inhibitors. AB - A quantitative structure-activity relationship (QSAR) study has been made on a novel series of pyrrole derivatives acting as lymphocyte-specific kinase (Lck) inhibitors. The Lck inhibition activity of compounds is found to be significantly correlated with their molar volume (MV) and surface tension (ST) and the hydrophobic constant of one of their substituents. Both the molar properties MV and ST of the compounds are found to have the negative effect but the hydrophobic property of R(2)-substituen is found to have the positive effect. This leads to suggest that the bulky molecules and the those with high surface tension will not be advantageous to the Lck inhibition, rather their R(2)-substituent with hydrophobic property will be conducive to the activity. PMID- 22548341 TI - Measuring the stiffness of bacterial cells from growth rates in hydrogels of tunable elasticity. AB - Although bacterial cells are known to experience large forces from osmotic pressure differences and their local microenvironment, quantitative measurements of the mechanical properties of growing bacterial cells have been limited. We provide an experimental approach and theoretical framework for measuring the mechanical properties of live bacteria. We encapsulated bacteria in agarose with a user-defined stiffness, measured the growth rate of individual cells and fit data to a thin-shell mechanical model to extract the effective longitudinal Young's modulus of the cell envelope of Escherichia coli (50-150 MPa), Bacillus subtilis (100-200 MPa) and Pseudomonas aeruginosa (100-200 MPa). Our data provide estimates of cell wall stiffness similar to values obtained via the more labour intensive technique of atomic force microscopy. To address physiological perturbations that produce changes in cellular mechanical properties, we tested the effect of A22-induced MreB depolymerization on the stiffness of E. coli. The effective longitudinal Young's modulus was not significantly affected by A22 treatment at short time scales, supporting a model in which the interactions between MreB and the cell wall persist on the same time scale as growth. Our technique therefore enables the rapid determination of how changes in genotype and biochemistry affect the mechanical properties of the bacterial envelope. PMID- 22548342 TI - Discovery of a novel series of potent and orally bioavailable phosphoinositide 3 kinase gamma inhibitors. AB - The phosphoinositide 3-kinases (PI3Ks) have been linked to an extraordinarily diversified group of cellular functions making these enzymes compelling targets for the treatment of disease. A large body of evidence has linked PI3Kgamma to the modulation of autoimmune and inflammatory processes making it an intriguing target for drug discovery. Our high-throughput screening (HTS) campaign revealed two hits that were nominated for further optimization studies. The in vitro activity of the first HTS hit, designated as the sulfonylpiperazine scaffold, was optimized utilizing structure-based design. However, nonoptimal pharmacokinetic properties precluded this series from further studies. An overlay of the X-ray structures of the sulfonylpiperazine scaffold and the second HTS hit within their complexes with PI3Kgamma revealed a high degree of overlap. This feature was utilized to design a series of hybrid analogues including advanced leads such as 31 with desirable potency, selectivity, and oral bioavailability. PMID- 22548343 TI - Is the wait-for-patient-to-come approach suitable for African newcomers to Alberta, Canada? AB - OBJECTIVES: A qualitative study was conducted to identify psychosocial barriers to providing and obtaining preventive dental care for preschool children among African recent immigrants. METHODS: Seven focus groups were conducted with 48 mothers of 3- to 5-year-old children from Ethiopian, Eritrean, and Somali communities in Edmonton. Participants had lived in Canada for 5 years or less. Three debriefing interviews were conducted with the community health workers who facilitated the focus groups in participants' first languages. Data analysis consisted of assigning codes, grouping codes into existing or new categories of barriers, grouping identified categories into domains, and organizing categories and domains around a general perspective of psychosocial barriers to prevention of caries. RESULTS: Barriers to prevention of early childhood caries (ECC) were associated with home-based prevention, early detection, and access to professional care. Barriers to parental prevention were related to health beliefs, knowledge, oral health approach, and skills. Barriers to early detection included perceived role of caregivers and dentists, perceived identity of ECC, ways of detecting cavities, and parental self-efficacy. Access barriers were related to parental knowledge of preventive services, attitudes toward dentists and dental services, English skills, and external constraints concerned dental insurance, social support, time, and transportation. CONCLUSIONS: Preventive interventions should be aimed at assisting primary caregivers with providing and obtaining adequate dental care for their children through enhancing oral health literacy, developing new set of oral health-related skills, reducing environmental constraints, and strengthening their intention of obtaining professional preventive dental services. PMID- 22548344 TI - Multistep drug intercalation: molecular dynamics and free energy studies of the binding of daunomycin to DNA. AB - Atomic-scale molecular dynamics and free energy calculations in explicit aqueous solvent are used to study the complex mechanism by which a molecule can intercalate between successive base pairs of the DNA double helix. We have analyzed the intercalation pathway for the anticancer drug daunomycin using two different methods: metadynamics and umbrella sampling. The resulting free energy pathways are found to be consistent with one another and point, within an equilibrium free energy context, to a three-step process. Daunomycin initially binds in the minor groove of DNA. An activated step then leads to rotation of the drug, coupled with DNA deformation that opens a wedge between the base pairs, bends DNA toward the major groove, and forms a metastable intermediate that resembles structures seen within the interfaces between DNA and minor-groove binding proteins. Finally, crossing a small free energy barrier leads to further rotation of daunomycin and full intercalation of the drug, reestablishing stacking with the flanking base pairs and straightening the double helix. PMID- 22548345 TI - The prevalence of mental health disorders amongst offenders on probation: a literature review. AB - BACKGROUND: There is increasing focus on addressing the mental health needs of offenders throughout the criminal justice system. However, there is currently a gap in the literature for a review of research into the prevalence of mental health disorders amongst offenders on probation. AIMS: To review existing literature on the prevalence of mental health disorders in probation populations in order to inform the provision of health services to this group. METHOD: A comprehensive review of the literature on the topic to date across ASSIA, Web of Science, IBSS, CINAHL and MEDLINE databases. RESULTS: A total of 18 papers were identified. Four of these studies were based on probation approved premises, six on probation psychiatric services and eight on broader probation populations. The prevalence of mental illness reported varies widely across these papers. CONCLUSION: One can tentatively conclude that there is a high prevalence of mental illness and high rates of co-morbidity in offenders on probation. However, variation in study settings and methodology make it difficult to reach firm conclusions on the likely prevalence of mental illness in probation populations from the existing literature. There is a need for further high-quality research in this area. PMID- 22548346 TI - Excellent lubricating behavior of Brasenia schreberi mucilage. AB - The present work reports an excellent lubrication property of an aquatic plant called Brasenia schreberi (BS). To investigate the lubrication characteristics of the BS mucilage, a novel measuring system is designed, and an ultralow friction coefficient about 0.005 between the mucilage and glass surface has been obtained. It is found that the ultralow friction is closely related to the structure of mucilage and water molecules in the mucilage. The microstructure analysis indicates that the mucilage surrounding BS forms a kind of polysaccharide gel with many nanosheets. A possible lubrication mechanism is proposed that the formation of hydration layers among these polymer nanosheets with plenty of bonded water molecules causes the ultralow friction. The excellent lubrication property has a potential application for reducing the friction between a glossy pill coated with such layer of mucilage and people's throats. PMID- 22548347 TI - Enhancement of activity and sulfur resistance of CeO2 supported on TiO2-SiO2 for the selective catalytic reduction of NO by NH3. AB - A series of novel metal-oxide-supported CeO(2) catalysts were prepared via the wet impregnation method, and their NH(3)-SCR activities were investigated. The Ce/TiO(2)-SiO(2) catalyst with a Ti/Si mass ratio of 3/1 exhibited superior NH(3) SCR activity and high N(2) selectivity in the temperature range of 250-450 degrees C. The characterization results revealed that the activity enhancement was correlated with the properties of the support material. Cerium was highly dispersed on the TiO(2)-SiO(2) binary metal oxide support, and the interaction of Ti and Si resulted in greater conversion of Ce(4+) to Ce(3+) on the surface of the catalyst compared to that on the single metal oxide supports. As a result of in the increased number of acid sites on Ce/TiO(2)-SiO(2) that resulted from the addition of SiO(2), the NH(3) adsorption capacity was significantly improved. All of these factors played significant roles in the high SCR activity. More importantly, Ce/TiO(2)-SiO(2) exhibited strong resistance to SO(2) and H(2)O poisoning. After the addition of SiO(2), the number of Lewis-acid sites was not decreased, but the number of Bronsted-acid sites on the TiO(2)-SiO(2) carrier was increased. The introduction of SiO(2) further weakened the alkalinity over the surface of the Ce/TiO(2)-SiO(2) catalyst, which resulted in sulfate not easily accumulating on the surface of the Ce/TiO(2)-SiO(2) catalyst in comparison with Ce/TiO(2). PMID- 22548348 TI - Tomentomimulol and mimulone B: two new C-geranylated flavonoids from Paulownia tomentosa fruits. AB - Two new discovered C-geranylated flavonoids tomentomimulol (1) and mimulone B (2) were isolated from the methanol extract of Paulownia tomentosa (Thunb). Steud. (Paulowniaceae) fruits by exhaustive chromatographic separation together with one known compound tanariflavanone D (3). The identification of compounds and structure elucidation was carried out using 1D and 2D NMR experiments, as well as mass spectroscopy, ultra-violet, infra red and CD experiments. PMID- 22548349 TI - Modified feed-forward neural network structures and combined-function-derivative approximations incorporating exchange symmetry for potential energy surface fitting. AB - The classical interchange (permutation) of atoms of similar identity does not have an effect on the overall potential energy. In this study, we present feed forward neural network structures that provide permutation symmetry to the potential energy surfaces of molecules. The new feed-forward neural network structures are employed to fit the potential energy surfaces for two illustrative molecules, which are H(2)O and ClOOCl. Modifications are made to describe the symmetric interchange (permutation) of atoms of similar identity (or mathematically, the permutation of symmetric input parameters). The combined function-derivative approximation algorithm (J. Chem. Phys. 2009, 130, 134101) is also implemented to fit the neural-network potential energy surfaces accurately. The combination of our symmetric neural networks and the function-derivative fitting effectively produces PES fits using fewer numbers of training data points. For H(2)O, only 282 configurations are employed as the training set; the testing root-mean-squared and mean-absolute energy errors are respectively reported as 0.0103 eV (0.236 kcal/mol) and 0.0078 eV (0.179 kcal/mol). In the ClOOCl case, 1693 configurations are required to construct the training set; the root-mean-squared and mean-absolute energy errors for the ClOOCl testing set are 0.0409 eV (0.943 kcal/mol) and 0.0269 eV (0.620 kcal/mol), respectively. Overall, we find good agreements between ab initio and NN prediction in term of energy and gradient errors, and conclude that the new feed-forward neural-network models advantageously describe the molecules with excellent accuracy. PMID- 22548350 TI - Child Development. In this issue. PMID- 22548351 TI - Does dampened physiological reactivity protect youth in aggressive family environments? AB - Is an attenuated physiological response to family conflict, seen in some youth exposed to early adversity, protective or problematic? A longitudinal study including 54 youth (average age 15.2 years) found that those with higher cumulative family aggression exposure showed lower cortisol output during a laboratory-based conflict discussion with their parents, and were less likely to show the normative pattern of increased cortisol reactivity to a discussion they rated as more conflictual. Family aggression interacted with cortisol reactivity in predicting youth adjustment: Adolescents from more aggressive homes who were also more reactive to the discussion reported more posttraumatic stress symptoms and more antisocial behavior. These results suggest that attenuated reactivity may protect youth from the negative consequences associated with aggressive family environments. PMID- 22548352 TI - Where the wild things are: informal experience and ecological reasoning. AB - Category-based induction requires selective use of different relations to guide inferences; this article examines the development of inferences based on ecological relations among living things. Three hundred and forty-six 6-, 8-, and 10-year-old children from rural, suburban, and urban communities projected novel diseases or insides from one species to an ecologically or taxonomically related species; they were also surveyed about hobbies and activities. Frequency of ecological inferences increased with age and with reports of informal exploration of nature, and decreased with population density. By age 10, children preferred taxonomic inferences for insides and ecological inferences for disease, but this pattern emerged earlier among rural children. These results underscore the importance of context by demonstrating effects of both domain-relevant experience and environment on biological reasoning. PMID- 22548353 TI - Treatment patterns, health-related quality of life and adherence to prophylaxis among haemophilia A patients in the United States. AB - Prophylaxis and adherence to prophylaxis are increasingly recognized as important factors for the health-related quality of life (HRQOL) of haemophilia patients. This study aims to assess treatment practices over time, HRQOL and adherence among severe haemophilia A patients in the US. Severe haemophilia A patients or their caregivers participated in a 2009 cross-sectional survey. HRQOL was measured using either PEDS-QL or SF-12; adherence was measured using the VERITAS Pro. Student t-tests evaluated differences between children vs. adults and self infusion status. A total of 117 respondents participated in the survey, capturing data for 64 adults (mean age = 37.9 years) and 53 children (mean age = 10.5 years). Although 96% of paediatric patients were currently receiving prophylaxis, only 32 (50%) adults reported receiving prophylaxis at some point in their life. Adults who have always been on prophylaxis reported better physical functioning and physical HRQOL (both P < 0.05) than adults who had not. The paediatric group reported better adherence compared to the adult group on the total scale (38 vs. 45.8, P < 0.05). Children <12 years had higher adherence than adolescents 12-18 years old (35.5 vs. 40.8; P < 0.05). Paediatric patients infused by family members showed better adherence than paediatric self-infusers (P < 0.05). This study showed different treatment patterns between paediatric and adult patients and how the patterns impacted HRQOL. It also provided the first standardized evaluation of adherence using the VERITAS-Pro in a US national sample. This study enhances understanding of treatment practices and adherence for the US haemophilia population and may offer insight into where adherence can be improved. PMID- 22548354 TI - The SAM, not the electrodes, dominates charge transport in metal monolayer//Ga2O3/gallium-indium eutectic junctions. AB - The liquid-metal eutectic of gallium and indium (EGaIn) is a useful electrode for making soft electrical contacts to self-assembled monolayers (SAMs). This electrode has, however, one feature whose effect on charge transport has been incompletely understood: a thin (approximately 0.7 nm) film-consisting primarily of Ga(2)O(3)-that covers its surface when in contact with air. SAMs that rectify current have been measured using this electrode in Ag(TS)-SAM//Ga(2)O(3)/EGaIn (where Ag(TS) = template-stripped Ag surface) junctions. This paper organizes evidence, both published and unpublished, showing that the molecular structure of the SAM (specifically, the presence of an accessible molecular orbital asymmetrically located within the SAM), not the difference between the electrodes or the characteristics of the Ga(2)O(3) film, causes the observed rectification. By examining and ruling out potential mechanisms of rectification that rely either on the Ga(2)O(3) film or on the asymmetry of the electrodes, this paper demonstrates that the structure of the SAM dominates charge transport through Ag(TS)-SAM//Ga(2)O(3)/EGaIn junctions, and that the electrical characteristics of the Ga(2)O(3) film have a negligible effect on these measurements. PMID- 22548355 TI - Depression as a predictor of falls amongst institutionalized elders. AB - OBJECTIVE: In this study, we set out to examine the combined effects of medical condition and depression status on fall incidents amongst institutionalized elderly people. METHODS: A cross-sectional study was carried out to investigate the fall history of institutionalized elders involving 286 subjects. Experiences of falls over the previous year were recorded, with at least two falls during the prior one-year period, or one injurious fall defined as 'fallers'. The Geriatric Depression Scale-15 was used as a screening instrument for depression status. RESULTS: Based on a multivariate logistic regression and stratification analysis, depression was found to have enhanced effects with various medical conditions on fall risk. As compared with the non-depressive reference group, a five-fold fall risk was discernible amongst depressed elders with multiple medications, whilst a six-fold risk was found amongst depressive elders using ancillary devices, along with a 11-fold amongst depressive elders with neural system diseases. CONCLUSIONS: This study provides the evidence of enhancing effects between depression and medical conditions on the risk of falls amongst institutionalized elderly people. Thus, depressed elders with neural system diseases, using ancillary devices or multiple medications, should be specifically listed as very high risk of falling amongst institutionalized elderly, and strictly prevent them from falls. Screening and treatment of depression could also be a useful strategy in the prevention of falls amongst institutionalized elderly with poor medical condition. PMID- 22548356 TI - Cdk2ap2 is a novel regulator for self-renewal of murine embryonic stem cells. AB - In this study we present data to support the role for Cdk2ap2 in regulating self renewal of mouse embryonic stem cells (mESCs) under permissive conditions, and cell survival during differentiation of the mESCs into terminally differentiated cell types. To understand the function of Cdk2ap2 during early development, we generated mESCs with homozygous disruption of the endogenous Cdk2ap2 locus (Cdk2ap2(tr/tr)). The Cdk2ap2(tr/tr) mESCs, when grown in a complete growth medium containing leukemia inhibitory factor (LIF), showed an early differentiation phenotype characterized by flattened colonies and a distinct intercellular boundary. We also observed downregulation of Nanog and upregulation in markers of mesoderm and endoderm differentiation, including Brachyury (T), Afp, and S100a, when compared to Wt mESCs. Cdk2ap2(tr/tr) mESCs were able to form embryoid bodies (EBs); however, those EBs were unhealthy and had an increased level of apoptosis. Furthermore, Cdk2ap2(tr/tr) mESCs were unable to form teratomas in severe combined immunodeficiency (SCID) mice. Cdk2ap2 under normal conditions has a biphasic expression, suggesting regulatory roles in early-versus late stem cell differentiation. These data begin to add to our understanding of how Cdk2ap2 may be involved in the regulation of self-renewal of stem cells during early embryogenesis. PMID- 22548357 TI - Transposon proliferation in an asexual parasitoid. AB - The widespread occurrence of sex is one of the most elusive problems in evolutionary biology. Theory predicts that asexual lineages can be driven to extinction by uncontrolled proliferation of vertically transmitted transposable elements (TEs), which accumulate because of the inefficiency of purifying selection in the absence of sex and recombination. To test this prediction, we compared genome-wide TE load between a sexual lineage of the parasitoid wasp Leptopilina clavipes and a lineage of the same species that is rendered asexual by Wolbachia-induced parthenogenesis. We obtained draft genome sequences at 15 20* coverage of both the sexual and the asexual lineages using next-generation sequencing. We identified transposons of most major classes in both lineages. Quantification of TE abundance using coverage depth showed that copy numbers in the asexual lineage exceeded those in the sexual lineage for DNA transposons, but not LTR and LINE-like elements. However, one or a small number of gypsy-like LTR elements exhibited a fourfold higher coverage in the asexual lineage. Quantitative PCR showed that high loads of this gypsy-like TE were characteristic for 11 genetically distinct asexual wasp lineages when compared to sexual lineages. We found no evidence for an overall increase in copy number for all TE types in asexuals as predicted by theory. Instead, we suggest that the expansions of specific TEs are best explained as side effects of (epi)genetic manipulations of the host genome by Wolbachia. Asexuality is achieved in a myriad of ways in nature, many of which could similarly result in TE proliferation. PMID- 22548358 TI - Dilator-assisted banding for managing complications associated with excessive hemodialysis access flow. AB - Excessive hemodialysis access flow can be associated with serious complications, such as ischemic steal syndrome and heart failure. Among the therapeutic approaches, endoluminal balloon-guided banding has the advantage of being minimally invasive. However, it requires fluoroscopic guidance. We here report a simpler approach, Dilator-assisted Banding (DAB), in which over-the-wire vascular dilators of known diameters are used as endoluminal-guides to achieve precision banding with or without fluoroscopic guidance. The dilators used are 10, 12, and 14 French, corresponding to 3.3, 4.0, and 4.7 mm in diameter, respectively. Of the seven treated patients with ischemic steal syndrome, three were males, mean age was 67.7 +/- 16.3 years, five were diabetics, all were hypertensive, five had fistulas, and two had grafts. Mean age of hemodialysis accesses was 17.2 +/- 8.4 months. Three patients had banding without fluoroscopic guidance, including two performed during fistula vein superficialization and basilic vein transposition. With follow-up of 2-12 months, all hemodialysis accesses remained functional. Six patients had complete resolution and one reported marked improvement of ischemic symptoms. In summary, DAB is a simple, effective, and economical flow-reduction alternative for managing ischemic steal syndrome and potentially other complications associated with excessive access flows. In addition, it can be safely performed without fluoroscopic guidance. PMID- 22548360 TI - Retinoic acid promotes proliferation of chicken primordial germ cells via activation of PI3K/Akt-mediated NF-kappaB signalling cascade. AB - As embryonic progenitors for the gametes, PGCs (primordial germ cells) proliferate and develop under strict regulation of numerous intrinsic and external factors. As the most active natural metabolite of vitamin A, all-trans RA (retinoic acid) plays pivotal roles in regulating development of various cells. The proliferating action of RA on PGCs was investigated along with the intracellular PI3K (phosphoinositide 3-kinase)/Akt (protein kinase B; also known as Akt)-mediated NF-kappaB (nuclear factor kappaB) signalling cascade. The results show that RA significantly promoted PGC proliferation in a dose- and time dependent manner, confirmed by BrdU (bromodeoxyuridine) incorporation and cell cycle analysis. However, this promoting effect was attenuated by sequential inhibitors of LY294002 for PI3K, KP372-1 for Akt and SN50 for NF-kappaB respectively. Western blot analysis showed increased Akt phosphorylation (Ser473) of PGCs after stimulation with RA, but this was abolished by LY294002 or KP372-1. Treatment with RA increased expression of NF-kappaB and decreased IkappaBalpha (inhibitory kappaBalpha) expression, which were inhibited by SN50. Blockade of PI3K or Akt activity inhibited NF-kappaB translocation from the cytoplasm to the nucleus. Finally, mRNA expression of cell cycle regulating genes [cyclin D1 and E, CDK6 (cyclin-dependent kinase 6) and CDK2] was up-regulated in the RA-treated cells. This stimulation was also markedly retarded by combined treatment with LY294002, KP372-1 and SN50. These results suggest that RA activates the PI3K/Akt and NF-kappaB signalling cascade to promote proliferation of the cultured chicken PGCs. PMID- 22548359 TI - A single-centre randomized controlled clinical trial on the adjunct treatment of intra-bony defects with autogenous bone or a xenograft: results after 12 months. AB - BACKGROUND: Limited evidence exists on the efficacy of regenerative treatment of peri-implantitis. MATERIAL AND METHODS: Subjects receiving antibiotics and surgical debridement were randomly assigned to placement of autogenous bone (AB) or bovine-derived xenograft (BDX) and with placement of a collagen membrane. The primary outcome was evidence of radiographic bone fill and the secondary outcomes included reductions of probing depth (PD) bleeding on probing (BOP) and suppuration. RESULTS: Twenty-two subjects were included in the AB and 23 subjects in the BDX group. Statistical analysis failed to demonstrate differences for 38/39 variables assessed at baseline. At 12 months, significant better results were obtained in the BDX group for bone levels (p < 0.001), BOP (p = 0.004), PI (p = 0.003) and suppuration (p < 0.01). When adjusting for number of implants treated per subject, a successful treatment outcome PD <= 5.0 mm, no pus, no bone loss and BOP at 1/4 or less sites the likelihood of defect fill was higher in the BDX group (LR: 3.2, 95% CI: 1.0-10.6, p < 0.05). CONCLUSIONS: Bovine xenograft provided more radiographic bone fill than AB. The success for both surgical regenerative procedures was limited. Decreases in PD, BOP, and suppuration were observed. PMID- 22548361 TI - Feasibility of computed tomography in awake dogs with traumatic pelvic fracture. AB - In veterinary medicine, general anesthesia or sedation is generally required to immobilize patients during computed tomography (CT) scanning. This may not be suitable in all patients because of risks of anesthesia. We evaluated the feasibility of pelvic CT examination in 14 awake animals with pelvic trauma. Physical restraint was applied by wrapping the patient in a towel and then taping to the CT table or by directly taping the patient to the CT table. The effect of patient positioning, cooperation on the CT table, preparation time for scanning, scanning time, frequency of repeat scans, image quality, and complications related to physical restraint were evaluated. Fractures were recorded and compared between radiography and CT. Ten of 14 dogs were scanned in lateral recumbency and four in sternal recumbency. All patients were cooperative with the exception of one that moved slightly during the scan. Both physical restraint methods were adequate for CT scanning. Patient preparation took less than 5 min while the scan time was typically less than 1 min. No repeat scans were required in any patient. The transverse CT image quality was good (10/14) or fair (4/14) for interpretation. When comparing the CT images to radiographs, more pelvic fractures were identified with CT than with radiography and a few patients were overdiagnosed based on radiographs. No complications or additional injuries associated with physical restraint were noticed. PMID- 22548362 TI - Triggered release of molecules across droplet interface bilayer lipid membranes using photopolymerizable lipids. AB - A combination of nonpolymerizable phospholipids (DPPC or DPhPC) and a smaller amount of cross-linking photopolymerizable phospholipids (23:2 DiynePC) is incorporated in an unsupported artificial lipid bilayer formed using the droplet interface bilayer (DIB) approach. The DIB is formed by contacting lipid monolayer coated aqueous droplets against each other in a dodecane-lipid medium. Cross linking of the photopolymerizable lipids incorporated in the DIB was obtained by exposure to UV-C radiation (254 nm), resulting in pore formation. The effect of cross-linking on the DIB properties was characterized optically by measuring the diffusion of selectively encapsulated dye molecules (calcein) from one droplet of the DIB to the other droplet. Changes in DIB conductivity due to UV-C exposure were investigated using current-voltage (I-V) measurements. The leakage of dye molecules across the DIB and the increase in DIB conductivity after UV-C exposure indicates the formation of membrane pores. The results indicate that the DIB approach offers a simple and flexible platform for studying phototriggered drug delivery systems in vitro. PMID- 22548363 TI - Technology-enhanced monitoring in psychotherapy and e-mental health. AB - Advances in technology increasingly facilitate data collection in the context of psychosocial and psychotherapeutic care. Such technology-enhanced assessments (e.g. via Internet-based systems and mobile devices) open new perspectives for research into processes related to mental health and well-being. The use of this knowledge for the development and refinement of (online and face-to-face) therapeutic interventions promises to contribute to an optimization of care. The aim of this paper is to provide an overview on how information and communication technologies may be used (a) to improve our understanding of illness development and recovery through longitudinal technology-enhanced assessment of symptoms and behaviors (e.g. outcome monitoring and ecological momentary assessment) and (b) to optimize care for mental disorders by integrating such monitoring assessments in specific interventions (e.g. ecological momentary interventions and supportive monitoring) in face-to-face or e-mental health settings. PMID- 22548364 TI - A new cyclododeca[d]oxazole derivative from Streptomyces spp. CIBYL1. AB - A novel secondary metabolite, N-trans-cinnamoyl 2-amino 3a,4,5,6,7,8,9,10,11,12,13,13a-dodecahydrocyclododeca[d]oxazole (1), was isolated from Streptomyces spp. CIBYL1, along with five known compounds, pimprinine (2), (3R,4S,5R,6R)-3,4,5,6-tetrahydro-4-hydroxy-3,5,6-trimethyl-2H-pyran-2-one (3), indolyl-3-carboxylic acid (4), 2-phenylacetamide (5) and di(1H-pyrrol-2 yl)methanone (6). The structures of these metabolites were elucidated on the basis of extensive analysis of spectroscopic data, including OR, IR, HRMS, 1D and 2D NMR data and chemical derivation. PMID- 22548366 TI - Potentially curative stereotactic body radiation therapy (SBRT) for single or oligometastasis to the lung. AB - BACKGROUND: To analyze the treatment outcomes of a potentially curative therapy, stereotactic body radiation therapy (SBRT), for patients with single or oligometastasis to the lungs. MATERIAL AND METHODS: Sixty-seven metastatic lung lesions in 57 patients were treated with SBRT between September 2001 and November 2010. All patients had single or oligo-metastasis to the lungs following a meticulous clinical work-up, including PET-CT scans. The lungs were the most common primary organ (33 lesions, 49.3%), followed by the head and neck (11 lesions, 16.4%), the liver (nine lesions, 13.5%), the colorectum (seven lesions, 10.4%), and other organs (seven lesions, 10.4%). Three different fractionation schedules were used: 50 Gy/5 fractions to four lesions (6.0%); 60 Gy/5 fractions to 44 lesions (65.7%); and 60 Gy/4 fractions to 19 lesions (28.3%). RESULTS: Local tumor progression occurred in three lesions (4.5%). The three-year actuarial local control rate was 94.5%. Tumors larger than or equal to 2.5 cm showed poorer local control (98.3% vs. 77.8%, p <0.01). Metastatic tumors from the liver and colorectum showed lower local control rates than those from other organs (77.8%, 85.7%, and 100%, p =0.04). The two-year overall survival rate was 57.2%. Patients with tumors smaller than 2.5 cm had more favorable survival rates (64.0% vs. 38.9% at two-year, p =0.032). Patients with extrathoracic disease had poorer survival rates (66.1% vs. 0% at two-year, p =0.003). Patients with disease free intervals longer than two years showed a trend toward good prognosis (71.1% vs. 51.1% at two-year, p =0.106). Grade 2 lung toxicity occurred in four patients (6.0%). One patient experienced Grade 5 lung toxicity following SBRT. CONCLUSION: SBRT for single or oligo-metastasis to the lung seems quite effective and safe. Tumor size, disease-free interval, and presence of extrathoracic disease are prognosticators for survival. PMID- 22548365 TI - Structure-based design of a novel series of potent, selective inhibitors of the class I phosphatidylinositol 3-kinases. AB - A highly selective series of inhibitors of the class I phosphatidylinositol 3 kinases (PI3Ks) has been designed and synthesized. Starting from the dual PI3K/mTOR inhibitor 5, a structure-based approach was used to improve potency and selectivity, resulting in the identification of 54 as a potent inhibitor of the class I PI3Ks with excellent selectivity over mTOR, related phosphatidylinositol kinases, and a broad panel of protein kinases. Compound 54 demonstrated a robust PD-PK relationship inhibiting the PI3K/Akt pathway in vivo in a mouse model, and it potently inhibited tumor growth in a U-87 MG xenograft model with an activated PI3K/Akt pathway. PMID- 22548368 TI - Thirty year trends in testicular cancer mortality in Europe: gaps persist between the East and West. PMID- 22548367 TI - Outcomes of cancer patients after unplanned admission to general intensive care units. AB - BACKGROUND: Acute admission to an intensive care unit (ICU) of cancer patients is considered with increasing frequency due to a better life expectancy and more aggressive therapies. The aim of this study was to determine the characteristics and outcomes of cancer patients with unplanned admissions to general ICUs, and to compare these with outcomes of critically ill patients without cancer. MATERIAL AND METHODS: All unplanned ICU admissions in the Netherlands collected in the National Intensive Care Evaluation registry between January 2007 and January 2011 were analyzed. RESULTS AND CONCLUSION: Of the 140,154 patients with unplanned ICU admission 10.9% had a malignancy. Medical cancer patients were more severely ill on ICU admission in comparison with medical non-cancer patients, as reflected by higher needs for mechanical ventilation (50.8% vs. 46.4%, p < 0.001) and vasopressors within 24 hours after admission (41.5% vs. 33.0%, p < 0.001), higher Acute Physiology and Chronic Health Evaluation (APACHE) IV scores (88.1 vs. 67.5, p < 0.001) and a longer ICU stay (5.1 vs. 4.6 days, p < 0.001). In contrast, surgical cancer patients only displayed a modestly higher APACHE IV score on admission when compared with non-cancer surgical patients, whereas the other afore mentioned parameters were lower in the surgical cancer patients group. In hospital mortality was almost twice as high in medical cancer patients (40.6%) as in medical patients without cancer (23.7%). In-hospital mortality of surgical cancer patients (17.4%) was slightly higher than in patients without cancer (14.6%). These data indicate that unplanned ICU admission is associated with a high mortality in patients with cancer when admitted for medical reasons. PMID- 22548369 TI - A phase II trial with bevacizumab and irinotecan for patients with primary brain tumors and progression after standard therapy. AB - The combination of irinotecan and bevacizumab has shown efficacy in the treatment of recurrent glioblastoma multiforme (GBM). A prospective, phase II study of 85 patients with various recurrent brain tumors was carried out. Primary endpoints were progression free survival (PFS) and response rate. MATERIAL AND METHODS: Patients with recurrent primary brain tumors with performance status 0-2 were eligible. Intravenous bevacizumab 10 mg/kg and irinotecan 125/340 mg/m(2) were administered every 14 days. Evaluation was carried out every eight weeks using MRI and Macdonald response criteria. Treatment was continued until progression. RESULTS: In total 85 patients were included with the following histologies: GBM (n = 32), glioma WHO gr. III (n = 33), glioma WHO gr. II (n = 12) and others (n = 8). Patients received a median of four cycles. ORR (overall response rate) for glioblastoma was 25% and 59% achieved stable disease (SD). Median PFS was 5.2 months. For grade III gliomas ORR was 21% and 45% had SD. Median PFS was 3.7 months. No objective responses occurred in grade II gliomas. In the non-glioma population, one PR as well as several long PFS times were observed. DISCUSSION AND CONCLUSION: The combination of bevacizumab and irinotecan is well tolerated and moderately efficacious in glioblastoma and glioma WHO gr. III. A majority of patients achieve at least disease stabilization. Prolonged progression-free survival in non-glioma patients warrants further research. PMID- 22548370 TI - For better or for worse: cooperation and competition in the legume-rhizobium symbiosis. PMID- 22548371 TI - Local adaptation in the model plant. PMID- 22548372 TI - Method of pacing does not affect the recurrence of syncope in carotid sinus syndrome. AB - INTRODUCTION: Pacemaker therapy is effective in reducing recurrent syncope in patients with symptomatic carotid sinus hypersensitivity (CSH), yet the optimal pacing modality for this syndrome is not known. The objective of this study is to prospectively investigate the impact of three pacing methods (DDDR vs DDDR with sudden bradycardia response [SBR] vs VVI) on recurrent syncope and quality of life. METHODS: Twenty-one patients with symptomatic CSH (syncope or near syncope) were randomized to VVI, DDDR, or DDDR with SBR on a double-blinded basis in a sequential crossover fashion with 6 months in each mode. The primary endpoints were recurrent events and quality of life (assessed by SF-36). The mean number of events and SF-36 scores were compared. RESULTS: At baseline, over the preceding 6 months, there were a total of 29 syncopal events and 258 presyncopal events among 21 patients. Following pacing in any mode, the total number of these syncopal events reduced to two in two patients (P < 0.001) and 17 presyncopal events (P < 0.001) in 12 patients. The mean number of events was not significantly different between the three pacing methods. SF-36 scores revealed some minor benefits of DDDR pacing versus baseline in the categories, but no pacing method was found to be superior. CONCLUSIONS: The study was unable to confirm the initial study hypothesis of a superiority of one pacing modality over another. Quality of life measures allude to potential benefit from DDDR pacing alone. PMID- 22548374 TI - Translocation of wild populations: conservation implications for the genetic diversity of the black-lipped pearl oyster Pinctada margaritifera. AB - Translocation has been widely studied as a tool for conservation management to restore or enhance degraded populations. On the contrary, few studies have been conducted on translocation for commercial purposes. In this study, we evaluate the genetic consequences of translocation of wild individuals of Pinctada margaritifera on farmed and adjacent wild populations. We tested the hypotheses that translocations would induce high genetic heterogeneity in farmed populations and this heterogeneity would then leak into the adjacent wild populations. In fact, farmed samples exhibit high levels of heterogeneity and low pairwise relatedness compared to wild populations, highlighting the pooling of genetically divergent populations into farms. We also demonstrate that this heterogeneity is transmitted to adjacent wild populations as a result of interbreeding. Adjacent wild populations tend to have higher genetic diversity values and greater pairwise relatedness coefficient with farmed populations than wild populations. Overall, pearl culture in French Polynesia promotes the mixing of unrelated individuals in farmed locations and reduces genetic divergence among geographically distant populations as well as among farmed and wild populations of a same lagoon. We also studied for the first time a farmed population originating from spat collected in a lagoon where release of hatchery-produced larvae occurred 10 years ago and we were able to identify four distinct genetic groups. These groups contribute highly to reproduction and caused considerable genetic drift in the lagoon, suggesting that hatchery-produced larvae are neither sustainable method for pearl culture nor for conserving the diversity of P. margaritifera in French Polynesia. PMID- 22548373 TI - Perfluoroalkyl acids in the Atlantic and Canadian Arctic Oceans. AB - We report here on the spatial distribution of C(4), C(6), and C(8) perfluoroalkyl sulfonates, C(6)-C(14) perfluoroalkyl carboxylates, and perfluorooctanesulfonamide in the Atlantic and Arctic Oceans, including previously unstudied coastal waters of North and South America, and the Canadian Arctic Archipelago. Perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS) were typically the dominant perfluoroalkyl acids (PFAAs) in Atlantic water. In the midnorthwest Atlantic/Gulf Stream, sum PFAA concentrations (?PFAAs) were low (77-190 pg/L) but increased rapidly upon crossing into U.S. coastal water (up to 5800 pg/L near Rhode Island). ?PFAAs in the northeast Atlantic were highest north of the Canary Islands (280-980 pg/L) and decreased with latitude. In the South Atlantic, concentrations increased near Rio de la Plata (Argentina/Uruguay; 350 540 pg/L ?PFAAs), possibly attributable to insecticides containing N-ethyl perfluorooctanesulfonamide, or proximity to Montevideo and Buenos Aires. In all other southern hemisphere locations, ?PFAAs were <210 pg/L. PFOA/PFOS ratios were typically >=1 in the northern hemisphere, ~1 near the equator, and <=1 in the southern hemisphere. In the Canadian Arctic, ?PFAAs ranged from 40 to 250 pg/L, with perfluoroheptanoate, PFOA, and PFOS among the PFAAs detected at the highest concentrations. PFOA/PFOS ratios (typically ?1) decreased from Baffin Bay to the Amundsen Gulf, possibly attributable to increased atmospheric inputs. These data help validate global emissions models and contribute to understanding of long range transport pathways and sources of PFAAs to remote regions. PMID- 22548376 TI - Identification of food-derived elastin peptide, prolyl-glycine (Pro-Gly), in human blood after ingestion of elastin hydrolysate. AB - Elastin hydrolysate has apparent beneficial effects, and the food-derived peptide prolyl-glycine (Pro-Gly) is present in human blood after oral ingestion. Following ingestion of elastin hydrolysate (10 g/60 kg body weight) by healthy human volunteers, peripheral blood was used to prepare plasma samples from which peptides were extracted by solid phase extraction and fractionated by size exclusion chromatography (SEC). Peptides in the SEC fractions were derivatized with phenyl isothiocyanate (PITC) and resolved by reversed phase (RP)-HPLC. Pro Gly was the major food-derived elastin peptide, reaching a maximum (18 MUM) at 30 min after ingestion, and decreasing to approximately 20% at 4 h after ingestion. Finally, in cell culture, levels of Pro-Gly in the medium above 0.1 MUg/mL significantly enhanced elastin synthesis of normal human dermal fibroblasts (NHDF) without affecting the rate of cell proliferation. PMID- 22548375 TI - Caregivers' relationship closeness with the person with dementia predicts both positive and negative outcomes for caregivers' physical health and psychological well-being. AB - Closer relationships between caregivers and care recipients with dementia are associated with positive outcomes for care recipients, but it is unclear if closeness is a risk or protective factor for the health and psychological wellbeing of caregivers. We examined 234 care dyads from the population-based Cache County Dementia Progression Study. Caregivers included spouses (49%) and adult offspring (51%). Care recipients mostly had dementia of the Alzheimer's type (62%). Linear mixed models tested associations between relationship closeness at baseline or changes in closeness prior to versus after dementia onset, with baseline levels and changes over time in caregiver affect (Affect Balance Scale, ABS), depression (Beck Depression Inventory, BDI), and mental and physical health (components of the Short-Form Health Survey, SF-12). After controlling for demographic characteristics of the caregiver, number of caregiver health conditions, and characteristics of the care recipient (type of dementia, functional ability, and behavioral disturbances), we found that higher baseline closeness predicted higher baseline SF-12 mental health scores (better mental health) and lower depression. Higher baseline closeness also predicted greater worsening over time in ABS and SF-12 mental health. In addition, caregivers who reported a loss of closeness in their relationship with the care recipient from pre- to post-dementia displayed improved scores on ABS and SF-12 mental health, but worse SF-12 physical health over the course of the study. These results suggest that closeness and loss of closeness in the care dyad may be associated with both positive and adverse outcomes for caregivers, both cross-sectionally and over time. PMID- 22548377 TI - Large thermoelectric figure-of-merits from SiGe nanowires by simultaneously measuring electrical and thermal transport properties. AB - The strongly correlated thermoelectric properties have been a major hurdle for high-performance thermoelectric energy conversion. One possible approach to avoid such correlation is to suppress phonon transport by scattering at the surface of confined nanowire structures. However, phonon characteristic lengths are broad in crystalline solids, which makes nanowires insufficient to fully suppress heat transport. Here, we employed Si-Ge alloy as well as nanowire structures to maximize the depletion of heat-carrying phonons. This results in a thermal conductivity as low as ~1.2 W/m-K at 450 K, showing a large thermoelectric figure of-merit (ZT) of ~0.46 compared with those of SiGe bulks and even ZT over 2 at 800 K theoretically. All thermoelectric properties were "simultaneously" measured from the same nanowires to facilitate accurate ZT measurements. The surface boundary scattering is prominent when the nanowire diameter is over ~100 nm, whereas alloying plays a more important role in suppressing phonon transport for smaller ones. PMID- 22548379 TI - Intramolecular hole transfer at sensitized TiO2 interfaces. AB - Three ruthenium compounds with triphenyl amine donors were anchored to nanocrystalline TiO(2) thin films for interfacial electron-transfer studies. Molecular tuning of reduction potentials enabled the extent of hole transfer from the photo-oxidized ruthenium center to the triphenyl amine to be tuned from zero to unity. Kinetic data revealed two new insights into the unwanted interfacial recombination reaction of the injected electrons with the oxidized compounds. First, recombination was highly sensitive to the concentration of oxidized compounds present at the interface. Second, a significant enhancement of the open circuit photovoltage was realized without a change in the recombination kinetics, behavior attributed to translation of the hole away from the interface thereby generating a larger surface dipole. PMID- 22548378 TI - Optimizing treatment for complex cases of childhood obsessive compulsive disorder: a preliminary trial. AB - Family factors such as conflict, blame, and poor cohesion have been found to attenuate response to cognitive behavior therapy (CBT) for pediatric obsessive compulsive disorder (OCD). This study examined the feasibility and acceptability of a brief, personalized intervention for cases of pediatric OCD complicated by these family features. Twenty youth with a primary Diagnostic and Statistical Manual of Mental Disorders (4th ed.) diagnosis of OCD (M age = 12.50 years; 55% male; 60% Caucasian) and their families participated. To be included in the study, families were required to evidence poor functioning on measures of blame, conflict, and/or cohesion. Eligible families were randomly assigned either to standard treatment (ST) with 12 weeks of individual child CBT that included weekly parent check-ins and psychoeducation or to Positive Family Interaction Therapy (PFIT), which consisted of 12 weeks of individual child CBT plus an additional 6 sessions of family treatment aimed at shifting family dynamics. Clinical outcomes were determined by blind independent evaluators using the Clinician's Global Impressions-Improvement (CGI-I) scale. All families completed the study. High levels of satisfaction were reported among participants in both arms of the study, despite the added burden of attending the PFIT sessions. Both mothers and fathers attended 95% of the PFIT family sessions. Families in the ST condition demonstrated a 40% response rate on the CGI-I; families in the PFIT condition demonstrated a 70% response rate. Treatment gains were maintained in both conditions at 3-month follow-up. Preliminary data suggest that PFIT is acceptable and feasible. Further testing and treatment development are needed to optimize outcomes for complicated cases of pediatric OCD. PMID- 22548380 TI - Structure--activity relationship and mode of action of N-(6-ferrocenyl-2 naphthoyl) dipeptide ethyl esters: novel organometallic anticancer compounds. AB - In this article, we report the findings of a comprehensive structure-activity relationship study of N-(6-ferrocenyl-2-naphthoyl) dipeptide ethyl esters, in which novel analogues were designed, synthesized, and evaluated in vitro for antiproliferative effect. Two new compounds, 2 and 16, showed potent nanomolar activity in the H1299 NSCLC cell line, with exceptional IC(50) values of 0.13 and 0.14 MUM, respectively. These compounds were also found to have significant activity in the Sk-Mel-28 malignant melanoma cell line (IC(50) values of 1.10 and 1.06 MUM, respectively). Studies were also conducted to elucidate the mode of action of these novel organometallic anticancer compounds. Cell cycle analysis in the H1299 cell line suggests these compounds induce apoptosis, while guanine oxidation studies confirm that 2 is capable of generating oxidative damage via a ROS-mediated mechanism. PMID- 22548381 TI - Close association between oral Candida species and oral mucosal disorders in patients with xerostomia. AB - OBJECTIVE: Heightened interest in oral health has lead to an increase in patients complaining of xerostomia, which is associated with various oral mucosal disorders. In this study, we investigated the relationship between Candida species and oral mucosal disorders in patients with xerostomia. SUBJECTS AND METHODS: We evaluated whole salivary flow rate and presence of oral mucosal disorders in 48 patients with xerostomia and 15 healthy controls. The number of Candida species was measured as colony-forming units after propagation on selective medium. Identification of Candida at the species level was carried out by polymerase chain reaction and restriction fragment length polymorphism analysis. We then examined the relationship between Candida species and oral mucosal symptoms. RESULTS: Compared with controls, patients with xerostomia exhibited significantly decreased whole salivary flow rate, increased rate of oral mucosal symptoms, and higher numbers of Candida. Salivary flow rate negatively correlated with the number Candida. Among patients with oral candidiasis, Candida albicans was isolated from the tongue mucosa and Candida glabrata was isolated from the angle of the mouth. CONCLUSION: These results suggest that particular Candida species are involved in the pathogenesis of oral mucosal disorders in patients with xerostomia. PMID- 22548382 TI - Calciphylaxis with normal renal function: treated with intravenous sodium thiosulfate. AB - Calciphylaxis is a rare and potentially life-threatening condition. It is thought to result from arterial calcification causing complete vascular occlusion and subsequent cutaneous infarction. Most often, it is a complication of end-stage renal failure or hyperparathyroidism; without either of these associated conditions, it is extremely rare. We report a case of calciphylaxis in a 58-year old white British man, who had received long-term oral prednisolone for asthma control, with prophylactic calcium supplementation. There was no history of renal failure, and the patient's parathyroid function was normal. He was found to be heterozygous for the Factor V Leiden mutation. The acute presentation was seemingly precipitated by an episode of trauma and subsequent compression bandaging. The patient responded promptly to intravenous sodium thiosulfate. To our knowledge, this is the first case with no history of renal failure and normal parathyroid function, precipitated by compression bandaging and with an associated Factor V Leiden mutation. PMID- 22548383 TI - Magnetic resonance imaging features of canine incomplete humeral condyle ossification. AB - Incomplete ossification of the humeral condyle (IOHC) is characterized by an intracondylar fissure located where the intercondylar physis is present in growing dogs. Its radiologic and computed tomographic features have been described but the magnetic resonance (MR) features have not been characterized. Our purpose was to further describe the range of MRappearances of IOHC, to assess the diagnostic capability of MRrelative to radiology, and to determine whether MRis able to identify the disease before a fissure forms. Thirty-eight elbow MRscans and radiographs, when available, were reviewed and divided into three groups. In Group 1 (affected elbows, n = 22), there was an intracondylar defect on MRwith variable appearance; the defect was not visible radiographically in 32% of the elbows. The main difference between Group 2 (nonaffected elbows, n = 6) and Group 3 (contralaterals to IOHC or to condylar fracture, without fissure, n = 10) was the appearance of the humeral condyle in short tau inversion recovery (STIR) sequences: all elbows in Group 2 had a homogeneous humeral condyle, whereas all but one in Group 3 were heterogeneous. One dog in Group 3 developed a complete condylar fissure 7 months after the first examination, when no evidence of an intracondylar defect had been detected. The MRappearance of IOHC is variable and a heterogeneous humeral condyle in STIR images without a clear defect may warn of the possibility for the subsequent development of a condylar fissure. PMID- 22548384 TI - Selection of patient for cardiac resynchronization therapy: role of QT corrected dispersion. AB - AIMS: About 30 to 50% of patients undergoing cardiac resynchronization therapy (CRT) may not show clinical or echocardiographic improvement, despite fulfilling guidelines recommendations for CRT. For this reason, we need a more accurate method to assess CRT eligibility. The aims of this study were to verify, on a 12 month follow-up, the usefulness of QT corrected dispersion (QTcD) in a patient's selection for CRT. METHODS: We stratified 53 patients who underwent CRT, into two groups based on the estimation of QTcD, that is, QTcD > 60 ms and QTcD <= 60 ms. In all patients were performed New York Heart Association (NYHA) class determination, six-minute walking test, QtcD, and QRS measurements, and complete echocardiographic assessment at 1, 3, 6, and 12 months after implantation. RESULTS: At baseline, there were no significant differences in clinical, echocardiographic, and electrocardiographic parameters duration between two groups. At 12-month follow-up between the two groups, there were significant differences in NYHA (1.2 +/- 0.4 vs 2 +/- 0.6; P < 0.01), six-minute walking distance (422 +/- 68 vs 364 +/- 68; P < 0.01), left ventricular (LV) ejection fraction (34 +/- 7% vs 28 +/- 6%; P < 0.01), LV end-diastolic diameter (57 +/- 7 vs 63 +/- 8; P < 0.01), and LV intraventricular dyssynchrony (24 +/- 14 vs 39 +/- 23; P < 0.01). CONCLUSION: This study suggests that QTc dispersion in addition to QRS duration could improve the sensitivity of electrocardiogram in a patient's selection for CRT. PMID- 22548385 TI - Sub-typing daily fatigue progression in chronic fatigue syndrome. AB - BACKGROUND: Activity logs involve patients writing down their activities and symptoms over 1 or more days. Aims This study sought to classify daily fatigue patterns among patients with chronic fatigue syndrome (CFS) using activity logs. METHOD: Fatigue intensity was self-reported every 30 min in a sample of 90 patients with CFS over 1 day. A cluster analysis using fatigue intensity, variability and slope was conducted. RESULTS: Three clusters emerged involving patients with different trajectories. One group evidenced high fatigue intensity, low variability, and fatigue intensity stayed the same over time. A second group had moderate fatigue intensity, high variability, and fatigue intensity decreased over time. A third group had moderate fatigue intensity, high variability, but fatigue intensity increased over time. The three clusters of patients differed on measures of actigraphy, pain and immune functioning. CONCLUSIONS: Activity logs can provide investigators and clinicians with valuable sources of data for understanding patterns of fatigue and activity among patients with CFS. PMID- 22548386 TI - Human adipose stem cell-conditioned medium increases survival of Friedreich's ataxia cells submitted to oxidative stress. AB - Friedreich's ataxia (FA) is a multisystemic disorder characterized by progressive gait, ataxia, and cardiomyopathy. There are few treatments for this disease; thus, we analyzed in vitro the possible beneficial effect of adult stem cells in FA. To this end, human adipose stem cells from healthy individuals and periodontal ligament cells from FA patients were isolated and cultured. FA cells are especially vulnerable to oxidative stress; thus, they were submitted to this condition and cultured in adipose stem cell-conditioned medium. This resulted in increased cell survival and upregulation of oxidative-stress-related genes as well as frataxin, among other genes. A number of trophic factors were shown to be expressed by the adipose stem cells, especially brain-derived neurotrophic factor (BDNF), which was also identified in the conditioned medium. The culture of the ataxic cells under oxidative stress and in the presence of this trophic factor confirmed its protective effect. Thus, this work demonstrates that adipose stem cell-conditioned medium from healthy individuals is capable of changing the transcription levels of oxidative-stress-related genes in cells that are particularly susceptible to this condition, avoiding cellular degeneration. Also, this work shows how neurotrophic factors, particularly BDNF, are capable of increasing cell survival in response to oxidative stress, which occurs in many neurodegenerative diseases. PMID- 22548388 TI - Effect of nitrogen doping on hydrogen storage capacity of palladium decorated graphene. AB - A high hydrogen storage capacity for palladium decorated nitrogen-doped hydrogen exfoliated graphene nanocomposite is demonstrated under moderate temperature and pressure conditions. The nitrogen doping of hydrogen exfoliated graphene is done by nitrogen plasma treatment, and palladium nanoparticles are decorated over nitrogen-doped graphene by a modified polyol reduction technique. An increase of 66% is achieved by nitrogen doping in the hydrogen uptake capacity of hydrogen exfoliated graphene at room temperature and 2 MPa pressure. A further enhancement by 124% is attained in the hydrogen uptake capacity by palladium nanoparticle (Pd NP) decoration over nitrogen-doped graphene. The high dispersion of Pd NP over nitrogen-doped graphene sheets and strengthened interaction between the nitrogen doped graphene sheets and Pd NP catalyze the dissociation of hydrogen molecules and subsequent migration of hydrogen atoms on the doped graphene sheets. The results of a systematic study on graphene, nitrogen-doped graphene, and palladium decorated nitrogen-doped graphene nanocomposites are discussed. A nexus between the catalyst support and catalyst particles is believed to yield the high hydrogen uptake capacities obtained. PMID- 22548387 TI - A review of traumatic brain injury trauma center visits meeting physiologic criteria from The American College of Surgeons Committee on Trauma/Centers for Disease Control and Prevention Field Triage Guidelines. AB - BACKGROUND: Traumatic brain injury (TBI) represents a serious subset of injuries among persons in the United States, and prehospital care of these injuries can mitigate both the morbidity and the mortality in patients who suffer from these injuries. Guidelines for triage of injured patients have been set forth by the American College of Surgeons Committee on Trauma (ACS-COT) in cooperation with the Centers for Disease Control and Prevention (CDC). These guidelines include physiologic criteria, such as the Glasgow Coma Scale (GCS) score, systolic blood pressure, and respiratory rate, which should be used in determining triage of an injured patient. OBJECTIVES: This study examined the numbers of visits at level I and II trauma centers by patients with a diagnosed TBI to determine the prevalence of those meeting physiologic criteria from the ACS-COT/CDC guidelines and to determine the extent of mortality among this patient population. METHODS: The data for this study were taken from the 2007 National Trauma Data Bank (NTDB) National Sample Program (NSP). This data set is a nationally representative sample of visits to level I and II trauma centers across the United States and is funded by the American College of Surgeons. Estimates of demographic characteristics, physiologic measures, and death were made for this study population using both chi-square analyses and adjusted logistic regression modeling. RESULTS: The analyses demonstrated that although many people who sustain a TBI and were taken to a level I or II trauma center did not meet the physiologic criteria, those who did meet the physiologic criteria had significantly higher odds of death than those who did not meet the criteria. After controlling for age, gender, race, Injury Severity Score (ISS), and length of stay in the hospital, persons who had a GCS score <=13 were 17 times more likely to die than TBI patients who had a higher GCS score (odds ratio [OR] 17.4; 95% confidence interval [CI] 10.7-28.3). Other physiologic criteria also demonstrated significant odds of death. CONCLUSIONS: These findings support the validity of the ACS-COT/CDC physiologic criteria in this population and stress the importance of prehospital triage of patients with TBI in the hopes of reducing both the morbidity and the mortality resulting from this injury. PMID- 22548389 TI - Light-responsive metabolite and transcript levels are maintained following a dark adaptation period in leaves of Arabidopsis thaliana. AB - * The effect of previous light conditions on metabolite and transcript levels was investigated in leaves of Arabidopsis thaliana during illumination and after light-enhanced dark respiration (LEDR), when dark respiration was measured. * Primary carbon metabolites and the expression of light-responsive respiratory genes were determined in A. thaliana leaves before and after 30 min of darkness following different light conditions. In addition, metabolite levels were determined in the middle of the night and the in vivo activities of cytochrome and alternative respiratory pathways were determined by oxygen isotope fractionation. * A large number of metabolites were increased in leaves of plants growing in or transiently exposed to higher light intensities. Transcript levels of respiratory genes were also increased after high light treatment. For the majority of the light-induced metabolites and transcripts, the levels were maintained after 30 min of darkness, where higher and persistent respiratory activities were also observed. The levels of many metabolites were lower at night than after 30 min of darkness imposed in the day, but respiratory activities remained similar. * The results obtained suggest that 'dark' respiration measurements, as usually performed, are probably made under conditions in which the overall status of metabolites is strongly influenced by the previous light conditions. PMID- 22548391 TI - Evaluation of the effect of disease duration in generalized vitiligo on its clinical response to narrowband ultraviolet B phototherapy. AB - BACKGROUND/PURPOSE: Narrowband ultraviolet B (NB-UVB) has been accepted as an effective therapy for generalized vitiligo. On the other hand, different factors seem to contribute to a good response. The purpose of this study is to evaluate the influence of disease duration on its clinical response to NB-UVB phototherapy. METHODS: In this open and uncontrolled study, vitiligo was considered 'recent' when the duration of disease was less than or equal to 4 years and 'long standing' when it was greater than 4 years. The patients received NB-UVB thrice weekly with an initial dose of 200 mJ/cm(2) and 10% increments at each subsequent treatment. After categorizing the clinical response to four groups (mild, moderate, good, and excellent), duration of disease and clinical response to NB-UVB were correlated statistically using the t-test. RESULTS: There were 63 patients: 34 women and 29 men, aged 6-60 years. The mean of disease duration was 10.13 +/- 9.1 years. Vitiligo was 'recent' in 26 and 'long standing' in 37 patients. The mean of overall response was 51.94 +/- 18.48%. Higher grades of response were more prevalent in patients with recent vitiligo than those with long-standing disease, and there was also statistically significant difference in overall response between these two groups of disease duration (P = 0.023). CONCLUSION: The early treatment of generalized vitiligo may enhance the chance of successful repigmentation. PMID- 22548392 TI - Sunburn protection as a function of sunscreen application thickness differs between high and low SPFs. AB - BACKGROUND: Sunscreens are an important component of healthy sun-protection behavior. To achieve satisfactory protection, sunscreens must be applied consistently, evenly and correctly. Consumers do not apply sunscreen properly and, therefore, do not achieve the protection indicated by the label 'sun protection factor' (SPF). The objective of the present study was to determine the actual sun(burn) protection given by a range of sunscreen application thickness levels for both low and high SPF formulas. SUBJECTS AND METHODS: Forty study subjects were recruited from each of three geographical regions in China. Sunscreens with label SPFs of 4, 15, 30, and 55 were tested at application levels of 0.5, 1.0, 1.5, and 2.0 mg/cm(2) in three laboratories using a standard SPF protocol. RESULTS: Sunscreens with lower SPFs (4 and 15) showed a linear dose response relationship with application level, but higher SPF (30 and 55) product protection was exponentially related to application thickness. CONCLUSION: Sunscreen protection is not related in one uniform way to the amount of product applied to human skin. Consumers may achieve an even lower than expected sunburn protection from high SPF products than from low SPF sunscreens. PMID- 22548393 TI - Accumulation of sunscreen in human skin after daily applications: a study of sunscreens with different ultraviolet radiation filters. AB - BACKGROUND/PURPOSE: Sunscreen applied to the skin provides a considerable sun protection factor (SPF) even after 8 h. Sunscreen use for consecutive days may therefore result in an accumulation of the product. This study investigated the consequences of accumulation for SPF. METHODS: Two sunscreens, one containing organic and one containing particle ultraviolet radiation (UVR) filters (SPF 30) (2 mg/cm(2)), were used. Areas on the back of 22 volunteers were applied with sunscreen on 5 consecutive days, once daily (12 volunteers) and three times daily (10 volunteers), and phototested. The SPF was determined on Days 1, 3 and 5. RESULTS: One daily application of sunscreen did not result in an accumulation in the skin that significantly affected the SPF. However, three daily applications provided a significantly higher SPF for both the organic (mean SPF 1.56) and particle (mean SPF 2.45) sunscreen at Day 5 compared to Day 1 (P = 0.023 for both sunscreens). CONCLUSION: Sunscreens accumulate in the skin when applied in the recommended amounts three times daily. In conjunction with other sun protection strategies, sunscreen application on consecutive days prior to UVR exposure can result in a basic skin protection, which may help to prevent severe sunburns on sun holidays. PMID- 22548394 TI - Clinical efficacy of flumetasone/salicylic acid ointment combined with 308-nm excimer laser for treatment of psoriasis vulgaris. AB - OBJECTIVE: To compare the clinical efficacy and safety of combining flumetasone ointment with 308-nm excimer laser therapy vs. 308-nm excimer laser monotherapy for the treatment of psoriasis vulgaris. METHOD: Forty patients with psoriasis vulgaris were recruited; 20 were treated with flumetasone ointment plus 308-nm excimer laser therapy, and the other 20 received only excimer laser monotherapy. The flumetasone ointment was applied topically twice a day, and laser treatments were scheduled twice weekly for a total of 10 treatments. Clinical efficacy was evaluated in a blinded manner by two independent physicians using photographs taken before and after treatment. RESULTS: Of the 40 patients who received and completed the entire course of therapy, the psoriasis area and severity index score was improved by 82.51 +/- 11.24% and 72.01 +/- 20.94% in the combination group and laser group, respectively (P > 0.05), and the average cumulative dose was 5.06 +/- 2.20 j/cm(2) in the combination group and 7.75 +/- 2.25 j/cm(2) in the laser-only group, respectively (P < 0.05). CONCLUSION: The clinical data suggest that combination treatment using flumetasone ointment and a 308-nm excimer laser is superior to laser monotherapy for treatment of psoriasis vulgaris. The combination therapy can increase effectiveness and decrease the total laser dose, thus potentially reducing side effects. PMID- 22548395 TI - Ultraviolet B radiation differentially modifies catechol-O-methyltransferase activity in keratinocytes and melanoma cells. AB - BACKGROUND: Catechol-O-methyltransferase (COMT) is a ubiquitous enzyme inactivating catecholic compounds. COMT is expressed also in human skin samples, and in melanoma cells it may be cytoprotective. A role of COMT in keratinocytes (HaCat) is unknown. OBJECTIVE: The objective of this study is: to investigate whether ultraviolet-B (UVB) radiation modifies COMT activity in melanocytes and HaCat and whether COMT inhibition plays a role in UVB-induced cell death. METHODS: Human cell lines of melanotic melanoma (SK-mel-1) and HaCat were used. COMT activity was evaluated under basal conditions and after UVB irradiation (311 nm) at a low (8 mJ/cm(2)) and a high dose (60 mJ/cm(2)). Tolcapone 1 MUM was used to inhibit COMT. RESULTS: Both SK-mel-1 and Ha-Cat cells express COMT activity. In SK-mel-1, COMT activity is reduced nearly 50% both 24 h and 48 h after a high dose UVB. In Ha-Cat cells, COMT activity increased 24 h after a high dose UVB but decreased at 48 h. Tolcapone increases significantly the cytotoxic effect of high dose UVB irradiation only in HaCat. High concentrations of tolcapone reduced melanin levels in melanoma cells parallel to reduced cell numbers. CONCLUSIONS: Ultraviolet radiation differentially modifies COMT activity in melanoma cells and HaCat. Furthermore, tolcapone increased death of HaCat after irradiation but did not affect melanoma cells. PMID- 22548396 TI - Comparison of the efficacy of ALA-PDT using an excimer-dye laser (630 nm) and a metal-halide lamp (600 to 740 nm) for treatment of Bowen's disease. AB - BACKGROUND/PURPOSE: Topical 5-aminolevulinic acid-based photodynamic therapy (ALA PDT) is an effective treatment for Bowen's disease (BD). In order to compare the efficacy of two different light sources, using either an excimer-dye laser (EDL) (630 nm) or a metal-halide lamp (MHL) (600 to 740 nm) a protocol for topical ALA PDT for treatment of BD of the extremities was established, and responses during 12 months follow-up were assessed. METHODS: From 25 patients a total of 26 lesions that had been histopathologically diagnosed as BD from 2005 to 2010 in the Department of Dermatology at the Aichi Medical University Hospital were randomly selected. The light source used for the topical ALA-PDT was EDL in 17 lesions and MHL in 9 lesions. The photosensitizing protoporphyrin IX that is produced within BD lesions 4 h after application of 20% ALA cream was mostly consumed after exposure to 100 J/cm(2) irradiation using 630 nm EDL. Each lesion was irradiated once a week for 3 weeks, for a total dosage of 300 J/cm(2) (100 mW/cm(2)). Patients were followed up clinically every 3 months for 12 months, and at 1 month after the final treatment lesions were evaluated histopathologically. RESULTS: Histologically, the complete response (CR) rate at 1-month follow-up was 82% (14/17 lesions) in the EDL treatment group and 100% (9/9 lesions) in the MHL treatment group (P > 0.05). The recurrence rate at 12 months after PDT was 46% (6/13 lesions, one patient lost to follow-up) in the EDL group and 0% in the MHL group (P < 0.05) (chi(2) test with Fisher's exact test). The average period before recurrence after EDL treatment was 6.5 months. CONCLUSION: A novel protocol for topical ALA-PDT in Japanese in Asian patients with BD was developed and implemented. The protocol improved the CR rate compared with previous studies. Moreover, the present results indicate that the efficacy of topical ALA PDT using MHL was superior to that using EDL for BD patients. PMID- 22548397 TI - Differentiation of HaCaT cell and melanocyte from their malignant counterparts using micro-Raman spectroscopy guided by confocal imaging. AB - BACKGROUND: Skin cancer is the most common type of cancer in humans. Current techniques for identifying normal and neoplastic tissues are either destructive or not sensitive and specific enough. Raman spectroscopy and confocal imaging may obviate many limitations of existing methods by providing noninvasive, high resolution, and real-time morphological and biochemical analysis of living tissues and cells. METHODS: We conducted micro-Raman spectroscopy studies on HaCaT cells, melanocytes (MC) and their malignant counterparts squamous cell carcinoma (SCC) and melanoma (MM) cells, respectively. Reflectance confocal imaging is used as guidance for the spectral measurements. RESULTS: Significant differences were found between the spectra of HaCaT cells and SCC cells, MC cells and MM cells, as well as all normal cells (HaCaT and MC) and all tumor cells (SCC and MM). Approximately 90% sensitivity and specificity was achieved for all the separations that we performed. CONCLUSION: Our results demonstrated the robust capability of confocal Raman spectroscopy in separating different cell lines. The acquired Raman spectra of major types of skin cells and their malignant counterparts will be useful for the interpretation of Raman spectra from in vivo skin. We believe it will eventually help diagnosis of skin cancer and other skin disease in clinical dermatology. PMID- 22548398 TI - Validation of skin surface microtopography as a measure of skin photoaging in a subtropical population aged 40 and over. AB - BACKGROUND: Evidence suggests that skin surface microtopography is a valid measure of photoaging among young adults, but whether this applies to older adults is unknown. METHODS: We investigated the association between degree of photoaging as measured by histological dermal elastosis and skin microtopography grades by decade of age from 40 to 89 years in a community sample in Australia. Skin surface replicas and punch biopsies were taken from 664 participants of the Nambour Skin Cancer Study. The association was assessed using ordinal logistic regression with proportional odds assumption, using histological dermal elastosis grades as outcome. RESULTS: There was significant increase in odds of higher skin surface microtopography grades with higher dermal elastosis grades for age groups below 70 years [40 to 49 years: odds ratio (OR) 2.96, 95% confidence interval (CI) 1.68-5.22; 50 to 59 years: OR 3.78, 95% CI 2.28-6.26; 60 to 69 years: OR 2.47, 95% CI 1.41-4.35). The association was not significant for those 70 years or older. CONCLUSION: Skin surface microtopography grading system is a valid measure of degree of dermal elastosis for middle-aged and older adults up to 69 years but appears not to be valid for adults 70 years or more living in a high sun exposure setting. PMID- 22548399 TI - Vitamin D deficiency in South Europe: effect of smoking and aging. AB - The main source of vitamin D is synthesis in the skin during exposure to ultraviolet radiation. The existence of photoaggravated diseases and the increasing incidence of skin cancer have prompted recommendations to avoid the sun. Here, we study the status of vitamin D in a healthy population and its relation to their habits of sun exposure. To do so, we designed a cross-sectional study that included 177 healthy people. We analyzed parameters about demographic data, sun exposure, and protection habits and estimated vitamin D dietary intake. We performed blood tests to measure serum 25-hydroxyvitamin D [25(OH)D], calcium, phosphorus, and intact parathyroid hormone. Mean levels (+/- standard deviation) of 25(OH)D were 24.0 (+/- 8.5) ng/ml. Seventy-six percent of the population did not reach recommended levels of vitamin D (30 ng/ml), including 4.5% who were vitamin D deficient (< 10 ng/ml). Levels were higher in young people (P = 0.04) and those with more sun exposure (P = 0.04). Smoking was associated with an increased risk of hypovitaminosis D (odds ratio, 1.8; 95% confidence interval, 1.00-3.35). On the basis of our findings, we should consider the risk of hypovitaminosis when we recommend sun avoidance, especially in some risk groups, because the sun is the most important source of this vitamin. PMID- 22548400 TI - Narrowband UVB phototherapy as a novel treatment for Netherton syndrome. AB - Netherton syndrome (NS) is a rare congenital ichthyosis that is characterized by impaired skin barrier function. Topical medications are cautiously used in NS since toxicity from systemic absorption is a major concern. Narrowband ultraviolet B phototherapy is an alternative therapeutic option that demonstrated its beneficial and practical use in a patient with NS. PMID- 22548401 TI - In vitro ultraviolet A irradiation decreases both release ability and gene expression of vascular endothelial growth factor-A from mast cells. AB - Ultraviolet A (UVA) rays penetrate the dermis, influencing the function of different cells, including mast cells, able to produce angiogenic factors. We investigated vascular endothelial growth factor (VEGF) release and gene expression from mast cells (MCs), after UVA irradiation in vitro. The release of VEGF-A by Human MCs-1 (HMC-1) was induced by calcium ionophore A23187 and phorbol 12 myristate 13 acetate (PMA). Half of the cells received increasing doses of UVA (5, 25 and 50 J/cm(2)), the unirradiated HMC-1 served as controls. VEGF release and VEGF's messenger ribonucleic acid (mRNA) were detected respectively by enzyme linked immunoabsorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR) analysis. Results showed a UVA dose-dependent inhibitory effect on VEGF-A release from HMC-1. In particular, the release ability was reduced by 71.2% with 5 J/cm(2); 85% with 25 J/cm(2) and 86.3% with 50 J/cm(2). The VEGF-A RNA expression was reduced after UVA irradiation with 5 J/cm(2). We speculated that, at least in vitro and at our experimental conditions, UVA irradiation decreases mast cells-VEGF release and gene-expression. PMID- 22548402 TI - Tomesa balneophototherapy in mild to severe psoriasis: a retrospective clinical trial in 174 patients. AB - Psoriasis is a chronic inflammatory skin disease with a high social and psychological impact on the quality of life of patients. Tomesa balneophototherapy is based on bathing in a magnesium-rich salt solution combined with exposure to narrowband ultraviolet B phototherapy. We conducted a retrospective clinical trial on 174 patients affected by mild to severe psoriasis undergoing Tomesa balneophototherapy. The basal course consisted of three to five sessions per week for a total of 30 sessions. Subsequently, patients could continue with a maintenance course of one session per week for a total of 30 sessions. We recorded a significant reduction of the mean Psoriasis Area and Severity Index (PASI) index with an achievement of at least PASI 75 in 52.1% of the 119 patients who completed the basal course and an improvement of the 'quality of life' of patients. The good efficacy obtained by this treatment, and the psychological impact on the quality of life of patients, demonstrated that Tomesa balneophototherapy could be a good option for the treatment of a chronic disease associated with psychological distress, like psoriasis. PMID- 22548403 TI - Multicenter study of preservative sensitivity in patients with suspected cosmetic contact dermatitis in Korea. AB - As many new cosmetic products are introduced into the market, attention must be given to contact dermatitis, which is commonly caused by cosmetics. We investigate the prevalence of preservative allergy in 584 patients with suspected cosmetic contact dermatitis at 11 different hospitals. From January 2010 to March 2011, 584 patients at 11 hospital dermatology departments presented with cosmetic contact dermatitis symptoms. These patients were patch-tested for preservative allergens. An irritancy patch test performed on 30 control subjects using allergens of various concentrations showed high irritancy rates. Preservative hypersensitivity was detected in 41.1% of patients. Allergens with the highest positive test rates were benzalkonium chloride (12.1%), thimerosal (9.9%) and methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) (5.5%). Benzalkonium chloride and chlorphenesin had the highest irritancy rate based on an irritancy patch test performed using various concentrations. Seven of 30 normal subjects had a positive irritant patch reading with 0.1% benzalkonium chloride and eight of 30 normal subjects had a positive irritant patch reading at 4 days with 0.5% chlorphenesin in petrolatum. Although benzalkonium chloride was highly positive for skin reactions in our study, most reactions were probably irritation. MCI/MI and thimerosal showed highly positive allergy reactions in our study. The optimum concentration of chlorphenesin to avoid skin reactions is less than 0.5%. PMID- 22548404 TI - Exome sequencing in a family with an X-linked lethal malformation syndrome: clinical consequences of hemizygous truncating OFD1 mutations in male patients. AB - Oral-facial-digital syndrome type 1 (OFD1; OMIM #311200) is an X-linked dominant disorder, caused by heterozygous mutations in the OFD1 gene and characterized by facial anomalies, abnormalities in oral tissues, digits, brain, and kidney; and male lethality in the first or second trimester pregnancy. We encountered a family with three affected male neonates having an 'unclassified' X-linked lethal congenital malformation syndrome. Exome sequencing of entire transcripts of the whole X chromosome has identified a novel splicing mutation (c.2388+1G > C) in intron 17 of OFD1, resulting in a premature stop codon at amino acid position 796. The affected males manifested severe multisystem complications in addition to the cardinal features of OFD1 and the carrier female showed only subtle features of OFD1. The present patients and the previously reported male patients from four families (clinical OFD1; Simpson-Golabi-Behmel syndrome, type 2 with an OFD1 mutation; Joubert syndrome-10 with OFD1 mutations) would belong to a single syndrome spectrum caused by truncating OFD1 mutations, presenting with craniofacial features (macrocephaly, depressed or broad nasal bridge, and lip abnormalities), postaxial polydactyly, respiratory insufficiency with recurrent respiratory tract infections in survivors, severe mental or developmental retardation, and brain malformations (hypoplasia or agenesis of corpus callosum and/or cerebellar vermis and posterior fossa abnormalities). PMID- 22548405 TI - Regulation of angiotensin II receptors beyond the classical pathway. AB - The RAS (renin-angiotensin system) plays a role not only in the cardiovascular system, including blood pressure regulation, but also in the central nervous system. AngII (angiotensin II) binds two major receptors: the AT(1) receptor (AngII type 1 receptor) and AT(2) receptor (AngII type 2 receptor). It has been recognized that AT(2) receptor activation not only opposes AT(1) receptor actions, but also has unique effects beyond inhibitory cross-talk with AT(1) receptor signalling. Novel pathways beyond the classical actions of RAS, the ACE (angiotensin-converting enzyme)/AngII/AT(1) receptor axis, have been highlighted: the ACE2/Ang-(1-7) [angiotensin-(1-7)]/Mas receptor axis as a new opposing axis against the ACE/AngII/AT(1) receptor axis, novel AngII-receptor-interacting proteins and various AngII-receptor-activation mechanisms including dimer formation. ATRAP (AT(1)-receptor-associated protein) and ATIP (AT(2)-receptor interacting protein) are well-characterized AngII-receptor-associated proteins. These proteins could regulate the functions of AngII receptors and thereby influence various pathophysiological states. Moreover, the possible cross-talk between PPAR (peroxisome-proliferator-activated receptor)-gamma and AngII receptor subtypes is an intriguing issue to be addressed in order to understand the roles of RAS in the metabolic syndrome, and interestingly some ARBs (AT(1) receptor blockers) have been reported to have an AT(1)-receptor-blocking action with a partial PPAR-gamma agonistic effect. These emerging concepts concerning the regulation of AngII receptors are discussed in the present review. PMID- 22548406 TI - The renin-angiotensin system, bone marrow and progenitor cells. AB - Modulation of the RAS (renin-angiotensin system), in particular of the function of the hormones AngII (angiotensin II) and Ang-(1-7) [angiotensin-(1-7)], is an important target for pharmacotherapy in the cardiovascular system. In the classical view, such modulation affects cardiovascular cells to decrease hypertrophy, fibrosis and endothelial dysfunction, and improves diuresis. In this view, excessive stimulation of AT(1) receptors (AngII type 1 receptors) fulfils a detrimental role, as it promotes cardiovascular pathogenesis, and this is opposed by stimulation of the AT(2) receptor (angiotensin II type 2 receptor) and the Ang (1-7) receptor encoded by the Mas proto-oncogene. In recent years, this view has been broadened with the observation that the RAS regulates bone marrow stromal cells and stem cells, thus involving haematopoiesis and tissue regeneration by progenitor cells. This change of paradigm has enlarged the field of perspectives for therapeutic application of existing as well as newly developed medicines that alter angiotensin signalling, which now stretches beyond cardiovascular therapy. In the present article, we review the role of AngII and Ang-(1-7) and their respective receptors in haematopoietic and mesenchymal stem cells, and discuss possible pharmacotherapeutical implications. PMID- 22548407 TI - Update on new aspects of the renin-angiotensin system in liver disease: clinical implications and new therapeutic options. AB - The RAS (renin-angiotensin system) is now recognized as an important regulator of liver fibrosis and portal pressure. Liver injury stimulates the hepatic expression of components of the RAS, such as ACE (angiotensin-converting enzyme) and the AT(1) receptor [AngII (angiotensin II) type 1 receptor], which play an active role in promoting inflammation and deposition of extracellular matrix. In addition, the more recently recognized structural homologue of ACE, ACE2, is also up-regulated. ACE2 catalyses the conversion of AngII into Ang-(1-7) [angiotensin (1-7)], and there is accumulating evidence that this 'alternative axis' of the RAS has anti-fibrotic, vasodilatory and anti-proliferative effects, thus counterbalancing the effects of AngII in the liver. The RAS is also emerging as an important contributor to the pathophysiology of portal hypertension in cirrhosis. Although the intrahepatic circulation in cirrhosis is hypercontractile in response to AngII, resulting in increased hepatic resistance, the splanchnic vasculature is hyporesponsive, promoting the development of the hyperdynamic circulation that characterizes portal hypertension. Both liver fibrosis and portal hypertension represent important therapeutic challenges for the clinician, and there is accumulating evidence that RAS blockade may be beneficial in these circumstances. The present review outlines new aspects of the RAS and explores its role in the pathogenesis and treatment of liver fibrosis and portal hypertension. PMID- 22548409 TI - Binding of organic ligands with Al(III) in dissolved organic matter from soil: implications for soil organic carbon storage. AB - The binding characteristics of organic ligands with Al(III) in soil dissolved organic matter (DOM) is essential to understand soil organic carbon (SOC) storage. In this study, two-dimensional (2D) FTIR correlation spectroscopy was developed as a novel tool to explore the binding of organic ligands with Al(III) in DOM present in soils as part of a long-term (21-year) fertilization experiment. The results showed that while it is a popular method for characterizing the binding of organic ligands and metals, fluorescence excitation emission matrix-parallel factor analysis can only characterize the binding characteristics of fluorescent substances (i.e., protein-, humic-, and fulvic like substances) with Al(III). However, 2D FTIR correlation spectroscopy can characterize the binding characteristics of both fluorescent and nonfluorescent (i.e., polysaccharides, lipids, and lignin) substances with Al(III). Meanwhile, 2D FTIR correlation spectroscopy demonstrated that the sequencing/ordering of organics binding with Al(III) could be modified by the use of long-term fertilization strategies. Furthermore, 2D FTIR correlation spectroscopy revealed that the high SOC content in the chemical plus manure (NPKM) treatment in the long term fertilization experiment can be attributed to the formation of noncrystalline microparticles (i.e., allophane and imogolite). In summary, 2D FTIR correlation spectroscopy is a promising approach for the characterization of metal-organic complexes. PMID- 22548410 TI - Strong divergence in trait means but not in plasticity across hatchery and wild populations of sea-run brown trout Salmo trutta. AB - There is ample evidence that organisms adapt to their native environment when gene flow is restricted. However, evolution of plastic responses across discrete environments is less well examined. We studied divergence in means and plasticity across wild and hatchery populations of sea-run brown trout (Salmo trutta) in a common garden experiment with two rearing environments (hatchery and a nearly natural experimental stream). Since natural and hatchery environments differ, this arrangement provides an experiment in contemporary adaptation across the two environments. A Q(ST) - F(ST) approach was used to investigate local adaptation in survival and growth over the first summer. We found evidence for divergent selection in survival in 1 year and in body length in both years and rearing environments. In general, the hatchery populations had higher survival and larger body size in both environments. Q(ST) in body size did not differ between the rearing environments, and constitutive divergence in the means was in all cases stronger than divergence in the plastic responses. These results suggest that in this system, constitutive changes in mean trait values are more important for local adaptation than increased plasticity. In addition, ex situ rearing conditions induce changes in trait means that are adaptive in the hatchery, but potentially harmful in the wild, suggesting that hatchery rearing is likely to be a suboptimal management strategy for trout populations facing selection in the stream environment. PMID- 22548411 TI - Depression, hippocampal volume changes, and cognitive decline in a clinical sample of older depressed outpatients and non-depressed controls. AB - OBJECTIVE: The aim of this study was to develop and test a model of depression, hippocampal changes, and cognitive decline. METHOD: Participants were 248 community-dwelling, depressed patients and 147 healthy, non-depressed individuals 60 years and older. Participants received a structured interview assessing current depressive symptoms and past depressive episodes, completed cognitive testing with the Mini Mental State Examination (MMSE), and underwent structural Magnetic Resonance Imaging (MRI) of the brain. For up to 10 years, assessment of depressive symptoms and MMSE administration was repeated at least annually, and MRI was repeated every two years. RESULTS: Regression analyses demonstrated that depression diagnosis at baseline predicted decrease in right (but not left) hippocampal volume over a four-year period. Analyses using structural equation modeling demonstrated that a decrease in left and right hippocampal volumes predicted decrease in MMSE score over four years. CONCLUSION: Results provide some evidence for relationships between depression and decrease in right hippocampal volume, and between hippocampal volume and MMSE score. This would be consistent with depression as a causal factor in subsequent cognitive decline. Plausible biological mechanisms include a glucocorticoid cascade or a facilitating effect of depression on amyloid-beta plaque formation. Future studies should examine the relationship between hippocampal volume and specialized memory measures, as well as between depression diagnosis and volume of other brain structures. PMID- 22548412 TI - Novel one-component positive-tone chemically amplified i-line molecular glass photoresists. AB - Maleopimaric acid, cycloaddition reaction product of rosin with maleic anhydride, was reacted with hydroxylamine to afford N-hydroxy maleopimarimide, which was then further esterified with 2-diazo-1-naphthoquinone-4-sulfonyl chloride (2,1,4 DNQ-Cl) to give N-hydroxy maleopimarimide sulfonate. The carboxylic acid group of the compound was then protected by the reaction of this compound with vinyl ether compounds to give the corresponding molecular glass compounds. Upon irradiation to 365 nm light, the 2,1,4-DNQ group undergo photolysis not only to be converted into indene carboxylic acid but also generate a few amount of sulfonic acid which can catalyze the deprotection of the acid labile group. So, novel one-component positive-tone chemically amplified i-line photoresists can be formed by the molecular glass compounds. The lithographic performance of the resists was evaluated using i-line exposure system with high photosensitivity and resolution. PMID- 22548413 TI - Evaluation of oral health related to body mass index. AB - OBJECTIVE: Poor oral health has previously been related to high body mass index (BMI). We aimed at exploring the link between BMI and several oral health markers, after adjustment for dietary patterns and plasma insulin, both of which could act as mediators. SUBJECTS AND METHODS: Dental examination was performed in a sample of 186 French subjects aged 35-64 years and selected from the general population to assess number of missing teeth, periodontitis, clinical attachment loss (CAL), probing pocket depth (PD), gingival index (GI) and plaque index (PI). Data collection also included a food-frequency questionnaire. BMI (considered as outcome variable) was categorized into quartiles, and as BMI<25; 25 <=BMI<30; and BMI >= 30 kg m(-2) . RESULTS: After adjustment for age, gender, education level, smoking, physical activity, energy intake and C-reactive protein, BMI was statistically associated with missing teeth, PD and PI, but not with CAL, GI or periodontitis. After additional adjustment for 'high-carbohydrate' diet and plasma insulin or HOMA (homeostasis model assessment) index for insulin resistance, the statistical relationship between BMI and oral variables remained significant only for PD and PI. CONCLUSIONS: Plaque index, reflecting dental plaque, and PD, closely linked with periodontal inflammation and infection, are statistically associated with high BMI and obesity, independently of dietary patterns and insulin resistance. PMID- 22548414 TI - Polyelectrolyte wrapping layers control rates of photothermal molecular release from gold nanorods. AB - Gold nanorods show great promise as light-controlled molecular release systems. Dye molecules were loaded within a variable number of polyelectrolyte multilayers wrapped around gold nanorods. The dye photoinduced release rate depended on the quantity and type of polyelectrolyte trapping layers and could be tuned by a factor of 100. Only two molecular capping layers were sufficient to turn off release. Comparison of the phototriggered molecular release rate to a pure thermal experiment provides an estimate of the effective temperature of the nanorod solution upon irradiation. PMID- 22548415 TI - Genome-wide association studies for hematological traits in swine. AB - Improving immune capacity may increase the profitability of animal production if it enables animals to better cope with infections. Hematological traits play pivotal roles in animal immune capacity and disease resistance. Thus far, few studies have been conducted using a high-density swine SNP chip panel to unravel the genetic mechanism of the immune capability in domestic animals. In this study, using mixed model-based single-locus regression analyses, we carried out genome-wide association studies, using the Porcine SNP60 BeadChip, for immune responses in piglets for 18 hematological traits (seven leukocyte traits, seven erythrocyte traits, and four platelet traits) after being immunized with classical swine fever vaccine. After adjusting for multiple testing based on permutations, 10, 24, and 77 chromosome-wise significant SNPs were identified for the leukocyte traits, erythrocyte traits, and platelet traits respectively, of which 10 reached genome-wise significance level. Among the 53 SNPs for mean platelet volume, 29 are located in a linkage disequilibrium block between 32.77 and 40.59 Mb on SSC6. Four genes of interest are located within the block, providing genetic evidence that this genomic segment may be considered a candidate region relevant to the platelet traits. Other candidate genes of interest for red blood cell, hemoglobin, and red blood cell volume distribution width also have been found near the significant SNPs. Our genome-wide association study provides a list of significant SNPs and candidate genes that offer valuable information for future dissection of molecular mechanisms regulating hematological traits. PMID- 22548416 TI - Interfacial electron transfer into functionalized crystalline polyoxotitanate nanoclusters. AB - Interfacial electron transfer (IET) between a chromophore and a semiconductor nanoparticle is one of the key processes in a dye-sensitized solar cell. Theoretical simulations of the electron transfer in polyoxotitanate nanoclusters Ti(17)O(24)(OPr(i))(20) (Ti(17)) functionalized with four p-nitrophenyl acetylacetone (NPA-H) adsorbates, of which the atomic structure has been fully established by X-ray diffraction measurements, are presented. Complementary experimental information showing IET has been obtained by EPR spectroscopy. Evolution of the time-dependent photoexcited electron during the initial 5 fs after instantaneous excitation to the NPA LUMO + 1 has been evaluated. Evidence for delocalization of the excitation over multiple chromophores after excitation to the NPA LUMO + 2 state on a 15 fs time scale is also obtained. While chromophores are generally considered electronically isolated with respect to neighboring sensitizers, our calculations show that this is not necessarily the case. The present work is the most comprehensive study to date of a sensitized semiconductor nanoparticle in which the structure of the surface and the mode of molecular adsorption are precisely defined. PMID- 22548417 TI - A compact intermediate state of calmodulin in the process of target binding. AB - Calmodulin undergoes characteristic conformational changes by binding Ca(2+), which allows it to bind to more than 300 target proteins and regulate numerous intracellular processes in all eukaryotic cells. We measured the conformational changes of calmodulin upon Ca(2+) and mastoparan binding using the time-resolved small-angle X-ray scattering technique combined with flash photolysis of caged calcium. This measurement system covers the time range of 0.5-180 ms. Within 10 ms of the stepwise increase in Ca(2+) concentration, we identified a distinct compact conformational state with a drastically different molecular dimension. This process is too fast to study with a conventional stopped-flow apparatus. The compact conformational state was also observed without mastoparan, indicating that the calmodulin forms a compact globular conformation by itself upon Ca(2+) binding. This new conformational state of calmodulin seems to regulate Ca(2+) binding and conformational changes in the N-terminal domain. On the basis of this finding, an allosteric mechanism, which may have implications in intracellular signal transduction, is proposed. PMID- 22548418 TI - Lead retention by broiler litter biochars in small arms range soil: impact of pyrolysis temperature. AB - Phosphorus-rich manure biochar has a potential for stabilizing Pb and other heavy metal contaminants, as well as serving as a sterile fertilizer. In this study, broiler litter biochars produced at 350 and 650 degrees C were employed to understand how biochar's elemental composition (P, K, Ca, Mg, Na, Cu, Pb, Sb, and Zn) affects the extent of heavy metal stabilization. Soil incubation experiments were conducted using a sandy, slightly acidic (pH 6.11) Pb-contaminated (19906 mg kg(-1) total Pb primarily as PbCO(3)) small arms range (SAR) soil fraction (<250 MUm) amended with 2-20 wt % biochar. The Pb stabilization in pH 4.9 acetate buffer reached maximum at lower (2-10 wt %) biochar amendment rate, and 350 degrees C biochar containing more soluble P was better able to stabilize Pb than the 650 degrees C biochar. The 350 degrees C biochar consistently released greater amounts of P, K, Mg, Na, and Ca than 650 degrees C biochar in both unbuffered (pH 4.5 sulfuric acid) and buffered (pH 4.9 acetate) systems, despite 1.9-4.5-fold greater total content of the 650 degrees C biochar. Biochars, however, did not influence the total extractable Pb over three consecutive equilibration periods consisting of (1) 1 week in pH 4.5 sulfuric acid (simulated leaching by rainfall), (2) 1 week in pH 4.9 acetate buffer (standard solution for toxicity characteristic leaching procedure), and (3) 1 h in pH 1.5 glycine at 37 degrees C (in vitro bioaccessibility procedure). Overall, lower pyrolysis temperature was favorable for stabilizing Pb (major risk driver of SAR soils) and releasing P, K, Ca, and other plant nutrients in a sandy acidic soil. PMID- 22548419 TI - Fumaric acid esters as a suitable first-line treatment for severe psoriasis: an Irish experience. PMID- 22548420 TI - Evaluation of a university general education health and wellness course delivered by lecture or online. AB - PURPOSE: To assess a single-semester university general education (GE) health and wellness course influence on physical activity (PA) and dietary habits among university students and to compare the course delivered through lecture or online for these outcomes. DESIGN: A 15-week intervention with pre-post one-group design, allowing for comparative assessments in dietary and PA habits across time by delivery method (classroom lecture vs. online). SETTING: A large Western university. PARTICIPANTS: Participants (n = 1638, female; n = 1333, male) were 82% university freshman or sophomores. INTERVENTION: Participants were required to take a GE health and wellness course either by classroom lecture or online. The lecture and online curriculum content were similar. Participation in the study was entirely voluntary and was not connected to course grade. MEASURES: PA and dietary outcomes were determined from questions used in the Behavioral Risk Factor Surveillance System survey and were assessed pre- and post-intervention. Other validated questions were used to assess fitness. ANALYSIS: The general linear model was utilized to determine group x period interactions when comparing the classroom lecture vs. online course. RESULTS: Students improved overall level of PA by 12%, daily minutes of moderate-intensity PA by 8%, and fitness level by 2%. Students improved fruit/vegetable consumption by 4%, bran/whole grain cereal consumption by 8%, and brown rice/whole wheat bread consumption by 11%. All improvements were statistically significant (p < .001) with percent values indicating the size of the effect. The classroom lecture course yielded stronger improvements in several PA and dietary outcomes than the online course. CONCLUSIONS: A single-semester university wellness course may positively influence multiple PA and dietary behaviors; however, classroom lecture may be superior to online delivery. PMID- 22548421 TI - Sedentary behaviors among Hispanic children: influences of parental support in a school intervention program. AB - PURPOSE: To examine the effect of parental support on sedentary behaviors among Hispanic children. DESIGN AND SETTING: A longitudinal quasi-experimental design with five waves of data collection was used to examine the effect of parental support on children's sedentary behaviors in a school-based intervention program in west Texas. SUBJECTS: Hispanic low-income parents and their children of 5 to 9 years (N = 416 child-parent dyads) over a 22-month period (1217 observations). INTERVENTION: Transformacion Para Salud was a multicomponent intervention program aimed at prevention and control of childhood overweight and obesity. It used a community-based participatory research approach, including nutrition education, physical exercise, gardening, and family involvement. MEASURES: Sedentary behaviors were measured by parents' report of their children's daily screen time per week, including TV/DVD, computer, Internet, and video games. Parental support was measured with parents' reported support for active living. ANALYSIS: Growth curve analysis was used to examine trajectories of sedentary behaviors of children. RESULTS: Response rate was over 70%. Parental support reduced children's sedentary behaviors. Girls were less sedentary than boys, but girls were less affected by parental support. The intervention was effective in reducing children's sedentary behaviors over time. CONCLUSION: It is important for school intervention programs to mobilize parents to provide more support to reduce sedentary behaviors. PMID- 22548422 TI - Associated pathways between neighborhood environment, community resource factors, and leisure-time physical activity among Mexican-American adults in San Diego, California. AB - PURPOSE: To examine pathways between individual, social, and environmental factors associated with leisure-time physical activity (LTPA) among Mexican American adults. DESIGN: Cross-sectional design using random-digit dialing to administer a structured telephone interview. SETTING: Mexican-American adults living in a U.S.-Mexican border community in San Diego, California (N = 672). MEASURES: Data were collected on LTPA, demographic characteristics, acculturation, and other psychosocial and environmental factors associated with LTPA. ANALYSIS: Structural equation modeling to test an a priori model of LTPA. RESULTS: Participants were mostly female (71%) with a mean age of 39 years (SD = 13). Only 32% of participants met PA guidelines in their leisure time, with men (39%) meeting the guidelines more than women (29%). Using structural equation modeling, neighborhood factors, both social and environmental, showed indirect relationships with meeting PA guidelines through community resource factors. Significant covariates included marital status and age. CONCLUSION: Individual, social, and environmental factors were associated with LTPA in this sample of Mexican-American adults. These findings can inform intervention studies that aim to increase LTPA in this population. PMID- 22548423 TI - Small business support of youth physical activity opportunities. AB - PURPOSE: Describe small business support for youth physical activity opportunities (YPAO) and identify factors associated with this support. DESIGN: Cross-sectional analysis of quantitative data relating business characteristics and support for YPAO. SETTING: Eight demographically heterogeneous, urban neighborhoods in a Midwest metropolitan area. SUBJECTS: Adult small business owners (n = 90; 65% response rate; mean age 48.4 years; 73.3% male; 45.2% minority). MEASURES: Neighborhood demographics from the 2000 U.S. Census and self reported business and owner characteristics. ANALYSIS: Multivariate analysis of variance was used to contrast business and owner characteristics between businesses that did and did not support YPAO. RESULTS: Businesses supporting YPAO had larger annual operating (F = 7.6; p = .018) and advertising budgets (F = 8.5; p = .009) and had younger owners (F = 6.1; p = .034), with sports backgrounds (chi(2) = 5.6; p = .018) and who felt businesses should support YPAO (chi(2) = 3.8; p = .048). Of the 46 businesses not supporting YPAO, 82.6% felt small businesses should support YPAO. The major reasons for nonsupport were difficulty identifying YPAO to support and not being asked for support. CONCLUSIONS: Business (e.g., budgets) and business owner characteristics (e.g., age), owner connectedness with YPAO, and the approach used for garnering support (active solicitation, clearly defined support mechanism) were associated with supporting YPAO. Additional business (e.g., annual revenues), owner (e.g., perceptions of YPAO), and environmental (e.g., crime rate, land use) factors should be examined as potential correlates. PMID- 22548424 TI - Unwillingness to participate in colorectal cancer screening: examining fears, attitudes, and medical mistrust in an ethnically diverse sample of adults 50 years and older. AB - PURPOSE: Identify the influence of medical mistrust, fears, attitudes, and sociodemographic characteristics on unwillingness to participate in colorectal cancer (CRC) screening. DESIGN: Cross-sectional, disproportionally allocated, stratified, random-digit-dial telephone questionnaire of noninstitutionalized households. SETTING: New York City, New York; Baltimore, Maryland; San Juan, Puerto Rico. SUBJECTS: Ethnically diverse sample of 454 adults >=50 years of age. MEASURES: Health status, cancer screening effectiveness, psychosocial factors (e.g., perceptions of pain, fear, trust), and CRC screening intentions using the Cancer Screening Questionnaire, which addresses a range of issues related to willingness of minorities to participate in cancer screening. ANALYSIS: Multivariate logistic regression was used to model the probability of reporting unwillingness to participate in CRC screening. RESULTS: Fear of embarrassment during screening (odds ratio [OR] = 10.72; 95% confidence interval [CI], 2.15 53.39), fear of getting AIDS (OR = 8.75; 95% CI, 2.48-30.86), fear that exam might be painful (OR = 3.43; 95% CI, 1.03-11.35), and older age (OR = 1.10; 95% CI, 1.04-1.17) were positively associated with unwillingness to participate in CRC screening. Fear of developing cancer (OR = .12; 95% CI, .03-.57) and medical mistrust (OR = .19; 95% CI, .06-.60) were negatively associated with unwillingness to screen. CONCLUSIONS: Findings suggest that CRC health initiatives should focus on increasing knowledge, addressing fears and mistrust, and normalizing CRC screening as a beneficial preventive practice, and should increase focus on older adults. PMID- 22548425 TI - Associations between the worksite environment and perceived health culture. AB - PURPOSE: Recognition regarding the importance of health culture in the worksite health promotion literature is growing; however, little empirical evidence exists to guide programmatic or research efforts. The purpose of this study is to examine the relationship between the health supporting structural features of the workplace and perceived health culture. DESIGN: Cross-sectional. SAMPLE: Twenty one worksites with culture data from 2467 employees from Western New York. MEASURES: The Heart Check (HC) and Lifegain Health Culture Audit (LHCA) were used to assess worksite environment and worksite health culture, respectively. ANALYSIS: Pearson r was used to examine the associations between HC factors and LHCA mean scores. Multiple linear regression was used to predict LHCA mean scores from selected HC factors. RESULTS: Adjusting for age and gender, several significant correlations between HC and LHCA scores were identified, ranging from r = .54 (p < .05) to r = .72 (p < .001). The HC Environmental Structure factor (HCES) and HC Communication factor (HCC) were significantly correlated to LHCA scores (r = .55 and r = .72, respectively; p < .01) but not to each other. A regression model combining HCES and HCC was found to be predictive of LHCA score (R(2) = .69, p < .001). CONCLUSIONS: Modifiable components of the worksite environment are strongly and positively related to employee perceptions of the worksite health culture. PMID- 22548426 TI - A university system-wide qualitative investigation into student physical activity promotion conducted on college campuses. AB - PURPOSE: This study aimed to examine college student physical activity promotion. DESIGN: A cross-sectional approach to qualitative research was used. SETTING: Southeastern state university system. PARTICIPANTS: Fourteen of 15 (93%) universities recruited were included in this study; 22 university employees participated in a semistructured interview. METHOD: Nonprobabilistic purposive and snowball sampling strategies were used to recruit individuals who were likely to be engaged in physical activity promotion efforts on their respective campuses. Thematic analyses lead to the identification of emerging themes that were coded and analyzed using NVivo software. RESULTS: Themes informed three main areas: key personnel responsible for promoting physical activity to students, actual physical activity promotion efforts implemented, and factors that influence student physical activity promotion. Results suggest that ecological approaches to promote physical activity on college campuses are underused, the targeting of mediators of physical activity in college students is limited, and values held by university administration influence campus physical activity promotion. CONCLUSION: Findings support recommendations for future research and practice. Practitioners should attempt to implement social ecological approaches that target scientifically established mediators of physical activity in college students. Replication of this study is needed to compare these findings with other types of universities, and to investigate the relationship between promotion activities (type and exposure) and physical activity behaviors of college students. PMID- 22548427 TI - The effect of a designed health education intervention on physical activity knowledge and participation of adults with intellectual disabilities. AB - PURPOSE: The purpose of this study was to assess novel methods of health education and promotion to increase physical activity among adults with intellectual disabilities. DESIGN: A pre-post delayed treatment design was employed to assess the effect of the intervention. SETTING: The intervention was administered at two agencies that serve adults with intellectual disabilities. SUBJECTS: Forty-two adults ranging in age from 19 to 62 with mild to moderate intellectual disability participated in the study. Participants were equally divided by gender. INTERVENTION: An eight-session intervention employed a combination of video instruction, pictorial memory tools, and interactive class activities as educational methods. MEASURES: Physical activity knowledge was evaluated using Illingworth, Moore, and McGillivray's Nutrition Activity Knowledge Scale (NAKS) and the Physical Activity Recommendations Assessment (PARA). Average daily minutes of physical activity were measured using dual-axis accelerometers. ANALYSIS: Paired and independent samples t-tests were used to assess the knowledge scales. Wilcoxon signed-rank tests and Mann-Whitney U-tests were used to assess physical activity participation. RESULTS: Overall, there were mean improvements in scores for both the NAKS (p < .05) and the PARA (p < .001) following the intervention. Physical activity also improved, but not significantly. CONCLUSION: The education and training methods used in this curriculum are promising for future health education programs in this population. Additional interventions may be necessary to improve physical activity participation. PMID- 22548428 TI - Validation of the measures of the transtheoretical model for exercise in an adult African-American sample. AB - PURPOSE: African-Americans have high rates of physical inactivity-related morbidity and mortality, thus effective interventions to increase exercise are necessary. Tailored interventions show promise, but measures need validation in this population. This study validated transtheoretical model measures for exercise in an African-American sample. DESIGN: Cross-sectional measure development. SETTING: Telephone survey of individuals in North Carolina. SUBJECTS: 521 African-American adults. MEASURES: Stages of change, decisional balance (pros and cons), self-efficacy and processes of change (POC) for regular exercise. ANALYSIS: Confirmatory factor analyses tested measurement models. Multivariate analyses examined relationships between each construct and stages of change. RESULTS: For decisional balance, the two-factor uncorrelated model was the most parsimonious good-fitting model (chi(235) = 158.76; comparative fit index [CFI], .92; average absolute standardized residual [AASR], .04), and alphas were good (pros alpha = .85 and cons alpha = .74). The one-factor model for self efficacy (alpha = .80) revealed an excellent fit (chi(29) = 45.51; CFI, .96; AASR, .03). For the POC subscales with good alphas (alpha = .62-.91), a 10-factor fully correlated model fit best (chi(2)[360] = 786.75; CFI, .91; AASR, .04). Multivariate analyses by stage of change replicated expected patterns for the pros, self-efficacy, and POC measures with medium-sized effects (eta(2) = .05 .13). Results by stage of change did not replicate for the cons scale. CONCLUSIONS: The structures of these measures replicated with good internal and external validity, except for the cons scale, which requires additional development. Results support the use of these measures in tailored interventions to increase exercise among African-Americans. PMID- 22548431 TI - Multilevel analysis of the physical health perception of employees: community and individual factors. AB - PURPOSE: To investigate whether the communities where employees reside are associated with employee perception of overall physical health after adjusting for individual factors. DESIGN: Retrospective cross-sectional. SETTING: Active employees from a large manufacturing company representing 157 zip code tabulation areas (ZCTAs) in Michigan. PARTICIPANTS: 22,012 active employees who completed at least one voluntary health risk appraisal (HRA) during 1999-2001. METHOD: Community deprivation and racial segregation at the ZCTA level were obtained using indices created from 2000 U.S. Census data. Demographics and HRA-related data (health-related behaviors, medical history, and quality of life indicators) at the individual level were used as independent variables. A two-level logistic regression model (employees nested in ZCTA) was used to model the probability of better self-rated health perception (SRH) (better health: 89.1% versus poor health: 10.9%). RESULTS: Relative to those living in highly deprived communities, employees residing in less-deprived communities showed 2.06 (95% confidence interval [CI], 1.57-2.72) and those living in moderately deprived communities showed 1.83 (95% CI, 1.42-2.35) increased odds of better SRH. After adjusting for individual-level variables, employees living in less-deprived communities had increased odds (1.31 [95% CI, 1.07-1.60]) and those living in moderately deprived communities had increased odds (1.33 [95% CI, 1.11-1.59]) of better SRH compared with individuals from highly deprived communities. The association of racial segregation with employees' SRH was mediated after adjusting for other variables. Individual-level variables showed significant statistical associations with SRH. CONCLUSION: Communities do have a modest association with SRH of the employees living there. After adjusting for individual-level and demographic variables, employees living in less/moderately deprived communities are more likely to perceive better physical health relative to those who live in highly deprived communities. PMID- 22548432 TI - Urban environment and children's active lifestyle: softGIS revealing children's behavioral patterns and meaningful places. AB - PURPOSE: To determine the relationship between (1) urban structure characteristics, (2) children's environmental experiences and active behavioral patterns, and (3) perceived health and body mass index (BMI). DESIGN: Cross sectional study. SETTING: City of Turku, western coast of Finland, 175,000 inhabitants. Average residential density of the studied settings was 17 housing units per hectare, proportion of green structure 43%, and proportion of population under 15 years old 17%. SUBJECTS: One thousand eight hundred thirty seven fifth (10-12 years old) and seventh (13-15 years old) graders from 54 schools in Turku. MEASURES: Self-reported behavioral patterns (activity of school travel mode, territorial range, mobility licenses, and distance to meaningful places) and environmental experiences (localized meaningful places, likability index, environmental fears) were gathered on the basis of locality with an Internet-based softGIS method. Self-reported BMI, perceived health, and daily symptoms were also queried. Geographic information system-based measures of urban structure (residential density, proportion of green structure, proportion of children), calculated within a 500-m buffer of each respondent's home, were used as independent variables. ANALYSIS: Mainly logistic regression analysis. RESULTS: After controlling for gender, age, and neighborhood socioeconomic status (proportion of academically educated), residential density was significantly associated with active travel mode to school and short distances to the meaningful places of children. The proportions of green structure and children had an association with nonactive transport, long distance to meaningful places, and small territorial range. We also found significant associations between active school travel mode and reduced risk of being overweight when controlled for gender and age but not when the proportion of academically educated was also controlled. The negative association between likability index and daily symptoms and positive association with perceived health remained significant after controlling for all three background variables. The only urban structure variable directly associated with good perceived health was the proportion of green structure around the child's home. CONCLUSION: Moderate urban density seems to have child-friendly characteristics such as an ability to promote active school journeys and to guarantee a short distance to meaningful places. The studied Finnish children expressed very few environmental fears, and the possibilities for them to independently use the opportunities of the urban environment were very high. The limitation of the study was that the socioeconomic background variables were extracted from register-based geographic grid data rather than from respondents. More refined measures of urban structure are also needed in future studies. PMID- 22548434 TI - Financial incentives for workplace health promotion: what is equitable, what is sustainable, and what drives healthy behaviors? PMID- 22548435 TI - A discussion with James O. Prochaska, PhD. Interview by Paul E. Terry. PMID- 22548436 TI - Comparison of body weight distribution, peak vertical force, and vertical impulse as measures of hip joint pain and efficacy of total hip replacement. AB - OBJECTIVE: To determine whether there is a difference between the ability of peak vertical force (PVF), vertical impulse (VI), and percentage body weight distribution (%BW(dist) ) in differentiating which leg is most affected by hip joint pain before total hip replacement (THR) surgery, and for measuring changes in limb use after THR surgery. STUDY DESIGN: Prospective clinical study. ANIMALS: Dogs (n = 47). METHODS: Ground reaction force (GRF) data were collected using a pressure-sensitive walkway the day before THR surgery and at ~3, 6, and 12 months postoperatively. PVF and VI expressed as a percentage of body weight (%PVF, %VI), and %BW(dist) were recorded. Regression models performed separately for each outcome were used for statistical analysis. RESULTS: When comparing limb use between the affected limb (AP) and the nonaffected limb (NP) preoperatively, differences between limbs were statistically significant when evaluated using PVF (P = .023), VI (P = .010), and %BW(dist) (P = .012). When evaluating the magnitude of absolute and percentage change difference in AP limb use preoperatively versus postoperatively, differences were statistically significant when evaluated using PVF (P < .001 and P = .001, respectively), VI (P = .001 and P < .001) and %BW(dist) (P < .001 and P < .001). CONCLUSION: There appeared to be no difference in the sensitivity of VI, PVF, and %BW(dist) for evaluating limb use before and after THR. PMID- 22548438 TI - Should adjustment disorder be conceptualized as transitional disorder? In pursuit of adjustment disorders definition. AB - BACKGROUND: The DSM classification of an adjustment disorder is frequently criticized for not being well differentiated from other disorders. AIMS: A possible reason for this is the vague definition of the term adjustment in social science literature. Hence, the current paper discusses the definition of adjustment and its implications for understanding maladjustment. METHOD: Differential definitions of the terms adjustment, adaptation, socialization and coping are outlined, leading to the proposition that each one of them represents a different type of demand that is imposed on an individual who encounters a transitional event. Moreover, the four types of demands might be the possible sources of maladjustment. CONCLUSION: Helping people in transition requires an identification of the source, or combination of sources, that have led to the adjustment problem first, followed by the implementation of an adequate helping approach. PMID- 22548440 TI - Molecular spectroscopy. PMID- 22548441 TI - Microdroplet growth mechanism during water condensation on superhydrophobic surfaces. AB - By promoting dropwise condensation of water, nanostructured superhydrophobic coatings have the potential to dramatically increase the heat transfer rate during this phase change process. As a consequence, these coatings may be a facile method of enhancing the efficiency of power generation and water desalination systems. However, the microdroplet growth mechanism on surfaces which evince superhydrophobic characteristics during condensation is not well understood. In this work, the sub-10 MUm dynamics of droplet formation on nanostructured superhydrophobic surfaces are studied experimentally and theoretically. A quantitative model for droplet growth in the constant base (CB) area mode is developed. The model is validated using optimized environmental scanning electron microscopy (ESEM) imaging of microdroplet growth on a superhydrophobic surface consisting of immobilized alumina nanoparticles modified with a hydrophobic promoter. The optimized ESEM imaging procedure increases the image acquisition rate by a factor of 10-50 as compared to previous research. With the improved imaging temporal resolution, it is demonstrated that nucleating nanodroplets coalesce to create a wetted flat spot with a diameter of a few micrometers from which the microdroplet emerges in purely CB mode. After the droplet reaches a contact angle of 130-150 degrees , its base diameter increases in a discrete steplike fashion. The droplet height does not change appreciably during this steplike base diameter increase, leading to a small decrease of the contact angle. Subsequently, the drop grows in CB mode until it again reaches the maximum contact angle and increases its base diameter in a steplike fashion. This microscopic stick-and-slip motion can occur up to four times prior to the droplet coalescence with neighboring drops. Lastly, the constant contact angle (CCA) and the CB growth models are used to show that modeling formation of a droplet with a 150 degrees contact angle in the CCA mode rather than in the CB mode severely underpredicts both the drop formation time and the average heat transfer rate through the drop. PMID- 22548439 TI - Rapid identification of a novel small molecule phosphodiesterase 10A (PDE10A) tracer. AB - A radiolabeled tracer for imaging therapeutic targets in the brain is a valuable tool for lead optimization in CNS drug discovery and for dose selection in clinical development. We report the rapid identification of a novel phosphodiesterase 10A (PDE10A) tracer candidate using a LC-MS/MS technology. This structurally distinct PDE10A tracer, AMG-7980 (5), has been shown to have good uptake in the striatum (1.2% ID/g tissue), high specificity (striatum/thalamus ratio of 10), and saturable binding in vivo. The PDE10A affinity (K(D)) and PDE10A target density (B(max)) were determined to be 0.94 nM and 2.3 pmol/mg protein, respectively, using [(3)H]5 on rat striatum homogenate. Autoradiography on rat brain sections indicated that the tracer signal was consistent with known PDE10A expression pattern. The specific binding of [(3)H]5 to rat brain was blocked by another structurally distinct, published PDE10A inhibitor, MP-10. Lastly, our tracer was used to measure in vivo PDE10A target occupancy of a PDE10A inhibitor in rats using LC-MS/MS technology. PMID- 22548443 TI - Urethral distension as a novel method to simulate sphincter insufficiency in the porcine animal model. AB - OBJECTIVES: To describe a novel animal model of intrinsic sphincter deficiency. METHODS: The study was carried out on 10 female pigs. Injury to the urethral sphincter was induced by distension of the urethra. This was obtained by using the balloon of an 18-F Dufour catheter for 5 min followed by its retraction through the urethra without draining the balloon. The urethral pressure profile was evaluated before injury, immediately postinjury and at day 28 postinjury in the experimental group (n = 5), and on day 1 and day 28 in the control uninjured group (n = 5). The maximal urethral closure pressure, the functional urethral length and the area under curve of the urethral pressure profile were measured. RESULTS: The mean maximal urethral closure pressure at the beginning of the experiment was 32 cmH(2) O, and the mean functional urethral length was 4.88 cm. The assessment at day 28 showed a reduction of the maximal urethral closure pressure (50% of the control, P > 0.05), the functional urethral length (52.5% of the control, P < 0.05) and the area under curve (52% of the control, P < 0.05) in injured pigs. Histologically, a fibrosis of the sphincter was detected without rupture of the muscle layer in all the samples. CONCLUSIONS: The proposed porcine model can be used to obtain intrinsic sphincter deficiency-like urodynamic findings without rupturing the sphincter. This methodology can be applied to investigate therapies for intrinsic sphincter deficiency. PMID- 22548442 TI - Activin A promotes hematopoietic fated mesoderm development through upregulation of brachyury in human embryonic stem cells. AB - The development of the hematopoietic system involves multiple cellular steps beginning with the formation of the mesoderm from the primitive streak, followed by emergence of precursor populations that become committed to either the endothelial or hematopoietic lineages. A number of growth factors such as activins and fibroblast growth factors (FGFs) are known to regulate the early specification of hematopoietic fated mesoderm, notably in amphibians. However, the potential roles of these factors in the development of mesoderm and subsequent hematopoiesis in the human have yet to be delineated. Defining the cellular and molecular mechanisms by which combinations of mesoderm-inducing factors regulate this stepwise process in human cells in vitro is central to effectively directing human embryonic stem cell (hESC) hematopoietic differentiation. Herein, using hESC-derived embryoid bodies (EBs), we show that Activin A, but not basic FGF/FGF2 (bFGF), promotes hematopoietic fated mesodermal specification from pluripotent human cells. The effect of Activin A treatment relies on the presence of bone morphogenetic protein 4 (BMP4) and both of the hematopoietic cytokines stem cell factor and fms-like tyrosine kinase receptor-3 ligand, and is the consequence of 2 separate mechanisms occurring at 2 different stages of human EB development from mesoderm to blood. While Activin A promotes the induction of mesoderm, as indicated by the upregulation of Brachyury expression, which represents the mesodermal precursor required for hematopoietic development, it also contributes to the expansion of cells already committed to a hematopoietic fate. As hematopoietic development requires the transition through a Brachyury+ intermediate, we demonstrate that hematopoiesis in hESCs is impaired by the downregulation of Brachyury, but is unaffected by its overexpression. These results demonstrate, for the first time, the functional significance of Brachyury in the developmental program of hematopoietic differentiation from hESCs and provide an in-depth understanding of the molecular cues that orchestrate stepwise development of hematopoiesis in a human system. PMID- 22548444 TI - Genotypic variation in yellow autumn leaf colours explains aphid load in silver birch. AB - * It has been suggested that autumn-migrating insects drive the evolution of autumn leaf colours. However, evidence of genetic variation in autumn leaf colours in natural tree populations and the link between the genetic variation and herbivore abundances has been lacking. * Here, we measured the size of the whole aphid community and the development of green-yellow leaf colours in six replicate trees of 19 silver birch (Betula pendula) genotypes at the beginning, in the middle and at the end of autumn colouration. We also calculated the difference between green leaf and leaf litter nitrogen (N) and estimated the changes in phloem sap N loading. * Autumn leaf colouration had significant genetic variation. During the last survey, genotypes that expressed the strongest leaf reflectance 2-4 wk earlier had an abundance of egg-laying Euceraphis betulae females. Surprisingly, the aphid community size during the first surveys explained N loss by the litter of different birch genotypes. * Our results are the first evidence at the tree intrapopulation genotypic level that autumn migrating pests have the potential to drive the evolution of autumn leaf colours. They also stress the importance of recognizing the role of late-season tree insect interactions in the evolution of herbivory resistance. PMID- 22548445 TI - Neonatal hemifacial spasm and fourth ventricle mass. AB - Congential hemifacial spasm is a rare condition that is characterized by the occurrence of paroxysmal hemifacial contractions in neonates. We review the clinical, neurophysiological, neuroimaging, and histopathological findings, as well as the differential diagnosis, therapeutic approach, and outcome of all the described cases. Moreover, we report two new cases including the ictal video electroencephalography recordings. Hemifacial spasm starts early in life, and is characterized by unilateral, involuntary, irregular tonic or clonic contractions of muscles innervated by the seventh cranial nerve. Hemifacial spasm is associated with eyelid blinking, and sometimes with breathing irregularities, hyperventilation, and/or other neurological manifestations (dystonic movements, nystagmus). Interictal and ictal video-electroencephalography did not reveal epileptiform abnormalities. In all cases, brain magnetic resonance imaging showed a mass involving the cerebellar peduncle, the cerebellar hemisphere, or the floor of the fourth ventricle. The semiology of the paroxysmal attacks is probably due to the activation of cranial nerve nuclei through intralesional hypersynchronous discharges, as shown by the intraoperative recordings and functional brain imaging described in the literature. We point out the importance of identifying such seizures in order to make an early diagnosis of the underlying cerebral lesion. PMID- 22548446 TI - Transthoracic fine needle aspiration resulting in implantation metastasis in the superficial tissues of the breast. PMID- 22548447 TI - Extending foldamer design beyond alpha-helix mimicry: alpha/beta-peptide inhibitors of vascular endothelial growth factor signaling. AB - Diverse strategies have been explored to mimic the surface displayed by an alpha helical segment of a protein, with the goal of creating inhibitors of helix mediated protein-protein interactions. Many recognition surfaces on proteins, however, are topologically more complex and less regular than a single alpha helix. We describe efforts to develop peptidic foldamers that bind to the irregular receptor-recognition surface of vascular endothelial growth factor (VEGF). Our approach begins with a 19-residue alpha-peptide previously reported by Fairbrother et al. (Biochemistry 1998, 37, 17754) to bind to this surface on VEGF. Systematic evaluation of alpha->beta replacements throughout this 19-mer sequence enabled us to identify homologues that contain up to ~30% beta residues, retain significant affinity for VEGF, and display substantial resistance to proteolysis. These alpha/beta-peptides can block VEGF-stimulated proliferation of human umbilical vein endothelial cells. PMID- 22548448 TI - Influence of environmental heterogeneity on genetic diversity and structure in an endemic southern Californian oak. AB - Understanding how specific environmental factors shape gene flow while disentangling their importance relative to the effects of geographical isolation is a major question in evolutionary biology and a specific goal of landscape genetics. Here, we combine information from nuclear microsatellite markers and ecological niche modelling to study the association between climate and spatial genetic structure and variability in Engelmann oak (Quercus engelmannii), a wind pollinated species with high potential for gene flow. We first test whether genetic diversity is associated with climatic niche suitability and stability since the Last Glacial Maximum (LGM). Second, we use causal modelling to analyse the potential influence of climatic factors (current and LGM niche suitability) and altitude in the observed patterns of genetic structure. We found that genetic diversity is negatively associated with local climatic stability since the LGM, which may be due to higher immigration rates in unstable patches during favourable climatic periods and/or temporally varying selection. Analyses of spatial genetic structure revealed the presence of three main genetic clusters, a pattern that is mainly driven by two highly differentiated populations located in the northern edge of the species distribution range. After controlling for geographic distance, causal modelling analyses showed that genetic relatedness decreases with the environmental divergence among sampling sites estimated as altitude and current and LGM niche suitability. Natural selection against nonlocal genotypes and/or asynchrony in reproductive phenology may explain this pattern. Overall, this study suggests that local environmental conditions can shape patterns of genetic structure and variability even in species with high potential for gene flow and relatively small distribution ranges. PMID- 22548449 TI - Association of polymorphisms in calpain 1, (mu/I) large subunit, calpastatin, and cathepsin D genes with meat quality traits in double-muscled Piemontese cattle. AB - Five single-nucleotide polymorphisms (SNPs) located in the calpain 1, (mu/I) large subunit (CAPN1), calpastatin (CAST), and cathepsin D (CTSD) genes were analyzed in a large sample of Piemontese cattle. The aim of this study was to evaluate allele and genotype frequencies of these SNPs and to investigate associations of CAPN1, CAST, and CTSD gene variants with meat quality traits. Minor allele frequencies ranged from 30 to 48%. The presence of the A allele at CAPN530 increased yellowness and drip loss. The CAST282 G allele was associated with an increased drip loss compared to the C allele, and the CAST2959 A allele decreased redness compared to the G allele. PMID- 22548450 TI - Co2+/Co+ redox tuning in methyltransferases induced by a conformational change at the axial ligand. AB - Density functional theory and quantum mechanics/molecular mechanics computations predict cob(I)alamin (Co(+)Cbx), a universal B(12) intermediate state, to be a pentacoordinated square pyramidal complex, which is different from the most widely accepted viewpoint of its tetracoordinated square planar geometry. The square pyramidality of Co(+)Cbx is inspired by the fact that a Co(+) ion, which has a dominant d(8) electronic configuration, forms a distinctive Co(+)--H interaction because of the availability of appropriately oriented filled d orbitals. This uniquely H-bonded Co(+)Cbx may have catalytic relevance in the context of thermodynamically uphill Co(2+)/Co(+) reduction that constitutes an essential component in a large variety of methyltransferases. PMID- 22548451 TI - Tough and transparent nylon-6 electrospun nanofiber reinforced melamine formaldehyde composites. AB - The use of nylon-6 electrospun nanofiber mats as reinforcement with synergistic effect in tensile strength and toughness for melamine-formaldehyde (MF) resin is highlighted in this article. Interestingly, there was a drastic effect of the wetting procedure of reinforcing fiber mat by the MF resin on the morphology and mechanical properties of the composites. The wetting of nylon fibers by passing through a solution of MF resin showed a core-shell morphology and a significant improvement in properties as compared to the dip-coating procedure for wetting of the fibers. Depending on the wt% of reinforcing nylon fiber mats, the composites could be considered as either fiber reinforced MF composites or MF glued nylon fibers. PMID- 22548453 TI - Pagetoid reticulosis in a prepubescent boy successfully treated with photodynamic therapy. AB - Pagetoid reticulosis or Woringer-Kolopp disease (WKD) is a rare variant of mycosis fungoides, consisting of localized patches or plaques containing intraepidermal proliferations of neoplastic T cells in a pagetoid distribution (similar to that of the adenocarcinomatous cells found in Paget disease of the nipple), which typically affects middle-aged and elderly men. We report a trial of photodynamic therapy (PDT) with topical aminolaevulinic acid (ALA), carried out on a 10-year-old boy with a solitary lesion of WKD on his foot, to avoid the long-term problems associated with the typical treatments for WKD of surgery and/or local irradiation. The plaque progressively flattened during treatment, and after nine PDT sessions over 13 months, the patient was clinically free of disease. PDT may be a viable alternative to surgery and local irradiation for localized cutaneous T-cell lymphoma, including WKD, especially in younger patients. PMID- 22548454 TI - N,N-addition of frustrated Lewis pairs to nitric oxide: an easy entry to a unique family of aminoxyl radicals. AB - The intramolecular cyclohexylene-bridged P/B frustrated Lewis pair [Mes(2)P C(6)H(10)-B(C(6)F(5))(2)] 1b reacts rapidly with NO to give the persistent FLP-NO aminoxyl radical 2b formed by P/B addition to the nitrogen atom of NO. This species was fully characterized by X-ray diffraction, EPR and UV/vis spectroscopies, C,H,N elemental analysis, and DFT calculations. The reactive oxygen-centered radical 2b undergoes a H-atom abstraction (HAA) reaction with 1,4 cyclohexadiene to give the diamagnetic FLP-NOH product 3b. FLP-NO 2b reacts with toluene at 70 degrees C in an HAA/radical capture sequence to give a 1:1 mixture of FLP-NOH 3b and FLP-NO-CH(2)Ph 4b, both characterized by X-ray diffraction. Structurally related FLPs [Mes(2)P-CHR(1)-CHR(2)-B(C(6)F(5))(2)] 1c, 1d, and 1e react analogously with NO to give the respective persistent FLP-NO radicals 2c, 2d, and 2e, respectively, which show similar HAA and O-functionalization reactions. The FLP-NO-CHMePh 6b derived from 1-bromoethylbenzene undergoes NO-C bond cleavage at 120 degrees C with an activation energy of E(a) = 35(2) kcal/mol. Species 6b induces the controlled nitroxide-mediated radical polymerization (NMP) of styrene at 130 degrees C to give polystyrene with a polydispersity index of 1.3. The FLP-NO systems represent a new family of aminoxyl radicals that are easily available by N,N-cycloaddition of C(2)-bridged intramolecular P/B frustrated Lewis pairs to nitric oxide. PMID- 22548455 TI - Evaluating the effectiveness of an integrated community continuum of care program for individuals with serious mental illness. AB - OBJECTIVE: To evaluate effectiveness of an "Continuum of Care Program" (CCCP) for persons with serious mental health conditions in reducing inpatient use, and building a continuum of integrated care that enhanced employment and residential stability. The program combined components of Assertive Community Treatment with a comprehensive wrap-around program. METHODS: A cohort of 1154 individuals admitted to four outpatient CCCPs between December 2003 and May 31 2004 was identified and followed for 1 year. Outcome measures included clinical functioning level, drug/alcohol use, employment, residential arrangement and inpatient use. Regression was employed to explain changes in outcomes between baseline and follow-up as a function of services. RESULTS: Statistically significant changes were seen over a 1-year period in all outcomes. Housing, employment and mental health improved, whereas inpatient utilization and level of care need increased. Older individuals receiving higher levels of care at baseline and those with higher case management and medical service utilization reported higher inpatient use. Outcomes also varied by provider suggesting the contribution of workforce differences to outcomes. CONCLUSIONS: Although significant, changes in outcomes were small. Outcome effectiveness was mixed and generally unrelated to services. These findings imply that significant changes in outcomes may require several years to obtain. PMID- 22548456 TI - Developmental Therapeutics Consortium report on study design effects on trial outcomes in chronic myeloid leukaemia. AB - BACKGROUND: Tyrosine kinase inhibitors (TKIs) have dramatically changed the treatment of chronic myeloid leukaemia (CML). Results from ongoing phase 3 trials with nilotinib [Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd)] and dasatinib [Dasatinib Versus Imatinib Study in Treatment-Naive CML CP Patients (DASISION)] in newly diagnosed patients with CML in chronic phase have demonstrated that these TKIs resulted in significant improvements in responses vs. imatinib. DESIGN: The Developmental Therapeutics Consortium (DTC) systematically reviewed the published literature to provide a comparative analysis of the ENESTnd and DASISION trial designs and data reported on each study. RESULTS: The recent approval of nilotinib and dasatinib based on these two pivotal studies offers physicians the option to optimise frontline treatment based on a patient's comorbidities, risk factors and tolerability profiles. Although nilotinib and dasatinib provide effective therapeutic options for the frontline treatment of CML, the lack of an evidenced-based, side-by-side comparison makes it difficult to directly compare these agents. CONCLUSIONS: Despite potential bias from differences in patient populations and study design, indirect cross-trial comparisons to determine the relative effectiveness of these agents will be performed by physicians. This DTC report provides a comprehensive summary of the study designs, protocols and results of the ENESTnd and DASISION trials, which will assist physicians in making informed decisions on the best treatment approach for their patients. PMID- 22548457 TI - Design, synthesis, and pharmacological characterization of indol-3-ylacetamides, indol-3-yloxoacetamides, and indol-3-ylcarboxamides: potent and selective CB2 cannabinoid receptor inverse agonists. AB - In our search for new cannabinoid receptor modulators, we describe herein the design and synthesis of three sets of indole-based ligands characterized by an acetamide, oxalylamide, or carboxamide chain, respectively. Most of the compounds showed affinity for CB2 receptors in the nanomolar range, with K(i) values spanning 3 orders of magnitude (377-0.37 nM), and moderate to good selectivity over CB1 receptors. Their in vitro functional activity as inverse agonists was confirmed in vivo in the formalin test of acute peripheral and inflammatory pain in mice, in which compounds 10a and 11e proved to be able to reverse the effect of the CB2 selective agonist COR167. PMID- 22548458 TI - Menispermaceae and the diversification of tropical rainforests near the Cretaceous-Paleogene boundary. AB - * Modern tropical rainforests have the highest biodiversity of terrestrial biomes and are restricted to three low-latitude areas. However, the actual timeframe during which tropical rainforests began to appear on a global scale has been intensely disputed. Here, we used the moonseed family (Menispermaceae), an important physiognomic and structural component of tropical rainforests on a worldwide basis, to obtain new insights into the diversification of this biome. * We integrated phylogenetic, biogeographic and molecular dating methods to analyse temporal and spatial patterns of global diversification in Menispermaceae. * Importantly, a burst of moonseed diversification occurred in a narrow window of time, which coincides with the Cretaceous-Paleogene (K-Pg) boundary. Our data also suggest multiple independent migrations from a putative ancestral area of Indo-Malay into other tropical regions. * Our data for Menispermaceae suggest that modern tropical rainforests may have appeared almost synchronously throughout the three major tropical land areas close to, or immediately following, the K-Pg mass extinction. PMID- 22548459 TI - Increase lymphangiogenesis in melanoma during pregnancy: correlation with the prolactin signalling pathway. PMID- 22548460 TI - Development of a fast screening and confirmatory method by liquid chromatography quadrupole-time-of-flight mass spectrometry for glucuronide-conjugated methyltestosterone metabolite in tilapia. AB - This paper describes the development of a fast method to screen and confirm methyltestosterone 17-O-glucuronide (MT-glu) in tilapia bile. The method consists of solid-phase extraction (SPE) followed by high-performance liquid chromatography-mass spectrometry. The system used was an Agilent 6530 Q-TOF with an Agilent Jet stream electrospray ionization interface. The glucuronide detected in the bile was characterized as MT-glu by comparison with a chemically synthesized standard. MT-glu was detected in bile for up to 7 days after dosing. Semiquantification was done with matrix-matched calibration curves, because MT glu showed signal suppression due to matrix effects. This method provides a suitable tool to monitor the illegal use of methyltestosterone in tilapia culture. PMID- 22548462 TI - NMR in chemistry--an evergreen. PMID- 22548461 TI - Health at the margins of migration: culture-centered co-constructions among Bangladeshi immigrants. AB - Increasingly, health scholars have been paying attention to the health experiences of immigrant communities, particularly in the backdrop of the increasing global flows of goods, services, and people across borders. In spite of the increasing public health emphasis on health outcomes of immigrants within the United States, immigrant communities are often constructed as monoliths and the voices of immigrant communities are traditionally absent from mainstream health policy and program discourses. The health experiences of immigrants, their access to resources, and the health trajectories through the life course followed by them and their descendants influence the deep-seated patterns of ethnic health disparities documented in the United States. It is against this backdrop then that the co-constructions of experiences of health among immigrants offer an entry point for understanding the intersections of migration and health, particularly as these intersections offer guidance for the development of culturally situated policies and programs. Based on the culture-centered approach, we seek to understand how low-income Bangladeshi immigrants in New York City, who live at the borders of mainstream American society, define, construct, and negotiate health issues through co-constructions of their localized experiences of health. PMID- 22548464 TI - Amine-functionalized SBA-15 with uniform morphology and well-defined mesostructure for highly sensitive chemosensors to detect formaldehyde vapor. AB - Amine-functionalized SBA-15 with uniform morphology and well-defined mesostructure was prepared using a postgrafting route. The morphology, mesostructure, and functionality of the materials were characterized by scanning electron microscopy, transmission electron microscopy, small-angle X-ray scattering, nitrogen adsorption-desorption, Fourier transform infrared spectroscopy, and solid-state nuclear magnetic resonance spectroscopy techniques. The results show that hexagonal lamelliform SBA-15 with a uniform particle size and short vertical channels plays two significant roles in uniformly dispersing amine-functionalizing groups and effectively adjusting the loadings of the functional groups within the mesopore channels. To confirm the potential application of the hybrids in gas sensors, using amine-functionalized SBA-15 as a sensing material and a quartz crystal microbalance as a transducer, a parts per billion level formaldehyde sensor with high sensitivity (response time about 11 s, recovery time about 15 s) and good chemoselectivity was achieved. This material holds great potential in the area of rapid, sensitive, and highly convenient formaldehyde detection. PMID- 22548463 TI - Therapist and patient perspectives on cognitive-behavioral therapy for older adults with hoarding disorder: a collective case study. AB - Utilizing a qualitative approach, the current study explored therapist and patient perspectives on a specialized cognitive-behavioral therapy (CBT) protocol for clinically significant hoarding in older adult patients. Data were derived from the following sources: (1) therapist observation; (2) CBT consultant observation; (3) clinical treatment notes; (4) participant feedback, including a focus group; and (5) participant in-session notes and completed homework assignments. Our findings showed that the value of homework, treatment session compliance, and deficits in executive functioning (prospective memory, planning, problem solving, and cognitive flexibility) were common themes among participants as viewed by the therapist. Patients reported that exposure exercises and the therapeutic relationship were the most helpful aspects of their treatment, while cognitive strategies had limited success. Our results suggest that treatment for hoarding in older adults may be improved by focusing on exposure therapy elements, remediating executive function deficits, providing simplified homework assignments, and decreasing the emphasis or modifying cognitive restructuring techniques. PMID- 22548465 TI - Safety of autologous bone marrow stromal cell transplantation in dogs with acute spinal cord injury. AB - OBJECTIVE: To assess the feasibility and safety of transplantation of autologous bone marrow stromal cell (BMSC) in dogs with acute spinal cord injury (SCI). STUDY DESIGN: An open-label single-arm trial. ANIMALS: Dogs (n = 7) with severe SCI from T6 to L5, caused by vertebral fracture and luxation. METHODS: Decompressive and stabilization surgery was performed on dogs with severe SCI caused by vertebral fracture and luxation. Autologous BMSCs were obtained from each dog's femur, cultured, and then injected into the lesion in the acute stage. Adverse events and motor and sensory function were observed for >1 year after SCI. RESULTS: Follow-up was 29-62 months after SCI. No complications (eg, infection, neuropathic pain, worsening of neurologic function) were observed. Two dogs walked without support, but none of the 7 dogs had any change in sensory function. CONCLUSIONS: Autologous BMSC transplantation is feasible and safe in dogs with acute SCI. Further studies are needed to determine the efficacy of this therapy. PMID- 22548466 TI - Dispersal and gene flow in the rare, parasitic Large Blue butterfly Maculinea arion. AB - Dispersal is crucial for gene flow and often determines the long-term stability of meta-populations, particularly in rare species with specialized life cycles. Such species are often foci of conservation efforts because they suffer disproportionally from degradation and fragmentation of their habitat. However, detailed knowledge of effective gene flow through dispersal is often missing, so that conservation strategies have to be based on mark-recapture observations that are suspected to be poor predictors of long-distance dispersal. These constraints have been especially severe in the study of butterfly populations, where microsatellite markers have been difficult to develop. We used eight microsatellite markers to analyse genetic population structure of the Large Blue butterfly Maculinea arion in Sweden. During recent decades, this species has become an icon of insect conservation after massive decline throughout Europe and extinction in Britain followed by reintroduction of a seed population from the Swedish island of Oland. We find that populations are highly structured genetically, but that gene flow occurs over distances 15 times longer than the maximum distance recorded from mark-recapture studies, which can only be explained by maximum dispersal distances at least twice as large as previously accepted. However, we also find evidence that gaps between sites with suitable habitat exceeding ~20km induce genetic erosion that can be detected from bottleneck analyses. Although further work is needed, our results suggest that M. arion can maintain fully functional metapopulations when they consist of optimal habitat patches that are no further apart than ~10km. PMID- 22548467 TI - High-pressure rate rules for alkyl + O2 reactions. 2. The isomerization, cyclic ether formation, and beta-scission reactions of hydroperoxy alkyl radicals. AB - The unimolecular reactions of hydroperoxy alkyl radicals (QOOH) play a central role in the low-temperature oxidation of hydrocarbons as they compete with the addition of a second O(2) molecule, which is known to provide chain-branching. In this work we present high-pressure rate estimation rules for the most important unimolecular reactions of the beta-, gamma-, and delta-QOOH radicals: isomerization to RO(2), cyclic ether formation, and selected beta-scission reactions. These rate rules are derived from high-pressure rate constants for a series of reactions of a given reaction class. The individual rate expressions are determined from CBS-QB3 electronic structure calculations combined with canonical transition state theory calculations. Next we use the rate rules, along with previously published rate estimation rules for the reactions of alkyl peroxy radicals (RO(2)), to investigate the potential impact of falloff effects in combustion/ignition kinetic modeling. Pressure effects are examined for the reaction of n-butyl radical with O(2) by comparison of concentration versus time profiles that were obtained using two mechanisms at 10 atm: one that contains pressure-dependent rate constants that are obtained from a QRRK/MSC analysis and another that only contains high-pressure rate expressions. These simulations reveal that under most conditions relevant to combustion/ignition problems, the high-pressure rate rules can be used directly to describe the reactions of RO(2) and QOOH. For the same conditions, we also address whether the various isomers equilibrate during reaction. These results indicate that equilibrium is established between the alkyl, RO(2), and gamma- and delta-QOOH radicals. PMID- 22548468 TI - Direct measurement of glyconanoparticles and lectin interactions by isothermal titration calorimetry. AB - Glyconanomaterials have shown high potential in applications including bioanalysis and nanomedicine. Here, a quantitative analytical technique, based on isothermal titration calorimetry, was developed to characterize the interactions between glyconanoparticles and lectins. By titrating lectins into the glyconanoparticle solution, the apparent dissociation constant, thermodynamic parameters, and the number of binding sites were derived simultaneously. For the glyconanoparticles-lectin binding pairs investigated, a 3-5 order of magnitude affinity enhancement over the free ligand-lectin interactions was observed which can be attributed to the multivalent ligand presentation on the nanoparticles. The impact of ligand density was also studied, and results showed that the affinity increased with the number of glycans on the nanoparticle. PMID- 22548469 TI - Commentary: What is the optimal PPI dosing following endoscopic haemostasis in acute ulcer bleeding? PMID- 22548471 TI - Letter: Mucosal injury with exposure to low-dose nonsteroidals. PMID- 22548472 TI - Structural study on 2,2'-(methylimino)bis(N,N-dioctylacetamide) complex with Re(VII)O4- and Tc(VII)O4- by 1H NMR, EXAFS, and IR spectroscopy. AB - The structures of the complex of 2,2'-(methylimino)bis(N,N-dioctylacetamide) (MIDOA) with M(VII)O(4)(-) (M = Re and Tc), which were prepared by liquid-liquid solvent extraction, were investigated by using (1)H nuclear magnetic resonance (NMR), extended X-ray absorption fine structure (EXAFS), and infrared (IR) spectroscopy. The (1)H NMR spectra of the complex of MIDOA with Re(VII)O(4)(-) prepared in the organic solution suggest the transfer of a proton from aqueous to organic solution and the formation of the H(+)MIDOA ion. The EXAFS spectra of the complexes of H(+)MIDOA with Re(VII)O(4)(-) and Tc(VII)O(4)(-) show only the M-O coordination of the aquo complexes, suggesting that the chemical state of M(VII)O(4)(-) was unchanged during the extraction process. The results from (1)H NMR and EXAFS, therefore, provide evidence of M(VII)O(4)(-)...H(+)MIDOA complex formation in the organic solution. The IR spectra of Re(VII)O(4)(-)...H(+)MIDOA and Tc(VII)O(4)(-)...H(+)MIDOA were analyzed based on the structures and the IR spectra that were calculated at the B3LYP/cc-pVDZ level. Comparison of the observed and calculated IR spectra demonstrates that an intramolecular hydrogen bond is formed in H(+)MIDOA, and the M(VII)O(4)(-) ion interacts with H(+)MIDOA through multiple C-H(n)...O hydrogen bonds. PMID- 22548473 TI - Highly sensitive surface-enhanced Raman spectroscopy (SERS) platforms based on silver nanostructures fabricated on polyaniline membrane surfaces. AB - Here, we demonstrate a facile synthesis of homogeneous Ag nanostructures fully covering the polyaniline (PANI) membrane surface simply by introducing organic acid in the AgNO(3) reaction solution, as an improved technique to fabricate well defined Ag nanostructures on PANI substrates through a direct chemical deposition method [Langmuir2010, 26, 8882]. It is found that the chemical nature of the acid is crucial to create a homogeneous nucleation environment for Ag growth, where, in this case, homogeneous Ag nanostructures that are assembled by Ag nanosheets are produced with the assistance of succinic acid and lactic acid, but only scattered Ag particles with camphorsulfonic acid. Improved surface wettability of PANI membranes after acid doping may also account for the higher surface coverage of Ag nanostructures. The Ag nanostructures fully covering the PANI surface are extremely sensitive in the detection of a target analyte, 4-mercaptobenzoic acid (4-MBA), using surface-enhanced Raman spectroscopy (SERS), with a detection limit of 10(-12) M. We believe the facilely fabricated SERS-active substrates based on conducting polymer-mediated growth of Ag nanostructures can be promising in the trace detection of chemical and biological molecules. PMID- 22548475 TI - Rapid cycling bipolar affective disorder and recurrent strokes secondary to high blood homocysteine. AB - INTRODUCTION: The interface between psychiatric disorders and organicity has been a matter for contentious debate. AIM: To report an interesting clinical case of moderate homocystinuria presenting with significant psychiatric and neurological deficits. METHOD: A case report highlighting the impact of homocystinuria on producing intractable rapid cycling bipolar affective disorder. DISCUSSION: Homocystinuria is a frequently missed cause for treatment-resistant bipolar affective disorder. PMID- 22548477 TI - Copper-catalyzed double borylation of silylacetylenes: highly regio- and stereoselective synthesis of syn-vicinal diboronates. AB - Phosphite-copper(I) complexes efficiently catalyzed the double borylation of internal silylated alkynes to provide vicinal diboronates with excellent regio- and stereoselectivity. The copper-catalyzed reaction between bis(pinacolato)diboron (B2pin2) and aryl-substituted silylacetylenes in the presence of MeOH resulted in double syn addition of the pinacolboronate moiety (Bpin) and H across the triple bond with complete selectivity. While the double borylation was highly efficient for aryl-substituted alkynylsilanes and silylacetylene, only monoborylation took place with alkyl-substituted alkynylsilanes to yield (Z)-(beta-borylvinyl)silanes under the developed catalytic conditions. PMID- 22548476 TI - Ultrasensitive detection of scrapie prion protein derived from ARQ and AHQ homozygote sheep by interspecies in vitro amplification. AB - Prions, infectious agents causing TSEs, are composed primarily of the pathogenic form (PrP(Sc)) of the PrP(C). The susceptibility of sheep to scrapie is determined by polymorphisms in the coding region of the PRNP, mainly at codons 136, 154, and 171. The efficiency of in vitro amplification of sheep PrP(Sc) seems to be linked also to the PrP genotype. PrP(Sc) derived from sheep with V(136)R(154)Q(171)-associated genotypes can be amplified efficiently by PMCA in the presence of additional polyanion such as poly A, but there are no reports that cite ultrasensitive detection of PrP(Sc) derived from sheep of other PrP genotypes. We report here that sheep PrP(Sc) derived from ARQ and AHQ homozygotes was amplified efficiently by serial PMCA using mouse brain homogenate as PrP(C) substrate. ARQ/ARQ PrP(Sc) was detected in infected brain homogenates diluted up to 10(-10) after five rounds of amplification, and AHQ/AHQ PrP(Sc) was detected in samples diluted up to 10(-8) after four rounds of amplification. On the other hand, amplification of PrP(Sc) from VRQ/ARQ sheep seemed to be less efficient under the experimental conditions used. The interspecies PMCA developed in this study may be useful in the detailed analysis of PrP(Sc) distribution in classical scrapie-infected ARQ and AHQ homozygote sheep. PMID- 22548478 TI - Photoelectrochemical water oxidation with photosystem II integrated in a mesoporous indium-tin oxide electrode. AB - We report on a hybrid photoanode for water oxidation consisting of a cyanobacterial photosystem II (PSII) from Thermosynechococcus elongatus on a mesoporous indium-tin oxide (mesoITO) electrode. The three-dimensional metal oxide environment allows for high protein coverage (26 times an ideal monolayer coverage) and direct (mediator-free) electron transfer from PSII to mesoITO. The oxidation of water occurs with 1.6 +/- 0.3 MUA cm(-2) and a corresponding turnover frequency of approximately 0.18 +/- 0.04 (mol O(2)) (mol PSII)(-1) s(-1) during red light irradiation. Mechanistic studies are consistent with interfacial electron transfer occurring not only from the terminal quinone Q(B), but also from the quinone Q(A) through an unnatural electron transfer pathway to the ITO surface. PMID- 22548479 TI - Dermal dendrocytes FXIIIA+ phagocytizing extruded mast cell granules in drug induced acute urticaria. AB - BACKGROUND: Few authors have been attempting between mast cells and dermal dendrocytes interactions on urticaria. OBJECTIVE: To describe the extruded mast cell granules and dermal dendrocytes in drug-induced acute urticaria. METHODS: Seven patients with drug-induced acute urticaria were enrolled in the study. We token skin biopsies of urticaria lesion and perilesional skin. The 14 fragments collected were processed to immunogold electron microscopy using single stains to tryptase and FXIIIa, besides double immunogold labeling with both. RESULTS: Some sections demonstrated mast cells in degranulation process, both in anaphylactic and piecemeal degranulation types. After double immunogold staining, 10 nm (FXIIIa) and 15 nm (Tryptase) gold particles were present together over the granules in mast cells indicating that tryptase and FXIIIa are each localized within the granules of these cells. Interestingly, we found a strong evidence of than the exocytosed mast cell granules contents both FXIIIa and tryptase immunolabeled are phagocytized by dermal dendrocytes. CONCLUSIONS: The current observations provide morphological evidence that the exocytosis-phagocytosis mechanisms of mast cell granules represents one pathophysiological example of mast cells-dermal dendrocytes interactions in urticaria. PMID- 22548480 TI - Trigoflavidols A-C, degraded diterpenoids with antimicrobial activity, from Trigonostemon flavidus. AB - Trigoflavidols A (1) and B (2), tetranorditerpenoid dimers possessing a rearrangement skeleton with a spiroketal core moiety, and trigoflavidol C (3), a hexanorditerpenoid, have been isolated from Trigonostemon flavidus along with two known compounds. Compounds 1 and 2 showed moderate antimicrobial activities (MIC values: 3.12-6.25 MUg/mL) against Staphylococcus aureus, 8(#)MRSA, and 82(#)MRSA, and 1, 2, and 5 showed weak activities (IC(50) values: 3.75-28.99 MUM) against various human tumor cell lines. PMID- 22548481 TI - Local and systemic N signaling are involved in Medicago truncatula preference for the most efficient Sinorhizobium symbiotic partners. AB - * Responses of the Medicago truncatula-Sinorhizobium interaction to variation in N2-fixation of the bacterial partner were investigated. * Split-root systems were used to discriminate between local responses, at the site of interaction with bacteria, and systemic responses related to the whole plant N status. * The lack of N acquisition by a half-root system nodulated with a nonfixing rhizobium triggers a compensatory response enabling the other half-root system nodulated with N2-fixing partners to compensate the local N limitation. This response is mediated by a stimulation of nodule development (number and size) and involves a systemic signaling mechanism related to the plant N demand. In roots co-infected with poorly and highly efficient strains, partner choice for nodule formation was not modulated by the plant N status. However, the plant N demand induced preferential expansion of nodules formed with the most efficient partners when the symbiotic organs were functional. The response of nodule expansion was associated with the stimulation of symbiotic plant cell multiplication and of bacteroid differentiation. * A general model where local and systemic N signaling mechanisms modulate interactions between Medicago truncatula and its Sinorhizobium partners is proposed. PMID- 22548482 TI - Pleistocene and ecological effects on continental-scale genetic differentiation in the bobcat (Lynx rufus). AB - The potential for widespread, mobile species to exhibit genetic structure without clear geographic barriers is a topic of growing interest. Yet the patterns and mechanisms of structure--particularly over broad spatial scales--remain largely unexplored for these species. Bobcats occur across North America and possess many characteristics expected to promote gene flow. To test whether historical, topographic or ecological factors have influenced genetic differentiation in this species, we analysed 1 kb mtDNA sequence and 15 microsatellite loci from over 1700 samples collected across its range. The primary signature in both marker types involved a longitudinal cline with a sharp transition, or suture zone, occurring along the Great Plains. Thus, the data distinguished bobcats in the eastern USA from those in the western half, with no obvious physical barrier to gene flow. Demographic analyses supported a scenario of expansion from separate Pleistocene refugia, with the Great Plains representing a zone of secondary contact. Substructure within the two main lineages likely reflected founder effects, ecological factors, anthropogenic/topographic effects or a combination of these forces. Two prominent topographic features, the Mississippi River and Rocky Mountains, were not supported as significant genetic barriers. Ecological regions and environmental correlates explained a small but significant proportion of genetic variation. Overall, results implicate historical processes as the primary cause of broad-scale genetic differentiation, but contemporary forces seem to also play a role in promoting and maintaining structure. Despite the bobcat's mobility and broad niche, large-scale landscape changes have contributed to significant and complex patterns of genetic structure. PMID- 22548483 TI - Trend of blood pressure control status in hypertensive outpatients: with special reference to elderly hypertensives. AB - Blood pressure (BP) control in hypertensives has improved; however, it still remains to be insufficient. We have investigated the trend in BP control status of the hypertensive patients followed for 10 years in hypertension clinic. Subjects included 133 patients who have been followed from the first visit during 1998-2000 to the last visit during 2008-2010. During the mean follow-up period of 10.5 years, average BP and body weight significantly (P < .01) decreased from 143 +/- 12/85 +/- 8 mm Hg to 129 +/- 14/68 +/- 11 mm Hg, and from 59.8 +/- 9.9 kg to 58.7 +/- 10.6 kg, respectively. The achievement rate of good BP control defined as <140/90 mm Hg and the number of antihypertensive drugs also increased significantly during this period (39.1%-77.5% and 1.3 +/- 1.0-2.2 +/- 1.1, respectively, P < .01). Blood pressure control improved and the number of antihypertensive drugs also increased in 45 patients who were older than 65 years at the last visit. The use of Ca channel blockers (CCBs), angiotensin II receptor antagonists, and diuretics increased significantly during this period. Results suggest that lifestyle modification including body weight reduction as well as intensive antihypertensive treatment contributed to the improved BP control in hypertensive patients including the elderly. PMID- 22548484 TI - Experimental and theoretical charge density distribution in a host-guest system: synthetic terephthaloyl receptor complexed to adipic acid. AB - The experimental charge density distributions in a host-guest complex have been determined. The host, 1,4-bis[[(6-methylpyrid-2-yl)amino]carbonyl]benzene (1) and guest, adipic acid (2). The molecular geometries of 1 and 2 are controlled by the presence in the complex of intermolecular hydrogen bonding interactions and the presence in the host 1 of intramolecular hydrogen bonding motifs. This system therefore serves as an excellent model for studying noncovalent interactions and their effects on structure and electron density, and the transferability of electron distribution properties between closely related molecules. For the complex, high resolution X-ray diffraction data created the basis for a charge density refinement using a pseudoatomic multipolar expansion (Hansen-Coppens formalism) against extensive low-temperature (T = 100 K) single-crystal X-ray diffraction data and compared with a selection of theoretical DFT calculations on the same complex. The molecules crystallize in the noncentrosymmetric space group P2(1)2(1)2(1) with two independent molecules in the asymmetric unit. A topological analysis of the resulting density distribution using the atoms in molecules methodology is presented along with multipole populations, showing that the host and guest structures are relatively unaltered by the geometry changes on complexation. Three separate refinement protocols were adopted to determine the effects of the inclusion of calculated hydrogen atom anisotropic displacement parameters on hydrogen bond strengths. For the isotropic model, the total hydrogen bond energy differs from the DFT calculated value by ca. 70 kJ mol(-1), whereas the inclusion of higher multipole expansion levels on anisotropic hydrogen atoms this difference is reduced to ca. 20 kJ mol(-l), highlighting the usefulness of this protocol when describing H-bond energetics. PMID- 22548485 TI - A painful blistering rash on the lower legs and perineum. PMID- 22548486 TI - A history of solution theory. PMID- 22548487 TI - Use of stable isotope dimethyl labeling coupled to selected reaction monitoring to enhance throughput by multiplexing relative quantitation of targeted proteins. AB - In this manuscript, we present a proof-of-concept study for targeted relative protein quantitation workflow using chemical labeling in the form of dimethylation, coupled with selected reaction monitoring (dimethyl-SRM). We first demonstrate close to complete isotope incorporation for all peptides tested. The accuracy, reproducibility, and linear dynamic range of quantitation are further assessed based on known ratios of nonhuman standard proteins spiked into human cerebrospinal fluid (CSF) as a model complex matrix. Quantitation reproducibility below 20% (CV < 20%) was obtained for analyte concentrations present at a dynamic range of 4 orders of magnitude lower than that of the background proteins. An error of less than 15% was observed when measuring the abundance of 44 out of 45 major human plasma proteins. Dimethyl-SRM was further examined by comparing the relative quantitation of eight proteins in human CSF with the relative quantitation obtained using synthetic heavy peptides coupled to stable isotope dilution-SRM (SID-SRM). Comparison between the two methods reveals that the correlation between dimethyl-SRM and SID-SRM is within 0.3-33% variation, demonstrating the accuracy of relative quantitation using dimethyl-SRM. Dimethyl labeling coupled with SRM provides a fast, convenient, and cost-effective alternative for relative quantitation of a large number of candidate proteins/peptides. PMID- 22548488 TI - Combination of Caspy2 and IP-10 gene therapy significantly improves therapeutic efficacy against murine malignant neoplasm growth and metastasis. AB - It has been shown that Caspy2, a zebrafish active caspase, can efficiently suppress the growth of malignant tumor. The present study was designed to test whether combined gene therapy with IP-10, a potent antitumor chemokine, and Caspy2 would improve therapy efficacy. Recombinant plasmid expressing both Caspy2 and IP-10 genes was mixed with DOTAP-cholesterol nanoparticles. Immunocompetent mice bearing CT26 colon carcinoma, B16-F10 melanoma, and 4T1 breast carcinoma were treated with the complex. We found that the combined gene therapy more efficiently inhibited tumor growth, while efficiently prolonging the survival of tumor-bearing animals, compared with monotherapy. Moreover, a significant reduction in spontaneous lung metastasis could be observed in the 4T1 breast carcinoma model. Infiltration of CD8(+) T lymphocytes was also observed. In addition, apoptotic cells were widely detected by TUNEL assay and caspase-3 immunostaining in coadministered tumor tissues. The combination treatment also successfully inhibited angiogenesis and tumor cell proliferation as assessed by CD31 and Ki-67 immunostaining, respectively. Furthermore, depletion of CD8(+) T lymphocytes could significantly abrogate the antitumor activity, whereas the depletion of CD4(+) cells or natural killer cells showed partial abrogation. Rechallenged CT26 tumors were rejected in all of the surviving mice treated by combination therapy. Our results suggest that combined therapy with Caspy2 and IP 10 can significantly enhance antitumor activity by acting as an immune response initiator, apoptosis inducer, and angiogenesis inhibitor, which may be important for further applications in clinical cancer therapy. PMID- 22548489 TI - Effects of hydrophobic substituents and salt on core-shell aggregates of hydrophobically modified chitosan: light scattering study. AB - In this study we examine two methods of enhancement of aggregation of hydrophobically modified chitosan in dilute aqueous solutions: by increasing the content of n-dodecyl substituents, favoring hydrophobic association, and by increasing the amount of added low molecular weight salt, screening the electrostatic repulsion between similarly charged aggregating chains. By static and dynamic light scattering it was demonstrated that at the growth of the content of hydrophobic groups in the polymer (2-4 mol %) and of the amount of salt in solution (0.025-0.1 M) the weight fraction of aggregates increases, but the aggregation number remains unchanged. This behavior was attributed to the core-shell structure of the aggregates, which provides a low surface energy and strong attraction of associating groups inside the core. At the same time, the effects of the content of hydrophobic groups in the polymer and the ionic strength of the solution on the radii of the aggregates are quite different. Increasing the content of hydrophobic groups induces growth of the gyration radii of the aggregates, but does not affect their hydrodynamic radii. These data suggest the expansion of the hydrophobic core of the aggregates and the contraction of their highly swollen shell. On the other hand, increasing the salt concentration leads to a decrease of both the gyration and hydrodynamic radii of the aggregates, which is due to partial screening of electrostatic repulsion between similarly charged units and lowering of the osmotic pressure of counterions confined inside the aggregates. PMID- 22548490 TI - Structure and properties of one-dimensional heterobimetallic polymers containing dicyanoaurate and dirhodium(II) fragments. AB - The synthesis and characterization of compound [Rh(2)(O(2)CEt)(4)(H(2)O)(2)] (1) and one-dimensional heterobimetallic polymers K(n){Rh(2)(O(2)CEt)(4)[Au(CN)(2)]}(n) (2) and K(n){Rh(2)(O(2)CMe)(4)[Au(CN)(2)]}(n).4nH(2)O (3), constructed from dirhodiumtetracarboxylato units, [Rh(2)(O(2)CR)(4)](+), and dicyanoaurate, [Au(CN)(2)](-), fragments are described. In both compounds 2 and 3 the resulting polymeric chains are nonlinear and have in common similar structural parameters, although the solid state supramolecular arrangement is very different. These structural differences explain the fact that complex 2 displays aurophilic interactions while this type of interactions are absent in complex 3. As a result, compound 2 shows rich blue luminescent properties whereas compound 3 is not luminescent. The electrical conductivity in solid state of compounds 2 and 3 is also studied. PMID- 22548491 TI - Challenges in international medicine: ethical dilemmas, unanticipated consequences, and accepting limitations. AB - While personal and organizational challenges occur in every area of health care, practitioners of international medicine face unique problems and dilemmas that are rarely discussed in training programs. Health professions schools, residency and fellowship programs, nongovernmental organizations (NGOs), and government programs have a responsibility to make those new to international medicine aware of the special circumstances that they may face and to provide methods for understanding and dealing with these circumstances. Standard "domestic" approaches to such challenges may not work in international medicine, even though these challenges may appear to be similar to those faced in other clinical settings. How should organizations ensure that well-meaning health intervention efforts do not cause adverse unintended sequelae? How should an individual balance respect for cultural uniqueness and local mores that may profoundly differ from his or her own beliefs, with the need to remain a moral agent true to one's self? When is acceptance the appropriate response to situations in which limitations of resources seem to preclude any good solution? Using a case-based approach, the authors discuss issues related to the four major international medicine domains: clinical practice (postdisaster response, resource limitations, standards of care), medical systems and systems development (prehospital care, wartime casualties, sustainable change, cultural awareness), teaching (instruction and local resources, professional preparation), and research (questionable funded studies, clinical trials, observational studies). It is hoped that this overview may help prepare those involved with international medicine for the challenges and dilemmas they may face and help frame their responses to these situations. PMID- 22548492 TI - First-degree relatives of patients with early-onset gastric carcinoma show even at young ages a high prevalence of advanced OLGA/OLGIM stages and dysplasia. AB - BACKGROUND: First-degree relatives (FDRs) of early-onset gastric carcinoma (EOGC) patients are at increased risk of cancer development. OLGA/OLGIM (Operative Link on Gastritis/Intestinal Metaplasia Assessment) classifications have been proposed for the identification of individuals at high risk of gastric cancer development. AIM: To estimate the prevalence and severity of premalignant conditions and lesions in FDRs of EOGC patients. METHODS: A case-control study was conducted encompassing 103 FDRs of EOGC patients (cases) and 101 age- and gender-matched controls, all submitted to upper GI endoscopy and OLGA and OLGIM used for staging as well as modified versions with exclusion of the biopsies from incisura angularis in the analysis. RESULTS: Helicobacter pylori infection was present in 82% of cases (P = 0.001). Atrophy was present in 70% of cases (OLGA stages I-IV). High-risk stages (III-IV) were identified only in cases (19%) (P < 0.001). Dysplasia was diagnosed only in cases (n = 7, P = 0.007). The application of OLGIM, modified OLGA and modified OLGIM classifications led to downgrade of stages in comparison with the original OLGA classification (27%, 15% and 30% respectively). In all classification systems, dysplastic lesions clustered (86%) in high-risk stages. CONCLUSIONS: FDRs of EOGC patients have, even at young ages, a high prevalence of H. pylori infection, high-risk OLGA and OLGIM stages and dysplasia. These patients should undergo accurate endoscopic observation with at least four biopsies in antrum and corpus to allow adequate staging and follow-up of premalignant conditions and lesions scored in high-risk stages, in accordance with international guidelines recently proposed. PMID- 22548493 TI - Compensatory immigration depends on adjacent population size and habitat quality but not on landscape connectivity. AB - 1. Populations experiencing localized mortality can recover in the short term by net movement of individuals from adjacent areas, a process called compensatory immigration or spillover. Little is known about the factors influencing the magnitude of compensatory immigration or its impact on source populations. Such information is important for understanding metapopulation dynamics, the use of protected areas for conservation, management of exploited populations and pest control. 2. Using two small, territorial damselfish species (Stegastes diencaeus and S. adustus) in their naturally fragmented habitat, we quantified compensatory immigration in response to localized mortality, assessed its impact on adjacent source populations and examined the importance of potential immigrants, habitat quality and landscape connectivity as limiting factors. On seven experimental sites, we repeatedly removed 15% of the initial population size until none remained and immigration ceased. 3. Immigrants replaced 16-72% of original residents in S. diencaeus and 0-69% in S. adustus. The proportion of the source population that immigrated into depleted areas varied from 9% to 61% in S. diencaeus and from 3% to 21% in S. adustus. In S. diencaeus, compensatory immigration was strongly affected by habitat quality, to a lesser extent by the abundance of potential immigrants and not by landscape connectivity. In S. adustus, immigration was strongly affected by the density of potential migrants and not by habitat quality and landscape connectivity. On two control sites, immigration in the absence of creation of vacancies was extremely rare. 4. Immigration occurred in response to localized mortality and was therefore compensatory. It was highly variable, sometimes producing substantial impacts on both depleted and source populations. The magnitude of compensatory immigration was influenced primarily by the availability of immigrants and by the potential improvement in territory quality that they could achieve by immigrating and not by their ability to reach the depleted area. PMID- 22548494 TI - Stent reconstruction of an injured parotid duct in a thoroughbred colt. AB - OBJECTIVE: To report successful use of stent repair for a chronically injured parotid duct in a thoroughbred colt. STUDY DESIGN: Clinical report. ANIMAL: A 2 year-old thoroughbred colt. METHODS: Chronic injury to the parotid duct was identified 4-cm caudal to the facial vessel notch on the ventral border of the right mandible. After careful surgical dissection of the surrounding firm fibrous tissue, the defect was temporarily stented using an 8-Fr human ureteral catheter (223600 ERU((r)) SOFT URETERAL((r)) , Laboratoires pharmaceutique, Betschdorf, France) to bridge the tissue loss. The rostral end of the catheter exited the oral cavity through a buccotomy stab incision at the level of the second premolar tooth of the maxilla. RESULTS: Primary wound healing occurred and the stent was maintained for 5 weeks with saliva drainage visible when the colt was fed. After stent removal, function was restored with good cosmesis. CONCLUSIONS: A tissue defect in the parotid duct can be repaired successfully by temporary use of a stent until wound healing occurs. PMID- 22548496 TI - Reactive arthritis: does screening stools by polymerase chain reaction for Shiga toxin-producing Escherichia coli (STEC) make sense? PMID- 22548495 TI - Detection and characterization of Shigella species isolated from food and human stool samples in Nabeul, Tunisia, by molecular methods and culture techniques. AB - AIMS: This study was designed to isolate Shigella spp. strains from food and stool samples by a combination of PCR and culture methods and characterize their serotypes, antibiotic resistance profiles, virulence genes and pulsed-field gel electrophoresis (PFGE) patterns to investigate possible clonal relationships amongst strains circulating. METHODS AND RESULTS: Six Shigella spp. strains were isolated from 280 food samples against 16 Shigella isolates from 236 stool samples of symptomatic patients and asymptomatic food handlers during the period from January 2007 to December 2009 in Public Health Regional Laboratory of Nabeul. The detection of ipaH, ipaBCD, ial, ShET-1 and ShET-2 was performed by a PCR technique with specific primers. CONCLUSIONS: The use of PCR technique improved the rate of detecting Shigella in stool samples from 6.7 to 14% and in food samples from 2.1 to 8.6%. Percentage of Shigella isolates and ipaH-specific PCR demonstrated a marked pattern of seasonality, increasing in summer and fall seasons for human and food isolates. Amongst the environmental strains, 50% of isolates were invasive. However, for the 16 clinical strains isolated, nine were found to be positive for both ial and ipaBCD gene and 11 were found to produce ShET-1 and/or ShET-2. XbaI PFGE analysis revealed the presence of a predominant clone amongst Shigella sonnei strains recovered from different sources circulating in Nabeul, Tunisia, throughout the years 2007-2009. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrated the existence of Shigella in food samples and dispersion of different virulence genes amongst these isolates, which appear to constitute an environmental source of epidemic spread. The clonal relationships amongst strains isolated from food elements and human stools indicate the incrimination of different kinds of foods as vehicle of transmission of Shigella, which are usually escaped from detection by traditional culture methods. PMID- 22548498 TI - Synthesis of natural cellulose-templated TiO2/Ag nanosponge composites and photocatalytic properties. AB - In this paper, TiO(2)/Ag sponge-like nanostructure composites have been prepared by the surface sol-gel method with the template of natural cellulose, which is relatively simple, low-cost, and environmentally friendly. The Ag nanoparticles are deposited on the TiO(2) nanosponges through UV irradiation photoreduction of silver nitrate solutions. The physicochemical properties of as-prepared composites are characterized by XRD, BET, SEM, TEM, XPS and UV-vis DRS techniques. The UV-light photocatalytic activities of the composites are evaluated through the photodegradation of two model organic molecules including RhB and salicylic acid. The experimental results show that the photocatalytic activities of TiO(2)/Ag nanosponge composites are superior to that of P25, pure TiO(2) nanoparticle aggregates synthesized by the hydrothermal method and pure TiO(2) nanosponge. The superior activities of TiO(2)/Ag nanosponge composite photocatalysts can be attributed to the unique nanosponge morphology, uniform dispersion of Ag nanoparticles, and strong interaction between Ag and TiO(2) nanosponges. PMID- 22548499 TI - Nonlinear optical molecular switches as selective cation sensors. AB - This work demonstrates that the recognition of cations by molecular switches can give rise to large contrasts of the second-order nonlinear optical (NLO) properties, which can therefore be used as a powerful and multi-usage detection tool. The proof of concept is given by evidencing, by means of ab initio calculations, the ability of spiropyran/merocyanine systems to selectively detect alkali, alkaline earth, and transition-metal cations. PMID- 22548500 TI - Metal-free ortho C-H borylation of 2-phenoxypyridines under mild conditions. AB - An efficient metal-free ortho C-H borylation has been developed via sequential borylation of substituted 2-phenoxypyridines with BBr3 following esterification with pinacol. The corresponding aryl boronates were obtained in good yields. The synthesized aryl boronates can be easily transformed into various useful products. Therefore, the present method makes functionalizations of aryl C-H bonds easy. PMID- 22548501 TI - PAP1 transcription factor enhances production of phenylpropanoid and terpenoid scent compounds in rose flowers. AB - * Floral scent is a complex trait of biological and applied significance. To evaluate whether scent production originating from diverse metabolic pathways (e.g. phenylpropanoids and isoprenoids) can be affected by transcriptional regulators, Arabidopsis PRODUCTION OF ANTHOCYANIN PIGMENT1 (PAP1) transcription factor was introduced into Rosa hybrida. * Color and scent profiles of PAP1 transgenic and control (beta-glucuronidase-expressing) rose flowers and the expression of key genes involved in the production of secondary metabolites were analyzed. To evaluate the significance of the scent modification, olfactory trials were conducted with both humans and honeybees. * In addition to increased levels of phenylpropanoid-derived color and scent compounds when compared with control flowers, PAP1-transgenic rose lines also emitted up to 6.5 times higher levels of terpenoid scent compounds. Olfactory assay revealed that bees and humans could discriminate between the floral scents of PAP1-transgenic and control flowers. * The increase in volatile production in PAP1 transgenes was not caused solely by transcriptional activation of their respective biosynthetic genes, but probably also resulted from enhanced metabolic flux in both the phenylpropanoid and isoprenoid pathways. The mechanism(s) governing the interactions in these metabolic pathways that are responsible for the production of specialized metabolites remains to be elucidated. PMID- 22548503 TI - Why research on resveratrol-mediated cardioprotection should not decelerate. PMID- 22548502 TI - Reaction to biological drugs: infliximab for the treatment of toxic epidermal necrolysis subsequently triggering erosive lichen planus. AB - Toxic epidermal necrolysis (TEN) is a rare, life-threatening skin reaction for which there is currently has no standardized treatment, despite its significant mortality. Biological agents such as tumour necrosis factor (TNF)-alpha antagonists are emerging as a novel treatment for patients with TEN. We report a 32-year-old woman who developed TEN secondary to sulfasalazine, which was treated with infliximab. The infliximab treatment subsequently triggered erosive lichen planus (LP) involving the mouth and vulva. Clinicians should be aware that TNF alpha antagonists can cause LP as a paradoxical complication of treatment. PMID- 22548504 TI - Enzymatic on-chip enhancement for high resolution genotyping DNA microarrays. AB - Antibiotic resistance among pathogenic microorganisms is emerging as a major human healthcare concern. While there are a variety of resistance mechanisms, many can be related to single nucleotide polymorphisms and for which DNA microarrays have been widely deployed in bacterial genotyping. However, genotyping by means of allele-specific hybridization can suffer from the drawback that oligonucleotide probes with different nucleotide composition have varying thermodynamic parameters. This results in unpredictable hybridization behavior of mismatch probes. Consequently, the degree of discrimination between perfect match and mismatch probes is insufficient in some cases. We report here an on-chip enzymatic procedure to improve this discrimination in which false-positive hybrids are selectively digested. We find that the application of CEL1 Surveyor nuclease, a mismatch-specific endonuclease, significantly enhances the discrimination fidelity, as demonstrated here on a microarray for the identification of variants of carbapenem resistant Klebsiella pneumoniae carbapenemases and monitored by end point detection of fluorescence intensity. Further fundamental investigations applying total internal reflection fluorescence detection for kinetic real-time measurements confirmed the enzymatic enhancement for SNP discrimination. PMID- 22548506 TI - The Way it was. PMID- 22548505 TI - Contrast agent Gd-EOB-DTPA (EOB.Primovist(r)) for low-field magnetic resonance imaging of canine focal liver lesions. AB - Contrast-enhanced magnetic resonance (MR) imaging with a new liver-specific contrast agent gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid (Gd EOB-DTPA; EOB.Primovist(r)) was studied in 14 normal beagles and 9 dogs with focal liver lesions. Gd-EOB-DTPA accumulates in normally functioning hepatocytes 20 min after injection. As with Gd-DTPA, it is also possible to perform a dynamic multiphasic examination of the liver with Gd-EOB-DTPA, including an arterial phase and a portal venous phase. First, a reliable protocol was developed and the appropriate timings for the dynamic study and the parenchymal phase in normal dogs using Gd-EOB-DTPA were determined. Second, the patterns of these images were evaluated in patient dogs with hepatic masses. The optimal time of arterial imaging was from 15 s after injection, and the optimal time for portal venous imaging was from 40 s after injection. Meanwhile, the optimal time to observe changes during the hepatobiliary phase was from 20 min after injection. In patient dogs, 11 lesions were diagnosed as malignant tumors; all were hypointense to the surrounding normal liver parenchyma during the hepatobiliary phase. Even with a low-field MR imaging unit, the sequences afforded images adequate to visualize the liver parenchyma and to detect tumors within an appropriate scan time. Contrast-enhanced MR imaging with Gd-EOB-DTPA provides good demarcation on low-field MR imaging for diagnosing canine focal liver lesions. PMID- 22548508 TI - Exploiting uncertain ecological fieldwork data with multi-event capture- recapture modelling: an example with bird sex assignment. AB - 1. Sex plays a crucial role in evolutionary life histories. However, the inclusion of sex in demographic analysis may be a challenge in fieldwork, particularly in monomorphic species. Although behavioural data may help us to sex individuals in the field, this kind of data is unlikely to be error free and is usually discarded. 2. Here we propose a multi-event capture-recapture model that enables us to exploit uncertain field observations regarding the sex of individuals based on behavioural or morphological criteria. The multi-event capture-recapture model allows us to account for sex uncertainty not restricting our ability to estimate the parameters of interest. In this case, by adding the confirmed sex of just a few individuals, we greatly improve the efficiency of the optimization algorithm. 3. Using such an approach, we analysed sex differences in demographic parameters (e.g. survival, transience and sex ratio) in a population of Audouin's gulls using observations from long-term fieldwork monitoring (1988 2007). We also assessed the probability of ascertaining sex over time and the probability of error for each field-sexing criterion. 4. We detected no strong effect of sex on either survival or transience probabilities, and both sexes showed a decreasing trend in survival over time and transience probability after recruitment increased with age and over time. The probability of ascertaining sex over time depended on observers' experience. Strikingly, courtship feeding (but not copulation) emerged as the most reliable clue for sexing individuals, which would suggest that Audouin's gulls engage in same-sex sexual behaviour such as same-sex mounting. 5. The present modelling emerged as a reliable method for estimating demographic parameters and state transition parameters in ecological studies in which field observations of sex or other individual states are assigned erroneously and uncertainly. This approach could also be useful for applied ecologists for assessing the reliability of their criteria for assigning sex or other individual covariates in the field, thereby permitting them to optimizing their field ecological protocols. PMID- 22548507 TI - Adsorption isotherms of cellulose-based polymers onto cotton fibers determined by means of a direct method of fluorescence spectroscopy. AB - We present a novel method for the measurement of polymer adsorption on fibers by employing fluorescently labeled polymers. The method itself can be used for any compound that either shows fluorescence or can be labeled with a fluorescent dye, which renders it ubiquitously applicable for adsorption studies. The main advantage of the method is that the choice of adsorbent is not limited to flat surfaces, thereby allowing the investigation of fibrous and porous systems. As an example of high interest for application we determined the adsorption isotherms of various polysaccharide-based polymers with different charges and different substituents on cotton fibers. These experiments show that the extent of adsorption depends not only on the charge conditions but also very much on the specific interactions between the polymer and fiber. For instance, the cationic hydroxyethyl cellulose can become bound to an extent similar to that of the anionic alginate, while the anionic carboxymethyl cellulose of similar charge density adsorbs much less under these conditions. This shows that the adsorption of polymers depends subtly on the details of the interaction between the polymer and fiber but can be determined with good precision with our direct fluorescence method. PMID- 22548509 TI - Shifting from the difficult patient to the difficult relationship: can ethics consultants really help? PMID- 22548510 TI - The "difficult" patient reconceived: an expanded moral mandate for clinical ethics. AB - Between 15 and 60% of patients are considered "difficult" by their treating physicians. Patient psychiatric pathology is the conventional explanation for why patients are deemed "difficult." But the prevalence of the problem suggests the possibility of a less pathological cause. I argue that the phenomenon can be better explained as a response to problematic interactions related to health care delivery. If there are grounds to reconceive the "difficult" patient as reacting to the perception of ill treatment, then there is an ethical obligation to address this perception of harm. Resolution of such conflicts currently lies with the provider and patient. But the ethical stakes place these conflicts into the province of the ethics consult service. As the resource for addressing ethical dilemmas, there is a moral mandate to offer assistance in the resolution of these ethically charged conflicts that is no less pressing than the more familiar terrain of clinical ethics consultation. PMID- 22548511 TI - "Difficult" patients or difficult relationships? PMID- 22548512 TI - Reconceiving the relationship and supporting physician responsibility. PMID- 22548513 TI - Reframing nonepileptic seizure patients' care: shifting the blame. PMID- 22548514 TI - Addressing "difficult patient" dilemmas: possible alternatives to the mediation model. PMID- 22548515 TI - Understanding communication to repair difficult patient-doctor relationships from within. PMID- 22548516 TI - Why some conflicts involving "'difficult' patients" should remain outside the province of the ethics consultation service. PMID- 22548517 TI - Difficult patients, difficult doctors: can consultants interrupt the "blame game"? PMID- 22548518 TI - Clinical ethics and patient satisfaction: the practical significance of distinguishing ethics and morals. PMID- 22548519 TI - Precommitting to serve the underserved. AB - In many countries worldwide, especially in sub-Saharan Africa, a shortage of physicians limits the provision of lifesaving interventions. One existing strategy to increase the number of physicians in areas of critical shortage is conditioning medical school scholarships on a precommitment to work in medically underserved areas later. Current practice is usually to demand only one year of service for each year of funded studies. We show the effectiveness of scholarships conditional on such precommitment for increasing physician supplies in underserved areas. Then we defend these scholarships against ethical worries that they constitute slavery contracts; rely on involuntary, biased, or unauthorized early consent by a young signatory; put excessive strains on signed commitments; give rise to domination; and raise suspicion of slavery contracts. Importantly, we find that scholarships involving far longer commitment than current practice allows would also withstand these worries. Policymakers should consider introducing conditional scholarships, including long-term versions, as a means to increasing the supply of physicians to medically underserved areas. PMID- 22548520 TI - Reciprocal responsibilities of medical scholarship students and their sponsors. PMID- 22548521 TI - What if medical graduates are right? PMID- 22548522 TI - Medical scholarships and the social determinants of health. PMID- 22548523 TI - Pursuing a less restrictive means to health equity. PMID- 22548524 TI - Reversing the brain drain: the role of medical schools. PMID- 22548526 TI - Triplet excimers of fluoroquinolones in aqueous media. AB - Generation of triplet eximers of 6-fluoro-7-piperazinyl-quinolone-3-carboxylic acids (FQs) have been detected in aqueous media using laser flash photolysis (LFP). These transient species (SS) are generated by self-quenching reactions of FQ triplet excited states such as pefloxacin (PFX), norfloxacin (NFX), the N acetylated form of NFX (ANFX), and its methyl ester (EANFX) with their ground states. In this context, self-quenching rate constants in the range of (1-7) * 10(8) M(-1) s(-1) were determined. The triplet excimers show transient absorption spectra with lambda(max) ca. 710 nm for SS(NFX), 740 nm for SS(PFX), and 620 nm for SS(ANFX) and E(ANFX), which are red-shifted with respect to their predecessors triplet excited states. These excimers can be also observed in the presence of phosphate buffer (PB). Experiments performed with NFX and ANFX at different PB concentrations showed that deprotonation processes are not involved in the generation of SS. The triplet multiplicity of the FQ excimers was confirmed by energy transfer reactions with naproxen. The correlation between fluorescence, intersystem crossing, excimer and photodegradation quantum yields of (A)NFX indicated that FQ self-quenching reactions are mainly a deactivation pathway. On the other hand, generation of FQ radical anions absorbing at lambda(max) ca. 620 nm has been observed by an efficient electron transfer reaction from Trp to NFX, PFX, and ANFX (rate constants ca. 1 * 10(9) M(-1) s( 1)). PMID- 22548527 TI - New metal-only Lewis pairs: elucidating the electronic influence of N heterocyclic carbenes and phosphines on the dative Pt-Al bond. AB - The synthesis and full characterization of a new heteroleptic N-heterocyclic carbene (NHC)-phosphine platinum(0) complex and formation of its corresponding alane adduct is reported. The influence of the ligands on the Lewis basic properties was studied via multinuclear NMR-spectroscopy, X-ray analyses, and density functional theory (DFT) calculations. Consistently, the effect of changing the halogens upon the Lewis acid properties of aluminum halides was studied by X-ray analysis and DFT calculations. PMID- 22548528 TI - Arthroscopic approach to the subextensorius recess of the lateral femorotibial joint of the foal. AB - OBJECTIVE: To (1) develop an arthroscopic approach to the subextensorius recess of the lateral femorotibial (LFT) joint in foals and (2) report its use in foals with LFT joint sepsis. STUDY DESIGN: (1) Anatomic study and (2) retrospective case series. SAMPLE POPULATION: (1) Cadaveric hind limbs (n = 32 foals) to delineate the anatomy of the subextensorius recess; 13 foal limbs for cadaver surgery to assess the approach to the subextensorius recess; and (2) foals (n = 8) with LFT joint sepsis. METHODS: (1) The LFT joint was distended and examined ultrasonographically. Dissection was used to document periarticular landmarks, potential distal arthroscopic portals, and assess iatrogenic damage after cadaveric surgery. (2) Retrieval of data from 8 foals with LFT joint sepsis treated using the arthroscopic approach. RESULTS: (1) The optimal arthroscopic approach to the distal subextensorius recess is craniolaterally, 8-10 cm distal to the tibial plateau, immediately caudal to the peroneus tertius muscle, through the long digital extensor muscle belly, entering the distal extent of the subextensorius recess. Thirteen limbs dissected after cadaver surgery had no iatrogenic damage to the peroneus tertius muscle or peroneal nerve. (2) Two foals were euthanized. Resolution of sepsis occurred in 6 foals, and all were sound at follow-up >9 months after surgery. CONCLUSION: The subextensorius recess may be safely accessed arthroscopically in foals. PMID- 22548529 TI - Alkane lengths determine encapsulation rates and equilibria. AB - A cylindrical capsule provides an environment for straight-chain alkanes that can properly fill the space through extended or compressed conformations. The encapsulation rates of a series of alkanes were examined and found to be dependent on guest length: the rates of uptake are C(9) > C(10) > C(11), while complex stability is in the reverse order, C(11) > C(10) > C(9). Direct competition experiments, pairwise or between all 3 alkanes, maintain this order as the longer alkanes sequentially displace the shorter ones. The distribution of species with time provides a clock for this complex system, which combines elements of self-sorting phenomena and dynamic combinatorial chemistry. The clock can be stopped by replacing the alkanes with the superior guest 4,4' dimethylazobenzene, then restarted by irradiation. PMID- 22548530 TI - Gutter method: noninvasive management of ingrown nails caused by epidermal growth factor inhibitor treatment. PMID- 22548531 TI - Effects of blood meal source on the reproduction of Culex pipiens quinquefasciatus (Diptera: Culicidae). AB - Culex pipiens quinquefasciatus were fed blood meals from a live chicken (LC), chicken blood in Alsever's (AC) solution, defibrinated bovine blood (DB), or bovine blood in citrate (CB) and incubated at 28 degrees C. The effects of different blood meal sources were evaluated with respect to rates of blood feeding and reproduction (i.e., fecundity and fertility) over two gonotrophic cycles. Mosquitoes that fed on the first blood meal were subjected to a second blood meal as follows (first blood meal / second blood meal): LC/LC, LC/DB, DB/DB, CB/CB, AC/AC. Fecundity and fertility of Cx. p. quinquefasciatus were significantly (P < 0.05) greater in mosquitoes fed LC blood; however, fecundity and fertility in different treatment groups varied by gonotrophic cycle. These results contribute to our understanding of the impact of blood meal source on feeding and reproduction in Cx. p. quinquefasciatus. The potential impacts of blood meal source on virus transmission experiments are discussed. PMID- 22548532 TI - Evaluation of a peridomestic mosquito trap for integration into an Aedes aegypti (Diptera: Culicidae) push-pull control strategy. AB - We determined the feasibility of using the BG-SentinelTM mosquito trap (BGS) as the pull component in a push-pull strategy to reduce indoor biting by Aedes aegypti. This included evaluating varying numbers of traps (1-4) and mosquito release numbers (10, 25, 50, 100, 150, 200, and 250) on recapture rates under screen house conditions. Based on these variations in trap and mosquito numbers, release intervals were rotated through a completely randomized design with environmental factors (temperature, relative humidity, and light intensity) and monitored throughout each experiment. Data from four sampling time points (05:30, 09:30, 13:30, and 17:30) indicate a recapture range among treatments of 66-98%. Furthermore, 2-3 traps were as effective in recapturing mosquitoes as 4 traps for all mosquito release numbers. Time trends indicate Day 1 (the day the mosquitoes were released) as the "impact period" for recapture with peak numbers of marked mosquitoes collected at 09:30 or 4 h post-release. Information from this study will be used to guide the configuration of the BGS trap component of a push-pull vector control strategy currently in the proof-of-concept stage of development in Thailand and Peru. PMID- 22548533 TI - Blood meal analysis, flavivirus screening, and influence of meteorological variables on the dynamics of potential mosquito vectors of West Nile virus in northern Italy. AB - An extended area of northern Italy has experienced several West Nile virus (WNV) outbreaks and the emergence of Usutu virus (USUV) during previous years. Our aim was to study some of the factors that could explain disease patterns in the Trentino region, where circulation was detected in human sera and sentinel chickens, but no human or equine cases were reported. We collected Culex species (Diptera: Culicidae) in peridomestic environments. The collected specimens were analyzed for feeding behavior, the influence of temperature and rainfall on the abundance of mosquitoes, and the occurrence of flaviviruses. Analysis of blood meals showed that Culex pipiens fed mainly on blackbirds (Turdus merula) and house sparrows (Passer domesticus), while Culex hortensis fed strictly on lizards. The abundance of Cx. pipiens females correlated positively with mean temperature and negatively with rainfall (one to four weeks before capture). This negative relationship could be due to the direct effect of the flushing of habitats together with an indirect effect of oviposition repellency. The mean weekly temperature influenced the abundance of Cx. hortensis. No flaviviruses were detected in the analyzed Culex mosquitoes. These data suggest a silent cycle at low enzootic transmission levels in the area. Furthermore, we present the first contribution to understanding the transmission role of Cx. pipiens mosquitoes in Italy by identifying vertebrate hosts to species level. PMID- 22548534 TI - Synchronous peaks in trap catches of malaria-infected mosquito species at Daeseongdong, a border village between North and South Korea. AB - Malaria continues to be a major health threat near the Demilitarized Zone (DMZ) that separates North and South Korea. Adult mosquitoes were collected from 20 July through 21 October, 2010 at Daeseongdong, a small village within the DMZ. Molecular techniques were used to identify Anopheles to species and for detection of Plasmodium vivax sporozoites in their head and thorax. Trap catches showed concordant peaks of Anopheles belenrae and An. kleini early in the study period and concordant peaks of An. pullus and An. sinensis later in the season. Three well defined peaks of the 107 sporozoite positive mosquitoes were observed: 34.6% were An. kleini, 23.4% were An. belenrae, 21.5% were An. sinensis, 19.6% were An. pullus, and 0.9% were An. lesteri. Estimation of the extrinsic incubation period from daily temperatures did not help identify preceding biting peaks of An. pullus and An. sinensis, when infection should have been acquired. We explore possible reasons for the sudden appearance and disappearance of sporozoite infected mosquitoes, including the influx of infected mosquitoes from adjoining areas, and weather patterns. Regular surveillance for infected mosquitoes near border areas of the Republic of Korea may provide advance warning of increased malaria risk potential. PMID- 22548535 TI - Spatial and temporal dynamics of Aedes aegypti larval sites in Bello, Colombia. AB - Counts of immature stages of the mosquito Aedes aegypti have been used to calculate several entomological indices of dengue vector abundance. Some studies have concluded that these indices can be used as indicators of dengue epidemic risk, while other studies have failed to find a predictive relationship. Ecological niche models have been able to predict distributional patterns in space and time, not only of vectors, but also of the diseases that they transmit. In this study, we used Landsat 7 ETM+ images and two niche-modeling algorithms to estimate the local-landscape ecological niche and the dynamics of Ae. aegypti larval habitats in Bello, Colombia, and to evaluate their potential spatial and temporal distribution. Our models showed low omission error with high confidence levels: about 13.4% of the area presents conditions consistently suitable for breeding across the entire study period (2002-2008). The proportion of neighborhoods predicted to be suitable showed a positive association with dengue case rates, whereas the vector-focused Bretau index had no relationship to case rates. As a consequence, niche models appear to offer a superior option for predictive evaluation of dengue transmission risk and anticipating the potential for outbreaks. PMID- 22548536 TI - Seasonal pattern of daily activity of Aedes caspius, Aedes detritus, Culex modestus, and Culex pipiens in the Po Delta of northern Italy and significance for vector-borne disease risk assessment. AB - The increasing concern about vector-borne diseases such as West Nile disease in northern Italy motivated our analysis of data on the mosquito fauna and the seasonal and daily flight patterns collected in 1998 in the Po Valley. Collections were performed once a week from May to November, with human landing collections and CO(2) traps. Culex pipiens was present from July to October and showed a clearly unimodal nocturnal flight habit. Culex modestus appeared in July August and showed a bimodal flight pattern, (main peak during the evening and a minor one in the morning). Aedes caspius was present from May to November (highest densities in July-August) and showed a bimodal flight pattern with a major crepuscular peak and a minor dawn peak in the morning. Aedes detritus was the most abundant species in May, with a crepuscular sharply bimodal flight pattern, particularly according to human landing collections. Sunset and sunrise time, in combination with the solar phase (that determines daylight duration and its trend of changing) were the main factors affecting flight behavior. Temperature, relative humidity, and wind speed differently affected the flight behavior of mosquito females according to the species. PMID- 22548537 TI - Occurrence of oriental flies associated with indoor and outdoor human remains in the tropical climate of north Malaysia. AB - Flies attracted to human remains during death investigations were surveyed in north Peninsular Malaysia. Six families, eight genera, and 16 species were identified from human remains, with the greatest fly diversity occurring on remains recovered indoors. The total relative frequency of species was led by Chrysomya megacephala (Fabricius, 1794) (46%), followed by Chrysomya rufifacies (Macquart, 1842) (22%), Sarcophaga (Liopygia) ruficornis (Fabricius, 1974) (5%), Sarcophaga spp. (4%), Synthesiomyia nudiseta Wulp, 1883 (6%), Megaselia spp. (3%), Megaselia scalaris (Loew, 1866), (2%), Megaselia spiracularis Schmitz, 1938 (2%), and Chrysomya villeneuvi Patton, 1922 (2%). Hemipyrellia tagaliana (Bigot, 1877), Desmometopa sp., Megaselia curtineura (Brues, 1909), Hemipyrellia ligurriens Wiedemann 1830, Ophyra sp., Sarcophaga princeps Wiedemann 1830, Piophila casei (Linnaeus, 1758), and unidentified pupae each represented 1%, respectively. PMID- 22548538 TI - Effects of landscape disturbance on mosquito community composition in tropical Australia. AB - Emerging infectious diseases are considered to be a growing threat to human and wildlife health. Such diseases might be facilitated by anthropogenic land-use changes that cause novel juxtapositions of different habitats and species and result in new interchanges of vectors, diseases, and hosts. To search for such effects in tropical Australia, we sampled mosquito populations across anthropogenic disturbance gradients of grassland, artificial rainforest edge, and rainforest interior. From >15,000 captured mosquitoes, we identified 26 species and eight genera. Surprisingly, there was no significant difference in community composition or species richness between forest edges and grasslands, but both differed significantly from rainforest interiors. Mosquito species richness was elevated in grasslands relative to the rainforest habitats. Seven species were unique to grasslands and edges, with another 13 found across all habitats. Among the three most abundant species, Culex annulirostris occurred in all habitat types, whereas Verrallina lineata and Cx. pullus were more abundant in forest interiors. Our findings suggest that the creation of anthropogenic grasslands adjacent to rainforests may increase the susceptibility of species in both habitats to transmission of novel diseases via observable changes and mixing of the vector community on rainforest edges. PMID- 22548539 TI - Characterization of mosquito larval habitats and assessment of insecticide resistance status of Anopheles gambiae senso lato in urban areas in southwestern Ghana. AB - The study was carried out to characterize potential larval habitats in the city of Sekondi with the aim of assessing the relative importance of anthropogenic and natural water bodies as larval habitats. Insecticide-resistance status of Anopheles gambiae senso lato in the southwestern part of the coastal savannah zone in Ghana was also assessed against four different classes of insecticides. Larval surveys were carried out in two communities that are separated by a lagoon. Although the lagoon was a potential mosquito larval habitat, we showed that it was not an important mosquito breeding site. The major larval habitats were anthropogenic, resulting from human behavior. Some of the organically polluted breeding sites were inhabited by both An. gambiae s.l. and Culex quinquefasciatus larvae. The data also showed that An. gambiae s.l. has currently developed a strong resistance to DDT and pyrethroid insecticides in southwestern Ghana, where the species was reported to be susceptible about a decade ago. The use of insecticides in households was implicated as a possible cause of the development of resistance among An. gambiae s.l. populations in the area. The management of insecticide resistance among malaria vectors needs urgent attention if insecticide-treated materials can continue to be used for malaria control. PMID- 22548540 TI - Analysis of post-blood meal flight distances in mosquitoes utilizing zoo animal blood meals. AB - We assessed the post-blood meal flight distance of four mosquito species in a unique environment using blood meal analysis. Mosquitoes were trapped at the Rio Grande Zoo in Albuquerque, NM, and the blood source of blood-engorged mosquitoes was identified. The distance from the enclosure of the animal serving as a blood source to the trap site was then determined. We found that mosquitoes captured at the zoo flew no more than 170 m with an average distance of 106.7 m after taking a blood meal. This is the first study in which the flight distance of wild mosquitoes has been assessed using blood meal analysis and the first in which zoo animals have served as the exclusive source of blood meals. PMID- 22548541 TI - Sand fly vectors (Diptera, Psychodidae) of American visceral leishmaniasis areas in the Atlantic Forest, State of Espirito Santo, southeastern Brazil. AB - The aim of this study was to evaluate the sand fly fauna of American visceral leishmaniasis (AVL) endemic areas within the Central Atlantic Forest Biodiversity Corridor, State of Espirito Santo, southeastern Brazil. The sand fly captures were performed between January, 1989 and December, 2003 in localities where autochthonous cases of AVL were recorded, as well as in their boundary areas. Sand flies were collected from surrounding houses and domestic animal shelters using two to five CDC automatic light traps, and manual captures were also performed using mouth aspirators in one illuminated Shannon trap during the first four hours of the night. We used cladistic analysis to determine the geographic relationships among the collected sand fly species as well as the index species for the occurrence of other sand flies. A total of 62,469 sand flies belonging to 17 species and eight genera was collected in 164 localities from nine municipalities with AVL records. The richness (S=17) and diversity (H=0.971) of sand flies were lower than in conservation areas and similar to modified environments in the Atlantic Forest of Espirito Santo. Lutzomyia longipalpis was identified in 79 localities. The cladistic analysis identified Evandromyia lenti as the index species for Lutzomyia longipalpis. The latter seems to be the main vector of AVL in the Central Atlantic Forest Biodiversity Corridor due to its high abundance and distribution matching the disease occurrence. Therefore, Evandromyia lenti may be used as an index species for the occurrence of Lutzomyia longipalpis. PMID- 22548542 TI - Seroprevalence of hantaviruses in small wild mammals trapped in South Korea from 2005 to 2010. AB - The seroprevalence of Hantaan virus (HTNV) in wild rodents in South Korea was analyzed. Wild rodents were trapped in 18 cities in eight provinces during 2005 2007 and on three islands and four mountains during 2008-2010. Sera were collected from 629 out of 933 trapped wild animals and examined for immunoglobulin G antibodies to HTNV using indirect immunofluorescence assays. Apodemus agrarius (80.1%) was the most frequently captured species at almost all trapping sites. The overall prevalence of HTNV antibodies was 0.26 (162/629). Seropositive individuals were more frequent in cities (32.2%, n=410) than on islands (14.0%, n=57) or mountains (13.6%, n= 162). HTNV antibody-positive rate was higher in the fall (29.6%, n=253) than in the spring (23.1%, n=376). A. agrarius had the highest prevalence of HTNV antibodies (26.9%, n=561) of all tested species. Considering all the individuals, the prevalence of HTNV antibodies was higher in males (29.2%, n=250) than in females (22.3%, n=305). Our results show that HTNV is widely distributed throughout South Korea, and that HTNV infection of wild rodents is affected by their habitat, species, sex, and season. PMID- 22548543 TI - Tree-hole breeding mosquitoes in Israel. AB - A survey was conducted to evaluate the number of tree-hole breeding mosquito species and their distribution in the six principal woodland types in Israel. Out of approximately 3,000 mature trees examined, only 38 contained holes that retained water for extended periods of time, and breeding mosquitoes were observed in 27 of them. Two specialized tree-hole breeders, Aedes pulchritarsis Rondani and Aedes geniculatus Oliver, were found breeding at several sites in northern Israel, always at locations 500 m above sea level (a.s.l) and with high annual precipitation. Aedes albopictus Skuse which, in Israel, is known as an opportunistic container breeder, was found in this study to have adapted remarkably well to breeding in tree holes and was found in most forest types investigated and in most tree species which had adequate tree holes. Two other species, Culiseta annulata Schrank and Culex pipiens Linnaeus instars, were found in one of the tree holes, but did not survive to reach maturity. PMID- 22548544 TI - Adult mosquito trap sensitivity for detecting exotic mosquito incursions and eradication: a study using EVS traps and the Australian southern saltmarsh mosquito, Aedes camptorhynchus. AB - Adult mosquito traps are commonly used in biosecurity surveillance for the detection of exotic mosquito incursions or for the demonstration of elimination. However, traps are typically deployed without knowledge of how many are required for detecting differing numbers of the target species. The aim of this study was to determine the sensitivity (i.e., detection probability) provided by carbon dioxide-baited EVS traps for adult female Australian southern saltmarsh mosquitoes, Aedes camptorhynchus, a recent biosecurity problem for New Zealand. A mark-release-recapture study of three concurrently released cohorts (sized 56, 296, and 960), recaptured over four days with a matrix of 20 traps, was conducted in Australia. The detection probability for different numbers of traps and cohorts of different sizes was determined by random sampling of recapture data. Detection probability ranged from approximately 0.3 for a single trap detecting a cohort of 56 mosquitoes to 1.0 (certainty of detection) when seven or more traps were used. For detection of adult Ae. camptorhynchus around a known source, a matrix of traps provides a strong probability of detection. Conversely, the use of single traps deployed over very large areas to detect mosquitoes of unknown entry pathway is unlikely to be successful. These findings have implications for the design of mosquito surveillance for biosecurity. PMID- 22548545 TI - Looking for the gold standard: assessment of the effectiveness of four traps for monitoring mosquitoes in Italy. AB - Several kinds of traps are available for the collection of Culicidae species creating nuisance problems and/or a potential risk of pathogen transmission. The choice of the most appropriate sampling device should take into consideration the objective of the monitoring activity (e.g., faunistic research, vector control evaluation, arbovirus surveillance, etc.), the ecological and behavioral characteristics of the target mosquito species, and the ecology of the sampling areas. However, there are few factual criteria technical personnel can rely on to choose the most suitable sampling method, particularly when the targets are represented by mosquito species in temperate areas. We carried out a Latin square experiment in three ecologically different settings in Mantua municipality (northern Italy) to compare the performance of four different traps targeting host-seeking mosquitoes: two traps specifically designed for mosquito monitoring purposes (Centers for Disease Control and Prevention CO(2) trap and Biogents BG Eisenhans de Luxe trap) and two designed to reduce mosquito densities in outdoor domestic settings (Activa Acti Power Trap PV 440 and Activa Acti Power Trap MT 250 Plus). Overall, 1,930 specimens belonging to nine species were collected and differences in the performance of the four traps with reference to their ability to detect overall species diversity, as well as to collect single species, were highlighted. These observations, coupled with an analysis of the costs associated with the trap's purchase, operation, and servicing, provide useful indications for the implementation of mosquito monitoring in temperate areas. PMID- 22548546 TI - Characterization of larval habitats of Anopheles albimanus, Anopheles pseudopunctipennis, Anopheles punctimacula, and Anopheles oswaldoi s.l. populations in lowland and highland Ecuador. AB - Recent collection data indicate that at least four potential malaria vectors occupy more widespread distributions within the Andean highlands than in the past. Since habitat elimination is an important aspect of malaria control, it is vital to characterize larval habitats for Anopheles species within both lowland and highland sites. To that end, 276 sites within Ecuador were surveyed between 2008 and 2010. Characteristics of Anopheles-present sites for four species were compared to Anopheles-absent sites within the same geographical range and also to Anopheles-absent sites within a highland range representing potential future habitats. Thermochron iButtons((c)) were used to describe the daily temperature variation within a subset of potential habitats. Anopheles albimanus (W.) was positively associated with permanent habitats, sand substrates, floating algae (cyanobacterial mats), and warmer temperatures in both comparisons. Anopheles pseudopunctipennis (T.) was associated with floating algae (cyanobacterial mats), warmer temperatures, and higher water clarity in both comparisons. Anopheles punctimacula (D.&K.) was negatively associated with floating algae and positively associated with dissolved oxygen in both comparisons. Anopheles oswaldoi s.l. (P.) was not significantly associated with any parameters more often than expected given larval-absent sites. The results indicate that minimum water temperatures might limit the upper altitudinal distribution of An. albimanus (18.7 degrees C) and An. pseudopunctipennis (16.0 degrees C). PMID- 22548547 TI - Wing size and shape variation of Phlebotomus papatasi (Diptera: Psychodidae) populations from the south and north slopes of the Atlas Mountains in Morocco. AB - The wing shape and size morphology of populations of the medically important phlebotomine sand fly, Phlebotomus papatasi, were examined in two endemic (south of the Atlas Mountains) and nonendemic (north of the Atlas Mountains) foci of cutaneous leishmaniasis by using geometric morphometrics in Morocco. Although it is present in all of Morocco, P. papatasi is the main vector of Leishmania major in only southern part of the Atlas Mountains. There are four major mountain ranges that serve as geographical barriers for species distribution in the study area and at least four gaps were recognized among these barriers. We found statistically significant differences in wing shape morphology between southern and northern populations. Analysis clearly recognized two main groups of populations on both sides of the mountains. The graphical depiction of Principal Component Analysis (PCA) and Canonical Variates Analysis (CVA) confirmed our morphometric study suggesting that the difference in wing morphology between the populations indicates that the population of P. papatasi shows phenotypic plasticity in the study area. According to centroid size analyses, which were used as measures of wing size differences among different sites, the north population of P. papatasi had relatively larger wings than the south population. PMID- 22548548 TI - The role of Palmyra palm trees (Borassus flabellifer) and sand fly distribution in northeastern India. AB - Visceral leishmaniasis (VL), known as Kala-azar in India, is a parasite transmitted by the bite of the sand fly vector Phlebotomus argentipes. Published information on the species indicates it is a poor flyer, mainly hopping and gliding. This study describes the vector as more arboreal than previously documented. Data collected indicate the ability of P. argentipes and Sergentomyia spp to attain vertical heights in Palmyra palm trees Borassus flabellifer up to 18.4 m above ground level. To determine if sand flies were either climbing the tree trunk to rest in the canopy or flying, sticky traps were set around the tree trunk and checked for captures overnight. CDC traps set in the palm tree canopy resulted in the capture of 5,067 sand flies, 3,990 of which were P. argentipes. Traps were set during daylight hours to determine if sand flies remained and rested in the canopy. A total of 128 sand flies were trapped over 29 trap days in the palm trees. With the CDC traps, 130 P. argentipes and no Sergentomyia spp were captured. The converse was true for the sticky traps set around tree trunks 3 m below the CDC traps. Of the 105 sand flies collected, only one was P. argentipes and 104 were Sergentomyia spp. As reported elsewhere, this indicates Sergentomyia spp tend to climb and hop, wheareas P. argentipes are capable of longer and more sustained flight. Data presented herein suggest that P. argentipes is more exophylic and exophagic than previously reported. These findings have implications for sand fly control. PMID- 22548549 TI - Temperature and density-dependent effects of larval environment on Aedes aegypti competence for an alphavirus. AB - Mosquito larvae experience multiple environmental stressors that may modify how subsequent adults interact with pathogens. We evaluated the effect of larval rearing temperature and intraspecific larval competition on adult mosquito immunity and vector competence for Sindbis virus (SINV). Aedes aegypti larvae were reared at two intraspecific densities (150 and 300 larvae) at 20 degrees C and 30 degrees C and the adults were fed artificially on citrated bovine blood containing 10(5) plaque forming units of SINV. Expression of cecropin, defensin, and transferrin was also evaluated in one- and five-day-old female adults. There was a direct relationship between larval density and SINV infection and dissemination rates at low temperature (20 degrees C) and an inverse relationship between larval density and SINV infection rate at high temperature (30 degrees C). Cecropin was only expressed in five-day-old adults that were raised at high temperature as larvae and was 20-fold over-expressed at low compared to high density treatments. Defensin and transferrin were under expressed in one-day-old adults and over-expressed in five-day-old adults in all competition-temperature combinations relative to low density treatments at 20 degrees C. These findings suggest that interaction between biotic and abiotic conditions of the larval environment may alter adult mosquito immunity resulting in enhanced vector competence for arboviruses. PMID- 22548550 TI - Is the expression of autogeny by Culex molestus Forskal (Diptera: Culicidae) influenced by larval nutrition or by adult mating, sugar feeding, or blood feeding? AB - Culex molestus Forskal is suspected to have been introduced into southern Australia during the 1940s. Investigations to determine factors influencing the expression of autogeny, the response of this mosquito to potential blood meals, and the subsequent influence on oviposition were undertaken. Immature mosquitoes raised at five feeding regimes had mortality rates, development rates, wing length, and autogenous egg raft size measured. All surviving female mosquitoes laid autogenous eggs but there was a significant difference between the mean number of eggs per raft. For mosquitoes raised at each of the feeding regimes, there was a significant linear relationship between the number of eggs per autogenous egg raft and wing length. Newly emerged mosquitoes were offered a blood meal (i.e., rodent) daily but no blood feeding occurred until the autogenous egg raft was laid. There was no statistical difference in the rate of autogenous oviposition or post-oviposition blood feeding between control or treatment groups. The results of this study indicate that Cx. molestus is perfectly adapted to subterranean habitats in close association with human habitation, but their preference to delay blood feeding until up to day 8 following emergence may reduce their relative importance as a vector of arboviruses. PMID- 22548551 TI - Energy-state dependent responses of Anopheles gambiae (Diptera: Culicidae) to simulated bednet-protected hosts. AB - In nature, Anopheles gambiae mosquitoes are found at various energy levels and such females must choose between seeking somatic energy from sugar sources and obtaining both somatic and gametic energy from blood hosts. We used a straight tube olfactometer containing a simulated unobtainable blood host (human foot smell protected by a net) as well as a sugar source (honey odor). We assessed female probing rate and residence time at the net as a function of energy state (0, 24, 48, 72-h starved). In our trials, 0-h starved females showed low response to human odor, low probing rate, and residence time at the human odor site. By contrast, both 48 and 72-h individuals showed high response to foot odor, longer residence time, and higher probing rates. Seventy-two-h females also flew towards the honey source less often than other groups. Our findings suggest that managing sugar sources might be a viable strategy for influencing mosquito biting behavior. PMID- 22548552 TI - The morphological variation of the eggs and genital plates of two morphotypes of Triatoma protracta Uhler, 1894. AB - The control of triatomine insects is necessary because these insects are the principal vectors of Trypanosoma cruzi, the agent of Chagas disease. Nevertheless, some of these vectors, such as Triatoma protracta, have not been studied adequately and their importance and taxonomic status has not yet been defined in detail and must be reevaluated in view of the continuing taxonomic uncertainties associated with the species. To help clarify the taxonomic status of T. protracta, the eggs and genital plates of two morphotypes were analyzed. Qualitative and quantitative morphological differences were observed in two morphotypes, designated T. p. protracta and T. p. nahuatlae according to Ryckman (1962). The morphotype T. p. protracta exhibited large and wide eggs with pores forming large padded polygonal structures, whereas the eggs of the morphotype T. p. nahuatlae were small and smooth. The size of the 9(th) genital urosternite was longer and wider in females in contrast to males in both morphotypes. However, these size differences were relatively greater in T. p. protracta. The high morphological variation found between the morphotypes of T. protracta suggests that they should be separated. Accordingly, it is probable that this group should be re-classified. PMID- 22548553 TI - Pyrethroid induced behavioral responses of Anopheles dirus, a vector of malaria in Thailand. AB - Contact and noncontact behavioral actions of wild-caught Anopheles dirus in response to the operational field dose of three synthetic pyrethroids (bifenthrin, alpha-cypermethrin and lambda-cyhalothrin) were evaluated using an exito-repellency test chamber. DEET was used as the repellency standard for comparison with the other three synthetic pyrethroids. Results showed that test specimens rapidly escaped from the test chamber when exposed to direct contact with a surface treated with each of the three synthetic pyrethroids and DEET. Alpha-cypermethrin demonstrated the strongest irritant action (84.9% escape), followed by DEET (77.0%), lambda-cyhalothrin (68.6%) and bifenthrin (68.3%). In the noncontact configuration, fewer mosquitoes escaped from the test chambers as compared to contact trials, although a significant escape response was still observed as compared to the controls (P<0.05). We conclude that An. dirus exhibits both irritant and repellent actions in response the three pyrethroids testing in this study. The information obtained will allow us to better understand the behavioral responses of vectors to various chemicals and provide guidance when designing control strategies for targeting specific disease vectors. PMID- 22548554 TI - Altitudinal genetic and morphometric variation among populations of Culex theileri Theobald (Diptera: Culicidae) from northeastern Turkey. AB - Enviromental conditions, including such important climatic variables as temperature and precipitation, change with altitude; thus, elevation plays a significant role in determining population and community structure in a variety of organisms. Using single nucleotide polymorphisms (SNPs) and geometric morphometrics, nine populations of Culex theileri Theobald occurring in different ecological subregions at altitudes between 808-2,130 m in northeastern Turkey were compared. The wing size and shape data indicate that there are significant phenotypic differences among them, while Cx theileri populations are not genetically differentiated in the northeast part of Turkey. The size and shape variation analysis of wings showed that there is a positive correlation between wing (body) size/shape and altitude. PMID- 22548555 TI - Nest Mosquito Trap quantifies contact rates between nesting birds and mosquitoes. AB - Accurate estimates of host-vector contact rates are required for precise determination of arbovirus transmission intensity. We designed and tested a novel mosquito collection device, the Nest Mosquito Trap (NMT), to collect mosquitoes as they attempt to feed on unrestrained nesting birds in artificial nest boxes. In the laboratory, the NMT collected nearly one-third of the mosquitoes introduced to the nest boxes. We then used these laboratory data to estimate our capture efficiency of field-collected bird-seeking mosquitoes collected over 66 trap nights. We estimated that 7.5 mosquitoes per trap night attempted to feed on nesting birds in artificial nest boxes. Presence of the NMT did not have a negative effect on avian nest success when compared to occupied nest boxes that were not sampled with the trap. Future studies using the NMT may elucidate the role of nestlings in arbovirus transmission and further refine estimates of nesting bird and vector contact rates. PMID- 22548556 TI - An annotated checklist of the horse flies (Diptera: Tabanidae) of Lebanon with remarks on ecology and zoogeography: Pangoniinae and Chrysopsinae. AB - Knowledge of the horse fly fauna (Diptera: Tabanidae) of Lebanon is fragmentary, while the local fauna of most neighboring countries has been fairly well researched. Within the framework of the 20-year project "The ecology and zoogeography of the Lepidoptera of the Near East," we regularly collected biting flies in the whole region, including Lebanon. During this time we recorded 14 horse fly species for two subfamilies in Lebanon: four Pangoniinae and ten Chrysopsinae. Only a single species, Chrysops flavipes Meigen, 1804, was known previously in Lebanon, but the following four Pangoniinae: Pangonius haustellatus (Fabricius, 1781), Pangonius obscuratus Loew, 1859, Pangonius argentatus (Szilady, 1923), and Pangonius fulvipes (Loew, 1859) and nine Chrysopsinae: Silvius appendiculatus Macquart, 1846, Silvius ochraceus Loew, 1858, Nemorius irritans (Ricardo, 1901), Nemorius vitripennis (Meigen, 1820), Chrysops buxtoniAusten, 1922, Chrysops compactusAusten, 1924, Chrysops caecutiens (Linnaeus, 1758), Chrysops italicus Meigen, 1804, and Chrysops hamatus Loew, 1858 are new records for the Lebanese fauna. The Tabanidae fauna of Lebanon is completely Palearctic and most species are of a Mediterranean distribution type. Lebanon or nearby northern Israel appears to be in the Levant, the southern geographical distribution border for the Pangoniinae and Chrysopsinae. PMID- 22548557 TI - The influence of larval density, food stress, and parasitism on the bionomics of the dengue vector Aedes aegypti (Diptera: Culicidae): implications for integrated vector management. AB - New larval control strategies for integrated vector management of Aedes aegypti are in high demand, including the use of biological control agents. Exposure of Aedes aegypti to parasites, starvation, and overcrowded conditions during larval development reduces the probability of survival to eclosion, can directly affect fitness parameters such as adult size and fecundity, and can affect the size, provisioning, and viability of eggs produced by females. We compared these parameters after exposing larvae to 1) abundant food at low larval densities, 2) food deprivation and high larval density, and 2) infection with the endoparasite Plagiorchis elegans, an entomopathogenic digenean trematode. Female mosquitoes that eclosed from larval conditions of starvation and overcrowding were smaller and laid fewer and smaller eggs than controls. The proportion of females to complete an oviposition cycle was reduced in the P. elegans-infected treatment group. Parasite load was negatively correlated with wing length and egg size. Infection of Ae. aegypti with P. elegans has sublethal effects and may reduce population-level reproductive output, but one-time low-density P. elegans exposure does not have sufficient effect on Ae. aegypti fitness parameters to be considered a viable biocontrol option. PMID- 22548558 TI - Epidemiological, virological, and entomological characteristics of dengue from 1978 to 2009 in Guangzhou, China. AB - To understand its unprecedented resurgence, we examined the epidemiological, virological, and entomological features of dengue in Guangzhou during 1978-2009. Cases reported to the Guangzhou Centre for Disease Control and Prevention and data from virological and entomological surveillance were analyzed from three periods: 1978-1988, 1989-1999, and 2000-2009. Although cases decreased over time: 6,649 (1978-1988) to 6,479 (1989-1999) to 2,526 (2000-2009), geographical expansion resulted in districts with an average incidence >2.5/100,000, increasing from five (1978-1988, 1989-1999) to seven (2000-2009). Age distribution (mean age: 34.9 years) provided a trend of increasing dengue incidence among adults, and there was a significantly higher incidence among men with a sex ratio of 1.15:1 (P<0.001). Cases occurred from May through November with a peak between August and October, and a long-term trend was characterized by a three to five-year cyclical pattern. The most frequently isolated serotypes were DENV-2 (1978-1988) and DENV-1 (1989-1999 and 2000-2009). Seasonal fluctuations in immature densities of Aedes albopictus (sole transmission vector in Guangzhou) were consistent with the dengue seasonality. After a 30-year apparent absence, DENV-3 had reemerged in 2009. The current epidemiological situation is highly conducive to periodic dengue resurgences. Thus, a high degree of surveillance and strict control measures in source reduction should be maintained. PMID- 22548559 TI - Combining two teaching techniques for young children on Aedes aegypti control: effects on entomological indices in western Mexico. AB - A study of the effect of educating four- to six-year-old children in mosquito control was recently conducted in a city in the state of Jalisco, western Mexico. Four neighborhood districts were selected. Children attending one kindergarten in each of two experimental districts were taught mosquito control with a video from the American Mosquito Control Association (AMCA), joined to the use of the AMCA Touch Table Technique. The entomological indices monitored in the study decreased significantly (P<0.05) in houses in the experimental districts, apparently because parents acted on the comments and suggestions of the children and eliminated or monitored containers used as oviposition sites by mosquitoes. Based on these results, combining both techniques for teaching children mosquito control is a potentially useful tool for control efforts in Mexico and other places in Latin America. PMID- 22548560 TI - Predation ability and non-consumptive effects of Notonecta sellata (Heteroptera: Notonectidae) on immature stages of Culex pipiens (Diptera: Culicidae). AB - Predators may have multiple effects on prey, including the mortality caused by consumption, but also non-consumptive effects when prey alter their life history traits in the presence of predators. This study aimed to describe the consumption ability and the non-consumptive effects of Notonecta sellata (Heteroptera: Notonectidae) on immature stages of Culex pipiens (Diptera: Culicidae). Results showed that adult N. sellata were capable of preying on all larval instars, although they consumed more individuals of the 2(nd) and 3(rd) instars. Immature mosquitoes raised in the presence of, but without contact with, predators showed a slower development and smaller-sized emerging adults than those raised in the control treatments. Similar survival rates were recorded in the predator and control treatments. The present study suggests that N. sellata adults negatively affect Cx. pipiens populations in two ways: a) by increasing immature stage mortality as a result of direct consumption and extended development times; and b) by reducing their number of offspring, as a result of delayed reproduction and a lower fecundity of adults. PMID- 22548561 TI - The effect of rainstorms on adult Anopheles funestus behavior and survival. AB - We describe the effect that the passage of a cold front, with a subsequent heavy rainstorm ten days later, had on a population of Anopheles funestus mosquitoes collected exiting houses or in light-traps from a village in southern Mozambique. Temperature effects explained 40% (r=0.634; p <0.001) of the variation in numbers of males collected and 19% of the variation in gravid females collected (r=0.437; p=0.033). The age structure of mosquitoes varied according to distance from the breeding site (chi(2) = 64.1, df 6, p <0.001). The proportion of parous insects that were caught in the light-traps with sacs (chi(2) = 6.33, d.f. 2, p=0.042) and young insects that had mated before being collected (chi(2) = 13,3, d.f. 2, p=0.001) were reduced on the night of the rain but this effect was short lived. It is concluded that the effect of rain on mosquito populations depends on the kind of water body used for larval development. PMID- 22548562 TI - Controlling and sampling adult sand flies with a fumigant containing permethrin and deltamethrin. AB - The efficacy of a new smoke-generating formulation (fumigant, MidMos Solutions Ltd., GB), containing the active ingredients permethrin and deltamethrin, was evaluated against adult sand flies in an apartment (280 m(3)), a semi-open large animal shelter (enclosing an area of 300 m(2)), a closed Bedouin animal tent (104 m(3)), and a garden (141 m(2)) enclosed by a stone wall. In each location, four cages with approx. 100 Phlebotomus papatasi were exposed to the fumigant 0.5 m and 2.0 m above ground for 15 and 60 min. Controls were kept in untreated similar rooms and there were two repetitions. In the apartment and the animal tent, a single cartridge caused 100% mortality within 15 min. In the large animal shelter, one fumigant caused mortality of 86% in the lower cages and 75% in the upper cages after 15 min. After 60 min, mortality was 94 and 87%, respectively. With two fumigants, mortality was 98.5 and 91% after 15 min and after 60 min all sand flies were dead. In the garden, one fumigant caused mortality of 93% in the lower cages and 85.5% in the upper cages after 15 min. After 60 min the mortality was 98 and 92%, respectively. With two fumigants, all flies were dead within 15 min. PMID- 22548563 TI - Anaplasma phagocytophilum in small mammals and ticks in northeast Florida. AB - Human anaplasmosis is an emerging tick-borne disease in the United States, but few studies of the causative agent, Anaplasma phagocytophilum, have been conducted in southeastern states. The aim of this study was to determine if A. phagocytophilum is present in small mammals and ticks in northeast Florida. Polymerase chain reaction assays designed to amplify portions of the major surface protein 2 gene (p44), 16S rDNA, and groESL operons were used to test rodent blood and tick DNA samples for the presence of A. phagocytophilum. Positive samples were confirmed by DNA sequence analysis. Anaplasma phagocytophilum DNA was detected in less than 5% of cotton mice and 45% of cotton rats from two sites in northeast Florida. Anaplasma phagocytophilum DNA was also confirmed in 1.3% of host-seeking adult Ixodes scapularis tested and 2.7% of host seeking adult Amblyomma americanum. This report describes the first DNA sequence data confirming strains of A. phagocytophilum in rodents and ticks in Florida. The DNA sequences of the msp2, 16S rDNA, and groESL gene fragments obtained in this study were highly similar to reference strains of human pathogenic strains of A. phagocytophilum. These findings suggest that A. phagocytophilum is present and established among some small mammal species in northeast Florida. Although the infection prevalence was low in the total number of ticks tested, the presence of A. phagocytophilum in two human biting tick species, one of which is a known competent vector, suggests that humans in this region may be at risk of granulocytic anaplasmosis caused by this pathogen. PMID- 22548564 TI - Cardiovascular defense challenges at the basic, clinical, and population levels. AB - Cardiovascular disease (CVD) is now the leading cause of mortality worldwide. Particularly in low and middle income countries, rapid urbanization and secondary factors, such as increasing obesity, poor diet, and lack of exercise, have combined to propel CVD into this position. Given the enormous scope of this problem and the complex cultural, societal, and political issues that are involved, an equally sophisticated and multipronged approach is required to combat CVD at the global level. In this review, we outline the basic, clinical, and population level challenges that we face in defending ourselves against this disease. PMID- 22548565 TI - Plaque neovascularization: defense mechanisms, betrayal, or a war in progress. AB - Angiogenesis is induced from sprouting of preexisting endothelial cells leading to neovascularization. Imbalance in the angiogenic and antiangiogenic mediators triggers angiogenesis, which may be physiological in the normal state or pathological in malignancy and atherosclerosis. Physiologic angiogenesis is instrumental for restoration of vessel wall normoxia and resolution inflammation, leading to atherosclerosis regression. However, pathological angiogenesis enhances disease progression, increasing macrophage infiltration and vessel wall thickness, perpetuating hypoxia and necrosis. In addition, thin-walled fragile neovessels may rupture, leading to intraplaque hemorrhage. Lipid-rich red blood cell membranes and free hemoglobin are detrimental to plaque composition, increasing inflammation, lipid core expansion, and oxidative stress. In addition, associated risk factors that include polymorphysms in the haptoglobin genotype and diabetes mellitus may modulate the features of plaque vulnerability. This review will focus on physiological and pathological angiogenesis in atherosclerosis and summarizes the current status of anti-vascular endothelial growth factor (VEGF) therapy, microvascular rarefaction, and possible statin mediated effects in atherosclerosis neovascularization. PMID- 22548566 TI - LDL-cholesterol versus HDL-cholesterol in the atherosclerotic plaque: inflammatory resolution versus thrombotic chaos. AB - Atherosclerosis is a complex disease in which many processes contribute to lesion development. Yet, it is well accepted that high serum levels of low-density lipoproteins (LDL) play a main role in the initiation and progression of atherosclerosis. Despite currently available optimal LDL-lowering therapies, a worrisome number of clinical events still occur. The protective effect of high density lipoproteins (HDL) in atherosclerosis, either by suppressing vascular-LDL accumulation, inflammation, oxidation, endothelial damage, and thrombosis, has supported the need of the use of HDL-raising therapies to address this residual risk. Results obtained in some studies, however, have shown that HDL quality, rather than quantity, should be the target of future pharmacological therapies. Here, we will first explore the mechanism by which excess LDL is fundamental in the development of atherosclerosis and its thrombotic complications, behaving as a factor that introduces chaos in the vascular wall. Afterwards, we will explore how functional HDL, through various cellular and molecular mechanisms, facilitates the resolution of this vascular chaos by suppression of atherosclerosis progression and induction of regression. PMID- 22548567 TI - Evolving role of molecular imaging for new understanding: targeting myofibroblasts to predict remodeling. AB - Containment of the process of cardiac remodeling is a prerequisite for prevention of development of heart failure (HF) after myocardial infarction. For personalization of therapeutic intervention strategy, it may be of benefit to identify the subset of patients who are at higher risk for development of HF. One such strategy may involve targeted imaging of various components involved in the remodeling process and interstitial fibrosis, including the myofibroblast. This cell type combines characteristics of fibroblasts and smooth muscle cells, and plays a crucial role in infarct healing and scar contraction. We define molecular targets on myofibroblasts and discuss the feasibility of molecular imaging of these cells for early detection and treatment of patients at risk for development of HF after myocardial infarction. PMID- 22548569 TI - Engineered arterial models to correlate blood flow to tissue biological response. AB - This paper reviews how biomedical engineers, in collaboration with physicians, biologists, chemists, physicists, and mathematicians, have developed models to explain how the impact of vascular interventions on blood flow predicts subsequent vascular repair. These models have become increasingly sophisticated and precise, propelling us toward optimization of cardiovascular therapeutics in general and personalizing treatments for patients with cardiovascular disease. PMID- 22548570 TI - A bird's-eye view of cell therapy and tissue engineering for cardiac regeneration. AB - Complete recovery of ischemic cardiac muscle after myocardial infarction is still an unresolved concern. In recent years, intensive research efforts have focused on mimicking the physical and biological properties of myocardium for cardiac repair. Here we show how heart regeneration approaches have evolved from cell therapy to refined tissue engineering. Despite progressive improvements, the best cell type and delivery strategy are not well established. Our group has identified a new population of cardiac adipose tissue-derived progenitor cells with inherent cardiac and angiogenic potential that is a promising candidate for cell therapy to restore ischemic myocardium. We also describe results from three strategies for cell delivery into a murine model of myocardial infarction: intramyocardial injection, implantation of a fibrin patch loaded with cells, and an engineered bioimplant (a combination of chemically designed scaffold, peptide hydrogel, and cells); dual-labeling noninvasive bioluminescence imaging enables in vivo monitoring of cardiac-specific markers and cell survival. PMID- 22548568 TI - Molecular targets in heart failure gene therapy: current controversies and translational perspectives. AB - Use of gene therapy for heart failure is gaining momentum as a result of the recent successful completion of phase II of the Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) trial, which showed clinical safety and efficacy of an adeno-associated viral vector expressing sarco-endoplasmic reticulum calcium ATPase (SERCA2a). Resorting to gene therapy allows the manipulation of molecular targets not presently amenable to pharmacologic modulation. This short review focuses on the molecular targets of heart failure gene therapy that have demonstrated translational potential. At present, most of these targets are related to calcium handling in the cardiomyocyte. They include SERCA2a, phospholamban, S100A1, ryanodine receptor, and the inhibitor of the protein phosphatase 1. Other targets related to cAMP signaling are reviewed, such as adenylyl cyclase. MicroRNAs are emerging as novel therapeutic targets and convenient vectors for gene therapy, particularly in heart disease. We propose a discussion of recent advances and controversies in key molecular targets of heart failure gene therapy. PMID- 22548571 TI - Umbilical cord blood for cardiovascular cell therapy: from promise to fact. AB - Endothelial recovery and cell replacement are therapeutic challenges for cardiovascular medicine. Initially employed in the treatment of blood malignancies due to its high concentration of hematological precursors, umbilical cord blood (UCB) is now a non-controversial and accepted source of both hematopoietic and non-hematopoietic progenitors for a variety of emerging cell therapies in clinical trials. Here, we review the current therapeutic potential of UCB, focusing in recent evidence demonstrating the ability of UCB-derived mesenchymal stem cells to differentiate into the endothelial lineage and to develop new vasculature in vivo. PMID- 22548572 TI - Heart repair: from natural mechanisms of cardiomyocyte production to the design of new cardiac therapies. AB - Most organs in mammals, including the heart, show a certain level of plasticity and repair ability during gestation. This plasticity is, however, compromised for many organs in adulthood, resulting in the inability to repair organ injury, including heart damage produced by acute or chronic ischemic conditions. In contrast, lower vertebrates, such as fish or amphibians, retain a striking regenerative ability during their entire life, being able to repair heart injuries. There is a great interest in understanding both the mechanisms that allow heart plasticity during mammalian fetal life and those that permit adult cardiac regeneration in zebrafish. Here, we revise strategies for cardiomyocyte production during development and in response to injury and discuss differential regeneration ability of teleosts and mammals. Understanding these mechanisms may allow establishing alternative therapeutic approaches to cope with heart failure in humans. PMID- 22548574 TI - The future: therapy of myocardial protection. AB - The main determinant of myocardial necrosis following an acute myocardial infarction (AMI) is duration of ischemia. Infarct size is a strong independent predictor of postinfarction mortality. Interventions able to protect the myocardium from death during an AMI (cardioprotection) are urgently needed. Myocardial injury associated with reperfusion (ischemia/reperfusion injury [I/R]) significantly contributes to the final necrotic size. Duration of ischemia can only be reduced by social and emergency medical services--hospital collaborative programs. However, for a given duration of ischemia, infarct size can be limited by reducing reperfusion injury. Despite the fact that several therapies have been shown to reduce I/R injury in animal models, translation to humans has been frustrating. The cost of developing new drugs able to reduce I/R injury is huge, and this is a major roadblock in the field of cardioprotection. Recent studies have proposed that old, inexpensive drugs--in human use for decades (e.g., beta blockers and cyclosporine, among others)--can reduce I/R injury when administered intravenously before coronary opening. The demonstration of such a cardioprotective effect should have a significant impact in the care of AMI patients. PMID- 22548575 TI - The links between complex coronary disease, cerebrovascular disease, and degenerative brain disease. AB - Our appreciation of the complexity of cardiovascular disease is growing rapidly. Consistent with the fact that the vasculature is an omnipresent system that carries blood to every organ in the body, an expanding number of conditions are now known to be directly associated with disturbed cardiovascular function or vascular pathology. In particular, cardiovascular disease has recently been implicated as playing a major role in dementia and other forms of degenerative brain disease. Here, we explore some of the many emerging relationships between cardiovascular risk factors, complex coronary artery disease, cerebrovascular disease, and degenerative brain disease. PMID- 22548573 TI - Energy metabolism plasticity enables stemness programs. AB - Engineering pluripotency through nuclear reprogramming and directing stem cells into defined lineages underscores cell fate plasticity. Acquisition of and departure from stemness are governed by genetic and epigenetic controllers, with modulation of energy metabolism and associated signaling increasingly implicated in cell identity determination. Transition from oxidative metabolism, typical of somatic tissues, into glycolysis is a prerequisite to fuel-proficient reprogramming, directing a differentiated cytotype back to the pluripotent state. The glycolytic metabotype supports the anabolic and catabolic requirements of pluripotent cell homeostasis. Conversely, redirection of pluripotency into defined lineages requires mitochondrial biogenesis and maturation of efficient oxidative energy generation and distribution networks to match demands. The vital function of bioenergetics in regulating stemness and lineage specification implicates a broader role for metabolic reprogramming in cell fate decisions and determinations of tissue regenerative potential. PMID- 22548576 TI - Optimal lipid targets for the new era of cardiovascular prevention. AB - Optimal lipid targets (OLT) should be the goal for all individuals treated in the new era of cardiovascular (CV) disease prevention. Evidence supports that average LDL cholesterol (LDL-C) values in Westernized populations are not optimal. Lessons from nature and science support a physiologic LDL-C target of <70 mg/dL. Clinical trial evidence further supports optimal LDL-C targets, although several critical questions remain unanswered. Using a calculated LDL-C may have limitations in clinical practice. Non-HDL-C cholesterol may be a better predictor of outcomes, and should therefore be provided on all laboratory reports. Specific HDL cholesterol (HDL-C) targets are significantly more complicated. Although a low HDL-C predicts a less favorable outcome independent of LDL-C level, an HDL-C level > 50 mg/dL is associated with lower CV risk. Clinical trials on HDL-C have thus far been disappointing. OLT should be the goal for all individuals as an important part of addressing global CV risk. PMID- 22548577 TI - Controversies in blood pressure goal guidelines and masked hypertension. AB - In uncomplicated hypertension, <140/90 mmHg is the treatment goal for individuals aged 18-79 and between 140 mmHg and 150 mmHg in those 80 years of age. Inhibitors of the renin-angiotensin-aldosterone system, as well as calcium channel blockers, are universally accepted as first-line therapy in uncomplicated hypertension, but controversy exists over the role of thiazide diuretics and beta blockers. Because at similar blood pressure (BP) levels, African Americans have more target organ damage than whites, a lower goal of <135/85 mmHg is recommended. In patients with coronary artery disease, diabetes, and chronic kidney disease, <130/80 mmHg is recommended. Masked hypertension, defined as normal clinic BP with a high average self-monitored or ambulatory BP, is prevalent in those with chronic kidney disease, diabetes, and obstructive sleep apnea. Masked hypertension is associated with worse outcome. Ambulatory BP monitoring for those at risk for masked hypertension needs to be incorporated into guidelines. PMID- 22548578 TI - Evolving diagnostic and prognostic imaging of the various cardiomyopathies. AB - Several noninvasive imaging modalities, particularly cardiac magnetic resonance (CMR), have of late provided important diagnostic and prognostic insights into various cardiomyopathies. Myocardial delayed enhancement on CMR after administration of contrast accurately delineates a scar, a powerful marker of poor prognosis in dilated cardiomyopathy. Also in heart failure, loss of integrity of the cardiac sympathetic nervous system, as demonstrated by reduced myocardial uptake of the radioisotope meta-iodo-benzylguanidine with nuclear imaging similarly provides information on outcomes. The presence/absence of a scar on CMR has emerged as an important diagnostic and/or prognostic tool for specific cardiomyopathies, such as Tako-Tsubo, sarcoidosis, or hypertrophic cardiomyopathy. In addition, the quantification of the myocardial parameter T2* on CMR has been validated for accurate quantification of iron myocardial overload and as the strongest predictor for incident heart failure. In these diseases, coronary angiography with computed tomography (CT) may be very useful in ruling out underlying coronary disease noninvasively. PMID- 22548579 TI - The evolving landscape of quality measurement for heart failure. AB - Heart failure (HF) is a major cause of mortality and morbidity, representing a leading cause of death and hospitalization among U.S. Medicare beneficiaries. Advances in science have generated effective interventions to reduce adverse outcomes in HF, particularly in patients with reduced left ventricular ejection fraction. Unfortunately, effective therapies for heart failure are often not utilized in an effective, safe, timely, equitable, patient-centered, and efficient manner. Further, the risk of adverse outcomes for HF remains high. The last decades have witnessed the growth of efforts to measure and improve the care and outcomes of patients with HF. This paper will review the evolution of quality measurement for HF, including a brief history of quality measurement in medicine; the measures that have been employed to characterize quality in heart failure; how the measures are obtained; how measures are employed; and present and future challenges surrounding quality measurement in heart failure. PMID- 22548580 TI - Atrial fibrillation, stroke, and quality of life. AB - Contemporary management of atrial fibrillation imposes many challenges, particularly in the setting of our aging population. In addition to well recognized consequences, such as stroke and mortality, emerging evidence relates atrial fibrillation to elevated risk of dementia, posing further therapeutic challenges. As the incidence of atrial fibrillation rises with age, the balance of controlling stroke risk and limiting major hemorrhage on anticoagulation has become increasingly critical in elderly patients. Appreciation of more extensive risk factors has made it possible to identify patients at very low risk of thromboembolism and higher risk of bleeding. However, practice guidelines in the United States and abroad have occasionally divergent viewpoints regarding how to best manage patients in various risk strata. Options for stroke prevention have expanded with novel antithrombotics and promising mechanical alternatives to anticoagulation, which may be at least as effective in preventing stroke without increasing bleeding risk. Catheter ablation has demonstrated impressive success at preventing atrial fibrillation recurrence in selected patients, and has the potential to further improve outcomes. In addition, the role of antiplatelet medications in patients deemed unsuitable for anticoagulation has been better clarified, although novel agents require further study to assess their impact on thromboembolism. High-bleeding risks associated with the concomitant use of multiple antithrombotics remains a major obstacle in patients with indications for both antiplatelet and anticoagulant therapy. PMID- 22548581 TI - Transcatheter aortic valve implantation and cerebrovascular events: the current state of the art. AB - Transcatheter aortic valve implantation (TAVI) has revolutionized the care of high-risk patients with severe calcific aortic stenosis. Those considered at high or prohibitive risk of major adverse outcomes with open surgical aortic valve replacement may now be offered an alternative less-invasive therapy. Despite the rapid evolution and clinical application of this new technology, recent studies have raised concerns about adverse cerebrovascular event rates in patients undergoing TAVI. In this review, we explore the current data both in relation to procedure-related silent cerebrovascular ischemic events, as well as clinically apparent stroke. The timing of neurological events and their prognostic implications are also examined. Finally, potential mechanisms of TAVI-related cerebrovascular injury are described, in addition to efforts to minimize their occurrence. PMID- 22548582 TI - Are we ignoring the dilated thoracic aorta? AB - The pathophysiology of thoracic aortic aneurysm (TAA) formation involves a complex interplay of genetic predisposition, cardiovascular risk factors, and hemodynamic forces. The medical community has resorted to the use of pharmacologic agents based on weak data transplanted from either abdominal aortic aneurysms (AAAs) or Marfan syndrome. However, aneurysms differ significantly based on their anatomic location and etiology. Epidemiologic and experimental data demonstrate that different genetic and nongenetic risk factors as well as diverse physiologic processes are responsible for the development and progression of sporadic TAA, familial TAA, and AAA. Therefore, these disease processes need to be considered as distinct entities and not hastily grouped together. The extrapolation of data from one aneurysmal disease process to another is still ill founded and potentially harmful. Clinical trials in TAA are required before medical therapies, such as beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins, or macrolide antibiotics, can be recommended. PMID- 22548583 TI - Is surgical root coverage effective for the treatment of cervical dentin hypersensitivity? A systematic review. AB - BACKGROUND: Cervical dentin hypersensitivity (CDH) is characterized by tooth pain arising from root exposure. The aim of the present systematic review is to survey the literature on the efficacy of surgical root coverage techniques at reducing CDH in cases of gingival recession. METHODS: An online electronic search was performed in PubMed, Web of Science, and Cochrane Library databases. Randomized clinical trials dating from the inception of the respective databases through November 2011 were selected. Studies addressing clinical parameters of periodontal plastic surgery outcomes and variables related to CDH in patients >=18 years of age were included. The studies were evaluated by two independent reviewers. For each article, methodologic quality, size effect, the periodontal parameters measured, study design, methods, and results were analyzed. RESULTS: Nine relevant articles were analyzed in the present review. A decrease in CDH was observed after periodontal surgery for root coverage. The risk of bias was considered low in two studies, and the size effect was considered large in one study. CONCLUSIONS: There is not enough scientific evidence to conclude that surgical root coverage procedures predictably reduce CDH. Well-conducted clinical trials are needed to establish scientific evidence that allows periodontists to indicate root coverage as treatment for CDH. PMID- 22548585 TI - Severe loss of clinical attachment level: an independent association with low hip bone mineral density in postmenopausal females. AB - BACKGROUND: Bone loss is a feature of both periodontitis and osteoporosis, and several studies have analyzed whether the periodontal destruction could have been influenced by systemic bone loss. The aim of this study is to assess the association between clinical attachment level (CAL) and bone mineral density (BMD) at the lumbar spine and hip, lifestyle, smoking, sociodemographic factors, and dental clinical variables in postmenopausal women. METHODS: One hundred forty eight women were interviewed using a structured written questionnaire and clinically examined. The periodontal examination, which was performed by calibrated investigators, included CAL, probing depth, gingival recession, bleeding on probing (BOP), visible plaque, supragingival calculus, and mean tooth loss. The sample was stratified into two groups: moderate and severe CAL. The moderate group had all sites with CAL <=5 mm. The severe group had >=1 site with CAL >5 mm. BMD, measured using dual-energy x-ray absorptiometry, was assessed at the lumbar spine, femoral neck, and total femur (grams per square centimeters). RESULTS: Severe CAL was identified in 86 women (58.1%). The multiple linear regression analysis using CAL (dependent variable), adjusted by menopause, education, and family income, demonstrated an inverse relationship of severe CAL with the BMD of the femoral neck (P = 0.015), as well as a positive association of severe CAL with tooth loss (P = 0.000), BOP (P = 0.004), and heavy smokers (P = 0.001). CONCLUSIONS: Our study demonstrated that severe CAL was associated with low BMD of the femoral neck and deleterious clinical dental parameters and smoking. Our findings suggest that, in addition to appropriate oral care, individuals with severe CAL may also require additional attention to their systemic bone health. PMID- 22548586 TI - Clinical effects of potassium-titanyl-phosphate laser and photodynamic therapy on outcomes of treatment of chronic periodontitis: a randomized controlled clinical trial. AB - BACKGROUND: The main objective of periodontal treatment is to control infection and thereby curb disease progression. Recent studies have demonstrated that adjunctive treatment procedures, such as laser irradiation or photodynamic therapy (PDT), may provide some additional benefit in the treatment of chronic periodontitis (CP). The aim of this randomized controlled trial is to clinically evaluate and compare the clinical effects of potassium-titanyl-phosphate (KTP) laser and PDT on outcomes of CP treatment. METHODS: Twenty-four patients with untreated CP were treated using a split-mouth study design in which the teeth in each quadrant were randomly treated by scaling and root planing (SRP) alone (group A), PDT followed by SRP (group B), or KTP laser followed by SRP (group C). The periodontal pockets were exposed to a KTP laser with the following parameters: 0.8 W output power, 50 milliseconds time on/50 milliseconds time off, 30 seconds per irradiation at 532 nm and 11.7 J/cm(2) fluence, with a flexible fiberoptic tip with a diameter of 200 um. The selected pockets were probed with a pressure-controlled probe, guided by stents. Clinical periodontal parameters assessed included plaque index, gingival index, bleeding on probing (BOP), probing depth (PD), and clinical attachment level (CAL), which were recorded at baseline and at 6 months after therapy. RESULTS: Statistical analysis demonstrated no differences between groups at baseline for all parameters (P >0.05). All treatments yielded significant improvements in terms of BOP and PD decrease and CAL gain compared to baseline values (P <0.05). Group C showed a greater reduction in PD compared to the other groups (P <0.05). In addition, group C showed a greater CAL gain compared to the other groups (P <0.05). CONCLUSION: In patients with CP, clinical outcomes from conventional periodontal treatment of deeper pockets can be improved by using adjunctive KTP laser. PMID- 22548587 TI - Obituary: Robert L. Reeves, DDS. PMID- 22548584 TI - Periodontal disease, hypertension, and blood pressure among older adults in Puerto Rico. AB - BACKGROUND: Current scientific evidence addressing the relationship between periodontitis and hypertension is limited to studies producing inconsistent results. METHODS: All participants of an ongoing representative cohort of Puerto Rican elderly who were >=70 years old and residing in the San Juan metropolitan area were invited to this cross-sectional study. Periodontal probing depth (PD) and attachment loss (AL) were summarized using the Centers for Disease Control and Prevention and the American Academy of Periodontology definition for severe periodontitis (>=2 teeth with AL >=6 mm and >=1 tooth with PD >=5 mm). Three repeated blood pressure (BP) measurements taken were averaged using a standardized auscultatory method. Information on hypertension history, use of antihypertensive medications, and potential confounders (age, sex, smoking, heavy and binge drinking, diabetes, use of preventive dental services, flossing, body mass index, consumption of fruits, vegetables, whole wheat bread, and high-fiber cereal) was collected during in-person interviews. High BP was defined as average systolic BP >=140 mm Hg or diastolic >=90 mm Hg. Multivariate logistic regression models were used to study the relationship between severe periodontitis, hypertension history, and high BP. RESULTS: The study population comprised 182 adults. In multivariate analysis, there was no association between severe periodontitis and hypertension history (odds ratio [OR] = 0.99; 95% confidence interval [CI]: 0.40 to 2.48). Severe periodontitis was associated with high BP, with OR of 2.93 (95% CI: 1.25 to 6.84), after adjusting for age, sex, smoking, and binge drinking. This association was stronger when restricted to those with hypertension or taking antihypertensive medications: OR = 4.20 (95% CI: 1.28 to 13.80). CONCLUSION: The results of this study suggest that periodontitis may contribute to poor BP control among older adults. PMID- 22548588 TI - Changes in masticatory performance and quality of life in individuals with chronic periodontitis. AB - BACKGROUND: This study evaluates the effect of periodontitis on masticatory performance and quality of life index. METHODS: Patients (n = 24; 23 to 76 years of age) with periodontal conditions ranging from healthy to generalized disease categorized by the alveolar bone height-to-tooth length (AB/T) ratio were separated into the following two groups: control (AB/T >50%) and test (AB/T <50%). The masticatory performance was evaluated through continuous mastication of a special device called a biocapsule. The Brazilian Oral Health Impact Profile (OHIP-14Br) questionnaire was used to assess the oral health-related quality of life. The Student t test was applied for independent samples (P <0.05) to evaluate the masticatory performance, and the Mann-Whitney U test was used to determine quality of life (P <0.05). RESULTS: There was a statistically significant difference in masticatory efficiency between groups (P = 0.006). Statistically significant differences were also observed in the following parameters: 1) physical pain (P = 0.003); 2) psychologic discomfort (P = 0.008); 3) physical disability (P = 0.033); and 4) OHIP-14Br total score (P = 0.001). The control group achieved the best indicators. Both the masticatory performance and quality of life indicators showed significant correlation with the alveolar bone height. CONCLUSION: The loss of periodontal supporting structures has negative effects on the masticatory performance and quality of life. PMID- 22548589 TI - Serum dextromethorphan/dextrorphan metabolic ratio for CYP2D6 phenotyping in clinical practice. AB - WHAT IS KNOWN AND OBJECTIVE: Accurate prediction of actual CYP2D6 metabolic activity may prevent some adverse drug reactions and improve therapeutic response in patients receiving CYP2D6 substrates. Dextromethorphan-to-dextrorphan metabolic ratio (MR(DEM/DOR)) is well established as a marker of CYP2D6 metabolizer status. The relationship between urine and plasma or serum MR(DEM/DOR) is not well established nor is there evidence of antimode for separation of intermediate and especially poor metabolizers (PM) from extensive metabolizers (EM). This study addressed whether CYP2D6 phenotyping using molar metabolic ratio of dextromethorphan to dextrorphan (MR(DEM/DOR)) in serum is usable and reliable in clinical practice as urinary MR(DEM/DOR). METHODS: We measured MR(DEM/DOR) in serum and CYP2D6 genotype in 51 drug-naive patients and 30 volunteers. Receiver-operator characteristic (ROC) analysis was used for the evaluation of optimum cut-off value for discriminating between extensive, intermediate and PM. In addition, we studied the correlation of serum MR(DEM/DOR) with urine MR(DEM/DOR) in the 30 healthy volunteers. RESULTS AND DISCUSSION: A trimodal distribution of log MR(DEM/DOR) in serum was observed, with substantial overlap between extensive and intermediate metabolizer groups. We obtained an acceptable cut-off serum MR(DEM/DOR) value to discriminate between PM and either extensive or extensive + intermediate metabolizers. Using serum MR(DEM/DOR), it seems to be unreliable to discriminate EM from intermediate metabolizers (IM). A strong correlation between serum MR(DEM/DOR) and urine MR(DEM/DOR) was found. WHAT IS NEW AND CONCLUSION: Serum MR(DEM/DOR) (3 h) correlated with MR(DEM/DOR) in urine (0-8 h). Serum MR(DEM/DOR) discriminated between extensive and PM and between extensive + intermediate and PM. Our CYP2D6 phenotyping using serum dextromethorphan/dextrorphan molar ratio appears reliable but requires independent validation. PMID- 22548590 TI - Preparation and chemistry of 3/5-halogenopyrazoles. PMID- 22548591 TI - Measurement and evaluation outcomes for mHealth communication: don't we have an app for that? PMID- 22548592 TI - The use of mobile communication technologies to improve the health of individuals and populations has great potential. Introduction. PMID- 22548593 TI - Advancing the science of mHealth. AB - Mobile health (mHealth) technologies have the potential to greatly impact health research, health care, and health outcomes, but the exponential growth of the technology has outpaced the science. This article outlines two initiatives designed to enhance the science of mHealth. The mHealth Evidence Workshop used an expert panel to identify optimal methodological approaches for mHealth research. The NIH mHealth Training Institutes address the silos among the many academic and technology areas in mHealth research and is an effort to build the interdisciplinary research capacity of the field. Both address the growing need for high quality mobile health research both in the United States and internationally. mHealth requires a solid, interdisciplinary scientific approach that pairs the rapid change associated with technological progress with a rigorous evaluation approach. The mHealth Evidence Workshop and the NIH mHealth Training Institutes were both designed to address and further develop this scientific approach to mHealth. PMID- 22548594 TI - A development and evaluation process for mHealth interventions: examples from New Zealand. AB - The authors established a process for the development and testing of mobile phone based health interventions that has been implemented in several mHealth interventions developed in New Zealand. This process involves a series of steps: conceptualization, formative research to inform the development, pretesting content, pilot study, pragmatic randomized controlled trial, and further qualitative research to inform improvement or implementation. Several themes underlie the entire process, including the integrity of the underlying behavior change theory, allowing for improvements on the basis of participant feedback, and a focus on implementation from the start. The strengths of this process are the involvement of the target audience in the development stages and the use of rigorous research methods to determine effectiveness. The limitations include the time required and potentially a less formalized and randomized approach than some other processes. This article aims to describe the steps and themes in the mHealth development process, using the examples of a mobile phone video messaging smoking cessation intervention and a mobile phone multimedia messaging depression prevention intervention, to stimulate discussion on these and other potential methods. PMID- 22548595 TI - Mobile health evaluation methods: the Text4baby case study. AB - Mobile phones have been shown effective in several public health domains. However, there are few evaluations of the effectiveness of mobile health in health promotion. Also, although many studies have referenced behavioral theory, none appears to have explicitly tested theoretical assumptions or demonstrated mechanisms of change. More robust evaluation models that incorporate theory and measurement of behavioral mediators are needed. As in all public health programs, mobile health operates within a social ecological context. For example, organizational- and individual-level programs seek to influence health and health care practices and individual health behaviors. New programs such as Text4baby demonstrate how theory and explicit testing of mediators can be incorporated in evaluations. There are challenges and opportunities facing mHealth evaluations given the nature of the mobile channel. Mobile communication is ubiquitous, available at all times and places, and thus experimental control is often difficult. Natural experiments using variation in dosage of mHealth and place- or location-based designs may increase experimental control. Text4baby is a text messaging program that provides prenatal care messages to pregnant women and new mothers. It uses a partnership model with health care facilities often serving as local implementation partners. The authors review a case example of the evaluation of Text4baby at Madigan Army Medical Center. Participants were randomized to usual prenatal care plus text messaging or usual care alone. The evaluation has a theoretical model of behavior change and measures mediators as well as behavioral outcomes. Results will inform how behavioral theory works within mobile health programs. PMID- 22548596 TI - Text4baby in the United States and Russia: an opportunity for understanding how mHealth affects maternal and child health. AB - Text4baby uses new technology to deliver health messages and engage pregnant women and new mothers in healthy behaviors. The authors describe the need for carefully conducted early adopter epidemiologic evaluation and describe one such evaluation in a women, infant, and children clinic population in the United States and its proposed adaptation for use among early users of Text4baby in Russia. Collaborative efforts among countries can guide international understanding and use of best practices of this emerging technology. PMID- 22548597 TI - The use of mobile phones for acute wound care: attitudes and opinions of emergency department patients. AB - There are a significant number of emergency department (ED) visits for lacerations each year. When individuals experience skin, soft tissue, or laceration symptoms, the decision to go to the ED is not always easy on the basis of the level of severity. For such cases, it may be feasible to use a mobile phone camera to submit images of their wound to a remote medical provider who can review and help guide their care choice decisions. The authors aimed to assess patient attitudes toward the use of mobile phone technology for laceration management. Patients presenting to an urban ED for initial care and follow-up visits for lacerations were prospectively enrolled. A total of 194 patients were enrolled over 8 months. Enrolled patients answered a series of questions about their injury and a survey on attitudes about the acceptability of making management decisions using mobile phone images only. A majority of those surveyed agreed that it was acceptable to send a mobile phone picture to a physician for a recommendation and diagnosis. Patients also reported few concerns regarding privacy and security and believe that this technology could be cost effective and convenient. In this study, the majority of patients had favorable opinions of using mobile phones for laceration care. Mobile phone camera images (a) may provide a useful modality for assessment of some acute wound care needs and (b) may decrease ED visits for a high-volume complaint such as acute wounds. PMID- 22548598 TI - Text2Quit: results from a pilot test of a personalized, interactive mobile health smoking cessation program. AB - Text messaging programs on mobile phones have shown some promise in helping people quit smoking. Text2Quit is an automated, personalized, and interactive mobile health program that sends text messages and e-mails timed around a participant's quit date over the course of 3 months. The text messages include pre- and post-quit educational messages, peer ex-smoker messages, medication reminders and relapse messages, and multiple opportunities for interaction. Study participants were university students (N = 23) enrolled in the Text2Quit program. Participants were surveyed at baseline and at 2 and 4 weeks after enrollment. The majority of participants agreed that they liked the program at 2 and 4 weeks after enrollment (90.5% and 82.3%, respectively). Support for text messages was found to be moderate and higher than that of the e-mail and web components. Of participants, 75% reported reading most or all of the texts. On average, users made 11.8 responses to the texts over a 4-week period, although responses declined after the quit date. The interactive feature for tracking cigarettes was the most used interactive feature, followed by the craving trivia game. This pilot test provides some support for the Text2Quit program. A future iteration of the program will include additional tracking features in both the pre-quit and post-quit protocols and an easier entry into the not-quit protocol. Future studies are recommended that identify the value of the interactive and personalized features that characterize this program. PMID- 22548599 TI - Why physicians should share PDA/smartphone findings with their patients: a brief report. AB - Many physicians use PDAs/smartphones in the presence of their patients. But how do patients perceive this behavior? This study tested the hypothesis that participants with increased knowledge about medical applications of PDAs/smartphones have more positive perceptions of physicians using them. The authors assigned 250 patients and/or family members in medical or pharmacy waiting rooms at 2 universities to either the control group or the treatment group. The treatment group viewed a brief presentation about how and why physicians use PDAs/smartphones, whereas the control group received no new information. All participants completed a survey about their knowledge (7 items) and perceptions (13 items) of physician use of PDAs/smartphones. The treatment group showed more favorable perceptions (p < .05) on 5 out of 13 survey items. In addition, in the control group, those who showed "high knowledge" had more favorable perceptions (p < .05) on 8 out of 13 survey items compared with control group participants with "low/moderate knowledge" levels. The authors concluded that even a small amount of information increases measurable perceptions. This study suggests that perhaps physicians should take time to share their PDA/smartphone findings with their patients to improve patients' perceptions of their use. PMID- 22548600 TI - Capitalizing on the characteristics of mHealth to evaluate its impact. AB - The field of mHealth has made significant advances in a short period of time, demanding a more thorough and scientific approach to understanding and evaluating its progress. A recent review of mHealth literature identified two primary research needs in order for mHealth to strengthen health systems and promote healthy behaviors, namely health outcomes and cost-benefits (Mechael et al., 2010 ). In direct response to the gaps identified in mHealth research, the aim of this paper is to present the study design and highlight key observations and next steps from an evaluation of the mHealth activities within the electronic health (eHealth) architecture implemented by the Millennium Villages Project (MVP) by leveraging data generated through mobile technology itself alongside complementary qualitative research and costing assessments. The study, funded by the International Development and Research Centre (IDRC) as part of the Open Architecture Standards and Information Systems research project (OASIS II) (Sinha, 2009 ), is being implemented on data generated by 14 MVP sites in 10 Sub Saharan African countries including more in-depth research in Ghana, Rwanda, Tanzania, and Uganda. Specific components of the study include rigorous quantitative case-control analyses and other epidemiological approaches (such as survival analysis) supplemented by in-depth qualitative interviews spread out over 18 months, as well as a costing study to assess the impact of mHealth on health outcomes, service delivery, and efficiency. PMID- 22548601 TI - Lessons from a community-based mHealth diabetes self-management program: "it's not just about the cell phone". AB - Cell phone-assisted self-management of diabetes offers a new approach to improving chronic care; however, introducing this new technology presents many challenges to a health care team. The George Washington University-District of Columbia Cell Phone Diabetes Project enrolled 32 patients with Type 2 diabetes from a community clinic using patients' cell phones connected to the Well Doc Diabetes Manager System with monitoring by case managers and monthly reports to primary care providers. Despite monetary incentives (cell phone rebates), dropout rate was high (50%), because of lack of use or inability to afford low-cost cell phone service. Active patients had sustained system use with improved diabetes standard-of-care goals and reduced hospitalizations and emergency department visits. On the basis of this pilot program, the authors assessed the multiple links in the chain (patients, case managers, primary care providers, support staff, medical record systems, disease management software, cell phones) that affect the success of a mHealth chronic care strategy. PMID- 22548602 TI - The economics of eHealth and mHealth. AB - While mHealth has the potential to overcome traditional obstacles to the delivery of health services to the poor in lower and middle-income countries--issues related to access, quality, time, and resources--there is little evidence as to whether the expected benefits and savings can be actualized on a large scale. As a first step to developing the investment case for mHealth, this article outlines some of the key economic and financial questions that need to be answered in developing in-country eHealth investments. The proposed questions focus on the costs of eHealth infrastructure; regulatory structures that provide incentives at different levels of the health delivery system to encourage investment in, and use of, eHealth; and measuring the outcomes of successful eHealth utilization, including anticipated return on investment. PMID- 22548603 TI - Effectiveness of mHealth behavior change communication interventions in developing countries: a systematic review of the literature. AB - Mobile health (mHealth) technologies and telecommunication have rapidly been integrated into the health care delivery system, particularly in developing countries. Resources have been allocated to developing mHealth interventions, including those that use mobile technology for behavior change communication (BCC). Although the majority of mobile phone users worldwide live in the developing world, most research evaluating BCC mHealth interventions has taken place in developed countries. The purpose of this study was to conduct a systematic review of the literature to determine how much evidence currently exists for mHealth BCC interventions. In addition to analyzing available research for methodological rigor and strength of evidence, the authors assessed interventions for quality, applying a set of 9 standards recommended by mHealth experts. The authors reviewed 44 articles; 16 (36%) reported evaluation data from BCC mHealth interventions in a developing country. The majority of BCC mHealth interventions were implemented in Africa (n = 10) and Asia (n = 4). HIV/AIDS (n = 10) and family planning/pregnancy (n = 4) were the health topics most frequently addressed by interventions. Studies did not consistently demonstrate significant effects of exposure to BCC mHealth interventions on the intended audience. The majority of publications (n = 12) described interventions that used two-way communication in their message delivery design. Although most publications described interventions that conducted formative research about the intended audience (n = 10), less than half (n = 6) described targeting or tailoring the content. Although mHealth is viewed as a promising tool with the ability to foster behavior change, more evaluations of current interventions need to be conducted to establish stronger evidence. PMID- 22548604 TI - Reaching remote health workers in Malawi: baseline assessment of a pilot mHealth intervention. AB - mHealth has great potential to change the landscape of health service delivery in less developed countries--expanding the reach of health information to frontline health workers in remote areas. Formative, process, and summative evaluation each play an important role in mHealth interventions. K4Health conducted a Health Information Needs Assessment in Malawi from July to September 2009 (formative evaluation) that found widespread use of cell phones among health workers offering new opportunities for knowledge exchange, especially in areas where access to health information is limited. K4Health subsequently designed an 18 month demonstration project (January 2010 to June 2011) to improve the exchange and use of family planning/reproductive health and HIV/AIDS knowledge among health workers, which included the introduction of a short message service (SMS) network. K4Health conducted a pretest of the mHealth intervention from June to October 2010. A baseline assessment was carried out in November 2010 before expanding the SMS network and included use of qualitative and quantitative measures and comparison groups (summative evaluation). Routinely collected statistics also guide the program (process evaluation). This article describes the approach and main findings of the SMS baseline study and contributes to a growing body of evidence measuring the effectiveness and efficiency of mHealth programs using a strong evaluation design. PMID- 22548605 TI - Perceived improvement in integrated management of childhood illness implementation through use of mobile technology: qualitative evidence from a pilot study in Tanzania. AB - This study examined health care provider and caretaker perceptions of electronic Integrated Management of Childhood Illness (eIMCI) in diagnosing and treating childhood illnesses. The authors conducted semi-structured interviews among caretakers (n = 20) and health care providers (n = 11) in the Pwani region of Tanzania. This qualitative study was nested within a larger quantitative study measuring impact of eIMCI on provider adherence to IMCI protocols. Caretakers and health care workers involved in the larger study provided their perceptions of eIMCI in comparison with the conventional paper forms. One health care provider from each participating health center participated in qualitative interviews; 20 caretakers were selected from 1 health center involved in the quantitative study. Interviews were conducted in Swahili and lasted 5-10 min each. Providers expressed positive opinions of eIMCI, noting that the personal digital assistants were faster and easier to use than were the paper forms and encouraged adherence to IMCI procedures. Caretakers also held a positive view of eIMCI, noting improved service from providers, more thorough examination of their child, and a perception that providers who used the personal digital assistants were more knowledgeable. Research indicates widespread nonadherence to IMCI guidelines, suggesting improved methods for implementing IMCI are necessary. The authors conclude that eIMCI represents a promising method for improving health care delivery because it improves health care provider and caretaker perception of the clinical encounter. Further investigation into this technology is warranted. PMID- 22548606 TI - Addressing HIV knowledge, risk reduction, social support, and patient involvement using SMS: results of a proof-of-concept study. AB - Men who have sex with men continue to be severely and disproportionately affected by the HIV/AIDS epidemic in the United States. Effective antiretroviral therapy has altered the HIV epidemic from being an acute disease to a chronic, manageable condition for many people living with HIV. The pervasiveness, low cost, and convenience of short message service suggests its potential suitability for supporting the treatment of conditions that must be managed over an extended period. The purpose of this proof-of-concept study was to develop, implement, and test a tailored short message service-based intervention for HIV-positive men who have sex with men. The messages focused on reducing risk-taking behaviors and enhancing HIV knowledge, social support, and patient involvement. Participants reported strong receptivity to the messages and the intervention. The authors detected a statistically significant increase in HIV knowledge and social support from baseline to follow-up. Among participants who received sexual risk reduction messages, the authors also detected a statistically significant reduction in reported risk behaviors from baseline to follow-up. Results confirm the feasibility of a tailored, short message service-based intervention designed to provide ongoing behavioral reinforcement for HIV-positive men who have sex with men. Future research should include a larger sample, a control group, multiple sites, younger participants, and longer term follow-up. PMID- 22548607 TI - You have an important message! Evaluating the effectiveness of a text message HIV/AIDS campaign in Northwest Uganda. AB - There is a growing interest in the effect of mobile phones in health care (mHealth) service delivery, but more research is needed to determine whether short message service (SMS)-based campaigns are appropriate for developing countries. This pilot study explored the efficacy of an mHealth campaign using SMS as a platform to disseminate and measure HIV/AIDS knowledge, and to promote HIV/AIDS testing at clinics in rural Uganda. Over a 1-month period, 13 HIV/AIDS quiz questions were sent to 10,000 mobile subscribers. Despite participation incentives, only one-fifth of the mobile subscribers responded to any of the questions. The campaign had proportionately limited success in increasing knowledge levels on a mass scale. Furthermore, the program design may be reinforcing entrenched knowledge gaps. The results suggest that it is important to be conservative when considering the potential overall effect of SMS-based programs. However, the authors recognize the potential of mHealth tools when extended to millions of mobile phone users as part of an integrated health campaign approach. The authors propose several steps to improve the program design to reach a larger portion of the intended audience and increase campaign effectiveness. PMID- 22548608 TI - Pseudomonas M162 confers protection against rainbow trout fry syndrome by stimulating immunity. AB - AIMS: To evaluate the antagonistic effect of Pseudomonas M162 against Flavobacterium psychrophilum. METHODS AND RESULTS: The antagonistic activity of M162 was tested in vivo and in vitro, and its mode of action examined by siderophore production and immunological responses of rainbow trout (Oncorhynchus mykiss) fry. Pseudomonas M162 inhibited the growth of Fl. psychrophilum in vitro and increased the resistance of the fish against the pathogen, resulting in a relative per cent survival (RPS) of 39.2%. However, the siderophores produced by M162 did not have an inhibitory effect on Fl. psychrophilum. In fish fed with M162, the probiotic colonized the gastrointestinal tract and stimulated peripheral blood leucocyte counts, serum lysozyme activity and total serum immunoglobulin levels after 3 weeks from the start of feeding. CONCLUSIONS: This study showed the potential of Pseudomonas M162 as a probiotic by reducing the mortalities that occurred during an experimental Fl. psychrophilum infection, resulting mainly through the immunostimulatory effects of the bacterium. SIGNIFICANCE AND IMPACT OF THE STUDY: Rainbow trout fry syndrome (RTFS) causes high mortalities during the early life stages of the fish's life cycle, partly because their adaptive immunity has not yet fully developed. Thus, immunomodulation by probiotics could be an effective prophylactic method against RTFS. PMID- 22548609 TI - Molecular characterization of monoclonal antibodies against aflatoxins: a possible explanation for the highest sensitivity. AB - We screened and established seven hybridoma cell lines that secrete anti aflatoxin monoclonal antibodies with different sensitivities. Among these antibodies, 1C11 exhibited the highest sensitivity against all four major kinds of aflatoxins (AFB1, AFB2, AFG1, and AFG2) (IC(50) 0.0012-0.018 ng mL(-1) in the enzyme linked immunosorbent assay (ELISA) system, visual limit of detection of 0.03-0.25 ng mL(-1)). To better understand the interactions between these antibodies and aflatoxins, as well as to guide their potential sensitivity improvement in recombinant antibodies, we used multiple sequence alignment and molecular modeling combined with molecular docking to clarify the molecular mechanism of the highest sensitivity of 1C11 against aflatoxins. Our results show that hydrogen bond and hydrophobic interaction formed by Ser-H49 and Phe-H103 in the antibody with the hapten played the most important roles in determining the binding affinity. Further experiments performed on antibody mutants, designed on the basis of the computational models, supported the prediction of the interaction mode between the antibody and the hapten. Although the factors that influence antibody sensitivity are highly interdependent, our experimental and modeling studies clearly demonstrate how structural differences influence the binding properties of antibodies against the target hapten with different sensitivities. PMID- 22548610 TI - Functionalized graphene sheets as a versatile replacement for platinum in dye sensitized solar cells. AB - Several techniques for fabricating functionalized graphene sheet (FGS) electrodes were tested for catalytic performance in dye-sensitized solar cells (DSSCs). By using ethyl cellulose as a sacrificial binder, and partially thermolyzing it, we were able to create electrodes which exhibited lower effective charge transfer resistance (<1 Omega cm(2)) than the thermally decomposed chloroplatinic acid electrodes traditionally used. This performance was achieved not only for the triiodide/iodide redox couple, but also for the two other major redox mediators used in DSSCs, based on cobalt and sulfur complexes, showing the versatility of the electrode. DSSCs using these FGS electrodes had efficiencies (eta) equal to or higher than those using thermally decomposed chloroplatinic acid electrodes in each of the three major redox mediators: I (eta(FGS) = 6.8%, eta(Pt) = 6.8%), Co (4.5%, 4.4%), S (3.5%, 2.0%). Through an analysis of the thermolysis of the binder and composite material, we determined that the high surface area of an electrode, as determined by nitrogen adsorption, is consistent with but not sufficient for high performing electrodes. Two other important considerations are that (i) enough residue remains in the composite to maintain structural stability and prevent restacking of FGSs upon the introduction of the solvent, and (ii) this residue must not disperse in the electrolyte. PMID- 22548612 TI - Feasibility and accuracy of ultrasound-guided sacroiliac joint injection in dogs. AB - Frozen cadaver specimens from three dogs were used to create a sectional anatomic atlas of the sacroiliac region. Frozen/thawed cadaver specimens from 12 dogs were used to develop an ultrasound-guided sacroiliac joint injection technique. Accuracy of the technique was tested in 15 additional canine cadaver specimens, using injectate containing blue dye and iodinated contrast medium. Sonoanatomic landmarks for consistently identifying a caudodorsal window into the canine sacroiliac joint space included the L7-S1 articular process joints, ilial wing, sacral wing, sacral lamina, and median sacral crest. Accuracy of ultrasound guided sacroiliac joint injection was not significantly affected by operator, but was affected by the tissue location targeted and the reference standard used for calculations. Accuracy of the technique was good for placing injectate into either the synchondrosis component, dorsal sacroiliac ligament or ventral sacroiliac ligament; fair to poor for placing injectate into the synovial component; and poor for placing injectate into all four sacroiliac soft tissue structures. Concurrent placement of injectate into extraarticular tissues occurred frequently. We conclude that ultrasound-guided sacroiliac joint injection is feasible for evaluation as a treatment method for lumbosacral region pain in dogs, but is not sufficiently accurate for localizing pain to the sacroiliac joint alone. PMID- 22548611 TI - Increased inducible heat shock protein 72 expression associated with PBMC isolated from patients with haematological tumours. AB - BACKGROUND: Heat shock protein 72 (Hsp72) is a highly inducible stress protein and molecular chaperone. Cancers have been shown to be associated with increased Hsp72 expression within the tumour itself and this may lead to resistance to apoptosis. METHODS: Peripheral blood mononuclear cells (PBMC) were isolated from patients diagnosed with chronic lymphocytic leukaemia (CLL) (n = 27) and chronic myelomonocytic leukaemia (CMML) (n = 16) and Hsp72 expression was characterized on both the cell surface and intracellularly by flow cytometry. To allow for comparison PBMC from breast cancer patients (n = 25) and healthy volunteers (n = 19) were included. RESULTS: Both lymphocytes and monocytes from CLL and CMML patients showed high levels of total Hsp72 expression (4-6 fold increase) in comparison to breast cancer and healthy subjects. The majority of Hsp72 in these tumours was determined to be cell-surface expressed (64-93% of cell total Hsp72). CONCLUSIONS: A correlation was observed between lymphocyte and monocyte total Hsp72 expression (p < 0.001) suggesting a common stress response pathway may exist in these blood cells and there are stress conditions present within the circulation. Hsp72 expression was not found to be related to white blood cell count. PMID- 22548613 TI - Ativan (Lorazepam). PMID- 22548614 TI - Genetics and genomics: unraveling new opportunities for addiction treatment and education. PMID- 22548615 TI - Current issues in peripheral neuropathy. AB - Twenty million people in the United States are estimated to have peripheral neuropathy. However, many patients are not aware of their diagnosis, are not given the diagnosis or being treated, or the diagnosis is delayed. Currently, the only treatments available for neuropathy are aimed at treating the underlying medical conditions that cause the neuropathy or treating symptoms such as pain. Neither treats the actual nerve fiber dysfunction or fiber loss, or helps nerve fibers regenerate. Idiopathic neuropathy, that is neuropathy for which a cause is not identified, is common, accounting in referral series for 25% in all neuropathy patients and 50% or more of patients with small fiber neuropathy. Currently, there is only one FDA-approved medication for a specific neuropathy (chronic inflammatory demyelinating polyneuropathy) while there are two FDA approved medications for diabetic neuropathy pain and four that are approved for post-herpetic neuralgia pain. For many patients with painful neuropathy, these medications are ineffective or not tolerated. Continued research into the underlying mechanisms of neuropathy and an increased understanding of nerve regeneration and neuropathic pain are needed to address this unmet medical need among patients with neuropathy. PMID- 22548616 TI - Reversing neuropathic deficits. AB - This is a brief review of several novel strategies for therapeutic approaches to axonal damage in peripheral neuropathies. Although not comprehensive, the review addresses the challenges in axonal regrowth, newly identified roadblocks to regeneration and the concept of collateral reinnervation to restore lost neurological function. PMID- 22548617 TI - Bioenergetics in diabetic neuropathy: what we need to know. AB - Progress in developing treatments for diabetic neuropathy is slowed by our limited understanding of how disturbances in metabolic substrates - glucose and fatty acids - produce nerve injury. In this review, we present the current oxidative stress hypothesis and experimental data that support it. We identify weaknesses in our understanding of diabetes-disordered metabolism in the neurovascular unit, that is, in critical cell types of the microvascular endothelium, peripheral sensory neurons, and supporting Schwann cells. Greater understanding of peripheral nervous system bioenergetics may provide insight into new drug therapies or improvements in dietary interventions in diabetes or even pre-diabetes. PMID- 22548618 TI - Impaired glucose tolerance and metabolic syndrome in idiopathic neuropathy. AB - Idiopathic neuropathy is one of the most common clinical problems encountered in general medical and neurological practices, accounting for up to 40% of all neuropathies in referral series. Several groups have reported an elevated prevalence of impaired glucose tolerance (IGT) in idiopathic neuropathy subjects, although the only carefully conducted case-control study suggested hypertriglyceridemia was a more important risk factor. The nature of the relationship between IGT and neuropathy is a subject of active debate. An evolving literature suggests metabolic syndrome, particularly dyslipidemia and obesity, are potent neuropathy risk factors for both idiopathic and diabetic neuropathy patients. Once established, diabetic neuropathy is likely to be very difficult to reverse. IGT-associated neuropathy, however, may be more amenable to therapy and could represent an ideal population in which to examine potential therapies for diabetes and obesity related neuropathies. Further research is needed to better define the epidemiological relation between IGT, metabolic syndrome, and neuropathy, its underlying pathophysiology, and to develop appropriate surrogate measures and clinical trials strategies. PMID- 22548619 TI - Treatments for diabetic neuropathy. AB - Diabetic neuropathy comprises disorders of peripheral nerve in diabetes patients after exclusion of other disorders and can be focal or diffuse. The focal diabetic neuropathies tend to resolve spontaneously and are treated by reassurance, physiotherapy and analgesia for painful symptoms. Diabetic sensorimotor polyneuropathy (DSP) is the most frequent form of diabetic neuropathy and effective disease-modifying treatment is not available beyond the interventions of optimal glycemic control, and possibly lifestyle and risk factor modification. In contrast, a recent evidence-based guideline shows that effective treatments for painful DSP include: pregabalin, amitriptyline, duloxetine, venlafaxine, gabapentin, opioids, nitrate sprays, capsaicin, and transcutaneous electrical nerve stimulation. The choice of treatment is guided by the clinical status of the individual patient. PMID- 22548620 TI - Autoimmune neuropathies: insights from animal models. AB - Autoimmune neuropathies comprise a diverse group of conditions resulting from an immune attack on the peripheral nervous system. In some of these disorders, the antigenic target has been identified. In other conditions such as chronic inflammatory demyelinating polyradiculoneuropathy, the initial trigger and the antigenic target remain elusive. Animal models have provided some important information regarding their pathogenetic mechanisms. This review summarizes the background information and recent highlights from studies in animal models such as experimental autoimmune neuritis and spontaneous autoimmune polyneuropathy in B7-2 knockout non-obese diabetic mice. PMID- 22548621 TI - Clinical trials in CIDP and chronic autoimmune demyelinating polyneuropathies. AB - The main chronic autoimmune neuropathies include chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), and anti myelin-associated glycoprotein (MAG) demyelinating neuropathy. On the basis of randomized controlled studies, corticosteroids, intravenous immunoglobulin (IVIg), and plasmapheresis provide short-term benefits in CIDP. MMN responds only to IVIg. Because in MMN and CIDP, IVIg infusions are required every 3-6 weeks to sustain benefits or long-term remissions, there is a need for "IVIg-sparing" agents. In CIDP, immunosuppressive drugs, such as azathioprine, cyclosporine, methotrexate, mycophenolate, and cyclophosphamide, are used, but controlled trials have not shown that they are effective. Controlled trials have also not shown benefit to any agents in anti-MAG neuropathy. However, clinicians use many immunosuppressive drugs in both settings, but all have potentially serious side effects and are only effective in some patients. Thus, there is a need for new therapies in the inflammatory and paraproteinemic neuropathies. New agents targeting T cells, B cells, and transmigration and transduction molecules are discussed as potential treatment options for new trials. The need for biomarkers that predict therapeutic responses or identify patients with active disease is emphasized, and the search for better scoring tools that capture meaningful changes after response to therapies is highlighted. PMID- 22548622 TI - Clinical research for neuropathies. AB - The National Institutes of Health (NIH) has a long-standing commitment to neuropathy research. From 2005-2009, the NIH has committed US $115 million each year. A collaborative effort between researchers and patients can accelerate the translation of pre-clinical discoveries into better treatments for neuropathy patients. Clinical trials are needed to test these new treatments, but they can only be implemented in a timely fashion if patients with neuropathies are willing to participate. This perspective focuses on the value of having various outlets for informing both the patients and the physicians about existing clinical research opportunities and on the potential benefit of establishing patient registries to help with trial recruitment. Once data have been collected, there is a need to broadly share the data in order to inform future trials, and a first step would be to harmonize data collection by using Common Data Elements (CDEs). PMID- 22548623 TI - Idiopathic neuropathy: new paradigms, new promise. AB - Idiopathic neuropathy, now designated as chronic idiopathic axonal polyneuropathy (CIAP), is a major public health problem in the United States. The disorder affects an estimated 5-8 million Americans, comprising about one-third of patients with neuropathy, based on data from referral centers. Typically, patients develop symptoms in the sixth decade or older. The onset is insidious, with numbness, paresthesias, and pain appearing over months to years. Although strength is generally preserved, the sensory loss and pain can be disabling. The clinical approach to this condition has evolved in important ways over the years, enabling improved diagnosis and characterization of this population. Current work has focused on identifying modifiable risk factors that may be associated with idiopathic neuropathy. The results may suggest that an underlying mechanism such as oxidative stress contributes to the development of CIAP. PMID- 22548624 TI - Testing the stress-gradient hypothesis with aquatic detritivorous invertebrates: insights for biodiversity-ecosystem functioning research. AB - 1. The stress-gradient hypothesis (SGH) states that environmental stress modulates species interactions, causing a shift from negative interactions to net positive interactions with increasing stress. 2. Potentially, this modulation of species interactions could in turn influence biodiversity-ecosystem function (B EF) relationships along stress gradients. Although the SGH has been extensively discussed in plant community ecology in the past two decades, it has received little attention from animal ecologists. 3. To explore whether the SGH could be applied to animal communities, we conducted a litter decomposition experiment with aquatic detritivorous invertebrates in which we manipulated litter quality and measured species interactions along this resource quality gradient. Litter quality was manipulated by presenting detritivores with leaves of plant species varying in specific leaf area and decomposition rate in streams. 4. We found a switch from negative to neutral interactions with increasing resource quality stress, in line with the SGH. However, by re-examining other published results with aquatic detritivores from the perspective of the SGH, we found that a diversity of patterns seem to characterize detritivore interactions along stress gradients. 5. Although the basic pattern proposed by the SGH may not apply to animal systems in general, we show that aquatic detritivore interactions do change along stress gradients, which underlines the importance of incorporating environmental stressors more explicitly in B-EF research. PMID- 22548625 TI - Computational study of cyclohexanone-monomer co-initiation mechanism in thermal homo-polymerization of methyl acrylate and methyl methacrylate. AB - This paper presents a systematic computational study of the mechanism of cyclohexanone-monomer co-initiation in high-temperature homopolymerization of methyl acrylate (MA) and methyl methacrylate (MMA). Previous experimental studies of spontaneous thermal homopolymerization of MA and MMA showed higher monomer conversion in the presence of cyclohexanone than xylene. However, these studies did not reveal the initiation mechanism(s) or the initiating species. To identify the initiation mechanism and the initiating species, we explore four different mechanisms, (1) Kaim, (2) Flory, (3) alpha-position hydrogen transfer, and (4) Mayo, using first-principles density functional theory (DFT) and second-order Moller-Plesset perturbation theory (MP2) calculations. Transition-state geometries for each mechanism are determined using B3LYP/6-31G* and assessed with MP2/6-31G*. Activation energies and rate constants are calculated using transition-state theory. The harmonic oscillator approximation and tunneling corrections are applied to compute the reaction rate constants. This study indicates that alpha-position hydrogen transfer and Mayo mechanisms have comparable barriers and are capable of generating monoradicals for initiating polymerization of MA and MMA; these two mechanisms can cause cyclohexanone monomer co-initiation in thermal polymerization of MA and MMA. PMID- 22548626 TI - Clinicopathologic observations on laryngoplasty failure in a horse. AB - OBJECTIVE: To report morphologic findings associated with laryngoplasty failure in a horse. STUDY DESIGN: Clinical report. ANIMALS: A 9-year-old Thoroughbred cross gelding. METHODS: Necropsy and histopathology were performed on a horse that died peracutely during anesthetic recovery after correction of a right dorsal displacement of the ascending colon. Three weeks earlier the horse had left laryngoplasty and ventriculocordectomy. RESULTS: Dissection of the larynx revealed that the laryngoplasty suture had pulled through the muscular process of the left arytenoid cartilage, which appeared grossly normal. Histopathology of the arytenoid muscular process revealed cartilage necrosis, granulation tissue, and inflammation around the cartilage and within the cartilage failure line, and small numbers of coccoid bacteria in a minority of cartilage canals. Multifocal cardiomyopathy and pulmonary congestion, edema, and hemorrhage were also observed histologically. CONCLUSION: Death was attributed to peracute pulmonary edema associated with cardiac abnormalities and airway obstruction from laryngoplasty failure. Morphologic changes in the muscular process indicate gradual progression toward laryngoplasty failure, possibly associated with suture-induced pressure necrosis and/or microscopic low-grade postoperative infection. PMID- 22548627 TI - Anti-neutrophil cytoplasmic antibody-positive neutrophilic dermatosis of the dorsal hands. AB - Neutrophilic dermatosis of the hands is a localized variant of Sweet syndrome (SS). It was first reported in 1995, and is an uncommon condition, with < 100 cases reported to date. The female preponderance, morphological and histological features, and response to treatment are similar to SS, but it differs in its distribution on the body. There may also be a lack of systemic features and inconsistent laboratory findings. Significantly, about half of all cases are associated with haematological problems, i.e. myelodysplasia and leukaemia. Other cases may be associated with ulcerative colitis or solid tumours. We describe a case of a 71-year-old man with neutrophilic dermatoses of the hands, who also had involvement of the lips. There was an associated rise in his anti-neutrophil cytoplasmic antibody level, which corresponded with the activity of the disease. PMID- 22548628 TI - Magnetic circular dichroism spectrum of the molybdenum(V) complex [Mo(O)Cl3dppe]: C-term signs and intensities for multideterminant excited doublet states. AB - The molybdenum(V) complex [Mo(O)Cl(3)dppe] [dppe = 1,2 bis(diphenylphosphino)ethane] is considered as a model system for a combined study of the electronic structure using UV/vis absorption and magnetic circular dichroism (MCD) spectroscopy. In order to determine the signs and MCD C-term intensities of the chlorido -> molybdenum charge-transfer transitions, it is necessary to take the splitting of the excited doublet states into sing-doublet and trip-doublet states into account. While transitions to the sing-doublet states are electric-dipole-allowed, those to the trip-doublet states are electric dipole-forbidden. As spin-orbit coupling within the manifold of sing-doublet states vanishes, configuration interaction between the sing-doublet and trip doublet states is required to generate the MCD C-term intensity. The most prominent feature in the MCD spectrum of [Mo(O)Cl(3)dppe] is a "double pseudo-A term", which consists of two corresponding pseudo-A terms centered at 27000 and 32500 cm(-1). These are assigned to the ligand-to-metal charge-transfer transitions from the p(pi) orbitals of the equatorial chlorido ligands to the Mo d(yz) and d(xz) orbitals. On the basis of the theoretical expressions developed by Neese and Solomon (Inorg. Chem. 1999, 38, 1847-1865), a general treatment of the MCD C-term intensity of these transitions is presented that explicitly considers the multideterminant character of the excited states. The individual MCD signs are determined from the corresponding transition densities derived from the calculated molecular orbitals of the title complex (BP86/LANL2DZ). PMID- 22548629 TI - Understanding biofilms--are we there yet? PMID- 22548630 TI - Exploring the birth and death of black holes and other creatures. AB - Astronomers and physicists of diverse interest are teaming up to study enigmatic cosmic phenomena, such as the life cycle of black holes. A "disruptive innovation" is about to emerge during the next decade: Advanced gravitational wave observatories. The emergence of gravitational-wave physics as a viable observational channel is expected to improve our understanding of the Universe in unprecedented and plausibly unexpected ways, and to enhance the capabilities of the astrophysics community. Detecting cosmic counterparts to gravitational-wave events would revolutionize our understanding of violent astrophysical processes, such as the birth and death of black holes and neutron stars. Although the vanguard of joint observational work with electromagnetic observatories has already rewarded us with a glimpse of the power of gravitational-wave astronomy, the most interesting science is yet to come. Many sources of gravitational-waves are expected to be observable through a broad set of messengers, including gamma rays, X-rays, optical, radio, and neutrino emission. Multimessenger investigations may be crucial for the first detection of gravitational-waves, and could provide the broadest scientific impact afterwards. This paper outlines some exciting aspects of transient multimessenger astronomy with gravitational-waves and highlights open questions that might be resolvable by Advanced or third generation gravitational-wave detector networks. In addition, we will use examples from current research to illustrate that the toolkit of fundamental research can enrich other fields, and that synergistic science can expand horizons here on Earth. PMID- 22548631 TI - A new family of cinchona-derived bifunctional asymmetric phase-transfer catalysts: application to the enantio- and diastereoselective nitro-Mannich reaction of amidosulfones. AB - A new family of bifunctional H-bond donor phase-transfer catalysts derived from cinchona alkaloids has been developed and evaluated in the enantio- and diastereoselective nitro-Mannich reaction of in situ generated N-Boc-protected imines of aliphatic, aromatic, and heteroaromatic aldehydes. Under optimal conditions, good reactivity and high diastereoselectivities (up to 24:1 dr) and enantioselectivities (up to 95% ee) were obtained using a 9-amino-9 deoxyepiquinidine-derived phase-transfer catalyst possessing a 3,5 bis(trifluoromethyl)phenylurea H-bond donor group at the 9-position. PMID- 22548632 TI - High-yielding, versatile, and practical [Rh(III)Cp*]-catalyzed ortho bromination and iodination of arenes. AB - We report a uniquely high-yielding, general, and practical ortho bromination and iodination reaction of different classes of aromatic compounds. This reaction occurs by Rh(III)-catalyzed C-H bond activation methodology and is therefore the first example of the application of this cationic catalyst for C-Br and C-I bond formation. PMID- 22548633 TI - Radiative ion-ion neutralization: a new gas-phase atmospheric pressure ion transduction mechanism. AB - All atmospheric pressure ion detectors, including photo ionization detectors, flame ionization detectors, electron capture detectors, and ion mobility spectrometers, utilize Faraday plate designs in which ionic charge is collected and amplified. The sensitivity of these Faraday plate ion detectors are limited by thermal (Johnson) noise in the associated electronics. Thus approximately 10(6) ions per second are required for a minimal detection. This is not the case for ion detection under vacuum conditions where secondary electron multipliers (SEMs) can be used. SEMs produce a cascade of approximately 10(6) electrons per ion impinging on the conversion dynode. Similarly, photomultiplier tubes (PMTs) can generate approximately 10(6) electrons per photon. Unlike SEMs, however, PMTs are evacuated and sealed so that they are commonly used under atmospheric pressure conditions. This paper describes an atmospheric pressure ion detector based on coupling a PMT with light emitted from ion-ion neutralization reactions. The normal Faraday plate collector electrode was replaced with an electrode "needle" used to concentrate the anions as they were drawn to the tip of the needle by a strong focusing electric field. Light was emitted near the surface of the electrode when analyte ions were neutralized with cations produced from the anode. Although radiative-ion-ion recombination has been previously reported, this is the first time ions from separate ionization sources have been combined to produce light. The light from this radiative-ion-ion-neutralization (RIIN) was detected using a photon multiplier such that an ion mobility spectrum was obtained by monitoring the light emitted from mobility separated ions. An IMS spectrum of nitroglycerin (NG) was obtained utilizing RIIN for tranducing the mobility separated ions into an analytical signal. The implications of this novel ion transduction method are the potential for counting ions at atmospheric pressure and for obtaining ion specific emission spectra for mobility separated ions. PMID- 22548634 TI - Evaluation of Leuconostoc mesenteroides YML003 as a probiotic against low pathogenic avian influenza (H9N2) virus in chickens. AB - AIM: The aims of the study were to isolate anti-H9N2 bacteria from Korean Kimchi isolates and to evaluate its performance in cell line, egg and in specific pathogen-free (SPF) chickens. METHODS AND RESULTS: Using Madin-Darby canine kidney (MDCK) cell line, 220 bacterial isolates were screened and the isolate YML003 was selected having pronounced antiviral activity against H9N2 virus. This isolate was identified as Leuconostoc mesenteroides by 16S rRNA gene sequencing. Anti-H9N2 activity of the strain was also evaluated by hemagglutination assay. Leuconostoc mesenteroides YML003 was assessed for its survival in gastric juice and 5% bile acid and the antibiotic susceptibility. Both live and heat-killed cells were selected for in vivo chicken feeding experiment. Body weight, immune index, serobiochemical parameters and splenic IFN-gamma production were assessed during selected intervals. Viral population in the trachea and cloacae were calculated by quantitative real-time reverse transcriptase PCR (qRT-PCR). CONCLUSIONS: Leuconostoc mesenteroides YML003 exhibited anti-H9N2 activity both in in vitro cell line as well as in vivo SPF chickens. SIGNIFICANCE AND IMPACT OF THE STUDY: This is a primary report on the anti-H9N2 activity by a Leuconostoc strain. Amid the increasing reports of avian influenza virus occurrence resulting in severe losses to the poultry industry, prophylactic administration of such probiotic strains are highly significant. PMID- 22548635 TI - From the editors. Health effects of exposure to PM2.5 and ozone. PMID- 22548636 TI - Miscommunicating risk, uncertainty, and causation: fine particulate air pollution and mortality risk as an example. AB - A recent paper in this journal (Fann et al., 2012) estimated that "about 80,000 premature mortalities would be avoided by lowering PM(2.5) levels to 5 MUg/m(3) nationwide" and that 2005 levels of PM(2.5) cause about 130,000 premature mortalities per year among people over age 29, with a 95% confidence interval of 51,000 to 200,000 premature mortalities per year.((1)) These conclusions depend entirely on misinterpreting statistical coefficients describing the association between PM(2.5) and mortality rates in selected studies and models as if they were known to be valid causal coefficients. But they are not, and both the expert opinions of EPA researchers and analysis of data suggest that a true value of zero for the PM(2.5) mortality causal coefficient is not excluded by available data. Presenting continuous confidence intervals that exclude the discrete possibility of zero misrepresents what is currently known (and not known) about the hypothesized causal relation between changes in PM(2.5) levels and changes in mortality rates, suggesting greater certainty about projected health benefits than is justified. PMID- 22548638 TI - Ten most important accomplishments in risk analysis, 1980-2010. PMID- 22548641 TI - Frequency of lower respiratory tract infections in relation to adaptive immunity in children with Down syndrome compared to their healthy siblings. AB - AIM: Children with Down syndrome (DS) experience respiratory tract infections (RTIs) more frequently than healthy children. We investigated whether this is related to different immunological characteristics associated with DS. METHODS: The study group consisted of 22 children with DS and 22 of their healthy, age range matched siblings. Data were collected on infections and hospitalizations because of lower RTIs. Immunoglobulin and IgG subclass levels in blood, as well as lymphocyte and T cell (subset) counts, were determined. RESULTS: The children with DS had a significantly higher frequency of lower RTIs and related hospitalization than their siblings. We also found significantly reduced IgG2 levels as well as significantly lower counts of total lymphocytes, CD4(+) T lymphocytes, CD4(+) invariant natural killer (iNKT) cells and regulatory T cells in the DS group. CONCLUSION: In children with DS, reduced levels of IgG2, total lymphocytes, T lymphocytes, iNKT cells and regulatory T cells might contribute to their higher susceptibility to lower RTIs. PMID- 22548642 TI - Engineering case report. Toluene and methyl ethyl ketone exposure from a commercially available contact adhesive. AB - A maintenance worker became ill after working indoors over the course of 3 days with a commercially available contact adhesive containing toluene and methyl ethyl ketone. Respiratory protection or local exhaust ventilation was not used. The worker subsequently suffered from numerous medical symptoms including tremors and elevated blood pressure. Magnetic resonance imaging documented the occurrence of encephalopathy. The worker has alleged that the cause of these effects was exposure to the vapors from the contact adhesive. The objective of this study was to characterize/estimate the level of the worker's exposure by obtaining air samples in an exposure chamber while performing similar activities under similar conditions. We found that the worker may have been exposed to approximately 159 ppm toluene and 58 ppm methyl ethyl ketone 8-hr time-weighted averages for 8 hr of adhesive application. The maximum 15-min average exposures were 233 ppm toluene and 85 ppm methyl ethyl ketone. PMID- 22548643 TI - Electrochemical activity of glucose oxidase on a poly(ionic liquid)-Au nanoparticle composite. AB - Glucose oxidase (GOx) adsorbed on an ionic liquid-derived polymer containing internally organized columns of Au nanoparticles exhibits direct electron transfer and bioelectrocatalytic properties towards the oxidation of glucose. The cationic poly(ionic liquid) provides an ideal substrate for the electrostatic immobilization of GOx. The encapsulated Au nanoparticles serve to both promote the direct electron transfer with the recessed enzyme redox centers and impart electronic conduction to the composite, allowing it to function as an electrode for electrochemical detection. PMID- 22548644 TI - Treatment of acne scars by fractional bipolar radiofrequency energy. AB - BACKGROUND/OBJECTIVE: A variety of modalities are available for the treatment of acne scars. This prospective, IRB-approved study evaluates the efficacy and tolerance of fractional bipolar RF energy in the treatment of facial acne scars. METHODS: Healthy subjects (n = 15, 13 females, aged 35.7 +/- 5.6 years [mean +/- SD], skin types I-V) with mild to moderate acne scars received three monthly treatments with a fractional bipolar RF device. Improvement and tolerance were evaluated at each visit, including a 1-month and 3-month follow-up visit. RESULTS: Ten subjects completed the study. Physician-assessed acne scar severity was significantly reduced at 1 month and 3 months. Adverse effects were limited to transient erythema. Dryness, bruising and crusting erosion were limited. Subject-assessed stinging/burning, stinging (alone), tingling, itching and burning were also limited and consistent with each treatment. Subject-assessed fine lines and wrinkles, brightness, tightness, acne scar texture, pigmentation were all improved significantly. Satisfaction was high in 67-92% of subjects. CONCLUSION: Fractional bipolar RF energy is a safe and effective modality for the treatment of acne scars. PMID- 22548645 TI - Coxofemoral joint radiography in standing cattle. AB - The objective of this study was to establish a technique for radiographic examination of the coxofemoral joint and adjacent bony structures in standing cattle. Left (or right) 30 degrees dorsal-right (or left) ventral radiographic views of the coxofemoral joint region of standing cattle (n = 10) with hind limb lameness were evaluated retrospectively. In addition, an experimental study of oblique laterolateral views of the coxofemoral joint region of a bovine skeleton at angles of 15-45 degrees was carried out to determine the optimal position for visualization of the hip region. In the 10 clinical patients, the bodies of the ilium and ischium, the acetabulum and proximal third of the femur could be assessed. Six of these cattle had fractures of the body of the ilium and body of the ischium, five with and one without involvement of the acetabulum, two had craniodorsal and one caudoventral luxation of the femur and one had a femoral neck fracture. The described laterodorsal-lateroventral radiographs of the hip region in standing cattle were suitable for assessing the coxofemoral joint, the proximal aspect of the femur and parts of the ischium, ilium and pubis. After testing the optimal angle on the skeleton, it was seen that distortion and superimposition were minimized by positioning the X-ray beam at an angle of 25 degrees to the horizontal plane. It can be concluded that the described technique improves the evaluation of injuries of the coxofemoral region in cattle. With the appropriate angle, the technique can also be applied in recumbent cattle. PMID- 22548646 TI - Effect of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, on bacteriuria and urinary tract infection in subjects with type 2 diabetes enrolled in a 12-week, phase 2 study. AB - OBJECTIVE: To examine the effects of canagliflozin, a sodium glucose co transporter 2 inhibitor that lowers blood glucose by increasing urinary glucose excretion (UGE), on asymptomatic bacteriuria and urinary tract infections (UTIs). RESEARCH DESIGN AND METHODS: In a randomized, double-blind, placebo-controlled, multicenter, dose-ranging phase 2 study, subjects with type 2 diabetes with inadequate glycemic control while receiving metformin were enrolled and randomized to one of seven arms - placebo; canagliflozin doses 50 mg, 100 mg, 200 mg, 300 mg daily, or 300 mg twice daily; and sitagliptin 100 mg daily - for 12 weeks. CLINICAL TRIAL REGISTRATION: This study is registered under Clinicaltrials.gov identification number NCT00642278. RESULTS: Canagliflozin increased renal glucose excretion by 35.4-61.6 mg/mg creatinine in the five dose groups. In the placebo group renal glucose excretion was increased by 1.9 mg/mg creatinine, and in the sitagliptin group it decreased by 1.9 mg/mg creatinine. Asymptomatic bacteriuria (ASB) were present in 6.4% of canagliflozin and 6.5% of placebo/sitagliptin (control) subjects at randomization and, at 12 weeks, in 7.7% and 6.3% of subjects, respectively (odds ratio [OR] 1.23; 95% confidence interval [CI], 0.45-3.89). For subjects with initially negative urine cultures at baseline, 3 out of 82 (3.7%) who received controls and 10 out of 207 (4.8%) who received canagliflozin developed bacteriuria (p = 0.76) at week 12. There were 21 adverse event (AE) reports of UTI; 16 (5.0%) in canagliflozin subjects and 5 (3.8%) in control subjects (OR 1.31; 95% CI, 0.45-4.68). CONCLUSIONS: In this trial, when compared with control subjects, canagliflozin increased UGE but was not associated with increased bacteriuria or AE reports of UTI. However, further studies enrolling larger numbers of subjects with longer term exposure to canagliflozin will be necessary to more fully understand the impact of this agent on the risk of developing UTI. PMID- 22548647 TI - Clinical impact of HSV-1 detection in the lower respiratory tract from hospitalized adult patients. AB - The occurrence and clinical impact of herpes simplex virus (HSV) were evaluated in 342 bronchoalveolar lavage specimens from 237 patients. HSV-1 and HSV-2 were detected in 32.1% and <1% of patients, respectively. A significant difference of HSV-1 prevalence and load was found in relation to admission to intensive care unit, mechanical ventilation and mortality within 28 days; in particular, a viral load >=10(5) copies/mL bronchoalveolar lavage fluid was significantly associated with critical features. No association was found with immune status or other characteristics. Nine of 21 (42.9%) cases of ventilator-associated pneumonia were positive for HSV-1, with poor outcome in six. PMID- 22548648 TI - Conspecific cues and breeding habitat selection in an endangered woodland warbler. AB - 1. Research on habitat selection has focused on the role of vegetative and geologic characteristics or antagonistic behavioural interactions. 2. Conspecifics can confer information about habitat quality and provide positive density-dependent effects, suggesting habitat selection in response to the presence of conspecifics can be an adaptive strategy. 3. We conducted a manipulative field experiment investigating use of conspecific location cues for habitat selection and consequent reproductive outcomes for the endangered golden cheeked warbler (Setophaga chrysoparia). We investigated the response in woodlands across a range of habitat canopy cover conditions typically considered suitable to unsuitable and using vocal cues presented during two time periods: pre-settlement and post-breeding. 4. Warblers showed a strong response to both pre-settlement and post-breeding conspecific cues. Territory density was greater than four times higher in treatment sample units than controls. The magnitude of response was higher for cues presented during the pre-settlement period. Positive response to conspecific cues was consistent even in previously unoccupied areas with low canopy cover typically considered unsuitable, resulting in aggregations of warblers in areas generally not considered potential habitat. 5. Pairing and reproductive success of males was not correlated with canopy cover, as commonly thought. Pairing success and fledging success increased with increasing territory density suggesting that conspecific density may be more important for habitat selection decisions than the canopy cover conditions typically thought to be most important. These results suggest the range of habitat within which birds can perform successfully may be greater than is typically observed. 6. Our results suggest the territory selection process may not be substantially influenced by competition in some systems. Settlement in response to conspecific cues produced aggregations within larger areas of similar vegetative characteristics. Understanding what cues drive habitat selection decisions and whether these cues are correlated with habitat quality is critical for conserving fitness-enhancing habitats, avoiding creation of ecological traps, generating accurate predictions of species distributions and understanding how occupancy relates to habitat suitability. PMID- 22548649 TI - Overexpression of RNA helicase p68 protein in cutaneous squamous cell carcinoma. AB - BACKGROUND: RNA helicase p68 is a prototypic DEAD-box RNA helicase. Recent studies indicate that p68 plays important role in cancer development and progression. However, the role of p68 protein expression in cutaneous squamous cell carcinoma (SCC) remains unknown. AIM: To elucidate the expression of p68 protein in cutaneous SCC. METHODS: The level of p68 protein was examined by double immunofluorescent staining in 24 samples of human cutaneous SCC tissue specimens and their adjacent tissues and in 6 normal foreskin samples to compare the expression of p68 with that of Ki-67. RESULTS: Overexpression of p68 protein was seen in all 24 SCC cases (100%), whereas very low expression of p68 was detected in normal foreskin. Moreover, p68 protein expression was higher in cases of cutaneous SCC with metastasis than in cases without metastasis. Additionally, p68 had a similar expression pattern to that of Ki-67. CONCLUSION: The high frequency of p68 expression in cutaneous SCC indicates that p68 might be involved in the development and progression of cutaneous SCC. PMID- 22548650 TI - Heptanuclear heterometallic [Cu6Ln] clusters: trapping lanthanides into copper cages with artificial amino acids. AB - Employment of the artificial amino acid 2-amino-isobutyric acid, aibH, in Cu(II) and Cu(II)/Ln(III) chemistry led to the isolation and characterization of 12 new heterometallic heptanuclear [Cu(6)Ln(aib)(6)(OH)(3)(OAc)(3)(NO(3))(3)] complexes consisting of trivalent lanthanide centers within a hexanuclear copper trigonal prism (aibH = 2-amino-butyric acid; Ln = Ce (1), Pr (2), Nd (3), Sm (4), Eu (5), Gd (6), Tb (7), Dy (8), Ho (9), Er (10), Tm (11), and Yb (12)). Direct curent magnetic susceptibility studies have been carried out in the 5-300 K range for all complexes, revealing the different nature of the magnetic interactions between the 3d-4f metallic pairs: dominant antiferromagnetic interactions for the majority of the pairs and dominant ferromagnetic interactions for when the lanthanide center is Gd(III) and Dy(III). Furthermore, alternating current magnetic susceptibility studies reveal the possibility of single-molecule magnetism behavior for complexes 7 and 8. Finally, complexes 2, 5-8, 10, and 12 were analyzed using positive ion electrospray mass spectrometry (ES-MS), establishing the structural integrity of the heterometallic heptanuclear cage structure in acetonitrile. PMID- 22548652 TI - Differences in triglyceride and cholesterol metabolism and resistance to obesity in male and female vitamin D receptor knockout mice. AB - A lean phenotype has been detected in vitamin D receptor (VDR) knockout mice; however, the gender differences in fat metabolism between male and female mice both with age and in response to a high-fat diet have not been studied before. The objective of our study was to assess changes in body and fat tissue weight, food intake and serum cholesterol and triglyceride in VDR knockout mice from weaning to adulthood and after a challenge of adult animals with a high-fat diet. Although VDR knockout mice of both sexes consumed more food than wild-type and heterozygous littermates, their body weight and the weight of fat depots was lower after 6 months on a diet with 5% crude fat content. When adult animals were challenged with a high-fat diet containing 21% crude fat content for 8 weeks, VDR knockout mice of both sexes had a significantly higher food intake but gained less weight than their wild-type littermates. Cholesterol levels were higher after 2 days on the high-fat diet in both sexes, but in the VDR knockout mice, less cholesterol was detected in the serum after 8 weeks. Wild-type male mice showed signs of fatty liver disease at the end of the experiment, which was not detected in the other groups. In conclusion, lack of the VDR receptor results in reduced fat accumulation with age and when adult mice are fed a high-fat diet, despite a higher food intake of VDR knockout mice relative to their wild-type littermates. These effects can be detected in both sexes. Wild-type male mice react with the highest weight gain and cholesterol levels of all groups and develop fatty liver disease after 8 weeks on a high-fat diet, while male VDR knockout mice appear to be protected. PMID- 22548653 TI - Li14Ln5[Si11N19O5]O2F2 with Ln = Ce, Nd--representatives of a family of potential lithium ion conductors. AB - The isotypic layered oxonitridosilicates Li(14)Ln(5)[Si(11)N(19)O(5)]O(2)F(2) (Ln = Ce, Nd) have been synthesized using Li as fluxing agent and crystallize in the orthorhombic space group Pmmn (Z = 2, Li(14)Ce(5)[Si(11)N(19)O(5)]O(2)F(2): a = 17.178(3), b = 7.6500(15), c = 10.116(2) A, R1 = 0.0409, wR2 = 0.0896; Li(14)Nd(5)[Si(11)N(19)O(5)]O(2)F(2): a = 17.126(2), b = 7.6155(15), c = 10.123(2) A, R1 = 0.0419, wR2 = 0.0929). The silicate layers consist of dreier and sechser rings interconnected via common corners, yielding an unprecedented silicate substructure. A topostructural analysis indicates possible 1D ion migration pathways between five crystallographic independent Li positions. The specific Li-ionic conductivity and its temperature dependence were determined by impedance spectroscopy as well as DC polarization/depolarization measurements. The ionic conductivity is on the order of 5 * 10(-5) S/cm at 300 degrees C, while the activation energy is 0.69 eV. Further adjustments of the defect chemistry (e.g., through doping) can make these compounds interesting candidates for novel oxonitridosilicate based ion conductors. PMID- 22548654 TI - [Beyond eugenics: posthumanism as Homo patiens denials]. AB - Throughout history there have been attempts to overcome human limitations by means of technique. The novelty of the 20th century has been to try to extirpate all the faults, the suffering, the disease, and even the death. This power has been attributed successively to machines (the futurism), to the genetic information (the eugenism) and to the electronic information (the posthumanism). In all cases, it's unknown the distinction between inevitable faults, ontological deficiencies, as the reality of death, and avoidable ones, sociological deficiencies, as the deaths due to circumstances as lack of drinkable water, of medicaments, wars or any other type of violence. The due way of confronting the human faults is to try to eradicate their avoidable causes and at the same time to understand the sense of those that cannot be avoided, as occasion of the self overcoming and the opening to the Transcendence. PMID- 22548651 TI - Brain-derived neurotrophic factor as a regulator of systemic and brain energy metabolism and cardiovascular health. AB - Overweight sedentary individuals are at increased risk for cardiovascular disease, diabetes, and some neurological disorders. Beneficial effects of dietary energy restriction (DER) and exercise on brain structural plasticity and behaviors have been demonstrated in animal models of aging and acute (stroke and trauma) and chronic (Alzheimer's and Parkinson's diseases) neurological disorders. The findings described later, and evolutionary considerations, suggest brain-derived neurotrophic factor (BDNF) plays a critical role in the integration and optimization of behavioral and metabolic responses to environments with limited energy resources and intense competition. In particular, BDNF signaling mediates adaptive responses of the central, autonomic, and peripheral nervous systems from exercise and DER. In the hypothalamus, BDNF inhibits food intake and increases energy expenditure. By promoting synaptic plasticity and neurogenesis in the hippocampus, BDNF mediates exercise- and DER-induced improvements in cognitive function and neuroprotection. DER improves cardiovascular stress adaptation by a mechanism involving enhancement of brainstem cholinergic activity. Collectively, findings reviewed in this paper provide a rationale for targeting BDNF signaling for novel therapeutic interventions in a range of metabolic and neurological disorders. PMID- 22548655 TI - [From crime to law. The decline of the legal protection of life]. AB - The new regulation of abortion as a right implies a decisive step in the decline of the legal protection of life in Spanish law. The current regulation embodied in the Organic Law 2 / 2010 called the Law of sexual and reproductive health and abortion is a radical change in Spanish law on this matter. What was a passing offense now become a right: there is no greater or more radical change, the voluntary death of embryonic child can be perpetrated for the benefit of the free development of personality of the mother, or the right to privacy or their ideological freedom. The abortion is configured as a right and also as one that overrides the right to conscientious objection.The new law of the unborn life is unprotected, at the mercy of the arbitrariness of the pregnant woman.The new regulation violates the text of Article 15 of the Constitution and is inconsistent with the constitutional jurisprudence on the matter. The issue of respect of human life can not ignore its intrinsic and pure legal logic: if there is a right to life, there can be no right to end it. PMID- 22548656 TI - [Neurocosmetics, transhumanism and eliminative materialism: toward new ways of eugenics]. AB - In this paper I present similarities and connections between Transhumanism and Eliminative Materialism. Concretely, I study the arguments with which in both positions it is defended a merely instrumental idea of human body and, because of that, one infinitely mouldable. First, I show the social relevance of this idea and its projections in phenomena as medicalization of human condition and, especially, cosmetic psychopharmacology. Besides, I denounce that such influences are caused by illegitimate transference of authority between philosophical and scientific forums. Second, according to my analysis, these new postmodern fashions of chemical sentimentalism (related with radical changes on personal identity and human nature) drive to new eugenic forms what I name autoeugenics. Finally, I call attention to the important role of utopian speeches about the science of tomorrow and super-human civilization in a Carpe Diem society. In my conclusions, I claim that historical reasoning or warnings about what is coming are not efficient strategies to control neither new psychopharmacological habits nor passivity generated by them. Returning social confidence in the power of reason to achieve reality (and other human beings) is, in my opinion, the best way to rehabilitate a more and more devalued human action. PMID- 22548657 TI - [Eugenics' extension in the Spanish health care system through the prenatal diagnosis]. AB - The wide implantation of strategies of sifted or prenatal selection close to laws that protect the destruction of the human life before the childbirth in the whole world, they are giving place to an increasing number of eugenic abortions. In Spain, the law 2/2010 of the sexual and reproductive health and voluntary interruption of pregnancy there has supposed the liberalization of the eugenic abortion without term limit. In we make concrete, the sanitary national and international policies of prenatal selection of Down's Syndrome, which they chase to facilitate the total or partial destruction before the childbirth of this human group, submitting it to a few particular conditions of existence during his prenatal life in those who will be an object of a series of technologies of selection, they might be qualified of genocidal policies if we consider the definition of genocide given by United Nations. In consequence, the sanitary agent who takes part without objection in the above mentioned programs promoted by the principal agents, meets turned into a necessary cooperator of the abortion who justifies itself in the supposition of "foetal risk". We can conclude that we are present at an eugenic drift of the prenatal diagnosis that is opposite to the ethical beginning of the medical profession. PMID- 22548658 TI - [The "evil ideology": description and critique of a policy against human nature]. AB - Ideological evil is to place certain ideals above the real and concrete human person, and has been a feature of the twentieth century totalitarian policies, particularly those who have checked out the life and dignity of human beings. Today this evil ideology embodied in the political and legislative impulses that reduce the scope of protection of life and question the dignity of vulnerable life stages (infants, mentally ill, dying). The most important case in Spain today has been the recent Organic Law 2/2010, the law clearly ideological, out of arguments that promote humanity and on the contrary a law that puts the life periods of future citizens in a dangerous area unprotected and dubious puts individual rights and a strong ideological impulses value of human dignity and fundamental rights that flow from it with are, in this case the protection of life and liberty of conscience. PMID- 22548659 TI - [Dependents and rationale: the human family]. AB - There are many concepts that influence bioethics, which can make it prosper or fail. We will focus here on two of them, namely the concept of dependency, which functions as a necessary complement of the concept of autonomy, and the concept of human family, which probably should work as a substitute in moral contexts of the notion of human species. In a deeper level, both dependency and human family, refer to another concept, endowed with a long philosophical tradition, that of human nature, which has become the center of debate in recent years. Modernity can be characterized as a search for autonomy. Autonomy in many ways is a desirable objective and fair. However, this one-sided emphasis on autonomy has led to a partial anthropology; hence the importance of developing also an anthropology of dependency, and emphasizing the links that connect the different members of the human family. PMID- 22548660 TI - [Twenty-five years of screening eugenics in Spain]. AB - Over the past 25 years, the incidence of newborns with congenital defects in Spain has fallen by 56.7% primarily due to the practice of "fetal risk" abortion, after prenatal diagnosis. In some cases, such as people with Down syndrome, the strategy involves the removal of 80-90% of those affected in pregnancy. After presenting the techniques used today and statistical data, we will make a reflection about the ethical justification for prenatal diagnosis programs and practice of "eugenic" abortion. PMID- 22548661 TI - [The silent disappearance: report of screening eugenics of people with Down syndrome]. AB - In this article, we try to reflext an avident fact: since the last 20 years, the percentage of births of Down Sindrome in Spain is decreasing. This fact is so silenciated in the mass media, that we can call "the silent dissapearance". But this is a bit of a more big problem more preocupated: the rejection of our society against the disabled people. For this, first, we present the facts, and then we will make a bioethical reflexion about the meaning of the rejection of disabled people, a serious fact that contradict the human responsability for others. PMID- 22548662 TI - [State policy at the end of life. The transformation of medical deontology]. AB - The contemporary state invades privacy in ways that affect even the end of life process. It develops public policies that can affect medical ethics. This limitation of power leaves the doctor's attention to the profession and may become a convenient code. PMID- 22548663 TI - [The rescue of the human in the patient who dies]. AB - In this article I discuss briefly a proposal for the recovery of the essential content of the concept of human nature through the careful attention to ethics which must be received by a terminal ill person in the last phase of life. I propose palliative medicine as a way to rescue the human mind in the life of dying patients to whom the fullness of nature and human dignity belongs. It's about recovering the original medical ethos through the exercise of the virtues through which staff can be trained to recognize the weak, the sick, miserable, the dispossessed are important, are worthy of medicine, used for science: are human and quite valid. PMID- 22548664 TI - [Patients' autonomy and right to the information: from the recognition of rights, to the loss of confidence. Reflections on the new regulation about patients' rights at the end of life]. AB - This paper analyses the evolution of physician-patient relationship in the last decades, and the way in which the law influences in it through the regulation of the patient's rights. It underlines the importance of defend patient's autonomy, and, at the same time, alerts to the risks of the widespread of the defensive healthcare. PMID- 22548665 TI - [Palliative care: accompanying persons at the end of life]. AB - The philosophy, the essence and the therapeutic goals of palliative care help the health professionals offer the patients a high quality assistance on their last stage of life. With both, a human and scientific view, it's possible to deal with the relief of suffer on all dimensions. PMID- 22548666 TI - [Secular bioethics and religious bioethics. Keys to a contemporary argument]. AB - Within the context of the contemporary plural debate, it is common to use the adjective secular as if it were the only manner to participate in the bioethical debate of Western multi-ethnic society. This situation gives rise to the question of whether there can be a religious contribution to the current bioethical debate. There are two possible answers. The first, an affirmative one, is centered on the fact that contemporary society is characterized by pluralistic and secular values on which is based the obligations of its members, defined by consensus through democratic procedures. In this context, religious contribution, as something from the private sphere, must be excluded. The alternative response to our central question may be negative, based on the assertion that human beings are identified as members of different value systems, many of them imbued with religious elements. From this point of view, the religious phenomenon would be one of the most important elements in the debate on cultural pluralism, because it guides, and serves as an inspiration of our conduct. This article aims to answer our central question by analyzing each of the two possible positions. The article is divided into two sections; the first analyses the significance of the term secular when it is employed in the sphere of bioethics and the second examines whether, within the scope of democratic societies, the current religious contribution to the bioethics debate has any legitimacy. The article ends with some conclusions. PMID- 22548667 TI - [Severe diseases with prenatal diagnosis]. AB - The aim of this article is to present the published information until this moment about the survival, long term effects and quality of life of the diseases named by the Bioethics Committee of the Spanish Society of Gynaecologist and Obstetricians (SEGO) as extremely severe and untreatable diseases, subsidiary of a Voluntary Termination of Pregnancy after the 22 weeks of gestational age, according to the Organic Law 2/2010 of Sexual and Reproductive Health and Voluntary Termination of Pregnancy. Health professionals must know the medical aspects, the therapeutics advances and the outcomes of these diseases, and it is a high standard of professional ethics to transmit this information to the progenitors. PMID- 22548668 TI - [Experiences and ethical questions of family members of patients with dementia]. AB - There are many decisions that family members of sufferers of Alzheimer's disease and other forms of dementia are forced to take to guarantee the well-being and quality of life of their loved ones and, of course, themselves. A little more than 12 years ago in Medina del Campo, Valladolid, there arose the need to inform and, what's more, to support a large number of people whose family members had been diagnosed with a devastating type of dementia that was practically unknown. The illness presented these families with a growing number of difficult-to resolve ethical dilemmas. This was the genesis of the Asociacion de Familiares de enfermos de Alzheimer (Association of Family Members of Sufferers of Alzheimer's), where baffled family members searching for responsible answers came looking for help to their practical problems that they felt unable to solve using only common sense. What follows are the details of several real situations, the most delicate of which, as the Association psychologist, I shared with the affected families. The cases below involved a dilemma when applying the basic principles of bioethics: non-maleficence, beneficence and respect for the autonomy of the diseased. PMID- 22548669 TI - Characterization of clinical multidrug-resistant Escherichia coli and Klebsiella pneumoniae isolates, 2007-2009, China. AB - Various resistance mechanisms facilitate the emergence and spread of multidrug resistance (MDR) phenotypes of Escherichia coli and Klebsiella pneumoniae. To elucidate the MDR mechanisms of E. coli and K. pneumoniae in China, we analyzed the antimicrobial susceptibilities of strains isolated from clinical samples in a large tertiary care hospital in Beijing, China, during 2007-2009 and characterized the isolates with a cefotaxime-ciprofloxacin-amikacin (CTX-CIP-AK) resistance pattern. In total, 98 and 52 clinical isolates of E. coli and K. pneumoniae, respectively, with a CTX-CIP-AK resistance pattern were subjected to antimicrobial susceptibility testing and screening of common beta-lactamase genes, plasmid-mediated quinolone resistance (PMQR) genes, quinolone resistance determining region (QRDR) substitutions, and 16S rRNA methylase genes by polymerase chain reaction amplification and DNA sequencing. Pulsed-field gel electrophoresis (PFGE) was used to determine the genetic relatedness of the isolates. Approximately 6.86% and 8.05% of the clinical E. coli and K. pneumoniae isolates, respectively, exhibited MDR phenotypes. The MDR K. pneumoniae isolates exhibited significantly higher ceftazidime resistance than the MDR E. coli isolates (90.4% vs. 76.5%, p=0.0339); a similar result was noted for piperacillin tazobactam resistance (28.8% vs. 2%, p=0.0001). The common resistance determinants among the MDR E. coli and K. pneumoniae isolates were as follows: CTX-M (88.8% vs. 82.7%), PMQR genes (70.4% vs. 90.4%), gyrA mutations (100% vs. 90.4%), and 16S rRNA methylase genes (93.9% vs. 94.2%). Half (50%) of the MDR E. coli isolates belonged to phylogenetic group D, followed by group A (39.8%). For the E. coli isolates, 94 PFGE patterns and 23 clusters were identified, whereas 51 PFGE patterns and 11 clusters were identified for the K. pneumoniae isolates. Clinical E. coli and K. pneumoniae isolates seem to have a low prevalence of MDR phenotypes in China. The great genetic variation indicates a considerable transmission of common resistance determinants, including a high prevalence of QRDR substitutions in E. coli and K. pneumoniae. PMID- 22548670 TI - Evaluation of Fbxw7 expression and its correlation with the expression of c-Myc, cyclin E and p53 in human hepatocellular carcinoma. AB - AIM: F-box and WD repeat domain-containing 7 (Fbxw7) is a cell cycle regulatory gene that targets for ubiquitination and proteasomal degradation various cell cycle regulators such as c-Myc and cyclin E. Defects in the Fbxw7 gene that lead to cell cycle re-entry and expedite the G1-S transition is thought to be one of the causes of cancer development. However, its expression and clinical importance for hepatocellular carcinoma (HCC) patients remains undetermined. This prompted us to investigate its expression level in HCC patients to establish its clinical significance. METHODS: Sixty surgically resected paired HCC and normal tumor adjacent tissues were freshly collected. Fbxw7 expression at both mRNA and protein level was examined by reverse transcription polymerase chain reaction and immunohistochemistry. The protein expression of c-Myc, cyclin E and p53 was evaluated by immunohistochemistry to identify correlations with Fbxw7. RESULTS: The mRNA and protein expression of Fbxw7 was significantly downregulated in the HCC tumor tissues compared to the normal tumor-adjacent tissues (P < 0.01, respectively). Fbxw7 protein was expressed at significantly lower levels in patients with high histological grade and advanced tumor-node-metastasis stage. In HCC tissues, Fbxw7 protein expression was negatively correlated with c-Myc, cyclin E and p53 (r = -0.459, P < 0.05; r = -0.573, P < 0.001; r = -0.579, P < 0.05, respectively). CONCLUSION: In HCC, reduced Fbxw7 expression closely correlated with clinicopathological characteristics and may have prognostic potential through the enhanced function of cell cycle regulatory proteins. PMID- 22548671 TI - Systems-based guiding principles for risk modeling, planning, assessment, management, and communication. AB - This article is grounded on the premise that the complex process of risk assessment, management, and communication, when applied to systems of systems, should be guided by universal systems-based principles. It is written from the perspective of systems engineering with the hope and expectation that the principles introduced here will be supplemented and complemented by principles from the perspectives of other disciplines. Indeed, there is no claim that the following 10 guiding principles constitute a complete set; rather, the intent is to initiate a discussion on this important subject that will incrementally lead us to a more complete set of guiding principles. The 10 principles are as follows: First Principle: Holism is the common denominator that bridges risk analysis and systems engineering. Second Principle: The process of risk modeling, assessment, management, and communication must be systemic and integrated. Third Principle: Models and state variables are central to quantitative risk analysis. Fourth Principle: Multiple models are required to represent the essence of the multiple perspectives of complex systems of systems. Fifth Principle: Meta modeling and subsystems integration must be derived from the intrinsic states of the system of systems. Sixth Principle: Multiple conflicting and competing objectives are inherent in risk management. Seventh Principle: Risk analysis must account for epistemic and aleatory uncertainties. Eighth Principle: Risk analysis must account for risks of low probability with extreme consequences. Ninth Principle: The time frame is central to quantitative risk analysis. Tenth Principle: Risk analysis must be holistic, adaptive, incremental, and sustainable, and it must be supported with appropriate data collection, metrics with which to measure efficacious progress, and criteria on the basis of which to act. The relevance and efficacy of each guiding principle is demonstrated by applying it to the U.S. Federal Aviation Administration complex Next Generation (NextGen) system of systems. PMID- 22548672 TI - Eliminating preventable, hemorrhage-related maternal mortality and morbidity. PMID- 22548673 TI - Magic angle magnetic resonance imaging of diode laser induced and naturally occurring lesions in equine tendons. AB - Magic angle magnetic resonance (MR) imaging consists of imaging tendons at 55 degrees to the magnetic field. In people, magic angle MR imaging is valuable for detection of chronic tendon lesions and allows calculation of tendon T1 values. Increased T1 values occur in people with chronic tendinopathy. The T1 values of normal equine tendons have been reported but there are no available data for abnormal equine tendons. Twelve limbs were studied. Two limbs had diode laser tendon lesions induced postmortem, four limbs had diode laser tendon lesions induced in vivo and six limbs had naturally occurring tendon lesions. The limbs were imaged at 1.5 T using both conventional MR imaging and magic angle MR imaging. The post-mortem laser induced lesions were identified only with magic angle MR imaging. The in vivo induced lesions and naturally occurring lesions were identified with both techniques but had a different appearance with the two imaging techniques. Magic angle imaging was helpful at identifying lesions that were hypointense on conventional imaging. Increased T1 values were observed in all abnormal tendons and in several tendons with a subjectively normal MR appearance. The increased T1 value may reflect diffuse changes in the biochemical composition of tendons. Magic angle imaging has potential as a useful noninvasive tool to assess the changes of the extracellular tendon matrix using T1 values. PMID- 22548674 TI - Rational design of high-spin biradicaloids in the isobenzofulvene and isobenzoheptafulvene series. AB - The relative energies of singlet biradicaloid and of triplet and singlet biradical electronic states for a series of benzannelated isobenzofulvenes and isobenzoheptafulvenes were calculated at the (u-)B3LYP/6-31G(d), full pi-space CASSCF-CASPT2 (<=14 pi-e(-)s), and full pi-space RASSCF-RASPT2 (<=24 pi-e(-)s) levels of theory. Both absolute and relative CASPT2 energies were reproduced quite well by the RASPT2 approach, which can be extended to much larger active spaces. RASPT2 (and DFT) calculations find that increasing benzannelation leads to triplet ground states in both hydrocarbon series, in violation of the classical principle of maximum bonding. This confirmed the expectations that the combined effects of resonance energy and aromaticity could compensate for the extra formal pi-bond of the biradicaloid singlet, and that the strong exchange coupling inherent to the embedded trimethylenemethane (TMM) would manifest itself in the biradicaloids. The relative energy of the biradicaloid singlet rises rapidly upon benzannelation, as pi-bonding between the high-energy delocalized GVB orbitals decreases. The underlying pi-orbital topology is revealed when this weak pi-bonding is artificially eliminated by a 1:1 mixing of the nondegenerate HOMO and LUMO to produce an overcorrelated valence bond (OCVB) orbital pair. For members of both biradicaloid series, the OCVB pairs are nondisjoint, revealing a limiting triplet preference with increasing benzannelation. Within the two electron, two-orbital approximation, the effects of pi-bonding in the singlet biradicaloids and orbital localization away from the acene pi-system in the triplet biradicals can be analyzed as perturbations of the singlet OCVB biradicals. The application of a VB-based spin coupling scheme is discussed, in which the unpaired electrons of these species can be considered both ferromagnetically and antiferromagnetically coupled, with the strength of the latter strongly dependent on the acene subunit. PMID- 22548675 TI - Systematic review and meta-analysis of randomized trials on probiotics for hepatic encephalopathy. AB - AIM: The objective of this systematic review and meta-analysis was to assess the efficacy of probiotics and synbiotics in patients with hepatic encephalopathy. METHODS: Eligible trials were identified by searching electronic databases including MEDLINE, the Cochrane Library, Science Citation Index and Embase, abstract proceedings, reference lists and ongoing trial registers until 13 October 2010. We included randomized controlled trials comparing probiotics and synbiotics with no intervention, placebo or lactulose in patients with hepatic encephalopathy. The primary outcome measure was improvement in hepatic encephalopathy. RESULTS were expressed as risk rates (RR) with confidence intervals (CI) and intertrial heterogeneity as I(2) . RESULTS: Seven trials with a total of 393 patients were analyzed. Compared to placebo or lactulose, treatment with probiotics or synbiotics significantly improved hepatic encephalopathy (RR = 1.40, 95% CI = 1.05-1.86, I(2) = 5%). Probiotics decreased arterial ammonia (weighted mean difference 15.95; 95% CI = 26.72-3.28; I(2) = 68%), but not venous ammonia (weighted mean difference 5.23; 95% CI = 21.77 11.30; I(2) = 89%). Treatment with probiotics or synbiotics did not significantly affect the psychometric tests. Overall adverse events were reported in four trials with no difference between probiotics and placebo groups (RR = 0.32, 95% CI = 0.04-2.57; I(2) = 59%). Regression analysis showed evidence of small-study effects. CONCLUSION: The present meta-analysis suggests that probiotics may be an effective treatment of hepatic encephalopathy, though rigorous evaluation in standardized, randomized, clinical trial with clinically relevant outcomes is still needed. PMID- 22548676 TI - Developmental defects of enamel in primary teeth: prevalence and associated factors. AB - BACKGROUND: Studies on the prevalence of enamel defects in the primary dentition as a whole are scarce, as most investigations examine specific population groups. OBJECTIVES: The aim of this study was to evaluate the prevalence of enamel defects in primary teeth and determine whether prematurity, birthweight, and socio-demographic variables are associated with such defects. DESIGN: A cross-sectional study was carried out with 381 children aged 3-5 years. Data were collected through clinical examinations and interviews with parents during the National Immunisation Day. The diagnosis of enamel defects was performed using the Developmental Defects of Enamel (DDE) Index. Through interviews, information was collected on socio-demographic aspects, pregnancy, birthweight, prematurity, and breastfeeding. Statistical analysis was performed using the SPSS program for Windows and involved descriptive analysis, Fisher's exact test, the chi-square test, and Poisson regression. RESULTS: The prevalence of developmental defects of enamel was 29.9%. Demarcated opacity was the most frequent type of defect. Children with a history of very low birthweight had a greater prevalence of enamels defects (PR, 2.7; 95% CI, 1.66-4.61). Prematurity and socio-demographic variables were not associated with enamel defects. CONCLUSION: Children with a history of very low birthweight had a greater frequency of enamel defects in primary teeth. PMID- 22548677 TI - Optimizing adherence in hypertension: a comparison of outcomes and costs using single tablet regimens vs individual component regimens. AB - BACKGROUND: Several studies have demonstrated that the use of single tablet regimens (STRs) in hypertension is associated with improved outcomes and reduced healthcare costs compared with individual component regimens. The objective was to carry out a retrospective analysis of a UK general practice population to test these conclusions in a UK context. METHOD: A retrospective cohort study was carried out using a primary care database (The Health Improvement Network; THIN), comparing 9929 hypertensive patients on STRs with 18,665 patients on individual component therapy. Data were collected for prescriptions, significant cardiovascular events, and out-patient referrals over a minimum follow-up period of 5 years after initiation of therapy. Current NHS costings were applied to the data, to arrive at an estimate of comparative resource use. RESULTS: There were significantly more cardiovascular events in the individual component group than those treated with a single tablet regimen. Five year event rates: 8.3% vs 13.6%; Absolute Risk Reduction (ARR) =5.3%; Number needed to treat (NNT) =18.9. After correction for potential confounders, the hazard ratio was 0.74 (95%CI=0.70 0.77), p<0.0001. Hospital admission costs were lower in the STR group, but drug costs were higher. Overall, the mean annual management cost per patient was similar in the two groups (L191.49 vs L189.35). KEY LIMITATIONS: The study was based on a retrospective cohort and the result may therefore be influenced by unidentified confounders. It was not possible to identify the reasons for individual prescriptions, some of which may have been issued for reasons other than hypertension. Costings for some components of the outcome could not be assessed from the dataset and are therefore omitted from the analysis. Finally, no attempt was made to distinguish outcomes associated with individual classes of anti-hypertensives. CONCLUSIONS: This study confirms the association observed by other authors that patients treated with STRs are less likely to experience serious cardiovascular events than those on individual component therapy. In a UK context this analysis has shown that potential hospital savings broadly offset the additional drug acquisition costs associated with STRs. These agents can therefore be considered cost neutral. PMID- 22548678 TI - A review of oxalate poisoning in domestic animals: tolerance and performance aspects. AB - Published data on oxalate poisoning in domestic animals are reviewed, with a focus on tolerance and performance. Oxalic acid is one of a number of anti nutrients found in forage. It can bind with dietary calcium (Ca) or magnesium (Mg) to form insoluble Ca or Mg oxalate, which then may lead to low serum Ca or Mg levels as well as to renal failure because of precipitation of these salts in the kidneys. Dietary oxalate plays an important role in the formation of Ca oxalate, and a high dietary intake of Ca may decrease oxalate absorption and its subsequent urinary excretion. Oxalate-rich plants can be supplemented with other plants as forage for domestic animals, which may help to reduce the overall intake of oxalate-rich plants. Non-ruminants appear to be more sensitive to oxalate than ruminants because in the latter, rumen bacteria help to degrade oxalate. If ruminants are slowly exposed to a diet high in oxalate, the population of oxalate-degrading bacteria in the rumen increases sufficiently to prevent oxalate poisoning. However, if large quantities of oxalate-rich plants are eaten, the rumen is overwhelmed and unable to metabolize the oxalate and oxalate-poisoning results. Based on published data, we consider that <2.0% soluble oxalate would be an appropriate level to avoid oxalate poisoning in ruminants, although blood Ca level may decrease. In the case of non-ruminants, <0.5% soluble oxalate may be acceptable. However, these proposed safe levels of soluble oxalate should be regarded as preliminary. Further studies, especially long-term studies, are needed to validate and improve the recommended safe levels in animals. This review will encourage further research on the relationships between dietary oxalate, other dietary factors and renal failure in domestic animals. PMID- 22548679 TI - Septic shock in a patient infected with Rickettsia sibirica mongolitimonae, Spain. AB - In 1996, the first human case of infection by Rickettsia sibirica subsp. mongolitimonae was described in France. Subsequently, other human cases were reported in the same country. The acronym LAR (lymphangitis-associated rickettsiosis) has been proposed to designate this disease because lymphangitis is one of the main clinical manifestations. Later, a few more cases were described in Portugal, South Africa, Egypt, Greece and Spain. We report a case of R. sibirica mongolitimonae infection as a cause of septic shock in a Spanish patient living in La Rioja (northern Spain). In addition, the broad clinical spectrum of this tick-borne disease is discussed. PMID- 22548680 TI - Real-time quantification of traces of biogenic volatile selenium compounds in humid air by selected ion flow tube mass spectrometry. AB - Biological volatilization of selenium, Se, in a contaminated area is an economical and environmentally friendly approach to phytoremediation techniques, but analytical methods for monitoring and studying volatile compounds released in the process of phytovolatilization are currently limited in their performance. Thus, a new method for real time quantification of trace amounts of the vapors of hydrogen selenide (H(2)Se), methylselenol (CH(3)SeH), dimethylselenide ((CH(3))(2)Se), and dimethyldiselenide ((CH(3))(2)Se(2)) present in ambient air adjacent to living plants has been developed. This involves the characterization of the mechanism and kinetics of the reaction of H(3)O(+), NO(+), and O(2)(+*) reagent ions with molecules of these compounds and then use of the rate constants so obtained to determine their absolute concentrations in air by selected ion flow tube mass spectrometry, SIFT-MS. The results of experiments demonstrating this method on emissions from maize (Zea mays) seedlings cultivated in Se rich medium are also presented. PMID- 22548687 TI - Hydrophobic zeolites for biofuel upgrading reactions at the liquid-liquid interface in water/oil emulsions. AB - HY zeolites hydrophobized by functionalization with organosilanes are much more stable in hot liquid water than the corresponding untreated zeolites. Silylation of the zeolite increases hydrophobicity without significantly reducing the density of acid sites. This hydrophobization with organosilanes makes the zeolites able to stabilize water/oil emulsions and catalyze reactions of importance in biofuel upgrading, i.e., alcohol dehydration and alkylation of m cresol and 2-propanol in the liquid phase, at high temperatures. While at 200 degrees C the crystalline structure of an untreated HY zeolite collapses in a few hours in contact with a liquid medium, the functionalized hydrophobic zeolites keep their structure practically unaltered. Detailed XRD, SEM, HRTEM, and BET analyses indicate that even after reaction under severe conditions, the hydrophobic zeolites retain their crystallinity, surface area, microporosity, and acid density. It is proposed that by preferentially anchoring hydrophobic functionalities on the external surface, the direct contact of bulk liquid water and the zeolite is hindered, thus preventing the collapse of the framework during the reaction in liquid hot water. PMID- 22548686 TI - Peripheral nerve stimulation for the treatment of postamputation pain--a case report. AB - Many amputees suffer from postamputation pain, which can be extremely debilitating, decrease quality of life, increase the risk of depression, and negatively affect interpersonal relationships and the ability to work. Present methods of treatment, including medications, are often unsatisfactory in reducing postamputation pain. Electrical stimulation of the nerve innervating the painful area could reduce the pain, but peripheral nerve stimulation is rarely used to treat postamputation pain because present methods require invasive surgical access and precise placement of the leads in close proximity (<= 2 mm) with the nerve. The present study investigated a novel approach to peripheral nerve stimulation in which a lead was placed percutaneously a remote distance (> 1 cm) away from the femoral nerve in a patient with severe residual limb pain (RLP) 33 years following a below-knee amputation. Electrical stimulation generated >= 75% paresthesia coverage, reduced RLP by > 60%, and improved quality of life outcomes as measured by the pain interference scale of the Brief Pain Inventory-Short Form (100% reduction in pain interference), Pain Disability Index (74% reduction in disability), and the Patient Global Impression of Change (very much improved) during a 2-week home trial. There were no adverse events. The ability to generate significant paresthesia coverage and pain relief with a single lead inserted percutaneously and remotely from the target nerve holds promise for providing relief of postamputation pain. PMID- 22548688 TI - Histology obtained by needle biopsy gives additional information on the prognosis of hepatocellular carcinoma. AB - AIM: Hepatocellular carcinomas (HCC) have a strong biological heterogeneity. Current prognostic scores do not include histology. Information on the behavior of HCC based on histology has been characterized on retrospective data and large tissue specimens. We aimed to assess the additional value of needle biopsy and keratin 19 (K19) assessment in a prospective manner. METHODS: Between 2003 and 2008, all patients with a confirmed diagnosis of HCC by a percutaneous or laparoscopic needle biopsy at the time of diagnosis, and of Barcelona Clinic Liver Cancer (BCLC) stage A, B or C, were included. The exclusion criterion was a palliative setting. Biopsies were scored for microvascular invasion, differentiation, K19, epithelial cell adhesion molecule and alpha-fetoprotein staining. Clinical and radiological features were registered at time of biopsy. The added value of K19 was assessed using Cox proportional hazards regression. RESULTS: Of 74 patients screened, we included 58 patients. Based on the BCLC, 41% presented with early disease (BCLC A), 16% with intermediate disease (BCLC B) and 43% with advanced disease (BCLC C). In nine patients (16%), K19 staining was positive. Median follow up was 54 months (range 1-74) and 43 patients (72%) died. BCLC classification predicted the prognosis accurately, but histology offered additional prognostic information. In multivariate analysis, K19 was a strong predictor of overall survival (hazard ratio 4.57, 95% confidence interval 1.86 10.6), which improved predictive performance. No needle tract dissemination was observed. CONCLUSION: Despite the possible problem of sampling error, needle biopsy offered additional prognostic information. This is especially the case for K19 staining. PMID- 22548689 TI - Maternal death from obstetric hemorrhage. AB - Obstetric hemorrhage remains the leading cause of maternal death in the United States, and 54% to 93% of these deaths may have been preventable. Leaders must honor the lives of women who die from obstetric hemorrhage by reviewing their deaths and sharing lessons learned. Shortening the current 3 to 7 year data gap will allow for timely initiation of quality improvement efforts. Designated leaders and researchers from the Association of Women's Health, Obstetric, and Neonatal Nurses are ideally positioned to lead these quality initiatives. PMID- 22548690 TI - Evaluation of a program to improve diabetes care through intensified care management activities and diabetes medication copayment reduction. AB - BACKGROUND: Medication copayment reduction can be integrated with disease management programs to incentivize patient engagement in chronic care management. While disease management programs in diabetes have been evaluated across a range of settings and designs, less is known regarding the effectiveness of copayment reduction as a component of disease management. OBJECTIVE: To evaluate the short term results of a diabetes-focused disease management program that included copayment reduction, care coordination, and patient goal setting, focusing on rates of evidence-based care processes and all-cause pharmacy and health care costs. METHODS: Blue Cross Blue Shield of Rhode Island offered large employer groups the opportunity to participate in a diabetes disease management initiative that featured reduced copayments (from $7/$25/$40 for generic, tier 2, and tier 3 drugs, respectively, to $0 for generic and $0-$2 for brand drugs) for diabetes related medications. In return for the copayment reduction, participants agreed to the following: (a) participate in care coordination with a case manager, (b) have an annual physical examination, (c) have a hemoglobin A1c blood test at least twice annually, and (d) have a low-density lipoprotein cholesterol (LDL-C) test at least once annually. Patients received personalized support provided by a registered nurse and dietician, disease-related education provided by nurses, and intensified case management services, including working with a health coach to establish healthy behavioral change goals. All study subjects were aged 18 years or older and had at least 1 ICD-9-CM code for diabetes and at least 1 claim for an antidiabetic drug during a 12-month measurement period, which was each subject's most recent 12-month period of continuous enrollment from January 1, 2008, through May 31, 2010. Administrative claims data were used to determine the percentage of intervention (participating) and nonintervention (nonparticipating) subjects from among all of the plan's employer groups who received at least once yearly monitoring of A1c, high-density lipoprotein cholesterol (HDL-C), and LDL C; medical attention (or drug therapy) for nephropathy; and an eye examination. We conducted multivariate logistic regression analyses to assess the effect of the intervention and other patient characteristics and comorbidities on rates of performance of these care processes, aggregating the 5 processes of care into an "all or none" single composite outcome. We also developed a propensity score weighted model to attempt to adjust for differences between the intervention and nonintervention groups resulting from the nonrandomized study design. Additionally, we quantified average plan payments to providers less patient copayments (i.e., net plan cost) per patient per year (PPPY) for the 12-month follow-up period and compared these costs for the intervention versus nonintervention groups. RESULTS: The study sample consisted of 9,698 patients with diabetes; 649 (6.7%) of whom participated in the intervention. 9,049 (93.3%) patients were identified by the insurer as patients with diabetes receiving usual care. Patients in the intervention and nonintervention groups were similarly likely to have all 5 recommended processes of care performed (40.1% vs. 38.9%, respectively, P = 0.543). Younger patients received all 5 recommended care processes less frequently than older patients (30.5%, 38.0%, and 47.0% for ages 18-48 years, 49-59 years, and 60 years or older, respectively, P < 0.001); in adjusted analyses, patients aged 60 years or older were approximately twice as likely to receive all 5 care processes compared with patients aged 18-48 years (odds ratio [OR] = 1.97, 95% CI = 1.75-2.21). Users of oral antidiabetic monotherapy were least likely to have these processes of care performed compared with users of multiple oral therapies (OR = 1.23, 95% CI = 1.11-1.36) and insulin (OR = 1.59, 95% CI = 1.41-1.78). PPPY prescription drug costs incurred by the plan were greater for intervention than comparison patients (means [SDs] of $3,139 [$3,426] vs. $2,854 [$3,938], respectively, P < 0.001); and the generic dispensing ratio was slightly lower (means [SDs] of 62.1% [22.4%] and 65.4% [23.0%], respectively, P < 0.001). There were no significant differences between the intervention and comparison groups in mean [SD] PPPY all-cause medical care costs ($7,475 [$17,601] vs. $8,577 [$22,972], respectively, P = 0.213) or total all-cause costs ($10,613 [$18,590] vs. $11,431 [$24,060], P = 0.666). CONCLUSIONS: Patients participating in this incentive program featuring diabetes medication copayment reduction and disease management components did not receive recommended care any more or less frequently than other enrolled members with diabetes. Younger patients and those utilizing oral antidiabetic monotherapy as their drug regimens were less likely to have the recommended processes of care performed. While prescription drug expenditures incurred by the plan were greater for intervention patients, between-group differences in total costs for medications and all-cause medical care were not statistically significant. Further follow-up is required to determine the success of this program over the longer term in promoting quality of care and achieving cost reductions and improved health outcomes. PMID- 22548691 TI - Effectiveness of Dader Method for pharmaceutical care on control of blood pressure and total cholesterol in outpatients with cardiovascular disease or cardiovascular risk: EMDADER-CV randomized controlled trial. AB - BACKGROUND: Although some studies have demonstrated that pharmacist intervention can improve drug therapy among patients with cardiovascular disease (CVD), more evidence derived from randomized controlled trials (RCTs) is needed, including assessment of the effect of community pharmacist interventions in patients with CVD. OBJECTIVE: To assess the effectiveness of the Dader Method for pharmaceutical care on achieving therapeutic goals for blood pressure (BP), total cholesterol (TC), and both BP and TC (BP/TC) in patients with CVD and/or high or intermediate cardiovascular (CV) risk attending community pharmacies in Spain. METHODS: Patients aged 25 to 74 years attending community pharmacies with a prescription for at least 1 drug indicated for CVD or CV risk factors were randomized to 2 groups: an intervention group that received pharmaceutical care, which was provided by specially trained pharmacists working in collaboration with physicians, and a control group that received usual care (routine dispensing counseling) and verbal and written counseling regarding CVD prevention. Patients were recruited from December 2005 to September 2006, and both groups were followed for 8 months. Study outcomes were assessed at baseline and at 16 and 32 weeks after randomization. The primary outcome measures were the proportions of patients achieving BP, TC, and BP/TC therapeutic goals (BP lower than 140/90 mm Hg for patients with uncomplicated hypertension and lower than 130/80 mm Hg for patients with diabetes, chronic kidney disease, or history of myocardial infarction or stroke; TC lower than 200 mg per dL for patients without CVD and lower than 175 mg per dL for patients with CVD). Secondary outcomes were mean BP and TC values. BP was assessed manually by the pharmacist after a 10-minute rest in the supine position. This measurement was performed twice for every participant, and the average of the 2 measurements was calculated. TC was measured by the pharmacist during the study visit using the enzymatic dry method. Statistical analyses were performed using 2-tailed McNemar tests, Pearson chi square tests, and Student's t-tests; P < 0.05 was considered statistically significant. RESULTS: 714 patients were included in the study (356 intervention, 358 control), and the mean [SD] age was 62.8 [8.1] years. The 2 groups were similar at baseline in clinical and demographic characteristics, including the proportion of patients at therapeutic goals for BP, TC, and BP/TC. After 8 months of follow-up, there were statistically significant differences in favor of pharmaceutical care in the proportions of patients who achieved therapeutic goals for BP (52.5% vs. 43.0%, P=0.017), TC (56.5% vs. 44.1%, P=0.001), and BP/TC (37.1% vs. 21.8%, P < 0.001). CONCLUSION: Compared with usual care plus written education, pharmaceutical care focused on patient evaluation and follow-up in collaboration with physicians improved the achievement of BP, TC, and BP/TC treatment goals in patients with CVD and/or high or intermediate CV risk attending community pharmacies in Spain. PMID- 22548692 TI - Reducing the volume of antibiotic prescriptions: a peer group intervention among physicians serving a community with special ethnic characteristics. AB - BACKGROUND: Antibiotics are a front-line weapon against many infectious diseases. However, antibiotic overuse is the key driver of drug resistance. Previously published studies have suggested benefits of using peer-to-peer education, working with group leaders to build trust and maintain confidentiality within a quality initiative. We hypothesized that working with physicians as a peer group might be beneficial in influencing antibiotic prescribing patterns. OBJECTIVE: To describe and evaluate a peer group model for an intervention to reduce the volume of antibiotic prescriptions among physicians with above average prescribing rates serving an Arab community in northern Israel. METHODS: Primary care physicians in a defined geographic area who served Arab communities and had high antibiotic prescribing rates--defined as above average number of antibiotic prescriptions per office visit compared with regional and organizational averages--were recruited for the intervention. All other physicians from the same region served as a comparison group. The intervention was administered during 2007 and was completed in early 2008. Four structured meetings scheduled 2 months apart, in which the group explored the issues related to antibiotic overuse, included the following topics: adherence to clinical guidelines; the special position physicians serving Arab communities hold and the influence it has on their practices; pressure due to consumer demands; and suggestions for possible strategies to face ethnic sensitivity, mainly because of the special ties the physicians have with their communities. T-tests for independent samples were used to perform between-group comparisons for each quarter and year of observation from 2006 through 2010, and t-tests for paired samples were used to compare pre intervention with post-intervention antibiotic prescribing rates. RESULTS: In the 2006 pre-intervention period, the antibiotic prescribing rates were 0.17 for the peer group (n = 11 physicians) and 0.15 for the comparison group (n = 72 physicians, P = 0.279). In 2008 following the intervention, rates were 0.12 and 0.14, respectively (P = 0.396). In the paired t-test analysis, rates declined significantly from 2006 to 2008 in the intervention group (P < 0.001) but not in the comparison group (P = 0.138). Antibiotic prescribing rates remained similar in 2009 and 2010. CONCLUSION: In the context of a community with special ethnic and cultural characteristics, an intervention relying on peer group techniques was associated with a modest reduction in the volume of antibiotic prescriptions. PMID- 22548693 TI - 10 tips for a great health care research article. PMID- 22548694 TI - Clonal complexes and virulence factors of Staphylococcus aureus from several cities in India. AB - BACKGROUND: Diseases from Staphylococcus aureus are a major problem in Indian hospitals and recent studies point to infiltration of community associated methicillin resistant S. aureus (CA-MRSA) into hospitals. Although CA-MRSA are genetically different from nosocomial MRSA, the distinction between the two groups is blurring as CA-MRSA are showing multidrug resistance and are endemic in many hospitals. Our survey of samples collected from Indian hospitals between 2004 and 2006 had shown mainly hospital associated methicillin resistant Staphylococcus aureus (HA-MRSA) carrying staphylococcal cassette chromosome mec (SCCmec) type III and IIIA. But S. aureus isolates collected from 2007 onwards from community and hospital settings in India have shown SCCmec type IV and V cassettes while several variations of type IV SCCmec cassettes from IVa to IVj have been found in other parts of the world. In the present study, we have collected nasal swabs from rural and urban healthy carriers and pus, blood etc from in patients from hospitals to study the distribution of SCCmec elements and sequence types (STs) in the community and hospital environment. We performed molecular characterization of all the isolates to determine their lineage and microarray of select isolates from each sequence type to analyze their toxins, virulence and immune-evasion factors. RESULTS: Molecular analyses of 68 S. aureus isolates from in and around Bengaluru and three other Indian cities have been carried out. The chosen isolates fall into fifteen STs with all major clonal complexes (CC) present along with some minor ones. The dominant MRSA clones are ST22 and ST772 among healthy carriers and patients. We are reporting three novel clones, two methicillin sensitive S. aureus (MSSA) isolates belonging to ST291 (related to ST398 which is live stock associated), and two MRSA clones, ST1208 (CC8), and ST672 as emerging clones in this study for the first time. Sixty nine percent of isolates carry Panton- Valentine Leucocidin genes (PVL) along with many other toxins. There is more diversity of STs among methicillin sensitive S. aureus than resistant ones. Microarray analysis of isolates belonging to different STs gives an insight into major toxins, virulence factors, adhesion and immune evasion factors present among the isolates in various parts of India. CONCLUSIONS: S. aureus isolates reported in this study belong to a highly diverse group of STs and CC and we are reporting several new STs which have not been reported earlier along with factors influencing virulence and host pathogen interactions. PMID- 22548695 TI - Influence of related donor age on outcomes after peripheral blood stem cell transplantation. AB - BACKGROUND AIMS: The rising use of allogeneic transplantation in older recipients necessitates considering older related donors. The effect of related donor age for peripheral blood stem cell allografts (PBSC) on graft maintenance and outcomes, independent of CD34(+)cell dose, has not been well-characterized. METHODS: HLA-related donors (98% siblings) underwent a uniform filgrastim-based mobilization regimen aiming to collect and infuse 5 * 10(6) CD34(+) cells/recipient kg. Donor and recipient age were modeled in multiple ways to account for the correlation, and outcomes reported by decade of donor age. RESULTS: The median donor and recipient ages were 52 years and 54 years, respectively. The mean CD34(+) cell dose infused was 5.6 * 10(6) CD34(+)/kg and 75% of patients received a narrow range between 4.4 and 6.6 * 10(6) CD34(+) cells/kg. Neither better PBSC mobilization nor higher CD34(+) content of allografts was significantly associated with engraftment or transplant outcomes. After adjusting for recipient age and other prognostic factors, older donor age by decade conferred a lower risk of non-relapse mortality (NRM) [hazard ratio (HR) = 0.64, 95% confidence interval (CI) 0.45-0.91, P = 0.013] and borderline improvement in overall survival (OS) (HR = 0.76, 95% CI 0.58-0.99, P = 0.045) without altering progression-free survival (PFS) (HR = 0.85, 95% CI 0.66-1.07, P = 0.18). CONCLUSIONS: Older donor age does not worsen outcome after matched related donor PBSC transplantation in patients receiving a narrow range CD34(+) cells. The relatively small sample size mandates that the finding of similar to improved outcomes for older related donor age must be confirmed in larger studies. PMID- 22548696 TI - Improved immunomagnetic enrichment of CD34(+) cells from umbilical cord blood using the CliniMACS cell separation system. AB - BACKGROUND AIMS: CD34(+) enrichment from cord blood units (CBU) is used increasingly in clinical applications involving ex vivo expansion. The CliniMACS instrument from Miltenyi Biotec is a current good manufacturing practice (cGMP) immunomagnetic selection system primarily designed for processing larger numbers of cells: a standard tubing set (TS) can process a maximum of 60 billion cells, while the larger capacity tubing set (LS) will handle 120 billion cells. In comparison, most CBU contain only 1-2 billion cells, raising a question regarding the optimal tubing set for CBU CD34(+) enrichment. We compared CD34(+) cell recovery and overall viability after CliniMACS processing of fresh CBU with either TS or LS. METHODS: Forty-six freshly collected CBU (<= 36 h) were processed for CD34(+) enrichment; 22 consecutive units were selected using TS and a subsequent 24 processed with LS. Cell counts and immunophenotyping were performed pre- and post-selection to assess total nucleated cells (TNC), viability and CD34(+) cell content. RESULTS: Two-sample t-tests of mean CD34(+) recovery and viability revealed significant differences in favor of LS (CD34(+) recovery, LS = 56%, TS = 45%, P = 0.003; viability, LS = 74%, TS = 59%, P = 0.011). Stepwise linear regression, considering pre-processing unit age, viability, TNC and CD34(+) purity, demonstrated statistically significant correlations only with the tubing set used and age of unit. CONCLUSIONS: For CD34(+) enrichment from fresh CBU, LS provided higher post-selection viability and more efficient recovery. In this case, a lower maximum TNC specification of TS was not predictive of better performance. The same may hold for smaller scale enrichment of other cell types with the CliniMACS instrument. PMID- 22548697 TI - Knowledge of performance is insufficient for implicit visuomotor rotation adaptation. AB - The ability to adapt is a fundamental and vital characteristic of the motor system. The authors altered the visual environment and focused on the ability of humans to adapt to a rotated environment in a reaching task, in the absence of continuous visual information about their hand location. Subjects could not see their arm but were provided with post trial knowledge of performance depicting hand path from movement onset to final position. Subjects failed to adapt under these conditions. The authors sought to find out whether the lack of adaptation is related to the number of target directions presented in the task, and planned 2 protocols in which subjects were gradually exposed to 22.5 degrees visuomotor rotation. These protocols differed only in the number of target directions: 8 and 4 targets. The authors found that subjects had difficulty adapting without the existence of continuous visual feedback of their performance regardless of the number of targets presented in task. In the 4-target protocol, some of the subjects noticed the rotation and explicitly aimed to the correct direction. The results suggest that real-time feedback is required for motor adaptation to visual rotation during reaching movements. PMID- 22548698 TI - Editorial: How nurses can support the Surviving Sepsis Campaign. PMID- 22548699 TI - A comparative analysis of protein targets of withdrawn cardiovascular drugs in human and mouse. AB - BACKGROUND: Mouse is widely used in animal testing of cardiovascular disease. However, a large number of cardiovascular drugs that have been experimentally proved to work well on mouse were withdrawn because they caused adverse side effects in human. METHODS: In this study, we investigate whether binding patterns of withdrawn cardiovascular drugs are conserved between mouse and human through computational dockings and molecular dynamic simulations. In addition, we also measured the level of conservation of gene expression patterns of the drug targets and their interacting partners by analyzing the microarray data. RESULTS: The results show that target proteins of withdrawn cardiovascular drugs are functionally conserved between human and mouse. However, all the binding patterns of withdrawn drugs we retrieved show striking difference due to sequence divergence in drug-binding pocket, mainly through loss or gain of hydrogen bond donors and distinct drug-binding pockets. The binding affinities of withdrawn drugs to their receptors tend to be reduced from mouse to human. In contrast, the FDA-approved and best-selling drugs are little affected. CONCLUSIONS: Our analysis suggests that sequence divergence in drug-binding pocket may be a reasonable explanation for the discrepancy of drug effects between animal models and human. PMID- 22548700 TI - Many faces of pancreaticobiliary reflux. AB - Pancreaticobiliary reflux may occur either as a result of an anatomically abnormal pancreaticobiliary junction or because of a functionally impaired sphincter despite a normal radiological appearance. It is associated with a wide spectrum of biliary diseases, including gall bladder and bile duct carcinoma. Pancreaticobiliary maljunction and related biliary reflux have been studied extensively in Southeast Asian populations and associations with choledochal cyst and biliary malignancy defined. However, reflux in the absence of ductal malunion has only been described relatively recently and its significance with respect to biliary malignancy requires clarification. We present four cases of pancreaticobiliary reflux to demonstrate the varied associations of this under recognized disorder and review the related management issues. PMID- 22548701 TI - Erectile dysfunction is more common in young to middle-aged HIV-infected men than in HIV-uninfected men. AB - INTRODUCTION: Erectile dysfunction (ED) is common among elderly men and patients suffering from chronic diseases, the latter probably including also HIV infection. No studies, however, compared the prevalence of ED in HIV-infected and HIV-uninfected individuals using the international index of erectile function (IIEF-15). AIM: The aim of this study is to compare ED prevalence in young to middle-aged men with and without HIV infection using the IIEF-15 questionnaire. METHODS: We conducted a cross-sectional, observational, controlled study on 444 HIV-infected men and 71 HIV-uninfected men. MAIN OUTCOMES MEASURES: The IIEF-15 questionnaire was used to assess ED. A cutoff score of <=25 of the erectile domain was used to diagnose ED. Serum testosterone, demographic, and anthropometric (weight, height, and body mass index [BMI]) characteristics were obtained from all participants. Statistics included the T-test, the Fisher's test, univariable and multivariable logistic regression, and univariate and multivariate Spearman's correlation analysis. RESULTS: The HIV-uninfected group was significantly younger than the HIV-infected group and presented a higher BMI (P < 0.001). The prevalence of mild, moderate, and severe ED was higher in HIV infected men than in HIV-uninfected men of all decades of age. In univariate analysis, HIV infection was associated with ED (odds ratio [OR] = 34.19, P < 0.001). In multivariable logistic regression analysis, HIV infection remained the strongest predictors of ED (OR = 42.26, P < 0.001) followed by hypogonadism, after adjusting for age and BMI. CONCLUSIONS: This study demonstrates a clear association between ED and HIV infection, after adjusting for age and BMI. Other than HIV infection, hypogonadism was associated with ED. In addition, the prevalence of ED was higher in HIV-infected men than in HIV-uninfected men, in all decades of age. The early onset of ED in HIV-infected men could be considered a peculiar clinical hallmark of HIV and confirms precocious aging in these patients. ED should be of concern to clinicians when managing HIV-infected men even if the latter are young or middle aged. PMID- 22548702 TI - Laparoscopic management of interstitial pregnancy: the "purse-string" technique. AB - We report five cases of interstitial pregnancy, treated between 2004 and 2010, to evaluate surgical and obstetric outcome of laparoscopic cornual resection with a "purse-string" technique. A hemostatic suture was passed at the base of the mass in a purse-string fashion prior to resection, to minimize intraoperative blood loss. Subsequent pregnancies were analysed, with a mean follow-up time of 48 months. The mean operating time was 39 min and mean blood loss 47 mL. Three of four patients who desired children delivered at term uneventfully. Laparoscopic cornual resection with a "purse-string" technique appears to be useful for treatment of early interstitial pregnancy. The technique ensures effective and safe treatment, with satisfactory obstetric outcome. PMID- 22548704 TI - The use of a continuous brachial plexus catheter to facilitate inpatient rehabilitation in a pediatric patient with refractory upper extremity complex regional pain syndrome. AB - BACKGROUND: The goal of interventional management of refractory pediatric complex regional pain syndrome is to facilitate early restoration of function to the affected extremity. These interventions are more complicated in children, as most do not tolerate these procedures without sedation. CASE REPORT: We report the first detailed description of a pediatric patient with complex regional pain syndrome refractory to medical management who had complete resolution of symptoms after brief inpatient rehabilitation involving continuous brachial plexus blockade and a multidisciplinary apaproach. CONCLUSION: Repeated interventional therapy for refractory, severe complex regional pain syndrome may not be feasible in children owing to the requirement for deep sedation or general anesthesia. A multidisciplinary apaproach of brief inpatient rehabilitation and continuous blockade via an indwelling pain catheter may provide a safer, more cost-effective means of restoring function in children with advanced disease. PMID- 22548703 TI - Creating and analyzing pathway and protein interaction compendia for modelling signal transduction networks. AB - BACKGROUND: Understanding the information-processing capabilities of signal transduction networks, how those networks are disrupted in disease, and rationally designing therapies to manipulate diseased states require systematic and accurate reconstruction of network topology. Data on networks central to human physiology, such as the inflammatory signalling networks analyzed here, are found in a multiplicity of on-line resources of pathway and interactome databases (Cancer CellMap, GeneGo, KEGG, NCI-Pathway Interactome Database (NCI-PID), PANTHER, Reactome, I2D, and STRING). We sought to determine whether these databases contain overlapping information and whether they can be used to construct high reliability prior knowledge networks for subsequent modeling of experimental data. RESULTS: We have assembled an ensemble network from multiple on-line sources representing a significant portion of all machine-readable and reconcilable human knowledge on proteins and protein interactions involved in inflammation. This ensemble network has many features expected of complex signalling networks assembled from high-throughput data: a power law distribution of both node degree and edge annotations, and topological features of a "bow tie" architecture in which diverse pathways converge on a highly conserved set of enzymatic cascades focused around PI3K/AKT, MAPK/ERK, JAK/STAT, NFkappaB, and apoptotic signaling. Individual pathways exhibit "fuzzy" modularity that is statistically significant but still involving a majority of "cross-talk" interactions. However, we find that the most widely used pathway databases are highly inconsistent with respect to the actual constituents and interactions in this network. Using a set of growth factor signalling networks as examples (epidermal growth factor, transforming growth factor-beta, tumor necrosis factor, and wingless), we find a multiplicity of network topologies in which receptors couple to downstream components through myriad alternate paths. Many of these paths are inconsistent with well-established mechanistic features of signalling networks, such as a requirement for a transmembrane receptor in sensing extracellular ligands. CONCLUSIONS: Wide inconsistencies among interaction databases, pathway annotations, and the numbers and identities of nodes associated with a given pathway pose a major challenge for deriving causal and mechanistic insight from network graphs. We speculate that these inconsistencies are at least partially attributable to cell, and context-specificity of cellular signal transduction, which is largely unaccounted for in available databases, but the absence of standardized vocabularies is an additional confounding factor. As a result of discrepant annotations, it is very difficult to identify biologically meaningful pathways from interactome networks a priori. However, by incorporating prior knowledge, it is possible to successively build out network complexity with high confidence from a simple linear signal transduction scaffold. Such reduced complexity networks appear suitable for use in mechanistic models while being richer and better justified than the simple linear pathways usually depicted in diagrams of signal transduction. PMID- 22548706 TI - Treatment extension may benefit female genotype 1 chronic hepatitis C patients with complete early virological response to peginterferon-alpha-2b and ribavirin combination therapy. AB - AIM: Little is known about the appropriate use of peginterferon-alpha-2b (PEG IFN-alpha-2b) or ribavirin (RBV) in genotype 1 chronic hepatitis C (CH-C) patients with complete early virological response (cEVR). Female patients, especially the older, are known to experience inferior treatment outcomes. METHOD: A total of 150 CH-C patients with cEVR treated for 48 weeks (n = 104) or 52-64 weeks (n = 46) with PEG IFN-alpha-2b and RBV combination therapy were retrospectively analyzed to evaluate the benefits of extended treatment. RESULTS: In the 48-week group, patients without a sustained virological response (SVR) were more often female (P = 0.004) and had received a significantly lower total RBV dose (P = 0.003) than those with SVR. The SVR rate in these female patients was similar to males with hepatitis C virus (HCV) RNA negativity at treatment week 8 (P = 0.413); however, it was lower than that in males with HCV RNA negativity at treatment week 12 (P = 0.005). In the 52-64-week group, although the total RBV dose (mg/kg) after treatment week 48 was less in females than in males (P = 0.027), the SVR rate in females was equivalent to that in males (P = 0.604). CONCLUSION: Genotype 1 CH-C patients treated with PEG IFN-alpha-2b and RBV combination therapy without SVR were more often female and had received a lower total RBV dose than males. The smaller SVR rate in female patients with cEVR compared to males may be overcome by extending treatment even if the RBV dose is lowered due to anemia. PMID- 22548705 TI - Temporally distinct roles for tumor suppressor pathways in cell cycle arrest and cellular senescence in Cyclin D1-driven tumor. AB - BACKGROUND: Cellular senescence represents a tumor suppressive response to a variety of aberrant and oncogenic insults. We have previously described a transgenic mouse model of Cyclin D1-driven senescence in pineal cells that opposes tumor progression. We now attempted to define the molecular mechanisms leading to p53 activation in this model, and to identify effectors of Cyclin D1 induced senescence. RESULTS: Senescence evolved over a period of weeks, with initial hyperproliferation followed by cell cycle arrest due to ROS production leading to activation of a DNA damage response and the p53 pathway. Interestingly, cell cycle exit was associated with repression of the Cyclin dependent kinase Cdk2. This was followed days later by formation of heterochromatin foci correlating with RB protein hypophosphorylation. In the absence of the Cdk4-inhibitor p18Ink4c, cell cycle exit was delayed but most cells eventually showed a senescent phenotype. However, tumors later arose from this premalignant, largely senescent lesion. We found that the p53 pathway was intact in tumors arising in a p18Ink4c-/- background, indicating that the two genes represent distinct tumor suppressor pathways. Upon tumor progression, both p18Ink4c-/- and p53-/- tumors showed increased Cdk2 expression. Inhibition of Cdk2 in cultured pre-tumorigenic and tumor cells of both backgrounds resulted in decreased proliferation and evidence of senescence. CONCLUSION: Our findings indicate that the p53 and the RB pathways play temporally distinct roles in senescence induction in Cyclin D1-expressing cells, and that Cdk2 inhibition plays a role in tumor suppression, and may be a useful therapeutic target. PMID- 22548707 TI - Molecular mechanism of ATP hydrolysis in F1-ATPase revealed by molecular simulations and single-molecule observations. AB - Enzymatic hydrolysis of nucleotide triphosphate (NTP) plays a pivotal role in protein functions. In spite of its biological significance, however, the chemistry of the hydrolysis catalysis remains obscure because of the complex nature of the reaction. Here we report a study of the molecular mechanism of hydrolysis of adenosine triphosphate (ATP) in F(1)-ATPase, an ATP-driven rotary motor protein. Molecular simulations predicted and single-molecule observation experiments verified that the rate-determining step (RDS) is proton transfer (PT) from the lytic water molecule, which is strongly activated by a metaphosphate generated by a preceding P(gamma)-O(beta) bond dissociation (POD). Catalysis of the POD that triggers the chain activation of the PT is fulfilled by hydrogen bonds between Walker motif A and an arginine finger, which commonly exist in many NTPases. The reaction mechanism unveiled here indicates that the protein can regulate the enzymatic activity for the function in both the POD and PT steps despite the fact that the RDS is the PT step. PMID- 22548708 TI - Efficacy of trazodone in antipsychotic-induced akathisia resistant to conventional treatment. PMID- 22548709 TI - Interfacial dynamics and rheology of polymer-grafted nanoparticles at air-water and xylene-water interfaces. AB - Particle-stabilized emulsions and foams offer a number of advantages over traditional surfactant-stabilized systems, most notably a greater stability against coalescence and coarsening. Nanoparticles are often less effective than micrometer-scale colloidal particles as stabilizers, but nanoparticles grafted with polymers can be particularly effective emulsifiers, stabilizing emulsions for long times at very low concentrations. In this work, we characterize the long time and dynamic interfacial tension reduction by polymer-grafted nanoparticles adsorbing from suspension and the corresponding dilatational moduli for both xylene-water and air-water interfaces. The dilatational moduli at both types of interfaces are measured by a forced sinusoidal oscillation of the interface. Surface tension measurements at the air-water interface are interpreted with the aid of independent ellipsometry measurements of surface excess concentrations. The results suggest that the ability of polymer-grafted nanoparticles to produce significant surface and interfacial tension reductions and dilatational moduli at very low surface coverage is a key factor underlying their ability to stabilize Pickering emulsions at extremely low concentrations. PMID- 22548710 TI - Applying the generic errors modeling system to obstetric hemorrhage quality improvement efforts. AB - Obstetric hemorrhage is an emergency situation in which clinicians can make errors that cause women to suffer preventable maternal morbidity and mortality. Scrutinizing commonly occurring obstetric hemorrhage-related practice errors by applying the generic errors modeling system, a research-based framework, to quality improvement efforts facilitates the identification of error specific reduction strategies. The common types of errors are skill-based, rule-based, and knowledge-based active and latent errors. PMID- 22548711 TI - Association of BDNF gene polymorphism with bipolar disorders in Han Chinese population. AB - Recent data suggest that brain-derived neurotrophic factor (BDNF) plays an essential role in neuronal plasticity and etiology of bipolar disorders (BPD). However, results from different studies have been inconsistent. In present study, 342 patients who met DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition) criteria for bipolar disorders type I (BPD-I) or type II (BPD-II) and 386 matched health controls were enrolled, and TaqMan((r)) SNP Genotyping Assays (Applied Biosystems, Foster City, CA, USA) were applied to detect the functional polymorphism rs6265 (Val66Met) of BDNF gene. Treatment response to lithium and valproate was retrospectively determined. The association between Val66Met polymorphism and BPD, treatment response to mood stabilizers, was estimated. The genotype and allele distribution of Val66Met polymorphism between BPD patients and control subjects showed significant difference (genotype: chi(2) = 6.18, df = 2, P = 0.046; allele: chi(2) = 5.01, df = 1, P = 0.025) with Met allele as risk factor for disease susceptibility (OR = 0.79, 95%CI as 0.64-0.97). The post hoc analysis interestingly showed that Met allele had opposite effect on the treatment response for BPD-I and BPD-II separately. For BPD-I patients, the response score in Val/Val group was significantly lower than that in Met allele carriers (t = -2.27, df = 144, P = 0.025); for BPD-II patients, the response score in Val/Val group was significantly higher than that in Met allele carriers (t = 2.33, df = 26, P = 0.028). Although these results should be interpreted with caution because of the limited sample for Val/Val genotype in BPD-II patients (N = 5), these findings strengthen the hypothesis that BDNF pathway gets involved in the etiology and pharmacology of BPD and suggest the differences between BPD-I and BPD-II. PMID- 22548712 TI - Rheolytic thrombectomy in patients with massive pulmonary embolism: a report of two cases and review of literature. AB - We present two cases of massive pulmonary embolism with persistent systolic hypotension but both have contraindications for thrombolysis. Therefore, rheolytic thrombectomy using AngioJet was performed and immediate haemodynamic improvement was achieved including blood pressure and symptoms. According to guidelines, catheter embolectomy or fragmentation may be considered as alternative to surgical treatment in massive pulmonary embolism patients when thrombolysis is absolutely contraindicated or has failed. Percutaneous catheter based interventional techniques include thrombus fragmentation, rheolytic thrombectomy, suction thrombectomy and rotational thrombectomy. With the existing literature review and our case, rheolytic thrombectomy for treatment of massive pulmonary embolism using AngioJet achieves a high procedural success rate (approximately 90%) n terms of improvement of haemodynamics, pulmonary perfusion and angiographic result but low complication rate. PMID- 22548714 TI - Nurses' beliefs, experiences and practice regarding complementary and alternative medicine in Taiwan. AB - AIM: To gain an insight into this issue, this study used a qualitative approach and aims to explore and describe nurses' beliefs, experiences and practice regarding complementary and alternative medicine in Taiwan. BACKGROUND: The integration of complementary and alternative medicine with conventional medicine has become more common worldwide in recent years. An increase in patient use and an expansion of nurses using complementary and alternative medicine has spawned further investigation. Most published studies have concentrated on the usage of complementary and alternative medicine in western societies and have focused principally on physicians' attitudes and practice patterns in this regard. Despite the large amount of time and the unique relationship that nurses share with their patients, little research has investigated the nurse's attitudes and practice regarding complementary and alternative medicine. Moreover, there has been no previous research into understanding this issue from the Taiwanese nursing perspective. DESIGN: A qualitative research design. METHOD: By using an exploratory, descriptive, qualitative approach, data were collected from 11 registered nurses. The methods of the data collection were in-depth, semi structured interviews, field notes and memos and the data were analysed using the constant comparative method. RESULTS: Three major categories emerged from the data; namely, a 'lack of clear definition', 'limited experience' and 'high interest' towards complementary and alternative medicine. These results suggest that the definition of complementary and alternative medicine is often unclear for nurses in Taiwan. Due to the organisational policies and personal knowledge base, very few nurses integrate complementary and alternative medicine into their daily practice. However, the nurses in Taiwan show a great desire to participate in complementary and alternative medicine continuing education programmes. CONCLUSIONS: This study is not only significant in filling the gap in the existing literature, but is also important in understanding this issue from the nurses' perspective, to offer a series of recommendations for policy, nursing education, nursing practice and suggestions for further research. RELEVANCE TO CLINICAL PRACTICE: This study highlights the importance of nursing attitude in the use of complementary and alternative medicine. Clinical nurses have the potential to provide appropriate information to their patients to ensure safe complementary and alternative medicine use. PMID- 22548713 TI - Trifluoroacetate is an allosteric modulator with selective actions at the glycine receptor. AB - Trifluoroacetic acid is a metabolite of the inhaled anesthetics halothane, desflurane and isoflurane as well as a major contaminant in HPLC-purified peptides. Ligand-gated ion channels, including cys-loop receptors such as the glycine receptor, have been the targets of peptide-based drug design and are considered to be likely candidates for mediating the effects of anesthetics in vivo, but the possible secondary contributions of contaminants and metabolites to these effects have not been studied. We used two-electrode voltage-clamp electrophysiology to test glycine, GABA(A) and 5-HT3 receptors expressed in Xenopus oocytes for their sensitivities to sodium trifluoroacetate. Trifluoroacetate (100 MUM-3mM) enhanced the currents elicited by low concentrations of glycine applied to alpha1 homomeric and alpha1beta heteromeric glycine receptors, but it had no effects when co-applied with a maximally effective glycine concentration. Trifluoroacetate had no effects on alpha1beta2gamma2S GABA(A) or 5-HT3A receptors at any GABA or serotonin concentration tested. The results demonstrate that trifluoroacetate acts as an allosteric modulator at the glycine receptor with greater specificity than other known modulators. These results have important implications for both the secondary effects of volatile anesthetics and the presence of contaminating trifluoroacetate in HPLC-purified peptides, which is potentially an important source of experimental variability or error that requires control. PMID- 22548715 TI - Significant time until catheter occlusion alerts in currently marketed insulin pumps at two basal rates. PMID- 22548716 TI - Psychosexual development in adolescents and adults with disorders of sex development--results from the German Clinical Evaluation Study. AB - INTRODUCTION: Both biological and psychosocial factors influence psychosexual development. High levels of pre- and postnatal androgens lead to more male typical behavior. So far, the influence of androgens on gender identity and sexual orientation is unclear. Disorders of sex development (DSDs) are heterogeneous genetic conditions with different levels of prenatal androgens resulting in variations of genital development. Through DSD, the role of the different factors, especially androgen exposure, on psychosexual development can be evaluated. AIM: The purpose of the study was to assess psychosexual development in adolescents and adults with different forms of DSD. METHODS: For the examination of psychosexual development of 66 adolescents and 110 adults with DSD, the authors used the Utrecht Gender Dysphoria Scale for adolescents, the Questionnaire of Gender Identity for adults, and a condition-specific DSD study questionnaire. Individuals were analyzed in four subgroups reflecting the karyotype, absence/presence of androgen effects, and gender of rearing. MAIN OUTCOME MEASURES: Main outcome measures used were gender identity, friendships, love and sexual relationships, and sexual orientation in adolescents and adults with DSD. RESULTS: Individuals with DSD did not show increased gender dysphoria. However, partnership and sexuality were identified to be difficult areas of life. Both adolescents and adults with DSD reported fewer experiences regarding love or sexual relationships compared with unaffected individuals. Especially men with DSD and undervirilization and women with DSD and androgen effects less often had a love relationship. Adult women with DSD and androgen effects more frequently engaged in love and sexual relationships with individuals of the same gender compared with women without DSD. CONCLUSION: Individuals with DSD experience atypical hormonal influences (higher levels of androgens in girls/women and lower levels in androgens in boys/men); however, they did not show increased gender dysphoria in this study. However, partnership and sexual relationships are difficult areas of life for adolescents and adults with DSD. We recommend that individuals with DSD should get support from a multiprofessional team with competency in assessing and counseling issues regarding relationships and sexuality. Contact to other individuals with DSD can be helpful for nonprofessional support and exchange of experiences. PMID- 22548717 TI - Serum concentrations and tissue expression of components of insulin-like growth factor-axis in females with type 2 diabetes mellitus and obesity: the influence of very-low-calorie diet. AB - We explored serum concentrations and mRNA expression of insulin-like-growth factor-1 (IGF-1) axis components in subcutaneous adipose tissue (SCAT) and peripheral monocytes (PM) of 18 healthy females, 11 obese non-diabetic females (OB) and 13 obese women with type 2 diabetes (T2DM) examined at baseline and after very-low-calorie diet (VLCD). T2DM women had decreased expression of IGF-1, IGF-1 receptor (IGF-1R), IGFBP-2 (IGF binding protein-2) and IGFBP-3 in SCAT and increased expression of IGF-1R in PM compared to control group. IGF-1R and IGFBP 3 mRNA expression in SCAT of OB was comparable to control group. In T2DM women VLCD increased serum levels and SCAT expression of IGFBP-2 and PM expression of IGFBP-3. We conclude that decreased IGF-1, IGF-1R and IGFBP-3 expression in SCAT and increased IGF-1R expression in PM of T2DM subjects might contribute to changes of fat differentiation capacity and to regulation of subclinical inflammation by PM, respectively. Increased SCAT and circulating IGFBP-2 and IGFBP-3 in PM might participate in metabolic improvements after VLCD. PMID- 22548718 TI - Antiphospholipid antibodies in relation to sterility/infertility. AB - Of the systemic autoimmune diseases that lead to sterility/infertility, antiphospholipid syndrome (APS) has an outstanding importance; it may be associated with abortion and premature birth which are included in its diagnostic criteria, as well as preeclampsia, pregnancy-induced hypertension, foetal retardation, miscarriage, stillbirth and sterility. Between 2004 and 2009, on the Department of Immunology in the Zala County Hospital, 100 female patients with sterility (st)/infertility (if) (33/67), (mean age: 34.08 years) underwent, in addition to history taking and physical examination, an assessment by immune serologic tests (ANA, anti-dsDNA, ENA-Profile, anti-TPO, a-sperm, aCL, aPS, abeta2GP1, aANX, and aPT). Positive aCL on two occasions could be demonstrated in 27/100 cases (27%) (st/if: 7/20). Among them 4 cases of primary APS have been diagnosed respectively. In the remaining 17 patients the clinical picture did not fulfil criteria. In addition to the twofold positive aCL, unusual antiphospholipid antibodies including abeta2GP1, aPS or both were present in 1/27, 2/27 and 1/27 patients, as well as aANX and aPT in 3/26 and 1/27 patients respectively. One-time positive aCL occurred in 16/100 women (16%) (st/if: 5/11); among them aPT and abeta2GP1 could be detected in 1/16 patient each. Based on the clinical picture, we raised the possibility of primary APS in 2/16 patients. Among the aCL-negative women, we found the unusual antibodies of APS in 8/57 patients (14%) including positivity of abeta2GP1, aPS, aPT and aANX in 4/57, 4/57, 2/57 and 3/57 patients respectively; taking the clinical criteria of APS into consideration, primary APS could be stated in 2/57 patients of them. The 32 pregnancies developed in the follow-up period upon administration of acetylsalicylic acid (ASA) and maintenance dose low molecular weight heparin (LMWH), together with prednisolone in patients with secondary APS, resulted in 23 deliveries and 5 miscarriages; 4 pregnancies are currently in progress. The results of our investigations highlight the significance of demonstrating latent autoimmune diseases in female patients with sterility/infertility, as barrenness can be terminated by the appropriate treatment of these conditions. PMID- 22548719 TI - Characterization of the HLA-C*07:01:01G allele group in European and African American cohorts. AB - The HLA-C*07:01:01G allele group consists of three nonsynonymous alleles, C*07:01:01, C*07:06 and C*07:18, plus C*07:01:02, which is synonymous to C*07:01:01. All of these alleles have identical exons 2, 3 and 4, but differ in exons 5 or 6. Therefore routine sequence-based typing (SBT) of exons 2 and 3 is unable to resolve these subtypes, resulting in ambiguous typing results in population and disease cohort studies. In the present study, we fully characterized C*07:01:01G subtypes in European and African Americans and examined their relative frequency distributions. In European Americans C*07:01:01G is predominantly represented by C*07:01:01 (94.4%), whereas C*07:01:02 (1.1%) and C*07:18 (4.5%) were detected relatively infrequently. In African Americans C*07:18 (42.4%) showed a high frequency similar to that of C*07:01:01 (44.7%) whereas C*07:06 was detected at a low frequency (4.7%). C*07:06 was found exclusively on B*44:03 carrying haplotypes in both ethnic groups, but C*07:18 showed multiple linkage relationships with HLA-B. These results demonstrate that C*07:01:01G as defined by routine SBT is a heterogeneous group of alleles, especially among individuals of African origin. If C*07:01:01G subtypes prove to bear divergent functional significance, it would be necessary to include these subtypes in routine HLA-C typing for clinical transplantation and disease association studies. PMID- 22548720 TI - Vitamin D receptor upregulation in alloreactive human T cells. AB - Vitamin D deficiency is adversely associated with diseases characterized by inflammation. The combination of the high incidence of vitamin D deficiency in patients undergoing allogeneic stem cell transplants (SCT) and the potential role of vitamin D deficiency in influencing graft-versus-host disease led us to further characterize the expression of VDR on alloreactive T cells. We hypothesized that vitamin D receptor expression may directly regulate alloreactive T cell responses. To overcome existing limitations in measuring VDR in bulk cellular populations, we developed a flow cytometric assay to measure cytoplasmic VDR in human T cells. Upon stimulation, VDR was expressed extremely early and exhibited sustained upregulation with chronic stimulation. VDR expression was also coupled to cytokine production, proliferation, and ERK1/2 phosphorylation. In addition, VDR exhibited a maturation stage-specific pattern of expression, with greatest expression on cells known to mediate GVHD, naive and early memory T cells. Alloreactive T cells upregulated VDR, whereas the nonreactive T cells did not. Finally, repletion of vitamin D in vitro was sufficient to significantly reduce alloreactive T cell responses. These data suggest that vitamin D effects on T cells may be important in reducing graft versus host disease (GVHD) in the allogeneic stem cell transplant setting. PMID- 22548721 TI - Association between CASP7 and CASP14 genetic polymorphisms and the risk of childhood leukemia. AB - Current evidence suggests that apoptosis and the cell cycle system play an important role in cancer development. To identify susceptible genetic markers in these mechanisms, we did an association study in 63 patients and 148 controls. A total of 304 SNPs in 31 gene regions were selected. We evaluated an association at a gene region level by computing the minimum P-value (minP) and doing the false discovery rate (FDR) test. Both SNP and gene-based analyses presented associations with the risk of childhood leukemia for 5 genes: CASP7, CASP14, CASP8AP2, MYC, and RIPK1 (P(trend)<0.05). There were statistically significant associations for CASP7 (rs12416109 and rs3814231, P(trend) = 0.002 and 0.009, respectively, minP = 0.013, FDR = 0.042) and CASP14 (rs8110862, P(trend)<0.001, minP = 0.002, FDR = 0.027). This study suggests that genetic polymorphisms in apoptosis and cell cycle related genes might play a role in childhood leukemia development. PMID- 22548722 TI - The bed and the bugs: interactions between the tumor microenvironment and cancer stem cells. AB - Tumors have been increasingly recognized as organs with a complexity that approaches, and may even exceed, that of healthy tissues. When viewed from this perspective, the biology of a tumor can be understood only by studying tumor cell heterogeneity and the microenvironment that is constructed during the course of tumorigenesis and malignant progression. Recent work has revealed the existence of cancer stem cells, the "bugs", with the capacity for self-renewal and tumor propagation. In addition, it is now recognized that the tumor microenvironment, the "bed", plays a critical role in supporting cancer stem cells and also may promote neoplasia and malignant progression. The interdependence of the cell intrinsic features of cancer, including the cancer stem cell "bugs" and the tumor microenvironment "bed", is only beginning to be understood. In this review, we highlight the rapidly evolving concepts about the interactions between tumor stem cells and their microenvironment, the insights gained from studying their normal tissue counterparts, and the questions and controversies surrounding this area of research, with an emphasis on breast and lung cancer. Finally, we address evidence supporting the notion that eliminating the bed as well as the bugs should lead to more effective and personalized cancer treatments that improve patient outcome. PMID- 22548724 TI - Induction of epithelial-mesenchymal transition by transforming growth factor beta. AB - Transforming growth factor beta (TGFbeta) is implicated in human malignancy. Tumors may escape the tumor suppressor activity of TGFbeta by mutating some of its signaling components. Carcinoma and stromal cells produce high amounts of TGFbeta which promotes epithelial-mesenchymal transition (EMT), tumor cell invasiveness and tumor angiogenesis, while suppressing immune responses against the tumor. Thus, TGFbeta has tumor suppressive as well as tumor promoting effects supporting metastasis. TGFbeta elicits the EMT response by activating complementary signaling cascades that mobilize embryonic transcription factors that reprogram the epithelial cell so that it acquires both progenitor-like, pro motility and mesenchymal features. Such nuclear reprogramming of carcinoma cells involves epigenetic and transcriptional regulation, the activity of miRNAs, and modulation of RNA splicing and mRNA translation, leading to the expression of key intracellular and membrane proteins together with a large pool of secreted factors that mediate and account for the phenotypic changes that accompany EMT. PMID- 22548723 TI - Complex changes in alternative pre-mRNA splicing play a central role in the epithelial-to-mesenchymal transition (EMT). AB - The epithelial-to-mesenchymal transition (EMT) is an important developmental process that is also implicated in disease pathophysiology, such as cancer progression and metastasis. A wealth of literature in recent years has identified important transcriptional regulators and large-scale changes in gene expression programs that drive the phenotypic changes that occur during the EMT. However, in the past couple of years it has become apparent that extensive changes in alternative splicing also play a profound role in shaping the changes in cell behavior that characterize the EMT. While long known splicing switches in FGFR2 and p120-catenin provided hints of a larger program of EMT-associated alternative splicing, the recent identification of the epithelial splicing regulatory proteins 1 and 2 (ESRP1 and ESRP2) began to reveal this genome-wide post transcriptional network. Several studies have now demonstrated the truly vast extent of this alternative splicing program. The global switches in splicing associated with the EMT add an important additional layer of post-transcriptional control that works in harmony with transcriptional and epigenetic regulation to effect complex changes in cell shape, polarity, and behavior that mediate transitions between epithelial and mesenchymal cell states. Future challenges include the need to investigate the functional consequences of these splicing switches at both the individual gene as well as systems level. PMID- 22548726 TI - Surgical treatment for large hepatocellular carcinoma: does size matter? AB - Despite significant progress in the management of hepatocellular carcinoma (HCC), patients with large HCC (defined as >10 cm) continue to present a significant challenge. The goal of this paper is to review the existing literature regarding large HCC, with emphasis on identifying the issues and challenges involved in approaching these tumours surgically. A computerized search was made of the Medline database from January 1992 to December 2010. The MESH heading 'large' or 'huge' in combination with the keyword 'hepatocellular carcinoma' was used. After excluding further studies that identified 'large' HCC as less than 10 cm and/or sequential publications with overlapping patient populations, the search produced a study population of 22 non-duplicated papers, reporting on a total of 5223 patients with HCC tumours >10 cm. Regarding resection for large HCC, the overall 5-year survival in these studies ranged from 25% to 45%, with few outliers on both sides, whereas in most studies, the 5-year disease-free survival ranged between 15% and 35%, with the only exception being studies with patients with single lesions and no cirrhosis showing disease-free survival of 41% and 56%, respectively. Risk factors identified included vascular invasion, cirrhosis, high level of alpha-fetoprotein and the presence of multiple lesions. Finally, liver transplantation, although an attractive concept, did not appear to offer a survival benefit in any of the studies. In conclusion, identifying the risk factors that affect the outcome in patients undergoing surgery for large HCC is critical. The reason is that surgical resection can have excellent outcomes in carefully selected patients. PMID- 22548727 TI - Living-donor liver transplantation for autoimmune hepatitis and autoimmune hepatitis-primary biliary cirrhosis overlap syndrome. AB - AIM: Recurrent autoimmune hepatitis (AIH) following liver transplantation has been reported in 20-30% of cases, mainly of Western populations. The aim of this study was to review our experience of living-donor liver transplantation (LDLT) in Japanese patients with AIH. METHODS: Among 375 adult (age >=18 years) LDLT performed at our center between 1996 and 2010, 16 (4.2%) were for patients with AIH (n = 12) or AIH-primary biliary cirrhosis overlap syndrome (n = 4). The patient and donor characteristics and post-transplantation course were reviewed. RESULTS: All recipients were female with a median age of 48 years (range, 21 58). Low-dose methylprednisolone and calcineurin inhibitors were continued in all patients. Acute cellular rejection occurred in 10 (63%), which was more frequent than in our overall series of 28.5% (107/375 cases). Overall survival rate was 81.2% at 5 years. At the end of the follow up (median, 6.0 years [range, 0.1 9.6]), 13 patients were alive with normal liver function tests (aspartate transaminase, 18 +/- 5 IU/mL; alanine transaminase, 16 +/- 8 IU/mL). None of the survivors exhibited liver function test results suspicious for recurrent AIH, which might indicate liver biopsy. CONCLUSION: Survival after LDLT for AIH and overlap syndrome was excellent and there was no evidence of clinical recurrence. The recurrence rate of AIH after liver transplantation may differ among countries, and requires further investigation. PMID- 22548725 TI - Influenza serological studies to inform public health action: best practices to optimise timing, quality and reporting. AB - BACKGROUND: Serological studies can detect infection with a novel influenza virus in the absence of symptoms or positive virology, providing useful information on infection that goes beyond the estimates from epidemiological, clinical and virological data. During the 2009 A(H1N1) pandemic, an impressive number of detailed serological studies were performed, yet the majority of serological data were available only after the first wave of infection. This limited the ability to estimate the transmissibility and severity of this novel infection, and the variability in methodology and reporting limited the ability to compare and combine the serological data. OBJECTIVES: To identify best practices for conduct and standardisation of serological studies on outbreak and pandemic influenza to inform public policy. METHODS/SETTING: An international meeting was held in February 2011 in Ottawa, Canada, to foster the consensus for greater standardisation of influenza serological studies. RESULTS: Best practices for serological investigations of influenza epidemiology include the following: classification of studies as pre-pandemic, outbreak, pandemic or inter-pandemic with a clearly identified objective; use of international serum standards for laboratory assays; cohort and cross-sectional study designs with common standards for data collection; use of serum banks to improve sampling capacity; and potential for linkage of serological, clinical and epidemiological data. Advance planning for outbreak studies would enable a rapid and coordinated response; inclusion of serological studies in pandemic plans should be considered. CONCLUSIONS: Optimising the quality, comparability and combinability of influenza serological studies will provide important data upon emergence of a novel or variant influenza virus to inform public health action. PMID- 22548728 TI - Migration associated with climate change: modern face of an ancient phenomenon. PMID- 22548729 TI - An added value for the hemoglobin content in reticulocytes (CHr) and the mean corpuscular volume (MCV) in the diagnosis of iron deficiency in postpartum anemic women. AB - INTRODUCTION: To evaluate the use of reticulocyte hemoglobin content (CHr) and mean corpuscular volume (MCV) to identify truly iron-deficient women with postpartum anemia (PPA), in order to reduce unnecessary iron supplementation. METHODS: Three hundred women with more than 500 mL of blood loss or clinical signs of anemia were divided in a control (Hb >= 10.5 g/dL, N = 150) and postpartum anemia group (PPA, Hb < 10.5 g/dL; N = 150). PPA women were given ferrous fumarate for a period of 4 weeks. Efficacy of the treatment was evaluated by comparing Hb, CHr, and MCV at baseline (T(0)) and after 4 weeks (T(4)). Using standard iron deficiency cut off values for MCV (80 fL) and CHr (28 pg) at T(0), we divided the PPA group of both parameters into two subgroups, one suggestive for iron deficiency and one suggestive for noniron deficiency. RESULTS: Irrespective of the parameter or the subdivision, delta Hb concentrations (T(4) T(0)) showed a similar increase in all PPA subgroups investigated. Both parameters in the PPA subgroups below their respective cut off value showed a significant improvement toward normalization, while the MCV and CHr in the PPA subgroups above their respective cut off value did not show any significant increase. CONCLUSION: Our data suggest that the etiology of the anemia in postpartum anemic women is not always iron deficiency. Using a combination of Hb, MCV and CHr, we increased the stringency to identify truly iron-deficient postpartum anemic women, thereby reducing unnecessary iron supplementation in those women with sufficient iron stores. PMID- 22548730 TI - Psychosocial work environment and prediction of quality of care indicators in one Canadian health center. AB - BACKGROUND: Few studies link organizational variables and outcomes to quality indicators. This approach would expose operant mechanisms by which work environment characteristics and organizational outcomes affect clinical effectiveness, safety, and quality indicators. QUESTION: What are the predominant psychosocial variables in the explanation of organizational outcomes and quality indicators (in this case, medication errors and length of stay)? The primary objective of this study was to link the fields of evidence-based practice to the field of decision making, by providing an effective model of intervention to improve safety and quality. METHODS: The study involved healthcare workers (n = 243) from 13 different care units of a university affiliated health center in Canada. Data regarding the psychosocial work environment (10 work climate scales, effort/reward imbalance, and social support) was linked to organizational outcomes (absenteeism, turnover, overtime), to the nurse/patient ratio and quality indicators (medication errors and length of stay) using path analyses. RESULTS: The models produced in this study revealed a contribution of some psychosocial factors to quality indicators, through an indirect effect of personnel- or human resources-related variables, more precisely: turnover, absenteeism, overtime, and nurse/patient ratio. Four perceptions of work environment appear to play an important part in the indirect effect on both medication errors and length of stay: apparent social support from supervisors, appreciation of the workload demands, pride in being part of one's work team, and effort/reward balance. CONCLUSIONS: This study reveals the importance of employee perceptions of the work environment as an indirect predictor of quality of care. Working to improve these perceptions is a good investment for loyalty and attendance. In general, better personnel conditions lead to fewer medication errors and shorter length of stay. PMID- 22548731 TI - Association of ATP binding cassette transporter G8 rs4148217 SNP and serum lipid levels in Mulao and Han nationalities. AB - BACKGROUND: The association of ATP binding cassette transporter G8 gene (ABCG8) rs4148217 single nucleotide polymorphism (SNP) and serum lipid profiles is still controversial in diverse racial/ethnic groups. Mulao nationality is an isolated minority in China. The aim of this study was to evaluate the association of ABCG8 rs4148217 SNP and several environmental factors with serum lipid levels in the Guangxi Mulao and Han populations. METHODS: A total of 634 subjects of Mulao nationality and 717 participants of Han nationality were randomly selected from our previous samples. Genotyping of the ABCG8 rs4148217 SNP was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. RESULTS: The genotypic and allelic frequencies of ABCG8 rs4148217 SNP were different between the two nationalities (P < 0.01 for each), the frequency of A allele was higher in Mulao than in Han. The A allele carriers in Han had lower high-density lipoprotein cholesterol (HDL-C) and apolipoprotein (Apo) A1 levels than the A allele noncarriers (P < 0.05 for each), whereas the A allele carriers in Mulao had lower ApoA1 levels than the A allele noncarriers (P < 0.05). Subgroup analyses showed that the A allele carriers in Han had lower HDL-C and higher triglyceride (TG) levels in females but not in males than the A allele noncarriers (P < 0.05 for each), and the A allele carriers in Mulao had lower ApoA1 levels in females but not in males than the A allele noncarriers (P < 0.05). The levels of TG and HDL-C in Han, and ApoA1 in Mulao were associated with genotypes in females but not in males (P < 0.05-0.01). Serum lipid parameters were also correlated with several environmental factors (P < 0.05-0.001). CONCLUSIONS: The ABCG8 rs4148217 SNP is associated with serum TG, HDL-C and ApoA1 levels in our study populations, but this association is different between the Mulao and Han populations. There is a sex (female)-specific association in both ethnic groups. PMID- 22548732 TI - Free tissue transfers at Hutt Hospital. AB - BACKGROUND: The Wellington Regional Plastic, Maxillofacial & Burns Unit based at Hutt Hospital provides comprehensive reconstructive services to central New Zealand with a population of 1.1 million. Free tissue transfer procedures in the Unit were audited to determine the indications and rate of usage in our population, our success and complication rates, and how these compare with published series. METHODS: Prospectively collected data on all free tissue transfer procedures between January 2006 and September 2010 were analysed. RESULTS: Two hundred and seven free flaps including 17 flap types being performed on 186 consecutive patients including 199 primary and 8 salvage flaps. Eighty-three percent were elective and 17% were acute cases. The majority of the flaps were used for head and neck (48%) and breast (31.5%) reconstruction. Ulnar forearm flap was the most commonly used fasciocutaneous flap. 18.8% of patients had major complications requiring return to theatre. Microsurgical revision was performed in nine (4.3%) flaps of which six were successfully salvaged. Overall, 13 flaps (6.3%) failed completely, giving an overall success rate of 93.7%. Haematoma requiring formal drainage occurred in 12 (5.8%) cases. DISCUSSION: The wide variety of flaps used reflects the very broad range of defects requiring free flap reconstruction. We show a free flap success rate of 93.7% in our medium sized regional unit. Our microsurgical revision rate of 4.3% is lower than the revision rate of 10% in reported series with high overall success rates. More consistent early detection of failing flaps is likely to further improve our overall success rate. PMID- 22548733 TI - Matrigel-based sprouting endothelial cell culture system from mouse corpus cavernosum is potentially useful for the study of endothelial and erectile dysfunction related to high-glucose exposure. AB - INTRODUCTION: A proper cavernous endothelial cell culture system would be advantageous for the study of the pathophysiologic mechanisms involved in endothelial dysfunction and erectile dysfunction (ED). AIM: To establish a nonenzymatic technique, which we termed the "Matrigel-based sprouting endothelial cell culture system," for the isolation of mouse cavernous endothelial cells (MCECs) and an in vitro model that mimics in vivo situation for diabetes-induced ED. METHODS: For primary MCEC culture, mouse cavernous tissue was implanted into Matrigel and sprouting cells from the tissue were subcultivated. To establish an in vitro model for diabetes-induced ED, the primary cultured MCECs were exposed to a normal-glucose (5 mmoL) or a high-glucose (30 mmoL) condition for 48 hours. MAIN OUTCOME MEASURES: The purity of isolated cells was determined by fluorescence-activated cell sorting analysis. MCECs incubated under the normal- or the high-glucose condition were used for Western blot, cyclic guanosine monophosphate (cGMP) quantification, and in vitro angiogenesis assay. RESULTS: We could consistently isolate high-purity MCECs (about 97%) with the Matrigel-based sprouting endothelial cell culture system. MCECs were subcultured up to the fifth passage and no significant changes were noted in endothelial cell morphology or purity. The phosphorylation of Akt and eNOS and the cGMP concentration were significantly lower in MCECs exposed to high glucose than in those exposed to normal glucose. MCECs exposed to the normal-glucose condition formed well organized capillary-like structures, whereas derangements in tube formation were noted in MCECs exposed to high glucose. The protein expression of transforming growth factor-beta1 (TGF-beta1) and phospho-Smad2 was significantly increased by exposure to high glucose. CONCLUSION: The Matrigel-based sprouting endothelial cell culture system is a simple, technically feasible, and reproducible technique for isolating pure cavernous endothelial cells in mice. An in vitro model for diabetic ED will be a valuable tool for evaluating the angiogenic potential of novel endogenous or synthetic modulators. PMID- 22548734 TI - The mechanism of pollination drop withdrawal in Ginkgo biloba L. AB - BACKGROUND: The pollination drop (PD) is a characteristic feature of many wind pollinated gymnosperms. Although accumulating evidence shows that the PD plays a critical role in the pollination process, the mechanism of PD withdrawal is still unclear. Here, we carefully observed the PD withdrawal process and investigated the underlying mechanism of PD withdrawal, which will aid the understanding of wind-pollination efficiency in gymnosperms. RESULTS: In Ginkgo biloba, PDs were secreted on the micropyle during the pollination period and persisted for about 240 h when not pollinated under laboratory conditions. The withdrawal of an isolated PD required only 1 h for evaporation, much less than a PD on the living ovule, which required 100 h. When pollinated with viable pollen, PDs withdrew rapidly within 4 h. In contrast, nonviable pollen and acetone-treated pollen did not cause PD withdrawal. Although 100% relative humidity significantly inhibited PD withdrawal, pollinated PDs still could withdraw completely within 48 h. Pollen grains of Cycas revoluta, which are similar to those of G. biloba, could induce PD withdrawal more rapidly than those of two distantly related gymnosperms (Pinus thunbergii and Abies firma) or two angiosperms (Paeonia suffruticosa and Orychophragmus violaceus). Furthermore, pollen of G. biloba and C. revoluta submerged immediately when encountering the PD, then sank to the bottom and entered the micropyle. The saccate pollen of P. thunbergii and A. firma submerged into the PD, but remained floating at the top and finally accumulated on the micropyle after PD withdrawal. In contrast, pollen of the angiosperms P. suffruticosa, Salix babylonica, and O. violaceus did not submerge, instead remaining clustered at the edge without entering the PD. CONCLUSIONS: We conclude that PD withdrawal is primarily determined by the dynamic balance between evaporation and ovule secretion, of which pollen is a critical stimulator. When conspecific pollen grains were submerged in the PD, ovule secretion was subsequently terminated and active absorption occurred. These processes cooperated to influence PD withdrawal. In addition, pollen grain behavior within PDs varied dramatically among taxa, and PDs played a role in distinguishing and transporting pollen in G. biloba. PMID- 22548735 TI - A dynamic model for tumour growth and metastasis formation. AB - A simple and fast computational model to describe the dynamics of tumour growth and metastasis formation is presented. The model is based on the calculation of successive generations of tumour cells and enables one to describe biologically important entities like tumour volume, time point of 1st metastatic growth or number of metastatic colonies at a given time. The model entirely relies on the chronology of these successive events of the metastatic cascade. The simulation calculations were performed for two embedded growth models to describe the Gompertzian like growth behaviour of tumours. The initial training of the models was carried out using an analytical solution for the size distribution of metastases of a hepatocellular carcinoma. We then show the applicability of our models to clinical data from the Munich Cancer Registry. Growth and dissemination characteristics of metastatic cells originating from cells in the primary breast cancer can be modelled thus showing its ability to perform systematic analyses relevant for clinical breast cancer research and treatment. In particular, our calculations show that generally metastases formation has already been initiated before the primary can be detected clinically. PMID- 22548736 TI - Gap-filling analysis of the iJO1366 Escherichia coli metabolic network reconstruction for discovery of metabolic functions. AB - BACKGROUND: The iJO1366 reconstruction of the metabolic network of Escherichia coli is one of the most complete and accurate metabolic reconstructions available for any organism. Still, because our knowledge of even well-studied model organisms such as this one is incomplete, this network reconstruction contains gaps and possible errors. There are a total of 208 blocked metabolites in iJO1366, representing gaps in the network. RESULTS: A new model improvement workflow was developed to compare model based phenotypic predictions to experimental data to fill gaps and correct errors. A Keio Collection based dataset of E. coli gene essentiality was obtained from literature data and compared to model predictions. The SMILEY algorithm was then used to predict the most likely missing reactions in the reconstructed network, adding reactions from a KEGG based universal set of metabolic reactions. The feasibility of these putative reactions was determined by comparing updated versions of the model to the experimental dataset, and genes were predicted for the most feasible reactions. CONCLUSIONS: Numerous improvements to the iJO1366 metabolic reconstruction were suggested by these analyses. Experiments were performed to verify several computational predictions, including a new mechanism for growth on myo-inositol. The other predictions made in this study should be experimentally verifiable by similar means. Validating all of the predictions made here represents a substantial but important undertaking. PMID- 22548737 TI - Visualization of blood drainage area from hypervascular hepatocellular carcinoma on ultrasonographic images during hepatic arteriogram: Comparison with depiction of drainage area on contrast-enhanced ultrasound. AB - AIM: Corona enhancement is the visualized drainage area from a hypervascular tumor observed on single-level dynamic computed tomography during hepatic arteriography (CTHA) and is thought to be a high-risk area for micrometastases. However, because it cannot be visualized with ordinary ultrasonography (US), we aimed to visualize corona enhancement on US by means of arterial injection of the contrast material and to measure its thickness. METHOD: Forty-one hypervascular hepatocellular carcinoma (HCC) cases were prospectively investigated. US during hepatic arteriography (USHA) was executed by means of selective injection of the contrast material perfluorobutane (Sonazoid) from the hepatic artery. Ordinary contrast-enhanced US with venous administration of contrast material and single level dynamic CTHA were also performed. RESULTS: Corona enhancement was observed in 36 cases (88%) on USHA and in 25 cases (61%) on single-level dynamic CTHA. The thickness of corona enhancement of 36 cases visualized with USHA ranged 3.1-18.4 mm and the mean thickness +/- standard deviation was 6.0 +/- 3.0 mm. Thickness of corona enhancement was less than 10.0 mm in 34 cases (94%). CONCLUSION: Corona enhancement could be visualized even on US images, and the average thickness of them was 6 mm. PMID- 22548739 TI - Increased susceptibility to kidney injury by transfer of genomic segment from SHR onto Dahl S genetic background. AB - The Dahl salt-sensitive (S) rat is a widely studied model of salt-sensitive hypertension and develops proteinuria, glomerulosclerosis, and renal interstitial fibrosis. An earlier genetic analysis using a population derived from the S and spontaneously hypertensive rat (SHR) identified eight genomic regions linked to renal injury in the S rat and one protective locus on chromosome 11. The "protective" locus in the S rat was replaced with the SHR genomic segment conferring "susceptibility" to kidney injury. The progression of kidney injury in the S.SHR(11) congenic strain was characterized in the present study. Groups of S and S.SHR(11) rats were followed for 12 wk on either a low-salt (0.3% NaCl) or high-salt (2% NaCl) diet. By week 12 (low-salt), S.SHR(11) demonstrated a significant decline in kidney function compared with the S. Blood pressure was significantly elevated in both strains on high salt. Despite similar blood pressure, the S.SHR(11) exhibited a more significant decline in kidney function compared with the S. The decline in S.SHR(11) kidney function was associated with more severe kidney injury including tubular loss, immune cell infiltration, and tubulointerstitial fibrosis compared with the S. Most prominently, the S.SHR(11) exhibited a high degree of medullary fibrosis and a significant increase in renal vascular medial hypertrophy. In summary, genetic modification of the S rat generated a model of accelerated renal disease that may provide a better system to study progression to renal failure as well as lead to the identification of genetic variants involved in kidney injury. PMID- 22548738 TI - Proposed megakaryocytic regulon of p53: the genes engaged to control cell cycle and apoptosis during megakaryocytic differentiation. AB - During endomitosis, megakaryocytes undergo several rounds of DNA synthesis without division leading to polyploidization. In primary megakaryocytes and in the megakaryocytic cell line CHRF, loss or knock-down of p53 enhances cell cycling and inhibits apoptosis, leading to increased polyploidization. To support the hypothesis that p53 suppresses megakaryocytic polyploidization, we show that stable expression of wild-type p53 in K562 cells (a p53-null cell line) attenuates the cells' ability to undergo polyploidization during megakaryocytic differentiation due to diminished DNA synthesis and greater apoptosis. This suggested that p53's effects during megakaryopoiesis are mediated through cell cycle- and apoptosis-related target genes, possibly by arresting DNA synthesis and promoting apoptosis. To identify candidate genes through which p53 mediates these effects, gene expression was compared between p53 knock-down (p53-KD) and control CHRF cells induced to undergo terminal megakaryocytic differentiation using microarray analysis. Among substantially downregulated p53 targets in p53 KD megakaryocytes were cell cycle regulators CDKN1A (p21) and PLK2, proapoptotic FAS, TNFRSF10B, CASP8, NOTCH1, TP53INP1, TP53I3, DRAM1, ZMAT3 and PHLDA3, DNA damage-related RRM2B and SESN1, and actin component ACTA2, while antiapoptotic CKS1B, BCL2, GTSE1, and p53 family member TP63 were upregulated in p53-KD cells. Additionally, a number of cell cycle-related, proapoptotic, and cytoskeleton related genes with known functions in megakaryocytes but not known to carry p53 responsive elements were differentially expressed between p53-KD and control CHRF cells. Our data support a model whereby p53 expression during megakaryopoiesis serves to control polyploidization and the transition from endomitosis to apoptosis by impeding cell cycling and promoting apoptosis. Furthermore, we identify a putative p53 regulon that is proposed to orchestrate these effects. PMID- 22548740 TI - Environment and reproductive health in China: challenges and opportunities. PMID- 22548741 TI - DNA barcoding of six Ceroplastes species (Hemiptera: Coccoidea: Coccidae) from China. AB - Ceroplastes Gray (wax scales) is one of the genera of Coccidae, most species of which are considered to be serious economic pests. However, identification of Ceroplastes species is always difficult owing to the shortage of easily distinguishable morphological characters. Mitochondrial cytochrome c oxidase I (COI) sequences (or DNA barcodes) and the D2 expansion segments of the large subunit ribosomal RNA gene 28S were used for accurate identification of six Ceroplastes species (C. floridensis Comstock, C. japonicus Green, C. ceriferus (Fabricius), C. pseudoceriferus Green, C. rubens Maskell and C. kunmingensis Tang et Xie) from 20 different locations in China. For COI data, low G.C content was found in all species, averaging about 20.4%. Sequence divergences (K2P) between congeneric species averaged 12.19%, while intra-specific divergences averaged 0.42%. All 112 samples fell into six reciprocally monophyletic clades in the COI neighbour-joining (NJ) tree. The NJ tree inferred from 28S showed almost same results, but samples of two closely related species, C. ceriferus and C. pseudoceriferus, were clustered together. This research indicates that the standard barcode region of COI can efficiently identify similar Ceroplastes species. This study provides an example of the usefulness of barcoding for Ceroplastes identification. PMID- 22548742 TI - Colorectal stenting for malignant obstruction: an 8-year clinical experience. AB - BACKGROUND: A substantial percentage of patients with colorectal cancer present with obstructive symptoms. In such patients, surgery is often required and is associated with significant morbidity and mortality. Colorectal stenting is an increasingly commonplace alternative with potentially fewer risks than open surgery. We present our clinical experience over an 8-year period with colorectal stenting in a major tertiary Australian hospital. METHODS: From 2000 to 2008, patients undergoing colorectal stenting were identified via medical records. Clinical data collected included patient demographics, tumour type, extent of metastatic disease, stent characteristics, technical and clinical success, acute and chronic complications, and long-term follow-up status. RESULTS: Thirty-five patients (69 +/- 13 years, 25 male) received a total of 39 stents. Technical success was achieved in 37 (95%), and clinical relief of obstruction was achieved in 34 (89%). One case was complicated by perforation at the time of procedure and three cases experienced delayed perforation. Reintervention was required in 17% of patients, all of whom had less than 50% hepatic volume replacement by metastatic disease. CONCLUSIONS: Colorectal stenting is a feasible and safe alternative for patients presenting with obstructive symptoms but the benefit may be restricted to patients with a short expected survival. PMID- 22548743 TI - Genotoxicity and molecular response of silver nanoparticle (NP)-based hydrogel. AB - BACKGROUND: Since silver-nanoparticles (NPs) possess an antibacterial activity, they were commonly used in medical products and devices, food storage materials, cosmetics, various health care products, and industrial products. Various silver NP based medical devices are available for clinical uses, such as silver-NP based dressing and silver-NP based hydrogel (silver-NP-hydrogel) for medical applications. Although the previous data have suggested silver-NPs induced toxicity in vivo and in vitro, there is lack information about the mechanisms of biological response and potential toxicity of silver-NP-hydrogel. METHODS: In this study, the genotoxicity of silver-NP-hydrogel was assayed using cytokinesis block micronucleus (CBMN). The molecular response was studied using DNA microarray and GO pathway analysis. RESULTS AND DISCUSSION: The results of global gene expression analysis in HeLa cells showed that thousands of genes were up- or down-regulated at 48 h of silver-NP-hydrogel exposure. Further GO pathway analysis suggested that fourteen theoretical activating signaling pathways were attributed to up-regulated genes; and three signal pathways were attributed to down-regulated genes. It was discussed that the cells protect themselves against silver NP-mediated toxicity through up-regulating metallothionein genes and anti oxidative stress genes. The changes in DNA damage, apoptosis and mitosis pathway were closely related to silver-NP-induced cytotoxicity and chromosome damage. The down-regulation of CDC14A via mitosis pathway might play a role in potential genotoxicity induced by silver-NPs. CONCLUSIONS: The silver-NP-hydrogel induced micronuclei formation in cellular level and broad spectrum molecular responses in gene expression level. The results of signal pathway analysis suggested that the balances between anti-ROS response and DNA damage, chromosome instability, mitosis inhibition might play important roles in silver-NP induced toxicity. The inflammatory factors were likely involved in silver-NP-hydrogel complex-induced toxic effects via JAK-STAT signal transduction pathway and immune response pathway. These biological responses eventually decide the future of the cells, survival or apoptosis. PMID- 22548744 TI - Efficacy and safety of prophylaxis with entecavir and hepatitis B immunoglobulin in preventing hepatitis B recurrence after living-donor liver transplantation. AB - AIM: Hepatitis B recurrence after liver transplantation can be reduced to less than 10% by combination therapy with lamivudine (LAM) and hepatitis B immunoglobulin (HBIG). The aim of this study was to evaluate the efficacy and safety of prophylaxis with entecavir (ETV), which has higher efficacy and lower resistance rates than LAM, combined with HBIG in preventing hepatitis B recurrence after living-donor liver transplantation (LDLT). METHODS: Twenty-six patients who received ETV plus HBIG (ETV group) after LDLT for hepatitis B virus (HBV)-related end-stage liver disease were analyzed by comparing with 63 control patients who had received LAM plus HBIG (LAM group). RESULTS: The survival rates of the patients treated with ETV plus HBIG was 73% after both 1 and 3 years, and there was no statistical difference between the patients in the ETV group and LAM group. No HBV recurrence was detected during the median follow-up period of 25.1 months in the ETV group, whereas the HBV recurrence rate was 4% at 3 years and 6% at 5 years in the LAM group. No patients had adverse effects related to ETV administration. CONCLUSION: ETV combined with HBIG provides effective and safe prophylaxis in preventing hepatitis B recurrence after LDLT. PMID- 22548745 TI - Spatiotemporal network motif reveals the biological traits of developmental gene regulatory networks in Drosophila melanogaster. AB - BACKGROUND: Network motifs provided a "conceptual tool" for understanding the functional principles of biological networks, but such motifs have primarily been used to consider static network structures. Static networks, however, cannot be used to reveal time- and region-specific traits of biological systems. To overcome this limitation, we proposed the concept of a "spatiotemporal network motif," a spatiotemporal sequence of network motifs of sub-networks which are active only at specific time points and body parts. RESULTS: On the basis of this concept, we analyzed the developmental gene regulatory network of the Drosophila melanogaster embryo. We identified spatiotemporal network motifs and investigated their distribution pattern in time and space. As a result, we found how key developmental processes are temporally and spatially regulated by the gene network. In particular, we found that nested feedback loops appeared frequently throughout the entire developmental process. From mathematical simulations, we found that mutual inhibition in the nested feedback loops contributes to the formation of spatial expression patterns. CONCLUSIONS: Taken together, the proposed concept and the simulations can be used to unravel the design principle of developmental gene regulatory networks. PMID- 22548746 TI - Stem Cell Research & Therapy in 2012. PMID- 22548747 TI - RNAi-mediated silencing of the HD-Zip gene HD20 in Nicotiana attenuata affects benzyl acetone emission from corollas via ABA levels and the expression of metabolic genes. AB - BACKGROUND: The N. attenuata HD20 gene belongs to the homeodomain-leucine zipper (HD-Zip) type I family of transcription factors and it has been previously associated with the regulation of ABA accumulation in leaves and the emission of benzyl acetone (BA; 4-phenyl-2-butanone) from night flowers. In this study, N. attenuata plants stably reduced in the expression of HD20 (ir-hd20) were generated to investigate the mechanisms controlling the emission of BA from night flowers. RESULTS: The expression of HD20 in corollas of ir-hd20 plants was reduced by 85 to 90% compared to wild-type plants (WT) without affecting flower morphology and development. Total BA emitted from flowers of ir-hd20 plants was reduced on average by 60%. This reduction occurred mainly at the late phase of BA emission and it was correlated with 2-fold higher levels of ABA in the corollas of ir-hd20 plants. When a 2-fold decline in ABA corolla levels of these plants was induced by salt stress, BA emissions recovered to WT levels. Supplying ABA to WT flowers either through the cuticle or by pedicle feeding reduced the total BA emissions by 25 to 50%; this reduction occurred primarily at the late phase of emission (similar to the reduction observed in corollas of ir-hd20 plants). Gene expression profiling of corollas collected at 12 pm (six hours before the start of BA emission) revealed that 274 genes changed expression levels significantly in ir-hd20 plants compared to WT. Among these genes, more than 35% were associated with metabolism and the most prominent group was associated with the metabolism of aromatic compounds and phenylpropanoid derivatives. CONCLUSIONS: The results indicated that regulation of ABA levels in corollas is associated with the late phase of BA emission in N. attenuata plants and that HD20 affects this latter process by mediating changes in both ABA levels and metabolic gene expression. PMID- 22548748 TI - Anti-type II collagen antibodies are associated with early radiographic destruction in rheumatoid arthritis. AB - INTRODUCTION: We have previously reported that high levels of antibodies specific for native human type II collagen (anti-CII) at the time of RA diagnosis were associated with concurrent but not later signs of inflammation. This was associated with CII/anti-CII immune complex (IC)-induced production of pro inflammatory cytokines in vitro. In contrast, anti-cyclic citrullinated peptide antibodies (anti-CCP) were associated both with late inflammation and late radiological destruction in the same RA cohort. We therefore hypothesized that anti-CII are also associated with early erosions. METHODS: Two-hundred-and-fifty six patients from an early RA cohort were included. Baseline levels of anti-CII, anti-CCP and anti-mutated citrullinated vimentin were analyzed with ELISA, and rheumatoid factor levels were determined by nephelometry. Radiographs of hands and feet at baseline, after one and after two years were quantified using the 32 joints Larsen erosion score. RESULTS: Levels of anti-CII were bimodally distributed in the RA cohort, with a small (3.1%, 8/256) group of very high outliers with a median level 87 times higher than the median for the healthy control group. Using a cut-off discriminating the outlier group that was associated with anti-CII IC-induced production of proinflammatory cytokines in vitro, baseline anti-CII antibodies were significantly (p = 0.0486) associated with increased radiographic damage at the time of diagnosis. Anti-CII-positive patient had also significantly increased HAQ score (p = 0.0303), CRP (p = 0.0026) and ESR (p = 0.0396) at the time of diagnosis but not during follow-up. The median age among anti-CII-positive subjects was 12 years higher than among the anti-CII-negative patients. CONCLUSION: In contrary to anti-CCP, anti-CII positive patients with RA have increased joint destruction and HAQ score at baseline. Anti-CII thus characterizes an early inflammatory/destructive phenotype, in contrast to the late appearance of an inflammatory/destructive phenotype in anti-CCP positive RA patients. The anti-CII phenotype might account for part of the elderly acute onset RA phenotype with rather good prognosis. PMID- 22548749 TI - Environmental lead after hurricane Katrina. PMID- 22548750 TI - Effects of intravenous injection of adipose-derived stem cells in a rat model of radiation therapy-induced erectile dysfunction. AB - INTRODUCTION: Radiation therapy (RT) for prostate cancer is frequently associated with posttreatment erectile dysfunction (ED). AIM: To investigate whether injection of adipose-derived stem cells (ADSCs) can ameliorate RT-associated ED. METHODS: Thirty male rats were divided into three groups. The control + phosphate buffered saline (PBS) group received tail-vein injection of PBS. The radiation + PBS group received radiation over the prostate and tail-vein injection of PBS. The radiation + ADSC group received radiation over the prostate and tail-vein injection of ADSCs, which were labeled with 5-ethynyl-2-deoxyuridine (EdU). Seventeen weeks later, erectile function was evaluated by intracavernous pressure (ICP) in response to electrostimulation of cavernous nerves (CNs). Penile tissue and major pelvic ganglia (MPG) were examined by immunofluorescence (IF) and EdU staining. MAIN OUTCOME MEASURES: Erectile function was measured by ICP. Protein expression was examined by IF, followed by image analysis and quantification. RESULTS: Radiation over the prostate caused a significant decrease in erectile function and in the expression of neuronal nitric oxide synthase (nNOS) in penis and MPG. Cavernous smooth muscle (CSM) but not endothelial content was also reduced. Injection of ADSCs significantly restored erectile function, nNOS expression, and CSM content in the irradiated rats. EdU-positive cells were visible in MPG. CONCLUSIONS: Radiation appears to cause ED via CN injury. ADSC injection can restore erectile function via CN regeneration. PMID- 22548751 TI - Infectious spondylodiscitis in patients with central venous catheters for haemodialysis: a retrospective study. AB - AIM: To evaluate the prevalence of infectious spondylodiscitis associated with central venous catheters (CVC) for haemodialysis. METHODS: Descriptive and retrospective research. Clinical histories of 830 patients with a CVC for haemodialysis in our unit were reviewed from January 1999 to December 2010. Clinical data associated with spondylodiscitis were collected. RESULTS: Five out of 830 patients reported infectious spondylodiscitis associated with their CVC for haemodialysis. Of the five cases, the average age was 66 years (range 59-72 years), there were four females and one male. Three had diabetic nephropathy. Site of CVC: four jugular, one femoral. Signs and symptoms: fever and leucocytosis 100%, lumbar pain 85%; positive blood cultures 60%; computed axial tomography and magnetic resonance imaging showing signs suggestive of spondylodiscitis or epidural abscess 100%. CONCLUSIONS: Although rare, infectious spondylodiscitis is a serious complication in haemodialysis patients with a CVC as vascular access. It is essential that any alarming sign of infection to be recorded daily and appropriate treatment to initiate in order to avoid fatal complications. PMID- 22548752 TI - Sexual function after surgery for early-stage cervical cancer: is there a difference in it according to the extent of surgical radicality? AB - INTRODUCTION: Approximately 15% of all cervical cancers are found in women under the age of 40. Sexual function is a matter of great importance for these women. However, the impact of the surgical radicality for cervical cancer on sexual function has not been established. AIMS: The aim of this study is to estimate the difference in postoperative sexual function in women with surgically treated early-stage cervical cancer according to the extent of surgical radicality. METHODS: One hundred and five women with early-stage cervical cancer treated by cervical conization (CC), radical trachelectomy (RT), and radical hysterectomy (RH) between January 2006 and December 2009 were asked to answer a validated questionnaire, the Female Sexual Function Index (FSFI). MAIN OUTCOME MEASURE: FSFI score. RESULTS: Eighty-one completed questionnaires from 39 (48.2%) women in the CC group, 18 (22.2%) in the RT group, and 24 (29.6%) in the RH group were studied. The FSFI total score for the CC group was 30.72 +/- 3.39, suggesting no sexual dysfunctioning. The FSFI total score for the RT and RH groups (21.78 +/- 4.17 and 22.40 +/- 4.09, respectively) demonstrated a globally compromised sexuality, based on a FSFI total score of 26.55 as the clinical cut-off for sexual dysfunction. The FSFI total scores in the RT and RH groups were significantly decreased compared to the CC group (P < 0.001). However, there were no significant differences between the RT and RH groups. CONCLUSIONS: The RT and RH groups, unlike the CC group, had compromised sexual function after the treatment of early-stage cervical cancer. PMID- 22548753 TI - Gnidia glauca flower extract mediated synthesis of gold nanoparticles and evaluation of its chemocatalytic potential. AB - BACKGROUND: Novel approaches for synthesis of gold nanoparticles (AuNPs) are of utmost importance owing to its immense applications in diverse fields including catalysis, optics, medical diagnostics and therapeutics. We report on synthesis of AuNPs using Gnidia glauca flower extract (GGFE), its detailed characterization and evaluation of its chemocatalytic potential. RESULTS: Synthesis of AuNPs using GGFE was monitored by UV-Vis spectroscopy and was found to be rapid that completed within 20 min. The concentration of chloroauric acid and temperature was optimized to be 0.7 mM and 50 degrees C respectively. Bioreduced nanoparticles varied in morphology from nanotriangles to nanohexagons majority being spherical. AuNPs were characterized employing transmission electron microscopy, high resolution transmission electron microscopy. Confirmation of elemental gold was carried out by elemental mapping in scanning transmission electron microscopic mode, energy dispersive spectroscopy and X-ray diffraction studies. Spherical particles of size ~10 nm were found in majority. However, particles of larger dimensions were in range between 50-150 nm. The bioreduced AuNPs exhibited remarkable catalytic properties in a reduction reaction of 4 nitrophenol to 4-aminophenol by NaBH4 in aqueous phase. CONCLUSION: The elaborate experimental evidences support that GGFE can provide an environmentally benign rapid route for synthesis of AuNPs that can be applied for various purposes. Biogenic AuNPs synthesized using GGFE exhibited excellent chemocatalytic potential. PMID- 22548754 TI - High-dose intravenous immunoglobulin in the treatment of adult patients with bullous pemphigoid. AB - High-dose intravenous immunoglobulin (IVIg) has only been sporadically used in the treatment of bullous pemphigoid (BP), as it is suggested as an adjuvant to systemic corticosteroids in progressive disease or when life-threatening complications are of concern with other therapeutic interventions. The aim of the present study was to report our observations in the treatment of adult BP patients with IVIg, in association with a focused literature review. In our Department we identified five patients (4 women, 1 man) who had received IVIg for BP relatively early in the course of their disease. These cases were added to the 36 adequately documented ones reported in the literature. Most of these patients (33/41) responded to treatment with IVIg and 7/33 responders remained clear one year after the onset of IVIg. However, the time for effective disease control after IVIg treatment depended positively on disease duration before treatment (P<0.01). In conclusion, despite the limited experience with its use, IVIg seems to be a useful therapeutic alternative to conventional modalities for selected BP patients, particularly if it is initiated promptly after BP diagnosis. PMID- 22548755 TI - Newly defined fracture pattern specific to Mason III radial head fractures: fracture description, management and outcomes using screw fixation. AB - BACKGROUND: Radial head fractures are the most common type of elbow fracture and are universally classified under the Mason classification system. Mason type III fractures are comminuted and are the most difficult to treat, generally requiring plating if possible, or more commonly arthroplasty or excision, which gives a variable outcome. We hypothesized that a new and specific fracture pattern of the radial head (Mason III) can be treated successfully with screw fixation. METHODS: Six patients presented to the senior surgeon's clinic with this unusual Mason III fracture pattern. In these patients, the fracture was acute, requiring an open reduction and internal fixation with the use of three headless compression screws. Average follow-up time was 21 months. Using serial X rays and the Broberg-Morrey elbow score, the six acute fractures were evaluated radiologically and functionally. RESULTS: All six patients had good to excellent results using the Broberg-Morrey scoring system. All patients showed radiological and clinical union within 3 months of injury. No patient required revision surgery or excision at a later date. DISCUSSION: We have recognized a specific type of comminuted and displaced Mason III radial head fracture that has not previously been described in the literature. This type of fracture is amenable to open reduction internal fixation with buried compression screws giving a good to excellent outcome, while avoiding the common consequences seen with a radial head excision, arthroplasty or plate fixation. PMID- 22548757 TI - Relationship between hospital volume and operative mortality for liver resection: Data from the Japanese Diagnosis Procedure Combination database. AB - AIM: The present study aimed to conduct a nationwide investigation on the relationship between hospital volume and outcomes following liver resection in Japan. We also discuss health policy implications of the results. METHODS: Using the Japanese Diagnosis Procedure Combination database, we identified 18 046 patients who underwent hepatic resection between July and December 2007-2009. Patients were subdivided into hospital-volume quartiles: very low- (<18/year), low- (18-35), high- (36-70) and very high-volume groups (>70). Multivariate logistic regression analysis for in-hospital mortality within 30 days of surgery was performed to analyze adjusted effects of various factors. RESULTS: Patients in the very high-volume group had a higher Charlson Comorbidity Index (P < 0.001) than those in the very low-volume group. Very low-volume hospitals were significantly less likely to perform extended lobectomy than very high-volume hospitals (5.4% vs 17.6%, P < 0.001). Crude in-hospital mortality within 30 days of surgery was 1.1% (0.6%, 0.8%, 1.9% and 3.0% for limited resection, segmentectomy, lobectomy and extended lobectomy, respectively). With reference to the very low-volume group, risk-adjusted odds ratios (95% confidence intervals) of low-, high- and very high-volume groups for overall mortality were 0.70 (0.48 1.02; P = 0.060), 0.52 (0.34-0.81; P = 0.004) and 0.16 (0.09-0.30; P < 0.001), respectively. CONCLUSION: There is a linear trend between higher hospital volume and lower in-hospital mortality of liver resection in Japan, particularly for lobectomy and extended lobectomy. Based on these results, regionalization of lobectomy and extended lobectomy in high-volume centers could be effective for reducing postoperative mortality. PMID- 22548756 TI - Gene regulation is governed by a core network in hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, and the mechanisms that lead to the disease are still relatively unclear. However, with the development of high-throughput technologies it is possible to gain a systematic view of biological systems to enhance the understanding of the roles of genes associated with HCC. Thus, analysis of the mechanism of molecule interactions in the context of gene regulatory networks can reveal specific sub-networks that lead to the development of HCC. RESULTS: In this study, we aimed to identify the most important gene regulations that are dysfunctional in HCC generation. Our method for constructing gene regulatory network is based on predicted target interactions, experimentally-supported interactions, and co-expression model. Regulators in the network included both transcription factors and microRNAs to provide a complete view of gene regulation. Analysis of gene regulatory network revealed that gene regulation in HCC is highly modular, in which different sets of regulators take charge of specific biological processes. We found that microRNAs mainly control biological functions related to mitochondria and oxidative reduction, while transcription factors control immune responses, extracellular activity and the cell cycle. On the higher level of gene regulation, there exists a core network that organizes regulations between different modules and maintains the robustness of the whole network. There is direct experimental evidence for most of the regulators in the core gene regulatory network relating to HCC. We infer it is the central controller of gene regulation. Finally, we explored the influence of the core gene regulatory network on biological pathways. CONCLUSIONS: Our analysis provides insights into the mechanism of transcriptional and post-transcriptional control in HCC. In particular, we highlight the importance of the core gene regulatory network; we propose that it is highly related to HCC and we believe further experimental validation is worthwhile. PMID- 22548758 TI - Isoenzyme expression changes in response to high temperature determine the metabolic regulation of increased glycolytic flux in yeast. AB - Qualitative phenotypic changes are the integrated result of quantitative changes at multiple regulatory levels. To explain the temperature-induced increase of glycolytic flux in fermenting cultures of Saccharomyces cerevisiae, we quantified the contributions of changes in activity at many regulatory levels. We previously showed that a similar temperature increase in glucose-limited cultivations lead to a qualitative change from respiratory to fermentative metabolism, and this change was mainly regulated at the metabolic level. In contrast, in fermenting cells, a combination of different modes of regulation was observed. Regulation by changes in expression and the effect of temperature on enzyme activities contributed much to the increase in flux. Mass spectrometric quantification of glycolytic enzymes revealed that increased enzyme activity did not correlate with increased protein abundance, suggesting a large contribution of post translational regulation to activity. Interestingly, the differences in the direct effect of temperature on enzyme kinetics can be explained by changes in the expression of the isoenzymes. Therefore, both the interaction of enzyme with its metabolic environment and the temperature dependence of activity are in turn regulated at the hierarchical level. PMID- 22548759 TI - De novo assembly of the carrot mitochondrial genome using next generation sequencing of whole genomic DNA provides first evidence of DNA transfer into an angiosperm plastid genome. AB - BACKGROUND: Sequence analysis of organelle genomes has revealed important aspects of plant cell evolution. The scope of this study was to develop an approach for de novo assembly of the carrot mitochondrial genome using next generation sequence data from total genomic DNA. RESULTS: Sequencing data from a carrot 454 whole genome library were used to develop a de novo assembly of the mitochondrial genome. Development of a new bioinformatic tool allowed visualizing contig connections and elucidation of the de novo assembly. Southern hybridization demonstrated recombination across two large repeats. Genome annotation allowed identification of 44 protein coding genes, three rRNA and 17 tRNA. Identification of the plastid genome sequence allowed organelle genome comparison. Mitochondrial intergenic sequence analysis allowed detection of a fragment of DNA specific to the carrot plastid genome. PCR amplification and sequence analysis across different Apiaceae species revealed consistent conservation of this fragment in the mitochondrial genomes and an insertion in Daucus plastid genomes, giving evidence of a mitochondrial to plastid transfer of DNA. Sequence similarity with a retrotransposon element suggests a possibility that a transposon-like event transferred this sequence into the plastid genome. CONCLUSIONS: This study confirmed that whole genome sequencing is a practical approach for de novo assembly of higher plant mitochondrial genomes. In addition, a new aspect of intercompartmental genome interaction was reported providing the first evidence for DNA transfer into an angiosperm plastid genome. The approach used here could be used more broadly to sequence and assemble mitochondrial genomes of diverse species. This information will allow us to better understand intercompartmental interactions and cell evolution. PMID- 22548762 TI - Troponin--past, present, and future. Foreword. PMID- 22548761 TI - Diagnostic accuracy of eye movements in assessing pedophilia. AB - INTRODUCTION: Given that recurrent sexual interest in prepubescent children is one of the strongest single predictors for pedosexual offense recidivism, valid and reliable diagnosis of pedophilia is of particular importance. Nevertheless, current assessment methods still fail to fulfill psychometric quality criteria. AIMS: The aim of the study was to evaluate the diagnostic accuracy of eye movement parameters in regard to pedophilic sexual preferences. METHOD: Eye movements were measured while 22 pedophiles (according to ICD-10 F65.4 diagnosis), 8 non-pedophilic forensic controls, and 52 healthy controls simultaneously viewed the picture of a child and the picture of an adult. Fixation latency was assessed as a parameter for automatic attentional processes and relative fixation time to account for controlled attentional processes. MAIN OUTCOME MEASURES: Receiver operating characteristic (ROC) analyses, which are based on calculated age-preference indices, were carried out to determine the classifier performance. Cross-validation using the leave-one-out method was used to test the validity of classifiers. RESULTS: Pedophiles showed significantly shorter fixation latencies and significantly longer relative fixation times for child stimuli than either of the control groups. Classifier performance analysis revealed an area under the curve (AUC) = 0.902 for fixation latency and an AUC = 0.828 for relative fixation time. The eye-tracking method based on fixation latency discriminated between pedophiles and non-pedophiles with a sensitivity of 86.4% and a specificity of 90.0%. Cross-validation demonstrated good validity of eye-movement parameters. CONCLUSIONS: Despite some methodological limitations, measuring eye movements seems to be a promising approach to assess deviant pedophilic interests. Eye movements, which represent automatic attentional processes, demonstrated high diagnostic accuracy. PMID- 22548760 TI - Sensory and sympathetic nerve fibers undergo sprouting and neuroma formation in the painful arthritic joint of geriatric mice. AB - INTRODUCTION: Although the prevalence of arthritis dramatically increases with age, the great majority of preclinical studies concerning the mechanisms that drive arthritic joint pain have been performed in young animals. One mechanism hypothesized to contribute to arthritic pain is ectopic nerve sprouting; however, neuroplasticity is generally thought to be greater in young versus old nerves. Here we explore whether sensory and sympathetic nerve fibers can undergo a significant ectopic nerve remodeling in the painful arthritic knee joint of geriatric mice. METHODS: Vehicle (saline) or complete Freund's adjuvant (CFA) was injected into the knee joint of 27- to 29-month-old female mice. Pain behaviors, macrophage infiltration, neovascularization, and the sprouting of sensory and sympathetic nerve fibers were then assessed 28 days later, when significant knee joint pain was present. Knee joints were processed for immunohistochemistry by using antibodies raised against CD68 (monocytes/macrophages), PECAM (endothelial cells), calcitonin gene-related peptide (CGRP; sensory nerve fibers), neurofilament 200 kDa (NF200; sensory nerve fibers), tyrosine hydroxylase (TH; sympathetic nerve fibers), and growth-associated protein 43 (GAP43; nerve fibers undergoing sprouting). RESULTS: At 4 weeks after initial injection, CFA-injected mice displayed robust pain-related behaviors (which included flinching, guarding, impaired limb use, and reduced weight bearing), whereas animals injected with vehicle alone displayed no significant pain-related behaviors. Similarly, in the CFA-injected knee joint, but not in the vehicle-injected knee joint, a remarkable increase was noted in the number of CD68+ macrophages, density of PECAM+ blood vessels, and density and formation of neuroma-like structures by CGRP+, NF200+, and TH+ nerve fibers in the synovium and periosteum. CONCLUSIONS: Sensory and sympathetic nerve fibers that innervate the aged knee joint clearly maintain the capacity for robust nerve sprouting and formation of neuroma-like structures after inflammation/injury. Understanding the factors that drive this neuroplasticity, whether this pathologic reorganization of nerve fibers contributes to chronic joint pain, and how the phenotype of sensory and sympathetic nerves changes with age may provide pharmacologic insight and targets for better controlling aging-related joint pain. PMID- 22548763 TI - Troponin--past, present, and future. AB - Cardiac troponin is the analyte of choice for the diagnosis of cardiac injury. It is highly specific for the heart and much more sensitive than prior biomarkers. Because of this increased sensitivity, clinicians have had to struggle with elevations in novel clinical situations. We have developed new understandings about coronary artery disease but also have begun to appreciate that many other entities as well can result in cardiac injury. As assays have increased in sensitivity over time, this trend has, if anything, accelerated. This review attempts to put the past, the present, and the future into a clinical perspective that will help clinicians. PMID- 22548764 TI - Reconstruction of elbow region defects using radial collateral artery perforator (RCAP)-based propeller flaps. AB - Perforator-based propeller flaps permit flap rotation up to 180 degrees . This ability to transfer skin from one longitudinal axis to another has led to the increasing use of perforator-based propeller flaps in extremity reconstruction, especially lower-extremity reconstruction. However, the application of perforator based propeller flaps to upper-extremity reconstruction is still limited. This article reports two cases of successful reconstruction of elbow region defects with radial collateral artery perforator (RCAP)-based propeller flaps. The elbow region has a variety of perforators available for perforator-based propeller flap reconstruction. Among them, the RCAP seems to be one of the most reliable options. This is because there are less anatomical variations of perforators' location on the lateral upper arm than on the medial upper arm. By using an RCAP perforator as a flap pedicle, the small-to-medium sized defects (<6 cm in diameter) around elbow regions can be closed primarily without skin grafts. PMID- 22548766 TI - Assessment tools in obesity - psychological measures, diet, activity, and body composition. AB - The global increase in the prevalence of obesity has led to an increased need for measurement tools for research, management and treatment of the obese person. The physical size limitations imposed by obesity, variations in body composition from that of normal weight, and a complex psychopathology all pose tremendous challenges to the assessment of an obese person. There is little published research regarding what tools can be used with confidence. This review is designed to provide researchers and clinicians with a guide to the current and emerging measurement tools specifically associated with obesity research and practice. Section 1 addresses psychological measures of well being. Sections 2, 3, and 4 focus on the assessment of food intake, activity, and body composition. All sections address basic challenges involved in the study and management of obesity, and highlight methodological issues associated with the use of common assessment tools. The best available methods for use in the obese both in research and clinical practice are recommended. PMID- 22548768 TI - Mapping human long bone compartmentalisation during ontogeny: a new methodological approach. AB - Throughout ontogeny, human bones undergo differentiation in terms of shape, size and tissue type; this is a complex scenario in which the variations in the tissue compartmentalisation of the cortical bone are still poorly understood. Currently, compartmentalisation is studied using methodologies that oversimplify the bone tissue complexity. Here, we present a new methodological approach that integrates a histological description and a mineral content analysis to study the compartmentalisation of the whole mineralised and non-mineralised tissues (i.e., spatial distribution in long bone sections). This new methodology, based on Geographical Information System (GIS) software, allows us to draw areas of interest (i.e., tracing vectorial shapes which are quantifiable) in raw images that are extracted from microscope and compared them spatially in a semi automatic and quantitative fashion. As an example of our methodology, we have studied the tibiae from individuals with different age at death (infant, juvenile and adult). The tibia's cortical bone presents a well-formed fibrolamellar bone, in which remodelling is clearly evidenced from early ontogeny, and we discuss the existence of "lines of arrested growth". Concurrent with the histological variation, Raman and FT-IR spectroscopy analyses corroborate that the mineral content in the cortical bone changes differentially. The anterior portion of the tibia remains highly pierced and is less crystalline than the rest of the cortex during growth, which is evidence of more active and continuous remodelling. Finally, while porosity and other "non-mineralised cavities" are largely modified, the mineralised portion and the marrow cavity size persist proportionally during ontogeny. PMID- 22548767 TI - Efficacy of omeprazole, famotidine, mosapride and teprenone in patients with upper gastrointestinal symptoms: an omeprazole-controlled randomized study (J FOCUS). AB - BACKGROUND: In Japan, treatment guidelines are lacking for patients with upper gastrointestinal symptoms. We aimed to compare the efficacy of different drugs for the treatment of uninvestigated upper gastrointestinal symptoms. METHODS: This was a randomized, open-label, parallel-group multicenter study. Helicobacter pylori-negative, endoscopically uninvestigated patients >= 20 years of age with upper gastrointestinal symptoms of at least moderate severity (Global Overall Symptom score [GOS] >= 4 on a 7-point Likert scale) were randomized to treatment with omeprazole (10 mg once daily), famotidine (10 mg twice daily), mosapride (5 mg three times daily) or teprenone (50 mg three times daily). The primary endpoint was sufficient relief of upper gastrointestinal symptoms after 4 weeks of treatment (GOS <= 2). UMIN clinical trial registration number: UMIN000005399. RESULTS: Of 471 randomized patients, 454 were included in the full analysis set. After 4 weeks of treatment, sufficient symptom relief was achieved by 66.9% of patients in the omeprazole group, compared with 41.0%, 36.3% and 32.3% in the famotidine, mosapride and teprenone groups, respectively (all, p < 0.001 vs omeprazole). There were no treatment-related adverse events. CONCLUSIONS: The favorable efficacy and safety profiles of omeprazole in relieving uninvestigated upper gastrointestinal symptoms support its use as first-line treatment in this patient group in Japan. Patients who show no improvement in symptoms despite PPI use, and those with alarm symptoms (such as vomiting, GI bleeding or acute weight loss) should receive further investigation, including prompt referral for endoscopy. TRIAL REGISTRATION: UMIN000005399. PMID- 22548769 TI - Disseminated Mycobacterium immunogenum infection presenting with septic shock and skin lesions in a renal transplant recipient. AB - Mycobacterium immunogenum is a relatively new species within the Mycobacterium chelonae-Mycobacterium abscessus group of rapidly growing mycobacteria (RGM). M. immunogenum was first characterized in 2001 and, similar to other RGM, is an ubiquitous environmental organism. This organism has most commonly been implicated in cutaneous infection in both healthy and immunosuppressed patients. To our knowledge, this is the first reported case of septic shock in the setting of disseminated M. immunogenum infection. Definitive identification of this organism requires gene sequencing at specialized centers, which may limit its detection. M. immunogenum is resistant to many anti-mycobacterial agents, and treatment can be especially challenging in transplant patients, given potential drug interactions and added toxicities. It is important to distinguish M. immunogenum from other RGM and determine the susceptibility profile to devise a successful treatment plan, particularly in the transplant population in which it can potentially cause severe, disseminated disease. PMID- 22548770 TI - Phylogenetic community ecology and the role of social dominance in sponge dwelling shrimp. AB - When functional traits are evolutionarily conserved, phylogenetic relatedness can serve as a proxy for ecological similarity to examine whether functional differences among species mediate community assembly. Using phylogenetic- and trait-based analyses, we demonstrate that sponge-dwelling shrimp (Synalpheus) assemblages are structured by size-based habitat filtering, interacting with competitive exclusion mediated by social system. Most shrimp communities were more closely related and/or more similar in size than randomized communities, consistent with habitat filtering facilitated by phylogenetically conserved body size. Those sponges with greater space heterogeneity hosted shrimp communities with greater size diversity, corroborating the importance of size in niche use. However, communities containing eusocial shrimp - which cooperatively defend territories - were less phylogenetically related and less similar in size, suggesting that eusociality enhances competitive ability and drives competitive exclusion. Our analyses demonstrate that community assembly in this diverse system occurs via traits mediating niche use and differential competitive ability. PMID- 22548771 TI - The presence of overactive bladder wet increased the risk and severity of erectile dysfunction in men with type 2 diabetes. AB - INTRODUCTION: Diabetes is a common risk factor for overactive bladder (OAB) syndrome and erectile dysfunction (ED). AIM: The study evaluated the risk factors of OAB and association of OAB and ED in type 2 diabetic men. METHODS: The diagnosis of ED and OAB was based on a self-administered questionnaire containing Sexual Health Inventory for Men (SHIM) and OAB symptom score (OABSS, 0-15, indicating increasing severity of symptoms), respectively. MAIN OUTCOME MEASURES: The clinical variables and diabetes-associated complications, including ED, which are risk factors for OAB, were evaluated. RESULTS: Of 453 consecutive subjects attending outpatient diabetic clinic with a mean age of 60.6 years, 25.4%, 10.2%, 81.9%, and 28.3% reported having OAB, OAB wet, ED, and severe ED, respectively. The OABSS is inversely associated with SHIM (correlation coefficient-0.275). The patients with OAB have significantly lower SHIM score, testosterone level, and serum albumin level, have more proportion of severe ED, were older, and have longer duration of diabetes mellitus (DM). After adjustment for age and duration of DM, the presence of severe ED was associated with OAB (odds ratio [OR] = 1.58), and severe ED (OR = 2.36), SHIM score (OR = 0.92), and serum albumin level (OR = 0.24) were risk factors for OAB wet (patients with urgency incontinence, once a week or more). The OR of ED in patients with OAB or OAB wet compared with no OAB was 1.82, and 3.61, respectively. Among the OAB components, urgency incontinence has the strongest impact on ED (OR = 4.06), followed by nocturia, urgency, and frequency. About 15.1% (N = 68) without OAB and ED are younger and have shorter DM duration, lower systolic BP, and higher serum albumin level after multivariate analysis compared with patients with OAB or ED. CONCLUSION: The presence of severe ED was significantly associated with OAB, especially OAB wet. The presence of OAB wet increased the risk and severity of ED. PMID- 22548772 TI - Differing effects of NT-3 and GDNF on dissociated enteric ganglion cells exposed to hydrogen peroxide in vitro. AB - Oxidative stress is widely recognized to contribute to neuronal death during various pathological conditions and ageing. In the enteric nervous system (ENS), reactive oxygen species have been implicated in the mechanism of age-associated neuronal loss. The neurotrophic factors, neurotrophin 3 (NT-3) and glial cell line-derived neurotrophic factor (GDNF), are important in the development of enteric neurons and continue to be expressed in the gut throughout life. It has therefore been suggested that they may have a neuroprotective role in the ENS. We investigated the potential of NT-3 and GDNF to prevent the death of enteric ganglion cells in dissociated cell culture after exposure to hydrogen peroxide (H(2)O(2)). H(2)O(2) treatment resulted in a dose-dependent death of enteric neurons and glial cells, as demonstrated by MTS assay, bis-benzimide and propidium iodide staining and immunolabelling. Cultures treated with NT-3 prior to exposure showed reduced cell death compared to untreated control or GDNF treated cultures. GDNF treatment did not affect neuronal survival in H(2)O(2) treated cultures. These results suggest that NT-3 is able to enhance the survival of enteric ganglion cells exposed to oxidative stress. PMID- 22548773 TI - Biotemplating rod-like viruses for the synthesis of copper nanorods and nanowires. AB - BACKGROUND: In the past decade spherical and rod-like viruses have been used for the design and synthesis of new kind of nanomaterials with unique chemical positioning, shape, and dimensions in the nanosize regime. Wild type and genetic engineered viruses have served as excellent templates and scaffolds for the synthesis of hybrid materials with unique properties imparted by the incorporation of biological and organic moieties and inorganic nanoparticles. Although great advances have been accomplished, still there is a broad interest in developing reaction conditions suitable for biological templates while not limiting the material property of the product. RESULTS: We demonstrate the controlled synthesis of copper nanorods and nanowires by electroless deposition of Cu on three types of Pd-activated rod-like viruses. Our aqueous solution-based method is scalable and versatile for biotemplating, resulting in Cu-nanorods 24 46 nm in diameter as measured by transmission electron microscopy. Cu2+ was chemically reduced onto Pd activated tobacco mosaic virus, fd and M13 bacteriophages to produce a complete and uniform Cu coverage. The Cu coating was a combination of Cu0 and Cu2O as determined by X- ray photoelectron spectroscopy analysis. A capping agent, synthesized in house, was used to disperse Cu-nanorods in aqueous and organic solvents. Likewise, reactions were developed to produce Cu nanowires by metallization of polyaniline-coated tobacco mosaic virus. CONCLUSIONS: Synthesis conditions described in the current work are scalable and amenable for biological templates. The synthesized structures preserve the dimensions and shape of the rod-like viruses utilized during the study. The current work opens the possibility of generating a variety of nanorods and nanowires of different lengths ranging from 300 nm to micron sizes. Such biological-based materials may find ample use in nanoelectronics, sensing, and cancer therapy. PMID- 22548774 TI - Use of medicines and adherence to standard treatment guidelines in rural community health centers, Timor-Leste. AB - The use of medicines and nurses'/midwives' adherence to standard treatment guidelines (STGs) were examined in Timor-Leste during the early stage of the nation's new health system development. A cross-sectional study was conducted as the quantitative element of mixed methods research. Retrospective samples from patient registration books and prospective observations were obtained in 20 randomly selected rural community health centers. The medicines use indicators, in particular the level of injection use, in Timor-Leste did not suggest overprescription. Prescribers with clinical nurse training prescribed significantly fewer antibiotics than those without such training (P < .01). The adjusted odds ratio of prescribing adherence for clinical nurse training, after accounting for confounders and prescriber clustering, was 6.6 (P < .01). STGs for nonphysician health professionals at the primary health care level have potential value in basic health care delivery, including appropriate use of medicines, in resource-limited communities when strategically developed and introduced. PMID- 22548775 TI - Monitoring of blood pressure among children and adolescents in a coastal province in China: results of a 2010 survey. AB - BACKGROUND: Several studies have provided ample evidence that hypertension in adults has its onset in childhood; children and adolescents with elevated blood pressure (BP) are more likely to become hypertensive adults. The present study examined the prevalence of relatively high BP among children and adolescents in Shandong, China. SUBJECTS AND METHODS: Data for this study were obtained from a large cross-sectional survey of schoolchildren carried out in 2010. A total of 38 860 students (19 481 boys and 19 379 girls) aged 7 to 17 years participated in this study. Relatively high BP status was defined as systolic blood pressure and/or diastolic blood pressure >=95th percentile for age and gender. RESULTS: Shandong children had a high BP level, with the 50th percentiles of systolic and diastolic blood pressure of children and adolescents aged 7 to 17 years in Shandong being above the reference values for Chinese children and adolescents by 3 to 12 mm Hg and 3 to 7 mm Hg for boys, and by 3 to 6 mm Hg and 3 to 5 mmHg for girls, respectively. The overall prevalence of relatively high BP was 26.22% for boys and 20.27% for girls. CONCLUSION: There is a high prevalence of relatively high BP among children and adolescents in Shandong, China. It has become a threatening hazard to children and adolescents and should arouse special attention. PMID- 22548776 TI - Lung cancer mortality among women in Xuan Wei, China: a comparison of spatial clustering detection methods. AB - The identification of spatial clusters of lung cancer mortality can be a useful instrument in detecting locations with high risk of this disease. This study compared 2 methods for identifying spatial clusters of village-level women lung cancer mortality rates in Xuan Wei. One used a local indicator of spatial association to detect which groups of neighboring villages had lung cancer mortality rates that were significantly related to each other. The other was a spatial scan technique that calculated a maximum likelihood ratio of lung cancer deaths relative to the underlying population in order to identify the group of villages with relatively higher risk. As each technique based its cluster detection process on its own criteria, different clusters of villages were identified. However, the overlapping indicated that the 2 methods illustrated different components of the same clusters. These spatial analytic techniques were complementary to each other and can be used jointly rather than separately. PMID- 22548777 TI - Measuring positive mental health: development of the Achutha Menon Centre Positive Mental Health Scale. AB - The authors developed a scale for positive mental health (PMH), which encompasses positive state of mind and positive functioning. The existing tools are inadequate to measure the construct, especially in a community where the self statement format of a scale is difficult to internalize. The authors constructed a tool from an initial item pool with the help of experts and validated it in a sample of 326 young people in the state of Kerala, India. Factor analysis gave 4 underlying factors for the construct of PMH. The scale (mean = 67.41 +/- 9.49) has Cronbach's alpha value of .76 and test-retest correlation of .84. Convergent validity with the PMH Inventory is .864; discriminant validity with the Mental Health Inventory is .422. The findings prove that the scale, named the Achutha Menon Centre Positive Mental Health Scale, is reliable and valid and can be used in both individual- and population-based studies for measuring PMH. PMID- 22548778 TI - Beliefs about the use of nonprescribed antibiotics among people in Yogyakarta City, Indonesia: a qualitative study based on the theory of planned behavior. AB - Although antibiotics are prescription-only medicine in Indonesia, they can be purchased without prescription. This qualitative study elicited beliefs about nonprescribed antibiotics use informed by the theory of planned behavior to develop a questionnaire for an expanded theory of planned behavior survey. Twenty five (N = 25) adults with experience of using nonprescribed antibiotics were interviewed. Content analysis was applied. Participants reported that the use of nonprescribed antibiotics was advantageous in term of saving time and money and of reducing the number of medicines that need to be purchased, in contrast to a perception of what occurs with medical prescriptions. Potential adverse effects, poor health outcomes, and antimicrobial resistance were the perceived disadvantages. Facilitators of such use were the availability of over-the-counter antibiotics and successful experience in using antibiotics. Medication for children was the perceived barrier to such use. Family members and friends, especially those with health education background, approved of such use. PMID- 22548779 TI - Noise-induced hearing loss and associated factors among vector control workers in a Malaysian state. AB - This study aims to determine the prevalence and associated factors of noise induced hearing loss (NIHL) among vector control workers in the state of Negeri Sembilan, Malaysia. This was an analytical cross-sectional study conducted on 181 vector control workers who were working in district health offices in a state in Malaysia. Data were collected using a self-administered questionnaire and audiometry. Prevalence of NIHL was 26% among this group of workers. NIHL was significantly associated with the age-group of 40 years and older, length of service of 10 or more years, current occupational noise exposure, listening to loud music, history of firearms use, and history of mumps/measles infection. Following logistic regression, age of more than 40 years and noise exposure in current occupation were associated with NIHL with an odds ratio of 3.45 (95% confidence interval = 1.68-7.07) and 6.87 (95% confidence interval = 1.54-30.69), respectively, among this group of vector control workers. PMID- 22548780 TI - Levels of adiponectin, a marker for PPAR-gamma activity, correlate with skin fibrosis in systemic sclerosis: potential utility as biomarker? AB - INTRODUCTION: Progressive fibrosis in systemic sclerosis (SSc) is linked to aberrant transforming growth factor beta (TGF-beta) signaling. Peroxisome proliferator-activated receptor gamma (PPAR-gamma) blocks fibrogenic TGF-beta responses in vitro and in vivo. Reduced expression and function of PPAR-gamma in patients with SSc may contribute to progression of fibrosis. Here we evaluated the levels of adiponectin, a sensitive and specific index of PPAR-gamma activity, as a potential fibrogenic biomarker in SSc. METHODS: Adiponectin levels were determined in the sera of 129 patients with SSc and 86 healthy controls, and serial determinations were performed in 27 patients. Levels of adiponectin mRNA in skin biopsies from SSc patients were assessed in an expression profiling microarray dataset. Regulation of adiponectin gene expression in explanted human subcutaneous preadipocytes and fibroblasts was examined by real-time quantitative PCR. RESULTS: Patients with diffuse cutaneous SSc had reduced serum adiponectin levels. A significant inverse correlation between adiponectin levels and the modified Rodnan skin score was observed. In longitudinal studies changes in serum adiponectin levels were inversely correlated with changes in skin fibrosis. Skin biopsies from a subset of SSc patients showed reduced adiponectin mRNA expression which was inversely correlated with the skin score. An agonist ligand of PPAR gamma potently induced adiponectin expression in explanted mesenchymal cells in vitro. CONCLUSIONS: Levels of adiponectin, reflecting PPAR-gamma activity, are correlated with skin fibrosis and might have potential utility as a biomarker in SSc. PMID- 22548781 TI - Spinal segmental and supraspinal mechanisms underlying the pain-relieving effects of spinal cord stimulation: an experimental study in a rat model of neuropathy. AB - Spinal cord stimulation (SCS) may alleviate certain forms of neuropathic pain; its mechanisms of action are, however, not fully understood. Previous studies have mainly been focused onto segmental spinal mechanisms, though there is evidence indicating a supraspinal involvement. This study aims to evaluate the relative importance of segmental and supraspinal mechanisms related to the activation of the dorsal columns (DCs). Rats were used to induce the spared nerve injury neuropathy and simultaneously subjected to chronic bilateral DC lesions at the C6-C8 level. Two pairs of miniature electrodes were implanted in each animal, with a monopolar system placed in the dorsal epidural space at a low thoracic level (below lesion) and a bipolar system placed onto the dorsal column nuclei (above lesion). Stimulation (50 Hz, 0.2 ms, 2-4V, 5 min) was applied via either type of electrodes, and tests for sensitivity to tactile and thermal stimuli were used to assess its inhibitory effects. Various receptor antagonists {bicuculline (GABA(A)), saclofen (GABA(B)), ketanserine (5HT(2)), methysergide (5HT(1-2)), phentolamine (alpha-adrenergic), propranolol (beta-adrenergic), sulpiride (D(2)/D(3) dopamine) or saline were injected prior to the SCS. Rostral and caudal stimulations produced a comparable inhibition of neuropathic manifestations, and these effects were attenuated by about 50% after DC lesions. Pretreatment with the various receptor antagonists differentially influenced the effects of rostral and caudal stimulation. Our findings suggest that both supraspinal and segmental mechanisms are activated by SCS, and that in this model with DC lesions, rostral and caudal stimulations may activate different synaptic circuitries and transmitter systems. PMID- 22548782 TI - Phase de-synchronization effects auditory gating in the ventral striatum but not auditory cortex. AB - The underlying mechanisms and involved brain areas in sensory gating of repetitive auditory stimuli remain unclear. Especially, the influence of the auditory cortex and the role of temporal precision are under debate. Our first objective was to analyze gating dynamics of local field potentials in the primary auditory cortex and the ventral striatum in an animal experiment, particularly, assessing the influence of the cortex. The second aim was to follow the hypothesis that auditory gating results from phase de-synchronization of evoked potentials in response to the second auditory stimulus. Local field potentials were recorded simultaneously in the auditory cortex and ventral striatum of awake Mongolian gerbils (n=15) during stimulation with trains of frequency-modulated tones. Gating was analyzed by amplitude ratios of the auditory potentials evoked by the first two stimuli in a train, as well as by time-frequency analyses and between-area phase coupling. The strength of auditory gating in the striatum was found to exceed that in the primary auditory cortex by more than 50%. While total signal-power was comparable between areas, energy in the striatum was primarily expressed in the non-phase-locked fraction. At the same time, energy in the auditory cortex remained phase-locked to the stimuli. Furthermore, we also observed a between-area phase unlocking during sound presentations. Phase de synchronization appears to be the candidate mechanism behind attenuation of responses to identical repetitive stimuli in the ventral striatum. We conclude that a direct inhibitory response suppression by the auditory cortex plays a minor role in this process. PMID- 22548783 TI - Histamine is required during neural stem cell proliferation to increase neuron differentiation. AB - Histamine in the adult central nervous system (CNS) acts as a neurotransmitter. This amine is one of the first neurotransmitters to appear during development reaching its maximum concentration simultaneously with neuron differentiation peak. This suggests that HA plays an important role in neurogenesis. We have previously shown that HA is able to increase neuronal differentiation of neural stem cells (NSCs) in vitro, by activating the histamine type 1 receptor. However the mechanism(s) by which HA has a neurogenic effect on NSCs has not been explored. Here we explore how HA is able to increase neuron phenotype. Cortex neuroepithelium progenitors were cultured and at passage two treatments with 100 MUM HA were given during cell proliferation and differentiation or only during differentiation. Immunocytochemistry was performed on differentiated cultures to detect mature neurons. To explore the expression of certain important transcriptional factors involved on asymmetric cell division and commitment, RT PCR and qRT-PCR were performed. Results indicate that HA is required during cell proliferation in order to increase neuron differentiation and suggest that this amine increases neuron commitment during the proliferative phase probably by rising prospero1 and neurogenin1 expression. PMID- 22548784 TI - Do calcineurin B-like proteins interact independently of the serine threonine kinase CIPK23 with the K+ channel AKT1? Lessons learned from a menage a trois. PMID- 22548785 TI - Identification of a Skp1-like protein interacting with SFB, the pollen S determinant of the gametophytic self-incompatibility in Prunus. AB - Many species in Rosaceae, Solanaceae, and Plantaginaceae exhibit S-RNase-based self-incompatibility (SI). In this system, the pistil and pollen specificities are determined by S-RNase and the S locus F-box protein, respectively. The pollen S determinant F-box protein in Prunus (Rosaceae) is referred to by two different terms, SFB (for S-haplotype-specific F-box protein) and SLF (for S locus F box), whereas it is called SLF in Solanaceae and Plantaginaceae. Prunus SFB is thought to be a molecule indispensable for its cognate S-RNase to exert cytotoxicity and to arrest pollen tube growth in incompatible reactions. Although recent studies have demonstrated the molecular function of SCF(SLF) in the SI reaction of Solanaceae and Plantaginaceae, how SFB participates in the Prunus SI mechanism remains to be elucidated. Here we report the identification of sweet cherry (Prunus avium) SFB (PavSFB)-interacting Skp1-like1 (PavSSK1) using a yeast (Saccharomyces cerevisiae) two-hybrid screening against the pollen cDNA library. Phylogenetic analysis showed that PavSSK1 belongs to the same clade as Antirrhinum hispanicum SLF-interacting Skp1-like1 and Petunia hybrida SLF interacting Skp1-like1 (PhSSK1). In yeast, PavSSK1 interacted not only with PavSFBs from different S haplotypes and Cullin1-likes (PavCul1s), but also with S locus F-box-likes. A pull-down assay confirmed the interactions between PavSSK1 and PavSFB and between PavSSK1 and PavCul1s. These results collectively indicate that PavSSK1 could be a functional component of the SCF complex and that PavSFB may function as a component of the SCF complex. We discuss the molecular function of PavSFB in self-/nonself-recognition in the gametophytic SI of Prunus. PMID- 22548786 TI - FluxMap: a VANTED add-on for the visual exploration of flux distributions in biological networks. AB - BACKGROUND: The quantification of metabolic fluxes is gaining increasing importance in the analysis of the metabolic behavior of biological systems such as organisms, tissues or cells. Various methodologies (wetlab or drylab) result in sets of fluxes which require an appropriate visualization for interpretation by scientists. The visualization of flux distributions is a necessary prerequisite for intuitive flux data exploration in the context of metabolic networks. RESULTS: We present FluxMap, a tool for the advanced visualization and exploration of flux data in the context of metabolic networks. The template-based flux data import assigns flux values and optional quality parameters (e. g. the confidence interval) to biochemical reactions. It supports the discrimination between mass and substance fluxes, such as C- or N-fluxes. After import, flux data mapping and network-based visualization allow the interactive exploration of the dataset. Various visualization options enable the user to adapt layout and network representation according to individual purposes. CONCLUSIONS: The Vanted add-on FluxMap comprises a comprehensive set of functionalities for visualization and advanced visual exploration of flux distributions in biological networks. It is available as a Java open source tool from http://www.vanted.org/fluxmap. PMID- 22548787 TI - Effects of a water-soluble curcumin protein conjugate vs. pure curcumin in a diabetic model of erectile dysfunction. AB - INTRODUCTION: Curcumin is involved in erectile signaling via elevation of cyclic guanosine monophosphate (cGMP). AIM: Assessment of the effects of water-soluble curcumin in erectile dysfunction (ED). METHODS: One hundred twenty male white albino rats were divided into: 1st and 2nd control groups with or without administration of Zinc protoporphyrin (ZnPP), 3rd and 4th diabetic groups with or without ZnPP, 5th diabetic group on single oral dose of pure curcumin, 6th diabetic group on pure curcumin administered daily for 12 weeks, 7th and 8th diabetic groups on single dose of water-soluble curcumin administered with or without ZnPP, 9th and 10th diabetic groups on water-soluble curcumin administered daily for 12 weeks with or without ZnPP. All curcumin dosage schedules were administered after induction of diabetes. MAIN OUTCOME MEASURES: Quantitative gene expression of endothelial nitric oxide synthase (eNOS), neuronal NOS (nNOS), inducible NOS (iNOS), heme oxygenase-1 (HO-1), nuclear transcription factor erythroid2 (Nrf2), NF-Kbeta, and p38. Cavernous tissue levels of HO and NOS enzyme activities, cGMP and intracavernosal pressure (ICP). RESULTS: Twelve weeks after induction of diabetes, ED was confirmed by the significant decrease in ICP. There was a significant decrease in cGMP, NOS, HO enzymes, a significant decrease in eNOS, nNOS, HO-1 genes and a significant elevation of NF-Kbeta, p38, iNOS genes. Administration of pure curcumin or its water-soluble conjugate led to a significant elevation in ICP, cGMP levels, a significant increase in HO-1 and NOS enzymes, a significant increase in eNOS, nNOS, HO-1, and Nrf2 genes, and a significant decrease in NF-Kbeta, p38, and iNOS genes. Water-soluble curcumin showed significant superiority and more prolonged duration of action. Repeated doses regimens were superior to single dose regimen. Administration of ZnPP significantly reduced HO enzyme, cGMP, ICP/ mean arterial pressure (MAP), HO-1 genes in diabetic groups. CONCLUSION: Water-soluble curcumin could enhance erectile function with more effectiveness and with more prolonged duration of action. PMID- 22548789 TI - Immunomodulatory effects of dietary beta-1,3-glucan from Euglena gracilis in rainbow trout (Oncorhynchus mykiss) immersion vaccinated against Yersinia ruckeri. AB - Potential immunostimulatory effects of orally administered beta-glucan were investigated in combination with immersion vaccination against enteric redmouth disease caused by Yersinia ruckeri in rainbow trout (Oncorhynchus mykiss). A linear, unbranched and pure (purity >=98%) beta-1,3-glucan (syn. paramylon) from the alga Euglena gracilis was applied at an inclusion level of 1% beta-glucan in feed administered at a rate of 1% biomass day(-1) for 84 consecutive days. Fish were vaccinated after two weeks of experimental feeding and bath challenged with live Y. ruckeri six weeks post-vaccination. Blood and head kidney were sampled at day 0, 13 (1 day pre-vaccination), 15, 55, 59 (day 3 post-challenge (p.c.)), 70 and 84. Vaccination induced significantly increased survival p.c., whereas the beta-glucan had no effect on survival in either unvaccinated or vaccinated fish. Expression in head kidney of genes related to the acute phase response, i.e. interleukin-1beta (IL-1beta), serum amyloid A (SAA), precerebellin, and hepcidin, was significantly different in vaccinated fish receiving beta-glucan compared to vaccinated controls at day 3 p.c., while no effect of beta-glucan was observed among unvaccinated fish. Significant interaction between beta-glucan and vaccination was found for the regulation of IL-1beta, tumour necrosis factor alpha, interferon-gamma, SAA, precerebellin and hepcidin p.c. For SAA, the significant effect of beta-glucan in vaccinated fish persisted at day 14 p.c. and 28 p.c. The difference in gene expression among vaccinated fish was mainly observed as down-regulations in vaccinated, beta-glucan fed fish compared to up regulations or no regulation in vaccinated controls. Slightly increased levels of plasma lysozyme activity were found in fish (both unvaccinated and vaccinated) receiving beta-glucan at day 3 p.c. compared to control fed groups. This was associated with a faster clearance of Y. ruckeri in unvaccinated fish receiving beta-glucan. In contrast to the trend towards a beneficial effect of beta-glucan on plasma lysozyme activity, a trend towards suppression of plasma antibodies was seen in both unvaccinated and vaccinated fish receiving beta-glucan. However, the effects of beta-glucan were not reflected in the survival curves, and the differences seen in plasma lysozyme activity and antibody levels may have counteracted and set off each other as well as counteracted any potential effect represented by the differences in gene expression found. PMID- 22548788 TI - No increased mortality from donor or recipient hepatitis B- and/or hepatitis C positive serostatus after related-donor allogeneic hematopoietic cell transplantation. AB - Limited data exist on allogeneic transplant outcomes in recipients receiving hematopoietic cells from donors with prior or current hepatitis B (HBV) or C virus (HCV) infection (seropositive donors), or for recipients with prior or current HBV or HCV infection (seropositive recipients). Transplant outcomes are reported for 416 recipients from 121 centers, who received a human leukocyte antigen-identical related-donor allogeneic transplant for hematologic malignancies between 1995 and 2003. Of these, 33 seronegative recipients received grafts from seropositive donors and 128 recipients were seropositive. The remaining 256 patients served as controls. With comparable median follow-up (cases, 5.9 years; controls, 6.7 years), the incidence of treatment-related mortality, survival, graft-versus-host disease, and hepatic toxicity, appears similar in all cohorts. The frequencies of hepatic toxicities as well as causes of death between cases and controls were similar. Prior exposure to HBV or HCV in either the donor or the recipient should not be considered an absolute contraindication to transplant. PMID- 22548790 TI - Changes of Treg and Th17 cells balance in the development of acute and chronic hepatitis B virus infection. AB - BACKGROUND: Many studies suggest that in chronic hepatitis B virus (HBV) infection regulate T (Treg) cells and interlukin-17-producing T help cells (Th17) are mutually antagonistic in the immune response. This study is aimed to reveal the cell differentiation environment and the significance of Treg and Th17 balance in the development of acute and chronic HBV infection. METHODS: Ten patients with acute HBV infection (AHB) and forty-eight patients with chronic HBV infection, including 12 asymptomatic HBV carriers (HBV carriers), 18 chronic hepatitis B patients (CHB) and 18 acute-on-chronic HBV-related liver failure (ACHBLF) were enrolled. Treg and Th17 cells differentiation related cytokine levels were detected by using ELISA. Flow cytometry was employed to count the Treg and Th17 frequency in peripheral blood. RESULTS: Compared to health controls both AHB and ACHBLF patients favoured Th17 cell differentiation, accompanied by a higher proportion of peripheral Th17 cells (P < 0.01) and high level of interleukin-17A (IL-17A) (P < 0.01). However, asymptomatic HBV carriers and CHB were conducive to Treg cell differentiation. In AHB and ACHBLF, peripheral blood IL-17A + CD4 + T cell frequency increased significantly compared with healthy controls. Changes of Treg and Th17 cell frequency were not completely consistent. Both CHB and ACHBLF had lower level of Treg/Th17 ratio than in health control (P < 0.05). Both plasm IL-17A levels (r = -0.72, p<0.001) and Th17 frequency(r = 0.49, p = 0.0003) negatively correlated with plasma HBV DNA load in patients with chronic HBV infection. In addition, both Th17 frequency and plasm IL-17A levels positively correlated with ALT (r = 0.33,p = 0.01 Vs r = 0.29, p = 0.04) and total bilirubin levels (r = 0.72,p<0.0001 Vs r = 0.53, p = 0.0001) in these chronic HBV-infected subjects. However, for AHB there were positive correlation between both Th17 frequency (r = 0.64, p = 0.04) and plasm IL-17A levels (r = 0.69, p = 0.02) with serum ALT levels, but no significant correlation between both HBV DNA level and total bilirubin level with Th17 frequency or plasm IL-17A levels were found. Furthermore, Treg/Th17 ratio was negatively correlated with total bilirubin levels (r = -0.41, p = 0.004) in chronic HBV-infected patients, especially in patients with ACHBLF (r = -0.69, p = 0.001) and positively correlated with viral load in these chronic HBV-infected subjects (r = 0.55, p<0.0001). CONCLUSIONS: Th17 cells are involved in acute and chronic HBV infection, especially in AHB and ACHBLF. CHB and ACHBLF patients manifested obvious Treg/Th17 ratio imbalance, which might be linked to disease progression and the continuous HBV infection. PMID- 22548791 TI - The syndrome of inappropriate antidiuretic hormone secretion (SIADH) associated with metastatic malignant melanoma. PMID- 22548792 TI - Plant traits affecting herbivory on tree recruits in highly diverse subtropical forests. AB - Differences in herbivory among woody species can greatly affect the functioning of forest ecosystems, particularly in species-rich (sub)tropical regions. However, the relative importance of the different plant traits which determine herbivore damage remains unclear. Defence traits can have strong effects on herbivory, but rarely studied geographical range characteristics could complement these effects through evolutionary associations with herbivores. Herein, we use a large number of morphological, chemical, phylogenetic and biogeographical characteristics to analyse interspecific differences in herbivory on tree saplings in subtropical China. Unexpectedly, we found no significant effects of chemical defence traits. Rather, herbivory was related to the plants' leaf morphology, local abundance and climatic niche characteristics, which together explained 70% of the interspecific variation in herbivory in phylogenetic regression. Our study indicates that besides defence traits and apparency to herbivores, previously neglected measures of large-scale geographical host distribution are important factors influencing local herbivory patterns among plant species. PMID- 22548793 TI - A national survey of independent living donor advocates: the need for practice guidelines. AB - In 2000, representatives of the transplant community convened for a meeting on living donation in an effort to provide recommendations to promote the welfare of living donors. One key recommendation included in the consensus statement was that all transplant centers which have performed living donor surgeries have an independent living donor advocate (ILDA) "whose only focus is on the best interest of the donor." The aims of this study were to begin to understand the sociodemographic characteristics, selection and training, and clinical practices of ILDAs. All US transplant centers performing living donor surgeries were contacted to identify the ILDA at their center. One hundred and twenty ILDAs completed an anonymous survey. Results indicated considerable variability with regard to the sociodemographic characteristics of ILDAs, how the ILDA was selected and trained, and the ILDAs' clinical practices, particularly ethical challenges encountered by ILDAs. The variability observed may result in differential selection of donors and could have a potential negative impact on the lives of both donors and transplant candidates. The variability in the background, training, and practice of ILDAs suggests the need for strategies, such as practice guidelines, to standardize the interaction between ILDAs and living donors. PMID- 22548794 TI - Stephen M. Levin: 1941-2012. PMID- 22548795 TI - Collagen fibril stiffening in osteoarthritic cartilage of human beings revealed by atomic force microscopy. AB - OBJECTIVE: This study aimed to characterize the in-situ mechanical property and morphology of individual collagen fibril in osteoarthritic cartilage using indentation-type atomic force microscopy (IT-AFM). METHODS: The specimens with intact articular cartilage (AC), mild to severe degenerated cartilage from osteoarthritis (OA) were collected with informed consent from the postmenopausal women who underwent hip or knee arthroplasty. The fresh specimens were cryo sectioned by layers with 50MUm thick for each from the articular surface to calcified cartilage, and then processed for AFM imaging and nanoindentation test. For each layer, a total of 20 collagen fibrils were randomly selected for testing. AFM tips with the nominal radius less than 10nm were employed for probing the individual collagen fibril, and the obtained cantilever deflection signal and displacement were recorded for calculating its elastic modulus. RESULTS: An intact AC exhibited a gradation in elastic modulus of collagen fibrils from articular surface (2.65 +/- 0.31 GPa) to the cartilage-bone interface (3.70 +/- 0.44 GPa). It was noted in mildly degenerated OA cartilage that the coefficient of variation for mechanical properties of collagen fibers, ranging from 25% to 48%, significantly increased as compared with intact one (12%). The stiffened collagen fibrils occurred at either articular surface (3.11 +/- 0.91 GPa) or the cartilage-bone interface (5.64 +/- 1.10 GPa), accompanied by loosely organized meshwork with advancement of OA cartilage degeneration. It was echoed by histological findings of OA cartilage, including fibrotic changes of surface region and tidemark irregularities. CONCLUSION: The stiffened collagen fibrils in AC occurred with OA onset and progression, not only at articular surface but also the cartilage-bone interface. PMID- 22548796 TI - Evaluation of native hyaline cartilage and repair tissue after two cartilage repair surgery techniques with 23Na MR imaging at 7 T: initial experience. AB - OBJECTIVE: To compare the sodium normalized mean signal intensity (NMSI) values between patients after bone marrow stimulation (BMS) and matrix-associated autologous chondrocyte transplantation (MACT) cartilage repair procedures. METHODS: Nine BMS and nine MACT patients were included. Each BMS patient was matched with one MACT patient according to age [BMS 36.7 +/- 10.7 (mean +/- standard deviation) years; MACT 36.9 +/- 10.0 years], postoperative interval (BMS 33.5 +/- 25.3 months; MACT 33.2 +/- 25.7 months), and defect location. All magnetic resonance imaging (MRI) measurements were performed on a 7 T system. Proton images served for morphological evaluation of repair tissue using the magnetic resonance observation of cartilage repair tissue (MOCART) scoring system. Sodium NMSI values in the repair area and morphologically normal cartilage were calculated. Clinical outcome was assessed right after MRI. Analysis of covariance, t-tests, and Pearson correlation coefficients were evaluated. RESULTS: Sodium NMSI was significantly lower in BMS (P = 0.004) and MACT (P = 0.006) repair tissue, compared to reference cartilage. Sodium NMSI was not different between the reference cartilage in MACT and BMS patients (P = 0.664), however it was significantly higher in MACT than in BMS repair tissue (P = 0.028). Better clinical outcome was observed in BMS than in MACT patients. There was no difference between MOCART scores for MACT and BMS patients (P = 0.915). We did not observe any significant correlation between MOCART score and sodium repair tissue NMSI (r = -0.001; P = 0.996). CONCLUSIONS: Our results suggest higher glycosaminoglycan (GAG) content, and therefore, repair tissue of better quality in MACT than in BMS patients. Sodium imaging might be beneficial in non-invasive evaluation of cartilage repair surgery efficacy. PMID- 22548797 TI - Dynamic compression improves biosynthesis of human zonal chondrocytes from osteoarthritis patients. AB - OBJECTIVE: We hypothesize that chondrocytes from distinct zones of articular cartilage respond differently to compressive loading, and that zonal chondrocytes from osteoarthritis (OA) patients can benefit from optimized compressive stimulation. Therefore, we aimed to determine the transcriptional response of superficial (S) and middle/deep (MD) zone chondrocytes to varying dynamic compressive strain and loading duration. To confirm effects of compressive stimulation on overall matrix production, we subjected zonal chondrocytes to compression for 2 weeks. DESIGN: Human S and MD chondrocytes from osteoarthritic joints were encapsulated in 2% alginate, pre-cultured, and subjected to compression with varying dynamic strain (5, 15, 50% at 1 Hz) and loading duration (1, 3, 12 h). Temporal changes in cartilage-specific, zonal, and dedifferentiation genes following compression were evaluated using quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR). The benefits of long-term compression (50% strain, 3 h/day, for 2 weeks) were assessed by measuring construct glycosaminoglycan (GAG) content and compressive moduli, as well as immunostaining. RESULTS: Compressive stimulation significantly induced aggrecan (ACAN), COL2A1, COL1A1, proteoglycan 4 (PRG4), and COL10A1 gene expression after 2 h of unloading, in a zone-dependent manner (P < 0.05). ACAN and PRG4 mRNA levels depended on strain and load duration, with 50% and 3 h loading resulting in highest levels (P < 0.05). Long-term compression increased collagen type II and ACAN immunostaining and total GAG (P < 0.05), but only S constructs showed more PRG4 stain, retained more GAG (P < 0.01), and developed higher compressive moduli than non-loaded controls. CONCLUSIONS: The biosynthetic activity of zonal chondrocytes from osteoarthritis joints can be enhanced with selected compression regimes, indicating the potential for cartilage tissue engineering applications. PMID- 22548799 TI - Asking the right questions: the relationship between incident ventilator associated pneumonia and mortality. AB - Whether ventilator-associated pneumonia is a manifestation of severity of illness or an independent cause of mortality in ventilator-dependent patients is not known. In this complex area, which cannot be readily subjected to randomized controlled trials, studies should focus on the underlying questions of relevance, how to improve care of ventilated patients. PMID- 22548800 TI - Retracted: Apoptosis of CT26 colorectal cancer cells induced by Clostridium difficile toxin A stimulates potent anti-tumor immunity. AB - Clostridium difficile toxin A (TcdA) is one of the main pathogenic factors released by C. difficile. Due to its potent cytotoxic and proinflammatory activities, we investigated the anti-tumor activity of TcdA. CT26 colorectal cancer cells were challenged with recombinant TcdA, and it was found that TcdA could induce apoptosis of CT26 cells. Calreticulin (CRT) exposure to the cell surface during TcdA-induced apoptosis suggested that this apoptosis may correlate with immunogenicity. Moreover, TcdA-treated apoptotic CT26 cells were highly immunogenic since they could stimulate DC activation, T-cell activation, and anti tumor activity. Furthermore, the anti-tumor immune response generated was specific and long-term. In summary, these studies demonstrate that C. difficile toxin A can induce apoptotic death of CT26 colorectal cancer cells and stimulate potent anti-tumor immunity. PMID- 22548798 TI - Molecular target based combinational therapeutic approaches in thyroid cancer. AB - BACKGROUND: Thyroid cancer, as with other types of cancer, is dependent on angiogenesis for its continued growth and development. Interestingly, estrogen has been shown to contribute to thyroid cancer aggressiveness in vitro, which is in full support of the observed increased incidence of thyroid cancer in women over men. Provided that estrogen has been observed to contribute to increased angiogenesis of estrogen responsive breast cancer, it is conceivable to speculate that estrogen also contributes to angiogenesis of estrogen responsive thyroid cancer. METHODS: In this study, three human thyroid cancer cells (B-CPAP, CGTH-W 1, ML-1) were treated with estrogen alone or estrogen and anti-estrogens (fulvestrant and 3,3'-diindolylmethane, a natural dietary compound) for 24 hours. The cell culture media was then added to human umbilical vein endothelial cell (HUVECs) and assayed for angiogenesis associated events. Vascular endothelial growth factor (VEGF) levels were also quantified in the conditioned media so as to evaluate if it is a key player involved in these observations. RESULTS: Conditioned medium from estrogen treated thyroid cancer cells enhanced phenotypical changes (proliferation, migration and tubulogenesis) of endothelial cells typically observed during angiogenesis. These phenotypic changes observed in HUVECs were determined to be modulated by estrogen induced secretion of VEGF by the cancer cells. Lastly, we show that VEGF secretion was inhibited by the anti-estrogens, fulvestrant and 3,3'-diindolylmethane, which resulted in diminished angiogenesis associated events in HUVECs. CONCLUSION: Our data establishes estrogen as being a key regulator of VEGF secretion/expression in thyroid cells which enhances the process of angiogenesis in thyroid cancer. These findings also suggest the clinical utility of anti-estrogens as anti-angiogenic compounds to be used as a therapeutic means to treat thyroid cancer. We also observed that 3,3'-diindolylmethane is a promising naturally occurring anti estrogen which can be used as a part of therapeutic regimen to treat thyroid cancer. PMID- 22548801 TI - Phenylbutyric acid induces the cellular senescence through an Akt/p21(WAF1) signaling pathway. AB - It has been well known that three sentinel proteins - PERK, ATF6 and IRE1 - initiate the unfolded protein response (UPR) in the presence of misfolded or unfolded proteins in the ER. Recent studies have demonstrated that upregulation of UPR in cancer cells is required to survive and proliferate. Here, we showed that long exposure to 4-phenylbutyric acid (PBA), a chemical chaperone that can reduce retention of unfolded and misfolded proteins in ER, induced cellular senescence in cancer cells such as MCF7 and HT1080. In addition, we found that treatment with PBA activates Akt, which results in p21(WAF1) induction. Interestingly, the depletion of PERK but not ATF6 and IRE1 also induces cellular senescence, which was rescued by additional depletion of Akt. This suggests that Akt pathway is downstream of PERK in PBA induced cellular senescence. Taken together, these results show that PBA induces cellular senescence via activation of the Akt/p21(WAF1) pathway by PERK inhibition. PMID- 22548802 TI - Detection of Transglutaminase 2 conformational changes in living cell. AB - Transglutaminase 2 (TG2) is a ubiquitous Ca(2+)-dependent protein cross-linking enzyme that is implicated in a variety of biological disorders. In in vitro experiments when Ca(2+) concentration was increased TG2 changed its conformation and was able to cross-link other proteins via formation of an isopeptide bond. However the mechanisms that regulate TG2 transamidation activity in cells are still unknown. In this study we have developed FRET-based method for monitoring TG2 conformation changes and, probably, cross-linking activity in living cells. Using this approach we have showed that a significant amount of TG2 within the cell is accumulated in perinuclear endosomes and has a cross-linking inactive conformation, while TG2 that is located beneath the cell membrane has a transamidation active conformation. After the induction of apoptosis cytoplasmic TG2 changed its conformation and activates while, TG2 in endosomes retained transamidation inactive conformation even at late stages of apoptosis. PMID- 22548804 TI - Toxoplasmosis in cord blood transplantation recipients. AB - Toxoplasmosis is a devastating opportunistic infection that can affect immunocompromised patients such as cord blood transplantation (CBT) recipients. The clinical characteristics of 4 toxoplasmosis CBT patients treated at our institution are reviewed, together with 5 cases collected from the literature. The rate of toxoplasmosis in our hospital was 6% in CBT recipients and 0.2% in other types of allogeneic hematopoietic stem cell transplantation (P < 0.001). Five patients (56%) presented disseminated toxoplasmosis and 4 patients (44%) had localized infection in the central nervous system. In 5 of the 9 patients considered (56%), cytomegalovirus viral replication had been detected before the clinical onset of toxoplasmosis. Seven patients (78%) had previously developed graft-versus-host disease. All patients who exhibited disseminated disease died due to Toxoplasma infection. Pre-transplant serology was positive in 1 patient, negative in 3 patients, and not performed in another. Only 1 of these 5 patients with disseminated disease had received Toxoplasma prophylaxis with cotrimoxazole. It could be concluded that mortality in CBT patients with disseminated toxoplasmosis is unacceptably high. The negative results of serology in the majority of these cases, and its unspecific clinical presentation, makes diagnosis exceedingly difficult. Better diagnostic tests and prophylaxis strategy are needed in CBT recipients. PMID- 22548803 TI - Revisiting the variation of clustering coefficient of biological networks suggests new modular structure. AB - BACKGROUND: A central idea in biology is the hierarchical organization of cellular processes. A commonly used method to identify the hierarchical modular organization of network relies on detecting a global signature known as variation of clustering coefficient (so-called modularity scaling). Although several studies have suggested other possible origins of this signature, it is still widely used nowadays to identify hierarchical modularity, especially in the analysis of biological networks. Therefore, a further and systematical investigation of this signature for different types of biological networks is necessary. RESULTS: We analyzed a variety of biological networks and found that the commonly used signature of hierarchical modularity is actually the reflection of spoke-like topology, suggesting a different view of network architecture. We proved that the existence of super-hubs is the origin that the clustering coefficient of a node follows a particular scaling law with degree k in metabolic networks. To study the modularity of biological networks, we systematically investigated the relationship between repulsion of hubs and variation of clustering coefficient. We provided direct evidences for repulsion between hubs being the underlying origin of the variation of clustering coefficient, and found that for biological networks having no anti-correlation between hubs, such as gene co-expression network, the clustering coefficient doesn't show dependence of degree. CONCLUSIONS: Here we have shown that the variation of clustering coefficient is neither sufficient nor exclusive for a network to be hierarchical. Our results suggest the existence of spoke-like modules as opposed to "deterministic model" of hierarchical modularity, and suggest the need to reconsider the organizational principle of biological hierarchy. PMID- 22548805 TI - "The archeologist's career ended in ruins": hemispheric differences in pun comprehension in autism. AB - Appropriate interpretation of figurative language involves inferring the speaker's intent by integrating word meaning with context. In disorders like autism, understanding intended and contextual meanings in language may pose a challenge. Such difficulties are prevalent even when individuals exhibit otherwise fluent language ability (Szatmari et al., 1990). A pun is a rhetorical technique in which a speaker deliberately invokes multiple meanings through a word or phrase likely resulting in a joke. Comprehending puns may involve identifying multiple meanings of a word, embedding it in right contexts, and understanding the underlying humor. This fMRI study investigated the brain responses associated with figures of speech like puns. In the fMRI scanner, participants read sentences containing puns (e.g. To write with a broken pencil is pointless) and control sentences (literal meaning) presented in a blocked design format. The participants' task was to silently read and understand one meaning (in the literal condition) or two meanings (in the pun condition). Participants with autism, relative to typical controls, showed an increase in overall activation while comprehending sentences containing puns, particularly within the right hemisphere as well as in relatively posterior brain areas. Overall, there was reduced response in left hemisphere areas, reduced response to humor, and more distributed recruitment of regions in autism relative to control participants. We also examined the relationship between symptom severity in autism and verbal ability with brain responses to pun comprehension finding negative and positive correlations respectively. Overall, the results from the present study suggest that individuals with autism resort to altered neural routes in comprehending language in general, and figurative language in particular. PMID- 22548806 TI - Coupling and robustness of intra-cortical vascular territories. AB - Vascular domains have been described as being coupled to neuronal functional units enabling dynamic blood supply to the cerebral cyto-architecture. Recent experiments have shown that penetrating arterioles of the grey matter are the building blocks for such units. Nevertheless, vascular territories are still poorly known, as the collection and analysis of large three-dimensional micro vascular networks are difficult. By using an exhaustive reconstruction of the micro-vascular network in an 18 mm(3) volume of marmoset cerebral cortex, we numerically computed the blood flow in each blood vessel. We thus defined arterial and venular territories and examined their overlap. A large part of the intracortical vascular network was found to be supplied by several arteries and drained by several venules. We quantified this multiple potential to compensate for deficiencies by introducing a new robustness parameter. Robustness proved to be positively correlated with cortical depth and a systematic investigation of coupling maps indicated local patterns of overlap between neighbouring arteries and neighbouring venules. However, arterio-venular coupling did not have a spatial pattern of overlap but showed locally preferential functional coupling, especially of one artery with two venules, supporting the notion of vascular units. We concluded that intra-cortical perfusion in the primate was characterised by both very narrow functional beds and a large capacity for compensatory redistribution, far beyond the nearest neighbour collaterals. PMID- 22548807 TI - Equality versus self-interest in the brain: differential roles of anterior insula and medial prefrontal cortex. AB - Everything else being the same, an equal outcome is generally preferred; however, an equitable allocation sometimes is possible only by sacrificing the total amount of resources available to society. Moreover, direct interests may interact with the perception of equality. Here, we have investigated individual preferences, and their neural basis, by employing a task in which an allocation of a fixed amount between the subject and another person (MS condition) or two third parties (TP condition) is randomly determined. The subject can accept or reject the outcome, in the same fashion as the Ultimatum Game: thus an unequal offer may be rejected at the cost of a loss in total amount. Behavioral results show preference for equal outcomes in TP and for equal and advantageous outcomes in MS. An activation of medial prefrontal cortex (mPFC), extending to the anterior middle cingulate cortex (aMCC), was found in MS unequal outcomes, particularly for disadvantageous outcomes and consequent rejections. The anterior insula (AI) was active for unequal outcomes, in both MS and TP. We propose that the equal treatment is a default social norm, and its violation is signaled by the AI, whereas aMCC/mPFC activation, negatively correlated to rejections, reflects the effort to overcome the default rule of equal treatment in favor of a self-advantageous efficiency. PMID- 22548810 TI - Anatomy and physiology of the right ventricle. AB - Under normal baseline conditions the unique anatomy, myocardial ultrastructure, and coronary physiology of the right ventricle (RV) reflect a high-volume low pressure pump. Early work described the RV as a passive conduit with minimal pumping capability. It is now appreciated that through a mechanism of ventricular interdependence, RV systolic function and diastolic load are extremely important in the prognosis and treatment of congestive heart failure, cardiac transplantation, pulmonary hypertension, congenital heart disease, and left ventricle assist devices. Magnetic resonance imaging with three-dimensional analysis has shown the complex geometry of the RV and the interaction of both ventricles within the pericardium. PMID- 22548809 TI - Go and no-go learning in reward and punishment: interactions between affect and effect. AB - Decision-making invokes two fundamental axes of control: affect or valence, spanning reward and punishment, and effect or action, spanning invigoration and inhibition. We studied the acquisition of instrumental responding in healthy human volunteers in a task in which we orthogonalized action requirements and outcome valence. Subjects were much more successful in learning active choices in rewarded conditions, and passive choices in punished conditions. Using computational reinforcement-learning models, we teased apart contributions from putatively instrumental and Pavlovian components in the generation of the observed asymmetry during learning. Moreover, using model-based fMRI, we showed that BOLD signals in striatum and substantia nigra/ventral tegmental area (SN/VTA) correlated with instrumentally learnt action values, but with opposite signs for go and no-go choices. Finally, we showed that successful instrumental learning depends on engagement of bilateral inferior frontal gyrus. Our behavioral and computational data showed that instrumental learning is contingent on overcoming inherent and plastic Pavlovian biases, while our neuronal data showed this learning is linked to unique patterns of brain activity in regions implicated in action and inhibition respectively. PMID- 22548808 TI - Examining ERP correlates of recognition memory: evidence of accurate source recognition without recollection. AB - Recollection is typically associated with high recognition confidence and accurate source memory. However, subjects sometimes make accurate source memory judgments even for items that are not confidently recognized, and it is not known whether these responses are based on recollection or some other memory process. In the current study, we measured event related potentials (ERPs) while subjects made item and source memory confidence judgments in order to determine whether recollection supported accurate source recognition responses for items that were not confidently recognized. In line with previous studies, we found that recognition memory was associated with two ERP effects: an early on-setting FN400 effect, and a later parietal old-new effect [late positive component (LPC)], which have been associated with familiarity and recollection, respectively. The FN400 increased gradually with item recognition confidence, whereas the LPC was only observed for highly confident recognition responses. The LPC was also related to source accuracy, but only for items that had received a high confidence item recognition response; accurate source judgments to items that were less confidently recognized did not exhibit the typical ERP correlate of recollection or familiarity, but rather showed a late, broadly distributed negative ERP difference. The results indicate that accurate source judgments of episodic context can occur even when recollection fails. PMID- 22548811 TI - Imaging of the right ventricle. AB - For many years, the right ventricle (RV) was considered less relevant in cardiac disease than its left counterpart, partly because of limited ability to noninvasively evaluate the RV with accuracy. From an earlier period when chest x ray and invasive contrast ventriculography were the only available imaging modalities, the development of ultrasound and nuclear techniques represented important steps forward for noninvasive RV assessment. Advances in echocardiography, computed tomography, and magnetic resonance imaging provide new insights into the anatomy and function of the RV, and its importance in health and disease. In this article, we review the current state of RV imaging. PMID- 22548812 TI - Right ventricular performance in congenital heart disease: a physiologic and pathophysiologic perspective. AB - Underappreciated is the fact that the right ventricle is often the primary determinant of long-term morbidity and mortality in patients with congenital heart disease. Right ventricular performance in these patients depends on a unique set of physiologic and pathophysiologic factors that are rarely considered in acquired heart disease. This article explores this unique physiology and pathophysiology in the hope that it will enhance understanding of a wide variety of congenital cardiac anomalies. PMID- 22548813 TI - Acute right ventricular infarction. AB - This article reviews the pathophysiology, hemodynamics, natural history, and management of patients with inferior myocardial infarction complicated by right ventricular infarction. Five key areas are highlighted in which advances may impact catheterization and laboratory management of these acutely ill patients. PMID- 22548814 TI - Right ventricular responses to massive and submassive pulmonary embolism. AB - It is critically important to quickly recognize and treat acute pulmonary embolism (PE). Submassive and massive PEs are associated with right ventricular (RV) dysfunction and may culminate in RV failure, cardiac arrest, and death. A rapid and coordinated diagnostic and management approach can maximize success and save lives. PMID- 22548816 TI - Right ventricular adaptation and maladaptation in chronic pulmonary arterial hypertension. AB - The right ventricle (RV) is not well suited to chronic pressure overload and often fails to adequately compensate. Mechanisms that allow the RV to respond to acute pressure overload often become maladaptive and contribute to its failure, including the effects of pulmonary hypertension on RV myocardial perfusion, the influence of interventricular dependence on RV function, and metabolic shifts in the RV myocardium from fatty acid to glycolysis. Medications to treat pulmonary hypertension have focused on pulmonary vasodilatation. Their effects on RV function may determine their effectiveness. How new medications affect right ventricular performance must be addressed. PMID- 22548817 TI - Right ventricular performance in chronic congestive heart failure. AB - Right ventricular physiology is characterized by its close relationship with the pulmonary circuit. The right ventricle can accommodate significant changes in preload, but is highly sensitive to increases in afterload. Progressive dilatation and dysfunction can initiate a cycle of oxygen supply-demand mismatch that ultimately leads to right ventricular failure. Echocardiography and cardiac magnetic resonance imaging are the primary modalities used for non-invasive assessment of right ventricular function. The management of right ventricular failure centers on the optimization of preload, afterload and contractility. Few targeted therapies exist, although novel agents have shown promise in early studies. PMID- 22548815 TI - Right ventricular dysfunction in chronic lung disease. AB - Right ventricular (RV) dysfunction arises in chronic lung disease when chronic hypoxemia and disruption of pulmonary vascular beds increase ventricular afterload. RV dysfunction is defined by hypertrophy with preserved myocardial contractility and cardiac output. RV hypertrophy seems to be a common complication of chronic and advanced lung disease. RV failure is rare, except during acute exacerbations of chronic lung disease or when multiple comorbidities are present. Treatment is targeted at correcting hypoxia and improving pulmonary gas exchange and mechanics. There are no data supporting the use of pulmonary hypertension-specific therapies for patients with RV dysfunction secondary to chronic lung disease. PMID- 22548818 TI - Right ventricular failure after cardiac surgery. AB - Right ventricular (RV) failure remains a major problem in cardiac surgery, particularly in the setting of heart transplantation and following institution of left ventricular support. Experimental studies have shown that RV function is derived from 2 sources: the free wall of the RV and the interventricular septum. Management of RV failure involves not only decreasing RV afterload, but also optimizing both contributions to RV function, which is best achieved by optimizing developed systemic pressure. Techniques for managing the pulmonary circulation and strategies for optimizing RV function in various clinical settings are presented. PMID- 22548819 TI - Right ventricular failure in patients with left ventricular assist devices. AB - Right ventricular (RV) failure that develops following LVAD placement is an important and challenging complication that occurs in approximately 15-25% of LVAD patients. Thus, a thorough evaluation that identifies pre-operative clinical predictors of RV failure is crucial to aid in the appropriate treatment and prognostication. Following LVAD implant, three major physiologic changes invariably occur that will influence RV function: an increase in RV preload, a decrease in RV afterload, and an alteration in RV contractility. Management strategies exist to minimize the likelihood and severity of RV failure post-LVAD. Further studies are needed that also focus on intermediate and late post-LVAD RV failure. PMID- 22548820 TI - Percutaneous mechanical support for the failing right heart. AB - Right ventricular (RV) failure is an increasingly common clinical problem that may require mechanical support. In contrast to severe left ventricular failure, RV failure is typically more reversible. Therefore, application of shorter-term percutaneous support devices is potentially attractive. Current innovations promise greater availability of such percutaneous RV support devices. This article considers the available mechanical approaches to provide hemodynamic support to treat profound RV failure in the common clinical scenarios in which percutaneous mechanical RV support may be most beneficial. PMID- 22548821 TI - The right ventricle. Foreword. PMID- 22548822 TI - Faces of right ventricular failure. PMID- 22548823 TI - The eroded genome of a Psychotria leaf symbiont: hypotheses about lifestyle and interactions with its plant host. AB - Several plant species of the genus Psychotria (Rubiaceae) harbour Burkholderia sp. bacteria within specialized leaf nodules. The bacteria are transmitted vertically between plant generations and have not yet been cultured outside of their host. This symbiosis is also generally described as obligatory because plants devoid of symbionts fail to develop into mature individuals. We sequenced for the first time the genome of the symbiont of Psychotria kirkii in order to shed some light on the nature of their symbiotic relationship. We found that the 4 Mb genome of Candidatus Burkholderia kirkii (B. kirkii) is small for a Burkholderia species and displays features consistent with ongoing genome erosion such as large proportions of pseudogenes and transposable elements. Reductive genome evolution affected a wide array of functional categories that may hinder the ability of the symbiont to be free-living. The genome does not encode functions commonly found in plant symbionts such as nitrogen fixation or plant hormone metabolism. Instead, a collection of genes for secondary metabolites' synthesis is located on the 140 kb plasmid of B. kirkii and suggests that leaf nodule symbiosis benefits the host by providing protection against herbivores or pathogens. PMID- 22548824 TI - Identification and characterization of a novel gene, c1orf109, encoding a CK2 substrate that is involved in cancer cell proliferation. AB - BACKGROUND: In the present study we identified a novel gene, Homo Sapiens Chromosome 1 ORF109 (c1orf109, GenBank ID: NM_017850.1), which encodes a substrate of CK2. We analyzed the regulation mode of the gene, the expression pattern and subcellular localization of the predicted protein in the cell, and its role involving in cell proliferation and cell cycle control. METHODS: Dual luciferase reporter assay, chromatin immunoprecipitation and EMSA were used to analysis the basal transcriptional requirements of the predicted promoter regions. C1ORF109 expression was assessed by western blot analysis. The subcellular localization of C1ORF109 was detected by immunofluorescence and immune colloidal gold technique. Cell proliferation was evaluated using MTT assay and colony-forming assay. RESULTS: We found that two cis-acting elements within the crucial region of the c1orf109 promoter, one TATA box and one CAAT box, are required for maximal transcription of the c1orf109 gene. The 5' flanking region of the c1orf109 gene could bind specific transcription factors and Sp1 may be one of them. Employing western blot analysis, we detected upregulated expression of c1orf109 in multiple cancer cell lines. The protein C1ORF109 was mainly located in the nucleus and cytoplasm. Moreover, we also found that C1ORF109 was a phosphoprotein in vivo and could be phosphorylated by the protein kinase CK2 in vitro. Exogenous expression of C1ORF109 in breast cancer Hs578T cells induced an increase in colony number and cell proliferation. A concomitant rise in levels of PCNA (proliferating cell nuclear antigen) and cyclinD1 expression was observed. Meanwhile, knockdown of c1orf109 by siRNA in breast cancer MDA-MB-231 cells confirmed the role of c1orf109 in proliferation. CONCLUSIONS: Taken together, our findings suggest that C1ORF109 may be the downstream target of protein kinase CK2 and involved in the regulation of cancer cell proliferation. PMID- 22548825 TI - Derivation of an interaction/regulation network describing pluripotency in human. AB - Identification of the key genes/proteins of pluripotency and their interrelationships is an important step in understanding the induction and maintenance of pluripotency. Experimental approaches have accumulated large amounts of interaction/regulation data in mouse. We investigate how far such information can be transferred to human, the species of maximum interest, for which experimental data are much more limited. To address this issue, we mapped an existing mouse pluripotency network (the PluriNetWork) to human. We transferred interaction and regulation links between genes/proteins from mouse to human on the basis of orthologous relationship of the genes/proteins (called interolog mapping). To reduce the number of false positives, we used four different methods: phylogenetic profiling, Gene Ontology semantic similarity, gene co-expression, and RNA interference (RNAi) data. The methods and the resulting networks were evaluated by a novel approach using the information about the genes known to be involved in pluripotency from the literature. The RNAi method proved best for filtering out unlikely interactions, so it was used to construct the final human pluripotency network. The RNAi data are based on human embryonic stem cells (hESCs) that are generally considered to be in a (primed) epiblast stem cell state. Therefore, we assume that the final human network may reflect the (primed) epiblast stem cell state more closely, while the mouse network reflects the (unprimed/naive) embryonic stem cell state more closely. PMID- 22548826 TI - Comparative morphology of the pyloric armature of adult mosquitoes (Diptera: Culicidae). AB - The structure of the pyloric armature, hypothesized to aid in blood-meal digestion or parasite resistance, was compared quantitatively among the following 8 species in 5 genera of adult mosquitoes from the southeastern United States: Aedes albopictus, Aedes japonicus, Aedes triseriatus, Anopheles punctipennis, Culex pipiens s.l., Culex restuans, Orthopodomyia signifera, and Toxorhynchites rutilus. Females differed significantly among species in the structure of spines composing the armature, with Aedes spp. forming one general group, Culex spp. another, and An. punctipennis and Or. signifera a third. Relationships of species based on structural characters of the armature were consistent with recent culicid phylogenies. Although pyloric armature has been noted in mosquitoes and other insects, this is the first quantitative investigation of the mosquito pyloric armature. PMID- 22548827 TI - Outcome Orientated Child and Adolescent Mental Health Services (OO-CAMHS): a whole service model. AB - The international evidence base on factors that most influence outcomes in mental health care finds that matching therapeutic intervention to diagnosis has a clinically insignificant impact on outcomes. Decades of outcome research into treatment of psychiatric disorders shows that, despite the development of many new techniques, the outcomes being achieved in studies 30 years ago are similar to those being achieved now. In the last few years, new service models that incorporate systems of feedback on progress and alliance have emerged and show promise with regards improving overall outcomes for mental health service users. Growing familiarity with this outcome literature, together with a desire to be part of a service that can continue to improve patient outcomes, led a small community Child and Adolescent Mental Health Services team to develop a new whole service model - Outcome Orientated Child and Adolescent Mental Health Services (OO-CAMHS). OO-CAMHS incorporates key aspects of the evidence base on what could make a differential positive impact on outcomes and relinquishes those aspects that do not. In this paper, we outline the evidence base on which OO-CAMHS is built, describe the key features of the approach and present some of the early findings on its impact. PMID- 22548828 TI - Gene regulatory network inference: evaluation and application to ovarian cancer allows the prioritization of drug targets. AB - BACKGROUND: Altered networks of gene regulation underlie many complex conditions, including cancer. Inferring gene regulatory networks from high-throughput microarray expression data is a fundamental but challenging task in computational systems biology and its translation to genomic medicine. Although diverse computational and statistical approaches have been brought to bear on the gene regulatory network inference problem, their relative strengths and disadvantages remain poorly understood, largely because comparative analyses usually consider only small subsets of methods, use only synthetic data, and/or fail to adopt a common measure of inference quality. METHODS: We report a comprehensive comparative evaluation of nine state-of-the art gene regulatory network inference methods encompassing the main algorithmic approaches (mutual information, correlation, partial correlation, random forests, support vector machines) using 38 simulated datasets and empirical serous papillary ovarian adenocarcinoma expression-microarray data. We then apply the best-performing method to infer normal and cancer networks. We assess the druggability of the proteins encoded by our predicted target genes using the CancerResource and PharmGKB webtools and databases. RESULTS: We observe large differences in the accuracy with which these methods predict the underlying gene regulatory network depending on features of the data, network size, topology, experiment type, and parameter settings. Applying the best-performing method (the supervised method SIRENE) to the serous papillary ovarian adenocarcinoma dataset, we infer and rank regulatory interactions, some previously reported and others novel. For selected novel interactions we propose testable mechanistic models linking gene regulation to cancer. Using network analysis and visualization, we uncover cross-regulation of angiogenesis-specific genes through three key transcription factors in normal and cancer conditions. Druggabilty analysis of proteins encoded by the 10 highest confidence target genes, and by 15 genes with differential regulation in normal and cancer conditions, reveals 75% to be potential drug targets. CONCLUSIONS: Our study represents a concrete application of gene regulatory network inference to ovarian cancer, demonstrating the complete cycle of computational systems biology research, from genome-scale data analysis via network inference, evaluation of methods, to the generation of novel testable hypotheses, their prioritization for experimental validation, and discovery of potential drug targets. PMID- 22548829 TI - Intraluminal polyethylene glycol stabilizes tight junctions and improves intestinal preservation in the rat. AB - Rapidly progressing mucosal breakdown limits the intestinal preservation time below 10 h. Recent studies indicate that intraluminal solutions containing polyethylene glycol (PEG) alleviate preservation injury of intestines stored in UW-Viaspan. We investigated whether a low-sodium PEG solution is beneficial for intestines stored in histidine-tryptophane-ketoglutarate (HTK) preservation solution. Rat intestines used as control tissue (group 1) were perfused with HTK, groups 2 and 3 received either a customized PEG-3350 (group 2) or an electrolyte solution (group 3) intraluminally before cold storage. Tissue injury, brush border maltase activity, zonula occludens-1 (ZO-1) and claudin-3 expression in the tight junctions (TJ) were analyzed after 8, 14 and 20 h. We measured epithelial resistance and permeability (Ussing chamber) after 8 and 14 h. Group 2 had superior morphology while maltase activity was similar in all groups. TJ proteins rapidly decreased and decolocalized in groups 1 3; these negative events were delayed in group 2, where colocalization persisted for about 14 h. Intestines in group 2 had higher epithelial resistance and lower permeability than the other groups. These results suggest that a customized PEG solution intraluminally reduces the intestinal preservation injury by improving several major epithelial characteristics without negatively affecting the brush-border enzymes or promoting edema. PMID- 22548830 TI - Interaction of the EGFR inhibitors gefitinib, vandetanib, pelitinib and neratinib with the ABCG2 multidrug transporter: implications for the emergence and reversal of cancer drug resistance. AB - Human ABCG2 is a plasma membrane glycoprotein that provides physiological protection against xenobiotics. ABCG2 also significantly influences biodistribution of drugs through pharmacological tissue barriers and confers multidrug resistance to cancer cells. Moreover, ABCG2 is the molecular determinant of the side population that is characteristically enriched in normal and cancer stem cells. Numerous tumors depend on unregulated EGFR signaling, thus inhibition of this receptor by small molecular weight inhibitors such as gefitinib, and the novel second generation agents vandetanib, pelitinib and neratinib, is a promising therapeutic option. In the present study, we provide detailed biochemical characterization regarding the interaction of these EGFR inhibitors with ABCG2. We show that ABCG2 confers resistance to gefitinib and pelitinib, whereas the intracellular action of vandetanib and neratinib is unaltered by the presence of the transporter. At higher concentrations, however, all these EGFR inhibitors inhibit ABCG2 function, thereby promoting accumulation of ABCG2 substrate drugs. We also report enhanced expression of ABCG2 in gefitinib-resistant non-small cell lung cancer cells, suggesting potential clinical relevance of ABCG2 in acquired drug resistance. Since ABCG2 has important impact on both the pharmacological properties and anti-cancer efficiencies of drugs, our results regarding the novel EGFR inhibitors should provide useful information about their therapeutic applicability against ABCG2 expressing cancer cells depending on EGFR signaling. In addition, the finding that these EGFR inhibitors efficiently block ABCG2 function may help to design novel drug-combination therapeutic strategies. PMID- 22548831 TI - Common bacterium induces histamine production in neutrophils. PMID- 22548832 TI - T1 mapping of the myocardium: intra-individual assessment of the effect of field strength, cardiac cycle and variation by myocardial region. AB - BACKGROUND: Myocardial T1 relaxation time (T1 time) and extracellular volume fraction (ECV) are altered in the presence of myocardial fibrosis. The purpose of this study was to evaluate acquisition factors that may result in variation of measured T1 time and ECV including magnetic field strength, cardiac phase and myocardial region. METHODS: 31 study subjects were enrolled and underwent one cardiovascular MR exam at 1.5 T and two exams at 3 T, each on separate days. A Modified Look-Locker Inversion Recovery (MOLLI) sequence was acquired before and 5, 10, 12, 20, 25 and 30 min after administration of 0.15 mmol/kg gadopentetate dimeglumine (Gd-DTPA; Magnevist) at 1.5 T (exam 1). For exam 2, MOLLI sequences were acquired at 3 T both during diastole and systole, before and after administration of Gd-DTPA (0.15 mmol/kg Magnevist).Exam 3 was identical to exam 2 except gadobenate dimeglumine was administered (Gd-BOPTA; 0.1 mmol/kg Multihance). T1 times were measured in myocardium and blood. ECV was calculated by (DeltaR1myocardium/DeltaR1blood)*(1-hematocrit). RESULTS: Before gadolinium, T1 times of myocardium and blood were significantly greater at 3 T versus 1.5 T (28% and 31% greater, respectively, p < 0.001); after gadolinium, 3 T values remained greater than those at 1.5 T (14% and 12% greater for myocardium and blood at 3 T with Gd-DTPA, respectively, p < 0.0001 and 18% and 15% greater at 3 T with Gd-BOPTA, respectively, p < 0.0001). However, ECV did not vary significantly with field strength when using the same contrast agent at equimolar dose (p = 0.2). Myocardial T1 time was 1% shorter at systole compared to diastole pre-contrast and 2% shorter at diastole compared to systole post-contrast (p < 0.01). ECV values were greater during diastole compared to systole on average by 0.01 (p < 0.01 to p < 0.0001). ECV was significantly higher for the septum compared to the non-septal myocardium for all three exams (p < 0.0001-0.01) with mean absolute differences of 0.01, 0.004, and 0.07, respectively, for exams 1, 2 and 3. CONCLUSION: ECV is similar at field strengths of 1.5 T and 3 T. Due to minor variations in T1 time and ECV during the cardiac cycle and in different myocardial regions, T1 measurements should be obtained at the same cardiac phase and myocardial region in order to obtain consistent results. PMID- 22548834 TI - A high-throughput core sampling device for the evaluation of maize stalk composition. AB - BACKGROUND: A major challenge in the identification and development of superior feedstocks for the production of second generation biofuels is the rapid assessment of biomass composition in a large number of samples. Currently, highly accurate and precise robotic analysis systems are available for the evaluation of biomass composition, on a large number of samples, with a variety of pretreatments. However, the lack of an inexpensive and high-throughput process for large scale sampling of biomass resources is still an important limiting factor. Our goal was to develop a simple mechanical maize stalk core sampling device that can be utilized to collect uniform samples of a dimension compatible with robotic processing and analysis, while allowing the collection of hundreds to thousands of samples per day. RESULTS: We have developed a core sampling device (CSD) to collect maize stalk samples compatible with robotic processing and analysis. The CSD facilitates the collection of thousands of uniform tissue cores consistent with high-throughput analysis required for breeding, genetics, and production studies. With a single CSD operated by one person with minimal training, more than 1,000 biomass samples were obtained in an eight-hour period. One of the main advantages of using cores is the high level of homogeneity of the samples obtained and the minimal opportunity for sample contamination. In addition, the samples obtained with the CSD can be placed directly into a bath of ice, dry ice, or liquid nitrogen maintaining the composition of the biomass sample for relatively long periods of time. CONCLUSIONS: The CSD has been demonstrated to successfully produce homogeneous stalk core samples in a repeatable manner with a throughput substantially superior to the currently available sampling methods. Given the variety of maize developmental stages and the diversity of stalk diameter evaluated, it is expected that the CSD will have utility for other bioenergy crops as well. PMID- 22548833 TI - Interleukin-1beta (IL-1beta) increases pain behavior and the blood glucose level: possible involvement of sympathetic nervous system. AB - The relationship between interleukin-1beta (IL-1beta)-induced nociception and the blood glucose level was studied in ICR mice. We found in the present study that intrathecal (i.t.) injection of IL-1beta increased pain behavior. In addition, i.t. IL-1beta injection caused an elevation of the blood glucose level. The time course study showed that maximal blood glucose level was observed 30 and 60 min after i.t. IL-1beta administration. Furthermore, i.t. injection of IL-1beta enhanced the blood glucose level when mice were orally fed with d-glucose. The i.t. administration of IL-1beta antagonist (AF12198) inhibited the hyperglycemia and pain behaviors induced by IL-1beta. We found in the present study that adrenal tyrosine hydroxylase (TH) mRNA level was also increased by i.t. IL-1beta injection. Furthermore, intraperitoneal (i.p.) pretreatment with phentolamine (an alpha(1)-adrenergic blocker) or yohimbine (an alpha(2)-adrenergic blocker) significantly attenuated the blood glucose level and pain behavior induced by IL 1beta administered i.t. However, the blood glucose level and pain behavior were not affected by butoxamine (a beta(2)-adrenergic blocker), whereas metoprolol (a beta(2)-adrenergic blocker) enhanced IL-1beta-induced blood glucose level and pain behavior in mice fed with d-glucose. However, its effect was not statistically significant. Our results suggest that IL-1beta administered i.t. increases the blood glucose level via an activation of alpha adrenergic nervous system. PMID- 22548836 TI - Decline of disease activity and autoantibodies to desmoglein 3 and envoplakin by oral prednisolone in paraneoplastic pemphigus with benign thymoma. PMID- 22548835 TI - Early microstructural white matter changes in patients with HIV: a diffusion tensor imaging study. AB - BACKGROUND: Previous studies have reported white matter (WM) brain alterations in asymptomatic patients with human immunodeficiency virus (HIV). METHODS: We compared diffusion tensor imaging (DTI) derived WM fractional anisotropy (FA) between HIV-patients with and without mild macroscopic brain lesions determined using standard magnetic resonance imaging (MRI). We furthermore investigated whether WM alterations co-occurred with neurocognitive deficits and depression. We performed structural MRI and DTI for 19 patients and 19 age-matched healthy controls. Regionally-specific WM integrity was investigated using voxel-based statistics of whole-brain FA maps and region-of-interest analysis. Each patient underwent laboratory and neuropsychological tests. RESULTS: Structural MRI revealed no lesions in twelve (HIV-MRN) and unspecific mild macrostructural lesions in seven patients (HIV-MRL). Both analyses revealed widespread FA alterations in all patients. Patients with HIV-MRL had FA-alterations primarily adjacent to the observed lesions and, whilst reduced in extent, patients with HIV MRN also exhibited FA-alterations in similar regions. Patients with evidence of depression showed FA-increase in the ventral tegmental area, pallidum and nucleus accumbens in both hemispheres, and patients with evidence of HIV-associated neurocognitive disorder showed widespread FA-reduction. CONCLUSION: These results show that patients with HIV-MRN have evidence of FA-alterations in similar regions that are lesioned in HIV-MRL patients, suggesting common neuropathological processes. Furthermore, they suggest a biological rather than a reactive origin of depression in HIV-patients. PMID- 22548837 TI - Phylogenetic placement of the enigmatic and critically endangered genus Saniculiphyllum (Saxifragaceae) inferred from combined analysis of plastid and nuclear DNA sequences. AB - Saniculiphyllum, a monotypic genus distributed in Southwest China, was thought to be extinct before our recent rediscovery. The taxonomic position of this genus has been enigmatic ever since its publication. It was originally treated as the only member of a distinct tribe Saniculiphylleae in the family Saxifragaceae. Some proposed a new family, Saniculophyllaceae, to accommodate this genus, although its affinities are clearly with members of Saxifragaceae. Here we analyzed six DNA regions, the nuclear ribosomal ITS and 26S rDNA and the plastid rbcL, matK, trnL-trnF, psbA-trnH genes, spacers, and intron to explore the phylogenetic position of Saniculiphyllum within Saxifragaceae. The combined nuclear and chloroplast dataset includes 63 ingroup species, representing all genera but Hieronymusia in the family. Results from likelihood, parsimony and Bayesian phylogenetic methods corroborate earlier results. Two clades of Saxifragaceae, the Heucheroid and Saxifragoid clades, were recovered. The topologies obtained from different analyses confirm the placement of Saniculiphyllum in Saxifragaceae, but our analyses reveal that Saniculiphyllum is embedded within the large Heucheroid clade. However, the closest relatives of Saniculiphyllum within the Heucheroid clade remain unclear. Combined with morphological data, our results suggest that Saniculiphyllum should best be regarded as a highly distinctive lineage within the Heucheroid clade of Saxifragaceae. Morphological novelties and conservation status of Saniculiphyllum are also presented. PMID- 22548838 TI - Tuberculous meningitis in a lung transplanted patient. AB - A 57-year-old female lung transplant recipient developed tuberculosis after quadruple maintenance immunosuppression for acute cellular rejection with respiratory compromise. Deteriorating neurological status led to cerebral imaging and lumbar puncture, which showed Mycobacterium tuberculosis. Tuberculous meningitis with elevated intracranial pressure was treated for 2 weeks on a neurosurgical ward, and intensive care therapy was necessary for another 2 weeks. Complete neurological recovery was achieved after 3 months. PMID- 22548839 TI - Single-center kidney paired donation: the Methodist San Antonio experience. AB - Many potential kidney transplant recipients are unable to receive a live donor transplant due to crossmatch or blood type incompatibility. Kidney paired donation increases access to live donor transplantation but has been significantly underutilized. We established a kidney paired donation program including consented incompatible donor/recipient pairs as well as compatible pairs with older non-human leukocyte antigen identical donors. Over a 3-year period, a total of 134 paired donor transplants were performed, including 117 incompatible pairs and 17 compatible pairs. All transplants were done with negative flow cytometry crossmatches and five were done with desensitization combined with paired donation. Kidney paired donation transplants included two way and three-way exchanges as well as three chains initiated by nondirected donors. Of the sensitized recipients transplanted by paired donation, 44% had calculated panel reactive antibody levels greater than 80%. Transplantation of females and prior transplant recipients was significantly higher with paired donation. Only three episodes of rejection occurred and no transplants were lost due to rejection. These data highlight the potential of kidney paired donation and suggest that all transplant centers should be actively engaged in paired donation to increase access to live donor transplantation. PMID- 22548840 TI - Pneumocystis pneumonia in hospitalized patients: a detailed examination of symptoms, management, and outcomes in human immunodeficiency virus (HIV)-infected and HIV-uninfected persons. AB - BACKGROUND: Pneumocystis jirovecii pneumonia (PCP) is a life-threatening infection for immunocompromised individuals. Robust data and clear guidelines are available for prophylaxis and treatment of human immunodeficiency virus (HIV) related PCP (HIV-PCP), yet few data and no guidelines are available for non-HIV related PCP (NH-PCP). We postulated that prevention and inpatient management of HIV-PCP differed from NH-PCP. METHODS: We performed a retrospective case review of all pathologically confirmed cases of PCP seen at the University of Alabama Medical Center from 1996 to 2008. Data on clinical presentation, hospital course, and outcome were collected using a standardized data collection instrument. Bivariate analysis compared prophylaxis, adjunctive corticosteroids, and clinical outcomes between patients with HIV-PCP and NH-PCP. RESULTS: Our analysis of the cohort included 97 cases of PCP; 65 HIV and 32 non-HIV cases. Non-HIV cases rarely received primary prophylaxis (4% vs. 38%, P = 0.01) and received appropriate antibiotics later in the course of hospitalization (5.2 days vs. 1.1 days, P < 0.005). Among transplant patients, NH-PCP was diagnosed a mean of 1066 days after transplantation and most patients were on low-dose corticosteroids (87%) at the time of disease onset. No significant differences in adjunctive corticosteroid use (69% vs. 77%, P = 0.39) and 90-day mortality (41% vs. 28%, P = 0.20) were detected. CONCLUSIONS: Patients who have undergone organ or stem cell transplant remain at risk for PCP for many years after transplantation. In our cohort, patients who developed NH-PCP were rarely given prophylaxis, and initiation of appropriate antibiotics was significantly delayed compared to cases of HIV-PCP. Medical providers should be aware of the ongoing risk for NH-PCP, even late after transplantation, and consider more aggressive approaches to both prophylaxis and earlier empirical therapy for PCP. PMID- 22548842 TI - Combination of media, biomaterials and extracellular matrix proteins to enhance the differentiation of neural stem/precursor cells into neurons. AB - The purpose of this study was to induce the differentiation of neural stem/precursor cells (NSPC) more towards neurons than glial cells by the combination of media, biomaterials and extracellular matrix (ECM) proteins. Considering the role of serum, 10% fetal bovine serum or its fractions were added to DMEM/F12 medium to examine the effect of the differentiation-promoting potential on cultured NSPC isolated from embryonic rat cerebral cortex. The NSPC were cultured for 7 days, after which differentiation was assayed using immunocytochemistry for lineage specific markers. It was demonstrated that molecules promoting neuron differentiation were present in serum with molecular weight <100 kDa, which could dominate the differentiation of NSPC principally into neurons in the presence of basic fibroblast growth factor. In contrast, NSPC were induced to differentiate predominantly into glial cell phenotypes in the presence of whole serum components. Based on medium containing serum fraction, semi-quantification showed that the MAP2-positive percentage of the immunoreactive ratio within migrated cells could be promoted over 85% by combining poly(ethylene-co-vinyl alcohol) biomaterial and fibronectin matrix protein. These results are very encouraging, since an environment favorable for neuronal differentiation should be useful in the development of strategies for controlling the behavior of NSPC in neuroscience research. PMID- 22548841 TI - Genetic variants of NOXA and MCL1 modify the risk of HPV16-associated squamous cell carcinoma of the head and neck. AB - BACKGROUND: The cooperation between phorbol 12-myristate 13-acetate induced protein 1 (NOXA) and myeloid cell leukemia 1 (MCL1) is critical in the intrinsic apoptotic pathway. Human papillomavirus 16 (HPV16), by inducing p53 and pRb-E2F degradation, may play an essential role in development of squamous cell carcinoma of the head and neck (SCCHN) through NOXA-MCL1 axis-mediated apoptosis. Therefore, genetic variants of NOXA and MCL1 may modify the SCCHN risk associated with HPV16 seropositivity. METHODS: HPV16 serology was obtained by immunoadsorption assay. Four functional SNPs in the promoter of NOXA (rs9957673, rs4558496) and MCL1 (rs9803935, rs3738485) were genotyped for 380 cases and 335 frequency-matched cancer-free controls of non-Hispanic whites. RESULTS: Associations between the four polymorphisms and SCCHN risk were not significant, while we observed a significantly joint effect on SCCHN risk between the polymorphisms and HPV16 seropositivity. Notably, this effect modification was particularly pronounced for oropharyngeal cancer in subgroups including never smokers, never drinkers and younger subjects. CONCLUSIONS: Our results suggested that polymorphisms of NOXA and MCL1 may modify the risk of HPV16-associated oropharyngeal cancer. The further identification of population subgroups at higher risk provides evidence that HPV-targeting treatment may help benefit SCCHN. However, larger studies are needed to validate our findings. PMID- 22548843 TI - A novel five-way translocation t(7;11;9;22;9)(q22;q13;q34;q11.2;q34) involving Ph chromosome in a patient of chronic myeloid leukemia: a case report. AB - About 5-10 % of chronic myelogenous leukemia (CML) patients show variant Philadelphia (Ph) translocations. The formation mechanisms and clinical significance of variant Ph translocations remain unclear. We report a CML case with a novel five-way complex translocation. Although the result of initial G banding was 46,XY,t(7;11;9)(q22;q13;q34),t(9;22)(q34;q11.2), fluorescence in situ hybridization (FISH) demonstrated t(7;11;9;22;9)(q22;q13;q34;q11.2;q34) consisting of sequential rearrangements involving five chromosomes. The patient was successfully treated by imatinib and obtained a major molecular response. To our knowledge, this is the tenth CML case with a complicated Ph translocation involving five chromosomes and the third one treated by imatinib. Good response with imatinib therapy suggested that a single-event rearrangement was involved in the chromosomal changes. PMID- 22548844 TI - Enhanced stability of horseradish peroxidase encapsulated in acetalated dextran microparticles stored outside cold chain conditions. AB - Micro- and nanoparticles have been shown to improve the efficacy of safer protein based (subunit) vaccines. Here, we evaluate a method of improving the vaccine stability outside cold chain conditions by encapsulation of a model enzyme, horseradish peroxidase (HRP), in an acid-sensitive, tunable biodegradable polymer, acetalated dextran (Ac-DEX). Vaccines that are stable outside the cold chain would be desirable for use in developing nations. Ac-DEX particles encapsulating HRP were prepared using two different methods, probe sonication and homogenization. These particles were stored under different storage conditions ( 20 degrees C, 4 degrees C, 25 degrees C or 45 degrees C) for a period of 3 months. On different days, the particles were characterized for various physical and chemical measurements. At all conditions, Ac-DEX particles remained spherical in nature, as compared to PLGA particles that fused together starting at day 3 at 45 degrees C. Furthermore, our results indicated that encapsulation of HRP in Ac DEX reduces its storage temperature dependence and enhances its stability outside cold chain conditions. Homogenized particles performed better than probe sonicated particles and retained 70% of the enzyme's initial activity as compared to free HRP that retained only 40% of the initial activity after 3 months of storage at 25 degrees C or 45 degrees C. Additionally, HRP activity was more stable when encapsulated in Ac-DEX, and the variance in enzyme activity between the different storage temperatures was not observed for either particle preparation. This suggests that storage at a constant temperature is not required with vaccines encapsulated in Ac-DEX particles. Overall, our results suggest that an Ac-DEX based micro-/nanoparticles system has wide applications as vaccines and drug delivery carriers, including those in developing nations. PMID- 22548845 TI - In-situ phase transition from microemulsion to liquid crystal with the potential of prolonged parenteral drug delivery. AB - This study is the first to investigate and demonstrate the potential of microemulsions (MEs) for sustained release parenteral drug delivery, due to phase transition behavior in aqueous environments. Phase diagrams were constructed with Miglyol 812N oil and a blend of (co)surfactants Solutol HS 15 and Span 80 with ethanol. Liquid crystal (LC) and coarse emulsion (CE) regions were found adjacent to the ME region in the water-rich corner of the phase diagram. Two formulations were selected, a LC-forming ME and a CE-forming ME and each were investigated with respect to their rheology, particle size, drug release profiles and particularly, the phase transition behavior. The spreadability in an aqueous environment was determined and release profiles from MEs were generated with gamma-scintigraphy. The CE-forming ME dispersed readily in an aqueous environment, whereas the LC-forming ME remained in a contracted region possibly due to the transition of ME to LC at the water/ME interface. Gamma-scintigraphy showed that the LC-forming ME had minimal spreadability and a slow release of (99m)Tc in the first-order manner, suggesting phase conversion at the interface. In conclusion, owing to the potential of phase transition, LC-forming MEs could be used as extravascular injectable drug delivery vehicles for prolonged drug release. PMID- 22548846 TI - Microwave absorption properties of Ni/(C, silicides) nanocapsules. AB - The microwave absorption properties of Ni/(C, silicides) nanocapsules prepared by an arc discharge method have been studied. The composition and the microstructure of the Ni/(C, silicides) nanocapsules were determined by means of X-ray diffraction, X-ray photoelectric spectroscopy, and transmission electron microscope observations. Silicides, in the forms of SiOx and SiC, mainly exist in the shells of the nanocapsules and result in a large amount of defects at the 'core/shell' interfaces as well as in the shells. The complex permittivity and microwave absorption properties of the Ni/(C, silicides) nanocapsules are improved by the doped silicides. Compared with those of Ni/C nanocapsules, the positions of maximum absorption peaks of the Ni/(C, silicides) nanocapsules exhibit large red shifts. An electric dipole model is proposed to explain this red shift phenomenon. PMID- 22548847 TI - Ageing, arterial blood pressure, body mass index, and diet. AB - For three decades we followed up for longevity indicators, including diet, arterial blood pressure, and body mass index 379 mobile, long-living persons from Croatia, now aged 70 to 92 years, of whom 167 men aged (78.6 +/- 4.0) years and 212 women aged (77.9 +/- 4.1) years. One hundred and ninety-five were from the continental and 184 from the coastal Croatia. The participants were examined in 1972, 1982, and again in 2006/7. Changes in body mass index (BMI), arterial blood pressure (ABP), and in answers to our Food Frequency Questionnaire about dietary habits were analysed using log-linear models. Over the last 24 years of aging (age 55 to 78 years) the subjects showed a statistically significant decrease in body mass and height and a significant increase in the systolic blood pressure. Diastolic blood pressure and BMI showed no significant changes over this period. Consumption of preserved and fresh meat, bread, and starch (potato, pastry and rice) dropped significantly with age, while the consumption of fish, fresh and cooked vegetables, fruit, and dairy products significantly increased. These dietary changes were not associated with changes in the systolic and diastolic ABP. About 80 % were overweight (BMI >25 kg m(-2)) throughout the follow-up, even though their body mass dropped significantly after the age of 55. However, their survival suggests that BMI may not be the best indicator of longevity or healthy aging. PMID- 22548848 TI - Influence of heredity and environment on peak bone density: a review of studies in Croatia. AB - One of the main determinants of who will develop osteoporosis is the amount of bone accumulated at peak bone density. There is poor agreement, however, on when peak bone density occurs. Ethnic differences were observed in age at peak bone density and their correlates. Since the diagnosis of osteoporosis and osteopaenia is based on the comparison between patients' bone mineral density (BMD) and optimal peak bone density in healthy young people (T-score), it is of great importance that each country should provide its own reference peak bone density data.This review article presents our published results on peak bone density in Croatia and compares them with findings in other populations. Our research included 18 to 25-year-old students from Zagreb University and their parents. The results showed that peak bone mass in young Croatian women was achieved before the age of twenty, but BMD continued to increase after the mid-twenties in the long-bone cortical skeleton. BMD was comparable to the values reported by the National Health and Nutrition Examination Survey (NHANES) and other studies that included the same age groups, except for the cortical part of the radius, where it was significantly lower. Men achieved peak bone density in the spine later than women, which cannot be explained by different diet or physical activity. As expected, heredity was more important for peak bone density than the environmental factors known to be important for bone health. However, the influence of heredity was not as strong as observed in most other populations. It was also weaker in the cortical than in the trabecular parts of the skeleton. Future research should include young adolescent population to define the exact age of achieving peak bone density in different skeletal sites. PMID- 22548849 TI - Subjective estimation of the quality of life in relation to neuroticism. AB - It is generally agreed that personality variables have a relatively consistent influence on the subjective estimation of different situations in everyday life and the way people react to them. The aim of this review was to summarise our previously published findings on the relationship between subjective estimation of one's quality of life and the personality trait neuroticism-emotional stability. We used the WHO Quality of Life--BREF or SF-36 questionnaires for the assessment of the quality of life, Cornell Index for the assessment of neuroticism, and The Social Readjustment Rating Scale for the evaluation of common stressors. Our results have shown that more emotionally stable participants (lower neuroticism) perceive their life better in quality and are more satisfied with their work environment. In addition, our results support the findings from other studies that women have higher neuroticism and lower quality of life scores than men. PMID- 22548850 TI - Regulation of sleepiness: the role of the arousal system. AB - Sleepiness is a widespread phenomenon in the busy industrial countries, and many studies have identified its significant negative impacts on individuals and society. Particularly important are the data that associate sleepiness with the risk of accidents at workplace and in transport, pointing to shift workers as the most vulnerable population. It is generally accepted that two basic physiological processes regulate sleepiness: homeostatic and circadian rhythmic processes. Recent research has proposed the third component regulating sleepiness, that is, the wake drive or the arousal system. The role of the arousal system in regulating sleepiness has partly been addressed by the studies of the pathophysiology of insomnia, which is often described as a disorder of hyperarousal. Experimental and correlational studies on the relation between sleepiness and arousal in good sleepers have generally indicated that both physiological and cognitive arousal are related to the standard measures of sleepiness. Taking into account the role of the arousal system in regulating sleepiness widens the possibilities for the management of sleep disorders and could also help in solving the problem of excessive sleepiness at work and the wheel. PMID- 22548851 TI - Reproductive toxicity of metals in men. AB - A combination of genetic, environmental and lifestyle factors contributes to adverse effects on the reproductive health in men. Metals are pervasive in food, water, air, tobacco smoke, and alcoholic beverages. Experimental studies suggest that many metals have adverse effects on the male reproductive function. However, information about reproductive effects of human exposure to metals is scarce and/or inconsistent. This review summarises the information from epidemiological studies of the effects of metal exposure on reproductive function in men. Factors capable of affecting these relationships were identified and discussed. A particular attention is given to the studies considering influence of concomitant exposure to various metals. These studies have generally confirmed that even moderate- to low-level exposure to lead affects certain reproductive parameters, and that exposure to cadmium affects the prostate function and serum testosterone levels. Adverse effects of mercury, manganese, chromium and arsenic on semen quality and altered serum hormone are less well documented. There is no clear evidence that boron exposure may impair reproductive health in men. Only a few studies have investigated reproductive effects of concomitant exposure to several metals and controlled for potential confounders. Future studies should consider the contribution of combined exposure to various metals and/or other factors that may influence individual susceptibility to reproductive health impairment in men. PMID- 22548852 TI - Arthropod allergens in urban homes. AB - Dust mites, cockroaches, and pets (cats, dogs) are common in homes worldwide, and many species are the source of potent allergens which cause allergic diseases. These diseases are influenced by genetic predisposition and environmental exposure. Generally, the levels of house dust mite (Der p 1 and Der f 1) and cockroach (Bla g 1, Bla g 2) allergens are used as markers of indoor exposure to arthropods.This article reviews the findings of allergens Der p 1, Der f 1, and Bla g 1 in randomly selected urban households in Zagreb (Croatia) measured from 2006 to 2010 and compares them with exposure to arthropod allergens in other countries. In short, house dust mite allergen levels in Croatian homes are low, but exposure is common; Der p 1 was found in 73 % and Der f 1 in 83 % of the households. By contrast, exposure to cockroach allergen Bla g 1 was both low and uncommon (13 %). Exposure to multiple allergens associated with sensitisation and asthma was not frequent in urban homes in Croatia. However, further studies should include monitoring of both arthropod and pet allergens in high-risk populations in inland and coastal Croatia. They should also investigate a complex dose-response relationship between exposure and sensitisation/asthma development, especially in early childhood. PMID- 22548853 TI - Pyroglyphid mites as a source of work-related allergens. AB - Pyroglyphid mites are primarily associated with allergen exposure at home; hence the name house dust mites. However, we have found numerous studies reporting pyroglyhid mite levels in public and occupational settings. This review presents the findings of house dust mite allergens (family Pyroglyphidae, species Dermatophagoides) as potential work-related risk factors and proposes occupations at risk of house dust mite-related diseases. Pyroglyphid mites or their allergens are found in various workplaces, but clinically relevant exposures have been observed in hotels, cinemas, schools, day-care centres, libraries, public transportation (buses, trains, taxies, and airplanes), fishing-boats, submarines, poultry farms, and churches. Here we propose a classification of occupational risk as low (occasional exposure to mite allergen levels up to 2 MUg g(-1)), moderate (exposure between 2 MUg g(-1) and 10 MUg g(-1)), and high (exposure >10 MUg g(-1)). The classification of risk should include factors relevant for indoor mite population (climate, building characteristics, and cleaning schedule). To avoid development or aggravation of allergies associated with exposure to house dust mites at work, occupational physicians should assess exposure risk at work, propose proper protection, provide vocational guidance to persons at risk and conduct pre-employment and periodic examinations to diagnose new allergy cases. Protection at work should aim to control dust mite levels at work. Measures may include proper interior design and regular cleaning and building maintenance. PMID- 22548854 TI - Non-thermal biomarkers of exposure to radiofrequency/microwave radiation. AB - This article gives a review or several hypotheses on the biological effects of non-thermal radiofrequency/microwave (RF/MW) radiation and discusses our own findings from animal and in vitro studies performed over the last decade. We have found that RF/MW radiation disturbs cell proliferation and leads to cell differentiation in the bone marrow, which is reflected in the peripheral blood of rats. Repeated RF/MW radiation can also temporarily disrupt melatonin turnover. The observed changes seem to be a sign of adaptation to stress caused by irradiation rather than of malfunction. The article looks further into the basic mechanisms of RF/MW biological action, including cell growth parameters, colony forming ability, viability, and the polar and apolar protein cytoskeleton structures. The observed reversible cell changes significantly obstructed cell growth. In contrast to the apolar intermediate proteins, the intracellular polar microtubule and actin fibres were damaged by radiation in a time-dependent manner. These significantly altered parameters can be considered as the biomarkers of exposure. Future research should combine dosimetry, experimental studies, and epidemiological data. PMID- 22548855 TI - Detection of melamine in a human renal uric acid stone by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). AB - BACKGROUND: The link between melamine-contaminated daily foodstuffs and urolithiasis formation has drawn an international concern. However, detection of melamine levels in urine may not completely represent external melamine exposure. Thus, finding an additional analytical method for the study of environmental melamine exposure and its adverse effect in humans is crucial. METHODS: Eleven adult patients diagnosed with uric acid urolithiasis were retrospectively analyzed. Melamine levels in their overnight one-spot urine samples were measured by a triple quadrupole liquid chromatography tandem mass spectrometry (LC-MS/MS). The compositions of stone samples were analyzed by the Fourier transform infrared (FTIR) spectrophotometer and matrix-assisted laser desorption/ionization time-of flight mass spectrometry (MALDI-TOF MS). RESULTS: Seven (63.6%) out of 11 patients had detectable melamine levels in their urine specimens (method of detection limit: 0.8 ng/ml). Three patients (27.3%) were highly suspected of having melamine-containing urolithiasis in FTIR spectra. In one of those three cases who still had available stored stone specimens, MALDI-TOF MS further confirmed melamine components in this male patient's stone specimens. In contrast, his urinary melamine level was below the detection limit by LC-MS/MS. CONCLUSIONS: Direct analysis of melamine in the composition of urolithiasis by MALDI-TOF MS can be an additional analytical method to evaluate for external melamine exposure. PMID- 22548857 TI - Wound healing primer. PMID- 22548856 TI - Lysosomal storage disorder 4+1 multiplex assay for newborn screening using tandem mass spectrometry: application to a small-scale population study for five lysosomal storage disorders. AB - BACKGROUND: We sought to modify a previously published tandem mass spectrometry method of screening for 5 lysosomal storage disorders (LSDs) in order to make it better suited for high-throughput newborn screening. METHODS: Two 3-mm dried blood spot (DBS) punches were incubated, each with a different assay solution. The quadruplex solution was used for screening for Gaucher, Pompe, Krabbe and Fabry diseases, while a separate solution was used for Niemann-Pick A/B disease. RESULTS: The mean activities of acid-beta-glucocerebrosidase (ABG), acid sphingomyelinase (ASM), acid glucosidase (GAA), galactocerebroside-beta galactosidase (GALC) and acid-galactosidase A (GLA) were measured on 5055 unidentified newborns. The mean activities (compared with their disease controls) were, 15.1 (0.35), 22.2 (1.34), 16.8 (0.51), 3.61 (0.23), and 20.7 (1.43) (MUmol/L/h), respectively. The number of specimens that fell below our retest level cutoff of <20% daily mean activity (DMA) for each analyte is: ABG (6), ASM (0), GAA (5), GALC (17), and GLA (2). CONCLUSIONS: This method provides a simplified and reliable assay for screening for five LSDs with clear distinction between activities from normal and disease samples. Advantages of this new method include significant decreases in processing time and the number of required assay solutions and overall decreased complexity. PMID- 22548858 TI - Nutrition and wound healing. PMID- 22548860 TI - Wound management. PMID- 22548859 TI - The impact of psychological stress on wound healing: methods and mechanisms. PMID- 22548861 TI - Wound debridement: therapeutic options and care considerations. PMID- 22548862 TI - Wound healing agents. PMID- 22548863 TI - Management of forearm compartment syndrome. PMID- 22548864 TI - Intra-abdominal hypertension: evolving concepts. PMID- 22548865 TI - Reconstruction of the foot after leg or foot compartment syndrome. PMID- 22548866 TI - Postoperative infections: prevention and management. PMID- 22548867 TI - Preface. PMID- 22548869 TI - Shark fin consumption may expose people to neurotoxic BMAA. PMID- 22548870 TI - Effects of chronic vardenafil treatment persist after end of treatment in rats with acute arteriogenic erectile dysfunction. AB - INTRODUCTION: In our previous study, chronic vardenafil treatment improved erectile function soon after the end of the treatment in rats with acute arteriogenic erectile dysfunction (ED). AIM: The aim of this study is to evaluate whether the effects of chronic vardenafil treatment persist after the end of treatment using rats with acute arteriogenic ED. METHODS: Rats were randomly divided into three groups: (i) control; (ii) ligation; and (iii) vardenafil + no treatment. Rats in the ligation and vardenafil + no treatment groups underwent ligature of the bilateral internal iliac arteries to induce acute arteriogenic ED and were subsequently treated with vehicle or vardenafil (4.0 mg/kg/day), respectively, for 3 weeks. Subsequently, all rats were kept for a further 2 weeks with no treatment. Rats in the control group underwent sham surgery. MAIN OUTCOME MEASURES: Erectile function was assessed by changes in intracavernous pressure (ICP). Smooth muscle (SM)/collagen ratios in corpus cavernosum were analyzed by Masson trichrome staining. Transforming growth factor-beta1 (TGF-beta1 ) mRNA and protein levels in corpus cavernosum (CC) were, respectively, evaluated by real time polymerase chain reaction (PCR) analysis and Western blotting analysis. RESULTS: ICP/mean arterial pressure (MAP) in the ligation group remained significantly lower than that in control group (P < 0.01). Despite no treatment for 2 weeks, ICP/MAP in the var + no treatment group remained significantly higher than that in ligation group (P < 0.05). SM/collagen ratio in the ligation group remained significantly lower when compared with the control group (P < 0.01). The ratio in the var + no treatment group remained significantly higher when compared with the ligation group at 2 weeks after the end of treatment (P < 0.05). TGF-beta(1) mRNA and protein levels did not differ among the groups. CONCLUSIONS: The effects of chronic vardenafil treatment on erectile function and penile structure persist, even after the end of treatment, in acute arteriogenic ED rats. PMID- 22548871 TI - Fitting hidden Markov models of protein domains to a target species: application to Plasmodium falciparum. AB - BACKGROUND: Hidden Markov Models (HMMs) are a powerful tool for protein domain identification. The Pfam database notably provides a large collection of HMMs which are widely used for the annotation of proteins in new sequenced organisms. In Pfam, each domain family is represented by a curated multiple sequence alignment from which a profile HMM is built. In spite of their high specificity, HMMs may lack sensitivity when searching for domains in divergent organisms. This is particularly the case for species with a biased amino-acid composition, such as P. falciparum, the main causal agent of human malaria. In this context, fitting HMMs to the specificities of the target proteome can help identify additional domains. RESULTS: Using P. falciparum as an example, we compare approaches that have been proposed for this problem, and present two alternative methods. Because previous attempts strongly rely on known domain occurrences in the target species or its close relatives, they mainly improve the detection of domains which belong to already identified families. Our methods learn global correction rules that adjust amino-acid distributions associated with the match states of HMMs. These rules are applied to all match states of the whole HMM library, thus enabling the detection of domains from previously absent families. Additionally, we propose a procedure to estimate the proportion of false positives among the newly discovered domains. Starting with the Pfam standard library, we build several new libraries with the different HMM-fitting approaches. These libraries are first used to detect new domain occurrences with low E-values. Second, by applying the Co-Occurrence Domain Discovery (CODD) procedure we have recently proposed, the libraries are further used to identify likely occurrences among potential domains with higher E-values. CONCLUSION: We show that the new approaches allow identification of several domain families previously absent in the P. falciparum proteome and the Apicomplexa phylum, and identify many domains that are not detected by previous approaches. In terms of the number of new discovered domains, the new approaches outperform the previous ones when no close species are available or when they are used to identify likely occurrences among potential domains with high E-values. All predictions on P. falciparum have been integrated into a dedicated website which pools all known/new annotations of protein domains and functions for this organism. A software implementing the two proposed approaches is available at the same address: http://www.lirmm.fr/~terrapon/HMMfit/ PMID- 22548872 TI - Changes in neurocognitive functioning following lung transplantation. AB - Although neurocognitive impairment is relatively common among patients with advanced lung disease, little is known regarding changes in neurocognition following lung transplantation. We therefore administered 10 tests of neurocognitive functioning before and 6 months following lung transplantation and sought to identify predictors of change. Among the 49 study participants, native diseases included chronic obstructive pulmonary disease (n = 22), cystic fibrosis (n = 12), nonfibrotic diseases (n = 11) and other (n = 4). Although composite measures of executive function and verbal memory scores were generally within normal limits both before and after lung transplantation, verbal memory performance was slightly better posttransplant compared to baseline (p < 0.0001). Executive function scores improved in younger patients but worsened in older patients (p = 0.03). A minority subset of patients (29%) exhibited significant cognitive decline (i.e. >1 standard deviations on at least 20% of tests) from baseline to posttransplant. Patients who declined were older (p < 0.004) and tended to be less educated (p = 0.07). Lung transplantation, like cardiac revascularization procedures, appears to be associated with cognitive decline in a subset of older patients, which could impact daily functioning posttransplant. PMID- 22548873 TI - The prevalence and role of human papillomavirus genotypes in primary cervical screening in the northeast of China. AB - BACKGROUND: Studies have shown that type-specific persistence of high-risk human papillomavirus (HPV) infection contributed significantly to cervical carcinogenesis. METHODS: In this population-based study (on 24041 women), we report on the prevalent genotypes of HPVs and the prevalent genotypes of HPV persistent infection in the northeast of China. RESULTS: Our results showed that in HPV infected women (45.6% in total), (95% CI, 44.97%-46.23%), 17.35% (95%CI, 16.87%-17.83%) suffered persistent infection. The most common high-risk HPV types in persistent positivity were HPV-16 (18.21%; 95%CI, 17.04%-19.38%), HPV-58 (13.2%; 95%CI, 12.17%-14.23%), HPV-18 (8.66%; 95%CI, 7.81%-9.51%), HPV-52 (7.06%; 95% CI, 6.28%-7.84%) and HPV-33 (6.78%; 95% CI, 6.02%-7.54%). The prevalence of persistent infections with HPV-16,-58, -18, -52 and 33 in cervicitis were lower compared to those in CIN (all P < 0.05). HPV-58, -33 and multiple HPV persistent positivity were significantly associated with older age (all P < 0.05). HPV-18 persistent positivity was significantly associated with adenocarcinoma and lymphatic metastasis (all P < 0.05). HPV-18 persistent positivity was associated with cervical cancer prognosis (P <0.0001). Multivariate analyses showed that HPV 18 persistent positivity, (RR = 1.704, 95%CI = 1.095-2.654, p = 0.028) and lymphatic metastasis (RR = 2.304, 95%CI = 1.354-3.254, P = 0.015) were independent predictors for 3-year survival in cervical cancer. CONCLUSIONS: we provided extensive results of HPV genotype prevalence and distribution in the northeast of China. HPV genotyping is worthwhile to perform because of its independent prognostic value in cervical cancer. PMID- 22548874 TI - Congenital ocular and adnexal disorders in reptiles. AB - Ocular and adnexal congenital disorders are those that manifest at birth and could involve single or multiple tissues. Several abnormalities have been reported in literature affecting reptilian ocular and/or adnexal tissues. The objectives of this review are: (i) review those disorders previously reported in reptile literature; (ii) present new cases; (iii) provide a basic classification of them according to the moment of occurrence and (iv) indirectly, encourage the clinician dealing with these cases to go further in their diagnosis. The authors consider that categorizing ocular and adnexal congenital disorders could help the clinician to deal with them. The categorization of these disorders required an intense review of cases previously reported in literature and allows the authors suspect that some of them could not have been accurately diagnosed according to the definitions of the anomalies and/or not accurately described. The authors consider that ocular and adnexal congenital disorders could have been underestimated in reptiles and further studies could be helpful to promote the description of new disorders and to expand the knowledge about those previously reported. The review will first describe abnormalities reported during organogenesis (describing possible etiopathogenesis, cases reported, an approach to their diagnosis and recommended therapeutic options).Then a mention of the ocular disorders occurring after organogenesis is made. These disorders are divided when possible in those affecting all or most part of the globe and those affecting only specific tissues (surface ectoderm, neurocrest and mesenchyma and neuroectoderm). PMID- 22548868 TI - Effectiveness of hand hygiene and provision of information in preventing influenza cases requiring hospitalization. AB - BACKGROUND: The objective of the study was to investigate the effectiveness of non-pharmacological interventions in preventing cases of influenza requiring hospitalization. METHODS: We performed a multicenter case-control study in 36 hospitals, in 2010 in Spain. Hospitalized influenza cases confirmed by reverse transcription polymerase chain reaction and three matched controls (two hospital and one community control) per case were selected. The use of non-pharmacological measures seven days before the onset of symptoms (frequency of hand washing, use of alcohol-based hand sanitizers and handwashing after touching contaminated surfaces) was collected. RESULTS: We studied 813 cases hospitalized for influenza and 2274 controls. The frequency of hand washing 5-10 times (adjusted odds ratio [aOR]=0.65) and >10 times (aOR=0.59) and handwashing after contact with contaminated surfaces (aOR=0.65) were protective factors and were dose-responsive (p<0.001). Alcohol-based hand sanitizers were associated with marginal benefits (aOR=0.82). CONCLUSIONS: Frequent handwashing should be recommended to prevent influenza cases requiring hospitalization. PMID- 22548875 TI - Enhanced photocatalysis by coupling of anatase TiO2 film to triangular Ag nanoparticle island. AB - In order to overcome the low utilization ratio of solar light and high electron hole pair recombination rate of TiO2, the triangular Ag nanoparticle island is covered on the surface of the TiO2 thin film. Enhancement of the photocatalytic activity of the Ag/TiO2 nanocomposite system is observed. The increase of electron-hole pair generation is caused by the enhanced near-field amplitudes of localized surface plasmon of the Ag nanoparticles. The efficiently suppressed recombination of electron-hole pair caused by the metal-semiconductor contact can also enhance the photocatalytic activity of the TiO2 film. PMID- 22548876 TI - Adrenal insufficiency following spinal cord injury: an underrecognized cause of hemodynamic instability? PMID- 22548877 TI - Metal-on-metal lumbar total disc arthroplasty: ready for prime time? PMID- 22548878 TI - The challenge of managing type II odontoid fractures. PMID- 22548879 TI - Suprasellar cysts. PMID- 22548880 TI - The contributions of an Ottoman Empire polyglot to spinal anatomy: an interesting historical insight into a little known period in the history of neurosurgery. PMID- 22548881 TI - Neurocysticercosis: is medical management innocuous? PMID- 22548882 TI - Endovascular deconstruction of the carotid artery: is there a role in the era of flow diversion? PMID- 22548883 TI - Angiogenesis detection in cerebral arteriovenous malformations: mediators and gene expression, and treatment hopes for the future. PMID- 22548885 TI - Development of neurological symptoms in patients with asymptomatic cerebral cysticercosis undergoing albendazol therapy for intestinal parasites. PMID- 22548884 TI - Atlantoaxial stabilization: a minimally invasive alternative. PMID- 22548886 TI - When do unruptured aneurysms deserve treatment based on natural history? Data and outcomes from the National Inpatient Sample database. PMID- 22548887 TI - Cavernous malformations of the thalamus: a relatively rare but controversial entity. PMID- 22548888 TI - Type II odontoid fractures: what to do? PMID- 22548889 TI - Intracranial dural arteriovenous fistulas: a treatment paradigm in flux. PMID- 22548890 TI - Historic background of spinal disorders. PMID- 22548891 TI - A critical analysis of the literature review in "Stereotactic radiosurgery for trigeminal pain secondary to benign skull base tumors" by Tanaka et al. and presentation of an algorithm for management of these tumors. PMID- 22548892 TI - The association between childhood maltreatment subtypes and current suicide risk among homeless men and women. AB - This study explored self-reports of five childhood maltreatment (CM) subtypes and their associations with current suicide risk in a sample of 500 homeless persons. Participants completed the Childhood Trauma Questionnaire and the Mini International Neuropsychiatric Interview. Individual, unique, and cumulative associations of CM subtypes and subtype combinations with suicide risk (no vs. low vs. moderate/high) were examined. In multivariate analyses, four of the five CM subtypes were associated with suicide risk in individual models, but not in a model that included all CM subtypes. The strongest associations were found for reports of multitype CM involving all five subtypes. Mental disorders and female sex were independently associated with suicide risk. Clinicians working with CM victims should be aware that homeless clients are likely to report multitype maltreatment and should assess a variety of CM experiences. Future studies need to further examine multitype maltreatment and suicidal behaviors in homeless populations with complex conditions. PMID- 22548893 TI - Childhood maltreatment among Hispanic women in the United States: an examination of subgroup differences and impact on psychiatric disorder. AB - Prevalence rates of childhood maltreatment among Hispanic women in the United States are presented separately for nativity status and ethnic origin subgroups, and the associations between different types of maltreatment and the development of anxiety and depressive disorders are examined. Analyses used self-report data from 1,427 Hispanic women who participated in the National Latino and Asian American Survey. Foreign-born Hispanic women compared to U.S.-born Hispanic women reported significantly lower rates of sexual assault and witnessing interpersonal violence, and a significantly higher rate of being beaten. Ethnic subgroups reported similar rates of maltreatment, with the exception of rape. Bivariate analyses were remarkably consistent in that regardless of nativity status or ethnic subgroup, each type of maltreatment experience increased the risk of psychiatric disorder. In multivariate models controlling for all types of victimization and proxies of acculturation, having been beaten and witnessing interpersonal violence remained significant predictors of both disorders, but sexual abuse increased risk of anxiety only. A significant interaction effect of family cultural conflict and witnessing violence on anxiety provided very limited support for the hypothesis that acculturation moderates the influence of maltreatment on mental health outcomes. Implications for culturally relevant prevention and intervention approaches are presented. PMID- 22548894 TI - A novel unbalanced de novo translocation der(5)t(4;5)(q26;q21.1) in adult T-cell precursor lymphoblastic leukemia. AB - We here describe a novel unbalanced de novo translocation der(5)t(4;5)(q26;q21.1) in a 39-year-old male diagnosed with acute T-cell lymphoblastic leukemia. Bone marrow (BM) was massively infiltrated with 85 % highly proliferative polymorphic T-cell precursors. Immunologically, the malignant cells stained positive for CD7, CD34, intracytoplasmic CD3+, TdT + and negative for CD3 and CD5. G-banded chromosome analysis of BM cells showed the normal karyotype 46,XY[25] whereas BAC-based aCGH analysis revealed partial gain of 4q and partial loss of 5q. Multicolor karyotyping confirmed the presence of an unbalanced der(5)t(4;5) as the sole structural abnormality. Subsequent high resolution oligonucleotide-based aCGH analysis showed that the der(5)t(4;5)(q26;q21.1) resulted in partial trisomy of 4q26qter (117,719,015 190,613,014) and partial monosomy of 5q21.1qter (100,425,442-180,857,866) and that there was no indication of any gene disruptions resulting from the breakages. Interphase FISH analysis using BAC-based specific probes for 4q26 and 5q21.1 confirmed the breakpoints and revealed approximately 80 % abnormal cells accordingly. At 4q26 the MIR1973 gene is located centromeric to the breakpoint in the copy number neutral region and the TRAM1L1 gene is located within the gained region. At 5q21.1 the genes ST8SIA4 and MIR548p are located centromeric to the breakpoint and no known genes up to approximately 1 Mb telomeric to the breakpoint in the copy number loss region. Interestingly, only the gene ST8SIA4 at 5q21.1 have been implicated in T-cell regulation as it encodes one of the key enzymes for polysialysation of surface proteins on dendritic cells which are important regulators for T-cell proliferation. The der(5)t(4;5) is thought to play a crucial role in the pathogenesis of acute T-ALL due to either gain of 4q, the loss of 5q, or deregulation of genes in proximity to the breakpoints. PMID- 22548896 TI - Neurocognitive functioning in patients recently diagnosed with bipolar disorder. AB - OBJECTIVES: Cognitive dysfunction in bipolar disorder (BD) is well established in the literature; however, there are few studies of neurocognition in patients early in the course of the illness. In this study we compare neurocognitive function in a cohort of first-contact mania patients with a healthy control group matched for age, gender, and education. METHODS: Patients with a first manic episode (FM) (n = 34) or previous untreated manic episodes (PM) (n = 21) were neuropsychologically tested following their first treated manic episode. A total of 110 matched healthy control comparison subjects were also tested. The following cognitive domains were evaluated: verbal and visual learning and memory, attention, processing speed, executive functioning, and IQ. Results were corrected for speed of processing differences and were compared with previously reported results for multiple-episode BD patients. RESULTS: BD patients early in their disease course showed impairments in psychomotor speed, attention, learning and memory, executive functioning, and IQ. When controlling for speed of processing, measures of visuoconstructive reasoning and motor dexterity remained statistically significant. Eighteen percent of FM and 16% of PM patients were found to have clinically significant neurocognitive impairment. No significant relationship between clinical symptoms and neurocognition was found. The first contact mania patients studied were found to have smaller neurocognitive deficits compared to multiple-episode patients in previous studies. CONCLUSIONS: Neurocognitive dysfunction is present in early BD and is clinically significant for a proportion of patients. Our findings also suggest that neurocognitive dysfunction may increase with illness progression. PMID- 22548895 TI - Meta-analysis of the association between cognitive abilities and everyday functioning in bipolar disorder. AB - OBJECTIVES: Neurocognitive deficits are common in bipolar disorder and contribute to functional disability. However, the degree to which general and specific cognitive deficits affect everyday functioning in bipolar disorder is unknown. The goal of this meta-analysis was to examine the magnitude of the effect of specific neurocognitive abilities on everyday functioning in bipolar disorder. METHODS: We conducted a comprehensive meta-analysis of studies that reported associations between performance on objective neuropsychological tasks and everyday functioning among individuals with bipolar disorder. From an initial pool of 486 papers, 22 studies met inclusion criteria, comprising a total of 1344 participants. Correlation coefficients were calculated for 11 cognitive domains and four measurement modalities for functioning. We also examined effect moderators, such as sample age, clinical state, and study design. RESULTS: The mean Pearson correlation between neurocognitive ability and functioning was 0.27, and was significant for all cognitive domains and varied little by cognitive domain. Correlations varied by methods of everyday functioning assessment, being lower for clinician and self-report than performance-based tasks and real-world milestones such as employment. None of the moderator analyses were significant. CONCLUSIONS: Overall, the strength of association between cognitive ability and everyday functioning in bipolar disorder is strikingly similar to that seen in schizophrenia, with little evidence for differences across cognitive domains. The strength of association differed to a greater extent according to functional measurement approach. PMID- 22548897 TI - Cross-diagnostic comparison of duration mismatch negativity and P3a in bipolar disorder and schizophrenia. AB - OBJECTIVES: Bipolar disorder and schizophrenia share common pathophysiological processes and may have similar perceptual abnormalities. Mismatch negativity (MMN) and P3a - event-related potentials associated with auditory preattentional processing - have been extensively studied in schizophrenia, but rarely in bipolar disorder. Furthermore, MMN and P3a have not been examined between diagnostic subgroups of patients with bipolar disorder. We evaluated MMN and P3a in patients with bipolar disorder compared to patients with schizophrenia and healthy controls. METHODS: MMN and P3a were assessed in 52 bipolar disorder patients, 30 schizophrenia patients, and 27 healthy control subjects during a duration-deviant auditory oddball paradigm. RESULTS: Significant MMN and P3a amplitude reductions were present in patients with bipolar disorder and schizophrenia relative to controls. The MMN reduction was more prominent in patients with schizophrenia than bipolar disorder, at a trend level. P3a did not differ significantly between patient groups. There were no MMN or P3a differences between patients with bipolar I (n = 34) and bipolar II (n = 18) disorder. Patients with bipolar I disorder failed to show lateralized MMN, in contrast to the other groups. No MMN or P3a differences were found between patients with bipolar disorder taking (n = 12) and not taking (n = 40) lithium, as well as between those taking (n = 30) and not taking (n = 22) antipsychotic medications. CONCLUSIONS: Patients with bipolar disorder showed deficits in preattentive auditory processing, including MMN deficits that are less severe and P3a deficits that are slightly more pronounced, than those seen in schizophrenia. PMID- 22548898 TI - Waiting to win: elevated striatal and orbitofrontal cortical activity during reward anticipation in euthymic bipolar disorder adults. AB - OBJECTIVE: Bipolar disorder may be characterized by a hypersensitivity to reward relevant stimuli, potentially underlying the emotional lability and dysregulation that characterizes the illness. In parallel, research highlights the predominant role of striatal and orbitofrontal cortical (OFC) regions in reward-processing and approach-related affect. We aimed to examine whether bipolar disorder, relative to healthy, participants displayed elevated activity in these regions during reward processing. METHODS: Twenty-one euthymic bipolar I disorder and 20 healthy control participants with no lifetime history of psychiatric disorder underwent functional magnetic resonance imaging (fMRI) scanning during a card guessing paradigm designed to examine reward-related brain function to anticipation and receipt of monetary reward and loss. Data were collected using a 3T Siemens Trio scanner. RESULTS: Region-of-interest analyses revealed that bipolar disorder participants displayed greater ventral striatal and right-sided orbitofrontal [Brodmann area (BA) 11] activity during anticipation, but not outcome, of monetary reward relative to healthy controls (p < 0.05, corrected). Whole-brain analyses indicated that bipolar disorder, relative to healthy, participants also displayed elevated left-lateral OFC (BA 47) activity during reward anticipation (p < 0.05, corrected). CONCLUSIONS: Elevated ventral striatal and OFC activity during reward anticipation may represent a neural mechanism for predisposition to expansive mood and hypo/mania in response to reward-relevant cues that characterizes bipolar disorder. Our findings contrast with research reporting blunted activity in the ventral striatum during reward processing in unipolar depressed individuals, relative to healthy controls. Examination of reward-related neural activity in bipolar disorder is a promising research focus to facilitate identification of biological markers of the illness. PMID- 22548899 TI - Hippocampal volumes in bipolar disorders: opposing effects of illness burden and lithium treatment. AB - OBJECTIVE: Hippocampal volume decrease associated with illness burden is among the most replicated findings in unipolar depression. The absence of hippocampal volume changes in most studies of individuals with bipolar disorder (BD) may reflect neuroprotective effects of lithium (Li). METHODS: We recruited 17 BD patients from specialized Li clinics, with at least two years of regularly monitored Li treatment (Li group), and compared them to 12 BD participants with < 3 months of lifetime Li exposure and no Li treatment within two years prior to the scanning (non-Li group) and 11 healthy controls. All BD patients had at least 10 years of illness and five episodes. We also recruited 13 Li-naive, young BD participants (15-30 years of age) and 18 sex- and age-matched healthy controls. We compared hippocampal volumes obtained from 1.5-T magnetic resonance imaging (MRI) scans using optimized voxel-based morphometry with small volume correction. RESULTS: The non-Li group had smaller left hippocampal volumes than controls (corrected p < 0.05), with a trend for lower volumes than the Li group (corrected p < 0.1), which did not differ from controls. Young, Li-naive BD patients close to the typical age of onset had comparable hippocampal volumes to controls. CONCLUSIONS: Whereas patients with limited lifetime Li exposure had significantly lower hippocampal volumes than controls, patients with comparable illness burden, but with over two years of Li treatment, or young Li-naive BD patients, showed hippocampal volumes comparable to controls. These results provide indirect support for neuroprotective effects of Li and negative effects of illness burden on hippocampal volumes in bipolar disorders. PMID- 22548900 TI - Depression in bipolar disorder versus major depressive disorder: results from the National Epidemiologic Survey on Alcohol and Related Conditions. AB - OBJECTIVES: To compare the clinical features and course of major depressive episodes (MDEs) occurring in subjects with bipolar I disorder (BD-I), bipolar II disorder (BD-II), and major depressive disorder (MDD). METHODS: Data were drawn from the National Epidemiologic Survey on Alcohol and Related Conditions (2001 2002), a nationally representative face-to-face survey of more than 43000 adults in the USA, including 5695 subjects with lifetime MDD, 935 with BD-I and lifetime MDE, and 494 with BD-II and lifetime MDE. Differences on sociodemographic characteristics and clinical features, course, and treatment patterns of MDE were analyzed. RESULTS: Most depressive symptoms, family psychiatric history, anxiety disorders, alcohol and drug use disorders, and personality disorders were more frequent-and number of depressive symptoms per MDE was higher-among subjects with BD-I, followed by BD-II, and MDD. BD-I individuals experienced a higher number of lifetime MDEs, had a poorer quality of life, and received significantly more treatment for MDE than BD-II and MDD subjects. Individuals with BD-I and BD-II experienced their first mood episode about ten years earlier than those with MDD (21.2, 20.5, and 30.4 years, respectively). CONCLUSIONS: Our results support the existence of a spectrum of severity of MDE, with highest severity for BD-I, followed by BD-II and MDD, suggesting the utility of dimensional assessments in current categorical classifications. PMID- 22548901 TI - Is bipolar disorder specifically associated with aggression? AB - OBJECTIVE: Several studies have suggested that bipolar disorder (BP) in adults is associated with aggressive behaviors. However, most studies have included only inpatients and have not taken into consideration possible confounding factors. The goal of the present study was to compare the prevalence of aggression in subjects with BP compared to subjects with other, non-BP psychopathology and healthy controls. METHODS: Subjects with bipolar I disorder (BP-I) and bipolar II disorder (BP-II) (n = 255), non-BP psychopathology (n = 85), and healthy controls (n = 84) were recruited. Aggression was measured using the Aggression Questionnaire (AQ). Group comparisons were adjusted for demographic and clinical differences (e.g., comorbid disorders) and multiple comparisons. The effects of the subtype of BP, current versus past episode, polarity of current episode, psychosis, the presence of irritable mania/hypomania only, and pharmacological treatment were examined. RESULTS: Subjects with BP showed significantly higher total and subscale AQ scores (raw and T-scores) when compared to subjects with non-BP psychopathology and healthy controls. Exclusion of subjects with current mood episodes and those with common comorbid disorders yielded similar results. There were no effects of BP subtype, polarity of the current episode, irritable manic/hypomanic episodes only, or current use of pharmacological treatments. Independent of the severity of BP and polarity of the episode, those in a current mood episode showed significantly higher AQ scores than those not in a current mood episode. Subjects with current psychosis showed significantly higher total AQ score, hostility, and anger than those without current psychosis. CONCLUSIONS: Subjects with BP display greater rates of anger and aggressive behaviors, especially during acute and psychotic episodes. Early identification and management of these behaviors is warranted. PMID- 22548903 TI - Platelet uptake of GABA and glutamate in patients with bipolar disorder. AB - OBJECTIVES: Gamma aminobutyric acid (GABA) and glutamate (Glu) are the major neurotransmitters of the human central nervous system, and their actions are determined by specific transporters. Several studies suggest that GABA- and Glu uptake mechanisms are modified in patients with bipolar disorder (BD). We explored the functionality of the GABA and Glu transporters in three groups of patients with BD, each with a different polarity of index episode (manic, depressive, or euthymic) at the time of blood draw. METHODS: Forty patients with a diagnosis of BD, according to DSM-IV-TR criteria, and 15 healthy subjects were enrolled in the study. GABA and Glu uptake were evaluated in freshly prepared platelets using [(3) H]GABA or [(3) H]glutamate. RESULTS: Compared to controls, GABA uptake was significantly increased in patients with depressive episodes and significantly decreased in subjects with manic episodes. Glu uptake was significantly increased in patients with index manic episodes and in euthymic patients compared to healthy controls. Moreover, a positive correlation was found between GABA platelet uptake and Hamilton Depression Rating Scale scores and between Glu platelet uptake and Young Mania Rating Scale scores in patients with manic episodes. CONCLUSIONS: We found a relationship between GABA- and Glu-uptake levels and the polarity of episodes in patients with BD. Our data suggest that the functionality of both GABA and Glu transporters could represent a useful neurobiological marker to characterize the real polarity of an index episode of illness in patients with BD. PMID- 22548902 TI - Six-month outcomes of customized adherence enhancement (CAE) therapy in bipolar disorder. AB - BACKGROUND: There are few psychosocial interventions specifically focused on improved treatment adherence in people with bipolar disorder (BD). Customized adherence enhancement (CAE) is a needs-based, manualized approach intended to improve medication adherence in individuals with BD. This was a six-month prospective trial of a CAE among 43 medication non-adherent individuals with BD who were receiving treatment in a community mental health clinic (CMHC). METHODS: CAE was flexibly administered in modules applied as indicated by an initial adherence vulnerabilities screening. Screening identified reasons for non adherence and modules were then administered using pre-set criteria. CAE effects were evaluated at six-week, three-month, and six-month follow-up. The six-month follow-up was our primary time point of interest. The primary outcome was change from baseline in adherence using the Tablets Routine Questionnaire (TRQ) and pill counts. Secondary outcomes included change from baseline in BD symptoms [Hamilton Depression Rating Scale (HAM-D), Young Mania Rating Scale (YMRS), and Brief Psychiatric Rating Scale (BPRS)]. RESULTS: Subjects completed 86% of scheduled sessions, with only two individuals (5%) not participating in any sessions. The number of dropouts at six months was 12 (28%). Mean baseline non-adherence by TRQ was 48% [standard error (SE) 4.8%] missed tablets within the previous week and 51% (4.1%) missed tablets within the previous month. At six-month follow-up, mean TRQ non-adherence improved to 25% (6.8%) missed tablets for the previous week (p = 0.002) and 21% (5.5%) for the previous month (p < 0.001). Symptoms improved, with a change in the baseline mean (SE) BPRS of 43.6 (1.8) versus an endpoint of 36.1 (2.3) (p = 0.001), and baseline mean (SE) HAM-D of 17.8 (1.1) versus an endpoint of 15.3 (1.6) (p = 0.044). CONCLUSION: CAE was associated with improvements in adherence, symptoms, and functional status. Controlled trials are needed to confirm these preliminary findings. PMID- 22548904 TI - Neurosyphilis presenting as mania. AB - OBJECTIVE: General paresis of the insane is a late and severe form of neurosyphilis characterized by nonspecific neuropsychiatric symptoms. There are a limited number of case reports of mood disorders presenting in neurosyphilis, with depressive illness being the most common. METHODS: We performed a literature review of case reports of secondary bipolar disorder induced by syphilitic infection. RESULTS: Herein reported is a case of a 53-year-old woman who initially presented with symptoms of mania and depression, mimicking bipolar disorder, but was subsequently diagnosed with general paresis of the insane. CONCLUSION: The present case report emphasizes that if a substantial delay occurs in syphilis diagnosis and management, the patient may have a very poor prognosis. PMID- 22548905 TI - Measuring the construct of executive control in schizophrenia: defining and validating translational animal paradigms for discovery research. AB - Executive control is an aspect of cognitive function known to be impaired in schizophrenia. Previous meetings of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) group have more precisely defined executive control in terms of two constructs: "rule generation and selection", and "dynamic adjustments of control". Next, human cognitive tasks that may effectively measure performance with regard to these constructs were identified to be developed into practical and reliable measures for use in treatment development. The aim of this round of CNTRICS meetings was to define animal paradigms that have sufficient promise to warrant further investigation for their utility in measuring these constructs. Accordingly, "reversal learning" and the "attentional set-shifting task" were nominated to assess the construct of rule generation and selection, and the "stop signal task" for the construct of dynamic adjustments of control. These tasks are described in more detail here, with a particular focus on their utility for drug discovery efforts. Presently, each assay has strengths and weaknesses with regard to this point and increased emphasis on improving practical aspects of testing, understanding predictive validity, and defining biomarkers of performance represent important objectives in attaining confidence in translational validity here. PMID- 22548906 TI - Studies raise questions about pavement sealers. PMID- 22548907 TI - Improved surgical safety after laparoscopic compared to open surgery for apparent early stage endometrial cancer: results from a randomised controlled trial. AB - AIM: To compare Total Laparoscopic Hysterectomy (TLH) and Total Abdominal Hysterectomy (TAH) with regard to surgical safety. METHODS: Between October 2005 and June 2010, 760 patients with apparent early stage endometrial cancer were enroled in a multicentre, randomised clinical trial (LACE) comparing outcomes following TLH or TAH. The main study end points for this analysis were surgical adverse events (AE), hospital length of stay, conversion from laparoscopy to laparotomy, including 753 patients who completed at least 6 weeks of follow-up. Postoperative AEs were graded according to Common Toxicity Criteria (V3), and those immediately life-threatening, requiring inpatient hospitalisation or prolonged hospitalisation, or resulting in persistent or significant disability/incapacity were regarded as serious AEs. RESULTS: The incidence of intra-operative AEs was comparable in either group. The incidence of post operative AE CTC grade 3+ (18.6% in TAH, 12.9% in TLH, p 0.03) and serious AE (14.3% in TAH, 8.2% in TLH, p 0.007) was significantly higher in the TAH group compared to the TLH group. Mean operating time was 132 and 107 min, and median length of hospital stay was 2 and 5 days in the TLH and TAH group, respectively (p<0.0001). The decline of haemoglobin from baseline to day 1 postoperatively was 2g/L less in the TLH group (p 0.006). CONCLUSIONS: Compared to TAH, TLH is associated with a significantly decreased risk of major surgical AEs. A laparoscopic surgical approach to early stage endometrial cancer is safe. PMID- 22548908 TI - Categorized or continuous? Strength of an association and linear regression. PMID- 22548909 TI - Leucine: a nutrient 'trigger' for muscle anabolism, but what more? PMID- 22548910 TI - Rafting for gallstones by slowing mass transit. PMID- 22548911 TI - Assessment of a four hour delay for urine samples stored without preservatives at room temperature for urinalysis. AB - OBJECTIVES: To determine whether urine storage at room temperature for up to 2h versus 4h changes urinalysis results. DESIGN AND METHODS: We compared the rejection rate at eight different hospital laboratories and concordance of urinalysis results (n=83; two laboratories) between urines analyzed within 2h and 4h after collection. RESULTS: The rejection rate at the two hour cutoff was significantly higher as compared to the four hour cutoff. The concordance between urinalysis results was 97-100% between the two and four hour analyses. CONCLUSION: Urine may be stored for up to 4h at room temperature without significant changes to the urinalysis results. PMID- 22548912 TI - Lipid fingerprinting in women with early-onset preeclampsia: a first look. AB - OBJECTIVES: The aim of this preliminary study was to characterize the plasma lipid profiling of women with preeclampsia. DESIGN AND METHODS: Plasma samples of 8 pregnant women with early-onset preeclampsia and 8 normal pregnant women were evaluated. Lipids were extracted from plasma using the Bligh-Dyer protocol. The extracts were subjected to MALDI-MS. Data matrix was exported for partial least squares discriminant analysis (PLS-DA) and a parameter VIP was employed to reflect the variable importance in the discriminant analysis. The major discriminant variables were selected and underwent to Mann-Whitney U test. RESULTS: A total of 1290 ions were initially identified and twelve m/z signals were highlighted as the most important lipids for the discrimination of patients with preeclampsia. The identification of these differential lipids was carried out through Lipid Database Search. CONCLUSIONS: The main classes identified were glycerophosphocholines [GP01], glycerophosphoserines [GP03], glycerophosphoglycerols [GP04], glycosyldiradylglycerols [GL05] and glycerophosphates [GP10]. PMID- 22548914 TI - Age-related changes in calbindin and calretinin immunoreactivity in the central auditory system of the rat. AB - Age-related changes in the levels of major intracellular calcium buffers are known to occur in different parts of the mammalian brain, including the central auditory pathway. In the present study, we evaluate with immunohistochemistry and the western blot technique the effect that aging has on the calbindin- and calretinin-expressing system of neurons in the higher structures of the central auditory pathway, in the inferior colliculus (IC), medial geniculate body (MGB) and auditory cortex (AC) of two rat strains, the slowly aging Long-Evans and the fast aging Fischer 344. Interestingly, the age-related changes demonstrated a similar character regardless of the rat strain. In the IC of young animals, the majority of calbindin and calretinin immuno-reactive (CB and CR-ir) cells were found in the dorsal and external cortices and only sparse positive cells were present in the central nucleus of the IC. With aging, the number of CB-ir and CR ir neurons decreased significantly in both the dorsal and external cortices. Furthermore, these declines were accompanied by an age-related reduction in the mean volumes of CB- and CR-ir neuronal somas. In the MGB of young rats, CB-ir neurons were present in abundant numbers in both the dorsal and ventral subdivisions, while CR-ir neurons were practically absent in this structure. With aging, the number and mean volume of CB-ir cells in the ventral subdivision of the MGB were significantly decreased. In comparison with the IC and MGB, age related numerical and volumetric declines of both CB-ir and CR-ir neurons in the AC were less pronounced. Western blot protein analysis revealed a pronounced age related decline in the levels of calbindin in both strains and in all examined brain regions. In contrast, the decline in calretinin levels with aging was less prominent, with a significant decline only in the IC of both strains. The observed age-related changes in the calbindin- and calretinin-expressing systems may contribute significantly to the deterioration of hearing function known as central presbycusis. PMID- 22548915 TI - The importance of intima-media thickness (IMT) measurements in monitoring of atherosclerosis progress after myocardial infarction. AB - PURPOSE: Intima-media thickness (IMT) assessed in peripheral arteries correlates with presence and progression of atherosclerosis in coronary arteries. IMT measurements may help to select high risk patients and evaluate the efficacy of the therapy used. AIM: The aim of the study was to assess the usefulness of ultrasonographic measurement of IMT in atherosclerosis progress monitoring in patients after myocardial infarction (MI). PATIENTS AND METHODS: 70 men (mean age 52.8 +/- 8.4) treated with PCI due to acute myocardial infarction, were enrolled in the study. All subjects underwent ultrasound examination of the IMT complex of: common carotid artery (CCA), carotid bulb and common femoral artery (CFA) during hospitalization and follow-up period (3.83 +/- 1.29 years). RESULTS: During the follow-up 3 patients (4.3%) were not on any medications, 8 pts (11.4%) were on reduced doses of beta-blocker, statin or ACE-I (non-compliant pts.). The others (compliant) - 59 pts (84.3%) received standard pharmacological treatment after MI. Nevertheless, an increase of IMT complex value after follow-up compared to initial IMT values of all examined peripheral arteries was observed (respectively: IMT CCA - 0.91 +/- 0.26 vs 1.10 +/- 0.36, p=0.002, IMT of carotid bulb - 1.31 +/- 0.55 vs 1.82 +/- 0.69, p=0.012, IMT CFA - 1.38 +/- 0.64 vs 1.97 +/- 0.75, p=0.014). Non-compliant patients had statistically significant higher IMT values after follow-up when compared to compliant subjects (1.62 vs 1.20, p= 0.017). Patients with higher IMT values were reported to have cardiac events more frequently during the follow-up (p<0.05). CONCLUSIONS: Our results provide evidence that ultrasonographic IMT complex assessment of peripheral arteries in everyday clinical practice allows monitoring efficacy of pharmacological therapy in CAD patients after MI. They also suggest treatment intensification if necessary. PMID- 22548913 TI - Age-related defects in TLR2 signaling diminish the cytokine response by alveolar macrophages during murine pneumococcal pneumonia. AB - Alveolar macrophages (AMs) are the first immune cells to respond to an invading pathogen and coordinate the inflammatory response within the lungs. Studies suggest that macrophages exhibit age-related deficiencies in Toll-like receptor (TLR) function; however, the impact of this dysfunction during pneumonia, the leading cause of infectious death in the elderly, and the underlying mechanisms responsible remain unclear. We examined disease severity in young, mature, and aged BALB/cBy mice following intratracheal infection with the Gram-positive bacteria Streptococcus pneumoniae (Spn). Both mature and aged mice failed to clear bacteria and as a result had increased mortality, tissue damage and vascular leakage. Early production of TNFalpha, IL-1beta, and IL-6 during pneumonia declined with age and was associated with an inability of isolated AMs to respond to pneumococcal cell wall (CW) and ethanol-killed Spn ex vivo. Total levels of TLR1 were unaffected by age and TLR2 surface expression was slightly yet significantly increased on aged AMs suggesting that intracellular TLR signaling defects were responsible for the age-related decline in cytokine responsiveness. Following infection of isolated AMs with live Spn, a significant age-related decline in TLR2-induced phosphorylation of p65 NFkappaB, JNK and p38 MAPK, and an increase in ERK phosphorylation was observed by immunoblotting. These data are the first to demonstrate that TLR2-dependent recognition of Spn by aged AMs is impaired and is associated with a delayed pro-inflammatory cytokine response in vivo along with enhanced susceptibility to pneumococcal pneumonia. PMID- 22548916 TI - The neural background of hyper-emotional aggression induced by post-weaning social isolation. AB - Post-weaning social isolation in rats is believed to model symptoms of early social neglect-induced externalizing problems including aggression-related problems. We showed earlier that rats reared in social isolation were hyper aroused during aggressive contacts, delivered substantially more attacks that were poorly signaled and were preferentially aimed at vulnerable body parts of opponents (head, throat and belly). Here we studied the neural background of this type of aggression by assessing the expression of the activation marker c-Fos in 22 brain areas of male Wistar rats submitted to resident-intruder conflicts. Post weaning social isolation readily produced the behavioral alterations noticed earlier. Social isolation significantly increased the activation of brain areas that are known to directly or indirectly control inter-male aggression. Particularly, the medial and lateral orbitofrontal cortices, anterior cingulate cortex, bed nucleus of the stria terminalis, medial and basolateral amygdala, hypothalamic attack area, hypothalamic paraventricular nucleus and locus coeruleus showed increased activations. This contrasts our earlier findings obtained in rats with experimentally induced hypoarousal, where abnormal attack patterns were associated with over-activated central amygdala, lateral hypothalamus, and ventrolateral periaqueductal gray that are believed to control predatory attacks. We have observed no similar activation patterns in rats socially isolated from weaning. In summary, these findings suggest that despite some phenotypic similarities, the neuronal background of hypo and hyperarousal associated abnormal forms of aggression are markedly different. While the neuronal activation patterns induced by normal rivalry and hypoarousal-driven aggression are qualitative different, hyperarousal-associated aggression appears to be an exaggerated form of rivalry aggression. PMID- 22548917 TI - Flow-evoked vasodilation is blunted in penile arteries from Zucker diabetic fatty rats. AB - INTRODUCTION: Endothelium-derived relaxing factors such as nitric oxide (NO), prostanoids, and endothelium-derived hyperpolarizing factor (EDHF) are thought to play an important role in vasodilation of penile arteries. AIM: The present study investigated the mechanisms involved in flow- and acetylcholine-induced vasodilation in penile arteries, and whether acetylcholine- and flow-mediated vasodilation is altered in Zucker diabetic fatty (ZDF) rats, a model of type 2 diabetes. Moreover, it was addressed whether enhanced myogenic tone may explain impaired flow-evoked vasodilation in arteries from ZDF rats. METHODS: Penile dorsal arteries obtained from lean control and ZDF rats were suspended in a pressure myograph, and flow- and acetylcholine-evoked vasodilation was measured as changes in arterial diameter. MAIN OUTCOME MEASURE: Changes in penile arterial diameter. RESULTS: Incubation with an inhibitor of NO synthase, asymmetric dimethyl-L-arginine (ADMA), and of cyclooxygenase, indomethacin, reduced acetylcholine but not flow-evoked vasodilation in penile arteries, while both responses were abolished by endothelial cell removal. Iberiotoxin, a blocker of large-conductance calcium-activated K+ (BK(Ca) ) channels, inhibited flow-evoked vasodilation. Flow-evoked vasodilation was reduced in arteries from ZDF rats in the absence, but not in the presence, of indomethacin plus ADMA. Elevation of intraluminal pressure increased myogenic tone, which was reduced in arteries from ZDF rats. CONCLUSION: The present findings show that flow evokes endothelium dependent EDHF-type vasodilation involving BK(Ca) channels in penile arteries. Flow-evoked vasodilation is reduced and only of EDHF-type in penile arteries from type 2 diabetic rats suggesting modulation of this pathway may restore endothelial function and preserve erection in diabetes. PMID- 22548918 TI - Accelerated maximum likelihood parameter estimation for stochastic biochemical systems. AB - BACKGROUND: A prerequisite for the mechanistic simulation of a biochemical system is detailed knowledge of its kinetic parameters. Despite recent experimental advances, the estimation of unknown parameter values from observed data is still a bottleneck for obtaining accurate simulation results. Many methods exist for parameter estimation in deterministic biochemical systems; methods for discrete stochastic systems are less well developed. Given the probabilistic nature of stochastic biochemical models, a natural approach is to choose parameter values that maximize the probability of the observed data with respect to the unknown parameters, a.k.a. the maximum likelihood parameter estimates (MLEs). MLE computation for all but the simplest models requires the simulation of many system trajectories that are consistent with experimental data. For models with unknown parameters, this presents a computational challenge, as the generation of consistent trajectories can be an extremely rare occurrence. RESULTS: We have developed Monte Carlo Expectation-Maximization with Modified Cross-Entropy Method (MCEM(2)): an accelerated method for calculating MLEs that combines advances in rare event simulation with a computationally efficient version of the Monte Carlo expectation-maximization (MCEM) algorithm. Our method requires no prior knowledge regarding parameter values, and it automatically provides a multivariate parameter uncertainty estimate. We applied the method to five stochastic systems of increasing complexity, progressing from an analytically tractable pure-birth model to a computationally demanding model of yeast-polarization. Our results demonstrate that MCEM(2) substantially accelerates MLE computation on all tested models when compared to a stand-alone version of MCEM. Additionally, we show how our method identifies parameter values for certain classes of models more accurately than two recently proposed computationally efficient methods. CONCLUSIONS: This work provides a novel, accelerated version of a likelihood based parameter estimation method that can be readily applied to stochastic biochemical systems. In addition, our results suggest opportunities for added efficiency improvements that will further enhance our ability to mechanistically simulate biological processes. PMID- 22548920 TI - Prospective analysis of human cytomegalovirus DNAemia and specific CD8+ T cell responses in lung transplant recipients. AB - In lung transplant recipients (LuTRs), human cytomegalovirus (HCMV) DNAemia may be associated with HCMV disease and reduced survival of the allograft. Because T cells are essential for controlling HCMV replication, we investigated in this prospective study whether the kinetics of plasma HCMV DNA loads in LuTRs are associated with HCMV-specific CD8+ T cell responses, which were longitudinally assessed using a standardized assay. Sixty-seven LuTRs were monitored during the first year posttransplantation, with a mean of 17 HCMV DNA PCR quantifications and 11.5 CD8+ T cell tests performed per patient. HCMV-specific CD8+ T cell responses displayed variable kinetics in different patients, differed significantly before the onset of HCMV DNAemia in LuTRs who subsequently experienced episodes of DNAemia with high (>1000 copies/mL) and low plasma DNA levels (p = 0.0046, Fisher's exact test), and were absent before HCMV disease. In HCMV-seropositive LuTRs, high-level DNAemia requiring preemptive therapy occurred more frequently when HCMV-specific CD8+ T cell responses fluctuated, were detected only after HCMV DNA detection, or remained undetectable (p = 0.0392, Fisher's exact test). Thus, our data indicate that HCMV-specific CD8+ T cells influence the magnitude of HCMV DNAemia episodes, and we propose that a standardized measurement of CD8+ T cell immunity might contribute to monitoring the immune status of LuTRs posttransplantation. PMID- 22548921 TI - Satellite-based estimates of ambient air pollution and global variations in childhood asthma prevalence. AB - BACKGROUND: The effect of ambient air pollution on global variations and trends in asthma prevalence is unclear. OBJECTIVES: Our goal was to investigate community-level associations between asthma prevalence data from the International Study of Asthma and Allergies in Childhood (ISAAC) and satellite based estimates of particulate matter with aerodynamic diameter < 2.5 um (PM2.5) and nitrogen dioxide (NO2), and modelled estimates of ozone. METHODS: We assigned satellite-based estimates of PM2.5 and NO2 at a spatial resolution of 0.1 degrees * 0.1 degrees and modeled estimates of ozone at a resolution of 1 degrees * 1 degrees to 183 ISAAC centers. We used center-level prevalence of severe asthma as the outcome and multilevel models to adjust for gross national income (GNI) and center- and country-level sex, climate, and population density. We examined associations (adjusting for GNI) between air pollution and asthma prevalence over time in centers with data from ISAAC Phase One (mid-1900s) and Phase Three (2001 2003). RESULTS: For the 13- to 14-year age group (128 centers in 28 countries), the estimated average within-country change in center-level asthma prevalence per 100 children per 10% increase in center-level PM2.5 and NO2 was -0.043 [95% confidence interval (CI): -0.139, 0.053] and 0.017 (95% CI: -0.030, 0.064) respectively. For ozone the estimated change in prevalence per parts per billion by volume was -0.116 (95% CI: -0.234, 0.001). Equivalent results for the 6- to 7 year age group (83 centers in 20 countries), though slightly different, were not significantly positive. For the 13- to 14-year age group, change in center-level asthma prevalence over time per 100 children per 10% increase in PM2.5 from Phase One to Phase Three was -0.139 (95% CI: -0.347, 0.068). The corresponding association with ozone (per ppbV) was -0.171 (95% CI: -0.275, -0.067). CONCLUSION: In contrast to reports from within-community studies of individuals exposed to traffic pollution, we did not find evidence of a positive association between ambient air pollution and asthma prevalence as measured at the community level. PMID- 22548922 TI - A comparison of survival outcomes and side effects of toremifene or tamoxifen therapy in premenopausal estrogen and progesterone receptor positive breast cancer patients: a retrospective cohort study. AB - BACKGROUND: In premenopausal women, endocrine adjuvant therapy for breast cancer primarily consists of tamoxifen alone or with ovarian suppressive strategies. Toremifene is a chlorinated derivative of tamoxifen, but with a superior risk benefit profile. In this retrospective study, we sought to establish the role of toremifene as an endocrine therapy for premenopausal patients with estrogen and/or progesterone receptor positive breast cancer besides tamoxifen. METHODS: Patients with early invasive breast cancer were selected from the breast tumor registries at the Sun Yat-Sen Memorial Hospital (China). Premenopausal patients with endocrine responsive breast cancer who underwent standard therapy and adjuvant therapy with toremifene or tamoxifen were considered eligible. Patients with breast sarcoma, carcinosarcoma, concurrent contralateral primary breast cancer, or with distant metastases at diagnosis, or those who had not undergone surgery and endocrine therapy were ineligible. Overall survival and recurrence free survival were the primary outcomes measured. Toxicity data was also collected and compared between the two groups. RESULTS: Of the 810 patients reviewed, 452 patients were analyzed in the study: 240 received tamoxifen and 212 received toremifene. The median and mean follow up times were 50.8 and 57.3 months, respectively. Toremifene and tamoxifen yielded similar overall survival values, with 5-year overall survival rates of 100% and 98.4%, respectively (p = 0.087). However, recurrence-free survival was significantly better in the toremifene group than in the tamoxifen group (p = 0.022). Multivariate analysis showed that recurrence-free survival improved independently with toremifene (HR = 0.385, 95% CI = 0.154-0.961; p = 0.041). Toxicity was similar in the two treatment groups with no women experiencing severe complications, other than hot flashes, which was more frequent in the toremifene patients (p = 0.049). No patients developed endometrial cancer. CONCLUSION: Toremifene may be a valid and safe alternative to tamoxifen in premenopausal women with endocrine-responsive breast cancer. PMID- 22548924 TI - Diffusion tensor and perfusion imaging of brain tumors in high-field MR imaging. AB - Diffusion tensor imaging (DTI) and perfusion-weighted imaging (PWI) are essential tools for diagnosing, differentiating, and monitoring brain tumors. High-field MRI provides higher signal-to-noise ratio, shorter scan time, and better image quality. One-stop multiparametric study, including DTI and PWI, is possible with high-field MRI in brain tumors. DTI can be used for assessing spatial relationship between major white matter tract and tumor, differentiating gliomas from nonglial tumors, and postoperative evaluation. PWI provides reliable biomarkers for glioma grading, therapeutic responses, and differential diagnosis of various brain tumors. With higher field strength, better-quality DTI and PWI can raise the diagnostic accuracy in brain tumors. PMID- 22548923 TI - A new analysis approach of epidermal growth factor receptor pathway activation patterns provides insights into cetuximab resistance mechanisms in head and neck cancer. AB - The pathways downstream of the epidermal growth factor receptor (EGFR) have often been implicated to play crucial roles in the development and progression of various cancer types. Different authors have proposed models in cell lines in which they study the modes of pathway activities after perturbation experiments. It is prudent to believe that a better understanding of these pathway activation patterns might lead to novel treatment concepts for cancer patients or at least allow a better stratification of patient collectives into different risk groups or into groups that might respond to different treatments. Traditionally, such analyses focused on the individual players of the pathways. More recently in the field of systems biology, a plethora of approaches that take a more holistic view on the signaling pathways and their downstream transcriptional targets has been developed. Fertig et al. have recently developed a new method to identify patterns and biological process activity from transcriptomics data, and they demonstrate the utility of this methodology to analyze gene expression activity downstream of the EGFR in head and neck squamous cell carcinoma to study cetuximab resistance. Please see related article: http://www.biomedcentral.com/1471-2164/13/160. PMID- 22548925 TI - Inflammation high-field magnetic resonance imaging. AB - Multiple sclerosis (MS) is the most common inflammatory demyelinating disorder of the central nervous system (CNS). MS has been subject to high-field magnetic resonance (MR) imaging research to a great extent during the past years, and much data has been collected that might be helpful in the investigation of other inflammatory CNS disorders. This article reviews the value of high-field MR imaging in examining inflammatory MS abnormalities. Furthermore, possibilities and challenges for the future of high-field MR imaging in MS are discussed. PMID- 22548926 TI - High-field imaging of neurodegenerative diseases. AB - High-field magnetic resonance (MR) imaging is showing potential for imaging of neurodegenerative diseases. 7 T MR imaging is beginning to be used in a clinical research setting and the theoretical benefits of higher signal-to-noise ratio, sensitivity to iron, improved MR angiography, and increased spectral resolution in spectroscopy are being confirmed. Despite the limited number of studies to date, initial results in patients with multiple sclerosis, Alzheimer disease, and Huntington disease show promising additional features in contrast that may help the diagnosis of these disorders. PMID- 22548927 TI - High-field magnetic resonance imaging for epilepsy. AB - Epileptogenic lesions are often subtle, do not change during life, and are easily overlooked, if spatial resolution and signal to noise ratio are inappropriate. 2D or more recently 3D-FLAIR sequences are best suited to detect small cortical dysplasias which are often located at the bottom of a sulcus. 3D-T1-weighted gradient echo sequences are used for multiplanar, curved surface reformations, and voxel-based analyses. 3 T MR imaging is currently the state-of-the-art imaging modality for patients with suspected structural epilepsies in which an epileptogenic lesion has not yet been found. PMID- 22548928 TI - Stroke: high-field magnetic resonance imaging. AB - Diagnostic modalities for the diagnosis of acute stroke have increased in number and quality. Magnetic resonance imaging has increasingly become a central tool for the management of patients with stroke. New sequences, such as diffusion and perfusion, provide insight into the infarcted core and the hypoperfused brain. The use of higher magnetic fields allows us to gain in signal strength, which can be used to improve imaging speed and/or resolution. Recent additional sequences allow perfusion without contrast and susceptibility-weighted imaging can help identify early bleeding. These new techniques should provide more information about the on going ischemic process. PMID- 22548929 TI - Vascular disorders--magnetic resonance angiography: brain vessels. AB - Magnetic resonance angiography (MRA) of the brain obtained at 3 T imaging has made a significant clinical impact. MRA benefits from acquisition at higher magnetic field strength because of higher available signal-to-noise ratio and improved relative background suppression due to magnetic field strength-related T1 lengthening. Parallel imaging techniques are ideally suited for high-field MRA. Many of the developments that have made 3 T MRA of the brain successful can be regarded as enabling technologies that are essential for further development of 7 T MRA, which brings additional challenges. PMID- 22548930 TI - Current state-of-the-art 1.5 T and 3 T extracranial carotid contrast-enhanced magnetic resonance angiography. AB - Recent advances in magnetic resonance (MR) hardware and software have improved the resolution and spatial coverage of head and neck first-pass contrast-enhanced (CE) MR angiography. Despite these improvements, high-quality submillimeter resolution 1.5 T and 3 T carotid CE MR angiography is not consistently available in the general radiology practice. This article reviews the important imaging parameters and potential pitfalls that affect carotid CE MR angiography image quality, and the dose and timing of the gadolinium-based contrast agent, and summarizes vendor-specific protocols for high-quality submillimeter-resolution carotid CE MR angiography at 1.5 and 3 T. PMID- 22548931 TI - Vascular disorders: insights from arterial spin labeling. AB - The introduction of high-field magnetic imaging (>=3 T) has made noninvasive arterial spin labeling (ASL) a realistic clinical option for perfusion assessment in vascular disorders. Combined with the advances provided by territorial imaging of individual intracerebral arteries and the measurement of vascular reactivity, ASL is a powerful tool for evaluating vascular diseases of the brain. This article evaluates its use in chronic cerebrovascular disease, stroke, moyamoya disease, and arteriovenous malformation, but ASL may also find applications in related diseases such as vascular dementia. PMID- 22548933 TI - Head and neck high-field imaging: oncology applications. AB - Head and neck imaging has benefited from 1.5 T magnetic resonance (MR) imaging, providing faster sequences, better soft tissue evaluation, and 3-axis imaging, with less radiation and iodine-based contrast injection. The US Food and Drug Administration has approved human MR imaging at high-field strength up to 4 T in clinical practice. 3 T MR imaging has become widely available, with the hope of significant advance in the evaluation of the head and neck region. This article reviews the benefits, disadvantages, and challenges of high-field imaging of the head and neck region, focusing on the imaging of head and neck cancer. PMID- 22548932 TI - High-field atherosclerotic plaque magnetic resonance imaging. AB - Manifestations of atherosclerotic plaque in different arterial beds range from perfusion deficits to overt ischemia such as stroke and myocardial infarction. Atherosclerotic plaque composition is associated with its propensity to rupture and cause vascular events. Magnetic resonance (MR) imaging of atherosclerotic plaque using clinical 1.5 T scanners can detect plaque composition. Plaque MR imaging at higher field strengths offers both opportunities and challenges to improving the high spatial resolution and contrast required for this type of imaging. This article summarizes the technological requirements required for high field plaque MR imaging and its application in detecting plaque components. PMID- 22548934 TI - Pediatric high-field magnetic resonance imaging. AB - High-field 3 T magnetic resonance (MR) imaging provides greater signal-to-noise ratio (SNR) compared with 1.5 T systems. Various MR imaging clinical applications in children can benefit from improvements resulting from this increased SNR. High resolution imaging of the brain, arterial spin labeling perfusion imaging, diffusion imaging, MR spectroscopy, and imaging of small anatomic parts are some areas in which these improvements can increase our clinical diagnostic capabilities. However, challenges inherent to 3 T imaging become more relevant in children. The use of 3 T imaging in children has allowed better diagnostic efficacy in neuroimaging, but certain technique modifications may be required for optimal imaging. PMID- 22548935 TI - Imaging of the spine at 3 tesla. AB - Magnetic resonance (MR) imaging at 3 T has proved superior to 1.5 T in the brain for detecting numerous pathologic entities including hemosiderin, tiny metastases, subtle demyelinating plaques, active demyelinating plaques, and some epileptogenic foci, as well as small aneurysms with MR angiography. 3 T is superior to most advanced imaging techniques including diffusion, diffusion tensor imaging, perfusion, spectroscopy and functional MR imaging. The increased signal/noise ratio at 3 T permits higher spatial resolution. Initially spine imaging at 3 T proved more difficult with less successful results. During the past 7 years, technological advances in magnet and surface coil design as well as improved radio frequency transmitters and pulse sequence design in combination with the large body of knowledge accrued by radiologists and physicists during a nine year experience with clinical imaging of the spine with the doubled B0, has resulted in 3 T MRI of the spine achieving a reputation similar to that for brain imaging. PMID- 22548936 TI - Ultrahigh-field magnetic resonance imaging: the clinical potential for anatomy, pathogenesis, diagnosis, and treatment planning in brain disease. AB - In this review, current (clinical) applications and possible future directions of ultrahigh-field (>=7 T) magnetic resonance (MR) imaging in the brain are discussed. Ultrahigh-field MR imaging can provide contrast-rich images of diverse pathologies and can be used for early diagnosis and treatment monitoring of brain disease. These images may provide increased sensitivity and specificity. Several limitations need to be overcome before worldwide clinical implementation can be commenced. Current literature regarding clinically based ultrahigh-field MR imaging is reviewed, and limitations and promises of this technique are discussed, as well as some practical considerations for the implementation in clinical practice. PMID- 22548937 TI - Ultrahigh-field magnetic resonance imaging: the clinical potential for anatomy, pathogenesis, diagnosis and treatment planning in neck and spine disease. AB - An increase of the magnetic field strength to ultrahigh-field yields advantageous as well as disadvantageous changes in physical effects. The beneficial increase in signal/noise ratio can be leveraged into higher spatiotemporal resolution, and an exacerbation of artifacts can impede ultrahigh-field imaging. With the successful introduction of intracranial and musculoskeletal imaging at 7 T, recent advances in coil design have created opportunities for further applications of ultrahigh-field magnetic resonance (MR) imaging in other parts of the body. Initial studies in 7 T neck and spine MR imaging have revealed promising insights and new challenges, demanding further research and methodological optimization. PMID- 22548941 TI - Preadmission glycemic control and changes to diabetes mellitus treatment regimen after hospitalization. AB - OBJECTIVE: To evaluate treatment patterns associated with diabetes medication regimen changes after hospitalization on the basis on preadmission hemoglobin A1c levels. METHODS: In this retrospective database analysis, patients with a diabetes diagnosis, hospitalization, and documented hemoglobin A1c level within the 90 days leading up to hospital admission were identified in an administrative claims database. Treatment regimens were assessed before and after hospitalization. The proportion of patients who had progression, reduction, or no change in therapy was compared across hemoglobin A1c subgroups: hemoglobin A1c <7.0%, hemoglobin A1c 7.0%-7.9%, and hemoglobin A1c >=8.0%. RESULTS: Four hundred patients were included (192 in hemoglobin A1c <7.0% group, 94 in hemoglobin A1c 7.0%-7.9% group, and 114 in hemoglobin A1c >=8.0% group). Demographically, hemoglobin A1c subgroups did not differ significantly (mean age, 57 years; 47.5% male). With respect to therapeutic regimen overall, 28%, 24%, and 48% of patients experienced progression, reduction, and no change, respectively. Across hemoglobin A1c subgroups, 37.7% of patients in the hemoglobin A1c >=8.0% subgroup had therapy progression compared with 26% and 20.2% in the hemoglobin A1c <7.0% and hemoglobin A1c 7.0%-7.9% subgroups, respectively (P = .032 and P = .006, respectively). Within the progression category, progression via insulin initiation was significantly higher in the hemoglobin A1c >=8.0% subgroup (55.8%) than in the hemoglobin A1c <7.0% subgroup (16%, P<.001), but not significantly higher than in the hemoglobin A1c 7.0%-7.9% subgroup (36.8%, P = .084). In the hemoglobin A1c >=8.0% subgroup, a lower percentage of patients, 35.1%, experienced no therapy change than in both the hemoglobin A1c <7.0% subgroup (52.6%) and the hemoglobin A1c 7.0%-7.9% subgroup (54.3%) (P = .003 and P = .006, respectively). There was no difference between subgroups in reduction of therapy. CONCLUSIONS: A higher proportion of patients with a hemoglobin A1c level >=8.0% had progression of their antidiabetes therapy after hospitalization and fewer patients had no change in therapy than those in lower hemoglobin A1c subgroups. These data suggest that clinicians may be using hemoglobin A1c measurements to guide discharge planning treatment decisions. PMID- 22548942 TI - Mixed corticomedullary carcinoma of the adrenal gland: a case report. AB - OBJECTIVE: To report the case of a 78-year-old woman with mixed corticomedullary carcinoma of the adrenal gland, and to review other reported lesions that exhibit clinical and/or histopathologic features of both adrenal cortical and medullary differentiation. METHODS: We describe the patient's clinical findings and laboratory test results, as well as the gross and histopathologic features of her tumor. We also review the literature pertaining to mixed corticomedullary adenomas and cortical tumors with clinical features of pheochromocytoma, and vice versa. RESULTS: A 78-year-old woman with a 10-cm left adrenal mass was hospitalized for management of hypertensive urgency. Laboratory workup revealed elevated urinary metanephrine excretion and elevated serum dehydroepiandrosterone sulfate levels. She underwent left adrenalectomy. Pathologic examination of the lesion showed mixed cortical and medullary histologic characteristics, as well as gross and microscopic evidence of malignancy. Including the present case, we identified 17 cases of neoplasms that exhibit features of mixed corticomedullary differentiation. CONCLUSIONS: This report represents the first documented case of mixed corticomedullary carcinoma. Several benign lesions combine clinical, biochemical, and/or histopathologic evidence of both adrenal cortical and medullary differentiation, including mixed corticomedullary adenomas and corticotropin-secreting pheochromocytomas. The differential diagnosis of a lesion with mixed cortical and medullary features should also include a malignant neoplasm. PMID- 22548938 TI - Current status and future perspectives of magnetic resonance high-field imaging: a summary. AB - There are several magnetic resonance (MR) imaging techniques that benefit from high-field MR imaging. This article describes a range of novel techniques that are currently being used clinically or will be used in the future for clinical purposes as they gain popularity. These techniques include functional MR imaging, diffusion tensor imaging, cortical thickness assessment, arterial spin labeling perfusion, white matter hyperintensity lesion assessment, and advanced MR angiography. PMID- 22548943 TI - Hyperinsulinism presenting in childhood and treatment by conservative pancreatectomy. AB - OBJECTIVE: To describe the uncommon presentation of hyperinsulinism in an 8-year old boy. METHODS: We describe the patient's clinical findings, results from biochemical and imaging studies, surgical approach, and outcome. The discussion encompasses a review of literature that provided the basis for the diagnostic and surgical approach applied to this patient's case. RESULTS: An obese 8.5-year-old boy initially presented with hypoglycemic seizures after initiation of dietary changes to treat obesity. Biochemical analysis indicated hyperinsulinism. Endoscopic ultrasonography showed no pancreatic lesions suggestive of insulinoma. Genetic studies identified no known mutations in the ABCC8, KCNJ11, GCK, or GLUD1 genes. Selective arterial calcium stimulation and hepatic venous sampling did not document a focal source for hyperinsulinism in the pancreas, and positron emission tomography with 18-fluoro-L-3,4-dihydroxyphenylalanine showed diffusely increased uptake in the pancreas. The patient ultimately required partial pancreatectomy because of continued hypoglycemia while taking diazoxide and octreotide. Intraoperative glucose monitoring directed the extent of surgical resection. A 45% pancreatectomy was performed, which resolved the hypoglycemia but led to impaired glucose tolerance after surgery. CONCLUSION: The unusual presentation of hyperinsulinism in childhood required a personalized approach to diagnosis and surgical management using intraoperative glucose monitoring that resulted in a conservative pancreatectomy. PMID- 22548944 TI - TheV-Go insulin delivery device used in clinical practice: patient perception and retrospective analysis of glycemic control. AB - OBJECTIVE: To describe patient perceptions regarding their experience and to report findings in a retrospective analysis of glycemic control in a cohort of patients who used the V-Go, a mechanical, 24-hour disposable, subcutaneous continuous insulin delivery device that delivers a preset basal infusion rate and on-demand insulin. METHODS: Patients used the V-Go and answered telephone surveys about their perception of device use. Corresponding clinical data were retrospectively collected before V-Go initiation, after 12 weeks of use, at the end of treatment, and 12 weeks after discontinuation. Analyses were performed with nonparametric statistical tests. RESULTS: Twenty-three patients participated. Mean values of the following characteristics were documented: patient age, 61 years; body mass index, 30 kg/m2; diabetes duration, 16 years; duration of insulin therapy, 7 years; average duration of V-Go use, 194 days; and mean total daily insulin dose, 50 U at baseline, 46 U while on V-Go, and 51 U after stopping V-Go treatment. Mean patient rating of the overall experience was 9.1 at 12 weeks on a scale from 1 to 10 (10 being most positive). Mean hemoglobin A1c value decreased from baseline (8.8% to 7.6%; [P = .005]) while using the V Go, and it increased to 8.2% after treatment. Fasting plasma glucose trended from 205 mg/dL at baseline to 135 mg/dL while using V-Go and increased to 164 mg/dL after V-Go was stopped. Weight was essentially unchanged. No differences in hypoglycemic events were found; site reactions were minor. CONCLUSION: Glycemic control improved when patients were switched to the V-Go for insulin delivery, and it deteriorated when the V-Go was discontinued. PMID- 22548945 TI - Apathetic thyrotoxicosis secondary to atypical subacute thyroiditis. AB - OBJECTIVE: To report a case of apathetic thyrotoxicosis with an etiology of subacute thyroiditis. METHODS: We describe the patient's clinical findings, laboratory findings, and clinical course. RESULTS: An 85-year-old woman with no history of thyroid disease presented with severe obtundation and altered mental status. Laboratory testing documented elevated free thyroxine and free triiodothyronine concentrations and a suppressed thyrotropin concentration. Thyroid antibodies were absent. A radioactive iodine study revealed severely diminished uptake, suggestive of thyroiditis. After a short course of steroids, the patient's mental status returned to baseline. Follow-up laboratory testing showed normalizing thyroid function. CONCLUSION: Even in the absence of a history of thyroid disease, we recommend considering thyroid dysfunction in the differential diagnosis of patients who present with altered mental status, particularly in the elderly population. PMID- 22548947 TI - Lack of correlation between antiobesity policy and obesity growth rates: review and analysis. AB - OBJECTIVE: To review federal, state, and local antiobesity policies and to assess their relationships with obesity growth rates. METHODS: We performed a literature review, acquired data from governmental Internet sources, and assessed the statistical correlation between state antiobesity policies and the concavity in obesity growth rates. RESULTS: State-by-state antiobesity policies in 3 categories-taxation of sugared beverages and snacks, physical education and physical activity in schools, and funding for bicycle trails-were found to have no significant immediate correlation with the change in obesity growth rates. CONCLUSIONS: Ineffective antiobesity legislation may be attributable to shortcomings in policy implementation. Behavioral economics and addressing large scale cultural issues may have critical roles in promoting more healthful lifestyles. We propose that a systems-based paradigm evaluating complex interactions among pathophysiological, cultural, political, economic, and behavioral components can improve antiobesity policy implementation and should therefore be a research focus. PMID- 22548946 TI - Pancreatic beta-cell dysfunction in polycystic ovary syndrome: the role of metformin. AB - OBJECTIVE: To determine whether the administration of 6 months of daily metformin treatment in women with polycystic ovary syndrome (PCOS) would significantly improve pancreatic beta-cell function as measured by an increase in the disposition index. METHODS: We enrolled women with PCOS from a private practice and from the Mount Sinai Hospital Endocrinology Clinic. All patients underwent frequently sampled intravenous glucose tolerance tests both on and off 500 to 1000 mg of twice daily metformin. Values of insulin sensitivity, glucose effectiveness, acute insulin response to glucose, and disposition index were calculated for each test. The product of acute insulin response to glucose and insulin sensitivity yielded the disposition index and estimated the degree of beta-cell compensation for insulin resistance. RESULTS: We enrolled 14 women. We observed no significant changes in insulin sensitivity, glucose effectiveness, or acute insulin response to glucose, disposition index, or distributed glucose at time 0 before or after metformin treatment. Patients with PCOS treated with metformin remained statistically on the same hyperbolic curve, which is consistent with previously reported results of the effect of metformin on beta cell function. In contrast, the proportional change in disposition index correlated significantly with the proportional change in insulin sensitivity. Patients whose insulin sensitivity decreased after treatment showed a proportional decrease in disposition index, while patients whose insulin sensitivity increased showed a proportional increase in disposition index. CONCLUSIONS: Our findings suggest that acute insulin response to glucose does not proportionately change to match change in insulin sensitivity. Thus, there may be a beta-cell defect in women with PCOS. PMID- 22548948 TI - Parkinson disease and metabolic bone disorders: a common connection that needs more attention. PMID- 22548949 TI - Association of low serum 25-hydroxyvitamin D levels in pregnancy with glucose homeostasis and obstetric and newborn outcomes. AB - OBJECTIVE: To evaluate the association of maternal serum 25-hydroxyvitamin D (25[OH]D) status with glucose homeostasis and obstetric and newborn outcomes in women screened for gestational diabetes mellitus (GDM). METHODS: Consecutive women were screened for GDM at 24 to 28 weeks' gestation during the months of maximal sunlight exposure in Spain (June through September). Serum 25(OH)D levels and parameters of glucose homeostasis were measured. Outcomes of the delivery and newborn were collected. RESULTS: Two hundred sixty-six women were screened. Vitamin D deficiency (25[OH]D <20 ng/mL) was observed in 157 women (59%). We observed an inverse correlation between 25(OH)D levels and hemoglobin A1c, homeostasis model assessment of insulin resistance, serum insulin, and fasting and 1-hour oral glucose tolerance test glucose levels (P<.001). With a 25(OH)D concentration less than 20 ng/mL, the odds ratios were 3.31 for premature birth (95% confidence interval, 1.52-7.19; P<.002) and 3.93 for cesarean delivery (95% confidence interval, 2.00-7.73; P<.001). A 25(OH)D concentration of 20 ng/mL had 79% sensitivity and 51% specificity for cesarean delivery and 80% sensitivity and 45% specificity for premature birth. The cutoffs with the best combination of sensitivity and specificity were 16 ng/mL for cesarean delivery (62.9% sensitivity and 61.2% specificity) and 14 ng/mL for premature birth (66.7% sensitivity and 71.0% specificity). CONCLUSIONS: In the population we sampled, vitamin D deficiency is very common during pregnancy. Lower 25(OH)D levels are associated with disorders of glucose homeostasis and adverse obstetric and newborn outcomes. PMID- 22548950 TI - Sex hormone-binding globulin and the risk for metabolic syndrome in children of South Asian Indian origin. AB - OBJECTIVE: To determine whether the plasma level of sex hormone-binding globulin (SHBG) identifies South Asian Indian children at risk for metabolic syndrome. METHODS: Adults and their children aged 5 to 9 years were recruited at the annual health fair at the Hindu temple serving the South Asian Indian community in Louisville, Kentucky. Anthropometric data were collected in adults and children, and blood pressure, lipid, and glucose levels were measured in adults. SHBG levels were measured in children using a fingerstick blood sample. In adults, metabolic syndrome was diagnosed according to the International Diabetes Federation criteria. Twelve months later, follow-up anthropometric data were obtained for a portion of the children. RESULTS: The study included 30 sets of parents and 30 children. The prevalence of metabolic syndrome among 310 adults attending the health fair was 42% in men and 39% in women. Children with 1 parent with metabolic syndrome had 24% lower SHBG levels that increased to 55% if both parents had metabolic syndrome. SHBG levels were inversely related to waist circumference and to body mass index percentile. Both SHBG and waist circumference predicted weight gain over 1 year in children. CONCLUSIONS Low SHBG levels were found in South Asian Indian children whose parents had attributes of metabolic syndrome. The dose dependency of SHBG is consistent with inheritance of a genetic trait, and if the results are applicable to other racial/ethnic groups, SHBG may be a useful marker to identify at-risk children for early intervention. PMID- 22548951 TI - Contribution of the dawn phenomenon to the fasting and postbreakfast hyperglycemia in type 1 diabetes treated with once-nightly insulin glargine. AB - OBJECTIVE: To observe the effect of the dawn phenomenon on basal glucose and postbreakfast hyperglycemia in patients with type 1 diabetes treated with once nightly insulin glargine and premeal insulin lispro. METHODS: In 49 study subjects consuming a fixed isocaloric (50% carbohydrate) diet of usual food, the insulin glargine dose was titrated from daily continuous glucose monitoring downloads to achieve a basal glucose goal of <130 mg/dL 4 hours after meals and during serial meal omissions but with fewer than 10% of readings at <70 mg/dL during 24 hours. Patients also performed self-monitoring of plasma glucose 7 times a day (before and 2 hours after each meal or omitted meal and at bedtime). RESULTS: The target mean basal glucose level was achieved only during the non dawn phenomenon period (1400 hours to 0400 hours). During the dawn phenomenon, the mean (standard deviation) basal glucose level increased from 118 (57) mg/dL at 0400 hours to 156 (67) mg/dL before the breakfast meal, a 32% increase (P = .00149). The mean self-monitored plasma glucose level with meal omission was 63.8% of that increase with a breakfast meal. CONCLUSION: The fasting morning glucose concentration is considerably elevated because of the dawn phenomenon. Targeting insulin titration to this glucose level may result in excessive basal insulin dosing for the non-dawn phenomenon periods of the day. The dawn phenomenon is a large component of the postbreakfast hyperglycemia. Rather than increasing the morning premeal insulin bolus, consideration should be given to pretreating the earlier dawn phenomenon with an insulin pump with use of a variable basal insulin rate. PMID- 22548952 TI - Visual vignette. Graves disease with anasarca. PMID- 22548953 TI - Does combination T4 and T3 therapy make sense? AB - OBJECTIVE: To evaluate the existing evidence regarding the combined use of levothyroxine and liothyronine to treat hypothyroidism. METHODS: Eleven published randomized controlled trials evaluating the efficacy and safety of combined levothyroxine and liothyronine therapy for hypothyroidism were reviewed and summarized. Related basic and clinical research findings were also incorporated for perspective. RESULTS: An initial randomized controlled trial reported symptomatic improvement in hypothyroid patients taking combined levothyroxine and liothyronine therapy compared with those taking levothyroxine therapy alone. Subsequently, multiple relatively small randomized controlled trials failed to demonstrate any subjective or objective benefit from combined levothyroxine and liothyronine therapy. A polymorphism (Thr92Ala) in the gene encoding the deiodinase 2 (D2) enzyme that converts thyroxine to triiodothyronine in the brain was later identified in about 16% of hypothyroid persons. This polymorphism may impair brain deiodinase activity in the presence of low brain thyroxine levels. One randomized controlled trial found that patients with the D2 Thr92Ala polymorphism had more baseline symptoms than those with the wild type D2 and experienced significantly greater symptomatic improvement in response to combined levothyroxine and liothyronine therapy. CONCLUSIONS: Most hypothyroid patients experience rapid symptomatic relief after institution of levothyroxine replacement therapy, but persistent symptoms remain in some despite what appears to be adequate levothyroxine therapy with normalization of the serum thyrotropin level. A thorough investigation is warranted in these patients to detect and treat other responsible lifestyle issues, medical conditions, and endocrine conditions. A subset of hypothyroid patients has a polymorphism in the gene encoding the D2 enzyme that may prevent full resolution of symptoms with levothyroxine therapy alone; these patients may benefit from combination levothyroxine and liothyronine therapy. PMID- 22548957 TI - Analysis of ZAP70 expression in adult acute lymphoblastic leukaemia by real time quantitative PCR. AB - BACKGROUND: ZAP70 gene expression is associated with poor prognosis in B-cell lymphoproliferative disorders especially chronic lymphocytic leukaemia (CLL) but its role in adult B-ALL has not been established. On diagnostic samples from 76 patients with adult ALL (65 with B-ALL and 11 with T-ALL) ZAP70 mRNA expression levels were studied by real time-quantitative PCR (RT-qPCR) analysis. FINDINGS: A broad distribution of ZAP70 expression was observed in ALL, ranging from 0.002 to 5.3 fold that of the ZAP70 positive Jurkat reference cell line. No association was observed between expression levels and the presence of specific cytogenetic abnormalities. Five cases, including one case of T-ALL, had ZAP70 expression above the level of the Jurkat reference cell line. CONCLUSIONS: Our results confirm the frequent expression of ZAP70 in adult ALL. Limited comparisons made did highlight poor-risk patients with high ZAP70 expression, but due to lack of clinical information on patient samples we were unable to directly assess the impact on disease prognosis. ZAP-70 may be an important laboratory assay in adult ALL and further studies are warranted to study a potential correlation with cytogenetic and other genetic markers. PMID- 22548954 TI - Prevention of type 1A diabetes mellitus. AB - OBJECTIVE: To review prediction of type 1 diabetes mellitus in light of current trials for prevention and novel preclinical therapies. METHODS: The stages in the development of type 1A diabetes are reviewed and strategies for prevention are discussed. RESULTS: From islet autoantibody testing of random cadaveric donors, it is apparent that approximately one-half million persons in the United States express multiple islet autoantibodies and are in the process of developing type 1A (immune-mediated) diabetes. It is now possible to predict not only risk for type 1A diabetes but also the approximate age of diabetes onset in children followed up from birth. In animal models, diabetes can be prevented. Some of the immunologic therapies effective in animal models are able to delay loss of insulin secretion in humans. CONCLUSIONS: None of the therapies studied to date in humans can completely arrest progressive loss of insulin secretion resulting from destruction of islet beta cells. Nevertheless, current knowledge of pathogenesis (targeting trimolecular recognition complex: major histocompatibility complex, peptide, T-cell receptor) and natural history combined with newer diagnostic methods allows accurate diagnosis and has stimulated the search for novel safe and effective preventive therapies. PMID- 22548958 TI - NPSR1 gene is associated with reduced risk of rheumatoid arthritis. AB - OBJECTIVE: Neuropeptide S receptor 1 (NPSR1) is a G protein-coupled receptor involved in immune response and is associated with several inflammatory diseases. We investigated the possible contribution of several polymorphisms in the intronic region of NPSR1 to rheumatoid arthritis (RA). METHODS: Genotyping of 7 single-nucleotide polymorphisms (SNP) was performed in a total of 1232 patients with RA and 983 healthy controls of Spanish white origin by real-time polymerase chain reaction technology, using the TaqMan 5'-allele discrimination assay. RESULTS: One out of the 7 SNP analyzed (rs740347) was associated with RA [p after Bonferroni correction (p(BNF)) = 1.2 * 10(-3), OR 0.73]. An association was also observed with rheumatoid factor-positive and shared epitope-positive RA (p(BNF) = 0.011, OR 0.73; p(BNF) = 0.037, OR 0.75, respectively). CONCLUSION: Our results show that variations in the NPSR1 intronic region are associated with low risk in patients with RA, supporting other evidence that this locus represents a common genetic factor in inflammatory diseases. PMID- 22548959 TI - Low levels of residual oil fly ash (ROFA) impair innate immune response against environmental mycobacteria infection in vitro. AB - Epidemiological studies have shown that pollution derived from industrial and vehicular transportation provokes adverse health effects causing broad spectrum of ambient respiratory diseases. Therefore, air pollution should be taken into account when microbial diseases are evaluated. Environmental mycobacteria (EM) are opportunist pathogens in a variety of immunocompromised patients eliciting significant impact on human morbidity and mortality. The aim of this study was to evaluate the in vitro effects of residual oil fly ash (ROFA) on the alveolar macrophages (AMs) response to opportunistic bacteria. AMs from young Wistar rats were obtained by bronchoalveolar lavage and co-cultured with Mycobacterium phlei (MOI 10). We exposed AM cultures to ROFA to characterize the effect of low ROFA concentrations (0, 2.5, and 5MUg/ml) and evaluated the response of pre-exposed AM against the bacilli. Low ROFA concentrations induced superoxide anion and nitrites production (p<0.001). Pre-exposure to ROFA (2.5 and 5MUg/ml) caused a significant reduction on TNFalpha (p<0.001) and superoxide anion (p<0.001) production but, did not modify the nitrite production when AM were co-cultured with M. phlei. In addition, ROFA significantly diminished AM killing ability in culture (p<0.001). Hence, our results indicate that pre-exposure to low levels of ROFA modifies the innate pulmonary defence mechanisms against environmental mycobacteria. PMID- 22548960 TI - Age-dependent and tissue-specific structural changes in the C57BL/6J mouse genome. AB - We tested the hypothesis that structural changes in the genome parallel age- and organ-specific phenotypes in conjunction with the differential transposition activities of retroelements. The genomes of the liver from C57BL/6J mice were larger than other organs, coinciding with an increase in genomic copies of certain retroelements. In addition, there were differential increments in the genome size of the liver with increasing age, which peaked at 5 weeks. The findings that the genome structure of an individual is variable depending on age and organ type in association with the transposition of retroelements may have broad implications in understanding biologic phenomena. PMID- 22548962 TI - Healthy Eating, Aerobic and Resistance Training in Youth (HEARTY): study rationale, design and methods. AB - PURPOSE: The objective of the Healthy Eating Aerobic and Resistance Training in Youth (HEARTY) trial (ClinicalTrials.Gov # NCT00195858) was to examine the effects of resistance training, with and without aerobic training, on percent body fat in sedentary, post-pubertal overweight or obese adolescents aged 14-18 years. This paper describes the HEARTY study rationale, design and methods. METHODS: After a 4-week supervised low-intensity exercise run-in period, 304 overweight or obese adolescents with a body mass index>=85th percentile for age and sex were randomized to 4 groups for 22 weeks (5 months): diet+aerobic exercise, diet+resistance exercise, diet+combined aerobic and resistance exercise, or a diet only waiting-list control. All participants received dietary counseling designed to promote healthy eating with a maximum daily energy deficit of -250 kcal. OUTCOMES: The primary outcome is percent body fat measured by Magnetic Resonance Imaging. Secondary outcomes include changes in anthropometry, regional body composition, resting energy expenditure, cardiorespiratory fitness, musculoskeletal fitness, cardiometabolic risk markers, and psychological health. SUMMARY: To our knowledge, HEARTY is the largest clinical trial examining effects of aerobic training, resistance training, and combined aerobic and resistance training on changes in adiposity and cardiometabolic risk markers in overweight and obese adolescents. The findings will have important clinical implications regarding the role that resistance training should play in the management of adolescent obesity and its co-morbidities. PMID- 22548963 TI - Prognostic gene signatures for patient stratification in breast cancer: accuracy, stability and interpretability of gene selection approaches using prior knowledge on protein-protein interactions. AB - BACKGROUND: Stratification of patients according to their clinical prognosis is a desirable goal in cancer treatment in order to achieve a better personalized medicine. Reliable predictions on the basis of gene signatures could support medical doctors on selecting the right therapeutic strategy. However, during the last years the low reproducibility of many published gene signatures has been criticized. It has been suggested that incorporation of network or pathway information into prognostic biomarker discovery could improve prediction performance. In the meanwhile a large number of different approaches have been suggested for the same purpose. METHODS: We found that on average incorporation of pathway information or protein interaction data did not significantly enhance prediction performance, but indeed greatly interpretability of gene signatures. Some methods (specifically network-based SVMs) could greatly enhance gene selection stability, but revealed only a comparably low prediction accuracy, whereas Reweighted Recursive Feature Elimination (RRFE) and average pathway expression led to very clearly interpretable signatures. In addition, average pathway expression, together with elastic net SVMs, showed the highest prediction performance here. RESULTS: The results indicated that no single algorithm to perform best with respect to all three categories in our study. Incorporating network of prior knowledge into gene selection methods in general did not significantly improve classification accuracy, but greatly interpretability of gene signatures compared to classical algorithms. PMID- 22548964 TI - Erectile dysfunction after plaque incision and grafting: short-term assessment of incidence and predictors. PMID- 22548961 TI - The meaning of mitochondrial movement to a neuron's life. AB - Cells precisely regulate mitochondrial movement in order to balance energy needs and avoid cell death. Neurons are particularly susceptible to disturbance of mitochondrial motility and distribution due to their highly extended structures and specialized function. Regulation of mitochondrial motility plays a vital role in neuronal health and death. Here we review the current understanding of regulatory mechanisms that govern neuronal mitochondrial transport and probe their implication in health and disease. This article is part of a Special Issue entitled: Mitochondrial dynamics and physiology. PMID- 22548965 TI - Diabetes, hypertension and hyperlipidemia: prevalence over time and impact on long-term survival after liver transplantation. AB - With increasing short-term survival, the transplant community has turned its focus to delineating the impact of medical comorbidities on long-term outcomes. Unfortunately, conditions such as diabetes, hypertension and hyperlipidemia are difficult to track and often managed outside of the transplant center by primary care providers. We collaborated with Kaiser Permanente Northern California to create a database of 598 liver transplant recipients, which incorporates diagnostic codes along with laboratory and pharmacy data. Specifically, we determined the prevalence of diabetes, hypertension and hyperlipidemia both before and after transplant and evaluated the influence of disease duration as a time-dependent covariate on posttransplant survival. The prevalence of these comorbidities increased steadily from the time of transplant to 7 years after transplant. The estimated risk for all-cause mortality (hazard ratio = 1.07 per year increment, 95% CI 1.01-1.13, p < 0.02) and mortality secondary to cardiovascular events, infection/multisystem organ failure and allograft failure (hazard ratio = 1.08 per year increment, 95% CI 1.00-1.16, p = 0.05) increased for each additional year of diabetes. No associations were found for duration of hypertension and hyperlipidemia. Greater attention to management of diabetes may mitigate its negative impact on long-term survival in liver transplant recipients. PMID- 22548966 TI - Alterations in echocardiographic and electrocardiographic features in Japanese professional soccer players: comparison to African-Caucasian ethnicities. AB - BACKGROUND: Scarce data are available regarding the electrocardiographic (ECG) and echocardiographic changes in athletes of Asian origin. DESIGN: We investigate the ECG and echocardiographic patterns in Japanese (J) compared with African Caribbean (AC) and Caucasian (C) athletes. METHODS: A total of 282 professional soccer players (68 J, 96 AC and 118 C) matched for age, gender, sport and level of achievement was examined. RESULTS: ECGs were without alterations in 62% of J (versus 69% of C, p = non significant and 44% of AC, p < 0.001). The most common alterations in J were sinus bradycardia (69%), incomplete right bundle branch block (RBBB; 43%), early repolarization (18%), isolated increase in R/S-wave (10%), Q-waves (9%). Remarkably, no J athlete showed deeply T-wave inversion, in contrast to 6% of AC (p < 0.05). Occasionally, J showed J-point upward/domed ST elevation with inverted/biphasic T-wave (6% versus 16.5% in AC, p < 0.01). J demonstrated larger left ventricular (LV) cavity compared with AC and C players (55.2 +/- 3.3 versus 52.2 +/- 3.8 and 53.9 +/- 3.7 mm, respectively, p < 0.01), with an important subset ( > 4%) presenting a markedly enlarged cavity (>60 mm), in the presence of normal systolic/diastolic function and no segmental abnormalities. Therefore, J showed a more eccentric remodelling compared with AC and C (relative wall thickness: 0.31 +/- 0.05, 0.38 +/- 0.06 and 0.36 +/- 0.06, respectively, p < 0.01). CONCLUSION: J players show the most eccentric LV remodelling compared with C and AC players. In association, certain training related ECG patterns, i.e. sinus bradycardia and isolated increase in R/S-wave voltage, are present in a larger proportion of J players than previously described in C players. Conversely, no J athlete showed deeply T-wave inversion, as commonly found in AC and occasionally in C. PMID- 22548967 TI - Calibration of an item bank for work capacity in cardiological rehabilitation patients. AB - BACKGROUND: Prevention of work loss is a core objective of cardiovascular rehabilitation. However, comprehensive and economic diagnostic instruments on work limitation are missing. The present study describes the calibration of an item bank for work capacity in cardiovascular rehabilitation patients. DESIGN AND METHODS: This study was based on an item pool (166 items) for assessing work capacity in orthopaedic rehabilitation patients. A total of 349 cardiovascular rehabilitation patients were recruited from 14 German rehabilitation inpatient centres. Exploratory factor analysis was used to determine underlying dimensions of work capacity. Rasch analysis was applied to test for fit of the model, item fit, unidimensionality, particularly local independence and differential item functioning using RUMM2030. RESULTS: Two independent factors (cognitive work capacity/physical work capacity) were found. Fitting of the data to the Rasch model was initially poor (significant item-trait interaction for both factors; p < 0.001). After rescoring disordered categories, excluding misfitting items and items with differential item functioning, 20 and 18 items remained for cognitive work capacity and physical work capacity. Item-trait interaction (cognitive work capacity p = 0.24; physical work capacity p = 0.95) and person separation index (cognitive work capacity = 0.81; physical work capacity = 0.85) were satisfactory. Unidimensionality was given for both factors. CONCLUSIONS: The calibrated item bank provides the basis to assess work capacity in cardiovascular rehabilitation patients, fulfilling high psychometric standards. Further, the item bank could be either used to develop a computer adaptive test or an economic short-form questionnaire. PMID- 22548969 TI - Offshore exploration to commence in the Arctic: can shell's oil-spill response plans keep up? PMID- 22548968 TI - Engineering the yeast Yarrowia lipolytica for the production of therapeutic proteins homogeneously glycosylated with Man8GlcNAc2 and Man5GlcNAc2. AB - BACKGROUND: Protein-based therapeutics represent the fastest growing class of compounds in the pharmaceutical industry. This has created an increasing demand for powerful expression systems. Yeast systems are widely used, convenient and cost-effective. Yarrowia lipolytica is a suitable host that is generally regarded as safe (GRAS). Yeasts, however, modify their glycoproteins with heterogeneous glycans containing mainly mannoses, which complicates downstream processing and often interferes with protein function in man. Our aim was to glyco-engineer Y. lipolytica to abolish the heterogeneous, yeast-specific glycosylation and to obtain homogeneous human high-mannose type glycosylation. RESULTS: We engineered Y. lipolytica to produce homogeneous human-type terminal-mannose glycosylated proteins, i.e. glycosylated with Man8GlcNAc2 or Man5GlcNAc2. First, we inactivated the yeast-specific Golgi alpha-1,6-mannosyltransferases YlOch1p and YlMnn9p; the former inactivation yielded a strain producing homogeneous Man8GlcNAc2 glycoproteins. We tested this strain by expressing glucocerebrosidase and found that the hypermannosylation-related heterogeneity was eliminated. Furthermore, detailed analysis of N-glycans showed that YlOch1p and YlMnn9p, despite some initial uncertainty about their function, are most likely the alpha 1,6-mannosyltransferases responsible for the addition of the first and second mannose residue, respectively, to the glycan backbone. Second, introduction of an ER-retained alpha-1,2-mannosidase yielded a strain producing proteins homogeneously glycosylated with Man5GlcNAc2. The use of the endogenous LIP2pre signal sequence and codon optimization greatly improved the efficiency of this enzyme. CONCLUSIONS: We generated a Y. lipolytica expression platform for the production of heterologous glycoproteins that are homogenously glycosylated with either Man8GlcNAc2 or Man5GlcNAc2 N-glycans. This platform expands the utility of Y. lipolytica as a heterologous expression host and makes it possible to produce glycoproteins with homogeneously glycosylated N-glycans of the human high-mannose type, which greatly broadens the application scope of these glycoproteins. PMID- 22548970 TI - Measuring mitochondrial protein synthesis to assess biogenesis. PMID- 22548972 TI - Sporadic hemangioblastoma of the kidney: a rare renal tumor. AB - Hemangioblastoma is a benign and morphologically distinctive tumor that can occur sporadically or in association with von Hippel-Lindau disease in approximately 25% of the cases, and which involves the central nervous system in the majority of the cases. Rare occurrences of hemangioblastoma in peripheral nerves and extraneural tissues have been reported. This report describes one case of sporadic renal hemangioblastoma happened in a 16-year-old Chinese female patient, presenting with hematuria, and low back pain. Histologically, the tumors were circumscribed, and composed of sheets of large polygonal cells traversed by arborizing thin-walled blood vessels. The diagnosis of hemangioblastoma was confirmed by negative immunostaining for cytokeratin, and positive staining for alpha-inhibin, S100 and neuron-specific enolase (NSE). This benign neoplasm which can be mistaken for various malignancies such as renal cell carcinoma, epithelioid hemangiopericytoma and epithelioid angiomyolipoma, deserves wider recognition for its occurrence as a primary renal tumor. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/5445834246942699. PMID- 22548973 TI - Continuous assessments of pressure comfort on a train -- a field-laboratory comparison. AB - Pressure variations on a train predominantly occur while trains are passing through tunnels. These aerodynamic effects may give rise to aural discomfort in railway passengers. We conducted a field study on the high speed railway track Cologne-Frankfurt/Main as well as a simulation study in our pressure chamber TITAN (DLR-Institute of Aerospace Medicine) with 31 subjects (mean age = 37.7, SD = 12.7; 51.6% male) to investigate pressure comfort for passengers. Continuous assessments of pressure events using sliders and retrospective assessments were acquired. Pressure variations were mostly tolerated. A comparison of field and laboratory setting revealed high congruency of continuous as well as retrospective assessments. A generalized estimating equation model identified pressure change attributes contributing to passengers' discomfort. Beside attributes of instantaneous pressure changes (e.g. high amplitudes, short durations), pressure events of the recent past significantly influenced current discomfort. Design engineers may use these findings to improve train and tunnel design. PMID- 22548974 TI - Evaluating the frequency of bacterial co-infections in children recruited into a malaria pathogenesis study in The Gambia, West Africa using molecular methods. AB - Systemic bacteraemia has been reported in children with severe Plasmodium falciparum malaria in Sub Saharan Africa, making the identification or exclusion of concurrent infections a prerequisite for adequate treatment and studies of the immune responses to particular infections. Given the overlap in clinical signs in humans between malaria and, for example, pneumonia, the true cause of severe illness is sometimes difficult to establish. Traditional microbiological culture methods employed to detect systemic bacteraemia are often time consuming and have modest sensitivity. Therefore, molecular methods have become increasingly used in the diagnosis of septicaemia. Here, we evaluated the usefulness of both broad range 16S rRNA PCR, in conjunction with DNA sequencing and species-specific PCR targeting of Streptococcus pneumoniae and non-typhoidal Salmonella, to screen for bacterial co-infections in blood samples from children enrolled in a malaria pathogenesis study. PCR revealed no test-positive results for these pathogens and DNA sequencing of 16S rRNA amplicons identified the presence of bacterial genomic DNA (most probably from environmental bacterial sources) in a large proportion of samples. We demonstrate that the issue of potential mixed bacteraemic infection and/or background bacterial genomic DNA, which may relate to co-migration of PCR amplicons on agarose gels, can be overcome by using denaturing gradient gel electrophoresis (DGGE). PCR for Plasmodium spp. was also performed on genomic DNA from bloods from Gambian children with pneumonia, in order to estimate the prevalence of Plasmodium/pneumonia co-infections in the study population. While 12.2% of samples were test-positive, parasite density was very low and did not vary significantly between cases and controls. PMID- 22548975 TI - Evaluation of a 15-week CHOP protocol for the treatment of canine multicentric lymphoma. AB - Dose intense CHOP protocols have been shown to improve outcome for people with non-Hodgkin's lymphoma, but evaluation of dose intense CHOP protocols for canine lymphoma is currently limited. The hypothesis of this retrospective study was that a 15-week dose intense CHOP protocol would have shorter treatment duration with similar efficacy to other doxorubicin-based multidrug protocols. Thirty-one client owned dogs with multicentric lymphoma were treated with a 15-week CHOP chemotherapy protocol with an overall response rate of 100% and a median progression-free interval (PFI) of 140 days [95% confidence interval (CI) 91-335 days]. Dogs that had two or more treatment delays had significantly prolonged PFI and overall survival in multivariate analysis. Dose intensity did not correlate with patient outcome. Dogs experiencing multiple treatment delays secondary to adverse events may receive their individual maximally tolerated dose while dogs with no adverse events may be underdosed. Future studies should focus on individual patient dose optimization. PMID- 22548976 TI - Molecular bases and clinical spectrum of early infantile epileptic encephalopathies. AB - Epilepsy can be a challenging diagnosis to make in the neonatal and infantile periods. Seizures in this age group may be due to a serious underlying cause that results in an epileptic encephalopathy. Early infantile epileptic encephalopathy (EIEE) is a progressive neurologic condition that exhibits concomitant cognitive and motor impairment, and is often associated with severe intellectual disability. This condition belongs to the group of age-dependent epileptic encephalopathies, and thus the clinical and electro-encephalographic features change with age as the central nervous system evolves. The molecular bases and the clinical spectrum associated with the early infantile epileptic encephalopathies continue to expand as new genetic discoveries are made. This review will highlight the molecular etiologies of early infantile epileptic encephalopathy, and the clinical and electro-encephalographic changes that take place in these epileptic phenotypes as the brain develops. PMID- 22548977 TI - Molecular cytogenetic characterization of an interstitial deletion of chromosome 21 (21q22.13q22.3) in a patient with dysmorphic features, intellectual disability and severe generalized epilepsy. AB - We report on a de novo interstitial deletion of chromosome 21q in a patient presenting with characteristic facial features, intellectual disability, and epilepsy. The deletion extent was about 4.9 Mb from position 37713441 bp (21q22.13) to position 42665162 bp (21q22.3) (NCBI36/hg18 map). Patients with partial monosomy 21 are quite rare; this anomaly has been associated with a wide spectrum of clinical signs, ranging from very mild to quite severe phenotypes. This variability results from variability in the deleted regions, thus accurate molecular definition of the chromosomal breakpoints is necessary to make better genotype-phenotype correlations. We compared our patient's phenotype with the few other patients reported in the literature and found to have similar deletion when analyzed by array CGH. The minimal overlapping region contains only two genes, DYRK1A and KCNJ6, which may play a major role in these patients' phenotype. PMID- 22548978 TI - Association between multiple sclerosis and erectile dysfunction: a nationwide case-control study. AB - BACKGROUND: Multiple sclerosis (MS) commonly affects young adults who may be sexually active, with sexual dysfunction being a significant, but often underestimated, symptom of MS. However, no large-scaled study has investigated the association between erectile dysfunction (ED) and MS in an Asian population to date. OBJECTIVE: The objective of this study is to estimate the association between ED and a prior diagnosis of MS using a population-based dataset with a case-control design in Taiwan. METHODS: The data were sourced from National Health Insurance Research Database. We identified 38,139 patients with ED as cases and randomly selected 262,848 subjects as controls. We then used conditional logistic regression to compute the odds ratio for having previously received a diagnosis of MS between cases and controls. RESULTS: The prevalence of prior MS was 0.037% and 0.015% for cases and controls, respectively (P < 0.001). Conditional logistic regression analysis revealed that cases were 2.23 times (95% confidence interval = 1.15-4.32) more likely to have been previously diagnosed with MS than controls after adjusting for monthly income, geographic location, hypertension, diabetes, coronary heart disease, hyperlipidemia, obesity, and alcohol abuse/alcohol dependence syndromes. CONCLUSIONS: This study revealed an association between ED and prior MS even after adjusting for potential confounders. PMID- 22548979 TI - Spontaneous pain in partial nerve injury models of neuropathy and the role of nociceptive sensory cover. AB - Spontaneous pain is difficult to measure in animals. One proposed biomarker of spontaneous pain is autotomy, a behavior frequently observed in rats with complete hindpaw denervation (the neuroma model of neuropathic pain). A large body of evidence suggests that this behavior reflects spontaneous dysesthesic sensations akin to phantom limb pain or anesthesia dolorosa. After partial paw denervation, such as in the spared nerve injury (SNI) model of neuropathic pain, autotomy is rare. Does this mean that spontaneous pain is absent? We denervated hindpaws in two stages: SNI surgery completed 7 or 28 days later by transection of the saphenous and sural nerves (SaSu). Minimal autotomy was evoked by the first stage. But it started rapidly after SaSu surgery rendered the limb numb, much more rapidly than after denervation in a single stage (neuroma model). The acceleration was proportional to the delay between the two surgeries. This "priming" effect of the first surgery indicates that the neural substrate of autotomy, spontaneous neuropathic pain, was not initiated by the onset of numbness, but rather by the first, SNI surgery. But the animal's pain experience was occult. The saphenous and sural nerves provided nociceptive sensory cover for the paw, preventing the behavioral expression of the spontaneous pain in the form of autotomy. The results support prior observations suggesting that partial nerve injury triggers spontaneous pain as well as allodynia, and illustrate the importance of nociceptive sensory cover in the prevention of self-inflicted limb injury. PMID- 22548980 TI - Acute hypoxia modifies regulation of neuroglobin in the neonatal mouse brain. AB - Among endogenous adaptive systems to hypoxia, neuroglobin, a recently discovered heme protein, was suggested as a novel oxygen-dependent neuroprotectant. We aimed to characterize i) maturational age-related regulation of neuroglobin in the developing mouse brain under normoxic and hypoxic conditions, and ii) the role of hypoxia-inducible transcription factors (HIFs) as possible mediators of O(2) dependent regulation of neuroglobin in vitro and in vivo. During early stages of postnatal brain maturation (P0-P14) neuroglobin mRNA levels significantly increased in developing mouse forebrains. By immunohistochemical analysis we confirmed expression of neuroglobin protein in the cytoplasm of developing neurons but not glial cells under normoxic conditions. Exposure of the immature brains (P0, P7) to acute (8% O(2), 6h) and chronic systemic hypoxia (10% O(2), 7 days) led to differential activation of neuroglobin varying with maturational stage (P0, P7) and severity of hypoxia. This observation may indicate that neuroglobin is involved in adaptive responses of immature neurons to acute hypoxia during an early stage of mouse brain maturation (P0). In response to activation of the HIF system by prolyl-4-hydroxylase inhibitor (FG-4497), neuroglobin mRNA expression was significantly up-regulated in primary mouse cortical neurons (DIV6) exposed to normoxia and hypoxia (1% O(2)) compared to non treated controls. In conclusion, present results strongly indicate that cerebral regulation of neuroglobin is related to maturational stage and that hypoxia induced neuroglobin up-regulation is modified by the HIF system. PMID- 22548981 TI - A unified computational model for revealing and predicting subtle subtypes of cancers. AB - BACKGROUND: Gene expression profiling technologies have gradually become a community standard tool for clinical applications. For example, gene expression data has been analyzed to reveal novel disease subtypes (class discovery) and assign particular samples to well-defined classes (class prediction). In the past decade, many effective methods have been proposed for individual applications. However, there is still a pressing need for a unified framework that can reveal the complicated relationships between samples. RESULTS: We propose a novel convex optimization model to perform class discovery and class prediction in a unified framework. An efficient algorithm is designed and software named OTCC (Optimization Tool for Clustering and Classification) is developed. Comparison in a simulated dataset shows that our method outperforms the existing methods. We then applied OTCC to acute leukemia and breast cancer datasets. The results demonstrate that our method not only can reveal the subtle structures underlying those cancer gene expression data but also can accurately predict the class labels of unknown cancer samples. Therefore, our method holds the promise to identify novel cancer subtypes and improve diagnosis. CONCLUSIONS: We propose a unified computational framework for class discovery and class prediction to facilitate the discovery and prediction of subtle subtypes of cancers. Our method can be generally applied to multiple types of measurements, e.g., gene expression profiling, proteomic measuring, and recent next-generation sequencing, since it only requires the similarities among samples as input. PMID- 22548982 TI - Longevity of neonatal ductal stenting for congenital heart diseases with duct dependent pulmonary circulation. AB - INTRODUCTION: Ductal stent (DS) in duct-dependent pulmonary circulation is less morbid than neonatal Blalock-Taussig shunt. However, there is concern if DS provides an adequately long palliation before definitive repair. METHODS: This is a retrospective review of clinical follow-up of all consecutive infants after successful DS performed by a single operator. They were divided into three anatomic groups. Group A neonates had balloon valvotomy for critical pulmonary stenosis or pulmonary atresia with intact ventricular septum, who needed DS patency until the right ventricle was adequate to provide antegrade pulmonary flows. Group B patients with tetralogy of Fallot and pulmonary atresia suited for later biventricular repair needed ductal patency until conduit surgery was completed. Group C patients with functionally univentricular hearts needed DS patency until bidirectional Glenn shunt completion. RESULTS: Among 22 infants, four Group A patients followed for 26-54 months after balloon pulmonary valvotomy had adequate oxygen saturation and needed only short-term DS patency. In six out of nine Group B patients, corrective biventricular repair using conduits was performed after 5-14 months at a body weight of 5-7.5 kg. Bidirectional Glenn shunt and confluence repair were performed in seven of nine Group C patients weighing 6-8.5 kg after 8-15 months. The hilar pulmonary artery growth in B and C groups was adequate for surgical repair. No patient needed stent redilatations or additional shunts on follow-up for hypoxia. Four patients had sudden death. CONCLUSIONS: The short-term patency of DS was adequate after balloon valvotomy for critical pulmonary stenosis or pulmonary atresia with intact ventricular septum. Duration of palliation by DS was also sufficient in univentricular hearts to allow adequate somatic growth before Glenn surgery. In patients with biventricular anatomy treated by DS, conduit repair had to be performed at a relatively early age. Interstage mortality was 18%. PMID- 22548985 TI - Progress in transplantation. PMID- 22548983 TI - A systematic review of the safety and efficacy of artemether-lumefantrine against uncomplicated Plasmodium falciparum malaria during pregnancy. AB - Malaria during pregnancy, particularly Plasmodium falciparum malaria, has been linked to increased morbidity and mortality, which must be reduced by both preventive measures and effective case management. The World Health Organization (WHO) recommends artemisinin-based combination therapy (ACT) to treat uncomplicated falciparum malaria during the second and third trimesters of pregnancy, and quinine plus clindamycin during the first trimester. However, the national policies of many African countries currently recommend quinine throughout pregnancy. Therefore, the aim of this article is to provide a summary of the available data on the safety and efficacy of artemether-lumefantrine (AL) in pregnancy. An English-language search identified 16 publications from 1989 to October 2011 with reports of artemether or AL exposure in pregnancy, including randomized clinical trials, observational studies and systematic reviews. Overall, there were 1,103 reports of AL use in pregnant women: 890 second/third trimester exposures; 212 first trimester exposures; and one case where the trimester of exposure was not reported. In the second and third trimesters, AL was not associated with increased adverse pregnancy outcomes as compared with quinine or sulphadoxine-pyrimethamine, showed improved tolerability relative to quinine, and its efficacy was non-inferior to quinine. There is evidence to suggest that the pharmacokinetics of anti-malarial drugs may change in pregnancy, although the impact on efficacy and safety needs to be studied further, especially since the majority of studies report high cure rates and adequate tolerability. As there are fewer reports of AL safety in the first trimester, additional data are required to assess the potential to use AL in the first trimester. Though the available safety and efficacy data support the use of AL in the second and third trimesters, there is still a need for further information. These findings reinforce the WHO recommendation to treat uncomplicated falciparum malaria with quinine plus clindamycin in early pregnancy and ACT in later pregnancy. PMID- 22548986 TI - Billing and reimbursement for advanced practice in solid organ transplantation. AB - Transplantation is considered the treatment of choice for end-stage organ failure in most organ systems. Kidney transplantation is cost-saving as compared with dialysis, and the cost utility of liver transplantation is favorable compared with other accepted medical interventions; nonetheless, transplantation is an expensive endeavor. As a result, both hospitals and payers have made considerable efforts to try to limit the costs associated with transplantation; these efforts have resulted in complicated reimbursement schemes and a variety of models to deliver care. It is in this context that many institutions have looked to incorporate advanced practice professionals in the care of transplant patients. The ability to use advanced practice professionals in a cost-effective manner can be enhanced by an understanding of how reimbursement in transplantation works and the legal and financial implications of their employment. PMID- 22548987 TI - Acute care nurse practitioners in transplantation: adding value to your program. AB - Nurse practitioners are nurses who are prepared at the graduate level. They exercise autonomy in clinical decision making, perform physical examinations and obtain health histories, diagnose and treat a variety of illnesses, provide education and counseling to patients, perform procedures, and ultimately provide cost-effective care. The role of the nurse practitioner evolved in the 1960s, when nurse practitioners filled a void in response to the nationwide shortage of physicians. Today, nurse practitioners specialize both by degree and by certification examination. There are several types of nurse practitioners, including acute care, adult, family practice, and pediatric. The incorporation of acute care nurse practitioners (ACNPs) in transplant programs is an emerging field and varies across the country from center to center. The goals of this article are to (1) identify implications for ACNPs in transplant, (2) discuss the value of using ACNPs in practice, and (3) explore billing and regulatory aspects of ACNPs in transplant programs. PMID- 22548988 TI - The role of clinical nurse educators in organ procurement organizations. AB - Clinical nurse educators are advanced practice nurses with preparation at the master's level or higher. Such nurses play an important role in organ procurement organizations. As leaders and members of the team, they provide structure and design to the training process. These educators oversee orientation of new employees, serve as mentors to preceptors, assess the learning needs of the organization, and provide ongoing training to veteran staff. Clinical nurse educators also contribute to continuous quality improvement for the organization and help to comply with regulatory standards. PMID- 22548989 TI - Working together as a team: adolescent transplant recipients and nurse practitioners. AB - Nurse practitioners are a critical part of the transplant team, enhancing the quality of patient care with their knowledge and skill with respect to disease specific populations of patients. Adolescent transplant recipients are a vulnerable population and require specific considerations. Nurse practitioners can successfully tailor care to the adolescent developmental stages in order to promote quality of life, adherence to the medical regimen, and successful transition to adult transplant centers and to minimize risk-taking behaviors. Teamwork between the patient's family and the entire transplant team is important to optimize not only the patient's health but also to ensure quality of life after transplant. Adolescents can be especially challenging after transplant, given their complex and evolving psychosocial and cognitive development. Nurse practitioners are in a unique position to be central in adolescents' successful adaptation to their medical condition. Facilitating identification and management of medication-related side effects, awareness of emotional health and quality of life, adherence to the medical regimen, and eventual transition to adult caregivers all remain critically important steps in care that are ideally suited for advance practice leadership. PMID- 22548990 TI - The role of advanced practice nurses in transplant center staffing. AB - CONTEXT: Despite increased rates of solid organ transplantation and frequent use of advanced practice nurses (APNs) to manage patients, no established staffing model including APNs and their roles exists. OBJECTIVE: To characterize the role and integration of APNs in the staffing models of existing transplant centers. DESIGN: Descriptive research using a researcher-designed survey of transplant APN professionals. PARTICIPANTS: 53 attendees of a national APN transplant clinical management symposium. MAIN OUTCOME MEASURE: Investigator-designed survey tool consisting of 21 questions delivered in a paper format with 1 open-ended question about adequacy of current staffing and ideas for improvement. RESULTS: 53 responses from staff members of 21 different transplant centers were collected. In addition to APNs, members of existing transplant staffing models were identified as licensed practical nurses, registered nurses, social workers, administrative assistants, and data managers. The primary responsibilities of APNs were both inpatient and outpatient, before and after transplant, and consisted primarily of collecting patients' medical histories, doing physical examinations, handling clinic visits, and education. Licensed practical and registered nurses handled pre-transplant referral management and phone triage duties. Social workers, administrative assistants, and data managers were responsible for social support, medical record management, and regulatory documentation, respectively. Most respondents (57%) found current staffing to be inadequate in their centers and suggested areas for improvement. CONCLUSION: APNs play a vital role in management of transplant patients. Transplant centers use APNs in different capacities, depending on the individual needs of the institution. Across institutions, support staff is crucial in the perception of adequate staffing. Additional research is needed to determine the most efficient use of APNs in transplant centers. PMID- 22548991 TI - Evidence-based practice and research: the challenge for transplant nursing. AB - Despite the initiative for nurses to engage in evidence-based practice and research, little is known about transplant nurses and the role they play in research and evidence-based practice in nursing care. The definition of evidence based practice and research and how it relates to the role of the transplant nurse, the facilitators and barriers to research and evidence-based practice, and the implications for the future of research and evidence-based practice in transplant nursing are addressed. PMID- 22548992 TI - Use of nurse practitioners in pediatric kidney transplant: a model for providing comprehensive care to children and families. AB - It is well documented that kidney transplantation is the treatment of choice for children with end-stage renal disease. Pediatric kidney transplant patients are a complex population because of their need for lifelong immunosuppression, potential for delayed growth and development, and increased risk of heart disease and cancer. Although many large pediatric kidney transplant programs use nurse practitioners, the role of the nurse practitioner is still emerging in relation to the transplant coordinator role. This article describes the practice of pediatric nurse practitioners caring for children who require a kidney transplant and why nurse practitioners are ideal for providing comprehensive care to this population. Transplant programs are regulated by the United Network for Organ Sharing and the Centers for Medicare and Medicaid Services. Both organizations require transplant programs to designate a transplant coordinator with the primary responsibility of coordinating clinical aspects of transplant care. Incorporating transplant coordinator activities into the role of the pediatric nurse practitioner is discussed as a model for providing care throughout the process of kidney transplantation. Transplant pediatric nurse practitioners are in a unique position to expand the care for pediatric kidney transplant patients by assuming the role of clinician, educator, administrator, and coordinator. PMID- 22548993 TI - Development of the center for living donation: incorporating the role of the nurse practitioner as director. AB - For decades, live organ donors have been cared for within the transplant program by the same team that cared for the recipient without any standardization, practice guidelines, or evidence-based evaluation. In an effort to improve the care of living donors, regulations and guidelines to dictate care and follow-up have been instituted. Practices still vary from center to center, and the quality of care that live donors receive also varies. A "Living Donor Center" focused solely on the care of actual and potential donors before and after donation is one way to provide the infrastructure to comply with regulatory mandates and deliver high-quality care to this specialized population of patients. A Center for Living Donation was developed within a Transplantation Institute to address the short- and long-term needs of live donors and confine all donor care to a team of experts led by a doctorally prepared nurse practitioner as the director. A transplant nurse practitioner is uniquely poised to assume such a role because of such competencies as clinical and professional leadership, ability to act as a change agent, communication skills, and ability to lead a multidisciplinary team. PMID- 22548994 TI - Effect of transplant education on nurses' attitudes toward organ donation and plans to work with transplant patients. AB - CONTEXT: Despite the increase in rates of solid organ transplantation in the past 2 decades, nurses are inconsistently educated regarding issues of organ donation and posttransplant care. OBJECTIVE: To characterize the attitudes of registered nurses before and after a graduate-level elective on issues in transplantation. DESIGN: Pre-experimental, pretest and posttest interventional study. PARTICIPANTS: 30 graduate students, who are registered nurses, who enrolled in a transplant elective at a university in the Southeastern United States. MAIN OUTCOME MEASURE: Investigator-designed survey tool consisting of 18 questions delivered in an electronic format. RESULTS: Statistically significant results were seen in nurses' attitudes toward encouraging others to become organ donors (P = .04), preparation to discuss transplantation with others (P< .001), advocacy to discuss transplantation among colleagues (P = .003), confidence in working with transplant patients (P = .005), confidence in speaking to communities about organ donation (P = .001), and plans to encourage others to get involved in transplantation (P = .03). CONCLUSION: These results support the need for providing focused education on transplantation issues to registered nurses, particularly in the academic setting. PMID- 22548995 TI - Interventions used by health care professionals to enhance medication adherence in transplant patients: a survey of current clinical practice. AB - CONTEXT: Although medication nonadherence is associated with severe complications including graft rejection and loss, its prevalence remains high among organ transplant recipients. Still, little information exists on clinical use of interventions to improve medication adherence. OBJECTIVE-To identify transplant health care professionals' methods of assessing medication adherence, classify the used interventions, and measure those interventions' perceived effectiveness. DESIGN, SETTING AND PARTICIPANTS: A 46-item questionnaire on adherence assessment and interventions was distributed at the 2010 International Transplant Nurses Society symposium in Germany. Data were analyzed by using descriptive statistics. RESULTS: Of 141 distributed questionnaires, 94 (67%) were returned. Respondents with no direct patient contact (9%, n = 8) were excluded. The most frequently used assessment strategy was patient self-reporting (60%, n = 52). On average, participants reported using 47% of the educational/cognitive, 44% of the counseling/behavioral, and 42% of the psychological/affective interventions listed. Training patients to self-administer medications and providing printed adherence information were the most frequently used interventions (79% each, n = 68), followed by providing printed medication instructions (69%, n = 59). Most respondents (90%, n = 77) reported combining interventions. The intervention perceived as most effective was medication self-administration training. CONCLUSION: Although available alternatives are demonstrably more effective for enhancing medication adherence, this sample relied more on educational interventions. PMID- 22548996 TI - Improving transplant discharge education using a structured teaching approach. AB - CONTEXT: Nonadherence to posttransplant regimens is common in transplant patients and has the potential for devastating consequences, including acute rejection, graft loss, decreased quality of life, and even death. Comprehensive education of patients and families that improves their understanding of posttransplant regimens and self-care techniques can increase adherence and improve outcomes. Transplant recipients have to learn a vast amount of complex information in a short period as they recover from major surgery and cope with the emotional stress of transplantation. It is not surprising that many patients report that they do not feel ready for discharge. OBJECTIVE: To describe the development, implementation, and outcomes of a comprehensive interdisciplinary patient education program. DESIGN: A quality improvement project. SETTING: A solid organ transplant unit of a large academic medical center. PARTICIPANTS: In-hospital transplant patients and their families and the interdisciplinary team. INTERVENTIONS: A comprehensive discharge education program that integrated written materials, patient and clinical pathways, and discharge instructions. MAIN OUTCOME MEASURE: Improved patient satisfaction with readiness for discharge and medication teaching. RESULTS: A postimplementation patient discharge survey using a 5-point Likert scale showed an increase in patients' understanding of medication dosage (3.6 to 4.6) and side effects (3.6 to 4.7), and satisfaction with the discharge teaching process (3.4 to 5.0). PMID- 22548997 TI - Low-dose gabapentin for intractable hiccups in a heart transplant recipient. AB - Intractable hiccups can be a serious complication in transplant recipients. Unfortunately, many of the pharmacotherapies used to stop hiccups are associated with severe side effects as well as drug-drug interactions with immunosuppressants. We report a case of a heart transplant recipient who had had intractable hiccups for 2 months, resulting in severe insomnia, diminished appetite, and weight loss. To treat the hiccups, treatment with oral baclofen (5 10 mg 3 times daily) was started. After 6 weeks of therapy, the baclofen was titrated down and discontinued because it had not stopped the hiccups and was causing severe central nervous system side effects. Gabapentin (100 mg twice daily) was then prescribed and within 24 hours of the start of that treatment, the hiccups had resolved completely. After 3 weeks of therapy, the patient had no side effects and the gabapentin was subsequently discontinued. One year after stopping the gabapentin, the patient remains free of hiccups. Gabapentin appears to be a promising medication for the treatment of intractable hiccups in thoracic transplant recipients because of its lack of serious side effects at low doses, rapid onset of action, and lack of drug-drug interactions with transplant medications. PMID- 22548998 TI - Takotsubo cardiomyopathy: its possible impact during adult donor care. AB - Takotsubo cardiomyopathy, the syndrome caused by an extreme release and circulation of catecholamines, shares several histopathological and clinical similarities with cardiac changes after brain death noted in animal investigations and human observation. Overwhelming stimulation of myocardial inotropic beta receptors may alter their responsiveness and induce other biochemical processes, producing reduced cardiac contractility. Treatment methods in Takotsubo cardiomyopathy that use extracorporeal circulatory support and medications that do not rely on beta-receptor stimulation and preemptive blockade of beta receptors or calcium channels before brain death may be relevant to donor care. PMID- 22548999 TI - Cardiopulmonary resuscitation of organ donors. PMID- 22549000 TI - Allograft involvement by lymphoproliferative disorders after lung transplantation: report from the PTLD. Int survey. AB - OBJECTIVE: Few cases of graft posttransplant lymphoproliferative disease (PTLD) in pulmonary transplant recipients have been reported. Published data on PTLD are pooled to analyze and compare characteristics, predictors, and prognosis of pulmonary PTLDs arising in lung allograft recipients. MATERIALS AND METHODS: PubMed and Google Scholar were searched for reports of lymphoproliferative disorders occurring within the graft in lung transplant recipients. Data from 23 studies were pooled and analyzed. RESULTS: Data from 137 patients (61 graft locations) with PTLD after lung transplantation were analyzed. Lung recipients with pulmonary graft PTLD were significantly more likely to have early-onset PTLD (70% vs 31%, respectively; P<.001). Lung graft PTLD also was associated with having tested negative for infection with Epstein-Barr virus before transplantation (P=.05). Log-rank test showed significantly higher survival rates for pulmonary transplant recipients with allograft complication than for recipients with PTLD elsewhere (P=.02). CONCLUSION: Pulmonary transplant recipients who show early symptoms of impaired graft function should be evaluated for a potential lung graft PTLD in addition to being assessed for risk of rejection. Further prospective studies with large populations of patients are needed to confirm these results. PMID- 22549003 TI - p38MAPK suppresses chronic pancreatitis by regulating HSP27 and BAD expression. AB - Mitogen-activated protein kinases (MAPKs) are ubiquitous proteins that function in both normal and stress-related pathophysiological states of the cell. This study aimed to analyze the importance of p38MAPK in pancreatic injury using WBN/Kob rats with spontaneous chronic pancreatitis. Male WBN/Kob rats were injected with the p38MAPK inhibitor SB203580, starting at the age of 4 weeks, and sacrificed 6 weeks later. Compared with vehicle-treated rats, p38 inhibitor treated rats exhibited a significant increase in pancreatic cell death and inflammation as assessed by histologic examination and myeloperoxidase activity, respectively. p38 inhibition decreased the expression of heat shock protein 27 (HSP27), an antioxidant protein, and enhanced accumulation of reactive oxygen species (ROS). In addition, the proapoptotic protein BAD was increased in the pancreas of rats treated with p38 inhibitor. In a pancreatic cell line (PANC-1), HSP27 knockdown augmented reactive oxygen species accumulation and cell death induced by tumor necrosis factor-alpha plus actinomycin D. In conclusion, p38MAPK suppresses chronic pancreatitis by upregulating HSP27 expression and downregulating BAD expression. PMID- 22549004 TI - Hepatitis E virus: what transplant physicians should know. AB - Hepatitis E virus (HEV) infection is an underdiagnosed disease in the developed world. In pediatric and adult organ transplant patients HEV infection can cause chronic hepatitis, which can lead to cirrhosis. Extra-hepatic manifestations, such as neurological symptoms and kidney injury, have been also reported in transplant patients. In this comprehensive minireview, we summarize the current knowledge on HEV infection in transplant patients, that is, its prevalence, incidence, natural history and therapy. PMID- 22549005 TI - Reconciling taxonomy and phylogenetic inference: formalism and algorithms for describing discord and inferring taxonomic roots. AB - BACKGROUND: Although taxonomy is often used informally to evaluate the results of phylogenetic inference and the root of phylogenetic trees, algorithmic methods to do so are lacking. RESULTS: In this paper we formalize these procedures and develop algorithms to solve the relevant problems. In particular, we introduce a new algorithm that solves a "subcoloring" problem to express the difference between a taxonomy and a phylogeny at a given rank. This algorithm improves upon the current best algorithm in terms of asymptotic complexity for the parameter regime of interest; we also describe a branch-and-bound algorithm that saves orders of magnitude in computation on real data sets. We also develop a formalism and an algorithm for rooting phylogenetic trees according to a taxonomy. CONCLUSIONS: The algorithms in this paper, and the associated freely-available software, will help biologists better use and understand taxonomically labeled phylogenetic trees. PMID- 22549006 TI - The administration of deferasirox in an iron-overloaded dialysis patient. PMID- 22549002 TI - Heme oxygenase-1 posttranslational modifications in the brain of subjects with Alzheimer disease and mild cognitive impairment. AB - Alzheimer disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Oxidative and nitrosative stress plays a principal role in the pathogenesis of AD. The induction of the heme oxygenase-1/biliverdin reductase-A (HO-1/BVR-A) system in the brain represents one of the earliest mechanisms activated by cells to counteract the noxious effects of increased reactive oxygen species and reactive nitrogen species. Although initially proposed as a neuroprotective system in AD brain, the HO-1/BVR-A pathophysiological features are under debate. We previously reported alterations in BVR activity along with decreased phosphorylation and increased oxidative/nitrosative posttranslational modifications in the brain of subjects with AD and those with mild cognitive impairment (MCI). Furthermore, other groups proposed the observed increase in HO-1 in AD brain as a possible neurotoxic mechanism. Here we provide new insights about HO-1 in the brain of subjects with AD and MCI, the latter condition being the transitional phase between normal aging and early AD. HO-1 protein levels were significantly increased in the hippocampus of AD subjects, whereas HO-2 protein levels were significantly decreased in both AD and MCI hippocampi. In addition, significant increases in Ser-residue phosphorylation together with increased oxidative posttranslational modifications were found in the hippocampus of AD subjects. Interestingly, despite the lack of oxidative stress-induced AD neuropathology in cerebellum, HO 1 demonstrated increased Ser-residue phosphorylation and oxidative posttranslational modifications in this brain area, suggesting HO-1 as a target of oxidative damage even in the cerebellum. The significance of these findings is profound and opens new avenues into the comprehension of the role of HO-1 in the pathogenesis of AD. PMID- 22549007 TI - Bleeding after glue injection in gastric varices. Rebleeding from a glue ulcer. PMID- 22549009 TI - Wrangling reactive nitrogen: strategies for mitigating pollution. PMID- 22549008 TI - Absence of actions of commonly used Chinese herbal medicines and electroacupuncture on myocardial infarct size. AB - BACKGROUND: Some studies have suggested that certain Chinese herbal remedies and acupuncture could limit ischemia/reperfusion damage. We sought to determine whether the commonly used single herb Danshen (DS), either alone or in combination with Jiang Xiang (JX), or electroacupuncture (EA) reduces myocardial infarct size. METHODS: An anesthetized rat model of proximal left coronary artery occlusion (30 minutes) and reperfusion (180 minutes) was used to measure infarct size (triphenyltetrazolium chloride) and ischemic risk zone (blue dye technique). Rats were either untreated (saline) or received an infusion of DS or DS + JX, starting 30 minutes prior to coronary occlusion. In a separate protocol, rats were untreated, received static needle (ND) placement without stimulation or EA at P5-P6 acupuncture points in the rat forearm starting 5 minutes before occlusion and lasting for 40 minutes, or starting 30 minutes before occlusion and lasting for 90 minutes. RESULTS: In the herbal experiments, myocardial infarct size expressed as a fraction of the ischemic risk zone was 0.43 +/- 0.06 in controls, 0.39 +/- 0.05 in the DS group, and 0.42 +/- 0.04 in the Danshen + JX groups (P = not significant [NS]). In the acupuncture study, there was no significant difference in infarct size as a fraction of the risk zone among the control group (0.38 +/- 0.04), the ND group (0.47 +/- 0.04), or the EA group (0.32 +/- 0.05). When EA was started 30 minutes prior to coronary occlusion and continued for 30 minutes into reperfusion, infarct size was 0.41 +/- 0.07 in controls and 0.38 +/- 0.10 in EA (P = NS). Neither herbs nor EA altered heart rate or blood pressure. In a separate study of 5 minutes of coronary occlusion plus reperfusion, EA failed to reduce ventricular arrhythmias. CONCLUSION: Our studies do not suggest a cardioprotective effect of DS or DS + JX or EA in an experimental model of myocardial ischemia/reperfusion. PMID- 22549010 TI - Long-term psychosexual and anatomical outcome after vaginal dilation or vaginoplasty: a comparative study. AB - INTRODUCTION: In patients with disorders of sex development requiring creation of a neovagina, a number of techniques are available, including surgical vaginoplasty and self-dilation therapy. Vaginal dilation therapy has been recommended as a first-line treatment because of its less invasive character and high success rate. However, no data exist on long-term psychosexual functioning after vaginal dilation as compared with that after vaginal surgery. AIMS: The aim of this study is to compare the psychosexual and anatomical outcome of women with congenital vaginal hypoplasia followed in the same clinical setting after vaginoplasty with that after vaginal dilation. METHODS: The sexual quality of life of 35 women at least 2 years after vaginoplasty (N = 15), vaginal dilation therapy (N = 8), or coital dilation/no treatment (N = 12) was investigated and compared with the Dutch test validation population (as control). MAIN OUTCOME MEASURES: Psychosexual functioning was assessed with the female sexual Function index, the female sexual distress scale-revised, and a semi-structured interview. A gynecological examination was performed to determine the anatomical outcome after both vaginal treatment regimens. RESULTS: After either treatment, 26% of these women had a shortened vaginal length of less than 6.6 cm, i.e., more than two standard deviations below the published mean value (9.6 +/- 1.5 cm). Irrespective of the treatment, 47% of the patients had (a) sexual dysfunction(s) and experienced sexual distress. However, after vaginoplasty, patients reported significantly more problems with lubrication (P = 0.025) than after self-dilation therapy. CONCLUSION: Both psychological and physical factors are predisposing for sexual difficulties. To optimize psychosexual comfort, the clinical management of women with vaginal hypoplasia needs to be multidisciplinary and individually tailored. With high success rates reported, vaginal dilation should remain the cornerstone of treatment. PMID- 22549011 TI - Pharmacokinetic study of 3-in-1 poly(ethylene glycol)-block-poly(D, L-lactic acid) micelles carrying paclitaxel, 17-allylamino-17-demethoxygeldanamycin, and rapamycin. AB - Concurrent delivery of multiple poorly water-soluble anticancer drugs has been a great challenge due to the toxicities exerted by different surfactants or organic solvents used in solubilizing individual drugs. We previously found that poly(ethylene glycol)-block-poly(D, L-lactic acid) (PEG-b-PLA) micelles can serve as a safe delivery platform for simultaneous delivery of paclitaxel (PTX), 17 allylamino-17-demethoxygeldanamycin (17-AAG), and rapamycin (RAP) to mice. The high tolerance of this polymeric micelle formulation by mice allowed us to investigate the pharmacokinetics of the 3 co-delivered drugs. In this study, it was shown that 3-in-1 PEG-b-PLA micelle delivering high doses of PTX, 17-AAG, and RAP (60, 60, and 30 mg/kg, respectively) significantly increased the values of the area under the plasma concentration-time curves (AUC) of PTX and RAP in mice compared to the drugs delivered individually, while the pharmacokinetic parameters of 17-AAG were similar in both 3-in-1 and single drug-loaded PEG-b-PLA micelle formulations. Moreover, pharmacokinetic study using 2-in-1 micelles indicated that the augmented AUC value of RAP was due to the co-delivery of 17 AAG, while the increase in AUC of PTX was more likely caused by the co-delivery of RAP. In contrast, when 3-in-1 and single drug-loaded PEG-b-PLA micelles were administrated at modest dose (PTX, 17-AAG, and RAP at 10, 10, and 5 mg/kg, respectively), pharmacokinetic differences of individual drugs between 3-in-1 and single drug formulations were eliminated. These results suggest that 3-in-1 PEG-b PLA micelles can concurrently deliver PTX, 17-AAG, and RAP without changing the pharmacokinetics of each drug at modest doses, but altered pharmacokinetic profiles emerge when drugs are delivered at higher doses. PMID- 22549012 TI - Cytotoxicity and immunological responses following oral vaccination of nanoencapsulated avian influenza virus H5 DNA vaccine with green synthesis silver nanoparticles. AB - DNA formulations provide the basis for safe and cost effective vaccine. Low efficiency is often observed in the delivery of DNA vaccines. In order to assess a new strategy for oral DNA vaccine formulation and delivery, plasmid encoding hemagglutinin (HA) gene of avian influenza virus, A/Ck/Malaysia/5858/04 (H5N1) (pcDNA3.1/H5) was formulated using green synthesis of sliver nanoparticles (AgNP) with polyethylene glycol (PEG). AgNP were successfully synthesized uniformly dispersed with size in the range of 4 to 18 nm with an average size of 11 nm. Cytotoxicity of the prepared AgNP was investigated in vitro and in vivo using MCF 7 cells and cytokine expression, respectively. At the concentration of -5 log10AgNP, no cytotoxic effects were detected in MCF-7 cells with 9.5% cell death compared to the control. One-day-old specific pathogen-free (SPF) chicks immunized once by oral gavage with 10 MUl of pcDNA3.1/H5 (200 ng/ml) nanoencapsulated with 40 MUl AgNP (3.7*10-2 MUg of Ag) showed no clinical manifestations. PCR successfully detect the AgNP/H5 plasmid from the duodenum of the inoculated chicken as early as 1h post-immunization. Immunization of chickens with AgNP/H5 enhanced both pro inflammatory and Th1-like expressions, although no significant differences were recorded in the chickens inoculated with AgNP, AgNP/pcDNA3.1 and the control. In addition, serum samples collected from immunized chickens with AgNP/H5 showed rapidly increasing antibody against H5 on day 14 after immunization. The highest average antibody titres were detected on day 35 post-immunization at 51.2+/-7.5. AgNP/H5 also elicited both CD4+ and CD8+ T cells in the immunized chickens as early as day 14 after immunization, at 7.5+/ 2.0 and 20+/-1.9 percentage, respectively. Hence, single oral administrations of AgNP/H5 led to induce both the antibody and cell-mediated immune responses as well as enhanced cytokine production. PMID- 22549013 TI - Structural characterisation of the polysaccharides from endemic Mongolian desert plants and their effect on the intestinal absorption of ovalbumin. AB - Using successive extractions with water and 0.7% aqueous ammonium oxalate, pectic polysaccharides were isolated from the following plants growing in the arid climate of Mongolia (Gobi): saxaul Haloxylon ammodendron Maxim., rhubarb Rheum nanum Sievers, Nitraria sibirica Pall., Peganum harmala L. and almond Amygdalus mongolica Maxim. The data obtained exhibited the primary synthesis of the cell wall pectic polysaccharides but not the middle lamellae water-soluble pectins in plants growing in the dry climatic zone. Both alpha-(1->4)-D-galacturonan and alpha-(1->4)-D-galacturonan, which was substituted with methyl groups, were found to be backbone of pectins. The L-arabinofuranose residues were identified as the main components of ramified regions. The pectins from almond differed from other pectins due to a high arabinose content. The data from NMR spectroscopy and methylation analyses demonstrated that pectic polysaccharides from almond included terminal, (1->5)-, (1->3)-linked and 3,5-substituted L-arabinofuranose residues and a small terminal D-galactopyranose and 2,5- and 2,3,5-substituted L arabinofuranose residue content. The pectic polysaccharides were found to decrease the absorption of ovalbumin (OVA) in the blood from the gut lumen. The serum OVA level was lower in mice fed with OVA mixed with the pectins compared with the control group, which was administered OVA alone. PMID- 22549014 TI - Bio-inspired step-climbing in a hexapod robot. AB - Inspired by the observation that the cockroach changes from a tripod gait to a different gait for climbing high steps, we report on the design and implementation of a novel, fully autonomous step-climbing maneuver, which enables a RHex-style hexapod robot to reliably climb a step up to 230% higher than the length of its leg. Similar to the climbing strategy most used by cockroaches, the proposed maneuver is composed of two stages. The first stage is the 'rearing stage,' inclining the body so the front side of the body is raised and it is easier for the front legs to catch the top of the step, followed by the 'rising stage,' maneuvering the body's center of mass to the top of the step. Two infrared range sensors are installed on the front of the robot to detect the presence of the step and its orientation relative to the robot's heading, so that the robot can perform automatic gait transition, from walking to step-climbing, as well as correct its initial tilt approaching posture. An inclinometer is utilized to measure body inclination and to compute step height, thus enabling the robot to adjust its gait automatically, in real time, and to climb steps of different heights and depths successfully. The algorithm is applicable for the robot to climb various rectangular obstacles, including a narrow bar, a bar and a step (i.e. a bar of infinite width). The performance of the algorithm is evaluated experimentally, and the comparison of climbing strategies and climbing behaviors in biological and robotic systems is discussed. PMID- 22549015 TI - Cancer bioinformatics: a new approach to systems clinical medicine. PMID- 22549016 TI - Use of social media by Western European hospitals: longitudinal study. AB - BACKGROUND: Patients increasingly use social media to communicate. Their stories could support quality improvements in participatory health care and could support patient-centered care. Active use of social media by health care institutions could also speed up communication and information provision to patients and their families, thus increasing quality even more. Hospitals seem to be becoming aware of the benefits social media could offer. Data from the United States show that hospitals increasingly use social media, but it is unknown whether and how Western European hospitals use social media. OBJECTIVE: To identify to what extent Western European hospitals use social media. METHODS: In this longitudinal study, we explored the use of social media by hospitals in 12 Western European countries through an Internet search. We collected data for each country during the following three time periods: April to August 2009, August to December 2010, and April to July 2011. RESULTS: We included 873 hospitals from 12 Western European countries, of which 732 were general hospitals and 141 were university hospitals. The number of included hospitals per country ranged from 6 in Luxembourg to 347 in Germany. We found hospitals using social media in all countries. The use of social media increased significantly over time, especially for YouTube (n = 19, 2% to n = 172, 19.7%), LinkedIn (n =179, 20.5% to n = 278, 31.8%), and Facebook (n = 85, 10% to n = 585, 67.0%). Differences in social media usage between the included countries were significant. CONCLUSIONS: Social media awareness in Western European hospitals is growing, as well as its use. Social media usage differs significantly between countries. Except for the Netherlands and the United Kingdom, the group of hospitals that is using social media remains small. Usage of LinkedIn for recruitment shows the awareness of the potential of social media. Future research is needed to investigate how social media lead to improved health care. PMID- 22549017 TI - Activin A induction of murine and ovine follicle-stimulating hormone beta transcription is SMAD-dependent and TAK1 (MAP3K7)/p38 MAPK-independent in gonadotrope-like cells. AB - Activins stimulate follicle-stimulating hormone (FSH) beta subunit (Fshb) gene transcription in pituitary gonadotrope cells. Previous studies suggest that activins signal via homolog of Drosophila mothers against decapentaplegic (SMAD) proteins to stimulate murine or porcine Fshb promoter activity in the gonadotrope like cell line, LbetaT2. In contrast, activins were suggested to regulate the ovine Fshb promoter via a SMAD-independent pathway involving TGFbeta associated kinase 1 (TAK1, MAP3K7) and p38 mitogen activated protein kinase (MAPK). Here, we examined roles for TAK1 and p38 in activin A-stimulated murine and ovine Fshb transcription. The TAK1 inhibitor 5Z-7-Oxozeanol (Oxo) significantly impaired fold activin A induction of murine and ovine Fshb promoter-reporters (Fshb-luc) in LbetaT2 cells, but only at concentrations 50-100 fold greater than its IC(50) for TAK1. Moreover, Oxo failed to inhibit activin A induction of endogenous Fshb mRNA levels or fold induction of Fshb-luc activity by a constitutively active form of the activin type I receptor (ALK4). Oxo, at a concentration 5-10 fold greater than its IC(50) for TAK1, attenuated TAK1/TAB2 stimulation of a p38 dependent reporter in the same cells. A Map3k7 siRNA impaired TAK1/TAB2 stimulated p38-dependent reporter activity, but failed to antagonize activin A stimulated Fshb-luc. Though TAK1 was previously suggested to act via p38 to stimulate the ovine Fshb promoter, activin A failed to stimulate p38 phosphorylation in LbetaT2 cells. In apparent contrast, however, the p38 inhibitors SB203580 and SB202190 concentration-dependently attenuated activin A induced Fshb-luc activity. Given the lack of p38 activation, we postulated that the inhibitors might non-selectively antagonize ALK4 activity. Indeed, both attenuated activin A-stimulated SMAD2 phosphorylation, consistent with direct antagonism of ALK4 kinase activity. Finally, we observed that RNA-mediated suppression of Smad4, and to a lesser extent Smad3, attenuated activin A induction of both murine and ovine Fshb promoter-reporters. Collectively, these data suggest that activin A signals via SMAD proteins, but not TAK1 or p38, to regulate murine and ovine Fshb transcription in gonadotrope-like cells. PMID- 22549018 TI - Is dengue and malaria co-infection more severe than single infections? A retrospective matched-pair study in French Guiana. AB - BACKGROUND: Dengue and malaria are two major arthropod-borne infections in tropical areas, but dual infections were only described for the first time in 2005. Reports of these concomitant infections are scarce and there is no evidence of more severe clinical and biological pictures than single infections. METHODS: To compare co-infections to dengue alone and malaria alone, a retrospective matched-pair study was conducted between 2004 and 2010 among patients admitted in the emergency department of Cayenne hospital, French Guiana. RESULTS: 104 dengue and malaria co-infection cases were identified during the study period and 208 individuals were matched in two comparison groups: dengue alone and malaria alone. In bivariate analysis, co-infection clinical picture was more severe than separated infections, in particular using the severe malaria WHO criteria. In multivariate analysis, independent factors associated with co-infection versus dengue were: masculine gender, CRP level > 50 mg/L, thrombocytopaenia < 50 109/L, and low haematocrit <36% and independent factors significantly associated with co infections versus malaria were red cells transfusion, low haematocrit < 36%, thrombocytopaenia < 50 109/L and low Plasmodium parasitic load < 0.001%. CONCLUSIONS: In the present study, dengue and malaria co-infection clinical picture seems to be more severe than single infections in French Guiana, with a greater risk of deep thrombocytopaenia and anaemia. PMID- 22549020 TI - Monitoring bone strontium levels of an osteoporotic subject due to self administration of strontium citrate with a novel diagnostic tool, in vivo XRF: a case study. AB - A previously developed in vivo X-ray fluorescence (IVXRF) I-125 based system was used to measure bone strontium levels non-invasively in an osteoporotic female volunteer. The volunteer was recruited in December 2008, as part of the Ryerson and McMaster University Strontium in Bone Research Study and measured at twice weekly, weekly and monthly intervals. Thirty minute measurements were taken at the finger and ankle bone sites, representing primarily cortical and trabecular bone, respectively and the strontium K-alpha X-ray peak at 14.16 keV was used in the analysis. Since the volunteer had no prior history of strontium based medications or supplementation, baseline natural strontium levels were obtained followed by a 24h measurement of first intake of strontium citrate supplements (680 mg Sr/day). While the baseline levels of 0.38 +/- 0.05 and 0.39 +/- 0.10 for the finger and ankle, respectively, were on par with those previously reported in Caucasians among twenty-two healthy non-supplementing strontium individuals by our group, an increase began to be seen after 24 hrs of 0.62 +/- 0.14 and 0.45 +/ 0.12 for the finger and ankle, respectively. By 120 h, the increase was statistically significant at 0.68 +/- 0.07 and 0.93 +/- 0.05, respectively. Further increases occurred within an interval of 90-180 days, with the most recent, after 800 days, at the finger and ankle being 7 and 15 times higher than the initial baseline reading. The intriguing results show bone strontium incorporation and retention follow a pattern, suggesting strontium levels, at least in the ankle, do not plateau within two to three years and will continue to increase over time, as an individual takes strontium supplements. The ability of this IVXRF system to monitor and measure bone strontium levels over time provides a useful diagnostic tool to help gain insight into strontium bone kinetics. PMID- 22549019 TI - Alternative classification and screening protocol for transitional lumbosacral vertebra in German shepherd dogs. AB - BACKGROUND: Lumbosacral transitional vertebra (LTV) is a common congenital and hereditary anomaly in many dog breeds. It predisposes to premature degeneration of the lumbosacral junction, and is a frequent cause of cauda equina syndrome, especially in German shepherd dogs. Ventrodorsal hip radiographs are most often used in diagnosis of LTV in screening programs. In this study, value of laterolateral lumbar spine radiographs as additions to ventrodorsal radiographs in diagnosis of LTV, and characteristics of LTV and the eighth lumbar vertebra (L8) in laterolateral radiographs were studied. Additionally, computed tomography (CT) features of different types of LTV were elucidated. METHODS: The ventrodorsal pelvic and laterolateral lumbar spine radiographs of 228 German shepherd dogs were evaluated for existence and type of LTV. Morphology of transverse processes was used in classification of LTV in ventrodorsal radiographs. The relative length of sixth (L6) and seventh (L7) vertebrae (L6/L7) was used in characterization of these vertebrae in laterolateral radiographs. CT studies were available for 16 dogs, and they were used for more detailed characterization of different types of LTV. Non-parametric chi2 statistics, generalized logit model for multinomial data, and one-way analysis of variance was used for statistical analyses. RESULTS: In all, 92 (40%) dogs had a LTV, the most common type being separation of first spinous process from the median crest of the sacrum in 62 dogs (67% of LTV). Eight dogs had eight lumbar vertebrae. Those dogs with LTV had longer L7 in relation to L6 than dogs with normal lumbosacral junctions. When L6/L7 decreased by 0.1 units, the proportion of dogs belonging to the group with L8 was 14-fold higher than in the group with normal lumbosacral junctions. L8 resembled first sacral vertebra (S1) in length and position and was therefore classified as one type of LTV. With CT it was shown that categorizing LTV, based on shape and visibility of transverse processes seen in ventrodorsal radiographs, could be misleading. CONCLUSIONS: We suggest that L8 be included as a part of the LTV complex, and the laterolateral radiographs of the lumbar spine be considered as an addition to ventrodorsal projections in the screening protocols for LTV. PMID- 22549021 TI - Antiplatelet therapy: to tailor or not to tailor? PMID- 22549022 TI - T cell-derived IL-10 and its impact on the regulation of host responses during malaria. AB - Despite intense research, malaria still is the one of the most devastating diseases killing more people than any other parasitic infection. In an attempt to control the infection, the host immune system produces a potent pro-inflammatory response. However, this response is also associated with complications, such as severe anaemia, hypoglycaemia and cerebral malaria. This pronounced production of pro-inflammatory cytokines response is a common feature of malaria caused by parasites infecting humans as well as rodents and primates. A balance between pro and anti-inflammatory responses may be fundamental to the elimination of the parasite without inducing excessive host pathology. IL-10 is a key cytokine that has been shown to have an important regulatory function in establishing this balance in malaria. Here we discuss which cells can produce IL-10 during infection, and present an overview of the evidence showing that T-cell derived IL 10 plays an important role in regulating malaria pathology. Many different subsets of T cells can produce IL-10, however, evidence is accumulating that it is effector Th1 CD4(+) T cells which provide the crucial source that down regulates inflammatory pathology during blood-stage malaria infections. PMID- 22549024 TI - Lack of evidence for integration of Trypanosoma cruzi minicircle DNA in South American human genomes. AB - Horizontal gene transfer involving kinetoplast DNA minicircles between Trypanosoma cruzi and its mammalian hosts has recently been proposed as a usual consequence of infection (Hecht et al., 2010). However, we have found no sequences longer than 29 bp perfectly matching minicircles of T. cruzi in the unassembled reads from Colombian and Peruvian human populations provided by the 1,000 Genome project (129 individuals in total, coverage from 1.4* to 36.3*, read length from 42 to 101 bp). The weak sequence matches that were identified are shared with a Finnish population used as a control from a non-endemic area. PMID- 22549023 TI - Trypanosoma brucei: chemical evidence that cathepsin L is essential for survival and a relevant drug target. AB - The protozoan parasite causing human African trypanosomiasis, Trypanosoma brucei, displays cysteine peptidase activity, the chemical inhibition of which is lethal to the parasite. This activity comprises a cathepsin B (TbCATB) and a cathepsin L (TbCATL). Previous RNA interference (RNAi) data suggest that TbCATB rather than TbCATL is essential to survival even though silencing of the latter was incomplete. Also, chemical evidence supporting the essentiality of either enzyme which would facilitate a target-based drug development programme is lacking. Using specific peptidyl inhibitors and substrates, we quantified the contributions of TbCATB and TbCATL to the survival of T. brucei. At 100 MUM, the minimal inhibitory concentration that kills all parasites in culture, the non specific cathepsin inhibitors, benzyloxycarbonyl-phenylalanyl-arginyl-diazomethyl ketone (Z-FA-diazomethyl ketone) and (l-3-trans-propylcarbamoyloxirane-2 carbonyl)-l-isoleucyl-l-proline methyl ester (CA-074Me) inhibited TbCATL and TbCATB by >99%. The cathepsin L (CATL)-specific inhibitor, ((2S,3S)-oxirane-2,3 dicarboxylic acid 2-[((S)-1-benzylcarbamoyl-2-phenyl-ethyl)-amide] 3-{[2-(4 hydroxy-phenyl)-ethyl]-amide}) (CAA0225), killed parasites with >99% inhibition of TbCATL but only 70% inhibition of TbCATB. Conversely, the cathepsin B (CATB) specific inhibitor, (l-3-trans-propylcarbamoyloxirane-2-carbonyl)-l-isoleucyl-l proline (CA-074), did not affect survival even though TbCATB inhibition at >95% was statistically indistinguishable from the complete inhibition by Z-FA diazomethyl ketone and CA-074Me. The observed inhibition of TbCATL by CA-074 and CA-074Me was shown to be facilitated by the reducing intracellular environment. All inhibitors, except the CATB-specific inhibitor, CA-074, blockaded lysosomal hydrolysis prior to death. The results suggest that TbCATL, rather than TbCATB, is essential to the survival of T. brucei and an appropriate drug target. PMID- 22549025 TI - In vitro cultured Neoparamoeba perurans causes amoebic gill disease in Atlantic salmon and fulfils Koch's postulates. AB - Amoebic gill disease (AGD) in marine farmed Atlantic salmon is of growing concern worldwide and remains a significant health issue for salmon growers in Australia. Until now the aetiological agent, Neoparamoeba perurans, has not been amenable to in vitro culture and therefore Koch's postulates could not be fulfilled. The inability to culture the amoeba has been a limiting factor in the progression of research into AGD and required the maintenance of an on-going laboratory-based infection to supply infective material. Culture methods using malt yeast agar with sea water overlaid and subculturing every 3-4 days have resulted in the establishment of a clonal culture of N. perurans, designated clone 4. Identity of the amoeba was confirmed by PCR. After 70 days in culture clone 4 infected Atlantic salmon, causing AGD, and was re-isolated from the infected fish. Diagnosis was confirmed by histology and the infectious agent identified by PCR and in situ hybridisation using oligonucleotide primers and probes previously developed and specific to N. perurans. This study has fulfilled Koch's postulates for N. perurans as a causative agent of AGD and illustrates its free-living and parasitic nature. PMID- 22549026 TI - Cattle tick vaccines: many candidate antigens, but will a commercially viable product emerge? AB - The cattle tick, Rhipicephalus microplus, is arguably the world's most economically important external parasite of cattle. Sustainable cattle tick control strategies are required to maximise the productivity of cattle in both large production operations and small family farms. Commercially available synthetic acaricides are commonly used in control and eradication programs, but indiscriminate practices in their application have resulted in the rapid evolution of resistance among populations in tropical and subtropical regions where the invasive R. microplus thrives. The need for novel technologies that could be used alone or in combination with commercially available synthetic acaricides is driving a resurgence of cattle tick vaccine discovery research efforts by various groups globally. The aim is to deliver a next-generation vaccine that has an improved efficacy profile over the existing Bm86-based cattle tick vaccine product. We present a short review of these projects and offer our opinion on what constitutes a good target antigen and vaccine, and what might influence the market success of candidate vaccines. The previous experience with Bm86-based vaccines offers perspective on marketing and producer acceptance aspects that a next-generation cattle tick vaccine product must meet for successful commercialisation. PMID- 22549027 TI - Factors influencing length of stay and mortality after first and second hip fractures: an event modeling analysis. AB - OBJECTIVE: The aim of this study was to investigate factors influencing length of stay and mortality in first and second hip fractures. DESIGN: This was a retrospective study with data analysis. SETTING: The study was conducted at a level 1 trauma center. PATIENTS: Six hundred and seventy-two patients treated for hip fractures (OTA 31-A, 31-B, 32-A1.1) over 30 months were split into 2 groups. 1FG: Six hundred and ten patients (90.8%) suffered a fracture for the first time. 2FG: Sixty-two patients (9.2%) had previously sustained contralateral fractures. INTERVENTION: Dynamic hip screws or cephalomedullary nails (31-A fractures); cephalomedullary nails (32-A1.1); dynamic hip screws or cannulated screws (undisplaced 31-B fractures); and hemiarthroplasty (displaced 31-B fractures) were used. MAIN OUTCOME MEASURES: Postoperative lengths of stay on trauma ward (LOS-T) on the rehabilitation unit (LOS-R) and in hospital (LOS-H) were calculated. Dates of death were recorded. Event analysis and structural equation modeling were used to assess the impact of second fractures, fracture types, age, gender, and ASA grades on these. RESULTS: : The 2 groups were comparable in gender distribution, ASA grades, fracture types, LOS, and mortality at 120 days. 2FG patients were older than 1FG (mean 83.3 vs 80.2 years) with a higher proportion being discharged to institutional care (35.5% vs 18.5%). Event modeling analysis showed that LOS-T was dependent on ASA grade, whereas mortality was dependent on ASA grade, age, and gender. Second fractures were not related to the risks of increased LOS-T, LOS-R, and mortality. CONCLUSIONS: Second fractures per se do not increase the risk of longer postoperative stay or higher mortality. Any observed effect on these outcomes in second fractures represents the influence of increasing age. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 22549028 TI - Orientation of the "Lisfranc screw". AB - The reduction and stabilization of diastases between the medial cuneiform and the base of second metatarsal after a Lisfranc ligament injury is a crucial objective in the open reduction and internal fixation of these injuries. To achieve this objective, a single screw is used. The present practice is to insert the screw directed from the medial cuneiform bone into the base of the second metatarsal. This technique trick describes an easier method of insertion of the screw and one that possibly provides a better fixation. PMID- 22549029 TI - Wind swept elbow: injury pattern and reconstruction. AB - Sweeping injuries of the elbow characterized by traumatic loss of medial or lateral epicondyles, collateral ligaments, and surrounding soft tissue result in loss of joint stability. Reconstruction of medial or lateral collateral ligaments is challenging due to loss of the cortical bone and the resultant difficulty in identifying the isometric attachment point. We describe a unique injury pattern and a surgical technique to restore joint stability using a bone tendon (Achilles) allograft. The technique was applied to 4 consecutive patients with a mean age of 35 (22-57) years and a mean follow-up of 20 months. Three patients with the lateral sweep injury had losses of the lateral epicondyle, lateral collateral ligament along with radial nerve palsy in 2. One patient with the medial sweep injury lost the medial epicondyle, medial collateral ligament, and had ulnar nerve palsy. All patients had an unstable ulnohumeral joint and underwent bone-tendon allograft (Achilles) reconstruction. The elbow joint was covered with a rotational radial forearm flap in 1 patient: myofasciocutaneous free gracilis flap in 1 and rotational fasciomyocutaneous latissimus dorsi flap in 2 patients. One patient had an open reduction and internal fixation of distal third humerus shaft fracture, intercalary nerve grafting to the ulnar nerve, and repair of the brachial artery. At the final follow-up, average elbow motion was 115 degrees. Radiographic bone-to-bone healing was achieved in all patients. According to the American Shoulder and Elbow Surgeon's Assessment; average patient rated pain, function, and satisfaction scores were 3.4, 2.3, and 5, respectively. The average Disabilities of the Arm, Shoulder and Hand questionnaire score was 25. The use of bone-tendon allograft to reconstruct collateral ligaments of the elbow restored the elbow stability with a satisfactory functional outcome (evidence: level 4). PMID- 22549030 TI - Mechanical failure after locking plate fixation of unstable intertrochanteric femur fractures. AB - OBJECTIVES: The aim of this study was analyze modes of mechanical failure in a consecutive cohort of patients and establish possible risk factors. DESIGN: This was a retrospective cohort study. SETTING: The study was conducted at an academic level-1 trauma center. PATIENTS: Twenty-nine patients (mean age 56 years, range 21-92; 45% males, 41% smokers, 17% diabetic, mean body mass index 26.9, range 20 56) with 30 OTA 31A3 fractures treated between 2003 and 2007 were included. TREATMENT: Operative fixation using 4.5-mm locking compression plate (LCP) proximal femur plate (Synthes, Paoli, PA). MAIN OUTCOME MEASUREMENTS: Mechanical failure was defined as loss of alignment of at least 10 degrees or shortening of at least 2 cm. Secondary outcomes included patient and fixation construct variables as possible predictors for mechanical failure. RESULTS: At 20 months of follow-up, 11 failures (37%) occurred. Mean time to failure was 18 weeks (range 2 84). Cumulative failure rates were 10%, 20%, 27%, and 33% at 1, 2, 6, and 12 months, respectively. The most frequent failure mode was varus collapse with screw cut out (5 cases). There was no statistically significant difference between groups with regards to age, body mass index, diabetes, or smoking habit. The presence of a "kickstand screw" and medial cortical reduction were not significantly different in cases with and without failure. Proximal screw number and type were similar in both groups. CONCLUSIONS: A high rate of mechanical failure can be expected with proximal locking plate fixation of unstable proximal femur fractures. The use of a "kickstand" screw could not be established to reduce the risk for mechanical failure. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 22549031 TI - Low-intensity pulsed ultrasound enhances BMP-7-induced osteogenic differentiation of human fracture hematoma-derived progenitor cells in vitro. AB - OBJECTIVE: To investigate the effect of the combined application of bone morphogenetic protein-7 (BMP-7) and low-intensity pulsed ultrasound (LIPUS) on human fracture hematoma-derived progenitor cells (HCs). METHODS: HCs were isolated from 6 patients. The cells were then divided into 4 groups and cultured: (1) control group, HCs cultured in growth medium without LIPUS; (2) LIPUS group, HCs cultured in growth medium with LIPUS; (3) BMP-7 group, HCs cultured in osteogenic medium containing BMP-7 without LIPUS; and (4) BMP-7 + LIPUS group, HCs cultured in osteogenic medium with LIPUS. Osteogenic differentiation potential and proliferation of HCs were compared among 4 groups. RESULTS: Alkaline phosphatase activity, the expression of osteogenic genes, and the mineralization of HCs in BMP-7 + LIPUS group were shown to be significantly increased compared with the other groups. However, LIPUS did not affect the proliferation of HCs in the presence or absence of BMP-7. CONCLUSIONS: These findings demonstrated for the first time the significant effect of LIPUS on the osteogenic differentiation of HCs in the presence of BMP-7. This study may provide significant evidence for the clinical combined application of BMP-7 and LIPUS for the treatment of acute bone fractures. PMID- 22549032 TI - Iatrogenic syndesmosis malreduction via clamp and screw placement. AB - OBJECTIVES: The purpose of this study was to assess the impact of variations in angulation of clamp placement to hold syndesmotic reduction and how subsequent syndesmotic screw placement affects malreduction of the syndesmosis. We hypothesized that an anatomic syndesmosis reduction cannot be reliably achieved with a clamp alone; and, inaccurate placement of intraoperative clamps and trans syndesmotic screws after reduction can malreduce the ankle syndesmosis. METHODS: After computed tomography scanning of the intact limbs, 14 cadaver legs were dissected; the syndesmosis was completely disrupted in all. Using planned drill holes, clamps were first placed at 0 degrees , 15 degrees , and 30 degrees angles from the fibula, then separate posterolateral, followed by lateral, screws were placed. After each intervention, the limb had a computed tomography scan so the fibular reduction could be evaluated precisely. RESULTS: Clamps placed at 15 degrees and 30 degrees significantly displaced the fibula in external rotation and caused significant overcompression of the syndesmosis. Thirty-degree lateral screws caused significant anteromedial displacement, external rotation, and overcompression of the syndesmosis. The 15 degrees posterolateral screws also caused significant external rotation and overcompression of the syndesmosis. CONCLUSIONS: Our study demonstrates that intraoperative clamping and fixation can cause statistically significant malreduction of the syndesmosis. This article should alert clinicians that clamp and screw placement can cause iatrogenic malreduction of the syndesmosis and make them aware that these dangers occur with specific clamp and screw angles in particular. PMID- 22549033 TI - Effect of negative pressure wound therapy on the elution of antibiotics from polymethylmethacrylate beads in a porcine simulated open femur fracture model. AB - OBJECTIVES: To determine whether negative pressure wound therapy (NPWT) affects antibiotic elution in simulated femur fractures treated with antibiotic impregnated polymethylmethacrylate (PMMA) beads and whether fascial closure between beads and sponge affects the outcome. METHODS: PMMA beads containing vancomycin and tobramycin were placed adjacent to bilateral corticotomies created in 20 anesthetized pigs. In 1 leg, NPWT was applied with the sponge either in direct contact with the beads or superficial to reapproximated fascia lata. The contralateral wound was conventionally closed. Vancomycin and tobramycin concentrations in wound drainage were measured every 12 hours for 72 hours, and tobramycin levels were measured in periosteal tissue obtained at 72 hours. RESULTS: Drainage vancomycin and tobramycin concentrations were highest at 12 hours and fell rapidly by 24 hours but remained steady thereafter. At each 12 hour interval, there were no significant differences in the vancomycin and tobramycin concentrations between NPWT and control wound drainage, although whether the fascia was closed or left open had an influence on vancomycin levels. The total vancomycin and tobramycin eluted into the drains was significantly less in the NPWT group with open fascia. The antibiotic levels measured in wound drainage remained above the minimum inhibitory concentration for common wound organisms throughout the study period. Neither NPWT nor fascial closure had a significant effect on tobramycin periosteal tissue concentrations. CONCLUSIONS: Concurrent application of NPWT with antibiotic impregnated PMMA beads to simulated open femur fractures in pigs did not decrease local antibiotic concentrations but did decrease the total amount of eluted vancomycin and tobramycin locally available when the fascia was left open. PMID- 22549034 TI - Recovery of erectile function after nerve-sparing laparoscopic radical prostatectomy in Japanese patients undergoing both subjective and objective assessments. AB - INTRODUCTION: The sexual potency rate following a radical prostatectomy can vary. In Japanese patients, sexual activity after nerve-sparing prostatectomy seems especially unfavorable. Most studies have assessed potency status subjectively using questionnaires. AIMS: The aim of this study is to evaluate the recovery of potency in Japanese patients after nerve-sparing laparoscopic prostatectomy (nsLRP) both subjectively and objectively. METHODS: Twenty-seven patients operated on with nsLRP (bilateral sparing in four patients, unilateral in 23 patients) were enrolled. The mean age of the patients was 60.1 years. Seventeen of 27 patients used type 5 phosphodiesterase inhibitors on demand at least 3 months after surgery. MAIN OUTCOME MEASURES: Subjective erectile function was examined by the international index of erectile function (IIEF)-15 and by the erection hardness score (EHS) questionnaires before and at 3, 6, and 12 months after surgery. Objective erectile function, with measurement of rigidity and tumescence of the penis, was evaluated by RigiScan-Plus as the erectile response to audio-visual stimulation. RESULTS: IIEF erectile function domain, IIEF-total, and EHS scores decreased significantly after surgery; they were almost half of pretreatment levels at 12 months after surgery. On the other hand, penile rigidity and tumescence measured by RigiScan also decreased significantly 3 months after surgery. However, these values gradually improved, and head nearly recovered at 12 months after surgery. At 12 months after surgery, recovery rates of penile rigidity and tumescence from baseline were rigidity 92.6% at tip and 96.3% at base, with tumescence of 87% at tip and 76% at base. CONCLUSIONS: Discrepancies were found between results of subjective and objective assessments of erectile function. From an objective viewpoint, the recovery of erectile function in Japanese patients after nsLRP was not bad. PMID- 22549035 TI - Chronic acetyl-L-carnitine alters brain energy metabolism and increases noradrenaline and serotonin content in healthy mice. AB - Acetyl-L-carnitine (ALCAR), the short-chain ester of carnitine, is a common dietary supplement readily available in health food stores, claimed to improve energy levels and muscle strength. ALCAR has numerous effects on brain and muscle metabolism, protects against neurotoxic insults and may be an effective treatment for certain forms of depression. However, little is known about the effect of chronic ALCAR supplementation on the brain metabolism of healthy mice. Here, we investigated ALCAR's effect on cerebral energy and neurotransmitter metabolism after supplementing the drinking water of mice with ALCAR for 25 days, providing a daily dose of about 0.5 g/kg. Thereafter the animals were injected with [1 (13)C]glucose, and (13)C incorporation into and levels of various metabolites were quantified in extracts of the hippocampal formation (HF) and cortex using (1)H- and (13)C-nuclear magnetic resonance (NMR) spectroscopy and high performance liquid chromatography (HPLC). Increased glucose levels were detected in both regions together with a decreased amount of [3-(13)C]lactate, but no alterations in incorporation of (13)C derived from [1-(13)C]glucose into the amino acids glutamate, GABA and glutamine. These findings are consistent with decreased metabolism of glucose to lactate but not via the TCA cycle. Higher amounts of the sum of adenosine nucleotides, phosphocreatine and the phosphocreatine/creatine ratio found in the cortex of ALCAR-treated mice are indicative of increased energy levels. Furthermore, ALCAR supplementation increased the levels of the neurotransmitters noradrenaline in the HF and serotonin in cortex, consistent with ALCAR's potential efficacy for depressive symptoms. Other ALCAR-induced changes observed included reduced amounts of GABA in the HF and increased myo-inositol. In conclusion, chronic ALCAR supplementation decreased glucose metabolism to lactate, resulted in increased energy metabolite and altered monoamine neurotransmitter levels in the mouse brain. PMID- 22549036 TI - The impact of socio-economic crisis on mental health of children and adolescents. PMID- 22549037 TI - [Depression telephone helpline: help seeking during the financial crisis]. AB - Mental health telephone help-lines usually play a significant role in mental health services system. Their importance is substantiated during periods of financial crisis, where the mental health of the population is gravely inflicted. Media reports have documented a large increase in calls made to mental health telephone help-lines around the world as a corollary to the global economic crisis; however, a systematic investigation of this observation is still lacking. In this context, the present study endeavours to fill this gap in the literature, while it adds strength to the handful of studies which have empirically supported the impact of the financial crisis on mental health in Greece. Data were extracted from information gleaned during the calls made to the Depression Telephone Helpline of the Greek University Mental Health Research Institute. The information entailed the reason for calling, the socio demographic and clinical profile of the person with mental health problems, his/her previous and current contacts with mental health professionals and the treatment he/she might be receiving. The results showed a steep increase in calls with direct or indirect reference to the economic crisis during the first half of 2010 and onwards. The callers who referred to the economic crisis manifested depressive symptomatology of clinical significance to a greater degree than callers who made no such reference. The latter exhibited increased levels of distress and agitation as well as drug/alcohol misuse. Concomitantly, a higher frequency of depressive symptomatology was discerned among the unemployed, whereas employed people were found to experience anxiety symptoms to a higher degree. The impact of the financial crisis on the mental health of the Greek population has been considerable, underscoring in this way the importance of mental health help-lines as emotional buffers and as guides for timely and appropriate service use in response to the emerging mental health problems. PMID- 22549038 TI - [Suicide rates and mental health services in Greece]. AB - Some studies have shown that access to mental health services can have an impact on mental health outcomes, including the suicide rates. The aim of the present study was to examine the relationship between regional and prefecture suicide rates (suicides per 100.000 residents) and both the number of primary and mental health-care service providers and the number of mental health infrastructures in Greece. Data were taken mainly from the Hellenic Statistical Authority (EL.STAT.) and the Ministry of Health for the period 2002-2009. Spearman correlations were used to examine the relationship between primary health-care, mental health providers and suicide rates per 100,000 residents at the prefecture, administrative region and geographical region levels. Men showed significantly higher suicide rates than women (U=-7.20, p<0.001). For the period 2002-2009, the highest suicide rate at the prefecture level were in Rethymno (6.99), Rodopi (5.62) and Zakynthos (5.28). For the same period, the highest suicide rates at the geographical level were in Peloponnisos (4.01), Ionian Islands (4.03) and Grete (3.65). Increase in suicide rates (2009 vs 2002-2009) was observed in the following geographical regions of Greece: Crete (4.76 vs 3.65), Thrace (4.45 vs 2.02) Central Greece (3.61 vs 1.39) Aegean Islands (3.03 vs 1.28). The highest correlations between suiciderutes and health services at the geographic regional level were found to be during the period 2007-2009, where suicide rates showed a significant negative correlation with privately practicing psychiatrists (rho= 0.71, p<0.05), privately practicing psychologists (rho=-0.56, p<0.05), pathologists (rho=-0.73, p<0.01), and the number of the official mental health services (psychiatric clinics, day centers, mobile mental health units etc.) (rho=-0.73, p<0.01). In conclusion it was found that at all regional levels, suicide rates were reversely related to the number of primary health-care and mental health service providers, as well as the number of mental health infrastructures in Greece. It should be noted that the running financial crisis in Greece seems to have many effects on quality of life, since the most common effects of an economic crisis are unemployment, spending power cuts,general insecurity and public spending retrenchment, including health related budget cuts. Having in mind the above situation, further analyses are needed to determine the relationship between mental health-care services, suicide rates and other psychosocial indices, in order to provide a strategic plan for a better design of mental health-care policy in Greece. PMID- 22549039 TI - [Prevalence of depression among the elderly]. AB - Depression is the most common mental health problem among older people, posing a critical impact on their well-being and the quality of life. The objective of the present study was to estimate the prevalence of depression in elderly population of an urban area and to investigate the association with various aggravating or protective factors. The sample consisted of 239 subjects, aged >60 years, members of "daycare centers for older people" (KAPI) in the municipality of Patras, W Greece. A questionnaire was developed to collect basic demographic and socioeconomic data, including three questions from the "European Health Interview Survey" (EHIS), regarding self-reported and/or by a physician diagnosed depression. Moreover, to all participants the Greek validated version of the Geriatric Depression Scale (GDS-15) was applied, to screen the elderly for depressive symptoms. The scores of the GDS were a) compared to the corresponding answers of the EHIS questions and b) associated to the various recorded basic parameters. Statistical analyses were performed using the SPSS v. 17.0. The results of the GDS indicated 45% of the studied population having depressive symptoms (36% moderate, 9% severe), while having ever been affected with chronic depression reported 49 (20.5%) and out of them 34 (66.8%) stated to have been diagnosed by a medical doctor. In detail, out of the 162 (67.8%) subjects reporting never have been affected by a depression, 37 (22.8%) and 8 (4.9%) screened positive for moderate and severe depressive symptoms, respectively. In 27 individuals who reported not to know if they have depression, 16 revealed depressive symptoms using the GDS. Depressive symptoms were more frequent in women (54.6% vs 37.4%, p=0.027), in not married, including divorced and widowed, compared to married (55.6% vs 38.9%, p=0.038) and in subjects living alone at home (62% vs 38.1%, p=0.003). Depressive symptoms were more frequent in elderly with chronic diseases compared to elderly without comorbidity (50.8% vs 27.5%, p=0.02). High prevalence of depressive symptoms in elderly population is evident, but rarely recognized. The systematic use of short GDS versions in Primary Care may increase detection rates of depression among the elderly. PMID- 22549040 TI - [Psychological and psychiatric problems in cancer patients: relationship to the localization of the disease]. AB - Cancer may be localized in a variety of areas in the human body. This localization is associated with significant issues concerning not only therapy and prognosis but also psychological and psychiatric problems that the patient may be confronted with. The psychic impact on the patient is determined to a significant degree by the symbolism the affected organ carries. The symbolic significance of a sick body area triggers emotions and sets in motion self defence mechanisms. In this way, patients deal with the new psychic reality that cancer creates. Therapeutic choices may include interventions, involving mutilation, which cause disfigurement and major consequences in the body image which result in narcissistic injuries. The phenomenology of anxiety and depressive disorders is connected to the affected body area. The appearance of cancer not only in sexual organs but also in other body areas, may disturb sexual function and therefore lead to sexual disorders. Especially, head and neck are connected with vital functions. This area of the body has had a major impact on psychic reality since early life. Complicated psychic functions have developed in relation to organs of the head and neck. Therefore, localization of cancer in this area leads to individual psychological and psychiatric problems, since eating and breathing are harmed, verbal communication becomes difficult and body image alters. Also, increased incidence of alcohol and nicotine abuse in these patients reflects special aspects of psychic structure and personality. Because of severe somatic symptoms and poor prognosis, lung cancer patients feel hopelessness and helplessness. Patients with gynaecological cancer are confronted with a disease that affects organs like breast and internal female sexual organs associated with femininity, attractiveness and fertility. Dietary habits are often a source of guilt for patients who suffer from cancer of the gastrointestinal tract. Additionally, stomas, as colostomy, affect body image and cause feelings of embarrassment with severe consequences on the patient's sense of wellbeing, his or her daily activities, interpersonal relationships or sexuality. Depressive symptoms often occur in prodromal stages of pancreatic cancer. Depression is a common diagnosis in patients with prostate cancer. Prostatectomy negatively affects patient's self-esteem, because it might be experienced as a threat to his sexual life. Disfigurement is related to skin cancer because of both cancer and surgical procedures. Therefore, it is a challenge for modern psycho-oncology to identify those patients who are vulnerable in developing psychiatric symptoms, to early diagnose anxiety and depression and to use psychotherapeutic interventions targeting individual psychological and psychiatric problems in relation to the localization of disease in the human body. PMID- 22549041 TI - [Clinical perfectionism and cognitive behavioral therapy]. AB - The present study constitutes a brief literature overview, in which the term of clinical perfectionism, its etiopathology, its assessment and its relation to psychopathology, as well as the therapeutic interventions based on the Cognitive Behavioral Model are discussed. According to Frost, perfectionism is associated with one's desire to achieve the greatest degree of performance and it is accompanied by an extremely strict evaluation of that particular performance. The relationship with oneself as well as the relationship with others are both characterised by high standards and demands which tend to exhaust one individual and dramatically toughen the development of proximity with the others. Perfectionism, as a personality trait, presents functional and dysfunctional elements for a person. Dysfunctional, clinical perfectionism -a term recently coined by researchers- has been linked to a number of disorders, such as social phobia, obsessive-compulsive disorder, eating disorders -anorexia and bulimia nervosa- depression and personality disorders. From a perfectionist's point of view, perfection exists and its attaintment is feasible. The existence of a particularly high and often unrealistic goal can lead the person to severe disappointment when this specific goal is not finally reached. A person with functional perfectionism is possible to set another, more achievable, goal next time, while a person with clinical perfectionism will interpret this failure as a sign of personal inadequacy and will either make another attempt to reach the same goal or will abandon the effort altogether. A sense of weakness and subsequent negative automatic thoughts are the aftermath of both the first and the second choice. Cognitive Behavioral Therapy focuses on the realisation that clinical perfectionism is undesirable, on the dispute of negative automatic thoughts and on the replacement of unfunctional cognitive schemas with other, more functional ones. In the therapeutic process, one individual can learn how to set specific and realistic goals, to focus on the process of a task instead of its result, to organise activities in a hierarchy depending on their significance and, finally, to feel fulfilled even if they have not brought a task to completion. It is a fact that the core schemas of clinical perfectionism are characterised by rigidity due to the excessive number of secondary benefits they provide for one person. The exploration of those benefits and the discovery of alternative sources of fulfillment are areas of therapeutic work. PMID- 22549042 TI - Familial hemiplegic migraine type 1 mutations W1684R and V1696I alter G protein mediated regulation of Ca(V)2.1 voltage-gated calcium channels. AB - Familial hemiplegic migraine type 1 (FHM-1) is a monogenic form of migraine with aura that is characterized by recurrent attacks of a typical migraine headache with transient hemiparesis during the aura phase. In a subset of patients, additional symptoms such as epilepsy and cerebellar ataxia are part of the clinical phenotype. FHM-1 is caused by missense mutations in the CACNA1A gene that encodes the pore-forming subunit of Ca(V)2.1 voltage-gated Ca(2+) channels. Although the functional effects of an increasing number of FHM-1 mutations have been characterized, knowledge on the influence of most of these mutations on G protein regulation of channel function is lacking. Here, we explored the effects of G protein-dependent modulation on mutations W1684R and V1696I which cause FHM 1 with and without cerebellar ataxia, respectively. Both mutations were introduced into the human Ca(V)2.1alpha(1) subunit and their functional consequences investigated after heterologous expression in human embryonic kidney 293 (HEK-293) cells using patch-clamp recordings. When co-expressed along with the human MU-opioid receptor, application of the agonist [d-Ala2, N-MePhe4, Gly ol]-enkephalin (DAMGO) inhibited currents through both wild-type (WT) and mutant Ca(V)2.1 channels, which is consistent with the known modulation of these channels by G protein-coupled receptors. Prepulse facilitation, which is a way to characterize the relief of direct voltage-dependent G protein regulation, was reduced by both FHM-1 mutations. Moreover, the kinetic analysis of the onset and decay of facilitation showed that the W1684R and V1696I mutations affect the apparent dissociation and reassociation rates of the Gbetagamma dimer from the channel complex, suggesting that the G protein-Ca(2+) channel affinity may be altered by the mutations. These biophysical studies may shed new light on the pathophysiology underlying FHM-1. PMID- 22549043 TI - Targeted knockdown of Cerkl, a retinal dystrophy gene, causes mild affectation of the retinal ganglion cell layer. AB - In order to approach the function of the retinal dystrophy CERKL gene we generated a novel knockout mouse model by cre-mediated targeted deletion of the Cerkl first exon and proximal promoter. The excised genomic region (2.3kb) encompassed the first Cerkl exon, upstream sequences including the proximal promoter and the initial segment of the first intron. The Cerkl-/- mice were viable and fertile. The targeted Cerkl deletion resulted in a knockdown more than a knockout model, given that alternative promoters (unreported at that time) directed basal expression of Cerkl (35%). In situ hybridizations and immunohistochemistry showed that this remnant expression was moderate in the photoreceptors and weak in the ganglion and inner cell layers. Morphological characterization of the Cerkl-/- retinas did not show any gross structural changes, even at 12 months of age. However, some clear and consistent signals of gliosis and retinal stress were detected by the statistically significant increase of i) the glial fibrillary antigen protein (GFAP) expression, and ii) apoptosis, as detected by TUNEL. Remarkably, consistent non-progressive perturbation (from birth up to 12 months of age) of ganglion cells was supported by the decrease of the Brn3a marker expression as well as the reduced oscillatory potentials in the electroretinographic recordings. In conclusion, the Cerkl-/- knockdown shows a mild retinal phenotype, with increased levels of cellular stress and apoptosis indicators, and clear signs of functional alteration at the ganglion cell layer, but no detectable morphological changes. PMID- 22549044 TI - Gene expression signatures modulated by epidermal growth factor receptor activation and their relationship to cetuximab resistance in head and neck squamous cell carcinoma. AB - BACKGROUND: Aberrant activation of signaling pathways downstream of epidermal growth factor receptor (EGFR) has been hypothesized to be one of the mechanisms of cetuximab (a monoclonal antibody against EGFR) resistance in head and neck squamous cell carcinoma (HNSCC). To infer relevant and specific pathway activation downstream of EGFR from gene expression in HNSCC, we generated gene expression signatures using immortalized keratinocytes (HaCaT) subjected to ligand stimulation and transfected with EGFR, RELA/p65, or HRASVal12D. RESULTS: The gene expression patterns that distinguished the HaCaT variants and conditions were inferred using the Markov chain Monte Carlo (MCMC) matrix factorization algorithm Coordinated Gene Activity in Pattern Sets (CoGAPS). This approach inferred gene expression signatures with greater relevance to cell signaling pathway activation than the expression signatures inferred with standard linear models. Furthermore, the pathway signature generated using HaCaT-HRASVal12D further associated with the cetuximab treatment response in isogenic cetuximab sensitive (UMSCC1) and -resistant (1CC8) cell lines. CONCLUSIONS: Our data suggest that the CoGAPS algorithm can generate gene expression signatures that are pertinent to downstream effects of receptor signaling pathway activation and potentially be useful in modeling resistance mechanisms to targeted therapies. PMID- 22549045 TI - Interruption of mother-to-infant transmission of hepatitis B: time to include selective antiviral prophylaxis? PMID- 22549046 TI - Hepatitis E. AB - Hepatitis E virus (HEV) was discovered during the Soviet occupation of Afghanistan in the 1980s, after an outbreak of unexplained hepatitis at a military camp. A pooled faecal extract from affected soldiers was ingested by a member of the research team. He became sick, and the new virus (named HEV), was detected in his stool by electron microscopy. Subsequently, endemic HEV has been identified in many resource-poor countries. Globally, HEV is the most common cause of acute viral hepatitis. The virus was not initially thought to occur in developed countries, but recent reports have shown this notion to be mistaken. The aim of this Seminar is to describe recent discoveries regarding HEV, and how they have changed our understanding of its effect on human health worldwide. PMID- 22549047 TI - Biomimetic chromatophores for camouflage and soft active surfaces. AB - Chromatophores are the pigment-containing cells in the skins of animals such as fish and cephalopods which have chromomorphic (colour-changing) and controllable goniochromic (iridescent-changing) properties. These animals control the optical properties of their skins for camouflage and, it is speculated, for communication. The ability to replicate these properties in soft artificial skin structures opens up new possibilities for active camouflage, thermal regulation and active photovoltaics. This paper presents the design and implementation of soft and compliant artificial chromatophores based on the cutaneous chromatophores in fish and cephalopods. We demonstrate artificial chromatophores that are actuated by electroactive polymer artificial muscles, mimicking the radially orientated muscles found in natural chromatophores. It is shown how bio inspired chromomorphism may be achieved using both areal expansion of dielectric elastomer structures and by the hydrostatic translocation of pigmented fluid into an artificial dermal melanophore. PMID- 22549048 TI - Suspect sweetener: arsenic detected in organic brown rice syrup. PMID- 22549049 TI - Measuring net protease activities in biological samples using selective peptidic inhibitors. AB - The measurement of activities from individual proteases in biological samples is difficult because of the numerous proteases, their overlapping activities, and the lack of specific substrates. We applied selective protease inhibitors based on bicyclic peptides (>2000-fold selective over related proteases) to block individual proteases, allowing the quantification of their net activities. In protease mixtures, activity contributions of the serine proteases plasma kallikrein and urokinase-type plasminogen activator (uPA) were accurately quantified. In a tumor extract, we could quantify uPA activity. Because bicyclic peptide inhibitors toward virtually any protease can be generated by phage display, the approach should be applicable to any protease. PMID- 22549050 TI - Bovine-associated MRSA ST398 in the Netherlands. AB - During routinely screening (50.000 milk samples on an annual basis) 14 MRSA ST398 strains were identified in the period of January 2008 to September 2008 in 14 different dairy herds located in the provinces Overijssel and Gelderland, The Netherlands. Molecular analysis was performed by Cfr9I PFGE, ST398-specific diagnostic PCR, spa typing, SCCmec typing and Panton-Valentine Leukocidin (PVL) gene PCR. The molecular analyses of 14 MRSA (one MRSA strain per herd) strains revealed that all strains belong to ST398 with 3 closely related spa types (t011, t108 and t889, all commonly found in pigs) and carry 2 different SCCmec types, IVa and V. All MRSA strains were resistant to two or more classes of antibiotics and also PVL negative. The majority of farms (n = 9, 64%) harboured combined livestock with both cows and pigs present. Our study contributes to the growing evidence that MRSA ST398 is transmitted among various animal species and can be considered as an etiological agent of mastitis in dairy cows. PMID- 22549051 TI - Slipped capital femoral epiphysis in a patient with knee pain. PMID- 22549053 TI - Rupture of breast implant shell must be differentiated from gel bleed. PMID- 22549054 TI - Start treatment early to avoid Charcot foot deformity. PMID- 22549052 TI - Bioassay-guided discovery of antibacterial agents: in vitro screening of Peperomia vulcanica, Peperomia fernandopoioana and Scleria striatinux. AB - BACKGROUND: The global burden of bacterial infections is high and has been further aggravated by increasing resistance to antibiotics. In the search for novel antibacterials, three medicinal plants: Peperomia vulcanica, Peperomia fernandopoioana (Piperaceae) and Scleria striatinux (Cyperaceae), were investigated for antibacterial activity and toxicity. METHODS: Crude extracts of these plants were tested by the disc diffusion method against six bacterial test organisms followed by bio-assay guided fractionation, isolation and testing of pure compounds. The minimum inhibitory (MIC) and minimum bactericidal (MBC) concentrations were measured by the microdilution method. The acute toxicity of the active extracts and cytotoxicity of the active compound were performed in mice and mammalian cells, respectively. RESULTS: The diameter of the zones of inhibition (DZI) of the extracts ranged from 7-13 mm on Escherichia coli and Staphylococcus aureus of which the methylene chloride:methanol [1:1] extract of Scleria striatinux recorded the highest activity (DZI = 13 mm). Twenty-nine pure compounds were screened and one, Okundoperoxide, isolated from S. striatinux, recorded a DZI ranging from 10-19 mm on S. aureus. The MICs and MBCs indicated that the Peperomias had broad-spectrum bacteriostatic activity. Toxicity tests showed that Okundoperoxide may have a low risk of toxicity with an LC50 of 46.88 MUg/mL. CONCLUSIONS: The antibacterial activity of these plants supports their use in traditional medicine. The pure compound, Okundoperoxide, may yield new antibacterial lead compounds following medicinal chemistry exploration. PMID- 22549055 TI - Implications of "not me" drugs for health systems: lessons from age related macular degeneration. PMID- 22549056 TI - Anti-vascular endothelial growth factor treatment for eye diseases. PMID- 22549058 TI - On nakedness at work. Embrace your inner nudist. PMID- 22549057 TI - Why using Avastin for eye disease is so difficult. PMID- 22549059 TI - The problem is with the players and the choice of inappropriate tools. PMID- 22549060 TI - Childhood obesity increases blood pressure in adolescence, study shows. PMID- 22549061 TI - Going beyond the written word. PMID- 22549062 TI - Doctors' numeracy and communication skills need to improve. PMID- 22549063 TI - Don't forget ophthalmic differential diagnoses of cluster headache. PMID- 22549064 TI - Study of mobile phone use and glioma risk was fatally flawed. PMID- 22549065 TI - Association of mobile phone use with adult brain cancer remains plausible. PMID- 22549067 TI - Robust methods are needed to investigate association between white rice consumption and type 2 diabetes. PMID- 22549069 TI - In defence of white rice. PMID- 22549070 TI - FDA should tighten post-marketing surveillance of prescription drugs, says Institute of Medicine. PMID- 22549071 TI - Income and job satisfaction fall among US doctors. PMID- 22549072 TI - Older people who self harm need long term follow-up to reduce suicide risk. PMID- 22549073 TI - Kidnapped British health worker is found murdered in Pakistan. PMID- 22549074 TI - Experts consider how to tackle overtreatment in US healthcare. PMID- 22549075 TI - Proximal shift of advanced adenomas in the large bowel--does it really exist? AB - INTRODUCTION: During the last decades, the proximal shift in the distribution of colorectal carcinomas (CRCs) has been described. It is uncertain whether the shift is the result of actual changes in CRC incidence or reflects population aging. Most CRCs develop as a result of malignant progression of benign epithelial neoplasms--advanced adenomas (AA). OBJECTIVES: The aim of the study was to investigate whether the proximal shift of AA occurs over time. PATIENTS AND METHODS: Two databases were used. The first one (RETRO) included consecutive patients of the Department of Gastroenterology treated between the years 1981 and 1994. The secondone (Colonoscopy Screening Program--CSP) included asymptomatic participants of the colonoscopy screening program recruited between 2000 and 2004 from the Warsaw region. Only patients with AA who underwent total colonoscopy were included in the analysis. AA was defined as adenoma of 10 mm or more in diameter, with high-grade neoplasia, and villous or tubulovillous morphology, or any combination of the above features. The analysis was conducted using 2 different definitions of the proximal segment in the large intestine--either splenic flexure or the bend between the descending and sigmoid colon. To compare the distribution of AA, a multiple logistic regression model was used. RESULTS: 41 of 200 patients (20.5%) in RETRO and 122 of 430 patients (28.4%) in CSP group, respectively, were found to have AA located proximally to the splenic flexure. No proximal shift of AA was found after age and sex adjustment (P>0.1). CONCLUSIONS: The risk of having proximal AA was similar in both groups. The results suggest the lack of proximal shift in the distribution of advanced colorectal adenomas. PMID- 22549076 TI - WISH cell line: from the antiviral system to a novel reporter gene assay to test the potency of human IFN-alpha and IFN-beta. AB - Interferons (IFNs) are potent biologically active proteins that are widely used as biopharmaceuticals, so their potency must be correctly identified. Usually, the biological activity is quantified by a bioassay based on its capacity to induce an antiviral state in target cells, but this type of assays is subject to virus manipulation-related issues and they show considerable intra- and inter assay variability. In this work, we generated a reporter gene assay (RGA) supported on the WISH-Mx/eGFP reporter cell line to determine human type I IFN activity. WISH cells were stably transfected with the enhanced green fluorescent protein (eGFP) gene under the control of type I IFN-inducible Mx2 promoter. This system implies the use of a standardized cell line for human IFN-potency analysis such as WISH cells and the simultaneous use of the sensitive reporter gene eGFP, having also several advantages when compared to antiviral activity assays and other RGAs: it can determine the potency of hIFN-alpha and hIFN-beta using only one cell line showing the highest expression of eGFP after 28h and being only observed in cells treated with type I IFNs due to the specificity of the Mx promoter. It is a sensitive assay and it represents a safe alternative when compared with the conventional antiviral tests. The cell line showed the same sensitivity along 57 generations, allowing its use during two months of successive culture. The inter- and intra-assay coefficients of variation were lower than 20%, demonstrating its reproducibility. In addition, this reporter cell line can be used for the conventional antiviral assay, either for hIFN-alpha or hIFN-beta. In conclusion, we have developed an alternative reporter system for the analysis of type I IFNs, in which its performance make it a suitable candidate to replace or complement conventional bioassays that are currently employed to measure IFN potency. PMID- 22549077 TI - A workflow-oriented framework-driven implementation and local adaptation of clinical information systems: a case study of nursing documentation system implementation at a tertiary rehabilitation hospital. AB - Health information systems are often designed and developed without integrating users' specific needs and preferences. This decreases the users' productivity, satisfaction, and acceptance of the system and increases the necessity for a local adaptation process to reduce the unwanted outcomes after implementation. A workflow-oriented framework developed in a previous study indicates that users' needs and preferences could be incorporated into the system when implementation follows the steps of the framework, eventually increasing satisfaction with and usefulness of the system. The overall goal of this study was to demonstrate application of the workflow-oriented framework to the implementation of a nursing documentation system at Spaulding Rehabilitation Hospital. In this case study, we present specific steps of implementing and adapting a health information system at a local site and raise critical questions that need to be answered in each step based on the workflow-oriented framework. PMID- 22549078 TI - Dehydrogenation inhibition on nano-Au/ZSM-5 catalyst: a novel route for anti coking in methanol to propylene reaction. AB - A novel route for anti-deactivation of methanol-to-propylene catalyst has been established through supporting nano-gold on ZSM-5, which efficiently reinforces the catalytic stability due to the effect of gold nanoparticles on the stabilization of dehydrogenation intermediates within the coking process. PMID- 22549079 TI - Landscape fire smoke as a cause of death: burning vegetation estimated to kill hundreds of thousands worldwide. PMID- 22549080 TI - Cellular uptake studies of two hexanuclear, carboxylate bridged, zinc ring structures using fluorescence microscopy. AB - Two hexanuclear zinc complexes have been structurally characterized, and evaluation against several cells showed selective toxicity. Cellular uptake revealed a non-specific process, resulting in accumulation within the cell cytoplasm. PMID- 22549082 TI - Type 1 Chiari malformation. PMID- 22549081 TI - Molecular dynamics and free energy studies on the carboxypeptidases complexed with peptide/small molecular inhibitor: mechanism for drug resistance. AB - As one potent plant protease inhibitor, potato carboxypeptidase inhibitor (PCI) can competitively inhibit insect digestive metallocarboxypeptidases (MCPs) through interfering with its digestive system that causes amino acid deficiencies and leading to serious developmental delay and mortality. However, this effective biological pest control is significantly impaired by the PCI-resistant insect MCPs. Therefore, deep understanding of the resistant mechanism of insect MCPs is particularly necessary for designing new durable pest control regimen and developing effective pesticides. In this study, the binding of PCI and small molecular inhibitor THI to insect PCI-sensitive/-resistant MCPs and human MCP was investigated by docking, molecular dynamics (MD) simulations and thermodynamic analysis. The structural analysis from MD simulations indicates that the PCI resistant mechanism of CPBHz is mainly dominated by the Trp277A, which changes the conformation of beta8-alpha9 loop and therefore narrow the access to the active site of CPBHz, prohibiting the entrance of the C termini tail of PCI. Additionally, the insertion of Gly247A weakens the stabilization of CPBHz and PCI through disrupting the hydrogen bond formation with its surrounding residues. Furthermore, the predicted binding free energies gives explanation of structure affinity relationship of PCI and THI with MCPs and suggest that the electrostatic energy is the main contribution term affecting the difference in binding affinities. Finally, the decomposition analysis of binding free energies infers that the key residues Glu72, Arg127, Ile247/Leu247 and Glu270 are critical for the binding of PCI/THI to MCPs. PMID- 22549083 TI - Inorganic-organic hybrid compounds based on novel lanthanide-antimony oxohalide nanoclusters. AB - Presented here is the assembly of two inorganic-organic hybrid compounds by the combination of novel praseodymium-antimony oxochloride clusters and dicarboxylic ligands co-directed by 2-MepyH and Fe(1,10-phen)(3) (or Fe(2,2'-bpy)(3)), which feature a two-fold interpenetrating three-dimensionally anionic network and a one dimensionally helical anionic chain, respectively. PMID- 22549084 TI - Transference of kettlebell training to strength, power, and endurance. AB - Kettlebells are a popular implement in many strength and conditioning programs, and their benefits are touted in popular literature, books, and videos. However, clinical data on their efficacy are limited. The purpose of this study was to examine whether kettlebell training transfers strength and power to weightlifting and powerlifting exercises and improves muscular endurance. Thirty-seven subjects were assigned to an experimental (EXP, n = 23; mean age = 40.9 +/- 12.9 years) or a control group (CON; n = 14; mean age = 39.6 +/- 15.8 years), range 18-72 years. The participants were required to perform assessments including a barbell clean and jerk, barbell bench press, maximal vertical jump, and 45 degrees back extensions to volitional fatigue before and after a 10-week kettlebell training program. Training was structured in a group setting for 2 d.wk(-1) for 10 weeks. A repeated measures analysis of variance was conducted to determine group * time interactions and main effects. Post hoc pairwise comparisons were conducted when appropriate. Bench press revealed a time * group interaction and a main effect (p < 0.05). Clean and jerk and back extension demonstrated a trend toward a time * group interaction, but it did not reach significance (p = 0.053). However, clean and jerk did reveal a main effect for time (p < 0.05). No significant findings were reported for maximal vertical jump. The results demonstrate a transfer of power and strength in response to 10 weeks of training with kettlebells. Traditional training methods may not be convenient or accessible for strength and conditioning specialists, athletes, coaches, and recreational exercisers. The current data suggest that kettlebells may be an effective alternative tool to improve performance in weightlifting and powerlifting. PMID- 22549085 TI - Comparison of three baseball-specific 6-week training programs on throwing velocity in high school baseball players. AB - Throwing velocity is an important baseball performance variable for baseball pitchers, because greater throwing velocity results in less time for hitters to make a decision to swing. Throwing velocity is also an important baseball performance variable for position players, because greater throwing velocity results in decreased time for a runner to advance to the next base. This study compared the effects of 3 baseball-specific 6-week training programs on maximum throwing velocity. Sixty-eight high school baseball players 14-17 years of age were randomly and equally divided into 3 training groups and a nontraining control group. The 3 training groups were the Throwers Ten (TT), Keiser Pneumatic (KP), and Plyometric (PLY). Each training group trained 3 d.wk(-1) for 6 weeks, which comprised approximately 5-10 minutes for warm-up, 45 minutes of resistance training, and 5-10 for cool-down. Throwing velocity was assessed before (pretest) and just after (posttest) the 6-week training program for all the subjects. A 2 factor repeated measures analysis of variance with post hoc paired t-tests was used to assess throwing velocity differences (p < 0.05). Compared with pretest throwing velocity values, posttest throwing velocity values were significantly greater in the TT group (1.7% increase), the KP group (1.2% increase), and the PLY group (2.0% increase) but not significantly different in the control group. These results demonstrate that all 3 training programs were effective in increasing throwing velocity in high school baseball players, but the results of this study did not demonstrate that 1 resistance training program was more effective than another resistance training program in increasing throwing velocity. PMID- 22549086 TI - Restoration of the work capacity of the skeletal muscle with electrical myostimulation. AB - The aim of this study was to evaluate the effects of applying mild electrical myostimulation (EMS) or passive rest (PR) on restoring the work capacity (WC) of the skeletal muscles in athletes. Nineteen long-distance runners participated in the study. They were divided into 2 groups according to the principle of rotation: a PR (control) and an EMS (experimental) group. They were examined before training and 10 minutes, 4 hours, and 18 hours after training. Muscle motor function was measured as the maximal voluntary contraction (MVC) and WC. The intensity of the arterial blood flow and the venous reserve volume with venous occlusion plethysmography, and the stroke volume, cardiac output, and heart rate with tetrapolar rheography were determined. The application of EMS significantly increased the MVC and WC of the calf muscles (p <= 0.05) compared with the corresponding parameters recorded after PR. The venous reserve volumes after PR (0.61 +/- 0.07 ml per 100 ml) and EMS (0.91 +/- 0.11 ml per 100 ml) differed significantly (p <= 0.05). Mild EMS is an effective local method of restoring the WC of the muscles. It is greatly superior to PR, which is the traditional way of recovering from exercise. The increased WC of the muscle was mediated by improved blood flow in the stimulated muscles and an increased venous blood pump. The systemic circulation, evaluated with cardiac indicators such as stroke volume, cardiac output, and heart rate, played no significant role in the effect. PMID- 22549087 TI - Effect of vehicle configuration on the performance of a submersible pulsed-jet vehicle at intermediate Reynolds number. AB - Recent results have demonstrated that pulsed-jet propulsion can achieve propulsive efficiency greater than that for steady jets when short, high frequency pulses are used, and the pulsed-jet advantage increases as Reynolds number decreases into the intermediate range (~50). An important aspect of propulsive performance, however, is the vehicle configuration. The nozzle configuration influences the jet speed and, in the case of pulsed-jets, the formation of the vortex rings with each jet pulse, which have important effects on thrust. Likewise, the hull configuration influences the vehicle speed through its effect on drag. To investigate these effects, several flow inlet, nozzle, and hull tail configurations were tested on a submersible, self-propelled pulsed-jet vehicle ('Robosquid' for short) for jet pulse length-to-diameter ratios (L/D) in the range 0.5-6 and pulsing duty cycles (St(L)) of 0.2 and 0.5. For the configurations tested, the vehicle Reynolds number (Re(upsilon)) ranged from 25 to 110. In terms of propulsive efficiency, changing between forward and aft facing inlets had little effect for the conditions considered, but changing from a smoothly tapered aft hull section to a blunt tail increased propulsive efficiency slightly due to reduced drag for the blunt tail at intermediate Re(upsilon). Sharp edged orifices also showed increased vehicle velocity and propulsive efficiency in comparison to smooth nozzles, which was associated with stronger vortex rings being produced by the flow contraction through the orifice. Larger diameter orifices showed additional gains in propulsive efficiency over smaller orifices if the rate of mass flow was matched with the smaller diameter cases, but using the same maximum jet velocity with the larger diameter decreased the propulsive efficiency relative to the smaller diameter cases. PMID- 22549089 TI - Research priorities for global measles and rubella control and eradication. AB - In 2010, an expert advisory panel convened by the World Health Organization to assess the feasibility of measles eradication concluded that (1) measles can and should be eradicated, (2) eradication by 2020 is feasible if measurable progress is made toward existing 2015 measles mortality reduction targets, (3) measles eradication activities should occur in the context of strengthening routine immunization services, and (4) measles eradication activities should be used to accelerate control and elimination of rubella and congenital rubella syndrome (CRS). The expert advisory panel also emphasized the critical role of research and innovation in any disease control or eradication program. In May 2011, a meeting was held to identify and prioritize research priorities to support measles and rubella/CRS control and potential eradication activities. This summary presents the questions identified by the meeting participants and their relative priority within the following categories: (1) measles epidemiology, (2) vaccine development and alternative vaccine delivery, (3) surveillance and laboratory methods, (4) immunization strategies, (5) mathematical modeling and economic analyses, and (6) rubella/CRS control and elimination. PMID- 22549088 TI - Cognitive outcome of offspring from dexamethasone-treated pregnancies at risk for congenital adrenal hyperplasia due to 21-hydroxylase deficiency. AB - OBJECTIVES: To test whether dexamethasone (DEX) treatment in pregnancies at risk for congenital adrenal hyperplasia (CAH) impairs cognitive functioning in the offspring. DESIGN: Observational follow-up of prenatally DEX-exposed offspring and controls. METHODS: Study 1 included 140 children aged 512 years: 67 DEX exposed (long-term: eight CAH girls) and 73 unexposed (with 15 CAH girls). Study 2 included 20 participants aged 11-24 years: seven DEX-exposed (long-term: one CAH woman) and 13 unexposed (with four CAH women). Neuropsychological testing was done in hospital settings or at patients' homes. Data analysis aimed at maximizing detection of the effects of DEX exposure. RESULTS: The vast majority of group comparisons were not marginally or conventionally significant. The few significant findings on short-term prenatal DEX exposure suggested more positive than adverse outcomes. By contrast, few significant findings in females with CAH and long-term DEX exposure indicated slower mental processing than in controls on several neuropsychological variables, although partial correlations of DEX exposure duration with cognitive outcome did not corroborate this association. CONCLUSIONS: Although our studies do not replicate a previously reported adverse effect of short-term prenatal DEX exposure on working memory, our findings on cognitive function in CAH girls with long-term DEX exposure contribute to concerns about potentially adverse cognitive after effects of such exposure. Yet, our studies are not definitive, and replications in larger samples are required. PMID- 22549090 TI - Indicators of therapeutic effect in FIT-06, a Phase II trial of a DNA vaccine, GTU((r))-Multi-HIVB, in untreated HIV-1 infected subjects. AB - BACKGROUND: Combination highly active antiretroviral therapy (HAART) has significantly decreased HIV-1 related morbidity and mortality globally transforming HIV into a controllable condition. HAART has a number of limitations though, including limited access in resource constrained countries, which have driven the search for simpler, affordable HIV-1 treatment modalities. Therapeutic HIV-1 vaccines aim to provide immunological support to slow disease progression and decrease transmission. We evaluated the safety, immunogenicity and clinical effect of a novel recombinant plasmid DNA therapeutic HIV-1 vaccine, GTU((r)) multi-HIVB, containing 6 different genes derived from an HIV-1 subtype B isolate. METHODS: 63 untreated, healthy, HIV-1 infected, adults between 18 and 40 years were enrolled in a single-blinded, placebo-controlled Phase II trial in South Africa. Subjects were HIV-1 subtype C infected, had never received antiretrovirals, with CD4 >= 350 cells/mm(3) and pHIV-RNA >= 50 copies/mL at screening. Subjects were allocated to vaccine or placebo groups in a 2:1 ratio either administered intradermally (ID) (0.5mg/dose) or intramuscularly (IM) (1mg/dose) at 0, 4 and 12 weeks boosted at 76 and 80 weeks with 1mg/dose (ID) and 2mg/dose (IM), respectively. Safety was assessed by adverse event monitoring and immunogenicity by HIV-1-specific CD4+ and CD8+ T-cells using intracellular cytokine staining (ICS), pHIV-RNA and CD4 counts. RESULTS: Vaccine was safe and well tolerated with no vaccine related serious adverse events. Significant declines in log pHIV-RNA (p=0.012) and increases in CD4+ T cell counts (p=0.066) were observed in the vaccine group compared to placebo, more pronounced after IM administration and in some HLA haplotypes (B*5703) maintained for 17 months after the final immunisation. CONCLUSIONS: The GTU((r))-multi-HIVB plasmid recombinant DNA therapeutic HIV-1 vaccine is safe, well tolerated and favourably affects pHIV RNA and CD4 counts in untreated HIV-1 infected individuals after IM administration in subjects with HLA B*57, B*8101 and B*5801 haplotypes. PMID- 22549091 TI - Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy. AB - BACKGROUND & AIMS: Homozygous loss of function mutations in interleukin-10 (IL10) and interleukin-10 receptors (IL10R) cause severe infantile (very early onset) inflammatory bowel disease (IBD). Allogeneic hematopoietic stem cell transplantation (HSCT) was reported to induce sustained remission in 1 patient with IL-10R deficiency. We investigated heterogeneity among patients with very early onset IBD, its mechanisms, and the use of allogeneic HSCT to treat this disorder. METHODS: We analyzed 66 patients with early onset IBD (younger than 5 years of age) for mutations in the genes encoding IL-10, IL-10R1, and IL-10R2. IL 10R deficiency was confirmed by functional assays on patients' peripheral blood mononuclear cells (immunoblot and enzyme-linked immunosorbent assay analyses). We assessed the therapeutic effects of standardized allogeneic HSCT. RESULTS: Using a candidate gene sequencing approach, we identified 16 patients with IL-10 or IL 10R deficiency: 3 patients had mutations in IL-10, 5 had mutations in IL-10R1, and 8 had mutations in IL-10R2. Refractory colitis became manifest in all patients within the first 3 months of life and was associated with perianal disease (16 of 16 patients). Extraintestinal symptoms included folliculitis (11 of 16) and arthritis (4 of 16). Allogeneic HSCT was performed in 5 patients and induced sustained clinical remission with a median follow-up time of 2 years. In vitro experiments confirmed reconstitution of IL-10R-mediated signaling in all patients who received the transplant. CONCLUSIONS: We identified loss of function mutations in IL-10 and IL-10R in patients with very early onset IBD. These findings indicate that infantile IBD patients with perianal disease should be screened for IL-10 and IL-10R deficiency and that allogeneic HSCT can induce remission in those with IL-10R deficiency. PMID- 22549093 TI - Effect of zinc in animal models of anxiety, depression and psychosis. AB - The role of zinc (Zn) in anxiety, depression and psychosis was studied in rodents. Zn was administered at doses of 15 and 20 mg/kg intraperitoneally for 7 days. Both doses of Zn reduced the immobility time and increased the swimming time in the modified forced swim test. In the elevated plus maze test, increases in the number of open arm entries and time spent in the open arms were observed with both doses of Zn. In the amphetamine (1 and 2 mg/kg subcutaneously) induced locomotor activity test both doses of Zn produced reduction in the total movement time, mean velocity and stereotypic movements. Extrapyramidal symptoms such as catalepsy in animals are usually observed with conventional antipsychotic agents; but in the present study, Zn at doses of 15 and 20 mg/kg did not produce any cataleptic state in mice. The results of the present study demonstrated the anxiolytic, antidepressant and antipsychotic-like effects of Zn metal ion, which may be due to its N-methyl d-aspartate receptor antagonistic activity. Concurrent administration of a lower dose of Zn with standard existing anxiolytic and antidepressant drugs in this study showed potentiating effect, suggesting that Zn could exert beneficial role when prescribed as add-on medicine in the psychiatric illnesses. The results obtained in this study are preliminary, as further research is required to confirm the exact role of Zn metal in the investigated central nervous system disorders. PMID- 22549092 TI - Basiliximab does not increase efficacy of corticosteroids in patients with steroid-refractory ulcerative colitis. AB - BACKGROUND & AIMS: Basiliximab is a chimeric monoclonal antibody that binds CD25 and thereby inhibits interleukin (IL)-2-mediated proliferation of lymphocytes. IL 2 might contribute to the resistance of T cells to corticosteroids. We investigated the efficacy and safety of basiliximab as a corticosteroid sensitizing agent in patients with corticosteroid-refractory ulcerative colitis (UC). METHODS: We studied 149 patients with moderate to severe UC (Mayo score >=6 and endoscopic subscore >=2) despite treatment for at least 14 days with oral prednisone (40-50 mg/day). Subjects were randomly assigned to groups that were given 20 mg (n = 46) or 40 mg (n = 52) basiliximab or placebo (n = 51) at weeks 0, 2, and 4. All subjects received 30 mg/day prednisone through week 2; the dose was reduced by 5 mg each week to 20 mg/day, which was maintained until week 8. At week 8, we compared the rates of clinical remission (Mayo score <=2, no subscore >1) for patients given basiliximab with the rate for patients given placebo. RESULTS: Twenty-eight percent of patients given placebo, 29% of those given the 40-mg dose of basiliximab, and 26% of those given the 20-mg dose of basiliximab achieved clinical remission (P = 1.00 vs placebo for each dose). Basiliximab was generally well tolerated. Six subjects who received basiliximab had serious adverse events (6.1%) compared with 2 who received placebo (3.9%; P = .72). In subjects given basiliximab, incomplete saturation of CD25 (<50%) on peripheral T cells was associated with the presence of anti-basiliximab antibodies (odds ratio, 21; 95% confidence interval, 2.4-184). CONCLUSIONS: Basiliximab does not increase the effect of corticosteroids in the induction of remission in outpatients with corticosteroid-resistant moderate to severe UC. PMID- 22549095 TI - Cyclosporin A causes impairment of the ventral prostate tissue structure of Wistar rats. AB - Cyclosporin A (CsA) is an immunosuppressive drug widely used in medicine to reduce the immune system activity and, therefore, the risk of organ rejection after transplantation. However, many side effects can be related to its use, such as, reduction in serum testosterone levels due to damage of the testis structure and, consequently, male infertility. The present study aims to evaluate the effects of chronic CsA administration on the ventral prostate tissue (15 mg/kg per d, for 56 days). Stereological, morphometrical, morphological and ultrastructural observations were employed. The plasmatic testosterone and glucose levels were measured. An androgen receptor (AR) immunohistochemical method was applied on ventral prostate sections. Apoptosis was detected with the terminal deoxynucleotidyl transferase dUTP nick end labeling technique. CsA treatment caused reduction in plasmatic testosterone levels and an increase in glycemia. The volume of all ventral prostate tissue components (lumen, epithelium and muscular and nonmuscular stroma) and ventral prostate weight were reduced in the CsA-treated group. Light and transmission electron microscopy confirmed epithelium atrophy of treated animals. There was no alteration of AR expression or apoptotic index. CsA chronic treatment in the therapeutic doses caused damage to prostate tissue of adult Wistar rats, probably due to increase in the glucose levels and reduction in the plasmatic testosterone levels. PMID- 22549094 TI - Protective effect of omega-3 polyunsaturated fatty acids (PUFAs) on sodium nitroprusside-induced nephrotoxicity and oxidative damage in rat kidney. AB - Sodium nitroprusside (SNP) a nitric oxide (NO) donor has proven toxic effects. Dietary omega-3 polyunsaturated fatty acid (PUFA) has been shown to reduce the severity of numerous ailments. Present study examined whether intake of fish oil (FO)/flaxseed oil (FXO, Omega Nutrition, St Vancouver, Canada) would have protective effect against SNP-induced toxicity. Male Wistar rats (150 +/- 10 g) were used in this study. Initially animals were divided into two groups: one fed on normal diet and the other on 15% FO/FXO for 15 days. On the 16th day, SNP (1.5 mg/kg body weight) was administered intraperitoneally for 7 days daily. After 7 days animals were killed, kidneys were harvested for further analysis. SNP induced nephrotoxicity by increasing serum creatinine and blood urea nitrogen, SNP significantly decreased malate dehydrogenase, glucose-6-phosphatase, fructose 1,6-bisphosphatase and malic enzyme but increased lactate dehydrogenase and glucose-6-phosphate dehydrogenase. Brush border membrane enzymes such as alkaline phosphatase, gamma-glutamyl transpeptidase and leucine amino peptidase were also decreased. The activity of catalase and glutathione peroxidase decreased concomitantly with increased lipid peroxidation, indicating that the significant kidney damage has been inflicted by SNP. Feeding of FO and FXO with SNP ameliorated the changes in various parameters caused by SNP. The results of the present study suggest that omega-3 PUFA-enriched FO and FXO from seafoods and plant sources, respectively, are similarly effective in reducing SNP-induced nephrotoxicity and oxidative damage. Thus, vegetarians who cannot consume FO can have similar health benefits from plant-derived omega-3 PUFA. PMID- 22549096 TI - Long-term retention of injected aluminium-26. AB - Data previously reported on the whole-body retention of aluminium-26 ((26)Al) in a male volunteer are extended to 8 years after intravenous administration as citrate, when only ~2% of the injected tracer remained. The extended data, combined with a report elsewhere of the late urinary and faecal excretion of (26)Al by this subject, reinforce indications that transdermal losses contribute to the clearance of systemic aluminium and mitigate its long-term accumulation from chronic exposure. PMID- 22549097 TI - Pharmacokinetics of levodopa/carbidopa microtablets versus levodopa/benserazide and levodopa/carbidopa in healthy volunteers. AB - OBJECTIVES: To compare bioavailability and pharmacokinetics of single doses of 3 different levodopa formulations given orally in healthy volunteers. Two marketed formulations, standard levodopa/carbidopa, 100/25 mg (LC-100), and dispersible levodopa/benserazide, 100/25 mg (LB-100), were used as reference formulations for a newly developed dispersible microtablet formulation of levodopa/carbidopa, 5/1.25 mg (LC-5). The microtablets are intended for individualized dosing of levodopa/carbidopa in Parkinson disease by means of an electronic dose dispenser with a built-in diary for symptom registration. METHODS: A single-dose, open, randomized, 3-way crossover study was performed in 19 healthy subjects. Concentrations of levodopa, carbidopa, and the metabolite 3-O-MD in plasma were determined after intake of 100 mg of levodopa, that is, one tablet of reference formulations and 20 microtablets of the new formulation. RESULTS: The LC-5 microtablets were bioequivalent to the LC-100 tablets in area under the curve (AUC) and maximum concentration in plasma (Cmax) for levodopa, and to the LB-100 tablets in AUC. The dispersible levodopa/benserazide formulation showed earlier time to Cmax and significantly higher Cmax for levodopa in plasma compared to the microtablets. Carbidopa showed larger interindividual variation in AUC and Cmax than levodopa, and the bioequivalence comparison LC-5/LC-100 for this compound did not reach the target. Nevertheless, comparison of 3-O-MD levels for LC-5/LC 100, assuming proportionality to levodopa levels, demonstrated bioequivalence. CONCLUSIONS: The new levodopa/carbidopa microtablets had a pharmacokinetic profile that would allow for a convenient switch of therapy from standard tablets. Frequent dose administration of levodopa/carbidopa microtablets with an electronic dose dispenser might offer an optimal oral drug delivery in Parkinson disease. PMID- 22549098 TI - Plasma asymmetric dimethylarginine in active rheumatoid arthritis: links with oxidative stress and inflammation. AB - INTRODUCTION: Endothelial dysfunction and accumulation of asymmetric dimethylarginine (ADMA) have been identified as independent predictors of future cardiovascular events in patients with coronary artery disease. OBJECTIVES: The aim of the study was to investigate the factors that determine increased accumulation of ADMA, an endogenous inhibitor of nitric oxide synthesis, in patients with rheumatoid arthritis (RA). PATIENTS AND METHODS: We studied 46 consecutive patients with RA (39 women, 7 men; mean age, 57 years [range, 23-75 years]) with active disease (mean Disease Activity Score 28 [DAS28], 5.2), without clinically overt cardiovascular disease and 50 controls matched for age, sex, hypertension, blood cholesterol, and glucose. We assessed the plasma levels of ADMA, symmetric dimethylarginine (SDMA), L-arginine, and the marker of oxidative stress, 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha). RESULTS: ADMA and SDMA levels were significantly higher in the RA group than in controls (0.58 +/-0.081 vs. 0.46 +/-0.045 MUmol/l, P <0.0001; 0.45 +/-0.07 vs. 0.36 +/-0.046 MUmol/l, P <0.0001; respectively). ADMA levels in the RA group correlated positively with fibrinogen (r = 0.70, P <0.00001), C-reactive protein (CRP; r = 0.88, P <0.00001), DAS28 (r = 0.44, P = 0.002) and Health Assessment Questionnaire scores (r = 0.39, P = 0.008), but not with age, renal function, or the medications used. 8-iso-PGF2alpha correlated positively with ADMA (r = 0.82), SDMA (r = 0.72), CRP (r = 0.76), fibrinogen (r = 0.57) (all, P <0.0001) and DAS28 (r = 0.44, P = 0.003). Regression analysis models showed that CRP was the only independent predictor of 8-iso-PGF2alpha and ADMA levels in RA. CONCLUSIONS: Our study is the first to show positive associations between plasma ADMA levels and the production of 8-isoprostanes and CRP in RA. PMID- 22549099 TI - May 2012 Letter to the Editor-in-Chief. PMID- 22549100 TI - Inflammatory immune responses in a reproducible mouse brain death model. AB - BACKGROUND: Brain death impairs donor organ quality and accelerates immune responses after transplantation. Detailed aspects of immune activation following brain death remain unclear. We have established a mouse model and investigated the immediate consequences of brain death and anesthesia on immune responses. METHODS: C57JBl/6 mice (n=6/group) were anesthetized with isoflurane (ISF) or ketamine/xylazine (KX); subsequently, animals underwent brain death induction and were followed for 3h under continuous ventilation. Blood pressure was monitored continuously and animals were resuscitated with normal saline to achieve normotension. Immune activation in brain dead animals was analyzed by IFNgamma ELispot, MLR, and flow-cytometry. Sham-operated and naive animals served as controls. RESULTS: Blood pressure remained stable in both BD/KX and BD/ISF animals during the 3h observation time. Brain death was linked to systemic immune activation: IFNgamma-expression of splenocytes and lymphocyte proliferation rates was significantly elevated subsequent to brain death (p<0.02, <0.01); T-cell activation markers CD28 and CD69 had increased in brain dead animals (p<0.03, <0.02). Isoflurane treatment in sham controls throughout the observation period (3.5h) revealed anesthesia associated IFNgamma-expression and lymphocyte activation which were not observed when animals were treated with ketamine/xylazine (p<0.04, <0.009). CONCLUSIONS: This study reports on a reproducible and hemodynamically stable brain death mouse model. Hemodynamic stability was not impacted through either isoflurane or ketamine/xylazine induction. Of clinical relevance, prolonged anesthesia with isoflurane had been linked to pro-inflammatory cytokine activation. Brain death caused systemic immune activation in organ donors. PMID- 22549101 TI - Hearts over time: cardiovascular mortality risk linked to long-term PM2.5 exposure. PMID- 22549102 TI - Does CT colonography have a role for population-based colorectal cancer screening? AB - Colorectal cancer (CRC) is the second most common cancer and second most common cause of cancer-related deaths in Europe. CRC screening has been proven to reduce disease-specific mortality and several European countries employ national screening programmes. These almost exclusively rely on stool tests, with endoscopy used as an adjunct in some countries. Computed tomographic colonography (CTC) is a potential screening test, with an estimated sensitivity of 88 % for advanced neoplasia >=10 mm. Recent randomised studies have shown that CTC and colonoscopy have similar yields of advanced neoplasia per screened invitee, indicating that CTC is potentially viable as a primary screening test. However, the evidence is not fully elaborated. It is unclear whether CTC screening is cost effective and the impact of extracolonic findings, both medical and economic, remains unknown. Furthermore, the effect of CTC screening on CRC-related mortality is unknown, as it is also unknown for colonoscopy. It is plausible that both techniques could lead to decreased mortality, as for sigmoidoscopy and gFOBT. Although radiation exposure is a drawback, this disadvantage may be over emphasised. In conclusion, the detection characteristics and acceptability of CTC suggest it is a viable screening investigation. Implementation will depend on detection of extracolonic disease and health-economic impact. Key Points * Meta analysis of CT colonographic screening showed high sensitivity for advanced neoplasia >=10mm. * CTC, colonoscopy and sigmoidoscopy screening all have similar yields for advanced neoplasia. * Good quality information regarding the cost effectiveness of CTC screening is lacking. * There is little good quality data regarding the impact of extracolonic findings. * CTC triage is not clinically effective in first round gFOBT/FIT positives. PMID- 22549103 TI - 18F-FDG uptake by spleen helps rapidly predict the dose level after total body irradiation in a Tibetan minipig model. AB - OBJECTIVES: To investigate whether (18)F- FDG uptake can be applied in dosimetry to facilitate the rapid and accurate evaluation of individual radiation doses after a nuclear accident. METHODS: Forty-eight Tibetan minipigs were randomised into a control group (n = 3) and treatment groups (n = 45). (18)F-FDG combined positron-emission tomography and computed tomography (PET/CT) were carried out before total body irradiation (TBI) and at 6, 24 and 72 h after receiving TBI doses ranging from 1 to 11 Gy. Spleen tissues and blood samples were also collected for histological examination, apoptosis and blood analysis. RESULTS: Mean standardised uptake values (SUVs) of the spleen showed significant differences between the experimental and the control groups. Spleen SUV at 6 h post-irradiation showed significant correlation with radiation dose; Spearman's correlation coefficient was 0.97 (P < 0.01). Histological observations showed that damage to the splenic lymphocyte became more severe with an increase in the radiation dose. Moreover, apoptosis was one of the major routes of splenic lymphocyte death, which was also confirmed by flow cytometry analysis. CONCLUSIONS: In the Tibetan minipig model, radiation doses have a close relationship with the (18)F-FDG uptake of the spleen. This finding suggests that (18)F-FDG PET/CT may be useful for the rapid detection of individual radiation doses. PMID- 22549104 TI - Automated tube potential selection for standard chest and abdominal CT in follow up patients with testicular cancer: comparison with fixed tube potential. AB - OBJECTIVE: To evaluate prospectively, in patients with testicular cancer, the radiation dose-saving potential and image quality of contrast-enhanced chest and abdominal CT with automated tube potential selection. METHODS: Forty consecutive patients with testicular cancer underwent contrast-enhanced arterio-venous chest and portal-venous abdominal CT with automated tube potential selection (protocol B; tube potential 80-140 kVp), which is based on the attenuation of the CT topogram. All had a first CT at 120 kVp (protocol A) using the same 64-section CT machine and similar settings. Image quality was assessed; dose information (CTDI(vol)) was noted. RESULTS: Image noise and attenuation in the liver and spleen were significantly higher for protocol B (P < 0.05 each), whereas attenuation in the deltoid and erector spinae muscles was similar. In protocol B, tube potential was reduced to 100 kVp in 18 chest and 33 abdominal examinations, and to 80 kVp in 5 abdominal CT examinations; it increased to 140 kVp in one patient. Image quality of examinations using both CT protocols was rated as diagnostic. CTDI(vol) was significantly lower for protocol B compared to protocol A (reduction by 12%, P < 0.01). CONCLUSION: In patients with testicular cancer, radiation dose of chest and abdominal CT can be reduced with automated tube potential selection, while image quality is preserved. PMID- 22549105 TI - Magnetic resonance imaging of the active second stage of labour: proof of principle. AB - OBJECTIVE: To prove that magnetic resonance imaging of foetal anatomy during the active second stage of vaginal delivery is feasible. MATERIALS AND METHODS: Initially, five pregnant volunteers around the 30th week of gestation were examined in an open MRI. Based on the findings, one vaginal delivery was acquired under real-time imaging. To monitor the birth status during image acquisition, an MR-compatible wireless cardiotocography (CTG) system was built. Single-shot sequence parameters were optimised to compensate motion artefacts during labour. RESULTS: Safety requirements to monitor the birth process under real-time MR imaging were met. High-resolution MR images were acquired immediately before and after delivery. In one patient, TSE single-shot cinematic sequences of the active second stage of labour were obtained. All sequences were adapted to tolerate movement of the mother and infant, as well as residual noise from the CTG. Furthermore, the MR imaging during labour showed only minor image artefacts. CONCLUSION: CTG-monitored acquisition of MRI series during the active second stage of delivery is feasible. Image quality should allow various further studies to improve models for birth simulation as well as potential investigation of obstructed labour and obstetric complications. PMID- 22549106 TI - Optimising diffusion-weighted MR imaging for demonstrating pancreatic cancer: a comparison of respiratory-triggered, free-breathing and breath-hold techniques. AB - OBJECTIVES: To compare respiratory-triggered, free-breathing, and breath-hold DWI techniques regarding (1) image quality, and (2) signal intensity (SI) and ADC measurements in pancreatic ductal adenocarcinoma (PDAC). METHODS: Fifteen patients with histopathologically proven PDAC underwent DWI prospectively at 1.5 T (b = 0, 50, 300, 600 and 1,000 s/mm(2)) with the three techniques. Two radiologists, independently and blindly, assigned total image quality scores [sum of rating diffusion images (lesion detection, anatomy, presence of artefacts) and ADC maps (lesion characterisation, overall image quality)] per technique and ranked them. The lesion SI, signal-to-noise ratio, mean ADC and coefficient of variation (CV) were compared. RESULTS: Total image quality scores for respiratory triggered, free-breathing and breath-hold techniques were 17.9, 16.5 and 17.1 respectively (respiratory-triggered was significantly higher than free-breathing but not breath-hold). The respiratory-triggered technique had a significantly higher ranking. Lesion SI on all b-values and signal-to-noise ratio on b300 and b600 were significantly higher for the respiratory-triggered technique. For respiratory-triggered, free-breathing and breath-hold techniques the mean ADCs were 1.201, 1.132 and 1.253 * 10(-3) mm(2)/s, and mean CVs were 8.9, 10.8 and 14.1 % respectively (respiratory-triggered and free-breathing techniques had a significantly lower mean CV than the breath-hold technique). CONCLUSION: In both analyses, respiratory-triggered DWI showed superiority and seems the optimal DWI technique for demonstrating PDAC. KEY POINTS : * Diffusion-weighted magnetic resonance imaging is increasingly used to detect pancreatic cancer * Images are acquired using various breathing techniques and multiple b-values * Breathing techniques used: respiratory-triggering, free-breathing and breath-hold * Respiratory-triggering seems the optimal breathing technique for demonstrating pancreatic cancer. PMID- 22549108 TI - Dampened circumrotation by CH...pi interactions in hydrogen bonded [2]rotaxanes. AB - Establishment of CH...pi interactions between the aliphatic axis and the benzylic amide macrocycle of hydrogen-bonded [2]rotaxanes causes a measurable interference in the pirouetting submolecular motion of these interlocked molecules. PMID- 22549107 TI - Contrast-induced nephropathy in patients with renal insufficiency undergoing contrast-enhanced MDCT. AB - OBJECTIVES: To evaluate the safety of contrast-enhanced MDCT in patients with renal impairment. METHODS: We conducted a retrospective review of 938 patients with stable renal insufficiency (eGFR between 15 and 60 ml/min) who underwent contrast-enhanced MDCT. SCr levels were measured at baseline and 48-72 h after contrast medium administration. The incidence of contrast-induced nephropathy (CIN) in the total study population was assessed. As a control group, 1,164 separate patients with renal insufficiency who did not receive contrast medium for CT were also reviewed. RESULTS: The overall incidence of CIN in the patient population with renal insufficiency was 6.1 %; the incidence was 4.4 %, 10.5 % and 10.0 % for patients whose eGFR was 45-60, 30-45 and <=30 ml/min, respectively (P < 0.01). In the control group, 5.8 % of patients showed an increase in the SCr level from the baseline. The increase in the SCr level showed no significant difference between the patients who received CM and those who did not (P = 0.82) CONCLUSIONS: The risk of CIN from contrast-enhanced MDCT in patients with renal insufficiency appeared to be low, and there was no significant difference in the incidence of CIN in comparison with patients who did not receive CM. KEY POINTS : * The contrast medium used for multidetector CT can induce nephropathy. * Contrast-induced nephropathy (CIN) developed in 6.1 % of patients with renal insufficiency. * However, nephropathy developed in 5.8 % of similar patients not receiving contrast medium. * Thus, the risk of CIN associated with MDCT appears to be low. * Special care should still be taken in patients with renal insufficiency. PMID- 22549109 TI - Photodynamic ion sensor systems with spiropyran: photoactivated acidity changes in plasticized poly(vinyl chloride). AB - We aim to introduce photoactivated optical ion sensors based on a triggered ion exchange process as novel dynamic tools. The quantification of the acidity change upon photoactivation of spiropyran within an organic membrane phase during photoexcitation is described here for the first time, suggesting a large pK(a) change of more than 6 orders of magnitude. PMID- 22549110 TI - Methodology validation, intra-subject reproducibility and stability of exhaled volatile organic compounds. AB - Robust methods for breath sampling and analysis are required for potential clinical applications. We have evaluated an improved sampling and experimental design, assessing instrumental and biological variability within and across breath measurements. Calibration curves for selected relevant volatile organic compounds (VOCs) were produced to look at the dynamic range and stability of analysis by gas chromatography/time-of-flight mass spectrometry. Linear responses were observed with R(2) > 95% and limits of detection in mid-range pg/ul. Overall experimental design, visualized by means of principal component analysis, demonstrated good clustering on quality control samples, background air and blanks, with dispersion observed as expected across human breath samples. Serial sampling while breathing VOC-filtered air for up to 30 min demonstrated marked variation in reproducibility of VOCs, with median intraclass correlation coefficient of 0.29 (interquartile range 0.16-0.71), with no apparent effect of disease status. We have shown that we can reliably detect VOCs at very low concentrations in exhaled breath samples, and that the reproducibility depends on (a) compound of interest; (b) length of time breathing VOC-filtered air. These parameters will require investigation in studies of potential breath biomarkers, and must be standardized if tests are to become clinically useful. PMID- 22549113 TI - Coordination and structural properties of encumbering 6-mesityl-2-picolinate complexes. AB - In an effort to enforce a sterically hindered environment in transition-metal and main-group 2-picolinate complexes, the synthesis of the encumbering derivative 6 mesityl-2-picolinate ((Mes)pic) is presented. The coordination and structural properties of (Mes)pic are demonstrated with a range of transition-metal and main group fragments. The 6-position mesityl group of (Mes)pic is shown to alter both the primary and secondary coordination spheres of metal centers relative to the ubiquitous and unencumbered parent 2-picolinate anion. PMID- 22549114 TI - Elevated noise power in gamma band related to negative symptoms and memory deficit in schizophrenia. AB - BACKGROUND: There is an increasing consideration for a disorganized cerebral activity in schizophrenia, perhaps relating to a synaptic inhibitory deficit in the illness. Noise power (scalp-recorded electroencephalographic activity unlocked to stimuli) may offer a non-invasive window to assess this possibility. METHODS: 29 minimally-treated patients with schizophrenia (of which 17 were first episodes) and 27 healthy controls underwent clinical and cognitive assessments and an electroencephalographic recording during a P300 paradigm to calculate signal-to-noise ratio and noise power magnitudes in the theta and gamma bands. RESULTS: In comparison to controls, a significantly higher gamma noise power was common to minimally-treated and first episode patients over P3, P4, T5 and Fz electrode sites. Those high values were directly correlated to negative symptom severity and inversely correlated to verbal memory scores in the patients. There were no differences in signal-to-noise ratio magnitudes among the groups. Gamma noise power at Fz discriminated significantly between patients and controls. No significant differences were found in theta noise power or in gamma noise power over the other electrode sites between the groups of patients and controls. LIMITATIONS: We have not assessed phase-locked and non-phase locked power changes, a complementary approach that may yield useful information. CONCLUSIONS: Gamma noise power may represent a useful and non-invasive tool for studying brain dysfunction in psychotic illness. These results suggest an inefficient activation pattern in schizophrenia. PMID- 22549111 TI - MGMT inhibition restores ERalpha functional sensitivity to antiestrogen therapy. AB - Antiestrogen therapy resistance remains a huge stumbling block in the treatment of breast cancer. We have found significant elevation of O(6) methylguanine DNA methyl transferase (MGMT) expression in a small sample of consecutive patients who have failed tamoxifen treatment. Here, we show that tamoxifen resistance is accompanied by upregulation of MGMT. Further we show that administration of the MGMT inhibitor, O(6)-benzylguanine (BG), at nontoxic doses, leads to restoration of a favorable estrogen receptor alpha (ERalpha) phosphorylation phenotype (high p-ERalpha Ser167/low p-ERalpha Ser118), which has been reported to correlate with sensitivity to endocrine therapy and improved survival. We also show BG to be a dual inhibitor of MGMT and ERalpha. In tamoxifen-resistant breast cancer cells, BG alone or in combination with antiestrogen (tamoxifen [TAM]/ICI 182,780 [fulvestrant, Faslodex]) therapy enhances p53 upregulated modulator of apoptosis (PUMA) expression, cytochrome C release and poly (ADP-ribose) polymerase (PARP) cleavage, all indicative of apoptosis. In addition, BG increases the expression of p21(cip1/waf1). We also show that BG, alone or in combination therapy, curtails the growth of tamoxifen-resistant breast cancer in vitro and in vivo. In tamoxifen-resistant MCF7 breast cancer xenografts, BG alone or in combination treatment causes significant delay in tumor growth. Immunohistochemistry confirms that BG increases p21(cip1/waf1) and p-ERalpha Ser167 expression and inhibits MGMT, ERalpha, p-ERalpha Ser118 and ki-67 expression. Collectively, our results suggest that MGMT inhibition leads to growth inhibition of tamoxifen-resistant breast cancer in vitro and in vivo and resensitizes tamoxifen-resistant breast cancer cells to antiestrogen therapy. These findings suggest that MGMT inhibition may provide a novel therapeutic strategy for overcoming antiestrogen resistance. PMID- 22549112 TI - Axitinib targeted cancer stemlike cells to enhance efficacy of chemotherapeutic drugs via inhibiting the drug transport function of ABCG2. AB - Stemlike cells have been isolated by their ability to efflux Hoechst 33342 dye and are called the side population (SP). We evaluated the effect of axitinib on targeting cancer stemlike cells and enhancing the efficacy of chemotherapeutical agents. We found that axitinib enhanced the cytotoxicity of topotecan and mitoxantrone in SP cells sorted from human lung cancer A549 cells and increased cell apoptosis induced by chemotherapeutical agents. Moreover, axitinib particularly inhibited the function of adenosine triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2) and reversed ABCG2-mediated multidrug resistance (MDR) in vitro. However, no significant reversal effect was observed in ABCB1-, ABCC1- or lung resistance-related protein (LRP)-mediated MDR. Furthermore, in both sensitive and MDR cancer cells axitinib neither altered the expression of ABCG2 at the mRNA or protein levels nor blocked the phosphorylation of AKT and extracellular signal-regulated kinase (ERK)1/2. In nude mice bearing ABCG2-overexpressing S1-M1-80 xenografts, axitinib significantly enhanced the antitumor activity of topotecan without causing additional toxicity. Taken together, these data suggest that axitinib particularly targets cancer stemlike cells and reverses ABCG2-mediated drug resistance by inhibiting the transporter activity of ABCG2. PMID- 22549115 TI - Pioglitazone adjunctive therapy for moderate-to-severe major depressive disorder: randomized double-blind placebo-controlled trial. AB - Thiazolidinediones have shown antidepressant effect in animal studies, as well as in some uncontrolled studies evaluating human subjects with concurrent major depressive disorder (MDD) and metabolic syndrome. Although these drugs are insulin sensitizers, they also have important anti-inflammatory, neuroprotective, and anti-excitotoxic properties. Thus, we hypothesized that they would show antidepressant effect in patients with MDD even if it was not accompanied by metabolic disturbances. In this double-blind placebo-controlled study, 40 patients with MDD (DSM-IV-TR) and Hamilton depression rating scale-17 (Ham-D) score >= 22 were randomized to citalopram plus pioglitazone (15 mg every 12 h) (n=20) or citalopram plus placebo (n=20) for 6 weeks. Patients were evaluated using Ham-D (weeks 0, 2, 4, 6). Repeated-measure analysis of variance (ANOVA) and analysis of covariance were used for comparison of scores between the two groups. Treatment response (>= 50% reduction in Ham-D score), remission (Ham-D score <= 7), and early improvement (>= 20% reduction in Ham-D score within the first 2 weeks) were compared between the two groups using Fisher's exact test. Pioglitazone showed superiority over placebo during the course of the trial (F(1, 38)=9.483, p=0.004). Patients in the pioglitazone group had significantly lower scores at all time points than the placebo group (P<0.01). Frequency of early improvement, response (week 6), and remission was significantly higher in the pioglitazone group (95%, 95%, 45%, respectively) than in the placebo (30%, 40%, 15% respectively) group (P<0.001, <0.001, 0.04, respectively). Frequency of side effects was similar between the two groups. Pioglitazone is a safe and effective adjunctive short-term treatment in patients with moderate-to-severe MDD even in the absence of metabolic syndrome and diabetes. PMID- 22549116 TI - Inhibition of the casein-kinase-1-epsilon/delta/ prevents relapse-like alcohol drinking. AB - During the past decade, it has been shown that circadian clock genes have more than a simple circadian time-keeping role. Clock genes also modulate motivational processes and have been implicated in the development of psychiatric disorders such as drug addiction. Recent studies indicate that casein-kinase 1epsilon/delta (CK1epsilon/delta)--one of the components of the circadian molecular clockwork might be involved in the etiology of addictive behavior. The present study was initiated to study the specific role of CK1epsilon/delta in alcohol relapse-like drinking using the 'Alcohol Deprivation Effect' model. The effect of CK1epsilon/delta inhibition was tested on alcohol consumption in long-term alcohol-drinking rats upon re-exposure to alcohol after deprivation using a four bottle free-choice paradigm with water, 5%, 10%, and 20% ethanol solutions, as well as on saccharin preference in alcohol-naive rats. The inhibition of CK1epsilon/delta with systemic PF-670462 (0, 10, and 30 mg/kg) injections dose dependently decreased, and at a higher dosage prevented the alcohol deprivation effect, as compared with vehicle-treated rats. The impact of the treatment was further characterized using nonlinear regression analyses on the daily profiles of drinking and locomotor activity. We reveal that CK1epsilon/delta inhibition blunted the high daytime alcohol intake typically observed upon alcohol re exposure, and induced a phase shift of locomotor activity toward daytime. Only the highest dose of PF-670462 shifted the saccharin intake daily rhythm toward daytime during treatment, and decreased saccharin preference after treatment. Our data suggest that CK1 inhibitors may be candidates for drug treatment development for alcoholism. PMID- 22549117 TI - N-acetylcysteine normalizes glutamate levels in cocaine-dependent patients: a randomized crossover magnetic resonance spectroscopy study. AB - Treatment with N-acetylcysteine (NAC) normalizes glutamate (Glu) homeostasis and prevents relapse in drug-dependent animals. However, the effect of NAC on brain Glu levels in substance-dependent humans has not yet been investigated. Proton magnetic resonance spectroscopy ((1)H MRS) was used to investigate Glu changes in the dorsal anterior cingulate cortex (dACC) after a single dose of NAC in cocaine dependent patients and normal controls. In an open-label, randomized, crossover study, 8 cocaine-dependent patients and 14 healthy controls underwent two scan sessions: one group receiving no compound and the other following a single administration of 2400 mg NAC. The Barratt Impulsiveness Scale was administered to examine the relation between dACC Glu levels and impulsivity. In the medication-free condition, Glu levels in the dACC were significantly higher in cocaine-dependent patients compared with healthy controls. After administration of NAC, Glu levels were reduced in the cocaine-dependent group, whereas NAC had no effect in healthy controls. Higher baseline Glu levels were associated with higher impulsivity, and both were predictive of greater NAC-induced Glu reduction. The current findings indicate that NAC can normalize elevated Glu levels in cocaine-dependent patients. These findings may have important implications for treatment, because abnormal Glu levels are related to relapse, and treatment with NAC prevented relapse in animal studies. Furthermore, clinical studies have indicated beneficial effects of NAC in cocaine-dependent patients, and the current study suggests that these beneficial effects might in part be mediated by the ability of NAC to normalize glutamatergic abnormalities. PMID- 22549118 TI - Anorexia nervosa and obesity are associated with opposite brain reward response. AB - Anorexia nervosa (AN) is a severe psychiatric disorder associated with food avoidance and malnutrition. In this study, we wanted to test whether we would find brain reward alterations in AN, compared with individuals with normal or increased body weight. We studied 21 underweight, restricting-type AN (age M 22.5, SD 5.8 years), 19 obese (age M 27.1, SD 6.7 years), and 23 healthy control women (age M 24.8, SD 5.6 years), using blood oxygen level-dependent functional magnetic resonance brain imaging together with a reward-conditioning task. This paradigm involves learning the association between conditioned visual stimuli and unconditioned taste stimuli, as well as the unexpected violation of those learned associations. The task has been associated with activation of brain dopamine reward circuits, and it allows the comparison of actual brain response with expected brain activation based on established neuronal models. A group-by-task condition analysis (family-wise-error-corrected P<0.05) indicated that the orbitofrontal cortex differentiated all three groups. The dopamine model reward learning signal distinguished groups in the anteroventral striatum, insula, and prefrontal cortex (P<0.001, 25 voxel cluster threshold), with brain responses that were greater in the AN group, but lesser in the obese group, compared with controls. These results suggest that brain reward circuits are more responsive to food stimuli in AN, but less responsive in obese women. The mechanism for this association is uncertain, but these brain reward response patterns could be biomarkers for the respective weight state. PMID- 22549119 TI - A common variant in ERBB4 regulates GABA concentrations in human cerebrospinal fluid. AB - The neuregulin 1 (NRG1) receptor ErbB4 is involved in the development of cortical inhibitory GABAergic circuits and NRG1-ErbB4 signaling has been implicated in schizophrenia (SCZ). A magnetic resonance spectroscopy ((1)H-MRS) study has demonstrated that a single-nucleotide polymorphism in ERBB4, rs7598440, influences human cortical GABA concentrations. Other work has highlighted the significant impact of this genetic variant on expression of ERBB4 in the hippocampus and dorsolateral prefrontal cortex in human post mortem tissue. Our aim was to examine the association of rs7598440 with cerebrospinal fluid (CSF) GABA levels in healthy volunteers (n=155). We detected a significant dose dependent association of the rs7598440 genotype with CSF GABA levels (G-allele standardized beta=-0.23; 95% CIs: -0.39 to -0.07; P=0.0066). GABA concentrations were highest in A homozygous, intermediate in heterozygous, and lowest in G homozygous subjects. When excluding subjects on psychotropic medication (three subjects using antidepressants), the results did not change (G-allele standardized beta=-0.23; 95% CIs: -0.40 to -0.07; P=0.0051). The explained variance in CSF GABA by rs7598440 in our model is 5.2% (P=0.004). The directionality of our findings agrees with the aforementioned (1)H-MRS and gene expression studies. Our observation therefore strengthens the evidence that the A allele of rs7598440 in ERBB4 is associated with increased GABA concentrations in the human central nervous system (CNS). To our knowledge, our finding constitutes the first confirmation that CSF can be used to study genotype-phenotype correlations of GABA levels in the CNS. Such quantitative genetic analyses may be extrapolated to other CSF constituents relevant to SCZ in future studies. PMID- 22549120 TI - On disruption of fear memory by reconsolidation blockade: evidence from cannabidiol treatment. AB - The search for reconsolidation blockers may uncover clinically relevant drugs for disrupting memories of significant stressful life experiences, such as those underlying the posttraumatic stress disorder. Considering the safety of systemically administered cannabidiol (CBD), the major non-psychotomimetic component of Cannabis sativa, to animals and humans, the present study sought to investigate whether and how this phytocannabinoid (3-30 mg/kg intraperitoneally; i.p.) could mitigate an established memory, by blockade of its reconsolidation, evaluated in a contextual fear-conditioning paradigm in rats. We report that CBD is able to disrupt 1- and 7-days-old memories when administered immediately, but not 6 h, after their retrieval for 3 min, with the dose of 10 mg/kg being the most effective. This effect persists in either case for at least 1 week, but is prevented when memory reactivation was omitted, or when the cannabinoid type-1 receptors were antagonized selectively with AM251 (1.0 mg/kg). Pretreatment with the serotonin type-1A receptor antagonist WAY100635, however, failed to block CBD effects. These results highlight that recent and older fear memories are equally vulnerable to disruption induced by CBD through reconsolidation blockade, with a consequent long-lasting relief in contextual fear-induced freezing. Importantly, this CBD effect is dependent on memory reactivation, restricted to time window of <6 h, and is possibly dependent on cannabinoid type-1 receptor-mediated signaling mechanisms. We also observed that the fear memories disrupted by CBD treatment do not show reinstatement or spontaneous recovery over 22 days. These findings support the view that reconsolidation blockade, rather than facilitated extinction, accounts for the aforementioned CBD results in our experimental conditions. PMID- 22549121 TI - Robust escalation of nicotine intake with extended access to nicotine self administration and intermittent periods of abstinence. AB - Although established smokers have a very regular pattern of smoking behavior, converging lines of evidence suggest that the escalation of smoking behavior is a critical factor in the development of dependence. However, the neurobiological mechanisms that underlie the escalation of smoking are unknown, because there is no animal model of the escalation of nicotine intake. On the basis of the pattern of smoking behavior in humans and presence of monoamine oxidase inhibitors in tobacco smoke, we hypothesized that the escalation of nicotine intake may only occur when animals are given extended-access (21 h per day) self-administration sessions after repeated periods of abstinence (24-48 h), and after chronic inhibition of monoamine oxidase using phenelzine sulfate. Intermittent access (every 24-48 h) to extended nicotine self-administration produced a robust escalation of nicotine intake, associated with increased responding under fixed- and progressive-ratio schedules of reinforcement, and increased somatic signs of withdrawal. The escalation of nicotine intake was not observed in rats with intermittent access to limited (1 h per day) nicotine self-administration or daily access to extended (21 h per day) nicotine self-administration. Moreover, inhibition of monoamine oxidase with daily administration of phenelzine increased nicotine intake by ~ 50%. These results demonstrate that the escalation of nicotine intake only occurs in animals given intermittent periods of abstinence with extended access to nicotine, and that inhibition of monoamine oxidase may contribute to the escalation of smoking, thus validating both an animal model of the escalation of smoking behavior and the contribution of monoamine oxidase inhibition to compulsive nicotine-seeking. PMID- 22549124 TI - Faculty prefer continuity with medical students in the emergency department. AB - INTRODUCTION: The aim of this investigation was to better understand emergency medicine (EM) faculty opinions as they relate to continuity with students. METHODS: This was a prospective cohort study of faculty supervising students completing an EM clerkship. Student schedules were aligned to maximise continuity with faculty. Faculty completed surveys prior to the start of the study and again at the end of the study period. RESULTS: Faculty generally indicated a favourable opinion regarding continuity with students. Significant change was noted in two survey questions from pre- to post-intervention: faculty reported higher motivation to teach and felt the students' learning experience was better with improved continuity. CONCLUSION: EM faculty express theoretical optimism regarding the value of improved continuity between teacher and learner. This positive sentiment persisted after actual experience with students on a shift allocation model that aligns faculty and student schedules. PMID- 22549125 TI - Standardization of BOD5/COD ratio as a biological stability index for MSW. AB - The control of biodegradable substances is the key issue in evaluating the short and long-term emission potential and environmental impact of a landfill. Aerobic and anaerobic indices, such as respirometric index (RI) and biomethane potential production (GB21), can be used in the estimation of the stability of solid waste samples. Previous studies showed different degrees of relationship between BOD5/COD ratio compared with RI4. Aim of this study is to standardize the parameter BOD5/COD ratio and to test the methodology under different operating conditions (dynamic or static leaching and leaching duration, 6 and 24-h) keeping constant temperature and liquid/solid ratio (L/S=10 l/kg(TS)), with the introduction of a COD fractioning method. The COD fractioning is based on the differentiation between the soluble fraction (COD(sol)) and the colloidal fraction (COD(coll)) using a flocculation method. The BOD5/COD and the BOD5/COD(sol) indices are both consistent and significant and can be used as stability indices. The BOD5/COD ratio does not seem to be influenced, for the same test duration, by the type of test, static or dynamic. In the same way the longer test duration (24-h) does not influence significantly the values of BOD5/COD ratio. As a consequence a leaching test duration of 6-h is preferable to avoid the beginning of the hydrolysis and oxidation processes. PMID- 22549122 TI - Cervical spine metastases: techniques for anterior reconstruction and stabilization. AB - The surgical management of cervical spine metastases continues to evolve and improve. The authors provide an overview of the various techniques for anterior reconstruction and stabilization of the subaxial cervical spine after corpectomy for spinal metastases. Vertebral body reconstruction can be accomplished using a variety of materials such as bone autograft/allograft, polymethylmethacrylate, interbody spacers, and/or cages with or without supplemental anterior cervical plating. In some instances, posterior instrumentation is needed for additional stabilization. PMID- 22549127 TI - Characterization of three pheromone-binding proteins (PBPs) of Helicoverpa armigera (Hubner) and their binding properties. AB - Three pheromone-binding proteins of Helicoverpa armigera were cloned and expressed in Escherichia coli. In order to characterize their physiological properties, ligand-binding experiments were performed using five biologically relevant substances including sex pheromones and interspecific signals. The results showed that one of the pheromone-binding proteins, HarmPBP1, binds strongly to each of the two principal pheromone components of H. armigera, (Z)-11 tetradecenal and (Z)-9-hexadecenal, but not to the interspecific signal (Z)-9 tetracecenal. The two remaining pheromone-binding proteins, HarmPBP2 and HarmPBP3, showed only weak affinities with the ligands tested. The 3-D structure of HarmPBP1 was predicted and the docking experiments indicate that the key binding site of (Z)-9-hexadecenal to HarmPBP1 includes Thr112, Lys111, and Phe119 whereas that of (Z)-11-tetradecenal includes Ser9, Trp37, Phe36, and Phe119. PMID- 22549128 TI - Bibliography. Current world literature. Cardiopulmonary resuscitation. PMID- 22549126 TI - BCR-JAK2 fusion as a result of a translocation (9;22)(p24;q11.2) in a patient with CML-like myeloproliferative disease. AB - Translocation (9;22)(q34;q11.2) resulting in BCR/ABL1 fusion at the molecular level is the hallmark of chronic myelogenous leukemia (CML). Variants of the Philadelphia translocation and complex translocations involving BCR have been reported in myeloproliferative disorders (MPD). A rare translocation, t(9;22)(p24;q11.2), resulting in a novel BCR-JAK2 fusion has been reported in a handful of cases of CML and acute myelogenous leukemia (AML). We present clinical pathological and cytogenetic evaluation of a patient with Philadelphia-chromosome negative CML/MPD harboring a t(9;22)(p24;q11.2) resulting in BCR-JAK2 fusion. Fluorescence in situ hybridization and molecular characterization of the translocation confirmed a BCR-JAK2 fusion and helped delineate the breakpoints upstream of exon 1 of minor cluster region of BCR gene and likely intron 18 of the JAK2 gene, resulting in an in-frame transcript This case provides convincing support, along with two previous case-reports, for a role for activation of the Janus kinase 2 in evolution of myeloproliferative disease. The recurrent, albeit rare, nature of the breakpoints within BCR and JAK2 suggests a potential new diagnostic target that should be interrogated in Ph-negative CML/MPD patients. PMID- 22549123 TI - Role of lumbar interspinous distraction on the neural elements. AB - The interspinous distraction devices are used to treat variable pathologies ranging from facet syndrome, diskogenic low back pain, degenerative spinal stenosis, diskopathy, spondylolisthesis, and instability. The insertion of a posterior element with an interspinous device (ISD) is commonly judged responsive to a relative kyphosis of a lumbar segment with a moderate but persistent increase of the spinal canal and of the foraminal width and area, and without influence on low-grade spondylolisthesis. The consequence is the need of shared specific biomechanical concepts to give for each degenerative problem the right indication through a critical analysis of all available experimental and clinical biomechanical data. We reviewed systematically the available clinical and experimental data about kyphosis, enlargement of the spinal canal, distraction of the interspinous distance, increase of the neural foramina, ligamentous structures, load of the posterior annulus, intradiskal pressure, strength of the spinous processes, degeneration of the adjacent segment, complications, and cost effectiveness of the ISD. The existing literature does not provide actual scientific evidence over the superiority of the ISD strategy, but most of the experimental and clinical data show a challenging potential. These considerations are applicable with different types of ISD with only few differences between the different categories. Despite--or because of--the low invasiveness of the surgical implantation of the ISD, this technique promises to play a major role in the future degenerative lumbar microsurgery. The main indications for ISD remain lumbar spinal stenoses and painful facet arthroses. A clear documented contraindication is the presence of an anterolisthesis. Nevertheless, the existing literature does not provide evidence of superiority of outcome and cost effectiveness of the ISD strategy over laminectomy or other surgical procedures. At this time, the devices should be used in clinical randomized independent trials in order to obtain more information concerning the most advantageous optimal indication or, in selected cases, to treat tailored indications. PMID- 22549129 TI - Pulmonary/Renal interaction: retraction. PMID- 22549131 TI - Exhaled nitric oxide (FENO) in non-pulmonary diseases. AB - Exhaled nitric oxide (F(E)NO) represents the only exhaled biomarker that has reached clinical practice even in primary care settings, due to the non invasiveness of its assessment and ease of repeat measurements, even in patients with severe airflow obstruction. While F(E)NO has been suggested as a readily determined biomarker that can aid in the diagnosis and management of asthma, its potential role in pathophysiology of non-pulmonary diseases is less clear and therefore remains to be established. The purpose of the present review is to highlight the current literature investigating the use of F(E)NO in the diagnosis and management of non-pulmonary diseases. PMID- 22549132 TI - Cardiac findings at necropsy in patients with chronic kidney disease maintained on chronic hemodialysis. AB - Studies of multiple hearts at necropsy are lacking in patients who have been on chronic hemodialysis for chronic kidney disease (CKD). We studied at necropsy 120 patients who had been treated with hemodialysis for more than 1 year (mean, 5.25 +/- 4.33 yr). Their ages ranged from 24 to 81 years (mean, 53 yr); 91 (76%) were men. Calcific deposits were present in the heart at necropsy in 74 (62%) patients: in the epicardial coronary arteries in all 74 (62%); in the mitral annular region in 52 (42%) patients, and in the aortic valve cusps in 42 (35%) patients. The frequency and quantity of the cardiac calcific deposits were significantly greater in the older compared with the younger patients, and in those with longer durations of hemodialysis compared with those with shorter durations. Despite the calcific deposits, which were sometimes huge, only 47 (39%) patients had 1 or more coronary arteries narrowed more than 75% in cross sectional area by atherosclerotic plaques, apparently no patient had clinical evidence of mitral stenosis, and 9 patients had clinical evidence of aortic valve stenosis. Thus, we found that CKD treated with hemodialysis is a major producer of cardiac calcific deposits, some of which can be massive. Only a minority of the calcific deposits, however, appeared to lead to cardiac dysfunction or myocardial ischemia during life. PMID- 22549134 TI - Hybridization-triggered isothermal signal amplification coupled with MutS for label-free and sensitive fluorescent assay of SNPs. AB - Combining the specific recognization of MutS protein for mismatched DNA sequences with the target-driven molecular switch that acts as both the template and primer of the polymerization reaction, a new label-free and sensitive fluorescent assay strategy for specific single-stranded DNA sequences or SNPs is proposed. PMID- 22549133 TI - alpha-Synuclein overexpressing transgenic mice show internal organ pathology and autonomic deficits. AB - While studying transgenic mice that overexpress human wildtype alpha-synuclein (Thy1-ASO, ASO) for typical brain alpha-synucleinopathy and central nervous system neuropathology, we observed progressive functional changes in the gastrointestinal and other peripheral organs. A more systematic study revealed that the gastrointestinal tract in ASO mice showed severe distension and blockage of the large intestine by 9-12 months of age. Functional assessments demonstrated a reduction in fecal water content and fecal pellet output, and increased whole gut transit time, in ASO mice compared to wildtype littermates, indicative of constipation, a symptom commonly reported by Parkinson's disease (PD) patients. Food intake was increased and body weight was decreased in 12 month old ASO mice, suggestive of metabolic abnormalities. Post-mortem histological analyses showed that human alpha-synuclein protein was robustly expressed in axonal fibers and in occasional cell bodies of the enteric nervous system, and in the heart of ASO mice. Accumulation of proteinase-K insoluble alpha-synuclein, reminiscent of neurodegenerative processes in PD was also observed. The functional and pathological changes we document here in ASO mice could relate to the autonomic deficits also seen in idiopathic and alpha-synuclein-mediated genetic forms of PD. These experimental data provide a foundation for therapeutic modeling of autonomic changes in PD and related alpha-synucleinopathies. PMID- 22549135 TI - Synergy between adiponectin and interleukin-1beta on the expression of interleukin-6, interleukin-8, and cyclooxygenase-2 in fibroblast-like synoviocytes. AB - To determine whether adiponectin may have synergistic effects in combination with the proinflammatory cytokine interleukin (IL)-1beta regarding the production of proinflammatory mediators during arthritic joint inflammation, synovial cells from rheumatoid arthritis (RA) patients were treated with adiponectin, IL-1beta, and their combination for 24 h. Culture supernatant was collected and analyzed by enzyme-linked immunosorbent assay for levels of IL-6, IL-8, prostaglandin E(2) (PGE(2)), vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMPs). Adiponectin-mediated intracellular signaling pathways were investigated to elucidate the molecular mechanisms underlying their synergy. The association of proinflammatory mediators with adiponectin was investigated in the synovial fluid of arthritis patients. Adiponectin functioned synergistically with IL-1beta to activate IL-6, IL-8, and PGE2 expression in RA fibroblast-like synoviocytes; Levels of VEGF, MMP-1, and MMP-13 were not synergistically stimulated. Adiponectin and IL-1beta each increased the expression of both adiponectin receptor 1 and IL-1 receptor 1. However, adiponectin and IL-1beta did not synergistically support the degradation of IkappaB-alpha or the nuclear translocation of NF-kappaB. Synergistically increased gene expression was significantly inhibited by MG132, an NF-kappaB inhibitor. Supporting the in vitro results, IL-6 and IL-8 levels were positively associated with adiponectin in synovial joint fluid from patients with RA, but not osteoarthritis (OA). In conclusion, adiponectin and IL-1beta may synergistically stimulate the production of proinflammatory mediators through unknown signaling pathways during arthritic joint inflammation. Adiponectin may be more important to the pathogenesis of RA than previously thought.